PMID- 29227678 TI - An Old Story in the Parallel Synthesis World: An Approach to Hydantoin Libraries. AB - An approach to the parallel synthesis of hydantoin libraries by reaction of in situ generated 2,2,2-trifluoroethylcarbamates and alpha-amino esters was developed. To demonstrate utility of the method, a library of 1158 hydantoins designed according to the lead-likeness criteria (MW 200-350, cLogP 1-3) was prepared. The success rate of the method was analyzed as a function of physicochemical parameters of the products, and it was found that the method can be considered as a tool for lead-oriented synthesis. A hydantoin-bearing submicromolar primary hit acting as an Aurora kinase A inhibitor was discovered with a combination of rational design, parallel synthesis using the procedures developed, in silico and in vitro screenings. PMID- 29227679 TI - Thermally Tunable Pickering Emulsions Stabilized by Carbon-Dot-Incorporated Core Shell Nanospheres with Fluorescence "On-Off" Behavior. AB - Lack of deep understanding of nanoparticle (NP) actions at oil/water interface set an obstacle to practical applications of Pickering emulsions. Fluorescence labels fabricated by incorporation of carbon dots (CDs) into poly(N isopropylacrylamide) (PNIPAM) matrix can not only mark the action of PNIPAM-based NPs in the interface but also reflect the colloidal morphologies of PNIPAM. In this work, we employed coaxial electrospraying for fabricating core-shell nanospheres of cellulose acetate encapsulated by PNIPAM, and facile incorporation of CDs in PNIPAM shells was achieved simultaneously. The coaxial electrosprayed NPs (CENPs) with temperature-dependent wettability can stabilize heptane and toluene in water at 25 degrees C, respectively, and reversible emulsion break can be triggered by temperature adjustment around the low critical solution temperature (LCST). Remarkably, CENP/CD composites exhibited a fluorescence "on off" behavior because of the volume phase transition of the PNIPAM shell. CENP/CD composites in Pickering emulsions clearly elucidated the motions of CENPs in response to temperature changes. At temperatures below the LCST, the CENP concentration played an important role in surface coverage of oil droplets. Specifically, the CENP concentration above the minimum concentration for complete emulsification of oil phase led to high surface coverage and two-domain adsorption of CENPs at the interface including primary monolayer anchoring of CENPs on droplets surrounded by interconnected CENP networks, which contributed to the superior stability of the emulsions. Moreover, CENP/CD composites can be recycled with well-preserved core-shell structure and stable fluorescent properties, which offers their great potential applications in sensors and imaging. PMID- 29227680 TI - Small-Band-Offset Perovskite Shells Increase Auger Lifetime in Quantum Dot Solids. AB - Colloidal quantum dots (CQDs) enable low-cost, high-performance optoelectronic devices including photovoltaics, photodetectors, LEDs, and lasers. Continuous wave lasing in the near-infrared remains to be realized based on such materials, yet a solution-processed NIR laser would be of use in communications and interconnects. In infrared quantum dots, long-lived gain is hampered by a high rate of Auger recombination. Here, we report the use of perovskite shells, grown on cores of IR-emitting PbS CQDs, and we thus reduce the rate of Auger recombination by up to 1 order of magnitude. We employ ultrafast transient absorption spectroscopy to isolate distinct Auger recombination phenomena and study the effect of bandstructure and passivation on Auger recombination. We corroborate the experimental findings with model-based investigations of Auger recombination in various CQD core-shell structures. We explain how the band alignment provided by perovskite shells comes close to the optimal required to suppress the Auger rate. These results provide a step along the path toward solution-processed near-infrared lasers. PMID- 29227681 TI - beta-Hydroxy-beta-methyl Butyrate Is More Potent Than Leucine in Inhibiting Starvation-Induced Protein Degradation in C2C12 Myotubes. AB - Leucine (Leu) and its metabolites alpha-ketoisocaproate (KIC) and beta-hydroxy beta-methyl butyrate (HMB) are potent regulators of protein turnover. The aim of this study was to compare the inhibitory effects of Leu, KIC, and HMB on protein degradation and to investigate the mechanisms involved. The results showed that the inhibitory effect of HMB (0.38 +/- 0.04) was more potent than that of Leu (0.76 +/- 0.04) and KIC (0.56 +/- 0.04, P < 0.01), and was significantly abolished in the presence of LY294002 (1.48 +/- 0.02) and rapamycin (1.96 +/- 0.02, P < 0.01). In the presence of insulin, the inhibitory effect of HMB (0.34 +/- 0.03) was still more effective than that of Leu (0.60 +/- 0.04) and KIC (0.57 +/- 0.08, P < 0.05). Interestingly, LY294002 treatment markedly attenuated the effect of HMB, while rapamycin treatment failed to exert the same effect. Thus, HMB appears to be more potent than Leu and KIC in inhibiting protein degradation in the absence or presence of insulin, and this inhibitory effect may be dependent on PI3K/Akt signaling pathway regardless of insulin, and mTOR signaling was only involved in this effect of HMB in the absence of insulin. PMID- 29227682 TI - Self-Attractive Hartree Decomposition: Partitioning Electron Density into Smooth Localized Fragments. AB - Chemical bonding plays a central role in the description and understanding of chemistry. Many methods have been proposed to extract information about bonding from quantum chemical calculations, the majority of them resorting to molecular orbitals as basic descriptors. Here, we present a method called self-attractive Hartree (SAH) decomposition to unravel pairs of electrons directly from the electron density, which unlike molecular orbitals is a well-defined observable that can be accessed experimentally. The key idea is to partition the density into a sum of one-electron fragments that simultaneously maximize the self repulsion and maintain regular shapes. This leads to a set of rather unusual equations in which every electron experiences self-attractive Hartree potential in addition to an external potential common for all the electrons. The resulting symmetry breaking and localization are surprisingly consistent with chemical intuition. SAH decomposition is also shown to be effective in visualization of single/multiple bonds, lone pairs, and unusual bonds due to the smooth nature of fragment densities. Furthermore, we demonstrate that it can be used to identify specific chemical bonds in molecular complexes and provides a simple and accurate electrostatic model of hydrogen bonding. PMID- 29227683 TI - Discovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity. AB - Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncology, with three approved by the FDA and over 60 others in clinical trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs. PMID- 29227685 TI - A Model for Methylmercury Uptake and Trophic Transfer by Marine Plankton. AB - Methylmercury (MeHg) concentrations can increase by 100 000 times between seawater and marine phytoplankton, but levels vary across sites. To better understand how ecosystem properties affect variability in planktonic MeHg concentrations, we develop a model for MeHg uptake and trophic transfer at the base of marine food webs. The model successfully reproduces measured concentrations in phytoplankton and zooplankton across diverse sites from the Northwest Atlantic Ocean. Highest MeHg concentrations in phytoplankton are simulated under low dissolved organic carbon (DOC) concentrations and ultraoligotrophic conditions typical of open ocean regions. This occurs because large organic complexes bound to MeHg inhibit cellular uptake and cell surface area to volume ratios are greatest under low productivity conditions. Modeled bioaccumulation factors for phytoplankton (102.4-105.9) are more variable than those for zooplankton (104.6-106.2) across ranges in DOC (40-500 MUM) and productivities (ultraoligotrophic to hypereutrophic) typically found in marine ecosystems. Zooplankton growth dilutes their MeHg body burden, but they also consume greater quantities of MeHg enriched prey at larger sizes. These competing processes lead to lower variability in MeHg concentrations in zooplankton compared to phytoplankton. Even under hypereutrophic conditions, modeled growth dilution in marine zooplankton is insufficient to lower their MeHg concentrations, contrasting findings from freshwater ecosystems. PMID- 29227684 TI - TaS3 Nanofibers: Layered Trichalcogenide for High-Performance Electronic and Sensing Devices. AB - Layered materials, like transition metal dichalcogenides, exhibit broad spectra with outstanding properties with huge application potential, whereas another group of related materials, layered transition metal trichalcogenides, remains unexplored. Here, we show the broad application potential of this interesting structural type of layered tantalum trisulfide prepared in a form of nanofibers. This material shows tailorable attractive electronic properties dependent on the tensile strain applied to it. Structure of this so-called orthorhombic phase of TaS3 grown in a form of long nanofibers has been solved and refined. Taking advantage of these capabilities, we demonstrate a highly specific impedimetric NO gas sensor based on TaS3 nanofibers as well as construction of photodetectors with excellent responsivity and field-effect transistors. Various flexible substrates were used for the construction of a NO gas sensor. Such a device exhibits a low limit of detection of 0.48 ppb, well under the allowed value set by environmental agencies for NOx (50 ppb). Moreover, this NO gas sensor also showed excellent selectivity in the presence of common interferences formed during fuel combustion. TaS3 nanofibers produced in large scale exhibited excellent broad application potential for various types of devices covering nanoelectronic, optoelectronic, and gas-sensing applications. PMID- 29227686 TI - Local Hybrid Density Functional for Interfaces. AB - Hybrid functionals are by now the state-of-the-art for the calculation of electronic properties of solids within density functional theory. The key to their performance is how a part of Fock exchange is mixed with a semilocal exchange-correlation functional. The choice of the mixing parameter is particularly critical in nonhomogeneous systems, such as an interface between two solid phases. In this work we propose a (non) local mixing function that is a functional of the electron density through an estimator of the local dielectric function. Using this mixing function to modify the PBE0 and the HSE06 hybrid functionals, we obtain band gaps and band-edge alignments at interfaces with an accuracy that is comparable to the one of the GW approximation. However, and in contrast to GW and other recent self-consistent schemes for the mixing parameter, our approach does not require the evaluation of the dielectric function and leads to a negligible increase of the computation time with respect to standard PBE0 or HSE06 hybrid calculations. PMID- 29227687 TI - Adsorption of Catalytic Nanoparticles onto Polymer Substrates for Controlled Deposition of Microcapsule Metal Shells. AB - Efficient encapsulation of small chemical molecules and their controlled targeted delivery provides a very important challenge to be overcome for a wide range of industrial applications. Typically rapid diffusion of these actives across capsule walls has so far prevented the development of a versatile widely applicable solution. In an earlier publication, we have shown that thin metal shells are able to permanently retain small molecules. The critical step in the microcapsule synthesis is the formation of a strongly adsorbed, dense monolayer of catalytic nanoparticles on the surface as this affects the secondary metal film quality. Control over Pt-nanoparticle adsorption density and a clear understanding of Pt-nanoparticle adsorption kinetics is therefore paramount. Maximising the density of heterogeneous catalysts on surfaces is generally of interest to a broad range of applications. In this work, transmission electron microscopy (TEM) and quartz crystal microbalance (QCM) are used to demonstrate that the concentration of nanoparticle polymer stabilizer used during particle synthesis and nanoparticle suspension concentration can be used to control nanoparticle surface adsorption density. We demonstrate that excess polymer, which is often used in nanoparticle synthesis but rarely discussed as an important parameter in the literature, can compete with and thus drastically affect the adsorption of the Pt-nanoparticles. PMID- 29227688 TI - Synthesis of Au-CdS@CdSe Hybrid Nanoparticles with a Highly Reactive Gold Domain. AB - We propose a novel route to synthesize semiconductor-gold hybrid nanoparticles directly in water, resulting in much larger gold domains than previous protocols (up to 50 nm) with very reactive surfaces which allow further functionalization. This method advances the possibility of self-assembly into complex structures with catalytic activity toward the reduction of nitro compounds by hydrides. The large size of these gold domains in hybrid particles supports efficient light scattering at the plasmon resonance frequency, making such structures attractive for single-particle studies. PMID- 29227689 TI - Emergent Electronic and Dielectric Properties of Interacting Nanoparticles at Finite Temperature. AB - Lead chalcogenide nanoparticle solids have been successfully integrated into certified solar cells and represent promising platforms for the design of novel photoabsorbers for photoelectrochemical cells. While much attention has been drawn to improving efficiency and device performance through altering the character of the individual nanoparticles, the role of interactions between nanoparticles is not yet well-understood. Using first-principles molecular dynamics and electronic structure calculations, we investigated the combined effect of temperature and interaction on functionalized lead chalcogenide nanoparticles (NPs). Here, we show that at finite temperature, interacting NPs are dynamical dipolar systems, with the average values of dipole moments and polarizabilities substantially increased with respect to those of the isolated building blocks. In addition, we show that the interacting NPs exhibit slightly smaller fundamental gaps that decrease as a function of temperature and that the radiative lifetimes of both the isolated NPs and the solids are greatly reduced at finite temperature compared to T = 0. Finally, we present a critical discussion of various results reported in the literature for the values of dipole moments of nanoparticles. PMID- 29227690 TI - Effect of the induction of transgenerational obesity on maternal-fetal parameters. AB - Maternal obesity can cause complications for both women and their offspring for generations. Therefore, we intended to verify the repercussions of induction of transgenerational obesity on biochemical parameters, reproductive performance, and congenital anomaly frequency in Wistar rats. Female rats were used from successive generations. The female rats of parental generation (F0, n=10) were mated to obtain their offspring (F1 generation). F1 female rats received a monosodium glutamate (MSG) solution to induce obesity (n=07) or vehicle (control, n=06) during the neonatal period. These adult female rats were classified as normal or obese using the Lee Index, mated, and delivered offspring (F2 generation), which were also evaluated for obesity using the Lee Index in adult life (F2MSG, n=13, born from obese dams) or non-obesity status (F2Control, n=12, born from control dams), and were mated in adulthood. During pregnancy, glycemia and an oral glucose tolerance test (OGTT) were analyzed. At term pregnancy, the females were sacrificed for serum biochemical profile, maternal reproductive outcomes, and fetal development. In F2MSG rats, body weight gain at early pregnancy, glycemia by OGTT, total cholesterol, high-density-lipoprotein, and alanine transaminase activity were higher compared with those of F2Control rats. F2MSG rats also presented a lower implantation number and gravid uterus weight, increased pre-implantation loss and anomaly frequency in their fetuses (F3 generation) compared with those of F2Control rats. Therefore, even without significant changes in body weight gain, obesity was established at the end of pregnancy of Wistar rats using other biomarkers. Additionally, these rats showed multiple adverse reproductive outcomes, confirming the deleterious effects that lead to obesity. PMID- 29227691 TI - Ultrasonic Modified Sweet Potato Pectin Induces Apoptosis like Cell Death in Colon Cancer (HT-29) Cell Line. AB - BACKGROUND: Pectin and especially modified citrus pectin possesses anticancer activity. Hence, the current study investigated anticancer activity of ultrasonic modified sweet potato pectin (SPP) on HT-29 cells to assess its potential as a cancer therapeutic agent. METHOD: The effect of ultrasonic treatment on SPP molecular weight, galacturonic acid content, degree of methoxylation, and neutral sugar was investigated. Moreover, the effect of sonicated variant on human HT-29 cell proliferation was assessed by MTT assay, cell cytotoxicity, and apoptosis by Annexin V/PI flow cytometer and caspase-3 activity was studied. RESULTS AND DISCUSSION: Sonication led up to seven-fold decrease in molecular weight. The degree of methoxylation (DM) decreased more than two-fold. Moreover, the galacturonic acid (GalA) content increased up to 92%, arabinose and galactose content increased. The SSPP inhibited cell proliferation with the IC50 values 0.5 mg/ml and 0.75 mg/ml for 400 W and 200 W SSPP, respectively. Moreover, 14.41 +/- 1.64% cell cytotoxicity was elicited by 400 W SSPP and 6.83 +/- 0.80% by 200 W SSPP. Both SSPPs induced apoptosis with 400 W SSPP eliciting 19.42% and 42.21% apoptosis at 0.1 and 0.5 mg/ml, while 200 W SSPP induced 13.79% and 39.50% apoptosis at 0.1 and 0.5 mg/ml, respectively. SSPP activity increased with both increased concentration and sonication intensity. PMID- 29227692 TI - Autonomous emergency braking systems adapted to snowy road conditions improve drivers' perceived safety and trust. AB - OBJECTIVE: This study investigated drivers' evaluation of a conventional autonomous emergency braking (AEB) system on high and reduced tire-road friction and compared these results to those of an AEB system adaptive to the reduced tire road friction by earlier braking. Current automated systems such as the AEB do not adapt the vehicle control strategy to the road friction; for example, on snowy roads. Because winter precipitation is associated with a 19% increase in traffic crashes and a 13% increase in injuries compared to dry conditions, the potential of conventional AEB to prevent collisions could be significantly improved by including friction in the control algorithm. Whereas adaption is not legally required for a conventional AEB system, higher automated functions will have to adapt to the current tire-road friction because human drivers will not be required to monitor the driving environment at all times. For automated driving functions to be used, high levels of perceived safety and trust of occupants have to be reached with new systems. The application case of an AEB is used to investigate drivers' evaluation depending on the road condition in order to gain knowledge for the design of future driving functions. METHODS: In a driving simulator, the conventional, nonadaptive AEB was evaluated on dry roads with high friction (MU = 1) and on snowy roads with reduced friction (MU = 0.3). In addition, an AEB system adapted to road friction was designed for this study and compared with the conventional AEB on snowy roads with reduced friction. Ninety six drivers (48 males, 48 females) assigned to 5 age groups (20-29, 30-39, 40-49, 50-59, and 60-75 years) drove with AEB in the simulator. The drivers observed and evaluated the AEB's braking actions in response to an imminent rear-end collision at an intersection. RESULTS: The results show that drivers' safety and trust in the conventional AEB were significantly lower on snowy roads, and the nonadaptive autonomous braking strategy was considered less appropriate on snowy roads compared to dry roads. As expected, the adaptive AEB braking strategy was considered more appropriate for snowy roads than the nonadaptive strategy. In conditions of reduced friction, drivers' subjective safety and trust were significantly improved when driving with the adaptive AEB compared to the conventional AEB. Women felt less safe than men when AEB was braking. Differences between age groups were not of statistical significance. CONCLUSIONS: Drivers notice the adaptation of the autonomous braking strategy on snowy roads with reduced friction. On snowy roads, they feel safer and trust the adaptive system more than the nonadaptive automation. PMID- 29227694 TI - Pulsed electric field-assisted sensitization of multidrug-resistant Candida albicans to antifungal drugs. AB - AIM: Determine the influence of pH on the inactivation efficiency of Candida albicans in pulsed electric fields (PEF) and evaluate the possibilities for sensitization of a drug-resistant strain to antifungal drugs. MATERIALS & METHODS: The effects of PEF (2.5-25 kVcm-1) with fluconazole, terbinafine and naftifine were analyzed at a pH range of 3.0-9.0. Membrane permeabilization was determined by flow cytometry and propidium iodide. RESULTS: PEF induced higher inactivation of C. albicans at low pH and increased sensitivity to terbinafine and naftifine to which the strain was initially resistant. Up to 5 log reduction in cell survival was achieved. CONCLUSION: A proof of concept that electroporation can be used to sensitize drug-resistant microorganisms was presented, which is promising for treating biofilm-associated infections. PMID- 29227696 TI - Structure of the Female Reproductive Tract in the Dungeness Crab (Cancer magister) and Implications for the Mating System. AB - Anatomical and behavioral aspects of reproduction in female Dungeness crab, Cancer magister, were investigated. Female crabs were collected over a two-year period and external indicators of reproductive condition were recorded. A subset of crabs was retained for macroscopic and histological examination of the reproductive tract. In addition, males and females were held in the laboratory for mating observations, thus providing females of known mating history for dissection. The spermatheca is of the "ventral type," i.e., the vagina and the oviduct open into the spermatheca in close proximity to each other. A novel organ that often contains sperm, the bursa, is separate and distinct from the spermatheca in both position and origin and is reported for the first time for a brachyuran crab. The bursa is located just inside the vulva, distal to the spermatheca, and opens into the vagina. The sperm plug of C. magister, described here for the first time, is unique in form among cancrids. The sperm plug is placed in the vagina by the first male to mate with a soft-shelled female and prevents subsequent access to the spermatheca. However, the sperm plug does not occlude the vulva nor prevent subsequent copulation; ejaculates from subsequent matings are deposited in the bursa. Hypotheses of the possible function of the bursa are discussed. PMID- 29227695 TI - Factors Associated with Home Meal Preparation and Fast-Food Sources Use among Low Income Urban African American Adults. AB - This study aimed to assess the factors associated with home meal preparation (HMP) and fast-food sources use (FFS) frequencies of low-income African-American adults and their healthy food beliefs and attitudes, food-related psychosocial factors, food acquisition patterns, food sources use, and BMI. We used cross sectional data from 295 adults living in Baltimore, USA. HMP was inversely associated with FFS, which had lower odds of HMP >=1 time/day and higher BMI scores. HMP was positively associated with positive beliefs and self-efficacy toward healthy foods, getting food from healthier food sources, and lower FFS. Higher odds of HMP >=1 time/day were associated with getting food from farmers' market and supermarkets or grocery stores. FFS had an inverse association with positive beliefs and self-efficacy toward healthy foods, and a positive association with less healthy food acquisition scores. Higher odds of FFS >=1 time/week were associated with getting food from corner stores, sit-down restaurants, and convenience stores. PMID- 29227697 TI - Chemical Mediation of Sperm Activity and Longevity in the Solitary Ascidians Ciona intestinalis and Ascidiella aspersa. AB - Sperm chemotaxis to compounds originating from eggs is common in solitary ascidians. This chemotactic response is associated with an increase in the activity level of the sperm. Here we examine the hypothesis that the period of sperm viability is reduced by the stimulation of increased activity by compounds associated with the eggs of solitary ascidians. The activity level and longevity of sperm from two species of solitary ascidian, Ciona intestinalis and Ascidiella aspersa, were measured after incubation in water that had been stored with homospecific eggs. Our results showed that the proportion of active sperm increased in homospecific egg water. This increase corresponded to a sharp decline in sperm longevity, which suggests a causal link between sperm activity and longevity. We suggest that sperm energy reserves are conserved in the absence of compounds associated with homospecific eggs, and that this may have significant ecological consequences for these organisms. Cross-reactivity in the chemotactic response of sperm from one species to the chemoattractant of another is common in ascidians, and increased sperm activity is associated with this response. Therefore, we investigated cross-reactivity in the activation of C. intestinalis and A. aspersa sperm to heterospecific egg water. Our results showed that A. aspersa sperm were activated by the egg water of C. intestinalis, resulting in a decline in sperm viability, but that this response was not reciprocated between the sperm of A. aspersa and the egg water of C. intestinalis. This suggests either that sperm of A. aspersa respond to compounds associated with the eggs with a higher degree of specificity than C. intestinalis sperm, or that compounds associated with A. aspersa eggs have more generalized activity than those of C. intestinalis. PMID- 29227698 TI - Conspecific Recognition and Host Choice in a Pea Crab, Pinnixa chaetopterana (Brachyura: Pinnotheridae). AB - The pea crab Pinnixa chaetopterana (Brachyura: Pinnotheridae) lives in the tubes of the host polychaetes Chaetopterus variopedatus and Amphitrite ornata. While attraction to host odor cues is common in symbiotes, P. chaetopterana resident in Chaetopterus tubes apparently show no attraction to water-borne cues from either host. Because crabs resident in Amphitrite tubes are significantly reduced in their maximum body size and thus clutch size, switching between hosts should occur. We therefore tested the hypothesis that the crabs use odor cues from conspecifics or from the competing crab Polyonyx gibbesi (Anomura: Porcellanidae) when locating a new host. Crabs collected from Amphitrite are significantly attracted to Chaetopterus hosts which contain a mixed sex pair of conspecifics. Females show a strong tendency to avoid hosts containing Polyonyx, but males do not. Neither sex is attracted to unoccupied Chaetopterus or Amphitrite hosts, but both are significantly attracted to isolated conspecifics. This attraction could serve as a reliable means of locating suitable new hosts when switching hosts in the field. Attraction to conspecific odors would also increase the chances of finding a suitable mate already present in a new host. PMID- 29227699 TI - A Chemical Cue Induces Settlement of Sydney Rock Oysters, Saccostrea commercialis, in the Laboratory and in the Field. AB - The physical and chemical nature of a substratum's surface, including the presence of dissolved compounds or a bacterial film, may induce the settlement of invertebrate larvae. Based on previous observations of (1) enhanced recruitment of Sydney rock oysters (Saccostrea commercialis) on concrete surfaces and (2) high alkalinity at the surface of concrete due to the leaching of calcium hydroxide (Ca(OH)2) from the cement, experiments were designed to test the hypothesis that a surface containing Ca(OH)2 enhances settlement of oysters. The effect of a biofilm on settlement of Sydney rock oysters was also tested. The results obtained from the field experiment differed slightly from those obtained in the laboratory. In both the laboratory and the field, Ca(OH)2 had a positive effect on settlement. No significant effect of a biofilm on settlement on concrete substrata was observed in either experiment; a positive effect of a biofilm on substrata made with sand only or on sandstone was seen in both the laboratory and the field. For the substrata made with Ca(OH)2 and sand, however, the effect of a biofilm was positive in the field but negative in the lab. Although the results from the lab and field experiments were similar, the discrepancy was crucial in accepting or rejecting one of the hypotheses under test. The results of the study demonstrated that (1) the effects of a biofilm on settlement vary with the substratum and (2) these oysters can respond to a chemical cue (Ca(OH)2) in the field. The ecological implications of the ability of larvae to select a habitat in response to chemical cues are discussed. PMID- 29227700 TI - Echinoid Bioerosion as a Major Structuring Force of Red Sea Coral Reefs. AB - Echinoid bioerosion is ecologically important as a limiting factor for reef growth. Diadema setosum and Echinometra mathaei are the most abundant sea urchins in the Gulf of Eilat, Red Sea. Bioerosion by these urchins was estimated from field experiments with urchins placed in underwater chambers. A novel methodology was developed for measuring the CaCO3 content of fecal pellets and total gut contents. This method is based on measurement of the amount of gas formed by total acidification of a mixed sample. The population density of the urchins was determined for the reef flat (depth 0.6-1 m) and the reef slope (depth 6-8 m). D. setosum, which erodes 310 mg individual-1 d-1, is much less abundant on the reef flat (0.1 individuals m-2) than on the reef slope (6.4 individuals m-2). In contrast, E. mathaei, which erodes 120 mg individual-1 d-1, is more dominant on the reef flat (10.5 individuals m-2) than on the reef slope (3.7 individuals m- 2). We estimate that echinoid bioerosion converts to carbonate sediments 7%-11% of the total reef flat calcification and 13%-22% of the total reef slope calcification. These findings emphasize the importance of echinoid bioerosion as a structuring force in the coral reef, and its potential importance to the dynamics of reef development. However, they imply that some previous studies may have overestimated the role of echinoid bioerosion, thus possibly underestimating internal bioerosion. PMID- 29227701 TI - Comparison of Temperature Effects on Heart Performance of the Dungeness Crab, Cancer magister, in vitro and in vivo. AB - A large percentage of physiological studies are based on isolated components of complex systems, but the question can always be posed, are the responses the same in isolation as when these components are under the homeostatic controls that exist in vivo? For cardiac performance in Cancer magister, the responses to temperature variation over the range 4 degrees to 20 degrees C are different in semi-isolated hearts than in intact animals. Cardiac performance in semi-isolated hearts was measured with a pressure transducer, a flow transducer, and electromyogram (EMG) electrodes, and in intact animals with pulsed Doppler flow probes. Heart rate increase in semi-isolated hearts was about one-third of that in intact animals. The cardiac output of semi-isolated hearts decreased with increasing temperature, whereas that of intact animals increased. Stroke volume decreased linearly in semi-isolated hearts. In intact animals, stroke volume decreased from 4 degrees to 12 degrees C, but remained relatively stable from 12 degrees to 20 degrees C. The ventricular pressure and the EMG amplitude of semi isolated hearts both decreased with increasing temperature. Double systolic contractions appeared both in semi-isolated hearts and in intact animals in the temperature range 13 degrees to 20 degrees C; this may represent a compensatory mechanism at extreme temperatures. The difference in cardiac performance between intact crabs and semi-isolated hearts reflects, almost certainly, extrinsic control in intact animals, including modulation by cardioregulatory nerves or neurohormonal modulation of the cardiac ganglion, myocardial contractility or changes in outflow resistance. PMID- 29227702 TI - Inorganic N Assimilation and Ammonium Pools in a Deep-Sea Mussel Containing Methanotrophic Endosymbionts. AB - Undescribed mussels (seep mytilid 1a) harboring methanotrophic endosymbionts exhibit high biomass around hydrocarbon seeps on the Louisiana Slope of the Gulf of Mexico. These mussels assimilate ammonium and nitrate present at high concentrations in their environment. Pathways of assimilation were investigated by enzyme activity measurements and 15N tracer experiments. Glutamine synthetase was detected in all freshly collected mussels tested. Nitrate reductase activity was not always observed. Exposure to 15NH3 resulted in the appearance of millimolar concentrations of 15NH3 within the symbiont-containing tissues. The concentration of internal 15NH3 was several times higher than in the medium and correlated with 15NH3 assimilation rate. These results indicate that exogenous 15NH3 was taken up into a large internal pool before it was assimilated. Our results do not indicate the extent to which ammonium pools were within the host or symbiont or whether ammonium assimilation was facilitated by either partner exclusively. The observation of elevated internal ammonium concentrations is inconsistent with the "depletion-diffusion" mechanism of nutrient uptake proposed for algal-invertebrate symbioses and is suggestive of active ammonium uptake mechanisms across the host surface. Exposure to 15NO3- also resulted in the appearance of 15NH3, with internal 15NH3 concentration correlated with 15NO3- assimilation rate. This result indicates that 15NO3- was reduced more rapidly than it was assimilated and that 15NH3 derived from 15NO3- may also enter an internal ammonium pool. Assimilation of nitrate in the presence of millimolar concentrations of internal ammonium and reduction of 15NO3- in excess of assimilation is consistent with the functioning of dissimilatory nitrate reduction pathways with ammonium as a major endproduct. Such a mechanism may operate in other chemosynthetic symbioses that exhibit dissimilatory nitrate reduction. PMID- 29227703 TI - Reversing the Life Cycle: Medusae Transforming into Polyps and Cell Transdifferentiation in Turritopsis nutricula (Cnidaria, Hydrozoa). AB - Organisms develop through a series of stages leading to sexually mature adults. In a few cases ontogeny reversal is possible, but it does not occur typically after the onset of sexual reproduction. All stages of the medusa Turritopsis nutricula, from newly liberated to fully mature individuals, can transform back into colonial hydroids, either directly or through a resting period, thus escaping death and achieving potential immortality. This is the first metazoan known to revert to a colonial, juvenile morph after having achieved sexual maturity in a solitary stage. Selective excision experiments show that the transformation of medusae into polyps occurs only if differentiated cells of the exumbrellar epidermis and part of the gastrovascular system are present, revealing a transformation potential unparalleled in the animal kingdom. PMID- 29227704 TI - Biochemical and Enzymatic Characterization of an Acetylcholinesterase From Nereis diversicolor (Annelida, Polychaeta): Comparison With the Cholinesterases of Eisenia fetida (Annelida, Oligochaeta). AB - This study constitutes the first report of a biochemical characterization, involving both substrates and inhibitors and electrophoretic analysis, of a cholinesterase (ChE) from a polychaete annelid (Nereis diversicolor). The ChE of N. diversicolor appears to be an acetylcholinesterase (AChE); i.e., it hydrolyzes acetylthiocholine iodide at a higher rate than other substrates and is inhibited by eserine but not by iso-OMPA. The ChEs of Eisenia fetida are different from that of N. diversicolor and include at least two types of PrChEs. The AChE activity is located principally in the anterior region of the worm (head) in N. diversicolor, whereas the ChE activity of E. fetida is located throughout the body. The electrophoretic characterization of N. diversicolor and E. fetida ChEs showed, respectively, six and two isoforms with disc-PAGE, and three (55,000, 47,000, and 17,000) and five molecular forms (628,000, 301,000, 235,000, 106,000, and 53,800) with PAGGE; substantial activity remained at the top of the PAGGE gel in both species. PMID- 29227705 TI - Thyroxine-Accelerated Larval Development in the Crown-of-Thorns Starfish, Acanthaster planci. AB - Dramatic population increases (outbreaks) of the coraleating crown-of-thorns starfish, Acanthaster planci, have resulted in damage to many Indo-Pacific coral reefs, especially on Australia's Great Barrier Reef. Research on factors that could affect Acanthaster distribution and abundance has included investigation of larval development, dispersal, settlement, and metamorphosis. For example, various substrates, particularly crustose coralline algae with bacterial surface films, induce Acanthaster's planktonic larvae to settle and metamorphose (1, 2). but little investigation has thus far been devoted to specific chemical substances that affect various phases of Acanthaster development. We report here that thyroxine, which accelerates development in three sea urchin species (3), also accelerates Acanthaster's developmental progress through larval stages and that this acceleration is concentration dependent. Our results suggest the need for research on possible roles of iodinated organic molecules in Acanthaster development in situ, and on the effects of additional substances known to accelerate the development of other echinoderm larvae. PMID- 29227706 TI - Spawning, in vitro Maturation, and Changes in Oocyte Electrophysiology Induced by Serotonin in Tivela stultorum. AB - Spawning was induced in both male and female Pismo clams by injecting 0.4 ml of 5 mM serotonin into the gonad. Spawned oocytes had already matured to metaphase I of meiosis or were undergoing germinal vesicle breakdown at the time of release. Prophase-arrested oocytes scraped from the ovaries of uninjected clams were induced to undergo germinal vesicle breakdown in vitro by incubating them with 0.22--0 MUM serotonin in seawater; the former concentration was optimal. In vitro matured oocytes were fertilizable and developed to larvae, whereas sperm penetrated prophase-arrested oocytes without activating them. Fertilization was more successful in slightly alkaline seawater (pH 8.5). The electrical response of oocytes to serotonin was studied by means of intracellular microelectrode recording. Resting potentials of prophase-arrested oocytes were between -60 and 80 mV and there was no immediate electrical response to perfusion with serotonin. However, about 10-15 min later (before germinal vesicle breakdown), membrane potentials usually began to drift slowly in the positive direction (net change by 40 min + 9 +/- 6.6 mV (SD; n = 8), whereas resting potentials of oocytes perfused with seawater alone usually drifted in the negative direction (-3 +/- 6.1 mV; n = 7). A dramatic increase in input resistance was consistently observed in oocytes induced to mature with serotonin, probably due to the inactivation of K+ channels, although this was not tested. Action potentials were always (7 out of 7 cases) present in maturing oocytes, but were detected only sometimes (7 of 14 cases) in prophase-arrested oocytes, presumably due to their lower input resistances. PMID- 29227707 TI - DNA-Synthesizing Cells in the Heart of Ascidia obliqua (Tunicata). AB - In vertebrate cardiomyocytes, DNA synthesis and mitosis occur in the presence of myofibrils. The myocardium of the adult vertebrates has no cambial elements. We have studied the ultrastructural features and replicative abilities of the heart cells of Ascidia obliqua, a representative of the tunicates, which are considered to be closely related to the immediate precursors of vertebrates. The ascidian heart is composed of a pericardium and a myocardium. The pericardium consists of mononucleated cells with well-developed Golgi complexes and expanded channels of rough endoplasmic reticulum. The myocardium consists of mono- and binucleated myoepithelial cells, whose polarity is recognizable in basement lamina underlying the basal surface; centrioles, cilia, and a welldeveloped Golgi complex located at the apical side; and cross-striated myofibers, one per cell, running along the basal membrane. Four hours after injection of tritiated thymidine ([3H]Tdr), labeled nuclei were found both in pericardial and myocardial cells. Electron microscope autoradiographs show that the [3H]Tdr-labeled nuclei in the myocardium belong to myofiber-containing cells. We failed to observe mitosis; however, the occurrence of centrioles and the high number of binucleated myocytes testify to the ability of these cells to undergo karyokinesis. Large numbers of [3H]Tdr labeled and prophasic nuclei have been observed in the raphe region, the site of transition of the pericardium into myocardium. The morphological features, such as loss of labyrinth junctions and the acquisition of gap junctions, that distinguish the cells of the raphe region from ordinary pericardial cells give evidence of their premyocytic nature. The resemblance of ascidian myocardium to the vertebrate embryonic one and the presence of cambial zone in the ascidian heart are discussed. PMID- 29227708 TI - Homeotic Transformation of Crab Walking Leg into Claw by Autotransplantation of Claw Tissue. AB - Homeotic transformation is defined as transformation of one body part into the likeness of something else. By autotransplantation of crab claw tissue into the autotomized stump of the fourth walking leg, the stump can regenerate a complete claw. Frozen claw tissue, sham operation, or walking leg tissue had no such activity. Contralateral autotransplantation of claw tissue into the autotomized stump of the fourth walking leg can induce the regeneration of a claw with normal handedness. Most of the transformed claws combined features of the claw and the walking leg, suggesting that both host and donor tissues play a role in regeneration. Three possible mechanisms that might account for limb transformation are discussed. Simple intercalary regeneration does not explain all of the observations, but some regulatory events might be taking place during regeneration. Two other processes--secretion of some morphogen by the claw tissue and alteration in the expression of Hox genes--offer alternatives that might explain the results of this study. PMID- 29227709 TI - A Review Study on the Beneficial Effects of Baduanjin. AB - AIM: Baduanjin, a Chinese traditional Qigong exercise that focuses on a mind-body integration, is considered to be an effective exercise in promoting health. Thus, we systematically and critically evaluated the emerging literature relating to the effects of Baduanjin on health outcomes. METHODS: We used seven English language electronic databases for the literature search. At least one health related parameter was reported in retrievable full-text Baduanjin intervention studies. RESULTS: A total of 22 eligible studies were included. The inter-rater reliability between two review authors was 94.4% for selecting eligible studies. The results of individual studies support the notion that Baduanjin may be effective as an adjunctive rehabilitation method for improving cognitive functions in addition to psychological and physiological parameters among different age groups and various clinical populations (e.g., Parkinson's disease, chronic neck pain, chronic fatigue syndrome-like illness, psychological illness). CONCLUSION: Before we draw a definitive conclusion relating to Baduanjin for health benefits, more methodologically rigorous studies with a long-term follow up assessment should be further conducted to examine the effects of Baduanjin on health-related parameters and disease-specific measures in different health conditions. This review lends insight for future studies on Baduanjin and its potential application in preventive medicine and rehabilitation science. PMID- 29227710 TI - Changing the Treatment Direction for Opiate Addiction: Dr. Dole's Research. AB - Under the leadership of Drs. Vincent P. Dole, Marie Nyswander, and Mary Jeanne Kreek, in collaboration with the psychologist, Norman Gordon and sociologist, Herman Joseph at The Rockefeller University beginning in the 1960s, the first medical treatment for heroin addiction was developed. Drs. Dole, Nyswander and Kreek also developed the first hypothesis of opiate addiction as a metabolic disease. This biological revolution challenged beliefs about addiction, spurred further research and challenged legal positions of the judiciary and the broader criminal justice system (Dole & Nyswander, 1967 ). PMID- 29227711 TI - Diffuse Chorangiomatosis as a Cause of Cardiomegaly, Microangiopathic Hemolytic Anemia and Thrombocytopenia in a Newborn. AB - INTRODUCTION: The hallmark of diffuse chorangiomatosis is capillary dysvasculogenesis, diffusely involving the placenta. It can cause massive placental enlargement and may have adverse fetal effects. CASE REPORT: A 32 weeks gestation male infant was born via cesarean section and had a placenta weighing 900 g. There was diffuse vascular proliferation involving the stem villi and intermediate villi. Short Nucleotide Polymorphism (SNP) microarray analysis of the placenta showed no biparental mosaicism or loss of heterozygosity, ruling out placental mesenchymal dysplasia. The infant also had cardiomegaly, microangiopathic hemolytic anemia and thrombocytopenia which spontaneously improved over time. CONCLUSION: Diffuse chorangiomatosis can be associated with hemolysis, thrombocytopenia and cardiomegaly in the newborn. However, once delivered, these findings can spontaneously resolve over time. PMID- 29227712 TI - A Comparison of Pain, Fatigue, Dyspnea and their Impact on Quality of Life in Pulmonary Rehabilitation Participants with Chronic Obstructive Pulmonary Disease. AB - In addition to dyspnea and fatigue, pain is a prevalent symptom in chronic obstructive pulmonary disease (COPD). Understanding the relative prevalence, magnitude, and interference with aspects of daily living of these symptoms can improve COPD management. Therefore, the purposes of this study were to: (1) compare the prevalence and magnitude of dyspnea, fatigue, and pain and how each limits aspects of daily living; (2) determine the association between pain and the other two symptoms; and (3) assess the impact of these symptoms on quality of life in COPD. Participants were recruited from pulmonary rehabilitation programs. Pain, dyspnea, and fatigue were measured using the Brief Pain Inventory (BPI), Brief Fatigue Inventory (BFI), and Dyspnea Inventory (DI), respectively. Quality of life was measured using the Clinical COPD Questionnaire (CCQ). The prevalence of dyspnea, fatigue, and pain were 93%, 77%, and 74%, respectively. Individuals with COPD reported similar severity scores of the three symptoms. Dyspnea interfered with general activity more than pain (F1.7,79.9 = 3.1, p < 0.05), whilst pain interfered with mood (F1.8, 82.7 = 3.6, p < 0.05) and sleep (F1,46 = 7.4, p < 0.01) more than dyspnea and fatigue. These three symptoms were moderately-to-highly correlated with each other (rho = 0.49-0.78, p < 0.01) and all individually impacted quality of life. In summary, pain is a common symptom in addition to dyspnea and fatigue in COPD; all three interfere similarly among aspects of daily living with some exceptions. Accordingly, management of COPD should include a multifaceted approach that addresses pain as well as dyspnea and fatigue. PMID- 29227713 TI - A Case Report of in Utero Williams Syndrome Arterial Malformation. AB - INTRODUCTION: Williams syndrome (WS), an autosomal dominant condition linked to gene deletions on chromosome 7, can cause supravalvular aortic narrowing and death. WS-associated mutations are believed to disrupt arterial elastin fibers, causing smooth muscle malformation, endomysial fibrosis and severe hypertension. Previous studies demonstrated arterial ultrastructural anomalies in adult WS patients. It is not presently known if the arterial phenotype of WS is also present in utero. CASE REPORT: A 34-week stillborn was delivered to a 28-year-old with genetically confirmed WS. Aortic tissue from the patient was compared with non-WS fetal aorta of similar gestational age using EM and light microscopy. Both sections were taken from the proximal aortic root. This demonstrated internal elastic lamina disruption, malformed elastic fibers, smooth muscle proliferation and abnormal collagen fibers, consistent with adult WS phenotype. CONCLUSION: Our analysis indicated the cardiovascular changes of WS in a fetus as young as 34 weeks. PMID- 29227714 TI - Mandate Repeal Provision Ends Health Care Calm. AB - Marketplace enrollment for 2018 has been robust in the face of several obstacles, but the ACA faces a new threat after the Senate's vote to repeal the individual mandate. PMID- 29227716 TI - Interventions to Address Sexual Problems in People With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Adaptation Summary. PMID- 29227715 TI - Human Papillomavirus Genome Integration and Head and Neck Cancer. AB - We conducted a critical review of human papillomavirus (HPV) integration into the host genome in oral/oropharyngeal cancer, reviewed the literature for HPV-induced cancers, and obtained current data for HPV-related oral and oropharyngeal cancers. In addition, we performed studies to identify HPV integration sites and the relationship of integration to viral-host fusion transcripts and whether integration is required for HPV-associated oncogenesis. Viral integration of HPV into the host genome is not required for the viral life cycle and might not be necessary for cellular transformation, yet HPV integration is frequently reported in cervical and head and neck cancer specimens. Studies of large numbers of early cervical lesions revealed frequent viral integration into gene-poor regions of the host genome with comparatively rare integration into cellular genes, suggesting that integration is a stochastic event and that site of integration may be largely a function of chance. However, more recent studies of head and neck squamous cell carcinomas (HNSCCs) suggest that integration may represent an additional oncogenic mechanism through direct effects on cancer-related gene expression and generation of hybrid viral-host fusion transcripts. In HNSCC cell lines as well as primary tumors, integration into cancer-related genes leading to gene disruption has been reported. The studies have shown that integration induced altered gene expression may be associated with tumor recurrence. Evidence from several studies indicates that viral integration into genic regions is accompanied by local amplification, increased expression in some cases, interruption of gene expression, and likely additional oncogenic effects. Similarly, reported examples of viral integration near microRNAs suggest that altered expression of these regulatory molecules may also contribute to oncogenesis. Future work is indicated to identify the mechanisms of these events on cancer cell behavior. PMID- 29227718 TI - Training chiropractic students in weight management counseling using standardized patients. AB - OBJECTIVE: The aim of this study was to describe and assess an activity that trained chiropractic students to counsel patients on weight management through the use of standardized patients. METHODS: This was a descriptive study using mixed methods. Students were trained to apply health behavior theory and the transtheoretical model. Standardized patients were given a case to portray with the students. Students had 15 minutes for the encounter. The encounters were assessed in 2 ways: (1) standardized patients answered a brief questionnaire about the students' performance, and (2) students answered a questionnaire about the utility of the intervention. Numerical data were extracted from the audiovisual management platform, and statistics were computed for each question. Comments made by students and patients were transferred verbatim for content analysis. RESULTS: A total of 102 students took part in the activity. Students' performance in the encounter was uniformly high, with over 90% "yes" responses to all questions except "gave me printed information material" and "discussed the printed material with me." The key issue identified in the comments by standardized patients was that students tended not to connect weight management with their chief complaint (low back pain). Nearly all students (97%) thought the activity would be useful to their future practice, and 97% felt it had increased their confidence in providing weight management counseling. CONCLUSION: This experiential activity was assessed to be useful to students' future practice and appeared to provide them with skills to successfully communicate with patients on weight management. PMID- 29227717 TI - Quercetin restores corticosteroid sensitivity in cells from patients with chronic obstructive pulmonary disease. AB - Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Oxidative stress from cigarette smoke and chronic inflammation is likely to induce this corticosteroid insensitivity. Quercetin is a polyphenol that has been reported to be an active oxygen scavenger as well as a functional adenosine monophosphate-activated protein kinase (AMPK) activator. The aim of this study was to investigate the effect of quercetin on corticosteroid responsiveness in COPD cells. Corticosteroid sensitivity was examined in human monocytic U937 cells exposed to cigarette smoke extract (CSE) and peripheral blood mononuclear cells (PBMC) collected from patients with COPD. Corticosteroid sensitivity was determined as the dexamethasone concentration causing 40% inhibition of tumor necrosis factor alpha-induced CXCL8 production (Dex-IC40) in the presence or absence of quercetin. In U937 cells, treatment with quercetin activated AMPK and induced expression of nuclear factor erythroid 2-related factor 2, and consequently reversed CSE-induced corticosteroid insensitivity. PBMC from patients with COPD showed corticosteroid insensitivity compared with those from healthy volunteers, and treatment with quercetin restored corticosteroid sensitivity. In conclusion, quercetin restores corticosteroid sensitivity, and has the potential to be a novel treatment in combination with corticosteroids in COPD. PMID- 29227719 TI - Comparison of interactive video test performance to overall class performance in a biomechanics course. AB - OBJECTIVE: This study compared interactive video test performance and students' overall class performance. The hypothesis was that there would be a difference in video test performance compared to overall class performance. METHODS: A total of 30 students participated in the pilot study from a master's level biomechanics course. Students completed four interactive video tests using EduCanon; content of videos included base of support, lever systems, scapulohumeral rhythm, and postural analysis. This content was reviewed with class discussion after completion of the interactive video test. The tests administered counted toward the participation portion of the final student grade. Student performance on the EduCanon interactive video test was compared to overall class grade using a paired t-test. RESULTS: All 30 students completed the 4 EduCanon interactive video tests. Final class grades were greater compared to cumulative EduCanon test performance. There was no difference between performance using interactive video testing compared to students' overall class performance ( t[29] = -1.43, p = .16). CONCLUSION: The results of this study did not support improved student assessment performance with incorporation of interactive video testing in the classroom environment. Continued research into new testing strategies is recommended to identify additional effective testing in the classroom. PMID- 29227720 TI - Important new indexing and citation opportunities for the Journal of Chiropractic Education. AB - This editorial discusses the recent inclusion of the Journal of Chiropractic Education in Scopus and places this accomplishment in context of the growth of the journal over the past 12 years. New open access reference cross-linking is also introduced. PMID- 29227721 TI - Chinese guidelines for childhood asthma 2016: Major updates, recommendations and key regional data. AB - OBJECTIVE: With increased industrialization and urbanization in China, pediatric asthma is becoming more prevalent. Despite a growing body of evidence, there remains a significant unmet need for adequate management of childhood asthma. The Subspecialty Group of Respiratory Diseases of the Society of Pediatrics, the Chinese Medical Association, and the editorial board of the Chinese Journal of Pediatrics have recently updated the "Guidelines for diagnosis and optimal management of asthma in children," first published in 2008. METHODS: This article reviews the major updates to the guidelines and covers the main recommendations for diagnosis, assessment, and treatment of pediatric asthma in China. Key regional data on epidemiology, clinical features, disease burden, knowledge among children and parents, and risk factors including pollution are provided to contextualize the recommendations. RESULTS: The major updates to the guidelines include: (1) A more practical definition of asthma; (2) assessment of asthma control that takes into account both current symptom control and future risk; (3) classification based on disease severity that corresponds with treatment step; (4) differentiation between difficult-to-treat and poorly controlled asthma; (5) an open-ended approach to pharmacological management; and (6) allergen immunotherapy (AIT) in mild- to moderate-persistent asthma. CONCLUSIONS: The updated "Guidelines for the diagnosis and optimal management of asthma in children (2016)" combine the latest national and international clinical evidence and experience to provide practical and reliable recommendations to Chinese clinicians. PMID- 29227722 TI - Glucose phosphate isomerase (GPI) Tadikonda: Characterization of a novel Pro340Ser mutation. AB - After a thirty-year lag, we serendipitously reestablished contact with a patient with glucose phosphate isomerase deficiency and hydrops fetalis first reported in 1987. We now provide a clinical update and provide results of mutation analysis in this patient, from Southern India. The patient now an adult female of 36 years of age has moderate anemia but requires no transfusions except with some intercurrent illnesses. Exome sequencing studies showed a homozygous c.1018C>T (Pro340Ser) mutation in exon 12 of the glucose phosphate isomerase gene and later confirmed by direct sequencing. This mutation has not been previously described. To our knowledge, this is also the first known homozygous mutation in the hydrophobic core of the protein and is a highly deleterious mutation by in silico analysis and by clinical history in the family. Flow cytometry studies of band 3 content with eosin maleimide showed a unique tail of red cells on histograms, reflecting the dense red cells (presumably ATP depleted) seen on blood smears; similar findings were seen in patients with pyruvate kinase and phosphoglycerate kinase deficiency. PMID- 29227723 TI - Interventions to Address Sexual Problems in People With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Adaptation of Cancer Care Ontario Guideline. AB - Purpose The adaptation of the Cancer Care Ontario (CCO) guideline Interventions to Address Sexual Problems in People With Cancer provides recommendations to manage sexual function adverse effects that occur as a result of cancer diagnosis and/or treatment. Methods ASCO staff reviewed the guideline for developmental rigor and updated the literature search. An ASCO Expert Panel ( Table A1 ) was assembled to review the guideline content and recommendations. Results The ASCO Expert Panel determined that the recommendations from the 2016 CCO guideline are clear, thorough, and based upon the most relevant scientific evidence. ASCO statements and modifications were added to adapt the CCO guideline for a broader audience. Recommendations It is recommended that there be a discussion with the patient, initiated by a member of the health care team, regarding sexual health and dysfunction resulting from cancer or its treatment. Psychosocial and/or psychosexual counseling should be offered to all patients with cancer, aiming to improve sexual response, body image, intimacy and relationship issues, and overall sexual functioning and satisfaction. Medical and treatable contributing factors should be identified and addressed first. In women with symptoms of vaginal and/or vulvar atrophy, lubricants in addition to vaginal moisturizers may be tried as a first option. Low-dose vaginal estrogen, lidocaine, and dehydroepiandrosterone may also be considered in some cases. In men, medication such as phosphodiesterase type 5 inhibitors may be beneficial, and surgery remains an option for those with symptoms or treatment complications refractory to medical management. Both women and men experiencing vasomotor symptoms should be offered interventions for symptomatic improvement, including behavioral options such as cognitive behavioral therapy, slow breathing and hypnosis, and medications such as venlafaxine and gabapentin.Additional information is available at: www.asco.org/survivorship-guidelines and www.asco.org/guidelineswiki . PMID- 29227724 TI - Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy in Early-Stage Invasive Breast Cancer. PMID- 29227725 TI - Interpretation of the Results of the MINDACT Study and Consequent Recommendations in the Updated ASCO Clinical Practice Guideline. PMID- 29227726 TI - Reply to J.L. Blum et al and S. Lange et al. PMID- 29227727 TI - A Randomized Clinical Trial Comparing the ELLIPTA and HandiHaler Dry Powder Inhalers in Patients With COPD: Inhaler-Specific Attributes and Overall Patient Preference. AB - This randomised, open-label, cross-over, placebo-containing inhaler study assessed patient preference indicators for ELLIPTA and HandiHaler dry powder inhalers in patients with COPD (NCT02786927; GSK identifier: 204983). The primary objective of this study was to assess patient preference between ELLIPTA and HandiHaler based on the number of steps needed to use the inhaler. Eligible patients >=40 years of age with COPD were randomised 1:1 to receive their current COPD medication plus a placebo-containing ELLIPTA or HandiHaler inhaler once daily for 7 +/- 2 days (treatment period 1); this was followed by a 7 +/- 2-day placebo treatment with the alternative inhaler. A 5-item questionnaire assessed inhaler-related patient preferences. A total of 212 patients (mean age, 65.1 years) were enrolled at 22 US sites; 73% had a COPD duration >=5 years. Median (range) exposure was 8 ( 5 , 13 ) days for ELLIPTA and 8 ( 1 , 16) days for HandiHaler. Significantly more patients preferred ELLIPTA to HandiHaler in terms of the number of steps to use and all secondary attributes (size, comfort of the mouthpiece, remaining doses, and ease of use of the two inhalers; all p < 0.001). Similar results were observed irrespective of the order of inhaler use. Eighteen patients (8%) reported at least one AE and two (<1%) patients reported four non fatal SAEs; none were related to the study treatment. Patient attitude toward a particular inhaler and their experiences in using it can affect adherence to therapy, which can in turn strongly influence effectiveness of inhaled medications. This study uses a robust methodology to assess patient preference. PMID- 29227728 TI - Use of low-level laser therapy in treatment of the androgenic alopecia, the first systematic review. AB - Alopecia is a common disease affecting more than half of the world total number of people. Alopecia exists in different types, but one of the most common of these types is the Androgenic Alopecia which has affected approximately 51% of the total number of males ranging between the age bracket of 40 years and 75 years. This type of alopecia is more common in females who are above the age of 65 years and above. Despite this widespread effect, much has not been done regarding identifying the possible drugs for treating this disease. At present, there exist only two possible medications that have been scientifically approved to cure this disease, include finasteride and minoxidil. Also, another possible form of treatment has been the case of hair transplantation. Despite the new possible treatment options available for treatment of different types of hair loss, there is a need for the invention for more efficient management and treatment options that are less costly, environmentally friendly, and most importantly human consumption friendly. Due to the recent evaluation that low level laser therapy stimulated hair growth. This systematic review and meta analysis was to determine whether the use of low-level laser therapy is an effective therapy for treatment of the Androgenic alopecia and also to some degree we reviewed the level of the patient's satisfaction. Some earlier studies had shown that the use of low-level laser therapy stimulated the hair growth when mice were treated with chemotherapy which was induced by the alopecia and also the other type of alopecia called alopecia areata. The researchers hypothesized that the primary mechanism of treating Androgenic alopecia to be the stimulation of the epidermal stem cells which are in the hair follicle making them bulge and shift the follicles into the anagen phase. PMID- 29227729 TI - From the Editor-in-Chief's Desk. PMID- 29227730 TI - Physical and Performance Characteristics Related to Unintentional Musculoskeletal Injury in Special Forces Operators: A Prospective Analysis. AB - CONTEXT: Seventy-seven percent of musculoskeletal injuries sustained by United States Army Special Forces Operators are preventable. Identification of predictive characteristics will promote the development of screening methods to augment injury-prevention programs. OBJECTIVE: To determine physical and performance characteristics that predict musculoskeletal injuries. SETTING: Clinical laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 95 Operators (age = 32.7 +/- 5.1 years, height = 179.8 +/- 6.9 cm, mass = 89.9 +/- 12.7 kg). MAIN OUTCOME MEASURE(S): Laboratory testing consisted of body composition, aerobic and anaerobic capacity, upper and lower body strength and flexibility, balance, and biomechanical evaluation. Injury data were captured for 12 months after laboratory testing. Injury frequencies, cross-tabulations, and relative risks (RRs) were calculated to evaluate the relationships between physical characteristics and injury proportions. Between-groups differences (injured versus uninjured) were assessed using appropriate t tests or Mann-Whitney U tests. RESULTS: Less shoulder-retraction strength (RR = 1.741 [95% confidence interval = 1.003, 3.021]), knee-extension strength (RR = 2.029 [95% confidence interval = 1.011, 4.075]), and a smaller trunk extension : flexion ratio (RR = 0.533 [95% confidence interval = 0.341, 0.831]) were significant risk factors for injury. Group comparisons showed less trunk strength (extension: P = .036, flexion: P = .048) and smaller right vertical ground reaction forces during landing ( P = .025) in injured Operators. Knee strength, aerobic capacity, and body mass index were less in the subgroup of spine-injured versus uninjured Operators ( P values = .013-.036). CONCLUSIONS: Knee-extension and shoulder retraction strength were risk factors for musculoskeletal injury in Operators. Less trunk-flexion and -extension strength, higher body mass index, lower aerobic capacity, and increased ground reaction forces during landing were characteristics that may also contribute to musculoskeletal injury. Having 2 or more risk factors resulted in a greater injury proportion (chi2 = 13.512, P = .015); however, more research is needed. Athletic trainers working in the military or similar high-demand settings can use these data to augment screening and injury-prevention protocols. PMID- 29227731 TI - Injuries in Japanese Junior Soccer Players During Games and Practices. AB - CONTEXT: Soccer is the most popular junior sport in the world. In junior sports, injury analysis and injury-prevention measures for players, especially those under 12 years of age, are urgently needed. OBJECTIVE: To prospectively study the incidence, sites, types, and mechanisms of injuries in elementary school-aged junior soccer players during games and practices. DESIGN: Descriptive epidemiology study. SETTING: Elementary school-aged junior soccer teams in Nagoya, Japan. PATIENTS OR OTHER PARTICIPANTS: Eighty-nine players in 5 community-based club teams of junior soccer (U-12, age range = 11-12 years; U 11, age range = 10-11 years; U-10, age <=10 years). MAIN OUTCOME MEASURE(S): Data on all game and practice injuries for the 2013-2014 season were collected using an injury report form. Injury rates were calculated according to injury site, type, and mechanism. RESULTS: The overall injury rate was 2.59/1000 athlete-hours (AHs). The game injury rate (GIR; 6.43/1000 AHs) was higher than the practice injury rate (PIR; 1.49/1000 AHs; P < .05). The most common anatomical areas of injury during games and practices were the lower limbs (62.5% and 4.02/1000 AHs versus 38.5% and 0.57/1000 AHs, respectively). Contusions (27.6%, n = 8) were the most frequent type of overall injuries. Most game injuries resulted from body contact (43.8%, 2.81/1000 AHs), whereas most practice injuries resulted from other types of contact (53.8%, 0.83/1000 AHs). CONCLUSIONS: The GIRs were higher than the PIRs in Japanese junior soccer players. A lower overall PIR suggested that players in the U-12 age group practiced under appropriate conditions. However, the higher GIR in this age category needs to be decreased. PMID- 29227732 TI - beta-8-Oxoguanine DNA Glycosylase Overexpression Reduces Oxidative Stress-Induced Mitochondrial Dysfunction and Apoptosis Through the JNK Signaling Pathway in Human Bronchial Epithelial Cells. AB - 8-Oxoguanine DNA glycosylase (OGG1) is responsible for repairing 8-oxo-7,8 dihydroguanine (8-oxoG). Our previous study demonstrated that alpha-OGG1 protects cells from oxidative damage-induced apoptosis and mitochondrial dysfunction in human lung cancer cells. However, the function of beta-OGG1 remains to be elucidated. In this study, we demonstrated that overexpressed beta-OGG1 has the same role as alpha-OGG1 in protecting human bronchial epithelial cells from apoptosis and mitochondrial dysfunction. Furthermore, flow cytometry, confocal microscopy, and western blotting showed that the overexpression of beta-OGG1 could block oxidant-induced apoptosis in human bronchial epithelial cells. Additionally, knocking down OGG1 enhanced oxidative damage-induced apoptosis and mitochondrial dysfunction, whereas the overexpression of beta-OGG1 had the opposite effects and led to the downregulation of Bax and PARP. The antiapoptotic function of beta-OGG1 involved the JNK signaling pathway. These findings suggest that beta-OGG1 and alpha-OGG1 have a similar function on preventing oxidative damage-mediated apoptosis and mitochondrial dysfunction; these effects might be important in the molecular events underlying oxidant-induced cytotoxicity. PMID- 29227733 TI - Identifying Patients with COPD in Need for Psychosocial Care Through Screening with the HSCL-25 and the CCQ Mental State. AB - High levels of psychological distress are documented in patients with COPD. This study investigates the extent to which patients with a high score on the Hopkins Symptoms Checklist-25 (HSCL-25) or with a high score on the Mental State scale of the Clinical COPD Questionnaire (CCQ) endorse a need for psychosocial care, and investigates several characteristics of patients with a need. Outpatients with COPD of the Department of Pulmonary Diseases of a University Medical Center were assessed with the HSCL-25, CCQ and a question on need for psychosocial care. For patients indicating a need, the percentage of patients with HSCL-25 >=39 was compared with the percentage of patients with CCQ Mental State >2 and tested with a Chi-square. In total 323 patients participated; 57% of them were distressed according to the HSCL-25 (>=39) and 20% according to the CCQ Mental State (>2); 28% reported a need for psychosocial care. For patients reporting a need for psychosocial care a higher percentage was identified by the HSCL-25 than by the CCQ Mental State (chi2 = 9.41, p <. 002) and they were younger than patients without a need (t = 4.48, p <. 001). No differences existed for sex, FEV1, FEV1% predicted or medical comorbidities. The HSCL-25 identified more patients in need than the CCQ Mental State scale. However, not all patients with a need were identified. No relationship was found between need for psychosocial care and illness variables or comorbidities. Distress screening is questioned as the most effective way to identity patients with COPD in need for psychosocial care. PMID- 29227735 TI - Effect of 8 weeks of concurrent plyometric and running training on spatiotemporal and physiological variables of novice runners. AB - Concurrent plyometric and running training has the potential to improve running economy (RE) and performance through increasing muscle strength and power, but the possible effect on spatiotemporal parameters of running has not been studied yet. The aim of this study was to compare the effect of 8 weeks of concurrent plyometric and running training on spatiotemporal parameters and physiological variables of novice runners. Twenty-five male participants were randomly assigned into two training groups; running group (RG) (n = 11) and running + plyometric group (RPG) (n = 14). Both groups performed 8 weeks of running training programme, and only the RPG performed a concurrent plyometric training programme (two sessions per week). Anthropometric, physiological (VO2max, heart rate and RE) and spatiotemporal variables (contact and flight times, step rate and length) were registered before and after the intervention. In comparison to RG, the RPG reduced step rate and increased flight times at the same running speeds (P < .05) while contact times remained constant. Significant increases in pre- and post training (P < .05) were found in RPG for squat jump and 5 bound test, while RG remained unchanged. Peak speed, ventilatory threshold (VT) speed and respiratory compensation threshold (RCT) speed increased (P < .05) for both groups, although peak speed and VO2max increased more in the RPG than in the RG. In conclusion, concurrent plyometric and running training entails a reduction in step rate, as well as increases in VT speed, RCT speed, peak speed and VO2max. Athletes could benefit from plyometric training in order to improve their strength, which would contribute to them attaining higher running speeds. PMID- 29227734 TI - Influenza immunization policies: Which could be the main reasons for differences among countries? AB - Despite the availability of effective prophylactic and therapeutic measures, influenza remains one of the most important infectious disease threats to the human population. Every year, seasonal influenza epidemics infect up to 30% of the population; a relevant portion of the ill are hospitalized, and more than a marginal number die. In an attempt to reduce the medical, social and economic burden of influenza, vaccines are recommended by many health authorities worldwide. However, not all countries have a national program for influenza immunization. The main aim of this paper is to list the differences among influenza immunization policies of various countries, highlighting the most important scientific reasons that may have led health authorities to make different decisions. The manuscript highlights that national influenza immunization policies can vary significantly from country to country. These differences arise from insufficient evidence of the relevance of influenza infection from a clinical, social and economic point of view. The lack of precise data on the true frequency and clinical relevance of influenza infection makes it nearly impossible to establish the economic burden of influenza. Moreover, it remains very difficult to evaluate the efficacy of the different influenza vaccines and whether their use is cost-effective considering the various types of people receiving them and the indirect advantages. Disparities among countries will be overcome only when more reliable data regarding all these aspects of influenza infection, particularly those related to the true impact of the disease, are precisely defined. PMID- 29227737 TI - Another step towards scientific transparency: Requiring research materials for publication. PMID- 29227736 TI - Older Patients' Recall of Online Cancer Information: Do Ability and Motivation Matter More than Chronological Age? AB - This study proposes and tests a model to provide a more comprehensive understanding of the contribution of chronological age versus age-related ability and motivation factors in explaining recall of online cancer information among older patients (n = 197). Results revealed that recall is not a matter of chronological age per se, but rather a matter of ability and motivation. Age related ability and motivation factors explained 37.9% of the variance in recall. Health literacy, involvement with the webpage, and satisfaction with the emotional support were positively associated with recall. Furthermore, recall was negatively related to frailty, anger, future time perspective, and perceived cognitive load. The findings pose relevant opportunities for tailoring interventions to improve online information provision for older cancer patients. PMID- 29227738 TI - Antibiotic Resistance of Helicobacter pylori in Iranian Children: A Systematic Review and Meta-Analysis. AB - Antibiotic therapy for children infected with Helicobacter pylori is important. However, resistance to antibiotics is one of the main causes of treatment failure. This study was designed to evaluate the prevalence pattern of antibiotic resistance of H. pylori in Iranian children using a systematic review and meta analysis of literature. A computerized search (until June 10, 2017) using related keywords in the national and international databases was performed. A total of 261 original articles on antibiotic resistance of H. pylori in Iranian children were collected. After screening for inclusion and exclusion criteria, six eligible articles were included in the meta-analysis. Resistance rates of H. pylori to different antibiotics were as follows: metronidazole: 71%, clarithromycin: 12.2%, amoxicillin: 20.4%, tetracycline: 8.4%, ampicillin: 21.4%, rifampin: 28.6%, furazolidone: 8.4%, ciprofloxacin: 16.2%, azithromycin: 19%, erythromycin: 15.3%, and nitrofurantoin: 0%. The prevalence of H. pylori resistance to metronidazole, amoxicillin, ampicillin, and rifampin among Iranian children was high. Therefore, a careful monitoring of antibiotic resistance to select the best treatment options and prevent treatment failure is required. Although resistance to some antibiotics such as clarithromycin, tetracycline, furazolidone, and ciprofloxacin was less prevalent, frequent consumption of these drugs in children should be controlled owing to their known adverse events. PMID- 29227739 TI - Chronic Exposure to External Low-Dose Gamma Radiation Induces an Increase in Anti inflammatory and Anti-oxidative Parameters Resulting in Atherosclerotic Plaque Size Reduction in ApoE-/- Mice. AB - Populations living in radiation-contaminated territories, such as Chernobyl and Fukushima, are chronically exposed to external gamma radiation and internal radionuclide contamination due to the large amount of 137Cs released in the environment. The effect of chronic low-dose exposure on the development of cardiovascular diseases remains unclear. Previously reported studies have shown that low-dose radiation exposure could lead to discrepancies according to dose rate. In this study, we examined the effect of very low-dose and dose-rate chronic external exposure on atherosclerosis development. ApoE-/- mice were chronically irradiated with a gamma source for 8 months at two different dose rates, 12 and 28 MUGy/h, equivalent to dose rates measured in contaminated territories, with a cumulative dose of 67 and 157 mGy, respectively. We evaluated plaque size and phenotype, inflammatory profile and oxidative stress status. The results of this study showed a decrease in plaque sizes and an increase in collagen content in ApoE-/- mice exposed to 28 MUGy/h for 8 months compared to nonexposed animals. The plaque phenotype was associated with an increase in anti inflammatory and anti-oxidative gene expression. These results suggest that chronic low-dose gamma irradiation induces an upregulation of organism defenses leading to a decrease in inflammation and plaque size. To our knowledge, this is the first study to describe the possible effect of chronic external very low-dose ionizing radiation exposure for 8 months. This work could help to identify the potential existence of a dose threshold, below that which harmful effects are not exhibited and beneficial effects are potentially observed. Furthermore, these findings permit consideration of the importance of dose rate in radiation protection. PMID- 29227740 TI - Women's strategies for coping with the impacts of domestic violence in Kyrgyzstan: A grounded theory study. AB - This paper provides an account of the adverse impacts of domestic violence on women in Kyrgyzstan and develops a grounded theory of coping among survivors of abuse. The results indicate that women adopt a range of strategies to prevent, avert, and minimize anticipated violence. Two key aspects of coping appeared in the narratives: 1) maintaining the status quo and 2) developing agency to resist the abuse. The results suggest that Government and nongovernmental organizations must take additional action to draw women to formal violence prevention services. Providing professional help at several levels (e.g., clinical, community, and societal) and promoting problem-focused strategies as part of therapeutic intervention are essential. PMID- 29227741 TI - New Subclass B1 Metallo-beta-Lactamase Gene from a Clinical Pathogenic Myroides odoratus Strain. AB - Myroides odoratus is a low-virulence opportunistic human pathogen. Infections caused by M. odoratus are not common, but reports are increasing in recent years. The biggest challenge for treatment is its resistance to most antibiotics. In 2015, we isolated a pathogenic multidrug-resistant strain of M. odoratus from a urinary tract infection (UTI) patient's urine sample. To report the experience in managing M. odoratus-related UTI and investigate the genetic mechanism of this carbapenem-resistant strain, we conducted a series of microbiological and molecular studies. The bacterial strain was identified as M. odoratus by 16S rRNA gene sequencing. The minimum inhibitory concentrations (MICs) of 17 antimicrobial agents were determined against this strain. Whole-genome sequencing was performed and screened for possible beta-lactamase genes. A beta-lactamase gene, blaMOC, was identified by whole-genome sequencing, then cloned and expressed in Escherichia coli DH5alpha to characterize its function. Antimicrobial susceptibility testing showed that the strain had relatively low MIC to levofloxacin and sulfamethoxazole/trimethoprim (SMZ/TMP). After unsuccessful empirical therapy, the UTI was controlled by levofloxacin in combination with SMZ/TMP. Whole-genome sequencing identified a subclass B1 metallo-beta-lactamase gene, blaMOC, which conferred resistance to most beta-lactams except for aztreonam and cefepime. In conclusion, a new beta-lactamase gene, blaMOC, was found in an isolate of M. odoratus. The broad antimicrobial resistance of this isolate is at least attributed partially to this gene. PMID- 29227742 TI - The Evaluation of a Compassion-Focused Therapy Group for Couples Experiencing a Dementia Diagnosis. AB - OBJECTIVES: This study evaluated the effectiveness of a Compassion-Focused Therapy (CFT) group on reducing anxiety, depression, and respiratory rate (RR) in people with dementia (PwD) and their spouses, and improving quality of life (QoL) of PwD. METHOD: Sixty-four participants completed six weekly CFT sessions. Baseline and post-intervention assessments were analyzed using t-tests and Reliability Change Index. RESULTS: Mean baseline and post-assessment anxiety and depression scores fell in the 'normal range'; although a significant reduction in depression with moderate effect was observed for PwD. Fifty-seven percent of PwD with borderline to abnormal baseline scores showed clinically significant improvement in anxiety and depression. For spouses, 80% showed clinically significant improvement in depression and 50% in anxiety. RR reduced for PwD and spouses with large and medium effects respectively. QoL of PwD improved with a large effect. CONCLUSIONS: CFT appears effective in improving QoL and depression in PwD and reducing RR in PwD and spouses. CFT reduces anxiety and depression in most PwD and spouses with borderline to abnormal symptoms. CLINICAL IMPLICATIONS: This study indicates benefits of a group-CFT intervention delivered to people with a range of dementia diagnosis and their spouses. The service should investigate whether individuals in greater distress are not accessing the group and improve engagement. PMID- 29227743 TI - The Impact of Latino Values and Cultural Beliefs on Brain Donation: Results of a Pilot Study to Develop Culturally Appropriate Materials and Methods to Increase Rates of Brain Donation in this Under-Studied Patient Group. AB - OBJECTIVES: Increasing the number of Latino persons with dementia who consent to brain donation (BD) upon death is an important public health goal that has not yet been realized. This study identified the need for culturally sensitive materials to answer questions and support the decision-making process for the family. METHODS: Information about existing rates of BD was obtained from the Alzheimer's Disease Centers. Several methods of data collection (query NACC database, contacting Centers, focus groups, online survey, assessing current protocol and materials) were used to give the needed background to create culturally appropriate BD materials. RESULTS: A decision was made that a brochure for undecided enrollees would be beneficial to discuss BD with family members. For those needing further details, a step-by-step handout would provide additional information. CONCLUSIONS: Through team collaboration and engagement of others in the community who work with Latinos with dementia, we believe this process allowed us to successfully create culturally appropriate informational materials that address a sensitive topic for Hispanic/Latino families. CLINICAL IMPLICATIONS: Brain tissue is needed to further knowledge about underlying biological mechanism of neurodegenerative diseases, however it is a sensitive topic. Materials assist with family discussion and facilitate the family's follow through with BD. PMID- 29227744 TI - Molecular Epidemiology of Klebsiella pneumoniae Strains Causing Bloodstream Infections in Adults. AB - Molecular epidemiology of Klebsiella pneumoniae bacteremic strains allows for a better understanding of preventive and therapeutic strategies. Clinical and microbiological characteristics of 348 K. pneumoniae bacteremia cases (2007-2009) were retrospectively characterized by multilocus sequence typing and extended spectrum beta-lactamases (ESBL) production. Overall, 223 (64.08%) cases were nosocomial (NA), 58 (16.67%) healthcare associated, and 67 (19.25%) community acquired. The main infection origins were urinary tract (16.6%, 50.0%, and 43.3%), biliary tract (10.8%, 24.2%, and 31.3%), and catheter-related infection (39.9%, 5.2%, and 0%). The 30-day mortality rate was around 20%. The rates of resistance were around 45% the highest being among NA cases, and ESBL production was detected in 7.2% of cases. A total of 161 different sequence types were grouped into 13 clonal sets by e-burst analysis. No relationship could be established between clonal sets and the origin of infection or the healthcare related settings. The high genetic variability among the isolates suggests their intrapatient endogenous origin. PMID- 29227745 TI - Florida State University's Institute for Family Violence Studies. AB - This article outlines the role of the Institute for Family Violence Studies (IFVS) within the Florida State University College of Social Work in navigating issues intersecting social work and the law ( http://familyvio.csw.fsu.edu/ ). By developing comprehensive state and national trainings for unique populations and conducting interdisciplinary research, the IFVS promotes public policy that benefits healthy families and decreases family and intimate partner violence. The crucial role of staff and students, the IFVS's collaborative alliances, and funding sources are highlighted. Projects such as the Clearinghouse on Supervised Visitation, the National Prevention Toolkit on Officer-Involved Domestic Violence, Successful Co-Parenting After Divorce, and the LGBTQ Family Life Project are described. Plans for future projects, as well as other new avenues for research, are summarized. PMID- 29227746 TI - Looking Back and Forward. PMID- 29227747 TI - Duration of continuous cropping with straw return affects the composition and structure of soil bacterial communities in cotton fields. AB - Salinized land in the China's Xinjiang Region is being reclaimed for continuous cotton production. The specific objectives of this field study were (i) to compare bacterial composition and diversity in unfarmed (i.e., unreclaimed) and continuously (5, 10, 15, and 20 years) cropped soils and (ii) to explore correlations between soil properties and the bacterial communities identified by Illumina MiSeq sequencing. The results showed that bacterial species richness and diversity increased for 10-15 years and then declined when salinized land was reclaimed for cotton production. Proteobacteria and Firmicutes were the dominant phyla in unfarmed soil. Continuous cropping reduced the abundance of Firmicutes but increased that of Chloroflexi, Acidobacteria, and Actinobacteria. Cluster analyses showed that the greatest similarities in bacterial communities were between the 5- and 10-year treatments and between the 15- and 20-year treatments. Soil pH, electrical conductivity, alkali-hydrolyzable N, and available P were significantly correlated with bacterial community distribution. Overall, cotton production improved soil physicochemical properties and altered the structure and composition of soil bacterial communities compared with unfarmed soil. These positive effects began to decrease after 10-15 years of continuous cotton production. PMID- 29227748 TI - Survival in signet ring cell carcinoma varies based on primary tumor location: a Surveillance, Epidemiology, and End Results database analysis. AB - BACKGROUND: The aim of this study was to investigate the survival of patients with signet ring cell carcinoma (SRCC) based on primary tumor location. METHODS: Patient data were obtained from the Surveillance, Epidemiology, and End Results database (1988-2012) with >=200 cases per tumor location. Cox regression analysis was used to investigate prognostic factors of cause-specific survival (CSS). RESULTS: We identified 24,171 patients. Of the patients, 63.4% had gastric SRCC, followed by colon (18.2%), esophageal (5.0%), rectal (3.5%), lung (3.1%), pancreatic (1.8%), breast (1.5%), bladder (1.3%), small intestine (1.1%), and gallbladder SRCC (1.0%). The 5-year CSS was 22.1%, 69.0%, 33.2%, 28.1%, 24.8%, 16.1%, 13.6%, 12.6%, 11.0%, 6.4% in patients with gastric, breast, colon, rectum, bladder, small intestine, esophageal, gallbladder, lung, and pancreatic SRCC, respectively (P < 0.001). Multivariate analyses showed that the primary tumor location was an independent prognostic factor of survival. Patients with lung, small intestine, and bladder SRCC had a comparable CSS to gastric SRCC, while breast and colorectal SRCC had better survival than gastric SRCC. Esophageal, gallbladder, and pancreatic SRCC were significantly associated with poor CSS compared with gastric SRCC. CONCLUSION: Our study suggests a major difference in survival of SRCC based on the primary tumor locations. PMID- 29227749 TI - Efficacy and Safety of Photoselective Vaporization of the Prostate with 120 W 532 nm Laser in Patients with Benign Prostatic Hyperplasia on Anticoagulation or Antiplatelet Therapy: Observations on Long-Term Outcomes. AB - OBJECTIVE: The objective of this study was to evaluate the safety and effectiveness of photoselective vaporization of the prostate (PVP) in the treatment of patients with benign prostatic hyperplasia (BPH) on anticoagulant or antiplatelet therapy. BACKGROUND: The "gold standard" of surgical treatment of BPH is transurethral resection of the prostate (TURP). Since the risk of complications associated with TURP is still significant, there is a continuous search for safer and equally effective procedures. One of them is PVP with a 532 nm potassium-titanyl-phosphate/lithium triborate (KTP/LBO) laser. MATERIALS AND METHODS: A total of 109 patients underwent PVP with the use of the GreenLight HPS 120 W laser. Sixty-five (59.6%) of the patients were on anticoagulants or antiplatelet drugs, whereas 44 (40.4%) patients were not. Various objective and subjective parameters were evaluated intra- and postoperatively along with a 5 year follow-up to compare the results and safety of PVP in these two groups of patients. RESULTS: No difference between the groups was found in intraoperative parameters, including operation and lasing time, as well as laser energy used. Also, no intraoperative complications were observed. There was no significant bleeding in any of the groups, and none of the patients required a blood transfusion. Catheterization and hospitalization time did not differ between both groups, and during the 5-year follow-up period, good objective and subjective results were observed, and the complication rates were comparable between the groups. CONCLUSIONS: Our results demonstrate that PVP for patients with BPH is an effective and safe procedure with satisfactory long-term outcomes. Anticoagulant and antiplatelet drugs did not significantly influence the results, or the complication rates. PMID- 29227750 TI - Genetic Polymorphisms in PRM1, PRM2, and YBX2 Genes are Associated with Male Factor Infertility. AB - AIMS: The etiology of infertility is still unknown in almost half of all male infertility patients. In sperm, DNA condensation differs from somatic and female gamete cells, with the protamine (PRM) gene and its transcription factor, Y-box binding protein 2 (YBX2), playing key roles in making the structure more compact. Protamine polymorphisms have been studied in different populations, but various results have been acquired. MATERIALS AND METHODS: In our study, we examined, for the first time in a Turkish population, the association between protamine gene alleles (PRM1 c.-190C>A, PRM1 c.197G>T, and PRM2 c.248C>T), and YBX2 (c.187T>C and c.1095 + 16A>G) and male infertility. This was accomplished using polymerase chain reaction-restriction fragment length polymorphism analyses of 100 infertile and 100 fertile Turkish men. Sperm DNA fragmentation analysis was performed using the Comet technique. RESULTS: We found that the AA and CA genotypes of the PRM1 c.-190C>A polymorphism had a significant association with infertility (p < 0.001) and the AA genotype was also highly significantly associated with high sperm DNA damage (p < 0.001). CONCLUSION: This study demonstrates that the PRM1 c.-190C>A polymorphism is associated with sperm DNA fragmentation, which may impact male infertility in the Turkish population. Further research with larger groups and in various other study populations will be required to clarify the impact of protamine and YBX2 gene polymorphisms on male infertility. PMID- 29227752 TI - Systemic Corticosteroid Therapy May Delay Viral Clearance in Patients with Middle East Respiratory Syndrome Coronavirus Infection. PMID- 29227751 TI - Molecular evolution and expression of oxygen transport genes in livebearing fishes (Poeciliidae) from hydrogen sulfide rich springs. AB - Hydrogen sulfide (H2S) is a natural toxicant in some aquatic environments that has diverse molecular targets. It binds to oxygen transport proteins, rendering them non-functional by reducing oxygen-binding affinity. Hence, organisms permanently inhabiting H2S-rich environments are predicted to exhibit adaptive modifications to compensate for the reduced capacity to transport oxygen. We investigated 10 lineages of fish of the family Poeciliidae that have colonized freshwater springs rich in H2S-along with related lineages from non-sulfidic environments-to test hypotheses about the expression and evolution of oxygen transport genes in a phylogenetic context. We predicted shifts in the expression of and signatures of positive selection on oxygen transport genes upon colonization of H2S-rich habitats. Our analyses indicated significant shifts in gene expression for multiple hemoglobin genes in lineages that have colonized H2S rich environments, and three hemoglobin genes exhibited relaxed selection in sulfidic compared to non-sulfidic lineages. However, neither changes in gene expression nor signatures of selection were consistent among all lineages in H2S rich environments. Oxygen transport genes may consequently be predictable targets of selection during adaptation to sulfidic environments, but changes in gene expression and molecular evolution of oxygen transport genes in H2S-rich environments are not necessarily repeatable across replicated lineages. PMID- 29227753 TI - The Magnitude of a Community's Health Needs and Nonprofit Hospitals' Progress in Meeting Those Needs: Are We Faced With a Paradox? AB - OBJECTIVES: Although most nonprofit hospitals are required to conduct periodic community health needs assessments (CHNAs), such assessments arguably are most critical for communities with substantial health needs. The objective of this study was to describe differences in progress in conducting CHNAs between hospitals located in communities with the greatest compared with the fewest health needs. METHODS: We used data on CHNA activity from the 2013 tax filings of 1331 US hospitals combined with data on community health needs from the County Health Rankings. We used bivariate and multivariate analyses to examine differences in hospitals' progress in implementing comprehensive CHNAs using 4 activities: (1) strategies to address identified needs, (2) participation in developing community-wide plans, (3) including CHNA into a hospital's operational plan, and (4) developing a budget to address identified needs. We compared progress in communities with the greatest and the fewest health needs using a comprehensive indicator comprising a community's socioeconomic factors, health behaviors, access to medical care, and physical environment. RESULTS: In 2013, nonprofit hospitals serving communities with the greatest health needs conducted an average of 2.5 of the 4 CHNA activities, whereas hospitals serving communities with the fewest health needs conducted an average of 2.7 activities. Multivariate analysis, however, showed a negative but not significant relationship between the magnitude of a community's health needs and a hospital's progress in implementing comprehensive CHNAs. CONCLUSIONS: Hospitals serving communities with the greatest health needs face high demand for free and reduced-cost care, which may limit their ability to invest more of their community benefit dollars in initiatives aimed at improving the health of the community. PMID- 29227754 TI - A Genetic Variant in miR-124 Decreased the Susceptibility to Esophageal Squamous Cell Carcinoma in a Chinese Kazakh Population. AB - AIMS: Esophageal squamous cell carcinoma (ESCC) is characterized by high prevalence and mortality worldwide, and it is very highly prevalent in China. ESCC is caused by various factors, including microRNAs (miRNAs) whose expression have been shown to play a major role in tumor generation. Single nucleotide polymorphisms (SNPs) in miRNAs could affect susceptibility to numerous cancers. This study aimed to evaluate the relationship between SNPs in miR-124 and ESCC risk in the Chinese Kazakh population. METHODS: A total of 239 Chinese Kazakh patients with ESCC and 227 healthy Chinese Kazakh individuals were recruited in this study. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to analyze the miR-124 rs531564 genotype. RESULTS: Allele G of the miR-124 rs531564 polymorphism significantly reduced the risk of ESCC in the Chinese Kazakh population [odds ratio (OR) = 0.711; 95% confidence interval (CI): 0.508-0.996; p = 0.047]. The dominant model indicated that the CG+GG genotypes were associated with significantly decreased ESCC risk compared to the CC genotype (adjusted OR = 0.586; 95% CI: 0.396-0.867; p = 0.007). Stratification analyses showed that compared with the CC genotype, the CG and CG+GG genotypes manifested reduced ESCC risks in the female group [CG vs. CC: OR = 0.472; 95% CI: 0.255-0.872; p = 0.016; (CG+GG) vs. CC: OR = 0.472; 95% CI: 0.255-0.872; p = 0.016] and the age group of <57 years old [CG vs. CC: OR = 0.456; 95% CI: 0.258 0.806; p = 0.006; (CG+GG) vs. CC: OR = 0.456; 95%CI: 0.258-0.806; p = 0.006]. The miR-124 rs531564 polymorphism showed no significant association with histological stage, lymph node metastasis, depth of invasion, or tumor/node/metastasis stage. CONCLUSIONS: Our findings are the first to be reported that the miR-124 rs531564 polymorphism decreased ESCC risk in the Chinese Kazakh population. PMID- 29227755 TI - Glycemic Variability Percentage: A Novel Method for Assessing Glycemic Variability from Continuous Glucose Monitor Data. AB - BACKGROUND: High levels of glycemic variability are still observed in most patients with diabetes with severe insulin deficiency. Glycemic variability may be an important risk factor for acute and chronic complications. Despite its clinical importance, there is no consensus on the optimum method for characterizing glycemic variability. METHOD: We developed a simple new metric, the glycemic variability percentage (GVP), to assess glycemic variability by analyzing the length of the continuous glucose monitoring (CGM) temporal trace normalized to the duration under evaluation. The GVP is similar to other recently proposed glycemic variability metrics, the distance traveled, and the mean absolute glucose (MAG) change. We compared results from distance traveled, MAG, GVP, standard deviation (SD), and coefficient of variation (CV) applied to simulated CGM traces accentuating the difference between amplitude and frequency of oscillations. The GVP metric was also applied to data from clinical studies for the Dexcom G4 Platinum CGM in subjects without diabetes, with type 2 diabetes, and with type 1 diabetes (adults, adolescents, and children). RESULTS: In contrast to other metrics, such as CV and SD, the distance traveled, MAG, and GVP all captured both the amplitude and frequency of glucose oscillations. The GVP metric was also able to differentiate between diabetic and nondiabetic subjects and between subjects with diabetes with low, moderate, and high glycemic variability based on interquartile analysis. CONCLUSION: A new metric for the assessment of glycemic variability has been shown to capture glycemic variability due to fluctuations in both the amplitude and frequency of glucose given by CGM data. PMID- 29227756 TI - Erratum. AB - Vall EA, Kibbe DL, Greene C, Smith KS, O'Connor JC. Leading the way in preventing childhood obesity in Georgia. Public Health Rep. 2017;132(suppl 2):3S-6S (Original DOI: 10.1177/0033354917722993) In the above referenced article, the author names were originally listed in the incorrect order. The correct order is given above. The order has also been corrected online and in print. PMID- 29227757 TI - The second agent effect: Interpersonal predictive coding in people with schizophrenia. AB - Interpersonal predictive coding (IPC) enables one to use the information conveyed by the communicative action of one agent to predict the response of another agent. IPC relies both on explicit reflective processes (processing of communicative intentions) and automatic reflexive processes (motor resonance). Predictive coding deficits may underlie positive symptoms in people with schizophrenia (SCZ), yet IPC has not been analyzed in SCZ. Thirty-nine SCZ and 22 controls (HC) completed a simultaneous masking detection task, during which they observed either communicative (Com) or individual (Ind) actions of agent A and had to report the presence of the agent B, who was shown in half of the trials. In line with previous findings, detection criterion was lowered after Com as compared to Ind, suggesting a higher tendency to report the presence of a second agent after observing agent A's communicative gestures . Surprisingly, this effect was found to a similar extent in both groups. Communicative criterion was linked to mentalizing abilities, but not to symptoms in SCZ. Finding that SCZ show similar IPC as HC adds to the previous evidence that reflexive processes may be relatively intact in patients. Furthermore, the level of reflective processes may be crucial for patients' social functioning. PMID- 29227758 TI - Better Open Than Intellectual: The Benefits of Investment Personality Traits for Learning. AB - The investment theory of adult intelligence posits that individual differences in knowledge attainment result from people's differences in cognitive ability and their propensity to apply and invest that ability, which is referred to as investment personality traits. Here, we differentiated intellectual (i.e., intellectual curiosity) and nonintellectual investment (i.e., openness to experience), and we tested their respective predictive validity for knowledge attainment in four independent lab-based studies (overall N = 649). Openness to experience was positively associated with knowledge attainment across all four studies, and this effect was by and large independent of cognitive ability. By contrast, intellectual curiosity was not related to knowledge attainment. The findings suggest that openness to experience, rather than intellectual curiosity, is the investment personality trait that broadly benefits learning and adult intelligence. PMID- 29227760 TI - The MJA 2017: the year in review, and looking forward to 2018. PMID- 29227761 TI - Safeguarding the health of future generations. PMID- 29227762 TI - Neville Wran's voice: how the Premier's Teflon-coated vocal cords came unstuck. PMID- 29227763 TI - Leadership lessons. PMID- 29227764 TI - Winhanga-duri-nya (to reflect). PMID- 29227765 TI - The clinical history. PMID- 29227766 TI - The aftermath of loss. PMID- 29227767 TI - Connecting basic science, clinical knowledge, research and patient communication. PMID- 29227768 TI - Understanding the function of health protection activities within public health practice. PMID- 29227769 TI - Mapping the historical causes of health inequalities. PMID- 29227770 TI - Dad's in hospital again. PMID- 29227771 TI - Cardamom angel. PMID- 29227772 TI - Mort-ified. PMID- 29227773 TI - Non-compliance. PMID- 29227774 TI - Tooth Fairy guilty of favouritism! AB - OBJECTIVES: To determine the proportion of children visited by the Tooth Fairy, the child-related factors that influence the likelihood of her visit, and the parent-related variables that affect the amount of money the Tooth Fairy leaves. DESIGN: Cross-sectional questionnaire study. SETTING: Zurich, Switzerland. PARTICIPANTS: 3617 parents of children (mean age of children, 6.8 years; 51.9% girls) who had lost at least one deciduous tooth received a self-developed questionnaire; 1274 questionnaires were returned (35.2%). MAIN OUTCOME MEASURES: Primary outcome variables were the Tooth Fairy's visit after tooth loss and the amount of money given in case of a visit. Child- and parent-related variables were assessed as predictors of the main outcomes. RESULTS: Most parents (71.0%) reported that the Tooth Fairy visited their child. She usually exchanged the lost tooth for money (55.8% of visits) or placed money next to the tooth (40.7%); rarely did she take the tooth without pecuniary substitution. The Tooth Fairy left an average of 7.20 Swiss francs (approximately AU$9.45). The Tooth Fairy favoured visiting for the teeth of older children (odds ratio [OR], per year, 1.87; 95% CI, 1.09-3.21), of boys (OR, 2.65; 95% CI, 1.09-6.42), and of children who believed in her (OR, 4.12; 95% CI, 1.77-9.64). The amount of money was influenced by maternal, but not paternal socio-demographic factors, including level of education (OR, per level, 0.78; 95% CI, 0.66-0.92) and country of origin (OR, Western countries v non-Western countries, 2.35; 95% CI, 1.20-4.62). CONCLUSIONS: The Tooth Fairy does not visit all children after tooth loss, displaying clear preferences in her choice of business partners. The odds of a visit are dramatically increased if she is believed in, and the value of a deciduous tooth is influenced by socio-demographic factors. PMID- 29227775 TI - Stereotactic neurosurgery. PMID- 29227776 TI - The Specialty and Naughty/Nice Tendency Audit (SANTA): which medical specialists can be trusted to follow recipes? AB - OBJECTIVE: To evaluate the influence of medical specialty on the likelihood of doctors making the Naughty or Nice lists this Christmas. DESIGN, SETTING, AND PARTICIPANTS: A quantitative observational study. Doctors in a medical parent Facebook group were asked about their specialty and their tendency to follow recipes. MAIN OUTCOME MEASURES: Self-reported tendency to follow the recipe (always, sometimes, never) as an indicator of rule-breaking behaviour, extrapolated as indicating Naughty (unlikely to follow a recipe) or Nice (always follow recipes) tendencies, and consequently the likelihood of being included in the Nice list this Christmas. RESULTS: The majority of doctors in only 19% of specialties made the Nice list. When aggregated, 92% of surgical specialties reported that they either never followed recipes or did so only occasionally. Similarly, 80% of physician specialties reported being Naughty. In contrast, 50% each of those in critical care specialties were Naughty or Nice. General practitioners comprised the largest single group of respondents, and only 8% identified as Nice. CONCLUSIONS: An overwhelming majority of medical parents were Naughty. As Santa makes his list and checks it twice, he will find out who is Naughty or Nice, and he may be surprised at the number of doctors who are on the wrong side of the inventory. When Santa Claus comes to town, he should be circumspect when indulging in any baked offerings by the Christmas tree, particularly those offered by surgeons and general practitioners. PMID- 29227778 TI - The "Christmas notch": a novel use for the punch biopsy blade. PMID- 29227777 TI - Towards a theoretically informed policy against a rakghoul plague outbreak. AB - A long time ago in a galaxy far, far away, the Sith Lord Karness Muur engineered the rakghoul plague, a disease that transformed infected humans into near mindless predatory rakghouls. At its peak, the disease infected millions of individuals, giving rise to armies of rakghouls on a number of planets. Whether rakghoul populations have persisted until this day is not known, making a rakghoul invasion on Earth not completely improbable. Further, a strategy for defence against an outbreak of the disease on Earth has not yet been proposed. To fill this glaring gap, we developed the first mathematical model of the population dynamics of humans and rakghouls during a rakghoul plague outbreak. Using New South Wales as a model site, we then obtained ensembles of model predictions for the outcome of the rakghoul plague in two different disease control strategy scenarios (population evacuation and military intervention), and in the absence thereof. Finally, based on these predictions, we propose a set of policy guidelines for successfully controlling and eliminating outbreaks of the rakghoul plague in Australian states. PMID- 29227779 TI - Terry's parrot died: adventures in voice recognition. PMID- 29227782 TI - The five stages of grief towards accepting a rejection letter. PMID- 29227781 TI - Going potty. PMID- 29227783 TI - Geeky side of medicine. PMID- 29227784 TI - Around the universities and research institutes. PMID- 29227785 TI - Patient-specific instruments: advantages and pitfalls. AB - Patient-specific instruments (PSI) aim to improve the accuracy of total knee replacement (TKR) based on computer-assisted preoperative planning. In this work, the authors describe the advantages and pitfalls of PSI based on their clinical experience. The main conclusion of this work is that PSI has direct impact on the logistical and technical features of TKR with some advantages and pitfalls. PMID- 29227786 TI - Novel anatomical-based surgical technique for positioning of the patellar component in total knee arthroplasty. AB - The patella remains one of the main sources of post-operative complication following total knee arthroplasty surgery. Optimal positioning of the patellar component is still a controversy with no clear-cut guidelines. Instead of choosing an empirical position, we described a novel surgical technique to better locate the patellar button based on the individual patellar anatomy of each patient. PMID- 29227787 TI - Major destructive asymptomatic lumbar Charcot lesion treated with three column resection and short segment reconstruction. Case report, treatment strategy and review of literature. AB - Charcot's spine is a long-term complication of spinal cord injury. The lesion is often localized at the caudal end of long fusion constructs and distal to the level of paraplegia. However, cases are rare and the literature relevant to the management of Charcot's arthropathy is limited. This paper reviews the clinical features, diagnosis, and surgical management of post-traumatic spinal neuroarthropathy in the current literature. We present a rare case of adjacent level Charcot's lesion of the lumbar spine in a paraplegic patient, primarily treated for traumatic spinal cord lesion 39 years before current surgery. We have performed end-to-end apposition of bone after 3 column resection of the lesion, 3D correction of the deformity, and posterior instrumentation using a four-rod construct. Although the natural course of the disease remains unclear, surgery is always favorable and remains the primary treatment modality. Posterior long segment spinal fusion with a four-rod construct is the mainstay of treatment to prevent further morbidity. Our technique eliminated the need for more extensive anterior surgery while preserving distal motion. PMID- 29227788 TI - Posterior-only surgical correction of adolescent idiopathic scoliosis: an Egyptian experience. AB - INTRODUCTION: The aim of this prospective case series study is to document safety and effectiveness of high density pedicle screws through posterior only approach with intraoperative wake-up test in correction of adolescent idiopathic scoliosis (AIS). METHODS: Between 2011 and 2015, all surgically treated patients for AIS were followed up for a minimum of 2 years. Clinical outcomes were evaluated using scoliosis research society-22 (SRS) questionnaire. All patients were classified according to Lenke classification. Major and minor curves Cobb angle as well as sagittal parameters were measured on whole spine X-rays. All patients underwent an intra-operative wake-up test after deformity correction and a minimum of 80% metal density of implants was used. RESULTS: This study included 50 patients. The mean age at time of surgery was 16.8 years. The mean follow-up period was 38.1 months. The mean correction rate for the coronal Cobb angle of the major curve was 79.12%, while that of the minor curve was 68.9%. The mean thoracic kyphosis angle was 38.4 degrees preoperatively, 29.76 degrees postoperatively and 30.36 degrees at the last follow-up. The mean SRS-22 questionnaire scores improved significantly at the last follow-up (P > 0.001). There were no neurological deficits at the wake-up test. No cases of pseudarthrosis or metal failure were encountered. CONCLUSION: This is a prospective study of at least 80% metal density pedicle screws technique and intra-operative wake-up test in Egyptian patients with AIS. It proved to be an effective and safe technique in correction of radiological parameters, with no neurological or implant related complications. It allowed excellent scoliotic and kyphotic curves correction with minimal loss of correction. On the whole it led to better quality of life. PMID- 29227789 TI - Identifying patterns of tobacco use among US middle and high school students: A latent class analysis. AB - OBJECTIVES: This study sought to (a) understand patterns of tobacco use among US middle and high school students based on their lifetime or current use of tobacco products: cigarettes, cigars, chewing tobacco, pipes, e-cigarettes, and hookah tobacco, and (b) examine differences in the underlying patterns by sociodemographic and tobacco-related characteristics (e.g., exposure to tobacco products, tobacco advertising, parental disapproval of tobacco use and feedback from healthcare providers). METHODS: We analyzed self-report data from the 2013 National Youth Tobacco Survey (n=18,046). Latent Class Analysis was conducted to identify patterns of tobacco use and tested how sociodemographic and tobacco related characteristics are associated with such patterns. RESULTS: Four subtypes of tobacco use were identified: "Very Low Risk (VLR)," "Lifetime Smoking (LS)," "Lifetime Multiple Tobacco Use (LMT)," and "Past Month Multiple Tobacco Use (PMT)." Latino and Asian American youth were more likely to be in PMT. Compared with students in LS, students in VLR were less likely to receive advice not to use tobacco from their healthcare providers, but more likely to have parental disapproval of smoking. Students in LMT (vs. LS) were more likely to use tobacco coupons and promotional materials, report greater access to tobacco, and receive advice from a healthcare professional. Students in PMT (vs. LS) were more likely to use coupons, take part in tobacco promotions, and be exposed to smoking in a vehicle. CONCLUSIONS: Our study suggests that it may be important to consider the underlying patterns and correlates of tobacco use in designing tobacco control programs for youth. PMID- 29227791 TI - Dynamic content exchange between liprotides. AB - Liprotides are complexes composed of partially denatured proteins and fatty acids in which the fatty acids form a micelle-like core surrounded by a shell of proteins. Liprotides, composed of alpha-lactalbumin (aLA) and oleic acid (OA), are similar in components and cytotoxicity to the original HAMLET protein-fatty acid complex. Liprotides composed of aLA and OA kill tumor cells by transferring the OA component to, and thus destabilizing, the cell membrane. Here we investigate liprotides' dynamics of transfer of contents between themselves and membranes using the hydrophobic fluorescent probe pyrene. We find that pyrene incorporated into liprotides is exchanged between liprotides within the dead time of a stopped-flow instrument, while the transfer to membranes occurs within 20s. Transfer kinetics was not affected by the presence of the membrane stabilizing lipid cholesterol. Thus, transfer is a remarkably rapid process which illustrates liprotides' efficacy as transporters of hydrophobic compounds. PMID- 29227792 TI - Nodal Stage: Is It a Prognostic Factor for Submandibular Gland Cancer? AB - PURPOSE: Submandibular gland cancer is relatively rare. The purpose of this study was to estimate 5-year overall survival (OS) and disease-free survival (DFS) and to identify prognostic factors associated with OS and DFS for submandibular cancer. MATERIALS AND METHODS: The authors implemented a retrospective cohort study and enrolled a sample of patients with submandibular gland cancer. The predictor variables were age, gender, tumor stage, nodal stage, margin status, and extracapsular spread. The outcome variables were 5-year OS and 5-year DFS. Kaplan-Meier methods were used to estimate survival and Cox hazards models were used to identify prognostic variables. RESULTS: The sample was composed of 52 patients with submandibular gland cancer (mean age, 47.4 yr; 51.9% men). The median follow-up was 81 months (range, 11 to 159 months). The 5-year OS and DFS rates were 76.9 and 67.3%, respectively. Fixed mass, positive neck node, and positive margin status were relevant predictors of OS and DFS. Nodal stage was the relevant independent predictor affecting the disease outcome of submandibular gland cancer. CONCLUSION: These results identified several important prognostic factors associated with survival rate in patients with submandibular gland cancer. These prognostic variables include symptoms at presentation, pathologic nodal status, and margin status. These outcomes suggest that heightening vigilance of clinical characteristics for this disease might provide the impetus for improving the survival rate. PMID- 29227790 TI - Interpersonal and intrapersonal emotional processes in individuals treated for alcohol use disorder and non-addicted healthy individuals. AB - INTRODUCTION: Prior work largely confirms the presence of various emotional processing deficits among individuals with an alcohol use disorder (AUD); however, their specificity and relevance still warrant investigation. The aim of the current study was to compare selected aspects of emotional processing (i.e., mental state recognition, alexithymia, and emotional intelligence) between individuals treated for an AUD and healthy individuals. METHODS: The AUD sample consisted of 92 abstinent men with AUD who were participating in an 8-week inpatient abstinence-based treatment program in Warsaw, Poland. The healthy control (HC) group consisted of 86 men recruited from the Medical University of Warsaw and the Nowowiejski Hospital administrative staff. Baseline information about demographics, psychopathological symptoms, and severity of alcohol problems was obtained. Mental states recognition was assessed using the Reading the Mind in the Eyes Test (RMET). Alexithymia was measured with the Toronto Alexithymia Scale (TAS-20). The Schutte Self-Report Emotional Intelligence Test (SSEIT) was used to measure emotional intelligence (EI). RESULTS AND CONCLUSIONS: After accounting for potentially confounding variables (demographics, severity of depression, anxiety symptoms) in MANCOVA models, patients with AUD presented deficits in identification and description of their own emotional states, as well as lower emotion regulation skills when compared to HCs. No between-group differences were observed in self-reported recognition of other people's emotions, social skills, and a behavioral measure of mental states recognition. Specific rather than general emotion-processing deficits in participants with AUD were identified, suggesting problems with processing of intrapersonal emotional signals. PMID- 29227793 TI - Bilateral Traumatic Caroticocavernous Fistulas: A Case Report and Review of the Literature. AB - A traumatic caroticocavernous fistula (CCF) is an acquired, abnormal communication between the internal carotid artery and the cavernous sinus, secondary to trauma. This rare condition can initially be misdiagnosed, because its presentation shares features common to those of facial trauma, which can result in serious complications. We describe a case of bilateral CCF in an adult patient after a road traffic accident. PMID- 29227794 TI - Does Different Mandibulectomy (Marginal vs Segmental) Affect the Prognosis in Patients With Oral Squamous Cell Carcinoma? AB - PURPOSE: It is unclear whether different mandibular surgical methods affect the prognosis of patients with oral squamous cell carcinoma (OSCC). Accordingly, the authors retrospectively compared the prognosis of patients who underwent marginal mandibulectomy (MG) or segmental mandibulectomy (SG) for OSCC and aimed to determine the factors influencing prognosis. MATERIALS AND METHODS: The authors conducted a retrospective cohort study of 82 patients with OSCC who underwent mandibulectomy at their hospital from January 2001 through January 2015. All patients had a biopsy-confirmed diagnosis of OSCC adjacent to the lower mandible. The local recurrence rate and survival rate after these 2 treatment modalities were analyzed using Kaplan-Meier survival analysis. At univariate and multivariate analyses, the Cox regression model was used to screen risk factors for recurrence, including pathologic grade, pT stage, mandibular involvement, lymph node metastasis, and method of mandibulectomy. Statistical significance was considered when P values were less than .05. RESULTS: Of the 82 patients, 39 underwent MG and 43 underwent SG. According to statistical analysis, age, gender, pathologic grade, tumor stage, mandibular involvement, and lymph node metastasis were similar between the 2 groups. The 3- and 5-year local recurrence rates were not significantly different between the 2 groups (P > .05). The 3- and 5-year survival rates were not significantly different between the 2 groups (P > .05). Poorly differentiated pathologic type was the only prognostic factor for OSCC at multivariate Cox regression analysis (P = .001). CONCLUSION: The results of this study suggest that MG is safe for some evaluated patients with OSCC. Of the prognostic factors studied, MG was not associated with worse prognosis; however, poorly differentiated OSCC affected the prognosis for oral carcinoma. PMID- 29227795 TI - Divergent effects of levetiracetam and tiagabine against spontaneous seizures in adult rats following neonatal hypoxia. AB - Animal models are valuable tools for screening novel therapies for patients who suffer from epilepsy. However, a wide array of models are necessary to cover the diversity of human epilepsies. In humans, neonatal hypoxia (or hypoxia-ischemia) is one of the most common causes of epilepsy early in life. Hypoxia-induced seizures (HS) during the neonatal period can also lead to spontaneous seizures in adulthood. This phenomenon, i.e., early-life hypoxia leading to adult epilepsy - is also seen in experimental models, including rats. However, it is not known which anti-seizure medications are most effective at managing adult epilepsy resulting from neonatal HS. Here, we examined the efficacy of three anti-seizure medications against spontaneous seizures in adult rats with a history of neonatal HS: (1) phenobarbital (PHB), the oldest epilepsy medicine still in use today; (2) levetiracetam (LEV); and (3) tiagabine (TGB). Both LEV and TGB are relatively new anticonvulsant drugs that are ineffective in traditional seizure models, but strikingly effective in other models. We found that PHB and LEV decreased seizures in adult rats with a history of HS, whereas TGB exacerbated seizures. These divergent drug effects indicate that the HS model may be useful for differentiating the clinical efficacy of putative epilepsy therapies. PMID- 29227796 TI - Dynamic functional disturbances of brain network in seizure-related cognitive outcomes. AB - Epilepsy is a prevalent neurologic disorder affecting approximately 50 million people worldwide. Cognitive dysfunction induced by seizures is one of the severe comorbidities of epilepsy and epileptic syndrome, which has a negative impact on epileptic patients' quality of life. Several mechanisms may be associated with cognitive impairment in patients with epilepsy. Here, we review how the dynamic functional alterations of brain network influence seizure-related cognitive outcomes. PMID- 29227797 TI - Anticonvulsant effects of acetaminophen in mice: Comparison with the effects of nonsteroidal anti-inflammatory drugs. AB - OBJECTIVE: The appropriate use of analgesic drugs based on their degree of analgesia and adverse effects is important for pain management. Although it has been reported that AM404, a metabolite of acetaminophen, has anticonvulsant effects in several animal seizure models, little is known about the relation between acetaminophen and seizures. We therefore investigated the effects of acetaminophen on seizure susceptibility in several mouse seizure and epilepsy models and compared the effects with those of nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: Anticonvulsant activity was evaluated in ICR mice using maximum electroshock-induced seizure tests and acute pentylenetetrazol-induced seizure tests. Electrical kindling via corneal stimulation and pentylenetetrazol administration were used to establish animal kindling epilepsy models. Proconvulsive activity was examined using an electroconvulsive shock test with low-stimulus currents. RESULTS: Acetaminophen showed slight, but not statistically significant, anticonvulsant activity in both the maximum electroshock-induced seizure test (300-600mg/kg i.p.) and acute pentylenetetrazol induced seizure test (100-600mg/kg i.p.). In contrast, acetaminophen exhibited significant anticonvulsant effects in corneal electroshock-kindled and pentylenetetrazol-kindled mice (ED50 values: 251 and 310mg/kg i.p., respectively). When the proconvulsive effects of NSAIDs were examined in the low current electroconvulsive shock-induced seizure model, the nonselective cyclooxygenase (COX)-1 and COX-2 inhibitors indomethacin, diclofenac, and loxoprofen induced dose-dependent proconvulsant activity. Celecoxib, a COX-2 selective inhibitor, had no proconvulsant activity. CONCLUSION: These findings suggest that acetaminophen has a significant anticonvulsant effect and that its profile is completely different from that of NSAIDs. PMID- 29227798 TI - Histological and MRI markers of white matter damage in focal epilepsy. AB - Growing evidence highlights the importance of white matter in the pathogenesis of focal epilepsy. Ex vivo and post-mortem studies show pathological changes in epileptic patients in white matter myelination, axonal integrity, and cellular composition. Diffusion-weighted MRI and its analytical extensions, particularly diffusion tensor imaging (DTI), have been the most widely used technique to image the white matter in vivo for the last two decades, and have shown microstructural alterations in multiple tracts both in the vicinity and at distance from the epileptogenic focus. These techniques have also shown promising ability to predict cognitive status and response to pharmacological or surgical treatments. More recently, the hypothesis that focal epilepsy may be more adequately described as a system-level disorder has motivated a shift towards the study of macroscale brain connectivity. This review will cover emerging findings contributing to our understanding of white matter alterations in focal epilepsy, studied by means of histological and ultrastructural analyses, diffusion MRI, and large-scale network analysis. Focus is put on temporal lobe epilepsy and focal cortical dysplasia. This topic was addressed in a special interest group on neuroimaging at the 70th annual meeting of the American Epilepsy Society, held in Houston December 2-6, 2016. PMID- 29227799 TI - Cognitive function after status epilepticus versus after multiple generalized tonic-clonic seizures. AB - OBJECTIVES: Status epilepticus (SE) is considered a risk for cognitive impairment. Studies have indicated that SE cause more cognitive decline than multiple lifetime generalized tonic clonic (GTC) seizures. The aim of the study was to investigate whether patients suffering from SE or from multiple lifetime GTC seizures have cognitive dysfunction, and if the disabilities differ between these groups. MATERIALS AND METHODS: Patients suffering from SE were evaluated shortly after the clinical post-ictal phase and again after one year. Their follow-up results were compared to results from patients with >=10 GTC seizures and a group of control subjects. Tests from Cambridge Neuropsychological Test Automated Battery (CANTAB) were used. Motor Screening Test (MOT) assessed motor speed, Delayed Matching to Sample (DMS) and Paired Associates Learning (PAL) assessed memory, and Stockings of Cambridge (SOC) assessed executive function. Estimated premorbid IQ and radiologically visible brain lesions were controlled for in adjusted results. Outcome measures were z-scores, the number of standard deviations a score deviates from the mean of a norm population. Negative z-scores indicate poor performance. RESULTS: After the clinical post-ictal phase, performances of SE patients were poor on all domains (n = 46). Mean z-scores with 95% confidence intervals were below zero for tests of psychomotor speed, executive thinking times and memory. Both SE patients at follow-up (n = 39) and patients with multiple GTC seizures (n = 24) performed poorer than controls (n = 20) on tests of memory. These group differences remained significant after covariate adjustments. SE patients at follow-up scored below patients with multiple GTC seizures on tests of psychomotor speed (mean difference -0.59, P = 0.020), but after adjusting for covariates this difference was no longer significant. CONCLUSIONS: Our data do not allow a firm conclusion as to whether SE is a more pronounced risk factor for cognitive dysfunction than repeated generalized tonic clonic seizures. In both patient groups, memory and learning dysfunction remained significant after adjusting for estimated premorbid IQ and structural brain lesions. PMID- 29227800 TI - Assessment of the neuropsychiatric comorbidities in Chinese children with epilepsy using the MINI-KID tool. AB - This study aimed to assess neuropsychiatric comorbidities and analyze risk factors in Chinese children with epilepsy. Children with epilepsy aged between 6 and 16 years from the Children's Hospital of Fudan University were included. Children with asthma and typically developing children were matched for age and gender, and served as control groups. Neuropsychiatric disorders were assessed by interviewing the parents or guardians using the Mini International Neuropsychiatric Interview for children (MINI-KID) (parent version). Basic information and clinical data were also collected using an author designed questionnaire. Multiple logistic regression analysis was done to identify the risk factors associated with neuropsychiatric comorbidities. In this study, 140 children with epilepsy, 70 children with asthma and 70 typically developing children were recruited. Neuropsychiatric disorders were significantly more common in children with epilepsy (41.4%) as compared with the asthma group (15.7%) and the control group (10.0%). Of the 58 children with epilepsy who had neuropsychiatric comorbidities, only 29.3% had been diagnosed before our study. Multivariate analysis revealed that a younger age at seizure onset (OR=0.877, 95%CI: 0.773~0.996), seizures occurring more than once monthly during the past year (OR=3.526, 95%CI: 1.177~10.562), polytherapy (OR=2.632, 95%Cl: 1.066~6.501) were all significantly associated with neuropsychiatric comorbidities in children with epilepsy. In conclusion, children with epilepsy are more likely to have neuropsychiatric comorbidities, and up to 70% of them were undiagnosed. Early screening, diagnosis and treatment of neuropsychiatric comorbidities in children with epilepsy may improve the long-term prognosis. PMID- 29227801 TI - An efficient and cost-effective tri-functional electrocatalyst based on cobalt ferrite embedded nitrogen doped carbon. AB - The development of efficient, cost-effective and long-lived electro-catalyst is necessary for the realization of practically viable water-splitting systems. A trifunctional electrocatalyst for water splitting (hydrogen evolution, oxygen reduction and oxygen evolution reaction, HER/ORR/OER) was designed via eco friendly and facial way. CoFe2O4 nanoparticles embedded in nitrogen doped mesoporous carbon were prepared using chicken egg white/albumin after pyrolysis at different temperatures, 700, 800, 900 and 1000 degrees C. The specific surface area, pore size and the interaction between CoFe2O4 nanoparticles and carbon matrix were tuned via pyrolysis temperature. The catalyst prepared at 900 degrees C, (N/CF-EC-900) exhibit superior catalytic activity as well as the superior stability than that other nanocomposites prepared and other commercial catalyst (Pt/C, RuO2) for water splitting. Our findings emphasize the importance of CoFe2O4 nanoparticles embedded in the carbon and suggest the catalytic activities with low onset potential, high current densities, small Tafel slope in basic medium. PMID- 29227802 TI - Prussian blue analogues derived magnetic FeCo alloy/carbon composites with tunable chemical composition and enhanced microwave absorption. AB - A series of magnetic FeCo alloy/carbon composites have been successfully prepared through in situ pyrolysis of Prussian blue analogues (PBAs) with different Fe/Co ratios. The Fe/Co ratio can affect the crystalline phase, particle size, and magnetic property of the FeCo alloy particles, as well as the relative graphitization degree of the carbon frameworks. As a result, the electromagnetic functions of these composites will be highly associated with the Fe/Co ratio, where high Co content is beneficial to the formation of strong dielectric loss and moderate Co content can facilitate the magnetic loss. When Fe/Co ratio reaches 1:1, the as-obtained composite (sample S4) displays excellent reflection loss characteristics with powerful absorption in a very broad frequency range (over -10 dB in 3.2-18.0 GHz), which is superior to those of single magnetic metal (Fe or Co)/carbon composite derived from PBAs, as well as many previously reported FeCo alloy/carbon composites. Electromagnetic analysis reveals that the excellent microwave absorption of sample S4 benefits from its preferable matching of characteristic impedance and good attenuation ability toward incident electromagnetic waves. These results provide new insight into the fabrication of carbon-based magnetic composites with enhanced microwave absorption by rationally manipulating the chemical composition of magnetic components. PMID- 29227803 TI - Editorial Comment. PMID- 29227807 TI - Reply by Authors. PMID- 29227805 TI - Erratum. PMID- 29227808 TI - Editorial Comment. PMID- 29227809 TI - Reply by Authors. PMID- 29227810 TI - Editorial Comment. PMID- 29227811 TI - Editorial Comment. PMID- 29227812 TI - Overexpression of Arginase 1 is linked to DNMT3A and TET2 mutations in lower grade myelodysplastic syndromes and chronic myelomonocytic leukemia. AB - Immune dysregulation is a common feature of myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), particularly in early stages. However, the genetic basis remains poorly understood. We recently reported that macrophages from mice deficient in tet methylcytosine dioxygenase 2 (Tet2), a model of MDS/CMML, are hyperinflammatory and have increased expression of arginase 1 (Arg1). In macrophages and myeloid derived suppressor cells (MDSCs) expression of Arg1 contributes to T-cell suppression and immune evasion by L arginine depletion, in the setting of chronic inflammation and cancer. Since human MDS and CMML are driven by TET2 mutations and associated with chronic inflammation, we hypothesized that arginase enzymatic activity and ARG1 expression would be increased in human MDS/CMML bone marrow. Elevated arginase activity was observed in bone marrow mononuclear cells of MDS and CMML patients with lower-grade features. Immunohistochemical studies confirmed that myelomonocytic cells overexpress ARG1. Additionally, mutations in the epigenetic regulators TET2 and DNMT3A corresponded to high ARG1 expression and activity. These findings suggest ARG1 is a biomarker of immune dysregulation in early MDS and CMML. Recent murine findings have implicated Tet2 and Dnmt3a in regulation of innate immunity. Our study suggests similar changes may be driven by human TET2 and DNMT3A mutations. PMID- 29227813 TI - Speed matters to raise molar radioactivity: Fast HPLC shortens the quality control of C-11 PET-tracers. AB - INTRODUCTION: The decision whether an in-house produced short-lived radiopharmaceutical can be applied in-vivo is based on (1) the fulfilment of all quality criteria; (2) the availability of enough radioactivity for subsequent imaging; and (3) a molar activity (MA) above the set limits to guarantee safe administration without competing occupancy of the non-radioactive compound; and (4) an activity concentration, which is high enough for the application in certain preclinical studies. Hence, time reduction can be of major importance to increase final product yields, MA and activity concentrations. Usually, optimization in this respect only focuses on the radiotracer preparation steps but especially quality control (QC) is rarely even mentioned. Therefore, aim of this work is the establishment of optimized conditions for chromatographic analysis using HPLC within the QC to enable a significant time reduction, which then directly leads to an increase in available amount of radioactive product as well as MA at the time of application. METHODS: An optimized set-up using ultra performance liquid chromatography ((U)HPLC) was established and tested on 7 carbon-11 labelled radiotracers used within patient routine or clinical trials. RESULTS: A drastic time reduction was achieved for all tracers. The optimized protocol lead to a gain of 5-7min (70-86% compared to the original set-up). CONCLUSIONS: An accelerated (U)HPLC method for radiotracers labelled with short lived radionuclides was successfully established and conditions were optimized for 7 clinically used radiotracers. The significant gain in QC time leads to a drastic increase in available radioactivity and specific activity at the time of tracer administration. PMID- 29227814 TI - Synthesis and evaluation of 99mTc/Re-tricarbonyl complexes of the triphenylphosphonium cation for mitochondrial targeting. AB - INTRODUCTION: Lipophilic delocalized cations accumulate in tumor cell mitochondria due to their higher transmembrane potential. In this work, this strategy was adopted for the development of 99mTc tumor-targeted imaging agents. METHODS: Two tridentate ligands containing the triphenylphosphonium cation, L1 (S cysteinyl) and L2 (N-iminodiacetate) as well as the respective 99mTc/ReL1 and 99mTc/ReL2 tricarbonyl complexes were synthesized. The effect of the ligands and the Re complexes on cell growth in U-87 MG glioblastoma cells was assessed. In vitro stability studies and measurement of logP of the 99mTc tracers was performed. The cellular and mitochondrial uptake of the 99mTc tracers in U-87 MG cells was evaluated. Biodistribution of 99mTcL1 and 99mTcL2 were performed on SCID mice bearing U-87 MG tumors. RESULTS: The ligands L1, L2 and the Re1 and ReL2 complexes were characterized spectroscopically. Single products 99mTcL1 and 99mTcL2, >90% stable in rat serum, were obtained. LogP was 0.40+/-0.14 for 99mTcL1 and -0.02+/-0.07 for 99mTcL2. L1, ReL1 and ReL2 caused no notable cytotoxicity and L2 was found to infer 40% inhibition of cellular growth at 10-5M as well as 80% cell death in culture at 10-4M. The cell uptake of 99mTcL1 and 99mTcL2 over 4h was 1.26+/-0.08% and 0.06+/-0.01% respectively, of which 13.41+/ 3.63% and 18.61+/-6.19% was distributed in the mitochondria respectively. The initial tumor uptake in mice was found to be >1% ID/g for both 99mTc tracers. CONCLUSIONS: In vitro mitochondrial and in vivo tumor targeting was observed, better in 99mTcL1, however these properties should be optimized in future studies. Advances in Knowledge and Implications for Patient Care: Continuous efforts in this direction may lead to a suitable mitochondrial-targeted 99mTc imaging agent for tumor detection. PMID- 29227815 TI - Meta-analysis of flap perfusion and donor site complications for breast reconstruction using pedicled versus free TRAM and DIEP flaps. AB - OBJECTIVES: The transverse rectus abdominis musculocutaneous (TRAM) flap is an important option for breast reconstruction. Several studies have recently evaluated whether a greater number of complications result from the use of pedicled TRAM (pTRAM) flaps versus either free TRAM (fTRAM) flaps or deep inferior epigastric artery perforator (DIEP) flaps. To clarify the evidence regarding this issue, we performed an objective meta-analysis of published studies. MATERIALS AND METHODS: A literature search of articles published between January 1, 1990, to January 1, 2017 was performed using the PubMed, EMBASE, Scopus, and Cochrane databases. Heterogeneity was statistically analyzed, and fixed effects and random effects models were used as appropriate. RESULTS: Eleven articles comparing pedicled TRAM (pTRAM) flaps with either free TRAM (fTRAM) or DIEP flaps were included. The articles evaluated a total of 3968 flaps, including 1891 pTRAM flaps, 866 fTRAM flaps, and 1211 DIEP flaps. Patients with fTRAM flaps had a significantly lower risk of fat necrosis and partial flap necrosis than those with pTRAM flaps. No difference was observed in total flap necrosis and hernia or bulge between fTRAM and pTRAM flaps. No difference was noted in flap complications between DIEP and pTRAM flaps except for hernia or bulge.. CONCLUSION: Although pTRAM flaps are being replaced by fTRAM and DIEP flaps, which exhibit fewer complications related to flap ischemia and donor site morbidity, it was unclear from the literature which flap type was most beneficial regarding flap vascularity and donor site morbidity. Hence, surgeons should choose the appropriate option based on their preferences and on patient factors.. PMID- 29227817 TI - Comparing granulocyte colony-stimulating factor filgrastim and pegfilgrastim to its biosimilars in terms of efficacy and safety: A meta-analysis of randomised clinical trials in breast cancer patients. AB - BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) are widely used to prevent neutropenia in cancer patients undergoing myelosuppressive chemotherapy. Several biosimilar medicines of G-CSF are now available, with their development involving a step-wise series of comparisons to demonstrate similarity to reference biologics. Randomised clinical trials (RCTs) are considered confirmatory, and for G-CSF biosimilars, patients with breast cancer (BC) undergoing myelosuppressive chemotherapy are the most sensitive population in which to confirm similarity. This meta-analysis aimed to compare the clinical efficacy and safety of approved or proposed G-CSF biosimilars (filgrastim or pegfilgrastim) with reference G-CSF in patients with BC. METHODS: A Medline literature search up to March 2017 identified RCTs comparing biosimilar G-CSF to reference in BC patients. The primary efficacy end-point was mean difference in duration of severe neutropenia (DSN). Secondary efficacy end-points were differences in depth of absolute neutrophil count (ANC) nadir, time to ANC recovery and incidence of febrile neutropenia. Safety analyses included calculation of risk ratios for bone pain events, myalgia events and serious adverse events. Random effect models were fitted to obtain the pooled estimates of the mean difference for continuous outcomes and the risk ratio for dichotomous outcomes and their corresponding 95% confidence intervals (CIs). FINDINGS: Eight eligible RCTs were included in this meta-analysis. Overall difference in DSN between reference and biosimilar medicines was not statistically significant (0.06 d [95% CI -0.05, 0.17]). The analysis of secondary efficacy end-points showed no significant differences between reference biologics and biosimilar medicines, as well as the analysis of bone pain events, myalgia events and serious adverse events. INTERPRETATION: This meta-analysis showed no significant differences in clinical efficacy and safety between biosimilar and reference G CSF in BC patients. PMID- 29227816 TI - The use of breast imaging for predicting response to neoadjuvant lapatinib, trastuzumab and their combination in HER2-positive breast cancer: Results from Neo-ALTTO. AB - AIM: To determine the value of mammography and breast ultrasound (US) in predicting outcomes in HER2 positive breast cancer patients (pts) within Neo ALTTO trial. PATIENTS AND METHODS: Mammography and US were required at baseline, week 6 and surgery. Two independent blinded investigators reviewed the measurements and assigned the corresponding response category. Pts showing complete or partial response according to RECIST (v1.1) were classified as responders. The association between imaging response at week 6 or prior to surgery was evaluated with respect to pathological complete response (pCR) and event-free Survival (EFS). RESULTS: Of the 455 pts enrolled in the trial, 267 (61%) and 340 (77%) had evaluable mammography and US at week 6; 248 (56%) and 309 (70%) pts had evaluable mammography and US prior to surgery. At week 6, 32% and 43% of pts were classified as responders by mammography and US, respectively. pCR rates were twice as high for responders than non-responders (week 6: 46% versus 23% by US, p < 0.0001; 41% versus 24% by mammography, p = 0.007). Positive and negative predictive values of mammography and US prior to surgery were 37% and 35%, and 82% and 70%, respectively. No significant correlation was found between response by mammography and/or US at week 6/surgery and EFS. CONCLUSIONS: Mammography and US were underused in Neo-ALTTO although US had the potential to assess early response whereas mammography to detect residual disease prior to surgery. Our data still emphasise the need for further imaging studies on pts treated with neoadjuvant HER2-targeted therapy. PMID- 29227818 TI - Neutrophil-lymphocyte ratio kinetics in patients with advanced solid tumours on phase I trials of PD-1/PD-L1 inhibitors. AB - BACKGROUND: Although the neutrophil-lymphocyte ratio (NLR) is prognostic in many oncological settings, its significance in the immunotherapy era is unknown. Mechanistically, PD-1/PD-L1 inhibitors may alter NLR. We sought to characterise NLR kinetics in patients with advanced solid tumours treated with PD-1/PD-L1 inhibitors. METHODS: Electronic records of patients treated with PD-1/PD-L1 inhibitors on phase I trials across three sites were reviewed. A high NLR (hNLR) was predefined as >5. Univariate logistic regression models were used for toxicity, response analyses and Cox models for overall survival (OS) and progression-free survival analyses. Landmark analyses were performed (cycle two, three). Longitudinal analysis of NLR was performed utilising a mixed effect regression model. RESULTS: The median OS for patients with hNLR was 8.5 months and 19.4 for patients with low NLR, (hazard ratio [HR] = 1.85, 95% confidence interval [CI] 1.15-2.96, p = 0.01). On landmark analysis, hNLR was significantly associated with inferior OS at all time points with a similar magnitude of effect over time (p < 0.05). On multivariate analysis, NLR was associated with OS (HR 1.06, 95% CI 1.01-1.11, p = 0.01). NLR did not correlate with increased immune toxicity. Longitudinally, NLR correlated with response: NLR decreased by 0.09 (95% CI: -0.15 to -0.02; p = 0.01) per month in responders compared with non responders. CONCLUSIONS: hNLR at baseline and during treatment is adversely prognostic in patients with advanced malignancies receiving PD-1/PD-L1 blockade. Importantly, NLR reduced over time in responders to immunotherapy. Taken together, these data suggest that baseline and longitudinal NLR may have utility as a unique biomarker to aid clinical decision-making in patients receiving immunotherapy. PMID- 29227819 TI - A questionnaire survey on road rage and anger-provoking situations in China. AB - This paper surveys the reactions of Chinese drivers when encountering anger provoking situations, including traffic congestion, pedestrians crossing the street illegally, being flashed by the high beams of cars traveling in the opposite direction, aberrant overtaking by other cars and when the car ahead drives slowly. A questionnaire survey found that 69.4% of participants wait when encountering traffic congestion and that 71% of drivers tolerate pedestrians crossing the street illegally; moreover, 61.3% of drivers are "angry but tolerant" when encountering aberrant overtaking. However, 51.3% of drivers become enraged when flashed by the high beams of cars traveling in the opposite direction, and 34.1% of participants turn on their own high beams to fight back. Moreover, 61.4% of participants are dissatisfied when the car ahead drives slowly or fails to move when a traffic light turns green, and 53% of participants honk or flash their lights to prompt the driver of the car ahead. The results show that males become irritated more easily than females in all situations, except those in which pedestrians cross the street illegally. Age is a factor only when drivers are flashed by high beams or overtaken by other cars illegally. Driving experience has an effect when drivers encounter traffic congestion, are flashed by high beams, or are overtaken by other cars illegally or when the car ahead drives slowly; novices with fewer than two years of driving experience display greater tolerance for these events. The occupation of a driver acts on his/her responses when he/she is overtaken by other cars illegally or flashed by high beams or when pedestrians cross the street illegally. For the most effective measures to prevent road rage, 53.64% of participants chose "plan the trip in advance", 57.14% chose "strengthen law enforcement", and 71.5% chose "improve public transportation". Females, young people, and novices pay more attention to these measures. PMID- 29227820 TI - The ultimate picture-the combination of live cell superresolution microscopy and single molecule tracking yields highest spatio-temporal resolution. AB - We are witnessing a breathtaking development in light (fluorescence) microscopy, where structures can be resolved down to the size of a ribosome within cells. This has already yielded surprising insight into the subcellular structure of cells, including the smallest cells, bacteria. Moreover, it has become possible to visualize and track single fluorescent protein fusions in real time, and quantify molecule numbers within individual cells. Combined, super resolution and single molecule tracking are pushing the limits of our understanding of the spatio-temporal organization even of the smallest cells to an unprecedented depth. PMID- 29227821 TI - Scan-rescan reproducibility of ventricular and atrial MRI feature tracking strain. AB - BACKGROUND: A feature tracking (FT) was designed to simultaneously extract myocardial strains in main cardiac chambers from cine MRI images. Its inter observer and scan-rescan reproducibility was assessed and sample sizes required to detect predefined longitudinal changes in strain values were provided. METHOD: FT was applied on left (LV) and right (RV) ventricles as well as left atrium (LA) of 21 individuals (66 +/- 10 years) who underwent 2 MRIs 2 weeks apart. Global peaks for radial, circumferential, longitudinal strains, radial motion fraction (Mr), fractional area change (FAC) and tricuspid annular plane excursion (TAPSE) were estimated. Inter-operator and inter-exam reproducibility were evaluated using coefficients of variations (CV) and intra-class correlation coefficients (ICC). RESULTS: Reproducibility of all measurements were good to excellent for inter-operator (LV:CV<6.5%, ICC>0.91; RV:CV<12%, ICC>0.86; LA:CV<14%, ICC>0.85) and inter-study (LV:CV<15%, ICC>0.65; RV:CV<20%, ICC>0.71; LA:CV<20.5%, ICC>0.83) evaluations. Reasonable sample sizes are required to detect a longitudinal difference of 10-15% in strain values (LV:5 to 33 individuals, RV:14 to 62 individuals, LA:4 to 65 individuals). CONCLUSIONS: FT-based functional evaluation of main heart chamber deformation from cine MRI is repeatable and thus suitable for follow-up. Strain measurements may help for the joint clinical evaluation of LV, RV or LA implication in various cardiomyopathies. PMID- 29227822 TI - Automated retinal health diagnosis using pyramid histogram of visual words and Fisher vector techniques. AB - Untreated age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma may lead to irreversible vision loss. Hence, it is essential to have regular eye screening to detect these eye diseases at an early stage and to offer treatment where appropriate. One of the simplest, non-invasive and cost-effective techniques to screen the eyes is by using fundus photo imaging. But, the manual evaluation of fundus images is tedious and challenging. Further, the diagnosis made by ophthalmologists may be subjective. Therefore, an objective and novel algorithm using the pyramid histogram of visual words (PHOW) and Fisher vectors is proposed for the classification of fundus images into their respective eye conditions (normal, AMD, DR, and glaucoma). The proposed algorithm extracts features which are represented as words. These features are built and encoded into a Fisher vector for classification using random forest classifier. This proposed algorithm is validated with both blindfold and ten-fold cross-validation techniques. An accuracy of 90.06% is achieved with the blindfold method, and highest accuracy of 96.79% is obtained with ten-fold cross-validation. The highest classification performance of our system shows the potential of deploying it in polyclinics to assist healthcare professionals in their initial diagnosis of the eye. Our developed system can reduce the workload of ophthalmologists significantly. PMID- 29227823 TI - LncRNA MALAT1 regulates sepsis-induced cardiac inflammation and dysfunction via interaction with miR-125b and p38 MAPK/NFkappaB. AB - This study aimed to explore the role of MALAT1 in sepsis-induced cardiac inflammation and dysfunction. We constructed the rat sepsis models through cecal ligation and puncture (CLP). The cardiac function, including left ventricular peak pressure (LVPP), left ventricular end diastolic pressure (LVEDP) and maximum rate of rise/fall of left ventricle pressure (+/-dp/dtmax) as well as the contents of serum cardiac troponin I (CTn-I), creatine kinase (CK), and creative kinase isoenzyme MB (CK-MB) were detected after modeling. Additionally, the blood cytokines levels including tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-1beta, IL-10, IL-17, and IFN-gamma and complement proteins of C5 and C5a after modeling were detected. Moreover, luciferase reporter assay was performed to investigate the regulatory miRNA of MALAT1. The protein expressions of p38 MAPK, NFkappaB, JAK2 and STAT3 were detected using western blot. MALAT1 expression was significantly upregulated in CLP-induced sepsis model. MALAT1 knockdown significantly increased LVSP and +dp/dsmax, decreased LVEDP and dp/dsmax of sepsis as well as levels of cTn-I, CK, CK-MB, TNF-alpha, IL-1beta, IL 6, IL-10, IL-17, IFN-gamma, C5 and C5a. MALAT1 was regulated by miR-125b, and miR 125b overexpression and MALAT1 knockdown had similar effects on sepsis rat models. Furthermore, MALAT1 induced cardiac dysfunction and inflammation in CLP models via activating p38 MAPK/NFkappaB. Our results suggest that MALAT1 aggravates cardiac inflammation and dysfunction in sepsis, which is achieved via interaction with miR-125b and p38 MAPK/NFkappaB. MALAT1 may serve as a diagnostic marker and therapeutic target in sepsis. PMID- 29227824 TI - Reduced inflammatory factor expression facilitates recovery after sciatic nerve injury in TLR4 mutant mice. AB - Toll-like receptors (TLRs) are extremely significant pattern recognition receptors. When nerve injury occurs, a variety of inflammatory factors are generated, leading to an exceedingly complex micro-environment. TLRs recognize damage-associated molecular patterns. To investigate the correlation between TLR4 and recovery after sciatic nerve injury, the model of sciatic nerve injury was conducted using TLR4-mutated mice (C3H/HeJ) and wild mice (C3H/HeN). Our goal was to identify short-stage and long-stage changes after sciatic nerve injury, mainly by checking the expression changes of inflammation factors in the short-stage and the differences in the recovery of the injured sciatic nerve in the long-stage. The results show that the increase of changes in the HeN group of IL-1beta, IL-6, TNF-alpha and MCP-1 are more obvious than in the HeJ group, with caspase1 expression higher and Nlrp3 expression lower in the former group. Further results reveal intense inflammation occurred in the HeN group showing more neutrophils and macrophages. Nlrp3 and caspase1 showed little difference by Immunohistochemistry, with Nlrp6 expression differing between the HeJ group and the HeN group. The results led us to conclude that better recovery of the injured sciatic nerve occurred in the HeJ group because the expression of GAP-43 and p75NTR was higher and had a better SFI figure. TLR4 mutation can decrease the expression of inflammatory factors and enhance the speed of recovery after sciatic nerve injury. The changes in the expression of Nlrp6, which are related to the TLR4 mutation, may influence recovery of the injured sciatic nerve. Further studies will be conducted to confirm these results. PMID- 29227825 TI - Engineering of single chain antibodies for solubility. AB - In the current study, we introduce a method to design intrinsically soluble single chain antibodies (scFvs) that can be easily produced in bacterial expression systems in a soluble form. Summarily, CDR loops are grafted on framework regions derived from intrinsically soluble subclass 3 (VH3 and VL3) human germline sequences. Framework-donor sequences should carry CDR loops of interest (in terms of canonical classes) and contain special residues in their hydrophobic cores. Recombinant variable fragments resultant from CDR grafting are subjected to 3D modeling, mutated (if necessary), and superposed to parental variable domains. Recombinant type 3 variable domains with the least RMSD (Root Mean-Square Deviation) values are chosen to constitute scFv moieties. The scFv designed using this method was shown to be soluble when expressed in bacterial cells. PMID- 29227826 TI - Enhancement of the lipid productivity and fatty acid methyl ester profile of Chlorella vulgaris by two rounds of mutagenesis. AB - In this study, we applied a second round of random mutagenesis using ethyl methanesulfonate to further increase the lipid productivity of a Chlorella vulgaris mutant strain. We generated a mutant (UV715-EMS25) with a lipid content and biomass that were respectively 67% and 35% higher than those of the wild type (WT). The highest achieved lipid productivity in UV715-EMS25 was 91 mg L-1 day-1. Gas chromatography-mass spectrophotometric analysis revealed that the fatty acid methyl ester content of the mutant was 3.9-fold higher compared with that of WT cells. Amounts of saturated and monounsaturated fatty acids were also higher in the mutant, while the total amounts of polyunsaturated fatty acids were lower. Finally, the mutant displayed superior lipid productivity compared with the WT during pilot-scale cultivation in a flat panel photobioreactor. All these results demonstrate that UV715-EMS25 is highly suitable for biodiesel production. PMID- 29227827 TI - Determining when a fracture occurred: Does the method matter? Analysis of the similarity of three different methods for estimating time since fracture of juvenile long bones. AB - Radiographic fracture date estimation is a critical component of skeletal trauma analysis in the living. Several timetables have been proposed for how the appearance of radiographic features can be interpreted to provide a likely time frame for fracture occurrence. This study compares three such timetables for pediatric fractures, by Islam et al. (2000), Malone et al. (2011), and Prosser et al. (2012), in order to determine whether the fracture date ranges produced by using these methods are in agreement with one another. Fracture date ranges were estimated for 112 long bone fractures in 96 children aged 1-17 years, using the three different timetables. The extent of similarity of the intervals was tested by statistically comparing the overlap between the ranges. Results showed that none of the methods were in perfect agreement with one another. Differences seen included the size of the estimated date range for when a fracture occurred, and the specific dates given for both the upper and lower ends of the fracture date range. There was greater similarity between the ranges produced by Malone et al. (2011) and both the other two studies than there was between Islam et al. (2000) and Prosser et al. (2012). The greatest similarity existed between Malone et al. (2011) and Islam et al. (2000). The extent of differences between methods can vary widely, depending on the fracture analysed. Using one timetable gives an average earliest possible fracture date of less than 2 days before another, but the range was extreme, with one method estimating minimum time since fracture as 25 days before another method for a given fracture. In most cases, one method gave maximum time since fracture as a week less than the other two methods, but range was extreme and some estimates were nearly two months different. The variability in fracture date estimates given by these timetables indicates that caution should be exercised when estimating the timing of a juvenile fracture if relying solely on one of the published guides. Future research should be undertaken to compare these methods on a population of known fracture timing, and to better understand the relationship between age of the individual, skeletal health, fracture healing rates, and radiographic characteristics of fracture healing. PMID- 29227828 TI - Examining the relationship between medical cannabis laws and cardiovascular deaths in the US. AB - BACKGROUND: Several countries and many U.S. states have allowed, for cannabis to be used as therapy to treat chronic conditions or pain., This has increased the use of cannabis, particularly among older people.Because cannabis has been linked to adverse cardiac events in the medical literature, there may be unintended consequences on increased use among older people. METHODS: We analyze cardiac related mortality data from the U.S. National Vital Statistics System for 1990 2014. We use difference-in-difference fixed-effects models to assess whether there are increased rates of cardiac-related mortality following passage of medical cannabis programs. We also analyze whether states with more liberal rules on dispensing cannabis show higher mortality rates. RESULTS: For men, there is a statistically significant 2.3% increase in the rate of cardiac death following passage. For women, there is a 1.3% increase that is also statistically significant. he effects increase or both men and women with age. The effects are also stronger in states with more a lax approach to cannabis dispensing. CONCLUSION: Policymakers should be aware of a potential unintended consequence of allowing broader use of cannabis, specifically for those more at risk of cardiovascular events. PMID- 29227830 TI - Cell surface markers for the identification and study of human naive pluripotent stem cells. AB - Characterisation of mouse pluripotent stem cells has revealed two distinct pluripotent states, naive and primed, that maintain characteristics of the pre and post implanted epiblast respectively. Recent studies have developed several culture systems that seek to recapitulate the naive phenomenon in human pluripotent stem cells. Therefore, robust methods to isolate these cells will be fundamental to assess their potential in modelling human development and disease. Here we review current methods for human naive pluripotent culture and collate a list of cell surface antigens that have been identified as markers to differentiate naive from primed human pluripotent stem cells. While these culture systems do display marker variability, and not all antigens mentioned were assessed in all methods, this review provides a resource for researchers of the human naive pluripotent stem cell state. SSEA-4, SSEA-3, CD24, CD75, CD7, CD77, CD130/GP130, CD57, CD90 and NLGN4X were all found to have a +/- expression profile in at least 2 methods, while +/- expression of Tra-1-81, CDH3, CD172a, CD107b, CD229 was reported in one method. Often it was reported that naive and primed cells could be defined using a low/medium/high expression of the following antigens TRA-1-60, PCDH1, GPR64, MHC Class I, however these markers were more likely to display expression pattern differences between methods. Studies using mouse naive cells indicate that they may have benefits over primed cells in modelling development and disease, and while it is yet to be determined if the same can be said about a human naive state, tools to identify this population should greatly further the field. PMID- 29227829 TI - A long noncoding RNA from the HBS1L-MYB intergenic region on chr6q23 regulates human fetal hemoglobin expression. AB - The HBS1L-MYB intergenic region (chr6q23) regulates erythroid cell proliferation, maturation, and fetal hemoglobin (HbF) expression. An enhancer element within this locus, highlighted by a 3-bp deletion polymorphism (rs66650371), is known to interact with the promoter of the neighboring gene, MYB, to increase its expression, thereby regulating HbF production. RNA polymerase II binding and a 50 bp transcript from this enhancer region reported in ENCODE datasets suggested the presence of a long noncoding RNA (lncRNA). We characterized a novel 1283bp transcript (HMI-LNCRNA; chr6:135,096,362-135,097,644; hg38) that was transcribed from the enhancer region of MYB. Within erythroid cells, HMI-LNCRNA was almost exclusively present in nucleus, and was much less abundant than the mRNA for MYB. HMI-LNCRNA expression was significantly higher in erythroblasts derived from cultured adult peripheral blood CD34+ cells which expressed more HBB, compared to erythroblasts from cultured cord blood CD34+ cells which expressed much more HBG. Down-regulation of HMI-LNCRNA in HUDEP-2 cells, which expressed mostly HBB, significantly upregulated HBG expression both at the mRNA (200-fold) and protein levels, and promoted erythroid maturation. No change was found in the expression of BCL11A and other key transcription factors known to modulate HBG expression. HMI-LNCRNA plays an important role in regulating HBG expression, and its downregulation can result in a significant increase in HbF. HMI-LNCRNA might be a potential therapeutic target for HbF induction treatment in sickle cell disease and beta-thalassemia. PMID- 29227831 TI - Generation of hiPSTZ16 (ISMMSi003-A) cell line from normal human foreskin fibroblasts. AB - Human foreskin fibroblasts from a commercial source were reprogrammed into induced pluripotent stem cells to establish a clonal stem cell line, hiPSTZ16 (ISMMSi003-A). These cells show a normal karyotype and full differentiation potential in teratoma assays. The described cells provide a useful resource in combination with other iPS cell lines generated from normal human foreskin fibroblasts to study source- and reprogramming method-independent effects in downstream applications. PMID- 29227832 TI - Functional characterization and phenotypic monitoring of human hematopoietic stem cell expansion and differentiation of monocytes and macrophages by whole-cell mass spectrometry. AB - The different facets of macrophages allow them to play distinct roles in tissue homeostasis, tissue repair and in response to infections. Individuals displaying dysregulated macrophage functions are proposed to be prone to inflammatory disorders or infections. However, this being a cause or a consequence of the pathology remains often unclear. In this context, we isolated and expanded CD34+ HSCs from healthy blood donors and derived them into CD14+ myeloid progenitors which were further enriched and differentiated into macrophages. Aiming for a comprehensive phenotypic profiling, we generated whole-cell mass spectrometry (WCMS) fingerprints of cell samples collected along the different stages of the differentiation process to build a predictive model using a linear discriminant analysis based on principal components. Through the capacity of the model to accurately predict sample's identity of a validation set, we demonstrate that WCMS profiles obtained from bona fide blood monocytes and respectively derived macrophages mirror profiles obtained from equivalent HSC derivatives. Finally, HSC-derived macrophage functionalities were assessed by quantifying cytokine and chemokine responses to a TLR agonist in a 34-plex luminex assay and by measuring their capacity to phagocytise mycobacteria. These functional read-outs could not discriminate blood monocytes-derived from HSC-derived macrophages. To conclude, we propose that this method opens new avenues to distinguish the impact of human genetics on the dysregulated biological properties of macrophages in pathological conditions. PMID- 29227834 TI - Personality pathology grows up: adolescence as a sensitive period. AB - There is mounting evidence that personality pathology, in particular, borderline pathology is a valid and reliable construct in adolescence, with prevalence, phenomenology, stability and risk factors similar to that of adult borderline personality disorder. Scientific evidence also delineates a marked separation of course and outcome of adolescent borderline personality disorder from other disorders and supports the efficacy of disorder-specific treatment. The current article addresses recent findings in these areas which point to adolescence as a sensitive period for the development for personality pathology. A conceptual model of psychopathology is presented wherein personality pathology is described as a qualitatively different level of psychopathology in the form of maladaptive self-other relatedness that is developmentally tied to identity formation in adolescence. PMID- 29227833 TI - Vitamin A deficiency in mice alters host and gut microbial metabolism leading to altered energy homeostasis. AB - Vitamin A deficiency (A-) is a worldwide public health problem. To better understand how vitamin A status influences gut microbiota and host metabolism, we systematically analyzed urine, cecum, serum and liver samples from vitamin A sufficient (A+) and deficient (A-) mice using 1H NMR-based metabolomics, quantitative (q)PCR and 16S rRNA gene sequencing coupled with multivariate data analysis. The microbiota in the cecum of A- mice showed compositional as well as functional shifts compared to the microbiota from A+ mice. Targeted 1H NMR analyses revealed significant changes in microbial metabolite concentrations including higher butyrate and hippurate and decreased acetate and 4 hydroxyphenylacetate in A+ relative to A- mice. Bacterial butyrate-producing genes including butyryl-CoA:acetate CoA-transferase and butyrate kinase were significantly higher in bacteria from A+ versus bacteria from A- mice. A- mice had disturbances in multiple metabolic pathways including alterations in energy (hyperglycemia, glycogenesis, TCA cycle and lipoprotein biosynthesis), amino acid and nucleic acid metabolism. A- mice had hyperglycemia, liver dysfunction, changes in bacterial metabolism and altered gut microbial communities. Moreover, integrative analyses indicated a strong correlation between gut microbiota and host energy metabolism pathways in the liver. Vitamin A regulates host and bacterial metabolism, and the result includes alterations in energy homeostasis. PMID- 29227835 TI - Rapid radiosynthesis of two [18F]-labeled nicotinamide derivatives for malignant melanoma imaging. AB - The rapid synthesis of two radiofluoronicotinamide derivatives, namely, [18F]MEL050 and [18F]MEL-2F has been simply performed starting from commercial materials. [18F]MEL-2F is a new, potential analogue PET-probe for melanoma imaging. [18F]MEL050 is already an excellent PET imaging probe for early specific diagnosis. The synthesis involves coupling step to obtain the precursor followed by radiofluorination. During the synthesis of the precursors different coupling reagents, such as HBTU, TFFH, HOBT, COMU and PyCIU have been applied. PyClU was found the best to reduce the coupling period to < 1h. The labeled compounds were isolated and purified by HPLC. In the in-vitro study three kinds of cells, namely, Melur (melanin free), KB-3 carcinoma cell line (non-melanoma) and B16-F10 melanoma cell line were used to evaluate the uptake of the radiotracers. PMID- 29227836 TI - Homogeneity assessment for grass samples used for organically bound tritium proficiency test. AB - The paper presents homogeneity check for dried grass batch to be used in an inter comparison exercise. When carrying out an inter-comparison exercise, the organizer must guarantee that the unsatisfactory result will not be imputed to the sample and sample's changeability. Therefore, in an inter-comparison exercise must carry on the homogeneity testing. In our study, the homogeneity was checked for two parameters, the hydrogen percentage (%H) and the organically bound tritium (OBT) activity concentration. Ten subsamples of 50g from bulk material were chosen using a stratified random selection. Two replicates from each package were analyzed for hydrogen content and OBT analysis. The homogeneity parameters were evaluated according to ISO 13528:2015. The two checked properties confirm that the batch of dried grass is sufficiently homogenous. PMID- 29227837 TI - Even in early childhood offspring alcohol expectancies correspond to parental drinking. AB - BACKGROUND: Research has found that children as young as preschoolers have an idea about the valence (positive vs. negative) and activation (arousal vs. sedation) of emotional change when adults drink alcohol. The development of alcohol expectancies at such a young age may be due to observed parental alcohol use. METHODS: Three measures of alcohol use (frequency, quantity and binge drinking) assessed among 115 fathers and 149 mothers were correlated with four alcohol expectancy factors (crossing valence and activation) of their offspring, aged three to six (70 boys and 82 girls). RESULTS: For both arousal and sedation expectancies and across alcohol use measures of both fathers and mothers, the greater parental alcohol use was, the higher their sons' negative and the lower positive alcohol expectancies were. For negative expectancies (particularly sedation, i.e., drinking when feeling sad or depressed), there was a stronger and more consistent association with paternal than with maternal drinking. For daughters, there was no consistent association between any expectancy factor and any parental drinking behavior. CONCLUSIONS: Already among preschoolers, parental drinking was found to be correlated with their sons' alcohol expectancies in the sense that they may observe and associate positive emotional consequences (feeling joyful, happy, calm, relaxed etc.) with moderate parental drinking and negative emotional consequences (feeling angry, nervous, sad, depressed etc.) with excessive drinking. This may be important for prevention, as expectancies have been found to be predominant predictors of early alcohol initiation and development of risky drinking in adolescence and beyond. PMID- 29227838 TI - Financial strain indirectly influences smoking cessation through withdrawal symptom severity. AB - BACKGROUND: Financial strain has an adverse impact on smoking cessation. However, the mechanisms through which financial strain influences cessation remain unclear. The purpose of the current study was to determine whether financial strain indirectly influenced smoking cessation through withdrawal symptom severity. METHODS: Participants (N=139) were primarily Black (63.3%) and female (57.6%) adults enrolled in a smoking cessation program at a safety-net hospital. A self-report financial strain questionnaire was completed one week prior to the scheduled quit date, and the Wisconsin Smoking Withdrawal Scale (WSWS) was completed on the day after the scheduled quit date. Biochemically-verified 7-day point prevalence abstinence was assessed four weeks after the scheduled quit date. Adjusted mediation analyses were conducted using the PROCESS macro for SPSS to evaluate the indirect effects of financial strain on smoking cessation via post-quit withdrawal symptom severity. RESULTS: Analyses indicated a significant indirect effect of financial strain on smoking cessation through total withdrawal symptom severity, B=0.027; 95% CI (0.003, 0.066); and specifically anger, B=0.035; 95% CI (0.008, 0.074), anxiety, B=0.021; 95% CI (0.001, 0.051), and sleep symptoms, B=0.015; 95% CI (0.005, 0.043). Greater pre-quit financial strain was associated with greater post-quit withdrawal symptom severity, which increased the likelihood of non-abstinence 4 weeks after the scheduled quit attempt. The direct effect of financial strain on smoking cessation was not significant in any of the mediation models. CONCLUSIONS: Findings: suggest that withdrawal severity is an underlying mechanism through which financial strain influences smoking cessation. PMID- 29227840 TI - The new drugs and the sea: The phenomenon of narco-terrorism. AB - Use of psychoactive substances and drug trafficking for funding purposes is a well-known practice acted by terrorist groups. Europe appears to be more and more involved in this mechanism, as both an active and passive element, and increased attention should be payed to this phenomenon by potentially interested actors. PMID- 29227839 TI - Medical marijuana laws and adolescent use of marijuana and other substances: Alcohol, cigarettes, prescription drugs, and other illicit drugs. AB - BACKGROUND: Historical shifts have taken place in the last twenty years in marijuana policy. The impact of medical marijuana laws (MML) on use of substances other than marijuana is not well understood. We examined the relationship between state MML and use of marijuana, cigarettes, illicit drugs, nonmedical use of prescription opioids, amphetamines, and tranquilizers, as well as binge drinking. METHODS: Pre-post MML difference-in-difference analyses were performed on a nationally representative sample of adolescents in 48 contiguous U.S. states. Participants were 1,179,372U.S. 8th, 10th, and 12th graders in the national Monitoring the Future annual surveys conducted in 1991-2015. Measurements were any self-reported past-30-day use of marijuana, cigarettes, non-medical use of opioids, amphetamines and tranquilizers, other illicit substances, and any past two-week binge drinking (5+ drinks per occasion). RESULTS: Among 8th graders, the prevalence of marijuana, binge drinking, cigarette use, non-medical use of opioids, amphetamines and tranquilizers, and any non-marijuana illicit drug use decreased after MML enactment (0.2-2.4% decrease; p-values:<0.0001-0.0293). Among 10th graders, the prevalence of substance use did not change after MML enactment (p-values: 0.177-0.938). Among 12th graders, non-medical prescription opioid and cigarette use increased after MML enactment (0.9-2.7% increase; p-values: <0.0001 0.0026). CONCLUSIONS: MML enactment is associated with decreases in marijuana and other drugs in early adolescence in those states. Mechanisms that explain the increase in non-medical prescription opioid and cigarette use among 12th graders following MML enactment deserve further study. PMID- 29227841 TI - Becoming enwinded: A new materialist take on smoking pleasure. AB - What might new materialist perspectives bring to our understanding of smoking pleasure? In this paper, I draw on this thinking to sketch out an alternative, non-unitary smoker who is at the mercy of the whims of the breeze - a yielding I will argue is key to smoking pleasure. With these intentions in mind, rather than thinking of what the biotechnology of cigarettes accomplishes in terms of the chemical delivery of pleasure, or adding to the multiply of social and cultural reasons anthropologists have tendered to account for it, I approach smoking pleasure in and through the medium of the smoky air. This approach permits examination of how nonhuman and human agents, like cigarettes, lungs, hands and other things form momentary and contingent relation in the air, as well as the role of the air itself in 'enwinding' the smoker. When smoking pleasure is explored from such a perspective, the smoker can be recast as part of a complex of relations that she does not fully control, rather than the agentic centre or principal arrayer of the nonhuman world. The pleasures of smoking, and the smoker herself, I argue, are emergent and come into being precisely in these relations: 'the smoker' originates, terminates, and is defined in and with elements, rather than being surely and certainly attached to a particular smoker subjectivity. Chief among the complex of things and elements that make the smoker and her pleasure is the air itself - and it is the air itself that is my primary informant in this paper. PMID- 29227842 TI - Ideation, social construction and drug policy: A scoping review. AB - Within drug policy scholarship there is a growing body of literature applying ideational and social constructionist approaches to address the complexity of drug policy making and the apparent failure of the evidence-based policy paradigm to free the process from controversy and contestation. Ideational approaches are concerned with the roles played by ideas and beliefs in policy making, while social construction explores the way policy problems are constructed, and agendas are set and delineated by dominant frames and narratives. Interest in these approaches has developed over the last two decades, but has rapidly gained momentum over the last five years. There has been limited reflection on the state of the field, therefore it is timely to conduct a review of the literature to assess the value of these approaches, capture emerging themes and issues, and identify gaps in the literature to support future research directions. Using the Arksey and O'Malley framework, a scoping review was conducted to survey the breadth of the field. Following database and hand searching, 48 studies from 1996 to 2016 were selected for inclusion in the review. A narrative synthesis was undertaken and the literature was grouped into five broad theoretical approaches: ideational policy theory, problem construction, narratives and frames (including media analysis), construction of target populations, and policy transfer and mobilities. The majority of the studies are focused on single countries and drug policy issues, with few studies undertaking comparative work or reflecting on general theoretical developments in the literature. This study found that the Arksey and O'Malley framework was effective in capturing a potentially diverse field of literature and demonstrates the importance of ideational and social constructionist approaches to drug policy scholarship. Further research is required to achieve expanded geographic coverage, test policy making models and undertake comparative work. PMID- 29227843 TI - Symbolic perceptions of methamphetamine: Differentiating between ice and shake. AB - BACKGROUND: Although public perceptions of methamphetamine (meth) consider all forms of the drug as the same, this is not true among those who use it. Our aim is to examine how those who use meth perceive two forms of meth (ice and shake) using the theoretical framework of symbolic boundaries. METHODS: We rely on data collected from a photo-ethnography with people who use methamphetamine in rural Alabama. The ethnography consisted of formal interviews (with 52 participants), informal observations, and photography. RESULTS: Participants had a strong preference for ice (49 of 52 preferred ice over shake). In discussing why they prefer ice they point to the various short- and long-term health problems associated with shake. This distinction allowed them to create symbolic definitions of shake as being dirty due to impure chemicals and its users as desperate. CONCLUSION: We argue that this symbolic differentiation of the two forms allows users to frame themselves as rational users (i.e., they avoid the unsafe form of meth) and shape use patterns and prevalence, with shake being used infrequently and often intravenously. PMID- 29227844 TI - Back to the core: A network approach to bolster harm reduction among persons who inject drugs. AB - BACKGROUND: Injecting drugs safely almost always includes the presence of one's social network, especially for the prevention of overdose. Yet, the systematic analysis of users' social networks has yet to be established as a focal method in harm reduction research, and interventions. METHODS: This study draws from 200 interviews with persons who inject drugs recruited from North America's first sanctioned supervised injection facility and a drug user's advocacy group. Respondents were asked about the individuals they personally considered as facilitators of harm reduction, and the relations between them. Collectively, these 200 respondents provided over 900 individuals whom they considered as members of their harm reduction network. The aim was to locate individuals that would potentially make the network denser (harm reduction champions) and users that were situated in the "periphery" of the network, and in practice, further away from the harm reduction core. RESULTS: Of the 1135 network members, 63 individuals formed the "core" of the harm reduction network, collectively reaching approximately 70% of individuals in the network. We also uncovered 31 individuals that acted as "articulation points"- these individuals were not as connected, but were more effective at reaching peripheral individuals. CONCLUSION: Former or current injecting drug users that were sampled were surrounded by a relatively rich harm reduction network, but the network approach showed that only a minority of individuals were true harm reduction "champions". Recruitment of a combination of well-connected harm reduction champions, and strategically connected articulation points, would be most effective in planning network interventions that encourage harm reduction behaviors among this population. PMID- 29227845 TI - Does d-cycloserine facilitate the effects of homework compliance on social anxiety symptom reduction? AB - BACKGROUND: Prior studies examining the effect of d-cycloserine (DCS) on homework compliance and outcome in cognitive-behavior therapy (CBT) have yielded mixed results. The aim of this study was to investigate whether DCS facilitates the effects of homework compliance on symptom reduction in a large-scale study for social anxiety disorder (SAD). METHODS: 169 participants with generalized SAD received DCS or pill placebo during 12-session exposure-based group CBT. Improvements in social anxiety were assessed by independent raters at each session using the Liebowitz social anxiety scale (LSAS). RESULTS: Controlling for LSAS at the previous session, and irrespective of treatment condition, greater homework compliance in the week prior related to lower LSAS at the next session. However, DCS did not moderate the effect of homework compliance and LSAS, LSAS on homework compliance, or the overall augmenting effect of DCS on homework compliance. Furthermore, LSAS levels were not predictive of homework compliance in the following week. CONCLUSION: The findings support the general benefits of homework compliance on outcome, but not a DCS-augmenting effect. The comparably small number of DCS-enhanced sessions in this study could be one reason for the failure to find a facilitating effect of DCS. PMID- 29227846 TI - Maternal human chorionic gonadotrophin concentrations in very early pregnancy and risk of hyperemesis gravidarum: A retrospective cohort study of 4372 pregnancies after in vitro fertilization. AB - OBJECTIVE: We investigated the association of human chorionic gonadotrophin (hCG) concentrations on a fixed day in very early pregnancy with development of hyperemesis gravidarum. STUDY DESIGN: This retrospective cohort study included 3107 singleton and 1265 twin pregnancies after in vitro fertilization treated at Department of Reproductive Medicine, Rikshospitalet, Oslo University Hospital, Norway in the period 1996-2013. Maternal serum hCG concentrations was measured on day 12 after embryo transfer. Information about development of hyperemesis gravidarum was obtained by individual linkage to the Medical Birth Registry of Norway. We studied hCG concentrations in very early pregnancy according to development of hyperemesis gravidarum, in singleton and twin pregnancies separately. We estimated the odds ratios for hyperemesis gravidarum with 95% confidence intervals according to quartiles of hCG concentrations. RESULTS: In twin pregnancies as compared to singleton pregnancies, we found higher mean maternal hCG concentrations (219 IU/L versus 130 IU/L, p<0.001 Student's t-test) and higher prevalence of hyperemesis gravidarum (2.7% versus 1.4%, p=0.002 chi squared test). However, both in singleton and in twin pregnancies, we found no significant difference in mean hCG concentrations between women who developed hyperemesis gravidarum and women who did not (Singletons: 122 IU/L versus 130 IU/L, p=0.504. Twins: 234 IU/L versus 219 IU/L, p=0.417 Student's t-test). We found no significant differences in odds ratios for developing hyperemesis gravidarum according to quartiles of hCG concentrations. CONCLUSIONS: We found no association of maternal hCG concentrations on a fixed day in early pregnancy with development of hyperemesis gravidarum. PMID- 29227847 TI - The impact of histological subtype in developing both ovarian and endometrial cancer: A longstanding nationwide incidence study. AB - OBJECTIVES: To estimate the incidence of ovarian cancer (OC) and endometrial cancer (EC) separately, as well as double cancers diagnosed in the same calendar year, and to relate the occurrences to histological subtype. STUDY DESIGN: All cases of epithelial OC and EC diagnosed in the Netherlands in 1989-2009 were related to population data. Histologically specific associations were made using the ratio of observed and expected incidence numbers, calculated with age specific incidence rates. RESULTS: 25,489 OC and 32,729 EC were analyzed, and 649 OC/EC. Life-time risks for OC and EC were 1.8% and 2.4%. Among OC, adenocarcinoma (18%) and serous cancers (33%) were the most prevalent subtypes. In EC, adenocarcinoma (39%) and endometrioid cancer (37%) were highest, with hardly any serous cancers. The observed incidence of OC/EC was 50-fold higher than expected (95% CI, 46-54). For patients aged <55years, the O/E ratio was 274, for the elderly 32, both findings are significant. Of the 2345 OC endometrioid subtype, 294 had EC (12.5%), whereas 1.1 was expected. In EC patients, no particular histological subtype was distinguished with a highly elevated occurrence of OC. The 680 serous EC patients had 11 double cancers (1.6%), of which 8 with the ovarian serous subtype. CONCLUSION: Strong relationships exist between malignancies in the ovary and a second primary malignancy in the endometrium, especially for the endometrioid subtype of ovarian cancer. Viewed from the endometrial site, no special subtype was noted, and the influence of endometrial serous adenocarcinoma in developing serous OC is not plausible. PMID- 29227848 TI - Development and evaluation of an improved laparoscopic myomectomy adopting intracapsular rotary-cut procedures. AB - OBJECTIVES: To develop and evaluate the efficacy and feasibility of Intracapsular Rotary-cut Procedure (IRCP) in laparoscopic myomectomy (LM). STUDY DESIGN: It is a retrospective study conducted in Peking University Shenzhen Hospital (PUSH) in Shenzhen, China. A total of 96 patients who were treated with LM because of big and moderate size of myomas in PUSH from January 2013 and December 2015 were enrolled in this study. Among them 35 were managed with IRCP -integrated LM as the study group, while the other 61 were treated with normal LM as the control group. The core steps of IRCP include minimized uterine incision, rotary cuttings in the fibroid inside the pseudocapsule, and preserving the fibers and vessels of the fibroid pseudocapsule. The operation data and outcome variables of each patient in the two groups were collected and compared to evaluate the efficacy and feasibility of this new improved surgery procedure. RESULTS: The ages, body mass indexes, main indication for myomectomy, and the diameters, numbers and types of the fibroids of patients in the two groups were similar. There is no significant difference in enucleation time and days of postoperative in-hospital staying between the two groups. In comparison with normal LM, application of IRCP significantly reduced the length of uterine incisions (P=0.000), the overall time of operations (P=0.001), and the time for uterine cavity suturing (P=0.000), and application of IRCP was also associated with less operation bleeding (P=0.003) and postoperative hemoglobin dropping (P=0.001). Five cases (8.2%) in the control group were referred to laparotomy, while no case was done so in the study group. No patient in the study group needed blood transfusion but six patients (9.8%) in the control group did. Follow-up to all the patients showed no uterine malignant tumor. CONCLUSIONS: Our study provided strong supportive evidences showing that Intracapsular Rotary-cut Procedures is safe and practicable. The less uterine incision length, less surgery time, and less bleeding than the normal LM procedures all suggests that IRCP should be adopted in LM for facilitation to the operation procedures, minimization of operative invasiveness, and protection to patients' infertility. PMID- 29227849 TI - Associations between long-term PM2.5 and ozone exposure and mortality in the Canadian Census Health and Environment Cohort (CANCHEC), by spatial synoptic classification zone. AB - Studies suggest that long-term chronic exposure to fine particulate matter air pollution can increase lung cancer mortality. We analyzed the association between long term PM2.5 and ozone exposure and mortality due to lung cancer, ischemic heart disease, and chronic obstructive pulmonary disease, accounting for geographic location, socioeconomic status, and residential mobility. Subjects in the 1991 Canadian Census Health and Environment Cohort (CanCHEC) were followed for 20years, and assigned to regions across Canada based on spatial synoptic classification weather types. Hazard ratios (HR) for mortality, were related to PM2.5 and ozone using Cox proportional hazards survival models, adjusting for socioeconomic characteristics and individual confounders. An increase of 10MUg/m3 in long term PM2.5 exposure resulted in an HR for lung cancer mortality of 1.26 (95% CI 1.04, 1.53); the inclusion in the model of SSC zone as a stratum increased the risk estimate to HR 1.29 (95% CI 1.06, 1.57). After adjusting for ozone, HRs increased to 1.49 (95% CI 1.23, 1.88), and HR 1.54 (95% CI 1.27, 1.87), with and without zone as a model stratum. HRs for ischemic heart disease fell from 1.25 (95% CI 1.21, 1.29) for exposure to PM2.5, to 1.13 (95% CI 1.08, 1.19) when PM2.5 was adjusted for ozone. For COPD, the 95% confidence limits included 1.0 when climate zone was included in the model. HRs for all causes of death showed spatial differences when compared to zone 3, the most populated climate zone. Exposure to PM2.5 was related to an increased risk of mortality from lung cancer, and both ozone and PM2.5 exposure were related to risk of mortality from ischemic heart disease, and the risk varied spatially by climate zone. PMID- 29227850 TI - Overrated adults: 4-year-olds' false belief understanding is influenced by the believer's age. AB - Children perceive adults as more knowledgeable than peers. We tested whether this general preconception influences preschoolers' performance in a false-belief task. Children (4- and 5-year-olds; N = 146) watched videos showing a peer protagonist or an adult protagonist experiencing events that should lead the protagonist to hold a false belief. Then children were asked to infer the protagonist's perception of the situation. Age of the protagonist influenced 4 year-olds' judgments but not 5-year-olds' judgments. Specifically, 4-year-olds' performance was at chance when presented with a peer protagonist. Their performance dropped further when presented with an adult protagonist and was significantly below chance. Children aged around 5 years performed above chance level regardless of whether they were presented with an adult or peer protagonist. This suggests that in the younger age group, children's tendency to regard adults as experts in general knowledge undermined their ability to accurately judge the possibility that an adult could hold a false belief. PMID- 29227851 TI - The specificity of reciprocity: Young children reciprocate more generously to those who intentionally benefit them. AB - Young children engage in direct reciprocity, but the mechanisms underlying such reciprocity remain unclear. In particular, prior work leaves unclear whether children's reciprocity is simply a response to receiving benefits (regardless of whether the benefits were intended) or driven by a mechanism of rewarding or preferring all benefactors (regardless of whom they benefited). Alternatively, perhaps children engage in genuine reciprocity such that they are particularly prosocial toward benefactors who intentionally provided them with benefits. Our findings support this third, richer possibility; the 3-year-olds who received benefits through the good intentions of a benefactor were subsequently more generous toward the benefactor than children who either (a) received the same benefits from the benefactor unintentionally or (b) observed the benefactor bestow the same benefits on another individual. Thus, young children are especially motivated to benefit those who have demonstrated goodwill toward them, suggesting, as one possible mechanism, an early sense of gratitude. PMID- 29227852 TI - Relationships between early literacy and nonlinguistic rhythmic processes in kindergarteners. AB - A growing number of studies report links between nonlinguistic rhythmic abilities and certain linguistic abilities, particularly phonological skills. The current study investigated the relationship between nonlinguistic rhythmic processing, phonological abilities, and early literacy abilities in kindergarteners. A distinctive aspect of the current work was the exploration of whether processing of different types of rhythmic patterns is differentially related to kindergarteners' phonological and reading-related abilities. Specifically, we examined the processing of metrical versus nonmetrical rhythmic patterns, that is, patterns capable of being subdivided into equal temporal intervals or not (Povel & Essens, 1985). This is an important comparison because most music involves metrical sequences, in which rhythm often has an underlying temporal grid of isochronous units. In contrast, nonmetrical sequences are arguably more typical to speech rhythm, which is temporally structured but does not involve an underlying grid of equal temporal units. A rhythm discrimination app with metrical and nonmetrical patterns was administered to 74 kindergarteners in conjunction with cognitive and preliteracy measures. Findings support a relationship among rhythm perception, phonological awareness, and letter-sound knowledge (an essential precursor of reading). A mediation analysis revealed that the association between rhythm perception and letter-sound knowledge is mediated through phonological awareness. Furthermore, metrical perception accounted for unique variance in letter-sound knowledge above all other language and cognitive measures. These results point to a unique role for temporal regularity processing in the association between musical rhythm and literacy in young children. PMID- 29227853 TI - Joint effect of education and age at childbirth on the risk of caesarean delivery: findings from Germany 2008-2015. AB - OBJECTIVES: This article aims at assessing the joint effect of maternal age and education on the risk of having a caesarean delivery. As high maternal education is often associated with lower caesarean-birth rates, but high-educated women tend to postpone motherhood, these effects may offset each other in traditional analyses. STUDY DESIGN: Secondary analysis of the data from the German Family Panel pairfam. METHODS: The interview-based data refer to 1020 births between 2008 and 2015. We analyse only reports from mothers and calculate logistic regression models. RESULTS: The caesarean delivery rate differs strongly between education levels, and low-educated women are at higher risk of having a caesarean delivery when controlling for parity and age. A positive age gradient is found, indicating a higher risk of caesarean section for older mothers. Without controlling for age, the association of education and caesarean section risk is weaker, i.e., effects of age and education partially level each other out. A model including an interaction term between age and education confirms this result. CONCLUSIONS: The risk of having a caesarean delivery does not differ between levels of education when maternal age is not taken into account. Lower maternal education and higher age are both positively associated with the risk of experiencing a caesarean section in Germany. However, as higher educated women tend to have their children later, effects of education and age weigh each other out. Preventive campaigns should target women with lower education and raise women's awareness on the risks associated with late motherhood. PMID- 29227854 TI - Surgical intervention in a complicated persistent chyle leak. AB - INTRODUCTION: Chyle leak following cervical surgery has a reported incidence of around 2% annually, and the injury primarily favors a left sided involvement. Our patient presented with a right sided neck persistent chyle leak status post cervical neck dissection and radiation therapy. Infection complicated the patient's clinical course, and he inevitably required a right sided VATS thoracic duct ligation. PRESENTATION OF CASE: The patient was a 53-year-old African American male, with a past medical history of T1N0 right tonsil carcinoma status post chemo-radiation in 2016. He was found to have a residual right-sided neck mass, and then underwent a total neck dissection of the mass and the involved lymph node levels. DISCUSSION: Our patient presented with a right sided lymphatic injury following a total cervical neck dissection. His presentation was uncharacteristic for that the chyle leak was on the right side of his neck, and that he subsequently developed cellulitis and bacteremia due to a prolonged period to surgical intervention. His refractory response to initial conservative measures could have been affected by his prior radiation treatment. CONCLUSION: Chyle leakage is a rare complication of total cervical neck dissection, and should always be considered even with right sided involvement. Conservative management is appropriate in the initial presentation; however, if a patient has a prior history of radiation treatment to the involved site, thoracic duct ligation implemented early may prevent complications such as infection, or a prolonged hospital stay. The following case report has been reported in line with the SCARE criteria. PMID- 29227855 TI - A case report of successful management of clostridium difficile colitis with antegrade Fidaxomicin through a mucous fistula obviating the need for subtotal colectomy. AB - INTRODUCTION: Clostridium difficile is the most common cause of healthcare associated infections and can have devastating morbidity and mortality. Traditional treatment algorithms involve intravenous metronidazole and enteric metronidazole or vancomycin. Fidaxomicin (DificidR) targets "switch regions" within RNA polymerases and effectively kills clostridium difficile bacteria and is typically administered orally primarily or through a naso/oro-gastric conduit. PRESENTATION OF CASE: 55-year-old with a recent elective surgical procedure was hospitalized with multifocal pneumonia and subsequently developed clostridium difficile colitis. This patient failed the standard medical therapy for clostridium difficile colitis, decompensated and required surgical exploration, partial colectomy and mucous fistula creation. Following her surgery, her clinical condition improved and her colitis resolved with the antegrade administration of fidaxomicin through her mucous fistula. DISCUSSION: Fidaxomicin is a newer to market therapeutic agent that has been shown to be effective in the treatment of clostridium difficile colitis. Previously studies have shown benefit of oral fidaxomicin therapy for fulminant clostridium difficile but our study case report describes the index case of topical fidaxomicin through a mucous fistula. CONCLUSION: In our case of fulminant clostridium difficile colitis, Fidaxomicin administered in an antegrade fashion through a mucous fistula may have reduced the need for total colectomy in the treatment of fulminant clostridium difficile colitis. PMID- 29227856 TI - Gastroduodenal artery aneurysm - Post traumatic pancreatic pseudocyst drainage - An interesting case. AB - BACKGROUND AND AIM: Pseudoaneurysms of the gastroduodenal artery (GDA) are rare and mostly associated with pancreatitis. However, they can occur as a possible complication following gastric or pancreatic surgery and thus prior recognition and prompt treatment is mandatory (Lee et al., 2009 [1]). We report a case of a ruptured GDA aneurysm in a patient who underwent roux-en-y-cystojejunostomy for traumatic pancreatic pseudocyst and this has rarely been reported in the literature. Our patient presented with melena one month post operatively. CT Angiogram showed pseudoaneurysm of the GDA and the origin of right gastroepiploic artery which was embolised. Our case highlights that GDA aneurysm must be considered in the differential for a patient who presents with melena following drainage of traumatic pancreatic pseudocyst and that it can be managed successfully with angioembolization. CASE PRESENTATION: A young boy was operated for traumatic pancreatic pseudocyst. One month later, he presented with the complaints of melena. Patient was resuscitated initially and then CT Angiogram was planned that showed pseudo aneurysm of the GDA and the origin of right gastroepiploic artery. The aneurysm was embolised and patient was sent home later on. On two months follow up the patient was doing well and had no episode of melena. CONCLUSION: GDA aneurysm are rare and should be suspected in a patient with GI hemorrhage after surgery for traumatic pancreatic pseudocyst. The investigation of choice is CT Angiography and endovascular angioembolization is the treatment modality of choice. PMID- 29227857 TI - Salvage esophagectomy with pancreatectomy for local recurrence of thoracic esophageal cancer after definitive chemoradiotherapy: A case report. AB - INTRODUCTION: We encountered a case of advanced thoracic esophageal cancer in which R0 resection was achieved by salvage esophagectomy with pancreatectomy, but relapse occurred in the early postoperative phase. PRESENTATION OF CASE: A 64 year-old man with lower intrathoracic esophageal cancer received chemoradiotherapy, and a complete response was achieved. Subsequently, however, lymph node relapse, with infiltration into the pancreas, was observed. Thus, subtotal esophageal resection, total gastrectomy, distal pancreatectomy, and splenectomy were performed. Hepatic relapse occurred 7 months after the surgery, and the patient died 18 months after the surgery. DISCUSSION: The surgical risk of salvage surgery is considered to be extremely high, however selected patients may benefit from highly invasive procedures. In this case, despite R0 resection was achieved by salvage esophagectomy with pancreatectomy, a relapse occurred in the early postoperative phase. The treatment outcome of esophageal cancer patients with infiltration into the pancreas was not favorable. CONCLUSIONS: Because the risk of postoperative complications and relapse is high in patients with advanced esophageal cancer undergoing esophagectomy with pancreatectomy, the applicability of surgery needs to be carefully considered. PMID- 29227858 TI - Bilateral ovarian angiosarcoma arising from the mature cystic teratomas - A case report and review of the literature. AB - INTRODUCTION: Ovarian teratomas undergo the malignant transformation in 0.2-2% of cases. The behavior of malignancies in mature cystic teratomas (MCT) is determined by their phenotype and not their derivation from germ cells. We can recognize pure angiosarcomas or as a part of other tumors like malignant mixed Mullerian tumors and adenosarcomas. PRESENTATION OF CASE: We present the first case of bilateral ovarian angiosarcoma arising from the mature teratomas. Due to widespread disease, we performed limited surgical procedure consisting of bilateral adnexectomy and omentectomy. Exploratory laparotomy in 44-year old patient showed massive ascites, necrotic tissue of omentum and bilateral tumors originating from both ovaries measuring 8 and 6cm with necrotic surface. Immunohistochemistry of the tumors showed positive staining for CD31, vimentin, desmin and focal positivity for CD34. DISCUSSION: Sarcomas of gynecologic origin are extremely rare tumors. They present with unspecified symptoms and are diagnosed in late stages of the disease. The appropriate management of angiosarcomas is difficult due to the rarity of disease and late stage of the diseases. Surgical therapy should contain the hysterectomy with bilateral salpingo-oophorectomy and omentectomy. Pelvic lymphadenectomy was not performed in published cases with no effect on patient survival. CONCLUSION: This work summarizes the current knowledge in the diagnosis and treatment of angiosarcomas arising in the mature teratomas. Promising results are expected from the trials devoted to antiangiogenic strategies in treatment of aggressive sarcomas. PMID- 29227859 TI - Waste biorefineries - integrating anaerobic digestion and microalgae cultivation for bioenergy production. AB - Commercialization of microalgal cultivation has been well realized in recent decades with the use of effective strains that can yield the target products, but it is still challenged by the high costs arising from mass production, harvesting, and further processing. Recently, more interest has been directed towards the utilization of waste resources, such as sludge digestate, to enhance the economic feasibility and sustainability of microalgae production. Anaerobic digestion for waste disposal and phototrophic microalgal cultivation are well characterized technologies in both fields. However, integration of anaerobic digestion and microalgal cultivation to achieve substantial economic and environmental benefits is extremely limited, and thus deserves more attention and research effort. In particular, combining these two makes possible an ideal 'waste biorefinery' model, as the C/N/P content in the anaerobic digestate can be used to produce microalgal biomass that serves as feedstock for biofuels, while biogas upgrading can simultaneously be performed by phototrophic CO2 fixation during microalgal growth. This review is thus aimed at elucidating recent advances as well as challenges and future directions with regard to waste biorefineries associated with the integration of anaerobic waste treatment and microalgal cultivation for bioenergy production. PMID- 29227860 TI - Respiratory syncytial virus in Brazilian infants - Ten years, two cohorts. AB - BACKGROUND: Each year, a considerable amount of children will experience at least one episode of acute viral bronchiolitis (AVB) during their first year of life. About 10% of them will be hospitalized, with significant physical and economic burdens. OBJECTIVES: To compare two cohorts of infants with AVB, from same region, in a ten-year interval, regarding epidemiologic factors and viral etiology. STUDY DESIGN: Cohorts: 142 (2004) and 172 (2014) infants at ages zero to 12 months; clinical diagnosis of AVB; medical care in hospital and genetic screening of nasopharyngeal secretion for respiratory viruses. RESULTS: The comparative analysis showed a difference in the percentage of respiratory syncytial virus (RSV) positive patients [2004 (33.1%); 2014 (70.3%)] (p<0.01). No differences were noted regarding gender, breastfeeding, tobacco exposure, crowding and maternal education. There was a difference as to the month of incidence (seasonality) of AVB (higher in April 2014). There was a higher age at attendance in the first cohort, and lower birth weight and gestational age ratios in the second cohort (p<0.05). There were no differences in hospitalization time, need of mechanical ventilation and number of deaths, however a difference regarding co-morbidities was noted (higher in 2004) (p<0.001). CONCLUSION: None of the analyzed variables had an impact on severity features. Virology and immunology must be considered in this kind of situation, by studying genetic variants and the maturation of the immune system in AVB by RSV or other viruses. PMID- 29227861 TI - Novel gene function and regulation in neocortex expansion. AB - The expansion of the neocortex during human evolution is due to changes in our genome that result in increased and prolonged proliferation of neural stem and progenitor cells during neocortex development. Three principal types of such genomic changes can be distinguished, first, novel gene regulation in human, second, novel function in human of genes existing in both human and non-human species, and third, novel, human-specific genes. The latter comprise both, increases in the copy number of genes existing also in non-human species, and the emergence of genes giving rise to unique, human-specific gene products. Examples of all these types of changes in the human genome have been identified, with ARHGAP11B constituting a paradigmatic example of a unique, human-specific protein. PMID- 29227862 TI - Genetic maps and patterns of cerebral cortex folding. AB - Folding of the cerebral cortex during brain development is a complex process that depends on the orchestrated action of a number of factors, including generation and proliferation of basal progenitor cells, and the radial migration of neurons. Patterns of primary cortical folding are stereotyped between individuals and across phylogeny, reflecting a strong genetic regulation of the underlying cellular mechanisms. Here we summarize recent findings on cellular and genetic mechanisms regulating this fascinating process that underlies expansion and functional complexification of the mammalian cerebral cortex. PMID- 29227863 TI - Phenotypic plasticity in the pancreas: new triggers, new players. AB - The pancreas has a very limited regenerative potential during homeostasis. Despite its quiescent nature, recent in vivo models suggest a certain degree of regeneration and cellular interconversion is possible within the adult pancreas. It has now become evident that cellular plasticity can be observed in essentially all cell types within the pancreas when provided with the right stress stimuli. In this review, we will focus on the latest findings uncovering phenotypic plasticity of different cell types in the pancreas, the molecular mechanisms behind such plasticity and how plasticity associated with pancreatic or non pancreatic cells could be harnessed in the generation of new insulin-producing beta cells. PMID- 29227864 TI - Present and future of modeling human brain development in 3D organoids. AB - Three-dimensional (3D) brain organoids derived from human pluripotent stem cells hold great potential to investigate complex human genetic states and to model aspects of human brain development and pathology. However, the field of brain organoids is still in its infancy, and their use has been limited by their variability and their inability to differentiate into 3D structures with reproducible anatomical organization. Here, starting from a review of basic principles of in vitro 'brain organogenesis', we discuss which aspects of human brain development and disease can be faithfully modeled with current brain organoid protocols, and discuss improvements that would allow them to become reliable tools to investigate complex features of human brain development and disease. PMID- 29227865 TI - Cytochrome b5 reductase is the component from neuronal synaptic plasma membrane vesicles that generates superoxide anion upon stimulation by cytochrome c. AB - In this work, we measured the effect of cytochrome c on the NADH-dependent superoxide anion production by synaptic plasma membrane vesicles from rat brain. In these membranes, the cytochrome c stimulated NADH-dependent superoxide anion production was inhibited by antibodies against cytochrome b5 reductase linking the production to this enzyme. Measurement of the superoxide anion radical generated by purified recombinant soluble and membrane cytochrome b5 reductase corroborates the production of the radical by different enzyme isoforms. In the presence of cytochrome c, a burst of superoxide anion as well as the reduction of cytochrome c by cytochrome b5 reductase was measured. Complex formation between both proteins suggests that cytochrome b5 reductase is one of the major partners of cytochrome c upon its release from mitochondria to the cytosol during apoptosis. Superoxide anion production and cytochrome c reduction are the consequences of the stimulated NADH consumption by cytochrome b5 reductase upon complex formation with cytochrome c and suggest a major role of this enzyme as an anti-apoptotic protein during cell death. PMID- 29227866 TI - Partnerships for Active Children in Elementary Schools (PACES): First year process evaluation. AB - Movement integration (MI) is a strategy within comprehensive school physical activity programs (CSPAP). School-university partnerships are recommended to leverage teachers' capacity to use MI. A mixed method process evaluation was conducted of the first year of implementing Partnerships for Active Children in Elementary Schools (PACES). Classroom teachers (N=12) from four schools participated. Data were collected in Fall 2014 (baseline) and Spring 2015 (~ four months of intervention) using the System for Observing Student Movement in Academic Routines and Transitions and semi-structured interviews. There were no significant differences between intervention classrooms and control classrooms MI promotion. Differences approaching significance (U=5, p=0.04, d=1.2) were observed when comparing classrooms that received two (community of practice, community-based participatory research) or three components (two components plus service learning) of the intervention and classrooms that received one (community of practice) or no components. Qualitative findings revealed that teachers in classrooms that were more successful responded more favorably to the intervention components than teachers in classrooms that were less successful. Quantitative and qualitative results supported the effectiveness of community-based participatory research as a component of PACES. This study provides information about MI process variables in the context of a CSPAP intervention. PMID- 29227867 TI - Associations between vitamin D status and atherosclerosis among Inuit in Greenland. AB - BACKGROUND AND AIMS: Low levels of vitamin D are suspected to be a risk factor for cardiovascular disease and atherosclerosis. The aim of this study was to assess the prevalence of subclinical atherosclerosis among Inuit in Greenland, and to evaluate the association with vitamin D status. We hypothesized that low vitamin D status could be associated with higher carotid intima-media thickness (IMT) as a marker of atherosclerosis. METHODS: 756 adults from the Inuit Health in Transition (IHIT) study carried out in Greenland in the period 2005-2010 were included. A blood sample donated in 1987 was available for a sub-sample of 102 individuals. Serum 25(OH)D3 from the IHIT study and the 1987 survey was used as a measure of vitamin D status. IMT measurements were conducted by ultrasound scanning. The prevalence of atherosclerosis was estimated, and the association between serum 25(OH)D3 and IMT measurements was examined by linear regression. RESULTS: The overall prevalence of subclinical atherosclerosis was 20.1% (n = 152). The linear regression analyses indicated a weak positive association between serum 25(OH)D3 level and IMT measurements from the IHIT study, though not statistically significant after adjustment for potential confounders (beta = 0.35% per 10 nmoL/L 25(OH)D3, p = 0.06). Linear regression analyses of the association between serum 25(OH)D3 level in the 1987 survey and IMT measurements also indicated a positive, though not statistically significant, association after adjustment (beta = 0.07% per 10 nmoL/L 25(OH)D3, p = 0.86). CONCLUSIONS: Our findings did not support the hypothesis of an association between low vitamin D levels and risk of atherosclerosis. PMID- 29227868 TI - Systemic mastocytosis associates with cardiovascular events despite lower plasma lipid levels. AB - BACKGROUND AND AIMS: Mast cells have been implicated in the development and progression of atherosclerosis in animal models and human autopsy studies. However, it is unknown whether long-term exposure to excess of mast cells is associated with cardiovascular disease (CVD) in humans. Our objective was to compare the prevalence of CVD and cardiovascular risk factors in patients with systemic mastocytosis (SM) and controls. METHODS: In 50 patients with SM and 50 age and sex matched controls, the history of CVD and presence of cardiovascular risk factors were assessed. Carotid ultrasound was performed to assess carotid intima-media thickness (C-IMT) and plaques presence. RESULTS: CVD events were more prevalent in SM patients compared to controls (20% vs. 6%, p = 0.04). The prevalence of C-IMT and carotid plaques was similar between patients with SM and controls. In multivariate analysis, CVD events were significantly associated with SM (OR 7.0 (95% CI 1.3-37.6), p = 0.02) and hypertension (OR 9.5 (95% CI 1.9 48.7), p = 0.01). The prevalence of diabetes, hypertension, obesity and smoking was similar between the two groups. Total cholesterol and LDL-C levels were significantly lower in SM patients than in the control group. (5.1 +/- 1.1 vs. 5.9 +/- 0.9 mmol/l, p < 0.05 and 2.9 +/- 0.8 vs. 3.5 +/- 0.7 mmol/l, p < 0.05, respectively). CONCLUSIONS: Despite lower plasma total cholesterol and LDL-C, the prevalence of CVD is higher in patients with SM compared to healthy controls. Beyond the setting of SM, this study can be considered as a proof of concept study, indicating the contribution of mast cells to CVD in humans. PMID- 29227869 TI - Reliability of oscillometric central blood pressure responses to lower limb resistance exercise. AB - BACKGROUND AND AIMS: Although it is well known that resistance training (RT) is beneficial for patients suffering from a variety of cardiovascular diseases, it remains underutilized as a rehabilitation tool as there is no reliable way to monitor the additional stress placed on the central organs. The current study aimed to determine between-day reliability of central haemodynamic indices using oscillometric pulse wave analysis (PWA) during progressive sub-maximal RT. METHODS: Nineteen healthy young males were tested on 3 different mornings in a fasted state. Central hemodynamic variables including augmentation index (AIx), AIx normalized to a heart rate of 75 beats per minute (AIx@75), central systolic blood pressure (cSBP), forwards (Pf) and backwards (Pb) wave reflection were determined at rest, as well as during leg extension RT at 10, 15 and 20% of maximal volitional contraction (MVC), and following 1 min and 5 min passive recovery. RESULTS: During RT at 10, 15 and 20% MVC, the intraclass correlation coefficient (ICC) values for AIx@75 (0.76-0.9), cSBP (0.74-0.78), Pf (0.75-0.82) and Pb (0.75-0.83) exceeded the criteria (0.75) for excellent reliability. During the 5 min recovery, the ICC values for AIx@75 (0.87-0.87), cSBP (0.69-0.7), Pf (0.63-0.67) and Pb (0.63-0.66) indicated good to excellent reliability. CONCLUSIONS: Clinically meaningful changes in central hemodynamic indices can be obtained during resistance training using oscillometric PWA devices. This technology holds potential for advancing resistance training prescription guidelines for patients with overt cardiovascular diseases. PMID- 29227870 TI - Impact of alcohol drinking on acetylcholine-induced coronary artery spasm in Korean populations. AB - BACKGROUND AND AIMS: Generally, immoderate alcohol consumption is associated with variant angina and accepted as one of the risk factors for coronary artery spasm (CAS), but evidence is lacking in this regard. The aim of this study is to evaluate the impact of alcohol consumption and drinking pattern on CAS by acetylcholine (ACH) provocation test and long-term clinical outcomes. METHODS: A total of 5491 patients with typical or atypical chest pain, without significant coronary artery disease, who underwent intracoronary ACH provocation test, were enrolled prospectively, and retrospectively analyzed in this study. They were divided into two groups according to their alcohol drinking status; the current alcohol (CA) drinking group (n = 1792), and non-CA group (n = 3699). To adjust for potential confounders, a propensity score matching (PSM) analysis was performed. The primary endpoint was incidence of CAS, and secondary endpoints were major adverse cardiac events (MACE) and recurrent angina requiring repeat coronary angiography (CAG) at 5 years. RESULTS: After PSM analysis, alcohol consumption was a strong risk factor for CAS. Furthermore, excessive alcohol consumption was correlated with a higher risk for CAS. As compared with the non CA group, the CA group showed worse angiographic and clinical findings, including higher incidence of CAS (58% vs. 62%, p = 0.016), spontaneous spasm (17% vs. 22%, p = 0.004), multi-vessel spasm (31% vs. 37%, p = 0.009), proximal epicardial spasm (39% vs. 46%, p = 0.002), ischemic electrocardiography changes such as T inversion (0.4% vs. 1.2%, p < 0.001) and chest pain (42% vs. 46%, p = 0.047) during ACH provocation test. However, the status and pattern of alcohol drinking had no influence on long-term clinical outcomes such as MACE or recurrent angina. CONCLUSIONS: Alcohol consumption is a strong risk factor for CAS, and excessive alcohol consumption was correlated with a higher risk for CAS. Further well designed studies are needed to confirm the results. PMID- 29227871 TI - Production of biogenic manganese oxides coupled with methane oxidation in a bioreactor for removing metals from wastewater. AB - Biogenic manganese oxide (BioMnOx) can efficiently adsorb various minor metals. The production of BioMnOx in reactors to remove metals during wastewater treatment processes is a promising biotechnological method. However, it is difficult to preferentially enrich manganese-oxidizing bacteria (MnOB) to produce BioMnOx during wastewater treatment processes. A unique method of cultivating MnOB using methane-oxidizing bacteria (MOB) to produce soluble microbial products is proposed here. MnOB were successfully enriched in a methane-fed reactor containing MOB. BioMnOx production during the wastewater treatment process was confirmed. Long-term continual operation of the reactor allowed simultaneous removal of Mn(II), Co(II), and Ni(II). The Co(II)/Mn(II) and Ni(II)/Mn(II) removal ratios were 53% and 19%, respectively. The degree to which Mn(II) was removed indicated that the enriched MnOB used utilization-associated products and/or biomass-associated products. Microbial community analysis revealed that methanol-oxidizing bacteria belonging to the Hyphomicrobiaceae family played important roles in the oxidation of Mn(II) by using utilization-associated products. Methane-oxidizing bacteria were found to be inhibited by MnO2, but the maximum Mn(II) removal rate was 0.49 kg m-3 d-1. PMID- 29227872 TI - Low levels of iron enhance UV/H2O2 efficiency at neutral pH. AB - While the presence of iron is generally not seen as favorable for UV-based treatment systems due to lamp fouling and decreased UV transmittance, we show that low levels of iron can lead to improvements in the abatement of chemicals in the UV-hydrogen peroxide advanced oxidation process. The oxidation potential of an iron-assisted UV/H2O2 (UV254 + H2O2 + iron) process was evaluated at neutral pH using iron levels below USEPA secondary drinking water standards (<0.3 mg/L). Para-chlorobenzoic acid (pCBA) was used as a hydroxyl radical (HO) probe to quantify HO steady state concentrations. Compounds degraded by different mechanisms including, carbamazepine (CBZ, HO oxidation) and N nitrosodimethylamine (NDMA, direct photolysis), were used to investigate the effect of iron on compound degradation for UV/H2O2 systems. The effects of iron species (Fe2+ and Fe3+), iron concentration (0-0.3 mg/L), H2O2 concentration (0 10 mg/L) and background water matrix (low-carbon tap (LCT) and well water) on HO production and compound removal were examined. Iron-assisted UV/H2O2 efficiency was most influenced by the target chemical and the water matrix. Added iron to UV/H2O2 was shown to increase the steady-state HO concentration by approximately 25% in all well water scenarios. While CBZ removal was unchanged by iron addition, 0.3 mg/L iron improved NDMA removal rates in both LCT and well water matrices by 15.1% and 4.6% respectively. Furthermore, the combination of UV/Fe without H2O2 was also shown to enhance NDMA removal when compared to UV photolysis alone indicating the presence of degradation pathways other than HO oxidation. PMID- 29227873 TI - Restraint use in older adults in home care: A systematic review. AB - OBJECTIVES: To get insight into restraint use in older adults receiving home care and, more specifically, into the definition, prevalence and types of restraint, as well as the reasons for restraint use and the people involved in the decision making process. DESIGN: Systematic review. DATA SOURCES: Four databases (i.e. Pubmed, CINAHL, Embase, Cochrane Library) were systematically searched from inception to end of April 2017. REVIEW METHODS: The study encompassed qualitative and quantitative research on restraint use in older adults receiving home care that reported definitions of restraint, prevalence of use, types of restraint, reasons for use or the people involved. We considered publications written in English, French, Dutch and German. One reviewer performed the search and made the initial selection based on titles and abstracts. The final selection was made by two reviewers working independently; they also assessed study quality. We used an integrated design to synthesise the findings. RESULTS: Eight studies were reviewed (one qualitative, seven quantitative) ranging in quality from moderate to high. The review indicated there was no single, clear definition of restraint. The prevalence of restraint use ranged from 5% to 24.7%, with various types of restraint being used. Families played an important role in the decision-making process and application of restraints; general practitioners were less involved. Specific reasons, other than safety for using restraints in home care were noted (e.g. delay to nursing home admission; to provide respite for an informal caregiver). CONCLUSIONS: Contrary to the current socio demographical evolutions resulting in an increasing demand of restraint use in home care, research on this subject is still scarce and recent. The limited evidence however points to the challenging complexity and specificity of home care regarding restraint use. Given these serious challenges for clinical practice, more research about restraint use in home care is urgently needed. PMID- 29227874 TI - Selecting passive dosimetry technologies for measuring the external dose of terrestrial wildlife. AB - Dosimeters attached to wild animals can be used to validate regulatory assessment approaches and models for estimating radiation exposure of wild animals. Such measurements are also necessary to ensure that robust dose-effect relationships can be developed from the results of field research programmes. This paper presents the first comprehensive evaluation of the different dosimetry technologies available for specifically measuring the external exposure of wildlife. Guidance is provided on the selection of appropriate passive dosimetry approaches for directly measuring external exposure of terrestrial wildlife under field conditions. The characteristics and performance of four available dosimetry technologies (thermoluminescent dosimeter (TLD), optically stimulated luminescent dosimeter (OSLD), radiophotoluminescent dosimeter (RPLD) and direct ion storage, (DIS)) are reviewed. Dosimeter properties, detection limit and dose range, study organisms and the intended application are variables that need to be considered when selecting a suitable dosimetry technology. Evaluated against these criteria, it is suggested that LiF based and Al2O3:C TLDs, OSLD and RPLD could all be used to estimate doses to wildlife. However, only LiF based TLDs have been used to directly measure wildlife doses in field studies to date. DIS is only suitable for comparatively large species (e.g. medium to large mammals), but has the advantage that temporal variation in dose can be recorded. In all cases, dosimeter calibration is required to ensure that the dose measurements reported can be interpreted appropriately for the organisms of interest. PMID- 29227875 TI - Soil-to-cassava transfer of naturally occurring radionuclides from communities along Ghana's oil and gas rich Tano Basin. AB - Soil-to-plant transfer factor (TF) is widely used to assess the impact of soil radioactivity on agricultural crops. The root crop cassava (Manihot esculenta) provides 30%-50% of the calories consumed in Sub-Saharan Africa and is widely used in South America. gamma-ray analysis was used to measure activity concentrations of 238U, 232Th, and 40K in cassava root and soil. The TF values for 238U, 232Th, and 40K were in the range 0.06-0.12, 0.01-0.10 and 0.04-0.28 respectively. The median transfer factors were 0.10 (238U), 0.04 (232Th) and 0.08 (40K). For 238U and 232Th, the highest TF values were 0.12 and 0.10 respectively. PMID- 29227876 TI - Temporal and spatial variations of 134Cs and 137Cs levels in the Sea of Japan and Pacific coastal region: Implications for dispersion of FDNPP-derived radiocesium. AB - To investigate the dispersion of Fukushima Dai-ichi Nuclear Power Plant (FDNPP) derived radiocesium in the Sea of Japan and western Pacific coastal region and determine the sources of radiocesium in these areas, we examined the temporal and spatial variations of 134Cs and 137Cs concentrations (activities) during 2011 2016 in seawaters around the western Japanese Archipelago, particularly in the Sea of Japan. In May 2013, the surface concentration of 134Cs was ~0.5 mBq/L (decay-corrected to March 11, 2011), and that of 137Cs exceeded the pre-accident level in this study area, where the effects of radiocesium depositions just after the FDNPP accident disappeared in surface waters in October 2011. Subsequently, radiocesium concentrations gradually increased during 2013-2016 (~0.5-1 mBq/L for 134Cs), exhibiting approximately homogeneous distributions in each year. The temporal and spatial variations of 134Cs and 137Cs concentrations indicated that FDNPP-derived radiocesium around the western Japanese Archipelago, including the Sea of Japan, has been supported by the Kuroshio Current and its branch, Tsushima Warm Current, during 2013-2016. However, in the Sea of Japan, the penetration of 134Cs was limited to depths of less than ~200 m during three years following the re-delivery of FDNPP-derived radiocesium. PMID- 29227877 TI - Spatial variations of 226Ra, 228Ra, 134Cs, and 137Cs concentrations in western and southern waters off the Korean Peninsula in July 2014. AB - We examined the spatial distributions of 226Ra, 228Ra, 134Cs, and 137Cs concentrations (activities) in seawater off the western and southern Korean Peninsula in July 2014. Radium-228 (and 226Ra) concentrations in water samples varied widely from 5 to 14 mBq/L (2-4 mBq/L), showing a negative correlation with salinity, particularly at the surface off the western Korean Peninsula. This indicates that the seawaters in this area are fundamentally comprised of 228Ra poor and high-saline Kuroshio Current water and 228Ra-rich and low-saline water (e.g., continental shelf water), with various mixing ratios. Although Fukushima Dai-ichi Nuclear Power Plant (FDNPP)-derived 134Cs was below the detection limit (<0.08 mBq/L) in waters off the western Korean Peninsula, low level 134Cs (0.1 0.2 mBq/L) was detected in waters off the southern Korean Peninsula accompanied by higher 137Cs concentrations (1.6-1.9 mBq/L) relative to that off the western Korean Peninsula. Combined with the lower radium concentrations, the detection of 134Cs is explained by mixing of FDNPP-derived radiocesium-contaminated Kuroshio Current water. PMID- 29227878 TI - Harm reduction-based and peer-supported hepatitis C treatment for people who inject drugs in Georgia. PMID- 29227879 TI - Re-thinking pre-drinking: Implications from a sample of teenagers who drink in private settings. PMID- 29227880 TI - The relationship between Australian harm minimisation alcohol education and student uptake, consumption and harm. AB - BACKGROUND: Alcohol use by young people is a public health concern in Australia because of the disproportionate harm they experience. Accordingly, governments have sought to protect young people, with school identified as an appropriate site for drug, including alcohol, prevention through education. School-based drug education programmes, however, have not been particularly effective, and even when individual programs report prevention benefits they can be criticised for being developed and evaluated by the same group. METHODS: This study involved secondary analysis of alcohol data from the 2011 and 2014 Australian Secondary Students Alcohol and Drug (ASSAD) surveys, to examine the relationship between the amount of alcohol education students reported receiving and their patterns of use and harm. Associations between the amount of alcohol education remembered and alcohol uptake, consumption, risky consumption and alcohol-related harm were measured using Logistic and Tobit regression techniques. As most alcohol education in Australia reflects harm minimisation aims, this research provides an independent, proxy assessment of the effect of harm minimisation education. RESULTS: In the 12- to 17-year-old student group, as a whole, there was a significant positive association between having tried alcohol and the level of alcohol education recalled. There were significant negative associations between the amount of alcohol consumed and the level of alcohol education recalled for drinkers and risky drinkers. There were no significant associations between alcohol-related harm and the level of alcohol education recalled for drinkers and risky drinkers. CONCLUSION: Providing more harm minimisation alcohol education did not persuade students to abstain from alcohol, but rather the reverse. Providing more harm minimisation education was influential in reducing consumption by students, particularly those drinking at risky levels. This should be considered indirectly beneficial in terms of minimising harm. However, the alcohol education provided to Australian students has not directly influenced their alcohol-related harm. PMID- 29227881 TI - Experiences with compulsory drug detention among people who inject drugs in Bangkok, Thailand: A qualitative study. PMID- 29227882 TI - Kalaban: Young drug users' engagements with law enforcement in the Philippines. AB - BACKGROUND: A violent 'war on drugs' continues to be waged in the Philippines, even as the use of drugs - particular methamphetamine - continues to rise. Furnishing contextual background to the current situation, this paper explores how long-running law enforcement approaches in the Philippines might be viewed by those in their receiving end by presenting findings of an ethnography among marginalized young men. METHODS: Semi-structured interviews and focus group discussions were conducted among 20 young men throughout a 12-month period of participant-observation from December 2011 to September 2013. FINDINGS: Young people make use of various 'tactics' to keep using drugs and evade law enforcement, even as drug use itself is a tactic in their everyday lives. A sense of hypocrisy and injustice, borne of their own experiences, informs their view of law enforcers, whom they call kalaban (enemy). They feel they are being unfairly targeted, but in their view, this danger is just part of the perils of their everyday lives. CONCLUSION: Young men's resort to various tactics speaks of an agency that is often ignored in public discourses. Their 'lay assessments of risks' and experience-based perceptions of law enforcement raises questions about the efficacy of fear-based anti-drug campaigns. Overall, the study offers an ethnographic argument against the punitive methods being employed by the Philippines, and for measures that reframe the relationship between police and young drug users - from hostility to trust. PMID- 29227883 TI - Associations between medical cannabis and other drug use among unstably housed women. AB - BACKGROUND: Several studies suggest that U.S. state-level legalization of cannabis for medical purposes may be associated with reductions in opioid use; yet its relationship with stimulant use, particularly in high-risk populations like unstably housed women, has received less attention. The purpose of this study was to estimate independent associations between medical and non-medical use of cannabis and use of stimulants and opioids among unstably housed women. METHODS: Cross-sectional data were analyzed from 245 women in the SHADOW study, a community based cohort in San Francisco, CA, in which HIV+ women were oversampled (126 HIV+ and 119 HIV-). RESULTS: Compared to no cannabis use in the past 6 months (51%), non-medical cannabis use (28%) was associated with a higher adjusted odds of using stimulants (Adjusted Odds Ratio [AOR]=4.34, 95% confidence interval [CI]: 2.17-8.70) and opioids (AOR=3.81, 95% CI: 1.78-8.15). Compared to no cannabis use, medical cannabis use (21%) was not significantly associated with stimulant or opioid use. Compared to non-medical cannabis use, however, medical cannabis use was associated with lower adjusted odds of using stimulants (AOR=0.42, 95% CI: 0.18-0.96). These associations were not modified by HIV status. CONCLUSIONS: Associations between use of cannabis and "street drugs" depend on whether the cannabis is obtained through a medical context. Interventions, research, and policy considering the influence of cannabis on the use of other drugs may benefit by distinguishing between medical and non-medical cannabis use. PMID- 29227884 TI - Corrigendum to "Characterization of an Sf-rhabdovirus-negative S. frugiperda cell line as an alternative host for recombinant protein production in the baculovirus insect cell system" [Protein Expr. Purif. 122 (2016) 45-55]. PMID- 29227886 TI - Traveling with blindness: A qualitative space-time approach to understanding visual impairment and urban mobility. AB - This paper draws from Hagerstrand's space-time framework to generate new insights on the everyday mobilities of individuals with visual impairments in the San Francisco Bay Area. While existing research on visual impairment and mobility emphasizes individual physical limitations resulting from vision loss or inaccessible public spaces, this article highlights and bridges both the behavioral and social processes that influence individual mobility. A qualitative analysis of sit-down and mobile interview data reveals that the space-time constraints of people with visual impairments are closely linked to their access to transportation, assistive technologies, and mobile devices. The findings deepen our understandings of the relationship between health and mobility, and present intervention opportunities for improving the quality of life for people with visual impairment. PMID- 29227885 TI - Neighbourhood social and physical environment and general practitioner assessed morbidity. AB - The aim of our study was to investigate the association between health enhancing and threatening, and social and physical aspects of the neighbourhood environment and general practitioner (GP) assessed morbidity of the people living there, in order to find out whether the effects of environmental characteristics add up or modify each other. We combined GP electronic health records with environmental data on neighbourhoods in the Netherlands. Cross-classified logistic multilevel models show the importance of taking into account several environmental characteristics and confounders, as social capital effects on the prevalence of morbidity disappear when other area characteristics are taken into account. Stratification by area socio-economic status, shows that the association between environmental characteristics and the prevalence of morbidity is stronger for people living in low SES areas. In low SES areas, green space seems to alleviate effects of air pollution on the prevalence of high blood pressure and diabetes, while the effects of green space and social capital reinforce each other. PMID- 29227887 TI - "There is not a safe space where they can find themselves to be free": (Un)safe spaces and the promotion of queer visibilities among township males who have sex with males (MSM) in Cape Town, South Africa. AB - Males who have sex with males (MSM) are prioritised in the global fight against HIV/AIDS, as a key affected population to receive HIV prevention, treatment, and HIV-related care and support (WHO, 2016). There is, however, limited empirical research conducted on how to engage communities of South African MSM in clinical HIV prevention research programs. The development of LGBTIQ safe spaces may potentially be a viable option to promote community-based engagement by bridging the divides between HIV-prevention researchers, marginalised queer populations, and other HIV-prevention stakeholders located in heteronormative spaces (Molyneux et al., 2016). We conducted ten in-depth, qualitative interviews with MSM safe space members who have been involved in HIV prevention research programs. Data were analysed using a thematic analytic strategy (Braun and Clarke, 2006). Our results indicate that the "safe spaces" currently operational in Cape Town are not stable spaces nor are they always safe, but they form part of a broader and much more long-term political and geographical strategy of inclusion and emancipation. PMID- 29227888 TI - Helping nursing students unblock empathy: A big idea from William James. PMID- 29227889 TI - Nursing and midwifery students' stress and coping during their undergraduate education programmes: An integrative review. AB - OBJECTIVES: The aim of this review is to examine the literature related to the sources of stress, coping mechanisms and interventions to support undergraduate nursing and midwifery students to cope with stress during their undergraduate education. DESIGN: Integrative literature review. DATA SOURCES: The databases CINAHL, PubMed and PsycINFO were searched for articles published between 2010 and 2016. Search terms in various combinations were used for example; student nurse, student midwife, undergraduate, stress, coping and interventions. REVIEW METHODS: An integrative review based on Whittemore and Knafl's approach was used to conduct the review. RESULTS: The search generated 25 articles that met the inclusion criteria. The key sources of stress emanated from clinical, academic and financial issues but predominantly from the clinical environment. Students used a variety of coping strategies, both adaptive and maladaptive. These appear to be influenced by their past and present circumstances such as, their needs, what was at stake and their options for coping. Interventions for student nurses/midwives to cope with stress were varied and in the early stages of development. Mindfulness showed some promising positive results. Interventions focussed on the individual level excluding the wider social context or organisation level. CONCLUSIONS: Stress is pervasive in all aspects of undergraduate nursing and midwifery education. Nursing and midwifery educators need to be aware of this impact and provide appropriate support to students in both the clinical and academic environments. Further research is needed to capture the experience of stress from the students' perspective as well as the barriers and facilitators to supporting students from the preceptors'/mentors' perspectives. Finally, more intervention studies are needed to identify and compare what interventions are effective in supporting students to cope with stress during their undergraduate education. PMID- 29227890 TI - A novel hydrophobically-modified polyelectrolyte for enhanced dewatering of clay suspension. AB - This work investigates the effect of multifunctional poly (N-isopropyl acrylamide/acrylic acid/N-tert-butylacrylamide) [p(NIPAM-AA-NTBA)] ternary polymer on the sedimentation of kaolin clay - a major fraction of oil sands tailings. A series of linear, uncross-linked p(NIPAM), p(NIPAM/AA), and p(NIPAM/AA/NTBM) were synthesized as random copolymers, where all monomer units were randomly arranged along the polymer backbone and connected by covalent bonds. The ternary copolymer, used as a flocculant, exhibited thermo-sensitivity, anionic nature, and hydrophobic association due to NIPAM, AA, and NTBM, respectively. As the ternary polymer is thermosensitive, it undergoes extended to coil-like conformation, i.e. hydrophilic to hydrophobic transition, above its lower critical solution temperature (LCST). The comonomers NIPAM (above LCST) and NTBM help expel water out of sediments due to their hydrophobicity, while AA promotes charge neutralization of the kaolin clay particles. The effect of number average molecular weight, charge density, and concentration of NTBM on settling behavior of kaolin suspension was examined. Settling test at 50 degrees C resulted in significantly higher settling rates compared to that at room temperature. Further, the quality of water recovered in each experiment was tested in terms of its turbidity. These results indicate that this novel ternary polymer can be employed to enhance the recovery of water from oil sands tailings containing clays. PMID- 29227891 TI - Changes in metal mobility assessed by EDTA kinetic extraction in three polluted soils after repeated phytoremediation using a cadmium/zinc hyperaccumulator. AB - Phytoextraction is one of the most promising technologies for the decontamination of metal-polluted agricultural soils. Effects of repeated phytoextraction by the cadmium (Cd)/zinc (Zn) hyperaccumulator Sedum plumbizincicola on metal (Cd, Zn, copper (Cu) and lead (Pb)) mobility were investigated in three contaminated soils with contrasting properties. EDTA kinetic extraction and the two first-order reactions model showed advantages in the assessment of soil metal mobility and clearly discriminated changes in metal fractions induced by phytoextraction. Repeated phytoextraction led to large decreases in readily labile (Q10) and less labile (Q20) fractions of Cd and Zn in all three soils with the sole exception of an increase in the Q20 of Zn in the highly polluted soil. However, Q10 fractions of soil Cu and Pb showed apparent increases with the sole exception of Pb in the acid polluted soil but showed a higher desorption rate constant (k1). Furthermore, S. plumbizincicola decreased the non-labile fraction (Q30) of all metals tested, indicating that the hyperaccumulator can redistribute soil metals from non-labile to labile fractions. This suggests that phytoextraction decreased the mobility of the metals hyperaccumulated by the plant (Cd and Zn) but increased the mobility of the metals not hyperaccumulated (Cu and Pb). Thus, phytoextraction of soils contaminated with mixtures of metals must be performed carefully because of potential increases in the mobility of non-hyperaccumulated metals in the soil and the consequent environmental risks. PMID- 29227892 TI - Effects of rare earth and acid rain pollution on plant chloroplast ATP synthase and element contents at different growth stages. AB - : Combined rare earth and acid rain pollution has become a new environmental problem, seriously affecting plant survival. The effects of these two kinds of pollutants on plant photosynthesis have been reported, but the micro mechanisms are not very clear. In this research, we studied the effects of lanthanum [La(III), 0.08, 1.20 and 2.40 mM] and acid rain (pH value = 2.5, 3.5 and 4.5) on the ATPase activity and gene transcription level and the functional element contents in rice leaf chloroplasts. The results showed that the combined 0.08 mM La(III) and pH 4.5 acid rain increased the ATPase activity and gene transcription level as well as contents of some functional elements. But other combined treatments of acid rain and La(III) reduced the ATPase activity and gene transcription level as well as functional element contents. The change magnitude of the above indexes at rice booting stage was greater than that in seedling stage or grain filling stage. These results reveal that effects of La(III) and acid rain on ATPase activity and functional element contents in rice leaf chloroplasts are related to the combination of La(III) dose and acid rain intensity and the plant growth stage. In addition, the changes in the ATPase activity were related to ATPase gene transcription level. This study would provide a reference for understanding the microcosmic mechanism of rare earth and acid rain pollution on plant photosynthesis and contribute to evaluate the possible environmental risks associated with combined La(III) and acid rain pollution. ONE SENTENCE SUMMARY: The effects of La(III) and acid rain on activity and gene transcription level of rice chloroplast ATPase and contents of functional elements were different at different growth stages. PMID- 29227893 TI - Targeted eco-pharmacovigilance for ketoprofen in the environment: Need, strategy and challenge. AB - Implementing "targeted" eco-pharmacovigilance(EPV) which focuses on individual or specific pharmaceuticals on a prioritised basis is a feasible, economical and customized approach to reduce the environmental concentrations and risks of pharmaceuticals. Non-steroidal anti-inflammatory drugs(NSAIDs) remaining in environment are a kind of priority hazard substances, due to a notable case that diclofenac residues caused the loss of more than 99% of vultures across the Indian sub-continent. Ketoprofen, as another widely used NSAID with comparable or even higher global consumption than diclofenac, in the environment has been shown to present a potential risk to non-target terrestrial and aquatic species. Based on the review of 85 articles reporting the analyses of ketoprofen residues in environment since 2010, we found that this NSAID frequently present in various environmental compartments around the world. Therefore, it is urgent to implement EPV targeting ketoprofen pollution. Here, we provide some recommendations for implementing the targeted EPV for ketoprofen, including: Closely monitoring ketoprofen in the natural environment; Reducing the residues of ketoprofen through source control; Encouraging urine source separation and treatment; Limiting the application of veterinary ketoprofen; Designing and constituting a framework system of targeted EPV. But some challenges, such as ambiguity in the accountability of the main bodies responsible for continued monitoring of ketoprofen residues, the lack of optimized urine source separation scenarios and procedure, the need for detailed design and application schemes of the framework system of targeted EPV, etc. should be addressed. PMID- 29227894 TI - Substance-induced psychotic symptoms in Borderline Personality Disorder among substance use disorder samples in Spain. AB - Substance-induced psychosis (SIP) is frequent in substance use disorder patients. However, little is known about the presence of SIP in Borderline Personality Disorder (BPD) and what the risk factors for the development of SIP in this population would be. A sample of 91 BPD drug-dependent patients attending an outpatient substance use disorder unit was evaluated. Comorbidity with Axis I and II was assessed using SCID-I and SCID-II. Psychoactive drug related variables were registered as well as the presence of the ninth criterion of DSM-IV-TR as a code of psychotic symptoms. A total of 50.5% of the sample were women. The most prevalent drug consumed was cocaine (67%) followed by cannabis (47.3%) and then alcohol (39.6%). A total of 62.8% people with BPD registered substance-induced psychosis symptoms in their lifetime. Notably, this study found these symptoms were not associated with the presence of psychotic symptoms registered in ninth criterion. Cocaine and cannabis consumption are associated with the presence of SIP in SUD-BPD patients. No other clinical variables were related in this sample. Further research studies are needed to find other risk factors for SIP in this patient group. PMID- 29227895 TI - Patients with OCD report lower quality of life after controlling for expert-rated symptoms of depression and anxiety. AB - BACKGROUND: One to three percent of the adult population suffers from obsessive compulsive disorders (OCD). Previous studies have also shown that, compared to controls, patients with OCD report a lower QoL. The latter is associated with self-rated symptoms of depression and anxiety. The aim of the present study was to compare the quality of life of OCD patients with that of healthy controls, while introducing expert-rated symptoms of depression and anxiety as covariates. Gender was also taken into account as an additional associated factor. METHOD: A total of 100 patients diagnosed with OCD (mean age: 32 years; 64% females) and healthy 100 controls (mean age: 31 years; 59% females; no discernible psychiatric disorder) took part in the present cross-sectional study. All participants completed questionnaires covering socio-demographic characteristics and dimensions of QoL. Experts rated participants' symptoms of OCD (Yale-Brown Obsessive-Compulsive Scale), anxiety (Hamilton Anxiety Rating Scale) and depression (Hamilton Depression Rating Scale). RESULTS: Compared to healthy controls, patients with OCD reported a lower QoL, and had higher symptoms of depression and anxiety. This pattern was particularly pronounced among female patients with OCD. QoL was lower in patients with OCD, even when controlling for depression and anxiety. Results from binary logistic regressions showed that female gender, low QoL and higher symptoms of OCD, depression and anxiety together predicted status as patient with OCD. CONCLUSIONS: Compared to healthy controls, patients with OCD have a poorer quality of life and this is independent of depression or anxiety, and is particularly pronounced among female patients. Thus, treatment of OCD might take into account patients' comorbidities and gender. PMID- 29227896 TI - Details of attention and learning change in first-episode schizophrenia. AB - Impaired attention and learning functions are common in schizophrenia. The details of this impairment, and how these change across time, are not well known. We aimed to compare the parameters of well-known attention and learning neuropsychological tests in first-episode schizophrenia (FES) patients and healthy controls in a 2-year follow-up period. The performance of 28-25 FES patients and pairwise matched healthy controls on the Continuous Performance Test Identical Pairs, the revised Hopkins Verbal Learning Test, and the revised Brief Visuospatial Memory Test was compared at baseline and 2 years later. The attention dysfunction of the FES group was driven by slow reaction time and a comparative failure to identify correct hits. The reaction time was reduced somewhat across time in the patient group. Regarding the learning tasks, both groups increased their number of correct answers across trials. However, at each trial, the patient group exhibited lower scores, with a trend towards better visual learning performance across time. In summary, the FES patients were impaired in most of the parameters of the attention and learning tasks. Across time, modest improvements in reaction time and visual learning were displayed in the FES group. However, this group never caught up with the control group. PMID- 29227898 TI - Responsiveness of the Personal and Social Performance scale in patients with schizophrenia. AB - The responsiveness (ability to detect change) of the Personal and Social Performance scale (PSP) is largely unknown, limiting its use as an outcome measure. The purpose of this study was to examine both internal and external responsiveness of the PSP in patients with schizophrenia in the acute phase. Eighty patients were administered the PSP and the Clinical Global Impression Severity scale (CGI-S) at admission and at discharge. We used the standardized effect size, the standardized response mean, and paired t-test for examining internal responsiveness. We examined the correlations between the changes in scores of the PSP and those of the CGI-S using Pearson's r for validating the external responsiveness. The results showed that the standardized effect sizes and standardized response means of the PSP were 0.74-1.74 and 0.68-1.72, respectively. The paired t-tests showed statistically significant difference (p<0.001). Moderate to good correlations (r=0.35-0.74) were found among the changes of the PSP with those of the CGI-S. The PSP showed substantial internal responsiveness and sufficient external responsiveness in patients with schizophrenia receiving treatment in the acute phase. The PSP appears useful as an outcome measure for detecting changes of social functioning over time. PMID- 29227897 TI - Sleep difficulties in college students: The role of stress, affect and cognitive processes. AB - Previous research indicates that sleep difficulties and stress are prevalent in college students. The main aim of the current study was to investigate the role of repetitive negative thinking (RNT), cognitive emotion regulation, and negative affect as mediators of the relationship between stress and sleep difficulties. We also intended to analyse the associations between all these variables and the gender differences. A sample of 549 college students completed self-report measures assessing the mentioned variables. Descriptive and correlational analyses showed significant differences between genders. In total sample, sleep difficulties were positively associated with perceived stress, negative affect, RNT and cognitive emotional strategies (rumination, self-blaming, catastrophizing, and acceptance). Mediation analyses suggested that in addition to the direct effect of stress on sleep difficulties, rumination and negative affect were important mediators in this relationship (after controlling gender). RNT did not mediate this association; however it was significantly associated to rumination and/or negative affect. These findings suggest that the effect of stress on sleep difficulties is strengthened by rumination and/or negative affect. The negative impact of RNT (content free) only occurs if associated to rumination and/or negative affect. PMID- 29227899 TI - Cardiac troponins and NT-proBNP in the forensic setting: Overview of sampling site, postmortem interval, cardiopulmonary resuscitation, and review of the literature. AB - The possible use of biochemical markers in the postmortem diagnosis of myocardial ischemia is well known in the forensic setting, though several issues have limited its widespread adoption. The study presented herein focuses of N-terminal pro-B-type natriuretic peptide, troponin T, and troponin I, and the possible influence due to sampling site chosen, postmortem interval elapsed, and cardiopulmonary resuscitation attempts. Comparisons were performed between antemortem serum levels of these markers and postmortem levels measured in pericardial fluid and postmortem serum samples obtained from different sampling sites (n=16). Levels of these markers were also compared in cases characterized by various postmortem intervals (n=48, consisting of 24 ischemic heart disease cases and 24 controls) as well as in cases with and without cardiopulmonary resuscitation (n=22, consisting of 14 cases of hanging and 8 cases of drug intoxication). Our results indicate that N-terminal pro-B-type natriuretic peptide, troponin T, and troponin I values determined in postmortem serum from femoral blood (collected up to 24h after death) do not differ significantly from those measured in venous blood antemortem serum samples (collected at the upper limbs). In addition, our results reveal that the time elapsed after death should always be taken into consideration when cardiac troponins are measured in postmortem samples. Lastly, our findings reveal the absence of statistically significant differences between levels of the tested biomarkers (in postmortem serum from femoral blood) in cases without cardiopulmonary resuscitation compared to cases with cardiopulmonary resuscitation (at least for postmortem intervals up to 24h). PMID- 29227900 TI - Exposures to fine particulate matter (PM2.5) and birthweight in a rural-urban, mother-child cohort in Tamil Nadu, India. AB - BACKGROUND: Exposure to PM2.5 (fine particulate matter =65 years, and higher for men than for women. According to the results of stratified analysis by gender, non-married men exhibited a greater risk of suicide than their married counterparts in all sub-analyses, but women aged 65 years or older showed no significant association between marital status and suicide. The suicide risk in divorced individuals was higher than for non-married individuals in both men and women. The meta-regression showed that gender, age, and sample size affected between-study variation. The results of the study indicated that non-married individuals have an aggregate higher suicide risk than married ones. In addition, gender and age were confirmed as important moderating factors in the relationship between marital status and suicide. PMID- 29227909 TI - Navigating the "No Man's Land" of TKI-Failed EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC): A Review. AB - As the leading cause of cancer-related mortality, lung cancer is a worldwide health issue that is overwhelmingly caused by smoking. However, a substantial minority (~25%) of patients with non-small cell lung cancer (NSCLC) has never smoked. In these patients, activating mutations of the epidermal growth factor receptor (EGFR) are more likely, which render their tumors susceptible for a finite period to treatment with EGFR tyrosine kinase inhibitors (TKIs) and confer a better prognosis than EGFR wild-type NSCLC. On progression, due to the inevitable insurgence of resistance, TKIs are generally followed by second- or third-line salvage chemotherapy until treatment failure, after which no standard treatment options are available, resulting in a poor prognosis and a high risk of death. With the focus of clinical attention on treatment with TKIs, few studies on optimal salvage therapies, including cytotoxic chemotherapy, after failure of EGFR TKIs have been reported. Despite a paucity of available data, the aim of this review is to summarize the "no-man's land" of TKI-failed EGFR-mutated NSCLC and expand on alternative strategies as well as potential future directions. PMID- 29227911 TI - Inhibin-A and inhibin-B in cyclic and pregnant mares, and mares with granulosa theca cell tumors: Physiological and diagnostic implications. AB - Studies in mares have examined serum inhibin concentrations using immuno-assays unable to distinguish dimeric inhibin-A from inhibin-B isoforms. Inhibin-A and inhibin-B immuno-assays were used to investigate concentrations in cyclic mares, young and old (6 vs 19 years old, respectively) mares following hemi-ovariectomy, mares during pregnancy and in mares with confirmed granulosa cell tumors (GCTs). Mares with inter-ovulatory intervals of 26 days had ovulatory peaks of inhibin-A averaging 80 pg/mL with a mid-cycle nadir of 5 pg/mL. Inhibin-A and inhibin-B concentrations were highly correlated (r = + 0.79, P < 0.01) though peak and nadir concentrations of inhibin-B were not significantly different. However, the ratio of inhibin-A to inhibin-B (A/B) changed significantly through the cycle, highest at ovulation and <1 (more inhibin-B than -A) at mid-cycle. Two mares with grossly extended inter-ovulatory intervals demonstrated mid-cycle inhibin-A (and inhibin-B) excursions suggestive of follicular waves. Follicle-stimulating hormone was negatively correlated with inhibin-A and -B concentrations in all 6 mares. Hemi-ovariectomy in young mares resulted in a significant decrease in inhibin-A and inhibin-B concentrations one day later (P < 0.05) but older mares did not, suggesting a possible extra-ovarian source(s) of these hormones. Both inhibin isoforms dropped to very low levels during pregnancy (P < 0.0001), inhibin-A (P < 0.0001) more rapidly than -B (P < 0.05), so that inhibin-B became the predominant measured form throughout most of gestation (P < 0.05). Mares with confirmed GCTs had elevated inhibin-B concentrations more reliably than inhibin-A but neither inhibin-A or -B was correlated with anti-Mullerian hormone concentrations. Collectively, concentrations of inhibin-A and -B were aligned with physiological events in healthy mares, though more pronounced cyclic changes were seen with inhibin-A. Inhibin-B concentrations were significantly associated with GCTs (P < 0.01), inhibin-A concentrations were not. While both inhibin-A and -B concentrations track physiological events such as cyclic follicular activity, only inhibin-B concentrations effectively signal ovarian neoplasia in mares. PMID- 29227912 TI - Annual variations in sexual hormones and births' frequency in female stump-tailed macaques (Macaca arctoides). AB - Although the breeding seasonality in Macaca arctoides have been studied over a long period of time, it is still controversial whether reproduction in this primate tend to increase during certain months of the year as it happens in most of the macaque species. Many authors have classified Macaca arctoides as not being seasonal species. Nonetheless, there were no reports, about seasonal variations of female sexual hormones to demonstrate that asseveration. Therefore, in the present study we collect 1611 fecal samples from June 2009 to November 2010 from 10 female stump-tailed macaques to measure 17beta-estradiol and progesterone concentrations. Also, we included the birth frequency per year, in order to identify if sexual hormones peaked at a certain period of the year, thus, births would be occurring six months later according to the gestation length of stump-tailed macaques. Our results indicate two mating seasons per year in stump-tailed macaques: one in July-August and a second one in November. The distribution of the birth frequency, throughout the year support these results. We conclude that stump-tail macaques have a discrete seasonality no different than most of macaques' species. PMID- 29227913 TI - History in health: health promotion's underexplored tool for change. AB - OBJECTIVES: This paper outlined an argument as to why history and historians should be included in a healthy settings approach. STUDY DESIGN: Qualitative descriptive study. METHODS: A narrative review of the literature across a broad cross-section of history, health promotion and public health disciplines was undertaken. RESULTS: Three reasons for including history were identified relating to the social role of history as a means of analysing social memory, of changing social narratives and by raising social consciousness. This allowed for a distinction between history in health and history of health. Precedents of this social role can be found in the fields of feminist and postcolonial histories, oral history and museums in health. CONCLUSION: Reasons for why historians and health promotion practitioners and researchers have not previously had working relationships were explored, as were some of the factors that would need to be considered for such relationships to work well, including the need to recognise different languages, different understandings of the role of history, and a potential lack of awareness of the health implications of historical work. PMID- 29227914 TI - Design and use of a folded four-ring double-tuned birdcage coil for rat brain sodium imaging at 9.4 T. AB - A folded four-ring quadrature birdcage coil was designed and constructed with a double-tune configuration of an outer high-pass coil for 1H (400 MHz) and inner low-pass coil for 23Na (105.72 MHz at 9.4 T). The coil was evaluated on the bench and in the scanner, comparing its performance with that of single-tuned coils and a large four-ring coil. All coils were tuned and matched and the isolation between two quadrature ports was found to be better than -13.7 dB for 1H and -27 dB for 23Na. Signal-to-noise ratios (SNRs) were calculated and 23Na flip angle maps were acquired. 23Na SNR of the folded four-ring reached ~93% of that obtained with the single-tuned coil. A set of in vivo1H and 23Na axial images to cover the whole rat brain were obtained. The performance of the folded four-ring coil and its benefit for 23Na imaging experiments have been demonstrated. This proposed four-ring coil could avoid length restrictions, e.g. the shoulders, by folding the outer rings vertically. This facilitates the construction of double tuned four-ring birdcage coils just to fit the head, leading to higher filling factors and better SNR. PMID- 29227915 TI - Novel 1,2,4-triazole derivatives as potential anticancer agents: Design, synthesis, molecular docking and mechanistic studies. AB - A series of novel compounds carrying 1,2,4-triazole scaffold was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines using MTT assay. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g showed remarkable antiproliferative activity against the tested cell lines. Compounds 8a, 8b, 8c, 8d, 10b, 10e, and 10 g with the least IC50 values in MTT assay were tested against three known anticancer targets including EGFR, BRAF and Tubulin. The results revealed that compounds 8c and 8d showed almost same BRAF inhibitory activity and were discovered to be potent inhibitors of cancer cell proliferation and were also observed to be strong Tubulin inhibitors. Moreover, 8c also showed the best EGFR inhibition with IC50 = 3.6 MUM. Finally molecular modeling studies were performed to explore the binding mode of the most active compounds to the target enzymes. PMID- 29227916 TI - Development of optimized conditions for Glaser-Hay bioconjugations. AB - The efficient preparation of protein bioconjugates represents a route to novel materials, diagnostics, and therapeutics. We previously reported a novel bioorthogonal Glaser-Hay reaction for the preparation of covalent linkages between proteins and a reaction partner; however, deleterious protein degradation was observed under extended reaction conditions. Herein, we describe the systematic optimization of the reaction to increase coupling efficiency and decrease protein degradation. Two optimized conditions were identified varying either the pH of the reaction or the bidentate ligand employed, allowing for more rapid conjugations and/or less protein oxidation. PMID- 29227917 TI - Design, synthesis, molecular docking of new lipophilic acetamide derivatives affording potential anticancer and antimicrobial agents. AB - Fifteen new substituted N-2-(2-oxo-3-phenylquinoxalin-1(2H)-yl) acetamides 5a-f, 6a-f, and 8a-c were synthesized by reacting ethyl 2-(2-oxo-3-phenylquinoxalin 1(2H)-yl)acetate with various primary amines including benzylamines, sulfonamides, and amino acids. The in vitro antimicrobial screening of the target compounds was screened to assess their antibacterial and antifungal activity. As a result, seven compounds namely; 5a, 5c, 5d, 6a, 6c, 8b and 8c showed a promising broad spectrum antibacterial activity against both Gram-positive and Gram-negative strains. Among these, the analogs 5c and 6d were nearly as equiactive as ciprofloxacin drug. Meanwhile, four compounds namely; 5c, 6a, 6f and 8c exhibited appreciable antifungal activity with MIC values range 33-40 mg/mL comparable with clotrimazole (MIC 25 mg/mL). In addition, the anticancer effects of the synthesized compounds were evaluated against three cancer lines. The data obtained revealed the benzylamines and sulpha derivatives were the most active compounds especially 5f and 6f ones. Further EGFR enzymatic investigation was carried out for these most active compounds 5f and 6f resulting in inhibitory activity by 1.89 and 2.05 uM respectively. Docking simulation was performed as a trial to study the mechanisms and binding modes of these compounds toward the enzyme target, EGFR protein kinase enzyme. The results revealed good compounds placement in the active sites and stable interactions similar to the co crystallized reference ligand. Collectively, the analogs 5f and 6f could be further utilized and optimized as good cytotoxic agents. PMID- 29227918 TI - Synthesis, anti-inflammatory, p38alpha MAP kinase inhibitory activities and molecular docking studies of quinoxaline derivatives containing triazole moiety. AB - A new series of 3-[2-(5-mercapto-4-phenyl-4H-1,2,4-traiazol-3-yl)ethyl] quinoxalin-2(1H)-one (5a-v) derivatives was synthesized and subjected to in vitro evaluation for anti-inflammatory activity (BSA anti-denaturation assay) and p38alpha MAPK inhibition. Few selected compounds (5a, 5e, 5f, 5g, 5h, 5l, 5q and 5u) were studied for their in vivo anti-inflammatory activity, ulcerogenicity and lipid peroxidation potential. Compounds 5e and 5f were found to be the most active in the series showing 83.45% and 84.15% anti-inflammatory activity respectively when compared to diclofenac sodium (83.22%). They were also found to have low ulcerogenic potential and lipid peroxidation. The p38alpha MAP kinase inhibition of the compounds 5e and 5f was also found to be slightly better than the standard SB 203580. The compounds were also docked against p38alpha MAP kinase enzyme in order to predict their binding mode. Compounds 5e and 5f showed stronger binding with an additional hydrogen bond interaction with ASP-168 which was not observed in SB 203580. PMID- 29227919 TI - A subject-specific biomechanical control model for the prediction of cervical spine muscle forces. AB - BACKGROUND: The aim of the present study is to propose a subject-specific biomechanical control model for the estimation of active cervical spine muscle forces. METHODS: The proprioception-based regulation model developed by Pomero et al. (2004) for the lumbar spine was adapted to the cervical spine. The model assumption is that the control strategy drives muscular activation to maintain the spinal joint load below the physiological threshold, thus avoiding excessive intervertebral displacements. Model evaluation was based on the comparison with the results of two reference studies. The effect of the uncertainty on the main model input parameters on the predicted force pattern was assessed. The feasibility of building this subject-specific model was illustrated with a case study of one subject. FINDINGS: The model muscle force predictions, although independent from EMG recordings, were consistent with the available literature, with mean differences of 20%. Spinal loads generally remained below the physiological thresholds. Moreover, the model behavior was found robust against the uncertainty on the muscle orientation, with a maximum coefficient of variation (CV) of 10%. INTERPRETATION: After full validation, this model should offer a relevant and efficient tool for the biomechanical and clinical study of the cervical spine, which might improve the understanding of cervical spine disorders. PMID- 29227920 TI - Efficacy evaluation of electric field frequency and temperature on dielectric properties of collagen cross-linked by glutaraldehyde. AB - Solid-state dielectric properties are reported for unmodified collagen (Col) and glutaraldehyde-modified collagen (Col-GA) over the frequency range from 100Hz to 100kHz and at temperatures from 25 to 145 degrees C. In the full temperature and frequency range the average values of the relative permittivity and dielectric loss for Col samples are higher than those recorded for Col-GA samples. The peak temperature of these both parameters associated with the release of loosely bound water is around 73 and 77 degrees C for Col and Col-GA samples, respectively. The activation energy for the reorientation and breaking of hydrogen bonds takes the values 32kJmol-1 for Col and 23kJmol-1 for Col-GA. The relative permittivity decrement and conductivity increment of Col-GA samples fall by 40 and 30% on average in the temperature range 25-75 degrees C, as compared to Col samples. Dielectric properties of Col-GA may be helpful in designing scaffolds for tissue engineering. PMID- 29227921 TI - Nanoparticulate delivery systems for alkyl gallates: Influence of the elaboration process on particle characteristics, drug encapsulation and in-vitro release. AB - PLA nanoparticles loaded with n-alkyl gallates (AGs) were prepared either by nanoprecipitation (NP) or by O/W emulsion/solvent evaporation (E/SE). A nonionic hydrophobically modified polysaccharide was used for surface coverage and for ensuring colloidal stability. Different parameters were systematically assessed to enhance the drug incorporation, with the aim of obtaining monomodal and narrow particle size distributions. The nanoparticles were characterized by 1H NMR, transmission electron microscopy (TEM) and laser light scattering granulometry. The colloidal stability of suspensions was evaluated after incubation in NaCl solutions and was maintained up to 1M NaCl. The mean particle diameter and the width of size distribution were found very similar for both processes (slightly lower diameters when using E/SE) with various drug loadings. The amount of encapsulated AG by E/SE was about twice that encapsulated by NP. The in-vitro release of AG was evaluated under sink conditions and no burst effect was observed. Release curves were successfully modeled using the Fick diffusion model with a constant diffusion coefficient and assuming non-swellable particles. Diffusion coefficients of AG loaded in nanoparticles prepared by NP were higher than those found in nanoparticles elaborated by E/SE. PMID- 29227922 TI - Evolution of virulence in Enterococcus faecium, a hospital-adapted opportunistic pathogen. AB - Enterococci are long-standing members of the human microbiome and they are also widely distributed in nature. However, with the surge of antibiotic-resistance in recent decades, two enterococcal species (Enterococcus faecalis and Enterococcus faecium) have emerged to become significant nosocomial pathogens, acquiring extensive antibiotic resistance. In this review, we summarize what is known about the evolution of virulence in E. faecium, highlighting a specific clone of E. faecium called ST796 that has emerged recently and spread globally. PMID- 29227923 TI - In vitro leishmanicidal and trypanocidal evaluation and magnetic properties of 7 amino-1,2,4-triazolo[1,5-a]pyrimidine Cu(II) complexes. AB - Two triazolopyrimidine complexes have been obtained from reaction between 7-amino 1,2,4-triazolo[1,5-a]pyrimidine (7atp) and Cu (II) salts. Crystal structures of [Cu2(MU-7atp)4Cl2]Cl2.4H2O (1) and [Cu2(MU-7atp)4(H2O)2](NO3)4.H2O (2) have been studied by X-ray diffraction methods and characterized by spectroscopic and thermal analysis. Magnetic studies of these dinuclear complexes have revealed the existence of moderate antiferromagnetic interactions between the copper ions, with J values of -91.2 and -96.1cm-1 respectively. It must be highlighted that the antiparasitic activity of these new complexes has been studied in vitro against three different strains of leishmania spp. and Trypanosoma cruzi, showing a higher efficacy than the 7atp ligand and the reference commercial drugs. PMID- 29227924 TI - Metal interactions with the transmembrane region of HupE Ni2+ transporter explain its efficiency. AB - Efficient nickel transport is crucial for the survival and virulence of various bacteria and fungi, with Ni2+ being required for the activity of nine enzymes such as [NiFe] hydrogenase, which catalyzes the reversible oxidation of molecular hydrogen for energy production. This work focuses on a region of transmembrane domain I from the HupE nickel transporter, highly conserved in the HupE/UreJ and NiCoT permease families, analyzing its interactions with native Ni2+ and two other metal ions (Cu2+ and Zn2+), which might interfere with nickel binding. Metal coordination sites are pointed out and thermodynamic parameters are discussed in detail. Their comparison to the previously studied periplasmic metal binding region satisfies our chemical curiosity and allows to draw conclusions about HupE metal specificity. The results of this study explain one of the reasons why HupE is a medium-affinity and low-capacity transporter - its periplasmic region, 22HVGLHADGTLAGLN35, binds Ni2+ with much higher affinity than the transmembrane 36HPFSGLDH43 one, which should transport the metal inside the cell. Moreover, the specificity of the transmembrane region is similar to that of the periplasmic one and to that of the full-length HupE - Cu2+ ions are able to outcompete Ni2+. PMID- 29227925 TI - Construction of highly efficient and stable ternary AgBr/Ag/PbBiO2Br Z-scheme photocatalyst under visible light irradiation: Performance and mechanism insight. AB - In this work, the novel ternary AgBr/Ag/PbBiO2Br Z-scheme photocatalysts were synthesized via a CTAB-assisted calcination process. The AgBr/Ag/PbBiO2Br composites were employed for the degradation of rhodamine B (RhB) and antibiotic bisphenol A (BPA) under visible light irradiation. Results showed that the obtained AgBr/Ag-3/PbBiO2Br displayed optimal photocatalytic performance, which could remove almost all RhB within 25 min and effectively decompose 82.3% of BPA in 120 min. Three-dimensional excitation-emission matrix fluorescence spectra (3D EEMs) were utilized for the purposes of fully grasping the behaviors of RhB molecules during the reaction process. Meanwhile, the effects of initial RhB concentration and co-existent electrolytes were investigated from the viewpoint of practical application. In addition, there was no obvious loss in degradation efficiency even after four cycles. The enhanced photocatalytic performances of AgBr/Ag/PbBiO2Br could be credited to the accelerated interfacial charge transfer process and the improved separation of the photogenerated electron-hole pairs. The existence of a small amount of metallic Ag played a significant role in preventing AgBr from being further photocorroded, resulting in the formation of a stable Z-scheme photocatalyst system. This study demonstrated that using metallic Ag as an electron mediator to construct Z-scheme photocatalytic system provided a feasible strategy in promoting the stability of Ag-based semiconductors. PMID- 29227926 TI - Enhanced photocatalytic H2-production activity of C-dots modified g-C3N4/TiO2 nanosheets composites. AB - As a new carbon-based material, carbon dots (C-dots) have got widely preference because of its excellent electronic transfer capability. In this work, a novel ternary layered C-dots/g-C3N4/TiO2 nanosheets (CGT) composite photocatalysts were prepared by impregnation precipitation methods. The optimal ternary CGT composite samples revealed high photocatalytic hydrogen evolution rate in triethanolamine aqueous solutions, which exceeded the rate of the optimal g-C3N4/TiO2 composite sample by a factor of 5 times. The improved photocatalytic activity is owed to the positive effects of C-dots and layered heterojunction structure of TiO2 nanosheets and g-C3N4 sheets. C-dots in the CGT composites can serve as electron reservoirs to capture the photo-induced electrons. The well-defined layered heterojunction structure of CGT provides the intimate contact and the strong interaction of anatase TiO2 nanosheets and g-C3N4 sheets via face-to-face orientation, which restrains the recombination of photogenerated charge carriers, and thus enhances the photocatalytic H2-production activity. Electron paramagnetic resonance and transient photocurrent response proved the strong interaction and improved interfacial charge transfer of TiO2 nanosheets and g C3N4 sheets, respectively. The mechanism of improving the photocatalytic H2 evolution activity was further confirmed by time-resolved fluorescence, electron paramagnetic resonance, transient photocurrent response and electrochemical impedance spectroscopy. PMID- 29227927 TI - New insight into the enhanced visible light-driven photocatalytic activity of Pd/PdCl2-doped Bi2WO6 photocatalysts. AB - A bismuth-based compound, Bi2WO6, was successfully synthesized using a facile hydrothermal method. Aiming to improve its photocatalytic activity under visible light irradiation, Pd/PdCl2 was first doped onto the surface of Bi2WO6 via a photo-reduction method. The prepared Pd/PdCl2-Bi2WO6 samples were characterized based on crystal structures, chemical states, atomic compositions, and morphologies as well as photoabsorption properties. In the screening tests for photocatalytic activity, the 4% Pd-Bi2WO6 sample performed with the highest removal efficiency with respect to the degradation of phenol in wastewater. This sample exhibited better in complete degradation of phenol under visible light irradiation, compared to TiO2 under ultraviolet irradiation. A possible mechanism for the enhanced visible light-driven photocatalytic activity by means of loading Bi2WO6 with Pd was also suggested. This work sheds light on the potential applications of noble metal nanoparticles in visible light-driven photocatalysis. PMID- 29227928 TI - Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease. AB - Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell permeable inhibitors that display anti-norovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography. PMID- 29227929 TI - Green approach for the synthesis of thiophenyl pyrazoles and isoxazoles by adopting 1,3-dipolar cycloaddition methodology and their antimicrobial activity. AB - A variety of N-((1,3-diphenyl-5-aryl-1H-pyrazol-4-yl)sulfonyl)thiophene-2 carboxamides (7) and N-((5-aryl-3-phenylisoxazol-4-yl)sulfonyl)thiophene-2 carboxamides (8) were prepared from (E)-N-(arylethenesulfonyl)thiophene-2 carboxamides (4) adopting 1,3-dipolar cycloaddition of nitrile imines and nitrile oxides generated from araldehyde phenylhydrazones and araldoximes in the presence of iodosobenzene and CTAB followed by oxidation with I2 in DMSO. The compounds 4f, 7e, 7f, 8e and 8f showed potential antibacterial activity against B. subtilis whereas 8e and 8f exhibited potential antifungal activity against A. niger. PMID- 29227930 TI - Synthesis and in vitro evaluation of novel substituted isatin-propylene-1H-1,2,3 triazole-4-methylene-moxifloxacin hybrids for their anti-mycobacterial activities. AB - Twelve novel substituted isatin-propylene-1H-1,2,3-triazole-4-methylene moxifloxacin hybrids 5a-l were designed, synthesized and screened for their in vitro anti-mycobacterial activities against drug-sensitive and multidrug resistant Mycobacterium tuberculosis as well as cytotoxicity in VERO cell line. All hybrids exhibited excellent activities against two Mycobacterium tuberculosis strains with minimum inhibitory concentration in the range from 0.05 to 2.0 MUg/mL. The most active hybrid 5i was 2-8 times more potent than the reference agents (moxifloxacin and rifampicin) in vitro against Mycobacterium tuberculosis H37Rv, while 2->2048 times more potent than the reference agents (moxifloxacin, rifampicin and isoniazid) in vitro against multidrug-resistant Mycobacterium tuberculosis. However, all hybrids (the 50% cytotoxic concentration/CC50: 2-32 MUg/mL) were much more cytotoxic than the parent moxifloxacin (CC50: 128 MUg/mL) against VERO cell line. Therefore, our further optimization will focus on their cytotoxicity reducing as well as activity enhancing. The structure-activity relationship of 1H-1,2,3-triazole-tethered isatin-fluoroquinolone hybrids was investigated, and the results could promote further development of the anti tuberculosis properties of this kind of hybrids. PMID- 29227931 TI - Synthesis and antibacterial evaluation of novel cationic chalcone derivatives possessing broad spectrum antibacterial activity. AB - There is an urgent need to identify new antibiotics with novel mechanisms that combat antibiotic resistant bacteria. Herein, a series of chalcone derivatives that mimic the essential properties of cationic antimicrobial peptides were designed and synthesized. Antibacterial activities against drug-sensitive bacteria, including Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Salmonella enterica, as well as clinical multiple drug resistant isolates of methicillin-resistant S. aureus (MRSA), KPC-2-producing and NDM-1 producing Carbapenem-resistant Enterobacteriaceae were evaluated. Representative compounds 5a (MIC: 1 MUg/mL against S. aureus, 0.5 MUg/mL against MRSA) and 5g (MIC: 0.5 MUg/mL against S. aureus, 0.25 MUg/mL against MRSA) showed good bactericidal activity against both Gram-positive and Gram-negative bacteria, including the drug-resistant species MRSA, KPC and NDM. These membrane-active antibacterial compounds were demonstrated to reduce the viable cell counts in bacterial biofilms effectively and do not induce the development of resistance in bacteria. Additionally, these representative molecules exhibited negligible toxicity toward mammalian cells at a suitable concentration. The combined results indicate that this series of cationic chalcone derivatives have potential therapeutic effects against bacterial infections. PMID- 29227932 TI - An overview of natural antimicrobials role in food. AB - The present paper aims to review the natural food preservatives with antimicrobial properties emphasizing their importance for the future of food manufacturing and consumers' health. The extraction procedures applied to natural antimicrobials will be considered, followed by the description of some natural preservatives' antimicrobial mechanism of action, including (i) membrane rupture with ATP-ase activity inhibition, (ii) leakage of essential biomolecules from the cell, (iii) disruption of the proton motive force and (iiii) enzyme inactivation. Moreover, a provenance-based classification of natural antimicrobials is discussed by considering the sources of origin for the major natural preservative categories: plants, animals, microbes and fungi. As well, the structure influence on the antimicrobial potential is considered. Natural preservatives could also constitute a viable alternative to address the critical problem of microbial resistance, and to hamper the negative side effects of some synthetic compounds, while meeting the requirements for food safety, and exerting no negative impact on nutritional and sensory attributes of foodstuffs. PMID- 29227933 TI - Synthesis, biological evaluation, and metabolic stability of phenazine derivatives as antibacterial agents. AB - Drug-resistant pathogens are a major cause of hospital- and community-associated bacterial infections in the United States and around the world. These infections are increasingly difficult to treat due to the development of antibiotic resistance and the formation of bacterial biofilms. In the paper, a series of phenazines were synthesized and evaluated for their in vitro antimicrobial activity against Gram positive (methicillin resistant staphylococcus aureus, MRSA) and Gram negative (Escherichia coli, E. coli) bacteria. The compound 6,9 dichloro-N-(methylsulfonyl)phenazine-1-carboxamide (18c) proved to be the most active molecule (MIC = 16 MUg/mL) against MRSA whereas 9-methyl-N (methylsulfonyl)phenazine-1-carboxamide (30e) showed good activity against both MRSA (MIC = 32 MUg/mL) and E. coli (MIC = 32 MUg/mL). Molecule 18c also demonstrated significant biofilm dispersion and inhibition against S. aureus. Preliminary studies indicate the molecules do not disturb bacterial membranes and there activity is not directly linked to the generation of reactive oxygen species. Compound 18c displayed minor toxicity against mammalian cells. Metabolic stability studies of the most promising compounds indicate stability towards phase I and phase II metabolizing enzymes. PMID- 29227934 TI - GABAA receptor activity modulating piperine analogs: In vitro metabolic stability, metabolite identification, CYP450 reaction phenotyping, and protein binding. AB - In a screening of natural products for allosteric modulators of GABAA receptors (gamma-aminobutyric acid type A receptor), piperine was identified as a compound targeting a benzodiazepine-independent binding site. Given that piperine is also an activator of TRPV1 (transient receptor potential vanilloid type 1) receptors involved in pain signaling and thermoregulation, a series of piperine analogs were prepared in several cycles of structural optimization, with the aim of separating GABAA and TRPV1 activating properties. We here investigated the metabolism of piperine and selected analogs in view of further cycles of lead optimization. Metabolic stability of the compounds was evaluated by incubation with pooled human liver microsomes, and metabolites were analyzed by UHPLC-Q-TOF MS. CYP450 isoenzymes involved in metabolism of compounds were identified by reaction phenotyping with SilensomesTM. Unbound fraction in whole blood was determined by rapid equilibrium dialysis. Piperine was the metabolically most stable compound. Aliphatic hydroxylation, and N- and O-dealkylation were the major routes of oxidative metabolism. Piperine was exclusively metabolized by CYP1A2, whereas CYP2C9 contributed significantly in the oxidative metabolism of all analogs. Extensive binding to blood constituents was observed for all compounds. PMID- 29227935 TI - Hematite (alpha-Fe2O3) - A potential Ce4+ carrier in red mud. AB - Cerium is the most abundant rare earth element (REE) within the waste product of alumina production (red mud), but its speciation in this complex material is still barely understood. Previous studies showed evidence for a correlation between Ce and the main constituent of red mud, iron oxides, which led us to investigate the most abundant iron oxide in red mud, hematite, as possible carrier phase for Ce. Synthetic hematite can incorporate up to 1.70+/-0.01wt% Ce, which leads to a systematical increase of all unit cell parameters. Investigations by extended X-ray absorption fine structure spectroscopy suggest an incorporation of Ce4+O6 into the hematite structure by a novel atomic arrangement, fundamentally different from the close-range order around Fe3+ in hematite. Samples of red mud were taken in Lauta (Saxony), Germany and analyzed by powder X-ray diffraction, inductively coupled plasma mass and optical emission spectrometry, electron microprobe analysis and X-ray absorption near-edge structure spectroscopy. Red mud samples consist of hematite (Fe2O3) (34-58wt%), sodalite (Na8Al6Si6O24Cl2) (4-30wt%), gibbsite (Al(OH)3) (0-25wt%), goethite (FeOOH) (10-23wt%), bohmite (AlOOH) (0-11wt%), rutile (TiO2) (4-8wt%), cancrinite (Na6Ca2Al6Si6O24(CO3)2) (0-5wt%), nordstrandite (Al(OH)3) (0-5wt%) and quartz (SiO2) (0-4wt%). While the main elemental composition is Fe>Al>Na>Ti>Ca (Si not included), the average concentration of REE is 1109+/-6mg/kg with an average Ce concentration of 464+/-3mg/kg. The main carrier of Ce was located in the Fe-rich fine-grained fraction of red mud (0.10wt% Ce2O3), while other potential Ce carriers like monazite, lead oxides, secondary Ce-minerals and particles of potentially anthropogenic origin are of subordinated relevance. Cerium in red mud occurs predominantly as Ce4+, which further excludes Ce3+ minerals as relevant sources. PMID- 29227936 TI - Application of fuzzy c-means clustering to PRTR chemicals uncovering their release and toxicity characteristics. AB - Increasing manufacture and usage of chemicals have not been matched by the increase in our understanding of their risks. Pollutant release and transfer register (PRTR) is becoming a popular measure for collecting chemical data and enhancing the public right to know. However, these data are usually in high dimensionality which restricts their wider use. The present study partitions Japanese PRTR chemicals into five fuzzy clusters by fuzzy c-mean clustering (FCM) to explore the implicit information. Each chemical with membership degrees belongs to each cluster. Cluster I features high releases from non-listed industries and the household sector and high environmental toxicity. Cluster II is characterized by high reported releases and transfers from 24 listed industries above the threshold, mutagenicity, and high environmental toxicity. Chemicals in cluster III have characteristics of high releases from non-listed industries and low toxicity. Cluster IV is characterized by high reported releases and transfers from 24 listed industries above the threshold and extremely high environmental toxicity. Cluster V is characterized by low releases yet mutagenicity and high carcinogenicity. Chemicals with the highest membership degree were identified as representatives for each cluster. For the highest membership degree, half of the chemicals have a value higher than 0.74. If we look at both the highest and the second highest membership degrees simultaneously, about 94% of the chemicals have a value higher than 0.5. FCM can serve as an approach to uncover the implicit information of highly complex chemical dataset, which subsequently supports the strategy development for efficient and effective chemical management. PMID- 29227937 TI - Identify stakeholders' understandings of life cycle assessment results on wastewater related issues. AB - To facilitate decision-making processes in waste management, it is important to not only evaluate environmental impacts, but also to measure how stakeholders form opinions and make choices based one valuation results. Life cycle assessments (LCAs) have been widely used to evaluate environmental impacts; however, LCAs cannot be used to measure how people make judgments based on evaluation results. As such, in this study, we combined LCA with conjoint analysis, an economic method that allows individuals to consider all factors and demonstrate their preferences simultaneously. We used this combined method in a case study on wastewater treatment, and obtained two major types of estimation results: (1) the relative importance of each impact category of LCA, and (2) the overall preferences of respondents for each alternative. This study also highlighted some issues regarding the combination of methodologies, such as the selection of impact categories in LCA, the conversion of impact categories into understandable attributes for conjoint analysis, and weaknesses in conjoint analysis that need to be addressed and corrected in future studies. PMID- 29227939 TI - Influence of a large urban park on the local urban thermal environment. AB - Green areas in the city can greatly improve the outdoor thermal environment, as well as mitigate the urban heat island effect by reducing summer air temperature. In a context of climate change, with the expected increase in temperature and intensity of heat waves, cooling by green areas is set to become increasingly important. In this study, field observations were carried out to investigate the thermal performance of a large urban vegetated park and its influence on thermal environment of the surrounding urban areas in Beijing, China. Measurements were conducted along a selected path during three summer days with clear skies and light winds by mobile traverses. The results showed that the park was cooler than the surrounding urban areas both during the daytime and at night. The mean air temperature differences between the park and the surrounding areas were in the range of 0.6-2.8 degrees C at different times, with a maximum of 4.8 degrees C observed at midnight. The results also found that as the distance from the park border increased, the ambient air temperature exhibited a gradually increasing trend. This indicated the park has a cooling effect on the urban environments adjacent to the park, and this cooling effect extended approximately 1.4km from the park boundary. The air temperature variations also depended strongly on the land cover characterizing the immediate environment of the measurement sites. Increasing the percent vegetation cover could significantly decrease air temperature, while the increase of percent impervious surface area would significantly increase it. PMID- 29227938 TI - The cumulative effect of air pollutants on the acute exacerbation of COPD in Shanghai, China. AB - BACKGROUND: Epidemiologic studies have shown the effect of air pollutants on acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, little is known regarding the dose-response relationship. This study aimed to investigate the cumulative effect of air pollutants on AECOPD. METHODS: We collected 101 patients with AECOPD from November 2010 through August 2011 in Shanghai. Multiple logistic regression was used to estimate associations between air pollutants and AECOPD. Poisson regression was then applied to determine the cumulative effect of air pollutants including particulate matter 10 (PM10), PM2.5, nitrogen dioxide (NO2), sulphur dioxide (SO2) and ozone (O3) on AECOPD, of which the seasonal variation was further explored. RESULTS: The monthly episodes of AECOPD were associated with the concentrations of PM2.5 (r=0.884, p<0.05) and NO2 (r=0.763, p<0.05). The cutoff value of PM2.5 and NO2 for predicting AECOPD was 83.0MUg/m3 and 53.5MUg/m3, respectively. It showed that per 10MUg/m3 increment in PM2.5 increased the relative risks (RR) for AECOPD was 1.09 with 3days cumulative effect in cold season, whereas 7days in warm season. The RR for AECOPD for per 10MUg/m3 increment in NO2 was 1.07, with a 5-day cumulative effect without seasonal variation. CONCLUSIONS: High consecutive levels of PM2.5 and NO2 increase the risk of developing AECOPD. Cumulative effect of PM2.5 and NO2 appears before the exacerbation onset. These gradations were more evident in the PM2.5 during different seasons. PMID- 29227940 TI - Use of magnetic biochars for the immobilization of heavy metals in a multi contaminated soil. AB - Modified biochars, including magnetic biochars, have been tested in water for the removal of inorganic pollutants. However, at present it is unknown if they possess benefits over conventional biochar materials in relation to land remediation. A paddy soil was collected near Liantang village in Lechang Pb-Zn mine area in Guangdong Province (China). The soil was polluted with Cd, Cu, Zn and Pb, with total contents of 1.4mg/kg, 80mg/kg, 1638mg/kg and 2463mg/kg, respectively. We prepared magnetic and conventional biochar from two feedstocks (poultry litter and Eucalyptus) at a temperature of 300 and 500 degrees C. A sequential extraction procedure for the speciation of heavy metals and a phytotoxicity test using rice were performed. Acid-soluble Cd in soils amended with PLB was 8 to 10% lower than in the control polluted soil. This figure was 27 to 29% for acid-soluble Zn and 59 to 63% for acid-soluble Cu. In some cases, differences were found between the heavy metal fractionation in samples amended with magnetic and conventional biochars. Plant biomass was unaffected by most treatments, but increased by 32% in the treatments containing magnetic poultry litter biochar. Our study shows that a careful choice of feedstock is of utmost importance for successful containment of heavy metals in a multi-contaminated mining area soil. An appropriate choice of feedstock (in the case of this study poultry litter vs. eucalyptus) was more determinant with respect to the mobility of pollutants than altering pyrolysis temperature or modifying surface properties through magnetization. However, surface modification through magnetization can have a significant impact on plant yield and offer comparative advantages in the management of some degraded landscapes. PMID- 29227941 TI - Extractive waste management: A risk analysis approach. AB - Abandoned mine sites continue to present serious environmental hazards because the heavy metals associated with extractive waste are continuously released into the environment, where they threaten human life and the environment. Remediating and securing extractive waste are complex, lengthy and costly processes. Thus, in most European countries, a site is considered for intervention when it poses a risk to human health and the surrounding environment. As a consequence, risk analysis presents a viable decisional approach towards the management of extractive waste. To evaluate the effects posed by extractive waste to human health and groundwater, a risk analysis approach was used for an abandoned nickel extraction site in Campello Monti in North Italy. This site is located in the Southern Italian Alps. The area consists of large and voluminous mafic rocks intruded by mantle peridotite. The mining activities in this area have generated extractive waste. A risk analysis of the site was performed using Risk Based Corrective Action (RBCA) guidelines, considering the properties of extractive waste and water for the properties of environmental matrices. The results showed the presence of carcinogenic risk due to arsenic and risks to groundwater due to nickel. The results of the risk analysis form a basic understanding of the current situation at the site, which is affected by extractive waste. PMID- 29227942 TI - The interaction between bacterial abundance and selected pollutants concentration levels in an arctic catchment (southwest Spitsbergen, Svalbard). AB - Persistent organic pollutants (POPs) have been a topic of interest in environmental sciences for >60years. POPs in the Arctic have been investigated since the 1970s, when first atmospheric measurements revealed the presence of these pollutants in the polar regions. Major contaminant transport routes to the Arctic include atmospheric and oceanic transport, as well as inflow from rivers and sea ice. The sources of pollutants, such as industry, power generators, vehicle and ship exhausts, introduce the PAHs, phenols, formaldehyde or metals into the Arctic. Transport via sea currents, however, can take several years. The highest concentration levels of total PAHs were observed in two samples from the tributaries in July 2015 and were 1069ngL-1 and 3141ngL-1 and in September 2015, the highest concentrations were observed in samples collected from Revvatnet lake and were 978ngL-1 and 1823ngL-1. The highest concentrations of trace elements in both months were 41MUgL-1 in the sample from the highest tributary (July 2015) and 79MUgL-1 in the same sample (September 2015). The purpose of this study was also to determine abundance of bacteria in the Arctic freshwater of different types. Microbes are omnipresent and represent diverse biological communities. In the freshwater ecosystems, microorganisms form the base of the food chain supporting higher trophic levels. Although microbes are generally thought to live in the warm regions of Earth, many of them develop in cold climates. In the Revelva catchment, the biggest number of bacteria were detected at the river estuary in July 2015 and at the sampling point located in the Revvatnet lake in September 2015. Generally, the bacterial abundance indices depended on nutrient levels to a small extent, showing the environment of the Revelva catchment not to be nutrient limited, which is in accordance with its rich biological life also in macroscale. PMID- 29227943 TI - Liver and fecal samples suggest differential exposure of red fox (Vulpes vulpes) to trans- and cis-bromadiolone in areas from France treated with plant protection products. PMID- 29227944 TI - Effects of starch-coating of magnetite nanoparticles on cellular uptake, toxicity and gene expression profiles in adult zebrafish. AB - Engineered magnetite nanoparticles (Fe3O4 NPs) have been used in many fields. To prevent particle agglomeration, stabilizers or coatings are often required. While such coatings have been shown to enhance performances, the environmental impact or toxicity of stabilized or coated Fe3O4 NPs remain poorly understood. In an effort to understand the impacts of such coatings on the toxicity of Fe3O4 NPs, we used the transcriptome sequencing (RNA-seq) technique to characterize the gill and liver transcriptomes from adult zebrafish when exposed to bare and starch stabilized Fe3O4 NPs for 7days, demonstrating remarkable differences in gene expression profiles, also known as differentially expressed genes (DEGs) profiles, in both tissues. Bare Fe3O4 NPs exerted greater toxicity than starch coated Fe3O4 NPs in gill; in contrast, starch-Fe3O4 NPs triggered more severe damage on liver, though both bare and stabilized NPs appeared to share similar regulatory mechanisms. Quantitative real-time polymerase chain reactions using six genes each for the two tissues verified the RNA-seq results. The surface coatings play an important role in determining the nanoparticle toxicity, which in turn modulate cell uptake and biological responses, consequently impacting the potential safety and efficacy of nanomaterials. PMID- 29227945 TI - A new framework proposal, towards a common EU agricultural policy, with the best sustainable practices for the re-use of olive mill wastewater. AB - The disposal of olive mill wastewater (OMW) is a serious environmental issue for the Mediterranean countries. However, there is still no common European legislation on the management and the re-use of OMW in agriculture, in the frame of sustainable crop management and the standards for the safe OMW disposal and re use are left to be set by each EU country, individually. This review paper presents the most effective and sustainable practices for OMW, (treatment, application and management), which can maximize the benefits of OMW on crops and soils, while minimizing the potential hazards for public health, thus promoting environmental sustainability. The findings of this synthetic work suggest that there is enough information and proven sustainable practices to go ahead with the initial formulation of a new consensual framework, environmentally acceptable, socially bearable and economically viable, that could hopefully help to set the standards for the re-use of olive mil wastewater and can lead to a common EU policy on the management and re-use of OMW. PMID- 29227946 TI - Cross-disciplinary links in environmental systems science: Current state and claimed needs identified in a meta-review of process models. AB - Terrestrial environmental systems are characterised by numerous feedback links between their different compartments. However, scientific research is organized into disciplines that focus on processes within the respective compartments rather than on interdisciplinary links. Major feedback mechanisms between compartments might therefore have been systematically overlooked so far. Without identifying these gaps, initiatives on future comprehensive environmental monitoring schemes and experimental platforms might fail. We performed a comprehensive overview of feedbacks between compartments currently represented in environmental sciences and explores to what degree missing links have already been acknowledged in the literature. We focused on process models as they can be regarded as repositories of scientific knowledge that compile findings of numerous single studies. In total, 118 simulation models from 23 model types were analysed. Missing processes linking different environmental compartments were identified based on a meta-review of 346 published reviews, model intercomparison studies, and model descriptions. Eight disciplines of environmental sciences were considered and 396 linking processes were identified and ascribed to the physical, chemical or biological domain. There were significant differences between model types and scientific disciplines regarding implemented interdisciplinary links. The most wide-spread interdisciplinary links were between physical processes in meteorology, hydrology and soil science that drive or set the boundary conditions for other processes (e.g., ecological processes). In contrast, most chemical and biological processes were restricted to links within the same compartment. Integration of multiple environmental compartments and interdisciplinary knowledge was scarce in most model types. There was a strong bias of suggested future research foci and model extensions towards reinforcing existing interdisciplinary knowledge rather than to open up new interdisciplinary pathways. No clear pattern across disciplines exists with respect to suggested future research efforts. There is no evidence that environmental research would clearly converge towards more integrated approaches or towards an overarching environmental systems theory. PMID- 29227947 TI - Virtual water trade of agricultural products: A new perspective to explore the Belt and Road. AB - The Belt and Road is an initiative of cooperation and development that was proposed by China. Moreover, most of the spanning countries faced water shortages and agriculture consumed a lot of water. Virtual water links water, food and trade and is an effective tool to ease water shortages. Therefore, this paper aims to understand the Belt and Road from the new perspective of virtual water trade of agricultural products. We considered agricultural products trade from 2001 to 2015. On the whole, the results indicated that China was in virtual water trade surplus with the countries along the Belt and Road. However, in terms of each country, >40 spanning countries were in virtual water trade surplus with China and eased water shortages. Russia had the largest net imported virtual water from China. Furthermore, the proportion of the grey water footprint that China exported to the spanning countries was much higher than that imported, no matter from the whole or different geographical regions. Moreover, more than half of the countries' virtual water trade with China conformed to the virtual water strategy, which helped to ease water crises. Furthermore, the products that they exported to China were mainly advantageous products that each spanning countries have. Virtual water trade is a new perspective to explore the Belt and Road. Agricultural products trade with China definitely benefits both the countries along the Belt and Road and China from the perspective of virtual water. The findings are beneficial for the water management of the countries along the Belt and Road and China, alleviating water shortages, encouraging the rational allocation of water resources in the various departments. They can provide references for optimizing trade structures as well. PMID- 29227948 TI - Points of attention in designing tools for regional brownfield prioritization. AB - The regeneration of brownfields has been increasingly recognized as a key instrument in sustainable land management, since free developable land (or so called "greenfields") has become a scare and more expensive resource, especially in densely populated areas. However, the complexity of these sites requires considerable efforts to successfully complete their revitalization projects, thus requiring the development and application of appropriate tools to support decision makers in the selection of promising sites where efficiently allocate the limited financial resources. The design of effective prioritization tools is a complex process, which requires the analysis and consideration of critical points of attention (PoAs) which has been identified considering the state of the art in literature, and lessons learned from previous developments of regional brownfield (BF) prioritization processes, frameworks and tools. Accordingly, we identified 5 PoAs, namely 1) Assessing end user needs and orientation discussions, 2) Availability and quality of the data needed for the BF prioritization tool, 3) Communication and stakeholder engagement 4) Drivers of regeneration success, and 5) Financing and application costs. To deepen and collate the most recent knowledge on the topics from scientists and practitioners, we organized a focus group discussion within a special session at the AquaConSoil (ACS) conference 2017, where participants were asked to add their experience and thoughts to the discussion in order to identify the most significant and urgent points of attention in BF prioritization tool design. The result of this assessment is a comprehensive table (Table 2), which can support problem owners, investors, service providers, regulators, public and private land managers, decision makers etc. in the identification of the main aspects (sub topics) to be considered and their relative influences and in the comprehension of the general patterns and challenges to be faced when dealing with the development of BF prioritization tools. PMID- 29227949 TI - A CBL-interacting protein kinase TaCIPK27 confers drought tolerance and exogenous ABA sensitivity in transgenic Arabidopsis. AB - Drought is one of the major environmental stresses to plants. The calcium sensor, calcineurin B-like (CBL) proteins, and their interacting protein kinases (CIPK) play important roles in responding to abiotic stresses. In this study, we functionally characterized a CIPK gene from Triticum aestivum designated TaCIPK27. The transcriptional levels of TaCIPK27 were increased both in roots and leaves after treatment with polyethylene glycol 8000, abscisic acid and H2O2. Besides, TaCIPK27 interacted with AtCBL1, AtCBL3, AtCBL4, AtCBL5 and AtCBL9 in yeast two-hybrid assays. Ectopic overexpression of TaCIPK27 positively regulates drought tolerance in transgenic Arabidopsis compared with controls, which was demonstrated by seed germination and survival rates experiments, as well as the detection of physiological indices including ion leakage, malonic dialdehyde and H2O2 contents and antioxidant enzyme activities under normal and drought conditions. Moreover, higher concentration of endogenous abscisic acid was detected under drought in TaCIPK27 transgenic plants. In addition, TaCIPK27 transgenic plants were more sensitive to exogenous abscisic acid treatment at seed germination and seedling stage. The expression levels of somedrought stress and abscisic acid related genes were up-regulated in TaCIPK27 transgenic plants. The results suggest that TaCIPK27 functions as a positive regulator under drought partly in an ABA-dependent pathway. PMID- 29227950 TI - Transcriptome sequencing of Paeonia suffruticosa 'Shima Nishiki' to identify differentially expressed genes mediating double-color formation. AB - Paeonia suffruticosa 'Shima Nishiki' is one of extremely rare double-color cultivars in the world. It usually shows the two beautiful colors of red and white in the same flower, and this trait undoubtedly makes the flowers more charming for the ornamental market. However, few studies have been done to unravel the molecular mechanisms of double-color formation in P. suffruticosa 'Shima Nishiki'. In this study, we measured the anthocyanin composition and concentration, and sequenced the transcriptomes of the red and white petals. We found that the total content of Pg-based glycosides was at a significantly higher level in the red petals. Furthermore, we assembled and annotated 92,671 unigenes. Comparative analyses of the two transcriptomes showed 227 differentially expressed genes (DEGs), among which 57 were up-regulated, and 170 were down regulated in the red petals. Subsequently, we identified 3 DEGs and the other 6 structural genes in the anthocyanin biosynthetic pathway including PsCHS, PsCHI, PsF3H, PsF3'H, PsDFR, PsANS, PsAOMT, PsMYB, and PsWD40. Among them, PsDFR and PsMYB expressed at a significantly higher level and showed positive correlations between their expression and anthocyanin concentration in the red petals. However, PsWD40 expressed at a significantly lower level and exhibited an inverse relationship in the red petals. Furthermore, we further confirmed the relative expression of the 9 candidate genes using quantitative real-time PCR. Based on the above results, we concluded that the significant differential expression of PsDFR, PsMYB and PsWD40 may play a key role in anthocyanin concentration in the red and white petals, thereby mediating double-color formation. These data will provide a valuable resource to better understand the molecular mechanisms of double-color formation of P. suffruticosa 'Shima Nishiki'. PMID- 29227951 TI - Transcriptome analysis reveals novel genes involved in anthocyanin biosynthesis in the flesh of peach. AB - Peach is an important deciduous fruit tree species. Anthocyanins play an important role in fruit color formation and, through linkage analysis, previous studies have identified and mapped the key genes regulating anthocyanins' accumulation to chromosomes 3 and 5 in two different germplasms. To understand the overall regulatory network of anthocyanins biosynthesis, genes co-expressed with these key genes were identified in the red-fleshed 'Tianjin Shui Mi' and white-fleshed 'Hakuho' germplasms. Analysis of their flesh anthocyanin contents revealed differences 15 days before maturation. Therefore, transcriptome analysis of the flesh of fruits belonging to these two germplasms was performed to search for genes that were up-regulated at the late stage of development of 'Tianjin Shui Mi' but not of 'Hakuho', and identified 183 genes. These genes were also analyzed in the flesh transcriptomes of peach fruits belonging to 30 peach varieties with different anthocyanin contents at maturation, and the Pearson's correlation coefficients between their expression levels and anthocyanin contents were determined. The results showed that 66 genes were significantly correlated to anthocyanin contents, most of which previously reported as regulatory, biosynthetic, and transporter genes involved in anthocyanins' regulatory network. The results of this study enrich the understanding of key genes involved in the biological pathway regulating anthocyanins biosynthesis. The genes mostly associated with anthocyanins biosynthesis presented in this study are of great importance for molecular marker-assisted breeding. PMID- 29227952 TI - Public health risk of trace metals in fresh chicken meat products on the food markets of a major production region in southern China. AB - Because most chickens are reared in intensive farms, where a range of feed additives are used routinely, concerns have been raised on the potential public health risk of chicken product consumption. This study was conducted to characterize the contents of trace metals in fresh chicken tissues (354 samples) on the food markets in Guangdong province of southern China, a major region of chicken production with heavy per capita chicken consumption, and to assess the public health risk from chronic dietary exposure to the trace metals through chicken consumption. With the exception of Cr, Ni, and Pb, the contents of trace metals were generally higher in the chicken giblets (livers, gizzards, hearts, and kidneys) compared to muscles (breasts and drumsticks). Chicken tissues from the urban markets generally contained higher levels of As, Cu, Mn, and Zn than those from the rural markets, while the contents of Pb were typically higher in the chicken muscles from the rural markets. Results of statistical analyses indicate that Cu, Zn, and As in the chicken tissues derived mainly from the feeds, which is consistent with the widespread use of Cu, Zn, and phenylarsenic compounds as feed supplements/additives in intensive poultry farming. No non carcinogenic risk is found with the consumption of fresh chicken meat products on the food markets, while approximately 70% of the adult population in Guangzhou and 30% of those in Lianzhou have bladder and lung cancer risk above the serious or priority level (10-4), which arises from the inorganic arsenic contained in the chicken tissues. These findings indicate that the occurrence of inorganic arsenic at elevated levels in chicken tissues on the food markets in Guangdong province poses a significant public health risk, thus the use of phenylarsenic feed additives in China's poultry farming should be significantly reduced and eventually phased out. PMID- 29227953 TI - Preparation of thiol-functionalized activated carbon from sewage sludge with coal blending for heavy metal removal from contaminated water. AB - Sewage sludge produced from wastewater treatment is a pressing environmental issue. Mismanagement of the massive amount of sewage sludge would threat our valuble surface and shallow ground water resources. Use of activated carbon prepared from carbonization of these sludges for heavy metal removal can not only minimize and stabilize these hazardous materials but also realize resources reuse. In this study, thiol-functionalized activated carbon was synthesized from coal-blended sewage sludge, and its capacity was examined for removing Cu(II), Pb(II), Cd(II) and Ni(II) from water. Pyrolysis conditions to prepare activated carbons from the sludge and coal mixture were examined, and the synthesized material was found to achieve the highest BET surface area of 1094 m2/g under 500 degrees C and 30 min. Batch equilibrium tests indicated that the thiol functionalized activated carbon had a maximum sorption capacity of 238.1, 96.2, 87.7 and 52.4 mg/g for Pb(II), Cd(II), Cu(II) and Ni(II) removal from water, respectively. Findings of this study suggest that thiol-functionalized activated carbon prepared from coal-blended sewage sludge would be a promising sorbent material for heavy metal removal from waters contaminated with Cu(II), Pb(II), Cd(II) and Ni(II). PMID- 29227954 TI - Impact of water chemistry on the behavior and fate of copper nanoparticles. AB - A full-factorial test design was applied to systematically investigate the contribution and significance of water chemistry parameters (pH, divalent cations and dissolved organic carbon (DOC) concentration) and their interactions on the behavior and fate of copper nanoparticles (CuNPs). The total amount of Cu remaining in the water column after 48 h of incubation was mostly influenced by divalent cation content, DOC concentration and the interaction of divalent cations and DOC. DOC concentration was the predominant factor influencing the dissolution of CuNPs, which was far more important than the effect of pH in the range from 6 to 9 on the dissolution of the CuNPs. The addition of DOC at concentrations ranging from 5 to 50 mg C/L resulted in a 3-5 fold reduction of dissolution of CuNPs after 48 h of incubation, as compared to the case without addition of DOC. Divalent cation content was found to be the most influential factor regarding aggregation behavior of the particles, followed by DOC concentration and the interaction of divalent cations and DOC. In addition, the aggregation behavior of CuNPs rather than particulate dissolution explained most of the variance in the sedimentation profiles of CuNPs. These results are meaningful for improved understanding and prediction of the behavior and fate of metallic NPs in aqueous environments. PMID- 29227955 TI - Developing and validating a perinatal depression screening tool in Kenya blending Western criteria with local idioms: A mixed methods study. AB - BACKGROUND: Routine screening for perinatal depression is not common in most primary health care settings. The U.S. Preventive Services Task Force only recently updated their recommendation on depression screening to specifically recommend screening during the pre- and postpartum periods. While practitioners in high-income countries can respond to this new recommendation by implementing one of several existing depression screening tools developed in Western contexts, such as the Edinburgh Postnatal Depression Scale (EPDS) or the Patient Health Questionnaire-9 (PHQ-9), these tools lack strong evidence of cross-cultural equivalence, validity for case finding, and precision in measuring response to treatment in developing countries. Thus, there is a critical need to develop and validate new screening tools for perinatal depression that can be used by lay health workers, primary health care personnel, and patients. METHODS: Working in rural Kenya, we used free listing, card sorting, and item analysis methods to develop a locally-relevant screening tool that blended Western psychiatric concepts with local idioms of distress. We conducted a validation study with a random sample of 193 pregnant women and new mothers to test the diagnostic accuracy of this scale along with the EPDS and PHQ-9. RESULTS: The sensitivity/specificity of the EPDS and PHQ-9 was estimated to be 0.70/0.72 and 0.70/0.73, respectively. This compared to sensitivity/specificity of 0.90/0.90 for a new 9-item locally-developed tool called the Perinatal Depression Screening (PDEPS). Across these three tools, internal consistency reliability ranged from 0.77 to 0.81 and test-retest reliability ranged from 0.57 to 0.67. The prevalence of depression ranges from 5.2% to 6.2% depending on the clinical reference standard. CONCLUSION: The EPDS and PHQ-9 are valid and reliable screening tools for perinatal depression in rural Western Kenya, the PDEPS may be a more useful alternative. At less than 10%, the prevalence of depression in this region appears to be lower than other published estimates for African and other low income countries. PMID- 29227956 TI - Different beta-alanine dimeric forms in trifluoromethanesulfonic acid salts. XRD and vibrational studies. AB - Two new crystalline salts: beta-alaninium trifluoromethanesulfonate (beta-AlaOTf) and bis(beta-alanine) trifluoromethanesulfonate (beta-2AlaOTf) were obtained. The former one contains diprotonated beta-alanine dimer, the latter one monoprotonated beta-alanine dimer. Both compounds were studied by single crystal XRD, vibrational (IR and Raman) spectroscopy and calorimetric method. The quantum mechanical calculations (DFT/B3LYP/6-311++G(2d,2p)) for the diprotonated dimer were carried out. The beta-AlaOTf salt crystallizes in the P1- space group of triclinic system (Z=2), the beta-2AlaOTf in the P21/m space group of monoclinic system (Z=2). The vibrational data for the studied compounds are discussed in relation to their crystal structure, and provide insight into the character of hydrogen bonds and beta-alanine protonation. The studied crystals do not exhibit phase transitions in the solid state. PMID- 29227957 TI - Synergistic cytotoxicity and mechanism of caffeine and lysozyme on hepatoma cell line HepG2. AB - The influences of caffeine, lysozyme and the joint application of them on the hepatoma cell line HepG2 proliferation inhibition and cell apoptosis were observed by 3-(4, 5-dimethyl-2-thiazyl)-2, 5-diphenyl-2H-tetrazolium bromide assay and Hoechst 33342, which showed the proliferation inhibition rate of the joint application on HepG2 cells was 47.21%, significantly higher than caffeine or lysozyme, and the joint application promoted the apoptosis of HepG2 cells obviously. Van't Hoff classical thermodynamics formula, the Foster theory of non radiation energy transfer and fluorescence phase diagram were used to manifest that the process of lysozyme binding to caffeine followed a two-state model, which was spontaneous at low temperature driven by enthalpy change, and the predominant intermolecular force was hydrogen bonding or Van der Waals force to stabilize caffeine-lysozyme complex with the distance 5.86nm. The attenuated total reflection-Fourier transform infrared spectra indicated that caffeine decreased the relative contents of alpha-helix and beta-turn, which inferred the structure of lysozyme tended to be "loose". Synchronous fluorescence spectra and ultraviolet spectra supported the above conclusion. The amino acid residues in the cleft of lysozyme were exposed and electropositivity was increased attributing to the loose structure, which were conducive to increasing caffeine concentration on the HepG2 cell surface by electrostatic interaction to show synergistic effect. PMID- 29227959 TI - Cyberbullying among adults with intellectual disabilities: Some preliminary data. AB - BACKGROUND: Recent studies show that youth with disabilities are at risk of experiencing cyberbullying. Nevertheless, the nature of this phenomenon among adults with intellectual disabilities has not been investigated. Therefore, the purpose of this study is to analyze the frequency and characteristics of cyberbullying and its correlates in individuals with intellectual disabilities attending training centers for adults with intellectual disabilities. METHODS AND PROCEDURES: A convenience sample of 269 participants (54.3% men and 35.7% women), aged 18-40 years was recruited from Chile (14.1%), Mexico (32%), and Spain (53.9%). RESULTS: The findings showed that 15.2% have been cyberbullied 9.7% are currently being cyberbullied. Being different was the main reason (97.7%) for being cyberbullied. The behaviors happen in educational settings (46.67%), leisure/free time activities (31.11%), and associations for people with disabilities (15.56%). Verbal aggressions (74.53%) were the most common cyberbullying behaviors. Those who were cyberbullied reported more inadequate use of mobile phone and Internet, as well as more unhealthy behaviors and depressive mood. CONCLUSIONS AND IMPLICATIONS: These findings support the need for further studies on adults with intellectual disabilities, as well as the need for implementing primary, secondary, and tertiary prevention programs. PMID- 29227958 TI - Limited access to special education services for school-aged children with developmental delay. AB - BACKGROUND: Current policy in Oregon limits eligibility of children diagnosed with developmental delay for school-based services. Due to eligibility definitions, children with developmental delay may face additional barriers transitioning from early intervention/early childhood special education into school-based special education services. AIMS: Examine the relationship between enrollment in school-based special education programs given a change in primary disability diagnosis. METHODS: Logistic regression models were fit for children who enrolled in early intervention/early childhood special education services with a primary disability diagnosis of developmental delay and changed primary disability diagnosis before third grade (n=5076). RESULTS: Odds of enrollment in future special education were greater in children with a change in primary disability diagnosis after the age of five in comparison to children that had a change in primary disability diagnosis before the age of five, while adjusting for demographic characteristics (adjusted odds ratio: 2.37, 95% CI 1.92, 2.92). CONCLUSION: Results suggest that children who are diagnosed with a developmental delay and exit early childhood special education due to maximum age of eligibility are more likely to enroll in special education compared to children without a gap in service access. IMPLICATIONS: Gaps in service access during early development are associated with the need for supportive services later on in life. PMID- 29227960 TI - A regularization path algorithm for support vector ordinal regression. AB - Support vector ordinal regression (SVOR) is a popular method for tackling ordinal regression problems. Solution path provides a compact representation of optimal solutions for all values of regularization parameter, which is extremely useful for model selection. However, due to the complicated formulation of SVOR (including multiple equalities and extra variables), there is still no solution path algorithm proposed for SVOR. In this paper, we propose a regularization path algorithm for SVOR which can track the two sets of variables of SVOR w.r.t. the regularization parameter. Technically, we use the QR decomposition to handle the singular matrices in the regularization path. Experiment results on a variety of datasets not only confirm the effectiveness of our regularization path algorithm, but also show the superiority of our regularization path algorithm on model selection. PMID- 29227961 TI - Global exponential stability and lag synchronization for delayed memristive fuzzy Cohen-Grossberg BAM neural networks with impulses. AB - This paper investigates the stability and lag synchronization for memristor-based fuzzy Cohen-Grossberg bidirectional associative memory (BAM) neural networks with mixed delays (asynchronous time delays and continuously distributed delays) and impulses. By applying the inequality analysis technique, homeomorphism theory and some suitable Lyapunov-Krasovskii functionals, some new sufficient conditions for the uniqueness and global exponential stability of equilibrium point are established. Furthermore, we obtain several sufficient criteria concerning globally exponential lag synchronization for the proposed system based on the framework of Filippov solution, differential inclusion theory and control theory. In addition, some examples with numerical simulations are given to illustrate the feasibility and validity of obtained results. PMID- 29227962 TI - The impact of an add-on video assisted structured aerobic exercise module on mood and somatic symptoms among women with depressive disorders: Study from a tertiary care centre in India. AB - BACKGROUND: The evidence in favor of exercise as a treatment for depression is compelling, but what kind of exercise, how much, how often, and at what intensity is necessary to make a significant difference. There is serious dearth of such data from India, in particular. We examined the impact of low-moderate intensity aerobic exercises on mood and somatic symptoms among women with depressive disorders. METHODS: A pre test- post test control group design was adopted with a sample size of 40 (20 subjects randomized to both experimental and control group) women inpatients diagnosed with depressive disorder at a tertiary care centre, Bengaluru, India. After pre-test, experimental group received 10 sessions of add on intervention (video assisted structured aerobic exercise module) and the control group received treatment as usual. Hamilton Depression Rating Scale (HDRS), Visual Analogue Mood Scale (VAMS) and Depression Somatic Symptom scale (DSSS) were used as clinical outcome measures. RESULTS: The estimated mean change within the group in HDRS was 4.30 (95% CI 3.15 to 5.44; p<0.001) in the experimental group as compared to 2.70 (95% CI 1.50 to 3.89; p<0.001) in control group. RMANOVA (F=4.08) revealed a significant reduction in mean mood score in HDRS in the experimental group as compared to the control group at p<0.05. There was no statistically significant reduction in mean somatic symptom score between the groups (p=0.142). CONCLUSION: The study findings support that add-on aerobic exercise is associated with significantly greater improvements in mood symptoms of women with depressive disorders, when performed in a structured and supervised setting. PMID- 29227964 TI - Prophylaxis of hereditary breast cancer. PMID- 29227963 TI - The development of a specific pathogen free (SPF) barrier colony of marmosets (Callithrix jacchus) for aging research. AB - A specific pathogen free (SPF) barrier colony of breeding marmosets (Callithrix jacchus) was established at the Barshop Institute for Longevity and Aging Studies. Rodent and other animal models maintained as SPF barrier colonies have demonstrated improved health and lengthened lifespans enhancing the quality and repeatability of aging research. The marmosets were screened for two viruses and several bacterial pathogens prior to establishing the new SPF colony. Twelve founding animals successfully established a breeding colony with increased reproductive success, improved health parameters, and increased median lifespan when compared to a conventionally housed, open colony. The improved health and longevity of marmosets from the SPF barrier colony suggests that such management can be used to produce a unique resource for future studies of aging processes in a nonhuman primate model. PMID- 29227965 TI - Human longevity: 25 genetic loci associated in 389,166 UK biobank participants. AB - We undertook a genome-wide association study (GWAS) of parental longevity in European descent UK Biobank participants. For combined mothers' and fathers' attained age, 10 loci were associated (p<5*10-8), including 8 previously identified for traits including survival, Alzheimer's and cardiovascular disease. Of these, 4 were also associated with longest 10% survival (mothers age >=90 years, fathers >=87 years), with 2 additional associations including MC2R intronic variants (coding for the adrenocorticotropic hormone receptor). Mother's age at death was associated with 3 additional loci (2 linked to autoimmune conditions), and 8 for fathers only. An attained age genetic risk score associated with parental survival in the US Health and Retirement Study and the Wisconsin Longitudinal Study and with having a centenarian parent (n=1,181) in UK Biobank. The results suggest that human longevity is highly polygenic with prominent roles for loci likely involved in cellular senescence and inflammation, plus lipid metabolism and cardiovascular conditions. There may also be gender specific routes to longevity. PMID- 29227967 TI - Monte Carlo simulations of electrical percolation in multicomponent thin films with nanofillers. AB - We developed a 2D disk-stick percolation model to investigate the electrical percolation behavior of an insulating thin film reinforced with 1D and 2D conductive nanofillers via Monte Carlo simulation. Numerical predictions of the percolation threshold in single component thin films showed good agreement with the previous published work, validating our model for investigating the characteristics of the percolation phenomena. Parametric studies of size effect, i.e., length of 1D nanofiller and diameter of 2D nanofiller, were carried out to predict the electrical percolation threshold for hybrid systems. The relationships between the nanofillers in two hybrid systems was established, which showed differences from previous linear assumption. The effective electrical conductance was evaluated through Kirchhoff's current law by transforming it into a resistor network. The equivalent resistance was obtained from the distribution of nodal voltages by solving a system of linear equations with a Gaussian elimination method. We examined the effects of stick length, relative concentration, and contact patterns of 1D/2D inclusions on electrical performance. One novel aspect of our study is its ability to investigate the effective conductance of nanocomposites as a function of relative concentrations, which shows there is a synergistic effect when nanofillers with different dimensionalities combine properly. Our work provides an important theoretical basis for designing the conductive networks and predicting the percolation properties of multicomponent nanocomposites. PMID- 29227966 TI - POT1 inhibits the efficiency but promotes the fidelity of nonhomologous end joining at non-telomeric DNA regions. AB - Robust DNA double strand break (DSB) repair and stabilized telomeres help maintain genome integrity, preventing the onset of aging or tumorigenesis. POT1 is one of the six factors in the shelterin complex, which protects telomeres from being recognized as DNA damages. TRF1 and TRF2, two other shelterin proteins, have been shown to participate in DNA DSB repair at non-telomeric regions, but whether POT1, which binds to single strand telomeric DNA at chromosomal ends, is involved in DNA DSB repair has not been assessed. Here we found that POT1 arrives at DNA damage sites upon the occurrence of DNA DSBs. It suppresses the efficiency of nonhomologous end joining (NHEJ), the major pathway for fixing DNA DSBs in mammals, but surprisingly promotes NHEJ fidelity. Mechanistic studies indicate that POT1 facilitates the recruitment of Artemis, which is a nuclease and promotes fidelity of NHEJ, to DNA damage sites. In addition, we found that overexpression of POT1 inhibits the protein stability of Lig3, which is the major regulator of alternative NHEJ (alt-NHEJ), therefore suppressing the efficiency of alt-NHEJ. Taken together we propose that POT1 is a key factor regulating the balance between the efficiency and fidelity of NHEJ at non-telomeric DNA regions. PMID- 29227968 TI - Summaries of articles in this issue. AB - Summaries of the articles in this issue are given in the PDF file. PMID- 29227969 TI - Correlation between luminescence and structural evolution of colloidal silicon nanocrystals synthesized under different laser fluences. AB - We present a detailed investigation of the structural evolution and photoluminescence (PL) properties of colloidal silicon (Si) nanocrystals (NCs) synthesized through femtosecond laser ablation at different laser fluences. It is shown that the mean size of colloidal Si NCs increases from ~0.97-2.37 nm when increasing laser fluence from 1.0-2.5 mJ cm-2. On the basis of structural characterization, temperature-dependent PL, time-resolved PL, and PL excitation spectra, we identify that the size-dependent spectral shift of violet emission is attributed to the quantum confinement effect. The localized excitons' radiative recombination via the oxygen-related surface states on the surface of the colloidal Si NCs is employed to explain the origin of the blue emission. PMID- 29227970 TI - Shot noise and electronic properties in the inversion-symmetric Weyl semimetal resonant structure. AB - Using the transfer matrix method, the authors combine the analytical formula with numerical calculation to explore the shot noise and conductance of massless Weyl fermions in the Weyl semimetal resonant junction. By varying the barrier strength, the structure of the junction, the Fermi energy, and the crystallographic angle, the shot noise and conductance can be tuned efficiently. For a quasiperiodic superlattice, in complete contrast to the conventional junction case, the effect of the disorder strength on the shot noise and conductance depends on the competition of classical tunneling and Klein tunneling. Moreover, the delta barrier structure is also vital in determining the shot noise and conductance. In particular, a universal Fano factor has been found in a single delta potential case, whereas the resonant structure of the Fano factor perfectly matches with the number of barriers in a delta potential superlattice. These results are crucial for engineering nanoelectronic devices based on this topological semimetal material. PMID- 29227971 TI - Association of -1082A>G Polymorphism in the Interleukin-10 Gene with Estimated Glomerular Filtration Rate in Type 2 Diabetes. AB - BACKGROUND/AIMS: The -1082A>G polymorphism (rs1800896) in the interleukin-10 (IL10) gene has been associated with type 2 diabetes and diabetic retinopathy, but its relationship with diabetic kidney disease (DKD) is uncertain. The aim of this case-control study was to investigate whether the -1082A>G polymorphism is associated with DKD in white Brazilians with type 2 diabetes mellitus. METHODS: Genotyping was done by real-time polymerase chain reaction for 597 type 2 diabetic outpatients. The definition of DKD was based on estimated glomerular filtration rate (eGFR) and albuminuria, and the patients were grouped in three categories: no DKD (n=249), mild to moderate DKD (n=222), and severe DKD (n=126). RESULTS: The frequency of the minor (G) allele in subjects without DKD did not differ from that observed in subjects with DKD (0.35 vs 0.39, respectively; P = 0.192). Genotype frequencies in subjects without DKD were not significantly different from those observed among patients with mild to moderate DKD or severe DKD. However, considering only the eGFR categories as an indicator of renal function, the AG genotype was independently associated with an increased risk of mildly to moderately decreased eGFR (G3a category) and GG genotype was independently associated with increased risk of kidney failure (G5 category) as compared with AA genotype. CONCLUSION: Our findings support the hypothesis that the -1082A>G polymorphism in the IL10 gene might be associated with DKD in white Brazilians with type 2 diabetes. PMID- 29227972 TI - Serum Hepcidin and Iron Indices Affect Anemia Status Differently According to the Kidney Function of Non-Dialysis Chronic Kidney Disease Patients: Korean Cohort Study For Outcome in Patients with Chronic Kidney Disease (KNOW-CKD). AB - BACKGROUND/AIMS: No studies have examined the association among serum hepcidin, iron indices, or anemia status based on the kidney function of non-dialysis chronic kidney disease (CKD) patients. METHODS: We reviewed data of 2238 patients from a large-scale multicenter prospective Korean study (2011-2016) and excluded 198 patients with missing data regarding serum hepcidin, hemoglobin, transferrin saturation (TSAT), ferritin, and usage of erythropoiesis-stimulating agents (ESA) or supplemental iron and 363 patients using ESA or supplemental iron. Finally, 1677 patients were included. RESULTS: The mean patient age was 53.5 years, and 65.4% were men. TSAT and serum hepcidin were significantly associated with anemia status, whereas serum ferritin was not, regardless of anemia severity. For patients with an estimated glomerular filtration rate (eGFR) >=45 mL/min/1.73 m2, a 10% increase of TSAT was associated with hemoglobin <13 g/dL (odds ratio [OR], 0.628; 95% confidence interval [CI], 0.515-0.765; P<0.001) and hemoglobin <11.5 g/dL (OR, 0.672; 95% CI, 0.476-0.950; P=0.024), whereas a 10-ng/mL increase of serum hepcidin was associated with hemoglobin <11.5 g/dL (OR, 1.379; 95% CI, 1.173-1.620; P<0.001) and hemoglobin <10.0 g/dL (OR, 1.360; 95% CI, 1.115-1.659; P=0.002) for patients with eGFR <45 mL/min/1.73 m2 according to multivariate logistic analysis. CONCLUSIONS: TSAT was associated with less severe anemia in early CKD patients. Serum hepcidin was associated with more severe anemia in advanced CKD patients. PMID- 29227973 TI - Will Canagliflozin Lend Credence to the Potential Effects of Sodium-Glucose Co Transporter 2 Inhibitors on Renal Endpoints in Diabetic Nephropathy. PMID- 29227974 TI - miR302a-3p May Modulate Renal Epithelial-Mesenchymal Transition in Diabetic Kidney Disease by Targeting ZEB1. AB - BACKGROUND: Recent study found that microRNA (miRNA) are involved in diabetic kidney disease (DKD). The objective of this study is to determine the role of miR302a-3p in the process of renal epithelial-mesenchymal transition (EMT) in DKD. METHODS: The miRNA expression profiling of the cell line stimulated by high glucose was performed by a microarray analysis. Then real-time polymerase chain reaction (PCR) were used to determine the expression of one of the miRNAs significantly upregulated in cell line stimulated by high glucose, miR302a-3p. miR302a-3p mimics and inhibitor were transfected to HK-2 cells following exposure to high glucose and normal glucose, respectively. The expressions of E-cadherin, vimentin, and Zinc finger E-box-binding protein 1 (ZEB-1) were determined by real time PCR and Western blot. Finally, the levels of miR302a-3p in the plasma of DKD patients were detected by real-time PCR, and then the relationship of miR302a-3p and urinary albumin excretion (UAE) or estimated glomerular filtration rate (eGFR) was analyzed. RESULTS: The expression of miR-302a-3p, 513a-5p, 1291 and the other 17 miRNA were increased significantly in HK-2 cell line after high glucose stimulation; on the other hand, miRNA490-3p, 638, 3203 and the other 19 miRNA were decreased significantly. In vitro, miR-302a-3p expression in HG group increased at 6 h and ascended to the highest level at 12 and 24 h and then gradually decreased from 48 to 72 h. More interesting, ZEB1 protein expression had an opposite change, which gradually decreased from 6 to 24 h and then gradually increased from 48 to 72 h. Moreover, overexpression of miR-302a-3p suppressed expression of ZEB1 in the post-transcriptional level and reversed high glucose-mediated downregulation of E-cadherin and upregulation of vimentin. Meanwhile, loss of miR-302a-3p expression can lead to EMT of HK-2 cells just as high glucose stimulation. Further study demonstrated that the expression of circulating miR-302a-3p was significantly increased in the diabetes mellitus (DM) with normoalbuminuria (DM group, n = 22) compared with control (healthy persons, n = 30) and then decreased in DM with microalbuminuria (DNE group, n = 20). Furthermore, its expression in DM with macroalbuminuria (DNC group, n = 18) was decreased significantly compared with DM group. Circulating miR-302a-3p had negative relevance with UAE in DNE group (r = -0.649, p = 0.002) and DNC group (r = -0.681, p = 0.006). Circulating miR-302a-3p had positive relevance with eGFR in DNC group (r = 0.486, p = 0.041). CONCLUSIONS: These findings suggest that miR 302a-3p may play a protective role by targeting ZEB1 in renal EMT in DKD. In view of these findings, it is conceivable that miR-302a-3p may serve as a potential novel target in pre-EMT states for the amelioration renal fibrosis seen in DKD. PMID- 29227975 TI - High Phosphate-Induced Calcification of Vascular Smooth Muscle Cells is Associated with the TLR4/NF-kappab Signaling Pathway. AB - BACKGROUND/AIMS: Hyperphosphatemia is one of the most notable features of chronic kidney disease (CKD). Numerous epidemiological and clinical studies have found that high serum phosphate concentrations are associated with calcification in the coronary arteries. However, the mechanisms underlying the vascular calcification induced by high phosphate have not been understood fully. METHODS: Vascular smooth muscle cells (VSMCs) were cultured in high-phosphate media to induce vascular calcification, which was detected by Alizarin red S staining. Gene expression and protein levels of differentiation markers were determined by real time RT-PCR and western blotting, respectively. Protein levels of phosphorylated NF-kappaB and TLR4 were detected by western blotting, and the role of NF kappaB/TLR4 was further confirmed by using an NF-kappaB inhibitor or TLR4 siRNA. RESULTS: Our results showed that high-phosphate media induced obvious calcification of VSMCs. Simultaneously, VSMC differentiation was confirmed by the increased expression of bone morphogenetic protein-2 and Runt-related transcription factor 2 and decreased expression of the VSMC-specific marker SM22alpha, which was accompanied by the increased expression of inflammatory cytokines. Moreover, a significant upregulation of TLR4 and phosphorylated NF kappaB was also detected in VSMCs with high-phosphate media. In contrast, VSMC calcification and the increased expression of inflammatory cytokines were markedly attenuated by pretreatment with TLR4 siRNA and pyrrolidine dithiocarbamic acid, an NF-kappaB inhibitor. CONCLUSION: These data suggest that high-phosphate conditions directly induce vascular calcification via the activation of TLR4/NF-kappaB signaling in VSMCs. Moreover, inhibition of the TLR4/NF-kappaB signaling pathway might be a key intervention to prevent vascular calcification in patients with CKD. PMID- 29227976 TI - Progesterone Receptor Isoforms, Nuclear Corepressor-1 and Steroid Receptor Coactivator-1 and B-Cell Lymphoma 2 and Akt and Akt Phosphorylation Status in Uterine Myomas after Ulipristal Acetate Treatment: A Systematic Immunohistochemical Evaluation. AB - OBJECTIVE: To investigate whether ulipristal acetate (UPA) treatment modifies the expression of progesterone receptor (PR), its nuclear cofactors steroid receptor coactivator-1 (SRC1) and nuclear corepressor-1 (NCoR1), prosurvival factor B-cell lymphoma 2 (Bcl-2), and Akt in uterine myomas. PATIENTS: Prospective study of 59 women with symptomatic myomas undergoing myomectomy. Forty-two patients were treated preoperatively with UPA; the remaining 17 were not and they served as controls. METHOD: Tissue microarrays were obtained from surgical specimens and immunohistochemistry was performed. Blinded quantification of expression of PR (PR-A vs. PR-B), coactivator SRC1 and corepressor NCoR1, and prosurvival factor Bcl-2, and Akt and evaluation of Akt phosphorylation levels. RESULTS: Compared with the control group, UPA does not alter PR protein levels or expression patterns in myomas, and the PR-A/PR-B ratio was similar, as well as cytoplasmic or nuclear expression of cofactors SRC1 and NCoR1. Bcl-2 was heterogeneously expressed throughout the samples and no significant modification in expression was evidenced. No significant difference was found in Akt expression and phosphorylation between treated and untreated myomas. CONCLUSION: This study did not find any significant change in the expression of the studied factors in myomas after UPA exposure. In conclusion, various theories on myomas cells proposed on the basis of in vitro studies are not supported in vivo. PMID- 29227977 TI - Red Blood Cell Distribution Width is an Independent Predictor of AKI and Mortality in Patients in the Coronary Care Unit. AB - BACKGROUND/AIMS: We investigated the hypothesis that RDW is an independent predictor of acute kidney injury (AKI) and mortality in patients in the coronary care unit (CCU). METHODS: In this prospective, observational study, we screened 412 adults admitted to the CCU at Zhongnan Hospital of Wuhan University from January 1, 2014 to June 1, 2015. AKI was defined based on the KDIGO-AKI criteria. The survivors were followed up for up to 2 years after hospital discharge. The primary endpoint of the study was the incidence of AKI, while the secondary endpoints of the study were in-hospital mortality and 2-year mortality. RESULTS: RDW was significantly correlated with the acute physiology and chronic health evaluation II (APACHEII) score, hemoglobin, mean corpuscular volume, inflammatory marker levels, nutrition and renal function at the time of CCU admission. The incidence of AKI was much higher in the high RDW group (RDW >=14.0%) than in the low RDW group, a finding that was confirmed by multivariable logistic regression, which showed that RDW was independently associated with the incidence of AKI (odds ratio (OR), 1.059, 95% coincidence interval (95% CI), 1.024-1.095, P=0.001). A total of 61 patients died during their hospital stay, and baseline RDW was also an independent predictor of in-hospital mortality (hazard ratio (HR), 1.129, 95% CI 1.005-1.268, P=0.041). Patients with a high RDW exhibited significantly higher 2-year mortality than patients with a low RDW during a median follow-up period of 19.8 months (P<0.001), and RDW independently predicted the risk of 2-year mortality (HR, 1.189, 95% CI 1.045 to 1.354, P=0.009) in the multivariate Cox proportional hazard analysis after adjustments for other clinical and laboratory variables. CONCLUSION: RDW is an independent predictor of AKI and mortality in patients in the CCU. PMID- 29227978 TI - Osterix Decreases the Chemosensitivity of Breast Cancer Cells by Upregulating GALNT14. AB - BACKGROUND/AIMS: Osterix (Osx), a key regulator of osteoblast differentiation and bone formation, has been recently reported to be associated with the progression of breast cancer. However, the precise roles of Osx in breast cancer remain unclear. METHODS: Drug sensitivity of the cancer cells was assessed using an 3 (4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Target genes were obtained by high-throughput Illumina sequencing and were confirmed in vitro and in vivo. Apoptosis was analysed by Hoechst staining and western blotting. A tissue microarray including 129 samples from breast cancer patients was used for immunohistochemistry (IHC) assays. RESULTS: Overexpression of Osx decreased the chemosensitivity of breast cancer cells, while knockdown of Osx increased the chemosensitivity of breast cancer cells. In particular, we found that the decreased chemosensitivity effect was significantly associated with elevated expression of the polypeptide N-acetylgalactosaminyltransferase 14 (GALNT14). Silencing of GALNT14 in Osx-overexpressed cells restored the decreased chemosensitivity. Conversely, overexpression of GALNT14 in Osx-knockdown cells abrogated the increased chemosensitivity in breast cancer cells. In addition, we revealed that Osx decreased GALNT14-dependent chemosensitivity by enhancing anti apoptosis. GALNT14 expression exhibited a significant association with breast cancer stages as well as the disease-free survival (DFS) rate. CONCLUSION: Osx plays an important role in the chemosensitivity and inhibition of Osx expression may represent a therapeutic strategy to enhance the chemosensitivity of breast cancer. PMID- 29227979 TI - Higher Serum Hepatocyte Growth Factor Concentration is Associated with Better Preservation of GFR in Hemodialysis Patients. AB - BACKGROUND/AIMS: Hemodialysis induces an intravascular inflammatory reaction which may further deteriorate renal function. We studied changes of serum interleukin 6 (IL6) and hepatocyte growth factor (HGF) concentrations during dialysis sessions, and at 12 month intervals. The synthesis of these cytokines in arterial endothelial cells in the presence of serum obtained from dialyzed patients was studied. Changes of the inflammatory reaction during 12 months of treatment were correlated with GFR. METHODS: The study was performed on a group of 30 uremic patients treated with hemodialysis. Serum samples were collected before the start of dialysis, 15 minutes, and 4 hours later, when the session was finished. Serum levels of IL6 and HGF were measured with ELISA, as was the effect of serum samples on the synthesis of these cytokines in arterial endothelial cells. RESULTS: At baseline hemodialysis induced an increase of serum IL6 (+10%) and HGF (+164%) levels at the end of the session. After 12 months of treatment predialysis serum IL 6 level was increased as compared to the beginning of the study (+22%), but no change in serum HGF level was observed. At that time the dialysis-induced rise of serum IL6 level was stronger than at the start (+18%), but the observed effect for HGF was weaker (+116%). An inverse correlation was observed between the dialysis-induced increase of HGF level and decrease of GFR after 12 months of study. The same relation was seen for HGF synthesis in the endothelium, but opposite for IL6 synthesis in the endothelium. CONCLUSIONS: We found that a higher HGF serum level during hemodialysis treatment is associated with a slower loss of residual renal function. PMID- 29227980 TI - Spectral-Domain Optical Coherence Tomography Angiography for the Diagnosis and Evaluation of Polypoidal Choroidal Vasculopathy. AB - PURPOSE: To compare the diagnostic ability of optical coherence tomography angiography (OCTA) with indocyanine green angiography (ICGA) in polypoidal choroidal vasculopathy (PCV). METHODS: Retrospective review of 47 eyes with PCV imaged with ICGA and OCTA. For each eye, it was determined which imaging modality better delineated the PCV complex. The presence of a branching vascular network (BVN) and polyp(s) were noted. RESULTS: PCV was better visualized with ICGA in 21 eyes (44.7%) and with OCTA in 9 eyes (19.2%). The results were comparable in 17 eyes (36.2%). Of the 44 eyes with BVN on ICGA, 41 eyes (93.2%) also showed BVN on OCTA. Of the 28 eyes with polyp(s) on ICGA, 22 eyes (78.6%) also showed polyp(s) on OCTA. Polyps were high-flow lesions or faint low-flow dilations on OCTA. CONCLUSION: OCTA readily detects BVNs and can detect most polyps, but in many cases ICGA is better able to detect the PCV complex. PMID- 29227981 TI - Gamma-Secretase Inhibitors Attenuate Neurotrauma and Neurogenic Acute Lung Injury in Rats by Rescuing the Accumulation of Hypertrophic Microglia. AB - BACKGROUND/AIMS: In response to traumatic brain injury (TBI), activated microglia exhibit changes in their morphology from the resting ramified phenotype toward the activated hypertrophic or amoeboid phenotype. Here, we provide the first description of the mechanism underlying the neuroprotective effects of gamma secretase inhibitors on TBI outcomes in rats. METHODS: The neuroprotective effects of gamma-secretase inhibitors such as LY411575 or CHF5074 on TBI-induced neurotoxicity were analysed using a neurological motor function evaluation, cerebral contusion assay, immunohistochemical staining for microglia phenotypes, lung injury score and Evans Blue dye extravasation assay of brain and lung oedema. RESULTS: Hypertrophic or amoeboid microglia accumulated in the injured cortex, the blood-brain-barrier was disrupted and neurological deficits and acute lung injury were observed 4 days after TBI in adult rats. However, a subcutaneous injection of LY411575 (5 mg/kg) or CHF5074 (30 mg/kg) immediately after TBI and once daily for 3 consecutive days post-TBI significantly attenutaed the accumulation of hypertrophic microglia in the injured brain, neurological injury, and neurogenic acute lung injury. CONCLUSION: Gamma-secretase inhibitors attenuated neurotrauma and neurogenic acute lung injury in rats by reducing the accumulation of hypertrophic microglia in the vicinity of the lesion. PMID- 29227982 TI - Epidemiologic Features Impacting the Presentation of Malaria in Children in Houston: ERRATUM. PMID- 29227983 TI - Bone-conducted Vestibular-evoked Myogenic Potentials Before and After Stapes Surgery. AB - OBJECTIVE: To identify whether stapes surgery causes otolith dysfunction using bone-conducted vestibular-evoked myogenic potentials (VEMPs). STUDY DESIGN: Prospective study. SETTING: Hyogo College of Medicine Hospital. PATIENTS: Twenty primary ears (19 otosclerosis, 1 congenital stapes fixation) in 17 patients (2 men, 15 women; mean age 51 yr, range 20-68 yr) who had normal cervical VEMP (cVEMP) and ocular VEMP (oVEMP) results with bone-conducted stimulation were included. INTERVENTION: Stapes surgery. MAIN OUTCOME MEASURE: Both VEMP tests with bone-conducted stimulation were performed before and after stapes surgery. The normalized p13-n23 amplitude of cVEMPs and the nI-pI amplitude of oVEMPs were measured within 3 months after stapes surgery. Then, the asymmetry ratio (AR) was calculated to examine the effect of surgery on otolith function. RESULTS: Seven patients complained of temporary dizziness postoperatively, but their symptoms disappeared within approximately a week. Deterioration of VEMPs of the operated ear was not seen in any ears. Significantly greater amplitude compared with the opposite ear was found for cVEMP in one ear and oVEMP in two ears after the surgery. Their VEMP results recovered to the normal range at 6 months postoperatively. CONCLUSIONS: These findings suggest that stapes surgery causes no or undetectably small otolith dysfunction from the perspective of VEMP evaluation. PMID- 29227985 TI - Low frequency of Fabry disease in patients with common heart disease. AB - PURPOSE: To test the hypothesis that undiagnosed patients with Fabry disease exist among patients affected by common heart disease. METHODS: Globotriaosylceramide in random whole urine using tandem mass spectroscopy, alpha galactosidase A activity in dried blood spots, and next-generation sequencing of pooled or individual genomic DNA samples supplemented by Sanger sequencing. RESULTS: We tested 2,256 consecutive patients: 852 women (median age 65 years (19 95)) and 1,404 men (median age 65 years (21-92)). The primary diagnoses were coronary artery disease (n = 994), arrhythmia (n = 607), cardiomyopathy (n = 138), and valvular disease (n = 568). Urinary globotriaosylceramide was elevated in 15% of patients and 15 males had low alpha-galactosidase A activity. GLA variants found included R118C (n = 2), D83N, and D313Y (n = 7); IVS6-22 C>T, IVS4 16 A>G, IVS2+990C>A, 5'UTR-10 C>T (n = 4), IVS1-581 C>T, IVS1-1238 G>A, 5'UTR-30 G>A, IVS2+590C>T, IVS0-12 G>A, IVS4+68A>G, IVS0-10 C>T, IVS2-81-77delCAGCC, IVS2 77delC. Although the pathogenicity of several of these missense mutations and complex intronic haplotypes has been controversial, none of the patients screened in this study were diagnosed definitively with Fabry disease. CONCLUSION: This population of patients with common heart disease did not contain a substantial number of patients with undiagnosed Fabry disease. GLA gene sequencing is superior to urinary globotriaosylceramide or alpha-galactosidase A activity in the screening for Fabry disease. PMID- 29227984 TI - MicroRNA-146b-5p Identified in Porcine Liver Donation Model is Associated with Early Allograft Dysfunction in Human Liver Transplantation. AB - BACKGROUND Poor transplant outcome was observed in donation after brain death followed by circulatory death (DBCD), since the donor organs suffered both cytokine storm of brain death and warm ischemia injury. MicroRNAs (miRNAs) have emerged as promising disease biomarkers, so we sought to establish a miRNA signature of porcine DBCD and verify the findings in human liver transplantation. MATERIAL AND METHODS MiRNA expression was determined with miRNA sequencing in 3 types of the porcine model of organ donation, including donation after brain death (DBD) group, donation after circulatory death (DCD) group, and DBCD group. Bioinformatics analysis was performed to reveal the potential regulatory behavior of target miRNA. Human liver graft biopsy samples after reperfusion detected by fluorescence in situ hybridization were used to verify the expression of target miRNA. RESULTS We compared miRNA expression profiles of the 3 donation types. The porcine liver graft miR-146b was significantly increased and selected in the DBCD group versus in the DBD and DCD groups. The donor liver expression of human miR 146b-5p, which is homologous to porcine miR-146b, was further examined in 42 cases of human liver transplantations. High expression of miR-146b-5p successfully predicted the post-transplant early allograft dysfunction (EAD) with the area under the ROC curve (AUC) 0.759 (P=0.004). CONCLUSIONS Our results revealed the miRNA signature of DBCD liver grafts for the first time. The miR 146b-5p may have important clinical implications for monitoring liver graft function and predicating transplant outcomes. PMID- 29227986 TI - Bcl-2 on the brink of breakthroughs in cancer treatment. PMID- 29227987 TI - Reviewing the future of the P53 field. PMID- 29227988 TI - Fire frequency drives decadal changes in soil carbon and nitrogen and ecosystem productivity. AB - Fire frequency is changing globally and is projected to affect the global carbon cycle and climate. However, uncertainty about how ecosystems respond to decadal changes in fire frequency makes it difficult to predict the effects of altered fire regimes on the carbon cycle; for instance, we do not fully understand the long-term effects of fire on soil carbon and nutrient storage, or whether fire driven nutrient losses limit plant productivity. Here we analyse data from 48 sites in savanna grasslands, broadleaf forests and needleleaf forests spanning up to 65 years, during which time the frequency of fires was altered at each site. We find that frequently burned plots experienced a decline in surface soil carbon and nitrogen that was non-saturating through time, having 36 per cent (+/-13 per cent) less carbon and 38 per cent (+/-16 per cent) less nitrogen after 64 years than plots that were protected from fire. Fire-driven carbon and nitrogen losses were substantial in savanna grasslands and broadleaf forests, but not in temperate and boreal needleleaf forests. We also observe comparable soil carbon and nitrogen losses in an independent field dataset and in dynamic model simulations of global vegetation. The model study predicts that the long-term losses of soil nitrogen that result from more frequent burning may in turn decrease the carbon that is sequestered by net primary productivity by about 20 per cent of the total carbon that is emitted from burning biomass over the same period. Furthermore, we estimate that the effects of changes in fire frequency on ecosystem carbon storage may be 30 per cent too low if they do not include multidecadal changes in soil carbon, especially in drier savanna grasslands. Future changes in fire frequency may shift ecosystem carbon storage by changing soil carbon pools and nitrogen limitations on plant growth, altering the carbon sink capacity of frequently burning savanna grasslands and broadleaf forests. PMID- 29227990 TI - Correction: Novel Role of NOX in Supporting Aerobic Glycolysis in Cancer Cells with Mitochondrial Dysfunction and as a Potential Target for Cancer Therapy. AB - [This corrects the article DOI: 10.1371/journal.pbio.1001326.]. PMID- 29227989 TI - Non-linear auto-regressive models for cross-frequency coupling in neural time series. AB - We address the issue of reliably detecting and quantifying cross-frequency coupling (CFC) in neural time series. Based on non-linear auto-regressive models, the proposed method provides a generative and parametric model of the time varying spectral content of the signals. As this method models the entire spectrum simultaneously, it avoids the pitfalls related to incorrect filtering or the use of the Hilbert transform on wide-band signals. As the model is probabilistic, it also provides a score of the model "goodness of fit" via the likelihood, enabling easy and legitimate model selection and parameter comparison; this data-driven feature is unique to our model-based approach. Using three datasets obtained with invasive neurophysiological recordings in humans and rodents, we demonstrate that these models are able to replicate previous results obtained with other metrics, but also reveal new insights such as the influence of the amplitude of the slow oscillation. Using simulations, we demonstrate that our parametric method can reveal neural couplings with shorter signals than non parametric methods. We also show how the likelihood can be used to find optimal filtering parameters, suggesting new properties on the spectrum of the driving signal, but also to estimate the optimal delay between the coupled signals, enabling a directionality estimation in the coupling. PMID- 29227991 TI - Predicting the pathogenicity of novel variants in mitochondrial tRNA with MitoTIP. AB - Novel or rare variants in mitochondrial tRNA sequences may be observed after mitochondrial DNA analysis. Determining whether these variants are pathogenic is critical, but confirmation of the effect of a variant on mitochondrial function can be challenging. We have used available databases of benign and pathogenic variants, alignment between diverse tRNAs, structural information and comparative genomics to predict the impact of all possible single-base variants and deletions. The Mitochondrial tRNA Informatics Predictor (MitoTIP) is available through MITOMAP at www.mitomap.org. The source code for MitoTIP is available at www.github.com/sonneysa/MitoTIP. PMID- 29227992 TI - Thalamocortical control of propofol phase-amplitude coupling. AB - The anesthetic propofol elicits many different spectral properties on the EEG, including alpha oscillations (8-12 Hz), Slow Wave Oscillations (SWO, 0.1-1.5 Hz), and dose-dependent phase-amplitude coupling (PAC) between alpha and SWO. Propofol is known to increase GABAA inhibition and decrease H-current strength, but how it generates these rhythms and their interactions is still unknown. To investigate both generation of the alpha rhythm and its PAC to SWO, we simulate a Hodgkin Huxley network model of a hyperpolarized thalamus and corticothalamic inputs. We find, for the first time, that the model thalamic network is capable of independently generating the sustained alpha seen in propofol, which may then be relayed to cortex and expressed on the EEG. This dose-dependent sustained alpha critically relies on propofol GABAA potentiation to alter the intrinsic spindling mechanisms of the thalamus. Furthermore, the H-current conductance and background excitation of these thalamic cells must be within specific ranges to exhibit any intrinsic oscillations, including sustained alpha. We also find that, under corticothalamic SWO UP and DOWN states, thalamocortical output can exhibit maximum alpha power at either the peak or trough of this SWO; this implies the thalamus may be the source of propofol-induced PAC. Hyperpolarization level is the main determinant of whether the thalamus exhibits trough-max PAC, which is associated with lower propofol dose, or peak-max PAC, associated with higher dose. These findings suggest: the thalamus generates a novel rhythm under GABAA potentiation such as under propofol, its hyperpolarization may determine whether a patient experiences trough-max or peak-max PAC, and the thalamus is a critical component of propofol-induced cortical spectral phenomena. Changes to the thalamus may be a critical part of how propofol accomplishes its effects, including unconsciousness. PMID- 29227993 TI - In vivo zebrafish morphogenesis shows Cyp26b1 promotes tendon condensation and musculoskeletal patterning in the embryonic jaw. AB - Integrated development of diverse tissues gives rise to a functional, mobile vertebrate musculoskeletal system. However, the genetics and cellular interactions that drive the integration of muscle, tendon, and skeleton are poorly understood. In the vertebrate head, neural crest cells, from which cranial tendons derive, pattern developing muscles just as tendons have been shown to in limb and trunk tissue, yet the mechanisms of this patterning are unknown. From a forward genetic screen, we determined that cyp26b1 is critical for musculoskeletal integration in the ventral pharyngeal arches, particularly in the mandibulohyoid junction where first and second arch muscles interconnect. Using time-lapse confocal analyses, we detail musculoskeletal integration in wild-type and cyp26b1 mutant zebrafish. In wild-type fish, tenoblasts are present in apposition to elongating muscles and condense in discrete muscle attachment sites. In the absence of cyp26b1, tenoblasts are generated in normal numbers but fail to condense into nascent tendons within the ventral arches and, subsequently, muscles project into ectopic locales. These ectopic muscle fibers eventually associate with ectopic tendon marker expression. Genetic mosaic analysis demonstrates that neural crest cells require Cyp26b1 function for proper musculoskeletal development. Using an inhibitor, we find that Cyp26 function is required in a short time window that overlaps the dynamic window of tenoblast condensation. However, cyp26b1 expression is largely restricted to regions between tenoblast condensations during this time. Our results suggest that degradation of RA by this previously undescribed population of neural crest cells is critical to promote condensation of adjacent scxa-expressing tenoblasts and that these condensations are subsequently required for proper musculoskeletal integration. PMID- 29227994 TI - Low cost, low tech SNP genotyping tools for resource-limited areas: Plague in Madagascar as a model. AB - BACKGROUND: Genetic analysis of pathogenic organisms is a useful tool for linking human cases together and/or to potential environmental sources. The resulting data can also provide information on evolutionary patterns within a targeted species and phenotypic traits. However, the instruments often used to generate genotyping data, such as single nucleotide polymorphisms (SNPs), can be expensive and sometimes require advanced technologies to implement. This places many genotyping tools out of reach for laboratories that do not specialize in genetic studies and/or lack the requisite financial and technological resources. To address this issue, we developed a low cost and low tech genotyping system, termed agarose-MAMA, which combines traditional PCR and agarose gel electrophoresis to target phylogenetically informative SNPs. METHODOLOGY/PRINCIPAL FINDINGS: To demonstrate the utility of this approach for generating genotype data in a resource-constrained area (Madagascar), we designed an agarose-MAMA system targeting previously characterized SNPs within Yersinia pestis, the causative agent of plague. We then used this system to genetically type pathogenic strains of Y. pestis in a Malagasy laboratory not specialized in genetic studies, the Institut Pasteur de Madagascar (IPM). We conducted rigorous assay performance validations to assess potential variation introduced by differing research facilities, reagents, and personnel and found no difference in SNP genotyping results. These agarose-MAMA PCR assays are currently employed as an investigative tool at IPM, providing Malagasy researchers a means to improve the value of their plague epidemiological investigations by linking outbreaks to potential sources through genetic characterization of isolates and to improve understanding of disease ecology that may contribute to a long-term control effort. CONCLUSIONS: The success of our study demonstrates that the SNP-based genotyping capacity of laboratories in developing countries can be expanded with manageable financial cost for resource constraint laboratories. This is a practical formula that reduces resource-driven limitations to genetic research and promises to advance global collective knowledge of infectious diseases emanating from resource limited regions of the world. PMID- 29227995 TI - Restoration of floodplain meadows: Effects on the re-establishment of mosses. AB - Vascular plants serve as target species for the evaluation of restoration success as they account for most of the plant species diversity and vegetation cover. Although bryophytes contribute considerably to the species diversity of meadows, they are rarely addressed in restoration projects. This project is a first step toward making recommendations for including mosses in alluvial floodplain restoration projects. The opportunity to assess the diversity and ecological requirements of mosses on floodplain meadows presented itself within the framework of a vegetation monitoring that took place in 2014 on meadows located along the northern Upper Rhine. In this area, large-scale meadow restoration projects have taken place since 1997 in both the functional and fossil floodplains. Other studies have shown that bryophytes are generally present in green hay used in restoration, providing inadvertent bryophyte introduction. We compared bryophyte communities in donor and restored communities and correlated these communities with environmental variables-taking into account that the mosses on the restoration sites possibly developed from green hay. This analysis provided insights as to which species of bryophytes should be included in future restoration projects, what diaspores should be used, and how they should be transferred. Data on bryophyte occurrence were gathered from old meadows, and from restoration sites. We found distinct differences in bryophyte composition (based on frequency) in restored communities in functional flood plains compared to donor communities. Generally, restoration sites are still characterized by a lower species-richness, with a significantly lower occurrence of rare and red listed species and a lower species-heterogeneity. In conclusion, our research establishes what mosses predominate in donor and restored alluvial meadows along the northern Upper River, and what microsite conditions favour particular species. This points the way to deliberate introduction of moss diaspores for more complete alluvial meadow restoration. PMID- 29227996 TI - Generation and phenotypic characterisation of a cytochrome P450 4x1 knockout mouse. AB - Cytochrome P450 4x1 (Cyp4x1) is expressed at very high levels in the brain but the function of this protein is unknown. It has been hypothesised to regulate metabolism of fatty acids and to affect the activity of endocannabinoid signalling systems, which are known to influence appetite and energy metabolism. The objective of the present investigation was to determine the impact of Cyp4x1 on body weight and energy metabolism by developing a line of transgenic Cyp4x1 knock out mice. Mice were developed with a global knock-out of the gene; the full length RNA was undetectable, and mice were viable and fertile. Both male and female Cyp4x1-knock out mice gained significantly more body weight on normal lab chow diet compared to control flox mice on the same genetic background. At necropsy, Cyp4x1-knock out male mice had significantly greater intra-abdominal fat deposits (P<0.01), and enlarged adipocytes. Metabolic rate and locomotor activity as inferred from VO2 measures and crossing of infrared beams in metabolic cages were not significantly affected by the mutation in either gender. The respiratory exchange ratio was significantly decreased in male knock out mice (P<0.05), suggesting a greater degree of fat oxidation, consistent with their higher adiposity. When mice were maintained on a high fat diet, VO2 was significantly decreased in both male and female Cyp4x1-knock out mice. We conclude that the Cyp4x1-knock out mouse strain demonstrates a mildly obese phenotype, consistent with the view that cytochrome P450 4x1 plays a role in regulating fat metabolism. PMID- 29227997 TI - Normalized emphysema scores on low dose CT: Validation as an imaging biomarker for mortality. AB - The purpose of this study is to develop a computed tomography (CT) biomarker of emphysema that is robust across reconstruction settings, and evaluate its ability to predict mortality in patients at high risk for lung cancer. Data included baseline CT scans acquired between August 2002 and April 2004 from 1737 deceased subjects and 5740 surviving controls taken from the National Lung Screening Trial. Emphysema scores were computed in the original scans (origES) and after applying resampling, normalization and bullae analysis (normES). We compared the prognostic value of normES versus origES for lung cancer and all-cause mortality by computing the area under the receiver operator characteristic curve (AUC) and the net reclassification improvement (NRI) for follow-up times of 1-7 years. normES was a better predictor of mortality than origES. The 95% confidence intervals for the differences in AUC values indicated a significant difference for all-cause mortality for 2 through 6 years of follow-up, and for lung cancer mortality for 1 through 7 years of follow-up. 95% confidence intervals in NRI values showed a statistically significant improvement in classification for all cause mortality for 2 through 7 years of follow-up, and for lung cancer mortality for 3 through 7 years of follow-up. Contrary to conventional emphysema score, our normalized emphysema score is a good predictor of all-cause and lung cancer mortality in settings where multiple CT scanners and protocols are used. PMID- 29227998 TI - The value of squamous cell carcinoma antigen (SCCa) to determine the lymph nodal metastasis in cervical cancer: A meta-analysis and literature review. AB - BACKGROUND: The diagnostic power of CT or MRI on the lymph node status was limited. Supplement measurements were needed to assist the diagnosis of lymph node metastasis. The SCCa was reported to be close related to lymph node status. But currently the clinical value of serum SCCa measurement in lymph node status has not been clearly defined. This meta-analysis was to investigate this topic on a large scale. METHOD: Searching the Pubmed, Embase, Cochrane library, CNKI and Wanfang database for SCC-Ag/SCCA/SCC-antigen and cervical cancer/tumor/carcinoma/neoplasm published in any language from Jan 1 1990 to Aug 1 2017. QUADAS (quality assessment of diagnostic accuracy studies) was used to evaluate the quality of the articles. An eligible set of data should include true positive, true negative, false positive and false negative number. Every set of data was extracted and analyzed by STATA 14.0. The forest plot and bivariate boxplot were utilized to evaluate the heterogeneity. The funnel graph was used to test the publication bias. The SROC curve was draw via random effect model and HSROC model. RESULT: 17 sets of data and 3985 patients were included for the diagnostic meta-analysis. There was heterogeneity, which was partially from SCCa cut-off value. The pooled sensitivity was 0.70 and specificity was 0.63. AUC was 0.73. Eight articles provided the relative risk value of lymphatic metastasis when SCCa increased. The relative risk of lymph node metastasis increased ranging from 2.3-40 as with different SCCa cut off value. CONCLUSION: The diagnostic value of SCCa for lymph nodal metastasis was medium and it was strongly related to lymph node status. Thus SCCa could assist imaging tests to detect lymph node metastasis. Besides, it was correlated with para-aortic lymph node metastasis. PMID- 29227999 TI - Ancient connections among the European rivers and watersheds revealed from the evolutionary history of the genus Telestes (Actinopterygii; Cypriniformes). AB - In order to better understand the complex geologic history of the Mediterranean area, we have analysed evolutionary history, phylogeographic structure and molecular diversity of freshwater fishes belonging to the genus Telestes. As primary freshwater fishes distributed largely in the Mediterranean basin, this genus represents a suitable model system for investigating the historical biogeography of freshwater drainage systems in southern Europe. In this investigation we have included samples representing all Telestes species and based our analyses on one mitochondrial and one nuclear gene. We have investigated phylogenetic structure inside the genus Telestes, estimated divergence times, reconstructed ancestral distribution ranges and described intraspecific molecular diversity. Diversification of Telestes started in the Early Miocene, when the ancestors of T. souffia, lineage comprising T. croaticus and T. fontinalis, and the one comprising T. pleurobipunctatus and T. beoticus got isolated. The remaining species are genetically more closely related and form a common cluster in the recovered phylogenetic trees. Complex geological history of southern Europe, including formation of continental bridges, fragmentation of landmass, closing of the sea corridor, local tectonic activities, led to complicated biogeographical pattern of this genus, caused by multiple colonization events and passovers between ancient rivers and water basins. Especially pronounced diversity of Telestes found in the Adriatic watershed in Croatia and Bosnia and Herzegovina is a consequence of a triple colonization of this area by different lineages, which led to an existence of genetically distinct species in neighboring areas. Significant intraspecific structuring is present in T. souffia, T. muticellus, T. croaticus and T. pleurobipunctatus. Besides in well-structured species, elevated levels of genetic polymorphism were found inside T. turskyi and T. ukliva, as a consequence of their old origin and unconstrained evolutionary history. PMID- 29228000 TI - An in vivo assessment of the cholesterol-lowering efficacy of Lactobacillus plantarum ECGC 13110402 in normal to mildly hypercholesterolaemic adults. AB - : Coronary heart disease (CHD) is one of the major causes of death and disability in industrialised countries, with elevated blood cholesterol an established risk factor. Total plasma cholesterol reduction in populations suffering from primary hypercholesterolemia may lower CHD incidence. This study investigated the cholesterol reducing capacity of Lactobacillus plantarum ECGC 13110402, a strain selected for its high bile salt hydrolase activity, in 49 normal to mildly hypercholesterolaemic adults. Primary efficacy outcomes included effect on blood lipids (total cholesterol (TC), low density lipoproteins (LDL-C), high density lipoproteins (HDL-C) and triacylgycerides (TAG), inflammatory biomarkers and occurrence/severity of gastrointestinal side effects to establish safety and tolerance of the intervention. Secondary outcomes included blood pressure, immune biomarkers, gut microbiota characterisation and metabonome changes. The study was run in a parallel, double blind, placebo controlled, randomised design in which the active group ingested 2x109 CFU encapsulated Lactobacillus plantarum ECGC 13110402 twice daily. Daily ingestion of the active treatment resulted in a statistically significant reduction in LDL-C in volunteers with baseline TC<5mM during the 0-12 week period (13.9%, P = 0.030), a significant reduction in TC in volunteers with baseline TC>=6mM in the 0-6 week period (37.6%, P = 0.045), a significant decrease in TAG (53.9% P = 0.030) and an increase in HDL-C (14.7%, P = 0.007) in the over 60 years population in the 6-12 week period. A statistically significant reduction in systolic blood pressure was also observed across the active study group in the 6-12-week period (6.6%, P = 0.003). No impact on gastrointestinal function and side effects was observed during the study. Similar to blood and urine metabonomic analyses, faecal metagenomics did not reveal significant changes upon active or placebo intake. The results of this study suggest that Lactobacillus plantarum ECGC 13110402 is a well-tolerated, natural probiotic, that may be used as an alternative or supplement to existing treatments to reduce cardiovascular risk. TRIAL REGISTRATION: Clinical trials.gov NCT03263104. PMID- 29228001 TI - Reinforcement learning produces dominant strategies for the Iterated Prisoner's Dilemma. AB - We present tournament results and several powerful strategies for the Iterated Prisoner's Dilemma created using reinforcement learning techniques (evolutionary and particle swarm algorithms). These strategies are trained to perform well against a corpus of over 170 distinct opponents, including many well-known and classic strategies. All the trained strategies win standard tournaments against the total collection of other opponents. The trained strategies and one particular human made designed strategy are the top performers in noisy tournaments also. PMID- 29228002 TI - Comparative cell cycle transcriptomics reveals synchronization of developmental transcription factor networks in cancer cells. AB - The cell cycle coordinates core functions such as replication and cell division. However, cell-cycle-regulated transcription in the control of non-core functions, such as cell identity maintenance through specific transcription factors (TFs) and signalling pathways remains unclear. Here, we provide a resource consisting of mapped transcriptomes in unsynchronized HeLa and U2OS cancer cells sorted for cell cycle phase by Fucci reporter expression. We developed a novel algorithm for data analysis that enables efficient visualization and data comparisons and identified cell cycle synchronization of Notch signalling and TFs associated with development. Furthermore, the cell cycle synchronizes with the circadian clock, providing a possible link between developmental transcriptional networks and the cell cycle. In conclusion we find that cell cycle synchronized transcriptional patterns are temporally compartmentalized and more complex than previously anticipated, involving genes, which control cell identity and development. PMID- 29228004 TI - Longitudinal assessment of anti-PGL-I serology in contacts of leprosy patients in Bangladesh. AB - BACKGROUND: Despite elimination efforts, the number of Mycobacterium leprae (M. leprae) infected individuals who develop leprosy, is still substantial. Solid evidence exists that individuals living in close proximity to patients are at increased risk to develop leprosy. Early diagnosis of leprosy in endemic areas requires field-friendly tests that identify individuals at risk of developing the disease before clinical manifestation. Such assays will simultaneously contribute to reduction of current diagnostic delay as well as transmission. Antibody (Ab) levels directed against the M.leprae-specific phenolic glycolipid I (PGL-I) represents a surrogate marker for bacterial load. However, it is insufficiently defined whether anti-PGL-I antibodies can be utilized as prognostic biomarkers for disease in contacts. Particularly, in Bangladesh, where paucibacillary (PB) patients form the majority of leprosy cases, anti-PGL-I serology is an inadequate method for leprosy screening in contacts as a directive for prophylactic treatment. METHODS: Between 2002 and 2009, fingerstick blood from leprosy patients' contacts without clinical signs of disease from a field-trial in Bangladesh was collected on filter paper at three time points covering six years of follow-up per person. Analysis of anti-PGL-I Ab levels for 25 contacts who developed leprosy during follow-up and 199 contacts who were not diagnosed with leprosy, was performed by ELISA after elution of bloodspots from filter paper. RESULTS: Anti-PGL-I Ab levels at intake did not significantly differ between contacts who developed leprosy during the study and those who remained free of disease. Moreover, anti-PGL-I serology was not prognostic in this population as no significant correlation was identified between anti-PGL-I Ab levels at intake and the onset of leprosy. CONCLUSION: In this highly endemic population in Bangladesh, no association was observed between anti-PGL-I Ab levels and onset of disease, urging the need for an extended, more specific biomarker signature for early detection of leprosy in this area. TRIAL REGISTRATION: ClinicalTrials.gov ISRCTN61223447. PMID- 29228006 TI - Sea Star Wasting Disease in Asterias forbesi along the Atlantic Coast of North America. AB - As keystone species, sea stars serve to maintain biodiversity and species distribution through trophic level interactions in marine ecosystems. Recently, Sea Star Wasting Disease (SSWD) has caused widespread mass mortality in several sea star species from the Pacific Coast of the United States of America (USA) and Asterias forbesi on the Atlantic Coast. A densovirus, named Sea Star associated Densovirus (SSaDV), has been associated with the wasting disease in Pacific Coast sea stars, and limited samples of A. forbesi. The goal of this research is to examine the pathogenesis of SSWD in A. forbesi on the Atlantic Coast of the USA and to determine if SSaDV is associated with the wasting disease in this species. Histological examination of A. forbesi tissues affected with SSWD showed cuticle loss, vacuolation and necrosis of epidermal cells, and oedema of the dermis, but no consistent evidence indicating the cause of the lesions. Challenge experiments by cohabitation and immersion in infected water suggest that the cause of SSWD is viral in nature, as filtration (0.22 MUm) of water from tanks with sea stars exhibiting SSWD did not prevent the transmission and progression of the disease. Death of challenged sea stars occurred 7-10 d after exposure to infected water or sea stars, and the infectivity crossed species (A. forbesi and Pateria miniata) with equal penetrance. Of the 48 stars tested by quantitative real time PCR, 29 (60%) were positive for the SSaDV VP1 gene. These stars represent field-collected sea stars from all geographical regions (South Carolina to Maine) in 2012-2015, as well as stars exposed to infected stars or water from affected tanks. However, a clear association between the presence of SSaDV and SSWD signs in experimental and field-collected A. forbesi was not found in this study. PMID- 29228003 TI - A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning. AB - The Pam/Highwire/RPM-1 (PHR) proteins are conserved intracellular signaling hubs that regulate synapse formation and axon termination. The C. elegans PHR protein, called RPM-1, acts as a ubiquitin ligase to inhibit the DLK-1 and MLK-1 MAP kinase pathways. We have identified several kinases that are likely to form a new MAP kinase pathway that suppresses synapse formation defects, but not axon termination defects, in the mechanosensory neurons of rpm-1 mutants. This pathway includes: MIG-15 (MAP4K), NSY-1 (MAP3K), JKK-1 (MAP2K) and JNK-1 (MAPK). Transgenic overexpression of kinases in the MIG-15/JNK-1 pathway is sufficient to impair synapse formation in wild-type animals. The MIG-15/JNK-1 pathway functions cell autonomously in the mechanosensory neurons, and these kinases localize to presynaptic terminals providing further evidence of a role in synapse development. Loss of MIG-15/JNK-1 signaling also suppresses defects in habituation to repeated mechanical stimuli in rpm-1 mutants, a behavioral deficit that is likely to arise from impaired glutamatergic synapse formation. Interestingly, habituation results are consistent with the MIG-15/JNK-1 pathway functioning as a parallel opposing pathway to RPM-1. These findings indicate the MIG-15/JNK-1 pathway can restrict both glutamatergic synapse formation and short term learning. PMID- 29228005 TI - RNA-seq reveals transcriptome changes in goats following myostatin gene knockout. AB - Myostatin (MSTN) is a powerful negative regulator of skeletal muscle mass in mammalian species that is primarily expressed in skeletal muscles, and mutations of its encoding gene can result in the double-muscling trait. In this study, the CRISPR/Cas9 technique was used to edit MSTN in Shaanbei Cashmere goats and generate knockout animals. RNA sequencing was used to determine and compare the transcriptome profiles of the muscles from three wild-type (WT) goats, three fibroblast growth factor 5 (FGF5) knockout goats (FGF5+/- group) and three goats with disrupted expression of both the FGF5 and MSTN genes (FM+/- group). The sequence reads were obtained using the Illumina HiSeq 2000 system and mapped to the Capra hircus reference genome using TopHat (v2.0.9). In total, 68.93, 62.04 and 66.26 million clean sequencing reads were obtained from the WT, FM+/- and FGF5+/- groups, respectively. There were 201 differentially expressed genes (DEGs) between the WT and FGF5+/- groups, with 86 down- and 115 up-regulated genes in the FGF5+/- group. Between the WT and FM+/- groups, 121 DEGs were identified, including 81 down- and 40 up-regulated genes in the FM+/- group. A total of 198 DEGs were detected between the FGF5+/- group and FM+/- group, with 128 down- and 70 up-regulated genes in the FM+/- group. At the transcriptome level, we found substantial changes in genes involved in fatty acid metabolism and the biosynthesis of unsaturated fatty acids, such as stearoyl-CoA dehydrogenase, 3-hydroxyacyl-CoA dehydratase 2, ELOVL fatty acid elongase 6 and fatty acid synthase, suggesting that the expression levels of these genes may be directly regulated by MSTN and that these genes are likely downstream targets of MSTN with potential roles in lipid metabolism in goats. Moreover, five randomly selected DEGs were further validated with qRT-PCR, and the results were consistent with the transcriptome analysis. The present study provides insight into the unique transcriptome profile of the MSTN knockout goat, which is a valuable resource for studying goat genomics. PMID- 29228007 TI - Conjugation of nitrated acetaminophen to Der p1 amplifies peripheral blood monocyte response to Der p1. AB - BACKGROUND: An association of acetaminophen use and asthma was observed in the International Study of Asthma and Allergies in Childhood study. However there are no clear mechanisms to explain an association between acetaminophen use and immunologic pathology. In acidic conditions like those in the stomach and inflamed airway, tyrosine residues are nitrated by nitrous and peroxynitrous acids. The resulting nitrotyrosine is structurally similar to 2,4-dinitrophenol and 2,4-dinitrochlorobenzene, known haptens that enhance immune responses by covalently binding proteins. Nitrated acetaminophen shares similar molecular structure. OBJECTIVE: We hypothesized the acetaminophen phenol ring undergoes nitration under acidic conditions, producing 3-nitro-acetaminophen which augments allergic responses by acting as a hapten for environmental allergens. METHODS: 3 nitro-acetaminophen was formed from acetaminophen in the presence of acidified nitrite, purified by high performance liquid chromatography, and assayed by gas chromatography mass spectrometry. Purified 3-nitro-acetaminophen was reacted with Dermatophagoides pteronyssinus (Der p1) and analyzed by mass spectrometry to identify the modification site. Human peripheral blood mononuclear cells proliferation response was measured in response to 3-nitro-acetaminophen and to 3 nitro-acetaminophen-modified Der p1. RESULTS: Acetaminophen was modified by nitrous acid forming 3-nitro-acetaminophen over a range of different acidic conditions consistent with airway inflammation and stomach acidity. The Der p1 protein-hapten adduct creation was confirmed by liquid chromatography-mass spectrometry proteomics modifying cysteine 132. Peripheral blood mononuclear cells exposed to 3-nitro-acetaminophen-modified Der p1 had increased proliferation and cytokine production compared to acetaminophen and Der p1 alone (n = 7; p < 0.05). CONCLUSION: These data suggests 3-nitro-acetaminophen formation and reaction with Der p1 provides a mechanism by which stomach acid or infection-induced low airway pH in patients could enhance the allergic response to proteins such as Der p1. PMID- 29228008 TI - When is working memory important for arithmetic? The impact of strategy and age. AB - Our ability to perform arithmetic relies heavily on working memory, the manipulation and maintenance of information in mind. Previous research has found that in adults, procedural strategies, particularly counting, rely on working memory to a greater extent than retrieval strategies. During childhood there are changes in the types of strategies employed, as well as an increase in the accuracy and efficiency of strategy execution. As such it seems likely that the role of working memory in arithmetic may also change, however children and adults have never been directly compared. This study used traditional dual-task methodology, with the addition of a control load condition, to investigate the extent to which working memory requirements for different arithmetic strategies change with age between 9-11 years, 12-14 years and young adulthood. We showed that both children and adults employ working memory when solving arithmetic problems, no matter what strategy they choose. This study highlights the importance of considering working memory in understanding the difficulties that some children and adults have with mathematics, as well as the need to include working memory in theoretical models of mathematical cognition. PMID- 29228009 TI - Prevalence of anemia and associated factors among pregnant women in Southern Ethiopia: A community based cross-sectional study. AB - BACKGROUND: Anemia is defined as a condition in which there is less than the normal hemoglobin (Hb) level in the body. During pregnancy; iron deficiency is associated with multiple adverse outcomes for both mother and infant. Most of the studies conducted in Ethiopia on anemia during pregnancy were conducted at institution level and associated factors are not well studied and documented. Independent factors like, food security status, dietary diversity and intestinal parasites infection were considered by only a few of them. Hence, the aim of this study was to determine the prevalence of anemia and associated factors among pregnant women in Lemo District, Southern Ethiopia. METHODS: Community based cross- sectional study was conducted from May-June 2015. Multistage sampling was used to include 507 study participants. Anaemia was diagnosed using HemoCue HB 301 and haemoglobin concentration <11 g/dl was classified as anaemic. Stool examinations were also done. Structured questionnaire was used as a tool to collect sociodemographic characteristics, individual dietary diversity and level of household food security data. Multivariate logistic regression model was employed to determine the effect of explanatory variables like level of education, level of household food security, dietary diversity, trimester of pregnancy, family planning before pregnancy, deworming, gravidity, iron intake in current pregnancy and soil transmitted helminthes on dependent variable anemia. RESULTS: The prevalence of anemia was 23.2% (95% CI: 19.5%-26.9%). Factors associated with anemia were: low socio-economic status (AOR = 2.03, 95% CI: 1.11 3.69), trimester second (AOR = 3.09, 95%CI: 1.41-6.79) and third (AOR = 3.68, 95% CI: 1.67-8.08), gravidity three to five (AOR = 1.78, 95% CI: 1.03-3.07) and six and above (AOR = 2.59, 95%CI: 1.37-4.92), not supplemented with iron (AOR = 1.72, 95% CI: 1.02-2.91), low dietary diversity score (AOR = 3.18, 95% CI: 1.37-7.37) and hookworm infection (AOR = 2.69, 95%CI: 1.34-5.39). CONCLUSION: Anemia has moderate public health significance in the area. Community-based interventions should be enhanced considering the identified associated factors. PMID- 29228010 TI - Nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) at a palliative care unit: A prospective single service analysis. AB - BACKGROUND: The emergence of multidrug-resistant bacterial microorganisms is a particular challenge for the health care systems. Little is known about the occurrence of methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant Gram-negative bacteria (MDRGNB) in patients of palliative care units (PCU). AIM: The primary aim of this study was to determine the carriage of MRSA among patients of a PCU at a German University Hospital and to assess whether the positive cases would have been detected by a risk-factor-based screening approach. DESIGN: Between February 2014 and January 2015 patients from our PCU were tested for MRSA carriage within 48 hours following admission irrespective of pre-existing risk factors. In addition, risk factors for MRSA colonization were assessed. Samples from the nostrils and, if applicable, from pre-existing wounds were analysed by standardized culture-based laboratory techniques for the presence of MRSA and of other bacteria and fungi. Results from swabs taken prior to admission were also recorded if available. RESULTS: 297 out of 317 patients (93.7%) fulfilled one or more MRSA screening criteria. Swabs from 299 patients were tested. The detection rate was 2.1% for MRSA. All MRSA cases would have been detected by a risk-factor-based screening-approach. Considering the detected cases and the results from swabs taken prior to admission, 4.1% of the patients (n = 13) were diagnosed with MRSA and 4.1% with MDRGNB (n = 13), including two patients with MRSA and MDRGNB (0.6%). The rate of MRSA carriage in PCU patients (4.1%) was elevated compared to the rate seen in the general cohort of patients admitted to our University Hospital (2.7%). CONCLUSIONS: PCU patients have an increased risk to carry MRSA compared to other hospitalized patients. Although a risk factor-based screening is likely to detect all MRSA carriers amongst PCU patients, we rather recommend a universal screening to avoid the extra effort to identify the few risk factor-negative patients (<7%). As we did not perform a systematic MDRGNB screening, further studies are needed to determine the true prevalence of MDRGNB amongst PCU patients. PMID- 29228012 TI - Correction: Positively selected amino acid replacements within the RuBisCO enzyme of oak trees are associated with ecological adaptations. AB - [This corrects the article DOI: 10.1371/journal.pone.0183970.]. PMID- 29228011 TI - Characterization of the Giardia intestinalis secretome during interaction with human intestinal epithelial cells: The impact on host cells. AB - BACKGROUND: Giardia intestinalis is a non-invasive protozoan parasite that causes giardiasis in humans, the most common form of parasite-induced diarrhea. Disease mechanisms are not completely defined and very few virulence factors are known. METHODOLOGY: To identify putative virulence factors and elucidate mechanistic pathways leading to disease, we have used proteomics to identify the major excretory-secretory products (ESPs) when Giardia trophozoites of WB and GS isolates (assemblages A and B, respectively) interact with intestinal epithelial cells (IECs) in vitro. FINDINGS: The main parts of the IEC and parasite secretomes are constitutively released proteins, the majority of which are associated with metabolism but several proteins are released in response to their interaction (87 and 41 WB and GS proteins, respectively, 76 and 45 human proteins in response to the respective isolates). In parasitized IECs, the secretome profile indicated effects on the cell actin cytoskeleton and the induction of immune responses whereas that of Giardia showed anti-oxidation, proteolysis (protease-associated) and induction of encystation responses. The Giardia secretome also contained immunodominant and glycosylated proteins as well as new candidate virulence factors and assemblage-specific differences were identified. A minor part of Giardia ESPs had signal peptides (29% for both isolates) and extracellular vesicles were detected in the ESPs fractions, suggesting alternative secretory pathways. Microscopic analyses showed ESPs binding to IECs and partial internalization. Parasite ESPs reduced ERK1/2 and P38 phosphorylation and NF-kappaB nuclear translocation. Giardia ESPs altered gene expression in IECs, with a transcriptional profile indicating recruitment of immune cells via chemokines, disturbances in glucose homeostasis, cholesterol and lipid metabolism, cell cycle and induction of apoptosis. CONCLUSIONS: This is the first study identifying Giardia ESPs and evaluating their effects on IECs. It highlights the importance of host and parasite ESPs during interactions and reveals the intricate cellular responses that can explain disease mechanisms and attenuated inflammatory responses during giardiasis. PMID- 29228013 TI - Occult RV systolic dysfunction detected by CMR derived RV circumferential strain in patients with pectus excavatum. AB - AIMS: To investigate the right ventricular (RV) strain in pectus excavatum (PE) patients using cardiac magnetic resonance tissue tracking (CMR TT). MATERIALS AND METHODS: Fifty consecutive pectus excavatum patients, 10 to 32 years of age (mean age 15 +/- 4 years), underwent routine cardiac magnetic resonance imaging (CMR) including standard measures of chest geometry and cardiac size and function. The control group consisted of 20 healthy patients with a mean age of 17 +/- 5 years. RV longitudinal and circumferential strain magnitude was assessed by a dedicated RV tissue tracking software. RESULTS: Fifty patients with images of sufficient quality were included in the analysis. The mean right and left ventricular ejection fractions were 55 +/- 5% and 59 +/- 4%. The RV global longitudinal strain was -21.88 +/- 4.63%. The RV circumferential strain at base, mid-cavity and apex were -13.66 +/- 3.09%, -11.31 +/- 2.79%, -20.73 +/- 3.45%, respectively. There was no statistically significant decrease in right ventricular or left ventricular ejection fraction between patients and controls (p > 0.05 for each). There was no significant difference in RV global longitudinal strain between two groups (-21.88 +/- 4.63 versus -21.99 +/- 3.58; p = 0.93). However, there was significant decrease in mid-cavity circumferential strain magnitude in pectus patients compared with controls (-11.31 +/- 2.79 versus -16.19 +/- 2.86; p < 0.001). PE patients had a significantly higher basal circumferential strain ( 13.66 +/- 3.09% versus -9.76 +/- 1.79; p < 0.001) as well as apical circumferential strain (-20.73 +/- 3.45% versus -12.07 +/- 3.38) than control group. CONCLUSION: Mid-cavity circumferential strain but not longitudinal strain is reduced in pectus excavatum patients. Basal circumferential strain as well as apical circumferential strain were increased as compensatory mechanism for reduced mid-cavity circumferential strain. Further studies are needed to establish clinical significance of this finding. PMID- 29228014 TI - A model for warfare in stratified small-scale societies: The effect of within group inequality. AB - In order to predict the features of non-raiding human warfare in small-scale, socially stratified societies, we study a coalitionary model of war that assumes that individuals participate voluntarily because their decisions serve to maximize fitness. Individual males join the coalition if war results in a net economic and thus fitness benefit. Within the model, viable offensive war ensues if the attacking coalition of males can overpower the defending coalition. We assume that the two groups will eventually fuse after a victory, with ranks arranged according to the fighting abilities of all males and that the new group will adopt the winning group's skew in fitness payoffs. We ask whether asymmetries in skew, group size and the amount of resources controlled by a group affect the likelihood of successful war. The model shows, other things being equal, that (i) egalitarian groups are more likely to defeat their more despotic enemies, even when these are stronger, (ii) defection to enemy groups will be rare, unless the attacked group is far more despotic than the attacking one, and (iii) genocidal war is likely under a variety of conditions, in particular when the group under attack is more egalitarian. This simple optimality model accords with several empirically observed correlations in human warfare. Its success underlines the important role of egalitarianism in warfare. PMID- 29228015 TI - Development of an iron-selective antioxidant probe with protective effects on neuronal function. AB - Iron accumulation, oxidative stress and calcium signaling dysregulation are common pathognomonic signs of several neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, Friedreich ataxia and Huntington's disease. Given their therapeutic potential, the identification of multifunctional compounds that suppress these damaging features is highly desirable. Here, we report the synthesis and characterization of N-(1,3-dihydroxy-2 (hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide, named CT51, which exhibited potent free radical neutralizing activity both in vitro and in cells. CT51 bound Fe2+ with high selectivity and Fe3+ with somewhat lower affinity. Cyclic voltammetric analysis revealed irreversible binding of Fe3+ to CT51, an important finding since stopping Fe2+/Fe3+ cycling in cells should prevent hydroxyl radical production resulting from the Fenton-Haber-Weiss cycle. When added to human neuroblastoma cells, CT51 freely permeated the cell membrane and distributed to both mitochondria and cytoplasm. Intracellularly, CT51 bound iron reversibly and protected against lipid peroxidation. Treatment of primary hippocampal neurons with CT51 reduced the sustained calcium release induced by an agonist of ryanodine receptor-calcium channels. These protective properties of CT51 on cellular function highlight its possible therapeutic use in diseases with significant oxidative, iron and calcium dysregulation. PMID- 29228017 TI - Two decades of climate driving the dynamics of functional and taxonomic diversity of a tropical small mammal community in western Mexico. AB - Understanding the effects of global climate disruption on biodiversity is important to future conservation efforts. While taxonomic diversity is widely studied, functional diversity of plants, and recently animals, is receiving increasing attention. Most studies of mammals are short-term, focus on temperate habitats, and rely on traits described in the literature rather than generating traits from observations. Unlike previous studies, this long-term field study assessed the factors driving the functional and taxonomic diversity of small mammal assemblages in dry tropical forests using both traits recorded from literature and a demographic database. We assessed the drivers (abundance and biomass, temperature and rainfall) of taxonomic richness and functional diversity for two rain-driven seasons in two adjacent but distinct forests-upland and lowland (arroyo or riparian) forests. Our analysis found that rainfall, both seasonal and atypical, was the primary factor driving functional and taxonomic diversity of small-mammal assemblages. Functional responses differed between the two types of forests, however, with effects being stronger in the harsher conditions of the upland forests than in the less severe conditions prevailing in the arroyo (riparian) forest. The latter also supports a richer, more diverse, and more stable small-mammal assemblage. These findings highlight the importance of climate to tropical biological diversity, as extreme climate events (hurricanes, droughts and floods) and disruption of rainfall patterns were shown to decrease biodiversity. They also support the need to preserve these habitats, as their high taxonomic diversity and functional redundancy makes them resilient against global climate disruption and local extreme events. Tropical dry forests constitute a potential reservoir for biodiversity and the ecosystem services they provide. Unfortunately, these forests are among the most endangered terrestrial ecosystems because of deforestation and the likely impacts of global climate disruption. PMID- 29228016 TI - Prevalence and molecular profiling of Epstein Barr virus (EBV) among healthy blood donors from different nationalities in Qatar. AB - BACKGROUND: The Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis. EBV is highly prevalent lymphotropic herpesvirus and has been linked to several malignancies. Transmission is generally by oral secretions, but can be through blood transfusions and organ transplantations. This study aimed to determine the seroprevalence, viremia rates, and circulating genotypes of EBV in healthy blood donors in Qatar. METHODS: Blood samples from 673 blood donors of different nationalities residing in Qatar (mainly Qatar, Egypt, Syria, Jordan, Pakistan, and India) were collected and tested for anti-EBV capsid (VCA; IgG & IgM), nuclear (EBNA; IgG), and early (EA-D; IgG) antigens. Avidity testing was determined when active infection was suspected. DNA was extracted from the buffy coat and subjected to EBV-DNA quantification using qRT-PCR. Genotyping was performed using nested-PCR targeting EBV-EBNA2 gene, and phylogeny by sequence analysis of the LMP-1 gene. RESULTS: 97.9% (673/659) of the samples were seropositive as indicated by the presence VCA-IgG, while 52.6% (354/673) had detectible EBV-DNA. EBV seroprevalence and viremia rates increased significantly with age. Genotyping of 51 randomly selected samples showed predominance of Genotype 1 (72.5%, 37/51) as compared to genotype 2 (3.5%), and mixed infections were detected in 4% of the samples. Sub-genotyping for these samples revealed that the Mediterranean strain was predominant (65.3%), followed by B95.8 prototype and North Carolina strains (12.2% each), and China1 strain (6%). CONCLUSION: As a first study to evaluate EBV infection in highly diverse population in Qatar, where expatriates represent more than 85% of the population, our results indicated high seroprevalence and viremia rate of EBV in different nationalities, with genotype 1 and Mediterranean strain being predominant. Clinical significance of these finding have not been investigated and shall be evaluated in future studies. PMID- 29228018 TI - Genome-wide association study identifies a locus associated with rotator cuff injury. AB - Rotator cuff tears are common, especially in the fifth and sixth decades of life, but can also occur in the competitive athlete. Genetic differences may contribute to overall injury risk. Identifying genetic loci associated with rotator cuff injury could shed light on the etiology of this injury. We performed a genome wide association screen using publically available data from the Research Program in Genes, Environment and Health including 8,357 cases of rotator cuff injury and 94,622 controls. We found rs71404070 to show a genome-wide significant association with rotator cuff injury with p = 2.31x10-8 and an odds ratio of 1.25 per allele. This SNP is located next to cadherin8, which encodes a protein involved in cell adhesion. We also attempted to validate previous gene association studies that had reported a total of 18 SNPs showing a significant association with rotator cuff injury. However, none of the 18 SNPs were validated in our dataset. rs71404070 may be informative in explaining why some individuals are more susceptible to rotator cuff injury than others. PMID- 29228019 TI - Loci and pathways associated with uterine capacity for pregnancy and fertility in beef cattle. AB - Infertility and subfertility negatively impact the economics and reproductive performance of cattle. Of note, significant pregnancy loss occurs in cattle during the first month of pregnancy, yet little is known about the genetic loci influencing pregnancy success and loss in cattle. To identify quantitative trait loci (QTL) with large effects associated with early pregnancy loss, Angus crossbred heifers were classified based on day 28 pregnancy outcomes to serial embryo transfer. A genome wide association analysis (GWAA) was conducted comparing 30 high fertility heifers with 100% success in establishing pregnancy to 55 subfertile heifers with 25% or less success. A gene set enrichment analysis SNP (GSEA-SNP) was performed to identify gene sets and leading edge genes influencing pregnancy loss. The GWAA identified 22 QTL (p < 1 x 10-5), and GSEA SNP identified 9 gene sets (normalized enrichment score > 3.0) with 253 leading edge genes. Network analysis identified TNF (tumor necrosis factor), estrogen, and TP53 (tumor protein 53) as the top of 671 upstream regulators (p < 0.001), whereas the SOX2 (SRY [sex determining region Y]-box 2) and OCT4 (octamer-binding transcription factor 4) complex was the top master regulator out of 773 master regulators associated with fertility (p < 0.001). Identification of QTL and genes in pathways that improve early pregnancy success provides critical information for genomic selection to increase fertility in cattle. The identified genes and regulators also provide insight into the complex biological mechanisms underlying pregnancy establishment in cattle. PMID- 29228020 TI - Transplantation of canine olfactory ensheathing cells producing chondroitinase ABC promotes chondroitin sulphate proteoglycan digestion and axonal sprouting following spinal cord injury. AB - Olfactory ensheathing cell (OEC) transplantation is a promising strategy for treating spinal cord injury (SCI), as has been demonstrated in experimental SCI models and naturally occurring SCI in dogs. However, the presence of chondroitin sulphate proteoglycans within the extracellular matrix of the glial scar can inhibit efficient axonal repair and limit the therapeutic potential of OECs. Here we have used lentiviral vectors to genetically modify canine OECs to continuously deliver mammalian chondroitinase ABC at the lesion site in order to degrade the inhibitory chondroitin sulphate proteoglycans in a rodent model of spinal cord injury. We demonstrate that these chondroitinase producing canine OECs survived at 4 weeks following transplantation into the spinal cord lesion and effectively digested chondroitin sulphate proteoglycans at the site of injury. There was evidence of sprouting within the corticospinal tract rostral to the lesion and an increase in the number of corticospinal axons caudal to the lesion, suggestive of axonal regeneration. Our results indicate that delivery of the chondroitinase enzyme can be achieved with the genetically modified OECs to increase axon growth following SCI. The combination of these two promising approaches is a potential strategy for promoting neural regeneration following SCI in veterinary practice and human patients. PMID- 29228021 TI - Inheritance mode and mechanisms of resistance to imidacloprid in the house fly Musca domestica (Diptera:Muscidae) from China. AB - Imidacloprid is a neonicotinoid insecticide that is effective against house fly, Musca domestica L., which is a major pest with the ability to develop resistance to insecticides. In the present study, we investigated the inheritance mode, the cross-resistance pattern and the mechanisms of resistance to imidacloprid. A near isogenic house fly line (N-IRS) with 78-fold resistance to imidacloprid was used to demonstrate the mode of inheritance. The overlapping confidence limits of LC50 values and the slopes of the log concentration-probit lines between the reciprocal F1 and F1' progenies suggest that imidacloprid resistance is inherited autosomally in the house fly. There was incomplete dominant inheritance in the F1 and F1' progenies, based on dominance values of 0.77 and 0.75, respectively. A monogenic inheritance model revealed that imidacloprid resistance is governed by more than one factor. Compared to the field strain (CFD), the N-IRS strain developed more cross-resistance to chlorfenapyr and no cross-resistance to chlorpyrifos and acetamiprid, but showed negative cross-resistance to beta cypermethrin and azamethiphos. Three synergists, diethyl malate (DEM), s,s,s tributylphosphorotrithioate (DEF), and piperonyl butoxide (PBO), showed significant synergism against to imidacloprid (4.55-, 4.46- and 3.34-fold respectively) in the N-IRS strain. However, both DEM and PBO had no synergism and DEF only exhibited slight synergism in the CSS strain. The activities of carboxylesterase (CarE), glutathione S-transferases (GSTs) and cytochrome P450 in the N-IRS strain were significantly higher than in the CSS strain. But similar synergistic potential of DEF to imidacloprid between the CSS and N-IRS strain suggested that GSTs and cytochrome P450 played much more important role than esterase for the N-IRS strain resistance to imidacloprid. These results should be helpful for developing an improved management strategy to delay the development of imidacloprid resistance in house fly. PMID- 29228022 TI - Can conditional cash transfers improve the uptake of nutrition interventions and household food security? Evidence from Odisha's Mamata scheme. AB - There is considerable global evidence on the effectiveness of cash transfers in improving health and nutrition outcomes; however, the evidence from South Asia, particularly India, is limited. In the context of India where more than a third of children are undernourished, and where there is considerable under-utilization of health and nutrition interventions, it is opportune to investigate the impact of cash transfer programs on the use of interventions. We study one conditional cash transfer program, Mamata scheme, implemented in the state of Odisha, in India that targeted pregnant and lactating women. Using survey data on 1161 households from three districts in the state of Odisha, we examine the effect of the scheme on eight outcomes: 1) pregnancy registration; 2) receipt of antenatal services; 3) receipt of iron and folic acid (IFA) tablets; 4) exposure to counseling during pregnancy; 5) exposure to postnatal counseling; 6) exclusive breastfeeding; 7) full immunization; and 8) household food security. We conduct regression analyses and correct for endogeneity using nearest-neighbor matching and inverse-probability weighting models. We find that the receipt of payments from the Mamata scheme is associated with a 5 percentage point (pp) increase in the likelihood of receiving antenatal services, a 10 pp increase in the likelihood of receiving IFA tablets, and a decline of 0.84 on the Household Food Insecurity Access Scale. These results provide the first quantitative estimates of effects associated with the Mamata scheme, which can inform the design of government policies related to conditional cash transfers. PMID- 29228023 TI - Task demands affect spatial reference frame weighting during tactile localization in sighted and congenitally blind adults. AB - Task demands modulate tactile localization in sighted humans, presumably through weight adjustments in the spatial integration of anatomical, skin-based, and external, posture-based information. In contrast, previous studies have suggested that congenitally blind humans, by default, refrain from automatic spatial integration and localize touch using only skin-based information. Here, sighted and congenitally blind participants localized tactile targets on the palm or back of one hand, while ignoring simultaneous tactile distractors at congruent or incongruent locations on the other hand. We probed the interplay of anatomical and external location codes for spatial congruency effects by varying hand posture: the palms either both faced down, or one faced down and one up. In the latter posture, externally congruent target and distractor locations were anatomically incongruent and vice versa. Target locations had to be reported either anatomically ("palm" or "back" of the hand), or externally ("up" or "down" in space). Under anatomical instructions, performance was more accurate for anatomically congruent than incongruent target-distractor pairs. In contrast, under external instructions, performance was more accurate for externally congruent than incongruent pairs. These modulations were evident in sighted and blind individuals. Notably, distractor effects were overall far smaller in blind than in sighted participants, despite comparable target-distractor identification performance. Thus, the absence of developmental vision seems to be associated with an increased ability to focus tactile attention towards a non-spatially defined target. Nevertheless, that blind individuals exhibited effects of hand posture and task instructions in their congruency effects suggests that, like the sighted, they automatically integrate anatomical and external information during tactile localization. Moreover, spatial integration in tactile processing is, thus, flexibly adapted by top-down information-here, task instruction-even in the absence of developmental vision. PMID- 29228024 TI - Detection of duo-schistosome infection from filtered urine samples from school children in Zambia after MDA. AB - Schistosomiasis is one of the major Neglected Tropical Diseases (NTDs) in sub Saharan Africa. In sub-Saharan Africa, two major human schistosome species namely Schistosoma mansoni and S. haematobium often occur sympatrically largely affecting children. Recognizing the public health impact of Schistosomiasis, the World Health Organization (WHO) is urging member states to regularly treat at least 75% and up to 100%, of all school-aged children at risk of morbidity. For control strategies based on targeted mass drug administration (MDA) to succeed it is essential to have a simple and sensitive test for monitoring the success of these interventions. Current available diagnostic tests, such as egg detection in stool by Kato-Katz (KK) for S. mansoni and detection of eggs or blood (hematuria) in urine for S. haematobium have reduced sensitivity in low intensity settings. The objective of the study was to evaluate active single or duo schistosome infections in school children following MDA using molecular diagnostics (PCR) on filtered urine samples and comparing that against traditional diagnostic tests. This cross-sectional study was conducted among 111 school children aged 7-15 years in Chongwe and Siavonga Districts in Zambia. Species-specific cell-free repeat DNA fragment were amplified from 111 filtered urine samples. Our approach detected eight times more positive cases (total 77) than by KK (9) for S. mansoni and six times more (total 72) than by hematuria (11) for S. haematobium and even more against urine filtration (77 compared to only 6). The same pattern was observed when stratified for age group and sex specific analysis with 100% sensitivity and specificity devoid of any cross amplification. In addition, 69 individuals (62%) were co-infected by both parasites. We have demonstrated a significantly higher prevalence of both species than indicated by the traditional tests and the persistent maintenance of reservoir of infection after MDA. Our approach is an effective means of detecting low intensity infection, which will enhance the effectiveness of surveillance and assess the impact of MDA control programs against schistosomiasis. PMID- 29228025 TI - A defect in the inner kinetochore protein CENPT causes a new syndrome of severe growth failure. AB - Primordial growth failure has been linked to defects in the biology of cell division and replication. The complex processes involved in microtubule spindle formation, organization and function have emerged as a dominant patho-mechanism in these conditions. The majority of reported disease genes encode for centrosome and centriole proteins, leaving kinetochore proteins by which the spindle apparatus interacts with the chromosomes largely unaccounted for. We report a novel disease gene encoding the constitutive inner kinetochore member CENPT, which is involved in kinetochore targeting and assembly, resulting in severe growth failure in two siblings of a consanguineous family. We herein present studies on the molecular and cellular mechanisms that explain how genetic mutations in this gene lead to primordial growth failure. In both, affected human cell lines and a zebrafish knock-down model of Cenpt, we observed aberrations in cell division with abnormal accumulation of micronuclei and of nuclei with increased DNA content arising from incomplete and/or irregular chromosomal segregation. Our studies underscore the critical importance of kinetochore function for overall body growth and provide new insight into the cellular mechanisms implicated in the spectrum of these severe growth disorders. PMID- 29228026 TI - Rapid analyses of dry matter content and carotenoids in fresh cassava roots using a portable visible and near infrared spectrometer (Vis/NIRS). AB - Portable Vis/NIRS are flexible tools for fast and unbiased analyses of constituents with minimal sample preparation. This study developed calibration models for dry matter content (DMC) and carotenoids in fresh cassava roots using a portable Vis/NIRS system. We examined the effects of eight data pre-treatment combinations on calibration models and assessed calibrations on processed and intact root samples. We compared Vis/NIRS derived-DMC to other phenotyping methods. The results of the study showed that the combination of standard normal variate and de-trend (SNVD) with first derivative calculated on two data points and no smoothing (SNVD+1111) was adequate for a robust model. Calibration performance was higher with processed than the intact root samples for all the traits although intact root models for some traits especially total carotenoid content (TCC) (R2c = 96%, R2cv = 90%, RPD = 3.6 and SECV = 0.63) were sufficient for screening purposes. Using three key quality traits as templates, we developed models with processed fresh root samples. Robust calibrations were established for DMC (R2c = 99%, R2cv = 95%, RPD = 4.5 and SECV = 0.9), TCC (R2c = 99%, R2cv = 91%, RPD = 3.5 and SECV = 2.1) and all Trans beta-carotene (ATBC) (R2c = 98%, R2cv = 91%, RPD = 3.5 and SECV = 1.6). Coefficient of determination on independent validation set (R2p) for these traits were also satisfactory for ATBC (91%), TCC (88%) and DMC (80%). Compared to other methods, Vis/NIRS-derived DMC from both intact and processed roots had very high correlation (>0.95) with the ideal oven-drying than from specific gravity method (0.49). There was equally a high correlation (0.94) between the intact and processed Vis/NIRS DMC. Therefore, the portable Vis/NIRS could be employed for the rapid analyses of DMC and quantification of carotenoids in cassava for nutritional and breeding purposes. PMID- 29228027 TI - An insulin resistance associated neural correlate of impulsivity in type 2 diabetes mellitus. AB - Central insulin resistance (IR) influences striatal dopamine (DA) tone, an important determinant of behavioral self-regulation. We hypothesized that an association exists between the degree of peripheral IR and impulse control, mediated by the impact of IR on brain circuits controlling the speed of executing "go" and/or "stop" responses. We measured brain activation and associated performance on a stop signal task (SST) in obese adults with type 2 diabetes (age, 48.1 +/- 6.9 yrs (mean +/- SD); BMI, 36.5 +/- 4.0 kg/m2; HOMA-IR, 7.2 +/- 4.1; 12 male, 18 female). Increasing IR, but not BMI, was a predictor of shorter critical stop signal delay (cSSD), a measure of the time window during which a go response can be successfully countermanded (R2 = 0.12). This decline was explained by an IR-associated increase in go speed (R2 = 0.13) with little impact of IR or BMI on stop speed. Greater striatal fMRI activation contrast in stop error (SE) compared with stop success (SS) trials (CONSE>SS) was a significant predictor of faster go speeds (R2 = 0.33, p = 0.002), and was itself predicted by greater IR (CONSE>SS vs HOMA-IR: R2 = 0.10, p = 0.04). Furthermore, this impact of IR on striatal activation was a significant mediator of the faster go speeds and greater impulsivity observed with greater IR. These findings suggest a neural mechanism by which IR may increase impulsivity and degrade behavioral self regulation. PMID- 29228028 TI - A novel indel variant in LDLR responsible for familial hypercholesterolemia in a Chinese family. AB - Familial hypercholesterolemia (FH) is an inherited disorder characterized by elevation of serum cholesterol bound to low-density lipoprotein. Mutations in LDLR are the major factors responsible for FH. In this study, we recruited a four generation Chinese family with FH and identified the clinical features of hypercholesterolemia. All affected individuals shared a novel indel mutation (c.1885_1889delinsGATCATCAACC) in exon 13 of LDLR. The mutation segregated with the hypercholesterolemia phenotype in the family. To analyze the function of the indel, we established stable clones of mutant and wild-type LDLR in Hep G2 cells. The mutant LDLR was retained in the endoplasmic reticulum (ER) and failed to glycosylate via the Golgi. Moreover, the membrane LDLR was reduced and lost the ability to take up LDL. Our data also expand the spectrum of known LDLR mutations. PMID- 29228029 TI - Pockets as structural descriptors of EGFR kinase conformations. AB - Epidermal Growth Factor Receptor (EGFR), a tyrosine kinase receptor, is one of the main tumor markers in different types of cancers. The kinase native state is mainly composed of two populations of conformers: active and inactive. Several sequence variations in EGFR kinase region promote the differential enrichment of conformers with higher activity. Some structural characteristics have been proposed to differentiate kinase conformations, but these considerations could lead to ambiguous classifications. We present a structural characterisation of EGFR kinase conformers, focused on active site pocket comparisons, and the mapping of known pathological sequence variations. A structural based clustering of this pocket accurately discriminates active from inactive, well-characterised conformations. Furthermore, this main pocket contains, or is in close contact with, ~65% of cancer-related variation positions. Although the relevance of protein dynamics to explain biological function has been extensively recognised, the usage of the ensemble of conformations in dynamic equilibrium to represent the functional state of proteins and the importance of pockets, cavities and/or tunnels was often neglected in previous studies. These functional structures and the equilibrium between them could be structurally analysed in wild type as well as in sequence variants. Our results indicate that biologically important pockets, as well as their shape and dynamics, are central to understanding protein function in wild-type, polymorphic or disease-related variations. PMID- 29228030 TI - Logistic regression analysis of conventional ultrasonography, strain elastosonography, and contrast-enhanced ultrasound characteristics for the differentiation of benign and malignant thyroid nodules. AB - The aim of the study is to screen the significant sonographic features by logistic regression analysis and fit a model to diagnose thyroid nodules. A total of 525 pathological thyroid nodules were retrospectively analyzed. All the nodules underwent conventional ultrasonography (US), strain elastosonography (SE), and contrast -enhanced ultrasound (CEUS). Those nodules' 12 suspicious sonographic features were used to assess thyroid nodules. The significant features of diagnosing thyroid nodules were picked out by logistic regression analysis. All variables that were statistically related to diagnosis of thyroid nodules, at a level of p < 0.05 were embodied in a logistic regression analysis model. The significant features in the logistic regression model of diagnosing thyroid nodules were calcification, suspected cervical lymph node metastasis, hypoenhancement pattern, margin, shape, vascularity, posterior acoustic, echogenicity, and elastography score. According to the results of logistic regression analysis, the formula that could predict whether or not thyroid nodules are malignant was established. The area under the receiver operating curve (ROC) was 0.930 and the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were 83.77%, 89.56%, 87.05%, 86.04%, and 87.79% respectively. PMID- 29228031 TI - Transcriptional profiling of PBMCs unravels B cell mediated immunopathogenic imprints of HCV vasculitis. AB - B cell depletion therapy using rituximab has been shown to be effective in achieving remission in patients with HCV-mixed cryoglobulinemic (MC) vasculitis. Previously, we have demonstrated abnormalities in peripheral immune cells involving neutrophils, chemotaxis, and innate immune activation among patients with HCV-MC vasculitis when compared to HCV patients without vasculitis. In this study, we evaluated the effect of B cell depletion therapy on transcriptional profiles of peripheral blood mononuclear cells before and after riruximab therapy, in order to unravel the pathogenic mechanism involved in HCV-MC vasculitis induced by abnormal B cell proliferation. DNA microarray analysis was performed using RNA from PBMCs from seven patients with HCV-MC vasculitis and seven normal volunteers. DNA was hybridized to Affymetrix U133A chips. After normalization, differentially expressed gene list with treatment was generated using partitional clustering. RT-PCR, flow cytometry, and enzyme immunoassay (EIA) was used to validate DNA microarray findings. Differentially expressed genes included B cells and non-B cell genes. Validation of genes using purified cell subsets demonstrated distinct effect of B cell depletion therapy on non-B cells, such as monocytes, T cells, and NK cells. Notably, B lymphocyte stimulator (BLyS) levels were persistently elevated in patients who subsequently relapsed. In conclusion, pathogenesis of HCV-MC vasculitis is mediated by abnormal proliferation of B cells, driven by BLyS, leading to significant effects on non-B cells in mediating symptomatology. Future therapeutics using a combination approach of B cell depletion and proliferation may be desired to achieve long term remission. PMID- 29228032 TI - Genome-wide identification of WRKY genes and their expression profiles under different abiotic stresses in Elaeis guineensis. AB - African oil palm (Elaeis guineensis) is an important oil crop grown in tropical region and sensitive to low temperature along with high tolerance to salt and drought stresses. Since the WRKY transcription factor family plays central roles in the regulation of plant stress tolerance, 95 genes belonging to the WRKY family were identified and characterized in oil palm genome. Gene structure analysis showed that EgWRKY genes have considerable variation in intron number (0 to 12) and gene length (477bp to 89,167 bp). Duplicated genes identification indicated 32 EgWRKY genes originated from segmental duplication and two from tandem duplication. Based on transcriptome data, most EgWRKY genes showed tissue specific expression patterns and their expression could be induced under cold stress. Furthermore, six EgWRKY genes with more than two-folded increased expression level under cold stress were validated by RT-qPCR, which has higher expression level in cold, drought and high salinity treatment. The identification and characterization of WRKY gene family showed that EgWRKY were associated with a wide range of abiotic stress responses in Elaeis guineensis and some EgWRKY members with high expression levels could be selected for further research in analyzing their functions in the stress response in African oil palm. PMID- 29228034 TI - On the relation between economic bubbles and effort gaps between sellers and buyers: An experimental study. AB - Economic bubbles are an empirical puzzle because they do not readily fit the notion of an efficient market. We argue that bubbles are associated with a conflict and a gap in the allocation of effort during negotiation by sellers and buyers. We examined 21 experimental asset markets where in one condition players could buy and sell and in the other they could either buy or sell. The results indicated that when making concurrent buying and selling decisions the mean number of asks for sellers was 71% higher than the number of bids for buyers. Similar findings emerge in a re-analysis of data from Lei et al. (2001). Importantly, bubbles only emerged in markets where the number of asks was larger than that of bids. These findings indicate that bubbles are associated with increased negotiation effort when acting as a seller and diminished effort when acting as a buyer. PMID- 29228033 TI - Visual mismatch negativity to vanishing parts of objects in younger and older adults. AB - We investigated visual mismatch negativity (vMMN) to vanishing parts of continuously present objects by comparing the event-related potentials (ERPs) to infrequently (deviant) and frequently (standard) disappearing parts of the objects. This paradigm both excludes low-level stimulus-specific adaptation differences between the responses to deviants and standards, and increases the ecological validity of the stimuli. In comparison to frequently disappearing parts of the stimulus objects, infrequently vanishing parts elicited posterior negative event-related brain activity (vMMN). However, no vMMN emerged to the reappearance of the same parts of the objects. We compared the ERPs of an older and a younger sample of participants. In the 120-180 ms time period vMMN was similar in the two age groups, but in the 180-220 ms time period vMMN emerged only in the younger participants. We consider this difference as an index of more elaborate automatic processing of infrequent stimulus changes in younger adults. PMID- 29228035 TI - Landscape effects on demersal fish revealed by field observations and predictive seabed modelling. AB - Nature conservation and fisheries management often focus on particular seabed features that are considered vulnerable or important to commercial species. As a result, individual seabed types are protected in isolation, without any understanding of what effect the mixture of seabed types within the landscape has on ecosystem functions. Here we undertook predictive seabed modelling within a coastal marine protected area using observations from underwater stereo-video camera deployments and environmental information (depth, wave fetch, maximum tidal speeds, distance from coast and underlying geology). The effect of the predicted substratum type, extent and heterogeneity or the diversity of substrata, within a radius of 1500 m around each camera deployment of juvenile gadoid relative abundance was analysed. The predicted substratum model performed well with wave fetch and depth being the most influential predictor variables. Gadus morhua (Atlantic cod) were associated with relatively more rugose substrata (Algal-gravel-pebble and seagrass) and heterogeneous landscapes, than Melanogrammus aeglefinus (haddock) or Merlangius merlangus (whiting) (sand and mud). An increase in M. merlangus relative abundance was observed with increasing substratum extent. These results reveal that landscape effects should be considered when protecting the seabed for fish and not just individual seabed types. The landscape approach used in this study therefore has important implications for marine protected area, fisheries management and monitoring advice concerning demersal fish populations. PMID- 29228036 TI - Supervised retinal vessel segmentation from color fundus images based on matched filtering and AdaBoost classifier. AB - The structure and appearance of the blood vessel network in retinal fundus images is an essential part of diagnosing various problems associated with the eyes, such as diabetes and hypertension. In this paper, an automatic retinal vessel segmentation method utilizing matched filter techniques coupled with an AdaBoost classifier is proposed. The fundus image is enhanced using morphological operations, the contrast is increased using contrast limited adaptive histogram equalization (CLAHE) method and the inhomogeneity is corrected using Retinex approach. Then, the blood vessels are enhanced using a combination of B-COSFIRE and Frangi matched filters. From this preprocessed image, different statistical features are computed on a pixel-wise basis and used in an AdaBoost classifier to extract the blood vessel network inside the image. Finally, the segmented images are postprocessed to remove the misclassified pixels and regions. The proposed method was validated using publicly accessible Digital Retinal Images for Vessel Extraction (DRIVE), Structured Analysis of the Retina (STARE) and Child Heart and Health Study in England (CHASE_DB1) datasets commonly used for determining the accuracy of retinal vessel segmentation methods. The accuracy of the proposed segmentation method was comparable to other state of the art methods while being very close to the manual segmentation provided by the second human observer with an average accuracy of 0.972, 0.951 and 0.948 in DRIVE, STARE and CHASE_DB1 datasets, respectively. PMID- 29228037 TI - Potential serum biomarkers and metabonomic profiling of serum in ischemic stroke patients using UPLC/Q-TOF MS/MS. AB - BACKGROUND: Stroke still has a high incidence with a tremendous public health burden and it is a leading cause of mortality and disability. However, biomarkers for early diagnosis are absent and the metabolic alterations associated with ischemic stroke are not clearly understood. The objectives of this case-control study are to identify serum biomarkers and explore the metabolic alterations of ischemic stroke. METHODS: Metabonomic analysis was performed using ultra performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry and multivariate statistical analysis was employed to study 60 patients with or without ischemic stroke (30 cases and 30 controls). RESULTS: Serum metabolic profiling identified a series of 12 metabolites with significant alterations, and the related metabolic pathways involved glycerophospholipid, sphingolipid, phospholipid, fat acid, acylcarnitine, heme, and purine metabolism. Subsequently, multiple logistic regression analyses of these metabolites showed uric acid, sphinganine and adrenoyl ethanolamide were potential biomarkers of ischemic stroke with an area under the receiver operating characteristic curve of 0.941. CONCLUSIONS: These findings provide insights into the early diagnosis and potential pathophysiology of ischemic stroke. PMID- 29228038 TI - Temporal dynamics of gene expression in heat-stressed Caenorhabditis elegans. AB - There is considerable insight into pathways and genes associated with heat-stress conditions. Most genes involved in stress response have been identified using mutant screens or gene knockdowns. Yet, there is limited understanding of the temporal dynamics of global gene expression in stressful environments. Here, we studied global gene expression profiles during 12 hours of heat stress in the nematode C. elegans. Using a high-resolution time series of increasing stress exposures, we found a distinct shift in gene expression patterns between 3-4 hours into the stress response, separating an initially highly dynamic phase from a later relatively stagnant phase. This turning point in expression dynamics coincided with a phenotypic turning point, as shown by a strong decrease in movement, survival and, progeny count in the days following the stress. Both detectable at transcriptional and phenotypic level, this study pin-points a relatively small time frame during heat stress at which enough damage is accumulated, making it impossible to recover the next few days. PMID- 29228039 TI - Biochemical studies of two lytic polysaccharide monooxygenases from the white-rot fungus Heterobasidion irregulare and their roles in lignocellulose degradation. AB - Lytic polysaccharide monooxygenases (LPMO) are important redox enzymes produced by microorganisms for the degradation of recalcitrant natural polysaccharides. Heterobasidion irregulare is a white-rot phytopathogenic fungus that causes wood decay in conifers. The genome of this fungus encodes 10 putative Auxiliary Activity family 9 (AA9) LPMOs. We describe the first biochemical characterization of H. irregulare LPMOs through heterologous expression of two CBM-containing LPMOs from this fungus (HiLPMO9H, HiLPMO9I) in Pichia pastoris. The oxidization preferences and substrate specificities of these two enzymes were determined. The two LPMOs were shown to cleave different carbohydrate components of plant cell walls. HiLPMO9H was active on cellulose and oxidized the substrate at the C1 carbon of the pyranose ring at beta-1,4-glycosidic linkages, whereas HiLPMO9I cleaved cellulose with strict oxidization at the C4 carbon of glucose unit at internal bonds, and also showed activity against glucomannan. We propose that the two LPMOs play different roles in the plant-cell-wall degrading system of H. irregulare for degradation of softwood and that the lignocellulose degradation mediated by this white-rot fungus may require collective efforts from multi-types of LPMOs. PMID- 29228040 TI - Consequences of supplying methyl donors during pregnancy on the methylome of the offspring from lactating and non-lactating dairy cattle. AB - The aim of this study was to evaluate the potential effects of methyl donor supplementation of pregnant animals in the presence or absence of a concomitant lactation on the methylome of the offspring. Twenty Holstein cows, 10 nulliparous (non-lactating while pregnant) and 10 multiparous (lactating while pregnant) were blocked by parity and randomly assigned to an i.m. weekly injections of a placebo (CTRL) or a solution containing methyl donors (MET). After calving, 5 calves randomly selected from each treatment (two born to non-lactating and three to lactating dams) were blood-sampled to determine their full methylome. There were more than 2,000 CpG differentially methylated between calves born to CTRL and those born to MET, and also between calves born to lactating and non-lactating dams. Most of the differences affected genes involved in immune function, cell growth regulation and differentiation, kinase activity, and ion channeling. We conclude that the coexistence of pregnancy and lactation affects the methylome of the offspring, and that supplementation of methyl donors early in gestation has also consequences on the methylome. PMID- 29228041 TI - Correction: Demographic History and Reproductive Output Correlates with Intraspecific Genetic Variation in Seven Species of Indo-Pacific Mangrove Crabs. AB - [This corrects the article DOI: 10.1371/journal.pone.0158582.]. PMID- 29228042 TI - Risk of thromboembolism in cisplatin versus carboplatin-treated patients with lung cancer. AB - INTRODUCTION: Carboplatin is widely used to treat lung cancer in the United States as an alternative to cisplatin. Several studies have demonstrated that cisplatin-based regimen is associated with a high frequency of thromboembolic complications. However, there has been limited investigation directly comparing the risk of thromboembolic events (TEEs) between cisplatin- and carboplatin treated patients with lung cancer. METHODS: All lung cancer patients treated with cisplatin or carboplatin at Wilmot Cancer Center, University of Rochester between 2011 and 2014 were included. Patient characteristics including exposure (cisplatin vs. carboplatin) and outcome (TEEs between the time of the first dose of cisplatin or carboplatin and 4 weeks after the last dose) were collected by reviewing electronic medical records. A Fisher's exact test was used to compare the proportion of incident TEEs between cisplatin and carboplatin groups. The risk of TEE associated with carboplatin compared to cisplatin was assessed using multiple logistic regression. RESULTS: Among 415 subjects, 317 patients (76.4%) received carboplatin and 98 (23.6%) patients received cisplatin. In the carboplatin group, 10.9% (33/302) of evaluable patients developed treatment related TEEs vs. 14.7% (14/95) in the cisplatin group. There was no significant difference in the risk of developing TEEs between the two groups (P = 0.32). However, 15.2% of carboplatin-related TEEs were arterial thromboses compared to none in the cisplatin group. CONCLUSIONS: The incidence of carboplatin-related TEEs was high in lung cancer patients without significant difference in the risk of developing TEEs between cisplatin and carboplatin groups. Potential use of prophylactic anticoagulation in all platinum-treated patients should be further investigated. PMID- 29228044 TI - Correction: The importance of public health, poverty reduction programs and women's empowerment in the reduction of child stunting in rural areas of Moramanga and Morondava, Madagascar. AB - [This corrects the article DOI: 10.1371/journal.pone.0186493.]. PMID- 29228043 TI - Novel systems for the application of isolated tensile, compressive, and shearing stimulation of distraction callus tissue. AB - BACKGROUND: Distraction osteogenesis is a procedure widely used for the correction of large bone defects. However, a high complication rate persists, likely due to insufficient stability during maturation. Numerical fracture healing models predict bone regeneration under different mechanical conditions allowing fixation stiffness optimization. However, most models apply a linear elastic material law inappropriate for the transient stresses/strains present during limb lengthening or segment transport. They are also often validated using in vivo osteotomy models lacking precise mechanical regulation due to the unavoidable stimulation of secondary interfragmentary motion during ambulation under finitely stiff fixation. Therefore, in order to create a robust numerical model of distraction osteogenesis, it is necessary to both characterize the new tissue's viscoelasticity during distraction and determine the influence of strictly isolated stimulation in each loading mode (tension, compression, and shear) to account for potential differences in mechanical and histological response. AIM: Two electromechanical fixators with integrated load cells were designed to precisely perform and monitor in vivo lateral distraction and isolated stimulation in sheep tibiae using a mobile, hydroxyapatite-coated titanium plate. The novel surgical procedure circumvents osteotomy, eliminating the undesirable and unquantifiable mechanical stimulation during ambulation. METHODS: After a 10-day post-surgery latency period, two 0.275 mm distraction steps were performed daily for 10 days. The load cell collected data before, during, and after each distraction step and was terminated after no less than one minute from the time of distraction. A 7-day consolidation period separated the distraction phase and 18-day stimulation phase. Stimulation was carried out in isolated tension, compression, or shear while recording force/time data. Each stimulation session consisted of 120 cycles with a magnitude of either 0.1 mm or 0.6 mm in the tension and compression groups and 1.0 mm in the shear group. The animals were euthanized after a 3-day holding period following stimulation. RESULTS: Our initial results show that the tissue progressively stiffens and maintains an increasingly large residual traction. The force curves during compressive stimulation show a progressive drift from compression toward tension. We hypothesize that this behavior may be due to the preferential flow of fluid outward from the tissue and a greater resistance to reabsorption during the plate's return to the starting position. PMID- 29228045 TI - Mycobacterial infection induces higher interleukin-1beta and dysregulated lung inflammation in mice with defective leukocyte NADPH oxidase. AB - Granulomatous inflammation causes severe tissue damage in mycobacterial infection while redox status was reported to be crucial in the granulomatous inflammation. Here, we used a NADPH oxidase 2 (NOX2)-deficient mice (Ncf1-/-) to investigate the role of leukocyte-produced reactive oxygen species (ROS) in mycobacterium induced granulomatous inflammation. We found poorly controlled mycobacterial proliferation, significant body weight loss, and a high mortality rate after M. marinum infection in Ncf1-/- mice. Moreover, we noticed loose and neutrophilic granulomas and higher levels of interleukin (IL)-1beta and neutrophil chemokines in Ncf1-/- mice when compared with those in wild type mice. The lack of ROS led to reduced production of IL-1beta in macrophages, whereas neutrophil elastase (NE), an abundant product of neutrophils, may potentially exert increased inflammasome-independent protease activity and lead to higher IL-1beta production. Moreover, we showed that the abundant NE and IL-1beta were present in the caseous granulomatous inflammation of human TB infection. Importantly, blocking of IL-1beta with either a specific antibody or a recombinant IL-1 receptor ameliorated the pulmonary inflammation. These findings revealed a novel role of ROS in the early pathogenesis of neutrophilic granulomatous inflammation and suggested a potential role of IL-1 blocking in the treatment of mycobacterial infection in the lung. PMID- 29228046 TI - Genome-wide microarray analysis leads to identification of genes in response to herbicide, metribuzin in wheat leaves. AB - Herbicides are an important component of weed management in wheat, particularly in the southeastern US where weeds actively compete with wheat throughout the winter for nutrients and reduce tillering and ultimately the yield of the crop. Some wheat varieties are sensitive to metribuzin, a low-cost non-selective herbicide, leading to leaf chlorosis, stand loss, and decreased yield. Knowledge of the genetics of herbicide tolerance in wheat is very limited and most new varieties have not been screened for metribuzin tolerance. The identification of genes associated with metribuzin tolerance will lead to the development of molecular markers for use in screening breeding lines for metribuzin tolerance. AGS 2035 and AGS 2060 were identified as resistant and sensitive to metribuzin in several previous field screening experiments as well as controlled condition screening of nine varieties in the present study. Genome-wide transcriptome profiling of the genes in AGS 2035 and AGS 2060 through microarray analysis identified 169 and 127 genes to be significantly (2-fold, P>0.01) up- and down regulated, respectively in response to metribuzin. Functional annotation revealed that genes involved in cell wall biosynthesis, photosynthesis and sucrose metabolism were highly responsive to metribuzin application. (Semi)quantitative RT-PCR of seven selected differentially expressed genes (DEGs) indicated that a gene coding for alkaline alpha-galactosidase 2 (AAG2) was specifically expressed in resistant varieties only after one and two weeks of metribuzin application. Integration of the DEGs into our ongoing mapping effort and identification of the genes within the QTL region showing significant association with resistance in future will aid in development of functional markers for metribuzin resistance. PMID- 29228047 TI - Stability of serum ferritin measured by immunoturbidimetric assay after storage at -80 degrees C for several years. AB - BACKGROUND: Iron deficiency (ID) may impair long-term neurological development when it occurs in young infants. In cohort studies, it is sometimes necessary to evaluate ID with sera kept frozen for several years. To assess ID, learned societies recommend measuring serum ferritin (SF) level combined with C-reactive protein level. The long-term stability of C-reactive protein in frozen samples is well established but not ferritin. METHODS: We measured SF level (immunoturbidimetric assay; in micrograms per liter) immediately after collection from 53 young adults recruited and followed-up in Porto, Portugal, from 2011 to 2013 (SF1), and then, in 2016 in two aliquots kept frozen at- 80 degrees C for 3 to 5 years: one without (SF2A) and one with (SF2B) intermediate thawing in 2014. We compared SF1 to SF2A then SF2B; statistical agreement was evaluated by the Bland and Altman method and the effect of intermediate thawing by regression modelling. RESULTS: Mean SF2A-SF1 and SF2B-SF1 differences were -2.1 (SD 7.0) and 48.9 (SD 66.9). Values for Bland and Altman 95% limits of agreement were higher for the comparison of SF2B and SF1 than SF2A and SF1: -82.2 to 179.9 and -15.8 to 11.8, respectively; the effect of thawing was highly significant (p <0.001). CONCLUSIONS: Agreement between SF values before and after 3 to 5 years of constant freezing at -80 degrees C was in a generally accepted range, which supports the hypothesis of ferritin's stability at this temperature for a long period. In long-term storage by freezing, intermediate thawing induced a major increase in values. PMID- 29228048 TI - Trends in the management levels of metabolic risk factors in middle-aged and elderly patients with type 2 diabetes mellitus: The Korean National Health and Nutrition Examination Survey 1998-2014. AB - The present study examined the temporal trends in the management of blood pressure, glucose, and lipid levels among middle-aged and elderly patients with type 2 diabetes using data from the Korean National Health and Nutrition Examination Survey (1998-2014). A total of 3,689 patients with diabetes were included and divided into middle-aged (30-64 years old) and elderly (>=65 years old) groups. Demographic and lifestyle data were obtained using a self-reported questionnaire, and trained medical staff obtained fasting blood samples and blood pressure data. Laboratory testing was performed to determine blood glucose, cholesterol, and triglyceride levels. In the multivariable adjusted models, significant decreasing trends in the prevalences of hyperglycemia and hypertension were observed in both age groups during 1998-2014, although no trends were observed for lipid levels. Based on the most recent survey, approximately 50% of patients with diabetes had hyperglycemia, and one-third of patients with diabetes and hypertension did not appropriately manage their blood pressure. In addition, 50% of the patients in both age groups did not manage their lipid profiles, and the management of lipid profiles did not improve in recent years. These results suggest that continuous follow-up is needed to effectively manage metabolic risk factors, especially lipid profiles, among patients with diabetes. PMID- 29228049 TI - Correction: Assessment of gold nanoparticles on human peripheral blood cells by metabolic profiling with 1H-NMR spectroscopy, a novel translational approach on a patient-specific basis. AB - [This corrects the article DOI: 10.1371/journal.pone.0182985.]. PMID- 29228051 TI - White blood cell differential count of maturation stages in bone marrow smear using dual-stage convolutional neural networks. AB - The white blood cell differential count of the bone marrow provides information concerning the distribution of immature and mature cells within maturation stages. The results of such examinations are important for the diagnosis of various diseases and for follow-up care after chemotherapy. However, manual, labor-intensive methods to determine the differential count lead to inter- and intra-variations among the results obtained by hematologists. Therefore, an automated system to conduct the white blood cell differential count is highly desirable, but several difficulties hinder progress. There are variations in the white blood cells of each maturation stage, small inter-class differences within each stage, and variations in images because of the different acquisition and staining processes. Moreover, a large number of classes need to be classified for bone marrow smear analysis, and the high density of touching cells in bone marrow smears renders difficult the segmentation of single cells, which is crucial to traditional image processing and machine learning. Few studies have attempted to discriminate bone marrow cells, and even these have either discriminated only a few classes or yielded insufficient performance. In this study, we propose an automated white blood cell differential counting system from bone marrow smear images using a dual-stage convolutional neural network (CNN). A total of 2,174 patch images were collected for training and testing. The dual-stage CNN classified images into 10 classes of the myeloid and erythroid maturation series, and achieved an accuracy of 97.06%, a precision of 97.13%, a recall of 97.06%, and an F-1 score of 97.1%. The proposed method not only showed high classification performance, but also successfully classified raw images without single cell segmentation and manual feature extraction by implementing CNN. Moreover, it demonstrated rotation and location invariance. These results highlight the promise of the proposed method as an automated white blood cell differential count system. PMID- 29228052 TI - Tools for fairness: Increased structure in the selection process reduces discrimination. AB - Employment discrimination causes problems at the labor market, and is hard to combat. Can increasing the degree of structure when selecting applicants increase fairness? Students were asked to perform a computerized selection task and were either provided with tools for systematizing information about the applicants (structured selection) or no such tools (unstructured selection). We hypothesized and found that a structured process, where employing recruitment tools rather than the recruiter's impressionistic judgment is key, improves the ability to identify job-relevant criteria and hence selecting more qualified applicants, even when in-group favoritism is tempting (e.g. when the outgroup applicants are more competent). Increasing structure helped recruiters select more competent applicants and reduced ethnic discrimination. Increasing the motivation to carefully follow the structured procedure strengthened these effects further. We conclude that structure pays off, and that motivational factors should be taken into account in order for it to have the optimal effect. PMID- 29228050 TI - Birth preparedness and complication readiness (BPCR) among pregnant women in hard to-reach areas in Bangladesh. AB - BACKGROUND: Birth preparedness and complication readiness aims to reduce delays in care seeking, promote skilled birth attendance, and facility deliveries. Little is known about birth preparedness practices among populations living in hard-to-reach areas in Bangladesh. OBJECTIVES: To describe levels of birth preparedness and complication readiness among recently delivered women, identify determinants of being better prepared for birth, and assess the impact of greater birth preparedness on maternal and neonatal health practices. METHODS: A cross sectional survey with 2,897 recently delivered women was undertaken in 2012 as part of an evaluation trial done in five hard-to-reach districts in rural Bangladesh. Mothers were considered well prepared for birth if they adopted two or more of the four birth preparedness components. Descriptive statistics and multivariable logistic regression were used for analysis. RESULTS: Less than a quarter (24.5%) of women were considered well prepared for birth. Predictors of being well-prepared included: husband's education (OR = 1.3; CI: 1.1-1.7), district of residence, exposure to media in the form of reading a newspaper (OR = 2.2; CI: 1.2-3.9), receiving home visit by a health worker during pregnancy (OR = 1.5; CI: 1.2-1.8), and receiving at least 3 antenatal care visits from a qualified provider (OR = 1.4; CI: 1.0-1.9). Well-prepared women were more likely to deliver at a health facility (OR = 2.4; CI: 1.9-3.1), use a skilled birth attendant (OR = 2.4, CI: 1.9-3.1), practice clean cord care (OR = 1.3, CI: 1.0 1.5), receive post-natal care from a trained provider within two days of birth for themselves (OR = 2.6, CI: 2.0-3.2) or their newborn (OR = 2.6, CI: 2.1-3.3), and seek care for delivery complications (OR = 1.8, CI: 1.3-2.6). CONCLUSION: Greater emphasis on BPCR interventions tailored for hard to reach areas is needed to improve skilled birth attendance, care seeking for complications and essential newborn care and facilitate reductions in maternal and neonatal mortality in low performing districts in Bangladesh. PMID- 29228053 TI - Traditional scientific data vs. uncoordinated citizen science effort: A review of the current status and comparison of data on avifauna in Southern Brazil. AB - Data generated by citizen science is particularly valuable in ecological research. If used discerningly with data from traditional scientific references, citizen science can directly contribute to biogeography knowledge and conservation policies by increasing the number of species records in large geographic areas. Considering the current level of knowledge on south Brazilian avifauna, the large volume of data produced by uncoordinated citizen science effort (CS), and the growing need for information on changes in abundance and species composition, we have compiled an updated, general list of bird species occurrence within the state of Parana. We have listed extinct, invasive and recently-colonizing species as well as indicator species of the state's vegetation types. We further assess the degree of knowledge of different regions within the state based on data from traditional scientific references, and the effect of including CS data in the same analysis. We have compiled data on 766 bird species, based on 70,346 individual records from traditional scientific references, and 79,468 from CS. Extinct and invasive species were identified by comparing their occurrence and abundance over a series of three time periods. Indicator species analysis pointed to the existence of three areas with bird communities typically found within the state: the Semideciduous Tropical Forest, the Tropical Rainforest and the junction of Grassland and Araucaria Moist Forest. We used rarefaction to measure sampling sufficiency, and found that rarefaction curves reached stabilization for all vegetation types except in Savanna. We observed differences in the level of knowledge of bird biodiversity among the microregions of the state, but including CS data, these differences were mitigated. The same effect was observed in other exploratory analyzes conducted here, emphasizing the fundamental importance of including CS data in macroecological studies. Production of easily accessible data and its unrestricted availability makes CS a very important tool, especially in highly diverse regions as the Neotropics, as it can offer a more accurate picture of bird composition in comparison to the exclusive use of traditional scientific references. PMID- 29228054 TI - Brain-to-brain hyperclassification reveals action-specific motor mapping of observed actions in humans. AB - Seeing an action may activate the corresponding action motor code in the observer. It remains unresolved whether seeing and performing an action activates similar action-specific motor codes in the observer and the actor. We used novel hyperclassification approach to reveal shared brain activation signatures of action execution and observation in interacting human subjects. In the first experiment, two "actors" performed four types of hand actions while their haemodynamic brain activations were measured with 3-T functional magnetic resonance imaging (fMRI). The actions were videotaped and shown to 15 "observers" during a second fMRI experiment. Eleven observers saw the videos of one actor, and the remaining four observers saw the videos of the other actor. In a control fMRI experiment, one of the actors performed actions with closed eyes, and five new observers viewed these actions. Bayesian canonical correlation analysis was applied to functionally realign observers' and actors' fMRI data. Hyperclassification of the seen actions was performed with Bayesian logistic regression trained on actors' data and tested with observers' data. Without the functional realignment, between-subjects accuracy was at chance level. With the realignment, the accuracy increased on average by 15 percentage points, exceeding both the chance level and the accuracy without functional realignment. The highest accuracies were observed in occipital, parietal and premotor cortices. Hyperclassification exceeded chance level also when the actor did not see her own actions. We conclude that the functional brain activation signatures underlying action execution and observation are partly shared, yet these activation signatures may be anatomically misaligned across individuals. PMID- 29228055 TI - Transcriptional profiling of sugarcane leaves and roots under progressive osmotic stress reveals a regulated coordination of gene expression in a spatiotemporal manner. AB - Sugarcane is one of the most important crops worldwide and is a key plant for the global production of sucrose. Sugarcane cultivation is severely affected by drought stress and it is considered as the major limiting factor for their productivity. In recent years, this plant has been subjected to intensive research focused on improving its resilience against water scarcity; particularly the molecular mechanisms in response to drought stress have become an underlying issue for its improvement. To better understand water stress and the molecular mechanisms we performed a de novo transcriptomic assembly of sugarcane (var. Mex 69-290). A total of 16 libraries were sequenced in a 2x100 bp configuration on a HiSeq-Illumina platform. A total of 536 and 750 genes were differentially up regulated along with the stress treatments for leave and root tissues respectively, while 1093 and 531 genes were differentially down-regulated in leaves and roots respectively. Gene Ontology functional analysis showed that genes related to response of water deprivation, heat, abscisic acid, and flavonoid biosynthesis were enriched during stress treatment in our study. The reliability of the observed expression patterns was confirmed by RT-qPCR. Additionally, several physiological parameters of sugarcane were significantly affected due to stress imposition. The results of this study may help identify useful target genes and provide tissue-specific data set of genes that are differentially expressed in response to osmotic stress, as well as a complete analysis of the main groups is significantly enriched under this condition. This study provides a useful benchmark for improving drought tolerance in sugarcane and other economically important grass species. PMID- 29228056 TI - Back and neck pain and function in females with adolescent idiopathic scoliosis: A follow-up at least 23 years after conservative treatment with a Milwaukee brace. AB - We aimed to explore the long-term outcomes of back and neck pain and functionality in adult females with adolescent idiopathic scoliosis (AIS), who had been treated with a Milwaukee brace, in a follow-up study a minimum of 23 years after the completion of the treatment, using radiological, clinical and socio-demographical data. Thirty AIS patients (scoliosis group-SG), were included in the study based on an extensive search of Pediatric Orthopedics and Traumatology Clinic charts. All treatments were successfully completed between 1974 and 1990. In all cases, scoliosis had not been detected before the age of 10 and was not combined with any major spinal deformities at the time when the brace treatment was implemented. In those patients, the Risser sign 4 and minimum two years post-menarche was defined as a maturity, after that time the brace treatment was completed. Patients were excluded from the study if they, at the time of the follow-up examinations, suffered from any other disease leading to trunk deformity. Forty patients met the criteria for inclusion, but due to change some personal details, not all of them were contacted. Finally, 30 women returned for a follow-up evaluation. Patients' follow-up period was mean 27.77 yrs. +/- SD 3.30 (range 23-35). Curvature change from the end of the treatment until the present day was mean 9.1 degrees +/- SD 7.64 (range 0-27). A control group of 42 healthy females (healthy controls group-HG) matching the age profile of the patient group was randomly selected for comparative purposes.Both SG and HG completed the Polish versions of the Revised Oswestry Lower Back Pain Disability Index (RODI), the Rolland-Morris Questionnaire (RMQ), the Quebec Back Pain Disability Scale (QDS), the Neck Disability Index (NDI) and the Copenhagen Neck Functional Disability Scale (CNFDS). Descriptive statistics were calculated for demographics and baseline questionnaire scores. To determine if the investigated sample sizes are equivalent, the chi-square test was used. The chi-square test was used to compare qualitative features between persons with scoliosis and healthy controls. In addition, a Mann-Whitney test was utilized to compare differences between both groups in regard to quantitative characteristics. To establish relations between quantitative data such as e.g. age, duration of brace application, apical translation, Cobb angle, and questionnaire results, we used Spearman's rank correlation (marked as rS). To determine dependency between quantitative and qualitative characteristics, e.g. between questionnaire numerical data and marital status, place of residence or curve type, ANOVA Kruskal-Wallis test was used. A p<0.05 indicates statistical significance. Statistical calculations were performed by Statistica software. In regards to RODI, RMQ, QDS, NDI and CNFDS (both for total scores and particular sub sections), statistically significant differences (p <0.001) between both samples were found, indicating higher levels of pain and neck and lower back pain-related disability among persons with scoliosis. Associations exist between RODI and RMQ (rS = 0.76) QDS (rS = 0.70), NDI (rS = 0.69) and CNFDS (rS = 0.60). RMQ was associated with QDS (rS = 0.71) and NDI (rS = 0.69), whereas QDS correlated with NDI (rS = 0.80) and CNFDS (rS = 0.60). NDI was also associated with CNFDS (rS = 0.81). Persons with scoliosis treated in adolescence with a Milwaukee brace display significant restrictions in everyday activities, due to lower back pain (LBP) and neck-related disabilities, compared to healthy controls. In addition, back pain is associated with curve progression in long-term follow-up after conservative treatment. Moreover, LBP-related disability coexists with restrictions experienced due to neck pain. PMID- 29228057 TI - N-acetylcysteine (NAC) ameliorates Epstein-Barr virus latent membrane protein 1 induced chronic inflammation. AB - Chronic inflammation results when the immune system responds to trauma, injury or infection and the response is not resolved. It can lead to tissue damage and dysfunction and in some cases predispose to cancer. Some viruses (including Epstein-Barr virus (EBV)) can induce inflammation, which may persist even after the infection has been controlled or cleared. The damage caused by inflammation, can itself act to perpetuate the inflammatory response. The latent membrane protein 1 (LMP1) of EBV is a pro-inflammatory factor and in the skin of transgenic mice causes a phenotype of hyperplasia with chronic inflammation of increasing severity, which can progress to pre-malignant and malignant lesions. LMP1 signalling leads to persistent deregulated expression of multiple proteins throughout the mouse life span, including TGFalpha S100A9 and chitinase-like proteins. Additionally, as the inflammation increases, numerous chemokines and cytokines are produced which promulgate the inflammation. Deposition of IgM, IgG, IgA and IgE and complement activation form part of this process and through genetic deletion of CD40, we show that this contributes to the more tissue destructive aspects of the phenotype. Treatment of the mice with N-acetylcysteine (NAC), an antioxidant which feeds into the body's natural redox regulatory system through glutathione synthesis, resulted in a significantly reduced leukocyte infiltrate in the inflamed tissue, amelioration of the pathological features and delay in the inflammatory signature measured by in vivo imaging. Reducing the degree of inflammation achieved through NAC treatment, had the knock on effect of reducing leukocyte recruitment to the inflamed site, thereby slowing the progression of the pathology. These data support the idea that NAC could be considered as a treatment to alleviate chronic inflammatory pathologies, including post-viral disease. Additionally, the model described can be used to effectively monitor and accurately measure therapies for chronic inflammation. PMID- 29228058 TI - Altered intragenic DNA methylation of HOOK2 gene in adipose tissue from individuals with obesity and type 2 diabetes. AB - AIMS/HYPOTHESIS: Failure in glucose response to insulin is a common pathology associated with obesity. In this study, we analyzed the genome wide DNA methylation profile of visceral adipose tissue (VAT) samples in a population of individuals with obesity and assessed whether differential methylation profiles are associated with the presence of type 2 diabetes (T2D). METHODS: More than 485,000 CpG genome sites from VAT samples from women with obesity undergoing gastric bypass (n = 18), and classified as suffering from type 2 diabetes (T2D) or not (no type 2 diabetes, NT2D), were analyzed using DNA methylation arrays. RESULTS: We found significant differential methylation between T2D and NT2D samples in 24 CpGs that map with sixteen genes, one of which, HOOK2, demonstrated a significant correlation between differentially hypermethylated regions on the gene body and the presence of type 2 diabetes. This was validated by pyrosequencing in a population of 91 samples from both males and females with obesity. Furthermore, when these results were analyzed by gender, female T2D samples were found hypermethylated at the cg04657146-region and the cg 11738485 region of HOOK2 gene, whilst, interestingly, male samples were found hypomethylated in this latter region. CONCLUSION: The differential methylation profile of the HOOK2 gene in individuals with T2D and obesity might be related to the attendant T2D, but further studies are required to identify the potential role of HOOK2 gene in T2D disease. The finding of gender differences in T2D methylation of HOOK2 also warrants further investigation. PMID- 29228059 TI - Does access to clinical study reports from the European Medicines Agency reduce reporting biases? A systematic review and meta-analysis of randomized controlled trials on the effect of erythropoiesis-stimulating agents in cancer patients. AB - Since 2010, the European Medicines Agency (EMA) has provided access to clinical study reports (CSRs). We requested CSRs for randomized controlled trials (RCTs) of erythropoiesis-stimulating agents (ESAs) in cancer patients from EMA and identified RCT publications with literature searches. We assessed CSR availability and completeness, the impact of unreported and unpublished data obtained from CSRs on the effects of ESAs on quality of life (QoL) of cancer patients, and discrepancies between data reported in the public domain and in CSRs. We used random-effects meta-analyses to evaluate the effect of ESAs on QoL measured with Functional Assessment of Cancer Therapy-Anemia (FACT-An), FACT Fatigue (FACT-F) and FACT-Anemia Total (FACT-An Total) stratified by data source and the impact of discrepancies on QoL, mortality, adverse events, and clinical effectiveness outcomes. We identified 94 eligible RCTs; CSRs or other study documentation were available for 17 (18%) RCTs at EMA. Median report length was 1,825 pages (range 72-14,569). Of 180 outcomes of interest reported in the EMA documentation, 127 (71%) were publicly available. For 80 of those (63%) we noted discrepancies, but these had little impact on the pooled effect estimates. Of 27 QoL outcomes reported in the CSRs, 17 (63%) were unpublished. Including six unpublished comparisons (pooled mean difference [MD] 0.20; 95% confidence interval [CI] -1.93, 2.33) reduced the pooled effect of ESAs for FACT-An from MD 5.51 (95% CI 4.20, 6.82) in published data to MD 3.21 (95% CI 1.38, 5.03), which is below a clinically important difference (defined as MD >=4). Effects were similar for FACT-F and FACT-An Total. Access to CSRs from EMA reduced reporting biases for QoL outcomes. However, EMA received documentation for a fraction of all RCTs on effects of ESAs in cancer patients. Additional efforts by other agencies and institutions are needed to make CSRs universally available for all RCTs. PMID- 29228060 TI - Model of hindlimb unloading in adult female rats: Characterizing bone physicochemical, microstructural, and biomechanical properties. AB - Prolonged bedrest and microgravity induce alterations to bone, leading to bone fragility and compromising the quality of life. In this study, we characterized the physicochemical changes, microstructure, and biomechanics of the femurs of female adult rats in response to hindlimb unloading for 21 days. Twenty 6-month old Wistar female rats were distributed into control (CON) and hindlimb unloading (HLU) groups. Analysis the in vivo bone mineral density (BMD) by dual energy x ray absorptiometry (DXA) from the femurs was performed at the beginning and end of the experiment; plasma levels of calcium, phosphorus, and alkaline phosphatase, tartrate-resistant acid phosphatase activity, assessed by spectrophotometry, and estradiol, measured by enzyme-linked immunosorbent assay, was performed after the experiment. We evaluated changes in the trabecular and cortical structure of the femur, after disuse, by micro-computed tomography with high resolution, for analysis of cortical porosity, Raman spectroscopy to measure the amount of physicochemical properties, and the biomechanical test to estimate the changes in biomechanical properties. Our results demonstrated that, after 21 days, HLU animals had decreased femoral BMD, deteriorated bone microarchitecture, particularly in the cortical compartment, with changes in the physicochemical properties and porosity, and reduced deformation capacity of the bone and resistance to the bone stresses. Nevertheless, this study showed the critical role of mechanical stimulation in maintaining the structure of the skeleton in female adults and that disuse, even for a few days, leads to microscopic changes in the structure of the bone matrix, which increases the risk of fracture. PMID- 29228061 TI - Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non natural amino acids. AB - As primary p53 antagonists, Mdm2 and the closely related Mdm4 are relevant cancer therapeutic targets. We have previously described a series of cell-permeable stapled peptides that bind to Mdm2 with high affinity, resulting in activation of the p53 tumour suppressor. Within this series, highest affinity was obtained by modification of an obligate tryptophan residue to the non-natural L-6 chlorotryptophan. To understand the structural basis for improved affinity we have solved the crystal structure of this stapled peptide (M011) bound to Mdm2 (residues 6-125) at 1.66 A resolution. Surprisingly, near identity to the structure of a related peptide (M06) without the 6-chloro modification is observed. Further analysis of linear and stapled peptides comprising 6-Me tryptophan provides mechanistic insight into dual Mdm2/Mdm4 antagonism and confirms L98 of Mdm4 as a mutable steric gate. The results also highlight a possible role of the flexible hinge region in determining Mdm2/Mdm4 plasticity. PMID- 29228062 TI - Market access and community size influence pastoral management of native and exotic livestock species: A case study in communities of the Cordillera Real in Bolivia's high Andean wetlands. AB - Grazing areas management is of utmost importance in the Andean region. In the valleys of the Bolivian Cordillera Real near La Paz, pastoralism constitutes the traditional way for people to insure food security and economical sustainability. In these harsh mountains, unique and productive wetlands sustained by glacial water streams are of utmost importance for feeding cattle herds during the dry season. After the colonization by the Spanish, a shift in livestock species has been observed, with the introduction of exotic species such as cows and sheep, resulting in a different impact on pastures compared to native camelid species llamas and alpacas. Here we explored some of the social-economical and environmental drivers that motivate Bolivian pastoralists to prefer exotic over native livestock species, based on 36 household surveys in the Cordillera Real. We constructed a Partial Least Squares Structural Equation Model in order to assess the relationships between these drivers. Our results suggest that the access to market influenced pastoralists to reshape their herd composition, by increasing the number of sheep. They also suggest that community size increased daily grazing time in pastures, therefore intensifying the grazing pressure. At a broader scale, this study highlights the effects of some social-economical and environmental drivers on mountain herding systems. PMID- 29228067 TI - Edema and Ulceration of the Lower Extremities-All That's Red Is Not Infection: A Teachable Moment. PMID- 29228068 TI - Emergency Department Stroke Care. PMID- 29228069 TI - Employment Status and Health Characteristics of Adults With Expanded Medicaid Coverage in Michigan. PMID- 29228070 TI - Importance of Hypotension and Its Definition After Cardiac Arrest. PMID- 29228063 TI - What matters in chronic Burkholderia cenocepacia infection in cystic fibrosis: Insights from comparative genomics. AB - Burkholderia cenocepacia causes severe pulmonary infections in cystic fibrosis (CF) patients. Since the bacterium is virtually untreatable by antibiotics, chronic infections persist for years and might develop into fatal septic pneumonia (cepacia syndrome, CS). To devise new strategies to combat chronic B. cenocepacia infections, it is essential to obtain comprehensive knowledge about their pathogenesis. We conducted a comparative genomic analysis of 32 Czech isolates of epidemic clone B. cenocepacia ST32 isolated from various stages of chronic infection in 8 CF patients. High numbers of large-scale deletions were found to occur during chronic infection, affecting preferentially genomic islands and nonessential replicons. Recombination between insertion sequences (IS) was inferred as the mechanism behind deletion formation; the most numerous IS group was specific for the ST32 clone and has undergone transposition burst since its divergence. Genes functionally related to transition metal metabolism were identified as hotspots for deletions and IS insertions. This functional category was also represented among genes where nonsynonymous point mutations and indels occurred parallelly among patients. Another category exhibiting parallel mutations was oxidative stress protection; mutations in catalase KatG resulted in impaired detoxification of hydrogen peroxide. Deep sequencing revealed substantial polymorphism in genes of both categories within the sputum B. cenocepacia ST32 populations, indicating extensive adaptive evolution. Neither oxidative stress response nor transition metal metabolism genes were previously reported to undergo parallel evolution during chronic CF infection. Mutations in katG and copper metabolism genes were overrepresented in patients where chronic infection developed into CS. Among professional phagocytes, macrophages use both hydrogen peroxide and copper for their bactericidal activity; our results thus tentatively point to macrophages as suspects in pathogenesis towards the fatal CS. PMID- 29228072 TI - An Implementation Guide to Reducing Overtreatment of Asymptomatic Bacteriuria. AB - Treatment of asymptomatic bacteriuria (ASB) frequently lacks appropriate indication, yet remains prevalent across settings. Numerous guidelines, professional societies, and campaigns such as Choosing Wisely advocate against this low-value practice. Efforts aimed at reducing unnecessary treatment of ASB demonstrate improved costs, and avoidable harm without increased risk of adverse events. We propose an evidence-based implementation guide to aid practitioners in reducing inappropriate treatment of ASB. PMID- 29228073 TI - Dying at Home-Our Grandfather's Great Escape. PMID- 29228071 TI - Associations Between Tau, beta-Amyloid, and Cognition in Parkinson Disease. AB - Importance: Multiple disease processes are associated with cognitive impairment in Parkinson disease (PD), including Lewy bodies, cerebrovascular disease, and Alzheimer disease. It remains unknown whether tau pathology relates to cognition in patients with PD without dementia. Objective: To compare tau aggregation in patients with PD who are cognitively normal (PD-CN), patients with PD with mild cognitive impairment (PD-MCI), and healthy control participants, and evaluate the relationships between beta-amyloid (Abeta), tau, and cognition in patients with PD who did not have dementia. Design, Setting, and Participants: This cross sectional study recruited 30 patients with Parkinson disease (15 with PD-CN and 15 with PD-MCI) from a tertiary care medical center and research institutions from July 2015 through October 2016. One patient with PD-MCI did not receive a magnetic resonance imaging scan and thus was excluded from all analyses; 29 patients with PD were included in the present study. Participants underwent tau positron emission tomographic (PET) scanning with fluorine 18-labeled AV-1451, Abeta PET scanning with carbon 11-labeled Pittsburgh compound B, magnetic resonance imaging, cognitive testing, and neurologic evaluation. Imaging measures were compared with 49 healthy control participants. Main Outcomes and Measures: Outcomes were tau PET measurements of groups of patients with PD-CN and PD-MCI. We hypothesized that tau aggregation across groups would be related to age and Abeta status. Results: Of the 78 participants, 47 (60%) were female, and the mean (SD) age was 71.1 (6.6) years. Six patients with PD (21%) were Abeta-positive, of whom 1 was mildly cognitively impaired; 23 were Abeta-negative (79%). (Of the 49 healthy controls, 25 were Abeta-negative and 24 Abeta-positive.) Voxelwise contrasts of whole-brain tau PET uptake between patients with PD-CN and patients with PD-MCI, and additionally between all patients with PD and Abeta-negative controls, did not reveal significant differences. Tau PET binding did not differ between patients with PD-MCI and PD-CN in brain regions reflecting Alzheimer disease Braak stages 1/2, 3/4, or 5/6, and did not differ from Abeta-negative healthy older adults. Mean (SD) tau PET binding was significantly elevated in Abeta-positive patients with PD relative to Abeta-negative patients with PD within brain regions reflecting Alzheimer disease Braak stage 3/4 (1.22 [0.07] vs 1.14 [0.07]; P = .03) and Braak stage 5/6 (1.20 [0.07] vs 1.11 [0.08]; P = .02). Conclusions and Relevance: These findings suggest that patterns of cortical Abeta and tau do not differ in people with PD-CN, people with PD-MCI, and healthy older adults. Age, Abeta, and tau do not differentiate patients with PD-CN and PD-MCI. Tau deposition is related to Abeta status and age in both people with PD and healthy older adults. Cognitive deficits in people with PD without dementia do not appear to reflect measureable Alzheimer disease. PMID- 29228074 TI - A Review of the Current Therapies, Challenges, and Future Directions of Transcranial Focused Ultrasound Technology: Advances in Diagnosis and Treatment. AB - Importance: Magnetic resonance imaging-guided focused ultrasound ablation has been approved for the treatment of refractory essential tremor and is being studied for other neurological indications, including dyskinesias and tremor in Parkinson disease, dystonia, neuropathic pain, obsessive-compulsive disorder, epilepsy, and brain tumors. Objective: To review the scientific foundations of FUS technology, existing neurological applications, and future advances. Evidence Review: PubMed was searched for the past 10 years using the terms "transcranial ultrasound," "focused ultrasound," and "neurological applications." Relevant references were selected from the author's reference collection. From the 2855 unique records, 243 publications were screened. After excluding abstracts detailing in vitro studies or non-neurological applications, 86 full texts were retrieved for qualitative review. Findings: Advances in the transducer design and electronic phase correction have allowed efficient focusing of ultrasounds for transcranial treatment. The mid-frequency (650 kHz) transducer can make small (4 6 mm in diameter) and precise (accuracy of <2 mm) brain lesions. The treatment monitoring is achieved via "live" anatomical thermography imaging and clinical feedback. The initial results from its clinical application in movement disorders are encouraging. Emerging applications in epilepsy and neurobehavioral and cognitive disorders are being explored. The low-frequency (220 kHz) transducer coupled with microbubbles can potentially enable targeted drug delivery for novel applications, such as Alzheimer disease and brain tumors. Finally, neuromodulation with subthreshold sonications may allow the interrogation of brain areas previously not accessible for electrical stimulation. Conclusions and Relevance: Transcranial focused ultrasound for both ablative and nonablative applications is noninvasive, making it suitable for selected patients who are not candidates for conventional surgical options. Future advancements in imaging and sonication algorithms will improve the safety and efficacy of this technology. PMID- 29228075 TI - Errors in Text. PMID- 29228076 TI - Deflazacort-New Costs of an Old Medicine. PMID- 29228078 TI - Error in Figure 3. PMID- 29228077 TI - Nusinersen for Spinal Muscular Atrophy: Are We Paying Too Much for Too Little? PMID- 29228080 TI - Profound Electrocardiogram Changes in a Patient With Liver Cirrhosis. PMID- 29228081 TI - Emergency Department Stroke Care-Reply. PMID- 29228079 TI - Effect of High-Intensity Treadmill Exercise on Motor Symptoms in Patients With De Novo Parkinson Disease: A Phase 2 Randomized Clinical Trial. AB - Importance: Parkinson disease is a progressive neurologic disorder. Limited evidence suggests endurance exercise modifies disease severity, particularly high intensity exercise. Objectives: To examine the feasibility and safety of high intensity treadmill exercise in patients with de novo Parkinson disease who are not taking medication and whether the effect on motor symptoms warrants a phase 3 trial. Design, Setting, and Participants: The Study in Parkinson Disease of Exercise (SPARX) was a phase 2, multicenter randomized clinical trial with 3 groups and masked assessors. Individuals from outpatient and community-based clinics were enrolled from May 1, 2012, through November 30, 2015, with the primary end point at 6 months. Individuals with idiopathic Parkinson disease (Hoehn and Yahr stages 1 or 2) aged 40 to 80 years within 5 years of diagnosis who were not exercising at moderate intensity greater than 3 times per week and not expected to need dopaminergic medication within 6 months participated in this study. A total of 384 volunteers were screened by telephone; 128 were randomly assigned to 1 of 3 groups (high-intensity exercise, moderate-intensity exercise, or control). Interventions: High-intensity treadmill exercise (4 days per week, 80%-85% maximum heart rate [n = 43]), moderate-intensity treadmill exercise (4 days per week, 60%-65% maximum heart rate [n = 45]), or wait-list control (n = 40) for 6 months. Main Outcomes and Measures: Feasibility measures were adherence to prescribed heart rate and exercise frequency of 3 days per week and safety. The clinical outcome was 6-month change in Unified Parkinson's Disease Rating Scale motor score. Results: A total of 128 patients were included in the study (mean [SD] age, 64 [9] years; age range, 40-80 years; 73 [57.0%] male; and 108 [84.4%] non-Hispanic white). Exercise rates were 2.8 (95% CI, 2.4-3.2) days per week at 80.2% (95% CI, 78.8%-81.7%) maximum heart rate in the high-intensity group and 3.2 (95% CI, 2.8-3.6; P = .13) days per week at 65.9% (95% CI, 64.2% 67.7%) maximum heart rate in the moderate-intensity group (P < .001). The mean change in Unified Parkinson's Disease Rating Scale motor score in the high intensity group was 0.3 (95% CI, -1.7 to 2.3) compared with 3.2 (95% CI, 1.4 to 5.1) in the usual care group (P = .03). The high-intensity group, but not the moderate-intensity group, reached the predefined nonfutility threshold compared with the control group. Anticipated adverse musculoskeletal events were not severe. Conclusions and Relevance: High-intensity treadmill exercise may be feasible and prescribed safely for patients with Parkinson disease. An efficacy trial is warranted to determine whether high-intensity treadmill exercise produces meaningful clinical benefits in de novo Parkinson disease. Trial Registration: clinicaltrials.gov Identifier: NCT01506479. PMID- 29228082 TI - Emergency Department Stroke Care. PMID- 29228084 TI - Response to "Does Stromal Vascular Fraction Supplementation Improve Facial Lipotransfer?" PMID- 29228083 TI - Low pO2 Contributes to Potential Error in Oxygen Saturation Calculations Using a Point-of-Care Assay. AB - Objectives: The present study addressed the accuracy of calculated oxygen saturation (sO2) using point-of-care (POC) testing compared with measured values on a blood gas analyzer. Methods: In total, 3,323 sO2 values were measured in 1,180 patients using a CO-oximeter (ABL 800 Flex; Radiometer, Copenhagen, Denmark). Measured parameters were then used to calculate an expected sO2 for the POC method (Abbott i-STAT; Abbott POC, Princeton, NJ). Cases in which calculated sO2 differed from measured sO2 by 10% or more were analyzed. Results: Of the 3,323 comparisons performed, 260 (8%) showed discrepancies (+/- >=10%) between measured and calculated sO2 values. Ninety-four of discrepant measurements (245 of 260) occurred when pO2 was less than 50 mm Hg. pH and bicarbonate distributions shifted to lower values in discrepant vs nondiscrepant cases. Conclusions: Our results suggest that the likelihood of discrepant sO2 is 27% among patients with pO2 less than 50 mm Hg. Direct measurement of sO2 by CO oximetry is strongly suggested in this clinical scenario. PMID- 29228085 TI - Immunolocalization of CD163+ Tumor-Associated Macrophages and Symmetric Proliferation of Ki-67 as Biomarkers to Differentiate New Different Grades of Laryngeal Dysplasia. AB - Objectives: To evaluate CD163+ tumor-associated macrophages (TAMs), Ki-67, and cyclin D1 to differentiate laryngeal dysplasia in the 2017 World Health Organization classification. Methods: Immunohistochemistry for CD163, Ki-67, and cyclin D1 was performed using paraffin-embedded specimens. CD163+ TAMs infiltrating the epithelium were estimated. Ki-67 and cyclin D1 were evaluated in four parts of the epithelium-basal, parabasal, middle third, and upper third layers. Results: In total, 133 specimens were analyzed, including low-grade dysplasia (n = 31), high-grade dysplasia (n = 49), carcinoma in situ (n = 23), and normal mucosa (n = 30). CD163+ TAMs infiltrating the epithelium were significantly higher in high-grade dysplasia than in low-grade dysplasia. In the basal layer, Ki-67+ and cyclin D1+ cells were overexpressed in high-grade dysplasia (P < .0001). The area under the curve was 0.958 for Ki-67 and 0.909 for CD163+ TAMs (P < .0001). Conclusions: CD163+ TAMs infiltrating the epithelium and Ki-67 overexpression in the basal layer may serve as biomarkers to differentiate low-grade dysplasia from high-grade dysplasia of the larynx. A symmetric proliferative pattern was observed during laryngeal carcinogenesis following Ki 67 overexpression. PMID- 29228086 TI - New Methods to Study the Microcirculation. AB - Essential hypertension is associated with structural alterations in the microvessels; in particular, an increase in the media thickness to internal lumen ratio of small resistance arteries (MLR) and a reduction in capillary density have been observed. The evaluation of the morphological characteristics of small resistance arteries in humans is challenging. The gold-standard method is generally considered to be the measurement by wire or pressure micromyography of MLR of subcutaneous small vessels obtained by local biopsies. However, noninvasive techniques for the evaluation of retinal arterioles were recently proposed; in particular, 2 approaches, scanning laser Doppler flowmetry (SLDF) and adaptive optics (AO), seem to provide useful information. Both of them provide an estimation of the wall to lumen ratio (WLR) of retinal arterioles. Moreover, a noninvasive measurement of basal and total capillary density may be obtained by videomicroscopy/capillaroscopy. It has been recently demonstrated that AO has a substantial advantage over SLDF in terms of evaluation of microvascular morphology, since WLR measured with AO is more closely correlated with the M/L of subcutaneous small arteries. The possibility to noninvasively assess in a reliable way, microvascular morphology in a clinical setting may represent a major advancement, since micromyography has substantial limitations in its application due to the local invasiveness of the procedure. PMID- 29228088 TI - Single Pill Combinations as Initial Therapy in the Management of Hypertension: What is Taking you so Long? PMID- 29228087 TI - Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. AB - Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Patients and methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Results: Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. Clinical trials registration: NCT01183780. PMID- 29228089 TI - Prophylactic Preprocedure Platelet Transfusion Is Associated With Increased Risk of Thrombosis and Mortality. AB - Objectives: We evaluated thrombosis and mortality rates of hospitalized patients receiving prophylactic platelet transfusion prior to an invasive procedure. Methods: Patient age and underlying medical condition(s), preprocedure and postprocedure platelet counts, type of procedure, number of platelet products transfused, and any complications were recorded on every prophylactic platelet given prior to an invasive procedure. Results: A total of 376 prophylactic transfusion recipients were identified. Nineteen (5%) thrombotic events were identified and 60 (16%) deaths occurred within 30 days of the preprocedure platelet transfusion. Most deaths were due to infection, sepsis, or organ failure, and none were due to bleeding or thrombosis. Conclusions: Preprocedure platelet transfusion is associated with an increased risk of thrombosis and 30 day mortality. Whether these findings are due to higher incidences of comorbidities and confounding or to cause and effect is not determinable from these data. This study highlights an association between prophylactic platelet transfusion and thrombosis and poor outcome, including death. PMID- 29228090 TI - Epstein-Barr Virus-Positive Extranodal Marginal Zone Lymphoma of Bronchial Associated Lymphoid Tissue in the Posttransplant Setting: An Immunodeficiency Related (Posttransplant) Lymphoproliferative Disorder? AB - Objectives: Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of hematolymphoid proliferations arising in the context of chronic immunosuppression. The common and indolent B-cell lymphomas, including extranodal marginal zone lymphomas (ENMZLs) of mucosa-associated lymphoid tissue (MALT), are excluded from the category of PTLD in the current World Health Organization classification. Methods: We report a case of Epstein-Barr virus (EBV)-positive bronchial-associated lymphoid tissue (BALT) lymphoma involving the lungs of a transplant patient. Results: Aside from history of cardiac transplant, young patient age, and EBV positivity, the histopathologic findings were indistinguishable from usual BALT lymphoma. Conclusions: We review the literature of ENMZL occurring in immunocompromised patients and present this case for consideration that this specific entity is a PTLD. We believe that additional studies might lend strength to the hypothesis that this particular group of EBV positive, posttransplant ENMZLs merits classification and management as PTLDs. PMID- 29228092 TI - Does Stromal Vascular Fraction Supplementation Improve Facial Lipotransfer? PMID- 29228091 TI - A randomized phase II study evaluating different maintenance schedules of nab paclitaxel in the first-line treatment of metastatic breast cancer: final results of the IBCSG 42-12/BIG 2-12 SNAP trial. AB - Background: The phase II SNAP trial was designed to evaluate the efficacy of alternative chemotherapy schedules for prolonged administration in HER2-negative metastatic breast cancer (MBC), after a short induction at conventional doses. Patients and methods: Between April 2013 and August 2015, 258 women untreated with chemotherapy for MBC were randomly assigned to receive three different maintenance chemotherapy schedules after three cycles of identical induction chemotherapy: arm A, nab-paclitaxel 150 mg/m2 days 1 and 15 Q28; arm B, nab paclitaxel 100 mg/m2 days 1, 8 and 15 Q28; arm C, nab-paclitaxel 75 mg/m2 days 1, 8, 15 and 22 Q28. Induction was three cycles nab-paclitaxel 150/125 mg/m2, days 1, 8 and 15 Q28. The primary objective was to evaluate the efficacy of each maintenance schedule, in terms of progression-free survival (PFS), as compared with the historical reference of 7-month median PFS reported by previous studies with first-line docetaxel. One-sample, one-sided log-rank tests were utilized. Quality-of-life (QoL) evaluation was carried out, and the global indicator for physical well-being was defined as the primary QoL end point; completion rates of QoL forms were >90%. Results: In total, 255 patients were assessable for the primary end point. After 18.2-month median follow-up, 182 PFS events were observed. Median PFS was 7.9 months [90% confidence interval CI 6.8-8.4] in arm A, 9.0 months (90% CI 8.1-10.9) in arm B and 8.5 months (90% CI 6.7-9.5) in arm C. PFS in arm B was significantly longer than the historical reference of first line docetaxel (P = 0.03). Grade >=2 sensory neuropathy was reported in 37.9%, 36.1% and 31.2% of the patients in arm A, B and C, respectively (Grade >=3 in 9.1%, 5.6% and 6.6% of the patients, respectively). Noteworthy, the QoL scores for sensory neuropathy did not worsen with prolonged nab-paclitaxel administration in any of the maintenance arms. Conclusion: The SNAP trial demonstrated that alternative nab-paclitaxel maintenance schedules with reduced dosages after a short induction at conventional doses are feasible and active in the first-line treatment of MBC. Registration: ClinicalTrials.gov NCT01746225. PMID- 29228093 TI - Correctness of Self-Reported Task Durations: A Systematic Review. AB - Objectives: Duration of tasks in a job is an essential interest in occupational epidemiology. Such duration is frequently measured using self-reports, which may, however, be associated with both bias and random errors. The present systematic literature review examines the correctness of self-reported durations of tasks, i.e. the extent to which they differ from more valid reference data due to either systematic or random errors, and factors influencing this correctness, with particular emphasis on the assessment of exposures of relevance to musculoskeletal disorders. Methods: The search for relevant studies included the databases ISI Web of Science, MEDLINE, EBSCO HOST, Proquest, and Psycnet. Results: Thirty-two articles were identified; of which, 23 examined occupational tasks and 9 examined non-occupational tasks. Agreement between self-reports and a more correct reference was reported for, in total, 182 tasks. Average proportional errors were, for most tasks, between -50% (i.e. underestimations) and +100%, with a dominance of overestimations; 22% of all results considered overestimations of 100% or more. For 15% of the 182 reported tasks, the mean difference between the self-reported and the reference duration value was <5%, and 20% of the 182 mean differences were between 5 and 20%. In general, respondents were able to correctly distinguish tasks of a longer duration from shorter tasks, even though the actual durations were not correct. A number of factors associated with the task per se appeared to influence agreement between self-reports and reference data, including type of task, true task duration, task pattern across time (continuous versus discontinuous), and whether the addressed task is composed of subtasks. The musculoskeletal health status of the respondent did not have a clear effect on the ability to correctly report task durations. Studies differed in key design characteristics and detail of information reported, which hampers a formal aggregation of results. Conclusions: The correctness of self-reported task durations is, at the best, moderate at the individual level, and this may present a significant problem when using self reports in task-based assessment of individual job exposures. However, average self-reports at the group level appear reasonably correct and may thus be a viable method in studies addressing, for instance, the relative occurrence of tasks in a production system. Due to the disparity of studies, definite conclusions on the quantitative effect on agreement of different modifiers are not justified, and we encourage future studies specifically devoted to understanding and controlling sources of bias in self-reported task durations. We also encourage studies developing decision support for when to apply or avoid self-reports to measure task durations, depending on study purpose and occupational setting. PMID- 29228094 TI - Neuroblastoma PTPome analysis unveils association of DUSP5 and PTPN1 expression with poor prognosis. PMID- 29228095 TI - An interview with Professor Mitinori Saitou. PMID- 29228096 TI - The New ACC/AHA Hypertension Guidelines for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. PMID- 29228097 TI - Comprehensive analysis of the clinical immuno-oncology landscape. AB - Advances from immuno-oncology (IO) are changing the standard of care of many types of cancer, and the paradigm of cancer treatments and drug development is being rewritten on a regular basis. Moreover, an unprecedented number of new investigational agents and companies are entering the field of IO. As such, it has become challenging for oncology physicians conducting clinical trials, industry veterans developing IO drugs, and even regulators reviewing novel IO agents to keep track of the rapidly evolving landscape. To help the key stake holders in the field understand the latest IO landscape, we sought to present an unbiased, neutral, scientifically curated, and timely updated analysis of all the current IO agents in clinical development and the clinical trials testing these agents. We based our analyses on information collected from numerous trusted and publicly available sources. We have developed two databases. One database tracks 2004 IO agents (940 in clinical stage and 1064 in preclinical stage) against 303 targets, from 864 companies; the other tracks 3042 active clinical trials of these agents with a target enrollment of 577 076 patients. This report provides key analyses of these data. Furthermore, we will discuss a number of important and actionable trends in the current IO landscape: a large number of companies developing agents against the same IO targets; a rapid increase in the number of anti-PD-1/L1 combination studies, many of which are testing the same combinations and following inefficient patterns; and a significant increase in the number of small, investigator-initiated studies. For each of the findings, we speculate the causes and discuss a few initiatives that aim to address some of these challenges. Finally, by making these landscape analyses available, we aspire to inform the cancer community as they seek to strive for efficiencies and innovation while avoiding duplication. PMID- 29228099 TI - Adaptation of Bone to Mechanical Strain. PMID- 29228098 TI - Association of Household Opioid Availability and Prescription Opioid Initiation Among Household Members. AB - Importance: Increases in prescription opioid use in the United States have been attributed to changing prescribing guidelines and attitudes toward pain relief; however, the spread of opioid use within households through drug diversion may also be a contributing factor. Objective: To investigate whether individuals living in a household with a prescription opioid user are more likely to initiate prescription opioids themselves, compared with individuals in households with a prescription nonsteroidal anti-inflammatory drug (NSAID) user. Design, Setting, and Participants: This was a retrospective cohort study using administrative health care claims data from 2000 to 2014 of commercial insurance beneficiaries sharing a health plan with continuous prescription drug coverage, without opioid or NSAID use in the prior year. Enrollees were followed from the date of the first prescription filled by a household member for an eligible opioid or NSAID until initiation of prescription opioids, disenrollment, or administrative censoring after 1 year or the end of follow-up on December 31, 2014. Risk of opioid initiation was derived from inverse probability-weighted (IPW) Kaplan Meier estimators that adjusted for potential confounders, prognostic factors, and predictors of censoring. Exposure: Outpatient pharmacy dispensing of a prescription opioid or prescription NSAID. Main Outcomes and Measures: Incident outpatient pharmacy fill for a prescription opioid by a household member. Results: From 2000 to 2014, 12 695 280 individuals were exposed to prescription opioids and 6 359 639 to prescription NSAIDS through an index prescription to a household member. The IPW estimated risk of opioid initiation in the subsequent year was 11.83% (95% CI, 11.81%-11.85%) among individuals exposed to prescription opioids in the household, compared with 11.11% (95% CI, 11.09%-11.14%) among individuals exposed to prescription NSAIDs, resulting in a risk difference of 0.71% (95% CI, 0.68%-0.74%). An unmeasured confounder that is modestly associated with the exposure (eg, prevalence difference = 0.9%) and the outcome (eg, risk difference = 0.9) after adjustment for all measured variables could explain our observed estimate of the overall risk difference (0.71%). Conclusions and Relevance: Living in a household with a prescription opioid user may increase risk of prescription opioid use, which may reflect both increased access to these products as well as shared risk factors, such as prescriber preference and prescription drug monitoring. PMID- 29228100 TI - Test-Retest Reliability and Minimal Detectable Change of the D2 Test of Attention in Patients with Schizophrenia. AB - Objective: The d2 Test of Attention (D2) is a commonly used measure of selective attention for patients with schizophrenia. However, its test-retest reliability and minimal detectable change (MDC) are unknown in patients with schizophrenia, limiting its utility in both clinical and research settings. The aim of the present study was to examine the test-retest reliability and MDC of the D2 in patients with schizophrenia. Method: A rater administered the D2 on 108 patients with schizophrenia twice at a 1-month interval. Test-retest reliability was determined through the calculation of the intra-class correlation coefficient (ICC). We also carried out Bland-Altman analysis, which included a scatter plot of the differences between test and retest against their mean. Systematic biases were evaluated by use of a paired t-test. Results: The ICCs for the D2 ranged from 0.78 to 0.94. The MDCs (MDC%) of the seven subscores were 102.3 (29.7), 19.4 (85.0), 7.2 (94.6), 21.0 (69.0), 104.0 (33.1), 105.0 (35.8), and 7.8 (47.8), which represented limited-to-acceptable random measurement error. Trends in the Bland-Altman plots of the omissions (E1), commissions (E2), and errors (E) were noted, presenting that the data had heteroscedasticity. Conclusions: According to the results, the D2 had good test-retest reliability, especially in the scores of TN, TN-E, and CP. For the further research, finding a way to improve the administration procedure to reduce random measurement error would be important for the E1, E2, E, and FR subscores. PMID- 29228101 TI - Spironolactone and Resistant Hypertension in Heart Failure With Preserved Ejection Fraction. AB - BACKGROUND: Recent evidence suggests that the mineralocorticoid receptor antagonist spironolactone should be the preferred fourth-line antihypertensive treatment in resistant hypertension (RHTN). Whether spironolactone improves blood pressure (BP) control in heart failure with preserved ejection fraction (HFpEF) and RHTN is unknown. METHODS: We identified patients with RHTN, defined as baseline systolic blood pressure (SBP) between 140 and 160 mm Hg on 3 or more medications, in the Americas cohort of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial, in which patients with HFpEF were randomized to spironolactone vs. placebo. We evaluated the effects of spironolactone vs. placebo on BP reduction in this group and related this to the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. RESULTS: We identified 403 participants in the Americas with RHTN. Compared to people without RHTN, those with RHTN were more frequently women, non-White, diabetics, with a higher left ventricular ejection fraction and body mass index, and a lower hemoglobin concentration. In the RHTN group, spironolactone resulted in a decrease of SBP: -6.1 (-8.9, -3.3); P < 0.001 and diastolic BP: -2.9 (-4.6, 1.2); P = 0.001 mm Hg during the first 8 months. BP became controlled after 4 weeks in 63% of patients receiving spironolactone vs. 46% receiving placebo (P = 0.003), with similar responses at 8 weeks, 4 and 8 months. Patients with RHTN derived similar overall benefit from spironolactone on the primary outcomes as those without. CONCLUSIONS: In HFpEF patients with RHTN, spironolactone lowered BP substantially and was associated with similar benefit as those without RHTN. CLINICAL TRIALS REGISTRATION: Trial Number NCT00094302 (ClinicalTrials.gov identifier). PMID- 29228102 TI - Benefits, Limitations, and Value of Abuse-Deterrent Opioids. PMID- 29228103 TI - Fertility impairment with defective spermatogenesis and steroidogenesis in male zebrafish lacking androgen receptor. AB - The pivotal role of androgen receptor (AR) in regulating male fertility has attracted much research attention in the past two decades. Previous studies have shown that total AR knockout would lead to incomplete spermatogenesis and lowered serum testosterone levels in mice, resulting in azoospermia and infertility. However, the precise physiological role of ar in controlling fertility of male fish is still poorly understood. In this study, we have established an ar knockout zebrafish line by transcription activator-like effectors nucleases. Homozygous ar mutant male fish with smaller testis size were found to be infertile when tested by natural mating. Intriguingly, a small amount of mature spermatozoa was observed in the ar mutant fish. These mature spermatozoa could fertilize healthy oocytes, albeit with a lower fertilization rate, by in vitro fertilization. Moreover, the expression levels of most steroidogenic genes in the testes were significantly elevated in the ar mutants. In contrast, the levels of estradiol and 11-ketotestosterone (11-KT) were significantly decreased in the ar mutants, indicating that steroidogenesis was defective in the mutants. Furthermore, the protein level of LHbeta in the serum decreased markedly in the ar mutants when compared with wild-type fish, probably due to the positive feedback from the diminished steroid hormone levels. PMID- 29228104 TI - An Interview with Dr Marisa Bartolomei. PMID- 29228105 TI - Metformin attenuates susceptibility to inflammation-induced preterm birth in mice with higher endocannabinoid levels. AB - Premature decidual senescence is a contributing factor to preterm birth. Fatty acid amide hydrolase mutant females (Faah-/-) with higher endocannabinoid levels are also more susceptible to preterm birth upon lipopolysaccharide (LPS) challenge due to enhanced decidual senescence; this is associated with mitogen activated protein kinase p38 activation. Previous studies have shown that mechanistic target of rapamycin complex 1 (mTORC1) contributes to decidual senescence and promotes the incidence of preterm birth. In this study, we sought to attenuate premature decidual aging in Faah-/- females by targeting mTORC1 and p38 signaling pathways. Because metformin is known to inhibit mTOR and p38 signaling pathways, Faah-/- females were treated with metformin. These mice had a significantly lower preterm birth incidence with a higher rate of live birth after an LPS challenge on day 16 of pregnancy; metformin treatment did not affect placentation or neonatal birth weight. These results were associated with decreased levels of p38, as well as pS6, a downstream mediator of mTORC1 activity, in day 16 Faah-/-decidual tissues. Since metformin treatment attenuates premature decidual senescence with limited side effects during pregnancy, careful use of this drug may be effective in ameliorating specific adverse pregnancy events. PMID- 29228106 TI - Proteomic analysis of good- and poor-quality human sperm demonstrates that several proteins are routinely aberrantly regulated. AB - Male infertility is a complex condition, and for the most part, all men produce defective spermatozoa, but infertile men have a tendency to produce more. Despite attempts to classify infertility, there is no definitive test. One approach would be to use protein biomarkers; however as yet, we still do not understand proteins that are differentially expressed within defective spermatozoa. As such, we took nine men (fertility status unknown) and used Percoll density gradients to isolate a population of good- and poor-quality sperm. For four of these men, we also obtained multiple ejaculations. The most noticeable differences between the Percoll-isolated fractions were motility and CMA3 staining. While the good sperm fraction produced cells with at least 80% forward progressive motility and low levels of CMA3 staining, the poor-quality sperm demonstrated less than 10% forward progressive motility and higher levels CMA3 staining. Using the technique of sequential window activation of all theoretical mass spectra, we quantified 2774 proteins and found 171 proteins to be significantly more abundant in the good sperm fraction, while 104 proteins were significantly more abundant in the lower sperm fraction (adjusted Benjamini-Hochberg significance of P < 0.018, minimum 2-fold difference). PMID- 29228108 TI - DGUOK recessive mutations in patients with CPEO, mitochondrial myopathy, parkinsonism and mtDNA deletions. PMID- 29228107 TI - The Impact of Antipsychotic Drugs on Long-term Care, Nursing Home Admission, and Death in Dementia Patients. AB - Background: Behavioral and psychological symptoms of dementia are commonly treated with antipsychotic drugs (APDs), which have been associated with adverse health effects. We examine the effect of APDs on long-term care (LTC), nursing home (NH) admission, and death of dementia patients. Methods: We used health claims data of the largest German health insurer from 2004 to 2010 and followed newly-diagnosed dementia patients aged 60 years and older into LTC, NH, and until death. Cox proportional hazards models were estimated to explore whether the risk of these outcomes differed between patients receiving haloperidol, melperone, risperidone, or quetiapine. Results: In a cohort of 6,930 dementia patients who were initially free of LTC dependency, APD users generally faced a twofold increased risk of LTC relative to nonusers. Quetiapine was the exception, showing a comparatively lower risk (HR = 1.64; CI = 1.35-1.98). Among 9,950 dementia patients initially living in private homes, the risk of moving into a NH was generally increased by about 50% among APD users relative to nonusers. Risk of death (N = 10,921) was significantly higher for haloperidol-, melperone-, and risperidone- but not for quetiapine users (HR = 0.91; CI = 0.78-1.08). The excess mortality associated with haloperidol and melperone was greater among patients living in private households. Conclusions: In our study, APDs appeared to accelerate adverse health outcomes in German dementia patients. Differentiating between the effect of antipsychotic drug use among dementia patients residing in private households and in NHs, we found that excess mortality for haloperidol and melperone users was higher in private settings. PMID- 29228109 TI - POLR3A variants in hereditary spastic paraplegia and ataxia. PMID- 29228110 TI - Autocorrelation Structure in the Macaque Dorsolateral, But not Orbital or Polar, Prefrontal Cortex Predicts Response-Coding Strength in a Visually Cued Strategy Task. AB - In previous work, we studied the activity of neurons in the dorsolateral (PFdl), orbital (PFo), and polar (PFp) prefrontal cortex while monkeys performed a strategy task with 2 spatial goals. A cue instructed 1 of 2 strategies in each trial: stay with the previous goal or shift to the alternative goal. Each trial started with a fixation period, followed by a cue. Subsequently, a delay period was followed by a "go" signal that instructed the monkeys to choose one goal. After each choice, feedback was provided. In this study, we focused on the temporal receptive fields of the neurons, as measured by the decay in autocorrelation (time constant) during the fixation period, and examined the relationship with response and strategy coding. The temporal receptive field in PFdl correlated with the response-related but not with the strategy-related modulation in the delay and the feedback periods: neurons with longer time constants in PFdl tended to show stronger and more prolonged response coding. No such correlation was found in PFp or PFo. These findings demonstrate that the temporal specialization of neurons for temporally extended computations is predictive of response coding, and neurons in PFdl, but not PFp or PFo, develop such predictive properties. PMID- 29228112 TI - Xenotransplantation-the current status and prospects. AB - Introduction: There is a continuing worldwide shortage of organs from deceased human donors for transplantation into patients with end-stage organ failure. Genetically engineered pigs could resolve this problem, and could also provide tissues and cells for the treatment of conditions such as diabetes, Parkinson's disease and corneal blindness. Sources of data: The current literature has been reviewed. Areas of agreement: The pathobiologic barriers are now largely defined. Research progress has advanced through the increasing availability of genetically engineered pigs and novel immunosuppressive agents. Life-supporting pig kidneys and islets have functioned for months or years in nonhuman primates. Areas of controversy: The potential risk of transfer of a pig infectious microorganism to the recipient continues to be debated. Growing points: Increased attention is being paid to selection of patients for initial clinical trials. Areas timely for developing research: Most of the advances required to justify a clinical trial have now been met. PMID- 29228113 TI - Fibroblast growth factor-2 and transforming growth factor-beta1 oppositely regulate miR-221 that targets thrombospondin-1 in bovine luteal endothelial cells. AB - Thrombospondin-1 (THBS1) affects corpus luteum (CL) regression. Highly induced during luteolysis, it acts as a natural anti-angiogenic, proapoptotic compound. THBS1 expression is regulated in bovine luteal endothelial cells (LECs) by fibroblast growth factor-2 (FGF2) and transforming growth factor-beta1 (TGFB1) acting in an opposite manner. Here we sought to identify specific microRNAs (miRNAs) targeting THBS1 and investigate their possible involvement in FGF2 and TGFB1-mediated THBS1 expression. Several miRNAs predicted to target THBS1 mRNA (miR-1, miR-18a, miR-144, miR-194, and miR-221) were experimentally tested. Of these, miR-221 was shown to efficiently target THBS1 expression and function in LECs. We found that this miRNA is highly expressed in luteal cells and in mid cycle CL. Consistent with the inhibition of THBS1 function, miR-221 also reduced Serpin Family E Member 1 [SERPINE1] in LECs and promoted angiogenic characteristics of LECs. Plasminogen activator inhibitor-1 (PAI-1), the gene product of SERPINE1, inhibited cell adhesion, suggesting that PAI-1, like THBS1, has anti-angiogenic properties. Importantly, FGF2, which negatively regulates THBS1, elevates miR-221. Conversely, TGFB1 that stimulates THBS1, significantly reduces miR-221. Furthermore, FGF2 enhances the suppression of THBS1 caused by miR-221 mimic, and prevents the increase in THBS1 induced by miR-221 inhibitor. In contrast, TGFB1 reverses the inhibitory effect of miR-221 mimic on THBS1, and enhances the upregulation of THBS1 induced by miR-221 inhibitor. These data support the contention that FGF2 and TGFB1 modulate THBS1 via miR-221. These in vitro data propose that dynamic regulation of miR-221 throughout the cycle, affecting THBS1 and SERPINE1, can modulate vascular function in the CL. PMID- 29228111 TI - Obligatory and facultative brain regions for voice-identity recognition. AB - Recognizing the identity of others by their voice is an important skill for social interactions. To date, it remains controversial which parts of the brain are critical structures for this skill. Based on neuroimaging findings, standard models of person-identity recognition suggest that the right temporal lobe is the hub for voice-identity recognition. Neuropsychological case studies, however, reported selective deficits of voice-identity recognition in patients predominantly with right inferior parietal lobe lesions. Here, our aim was to work towards resolving the discrepancy between neuroimaging studies and neuropsychological case studies to find out which brain structures are critical for voice-identity recognition in humans. We performed a voxel-based lesion behaviour mapping study in a cohort of patients (n = 58) with unilateral focal brain lesions. The study included a comprehensive behavioural test battery on voice-identity recognition of newly learned (voice-name, voice-face association learning) and familiar voices (famous voice recognition) as well as visual (face identity recognition) and acoustic control tests (vocal-pitch and vocal-timbre discrimination). The study also comprised clinically established tests (neuropsychological assessment, audiometry) and high-resolution structural brain images. The three key findings were: (i) a strong association between voice identity recognition performance and right posterior/mid temporal and right inferior parietal lobe lesions; (ii) a selective association between right posterior/mid temporal lobe lesions and voice-identity recognition performance when face-identity recognition performance was factored out; and (iii) an association of right inferior parietal lobe lesions with tasks requiring the association between voices and faces but not voices and names. The results imply that the right posterior/mid temporal lobe is an obligatory structure for voice identity recognition, while the inferior parietal lobe is only a facultative component of voice-identity recognition in situations where additional face identity processing is required. PMID- 29228114 TI - Effects of exportin 1 on nuclear transport and meiotic resumption in porcine full grown and growing oocytes. AB - Exportin 1 (XPO1) is a nuclear transport receptor involved in the nuclear export of majority proteins in somatic cells. In mammalian oocytes, however, only the presence of XPO1 has been reported at mRNA and protein levels, and the definitive functions of XPO1 and its effects on the meiotic maturation of oocytes have never been directly examined. In the present study, the expression state and the nuclear-export function of porcine XPO1 were analyzed in porcine oocytes. In addition, we investigated the effects of the overexpression and inhibition of XPO1 on meiotic regulation in full-grown and growing oocytes by mRNA injection and inhibitor treatment. Endogenous XPO1 was stably expressed in porcine oocytes during the germinal vesicle (GV) stage, and the expression of exogenous XPO1 significantly decreased the nuclear localization of XPO1 cargos, snurportin 1, and WEE1B. Inhibition of XPO1 by a specific inhibitor, leptomycin B, delayed the GV breakdown (GVBD), whereas the overexpression of XPO1 by mRNA injection accelerated the GVBD. XPO1 overexpression overcame the meiotic arrest induced by WEE1B expression in full-grown oocytes. Surprisingly, the GVBD of porcine growing oocytes, which could not resume meiosis by the maturation culture in vitro, was induced by the expression of exogenous XPO1. These results showed the presence of XPO1 and its function as a nuclear export receptor in mammalian oocytes, including growing oocytes, and they suggest that the regulation of nuclear transport has a large influence on the GV maintenance and meiotic resumption of oocytes. PMID- 29228115 TI - The oviduct: from sperm selection to the epigenetic landscape of the embryo. AB - The mammalian oviduct is the place where life begins as it is the site of fertilization and preimplantation embryo development. Recent research has highlighted the important role played by the oviduct both in sperm selection for natural fertilization and in the genetic and epigenetic reprogramming of preimplantation embryo development. This review examines oviduct fluid composition with a special emphasis on exosomes and the role played by the oviduct in sperm selection, early embryo development, and in reshaping the epigenetic landscape of the embryo. In addition, the implications of data obtained for improving assisted reproductive technologies are discussed. PMID- 29228116 TI - IL-17 in atherosclerosis: the good and the bad. PMID- 29228117 TI - Aneuploidy: an important model system to understand salient aspects of functional genomics. AB - Maintaining a balance in gene dosage and protein activity is essential to sustain normal cellular functions. Males and females have a wide range of genetic as well as epigenetic differences, where X-linked gene dosage is an essential regulatory factor. Basic understanding of gene dosage maintenance has emerged from the studies carried out using mouse models with FCG (four core genotype) and chromosomal aneuploidy as well as from mono-chromosomal hybrid cells. In mammals, aneuploidy often leads to embryonic lethality particularly in early development with major developmental and structural abnormalities. Thus, in-depth analysis of the causes and consequences of gene dosage alterations is needed to unravel its effects on basic cellular and developmental functions as well as in understanding its medical implications. Cells isolated from individuals with naturally occurring chromosomal aneuploidy can be considered as true representatives, as these cells have stable chromosomal alterations/gene dosage imbalance, which have occurred by modulation of the basic molecular machinery. Therefore, innovative use of these natural aneuploidy cells/organisms with recent molecular and high throughput techniques will provide an understanding of the basic mechanisms involved in gene dosage balance and the related consequences for functional genomics. PMID- 29228118 TI - Where is the TMT? GC-MS analyses of fox feces and behavioral responses of rats to fear-inducing odors. AB - TMT (2,5-dihydro-2,4,5-trimethylthiazoline) is known as a component of fox feces inducing fear in rodents. However, no recent chemical analyses of fox feces are available, and few studies make direct comparisons between TMT and fox feces. Fox feces from 3 individuals were used to prepare 24 samples to be analyzed for the presence of TMT using gas chromatography-mass spectrometry (GC-MS). When TMT was added in low amounts (50-2000 nmol/g), TMT was detected in 10 out of 11 samples. When no TMT was added, TMT was detected in only 1 out of 13 samples. In a second experiment, we tested the behavioral response of male Brown Norway (BN) and Wistar rats to either fox feces, a low amount of TMT (0.6 nmol) or 1-hexanol. TMT induced freezing in the rats, but fox feces induced significantly more freezing episodes and longer total duration of freezing in both rat strains. In experiment 3, male BN rats were exposed over several days to fox feces, rat feces, 1 hexanol, cadaverine, 2-phenylethylamine, and TMT, one odor at a time. Fox feces induced significantly more freezing episodes of a longer total duration than any of the other odors, with rat feces and 1-hexanol giving rise to the lowest amount of freezing. This finding, together with our inability to verify the presence of TMT in fox feces, indicates that the concentration of TMT in our fox feces samples was below 50 nmol/g. It may also be that other compounds in fox feces play a role in its fear-inducing properties. PMID- 29228119 TI - Rostro-caudal Connectional Heterogeneity of the Dorsal Part of the Macaque Prefrontal Area 46. AB - Based on neural tracer injections we found evidence for 3 connectionally distinct sectors of the dorsal part of the macaque prefrontal area 46 (46d), located at different rostro-caudal levels. Specifically, a rostral sector displayed an almost exclusive and extensive intraprefrontal connectivity and extraprefrontal connections limited to superior temporal areas and the caudal cingulate area 31. Conversely, both a middle and a caudal sector were characterized by robust, topographically organized connections with parietal and frontal sensorimotor areas. Both these sectors shared connections with caudal and medial superior parietal areas (V6A and PGm) where visuospatial information is combined with gaze and arm-related signals for visuomotor control of arm reaching and/or eye movements. However, the caudal sector was preferentially connected to parietal and frontal oculomotor areas, whereas the middle one was preferentially connected to skeletomotor, mostly arm-related, parietal and premotor areas. The present study provides evidence for a rostro-caudal organization of area 46d similar to that described for the ventrolateral prefrontal cortex, in which more caudal areas are relatively more directly involved in controlling different aspects of motor behavior and more rostral areas are most likely involved in higher order, possibly more abstract, cognitive functions. PMID- 29228120 TI - Exploring Individual Brain Variability during Development based on Patterns of Maturational Coupling of Cortical Thickness: A Longitudinal MRI Study. AB - Structural covariance has recently emerged as a tool to study brain connectivity in health and disease. The main assumption behind the phenomenon of structural covariance is that changes in brain structure during development occur in a coordinated fashion. However, no study has yet explored the correlation of structural brain changes within individuals across development. Here, we used longitudinal magnetic resonance imaging scans from 141 normally developing children and adolescents (scanned 3 times) to introduce a novel subject-based maturational coupling approach. For each subject, maturational coupling was defined as similarity in the trajectory of cortical thickness (across the time points) between any two cortical regions. Our approach largely captured features seen in population-based structural covariance, and confirmed strong maturational coupling between homologous and near-neighbor cortical regions. Stronger maturational coupling among several homologous regions was observed for females compared to males, possibly indicating greater interhemispheric connectivity in females. Developmental changes in maturational coupling within the default-mode network (DMN) aligned with developmental changes in structural and functional DMN connectivity. Our findings indicate that patterns of maturational coupling within individuals may provide mechanistic explanation for the phenomenon of structural covariance, and allow investigation of individual brain variability with respect to cognition and disease vulnerability. PMID- 29228121 TI - Low-dose bisphenol A activates the ERK signaling pathway and attenuates steroidogenic gene expression in human placental cells. AB - Bisphenol A (BPA) is an industrial material used for many plastic products and is considered an endocrine disruptor. BPA can be released into the environment and can spread through the food chain. It is well known that BPA exposure leads to lesions, especially in the reproductive system. According to previous studies, BPA reduces newborn numbers in pregnant mice and affects placentation. The placenta is a special endocrine organ during pregnancy. It secretes important hormones, such as progesterone and estrogen, to maintain gestation. In steroid hormone synthesis, two specific enzymes are important: P450scc (CYP11A1) converts cholesterol to pregnenolone and aromatase (CYP19) induces androgen conversion to estrogen.To determine the effects of a low dose of BPA on hormone synthesis in the placenta, we used JEG-3 cells as a model. We found that the steroidogenic genes CYP11A1 and CYP19 were downregulated in human tissues by detectable concentrations of BPA (1-1000 nM), which do not affect cell viability. Furthermore, we demonstrated that BPA influenced the ERK signaling pathway and resulted in hormone reductions. An analysis of trophoblasts in primary culture from a term human placenta showed the same phenomena. Our data demonstrate that treatment with a low dose of BPA does not affect human placental cell survival, but decreases hormone production via to the downregulation of steroidogenic genes and ERK signaling pathway changes. PMID- 29228122 TI - Tennessee's In-state Vulnerability Assessment for a "Rapid Dissemination of Human Immunodeficiency Virus or Hepatitis C Virus Infection" Event Utilizing Data About the Opioid Epidemic. AB - Background: Knowing which factors contribute to county-level vulnerability to a human immunodeficiency virus (HIV)/hepatitis C virus (HCV) outbreak, and which counties are most vulnerable, guides public health and clinical interventions. We therefore examined the impact of locally available indicators related to the opioid epidemic on prior national models of HIV/HCV outbreak vulnerability. Methods: Tennessee's 95 counties were the study sample. Predictors from 2012 and 2013 were used, mirroring prior methodology from the US Centers for Disease Control and Prevention (CDC). Acute HCV incidence was the proxy measure of county level vulnerability. Seventy-eight predictors were identified as potentially predictive for HIV/HCV vulnerability. We used multiple dimension reduction techniques to determine predictors for inclusion and Poisson regression to generate a composite index score ranking county-level vulnerability for HIV/HCV. Results: There was overlap of high-risk counties with the national analysis (25 of 41 counties). The distribution of vulnerability reinforces earlier research indicating that eastern Tennessee is at particularly high risk but also demonstrates that the entire state has high vulnerability. Conclusions: Prior research placed Tennessee among the top states for opioid prescribing, acute HCV infection, and greatest risk for an HIV/HCV outbreak. Given this confluence of risk, the Tennessee Department of Health expanded upon prior work to include more granular, local data, including on opioid prescribing. We also explored nonfatal and fatal overdoses. The more complete statewide view of risk generated, not only in eastern counties but also in the western corridor, will enable local officials to monitor vulnerability and better target resources. PMID- 29228123 TI - Role of yes-associated protein 1, angiomotin, and mitogen-activated kinase kinase 1/2 in development of the bovine blastocyst. AB - The morula-stage embryo is transformed into a blastocyst composed of epiblast, hypoblast, and trophectoderm (TE) through mechanisms that, in the mouse, involve the Hippo signaling and mitogen-activated kinase (MAPK) pathways. Using the cow as an additional model, we tested the hypotheses that TE and hypoblast differentiation were regulated by the Hippo pathway regulators, yes-associated protein 1 (YAP1) and angiomotin (AMOT), and MAPK kinase 1/2 (MAPK1/2). The presence of YAP1 and CDX2 in the nucleus and cytoplasm of MII oocytes and embryos was evaluated by immunofluorescence labeling. For both molecules, localization changed from cytoplasmic to nuclear as development advanced. Inhibition of YAP1 activity, either by verteporfin or a YAP1 targeting GapmeR, reduced the percent of zygotes that became blastocysts, the proportion of blastocysts that hatched and numbers of CDX2+ cells in blastocysts. Moreover, the YAP1-targeting GapmeR altered expression of 15 of 91 genes examined in the day 7.5 blastocyst. Treatment of embryos with an AMOT targeting GapmeR did not affect blastocyst development or hatching but altered expression of 16 of 91 genes examined at day 7.5 and reduced the number of CDX2+ nuclei and YAP1+ nuclei in blastocysts at day 8.5 of development. Inhibition of MAPK1/2 with PD0325901 did not affect blastocyst development but increased the number of epiblast cells. Results indicate a role for YAP1 and AMOT in function of TE in the bovine blastocyst. YAP1 can also affect function of the epiblast and hypoblast, and MAPK signaling is important for inner cell mass differentiation by reducing epiblast numbers. PMID- 29228124 TI - Association of estimated glomerular filtration rate with muscle function in older persons who have fallen. AB - Background: studies suggest that estimated glomerular filtration rate (eGFR) is less reliable in older persons and that a low serum-creatinine might reflect reduced muscle mass rather than high kidney function. This study investigates the possible relationship between eGFR and multiple elements of physical performance in older fallers. Methods: baseline data of the IMPROveFALL-study were examined in participants >=65 years. Serum-creatinine based eGFR was classified as normal (>=90 ml/min), mildly reduced (60-89 ml/min) or moderately-severely reduced (<60 ml/min). Timed-Up-and-Go-test and Five-Times-Sit-to-Stand-test were used to assess mobility; calf circumference and handgrip strength to assess muscle status. Ancova models adjusted for age, sex, Charlson comorbidity index and body mass index were performed. Results: a total of 578 participants were included. Participants with a normal eGFR had lower handgrip strength than those with a mildly reduced eGFR (-9.5%, P < 0.001) and those with a moderately-severely reduced eGFR (-6.3%, P = 0.033) with mean strengths of 23.4, 25.8 and 24.9 kg, respectively. Participants with a normal eGFR had a smaller calf circumference than those with a mildly reduced eGFR (35.5 versus 36.5 cm, P = 0.006). Mean time to complete the mobility tests did not differ. Conclusions: in this study we found that older fallers with an eGFR >= 90 ml/min had smaller calf circumference and up to 10% lower handgrip strength than those with a reduced eGFR. This lower muscle mass is likely to lead to an overestimation of kidney function. This outcome therefore supports the search for biomarkers independent of muscle mass to estimate kidney function in older persons. PMID- 29228125 TI - Myeloid Neoplasms Following Solid Organ Transplantation: Clinicopathologic Studies of 23 Cases. AB - Objectives: Myeloid neoplasms (MNs) after solid organ transplant are rare, and their clinicopathologic features have not been well characterized. Methods: We retrospectively analyzed 23 such cases. Results: The ages ranged from 2 to 76 years, with a median of 59 years at the diagnosis. The median interval between the transplant and diagnosis was 56 months (range, 8-384 months). The transplanted organs included liver in five, kidney in six, lung in five, heart in six, and heart/lung in one case(s). The types of MN included acute myeloid leukemia (AML) in 12, myelodysplastic syndrome (MDS) in five, chronic myelogenous leukemia (CML) in four, and myeloproliferative neoplasms (MPNs) in two cases. Cytogenetics demonstrated clonal abnormalities in 18 (78.3%) cases, including unbalanced changes in 10 (55.6%), Philadelphia chromosome in four (22.2%), and other balanced aberrations in four (22.2%) cases. Thirteen (56.5%) patients died, with an estimated median survival of 9 months. With disease stratification, AML and MDS have short median survivals (3.5 and 7 months, respectively), with an initial precipitous decline of the survival curve. Conclusions: Posttransplant MNs have a latency period between that seen in AML/MDS related to alkylators and that associated with topoisomerase II inhibitors. The cytogenetic profile suggests a mutagenic effect on leukemogenesis. The clinical outcome for AML/MDS is dismal, with death occurring at an early phase of treatment. PMID- 29228126 TI - Error in Introduction. PMID- 29228128 TI - Evaluation of a novel infra-red endoscopy system in the assessment of early neoplasia in Barretts esophagus: pilot study from a single center. AB - Infrared endoscopy (IRE) has been shown to be useful in detecting submucosal (SM) invasion in early gastric cancer. Its role in the endoscopic assessment of Barrett's neoplasia has not been reported to date. We aimed in this study to evaluate the role of IRE in the detection and characterization of early neoplastic lesions within Barrett's esophagus (BE). The secondary aim was to explore its usefulness for the assessment of the presence of submucosal invasion in these early neoplastic Barrett's lesions. We included in the study patients with dysplastic BE who were referred to our institution for endoscopic therapy of a previously diagnosed early Barrett's neoplasia. An examination with white light high resolution endoscopy (HRE) and near IRE after intravenous injection of indocyanine green was performed for all patients using an infrared endoscope prototype. Staining on IRE and correlation with final histological staging by endoscopic mucosal resection/surgery or histological diagnosis on mapping biopsies was analyzed. A total of 23 patients were enrolled in our study: 17 of them with 19 visible lesions and 6 patients with flat BE and no lesions. Staining on IRE was noted in 18 cases: 17 (94%) had at least high grade dysplasia (HGD). No stain was noted in 7 cases: final histology was =HGD in 2 (29%). There was statistically significant difference between cases with no stain and any staining on IRE with regard to the presence of >=HGD [2/7 (29%) vs. 17/18 (94%) P = 0.0022]. Stain was reported as faint in 12 and dense in 6. All 6 cases with dense staining had at least HGD. We concluded that IRE can provide additional information to the currently available white light endoscopy for detecting early neoplastic lesions within BE. IRE also allows detecting HGD and most advanced histology in BE. Usefulness of IRE to detect submucosal involvement in early Barrett's neoplastic lesions needs to be assessed further in larger cohort studies. PMID- 29228127 TI - Antibiotic Resistance and the Risk of Recurrent Bacteremia. AB - Background: Direct health effects of antibiotic resistance are difficult to assess. We quantified the risk of recurrent bacteremia associated with resistance. Methods: We extracted antimicrobial susceptibility testing data on blood isolates from the Dutch surveillance system for antimicrobial resistance between 2008 and 2017. First and first recurrent (4-30 days) bacteremia episodes were categorized as susceptible, single nonsusceptible, or co-nonsusceptible to third-generation cephalosporins without or with carbapenems (Enterobacteriaceae), ceftazidime without or with carbapenems (Pseudomonas species), aminopenicillins without or with vancomycin (Enterococcus species), or as methicillin-sensitive/ resistant S. aureus (MSSA/MRSA). We calculated risks of recurrent bacteremia after nonsusceptible vs susceptible first bacteremia, estimated the crude population attributable effect of resistance for the Netherlands, and calculated risks of nonsusceptible recurrent bacteremia after a susceptible first episode. Results: Risk ratios for recurrent bacteremia after a single- and co nonsusceptible first episode, respectively, vs susceptible first episode, were 1.7 (95% confidence interval [CI], 1.5-2.0) and 5.2 (95% CI, 2.1-12.4) for Enterobacteriaceae, 1.3 (95% CI, 0.5-3.1) and 5.0 (95% CI, 2.9-8.5) for Pseudomonas species, 1.4 (95% CI, 1.2-1.7) and 1.6 (95% CI, 0.6-4.2) for Enterococcus species, and 1.6 (95% CI, 1.1-2.4) for MRSA vs MSSA. The estimated population annual number of recurrent bacteremias associated with nonsusceptibility was 40. The risk of nonsusceptible recurrent bacteremia after a susceptible first episode was at most 0.4% (Pseudomonas species). Conclusions: Although antibiotic nonsusceptibility was consistently associated with higher risks of recurrent bacteremia, the estimated annual number of additional recurrent episodes in the Netherlands (40) was rather limited. PMID- 29228129 TI - Prenatal Exposure to Di(2-Ethylhexyl) Phthalate Causes Long-Term Transgenerational Effects on Female Reproduction in Mice. AB - Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer in many consumer products. Although DEHP is a known endocrine disruptor, little is known about the effects of DEHP exposure on female reproduction. Thus, this study tested the hypothesis that prenatal DEHP exposure affects follicle numbers, estrous cyclicity, and hormone levels in multiple generations of mice. Pregnant CD-1 mice were orally dosed with corn oil (vehicle control) or DEHP (20 and 200 ug/kg/d and 500 and 750 mg/kg/d) from gestational day 11 until birth. The F1 females were mated with untreated males to create the F2 generation, and the F2 females were mated with untreated males to create the F3 generation. At 1 year, ovaries, hormones, and estrous cycles were analyzed in each generation. Prenatal DEHP exposure altered estrous cyclicity (750 mg/kg/d), increased the presence of ovarian cysts (750 mg/kg/d), and decreased total follicle numbers (750 mg/kg/d) in the F1 generation. It also decreased anogenital distance (200 ug/kg/d) and altered follicle numbers (200 ug/kg/d and 500 mg/kg/d) in the F2 generation, and it altered estrous cyclicity (20 and 200 ug/kg/d and 500 and 750 mg/kg/d) and decreased folliculogenesis (200 ug/kg/d and 500 mg/kg/d) in the F3 generation. Further, prenatal DEHP increased estradiol levels (F1 and F3), decreased testosterone levels (F1, F2, and F3), decreased progesterone levels (F2), altered gonadotropin hormone levels (F1 and F3), and decreased inhibin B levels (F1 and F3). Collectively, these data show that prenatal exposure to DEHP has multigenerational and transgenerational effects on female reproduction and it may accelerate reproductive aging. PMID- 29228131 TI - Synaptic Potentiation at Basal and Apical Dendrites of Hippocampal Pyramidal Neurons Involves Activation of a Distinct Set of Extracellular and Intracellular Molecular Cues. AB - In the central nervous system, several forms of experience-dependent plasticity, learning and memory require the activity-dependent control of synaptic efficacy. Despite substantial progress in describing synaptic plasticity, mechanisms related to heterogeneity of synaptic functions at local circuits remain elusive. Here we studied the functional and molecular aspects of hippocampal circuit plasticity by analyzing excitatory synapses at basal and apical dendrites of mouse hippocampal pyramidal cells (CA1 region) in acute brain slices. In the past decade, activity of metalloproteinases (MMPs) has been implicated as a widespread and critical factor in plasticity mechanisms at various projections in the CNS. However, in the present study we discovered that in striking contrast to apical dendrites, synapses located within basal dendrites undergo MMP-independent synaptic potentiation. We demonstrate that synapse-specific molecular pathway allowing MMPs to rapidly upregulate function of NMDARs in stratum radiatum involved protease activated receptor 1 and intracellular kinases and GTPases activity. In contrast, MMP-independent scaling of synaptic strength in stratum oriens involved dopamine D1/D5 receptors and Src kinases. Results of this study reveal that 2 neighboring synaptic systems differ significantly in extracellular and intracellular cascades that control synaptic gain and provide long-searched transduction pathways relevant for MMP-dependent synaptic plasticity. PMID- 29228132 TI - Vivax Malaria Chemoprophylaxis: The Role of Atovaquone-Proguanil Compared to Other Options. AB - Background: Atovaquone-proguanil is considered causal prophylaxis (inhibition of liver-stage schizonts) for Plasmodium falciparum; however, its causal prophylactic efficacy for Plasmodium vivax is not known. Travelers returning to nonendemic areas provide a unique opportunity to study P. vivax prophylaxis. Methods: In a retrospective observational study, for 11 years, Israeli rafters who had traveled to the Omo River in Ethiopia, a highly malaria-endemic area, were followed for at least 1 year after their return. Malaria prophylaxis used during this period included mefloquine, doxycycline, primaquine, and atovaquone proguanil. Prophylaxis failure was divided into early (within a month of exposure) and late malaria. Results: Two hundred fifty-two travelers were included in the study. Sixty-two (24.6%) travelers developed malaria, 56 (91.9%) caused by P. vivax, with 54 (87.1%) cases considered as late malaria. Among travelers using atovaquone-proguanil, there were no cases of early P. falciparum or P. vivax malaria. However, 50.0% of atovaquone-proguanil users developed late vivax malaria, as did 46.5% and 43.5% of mefloquine and doxycycline users, respectively; only 2 (1.4%) primaquine users developed late malaria (P < .0001). Conclusions: Short-course atovaquone-proguanil appears to provide causal (liver schizont stage) prophylaxis for P. vivax, but is ineffective against late, hypnozoite reactivation-related attacks. These findings suggest that primaquine should be considered as the chemoprophylactic agent of choice for areas with high co-circulation of P. falciparum and P. vivax. PMID- 29228130 TI - Acute Retroviral Syndrome Is Associated With High Viral Burden, CD4 Depletion, and Immune Activation in Systemic and Tissue Compartments. AB - Background: Many individuals with acute human immunodeficiency virus infection (AHI) experience acute retroviral syndrome (ARS), which is associated with adverse long-term clinical outcomes. Methods: Participants presenting for voluntary human immunodeficiency virus (HIV) testing were enrolled during AHI in Bangkok, Thailand. ARS was defined by >=3 qualifying signs/symptoms. HIV burden, immunophenotypes, and biomarkers were stratified by ARS diagnosis at enrollment and after up to 96 weeks of antiretroviral therapy (ART). Results: From 212382 samples screened, 430 participants were enrolled during AHI, including 335 (78%) with ARS. Median age was 26 years and 416 (97%) were men. Sixty (14%) underwent sigmoid biopsy and 105 (24%) underwent lumbar puncture during AHI. Common symptoms included fever (93%), fatigue (79%), pharyngitis (67%), and headache (64%). Compared to those without ARS, participants with ARS were in later Fiebig stages with higher HIV RNA in blood, colon, and cerebrospinal fluid; higher total HIV DNA in blood; CD4 depletion in blood and colon; and elevated plasma tumor necrosis factor alpha (TNF-alpha), C-reactive protein, and D-dimer (all P < .05). Subgroup analyses of Fiebig I/II participants (95 with ARS, 69 without) demonstrated similar findings. After 96 weeks of ART, TNF-alpha and interleukin 6 were elevated in the ARS group (P < .05) but other biomarkers equilibrated. Conclusions: ARS was associated with high viral burden, CD4 depletion, and immune activation across multiple body compartments during AHI and prior to ART. Persistent inflammation despite suppressive ART could contribute to increased morbidity in individuals who experience ARS. PMID- 29228133 TI - Regional Epidemiology of Methicillin-Resistant Staphylococcus aureus Among Adult Intensive Care Unit Patients Following State-Mandated Active Surveillance. AB - Background: In 2007, Illinois became the first state in the United States to mandate active surveillance of methicillin-resistant Staphylococcus aureus (MRSA). The Illinois law applies to intensive care unit (ICU) patients; contact precautions are required for patients found to be MRSA colonized. However, the effectiveness of a legislated "search and isolate" approach to reduce MRSA burden among critically ill patients is uncertain. We evaluated whether the prevalence of MRSA colonization declined in the 5 years after the start of mandatory active surveillance. Methods: All hospitals with an ICU having >=10 beds in Chicago, Illinois, were eligible to participate in single-day serial point prevalence surveys. We assessed MRSA colonization among adult ICU patients present at time of survey using nasal and inguinal swab cultures. The primary outcome was region wide MRSA colonization prevalence over time. Results: All 25 eligible hospitals (51 ICUs) participated in serial point prevalence surveys over 8 survey periods (2008-2013). A total of 3909 adult ICU patients participated in the point prevalence surveys, with 432 (11.1%) found to be colonized with MRSA (95% confidence interval [CI], 10.1%-12.0%). The MRSA colonization prevalence among patients was unchanged during the study period; year-over-year relative risk for MRSA colonization was 0.97 (95% CI, .89-1.05; P = .48). Conclusions: MRSA colonization prevalence among critically ill adult patients did not decline during the time period following legislatively mandated MRSA active surveillance. Our findings highlight the limits of legislated MRSA active surveillance as a strategy to reduce MRSA colonization burden among ICU patients. PMID- 29228135 TI - Reply: DGUOK recessive mutations in patients with CPEO, mitochondrial myopathy, parkinsonism and mtDNA deletions. PMID- 29228134 TI - Genotype-Specific Measles Transmissibility: A Branching Process Analysis. AB - Background: Substantial heterogeneity in measles outbreak sizes may be due to genotype-specific transmissibility. Using a branching process analysis, we characterize differences in measles transmission by estimating the association between genotype and the reproduction number R among postelimination California measles cases during 2000-2015 (400 cases, 165 outbreaks). Methods: Assuming a negative binomial secondary case distribution, we fit a branching process model to the distribution of outbreak sizes using maximum likelihood and estimated the reproduction number R for a multigenotype model. Results: Genotype B3 is found to be significantly more transmissible than other genotypes (P = .01) with an R of 0.64 (95% confidence interval [CI], .48-.71), while the R for all other genotypes combined is 0.43 (95% CI, .28-.54). This result is robust to excluding the 2014 2015 outbreak linked to Disneyland theme parks (referred to as "outbreak A" for conciseness and clarity) (P = .04) and modeling genotype as a random effect (P = .004 including outbreak A and P = .02 excluding outbreak A). This result was not accounted for by season of introduction, age of index case, or vaccination of the index case. The R for outbreaks with a school-aged index case is 0.69 (95% CI, .52-.78), while the R for outbreaks with a non-school-aged index case is 0.28 (95% CI, .19-.35), but this cannot account for differences between genotypes. Conclusions: Variability in measles transmissibility may have important implications for measles control; the vaccination threshold required for elimination may not be the same for all genotypes or age groups. PMID- 29228136 TI - CD177+ neutrophils suppress epithelial cell tumourigenesis in colitis-associated cancer and predict good prognosis in colorectal cancer. AB - Neutrophils are found to be infiltrated in tumour tissues of patients with colitis-associated cancer (CAC) and colorectal cancer (CRC), and CD177 is mainly expressed in neutrophils. In our study, expression of CD177 in tumour tissues from patients with CAC or CRC was analysed byquantitative real-time polymerase chain reaction, flow cytometry and immunohistochemistry. We recruited 378 patients with CRC, determined CD177 expression in tumours and examined its correlation with clinicopathological features. Moreover, CAC model was induced in wild-type and CD177-/- mice by azoxymethane/dextran sodium sulphate. CD177+ neutrophils were significantly increased in colon tumour tissues from patients with CRC or CAC compared with controls. Expression of CD177 mRNA and percentages of CD177+ neutrophils were also markedly increased in tumour tissues from CRC patients compared with controls. Patients with high density of CD177+ neutrophils had better overall survival and disease-free survival compared with controls. Multivariate analyses revealed that the density of CD177+ neutrophils was an independent factor in predicting overall survival and disease-free survival. Consistently, CD177 depletion aggravated azoxymethane/dextran sodium sulphate induced CAC in mice. Expression of Ki67 and proliferating cell nuclear antigen was increased in tumour tissues from CD177-/- mice compared with wild-type counterparts. Moreover, CD177-/- neutrophils failed to migrate in response to fMLP[AU: Please expand fMLP, DN, TNM and HIF-1alpha.] stimulation compared with wild-type controls. Our data indicate that CD177+ neutrophils suppress epithelial cell tumourigenesis and act as an independent factor in predicting the prognosis in patients with CRC. CD177+ neutrophils may serve as a novel therapeutic target in the treatment and predict the prognosis of CAC and CRC. PMID- 29228138 TI - American Society of Anesthesiologists physical status facilitates risk stratification of elderly patients undergoing thoracoscopic lobectomy. AB - OBJECTIVES: Accurate risk assessments are particularly important for elderly patients being considered for lobectomy. Considering the positive effects of the thoracoscopic approach on postoperative outcomes, we sought to review the reliability of the established risk factors for elderly patients undergoing thoracoscopic lobectomy. METHODS: From January 2009 to March 2016, 441 patients in our institution underwent thoracoscopic lobectomy for early-stage lung cancer. Clinical outcomes were compared between elderly (>70 years, n = 176) and younger patients (n = 265). RESULTS: There was no significant difference in postoperative mortality and morbidity between elderly and younger patients. In the regression analyses restricted to elderly patients, American Society of Anesthesiologists physical status (ASA-PS) was the single strong predictor of postoperative morbidity. The odds of pulmonary and cardiopulmonary complications increased nearly 6- and 3-fold, respectively, in those with ASA-PS Grade 3 compared with patients with ASA-PS Grade <3. Additionally, male gender was found to have a possible causal effect of pulmonary complication in elderly patients. After confounder adjustment using propensity score matching, the generalized linear mixed model revealed more than an 8-fold increase in the odds of pulmonary complications in elderly men compared with elderly women. To check the robustness of the above-mentioned finding, inverse probability of treatment weighting was used as an alternative analysis indicating a weaker but still substantively significant effect of male gender, with an odds ratio >3. CONCLUSIONS: Our results suggest that ASA-PS is a strong predictor of morbidity among elderly patients considered for thoracoscopic lobectomy. Compared with elderly women, elderly men are particularly prone to postoperative pulmonary complications. PMID- 29228139 TI - Authorship characteristics of orthodontic randomized controlled trials, systematic reviews, and meta-analyses in non-orthodontic journals with impact factor. AB - Background/Objective: This study was conducted to explore authorship characteristics and publication trends of all orthodontic randomized controlled trials (RCTs), systematic reviews (SRs), and meta-analyses (MAs) published in non orthodontic journals with impact factor (IF). Materials and methods: Appropriate research strategies were developed to search for all articles published until December 2015, without restrictions regarding language or publication status. The initial search generated 4524 results, but after application of the inclusion criteria, the final number of articles was reduced to 274 (SRs: 152; MAs: 36; and RCTs: 86). Various authorship characteristics were recorded for each article. Frequency distributions for all parameters were explored with Pearson chi-square for independence at the 0.05 level of significance. Results: More than half of the included publications were SRs (55.5 per cent), followed by RCTs (31.4 per cent) and MAs (13.1 per cent); one hundred seventy-eight (65 per cent) appeared in dental journals and 96 (35 per cent) were published in non-dental journals. The last decade was significantly more productive than the period before 2006, with 236 (86.1 per cent) articles published between 2006 and 2015. European countries produced 51.5 per cent of the total number of publications, followed by Asia (18.6 per cent) and North America (USA and Canada; 16.8 per cent). Limitations: Studies published in journals without IF were not included. Conclusions/Implications: Level-1 evidence orthodontic literature published in non-orthodontic journals has significantly increased during 2006-15. This indicates a larger interest of other specialty journals in orthodontic related studies and a trend for orthodontic authors to publish their work in journals with impact in broader fields of dentistry and medicine. PMID- 29228137 TI - Association of Gnrhr mRNA With the Stem Cell Determinant Musashi: A Mechanism for Leptin-Mediated Modulation of GnRHR Expression. AB - The cyclic expression of pituitary gonadotropin-releasing hormone receptors (GnRHRs) may be an important checkpoint for leptin regulatory signals. Gonadotrope Lepr-null mice have reduced GnRHR levels, suggesting these receptors may be leptin targets. To determine if leptin stimulated GnRHR directly, primary pituitary cultures or pieces were exposed to 1 to 100 nM leptin. Leptin increased GnRHR protein levels and the percentages of gonadotropes that bound biotinylated analogs of gonadotropin-releasing hormone (bio-GnRH) but had no effect on Gnrhr messenger RNA (mRNA). An in silico analysis revealed three consensus Musashi (MSI) binding elements (MBEs) for this translational control protein in the 3' untranslated region (UTR) of Gnrhr mRNA. Several experiments determined that these Gnrhr mRNA MBE were active: (1) RNA electrophoretic mobility shift assay analyses showed that MSI1 specifically bound Gnrhr mRNA 3'-UTR; (2) RNA immunoprecipitation of pituitary fractions with MSI1 antibody pulled down a complex enriched in endogenous MSI protein and endogenous Gnrhr mRNA; and (3) fluorescence reporter assays showed that MSI1 repressed translation of the reporter coupled to the Gnrhr 3'-UTR. In vitro, leptin stimulation of pituitary pieces reduced Msi1 mRNA in female pituitaries, and leptin stimulation of pituitary cultures reduced MSI1 proteins selectively in gonadotropes identified by binding to bio-GnRH. These findings show that leptin's direct stimulatory actions on gonadotrope GnRHR correlate with a direct inhibition of expression of the posttranscriptional regulator MSI1. We also show MSI1 interaction with the 3' UTR of Gnrhr mRNA. These findings now open the door to future studies of leptin modulated posttranscriptional pathways. PMID- 29228140 TI - Orientations for the successful categorization of facial expressions and their link with facial features. AB - Horizontal information was recently suggested to be crucial for face identification. In the present paper, we expand on this finding and investigate the role of orientations for all the basic facial expressions and neutrality. To this end, we developed orientation bubbles to quantify utilization of the orientation spectrum by the visual system in a facial expression categorization task. We first validated the procedure in Experiment 1 with a simple plaid detection task. In Experiment 2, we used orientation bubbles to reveal the diagnostic-i.e., task relevant-orientations for the basic facial expressions and neutrality. Overall, we found that horizontal information was highly diagnostic for expressions-surprise excepted. We also found that utilization of horizontal information strongly predicted performance level in this task. Despite the recent surge of research on horizontals, the link with local features remains unexplored. We were thus also interested in investigating this link. In Experiment 3, location bubbles were used to reveal the diagnostic features for the basic facial expressions. Crucially, Experiments 2 and 3 were run in parallel on the same participants, in an interleaved fashion. This way, we were able to correlate individual orientation and local diagnostic profiles. Our results indicate that individual differences in horizontal tuning are best predicted by utilization of the eyes. PMID- 29228141 TI - The source of visual size adaptation. AB - Size adaptation describes the tendency of the visual system to adjust neural responsiveness of size representations after prolonged exposure to particular stimulations. A larger (or smaller) adaptor stimulus influences the perceived size of a similar test stimulus shown subsequently. Size adaptation may emerge on various processing levels. Functional representations of the adaptor to which the upcoming stimulus is adapted may be coded early in the visual system mainly reflecting retinal size. Alternatively, size adaptation may involve higher order processes that take into account additional information such as an object's estimated distance from the observer, hence reflecting perceived size. The present study investigated whether size adaptation is based on the retinal or the perceived size of an adaptor stimulus. A stimulus' physical and perceived sizes were orthogonally varied using perceived depth via binocular disparity, employing polarized 3D glasses. Four different adaptors were used, which varied in physical size, perceived size, or both. Two pairs of adaptors which were identical in physical size did not cause significantly different adaptation effects although they elicited different perceived sizes which were sufficiently large to produce differential aftereffects when induced by stimuli that physically differed in size. In contrast, there was a significant aftereffect when adaptors differed in physical size but were matched in perceived size. Size adaptation was thus unaffected by perceived size and binocular disparity. Our data suggest that size adaptation emerges from neural stages where information from both eyes is still coded in separate channels without binocular interactions, such as the lateral geniculate nucleus. PMID- 29228142 TI - Beauty at a glance: The feeling of beauty and the amplitude of pleasure are independent of stimulus duration. AB - Over time, how does beauty develop and decay? Common sense suggests that beauty is intensely felt only after prolonged experience of the object. Here, we present one of various stimuli for a variable duration (1-30 s), measure the observers' pleasure over time, and, finally, ask whether they felt beauty. On each trial, participants (N = 21) either see an image that they had chosen as "movingly beautiful," see an image with prerated valence, or suck a candy. During the stimulus and a further 60 s, participants rate pleasure continuously using a custom touchscreen web app, EmotionTracker.com. After each trial, participants judge whether they felt beauty. Across all stimulus kinds, durations, and beauty responses, the dynamic pleasure rating has a stereotypical time course that is well fit by a one-parameter model with a brief exponential onset (roughly 2.5 s), a sustained plateau during stimulus presentation, and a long exponential decay (roughly 70 s). Across conditions, only the plateau amplitude varies. Beauty and pleasure amplitude are nearly independent of stimulus duration. The final beauty rating is positively correlated with pleasure amplitude (r = 0.60), and nearly independent of duration (r = 0.10). Beauty's independence from duration is unlike Bentham's 18th-century notion of value (utility), which he supposed to depend on the product of pleasure amplitude and duration. Participants report having felt pleasure as strongly after a mere 1 s stimulus as after longer durations, up to 30 s. Thus, we find that amplitude of pleasure is independent of stimulus duration. PMID- 29228143 TI - Accountable Care at the Frontlines of a Health System: Bridging Aspiration and Reality. PMID- 29228144 TI - Randomized Controlled Trial of Daily Text Messages to Support Adherence to Preexposure Prophylaxis in Individuals at Risk for Human Immunodeficiency Virus: The TAPIR Study. AB - Background: Adherence is critical for efficacy of tenofovir disoproxil fumarate/emtricitabine (FTC) as preexposure prophylaxis (PrEP). Methods: Between February 2013 and February 2016, 398 men who have sex with men and transgender women were randomized 1:1 to receive individualized texting for adherence building (iTAB) or standard care (SoC) for 48 weeks. The primary endpoint was dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations at both week 12 and the last on-drug visit of >719 fmol/punch (ie, adequate adherence). Secondary outcomes included DBS TFV-DP concentrations of >1246 fmol/punch (ie, near-perfect adherence) and plasma FTC >350 ng/mL (consistent with dosing within the past 24 hours). Results: Concentrations >719 fmol/punch of TFV-DP were found in 88.6% of participants at week 12 and 82.5% at week 48. For the primary endpoint, the study arms did not differ (72.0% in iTAB and 69.2% in SoC; P > .05). For the secondary composite endpoint of >1246 fmol/punch the iTAB arm was superior to SoC (33.5% vs 24.8%; P = .06), reaching statistical significance when adjusting for age (odds ratio, 1.56 [95% confidence interval, 1.00-2.42]; P < .05). At week 48, iTAB was superior to SoC for near-perfect adherence (51.0% vs 37.4%; P = .02). At week 12, iTAB was superior to SoC for dosing in past 24 hours by plasma FTC (47.5% vs 33.3%; P = .007), but not at weeks 24, 36, and 48 (all P > .05). Conclusions: Automated text messaging is a low-burden tool that improves durability of near-perfect PrEP adherence. Clinical Trials Registration: NCT01761643. PMID- 29228145 TI - Rejuvenating the Face: An Analysis of 100 Absorbable Suture Suspension Patients. AB - Background: Absorbable suture suspension (Silhouette InstaLift, Sinclair Pharma, Irvine, CA) is a novel, minimally invasive system that utilizes a specially manufactured synthetic suture to help address the issues of facial aging, while minimizing the risks associated with historic thread lifting modalities. Objectives: The purpose of the study was to assess the safety, efficacy, and patient satisfaction of the absorbable suture suspension system in regards to facial rejuvenation and midface volume enhancement. Methods: The first 100 treated patients who underwent absorbable suture suspension, by the senior author, were critically evaluated. Subjects completed anonymous surveys evaluating their experience with the new modality. Results: Survey results indicate that absorbable suture suspension is a tolerable (96%) and manageable (89%) treatment that improves age related changes (83%), which was found to be in concordance with our critical review. Conclusions: Absorbable suture suspension generates high patient satisfaction by nonsurgically lifting mid and lower face and neck skin and has the potential to influence numerous facets of aesthetic medicine. The study provides a greater understanding concerning patient selection, suture trajectory, and possible adjuvant therapies. Level of Evidence 4: PMID- 29228146 TI - Identification and characterization of a specific 13-miRNA expression signature during follicle activation in the zebrafish ovary. AB - Ovarian folliculogenesis is always of great interest in reproductive biology. However, the molecular mechanisms that control follicle development, particularly the early phase of follicle activation or recruitment, still remain poorly understood. In an attempt to decipher the gene networks and signaling pathways involved in such transition, we conducted a transcriptomic analysis (RNA-seq) on zebrafish primary growth (PG, stage I; inactive) and previtellogenic (PV, stage II; activated) follicles. A total of 118 unique microRNAs (miRNAs) (11 downregulated and 83 upregulated during PG/PV transition) and 56711 unique messenger RNAs (mRNAs) (1839 downregulated and 7243 upregulated during PG/PV transition) were identified. Real-time quantitative polymerase chain reaction analysis confirmed differential expression of 46 miRNAs from 66 candidates (66.67%). Among which, we chose to focus on 13 miRNAs (let-7a, -7b, -7c-5p, -7d 5p, -7h, -7i; miR-21, -23a-3p, -27c-3p, -107a-3p, -125b-5p, -145-3p, and -202-5p) that exhibited significant differential expression between PG and PV follicles (P <= 0.045*). With this 13-miRNA expression signature alone, PG follicles can be well differentiated from PV follicles by hierarchical clustering, suggesting their functional relevance during PG-to-PV transition. By overlaying predicted target genes and the differentially expressed mRNAs revealed by the RNA-seq analysis, especially those showing reciprocal miRNA-mRNA expression patterns, we shortlisted a panel of miRNA downstream targets for luciferase reporter validation. The reporter assay confirmed the interactions of let-7i:: atg4a (P = 0.01*), miR-202-5p::c23h20orf24 (P = 0.0004***), and miR-144-5p::ybx1 (P = 0.003**), implicating these potential miRNA-mRNA gene pairs in follicle activation during folliculogenesis. Our transcriptomic data analyses suggest that miRNA-mediated post-transcriptional control may represent an important mechanism underlying follicle activation. PMID- 29228147 TI - Association of Early Postresuscitation Hypotension With Survival to Discharge After Targeted Temperature Management for Pediatric Out-of-Hospital Cardiac Arrest: Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Out-of-hospital cardiac arrest (OHCA) occurs in more than 6000 children each year in the United States, with survival rates of less than 10% and severe neurologic morbidity in many survivors. Post-cardiac arrest hypotension can occur, but its frequency and association with survival have not been well described during targeted temperature management. Objective: To determine whether hypotension is associated with survival to discharge in children and adolescents after resuscitation from OHCA. Design, Setting, and Participants: This post hoc secondary analysis of the Therapeutic Hypothermia After Pediatric Cardiac Arrest (THAPCA) trial included 292 pediatric patients older than 48 hours and younger than 18 years treated in 36 pediatric intensive care units from September 1, 2009, through December 31, 2012. Participants underwent therapeutic hypothermia (33.0 degrees C) vs therapeutic normothermia (36.8 degrees C) for 48 hours. All participants had hourly systolic blood pressure measurements documented during the initial 6 hours of temperature intervention. Hourly blood pressures beginning at the time of temperature intervention (time 0) were normalized for age, sex, and height. Early hypotension was defined as a systolic blood pressure less than the fifth percentile during the first 6 hours after temperature intervention. With use of forward stepwise logistic regression, covariates of interest (age, sex, initial cardiac rhythm, any preexisting condition, estimated duration of cardiopulmonary resuscitation [CPR], primary cause of cardiac arrest, temperature intervention group, night or weekend cardiac arrest, witnessed status, and bystander CPR) were evaluated in the final model. Data were analyzed from February 5, 2016, through June 13, 2017. Exposures: Hypotension. Main Outcomes and Measure: Survival to hospital discharge. Results: Of 292 children (194 boys [66.4%] and 98 girls [33.6%]; median age, 23.0 months [interquartile range, 5.0 105.0 months]), 78 (26.7%) had at least 1 episode of early hypotension. No difference was observed between the therapeutic hypothermia and therapeutic normothermia groups in the prevalence of hypotension during induction and maintenance (73 of 153 [47.7%] vs 72 of 139 [51.8%]; P = .50) or rewarming (35 of 118 [29.7%] vs 19 of 95 [20.0%]; P = .10) during the first 72 hours. Participants who had early hypotension were less likely to survive to hospital discharge (20 of 78 [25.6%] vs 93 of 214 [43.5%]; adjusted odds ratio, 0.39; 95% CI, 0.20 0.74). Conclusions and Relevance: In this post hoc secondary analysis of the THAPCA trial, 26.7% of participants had hypotension within 6 hours after temperature intervention. Early post-cardiac arrest hypotension was associated with lower odds of discharge survival, even after adjusting for covariates of interest. PMID- 29228148 TI - Rapid screening method for detecting highly pathogenic Streptococcus intermedius strains carrying a mutation in the lacR gene. AB - Streptococcus intermedius is a member of the normal human commensal flora and secretes a human-specific cytolysin intermedilysin (ILY) as a major virulence factor. Expression of ily is repressed by LacR and loss-of-function mutations of LacR are observed in many ILY high-producing strains isolated from deep-seated abscesses, suggesting that high ILY production is necessary for increased virulence. However, because ILY exhibits no beta-hemolysis on animal blood agar plates, differentiating ILY high- and low-producing strains using conventional laboratory methods is not possible. Interestingly, S. intermedius also produces glycosidases, including MsgA and NanA, which exhibit N-acetyl-beta-d glucosaminidase and neuraminidase activities, respectively. Moreover, MsgA expression, but not NanA, is negatively regulated by LacR. Here we measured the activities of MsgA, NanA and ILY in strains isolated from clinical specimens and dental plaque to determine the correlation between these glycosidase activities and ILY hemolytic activity. Hemolytic activity showed a strong positive correlation with MsgA and a weak negative correlation with NanA activities. Therefore, we calculated the ratio of MsgA and NanA activity (M/N ratio). This value showed a stronger positive correlation (r = 0.81) with ILY hemolytic activity and many strains with high M/N ratios (>2) were ILY-high producers with loss-of-function mutations in LacR. PMID- 29228149 TI - Outcome after transvascular transcatheter aortic valve implantation in 2016. AB - Aims: We analysed the number of procedures, complications, and in-hospital mortality rates of all patients undergoing transvascular transcatheter aortic valve implantation (TV-TAVI) in comparison to isolated surgical aortic valve replacement (iSAVR) from 2014 to 2016 in Germany. Methods and results: All aortic valve procedures performed in Germany are mandatorily registered in a quality control program. More than 15 000 TV-TAVI procedures were performed in 2016 in Germany. Especially the number of post-procedural complications declined within the last few years, including new pacemaker implantations (2015: 12.6% vs. 2016: 11.4%, P = 0.002) and vascular complications (2015: 8.5% vs. 2016: 7.1%; P < 0.001). Thus, in 2016 the overall in-hospital mortality rate after TV-TAVI was 2.6%, which is for the first time numerically below that of iSAVR, which was 2.9% (P = 0.19). A stratified analysis according to the German aortic valve score shows a lower observed than expected in-hospital mortality rate for TV-TAVI (O/E 0.68). Additionally, the in-hospital mortality was significantly lower after TV TAVI than after iSAVR in the very high- (11.3% vs. 23.6%; P < 0.001), in the high (4.1% vs. 9.2%; P < 0.001), and in the intermediate-risk group (3.0% vs. 4.6%; P = 0.016) and was similar to that of iSAVR in low-risk patients (1.6% vs. 1.4%; P = 0.4). Conclusion: The overall in-hospital mortality after TV-TAVI was numerically lower than after iSAVR in 2016 for the first time. In the low risk group in-hospital mortality was similar, whereas in all other risk groups in hospital mortality after TV-TAVI was significantly lower than after SAVR. This is likely to contribute to a redefinition of the standard of care in the future. PMID- 29228150 TI - Quadricuspid mitral valve: a rare phenotype associated with hypertrophic cardiomyopathy. PMID- 29228151 TI - Multimodal Treatment of the School-aged Child With Attention Deficit/Hyperactivity Disorder. PMID- 29228152 TI - Effectiveness of nutritional interventions addressed to elderly persons: umbrella systematic review with meta-analysis. AB - Background: The number of Europeans aged over 65 will double between 2010 and 2060, reaching 30% of the European population. Nutrition is emerging as a key element of healthy life since both obesity and malnutrition are established risk factors for morbidity and disability. The aim of this umbrella review (UR) is to summarize the findings of all current systematic reviews (SRs) and meta-analyzes (MAs) on the effectiveness of nutritional intervention designed to promote healthy aging in older individuals. Methods: Eligible articles published in English or Italian between January 2000 and May 2016 were identified in six databases. Only studies that analyzed nutritional interventions in the population of 65 years and over, or papers specifically targeting older adults were deemed eligible. Results: Twenty-eight papers, out of which twenty-five SRs and three MAs, met the inclusion criteria and were included in this umbrella SR. Supplementation with vitamin D and other kind of products was highly effective in preventing falls and fractures. Furthermore, several interventions, ranging from the prescription of supplements to environmental and organizational programs, resulted in an improvement in energy and protein intake, as well as positive weight outcomes. Positive findings were also found for the elderly at risk of malnutrition and for older patients with dementia. Conclusions: The findings of this UR indicate that the use of a wide range of supplements and environmental and organizational intervention improve a number of anthropometric, nutritional and functional indices in the elderly. PMID- 29228153 TI - Adaptation of Bone to Mechanical Strain-Reply. PMID- 29228155 TI - Quality of and access to green space in relation to psychological distress: results from a population-based cross-sectional study as part of the EURO-URHIS 2 project. PMID- 29228154 TI - Comparative transcriptomic analysis of human placentae at term and preterm delivery. AB - Preterm birth affects 1 out of every 10 infants in the United States, resulting in substantial neonatal morbidity and mortality. Currently, there are few predictive markers and few treatment options to prevent preterm birth. A healthy, functioning placenta is essential to positive pregnancy outcomes. Previous studies have suggested that placental pathology may play a role in preterm birth etiology. Therefore, we tested the hypothesis that preterm placentae may exhibit unique transcriptomic signatures compared to term samples reflective of their abnormal biology leading to this adverse outcome. We aggregated publicly available placental villous microarray data to generate a preterm and term sample dataset (n = 133, 55 preterm placentae and 78 normal term placentae). We identified differentially expressed genes using the linear regression for microarray (LIMMA) package and identified perturbations in known biological networks using Differential Rank Conservation (DIRAC). We identified 129 significantly differentially expressed genes between term and preterm placenta with 96 genes upregulated and 33 genes downregulated (P-value <0.05). Significant changes in gene expression in molecular networks related to Tumor Protein 53 and phosphatidylinositol signaling were identified using DIRAC. We have aggregated a uniformly normalized transcriptomic dataset and have identified novel and established genes and pathways associated with developmental regulation of the placenta and potential preterm birth pathology. These analyses provide a community resource to integrate with other high-dimensional datasets for additional insights in normal placental development and its disruption. PMID- 29228156 TI - Feedback regulation of TGF-beta signaling. AB - Transforming growth factor beta (TGF-beta) is a multi-functional polypeptide that plays a critical role in regulating a broad range of cellular functions and physiological processes. Signaling is initiated when TGF-beta ligands bind to two types of cell membrane receptors with intrinsic Ser/Thr kinase activity and transmitted by the intracellular Smad proteins, which act as transcription factors to regulate gene expression in the nucleus. Although it is relatively simple and straight-forward, this TGF-beta/Smad pathway is regulated by various feedback loops at different levels, including the ligand, the receptor, Smads and transcription, and is thus fine-tuned in terms of signaling robustness, duration, specificity, and plasticity. The precise control gives rise to versatile and context-dependent pathophysiological functions. In this review, we firstly give an overview of TGF-beta signaling, and then discuss how each step of TGF-beta signaling is finely controlled by distinct modes of feedback mechanisms, involving both protein regulators and miRNAs. PMID- 29228158 TI - Percutaneous left atrial appendage occlusion in atrial fibrillation patients with a contraindication to oral anticoagulation: a focused review. AB - Stroke is the most feared complication of atrial fibrillation (AF). Although oral anticoagulation with non-vitamin K antagonist and non-vitamin K antagonist oral anticoagulants (NOACs) have been established to significantly reduce risk of stroke, real-world use of these agents are often suboptimal due to concerns for adverse events including bleeding from both patients and clinicians. Particularly in patients with previous serious bleeding, oral anticoagulation may be contraindicated. Left atrial appendage occlusion (LAAO), mechanically targeting the source of most of the thrombi in AF, holds an immense potential as an alternative to OAC in management of stroke prophylaxis. In this focused review, we describe the available evidence of various LAAO devices, detailing data regarding their use in patients with a contraindication for oral anticoagulation. Although some questions of safety and appropriate use of these new devices in patients who cannot tolerate anticoagulation remain, LAAO devices offer a significant step forward in the management of patients with AF, including those patients who may not be able to be prescribed OAC at all. Future studies involving patients fully contraindicated to OAC are warranted in the era of LAAO devices for stroke risk reduction. PMID- 29228159 TI - Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. AB - Aims: Functional alterations of epicardial coronary arteries or coronary microcirculation represent a frequent cause of myocardial infarction and non obstructive coronary arteries (MINOCA). We aimed at assessing the prognostic value of intracoronary provocative tests in patients presenting with MINOCA and in which other causes of MINOCA have been excluded. Methods and results: We prospectively evaluated patients with a diagnosis of MINOCA, excluding patients with aetiologies other than suspected coronary vasomotor abnormalities. Immediately after coronary angiography, an invasive provocative test using acetylcholine or ergonovine was performed. The incidence of death from any cause, cardiac death, and recurrence of acute coronary syndrome (ACS) was assessed at follow-up. We also assessed angina status using Seattle Angina Questionnaires (SAQ). We enrolled 80 consecutive patients [mean age 63.0 +/- 10.7 years, 40 (50%) male]. Provocative test was positive in 37 (46.2%) patients without any complication. Among patients with a positive test, epicardial spasm was detected in 24 (64.9%) patients and microvascular spasm in 13 (35.1%) patients. After a median follow-up of 36.0 (range 12.0-60.0) months, patients with a positive test had a significantly higher occurrence of death from any cause [12 (32.4%) vs. 2 (4.7%); P = 0.002], cardiac death [7 (18.9%) vs. 0 (0.0%); P = 0.005], and readmission for ACS [10 (27.0%) vs. 3 (7.0%); P = 0.015] as well as a worse angina status as assessed by SAQ [Seattle score: 88.0 (33.0-100.0) vs. 100.0 (44.0-100.0); P = 0.001] when compared with patients with a negative test. Conclusions: We demonstrate that in patients presenting with MINOCA and suspected coronary vasomotor abnormalities, a positive provocative test for spasm is safe and identifies a high-risk subset of patients. PMID- 29228157 TI - Gut Epithelial Vitamin D Receptor Regulates Microbiota-Dependent Mucosal Inflammation by Suppressing Intestinal Epithelial Cell Apoptosis. AB - Recent studies show that colonic vitamin D receptor (VDR) signaling protects the mucosal epithelial barrier and suppresses colonic inflammation, but the underlying molecular mechanism remains to be fully understood. To investigate the implication of colonic VDR downregulation seen in patients with inflammatory bowel disease, we assessed the effect of gut epithelial VDR deletion on colonic inflammatory responses in an experimental colitis model. In a 2,4,6 trinitrobenzenesulfonic acid-induced colitis model, mice carrying VDR deletion in gut epithelial cells [VDRflox/flox (VDRf/f);Villin-Cre or VDRDeltaIEC] or in colonic epithelial cells (VDRf/f;CDX2-Cre or VDRDeltaCEC) developed more severe clinical colitis than VDRf/f control mice, characterized by more robust T-helper (TH)1 and TH17 responses, with greater increases in mucosal interferon (IFN) gamma+, interleukin (IL)-17+, and IFN-gamma+IL-17+ T cells. Accompanying the severe mucosal inflammation was more profound colonic epithelial cell apoptosis in the mutant mice. Treatment with caspase inhibitor Q-VD-OPh dramatically reduced colitis severity and attenuated TH1 and TH17 responses in VDRDeltaCEC mice. The blockade of cell apoptosis also prevented the increase in mucosal CD11b+CD103+ dendritic cells (DCs), known to be critical for TH17-cell activation. Moreover, depletion of gut commensal bacteria with antibiotics eliminated the robust TH1 and TH17 responses and CD11b+CD103+ DC induction. Taken together, these observations demonstrate that gut epithelial VDR deletion aggravates epithelial cell apoptosis, resulting in increases in mucosal barrier permeability. Consequently, invading luminal bacteria activate CD11b+CD103+ DCs, which promote mucosal TH1 and TH17 responses. Therefore, gut epithelial VDR signaling controls mucosal inflammation by suppressing epithelial cell apoptosis. PMID- 29228160 TI - Effect of Financial Incentives on Breastfeeding: A Cluster Randomized Clinical Trial. AB - Importance: Although breastfeeding has a positive effect on an infant's health and development, the prevalence is low in many communities. The effect of financial incentives to improve breastfeeding prevalence is unknown. Objective: To assess the effect of an area-level financial incentive for breastfeeding on breastfeeding prevalence at 6 to 8 weeks post partum. Design, Setting, and Participants: The Nourishing Start for Health (NOSH) trial, a cluster randomized trial with 6 to 8 weeks follow-up, was conducted between April 1, 2015, and March 31, 2016, in 92 electoral ward areas in England with baseline breastfeeding prevalence at 6 to 8 weeks post partum less than 40%. A total of 10 010 mother infant dyads resident in the 92 study electoral ward areas where the infant's estimated or actual birth date fell between February 18, 2015, and February 17, 2016, were included. Areas were randomized to the incentive plus usual care (n = 46) (5398 mother-infant dyads) or to usual care alone (n = 46) (4612 mother infant dyads). Interventions: Usual care was delivered by clinicians (mainly midwives, health visitors) in a variety of maternity, neonatal, and infant feeding services, all of which were implementing the UNICEF UK Baby Friendly Initiative standards. Shopping vouchers worth L40 (US$50) were offered to mothers 5 times based on infant age (2 days, 10 days, 6-8 weeks, 3 months, 6 months), conditional on the infant receiving any breast milk. Main Outcomes and Measures: The primary outcome was electoral ward area-level 6- to 8-week breastfeeding period prevalence, as assessed by clinicians at the routine 6- to 8-week postnatal check visit. Secondary outcomes were area-level period prevalence for breastfeeding initiation and for exclusive breastfeeding at 6 to 8 weeks. Results: In the intervention (5398 mother-infant dyads) and control (4612 mother infant dyads) group, the median (interquartile range) percentage of women aged 16 to 44 years was 36.2% (3.0%) and 37.4% (3.6%) years, respectively. After adjusting for baseline breastfeeding prevalence and local government area and weighting to reflect unequal cluster-level breastfeeding prevalence variances, a difference in mean 6- to 8-week breastfeeding prevalence of 5.7 percentage points (37.9% vs 31.7%; 95% CI for adjusted difference, 2.7% to 8.6%; P < .001) in favor of the intervention vs usual care was observed. No significant differences were observed for the mean prevalence of breastfeeding initiation (61.9% vs 57.5%; adjusted mean difference, 2.9 percentage points; 95%, CI, -0.4 to 6.2; P = .08) or the mean prevalence of exclusive breastfeeding at 6 to 8 weeks (27.0% vs 24.1%; adjusted mean difference, 2.3 percentage points; 95% CI, -0.2 to 4.8; P = .07). Conclusions and Relevance: Financial incentives may improve breastfeeding rates in areas with low baseline prevalence. Offering a financial incentive to women in areas of England with breastfeeding rates below 40% compared with usual care resulted in a modest but statistically significant increase in breastfeeding prevalence at 6 to 8 weeks. This was measured using routinely collected data. Trial Registration: International Standard Randomized Controlled Trial Registry: ISRCTN44898617. PMID- 29228161 TI - Reductive tetrachloroethene dehalogenation in the presence of oxygen by Sulfurospirillum multivorans: physiological studies and proteome analysis. AB - Reductive dehalogenation of organohalides is carried out by organohalide respiring bacteria (OHRB) in anoxic environments. The tetrachloroethene (PCE) respiring Epsilonproteobacterium Sulfurospirillum multivorans is one of few OHRB able to respire oxygen. Therefore, we investigated the organism's capacity to dehalogenate PCE in the presence of oxygen, which would broaden the applicability to use S. multivorans, unlike other commonly oxygen-sensitive OHRB, for bioremediation, e.g. at oxic/anoxic interphases. Additionally, this has an impact on our understanding of the global halogen cycle. Sulfurospirillum multivorans performs dehalogenation of PCE to cis-1,2-dichloroethene at oxygen concentrations below 0.19 mg/L. The redox potential of the medium electrochemically adjusted up to +400 mV had no influence on reductive dehalogenation by S. multivorans in our experiments, suggesting that higher levels of oxygen impair PCE dechlorination by inhibiting or inactivating involved enzymes. The PCE reductive dehalogenase remained active in cell extracts of S. multivorans exposed to 0.37 mg/L oxygen for more than 96 h. Analysis of the proteome revealed that superoxide reductase and cytochrome peroxidase amounts increased with 5% oxygen in the gas phase, while the response to atmospheric oxygen concentrations involved catalase and hydrogen peroxide reductase. Taken together, our results demonstrate that reductive dehalogenation by OHRB is not limited to anoxic conditions. PMID- 29228162 TI - Prospective Memory in Depression: Review of an Emerging Field. AB - Depressive disorders have been linked to a variety of neuropsychological deficits, including in the areas of processing speed, memory, and executive functioning. These neurocognitive disturbances may contribute to the impairments in daily functioning often experienced by those suffering with depression. Prospective memory (PM), which refers to remembering to execute a previously formed intention at some point in the future, has been shown to play a critical role in daily functioning and may be particularly relevant in the context of depression. In this review, we synthesize the literature on PM and its relation to depression. We also put forth a new five-phase model of PM through which we frame our discussion of the existing literature on PM and depression. The results of this review reveal that PM deficits emerge in those tasks that place the greatest demands on executive functioning (e.g., monitoring for a PM cue, maintaining an intention over a delay). We conclude the review by highlighting the potential clinical relevance of these findings and proposing directions for future research. PMID- 29228163 TI - Ethical Challenges Confronted When Providing Nusinersen Treatment for Spinal Muscular Atrophy. AB - The US Food and Drug Administration's December 2016 approval of nusinersen for the treatment of patients with all subtypes of spinal muscular atrophy ushered in a new era for patients with spinal muscular atrophy, their families, and all those involved in their care. The extreme cost of the medication and the complicated logistical requirements for administering nusinersen via lumbar puncture have created practical challenges that raise important ethical considerations. We discuss 6 challenges faced at the institutional level in the United States: cost, limited evidence, informed consent, treatment allocation, fair distribution of responsibilities, and transparency with stakeholders. These challenges must be understood to ensure that patients with spinal muscular atrophy benefit from treatment, are protected from harm, and are treated fairly. PMID- 29228164 TI - Liver fat content, non-alcoholic fatty liver disease, and ischaemic heart disease: Mendelian randomization and meta-analysis of 279 013 individuals. AB - Aims: In observational studies, non-alcoholic fatty liver disease (NAFLD) is associated with high risk of ischaemic heart disease (IHD). We tested the hypothesis that a high liver fat content or a diagnosis of NAFLD is a causal risk factor for IHD. Methods and results: In a cohort study of the Danish general population (n = 94 708/IHD = 10 897), we first tested whether a high liver fat content or a diagnosis of NAFLD was associated observationally with IHD. Subsequently, using Mendelian randomization, we tested whether a genetic variant in the gene encoding the protein patatin-like phospholipase domain containing 3 protein (PNPLA3), I148M (rs738409), a strong and specific cause of high liver fat content and NAFLD, was causally associated with the risk of IHD. We found that the risk of IHD increased stepwise with increasing liver fat content (in quartiles) up to an odds ratio (OR) of 2.41 (1.28-4.51)(P-trend = 0.004). The corresponding OR for IHD in individuals with vs. without NAFLD was 1.65 (1.34 2.04)(P = 3*10-6). PNPLA3 I148M was associated with a stepwise increase in liver fat content of up to 28% in MM vs. II-homozygotes (P-trend = 0.0001) and with ORs of 2.03 (1.52-2.70) for NAFLD (P = 3*10-7), 3.28 (2.37-4.54) for cirrhosis (P = 4*10-12), and 0.95 (0.86-1.04) for IHD (P = 0.46). In agreement, in meta-analysis (N = 279 013/IHD = 71 698), the OR for IHD was 0.98 (0.96-1.00) per M-allele vs. I-allele. The OR for IHD per M-allele higher genetically determined liver fat content was 0.98 (0.94-1.03) vs. an observational estimate of 1.05 (1.02-1.09)(P for comparison = 0.02). Conclusion: Despite confirming the known observational association of liver fat content and NAFLD with IHD, lifelong, genetically high liver fat content was not causally associated with risk of IHD. These results suggest that the observational association is due to confounding or reverse causation. PMID- 29228165 TI - Repair versus replacement for the surgical correction of tricuspid regurgitation: a meta-analysis. AB - OBJECTIVES: Tricuspid valve repair (TVr) has both a theoretical advantage in preserving right ventricular function and disadvantages such as a higher risk of repair failure in the long-term compared with tricuspid valve replacement (TVR). This study was conducted to compare the results of TVr with those of TVR to find an optimal treatment option. METHODS: A literature search of 5 databases was performed. The primary outcome was all-cause mortality. Secondary outcomes were tricuspid reoperation and valve-related events. Subgroup analyses were performed according to the risk of bias, year of publication and proportions of patients with tricuspid regurgitation Grade >=3, functional aetiology and isolated tricuspid valve surgery. Publication bias was explored using the funnel plot and Egger's test. RESULTS: Seventeen retrospective studies involving 4561 patients (TVr group = 3432 patients and TVR group = 1129 patients) were included. A pooled analysis showed that the risk of all-cause mortality was significantly higher in the TVR group than in the TVr group [hazard ratio (95% confidence interval) 1.59 (1.26-2.00)]. There were no significant differences in tricuspid valve reoperation in 6 studies and valve-related events in 5 studies between the TVR and TVr groups [hazard ratio (95% confidence interval) 1.30 (0.88-1.91) and 1.47 (0.91-2.38), respectively]. None of the subgroup analyses demonstrated a significant difference in the hazard ratio of all-cause mortality. No publication bias was identified for the primary and secondary outcomes. CONCLUSIONS: This meta-analysis indicates that TVr is more beneficial compared with TVR in terms of all-cause mortality. From the available data, TVr is not associated with an increased risk of tricuspid reoperation compared with TVR. PMID- 29228166 TI - Long-term results of concurrent chemoradiotherapy with daily-low-dose continuous infusion of 5-fluorouracil and cisplatin (LDFP) for Stage I-II esophageal carcinoma. AB - We investigated long-term treatment outcomes and the feasibility of chemoradiotherapy consisting of daily-low-dose 5-fluorouracil and cisplatin (LDFP) chemotherapy plus radiotherapy for Stage I-II squamous cell esophageal cancer. Treatment records from the 2000 through 2008 period were reviewed retrospectively. Fractionated radiotherapy was performed with a total dose of 60 Gy delivered in 2 Gy per fraction. LDFP chemotherapy, as continuous infusion of 200 mg/m2 5-fluorouracil combined with one hour infusion of 4 mg/m2 cisplatin, was administered on the same days as radiotherapy. Survival was calculated by the Kaplan-Meier method. Survival, responses, failure patterns, and toxicities were evaluated. Seventy-six (47 stage I and 29 stage II) patients were analyzed with a median follow-up of 93.6 months. The 8-year overall survival (OS), progression free survival (PFS) and cause-specific survival (CSS) rates were 63.4%, 49.8%, and 76.7%, respectively. The 8-year OS, PFS, and CSS for stage I and stage II patients were 71.0%/56.1%/82.9% and 45.2%/40.2%/66.6%, respectively. Sixty-eight patients (89.5%) completed the treatment regimen. A complete response (CR) was achieved in 68 patients (89.5%). Twenty-five patients (36.8%) experienced recurrence after CR. The failure patterns were (overlap included): local failure (n = 12), nodal metastasis (n = 12), distant metastasis (n = 3), details unknown (n = 2). Salvage therapy was performed for local failure; endoscopic therapy (n = 7) or surgery (n = 2). Six patients remain alive without relapse after salvage endoscopic therapy. Major Grade 3 or higher acute adverse events were leukopenia (22%), anorexia (17%), and esophagitis (11%). Major late toxicities (Grade 3 or 4) involved pericardial effusion (12%), pleural effusion (4%), and esophageal stenosis (3%). Chemoradiotherapy with LDFP provided favorable long-term survival with acceptable toxicity for Stage I-II squamous cell esophageal cancer. The tumor response was excellent, but close endoscopic follow-up is essential for detecting and treating local recurrence. PMID- 29228167 TI - U-shaped relationship of HDL and risk of infectious disease: two prospective population-based cohort studies. AB - Aims: Preclinical evidence has indicated that HDL may play an important role in the immune system; however, very little is known about the role of HDL in the immune system in humans. We tested the hypothesis that low and high concentrations of HDL cholesterol are associated with risk of infectious disease in the general population. Methods and results: We included 97 166 individuals from the Copenhagen General Population Study and 9387 from the Copenhagen City Heart Study with measurements of HDL cholesterol at baseline. The primary endpoint was any infectious disease requiring hospital admission, ascertained in the Danish health registries from baseline in 2003-13 or 1991-94 through 2014; 9% and 31% of individuals in the two studies experienced one or more infectious disease events. Using restricted cubic splines, there was a U-shaped association between concentrations of HDL cholesterol and risk of any infection. Following multifactorial adjustment, individuals with HDL cholesterol below 0.8 mmol/L (31 mg/dL) and above 2.6 mmol/L (100 mg/dL) had hazard ratios for any infection of 1.75 (95% confidence interval 1.31-2.34) and 1.43 (1.16-1.76), compared to those with HDL cholesterol of 2.2-2.3 mmol/L (85-95 mg/dL). In the Copenhagen City Heart Study, corresponding hazard ratios for any infection were 2.00 (1.16-3.43) and 1.13 (0.80-1.60). Conclusion: Low and high HDL cholesterol concentrations found in 21% and 8% of individuals were associated with higher risk of infectious disease in the general population. These findings do not necessarily indicate causality. PMID- 29228168 TI - Glutamate residues at positions 162 and 164 influence the beta-lactamase activity of SHV-14 obtained from Klebsiella pneumoniae. AB - Extensive production of SHV-14 beta-lactamase makes Klebsiella pneumoniae resistant to beta-lactams. The presence of omega-loop has been reported to influence the beta-lactamase activity, which is also present in SHV-14. Its omega loop has three glutamates in nearly alternating positions 162, 164 and 167 but their concise role on the behaviour of SHV-14 is unknown. To uncover the influence of each glutamate on SHV-14, we replaced glutamates with alanine and estimated the effect of each mutation by assessing the change in beta-lactam sensitivities in the surrogate Escherichia coli cells and catalytic efficiencies for hydrolysis with the purified proteins. On expression, the clone of wild-type SHV-14 aggravated the resistance of host by 60-500 folds against penicillin and cephalosporin groups of antibiotics. However, the expression of mutated enzymes (especially E164A) substantially reduced the resistance level as compared to the wild type, and the results were in synchrony with the estimated enzymatic efficiencies of wild-type and mutated proteins. Therefore, with further support from the in silico analysis, we hypothesise that mutation at the glutamate residues in the omega-loop of SHV-14 can considerably modulate the beta-lactam sensitivity and hydrolysis, thus revealing the importance of such glutamates as the target for inhibitor design in future. PMID- 29228169 TI - Endothelial permeability, LDL deposition, and cardiovascular risk factors-a review. AB - Early atherosclerosis features functional and structural changes in the endothelial barrier function that affect the traffic of molecules and solutes between the vessel lumen and the vascular wall. Such changes are mechanistically related to the development of atherosclerosis. Proatherogenic stimuli and cardiovascular risk factors, such as dyslipidaemias, diabetes, obesity, and smoking, all increase endothelial permeability sharing a common signalling denominator: an imbalance in the production/disposal of reactive oxygen species (ROS), broadly termed oxidative stress. Mostly as a consequence of the activation of enzymatic systems leading to ROS overproduction, proatherogenic factors lead to a pro-inflammatory status that translates in changes in gene expression and functional rearrangements, including changes in the transendothelial transport of molecules, leading to the deposition of low-density lipoproteins (LDL) and the subsequent infiltration of circulating leucocytes in the intima. In this review, we focus on such early changes in atherogenesis and on the concept that proatherogenic stimuli and risk factors for cardiovascular disease, by altering the endothelial barrier properties, co-ordinately trigger the accumulation of LDL in the intima and ultimately plaque formation. PMID- 29228170 TI - Biotransformation of trinitrotoluene by Citrobacter sp. YC4 and evaluation of its cyto-toxicological effects. AB - Trinitrotoluene (TNT) is an explosive chemical generally used for military, civil and industrial purposes. Therefore, TNT residue can be found in soil and ground water as an environmental pollutant. The environmental control of TNT pollution has become a critical issue because of its potential toxicity and carcinogenicity. The aim of this study is to evaluate the cyto-toxicological effects of TNT after bioremediation. Citrobacter sp. YC4 is able to utilize TNT as a sole nitrogen source. Citrobacter sp. YC4 cells grown in medium with TNT as the sole nitrogen source (TNT-N) were able to rapidly degrade TNT, in contrast to cells grown in Luria Bertani medium as determined by resting cell suspension. The concentration of TNT decreased from 100 to 0 ppm within 10 h in the solution containing TNT mixed with TNT-N-grown YC4. The cytotoxicity of TNT and its degradation products generated by TNT-N-grown YC4 were assessed by WST-1-based cell cytotoxicity assays. Our results showed that the cytotoxic potential of solutions containing TNT decreased almost to the level of the control after a 1-h incubation with TNT-N-grown YC4 cells. The rapid conversion of TNT into possibly less toxic products by Citrobacter sp. YC4 proposes a bioremediation prospection. PMID- 29228171 TI - Gene Graphics: a genomic neighborhood data visualization web application. AB - Summary: The examination of gene neighborhood is an integral part of comparative genomics but no tools to produce publication quality graphics of gene clusters are available. Gene Graphics is a straightforward web application for creating such visuals. Supported inputs include National Center for Biotechnology Information gene and protein identifiers with automatic fetching of neighboring information, GenBank files and data extracted from the SEED database. Gene representations can be customized for many parameters including gene and genome names, colors and sizes. Gene attributes can be copied and pasted for rapid and user-friendly customization of homologous genes between species. In addition to Portable Network Graphics and Scalable Vector Graphics, produced representations can be exported as Tagged Image File Format or Encapsulated PostScript, formats that are standard for publication. Hands-on tutorials with real life examples inspired from publications are available for training. Availability and implementation: Gene Graphics is freely available at https://katlabs.cc/genegraphics/ and source code is hosted at https://github.com/katlabs/genegraphics. Contact: katherinejh@ufl.edu or remizallot@ufl.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228172 TI - SPRING: a kinetic interface for visualizing high dimensional single-cell expression data. AB - Motivation: Single-cell gene expression profiling technologies can map the cell states in a tissue or organism. As these technologies become more common, there is a need for computational tools to explore the data they produce. In particular, visualizing continuous gene expression topologies can be improved, since current tools tend to fragment gene expression continua or capture only limited features of complex population topologies. Results: Force-directed layouts of k-nearest-neighbor graphs can visualize continuous gene expression topologies in a manner that preserves high-dimensional relationships and captures complex population topologies. We describe SPRING, a pipeline for data filtering, normalization and visualization using force-directed layouts and show that it reveals more detailed biological relationships than existing approaches when applied to branching gene expression trajectories from hematopoietic progenitor cells and cells of the upper airway epithelium. Visualizations from SPRING are also more reproducible than those of stochastic visualization methods such as tSNE, a state-of-the-art tool. We provide SPRING as an interactive web-tool with an easy to use GUI. Availability and implementation: https://kleintools.hms.harvard.edu/tools/spring.html, https://github.com/AllonKleinLab/SPRING/. Contact: calebsw@gmail.com or allon_klein@hms.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228173 TI - Group A streptococcal M-like proteins: From pathogenesis to vaccine potential. AB - M and M-like surface proteins from group A Streptococcus (GAS) act as virulence factors and have been used in multiple vaccine candidates. While the M protein has been extensively studied, the two genetically and functionally related M-like proteins, Mrp and Enn, although present in most streptococcal strains have been relatively less characterised. We compile the current state of knowledge for these two proteins, from discovery to recent studies on function and immunogenicity, using the M protein for comparison as a prototype of this family of proteins. We focus on the known interactions between M-like proteins and host ligand proteins, and analyse the genetic data supporting these interactions. We discuss known and possible functions of M-like proteins during GAS infections, and highlight knowledge gaps where further investigation is warranted. PMID- 29228175 TI - SANA NetGO: a combinatorial approach to using Gene Ontology (GO) terms to score network alignments. AB - Motivation: Gene Ontology (GO) terms are frequently used to score alignments between protein-protein interaction (PPI) networks. Methods exist to measure GO similarity between proteins in isolation, but proteins in a network alignment are not isolated: each pairing is dependent on every other via the alignment itself. Existing measures fail to take into account the frequency of GO terms across networks, instead imposing arbitrary rules on when to allow GO terms. Results: Here we develop NetGO, a new measure that naturally weighs infrequent, informative GO terms more heavily than frequent, less informative GO terms, without arbitrary cutoffs, instead downweighting GO terms according to their frequency in the networks being aligned. This is a global measure applicable only to alignments, independent of pairwise GO measures, in the same sense that the edge-based EC or S3 scores are global measures of topological similarity independent of pairwise topological similarities. We demonstrate the superiority of NetGO in alignments of predetermined quality and show that NetGO correlates with alignment quality better than any existing GO-based alignment measures. We also demonstrate that NetGO provides a measure of taxonomic similarity between species, consistent with existing taxonomic measuresa feature not shared with existing GObased network alignment measures. Finally, we re-score alignments produced by almost a dozen aligners from a previous study and show that NetGO does a better job at separating good alignments from bad ones. Availability and implementation: Available as part of SANA. Contact: whayes@uci.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228174 TI - Cardiovascular Risk in Early Psychosis: Relationship with Inflammation and Clinical Features 6 Months after Diagnosis. AB - Background: We aimed to investigate the state of cardiovascular risk/protection factors in early psychosis patients. Methods: A total 119 subjects were recruited during the first year after their first episode of psychosis. Eighty-five of these subjects were followed during the next 6 months. Cardiovascular risk/protection factors were measured in plasma and co-variated by sociodemographic/clinical characteristics. Multiple linear regression models detected the change of each biological marker from baseline to follow-up in relation to clinical scales, antipsychotic medication, and pro-/antiinflammatory mediators. Results: Glycosylated hemoglobin is a state biomarker in first episode of psychosis follow-up patients and inversely correlated to the Global Assessment of Functioning scale. We found opposite alterations in the levels of VCAM-1 and E selectin in first episode of psychosis baseline conditions compared with control that were absent in the first episode of psychosis follow-up group. Adiponectin levels decreased in a continuum in both pathological time points studied. E Selectin plasma levels were inversely related to total antipsychotic equivalents and adiponectin levels inversely co-related to the Global Assessment of Functioning scale. Finally, adiponectin levels were directly related to antiinflammatory nuclear receptor PPARgamma expression in first episode of psychosis baseline conditions and to proinflammatory nuclear factor nuclear factor kappaB activity in follow-up conditions, respectively. Conclusions: Our results support the need for integrating cardiovascular healthcare very early after the first episode of psychosis. PMID- 29228176 TI - Screening and identification of immunoactive FlaB protein fragments of Treponema pallidum for the serodiagnosis of syphilis. AB - Flagellin is a classical pathogen-associated molecular pattern that can evoke a robust immune response. We have demonstrated previously that three full-length flagellins of Treponema pallidum, namely FlaB1, FlaB2 and FlaB3, did have diagnostic value in the serodiagnosis of syphilis. Here, we selected and constructed three recombinant fragments of each complete FlaB, both the conserved N-terminal and the C-terminal region, and the middle variable part, with the goal of exploring fragments unique to Treponema pallidum for use as antigen targets in a fragment-based serological test. The diagnostic performance of fragments was evaluated using different panels of serum specimens (= 332) by indirect IgG enzyme-linked immunosorbent assay. The data showed that all the conserved fragments exhibited excellent sensitivities (91.1-95.0%) but poor specificities (64.1-78.4%), while the three middle regions demonstrated higher sensitivities and specificities for detecting IgG antibody, with 92.7% and 96.1% for FlaB1M ('B1M'), 91.6% and 94.8% for B2M, and 95.0% and 100% for B3M, respectively. In comparison, the sensitivity and specificity of Architect Syphilis TP was found to be 95.5% and 94.8%, respectively. These findings revealed that the middle portion of each FlaB had epitopes specific for Treponema pallidum and identified B3M as a promising candidate antigen for the serodiagnosis of syphilis. PMID- 29228177 TI - Poly(3-hydroxybutyrate) hyperproduction by a global nitrogen regulator NtrB mutant strain of Paracoccus denitrificans PD1222. AB - Paracoccus denitrificans PD1222 accumulates short-length polyhydroxyalkanoates, poly(3-hydroxybutyrate), under nitrogen-deficient conditions. Polyhydroxybutyrate metabolism requires the 3-ketoacyl-CoA thiolase PhaA, the acetoacetyl-CoA dehydrogenase/reductase PhaB and the synthase PhaC for polymerization. Additionally, P. denitrificans PD1222 grows aerobically with nitrate as sole nitrogen source. Nitrate assimilation is controlled negatively by ammonium through the two-component NtrBC system. NtrB is a sensor kinase that autophosphorylates a histidine residue under low-nitrogen concentrations and, in turn, transfers a phosphoryl group to an aspartate residue of the response regulator NtrC protein, which acts as a transcriptional activator of the P. denitrificans PD1222 nasABGHC genes. The P. denitrificans PD1222 NtrB mutant was unable to use nitrate efficiently as nitrogen source when compared to the wild type strain, and it also overproduced poly(3-hydroxybutyrate). Acetyl-CoA concentration in the P. denitrificans PD1222 NtrB mutant strain was higher than in the wild-type strain. The expression of the phaC gene was also increased in the NtrB mutant when compared to the wild-type strain. These results suggest that accumulation of poly(3-hydroxybutyrate) in the NtrB mutant strain of PD1222 responds to the high levels of acetyl-CoA that accumulate in the cytoplasm as consequence of its inability to efficiently use nitrate as nitrogen source. PMID- 29228178 TI - Genome sequence analysis of a hypermucoviscous/hypervirulent and MDR CTX-M 15/K19/ST29 Klebsiella pneumoniae isolated from human infection. AB - The emergence of hypervirulent Klebsiella pneumoniae (hvKP) with multidrug resistance (MDR) profile is a worrisome public health issue. We report the first draft genome sequence of a hypermucoviscous (positive string test) and MDR K. pneumoniae serotype K19, belonging to ST29, isolated from human infection. This strain harboured multiple antimicrobial resistance genes, including blaCTX-M-15, besides yersiniabactin and type 3 fimbriae virulence genes. In vivo experiments carried out with the Galleria mellonella infection model revealed that K. pneumoniae K19/ST29 killed 100% of the larvae at 24 h post-infection, in a similar way to the known hypermucoviscous hvKP K1/ST23 lineage. PMID- 29228181 TI - The promises of microalgae-still a long way to go. AB - Over the past decades, interest in microalgae has grown exponentially. Especially industrial applications, such as biodiesel production from microalgae were hyped in the early 2000s. But since the first attempts to commercialise microalgae derived products for energy applications, only a few developments made it to the market. What is hindering the full exploitation of this valuable resource for food, feed, and energy applications? This opinion paper reflects on the state of the art of industrial microalgae culturing and the knowledge gaps which still need to be filled jointly by academia and industry. PMID- 29228179 TI - A Large Panel of Drosophila simulans Reveals an Abundance of Common Variants. AB - The rapidly expanding availability of large NGS data sets provides an opportunity to investigate population genetics at an unprecedented scale. Drosophila simulans is the sister species of the model organism Drosophila melanogaster, and is often presumed to share similar demographic history. However, previous population genetic and ecological work suggests very different signatures of selection and demography. Here, we sequence a new panel of 170 inbred genotypes of a North American population of D. simulans, a valuable complement to the DGRP and other D. melanogaster panels. We find some unexpected signatures of demography, in the form of excess intermediate frequency polymorphisms. Simulations suggest that this is possibly due to a recent population contraction and selection. We examine the outliers in the D. simulans genome determined by a haplotype test to attempt to parse the contribution of demography and selection to the patterns observed in this population. Untangling the relative contribution of demography and selection to genomic patterns of variation is challenging, however, it is clear that although D. melanogaster was thought to share demographic history with D. simulans different forces are at work in shaping genomic variation in this population of D. simulans. PMID- 29228180 TI - Longitudinal structural and molecular neuroimaging in agrammatic primary progressive aphasia. AB - The agrammatic variant of primary progressive aphasia affects normal grammatical language production, often occurs with apraxia of speech, and is associated with left frontal abnormalities on cross-sectional neuroimaging studies. We aimed to perform a detailed assessment of longitudinal change on structural and molecular neuroimaging to provide a complete picture of neurodegeneration in these patients, and to determine how patterns of progression compare to patients with isolated apraxia of speech (primary progressive apraxia of speech). We assessed longitudinal structural MRI, diffusion tensor imaging and 18F-fluorodeoxyglucose PET in 11 agrammatic aphasia subjects, 20 primary progressive apraxia of speech subjects, and 62 age and gender-matched controls with two serial assessments. Rates of change in grey matter volume and hypometabolism, and white matter fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity were assessed at the voxel-level and for numerous regions of interest. The greatest rates of grey matter atrophy in agrammatic aphasia were observed in inferior, middle, and superior frontal gyri, premotor and motor cortices, as well as medial temporal lobe, insula, basal ganglia, and brainstem compared to controls. Longitudinal decline in metabolism was observed in the same regions, with additional findings in medial and lateral parietal lobe. Diffusion tensor imaging changes were prominent bilaterally in inferior and middle frontal white matter and superior longitudinal fasciculus, as well as right inferior fronto occipital fasciculus, superior frontal and precentral white matter. More focal patterns of degeneration of motor and premotor cortex were observed in primary progressive apraxia of speech. Agrammatic aphasia showed greater rates of grey matter atrophy, decline in metabolism, and white matter degeneration compared to primary progressive apraxia of speech in the left frontal lobe, predominantly inferior and middle frontal grey and white matter. Correlations were also assessed between rates of change on neuroimaging and rates of clinical decline. Progression of aphasia correlated with rates of degeneration in frontal and temporal regions within the language network, while progression of parkinsonism and limb apraxia correlated with degeneration of motor cortex and brainstem. These findings demonstrate that disease progression in agrammatic aphasia is associated with widespread neurodegeneration throughout regions of the language network, as well as connecting white matter tracts, but also with progression to regions outside of the language network that are responsible for the development of motor symptoms. The fact that patterns of progression differed from primary progressive apraxia of speech supports the clinical distinction of these syndromes. PMID- 29228182 TI - PEITH(Theta): perfecting experiments with information theory in Python with GPU support. AB - Motivation: Different experiments provide differing levels of information about a biological system. This makes it difficult, a priori, to select one of them beyond mere speculation and/or belief, especially when resources are limited. With the increasing diversity of experimental approaches and general advances in quantitative systems biology, methods that inform us about the information content that a given experiment carries about the question we want to answer, become crucial. Results: PEITH(Theta) is a general purpose, Python framework for experimental design in systems biology. PEITH(Theta) uses Bayesian inference and information theory in order to derive which experiments are most informative in order to estimate all model parameters and/or perform model predictions. Availability and implementation: https://github.com/MichaelPHStumpf/Peitho. Contact: m.stumpf@imperial.ac.uk or juliane.liepe@mpibpc.mpg.de. PMID- 29228184 TI - Editorial: Editorial for the virtual issue on microbiome. PMID- 29228183 TI - Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5. AB - The hereditary spastic paraplegias are an expanding and heterogeneous group of disorders characterized by spasticity in the lower limbs. Plasma biomarkers are needed to guide the genetic testing of spastic paraplegia. Spastic paraplegia type 5 (SPG5) is an autosomal recessive spastic paraplegia due to mutations in CYP7B1, which encodes a cytochrome P450 7alpha-hydroxylase implicated in cholesterol and bile acids metabolism. We developed a method based on ultra performance liquid chromatography electrospray tandem mass spectrometry to validate two plasma 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27 OHC) as diagnostic biomarkers in a cohort of 21 patients with SPG5. For 14 patients, SPG5 was initially suspected on the basis of genetic analysis, and then confirmed by increased plasma 25-OHC, 27-OHC and their ratio to total cholesterol. For seven patients, the diagnosis was initially based on elevated plasma oxysterol levels and confirmed by the identification of two causal CYP7B1 mutations. The receiver operating characteristic curves analysis showed that 25 OHC, 27-OHC and their ratio to total cholesterol discriminated between SPG5 patients and healthy controls with 100% sensitivity and specificity. Taking advantage of the robustness of these plasma oxysterols, we then conducted a phase II therapeutic trial in 12 patients and tested whether candidate molecules (atorvastatin, chenodeoxycholic acid and resveratrol) can lower plasma oxysterols and improve bile acids profile. The trial consisted of a three-period, three treatment crossover study and the six different sequences of three treatments were randomized. Using a linear mixed effect regression model with a random intercept, we observed that atorvastatin decreased moderately plasma 27-OHC (~30%, P < 0.001) but did not change 27-OHC to total cholesterol ratio or 25-OHC levels. We also found an abnormal bile acids profile in SPG5 patients, with significantly decreased total serum bile acids associated with a relative decrease of ursodeoxycholic and lithocholic acids compared to deoxycholic acid. Treatment with chenodeoxycholic acid restored bile acids profile in SPG5 patients. Therefore, the combination of atorvastatin and chenodeoxycholic acid may be worth considering for the treatment of SPG5 patients but the neurological benefit of these metabolic interventions remains to be evaluated in phase III therapeutic trials using clinical, imaging and/or electrophysiological outcome measures with sufficient effect sizes. Overall, our study indicates that plasma 25-OHC and 27-OHC are robust diagnostic biomarkers of SPG5 and shall be used as first-line investigations in any patient with unexplained spastic paraplegia. PMID- 29228185 TI - DNCON2: improved protein contact prediction using two-level deep convolutional neural networks. AB - Motivation: Significant improvements in the prediction of protein residue-residue contacts are observed in the recent years. These contacts, predicted using a variety of coevolution-based and machine learning methods, are the key contributors to the recent progress in ab initio protein structure prediction, as demonstrated in the recent CASP experiments. Continuing the development of new methods to reliably predict contact maps is essential to further improve ab initio structure prediction. Results: In this paper we discuss DNCON2, an improved protein contact map predictor based on two-level deep convolutional neural networks. It consists of six convolutional neural networks-the first five predict contacts at 6, 7.5, 8, 8.5 and 10 A distance thresholds, and the last one uses these five predictions as additional features to predict final contact maps. On the free-modeling datasets in CASP10, 11 and 12 experiments, DNCON2 achieves mean precisions of 35, 50 and 53.4%, respectively, higher than 30.6% by MetaPSICOV on CASP10 dataset, 34% by MetaPSICOV on CASP11 dataset and 46.3% by Raptor-X on CASP12 dataset, when top L/5 long-range contacts are evaluated. We attribute the improved performance of DNCON2 to the inclusion of short- and medium-range contacts into training, two-level approach to prediction, use of the state-of-the-art optimization and activation functions, and a novel deep learning architecture that allows each filter in a convolutional layer to access all the input features of a protein of arbitrary length. Availability and implementation: The web server of DNCON2 is at http://sysbio.rnet.missouri.edu/dncon2/ where training and testing datasets as well as the predictions for CASP10, 11 and 12 free-modeling datasets can also be downloaded. Its source code is available at https://github.com/multicom-toolbox/DNCON2/. Contact: chengji@missouri.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228186 TI - Aether: leveraging linear programming for optimal cloud computing in genomics. AB - Motivation: Across biology, we are seeing rapid developments in scale of data production without a corresponding increase in data analysis capabilities. Results: Here, we present Aether (http://aether.kosticlab.org), an intuitive, easy-to-use, cost-effective and scalable framework that uses linear programming to optimally bid on and deploy combinations of underutilized cloud computing resources. Our approach simultaneously minimizes the cost of data analysis and provides an easy transition from users' existing HPC pipelines. Availability and implementation: Data utilized are available at https://pubs.broadinstitute.org/diabimmune and with EBI SRA accession ERP005989. Source code is available at (https://github.com/kosticlab/aether). Examples, documentation and a tutorial are available at http://aether.kosticlab.org. Contact: chirag_patel@hms.harvard.edu or aleksandar.kostic@joslin.harvard.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228187 TI - Extracellular nucleic acids of the marine bacterium Rhodovulum sulfidophilum and recombinant RNA production technology using bacteria. AB - Extracellular nucleic acids of high molecular weight are detected ubiquitously in seawater. Recent studies have indicated that these nucleic acids are, at least in part, derived from active production by some bacteria. The marine bacterium Rhodovulum sulfidophilum is one of those bacteria. Rhodovulumsulfidophilum is a non-sulfur phototrophic marine bacterium that is known to form structured communities of cells called flocs, and to produce extracellular nucleic acids in culture media. Recently, it has been revealed that this bacterium produces gene transfer agent-like particles and that this particle production may be related to the extracellular nucleic acid production mechanism. This review provides a summary of recent physiological and genetic studies of these phenomena and also introduces a new method for extracellular production of artificial and biologically functional RNAs using this bacterium. In addition, artificial RNA production using Escherichia coli, which is related to this topic, will also be described. PMID- 29228188 TI - The impact of environmental factors on carbon dioxide fixation by microalgae. AB - Microalgae are among the most productive biological systems for converting sunlight into chemical energy, which is used to capture and transform inorganic carbon into biomass. The efficiency of carbon dioxide capture depends on the cultivation system configuration (photobioreactors or open systems) and can vary according to the state of the algal physiology, the chemical composition of the nutrient medium, and environmental factors such as irradiance, temperature and pH. This mini-review is focused on some of the most important environmental factors determining photosynthetic activity, carbon dioxide biofixation, cell growth rate and biomass productivity by microalgae. These include carbon dioxide and O2 concentrations, light intensity, cultivation temperature and nutrients. Finally, a review of the operation of microalgal cultivation systems outdoors is presented as an example of the impact of environmental conditions on biomass productivity and carbon dioxide fixation. PMID- 29228189 TI - A snapshot of 3649 Web-based services published between 1994 and 2017 shows a decrease in availability after 2 years. AB - Background: The long-term availability of online Web services is of utmost importance to ensure reproducibility of analytical results. However, because of lack of maintenance following acceptance, many servers become unavailable after a short period of time. Our aim was to monitor the accessibility and the decay rate of published Web services as well as to determine the factors underlying trends changes. Methods: We searched PubMed to identify publications containing Web server-related terms published between 1994 and 2017. Automatic and manual screening was used to check the status of each Web service. Kruskall-Wallis, Mann Whitney and Chi-square tests were used to evaluate various parameters, including availability, accessibility, platform, origin of authors, citation, journal impact factor and publication year. Results: We identified 3649 publications in 375 journals of which 2522 (69%) were currently active. Over 95% of sites were running in the first 2 years, but this rate dropped to 84% in the third year and gradually sank afterwards (P < 1e-16). The mean half-life of Web services is 10.39 years. Working Web services were published in journals with higher impact factors (P = 4.8e-04). Services published before the year 2000 received minimal attention. The citation of offline services was less than for those online (P = 0.022). The majority of Web services provide analytical tools, and the proportion of databases is slowly decreasing. Conclusions. Almost one-third of Web services published to date went out of service. We recommend continued support of Web based services to increase the reproducibility of published results. PMID- 29228190 TI - Assessing the diversity of the g23 gene of T4-like bacteriophages from Lake Baikal with high-throughput sequencing. AB - Based on second generation sequencing (MiSeq platform, Illumina), we determined the genetic diversity of T4-like bacteriophages of the family Myoviridae by analysing fragments of the major capsid protein gene g23 in the plankton of Lake Baikal. The sampling depth in our study was significantly higher than in those obtained by the Sanger method before. We obtained 33 701 sequences of the g23 gene fragments, 141 operational taxonomic units (OTUs) of which were identified. 86 OTUs (60.9%) had the closest relatives from lakes Bourget and Annecy, and 28 OTUs (19.8%) had the highest identity with the Baikal g23 clones, which had been previously identified in the northern and southern basins of the lake by the Sanger method. The remaining OTUs were similar to the clones from other ecosystems. We showed a high genetic diversity of T4-type bacteriophages and a genetic difference with the phage communities from other ecosystems. PMID- 29228191 TI - FROGS: Find, Rapidly, OTUs with Galaxy Solution. AB - Motivation: Metagenomics leads to major advances in microbial ecology and biologists need user friendly tools to analyze their data on their own. Results: This Galaxy-supported pipeline, called FROGS, is designed to analyze large sets of amplicon sequences and produce abundance tables of Operational Taxonomic Units (OTUs) and their taxonomic affiliation. The clustering uses Swarm. The chimera removal uses VSEARCH, combined with original cross-sample validation. The taxonomic affiliation returns an innovative multi-affiliation output to highlight databases conflicts and uncertainties. Statistical results and numerous graphical illustrations are produced along the way to monitor the pipeline. FROGS was tested for the detection and quantification of OTUs on real and in silico datasets and proved to be rapid, robust and highly sensitive. It compares favorably with the widespread mothur, UPARSE and QIIME. Availability and implementation: Source code and instructions for installation: https://github.com/geraldinepascal/FROGS.git. A companion website: http://frogs.toulouse.inra.fr. Contact: geraldine.pascal@inra.fr. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228192 TI - Quantitative analysis of O2 and Fe2+ profiles in gradient tubes for cultivation of microaerophilic Iron(II)-oxidizing bacteria. AB - The classical approach for the cultivation of neutrophilic microaerophilic Fe(II) oxidizing bacteria is agar-based gradient tubes where these bacteria find optimal growth conditions in opposing gradients of oxygen (O2) and dissolved Fe(II) (Fe2+). The goals of this study were to quantify the temporal development of O2 and Fe2+ concentrations over time, to compare abiotic and microbially inoculated tubes and to test the suitability of different Fe(II)-sources for the cultivation of freshwater and marine microaerophilic Fe(II)-oxidizers. O2 and Fe2+ gradients were monitored on a high spatial resolution as a function of time applying amperometric and voltammetric microsensors. Fe(II)-oxidizers could be cultivated well with FeS and zero-valent iron powder as Fe(II)-source, but FeCO3 and FeCl2 are extremely sensitive for this application. Fe(III) minerals accumulated in inoculated tubes within the first days in regions with an O2 concentration of 20 40 MUM and were confirmed to be related to bacterial growth. Microbial Fe(II) oxidation could compete only for the first days with the abiotic reaction after which heterogeneous Fe(II) oxidation, catalyzed by Fe(III) minerals, dominated. Our results imply that transfer of cultures to fresh tubes within 48-72 h is crucial to provide optimal growth conditions for microaerophilic Fe(II) oxidizers, particularly for the isolation of new strains. PMID- 29228193 TI - DeepSF: deep convolutional neural network for mapping protein sequences to folds. AB - Motivation: Protein fold recognition is an important problem in structural bioinformatics. Almost all traditional fold recognition methods use sequence (homology) comparison to indirectly predict the fold of a target protein based on the fold of a template protein with known structure, which cannot explain the relationship between sequence and fold. Only a few methods had been developed to classify protein sequences into a small number of folds due to methodological limitations, which are not generally useful in practice. Results: We develop a deep 1D-convolution neural network (DeepSF) to directly classify any protein sequence into one of 1195 known folds, which is useful for both fold recognition and the study of sequence-structure relationship. Different from traditional sequence alignment (comparison) based methods, our method automatically extracts fold-related features from a protein sequence of any length and maps it to the fold space. We train and test our method on the datasets curated from SCOP1.75, yielding an average classification accuracy of 75.3%. On the independent testing dataset curated from SCOP2.06, the classification accuracy is 73.0%. We compare our method with a top profile-profile alignment method-HHSearch on hard template based and template-free modeling targets of CASP9-12 in terms of fold recognition accuracy. The accuracy of our method is 12.63-26.32% higher than HHSearch on template-free modeling targets and 3.39-17.09% higher on hard template-based modeling targets for top 1, 5 and 10 predicted folds. The hidden features extracted from sequence by our method is robust against sequence mutation, insertion, deletion and truncation, and can be used for other protein pattern recognition problems such as protein clustering, comparison and ranking. Availability and implementation: The DeepSF server is publicly available at: http://iris.rnet.missouri.edu/DeepSF/. Contact: chengji@missouri.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228194 TI - Microbial carbon dioxide fixation: new tricks for an old game. AB - The exploitation of petroleum as energy and material source opened unprecedented possibilities for the development of our human societies, but only now we realize that the use of fossil resources comes at devastatingly high environmental costs. Consequently, our efforts to tap other carbon sources are steadily increasing. Industrial microbiology has the potential to use carbon dioxide directly as carbon source, thereby converting a foe into a friend. This thematic issue of FEMS Microbiology Letters sheds some light on recent developments for the understanding of microbial pathways for carbon dioxide fixation and on strategies for their industrial exploitation. PMID- 29228196 TI - Data discovery with DATS: exemplar adoptions and lessons learned. AB - The DAta Tag Suite (DATS) is a model supporting dataset description, indexing, and discovery. It is available as an annotated serialization with schema.org, a vocabulary used by major search engines, thus making the datasets discoverable on the web. DATS underlies DataMed, the National Institutes of Health Big Data to Knowledge Data Discovery Index prototype, which aims to provide a "PubMed for datasets." The experience gained while indexing a heterogeneous range of >60 repositories in DataMed helped in evaluating DATS's entities, attributes, and scope. In this work, 3 additional exemplary and diverse data sources were mapped to DATS by their representatives or experts, offering a deep scan of DATS fitness against a new set of existing data. The procedure, including feedback from users and implementers, resulted in DATS implementation guidelines and best practices, and identification of a path for evolving and optimizing the model. Finally, the work exposed additional needs when defining datasets for indexing, especially in the context of clinical and observational information. PMID- 29228197 TI - Efficacy of 13 Commercial Household Aerosol Insecticides Against Aedes aegypti (Diptera: Culicidae) From Morelos, Mexico. AB - In Mexico, Aedes aegypti (L.) (Diptera: Culicidae) is the primary vector of Dengue, Zika, and Chikungunya viruses. Control programs include community participation using personal protection such as household aerosol insecticides. In both, urban or rural areas, the use of aerosol insecticides is a common practice to avoiding mosquito biting. Thus, information on the efficacy of commercial products must be available. This study reports the efficacy of 13 household aerosol insecticides against Ae. aegypti from an endemic dengue area in Mexico. To test each insecticide, six netting cages, containing 10 non-blood fed female mosquitoes each one, were placed in different locations inside a bedroom. Readings at 30 min and 24 h after exposure were recorded. No products showed 100% mortality after 30 min of exposure. Only three products killed the 100% of the individuals 24 h after exposure. Results showed a high mortality variance among insecticides. Location in the room also impacts the insecticide efficacy. Mosquitoes located inside cabinets or with behind an obstacle (preventing an accurate insecticide exposure) showed lower mortalities. Products and spraying methods could and should be improved. PMID- 29228195 TI - Structural connectivity of right frontal hyperactive areas scales with stuttering severity. AB - A neuronal sign of persistent developmental stuttering is the magnified coactivation of right frontal brain regions during speech production. Whether and how stuttering severity relates to the connection strength of these hyperactive right frontal areas to other brain areas is an open question. Scrutinizing such brain-behaviour and structure-function relationships aims at disentangling suspected underlying neuronal mechanisms of stuttering. Here, we acquired diffusion-weighted and functional images from 31 adults who stutter and 34 matched control participants. Using a newly developed structural connectivity measure, we calculated voxel-wise correlations between connection strength and stuttering severity within tract volumes that originated from functionally hyperactive right frontal regions. Correlation analyses revealed that with increasing speech motor deficits the connection strength increased in the right frontal aslant tract, the right anterior thalamic radiation, and in U-shaped projections underneath the right precentral sulcus. In contrast, with decreasing speech motor deficits connection strength increased in the right uncinate fasciculus. Additional group comparisons of whole-brain white matter skeletons replicated the previously reported reduction of fractional anisotropy in the left and right superior longitudinal fasciculus as well as at the junction of right frontal aslant tract and right superior longitudinal fasciculus in adults who stutter compared to control participants. Overall, our investigation suggests that right fronto-temporal networks play a compensatory role as a fluency enhancing mechanism. In contrast, the increased connection strength within subcortical-cortical pathways may be implied in an overly active global response suppression mechanism in stuttering. Altogether, this combined functional MRI diffusion tensor imaging study disentangles different networks involved in the neuronal underpinnings of the speech motor deficit in persistent developmental stuttering. PMID- 29228198 TI - The contribution of alcohol to the East-West life expectancy gap in Europe from 1990 onward. AB - Background: Central and Eastern European (CEE) countries have lower life expectancies and higher alcohol-attributable mortality than Western European countries. We examine the contribution of alcohol consumption to mortality across Europe, and specifically to the East-West life expectancy gap from 1990 onward. Methods: We retrieved alcohol-attributable mortality rates (GBD Study 2013) and all-cause mortality rates (Human Mortality Database) by age and sex for nine CEE countries and for the EU-15 countries. We assessed country-specific potential gains in life expectancy (PGLE) by eliminating alcohol-attributable mortality using associated single decrement life tables. We decomposed the life expectancy differences between each CEE country and the EU-15 population-weighted average for 1990-2012/13 into alcohol-attributable and non-alcohol-attributable mortality. Results: In 2012/13, the PGLE for men and women were, respectively, 2.15 and 1.00 years in the CEE region and 0.90 and 0.44 years in the EU-15 region. The contribution of alcohol to the East-West gap in life expectancy was largest among men in Russia {2.88 years [uncertainty interval (UI): 1.57-4.06]}, Belarus [3.70 years (UI: 1.75-5.45)] and Ukraine [2.47 years (UI: 0.90-3.88)]. The relative contributions increased in most of the countries between 1990 and 2005 (on average, from 17.0% to 25.4% for men, and from 14.7% to 22.5% for women), and declined thereafter (20.2% for men and 20.5% for women in 2012/13). Conclusions: Alcohol contributed substantially to the East-West life expectancy gap in Europe, and to its increase (1990-2005) and decline (2005 onward). Diminishing alcohol consumption in CEE countries to Western European levels can contribute to mortality convergence across Europe. PMID- 29228199 TI - New Neoplasm During GH Replacement in Adults With Pituitary Deficiency Following Malignancy: A KIMS Analysis. AB - Context: Data on the association between growth hormone (GH) replacement in patients with GH deficiency (GHD) after malignancies and new neoplasms show conflicting results. Objective: To clarify the incidence of new malignant neoplasm in childhood-onset (CO) and adult-onset (AO) adult cancer survivors (CSs). Design: Retrospective comparison of CO-CS and AO-CS with CO idiopathic GHD (IGHD) and AO nonfunctioning pituitary adenoma (NFPA) patients and with the general population [standardized incidence ratio (SIR)]. Setting: Data from the Pfizer International Metabolic Database study (KIMS). Patients: CO-CS [n = 349; 50.4% females; mean baseline (MBL) IGF-I standard deviation score (SDS), -2.4], IGHD (n = 619; 35.7% females; MBL IGF-I SDS, -3.4), AO-CS (n = 174; 42.5% females; MBL IGF-I SDS, -1.4), and NFPA (n = 2449; 38.1% females; MBL IGF-I SDS, 1.0). Main Outcome Measures: SIRs of malignant neoplasms. Results: After a median follow-up of 5.9 years (2192 patient-years), 15 CO-CS (4.3%) had developed 16 new neoplasms. The SIR was 10.4 [95% confidence interval (CI), 5.9 to 16.9] and 6.5 (95% CI, 3.0 to 12.4) after exclusion of seven patients with skin cancers. In IGHD, three malignant neoplasms (0.5%) were observed after a median follow-up of 5.4 years (3908 patient-years; SIR, 0.47; 95% CI, 0.09 to 1.37). New malignant neoplasms occurred in three AO-CS (1.7%; SIR, 1.1; 95% CI, 0.2 to 3.2) and 146 NFPA patients (153 cases, 6.0%; SIR, 1.1; 95% CI, 0.9 to 1.2) after a median follow-up of 4.9 (1024 patient-years) and 5.6 years (15,215 patient-years). Conclusions: The risk of second malignant neoplasms was increased in CO-CS but not in AO-CS, which illustrates the need to closely follow patients on GH replacement because of a prior malignancy. PMID- 29228200 TI - ECT Has Greater Efficacy Than Fluoxetine in Alleviating the Burden of Illness for Patients with Major Depressive Disorder: A Taiwanese Pooled Analysis. AB - Background: The burden of major depressive disorder includes suffering due to symptom severity, functional impairment, and quality of life deficits. The aim of this study was to compare the differences between electroconvulsive therapy and pharmacotherapy in reducing such burdens. Methods: This was a pooled analysis study including 2 open-label trials for major depressive disorder inpatients receiving either standard bitemporal and modified electroconvulsive therapy with a maximum of 12 sessions or 20 mg/d of fluoxetine for 6 weeks. Symptom severity, functioning, and quality of life were assessed using the 17-item Hamilton Rating Scale for Depression, the Modified Work and Social Adjustment Scale, and SF-36. Side effects following treatment, including subjective memory impairment, nausea/vomiting, and headache, were recorded. The differences between these 2 groups in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, quality of life, side effects, and time to response (at least a 50% reduction of 17-item Hamilton Rating Scale for Depression) and remission (17 item Hamilton Rating Scale for Depression <=7) following treatment were analyzed. Results: Electroconvulsive therapy (n=116) showed a significantly greater reduction in 17-item Hamilton Rating Scale for Depression, Modified Work and Social Adjustment Scale, and quality of life deficits and had significantly shorter time to response/remission than fluoxetine (n=126). However, the electroconvulsive therapy group was more likely to experience subjective memory impairment and headache. Conclusions: Compared with fluoxetine, electroconvulsive therapy was more effective in alleviating the burden of major depressive disorder and had a substantially increased speed of response/remission in the acute phase. Increased education and information about electroconvulsive therapy for clinicians, patients, and their families and the general public is warranted. PMID- 29228202 TI - Activity of ceftazidime/avibactam against problem Enterobacteriaceae and Pseudomonas aeruginosa in the UK, 2015-16. AB - Background: Ceftazidime/avibactam combines an established oxyimino-cephalosporin with the first diazabicyclooctane beta-lactamase inhibitor to enter clinical use. We reviewed its activity against Gram-negative isolates, predominantly from the UK, referred for resistance investigation in the first year of routine testing, beginning in July 2015. Methods: Isolates were as received from referring laboratories; there is a bias to submit those with suspected carbapenem resistance. Identification was by MALDI-TOF mass spectroscopy, and susceptibility testing by BSAC agar dilution. Carbapenemase genes were sought by PCR; other resistance mechanisms were inferred using genetic data and interpretive reading. Results: Susceptibility rates to ceftazidime/avibactam exceeded 95% for: (i) Enterobacteriaceae with KPC, GES or other Class A carbapenemases; (ii) Enterobacteriaceae with OXA-48-like enzymes; and (iii) for ESBL or AmpC producers, even when these had impermeability-mediated ertapenem resistance. Almost all isolates with metallo-carbapenemases were resistant. Potentiation of ceftazidime by avibactam was seen for 87% of ceftazidime-resistant Enterobacteriaceae with 'unassigned' ceftazidime resistance mechanisms, including two widely referred groups of Klebsiella pneumoniae where no synergy was seen between cephalosporins and established beta-lactamase inhibitors. Potentiation here may be a diazabicyclooctane/cephalosporin enhancer effect. Activity was seen against Pseudomonas aeruginosa with derepressed AmpC, but not for those with efflux-mediated resistance. Conclusions: Of the available beta-lactams or inhibitor combinations, ceftazidime/avibactam has the widest activity spectrum against problem Enterobacteriaceae, covering all major types except metallo carbapenemase producers; against P. aeruginosa it has a slightly narrower spectrum than ceftolozane/tazobactam, which also covers efflux-type resistance. PMID- 29228201 TI - Widespread brain tau and its association with ageing, Braak stage and Alzheimer's dementia. AB - See Herholz (doi:10.1093/brain/awx340) for a scientific commentary on this article.Autopsy data have proposed that a topographical pattern of tauopathy occurs in the brain with the development of dementia due to Alzheimer's disease. We evaluated the findings of tau-PET to better understand neurofibrillary tangle development as it is seen in cognitively unimpaired and impaired individuals. The evolution of Alzheimer's disease tauopathy in cognitively unimpaired individuals needs to be examined to better understand disease pathogenesis. Tau-PET was performed in 86 cognitively impaired individuals who all had abnormal amyloid levels and 601 cognitively unimpaired individuals. Tau-PET findings were assessed for relationships with clinical diagnosis, age, and regional uptake patterns relative to Braak stage. Regional and voxel-wise analyses were performed. Topographical findings from tau-PET were characterized using hierarchical clustering and clinical characteristic-based subcategorization. In older cognitively unimpaired individuals (>=50 years), widespread, age-related elevated tau signal was seen among those with normal or abnormal amyloid status as compared to younger cognitively unimpaired individuals (30-49 years). More frequent regional tau signal elevation throughout the brain was seen in cognitively unimpaired individuals with abnormal versus normal amyloid. Elevated tau signal was seen in regions that are considered high Braak Stage in cognitively unimpaired and cognitively impaired individuals. Hierarchical clustering and clinical characteristic-based categorizations both showed different patterns of tau signal between groups such as greater tau signal in frontal regions in younger onset Alzheimer's disease dementia participants (most of whom had a dysexecutive clinical presentation). Tau-PET signal increases modestly with age throughout the brain in cognitively unimpaired individuals and elevated tau is seen more often when amyloid brain accumulation is present. Tau signal patterns in cognitively unimpaired correspond to early Braak stage but also suggest tangle involvement in extra-medial temporal and extra-temporal regions that are considered more advanced in the Braak scheme even when amyloid negative. Our findings also suggest the possibility of widespread development of early tangle pathology rather than a pattern defined exclusively by adjacent, region-to-region spread, prior to onset of clinical symptoms. Distinct patterns of neurofibrillary tangle deposition in younger-onset Alzheimer's disease dementia versus older-onset Alzheimer's disease dementia provide evidence for variability in regional tangle deposition patterns and demonstrate that different disease phenotypes have different patterns of tauopathy. Pathological correlation with imaging is needed to assess the implications of these observations. PMID- 29228203 TI - In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson's disease. AB - See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ~3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline. PMID- 29228204 TI - Decreased Resting-State Interhemispheric Functional Connectivity Correlated with Neurocognitive Deficits in Drug-Naive First-Episode Adolescent-Onset Schizophrenia. AB - Background: Given that adolescence is a critical epoch in the onset of schizophrenia, studying aberrant brain changes in adolescent-onset schizophrenia, particularly in patients with drug-naive first-episode schizophrenia, is important to understand the biological mechanism of this disorder. Previous resting-state functional magnetic resonance imaging studies have shown abnormal functional connectivity in separate hemispheres in patients with adult-onset schizophrenia. Our aim to study adolescent-onset schizophrenia can provide clues for the early aetiology of schizophrenia. Method: A total of 48 drug-naive, first episode, adolescent-onset schizophrenia outpatients and 31 healthy controls underwent resting-state functional magnetic resonance imaging scans. Data were subjected to voxel-mirrored homotopic connectivity and support vector machine analyses. Results: Compared with the healthy controls, the adolescent-onset schizophrenia group showed significantly lower voxel-mirrored homotopic connectivity values in different brain regions, including the fusiform gyrus, superior temporal gyrus/insula, precentral gyrus, and precuneus. Decreased voxel mirrored homotopic connectivity values in the superior temporal gyrus/insula were significantly correlated with Trail-Making Test: Part A performance (r = -0.437, P = .002). A combination of the voxel-mirrored homotopic connectivity values in the precentral gyrus and precuneus may be used to discriminate patients with adolescent-onset schizophrenia from controls with satisfactory classification results, which showed sensitivity of 100%, specificity of 87.09%, and accuracy of 94.93%. Conclusion: Our findings highlight resting-state interhemispheric FC abnormalities within the sensorimotor network of patients with adolescent-onset schizophrenia and confirm the relationship between adolescent-onset schizophrenia and adult-onset schizophrenia. These findings suggest that reduced interhemispheric connectivity within the sensorimotor network has a pivotal role in the pathogenesis of schizophrenia. PMID- 29228206 TI - Airway and hard tissue dimensions in children treated with early and later timed cervical headgear-a randomized controlled trial. AB - Background: A Kloehn-type cervical headgear (CH) aims to correct skeletal jaw discrepancy in Class II children. A few studies have reported CH treatment effects on airway dimensions, but none of them have been randomized according to timing. Objectives: To evaluate related craniofacial structures and pharyngeal airway dimensions in children with a Class II occlusion treated with CH and randomized into early and late treatment groups. Trial design: Randomized, parallel-group, prospective controlled trial. Methods: The material comprised 67 seven-year-old children with a Class II occlusion. Sealed-envelope randomization in 1:1 ratio was used to divide the children into two equal groups. In the early group (EG, n = 33), CH treatment was started immediately or after eruption of the first maxillary molars. In the second, late group (LG, n = 34), the active CH treatment was started about one and half year later. The active CH treatment was continued in both groups until normal Class I occlusion on first molars was achieved. Cephalometric radiographs were taken from both groups at the beginning of follow-up (T0), at the beginning of CH treatment of the second group (T1), and at the end of CH treatment of the second group (T2). Changes in cephalometric measurements were used as primary outcomes. Blinding was applicable for outcome assessment. Results: Fifty-six children completed the study. The posterior change in the position of the maxilla was significant for early treatment males at T0-T1 (SNA; P < 0.001, ANB; P = 0.009) and T0-T2 (SNA; P = 0.012). The palato mandibular angle (PL-ML) decreased during T0-T1 in early treatment females (P = 0.018) and early treatment males (P = 0.037). The retroglossal airway increased (P = 0.010) in early treatment males at T0-T1. Highly significant positive correlations (P < 0.001) between skeletal and upper airway dimensions during early CH treatment were found in males. No harms were encountered. Conclusions: Despite the effective CH treatment, no harmful upper airway changes were found. Clinical Registration: NCT02010346. PMID- 29228205 TI - Associations between polymorphisms in genes related to estrogen metabolism and function and prostate cancer risk: results from the Prostate Cancer Prevention Trial. AB - Substantial preclinical data suggest estrogen's carcinogenic role in prostate cancer development; however, epidemiological evidence based on circulating estrogen levels is largely null. Compared with circulating estrogen, the intraprostatic estrogen milieu may play a more important role in prostate carcinogenesis. Using a nested case-control design in the Prostate Cancer Prevention Trial (PCPT), we examined associations of genetic variants of genes that are involved in estrogen synthesis, metabolism and function with prostate cancer risk. A total of 25 potentially functional single nucleotide polymorphisms (SNPs) in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined in whites only. Controls (n = 1380) were frequency matched to cases on age, PCPT treatment arm, and family history (n = 1506). Logistic regression models adjusted for age and family history were used to estimate odds ratios (OR) and 95% confidence intervals (CI) separately in the placebo and finasteride arms. SNPs associated with prostate cancer risk differed by treatment arm. The associations appeared to be modified by circulating estrogen and androgen levels. CYP19A1 was the only gene harboring SNPs that were significantly associated with risk in both the placebo and finasteride arms. Haplotype analysis with all three CYP19A1 SNPs genotyped (rs700518, rs2445765, rs700519) showed that risk-allele haplotypes are associated with the increased prostate cancer risk in both arms when comparing with the non risk allele haplotype. In conclusion, associations between SNPs in estrogen related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment. PMID- 29228207 TI - Effectiveness of live attenuated influenza vaccine in preventing amoxicillin prescribing in preschool children: a self-controlled case series study. AB - Objectives: To determine the effectiveness of live attenuated influenza vaccine (LAIV) in reducing amoxicillin prescribing in preschool children in primary care. Patients and methods: We used The Health Improvement Network (THIN), a large primary care database from the United Kingdom. We included children aged 2 to 4 years old at the start of either the 2013/14 or the 2014/15 winter season, with at least one amoxicillin prescription between September and May, irrespective of LAIV vaccination status. We used the self-controlled case series method to estimate influenza vaccine effectiveness (VE). Results: The total study sample included 33 137 children from 378 general practices during the two winter seasons. Of these children, 43.4% with at least one amoxicillin prescription had been vaccinated. The rate of amoxicillin prescribing was significantly reduced during periods of influenza vaccine immunity. The associated VE for amoxicillin prescribing was 12.8% (95% CI 6.9%, 18.3%) in 2013/14 and 14.5% (9.6%, 19.2%) in 2014/15. Given a VE of 14.5%, we estimated that amoxicillin prescribing could have been reduced by 5.6% if LAIV uptake in children aged 2-4 years increased to 50% in the 2014/15 winter season. Conclusions: Influenza vaccination of young children may contribute to a reduction in the prescribing of amoxicillin, one of the most commonly prescribed antibiotics in primary care. Further studies are required to confirm the size of the effect. PMID- 29228208 TI - Advances in Serodiagnostic Testing for Lyme Disease Are at Hand. AB - The cause of Lyme disease, Borrelia burgdorferi, was discovered in 1983. A 2 tiered testing protocol was established for serodiagnosis in 1994, involving an enzyme immunoassay (EIA) or indirect fluorescence antibody, followed (if reactive) by immunoglobulin M and immunoglobulin G Western immunoblots. These assays were prepared from whole-cell cultured B. burgdorferi, lacking key in vivo expressed antigens and expressing antigens that can bind non-Borrelia antibodies. Additional drawbacks, particular to the Western immunoblot component, include low sensitivity in early infection, technical complexity, and subjective interpretation when scored by visual examination. Nevertheless, 2-tiered testing with immunoblotting remains the benchmark for evaluation of new methods or approaches. Next-generation serologic assays, prepared with recombinant proteins or synthetic peptides, and alternative testing protocols, can now overcome or circumvent many of these past drawbacks. This article describes next-generation serodiagnostic testing for Lyme disease, focusing on methods that are currently available or near-at-hand. PMID- 29228210 TI - Cholesterol blocks spontaneous insertion of membrane proteins into liposomes of phosphatidylcholine. AB - Spontaneous insertion of membrane proteins into liposomes formed from Escherichia coli polar phospholipids is blocked by diacylglycerol (DAG) at a physiological level. We found that cholesterol also blocks this spontaneous insertion, although a much larger amount is necessary for sufficient blockage. Reversely, sphingomyelin enhanced the spontaneous insertion. DAG at a physiological level was found not to block spontaneous insertion into liposomes formed from phosphatidylcholine (PC), while non-physiologically high concentrations of DAG reduced it. On the other hand, cholesterol blocked the spontaneous insertion into PC liposomes at a physiological level, explaining that both PC and cholesterol are absent in E. coli. While sphingomyelin did not enhance spontaneous insertion into PC liposomes, the effect of cholesterol on blockage of spontaneous insertion was dominant over that of sphingomyelin, suggesting that cholesterol functions as a blocker of disordered spontaneous insertion in eukaryotic cells. Lower amount of cholesterol was necessary to block spontaneous insertion into ER-mimic liposomes, explaining that ER membranes contain less amount of cholesterol. These results also explain that cholesterol, but not DAG, is involved in blockage of spontaneous insertion in eukaryotic cells, since DAG plays an important role as a second messenger in signal transduction. PMID- 29228209 TI - CD38 knockout suppresses tumorigenesis in mice and clonogenic growth of human lung cancer cells. AB - The ectodomain of the plasma membrane ectoenzyme CD38 functions as both an NAD glycohydrolase and an ADP-ribosyl cyclase by catalyzing, respectively, the conversion of NAD to nicotinamide and ADP-ribose or cyclic ADP-ribose. CD38 is attracting particular attention in cancer therapy. An anti-CD38 monoclonal antibody (daratumumab) was approved for treatment of patients with multiple myeloma. However, the role of CD38 in non-hematological malignancies has not been explored. Previously, we reported that ADP-ribose-acceptor hydrolase (ARH)-1 deficiency in mice was associated with tumor development. In the present study, we found that in wild-type and ARH1-deficient mice deletion of the CD38 gene reduced tumor formation. Significant reductions in tumor number were observed in lymphomas, adenocarcinomas and hemangio/histolytic sarcomas. Consistent with a role for CD38 in tumorigenesis, CRISPR/Cas9-based knockout of CD38 in A549 human adenocarcinoma cells inhibited anchorage-independent cell growth, cell invasion and xenograft growth in nude mice. CD38 mRNA and protein expression were evaluated in human lung cancer cell lines and in human lung cancer specimens. CD38 overexpression in tumor cells was identified in 11 of 27 patient samples. In addition, some human lung cancer cell lines had dramatically higher CD38 mRNA and protein expression than normal cells. Consistent with these observations, search of the Oncomine database showed that some human lung adenocarcinomas had higher CD38 mRNA levels compared to normal lung tissues. In total, our data are consistent with the conclusion that CD38 plays a role in murine and human lung tumorigenesis and that anti-CD38 treatment may have therapeutic potential in lung cancer. PMID- 29228212 TI - Impact of body mass index on outcomes following mitral surgery: does an obesity paradox exist? AB - OBJECTIVES: This study was conducted to clarify the relationship between body mass index and mitral valve (MV) surgery and to determine whether an 'obesity paradox' exists in the context of surgery for degenerative MV disease. METHODS: In this retrospective single-centre study, we analysed data from 715 patients who underwent mitral surgery for degenerative disease from 2000 to 2015. Patients were classified according to body mass index: underweight (<20 kg/m2), normal weight (20-24.99 kg/m2), overweight (25-29.99 kg/m2) and obese (>=30 kg/m2). Early and long-term results were investigated. Multivariable analysis was conducted to identify risk factors for long-term mortality. RESULTS: Mean follow up was 67 +/- 44 months (range 0-190 months). There were no differences between groups regarding 30-day mortality (P = 0.35), stroke (P = 0.45), reoperation for bleeding (P = 0.9) and length of hospital stay (P = 0.31). Obese patients were at increased risk of acute kidney injury when compared with normal weight patients (17% vs 5%; P = 0.03) but not when compared with the other groups; this was confirmed within the subgroup with depressed ejection fraction (42% vs 10%, P = 0.02). No differences in long-term survival were found across groups for all patients (P = 0.62) and for patients with depressed ejection fraction (P = 0.6), with a trend towards worse survival in obese patients undergoing MV repair (P = 0.06). Survival in obese patients undergoing repair was significantly worse than that in obese patients undergoing replacement (P = 0.04). CONCLUSIONS: An 'obesity paradox' was not demonstrated after surgery for degenerative MV disease. Obese patients are more prone to acute kidney injury and have worse late survival after MV repair. PMID- 29228211 TI - Asymmetry of post-mortem neuropathology in behavioural-variant frontotemporal dementia. AB - Antemortem behavioural and anatomic abnormalities have largely been associated with right hemisphere disease in behavioural-variant frontotemporal dementia, but post-mortem neuropathological examination of bilateral hemispheres remains to be defined. Here we measured the severity of post-mortem pathology in both grey and white matter using a validated digital image analysis method in four cortical regions sampled from each hemisphere in 26 patients with behavioural-variant frontotemporal dementia, including those with frontotemporal degeneration (i.e. tau = 9, TDP-43 = 14, or FUS = 1 proteinopathy) or Alzheimer's pathology (n = 2). We calculated an asymmetry index based on the difference in measured pathology from each left-right sample pair. Analysis of the absolute value of the asymmetry index (i.e. degree of asymmetry independent of direction) revealed asymmetric pathology for both grey and white matter in all four regions sampled in frontototemporal degeneration patients with tau or TDP-43 pathology (P <= 0.01). Direct interhemispheric comparisons of regional pathology measurements within subjects in the combined tauopathy and TDP-43 proteinopathy group found higher pathology in the right orbitofrontal grey matter compared to the left (P < 0.01) and increased pathology in ventrolateral temporal lobe grey matter of the left hemisphere compared to the right (P < 0.02). Preliminary group-wise comparisons between tauopathy and TDP-43 proteinopathy groups found differences in patterns of interhemispheric burden of grey and white matter regional pathology, with greater relative white matter pathology in tauopathies. To test the association of pathology measurement with ante-mortem observations, we performed exploratory analyses in the subset of patients with imaging data (n = 15) and found a direct association for increasing pathologic burden with decreasing cortical thickness in frontotemporal regions on ante-mortem imaging in tauopathy (P = 0.001) and a trend for TDP-43 proteinopathy (P = 0.06). Exploratory clinicopathological correlations demonstrated an association of socially-inappropriate behaviours with asymmetric right orbitofrontal grey matter pathology, and reduced semantically-guided category naming fluency was associated asymmetric white matter pathology in the left ventrolateral temporal region. We conclude that pathologic disease burden is distributed asymmetrically in behavioural-variant frontotemporal dementia, although not universally in the right hemisphere, and this asymmetry contributes to the clinical heterogeneity of the disorder. The basis for this asymmetric profile is enigmatic but may reflect distinct species or strains of tau and TDP-43 pathologies with propensities to spread by distinct cell- and region-specific mechanisms. Patterns of region-specific pathology in the right hemisphere as well as the left hemisphere may play a role in antemortem clinical observations, and these observations may contribute to antemortem identification of molecular pathology in frontotemporal degeneration. PMID- 29228213 TI - Contemporary incidence of stroke (focal infarct and/or haemorrhage) determined by neuroimaging and neurodevelopmental disability at 12 months of age in neonates undergoing cardiac surgery utilizing cardiopulmonary bypass. AB - OBJECTIVES: When evaluated prospectively, acute brain injury is reported in up to 75% of neonates undergoing cardiopulmonary bypass (CPB), predominantly white matter injury rather than stroke. This study investigates the incidence of stroke (focal infarct and/or haemorrhage) detected by neuroimaging in contemporary clinical practice, whereby magnetic resonance imaging/computed tomography routinely occurs in response to clinical events, comparing those undergoing the Norwood procedure with those undergoing other neonatal procedures involving CPB, and defines the relationship between stroke and neurodevelopmental disability (NDD) at 12 months of age. METHODS: One hundred and twenty neonates underwent CPB between July 2011 and December 2014: 25 Norwood procedures and 95 non-Norwood procedures. Data were retrospectively collected including clinical data and 12 month neurodevelopmental assessment using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). RESULTS: Stroke was detected in 12% of neonates in current clinical practice: 24% of the Norwood group vs 8% of the non Norwood group (P = 0.03). Significant predictors of stroke in the univariate analysis included the Norwood procedure, lowest operative temperature and use of extracorporeal membrane oxygenation (P < 0.05). The lowest operative temperature and use of extracorporeal membrane oxygenation remained significant in the multivariate analysis (P < 0.05). Fifty-seven percent were assessed using the BSID-III assessment, and 68% demonstrated NDD in at least 1 subscale. In neonates who suffered stroke, the incidence of NDD was significantly greater in 4/5 subscales compared with those with no injury (P < 0.05). The Norwood group had a significantly greater incidence of NDD in 2/5 subscales when compared with the non-Norwood group (P < 0.05). CONCLUSIONS: Stroke, established by neuroimaging in contemporary clinical practice, was detected in 12% of neonates having CPB, and those undergoing the Norwood procedure have a 3-fold risk of injury. Stroke was associated with NDD at 12 months of age. PMID- 29228214 TI - Oestrogen receptor β ligand acts on CD11c+ cells to mediate protection in experimental autoimmune encephalomyelitis. AB - Oestrogen treatments are neuroprotective in a variety of neurodegenerative disease models. Selective oestrogen receptor modifiers are needed to optimize beneficial effects while minimizing adverse effects to achieve neuroprotection in chronic diseases. Oestrogen receptor beta (ERβ) ligands are potential candidates. In the multiple sclerosis model chronic experimental autoimmune encephalomyelitis, ERβ-ligand treatment is neuroprotective, but mechanisms underlying this neuroprotection remain unclear. Specifically, whether there are direct effects of ERβ-ligand on CD11c+ microglia, myeloid dendritic cells or macrophages in vivo during disease is unknown. Here, we generated mice with ERβ deleted from CD11c+ cells to show direct effects of ERβ ligand treatment in vivo on these cells to mediate neuroprotection during experimental autoimmune encephalomyelitis. Further, we use bone marrow chimeras to show that ERβ in peripherally derived myeloid cells, not resident microglia, are the CD11c+ cells mediating this protection. CD11c+ dendritic cell and macrophages isolated from the central nervous system of wild type experimental autoimmune encephalomyelitis mice treated with ERβ-ligand expressed less iNOS and T-bet, but more IL-10, and this treatment effect was lost in mice with specific deletion of ERβ in CD11c+ cells. Also, we extend previous reports of ERβ-ligand’s ability to enhance remyelination through a direct effect on oligodendrocytes by showing that the immunomodulatory effect of ERβ-ligand acting on CD11c+ cells is necessary to permit the maturation of oligodendrocytes. Together these results demonstrate that targeting ERβ signalling pathways in CD11c+ myeloid cells is a novel strategy for regulation of the innate immune system in neurodegenerative diseases. To our knowledge, this is the first report showing how direct effects of a candidate neuroprotective treatment on two distinct cell lineages (bone marrow derived myeloid cells and oligodendrocytes) can have complementary neuroprotective effects in vivo.awx315media15688130498001. PMID- 29228216 TI - Recurrence following curative intended surgery for an adenocarcinoma in the gastroesophageal junction: a retrospective study. AB - Recurrence following a resection for an adenocarcinoma of the gastroesophageal junction leads to reduced long-term survival. This study aims to identify risk factors associated with recurrence, recurrence localization, time to recurrence, and long-term survival. All patients undergoing curative intended resection for an adenocarcinoma of the gastroesophageal junction at Rigshospitalet between June 2003 and December 2011 were identified through a prospectively maintained nationwide database and enrolled in this study. Only histologically verified recurrence was considered eligible. Recurrence within six months, microscopically incomplete resection margins, and death within eight weeks were excluded. A total of 348 patients were included in this study. Biopsy-verified recurrence occurred in 120 patients (34.5%), with 32 local (9.2%), and 88 distant (25.3%) recurrences. Lymph node metastases was associated with an increased risk of recurrence (hazard ratio; [95% confidence interval]: HR = 2.7; [1.7-4.3], P < 0.001). Median time to local versus distant recurrence was 18 months (interquartile range (IQR): 9-37 months) versus 17 months (IQR: 11-27 months), P = 0.96, respectively. A trend toward local recurrence was identified if patients had anastomotic leakage (HR = 2.64; [0.89-7.86], P = 0.08). Survival was inversely associated with recurrence, but a survival comparison between local and distant recurrences showed no significant difference: median survival time was 28 months (IQR: 17-43 months) versus 24 months (IQR: 16-36 months), P = 0.45, respectively. A trend toward local recurrence was seen if the patient had an anastomotic leakage event. However, no factors were associated with site-specific recurrence (local vs. distant). PMID- 29228215 TI - Mitochondria Are Critical for BDNF-Mediated Synaptic and Vascular Plasticity of Hippocampus following Repeated Electroconvulsive Seizures. AB - Background: Electroconvulsive therapy is a fast-acting and efficient treatment of depression used in the clinic. The underlying mechanism of its therapeutic effect is still unclear. However, recovery of synaptic connections and synaptic remodeling is thought to play a critical role for the clinical efficacy obtained from a rapid antidepressant response. Here, we investigated the relationship between synaptic changes and concomitant nonneuronal changes in microvasculature and mitochondria and its relationship to brain-derived neurotrophic factor level changes after repeated electroconvulsive seizures, an animal model of electroconvulsive therapy. Methods: Electroconvulsive seizures or sham treatment was given daily for 10 days to rats displaying a genetically driven phenotype modelling clinical depression: the Flinders Sensitive and Resistant Line rats. Stereological principles were employed to quantify numbers of synapses and mitochondria, and the length of microvessels in the hippocampus. The brain derived neurotrophic factor protein levels were quantified with immunohistochemistry. Results: In untreated controls, a lower number of synapses and mitochondria was accompanied by shorter microvessels of the hippocampus in "depressive" phenotype (Flinders Sensitive Line) compared with the "nondepressed" phenotype (Flinders Resistant Line). Electroconvulsive seizure administration significantly increased the number of synapses and mitochondria, and length of microvessels both in Flinders Sensitive Line-electroconvulsive seizures and Flinders Resistant Line-electroconvulsive seizures rats. In addition, the amount of brain-derived neurotrophic factor protein was significantly increased in Flinders Sensitive Line and Flinders Resistant Line rats after electroconvulsive seizures. Furthermore, there was a significant positive correlation between brain derived neurotrophic factor level and mitochondria/synapses. Conclusion: Our results indicate that rapid and efficient therapeutic effect of electroconvulsive seizures may be related to synaptic plasticity, accompanied by brain-derived neurotrophic factor protein level elevation and mitochondrial and vascular support. PMID- 29228217 TI - p19Arf inhibits aggressive progression of H-ras-driven hepatocellular carcinoma. AB - Arf, a well-established tumor suppressor, is either mutated or downregulated in a wide array of cancers. However, its role in hepatocellular carcinoma (HCC) progression is controversial. Conflicting observations have been published regarding its expression in HCC. In this study, we provide clear genetic evidence demonstrating a protective role of p19Arf in hepatocarcinogenesis. Using Ras induced mouse model, we show that p19Arf deficiency accelerates progression of aggressive HCC in vivo. To investigate the role of p14ARF in human liver cancers, we analyzed its expression in human HCC using immunohistochemistry (IHC). We observe lack of nucleolar p14ARF in 43.02% of human HCC samples and that low expression of p14ARF strongly correlates with the early onset of HCC. Importantly, cirrhotic livers that did not progress to HCC harbor higher expression of the p14ARF protein in hepatocytes compared with that in cirrhotic livers with HCC. These results are significant because they suggest that nucleolar p14ARF can be used as early prognostic marker in chronic liver disease to reliably identify patients with high risk for developing liver cancer. Currently, there is no effective systemic therapy for advanced liver cancer; hence, more efficient patient screening and early detection of HCC would significantly contribute to the eradication of this devastating disease. PMID- 29228219 TI - Why Phenotype Robustness Promotes Phenotype Evolvability. AB - Robustness and evolvability are fundamental characteristics of life whose relationship has intrigued generations of biologists. Studies of several genotype phenotype maps (GPMs) such as the map between short DNA sequences and their bindings to transcription factors showed that phenotype robustness (PR) promotes phenotype evolvability (PE), but the underlying reason is unclear. Here, we show mathematically that the expected PE is a monotonically increasing function of the expected PR in random GPMs. Population genetic simulations confirm that increasing PR raises the probability that a target phenotype appears in a population within a given time, under empirical as well as randomly rewired GPMs. These and other results demonstrate that the positive correlation between PR and PE is mathematical rather than biological. Hence, it is unsurprising to observe this correlation in every empirical GPM investigated, although the magnitude of the correlation may vary due to influences of various biological factors. PMID- 29228220 TI - The burden of presumed tuberculosis in hospitalized children in a resource limited setting in Papua New Guinea: a prospective observational study. AB - Background: In Papua New Guinea, TB is considered to be a major public health problem, but little is known about the prevalence and prognosis of presumed TB in children. Methods: As part of a prospective hospital-based surveillance on the northern coast of mainland Papua New Guinea, the authors investigated the admission prevalence and case fatality rate associated with presumed TB over a 6 year period (2011-2016). All children admitted who were diagnosed with TB were followed-up until discharge or death. Results: Of 8992 paediatric admissions, 734 patients (8.2%) were diagnosed with presumed TB and there were 825 deaths, with TB accounting for 102 (12.4%). Extrapulmonary TB was the final diagnosis in 384 admissions {prevalence 4.3% [384/8992 (95% CI 3.9-4.7)]} with a case fatality rate of 21.4% [82/384 (95% CI 17.4-25.9)]. TB meningitis, disseminated TB and pericardial TB had high case fatality rates of 29.0% (53/183), 28.9% (11/38) and 25% (4/16), respectively. Severe malnutrition was more common in patients with pulmonary compared with extrapulmonary TB (25.4% vs 15.6%; p<0.01). Conclusions: Improved community-based case detection strategies, routine BCG vaccinations and other effective forms of TB control need revitalization and sustainability to reduce the high case fatality rates associated with childhood TB in Papua New Guinea. PMID- 29228218 TI - Nonhuman Primate Models and Understanding the Pathogenesis of HIV Infection and AIDS. AB - Research using nonhuman primates (NHPs) as models for human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) has resulted in tremendous achievements not only in the prevention and treatment of HIV, but also in biomedical research more broadly. Once considered a death sentence, HIV infection is now fairly well controlled with combination antiretroviral treatments, almost all of which were first tested for efficacy and safety in nonhuman primates or other laboratory animals. Research in NHP has led to "dogma changing" discoveries in immunology, infectious disease, and even our own genetics. We now know that many of our genes are retroviral remnants, or developed in response to archaic HIV-like retroviral infections. Early studies involving blood from HIV patients and in experiments in cultured tissues contributed to confusion regarding the cause of AIDS and impeded progress in the development of effective interventions. Research on the many retroviruses of different NHP species have broadened our understanding of human immunology and perhaps even our origins and evolution as a species. In combination with recent advances in molecular biology and computational analytics, research in NHPs has unique potential for discoveries that will directly lead to new cures for old human and animal diseases, including HIV/AIDS. PMID- 29228221 TI - Oncogenic potential of hepatitis B virus subgenotype D1 surpasses D3: significance in the development of hepatocellular carcinoma. AB - Despite widespread distribution of hepatitis B virus (HBV)-genotype D, the clinical implications of its ten subgenotypes (D1-D10) have not been well documented. Here, we have investigated the impact of two major circulating HBV/D subgenotypes, D1 and D3 in Eastern India towards pathogenesis of liver disease progression to hepatocellular carcinoma (HCC). HBV subgenotypes were determined using full-length genome sequences of HBV isolates from patients with chronic hepatitis B (CHB), liver cirrhosis (LC) and HCC. Impact of D1 and D3 on viral lifecycle and disease progression was assessed by several in vitro assays. Phylogenetic tree analysis revealed that HBV/D1 and HBV/D3 were the two predominating HBV subgenotypes circulating in Eastern India. Interestingly, the frequency of patients infected with HBV/D1 was noticed progressively rising from CHB to HCC through LC while the increasing frequency of HBV/D3 declined suddenly in HCC implicating HBV/D1 might have greater oncogenic potential than HBV/D3. Similar to higher viral load noted in HCC patients infected with HBV/D1 than HBV/D3, the larger amount of intracellular/extracellular viral DNA and secreted HBsAg levels in transfected cell lines also implicated that HBV/D1 might replicate faster than HBV/D3. Again, higher expression of marker genes related to endoplasmic reticulum stress, epithelial-mesenchymal transition, DNA double strand breaks, angiogenesis etc. and faster rate of cellular migration and anchorage independent growth cumulatively suggested that compared to HBV/D3, HBV/D1 generates more liver injuries which eventually culminates into HCC. Therefore, our results highlight the importance of determination of subgenotypes of HBV in CHB patients, so that high-risk individual can be monitor periodically that may help to detect HCC at early stages. PMID- 29228222 TI - Human Microbiomes Influence Cancer Therapy. PMID- 29228223 TI - Updates to the National Cancer Institute's PDQ Information from Recently Published Oncology Research. PMID- 29228224 TI - Relationship between Escherichia coli growth rate and bacterial susceptibility to ciprofloxacin. AB - The effect of Escherichia coli growth rate on its susceptibility to ciprofloxacin was investigated using bacteria grown on different carbon sources and harboring mutations in genes encoding tricarboxylic acid cycle enzymes. A 1-h treatment of the wild type (wt) grown on glucose, succinate, malate, alpha-ketoglutarate or acetate with 0.3 MUg ml-1 ciprofloxacin decreased the number of surviving cells (CFU ml-1), 560, 110, 74, 62 and 5 times, respectively. Among the mutants tested, sucB strain, which grew 1.75 times slower than wt, was 7.4-fold more tolerant to 0.3 MUg ml-1 of ciprofloxacin than wt. Strong inverse correlations between log(CFU ml-1) after 1-h exposure to 0.3 and 3.0 MUg ml-1 ciprofloxacin and the specific growth rate prior to antibiotic treatment (r = - 0.93 and -0.96, respectively) were observed. Data from the current and previous studies on the inhibitory effect of ciprofloxacin on cultures exhibiting a wide range of growth rates (0.01-1.3 h-1) were collated. Statistical analysis revealed a significant inverse correlation between log(CFU ml-1) after exposure to 3.0 MUg ml-1 of ciprofloxacin and the specific bacterial growth rate prior to antibiotic exposure (r = -0.92). These data may be used in a design of antibiotic treatment protocols. PMID- 29228225 TI - Identification of pathogenic Aspergillus isolates from captive birds in Australia. AB - Aspergillosis is a major cause of severe respiratory disease in birds. The prevalence of cryptic section Fumigati and other non-Aspergillus fumigatus species as causative agents is unknown. Species identity was determined in 30 isolates from affected birds from zoos, pet birds and poultry by PCR of the ITS1 5.8S-ITS2 and partial beta-tubulin genes. The most prevalent isolate was A. fumigatus sens. str. in 87% (26) cases. Other Aspergillus species were identified in 13% (4) cases, including A. restrictus (1), A. flavus sens. str. (2), and A. nidulans-clade (1). This is the first report of A. restrictus causing avian disease. PMID- 29228226 TI - Vedolizumab-Associated Pancreatitis in Paediatric Ulcerative Colitis: Functional Selectivity of the alpha4beta7integrin and MAdCAM-1 Pathway? PMID- 29228227 TI - Cold Tolerance and Supercooling Capacity of the Redbanded Stink Bug (Hemiptera: Pentatomidae). AB - The redbanded stink bug Piezodorus guildinii (Westwood) (Hemiptera: Pentatomidae) is an invasive stink bug species in the United States. First documented as a soybean pest in Louisiana in the year 2000, this species continues to spread in the Mid-South region of the United States. We designed laboratory and field studies to investigate supercooling points, lethal exposure time (LT), critical thermal minimum (CTmin), and winter mortality of this species. The mean supercooling points (SCP) +/- SE of adult field collected P. guildinii ranged from -8.3 +/- 0.2 degrees C (highest) in March to -11.0 +/- 0.2 degrees C (lowest) in January. Significant differences in SCP occurred over the months and between sexes with significant interactions between month and sex. The CTmin was significantly different between adults and nymphs (third, fourth, and fifth instars combined). LT50 and LT90 were evaluated at subzero temperatures of 0 degrees C, -2 degrees C, and -5 degrees C. There were significant differences in LT50 and LT90 among the temperature treatments. Winter survival significantly differed between the two study years and decreased with progression of winter months. PMID- 29228228 TI - The Moonshot Initiative and the Future of Cancer Research. PMID- 29228229 TI - Variable plasmid fitness effects and mobile genetic element dynamics across Pseudomonas species. AB - Mobile genetic elements (MGE) such as plasmids and transposons mobilise genes within and between species, playing a crucial role in bacterial evolution via horizontal gene transfer (HGT). Currently, we lack data on variation in MGE dynamics across bacterial host species. We tracked the dynamics of a large conjugative plasmid, pQBR103, and its Tn5042 mercury resistance transposon, in five diverse Pseudomonas species in environments with and without mercury selection. Plasmid fitness effects and stability varied extensively between host species and environments, as did the propensity for chromosomal capture of the Tn5042 mercury resistance transposon associated with loss of the plasmid. Whereas Pseudomonas fluorescens and Pseudomonas savastanoi stably maintained the plasmid in both environments, the plasmid was highly unstable in Pseudomonas aeruginosa and Pseudomonas putida, where plasmid-free genotypes with Tn5042 captured to the chromosome invaded to higher frequency under mercury selection. These data confirm that plasmid stability is dependent upon the specific genetic interaction of the plasmid and host chromosome rather than being a property of plasmids alone, and moreover imply that MGE dynamics in diverse natural communities are likely to be complex and driven by a subset of species capable of stably maintaining plasmids that would then act as hubs of HGT. PMID- 29228230 TI - Efficacy of Home Telemonitoring versus Conventional Follow-up: A Randomized Controlled Trial among Teenagers with Inflammatory Bowel Disease. AB - Background and Aims: Conventional follow-up of teenagers with inflammatory bowel diseases [IBD] is done during scheduled outpatient visits regardless of how well the patient feels. We designed a telemonitoring strategy for early recognition of flares and compared its efficacy with conventional follow-up. Methods: We used a multicentre randomized trial in patients aged 10-19 years with IBD in clinical remission at baseline. Participants assigned to telemonitoring received automated alerts to complete a symptom score and send a stool sample for measurement of calprotectin. This resulted in an individual prediction for flare with associated treatment advice and test interval. In conventional follow-up the health check interval was left to the physician's discretion. The primary endpoint was cumulative incidence of disease flares. Secondary endpoints were percentage of participants with a positive change in quality-of-life and cost-effectiveness of the intervention. Results: We included 170 participants [84 telemonitoring; 86 conventional follow-up]. At 52 weeks the mean number of face-to-face visits was significantly lower in the telemonitoring group compared to conventional follow up [3.6 vs 4.3, p < 0.001]. The incidence of flares [33 vs 34%, p = 0.93] and the proportion of participants reporting positive change in quality-of-life [54 vs 44%, p = 0.27] were similar. Mean annual cost-saving was ?89 and increased to ?360 in those compliant to the protocol. Conclusions: Telemonitoring is as safe as conventional follow-up, and reduces outpatient visits and societal costs. The positive impact on quality-of-life was similar in the two groups. This strategy is attractive for teenagers and families, and health professionals may be interested in using it to keep teenagers who are well out of hospital and ease pressure on overstretched outpatient services. Trial registration: NTR3759 [Netherlands Trial Registry]. PMID- 29228231 TI - Novel echocardiographic method to assess left ventricular chamber stiffness and elevated end-diastolic pressure based on time-velocity integral measurements of pulmonary venous and transmitral flows. AB - Aims: The detection of increased left ventricular (LV) chamber stiffness may play an important role in assessing cardiac patients with potential but not overt heart failure. A non-invasive method to estimate it is not established. We investigated whether the echocardiographic backward/forward flow volume ratio from the left atrium (LA) during atrial contraction reflects the LV chamber stiffness. Methods and results: We studied 62 patients who underwent cardiac catheterization and measured their left ventricular end-diastolic pressure (LVEDP) and pressure increase during atrial contraction (DeltaPa) from the LV pressure waveform. Using the echocardiographic biplane method of disks, we measured the LV volume change during atrial contraction indexed to the body surface area (DeltaVa), and DeltaPa/DeltaVa was calculated as a standard for the LV operating chamber stiffness. Using pulsed Doppler echocardiography, we measured the time-velocity integral (TVI) of the backward pulmonary venous (PV) flow during atrial contraction (IPVA) and the ratio of IPVA to the PV flow TVI throughout a cardiac cycle (FPVA). We also measured the TVI of the atrial systolic forward transmitral flow (IA) and the ratio of the IA to the transmitral TVI during a cardiac cycle (FA) and calculated IPVA/IA and FPVA/FA. IPVA/IA and FPVA/FA were well correlated with DeltaPa/DeltaVa (r = 0.79 and r = 0.81) and LVEDP (r = 0.73 and r = 0.77). The areas under the ROC curve to discriminate LVEDP >18 mmHg were 0.90 for IPVA/IA and 0.93 for FPVA/FA. Conclusion: The FPVA/FA, the backward/forward flow volume ratio from the LA during atrial contraction, is useful for non-invasive assessments of LV chamber stiffness and elevated LVEDP. PMID- 29228232 TI - External validation of two web-based postoperative nomograms predicting the probability of early biochemical recurrence after radical prostatectomy: a retrospective cohort study. AB - The present study aimed to validate and compare the predictive accuracies of the Memorial Sloan Kettering Cancer Center (MSKCC) and Johns Hopkins University (JHU) web-based postoperative nomograms for predicting early biochemical recurrence (BCR) after radical prostatectomy (RP) and to analyze clinicopathological factors to predict early BCR after RP using our dataset. The c-index was 0.72 (95% confidence (CI): 0.61-0.83) for the MSKCC nomogram and 0.71 (95% CI: 0.61-0.81) for the and JHU nomogram, demonstrating fair performance in the Japanese population. Furthermore, we statistically analyzed our 174 patients to elucidate prognostic factors for early BCR within 2 years. Lymphovascular invasion (LVI) including lymphatic vessel invasion (ly) was a significant predictor of early BCR in addition to common variables (pT stage, extraprostatic extension, positive surgical margin and seminal vesicle invasion). LVI, particularly ly, may provide a good predictor of early BCR after RP and improve the accuracy of the nomograms. PMID- 29228233 TI - Exploring the evidence base for Tier 3 specialist weight management interventions for children aged 2-18 years in the UK: a rapid systematic review. AB - Background: The impact of specialist weight management services (Tier 3) for children with severe and complex obesity in the UK is unclear. This review aims to examine the impact of child Tier 3 services in the UK, exploring service characteristics and implications for practice. Methods: Rapid systematic review of any study examining specialist weight management interventions in any UK setting including children (2-18 years) with a body mass index >99.6th centile or >98th centile with comorbidity. Results: Twelve studies (five RCTs and seven uncontrolled) were included in a variety of settings. Study quality was moderate or low and mean baseline body mass index z-score ranged from 2.7 to 3.6 units. Study samples were small and children were predominantly older (10-14 years), female and white. Multidisciplinary team composition and eligibility criteria varied; dropout ranged from 5 to 43%. Improvements in zBMI over 1-24 months ranged from -0.13 to -0.41 units. Conclusions: Specialist weight management interventions for children with severe obesity demonstrated a reduction in zBMI, across a variety of UK settings. Studies were heterogeneous in content and thus conclusions on service design cannot be drawn. There is a paucity of evidence for Tier 3 services for children, and further research is required. PMID- 29228235 TI - The potential role of external venous supports in coronary artery bypass graft surgery. AB - Despite the apparent superiority of arterial conduits for coronary artery bypass grafting (CABG), the long saphenous vein remains the most commonly used graft. The high failure rate of long saphenous vein grafts (SVGs) over time is therefore an important limiting factor for the long-term outcomes of CABG. Various methods to improve SVG patency have been proposed, although few have had a significant impact on clinical practice. External SVG supports have been a focus of research over the past 50 years, with their use intended to minimize well-documented pathophysiological changes that occur in the SVG following implantation into the coronary circulation. These devices have been trialled extensively in animal models to assess their impact on both the morphology and the function of vascular conduits. Recently, a number of studies have been conducted in patients, leading to a substantial development in their design and the accumulation of a large body of evidence attesting to their potential benefit in CABG. In this review, we briefly discuss the proposed mechanism of action of external SVG supports and then evaluate the results from animal studies and more recent research assessing their use in CABG patients. Finally, we conclude that newer models of external stents have the potential to improve long-term outcomes in SVG. PMID- 29228234 TI - Tgfbr2 inactivation facilitates cellular plasticity and development of Pten-null prostate cancer. AB - Mutations in tumors can create a state of increased cellular plasticity that promotes resistance to treatment. Thus, there is an urgent need to develop novel strategies for identifying key factors that regulate cellular plasticity in order to combat resistance to chemotherapy and radiation treatment. Here we report that prostate epithelial cell reprogramming could be exploited to identify key factors required for promoting prostate cancer tumorigenesis and cellular plasticity. Deletion of phosphatase and tensin homolog (Pten) and transforming growth factor beta receptor type 2 (Tgfbr2) may increase prostate epithelial cell reprogramming efficiency in vitro and cause rapid tumor development and early mortality in vivo. Tgfbr2 ablation abolished TGF-beta signaling but increased the bone morphogenetic protein (BMP) signaling pathway through the negative regulator Tmeff1. Furthermore, increased BMP signaling promotes expression of the tumor marker genes ID1, Oct4, Nanog, and Sox2; ID1/STAT3/NANOG expression was inversely correlated with patient survival. Thus, our findings provide information about the molecular mechanisms by which BMP signaling pathways render stemness capacity to prostate tumor cells. PMID- 29228237 TI - Coinfections in Hospitalized Children With Community-Acquired Pneumonia: What Does This Mean for the Clinician? PMID- 29228236 TI - Spatial Niche Separation on the Periphery Range of Argiope bruennichi and Its Effect With Araneus quadratus (Araneae: Araneidae). AB - Recent decades have witnessed an intensified expansion of thermophilic organisms from southern into northern Europe. Argiope bruennichi, an orb-weaver spider species, is extending its range relatively fast and gradually becoming a common species in Europe. The aim of this study was to investigate how this relatively newly-come taxon is affecting another orb-weaver spider species and whether it demonstrates features of an invasive species. Interactions were examined between this species and another dominant species with similar body and web size, Araneus quadratus. The study areas were located in two adjacent regions in northeast Poland: the warmer Mazury Lake District and the colder Suwalki Lake District. The areas differed in both population density of the studied species as well as in climatic conditions. Six study sites were selected in each region. In the Mazury Lake District, A. bruennichi was more frequent than A. quadratus; this relationship was reversed in the Suwalki Lake District. We measured the height of the web hub above the ground and the height of the plants to which webs were fixed. Web location height was chosen as an indicator of the interaction. The results indicate that A. quadratus located its webs higher than A. bruennichi, regardless of species abundance and region. A. bruennichi does not exert a significant negative impact on A. quadratus web placement. The two species clearly prefer different heights, which in turn may determine the kind of prey they catch. PMID- 29228240 TI - Contrast of positively charged oxide precipitate in out-lens, in-lens and in column SE image. AB - Modern scanning electron microscopes are usually equipped with multiple detectors and enable simultaneous collection of two or even three secondary electron images. The secondary electrons become divided between the detectors in dependence on their initial kinetic energy and emission angle. In this study, sharing of the secondary electrons by out-lens, in-lens and in-column detectors has been systematically investigated. Energy filtering of the signal electrons is demonstrated by separation of the voltage and the topographical contrast in the micrographs obtained by out-lens and in-lens/in-column detectors. The presence of two detectors inside the electron column enables further filtering of the low kinetic energy secondary electrons, which results to unusual contrasts and phenomena. In this paper, inversion of the contrast sign between a positively charged oxide particle and conductive steel matrix (i.e. voltage contrast) in SE images collected under specific imaging conditions is demonstrated. PMID- 29228241 TI - Speech Intelligibility and Personality Peer-ratings of Young Adults With Cochlear Implants. AB - Speech intelligibility, or how well a speaker's words are understood by others, affects listeners' judgments of the speaker's competence and personality. Deaf cochlear implant (CI) users vary widely in speech intelligibility, and their speech may have a noticeable "deaf" quality, both of which could evoke negative stereotypes or judgments from peers. In this study, college students with typical hearing (TH) used semantic differential scales to rate speech samples of highly intelligible TH young adults and age-matched CI users with high or low intelligibility (CI-Hi, CI-Lo) on personality traits related to competence (intelligence, achievement), friendship skills (friendliness, popularity), and attractiveness as a friend (extraversion, dependability). Judges rated TH positively, CI-Lo negatively, and CI-Hi as intermediate, even though CI-Hi were as intelligible as TH. Both CI user groups were rated as friendly but unattractive as friends (insecure, shy, boring, unpopular, does not "sound like someone who could be my friend"), underlining the role of deaf speech quality in peer judgments. Such negative first impressions are likely to affect CI users' social interactions and friendships, highlighting the importance of speech intelligibility and quality for CI users and calling for education on deafness and deaf speech for TH peers. PMID- 29228242 TI - Mortality risk prediction in infective endocarditis surgery: reliability analysis of specific scores. AB - OBJECTIVES: We assessed the prognostic utility of risk scores in surgery for infective endocarditis (IE) to evaluate their reliability in mortality risk prediction. METHODS: An observational retrospective study was developed to include all patients who underwent surgery for active IE from 2002 to 2016. Classical and endocarditis-specific risk scores were calculated. RESULTS: A total of 180 patients were included in the study. The 30-day mortality rate was 26.82% [95% confidence interval (CI) 20.26-33.20%]. Classical risk scores were confirmed to have a suboptimal prognostic ability. Therefore, 4 IE-specific risk scores were calculated. Discrimination was evaluated using the area under the receiver operating characteristic curve. It was 0.76 (95% CI 0.68-0.82) for the Society of Thoracic Surgeons-IE (STS-IE) score; 0.68 (95% CI 0.58-0.76) for the De Feo Cotrufo score; 0.73 (95% CI 0.66-0.79) for the PALSUSE score and 0.65 (95% CI 0.57-0.72) for the Costa score. The STS-IE score had higher discrimination when compared with the De Feo-Cotrufo score (P = 0.055) and the Costa score (P = 0.024); however, there was no significant difference when we compared the STS-IE score with the PALSUSE score (P = 0.58). Calibration was assessed using the Hosmer-Lemeshow test; an adequate calibration was confirmed in all 4 scores. CONCLUSIONS: Specific risk scores had better prognostic performance than classical risk scores. The STS-IE score had the highest discrimination and was adequately calibrated. The PALSUSE score also showed optimal discrimination and calibration. The De Feo-Cotrufo score had a lower discrimination in our sample; however, the De Feo-Cotrufo score is recommended in the current guidelines. The Costa score had the lowest discrimination. PMID- 29228243 TI - Normalized serum eosinophil peroxidase levels are inversely correlated with esophageal eosinophilia in eosinophilic esophagitis. AB - Eosinophil peroxidase is an eosinophil-specific, cytoplasmic protein stored in the secondary granules of eosinophils. While eosinophil peroxidase deposition is increased in the esophagus in eosinophilic esophagitis (EOE), its potential role as a peripheral marker is unknown. This study aims to examine the relationship between serum eosinophil peroxidase and esophageal eosinophilia in eosinophilic esophagitis. Prospectively collected serum from 19 subjects with incident EoE prior to treatment and 20 non-EoE controls were tested for serum eosinophil peroxidase, eosinophilic cationic protein, and eosinophil derived neurotoxin using ELISA. Matching esophageal tissue sections were stained and assessed for eosinophil peroxidase deposition using a histopathologic scoring algorithm. Mean peripheral blood absolute eosinophil counts in eosinophilic esophagitis subjects were significantly elevated compared to controls (363 vs. 195 cells/MUL, P = 0.008). Absolute median serum eosinophil peroxidase, eosinophil cationic protein, and eosinophil derived neurotoxin did not differ between groups; however, when normalized for absolute eosinophil counts, eosinophilic esophagitis subjects had significantly lower median eosinophil peroxidase levels (2.56 vs. 6.96 ng/mL per eos/MUL, P = 0.002, AUC 0.79 (0.64, 0.94 95% CI)). Multivariate analysis demonstrated this relationship persisted after controlling for atopy. Esophageal biopsies from eosinophilic esophagitis subjects demonstrated marked eosinophil peroxidase deposition (median score 46 vs. 0, P < 0.0001). Normalized eosinophil peroxidase levels inversely correlated with esophageal eosinophil density (r = 0.41, P = 0.009). In contrast to marked tissue eosinophil degranulation, circulating eosinophils appear to retain their granule proteins in EoE. Investigations of normalized serum eosinophil peroxidase levels as a biomarker of EoE are ongoing. PMID- 29228245 TI - New Record of Wyeomyia mitchellii (Diptera: Culicidae) on Guam, United States. AB - Wyeomyia (Wyeomyia) mitchellii (Theobald) (Diptera: Culicidae) was recovered for the first time on Guam, United States of America, in 2017. Larval specimens were collected from water-filled axils of bromeliads during a larval survey carried out in a residential neighborhood of the Chalan Pago/Ordot area. Native to the New World, Wy. mitchellii has likely made its way to the Pacific Islands through the possibly illegal import of ornamental bromeliads. While this mosquito does not represent a significant threat to public health, this finding highlights the vulnerability of the Pacific Islands to the introduction of exotic species, including mosquito species that may increase public health risks. PMID- 29228244 TI - Prokaryote composition and predicted metagenomic content of two Cinachyrella Morphospecies and water from West Papuan Marine Lakes. AB - Certain sponge species are difficult to identify using classical taxonomic characters, and other techniques are often necessary. Here we used 454 pyrosequencing of the 16S rRNA gene to investigate bacterial and archaeal communities of two distinct Cinachyrella morphospecies collected from two Indonesian marine lakes with differing degrees of connection to the surrounding sea. Our main goal was to assess whether these morphospecies hosted distinct bacterial and archaeal communities and to what extent these differed from those found in lake water. A recently developed bioinformatic tool (PICRUSt) was used to predict metagenomic gene content of the studied communities. Compositionally, sponge samples clustered according to morphospecies as opposed to marine lake indicating that each morphospecies hosted distinct bacterial and archaeal communities. There were, however, also differences in higher taxon abundance among lakes. In the less connected lake, for example, both Cinachyrella morphospecies had higher levels of the order Synechococcales. With respect to metabolic gene content, although there were pronounced differences in predicted enrichment between both morphospecies, both were putatively enriched for KOs involved in pathways related to stress response, energy metabolism, environmental information processing and the production of secondary metabolites compared to prokaryote communities in water. These morphospecies may thus prove to be interesting sources of novel compounds of potential pharmaceutical and/or biotechnological importance. PMID- 29228246 TI - Clinical impact of Candida spp. biofilm production in a cohort of patients with candidemia. AB - Persistent candidemia refers to the continued isolation of the same Candida species in the blood of a candidemic patient despite appropriate therapy. Despite the clinical importance of persistent candidemia, studies have superficially addressed the biological conditions behind this phenomenon. The aim of this study was to evaluate the correlation between the biofilm-forming ability by Candida bloodstream isolates and the persistence of infection. A total of 55 isolates of Candida were tested and characterized in two groups: (i) group I, which included seven patients with persistent candidemia, and (ii) group II, which included 18 patients with nonpersistent candidemia. Microorganisms were identified at the species level by sequencing the internal transcribed spacer (ITS) region of ribosomal DNA (rDNA). Biofilm quantification was evaluated by the crystal violet staining method and confocal scanning laser microscopy (CSLM). Molecular tests confirmed the identification of Candida albicans (92% group I and 94% group II) and Candida dubliniensis isolates (8% group I and 6% group II). All 55 isolates were able to form biofilms, but a higher biofilm mass was produced by C. albicans/C. dubliniensis strains cultured from the persistent group (P < .05). Our data suggest that Candida sp. biofilm production should be considered a relevant biologic variable in explaining patients who fail to clear a bloodstream infection despite adequate antifungal treatment with triazoles. PMID- 29228247 TI - A Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Phase I Study of Analgesic/Antihyperalgesic Properties of ASP8477, a Fatty Acid Amide Hydrolase Inhibitor, in Healthy Female Subjects. AB - Objectives: To evaluate the analgesic/antihyperalgesic effect of ASP8477. Design: Randomized, double-blind, double-dummy, cross-over, placebo- and active comparator-controlled study. Setting: HPR Dr. Schaffler GmbH, Munich, Germany. Subjects: Healthy female subjects aged 18-65 years. Methods: Eligible subjects were randomly assigned to one of six treatment sequences and received multiple ascending doses of ASP8477, duloxetine, and placebo over three treatment periods (each consisting of 21-day dosing separated by 14-day washout periods). On the last day of each dose level, laser evoked potentials (LEPs) and visual analog scales (VAS pain) on capsaicin-treated skin at baseline and at multiple postdose time points were assessed. The primary end point was the difference in LEP N2-P2 peak-to-peak (PtP) amplitudes for ASP8477 100 mg vs placebo. Results: Twenty-five subjects were randomized. In all subjects, LEP N2-P2 PtP amplitudes were numerically lower for ASP8477 100 mg vs placebo (P = 0.0721); in subjects who demonstrated positive capsaicin skin effects, a greater mean difference of -2.24 uV (P = 0.0146) was observed. Across all doses, LEP N2-P2 PtP amplitudes were lower for duloxetine compared with ASP8477 (mean difference -3.80 uV; P < 0.0001) or placebo (mean difference -5.21 uV; P < 0.0001). The effect of ASP8477 (all doses) on down-scoring the VAS pain score was significant compared with placebo (mean difference -2.55%; P < 0.0007). Conclusions: ASP8477 was well tolerated in this study. Analysis of all subjects did not demonstrate a significant difference in LEP for ASP8477 100 mg over placebo but did in subjects who demonstrated positive capsaicin skin effects. PMID- 29228248 TI - Comparison of the intestinal mucosal microbiota in dogs diagnosed with idiopathic inflammatory bowel disease and dogs with food-responsive diarrhea before and after treatment. AB - We report the first study to evaluate the intestinal mucosal microbiota of dogs with inflammatory bowel disease (IBD) and dogs with food-responsive diarrhea (FRD) before and after treatment. It was hypothesized that differences in the microbial composition exist between both disease groups and within groups pre- vs. post-treatment. Duodenal and colonic biopsies were obtained endoscopically from 24 dogs (15 FRD, 9 IBD) before and after treatment. The intestinal microbiota was evaluated by Illumina sequencing of the bacterial 16S rRNA gene. The global bacterial composition did not differ between IBD and FRD dogs, nor between treatment status. However, several bacterial taxa showed a difference in abundance. Comparing disease groups, an unclassified genus of Neisseriaceae was abundant in the duodenum in the IBD group, whereas Bilophila occurred more frequently in the duodenum and Burkholderia in the colon of FRD dogs. Comparing the microbiota pre- and post-treatment revealed Enterococcus, Corynebacterium and Proteobacteria to be enriched in the duodenum of FRD dogs pre-treatment, while Bacteroides was abundant in the colon post-treatment. In dogs with IBD, Bacteroides also reached significant abundance in the colon post-treatment. In conclusion, some differences in individual bacterial taxa were identified between IBD and FRD dogs and between treatment status. PMID- 29228249 TI - Autofluorescence for the diagnosis of visceral pleural invasion in non-small-cell lung cancer. AB - OBJECTIVES: This study was conducted to evaluate the accuracy of autofluorescence as a mode of diagnosis for visceral pleural invasion of non-small-cell lung cancer compared with white-light by means of clinical questions to several thoracic surgeons. METHODS: Eight independent thoracic surgeons evaluated visceral pleural invasion in 25 cases of non-small-cell lung cancer attached to the visceral pleura on lung windows of preoperative computed tomography images. At the first study meeting to evaluate the accuracy of visceral pleural invasion diagnosis using conventional white-light images, the surgeons diagnosed visceral pleural invasion based on information in preoperative computed tomography images, histological types and videos recorded with white-light mode using a thoracoscope. At the second study meeting to evaluate the accuracy of visceral pleural invasion diagnosis using autofluorescence, the same surgeons diagnosed visceral pleural invasion based on information in 2 videos recorded in white light mode and in autofluorescence mode using the thoracoscope. RESULTS: The overall average sensitivity, specificity and accuracy of visceral pleural invasion diagnosis by white-light versus autofluorescence mode were 64.6% vs 83.3%, 53.9% vs 73.7% and 56.5% vs 76.0%, respectively. CONCLUSIONS: The sensitivity, specificity and accuracy of visceral pleural invasion diagnosis was improved through the additional use of the autofluorescence mode compared with the white-light mode alone. PMID- 29228250 TI - Higher Contrast Requirement for Letter Recognition and Macular RGC+ Layer Thinning in Glaucoma Patients and Older Adults. AB - Purpose: Growing evidence suggests the involvement of the macula even in early stages of glaucoma. However, little is known about the impact of glaucomatous macular damage on central pattern vision. Here we examine the contrast requirement for letter recognition and its relationship with retinal thickness in the macular region. Methods: A total of 40 participants were recruited: 13 patients with glaucoma (mean age = 65.6 +/- 6.6 years), 14 age-similar normally sighted adults (59.1 +/- 9.1 years), and 13 young normally sighted adults (21.0 +/- 2.0 years). For each participant, letter-recognition contrast thresholds were obtained using a letter recognition task in which participants identified English letters presented at varying retinal locations across the central 12 degrees visual field, including the fovea. The macular retinal ganglion cell plus inner plexiform (RGC+) layer thickness was also evaluated using spectral-domain optical coherence tomography (SD-OCT). Results: Compared to age-similar normal controls, glaucoma patients exhibited a significant increase in letter-recognition contrast thresholds (by 236%, P < 0.001) and a significant decrease in RGC+ layer thickness (by 17%, P < 0.001) even after controlling for age, pupil diameter, and visual acuity. Compared to normal young adults, older adults showed a significant increase in letter-recognition contrast thresholds and a significant decrease in RGC+ layer thickness. Across all subjects, the thickness of macular RGC+ layer was significantly correlated with letter-recognition contrast thresholds, even after correcting for pupil diameter and visual acuity (r = -0.65, P < 0.001). Conclusions: Our results show that both glaucoma and normal aging likely bring about a thinning of the macular RGC+ layer; the macular RGC+ layer thickness appears to be associated with the contrast requirements for letter recognition in central vision. PMID- 29228252 TI - Retinal Reflectivity Measurement for Cone Impairment Estimation and Visual Assessment After Diabetic Macular Edema Resolution (RECOVER-DME). AB - Purpose: Photoreceptor loss has been suspected of being involved in incomplete visual recovery after diabetic macular edema (DME) resolution. Recent studies have shown that cone density in the perifoveal area could be estimated by in vivo measurements of the outer retinal reflectivity on optical coherence tomography (OCT). The main objective of this study was to assess the photoreceptor layer reflectivity after DME resolution and to determine its relationship with final visual acuity (VA). Methods: In this cross-sectional case-control study, 77 eyes of 58 patients were divided into three groups: a first group (n = 34) encompassed eyes with resolved DME (R-DME), a second group (n = 24) corresponded to diabetic eyes without DME (no-DME), and a third group (n = 19) comprised a control group of nondiabetic healthy eyes. Outer retinal reflectivity was measured on volumetric spectral-domain (SD)-OCT scans acquired 3 months after DME resolution, from the photoreceptor ellipsoid zone (EZ) and the retinal pigment epithelium (RPE). Results: The mean DME duration was 26.5 +/- 13.4 months in the R-DME group. EZ reflectivity was 19.8% lower (P < 0.0001) in this group compared to diabetic eyes without DME and 26.5% lower (P < 0.0001) than in nondiabetic control eyes. Reflectivity was 7.8% lower in the no-DME group compared to controls (P < 0.0001). RPE reflectivity was comparable among the three groups (P > 0.05). VA was significantly correlated with EZ reflectivity in diabetic patients (r2 = 0.57; P < 0.0001). Reflectivity tended to decrease with prolonged DME duration without reaching statistical significance (P = 0.10). Conclusions: DME significantly impacts the photoreceptor layer. This impairment can be estimated by measuring outer retinal reflectivity on OCT images after edema resorption. We also provide evidence that in diabetic eyes without a history of DME, there is early photoreceptor loss, or at least outer segment (OS) disorganization, in addition to the inner retinal degeneration reported previously. This suggests the neurodegenerative process in diabetes. This quantitative approach may help monitor neuroprotective strategies to rescue photoreceptor cells in diabetic eyes. PMID- 29228251 TI - The Magnitude and Time Course of IOP Change in Response to Body Position Change in Nonhuman Primates Measured Using Continuous IOP Telemetry. AB - Purpose: To study the effect and time course of body position changes on IOP in nonhuman primates. Methods: We recorded continuous bilateral IOP measurements with a wireless telemetry implant in three rhesus macaques in seven different body positions. IOP measurements were acquired in the seated-upright, standing, prone, supine, right and left lateral decubitus positions (LDPs), and head-down inverted positions. Continuous IOP was recorded for 90 seconds in each position before returning to a supine reference position until IOP stabilized; measurements were averaged after IOP stabilized at each position. Results: Head down inversion increased IOP an average of 8.9 mm Hg, compared to the supine reference. In the LDP, IOP decreased an average of 0.5 mm Hg in the nondependent eye (i.e., the higher eye), while the fellow dependent (i.e., lower) eye increased an average of 0.5 mm Hg, compared to supine reference. Standing and seated positions decreased IOP 1.5 and 2.2 mm Hg, respectively, compared with supine reference. IOP changes occurred within 4 to 15 seconds of a body position change, and timing was affected by the speed at which body position was changed. Compared to the IOP in the supine position, the IOP in the inverted, prone, and seated positions was significantly different (P = 0.0313 for all). The IOP in the standing position was not statistically different from the IOP in the supine position (P = 0.094). In addition, the IOP was significantly different between the nondependent eye and the dependent eye in the LDPs compared to the supine position (P = 0.0313). Conclusions: Body position has a significant effect on IOP and those changes persist over time. PMID- 29228253 TI - Rare, Potentially Pathogenic Variants in ZNF469 Are Not Enriched in Keratoconus in a Large Australian Cohort of European Descent. AB - Purpose: The Zinc Finger Protein 469 (ZNF469) gene has been proposed as a candidate gene for keratoconus due to the association of an upstream polymorphism (rs9938149) with the disease in two independent studies, and the role of the gene in the autosomal recessive disease Brittle Cornea Syndrome. Coding variants in ZNF469 have been assessed for association with keratoconus in several small studies, with conflicting results. We assessed rare, potentially pathogenic variants in ZNF469 for enrichment in keratoconus patients in a cohort larger than all previous studies combined. Methods: ZNF469 was sequenced in 385 Australian keratoconus patients of European descent, 346 population controls, and 230 ethnically matched screened controls by either whole exome sequencing or targeted gene sequencing. The frequency of rare and very rare potentially pathogenic variants was compared between cases and controls using chi2 or Fisher's exact tests and further explored using a gene based test (Sequence Kernel Association Test [SKAT]), weighting on the rarity of variants. Results: A total of 49 rare, including 33 very rare, potentially pathogenic variants were identified across all groups. No enrichment of rare or very rare potentially pathogenic variants in ZNF469 was observed in our cases compared to the control groups following analysis using chi2 or Fisher's exact tests. This finding was further supported by the SKAT results, which found no significant difference in the frequency of variants predicted to be damaging between cases and either control group (P = 0.06). Conclusions: Rare variants in ZNF469 do not contribute to keratoconus susceptibility and do not account for the association at rs9938149. PMID- 29228254 TI - Structural and functional analysis of an OB-fold in human Ctc1 implicated in telomere maintenance and bone marrow syndromes. AB - The human CST (Ctc1, Stn1 and Ten1) complex binds the telomeric overhang and regulates telomere length by promoting C-strand replication and inhibiting telomerase-dependent G-strand synthesis. Structural and biochemical studies on the human Stn1 and Ten1 complex revealed its mechanism of assembly and nucleic acid binding. However, little is known about the structural organization of the multi-domain Ctc1 protein and how each of these domains contribute to telomere length regulation. Here, we report the structure of a central domain of human Ctc1. The structure reveals a canonical OB-fold with the two identified disease mutations (R840W and V871M) contributing to the fold of the protein. In vitro assays suggest that although this domain is not contributing directly to Ctc1's substrate binding properties, it affects full-length Ctc1 localization to telomeres and Stn1-Ten1 binding. Moreover, functional assays show that deletion of the entire OB-fold domain leads to significant increase in telomere length, frequency of internal single G-strands and fragile telomeres. Our findings demonstrate that a previously unknown OB-fold domain contributes to efficient Ctc1 telomere localization and chromosome end maintenance. PMID- 29228256 TI - Diversity patterns of microbial eukaryotes mirror those of bacteria in Antarctic cryoconite holes. AB - Ice-lidded cryoconite holes on glaciers in the Taylor Valley, Antarctica, provide a unique system of natural mesocosms for studying community structure and assembly. We used high-throughput DNA sequencing to characterize both microbial eukaryotic communities and bacterial communities within cryoconite holes across three glaciers to study similarities in their spatial patterns. We expected that the alpha (phylogenetic diversity) and beta (pairwise community dissimilarity) diversity patterns of eukaryotes in cryoconite holes would be related to those of bacteria, and that they would be related to the biogeochemical gradient within the Taylor Valley. We found that eukaryotic alpha and beta diversity were strongly related to those of bacteria across scales ranging from 140 m to 41 km apart. Alpha diversity of both was significantly related to position in the valley and surface area of the cryoconite hole, with pH also significantly correlated with the eukaryotic diversity. Beta diversity for both bacteria and eukaryotes was significantly related to position in the valley, with bacterial beta diversity also related to nitrate. These results are consistent with transport of sediments onto glaciers occurring primarily at local scales relative to the size of the valley, thus creating feedbacks in local chemistry and diversity. PMID- 29228255 TI - Community-wide intervention and population-level physical activity: a 5-year cluster randomized trial. AB - Background: Evidence from a limited number of short-term trials indicates the difficulty in achieving population-level improvements in physical activity (PA) through community-wide interventions (CWIs). We sought to evaluate the effectiveness of a 5-year CWI for promoting PA in middle-aged and older adults using a cluster randomized design. Methods: We randomized 12 communities in Unnan, Japan, to either intervention (9) or control (3). Additionally, intervention communities were randomly allocated to three subgroups by different PA types promoted. Randomly sampled residents aged 40-79 years responded to the baseline survey (n = 4414; 74%) and were followed at 1, 3 and 5 years (78-83% response rate). The intervention was a 5-year CWI using social marketing to promote PA. The primary outcome was a change in recommended levels of PA. Results: Compared with control communities, adults achieving recommended levels of PA increased in intervention communities [adjusted change difference = 4.6 percentage points (95% confidence interval: 0.4, 8.8)]. The intervention was effective for promoting all types of recommended PAs, i.e. aerobic (walking, 6.4%), flexibility (6.1%) and muscle-strengthening activities (5.7%). However, a bundled approach, which attempted to promote all forms of PAs above simultaneously, was not effective (1.3-3.4%, P >= 0.138). Linear dose-response relationships between the CWI awareness and changes in PA were observed (P <= 0.02). Pain intensity decreased in shoulder (intervention and control) and lower back (intervention only) but there was little change difference in all musculoskeletal pain outcomes between the groups. Conclusions: The 5-year CWI using the focused social marketing strategy increased the population-level of PA. PMID- 29228257 TI - Physiological response of Prorocentrum lima (Dinophyceae) to varying light intensities. AB - The benthic dinoflagellate Prorocentrum lima is among the most common toxic morphospecies with a cosmopolitan distribution. This study explored if strains from different environments and different morphotypes, isolated from three locations in the Atlantic Iberian Peninsula and two from the Mediterranean Sea, showed different responses to varying light regimes, after confirming that all strains belonged to the same ribotype. Growth rates and photosynthetic parameters such as Fo, Fv/Fm, and rETRmax were analysed with a Coulter counter, a water-PAM and a fast repetition rate fluorometer. The photosynthetic properties were investigated in a high light stress experiment using strains acclimated to low light (LL) and high light (HL). The highest growth rate was 0.23 day-1 at 80 and 100 MUmol photons m-2 s-1 for strains Dn150EHU and Dn60EHU, originated from different locations. Under control conditions (18 degrees C and 90 MUmol photons m-2 s-1), growth rate was on average 0.10 day-1. The HL stress exposure induced photodamage to all strains and the recovery period was not sufficiently long for full recovery of Fv/Fm. However, cells acclimated to HL showed a better recovery than the LL acclimated ones. Furthermore, some assumptions are discussed in relation to strains' original location. PMID- 29228258 TI - Reply to the article 'In defense of Bacillus thuringiensis, the safest and most successful microbial insecticide available to humanity-a response to EFSA'. PMID- 29228260 TI - Molecular detection of Enterocytozoon bieneusi from bats in South Korea. AB - Enterocytozoon bieneusi, which has recently been re-classified as a fungus, was identified in 5.2% (3/58) bat intestinal tissues and 1.9% (4/210) bat feces collected in South Korea. The positive cases were classified into six genotypes including four novel genotypes, KBAT1-KBAT4, based on sequence analysis of the E. bieneusi internal transcribed spacer (ITS) region. In addition, a novel genotype, KBAT3, belonged to group 1, which is considered having zoonotic potential by phylogenetic analysis of the E. bieneusi ITS region. This study expands our knowledge of the host range of E. bieneusi. PMID- 29228259 TI - The non-specific adenine DNA methyltransferase M.EcoGII. AB - We describe the cloning, expression and characterization of the first truly non specific adenine DNA methyltransferase, M.EcoGII. It is encoded in the genome of the pathogenic strain Escherichia coli O104:H4 C227-11, where it appears to reside on a cryptic prophage, but is not expressed. However, when the gene encoding M.EcoGII is expressed in vivo - using a high copy pRRS plasmid vector and a methylation-deficient E. coli host-extensive in vivo adenine methylation activity is revealed. M.EcoGII methylates adenine residues in any DNA sequence context and this activity extends to dA and rA bases in either strand of a DNA:RNA-hybrid oligonucleotide duplex and to rA bases in RNAs prepared by in vitro transcription. Using oligonucleotide and bacteriophage M13mp18 virion DNA substrates, we find that M.EcoGII also methylates single-stranded DNA in vitro and that this activity is only slightly less robust than that observed using equivalent double-stranded DNAs. In vitro assays, using purified recombinant M.EcoGII enzyme, demonstrate that up to 99% of dA bases in duplex DNA substrates can be methylated thereby rendering them insensitive to cleavage by multiple restriction endonucleases. These properties suggest that the enzyme could also be used for high resolution mapping of protein binding sites in DNA and RNA substrates. PMID- 29228261 TI - Growth and carotenogenesis in Rhodosporidium diobovatum IMB Y-5023: effects of culture medium and illumination intensity. AB - The oleaginous yeast Rhodosporidium diobovatum is a poorly described producer of carotenoids and may be of interest in biotechnology. This study investigated the effects of culture medium and illumination on effective carotenoid production by R. diobovatum IMB Y-5023. Yeast was cultured on carrot, bran extract, and modified yeast malt (YM) medium at illuminations in the 0-5000 lx range. Biomass, total carotenoids and their profile were assessed after cultivation. In order to compare samples, cluster analysis and principal component analysis were used to visualize the relationships between the variables and samples. Results show that it is not illumination but culture medium that is the main factor determining the quantity and proportions of carotenoids produced by R. diobovatum IMB Y-5023. The yeast grew and produced pigments throughout the tested range of illumination intensity. The modified YM medium was optimal for carotenogenesis. In cultures on that medium, the highest carotenoid yields of 24.98 mg g-1 dry cell weight and 77 mg L-1 were recorded. It was found that this yeast is capable of assimilating oligosaccharides and can grow and produce carotenoids in low-glucose media containing DP3 and DP4. Moreover R. diobovatum IMB Y-5023 produced lycopene as the main pigment independently of the culture conditions. PMID- 29228263 TI - Chromosomal Abnormalities in Offspring of Young Cancer Survivors: A Population Based Cohort Study in Denmark. AB - To examine whether cancer survivors diagnosed before age 35 years are more likely to have offspring with chromosomal abnormalities than their siblings, chromosomal abnormalities were determined in a population-based cohort of 14 611 offspring (14 580 live-born children and 31 fetuses) of 8945 Danish cancer survivors and 40 859 offspring (40 794 live-born children and 65 fetuses) of 19 536 siblings. Chromosomal abnormalities include numeric and structural abnormalities. Odds ratios were estimated by multiple logistic regression models comparing the risk of chromosomal abnormalities among survivors' offspring with that in siblings' offspring. In a subgroup of survivors with gonadal radiation doses (mean = 0.95 Gy for males and 0.91 Gy for females), no indication of a dose response was found. Overall, no increased risk of chromosomal abnormalities among survivors' offspring was observed compared with their siblings' offspring (odds ratio = 0.99, 95% confidence interval = 0.67 to 1.44, two-sided P = .94), with similar risk between male and female survivors. Cancer survivors were not more likely than their siblings to have children with a chromosomal abnormality. PMID- 29228262 TI - LTR Retrotransposons Show Low Levels of Unequal Recombination and High Rates of Intraelement Gene Conversion in Large Plant Genomes. AB - The accumulation and removal of transposable elements (TEs) is a major driver of genome size evolution in eukaryotes. In plants, long terminal repeat (LTR) retrotransposons (LTR-RTs) represent the majority of TEs and form most of the nuclear DNA in large genomes. Unequal recombination (UR) between LTRs leads to removal of intervening sequence and formation of solo-LTRs. UR is a major mechanism of LTR-RT removal in many angiosperms, but our understanding of LTR-RT associated recombination within the large, LTR-RT-rich genomes of conifers is quite limited. We employ a novel read-based methodology to estimate the relative rates of LTR-RT-associated UR within the genomes of four conifer and seven angiosperm species. We found the lowest rates of UR in the largest genomes studied, conifers and the angiosperm maize. Recombination may also resolve as gene conversion, which does not remove sequence, so we analyzed LTR-RT-associated gene conversion events (GCEs) in Norway spruce and six angiosperms. Opposite the trend for UR, we found the highest rates of GCEs in Norway spruce and maize. Unlike previous work in angiosperms, we found no evidence that rates of UR correlate with retroelement structural features in the conifers, suggesting that another process is suppressing UR in these species. Recent results from diverse eukaryotes indicate that heterochromatin affects the resolution of recombination, by favoring gene conversion over crossing-over, similar to our observation of opposed rates of UR and GCEs. Control of LTR-RT proliferation via formation of heterochromatin would be a likely step toward large genomes in eukaryotes carrying high LTR-RT content. PMID- 29228264 TI - Co-invading symbiotic mutualists of Medicago polymorpha retain high ancestral diversity and contain diverse accessory genomes. AB - Exotic, invasive plants and animals can wreak havoc on ecosystems by displacing natives and altering environmental conditions. However, much less is known about the identities or evolutionary dynamics of the symbiotic microbes that accompany invasive species. Most leguminous plants rely upon symbiotic rhizobium bacteria to fix nitrogen and are incapable of colonizing areas devoid of compatible rhizobia. We compare the genomes of symbiotic rhizobia in a portion of the legume's invaded range with those of the rhizobium symbionts from across the legume's native range. We show that in an area of California the legume Medicago polymorpha has invaded, its Ensifer medicae symbionts: (i) exhibit genome-wide patterns of relatedness that together with historical evidence support host symbiont co-invasion from Europe into California, (ii) exhibit population genomic patterns consistent with the introduction of the majority of deep diversity from the native range, rather than a genetic bottleneck during colonization of California and (iii) harbor a large set of accessory genes uniquely enriched in binding functions, which could play a role in habitat invasion. Examining microbial symbiont genome dynamics during biological invasions is critical for assessing host-symbiont co-invasions whereby microbial symbiont range expansion underlies plant and animal invasions. PMID- 29228265 TI - Complete motif analysis of sequence requirements for translation initiation at non-AUG start codons. AB - The initiation of mRNA translation from start codons other than AUG was previously believed to be rare and of relatively low impact. More recently, evidence has suggested that as much as half of all translation initiation utilizes non-AUG start codons, codons that deviate from AUG by a single base. Furthermore, non-AUG start codons have been shown to be involved in regulation of expression and disease etiology. Yet the ability to gauge expression based on the sequence of a translation initiation site (start codon and its flanking bases) has been limited. Here we have performed a comprehensive analysis of translation initiation sites that utilize non-AUG start codons. By combining genetic reporter, cell-sorting, and high-throughput sequencing technologies, we have analyzed the expression associated with all possible variants of the -4 to +4 positions of non-AUG translation initiation site motifs. This complete motif analysis revealed that 1) with the right sequence context, certain non-AUG start codons can generate expression comparable to that of AUG start codons, 2) sequence context affects each non-AUG start codon differently, and 3) initiation at non-AUG start codons is highly sensitive to changes in the flanking sequences. Complete motif analysis has the potential to be a key tool for experimental and diagnostic genomics. PMID- 29228267 TI - The effects of sex-biased gene expression and X-linkage on rates of sequence evolution in Drosophila. AB - A faster rate of adaptive evolution of X-linked genes compared with autosomal genes (the faster-X effect) can be caused by the fixation of recessive or partially recessive advantageous mutations. This effect should be largest for advantageous mutations that affect only male fitness, and least for mutations that affect only female fitness. We tested these predictions in Drosophila melanogaster by using coding and functionally significant non-coding sequences of genes with different levels of sex-biased expression. Consistent with theory, nonsynonymous substitutions in most male-biased and unbiased genes show faster adaptive evolution on the X. However, genes with very low recombination rates do not show such an effect, possibly as a consequence of Hill-Robertson interference. Contrary to expectation, there was a substantial faster-X effect for female-biased genes. After correcting for recombination rate differences, however, female-biased genes did not show a faster X-effect. Similar analyses of non-coding UTRs and long introns showed a faster-X effect for all groups of genes, other than introns of female-biased genes. Given the strong evidence that deleterious mutations are mostly recessive or partially recessive, we would expect a slower rate of evolution of X-linked genes for slightly deleterious mutations that become fixed by genetic drift. Surprisingly, we found little evidence for this after correcting for recombination rate, implying that weakly deleterious mutations are mostly close to being semidominant. This is consistent with evidence from polymorphism data, which we use to test how models of selection that assume semidominance with no sex-specific fitness effects may bias estimates of purifying selection. PMID- 29228266 TI - Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria. AB - Accuracy of protein synthesis is enabled by the selection of amino acids for tRNA charging by aminoacyl-tRNA synthetases (ARSs), and further enhanced by the proofreading functions of some of these enzymes for eliminating tRNAs mischarged with noncognate amino acids. Mouse models of editing-defective cytoplasmic alanyl tRNA synthetase (AlaRS) have previously demonstrated the importance of proofreading for cytoplasmic protein synthesis, with embryonic lethal and progressive neurodegeneration phenotypes. Mammalian mitochondria import their own set of nuclear-encoded ARSs for translating critical polypeptides of the oxidative phosphorylation system, but the importance of editing by the mitochondrial ARSs for mitochondrial proteostasis has not been known. We demonstrate here that the human mitochondrial AlaRS is capable of editing mischarged tRNAs in vitro, and that loss of the proofreading activity causes embryonic lethality in mice. These results indicate that tRNA proofreading is essential in mammalian mitochondria, and cannot be overcome by other quality control mechanisms. PMID- 29228268 TI - Low and constant micafungin concentrations may be sufficient to lead to resistance mutations in FKS2 gene of Candida glabrata. AB - We studied the ability of five echinocandin-susceptible C. glabrata isolates to acquire in vitro resistance to anidulafungin and micafungin. All isolates became phenotypically resistant after 2-4 days of exposure to low and constant micafungin concentrations (P < .05). Mutations in the HS1 region of the FKS2 gene were found in all isolates. The acquisition of resistance was not related to the previous use of antifungal treatment in the patients or the presence of mutations at MSH2 gene. We found differences (P < .0001) in the median survival of Galleria mellonella larvae infected with FKS2 mutant isolates (5 days) and wild-type isolates (3 days). PMID- 29228269 TI - Electroactive haloalkaliphiles exhibit exceptional tolerance to free ammonia. AB - Electrochemical activity in bacteria has been observed in numerous environments and conditions. However, enrichments in circumneutral freshwater media where acetate is the main electron donor seem to invariably lead to the dominance of Geobacter spp. Here we report on an electroactive bacterial consortium which was enriched on acetate as electron donor, but in a medium which reproduces hydrolysed urine (high pH, high salinity and high free ammonia). The consortium was found to be free of Geobacter species, whereas a previously undescribed community dominated by species closely related to Pseudomonas and Desulfuromonas was established. The salient features of this community were as follows: (i) high electroactivity, with anodic current densities up to 47.4 +/- 2.0 A m-2; (ii) haloalkaliphilicity, with top performance at a medium pH of 10 and 19.5 +/- 0.5 mS cm-1; and (iii) a remarkably high tolerance to free ammonia toxicity at over 2200 mgNH3-N L-1. This community is likely to find applications in microbial electrochemical technology for nutrient recovery from source-separated urine. PMID- 29228270 TI - Influenza A virus subtype H9N2 infection disrupts the composition of intestinal microbiota of chickens. AB - The impact of low pathogenic influenza viruses such as subtype H9N2, which infect the respiratory and the gastrointestinal tracts of chickens, on microbial composition are not known. Twenty-day-old specific pathogen-free chickens were assigned to two treatment groups, control (uninfected) and H9N2-infected (challenged via the oral-nasal route). Fecal genomic DNA was extracted, and the V3-V4 regions of the 16S rRNA gene were sequenced using the Illumina Miseq(r) platform. Sequences were curated using Mothur as described in the MiSeq SOP. Infection of chickens with H9N2 resulted in an increase in phylum Proteobacteria, and differential enrichment with the genera Vampirovibrio, Pseudoflavonifractor, Ruminococcus, Clostridium cluster XIVb and Isobaculum while control chickens were differentially enriched with genera Novosphingobium, Sphingomonas, Bradyrhizobium and Bifidobacterium. Analysis of pre- and post-H9N2 infection of the same chickens showed that, before infection, the fecal microbiota was characterized by Lachnospiracea and Ruminococcaceae family and the genera Clostridium sensu stricto, Roseburia and Lachnospiraceae incertae sedis. However, post-H9N2 infection, class Deltaproteobacteria, orders Clostridiales and Bacteroidiales and the genus Alistipes were differentially enriched. Findings from the current study show that influenza virus infection in chickens results in the shift of the gut microbiota, and the disruption of the host-microbial homeostasis in the gut might be one of the mechanisms by which influenza virus infection is established in chickens. PMID- 29228271 TI - LitPathExplorer: a confidence-based visual text analytics tool for exploring literature-enriched pathway models. AB - Motivation: Pathway models are valuable resources that help us understand the various mechanisms underpinning complex biological processes. Their curation is typically carried out through manual inspection of published scientific literature to find information relevant to a model, which is a laborious and knowledge-intensive task. Furthermore, models curated manually cannot be easily updated and maintained with new evidence extracted from the literature without automated support. Results: We have developed LitPathExplorer, a visual text analytics tool that integrates advanced text mining, semi-supervised learning and interactive visualization, to facilitate the exploration and analysis of pathway models using statements (i.e. events) extracted automatically from the literature and organized according to levels of confidence. LitPathExplorer supports pathway modellers and curators alike by: (i) extracting events from the literature that corroborate existing models with evidence; (ii) discovering new events which can update models; and (iii) providing a confidence value for each event that is automatically computed based on linguistic features and article metadata. Our evaluation of event extraction showed a precision of 89% and a recall of 71%. Evaluation of our confidence measure, when used for ranking sampled events, showed an average precision ranging between 61 and 73%, which can be improved to 95% when the user is involved in the semi-supervised learning process. Qualitative evaluation using pair analytics based on the feedback of three domain experts confirmed the utility of our tool within the context of pathway model exploration. Availability and implementation: LitPathExplorer is available at http://nactem.ac.uk/LitPathExplorer_BI/. Contact: sophia.ananiadou@manchester.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228272 TI - An investigation into the possible regulation of the expression of genes by yapA in Talaromyces marneffei using the qRT- PCR method. AB - The pathogenic dimorphic fungus Talaromyces marneffei is known to cause a fatal systemic mycosis in immunocompromised patients, especially in HIV patients in Southeast Asia. The basic leucine-zipper (bZip) transcription factor gene, yapA, has been identified in T. marneffei. A prior study described that yapA was involved in the oxidative and nitrosative stress response in T. marneffei. Interestingly, an essential role of Saccharomyces cerevisiae Yap1p in the oxidative stress response is the activation of the transcription of its target genes. To identify the target genes of yapA in T. marneffei, the qRT-PCR method were used in this study. Investigation into the expression of genes which are probably regulated by yapA revealed that yapA controlled the expression of cat1 (catalase), cpeA (catalase-peroxidase), sodA (copper, zinc superoxide dismutase), gcs1 (glutamate-cysteine ligase), glr1 (glutathione oxidoreductase), trr1/trr2 (thioredoxin reductase), and trxA (thioredoxin) during stress conditions in all forms of conidium, mycelium, and yeast phase. An exception to this was the expression of cat1 under conditions of oxidative stress in the mould phase with a similar relative expression level in all of the wild-type, mutant and complemented strains. These genes are involved in response against oxidative stress and nitrosative stress in this fungus. The data showed that they could be regulated by the yapA gene during stress conditions. Moreover, the yapA gene is also known to control red pigment production by inhibiting the regulation of the five polyketide synthase (pks) genes, pks3 (polyketide synthase), rp1 (transcription activator), rp2 (beta-subunit fatty acid synthase), rp3 (alpha subunit fatty acid synthase), and rp4 (oxidoreductase) in the mould phase. In addition, it also regulates transcription in the laccase gene cluster including lac (extracellular dihydrogeodin oxidase/laccase), and multicopper oxidase encoding genes (PMAA_050860, PMAA_072680, PMAA_085520, PMAA_082010, and PMAA_082060) in all stages of the T. marneffei lifecycle (conidia, mould, and yeast phase). This study suggests the importance of the role of the yapA gene in the stress response and virulence of T. marneffei. PMID- 29228273 TI - Direct detection of Exophiala and Scedosporium species in sputa of patients with cystic fibrosis. AB - Detection of species of Exophiala and Scedosporium in the respiratory tracts of cystic fibrosis (CF) patients remains controversial because of highly variable results. The results of our study suggested a significantly higher prevalence and more complex colonization than previously estimated. Approximately 17% (27/162) of clinical sputum samples were found to be positive for Exophiala dermatitidis and 30% (49/162) were positive for Scedosporium apiospermum / S. boydii species complex determined by reverse line blot (RLB) hybridization. In contrast, only 14.2% (23/162) and 1.2% (2/162) of clinical sputa were positive for E. dermatitidis and S. apiospermum / S. boydii species complex when tested by culture, respectively. Molecular detection methods, such as loop-mediated isothermal amplification (LAMP) or reverse line blot (RLB) hybridization, have the potential to become powerful alternatives to selective culture, providing a more realistic understanding on the prevalence of E. dermatitidis and S. apiospermum / S. boydii species complex in the respiratory tract of CF patients. PMID- 29228274 TI - Screening the ToxCast Phase 1 Chemical Library for Inhibition of Deiodinase Type 1 Activity. AB - Thyroid hormone (TH) homeostasis is dependent upon coordination of multiple key events including iodide uptake, hormone synthesis, metabolism, and elimination, to maintain proper TH signaling. Deiodinase enzymes catalyze iodide release from THs to interconvert THs between active and inactive forms, and are integral to hormone metabolism. The activity of deiodinases has been identified as an important endpoint to include in the context of screening chemicals for TH disruption. To begin to address the potential for chemicals to inhibit these enzymes an adenovirus expression system was used to produce human deiodinase type 1 (DIO1) enzyme, established robust assay parameters for nonradioactive determination of iodide release by the Sandell-Kolthoff method, and employed a 96 well plate format for screening chemical libraries. An initial set of 18 chemicals was used to establish the assay, along with the known DIO1 inhibitor 6 propylthiouracil as a positive control. An additional 292 unique chemicals from the EPA's ToxCast phase 1_v2 chemical library were screened. Chemicals were initially screened at a single high concentration of 200 uM to identify potential DIO1 inhibitors. There were 50 chemicals, or 17% of the TCp1_v2 chemicals tested, that produced >20% inhibition of DIO1 activity. Eighteen of these inhibited DIO1 activity >50% and were further tested in concentration-response mode to determine IC50s. This work presents an initial effort toward identifying chemicals with potential for affecting THs via inhibition of deiodinases and sets the foundation for further testing of large chemical libraries against DIO1 and the other deiodinase enzymes involved in TH function. PMID- 29228275 TI - Mating-type switching in CBS 732T derived subcultures unveils potential genetic and phenotypic novelties in haploid Zygosaccharomyces rouxii. AB - In haploid Saccharomyces cerevisiae, a complex recombination system regulates mating-type switching and requires one MAT expression locus, two donor cassettes (HML and HMR) and the HO endonuclease that catalyses gene conversion. Zygosaccharomyces rouxii is the most distant species from S. cerevisiae with a functional HO, but with a poorly understood mating-type switching. Here, we described that two subcultures of the type strain CBS 732T underwent the alpha to a genotype switching leading to mixed MATalpha and MATa populations. Remarkably, during this event the donor cassette was copied into the MAT locus, except for its own 3? end, resulting in a new MATa2 gene copy different from the silenced HMRa2. Moreover, CBS 732T cells bypassed the cell-cycle control, which oversees HO transcription in S. cerevisiae, and expressed HO at the stationary phase. Despite HO dysregulation, mating-type switching seemed to occur rarely or belatedly during CBS 732T colony formation in most of the tested conditions. When morphology and mating behaviour were analysed, two subcultures displayed distinct outcross fertility responses. Overall, our data support that mating-type switching causes genotype instability and phenotypic novelties in CBS 732T, and open the question whether this mechanism is shared by other Z. rouxii haploid homothallic strains. PMID- 29228276 TI - Authors' Response. PMID- 29228277 TI - How Should We Determine the Importance of Research? PMID- 29228278 TI - Zinc finger protein 274 regulates imprinted expression of transcripts in Prader Willi syndrome neurons. AB - Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity and is caused by the absence of paternal contribution to chromosome 15q11-q13. Using induced pluripotent stem cell (iPSC) models of PWS, we previously discovered an epigenetic complex that is comprised of the zinc-finger protein ZNF274 and the SET domain bifurcated 1 (SETDB1) histone H3 lysine 9 (H3K9) methyltransferase and that silences the maternal alleles at the PWS locus. Here, we have knocked out ZNF274 and rescued the expression of silent maternal alleles in neurons derived from PWS iPSC lines, without affecting DNA methylation at the PWS-Imprinting Center (PWS-IC). This suggests that the ZNF274 complex is a separate imprinting mark that represses maternal PWS gene expression in neurons and is a potential target for future therapeutic applications to rescue the PWS phenotype. PMID- 29228279 TI - In Vitro Model of Fully Differentiated Human Nasal Epithelial Cells Infected With Rhinovirus Reveals Epithelium-Initiated Immune Responses. AB - Human rhinoviruses (HRVs) are the commonest cause of the common cold. While HRV is less pathogenic than other respiratory viruses, it is frequently associated with exacerbation of chronic respiratory diseases such as rhinosinusitis and asthma. Nasal epithelial cells are the first sites of viral contact, immune initiation, and airway interconnectivity, but there are limited studies on HRV infection of nasal epithelial cells. Hence, we established a model of HRV infection of in vitro-differentiated human nasal epithelial cells (hNECs) derived from multiple individuals. Through HRV infection of hNECs, we found that HRV mainly targeted ciliated cells and preferentially induced type I and III interferon antiviral pathways. Quantitative polymerase chain reaction analysis of inflammatory genes suggested predominant type 1 immunity signaling and recruitment, with secreted CXCL9, IP-10, CXCL11, and RANTES as likely initiators of airway inflammatory responses. Additionally, we further explored HRV bidirectional release from the hNECs and identified 11 associated genes. Other HRV interactions were also identified through a systematic comparison with influenza A virus infection of hNECs. Overall, this in vitro hNEC HRV infection model provides a platform for repeatable and controlled studies of different individuals, thus providing novel insights into the roles of human nasal epithelium in HRV interaction and immune initiation. PMID- 29228280 TI - New intronic Fibroblast Growth Factor Receptor 1 (FGFR1) mutation leading to disrupted splicing and Kallmann syndrome. AB - Congenital hypogonadotropic hypogonadism (CHH), which can present with a defective sense of smell (Kallmann syndrome, KS), is a clinically and genetically heterogeneous disorder. Over 31 genes have been associated with CHH, but most of the patients still lack a molecular genetic diagnosis. Some cases may be explained by mutations that disrupt the splicing of already established CHH genes but that are unrecognized either because they are located deep in introns or are not predicted to disrupt splicing. Here we identified a patient with a previously unreported Fibroblast Growth Factor Receptor 1 (FGFR1) mutation, c.1664-9T>G, that leads to the skipping of exon 13 of FGFR1. Notably, the mutation was not predicted to cause a significant alteration in the splicing motif but in vitro analysis confirmed the pathogenicity of the mutation. Our results thus reveal a new splicing-affecting mutation in FGFR1 and suggest that all new sequence variants located close to exon/intron boundaries should be experimentally investigated for pathogenicity, rather than relying solely on computer prediction programs. PMID- 29228281 TI - The intriguing evolution of effect sizes in biomedical research over time: smaller but more often statistically significant. AB - Background: In medicine, effect sizes (ESs) allow the effects of independent variables (including risk/protective factors or treatment interventions) on dependent variables (e.g., health outcomes) to be quantified. Given that many public health decisions and health care policies are based on ES estimates, it is important to assess how ESs are used in the biomedical literature and to investigate potential trends in their reporting over time. Results: Through a big data approach, the text mining process automatically extracted 814 120 ESs from 13 322 754 PubMed abstracts. Eligible ESs were risk ratio, odds ratio, and hazard ratio, along with their confidence intervals. Here we show a remarkable decrease of ES values in PubMed abstracts between 1990 and 2015 while, concomitantly, results become more often statistically significant. Medians of ES values have decreased over time for both "risk" and "protective" values. This trend was found in nearly all fields of biomedical research, with the most marked downward tendency in genetics. Over the same period, the proportion of statistically significant ESs increased regularly: among the abstracts with at least 1 ES, 74% were statistically significant in 1990-1995, vs 85% in 2010-2015. Conclusions: whereas decreasing ESs could be an intrinsic evolution in biomedical research, the concomitant increase of statistically significant results is more intriguing. Although it is likely that growing sample sizes in biomedical research could explain these results, another explanation may lie in the "publish or perish" context of scientific research, with the probability of a growing orientation toward sensationalism in research reports. Important provisions must be made to improve the credibility of biomedical research and limit waste of resources. PMID- 29228282 TI - Proteolytic inactivation of ADAMTS13 by plasmin in human plasma: risk of thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is caused by inactivation of a von Willebrand factor (VWF)-cleaving enzyme, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), which leads to platelet-rich thrombi comprising unusually large VWF multimers. We have found that ADAMTS13 can bind to the inactivated form of plasmin. In addition, plasmin cleaves purified ADAMTS13 into several fragments and inactivates it. Hence, we hypothesized that activation of plasminogen to plasmin becomes a new-onset factor for TTP due to ADAMTS13 inactivation. Plasmin was added exogenously or activated from plasminogen by streprokinase addition in human plasma (HP). ADAMTS13 digestion and effects of the digestion on ADAMTS13 activity were evaluated. Exogenous plasmin cleaved ADAMTS13 into several fragments, but a portion of ADAMTS13 remained in full-length form. Digestion profile of ADAMTS13 with streprokinase added exogenously in HP was similar to that of ADAMTS13 with exogenous plasmin. ADAMTS13 activity measured using FRETS-VWF73 decreased to ~40% compared with that for normal plasma. Endogenous VWF multimer-cleaving activity was attenuated more severely (~10%). These data suggest that endogenous plasmin cleaves ADAMTS13 into fragments and reduces its activity to ~10%. We suggest that endogenous plasmin activation alone is not sufficient to cause TTP, but plasmin activation with ADAMTS13 deficiency might increase the risk of TTP onset. PMID- 29228283 TI - Interaction of Neisseria meningitidis Group X N-acetylglucosamine-1 phosphotransferase with its donor substrate. AB - Neisseria meningitidis Group X is an emerging cause of bacterial meningitis in Sub-Saharan Africa. The capsular polysaccharide of Group X is a homopolymer of N acetylglucosamine alpha(1-4) phosphate and is a vaccine target for prevention of disease associated with this meningococcal serogroup. We have demonstrated previously that the formation of the polymer is catalyzed by a phosphotransferase which transfers N-acetylglucosamine-1-phosphate from UDP-N-acetylglucosamine to the 4-hydroxyl of the N-acetylglucosamine on the nonreducing end of the growing chain. In this study, we use substrate analogs of UDP-GlcNAc to define the enzyme/donor substrate interactions critical for catalysis. Our kinetic analysis of the phosphotransferase reaction is consistent with a sequential mechanism of substrate addition and product release. The use of novel uracil modified analogs designed by Wagner et al. enabled us to assess whether the CsxA-catalyzed reaction is consistent with a donor dependent conformational change. As expected with this model for glycosyltransferases, UDP-GlcNAc analogs with bulky uracil modifications are not substrates but are inhibitors. An analog with a smaller iodo uracil substitution is a substrate and a less potent inhibitor. Moreover, our survey of analogs with modifications on the N-acetylglucosamine residue of the sugar nucleotide donor highlights the importance of substituents at C2 and C4 of the sugar residue. The hydroxyl group at C4 and the structure of the acyl group at C2 are very important for specificity and substrate interactions during the polymerization reaction. While most analogs modified at C2 were inhibitors, acetamido analogs were also substrates suggesting the importance of the carbonyl group. PMID- 29228284 TI - The Relationship of PROMIS Pain Interference and Physical Function Scales. AB - Objectives: To examine the relationship between the Patient Reported Outcome Measurement Information System (PROMIS) Pain Interference (PI) and PROMIS Physical Function (PF) scales in patients with spinal pain at a university spine center. Design: Retrospective analysis of prospectively collected patient reported outcome data at a university spine clinic. Pearson correlation was done to examine the relationship of the PROMIS PF and PROMIS PI scores. Age, gender, and race were analyzed by subgroups on the PROMIS Physical Function and Pain Interference score. Linear regression analyzed predictive relationships. Statistical significance was set at P < 0.05. Results: A total of 1,992 participants completed an assessment, with 1,923 completing the PF CAT and 1,927 the PI CAT. Participants' mean age was 52.8 years (range = 18-94 years, SD = 6.5 years). Correlation analysis of the PROMIS PF with the PROMIS PI showed a Pearson correlation value of -0.717 (P < 0.05). There was a strong linear relationship with a high negative correlation between PF CAT and PI CAT. The PI CAT predicted PF CAT scores (beta = -0.707, P < 0.001). Conclusions: For patients with pain from spinal origin, there is a strong negative correlation between self-reported physical function and pain interference related to physical, social, and mental health. The predictive relationship of function from pain scores supports the PROMIS PI being used as an important adjunct measure of physical function in patients with spinal pain. PMID- 29228285 TI - Matrix factorization-based data fusion for the prediction of lncRNA-disease associations. AB - Motivation: Long non-coding RNAs (lncRNAs) play crucial roles in complex disease diagnosis, prognosis, prevention and treatment, but only a small portion of lncRNA-disease associations have been experimentally verified. Various computational models have been proposed to identify lncRNA-disease associations by integrating heterogeneous data sources. However, existing models generally ignore the intrinsic structure of data sources or treat them as equally relevant, while they may not be. Results: To accurately identify lncRNA-disease associations, we propose a Matrix Factorization based LncRNA-Disease Association prediction model (MFLDA in short). MFLDA decomposes data matrices of heterogeneous data sources into low-rank matrices via matrix tri-factorization to explore and exploit their intrinsic and shared structure. MFLDA can select and integrate the data sources by assigning different weights to them. An iterative solution is further introduced to simultaneously optimize the weights and low rank matrices. Next, MFLDA uses the optimized low-rank matrices to reconstruct the lncRNA-disease association matrix and thus to identify potential associations. In 5-fold cross validation experiments to identify verified lncRNA disease associations, MFLDA achieves an area under the receiver operating characteristic curve (AUC) of 0.7408, at least 3% higher than those given by state-of-the-art data fusion based computational models. An empirical study on identifying masked lncRNA-disease associations again shows that MFLDA can identify potential associations more accurately than competing models. A case study on identifying lncRNAs associated with breast, lung and stomach cancers show that 38 out of 45 (84%) associations predicted by MFLDA are supported by recent biomedical literature and further proves the capability of MFLDA in identifying novel lncRNA-disease associations. MFLDA is a general data fusion framework, and as such it can be adopted to predict associations between other biological entities. Availability and implementation: The source code for MFLDA is available at: http://mlda.swu.edu.cn/codes.php? name = MFLDA. Contact: gxyu@swu.edu.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228287 TI - Azole-resistant and -susceptible Aspergillus fumigatus isolates show comparable fitness and azole treatment outcome in immunocompetent mice. AB - No data are available on the in vivo impact of infections with in vitro azole resistant Aspergillus fumigatus in immunocompetent hosts. Here, the aim was to investigate fungal fitness and treatment response in immunocompetent mice infected with A. fumigatus (parental strain [ps]) and isogenic mutants carrying either the mutation M220K or G54W (cyp51A). The efficacy of itraconazole (ITC) and posaconazole (PSC) was investigated in mice, intravenously challenged either with a single or a combination of ps and mutants (6 * 105 conidia/mouse). Organ fungal burden and clinical parameters were measured. In coinfection models, no fitness advantage was observed for the ps strain when compared to the mutants (M220K and G54W) independent of the presence or absence of azole-treatment. For G54W, M220K, and the ps, no statistically significant difference in ITC and PSC treatment was observed in respect to fungal kidney burden. However, clinical parameters suggest that in particular the azole-resistant strain carrying the mutation G54W caused a more severe disease than the ps strain. Mice infected with G54W showed a significant decline in body weight and lymphocyte counts, while spleen/body weight ratio and granulocyte counts were increased. In immunocompetent mice, in vitro azole-resistance did not translate into therapeutic failure by either ITC or PSC; the immune system appears to play the key role in clearing the infection. PMID- 29228288 TI - Outcome Measures Used in Pulmonary Rehabilitation in Patients With Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Systematic Review. AB - Background: Conflicting results about the effects of community-based pulmonary rehabilitation in acute exacerbations of chronic obstructive pulmonary disease (AECOPD) exist, possibly because the variety of outcome measures used and the lack of appropriate measurement properties hinder the development of pulmonary rehabilitation guidelines. Purpose: The purpose of this study was to identify and review the measurement properties of patient-reported outcome measures (PROMs) and clinical outcome measures of AECOPD that are used in pulmonary rehabilitation and that can be easily applied in a community setting. Data Sources: PubMed, Web of Science, Scopus, and CINAHL were searched up to July 1, 2016. Study Selection: Phase 1 identified outcome measures used in pulmonary rehabilitation for AECOPD. Phase 2 reviewed the measurement properties of the identified outcome measures. Data Extraction: One reviewer extracted the data and 2 reviewers independently assessed the methodological quality of the studies and the measurement properties of the outcome measures by using the Consensus-Based Standards for the Selection of Health Status Measurement Instruments (COSMIN) recommendations. Data Synthesis: Twenty-three PROMs and 18 clinical outcome measures were found. The outcome measures most used were the St George Respiratory Questionnaire (n = 15/37 studies) and the 6-minute walk test (n = 21/37 studies). Thirty-two studies described the measurement properties of 22 PROMs and 7 clinical outcome measures. The methodological quality of the studies was mostly poor, and the measurement properties were mostly indeterminate. The outcome measure exhibiting more robust properties was the COPD Assessment Test. Limitations: A Number of studies were not found with the validated search strategy used and were included a posteriori; the fact that 3 studies presented combined results- for patients who were stable and patients with exacerbation-affected the conclusions that can be drawn. Conclusions: A Large variety of outcome measures have been used; however, studies on their measurement properties are needed to enhance the understanding of community pulmonary rehabilitation for AECOPD. PMID- 29228289 TI - Clinical Practice Guideline for Physical Therapy Assessment and Treatment in Patients With Nonspecific Neck Pain. AB - The Royal Dutch Society for Physical Therapy (KNGF) issued a clinical practice guideline for physical therapists that addresses the assessment and treatment of patients with nonspecific neck pain, including cervical radiculopathy, in Dutch primary care. Recommendations were based on a review of published systematic reviews.During the intake, the patient is screened for serious pathologies and corresponding patterns. Patients with cervical radiculopathy can be included or excluded through corresponding signs and symptoms and possibly diagnostic tests (Spurling test, traction/distraction test, and Upper Limb Tension Test). History taking is done to gather information about patients' limitations, course of pain, and prognostic factors (eg, coping style) and answers to health-related questions.In case of a normal recovery (treatment profile A), management should be hands-off, and patients should receive advice from the physical therapist and possibly some simple exercises to supplement "acting as usual."In case of a delayed/deviant recovery (treatment profile B), the physical therapist is advised to use, in addition to the recommendations for treatment profile A, forms of mobilization and/or manipulation in combination with exercise therapy. Other interventions may also be considered. The physical therapist is advised not to use dry needling, low-level laser, electrotherapy, ultrasound, traction, and/or a cervical collar.In case of a delayed/deviant recovery with clear and/or dominant psychosocial prognostic factors (treatment profile C), these factors should first be addressed by the physical therapist, when possible, or the patient should be referred to a specialist, when necessary.In case of neck pain grade III (treatment profile D), the therapy resembles that for profile B, but the use of a cervical collar for pain reduction may be considered. The advice is to use it sparingly: only for a short period per day and only for a few weeks. PMID- 29228286 TI - Cut-and-Paste Transposons in Fungi with Diverse Lifestyles. AB - Transposable elements (TEs) shape genomes via recombination and transposition, lead to chromosomal rearrangements, create new gene neighborhoods, and alter gene expression. They play key roles in adaptation either to symbiosis in Amanita genus or to pathogenicity in Pyrenophora tritici-repentis. Despite growing evidence of their importance, the abundance and distribution of mobile elements replicating in a "cut-and-paste" fashion is barely described so far. In order to improve our knowledge on this old and ubiquitous class of transposable elements, 1,730 fungal genomes were scanned using both de novo and homology-based approaches. DNA TEs have been identified across the whole data set and display uneven distribution from both DNA TE classification and fungal taxonomy perspectives. DNA TE content correlates with genome size, which confirms that many transposon families proliferate simultaneously. In contrast, it is independent from intron density, average gene distance and GC content. TE count is associated with species' lifestyle and tends to be elevated in plant symbionts and decreased in animal parasites. Lastly, we found that fungi with both RIP and RNAi systems have more total DNA TE sequences but less elements retaining a functional transposase, what reflects stringent control over transposition. PMID- 29228290 TI - Letter: Primary Modality for Medically Refractory Trigeminal Neuralgia: Microvascular Decompression or Gamma Knife Therapy? PMID- 29228291 TI - The disappearing basal ganglia sign. PMID- 29228292 TI - Recombination directionality factor gp3 binds phiC31 integrase via the zinc domain, potentially affecting the trajectory of the coiled-coil motif. AB - To establish a prophage state, the genomic DNA of temperate bacteriophages normally becomes integrated into the genome of their host bacterium by integrase mediated, site-specific DNA recombination. Serine integrases catalyse a single crossover between an attachment site in the host (attB) and a phage attachment site (attP) on the circularized phage genome to generate the integrated prophage DNA flanked by recombinant attachment sites, attL and attR. Exiting the prophage state and entry into the lytic growth cycle requires an additional phage-encoded protein, the recombination directionality factor or RDF, to mediate recombination between attL and attR and excision of the phage genome. The RDF is known to bind integrase and switch its activity from integration (attP x attB) to excision (attL x attR) but its precise mechanism is unclear. Here, we identify amino acid residues in the RDF, gp3, encoded by the Streptomyces phage phiC31 and within the phiC31 integrase itself that affect the gp3:Int interaction. We show that residue substitutions in integrase that reduce gp3 binding adversely affect both excision and integration reactions. The mutant integrase phenotypes are consistent with a model in which the RDF binds to a hinge region at the base of the coiled-coil motif in phiC31 integrase. PMID- 29228293 TI - Providing Mental Health Care for the Complex Older Veteran: Implications for Social Work Practice. AB - Mental health conditions are underdiagnosed and undertreated in older veterans, as with all older adults. Social workers bring an important perspective to the interdisciplinary team for the care of older veterans with mental health conditions. In this study authors assessed 50 older veterans referred for mental health treatment (mean age = 74.52 years, SD = 6.48) with standardized measures of depression, posttraumatic stress disorder (PTSD), and cognitive impairment. At initial assessment, 24 percent had moderate depression, 30 percent had PTSD, and 62 percent (n = 31) had (mostly mild) cognitive impairment based on cut scores. These conditions were often comorbid with each other and with social (60 percent), retirement (26 percent), bereavement (32 percent), and financial (36 percent) stressors. Depression improved after three months of treatment [t(30) = 2.12, p = .04], but those with comorbid PTSD or social stressors had more depressive symptoms at follow-up [R2 = .36, F(4, 26) = 3.57, p = .02]. Interdisciplinary care is essential to address the multiple comorbidities and practical complexities of geriatric mental health care. Social workers play a valuable role on the interprofessional team in addressing these complexities. PMID- 29228294 TI - Accurate mapping of tRNA reads. AB - Motivation: Many repetitive DNA elements are transcribed at appreciable expression levels. Mapping the corresponding RNA sequencing reads back to a reference genome is notoriously difficult and error-prone task, however. This is in particular true if chemical modifications introduce systematic mismatches, while at the same time the genomic loci are only approximately identical, as in the case of tRNAs. Results: We therefore developed a dedicated mapping strategy to handle RNA-seq reads that map to tRNAs relying on a modified target genome in which known tRNA loci are masked and instead intronless tRNA precursor sequences are appended as artificial 'chromosomes'. In a first pass, reads that overlap the boundaries of mature tRNAs are extracted. In the second pass, the remaining reads are mapped to a tRNA-masked target that is augmented by representative mature tRNA sequences. Using both simulated and real life data we show that our best practice workflow removes most of the mapping artefacts introduced by simpler mapping schemes and makes it possible to reliably identify many of chemical tRNA modifications in generic small RNA-seq data. Using simulated data the FDR is only 2%. We find compelling evidence for tissue specific differences of tRNA modification patterns. Availability and implementation: The workflow is available both as a bash script and as a Galaxy workflow from https://github.com/AnneHoffmann/tRNA-read-mapping. Contact: fabian@tbi.univie.ac.at. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29228295 TI - Assessment of patient safety culture in private and public hospitals in Peru. AB - Objective: To assess the patient safety culture in Peruvian hospitals from the perspective of healthcare professionals, and to test for differences between the private and public healthcare sectors. Patient safety is defined as the avoidance and prevention of patient injuries or adverse events resulting from the processes of healthcare delivery. Design: A non-random cross-sectional study conducted online. Setting: An online survey was administered from July to August 2016, in Peru. This study reports results from Lima and Callao, which are the capital and the port region of Peru. Participants: A total of 1679 healthcare professionals completed the survey. Participants were physicians, medical residents and nurses working in healthcare facilities from the private sector and public sector. Main outcomes: Assessment of the degree of patient safety and 12 dimensions of patient safety culture in hospital units as perceived by healthcare professionals. Results: Only 18% of healthcare professionals assess the degree of patient safety in their unit of work as excellent or very good. Significant differences are observed between the patient safety grades in the private sector (37%) compared to the public sub-sectors (13-15%). Moreover, in all patient safety culture dimensions, healthcare professionals from the private sector give more favorable responses for patient safety, than those from the public sub-systems. The most significant difference in support comes from patient safety administrators through communication and information about errors. Conclusions: Overall, the degree of patient safety in Peru is low, with significant gaps that exist between the private and the public sectors. PMID- 29228296 TI - PAQR4 has a tumorigenic effect in human breast cancers in association with reduced CDK4 degradation. AB - Progestin and adipoQ receptor 4 (PAQR4) is a member of the PAQR family, and the members within this family are involved in the regulation of a number of biological processes including metabolism and cancer development. The potential function of PAQR4 in human cancers is unknown. Analysis of ONCOMINE database reveals that PAQR4 is highly expressed in human breast cancers. We confirmed this finding by analyzing 82 human breast cancers samples. PAQR4 mRNA level was significantly upregulated in human breast cancer samples compared with their corresponding para-cancerous histological normal tissues (P < 0.0001). The mRNA level of PAQR4 was negatively correlated with disease-free survival (P < 0.0001) and overall survival of the patients (P = 0.001). Knockdown of PAQR4 in human breast cancer cells SUM159 and MCF7 suppressed cell proliferation. In contrast, overexpression of PAQR4 in SUM159 cells enhanced cell proliferation and colony formation. In a tumor xenograft model, overexpression of PAQR4 promoted tumor growth of SUM159 cells in vivo, while PAQR4 knockdown suppressed the tumor growth. PAQR4 was able to negatively regulate cyclin-dependent kinases 4 (CDK4) protein level in the breast cancer cells. Knockdown of PAQR4 accelerated degradation of CDK4 together with upregulation of CDK4 polyubiquitination. On the other hand, overexpression of PAQR4 slowed down CDK4 protein degradation and reduced CDK4 polyubiquitination. Collectively, these data at the cellular, animal and human levels indicate that PAQR4 has a tumorigenic effect on human breast cancers, and such effect is associated with a modulatory activity of PAQR4 on protein degradation of CDK4. PMID- 29228297 TI - Density Dependence, Landscape, and Weather Impacts on Aquatic Aedes japonicus japonicus (Diptera: Culicidae) Abundance Along an Urban Altitudinal Gradient. AB - The Asian Bush Mosquito, Aedes (Finlaya) japonicus japonicus (Theobald) is an important globally invasive mosquito species. In comparison with other major invasive mosquitoes, relatively little is known about Ae. j. japonicus population dynamics in the field. Here, we present results from a 54-biweek long study of Ae. j. japonicus abundance in ovitraps set across the altitudinal gradient of Mt. Konpira, Nagasaki, Japan. Spatially, we found that Ae. j. japonicus fourth instar larvae (Aj4il) were more abundant at the base and top of Mt. Konpira and in ovitraps with more platykurtic water temperature (WT) distributions. In contrast, we found that temporally Aj4il were more abundant when ovitrap WT was more leptokurtic with 2 weeks of lag, and with high relative humidity SD with 2 months of lag. We also found that Aj4il were unlikely present when ovitrap WT was below 12.41 degrees C. Parameter estimates for the Ricker model suggested that Ae. j. japonicus population growth was under density-dependence regulation, with a stable population dynamics whose fluctuations were associated with changes in ovitrap WT kurtosis and demographic stochasticity. Our results suggest that Aj4il abundance is more sensitive to temperature changes in kurtosis than mean values, potentially limiting the predictive ability of Ae. j. japonicus niche models based on the increase of average temperatures with global warming, and suggesting this mosquito species has a relatively coarse-grained response to temperature changes. PMID- 29228298 TI - SeedStor: A Germplasm Information Management System and Public Database. AB - SeedStor (https://www.seedstor.ac.uk) acts as the publicly available database for the seed collections held by the Germplasm Resources Unit (GRU) based at the John Innes Centre, Norwich, UK. The GRU is a national capability supported by the Biotechnology and Biological Sciences Research Council (BBSRC). The GRU curates germplasm collections of a range of temperate cereal, legume and Brassica crops and their associated wild relatives, as well as precise genetic stocks, near isogenic lines and mapping populations. With >35,000 accessions, the GRU forms part of the UK's plant conservation contribution to the Multilateral System (MLS) of the International Treaty for Plant Genetic Resources for Food and Agriculture (ITPGRFA) for wheat, barley, oat and pea. SeedStor is a fully searchable system that allows our various collections to be browsed species by species through to complicated multipart phenotype criteria-driven queries. The results from these searches can be downloaded for later analysis or used to order germplasm via our shopping cart. The user community for SeedStor is the plant science research community, plant breeders, specialist growers, hobby farmers and amateur gardeners, and educationalists. Furthermore, SeedStor is much more than a database; it has been developed to act internally as a Germplasm Information Management System that allows team members to track and process germplasm requests, determine regeneration priorities, handle cost recovery and Material Transfer Agreement paperwork, manage the Seed Store holdings and easily report on a wide range of the aforementioned tasks. PMID- 29228299 TI - Development of cell-penetrating bispecific antibodies targeting the N-terminal domain of androgen receptor for prostate cancer therapy. AB - Castration-resistant prostate cancer cells exhibit continued androgen receptor signaling in spite of low levels of ligand. Current therapies to block androgen receptor signaling act by inhibiting ligand production or binding. We developed bispecific antibodies capable of penetrating cells and binding androgen receptor outside of the ligand-binding domain. Half of the bispecific antibody molecule consists of a single-chain variable fragment of 3E10, an anti-DNA antibody that enters cells. The other half is a single-chain variable fragment version of AR441, an anti-AR antibody. The resulting 3E10-AR441 bispecific antibody enters human LNCaP prostate cells and accumulates in the nucleus. The antibody binds to wild-type, mutant and splice variant androgen receptor. Binding affinity of 3E10 AR441 to androgen receptor (284 nM) was lower than that of the parental AR441 mAb (4.6 nM), but could be improved (45 nM) through alternative placement of the affinity tags, and ordering of the VH and VK domains. The 3E10-AR441 bispecific antibody blocked genomic signaling by wild-type or splice variant androgen receptor in LNCaP cells. It also blocked non-genomic signaling by the wild-type receptor. Furthermore, bispecific antibody inhibited the growth of C4-2 prostate cancer cells under androgen-stimulated conditions. The 3E10-AR441 biAb can enter prostate cancer cells and inhibits androgen receptor function in a ligand independent manner. It may be an attractive prototype agent for prostate cancer therapy. PMID- 29228300 TI - DNA synthesis by fragment assembly using extra-cellular DNA delivered by artificial controlled horizontal transfer. AB - DNA synthesis in the Bacillus subtilis cells has become possible using extra cellular DNA. Generally, purified DNAs in a test tube have been required to introduce into the host cells for molecular cloning technology in the laboratory. We have developed a cell lysis technique for natural transformation using stable extra-cellular plasmid DNAs, in which the extra-cellular plasmid DNAs are released from lysed Escherichia coli cells. DNA synthesis then proceeds by fragment assembly using the stable extracellular DNAs, without biochemical purification. DNA synthesis of the mouse mitochondrial genome in B. subtilis genome was illustrated using four E. coli strains with plasmid DNAs carrying contiguous DNA fragments. In the natural environment, unpurified extra-cellular DNAs contribute to the gene delivery during horizontal gene transfer (HGT). The technology introduced in the present study mimics HGT and should have a wide range of applications. PMID- 29228301 TI - Targeted inhibition of Janus kinases abates interfon gamma-induced invasive behaviour of fibroblast-like synoviocytes. AB - Objectives: The aim was to explore the function of the T-cell cytokine IFNgamma for mesenchymal tissue remodelling in RA and to determine whether IFNgamma signalling controls the invasive potential of fibroblast-like synoviocytes (FLS). Methods: To assess architectural responses, FLS were cultured in three dimensional micromasses. FLS motility was analysed in migration and invasion assays. Signalling events relevant to cellular motility were defined by western blots. Baricitinib and small interfering RNA pools were used to suppress Janus kinase (JAK) functions. Results: Histological analyses of micromasses revealed unique effects of IFNgamma on FLS shape and tissue organization. This was consistent with accelerated migration upon IFNgamma stimulation. Given that cell shape and cell motility are under the control of the focal adhesion kinase (FAK), we next analysed its activity. Indeed, IFNgamma stimulation induced the phosphorylation of FAK-Y925, a phosphosite implicated in FAK-mediated cell migration. Small interfering RNA knockdown of JAK2, but not JAK1, substantially abrogated FAK activation by IFNgamma. Correspondingly, IFNgamma-induced FAK activation and invasion of FLS was abrogated by the JAK inhibitor, baricitinib. Conclusion: Our study contributes insight into the synovial response to IFNgamma and reveals JAK2 as a potential therapeutic target for FLS-mediated joint destruction in arthritis, especially in RA. PMID- 29228302 TI - Susceptibility of HLA-E*01:03 Allele Carriers to Develop Cytomegalovirus Replication After Living-Donor Kidney Transplantation. AB - Cytomegalovirus (CMV) causes serious complications among solid organ transplant recipients. We report the positive correlation between the presence of the HLA E*01:03 allele in living-donor kidney recipients and CMV reactivation during the first year after transplantation. Thus, HLA-E genotyping may help identify CMV replication-prone patients who require individualized patient-based CMV management. PMID- 29228303 TI - Identifying Possible Pheromones of Cerambycid Beetles by Field Testing Known Pheromone Components in Four Widely Separated Regions of the United States. AB - The pheromone components of many cerambycid beetles appear to be broadly shared among related species, including species native to different regions of the world. This apparent conservation of pheromone structures within the family suggests that field trials of common pheromone components could be used as a means of attracting multiple species, which then could be targeted for full identification of their pheromones. Here, we describe the results of such field trials that were conducted in nine states in the northeastern, midwestern, southern, and western United States. Traps captured 12,742 cerambycid beetles of 153 species and subspecies. Species attracted in significant numbers to a particular treatment (some in multiple regions) included 19 species in the subfamily Cerambycinae, 15 species in the Lamiinae, one species in the Prioninae, and two species in the Spondylidinae. Pheromones or likely pheromones for many of these species, such as 3-hydroxyhexan-2-one and syn- and anti-2,3-hexanediols for cerambycine species, and fuscumol and/or fuscumol acetate for lamiine species, had already been identified. New information about attractants (in most cases likely pheromone components) was found for five cerambycine species (Ancylocera bicolor [Olivier], Elaphidion mucronatum [Say], Knulliana cincta cincta [Drury], Phymatodes aeneus LeConte, and Rusticoclytus annosus emotus [Brown]), and five lamiine species (Ecyrus dasycerus dasycerus [Say], Lepturges symmetricus [Haldeman], Sternidius misellus [LeConte], Styloleptus biustus biustus [LeConte], and Urgleptes signatus [LeConte]). Consistent attraction of some species to the same compounds in independent bioassays demonstrated the utility and reliability of pheromone-based methods for sampling cerambycid populations across broad spatial scales. PMID- 29228304 TI - JPP Student Journal Club Commentary: Toward a More Complete Understanding of Disruption and Resilience Among Latino and Non-Latino White Youth With Spina Bifida. PMID- 29228305 TI - Familial Cancer Clustering in Urothelial Cancer: A Population-Based Case-Control Study. AB - Background: Family history of bladder cancer confers an increased risk for concordant and discordant cancers in relatives. However, previous studies investigating this relationship lack any correction for smoking status of family members. We conducted a population-based study of cancer risks in relatives of bladder cancer patients and matched controls with exclusion of variant subtypes to improve the understanding of familial cancer clustering. Methods: Case subjects with urothelial carcinoma were identified using the Utah Cancer Registry and matched 1:5 to cancer-free controls from the Utah Population Database. Cox regression was used to determine the risk of cancer in first-degree relatives, second-degree relatives, first cousins, and spouses. A total of 229 251 relatives of case subjects and 1 197 552 relatives of matched control subjects were analyzed. To correct for smoking status, we performed a secondary analysis excluding families with elevated rates of smoking-related cancers. All statistical tests were two-sided. Results: First- and second-degree relatives of case subjects had an increased risk for any cancer diagnosis (hazard ratio [HR] = 1.06, 95% confidence interval [CI] = 1.03 to 1.09, P < .001; HR = 1.04, 95% CI = 1.02 to 1.07, P = .001) and urothelial cancer (HR = 1.73, 95% CI = 1.50 to 1.99, P < .001; HR = 1.35, 95% CI = 1.21 to 1.51, P < .001). Site-specific analysis found increased risk for bladder (HR = 1.69, 95% CI = 1.47 to 1.95, P < .001), kidney (HR = 1.30, 95% CI = 1.08 to 1.57, P = .006), cervical (HR = 1.25, 95% CI = 1.06 to 1.49, P = .01), and lung cancer (HR = 1.34, 95% CI = 1.19 to 1.51, P < .001) in first-degree relatives. Second-degree relatives had increased risk for bladder (HR = 1.35, 95% CI = 1.2 to 1.5, P < .001) and thyroid cancer (HR = 1.18, 95% CI = 1.03 to 1.35, P = .02). Spouses showed an increased risk for laryngeal (HR = 2.68, 95% CI = 1.02 to 7.05, P = .04) and cervical cancer (HR = 1.57, 95% CI = 1.13 to 2.17, P = .007). These results did not substantively change after correction for suspected smoking behaviors. Conclusion: Our results suggest familial urothelial cancer clustering independent of smoking, with increased risk in relatives for both concordant and discordant cancers, suggesting shared genetic or environmental roots. Identifying families with statistically significant risks for non-smoking-related urothelial cancer would be extremely informative for genetic linkage studies. PMID- 29228306 TI - 25S rDNA genotype and antifungal susceptibility of clinical Candida albicans in Ouagadougou (Burkina Faso). AB - The present investigation aimed to assess the prevalence of genotypes of C. albicans in Ouagadougou and to analyze the relationship between the genetic diversity and antifungal susceptibility. Ninety-six clinical strains are included. They were diagnosed as C. albicans using germ tube test, chlamydospore formation, and Api-Candida test. Genotyping was performed using PCR targeting 25S rDNA. Antifungal susceptibilities were tested based on the disk diffusion method. The genotypes A (85.4%) was predominant followed by genotypes B (10.4%) and C (4.2%). The highest resistance rate with genotype A was obtained with fluconazole (74.4%). A resistance to amphotericin B was observed with genotypes A (29.3%) and B (30%). PMID- 29228307 TI - Superordinate Precision: An Examination of Academic Writing Among Bilingual Deaf and Hard of Hearing Students. AB - Academic English is an essential literacy skill area for success in post secondary education and in many work environments. Despite its importance, academic English is understudied with deaf and hard of hearing (DHH) students. Nascent research in this area suggests that academic English, alongside American Sign Language (ASL) fluency, may play an important role in the reading proficiency of DHH students in middle and high school. The current study expands this research to investigate academic English by examining student proficiency with a sub-skill of academic writing called superordinate precision, the taxonomical categorization of a term. Currently there is no research that examines DHH students' proficiency with superordinate precision. Middle and high school DHH students enrolled in bilingual schools for the deaf were assessed on their ASL proficiency, academic English proficiency, reading comprehension, and use of superordinate precision in definitions writing. Findings indicate that student use of superordinate precision in definitions writing was correlated with ASL proficiency, reading comprehension, and academic English proficiency. It is possible that degree of mastery of superordinate precision may indicate a higher overall level of proficiency with academic English. This may have important implications for assessment of and instruction in academic English literacy. PMID- 29228308 TI - RXRalpha-enriched cancer stem cell-like properties triggered by CDDP in head and neck squamous cell carcinoma (HNSCC). AB - Retinoid X receptor-alpha (RXRalpha) is a kind of nuclear receptor and is a target of cancer prevention and treatment in various types of cancers. Cancer stem cells (CSCs) are regarded as the main cause of carcinoma metastasis, tumor recurrence and chemotherapy resistance. So far, the mechanism how RXRalpha regulates CSCs remains unknown. In the present study, we found that RXRalpha was upregulated in head and neck squamous cell carcinoma (HNSCC) tissues and the enriched HNSCC CSCs. Overexpression of RXRalpha was able to expand the CSC-like properties in HNSCC cells, whereas knockdown of RXRalpha could repress the stemness respectively. Meanwhile, low doses of cisplatin (CDDP) increased the CSC like properties and RXRalpha expression in HNSCC cells. Also, Wnt signaling pathway played a significant role in CDDP-induced CSCs. Simultaneously, curcumin, a plant polyphenol, which is an effective anticancer compound, exhibited an inhibitory effect in the HNSCC CSCs induced by CDDP in vitro and in vivo. Via inhibition of RXRalpha, curcumin suppressed CSC-like phenotypes induced by CDDP. These findings may suggest a novel mechanism for HNSCC treatment. PMID- 29228309 TI - PRP8 intein in dermatophytes: Evolution and species identification. AB - Dermatophytes are keratinophilic fungi belonging to the family Arthrodermataceae. Despite having a monophyletic origin, its systematics has always been complex and controversial. Sequencing of nuclear ribosomal ITS and D1/D2 rDNA has been proposed as an efficient tool for identifying species in this group of fungi, while multilocus analyses have been used for phylogenetic species recognition. However, the search for new markers, with sequence and size variation, which enable species identification in only one polymerase chain reaction (PCR) step, is very attractive. Inteins seems to fulfill these characteristics. They are self splicing genetic elements present within housekeeping coding genes, such as PRP8, that codify the most important protein of the spliceosome. The PRP8 intein has been described for Microsporum canis in databases but has not been studied in dermatophytes in any other published work. Thus, our aim was to determine the potential of this intervening element for establishing phylogenetic relationships among dermatophytes and for identifying species. It was found that all studied species have a full-length PRP8 intein with a Homing Endonuclease belonging to the family LAGLIDADG. Phylogenetic analyses were consistent with other previous phylogenies, confirming Epidermophyton floccosum in the same clade of the Arthroderma gypseum complex, Microsporum audouinii close to M. canis, differentiating A. gypseum from Arthroderma incurvatum, and in addition, better defining the Trichophyton interdigitale and Trichophyton rubrum species grouping. Length polymorphism in the HE region enables identification of the most relevant Microsporum species by a simple PCR-electrophoresis assay. Intein PRP8 within dermatophytes is a powerful additional tool for identifying and systematizing dermatophytes. PMID- 29228310 TI - Concomitant atrial fibrillation surgery: worth the effort? AB - Concomitant surgery for atrial fibrillation is a conceptually and clinically difficult area of cardiac surgical decision making. This review introduces the pathophysiological background, provides insight and guidance for cardiac surgeons on some of the conflicting evidence and claims, and explores the fields in which further research may help elucidate a cardiac surgical clinical strategy for tackling this common and potentially lethal form of arrhythmia. PMID- 29228311 TI - A new method for post-translationally labeling proteins in live cells for fluorescence imaging and tracking. AB - We present a novel method to fluorescently label proteins, post-translationally, within live Saccharomycescerevisiae. The premise underlying this work is that fluorescent protein (FP) tags are less disruptive to normal processing and function when they are attached post-translationally, because target proteins are allowed to fold properly and reach their final subcellular location before being labeled. We accomplish this post-translational labeling by expressing the target protein fused to a short peptide tag (SpyTag), which is then covalently labeled in situ by controlled expression of an open isopeptide domain (SpyoIPD, a more stable derivative of the SpyCatcher protein) fused to an FP. The formation of a covalent bond between SpyTag and SpyoIPD attaches the FP to the target protein. We demonstrate the general applicability of this strategy by labeling several yeast proteins. Importantly, we show that labeling the membrane protein Pma1 in this manner avoids the mislocalization and growth impairment that occur when Pma1 is genetically fused to an FP. We also demonstrate that this strategy enables a novel approach to spatiotemporal tracking in single cells and we develop a Bayesian analysis to determine the protein's turnover time from such data. PMID- 29228312 TI - Susceptibility of Lobesia botrana (Lepidoptera: Tortricidae) to chlorantraniliprole in the Emilia Romagna Region of Northeast Italy. AB - The European grapevine moth, Lobesia botrana (Denis & Schiffermuller) (Lepidoptera: Tortricidae), is regarded as the most important insect pest of wine grapes in Europe. If not properly controlled, it can cause significant direct and indirect yield losses due to secondary infections of grape berries by Botrytis cinerea. For these reasons, it is important to preserve the activity of insecticides used against this pest, as the number of insecticidal mode of actions available to control Lepidoptera species on wine grapes in Europe is limited. Following a report of suboptimal control of L. botrana after field applications of chlorantraniliprole-containing products, an extensive monitoring program was conducted in the Emilia Romagna Region of North East Italy to determine L. botrana susceptibility to chlorantraniliprole. This study consisted of 11 bioassays conducted with chlorantraniliprole on L. botrana populations collected in the Emilia Romagna Region in 2014-2016, 5-7 years after its introduction into the market. Bioassay results were compared to results previously obtained from the chlorantraniliprole pre-comercialization baseline susceptibility survey conducted from 2007 to 2011. The Lethal Concentration values obtained for field populations of L. botrana in this study are comparable to those reported for the pre-comercialization susceptibility baseline. We demonstrate that there is no significant change in L. botrana susceptibility to chlorantraniliprole in the Emilia Romagna Region. Emphasis should be given to implement appropriate insecticide resistance management strategies, including nonchemical agronomic practices and biological control methods, to preserve effective insecticides like chlorantraniliprole for future use in controlling the European grapevine moth. PMID- 29228313 TI - Transfusion of red blood cells in coronary surgery: is there an effect on long term mortality when adjusting for risk factors and postoperative complications? AB - OBJECTIVES: The aim of this study was to compare long-term mortality in patients undergoing primary isolated coronary artery bypass grafting who received >=1 units of red blood cells (RBCs) or no RBCs. We hypothesized that a possible difference in long-term mortality was due to preoperative morbidity and/or postoperative morbidity. METHODS: This prospective cohort study, part of the Cardiac Surgery Outcome Study (CaSOS) at St. Olavs University Hospital, Trondheim, Norway, included patients operated on from 2000 through 2014 (n = 4014) and excluded those with large intra- or postoperative blood loss or 30-day mortality. Observed mortality from 30 days to 15 years postoperatively was compared between patients who received RBC transfusion and those who did not. Cox regression analysis was performed with unadjusted models, adjusting for pre- and intraoperative covariates, and with further adjustment for postoperative complications. Sensitivity analyses were performed with propensity score matching or including 30-day mortality. RESULTS: The unadjusted hazard ratio (HR) for long term mortality was 2.10 (1.81-2.43; P < 0.01) for transfused patients. After adjusting for pre- and intraoperative variables, the HR was 1.26 (1.04-1.53; P = 0.02). With further adjustment for postoperative complications, RBC transfusion was no longer significant and the HR was 1.19 (0.98-1.44; P = 0.08). These results were supported by the sensitivity analyses. CONCLUSIONS: The study indicated that most of the association between RBC transfusion and long-term mortality following primary isolated coronary artery bypass grafting was due to confounders, especially from postoperative complications. PMID- 29228314 TI - Demodifying RNA for Transcriptomic Analyses of Archival Formalin-Fixed Paraffin Embedded Samples. AB - Archival formalin-fixed paraffin-embedded (FFPE) tissue samples offer a vast but largely untapped resource for genomic research. The primary technical issues limiting use of FFPE samples are RNA yield and quality. In this study, we evaluated methods to demodify RNA highly fragmented and crosslinked by formalin fixation. Primary endpoints were RNA recovery, RNA-sequencing quality metrics, and transcriptional responses to a reference chemical (phenobarbital, PB). Frozen mouse liver samples from control and PB groups (n = 6/group) were divided and preserved for 3 months as follows: frozen (FR); 70% ethanol (OH); 10% buffered formalin for 18 h followed by ethanol (18F); or 10% buffered formalin (3F). Samples from OH, 18F, and 3F groups were processed to FFPE blocks and sectioned for RNA isolation. Additional sections from 3F received the following demodification protocols to mitigate RNA damage: short heated incubation with Tris-Acetate-EDTA buffer; overnight heated incubation with an organocatalyst using 2 different isolation kits; or overnight heated incubation without organocatalyst. Ribo-depleted, stranded, total RNA libraries were built and sequenced using the Illumina HiSeq 2500 platform. Overnight incubation (+/- organocatalyst) increased RNA yield >3-fold and RNA integrity numbers and fragment analysis values by > 1.5- and >3.0-fold, respectively, versus 3F. Postsequencing metrics also showed reduced bias in gene coverage and deletion rates for overnight incubation groups. All demodification groups had increased overlap for differentially expressed genes (77%-84%) and enriched pathways (91% 97%) with FR, with the highest overlap in the organocatalyst groups. These results demonstrate simple changes in RNA isolation methods that can enhance genomic analyses of FFPE samples. PMID- 29228315 TI - Comparison of Neoadjuvant Nab-Paclitaxel+Carboplatin vs Nab Paclitaxel+Gemcitabine in Triple-Negative Breast Cancer: Randomized WSG-ADAPT-TN Trial Results. AB - Background: Pathological complete response (pCR) is associated with improved prognosis in triple-negative breast cancer (TNBC). The optimal chemotherapy regimen is unclear. Weekly nab-paclitaxel vs conventional paclitaxel or addition of carboplatin to anthracycline-taxane results in higher pCR rates with uncertain survival impact. We evaluated carboplatin vs gemcitabine with a nab-paclitaxel backbone as a short 12-week A-free regimen with a focus on early response. Methods: Patients with TNBC (estrogen receptor/progesterone receptor < 1%, human epidermal growth factor receptor 2-negative, cT1c-cT4c, cN0/+) were randomly assigned to A: nab-paclitaxel 125 mg/m2/gemcitabine 1000 mg/m2 d1,8 three times weekly (q3w); vs B: nab-paclitaxel 125 mg/m2/carboplatin AUC2 day 1,8 q3w. The trial was powered for a pCR (ypT0/is ypN0) comparison by therapy arm and early response (defined as Ki-67 decrease >30% or < 500 invasive tumor cells in the three-week serial biopsy). All statistical tests were two-sided. Results: A total of 336 patients were enrolled (48 centers, arms A/B: n = 182/154). The median age was 50 years. At baseline (A vs B), 62.6% and 62.9% had cT2-4c tumors; 86.8% and 90.9% completed therapy per protocol, respectively. pCR favored arm B (28.7%, 95% CI = 0.22 to 0.36, vs 45.9%, 95% CI = 0.38 to 0.54; 95% CI(dBA) = 6.2% to 27.9%, P = .002) and was lower in nonresponders than in early responders (19.5% vs 44.4%, P < .001) or in patients with unclassifiable early response (50.0%). The nab-paclitaxel/gemcitabine was associated with more frequent dose reductions (20.6% vs 11.9%, P = .04), treatment-related serious adverse events (11.1% vs 5.3%, P = .07), grade 3-4 infections (7.2% vs 2.6%, P = .07), and grade 3-4 ALAT elevations (11.7 vs 3.3%, P = .01). Conclusions: This first large randomized trial suggests high efficacy and excellent tolerability of a neoadjuvant nab paclitaxel/carboplatin regimen, superior to nab-paclitaxel/gemcitabine in TNBC. De-escalation of further chemotherapy in patients with early pCR after a short anthracycline-free regimen is a promising field of future research. Early necrotic morphological changes and/or proliferation decrease after the first therapy cycle seem to be associated with subsequent pCR. PMID- 29228316 TI - Identification of a Critical Window for Ganciclovir-Induced Disruption of Testicular Development in Rats. AB - Ganciclovir (GCV) has been implicated in the development of testicular alterations. Exposure on gestational day (GD) 10 in rats induced permanent effects, including focal reduction or absence of germ cells (Sertoli cell-only tubules). Because the timing of exposure can be critical for testicular effects, we exposed rat dams to 300 mg/kg GCV (3 100 mg/kg subcutaneous injections) on GD10, 14 and 19, when germ cells have high rates of migration, proliferation and are mitotically quiescent, respectively. Males exposed to GCV in utero on GD10 and 14 were evaluated for androgenization markers, serum and fecal androgens, and testicular histomorphometry at adulthood. Double-labeling immunofluorescence for DAZL and Ki67 were used to assess gonocytes number and the proliferative activity of germ and somatic cells in fetal testes on GD15 and 20, ie, 24 h after GCV exposure. Adult rats exposed on GD14 showed delayed puberty onset, despite normal androgen levels. Also, there was a 50% reduction in testicular weight and about 30% of seminiferous tubules lacking germ cells. Effects on GD10 animals were less pronounced. In the fetal testis, the number of gonocytes was reduced by 50% in rats exposed on GD14, but normal in GD19 fetuses. GCV also reduced Sertoli cell proliferation immunolabeling in GD19 fetuses and Sertoli cell number in adults. In conclusion, GCV toxicity on germ cells seems to be linked to their proliferation rate and GD14 is a critical window in rats, when GCV exposure causes an acute massive loss of germ cells that persists until adulthood. PMID- 29228318 TI - Microcystin-Leucine-Arginine Induces Tau Pathology Through Balpha Degradation via Protein Phosphatase 2A Demethylation and Associated Glycogen Synthase Kinase 3beta Phosphorylation. AB - Microcystin-leucine-arginine (MC-LR) has been implicated as a potential environmental factor in Alzheimer's disease because of its potent inhibition of protein phosphatase 2A (PP2A) activity, but experimental evidence to support its detailed neurotoxic effects and their underlying mechanisms has been lacking. The present study investigated the role of PP2A catalytic subunit (PP2Ac) demethylation and its link with glycogen synthase kinase-3beta (GSK)-3beta in tau hyperphosphorylation induced by MC-LR. The results showed that MC-LR treatment significantly increased demethylation of PP2Ac, with a concomitant increase in GSK-3beta phosphorylation at Ser9 resulting in elevated tau hyperphosphorylation at PP2A-favorable sites in SH-SY5Y cells and rat hippocampus. Coimmunoprecipitation experiments showed that MC-LR treatment dissociated PP2Ac from Balpha, making it incompetent in binding tau, thus causing tau hyperphosphorylation. Moreover, we found that inhibition of PP2A resulted in an increase in phosphorylation of GSK-3beta at Ser9 and a decrease in GSK-3beta activity, which further promoted demethylation of PP2Ac induced by MC-LR. These findings suggest a scenario in which MC-LR-mediated demethylation of PP2Ac is associated with GSK-3beta phosphorylation at Ser9 and contributes to dissociation of Balpha from PP2Ac, which would result in Balpha degradation and disruption of PP2A/Balpha-tau interactions, thus promoting tau hyperphosphorylation and paired helical filaments-tau accumulation and, consequently, axonal degeneration and cell death. PMID- 29228319 TI - Letter to the Editor Regarding Albert O. et al. (2017). Identifying Greener and Safer Plasticizers: A Four-Step Approach. PMID- 29228317 TI - Leukocyte Telomere Length at Birth and During the Early Life of Children Exposed to but Uninfected With HIV After In Utero Exposure to Antiretrovirals. AB - Background: Maternal combination antiretroviral therapy (cART) during pregnancy could impact the health of human immunodeficiency virus (HIV)-exposed, HIV uninfected (HEU) children, because some antiretrovirals cross the placenta and can inhibit telomerase. Our objective was to compare leukocyte telomere length (LTL) in HEU children and HIV-unexposed, HIV-uninfected (HUU) children at birth and in early life and to investigate any relationship with cART exposure. Methods: HEU and HUU children's blood LTL was compared cross-sectionally at birth, and during the first three years of life. Longitudinal HEU LTL dynamics was evaluated over that same period. Results: At birth, the LTL in HEU children (n = 114) was not shorter than that in HUU children (n = 86), but female infants had longer LTL than male infants. Maternal cART (duration or type) showed no association with shorter infant LTL. Among 214 HEU children age- and sex-matched at a 1:1 ratio to HUU children, LTL declined similarly in both groups. In a longitudinal analysis, LTL attrition in HEU children was rapid from birth to 1 year of age and gradual thereafter. Zidovudine prophylaxis did not significantly alter LTL. Conclusions: Our results indicate that from birth to 3 years of age, the LTL in HEU children is not negatively affected by exposure to maternal HIV infection and cART, at least not to the regimens used within this Canadian cohort, a reassuring finding. PMID- 29228320 TI - Overexpression of ZRF1 is related to tumor malignant potential and a poor outcome of gastric carcinoma. AB - Zuotin-related factor 1 (ZRF1) is a recently characterized epigenetic factor involved in transcriptional regulation and is highly overexpressed in several malignancies, but it is not known whether it plays a role in gastric cancer (GC). In this study, we investigated whether ZRF1 acts as a cancer-promoting gene through its activation/overexpression in GC. We analyzed five GC cell lines and 133 primary tumors, which had been curatively resected in our hospital between 2001 and 2003. Overexpression of ZRF1 was detected in GC cell lines (four out of five lines, 80.0%) and was detected in primary tumor samples of GC (52 out of 133 cases, 39.1%) and significantly correlated with differentiated histological type, venous invasion, lymphatic invasion, advanced stage and a higher recurrence rate. ZRF1-overexpressing tumors had a worse survival rate than those with non expressing tumors (P < 0.01, log-rank test). ZRF1 positivity was independently associated with a worse outcome in the multivariate analysis (P < 0.01; hazard ratio 4.92; 95% confidence interval: 1.6-21.1). In ZRF1-overexpressing GC cells, knockdown of ZRF1 using specific siRNAs inhibited the cell proliferation, migration and invasion and induced apoptosis in a p53-dependent manner. These findings suggest that ZRF1 plays a crucial role in tumor malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC. PMID- 29228321 TI - A conceptual framework for understanding the mechanism of action of community health workers services: the centrality of social support. AB - Objective: To propose an empirically derived and theoretically-informed mechanism to explain how Community Health Workers (CHWs) bring about health gain in clients in England. Methods: We undertook in-depth interviews (n = 43) with CHWs and service staff working in four case studies selected using maximum variation sampling. Interviewees were encouraged to talk about the service, how they had become involved with the service, the CHW role and relationship with clients. Findings: We identified the provision of social support to be central to the mechanism of CHW-mediated health gain. Appropriate social support provision comprised three inter-related elements; needs assessment, social support delivery and client engagement. This mechanism is dependent on the personal characteristics of CHWs and of the roles they are employed or volunteer to carry out. Conclusion: A range of CHW characteristics can influence the social support process, but these are context-dependent and move beyond simple notions of CHW similarity to the client. This finding has important policy implications for the development and implementation of CHW services in high income countries with super-diverse populations. PMID- 29228322 TI - TLR9 stimulation induces increase in fungicidal activity of human dendritic cells challenged with Paracoccidioides brasiliensis. AB - Microorganisms killing by dendritic cells (DCs) is an important effector mechanism during innate immune response, as it can avoid dissemination of infection during migration of these cells toward draining lymph nodes. However, this function depends on pattern recognition receptors (PRRs) to which the microorganism will bind in these cells. Regarding this, TLR9 activation, by stimulating the oxidative metabolism, induces increase in microbicidal activity of these cells. Accordingly, we showed that DCs treatment with a TLR9 agonist results in an increase in fungicidal activity of these cells against the fungus Paracoccidioides brasiliensis (Pb), which however, was not associated to higher H2O2 levels. PMID- 29228323 TI - Evaluation of a genus-specific ELISA and a commercial Aspergillus Western blot IgG(r) immunoblot kit for the diagnosis of aspergillosis in common bottlenose dolphins (Tursiops truncatus). AB - Aspergillosis is a fungal infection with high mortality and morbidity rates. As in humans, its definitive diagnosis is difficult in animals, and thus new laboratory tools are required to overcome the diagnostic limitations due to low specificity and lack of standardization. In this study of common bottlenose dolphins (Tursiops truncatus), we evaluated the diagnostic performance of a new commercial immunoblot kit that had been initially developed for the serologic diagnosis of chronic aspergillosis in humans. Using this in a quantitative approach, we first established its positive cutoff within an observation cohort of 32 serum samples from dolphins with "proven" or "probable" diagnosis of aspergillosis and 55 negative controls. A novel enzyme-linked immunosorbent assay (ELISA) test was also developed for detecting anti-Aspergillus antibodies, and results were compared between the two assays. Overall, the diagnostic performance of immunoblot and ELISA were strongly correlated (P < .0001). The former showed lower sensitivity (65.6% versus 90.6%), but higher specificity (92.7% vs. 69.1%), with no cross-reaction with other fungal infections caused by miscellaneous non Aspergillus genera. When assessing their use in a validation cohort, the immunoblot kit and the ELISA enabled positive diagnosis before mycological cultures in 42.9% and 33.3% subjects addressed for suspicion of aspergillosis, respectively. There was also significant impact of antifungal treatment on the results of the two tests (P < .05). In all, these new serological methods show promise in aiding in the diagnosis of aspergillosis in dolphins, and illustrate the opportunity to adapt commercial reagents directed for human diagnostics to detect similar changes in other animals. PMID- 29228325 TI - Episodic Migraine and White Matter Hyperintensities: Association of Pain Lateralization. AB - Background: Migraine pathophysiology involves a neuronal mechanism that is closely associated with the neuronal activation of peripheral trigeminal nociceptive pathways. It also involves a vascular mechanism that is supported by studies concerning the presence of migraine with aura in various vascular diseases. Migraine is associated with silent infarct-like lesions and white matter hyperintensities (WMHs) that can be encountered during magnetic resonance imaging. In this study, we aimed to demonstrate the migraine-WMH link based on pain lateralization. Methods: We recruited 628 episodic migraine patients and examined their cranial magnetic resonance images regarding the presence of deep, subcortical, and periventricular WMHs. We sought to identify an association between lesion occurrence and pain side. Results: We found that the patients had more deep/subcortical hyperintensities in the cerebral hemisphere that was ipsilateral to the pain side (k = 0.421). Periventricular hyperintensities were not associated with the pain side (P = 0.768). Conclusions: Based on our study results, we concluded that pain in episodic migraine is associated with the occurrence of WMHs in the cerebral hemispheres. PMID- 29228324 TI - USP9X controls translation efficiency via deubiquitination of eukaryotic translation initiation factor 4A1. AB - Controlling translation initiation is an efficient way to regulate gene expression at the post-transcriptional level. However, current knowledge regarding regulatory proteins and their modes of controlling translation initiation is still limited. In this study, we employed tandem affinity purification and mass spectrometry to screen for unknown proteins associated with the translation initiation machinery. Ubiquitin specific peptidase 9, X-linked (USP9X), was identified as a novel binding partner, that interacts with the eukaryotic translation initiation factor 4B (eIF4B) in a mRNA-independent manner. USP9X-deficient cells presented significantly impaired nascent protein synthesis, cap-dependent translation initiation and cellular proliferation. USP9X can selectively alter the translation of pro-oncogenic mRNAs, such as c-Myc and XIAP. Moreover, we found that eIF4A1, which is primarily ubiquitinated at Lys-369, is the substrate of USP9X. USP9X dysfunction increases the ubiquitination of eIF4A1 and enhances its degradation. Our results provide evidence that USP9X is a novel regulator of the translation initiation process via deubiquitination of eIF4A1, which offers new insight in understanding the pivotal role of USP9X in human malignancies and neurodevelopmental disorders. PMID- 29228326 TI - Three-dimensional printing: to guide management of a right coronary artery to left ventricular fistula. PMID- 29228328 TI - Hypervascular Vestibular Schwannomas: Clinical Characteristics, Angiographical Classification, and Surgical Considerations. AB - BACKGROUND: There is a rare type of vestibular schwannoma, scarcely discussed in the literature, known as a hypervascular vestibular schwannoma (HVS). OBJECTIVE: To evaluate its biological characteristics, angiographical classification, surgical outcomes, and the significance for surgical consideration, using a large series of this clinical entity. METHODS: The definition for HVS in this study was the tumor stain from the vertebrobasilar system (VBS) in angiography. The authors conducted a retrospective analysis of 36 patients who were angiographically diagnosed with HVS and underwent surgery between 2008 and 2015. Their biological findings and their surgical outcomes were compared with non-HVS subjects. With regard to the tumor feeders and AV shunt, we classified HVS into 5 types. RESULTS: HVS occurred more commonly in younger subjects (mean: 39.4 yr), as a larger solid tumor with multiple flow voids (mean: 34.1 mm), and involved higher levels of cerebrospinal fluid protein (mean: 202 mg/dl) and a higher MIB1-index (mean: 4.3%). The average resection rate for these 36 cases was 95.3%, and recurrence was seen in 6 cases (16.7%). Compared with non-HVS, the extent of tumor resection was significantly lower, and the recurrence rate was significantly higher. Especially in HVS type 2B (the tumor stain is fed by the VBS and the external carotid artery, with an arteriovenous shunt from the VBS), the recurrence-free survival duration was significantly shorter compared with other HVS types and non-HVS, and HVS type 2B exhibited an identifiable risk factor for recurrence. CONCLUSION: HVS have the distinct clinical characteristics compared with those of non-HVS subjects. PMID- 29228327 TI - Most m6A RNA modifications in protein-coding regions are evolutionarily unconserved and likely nonfunctional. AB - Methylation of the adenosine base at the nitrogen-6 position (m6A) is the most prevalent internal posttranscriptional modification of mRNAs in many eukaryotes. Despite the rapid progress in the transcriptome-wide mapping of m6As, identification of proteins responsible for writing, reading, and erasing m6As, and elucidation of m6A functions in splicing, RNA stability, translation, and other processes, it is unknown whether most observed m6A modifications are functional. To address this question, we respectively analyze the evolutionary conservation of yeast and human m6As in protein-coding regions. Relative to comparable unmethylated As, m6As are overall no more conserved in yeasts and only slightly more conserved in mammals. Furthermore, yeast m6As and comparable unmethylated As have no significant difference in single nucleotide polymorphism (SNP) density or SNP site frequency spectrum. The same is true in human. The methylation status of a gene, not necessarily the specific sites methylated in the gene, is subject to purifying selection for no more than ~20% of m6A-modified genes. These observations suggest that most m6A modifications in protein-coding regions are nonfunctional and nonadaptive, probably resulting from off-target activities of m6A methyltransferases. In addition, our reanalysis invalidates the recent claim of positive selection for newly acquired m6A modifications in human evolution. Regarding the small number of evolutionarily conserved m6As, evidence suggests that a large proportion of them are likely functional; they should be prioritized in future functional characterizations of m6As. Together, these findings have important implications for understanding the biological significance of m6A and other posttranscriptional modifications. PMID- 29228329 TI - Reliance on deep soil water in the tree species Argania spinosa. AB - In South-western Morocco, water scarcity and high temperature are the main factors determining species survival. Argania spinosa (L.) Skeels is a tree species, endemic to Morocco, which is suffering from ongoing habitat shrinkage. Argan trees play essential local ecological and economic roles: protecting soils from erosion, shading different types of crops, helping maintain soil fertility and, even more importantly, its seeds are used by the local population for oil production, with valuable nutritional, medicinal and cosmetic purposes. The main objective of this study was to identify the sources of water used by this species and to assess the effect of water availability on the photosynthetic rate and stem water potential in two populations: one growing on the coast and a second one 10 km inland. Stem water potential, photosynthetic rate and xylem water isotopic composition (delta18O) were seasonally monitored during 2 years. Trees from both populations showed a similar strategy in the use of the available water sources, which was strongly dependent on deep soil water throughout the year. Nevertheless, during the wet season or under low precipitation a more complex water uptake pattern was found with a mixture of water sources, including precipitation and soil at different depths. No evidence was found of the use of either groundwater or atmospheric water in this species. Despite the similar water-use strategy, the results indicate that Argania trees from the inland population explored deeper layers than coastal ones as suggested by more depleted delta18O values recorded in the inland trees and better photosynthetic performance, hence suggesting that the coastal population of A. spinosa could be subjected to higher stress. PMID- 29228330 TI - Spliceosomal protein U1A is involved in alternative splicing and salt stress tolerance in Arabidopsis thaliana. AB - Soil salinity is a significant threat to sustainable agricultural production worldwide. Plants must adjust their developmental and physiological processes to cope with salt stress. Although the capacity for adaptation ultimately depends on the genome, the exceptional versatility in gene regulation provided by the spliceosome-mediated alternative splicing (AS) is essential in these adaptive processes. However, the functions of the spliceosome in plant stress responses are poorly understood. Here, we report the in-depth characterization of a U1 spliceosomal protein, AtU1A, in controlling AS of pre-mRNAs under salt stress and salt stress tolerance in Arabidopsis thaliana. The atu1a mutant was hypersensitive to salt stress and accumulated more reactive oxygen species (ROS) than the wild-type under salt stress. RNA-seq analysis revealed that AtU1A regulates AS of many genes, presumably through modulating recognition of 5' splice sites. We showed that AtU1A is associated with the pre-mRNA of the ROS detoxification-related gene ACO1 and is necessary for the regulation of ACO1 AS. ACO1 is important for salt tolerance because ectopic expression of ACO1 in the atu1a mutant can partially rescue its salt hypersensitive phenotype. Our findings highlight the critical role of AtU1A as a regulator of pre-mRNA processing and salt tolerance in plants. PMID- 29228331 TI - Clinical characteristics and outcomes of patients with chronic disseminated candidiasis who need adjuvant corticosteroid therapy. AB - We performed a retrospective study involving 21 patients with chronic disseminate candidiasis (CDC) and 38 patients with candidemia. Neutropenia of >2 weeks' duration was more common in those with CDC (71%) than in those with candidemia (26%, P < .001), and the azole-resistant rate in patients with CDC (5%) was lower than that in those with candidemia (29%, P = .03). Of the 21 patients with CDC, five (24%) needed adjuvant corticosteroid therapy due to persistent debilitating fever (median, 19 days). Rapid defervescence (median, 5 days) occurred after adjuvant corticosteroid therapy. However, there were no significant differences in 90-day mortality between CDC patients with and without corticosteroid therapy. Further prospective data are needed to define the role of steroids in this setting. PMID- 29228332 TI - Prespacer processing and specific integration in a Type I-A CRISPR system. AB - The CRISPR-Cas system for prokaryotic adaptive immunity provides RNA-mediated protection from viruses and mobile genetic elements. Adaptation is dependent on the Cas1 and Cas2 proteins along with varying accessory proteins. Here we analyse the process in Sulfolobus solfataricus, showing that while Cas1 and Cas2 catalyze spacer integration in vitro, host factors are required for specificity. Specific integration also requires at least 400 bp of the leader sequence, and is dependent on the presence of hydrolysable ATP, suggestive of an active process that may involve DNA remodelling. Specific spacer integration is associated with processing of prespacer 3' ends in a PAM-dependent manner. This is reflected in PAM-dependent processing of prespacer 3' ends in vitro in the presence of cell lysate or the Cas4 nuclease, in a reaction consistent with PAM-directed binding and protection of prespacer DNA. These results highlight the diverse interplay between CRISPR-Cas elements and host proteins across CRISPR types. PMID- 29228334 TI - Clinical and epidemiological characterization of histoplasmosis cases in a nonendemic area, Connecticut, United States. AB - We performed a retrospective analysis of histoplasmosis cases diagnosed at our institution in New Haven, Connecticut, from 2005 to 2015. Among 12 cases of active histoplasmosis, seven were immunosuppressed and five had human immunodeficiency virus (HIV). Eleven patients reported travel to potentially endemic areas at a median of 105 days prior to presentation; travel to the Caribbean was most common (n = 6). Median time to diagnosis from symptom onset and first Histoplasma antigen testing were 41 and 28 days, respectively. Consistent with reports from other non-endemic areas, our findings suggest that the epidemiology of histoplasmosis may differ in Connecticut, potentially contributing to delayed diagnoses. PMID- 29228335 TI - Gram-scale production of recombinant microbial enzymes in shake flasks. AB - Heterologous production of recombinant proteins is a cornerstone of microbiological and biochemical research as well as various biotechnological processes. Yields and quality of produced proteins have a tremendous impact on structural and enzymology studies, development of new biopharmaceuticals and establishing new biocatalytic processes. Majority of current protocols for recombinant protein expression in Escherichia coli exploit batch cultures with complex media, often providing low yields of the target protein due to oxygen transfer limitation, rapid depletion of carbon sources and pH changes during the cultivation. Recently introduced EnBase technology enables fed-batch-like cultivations in shake flasks with continuous glucose release from a soluble starch. In this study, we critically compare the yields of fourteen model enzymes in E. coli cultured in a novel semi-defined medium and in a complex medium. Significant improvements of the volumetric yields 2-31 times were observed for all tested enzymes expressed in enzymatic fed-batch-like cultures with no adverse impact on enzyme structure, stability or activity. Exceptional yields, higher than 1 g of protein per liter of culture, were obtained with six enzymes. We conclude that the novel semi-defined medium tested in this study provides a robust improvement of protein yields in shake flasks without investment into costly bioreactors. PMID- 29228333 TI - DNAAF1 links heart laterality with the AAA+ ATPase RUVBL1 and ciliary intraflagellar transport. AB - DNAAF1 (LRRC50) is a cytoplasmic protein required for dynein heavy chain assembly and cilia motility, and DNAAF1 mutations cause primary ciliary dyskinesia (PCD; MIM 613193). We describe four families with DNAAF1 mutations and complex congenital heart disease (CHD). In three families, all affected individuals have typical PCD phenotypes. However, an additional family demonstrates isolated CHD (heterotaxy) in two affected siblings, but no clinical evidence of PCD. We identified a homozygous DNAAF1 missense mutation, p.Leu191Phe, as causative for heterotaxy in this family. Genetic complementation in dnaaf1-null zebrafish embryos demonstrated the rescue of normal heart looping with wild-type human DNAAF1, but not the p.Leu191Phe variant, supporting the conserved pathogenicity of this DNAAF1 missense mutation. This observation points to a phenotypic continuum between CHD and PCD, providing new insights into the pathogenesis of isolated CHD. In further investigations of the function of DNAAF1 in dynein arm assembly, we identified interactions with members of a putative dynein arm assembly complex. These include the ciliary intraflagellar transport protein IFT88 and the AAA+ (ATPases Associated with various cellular Activities) family proteins RUVBL1 (Pontin) and RUVBL2 (Reptin). Co-localization studies support these findings, with the loss of RUVBL1 perturbing the co-localization of DNAAF1 with IFT88. We show that RUVBL1 orthologues have an asymmetric left-sided distribution at both the mouse embryonic node and the Kupffer's vesicle in zebrafish embryos, with the latter asymmetry dependent on DNAAF1. These results suggest that DNAAF1-RUVBL1 biochemical and genetic interactions have a novel functional role in symmetry breaking and cardiac development. PMID- 29228336 TI - Thoracic Park: cardiac MRI reveals massive thoracic varices as consequence of inferior vena cava ligation. PMID- 29228338 TI - Operative Nuances of Stereotactic Leksell Frame-Based Depth Electrode Implantation. AB - Background: For intracranial electroencephalographic monitoring, stereotactically implanted depth electrodes are increasingly used at epilepsy centers around the world. Objective: To identify pearls and pitfalls from our experience with stereotactic Leksell (Elekta AB, Stockhom, Sweden) frame-based depth electrode implantation. Methods: An intraoperative video of the implantation technique was recorded. Results: A detailed description and a video on how to implant depth electrodes using the stereotactic Leksell frame is provided. Conclusion: Neurosurgeons implanting depth electrodes for intracranial electroencephalographic monitoring might find the technical nuances and caveats described in this technical note useful for their practice. PMID- 29228337 TI - Triplex-forming oligonucleotides: a third strand for DNA nanotechnology. AB - DNA self-assembly has proved to be a useful bottom-up strategy for the construction of user-defined nanoscale objects, lattices and devices. The design of these structures has largely relied on exploiting simple base pairing rules and the formation of double-helical domains as secondary structural elements. However, other helical forms involving specific non-canonical base-base interactions have introduced a novel paradigm into the process of engineering with DNA. The most notable of these is a three-stranded complex generated by the binding of a third strand within the duplex major groove, generating a triple helical ('triplex') structure. The sequence, structural and assembly requirements that differentiate triplexes from their duplex counterparts has allowed the design of nanostructures for both dynamic and/or structural purposes, as well as a means to target non-nucleic acid components to precise locations within a nanostructure scaffold. Here, we review the properties of triplexes that have proved useful in the engineering of DNA nanostructures, with an emphasis on applications that hitherto have not been possible by duplex formation alone. PMID- 29228339 TI - Thresholds for decision-making: informing the cost-effectiveness and affordability of rotavirus vaccines in Malaysia. AB - Cost-effectiveness thresholds (CETs) based on the Commission on Macroeconomics and Health (CMH) are extensively used in low- and middle-income countries (LMICs) lacking locally defined CETs. These thresholds were originally intended for global and regional prioritization, and do not reflect local context or affordability at the national level, so their value for informing resource allocation decisions has been questioned. Using these thresholds, rotavirus vaccines are widely regarded as cost-effective interventions in LMICs. However, high vaccine prices remain a barrier towards vaccine introduction. This study aims to evaluate the cost-effectiveness, affordability and threshold price of universal rotavirus vaccination at various CETs in Malaysia. Cost-effectiveness of Rotarix and RotaTeq were evaluated using a multi-cohort model. Pan American Health Organization Revolving Fund's vaccine prices were used as tender price, while the recommended retail price for Malaysia was used as market price. We estimate threshold prices defined as prices at which vaccination becomes cost effective, at various CETs reflecting economic theories of human capital, societal willingness-to-pay and marginal productivity. A budget impact analysis compared programmatic costs with the healthcare budget. At tender prices, both vaccines were cost-saving. At market prices, cost-effectiveness differed with thresholds used. At market price, using 'CMH thresholds', Rotarix programmes were cost-effective and RotaTeq were not cost-effective from the healthcare provider's perspective, while both vaccines were cost-effective from the societal perspective. Using other CETs, both vaccines were not cost-effective at market price, from the healthcare provider's and societal perspectives. At tender and cost-effective prices, rotavirus vaccination cost ~1 and 3% of the public health budget, respectively. Using locally defined thresholds, rotavirus vaccination is cost-effective at vaccine prices in line with international tenders, but not at market prices. Thresholds representing marginal productivity are likely to be lower than those reflecting human capital and individual preference measures, and may be useful in determining affordable vaccine prices. PMID- 29228340 TI - Hydrophobicity diversity in globular and nonglobular proteins measured with the Gini index. AB - Amino acids and their properties are variably distributed in proteins and different compositions determine all protein features, ranging from solubility to stability and functionality. Gini index, a tool to estimate distribution uniformity, is widely used in macroeconomics and has numerous statistical applications. Here, Gini index is used to analyze the distribution of hydrophobicity in proteins and to compare hydrophobicity distribution in globular and intrinsically disordered proteins. Based on the analysis of carefully selected high-quality data sets of proteins extracted from the Protein Data Bank (http://www.rcsb.org) and from the DisProt database (http://www.disprot.org/), it is observed that hydrophobicity is distributed in a more diverse way in intrinsically disordered proteins than in folded and soluble globular proteins. This correlates with the observation that the amino acid composition deviates from the uniformity (estimate with the Shannon and the Gini-Simpson indices) more in intrinsically disordered proteins than in globular and soluble proteins. Although statistical tools tike the Gini index have received little attention in molecular biology, these results show that they allow one to estimate sequence diversity and that they are useful to delineate trends that can hardly be described, otherwise, in simple and concise ways. PMID- 29228341 TI - Response to Letter From Rainer Otter Regarding Albert O. et al. (2017). Identifying Greener and Safer Plasticizers: A Four-Step Approach. PMID- 29228342 TI - A highly asynchronous developmental program triggered during germination of dormant akinetes of filamentous diazotrophic cyanobacteria. AB - Germination of akinetes of filamentous heterocyst-forming cyanobacteria of the order Nostocales is an essential process that ensures survival and recolonization after long periods of unfavorable conditions, as desiccation, cold and low light. We studied the morphological, physiological and metabolic changes that occur during germination of akinetes in two model species of cell differentiation, Anabaena variabilis ATCC 29413 and Nostoc punctiforme ATCC 29133, which live in different habitats. We characterized the akinete envelopes and showed their similarity to envelopes of N2-fixing heterocysts. Akinete germination started inside the envelopes and was dependent on light intensity but independent of nitrogen supply. During the germination of A. variabilis akinetes, cell division and heterocyst differentiation were highly accelerated. The energy for cell division was initially supplied by respiration of glycogen and subsequently by photosynthesis. By contrast, during germination of N. punctiforme akinetes, cell division and heterocyst differentiation were slow. During the initial 15-20 h, N. punctiforme akinetes increased in volume and some burst. Only then did intact akinetes start to divide and fully germinate, possibly fueled by nutrients released from dead akinetes. The different strategies used by these different cyanobacteria allow successful germination of dormant cells and recolonization under favorable conditions. PMID- 29228343 TI - Long-Term Outcome Following Stereotactic Radiosurgery for Glomus Jugulare Tumors: A Single Institution Experience of 20 Years. AB - BACKGROUND: Glomus jugulare tumors (GJTs) are rare benign tumors, which pose significant treatment challenges due to proximity to critical structures. OBJECTIVE: To evaluate the long-term clinical and radiological outcome in patients undergoing stereotactic radiosurgery (SRS) for GJTs through retrospective study. METHODS: Forty-two patients with 43 GJTs were treated using Gamma Knife radiosurgery (GKRS; Elekta AB, Stockholm, Sweden) at our institute from 1997 to 2016. Clinical, imaging, and radiosurgery data were collected from an institutional review board approved database. RESULTS: Most patients were females (n = 35, 83.3%) and median age was 61 yr (range 23-88 yr). Median tumor volume and diameter were 5 cc and 3 cm, respectively, with a median follow-up of 62.3 mo (3.4-218.6 mo). Overall, 20 patients (47.6%) improved clinically and 14 (33.3%) remained unchanged at last follow-up. New onset or worsening of hearing loss was noted in 6 patients (17.2%) after SRS. The median prescription dose to the tumor margin was 15 Gy (12-18 Gy). Median reduction in tumor volume and maximum tumor diameter at last follow-up was 33.3% and 11.54%, respectively. The 5-yr and 10-yr tumor control rates were 87% +/- 6% and 69% +/- 13%, respectively. There was no correlation between maximum or mean dose to the internal acoustic canal and post-GK hearing loss (P > .05). CONCLUSION: SRS is safe and effective in patients with GJTs and results in durable, long-term control. SRS has lower morbidity than that associated with surgical resection, particularly lower cranial nerve dysfunction, and can be a first-line management option in these patients. PMID- 29228344 TI - Relationship Between Interrectus Distance and Symptom Severity in Women With Diastasis Recti Abdominis in the Early Postpartum Period. AB - Background: Diastasis recti abdominis (DrA) is associated with negative body image, musculoskeletal pain and dysfunction, and perhaps urogynecological complaints. The severity of DrA has traditionally been determined by measuring the interrectus distance (IRD); however, the relationship between IRD and symptoms in women with DrA is unclear. Objective: The objective of the study was to investigate the relationship between IRD and symptom severity in women with DrA in the early postpartum period. Design: This study used a cross-sectional design. Methods: Thirty-two women with DrA were assessed at 3 weeks postpartum. The IRD was measured using ultrasound imaging. Symptom severity was assessed using the Multidimensional Body-Self Relations Questionnaire subscales (body image), visual analog scales (abdominal, low back, and pelvic pain intensity), the Modified Oswestry Index (disability due to low back pain), and the Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire (urogynecological dysfunction). Spearman correlation coefficients (rho) between IRD and each outcome were calculated and tested using 1-tailed significance (adjusted alpha = .009). Results: The group median IRD was 2.97 cm (interquartile range = 1.65 cm), with the largest IRD in the sample being 7.97 cm. The IRD was significantly correlated with worst abdominal pain in the last 24 hours (rho = 0.45, P = .005) and with overall body image (rho = -0.44, P = .006) but not with the other outcomes. Limitations: Women in the sample were primiparous, were in the early (3 weeks) postpartum period, had relatively low body mass indexes (mean = 25.0 kg/m2) considering that they had recently given birth, were all breast-feeding, and had a narrow age range (27-35 years old). These factors limited the generalizability of our results to all women with DrA. Conclusions: This preliminary work suggests that, in the early postpartum period, IRD as a measure of DrA severity is meaningful for body image. PMID- 29228345 TI - Mechanisms and mediators of hypertension induced by erythropoietin and related molecules. AB - Hypertension is a common but frequently overlooked adverse effect of erythropoietin (EPO) therapy. Underreporting of hypertension with EPO is likely due to either more aggressively managing hypertension through the prescription of antihypertensive drugs or closer attention to dry weight. The purpose and focus of this review is to critically evaluate the mechanisms of EPO-induced hypertension. Preclinical data are considered first, followed by clinical data where available. Mediated by a variety of molecules, there is an imbalance in the vascular tone favoring net vasoconstriction that mediates EPO-induced hypertension. Animal studies show the primary importance of chronic kidney disease in the genesis of EPO-induced hypertension. Preclinical studies show deranged regulation of the nitric oxide, endothelins and porstanoids and the sympathoadrenal and renin-angiotensin pathways as causes of EPO-induced hypertension. Human studies suggest that EPO administration is also associated with increased responsiveness to catecholamines and angiotensin II on vascular tissue; in addition, hypoxia-induced vasodilation may be impaired in those with EPO-induced hypertension. There is little evidence for EPO as a direct vasoconstrictor or its effect on blood viscosity as a mechanism of EPO-induced hypertension. EPO-induced hypertension, at least in part, appears to be independent of an increase in hemoglobin, because experiments show that hemoglobin may be increased by EPO without an increase in blood pressure (BP) by simply treating the animals with EPO-binding protein and that treatment with EPO in the setting of iron deficiency may not increase hemoglobin but may still increase BP. However, experimental data are not consistent across studies and better mechanistic designs are needed, especially in patients with chronic kidney disease, to dissect the precise mechanism of EPO-induced hypertension. Animal studies suggest that hypoxia-inducible factor stablizers may induce hypertension by provoking calcification and augmenting chronic intermittent hypoxia as occurs in sleep apnea. Others show that there may be an antihypertensive effect via kidney repair. Whether these drugs will alter the risk of hypertension compared with EPO remains to be seen. PMID- 29228346 TI - The use of ultrasound in detecting and defining ground-glass opacities: results of an ex vivo evaluation. AB - OBJECTIVES: To evaluate the role of ultrasound in detecting and defining ground glass opacities (GGOs) in surgical specimens of patients undergoing thoracoscopic diagnostic resection. METHODS: We performed an observational single-centre study of all consecutive patients undergoing thoracoscopic diagnostic resection of GGOs. In each patient, the specimen was scanned with ultrasound; then, a needle was inserted into the lesion to facilitate its detection by the pathologist. We evaluated the rate of detection with ultrasound, compared the size and depth measurements of the lesions as determined from ultrasound scans with those from the histological specimens and correlated the ultrasound findings with the histological subtypes of adenocarcinomas. RESULTS: We reviewed 17 tissue samples. The final diagnoses were 1 (6%) atypical adenomatous hyperplasia, 5 (29%) adenocarcinomas in situ, 4 (24%) minimally invasive adenocarcinomas and 7 (41%) invasive adenocarcinomas. All tumours were successfully identified using ultrasound. The size (P = 0.87) and depth (P = 0.25) of the lesions measured with ultrasound did not significantly differ from the measurements obtained from the histological specimens. In addition, ultrasound size (r = 0.945; P < 0.0001) and depth (r = 0.588; P = 0.013) were significantly correlated with the pathological measurements. All lesions with hyperechoic findings (n = 6) were pure GGOs, whereas lesions with mixed echoic (n = 11) patterns were mixed GGOs. We were unable to differentiate the histological subtypes of adenocarcinomas using the ultrasound scans. CONCLUSIONS: Detection of GGOs on ultrasound scans is feasible, but differentiation of the histological subtypes of adenocarcinomas is not possible. The next step is to evaluate the intraoperative reproducibility of our results. PMID- 29228347 TI - Exposure of Mice to 1,2-Dichloropropane Induces CYP450-Dependent Proliferation and Apoptosis of Cholangiocytes. AB - 1,2-Dichloropropane (1,2-DCP) has been used as a paint remover in the industry. The International Agency for Research on Cancer reclassified this compound recently to group 1 (carcinogenic to humans) based on epidemiological studies of cholangiocarcinoma among offset-color proof-printing workers exposed to 1,2-DCP in Japan. Two-year rodent carcinogenicity bioassays demonstrated that 1,2-DCP induced tumors in liver and lung, but not in bile duct. The present study was designed to assess the toxic effects of 1,2-DCP on proliferation and apoptosis in mice bile duct and the role of cytochrome P450 (CYP450) in any such effect. Male C57BL/6JJcl mice were cotreated or untreated with 1-aminobenzotriazole (1-ABT), a CYP450 inhibitor, and exposed to inhalation of 1,2-DCP at 0, 50, or 250 ppm alone, or at 0, 50, 250, or 1250 ppm 8 h/day for 4 weeks. Exposure to 1,2-DCP increased proliferation and apoptosis of cholangiocytes and induced severe hepatic damage, but had no effect on the lungs. Cotreatment with 1-ABT abrogated the effects of 1,2-DCP on proliferation and apoptosis of cholangiocytes. The results revealed that 1,2-DCP induces proliferation and apoptosis of cholangiocytes and that this effect is mediated through CYP450. PMID- 29228348 TI - Flaxseed supplementation on glucose control and insulin sensitivity: a systematic review and meta-analysis of 25 randomized, placebo-controlled trials. AB - Context: The results of human clinical trials investigating the effects of flaxseed on glucose control and insulin sensitivity are inconsistent. Objective: The present study aimed to systematically review and analyze randomized controlled trials assessing the effects of flaxseed consumption on glycemic control. Data Sources: PubMed, Medline via Ovid, SCOPUS, EMBASE, and ISI Web of Sciences databases were searched up to November 2016. Study Selection: Clinical trials in which flaxseed or its products were administered as an intervention were included. Data Extraction: The outcomes were fasting blood glucose, insulin concentration, insulin resistance (HOMA-IR), insulin sensitivity (QUIKI), and hemoglobin A1c (HbA1c). Results: A total of 25 randomized clinical trials (30 treatment arms) were included. Meta-analysis suggested a significant association between flaxseed supplementation and a reduction in blood glucose (weighted mean difference [WMD], -2.94 mg/dL; 95%CI, -5.31 to - 0.56; P = 0.015), insulin levels (WMD, -7.32 pmol/L; 95%CI, -11.66 to -2.97; P = 0.001), and HOMA-IR index (WMD, -0.49; 95%CI,: -0.78 to - 0.20; P = 0.001) and an increase in QUIKI index (WMD, 0.019; 95%CI, 0.008-0.031; P = 0.001). No significant effect on HbA1c (WMD, -0.045%; 95%CI, -0.16 to - 0.07; P = 0.468) was found. In subgroup analysis, a significant reduction in blood glucose, insulin, and HOMA-IR and a significant increase in QUIKI were found only in studies using whole flaxseed but not flaxseed oil and lignan extract. Furthermore, a significant reduction was observed in insulin levels and insulin sensitivity indexes only in the subset of trials lasting >=12 weeks. Conclusions: Whole flaxseed, but not flaxseed oil and lignan extract, has significant effects on improving glycemic control. Further studies are needed to determine the benefits of flaxseed on glycemic parameters. PMID- 29228349 TI - Genome-Wide SNPs Identify Limits to Connectivity in the Extreme Freshwater Disperser, Spangled Perch Leiopotherapon unicolor (Terapontidae). AB - The utility of restriction-site associated DNA sequencing (RADseq) to resolve fine-scale population structure was tested on an abundant and vagile fish species in a tropical river. Australia's most widespread freshwater fish, the "extreme disperser" Leiopotherapon unicolor was sampled from 6 locations in an unregulated system, the Daly River in Australia's Northern Territory. Despite an expectation of high connectivity based on life history knowledge of this species derived from arid zone habitats, L. unicolor was not a panmictic population in the tropical lower Daly. Using ~14000 polymorphic RADseq loci, we found a pattern of upstream versus downstream population subdivision and evidence for differentiation among tributary populations. The magnitude of population structure was low with narrow confidence intervals (global FST = 0.014; 95% CI = 0.012-0.016). Confidence intervals around pairwise FST estimates were all nonzero and consistent with the results of clustering analyses. This population structure was not explained by spatially heterogeneous selection acting on a subset of loci, or by sampling groups of closely related individuals (average within-site relatedness ~ 0). One implication of the low but significant structure observed in the tropics is the possibility that L. unicolor may exhibit contrasting patterns of migratory biology in tropical versus arid zone habitats. We conclude that the RADseq revolution holds promise for delineating subtle patterns of population subdivision in species characterized by high within-population variation and low among-population differentiation. PMID- 29228350 TI - Obstructive hydrocephalus due to intracerebral alveolar echinococcosis. PMID- 29228351 TI - Defensive behaviors of the new mealybug citrus pest, Delottococcus aberiae (Hemiptera: Pseudococcidae), against three generalist parasitoids. AB - Delottococcus aberiae De Lotto (Hemiptera: Pseudococcidae) is an invasive mealybug that has become a citrus pest in Europe. This mealybug species causes serious damage because it deforms the fruits. Here, we studied the defensive behavior of D. aberiae when it was attacked by three parasitoid species: Acerophagus angustifrons (Gahan), Anagyrus sp. near pseudoccoci (Girault), and Leptomastix algirica Trjapitzin (Hymenoptera: Encyrtidae). Anagyrus sp. near pseudoccoci and L. algirica detected and accepted nymphs and adult females of D. aberiae, whereas A. angustifrons only accepted adults. We recorded four defensive responses of D. aberiae to parasitoid attacks: abdominal flipping, swiveling around the inserted stylet, withdrawing the stylet and walking away, and, occasionally, they secreted ostiolar fluids. Despite these defensive behaviors, the mealybug did not escape parasitism from any of the tested parasitoids, even though A. angustifrons needed more than 15 min to parasitize. We also analyzed the nutritional value of the honeydew excreted by D. aberiae for A. angustifrons and A. sp. near pseudococci. Females and males of these parasitoids lived more than 28 d when fed sucrose, but they lived fewer than 3 d when fed D. aberiae honeydew. Therefore, D. aberiae excretes honeydew of poor quality for parasitoids. The consequences of these biological traits of D. aberiae for its biological control are discussed. PMID- 29228352 TI - Tumour necrosis factor-alpha in uraemic serum promotes osteoblastic transition and calcification of vascular smooth muscle cells via extracellular signal regulated kinases and activator protein 1/c-FOS-mediated induction of interleukin 6 expression. AB - Background: Vascular calcification is enhanced in uraemic chronic haemodialysis patients, likely due to the accumulation of midsize uraemic toxins, such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Here we have assessed the impact of uraemia on vascular smooth muscle cell (VSMC) calcification and examined the role of IL-6 and TNF-alpha as possible mediators and, most importantly, its underlying signalling pathway in VSMCs. Methods: VSMCs were incubated with samples of uraemic serum obtained from patients treated with haemodialysis for renal failure in the Permeability Enhancement to Reduce Chronic Inflammation-I clinical trial. The VSMCs were assessed for IL-6 gene regulation and promoter activation in response to uraemic serum and TNF-alpha with reporter assays and electrophoretic mobility shift assay and for osteoblastic transition, cellular calcification and cell viability upon osteogenic differentiation. Results: Uraemic serum contained higher levels of TNF-alpha and IL-6 compared with serum from healthy individuals. Exposure of VSMCs to uraemic serum or recombinant TNF-alpha lead to a strong upregulation of IL-6 mRNA expression and protein secretion, which was mediated by activator protein 1 (AP-1)/c-FOS-pathway signalling. Uraemic serum induced osteoblastic transition and calcification of VSMCs could be strongly attenuated by blocking TNF-alpha, IL-6 or AP-1/c-FOS signalling, which was accompanied by improved cell viability. Conclusion: These results demonstrate that uraemic serum contains higher levels of uraemic toxins TNF-alpha and IL-6 and that uraemia promotes vascular calcification through a signalling pathway involving TNF-alpha, IL-6 and the AP-1/c-FOS cytokine signalling axis. Thus treatment modalities aiming to reduce systemic TNF-alpha and IL-6 levels in chronic haemodialysis patients should be evaluated in future clinical trials. PMID- 29228354 TI - Prolonged exposure does not increase soil microbial community compositional response to warming along geothermal gradients. AB - Global change is expected to affect soil microbial communities through their responsiveness to temperature. It has been proposed that prolonged exposure to elevated temperatures may lead to progressively larger effects on soil microbial community composition. However, due to the relatively short-term nature of most warming experiments, this idea has been challenging to evaluate. The present study took the advantage of natural geothermal gradients (from +1 degrees C to +19 degrees C above ambient) in two subarctic grasslands to test the hypothesis that long-term exposure (>50 years) intensifies the effect of warming on microbial community composition compared to short-term exposure (5-7 years). Community profiles from amplicon sequencing of bacterial and fungal rRNA genes did not support this hypothesis: significant changes relative to ambient were observed only starting from the warming intensity of +9 degrees C in the long term and +7 degrees C/+3 degrees C in the short term, for bacteria and fungi, respectively. Our results suggest that microbial communities in high-latitude grasslands will not undergo lasting shifts in community composition under the warming predicted for the coming 100 years (+2.2 degrees C to +8.3 degrees C). PMID- 29228353 TI - The Roles of P53 and Its Family Proteins, P63 and P73, in the DNA Damage Stress Response in Organogenesis-Stage Mouse Embryos. AB - Members of the P53 transcription factor family, P53, P63, and P73, play important roles in normal development and in regulating the expression of genes that control apoptosis and cell cycle progression in response to genotoxic stress. P53 is involved in the DNA damage response pathway that is activated by hydroxyurea in organogenesis-stage murine embryos. The extent to which P63 and P73 contribute to this stress response is not known. To address this question, we examined the roles of P53, P63, and P73 in mediating the response of Trp53-positive and Trp53 deficient murine embryos to a single dose of hydroxyurea (400 mg/kg) on gestational day 9. Hydroxyurea treatment downregulated the expression of Trp63 and upregulated Trp73 in the absence of effects on the levels of Trp53 transcripts; Trp73 upregulation was P53-dependent. At the protein level, hydroxyurea treatment increased the levels and phosphorylation of P53 in the absence of effects on P63 and P73. Upregulation of the expression of genes that regulate cell cycle arrest and apoptosis, Cdkn1a, Rb1, Fas, Trp53inp1, and Pmaip1, was P53-dependent in hydroxyurea-treated embryos. The increase in cleaved caspase-3 and cleaved mammalian sterile-20-like-1 kinase levels induced by hydroxyurea was also P53-dependent; in contrast, the increase in phosphorylated H2AX, a marker of DNA double-strand breaks, in response to hydroxyurea treatment was only partially P53-dependent. Together, our data show that P53 is the principal P53 family member that is activated in the embryonic DNA damage response. PMID- 29228355 TI - Pulmonary lymphangioleiomyomatosis and fertility treatment. PMID- 29228356 TI - Dietary intervention rescues myopathy associated with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with complex symptomology. In addition to a predisposition to tumors, children with NF1 can present with reduced muscle mass, global muscle weakness, and impaired motor skills, which can have a significant impact on quality of life. Genetic mouse models have shown a lipid storage disease phenotype may underlie muscle weakness in NF1. Herein we confirm that biopsy specimens from six individuals with NF1 similarly manifest features of a lipid storage myopathy, with marked accumulation of intramyocellular lipid, fibrosis, and mononuclear cell infiltrates. Intramyocellular lipid was also correlated with reductions in neurofibromin protein expression by western analysis. An RNASeq profile of Nf1null muscle from a muscle-specific Nf1 knockout mouse (Nf1MyoD-/-) revealed alterations in genes associated with glucose regulation and cell signaling. Comparison by lipid mass spectrometry demonstrated that Nf1null muscle specimens were enriched for long chain fatty acid (LCFA) containing neutral lipids, such as cholesterol esters and triacylglycerides, suggesting fundamentally impaired LCFA metabolism. The subsequent generation of a limb-specific Nf1 knockout mouse (Nf1Prx1-/-) recapitulated all observed features of human NF1 myopathy, including lipid storage, fibrosis, and muscle weakness. Collectively, these insights led to the evaluation of a dietary intervention of reduced LCFAs, and enrichment of medium-chain fatty acids (MCFAs) with L-carnitine. Following 8-weeks of dietary treatment, Nf1Prx1-/- mice showed a 45% increase in maximal grip strength, and a 71% reduction in intramyocellular lipid staining compared with littermates fed standard chow. These data link NF1 deficiency to fundamental shifts in muscle metabolism, and provide strong proof of principal that a dietary intervention can ameliorate symptoms. PMID- 29228357 TI - Surfactant and heavy metal interaction in poplar: a focus on SDS and Zn uptake. AB - Surfactants are widely used detergent ingredients and, thanks to their chemical properties, they are applied for remediation of sites polluted by heavy metals and organic contaminants, both in soil flushing and in phytoremediation. However, their direct effects on tree physiology especially in consociation with heavy metal pollution, as well as their possible absorption by plants, have not been appropriately investigated. In order to evaluate plant uptake/translocation of the surfactant sodium dodecyl sulfate (SDS) and the heavy metal zinc (Zn) in Populus alba L. Villafranca clone, SDS was applied alone (0.5 mM) or in combination with Zn (1 mM). Physiological effects on plant growth and photosynthetic performance were investigated. An increasing trend of Zn translocation towards basal leaves as a consequence of SDS co-treatment (1 mM Zn + 0.5 mM SDS; P = 0.03) was observed, proving the ability of SDS to improve heavy metals translocation. However, SDS exposure (both in 0.5 mM SDS and 1 mM Zn + 0.5 mM SDS treated plants) resulted in the appearance of foliar necrosis that expanded with an acropetal trend and finally led to leaf abscission. This phenotype may be caused by the emergence of an additional stress during the experimental trial, which could be related to the dissociation of sodium (Na) ions from the dodecyl sulfate molecules in the hydroponic system. In fact, while liquid chromatography-tandem mass spectrometry measurements revealed that dodecyl sulfate is mainly retained at root levels, Na is translocated to the aerial parts of the plant. PMID- 29228359 TI - Comment on: Hereditary hemochromatosis arthropathy and Doppler ultrasound findings of synovitis. PMID- 29228358 TI - Theta resting EEG in TPJ/pSTS is associated with individual differences in the feeling of being looked at. AB - Direct eye gaze is a powerful stimulus in social interactions, yet people vary considerably in the range of gaze lines that they accept as being direct (cone of direct gaze, CoDG). Here, we searched for a possible neural trait marker of these individual differences. We measured the width of the CoDG in 137 healthy participants and related their individual CoDG to their neural baseline activation as measured with resting electroencephalogram. Using a source localization technique, we found that resting theta current density in the left temporo-parietal junction (TPJ) and adjacent posterior superior temporal sulcus (pSTS) was associated with the width of CoDG. Our findings suggest that the higher the baseline cortical activation in the left TPJ/pSTS, the wider the CoDG and thus the more liberal the individuals' judgments were in deciding whether a looker stimulus was making eye contact or not. This is a first demonstration of the neural signatures underlying individual differences in the feeling of being looked at. PMID- 29228360 TI - Dissecting the rootstock control of scion transpiration using model-assisted analyses in grapevine. AB - How rootstocks contribute to the control of scion transpiration under drought is poorly understood. We investigated the role of root characteristics, hydraulic conductance and chemical signals (abscisic acid, ABA) in the response of stomatal conductance (gs) and transpiration (E) to drought in Cabernet Sauvignon (Vitis vinifera) grafted onto drought-sensitive (Vitis riparia) and drought-tolerant (Vitis berlandieri * Vitis rupestris 110R) rootstocks. All combinations showed a concomitant reduction in gs and E, and an increase in xylem sap ABA concentration during the drought cycle. Cabernet Sauvignon grafted onto 110R exhibited higher gs and E under well-watered and moderate water deficit, but all combinations converged as water deficit increased. These results were integrated into three permutations of a whole-plant transpiration model that couples both chemical (i.e., ABA) and hydraulic signals in the modelling of stomatal control. Model comparisons revealed that both hydraulic and chemical signals were important for rootstock-specific stomatal regulation. Moreover, model parameter comparison and sensitivity analysis highlighted two major parameters differentiating the rootstocks: (i) ABA biosynthetic activity and (ii) the hydraulic conductance between the rhizosphere and soil-root interface determined by root system architecture. These differences in root architecture, specifically a higher root length area in 110R, likely explain its higher E and gs observed at low and moderate water deficit. PMID- 29228361 TI - Identification of clinical isolates of Aspergillus, including cryptic species, by matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). AB - An expanded library of matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been constructed using the spectra generated from 42 clinical isolates and 11 reference strains, including 23 different species from 8 sections (16 cryptic plus 7 noncryptic species). Out of a total of 379 strains of Aspergillus isolated from clinical samples, 179 strains were selected to be identified by sequencing of beta-tubulin or calmodulin genes. Protein spectra of 53 strains, cultured in liquid medium, were used to construct an in-house reference database in the MALDI-TOF MS. One hundred ninety strains (179 clinical isolates previously identified by sequencing and the 11 reference strains), cultured on solid medium, were blindy analyzed by the MALDI-TOF MS technology to validate the generated in-house reference database. A 100% correlation was obtained with both identification methods, gene sequencing and MALDI-TOF MS, and no discordant identification was obtained. The HUVR database provided species level (score of >=2.0) identification in 165 isolates (86.84%) and for the remaining 25 (13.16%) a genus level identification (score between 1.7 and 2.0) was obtained. The routine MALDI-TOF MS analysis with the new database, was then challenged with 200 Aspergillus clinical isolates grown on solid medium in a prospective evaluation. A species identification was obtained in 191 strains (95.5%), and only nine strains (4.5%) could not be identified at the species level. Among the 200 strains, A. tubingensis was the only cryptic species identified. We demonstrated the feasibility and usefulness of the new HUVR database in MALDI-TOF MS by the use of a standardized procedure for the identification of Aspergillus clinical isolates, including cryptic species, grown either on solid or liquid media. PMID- 29228362 TI - Adult-onset tumour necrosis factor receptor-associated periodic syndrome presenting as transfusion-dependent refractory haemophagocytosis. PMID- 29228363 TI - Testing for coccidioidomycosis in emergency departments in Arizona. AB - Testing practices for coccidioidomycosis in the emergency department are poorly understood. We described characteristics of patients tested for coccidioidomycosis in emergency departments in Arizona and examined coccidioidomycosis testing among community-acquired pneumonia (CAP) patients. Emergency department visit records for patients tested for coccidioidomycosis and CAP patients were extracted from the Arizona hospital discharge database. In sum, 2.8% of CAP patients were tested for coccidioidomycosis. The proportion of patients tested varied substantially by healthcare facility and provider. PMID- 29228364 TI - Age-dependent changes in mean and variance of gene expression across tissues in a twin cohort. AB - Changes in the mean and variance of gene expression with age have consequences for healthy aging and disease development. Age-dependent changes in phenotypic variance have been associated with a decline in regulatory functions leading to increase in disease risk. Here, we investigate age-related mean and variance changes in gene expression measured by RNA-seq of fat, skin, whole blood and derived lymphoblastoid cell lines (LCLs) expression from 855 adult female twins. We see evidence of up to 60% of age effects on transcription levels shared across tissues, and 47% of those on splicing. Using gene expression variance and discordance between genetically identical MZ twin pairs, we identify 137 genes with age-related changes in variance and 42 genes with age-related discordance between co-twins; implying the latter are driven by environmental effects. We identify four eQTLs whose effect on expression is age-dependent (FDR 5%). Combined, these results show a complicated mix of environmental and genetically driven changes in expression with age. Using the twin structure in our data, we show that additive genetic effects explain considerably more of the variance in gene expression than aging, but less that other environmental factors, potentially explaining why reliable expression-derived biomarkers for healthy aging have proved elusive compared with those derived from methylation. PMID- 29228365 TI - Notch4 Negatively Regulates the Inflammatory Response to Mycobacterium tuberculosis Infection by Inhibiting TAK1 Activation. AB - Tuberculosis, caused by Mycobacterium tuberculosis infection, remains a global threat to human health, but knowledge of the molecular mechanisms underlying the pathogenesis of tuberculosis is still limited. Although Notch4, a member of the Notch receptor family, is involved in the initiation of mammary tumors, its function in M. tuberculosis infection remains unclear. In this study, we found that Notch4-deficient mice were more resistant to M. tuberculosis infection, with a much lower bacterial burden and fewer pathological changes in the lungs. Notch4 inhibited M. tuberculosis-induced production of proinflammatory cytokines by interaction with TAK1 and inhibition of its activation. Furthermore, we found that Notch intracellular domain 4 prevented TRAF6 autoubiquitination and suppressed TRAF6-mediated TAK1 polyubiquitination. Finally, Notch inhibitors made mice more resistant to M. tuberculosis infection. These results suggest that Notch4 is a negative regulator of M. tuberculosis-induced inflammatory response, and treatment with a Notch inhibitor could serve as a new therapeutic strategy for tuberculosis. PMID- 29228367 TI - How Social Structure Drives the Population Dynamics of the Common Vampire Bat (Desmodus rotundus, Phyllostomidae). AB - Social systems are major drivers of population structure and gene flow, with important effects on dynamics and dispersal of associated populations of parasites. Among bats, the common vampire bat (Desmodus rotundus) has likely one of the most complex social structures. Using autosomal and mitochondrial markers on vampires from Mexico, French Guiana, and North Brazil, from both roosting and foraging areas, we observed an isolation by distance at the wider scale and lower but significant differentiation between closer populations (<50 km). All populations had a low level of relatedness and showed deviations from Hardy Weinberg equilibrium and a low but significant inbreeding coefficient. The associated heterozygote deficiency was likely related to a Wahlund effect and to cryptic structures, reflecting social groups living in syntopy, both in roosting and foraging areas, with only limited admixture. Discrepancy between mitochondrial and nuclear markers suggests female philopatry and higher dispersal rates in males, associated with peripheral positions in the groups. Vampires are also the main neotropical reservoir for rabies virus, one of the main lethal pathogens for humans. Female social behaviors and trophallaxis may favor a rapid spread of virus to related and unrelated offspring and females. The high dispersal capacity of males may explain the wider circulation of viruses and the inefficacy of bat population controls. In such opportunistic species, gene connectivity should be considered for management decision making. Strategies such as culling could induce immigration of bats from neighboring colonies to fill vacant roosts and feeding areas, associated with the dispersal of viral strains. PMID- 29228366 TI - Genotype influences day-to-day variability in sleep in Drosophila melanogaster. AB - Patterns of sleep often vary among individuals. But sleep and activity may also vary within an individual, fluctuating in pattern across time. One possibility is that these daily fluctuations in sleep are caused by the underlying genotype of the individual. However, differences attributable to genetic causes are difficult to distinguish from environmental factors in outbred populations such as humans. We therefore employed Drosophila as a model of intra-individual variability in sleep using previously collected sleep and activity data from the Drosophila Genetic Reference Panel, a collection of wild-derived inbred lines. Individual flies had significant daily fluctuations in their sleep patterns, and these fluctuations were heritable. Using the standard deviation of sleep parameters as a metric, we conducted a genome-wide association study. We found 663 polymorphisms in 104 genes associated with daily fluctuations in sleep. We confirmed the effects of 12 candidate genes on the standard deviation of sleep parameters. Our results suggest that daily fluctuations in sleep patterns are due in part to gene activity. PMID- 29228369 TI - Nicotine gum as a therapeutic approach for low blood pressure in Parkinson's disease: A randomized pilot study. AB - Introduction: One cause for low blood pressure (BP) in Parkinson's disease (PD) is denervation of the sympathetic nervous system and reduced levels of norepinephrine. Nicotine increases heart rate and BP acutely by causing sympathetic stimulation. The absorption rate of nicotine gum is relatively quick and is absorbed at a constant rate. Our objective was to evaluate how nicotine gum affects acute low BP in PD. Methods: Ten subjects (age 69.3+/-8.8) completed this double blind, placebo controlled, cross-over design trial using nicotine gum (4 mg) and placebo gum on two separate days. The gum was administered for 30 minutes. BP was recorded every 10 minutes for 90 minutes. Results: On the nicotine gum treatment day, the baseline SBP was 94.8 (SD 4.4), and it increased in a parabolic pattern to be 115.8 (SD 11.2) in 20 minutes, 124.2 (SD 9.3) in 40 minutes, and 133.2 (SD 13.1) in 60 minutes reaching the highest value, and then decreased to be 121.6 (SD 10.4) in 90 minutes. On the placebo day, the baseline SBP 95.2 (SD 3.0) didn't show an outstanding change with the mean SBP values from 93.0 to 95.7 (SD from 2.1 to 3.7) at all time points. Conclusions: Our data suggests that 4 mg of nicotine gum can increase SBP within 10 minutes of administration. It is strongly warranted that further research should pursue the use of nicotine gum as an intervention to treat acute episodes of low BP in individuals with PD. PMID- 29228368 TI - The Oncolytic Virus MG1 Targets and Eliminates Cells Latently Infected With HIV 1: Implications for an HIV Cure. AB - Cells latently infected with human immunodeficiency virus (HIV) evade immune- and drug-mediated clearance. These cells harbor intracellular signaling defects, including impairment of the antiviral type I interferon response. Such defects have also been observed in several cancers and have been exploited for the development of therapeutic oncolytic viruses, including the recombinant Maraba virus (MG1). We therefore hypothesized that MG1 would infect and eliminate cells latently infected with HIV-1, while sparing healthy uninfected cells. Preferential infection and elimination by MG1 was first demonstrated in cell lines latently infected with HIV-1. Following this, a reduction in HIV-1 DNA and inducible HIV-1 replication was observed following MG1 infection of latently infected, resting CD4+ T cells generated using an in vitro model of latency. Last, MG1 infection resulted in a reduction in HIV-1 DNA and inducible HIV-1 replication in memory CD4+ T cells isolated from effectively treated, HIV-1 infected individuals. Our results therefore highlight a novel approach to eliminate the latent HIV-1 reservoir. PMID- 29228371 TI - Introduction to a Special Issue: Childbirth History is Everyone's History. PMID- 29228372 TI - A novel, tomographic imaging probe for rapid diagnosis of fungal keratitis. AB - Fungal keratitis is a leading cause of ocular morbidity and blindness in developing countries. Diagnosing fungal keratitis currently relies on a comparative evaluation of corneal biopsy or scraping using a direct microscopy and culture results. These methods not only carry the risk of developing complications due to the invasive tissue sampling but also are largely limited by diagnostic speed and accuracy, making it difficult to initiate timely appropriate antifungal therapy. Therefore, rapid and noninvasive diagnostic tools are a pressing need for improved outcomes for fungal keratitis. Taking advantage of the highly specific fungal cell targeting properties of caspofungin, we have developed a fluorescent chemical probe with high selectivity against fungal pathogens. Utilizing fluorescence imaging technology, we have demonstrated a highly specific and sensitive detection of Aspergillus in a fungal keratitis model in mice as early as 5 min post-topical application of the probe. Our results indicate that a fluorescence-mediated platform can be used as a rapid (<10 min) alternative to conventional methods for detecting Aspergillus, and potentially other fungi, in fungal infections of the cornea. PMID- 29228370 TI - An NF-kappaB signature predicts low-grade glioma prognosis: a precision medicine approach based on patient-derived stem cells. AB - Background: While recent genome-wide association studies have suggested novel low grade glioma (LGG) stratification models based on a molecular classification, we explored the potential clinical utility of patient-derived cells. Specifically, we assayed glioma-associated stem cells (GASC) that are patient-derived and representative of the glioma microenvironment. Methods: By next-generation sequencing, we analyzed the transcriptional profile of GASC derived from patients who underwent anaplastic transformation either within 48 months (GASC-BAD) or >=7 years (GASC-GOOD) after surgery. Gene set enrichment and pathway enrichment analyses were applied. The prognostic role of a nuclear factor-kappaB (NF-kappaB) signature derived from GASC-BAD was tested in 530 newly diagnosed diffuse LGG patients comprised within The Cancer Genome Atlas (TCGA) database. The prognostic value of the GASC upstream regulator p65 NF-kappaB was assessed, by univariate and multivariate Cox analyses, in a single center case study, including 146 grade II LGGs. Results: The key elements differentiating the transcriptome of GASC isolated from LGG with different prognoses were mostly related to hallmarks of cancer (eg, inflammatory/immune process, NF-kappaB activation). Consistently, the NF-kappaB signature extrapolated from the GASC study was prognostic in the dataset of TCGA. Finally, the nuclear expression of the NF-kB-p65 protein, assessed using an inexpensive immunohistochemical method, was an independent predictor of both overall survival and malignant progression-free survival in 146 grade II LGGs. Conclusion: This study demonstrates for the first time the independent prognostic role of NF-kB activation in LGG and outlines the role of patient-based stem cell models as a tool for precision medicine approaches. PMID- 29228373 TI - Medical treatment or surgery for colorectal endometriosis? Results of a shared decision-making approach. AB - STUDY QUESTION: What is the degree of patient satisfaction in women with symptomatic colorectal endometriosis who choose medical or surgical treatment after a shared decision-making (SDM) process? SUMMARY ANSWER: The degree of satisfaction with treatment was high both in women who chose medical treatment with a low-dose oral contraceptive (OCP) or a progestin, and in those who chose to undergo surgical resection of bowel endometriosis. WHAT IS KNOWN ALREADY: Hormonal therapies and surgery for colorectal endometriosis have been investigated in non-comparative studies with inconsistent results. STUDY DESIGN, SIZE, DURATION: Parallel cohort study conducted on 87 women referring to our centre with an indication to surgery for colorectal endometriosis. A standardised SDM process was adopted, allowing women to choose their preferred treatment. Median follow-up was 40 [18-60] months in the medical therapy group and 45 [30 67] in the surgery group. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients with endometriosis infiltrating the proximal rectum, the rectosigmoid junction, and the sigmoid, not causing severe sub-occlusive symptoms were enroled. A total of 50 patients chose treatment with an OCP (n = 12) or a progestin (n = 38), whereas 37 women confirmed their previous indication to surgery. Patient satisfaction was graded according to a 5-category scale. Variations in bowel and pain symptoms were measured by means of a 0-10 numeric rating scale. Constipation was assessed with the Knowles-Eccersley-Scott Symptom Questionnaire (KESS), health-related quality of life with the Short Form-12 questionnaire (SF-12), psychological status with the Hospital Anxiety and Depression scale (HADS) and sexual functioning with the Female Sexual Function Index (FSFI). MAIN RESULTS AND THE ROLE OF CHANCE: Six women in the medical therapy group requested surgery because of drug inefficacy (n = 3) or intolerance (n = 3). Seven major complications were observed in the surgery group (19%). At 12-month follow-up, 39 (78%) women in the medical therapy group were satisfied with their treatment, compared with 28 (76%) in the surgery group (adjusted odds ratio (OR), 1.37; 95% confidence interval (CI), 0.45-4.15; intention-to-treat analysis). Corresponding figures at final follow-up assessment were 72% in the former group and 65% in the latter one (adjusted OR, 1.74; 95% CI, 0.62-4.85). The 60-month cumulative proportion of dissatisfaction-free participants was 71% in the medical therapy group compared with 61% in the surgery group (P = 0.61); the Hazard incidence rate ratio was 1.21 (95% CI, 0.57-2.62). Intestinal complaints were ameliorated by both treatments. Significant between-group differences in favour of medical treatment were observed at 12-month follow-up in diarrhoea, dysmenorrhoea, non-menstrual pelvic pain and SF-12 physical component scores. The total HADS score improved significantly in both groups, whereas the total FSFI score improved only in women who chose medical therapy. LIMITATIONS REASONS FOR CAUTION: As treatments were not randomly assigned, selection bias and confounding are likely. The small sample size exposes to the risk of type II errors. WIDER IMPLICATIONS OF THE FINDINGS: When adequately informed and empowered through a SDM process, most patients with non-occlusive colorectal endometriosis who had already received a surgical indication, preferred medical therapy. The possibility of choosing the preferred treatment may allow maximisation of the potential effect of the interventions. STUDY FUNDING/COMPETING INTEREST(S): This study was financed by Italian fiscal contribution '5 * 1000'-Ministero dell'Istruzione, dell'Universita e della Ricerca-devolved to Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy. P.V., M.P.F., R.R., D.D., A.R., P.M., O.D.G. and M.C. declare that they have no conflicts of interest. E.S. received grants from Ferring and Serono. PMID- 29228374 TI - Quantitative Trait Loci Mapping of Western Corn Rootworm (Coleoptera: Chrysomelidae) Host Plant Resistance in Two Populations of Doubled Haploid Lines in Maize (Zea mays L.). AB - Over the last 70 yr, more than 12,000 maize accessions have been screened for their level of resistance to western corn rootworm, Diabrotica virgifera virgifera (LeConte; Coleoptera: Chrysomelidae), larval feeding. Less than 1% of this germplasm was selected for initiating recurrent selection or other breeding programs. Selected genotypes were mostly characterized by large root systems and superior root regrowth after root damage caused by western corn rootworm larvae. However, no hybrids claiming native (i.e., host plant) resistance to western corn rootworm larval feeding are currently commercially available. We investigated the genetic basis of western corn rootworm resistance in maize materials with improved levels of resistance using linkage disequilibrium mapping approaches. Two populations of topcrossed doubled haploid maize lines (DHLs) derived from crosses between resistant and susceptible maize lines were evaluated for their level of resistance in three to four different environments. For each DHL topcross an average root damage score was estimated and used for quantitative trait loci (QTL) analysis. We found genomic regions contributing to western corn rootworm resistance on all maize chromosomes, except for chromosome 4. Models fitting all QTL simultaneously explained about 30 to 50% of the genotypic variance for root damage scores in both mapping populations. Our findings confirm the complex genetic structure of host plant resistance against western corn rootworm larval feeding in maize. Interestingly, three of these QTL regions also carry genes involved in ascorbate biosynthesis, a key compound we hypothesize is involved in the expression of western corn rootworm resistance. PMID- 29228375 TI - Influence of temperature on in vitro zoosporogenesis of Pythium insidiosum. AB - This study verified the influence of different temperatures on P. insidiosum in vitro zoosporogenesis. P. insidiosum isolates (n = 26) were submitted to zoosporogenesis and incubated at 5 degrees C, 15 degrees C, 20 degrees C and 37 degrees C (1st stage). Grass fragments were evaluated under optical microscopy at 4, 8, and 24 hours of incubation. Afterward, all isolates were incubated at 37 degrees C and assessed at the same periods of time (2nd stage). The development of hyphae, presence of vesicles, zoosporangia and zoospores were checked. Only the presence of short hyphae was observed at 5 degrees C. At 15 degrees C, the hyphae were either under development or elongated and two isolates produced zoospores. When the isolates were submitted to 20 degrees C for 4 hours, the presence of long and mycelial hyphae, vesicles, zoosporangia and zoospores was observed, which also happened at the other periods evaluated. In the second stage, the isolates which were initially at 5 degrees C and 15 degrees C evidenced long developing hyphae with the presence of vesicles, zoosporangia, and zoospores within 4 hours of incubation, and these characteristics were kept at the other evaluated periods. The isolates kept at 37 degrees C showed evident zoosporogenesis in the first 4 hours of evaluation. It was concluded that temperatures of 20 degrees C and 37 degrees C support P. insidiosum zoosporogenesis process. On the other hand, 5 degrees C and 15 degrees C temperatures do not kill the microorganism. PMID- 29228376 TI - Effects of Cyclophosphamide and/or Doxorubicin in a Murine Model of Postchemotherapy Cognitive Impairment. AB - Postchemotherapy cognitive impairment, or PCCI, is a common complaint, particularly among breast cancer patients. However, the exact nature of PCCI appears complex. To model the human condition, ovariectomized C57BL/6J mice were treated intravenous weekly for 4 weeks with saline, 2 mg/kg doxorubicin (DOX), 50 mg/kg cyclophosphamide (CYP), or DOX + CYP. For the subsequent 10 weeks, mice were assessed on several behavioral tests, including those measuring spatial learning and memory. After sacrifice, hippocampal spine density and morphology in the dentate gyrus, CA1, and CA3 regions were measured. Additionally, hippocampal levels of total glutathione, glutathione disulfide, MnSOD, CuZnSOD, and cytokines were measured. Body weight decreased in all groups during treatment, but recovered post-treatment. Most behaviors were unaffected by drug treatment: Open field activity, motor coordination, grip strength, water maze and Barnes maze performance, buried food test performance, and novel object and object location recognition tests. There were some significant effects of CYP and DOX + CYP treatment during the initial test of home cage behavior, but these did not persist into the second and third test times. Density of stubby spines, but not mushroom or thin spines, in the dentate gyrus was significantly decreased in the DOX, CYP, and DOX + CYP treatment groups. There were no significant effects in the CA1 or CA3 regions. CuZnSOD levels were significantly increased in DOX + CYP treated mice; other hippocampal antioxidant levels were unaffected. Most cytokines showed no treatment-related effects, but IL-1beta, IL-6, and IL-12 were slightly reduced in mice treated with DOX + CYP. Although the animal model, route of exposure, and DOX and CYP doses used here were reflective of human exposure, there were only sporadic effects due to chemotherapeutic treatment. PMID- 29228377 TI - Genotyping of Pneumocystis jirovecii in colonized patients with various pulmonary diseases. AB - Pneumocystis jirovecii is an opportunistic fungus causing Pneumocystis pneumonia primarily in immunosuppressed patients. However, immunocompetent individuals may become colonized and, as asymptomatic carriers, serve as reservoirs of the pathogen. Moreover, these asymptomatic carriers are at higher risk of developing pneumonia if favorable conditions occur. This study aimed to determine the prevalence of P. jirovecii in patients with various pulmonary diseases and to characterize the genetic diversity of organisms circulating in the studied population. Bronchial washing specimens from 105 patients were tested for presence of P. jirovecii using nested polymerase chain reaction (PCR) targeting the mtLSU rRNA gene, as well as immunofluorescence microscopy. Multilocus sequence typing involving analysis of three loci-mtLSU rRNA, CYB, and SOD-was used for genotyping analysis. P. jirovecii DNA was detected in 17 (16.2%) patients. Amplification of the SOD locus was successful only in five cases (29.4% of the positive patients), while mtLSU rRNA and CYB were genotyped in all positive samples. Therefore, combined genotypes were identified based only on mtLSU rRNA and CYB loci. Eight different genotypes were identified, with Pj 1 and Pj 2 being the most prevalent (29.4% of patients each). There was no statistical correlation between these genotypes and demographic or clinical data; however, we found that infection with mutant CYB strains occurred only in patients diagnosed with lung cancer. Of the potential predictors examined, only immunosuppressive treatment was significantly associated with colonization. In conclusion, patients with various respiratory diseases, especially when immunosuppressed, are at risk of Pneumocystis colonization. PMID- 29228378 TI - Neural mechanisms mediating degrees of strategic uncertainty. AB - In social interactions, strategic uncertainty arises when the outcome of one's choice depends on the choices of others. An important question is whether strategic uncertainty can be resolved by assessing subjective probabilities to the counterparts' behavior, as if playing against nature, and thus transforming the strategic interaction into a risky (individual) situation. By means of functional magnetic resonance imaging with human participants we tested the hypothesis that choices under strategic uncertainty are supported by the neural circuits mediating choices under individual risk and deliberation in social settings (i.e. strategic thinking). Participants were confronted with risky lotteries and two types of coordination games requiring different degrees of strategic thinking of the kind 'I think that you think that I think etc.' We found that the brain network mediating risk during lotteries (anterior insula, dorsomedial prefrontal cortex and parietal cortex) is also engaged in the processing of strategic uncertainty in games. In social settings, activity in this network is modulated by the level of strategic thinking that is reflected in the activity of the dorsomedial and dorsolateral prefrontal cortex. These results suggest that strategic uncertainty is resolved by the interplay between the neural circuits mediating risk and higher order beliefs (i.e. beliefs about others' beliefs). PMID- 29228379 TI - LETTER TO THE EDITOR: THE ABSORPTION PROPERTIES OF LEAD-FREE GARMENTS FOR USE IN RADIATION PROTECTION. PMID- 29228380 TI - Elderly versus nonelderly patients with invasive aspergillosis in the ICU: a comparison and risk factor analysis for mortality from the AspICU cohort. AB - Data regarding the epidemiology and diagnosis of invasive aspergillosis in the critically ill population are limited, with data regarding elderly patients (>=75 years old) even scarcer. We aimed to further compare the epidemiology, characteristics and outcome of elderly versus nonelderly critically ill patients with invasive aspergillosis (IA) Prospective, international, multicenter observational study (AspICU) including adult intensive care unit (ICU) patients, with a culture and/or direct examination and/or histopathological sample positive for Aspergillus spp. at any site. We compared clinical characteristics and outcome of IA in ICU patients using two different diagnostic algorithms. Elderly and nonelderly ICU patients with IA differed in a number of characteristics, including comorbidities, clinical features of the disease, mycology testing, and radiological findings. No difference regarding mortality was found. According to the clinical algorithm, elderly patients were more likely to be diagnosed with putative IA. Elderly patients had less diagnostic radiological findings and when these findings were present they were detected late in the disease course. The comparison between elderly survivors and nonsurvivors demonstrated differences in clinical characteristics of the disease, affected sites and supportive therapy needed. All patients who were diagnosed with proven IA died. Increased vigilance combined with active search for mycological laboratory evidence and radiological confirmation are necessary for the timely diagnosis of IA in the elderly patient subset. Although elderly state per se is not a particular risk factor for mortality, a high SOFA score and the decision not to administer antifungal therapy may have an impact on survival of elderly patients. PMID- 29228381 TI - Etiology and Impact of Coinfections in Children Hospitalized With Community Acquired Pneumonia. AB - Background: Recognition that coinfections are common in children with community acquired pneumonia (CAP) is increasing, but gaps remain in our understanding of their frequency and importance. Methods: We analyzed data from 2219 children hospitalized with CAP and compared demographic and clinical characteristics and outcomes between groups with viruses alone, bacteria alone, or coinfections. We also assessed the frequency of selected pairings of codetected pathogens and their clinical characteristics. Results: A total of 576 children (26%) had a coinfection. Children with only virus detected were younger, more likely to be black, and more likely to have comorbidities such as asthma, compared with children infected with typical bacteria alone. Children with virus-bacterium coinfections had a higher frequency of leukocytosis, consolidation on chest radiography, parapneumonic effusions, intensive care unit admission, and need for mechanical ventilation and an increased length of stay, compared with children infected with viruses alone. Virus-virus coinfections were generally comparable to single-virus infections, with the exception of the need for oxygen supplementation, which was higher during the first 24 hours of hospitalization in some virus-virus pairings. Conclusions: Coinfections occurred in 26% of children hospitalized for CAP. Children with typical bacterial infections, alone or complicated by a viral infection, have worse outcomes than children infected with a virus alone. PMID- 29228382 TI - Long-Term Neurological and Radiological Results of Consecutive 63 Unruptured Anterior Communicating Artery Aneurysms Clipped via Lateral Supraorbital Keyhole Minicraniotomy. AB - BACKGROUND: Treatments for unruptured anterior communicating artery (AcomA) aneurysm have relatively high morbidity. OBJECTIVE: To assess the lateral supraorbital keyhole approach for safe and complete clipping of unruptured AcomA aneurysm and evaluate the long-term clinical and radiological outcomes, including cognitive and depressive status. METHODS: A total of 63 patients (aged 41-79 yr, mean 64 yr) with relatively small AcomA aneurysms clipped via the lateral supraorbital approach were retrospectively analyzed among the 105 AcomA aneurysms treated by clipping from 2005 to 2014. Neurological and cognitive functions were examined by several scales, including the modified Rankin Scale (mRS) and Mini Mental Status Examination. The depressive state was assessed using the Beck Depression Inventory and Hamilton Depression Scale. The state of clipping was assessed 1 yr and then every few years after the operation by 3-dimensional computed tomography angiography. RESULTS: Complete neck clipping was confirmed in 62 aneurysms (98.4%). Perioperative complications occurred in 5 patients (5/63; mild frontalis muscle weakness in 3, anosmia in 1, and meningitis in 1). The mean clinical follow-up period was 5.2 +/- 2.1 yr. No patient showed an mRS score more than 2 and all were completely independent in daily life. The depression scores were significantly improved after surgery. The overall mortality was 0% and overall morbidity (mRS score > 2 or Mini-Mental Status Examination score < 24) was 1.6%. All completely clipped aneurysms did not show any recurrence during the mean follow-up period of 4.9 +/- 2.1 yr. CONCLUSION: Lateral supraorbital keyhole approach to clip relatively small unruptured AcomA aneurysm promises less invasive and durable treatment. PMID- 29228383 TI - Oral fungal-bacterial biofilm models in vitro: a review. AB - Inclusion of fungi as commensals in oral biofilm is an important innovation in oral biology, and this work aimed to review the literature on the available biofilm and related disease in vitro models. Actually, thousands of bacterial and around one hundred of fungal phylotypes can colonize the oral cavity. Taxonomic profiling combined with functional expression analysis has revealed that Candida albicans, Streptococcus mutans and prominent periodontopathogens are not always present or numerically important in candidiasis, caries, or periodontitis lesions. However, C. albicans combined with Streptococcus spp. co-increase their virulence in invasive candidiasis, early childhood caries or peri-implantitis. As Candida species and many other fungi are also members of oral microcosms in healthy individuals, mixed fungal-bacterial biofilm models are increasingly valuable investigative tools, and new fungal-bacterial species combinations need to be investigated. Here we review the key points and current methods for culturing in vitro mixed fungal-bacterial models of oral biofilms. According to ecosystem under study (health, candidiasis, caries, periodontitis), protocol design will select microbial strains, biofilm support (polystyrene plate, cell culture, denture, tooth, implant), pre-treatment support (human or artificial saliva) and culture conditions. Growing mixed fungal-bacterial biofilm models in vitro is a difficult challenge. But reproducible models are needed, because oral hygiene products, food and beverage, medication, licit and illicit drugs can influence oral ecosystems. So, even though most oral fungi and bacteria are not cultivable, in vitro microbiological models should still be instrumental in adapting oral care products, dietary products and care protocols to patients at higher risk of oral diseases. Microbial biofilm models combined with oral epithelial cell cultures could also aid in understanding the inflammatory reaction. PMID- 29228384 TI - Letter: Is Serum Glial Fibrillary Acidic Protein a Comprehensive Marker for High Grade Glioma? PMID- 29228385 TI - Secondhand Smoke Exposure in Primary School Children: A Survey in Dhaka, Bangladesh. AB - Introduction: We report on second-hand smoke (SHS) exposure based on saliva cotinine levels among children in Bangladesh-a country with laws against smoking in public places. Methods: A survey of primary school children from two areas of the Dhaka district was conducted in 2015. Participants completed a questionnaire and provided saliva samples for cotinine measurement to assess SHS exposure with a cut-off range of >=0.1ng/mL. Results: Four hundred and eighty-one children studying in year-5 were recruited from 12 primary schools. Of these, 479 saliva samples were found sufficient for cotinine testing, of which 95% (453/479) were positive for recent SHS exposure. Geometric mean cotinine was 0.36 (95% CI = 0.32 to 0.40); 43% (208/479) of children lived with at least one smoker in the household. Only 21% (100/479) reported complete smoking restrictions for residents and visitors; 87% (419/479) also reported being recently exposed to SHS in public spaces. Living with a smoker and number of tobacco selling shops in the neighborhood had positive associations with recent SHS exposure. Conclusions: Despite having a ban on smoking in public places, recent SHS exposure among children in Bangladesh remains very high. There is an urgent need to reduce exposure to SHS in Bangladeshi children. Implications: Children bear the biggest burden of disease due to SHS exposure than any other age group. However, children living in many high-income countries have had a sharp decline in their exposure to SHS in recent years. What remains unknown is if children living in low-income countries are still exposed to SHS. Our study suggests that despite having a ban on smoking in public places, most primary school children in Dhaka, Bangladesh are still likely to be exposed to SHS. PMID- 29228386 TI - Efficacy of Solution-Focused Brief Therapy for Distress among Parents of Children with Congenital Heart Disease in China. AB - Chinese parents of children with congenital heart disease (CHD) experience significant psychological distress due to the child's illness and hospitalization. Unfortunately, there are few psychosocial interventions for parental distress in China. This pilot study aimed to examine the efficacy of solution-focused brief therapy (SFBT) in a Chinese hospital for parental distress using a randomized controlled trial design. The participants included 40 Chinese parents of a currently hospitalized child diagnosed with CHD who were assessed to have psychological distress. Parents were randomized into either the intervention (n = 25) or the hospital medical social work treatment as usual (TAU) (n = 28) group. The Chinese Brief Symptom Inventory-18 and Chinese version of Herth Hope Index were administered before and after the interventions. Results of the intent to-treat analysis indicated a significant decrease in parental distress and increase in parents' levels of hope in the intervention group compared with the TAU group. This study supported SFBT administered in a hospital setting as a promising intervention for reducing distress among Chinese parents with children diagnosed with CHD. PMID- 29228387 TI - Association between rs1051730 and smoking during pregnancy in Dutch women. AB - Introduction: The common genetic variant (rs1051730) in the 15q24 nicotinic acetylcholine receptor gene cluster CHRNA5-CHRNA3-CHRNB4 was associated with smoking quantity and has been reported to be associated also with reduced ability to quit smoking in pregnant women but results were inconsistent in non pregnant women. The aim of this study was to explore the association between rs1051730 and smoking cessation during pregnancy in a sample of Dutch women. Methods: Data on smoking during pregnancy were available from 1,337 women who ever smoked registered at the Netherlands Twin Register (NTR). Logistic regression was used to assess evidence for association of rs1051730 genotype on smoking during pregnancy. In a subsample of 561 women we investigated the influence of partner's smoking. Educational attainment and year of birth were used as covariates in both analyses. Results: There was evidence for a significant association between having 1 or more T allele's of the rs1051730 polymorphism and the likelihood of smoking during pregnancy (P = 0.03, odds ratio = 1.28, 95% confidence interval: 1.02, 1.61). However, this association attenuated when adjusting for birth cohort and educational attainment (P = 0.37, odds ratio = 1.12, 95% confidence interval: 0.87, 1.43). In the subsample, Smoking spouse was highly associated with smoking during pregnancy, even when educational attainment and birth cohort were included in the model. Conclusions: Our results did not support a strong association between this genetic variant and smoking during pregnancy. However, a strong association was observed with smoking behavior of the partner, regardless of the genotype of the women. Implications: The present study emphasizes the importance of social influences like spousal smoking on smoking behavior of pregnant women. Further research is needed to address the role of rs1051730 genetic variant in influencing smoking cessation and the interaction with important environmental factors like smoking behavior of the partner. PMID- 29228388 TI - Caspase Inhibition Reduces Hepatic Tissue Factor-Driven Coagulation In Vitro and In Vivo. AB - Tissue factor (TF) is the primary activator of the blood coagulation cascade. Liver parenchymal cells (ie, hepatocytes) express TF in a molecular state that lacks procoagulant activity. Hepatocyte apoptosis is an important feature of acute and chronic liver diseases, and Fas-induced apoptosis increases hepatocyte TF procoagulant activity in vitro. We determined the impact of a pan-caspase inhibitor, IDN-7314, on hepatocyte TF activity in vitro and TF-mediated coagulation in vivo. Treatment of primary mouse hepatocytes with the Fas death receptor ligand (Jo2, 0.5 MUg/ml) for 8 h increased hepatocyte TF procoagulant activity and caused release of TF-positive microvesicles. Pretreatment with 100 nM IDN-7314 abolished Jo2-induced caspase-3/7 activity and significantly reduced hepatocyte TF procoagulant activity and release of TF-positive microvesicles. Treatment of wild-type C57BL/6 mice with a sublethal dose of Jo2 (0.35 mg/kg) for 4.5 h increased coagulation, measured by a significant increase in plasma thrombin-antithrombin and TF-positive microvesicles. Total plasma microvesicle associated TF activity was reduced in mice lacking hepatocyte TF; suggesting TF positive microvesicles are released from the apoptotic liver. Fibrin(ogen) deposition increased in livers of Jo2-treated wild-type mice and colocalized primarily with cleaved caspase-3-positive hepatocytes. Pretreatment with IDN-7314 reduced caspase-3 activation, prevented the procoagulant changes in Jo2-treated mice, and reduced hepatocellular injury. Overall, the results indicate a central role for caspase activity in TF-mediated activation of coagulation following apoptotic liver injury. Moreover, the results suggest that liver-selective caspase inhibition may be a putative strategy to limit procoagulant and prothrombotic changes in patients with chronic liver disease. PMID- 29228389 TI - High-resolution melting analysis: A novel approach for clade differentiation in Pythium insidiosum and pythiosis. AB - Pythium insidiosum causes life-threatening human pythiosis. Based on phylogenetic analysis using internal transcribed spacer (ITS) region, mitochondrial cytochrome C oxidase II (COX2) gene, intergenic spacer (IGS) region and exo-1,3-beta glucanase gene (exo1), P. insidiosum is classified into clade ATH, BTH, and CTH related to geographic distribution. At present, polymerase chain reaction in any of these specific regions with DNA sequencing is the only technique to provide clade diagnosis. In this study, P. insidiosum-specific primers targeting COX2 gene were designed and used in real-time quantitative polymerase chain reaction (qPCR) with subsequent high-resolution melting (HRM) to provide rapid identification as well as clade classification for P. insidiosum. Based on the qPCR-HRM method, 15 P. insidiosum isolates could be differentiated from 28 related organisms with 100% specificity and 1 pg limit of detection. This technique was, in addition, directly tested on clinical samples from proved human pythiosis cases: nine corneal scrapes and six arterial clots. The qPCR-HRM results of all nine corneal samples were a 100% match with the results from the conventional PCR at clade level. However, the qPCR-HRM results of arterial clot samples were only matched with the nucleotide sequencing results from the conventional PCR at species level. In conclusion, the qPCR-HRM is a simple one closed tube, inexpensive and user-friendly method to identify P. insidiosum into clade level. PMID- 29228391 TI - Arsenic Attenuates Heparin-Binding EGF-Like Growth Factor/EGFR Signaling That Promotes Matrix Metalloprotease 9-Dependent Astrocyte Damage in the Developing Rat Brain. AB - We earlier reported that exposure to arsenic at concentrations in ground water of India attenuated glial fibrillary acidic protein (GFAP) during brain development. Here, we validated the effects and explored mechanism in cultured astrocytes and developing rat brain. We hypothesized participation of epidermal growth factor receptor (EGFR), known to regulate GFAP. We found that arsenic inactivated EGFR, marked by reduced phospho-EGFR in astrocytes. Screening EGFR ligands revealed an arsenic-mediated attenuation in cellular and secreted-Heparin-binding EGF-like growth factor (HB-EGF). Furthermore, we observed that recombinant-HB-EGF cotreatment with arsenic blocked reduction in HB-EGF, secreted-HB-EGF and phospho EGFR, which could be reversed by EGFR-inhibitor, gefitinib, suggesting that arsenic attenuated an HB-EGF/EGFR loop in astrocytes. This reduced HB-EGF/EGFR was essentially responsible for arsenic-induced astrocyte damage, obvious from a recombinant-HB-EGF-mediated recovery in GFAP levels and astrocyte morphology and reduction in astrocyte apoptosis, and the reverse by gefitinib. We found that arsenic also suppressed neuronal HB-EGF levels, which additionally contributed towards astrocyte damage. Exploring the pathways downstream of reduced HB EGFR/EGFR revealed that an upregulated matrix metalloproteinase 9 (MMP9) within the astrocytes ultimately led to apoptosis and GFAP loss. Astrocytes and MMPs are known to regulate the blood-brain barrier (BBB) integrity, and hence we examined the effects of arsenic on BBB. We detected an arsenic-mediated increased BBB permeability, which could be blocked by recombinant-HB-EGF and MMP9 inhibitor, SB 3CT. Thus, our study indicates that via reduced astrocyte and neuronal HB-EGF signaling, arsenic may induce MMP9 levels and GFAP loss in astrocytes, which might adversely affect BBB integrity of the developing rat brain. PMID- 29228390 TI - Altered brain morphology after focal radiation reveals impact of off-target effects: implications for white matter development and neurogenesis. AB - Background: Children with brain tumors treated with cranial radiation therapy (RT) often exhibit cognitive late effects, commonly associated with reduced white matter (WM) volume and decreased neurogenesis. The impact of radiation damage in particular regions or tissues on brain development as a whole has not been elucidated. Methods: We delivered whole-brain or focal radiation (8 Gy single dose) to infant mice. Focal treatments targeted white matter (anterior commissure), neuronal (olfactory bulbs), or neurogenic (subventricular zone) regions. High-resolution ex vivo MRI was used to assess radiation-induced volume differences. Immunohistochemistry for myelin basic protein and doublecortin was performed to assess associated cellular changes within white matter and related to neurogenesis, respectively. Results: Both whole-brain and focal RT in infancy resulted in volume deficits in young adulthood, with whole-brain RT resulting in the largest deficits. RT of the anterior commissure, surprisingly, showed no impact on its volume or on brain development as a whole. In contrast, RT of the olfactory bulbs resulted in off-target volume reduction in the anterior commissure and decreased subventricular zone neurogenesis. RT of the subventricular zone likewise produced volume deficits in both the olfactory bulbs and the anterior commissure. Similar off-target effects were found in the corpus callosum and parietal cortex. Conclusions: Our results demonstrate that radiation damage locally can have important off-target consequences for brain development. These data suggest that WM may be less radiosensitive than volume change alone would indicate and have implications for region-sparing radiation treatments aimed at reducing cognitive late effects. PMID- 29228392 TI - Hepatic Pharmacokinetics and Pharmacodynamics With Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir Treatment and Variable Ribavirin Dosage. AB - Background: It is unknown whether ribavirin (RBV) coadministration modifies the early rate of decline of hepatitis C virus (HCV) RNA in the liver versus plasma compartments, specifically. Methods: This partially randomized, open-label, phase 2 study enrolled treatment-naive, noncirrhotic patients with HCV genotype 1a. Patients were randomized 1:1 into Arms A and B, and then enrolled in Arm C. Patients received ombitasvir/paritaprevir/ritonavir plus dasabuvir for 12 weeks with either: no RBV for the first 2 weeks followed by weight-based dosing thereafter (Arm A), weight-based RBV for all 12 weeks (Arm B), or low-dose RBV (600 mg) once daily for all 12 weeks. Fine needle aspiration (FNA) was used to determine HCV RNA decline within liver. Results: Baseline HCV RNA was higher and declined more rapidly in plasma than liver; however, RBV dosing did not impact either median plasma or liver HCV RNA decline during the first 2 weeks of treatment. Liver-to-plasma drug concentrations were variable over time. The most common adverse event was pain associated with FNA. Conclusions: Coadministration of RBV had minimal visible impact on the plasma or liver kinetics of HCV RNA decline during the first 2 weeks of treatment, regardless of RBV dosing. PMID- 29228393 TI - Quantifying the Arousal Threshold Using Polysomnography in Obstructive Sleep Apnea. AB - Study Objectives: Precision medicine for obstructive sleep apnea (OSA) requires noninvasive estimates of each patient's pathophysiological "traits." Here, we provide the first automated technique to quantify the respiratory arousal threshold-defined as the level of ventilatory drive triggering arousal from sleep using diagnostic polysomnographic signals in patients with OSA. Methods: Ventilatory drive preceding clinically scored arousals was estimated from polysomnographic studies by fitting a respiratory control model (Terrill et al.) to the pattern of ventilation during spontaneous respiratory events. Conceptually, the magnitude of the airflow signal immediately after arousal onset reveals information on the underlying ventilatory drive that triggered the arousal. Polysomnographic arousal threshold measures were compared with gold standard values taken from esophageal pressure and intraoesophageal diaphragm electromyography recorded simultaneously (N = 29). Comparisons were also made to arousal threshold measures using continuous positive airway pressure (CPAP) dial downs (N = 28). The validity of using (linearized) nasal pressure rather than pneumotachograph ventilation was also assessed (N = 11). Results: Polysomnographic arousal threshold values were correlated with those measured using esophageal pressure and diaphragm EMG (R = 0.79, p < .0001; R = 0.73, p = .0001), as well as CPAP manipulation (R = 0.73, p < .0001). Arousal threshold estimates were similar using nasal pressure and pneumotachograph ventilation (R = 0.96, p < .0001). Conclusions: The arousal threshold in patients with OSA can be estimated using polysomnographic signals and may enable more personalized therapeutic interventions for patients with a low arousal threshold. PMID- 29228394 TI - The Psychiatric Risk Gene Transcription Factor 4 (TCF4) Regulates Neurodevelopmental Pathways Associated With Schizophrenia, Autism, and Intellectual Disability. AB - Background: Common genetic variants in and around the gene encoding transcription factor 4 (TCF4) are associated with an increased risk of schizophrenia. Conversely, rare damaging TCF4 mutations cause Pitt-Hopkins syndrome and have also been found in individuals with intellectual disability (ID) and autism spectrum disorder (ASD). Methods: Chromatin immunoprecipitation and next generation sequencing were used to identify the genomic targets of TCF4. These data were integrated with expression, epigenetic and disease gene sets using a range of computational tools. Results: We identify 10604 TCF4 binding sites in the genome that were assigned to 5437 genes. De novo motif enrichment found that most TCF4 binding sites contained at least one E-box (5'-CAtcTG). Approximately 77% of TCF4 binding sites overlapped with the H3K27ac histone modification for active enhancers. Enrichment analysis on the set of TCF4 targets identified numerous, highly significant functional clusters for pathways including nervous system development, ion transport and signal transduction, and co-expression modules for genes associated with synaptic function and brain development. Importantly, we found that genes harboring de novo mutations in schizophrenia (P = 5.3 * 10-7), ASD (P = 2.5 * 10-4), and ID (P = 7.6 * 10-3) were also enriched among TCF4 targets. TCF4 binding sites were also found at other schizophrenia risk loci including the nicotinic acetylcholine receptor cluster, CHRNA5/CHRNA3/CHRNB4 and SETD1A. Conclusions: These data demonstrate that TCF4 binding sites are found in a large number of neuronal genes that include many genetic risk factors for common neurodevelopmental disorders. PMID- 29228395 TI - Brain Stem Cavernous Malformations: Operative Nuances of a Less-Invasive Resection Technique. AB - BACKGROUND: Different operative techniques are reported for the resection of brainstem cavernous malformations (BSCMs). The senior author has previously reported on a less-invasive technique of entering the brain stem with piecemeal removal of BSCMs, especially the deep-seated ones. OBJECTIVE: To present a larger series of these lesions, emphasizing the approach to the brain stem via case selection. We discuss the nuances of the less-invasive operative technique through case illustrations and intraoperative videos. METHODS: A retrospective review of 46 consecutive cases of BSCMs, with their clinical and radiographic data, was performed. Nine cases were selected to illustrate 7 different operative approaches, and discuss surgical nuances of the less-invasive technique unique to each. RESULTS: Postoperative morbidity, defined as an increase in modified Rankin Scale, was observed in 5 patients (10.9%). A residual BSCM was present in 2 patients (4.3%); both underwent reoperation to remove the remainder. At follow-up of 31.1 +/- 27.8 mo, 3 patients experienced recurrence (6.5%). Overall, 65% of our patients improved, 20% stayed the same, and 11% worsened postsurgery. Two patients died, yielding a mortality of 4.3%. CONCLUSION: Using the less-invasive resection technique for piecemeal BSCM removal, in appropriately selected patients, has yielded comparable to improved patient outcomes over existing large series. In our experience, lateral, anterolateral, and posterolateral approaches are favorable over direct midline (dorsal or ventral) approaches. A thorough understanding of brain-stem safe-entry zones, in conjunction with appropriate approach selection, is key to a good outcome in challenging cases. PMID- 29228396 TI - Comment on: Hereditary haemochromatosis arthropathy and Doppler ultrasound findings of synovitis: reply. PMID- 29228397 TI - Yeast identification by sequencing, biochemical kits, MALDI-TOF MS and rep-PCR DNA fingerprinting. AB - No study has comprehensively evaluated the performance of 28S nrDNA and ITS sequencing, commercial biochemical test kits, MALDI-TOF MS platforms, and the emerging rep-PCR DNA fingerprinting technology using a cohort of yeast strains collected from a clinical microbiology laboratory. In this study, using 71 clinically important yeast isolates (excluding Candida albicans) collected from a single centre, we determined the concordance of 28S nrDNA and ITS sequencing and evaluated the performance of two commercial test kits, two MALDI-TOF MS platforms, and rep-PCR DNA fingerprinting. 28S nrDNA and ITS sequencing showed complete agreement on the identities of the 71 isolates. Using sequencing results as the standard, 78.9% and 71.8% isolates were correctly identified using the API 20C AUX and Vitek 2 YST ID Card systems, respectively; and 90.1% and 80.3% isolates were correctly identified using the Bruker and Vitek MALDI-TOF MS platforms, respectively. Of the 18 strains belonging to the Candida parapsilosis species complex tested by DiversiLab automated rep-PCR DNA fingerprinting, all were identified only as Candida parapsilosis with similarities >=93.2%, indicating the misidentification of Candida metapsilosis and Candida orthopsilosis. However, hierarchical cluster analysis of the rep-PCR DNA fingerprints of these three species within this species complex formed three different discrete clusters, indicating that this technology can potentially differentiate the three species. To achieve higher accuracies of identification, the databases of commercial biochemical test kits, MALDI-TOF MS platforms, and DiversiLab automated rep-PCR DNA fingerprinting needs further enrichment, particularly for uncommonly encountered yeast species. PMID- 29228398 TI - Organophosphorus Compounds at 80: Some Old and New Issues. AB - One of the major classes of pesticides is that of the organophosphates (OPs). Initial developments date back almost 2 centuries but it was only in the mid 1940s that OPs reached a prominent status as insecticides, a status that, albeit declining, is still ongoing. OPs are highly toxic to nontarget species including humans, the primary effects being an acute cholinergic toxicity (responsible for thousands of poisoning each year) and a delayed polyneuropathy. Several issues of current debate and investigation on the toxicology of OPs are discussed in this brief review. These include (1) possible additional targets of OPs, (2) OPs as developmental neurotoxicants, (3) OPs and neurodegenerative diseases, (4) OPs and the "aerotoxic syndrome," (5) OPs and the microbiome, and (6) OPs and cancer. Some of these issues have been debated and studied for some time, while others are newer, suggesting that the study of the toxicology of OPs will remain an important scientific and public health issue for years to come. PMID- 29228399 TI - Effects of glucose and sucrose on mood: a systematic review of interventional studies. AB - Context: Glucose is the main energy source for the brain, and as such, manipulation of glucose supply may affect brain function. It has been suggested that a change in blood glucose may influence mood. Objective: The aim of this review was to investigate the potential effects of glucose and sucrose, compared with placebo, on mood. Data Sources: The electronic databases PubMed and Scopus were searched. Reference lists of selected articles were checked manually. Data Extraction: Randomized controlled trials or crossover trials comparing the effects of glucose or sucrose on mood that were published up to May 2017 were eligible. Potentially eligible articles were selected independently by 2 reviewers. Results: In total, 19 studies were found. Thirteen studies investigated the effects of glucose consumption compared with placebo on mood. Seven of these 13 studies found no effect of glucose on mood. The other 6 studies found small and partial effects that may also be due to other factors like palatability and expectation. Seven of the 19 studies investigated the effects of sucrose ingestion versus placebo on mood. None of these studies found a positive effect on mood, and 1 study observed an adverse effect. One of the studies investigated the effects of both glucose and sucrose. Conclusions: The results from this review show limited effects of glucose ingestion on mood and no effect of sucrose on mood. PMID- 29228401 TI - Middle Cerebral Artery Doppler Changes following Fetal Transfusion Performed with and without Fetal Anesthesia. AB - OBJECTIVE: The objective of this study was to test the association between fetal intravenous anesthesia and the change in middle cerebral artery peak systolic velocity (MCA-PSV) in patients undergoing intrauterine transfusion (IUT) for suspected fetal anemia. STUDY DESIGN: We retrospectively examined data from all patients who underwent IUT via umbilical cord route from 2007 to 2016. We calculated the change of the MCA-PSV multiple of median (MoM) as the difference in MCA-PSV MoM between the pre- and immediate postoperative measurements for the first IUT. The change in MCA-PSV MoM was compared between those who did and did not receive fetal anesthesia using Kruskal-Wallis' testing. RESULTS: Of 62 patients, 37 (59.7%) received intravenous fetal anesthesia and 25 (40.3%) did not. The change in MCA-PSV MoM did not differ between those who did and did not receive fetal anesthesia (median: 0.57 [interquartile range, IQR: +0.42 to +0.76] vs. median 0.57 [IQR: +0.40 to +0.81], p = 1.000). The relationship remained insignificant when stratifying by gestational age, length of procedure, initial MCA-PSV, and when excluding hydropic fetuses. CONCLUSION: Among women undergoing IUT, there was no evidence that the use of fetal anesthesia was associated with a change in the pre- versus postoperative change in MCA-PSV MoM. PMID- 29228400 TI - Informal care and sleep disturbance among caregivers in paid work: Longitudinal analyses from a large community-based Swedish cohort study. AB - Study objectives: To examine cross-sectionally and prospectively whether informal caregiving is related to sleep disturbance among caregivers in paid work. Methods: Participants (N=21 604) in paid work from the Swedish Longitudinal Occupational Survey of Health. Sleeping problems were measured with a validated scale of sleep disturbance (Karolinska Sleep Questionnaire). Random-effects modelling was used to examine the cross-sectional association between informal caregiving (self-reports: none, up to 5h per week, over 5h per week) and sleep disturbance. Potential socio-demographic and health confounders were controlled for and interactions between caregiving and gender included. Longitudinal random effects modelling of the effects of changes in reported informal caregiving upon sleep disturbance and change in sleep disturbance were performed. Results: In multivariate analyses controlling for socio-demographics, health factors and work hours, informal caregiving was associated cross-sectionally with sleep disturbance in a dose-response relationship (compared to no caregiving, up to 5h of caregiving: beta = .03; 95% CI: .01; .06, over 5h: beta = .08; 95% CI: .02; .13), results which varied by gender. Cessation of caregiving was associated with reductions in sleep disturbance (beta = -.08; 95% CI: -.13; -.04). Conclusions: This study provides evidence for a causal association of provision of informal care upon subjective sleep disturbance. Even low intensity care provision was related to sleep disturbance among this sample of carers in paid work. The results highlight the importance of addressing sleep disturbance in caregivers. PMID- 29228402 TI - Lymph node metastasis in early gastric adenocarcinoma in the United States of America. AB - BACKGROUND AND STUDY AIMS: Localized approaches are being increasingly used in the management of early gastric adenocarcinoma; however, there are limited data on lymph node metastasis in the US population. This study examined the incidence and predictors of lymph node involvement for early-stage gastric adenocarcinomas in the USA. PATIENTS AND METHODS: Data were abstracted from the national SEER database from 2004 to 2013. Exclusion criteria included: cases with unknown tumor characteristics, unknown patient characteristics, metastatic disease, neoadjuvant radiation, and lack of surgical resection or lymph node evaluation. Univariate and multivariable analyses were conducted to assess the relationship of tumor stage, grade, and size, and patient sex, race, and age with nodal involvement. RESULTS: 43 769 cases of gastric adenocarcinoma were initially abstracted. After exclusions, 1577 patients remained for analysis. Multivariable analysis revealed that tumor stage (P < 0.001), grade (P = 0.008), and size (P < 0.001) were independent predictors of nodal metastasis. For low grade T1a tumors, nodal metastasis was present in 1.7 %, 1.7 %, 4.5 %, 4.1 %, and 20 % of tumors 0 - 1 cm, 1 - 2 cm, 2 - 3 cm, 3 - 4 cm, and >= 4 cm in size, respectively (P < 0.001), and in 8.4 %, 18.0 %, 19.5 %, 22.0 %, and 35.8 % of T1b tumors, respectively (P < 0.001). CONCLUSIONS: Low grade T1a tumors < 4 cm in size have low rates of nodal metastasis in the US population and may warrant consideration for local resection. Larger, higher grade T1b tumors have high rates of nodal metastasis in the US population and lymph node dissection may be indicated for patients who are surgical candidates. PMID- 29228403 TI - Anterior Cruciate Ligament Mechanoreceptors and their Potential Importance in Remnant-Preserving Reconstruction: A Review of Basic Science and Clinical Findings. AB - Mechanoreceptors, within the anterior cruciate ligament (ACL), are believed to have importance in proprioception, contributing to dynamic knee stability. The potential for reinnervation of the ACL graft is one of the proposed advantages of remnant-preserving reconstruction. The aim of this review is to summarize advances in the basic science underpinning this function, alongside recent clinical studies, to define the current role for remnant-preservation.A comprehensive systematic review was performed using PubMed and Medline searches. Studies were analyzed with particular focus placed on the methodology used to either identify mechanoreceptors or test proprioception.Contemporary work, using immunohistological staining, has shown mechanoreceptors primarily within proximity to the bony attachments of the ACL (peripherally in the subsynovial layer). The number of these receptors has been shown to decrease rapidly, following rupture, with adhesion to the posterior cruciate ligament slowing this decline. Recent studies have shown proprioceptive deficits, in both the injured and contralateral knees, with the clinical relevance of findings limited by testing methodology and the small differences found. The advantages of remnant preservation, seen primarily in animal studies, have not been shown in systematic reviews or meta-analysis of clinical studies.The potential for reinnervation of the graft is likely time-dependent and reliant on continued loading of the remnant. Therefore, current clinical use and future research should focus on preserving remnants within 6 months of injury that remain loaded by adherence to the posterior cruciate ligament. Subsequent testing should account for central neurological changes and focus on clinically relevant outcomes. PMID- 29228404 TI - Chondrocyte Viability at Time of Transplantation for Osteochondral Allografts Preserved by the Missouri Osteochondral Preservation System versus Standard Tissue Bank Protocol. AB - The Missouri Osteochondral Preservation System (MOPS) has been reported to effectively preserve osteochondral allografts (OCAs) twice as long as current tissue bank protocols in preclinical studies. However, viability of OCAs preserved using the MOPS protocol at the time of clinical implantation compared with the current standard of care (SOC) is not known. Viable chondrocyte density (VCD) at time of transplantation will be significantly higher in OCAs preserved using the MOPS protocol compared with OCAs preserved using the current tissue bank protocol and will significantly affect clinical complication rates. Femoral condyle OCAs were obtained from American Association of Tissue Banks accredited tissue banks for clinical use. The OCAs were stored using the current SOC protocol for each respective tissue bank (n = 26) or the MOPS protocol (n = 50). Nonimplanted femoral condyle OCA tissue normally discarded after surgery was collected and assessed for VCD within 1 hour after surgery. Control OCA samples (n = 34) were obtained from one tissue bank. VCD was determined using a validated cell viability assay. Patients (n = 76) had in-clinic follow-up at least 6 months after OCA transplantation. At the time of clinical implantation, mean storage time for OCAs in the SOC cohort was 20.4 days, and in the MOPS cohort was 44.2 days, after procurement. VCD in OCAs in the MOPS cohort was not significantly different from normal healthy cartilage VCD and 100% were above the desired minimum essential level 70% of control VCD at the time of transplantation. VCD in OCAs in the SOC cohort was significantly (p < 0.001) lower than controls and MOPS, and only 27% were above 70% of control VCD at the time of transplantation. MOPS preserves OCA chondrocyte viability at significantly higher levels than current tissue bank storage protocols for a longer period of time after procurement. All MOPS-preserved OCAs exceeded minimum essential VCD levels for up to 56 days after procurement. PMID- 29228405 TI - ? PMID- 29228406 TI - ? PMID- 29228407 TI - [Sport after Total Knee and Hip Arthroplasty]. AB - The introduction of new materials and better implant coatings seems to provide the prerequisites for more intense physical activities after total joint arthroplasties of the lower extremity. Despite recent advances in implant design and materials, recommendations for sport after total joint arthroplasty have not been updated over the past 20 years. The introduction of modern uncemented fixation as well as highly cross-linked polyethylene into total hip arthroplasty allow for a more active life-style without an increased risk of loosening or complications. This publication reviews the literature and presents the current knowledge to provide guidelines for orthopaedic surgeons treating patients after total joint replacement surgery. PMID- 29228408 TI - [Biomechanical Evaluation of Rehabilitation after Surgical Repair of Achilles Tendon Ruptures]. AB - Background Muscles and tendons are subjected to a high level of stress in everyday life and sports. This often leads to injuries and is associated with training failure and reduced performance as well as with high costs for treatment and rehabilitation. Fast and successful treatment is therefore very important, both from an athletic and economic point of view. This study aims to demonstrate the relevance of biomechanical procedures for the objective monitoring of rehabilitation. At the same time, the results are to be used to establish progress and evaluation criteria for an efficient and controlled rehabilitation. Patients and methods In a retrospective study, a total of 42 patients were evaluated biomechanically after surgical repair of a complete Achilles tendon rupture 18 (18 W) and 26 weeks (26 W) postoperatively. Ground reaction forces in barefoot walking on a treadmill as well as isokinetic maximum strength for the plantar flexors and dorsal extensors were assessed. Results The push-off force on the injured side increased from 0.88 (18 W) to 0.95 (26 W). The percentage of heel contact time on the injured side was 59 % at 18 W and 55 % at 26 W. Plantar flexion torque increased from 70 Nm (18 W) to 90 Nm (26 W) on average on the injured side. The percentage of the plantar flexion deficit (injured/non-injured side) decreased from 34 % to 21 % on the two postoperative measuring dates. Conclusions The described biomechanical methods allow for a quantitative assessment and an objective control of the rehabilitation process. The results can also be used for the definition of evaluation and progression criteria in order to assess the progress of a patient's therapy and to guide the rehabilitation process in a controlled manner. PMID- 29228409 TI - Short-Term Effects of Combined High-Intensity Strength and Sprint Interval Training on Anthropometric Characteristics and Physical Performance of Elite Team Handball Players. AB - Muscular strength and speed are critical physical factors in determining the technical and tactical skills of elite team handball players. This study thus investigated the effect of high-intensity muscular strength and sprint interval training (SIT) on lower limb explosive performance and anthropometric characteristics in 22 male handball athletes aged 20.2 +/- 0.1 years. A training group (TG, n = 12) and a control group (CG, n = 10) were followed over 8 weeks parallel to regular handball training. The TG received combined additional high intensity muscular strength and interval training twice per week during this period. The muscular training was comprised of 3 - 4 sets of 70 - 85 % of 1-RM (repetition maximum) of dynamic back half squat exercise; followed immediately by a short sprint program with 4, 5, and 6 maximal intensity repetitions of 30 m runs. Strength (1-RM of the half back-squat and bench press), first step (V1S), first 5 m (V5 m), squat jumps (SJ), counter movement jumps (CMJ) and the Modified Agility Test (MAT) were tested at the beginning and end of the study. Significant interaction effects (group * time) were observed for all parameters (eta2 range: 0.531 (MAT) to 0.829 (First 5 m)). All 10 parameters showed relevant intervention effects (d> 0.5) in the TG (highest intervention effect: CMJ: d = 4.05), the mean effect size being d = 1.85. In contrast, scores for the CG either remained unchanged or decreased (d = -0.24). We conclude that combined high-intensity strength and sprint interval training during the competitive season should be recommended to elite male handball players as a means of improving handball related performance characteristics without compromising other critical aspects of the individual's performance. PMID- 29228410 TI - Clinical Course of Eosinophilic Cellulitis. AB - The patient was a previously healthy 23-year-old woman who made an outpatient visit to our hospital's Department of General Internal Medicine after developing pain and edema of the lower legs a week earlier. The patient was diagnosed with eosinophilic cellulitis (EC) based on an increased eosinophil count of 5,418/mm3 and the results of a skin biopsy of the lower leg that showed eosinophilic infiltration of the dermal tissue. Her condition improved after oral prednisone therapy. EC presents clinically as edema and eosinophilia. Therefore, in many cases, patients make an outpatient visit to the internal medicine department. In the present study, the clinical course of nine patients diagnosed with EC as outpatients at our Department of General Internal Medicine over the past 10 years was examined. PMID- 29228411 TI - Management of Breast Cancer in Adjuvant Chemotherapy Settings in the Kanagawa Breast Oncology Group. AB - OBJECTIVE: Many different options for adjuvant chemotherapy are recommended in guidelines for the treatment of breast cancer. Therapeutic strategies vary among physicians. The major goals for this project were to gain a better understanding of how biomarkers are integrated into practice and how physicians select adjuvant chemotherapy. METHODS: We assembled a questionnaire with 23 example scenarios of breast cancer cases, including 6 items relevant to postoperative adjuvant therapy. During October-November 2012, the questionnaire was submitted to 131 physicians engaged in breast cancer treatment in Kanagawa Prefecture, Japan. RESULTS: Forty-eight physicians responded to the questionnaire, 46 of whom provided valid responses. Their responses revealed a notable lack of consensus regarding therapeutic choices. We analyzed 6 scenarios relevant to postoperative adjuvant therapy. In general, the selection of postoperative adjuvant therapy appeared to be based on hormone sensitivity, human epidermal growth factor receptor 2 (HER2) expression, lymph node metastasis, tumor size, histological/nuclear grade, vascular/lymphatic system invasion, Ki67 level, Oncotype DX score, and the patient's age. CONCLUSION: Given the varied therapeutic choices that we observed, clinical research is needed to provide appropriate, unified therapeutic strategies. PMID- 29228412 TI - A Case of Eosinophilic Myocarditis Associated with Cardiogenic Shock. AB - The patient was a 32-year-old man with a previous history of bronchial asthma. He was admitted with chief complaints of dyspnea and skin rash associated with itching of the palms and soles of the feet, which began 2 weeks earlier. Because of the presence of cardiac failure and increase in the peripheral blood eosinophil count, eosinophilic myocarditis (EM) was suspected. His blood pressure gradually decreased and the patient went into cardiogenic shock. Therefore, endomyocardial biopsy was performed and was immediately followed by corticosteroid therapy and intra-aortic balloon pump (IABP) placement. With the findings of eosinophil infiltration associated with myocardial interstitial edema on endomyocardial biopsy, EM was diagnosed. In this case, early therapeutic intervention led to resolution of shock resolved and improvement of the peripheral blood eosinophilia and cardiac function; the patient was discharged 33 days after the onset of symptoms. EM is a rare cardiomyopathy in which myocardial eosinophil infiltration is seen. Although it has been perceived as having a mild clinical course, this report described a severe case of EM associated with cardiogenic shock, which improved as a result of early diagnosis and therapeutic intervention. PMID- 29228413 TI - Estimating Vector-borne Viral Infections in the Urban Setting of the 2020 Tokyo Olympics, Japan, Using Mathematical Modeling. AB - The first domestic outbreak of dengue fever in Japan since 1945 was reported in Tokyo in 2014. Meanwhile, daily mean summer temperatures are expected to continue to rise world-wide. Such conditions are expected to increase the risk of an arbovirus outbreak at the 2020 Tokyo Olympic Games. To address this possibility, the present study compared estimates of the risk of infection by dengue, chikungunya, and Zika viruses in urban areas. To compare the risk of infection by arboviruses transmitted by Ae. albopictus mosquitoes, the reproduction number for each of three arboviruses was estimated under the environmental conditions associated with the 2014 dengue outbreak in Tokyo, and additionally under conditions assuming a daily mean temperature elevation of 2 degrees C. For dengue, chikungunya, and Zika, the estimated distributions of R0 were independently fitted to gamma distributions yielding median R0 values of 1.00, 0.46, and 0.36, respectively. If the daily mean temperature were to rise from 28 degrees C to 30 degrees C, our model predicts increases of the median R0 of 18% for dengue, 4.3% for chikungunya, and 11.1% for Zika. Strengthening of the public health responsivity for these emerging arboviral diseases will be needed in preparation for the 2020 Olympic Games in Tokyo. PMID- 29228414 TI - Temporal Changes of Inflammatory Cytokine Profiles in Epithelial Lining Fluid in a Canine Lung Transplant Model. AB - OBJECTIVES: Ischemia-reperfusion injury resulting in post-transplant lung dysfunction involves a complicated network of cytokines that has yet to be fully investigated. We analyzed temporal changes in cytokine levels in epithelial lining fluid (ELF) from the distal airways of a canine lung transplantation model. METHODS: Ischemic time was set to 18 hours to enhance lung injury in a left single-lung transplantation model. ELF was collected via bronchoscopic microsampling, a minimally-invasive technique allowing repeated sampling, hourly up to 5 hours after reperfusion started. We compared levels of pro-inflammatory cytokines in ELF with those at baseline (time zero), and with a sham-operated control group. RESULTS: Concentrations of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) significantly increased immediately after the start of lung reperfusion in the transplant group relative to the sham group (P < 0.005 and P < 0.05, respectively); both were sustained through the 5 hours. Interferon gamma (IFN-gamma levels were significantly reduced 3 h after reperfusion started (P < 0.05). CONCLUSIONS: We found time- and cytokine-dependent changes in TNF alpha, IL-6, and IFN-gamma in ELF from the lung transplantation model. These specific changes in the cytokine profile may relate to the mechanism underlying post-transplant lung dysfunction. PMID- 29228415 TI - The Implementation of a Hospital-wide Practice for the Selective Use of Carbapenems Based on the Monitoring of Susceptibility of Pseudomonas aeruginosa Isolates. AB - OBJECTIVES: To control carbapenem-resistant Pseudomonas aeruginosa, we implemented a hospital-wide policy concerning the selective use of carbapenems based on the monitoring of P. aeruginosa isolates for susceptibility to five carbapenems using a customized dry plate method. In this study, we retrospectively investigated the outcome of our measures to control carbapenem resistant P. aeruginosa. METHODS: To select effective carbapenems, 100 clinical isolates were collected, and the minimum inhibitory concentration (MIC) to 5 carbapenems (IPM/CS, MEPM, DRPM, BIPM and PAPM/BP) was monitored using a customized dry plate method from 2006 to 2013. Carbapenems, which were associated with a high rate of drug resistance in P. aeruginosa, were restricted from use during our intervention study. The antimicrobial use density per 100 bed-days (AUD100) of carbapenems and the detection rates of carbapenem (IPM/CS and MEPM) resistant P. aeruginosa were determined during the period of the intervention. RESULTS: The isolates consistently showed higher rates of drug-resistant P. aeruginosa in IPM/CS and PAPM/BP. Thus, DRPM, MEPM and BIPM were adopted for hospital-wide use. The detection rates of all IPM/Cs and MEPM-resistant P. aeruginosa significantly decreased. Meanwhile, the consumption of carbapenems showed an increasing trend. CONCLUSIONS: The outcome of the hospital-wide implementation of the selective use of carbapenems based on periodic monitoring of the susceptibility of P. aeruginosa isolates was retrospectively studied. Implementation of this measure might have contributed in part to the control of carbapenem-resistant P. aeruginosa in our hospital. PMID- 29228416 TI - Dental health in patients affected by alcohol use disorders: a cross-sectional study. AB - OBJECTIVE: Chronic alcohol abuse represents a risk factor for oral diseases, in particular, oral cancer. Periodontal disease has been showed to be involved in the pathophysiology of cardiovascular and metabolic diseases, such as atherosclerosis and liver steatosis. The role of chronic alcohol consumption on periodontitis is still controversial. The aim of the study was to evaluate the effect of chronic alcohol abuse on oral health. PATIENTS AND METHODS: Twenty three alcohol use disorders (AUD) patients and twenty-three healthy social drinkers underwent an oral examination by trained oral clinicians in order to evaluate oral and dental health. A questionnaire assessing oral hygiene was administered together with the evaluation of DMFT (decayed, missing, filled teeth), SLI (Silness-Loe plaque index) and CPI (community periodontal index of treatment needs) scores. RESULTS: Alcoholic patients showed significantly lower oral hygiene scores compared to controls. Alcoholic patients showed significantly poorer scores at DMFT, SLI and CPI tests. Moreover, among alcoholics, smokers showed a significantly poorer oral health than non-smokers. CONCLUSIONS: Chronic alcohol abuse increases the risk of dental and periodontal diseases. Smoking represents a significant co-factor. The practice of basic oral hygiene and the access to professional dental care should be encouraged among AUD patients in order to reduce oral diseases. PMID- 29228417 TI - MiR-155 affects renal carcinoma cell proliferation, invasion and apoptosis through regulating GSK-3beta/beta-catenin signaling pathway. AB - OBJECTIVE: Glycogen Synthase Kinase-3beta (GSK-3beta) negatively regulates Wnt/beta-catenin signaling pathway through degrading beta-catenin protein. It plays an inhibitory role in various tumors, while the influence in the pathogenesis of renal carcinoma has not been elucidated. MicroRNA-155 (MiR-155) was found to be upregulated in renal carcinoma tissue. Bioinformatics analysis revealed the complementary binding site between miR-155 and 3'-UTR of GSK-3beta. This study investigated the influence of miR-155 in regulating GSK-3beta expression, Wnt/beta-catenin signaling pathway activity, and renal carcinoma cell proliferation, invasion, and apoptosis. PATIENTS AND METHODS: The targeted regulatory relationship between miR-155 and GSK-3beta were tested by dual luciferase assay. Renal carcinoma tissue and benign renal tissue were collected to detect miR-155 and GSK-3beta expressions. MiR-155, GSK-3beta, and beta-catenin levels were compared between HK-2 and 786-O cells. Renal carcinoma 786-O cells were cultured in vitro and divided into four groups, including miR-NC, anti-miR 155, pIRES2-blank, and pIRES2-GSK-3beta groups. Cell apoptosis was evaluated by flow cytometry. Cell invasion was determined by transwell assay. Cell proliferation was assessed by EdU staining. RESULTS: MiR-155 targeted regulated GSK-3beta expression. MiR-155 and beta-catenin expressions were significantly increased, while GSK-3beta level was significantly declined in renal carcinoma tissue compared with benign renal tissue. MiR-155 and beta-catenin expressions were significantly elevated, whereas GSK-3beta level was significantly downregulated in 786-O cells compared with HK-2 cells. Anti-miR-155 or pIRES2-GSK 3beta transfection significantly up-regulated GSK-3beta expression, attenuated beta-catenin level, restrained cell proliferation and invasion, and enhanced cell apoptosis. CONCLUSIONS: MiR-155 promoted renal carcinoma pathogenesis. Inhibition of miR-155 increased GSK-3beta expression, attenuated Wnt/beta-catenin signaling pathway, weakened proliferation and invasion, and facilitated apoptosis in renal carcinoma cells. PMID- 29228418 TI - Long noncoding RNA HOXD-AS1 regulates proliferation of cervical cancer cells by activating Ras/ERK signaling pathway. AB - OBJECTIVE: To investigate the effects of HOXD cluster antisense RNA 1 (HOXD-AS1) in cervical cancer and its underlying mechanism. PATIENTS AND METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR) was used to examine the expression of HOXD-AS1 in human cervical cancer tissues. x2-test was used for analyzing the association of HOXD-AS1 expression and clinical parameters. Cell viability, colony formation capacity, and phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) in treated HeLa and CaSki cells were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, colony formation assay, and Western blot analysis, respectively. RESULTS: The results indicated that HOXD-AS1 was upregulated in cervical cancer cells significantly. Meanwhile, HOXD-AS1 expression was involved in tumor-node metastasis stages, lymphovascular invasion, lymph node metastasis, as well as recurrence. HOXD-AS1 knockdown remarkably suppressed cervical cancer cell proliferation, colony formation capacity, and the Ras/ERK signaling pathway in vitro. Furthermore, xenograft assays confirmed the results in vivo. CONCLUSIONS: Our data elucidate that silencing HOXD-AS1 remarkably suppresses cell growth by inactivating the Ras/ERK pathway in cervical cancer, providing a more detailed understanding of cervical cancer pathogenesis and providing a possible theoretical foundation for long non-coding RNA for the diagnosis and therapy for cervical cancer. PMID- 29228419 TI - Expression and clinical significance of long-non-coding RNA GHET1 in pancreatic cancer. AB - OBJECTIVE: To investigate the expression level and biological function of long non-coding RNA gastric carcinoma high expressed transcript 1 (lncRNA-GHET1) in pancreatic ductal adenocarcinoma (pancreatic cancer for short), to analyze the correlation between the expression of GHET1 and clinicopathological features and to explore the role and clinical significance of GHET1 in the development and progression of pancreatic cancer. PATIENTS AND METHODS: The relative expression of GHET1 in 5 human pancreatic cancer cell lines was detected by quantitative Real-time polymerase chain reaction (qRT-PCR). The specific interference sequence of GHET1 was designed and transiently transfected into pancreatic cancer cells. qRT-PCR assay was used to detect the interference efficiency. Cell counting kit-8 (CCK-8) assay was used to detect the effect of the interference with GHET1 on the proliferation of pancreatic cancer cells. Flow cytometry was used to detect the effect of the interference with GHET1 on the cycle distribution and apoptosis. qRT-PCR was used to detect the relative expression of GHET1 in pancreatic cancer tissues compared with that in cancer-adjacent tissues. The correlation between the expression of GHET1 and the pathological features of pancreatic cancer patients was analyzed. RESULTS: The expression of GHET1 in human pancreatic cancer cells was relatively high. The results of CCK-8 showed that the proliferation of tumor cells was inhibited after the interference with GHET1 expression. The results of flow cytometry showed that the expression of GHET1 was blocked at G1/G0 phase, and the apoptosis rate was increased. The results of qRT PCR showed that the expression of GHET1 was upregulated in pancreatic cancer tissues of 49 out of 64 patients compared with that in cancer-adjacent tissues, and the highly expressed GHET1 was positively correlated with the tumor, node and metastasis (TNM) staging of pancreatic cancer. CONCLUSIONS: Highly expressed GHET1 promotes the proliferation of pancreatic cancer, inhibits apoptosis and is related to TNM staging. The expression of GHET1 can be used as a potential molecular marker for the prognosis and therapeutic target of pancreatic cancer. PMID- 29228420 TI - Knockdown of long noncoding RNA linc-ITGB1 suppresses migration, invasion of hepatocellular carcinoma via regulating ZEB1. AB - OBJECTIVE: This research focuses on the influence of linc-ITGB1 on the metastasis of hepatocellular carcinoma and further explores its underlying mechanism. PATIENTS AND METHODS: A total of 70 hepatocellular carcinoma patients were chosen for our study. RT-qPCR was used for detecting the expression level of linc-ITGB1 in their cancer tissues. Moreover, the expression level of linc-ITGB1 was also detected in hepatocellular carcinoma cell lines. Furthermore, whether linc-ITGB1 could affect the migrated and invaded ability of hepatocellular carcinoma cells was determined by wound healing assay and transwell assay. We further explored the potential mechanism by RT-qPCR and Western blot assay. RESULTS: Linc-ITGB1 expression level in hepatocellular carcinoma tissues was remarkably higher than that in adjacent tissues. Moreover, migrated and invaded ability of hepatocellular carcinoma cells was inhibited through knockdown of linc-ITGB1. Further study revealed that silenced linc-ITGB1 inhibited the expression of ZEB1 and then suppressed epithelial to mesenchymal transition (EMT), which was important during the metastasis of hepatocellular carcinoma. Moreover, the inhibition of cell invasion by silenced linc-ITGB1 could be rescued through overexpression of ZEB1 in hepatocellular carcinoma. CONCLUSIONS: The results indicate that linc-ITGB1, a novel oncogene in tumorigenesis, could promote the metastasis and EMT via ZEB1, which may offer a possible therapeutic target in hepatocellular carcinoma. PMID- 29228421 TI - MiR-377 suppresses cell proliferation and metastasis in gastric cancer via repressing the expression of VEGFA. AB - OBJECTIVE: In recent years, microRNAs have been identified to participate in tumor genesis and progression of different tumors including gastric cancer. However, the role of miR-377 played in gastric cancer (GC), and its mechanisms have not been demonstrated. PATIENTS AND METHODS: We detected miR-377 expression level in 86 GC and adjacent normal tissue samples by quantitative reverse transcription PCR (qRT-PCR) as well as in GC cell lines. The relationship between miR-377 and clinical pathological features was analyzed. Using miR-377 mimics and inhibitors, we interfered with miR-377 level and employed several functional experiments to study the miR-377 effects on cell proliferation, migration, and invasion. Western blot assay and dual-luciferase assay were used to verify the target of miR-377. RESULTS: miR-377 expressed significantly lower in GC tissues and cell lines compared to normal tissues and GES-1 cells. Overexpression of miR 377 inhibited cell growth, migration and invasion, while downregulation miR-377 obviously promoted cell growth and metastasis. Furthermore, vascular endothelial growth factor A (VEGFA) was confirmed as a direct target of miR-377 and reversed the influence of mir-377 over-expression. CONCLUSIONS: miR-377 expressed lower in GC and suppressed cell proliferation, migration and invasion partly via repressing the VEGFA expression, which could provide a potential target for GC diagnosis and therapy. PMID- 29228422 TI - MicroRNA-582-5p suppressed gastric cancer cell proliferation via targeting AKT3. AB - OBJECTIVE: To dissect the functioning mode of miR-582-5p on gastric cancer cell growth and provide therapeutic targets for gastric cancer. PATIENTS AND METHODS: Relative expression levels of miR-582-5p in human gastric cancer tissue samples and gastric cancer-derived cell lines were measured by using quantitative Real time PCR. Cell proliferation and viability capacities were assessed by cell counting kit-8 (CCK8) assay and colony formation assay. Cell apoptosis and cell cycle distribution were identified by flow cytometry. Downstream target gene was confirmed by using luciferase and Western blotting assays. RESULTS: MiR-582-5p was downregulated in gastric cancer tissues when compared with para-carcinoma tissues (n=42). Overexpressed miR-582-5p could attenuate cell proliferation and viability capacities, as well as promoted cell apoptosis and cell cycle arrest at G0/G1 phase. AKT3 was chosen as the target gene of miR-582-5p by bioinformatics analysis and luciferase reporter assay. Moreover, restoration of AKT3 could impair tumor suppression role of miR-582-5p on gastric cancer growth. CONCLUSIONS: MiR-582-5p exerted tumor-suppressive effects on gastric cancer growth via targeting AKT3 in vitro, which provided an innovative and candidate target for diagnosis and treatment of gastric cancer. PMID- 29228423 TI - CD44V6 regulates gastric carcinoma occurrence and development through up regulating VEGF expression. AB - OBJECTIVE: Gastric carcinoma (GC) is one of the most common malignant tumors around the world. It is featured as high morbidity, poor prognosis, and short survival, thus seriously threats to the quality of life. The mechanism of GC is still unclear, leading to a difficulty in the treatment. CD44V6 plays an important role in tumorigenesis and progression, while its role in GC still needs further elucidation. PATIENTS AND METHODS: GC tissue and para-carcinoma tissue were collected from patients in different tumor-mode-metastasis (TNM) stages. CD44V6 and vascular endothelial growth factor (VEGF) expressions were detected by real-time PCR and Western blot. Their correlations with the clinicopathological characteristics of GC were analyzed. GC cell line SGC-7901 was cultured in vitro and divided into control, scramble group, and CD44V6 small interfering RNA (siRNA) group. Cell proliferation was assessed by 3-(4,5-dimethyl-2-thiazolyl) 2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell apoptosis was evaluated by caspase 3 activity assay. RESULTS: CD44V6 and VEGF protein expressions significantly increased in GC tissue compared with adjacent normal control (p < 0.05). CD44V6 expression was correlated with differentiation, lymph node metastasis, and TNM staging (p < 0.05). CD44V6 was positively correlated with VEGF (p < 0.05). CD44V6 siRNA reduced CD44V6 and VEGF expressions in SGC-7901, inhibited cell proliferation, and enhanced caspase 3 activity compared with control (p < 0.05). CONCLUSIONS: CD44V6 participates in GC occurrence and development by up-regulating VEGF expression. Targeting CD44V6 regulates GC progression through inhibiting VEGF expression, promoting cell apoptosis, and restraining cell proliferation. PMID- 29228424 TI - Circulating SHIP2 mRNA as a novel biomarker in the diagnosis and prognosis of gastric cancer. AB - OBJECTIVE: Previous studies showed the aberrant expression of Src homology 2 containing inositol 5-phosphatase 2 (SHIP2) in GC tissue. However, the exact role of circulating SHIP2 in GC remains unclear. The aim of this manuscript was to analyze potential diagnostic and prognostic value of circulating SHIP2 levels in GC. PATIENTS AND METHODS: Circulating SHIP2 expression was detected in the plasma of 156 GC patients and 60 healthy controls by qRT-PCR. The receiver operating characteristic (ROC) curves were plotted to explore the reliability of circulating SHIP2 in detecting GC. Survival curves were estimated using the Kaplan-Meier method, and differences between them were evaluated by the log-rank test. The influence of each variable on survival was examined by the Cox multivariate regression analysis. RESULTS: Our research showed that the expression levels of circulating SHIP2 in plasma of GC patients were lower than in healthy controls (p < 0.05). Decreased circulating SHIP2 mRNA expression was negatively correlated with clinical stage (p = 0.004), lymph node metastasis (p= 0.003) and distant metastasis (p = 0.025). ROC curve analysis showed that circulating SHIP2 may be a useful marker for discriminating cases from healthy controls. In addition, patients with low circulating SHIP2 mRNA level had poorer overall survival than those with high circulating SHIP2 mRNA level (p = 0.006). Moreover, multivariate analysis indicated that the level of circulating SHIP2 mRNA expression was an independent prognostic indicator (p = 0.005) for the survival of patients with GC. CONCLUSIONS: The present study indicated that decreased plasma SHIP2 mRNA level might be a novel diagnostic and prognostic biomarker for GC patients. This conclusion should be further assessed in randomized clinical trials. PMID- 29228425 TI - Up-regulation of LINC00346 inhibits proliferation of non-small cell lung cancer cells through mediating JAK-STAT3 signaling pathway. AB - OBJECTIVE: To investigate the expression levels of LINCRNA00346 in tissues and cells in patients with non-small cell lung cancer (NSCLC) and its biological function. PATIENTS AND METHODS: The relative expression levels of LINC 00346 in 70 cases of tissues and cells in NSCLC patients were detected via quantitative reverse transcription polymerase chain reaction (qRT-PCR). The specific interference sequences of LINC 00346 were designed and the transfection efficiency after 48 h was detected. The effect of LINC 00346 on the proliferation capacity of NSCLC cells was studied via cell counting kit-8 (CCK-8) assay. After the interference in LINC 00346 expression in NSCLC cells, the changes in cell cycle and apoptosis were detected via flow cytometry. The nude-mouse transplanted tumor model was established to study the effect of LINC 00346 on in vivo tumorigenic ability of tumor cells. After the interference in LINC 00346 expression, the changes in expressions of molecular markers in the downstream signaling pathway were detected via Western blotting. RESULTS: The LINC 00346 expressions were relatively high in 50 cases of tissues and 5 kinds of tumor cells in NSCLC patients. After the interference in LINC 00346 expression, the apoptosis of tumor cells was promoted, the cell proliferation was inhibited, and the cell cycle was arrested in G1-G0 phase. The animal experiment revealed that the interference in LINC 00346 expression could inhibit the in vivo tumorigenic ability of tumor cells. Western blotting showed that LINC 00346 could exert its function through partially regulating the Janus kinase/signal transducer and activator of transcription 3 (JAK-STAT3) signaling pathway. CONCLUSIONS: The expressions of LINC 00346 were relatively high in NSCLC tissues and cells. LINC 00346 promotes the proliferation and inhibits the apoptosis of NSCLC cells through regulating the JAK-STAT3 signaling pathway. PMID- 29228426 TI - LncRNA HOTAIR contributes to the tumorigenesis of nasopharyngeal carcinoma via up regulating FASN. AB - OBJECTIVE: The therapeutic options for nasopharyngeal carcinoma (NPC) treatment have been restricted mainly to radiotherapy or chemotherapy, and the clinical treatment effect remains unsatisfactory. The primary purpose of this study was to investigate the molecular mechanisms of NPC and to find effective novel therapeutic targets for NPC. PATIENTS AND METHODS: In order to analyze the expression level of lncRNA HOTAIR and FASN in human NPC clinical tissues or NPC cells, total RNA was extracted with TRIzol and the relative mRNA expression levels were detected by quantitative Real-time PCR. The endogenous expression of HOTAIR was modulated using lentivirus vectors transfection. The protein levels of Fatty acid synthase (FASN), p21 and MMP-9 in NPC cells were determined by Western blot when HOTAIR was knockdown. A free Fatty acid quantitation assay was performed to detect the intracellular free Fatty acid in NPC cells. The CCK-8 and colony formation assays were performed for cell viability and proliferation determination. The cell cycle of NPC cells was also determined by flow cytometric analysis. A matrigel invasion assay was performed to analyze the invasive ability of NPC cells. RESULTS: In this study, we observed a significant upregulation of lncRNA HOTAIR in NPC cells and clinical NPC specimens. The expression of Fatty acid synthase (FASN) was positively correlated to HOTAIR in NPC specimens. Knockdown of HOTAIR led to downregulation of FASN in NPC cells, thus suppressing cell proliferation and invasion. Additionally, de novo synthesis of cellular free fatty acid in NPC cells was inhibited when HOTAIR was knockdown. Furthermore, the protein levels of MMP-9 and p21 were downregulated when HOTAIR was knockdown. CONCLUSIONS: We suggest that HOTAIR is important in the progression and recurrence of NPC, perhaps through upregulating FASN. Targeting HOTAIR may be an effective therapeutic strategy for NPC. PMID- 29228427 TI - MiR-155 regulates lymphoma cell proliferation and apoptosis through targeting SOCS3/JAK-STAT3 signaling pathway. AB - OBJECTIVE: Janus kinase (JAK)- signal transducer and activator of transcription (STAT) signaling pathway participates in regulating cell proliferation, differentiation, and apoptosis, and related to lymphoma. Suppressors of cytokine signaling 3 (SOCS3) is a negative regulator of the JAK-STAT signaling pathway. SOCS3 reduction and miR-155 up-regulation are associated with lymphoma pathogenesis. Bioinformatics analysis showed the complementary binding site between miR-155 and SOCS3. This study aimed to investigate the role of miR-155 in regulating SOCS3/JAK-STAT signaling pathway and affecting diffuse large B cell lymphoma (DLBCL) cell proliferation and apoptosis. PATIENTS AND METHODS: DLBCL tumor sample was collected from the patients in our hospital. Lymphatic tissue derived from reactive lymphoid hyperplasia patients were selected as control. MicroRNA-155 (MiR-155) and SOCS3 expressions were detected. Dual luciferase assay was used to verify the targeted relationship between miR-155 and SOCS3. OCI-LY10 cells were cultured in vitro and divided into five groups, including miR-NC, miR 155 inhibitor, pIRES2-Blank, pIRES2-SOCS3, and miR-155 + pIRES2-SOCS3 groups. SOCS3, p-JAK1, p-JAK2, p-STAT3, and Survivin expressions were tested. Cell apoptosis and proliferation were detected by flow cytometry. RESULTS: MiR-155 expression significantly increased, while SOCS3 level declined in DLBCL tissue compared with control. MiR-155 targeted regulated SOCS3 expression. MiR-155 inhibitor and/or pIRES2-SOCS3 transfection markedly up-regulated SOCS3 expression, reduced p-JAK1, p-JAK2, p-STAT3, and Survivin levels, attenuated cell proliferation, and enhanced cell apoptosis in OCI-LY10 cells. CONCLUSIONS: Down regulation of miR-155 inhibited DLBCL cell proliferation and facilitated apoptosis through up-regulating SOCS3 expression to suppress JAK-STAT3 signaling pathway. PMID- 29228428 TI - Inhibition of MMPs Cat G and downregulates the signaling of TGF-beta/Smad in chronic photodamaged human fibroblasts. AB - OBJECTIVE: To understand the action of Cathepsin G (Cat G) and matrix metalloproteases (MMPs) on the beta/Smad pathway of transforming growth factor beta (TGF-beta) in chronically photodamaged human fibroblasts. Cat G plays a significant role in the process of skin photoaging and in collagen synthesis and degradation which is induced by UV irradiation it could interact with TGF beta/Smad signaling. No available studies have thoroughly explored its molecular mechanisms of photoaging regulation. PATIENTS AND METHODS: Fibroblasts were divided into 4 groups: (1) control, (2) UVA irradiation of 25 J/cm2, (3) UVA irradiation of 25 J/cm2 + MMPs inhibitor, and (4) 25 J/cm2 UVA irradiation + Cat G inhibitor. All treatments were repeated daily for 21 days. Western blot and ELISA was employed to detect Protein levels for Cat G, MMPs, and several smads. RESULTS: Compared to UVA-irradiated cells, the addition of MMPs inhibitor downregulated the expression of smad2, smad3, and smad4 as well as TGF-beta. The addition of Cat G inhibitor downregulated the expression of smad2, smad3, and smad4 as well as TGF-beta. These data suggest that TGF-beta/Smad signaling was decreased by inhibition of MMPs and Cat G decreased in chronically human fibroblasts which are photo-damaged. CONCLUSIONS: These results may help expand our knowledge of mechanisms mediating photoaging and is possibly instrumental to the exploration of novel anti-photoaging treatments. PMID- 29228429 TI - Peripheral blood CD8+ T-cell profiles in patients with psoriatic arthritis: a cross-sectional case-control study. AB - OBJECTIVE: While CD4+ T-cells are traditionally regarded as the main pathogenic T cell subpopulation in psoriatic arthritis (PsA), the role of circulating CD8+ T cells remains poorly characterized. We evaluated the differential representation of CD8+ T-cell subpopulations in peripheral blood (PB) of PsA patients. PATIENTS AND METHODS: CD8+IL-17+, CD8+IFNgamma+ and CD8+IL-17-IL-22+ T-cells were evaluated by flow-cytometry in 25 consecutive PsA patients, 7 rheumatoid arthritis (RA) patients, 16 patients with psoriasis, and 26 healthy controls (HC). RESULTS: We observed a significant expansion of circulating IFN-gamma producing CD8+ T-cells in PsA when compared to psoriasis [21.2 (6.9-55.8)% vs. 3.8 (0.7-11.8)%, p < 0.0001] and HC samples [21.2 (6.9-55.8)% vs. 4.05 (0.44 19.8)%, p < 0.0001]. A frequency of circulating IFN-gamma producing CD8+T-cells >= 9% distinguished PsA from psoriasis patients with a specificity of 84% and a sensitivity of 87.5% [AUC = 0.9 (0.80-0.99), p < 0.0001]. In addition, we found a significant expansion of circulating IL-17 producing CD8+ T cells in RA patients when compared to PsA, psoriasis and HC samples. By contrast, there were no significant between-group differences in the prevalence of circulating IL-22 producing CD8+ T-cells. In PsA patients there was a significant correlation between number of swollen joints and frequency of circulating IFN-gamma producing CD8+ T-cells, and between extent and severity of psoriasis and frequency of circulating IL-17 producing CD8+ T-cells. CONCLUSIONS: Circulating IFNgamma producing CD8+ T-cells are raised in PsA when compared to psoriasis, suggesting a potential pathogenetic involvement of CD8+ T-cells and IFNgamma production in chronic joint inflammation and damage. The significant enrichment of circulating IL-17 producing CD8+ T-cells in RA when compared to PsA warrants functional characterization and confirmation in larger studies. We found no significant enrichment of circulating IL-22 producing CD8+ T-cells in PsA, RA and psoriasis. PMID- 29228430 TI - Mediation of inflammation, obesity and fatty liver disease by advanced glycation endoproducts. AB - OBJECTIVE: Fatty liver may induce various complications including chronic hepatitis or liver cirrhosis, and is frequently occurred in obesity individuals. Advanced glycosylation end products (AGEs) were known to play a critical role in multiple liver diseases. This study, therefore, aimed to study the effect of AGEs on obesity, related liver cirrhosis and inflammation, on an obesity fatty liver rat model. MATERIALS AND METHODS: A total of 60 Sprague Dawley (SD) rats were randomly divided into control, model and AGEs inhibitor groups (n=20 each). AGEs level, body weight and liver function were examined in each animal, followed by hematoxylin-eosin (HE) staining to detect the pathological change of liver. Further Real-time PCR and enzyme-linked immunosorbent assay (ELISA) were employed to detect inflammatory cytokine levels including tumor necrosis factor (TNF) alpha and interleukin (IL)-6. RESULTS: AGEs level was significantly elevated in obesity fatty liver model rats, which also had higher total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) levels, along with deteriorated liver function and higher TNF-alpha and IL-6 levels. The application of AGEs inhibitor aminoguanidine significantly improved liver functions and lower TNF-alpha or IL-6 levels when compared to the model group (p<0.05 in all cases). CONCLUSIONS: Obesity fatty liver can promote AGEs level, further causing pathological changes and increased secretion of inflammatory cytokines. The inhibition of AGEs can improve the metabolism of fatty acids, decrease inflammatory cytokines and benefit the treatment of obesity fatty liver. PMID- 29228431 TI - The association of pancreatic cystosis and IPMN in cystic fibrosis: case report and literature review. AB - Pancreatic cystosis is a rare presentation of cystic fibrosis involving pancreatic gland. To date, only very few cases of pancreatic cystosis have been described in literature. Pancreatic cystosis may begin during the second decade of life and is the rarest presentation of cystic fibrosis. This disease is characterized by the presence of multiloculated cysts without ductal system communication of different sizes in all the pancreatic tissue. Herein, we report a case of a young woman affected by cystic fibrosis that was admitted to our Pancreatic Centre to evaluate a picture of diffuse multiloculated pancreatic cysts. After magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) assessment, we perform the diagnosis of the concomitant presence of the rare condition of pancreatic cystosis with Branch Duct-Intraductal Papillary Mucinous Neoplasm (BD-IPMN). To our knowledge, this is the first reported case of a cystic fibrosis patient with the combination of pancreatic cystosis and IPMN. PMID- 29228432 TI - Analysis of risk factors and prevention strategies of post-ERCP pancreatitis. AB - OBJECTIVE: To analyze the relevant risk factors and preventive measures for post endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis (PEP) so as to improve the diagnosis and treatment levels of ERCP, thus reducing the prevalence rate of PEP. PATIENTS AND METHODS: The clinical data of 278 patients receiving ERCP from January 2014 to December 2016 were retrospectively analyzed. First, the univariate analysis was conducted for the factors such as gender, age, diameter of common bile duct, whether development occurred in the pancreatic duct and other factors. Then, the multivariate logistic regression analysis was performed for factors showing statistical significance in the univariate analysis so as to analyze the independent risk factors for PEP. RESULTS: The success rate of ERCP included in the study was 97.12%. The prevalence rate of PEP was 8.27%. Univariate analysis results showed that the prevalence rate of PEP in the group of patients younger than 60 years old was higher than that in the group of patients older than 60 years old (14.14% vs. 5.03%, p = 0.016); the prevalence rate of PEP in the group of patients with intubation difficulty was higher than that in the group of patients without intubation difficulty (19.61% vs. 5.73%, p = 0.004); the prevalence rate of PEP in the group of patients with operation time more than 60 min was higher than that in the group of patients with operation time less than 60 min (18.60% vs. 6.38%, p = 0.034); the prevalence rate of PEP in the group of patients with the pancreatic duct development was higher than that in the group of patients without the pancreatic duct development (50% vs. 6.72%, p < 0.001); the prevalence rate of PEP in the group of patients placed with nasobiliary drainage catheters was not higher than that in the group of patients not placed with nasobiliary drainage catheters (18.00% vs. 2.81%, p < 0.001). The above five relevant factors were included in the logistic regression equation for the multivariate analysis, which showed that the age less than 60 years old (p = 0.002) and the pancreatic duct development (p = 0.004) were independent risk factors for PEP, and nasobiliary drainage (p = 0.003) was a protective factor for PEP. CONCLUSIONS: The occurrence of PEP is associated with the age less than 60 years old, the pancreatic duct development, intubation difficulty and overlong operation time. Among them, the pancreatic duct development and the age less than 60 years old are independent risk factors for PEP. Placing nasobiliary drainage catheters after operation, avoiding the pancreatic duct development, improving the success rate of intubation, reducing ERCP operation time and other methods, can effectively reduce the occurrence of PEP. PMID- 29228433 TI - The relationship between small intestinal bacterial overgrowth and irritable bowel syndrome. AB - OBJECTIVE: To explore the relationship between small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS). PATIENTS AND METHODS: Fifty IBS patients in the hospital from January 2015 to December 2015 were assigned to the treatment group, and 50 healthy persons were assigned to the control group. Lactulose hydrogen and methane breath test were performed to measure the percentage of SIBO and oro-cecal transit time (OCTT) in treatment group and control group. These subjects were further assigned to negative SIBO group and positive SIBO group to analyze the scores of symptoms. RESULTS: The percentage of positive SIBO in the treatment group (72%, 36/50) was significantly higher (p<0.05) than the control group (38%, 19/50). The scores of symptoms on the episode of IBS were not significantly different between the positive SIBO subgroup and the negative SIBO subgroup. The scores of symptoms in breath test were not significantly different between the positive SIBO subgroup and the negative SIBO subgroup. The OCTT in the treatment group (69.34+/-1.27 min) was significantly lower (p<0.05) than the control group (85.16+/-1.75 min). The OCTT in the positive SIBO group (88.57+/-4.62 min) was significantly higher (p<0.05) than the control group (73.42+/-5.25 min). The results of lactulose hydrogen and methane breath test in the treatment group were positively correlated (r = 0.987, p<0.01). The results of lactulose hydrogen and methane breath test in the control group after oral administration of lactulose were also positively correlated (r = 0.736, p<0.01). CONCLUSIONS: SIBO was related to IBS and could prolong OCTT, yet not worsen IBS. PMID- 29228434 TI - Functional roles of exosomes in cardiovascular disorders: a systematic review. AB - Cardiovascular diseases are major causes of people death associated with high mortality and disability. Exosomes are nanosized extracellular vesicles containing protein, lipid, transcription factors, mRNAs, non-coding RNA (ncRNA) and nucleic acid contents, which are critical players of intercellular communication via long-range signals or cell-to-cell contact. The emergence of exosomes provides favorable strategies for the diagnosis and treatment of cardiovascular diseases. Exosomes-based molecular mechanisms are important for developing novel therapeutic approaches for cardiovascular events. In this review, we will (1) provide insights into the detrimental and beneficial effects of exosomes on cardiovascular physiology, (2) summarize the underlying biological mechanisms of the exosome in cardiovascular events, (3) investigate the therapeutic value of exosomes for cardiovascular disorders. PMID- 29228435 TI - Review of recent advances in the management of hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a complex but common monogenic cardiovascular disorder characterized by unexplained non dilated left ventricular (LV) thickening in the absence of another cardiac or systemic disease. The condition is associated with sudden and unexpected death in young individuals including trained athletes. HCM represents a genetic disorder caused by mutations in genes encoding sarcomeric proteins of the cardiac myocyte. This review article discusses the genetics behind HCM, its clinical presentation, and diagnosis and the present-day pharmacological management of HCM. PMID- 29228436 TI - The effect of ventilator mask atomization inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of COPD in acute exacerbation period on circulating levels of inflammation and prognosis. AB - OBJECTIVE: We investigated the effects of ventilator mask atomization inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of acute exacerbation COPD (AECOPD) on circulating levels of inflammatory factors and prognosis. PATIENTS AND METHODS: A total of 86 cases of patients on ventilator support were randomly divided into control group and observation group with 43 cases each. The control group was administered routine treatment including basic disease treatment, anti-infection, maintenance of a stable internal environment, nutritional support, oxygen inhalation and so on. The control group was administered saline through a ventilator mask. The observation group was treated with atomized inhalation of ipratropium bromide and budesonide suspension and oxygen flow 3-5 L/min, 15-20 min/time and twice a day for 1 week. The treatment effects were compared. RESULTS: Serum TNF-alpha, IL-6, and CRP levels were decreased in both groups after treatment, but levels in the observation group were significantly lower than those of the control group; differences were statistically significant (p < 0.05). Forced vital capacity (FVC), forced expiratory volume (FEV1), FEV1/FVC and maximal expiratory flow rate in the observation group were significantly higher than those in the control group after treatment (p < 0.05). After treatment, the PaO2, SpO2 and respiratory failure index (RFI) of the observation group were significantly higher than those of the control group. The PaCO2 levels of the observation group were lower than those of the control group. The differences were statistically significant (p < 0.05). The clinical efficacy of the observation group was better than that of the control group; the ventilation time and total treatment time was significantly shorter and the differences were statistically significant (p < 0.05). CONCLUSIONS: The ventilator mask atomizing inhalation of ipratropium bromide and budesonide suspension liquid in the treatment of AECOPD can significantly improve circulating inflammatory reaction, improve lung function and blood gas levels, increase the treatment efficiency, and shorten the treatment time. PMID- 29228437 TI - Shisha smoking: impact on cognitive functions impairments in healthy adults. AB - OBJECTIVE: Shisha smoking is becoming highly prevalent and is a predominant mode of tobacco use particularly amongst the young generation around the globe. This study aims to investigate whether or not shisha smoking impairs the cognitive functioning in adolescents. SUBJECTS AND METHODS: We recruited 65 (32 control subjects and 33 shisha smokers) apparently healthy male volunteers. The first group consisted of 33 volunteer male shisha smoker subjects with mean age 24.45+/ 2.93 (mean +/- SD) years. The second group consists of 32 subjects with mean age 23.31+/-2.68 (mean +/- SD) years who did not smoke shisha. Age, gender, weight, height, ethnicity, educational and socioeconomic status of a matched design was used to appraise the impact of shisha smoking on cognitive functions. The cognitive function's outcome variables were the response time (Attention Switching Task-AST), (Complex Reaction Time-CRT task) and the percentage of correct answers (Pattern Recognition Memory PRM-task). Cognitive functions were assessed by using Cambridge Neuropsychological Automated Battery (CANTAB). RESULTS: Shisha smokers showed significant decline in cognitive performances AST Latency (p=0.03); AST-Congruent (p=0.05); AST-Incongruent (p=0.05); mean CRT (p=0.001); CRT % (p=0.01); PRM (p=0.024) compared to their matched control. CONCLUSIONS: Cognitive functions including attention, alertness, and memory were significantly impaired in healthy adult shisha smokers compared to non-shisha smokers. PMID- 29228439 TI - Beneficial effects of low-level laser irradiation on senile osteoporosis in rats. AB - OBJECTIVE: To investigate the effect of low-level laser irradiation (LLLI) on bone mineral density (BMD), bone structures, bone biomechanical properties and bone metabolism in senile osteoporosis, and to explore a relatively more secure and effective way to prevent and treat osteoporosis. MATERIALS AND METHODS: Sprague-Dawley (SD) male rats at different age stages (4 months old, 12 months old and 20 months old) were selected and randomly divided into six groups. The rats in the treatment group were treated with LLLI for 12 weeks, and then the microstructure of bones was analyzed by micro-computed tomography (micro-CT) scanning. The biomechanical indexes of the femur were detected by the three-point bending test. Levels of the blood calcium (Ca)2+, blood phosphorus (P)3+, urine Ca, urine P and urine creatinine (CREA) were detected using an automatic biochemical analyzer. The contents of serum osteocalcin (OCN) and bone alkaline phosphatase (BAP) were measured by enzyme-linked immunosorbent assay (ELISA). The bone formation rate (BFR) was analyzed by double fluorescent labeling with calcein and tetracycline. Hematoxylin and eosin (HE) staining and toluidine blue staining were used to analyze the number of bone marrow osteoblasts and adipocytes. RESULTS: Micro-CT results showed that compared with those in the young group, the bone mineral density (BMD) in the old group was significantly decreased, and the trabecular microstructure was seriously damaged. LLLI could significantly enhance the BMD and improve the damage to the trabecular microstructure; the three-point bending test revealed that LLLI could significantly improve the biomechanical properties and enhance the mechanical strength of the femur in the old group; the biochemical analysis showed that LLLI could significantly reduce Ca and P losses and elevate the levels of serum BAP and OCN; the bone histomorphology analysis results indicated that LLLI could increase BFR and mineral apposition rate (MAR), increase the number of osteoblasts and decrease the number of adipocytes in the bone marrow in the old group. CONCLUSIONS: LLLI can effectively improve osteoporosis, increase BMD, improve bone structure and improve bone biomechanical properties in old rats; at the same time, it increases the levels of serum BAP and OCN and the number of osteoblasts in the bone marrow, suggesting that the osteogenesis function of osteoblasts is enhanced. PMID- 29228438 TI - Analgesic effect of dezocine in different doses on elderly patients undergoing abdominal operation under general anesthesia and its influence on stress response to postoperative tracheal extubation. AB - OBJECTIVE: To study the analgesic effect of dezocine in different doses on elderly patients undergoing abdominal operation under general anesthesia and to investigate the influence of dezocine on stress response to postoperative tracheal extubation. PATIENTS AND METHODS: A total of 76 elderly patients undergoing abdominal operation under general anesthesia and postoperative analgesia in our hospital from January 2015 to January 2016 were selected, and patients treated with fentanyl were selected as the control group (fentanyl: 10 MUg/kg, n=19). The patients were randomly divided into low-dose group (dezocine: 0.05 mg/kg, n=19), medium-dose group (dezocine: 0.1 mg/kg, n=19) and high-dose group (dezocine: 0.15 mg/kg, n=19). The patients in each group were intravenously injected with 0.1 mg/kg tropisetron. The tracheal catheter was withdrawn from patients in each group; the heart rate (HR), respiratory rate (RR), mean arterial pressure (MAP) and saturation of pulse oxygen (SpO2) of patients in each group before and at 10 min after tracheal extubation were recorded in detail; moreover, the visual analogue scale (VAS) score, Ramsay sedation score, occurrence rate of adverse reactions, Bruggrmann comfort scale (BCS) score and times of pressing analgesia pump after operation of patients in the four groups were evaluated at 4, 8, 12, 24 and 48 h after operation. RESULTS: Compared with those before operation, there were no statistically significant differences in HR, RR, MAP and SPO2 of patients in low-dose group, medium-dose group and high-dose group at 10 min after tracheal extubation, and HR, RR, MAP and SPO2 of patients in control group were significantly increased after tracheal extubation (p<0.05). The VAS scores of patients in low-dose group within 48 h were significantly higher than those in control group, medium-dose group and high-dose group (p<0.05). The Ramsay sedation scores of patients in low-dose group and medium-dose group were significantly lower than those in control group and high-dose group (p<0.05), and the BCS score of patients in low-dose group was lower than those in medium-dose group, high-dose group, and control group (p<0.05). Besides, the occurrence rates of postoperative adverse reactions of patients in control group and low-dose group were higher than those in medium-dose group and high-dose group (p<0.05), the times of pressing analgesia pump after operation of patients in low-dose group were more than those in control group, medium-dose group and high-dose group (p<0.05), and the times were reduced successively in low-dose group, medium dose group, and high-dose group. Finally, the results of correlation analysis showed that the dose of dezocine was positively correlated with the Ramsay sedation score, but negatively correlated with the VAS score of patients. CONCLUSIONS: Dezocine can effectively enhance the analgesic effect on elderly patients receiving abdominal operation under general anesthesia in a dose dependent manner. Moreover, dezocine can significantly reduce the stress response of elderly patients to postoperative tracheal extubation, and reduce the occurrence rate of adverse complications after abdominal operation under general anesthesia. PMID- 29228440 TI - Metformin regulates tight junction of intestinal epithelial cells via MLCK-MLC signaling pathway. AB - OBJECTIVE: To observe the effect of metformin on the tight junction of intestinal epithelial cells and its relevant mechanism. MATERIALS AND METHODS: Caco-2 cell monolayers were incubated with or without tumor necrosis factor-alpha (TNF-alpha) (10 ng/mL) in the absence or presence of indicated concentrations of metformin. Transepithelial electrical resistance (TEER) was measured at various time points. Caco-2 cell permeability was assessed using fluorescein permeability test. Immunofluorescence was used to detect the distribution of tight junction protein. Western blotting and Real-Time PCR were used to detect the expression of tight junction protein and Myosin light chain kinase (MLCK)-Myosin light chain (MLC) signaling pathway. RESULTS: Metformin attenuates the effects of TNF-alpha on Caco 2 cell TEER and paracellular permeability, prevents TNF-alpha-induced morphological disruption of tight junctions, ameliorates the inhibiting effect of TNF-alpha on epithelial tight junction-related protein expression and suppresses the TNF-alpha-induced increase in MLCK production. CONCLUSIONS: Metformin can stabilize and up-regulate tight junction protein by inhibiting MLCK-MLC signaling pathway, thus ameliorating the tight junction of intestinal epithelial cells. PMID- 29228441 TI - Correlation between individual inflammation genetic profile and platelet rich plasma efficacy in hair follicle regeneration: a pilot study reveals prognostic value of IL-1a polymorphism. AB - OBJECTIVE: Hair loss generates severe psychosocial implications. To date, exploring the prognostic factors of possible clinical benefit of autologous blood concentrate platelet rich plasma (PRP) was failed. The aim of our pilot study was to explore the correlation between the individual inflammation genetic profile and PRP efficacy in the treatment of hair follicle regeneration. PATIENTS AND METHODS: 41 volunteers (25 men, 16 women) took part in this retrospective study. All the patients were scheduled for 4 sessions of PRP application with intervals of 40-60 days. All the patients were checked up at 6 weekly intervals for 6 months and, then, at the end of the first year. A panel of 5 polymorphisms on 4 genes (IL-1a, IL-1b, IL-6, and IL-10) implicated in the individual genetic inflammation profile were performed. RESULTS: A significant increase rate in hair density was noticed after the third month of treatment in 32/41 (78%) of the subjects. We found an interesting association between the pro-inflammatory cytokine IL-1alpha polymorphism C>A (rs17561) and responders to PRP treatment. The cases carrying C/C genotype (coding for Ser114) were 21 (66%) in responders and only 2 (22%) in non-responders (p<0.05). In addition, about IL-1a, the frequency of G/G genotype in responder patients was over two times lower in responder (31%) than in non-responder patients (78%). CONCLUSIONS: Our pilot study demonstrated a correlation between the individual genetic inflammatory profile and the efficacy of the PRP treatment in males. On the contrary, in females, it showed a negative correlation. IL-1a could be used as a prognostic value for PRP efficacy. Also, these results provide preliminary evidence that may encourage the design of controlled clinical trials to properly test this modus operandi on a large number of subjects. PMID- 29228442 TI - A novel boswellic acids delivery form (Casperome(r)) in the management of musculoskeletal disorders: a review. AB - Standard pharmacological treatment of musculoskeletal conditions is often associated with relevant side effects. Botanical preparations endowed with a good tolerability profile, therefore, could have a role in the management of these disorders. Among different natural products, Boswellia serrata extracts have long been used for the treatment of musculoskeletal disorders, given their marked anti inflammatory activity and their ability to promote tissue regeneration. However, standard preparations of Boswellia serrata show overall modest pharmacokinetic properties, a limitation which may ultimately lead to reduced efficacy. In an effort to improve the pharmacokinetic properties, Casperome(r), a lecithin-based formulation of Boswellia serrata extract representing the whole natural bouquet, has been developed. This formulation was effective in the treatment of Achilles tendonitis, epicondylitis, radiculopathies, ankle sprains and sport injuries as shown in several clinical studies, the majority of which with a randomized design and all evaluating a number of well-recognized parameters of efficacy for the therapy of musculoskeletal disorder. All studies were consistent in showing a prompt decrease of pain and improvement of functionality of the affected area after supplementation with Casperome(r), without any relevant adverse effect. Remarkably, these symptomatic improvements were paralleled by reduced plasmatic levels of inflammatory markers and by a diminished need for rescue analgesics. On these bases, Casperome(r) may have a role in the treatment of musculoskeletal disorders. Clinical studies in other similar conditions (e.g., osteoarthritis) appear warranted to further investigate the efficacy of this botanical product in more specific settings. PMID- 29228443 TI - Postoperative deep wound dehiscence of thoracotomy with isolation of Corynebacterium tuberculostearicum: surgical site infection or colonization? AB - OBJECTIVE: Infections with Corynebacterium tuberculostearicum are very rare as in most of the cases its isolation is associated with tissue colonization rather than infection. CASE REPORT: An 80-year old female patient was sent to the consultation hour of thoracic surgery for evaluation of a symptomatic persistent unilateral pleural effusion of her right lung. The differential diagnosis included either the presence of a chronic pleural empyema or the presence of malignancy. After excluding a malignancy, a decortication of the middle and lower lobe was performed, as the two lobes could not significantly re-expand. The course was further complicated by the presence of two-times deep wound dehiscence, which made necessary a rethoracotomy. The microbiologic results of the biopsies revealed the presence of only Corynebacterium tuberculostearicum with an initially questionable clinical relevance. As soon as the antibiotic treatment for Corynebacterium tuberculostearicum began, together with the use of vacuum-assisted therapy (VAC), the closure of the thoracotomy was accelerated. CONCLUSIONS: Clinically relevant surgical site infections with Corynebacterium species in thoracic surgery are difficult to distinguish. Nevertheless, its combined surgical and antibiotic treatment is warranted when its relevance is questionable due to its resistance to broad-spectrum antibiotics as well as to its potential for the complicated clinical course. PMID- 29228444 TI - Rectal indomethacin or intravenous gabexate mesylate as prophylaxis for acute pancreatitis post-endoscopic retrograde cholangiopancreatography. AB - OBJECTIVE: We aimed to evaluate the results in our case series of AP ERCP over the last three years. The prophylaxis for acute pancreatitis (AP) post-endoscopic retrograde cholangiopancreatography (ERCP) consists of rectal indomethacin, but some studies are not concordant. PATIENTS AND METHODS: We compared 241 ERCP performed from January 2014 to February 2015 with intravenous gabexate mesylate (Group A), with the 387 ERCP performed from March 2015 to December 2016 with rectal indomethacin (Group B) as prophylaxis for AP post-ERCP. RESULTS: There were 8 (3.31%) AP post-ERCP in Group A vs. 4 (1.03%) in Group B. CONCLUSIONS: Rectal indomethacin shows a better statistically significant performance than intravenous gabexate mesylate in the prophylaxis of AP post-ERCP, besides being cheaper. PMID- 29228445 TI - The protective effect and its mechanism of 3-n-butylphthalide pretreatment on cerebral ischemia reperfusion injury in rats. AB - OBJECTIVE: To investigate the potential effect of 3-n-butylphthalide (NBP) pretreatment on the cerebral ischemia/reperfusion injury in rats and the relevant mechanism. MATERIALS AND METHODS: A total of 90 rats was divided into three groups: Sham operation group (Sham group), ischemia-reperfusion group (I-R group), and NBP pretreatment group (NBP group 75 mg.kg-1.d-1 gavage). Pre treatment was given once a day within 1 week before establishing the rat model of cerebral ischemia-reperfusion injury. The middle cerebral artery occlusion (MACO) rat models were established with the improved Longa-Zea method on the 7th day after ischemia for 2 h and reperfusion for 24 h in all the rats. We detected the cerebral infarction, the pathologic change of brain, the apoptosis of nerve cell, the production levels of reactive oxygen species (ROS), the content of malonaldehyde (MDA) and the activity of superoxide dismutase (SOD), the water content and the permeability of blood-brain barriers (BBB). In addition, we also observed the expressions of mitogen-activated protein kinase (MAPK, p-38, JNK, ERK1/2) and cleaved caspase-3 in the hippocampus tissues. RESULTS: Compared with Sham group, we discovered that NBP significantly reduced infarction area, cell apoptosis, BBB damage and water content. Further, we found that NBP could also decrease ROS and MDA, and increase SOD activity in brain tissues of rats with a cerebral ischemia-reperfusion injury. Moreover, results showed that NBP also inhibited the levels p38 and JNK. CONCLUSIONS: NBP protected the cerebral from I/R injury, providing ideas for the expansion of clinical adaptability of NBP and possible approaches for its application. PMID- 29228446 TI - Telmisartan reduces arrhythmias through increasing cardiac connexin43 by inhibiting IL-17 after myocardial infarction in rats. AB - OBJECTIVE: To observe the expressions of myocardial connexin43 (Cx43) and interleukin-17 (IL-17) in acute myocardial infarction (AMI) rats and investigate its possible mechanism of telmisartan in the prevention and treatment of arrhythmia in AMI. MATERIALS AND METHODS: Sprague Dawley (SD) rats were selected and myocardial infarction model was established. After the successful modeling, the rats were randomly divided into three groups: Sham group, MI group, Telm group. Ventricular arrhythmias was induced by the programmed electrical stimulation at 2, 4, 8 weeks. After 8 weeks, rats were sacrificed and heart tissues were collected for immunohistochemistry and Western blot detection. RESULTS: Telmisartan reduced the induction rate of ventricular arrhythmia after myocardial infarction in rats. Telmisartan increased the Cx43 expression while reduced the IL-17 expression in myocardial infarction in rats. Moreover, there was a negative correlation between the expressions of Cx43 and IL-17 after myocardial infarction. CONCLUSIONS: Telmisartan can reduce the occurrence rate of malignant arrhythmias after myocardial infarction, whose mechanism may be increasing the Cx43 expression through inhibition of IL-17 expression. PMID- 29228447 TI - Ethical and medico-legal remarks on uterus transplantation: may it solve uterine factor infertility? AB - Uterus transplantation was firstly tested with animal trials sixty-five years ago. Despite several successful attempts in human subjects, the different procedures still lay at the experimental stage, in need of further studies and investigations before they can be considered as standard clinical practices. Uterus transplant cannot be regarded as a life-saving procedure, but rather a method to restore woman ability to procreate, when lost, thus improving her quality of life. Uterus transplant is a complex surgical procedure and presents significant health threats. Medical staff should therefore always obtain informed consent from patients, emphasizing such risks. Before that, women undergoing uterine transplants should be thoroughly informed about the hazards inherent to the procedure and especially about the dangers of immunosuppressant drugs, administered after the surgery which may injure the fetus, eventually formed in the restored organ and even lead to its death, thus nullifying the purpose of the transplant itself. Therefore, the risk-benefit ratio of uterus transplantation needs to be carefully assessed and described. PMID- 29228448 TI - Experimental study on the prevention of liver cancer angiogenesis via miR-126. AB - OBJECTIVE: The aim of the present work was to study the prevention of liver cancer angiogenesis via miR-126. For this purpose, experimentations were conducted. MATERIALS AND METHODS: The precursor sequence of miR-126 was amplified in the DNA of human liver cancer cell lines. We, therefore, constructed the overexpression and interference vectors of miR-126 in vitro; which were respectively transferred to liver cancer cells in the logarithmic phase and inoculated under both sides of the back skin of Balb/c-nu nude mice aged 4-6 weeks with 10 mu l (1 x 105) cell suspension. The experiment consisted of non vector control group, miR-126 overexpression group, and miR-126 inhibition group. Eight weeks later, the mice were sacrified; the tumor volumes and serum ALT, AFP, VEGF levels were compared. VEGF expression, as well as the microvascular density of the liver tissues, was detected via immunohistochemistry. RESULTS: Tumors volumes, serum ALT, AFP and VEGF levels and positive rates of VEGF were low in the miR-126 overexpression group and high in the miR-126 inhibition group, the difference being statistically significant (p < 0.05). CONCLUSIONS: At the end of this study, we conclude that miR-126 inhibits liver cancer angiogenesis. PMID- 29228449 TI - IGFBP2 induces SPRY1 expression via NF-kappaB signaling pathway in glioblastoma multiforme (GBM). AB - OBJECTIVE: Gliomas are accompanied with high mortality owning to their invasive peculiarity and vulnerability to drug resistance. miR-21 is a vital oncogenic miRNA that regulates drug resistance of tumor cells. This study aims to elucidate the function of miR-21 in human glioma cells resistant to carmustine (BCNU) and to demonstrate the underlying molecular mechanism. MATERIALS AND METHODS: BCNU sensitive cells (SWOZ2 cells) were transfected with miR-21 agomir and negative control, and BCNU-resistance cells (SWOZ2-BCNU cells) were transfected with miR 21 antagomir and negative control. The Real-time fluorescence quantitative PCR was used to detect and compare the levels of miR-21expression between SWOZ2-BCNU and SWOZ2 cells. The drug sensitivity of these cells to BCNU was determined by Cell Counting Kit-8 (CCK-8) assay. The protein expression of Spry2 was detected by Western blotting. RESULTS: The expression level of miR-21 was remarkably higher in SWOZ2-BCNU cells than that in SWOZ2 cells. The half-maximal inhibitory concentration (IC50) of BCNU was obviously higher for SWOZ2-BCNU cells than that for SWOZ2 cells. Besides, we found that aberrant expression of miR-21 in SWOZ2 BCNU cells is responsible for glioma BCNU-resistance. Consistently, Spry2 protein levels were significantly reduced in SWOZ2-BCNU as well as in miR-21 agomir transfected cells, inversely correlated to miR-21 expression. The results of si Spry2 co-transfection suggested that the effect of miR-21 on glioma BCNU resistance is mediated through Spry2. CONCLUSIONS: miR-21 enhances the resistance of human glioma cells to BCNU by decreasing the expression of Spry2 protein. Thus, Spry2 may be a novel therapeutic target for treating glioma BCNU resistance. PMID- 29228451 TI - RG108 induces the apoptosis of endometrial cancer Ishikawa cell lines by inhibiting the expression of DNMT3B and demethylation of HMLH1. AB - OBJECTIVE: The effects of DNA methyltransferase (DNMT) inhibitor RG108 on the proliferation and apoptosis of endometrial cancer was investigated, and whether its mechanism was related to the inhibition of DNMT3B, thereby affecting the human mutL homolog 1 (hMLH1) methylation status and its expression, was further studied. MATERIALS AND METHODS: Culture of human endometrial cancer Ishikawa cell lines: cells grew adhering to the wall in Roswell Park Memorial Institute-1640 (RPMI-1640) medium (supplemented with 10% fetal bovine serum (FBS) and 2 mM L glutamic acid). After the cells were treated with RG108, the changes in cell viability were detected via methyl thiazolyl tetrazolium (MTT) assay. The effect of RG108 on cell cycle was detected via flow cytometry, and its effect on cell apoptosis was detected via flow cytometry and TUNEL. Moreover, the methylation status of hMLH1gene in endometrial cancer cells was detected via methylation specific-PCR (MSP), and the changes in DNMT3Band hMLH1 expressions were detected via RT-PCR and Western blotting, respectively. RESULTS: MTT results showed that RG108 inhibited the cell viability in a dose-dependent and time-dependent manner. Flow cytometry revealed that RG108 blocked the cell cycle in G2/M phase and promoted the apoptosis, and TUNEL assay further proved that RG108 promoted the apoptosis. It was found in the detection via MSP that the methylated hMLH1 gene was significantly reduced after 72 h of treatment with RG108. Besides, RT-PCR and Western blotting showed that RG108 inhibited the DNMT3B expression and activated the hMLH1 expression. CONCLUSIONS: The demethylation drug RG108 can significantly inhibit the proliferation of endometrial cancer cells, block the cell cycle in the G2/M phase and induce the cell apoptosis, which is a new candidate drug in the treatment of endometrial cancer. RG108 realizes the hMLH1 demethylation and increases the hMLH1 expression through inhibiting the expression of DNMT3B. PMID- 29228450 TI - MiR-21 enhanced glioma cells resistance to carmustine via decreasing Spry2 expression. AB - OBJECTIVE: Gliomas are accompanied with high mortality owning to their invasive peculiarity and vulnerability to drug resistance. miR-21 is a vital oncogenic miRNA that regulates drug resistance of tumor cells. This study aims to elucidate the function of miR-21 in human glioma cells resistant to carmustine (BCNU) and to demonstrate the underlying molecular mechanism. MATERIALS AND METHODS: BCNU sensitive cells (SWOZ2 cells) were transfected with miR-21 agomir and negative control, and BCNU-resistance cells (SWOZ2-BCNU cells) were transfected with miR 21 antagomir and negative control. The Real-time fluorescence quantitative PCR was used to detect and compare the levels of miR-21expression between SWOZ2-BCNU and SWOZ2 cells. The drug sensitivity of these cells to BCNU was determined by Cell Counting Kit-8 (CCK-8) assay. The protein expression of Spry2 was detected by Western blotting. RESULTS: The expression level of miR-21 was remarkably higher in SWOZ2-BCNU cells than that in SWOZ2 cells. The half-maximal inhibitory concentration (IC50) of BCNU was obviously higher for SWOZ2-BCNU cells than that for SWOZ2 cells. Besides, we found that aberrant expression of miR-21 in SWOZ2 BCNU cells is responsible for glioma BCNU-resistance. Consistently, Spry2 protein levels were significantly reduced in SWOZ2-BCNU as well as in miR-21 agomir transfected cells, inversely correlated to miR-21 expression. The results of si Spry2 co-transfection suggested that the effect of miR-21 on glioma BCNU resistance is mediated through Spry2. CONCLUSIONS: miR-21 enhances the resistance of human glioma cells to BCNU by decreasing the expression of Spry2 protein. Thus, Spry2 may be a novel therapeutic target for treating glioma BCNU resistance. PMID- 29228452 TI - Establishment and analysis of the prediction model for cervical squamous cell carcinoma. AB - OBJECTIVE: This study aimed to construct a prediction model for cervical squamous cell carcinoma and evaluate its accuracy in diagnosing cervical squamous cell carcinoma. PATIENTS AND METHODS: Fifty patients with initially histopathologically confirmed cervical squamous cell carcinoma and 150 patients with initially histopathologically confirmed cervical intraepithelial neoplasia (CIN) were enrolled. The high-risk human papillomavirus (HR-HPV) infection, human telomerase mRNA component (hTERC) gene and cell-myc (c-myc) gene amplification, and minichromosome maintenance protein 5 (MCM5) protein expression were detected. The indicators related to cervical cancer were screened. The regression model was established to predict cervical squamous cell carcinoma with backward logistic stepwise regression method, and the accuracy of the model was evaluated. RESULTS: Histograms for HR-HPV infection and viral load, hTERC and c-myc gene amplification, and MCM5 protein expression were constructed. There was a linear relationship between hTERC (X1), HR-HPV viral load (X2), MCM5 (X5) and the regression equation. Also, hTERC (X1), HR-HPV viral load (X2) and MCM5 (X5) were correlated with cervical squamous cell carcinoma. The regression model Logit (p) = -66.283 + 0.042 X1 + 0.061 X2 + 0.052 X5 was established. The model-fitting effect and prediction accuracy were evaluated, HL test p = 1 (p > 0.05). The model fitting effect was good, Cox-Sn ell R2 was 0.643 and Nagelkerke R2 was 0.958. The high accuracy of the model was 98.5%. CONCLUSIONS: The fitting-effect of the regression model established by hTERC gene expression, HR-HPV viral load and MCM5 protein was good. The prediction accuracy of the model for cervical squamous cell carcinoma was high. The combined test of hTERC gene amplification, HR-HPV viral load and MCM5 protein could be used to predict and evaluate cervical squamous cell carcinoma. PMID- 29228453 TI - Effects of erythropoietin on spontaneous and oxytocin induced myometrial contractions in the nonpregnant rat. AB - OBJECTIVE: Erythropoietin (EPO) is a glycoprotein hormone that regulates erythropoiesis. EPO activity has also been detected in a variety of tissue including the nervous system, and female and male reproductive organs. It has been shown that EPO causes relaxation in vascular smooth muscle. In the present study, we have investigated effects of EPO on spontaneous and oxytocin-induced contractions of non-pregnant rat myometrium. MATERIALS AND METHODS: Myometrial stripes were obtained from adult Wistar rats at the oestrous stage. The samples were placed in an isolated organ chamber under physiological conditions and 1 g passive tension. Epoetin beta (rEPO) was added cumulatively at 0.1, 1 and 10 IU/ml concentrations to the myometrial samples showing regular spontaneous contractions for periods of 30 min. Frequency and amplitude of contractions were electrophysiologically recorded and analyzed by using a BIOPAC data acquisition system. RESULTS: rEPO inhibited both area under curve and frequency of spontaneous contractions (ANOVA, n1, 2 = 9, f1 = 20.938, f2 = 20.492, p1,2 = 0.000). The inhibitory effect was insignificant at 0.1 mIU/ml rEPO level (Tukey HSD, p1 = 0.051, p2 = 0.581). In the oxytocin treated myometrial samples, a single dose of 1 IU/ml rEPO was studied. The area under curve and frequency values of these samples were inhibited by rEPO (Student's t-test, n = 9, t1 = 4.776, p1 = 0.000; t2 = 2.835, p2 = 0.012, respectively). CONCLUSIONS: rEPO inhibited spontaneous and oxytocin-induced rat myometrial contractions at 1 and 10 IU/ml concentrations. It appeared that the effect was dose-dependent. PMID- 29228454 TI - New semiparametric method for predicting high-cost patients. AB - Motivated by the Medical Expenditure Panel Survey containing data from individuals' medical providers and employers across the United States, we propose a new semiparametric procedure for predicting whether a patient will incur high medical expenditure. Problems of the same nature arise in many other important applications where one would like to predict if a future response occurs at the upper (or lower) tail of the response distribution. The common practice is to artificially dichotomize the response variable and then apply an existing classification method such as binomial regression or a classification tree. We propose a new semiparametric prediction rule to classify whether a future response occurs at the upper tail of the response distribution. The new method can be considered a semiparametric estimator of the Bayes rule for classification and enjoys some nice features. It does not require an artificially dichotomized response and better uses the information contained in the data. It does not require any parametric distributional assumptions and tends to be more robust. It incorporates nonlinear covariate effects and can be adapted to construct a prediction interval and hence provides more information about the future response. We provide an R package plaqr to implement the proposed procedure and demonstrate its performance in Monte Carlo simulations. We illustrate the application of the new method on a subset of the Medical Expenditure Panel Survey data. PMID- 29228455 TI - Prognostic significance of neoadjuvant rectal score in locally advanced rectal cancer after neoadjuvant chemoradiotherapy and construction of a prediction model. AB - AIM: To evaluate the prognostic significance of neoadjuvant rectal (NAR) score after neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC), and to develop a nomogram predicting disease-free survival (DFS). METHOD: A total of 522 LARC patients undergoing nCRT and surgery were included. NAR scores were calculated using the equation [5pN-3(cT-pT) + 12]^2/9.61, and classified as low (<8), intermediate (8-16), and high (>16). Clinicopathological and survival outcomes were compared. Cox regression analysis was performed to identify risk factors of DFS. A predicting nomogram was developed and validated internally. RESULTS: For NAR score classification, 193 (37.0%) were low, 183 (35.0%) were intermediate, and 146 (28.0%) were high. Higher NAR score was associated with fewer pCR, lower tumor regression grade (TRG), and higher ypTNM stage. A total of 5-year DFS for low, intermediate, and high NAR groups was 85.6%, 71.9%, and 47.2%, respectively (P < 0.001). NAR score (HR = 2.488, P = 0.002), TRG (HR = 2.811, P = 0.047), CRM involvement (HR = 2.703, P = 0.002), and IMA nodal metastasis (HR = 2.441, P = 0.001) were independent prognostic factors of DFS. A predicting nomogram was developed with C-index of 0.701. CONCLUSION: NAR score could help in predicting DFS after nCRT. A nomogram was developed to identify subpopulations with aggressive tumors during clinical decision-making. PMID- 29228456 TI - Reply to comment on: Incidence and predictors of postoperative delirium after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy. PMID- 29228457 TI - Stereoselective Transfer Semi-Hydrogenation of Alkynes to E-Olefins with N Heterocyclic Silylene-Manganese Catalysts. AB - The synthesis and structures of the first SiII -donor supported manganese(II) complexes [L1]MnCl2 , [L2]MnCl2 , and [L3]2 MnCl2 are reported, bearing a pincer type bis(NHSi)-pyridine ligand L1, bidentate bis(NHSi)-ferrocene ligand L2, and two monodentate NHSi ligands L3 (NHSi = N-heterocyclic silylene), respectively. They act as unprecedented very active and stereoselective Mn-based precatalysts (1 mol % loading) in transfer semi-hydrogenations of alkynes to give the corresponding E-olefins using ammonia-borane as a convenient hydrogen source under mild reaction conditions. Complex [L1]MnCl2 shows the best catalytic performance with quantitative conversion rates and excellent E stereoselectivities (up to 98 %) for different alkyne substrates. Different types of functional groups can be tolerated, except CN, NH2 , NO2 , and OH groups at the phenyl group of 1-phenyl substituted alkynes. PMID- 29228458 TI - Seeing the signs: Using the course of residual depressive symptomatology to predict patterns of relapse and recurrence of major depressive disorder. AB - BACKGROUND: Major depressive disorder (MDD) is characterized by high relapse/recurrence rates. Predicting individual patients' relapse/recurrence risk has proven hard, possibly due to course heterogeneity among patients. This study aimed to (1) identify homogeneous data-driven subgroups with different patterns of relapse/recurrence and (2) identify associated predictors. METHODS: For a year, we collected weekly depressive symptom ratings in 213 primary care MDD patients. Latent class growth analyses (LCGA), based on symptom-severity during the 24 weeks after no longer fulfilling criteria for the initial major depressive episode (MDE), were used to identify groups with different patterns of relapse/recurrence. Associations of baseline predictors with these groups were investigated, as were the groups' associations with 3- and 11-year follow-up depression outcomes. RESULTS: LCGA showed that heterogeneity in relapse/recurrence after no longer fulfilling criteria for the initial MDE was best described by four classes: "quick symptom decline" (14.0%), "slow symptom decline" (23.3%), "steady residual symptoms" (38.7%), and "high residual symptoms" (24.1%). The latter two classes showed lower self-esteem at baseline, and more recurrences and higher severity at 3-year follow-up than the first two classes. Moreover, the high residual symptom class scored higher on neuroticism and lower on extraversion and self-esteem at baseline. Interestingly, the steady residual symptoms and high residual symptoms classes still showed higher severity of depressive symptoms after 11 years. CONCLUSION: Some measures were associated with specific patterns of relapse/recurrence. Moreover, the data-driven relapse/recurrence groups were predictive of long-term outcomes, suggesting that patterns of residual symptoms could be of prognostic value in clinical practice. PMID- 29228459 TI - Axillary reverse mapping with indocyanine green or isosulfan blue demonstrate similar crossover rates to radiotracer identified sentinel nodes. AB - BACKGROUND: Sentinel lymph node (SLN) resection is imperative for breast cancer staging. Axillary reverse mapping (ARM) can preserve arm draining nodes and lymphatics during surgery. ARM is generally performed with isosulfan blue (ISB), restricting its use for concurrent SLN biopsy. Indocyanine green (ICG) could serve as an alternative to ISB for ARM procedures. METHODS: SLN mapping and biopsy was performed via periareolar injection of 99 technetium-sulfur colloid (99m TcSc, TSC). ISB and ICG were injected in the upper arm. Blue-stained lymphatics or nodes were visualized in the axilla; ICG was identified using the SPY Elite(r) system. RESULTS: Twenty-three patients underwent SLN biopsy with or without axillary node dissection and ARM procedures. Twenty of these patients had at least one hot node; 12 patients had SLNs that were only hot, 6 hot/blue/fluorescent, and 2 hot/fluorescent. Overall, crossover of ARM agents with SLNs occurred in 8 cases. Inspection of the axillary cavity after SLN biopsy revealed fluorescent lymphatics and nodes remaining in 14 and 7 patients, respectively. Blue lymphatics and blue nodes were detected in fewer cases. CONCLUSION: Nearly one-third of patients showed crossover between breast and arm draining nodes, which provides insight as to why some patients develop lymphedema symptoms after SLN biopsy. ICG and ISB identify similar numbers of SLNs. As such ICG could substitute for ISB in ARM procedures. PMID- 29228461 TI - Imaging of liposarcomas for clinicians: Characteristic features and differential considerations. AB - Liposarcoma (LPS) is a malignancy of fat and one of the most common soft tissue sarcomas. There are three major subtypes of LPS: Well-differentiated / dedifferentiated, myxoid, and pleomorphic. We review the imaging features of LPS in the abdomen and extremities, describe features that help differentiate the subtypes, and provides alternative considerations for fat-containing lesions (many benign) that can mimic LPS. PMID- 29228460 TI - Emissive Synthetic Cofactors: Enzymatic Interconversions of tz A Analogues of ATP, NAD+ , NADH, NADP+ , and NADPH. AB - A series of enzymatic transformations, which generate visibly emissive isofunctional cofactors based on an isothiazolo[4,3-d]pyrimidine analogue of adenosine (tz A), was developed. Nicotinamide adenylyl transferase condenses nicotinamide mononucleotide and tz ATP to yield Ntz AD+ , which can be enzymatically phosphorylated by NAD+ kinase and ATP or tz ATP to the corresponding Ntz ADP+ . The latter can be engaged in NADP-specific coupled enzymatic transformations involving conversion to Ntz ADPH by glucose-6-phosphate dehydrogenase and reoxidation to Ntz ADP+ by glutathione reductase. The Ntz ADP+ /Ntz ADPH cycle can be monitored in real time by fluorescence spectroscopy. PMID- 29228462 TI - Clinical features and survival of gastric cancer patients with DNA mismatch repair deficiency. AB - Patients with germline DNA mismatch repair deficiency (dMMR) have an increased risk of gastric cancer. From our institutional database, we identified 12 patients with germline dMMR gastric cancer. Ten patients (83%) underwent surgical resection, with a 5-year overall survival rate of 88%. None of the three patients who received preoperative therapy and five patients with recurrent or metastatic disease experienced a significant response to 5-fluorouracil-based chemotherapy. PMID- 29228463 TI - Transition-Metal-Catalyzed Selective Functionalization of C(sp3 )-H Bonds in Natural Products. AB - Direct functionalization of natural products is important for studying the structure-activity and structure-property relationships of these molecules. Recent advances in the transition-metal-catalyzed functionalization of C(sp3 )-H bonds, the most abundant yet inert bonds in natural products, have allowed natural product derivatives to be created selectively. Strategies to achieve such transformation are reviewed. PMID- 29228464 TI - Incidence and predictors of postoperative delirium after cytoreduction surgery hyperthermic intraperitoneal chemotherapy: Methodological issues. PMID- 29228465 TI - Ligand-Induced Dimerization of a Truncated Parallel MYC G-Quadruplex. AB - Binding of an indoloquinoline derivative with an aminoalkyl side chain to a truncated sequence from the MYC promoter region was studied through isothermal titration calorimetry (ITC). The targeted MYC3 sequence lacks 3'-flanking nucleotides and forms a monomeric parallel quadruplex (G4) with a blunt-ended 3' outer tetrad under the solution conditions employed. Analysis of ITC isotherms reveals multiple binding equilibria with the initial formation of a 1:2 ligand/quadruplex complex. Evaluation of electrophoretic mobilities as well as NMR spectral data confirm ligand-induced dimerization of MYC3 quadruplexes with the ligand sandwiched between the two 3'-outer tetrads. Additional ligand molecules in excess bind to the 5'-outer tetrads of the sandwich complex. Such a ligand-promoted G4 dimerization may be exploited for the controlled assembly or disassembly of G4 aggregates to expand on present quadruplex-based technologies. PMID- 29228466 TI - Concomitant organ resection does not improve outcomes in primary retroperitoneal well-differentiated liposarcoma: A retrospective cohort study at a major sarcoma center. AB - BACKGROUND: We investigated whether concomitant organ removal as part of the primary resection of RP WDLPS confers an outcome advantage in patients treated at a major sarcoma center. METHODS: The departmental sarcoma database was reviewed to identify patients with RP WDLPS who underwent initial surgical resection for primary disease at MD Anderson Cancer Center during the study period 1995-2011. We retrospectively reviewed medical records and examined associations between clinicopathologic variables and overall survival (OS) as well as disease-free survival (DFS). RESULTS: Among 83 patients included in this study, 76 patients (92%) underwent complete resection (R0/R1). Concomitant organ resections were performed in 38 patients (46%). Invasion of the resected organ/s was seen in six patients (7%). Estimated OS was 11.3 years (5-year OS, 86%), and DFS was 5.4 years (5-year DFS, 51%). By multivariate analysis, concomitant organ resection was not associated with improved OS (P = 0.428) or DFS (P = 0.946), and lack of organ resection was associated with a lower risk of postoperative complications (P = 0.01). CONCLUSIONS: Concomitant organ resection was not associated with a survival benefit in RP WDLPS in this study. In patients with primary RP WDLPS, we recommend selective resection of contiguous organs only if there is clinical suspicion of invasion. PMID- 29228467 TI - Neoadjuvant systemic therapy for regionally advanced melanoma. AB - BACKGROUND: Patients with regionally advanced melanoma are at high risk of distant failure and unlikely to be cured by surgery alone. Neoadjuvant therapy may provide benefit in these patients. OBJECTIVES: To evaluate our experience with neoadjuvant systemic therapy in high-risk stage III patients. METHODS: Retrospective review of patients with advanced stage III disease who received neoadjuvant therapy between August 2009 and August 2016 at Mayo Clinic Rochester. RESULTS: Twenty-three cases met our inclusion criteria, 16 with resectable disease and 7 with unresectable disease. No patients with resectable disease and one patient with borderline resectable disease progressed regionally, prohibiting surgical resection. Five of seven patients with unresectable disease were down staged to a resectable state. Six of twenty-three (26%) had a CR and five are alive at last follow-up. Fifteen of twenty three patients (65%) progressed with a median progression free survival of 11 months; however, the 5 year overall survival estimate was 84%. CONCLUSIONS: Neoadjuvant systemic therapy is a reasonable approach for patients with advanced but resectable/borderline resectable disease and the risk of losing regional control is low. Our data also suggest some patients with unresectable disease will be converted to resectable and a complete clinical response to treatment can be obtained in approximately one quater of patients. PMID- 29228468 TI - Characterization of forsythoside A metabolites in rats by a combination of UHPLC LTQ-Orbitrap mass spectrometer with multiple data processing techniques. AB - Forsythoside A (FTA), the main active constituent isolated from Fructus Forsythiae, has various biological functions including anti-oxidant, anti-viral and anti-microbial activities. However, while research on FTA has been mainly focused on the treatment of diseases on a material basis, FTA metabolites in vivo have not been comprehensively evaluated. Here, a rapid and sensitive method using a UHPLC-LTQ-Orbitrap mass spectrometer with multiple data processing techniques including high-resolution extracted ion chromatograms, multiple mass defect filters and diagnostic product ions was developed for the screening and identification of FTA metabolites in rats. As the result, a total of 43 metabolites were identified in biological samples including 42 metabolites in urine, 22 metabolites in plasma and 15 metabolites in feces. These results demonstrated that FTA underwent a series of in vivo metabolic reactions including methylation, dimethylation, sulfation, glucuronidation, diglucuronidation, cysteine conjugation and their composite reactions. The research enhanced our understanding of FTA metabolism and built a foundation for further toxicity and safety studies. PMID- 29228469 TI - Simultaneous determination of etonogestrel and ethinyl estradiol in human plasma by UPLC-MS/MS and its pharmacokinetic study. AB - A selective, sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry method was developed and validated for the simultaneous determination of etonogestrel (ENG) and ethinyl estradiol (EE) in human plasma. The analytes and their deuterated internal standards, ENG-d7 and EE-d4, were extracted from plasma samples by solid-phase extraction on HyperSepTM Retain PEP cartridges. The chromatographic analysis was performed on an Acquity UPLC HSS Cyano column, 100 A (50 * 2.1 mm, 1.8 MUm), column using gradient mobile phase, acetonitrile and 2.0 mm ammonium trifluoroacetate at 0-1.7 min (65:35, v/v) and 1.8-2.7 min (95:5, v/v) with 0.250 mL/min flow rate. Analytes and IS protonated precursor -> product ion transitions (ENG, m/z 325.2 -> 257.2; EE, m/z 530.2 -> 171.2; ENG-d7, m/z 332.2 -> 263.2; EE-d4, m/z 534.2 -> 171.2) were monitored on a Triple Quadrupole Mass spectrometer (TQMS), operating in multiple reaction monitoring and positive ionization mode. The calibration curves were established at 10.00-2500 pg/mL for ENG and 1.500-150.0 pg/mL for EE with a correlation coefficient (r2 ) >=0.9996 for both. The validated method was successfully applied to support a bioequivalence study of 0.15 mg ENG and EE 0.03 mg tablet formulation, administered in 24 healthy Indian females. Method reliability was assessed by reanalysis of 94 incurred study samples. PMID- 29228470 TI - Melanoma patterns of care in Ontario: A call for a strategic alignment of multidisciplinary care. AB - BACKGROUND AND OBJECTIVES: Variability in melanoma management has prompted concerns about equitable and timely treatment. We investigated patterns of melanoma diagnosis and treatment using population-level data. METHODS: Patients with invasive cutaneous melanoma were identified retrospectively from the Ontario Cancer Registry (2003-2012) and deterministically linked with administrative databases to identify incidence, disease characteristics, geographic origin, and multimodal treatment within a year of diagnosis. Melanoma treatment was categorized as inadequate or adequate based on multidisciplinary clinical algorithms. Multivariable logistic regression was used to model factors associated with treatment adequacy. RESULTS: From 2003 to 2012, 22 918 patients with invasive melanoma were identified with annual age/sex standardized incidence rates of 11.7-14.3/100 000 for females and 13.4-15.9/100 000 for males. Melanoma occurred at median age of 62 and primarily on extremities (43.9%). Within 1 year after diagnosis, 86.7% of patients received surgery as primary therapy. A total of 2312 (10.6%) patients received inadequate or no treatment after diagnosis. Receiving adequate treatment was associated with consultation with dermatology (OR 1.92, CI 1.71-2.14), plastic surgery (OR 4.80, CI 4.32-5.34), or general surgery (OR 2.15, CI 1.94-2.38). CONCLUSIONS: Significant variation exists in melanoma management and nearly one in nine patients is inadequately treated. Referral to sub-specialized providers is critical for ensuring appropriate care. PMID- 29228471 TI - Mass spectrometry for protein sialoglycosylation. AB - Sialic acids are a family of structurally unique and negatively charged nine carbon sugars, normally found at the terminal positions of glycan chains on glycoproteins and glycolipids. The glycosylation of proteins is a universal post translational modification in eukaryotic species and regulates essential biological functions, in which the most common sialic acid is N-acetyl-neuraminic acid (2-keto-5-acetamido-3,5-dideoxy-D-glycero-D-galactononulopyranos-1-onic acid) (Neu5NAc). Because of the properties of sialic acids under general mass spectrometry (MS) conditions, such as instability, ionization discrimination, and mixed adducts, the use of MS in the analysis of protein sialoglycosylation is still challenging. The present review is focused on the application of MS related methodologies to the study of both N- and O-linked sialoglycans. We reviewed MS based strategies for characterizing sialylation by analyzing intact glycoproteins, proteolytic digested glycopeptides, and released glycans. The review concludes with future perspectives in the field. PMID- 29228473 TI - Population Pharmacokinetics of Desvenlafaxine: Pharmacokinetics in Korean Versus US Populations. AB - Desvenlafaxine exposure in Korean and US populations was compared using population pharmacokinetic (PK) analysis. Data from a single- and multiple-dose study of desvenlafaxine (50, 100, and 200 mg) in 30 healthy Korean subjects were added to a population PK model previously developed using sparse PK samples from patients with major depressive disorder, including 140 Korean patients, combined with rich PK data from healthy volunteers. The structural PK model was an open 1 compartment linear disposition model with parallel first-order and 0-order inputs. The effects of Korean status on apparent oral clearance (CL/F) and apparent volume of distribution (V/F) were tested against the base model separately. External validation results indicated good agreement between the model predictions and observed desvenlafaxine concentrations for Korean subjects. The geometric mean CL/F and V/F of Korean subjects were 9.1% and 16.7% lower, respectively, than those of US subjects, who had a 20% higher mean body weight. Results for patients with major depressive disorder were similar. There were no meaningful differences for weight-normalized CL/F and V/F values between Korean and US subjects or patients. The minor differences in CL/F and V/F observed between Korean and US populations appear to be solely due to lower body weights in the Korean population. PMID- 29228472 TI - The epidemiology of stroke in Africa: A systematic review of existing methods and new approaches. AB - Accurate epidemiological surveillance of the burden of stroke is direly needed to facilitate the development and evaluation of effective interventions in Africa. The authors therefore conducted a systematic review of the methodology of stroke epidemiological studies conducted in Africa from 1970 to 2017 using gold standard criteria obtained from landmark epidemiological publications. Of 1330 articles extracted, only 50 articles were eligible for review grouped under incidence, prevalence, case-fatality, health-related quality of life, and disability adjusted life-years studies. Because of various challenges, no study fulfilled the criteria for an excellent stroke incidence study. The relatively few stroke epidemiology studies in Africa have significant methodological flaws. Innovative approaches leveraging available information and communication technology infrastructure are recommended to facilitate rigorous epidemiological studies for accurate stroke surveillance in Africa. PMID- 29228474 TI - Controlled Electrospray Generation of Nonspherical Alginate Microparticles. AB - Electrospraying is a technique used to generate microparticles in a high throughput manner. For biomedical applications, a biocompatible electrosprayed material is often desirable. Using polymers, such as alginate hydrogels, makes it possible to create biocompatible and biodegradable microparticles that can be used for cell encapsulation, to be employed as drug carriers, and for use in 3D cell culturing. Evidence in the literature suggests that the morphology of the biocompatible microparticles is relevant in controlling the dynamics of the microparticles in drug delivery and 3D cell culturing applications. Yet, most electrospray-based techniques only form spherical microparticles, and there is currently no widely adopted technique for producing nonspherical microparticles at a high throughput. Here, we demonstrate the generation of nonspherical biocompatible alginate microparticles by electrospraying, and control the shape of the microparticles by varying experimental parameters such as chemical concentration and the distance between the electrospray tip and the particle solidification bath. Importantly, we show that these changes to the experimental setup enable the synthesis of different shaped particles, and the systematic change in parameters, such as chemical concentration, result in monotonic changes to the particle aspect ratio. We expect that these results will find utility in many biomedical applications that require biocompatible microparticles of specific shapes. PMID- 29228475 TI - Persistente Ulzera durch Crack-Konsum. PMID- 29228476 TI - Keystone Flap zur Deckung grobetaer Weichteildefekte des Handruckens. PMID- 29228478 TI - Lichen ruber-artiges Arzneimittelexanthem unter Anti-PD-1-Therapie. PMID- 29228477 TI - Regionale facharztliche Versorgung und demographischer Wandel in Deutschland - Szenarien zur dermatologischen Versorgung im Jahr 2035. AB - HINTERGRUND: Mithilfe der Bedarfsplanungsrichtlinie des Gemeinsamen Bundesausschusses soll die medizinische Versorgung in Deutschland flachendeckend sichergestellt werden. Kalkulatorische Grobetae zur Abbildung der raumlichen Versorgungssituation ist der "korrigierte Versorgungsgrad". Vor dem Hintergrund des demographischen Wandels und bereits heute existenter Wiederbesetzungsschwierigkeiten steht die Frage, wie sich die dermatologische Versorgung kleinraumig entwickeln wird. METHODIK: Mit bundesweiten Daten zu Hautarztstandorten sowie aktuellen und prognostizierten Bevolkerungszahlen auf Kreisebene wurde auf Basis der aktuellen Bedarfsplanungsrichtlinie der korrigierte Versorgungsgrad in drei Wiederbesetzungsszenarien (Szenario 1: 100%ige Wiederbesetzung, Szenario 2: Wegfall eines Arztsitzes je Planungsbereich, Szenario 3: Wegfall von zwei Arztsitzen in landlichen Planungsbereichen) fur das Prognosejahr 2035 exemplarisch berechnet. ERGEBNISSE: Wahrend sich in Szenario 1 die Versorgungssituation von 2014 auf 2035 in einigen Teilraumen sogar verbessern wurde (n = 3 nicht mehr unterversorgt), zeigen die wahrscheinlicheren Szenarien 2 und 3 mit dem Wegfall einzelner Arztstandorte und dem altersselektiven Wanderungsverhalten, dass ganze Regionen in die Unterversorgung gelangen konnten. SCHLUSSFOLGERUNGEN: Es ist davon auszugehen, dass die raumliche Heterogenitat der dermatologischen Versorgung unter Berucksichtigung des demographischen Wandels zunehmen wird. Weitere Anstrengungen in der Bedarfsplanung, aber auch hinsichtlich kreativer Versorgungsmodelle und interkommunaler Kooperation sind erforderlich, um die Versorgung dem demographischen Wandel sowie veranderten Lebensentwurfen junger Mediziner anzupassen. PMID- 29228479 TI - Hochdosierte intravenose Immunglobuline bei dermatologischen Autoimmunerkrankungen. PMID- 29228480 TI - Therapie infantiler Hamangiome. PMID- 29228481 TI - Erfolgreiche Behandlung einer Cheilitis granulomatosa mit Infliximab bei Kindern. PMID- 29228482 TI - Qualitat von Sachverstandigengutachten zum berufsbedingten Hautkrebs durch naturliches UV-Licht. PMID- 29228483 TI - Kalzifizierte Bursitis praepatellaris bei limitierter kutaner systemischer Sklerodermie. PMID- 29228484 TI - Das infantile Hamangiom: Pathogenese und Wirkmechanismus von Propranolol. PMID- 29228485 TI - Therapierefraktares Exanthem eines sechs Monate alten Sauglings. PMID- 29228486 TI - Unerwarteter Nachweis eines neu aufgetretenen Melanoms mittels PET-CT bei einer Patientin mit lymphogen metastasiertem malignen Melanom. PMID- 29228487 TI - Lymphangiosarkom der Hufte in einem nicht bestrahlten kongenitalen Lymphangiom. PMID- 29228488 TI - 27. Deutscher Hautkrebskongress der ADO in Mainz ging erfolgreich zu Ende. PMID- 29228490 TI - Tagungsbericht der Jahrestagung des Arbeitskreises Psychosomatische Dermatologie (APD) am 30.09.2017 in Bonn. PMID- 29228489 TI - S2k-Leitlinie - Kutane Lymphome Update 2016 - Teil 1: Klassifikation und Diagnostik (ICD10 C82 - C86). PMID- 29228491 TI - Regional healthcare delivery and demographic change in Germany - scenarios for dermatological care in 2035. AB - BACKGROUND: The 'demand planning guidelines' issued by the Federal Joint Committee are meant to ensure nationwide delivery of healthcare in Germany. The calculatory variable used to reflect the actual care situation in relation to a given geographical entity is referred to as 'adjusted supply rate'. Against the backdrop of demographic change and already existing problems in replacing retiring physicians, the question arises as to how future dermatological care will evolve at the regional level. METHODS: Using current 'demand planning guidelines' as well as nationwide data on the location of dermatologists and current and projected population figures at the county level, the adjusted supply rate - in terms of dermatological care - was calculated for the year 2035 based on three possible scenarios (scenario 1: 100 % replacement of retiring dermatologists; scenario 2: non-replacement of one dermatologist per planning area; and scenario 3: non-replacement of two dermatologists in rural areas). RESULTS: While scenario 1 shows an actual improvement in regional dermatological care in certain areas between 2014 and 2035 (n = 3 no longer undersupplied), the more likely scenarios 2 and 3 are potentially associated with considerable regional undersupply. CONCLUSIONS: Taking demographic change into account, it is safe to assume that the geographical heterogeneity of dermatological care will increase. This requires greater effort not only in terms of demand planning but also with regard to offering alternative methods of delivering healthcare and intercommunal cooperation. In this context, the objective will be to adapt healthcare delivery to changes both in demography as well as in the plans young physicians have for their own lives. PMID- 29228492 TI - Das Interesse an Solarien und Sonnenschutz im deutschsprachigen Raum. PMID- 29228493 TI - Erythematos-livide Plaques an beiden Unterschenkeln. PMID- 29228494 TI - Nachruf fur Prof. Dr. Heinz Flegel (geb. 26.10.1923 - gest. 28.10.2017). PMID- 29228497 TI - Kongresskalender 2017. PMID- 29228496 TI - Nebenwirkungen von subkutanen, medikamentenfreisetzenden Implantaten zur Behandlung von Opioid-Drogenabhangigkeit. PMID- 29228498 TI - Calcific prepatellar bursitis in a patient with limited cutaneous systemic sclerosis. PMID- 29228499 TI - High-dose intravenous immunoglobulins for the treatment of dermatological autoimmune diseases. AB - Based on their immunomodulatory properties, high-dose intravenous immunoglobulins (IVIGs) are successfully used in the treatment of various dermatological autoimmune diseases, in particular pemphigus vulgaris and dermatomyositis. In autoimmune bullous diseases, IVIGs can be used in an adjuvant setting (second- or third-line therapy) once combined immunosuppressive regimens have failed. In dermatomyositis, IVIGs may already be employed as an adjuvant second-line therapy after failure of corticosteroid monotherapy. In scleromyxedema, IVIGs may be considered as first-line treatment, given the lack of effective and safe alternatives. Other potential indications for IVIGs may include severe recalcitrant cases of systemic vasculitis and systemic lupus erythematosus. Toxic epidermal necrolysis may be an indication for high-dose IVIGs if administered early. Common, readily manageable side effects include nausea, headache, fatigue, and febrile infusion reactions. Severe adverse events such as thromboembolic events, anaphylaxis, and acute renal failure are very uncommon. The risk of viral transmission is very low. Potential mechanisms of action include upregulation of inhibitory Fc receptors, reduction of the half-life of endogenous immunoglobulins due to displacement from protective receptor sites, neutralization of autoantibodies by anti-idiotypic antibodies, as well as inhibition of complement activation. PMID- 29228500 TI - Cyclical haematochezia: an uncommon cause of lower gastrointestinal bleeding. PMID- 29228501 TI - Hepatitis C virus clearance by direct-acting antiviral treatments and impact on insulin resistance in chronic hepatitis C patients. AB - BACKGROUND AND AIM: Chronic hepatitis C virus (HCV), particularly genotype 1, is associated with insulin resistance (IR) and diabetes. This study evaluated the impact of HCV clearance by all-oral direct-acting antiviral treatments on IR and glycemic control. METHODS: Included in this prospective case-control study were 133 consecutive HCV-genotype 1 patients with advance liver fibrosis (F3-F4) without type 2 diabetes. Sixty eight were treated with direct-acting antiviral and 65 were untreated. Liver fibrosis was assessed by transient elastography. Pre treatment, end-treatment, and 3 months post-treatment withdrawal IR homeostasis was assessed by homeostatic model assessment (HOMA)-IR, HOMA-S, and HOMA-B. RESULTS: At baseline, treated, and untreated patients showed similar liver fibrosis levels, HOMA-IR was 4.90 +/- 4.62 and 4.64 +/- 5.62, respectively. HOMA IR correlated with HCV RNA levels. At the end of treatment, all patients cleared HCV RNA, regardless of liver fibrosis and body mass index, and a reduction in HOMA-IR at 2.42 +/- 1.85 was showed (P < 0.001); in addition, increased insulin sensitivity, decreased insulin secretion, reduction of serum glucose, and insulin levels were observed. Data were confirmed 3 months after treatment withdrawal in the 65 patients who cleared HCV. No variation occurred in untreated patients. Overall, 76.5% of sustained virologic response patients showed IR improvements, of which 41.2% normalized IR. Improvement of IR was strictly associated with HCV clearance; however, patients with the highest levels of fibrosis remain associated with some degree of IR. CONCLUSIONS: The data underline a role of HCV in development of IR and that viral eradication reverses IR and improves glycemic control and this could prevent IR-related clinical manifestations and complications. PMID- 29228503 TI - An Integrated Framework for Environmental Multi-Impact Spatial Risk Analysis. AB - Quantitative risk analysis is being extensively employed to support policymakers and provides a strong conceptual framework for evaluating decision alternatives under uncertainty. Many problems involving environmental risks are, however, of a spatial nature, i.e., containing spatial impacts, spatial vulnerabilities, and spatial risk-mitigation alternatives. Recent developments in multicriteria spatial analysis have enabled the assessment and aggregation of multiple impacts, supporting policymakers in spatial evaluation problems. However, recent attempts to conduct spatial multicriteria risk analysis have generally been weakly conceptualized, without adequate roots in quantitative risk analysis. Moreover, assessments of spatial risk often neglect the multidimensional nature of spatial impacts (e.g., social, economic, human) that are typically occurring in such decision problems. The aim of this article is therefore to suggest a conceptual quantitative framework for environmental multicriteria spatial risk analysis based on expected multi-attribute utility theory. The framework proposes: (i) the formal assessment of multiple spatial impacts; (ii) the aggregation of these multiple spatial impacts; (iii) the assessment of spatial vulnerabilities and probabilities of occurrence of adverse events; (iv) the computation of spatial risks; (v) the assessment of spatial risk mitigation alternatives; and (vi) the design and comparison of spatial risk mitigation alternatives (e.g., reductions of vulnerabilities and/or impacts). We illustrate the use of the framework in practice with a case study based on a flood-prone area in northern Italy. PMID- 29228502 TI - Giant hepatic hydatid extending subcutaneously to the anterior abdomen piercing the rectus sheath. PMID- 29228504 TI - Dynamic borrowing through empirical power priors that control type I error. AB - In order for historical data to be considered for inclusion in the design and analysis of clinical trials, prospective rules are essential. Incorporation of historical data may be of particular interest in the case of small populations where available data is scarce and heterogeneity is not as well understood, and thus conventional methods for evidence synthesis might fall short. The concept of power priors can be particularly useful for borrowing evidence from a single historical study. Power priors employ a parameter gamma ? [ 0 , 1 ] that quantifies the heterogeneity between the historical study and the new study. However, the possibility of borrowing data from a historical trial will usually be associated with an inflation of the type I error. We suggest a new, simple method of estimating the power parameter suitable for the case when only one historical dataset is available. The method is based on predictive distributions and parameterized in such a way that the type I error can be controlled by calibrating to the degree of similarity between the new and historical data. The method is demonstrated for normal responses in a one or two group setting. Generalization to other models is straightforward. PMID- 29228505 TI - A Spatio-Temporal Exposure-Hazard Model for Assessing Biological Risk and Impact. AB - We developed a simulation model for quantifying the spatio-temporal distribution of contaminants (e.g., xenobiotics) and assessing the risk of exposed populations at the landscape level. The model is a spatio-temporal exposure-hazard model based on (i) tools of stochastic geometry (marked polygon and point processes) for structuring the landscape and describing the exposed individuals, (ii) a dispersal kernel describing the dissemination of contaminants from polygon sources, and (iii) an (eco)toxicological equation describing the toxicokinetics and dynamics of contaminants in affected individuals. The model was implemented in the briskaR package (biological risk assessment with R) of the R software. This article presents the model background, the use of the package in an illustrative example, namely, the effect of genetically modified maize pollen on nontarget Lepidoptera, and typical comparisons of landscape configurations that can be carried out with our model (different configurations lead to different mortality rates in the treated example). In real case studies, parameters and parametric functions encountered in the model will have to be precisely specified to obtain realistic measures of risk and impact and accurate comparisons of landscape configurations. Our modeling framework could be applied to study other risks related to agriculture, for instance, pathogen spread in crops or livestock, and could be adapted to cope with other hazards such as toxic emissions from industrial areas having health effects on surrounding populations. Moreover, the R package has the potential to help risk managers in running quantitative risk assessments and testing management strategies. PMID- 29228506 TI - JOR Virtual Issue on stem cells in orthopaedics. PMID- 29228507 TI - Pancreatic cleft mimicking traumatic pancreatic transection. PMID- 29228508 TI - Cranial Backspatter Pattern Production Utilizing Human Cadavers. AB - A backspatter pattern results from blood drops that travel retrograde to an applied external force. Historically, an array of animals and nonhuman objects have been used to create and study backspatter patterns. In this study, backspatter patterns captured on foam core targets that were placed 45.72 cm (18 in) behind the impact site (occipital area of the skull) were produced by cranial gunshots to human cadavers that were reinfused with fresh defibrinated bovine blood. These patterns were compared to the backspatter patterns produced by shooting blood-soaked sponges, a typical simulant used in controlled studies of backspatter pattern production and characteristics. The backspatter pattern produced by shooting an actual human head was found to be different than those of blood-soaked sponges in the number of stains produced, the size and size range of the stains, and the stain dispersion patterns. PMID- 29228509 TI - C-learning: A new classification framework to estimate optimal dynamic treatment regimes. AB - A dynamic treatment regime is a sequence of decision rules, each corresponding to a decision point, that determine that next treatment based on each individual's own available characteristics and treatment history up to that point. We show that identifying the optimal dynamic treatment regime can be recast as a sequential optimization problem and propose a direct sequential optimization method to estimate the optimal treatment regimes. In particular, at each decision point, the optimization is equivalent to sequentially minimizing a weighted expected misclassification error. Based on this classification perspective, we propose a powerful and flexible C-learning algorithm to learn the optimal dynamic treatment regimes backward sequentially from the last stage until the first stage. C-learning is a direct optimization method that directly targets optimizing decision rules by exploiting powerful optimization/classification techniques and it allows incorporation of patient's characteristics and treatment history to improve performance, hence enjoying advantages of both the traditional outcome regression-based methods (Q- and A-learning) and the more recent direct optimization methods. The superior performance and flexibility of the proposed methods are illustrated through extensive simulation studies. PMID- 29228511 TI - Gastric cancer with solitary liver metastasis accompanied by cyst formation. PMID- 29228510 TI - Left behind and left out: The impact of the school environment on young people with continence problems. AB - OBJECTIVES: To explore the impact of the secondary school environment on young people with continence problems. DESIGN: In-depth qualitative semi-structured interviews. METHODS: We interviewed 20 young people aged 11-19 years (11 female and nine male) with continence problems (daytime wetting, bedwetting, and/or soiling). Interviews were conducted by Skype (n = 11) and telephone (n = 9). Transcripts were analysed using inductive thematic analysis. RESULTS: We generated five main themes: (1) Boundaries of disclosure: friends and teachers; (2) Social consequences of avoidance and deceit; (3) Strict and oblivious gatekeepers; (4) Intimate actions in public spaces; and (5) Interrupted learning. CONCLUSION: Disclosure of continence problems at school to both friends and teachers was rare, due to the perceived stigma and fears of bullying and social isolation. The lack of disclosure to teachers and other school staff, such as pastoral care staff, creates challenges in how best to support these young people. Young people with continence problems require unrestricted access to private and adequate toilet facilities during the school day. There is a need for inclusive toilet access policies and improved toilet standards in schools. Addressing the challenges faced by young people with continence problems at school could help to remove the barriers to successful self-management of their symptoms. It is particularly concerning that young people with continence problems are at higher risk of academic underachievement. Increased support at school is needed to enable young people with continence problems to achieve their academic potential. Statement of Contribution What is already known on this subject? Continence problems are among the most common paediatric health problems Self-management of continence problems requires a structured schedule of fluid intake and bladder emptying Inadequate toilet facilities and restricted access make it difficult for young people to manage their incontinence What does this study add? Improvement is needed in teacher understanding of the needs of young people with continence problems Young people are reluctant to disclose continence problems due to perceived stigma and fear of social isolation Young people with continence problems may be at increased risk of academic underachievement. PMID- 29228512 TI - Surgical management decreases disease recurrence risk in recurrent pyogenic cholangitis. AB - BACKGROUND: Recurrent pyogenic cholangitis (RPC) has a high risk of disease recurrence. We present our experience with RPC and examine the factors associated with disease recurrence. METHODS: We performed a retrospective review of all patients with RPC treated at two tertiary institutions between January 1990 and December 2013. Patients with liver atrophy and/or abscess were categorized as being associated with parenchymal disease (PD). RESULTS: We studied 157 patients with a median age of 59.0 (interquartile range (IQR): 47.0-70.0) years and a median follow-up duration of 71.0 (IQR: 26.0-109.0) months. There were 64 (40.8%) and 93 (59.2%) patients with and without associated PD, respectively. Disease recurrence rate was 43.9% in our overall cohort through the course of follow-up. Surgical treatment was an independent prognostic factor for decreased disease recurrence risk (hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.18-0.87, P = 0.021). Stratified analysis revealed that liver resection was prognostic for lower risk of disease recurrence among patients with PD (HR 0.38, 95% CI 0.15 0.94, P = 0.036), while biliary bypass was prognostic for lower risk of disease recurrence among patients without PD (HR 0.30, 95% CI 0.15-0.61, P = 0.001). The overall post-operative complication rate among surgically treated patients was 31.1%, and the presence of bilobar stones was found to be independently associated with higher odds of post-operative complications (odds ratio 3.51, 95% CI 1.26-9.81, P = 0.017). CONCLUSION: Surgical treatment is associated with decreased recurrence risk in RPC, but with significant post-operative morbidity. Where surgery is deemed appropriate, patients with and without PD are likely to benefit from liver resection and biliary bypass, respectively. PMID- 29228513 TI - An Analysis of The Morbidity and Mortality of Diabetes Mellitus in a Forensic Context. AB - To investigate the spectrum of diseases seen in diabetes mellitus in a forensic context, all autopsy reports of diabetic individuals who presented to Forensic Science, South Australia (FSSA), over a 5-year period from 2005 to 2009 were studied. The leading cause of death was cardiovascular disease (55.0%), followed by unnatural deaths (15.4%) and infections (9.4%). In type 1 diabetics, principal causes of death included cardiovascular disease (44.7%), acute metabolic complications (18.7%), unnatural deaths (17.9%), and infections (8.9%). However, frequencies of these diseases differed in type 2 diabetics, with cardiovascular events responsible for 56.6% of cases, followed by unnatural deaths (15.0%) and infections (10.9%). A larger number of male deaths were seen in all disease categories, except respiratory and gastrointestinal where the frequencies were similar to females. Cardiovascular disease was the leading overall cause of death across all ages except in those under the age of 30 where metabolic complications were more common. PMID- 29228514 TI - Gait speed predicts post-operative medical complications in elderly gastric cancer patients undergoing gastrectomy. AB - BACKGROUND: Gait speed is a clinical outcome that can measure the physical performance of elderly gastric patients. The purpose of this study was to determine the importance of gait speed in predicting post-operative morbidities in elderly patients undergoing curative gastrectomy. METHODS: We conducted a prospective study of 357 elderly patients (>=65 years old) undergoing curative gastrectomy. Preoperative gait speed was measured in a 6-m well-lit and unobstructed hallway. Patients were followed up for the post-operative clinical outcomes. Factors contributing to the post-operative morbidities were analysed using univariate and multivariate analyses. RESULTS: Slow gait speed was present in 95 out of 357 patients (26.61%) which was significantly associated with age (P < 0.001), gender (P = 0.016), plasma albumin (P < 0.001), American Society of Anesthesiologists grade (P = 0.012), tumour-node-metastasis grade (P = 0.007), sarcopenia (P < 0.001), handgrip (P < 0.001) and post-operative medical complications (P = 0.022). In univariate analysis, age (P = 0.015) and slow gait speed (P = 0.029) were risk factors of post-operative complications. In multivariate analysis, we found that age (P < 0.001) and slow gait speed (P = 0.029) were independent predictors of post-operative medical complications. CONCLUSION: Slow gait speed is an independent predictor of post-operative medical complications in elderly patients undergoing curative gastrectomy. Those patients should be managed with appropriate perioperative nutritional support and physical exercise which can improve gait speed and reduce the risk of post-operative medical complications. PMID- 29228515 TI - Aging and Cardiometabolic Risk in European HEMS Pilots: An Assessment of Occupational Old-Age Limits as a Regulatory Risk Management Strategy. AB - Old-age limits are imposed in some occupations in an effort to ensure public safety. In aviation, the "Age 60 Rule" limits permissible flight operations conducted by pilots aged 60 and over. Using a retrospective cohort design, we assessed this rule's validity by comparing age-related change rates of cardiometabolic incapacitation risk markers in European helicopter emergency medical service (HEMS) pilots near age 60 with those in younger pilots. Specifically, individual clinical, laboratory, and electrocardiogram (ECG)-based risk markers and an overall cardiovascular event risk score were determined from aeromedical examination records of 66 German, Austrian, Polish, and Czech HEMS pilots (average follow-up 8.52 years). Risk marker change rates were assessed using linear mixed models and generalized additive models. Body mass index increases over time were slower in pilots near age 60 compared to younger pilots, and fasting glucose levels increased only in the latter. Whereas the lipid profile remained unchanged in the latter, it improved in the former. An ECG-based arrhythmia risk marker increased in younger pilots, which persisted in the older pilots. Six-month risk of a fatal cardiovascular event (in or out of cockpit) was estimated between 0% and 0.3%. Between 41% and 95% of risk marker variability was due to unexplained time-stable between-person differences. To conclude, the cardiometabolic risk marker profile of HEMS pilots appears to improve over time in pilots near age 60, compared to younger pilots. Given large stable interindividual differences, we recommend individualized risk assessment of HEMS pilots near age 60 instead of general grounding. PMID- 29228516 TI - Refining Prediction in Treatment-Resistant Depression: Results of Machine Learning Analyses in the TRD III Sample. AB - OBJECTIVE: The study objective was to generate a prediction model for treatment resistant depression (TRD) using machine learning featuring a large set of 47 clinical and sociodemographic predictors of treatment outcome. METHOD: 552 Patients diagnosed with major depressive disorder (MDD) according to DSM-IV criteria were enrolled between 2011 and 2016. TRD was defined as failure to reach response to antidepressant treatment, characterized by a Montgomery-Asberg Depression Rating Scale (MADRS) score below 22 after at least 2 antidepressant trials of adequate length and dosage were administered. RandomForest (RF) was used for predicting treatment outcome phenotypes in a 10-fold cross-validation. RESULTS: The full model with 47 predictors yielded an accuracy of 75.0%. When the number of predictors was reduced to 15, accuracies between 67.6% and 71.0% were attained for different test sets. The most informative predictors of treatment outcome were baseline MADRS score for the current episode; impairment of family, social, and work life; the timespan between first and last depressive episode; severity; suicidal risk; age; body mass index; and the number of lifetime depressive episodes as well as lifetime duration of hospitalization. CONCLUSIONS: With the application of the machine learning algorithm RF, an efficient prediction model with an accuracy of 75.0% for forecasting treatment outcome could be generated, thus surpassing the predictive capabilities of clinical evaluation. We also supply a simplified algorithm of 15 easily collected clinical and sociodemographic predictors that can be obtained within approximately 10 minutes, which reached an accuracy of 70.6%. Thus, we are confident that our model will be validated within other samples to advance an accurate prediction model fit for clinical usage in TRD. PMID- 29228518 TI - Childhood Trauma Is Associated With Poorer Cognitive Performance in Older Adults. AB - OBJECTIVE: Childhood trauma is common and associated with both worse cognitive performance and disruption to the hypothalamic-pituitary-adrenal axis in younger adults. The extent to which these associations persist into older adulthood remains unknown. The aim of this study was to investigate self-reported childhood trauma in relation to cognitive performance, and the extent to which cortisol explained this association, in 2 independent samples of older adults. METHODS: In this cross-sectional study, participants in the discovery sample (N = 76) consisted of older adults with a DSM-IV diagnosis of generalized anxiety disorder (N = 57) and age-equated psychiatrically healthy comparison subjects (N = 19) who were referred largely through primary care clinics between 2004-2006. The replication sample (N = 48) consisted of older adults with DSM-IV anxiety or depressive disorders recruited between 2012-2013. Participants were administered the Early Trauma Inventory Self-Report-Short Form and a neuropsychological assessment (primary outcome). RESULTS: Across both samples, childhood trauma was significantly associated with worse performance on measures of processing speed, attention, and executive functioning. The effect of trauma exposure was stronger when general, physical, and sexual traumatic events were examined specifically (all P < .05). Childhood trauma was not associated with cortisol levels, and cortisol did not explain the association between trauma and cognitive functioning. CONCLUSIONS: Self-reported traumatic events experienced in childhood are associated with poorer cognitive performance in anxious and depressed older adults. Findings demonstrate a deleterious impact of childhood trauma on brain health in old age. PMID- 29228517 TI - Cost-Effectiveness of Internet-Based Cognitive-Behavioral Treatment for Bulimia Nervosa: Results of a Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the cost-effectiveness of Internet-based cognitive behavioral therapy for bulimia nervosa (CBT-BN) compared to face-to-face delivery of CBT-BN. METHODS: This study is a planned secondary analysis of data from a randomized clinical trial. Participants were 179 adults (98% female, mean age = 28 years) meeting DSM-IV criteria for bulimia nervosa who were randomized to group face-to-face or group Internet-based CBT-BN for 16 sessions during 20 weeks. The cost-effectiveness analysis was conducted from a third-party payor perspective, and a partial societal perspective analysis was conducted to investigate cost-utility (ie, cost per gain in quality-adjusted life-years) and patient out-of-pocket travel-related costs. Net health care costs were calculated from protocol and nonprotocol health care services using third-party payor cost estimates. The primary outcome measure in the clinical trial was abstinence from binge eating and purging, and the trial start and end dates were 2008 and 2016. RESULTS: The mean cost per abstinent patient at posttreatment was $7,757 (95% confidence limit [CL], $4,515, $13,361) for face-to-face and $11,870 (95% CL, $6,486, $22,188) for Internet-based CBT-BN, and at 1-year follow-up was $16,777 (95% CL, $10,298, $27,042) for face-to-face and $14,561 (95% CL, $10,165, $21,028) for Internet-based CBT-BN. There were no statistically significant differences between treatment arms in cost-effectiveness or cost-utility at posttreatment or 1-year follow-up. Out-of-pocket patient costs were significantly higher for face-to-face (mean [95% CL] = $178 [$127, $140]) than Internet-based ($50 [$50, $50]) therapy. CONCLUSIONS: Third-party payor cost-effectiveness of Internet-based CBT-BN is comparable with that of an accepted standard. Internet based dissemination of CBT-BN may be a viable alternative for patients geographically distant from specialist eating disorder services who have an unmet need for treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00877786. PMID- 29228519 TI - Large-scale surveillance study of the safety and effectiveness of entecavir in Korean patients with chronic hepatitis B. AB - BACKGROUND/AIMS: Entecavir (ETV) is effective and safe antiviral agent against hepatitis B virus (HBV) in clinical and real-world setting but, most studies were performed in single institute or have limitation in patient's number. A large scale nation-wide real-world surveillance study was carried out to investigate safety, efficacy and clinical effectiveness of ETV in Korean patients with chronic hepatitis B (CHB). METHODS: Between 2006 and 2012, 3,444 patients were enrolled from 132 Korean institutions. For the safety assessment, investigators recorded the occurrence of observed and patient-reported adverse events (AEs), as well as laboratory abnormalities. Efficacy, which consisted of change in HBV DNA and alanine aminotransferase (ALT), was evaluated in patients who had received at least 16 weeks of ETV treatment. Overall clinical effectiveness, based on improvement of ALT, HBV DNA and patient's symptoms, was evaluated by physicians. RESULTS: Of the patients, 3,367 were evaluated for safety and 3,115 for efficacy and clinical effectiveness. Three hundred and eighty AEs were reported in 255 cases (7.57%), and 67 adverse drug reactions in 54 cases (1.6%). Serious AEs (SAE) were 19 events in nine cases (0.27%). Serious adverse drug reactions (SADR) were three events in two cases (0.06%), and unexpected SAE/SADR were three events in two cases (0.06%). Medical history and concomitant medications were factors inf luencing incidence rates of AEs. Overall clinical effectiveness rate was 96.53%, which was clinically assessed as marked improved or improved state. CONCLUSIONS: This study showed that ETV was well tolerated and clinically effective in Korean patients with CHB in a real-world nation-wide setting. PMID- 29228520 TI - The Significance of TROP2 Expression in Predicting BRAF Mutations in Papillary Thyroid Carcinoma. AB - BACKGROUND: Trophoblast antigen 2 (TROP2) is a human trophoblast cell-surface glycoprotein that is overexpressed in several types of epithelial cancers, and is suggested to be associated with an unfavorable prognosis. BRAF mutations are the most common genetic alteration in papillary thyroid carcinoma (PTC). We evaluated the correlation between TROP2 expression and BRAF mutation in PTC. METHODS: First, we carried out pyrosequencing for BRAF mutations and immunohistochemistry for TROP2 expression with a tissue microarray consisting of 52 PTC cases. Membranous staining in at least 5% of tumor cells was designated as positive staining and we analyzed the relationship between TROP2 expression and diverse clinicopathological factors, including BRAF mutation. Second, we tested TROP2 mRNA expression in three thyroid cancer cell lines with BRAF mutations (BCPAP, SNU790, and 8505C) and a normal thyroid cell line. Additionally, we checked TROP2 protein levels in a normal thyroid cell line after introduction of the BRAF V600E mutation. RESULTS: In this study, 21 of 26 cases with BRAF mutation showed TROP2 immunoreactivity, whereas all 26 cases without BRAF mutation showed no immunoreactivity for TROP2 with a statistically significant difference (p<.001). Upregulation of TROP2 mRNA was observed in all three thyroid cancer cell lines, but not in the normal thyroid cell line. Interestingly, however, the TROP2 expression was increased in the normal thyroid cell line after introduction of the BRAF V600E mutation. CONCLUSIONS: Based on these results, we concluded that TROP2 expression is significantly associated with BRAF mutation and that TROP2 immunohistochemistry could be used for predicting BRAF mutations or diagnosing papillary thyroid carcinoma. PMID- 29228521 TI - Intercalated Treatment Following Rebiopsy Is Associated with a Shorter Progression-Free Survival of Osimertinib Treatment. AB - PURPOSE: Epidermal growth factor receptor (EGFR) T790M mutation serves as an important predictor of osimertinib efficacy. However, little is known about how it works among patients with various timings of T790M emergence and treatment. Materials and Methods: Advanced EGFR-mutant lung adenocarcinoma patients with positive T790M mutation in tumor were retrospectively enrolled and observed to determine the outcomes of osimertinib treatment. We evaluated the association between patients' characteristics and the efficacy of osimertinib treatment, particularly with respect to the timing of T790M emergence and osimertinib prescription. RESULTS: A total of 91 patients were enrolled, including 14 (15.4%) with primary and 77 (84.6%) with acquired T790M mutation. The objective response rate and disease controlratewere 60.9% and 85.1%, respectively. The median progression-free survival (PFS) and overall survival were 11.5 months (95% confidence interval [CI], 9.0 to 14.0) and 30.4 months (95% CI, 11.3 to 49.5), respectively. There was no significant difference in response rate and PFS between primary and acquired T790M populations. In the acquired T790M subgroup, patientswho received osimertinib after T790M had been confirmed by rebiopsy had a longer PFS than those with intercalated treatments between rebiopsy and osimertinib prescription (14.0 months [95% CI, 9.0 to 18.9] vs. 7.2 months [95% CI, 3.7 to 10.8]; adjusted hazard ratio, 0.48 [95% CI, 0.24 to 0.98; p=0.043]). Rebiopsy timing did not influence the outcome. CONCLUSION: Osimertinib prescription with intercalated treatment following rebiopsy but not the timing of T790M emergence influenced the treatment outcome. We suggest that it is better to start osimertinib treatment once T790M mutation has been confirmed by biopsy. PMID- 29228522 TI - Factors affecting satisfaction with cancer information provided through the social networking services of the National Cancer Information Center in Korea. AB - OBJECTIVES: This study aimed to identify the characteristics of social networking service (SNS) users and to assess the relationship of those factors to user satisfaction with the SNSs of the National Cancer Information Center (NCIC) in South Korea. METHODS: A Web-based survey was completed by 1,670 users of the NCIC SNSs, who provided data on the sources they consulted for information about cancer, determinants of SNS use, sources of NCIC SNS awareness, the time of day they used the SNS, and their satisfaction level. RESULTS: Facebook users mainly became aware of the NCIC SNSs through an acquaintance's recommendation, while Twitter was accessed through other SNSs or blogs. Users in their 30s were less satisfied with the NCIC SNSs than those in their teens and 20s. Browsing for cancer-related information on the Internet, prioritizing information quality, and engaging in active use were related to a high level of satisfaction with the NCIC SNSs. Individuals who were exposed to the NCIC SNSs through other SNSs or printed materials were less satisfied with their experience of the NCIC SNSs than those who received a recommendation from an acquaintance. CONCLUSIONS: These findings may act as a catalyst to guide public health agencies to enhance their use of SNSs. PMID- 29228523 TI - Advanced Therapeutic Gastrointestinal Endoscopy in Children - Today and Tomorrow. AB - Gastrointestinal (GI) endoscopy plays an indispensable role in the diagnosis and management of various pediatric GI disorders. While the pace of development of pediatric GI endoscopy has increased over the years, it remains sluggish compared to the advancements in GI endoscopic interventions available in adults. The predominant reasons that explain this observation include lack of formal training courses in advanced pediatric GI interventions, economic constraints in establishing a pediatric endoscopy unit, and unavailability of pediatric-specific devices and accessories. However, the situation is changing and more pediatric GI specialists are now performing complex GI procedures such as endoscopic retrograde cholangiopancreatography and endoscopic ultrasonography for various pancreatico-biliary diseases and more recently, per-oral endoscopic myotomy for achalasia cardia. Endoscopic procedures are associated with reduced morbidity and mortality compared to open surgery for GI disorders. Notable examples include chronic pancreatitis, pancreatic fluid collections, various biliary diseases, and achalasia cardia for which previously open surgery was the treatment modality of choice. A solid body of evidence supports the safety and efficacy of endoscopic management in adults. However, additions continue to be made to literature describing the pediatric population. An important consideration in children includes size of children, which in turn determines the selection of endoscopes and type of sedation that can be used for the procedure. PMID- 29228524 TI - Evaluation of Antibody and Cytokines Responses in Intranasally and Intramuscularly Administrated BALB/C Mice With Influenza Virus-Like Particle. AB - We previously developed an influenza virus like particle with HA, M, and NA proteins using Bac-to-Bac expression system and SF9 cell line. To evaluate the immunogenicity of our construct, we assessed the humoral, cytokine induced by H1N1-VLP in BALB/c mice immunized intranasally and intramuscularly. Enzyme-linked immunosorbent assay and Relative quantitative real-time PCR were used to evaluate the antibody (IgG and IgA) and mRNA levels of IL-6, IL-4, IL-10 and IFN-g in PBMCs. Our results showed that VLP was capable of intranasal (I.N.) and intramuscular (I.M.) induction of serum IgG and IgA responses. Interestingly, I.N. route induced higher IgG and IgA titer than I.M. route, which was statistically significant. Moreover, mRNA levels of IL-6 (4.2-4.5 folds), IFN-g (5.5-5.7 folds), and the anti-inflammatory cytokine IL-10 (2.5-3 folds) and IL-4 (2.4-2.8 folds) were significantly elevated in mice immunized I.N. and I.M. with H1N1-VLP compared to the control group. Our findings indicated that a non infectious genome-less VLP approach mimics parenteral virus with multiple viral antigens and epitopes that stimulate a diverse set of immune responses such as innate immunity, specific serum IgG antibody, cell-mediated immunity, and local antibodies. PMID- 29228525 TI - Sleep Apnea and Idiopathic Leg Edema: A Case Control Study. AB - Idiopathic leg edema is subject to a lot of debates among physicians. Recently sleep apnea was stated to be the cause. We sought to investigate this matter in a sample of Iranian patients with idiopathic leg edema. In this case-control study, 110 patients were selected based on our inclusion/exclusion criteria and allocated to the case (with idiopathic edema, n=55) and control (without edema, n=55) groups. Sex, age, weight, height, and body mass index (BMI) of all subjects were recorded. We evaluated daytime somnolence of all patients using Epworth sleepiness scale and then calculated Apnea, hypopnea index (AHI) using ResMed ApneaLink and AHI>=15 were considered as sleep apnea. Age and sex of both groups were not significantly different. Cases had higher BMI than control groups (P=0.03), but they were not significantly different for obesity (P=0.197). AHI was significantly higher in cases (17.85+/-24.31 vs. 9+/-7.37 P=0.012). Daytime somnolence (cases 8.18+/-5.3 vs. controls 6.5+/-3.3) was also higher in cases. Overall Odds ratio of leg edema and sleep apnea was 3.068 (P=0.025), but it wasn't significant in the two genders. Idiopathic bilateral leg edema is strongly associated with sleep apnea. Routine sleep apnea assessment in patients with idiopathic bilateral leg edema is recommended for both genders. PMID- 29228526 TI - Study of Serum Malondialdehyde Level in Opioid and Methamphetamine Dependent Patients. AB - Opioid compound and methamphetamine are commonly used in drug abuse; these can disrupt the normal function of cellular and molecular systems, leading to several events such as oxidative stress, aging, apoptosis, and necrosis. Malondialdehyde (MDA) is the most important biomarker for evaluation of oxidative stress and determination of lipid peroxidation. In this study, 42 drug abusers and 22 healthy persons participated as case and control groups, respectively. MDA in volunteer sera was determined by high-performance liquid chromatography (HPLC) with fluorescence detection after pre-column derivatization using thiobarbituric acid. The analysis was performed on a ODS column by spectrofluorometer detection, operated at excitation of 515 nm and emission of 535 nm. A mixture of phosphate buffer (0.05 M, pH 6.8), containing potassium monobasic phosphate and methanol (60:40, v/v) at a flow rate of 1 ml/min, was used as the mobile phase. The retention time of MDA-TBA was 3.2 min. Our findings showed that the MDA level increased in the opioid and methamphetamine abusers when compared to the control group (P<0.05); however, no significant difference was observed between the opioid and methamphetamine groups. A state of oxidative stress during biological processes leads to lipid peroxidation, DNA damage, biomolecule dysfunctions, and many other diseases. Since it is impossible to eradicate the drug addiction, we should reduce the side effects of drug abuse, such as oxidative stress, by intake of proper nutrition and antioxidants. PMID- 29228527 TI - Synergistic Effects of Resistin and Visfatin as Adipocyte Derived Hormones on Telomerase Gene Expression in AGS Gastric Cancer Cell Line. AB - Recently suggested that adipocytokines may play a role in pathogenesis and progression of certain cancers, especially in gastric cancer. The previous study showed Resistin and Visfatin, as adipocyte derived hormones, separately increases telomerase (hTERT) gene, the aim of this study is investigating synergic effects of Resistin and Visfatin on telomerase gene expression, in AGS gastric cancer cell line. In this study, human gastric cancer AGS cell line was selected. After stimulation with increasing concentrations of Resistin and Visfatin recombinant proteins for 24 and 48 hours, cell proliferation was assessed by XTT assay. In order to investigate the telomerase gene expression affected by these proteins, total RNA was extracted, cDNA was synthesized, and expression of hTERT mRNA was carried out by real-time reverse transcription polymerase chain reaction. After Resistin and Visfatin, recombinant proteins treatment was increased the gastric cell line proliferation and expression of Human Telomerase Reverse Transcriptase (hTERT), but co-stimulation with Resistin and Visfatin showed greater inducible effects on cell proliferation and telomerase gene expression in comparison with the stimulatory effect of the individual hormone. This study has shown Resistin, and Visfatin synergistically increased gastric cancer cell proliferation and enhanced the telomerase gene expression. These data showed that these two hormones in gastric cancer tissue could cooperatively accelerate cancer cell growth via enhancing the telomerase expression as a cancer gene. PMID- 29228528 TI - The Dilemma of Irrational Antibiotic and Corticosteroid Prescription in Iran: How Much It Can Affect the Medicine Expenditures? AB - In recent years the high cost of medicines and the lack of it were one of the major problems in developing countries that despite numerous efforts to solve the root causes of this problem, the issue remains, unfortunately. Therefore, this study aimed to assess the impact of antibiotics and corticosteroids prescription on the medicines expenditures. This was descriptive-analytical study that conducted to assess the function of medical expenditures through prescription letters and analysis the factors affecting medicine expenditures. We used the data of 91,994,667 selected prescription letters that were collected by the Ministry of the Health and Medical Education (MOHME) throughout the country in the year 2011 which was analyzed through a logarithmic regression model and OLS estimator. The average number of prescription items in each prescription letter were varied from 2.7 to 3.6, and the average price of each letter was varied from 30223 to 69986 Rials. Between 39 to 61 percent of prescription letters containing antibiotic items and between 15 and 35% of them contain corticosteroids. Also, the impact of antibiotic and corticosteroid prescriptions on the average expenditure of prescription letters were -1.4 and 0.032 respectively. Excessive and irrational prescribing had the greatest impact on medicine expenditures. On the other hand, the expenditure of prescription letters had the negative elasticity to antibiotics prescription and relatively inelastic for corticosteroids. So, raising the price of medications to reduce the use of them could not play a successful role in a control policy. PMID- 29228529 TI - Efficacy of Bronchial Washing and Brushing Cytology in the Diagnosis of Non Neoplastic Lung Diseases. AB - Flexible fiberoptic bronchoscopy is often the initial technique for diagnosis of lung and bronchial tumors. Many studies have shown the high accuracy rate of bronchial washing and brushing cytology in the evaluation of neoplastic and non neoplastic bronchopulmonary lesions. The aim of this study is to emphasize the value of the bronchial cytologic findings for diagnosis of non-neoplastic bronchopulmonary lesions. In a cross-sectional study, we retrieved all cases with bronchial washing and brushing cytology from 21 Mach 2014 to 21 December 2015. The slides of 100 patients with negative cytological reports were reviewed and concomitantly correlated with history, physical examination, clinical and pathologic documents. The cases with insufficient clinical and pathological diagnostic documents were rejected. The results classified in subgroups according to final diagnosis and cytological findings were discussed. We evaluated 100 cases that were previously had negative cytological reports.60 cases were male, and 40 cases were female with male to female ratio: 6/4. The age range was between 21 to 88 with the mean age of 57 years. Regarding lung cancer, 31% of cases were false negative. Causes of these falsely negative reports were been errors in screening, low cellularity, unsatisfactory smears and poor fixation. 23% were known cases of tuberculosis with some cytological findings including inflammation, necrotic calcified deposits, multinucleated giant cell and reserve cell hyperplasia. 19% were pneumonic patients with smears demonstrating inflammation, curschmann's spiral and reserve cell hyperplasia. Other non neoplastic cases included in this study were asthma, granulomatous inflammation, rheumatoid arthritis, sarcoidosis, Wegener, SLE, heart failure, hydatid cyst, interstitial lung disease, and end stage renal disease. Cytological specimens from patients underwent bronchoscopic washing and brushing should be carefully examined. In situations with negative cytologic results, correlation with history, imaging and biopsy specimen is mandatory. PMID- 29228530 TI - Electronic Health Record Implementation: A SWOT Analysis. AB - Electronic Health Record (EHR) is one of the most important achievements of information technology in healthcare domain, and if deployed effectively, it can yield predominant results. The aim of this study was a SWOT (strengths, weaknesses, opportunities, and threats) analysis in electronic health record implementation. This is a descriptive, analytical study conducted with the participation of a 90-member work force from Hospitals affiliated to Tehran University of Medical Sciences (TUMS). The data were collected by using a self structured questionnaire and analyzed by SPSS software. Based on the results, the highest priority in strength analysis was related to timely and quick access to information. However, lack of hardware and infrastructures was the most important weakness. Having the potential to share information between different sectors and access to a variety of health statistics was the significant opportunity of EHR. Finally, the most substantial threats were the lack of strategic planning in the field of electronic health records together with physicians' and other clinical staff's resistance in the use of electronic health records. To facilitate successful adoption of electronic health record, some organizational, technical and resource elements contribute; moreover, the consideration of these factors is essential for HER implementation. PMID- 29228531 TI - Kleefstra Syndrome: The First Case Report From Iran. AB - Kleefstra Syndrome is characterized by severe mental retardation, brachycephaly, microcephaly, epileptic seizures, distinct facial features, and infantile weak muscle tone and heart defects. Deletion of EHMT1 is the main player in 75% of cases. Because of blurriness in genotype-phenotype correlation through clinical and molecular features of both 9q34.3 microdeletion patients and those with an intragenic EHMT1 mutation in Kleefstra Syndrome, genetic characterization of patients with clinical symptoms of such spectrum is desirable. We report the first Kleefstra Syndrome patient in Iran characterized through genetic approaches. Our report could improve KS diagnosis in Iran and prepare PND and PGs options for involved families. PMID- 29228532 TI - Pericentric Inversion of Chromosome 9 in an Infant With Ambiguous Genitalia. AB - Pericentric inversion of Chromosome 9 is one of the most common chromosomal abnormalities, which could be associated with various manifestations in some cases. Herein, a patient is presented with ambiguous genitalia that karyotyping revealed pericentric inversion of Chromosome 9 (p12,q13). Pericentric inversion of Chromosome 9 could be considered in the list of differential diagnosis of those with ambiguous genitalia, while chromosomal karyotype and culture could be recommended in children with ambiguous genitalia. PMID- 29228533 TI - Denosumab Treatment of Severe Disuse Osteoporosis in a Boy With Spinal Muscular Atrophy. AB - Denosumab is a fully human recombinant monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand. Denosumab is used in the treatment of postmenopausal osteoporosis and cancer-related bone disorders. There are only very scarce data on denosumab treatment in children. 14-year-old boy with spinal muscular atrophy (SMA) and severe disuse osteoporosis (spinal bone mineral density L1-L4 BMD-6.2SD Z-score) and two prevalent fragility fractures was treated with denosumab. He received 60 mg subcutaneous injection at the baseline and seven months later. Six months after the initial injection there was a 19% increase in L1-L4 BMD. The injections were well tolerated without any adverse reactions. Calcemia remained stable (2.3-2.4 mmol/L). He was scheduled for the third denosumab injection six months later. Prior to this date, he acquired pneumonia and died due to respiratory failure, which is a frequent cause of death in patients with SMA. There was no relation to the denosumab treatment. In conclusion, one dose of denosumab significantly increased BMD in a child with severe osteoporosis. PMID- 29228534 TI - A Case With Short Stature, Growth Hormone Deficiency and 46, XX, Xq27-qter Deletion. AB - We report a case of 11-year-old girl with growth retardation and 46, XX, Xq27 qter deletion. The endocrinologic evaluation revealed growth hormone deficiency. In karyotype analysis 46, XX, Xq27-qter deletion was determined. The deletion of terminal region of chromosome 27 is most commonly being detected during the evaluation of infertility, premature ovarian insufficiency or in screening for fragile X carrier status. To our knowledge, this is the first reported case with 46, XX, Xq27-qter deletion and growth hormone deficiency. Furthermore, this case might facilitate future search for candidate genes involved in growth hormone deficiency. PMID- 29228535 TI - The Role of PIEZO2 in Human Mechanosensation. PMID- 29228536 TI - Rabbit anti-human T-lymphocyte globulin and hematopoietic transplantation. PMID- 29228537 TI - Casein kinase1alpha activators, a precision weapon for CRC. PMID- 29228538 TI - A triad of NRP2, DLX and p53 proteins in lung cancer metastasis. PMID- 29228539 TI - The enigmatic role(s) of P2RY8-CRLF2. PMID- 29228540 TI - Optimizing arginine deprivation for hard-to-treat cancers. PMID- 29228541 TI - No vehicle, no problem. PMID- 29228542 TI - CHIPped balance of proteostasis and longevity. PMID- 29228543 TI - Targeting the leukemic bone marrow microenvironment. PMID- 29228544 TI - Diurnal liver mass is associated with ribosome biogenesis. PMID- 29228545 TI - Early death in pediatric cancer: remaining questions and next steps. PMID- 29228546 TI - Synthetic human leukemia models: towards precision medicine. PMID- 29228547 TI - Integrated genomic analysis of clear cell ovarian cancers identified PRKCI as a potential therapeutic target. AB - Clear cell ovarian cancer (CCOC) is an epithelial ovarian cancer histotype with unique pathologic, biologic and clinical features. Despite its worse prognosis than serous ovarian cancer (SOC), the genomic landscape of CCOC is less well defined. Integrated genomic analysis of CCOC allows the identification of potential therapeutic targets to improve the treatment of this tumor. Using comparative genomic hybridization and gene expression profiling, we have screened 12 CCOC cell lines and 40 tumors to identify 45 amplified and overexpressed genes. Pathways analysis of these genes identified 19 genes with cancer-related functions. Of these, PRKCI is one of the most frequently amplified and overexpressed genes and its expression induced cancer cell proliferation and migration/invasion in vitro as well as tumor growth in vivo. Targeting PRKCI by small molecule inhibitor, sodium aurothiomalate (ATM), significantly reduced the in vivo tumor growth and may be a new therapeutic strategy to improve the treatment of CCOC. PMID- 29228548 TI - Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy. AB - Anti-angiogenesis therapy has shown clinical benefit in patients with high-grade serous ovarian cancer (HGSC), but adaptive resistance rapidly emerges. Thus, approaches to overcome such resistance are needed. We developed the setting of adaptive resistance to anti-VEGF therapy, and performed a series of in vivo experiments in both immune competent and nude mouse models. Given the pro angiogenic properties of tumor-associated macrophages (TAMs) and the dominant role of CSF1R in macrophage function, we added CSF1R inhibitors following emergence of adaptive resistance to anti-VEGF antibody. Mice treated with a CSF1R inhibitor (AC708) after anti-VEGF antibody resistance had little to no measurable tumor burden upon completion of the experiment while those that did not receive a CSF1R inhibitor still had abundant tumor. To mimic clinically used regimens, mice were also treated with anti-VEGF antibody and paclitaxel until resistance emerged, and then a CSF1R inhibitor was added. The addition of a CSF1R inhibitor restored response to anti-angiogenesis therapy, resulting in 83% lower tumor burden compared to treatment with anti-VEGF antibody and paclitaxel alone. Collectively, our data demonstrate that the addition of a CSF1R inhibitor to anti VEGF therapy and taxane chemotherapy results in robust anti-tumor effects. PMID- 29228549 TI - ERbeta inhibits cyclin dependent kinases 1 and 7 in triple negative breast cancer. AB - Triple negative breast cancer (TNBC), which comprises approximately 15% of all primary breast cancer diagnoses, lacks estrogen receptor alpha, progesterone receptor and human epidermal growth factor receptor 2 expression. However, we, and others, have demonstrated that approximately 30% of TNBCs express estrogen receptor beta (ERbeta), a nuclear hormone receptor and potential drug target. Treatment of ERbeta expressing MDA-MB-231 cells with estrogen or the ERbeta selective agonist, LY500307, was shown to result in suppression of cell proliferation. This inhibitory effect was due to blockade of cell cycle progression. In vivo, estrogen treatment significantly repressed the growth of ERbeta expressing MDA-MB-231 cell line xenografts. Gene expression studies and ingenuity pathway analysis identified a network of ERbeta down-regulated genes involved in cell cycle progression including CDK1, cyclin B and cyclin H. siRNA mediated knockdown or drug inhibition of CDK1 and CDK7 in TNBC cells resulted in substantial decreases in proliferation regardless of ERbeta expression. These data suggest that the tumor suppressive effects of ERbeta in TNBC result from inhibition of cell cycle progression, effects that are in part mediated by suppression of CDK1/7. Furthermore, these data indicate that blockade of CDK1/7 activity in TNBC may be of therapeutic benefit, an area of study that has yet to be explored. PMID- 29228550 TI - Regulation of XPC deubiquitination by USP11 in repair of UV-induced DNA damage. AB - Nucleotide excision repair (NER) is the most versatile DNA repair pathway for removing DNA damage caused by UV radiation and many environmental carcinogens. NER is essential for suppressing tumorigenesis in the skin, lungs and brain. Although the core NER proteins have been identified and characterized, molecular regulation of NER remains poorly understood. Here we show that ubiquitin-specific peptidase 11 (USP11) positively regulates NER by deubiquitinating xeroderma pigmentosum complementation group C (XPC) and promoting its retention at the DNA damage sites. In addition, UV irradiation induces both USP11 recruitment to the chromatin and USP11 interaction with XPC in an XPC-ubiquitination-dependent manner. Furthermore, we found that USP11 is down-regulated in chronically UV exposed mouse skin and in skin tumors from mice and humans. Our findings indicate that USP11 plays an important role in maintaining NER capacity, and suggest that USP11 acts as a tumor suppressor via its role in DNA repair. PMID- 29228551 TI - Human cytomegalovirus and Herpes Simplex type I virus can engage RNA polymerase I for transcription of immediate early genes. AB - Human cytomegalovirus (HCMV) utilizes RNA polymerase II to transcribe viral genes and produce viral mRNAs. It can specifically target the nucleolus to facilitate viral transcription and translation. As RNA polymerase I (Pol I)-mediated transcription is active in the nucleolus, we investigated the role of Pol I, along with relative contributions of the human Pol II and Pol III, to early phases of viral transcription in HCMV infected cells, compared with Herpes Simplex Virus-1 (HSV-1) and Murine cytomegalovirus (MCMV). Inhibition of Pol I with siRNA or the Pol I inhibitors CX-5461 or Actinomycin D (5nM) resulted in significantly decreased IE and pp65 mRNA and protein levels in human fibroblasts at early times post infection. This initially delayed replication was compensated for later during the replication process, at which stage it didn't significantly affect virus production. Pol I inhibition also reduced HSV-1 ICP0 and gB transcripts, suggesting that some herpesviruses engage Pol I for their early transcription. In contrast, inhibition of Pol I failed to affect MCMV transcription. Collectively, our results contribute to better understanding of the functional interplay between RNA Pol I-mediated nucleolar events and the Herpes viruses, particularly HCMV whose pathogenic impact ranges from congenital malformations and potentially deadly infections among immunosuppressed patients, up to HCMV's emerging oncomodulatory role in human tumors. PMID- 29228552 TI - Social-demographics, health behaviors, and telomere length in the Mexican American Mano a Mano Cohort. AB - In the current study, we examined cross-sectional associations among social demographics, lifestyle behaviors, and relative telomere length (RTL) in peripheral blood leukocytes, as well as longitudinal relationships among major chronic diseases, weight gain, and RTL, among 12,792 Mexican Americans aged 20 to 85 years in the Mano-A-Mano, the Mexican American Cohort. As expected, RTL was inversely correlated with age (rho=-0.15, rho<0.001). In the multivariate analysis, we found that RTL was positively correlated with levels of education (rho=0.021), self-insurance (rho=0.041), body mass index (BMI) (rho<0.001), and sleeping time per day (rho for trend<0.001), and RTL was inversely correlated with sitting time per day (rho for trend =0.001). In longitudinal analysis, we found that longer RTL was modestly but positively associated with increased risks of overall cancer (adjusted hazard ratio (adj.HR)=1.05, 95% conference interval (95%CI)=1.02-1.09). In quartile analysis, 4th quartile (longest RTL) was associated with 1.53-fold increased risk of overall cancer (adj.HR=1.53, 95%CI=1.11-2.10), compared to 1st quartile (shortest RTL). RTL was reversely associated with the risk of type-2 diabetes (adj.HR=0.89, 95%CI=0.82-0.94). In quartile analysis, 4th quartile (longest RTL) was associated with 48% decreased risk of typle-2 diabetes (adj.HR=0.52, 95%CI=0.32-0.70), compared to 1st quartile (shortest RTL). In addition, longer RTL was a positive predictor of at least 10% weight gain (adj.HR=1.03, 95%CI=1.00-1.05). In summary, our results in Mexican Americans support the notion that telomere length is a biological mechanism by which social demographics and health behaviors "get under the skin" to affect health. PMID- 29228553 TI - Activation of Nrf2-mediated anti-oxidant genes by antrodin C prevents hyperglycemia-induced senescence and apoptosis in human endothelial cells. AB - In the present study, we investigated the effects of antrodin C (ADC), a maleimide derivative isolated from mycelia of Antrodia cinnamomea, on high glucose (HG, 30 mM)-accelerated endothelial dysfunction in vitro. HG-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs) was significantly ameliorated by ADC. In addition, treatment with ADC significantly prevented HG induced senescence, growth arrest at the G1-S transition phase and apoptosis in HUVECs. Moreover, the increased level of intracellular reactive oxygen species (ROS) under HG condition was significantly ameliorated by ADC. Further analysis revealed that ADC-mediated anti-oxidant effects were due to up-regulation of cellular anti-oxidant genes, such as HO-1 and NQO-1 via promotion of the transcriptional activity of Nrf2, which was further confirmed by the failure of ADC to protect HUVECs from HG-induced dysfunction under HO-1 inhibition or Nrf2 silencing. Furthermore, hyperosmotic glucose (HOG, 60 mM)-induced uncontrolled production of ROS, rapid apoptotic cell death and HUVEC injury were significantly prevented by ADC, whereas these preventive effects were barely observed in HO-1 inhibited or Nrf2 silenced cells. Taken together, these results suggest that ADC may represent a promising intervention in diabetic-associated cardiovascular diseases by activating the Nrf2-dependent cellular anti-oxidant defense system. PMID- 29228555 TI - Circulating betatrophin is associated with insulin resistance in humans: cross sectional and interventional studies in vivo and in vitro. AB - Betatrophin has a closely relationship with metabolism. However, its effect on metabolism disorder remains unclear. This study was comprised of a series of cross-sectional and interventional studies in vivo and vitro. PCOS women with IR and healthy women were recruited from the general population and outpatients. Plasma betatrophin levels were measured with ELISA. Insulin sensitivity was assessed with EHC. Gene expressions at mRNA and protein levels were determined with RT-PCR and Western blotting. Influences of insulin, metformin, rosiglitazone and over- or knockdown-expression of betatrophin were analyzed ex vivo. Our results indicated that IR women had higher betatrophin levels compared with the controls. Circulating betatrophin was positively correlated with BMI, WHR, Fat%, triglyceride, total cholesterol, LDL-C, AUCglucose and AUCinsulin, luteinizing Hormone, FAI and HOMA-IR but negatively with M-value. Metformin treatment in PCOS women with IR led to a reduction of betatrophin levels. Insulin stimulation in hepatocytes increased betatrophin expression. Metformin or rosiglitazone led to a reduction of betatrophin expression in insulin-stimulated hepatocytes. In hepatocytes/macrophages co-culture systems, betatrophin expression was significantly increased, whereas this increase was eliminated by rosiglitazone. In hepatocytes, overexpression and knockdown of betatrophin decreased or increased insulin-stimulated insulin receptor, protein kinase B and insulin receptor substrate-1 phosphorylation respectively. Serum from metformin-treated women with IR decreased betatrophin expression and reinforced insulin signals. Thus, the present study provides the in vivo and in vitro evidence, suggesting that there is a cell cross-talking between hepatocytes with macrophages for the regulating betatrophin and it may be a useful marker for IR and metabolic disorders. PMID- 29228554 TI - Systemic analysis of gene expression profiles in porcine granulosa cells during aging. AB - Current studies have revealed that aging is a negative factor that suppresses granulosa cell functions and causes low fertility in women. However, the difference in gene expression between normal and aging granulosa cells remains undefined. Therefore, the aim of this study was to investigate the gene expression profiles of granulosa cells during aging. Granulosa cells from young healthy porcine ovaries were aged in vitro by prolonging the culture time (for 48h). First, the extracellular ultrastructure was observed by scanning electron microscopy followed by RNA-seq and KEGG pathway analysis. The results showed that the extracellular ultrastructure was significantly altered by aging; cell membranes were rough, and cavitations were found. Moreover, the formations of filopodia were greatly reduced. RNA-seq data revealed that 3411 genes were differentially expressed during aging, of which 2193 genes were up-regulated and 1218 genes were down-regulated. KEGG pathway analysis revealed that 25 pathways including pathway in cancer, PI3K-Akt signaling pathway, focal adhesion, proteoglycans in cancer, and cAMP signaling pathway were the most changed. Moreover, several high differentially expressed genes (CEBPB, CXCL12, ANGPT2, IGFBP3, and BBOX1) were identified in aging granulosa cells, The expressions of these genes and genes associated with extracellular matrix remodeling associated genes (TIMP3, MMP2, MMP3, and CTGF), energy metabolism associated genes (SLC2A1, PPARgamma) and steroidogenesis associated genes (StAR, CYP11A1 and LHCGR) were confirmed by quantitative PCR. This study identifies the differently changed pathways and their related genes, contributes to the understanding of aging in granulosa cells, and provides an important foundation for further studies. PMID- 29228556 TI - Riemerella anatipestifer M949_0459 gene is responsible for the bacterial resistance to tigecycline. AB - Based on its important role in last-line therapeutics against multidrug-resistant bacteria, tigecycline has been increasingly important in treating infections. However, mounting reports on tigecycline-resistant bacterial strains isolated from different sources are of concern, and molecular mechanisms regarding tigecycline resistance are poorly understood. Riemerella anatipestifer is a Gram negative, non-motile, non-spore-forming, rod-shaped bacterium, which causes fibrinous pericarditis, perihepatitis, and meningitis in infected ducks. We previously constructed a random transposon mutant library using Riemerella anatipestifer strain CH3, in present study, we described that Riemerella anatipestifer M949_0459 gene is responsible for the bacterial resistance to tigecycline. Using the minimum inhibitory concentration assay, a mutant strain showed significantly increased (about six-fold) tigecycline susceptibility. Subsequently, the knocked-down gene was identified as M949_0459, a putative flavin adenine dinucleotide-dependent oxidoreductase. To confirm the resistance function, M949_0459 gene was overexpressed in Escherichia coli strain BL21, and the minimum inhibitory concentration analysis showed that the gene product conferred resistance to tigecycline. Additionally, expression of the M949_0459 gene under treatment with tigecycline was measured with quantitative real-time PCR. Results showed that the mRNA expression of M949_0459 gene was elevated under tigecycline treatment with dose range of 1-10 mg/L, and peaked at 4 mg/L. Moreover, two kinds of efflux pump inhibitors, carbonyl cyanide m-chlorophenyl hydrazone and phenylalanine arginyl beta-naphthylamide were tested, which showed no function on tigecycline resistance in the strain CH3. Our results may provide insights into molecular mechanisms for chemotherapy in combating Riemerella anatipestifer infections. PMID- 29228557 TI - Peripheral blood microRNAs expression is associated with infant respiratory syncytial virus infection. AB - MicroRNAs respond to the inflammatory responses induced by RNA virus infection. In this study, we investigated the specific microRNA profile in the peripheral blood of infants infected with respiratory syncytial virus (RSV). Blood specimens were analyzed using microRNA microarrays, followed by quantitative RT-PCR. A specific microRNA profile in the peripheral blood of RSV-infected infants was identified for the first time. MiR-106b-5p, miR-20b-5p, and miR-342-3p were upregulated, while miR-320e, miR-320d, miR-877-5p, miR-122-5p, and miR-92b-5p were downregulated. Pathway analysis indicated that the dysregulated microRNAs were involved in inflammatory and immune responses, including Wnt, TGF-beta, insulin, and T and B cell receptor signaling. These results demonstrate that RSV infection associates with a distinct microRNA fingerprint and suggest that RSV induces inflammatory responses in infants. PMID- 29228558 TI - 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol ameliorates arthritic joints through reducing neutrophil infiltration mediated by IL-6/STAT3 and MIP-2 activation. AB - The pathogenesis of rheumatoid arthritis (RA) has been implicated neutrophil extracellular traps (NETs) formation which could generate autoantigen. Neutrophil contributes to initiate and maintain the inflammatory process in the joint. In this study, we show that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) decreases neutrophil migration by regulating the activity of STAT3, a regulator of IL-6 and MIP-2 expression. PLAG caused a decrease in IL-6 production in the RAW264.7 macrophage cell line and in rheumatoid arthritis-fibroblast-like synoviocytes via the regulation of STAT3 signaling without affecting NF-kappaB signaling. In a mouse model of collagen-induced arthritis (CIA), arthritic symptoms were recapitulated, with increased IL-6 level in the synovium, and PLAG treatment restored IL-6 to a level comparable to that achieved with commercial therapeutics (such as Remicade or methotrexate). Staining of joint tissue with neutrophil-specific antibody showed that PLAG significantly reduced the infiltration of neutrophils into the joint synovium of CIA mice. The inhibitory effect of PLAG on IL-6/STAT3 or MIP-2 signaling also reduced the migration of differentiated neutrophils in vitro. Therefore, PLAG inhibits the infiltration of destructive neutrophils into inflammatory sites, and can be utilized as a potent therapeutic agent for the treatment of sustained inflammation and joint destruction. PMID- 29228559 TI - Initial experience of anti-PD1 therapy with nivolumab in advanced hepatocellular carcinoma. AB - Purpose: To evaluate efficacy and safety of anti-PD1 therapy with nivolumab for treatment of advanced hepatocellular carcinoma (HCC). Methods: From Jan 2016 to Jan 2017, eleven cases of HCC (average age of 51.8-year), 4 at stage B and 7 at stage C, according to Barcelona Clinic Liver Cancer staging, were treated with nivolumab. There were 4 patients with lung metastasis, 1 with portal vein tumor thrombus, 1 with abdominal metastasis and 1 with bone metastasis. The protocol was nivolumab, 3 mg/kg, on day 1, q3w. All patients were treated for more than 4 cycles. During anti-PD1 treatment period, 6 patients also received sorafenib and 1 patient received cytokine-induced killer cell therapy. Objective response and clinical adverse events were evaluated retrospectively. Results: Patients underwent a total of 80 cycles of nivolumab therapy, ranging between 4 and 18 cycles per patient. Nivolumab was associated with a disease control rate of 81.8%, with an objective response of 63.6% (Modified Response Evaluation Criteria in Solid Tumors). No adverse effects related to nivolumab were noted. Conclusion: Our experience shows that nivolumab could achieve acceptable outcome in HCC patients and may serve as an optional treatment, especially for patients who failed to gain a benefit from routine treatments. PMID- 29228560 TI - MerTK is a novel therapeutic target in gastric cancer. AB - Introduction: The role of MerTK has not been assessed in gastric cancer (GC). The aim of this study was to identify a subgroup of GC patients with MerTK tumor overexpression, and to evaluate MerTK as a potential therapeutic target in this disease. Methods: Protein and mRNA expression of MerTK were evaluated, and other various in vitro analyses including shRNA transfection, cell cycle anslysis, MTS assay and colony forming assay were carried out with GC cell lines and GC patient derived cells (PDCs). Results: shRNA-mediated knockdown of MerTK resulted in inhibition of cell growth, as well as increased cellular apoptosis in MerTK positive GC cells. Out of 192 GC patients, 16 (8.3%) patients showed strong protein expression and they had a significantly shorter overall survival compared to those with no MerTK expression. In 54 cases of GC PDCs, 4 cases (7.4%) showed mRNA overexpression, which was comparable to the protein expression rate. When we administered UNC1062, a novel MerTK-selective small molecular tyrosine kinase inhibitor, proliferation of MerTK overexpressing GC cells and PDCs were considerably inhibited. Conclusion: MerTK may be involved in GC carcinogenesis, and it could be a potential novel therapeutic target in GC patients. PMID- 29228561 TI - Enantiomerically pure beta-dipeptide derivative induces anticancer activity against human hormone-refractory prostate cancer through both PI3K/Akt-dependent and -independent pathways. AB - The use of peptides that target cancer cells and induce anticancer activities through various mechanisms is developing as a potential anticancer strategy. KUD983, an enantiomerically pure beta-dipeptide derivative, displays potent activity against hormone-refractory prostate cancer (HRPC) PC-3 and DU145 cells with submicromolar IC50. KUD983 induced G1 arrest of the cell cycle and subsequent apoptosis associated with down-regulation of several related proteins including cyclin D1, cyclin E and Cdk4, and the de-phosphorylation of RB. The levels of nuclear and total c-Myc protein, which could increase the expression of both cyclin D1 and cyclin E, were profoundly inhibited by KUD983. Furthermore, it inhibited PI3K/Akt and mTOR/p70S6K/4E-BP1 pathways, the key signaling in multiple cellular functions. The transient transfection of constitutively active myristylated Akt (myr-Akt) cDNA significantly rescued KUD983-induced caspase activation but did not blunt the inhibition of mTOR/p70S6K/4E-BP1 signaling cascade suggesting the presence of both Akt-dependent and -independent pathways. Moreover, KUD983-induced effect was enhanced with the down-regulation of anti apoptotic Bcl-2 members (e.g., Bcl-2, and Mcl-1) and IAP family members (e.g., survivin). Notably, KUD983 induced autophagic cell death using confocal microscopic examination, tracking the level of conversion of LC3-I to LC3-II and flow cytometric detection of acidic vesicular organelles-positive cells. In conclusion, the data suggest that KUD983 is an anticancer beta-dipeptide against HRPCs through the inhibition of cell proliferation and induction of apoptotic and autophagic cell death. The suppression of signaling pathways regulated by c-Myc, PI3K/Akt and mTOR/p70S6K/4E-BP1 and the collaboration with down-regulation of Mcl 1 and survivin may explain KUD983-induced anti-HRPC mechanism. PMID- 29228562 TI - Clinical mutational profiling of 1006 lung cancers by next generation sequencing. AB - Analysis of lung adenocarcinomas for actionable mutations has become standard of care. Here, we report our experience using next generation sequencing (NGS) to examine AKT1, BRAF, EGFR, ERBB2, KRAS, NRAS, and PIK3CA genes in 1006 non-small cell lung cancers in a clinical diagnostic setting. NGS demonstrated high sensitivity. Among 760 mutations detected, the variant allele frequency (VAF) was 2-5% in 33 (4.3%) mutations and 2-10% in 101 (13%) mutations. A single bioinformatics pipeline using Torrent Variant Caller, however, missed a variety of EGFR mutations. Mutations were detected in KRAS (36% of tumors), EGFR (19%) including 8 (0.8%) within the extracellular domain (4 at codons 108 and 4 at codon 289), BRAF (6.3%), and PIK3CA (3.7%). With a broader reportable range, exon 19 deletion and p.L858R accounted for only 36% and 26% of EGFR mutations and p.V600E accounted for only 24% of BRAF mutations. NGS provided accurate sequencing of complex mutations seen in 19% of EGFR exon 19 deletion mutations. Doublet (compound) EGFR mutations were observed in 29 (16%) of 187 EGFR-mutated tumors, including 69% with two non-p.L858R missense mutations and 24% with p.L858 and non-p.L858R missense mutations. Concordant VAFs suggests doublet EGFR mutations were present in a dominant clone and cooperated in oncogenesis. Mutants with predicted impaired kinase, observed in 25% of BRAF-mutated tumors, were associated with a higher incidence of concomitant activating KRAS mutations. NGS demonstrates high analytic sensitivity, broad reportable range, quantitative VAF measurement, single molecule sequencing to resolve complex deletion mutations, and simultaneous detection of concomitant mutations. PMID- 29228563 TI - Riluzole: a potential therapeutic intervention in human brain tumor stem-like cells. AB - A small subpopulation of tumor stem-like cells has the capacity to initiate tumors and mediate radio- and chemoresistance in diverse cancers hence also in glioblastoma (GBM). It has been reported that this capacity of tumor initiation in the brain is mainly dependent on the body's nutrient supply. This population of so-called brain tumor initiating or brain tumor stem-like cells (BTSCs) is able to extract nutrients like glucose with a higher affinity. Riluzole, a drug approved for treating amyotrophic lateral sclerosis (ALS), was reported to possess anticancer properties, affecting the glutamate metabolism. We report that riluzole treatment inhibits the growth of brain tumor stem-like cells enriched cultures isolated from two human glioblastomas. The effects of riluzole on these cells were associated with an inhibition of a poor prognostic indicator: glucose transporter 3 (GLUT3). A decrease in GLUT3 is associated with a decrease in the p Akt/HIF1alpha pathway. Further, downregulation of the DNA (Cytosine-5-) methyltransferase 1 (DNMT1) gene that causes hypermethylation of various tumor suppressor genes and leads to a poor prognosis in GBM, was detected. Two hallmarks of cancer cells-proliferation and cell death-were positively influenced by riluzole treatment. Finally, we observed that riluzole reduced the tumor growth in in vivo CAM assay, suggesting it could be a possible synergistic drug for the treatment of glioblastoma. PMID- 29228564 TI - Inhibitors of the PI3K/mTOR pathway prevent STAT5 phosphorylation in JAK2V617F mutated cells through PP2A/CIP2A axis. AB - Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors. We found that PI3K/mTOR-dependent phosphorylation of STAT5b serine residues involves Protein Phosphatase 2A and its repressor CIP2A. The levels of CIP2A were found increased in cells harboring the JAK2V617F mutation, and we provide evidence of a correlation between clinical responses and the extent of CIP2A downregulation in myelofibrosis patients receiving the mTOR inhibitor RAD001 in a phase II clinical trial. To achieve maximal inhibition of STAT5 phosphorylation, we combined ruxolitinib with BKM120, a PI3K inhibitor, and RAD001, an mTOR inhibitor, obtaining improved efficacy in JAK2V617F mutated cell lines, primary patients' cells, and JAK2V617F knock-in mice. These findings contribute to understanding the effectiveness of PI3K/mTOR inhibitors in MPN and argue for the rationale to develop combination clinical trials. PMID- 29228565 TI - Nucleoside analogs treatment delay the onset of hepatocellular carcinoma in patients with HBV-related cirrhosis. AB - Whether Nucleos(t)ide analogs(NA) treatment can delay the onset of HCC remains unclear. We retrospectively analyzed the clinical data of patients with HBV related cirrhosis and HCC from 2000 to 2012. Cox proportional hazards model was used to explore the association between NA treatment and postponement of HCC development, the dependent variable was time interval from cirrhosis treatment towards the onset of HCC, and the covariates included age, sex, family history, compensation status at baseline. A total of 1155 HCC patients treated with NAs (n = 528, lamivudine, adefovir, entecavir) and non NA (n = 627) for more than 24 months before the occurrence of HCC were incorporated into the cohort. Compared with the non-NA group, NAs therapy was associated with delaying the onset of HCC in patients with cirrhosis. Significant factors were: adefovir treatment (n = 181; p = 0.0072; HR: 0.792; 90% CI: 0.687-0.914), entecavir treatment (n = 83; p = 0.0068; HR: 0.716; 90% CI: 0.585-0.877), lamivudine switched to adefovir treatment (n = 95, p = 0.0808; HR: 0.822; 90% CI: 0.684 to 0.989). But Lamivudine monotherapy was not a significant factor (n = 102; p = 0.6877; HR: 1.045; 90% CI: 0.873-1.250). Long-term NA treatment (> 6 months, except for lamivudine monotherapy) can delay the onset of HCC in patients with HBV-related cirrhosis, and applying high barrier NA to resistance is important in these patients. PMID- 29228566 TI - Targeting CXCR4 with [68Ga]Pentixafor: a suitable theranostic approach in pleural mesothelioma? AB - C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [68Ga]Pentixafor in malignant pleural mesothelioma. Six patients with pleural mesothelioma underwent [68Ga]Pentixafor-PET/CT. 2' [18F]fluoro-2'-deoxy-D-glucose ([18F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up. Whereas [18F]FDG-PET depicted active lesions in all patients, [68Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [68Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed. In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy. PMID- 29228567 TI - Biomarker significance of plasma and tumor miR-21, miR-221, and miR-106a in osteosarcoma. AB - Osteosarcoma is the most common malignant bone tumor in children and young adults. Despite the use of surgery and multi-agent chemotherapy, osteosarcoma patients who have a poor response to chemotherapy or develop relapses have a dismal outcome. Identification of biomarkers for active disease may help to monitor tumor burden, detect early relapses, and predict prognosis in these patients. In this study, we examined whether circulating miRNAs can be used as biomarkers in osteosarcoma patients. We performed genome-wide miRNA profiling on a discovery cohort of osteosarcoma and control plasma samples. A total of 56 miRNAs were upregulated and 164 miRNAs were downregulated in osteosarcoma samples when compared to control plasma samples. miR-21, miR-221 and miR-106a were selected for further validation based on their known biological importance. We showed that all three circulating miRNAs were expressed significantly higher in osteosarcoma samples than normal samples in an independent cohort obtained from the Children's Oncology Group. Furthermore, we demonstrated that miR-21 was expressed significantly higher in osteosarcoma tumors compared with normal bone controls. More importantly, lower expressions of miR-21 and miR-221, but not miR 106a, significantly correlated with a poor outcome. In conclusion, our results indicate that miR-21, miR-221 and miR-106a were elevated in the circulation of osteosarcoma patients, whereas tumor expressions of miR-21 and miR-221 are prognostically significant. Further investigation of these miRNAs may lead to a better prognostic method and potential miRNA therapeutics for osteosarcoma. PMID- 29228568 TI - Sitagliptin and oral cancer risk in type 2 diabetes patients. AB - The reimbursement database of the Taiwan's National Health Insurance was used to evaluate oral cancer risk after sitagliptin use. Patients newly diagnosed of type 2 diabetes during 1999-2008 were recruited. A 1:1 propensity score matched-pair sample of 39195 ever users and 39195 never users were followed up until December 31, 2011. Cox regression incorporated with the inverse probability of treatment weighting using propensity score was used to estimate hazard ratios. Results showed that the overall hazard ratio was not statistically significant (0.956, 95% confidence interval: 0.652-1.401). However, in tertile analyses, the hazard ratio for the first (< 7.47 months), second (7.47-15.63 months) and third (> 15.63 months) tertile of cumulative duration was 1.563 (0.963-2.537), 1.236 (0.738-2.071) and 0.345 (0.164-0.725), respectively; and was 1.575 (0.963-2.575), 1.224 (0.738-2.033) and 0.347 (0.165-0.731), respectively, for the first (< 19,600 mg), second (19,600-42,200 mg) and third (> 42,200 mg) tertile of cumulative dose. Sensitivity analyses after excluding patients who developed any other cancer during follow-up did not change the results substantially. Additionally, the risk of oral diseases that may predispose to oral cancer (i.e., "gingival and periodontal diseases" and/or "oral mucosal lesions") paralleled the risk pattern of oral cancer, suggesting a possible explanation for the risk change of oral cancer related to sitagliptin. In conclusion, sitagliptin may reduce oral cancer risk when the cumulative duration is > 15.63 months or the cumulative dose is > 42,200 mg. PMID- 29228569 TI - The effects of blueberry anthocyanins on histone acetylation in rat liver fibrosis. AB - To determine the effects ofanthocyanins from blueberries on hepatic stellate cell (HSCs-T6) and on histone acetylation during liver fibrosis induced by CCl4 in rats. Fifty male SD rats weighing 180 +/- 20g were randomly placed into a control group, a hepatic fibrosis group, a blueberry treatment group, a blueberry intervention group, and a natural recovery group. After the rats were sacrificed, the livers and the liver indexes were measured, and the pathological changes were observed by HE staining and Masson staining. The blood was analyzed for the four indexes of liver fibrosis and liver function; nucleoprotein from liver tissues and karyoplasm were isolated to determine the expression of acH3K9, acH3K14, and acH3K18 by Western blotting. Compared with the lethal rate of the control group, the median lethal rate of HSCs-T6 cells treated with a the 50MUmol/L concentration was 66.94% (P < 0.05). The protein expression on alpha-SMA, type I collagen, TIMP1 significantly decreased (P < 0.05) following treatment with 50 ug/ml of anthocyanin for 36 h; moreover, the expression of acH3K9, acH3K14 and acH3K18 modification were up-regulated (P < 0.05). Furthermore, compared with the liver in the model group, the liver in the intervention group showed the most obvious improvement (P < 0.01), and its karyoplasm had increased expression of acH3K9, acH3K14 and acH3K18 (P<0.01). Regulating histone acetylation could improve liver function and liver fibrosis indexes in rats with hepatic fibrosis. The mechanism might be related to certain genes that promote apoptosis, so as to inhibit the effect of anti hepatic fibrosis. PMID- 29228571 TI - Identification of a novel de novo ANK1 R1426* nonsense mutation in a Chinese family with hereditary spherocytosis by NGS. AB - Hereditary spherocytosis (HS) is an inherited heterogeneous hemolytic anemia, characterized by the presence of spherical-shaped erythrocytes on the peripheral blood smear, and the clinical manifestation ranges from asymptomatic to severely anemic, and transfusion-dependent patients. Mutations in at least five genes (ANK1, EPB42, SLC4A1, SPTA1, and SPTB) have been identified so far, and mutations of ANK1 gene are responsible for the majority of all HS cases. In this study, targeted next generation sequencing (NGS) was applied to identify a novel de novo ANK1 c.4276C>T (p.R1426*) nonsense mutation in a Chinese family with a patient of HS who was diagnosed clinically with only 10% spherical-shaped erythrocytes in the peripheral blood and received splenectomy. Sanger sequencing further confirmed that only the patient carried heterozygous ANK1 c.4276C>T nonsense mutation, while none of his parents or his young brother carried this mutation. Moreover, consistent with the genetic findings, the anemia was ameliorated after splenectomy. RBCs increased from 2.74 * 1012/L pre-surgery to 4.76 * 1012/L one month post-surgery, and hemoglobin increased from 66g/L to 126g/L respectively. This is the first report of ANK1 c.4276C>T (p.R1426*) heterozygous nonsense mutation responsible for HS. Our results also demonstrate that targeted NGS may provide a powerful approach for rapid genetic test of HS. PMID- 29228570 TI - Keratin 8 reduces colonic permeability and maintains gut microbiota homeostasis, protecting against colitis and colitis-associated tumorigenesis. AB - Keratin 8 (CK8) is the major component of the intermediate filaments of simple or single-layered epithelia. Gene targeting mice model suggest that CK8 is involved in colonic active ion transport, colorectal hyperplasia and inflammation. In the present study, we found that CK8 is downregulated in the colon during DSS-induced colitis and AOM/DSS-induced colitis-associated colorectal cancer (CAC) development. In human patients with colon cancer, CK8 is downregulated. Using CK8 heterozygous knockout mice (CK8+/-), we found that CK8+/- mice are highly susceptible to DSS-induced colitis and more prone to AOM/DSS-induced CAC than wild type (WT) mice. The colonic permeability is increased with DSS or AOM/DSS treatment, leading to alteration of gut microbiota in CK8+/- mice with CAC. Metagenomic analysis of fecal microbiota suggests Firmicutes and Proteobacteria are increased in CK8+/- mice with CAC, while Bacteroidetes and Verrucomicrobia are decreased. Antibiotic treatment decreases the incidence of colorectal cancer tumorigenesis and TLR4 inhibitor attenuates the susceptibility of CK8+/- mice to DSS-induced colitis. These data suggest CK8 protects mice from colitis and colitis-associated colorectal cancer by modulating colonic permeability and gut microbiota composition homeostasis. PMID- 29228572 TI - Gemcitabine/cisplatin induction chemotherapy before concurrent chemotherapy and intensity-modulated radiotherapy improves outcomes for locoregionally advanced nasopharyngeal carcinoma. AB - Addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CC) is an encouraging first-line treatment strategy for patients with locoregionally advanced nasopharyngeal carcinoma (NPC). We evaluated the clinical efficacy and toxicity of addition of gemcitabine plus cisplatin (GP) IC to intensity-modulated radiotherapy (IMRT) and CC for patients with locoregionally advanced NPC. At a median follow-up duration of 48 months (10-59 months), 4-year local relapse-free survival (LRFS) was 86.9%, regional relapse-free survival (RRFS) was 90.6%, distant metastasis-free survival (DMFS) was 79.8%, progression-free survival (PFS) was 77.0%, and overall survival (OS) was 81.9%. Univariate analysis revealed that T stage, N stage, clinical stage, and CC correlated with OS, while N stage and clinical stage correlated with PFS. In multivariate analysis, T4 was a prognostic indicator of poor OS and PFS, and N3 was a prognostic indicator of poor OS. Having received >= 2 cycles of IC was prognostic of better RRFS. During IC, grade 3-4 thrombocytopenia occurred in 10 patients, and grade 3-4 leukocytopenia was observed in 16 patients. Two patients developed mild liver dysfunction. These findings indicate that GP-based IC followed by CC has promising efficacy with acceptable toxicities. PMID- 29228573 TI - Pnma5 is essential to the progression of meiosis in mouse oocytes through a chain of phosphorylation. AB - PNMA (paraneoplastic antigen MA) family includes Pnma1-6. Although other members have been found to be involved in paraneoplastic neurological disorders, death receptor-dependent apoptosis, and tumorigenesis, Pnma5 was thought to be a female fertility factor, as indicated by one genome-wide study. But until now there have not been any further functional studies about Pnma5 in female meiosis. Our preliminary study indicated that Pnma5 might play important roles in meiosis. To further address this, Pnma5 was knocked down in in-vitro maturated (IVM) mouse oocytes, which are common models for mammalian female meiosis, by specific siRNA, and results showed that the loss of Pnma5 significantly delayed the progression of meiosis I and increased chromosome segregation errors during anaphase I. In in vitro fertilization (IVF), Pnma5 knockdown caused significantly lower fertilization. To assess how it affects meiosis, Pnma5 knockdown was found to significantly decrease the stability of spindle microtubules and altered F-actin organization within actin cap regions, cause significantly abnormal mitochondria aggregation and lower ATP concentration. Next we have found that phosphorylation at Thr533 re-located Pnma5 strongly to spindles & cortex and was required for the phosphorylation of Akt and Gsk3beta, while Src and Erk1/2 phosphorylation was required for the phosphorylation of Pnma5, indicating that phosphorylated Pnma5 is the active form and subsequently activates Akt and Gsk3beta. Collectively this study suggests that Pnma5 is important for meiosis and is the pivot of Src >Erk1/2->Pnma5->Akt->Gsk3beta pathway. PMID- 29228574 TI - Microfluidic hydrodynamic focusing synthesis of polymer-lipid nanoparticles for siRNA delivery. AB - Small interfering RNAs (siRNAs) are promising as therapeutics for intractable diseases such as cancer. However, efficient and safe delivery of siRNAs in vivo remains a challenge. Polymer-lipid hybrid nanoparticles (P/LNPs) have been evaluated for therapeutic delivery of siRNA. In this study, a microfluidic hydrodynamic focusing (MF) system was used to prepare P/LNPs loaded with VEGF siRNA. P/LNPs made by MF were smaller in particle size and had narrower size distribution compared to P/LNPs formed by bulk mixing (BM). MF-synthesized P/LNPs demonstrated low vehicle cytotoxicity and potent tumor cell inhibition in vitro. In addition, P/LNPs produced by the microfluidic chip exhibited prolonged blood circulation and increased AUC after i.v. injection compared to free siRNA. Furthermore, P/LNPs synthesized by MF induced greater down-regulation of VEGF mRNA and protein levels as well as greater tumor inhibition in a xenograft tumor model. Taken together, P/LNPs prepared by MF have been shown to be an effective and safe therapeutic siRNA delivery system for cancer treatment both in vitro and in vivo. PMID- 29228575 TI - Ammonium glycyrrhizin counteracts liver injury caused by lipopolysaccharide/amoxicillin-clavulanate potassium. AB - We treated isolated chicken primary hepatocytes with lipopolysaccharide/amoxicillin clavulanate potassium (LPS/AC) to model liver injury and investigate its underlying mechanisms. We also used this model to assess the cytoprotective effects of compound ammonium glycyrrhizin (CAG) in vitro. LPS/AC-induced injury decreased cell viability and increased the activity of serum aspartate transaminase and alanine transaminase. Levels of superoxide dismutase, glutathione, and glutathione peroxidase were lower than control, while levels of the oxidative product malondialdehyde and reactive oxygen species were higher. Treatment with CAG for 24 h ameliorated these changes. Caspase-3 activity assays and flow cytometry revealed increased apoptosis in the model group. However, apoptosis decreased after CAG treatment, as confirmed by Hoechst 33342 staining. We also observed changes in mitochondrial ultrastructure. Real-time PCR and western blot analyses showed that CAG treatment downregulated LPS/AC-induced RNA expression of caspase-3, caspase-9, bax, cytochrome c, and fas, and upregulated the expression of bcl-2. Mitochondrial cytochrome c was released into the cytosol and the inner mitochondrial membrane potential (DeltaPsim) was decreased. Our results highlight CAG as a potential therapeutic agent to counteract LPS/AC-induced liver injury. PMID- 29228576 TI - Comparison of tumor biology of two distinct cell sub-populations in lung cancer stem cells. AB - Characterization of the stem-like properties of cancer stem cells (CSCs) remain indirect and qualitative, especially the ability of CSCs to undergo asymmetric cell division for self renewal and differentiation, a unique property of cells of stem origin. It is partly due to the lack of stable cellular models of CSCs. In this study, we developed a new approach for CSC isolation and purification to derive a CSC-enriched cell line (LLC-SE). By conducting five consecutive rounds of single cell cloning using the LLC-SE cell line, we obtained two distinct sub population of cells within the Lewis lung cancer CSCs that employed largely symmetric division for self-renewal (LLC-SD) or underwent asymmetric division for differentiation (LLC-ASD). LLC-SD and LLC-ASD cell lines could be stably passaged in culture and be distinguished by cell morphology, stem cell marker, spheroid formation and subcutaneous tumor initiation efficiency, as well as orthotopic lung tumor growth, progression and survival. The ability LLC-ASD cells to undergo asymmetric division was visualized and quantified by the asymmetric segregation of labeled BrdU and NUMB to one of the two daughter cells in anaphase cell division. The more stem-like LLC-SD cells exhibited higher capacity for tumorigenesis and progression and shorter survival. As few as 10 LLC-SD could initiate subcutaneous tumor growth when transplanted to the athymic mice. Collectively, these observations suggest that the SD-type of cells appear to be on the top of the hierarchical order of the CSCs. Furthermore, they have lead to generated cellular models of CSC self-renewal for future mechanistic investigations. PMID- 29228577 TI - EGR1 regulates cellular metabolism and survival in endocrine resistant breast cancer. AB - About 70% of all breast cancers are estrogen receptor alpha positive (ER+; ESR1). Many are treated with antiestrogens. Unfortunately, de novo and acquired resistance to antiestrogens is common but the underlying mechanisms remain unclear. Since growth of cancer cells is dependent on adequate energy and metabolites, the metabolomic profile of endocrine resistant breast cancers likely contains features that are deterministic of cell fate. Thus, we integrated data from metabolomic and transcriptomic analyses of ER+ MCF7-derived breast cancer cells that are antiestrogen sensitive (LCC1) or resistant (LCC9) that resulted in a gene-metabolite network associated with EGR1 (early growth response 1). In human ER+ breast tumors treated with endocrine therapy, higher EGR1 expression was associated with a more favorable prognosis. Mechanistic studies showed that knockdown of EGR1 inhibited cell growth in both cells and EGR1 overexpression did not affect antiestrogen sensitivity. Comparing metabolite profiles in LCC9 cells following perturbation of EGR1 showed interruption of lipid metabolism. Tolfenamic acid, an anti-inflammatory drug, decreased EGR1 protein levels and synergized with antiestrogens in inhibiting cell proliferation in LCC9 cells. Collectively, these findings indicate that EGR1 is an important regulator of breast cancer cell metabolism and is a promising target to prevent or reverse endocrine resistance. PMID- 29228578 TI - Association of single-nucleotide polymorphisms in the RAGE gene and its gene- environment interactions with diabetic nephropathy in Chinese patients with type 2 diabetes. AB - Aims: To investigate the association of several single nucleotide polymorphisms (SNPs) within RAGE gene and additional gene- smoking interaction with diabetic nephropathy (DN) risk in Chinese patients with type 2 diabetes mellitus (T2DM). Methods: A total of 865 participants (570 males, 295 females) were selected, including 430 T2DM complicated DN patients and 435 controls (T2DM patients without DN). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among SNPs and smoking. Logistic regression was performed to investigate impact of 4 SNPs within RAGE gene, additional gene- smoking interaction on DN risk. Results: DN risk was significantly higher in carriers with the C allele of rs1800625 than those with TT genotype, adjusted OR (95%CI) =1.57 (1.16-2.17), and higher in carriers with the T allele of rs184003 than those with GG genotype, adjusted OR (95%CI) = 1.64 (1.21-2.12). GMDR model indicated a significant two-locus model (p=0.0010) involving rs1800625 and smoking, the cross-validation consistency of this two- locus model was 10/ 10, and the testing accuracy was 60.72%. We also conducted stratified analysis for the significant models in the GMDR analysis by using logistic regression. We found that current smokers with rs1800625- TC or CC genotype have the highest DN risk, compared with never- smokers with rs1800625- TT genotype, OR (95%CI) = 2.92 (1.94 -3.96), after covariates adjustment. Conclusions: We found that the C allele of rs1800625 and the T allele of rs184003 within RAGE gene, interaction between rs1800625 and smoking were all associated with increased DN risk. PMID- 29228579 TI - A genetic variant in SLC28A3, rs56350726, is associated with progression to castration-resistant prostate cancer in a Korean population with metastatic prostate cancer. AB - Background: Genetic variation which related with progression to castration resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT) has not been elucidated in patients with metastatic prostate cancer (mPCa). Therefore, we assessed the association between genetic variats in mPCa and progession to CRPC. Results: Analysis of exome genotypes revealed that 42 SNPs were significantly associated with mPCa. The top five polymorphisms were statistically significantly associated with metastatic disease. In addition, one of these SNPs, rs56350726, was significantly associated with time to CRPC in Kaplan-Meier analysis (Log-rank test, p = 0.011). In multivariable Cox regression, rs56350726 was strongly associated with progression to CRPC (HR = 4.172 95% CI = 1.223-14.239, p = 0.023). Materials and Methods: We assessed genetic variation among 1000 patients with PCa with or without metastasis, using 242,221 single nucleotide polymorphisms (SNPs) on the custom HumanExome BeadChip v1.0 (Illuminam Inc.). We analyzed the time to CRPC in 110 of the 1000 patients who were treated with ADT. Genetic data were analyzed using unconditional logistic regression and odds ratios calculated as estimates of relative risk of metastasis. We identified SNPs associated with metastasis and analyzed the relationship between these SNPs and time to CRPC in mPCa. Conclusions: Based on a genetic variation, the five top SNPs were observed to associate with mPCa. And one (SLC28A3, rs56350726) of five SNP was found the association with the progression to CRPC in patients with mPCa. PMID- 29228580 TI - Posttransplant lymphoproliferative disorders in kidney transplant recipients: a retrospective cohort analysis over two decades in Hong Kong. AB - Objective: To characterize the posttransplant lymphoproliferative disorders (PTLD) including the Epstein-Barr virus (EBV) status, histological subgroups, site of occurrence and the clinical outcome in the Chinese kidney transplant recipients. Methods: A retrospective cohort study of 1, 227 adult kidney transplant recipients who were followed up in two transplant centers in Hong Kong over two decades. Results: 23 (1.9%) patients developed PTLD. Median duration from transplant to PTLD was 104 (5-252) months. Six patients (26.1%) had early PTLD and 17 (73.9%) had late PTLD. Ten (43%) developed PTLD >10 years after transplant. All patients in early PTLD group were EBV-positive. In the late PTLD group, 60% were EBV-negative and 40% EBV-positive. More than 90% of cases were monomorphic PTLD with majority being diffuse large B cell lymphoma. Bone marrow was the most common extranodal site. The overall treatment response rate was 52.2 %. None of the patients developed rejection or relapse after PTLD. At a median follow-up of 9 (1-79) months after PTLD, 18 patients died. Patient survival was 48% at 1 year and 30% at 3 years and death-censored allograft survival was 82% at 1year and 73% at 3 years. Conclusion: Late PTLD is common. Careful adjustment of immunosuppression, close monitoring of patients, increased awareness and early detection of the disease are essential. PMID- 29228581 TI - A multiplex liquid-chip assay based on Luminex xMAP technology for simultaneous detection of six common respiratory viruses. AB - We utilized one-step multiplex reverse transcription-PCR (RT-PCR) and Luminex xMAP technology to develop a respiratory multiplex liquid-chip assay (rMLA) for simultaneous detection of 6 common respiratory viruses, including influenza virus type A (FluA) and type B (FluB), para-influenza virus type 3 (PIV-3), respiratory syncytial virus (RSV), human metapneumovirus (MPV) and a threatening virus to China, Middle East Respiratory Syndrome coronavirus (MERS-CoV). Performance of rMLA was evaluated by comparing with real-time RT-PCR. Detection data from clinical specimens showed that the rMLA had diagnostic sensitivities of 97.10% for FluA, 94.59% for FluB, 98.68% for PIV-3, 94.87% for RSV and 95.92% for MPV (No Data for MERS-CoV due to the lack of positive specimens). Data of analytical sensitivities showed that the detection limits of the rMLA assay were 5-25 viral RNA copies per MUl for FluA, FluB, PIV-3 and MERS-CoV, approximate to the real time RT-PCR assay; while the values were 8 and 22copies/MUl for MPV and RSV, lower than the real-time RT-PCR(78 and 114 copies/MUl respectively). The results indicated that the rMLA is a sensitive, specific detection tool and comparable to real-time RT-PCR, especially suitable for high-throughput detection of respiratory specimens. PMID- 29228582 TI - Comparative study of macrophages in naked mole rats and ICR mice. AB - The domestic and foreign scholars have studied naked mole rats more focused on the respect such as its long life, resistant to low oxygen, little spontaneous tumor, but the study of the immune system is little. In this study, we compared the anatomy and tissue morphology of NMR and ICR mouse spleens and found that the gross appearance of the NNMR spleen differed from ICR. There were more macrophages in NNMR spleens than in ICR spleens. Furthermore, we focused on the differences of macrophages. We compared their phagocytic capabilities and the data showed that NNMR macrophages are more phagocytic than ICR mouse macrophages. We also used polyI:C and LPS to stimulate the NMR and ICR macrophages and then measured the immune response as expression of certain TLR signaling molecules. After stimulation, there was a lower increase in apoptosis of NMR macrophages than ICR macrophages and a non-significant increased expression of TLRs in NMR macrophages than in ICR macrophages. In contrast, NF-kappaB proteins increased more significantly in NMR's than in ICR's and the expression of downstream cytokines in NMR macrophages also increased more than in ICR macrophages. Based on these results, we hypothesize that in addition to being able to eat foreign matter, NMR macrophages can activate the TLRs, start the NF-kappaB and produce a large number of cytokines to enhance immune response, so as to protect the body from outside interference when the virus or bacteria invading. PMID- 29228583 TI - Development and validation of nomogram based on miR-203 and clinicopathological characteristics predicting survival after neoadjuvant chemotherapy and surgery for patients with non-metastatic osteosarcoma. AB - Background: Recently, nomograms have been used as models for risk prediction in malignant tumor because they can predict the outcome of interest for a certain individual based on many variables. This study aimed to establish an effective prognostic nomogram for osteosarcoma based on the clinicopathological factors and microRNA-203. Results: The results showed that miR-203 expression was significantly lower in osteosarcoma tissues compared with the corresponding adjacent tissues (P < 0.001). Patients with low miR-203 expression had poor overall survival (OS) in osteosarcoma. The histological type, tumor size, AJCC stage and miR-203 expression were integrated in the nomogram. The nomogram showed significantly better prediction of OS than for patients with non-metastatic osteosarcoma. The ROC curve also showed higher specificity and sensitivity for predicting 3- and 5-year osteosarcoma patients' survival compared with AJCC stage. The decision curve analysis also indicated more potential of clinical application of the nomogram compared with AJCC staging system. Moreover, our findings were supported by the validation cohort. Materials and Methods: We retrospectively investigated 301 patients with non-metastatic osteosarcoma. Data from primary cohort (n = 198) were used to develop multivariate nomograms. This nomogram was internally validated for discrimination and calibration with bootstrap samples and was externally validated with an independent patient cohort (n = 103). Conclusions: Our proposed nomogram showed more accurate prognostic prediction for patients with non-metastatic osteosarcoma. PMID- 29228584 TI - Combination of CALR and PDIA3 is a potential prognostic biomarker for non-small cell lung cancer. AB - Proteomic-based approaches for biomarker discovery are promising strategies used in cancer research. In this study, we performed quantitative proteomic analysis on 16 paired samples of non-small cell lung cancer (NSCLC) and adjacent non-tumor lung tissues using label-free quantitative proteomics and liquid chromatography tandem mass spectrometry/mass spectrometry (LC-MS/MS) to identify differentially expressed proteins. A total of 91 proteins were differentially expressed in NSCLC compared with adjacent non-tumor lung tissues among 4047 identified proteins (fold change > 1.5 or < 0.67, P < 0.05). Gene ontology (GO) analysis, Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis and ingenuity pathway analysis (IPA) of 91 dysregulated proteins showed that they were related to the cancer-associated biological processes. We confirmed that the candidate proteins, calreticulin (CALR) and protein disulfide isomerase family A member 3 (PDIA3) were overexpressed in NSCLC by real-time PCR using 20 paired samples and western blot using 5 paired samples. PDIA3 expression was highly associated with CALR expression (Spearman r = 0.345, P = 0.001) and they were co-localized and interacted with each other in A549 and H460 cells. Moreover, survival analysis performed in tissue microarray with 88 samples indicated that low expression of both CALR and PDIA3 in NSCLC was positively associated with poor overall survival. Combination of CALR and PDIA3 might serve as an efficient biomarker and improved the prediction of NSCLC prognosis significantly (P = 0.023). Our results collectively provide a potential biomarker dataset for NSCLC prognosis, especially the prognostic value of combined expression of CALR and PDIA3. PMID- 29228585 TI - Role of the JAK2/STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications. AB - This study investigated the role of the JAK2/STAT3/SOCS pathway in type 2 diabetes mellitus (T2DM) and macrovascular complications (DV) (T2DM+DV) conditions. Human umbilical vein endothelial cells (HUVECs) were co-cultured with human monocytes (THP-1) and exposed to peripheral blood sera from 30 T2DM patients, 30 patients with T2DM+DV and 30 healthy controls; the groups were divided into the control, T2DM, DV, T2DM+AG490 and DV+AG490 groups. Chemotaxis of treated HUVECs toward THP-1 cells was assessed using Transwell migration. The mRNA expression of JAK2, STAT3, VEGF and FLT1 was evaluated using RT-PCR, whereas the protein levels of ICAM-1, p-JAK2, JAK2, STAT3, p-STAT3, SOCS1 and SOCS3 were determined using western blotting. p-STAT3 was observed using immunofluorescence. The IL-1beta concentrations were assessed by ELISA. AG90 was used as a specific inhibitor of JAK2/STAT3 signaling. The chemotaxis assays revealed a migratory order of DV>DM>control, and AG490 treatment decreased chemotaxis. Additionally, p STAT3 fluorescence was noticeably increased in the DM group and more so in the DV group. The mRNA expression of JAK2, STAT3, VEGF and FLT1 and the protein levels of ICAM-1, p-JAK2, p-STAT3, SOCS1 and SOCS3 were significantly higher in the T2DM and DV groups than in the control group and in the AG490-treated groups than in the untreated groups. The supernatant concentrations of IL-1beta in the DV and T2DM groups were higher than those in the control group, and treatment with AG490 decreased the IL-1beta concentration. The JAK2/STAT3/SOCS axis contributes to the development of DV by mediating inflammation associated with vascular endothelial cells and/or monocytes. PMID- 29228586 TI - Targeting intercellular adhesion molecule-1 prolongs survival in mice bearing bevacizumab-resistant glioblastoma. AB - Intercellular cell adhesion molecule 1 (ICAM-1; also known as CD54) is overexpressed in bevacizumab-resistant glioblastoma. In the present study, we tested our hypothesis that highly expressed ICAM-1 mediates glioblastoma's resistance to antiangiogenic therapy. We validated ICAM-1 overexpression in tumors resistant to antiangiogenic therapy using real-time polymerase chain reaction, immunohistochemistry, and Western blotting. We also detected ICAM1 expression in most glioma stem cells (GSCs). We investigated the mechanism of ICAM-1 overexpression after bevacizumab treatment and found that ICAM-1 protein expression was markedly increased in a time-dependent manner in GSC11 and GSC17 cells under hypoxic conditions in vitro. We also found that hypoxia induced ICAM 1 overexpression through the up-regulation of phosphorylated signal transducer and activator of transcription (p-STAT3). Hypoxia-induced p-STAT3 increased the mRNA transcription of ICAM-1, which we could inhibit with the STAT3 inhibitor AZD1480. Next, we used GFP-tagged ICAM-1 shRNA lentivirus to knock down ICAM-1 in GSC11 and GSC17 glioma cell lines. Then, we injected shICAM-1 GSC11 and scramble glioma stem cells into the brains of nude mice. Mice bearing tumors from shICAM-1 GSC11 cells survived significantly longer than mice injected with control cells did. The tumor sizes was significantly decreased in mice bearing tumors from shICAM-1 cells than that in mice bearing tumors from GFP-tagged GSC11 control cells. Knocking down ICAM-1 suppressed tumor invasion in vitro and in vivo and inhibited macrophage infiltration to the tumor site in bevacizumab-treated mice. Our findings suggest that ICAM-1 is a potentially important mediator of tumor migration and invasion in bevacizumab-resistant glioblastoma. Targeting ICAM-1 may provide a new strategy for enhancing the efficacy of antiangiogenic therapy against glioblastoma and preventing the invasive phenotype of the disease. PMID- 29228587 TI - Chronic myeloid leukemia progenitor cells require autophagy when leaving hypoxia induced quiescence. AB - Albeit tyrosine kinase inhibitors anti-Abl used in Chronic Myeloid Leukemia (CML) block the deregulated activity of the Bcr-Abl tyrosine kinase and induce remission in 90% of patients, they do not eradicate immature hematopoietic compartments of leukemic stem cells. To elucidate if autophagy is important for stem cell survival and/or proliferation, we used culture in low oxygen concentration (0.1% O2 for 7 days) followed back by non-restricted O2 supply (normoxic culture) to mimic stem cell proliferation and commitment. Knockdown of Atg7 expression, a key player in autophagy, in K562 cell line inhibited autophagy compared to control cells. Upon 7 days at 0.1% O2 both K562 and K562 shATG7 cells stopped to proliferate and a similar amount of viable cells remained. Back to non restricted O2 supply K562 cells proliferate whereas K562 shATG7 cells exhibited strong apoptosis. Using immunomagnetic sorted normal and CML CD34+ cells, we inhibited the autophagic process by lentiviral infection expressing shATG7 or using a Vps34 inhibitor. Both, normal and CML CD34+ cells either competent or deficient for autophagy stopped to proliferate in hypoxia. Surprisingly, while normal CD34+ cells proliferate back to non restricted O2 supply, the CML CD34+ cells deficient for autophagy failed to proliferate. All together, these results suggest that autophagy is required for CML CD34+ commitment while it is dispensable for normal CD34 cells. PMID- 29228588 TI - Interleukin-17A-promoted MSC2 polarization related with new bone formation of ankylosing spondylitis. AB - It's still unknown how over-hyperplasia of tissue such like new bone formation (NBF) developed in ankylosing spondylitis (AS). We found low level of IL-17A promoted TLR4+MSC1 polarization with suppressed osteogenic differentiation through JAK2/STAT3 pathway, while high level of IL-17A promoted TLR3+MSC2 polarization with enhanced osteogenic differentiation through WNT10b/RUNX2 pathway. Furthermore, both proteoglycan-induced spondylitis (PGISp) mouse model and AS patients without NBF showed MSC1 polarization, up-regulated JAK2/STAT3 pathway and high level of IL-17A (peripherally, but not locally), but those with NBF showed MSC2 polarization, up-regulated WNT10b/RUNX2 pathway and high expression of IL-17A at local site. Results showed NBF of AS was induced by MSC2 polarization that was promoted by high level of IL-17A, and may be treated by suppressing local MSC2 polarization. PMID- 29228589 TI - Comparison of Echinococcus multilocularis and Echinococcus granulosus hydatid fluid proteome provides molecular strategies for specialized host-parasite interactions. AB - Alveolar and cystic echinococcoses, caused by the metacestodes of Echinococcus multilocularis and E. granulosus, are prevalent in several regions and invoke deleterious zoonotic helminthiases. Hydatid fluid (HF), which contains proteinaceous and non-proteinaceous secretions of the parasite- and host-derived components, critically affects the host-parasite interplay and disease progression. We conducted HF proteome profiling of fully mature E. multilocularis vesicle (nine months postinfection) and E. granulosus cyst (stage 2). We identified 120 and 153 proteins, respectively, in each fluid. Fifty-six and 84 proteins represented distinct species; 44 and 66 were parasites, and 12 and 18 were host-derived proteins. The five major parasite protein populations, which included antigen B isoforms, metabolic enzymes, proteases and inhibitors, extracellular matrix molecules (ECMs), and developmental proteins, were abundantly distributed in both fluids and also exclusively in one sample or the other. Carbohydrate-metabolizing enzymes were enriched in E. granulosus HF. In the E. multilocularis HF, proteins that constitute ECMs, which might facilitate adhesion and cytogenesis, were highly expressed. Those molecules had physical and functional relationships along with their biochemical properties through protein protein interaction networks. Twelve host-derived proteins were largely segregated to serum components. The major proteins commonly and uniquely detected in these HFs and their symbiotic interactome relationships might reflect their biological roles in similar but distinct modes of maturation, invasion, and the longevity of the parasites in the hosts. PMID- 29228590 TI - Precision and recall oncology: combining multiple gene mutations for improved identification of drug-sensitive tumours. AB - Cancer drug therapies are only effective in a small proportion of patients. To make things worse, our ability to identify these responsive patients before administering a treatment is generally very limited. The recent arrival of large scale pharmacogenomic data sets, which measure the sensitivity of molecularly profiled cancer cell lines to a panel of drugs, has boosted research on the discovery of drug sensitivity markers. However, no systematic comparison of widely-used single-gene markers with multi-gene machine-learning markers exploiting genomic data has been so far conducted. We therefore assessed the performance offered by these two types of models in discriminating between sensitive and resistant cell lines to a given drug. This was carried out for each of 127 considered drugs using genomic data characterising the cell lines. We found that the proportion of cell lines predicted to be sensitive that are actually sensitive (precision) varies strongly with the drug and type of model used. Furthermore, the proportion of sensitive cell lines that are correctly predicted as sensitive (recall) of the best single-gene marker was lower than that of the multi-gene marker in 118 of the 127 tested drugs. We conclude that single-gene markers are only able to identify those drug-sensitive cell lines with the considered actionable mutation, unlike multi-gene markers that can in principle combine multiple gene mutations to identify additional sensitive cell lines. We also found that cell line sensitivities to some drugs (e.g. Temsirolimus, 17-AAG or Methotrexate) are better predicted by these machine learning models. PMID- 29228591 TI - Up-regulation of angiotensin-converting enzyme in response to acute ischemic stroke via ERK/NF-kappaB pathway in spontaneously hypertensive rats. AB - Cerebral ischemic stroke is usually caused by a temporary or permanent decrease in blood supply to the brain. Despite general progress in diagnosis and treatment, the prognosis of stroke is still unsatisfactory, and more detailed potential mechanisms are needed to investigate underlying the pathological process. Here, we showed that serum angiotensin-converting enzyme (ACE) concentration was positively correlated with infarct volume after acute ischemic stroke (AIS). Moreover, using a permanent middle cerebral artery occlusion rat model, we indicated for the first time that increased ACE expression in response to AIS was regulated by the ERK/NF-kappaB pathway in peri-infarct regions. More importantly, we disclosed that angiotensin II type 1 receptors were implicated in up-regulation of ACE expression in peri-infarct regions. These findings offer insight into ACE expression and activity in response to stroke, and further our understanding of ACE mechanisms. PMID- 29228592 TI - Long non-coding RNA LINC00959 predicts colorectal cancer patient prognosis and inhibits tumor progression. AB - Long non-coding RNAs (lncRNAs) are increasingly implicated in tumorigenesis and cancer progression. This study focused on the relationship between the lncRNA LINC00959 and colorectal cancer (CRC). We found that LINC00959 expression was lower in CRC tissues than normal colorectal mucosae. High LINC00959 expression was negatively associated with TNM stage, distant metastasis, and lymphatic metastasis, and correlated with a better prognosis in 87 CRC cases. In vitro, LINC00959 knockdown enhanced colon cancer cell proliferation, invasion, and migration; upregulated N-cadherin and vimentin; and downregulated E-cadherin and Caspase-3. LINC00959 overexpression produced the opposite effects. These data suggest that LINC00959 inhibits tumor cell invasion and migration by suppressing epithelial-mesenchymal transition and promotes apoptosis through Caspase-3. LINC00959 may be a tumor suppressor and useful prognostic biomarker in CRC. PMID- 29228594 TI - Bone-strengthening pill (BSP) promotes bone cell and chondrocyte repair, and the clinical and experimental study of BSP in the treatment of osteonecrosis of the femoral head. AB - About 1 in 3 people suffer from bone and joint disease, which is a disease of bone and cartilage cells. Osteonecrosis of the femoral head (ONFH) is a typical example of bone and joint disease involving bone cell necrosis. Osteonecrosis of the femoral head leads to the occurrence of premature osteoarthritis of the hip and collapse of the cartilage cells, and there is currently no effective drug treatment available. In order to study the effects of "bone-strengthening pill" (BSP) on the repair of bone and cartilage cells, we investigated the potential effects of the herbal mixture BSP in an animal model of avascular necrosis of the femoral head and in patients. Results showed that 90% of rats injected with prednisone developed ONFH, whereas BSP administration prevented ONFH development in 70% of prednisone-injected rats. We evaluated the constituents of BSP by HPLC fingerprinting. We also evaluated the clinical efficacy of BSP in a double-blind, randomized, controlled trial of 300 patients with ONFH. The response rate was found to be higher in the treatment group than in the control group, with a response rate of 82% in the treatment group. Treatment with BSP also significantly reduced pain, improved hip function, reduced lameness, and improved pathology by X-ray and MRI analysis, compared with patients who did not receive BSP. These results suggest that BSP treatment inhibits and reverses necrosis of the femoral head bone cells and cartilage cells to repair the femoral head, promote the repair of bone and cartilage diseases. PMID- 29228593 TI - Proteasome inhibitor bortezomib enhances the effect of standard chemotherapy in small cell lung cancer. AB - Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A. FOXM1 was strongly expressed in patient derived SCLC samples (n=123) and its nuclear localization was associated with the proliferation marker Ki-67. Both proteasome inhibitors successfully inhibited FOXM1 expression leading to a significantly reduced proliferation and a decreased mitotic rate along with cell cycle arrest and apoptosis induction. These effects were further enhanced by addition of bortezomib to standard chemotherapy. Treatment of mice bearing chemoresistant SCLC xenografts with bortezomib reduced the mean bioluminescence signal of tumors by 54%. Similarly, treatment with cisplatin as a standard chemotherapy reduced the mean bioluminescence signal of tumors by 58%. However, in combination with standard chemotherapy bortezomib further reduced the mean bioluminescence signal by 93% (p=0.0258). In conclusion, we demonstrate the effect of bortezomib in inhibiting FOXM1 expression and thus in sensitizing resistant SCLC cells to standard chemotherapy. Thus, addition of bortezomib to standard chemotherapy might potently improve SCLC therapy, particularly in an extensive cancer stage. PMID- 29228595 TI - Age-specific impact on the survival of gastric cancer patients with distant metastasis: an analysis of SEER database. AB - The age-specific impact on the survival of gastric cancer patients with distant metastasis is still unclear. In this study, we identified 11, 299 gastric cancer patients with distant metastasis between 2004 and 2013 from Surveillance, Epidemiology, and End Results population-based dataset. Patients were divided into young (<=60) and elderly groups (>60). Kaplan-Meier methods and multivariable Cox regression were used for the analysis of long-term survival outcomes and risk factors. There were significant differences between the two groups in terms of race, primary site, grade, histologic type, surgery, marital status and clinical T stage (P<0.05). The 1- and 3-year cancer specific survival rates were 29.0% and 6.2% in young group and 22.8% and 4.8% in elderly group in both univariate (X2=116.430, P<0.001) and multivariate analysis (P<0.001). Young patients had significantly better 1- and 3-year cancer specific survival than elderly patients in each T stage. Age was further validated as an independent survival factor in all T stages (T1, T2, T3, T4 and TX, P<0.05). In conclusion, age was an independent prognostic factor for gastric cancer patients with distant metastasis. PMID- 29228596 TI - CYP19A1 polymorphisms associated with coronary artery disease and circulating sex hormone levels in a Chinese population. AB - Background: The relationship between CYP19A1 genetic polymorphisms and coronary artery disease (CAD) remains unclear. Thus, the aim of the present study was to investigate the association of CYP19A1 genetic polymorphisms with CAD in Han and Uygur populations and to characterize the association between the levels of sex hormones and aromatase with single-nucleotide polymorphisms (SNPs) in CYP19A1 genes in Chinese women. Results: There were significant differences in the genotype distributions of rs2236722 and rs4646 between CAD patients and control subjects in the Uygur population. The rs4646 was found to be associated with CAD in the dominant model (CC vs. CA + AA) and the additive model (CA vs. CC + AA) (both P <= 0.001). The difference remained statistically significant after multivariate adjustment (OR = 0.483, 95% CI: 0.338-0.690, P = 0.000; and OR = 1.844, 95% CI: 1.300-2.617, P = 0.001, respectively). In normal Uygur postmenopausal women, there were significant differences in the genotype distributions of rs4646 and the circulating hormone and aromatase levels between CAD patients and control subjects. The differences in estradiol and aromatase levels remained statistically significant after multivariate adjustment (OR = 0.889, 95% CI: 0.817-0.969, P = 0.007; and OR = 0.947, 95% CI: 0.936-0.957, P = 0.000, respectively). Additionally, there were differences in sex hormone levels between the different ethnicities among the Xinjiang Chinese population. Materials and Methods: Among a total of 1,064 Han individuals (614 men and 450 women) and 790 Uygur individuals (484 men and 306 women), 498 postmenopausal women (265 Han and 233 Uygur individuals) were selected. Four SNPs (rs2236722, rs2304463, rs4646, and rs4275794) were genotyped using the improved multiplex ligation detection reaction (iMLDR) technique. The estradiol and testosterone levels were determined using a radioimmunoassay based on GC-2016gamma. In addition, an enzyme-linked immunosorbent assay (ELISA) was performed to determine the serum P450 aromatase levels. Conclusions: The results of this study indicate that the rs2236722 and rs4646 of the CYP19A1 gene are associated with CAD and circulating sex hormone levels in the Xinjiang population of China. PMID- 29228597 TI - Diversity index as a novel prognostic factor in breast cancer. AB - Intratumoral genetic heterogeneity leads to tumor progression and therapeutic resistance. However, due to the difficulty associated with its assessment, the use of this heterogeneity as a prognostic or predictive marker remains limited. To investigate the significance of the Shannon diversity index of gene copy number variation as a tool for measuring genetic heterogeneity in breast cancer, we performed fluorescence in situ hybridization of c-MYC in two sets of invasive breast cancer samples and correlated the Shannon index of c-MYC copy number variation with clinicopathologic features and patient survival. The Shannon index was correlated with average c-MYC copy number and was higher in tumors in which c MYC was amplified and in those with c-MYC genetic or regional heterogeneity. A high Shannon index was associated with adverse pathologic features including high histologic grade, lymphovascular invasion, p53 overexpression, high Ki-67 proliferation index and negative hormone receptor status. It was also associated with poor disease-free survival in the whole group, in a subgroup excluding c-MYC amplified cases, and in the hormone receptor-positive subgroup of both a test and a validation set. A high Shannon index for FGFR1 gene copy number variation was also an independent adverse prognostic factor. Our findings suggest that the Shannon diversity index is a measure of intratumoral heterogeneity and can be used as a prognostic factor in breast cancer. PMID- 29228598 TI - Analysis of molecular evolution of nucleocapsid protein in Newcastle disease virus. AB - The present study investigated the molecular evolution of nucleocapsid protein (NP) in different Newcastle disease virus (NDV) genotypes. The evolutionary timescale and rate were estimated using the Bayesian Markov chain Monte Carlo (MCMC) method. The p-distance, Bayesian skyline plot (BSP), and positively selected sites were also analyzed. The MCMC tree indicated that NDV diverged about 250 years ago with a rapid evolution rate (1.059 * 10-2 substitutions/site/year) and that different NDV genotypes formed three lineages. The p-distance results reflected the great genetic diversity of NDV. BSP analysis suggested that the effective population size of NDV has been increasing since 2000 and that the basic reproductive number (R0) of NDV ranged from 1.003 to 1.006. The abundance of negatively selected sites in the NP and the mean dN/dS value of 0.07 indicated that the NP of NDV may have undergone purifying selection. However, the predicted positively selected site at position 370 was located in the known effective epitopic region of the NP. In conclusion, although NDV evolved at a high rate and showed great genetic diversity, the structure and function of the NP had been well conserved. However, R0>1 suggests that NDV might have been causing an epidemic since the time of radiation. PMID- 29228599 TI - Chicken bile powder protects against alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice. AB - This study explored the effects of chicken bile powder (CBP), a 2000-year-old Chinese medicine, on alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. CBP treatment for 14 days significantly ameliorated ANIT induced changes in serum alanine aminotransferase, aspartate aminotransferase, bile acids, bilirubin, gamma-glutamyl transpeptidase, alkaline phosphatase, and liver tissue morphology. Serum metabolomics showed changes in 24 metabolites in ANIT-exposed mice; 16 of these metabolites were reversed by CBP treatment via two main pathways (bile acid biosynthesis and arachidonic acid metabolism). Additionally, CBP administration markedly increased fecal and biliary bile acid excretion, and reduced total and hydrophobic bile acid levels in the livers of cholestatic mice. Moreover, CBP increased liver expression of bile acid efflux transporters and metabolic enzymes. It also attenuated ANIT-induced increases in hepatic nuclear factor-kappaB-mediated inflammatory signaling, and increased liver expression of the nuclear farnesoid X receptor (FXR) in cholestatic mice. CBP also activated FXR in vitro in HEK293T cells expressing mouse Na+ taurocholate cotransporting polypeptide. It did not ameliorate the ANIT-induced liver injuries in FXR-knockout mice. These results suggested that CBP provided protection from cholestatic liver injury by restoring bile acid homeostasis and reducing inflammation in a FXR-dependent manner. PMID- 29228600 TI - Non-invasive in vivo molecular imaging of intra-articularly transplanted immortalized bone marrow stem cells for osteoarthritis treatment. AB - Pathophysiology of osteoarthritis (OA) is characterized by progressive loss of articular cartilage in the knee-joints. To impart regenerative ability in lowly metabolizing chondrocytes, the bone marrow stem cells (BMSCs) has recently been recognized as a superior alternative treatment for OA. However, study of primary BMSCs-mediated chondrogenesis is difficult due to progressive cellular aging and replicative senescence. To obtain a therapeutic cell population for OA, BMSCs were immortalized by human papilloma virus (HPV)-16 E6/E7 along with mCherry luciferase (mCL), a gene marker for non-invasive imaging, and designated as iBMSCs-mCL. Next, their cell morphology, population doubling time (PDT) and colony forming ability (CFU) were evaluated. Furthermore, pluripotency and immunophenotypic markers were investigated. To deduce therapeutic ability, iBMSCs mCL were intra-articularly injected into right knee of anterior cruciate ligament transaction (ACLT)-OA mice model and tracked through non-invasive bioluminescence imaging. Cell morphology of iBMSCs-mCL was similar to parental BMSCs. PDT and CFU ability of iBMSCs-mCLs were significantly increased. Pluripotency and immunophenotypic markers were highly expressed in iBMSC-mCL. Long-term survival and tri-lineage differentiation particularly chondrogenic potential of iBMSCs-mCL were also demonstrated in vitro and then in vivo which was monitored through non invasive imaging. Intensive bioluminescent signals in iBMSCs-mCL administered knee-joint indicated a marked in vivo survival and proliferation of iBMSCs-mCL. Immunohistochemical staining for type II collagen (IHC of Col II) and alcian blue & safranin o staining of proteoglycans also corroborated cartilage regeneration by iBMSCs-mCL. Conclusively, iBMSCs-mCL maintains stemness and in vivo cartilage regeneration potential suggesting a promising avenue for development of OA therapeutics. PMID- 29228601 TI - Genome-wide analysis of circular RNAs in prenatal and postnatal muscle of sheep. AB - Circular RNAs (circRNAs), a type of non-coding RNA with circular structure, were generated by back splicing and widely expressed in animals and plants. Recent studies have shown that circRNAs extensively participate in cell proliferation, cell differentiation, cell autophagy and other biological processes. However, the role and expression of circRNAs in the development and growth of muscle have not been studied in sheep. In our study, we first used RNA-seq to study the circRNAs in prenatal and postnatal longissimus dorsi muscle of sheep. A total of 6113 circRNAs were detected from the RNA-seq data. Several circRNAs were identified using reverse transcription PCR, DNA sequencing and RNase R digestion experiments. The expression levels of several circRNAs in prenatal and postnatal muscle were confirmed by Real-Time RT-PCR. The gene ontology (GO) and KEGG enrichment analysis of the host gene of the circRNAs showed that these circRNAs were mainly involved in the growth and development of muscle related signaling pathways. These circRNAs might sponge microRNAs (miRNAs) in predicted circRNA miRNA-mRNA networks. The circRNAs expression profiles in muscle provided an important reference for the study of circRNAs in sheep. PMID- 29228602 TI - FBXW8-dependent degradation of MRFAP1 in anaphase controls mitotic cell death. AB - Mof4 family associated protein 1 (MRFAP1) is a 14 kDa nuclear protein, which involves in maintaining normal histone modification levels by negatively regulating recruitment of the NuA4 (nucleosome acetyltransferase of H4) histone acetyltransferase complex to chromatin. MRFAP1 has been identified as one of the most up-regulated proteins after NEDD8 (neural precursor cell expressed developmentally down-regulated 8) inhibition in multiple human cell lines. However, the biological function of MRFAP1 and the E3 ligase that targets MRFAP1 for destruction remain mysterious. Here we show, by using an immunoprecipitation based proteomics screen, that MRFAP1 is an interactor of the F-box protein FBXW8. MRFAP1 is degraded by means of the ubiquitin ligase Cul7/FBXW8 during mitotic anaphase-telophase transition and accumulated in mitotic metaphase. Overexpression of FBXW8 increased the polyubiquitination and decreased the stability of MRFAP1, whereas knockdown of FBXW8 prolonged the half-life of MRFAP1. Moreover, forced expression of MRFAP1 in HeLa cells caused growth retardation and genomic instability, leading to severe mitotic cell death. Thus, Cul7/FBXW8-mediated destruction of MRFAP1 is a regulatory component monitoring the anaphase-telophase transition and preventing genomic instability. PMID- 29228603 TI - Elevating VEGF-A and PDGF-BB secretion by salidroside enhances neoangiogenesis in diabetic hind-limb ischemia. AB - Hind-limb ischemia (HLI) is one of the major complication of diabetic patients. Angiogenesis potential in diabetic patients is severely disrupted, and the mechanism underlying it has not been fully elucidated, making it an obstacle for developing an efficient therapeutic angiogenesis strategy. Skeletal muscle cells, through their paracrine function, had been known to be critical for neoangiogenesis. Here we found that hyperglycemia upregulates the expression of skeletal muscle cells prolyl hydroxylase domain 3 (PHD3), which resulted in the decrease of the secretion of angiogenic factors, especially VEGF-A and PDGF-BB. We showed that treatment with salidroside, a small molecule drug, significantly suppresses PHD3 expression and increases VEGF-A and PDGF-BB secretion from skeletal muscle cells, which in turn enhances the proliferation and migration potentials of endothelial and smooth muscle cells. Finally, we demonstrated that intramuscular injection of salidroside into the ischemic hind limbs of diabetic HLI model mice could efficiently induce neoangiogenesis and blood perfusion recovery. Thus, our novel findings not only reveal the effects of hyperglycemia on the angiogenesis potential of skeletal muscle cells and the mechanism underlying it, but also provides a novel finding suggesting that salidroside might be a potential small molecule drug for diabetic HLI. PMID- 29228604 TI - Bcl-3 is a novel biomarker of renal fibrosis in chronic kidney disease. AB - Progressive renal fibrosis in chronic kidney disease (CKD) greatly contributes to end-stage renal failure and is associated with high mortality. The identification of renal fibrosis biomarkers for the diagnosis and the monitoring of disease progression in CKD is urgently needed. Whole-transcriptomic analysis of renal tissues in a unilateral ureteral obstruction (UUO) mouse model revealed that the mRNA level of Bcl-3, an atypical member of the IkappaB family, was induced 6.3 fold 2 days after UUO. Compared with renal tissues in sham-operated mice, increases in Bcl-3 mRNA and protein in the renal tissues in the UUO model were accompanied with increases in other markers of renal fibrosis, including human epididymis protein 4 (HE4), a recently identified biomarker of renal fibrosis. Immunohistochemical analysis revealed that both Bcl-3 and HE4 were located in the plasma of renal tubule cells. Serum protein levels of Bcl-3 and HE4 rose with the development of renal fibrosis in UUO mouse model. We found that the serum protein levels of both HE4 and Bcl-3 were elevated in CKD patients compared with healthy controls. Moreover, a significant positive correlation between Bcl-3 and HE4 (r = 0.939, p < 0.0001) was observed in CKD patients. These data suggest that Bcl-3 can serve as a novel valuable biomarker of renal fibrosis in CKD. PMID- 29228605 TI - A case-control study on risk factors of breast cancer in Han Chinese women. AB - This study aimed to investigate risk factors associated with breast cancer among Han Chinese women in northern and eastern China. A matched case-control study involving 1489 patients with breast cancer and 1489 controls was conducted across 21 hospitals in 11 provinces in China, from April 2012 to April 2013. We developed a structured questionnaire to record information from face-to-face interviews with participants. Student's t-tests, Pearson's chi-square tests, and univariate and multivariate conditional logistic regression analyses were used to identify variables with significant differences between the case and control groups. Ten variables were identified (P<0.05): location, economic status, waist to-hip ratio, menopause, family history of breast cancer, present life satisfaction, sleep satisfaction, milk products, behavior prevention scores, and awareness of breast cancer. We identified a comprehensive range of factors related to breast cancer, among which several manageable factors may contribute to breast cancer prevention. Further prospective studies concerning psychological interventions, sleep regulation, health guidance, and physical exercise are required. A screening model for high-risk populations should be put on the agenda. PMID- 29228606 TI - Identifying tumor promoting genomic alterations in tumor-associated fibroblasts via retrovirus-insertional mutagenesis. AB - Tumor-associated fibroblasts (TAFs) are often essential for solid tumor growth. However, few genetic or epigenetic alterations have been found in TAFs during the progression of solid tumors. Employing a tumor-stromal cell co-injection model, we adapted here retroviral-insertional mutagenesis to stromal cells to identify novel tumor-associated genes in TAFs. We successfully identified 20 gene candidates that might modulate tumor growth if altered in TAFs at genomic level. To validate our finding, the function of one of the candidate genes, tubulin tyrosine ligase (Ttl), was further studied in TAFs from fibrosarcoma, colon, breast and hepatocarcinoma. We demonstrated that down-regulated TTL expression in TAFs indeed promoted tumor growth in mice. Interestingly, decreased expression of TTL in tumor stromal cells also correlated with poor outcome in human colon carcinoma. Thus, the co-injection model of tumor cells with retrovirus-modified fibroblasts proved a valid method to identify tumor-modulating genes in TAFs, allowing for a deeper insight into the role of the stroma for tumor development. PMID- 29228607 TI - Clinical significance and biological function of fucosyltransferase 2 in lung adenocarcinoma. AB - Fucosylation, which is catalyzed by fucosyltransferases (FUTs), is one of the most important glycosylation events involved in cancer. Studies have shown that fucosyltransferase 8 (FUT8) is overexpressed in NSCLC and promotes lung cancer progression. However, there are no reports about the pathological role of fucosyltransferase 2 (FUT2) in lung cancer. To identify FUT2 associated with lung cancer, the expression and clinical significance of FUT2 in lung cancer was investigated by Real-Time PCR, Immunohistochemistry and Western Blot. In addition, we investigated the effect of knockdown FUT2 in lung adenocarcinoma cells. The results showed that the expression of FUT2 in lung adenocarcinoma is higher than that in adjacent noncancerous tissues. Knocking down FUT2 in A549 and H1299 cells decreased cell proliferation, migration and invasion, and increased cell apoptosis compared to corresponding control cells. Furthermore, Western Blot showed that knockdown FUT2 can impact the expression of migration-associated and apoptosis-associated proteins in A549 cells. Our results suggest that FUT2 may be associated with lung adenocarcinoma development and thus is a potential biomarker or/and therapeutic target in lung adenocarcinoma. PMID- 29228608 TI - Expression of miR-195 is associated with chemotherapy sensitivity of cisplatin and clinical prognosis in gastric cancer. AB - Gastric cancer has higher morbidity and mortality than other cancers for the low diagnosis rate and few therapies. MiR-195 has been reported to be involved in the occurrence, development and prognosis of various cancers. However, the function of miR-195 in gastric cancer remains largely unknown. Herein, the aims of this study were to probe the functional mechanism of miR-195 and its chemotherapy sensitivity as well as clinical prognosis in gastric cancer. We screened out low expressed miR-195 through microarray analysis and further confirmed miR-195 was widely down-regulated in gastric cancer cells. Subsequently, AKT3 was identified as the direct target gene of miR-195 by target gene prediction software, dual luciferase reporter assay and western blot. Functional assays indicated that miR 195 acted as a tumor suppressor through regulating the proliferative, migrated and invasive properties of gastric cancer cells in vitro, and intratumoral delivery of miR-195 significantly suppressed tumor growth in vivo. Additionally, we also found miR-195 overexpression could enhance the chemotherapy sensitivity of cisplatin in gastric cancer cells and prolong the overall survival and progression free survival of gastric cancer patients. Collectively, our findings demonstrate miR-195 may be of great significance on early diagnosis of gastric cancer, providing the theoretical basis for prognosis and recurrence risk. PMID- 29228609 TI - Bacteriome and mycobiome associations in oral tongue cancer. AB - Squamous cell carcinoma of the oral (mobile) tongue (OMTC), a non-human papilloma virus-associated oral cancer, is rapidly increasing without clear etiology. Poor oral hygiene has been associated with oral cancers, suggesting that oral bacteriome (bacterial community) and mycobiome (fungal community) could play a role. While the bacteriome is increasingly recognized as an active participant in health, the role of the mycobiome has not been studied in OMTC. Tissue DNA was extracted from 39 paired tumor and adjacent normal tissues from patients with OMTC. Microbiome profiling, principal coordinate, and dissimilarity index analyses showed bacterial diversity and richness, and fungal richness, were significantly reduced in tumor tissue (TT) compared to their matched non-tumor tissues (NTT, P<0.006). Firmicutes was the most abundant bacterial phylum, which was significantly increased in TT compared to NTT (48% vs. 40%, respectively; P=0.004). Abundance of Bacteroidetes and Fusobacteria were significantly decreased in TT compared to matched NTT (P<=0.003 for both). Abundance of 22 bacterial and 7 fungal genera was significantly different between the TT and NTT, including Streptococcus, which was the most abundant and significantly increased in the tumor group (34% vs. 22%, P<0.001). Abundance of fungal genus Aspergillus in TT correlated negatively with bacteria (Actinomyces, Prevotella, Streptococcus), but positively with Aggregatibacter. Patients with high T-stage disease had lower mean differences between TT and NTT compared with patients with low T-stage disease (0.07 vs. 0.21, P=0.04). Our results demonstrate differences in bacteriome and mycobiome between OMTC and their matched normal oral epithelium, and their association with T-stage. PMID- 29228610 TI - Targeting Polo-like kinase 1 in SMARCB1 deleted atypical teratoid rhabdoid tumor. AB - Atypical teratoid rhabdoid tumor (ATRT) is an aggressive and malignant pediatric brain tumor. Polo-like kinase 1 (PLK1) is highly expressed in many cancers and essential for mitosis. Overexpression of PLK1 promotes chromosome instability and aneuploidy by overriding the G2-M DNA damage and spindle checkpoints. Recent studies suggest that targeting PLK1 by small molecule inhibitors is a promising approach to tumor therapy. We investigated the effect of PLK1 inhibition in ATRT. Gene expression analysis showed that PLK1 was overexpressed in ATRT patient samples and tumor cell lines. Genetic inhibition of PLK1 with shRNA potently suppressed ATRT cell growth in vitro. Treatment with the PLK1 inhibitor BI 6727 (Volasertib) significantly decreased cell growth, inhibited clonogenic potential, and induced apoptosis. BI6727 treatment led to G2-M phase arrest, consistent with PLK1's role as a critical regulator of mitosis. Moreover, inhibition of PLK1 by BI6727 suppressed the tumor-sphere formation of ATRT cells. Treatment also significantly decreased levels of the DNA damage proteins Ku80 and RAD51 and increased gamma-H2AX expression, indicating that BI 6727 can induce DNA damage. Importantly, BI6727 significantly enhanced radiation sensitivity of ATRT cells. In vivo, BI6727 slowed growth of ATRT tumors and prolonged survival in a xenograft model. PLK1 inhibition is a compelling new therapeutic approach for treating ATRT, and the use of BI6727 should be evaluated in clinical studies. PMID- 29228611 TI - Proteogenomic characterization and integrative analysis of glioblastoma multiforme. AB - Glioblastoma multiforme (GBM), the most aggressive and lethal primary brain tumor, is characterized by very low life expectancy. Understanding the genomic and proteogenomic characteristics of GBM is essential for devising better therapeutic approaches.Here, we performed proteomic profiling of 8 GBM and paired normal brain tissues. In parallel, comprehensive integrative genomic analysis of GBM was performed in silico using mRNA microarray and sequencing data. Two whole transcript expression profiling cohorts were used - a set of 3 normal brain tissues and 22 glioma tissue samples and a cohort of 5 normal brain tissues and 49 glioma tissue samples. A validation cohort included 529 GBM patients from The Cancer Genome Atlas datasets. We identified 36 molecules commonly changed at the level of the gene and protein, including up-regulated TGFBI and NES and down regulated SNCA and HSPA12A. Single amino acid variant analysis identified 200 proteins with high mutation rates in GBM samples. We further identified 14 differentially expressed genes with high-level protein modification, among which NES and TNC showed differential expression at the protein level. Moreover, higher expression of NES and TNC mRNAs correlated with shorter overall survival, suggesting that these genes constitute potential biomarkers for GBM. PMID- 29228612 TI - MiR-204 enhances mitochondrial apoptosis in doxorubicin-treated prostate cancer cells by targeting SIRT1/p53 pathway. AB - Chemotherapy is important for adjuvant treatment of prostate cancer. However, some cancer cells exhibited low sensitivity to chemotherapeutic agents. We are supposed to sensitize these prostate cancer cells to chemotherapeutic agents such as doxorubicin. Previous reports have suggested that microRNAs (miRNAs) regulate chemosensitivity in various cancers. In the present study, we observed that expression level of miR-204 was decreased in prostate cancer cell lines and patients' tumors. Furthermore, we found that restore of miR-204 dramatically enhanced the cytotoxicity of doxorubicin (DOX) against prostate cancer cell lines C4-2 and LNCaP carrying wild type (WT) p53. Mechanically, miR-204 in prostate cancer cells targets SIRT1 which is a histone deacetylase, and thus decreasing deacetylation of p53. As the results, acetylated p53 induced by DOX upregulates the expression of Noxa and Puma followed by induction of mitochondrial apoptosis. These data demonstrate that restore of miR-204 in prostate cancer cells enhances the mitochondrial apoptosis induced by doxorubicin by targeting the SIRT1/p53 pathway. PMID- 29228613 TI - The incidence and prognosis of nasopharyngeal carcinoma patients with family history. AB - Purpose: Epidemiological data showed that nasopharyngeal carcinoma (NPC) was a regional malignancy. It suggested that genetic factor may play an important role in tumorigenesis of NPC. The aim was to investigate the incidence and the prognosis of NPC patients with family history. Methods: The clinical data of patients with NPC treated in Fudan University Shanghai Cancer Center from January 2008 to December 2012 were reviewed, and the patients with family history were selected. The prognosis of patients with family history was follow-up. The 5-year overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were analyzed by Kaplan-Meier and log-rank test. Cox proportional hazard model was used for multivariate analysis. Results: There were 3.64% (135/3706) NPC patients with family history of NPC. Eighty-three percent (112/135) patients had only one family member suffering from NPC previously, and 74.1% (100/135) patients who had family history only in first degree family members. Excluding five patients lost to follow-up, 130 patients were eventually used to analyze the prognosis. The 5-year OS, LRFS, and DMFS rates of all patients with family history were 84.1%, 83.4%, and 83.8%, respectively. There were no significant differences of OS, LRFS and DMFS between one relative group and at least two relatives group. In addition, the degree of NPC had no association with OS, LRFS and DMFS, respectively. Conclusion: Our results showed that there was an incidence rate of 3.64% NPC patients with family history. These patients had a satisfied prognosis, and the prognosis of NPC patients with family history in different degree or numbers of relatives had no significant differences. PMID- 29228614 TI - Dual effects of radiation bystander signaling in urothelial cancer: purinergic activation of apoptosis attenuates survival of urothelial cancer and normal urothelial cells. AB - Radiation therapy (RT) delivers tumour kill, directly and often via bystander mechanisms. Bladder toxicity is a dose limiting constraint in pelvic RT, manifested as radiation cystitis and urinary symptoms. We aimed to investigate the impact of radiation-induced bystander signaling on normal/cancer urothelial cells. Human urothelial cancer cells T24, HT1376 and normal urothelial cells HUC, SV-HUC were used. Cells were irradiated and studied directly, or conditioned medium from irradiated cells (CM) was transferred to naive, cells. T24 or SV-HUC cells in the shielded half of irradiated flasks had increased numbers of DNA damage foci vs non-irradiated cells. A physical barrier blocked this response, indicating release of transmitters from irradiated cells. Clonogenic survival of shielded T24 or SV-HUC was also reduced; a physical barrier prevented this phenomenon. CM-transfer increased pro-apoptotic caspase-3 activity, increased cleaved caspase-3 and cleaved PARP expression and reduced survival protein XIAP expression. This effect was mimicked by ATP. ATP or CM evoked suramin-sensitive Ca2+-signals. Irradiation increased [ATP] in CM from T24. The CM-inhibitory effect on T24 clonogenic survival was blocked by apyrase, or mimicked by ATP. We conclude that radiation-induced bystander signaling enhances urothelial cancer cell killing via activation of purinergic pro-apoptotic pathways. This benefit is accompanied by normal urothelial damage indicating RT bladder toxicity is also bystander-mediated. PMID- 29228615 TI - Combined therapy of colon carcinomas with an oncolytic adenovirus and valproic acid. AB - The anti-tumor potential of oncolytic adenoviruses (CRAds) has been demonstrated in preclinical and clinical studies. While these agents failed to eradicate tumors when used as a monotherapy, they may be more effective if combined with conventional treatments such as radiotherapy or chemotherapy. This study seeks to evaluate the combination of a CRAd bearing a ?24 deletion in E1A with valproic acid (VPA), a histone deacetylase inhibitor, for the treatment of human colon carcinomas. This combination led to a strong inhibition of cell growth both in vitro and in vivo compared to treatment with CRAd or VPA alone. This effect did not stem from a better CRAd replication and production in the presence of VPA. Inhibition of cell proliferation and cell death were induced by the combined treatment. Moreover, whereas cells treated only with CRAd displayed a polyploidy (> 4N population), this phenotype was increased in cells treated with both CRAd and VPA. In addition, the increase in polyploidy triggered by combined treatment with CRAd and VPA was associated with the enhancement of H2AX phosphorylation (gammaH2AX), a hallmark of DNA damage, but also with a decrease of several DNA repair proteins. Finally, viral replication (or E1A expression) was shown to play a key role in the observed effects since no enhancement of polyploidy nor increase in gammaH2AX were found following cell treatment with a replication deficient Ad and VPA. Taken together, our results suggest that CRAd and VPA could be used in combination for the treatment of colon carcinomas. PMID- 29228616 TI - MicroRNA-610 inhibits tumor growth of melanoma by targeting LRP6. AB - Accumulating evidence showed that aberrant miRNAs expression was involved in initiation and progression of melanoma. However, the investigation of different miRNAs in melanoma remain attractive. In this research, we demonstrated that miR 610 expression was decreased in melanoma tissues and cell lines. The clinical data showed that the reduced miR-610 expression was obviously associated with adverse prognostic characteristics. Furthermore, our results suggested that miR 610 had a function of prognostic indicator for 5-year predicted-survival of melanoma patients. The ectopic overexpression of miR-610 suppressed cell proliferation, cell cycle progression and promoted apoptosis while miR-610 knockdown reversed the effect in vitro and in vivo. Additionally, miR-610 could modulate LRP6 by directly interacting to its 3'-UTR. In clinical samples of melanoma, miR-610 inversely correlated with LRP6. The biological function of miR 610 on melanoma cells was abrogated by alternation of LRP6 expression. In summary, our research indexed that miR-610 had a function of tumor suppressor in regulating the proliferation, cell cycle and apoptosis of melanoma via targeting LRP6. Hence, it may represent a novel potential therapeutic target and prognostic marker for melanoma. PMID- 29228617 TI - Decreased long non-coding RNA MTM contributes to gastric cancer cell migration and invasion via modulating MT1F. AB - The role of long non-coding RNAs (lncRNA) on gastric cancer (GC) are an emerging field. Here, we focused on a cancer-related lncRNA MTM and tried to explore its correlation with the development of GC. The expression of MTM was detected by qRT PCR in GC cell lines and tissues. The relationship between MTM level and clinicopathological factors was then analyzed. Cell biological assays with overexpression or co-transfection approaches were examined to probe the functional relevance of this lncRNA and its potential targets. The results showed that MTM expression was significantly lower in GC cell lines and tissues, and closely correlated with lymphatic metastasis, invasive depth, tumor staging and overall survival. Overexpression of MTM significantly inhibited GC cell migration and invasion, suppressed cell proliferation and induced cell apoptosis. In addition, we found a positive correlation between the expression level of MTM and MT1F both in cell and tissue samples. MT1F overexpression decreased GC cell migration and invasion, while knockdown of MT1F restored cell migration and invasion in MTM-overexpressing GC cells, suggesting MT1F as a key target of MTM. Conclusively, abnormal decreased expression of MTM was observed in human GC, which might contribute to gastric carcinogenesis by modulating MT1F expression. PMID- 29228618 TI - Calcium homeostasis and endoplasmic reticulum stress are involved in Salvianolic acid B-offered protection against cardiac toxicity of arsenic trioxide. AB - Arsenic trioxide (ATO) is a potent anticancer agent used to treat acute promyelocytic leukemia. However, its cardiotoxicity limits ATO's widespread clinical use. Previous studies demonstrated that ATO may aggravate Ca2+ overload and promote endoplasmic reticulum stress (ERS). Salvianolic acid B (Sal B) is cardioprotective against ATO and enhances ATO's anticancer activities. The present study assessed whether the Sal B protective effect was related to maintenance of Ca2+ homeostasis and inhibition of ER stress. Male BALB/c mice were injected with ATO or ATO+Sal B once a day via the tail vein for 2 weeks. We then detected the effects of Sal B in real time using adult rat ventricular cardiomyocytes in vitro using an IonOptix MyoCam system. Sal B treatment alleviated ATO-induced abnormal cardiac contractions and Ca2+ homeostasis imbalance. Sal B increased sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity, regulated Ca2+ handling protein expression, and decreased expression of ERS proteins. Our results demonstrate that the cardioprotective effect of Sal B correlates with SERCA modulation, maintenance of Ca2+ homeostasis, and inhibition of ER stress. These findings suggest Sal B may ameliorate ATO cardiotoxicity during clinical application. PMID- 29228619 TI - Fibrin-bearing microparticles: marker of thrombo-embolic events in pancreatic and colorectal cancers. AB - Background: Microparticles (MPs) are plasma membrane-derived extracellular vesicles present in the bloodstream. We have described a specific signature of MPs, called microparticulosome, in colorectal (CRC) and pancreatic (PC) cancers. We observed that levels of fibrin-bearing MPs were significantly increased in patients suffering from PC and CRC in comparison with control groups. Here, we hypothesised that fibrin-MPs may constitute a relevant biomarker of thrombosis associated with cancer. The objective was to compare the microparticulosome signature between patients presenting with thrombo-embolic event and those without. Methods: Patients with CRC and PC were prospectively included and divided in those with thrombo-embolic events (Group A) and those without (Group B).MPs were analyzed by flow cytometer, combining the analysis of Annexin V positive with characterization of their origin and determination of their procoagulant activities. D-dimer levels were measured in the same samples. Results: We included 118 patients, divided in 19 patients with thrombo embolic event and 99 patients without. Fibrin-bearing MPs levels were significantly higher in presence of thrombo-embolic events, contrary to D-dimers levels. Fibrin bearing MPs were more frequently produced by erythrocytes, endothelial cells or Ep-CAM+cells than platelets or leukocytes. Overall survival was shorter in case of thrombo-embolic events than without. The most frequent genes expressed by MPs derived from PC or CRC were implicated in metastatic diffusion of tumor cells, drug resistance, coagulation and inflammation. Conclusion: Circulating MPs, particularly fibrin-bearing MPs, could be used as a new biomarker to predict cancer-associated thrombo-embolic events and poor survival. PMID- 29228620 TI - Unfavorable efficacy to 131I ablation in BRAFV600E mutant papillary thyroid carcinoma with positive TgAb. AB - The BRAFV600E mutation has shown a close relationship of aggressiveness in papillary thyroid carcinoma (PTC), while it remains unclear about its influence on the therapeutic response. As a common clinicopathologic risk factor, thyroglobulin antibody (TgAb) may have a correlation of prognosis in PTC. The objective was to investigate the relationship between BRAFV600E mutation and TgAb, and their combined effect on efficacy to radioiodine remnant ablation (RRA). This was a retrospective study including 298 PTC patients and they were divided into four groups according to the combined status. The BRAFV600E mutation rates declined along with increasing TgAb levels in the entire cohort. The ablative efficacy in terms of success or failure rate was statistically different among four groups (89.7%, 74.1%, 67.5%, 57.8%, respectively, P=0.009), group with both positive BRAF and TgAb presented the lowest efficacy. The combined status was associated with the poor efficacy to RRA independently (P=0.029). Among patients with positive TgAb, the effect of RRA in reducing TgAb level might be weakened in BRAF mutant status. The combined status of BRAFV600E mutation and positive TgAb predicts low efficacy to RRA and might be served as an independent unfavorable prognostic factor for PTC. BRAF mutant might weaken the effect of RRA in reducing TgAb levels in PTCs. PMID- 29228621 TI - Synergism of ursolic acid and cisplatin promotes apoptosis and enhances growth inhibition of cervical cancer cells via suppressing NF-kappaB p65. AB - Objective: This study was designed to investigate the effect of combination of ursolic acid (UA) with cisplatin (DDP) on cervical cancer cell proliferation and apoptosis. Methods: The mRNA and protein expressions of nuclear factor-kappa B (NF-kappaB) p65 in cervical cancer cells were examined using RT-PCR and western blot. MTT and colony formation assays were performed to examine the DDP toxicity and the proliferation ability of cervical cancer cells. Cell morphology was observed by means of Hoechst33258 and transmission electron microscopy (TEM). The apoptosis rate and cell cycle were assessed through flow cytometry assay. Western blot was used to detect the expression of apoptosis-related molecules. Results: The mRNA and protein expressions of NF-kappaB p65 in cervical cancer cells were significantly higher than that in cervical epithelial cells. The combined treatment of UA and DDP inhibited cervical cancer cell growth and promoted apoptosis more effectively than DDP treatment or UA treatment alone (P < 0.05). Compared with the DDP group and UA group, the expressions of Bcl-2 and NF-kappaB p65 in DDP +UA group were decreased, while the expressions of Bax, Caspase-3 and PARP cleavage were observably increased. The expression of nuclear NF-kappaB p65 significantly reduced in UA group and DDP +UA group. si-p65 group displayed a decrease of cell proliferation ability and led to a significant reduction in the number of SiHa cell colony formation. Conclusion: The combination of UA with DDP could more effectively inhibit SiHa cells proliferation and facilitate cell apoptosis through suppressing NF-kappaB p65. PMID- 29228622 TI - Comparison between liver resection and liver transplantation on outcomes in patients with solitary hepatocellular carcinoma meeting UNOS criteria: a population-based study of the SEER database. AB - Liver resection (LR) and liver transplantation (LT) are potential curative treatment methods for early hepatocellular carcinoma (HCC). However, it is controversial which treatment is more beneficial to patients with solitary HCC meeting the United Network for Organ Sharing (UNOS) criteria (single lesion, diameter<=50mm, no vascular invasion, no extrahepatic metastasis). We retrieved patients with solitary HCC meeting UNOS criteria diagnosed between 2004-2013 from the Surveillance Epidemiology and End Results (SEER) database. Multivariate Cox proportional hazards regression models were used to evaluate the impact of surgery type (LR/LT) on overall survival (OS) and disease-specific survival (DSS) in both the whole study group and subgroups. Our analyses show that LT Patients had significantly superior OS (Adjusted HR (95% CI): 0.39 [0.26-0.59]) and DSS (Adjusted HR (95% CI): 0.19 [0.10-0.35]) than those receiving LR, although compared with the 288 patients receiving LR, the 258 patients receiving LT had younger age, smaller tumor size, and higher fibrosis score (P<0.001). Subgroup analyses identified significant interactions between surgery type (LR/LT) and gender (Male/Female) in both OS (P=0.02) and DSS (P=0.02). Male patients benefit more from LT compared with LR in both OS (Adjusted HR (95% CI): 0.29 [0.18-0.47]) and DSS (Adjusted HR (95% CI): 0.10 [0.05-0.21]), but there is no difference between patients receiving LT and LR in female patients. In conclusion, LT is associated with superior survival than LR in patients with solitary HCC meeting UNOS criteria. Moreover, male patients benefits more from LT than LR, while female patients do not show different outcomes between the two procedures. PMID- 29228624 TI - Platelet microparticle-mediated transfer of miR-939 to epithelial ovarian cancer cells promotes epithelial to mesenchymal transition. AB - Epithelial ovarian cancer (EOC) patients frequently suffer from thrombocytosis, which leads to a poor prognosis. However, the mechanism underlying platelet regulation of biological behavior in EOC remains unclear. The associations between clinicopathological characteristics and thrombocytosis in 171 EOC patients were studied, preoperative thrombocytosis was significantly associated with the stage, metastasis scope, level of preoperative CA125 and overall survival. When SKOV3 cells were cocultured with platelet microparticles (PMPs), the expression of molecules associated with epithelial-mesenchymal transition (EMT) was increased. The proliferation and migration of SKOV3 cells were also enhanced. Based on the miRNA microarray of the PMPs derived between thrombin stimulating and apoptotic platelets, we demonstrated that over-expression or complete knockdown of miR-939 in the SKOV3 cells strengthened or weakened EMT. Secretory phospholipase A2 type IIA (sPLA2-IIa) has been shown to mediate PMPs intake by SKOV3 cells. The knockdown of sPLA2-IIa in SKOV3 cells verified that PMPs were involved in crosstalk during the regulation of cancer cells by transferring miRNA. This study revealed an important role for PMPs in the crosstalk of platelets and cancer cells through miR-939 shedding mediated by sPLA2-IIa, which enables EOC to undergo EMT and enhances cancer progression. Our findings pave the way for developing a novel therapeutic strategy for EOC targets such as PMPs, miR-939 or sPLA2-IIa. PMID- 29228623 TI - Linking CREB function with altered metabolism in murine fibroblast-based model cell lines. AB - The cAMP-responsive element binding protein CREB is frequently overexpressed and activated in tumors of distinct histology, leading to enhanced proliferation, migration, invasion and angiogenesis as well as reduced apoptosis. The de regulated expression of CREB might be linked with transcriptional as well as post transcriptional regulation mechanisms. We show here that altered CREB expression levels and function are associated with changes in the cellular metabolism. Using comparative proteome-based analysis an altered expression pattern of proteins involved in the cellular metabolism in particular in glycolysis was found upon CREB down-regulation in HER-2/neu-transfected cell lines. This was associated with diminished expression levels of the glucose transporter 1, reduced glucose uptake and reduced glycolytic activity in HER-2/neu-transfected cells with down regulated CREB when compared to HER-2/neu+ cells. Furthermore, hypoxia-induced CREB activity resulted in changes of the metabolism in HER-2/neu transfected cells. Low pH values in the supernatant of HER-2/neu transformants were restored by CREB down-regulation, but further decreased by hypoxia. The altered intracellular pH values were associated with a distinct expression of lactate dehydrogenase, and its substrate lactate. Moreover, enhanced phosphorylation of CREB on residue Ser133 was accompanied by a down-regulation of pERK and an up regulation of pAKT. CREB promotes the detoxification of ROS by catalase, therefore protecting the mitochondrial activity under oxidative stress. These data suggest that there might exists a link between CREB function and the altered metabolism in HER-2/neu-transformed cells. Thus, targeting these altered metabolic pathways might represent an attractive therapeutic approach at least for the treatment of patients with HER-2/neu overexpressing tumors. PMID- 29228625 TI - Long noncoding RNA SFTA1P promoted apoptosis and increased cisplatin chemosensitivity via regulating the hnRNP-U-GADD45A axis in lung squamous cell carcinoma. AB - Chemotherapeutic insensitivity remains one of the major obstacles in clinical treatment of lung squamous cell carcinoma (LSCC). Recently, increasing evidence has suggested that long non-coding RNAs (lncRNAs) promote tumorigenesis in many cancer types. However, the potential biological roles and regulatory mechanisms of lncRNAs in response to cisplatin treatment are poorly understood. Here, we found that lncRNA SFTA1P (surfactant associated 1, pseudogene), highly expressed in lung, was down-regulated in LSCC tissues and could be induced upon cisplatin treatment in LSCC cells. Elevated SFTA1P induced apoptosis and enhanced the sensitivity to cisplatin of LSCC cells. We further identified that hnRNP-U (heterogeneous nuclear ribonucleoprotein U) was down-regulated in LSCCs and positively correlated with patients' poor prognosis as well as SFTA1P. Mechanistic studies revealed that SFTA1P could up-regulate hnRNP-U expression. In addition, we identified that hnRNP-U enhanced cisplatin-induced apoptosis through up-regulation of GADD45A, high expression of which was correlated with good prognosis in LSCC patients. Our findings demonstrated that SFTA1P might serve as a useful biomarker for LSCC diagnosis and a predictor for cisplatin chemotherapy response in patients with LSCC. PMID- 29228626 TI - Boosting the effects of hyperthermia-based anticancer treatments by HSP90 inhibition. AB - Hyperthermia - application of supra-physiological temperatures to cells, tissues or organs - is a pleiotropic treatment that affects most aspects of cellular metabolism, but its effects on DNA are of special interest in the context of cancer research and treatment. Hyperthermia inhibits repair of various DNA lesions, including double-strand breaks (DSBs), making it a powerful radio- and chemosensitizer, with proven clinical efficacy in therapy of various types of cancer, including tumors of head and neck, bladder, breast and cervix. Among the challenges for hyperthermia-based therapies are the transient character of its effects, the technical difficulties in maintaining uniformly elevated tumor temperature and the acquisition of thermotolerance. Approaches to reduce or eliminate these challenges could simplify the application of hyperthermia, boost its efficacy and improve treatment outcomes. Here we show that a single, short treatment with a relatively low dose of HSP90 inhibitor Ganetespib potentiates cytotoxic as well as radio- and chemosensitizing effects of hyperthermia and reduces thermotolerance in cervix cancer cell lines. Ganetespib alone, applied at this low dose, has virtually no effect on survival of non-heated cells. Our results thus suggest that HSP90 inhibition can be a safe, simple and efficient approach to improving hyperthermia treatment efficacy and reducing thermotolerance, paving the way for in vivo studies. PMID- 29228627 TI - Increased Jab1/COPS5 is associated with therapeutic response and adverse outcome in lung cancer and breast cancer patients. AB - Adjuvant chemotherapy has been established as standard treatment for advanced cancer among multidisciplinary therapies. A simple and instructive biomarker for therapeutic response and recurrence is needed to evaluate the therapeutic effect. Jab1/COPS5 level has been shown to be associated with tumor progression and poor outcomes in many types of cancer patients. This study aims to further evaluate the clinical and prognostic value of Jab1/COPS5 level as a biomarker in lung and breast cancer patients receiving adjuvant chemotherapy. In this study, data of 88 lung cancer and 76 breast cancer patients were retrospectively collected and analyzed to identify the relationship between the Jab1/COPS5 level and the clinical progression and outcome of these patients. Lung cancer patients with increased Jab1/COPS5 level tend to be non-responsive to chemotherapy. Relapsed breast cancer patients had an increased Jab1/COPS5 level and breast cancer patients with increased Jab1/COPS5 level had significantly shorter disease-free survival and overall survival. In a multivariate survival analysis, histological type and Jab1/COPS5 were associated with disease-free survival and overall survival. The Jab1/COPS5 level was found to be a possible biomarker for clinical response to chemotherapy in lung cancer patients and for postoperative relapse in breast cancer patients who received adjuvant chemotherapy. In conclusion, this study identified Jab1/COPS5 as novel prognostic markers for lung cancer and breast cancer. PMID- 29228628 TI - Drug sensitivity profiling identifies potential therapies for lymphoproliferative disorders with overactive JAK/STAT3 signaling. AB - Constitutive JAK/STAT3 signaling contributes to disease progression in many lymphoproliferative disorders. Recent genetic analyses have revealed gain-of function STAT3 mutations in lymphoid cancers leading to hyperactivation of STAT3, which may represent a potential therapeutic target. Using a functional reporter assay, we screened 306 compounds with selective activity against various target molecules to identify drugs capable of inhibiting the cellular activity of STAT3. Top hits were further validated with additional models including STAT3-mutated natural killer (NK)-cell leukemia/lymphoma cell lines and primary large granular lymphocytic (LGL) leukemia cells to assess their ability to inhibit STAT3 phosphorylation and STAT3 dependent cell viability. We identified JAK, mTOR, Hsp90 and CDK inhibitors as potent inhibitors of both WT and mutant STAT3 activity. The Hsp90 inhibitor luminespib was highly effective at reducing the viability of mutant STAT3 NK cell lines and LGL leukemia patient samples. Luminespib decreased the phosphorylation of mutant STAT3 at Y705, whereas JAK1/JAK2 inhibitor ruxolitinib had reduced efficacy on mutant STAT3 phosphorylation. Additionally, combinations involving Hsp90, JAK and mTOR inhibitors were more effective at reducing cell viability than single agents. Our findings show alternative approaches to inhibit STAT3 activity and suggest Hsp90 as a therapeutic target in lymphoproliferative disorders with constitutively active STAT3. PMID- 29228629 TI - Type 2 diabetes mellitus is more prevalent among patients with thyroid carcinoma and influences overall survival: a propensity score matching analysis. AB - The relationship between Type 2 Diabetes Mellitus(T2DM) and cancer risk has been investigated for more than a decade. Many types of cancer were confirmed to be related with T2DM. The aim of this study is to identify the relationship between T2DM and the prevalence and long-term survivals of Thyroid Carcinoma(TC) using propensity score matching. In present study, 1658 thyroid nodule patients who were diagnosis in Beijing Shijitan hospital were divided into two groups: the TC group (N = 455, 27.4%), and the benign thyroid nodule(BTN) group (N = 1203, 73.6%). Propensity scores analyses were used to compare the overall survival (OS) and recurrence-free survival (RFS) between patients with or without T2DM. After propensity scores analyses, the prevalance of T2DM was significantly increased in the TC group compared with BTN group. Of the 455 TC patients, with T2DM in thyroid carcinoma was associated with increasing 1-, 3-, 5-year OS rates from 98.8, 76.5, and 70.9% to 99.7, 92.2, and 82.7%, respectively (P=0.017). While the 1-, 3-, and 5-year RFS rates in the group with T2DM were 92.3, 69.5, and 58.3%, which were significantly lower than those in the group without T2DM (97.6, 82.7, and 72.4%, P=0.009). After propensity scores analyses, with T2DM was significantly associated with increased risks of OS and RFS in the entire TC cohort. PMID- 29228630 TI - Transplantation of iPS cell-derived neural progenitors overexpressing SDF-1alpha increases regeneration and functional recovery after ischemic stroke. AB - Ischemic stroke is a leading cause of human death and disability while clinical treatments are limited. The adult brain possesses endogenous regenerative activities that may benefit tissue repair after stroke. Trophic factors such as stromal cell-derived factor 1 alpha (SDF-1alpha) are upregulated in the ischemic brain, which promote endogenous regeneration. The regenerative response, however, is normally insufficient. Transplantation of exogenous cells has been explored as regenerative therapies. One promising cell type for transplantation is induced pluripotent stem (iPS) cells which are cells genetically reprogrammed from adult somatic cells. We hypothesized that transplanting neural progenitor cells derived from iPS cells (iPS-NPCs) could provide cell replacement and trophic support. The trophic factor SDF-1alpha was overexpressed in iPS-NPCs by lentiviral transduction to test if SDF-1alpha could increase regeneration in the ischemic brain. These SDF-1alpha-iPS-NPCs were differentiated in vitro to express mature neuronal and synaptic markers. Differentiated cells expressed functional Na+ and K+ channels, and fired action potentials. In the oxygen glucose deprivation (OGD) test, SDF-1alpha-iPS-NPCs survived significantly better compared to control iPS NPCs. In mice subjected to focal cerebral ischemia in the sensorimotor cortex, iPS-NPCs and SDF-1alpha-iPS-NPCs were intracranially transplanted into the ischemic cortex 7 days after stroke. Neuronal differentiation of transplanted cells was identified using NeuN 14 days after transplantation. Mice that received SDF-1alpha-iPS-NPCs had greater numbers of NeuN/BrdU and Glut-1/BrdU co-labeled cells in the peri-infarct area and improved locomotion compared to the control iPS-NPC transplantation. Thus, SDF-1alpha upregulation in transplanted cells may be a therapeutic strategy to enhance endogenous neurovascular repair after ischemic stroke in adult mice. PMID- 29228631 TI - Identification of differentially expressed genes, lncRNAs and miRNAs which are associated with tumor malignant phenotypes in hepatoblastoma patients. AB - Hepatoblastoma (HB) is one of the most common hepatic malignancies in the pediatric population. HB are composed of a variety of tumors, which derived from different origins and had varying clinical outcomes. However, the unclear underlying mechanisms of HB limited exploring novel biomarkers and effective therapeutic targets. We searched microarray datasets on Gene Expression Omnibus (GEO) database and selected GSE75271 and GSE75283 datasets for comprehensive analysis. Weighted gene correlation network analysis (WGCNA) was employed to identify genes which were associated with tumor malignant phenotypes, including HB subtypes, Cairo classification and tumor stage. Coexpression analysis of identified genes was also performed and lncRNA-miRNA-mRNA network was finally conducted. Our results showed that a total of 22 lncRNAs, 13 miRNAs and 66 mRNAs were identified to be associated with tumor malignant phenotypes. Mechanistically, these molecules might promote the malignant phenotypes via regulating metabolic pathways. Among of them, 6 miRNAs (hsa-miR-106b, hsa-miR 130b, hsa-miR-19a, hsa-miR-19b, hsa-miR-20a and hsa-miR-301a), 8 lncRNAs (NR_102317, XR_245338, XR_428373, XR_924945, XR_929728, XR_931611, XR_935074 and XR_946696), and 6 mRNAs (EGFR, GAREM, INSIG1, KRT81, SAR1B and SDC1) were selected to conduct a lncRNA-miRNA-mRNA network. Taken together, our findings provide evidence for exploring molecular mechanisms of HB. Those identified malignant phenotype-associated molecules might be potential biomarkers and anti cancer therapeutic targets in future. PMID- 29228632 TI - Survival benefit of anti-angiogenic agents in patients with previously treated advanced gastric or gastroesophageal junction cancer: a meta-analysis. AB - There is a debate as to whether anti-angiogenic molecular agents can produce survival benefits in patients with previously treated advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC). We performed this meta-analysis of randomized trials to evaluate the survival outcomes of an anti-angiogenic agent versus placebo in the salvage treatment of advanced GC or GEJC. Electronic databases were searched for eligible studies. From the four studies, 910 patients with previously treated advanced GC or GEJC were included in the meta-analysis. Compared with placebo, anti-angiogenic targeted agents significantly improved progression-free survival (hazard ratio = 0.37 [95% confidence interval, 0.26 0.53], P < 0.00001). In terms of overall survival, anti-angiogenic agents induced 36% reduction in the risk for death (hazard ratio = 0.64 [95% confidence interval, 0.48-0.86], P = 0.002). In conclusion, this meta-analysis demonstrates that anti-angiogenic agents can prolong survival in patients with previously treated advanced GC or GEJC. This finding suggests that anti-angiogenic therapy can be a considerable option in patients who are not candidates for further chemotherapy. PMID- 29228634 TI - Body mass index and incidence of nonaggressive and aggressive prostate cancer: a dose-response meta-analysis of cohort studies. AB - The relationship between body mass index (BMI) and incidence of prostate cancer is still inconclusive. We performed a dose-response meta-analysis of eligible cohort studies to evaluate potential association of BMI with prostate cancer risk by subtype of prostate cancer (nonaggressive and aggressive). A comprehensive literature search was performed in PubMed and Web of Science databases through March 22, 2017. Linear and non-linear dose-response meta-analyses were carried out to evaluate the effects of BMI on incidence of prostate cancer. A total of 21 cohort or nested case-control studies (17 for nonaggressive and 21 for aggressive prostate cancer) were included in this meta-analysis. For nonaggressive prostate cancer, the pooled relative risk (RR) per 5 kg/m2 increment of BMI with 95% confidence interval (CI) was 0.96 (95% CI 0.92-1.00). Sensitivity analysis indicated that this result was not robust and steady. For aggressive prostate cancer, a significant linear direct relationship with BMI (RR, 1.07; 95% CI 1.03 1.12) for every 5 kg/m2 increase was observed. Statistically significant heterogeneity was detected for nonaggressive prostate cancer (P = 0.020, I2 = 46.1%) but not for aggressive prostate cancer (P = 0.174, I2 = 22.4%). In conclusion, BMI level may be positively associated with aggressive prostate cancer risk. Further large prospective cohort studies are warranted to confirm the findings from our study. PMID- 29228635 TI - Prognostic impact and implications of extracapsular lymph node spread in Borrmann type IV gastric cancer. AB - The purpose of this study was to evaluate the relationship between extracapsular lymph node spread (ECS) and clinicopathology and its influence on the prognosis in patients with Borrmann type IV gastric cancer. Between 2002 and 2014, clinical data were reviewed from 486 patients with Borrmann type IV gastric cancer who underwent curative resection. Of the 486 patients, lymph node metastasis was found in 456. ECS was detected in 213 (46.7%) patients with lymph node metastasis. A positive lymph node with ECS was significantly correlated with the N category, lymphatic/venous invasion, tumor location, and TNM stage. For the whole patients, the mean OS was 34.7 months, and the 5-year OS rate was 15.5%. The 5-year OS rate of node-negative patients was 48%, for node-positive patients without ECS 18.7%, and for node-positive patients with ECS 5.7% (P = 0.000). In a multivariate analysis, adjusted for tumor location, lymphatic/venous invasion, body mass index (BMI), and TNM stages, ECS remained an independent prognostic factor. For patients with the same N category and TNM stage, those with ECS still had a worse survival rate. Recurrent sites were confirmed in 367 patients. The most frequent recurrent site was the peritoneum. There was a significant difference between ECS+ (N = 150) and ECS- (N = 142) patients (P = 0.008). Our results suggested that ECS was an independent prognostic value for Borrmann type IV gastric cancer patients with curative resection and a subgroup indicated a significantly worse long-term survival for patients with the same N or TNM stages. ECS+ was an adverse factor for peritoneal metastasis. PMID- 29228633 TI - Associations between inflammatory gene polymorphisms (TNF-alpha 308G/A, TNF-alpha 238G/A, TNF-beta 252A/G, TGF-beta1 29T/C, IL-6 174G/C and IL-10 1082A/G) and susceptibility to osteosarcoma: a meta-analysis and literature review. AB - Associations between inflammatory gene polymorphisms (TNF-alpha 308G/A, TNF-alpha 238G/A, TNF-beta 252A/G, TGF-beta1 29T/C, IL-6 174G/C and IL-10 1082A/G) and osteosarcoma (OS) risk remain unclear. We conducted a systematic search to retrieve studies that investigated associations between inflammatory gene polymorphisms and OS risk. Nine studies that met the inclusion criteria were finally recruited in this meta-analysis. Overall, there was a significant association between TNF-alpha 308G/A, IL-10 1082A/G and OS risk, while there was no significant association between TNF-alpha 238G/A, TNF-beta 252A/G and IL-6 174G/C and OS risk. Our subgroup analysis showed a significant association between IL-6 174G/C and IL-10 1082A/G and OS risk in Asians, while no such significant correlation was observed with TNF-alpha 308G/A, TNF-alpha 238G/A, TNF beta 252A/G and TGF-beta1 29T/C polymorphisms. In Caucasians, there was a significant association between TNF-alpha 238G/A and the decreased incidence of OS. In conclusion, inflammatory gene polymorphisms play a key role in the occurrence and progression of OS. IL-6 174G/C polymorphism was obviously associated with OS risk in Asians, while TNF-alpha 238G/A polymorphism seemed to be associated with the decreased susceptibility to OS in Caucasians as Altman and Bland test indicated. Although controversial results were observed between IL-10 1082A/G and OS risk in Asians and Caucasians, it is difficult to make a definite conclusion about the role of IL-10 1082A/G polymorphism in the etiology of OS because our Altman and Bland test showed no good evidence to support a different effect in Asians and Caucasians. PMID- 29228636 TI - The efficacy of 40 mg versus dose de-escalation to less than 40 mg of afatinib (Giotrif) as the first-line therapy for patients with primary lung adenocarcinoma harboring favorable epidermal growth factor mutations. AB - The choice of a first-line therapy for lung cancer is a crucial decision that can impact the survival as well as the quality of life of a patient. Inhibitors of epidermal growth factor receptor (EGFR) such as afatinib, erlotinib, and gefitinib have previously been used to treat non-small cell lung cancer harboring favorable EGFR mutations. Although afatinib has greater efficacy than other EGFR inhibitors, adverse events related to its use can result in the discontinuation of the therapy. In this study, we compared the therapeutic efficacy in lung cancer patients of a regimen of 40 mg/day of afatinib with that of a lower dose regimen of <40 mg/day resulting either from a lower starting dose of 30 mg/day or dose adjustment. Seventy-nine patients were treated with 40 mg/day and 67 received de-escalated doses of <40 mg/day. There was no significant difference in the clinical characteristics of the two groups except that the proportion of patients with a body weight of 50 kg or more was greater in the 40 mg/day group. Otherwise, there were no significant differences between the two groups in the average time to treatment failure (TTF), the rates at which the administration of a second-line therapy was necessary, or the frequency and severity of adverse events. Overall, these results suggest that it is possible to calibrate the dosage of afatinib to suit individual patient parameters such as low body weight, and that such calibration can be advised based on the given patient's individual experience of the drug. PMID- 29228637 TI - Sorafenib improves lipiodol deposition in transarterial chemoembolization of Chinese patients with hepatocellular carcinoma: a long-term, retrospective study. AB - Objective: Though synergy of sorafenib and transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC) is well discussed in previous reports, association of lipiodol retention by sorafenib addition to TACE with the survival outcomes remain elusive. Therefore, we studied the impact of sorafenib addition to TACE on survival outcomes mediated by lipiodol retention. Materials and Methods: This is a long-term, retrospective, single-center study using medical records of patients diagnosed with HCC at the Department of Interventional Radiology of Zhengzhou University Affiliated Cancer Hospital (China) between April 2004 and March 2012. Results: Lipiodol deposition of > 50% was significantly increased in TACE + sorafenib group (70.87%) compared to TACE alone group (45.11%) (P = 0.0001). Significant increase in lipiodol deposition with sorafenib treatment was observed compared to TACE alone group (OR = 0.449, P = 0.041). The median overall survival in TACE + sorafenib and TACE alone groups were 38 months [95% CI = 9.772-56.228] and 31 months [95% CI = 21.855-40.145] respectively. Also, the hazard of death was comparatively greater in TACE alone group than TACE + sorafenib group [HR = 1.071]. Response rate to the therapy significantly increased after sorafenib administration to TACE patients, [compared to TACE alone treatment [69/103 (66.99%)] vs 55/133 (41.35%)], P = 0.0001. Conclusions: Lipiodol deposition is significantly increased upon sorafenib addition after TACE. However, there was no significant impact of lipiodol deposition on the survival benefits exerted by the synergistic combination and hence, future prospective trails are warranted to validate the findings of this study. PMID- 29228638 TI - Thoracic radiation-induced pleural effusion and risk factors in patients with lung cancer. AB - The risk factors and potential practice implications of radiation-induced pleural effusion (RIPE) are undefined. This study examined lung cancer patients treated with thoracic radiation therapy (TRT) having follow-up computed tomography (CT) or 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. Increased volumes of pleural effusion after TRT without evidence of tumor progression was considered RIPE. Parameters of lung dose-volume histogram including percent volumes irradiated with 5-55 Gy (V5-V55) and mean lung dose (MLD) were analyzed by receiver operating characteristic analysis. Clinical and treatment-related risk factors were detected by univariate and multivariate analyses. 175 out of 806 patients receiving TRT with post-treatment imaging were included. 51 patients (24.9%) developed RIPE; 40 had symptomatic RIPE including chest pain (47.1%), cough (23.5%) and dyspnea (35.3%). Female (OR = 0.380, 95% CI: 0.156-0.926, p = 0.033) and Caucasian race (OR = 3.519, 95% CI: 1.327-9.336, p = 0.011) were significantly associated with lower risk of RIPE. Stage and concurrent chemotherapy had borderline significance (OR = 1.665, p = 0.069 and OR = 2.580, p = 0.080, respectively) for RIPE. Patients with RIPE had significantly higher whole lung V5-V40, V50 and MLD. V5 remained as a significant predictive factor for RIPE and symptomatic RIPE (p = 0.007 and 0.022) after adjusting for race, gender and histology. To include, the incidence of RIPE is notable. Whole lung V5 appeared to be the most significant independent risk factor for symptomatic RIPE. PMID- 29228639 TI - Role of melatonin combined with exercise as a switch-like regulator for circadian behavior in advanced osteoarthritic knee. AB - Here, we show the role of melatonin combined with or without exercise as a determinant of multicellular behavior in osteoarthritis. We address the relationship between the molecular components governing local circadian clock and changes in the osteoarthritic musculoskeletal axis. Melatonin was injected subcutaneously in animals with advanced knee osteoarthritis (OA) for 4 weeks. Concurrently, moderate treadmill exercise was applied for 30 min/day. Morphometric, histological, and gene/protein-level analyses were performed in the cartilage, synovium, bone, and gastrocnemius muscle. Primary cultured chondrocytes repeatedly exposed to TNF-alpha were used in an in vitro study. The symptoms of OA include gait disturbance, osteophyte formation, and abnormal metabolism of the extracellular matrix (ECM) of the cartilage. Low-level expression of clock genes was accompanied by aberrant changes in cartilage specimens. Nanomolar doses of melatonin restored the expression of clock controlled genes and corrected the abnormal chondrocyte phenotype. Melatonin combined with or without exercise prevented periarticular muscle damage as well as cartilage degeneration. But prolonged melatonin administration promoted the proteolytic cleavage of RANKL protein in the synovium, leading to severe subchondral bone erosion. These musculoskeletal changes apparently occurred via the regulation of molecular clock components, suggesting a role of melatonin as a switch-like regulator for the OA phenotype. PMID- 29228640 TI - Comparison of primary endpoints between publications, registries, and protocols of phase III cancer clinical trials. AB - Background: Decisions by leading journals to require trial registration and to make protocols of phase III randomized clinical trials (RCTs) publicly accessible were landmark events in clinical trial reporting. Materials and Methods: We identified phase III cancer RCTs published between 2013 and 2015 in New England Journal of Medicine (NEJM), The Lancet, The lancet Oncology, JAMA and Journal of Clinical Oncology (JCO). Results: We identified 345 reports of phase III RCTs of which 217 (62.9%) had available protocols. The availability rates for NEJM, The Lancet, The Lancet Oncology, JAMA and JCO were 98.0%, 33.3%, 22.7%, 55.6% and 88.3%, respectively. Journal and publication year were significantly associated with protocol availability. Eight of 215 trials (3.7%) with English language protocols had a discrepancy in primary endpoints between publication and protocol. Discrepancies of primary endpoints between protocol and registration existed in 16 (7.7%) of 209 trials. Conclusions: The policy of providing protocols with articles reporting RCTs has not been enforced rigorously. Selective reporting of primary endpoints only remains in a small fraction of phase III trials. Further improvement in consistency between primary endpoints registered and that in protocol is necessary. PMID- 29228641 TI - BRCA mutations in the manifestation and treatment of ovarian cancer. AB - BRCA genes are important for the integrity and stability of genetic material and play key roles in repairing DNA breaks via high fidelity homologous recombination. BRCA mutations are known to predispose carriers to gynecological malignancies, accounting for a majority of hereditary OC cases. Known to be lethal, OC is difficult to detect and control. Testing for BRCA mutations is a key step in the risk assessment, prognosis, treatment and prevention of OC and current clinical guidelines recommend BRCA mutation testing for all OCs of epithelial origin. Studies have established that ovarian tumors harboring BRCA mutations have distinct molecular and histo-pathological features that can be exploited for effective, targeted treatment. Deficiencies in DNA repair pathways that arise as a result of BRCA mutations make them hypersensitive to DNA-damaging treatments such as platinum chemotherapy and PARP inhibitors. Different combinations of treatment regimens which have the potential to greatly improve prognosis and disease outcomes are currently being evaluated. However, the issue of developing resistance to these treatments remains unresolved. This review emphasizes unique features of BRCA mutated OC and outlines the lay of the land in terms of diagnosis and treatment, while aiming to unravel the challenges that are part of its management. PMID- 29228642 TI - Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer. AB - The membrane-bound molecules programmed death 1 (PD-1) and its ligand PD-L1 (PD 1/PD-L1) belong to the immune checkpoint pathway. PD-1 pathway downregulates effector T cells in immune response, thereby causing immune suppression. Recent studies have revealed that membrane-bound PD-1 and PD-L1 also have soluble forms. These soluble forms increase the complexity and diversity of the composition and function of the PD-1/PD-L1 signaling pathway. However, the exact roles of these molecules remain unknown. The objective of this systematic review was to elucidate the biological significance of soluble PD-1/PD-L1 in human cancers and evaluate whether they are potential diagnostic, therapeutic, or prognostic biomarkers. We expect to provide new clues for future research on soluble PD-1/PD L1 pathway in human malignant tumors. PMID- 29228643 TI - Estrogen and estrogen receptors in the modulation of gastrointestinal epithelial secretion. AB - Gastrointestinal (GI) epithelial ion transport is physiologically important in many aspects of humans, such as in maintaining fluid balance of whole body, and also plays a role in the development and progression of common GI disease. Estrogen and estrogen receptors have been shown to modulate the activity of epithelial ion secretion in GI tract. This review aims to address the current state of knowledge about the role of estrogen and estrogen receptors in modulation of GI epithelial secretion and to elucidate the underlying mechanisms. We highlight the recent findings regarding the importance of estrogen and estrogen receptors in GI epithelia protection and body fluid balance by modulation of gastrointestinal epithelial HCO3- and Cl- secretion, especially current information about the regulatory mechanisms of duodenal HCO3- secretion based on our study in this field. Since there are no reviews on this topic but only few papers to address the main issues, we hope to timely provide new perspectives for the association between estrogen and GI disease. PMID- 29228644 TI - Exosomes in diagnosis and therapy of prostate cancer. AB - Exosomes are small vesicular bodies released by a variety of cells. Exosomes contain miRNAs, mRNAs and proteins with the potential to regulate signaling pathways in recipient cells. Exosomes deliver nucleic acids and proteins to mediate the communication between cancer cells and stroma cells. In this review, we summarize recent progress in our understanding of the role of exosomes in prostate cancer. The tumorigenesis, metastasis and drug resistance of prostate cancer are associated with the cargos of exosomes such as miRNAs, lncRNAs and proteins. In addition, prostate cancer cells modulate surrounding stromal cells via the exosomes. Affected stromal cells employ the exosomes to modulate microenvironment and promote tumor growth and metastasis. Exosomes derived from prostate cancer cells contribute to cancer chemoresistance. The lipid bilayer membrane of the exosomes makes them promising carriers of drugs and other therapeutic molecules targeting prostate cancer. Furthermore, exosomes can be detected and isolated from various body fluids for the diagnosis of prostate cancer. PMID- 29228645 TI - Pro-invasive properties of Snail1 are regulated by sumoylation in response to TGFbeta stimulation in cancer. AB - Transforming growth factor beta (TGFbeta) is a key regulator of epithelial-to mesenchymal transition (EMT) during embryogenesis and in tumors. The effect of TGFbeta, on EpsilonMUTau, is conveyed by induction of the pro-invasive transcription factor Snail1. In this study, we report that TGFbeta stimulates Snail1 sumoylation in aggressive prostate, breast and lung cancer cells. Sumoylation of Snail1 lysine residue 234 confers its transcriptional activity, inducing the expression of classical EMT genes, as well as TGFbeta receptor I (TbetaRI) and the transcriptional repressor Hes1. Mutation of Snail1 lysine residue 234 to arginine (K234R) abolished sumoylation of Snail1, as well as its migratory and invasive properties in human prostate cancer cells. An increased immunohistochemical expression of Snail1, Sumo1, TbetaRI, Hes1, and c-Jun was observed in aggressive prostate cancer tissues, consistent with their functional roles in tumorigenesis. PMID- 29228646 TI - Discordance of pathological thin melanoma thickness and T stage in SEER registry: impacts on clinical management and research directions. AB - Background: Ultrathin melanoma was previously demonstrated to have higher risk for melanoma-specific mortality using SEER database. However, these guideline changing conclusions has been recently challenged by miscoding of thickness. This present study was performed to assess the prognosis of thin and ultrathin melanoma using only surgically-treated, pathologically confirmed and after removal of discordant cases. Methods: Melanoma patients from SEER database who were initially diagnosed with histologically confirmed and surgically treated melanoma from 1998 to 2012 were included. Subjects with discordance between T stage and tumor thickness were excluded. Kaplan-Meier curves, log-rank test and multivariate Cox proportional hazards regression models were used. Results: 55,754 patients met the strict inclusion criteria, but 16 (0.02%) and 803 (1.4%) patients were removed due to T0 stage and discordance between T stage and thickness, respectively. Therefore, 54,935 patients entered the analyses, among which 52,751 were LN negative and 2,184 were LN positive. In either overall or LN negative patients, a straightforward dose-effect relationship of larger thickness with increasing mortality was observed. In contrast, in LN positive patients, the T1 subgroup demonstrated a similar survival with tumors in T2 mm subgroup. Multivariable analysis revealed same pattern, and significant interaction between T stage and LN involvement was found. Further categorizing T1 melanoma into 10 equal 0.10 mm increments demonstrated an unexpected "N"-shaped pattern of mortality in overall and LN negative ultrathin melanoma but not in LN positive melanoma. Conclusions: No difference in mortality was observed in T1-3 tumors with LN involvement. External and independent validation studies are warranted. PMID- 29228647 TI - Timing of transcription during the cell cycle: Protein complexes binding to E2F, E2F/CLE, CDE/CHR, or CHR promoter elements define early and late cell cycle gene expression. AB - A central question in cell cycle control is how differential gene expression is regulated. Timing of expression is important for correct progression through the cell cycle. E2F, CDE, and CHR promoter sites have been linked to transcriptional repression in resting cells and activation during the cell cycle. Further, the DREAM complex binds CHR or CDE/CHR elements of G2/M genes resulting in repression during G0/G1. Here, we show that DREAM also binds to E2F sites of S phase genes in quiescence and upon p53 activation. Furthermore, we describe a novel class of promoter sites, the CHR-like elements (CLE), which can support binding of DREAM to E2F elements. Activation of such S phase genes is achieved through binding of E2F1-3/DP complexes to E2F sites. In contrast, the activating MuvB complexes MMB and FOXM1-MuvB bind to CHR elements and mediate peak expression in G2/M. In conclusion, data presented here in combination with earlier results leads us to propose a model that explains how DREAM can repress early cell cycle genes through E2F or E2F/CLE sites and late genes through CHR or CDE/CHR elements. Also p53-dependent indirect transcriptional repression through the p53-p21-Cyclin/CDK DREAM-E2F/CLE/CDE/CHR pathway requires DREAM binding to E2F or E2F/CLE sites in early cell cycle genes and binding of DREAM to CHR or CDE/CHR elements of late cell cycle genes. Specific timing of activation is achieved through binding of E2F1-3/DP to E2F sites and MMB or FOXM1-MuvB complexes to CHR elements. PMID- 29228648 TI - Risk factors for postoperative renal dysfunction following open surgical repair of abdominal aortic aneurysms retrospective analysis. AB - Objectives: To identify the risk factors for postoperative renal dysfunction after open surgical repair (OSR) of abdominal aortic aneurysms (AAAs) and to establish a scoring system. Results: The overall 30-day mortality rates were 22.0%(ruptured) vs 2.6% (unruptured), respectively. For the ruptured group, the independent risk factors were hemodynamic instability (P = 0.002) blood loss >1 L (P = 0.041) and preoperative creatinine >150 MUmol/L (P < 0.001). By contrast, for the unruptured group, factors were smoking (P = 0.028), blood loss >1 L (P = 0.018), and antihypertensive drugs (P < 0.001). The areas under the curve of the WCRDA scoring system are 0.794 (95% confidence interval (CI) 0.686-0.902, P < 0.001) and 0.811 (95% CI 0.691-0.932, P < 0.001) for the ruptured and unruptured groups, respectively. Conclusions: Hemodynamic instability, blood loss >1 L and Hb <90 g/L are independent risk factors for postoperative renal dysfunction following rAAA OSR, whereas smoking, blood loss >1 L, and antihypertensive drugs are independent risk factors. WCRDA performs well in predicting postoperative renal dysfunction. Materials and Methods: 287 patients from the Vascular Department of West China Hospital, Sichuan University, who were planned to perform OSR for AAA from November 2003 to January 2017. 274 patients underwent OSR for AAA were finally included in the study. A total of 118 patients had ruptured AAA and 156 unruptured AAA.The patients were divided into the ruptured and unruptured groups. Logistic regression was used to identify the independent risk factors for postoperative renal dysfunction. The receiver operating characteristic curve was used to evaluate the scoring system. PMID- 29228649 TI - Combination of dual serum fluorescence, AFP and hepatic function tests is valuable to identify HCC in AFP-elevated liver diseases. AB - Serum alpha-fetoprotein (AFP) levels elevated in benign liver diseases (BLD) represent a challenge in hepatocellular carcinoma (HCC) diagnosis. The present study aimed to develop a simple method to identify HCC in AFP-elevated liver diseases based on combining serum fluorescence and general clinical data. Serum specimens and clinical data were collected from 201 HCC and 117 BLD (41 liver cirrhosis, 76 chronic hepatitis) patients with abnormal serum AFP levels. Dual serum fluorescence (autofluorescence and cell-free DNA-related fluorescence) intensities were sequentially measured and expressed as 6 fluorescence indicators. The diagnostic value of these fluorescence and clinical data were evaluated alone and in combination by the area under receiver operating characteristic curve (AUROC). All fluorescence indicators significantly differed between HCC and BLD and some of them were more valuable for diagnosing HCC than AFP (AUROC 0.782-0.801 vs. 0.752). The diagnostic model established with fluorescence indicators, AFP, hepatic function tests and age showed that AUROC, sensitivity, specificity and accuracy were 0.958 (95% CI 0.936-0.979), 92.0%, 88.9% and 92.3%, respectively, and positive rates in AFP-negative, early and small HCCs were 73.8%, 81.6% and 74.3%, respectively. In conclusion, the combination of dual serum fluorescence, AFP, hepatic function tests and age is simple and valuable for identifying HCC in serum AFP-elevated liver diseases. PMID- 29228650 TI - Ultrasensitive plasma ctDNA KRAS assay for detection, prognosis, and assessment of therapeutic response in patients with unresectable pancreatic ductal adenocarcinoma. AB - Precision oncology requires sensitive and specific clinical biomarkers. Carbohydrate Antigen 19-9 (CA19-9) is widely used in pancreatic ductal adenocarcinoma (PDA) but lacks sensitivity and specificity. Nearly all PDAs harbor somatic KRAS mutations, nominating circulating tumor DNA (ctDNA) KRAS as an alternative disease biomarker, however, variable clinical performance has limited its clinical utility. We applied an ultrasensitive, PCR mutation enrichment, next generation sequencing ctDNA KRAS assay in a large cohort of patients with unresectable PDA (N = 189) recruited to the BIOPAC study between 2008-2015. Baseline and longitudinal serum CA19-9 and plasma ctDNA KRAS were correlated with time to progression (TTP) and overall survival (OS). Baseline ctDNA KRAS detection rate was 93.7% (86.4% in patients with non-elevated CA19-9). ctDNA KRAS and CA19-9 were positively correlated yet independently associated with TTP and OS (ctDNA KRAS p = 0.0018 and 0.0014; CA19-9 p = 0.0294 and 0.0007, respectively). A generated model quantitating longitudinal ctDNA KRAS correctly assessed greater than 80% of patient responses. Quantitative detection of KRAS ctDNA is an informative prognostic biomarker, complementary to CA19-9 in patients with unresectable PDA. Longitudinal ctDNA KRAS may inform therapeutic decision making and provides a kinetically dynamic and quantitative metric of patient response. PMID- 29228651 TI - Dietary feeding of freeze-dried whole cranberry inhibits intestinal tumor development in Apcmin/+ mice. AB - It is increasingly perceived that dietary components have been linked with the prevention of intestinal cancer. Cranberry is a rich source of phenolic constituents and non-digestible fermentable dietary fiber, which shows anti proliferation effect in colorectal cancer cells. Herein, we investigated the efficacy of long-term cranberry diet on intestinal adenoma formation in Apcmin/+ mice. Apcmin/+ mice were fed a basal diet or a diet containing 20% (w/w) freeze dried whole cranberry powder for 12 weeks, and the number and size of tumors were recorded after sacrifice. Our results showed that cranberry strongly prevented the growth of intestinal tumors by 33.1%. Decreased cell proliferation and increased apoptosis were observed in tumors of cranberry-fed mice. Cranberry diet reduced the expression profile of colonic inflammatory cytokines (IFN-gamma, IL 1beta and TNF-alpha) accompanied with increased levels of anti-inflammatory cytokines (IL-4 and IL-10). Moreover, the number of colonic goblet cells and MUC2 production were increased, and the intestinal barrier function was also improved. In addition, cranberry diet increased caecal short chain fatty acids concentrations, and down-regulated epidermal growth factor receptor signaling pathway. These data firstly show the efficacy and associated mechanisms of cranberry diet on intestinal tumor growth in Apcmin/+ mice, suggesting its chemopreventive potential against intestinal cancer. PMID- 29228652 TI - Clinical characteristics and programmed cell death ligand-1 expression in adenocarcinoma in situ and minimally invasive adenocarcinoma of lung. AB - Objectives: According to the IASLC/ATS/ERS 2011 classification, there are two new conceptions of lung adenocarcinoma, adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), which are very early stages of lung adenocarcinoma. This study aimed to analyze clinical features of AIS and MIA and determine the expression profile of PD-L1 in AIS and MIA. Results: In all 274 patients, 77 were diagnosed as AIS and 197 as MIA. We accidentally found 4 patients with recurrence, which were all MIA. The median age of the patients at diagnosis was both 52 years. 71.4% were female in AIS as while as 71.1% in MIA. 36.4% patients were observed with ever symptoms in AIS and 28.9% in MIA. 12.9% and 8.6% had smoking history respectively in AIS an MIA. All AIS and MIA cases were PD-L1 negative. There was significant association between symptoms and more mild progression of nodules in chest CT before surgery. Materials and Methods: We analyzed some clinical features of 274 patients including age, sex, smoking history, family history, surgery, EGFR mutation, ALK, ROS-1, serum CEA level et al. The expression of PD-L1 was evaluated by immunohistochemical analysis in 37 specimens of MIA and 17 specimens of AIS. Conclusions: There are no significant differences between AIS and MIA in clinical features. AIS and MIA almost do not express PD-L1 protein and without any lymph node metastasis. The surgery intervention is supposed to be as small as possible. PMID- 29228653 TI - Overexpression of CAPN2 promotes cell metastasis and proliferation via AKT/mTOR signaling in renal cell carcinoma. AB - The calpain 2 (CAPN2) is upregulated in various malignant carcinomas. Previous studies have reported that CAPN2 functioned as an oncogenic factor in human cancers. However, its clinical role and potential effects on cell metastasis and proliferation in renal cell carcinoma (RCC) remain unknown. In this study, we evaluated the mRNA and protein levels of CAPN2 in human RCC specimens, matched normal specimens, and RCC cell lines using quantitative Real-time PCR (RT-PCR) and western blot. Immunohistochemistry of 74 RCC tissues in a tissue microarrays (TMAs) and normal kidney tissues were performed. Kaplan-Meier survival curve analyses were conducted to measure the correlation between CAPN2 and tumor prognosis. Cell migration, invasion and proliferation were detected by transwell assays and Cell Counting Kit-8 (CCK-8) assays. CAPN2 exhibited a significant overexpression in human RCC tissues and cell lines compared with adjacent non tumor tissues and normal human proximal tubule epithelial cell line HK-2. Strong staining of CAPN2 was associated with higher clinical stage and histological grade. In addition, sh-CAPN2 could significantly inhibit migration, invasion and proliferation of 769-P and CAKI-1 cells. Conversely, increased cell biological behaviors were observed in CAPN2-OV CAKI-2 cells. Moreover, the subsequent mechanism investigation suggested that CAPN2 promoted tumor progression by activating AKT/mTOR signaling, enhancing epithelial mesenchymal transition (EMT) and MMP9 levels. The present study indicates that CAPN2 may act as a prominent indicator for RCC progression and a novel therapeutic target for RCC patients. PMID- 29228654 TI - Lack of chemopreventive effects of P2X7R inhibitors against pancreatic cancer. AB - Pancreatic cancer (PC) is an almost uniformly lethal disease with inflammation playing an important role in its progression. Sustained stimulation of purinergic receptor P2X7 drives induction of NLRP inflammasome activation. To understand the role of P2X7 receptor and inflammasome, we performed transcriptomic analysis of p48Cre/+-LSL-KrasG12D/+ mice pancreatic tumors by next generation sequencing. Results showed that P2X7R's key inflammasome components, IL-1beta and caspase-1 are highly expressed (p < 0.05) in pancreatic tumors. Hence, to target P2X7R, we tested effects of two P2X7R antagonists, A438079 and AZ10606120, on pancreatic intraepithelial neoplasms (PanINs) and their progression to PC in p48Cre/+-LSL KrasG12D/+ mice. Following dose optimization studies, for chemoprevention efficacy, six-week-old p48Cre/+-LSL-KrasG12D/+ mice (24-36/group) were fed modified AIN-76A diets containing 0, 50 or 100 ppm A438079 and AZ10606120 for 38 weeks. Pancreata were collected, weighed, and evaluated for PanINs and PDAC. Control diet-fed male mice showed 50% PDAC incidence. Dietary A438079 and AZ10606120 showed 60% PDAC incidence. A marginal increase of PanIN 3 (carcinoma in-situ) was observed in drug-treated mice. Importantly, the carcinoma spread in untreated mice was 24% compared to 43-53% in treatment groups. Reduced survival rates were observed in mice exposed to P2X7R inhibitors. Both drugs showed a decrease in caspase-3, caspase-1, p21 and Cdc25c. Dietary A438079 showed modest inhibition of P2X7R, NLRP3, and IL-33, whereas AZ10606120 had no effects. In summary, targeting the P2X7R pathway by A438079 and AZ10606120 failed to show chemopreventive effects against PC and slightly enhanced PanIN progression to PDAC. Hence, caution is needed while treating high-risk individuals with P2X7R inhibitors. PMID- 29228655 TI - LncRNA-SVUGP2 suppresses progression of hepatocellular carcinoma. AB - Numerous studies indicate that long noncoding RNAs (lncRNAs) are dysregulated in hepatocellular carcinoma (HCC) and might serve as potential diagnostic biomarkers and therapeutic targets of HCC. Therefore, it is interesting to globally identify the lncRNAs altered in HCC. In our study, we used microarray to profile the levels of lncRNAs and mRNAs in three pairs of HCC and their adjacent noncancerous samples. We found lncRNA-SVUGP2, which is a splice variant of the UGP2 gene, was down-regulated in HCC samples and correlates with a better prognosis in patients with HCC. Overexpression of lncRNA-SVUGP2 in HepG2 and Hep3B liver cancer cells suppresses cell proliferation in vitro and tumor growth in vivo. Moreover, lncRNA SVUGP2 suppresses the invasion ability of liver cancer cell lines and downregulates the mRNA and protein levels of MMP2 and 9. Additionally, lncRNA SVUGP2 positively or negatively correlates with many mRNAs in liver cancer tissues, indicating it is multifunctional in regulating carcinogenesis. PMID- 29228656 TI - Increased PDGFR-beta and VEGFR-2 protein levels are associated with resistance to platinum-based chemotherapy and adverse outcome of ovarian cancer patients. AB - Despite frequent initial response rates of epithelial ovarian cancer to platinum based chemotherapy the majority of patients develop drug resistance. Our aim was to evaluate differential expression of signaling-pathway proteins in platinum sensitive versus platinum-resistant primary epithelial ovarian cancer specimens to identify predictive biomarkers for treatment response. 192 patients were studied comprising of independent training (n = 89) and validation (n = 103) cohorts. Full-length proteins were extracted from paraffin-embedded samples including multiple regions per tumor to account for intratumoral heterogeneity. Quantitative reverse-phase-protein-arrays were used to analyze protein and phospho-protein levels of 41 signaling molecules including growth-factor receptors, AKT and MAPK signaling pathways as well as angiogenesis and cell adhesion. Platinum-resistant ovarian cancers (56/192) demonstrated significantly higher intratumoral levels of the angiogenesis-associated growth-factor receptors PDGFR-beta and VEGFR2 compared to platinum-sensitive tumors. In addition, patients with high PDGFR-beta expression had significantly shorter overall and progression-free survival (HR 3.6 and 2.4; p < 0.001). The prognostic value of PDGFR-beta and VEGFR2 was confirmed in publicly available microarray-datasets. High intratumoral levels of the angiogenesis-related growth-factor receptors PDGFR-beta and VEGFR2 might serve as novel predictive biomarkers to identify primary resistance to platinum-based chemotherapy. Those ovarian cancer patients might particularly benefit from additional anti-vascular therapy including anti VEGF antibody or receptor tyrosine-kinase-inhibitor therapy. PMID- 29228657 TI - Alpha-glucosidase inhibitor use is associated with decreased colorectal neoplasia risk in patients with type 2 diabetes mellitus receiving colonoscopy: a retrospective study. AB - Purpose: The purpose of this study was to clarify the factors that influence the incidence of colorectal neoplasia in patients with type 2 diabetes mellitus (DM). Study Design and Setting: Among a total of 1176 patients who underwent total colonoscopy at our hospital, we retrospectively analyzed 168 patients with type 2 DM. Univariate and multivariate logistic regression analyses were then performed to identify the risk factors associated with colorectal neoplasia. Results: A multivariate analysis of these patients demonstrated that male gender (odds ratio [OR] = 4.04, 95% confidence interval [CI] = 1.67-10.37, p = 0.002), taking statins (OR = 4.59, 95% CI = 1.69-13.43, p = 0.003), taking alpha glucosidase inhibitor (alpha-GI) (OR = 0.35, 95% CI = 0.13-0.87, p = 0.023) and taking low dose aspirin (LDA) (OR = 0.32, 95% CI = 0.10-0.95, p = 0.040) were independent factors associated with an increased (male gender and statins) or decreased (alpha-GI and LDA) risk of colorectal neoplasia. Conclusions: While male gender and taking statins are risk factors, taking alpha-GI as well as LDA may reduce the risk of colorectal neoplasia in patients with type2 DM. PMID- 29228658 TI - DNA methylation landscape of hepatoblastomas reveals arrest at early stages of liver differentiation and cancer-related alterations. AB - Hepatoblastomas are uncommon embryonal liver tumors accounting for approximately 80% of childhood hepatic cancer. We hypothesized that epigenetic changes, including DNA methylation, could be relevant to hepatoblastoma onset. The methylomes of eight matched hepatoblastomas and non-tumoral liver tissues were characterized, and data were validated in an independent group (11 hepatoblastomas). In comparison to differentiated livers, hepatoblastomas exhibited a widespread and non-stochastic pattern of global low-level hypomethylation. The analysis revealed 1,359 differentially methylated CpG sites (DMSs) between hepatoblastomas and control livers, which are associated with 765 genes. Hypomethylation was detected in hepatoblastomas for ~58% of the DMSs with enrichment at intergenic sites, and most of the hypermethylated CpGs were located in CpG islands. Functional analyses revealed enrichment in signaling pathways involved in metabolism, negative regulation of cell differentiation, liver development, cancer, and Wnt signaling pathway. Strikingly, an important overlap was observed between the 1,359 DMSs and the CpG sites reported to exhibit methylation changes through liver development (p<0.0001), with similar patterns of methylation in both hepatoblastomas and fetal livers compared to adult livers. Overall, our results suggest an arrest at early stages of liver cell differentiation, in line with the hypothesis that hepatoblastoma ontogeny involves the disruption of liver development. This genome-wide methylation dysfunction, taken together with a relatively small number of driver genetic mutations reported for both adult and pediatric liver cancers, shed light on the relevance of epigenetic mechanisms for hepatic tumorigenesis. PMID- 29228659 TI - Prospective randomized phase II study of FOLFIRI versus FOLFOX7 in advanced gastric adenocarcinoma: a Chinese Western Cooperative Gastrointestinal Oncology Group Study. AB - Until now, no standard chemotherapy has been widely accepted for advanced gastric cancer (GC). The current research aimed to compare folinic acid, fluorouracil with irinotecan (mFOLFIRI) or with oxaliplatin (mFOLFOX7) as first-line treatments in patients with locally advanced GC in an open, randomized, phase II study. Previously untreated metastatic or recurrent GC patients with measurable disease received mFOLFIRI (arm A) or mFOLFOX7 (arm B) every 2 weeks. The defined second-line treatment was mFOLFOX7 for arm A and mFOLFIRI for arm B. Primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), disease control rate (DCR) and toxicity. The evaluable population consisted of 128 patients (54 in arm A; 74 in arm B). Median PFS of arm A was 2.9 months (m) (95% confidence interval, CI, 1.9 to 4.1 m) versus 4.1 m (95% CI, 3.2 to 4.8 m) for arm B (p = 0.109). Median OS was 9.9 months (95% CI, 6.0 to 13.5 m) for arm A versus 12.0 m for arm B (95% CI, 10.3 to 13.7m; p = 0.431). DCRs for arm A and arm B were 59.3% and 66.3%, respectively (p = 0.850). In subgroup analysis of the patients who completed both treatment lines per protocol, the median first-line PFS was 2.1 m for the mFOLFIRI/mFOLFOX7arm versus 8.0 m for the mFOLFOX7/mFOLFIRI arm (p = 0.053), and the median second-line PFS values were 1.2 m versus 5.1 m (p = 0.287). Total PFS and OS were 8.1m and 11.0 m for the mFOLFIRI/mFOLFOX7 group compared with 12.2m and 20.2 m for the mFOLFOX7/mFOLFIRI group (p = 0.008, p = 0.030). Both regimens were well-tolerated with acceptable and manageable toxicities. Hence, there was no significant difference in the PFS or DCR. However, mFOLFOX7 followed by mFOLFIRI might have a better OS. PMID- 29228660 TI - Motor deficits are independent of axonopathy in an Alzheimer's disease mouse model of TgCRND8 mice. AB - There have been an increasing number of reports of non-cognitive symptoms in Alzheimer's disease (AD). Some symptoms are associated with the loss of motor functions, e.g. gait disturbances, disturbed activity level and balance. Consistent with clinical findings, several AD mouse models harboring amyloid pathology develop motor impairment. Although the factors that contribute to the motor deficits have not yet been determined, it has been suggested that axonopathy is one of the key factors that may contribute to this particular feature of the disease. Our previous study found that TgCRND8 mice exhibited profound motor deficits as early as 3 months old. In this study, we explored the possible factors that may be related to motor deficits in TgCRND8 mice. Results from silver, neurofilament and amyloid precursor protein (APP) staining revealed no axonopathy occurred in the brain and spinal cord of TgCRND8 mice at the age of 3 months. Anterograde labeling of corticospinal tract of spinal cord and electronic microscopy (EM) analysis showed that no axonopathy occurred in TgCRND8 mice at the age of 3 months. According to these results, it could be concluded that no axonal alterations were evident in the TgCRND8 mice when motor deficits was overt. Thus, axonopathy may play a less prominent role in motor deficits in AD. These results suggest that mechanisms by which motor function undergo impairment in AD need to be further studied. PMID- 29228661 TI - Interactions between ACYP2 genetic polymorphisms and environment factors with susceptibility to ischemic stroke in a Han Chinese Population. AB - Aims: To investigate the association of several single nucleotide polymorphisms (SNPs) within ACYP2 gene and additional gene- environment interaction with ischemic stroke (IS) risk in a Chinese population. Results: IS risk was significantly higher in carriers with the G allele of rs11896604 than those with CC genotype (CG or GG versus CC), adjusted OR (95%CI) =1.60 (1.18-2.20), and higher in carriers with the A allele of rs12615793 than those with GG genotype (GA or AA versus GG), adjusted OR (95%CI) = 1.66 (1.24-2.15). GMDR model shown a significant two-locus model (p = 0.0010) involving rs11896604 and alcohol drinking, and a significant two-locus model (p = 0.0010) involving rs12615793 and smoking. Current smokers with rs12615793- GA or AA genotype have the highest IS risk, compared to never- smokers with rs12615793-GG genotype, OR (95%CI) = 2.72 (1.64-3.86); current drinkers with rs11896604-CG or GG genotype have the highest IS risk, compared to never- drinkers with rs11896604-CC genotype, OR (95%CI) = 2.51 (1.70-3.40). Materials and Methods: A total of 1202 participants (660 males, 542 females) were selected, including 600 IS patients and 602 control participants. The mean age of all participants was 68.2 +/- 15.8 years. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination. Logistic regression was performed to investigate the impact of 4 SNPs within ACYP2 gene, additional gene-smoking or drinking interaction on IS risk. Conclusions: We found that the G allele of rs11896604 and the A allele of rs12615793 within ACYP2 gene, rs12615793- smoking interaction, and rs11896604-alcohol drinking interaction were all associated with increased IS risk. PMID- 29228662 TI - Changes in programmed death-ligand 1 expression during cisplatin treatment in patients with head and neck squamous cell carcinoma. AB - Programmed death-ligand 1 (PD-L1) expression is regarded as a predictive marker for anti-PD-1/PD-L1 therapy. The purpose of study was to explore the changes in PD-L1 expression in head and neck squamous cell carcinoma (HNSCC) during treatment. Paired HNSCC tissues prior to and after cisplatin-based treatment were evaluated to determine PD-L1 protein expression by immunohistochemistry. Among the 35 HNSCC patient samples, PD-L1 expression status changed after treatment in 37.1% (13/35) of samples. Among the 13 patients whose baseline PD-L1 was negative, PD-L1 expression was increased in 9 cases (69.2%) and remained negative in 4 cases (30.8%, P = 0.003). Patients exposed to cisplatin generally showed PD L1 up-regulation (83.3%, P = 0.037) compared to those not exposed to cisplatin (57.1%, P = 0.072). To validate these findings in vitro, changes in PD-L1 expression in HNSCC cell lines (Detroit-562, PCI-13, SNU-1041, SNU-1066, SNU 1076, and FaDu) were analyzed by western blotting and flow cytometry after treatment with cisplatin and interferon-gamma. In HNSCC cell lines, PD-L1 expression was significantly up-regulated after cisplatin, along with phosphor MAPK/ERK kinase up-regulation. In conclusion, PD-L1 expression in HNSCC may be altered during cisplatin treatment, activating the MAPK/ERK kinase pathway. PMID- 29228663 TI - Targeting PLK1 as a novel chemopreventive approach to eradicate preneoplastic mucosal changes in the head and neck. AB - Head and neck squamous cell carcinomas (HNSCC) and local relapses thereof develop in preneoplastic fields in the mucosal linings of the upper aerodigestive tract. These fields are characterized by tumor-associated genetic changes, are frequently dysplastic and occasionally macroscopically visible. Currently, no adequate treatment options exist to prevent tumor development. Array-based screening with a panel of tumor-lethal small interfering RNAs (siRNAs) identified Polo-like kinase 1 (PLK1) as essential for survival of preneoplastic cells. Inhibition of PLK1 caused cell death of preneoplastic and HNSCC cells, while primary cells were hardly affected. Both siRNAs and small molecule inhibitors caused a strong G2/M cell cycle arrest accompanied by formation of monopolar spindles. In a xenografted mouse model PLK1 caused a significant tumor growth delay and cures, while chemoradiation had no effect. Thus, PLK1 seems to be a promising target for chemopreventive treatment of preneoplastic cells, and could be applied to prevent HNSCC and local relapses. PMID- 29228664 TI - Chromatin remodeling protein MORC2 promotes breast cancer invasion and metastasis through a PRD domain-mediated interaction with CTNND1. AB - MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein with emerging roles in the regulation of DNA damage response and gene transcription, but its mechanistic role in breast cancer development and progression remains unexplored. Here, we show that MORC2 promoted breast cancer invasion and metastasis and these effects depended on a proline-rich domain (PRD) within its carboxy-terminal region spanning residues 601-734. Induced expression of wild-type MORC2 did not significantly affect cell proliferation and cell-cycle progression, but promoted breast cancer cell migration and invasion in vitro and metastatic lung colonization in vivo. The PRD domain was dispensable for the protein stability and subcellular localization of MORC2, but depletion of the PRD domain substantially suppressed MORC2-mediated migration, invasion, and metastasis. Proteomic and biochemical analyses further demonstrated that wild type MORC2, but not PRD deletion mutant, interacted with catenin delta 1 (CTNND1), a cadherin-associated protein that participates in tumor invasion and metastasis. Moreover, knockdown of endogenous CTNND1 by short hairpin RNAs suppressed the migratory and invasive potential of MORC2-expressing cells. Taken together, these results suggest that MORC2 promotes breast cancer invasion and metastasis through its PRD domain-mediated interaction with CTNND1. PMID- 29228665 TI - Risk factors for human papillomavirus infection prevalent among Uyghur women from Xinjiang, China. AB - We investigated the incidence of HPV and risk factors for infection among rural Uyghur women in the Xinjiang province of northwestern China, where there is a high incidence of cervical cancer. We used the careHPV kit to test 6000 sexually active Uyghur women aged 21 to 60 years for HPV, and conducted a comprehensive questionnaire survey to identify relevant HPV infection factors. Our data show the HPV infection rate to be 8.42%, which is lower than 11.7% reported worldwide, despite the higher cervical cancer incidence. Multivariate logistic regression revealed that Uyghur women that had (a) poor personal hygiene and care; (b) no previous gynecological examination; (c) a higher education level; (d) unprotected sex and inadequate personal hygiene; (e) used their fingers for vaginal cleaning (f) smoking husbands and (j) used sanitary napkins or toilet paper during menstruation or used clod as the bathroom wipe material were at greater risk for HPV infection. This suggests that proper interventions that improve personal hygiene, including not using ones fingers for vaginal cleaning, use of condoms, regular gynecological exams and a reduction in smoking by spouses could lower the cervical cancer risk by lowering HPV infection rates. In addition, increasing awareness among more educated women regarding HPV and implementation of effective interventions could reduce the risk of HPV infection in Uyghur women. PMID- 29228666 TI - Granulocyte colony stimulating factor treatment in non-alcoholic fatty liver disease: beyond marrow cell mobilization. AB - Protective effects of granulocyte colony stimulating factor (G-CSF) in acute liver injury via marrow cell mobilization have been reported in several studies. But exact mode of action and optimal protocol of G-CSF has been still doubt in chronic disease. Here we investigated mode of action and optimization of G-CSF as a treatment for non-alcoholic fatty liver disease (NAFLD). Various doses of conventional G-CSF (30 MUg/kg once weekly, once daily for 5 days, twice weekly) and long acting G-CSF (30 MUg/kg once a month) were evaluated in two kinds of NAFLD animal models to optimize the G-CSF protocol. G-CSF receptor expression highest increased in NAFLD model among various liver diseases compare to control (NAFLD: 14.7 times, alcohol hepatitis: 7.1 times, cirrhosis: 2.4 times, and ischemia reperfusion: 6.8 times). G-CSF treatment reduced intrahepatic fat accumulation, and inflammation in two kinds of NAFLD animal models. G-CSF increased PI3K/Akt expression in hepatocyte as well as decreased apoptotic drive (increased Bcl-2 expression and decreased Bax expression) in animal model. Five day consecutive G-CSF treatment and once a month long acting G-CSF increased marrow derived stem cell marker in peripheral blood. But twice a week conventional G-CSF treatment did not increased CD34+ cell in peripheral blood and liver neither. Not only high dose G-CSF (once daily for 5 days) but also hepatotropic dose G-CSF (twice a week) significantly reduced hepatocyte apoptosis via PI3K and Akt pathway activation without marrow cell mobilization in NAFLD animal model. PMID- 29228667 TI - Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway. AB - Sepsis-induced brain injuries increase mortality, morbidity, cognitive impairment and lack of effective therapeutic treatment. Previous studies have suggested that metformin provides neuroprotective effects against ischemia, brain trauma and other brain damage, but whether metformin protects a septic brain remains unknown. Thus, the aim of this study is to investigate the possible effects and the mechanism of metformin against septic brain damage using the cecal ligation and puncture (CLP) model. Mice were randomly divided into five groups: the Sham group, CLP group, CLP+ Met group, CLP+ vehicle group and CLP+ Met+ LY group. The survival percentage and brain water content were examined, and the Morris water maze was conducted to determine the protective effect of metformin. Neuronal apoptosis in the cerebral cortex, striatum and hippocampus was examined using TUNEL assay and immunohistochemistry, and western blot was applied to measure the expression of p-Akt. The results indicate that metformin can increase survival percentage, decrease brain edema, preserve the blood-brain barrier (BBB) and improve cognitive function. Metformin also reduced the neuronal apoptosis induced by sepsis and increased the phosphorylation of Akt. However, the protective effect of metformin can be reversed by LY294002, a PI3K inhibitor. In summary, our results demonstrate that metformin can exert a neuroprotective effect by activating the PI3K/Akt signaling pathway. PMID- 29228668 TI - TSC-22 inhibits CSF-1R function and induces apoptosis in cervical cancer. AB - Colony stimulating factor 1 receptor (CSF-1R) regulates the monocyte/macrophage system, which is an essential component of cancer development. Therefore, CSF-1R might be an effective target for anti-cancer therapy. The overexpression of transforming growth factor (TGF)-beta stimulated clone-22 (TSC-22) inhibits cancer cell proliferation and induces apoptosis, and TSC-22 is emerging as a key factor in tumorigenesis. In this study, we discovered CSF-1R as a new interacting partner of TSC-22 and identified its elevated expression in cervical cancer cells. In particular, we found that TSC-22 interacted with the intracellular tyrosine kinase insert domain (539-749) of CSF-1R, which activates the AKT and ERK signaling pathways. This binding blocked AKT and ERK signaling, thereby suppressing the transcriptional activity of NF-kappaB. The overexpression of TSC 22 significantly decreased CSF-1R protein levels, affecting their autocrine loop. TSC-22 injected into a xenograft mouse model of human cervical cancer markedly inhibited tumor growth. The reduction of CSF-1R protein significantly suppresses cervical cancer cell proliferation and motility and induces apoptotic cell death. This association between TSC-22 and CSF-1R could be used as a novel therapeutic target and prognostic marker for cervical cancer. PMID- 29228669 TI - NUP37, a positive regulator of YAP/TEAD signaling, promotes the progression of hepatocellular carcinoma. AB - Activation of YAP/TEAD signaling is very common in the progression of HCC (Hepatocellular carcinoma). Nuclear pore complex (NPC) regulates the shuttling of proteins between cytoplasm and nucleus. Nuclear accumulation of YAP protein has been observed in the majority of HCC tissues. However, whether NPC could regulate the YAP/TEAD signaling remains unknown. In this study, it was found NUP37, the component of NPC, significantly up-regulated in HCC clinical samples and mouse model. Over-expression of NUP37 promoted the growth, migration and invasion of HCC cells, while knocking down the expression of NUP37 inhibited the growth, migration, invasion and metastasis of HCC cells and improved the survival of the mouse model. NUP37 interacted with YAP and activated YAP/TEAD signaling by enhancing the interaction between YAP and TEAD. Taken together, these data demonstrated the oncogenic roles of NUP37 in the progression of HCC and suggested that NUP37 might be a promising therapeutic target. PMID- 29228670 TI - LncRNA as ceRNAs may be involved in lactation process. AB - The main function of the mammary gland is to secret milk for newborn growth. Milk production process is regulated by hormones, growth factors, noncoding RNAs and other factors locally. Long non-coding RNAs (lncRNAs), one type of recently discovered non-coding RNA, have been found in mammary gland and some studies suggested lncRNA may play important roles in mammary gland development. Competing endogenous RNAs (ceRNAs) are emerging to compete for miRNA binding and, in turn, regulate each other. In the current study, we sequenced mRNA, miRNA and lncRNA in goat mammary tissue at 2 points in lactation (early and mature). All data were co expressed together from the same samples. Our data showed that the ceRNAs up regulated during the mature lactation phase were associated with lipid, protein, carbon and amino acid synthesis and metabolism. This correlates with the function of the mature lactation phase: i.e. the continuous production of large amounts of milk, rich in proteins, lipids, amino acids and other nutrients. Alternately, the ceRNAs up-regulated during early lactation were associated with PI3K-AKT pathways and ECM-receptor interactions; these fulfil the functional role of preparing the mammary gland for full lactation. Therefore, the results suggest that ceRNAs work synergistically during different developmental stages to regulate specific functions associated with lactation control. This study suggests that ceRNAs (lncRNA-mRNA) may be involved in lactation process. PMID- 29228671 TI - Metformin ameliorates skeletal muscle insulin resistance by inhibiting miR-21 expression in a high-fat dietary rat model. AB - Insulin resistance (IR) plays a major role in the pathogenesis of abdominal obesity, hypertension, coronary heart disease, atherosclerosis and diabetes. miR 21 and TGF-beta/smads is closely related to IR. However, it remained elusive whether metformin improved skeletal muscle insulin resistance (IRSM) by regulating miR-21 and its target signal TGF-beta1/smads expression. In this study, high-fat diet rats with IR model and IR-skeletal muscle L6 cells (L6-SMCs) model were established, insulin sensitive index (ISI) and Homeostasis model assessment of IR (HOMA-IR) were applied, miR-21 and TGF-beta1/smads mRNA expression were examined by RT-PCR, smad3 and smad7 protein were detected by western-blotting and laser scanning confocal microscopy (LSCM), the valid target of miR-21 was detected by luciferase reporter gene assay. Here, we found that metformin dose-dependently decreased miR-21 expression, accompanied by the decrease of HOMA-IR and the increase of HOMA-ISI. Luciferase report gene assay showed that smad7 was an effective target of miR-21. miR-21 overexpression directly downregulated smad7 and indirectly upregulated smad3 expression. Interestingly, miR-21 expression positively correlated with HOMA-IR and negatively correlated with HOMA-ISI. In conclusion, our results demonstrated that metformin improved IRSM by inhibiting miR-21 expression, and that miR-21 may be one of the therapeutic targets for IR. PMID- 29228672 TI - PTEN regulates spindle assembly checkpoint timing through MAD1 in interphase. AB - The spindle assembly checkpoint (SAC) restrains anaphase progression to ensure all chromosomes attach properly to the spindle. Although SAC timing has been extensively investigated in mitosis, its mechanism of regulation in interphase is unclear. We report that PTEN functions as a crucial activator of SAC timing and protects chromosome segregation under both spindle poison treated and untreated conditions. We show that PTEN physically interacts with MAD1 and promotes its dimerization and localization in the nuclear pore. Consequently, PTEN is important for the formation of the mitotic checkpoint complex (MCC) in interphase. We propose PTEN/MAD1 signaling is essential for maintenance of SAC timing and chromosome integrity. PMID- 29228673 TI - Inhibition of pressure-activated cancer cell adhesion by FAK-derived peptides. AB - Forces within the surgical milieu or circulation activate cancer cell adhesion and potentiate metastasis through signaling requiring FAK-Akt1 interaction. Impeding FAK-Akt1 interaction might inhibit perioperative tumor dissemination, facilitating curative cancer surgery without global FAK or AKT inhibitor toxicity. Serial truncation and structurally designed mutants of FAK identified a seven amino acid, short helical structure within FAK that effectively competes with Akt1-FAK interaction. Adenoviral overexpression of this FAK-derived peptide inhibited pressure-induced FAK phosphorylation and AKT-FAK coimmunoprecipitation in human SW620 colon cancer cells briefly exposed to 15mmHg increased pressure, consistent with laparoscopic or post-surgical pressures. Adenoviral FAK-derived peptide expression prevented pressure-activation of SW620 adhesion not only to collagen-I-coated plates but also to murine surgical wounds. A scrambled peptide did not. Finally, we modeled operative shedding of tumor cells before irrigation and closure by transient cancer cell adhesion to murine surgical wounds before irrigation and closure. Thirty minute preincubation of SW620 cells at 15mmHg increased pressure impaired subsequent tumor free survival in mice exposed to cells expressing the scrambled peptide. The FAK-derived sequence prevented this. These results suggest that blocking FAK-Akt1 interaction may prevent perioperative tumor dissemination and that analogs or mimics of this 7 amino acid FAK-derived peptide could impair metastasis. PMID- 29228674 TI - The regulatory role of aberrant Phosphatase and Tensin Homologue and Liver Kinase B1 on AKT/mTOR/c-Myc axis in pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine tumor (pNET) is an uncommon type of pancreatic neoplasm. Low Phosphatase and Tensin Homologue (PTEN) expression and activation of the mechanistic target of rapamycin (mTOR) pathway have been noted in pNETs, and the former is associated with poor survival in pNET patients. Based on the results of the RADIANT-3 study, everolimus, an oral mTOR inhibitor, has been approved to treat advanced pNETs. However, the exact regulatory mechanism for the mTOR pathway in pNETs remains largely unknown. PTEN and liver kinase B1 (LKB1) are well-known for their regulatory role in the mTOR pathway. We evaluated the expression of PTEN and LKB1 in 21 pNET patients, and low PTEN and LKB1 expression levels were noted in 48% and 24% of the patients, respectively. Loss of PTEN and LKB1 synergistically promoted cell proliferation of pNET, attenuated the sensitivity of cells to mTOR inhibitors and enhanced c-Myc expression, which back regulated PTEN, AKT, mTOR and its downstream effectors. For pNET cells with low expression levels of PTEN and LKB1, silencing the expression of c-Myc by shRNA reduced their proliferative rate, while adding either c-Myc inhibitor or AMP activated protein kinase activator reversed their resistance to mTOR inhibitors in vitro and in vivo. Furthermore, high c-Myc expression was subsequently identified in 81% of pNETs, suggesting that up-regulation of c-Myc expression in pNETs may occur through PTEN/LKB1-dependent and PTEN/LKB1-independent regulation. The results delineated the regulation of PTEN and LKB1 on the AKT/mTOR/c-Myc axis and suggested that both c-Myc and mTOR are potential therapeutic targets for pNET. PMID- 29228675 TI - Evaluation of protective efficacy of three novel H3N2 canine influenza vaccines. AB - Canine influenza virus (CIV) has the potential risk to spread in different areas and dog types. Thus, there is a growing need to develop an effective vaccine to control CIV disease. Here, we developed three vaccine candidates: 1) a recombinant pVAX1 vector expressing H3N2 CIV hemagglutinin (pVAX1-HA); 2) a live attenuated canine adenovirus type 2 expressing H3N2 CIV hemagglutinin (rCAV2-HA); and 3) an inactivated H3N2 CIV (A/canine/Guangdong/01/2006 (H3N2)). Mice received an initial intramuscular immunization that followed two booster injections at 2 and 4 weeks post-vaccination (wpv). The splenic lymphocytes were collected to assess the immune responses at 6 wpv. The protective efficacy was evaluated by challenging H3N2 CIV after vaccination (at 6 wpv). Our results demonstrated that all three vaccine candidates elicited cytokine and antibody responses in mice. The rCAV2-HA vaccine and the inactivated vaccine generated efficient protective efficacy in mice, whereas limited protection was provided by the pVAX1-HA DNA vaccine. Therefore, both the rCAV2-HA live recombinant virus and the inactivated CIV could be used as potential novel vaccines against H3N2CIV. This study provides guidance for choosing the most appropriate vaccine for the prevention and control of CIV disease. PMID- 29228676 TI - Genes with mutation significance were highly associated with the clinical pattern of patients with breast cancer. AB - In the United States, breast cancer is the second leading cause of cancer death in women. Over the past 20 years, breast cancer incidence and mortality rates increased rapidly in developing regions. We aimed to identify the gene mutation patterns that associated with the clinical patterns, including survival status, histo-pathological classes and so forth, of breast cancer. We retrieved 1098 cases of the clinical information, and level-3 legacy data of mRNA expression level, protein expression data and mutation files from GDC data portal. The genes with mutation significance were obtained. We studied the impacts of mutation types on the expression levels of mRNA and protein. Different statistics methods were used to calculate the correlation between the mutation types and the expression data or histo-clinical measures. There were 24 genes with mutation significance identified. The most mutated genes were selected to study the role of specific mutations played on the patients with breast cancer. One interesting finding was the missense mutations on TP53 were related with high expression levels of mRNA and protein. The missense mutations on TP53 were highly related with the morphology, race, ER status, PR status and HER2 Status, while the truncated mutations were only related with the morphology, ER status and PR status. The missense mutation on PIK3CA was highly associated with the morphology, race, ER status and PR status. The mutants with different mutants and the wild type of the most mutated genes had different impacts on the histo clinical measures that might help personalized therapy. PMID- 29228677 TI - Copper or/and arsenic induce oxidative stress-cascaded, nuclear factor kappa B dependent inflammation and immune imbalance, trigging heat shock response in the kidney of chicken. AB - Excessive amount of copper (Cu) and inorganic arsenic (iAs) coexists in drinking water in many regions, this is associated with high risk of nephropathy, defined as chronic structural and functional disorders of the kidney. However, the underlying mechanisms are not well understood. In this study, a total of 72 day old Hy-line chickens were exposed to 300 mg/kg copper sulphate or/and 30 mg/kg arsenic trioxide for 12 weeks. Indicators of oxidative stress, inflammation and heat shock proteins (HSPs) production were analyzed in kidney. The results showed that, when the toxicant was administrated alone, there is an antagonism between redox homeostasis during the first 4 weeks, which follows a collapse of antioxidant system manifested by damaged biomembrane structure. What's worse, oxidative damage-cascaded histopathological lesions were accompanied by increases of proinflammatory mediators and an imbalance of "Th1/Th2 drift" (Th, helper T cell) regulated by nuclear factor kappa B (NF-kappaB). Simultaneously, intense heat shock response went with the organism. The above-mentioned renal lesions and indicators changes were time-dependent, more complex and deteriorated effects were observed in Cu/iAs combined groups compared with the others. This study supports Cu and iAs have a synergistic type on the nephro-toxicological process additively. In conclusion, oxidative stress and inflammatory induced by Cu or/and iAs are potential mechanisms in their nephrotoxicity, increased heat shock response may play a renoprotection function in tissues damage. PMID- 29228678 TI - High expression of PDLIM5 facilitates cell tumorigenesis and migration by maintaining AMPK activation in prostate cancer. AB - PDZ and LIM domain 5 (PDLIM5) is a cytoskeleton-associated protein and has been shown to bind to a variety of proteins through its specific domain, thereby acting to regulate cell migration and tumor progression. Here, we found that PDLIM5 was abnormally upregulated in prostate cancer (PCa) tissues as compared with that in normal prostate tissue. ONCOMINE microarray data mining showed that PDLIM5 was closely correlated with the prognosis of PCa in terms of Gleason score, tumor metastasis and biochemical recurrence. Lentivirus-mediated short hairpin RNA (shRNA) knockdown of PDLIM5 inhibited cell proliferation and colony formation, arrested hormone independent PCa cells DU145 and PC-3 in G2/M phase, and induced apoptosis. Meanwhile, silencing PDLIM5 inhibited migration and invasion of tumor cells by reversing the mesenchymal phenotype and a similar result was confirmed in a xenograft nude mouse model. Finally, we found PDLIM5 plays a crucial role in regulating malignant tumor cell proliferation, invasion and migration by binding to AMPK and affecting its activation and degradation, and may therefore prove to be a potential oncogenic gene in the development and progression of PCa. PMID- 29228679 TI - Prognostic value of the C-reactive protein/Albumin Ratio (CAR) in patients with operable soft tissue sarcoma. AB - Background: The preoperative C-reactive protein/Albumin ratio (CAR) is valuable for predicting the prognosis of patients with various types of cancers. The aim of the present study is to investigate the prognostic value of the preoperative CAR and compare it with other systemic inflammatory response markers in patients with soft tissue sarcoma (STS). Methods: This retrospective study included 206 patients with STS. The optimal cutoff value of the CAR was determined by receiver operating characteristic (ROC) analysis. The impact of the CAR and other clinicopathological features on overall survival (OS) and disease-free survival (DFS) was evaluated using univariate and multivariate Cox regression analyses. Kaplan-Meier survival analyses were used to compare groups classified by the CAR. Additionally, the area under the receiver operating characteristic curve (AUC) was used to compare the predictive ability of the CAR, high-sensitivity modified Glasgow prognostic score (Hs-mGPS), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR). Results: The optimal cut-off value of the CAR was 0.1035 according to the ROC analysis. An increased CAR (>=0.1035) was significantly associated with older age, larger tumor size, deep tumor location, higher tumor grade and more advanced American Joint Committee on Cancer (AJCC) stage (all P<0.05). Patients with an elevated CAR (>=0.1035) exhibited a shorter median survival time and lower 5-year OS rate than those with a CAR<0.1035 (68.2 vs 115.8 months, P = 0.000; 44.6% vs 80.9%, P = 0.000, respectively). The results of a multivariate analysis indicated that the CAR (Hazard ratio (HR) 2.47, 95% confidence interval (CI) 1.47-4.14, P = 0.001) was an independent prognostic factor for OS along with tumor grade (P<0.05). Additionally, the CAR exhibited a greater AUC value (0.662) than the NLR and PLR, but the value was equal to the Hs mGPS. Conclusions: The preoperative CAR is an independent prognostic factor predicting prognosis in STS and exhibits superior prognostic ability compared to the established inflammation-based prognostic indices. PMID- 29228680 TI - Long noncoding RNA MIAT promotes non-small cell lung cancer proliferation and metastasis through MMP9 activation. AB - Long noncoding RNAs (lncRNAs) play crucial roles in carcinogenesis. Myocardial infarction-associated transcript (MIAT), originally isolated as a candidate gene for myocardial infarction, has been found to act as an oncogene in chronic lymphocytic leukaemias and neuroendocrine prostate cancer (NEPC); however, little is known about its expression pattern, biological function, and underlying mechanism in non-small cell lung cancer (NSCLC). In this study, we observed that MIAT expression was upregulated in NSCLC, and its overexpression was associated with advanced tumor stage. Moreover, MIAT knockdown decreased cell proliferation, migration, invasion, and cell cycle arrested in G1 phase. Mechanistic investigation revealed that MIAT could interact with histone methyltransferase mixed-lineage leukemia (MLL). MIAT silencing impeded the binding of MLL on the matrix metalloproteinase 9 (MMP9) promoter region and epigenetically reduced MMP9 transcriptional activity. Overall, our findings suggest that MIAT expression is associated with NSCLC and may be one of the critical targets in progression and metastasis in NSCLC. PMID- 29228682 TI - Epidermal PPARgamma influences subcutaneous tumor growth and acts through TNF alpha to regulate contact hypersensitivity and the acute photoresponse. AB - It is known that ultraviolet B (UVB) induces PPARgamma ligand formation while loss of murine epidermal PPARgamma (Pparg-/-epi) promotes UVB-induced apoptosis, inflammation, and carcinogenesis. PPARgamma is known to suppress tumor necrosis factor-alpha (TNF-alpha) production. TNF-alpha is also known to promote UVB induced inflammation, apoptosis, and immunosuppression. We show that Pparg-/-epi mice exhibit increased baseline TNF-alpha expression. Neutralizing Abs to TNF alpha block the increased photo-inflammation and photo-toxicity that is observed in Pparg-/-epi mouse skin. Interestingly, the increase in UVB-induced apoptosis in Pparg-/-epi mice is not accompanied by a change in cyclobutane pyrimidine dimer clearance or in mutation burden. This suggests that loss of epidermal PPARgamma does not result in a significant alteration in DNA repair capacity. However, loss of epidermal PPARgamma results in marked immunosuppression using a contact hypersensitivity (CHS) model. This impaired CHS response was significantly alleviated using neutralizing TNF-alpha antibodies or loss of germline Tnf. In addition, the PPARgamma agonist rosiglitazone reversed UVB induced systemic immunosuppression (UV-IS) as well as UV-induced growth of B16F10 melanoma tumor cells in syngeneic mice. Finally, increased B16F10 tumor growth was observed when injected subcutaneously into Pparg-/-epi mice. Thus, we provide novel evidence that epidermal PPARgamma is important for cutaneous immune function and the acute photoresponse. PMID- 29228681 TI - Cyclophosphamide causes osteoporosis in C57BL/6 male mice: suppressive effects of cyclophosphamide on osteoblastogenesis and osteoclastogenesis. AB - The clinical evidence indicated that cyclophosphamide (CPD), one of the chemotherapy drugs, caused severe deteriorations in bones of cancer patients. However, the exact mechanisms by which CPD exerts effects on bone remodeling is not yet fully elucidated. Therefore, this study was performed to investigate the role and potential mechanism of CPD in osteoblastogenesis and osteoclastogenesis. Here it was found that CPD treatment (100mg/kg/day) for 7 days led to osteoporosis phenotype in male mice. CPD inhibited osteoblastogenesis as shown by decreasing the number and differentiation of bone mesenchymal stem cells (MSCs) and reducing the formation and activity of osteoblasts. Moreover, CPD suppressed the osteoclastogenesis mediated by receptor activator for nuclear factor-kappa B ligand (RANKL) as shown by reducing the maturation and activity of osteoclasts. At the molecular level, CPD exerted inhibitory effect on the expression of components (Cyclin D1, beta-catenin, Wnt 1, Wnt10b) of Wnt/beta-catenin signaling pathway in MSCs and osteoblasts-specific factors (alkaline phosphatase, Runx2, and osteocalcin). CPD also down-regulated the expression of the components (tumor necrosis factor receptor-associated factor 6, nuclear factor of activated T-cells cytoplasm 1, c-Fos and NF-kappaB) of RANKL signaling pathway and the factors (matrix metalloproteinase 9, cathepsin K, tartrate-resistant acid phosphates and carbonic anhydrase II) for osteoclastic activity. Taken together, this study demonstrated that the short-term treatment of CPD induced osteoporosis in mice and the underlying mechanism might be attributed to its marked suppression on osteoblastogenesis and osteoclastogenesis, especially the effect of CPD on bone formation might play a dominant role in its detrimental effects on bone remodeling. PMID- 29228683 TI - Lenalidomide overcomes the immunosuppression of regulatory CD8+CD28- T-cells. AB - Although lenalidomide and pomalidomide are well-established treatment options in patients with multiple myeloma, their immune-modulating effects are not fully understood. While CD8+CD28- regulatory T-cells in patients with hematologic disorders display a known immune-escape mechanism, we show that lenalidomide can overcome the immunosuppressive impact of CD8+CD28- T-cells. We analyzed in vitro the antigen-specific T-cell responses of healthy donors and patients with multiple myeloma with or without the addition of autologous CD8+CD28- T-cells in the absence and presence of lenalidomide. We found that lenalidomide enhances the antigen-specific secretion of IFN-gamma and Granzyme B despite the addition of CD8+CD28- T-cells. Furthermore, we showed that lenalidomide inhibits the IL-6 secretion of mononuclear cells, triggered by CD8+CD28- T-cells. The addition of IL-6 counteracts the action of lenalidomide based stimulation of IFN-gamma secretion and induction of T-cell maturation but not the secretion of Granzyme B. Surprisingly, pomalidomide failed to induce IL-6 suppression and displayed immunostimulating effects only after a prolonged incubation time. Analysis of the IL-6 modulating cereblon-binding protein KPNA2 showed the similar degradation capacity of lenalidomide and pomalidomide without explaining the divergent effects. In conclusion, we showed that IL-6 and lenalidomide, but not pomalidomide, are opponents in a myeloma-antigen specific T-cell model. PMID- 29228684 TI - Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras activated mTOR signalling. AB - Regulation of T cell function in the steady state is mediated by co-inhibitory receptors or immune checkpoints such as PD-1, CTLA-4, TIM-3 and LAG-3. Persistent antigen stimulation, during chronic viral infections and cancer, results in sustained expression of multiple co-inhibitory receptors and subsequently poor effector T cell function. Immune checkpoint blockade using monoclonal antibodies against PD-1, PDL-1 and CTLA-4 has been implemented as an immunotherapy strategy- resulting in restoration of T cell function and reduction of viral load or tumour growth. Immunomodulatory roles of commonly used cholesterol-lowering medications, atorvastatin and other statins, are widely documented. We have previously shown that atorvastatin can inhibit HIV-1 infection and replication. Here, for the very first time we discovered that atorvastatin also regulates activated T cell function by mediating downregulation of multiple co-inhibitory receptors, which corresponded with increased IL-2 production by stimulated T cells. In addition, we found that atorvastatin treatment reduces expression of mTOR and downstream T cell effector genes. We demonstrate a novel mechanism showing that atorvastatin inhibition of Ras-activated MAPK and PI3K-Akt pathways, and subsequent mTOR signalling promotes gross downregulation of co-inhibitory receptors. Thus, our results suggest that statins may hold particular promise in reinvigorating T cell function in chronic conditions. PMID- 29228685 TI - EB1 phosphorylation mediates the functions of ASK1 in pancreatic cancer development. AB - Pancreatic cancer has a poor prognosis due to its rapid rate of metastasis and frequent late-stage diagnosis. An improved understanding of the molecular mechanisms underlying this disease is urgently needed to promote the development of improved diagnostic tools and more effective therapies. Apoptosis signal regulating kinase 1 (ASK1) has been shown to be overexpressed in pancreatic cancer and to promote the proliferation of pancreatic cancer cells in a kinase activity-dependent manner. However, the molecular mechanisms by which ASK1 promotes cell proliferation remain to be elucidated. In this study, we report that the phosphorylation of end-binding protein 1 (EB1) at threonine 206 (pT206 EB1), which is catalyzed by ASK1, is increased in pancreatic cancer tissues. We further find that the level of pT206-EB1 correlates with that of ASK1 in cancer tissues. Additionally, ASK1 localizes to spindle poles, and knockdown of ASK1 results in the formation of multipolar spindles. Moreover, we show that depletion of ASK1 or disruption of EB1 phosphorylation inhibits spindle microtubule dynamics in pancreatic cancer cells. Collectively, these findings suggest that EB1 phosphorylation mediates the functions of ASK1 in pancreatic cancer development. PMID- 29228686 TI - Dl-3n-butylphthalide reduces epileptiform activity through GluA2-lacking calcium permeable AMPARs in epilepsy models. AB - Epilepsy is the most prevalent chronic neurological disorder, and its pathological mechanism indicates that an imbalance between excitatory and inhibitory neurotransmission leads to neuronal hyperexcitability. Previous studies have suggested that dl-3n-butylphthalide (NBP) regulates the excitatory neurotransmitter glutamate in the brains of epileptic mice, however, the mechanisms are unknown. We investigated behavioral and electrophysiological factors in rats using NBP. In an in vivo pentylenetetrazole (PTZ)-induced epileptic seizure animal model, NBP decreased the generalized tonic-clonic seizure (GTCS) severity. In an acute hippocampal slice 4-aminopyridine (4-AP) epilepsy model in vitro, NBP decreased the epileptiform activity and miniature excitatory postsynaptic current (mEPSC) amplitude; there was no change in the miniature inhibitory postsynaptic current (mIPSC) amplitude or frequency. This effect suggested changes in excitatory synaptic transmission, which was altered through postsynaptic GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs). These findings showed that NBP suppressed epileptiform activity in these epilepsy models and provided the first detailed electrophysiological analysis of the impact of NBP in epilepsy models, which may be employed in future experimental or clinical therapies for patients with epilepsy. PMID- 29228687 TI - Interactions between RASA2, CADM1, HIF1AN gene polymorphisms and body fatness with breast cancer: a population-based case-control study in China. AB - Genome-wide association studies (GWAS) have indicated that gene polymorphisms in alleles of RAS p21 protein activator 2 (RASA2), cell adhesion molecule 1 (CADM1) and hypoxia inducible factor 1 alpha subunit inhibitor (HIF1AN) are associated with the risk of obesity. In this study, we explored the interactions between candidate SNPs of RASA2 (rs16851483), CADM1 (rs12286929) and HIF1AN (rs17094222) and body fatness for breast cancer risk. Unconditional logistic regression models were applied to measure the associations of related factors with breast cancer by odds ratios (ORs) and 95% confidence intervals (CIs). It was observed that cases had a statistically higher body mass index (BMI >= 28 kg/m2, OR = 1.77), waist circumference (WC >= 90cm, OR = 2.89) and waist-to-hip ratio (WHR >= 0.9, OR = 3.41) as compared to controls. Significant differences were also found in the genotype distributions of RASA2 rs16851483 T/T homozygote and CADM1 rs12286929 G/A heterozygote between cases and controls, with an OR of 1.68 (95% CI: 1.10 2.56) and 0.80 (95% CI: 0.64-0.99), respectively. Furthermore, significant interactions were observed between polymorphisms of three genes and body fatness for the risk of breast cancer based on both additive and multiplicative scales. These results of our study suggest that body fatness possibly plays an important role in the development of breast cancer and this risk might be modified by specific genotypes of some potential genes, especially for obese women in China. PMID- 29228688 TI - Altered follicular helper T cell impaired antibody production in a murine model of myelodysplastic syndromes. AB - Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic diseases which have a high risk of progressing to acute myeloid leukemia. MDS patients have immunologic deficiency, including T and B cells dysfunction. Follicular T helper cells (Tfh, CD4+CXCR5+) are an important subset of helper T cells which help to the formation of germinal centers and B cells differentiation. In this study, we investigated the proportion and function of Tfh using NUP98-HOXD13 transgenic (NHD13) mice model with MDS phenotype. The proportion of Tfh from bone marrow and spleen of NHD13 mice decreased compared with wild type (WT) mice tested by flow cytometry. In NHD13 mice spleens, there were decreased CXCR5+ cells and increased PD-1+ cells using immunohistochemistry. The active markers (ICOS, CD40L and OX40) expressed on Tfh of NHD13 mice were decreased. In contrast, PD-1 expression on Tfh of NHD13 mice was higher than that of WT mice. After coculture with Tfh from NHD13 mice, IgG and IgM production of B cells were decreased. In conclusion, the proportion and function of Tfh in the MDS mice model were altered. The dysfunction and reduction of Tfh may inhibit B cells differentiation and antibody production. Abnormal Tfh might contribute to the immune tolerance promoting the progression of MDS. PMID- 29228689 TI - Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma. AB - Malignant mesothelioma originates from mesothelial cells and is a cancer type that aggressively invades into the surrounding tissue, has poor prognosis and no effective treatment. Gremlin-1 is a cysteine knot protein that functions by inhibiting BMP-pathway activity during development. BMP-independent functions have also been described for gremlin-1. We have previously shown high gremlin-1 expression in mesothelioma tumor tissue. Here, we investigated the functions of gremlin-1 in mesothelioma cell migration and invasive growth. Gremlin-1 promoted mesothelioma cell sprouting and invasion into three dimensional collagen and Matrigel matrices. The expression level of gremlin-1 was linked to changes in the expression of SNAI2, integrins, matrix metalloproteinases (MMP) and TGF-beta family signaling - all previously associated with a mesenchymal invasive phenotype. Small molecule inhibitors of MMPs completely blocked mesothelioma cell invasive growth. In addition, inhibitors of TGF-beta receptors significantly reduced invasive growth. This was associated with reduced expression of MMP2 but not SNAI2, indicating that gremlin-1 has both TGF-beta pathway dependent and independent mechanisms of action. Results of in vivo mesothelioma xenograft experiments indicated that gremlin-1 overexpressing tumors were more vascular and had a tendency to send metastases. This suggests that by inducing a mesenchymal invasive cell phenotype together with enhanced tumor vascularization, gremlin-1 drives mesothelioma invasion and metastasis. These data identify gremlin-1 as a potential therapeutic target in mesothelioma. PMID- 29228690 TI - Cartilage oligomeric matrix protein promotes prostate cancer progression by enhancing invasion and disrupting intracellular calcium homeostasis. AB - Cartilage oligomeric matrix protein (COMP) was recently implicated in the progression of breast cancer. Immunostaining of 342 prostate cancer specimens in tissue microarrays showed that COMP expression is not breast cancer-specific but also occurs in prostate cancer. The expression of COMP in prostate cancer cells correlated with a more aggressive disease with faster recurrence. Subcutaneous xenografts in immunodeficient mice showed that the prostate cancer cell line DU145 overexpressing COMP formed larger tumors in vivo as compared to mock transfected cells. Purified COMP bound to and enhanced the invasion of DU145 cells in vitro in an integrin-dependent manner. In addition, intracellular COMP expression interfered with cellular metabolism by causing a decreased level of oxidative phosphorylation with a concurrent upregulation of lactate production (Warburg effect). Further, expression of COMP protected cells from induction of apoptosis via several pathways. The effect of COMP on metabolism and apoptosis induction was dependent on the ability of COMP to disrupt intracellular Ca2+ signalling by preventing Ca2+ release from the endoplasmic reticulum. In conclusion, COMP is a potent driver of the progression of prostate cancer, acting in an anti-apoptotic fashion by interfering with the Ca2+ homeostasis of cancer cells. PMID- 29228691 TI - Berberine attenuated pro-inflammatory factors and protect against neuronal damage via triggering oligodendrocyte autophagy in spinal cord injury. AB - Berberine exerts neuroprotective effect in neuroinflammation and neurodegeneration disease. However, berberine effect in acute spinal cord injury is yet to be elucidated. Herein, we investigated the neuroprotective effect of berberine in spinal cord injury (SCI). Sprague-Dawley rats were subjected to SCI by an intraperitoneal injection of berberine post-injury. The neurobehavioral recovery, cytokines of pro-inflammatory factors (TNF-alpha and IL-1beta), autophagy-related proteins (LC3B, ATG16L, ATG7), and apoptosis-related protein cleaved caspase-3 were determined. The expressions of 2', 3'-cyclic-nucleotide 3' phosphodiesterase (CNPase), marker of oligodendrocyte, autophagy-related proteins ATG5 and neurons at the ventral horn were assessed. In vitro, the contents of the pro-inflammatory factors, TNF-alpha and IL-1beta, were detected in the lipopolysaccharide (LPS)-treated primary spinal neuron. Berberine significantly improved the neurobehavior BBB score and attenuated the cytokines of pro inflammatory factors in cerebrospinal fluid post-SCI. In addition, berberine upregulated CNPase positive oligodendrocyte expressing ATG5, promoted neuronal survival and reduced the cleaved caspase-3 expression after SCI. In primary spinal neuron, the LPS-induced inflammatory factors could be reduced by berberine, whereas the autophagy inhibitor, 3-Methyladenine reverses the effect. Berberine attenuated inflammation of the injured spinal cord and reduced the neuronal apoptosis via triggering oligodendrocyte autophagy in order to promote neuronal recovery. PMID- 29228692 TI - Epigenetic landscape change analysis during human EMT sheds light on a key EMT mediator TRIM29. AB - Epithelial to mesenchymal transition (EMT) is a key trans-differentiation process, which plays a critical role in physiology and pathology. Although gene expression changes in EMT have been scrutinized, study of epigenome is in its infancy. To understand epigenetic changes during TWIST-driven EMT, we used the AcceSssIble assay to study DNA methylation and chromatin accessibility in human mammary epithelial cells (HMECs). The DNA methylation changes were found to have functional significance in EMT - i.e. methylated genes were enriched for E-box motifs that can be recognized by TWIST, at the promoters suggesting a potential targeting phenomenon, whereas the demethylated regions were enriched for pro metastatic genes, supporting the role of EMT in metastasis. TWIST-induced EMT triggers alterations in chromatin accessibility both independent of and dependent on DNA methylation changes, primarily resulting in closed chromatin conformation. By overlapping the genes, whose chromatin structure is changed during early EMT and a known "core EMT signature", we identified 18 driver candidate genes during EMT, 14 upregulated and 4 downregulated genes with corresponding chromatin structure changes. Among 18 genes, we focused on TRIM29 as a novel marker of EMT. Although loss of TRIM29 is insufficient to suppress CDH, it is enough to induce CDH2 and VIM. Gene functional annotation analysis shows the involvement of TRIM29 in epidermal development, cell differentiation and cell migration. Taken together, our results provide a robust snapshot of chromatin state during human EMT and identify TRIM29 as a core mediator of EMT. PMID- 29228693 TI - Bone marrow stem cells-derived extracellular matrix is a promising material. AB - The extracellular matrix(ECM), which is primarily composed of collagens and proteoglycans, plays a key role in cell proliferation, differentiation, and migration and interactions between cells. In this study, we produced chitosan/gelatin/bone marrow stem cells-derived extracellular matrix(C/G/BMSCs dECM) scaffolds via lyophilization and cross-linking, and chitosan/gelatin(C/G) scaffolds were used as controls. For the C/G/BMSCs-dECM scaffolds, the average pore size was 289.17 +/- 80.28 MUm; the average porosity was 89.25 +/- 3.75%; the average compressive modulus was 0.82 +/- 0.07 MPa; and the average water uptake ratio was 13.81 +/- 1.00. In vitro, the C/G/BMSCs-dECM scaffolds promoted bone marrow stem cells(BMSCs) attachment and proliferation. Moreover, improved osteogenic differentiation was observed for these scaffolds. Thus, C/G/BMSCs-dECM is a promising material for bone tissue engineering. PMID- 29228694 TI - The EZH2 inhibitor GSK343 suppresses cancer stem-like phenotypes and reverses mesenchymal transition in glioma cells. AB - Enhancer of zeste homolog 2 (EZH2) is the catalytic unit of polycomb repressive complex 2 (PRC2) which epigenetically silences many genes involved in tumor suppressive mechanisms via the trimethylation of lysine 27 of histone H3 (H3K27me3). We recently found that overexpression of EZH2 was associated with poor outcome of glioblastoma (GBM). In this study, we examined the antitumor effects of the EZH2 inhibitor GSK343 on glioma cells in vitro and in vivo. The proliferation and cell cycle of glioma cells was measured. Wound healing assay and transwell invasion assay were performed to evaluate the capacity of migration and invasion of glioma cells. Western blot, qPCR, immunoprecipitation and fluorescent staining were used to test the levels of EZH2 and associated proteins. Spheroid formation assay and clonogenic assays were conducted to assess the stemness of glioma stem cells. Finally, the effect of GSK343 was measured through a nude mice model with intracranially xenotransplanted glioma. We found that GSK343 reduced proliferation, attenuated cell motility and reversed epithelial-mesenchymal transition in U87 and LN229 glioma cells. GSK343 also suppressed the stemness of cell lines and patient derived glioma stem cells. Further, GSK343 inhibited histone H3K27 methylation and upregulated the expression of EZH2 target genes thereby regulating the levels of markers involved in epithelial-mesenchymal transition and stemness. Taken together, our results indicate that GSK343 could be a potential drug against glioblastoma. PMID- 29228696 TI - MP0250, a VEGF and HGF neutralizing DARPin(r) molecule shows high anti-tumor efficacy in mouse xenograft and patient-derived tumor models. AB - Background: The VEGF/VEGFR and the HGF/cMET pathways are key mediators of the interplay of tumor cells and their microenvironment. However, inhibition of VEGF has been shown to produce only limited clinical benefit and inhibition of the activation of cMET by HGF has not translated into clinical benefit in pivotal trials. MP0250, a DARPin(r) molecule that specifically inhibits both VEGF and HGF has been developed to explore the clinical potential of dual inhibition of these pathways. Results: MP0250 binding to VEGF and HGF inhibited downstream signalling through VEGFR2 and cMET resulting in inhibition of proliferation of VEGF- and HGF dependent cells. Antitumor activity was demonstrated in VEGF- and HGF-dependent xenograft and syngeneic models with activity superior to that of individual VEGF- and HGF-blocking DARPin(r) molecules. Combination therapy studies showed potentiation of the antitumor activity of chemotherapy and immunotherapy agents, including an anti-PD1 antibody. Materials and Methods: Potency of MP0250 was assessed in cellular models and in a variety of xenograft models as monotherapy or in combination with standard-of-care drugs. Conclusions: Dual inhibition of VEGF and HGF by MP0250 produced powerful single agent and combination antitumor activity. This, together with increasing understanding of the role of the HGF/cMET pathway in resistance to VEGF (and other agents), supports testing of MP0250 in the clinic. PMID- 29228695 TI - Regulatory activity based risk model identifies survival of stage II and III colorectal carcinoma. AB - Clinical and pathological indicators are inadequate for prognosis of stage II and III colorectal carcinoma (CRC). In this study, we utilized the activity of regulatory factors, univariate Cox regression and random forest for variable selection and developed a multivariate Cox model to predict the overall survival of Stage II/III colorectal carcinoma in GSE39582 datasets (469 samples). Patients in low-risk group showed a significant longer overall survival and recurrence free survival time than those in high-risk group. This finding was further validated in five other independent datasets (GSE14333, GSE17536, GSE17537, GSE33113, and GSE37892). Besides, associations between clinicopathological information and risk score were analyzed. A nomogram including risk score was plotted to facilitate the utilization of risk score. The risk score model is also demonstrated to be effective on predicting both overall and recurrence-free survival of chemotherapy received patients. After performing Gene Set Enrichment Analysis (GSEA) between high and low risk groups, we found that several cell-cell interaction KEGG pathways were identified. Funnel plot results showed that there was no publication bias in these datasets. In summary, by utilizing the regulatory activity in stage II and III colorectal carcinoma, the risk score successfully predicts the survival of 1021 stage II/III CRC patients in six independent datasets. PMID- 29228699 TI - Iron depletion is a novel therapeutic strategy to target cancer stem cells. AB - Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs. PMID- 29228698 TI - Osteopontin is involved in TLR4 pathway contributing to ovarian cancer cell proliferation and metastasis. AB - Tumor cell proliferation and metastasis are critical for tumor progression and lead to death of cancer patients. TLR4 is a member of the toll-like receptor (TLR) family, which promotes tumor growth, metastasis and immune escape. Osteopontin (OPN), a phosphorylated glycoprotein extensively expressed in multiple cell-types, plays important roles in tumorigenesis, metastasis and infiltration, and participates in signal transduction of innate immunity. However, it is unclear whether TLR4 has any relationship with OPN. The current study investigated the role of TLR4 and OPN in tumor proliferation and metastasis, and the potential effect of TLR4 signaling on OPN using the human ovarian cancer cell line HO-8910PM. High expression levels of TLR4 and OPN were detected in HO-8910PM cells, which promoted the proliferation, migration and invasion of tumor cells. Lipopolysaccharide (LPS) induced activation of TLR4 up regulated OPN, increasing the malignant phenotype of cells. RNAi-mediated knockdown of OPN reduced significantly the metastatic phenotype activated by TLR4. Taken together, our study demonstrates that OPN contributes to the ovarian cancer cell proliferation and metastasis, which is activated by TLR4 signaling pathway. It provides new insights for the mechanisms of tumor development and metastasis, and suggests targeting TLR4 and OPN as an intervention in the ovarian cancer treatment. PMID- 29228697 TI - EGFR mutation, smoking, and gender in advanced lung adenocarcinoma. AB - Purpose: In the current targeted therapy era, information on the effect of smoking in epidermal growth factor receptor (EGFR)-mutant lung cancer patients is scarce. Results: In total, 11,678 adenocarcinoma patients were enrolled. Of these, 33.3% and 91.8% of male and female patients were non-smokers, respectively. An increased amount of smoking (P < 0.001 for trend), fewer smoke free years (P < 0.001 for trend), and younger age of smoking initiation (P = 0.034 for trend) were all associated with significantly lower EGFR mutation rates. Smokers had a shorter median overall survival (OS) among both EGFR-mutant and EGFR-wild type patients (17.8 vs. 21.1 months, and 7.9 vs. 11.4 months respectively; both P < 0.001). Among patients with EGFR-mutant adenocarcinoma, younger smokers were associated with shorter OS (P = 0.047). In multivariate analysis, female gender was an independent prognostic factor for OS (hazard ratio: 0.86 [95% confidence interval {CI}: 0.80-0.93]; P < 0.001 in the EGFR mutant group and 0.88 [95% CI: 0.81-0.96]; P = 0.004 in the EGFR-wild type group). Materials and Methods: We reviewed the National Lung Cancer database (Taiwan) to assess the impact of smoking on the EGFR mutation rate and survival in advanced lung adenocarcinoma patients during 2011 and 2014 retrospectively. Conclusions: Smoking was associated with lower incidence of EGFR mutation rate and reduced OS of advanced lung adenocarcinoma patients in a dose-dependent manner. In addition to EGFR mutation and smoking, gender also plays an important role in survival among these patients. PMID- 29228700 TI - Association of IFNGR1 and IFNG genetic polymorphisms with the risk for pulmonary tuberculosis in the Chinese Tibetan population. AB - Interferon-gamma (IFNG) and its receptor (IFNGR1) are principal genes that associated with tuberculosis. In the current study we aimed to explore the genetic association of polymorphisms of IFNG and IFNGR1 with the risk of pulmonary tuberculosis (PTB) in the Chinese Tibetan population. We selected 467 PTB patients and 503 healthy controls to genotype 9 single nucleotide polymorphisms (SNPs). The unconditional logistic regression analysis was applied for assessing the associations, and the risk of PTB were evaluated by calculating the odds ratio (OR) and 95% confidence interval (CI). The results showed that mutants of rs9376268, rs1327475 and rs1327474 in IFNGR1 played a protective role in the PTB risk under genotype, dominant and additive model (P<0.05). On the contrary, minor allele "A" of rs2069705 in IFNG significantly increased the risk of PTB under genotype, dominant and additive model (P<0.05). However, after Bonferroni's multiple adjustment was applied to our data, which level of significant was set at P<0.0011 (0.05/45). Only variant of rs9376268 was significantly associated decrease the PTB susceptibility under additive model (OR=0.73, 95%CI=0.61-0.88, P<0.001). Furthermore, in the haplotype analysis, we found that the haplotypes "C-G-G-A-C", "C-G-A-G-T" and "T-A-G-G-T" of rs9376267 rs9376268-rs1327475-rs7749390-rs1327474 block were extremely decreased the PTB risk (P<0.01), however, the haplotypes "C-G-G-A-T", "T-G-G-G-T" and "C-G-G-G-T" of the block were extremely increased the PTB risk (P<0.01). These results suggested that variants of IFNGR1 may have a close relation with the PTB risk in Chinese Tibetan population. PMID- 29228702 TI - LncRNA and mRNA profiling during activation of tilapia macrophages by HSP70 and Streptococcus agalactiae antigen. AB - Objectives: To investigate the lncRNA profiling during tilapia peritoneal macrophages (TPMs) activation and discuss the relationship between lncRNA and mRNA. Materials and Methods: RNA sequencing was used to investigate the lncRNA and mRNA profiles of TPMs activation following stimulation with Streptococcus agalactiae (Sa) antigen, heat shock protein 70 (HSP70) and HSP70+Sa. The expressions of lncRNA and mRNA were confirmed by qPCR. 356 lncRNA, 10173 mRNA and 1782 transcripts of uncertain coding potential (TUCP) were differentially expressed by pairwise comparison. These lncRNAs were shorter in length, fewer in exon number and higher in expression levels as compared with mRNAs. 683 lncRNAs and 4320 mRNAs were co-located, while 316 lncRNAs and 9997 mRNAs were in co expression networks. Seven mRNAs (ANKRD34A, FMODA, GJA3, CNTN5, BMP10, BAI2 and HS3ST6) were involved in both networks of LNC_00035 and LNC_000466. Differentially expressed genes were involved in signaling pathways, such as "phosphorylation", "cytokine-cytokine receptor interaction", "endocytosis" and "MHC protein complex". LNC_000792, LNC_000215, LNC_000035 and LNC_000310, with cis and/or trans relationships with mRNAs, were also involved in ceRNA network. Conclusions: These results might represent the first identified expression profile of lncRNAs and mRNAs in tilapia macrophages activated by HSP70 and Sa. PMID- 29228701 TI - A systematic assessment of chemical, genetic, and epigenetic factors influencing the activity of anticancer drug KP1019 (FFC14A). AB - KP1019 ([trans-RuCl4(1H-indazole)2]; FFC14A) is one of the promising ruthenium based anticancer drugs undergoing clinical trials. Despite the pre-clinical and clinical success of KP1019, the mode of action and various factors capable of modulating its effects are largely unknown. Here, we used transcriptomics and genetic screening approaches in budding yeast model and deciphered various genetic targets and plethora of cellular pathways including cellular signaling, metal homeostasis, vacuolar transport, and lipid homeostasis that are primarily targeted by KP1019. We also demonstrated that KP1019 modulates the effects of TOR (target of rapamycin) signaling pathway and induces accumulation of neutral lipids (lipid droplets) in both yeast and HeLa cells. Interestingly, KP1019 mediated effects were found augmented with metal ions (Al3+/Ca2+/Cd2+/Cu2+/Mn2+/Na+/Zn2+), and neutralized by Fe2+, antioxidants, osmotic stabilizer, and ethanolamine. Additionally, our comprehensive screening of yeast histone H3/H4 mutant library revealed several histone residues that could significantly modulate the KP1019-induced toxicity. Altogether, our findings in both the yeast and HeLa cells provide molecular insights into mechanisms of action of KP1019 and various factors (chemical/genetic/epigenetic) that can alter the therapeutic efficiency of this clinically important anticancer drug. PMID- 29228703 TI - Dual inhibition of BRD4 and PI3K-AKT by SF2523 suppresses human renal cell carcinoma cell growth. AB - Bromodomain-containing protein 4 (BRD4) and PI3K-AKT are both important for renal cell carcinoma (RCC) development and progression. SF2523 is a BRD4 and PI3K-AKT dual inhibitor. The present study demonstrated that SF2523 was cytotoxic and anti proliferative to established RCC cell lines (786-O and A498) and primary human RCC cells. SF2523 induced activation of caspase and apoptosis in RCC cells. Further, SF2523 disrupted RCC cell cycle progression and inhibited cell migration in vitro. At the signaling level, SF2523 in-activated PI3K-AKT-mTOR, and downregulated BRD4-dependent proteins, Bcl-2 and Myc, in RCC cells. Remarkably, SF2523 was more efficient than Wortmannin (the PI3K inhibitor) and JQ1 (the BRD4 specific inhibitor) in killing RCC cells. In vivo, SF2523 administration at well tolerated doses suppressed 786-O xenograft tumor growth in severe combined immunodeficient (SCID) mice. Together, our results suggest that concurrent blockage of BRD4 and PI3K-AKT signalings by SF2523 efficiently inhibits RCC cell growth in vitro and in vivo. PMID- 29228704 TI - Role of HIF-1a in regulating autophagic cell survival during cerebral ischemia reperfusion in rats. AB - Hypoxia-inducible factor-1a (HIF-1a) plays a beneficial role during cerebral ischemia reperfusion (IR), but the underlying molecular mechanisms are not completely understood. Here, we aimed to investigate the effects and molecular regulation of HIF-1a on brain cell apoptosis and autophagy during IR. We found that augmentation of HIF-1a in re-perfused hematopoietic cells significantly reduced brain damage, alleviated brain edema and improved neural function during IR, seemingly through two HIF-1a target genes BNIP3 and NIX, which were critical regulators for cell apoptosis and autophagic cell survival. in vitro, HIF-1a induced up-regulation of BNIP3 and NIX in human cortical neuron cells, HCN-1A. Inhibition of BNIP3 and NIX significantly attenuated HIF-1a-suppressed cell apoptosis and HIF-1a-induced cell autophagy. Together, these data suggest that HIF-1a may ameliorate brain damages during IR through BNIP3 and NIX -dependent augmentation of autophagic cell survival and reduction in cell apoptosis. PMID- 29228707 TI - PD-L1 immunohistochemical assays for assessment of therapeutic strategies involving immune checkpoint inhibitors in non-small cell lung cancer: a comparative study. AB - Although immune checkpoints inhibitors have exhibited promising activity in clinical trials in non-small cell lung cancer (NSCLC) patients, the current programmed cell death-ligand 1 (PD-L1) assays are inconsistent in terms of the staining analysis and scoring system used. To verify the interchangeability of the available PD-L1 assays, we performed immunohistochemistry using three antibody clones used in clinical trials (22C3, SP263, and SP142) and the E1L3N clone as a laboratory developed test for 97 resected NSCLC specimens. Matched tissue microarray specimens were also stained. Staining with 22C3 yielded a greater proportion of stained tumor cells, whereas SP142 staining consistently labelled fewer tumor cells. However, when various cut-off criteria were applied, the positivity rates for PD-L1 were similar, with high concordance, under assay specific cut-offs. Moreover, seven cases of discordant PD-L1 expression between the resected specimen and matched tissue microarray specimens were observed. In conclusion, despite of inter-assay variability of the PD-L1 status in NSCLC, the positivity rate appears to be similar under assay-specific criteria. Hence, an appropriate clinically defined algorithm or cut-off should be separately applied for each assay. Moreover, multiple biopsy specimens from different tumor areas should be obtained to reduce false results due to intratumoral heterogeneity in PD-L1 expression. PMID- 29228705 TI - YAP1 inhibition radiosensitizes triple negative breast cancer cells by targeting the DNA damage response and cell survival pathways. AB - The Hippo pathway is an evolutionarily conserved signaling pathway that regulates proliferation and apoptosis to control organ size during developmental growth. Yes-associated protein 1 (YAP1), the terminal effector of the Hippo pathway, is a transcriptional co-activator and a potent growth promoter that has emerged as a critical oncogene. Overexpression of YAP1 has been implicated in promoting resistance to chemo-, radiation and targeted therapy in various cancers. However, the role of YAP1 in radioresistance in triple-negative breast cancer (TNBC) is currently unknown. We evaluated the role of YAP1 in radioresistance in TNBC in vitro, using two approaches to inhibit YAP1: 1) genetic inhibition by YAP1 specific shRNA or siRNA, and 2) pharmacological inhibition by using the small molecule inhibitor, verteporfin that prevents YAP1 transcriptional activity. Our findings demonstrate that both genetic and pharmacological inhibition of YAP1 sensitizes TNBC cells to radiation by inhibiting the EGFR/PI3K/AKT signaling axis and causing an increased accumulation of DNA damage. Our results reveal that YAP1 activation exerts a protective role for TNBC cells in radiotherapy and represents a pharmacological target to enhance the anti-tumor effects of DNA damaging modalities in the treatment of TNBC. PMID- 29228706 TI - Pharmacological Rac1 inhibitors with selective apoptotic activity in human acute leukemic cell lines. AB - Rac1 GTPase has long been recognized as a critical regulatory protein in different cellular and molecular processes involved in cancer progression, including acute myeloid leukemia. Here we show the antitumoral activity of ZINC69391 and 1A-116, two chemically-related Rac1 pharmacological inhibitors, on a panel of four leukemic cell lines representing different levels of maturation. Importantly, we show that the main mechanism involved in the antitumoral effect triggered by the Rac1 inhibitors comprises the induction of the mitochondrial or intrinsic apoptotic pathway. Interestingly, Rac1 inhibition selectively induced apoptosis on patient-derived leukemia cells but not on normal mononuclear cells. These results show the potential therapeutic benefits of targeting Rac1 pathway in hematopoietic malignancies. PMID- 29228708 TI - Blood biomarkers in adults with lymph node enlargement contribute to diagnostic significance of malignancy. AB - Lymph node enlargement is a common presentation and has a possibility of malignancy like lymphoma that requires early diagnosis. This study aims to analyze the clinical characteristics of these patients and finds out useful predictors of malignant diseases. We retrospectively investigated 81 patients with lymph node enlargement between July 2, 2014 and May 17, 2016. The characteristics and laboratory findings were evaluated combining with the final diagnosis. The diagnoses were malignancy in 51 patients and benign lymphadenopathy in 30 patients. Increased beta2-microglobulin (B2M) (P = 0.012) was found to be associated with malignant diseases, and level of 3699.5 MUg/L was used as a cut-off value to differentiate the malignancies from benign diseases, offering 63.4% sensitivity and 87.0% specificity. Immunoglobulin G (IgG) (P = 0.038) levels were significantly lower in malignant group, whose receiver operating characteristic curve showed that level of 1121.5 mg/dl had sensitivity and specificity as 58.5% and 82.6%. Moreover, through analysis of cytokines, we found interleukin-10 (IL-10) levels were elevated in malignant group compared with benign group. Serum B2M and IgG levels were concluded to be useful parameters for predicting malignancies. Besides, increased IL-10 levels indicated a higher risk of malignancy in some way. PMID- 29228709 TI - Targeting LncRNA HOTAIR suppresses cancer stemness and metastasis in oral carcinomas stem cells through modulation of EMT. AB - Increasing evidence indicates that long non-coding RNAs (lncRNAs) regulate diverse cellular processes, such as cell growth, apoptosis and tumorigenesis. However, the functional roles of lncRNAs and mechanistic analysis of their interplays with oncogenic pathways in oral cancer remain largely unknown. In the current study, we examined the significance of lncRNA HOTAIR (HOX transcript antisense RNA) in tumor progression of oral squamous cell carcinomas (OSCC). We found the expression of HOTAIR was upregulated in tumor tissues, especially in the metastatic samples. And it was also observed in metastatic OSCC cell lines. Silence of HOTAIR in oral carcinomas stem cells (OCSC) significantly inhibited their cancer stemness, invasiveness and tumourigenicity in xenotransplantation models. By contrast, overexpression of HOTAIR in OSCC enhanced their metastatic potential and epithelial-mesenchymal transition (EMT) characteristics. And we showed that the expression of HOTAIR was positively related to mesenchymal markers and inversely correlated with epithelial marker in clinical samples. Moreover, Kaplan-Meier survival analysis suggested that high level of HOTAIR was a strong predictor of poor survival in OSCC patients. Collectively, our data demonstrated that HOTAIR-mediated cancer stemness and metastasis are associated with the regulation of EMT and HOTAIR may serve as a therapeutic target in OSCC. PMID- 29228710 TI - Irisin treatment improves healing of dystrophic skeletal muscle. AB - Background: Irisin is an exercise induced myokine that is shown to promote browning of adipose tissue and hence, increase energy expenditure. Furthermore, our unpublished results indicate that Irisin improves myogenic differentiation and induces skeletal muscle hypertrophy. Since exercise induced skeletal muscle hypertrophy improves muscle strength, we wanted to investigate if ectopic injection of Irisin peptide improves skeletal muscle function in a mouse model of muscular dystrophy. This utility of Irisin peptide is yet to be studied in animal models. Methods: In order to test this hypothesis, we expressed and purified recombinant murine Irisin peptide from E. coli. Three- to six-week-old male mdx mice were injected IP with either vehicle (dialysis buffer) or Irisin recombinant peptide for two or four weeks, three times-a-week. Results: Irisin injection increased muscle weights and enhanced grip strength in mdx mice. Improved muscle strength can be attributed to the significant hypertrophy observed in the Irisin injected mdx mice. Moreover, Irisin treatment resulted in reduced accumulation of fibrotic tissue and myofiber necrosis in mdx mice. In addition, Irisin improved sarcolemmal stability, which is severely compromised in mdx mice. Conclusion: Irisin injection induced skeletal muscle hypertrophy, improved muscle strength and reduced necrosis and fibrotic tissue in a murine dystrophy model. These results demonstrate the potential therapeutic value of Irisin in muscular dystrophy. PMID- 29228711 TI - At seeming safe concentrations, synergistic effects of PM2.5 and formaldehyde co exposure induces Alzheimer-like changes in mouse brain. AB - Alzheimer's disease (AD) is a serious, common, global disease, yet its etiology and pathogenesis are incompletely understood. Air pollution is a multi-pollutants co-exposure system, which may affect brain. The indoor environment is where exposure to both air particulate matter (<2.5 MUm in diameter) (PM2.5) and formaldehyde (FA) can occur simultaneously. Whether exposure to such a multi pollutant (PM2.5 plus FA) mixture contributes to the development of AD, and whether there is a difference between exposure to PM2.5 or FA alone needs to be investigated. To determine the objective, C57BL/6J mice were exposed daily to PM2.5 (0.193 mg/Kg/day), FA (0.155 mg/Kg/day) or multi-pullutants (0.193 mg/Kg/day PM2.5 plus 0.155 mg/Kg/day FA) for one week. AD-like changes and upstream events were investigated after exposure. The results showed that exposure to PM2.5 or FA alone in this study had little or no adverse effects on the mouse brain. However, some AD-like pathologies were detected after multi pullutants co-exposure. This work suggested PM2.5 plus FA co-exposure has more potential to induce AD-like pathologies than exposure alone. Oxidative stress and inflammation may be involved into the toxic mechanisms. Synergistic effects of co exposure may induce the hygienic or safety standards of each pollutant not safe. PMID- 29228712 TI - The cargo protein MAP17 (PDZK1IP1) regulates the immune microenvironment. AB - Inflammation is a complex defensive response activated after various harmful stimuli allowing the clearance of damaged cells and initiating healing and regenerative processes. Chronic, or pathological, inflammation is also one of the causes of neoplastic transformation and cancer development. MAP17 is a cargo protein that transports membrane proteins from the endoplasmic reticulum. Therefore, its overexpression may be linked to an excess of membrane proteins that may be recognized as an unwanted signal, triggering local inflammation. Therefore, we analyzed whether its overexpression is related to an inflammatory phenotype. In this work, we found a correlation between MAP17 expression and inflammatory phenotype in tumors and in other inflammatory diseases such as Crohn's disease, Barrett's esophagus, COPD or psoriasis. MAP17 expression correlated also with the markers of inflammation HLAs, BBS10, HERC2, ADNP and PYCARD. Furthermore, we found that MAP17 expression directly regulates NFAT2 and IL-6 activation, inducing the differentiation of monocytes to dendritic cells and suggesting a causal role of MAP17 in inflammation. Immunohistochemistry confirms local inflammation, mainly CD45+ cells, at the site of expression of MAP17, at least in tumors, Crohn's and psoriasis. Therefore, our data indicates that the overexpression of the protein MAP17 plays important role in diseases involving chronic inflammation. PMID- 29228713 TI - Cell surface Thomsen-Friedenreich proteome profiling of metastatic prostate cancer cells reveals potential link with cancer stem cell-like phenotype. AB - The tumor-associated Thomsen-Friedenreich glycoantigen (TF-Ag) plays an important role in hematogenous metastasis of multiple cancers. The LTQ Orbitrap LC-MS/MS mass spectrometry analysis of cell surface TF-Ag proteome of metastatic prostate cancer cells reveals that several cell surface glycoproteins expressing this carbohydrate antigen in prostate cancer (CD44, alpha2 integrin, beta1 integrin, CD49f, CD133, CD59, EphA2, CD138, transferrin receptor, profilin) are either known as stem cell markers or control important cancer stem-like cell functions. This outcome points to a potential link between TF-Ag expression and prostate cancer stem-like phenotype. Indeed, selecting prostate cancer cells for TF-Ag expression resulted in the enrichment of cells with stem-like properties such as enhanced clonogenic survival and growth, prostasphere formation under non differentiating and differentiating conditions, and elevated expression of stem cell markers such as CD44 and CD133. Further, the analysis of the recent literature demonstrates that TF-Ag is a common denominator for multiple prostate cancer stem-like cell populations identified to date and otherwise characterized by distinct molecular signatures. The current paradigm suggests that dissemination of tumor cells with stem-like properties to bone marrow that occurred before surgery and/or radiation therapy is largely responsible for disease recurrence years after radical treatment causing a massive clinical problem in prostate cancer. Thus, developing means for destroying disseminated prostate cancer stem-like cells is an important goal of modern cancer research. The results presented in this study suggest that multiple subpopulation of putative prostate cancer stem-like cells characterized by distinct molecular signatures can be attacked using a single target commonly expressed on these cells, the TF-Ag. PMID- 29228714 TI - Unique expression signatures of circular RNAs in response to DNA tumor virus SV40 infection. AB - Circular RNAs (circRNAs), identified as a class of widely expressed endogenous regulatory RNAs, are involved in diverse physiological and pathological processes. However, their role in viral pathogenesis and cellular antiviral response remains unexplored. In this study, a potent DNA tumor virus, simian virus 40 (SV40), was used as a model to investigate the viral influences on cellular circRNA transcriptome. Using RNA-seq, 15,241 putative circRNAs were identified de novo from 5,057 parental genes in monkey kidney-derived Vero cells. The expression of selected circRNAs was confirmed by reverse transcription polymerase chain reaction and Sanger sequencing. Further analysis showed that most circRNAs comprised multiple exons, and most parental genes produced multiple circRNA isoforms. A total of 134 significantly dysregulated circRNAs, including 103 upregulated and 31 downregulated circRNAs, were found after SV40 infection. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that various cancer-related pathways, including p53 and Wnt pathway, could be affected by SV40 infection via the alteration of the circRNA hosting genes. Moreover, diverse cellular immune pathways, including Toll-like receptor pathway and Janus kinase-signal transducer and activator of transcription pathway, could also be affected by SV40 infection. An integrated circRNA-miRNA gene analysis suggested the putative function of circRNAs as cellular and viral miRNA decoys to indirectly regulate the gene expression during SV40 infection. This study presented the first comprehensive expression and functional profile of circRNAs in response to SV40 infection, thus providing new insights into the mechanisms of viral pathogenesis and cellular immune response. PMID- 29228716 TI - Sox2 modulates motility and enhances progression of colorectal cancer via the Rho ROCK signaling pathway. AB - Sox2 (Sry-box2) is essential for a variety of stem cells and is also expressed in colorectal cancer (CRC). However, the underlying mechanism by which Sox2 enhances CRC progression remains unclear. In the present study, we show that elevated Sox2 expression is significantly correlated with poor clinical prognosis. CRC is phenotypically heterogeneous, and harbors several subtypes of cancer cells. Elevated Sox2 expression was always detected in rounded-shape cells, which co located to poorly differentiated regions, the invasive frontier and metastatic lesions. Knockdown of Sox2 in CRC cells not only decreased the number of round shaped cells, but also suppressed cell migration, invasion as well as attenuated colony forming capacity and tumorigenicity. By contrast, overexpression of Sox2 in CRC cells was associated with up-regulation of multidrug resistance genes and accelerated CRC progression. Moreover, Sox2 conferred activation of Rho-ROCK signaling, whereas inhibition of ROCK signaling decreased cell migration, invasion, colony formation and self-renewal of CRC. Our results reveal that CRC is phenotypically and functionally heterogeneous. Elevated Sox2 expression activates the Rho-ROCK pathway, which in turn changes cell morphology and promotes cell migration and progression. PMID- 29228715 TI - Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas. AB - Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA. For different case-control comparisons, we report models including between 1-14 candidate SNPs. A genome-wide significant association of rs17659990 (P=5.43*10-9, DOCK3, chromosome 3p21.2) with colorectal cancer risk was observed. Furthermore, 56 SNPs known to influence susceptibility to colorectal cancer and advanced adenoma were tested in a hypothesis-driven approach and several of them were found to be relevant in our Austrian cohort. After correction for multiple testing (alpha=8.9*10-4), the most significant associations were observed for SNPs rs10505477 (P=6.08*10-4) and rs6983267 (P=7.35*10-4) of CASC8, rs3802842 (P=8.98*10-5, COLCA1,2), and rs12953717 (P=4.64*10-4, SMAD7). All previously unreported SNPs demand replication in additional samples. Reanalysis of existing GWAS datasets using model selection as tool to detect SNPs associated with a complex trait may present a promising resource to identify further genetic risk variants not only for colorectal cancer. PMID- 29228717 TI - Somatic PRDM2 c.4467delA mutations in colorectal cancers control histone methylation and tumor growth. AB - The chromatin modifier PRDM2/RIZ1 is inactivated by mutation in several forms of cancer and is a putative tumor suppressor gene. Frameshift mutations in the C terminal region of PRDM2, affecting (A)8 or (A)9 repeats within exon 8, are found in one third of colorectal cancers with microsatellite instability, but the contribution of these mutations to colorectal tumorigenesis is unknown. To model somatic mutations in microsatellite unstable tumors, we devised a general approach to perform genome editing while stabilizing the mutated nucleotide repeat. We then engineered isogenic cell systems where the PRDM2 c.4467delA mutation in human HCT116 colorectal cancer cells was corrected to wild-type by genome editing. Restored PRDM2 increased global histone 3 lysine 9 dimethylation and reduced migration, anchorage-independent growth and tumor growth in vivo. Gene set enrichment analysis revealed regulation of several hallmark cancer pathways, particularly of epithelial-to-mesenchymal transition (EMT), with VIM being the most significantly regulated gene. These observations provide direct evidence that PRDM2 c.4467delA is a driver mutation in colorectal cancer and confirms PRDM2 as a cancer gene, pointing to regulation of EMT as a central aspect of its tumor suppressive action. PMID- 29228718 TI - Increased single-strand annealing rather than non-homologous end-joining predicts hereditary ovarian carcinoma. AB - Mutations in genes encoding DNA double-strand break (DSB) repair components, especially homologous recombination (HR) proteins, were found to predispose to breast and ovarian cancer. Beyond high penetrance risk gene mutations underlying monogenic defects, low risk gene mutations generate polygenic defects, enlarging the fraction of individuals with a predisposing phenotype. DSB repair dysfunction opens new options for targeted therapies; poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for BRCA-mutated and platinum-responsive ovarian cancers. In this work, we performed functional analyses in peripheral blood lymphocytes (PBLs) using a case-control design. We examined 38 women with familial history of breast and/or ovarian cancer, 40 women with primary ovarian cancer and 34 healthy controls. Using a GFP-based test we analyzed error-prone DSB repair mechanisms which are known to compensate for HR defects and to generate chromosomal instabilities. While non-homologous end-joining (NHEJ) did not discriminate between cases and controls, we found increases of single-strand annealing (SSA) in women with familial risk vs. controls (P=0.016) and patients with ovarian cancer vs. controls (P=0.002). Consistent with compromised HR we also detected increased sensitivities to carboplatin in PBLs from high-risk individuals (P<0.0001) as well as patients (P=0.0011) compared to controls. Conversely, neither PARP inhibitor responses nor PARP activities were altered in PBLs from the case groups, but PARP activities increased with age in high-risk individuals, providing novel clues for differential drug mode-of-action. Our findings indicate the great potential of detecting SSA activities to deliver an estimate of ovarian cancer susceptibility and therapeutic responsiveness beyond the limitations of genotyping. PMID- 29228719 TI - Levels of Leydig cell autophagy regulate the fertility of male naked mole-rats. AB - Fertility is abolished in nonbreeding males in colonies of natal naked mole-rats (NMRs). Although spermatogenesis occurs in both breeding and nonbreeding male NMRs, the mechanisms underlying the differences in fertility between breeders and nonbreeders remain unexplored. In this study, a significant decrease in autophagy was observed in Leydig cells of the testis from nonbreeding male NMRs. This alteration was visualised as a significant decrease in the levels of autophagy related gene 7 (Atg7), Atg5, microtubule-associated protein 1A/B light chain 3 (LC3-II/I) and the number of autophagosomes and an increase in P62 levels using Western blotting analyses. Furthermore, monodansylcadaverine (MDC) staining and Western blot analyses revealed that testosterone production decreased in nonbreeding male NMR Leydig cells, this decrease was associated with a reduction in autophagy. Primary Leydig cells from breeding and nonbreeding male NMRs were processed to investigate the effect of an autophagy inhibitor (3-MA, 3 methyladenine) or an autophagy activator (rapamycin) on testosterone production. Rapamycin induced an increase in testosterone production in NMR Leydig cells, whereas 3-MA had the opposite effect. Consequently, spermatogenesis, the weight of the testis, and androgen levels were dramatically reduced in nonbreeding male NMRs. While rapamycin treatment restored the fertility of nonbreeding male NMRs. Based on these results, inadequate autophagy correlates with a decrease in steroid production in nonbreeding male NMR Leydig cells, which may ultimately influence the spermatogenesis and fertilities of these animals. PMID- 29228720 TI - Gastric myoelectric activity during cisplatin-induced acute and delayed emesis reveals a temporal impairment of slow waves in ferrets: effects not reversed by the GLP-1 receptor antagonist, exendin (9-39). AB - Preclinical studies show that the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin (9-39), can reduce acute emesis induced by cisplatin. In the present study, we investigate the effect of exendin (9-39) (100 nmol/24 h, i.c.v), on cisplatin (5 mg/kg, i.p.)-induced acute and delayed emesis and changes indicative of 'nausea' in ferrets. Cisplatin induced 37.2 +/- 2.3 and 59.0 +/- 7.7 retches + vomits during the 0-24 (acute) and 24-72 h (delayed) periods, respectively. Cisplatin also increased (P<0.05) the dominant frequency of gastric myoelectric activity from 9.4 +/- 0.1 to 10.4 +/- 0.41 cpm and decreased the dominant power (DP) during acute emesis; there was a reduction in the % power of normogastria and an increase in the % power of tachygastria; food and water intake was reduced. DP decreased further during delayed emesis, where normogastria predominated. Advanced multifractal detrended fluctuation analysis revealed that the slow wave signal shape became more simplistic during delayed emesis. Cisplatin did not affect blood pressure (BP), but transiently increased heart rate, and decreased heart rate variability (HRV) during acute emesis; HRV spectral analysis indicated a shift to 'sympathetic dominance'. A hyperthermic response was seen during acute emesis, but hypothermia occurred during delayed emesis and there was also a decrease in HR. Exendin (9-39) did not improve feeding and drinking but reduced cisplatin-induced acute emesis by ~59 % (P<0.05) and antagonised the hypothermic response (P<0.05); systolic, diastolic and mean arterial BP increased during the delayed phase. In conclusion, blocking GLP-1 receptors in the brain reduces cisplatin-induced acute but not delayed emesis. Restoring power and structure to slow waves may represent a novel approach to treat the side effects of chemotherapy. PMID- 29228721 TI - DEK promoted EMT and angiogenesis through regulating PI3K/AKT/mTOR pathway in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer associated with poor prognosis. As an oncogene, DEK involves in regulation of various cellular metabolisms and plays an important role in tumor growth and progression. Increasing evidences suggested that abnormal expression of DEK is closely related to multiple malignant tumors. However, the possible involvement of DEK in epithelial to mesenchymal transition (EMT) and angiogenesis in TNBC remains unclear. In the present study, we revealed that the over-expression of DEK was significantly correlated with clinical stage, differentiation, and lymph node (LN) metastasis of TNBC and indicated poor overall survival of TNBC patients. Moreover, we demonstrated that DEK depletion could significantly reduce cell proliferation, migration, invasion and angiogenesis in vitro. We also found that DEK promoted cancer cell angiogenesis and metastasis by activating the PI3K/AKT/mTOR pathway. Furthermore, we revealed the inhibitory effect of DEK depletion on tumor growth and progression in a xenograft tumor model in mice. These data indicated that DEK promotes TNBC cell proliferation, angiogenesis, and metastasis via PI3K/AKT/mTOR signaling pathway, and therefore, it might be a potential target in TNBC therapy. PMID- 29228722 TI - Prognostic factors for histiocytic and dendritic cell neoplasms. AB - Histiocytic and dendritic cell neoplasms are rare and poorly studied. We report the clinical characteristics and prognostic factors in such cases in Japan. We investigated the clinical characteristics and survival in 87 adult patients with histiocytic and dendritic cell neoplasms. Fifty patients had histiocytic sarcoma, 12 had Langerhans cell histiocytosis, 11 had follicular dendritic cell sarcoma, 8 had Langerhans cell sarcoma, 6 had interdigitating cell sarcoma and 1 had indeterminate dendritic cell sarcoma. The median follow-up period was 18.0 (range: 9.6-71.8) months, and median overall survival (OS) was 23.5 months. The 2 year OS rate was 49.2%. In the multivariate analysis, elevated lactate dehydrogenase (LDH) (p =.004), ECOG performance status (PS) 2-4 (p =.006), and Ann Arbor stage III-IV (p =.008) affected OS. Stratification by elevated LDH, ECOG PS 2-4, and Ann Arbor stage III-IV allowed classification of patients into low risk, intermediate risk, and high risk groups. The same classification was applicable for HS and non-HS categories. In the rare neoplasms of histiocytic and dendritic cell sarcoma, ECOG PS, Ann Arbor stage, and LDH are important prognostic factors for predicting survival. PMID- 29228723 TI - An NGS-based approach for the identification of sex-specific markers in snakehead (Channa argus). AB - We described a next generation sequencing (NGS)-based approach to identify sex specific markers and subsequently determine whether a species has male or female heterogamety. To test the accuracy of this technique, we examined the snakehead (Channa argus), which is economically important freshwater fish in China. Males grow faster than females, and there is significant interest in developing methods to skew breeding towards all-males to increase biomass yields. NGS was conducted on DNAs of individual female and male, the male reads were spitted into 60 bp K mers and aligned to the female reference genome assembled by female reads, unaligned male K-mers-60 were kept in next filter process. Meanwhile, DNA sample of 48 females was pooled and sequenced, this data was further used to filter out the previous unaligned male K-mers-60. Hence, numbers of candidate Y chromosome specific sequences were screened out, their sex-specificity were validated in wild snakeheads through PCR amplification. Finally, three Y chromosome-specific fragments (Contig-275834, Contig-359642, and Contig-418354) were identified, and specific primers were obtained to distinguish the sex of snakehead. Additionally, a pair of primers of Contig-275834 (275834X/Y-F and 275834X/Y-R) was exploited to distinguish XX females, XY males, and YY super-males, whose amplification products of different lengths were produced for different sexes. Therefore, our work demonstrated the ability of NGS data in identification of sex-specific markers, and the pipeline adopted in our study could be applied in any species of sex differentiation. Furthermore, the sex-specific markers have tremendous potential for improving the efficiency of all-male breeding practices in snakehead. PMID- 29228724 TI - Transforming growth factor beta-induced epithelial to mesenchymal transition requires the Ste20-like kinase SLK independently of its catalytic activity. AB - Invasion can be stimulated in vitro using the soluble ligand transforming growth factor-beta (TGFbeta) to induce a process called epithelial-to-mesenchymal transition (EMT) characterized by cell-cell junction breakdown and an invasive phenotype. We have previously demonstrated a role for Ste20-like kinase SLK cell migration and invasion. Here we show that SLK depletion in NMuMG mammary epithelial cells significantly impairs their TGFbeta-induced migration and invasion. Immunofluorescence studies show that a fraction of SLK localizes to E cadherin-positive adherens junction and that SLK impairs the breakdown of cell cell contacts. We find that SLK-depleted cultures express significantly lower levels of vimentin protein as well as Snai1 and E-cadherin mRNA levels following TGF-beta treatment. Surprisingly, our data show that SLK depletion does not affect the activation and nuclear translocation of Smad3. Furthermore, we show that expression of a dominant negative kinase does not impair tight junction breakdown and rescues Snai1 mRNA expression levels. Together these data suggest that SLK plays a novel role in TGFbeta-induced EMT, independent of Smads, in a kinase activity-independent manner. PMID- 29228725 TI - Distinct clinical characteristics draw a new prognostic model for splenic marginal zone lymphoma in HBV high prevalent region. AB - Splenic marginal zone lymphoma (SMZL) is a rare indolent B-cell neoplasm with hepatitis virus supposed to involve in the pathogenesis. The characteristics of SMZL derived from Caucasia population and high hepatitis C virus (HCV) infection region have been widely investigated, but few was reported in the Eastern population with HBV prevalent region. We analyzed the clinical characteristics, cytogenetic aberrations and prognostic factors in 160 SMZL patients from China. 25 patients (16%) were HBsAg-positive and 54 (34%) patients with resolved HBV infection. IGH gene usage was analyzed in 39 patients. The preferential usages of IGHV genes were IGHV1-2 (26%), followed by IGHV4-34 (18%) and IGHV2-70 (10%). The patients with HBV infection presented biased IGHV-D-J rearrangements and mutational status. Using three independent factors hemoglobin level, HBsAg positivity and complex karyotype, we developed a new hierarchical prognostic model, which showed a better c-index than the previously reported IIL and HPLL scoring systems in SMZL. In conclusion, SMZL in HBV prevalent region have unique clinical and biological characteristics and new prognostic scoring model should be adopted in this population. PMID- 29228726 TI - Tyrosine kinase inhibitors show different anti-brain metastases efficacy in NSCLC: A direct comparative analysis of icotinib, gefitinib, and erlotinib in a nude mouse model. AB - Brain metastasis is an increasing problem in non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, and icotinib, are reported to be effective in patients with brain metastases. However, direct comparative studies of the pharmacokinetics and efficacy of these three drugs in treating brain metastases are lacking. In the present investigation, we found that gefitinib penetrated the blood-tumor barrier and was distributed to brain metastases more effectively than erlotinib or icotinib in a nude mouse model. The 1-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 9.82+/-1.03%, 4.83+/-0.25%, and 2.62+/ 0.21%, respectively. The 2-h ratio of brain metastases to plasma concentration for gefitinib, erlotinib, and icotinib was 15.11+/-2.00%, 5.73+/-1.31%, and 2.69+/-0.31%, respectively. Gefitinib exhibited the strongest antitumor activity (pgefitinib vs. erlotinib=0.005; pgefitinib vs. icotinib=0.002). Notably, erlotinib exhibited a better treatment efficacy than icotinib (p=0.037). Consistently, immunohistochemical data showed that TKIs differentially inhibit the proliferation of metastatical tumor cells. Gefitinib and erlotinib markedly inhibited the proliferation of tumor cells, while there were more ki-67-positive tumor cells in the icotinib group. Additionally, gefitinib inhibited the phosphorylation of EGFR better than the other drugs, whereas pEGFR expression levels in erlotinib groups were lower than levels in the icotinib group (pgefitinib vs. erlotinib=0.995; pgefitinib vs. icotinib=0.028; perlotinib vs. icotinib=0.042).Altogether, our findings suggest that gefitinib and erlotinib can inhibit the growth of PC-9-luc brain tumors. Gefitinib demonstrated better antitumor activity and penetration rate in brain metastases than erlotinib or icotinib. PMID- 29228727 TI - Prohibitin-mediated mitochondrial ubiquitination during spermiogenesis in Chinese mitten crab Eriocheir sinensis. AB - The sperm of Eriocheir sinensis has a cup-shaped nucleus that contains several mitochondria embedded at the opening of the cup. The acrosome vesicle also contains derivants of mitochondria. The mitochondria distribution pattern involves a decrease in the number and changes in the structure and transportation of these organelles. The decreased number of sperm mitochondria is achieved through autophagy or the ubiquitination pathway. Prohibitin (PHB), the mitochondria inner membrane protein, is an evolutionarily highly conserved protein, is closely associated with spermatogenesis and sperm quality control and is also a potential substrate of ubiquitination. However, whether PHB protein mediates the ubiquitination pathway of sperm mitochondria in crustacean animals remains poorly understood. In the present study, we revealed that PHB, a substrate of ubiquitin, participates in the ubiquitination and degradation of mitochondria during spermiogenesis in E. sinensis. To confirm this finding, we used shRNA interference to reduce PHB expression and an overexpression technique to increase PHB expression in vitro. The interference experiment showed that the reduced PHB expression directly affected the polyubiquitination level and mitochondria status, whereas PHB overexpression markedly increased the polyubiquitination level. In vitro experiments also showed that PHB and its ubiquitination decide the fate of mitochondria. PMID- 29228728 TI - Protein tyrosine phosphatase receptor-type delta acts as a negative regulator suppressing breast cancer. AB - Protein tyrosine phosphatase receptor-type delta (PTPRD) is frequently inactivated in human cancers. This study investigated the role of PTPRD in the regulation of stemness, epithelial-mesenchymal transition (EMT), and migration and invasion in breast cancer cells. In vitro, PTPRD silencing using siRNA enhanced the stem cell-like properties of breast cancer cells, including their mammosphere- and holoclone-forming abilities, and it promoted tumorigenicity in vivo. PTPRD knockdown also increased the CD44+/CD24- breast cancer stem cell (BCSC) population and the expression of the stem cell markers ALDH1 and OCT4. It also promoted migration and invasion by breast cancer cell, EMT, and activation of signal transducer and activator of transcription 3 (STAT3). BCSCs expressed low levels of PTPRD, displayed mesenchymal phenotypes, and were more sensitive to IL-6-mediated STAT3 activation than non-BCSCs. PTPRD expression was upregulated by IL-6 in breast cancer cells, thereby establishing a negative feedback circuit by which IL-6 induced canonical STAT3 phosphorylation and transiently upregulated PTPRD, which in turn dephosphorylated STAT3 and prevented downstream signaling via the IL-6/STAT3 cascade. These data suggest that therapies aimed at restoring or enhancing PTPRD expression may be effective in controlling breast cancer progression and metastasis. PMID- 29228729 TI - Development and validation of a model for staging hepatic fibrosis for chronic hepatitis B patients with E antigen-positive. AB - Background: Interest is growing in the use of non-invasive techniques for complementing liver biopsy for liver fibrosis assessment. We aimed to prospectively evaluate liver histology in chronic hepatitis B (CHB) patients with e-antigen positivity, and develop and validate a novel scoring system-e-antigen positive CHB liver fibrosis (EPLF) score-for noninvasively predicting the fibrosis stages. Methods: We identified the baseline variables associated with fibrosis stage (MATAVIR score, F0-F4) in 212 CHB patients with e-antigen positivity. These significant variables were used to develop the EPLF scoring system. The EPLF score equation was developed based on the prediction of fibrosis stages via multivariate ordered logistic regression analysis. The diagnostic powers of the EPLF score and several non-invasive markers were assessed through an area under the receiver operating characteristic curve (AUROC) analyses. This EPLF score model was validated in another set of 208 similar patients. Results: The natural logarithms of serum albumin, HBeAg, and HBsAg levels were selected as significant independent variables for the EPLF score equation. The EPLF score had good diagnostic power (AUROC, 0.72-0.90, p<0.001) and good diagnostic accuracy (72-85%), with a high positive predictive value (80.8-92.8%) for each fibrosis stage in the test group. Similar results were observed in the validation group (AUROC, 0.73-0.89, p<0.001). The EPLF score exhibited a strong correlation with fibrosis stage (r=0.67, p<0.001), and was the preferable non-invasive marker for staging liver fibrosis. Conclusion: In e-antigen-positive patients with CHB, the EPLF score could serve as a potential non-invasive marker of liver fibrosis stage. PMID- 29228730 TI - Wisp2 disruption represses Cxcr4 expression and inhibits BMSCs homing to injured liver. AB - Liver regeneration/repair is a compensatory regrowth following acute liver failure, and bone marrow-derived mesenchyme stem cell (BMSC) transplantation is an effective therapy that promotes liver regeneration/repair. Wnt1 inducible signaling pathway protein 2 (Wisp2) is highly expressed in BMSCs, however, its function remains unclear. In this work, we used clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein -9 nuclease (CRISPR/Cas9) genome editing technology to knockdown Wisp2 in BMSCs, and these modified cells were then transplanted into rats which were induced by the 2-AAF/PH. By linking the expression of Cas9 to green fluorescent protein (GFP), we tracked BMSCs in the rats. Disruption of Wisp2 inhibited the homing of BMSCs to injured liver and aggravated liver damage as indicated by remarkably high levels of ALT and AST. Moreover, the key factor in BMSC transplantation, C-X-C chemokine receptor type 4 (Cxcr4), was down-regulated in the Wisp2 depleted BMSCs and had a lower expression in the livers of the corresponding rats. By tracing the GFP marker, more BMSCs were observed to differentiate into CD31 positive endothelial cells in the functional Wisp2 cells but less in the Wisp2 gene disrupted cells. In summary, Wisp2 promotes the homing of BMSCs through Cxcr4 related signaling during liver repair in rats. PMID- 29228732 TI - Hoxa9 and Hoxa10 induce CML myeloid blast crisis development through activation of Myb expression. AB - Mechanisms underlying the progression of Chronic Myeloid Leukemia (CML) from chronic phase to myeloid blast crisis are poorly understood. Our previous studies have suggested that overexpression of SETBP1 can drive this progression by conferring unlimited self-renewal capability to granulocyte macrophage progenitors (GMPs). Here we show that overexpression of Hoxa9 or Hoxa10, both transcriptional targets of Setbp1, is also sufficient to induce self-renewal of primary myeloid progenitors, causing their immortalization in culture. More importantly, both are able to cooperate with BCR/ABL to consistently induce transformation of mouse GMPs and development of aggressive leukemias resembling CML myeloid blast crisis, suggesting that either gene can drive CML progression by promoting the self-renewal of GMPs. We further identify Myb as a common critical target for Hoxa9 and Hoxa10 in inducing self-renewal of myeloid progenitors as Myb knockdown significantly reduced colony-forming potential of myeloid progenitors immortalized by the expression of either gene. Interestingly, Myb is also capable of immortalizing primary myeloid progenitors in culture and cooperating with BCR/ABL to induce leukemic transformation of mouse GMPs. Significantly increased levels of MYB transcript also were detected in all human CML blast crisis samples examined over chronic phase samples, further suggesting the possibility that MYB overexpression may play a prevalent role in driving human CML myeloid blast crisis development. In summary, our results identify overexpression of HOXA9, HOXA10, and MYB as critical drivers of CML progression, and suggest MYB as a key therapeutic target for inhibiting the self-renewal of leukemia-initiating cells in CML myeloid blast crisis patients. PMID- 29228731 TI - Impact of anger emotional stress before pregnancy on adult male offspring. AB - Previous studies have reported that maternal chronic stress or depression is linked to an increased risk of affective disorders in progeny. However, the impact of maternal chronic stress before pregnancy on the progeny of animal models is unknown. We investigated the behaviors and the neurobiology of 60-day old male offspring of female rats subjected to 21 days of resident-intruder stress before pregnancy. An anger stressed parental rat model was established using the resident-intruder paradigm and it was evaluated using behavioral tests. Anger stressed maternal rats showed a significant increase in locomotion and aggression but a reduction in sucrose preference. Offspring subjected to pre gestational anger stress displayed enhanced aggressive behaviors, reduced anxiety, and sucrose preference. Further, offspring subjected to pre-gestational stress showed significant impairments in the recognition index (RI) on the object recognition test and the number of platform crossings in the Morris water maze test. The monoaminergic system was significantly altered in pre-gestationally stressed offspring, and the expression of phosphorylated cyclic adenosine monophosphate response element binding protein (P-CREB), brain-derived neurotrophic factor (BDNF), and serotonin transporter (SERT) levels in pre gestational stressed offspring were altered in some brain regions. Fluoxetine was used to treat pre-gestational stressed maternal rats and it significantly reduced the changes caused by stress, as evidenced by both behaviors and neural biochemical indexes in the offspring in some but not all cases. These findings suggest that anger stress before pregnancy could induce aggressive behaviors, cognitive deficits, and neurobiological alterations in offspring. PMID- 29228733 TI - Investigating the association between diet and risk of head and neck cancer in Taiwan. AB - Most studies reporting an inverse association between the consumption of vegetables and fruits and head and neck cancer (HNC) risk were conducted in Western populations and only a few included East Asians. The current case-control study investigated the association between diet and HNC risk using data of 838 HNC cases and 998 controls from a case-control study of HNC conducted in Taiwan. Each participant was asked about their consumption of fresh vegetables, pickled vegetables, fresh fruits, citrus fruits, meat, processed meat, fish, egg, and dairy products. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with each food category, adjusted for sex, age, education, and use of alcohol, betel quid and cigarette. An inverse association was observed between HNC risk and daily intake of fresh vegetables (OR = 0.44, 95% CI: 0.20-0.95, p-trend = 0.002) or fruits (OR = 0.55, 95% CI: 0.43-0.72, p-trend = 0.00001). Individuals who did not consume fresh fruits and vegetables daily had more than double the risk of HNC compared to those with daily intake of vegetables and fruits (OR= 2.24, 95% CI: 1.54-3.25). The results of the current study supported an inverse association between the consumption of fresh vegetables and fruits and HNC risk. In addition to cessation of cigarette smoking and betel quid chewing and reduction of alcohol drinking, a public health campaign for preventing the occurrence of HNC should promote a healthy diet that contains plenty of fresh vegetables and fruits. PMID- 29228734 TI - Cutaneous melanoma primary site is linked to nevus density. AB - There are at least two pathways driving cutaneous melanoma; one is linked to an inherent melanoma susceptibility to nevi development and the second to environmental cumulative ultraviolet light exposure. In this study, we examined the relation between nevus density, accrued sun damage and the site of primary melanoma excision. In a series of 888 consecutive cutaneous melanoma patients, melanomas appearing in skin areas with a high relative nevus density were most prominent in men, with an elevated nevus count, at sites without solar elastosis, but with an epidemiological history of previous sunburn. The present study associates melanoma development to sites with high nevus density. Our study supports more careful surveillance of body areas with increased nevus density in patients with high total body number of nevi, especially when they report a history of sunburns at these sites. PMID- 29228735 TI - Verteporfin inhibits gastric cancer cell growth by suppressing adhesion molecule FAT1. AB - Gastric cancer (GC) is a leading cause of death worldwide and in urgent need of targeted drug development. In the current, we investigated the ability of a repositioned drug verteporfin (VP), originally a treatment for macular degeneration, to inhibit GC cell growth. VP inhibited growth of various GC cell lines. Gene expression profiling of GC cell lines treated with VP revealed that migration-related genes and those with oncogenic potential were down-regulated. Of these genes, we found that FAT1, an adhesion molecule promoting cell invasion, was highly suppressed by VP. Silencing of FAT1 suppressed cell migration and invasion as VP did. FAT1 expression was up-regulated in tumors, and patients with high FAT1-expressing tumors had a worse prognosis. We propose that VP- targeting FAT1 to suppress metastatic potential is a promising therapeutic strategy against GC. PMID- 29228736 TI - Bleeding risk with dabigatran, rivaroxaban, warfarin, and antiplatelet agent in Asians with non-valvular atrial fibrillation. AB - It is not understood if dabigatran or rivaroxaban are superior to antiplatelet agents (AA) for safety outcomes in Asians with non-valvular atrial fibrillation (NVAF). In this study we evaluated the bleeding risk of dabigatran, rivaroxaban, warfarin and AA in Asians with NVAF. This national retrospective cohort study analyzed 6,600, 3,167, 5,338 and 8,238 consecutive NVAF patients taking dabigatran, rivaroxaban, warfarin or AAs (including aspirin, clopidogrel or ticlopidine), respectively, from June 1, 2012 to December 31, 2013. Propensity score weighting was used to balance covariates across study groups. Patients were followed until the first occurrence of any bleeding outcome or the end of the study. The CHA2DS2-VASc scores were 4.1+/-1.6, 4.1+/-1.6, 3.3+/-1.8 and 2.4+/-1.6 for the dabigatran, rivaroxaban, warfarin, and AA groups, respectively. There were 5,822 (88.2%) and 164 (5.2%) patients taking low dose dabigatran and rivaroxaban, respectively. Hazard ratios (95% confidence intervals) for dabigatran, rivaroxaban, or warfarin versus AA were: intracranial hemorrhage, 0.36 (0.23-0.57;PP=0.0037) and 1.34 (0.89-2.02;P=0.1664); gastrointestinal bleeding, 0.44 (0.32-0.59;PP=0.0189); and all hospitalized major bleeding, 0.41 (0.32-0.53;PP=0.0644) and 0.90 (0.70-1.16;P=0.4130) after adjustment. The risk reduction of all major bleeding for dabigatran versus AA persisted on subgroup analysis. In conclusion, we observed that dabiagtran was associated with a lower risk of all major bleeding in Asians with NVAF, whereas rivaroxaban had a similar risk of all major bleeding compared with antiplatelet agents after adjustment of comorbidities. PMID- 29228737 TI - Reduced m6A mRNA methylation is correlated with the progression of human cervical cancer. AB - The m6A mRNA methylation involves in mRNA splicing, degradation and translation. Recent studies have revealed that reduced m6A mRNA methylation might promote cancer development. However, the role of m6A mRNA methylation in cervical cancer development remains unknown. Therefore, we investigated the role of m6A methylation in cervical cancer in the current study. We first evaluated the m6A mRNA methylation level in 286 pairs of cervical cancer samples and their adjacent normal tissues by dot blot assay. Then the role of m6A on patient survival rates and cervical cancer progression were assessed. The m6A level was significantly reduced in the cervical cancer when comparing with the adjacent normal tissue. The m6A level reduction was significantly correlated with the FIGO stage, tumor size, differentiation, lymph invasion and cancer recurrence. It was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with cervical cancer. Reducing m6A level via manipulating the m6A regulators expression promoted cervical cancer cell proliferation. And increasing m6A level significantly suppressed tumor development both in vitro and in vivo. Our results showed that the reduced m6A level is tightly associated with cervical cancer development and m6A mRNA methylation might be a potential therapeutic target in cervical cancer. PMID- 29228738 TI - CD24, CD27, CD36 and CD302 gene expression for outcome prediction in patients with multiple myeloma. AB - Multiple myeloma (MM) is a B cell neoplasia characterized by clonal plasma cell (PC) proliferation. Minimal residual disease monitoring by multi-parameter flow cytometry is a powerful tool for predicting treatment efficacy and MM outcome. In this study, we compared CD antigens expression between normal and malignant plasma cells to identify new potential markers to discriminate normal from malignant plasma cells, new potential therapeutic targets for monoclonal-based treatments and new prognostic factors. Nine genes were significantly overexpressed and 16 were significantly downregulated in MMC compared with BMPC (ratio >=2; FDR CD24, CD27, CD36 and CD302) was associated with a prognostic value in two independent cohorts of patients with MM (HM cohort and TT2 cohort, n=345). The expression level of these four genes was then used to develop a CD gene risk score that classified patients in two groups with different survival (P = 2.06E-6) in the HM training cohort. The prognostic value of the CD gene risk score was validated in two independent cohorts of patients with MM (TT2 cohort and HOVON65/GMMGHD4 cohort, n=282 patients). The CD gene risk score remained a prognostic factor that separated patients in two groups with significantly different overall survival also when using publicly available data from a cohort of relapsing patients treated with bortezomib (n=188). In conclusion, the CD gene risk score allows identifying high risk patients with MM based on CD24, CD27, CD36 and CD302 expression and could represent a powerful tool for simple outcome prediction in MM. PMID- 29228739 TI - Regulatory role of NKG2D+ NK cells in intestinal lamina propria by secreting double-edged Th1 cytokines in ulcerative colitis. AB - The role of intestinal lamina propria (LP) NKG2D+ NK cells is unclear in regulating Th1/Th2 balance in ulcerative colitis (UC). In this study, we investigated the frequency of LP NKG2D+ NK cells in DSS-induced colitis model and intestinal mucosal samples of UC patients, as well as the secretion of Th1/Th2/Th17 cytokines in NK cell lines after MICA stimulation. The role of Th1 cytokines in UC was validated by bioinformatics analysis. We found that DSS induced colitis in mice was characterized by a Th2-mediated process. In acute phrase, the frequency of LP NKG2D+ lymphocytes increased significantly and decreased in remission, while the frequency of LP NKG2D+ NK cells decreased significantly in acute phase and increased in remission. No obvious change was found in the frequency of total LP NK cells. Similarly, severe UC patients had a higher expression of mucosal NKG2D and a lower number of NKG2D+ NK cells than mild to moderate UC. In NK cell lines, the MICA stimulation could induce a predominant secretion of Th1 cytokines (TNF, IFN-gamma). Furthermore, in bioinformatics analysis, mucosal Th1 cytokine of TNF, showed a double-edged role in UC when compared to the Th1-mediated disease of Crohn's colitis. In conclusion, LP NKG2D+ NK cells partially played a regulatory role in UC through secreting Th1 cytokines to regulate the Th2-predominant Th1/Th2 imbalance, despite of the concomitant pro-inflammatory effects of Th1 cytokines. PMID- 29228740 TI - Downregulation of semaphorin 3E promotes hallmarks of experimental chronic allergic asthma. AB - Guidance cues such as semaphorins are attractive novel therapeutic targets for allergic disorders. We have previously described an inhibitory effect of semaphorin 3E (Sema3E) on human airway smooth muscle cell function. We have further addressed a canonical role for Sema3E in acute model of allergic asthma in vivo. Considering the chronic nature of the disease, the potential implication of Sema3E to alleviate long-lasting deficits should be investigated. Expression of Sema3E in a chronic model of allergic asthma was assessed after exposure to house dust mite (HDM) as a clinically relevant allergen. Chronic features of allergic asthma including airway hyper-responsiveness (AHR), inflammation, and remodeling were studied in Sema3E-deficient mice. Additionally, the effect of exogenous Sema3E treatment was evaluated in prophylactic and therapeutic experimental models. We have demonstrated that expression of Sema3E is robustly suppressed in the airways upon chronic HDM exposure. Chronic allergic airway disease was significantly augmented in Sema3E-deficient mouse model which was associated with an increased AHR, remodeling, and Th2/Th17 inflammation. Intranasal Sema3E administration restored chronic deficits of allergic asthma in mice. Data from this study unveil a key regulatory role of Sema3E in chronic course of asthma via orchestration of impaired inflammatory and remodeling responses. PMID- 29228741 TI - Autophagy inhibition sensitizes LY3023414-induced anti-glioma cell activity in vitro and in vivo. AB - PI3K-AKT-mTOR signaling is a valuable treatment target for human glioma. LY3023414 is a novel, highly-potent and pan PI3K-AKT-mTOR inhibitor. Here, we show that LY3023414 efficiently inhibited survival and proliferation of primary and established human glioma cells. Meanwhile, apoptosis activation was observed in LY3023414-treated glioma cells. LY3023414 blocked AKT-mTOR activation in human glioma cells. Further studies show that LY3023414 induced feedback activation of autophagy in U251MG cells. On the other hand, autophagy inhibition via adding pharmacological inhibitors or silencing Beclin-1/ATG-5 significantly potentiated LY3023414-induced glioma cell apoptosis. In vivo studies demonstrated that U251MG xenograft tumor growth in mice was suppressed by oral administration of LY3023414. Remarkably, LY3023414's anti-tumor activity was further augmented against the Beclin-1-silenced U251MG tumors. Together, our results suggest that targeting PI3K-AKT-mTOR cascade by LY3023414 inhibits human glioma cell growth in vitro and in vivo. Autophagy inhibition could further sensitize LY3023414 against human glioma cells. PMID- 29228742 TI - Pretreatment nutritional risk scores and performance status are prognostic factors in esophageal cancer patients treated with definitive chemoradiotherapy. AB - This study evaluated the prognostic effects of nutritional risk scores and performance status (PS) on unresectable locally advanced esophageal cancer (LAEC) patients who were treated with definitive concurrent chemoradiotherapy (dCRT). A total of 202 LAEC patients from four different cancer centers were retrospectively reviewed. Nutritional risk and PS were measured using the Nutritional Risk Screening 2002 (NRS-2002) scores and Eastern Cooperative Oncology Group (ECOG) scales. Outcomes were clinical response rate, overall survival (OS) and progression-free survival (PFS). Multivariate analysis of predictive factors of response to dCRT and survival were performed using a logistic regression and a Cox model, respectively. The majority of patients (71.8%) had an ECOG PS score of 0-1, and 52.5% (n=106) of patients were identified as having nutritional risk (NRS-2002 >=3) upon treatment initiation. There was no correlation between NRS-2002 scores and ECOG PS (Spearman's rho=0.046; P=0.516). In multivariate analysis, NRS-2002 scores (P=0.002, HR 2.805, 95%CI: 1.445-5.446) and ECOG PS (P=0.015, HR 2.719, 95%CI: 1.218-6.067) were independent prognostic factors for the response to dCRT. NRS-2002 scores (OS: HR 1.530, 95%CI 1.059-2.209; P=0.023; PFS: HR 1.517, 95%CI 1.105-2.082; P=0.010) and ECOG PS (OS: HR 1.729, 95%CI 1.185-2.522; P=0.005; PFS: HR 1.678, 95%CI 1.179-2.387; P=0.004) were both independent prognostic factors for OS and PFS. In conclusions, NRS-2002 scores and ECOG PS scales both have prognostic effects on clinical response and survival in LAEC, but a significant association of NRS-2002 scores and ECOG PS were not observed. PMID- 29228743 TI - Prognostic role of DEK in human solid tumors: a meta-analysis. AB - Recently, the oncogenic role of DEK has been recognized in several cancer types. However, its prognostic role in human solid tumor remains unclear. Thus, the present meta-analysis, based on 14 published studies (2208 patients) searched from PubMed, Web of Science, and EMBASE databases, assessed the prognostic value of DEK in human solid tumors. Furthermore, the pooled hazard ratio (HR) for overall survival (OS) was evaluated with fixed-effects models. A subgroup analysis was also performed according to the patients' ethnicities and tumor types. Data from these published studies were extracted, and the results showed that the overexpression of DEK was significantly associated with poor OS in human solid tumors. The combined hazards ratio was (HR = 1.83; 95% CI, 1.64-2.05, P < 0.00001) for OS (univariable analysis) with a fixed-effects model without any significant heterogeneity (P = 0.71, I2 = 0%). The combined HR was (HR = 1.70; 95% CI, 1.48-1.96, P < 0.00001) for OS (multivariable analysis) with a fixed effects model, and no significant heterogeneity was observed (P = 0.36, I2 = 9%). Therefore, the overexpression of DEK was correlated with poor survival in human solid tumors, which suggests that the expression status of DEK is a valuable biomarker for the prediction of prognosis and serves as a novel therapeutic target in human solid tumors. PMID- 29228744 TI - Association between polymorphism within interleukin related genes and Graves' disease: a meta-analysis of 22 case-control studies. AB - Graves' disease (GD) is a common autoimmune disorder with a genetic predisposition. There is strong evidence to suggest that both Th1 and Th2 circulating cytokines are involved in the development of GD. In this study, we conducted a meta-analysis to assess the impact of seven variations of five IL related genes on the susceptibility to GD. A total of 22 case-control studies involving 5338 GD patients and 6446 healthy controls were included. The results showed that only one SNP rs1800795 in IL-6 was significantly associated with GD in homozygous model (CC vs. GG: OR = 2.714, 95% CI = 1.047-7.039, p = 0.04), heterozygous model (CG vs. GG: OR = 1.295, 95% CI = 1.013-1.655, p = 0.039), dominant model (CC+CG vs. GG: OR = 1.418, 95% CI = 1.122-1.793, p = 0.003) and additive model (C vs. G: OR = 1.432, 95% CI = 1.087-1.886, p = 0.011).To explain the heterogeneity, we performed the subgroup analysis by ethnicity. The ethnicity stratification revealed that the association between rs1800795 and GD tended to be much stronger for Asian than European population in homozygous, dominant, recessive, and additive models. The remaining 6 SNPs in 4 genes did not show any significant association with GD in any genetic models. Together, our data support that rs1800795 within the IL-6 gene confers genetic susceptibility for GD. Future large-scale studies are required to validate the associations between IL-6 and others IL-related genes and GD. PMID- 29228745 TI - Prognostic role of the pre-treatment platelet-lymphocyte ratio in pancreatic cancer: a meta-analysis. AB - Background and Aims: Recently, the pre-treatment platelet-lymphocyte ratio (PLR), which is based on blood parameters, was accepted as a prognostic factor for patients with various cancers. Numerous studies have investigated the prognostic role of the PLR in pancreatic cancer; however, it remains unclear. Therefore, we conducted this meta-analysis to evaluate the relationship between the pre treatment PLR and overall survival (OS) in pancreatic cancer. Materials and Methods: We performed a systematic literature search of the PubMed, Embase and Web of Science databases for relevant studies that explored the prognostic role of the pre-treatment PLR in pancreatic cancer. The hazard ratios (HRs) and 95% confidence intervals (CIs) related to OS were pooled using a random effects model. Results: Fourteen retrospective cohort studies involving 2,260 patients were included in this meta-analysis. Compared with low PLR, high PLR was a predictor of shorter OS (HR = 1.24, 95% CI: 1.10-1.39, I2 = 74%). Conclusions: In this meta-analysis, high pre-treatment PLR was a bio-predictor of short OS in patients with pancreatic cancer, suggesting that PLR could be used to predict prognosis of patients with pancreatic cancer before treatment. However, additional well-designed and large-scale studies are necessary. PMID- 29228746 TI - Alcohol drinking and gastric cancer risk: a meta-analysis of observational studies. AB - Background: Many studies investigated the association between alcohol drinking and gastric cancer risk, but the results were controversial. We performed a meta analysis of observational studies to explore the association. Materials and Methods: We searched PubMed to identify the relevant studies that reported the association between alcohol drinking and gastric cancer risk up to December 31, 2016. We pooled relative risks (RRs) in random effects model and performed dose response analysis to quantify the association. Cochran Q test and I2 analyses were used to evaluate the heterogeneity. Meta-regression, subgroup, sensitivity and publication bias analyses were also performed. Results: 75 studies were included in our study. The pooled RR of high vs low total alcohol drinking was 1.25 (95% CI, 1.15-1.37, P < 0.001), and a nonlinear association was further observed. Subgroup analysis showed that alcohol drinking significantly associated with the risk of gastric noncardia cancer (RR, 1.19; 95% CI, 1.01-1.40, P = 0.033), but not with the risk of gastric cardia cancer (RR, 1.16; 95% CI, 0.98 1.39, P = 0.087). Notably, the pooled RRs of high vs low analyses were 1.13 (95% CI, 1.03-1.24, P = 0.012) for beer drinking, 1.22 (95% CI, 1.06-1.40, P = 0.005) for liquor drinking, and 0.99 (95% CI, 0.84-1.16, P = 0.857) for wine drinking. Conclusions: Our meta-analysis found a nonlinear association between alcohol drinking and gastric cancer risk, and heavy drinking level was strongly related to gastric cancer risk. Beer and liquor had significant positive associations with gastric cancer risk, while wine drinking would not increase gastric cancer risk. These results need to be verified in future research. PMID- 29228747 TI - The association of matrix metalloproteinase-9 promoter polymorphisms with gastric cancer risk: a meta-analysis. AB - Purpose: A variety of studies have observed that the single nucleotide polymorphisms (SNPs) matrix metalloproteinase-9 (MMP-9) gene may be associated with the risk of gastric cancer(GC), and a cytosine (C) to thymine (T) mutation at the -1562 site of the MMP-9 gene promoter is reported to be closely related to the susceptibility. However, because of the conflicting results of these studies, we undertook a systematic meta-analysis to assess the association between the SNPs and the risk of gastric cancer. Materials and Methods: A computerised literature search was conducted within the databases of PubMed, EMBASE, and ISI Web of Knowledge for studies on the genetic association of MMP-9-1562C/T and gastric cancer published from 2004 to 2015. The pooled odds ratio (OR) and 95% confidence intervals (CI) were estimated for each genotype using the dominant, recessive, co-dominant, and allelic models of the matrix metalloproteinase 9. Results: Our analysis indicated a significant association of MMP-9-1562C/T with gastric cancer (dominant model [CT+TT/CC]: OR = 1.121, 95% CI = 0.965-1.304; recessive model [CC+CT/TT]: OR = 1.663, 95% CI = 1.148-2.408; co-dominant model [TT/CC]: OR = 1.666, 95% CI = 1.127-2.461; [CT/CC]: OR = 1.078, 95% CI = 0.923 1.259; allelic model [T/C]: OR = 1.150, 95% CI =1.014-1.304). Conclusions: Our meta-analysis results demonstrated that MMP-9-1562C/T promoter polymorphisms increase the risk of developing gastric cancer. PMID- 29228748 TI - The role of anti-EGFR agents in the first-line treatment of advanced esophago gastric adenocarcinoma: a meta-analysis. AB - The role of anti-epidermal growth factor receptor (EGFR) therapy is controversial in patients with esophago-gastric adenocarcinoma. We performed this meta-analysis to evaluate whether the addition of an anti-EGFR agent to chemotherapy can produce survival benefits in patients with advanced esophageal adenocarcinoma, gastric adenocarcinoma, or gastroesophageal junction adenocarcinoma. Electronic databases were searched for eligible randomized studies. From six studies, 1,817 patients were included in the meta-analysis of hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS). Compared with chemotherapy alone, anti-EGFR agents in combination with chemotherapy were significantly associated with shorter PFS (HR = 1.14 [95% confidence interval {CI}, 1.01-1.28], P = 0.03). In terms of OS, the addition of an anti-EGFR agent to chemotherapy showed no advantage (HR = 1.10 [95% CI, 0.98-1.23], P = 0.11). In addition, the combination of an anti-EGFR agent with chemotherapy significantly increased some grade 3/4 toxicities including diarrhea (risk ratio {RR} = 1.42, [95% CI, 1.03-1.94], P = 0.03), mucositis (RR = 3.30 [95% CI, 1.54-7.07], P = 0.002), and skin rash (RR = 6.82 [95% CI, 3.15-14.78], P < 0.00001). In conclusion, this meta-analysis indicates that the addition of an anti-EGFR agent to chemotherapy conveys no additional benefit for patients with advanced esophago gastric adenocarcinoma. As of now, anti-EGFR agents should not be used in the first-line treatment of adenocarcinoma of the upper gastrointestinal tract. PMID- 29228749 TI - The BCL2L11 deletion polymorphism is not associated with imatinib resistance in chronic myeloid leukemia patients: meta-analysis. AB - A common deletion polymorphism of the gene Bcl-2 like protein 11 (BCL2L11, BIM) has been reported to cause tyrosine kinase inhibitors (TKIs) resistance in several malignant tumors. However, the conclusions were not consistent in chronic myeloid leukemia (CML) individuals. In order to obtain a reliable conclusion, we systematically searched PubMed, Embase, Web of Science, Chinese Biomedical Database, and China National Knowledge Infrastructure and performed the meta analysis. Six published articles contain 760 East Asian patients were identified from these electronic databases. The methodological quality of one included trial was high, and the others were moderate. Meta-analysis showed that the rate of TKI resistance between the BIM deletion and wild-type group were no statistical significance (OR = 1.24, 95% CI 0.79-1.95). In conclusion, BIM deletion may not a predictor of TKI resistance in CML individuals in East Asia. PMID- 29228750 TI - Dietary fat intake and risk of esophageal carcinoma: a meta-analysis of observational studies. AB - Dietary fat intake is potentially associated with the onset of esophageal carcinoma (EC), but evidence from observational studies has remained unclear. This study aimed to evaluate the role of fat intake in the development of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). A systematic search was conducted in PubMed and Web of Science to identify all relevant studies. Study-specific relative risks (RR) for the highest versus the lowest intake categories and 95% confidence intervals (CI) were pooled using a random-effects model. Seventeen case-control studies (2058 EAC cases, 1581 ESCC cases and 11696 controls) and two prospective cohort studies (494, 978 participants and 630 EAC cases and 215 ESCC cases) were identified. In EAC, the RRs (95% CI) were 1.69 (1.14-2.50) for total fat intake, 1.88 (1.28-2.77) for saturated fat (SFA) intake, 1.04 (0.86-1.27) for polyunsaturated fat (PUFA) intake and 1.70 (1.01-2.84) for monounsaturated fat (MUFA) intake. In ESCC, the RRs (95% CI) were 1.12 (0.84-1.51) for total fat, 1.38 (0.91-2.08) for SFA, 0.95 (0.55-1.62) for PUFA and 1.04 (0.65-1.66) for MUFA. In conclusion, total fat, SFA and MUFA intake were associated with EAC risk, but fat intake showed no significant association with ESCC risk. Large-scale prospective cohort studies are needed to confirm our findings. PMID- 29228751 TI - Comparisons of health-related quality of life among surgery and radiotherapy for localized prostate cancer: a systematic review and meta-analysis. AB - The objective of this study is to compare health-related quality of life (QOL) outcomes between radical prostatectomy (RP) and external beam radiation therapy (EBRT) for localized prostate cancer. PubMed, EMBASE, the Cochrane Library and Web of Science (to July 2017) were searched. Pooled analysis of each domain specific score was calculated in relevant studies, and its change with follow-up time was explored by sub-group analysis. A total of six studies containing 4423 patients were included. Men underwent RP was associated with worse urinary and sexual domain score than EBRT (standardized mean difference (SMD) = -0.59, -0.58; 95% confidence interval (CI) = -0.73 to -0.45, -0.72 to -0.44). In contrast, EBRT group had lower bowel domain score than RP group (SMD = 0.42, 95% CI = 0.33 to 0.52). The sub-group analysis revealed the most severe urinary and sexual QOL in RP as well as bowel QOL in EBRT group all happened in the first month post operation. The different performance of two treatments in three QOL domains diminished afterwards. Health-related QOL should be considered comprehensively when planning follow-up for men after RP or EBRT for localized prostate cancer. PMID- 29228752 TI - Nonsteroidal anti-inflammatory drugs using and risk of head and neck cancer: a dose-response meta analysis of prospective cohort studies. AB - Conflicting results identifying the relationship between nonsteroidal anti inflammatory drugs using and head and neck cancer risk. Therefore, we performed this meta-analysis to clarify and quantitative assessed the relationship between nonsteroidal anti-inflammatory drugs using and head and neck cancer risk. Up to March 2017, 11 original publications were included in this meta-analysis. Our results showed statistically significant association between nonsteroidal anti inflammatory drugs using and head and neck cancer risk reduction. Subgroups analysis indicated that Aspirin, COX 2 inhibitors, Ibuprofen and Other NSAIDs were associated with a significantly risk reduction of head and neck cancer. Furthermore, nonsteroidal anti-inflammatory drugs using was associated with a significantly lower risk of oral and oropharynx cancer, larynx cancer and hypopharynx cancer. In addition, increasing nonsteroidal anti-inflammatory drugs using (per 2 prescriptions/week increment) was associated with a 4% reduction in head and neck cancer risk, 5% reduction of aspirin using and 6% reduction of other nonsteroidal anti-inflammatory drugs using. Considering these promising results, increasing nonsteroidal anti-inflammatory drugs using might provide health benefits. More studies and large sample size are warranted to validate this association. PMID- 29228753 TI - The best surgical strategy for anal fistula based on a network meta-analysis. AB - Objective: To determine a superior surgical treatment for anal fistula through a network meta-analysis and to provide the best direction for development in this field. Methods: We conducted a systematic literature search of the PubMed, Embase and Cochrane Library databases and extracted data from randomized controlled trials, which compared healing time, incontinence and recurrence associated with surgical strategies for anal fistula. A network meta-analysis was conducted using ADDIS software by evaluating the 3 parameters. Cumulative probability values were utilized to rank the strategies under examination. Inconsistencies were also tested using node-splitting models. Results: Twenty articles with 1663 patients were included. Fistulotomy plus marsupialisation had the shortest healing time (P = 0.69). Seton placement was the best procedure to avoid postoperative incontinence (P = 0.66). Fistulectomy exhibited the lowest recurrence rate (Probability P = 0.40). In general, fistulotomy plus marsupialisation and surgical ligation plus biomaterial plugging revealed superior clinical efficacy. Node-splitting model testing revealed that no significant inconsistency existed in this research. Conclusions: Fistulotomy plus marsupialisation exhibited preliminary superior surgical utility for anal fistula. Additionally, combination of surgical treatment with biomaterials may provide better clinical efficacy. These techniques may warrant consideration for future development in this field. PMID- 29228754 TI - Optimized ROI size on ADC measurements of normal pancreas, pancreatic cancer and mass-forming chronic pancreatitis. AB - Objectives: To investigate the effects of region of interest (ROI) sizes on apparent diffusion coefficient (ADC) measurements for the differentiation of normal pancreas (NP), pancreatic ductal adenocarcinoma (PDAC) and mass-forming chronic pancreatitis (MFCP). Results: There were no significant differences for the mean ADCs measured by 12 different-size ROIs for MFCP, or PDAC and NP (P = 0.858-1.0). With the increase of ROI size (>= 55 mm2), ADCs of PDAC were significantly lower than those of NP (all P < 0.05), but there was no difference of the accuracy in ADC for differentiating the two groups only at a ROI size of 214 mm2. When ROI size was above 99 mm2, ADCs of MFCP were significantly lower than those of NP (all P < 0.05). There were no significant differences for any of the mean ADCs measured by 12 different-size ROIs between PDAC and MFCP (P > 0.05). Materials and Methods: Diffusion-weighted imaging (DWI) was performed on 89 participants: 64 with PDAC, 7 with MFCP, as well as 18 healthy volunteers. ADC maps were created using mono-exponential model. A homemade software was used to measure the mean ADC values of 12 concentric round ROIs (areas: 15, 46, 55, 82, 99, 121, 134, 152, 161, 189, 214, 223, and 245 mm2) for the mass of lesions and the NP tissue. Conclusions: In ADC measurements, the optimized ROI size is 214 mm2 for the differentiation of PDAC and NP; ROI size of >= 99 mm2 is recommended to differentiate between MFCP and NP. ADC was not useful for the differentiation of PDAC and MFCP. PMID- 29228755 TI - Long-term supplementation of decaffeinated green tea extract does not modify body weight or abdominal obesity in a randomized trial of men at high risk for prostate cancer. AB - Background: Evidence continues to demonstrate the role of obesity in prostate carcinogenesis and prognosis, underscoring the need to identify and continue to evaluate the effective interventions to reduce obesity in populations at high risk. The aim of the study was to determine the effect of daily consumption of decaffeinated green tea catechins (GTC) formulation (Polyphenon E(r) (PolyE)) for 1 year on biomarkers of obesity in men who are at high risk for prostate cancer. Materials and Methods: A randomized, double-blinded trial was conducted targeting 97 men diagnosed with HGPIN or ASAP. Subjects were randomized to receive GTC (PolyE) (n = 49) or placebo (n = 48) for 1 year. Anthropometric data were collected at baseline, 6 and 12 months and data analyzed to observe change in weight, body mass index (indicator of obesity) and waist: hip ratio (indicator of abdominal obesity). Results: Decaffeinated GTC containing 400 mgs of the bioactive catechin, EGCG administered for 1 year to men diagnosed with ASAP and HGPIN appears to be bioavailable, well tolerated but not effective in reducing biomarkers of obesity including body weight, body mass index and waist: hip ratio. Conclusions: The results of our trial demonstrates that men who are obese and at high risk for prostate cancer should resort to effective weight management strategies to reduce obesity and not resort to ineffective measures such as taking supplements of green tea to reduce biomarkers of obesity. Changes in body mass index and abdominal obesity seen in other studies were potentially due to caffeine and not GTC. PMID- 29228756 TI - Interim PET-CT may predict PFS and OS in T-ALL/LBL adult patients. AB - T lymphoblastic leukemia/lymphoma (T-ALL/LBL) is highly aggressive. Although intensive chemotherapies such as ALL-type regimens are commonly used, about half adult patients eventually relapse and die of T-ALL/LBL. Overwhelming evidences have confirmed that interim PET can predict survival outcomes and guide subsequent treatments in Hodgkin lymphoma. However, whether interim PET-CT can predict survival outcomes or not in T-ALL/LBL patients remains unclear. 47 adult patients of T-ALL/LBL were retrospectively reviewed. Interim PET-CT was done after induction therapy and evaluated according to the International Harmonization Project criteria. After induction therapy, interim PET-CT was positive in 19 patients (40.4%). After a median follow up time of 34 months, the 2-year and 3-year progression free survival (PFS) rate were 39% and 30%, respectively, and the 2-year and 3-year overall survival (OS) rate were 54% and 45%, respectively. Using Kaplan-Meier survival analysis, it was found that interim PET-CT positivity correlated with significantly inferior PFS and OS (2 year PFS rate for patients with positive or negative interim PET were 21.1% or 56.0%, respectively, p = 0.002; 2-year OS rate for patients with positive or negative interim PET were 31.6% or 63.7%, respectively, p = 0.010). However, there was no significant relationship between PFS, OS and bone marrow infiltration, lactate dehydrogenase level, and stages (p > 0.05). Interim PET-CT may predict PFS and OS in adult patients of T-ALL/LBL, which needs to be validated in prospective clinical trials. The optimal criteria for interim PET-CT evaluation and risk-adapted treatment strategy determined by interim PET-CT should be investigated in future clinical practice. PMID- 29228757 TI - Disrupted functional connectivity between perirhinal and parahippocampal cortices with hippocampal subfields in patients with mild cognitive impairment and Alzheimer's disease. AB - Most patients with mild cognitive impairment and Alzheimer's disease can initially present memory loss. The medial temporal lobes are the brain regions most associated with declarative memory function. As sub-components of the MTL, the perirhinal cortex, parahippocampal cortex and hippocampus have also been identified as playing important roles in memory. The functional connectivity between hippocampus subfields and perirhnial cortices as well as parahippocampal cortices among normal cognition controls (NC group, n=33), mild cognitive impairment (MCI group, n=31) and Alzheimer's disease (AD group, n=27) was investigated in this study. The result shows significant differences of functional connectivity in 3 pairs of regions among NC group, MCI group and AD group: right perirhinal cortex with right hippocampus tail, left perirhinal cortex with right hippocampus tail, and right parahippocampal cortex with right hippocampus head. Clustering methods were used to classify NC group, MCI group and AD group (accuracy=100%) as well as different subtypes of mild cognitive impairment patients based on functional alterations. Functional connectivity disrupted between perirhinal and parahippocampal cortex with hippocampal subfields, which may provide a better understanding of the neurodegenerative progress of MCI and AD. PMID- 29228758 TI - Elevated serum fibrinogen level is an independent risk factor for IgA nephropathy. AB - Background: IgA nephropathy is a primary cause of renal failure, and inflammation and renal fibrosis are the main mechanisms leading to kidney damage. The serum fibrinogen level is closely related to inflammatory states, but its relationship to the prognosis of IgA nephropathy (IgAN) is unclear. Materials and Methods: 1053 patients diagnosed with IgAN after renal biopsy were enrolled from two Nephrology Departments. Demographic and clinical data and histopathological features were collected. The patients were divided into four groups (Q1-Q4) according to the serum fibrinogen levels at the time of renal biopsy, and the relationships of serum fibrinogen levels with other risk factors and the prognosis of IgAN were investigated. Results: 672 patients with proven primary IgAN were included in this study, which included a median follow-up of 36 months. Patients with higher serum fibrinogen levels had elevated serum creatinine levels, 24-hour urinary protein, and blood pressure compared with patients with the lowest levels of serum fibrinogen as well as severe renal damage at the time of renal biopsy. Univariate and multivariate Cox regression analyses confirmed that the serum fibrinogen level at the time of renal biopsy was significantly related to the prognosis of patients with IgAN. Conclusions: In patients with IgAN, an elevated serum fibrinogen level at the time of renal biopsy is associated with poor renal outcomes, which suggests the need for more aggressive early interventions. Greater benefits of aggressive treatments were observed in patients with higher serum fibrinogen levels. PMID- 29228759 TI - Combination of primary tumor location and mismatch repair status guides adjuvant chemotherapy in stage II colon cancer. AB - Background: Current opinions on the benefits of adjuvant chemotherapy for stage II colon cancer are divided and reformative election of these patients is required. We examined whether the primary tumor location based on mismatch repair status and other risk factors could better inform the current guideline. Materials and Methods: A total of 673 consecutive patients with stage II colon cancer were included in the analysis. Differences in the common clinicopathological factors between left-sided colon cancer and right-sided colon cancer were analyzed using Fisher's exact analysis. Kaplan-Meier analysis was used to distinguish the survival difference by primary tumor location and/or MMR status. Results: RCC had a shorter overall survival (P = 0.001) and Disease-free survival (P = 0.050) than LCC but was associated with survival benefit from adjuvant chemotherapy (P = 0.001 and P = 0.011 for OS and DFS, respectively). Mismatch repair-proficient had a shorter OS (P = 0.036) and disease free survival (P = 0.034) than mismatch-repair deficient but chemotherapy improved the OS (P = 0.007). When the primary tumor location and MMR status were combined, the PMMR/RCC was the only subgroup that could benefit from adjuvant chemotherapy (P < 0.001 and P = 0.002 for OS and DFS, respectively). Other tumors such as DMMR/RCC, DMMR/LCC, and PMMR/LCC did not benefit. Conclusions: The observed survival benefits in PMMR/RCC patients treated with adjuvant chemotherapy will allow better selection of patients for chemotherapy who are in stage II. PMID- 29228760 TI - Development and validation of a prognostic nomogram for colorectal cancer after radical resection based on individual patient data from three large-scale phase III trials. AB - Background: Few prediction models have so far been developed and assessed for the prognosis of patients who undergo curative resection for colorectal cancer (CRC). Materials and Methods: We prepared a clinical dataset including 5,530 patients who participated in three major randomized controlled trials as a training dataset and 2,263 consecutive patients who were treated at a cancer-specialized hospital as a validation dataset. All subjects underwent radical resection for CRC which was histologically diagnosed to be adenocarcinoma. The main outcomes that were predicted were the overall survival (OS) and disease free survival (DFS). The identification of the variables in this nomogram was based on a Cox regression analysis and the model performance was evaluated by Harrell's c-index. The calibration plot and its slope were also studied. For the external validation assessment, risk group stratification was employed. Results: The multivariate Cox model identified variables; sex, age, pathological T and N factor, tumor location, size, lymphnode dissection, postoperative complications and adjuvant chemotherapy. The c-index was 0.72 (95% confidence interval [CI] 0.66-0.77) for the OS and 0.74 (95% CI 0.69-0.78) for the DFS. The proposed stratification in the risk groups demonstrated a significant distinction between the Kaplan-Meier curves for OS and DFS in the external validation dataset. Conclusions: We established a clinically reliable nomogram to predict the OS and DFS in patients with CRC using large scale and reliable independent patient data from phase III randomized controlled trials. The external validity was also confirmed on the practical dataset. PMID- 29228761 TI - Targeting tumor-associated carbohydrate antigens: a phase I study of a carbohydrate mimetic-peptide vaccine in stage IV breast cancer subjects. AB - Tumor-associated carbohydrate antigens (TACAs) support cell survival that could be interrupted by anti-TACA antibodies. Among TACAs that mediate cell survival signals are the neolactoseries antigen Lewis Y (LeY) and the ganglioside GD2. To induce sustained immunity against both LeY and GD2, we developed a carbohydrate mimicking peptide (CMP) as a surrogate pan-immunogen that mimics both. This CMP, referred to as P10s, is the N-terminal half of a peptide vaccine named P10s PADRE, the C-terminal half of which (PADRE) is a Pan-T-cell epitope. A Phase I dose-escalation trial of P10s-PADRE plus adjuvant MONTANIDETM ISA 51 VG was conducted in subjects with metastatic breast cancer to test 300 and 500 MUg/injection in two cohorts of 3 subjects each. Doses of the P10s-PADRE vaccine were administered to research participants subcutaneously on weeks 1, 2, 3, 7 and 19. Antibody responses to P10s, GD2, and LeY were measured by ELISA. The P10s PADRE vaccine induced antibodies specifically reactive with P10s, LeY and GD2 in all 6 subjects. Serum antibodies displayed Caspase-3-dependent apoptotic functionality against LeY or GD2 expressing breast cancer cell lines. Immunization with the P10s-PADRE vaccine was well-tolerated and induced functional antibodies, and the data suggest potential clinical benefit. PMID- 29228763 TI - Prevention of erosions by a surface sealant and adhesives under abrasive conditions AB - It was the aim of the current in vitro study to test the erosion-preventive potential of an experimental surface sealant (K-0184) and currently marketed self etch adhesive systems under abrasive conditions. Ninety-six dentine specimens were randomly allocated to eight groups (n=12): (1) positive control (no treatment), (2) K-0184, (3) Shield Force Plus, (4) Xeno Select, (5) Scotchbond Universal, (6) Adhese Universal, (7) OptiBond All-In-One, and (8) Clearfil SE Bond. Before and after sealing, dentine specimens were measured profilometrically to determine the layer thickness of the protective agents.During 12 days, the specimens were demineralized daily for 5 min using hydrochloric acid (pH=3) and abraded by applying 600 brushing strokes (F=2.5 N). Calcium content in the hydrochloric acid was determined using atomic absorption spectroscopy.Calcium concentration was consistently highest in the positive control group (p<0.05 compared to all other groups). The lowest cumulated Ca release was measured for K 0184; it differed significantly (p<0.05) from that determined in groups 4, 6, and 7. K-0184 also had the highest layer thickness (p<0.05 compared to all other groups). It was concluded that the experimental surface sealant K-0184 and the adhesive systems Xeno Select, Scotchbond Universal, Adhese Universal, and Clearfil SE Bond prevent dentine erosion under the current abrasive conditions with a total of 7,200 brush strokes. PMID- 29228766 TI - The effects of addition of coenzyme Q10 to metformin on sirolimus-induced diabetes mellitus. AB - Background/Aims: This study was performed to determine whether adding coenzyme Q10 (CoQ10) to metformin (MET) has a beneficial effect as a treatment for sirolimus (SRL)-induced diabetes mellitus (DM). Methods: DM was induced in rats by daily treatment with SRL (0.3 mg/kg, subcutaneous) for 28 days, and animals were treated with CoQ10 (20 mg/kg, oral) and MET (250 mg/kg, oral) alone or in combination for the latter 14 days of SRL treatment. The effects of CoQ10 and MET on SRL-induced DM were assessed with the intraperitoneal glucose tolerance test (IPGTT) and by determining plasma insulin concentration and the homeostatic model assessment of insulin resistance (HOMA-R) index. We also evaluated the effect of CoQ10 on pancreatic islet size, apoptosis, oxidative stress, and mitochondria morphology. Results: IPGTT revealed overt DM in SRL-treated rats. The addition of CoQ10 to MET further improved hyperglycemia, decreased HOMA-R index, and increased plasma insulin concentration compared with the SRL group than MET alone therapy. While SRL treatment induced smaller islets with decreased insulin staining intensity, the combination of CoQ10 and MET significantly improved insulin staining intensity, which was accompanied by a reduction in oxidative stress and apoptosis. In addition, co-treatment of CoQ10 and MET significantly increased the levels of antiperoxidative enzymes in the pancreas islet cells compared with MET. At the subcellular level, addition of CoQ10 to MET improved the average mitochondrial area and insulin granule number. Conclusions: Addition of CoQ10 to MET has a beneficial effect on SRL-induced DM compared to MET alone. PMID- 29228764 TI - Ultrasonographic quantification of pleural effusion: comparison of four formulae. AB - PURPOSE: The purpose of this study was to evaluate the correlations of ultrasonographically estimated volumes of pleural fluid with the actual effusion volume in order to determine the most reliable formula. METHODS: In 32 consecutive patients with clinically diagnosed pleural effusion, an ultrasound estimation was made of the volume of effusion using four different formulae, including two in the erect position and two in the supine position. Closed-tube thoracostomy drainage using a 28-Fr chest tube was performed. The total drainage was calculated after confirmation of full lung re-expansion and complete drainage by plain chest radiographs and ultrasound. The ultrasonographically estimated volume was compared to the actual total volume drained as the gold standard. RESULTS: There were 14 female and 18 male subjects. The mean age of all subjects was 41.56+/-18.34 years. Fifty percent of the effusions were in the left hemithorax. Metastatic disease accounted for the plurality of effusions (31.2%). The mean total volume drained for all the subjects was 2,770+/-1,841 mL. The ultrasonographically estimated volumes for the erect 1, erect 2, supine 1, and supine 2 formulae were 1,816+/-753 mL, 1,520+/-690 mL, 2,491+/-1,855 mL, and 1,393+/-787 mL, respectively. The Pearson correlation coefficients (r) for the estimate of each formula were 0.75, 0.81, 0.62, and 0.63, respectively. CONCLUSION: Although both erect formulae showed similar correlations, the erect 2 formula (Goecke 2) was most closely correlated with the actual volume drained. PMID- 29228767 TI - Revealing Electron-Electron Interactions within Lewis Pairs in Chemical Systems. AB - The so-called "Lewis pair" is a ubiquitous phenomenon in chemistry and is often used as an intuitive construct to predict and rationalize chemical structure and behavior. Concepts from the very general Valence Shell Electron Pair Repulsion (VSEPR) model to the most esoteric reaction mechanism routinely rely on the notion that electrons tend to exist in pairs and that these pairs can be thought of as being localized to a particular region of space. It is precisely this localization that allows one to intuit how these pairs might behave, generally speaking, so that reasonable predictions may be made regarding molecular structure, intermolecular interactions, property trends, and reaction mechanisms, etc. Of course, it is rather unfortunate that the Lewis model is entirely qualitative and yields no information regarding how any specific electron pair is distributed. Here we demonstrate a novel electronic structure analysis technique that predicts and analyzes precise quantitative details about the relative and absolute distribution of individual electron pairs. This Single Electron Pair Distribution Analysis (SEPDA) reveals quantitative details about the distribution of the well-known Lewis pairs, such as how they are distributed in space and how their relative velocities change in various chemical contexts. We show that these distributions allow one to image the explicitly pairwise electronic behavior of bonds and lone pairs. We further demonstrate how this electronic behavior changes with several conditions to explore the nature of the covalent chemical bond, non covalent interactions, bond formation, and exotic 3-center-2-electron species. It is shown that indications of the strength of bonded and non-bonded interactions may also be gleaned from such distributions and SEPDA can be used as a tool to differentiate between interaction types. We anticipate that SEPDA will be of broad utility in a wide variety of chemical contexts because it affords a very detailed, visual and intuitive analysis technique that is generally applicable. PMID- 29228768 TI - Recovery of mrs3Deltamrs4Delta Saccharomyces cerevisiae Cells under Iron Sufficient Conditions and the Role of Fe580. AB - Mrs3 and Mrs4 are mitochondrial inner membrane proteins that deliver an unidentified cytosolic iron species into the matrix for use in iron-sulfur cluster (ISC) and heme biosynthesis. The Mrs3/4 double-deletion strain (DeltaDelta) grew slowly in iron-deficient glycerol/ethanol medium but recovered to wild-type (WT) rates in iron-sufficient medium. DeltaDelta cells grown under both iron-deficient and iron-sufficient respiring conditions acquired large amounts of iron relative to WT cells, indicating iron homeostatic dysregulation regardless of nutrient iron status. Biophysical spectroscopy (including Mossbauer, electron paramagnetic resonance, and electronic absorption) and bioanalytical methods (liquid chromatography with online inductively coupled plasma mass spectrometry detection) were used to characterize these phenotypes. Anaerobically isolated mitochondria contained a labile iron pool composed of a nonheme high-spin FeII complex with primarily O and N donor ligands, called Fe580. Fe580 likely serves as feedstock for ISC and heme biosynthesis. Mitochondria from respiring DeltaDelta cells grown under iron-deficient conditions were devoid of Fe580, ISCs, and hemes; most iron was present as FeIII nanoparticles. O2 likely penetrates the matrix of slow-growing poorly respiring iron-deficient DeltaDelta cells and reacts with Fe580 to form nanoparticles, thereby inhibiting ISC and heme biosynthesis. Mitochondria from iron-sufficient DeltaDelta cells contained ISCs, hemes, and Fe580 at concentrations comparable to those of WT mitochondria. The matrix of these mutant cells was probably sufficiently anaerobic to protect Fe580 from degradation by O2. An ~1100 Da manganese complex, an ~1200 Da zinc complex, and an ~5000 Da copper species were also present in DeltaDelta and WT mitochondrial flow-through solutions. No lower mass copper complex was evident. PMID- 29228769 TI - Straight Access to Indoles from Anilines and Ethylene Glycol by Heterogeneous Acceptorless Dehydrogenative Condensation. AB - The development of original strategies for the preparation of indole derivatives is a major goal in drug design. Herein, we report the first straight access to indoles from anilines and ethylene glycol by heterogeneous catalysis, based on an acceptorless dehydrogenative condensation, under noninert conditions. In order to achieve high selectivity, a combination of Pt/Al2O3 and ZnO have been found to slowly dehydrogenate ethylene glycol generating, after condensation with the amine and tautomeric equilibrium, the corresponding pyrrole-ring unsubstituted indoles. PMID- 29228770 TI - Polyelectrolyte Capping As Straightforward Approach toward Manipulation of Diffusive Transport in MOF Films. AB - We present experimental results demonstrating the suitability of polyelectrolyte capping as a simple and straightforward procedure to modify hydrophilic/hydrophobic character of porous films, thus allowing additional control on transport properties. In particular, we synthesized ZIF-8 metal organic framework (MOF) films, an archetypal hydrophobic zeolitic imidazolate framework, constituted by Zn2+ ions tetrahedrally coordinated with bidentate 2 methylimidazolate organic linker, and poly(4-styrenesulfonic acid) as capping agent (PSS). MOF films were synthesized via sequential one pot (SOP) steps over conductive substrates conveniently modified with primer agents known to enhance heterogeneous nucleation, followed by dip-coating with PSS aqueous solutions. Crystallinity, morphology, and chemical composition of ZIF-8 films were confirmed with traditional methods. Continuous electron density depth profile obtained with synchrotron light X-ray reflectivity (XRR) technique, suggest that PSS capped films do not adopt segregated configurations in which PSS remains surface confined. This affects functional properties conferred by PSS capping, which were assessed using cyclic voltammetry with both positively and negatively charged redox probe molecules. Furthermore, taking advantage of the control attained, we successfully carried in situ synthesis of film-hosted d-block metal nanoparticles (Au and Pt-NPT@5x-ZIF-8+PSS) via direct aqueous chemical reduction of precursors (diffusion-reaction approach). PMID- 29228762 TI - Phosphodiesterase type 5 and cancers: progress and challenges. AB - Cancers are an extraordinarily heterogeneous collection of diseases with distinct genetic profiles and biological features that directly influence response patterns to various treatment strategies as well as clinical outcomes. Nevertheless, our growing understanding of cancer cell biology and tumor progression is gradually leading towards rational, tailored medical treatments designed to destroy cancer cells by exploiting the unique cellular pathways that distinguish them from normal healthy counterparts. Recently, inhibition of the activity of phosphodiesterase type 5 (PDE5) is emerging as a promising approach to restore normal intracellular cyclic guanosine monophosphate (cGMP) signalling, and thereby resulting into the activation of various downstream molecules to inhibit proliferation, motility and invasion of certain cancer cells. In this review, we present an overview of the experimental and clinical evidences highlighting the role of PDE5 in the pathogenesis and prevention of various malignancies. Current data are still not sufficient to draw conclusive statements for cancer patient management, but could provide further rational for testing PDE5-targeting drugs as anticancer agents in clinical settings. PMID- 29228771 TI - Curcumin Derivative Epigenetically Reactivates Nrf2 Antioxidative Stress Signaling in Mouse Prostate Cancer TRAMP C1 Cells. AB - The carcinogenesis of prostate cancer (PCa) in TRAMP model is highly correlated with hypermethylation in the promoter region of Nrf2 and the accompanying reduced transcription of Nrf2 and its regulated detoxifying genes. We aimed to investigate the effects of (3E,5E)-3,5-bis-(3,4,5-trimethoxybenzylidene) tetrahydro-thiopyran-4-one (F10) and (3E,5E)-3,5-bis-(3,4,5-trimethoxy benzylidene)-tetrahydropyran-4-one (E10), two synthetic curcumin derivatives, on restoring Nrf2 activity in TRAMP C1 cells. HepG2-C8 cells transfected with an antioxidant-response element (ARE)-luciferase vector were treated with F10, E10, curcumin, and sulforaphane (SFN) to compare their effects on Nrf2-ARE pathways. We performed real-time quantitative PCR and Western blotting to investigate the effects of F10 and E10 on Nrf2, correlated phase II detoxification genes. We also measured expression and activity of DNMTand HDAC enzymes. Enrichment of H3K27me3 on the promoter region of Nrf2 was explored with a chromatin immunoprecipitation (ChIP) assay. Methylation of the CpG region in Nrf2 promoter was doubly examined by bisulfite genomic sequencing (BGS) and methylation DNA immunoprecipitation (MeDIP). Compared with curcumin and SFN, F10 is more potent in activating Nrf2 ARE pathways. Both F10 and E10 enhanced level of Nrf2 and the correlated phase II detoxifying genes. BGS and MeDIP assays indicated that F10 but not E10 hypomethylated the Nrf2 promoter. F10 also downregulated the protein level of DNMT1, DNMT3a, DNMT3b, HDAC1, HDAC4, and HDAC7 and the activity of DNMTs and HDACs. F10 but not E10 effectively reduced the accumulation of H3k27me3 on the promoter of Nrf2. F10 and E10 can activate the Nrf2-ARE pathway and increase the level of Nrf2 and correlated phase II detoxification genes. The reactivation effect on Nrf2 by F10 in TRAMP C1 may come from demethylation, decrease of HDACs, and inhibition of H3k27me3 accumulation. PMID- 29228772 TI - Interfacing DNA Oligonucleotides with Calcium Phosphate and Other Metal Phosphates. AB - Calcium phosphate (CaP) has long been used for DNA delivery, although its fundamental interaction with DNA, especially with single-stranded DNA oligonucleotides, remains to be fully understood. Using fluorescently labeled oligonucleotides, we herein studied DNA adsorption isotherm and the effect of DNA length and sequence. Longer DNAs are adsorbed more strongly, and at neutral pH, poly-C DNAs are adsorbed more than the other three DNA homopolymers. However, at near pH 11, the pH of CaP synthesis, T30 DNA is adsorbed more strongly than C30 or A30. This can explain why T30 and G30 can fully inhibit the growth of CaP, while A30 and C30 only retarded its growth kinetics. DNA adsorption also reduces aggregation of CaP. DNA desorption experiments were carried out using concentrated urea, thymidine, or inorganic phosphate as competitors, and desorption was observed only in the presence of phosphate, suggesting that DNA uses its phosphate backbone to interact with the CaP surface. Desorption was also promoted by raising the NaCl concentration suggesting the electrostatic nature of interaction. Finally, ten different metal phosphate materials were synthesized by co-precipitating each metal ion (Ce3+, Fe3+, Ca2+, Ni2+, Zn2+, Mn2+, Ba2+, Cu2+, Sr2+, Co2+), and DNA adsorption by these phosphate precipitants was found to be related to their surface charge and metal chemistry. This work has revealed fundamental surface science of DNA adsorption by CaP and other metal phosphate salts, and this knowledge might be useful for gene delivery, biomineralization, and DNA-directed assembly of metal phosphate materials. PMID- 29228773 TI - Interfacial Synthesis of Highly Stable CsPbX3/Oxide Janus Nanoparticles. AB - The poor stability of CsPbX3 (X = Cl, Br, I) nanocrystals (NCs) has severely impeded their practical applications. Although there are some successful examples on encapsulating multiple CsPbX3 NCs into an oxide or polymer matrix, it has remained a serious challenge for the surface modification/encapsulation using oxides or polymers at a single particle level. In this work, monodisperse CsPbX3/SiO2 and CsPbBr3/Ta2O5 Janus nanoparticles were successfully prepared by combining a water-triggered transformation process and a sol-gel method. The CsPbBr3/SiO2 NCs exhibited a photoluminescence quantum yield of 80% and a lifetime of 19.8 ns. The product showed dramatically improved stability against destruction by air, water, and light irradiation. Upon continuous irradiation by intense UV light for 10 h, a film of the CsPbBr3/SiO2 Janus NCs showed only a slight drop (2%) in the PL intensity, while a control sample of unmodified CsPbBr3 NCs displayed a 35% drop. We further highlighted the advantageous features of the CsPbBr3/SiO2 NCs in practical applications by using them as the green light source for the fabrication of a prototype white light emitting diode, and demonstrated a wide color gamut covering up to 138% of the National Television System Committee standard. This work not only provides a novel approach for the surface modification of individual CsPbX3 NCs but also helps to address the challenging stability issue; therefore, it has an important implication toward their practical applications. PMID- 29228774 TI - Supramolecular Hydrogel Derived from a C3-Symmetric Boronic Acid Derivative for Stimuli-Responsive Release of Insulin and Doxorubicin. AB - A C3-symmetric triazine based triboronic acid (HG1) was designed and synthesized. HG1 was found to give hydrogel in DMSO-water (1:9). The hydrogel was rheo reversible and thermoreversible over a few cycles. Single-crystal X-ray diffraction (SXRD) studies on the crystals of HG1 established the presence of honeycomb network in which solvent molecules (DMSO and water) were occluded. SXRD data corroborated well with the hypothesis based on which HG1 was designed. Stimuli responsive release (in vitro) of insulin and doxorubicin from the hydrogel was also achieved. PMID- 29228775 TI - Effects of Ceramide and Dihydroceramide Stereochemistry at C-3 on the Phase Behavior and Permeability of Skin Lipid Membranes. AB - Ceramides (Cer) are key components of the skin permeability barrier. Sphingosine based CerNS and dihydrosphingosine-based CerNdS (dihydroCer) have two chiral centers; however, the importance of the correct stereochemistry in the skin barrier Cer is unknown. We investigated the role of the configuration at C-3 of CerNS and CerNdS in the organization and permeability of model skin lipid membranes. Unnatural l-threo-CerNS and l-threo-CerNdS with 24-C acyl chains were synthesized and, along with their natural d-erythro-isomers, incorporated into membranes composed of major stratum corneum lipids (Cer, free fatty acids, cholesterol, and cholesteryl sulfate). The membrane microstructure was investigated by X-ray powder diffraction and infrared spectroscopy, including deuterated free fatty acids. Inversion of the C-3 configuration in CerNS and CerNdS increased phase transition temperatures, had no significant effects on lamellar phases, but also decreased the proportion of orthorhombic packing and decreased lipid mixing in the model membranes. These changes in membrane organization resulted in membrane permeabilities that ranged from unchanged to 5 fold higher (depending on the permeability markers, namely, water loss, electrical impedance, flux of theophylline, and flux of indomethacin) compared to membranes with natural CerNS/NdS isomers. Thus, the physiological d-erythro stereochemistry of skin Cer and dihydroCer appears to be essential for their correct barrier function. PMID- 29228776 TI - Photosensitive Cationic Azobenzene Surfactants: Thermodynamics of Hydration and the Complex Formation with Poly(methacrylic acid). AB - In this computational work, we investigate the photosensitive cationic surfactants with the trimethylammonium or polyamine hydrophilic head and the azobenzene-containing hydrophobic tail. The azobenzene-based molecules are known to undergo a reversible trans-cis-trans isomerization reaction when subjected to UV-visible light irradiation. Combining the density functional theory and the all atom molecular dynamics simulations, the structural and the hydration properties of the trans- and the cis-isomers and their interaction with the oppositely charged poly(methacrylic acid) in aqueous solution are investigated. We establish and quantify the correlations of the molecular structure and the isomerization state of the surfactants and their hydrophilicity/hydrophobicity and the self assembling altered by light. For this reason, we compare the hydration free energies of the trans- and the cis-isomers. Moreover, the investigations of the interaction strength between the azobenzene molecules and the polyanion provide additional elucidations of the recent experimental and theoretical studies on the light triggered reversible deformation behavior of the microgels and the polymer brushes loaded with azobenzene surfactants. PMID- 29228777 TI - Fast and Strong Adsorption of Native Oligonucleotides on Citrate-Coated Gold Nanoparticles. AB - The adsorption of oligonucleotides on citrate-coated gold nanoparticles (AuNPs) is studied under conditions "right after the synthesis", i.e., in a weak citrate solution at a pH value close to neutral (5.8 +/- 0.2). We found that short-term elevation of reaction temperature under these conditions provides fast and strong adsorption of oligonucleotides on the surface of AuNPs. The affinity of oligonucleotides to AuNPs depends on the length of the oligonucleotide and its nucleotide composition. The shortest oligonucleotide in this study, T6, is the most affine, having the equilibrium binding constant KD = 0.10 +/- 0.04 nM and the highest surface density-up to 200 molecules per one particle. Olygothymidylates are at least as affine to AuNPs as oligoadenylates, while oligocytidilates show the lowest affinity. We also studied the interaction of resulting DNA/AuNPs with a series of low- and high-molecular thiols, which provide a variety of operations with adsorbed oligonucleotides: displacement (complete or partial) and encapsulation in a secondary shell. These experiments imitate someway the conditions in a living cell or serum, and show that DNA/AuNPs obtained by this method can be applied in a number of bionanotechnological applications, including delivery of nucleic acid therapeutics and theranostics. PMID- 29228778 TI - Effects of Calcium Ions on the Solubility and Rheological Behavior of a C22 Tailed Hydroxyl Sulfobetaine Surfactant in Aqueous Solution. AB - Effects of calcium ions (Ca2+) on the solubility, aggregate structure, and rheological behavior of a C22-tailed zwitterionic surfactant, erucyl dimethyl amidopropyl hydroxyl sulfobetaine (EHSB), have been investigated in aqueous solution. In comparison with sodium ions (Na+), Ca2+ ions exhibit a much higher efficiency in decreasing the Krafft temperature (TK) of EHSB. Specifically, contrary to Na+ ions which have no obvious effect on the rheological properties of the EHSB solution, Ca2+ ions increase the viscosity of the EHSB solution at lower EHSB concentration, and enhance its elasticity at higher EHSB concentration. Moreover, Ca2+ ions raise the temperature needed for the elastic to-viscous transition of the EHSB solution at higher concentration. At lower EHSB concentration, the hydrophobic interaction between the ultralong hydrocarbon chains induces a tighter packing of the hydrophobic chains by forming a more stretched configuration, while at higher EHSB concentration, the electrostatic attraction between Ca2+ ions and the sulfonate groups of EHSB induces a tighter packing of the headgroups by forming Ca2+-mediated bridges among the EHSB headgroups. Besides, the above interactions may strengthen the hydrogen bonding of OH groups and/or of C?O amide groups, which in turn facilitates the compact packing of the surfactant molecules in aggregates and promotes the growth and entanglement of wormlike micelles. Thus, the EHSB solution shows Ca2+-dependent rheological behaviors. The solubility and rheological properties of the ultralong chain surfactant solution can be simultaneously improved with the addition of divalent Ca2+ ions. PMID- 29228780 TI - Vocalizations of minimally verbal children with autism spectrum disorder across the school year. AB - Little is known about the language trajectories of minimally verbal school-aged children with autism spectrum disorders. The present investigation conducted observations across two elementary schools over an entire school year to analyze the vocal language development of nine minimally verbal children with autism spectrum disorder between the ages of 6 and 10 years, and their educational service providers. A Language Environment AnalysisTM device automatically recorded and disaggregated over 743 h of data on child vocalizations, and vocal interactions with adults. Vocalizations did not increase for eight of the nine participants, and conversational counts between participants and adults were near zero across the entire year. These results speak to the need for additional research examining language development and potential intervention strategies among minimally verbal children with autism spectrum disorder. PMID- 29228781 TI - Targeting Oxidative Stress Using Nanoparticles as a Theranostic Strategy for Cardiovascular Diseases. AB - SIGNIFICANCE: Nanomedicine is an application of nanotechnology that provides solutions to unmet medical challenges. The unique features of nanoparticles, such as their small size, modifiable components, and diverse functionality, make them attractive and suitable materials for novel diagnostic, therapeutic, or theranostic applications. Cardiovascular diseases (CVDs) are the major cause of noncommunicable illness in both developing and developed countries. Nanomedicine offers novel theranostic options for the treatment of CVDs. Recent Advances: Many innovative nanoparticles to target reactive oxygen species (ROS) have been developed. In this article, we review the characteristics of nanoparticles that are responsive to ROS, their limitations, and their potential clinical uses. Significant advances made in diagnosis of atherosclerosis and treatment of acute coronary syndrome using nanoparticles are discussed. CRITICAL ISSUES: Although there is a tremendous potential for the nanoparticle applications in medicine, their safety should be considered while using in humans. We discuss the challenges that may be encountered with some of the innovative nanoparticles used in CVDs. FUTURE DIRECTIONS: The unique properties of nanoparticles offer novel diagnostic tool and potential therapeutic strategies. However, nanomedicine is still in its infancy, and further in-depth studies are needed before wide clinical application is achieved. Antioxid. Redox Signal. 00, 000-000. PMID- 29228779 TI - Tuning Enzyme/alpha-Zr(IV) Phosphate Nanoplate Interactions via Chemical Modification of Glucose Oxidase. AB - Using glucose oxidase (GOx) and alpha-Zr(IV) phosphate nanoplates (alpha-ZrP) as a model system, a generally applicable approach to control enzyme-solid interactions via chemical modification of amino acid side chains of the enzyme is demonstrated. Net charge on GOx was systematically tuned by appending different amounts of polyamine to the protein surface to produce chemically modified GOx(n), where n is the net charge on the enzyme after the modification and ranged from -62 to +95 electrostatic units in the system. The binding of GOx(n) with alpha-ZrP nanosheets was studied by isothermal titration calorimetry (ITC) as well as by surface plasmon resonance (SPR) spectroscopy. Pristine GOx showed no affinity for the alpha-ZrP nanosheets, but GOx(n) where n >= -20 showed binding affinities exceeding (2.1 +/- 0.6) * 106 M-1, resulting from the charge modification of the enzyme. A plot of GOx(n) charge vs Gibbs free energy of binding (DeltaG) for n = +20 to n = +65 indicated an overall increase in favorable interaction between GOx(n) and alpha-ZrP nanosheets. However, DeltaG is less dependent on the net charge for n > +45, as evidenced by the decrease in the slope as charge increased further. All modified enzyme samples and enzyme/alpha ZrP complexes retained a significant amount of folding structure (examined by circular dichroism) as well as enzymatic activities. Thus, strong control over enzyme-nanosheet interactions via modulating the net charge of enzymes may find potential applications in biosensing and biocatalysis. PMID- 29228782 TI - Antioxidant defence in the brain of 1-d-old chickens exposed in ovo to acrylamide. AB - 1. Acrylamide (ACR) is a potent neurotoxicant, although information on its toxic influence on the developing neural system is still limited. The effects of in-ovo injected ACR on the antioxidant system activity in the brain of newly hatched chickens was examined. This model eliminated the mother's contribution to embryonic development. It was also recognised as an adequate model for animal embryonic development. 2. ACR was injected on d 4 of embryogenesis - in doses of 1.25 and 2.50 mg/egg (n = 40 eggs/group/120 eggs). The doses corresponded well with ACR doses used in other animal studies and their concentrations in certain animal feeds. 3. Mortality and incidences of malformations were not found to increase significantly. Significant depletion of glutathione was detected in the cerebellum, cerebrum and medulla oblongata of specimens exposed to the highest doses of ACR. Enzymatic activity was affected by the highest ACR doses. Glutathione peroxidase (GPx) activity increased significantly in the cerebrum, medulla oblongata and the hypothalamus. Superoxide dismutase (SOD) activity increased significantly in hypothalamus and decreased in cerebellum and cerebrum. A significant depletion of catalase (CAT) activity was detected in cerebellum. In the hypothalamus, the increased SOD/GPx and SOD/CAT ratios suggest the risk of H2O2. 4. It was concluded that ACR significantly influences the antioxidative defence in the chicken brain at doses of 1.25 and 2.50 mg/egg. PMID- 29228783 TI - Training in Integrative Therapies Increases Self-Efficacy in Providing Nondrug Therapies and Self-Confidence in Offering Compassionate Care. AB - BACKGROUND: Patient demand and clinician interest have driven professional training in integrative therapies, but few rigorous evaluations have been published. METHODS: This project evaluated the proof of concept of training in acupressure, guided imagery, massage, and Reiki on clinicians' sense of self efficacy in providing nondrug therapies, self-confidence in providing compassionate care, and engagement with work. RESULTS: Three out of 4 topics met minimum enrollment numbers; 22 of 24 participants completed follow-up as well as pretraining surveys. All would recommend the training to others and planned changes in personal and professional care. There were significant improvements in self-efficacy in using nondrug therapies, confidence in providing compassionate care, and unplanned absenteeism ( P < .05 for each). CONCLUSION: Training in integrative therapies is feasible and associated with significant improvements in clinicians' sense of self-efficacy, confidence in providing compassionate care, and engagement with work. Additional studies are needed to determine the impact on quality of care and long-term workforce engagement. PMID- 29228784 TI - Efficacy of Berberine Alone and in Combination for the Treatment of Hyperlipidemia: A Systematic Review. AB - The objective of this review is to identify, summarize, and evaluate clinical trials of berberine for the treatment of hyperlipidemia and other dyslipidemias. A literature search for randomized, controlled trials of berberine that assessed at least 2 lipid values as endpoints resulted in identification of 12 articles that met criteria. The majority of evaluated articles consistently suggest that berberine has a beneficial effect on low-density lipoprotein (reductions ranging from approximately 20 to 50 mg/dL) and triglycerides (reductions ranging from approximately 25 to 55 mg/dL). Common study limitations included lack of reporting of precision in their endpoints, description of blinding, transparency in flow of patients, and reporting of baseline concomitant medications. Berberine could serve as an alternative for patients who are intolerant to statins, patients resistant to starting statin therapy but who are open to alternative treatments, and for low-risk patients not indicated for statin therapy. PMID- 29228785 TI - An Overview on Indications and Chemical Composition of Aromatic Waters (Hydrosols) as Functional Beverages in Persian Nutrition Culture and Folk Medicine for Hyperlipidemia and Cardiovascular Conditions. AB - Hydrosol beverages in Persian nutrition culture and ethnomedicine are the side products of essential oil industry that are used as delicious drinks or safe remedies. To investigate indications and chemical composition of hydrosol beverages for hyperlipidemia and cardiovascular conditions, Fars province was selected as the field of study. Ethnomedical data were gathered by questionnaires. The constituents of hydrosols were extracted with liquid/liquid extraction and analyzed by gas chromatography-mass spectrometry. Statistical analysis were used to cluster their constituents and find the relevance of their composition. A literature survey was also performed on plants used to prepare them. Thymol was the major or second major component of these beverages, except for wormwood and olive leaf hydrosols. Based on clustering methods, although some similarities could be found, composition of barberry, will fumitory, dill, and aloe hydrosols have more differences than others. These studies may help in developing some functional beverages or new therapeutics. PMID- 29228787 TI - Health Promotion Potential of Vegetables Cultivated in Northern Thailand: A Preliminary Screening of Tannin and Flavonoid Contents, 5alpha-Reductase Inhibition, Astringent Activity, and Antioxidant Activities. AB - Many of scientific evidences suggest that regular consumption of fruits and vegetables can prevent chronic diseases. In Northern Thailand, there are many vegetables that are usually consumed by local people. In this study, 17 local vegetables were selected and extracted with 95% ethanol. The extracts were screened for 5alpha-reductase inhibitory activity, total tannin and flavonoid contents, astringent and antioxidant activities. The results showed that Spondias pinnata and Ocimum americanum had the highest tannin and flavonoid content, respectively. Neptunia oleracea was the most potent 5alpha-reductase inhibitor. For antioxidant activities, S pinnata was the most potent ABTS (2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid)) radical scavenger and the most potent ferric reducer. Polygonatum odoratum was the most potent hydrogen peroxide scavenger and Leucaena leucocephala was the most potent DPPH (2,2-diphenyl-1 picrylhydrazyl) radical scavenger among the tested samples. This suggests that local vegetables in Northern Thailand have a health promotion potential, which can be further developed as nutritional supplements, preventive medicines, and topical products for cosmetic purposes. PMID- 29228788 TI - Understanding the experiences of middle school girls who have received help for non-suicidal self-injury. AB - This study aimed to understand the experiences of middle school girls who have engaged in non-suicidal self-injury (NSSI) and have received professional help for these behaviors. Participants described engaging in NSSI in response to uncomfortable feelings and invasive negative thoughts. They reported that engaging in NSSI decreased their uncomfortable feelings. While each participant had at least one person in her life who knew about her NSSI, participants did not feel supported or validated by these people. Participants were not completely honest with their therapists because they were afraid of being misunderstood, dismissed, or getting others into trouble. Despite these things, participants wanted support and understanding about who they are as unique individuals, why they are struggling, and why they self-injure. They also wanted to be in a transparent therapeutic relationship where they felt respected and accepted. Unfortunately, they did not describe relationships with their therapists as possessing these qualities. Professionals would better meet the need of adolescents by clearly discussing confidentiality, boundaries, conveying respect and acceptance, and recognizing the uniqueness of their clients. Assessing for self-harm and treatment reluctance should be done in the context of resistance to therapy and a sensitivity to judgment. PMID- 29228786 TI - Oxidative Stress Induces Disruption of the Axon Initial Segment. AB - The axon initial segment (AIS), the domain responsible for action potential initiation and maintenance of neuronal polarity, is targeted for disruption in a variety of central nervous system pathological insults. Previous work in our laboratory implicates oxidative stress as a potential mediator of structural AIS alterations in two separate mouse models of central nervous system inflammation, as these effects were attenuated following reactive oxygen species scavenging and NADPH oxidase-2 ablation. While these studies suggest a role for oxidative stress in modulation of the AIS, the direct effects of reactive oxygen and nitrogen species (ROS/RNS) on the stability of this domain remain unclear. Here, we demonstrate that oxidative stress, as induced through treatment with 3 morpholinosydnonimine (SIN-1), a spontaneous ROS/RNS generator, drives a reversible loss of AIS protein clustering in primary cortical neurons in vitro. Pharmacological inhibition of both voltage-dependent and intracellular calcium (Ca2+) channels suggests that this mechanism of AIS disruption involves Ca2+ entry specifically through L-type voltage-dependent Ca2+ channels and its release from IP3-gated intracellular stores. Furthermore, ROS/RNS-induced AIS disruption is dependent upon activation of calpain, a Ca2+-activated protease previously shown to drive AIS modulation. Overall, we demonstrate for the first time that oxidative stress, as induced through exogenously applied ROS/RNS, is capable of driving structural alterations in the AIS complex. PMID- 29228789 TI - A Mechanistic Review on Medicinal Plants Used for Diabetes Mellitus in Traditional Persian Medicine. AB - Diabetes mellitus is the most common endocrine disorder and a major cause of morbidity and mortality. Traditional medicines worldwide suggest a wide range of natural remedies for the prevention and treatment of chronic disorders, including diabetes mellitus. This mechanistic review aims to highlight the significance of medicinal plants traditionally used as dietary supplements in Persian medicine in adjunct with restricted conventional drugs for the prevention and treatment of diabetes mellitus. Mounting evidence suggests that these natural agents perform their protective and therapeutic effect on diabetes mellitus via several cellular mechanisms, including regeneration of pancreatic beta cell, limitation of glycogen degradation and gluconeogenesis, anti-inflammatory, immunoregulatory, antiapoptosis, antioxidative stress, as well as modulation of intracellular signaling transduction pathways. In conclusion, traditional medicinal plants used in Persian medicine can be considered as dietary supplements with therapeutic potential for diabetes mellitus and maybe potential sources of new orally active agent(s). PMID- 29228790 TI - An Evidence-Based Study on Medicinal Plants for Hemorrhoids in Medieval Persia. AB - Hemorrhoids is one of the most common gastrointestinal diseases. There are several therapeutic options associated with some complications. Therefore, researchers look for traditional medicines as a potential resource for introduction of new natural drugs. The current study reports an evidence-based review of herbal remedies for hemorrhoids in traditional Persian medicine. A comprehensive survey about hemorrhoids on the most important manuscripts of traditional Persian medicine was done. Then, scientific data banks were searched for possible related properties of each herb in the conventional medicine. We reported some historical aspects of traditional Persian medicine view on classification, examination, and predisposing factors of hemorrhoids. In addition, we have reported 105 medicinal plants belonging to 51 families. More than half of the reported herbs exhibited anti-inflammatory and analgesic effects. Although lack of human studies regarding the mentioned herbs is noted, positive results from experimental findings can be considered for new drug discovery supported by traditional and medieval experiences. PMID- 29228792 TI - Silymarin, Olibanum, and Nettle, A Mixed Herbal Formulation in the Treatment of Type II Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial. AB - Silybum marianum (L) Gaertn (milk thistle) seeds, Urtica dioica L (nettle) leaves, and Boswellia serrata (olibanum gum) resin are used traditionally by Iranian diabetic patients. The aim of this study was to evaluate the antihyperglycemic effects of these herbs in an herbal formulation in patients with type II diabetes mellitus. Sixty patients diagnosed as type II diabetes mellitus with fasting blood glucose level from 150 to 180 mg/dL, glycosylated hemoglobin level from 7.5% to 8.5%, and on oral antihyperglycemic drugs, were allocated to receive the mix herbal formulation or placebo for 90 days in a double-blind randomized placebo-controlled clinical trial. The mean serum fasting blood glucose, glycosylated hemoglobin, and triglyceride in the herbal drug group were significantly less than placebo group's values after 3 months of the intervention. The study showed a potential antihyperglycemic and triglyceride lowering effect of the herbal formulation, while it did not have any significant cholesterol or blood pressure lowering effect. PMID- 29228791 TI - The Protective Effect of Hydroalcoholic Extract of Zingiber officinale Roscoe (Ginger) on Ethanol-Induced Reproductive Toxicity in Male Rats. AB - This study was conducted to evaluate the prophylactic effect of ginger extract on ethanol-induced reproductive toxicity in male rats. Twenty-eight adult male Sprague-Dawley rats were randomly divided into 4 groups and treated daily for 28 days as follows: control, control-ginger (1 g/kg of body weight [BW]/day by gavage), ethanol group (ethanol 4 g/kg of BW/day by gavage), and ginger-ethanol group. At the end of the experiment, all the rats were sacrificed and their testes were removed and used for measurement of the total homocysteine (tHcy), trace elements, antioxidant enzymes activity, and malondialdehyde (MDA). The results in the ethanol group indicate that ethanol decreased antioxidant enzymes activity and increased MDA and tHcy compared with the control groups ( P < .05). In ginger-ethanol group, ginger improved antioxidant enzymes activity and reduced tHcy and MDA compared to ethanol group ( P < .05). It can be concluded that ginger protects the ethanol-induced testicular damage and improves the hormonal levels, trace elements, antioxidant enzymes activity, and decreases tHcy and MDA. PMID- 29228793 TI - Effects of Shambhavi Mahamudra Kriya, a Multicomponent Breath-Based Yogic Practice ( Pranayama), on Perceived Stress and General Well-Being. AB - Stress-induced disorders such as anxiety represent the leading causes of adult disability worldwide. Previous studies indicate that yoga and other contemplative practices such as pranayama, or controlled yogic breathing techniques, may be effective in the treatment of mood disorders and stress. In this study, 142 individuals (mean age = 43 years; SD = 13.90) participated in a 3-day retreat program during which they learned Shambhavi Mahamudra kriya, which is a yogic practice that includes both deep breathing and meditation techniques. Participants were instructed to practice the kriya each day for 21 minutes. After 6 weeks of daily practice, participants reported subjectively lower levels of perceived stress (Perceived Stress Scale) and higher levels of general well-being (General Well-Being Scale) compared to baseline. These results support the notion that Shambhavi Mahamudra kriya may represent a natural treatment for stress reduction. PMID- 29228794 TI - Learning to BREATHE: A Pilot Study of a Mindfulness-Based Intervention to Support Marginalized Youth. AB - Mindfulness-based curricular interventions can support adolescents who are at risk of school failure as they negotiate the transition from high school into young adulthood. Researchers hypothesized that a 6-week mindfulness-based intervention would lower participants' perceived stress while increasing their reported levels of self-esteem. Participants (N = 23) ranged in age from 17 to 20 years while the majority were male students of color. Pre- and postintervention survey mean responses revealed statistically significant differences on the Single-Item Self-Esteem Scale and 3 items on the Perceived Stress Scale (with small to moderate effect sizes). Postintervention focus group (n = 8) data indicated that the most valued daily practice was the body scan technique. Open coding of the focus group data also revealed several key themes in the form of overarching codes as participants discussed intervention benefits. These included ( a) self-regulation, ( b) attention-awareness, and ( c) positive thinking. PMID- 29228795 TI - Comparing Vitamin A and Moist Chamber in Preventing Ocular Surface Disorders. AB - The present study was conducted to determine the effectiveness of vitamin A eye ointment (VAEO) and moist chamber (MC) in preventing ocular surface disorders (OSD) in intensive care unit (ICU) patients. A total of 38 eligible patients were selected for participation in the present clinical trial. All the patients were randomly administered VAEO in one eye every 6 hr for 5 days and had a polyethylene cover (PC) placed on their other eye to create an MC that was replaced every 12 hr as well. The results of Schirmer's test also increased by 2.06 mm in the VAEO group ( p < .001), while they showed a slight reduction by 0.15 mm in the MC group ( p = .669). VAEO was more effective in preventing OSD in ICU patients than MC and is, therefore, recommended to be used as a method of preventing OSD. PMID- 29228796 TI - Component-resolved microarray analysis of IgE sensitization profiles to Felis catus major allergen molecules in Russian cat-allergic patients. AB - We aimed to determine the profile of IgE reactivity to three major cat allergens, Fel d 1, Fel d 2 and Fel d 4, in cat-allergic patients in the Moscow region in Russia. sIgE levels to recombinant proteins expressed in Escherichia coli (Fel d 1 and Fel d 4) and to Fel d 2 protein purified from cat serum were measured using a microarray method developed in our laboratory. Sera from 174 anonymous subjects with a positive reaction (>=0.35 IU/mL) to cat dander extract (e1, ImmunoCAP) and 56 negative controls were used for IgE testing. Fel d 1 was recognized by 92.5%, Fel d 2 by 29.9% and Fel d 4 by 39.1% of the tested patient sera. The sensitivity to these three proteins was approximately 98% compared to cat dander extract (correlation coefficient to ImmunoCAP is 0.94 with PPV = 0.99 and NPV = 0.95). These predictive values appeared to be even more statistically significant than the divergence between the ISAC IgE test and the extract-based singleplex ImmunoCAP. The combination of the three investigated proteins (Fel d 1, Fel d 2 and Fel d 4) is suitable for in vitro molecular (serological) diagnosis of cat allergy in this region as a complement to cat dander extract. Moreover, with this method, we found distinction between Fel d 2 and other Feline sIgEs formation. PMID- 29228797 TI - In situ microstructure and rheological behavior of yeast biofilms from the juice processing industries. AB - The factors affecting the mechanical properties of biofilms formed by yeast species (Rhodotorula mucilaginosa, Candida krusei, C. kefyr and C. tropicalis) isolated from the juice processing industries have been investigated. Variables studied were: the food matrix (apple/pear juice), the sugar concentration (6/12 degrees Bx) and the hydrodynamic conditions (static/turbulent flow). A range of environmental cues were included as the mechanical properties of biofilms are complex. Yeast counts were significantly higher in turbulent flow compared with under static conditions. The thickness of the biofilm ranged from 38 to 148 MUm, from static to turbulent flow. Yeast biofilms grown under turbulent flow conditions were viscoelastic with a predominant solid-like behavior and were structurally stronger than those grown under static conditions, indicating gel type structures. Only the type of flow had a significant effect on [Formula: see text] and G*. Flow velocity and nutrient status modulated the biofilm thickness, the biomass and the mechanical properties. A better knowledge of the factors controlling biofilm formation will help in the development of control strategies. PMID- 29228798 TI - Charge-induced geometrical reorganization of DNA oligonucleotides studied by tandem mass spectrometry and ion mobility. AB - Mass spectrometry is applied as a tool for the elucidation of molecular structures. This premises that gas-phase structures reflect the original geometry of the analytes, while it requires a thorough understanding and investigation of the forces controlling and affecting the gas-phase structures. However, only little is known about conformational changes of oligonucleotides in the gas phase. In this study, a series of multiply charged DNA oligonucleotides (n = 15 40) has been subjected to a comprehensive tandem mass spectrometric study to unravel transitions between different ionic gas-phase structures. The nucleobase sequence and the chain length were varied to gain insights into their influence on the geometrical oligonucleotide organization. Altogether, 23 oligonucleotides were analyzed using collision-induced fragmentation. All sequences showed comparable correlation regarding the characteristic collision energy. This value that is also a measure for stability, strongly correlates with the net charge density of the precursor ions. With decreasing charge of the oligonucleotides, an increase in the fragmentation energy was observed. At a distinct charge density, a deviation from linearity was observed for all studied species, indicating a structural reorganization. To corroborate the proposed geometrical change, collisional cross-sections of the oligonucleotides at different charge states were determined using ion mobility-mass spectrometry. The results clearly indicate that an increase in charge density and thus Coulomb repulsion results in the transition from a folded, compact form to elongated structures of the precursor ions. Our data show this structural transition to depend mainly on the charge density, whereas sequence and size do not have an influence. PMID- 29228799 TI - Calprotectin in patients with chronic rheumatoid arthritis correlates with disease activity and responsiveness to methotrexate. AB - OBJECTIVE: Calprotectin (myeloid-related protein 8/14) is elevated in inflammatory diseases and a correlation of serum calprotectin and disease activity in rheumatoid arthritis (RA) has been shown. In this study, we investigated plasma calprotectin as a disease marker in patients with chronic RA treated with methotrexate (MTX) monotherapy and compared plasma calprotectin with C-reactive protein (CRP) in this matter. METHODS: Seventy-six patients with chronic RA were included in this open prospective study and of these 40 were included prior to initiation of MTX therapy. The patients were followed with laboratory and clinical parameters for 52-56 weeks. Plasma calprotectin was analyzed at the start of study and at various intervals. Radiographic evaluation was performed at baseline and after 17.2 months and progression in joint destruction was measured with Larsen score. The response to MTX was evaluated according to the American College of Rheumatology criteria. RESULTS: Patients starting MTX treatment had significantly higher levels of plasma calprotectin compared to patients well established on MTX therapy (p = .008). Among the 40 patients naive to MTX, 25 responded to MTX therapy and serum calprotectin decreased significantly in these patients (p = .0007). The radiographic damage showed no relation to calprotectin. CONCLUSIONS: Plasma calprotectin is associated with disease activity in patients with chronic RA and is more strongly correlated to MTX response compared to CRP. The role of calprotectin as a disease marker is promising and the advantages compared to CRP needs to be further investigated. PMID- 29228800 TI - Fifth Metatarsal Jones Fractures in the Athlete. AB - : Fifth metatarsal fractures, otherwise known as "Jones" fractures, occur commonly in athletes and nonathletes alike. While recent occurrence in the popular elite athlete has increased public knowledge and interest in the fracture, this injury is common at all levels of sport. This review will focus on all three types of Jones fractures. The current standard for treatment is operative intervention with intramedullary screw fixation. Athletes typically report an acute episode of lateral foot pain, described as an ache. Radiographic imaging with multiple views of the weightbearing injured foot are needed to confirm diagnosis. If these images are inconclusive, further magnetic resonance imaging (MRI) or computed tomography (CT) is used. Nonoperative treatment is not commonly used as the sole treatment, except when following reinjury of a stable screw fixation. While screw selection is still controversial, operative treatment with intramedullary screw fixation is the standard approach. Technical tips on screw displacement are provided for Torg (types I, II, III) fractures, cavovarus foot fractures, recurrent fractures, revision surgery, occult fractures/high grade stress reactions, and Jones' variants. Excellent clinical outcomes can be expected in 80% to 100% of patients when using the intramedullary screw fixation to "fit and fill" the medullary canal with threads across the fracture site. Most studies show the timing for return to sports with optimal healing to be seven to twelve weeks after fixation. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 29228801 TI - Ocimum gratissimum Ameliorates Gentamicin-Induced Kidney Injury but Decreases Creatinine Clearance Following Sub-Chronic Administration in Rats. AB - The effects of aqueous extract of Ocimum gratissimum leaf (AOGL) on the renal function of rats with gentamicin-induced nephrotoxicity were investigated. This study involved the use of forty five (45) adult male Wistar rats (housed in separate metabolic cages) such that graded doses of OAGL were administered to the experimental groups (p.o.) for 28 days after exposure to gentamicin toxicity (100 mg/kg i.p.) for 1 week. At the end of the study, comparisons of some indices of renal function as well as antioxidant status (GSH and TBARS) were made between the control, toxic and AOGL-treated groups at P < 0.05. The result showed that gentamicin treatment caused significant increase ( P < .05) in urine output, urea, creatinine, total protein, relative kidney weight, and TBARS, as well as significant decrease ( P < .05) in urine creatinine and GSH levels. Post treatment with graded doses of AOGL caused significant increase in food consumption, GSH, urine, and plasma creatinine, as well as significant decrease ( P < .05) in relative kidney weight, TBARS, and urine total protein. There was an appreciable difference in the kidney histology of the AOGL-treated groups when compared with the toxic control. Hence, the extract has therapeutic potential in the management of gentamicin-induced kidney injury, although a risk profile of renal dysfunction is not unlikely from 28 days of administration as evident by the decrease in creatinine clearance. PMID- 29228802 TI - Role of serotonin hormone in weight regain after sleeve gastrectomy. AB - Laparoscopic sleeve gastrectomy (LSG) is gaining popularity as bariatric surgery, a small percentage of subjects regain weight after surgery. This study was designed to evaluate body weight changes over a period of two years after LSG and investigate the role of serotonin in regulating energy balance. This is a prospective cohort study. A total of 92 patients with morbid obesity (64 women and 28 men) underwent LSG. All the participants were subjected to physical examination and detailed medical history. Anthropometric measurements were accomplished pre-operative and post-operatively at a frequency of four times per year for two years follow-up. Laboratory investigations were performed pre operatively, and one and two years post-operatively. Blood samples were collected in the fasting state; for glucose, lipid profile and hormonal assays. Hormones measured were plasma insulin, leptin, serotonin and ghrelin. Results revealed that 35.7% weight loss occurred after one year. However, there was variability in the individual weight loss curve during the period between the first and second post-operative years. Thus, patients were divided into two groups: group I included 78 patients (84%) who maintained the lost weight, and group II included 14 patients (16.0%) who regained weight within 24 months post-operatively. Correlation with BMI revealed positive correlation with leptin and serotonin, whilst negative correlation with ghrelin in group II patients. Mechanisms of weight loss after LSG are not only attributable to gastric restriction but also to the neurohormonal changes. In addition, serotonin may possibly contribute to the interplay of regulatory systems of energy homeostasis. PMID- 29228803 TI - In Vitro Human Placental Studies to Support Adenovirus-Mediated VEGF DDeltaNDeltaC Maternal Gene Therapy for the Treatment of Severe Early-Onset Fetal Growth Restriction. AB - Severe fetal growth restriction (FGR) affects 1 in 500 pregnancies, is untreatable, and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) is one cause. Transduction of uterine arteries in normal and FGR animal models using an adenovirus (Ad) encoding VEGF isoforms increases UBF and improves fetal growth in utero. Understanding potential adverse consequences of this therapy before first-in-woman clinical application is essential. The aims of this study were to determine whether Ad.VEGF-DDeltaNDeltaC (1) transfers across the human placental barrier and (2) affects human placental morphology, permeability and primary indicators of placental function, and trophoblast integrity. Villous explants from normal term human placentas were treated with Ad.VEGF-DDeltaNDeltaC (5 * 107-10 virus particles [vp]/mL), or virus formulation buffer (FB). Villous structural integrity (hematoxylin and eosin staining) and tissue accessibility (LacZ immunostaining) were determined. Markers of endocrine function (human chorionic gonadotropin [hCG] secretion) and cell death (lactate dehydrogenase [LDH] release) were assayed. Lobules from normal and FGR pregnancies underwent ex vivo dual perfusion with exposure to 5 * 1010 vp/mL Ad.VEGF-DDeltaNDeltaC or FB. Perfusion resistance, para-cellular permeability, hCG, alkaline phosphatase, and LDH release were measured. Ad.VEGF-DDeltaNDeltaC transfer across the placental barrier was assessed by quantitative polymerase chain reaction in DNA extracted from fetal-side venous perfusate, and by immunohistochemistry in fixed tissue. Villous explant structural integrity and hCG secretion was maintained at all Ad.VEGF-DDeltaNDeltaC doses. Ad.VEGF DDeltaNDeltaC perfusion revealed no effect on placental permeability, fetoplacental vascular resistance, hCG secretion, or alkaline phosphatase release, but there was a minor elevation in maternal-side LDH release. Viral vector tissue access in both explant and perfused models was minimal, and the vector was rarely detected in the fetal venous perfusate and at low titer. Ad.VEGF-DDeltaNDeltaC did not markedly affect human placental integrity and function in vitro. There was limited tissue access and transfer of vector across the placental barrier. Except for a minor elevation in LDH release, these test data did not reveal any toxic effects of Ad.VEGF-DDeltaNDeltaC on the human placenta. PMID- 29228804 TI - Treatment of Postoperative Sore Throat With the Aid of the Homeopathic Remedy Arnica montana: A Report of Two Cases. AB - We present 2 cases of severe postoperative sore throat, hoarseness, aphonia, and dysphagia, after a laryngeal mask insertion, who were treated successfully with the homeopathic remedy Arnica montana. Three doses of Arnica montana 200CH were given to the patients over 36 hours. Although the symptoms were very intense, the remedy was very effective and cleared most of the symptoms in 48 hours. PMID- 29228805 TI - Biochemical Effects of Aqueous Extract of Persea americana (Mill) on the Myocardium of Left Ventricle of High Salt-Fed Adult Wistar Rats. AB - BACKGROUND: The cardioprotective effects of Persea americana extract was investigated on biochemical activities of high salt-fed adult Wistar rats in this study. METHOD: Forty healthy Wistar rats of both sexes weighing 120 to 150 g were randomly assigned into 8 groups of 5 rats each (groups A, B, C, D, E, F, G, and H). Rats in groups A, F, G, and H were fed with standard laboratory pellets, while groups B, C, D, and E were fed on the high-salt diet for 4 weeks. Concomitantly, daily administration of 50, 100, and 150 mg/kg of the P americana extract were given orally to groups C and F, D and G, and E and H, respectively, while rats in groups A and B were administered distilled water. Blood samples were taken by cardiac puncture; concentration of sodium ion, potassium ion, nitric oxide, and activity of lactate dehydrogenase were determined. One-way analysis of variance was used to analyze data, followed by Student-Newman-Keuls (SNK) test for multiple comparison. RESULTS: Results revealed that concentration of potassium ion and nitric oxide was significantly lower ( P < .05) in high salt fed groups. Sodium ion concentration and activity of lactate dehydrogenase were higher in high salt-fed group while P americana prevented biochemical perturbations in other experimental groups. CONCLUSION: In conclusion, high salt diet induced biochemical alterations which were significantly protected by oral administration of P americana extract. PMID- 29228806 TI - A Pilot Online Mindfulness Intervention to Decrease Caregiver Burden and Improve Psychological Well-Being. AB - Interventions to reduce caregiver burden are of great interest as the number of informal family caregivers continues to grow. The purpose of this study was to test the feasibility of an online mindfulness meditation intervention for community-dwelling older adult caregivers and to evaluate its impact on quality of life, caregiver burden, and psychological well-being. A total of 40 caregivers were recruited from 2 community center support groups to participate in an 8-week online mindfulness intervention. Pre and post surveys were administered. Retention rates were high with 55% completing the post surveys and attending at least 5 out of 8 sessions. Matched pairs t test indicated that the intervention reduced caregiver burden, perceived stress, anxiety, and loneliness and improved mental well-being. Online interventions offer flexibility for caregivers regardless of their responsibilities. Future research should expand this opportunity and explore the scalability of online mindfulness interventions. PMID- 29228807 TI - Trends in carisoprodol abuse and misuse after regulatory scheduling: a retrospective review of California poison control calls from 2008 to 2015. AB - BACKGROUND: In January 2012, carisoprodol was classified as a Schedule IV substance under the controlled substances act from a previously non-controlled, non-scheduled classification. Carisoprodol is marketed as a skeletal muscle relaxant and is commonly cited for its abuse potential. OBJECTIVES: We aimed to compare volume of calls involving carisoprodol abuse or misuse to a statewide poison control system before and after the scheduling change. METHODS: Data were extracted from poison control calls coded as "misuse/abuse" involving carisoprodol from four years before (2008 to 2011) and four years after (2012 to 2015) the scheduling change. The volume of calls from pre- and post-scheduling change was compared after adjusting for yearly California census data. RESULTS: The number of calls related to carisoprodol abuse or misuse was significantly decreased in the four years following the change compared to the four years before. CONCLUSION: Scheduling of carisoprodol was temporally related to decreased exposures as reported to California Poison Control Centers. Governmental regulation may impact a drug's potential for abuse. PMID- 29228808 TI - Variation in Phytochemical Composition Reveals Distinct Divergence of Aloe vera (L.) Burm.f. From Other Aloe Species: Rationale Behind Selective Preference of Aloe vera in Nutritional and Therapeutic Use. AB - In the present study, we have phytochemically characterized 5 different abundant Aloe species, including Aloe vera (L.) Burm.f., using silylation followed by Gas Chromatography-Mass Spectrometry technique and compared the data using multivariate statistical analysis. The results demonstrated clear distinction of the overall phytochemical profile of A vera, highlighted by its divergent spatial arrangement in the component plot. Lowest correlation of the phytochemical profiles were found between A vera and A aristata Haw. (-0.626), whereas highest correlation resided between A aristata and A aspera Haw. (0.899). Among the individual phytochemicals, palmitic acid was identified in highest abundance cumulatively, and carboxylic acids were the most predominant phytochemical species in all the Aloe species. Compared to A vera, linear correlation analysis revealed highest and lowest correlation with A aspera ( R2 = 0.9162) and A aristata ( R2 = 0.6745), respectively. Therefore, A vera demonstrated distinct spatial allocation, reflecting its greater phytochemical variability. PMID- 29228809 TI - Attenuation of Oxidative Stress and Inflammation by Portulaca oleracea in Streptozotocin-Induced Diabetic Rats. AB - The present study was designed to investigate the protective effect of the aqueous extract of Portulaca oleracea against hyperglycemic, oxidative damage and inflammation in the serum of streptozotocin (STZ)-induced diabetic rats. In the present study, the rats were divided into the following groups of 8 animals each: control, untreated diabetic, 3 Portulaca oleracea (100, 200, 400 mg/kg/d)-treated diabetic groups. At the end of the 4-week period, glucose, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), malondialdehyde (MDA), glutathione (GSH), and total antioxidant status (TAS) levels were measured. STZ caused an elevation in the serum levels of glucose, MDA, IL-6, and TNF-alpha with reduction in the levels of GSH and TAS ( P < .01). Portulaca oleracea ameliorated glucose, MDA, IL-6, TNF-alpha, GSH, and TAS levels in diabetic groups versus to the untreated groups ( P < .05). Taken together, Portulaca oleracea prevented hyperglycemia by preventing the oxidative stress and inflammation. PMID- 29228810 TI - Systematic Review and Meta-analysis of Endostar Combined With Transcatheter Arterial Chemoembolization (TACE) Versus TACE Alone for Hepatocellular Carcinoma. AB - Many studies have investigated the efficacy of Endostar combined with transcatheter arterial chemoembolization (TACE) versus TACE alone for hepatocellular carcinoma (HCC). A systematic review was conducted to evaluate the efficacy of Endostar. PubMed, Embase, and other databases were searched, and meta analysis was performed using RevMan 5.3 software. Nine studies, all of which were clinical randomized controlled trials, involving 411 participants were included. The overall response rate, disease control rate and alpha-fetoprotein negative conversion ratio, and the 6- and 12-month survival rate of HCC patients treated with combined Endostar and TACE were higher than those treated with TACE alone ( P < .01). Furthermore, the incidence of tumor progression was low after Endostar treatment ( P = .005). The incidence of adverse effects (leukocytopenia, liver function damage, and vomiting) was similar in Endostar with TACE and in TACE alone ( P > .05). However, large studies and more randomized trials are necessary to determine the effects of Endostar on HCC. PMID- 29228811 TI - Long-Term Effectiveness of Two Educational Methods on Knowledge, Attitude, and Practice Toward Palliative Care Consultation Services Among Nursing Staff: A Longitudinal Follow-Up Study. AB - This experimental study investigated long-term effectiveness of two educational methods on knowledge, attitude, and practice (KAP) about palliative care consultation services (PCCS) among nurses, recruited from a medical center located in Northern Taiwan in 2015, using a stratified cluster sampling method, with 88 participants in multimedia (experimental) and 92 in traditional paper education (control) group. Data were collected using KAP-PCCS questionnaire before education, immediately after, and 3rd and 6th month after education. Results showed that both K-PCCSI and P-PCCSI significantly increased immediately after, and at the 3rd month after education for the experimental group; the K PCCSI remained significantly higher for the experimental group at the 6th month. The highest increase in scores for both K-PCCSI and P-PCCSI was observed at the 3rd month. There was no significant change in A-PCCS in both groups after follow up periods, when compared before education. Therefore, using multimedia every 3 months to continue strengthening their knowledge may increase the referrals of terminal patients to PCCS. PMID- 29228812 TI - Decline in the Use of Medicalized Yoga Between 2002 and 2012 While the Overall Yoga Use Increased in the United States: A Conundrum. AB - We analyzed the National Health Institute Survey Alternative Medicine supplement yoga data for 2002, 2007, and 2012 to answer the following questions: (1) Do the claims about increase in the use of yoga hold true at the level of specific health problems? (2) Do trends support a proposition that yoga is believed to be helpful in amelioration of disease conditions? (3) Do the prescribing patterns of health care providers correspond with the increasing popularity of yoga? Data were analyzed using SAS software, version 9.4. Response percentages were compared using chi-square test after adjusting for age. Between 2002 and 2012, use of yoga increased but adherence failed to increase, and use for specific health problems and for back pain declined; use of health care providers' referral-driven yoga declined between 2007 and 2012. All results were statistically significant. Our results suggest that the use of medicalized yoga declined between 2002 and 2012. PMID- 29228813 TI - Atypical location of unusual supratentorial neurenteric cyst: a case report. AB - We report a case of a right anterior clinoid process (ACP) neurenteric cyst which presented with gradual impairment of vision in the right eye. Imaging suggested an infective cystic lesion. In view of rapid visual loss urgent surgery was conducted. Erosion of the ACP was found from where white mucus like material was aspirated. The cyst wall was completely excised. Immunohistochemistry indicated an endodermal origin of the cyst. PMID- 29228814 TI - Cold-adapted enzymes produced by fungi from terrestrial and marine Antarctic environments. AB - Antarctica is the coldest, windiest, and driest continent on Earth. In this sense, microorganisms that inhabit Antarctica environments have to be adapted to harsh conditions. Fungal strains affiliated with Ascomycota and Basidiomycota phyla have been recovered from terrestrial and marine Antarctic samples. They have been used for the bioprospecting of molecules, such as enzymes. Many reports have shown that these microorganisms produce cold-adapted enzymes at low or mild temperatures, including hydrolases (e.g. alpha-amylase, cellulase, chitinase, glucosidase, invertase, lipase, pectinase, phytase, protease, subtilase, tannase, and xylanase) and oxidoreductases (laccase and superoxide dismutase). Most of these enzymes are extracellular and their production in the laboratory has been carried out mainly under submerged culture conditions. Several studies showed that the cold-adapted enzymes exhibit a wide range in optimal pH (1.0-9.0) and temperature (10.0-70.0 degrees C). A myriad of methods have been applied for cold-adapted enzyme purification, resulting in purification factors and yields ranging from 1.70 to 1568.00-fold and 0.60 to 86.20%, respectively. Additionally, some fungal cold-adapted enzymes have been cloned and expressed in host organisms. Considering the enzyme-producing ability of microorganisms and the properties of cold-adapted enzymes, fungi recovered from Antarctic environments could be a prolific genetic resource for biotechnological processes (industrial and environmental) carried out at low or mild temperatures. PMID- 29228815 TI - Acute and Subchronic Toxicity Studies of Aqueous Extract of Desmodium adscendens (Sw) DC. AB - Extracts of Desmodium adscendens (Sw) DC are used for the treatment of various diseases but limited toxicological evaluations have been done on the medicinal plant. This study investigates toxicity effects of the leave extract of D adscendens, and the possibility of drug-drug interaction of the plant extract when co-administered with other drugs. Oral administrations of leaf extract of D adscendens to white Wistar rats in an acute toxicity studies allowed the estimation of an LD50 (median lethal dose) value of 1122 mg/kg body weight. In a subchronic toxicity studies, the plant extract caused a decrease in zoxazolamine paralysis time and prevented thiopentone from causing sleep in test animals compared to controls. Overall, the results are consistent with the plant extract being safe at the doses administered in humans. However, the induction of the CYP enzymes is an indication of a possible drug interaction when the plant extract is co-administered with other drugs. PMID- 29228816 TI - Ingestion of an Oral Hyaluronan Solution Improves Skin Hydration, Wrinkle Reduction, Elasticity, and Skin Roughness: Results of a Clinical Study. AB - Intake of oral supplements with the aim of a cutaneous antiaging effect are increasingly common. Hyaluronic acid (HA) is a promising candidate, as it is the key factor for preserving tissue hydration. In our practice study, we evaluated the effect of an oral HA preparation diluted in a cascade-fermented organic whole food concentrate supplemented with biotin, vitamin C, copper, and zinc (Regulatpro Hyaluron) on skin moisture content, elasticity, skin roughness, and wrinkle depths. Twenty female subjects with healthy skin in the age group of 45 to 60 years took the product once daily for 40 days. Different skin parameters were objectively assessed before the first intake, after 20 and after 40 days. Intake of the HA solution led to a significant increase in skin elasticity, skin hydration, and to a significant decrease in skin roughness and wrinkle depths. The supplement was well tolerated; no side effects were noted throughout the study. PMID- 29228817 TI - Cangrelor in Percutaneous Coronary Intervention: Current Status and Perspectives. AB - Cangrelor is an intravenously administered P2Y12 receptor antagonist with very fast, potent, and quickly reversible action. In the CHAMPION PHOENIX trial, cangrelor provided an improved anti-ischemic protection compared with clopidogrel, without increasing the risk of severe bleeding. Cangrelor is currently approved by drug regulating authorities for patients undergoing percutaneous coronary intervention (PCI) without prior treatment with a P2Y12 receptor antagonist and not receiving a glycoprotein IIb/IIIa inhibitor, while its use is endorsed with a class IIb recommendation by the European Society of Cardiology guidelines. Several subanalyses of CHAMPION PHOENIX trial have tried to elucidate the role of cangrelor in PCI, including its usefulness during a 2 hour landmark analysis, impact on intraprocedural stent thrombosis, and reduction in myocardial infarction (MI) rate. The influence of gender, geographic region, access site, and bivalirudin use on cangrelor's effects has also been reported. In patients with ST elevation MI and in clinical scenarios of disturbed absorption of oral antiplatelet agents or in need of an intravenous agent, cangrelor may surpass oral agents' drawbacks. Transitioning to an oral agent is mandatory following cangrelor infusion discontinuation, although ticagrelor may be administered earlier without any pharmacodynamic interaction. Nevertheless, the clinical role of cangrelor in conjunction with administration of prasugrel or ticagrelor remains unclear. Accruing real-life experience is expected to improve our understanding of cangrelor's role in everyday clinical practice. PMID- 29228818 TI - Evaluation of Herbal Concoctions Sold at Ga Maja (Limpopo Province) in South Africa and In Vitro Pharmacological Evaluation of Plants Used to Manufacture the Concoctions. AB - The aim of the study was to evaluate the biological activities and safety of commercial herbal concoctions manufactured in Ga Maja (Limpopo province). Microbial contamination was evaluated by spread-plating the concoctions on agar plates. The VITEK 2 instrument was used for identification of the pure cultures. Nutritional content of the concoctions was determined. Thin layer chromatography was used to analyze the chemical constituents of the extracts. The microdilution assay and bioautography were used to evaluate antimicrobial activity against selected microorganisms. Sodium, potassium, and zinc were elements most abundant in the concoctions. Phytochemical screening revealed the presence of various phytoconstituents. Acetone extracts of Hypoxis hemerocallidea and Kirkia wilmsii extracts had antioxidant activity. The minimum inhibitory concentrations values against test bacteria ranged between 0.02 and 0.63 mg/mL. Further studies are required to isolate bioactive compounds and evaluate their cytotoxicity. Caution in the consumption of the herbal mixtures should be adhered to. PMID- 29228819 TI - Formulation and ex vivo-in vivo evaluation of pH-triggered brimonidine tartrate in situ gel for the glaucoma treatment using application of 32 factorial design. AB - CONTEXT: Short residence time, poor bioavailability and poor permeability are the major problems for conventional eye drops treatment. OBJECTIVE: The aim of this article is to develop, optimize and ex vivo-in vivo investigation of brimonidine tartrate in situ gel as compared to marketed eye drops for the treatment of glaucoma. MATERIALS AND METHODS: The effect of independent variables, namely concentrations of polymers, on various dependent variables like viscosity at physiological pH and in vitro drug release were studied by using 32 factorial design. Further the optimized formulation was characterized for ex vivo and in vivo study. RESULTS AND DISCUSSION: Experimental data demonstrated that optimized in situ gel formulation (F8) showed in vitro-ex vivo sustained release profile with polymer composites carbopol 974P and HPMC K4M. After 5 h of ex vivo transcorneal permeation study, the amount recovered from the corneal surface on the donor chamber 12.40% (124 ug) and the amount collected from the receptor chamber 76.8% (760 ug) of the initial dose 1 mg. The total amount recovered from the permeation experiment was 89.2%. Bioadhesive carbopol 974P and viscosity HPMC K4M composites optimized formulation (F 8) produce greater influence on the duration of drug action and improved intraocular pressure reduction activity as compared to marketed eye drop solution in in vivo study. CONCLUSION: The developed in situ gelling system as a promising ophthalmic formulation to prolong the drug lowering effect on the intraocular pressure. PMID- 29228820 TI - Associations between Depressive Symptomatology and Neurocognitive Impairment in HIV/AIDS. AB - OBJECTIVE: Mood disorders and neurocognitive impairments are debilitating conditions among patients with HIV/AIDS. How these comorbidities interact and their relationships to systemic factors remain uncertain. Herein, we investigated factors contributing to depressive symptomatology (DS) in a prospective cohort of patients with HIV/AIDS in active care that included neuropsychological assessment. METHODS: Among patients with HIV/AIDS receiving combination antiretroviral therapy (cART) and ongoing clinical assessments including measures of sleep, health-related quality of life (HQoL), neuropsychological testing, and mood evaluation (Patient Health Questionnaire-9 [PHQ-9]) were performed. Univariate and multivariate analyses were applied to the data. RESULTS: In 265 persons, 3 categories of DS were established: minimal (PHQ-9: 0-4; n = 146), mild (PHQ-9: 5-9; n = 62), and moderate to severe (PHQ-9: 10+; n = 57). Low education, unemployment, diabetes, reduced adherence to treatment, HIV-associated neurocognitive disorders (HAND), low health-related quality of life (HQoL), reduced sleep times, and domestic violence were associated with higher PHQ-9 scores. Motor impairment was also associated with more severe DS. In a multinomial logistic regression model, only poor HQoL and shorter sleep duration were predictive of moderate to severe depression. In this multivariate model, the diagnosis of HAND and neuropsychological performance (NPz) were not predictive of DS. CONCLUSIONS: Symptoms of depression are common (45%) in patients with HIV/AIDS and represent a substantial comorbidity associated with multiple risk factors. Our results suggest that past or present immunosuppression and HAND are not linked to DS. In contrast, sleep quality and HQoL are important variables to consider in screening for mood disturbances among patients with HIV/AIDS and distinguishing them from neurocognitive impairments. PMID- 29228821 TI - Public Expenditures for Mental Health Services in Canadian Provinces: Depenses publiques pour les services de sante mentale dans les provinces canadiennes. AB - OBJECTIVE: The purpose of this study is to measure provincial spending for mental health services in fiscal year (FY) 2013 and to compare these cost estimates to those of FY 2003. METHODS: This study estimated the costs of publicly funded provincial mental health services in FY 2013 and compared them to the estimates for FY 2003 from a previously published report. Our data were obtained from publicly accessible databases. The cross-year cost comparisons for provincial mental health services were restricted to general and psychiatric hospital inpatients, clinical payments to physicians and psychologists, and prescribed psychotropic medications. Total public expenditures were inflation adjusted and expressed per capita and as a percentage of the total provincial health spending. RESULTS: Total public spending for mental health and addiction programs/services was estimated to be $6.75 billion for FY 2013. The largest component of the expenditures was hospital inpatient services ($4.02 billion, 59.6%), followed by clinical payments to physicians or psychologists ($1.69 billion, 25%), and then publicly funded prescribed psychotherapeutic medications ($1.04 billion, 15.4%). Nationally, the portion of total public spending on health that was spent on mental health decreased from FY 2003 to FY 2013 from 5.4% to 4.9%. CONCLUSION: Our results reveal that mental health spending, as a proportion of public health care expenditures, decreased in the decade from FY 2003 to FY 2013. Due to large differences in how the provinces report community mental health services, we still lack a comprehensive picture of the mental health system. PMID- 29228822 TI - Effects of an Herbal Combination on Glycemic Control and Lipid Profile in Diabetic Women: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. AB - The present study was conducted to explore the efficacy and safety of a herbal combination in the treatment of women with hyperlipidemic type 2 diabetes. The herbal combination capsule (600 mg) contained Terminalia chebula fruit extract (200 mg), Commiphora mukul (200 mg), and Commiphora myrrha oleo-gum-resin (200 mg), and the placebo capsule contained 600 mg toast powder. The patients in one group took the herbal combination and those in the other group took placebo capsules 3 times a day for 3 months. In the herbal combination-treated patients, the fasting blood glucose, total cholesterol, and low-density lipoprotein cholesterol levels were decreased and hidh-density lipoprotein cholesterol levels was increased significantly at the endpoint compared with the placebo and baseline. Other blood parameters such as glycosylated hemoglobin, triglyceride, blood urea nitrogen, creatinine, SGOT, and SGPT levels were not significantly changed after 3 months in both groups. In conclusion, the herbal combination improves glycemic control and lipid profile in women with hyperlipidemic type 2 diabetes without any adverse events. PMID- 29228823 TI - Current practice in the rehabilitation of complex regional pain syndrome: a survey of practitioners. AB - INTRODUCTION: International clinical guidelines for Complex Regional Pain Syndrome recommend a wide range and variation of rehabilitation therapies as the core treatment. It is likely that most therapists employ a range of approaches when managing people with Complex Regional Pain Syndrome but a recent Cochrane review identified little evidence relating to the effectiveness of multi-modal rehabilitation. There is need for up to date trials of rehabilitation for Complex Regional Pain Syndrome, but in order to develop a clear model of best practice that can be rigorously evaluated we need to understand current practice. METHOD: An electronic survey was disseminated internationally to clinicians involved in the rehabilitation of individuals with Complex Regional Pain Syndrome. The survey aimed to establish which criteria are used for diagnosis and which modalities clinicians use to treat Complex Regional Pain Syndrome and which they consider ineffective or harmful. RESULTS: 132 valid responses were received. A third of participants did not use any established criteria to diagnose Complex Regional Pain Syndrome. Current practice commonly included patient education, encouragement of self-management, and physical exercises. Cortically directed treatments such as graded motor imagery and psychological approaches were often incorporated into treatment whereas pain provocative therapies, splinting, contrast bathing, and cold and heat therapy were rarely used in the acute or chronic phase of Complex Regional Pain Syndrome. CONCLUSION: A broad range of modalities are currently used in Complex Regional Pain Syndrome rehabilitation. Practice appears to be characterized by educational and exercise based interventions delivered in a pain-contingent manner which largely echoes recommendations in international clinical guidelines. Implications for Rehabilitation: Patients with Complex Regional Pain Syndrome suffer from a painful and disabling condition for which we still do not know the best treatment options. From our survey sample most clinicians use treatments recommended in the international guidelines. A large proportion of clinicians from our survey sample are not using internationally recognized diagnostic criteria and we therefore recommend that clinicians become familiar with these criteria and use them for all suspected Complex Regional Pain Syndrome cases. PMID- 29228824 TI - Development of novel bioadhesive granisetron hydrochloride spanlastic gel and insert for brain targeting and study their effects on rats. AB - The aim of this study was to formulate granisetron hydrochloride (GH) spanlastic in mucoadhesive gels and lyophilized inserts for intranasal administration to improve GH bioavailability and brain targeting. Carpapol 934 and HPMC were incorporated in GH spanlastic in nasal gels (GHSpNGs). Gelatin and HPMC as matrix former, glycine as a collapse protecting and mannitol as an insert filler and sweeting agent were used to prepare GH spanlastic loaded in lyophilized inserts (GHSpNIs). The prepared GHSpNGs were characterized for pH measurement, drug content, rheology, and in vitro drug release. The prepared GHSpNIs were characterized for drug content, surface pH, GH release, and mucoadhesion. Biological investigations including pharmacokinetics studies and brain drug targeting efficiency dimensions were performed on rats (LC-MS/MS). The results showed thixotropic pseudoplastic gels and white insert with pH values in a physiological range, drug content (89.9-98.6%), (82.4-98.38%) for gel and insert, respectively and rapid release rate of GH. Biological studies showed that Cmax and AUC0-6 h in brain and plasma after intranasal administration of gel and insert were higher compared to IV administration of GH solution. A high brain targeting efficiency (199.3%, 230%) for gel and insert, respectively and a direct nose to brain transport (49.8%, 56.95%) for gel and insert, respectively confirmed that there is a direct nose to brain transport of GH following nasal administration of GH spanlastic loaded in nasal gel and insert. GHSpNIs can be considered as potential novel drug delivery system intended for brain targeting via the nasal rout of administration than GHSpNGs. PMID- 29228825 TI - Efficacy and nephrotoxicity associated with various colistin dosing schemas for the treatment of multidrug resistant (MDR) infections. PMID- 29228827 TI - Conservative versus active management in HELLP syndrome: results from a cohort study. AB - OBJECTIVE: HELLP syndrome exposes to severe maternal and fetal complications. Prompt delivery is thus recommended after 34 weeks of gestation, or earlier in case of nonreassuring maternofetal conditions. However, no consensus has been raised in the treatment of HELLP syndrome occurring before 34 weeks of gestation, when both maternal and fetal conditions are stable: it remains still unclear whether an active attitude should be prioritized over expectant management. Herein, we aimed to compare mother and child outcomes according to the type of obstetrical management, either active or conservative. STUDY DESIGN: Retrospective and multicenter study involving two tertiary care units. In Center A, obstetrical attitude consisted in expectant management: all women received full antenatal betamethasone therapy and pregnancy was prolonged until maternal or fetal follow up indicated delivery. In Center B, management was active: all deliveries were initiated within 48 hours following diagnosis. RESULTS: From 2003 to 2011, 118 patients were included (87 in Center A, 31 in Center B). Both groups of patients were similar regarding maternal and fetal features at baseline. Active management led to increased risks of post-partum hemorrhage (relative risks (RR) = 5.38, 95%CI: 1.2-24.06) and neonatal morbidity including respiratory distress syndrome (RR = 3.1, 95%CI: 1.4-7.1), sepsis (RR = 2.5, 95%CI: 1.1-6.0), necrotizing enterocolitis (RR = 4.8, 95%CI: 1.1-21.2), intracerebral hemorrhage (RR = 5.4, 95%CI: 2.1-13.6), and blood transfusion (RR = 6.1, 95%CI: 1.7-21.7). CONCLUSIONS: Conservative management may be beneficial for both mother and newborn in patients with stable HELLP syndrome. Identification of maternal and fetal specific prognostic factors would allow a better stratification of women with HELLP syndrome according to illness progressive potential, resulting in a more personalized management. PMID- 29228826 TI - Synthesis, physicochemical properties and ocular pharmacokinetics of thermosensitive in situ hydrogels for ganciclovir in cytomegalovirus retinitis treatment. AB - Ganciclovir (GCV) is one of the most widely used antiviral drugs for the treatment of cytomegalovirus (CMV) retinitis. In this context, the aim of this study was to design in situ thermosensitive hydrogels for GCV ocular delivery by intravitreal injection to achieve sustained drug release behavior and improved ocular bioavailability in the treatment of CMV retinitis. A thermosensitive poly (beta-butyrolactone-co-lactic acid)-polyethylene glycol-poly (beta-butyrolactone co-lactic acid) (PBLA-PEG-PBLA) triblock copolymer was synthesized by ring opening polymerization and characterization. The GCV-loaded PBLA-PEG-PBLA in situ hydrogels (15%, w/w) were then prepared with drug concentration at 2 mg.mL-1 and the gelation temperatures, rheological properties, in vitro degradation and syringeability of in situ hydrogels for intravitreal injection were also investigated. Membraneless dissolution model was used to explore drug release behavior of PBLA-PEG-PBLA in situ hydrogel. The results indicated that more than 45 and 85% of GCV can be released within 24 and 96 h, respectively, which was verified by a non-Fickian diffusion mechanism. In vivo ocular pharmacokinetics study showed that area under drug-time curve (AUC) and half-life of PBLA-PEG-PBLA in situ hydrogel was higher (AUC was 61.80 MUg.mL-1.h (p < .01) and t1/2 was 10.29 h in aqueous humor; AUC was 1008.66 MUg.mL-1.h (p < .01) and t1/2 was 13.26 h (p < .01) in vitreous) than GCV injection with extended therapeutic activity. Based on obtained results, it was concluded that the thermosenstive PBLA-PEG-PBLA in situ hydrogel is a promising carrier of GCV for intravitreal injection. PMID- 29228828 TI - Trace elements profiles of maternal blood, umbilical cord blood, and placenta in Beijing, China. AB - AIM: Profiles of heavy metals such as chromium (Cr), manganese (Mn), arsenic (As), lead (Pb), and cadmium (Cd), and micronutrients such as ferrum (Fe), copper (Cu), zinc (Zn), and selenium (Se) in maternal and umbilical cord blood clots were investigated for assessing placenta function in the transport of micronutrients or heavy metal pollutants. METHODS: Correlations between contents of elements in the two tissues were also analyzed. RESULTS: Significantly lower levels of Cr, Pb, and Cd in umbilical cord blood clots than in maternal blood clots, and negative relationship between lead levels in maternal and umbilical cord blood (r = -.334, p = .016). Concentration of Mn in cord blood was significantly higher than that in maternal blood clots and positively related to the maternal level. The data also show that the placenta may work most strongly as a barrier against Cd and protects fetus from its harmful effect, while plays almost no role in preventing the transportation of As, Mn, and Pb. CONCLUSIONS: In conclusion, pregnant women should avoid exposure to environment polluted with heavy metals, particularly with As, Mn, and Pb. PMID- 29228830 TI - Twelve tips on how to provide self-regulated learning (SRL) enhanced feedback on clinical performance. AB - The provision of self-regulated learning (SRL) enhanced feedback on performing clinical skills and making a clinical diagnosis recognizes the importance of feedback on the use of key SRL processes. In contrast to the broader concept of self-directed learning, SRL has a specific focus on the individual learner's approach to achieve a task, including their planning, self-monitoring, and future adaptations. The key SRL processes can be identified using structured microanalysis during the clinical task and feedback to the learner using the tips outlined in this article. It is essential that SRL enhanced feedback is integrated with best practice on providing feedback to ensure that its potential is achieved. PMID- 29228829 TI - Vanadium pentoxide increased PTEN and decreased SHP1 expression in NK-92MI cells, affecting PI3K-AKT-mTOR and Ras-MAPK pathways. AB - Vanadium is an air pollutant that imparts immunosuppressive effects on NK cell immune responses, in part, by dysregulating interleukin (IL)-2/IL-2R-mediated JAK signaling pathways and inducing apoptosis. The aim of the present study was to evaluate effects of vanadium pentoxide (V2O5) on other IL-2 receptor-mediated signaling pathways, i.e. PI3K-AKT-mTOR and Ras-MAPK. Here, IL-2-independent NK 92MI cells were exposed to different V2O5 doses for 24 h periods. Expression of PI3K, Akt, mTOR, ERK1/2, MEK1, PTEN, SHP1, BAD and phosphorylated forms, as well as caspases-3, -8, -9, BAX and BAK in/on the cells were then determined by flow cytometry. The results show that V2O5 was cytotoxic to NK cells in a dose-related manner. Exposure increased BAD and pBAD expression and decreased that of BAK and BAX, but cell death was not related to caspase activation. At 400 uM V2O5, expression of PI3K-p85 regulatory subunit increased 20% and pPI3K 50%, while that of the non-pPI3K 110alpha catalytic subunit decreased by 20%. At 200 MUM, V2O5 showed significant decrease in non-pAkt expression (p < 0.05); the decrease in pAkt expression was significant at 100 MUM. Non-pmTOR expression displayed a significant downward trend beginning at 100 MUM. Expressions of pMEK-1/2 and pERK 1/2 increased substantially at 200 MUM V2O5. No differences were found with non phosphorylated ERK-1/2. PTEN expression increased significantly at 100 MUM V2O5 exposure whereas pPTEN decreased by 18% at 25 MUM V2O5 concentrations, but remained unchanged thereafter. Lastly, V2O5 at all doses decreased SHP1 expression and increased expression of its phosphorylated form. These results indicated a toxic effect of V2O5 on NK cells that was due in part to dysregulation of signaling pathways mediated by IL-2 via increased PTEN and decreased SHP1 expression. These results can help to explain some of the known deleterious effects of this particular form of vanadium on innate immune responses. PMID- 29228831 TI - Need for further research on environmental factors in the etiology of congenital anomalies in the eastern Mediterranean region (EMR). PMID- 29228832 TI - NADPH oxidase 4 mediates ROS production in radiation-induced senescent cells and promotes migration of inflammatory cells. AB - Excessive DNA damage induced by ionising radiation (IR) to normal tissue cells is known to trigger cellular senescence, a process termed stress-induced premature senescence (SIPS). SIPS is often accompanied by the production of reactive oxygen species (ROS), and this is reported to be important for the initiation and maintenance of SIPS. However, the source of ROS during SIPS after IR and their significance in radiation-induced normal tissue damage remain elusive. In the present study, we tested the hypothesis that the NADPH oxidase (NOX) family of proteins mediates ROS production in SIPS-induced cells after IR and plays a role in SIPS-associated biological events. X-irradiation of primary mouse embryonic fibroblasts (MEFs) resulted in cellular senescence and the concomitant increase of intracellular ROS. Among all six murine NOX isoforms (NOX1-4 and DUOX1/2), only NOX4 was detectable under basal conditions and was upregulated following IR. In addition, radiation-induced ROS production was diminished by genetic or pharmacological inhibition of NOX4. Meanwhile, NOX4 deficiency did not affect the induction of cellular senescence after IR. Furthermore, the migration of human monocytic U937 cells to the culture medium collected from irradiated MEFs was significantly reduced by NOX4 inhibition, suggesting that NOX4 promotes the recruitment of inflammatory cells. Collectively, our findings imply that NOX4 mediates ROS production in radiation-induced senescent cells and contributes to normal tissue damage after IR via the recruitment of inflammatory cells and the exacerbation of tissue inflammation. PMID- 29228833 TI - In vitro/in silico approach in the development of simvastatin-loaded self microemulsifying drug delivery systems. AB - OBJECTIVE: The aims of this study were to formulate simvastatin (SV)-loaded self microemulsifying drug delivery systems (SMEDDS), and explore the potential of these drug delivery systems to improve SV solubility, and also to identify the optimal place in the gastrointestinal (GI) tract for the release of SV using coupled in vitro/in silico approach. SIGNIFICANCE: In comparison to other published results, this study considered the extensive pre-systemic clearance of SV, which could significantly decrease its systemic and hepatic bioavailability if SV is delivered into the small intestine. METHODS: SV-loaded SMEDDS were formulated using various proportions of oils (PEG 300 oleic glycerides, propylene glycol monocaprylate, propylene glycol monolaurate), surfactant (PEG 400 caprylic/capric glycerides) and cosurfactant (polysorbate 80) and subjected to characterization, and physiologically-based pharmacokinetic (PBPK) modeling. RESULTS: According to the in vitro results, the selected SMEDDS consisted of 10.0% PEG 300 oleic glycerides, 67.5% PEG 400 caprylic/capric glycerides, and 22.5% polysorbate 80. The use of acid-resistant capsules filled with SV-loaded SMEDDS was found helpful in protecting the drug against early degradation in proximal parts of the GI tract, however, in silico simulations indicated that pH controlled drug release system that dissolve in the distal parts of the intestine might further improve SV bioavailability (up to 7.20%). CONCLUSION: The obtained results suggested that combined strategy for the improvement of SV bioavailability should comprise solubility enhancement and delayed drug release. The developed SV-specific PBPK model could potentially be used to assess the influence of formulation factors on drug absorption and disposition when developing SV oral dosage forms. PMID- 29228834 TI - Quality of life and its related factors for adults with autism spectrum disorder. AB - PURPOSE: Improved quality of life is an important outcome for adults with autism spectrum disorder. However, little research has examined factors associated with quality of life among adults with autism spectrum disorder. METHOD: This study comparing 66 adults with autism spectrum disorder (intelligence quotient > 70) aged 20-38 years with neuro-typical adults investigated their quality of life and related factors. All the participants were interviewed with questionnaires by a registered occupational therapist. RESULTS: Participants with autism spectrum disorder scored significantly lower in all domains of quality of life than did the controls. Adults with autism spectrum disorder reported higher anxiety level, more loneliness, and higher scores on four sensory quadrants than neuro-typical adults. The predictors of the physical health domain were anxiety and sensation sensitivity behaviors. Loneliness and sensation-sensitivity behaviors were predictive of the psychological health domain. Comorbid psychiatric disorders and loneliness were predictive of the social relationship domain. CONCLUSIONS: Adults with autism spectrum disorder need more supportive social contexts and interventions to improve their quality of life. Social relationships, psychological health, and sensory processing difficulty must be considered when designing treatment programs for adults with autism spectrum disorder. Implications for Rehabilitation Adults with autism spectrum disorder scored significantly lower in all domains of quality of life than did the neuro-typical adults. Occupational therapy can provide more supportive social contexts and interventions on social relationship and sensory processing difficulty to improve their quality of life. Understanding factors associated with quality of life among adults with autism spectrum disorder can contribute to address their needs. Occupational therapy can facilitate health promotion through working with adults with autism spectrum disorder. Social relationships, psychological health, and sensory processing difficulty must be considered when designing treatment programs for adults with autism spectrum disorder. PMID- 29228835 TI - The self-management balancing act of spousal care partners in the case of Parkinson's disease. AB - BACKGROUND: Living with and caring for someone with chronic illness can lead to limitations in activity and social participation for the care partner. Past research emphasizes the importance of care partners taking care of themselves physically and emotionally so they can stay healthy to support the care recipient. There is little information regarding how the care partner takes care of their own social lives. The purpose of this study was to explore the concept of social self-management from the perspective of spousal care partners of people with Parkinson's disease. METHOD: Twenty spousal care partners of people with Parkinson's disease were interviewed three times. A grounded theory approach informed data analysis. RESULTS: Findings that emerged from the data focused on balance in activities, support, and emotions and were summarized into three main themes: (1) Activities: Caregiving and beyond; (2) Strategies to support self and spouse; and (3) Emotional impact: Burden and compassion. CONCLUSION: This research shows that care partners want to retain social participation and provides support for the importance of addressing the socio-emotional needs of care partners of people with a chronic disease. Interventions that guide care partners to take care of their spectrum of needs may lead to healthier, positive relationships. Implications for rehabilitation The focus of rehabilitation is often on the person diagnosed with the chronic condition. Living with and caring for someone with a chronic illness, such as Parkinson's disease, can lead to limitations in activity and social participation for the care partner. Including care partners in the rehabilitation process is key to helping maintain their health and well-being. Learning caregiving and self-management strategies may help care partners support their loved ones while staying socially engaged. PMID- 29228836 TI - Complete mtDNA sequencing reveals mutations m.9185T>C and m.13513G>A in three patients with Leigh syndrome. AB - The most common mitochondrial disorder in children is Leigh syndrome, which is a progressive and genetically heterogeneous neurodegenerative disorder caused by mutations in nuclear genes or mitochondrial DNA (mtDNA). In the present study, a novel and robust method of complete mtDNA sequencing, which allows amplification of the whole mitochondrial genome, was tested. Complete mtDNA sequencing was performed in a cohort of patients with suspected mitochondrial mutations. Patients from Latvia and Lithuania (n = 92 and n = 57, respectively) referred by clinical geneticists were included. The de novo point mutations m.9185T>C and m.13513G>A, respectively, were detected in two patients with lactic acidosis and neurodegenerative lesions. In one patient with neurodegenerative lesions, the mutation m.9185T>C was identified. These mutations are associated with Leigh syndrome. The present data suggest that full-length mtDNA sequencing is recommended as a supplement to nuclear gene testing and enzymatic assays to enhance mitochondrial disease diagnostics. PMID- 29228837 TI - Feeling inadequate: Residents' stress and learning at primary care clinics in the United States. AB - BACKGROUND: Educators hope that residents' experiences in primary care continuity clinics will influence more trainees to enter primary care careers. Unfortunately, evidence shows that outpatient primary care training in the United States is stressful and fails to promote primary care careers. We conducted qualitative interviews with residents to understand the source of stress and to explain this failure. METHODS: In-person individual interviews were conducted with 37 primary care residents training at outpatient clinics in the US. Analysis used the constant comparative method and included open and focused coding, allowing themes to emerge inductively from the data. RESULTS: 73% of residents interviewed reported negative emotions about clinic. Beyond stress, residents reported feeling inadequate as primary care physicians at clinic. Four factors contributed: mental distractions, unfamiliarity with primary care medicine, management of outpatients, and relationships with patients. Residents' comparisons of hospital-based and outpatient experiences favored the former in relation to the four factors. CONCLUSIONS: Residents feel unprepared for primary care and inadequate as primary care physicians, and these feelings discourage them from practicing primary care. This phenomenon must be studied within the entire context of residency, as residents' attitudes about their outpatient experiences were shaped in relation to their inpatient experiences. PMID- 29228838 TI - Beyond competency-based continuing professional development. AB - Competency based medical education (CBME) has become the default for undergraduate and post-graduate medical education (PGME) but its role in continuing professional development (CPD) is under discussion. Some critical differences between CPD and PGME are identified and these differences applied to: the relative roles of competence and performance; existing criticisms of CBME; heutagogy as a learning theory; and post-modernism as an underlying philosophical perspective. The argument is made that the characteristics of CPD fit with performance based medical education, a heutagogical learning theory, a focus on capabilities, rather than competencies; and a post-modern perspective. PMID- 29228839 TI - Validation of Fatigue Impact Scale with various item sets - a Rasch analysis. AB - PURPOSE: Fatigue is a symptom in patients with chronic gastrointestinal (GI) and liver diseases. Different instruments have been developed to assess the severity of fatigue and the 40-item Fatigue Impact Scale (FIS) is among the most widely used. Shorter versions of FIS include the 21-item Modified Fatigue Impact Scale (MFIS), and an eight-item version for everyday use. The study aimed to assess construct validity, reliability, and sufficiency of the raw score of the original FIS with 40 items, and examine the sufficiency of the 21 items from the Modified scale and the eight items of the Daily Fatigue Impact Scale (D-FIS), all of which are embedded in the 40-item scale. METHODS: Patients with chronic GI or liver disease (n = 354) completed the FIS with 40 items. The majority (57%) was under the age of 55 years and approximately half were females (48%). Various item sets of FIS were derived which showed fit to the Rasch model. RESULTS: Local dependency and multidimensionality in FIS and the 21-item Modified scale were resolved with a testlet solution but the D-FIS showed local dependency and multidimensionality and differential item functioning (DIF) still remained. Two new item sets fulfilling unidimensionality and no DIF are suggested, one with 15 items and a six-item scale for daily use. The transformation table shows score interval scale estimates for all these item sets. CONCLUSIONS: Both the FIS and the Modified scale can be used to measure fatigue albeit requiring some adjustment for DIF. The eight-item D-FIS is more problematic, and its summed score is not valid. Alternative 15- and 6-item versions presented in this paper can offer valid summed scores, and the transformation table allows transformation of raw scores and comparisons across all versions. Implications for rehabilitation The Fatigue Impact Scale and the Modified Fatigue Impact Scale can be used to measure fatigue after adjustments for differential item functioning. Alternative 15- and 6-item versions of Fatigue Impact Scale offer valid summed scores. The summed score for the Daily Fatigue Impact Scale is not valid. A transformation table with raw scores and Rasch transformed interval scale metric makes it possible to compare scores derived from the Fatigue Impact Scale, the Modified Fatigue Impact Scale and the proposed 15- and 6-item versions of Fatigue Impact Scale for research and/or clinical use. PMID- 29228841 TI - Correction to: Anesthetic management of amniotic fluid embolism- A multi-center, retrospective, cohort study. PMID- 29228843 TI - Correction to: Haj Yahya et al., Development of a nomogram for prediction of successful membrane sweeping. PMID- 29228840 TI - Investigational PD-1 inhibitors in HL and NHL and biomarkers for predictors of response and outcome. AB - INTRODUCTION: Inhibitors against the PD-1/PD-L1 pathway are revolutionizing the treatment and management of malignancies. Areas covered: We summarize our current understanding of the function of PD-1, its role in immune evasion, the clinical data available that support the use of PD-1 antagonist in Hodgkin and non-Hodgkin lymphomas, and potential predictors of response. Expert opinion: We anticipate that in the next 10 years, agents that modulate the immune system such as PD-1 antagonists will be increasingly used in favor over traditional cytotoxic chemotherapeutic agents. PD-1 antagonists will be combined with future immunotherapies or used as adjuncts to cellular therapy to boost tumor-specific immune responses. PMID- 29228842 TI - Mammary Analogue Secretory Carcinoma of the Thyroid Mimicking Locally Advanced Papillary Thyroid Carcinoma: A Rare Case Report. AB - Mammary analogue secretory carcinoma (MASC) harboring ETV6 gene rearrangements was first described in the salivary gland with a relatively favorable prognosis and a possible molecular therapeutic target with pan-Trk inhibitors. Recently, primary MASC of the thyroid gland has been reported. We report a case of a 4.0 cm MASC arising from the left thyroid of a 58-year-old female with extrathyroidal extension. Initially, it was diagnosed by fine needle aspiration as suspicious for papillary thyroid carcinoma (PTC) and subsequently called a poorly differentiated carcinoma on resection. A final diagnosis of primary MASC of the thyroid was confirmed after an expanded immunohistochemical panel and identification of an ETV6 gene rearrangement by fluorescence in situ hybridization. Morphologically, the tumor was composed of solid, microcystic and focally papillary growth with dense fibrotic stroma and necrosis. Overlapping cytological features with PTC were identified, including foci of enlarged cells with irregular nuclear membranes/grooves. However, most of the cells contained prominent nucleoli with intraluminal and intracytoplasmic eosinophilic secretions. Immunohistochemically, the tumor cells were strongly positive for pancytokeratin, cytokeratin 7, PAX8, mammaglobin, and GCDFP-15, with rare staining for GATA3 and S100 and negative for TTF-1 and thyroglobulin. We report a rare case of a primary thyroid MASC, initially misdiagnosed as PTC. Pathologists should be aware of this entity and, given the similarities to PTC, have a high index of suspicion, prompting the addition of immunohistochemical and molecular studies. Furthermore, an accurate diagnosis is important because of the possible prognostic and treatment implications. PMID- 29228844 TI - The adherence to the therapy in inflammatory bowel disease: beyond the number of the tablets. AB - OBJECTIVES: The therapy of the inflammatory bowel diseases is quite complex. A partial compliance increases the relapse probability and the health expenditure. The aim of the study is to correctly study the adherence to the therapy in a single centre eliminating the bias of a different relationship of trust with different doctors. MATERIALS AND METHODS: We conducted a blind prospective study on the adherence evaluated for mesalazine. RESULTS: Three hundred and seventy-six patients were included in the final analysis. Of the patients, 57.4% never missed a single dose of mesalazine, 29.3% missed one or two doses, 7.4% missed three to four doses, 5.9% missed more than five doses. A greater adherence among males (p = .015) and, in ulcerative colitis, among the group with a disease duration of <2 years compared to the one with a disease duration between 2 and 5 years (p = .04) were found. In Crohn's diseases, among the patients who had never undergone to surgical interventions, the adherence was 49.6%, compared to 51.9% among patients who underwent to one surgical resection and 78.6% among patients underwent to multiple surgical resections (p = .001). CONCLUSIONS: The factors influencing the adherence to the therapy are only partly related to the prescribed therapy, but also to factors affecting the patient life: to increase the adherence rate it would be necessary not only interventions on the posology but also the psychological support to the patient at the time of the visit. PMID- 29228845 TI - Correction to: Choi et al., Diagnostic usefulness of the QuantiFERON-TB gold in tube test (QFT-GIT) for tuberculous vertebral osteomyelitis. PMID- 29228846 TI - Anatomical location of metastatic lymph nodes: an indispensable prognostic factor for gastric cancer patients who underwent curative resection. AB - BACKGROUND: Although the numeric-based lymph node (LN) staging was widely used in the worldwide, it did not represent the anatomical location of metastatic lymph nodes (MLNs) and not reflect extent of LN dissection. Therefore, in the present study, we investigated whether the anatomical location of MLNs was still necessary to evaluate the prognosis of node-positive gastric cancer (GC) patients. METHODS: We reviewed 1451 GC patients who underwent radical gastrectomy in our institution between January 1986 and January 2008. All patients were reclassified into several groups according to the anatomical location of MLNs and the number of MLNs. The prognostic differences between different patient groups were compared and clinicopathologic features were analyzed. RESULTS: In the present study, both anatomical location of MLNs and the number of MLNs were identified as the independent prognostic factors (p < .01). The patients with extraperigastric LN involvement showed a poorer prognosis compared with the perigastric-only group (p < .001). For the N1-N2 stage patients, the prognostic discrepancy was still observed among them when the anatomical location of MLNs was considered (p < .05). For the N3-stage patients, although the anatomical location of MLNs had no significant effect on the prognosis of these patients, the higher number of MLNs in the extraperigastric area was correlated with the unfavorable prognosis (p < .05). CONCLUSION: The anatomical location of MLNs was an important factor influencing the prognostic outcome of GC patients. To provide more accurate prognostic information for GC patients, the anatomical location of MLNs should not be ignored. PMID- 29228847 TI - Comparison of the effectiveness of IPSS and VPSS without any help in LUTS patients: a prospective study. AB - AIM: To compare the correlation of visual prostate symptom score (VPSS) and international prostate symptom score (IPSS). To investigate the effect of educational level and age in the responses to VPSS and IPSS. METHOD: Three hundred and nine patients who gave consent and applied via LUTS to our institution were included in this study. They were requested to fill IPSS and VPSS. The patients were divided into two groups as middle-aged and elderly with a cutoff point of 65 years. They were divided into six groups based on educational level. SPSS was used for the statistical evaluation. RESULTS: The mean age of the patients was 61.5 +/- 8.9 years. The correlation was found between IPSS and VPSS (p < .05). Education was found not to contribute for answering IPSS and VPSS (p = .332 and .138, respectively). No difference was found between the middle-aged and elderly groups in terms of the rates of inability to answer IPSS and VPSS (p = .177 and .681, respectively). CONCLUSIONS: There is a correlation between VPSS and IPSS. VPSS can be used as an auxiliary or alternative tool instead of IPSS in evaluating LUTS; however, has no superiority to IPSS in elderly group. Currently, the best option to exclude bias in illiterate group is VPSS. PMID- 29228848 TI - Comparative study of surgical and conservative treatments for fifth metatarsal base avulsion fractures (type I) in young adults or athletes. AB - PURPOSE: This study aimed to investigate the therapeutic effects and complications of minimally invasive surgery in treating displaced avulsion fractures (2-3 mm) of fifth metatarsal base zone I in young adults or athletes. METHODS: Forty-six patients with displaced fifth metatarsal base avulsion fractures were assigned to operative and nonoperative groups by randomization. Patients in nonoperative group were immobilized with plaster, while patients in operative group were treated with closed reduction and fixation with a percutaneous screw. RESULTS: All patients were followed up for 14 months on average (ranging from 12 to 24 months). All cases got primary union except for three patients in nonoperative group with malunion and two with frequent mild to moderate plantar pain. The American Orthopaedic Foot and Ankle Society score was significantly better in operative group at 6 months after treatment ( p < 0.05) but not significantly different at 12 months after treatment ( p > 0.05). The average time of full weight bearing and returning to work was significantly shorter in operative group than nonoperative group ( p < 0.05). CONCLUSION: In young adults or athletes with displaced avulsion fractures of fifth metatarsal base zone I, closed reduction and percutaneous screw fixation provides anatomical stable fixation and early mobilization. PMID- 29228849 TI - Using Prosopagnosia to Test and Modify Visual Recognition Theory. AB - Biederman's contemporary theory of basic visual object recognition (Recognition by-Components) is based on structural descriptions of objects and presumes 36 visual primitives (geons) people can discriminate, but there has been no empirical test of the actual use of these 36 geons to visually distinguish objects. In this study, we tested for the actual use of these geons in basic visual discrimination by comparing object discrimination performance patterns (when distinguishing varied stimuli) of an acquired prosopagnosia patient (LB) and healthy control participants. LB's prosopagnosia left her heavily reliant on structural descriptions or categorical object differences in visual discrimination tasks versus the control participants' additional ability to use face recognition or coordinate systems (Coordinate Relations Hypothesis). Thus, when LB performed comparably to control participants with a given stimulus, her restricted reliance on basic or categorical discriminations meant that the stimuli must be distinguishable on the basis of a geon feature. By varying stimuli in eight separate experiments and presenting all 36 geons, we discerned that LB coded only 12 (vs. 36) distinct visual primitives (geons), apparently reflective of human visual systems generally. PMID- 29228850 TI - Three-dimensional kinematics of the lunate, hamate, capitate and triquetrum with type 1 or 2 lunate morphology. AB - The purpose of this study was to investigate the differences in three-dimensional carpal kinematics between type 1 and 2 lunates. We studied 15 instances of wrist flexion to extension (nine type 1, six type 2), 13 of radial to ulnar deviation (seven type 1, six type 2), and 12 of dart-throwing motion (six each of type 1 and 2) in 25 normal participants based on imaging with computerized tomography. Mean proximal translation of the distal articular midpoint of the triquetrum relative to type 2 lunates during wrist radioulnar deviation was 2.9 mm (standard deviation (SD) 0.7), which was significantly greater than for type 1 lunates, 1.6 mm (SD 0.6). The hamate contacted the lunate in ulnar deviation and ulnar flexion of wrists with type 2 lunates but not with type 1. We conclude that the four corner kinematics of the wrist joint are different between type 1 and 2 lunates. PMID- 29228851 TI - Volar locking plate fixation versus external fixation of distal radius fractures: a meta-analysis. AB - This meta-analysis evaluates reported outcomes of volar locking plates versus external fixation for management of distal radius fractures. A comprehensive literature search was carried out using PubMed, embase, MEDLINE, and the Cochrane Library. Multiple outcomes were analysed: study characteristics, objective/subjective outcome measures, radiographic parameters, and complication rates. Nine studies containing 780 participants met the outlined inclusion criteria. Disabilities of the arm, shoulder, and hand scores significantly favoured volar locking plates, but only at 3 months was the difference clinically meaningful. Grip strength, extension, and supination were better in the volar locking plates group in the early post-operative period, but were similar at 12 months. Ulnar variance was better restored by volar locking plates. The volar locking plates group was associated with higher re-operation rate, and the external fixation group had a higher infection rate. Current literature suggests that volar locking plates can provide better subjective scores and radiographic parameters, especially in the first 3 months, but may be associated with a higher re-operation rate. PMID- 29228852 TI - Metallosis and carpal tunnel syndrome following total wrist arthroplasty. PMID- 29228853 TI - Directional Limits on Motion Transparency Assessed Through Colour-Motion Binding. AB - Motion-defined transparency is the perception of two or more distinct moving surfaces at the same retinal location. We explored the limits of motion transparency using superimposed surfaces of randomly positioned dots defined by differences in motion direction and colour. In one experiment, dots were red or green and we varied the proportion of dots of a single colour that moved in a single direction ('colour-motion coherence') and measured the threshold direction difference for discriminating between two directions. When colour-motion coherences were high (e.g., 90% of red dots moving in one direction), a smaller direction difference was required to correctly bind colour with direction than at low coherences. In another experiment, we varied the direction difference between the surfaces and measured the threshold colour-motion coherence required to discriminate between them. Generally, colour-motion coherence thresholds decreased with increasing direction differences, stabilising at direction differences around 45 degrees . Different stimulus durations were compared, and thresholds were higher at the shortest (150 ms) compared with the longest (1,000 ms) duration. These results highlight different yet interrelated aspects of the task and the fundamental limits of the mechanisms involved: the resolution of narrowly separated directions in motion processing and the local sampling of dot colours from each surface. PMID- 29228854 TI - The design and development of MyT1DHero: A mobile app for adolescents with type 1 diabetes and their parents. AB - Introduction Type 1 diabetes impacts approximately 1.25 m Americans, many of them young children. As a child grows, there is a transition towards independence and they must learn to manage their diabetes independently. The objective of this study was to design, develop and conduct a prototype test to assess the satisfaction and feasibility of a mobile app for adolescents with type 1 diabetes and their parents to aid in this transition. Methods Ten parent/adolescent groups used MyT1DHero for four weeks. They were given a pre-test/post-test survey regarding family conflict with three tasks of diabetes management and the general tone of family communication. At post-test they were asked questions regarding their satisfaction and perception of ease of use of the app. They also participated in short interviews regarding the app. Additionally, we used server data to examine actual app usage. Results The parents' perceptions of conflict around the results of the blood sugar tests increased ( t(9) = 2.71, p = .02) as did perceptions of conflict around logging the blood sugar results ( t(9) = 3.67, p = .005). The adolescents perceived increased conflict surrounding the results around logging the blood sugars results ( t(9) = 3.09, p = .01).There was no change in the tone of general family communication. During the prototype testing, we discovered that the app crashed repeatedly and several of the functions were not working properly. In the interview data, three main themes emerged, app crashing issues, problems with notifications and positive feedback. Discussion Through this process, all of the reported issues were corrected and new features were planned for subsequent versions. A smartphone application has the potential to be a novel intervention for engaging adolescents and their parents in positive communication to support type 1 diabetes management. PMID- 29228855 TI - Effects of telephone call intervention on cardiovascular risk factors in type 2 diabetes mellitus: A meta-analysis. AB - Background Mobile health interventions utilising telephone calls are promising tools for diabetes management. However, there is still a lack of convincing evidence demonstrating their beneficial effects on cardiovascular risk factors. The aim of this meta-analysis of randomised controlled trials was to assess the effect of telephone calls on glycaemic control and other cardiovascular risk factors in type 2 diabetes mellitus patients. Methods Two independent reviewers searched three online databases (PubMed, the Cochrane Library and EMBASE) to identify relevant English-language randomised controlled trials up to September 2017. Randomised controlled trials that assessed the effects of telephone calls on glycaemic control and other cardiovascular risk factors in type 2 diabetes mellitus patients were included. Effect size was calculated for changes in glycosylated haemoglobin A1c, weight, blood pressure and lipid levels using fixed or random-effects models. Results Eighteen studies involving 3954 patients were included in the meta-analysis. Compared with usual care, telephone calls significantly decreased glycosylated haemoglobin A1c, by 0.12% (95% confidence interval: -0.22% to -0.02%). Univariate regression analysis showed that none of the covariates (number of participants, baseline age, baseline glycosylated haemoglobin A1c, duration of diabetes, call maker, number of calls and duration of study) had an impact on glycosylated haemoglobin A1c. For other cardiovascular risk factors, telephone calls significantly reduced systolic blood pressure by 0.19 mm Hg (95% confidence interval: -0.34% to -0.03%) but non-significantly changed diastolic blood pressure, body mass index, low-density lipoprotein cholesterol, total cholesterol, triglyceride or high-density cholesterol levels. Conclusions This meta-analysis supports the hypothesis that telephone calls offer moderate benefits for glycosylated haemoglobin A1c and systolic blood pressure reduction among type 2 diabetes mellitus patients. However, the data remain insufficient regarding the association of telephone calls with lowered diastolic blood pressure, body mass index or improved lipoprotein profiles. PMID- 29228857 TI - Corrigendum. PMID- 29228856 TI - Uncovering the proteome response of murine neuroblastoma cells against low-dose exposure to saxitoxin. AB - The potent neurotoxin saxitoxin produced by both marine and freshwater phytoplankton causes paralytic shellfish poisoning syndrome. The toxicity and mode of action of the acute exposure of high-dose saxitoxin have been intensively studied for decades; however, the potential risk of exposure of low-dose saxitoxin remained to be uncovered. Here we present a proteomics study of murine neuroblastoma N2A cell with low-dose saxitoxin exposure (1 nM and 10 nM, 24-h intoxication). Differential proteins were profiled by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). A total of 9 proteins, including 14-3-3 beta (1433B), alpha enolase (ENO1) and cofilin 2 (CFL2), were altered by the low-dose saxitoxin exposure. We further validated the expressions of 1433B, ENO1 and CFL2 by Western blot analysis and the enzyme-linked immunosorbent assay. These 9 proteins involve cell apoptotic pathways, cell skeleton maintenance, membrane potentials and mitochondrial functions. Modulation of these 9 proteins by low-dose saxitoxin exposure could correlate to the reports on genotoxicity and neurotoxicity induced by saxitoxin. This study also suggested other potential risks of saxitoxin. PMID- 29228859 TI - Summary of 2017 ESC guidelines on valvular heart disease, peripheral artery disease, STEMI and on dual antiplatelet therapy. AB - During the ESC congress in September 2017 in Barcelona, the new ESC guidelines were presented and are now available on the ESC website. The new guidelines cover management recommendations on following cardiovascular items: valvular heart disease, peripheral artery disease, ST elevation myocardial infarction (STEMI) and on dual antiplatelet therapy. The present document gives a summary of these guidelines and highlights the most important recommendations and changes in the management of these diseases. It will help to increase awareness about the new guidelines and may stimulate to consult the full document for specific items. Ultimately, the authors hope that this document will enhance implementation of new ESC guidelines in daily clinical practice. PMID- 29228858 TI - Common Patterns of Regional Brain Injury Detectable by Diffusion Tensor Imaging in Otherwise Normal-Appearing White Matter in Patients with Early Moderate to Severe Traumatic Brain Injury. AB - Traumatic brain injury (TBI) alters the lives of millions of people every year. Although mortality rates have improved, attributed to better pre-hospital care and reduction of secondary injury in the critical care setting, improvements in functional outcomes post-TBI have been difficult to achieve. Diffusion-tensor imaging (DTI) allows detailed measurement of microstructural damage in regional brain tissue post-TBI, thus improving our understanding of the extent and severity of TBI. Twenty subjects were recruited from a neurological intensive care unit and compared to 18 healthy control subjects. Magnetic resonance imaging (MRI) scanning was performed on a 3.0-Tesla Siemens TIM Trio Scanner (Siemens Medical Solutions, Erlangen, Germany) including T1- and T2-weighted sequences and DTI. Images were processed using DTIStudio software. SAS (SAS Institute Inc., Cary, NC) was used for statistical analysis of group differences in 14 brain regions (25 regions of interests [ROIs]). Seventeen TBI subjects completed scanning. TBI and control subjects did not differ in age or sex. All TBI subjects had visible lesions on structural MRI. TBI subjects had seven brain regions (nine ROIs) that showed significant group differences on DTI metrics (fractional anisotropy, radial diffusion, or mean diffusion) compared to noninjured subjects, including the corpus callosum (genu and splenium), superior longitudinal fasciculus, internal capsule, right retrolenticular internal capsule, posterior corona radiata, and thalamus. However, 16 ROIs showed relatively normal DTI measures. Quantitative DTI demonstrates multiple areas of microstructual injury in specific normal-appearing white matter brain regions. DTI may be useful for assessing the extent of brain injury in patients with early moderate to severe TBI. PMID- 29228861 TI - A retrospective study of traumatic dental injuries in primary dentition: treatment outcomes of splinting. AB - OBJECTIVE: Splinting in primary dentition is limited to several traumatic dental injuries. The prognosis associated with splint use has not been fully investigated. In this study, we investigated the outcomes of traumatic injuries in primary teeth treated with splinting. MATERIALS AND METHODS: We retrospectively analysed 137 children with root fractures and lateral and extrusive luxation injuries to their primary teeth who were treated with semi rigid splints between 2010 and 2016. Treatment outcomes were analysed in patients with follow-up periods of >6 months. The outcomes of splinting were based on clinical and radiographic evaluations performed during follow-up examinations. RESULTS: In total, 182 primary teeth were examined, and of these, 90 teeth were treated using semi-rigid splints. In the splint group, pathological root resorption (31.1%) was the most common complication, whereas pathological tooth loss (25.0%) was found most common in the observation group. Splinting in root fractures showed a good prognosis, whereas in lateral and extrusive luxations, it did not (p < .05). There were no relationship between treatment delay and prognosis (p > .05). CONCLUSIONS: Depending on the type of luxation, splint therapy results in acceptable outcomes and may be a feasible treatment option. PMID- 29228862 TI - Oculomotor Cognitive Control Abnormalities in Australian Rules Football Players with a History of Concussion. AB - This study used oculomotor, cognitive, and multi-modal magnetic resonance imaging (MRI) measures to assess for neurological abnormalities in current asymptomatic amateur Australian rules footballers (i.e., Australia's most participated collision sport) with a history of sports-related concussion (SRC). Participants were 15 male amateur Australian rules football players with a history of SRC greater than 6 months previously, and 15 sex-, age-, and education-matched athlete control subjects that had no history of neurotrauma or participation in collision sports. Participants completed a clinical interview, neuropsychological measures, and oculomotor measures of cognitive control. MRI investigation involved structural imaging, as well as diffusion tensor imaging and resting state functional MRI sequences. Despite no group differences on conventional neuropsychological tests and multi-modal MRI measures, Australian rules football players with a history of SRC performed significantly worse on an oculomotor switch task: a measure of cognitive control that interleaves the response of looking towards a target (i.e., a prosaccade) with the response of looking away from a target (i.e., an antisaccade). Specifically, Australian footballers performed significantly shorter latency prosaccades and found changing from an antisaccade trial to a prosaccade trial (switch cost) significantly more difficult than control subjects. Poorer switch cost was related to poorer performance on a number of neuropsychological measures of inhibitory control. Further, when comparing performance on the cognitively more demanding switch task with performance on simpler, antisaccade/prosaccades tasks which require a single response, Australian footballers demonstrated a susceptibility to increased cognitive load, compared to the control group who were unaffected. These initial results suggest that current asymptomatic amateur Australian rules football players with a history of SRC may have persisting, subtle, cognitive changes, which are demonstrable on oculomotor cognitive measures. Future studies are required in order to further elucidate the full nature and clinical relevance of these findings. PMID- 29228864 TI - Multimedia Education Reduces Anxiety in Lung Transplant Patients. AB - CONTEXT: A significant contribution to the success of lung transplantation is the recipient's ability to self-manage a multidrug regimen and follow complex instructions. Effective education has always been an integral component of the process of preparing patients to care for themselves post lung transplant. Impaired cognition, anxiety, and psychological distress, however, can decrease the retention of posttransplant care information provided during education sessions. OBJECTIVE: This quality improvement project evaluated whether a multimedia education method compared to standard education method improves posttransplant care knowledge, anxiety, and satisfaction with the education experience in lung transplant patients and their caregivers. METHODS: Two education methods groups, comprised of transplant patients and their primary caregivers, were compared: (1) historic control group who received the standard education (n = 19 dyads) and (2) multimedia group who received the new multimedia education (n = 18 dyads). Knowledge of posttransplant care was evaluated in both groups before and after receiving the education. A satisfaction survey was administered at the end of the education program. RESULTS: A significantly higher percentage of patients receiving the multimedia method reported gains in posttransplant care knowledge ( P = .05), less anxiety about the transplant surgery ( P = .02), and satisfaction with the education method ( P = .02) when compared to those receiving the standard method. Caregivers and transplant team member also indicated that the multimedia method was more effective than the standard method. CONCLUSION: Multimedia methods decrease anxiety and increase satisfaction with the education experience when preparing patients for lung transplantation. PMID- 29228865 TI - Sterilization of those with intellectual disability: Evolution from non consensual interventions to strict safeguards. AB - Non-consensual sterilization is one of the characteristic historical abuses that took place mainly in the first half of the 20th century. People with intellectual disability (ID) were a prime target as part of the ideology of negative eugenics. In certain jurisdictions, laws were in force for several decades that permitted sterilization without the need for consent or with consent from third parties. The long-term adverse effects on those sterilized against their will have only more recently been recognized. In the latter half of the 20th century, human rights treaties were introduced and developed; they have, in the main, curbed sterilization abuses. Courts have developed more stringent criteria for making decisions on applications for sterilization, and nowadays there are mostly adequate safeguards in place to protect those with ID from non-consensual sterilization. The only exception should be the particular case in which, all medical and social factors having been taken into account, sterilization is overwhelmingly thought to be the right decision for the individual unable to give consent. PMID- 29228863 TI - Parallel Evaluation of Two Potassium Channel Blockers in Restoring Conduction in Mechanical Spinal Cord Injury in Rat. AB - Myelin damage is a hallmark of spinal cord injury (SCI), and potassium channel blocker (PCB) is proven effective to restore axonal conduction and regain neurological function. Aiming to improve this therapy beyond the U.S. Food and Drug Administration-approved 4-aminopyridine (4-AP), we have developed multiple new PCBs, with 4-aminopyridine-3-methanol (4-AP-3-MeOH) being the most potent and effective. The current study evaluated two PCBs, 4-AP-3-MeOH and 4-AP, in parallel in both ex vivo and in vivo rat mechanical SCI models. Specifically, 4 AP-3-MeOH induced significantly greater augmentation of axonal conduction than 4 AP in both acute and chronic injury. 4-AP-3-MeOH had no negative influence on the electrical responsiveness of rescued axons whereas 4-AP-recruited axons displayed a reduced ability to follow multiple stimuli. In addition, 4-AP-3-MeOH can be applied intraperitoneally at a dose that is at least 5 times higher (5 mg/kg) than that of 4-AP (1 mg/kg) in vivo. Further, 5 mg/kg of 4-AP-3-MeOH significantly improved motor function whereas both 4-AP-3-MeOH (1 and 5 mg/kg) and, to a lesser degree, 4-AP (1 mg/kg) alleviated neuropathic pain-like behavior when applied in rats 2 weeks post-SCI. Based on these and other findings, we conclude that 4-AP-3-MeOH appears to be more advantageous over 4-AP in restoring axonal conduction because of the combination of its higher efficacy in enhancing the amplitude of compound action potential, lesser negative effect on axonal responsiveness to multiple stimuli, and wider therapeutic range in both ex vivo and in vivo application. As a result, 4-AP-3-MeOH has emerged as a strong alternative to 4-AP that can complement the effectiveness, and even partially overcome the shortcomings, of 4-AP in the treatment of neurotrauma and degenerative diseases where myelin damage is implicated. PMID- 29228866 TI - Kinematics optimization and static analysis of a modular continuum robot used for minimally invasive surgery. AB - For the outstanding compliance and dexterity of continuum robot, it is increasingly used in minimally invasive surgery. The wide workspace, high dexterity and strong payload capacity are essential to the continuum robot. In this article, we investigate the workspace of a cable-driven continuum robot that we proposed. The influence of section number on the workspace is discussed when robot is operated in narrow environment. Meanwhile, the structural parameters of this continuum robot are optimized to achieve better kinematic performance. Moreover, an indicator based on the dexterous solid angle for evaluating the dexterity of robot is introduced and the distal end dexterity is compared for the three-section continuum robot with different range of variables. Results imply that the wider range of variables achieve the better dexterity. Finally, the static model of robot based on the principle of virtual work is derived to analyze the relationship between the bending shape deformation and the driven force. The simulations and experiments for plane and spatial motions are conducted to validate the feasibility of model, respectively. Results of this article can contribute to the real-time control and movement and can be a design reference for cable-driven continuum robot. PMID- 29228868 TI - Solitary Fibrous Tumors in Pediatric Patients: A Rare and Potentially Overdiagnosed Neoplasm, Confirmed by STAT6 Immunohistochemistry. AB - Pathological diagnosis of solitary fibrous tumor (SFT) in the pediatric population is challenging, as it occurs uncommonly in this age-group and resembles other spindle cell neoplasms. SFT contains a NAB2-STAT6 fusion gene, which can be reliably detected using STAT6 immunohistochemistry. Positive staining is highly sensitive and specific. We sought to investigate the utility of STAT6 immunohistochemistry, to show how commonly SFT was historically recognized at 3 academic pediatric institutions, to reclassify them when appropriate, and to demonstrate features of major mimics of SFT. Our series included cases with a previous diagnosis of SFT or for which SFT was among key considerations, from 3 major academic pediatric hospitals seen over the past 30 years. Of 18 tumors identified, only 3 tumors from 2 patients demonstrated positive STAT6 staining as well as the typical histology and immunophenotype seen in SFT. The remaining 15 tumors were reclassified based on morphology, additional immunohistochemistry and fluorescence in situ hybridization as desmoid-type fibromatosis (3 tumors), nerve sheath/neural tumors (3 tumors), low-grade fibromyxoid sarcoma, medallion-like dermal fibroma, poorly differentiated Sertoli cell tumor, nodular/proliferative fasciitis, calcifying fibrous tumor, aneurysmal bone cyst of soft tissue, STAT6-negative SFT with adipocytic differentiation, undifferentiated small round blue cell tumor, and scar (1 tumor each). Our study confirms that SFT is rare in the pediatric population and that it is potentially overdiagnosed. STAT6 immunohistochemistry is recommended to confirm the diagnosis of SFT in the pediatric population. PMID- 29228867 TI - Long non-coding RNA CCAT1 promotes multiple myeloma progression by acting as a molecular sponge of miR-181a-5p to modulate HOXA1 expression. AB - Multiple myeloma (MM) is the second most common hematological cancer all over the world. Long non-coding RNA (lncRNA) colon cancer associated transcript-1 (CCAT1) has been reported to play important roles in the development and progression of multiple human malignancies. However, little is known about its functional role and molecular mechanism in MM. The aim of this study was to investigate the clinical and biological significance of CCAT1 in MM. Our data showed that the relative expression levels of CCAT1 were significantly upregulated in MM tissues and cell lines compared with healthy donors and normal plasma cells (nPCs). High expression of CCAT1 was correlated shorter overall survival of MM patients. CCAT1 knockdown significantly inhibited cell proliferation, induced cell cycle arrest at G0/G1 phase and promoted cell apoptosis in vitro, and suppressed tumor growth in vivo. MiR-181a-5p was a direct target of CCAT1, and repression of miR-181a-5p could rescue the inhibition of CCAT1 knockdown on MM progression. In addition, CCAT1 positively regulated HOXA1 expression through sponging miR-181a-5p in MM cells.taken together, lncRNA CCAT1 exerted an oncogenic role in MM by acting as a ceRNA of miR-181a-5p. These results suggest that CCAT1 may serve as a novel diagnostic marker and therapeutic target for MM. PMID- 29228870 TI - Augmented photocatalytic, antibacterial and antifungal activity of prunosynthetic silver nanoparticles. AB - The present study has demystified the first and single step prunosynthesis of the spherical silver nanoparticles (AgNPs) from aqueous fruit extract of angiospermic plant, Prunus cerasifera, which has remarkable fusion of reducing cum stabilizing bioactive components (phenols, anthocyanins, carotenoids, flavonoids, organic acids, tannins and vitamins). Highly stable prunosynthetic AgNPs with 2.04 nm average crystallite size were synthesized in dark and in sunlight at optimized condition of temperature, time and P. cerasifera concentration. Synthesized nanoparticles were characterized through UV-Vis, FTIR, XRD, TGA, SEM and GCMS. Photocatalytic activity of prunosynthetic AgNPs was evaluated for methyl red, erichrome black, methyl blue, bromophenol blue and bromocresol green via UV-Vis. Degradation was achieved (<15 minutes) and expressed as pseudo-first-order kinetics. Prunosynthetic AgNPs demonstrated broad spectrum dose-dependent inhibition (in vitro) in comparison to standard antimicrobial drugs against pathogenic strains X. citri, P. syringae, A. niger, A. flavus, A. fumigatus, A. terreus, P. chrysogenum, F. solani and L. theobromae. Photocatalytic degradation results show the nanobioremediation potential of prunosynthetic AgNPs in indemnifying the persistent environmental pollutants. From the inherently higher inhibition rates for biomimetic prunosynthetic AgNPs, it is envisioned that these can be commercialized as future "green" nanobactericide and nanofungicide at industrial scale economically from nontoxic phytoconstituents. PMID- 29228869 TI - Tumour-suppressive microRNA-424-5p directly targets CCNE1 as potential prognostic markers in epithelial ovarian cancer. AB - An accumulated evidence supports that MicroRNAs (miRNAs) have shown a prominent role in pathological processes and different tumor onset. However, to date, the potential functional roles and molecular mechanisms by how microRNA-424-5p(miR 424-5p) affects cancer cell proliferation are greatly unclear, especially in epithelial ovarian cancer(EOC).In this study, we demonstrated that miR-424-5p was significantly down-regulated in EOC tissues and cell lines. The level of miR-424 5p was negatively correlated with tumor size, TNM stage, pathological grade, lymphatic metastasis of EOC. Restoring miR-424-5p expression in EOC cells dramatically suppressed cell proliferation and caused an accumulation of cells in G1 phase, and thus contributed to better prognosis of EOC patients. Mechanistically, miR-424-5p inhibits CCNE1 expression through targeting CCNE1 3'UTR, and subsequent arrest cell cycle in G1/G0 phase by inhibiting E2F1-pRb pathway. This study revealed functional and mechanistic links between miR-424-5p and CCNE1 in the progression of EOC and provide an important insight into that miR-424-5p may serve as a therapeutic target in EOC. PMID- 29228871 TI - Successful Endovascular Management of a Transplant Renal Artery Pseudoaneurysm Complicated With Arterioureteral Fistula. AB - We report a case of renal artery pseudoaneurysm at the anastomosis site complicated with arterioureteral fistula (AUF) in a 57-year-old kidney transplant recipient who presented with intermittent massive hematuria at one month post transplant. We successfully treated the pseudoaneurysm and AUF with endovascular covered stent implantation. The diagnosis of AUF is rare and it is a condition that occurs in patients with previous pelvic or vascular surgery, chronic ureteral catheterization and radiotherapy. This diagnosis requires the expertise of the urologist, vascular surgeon and interventional radiologist. The fistula most often occur in the iliac arteries and are often associated with pseudoaneurysms or abscesses. Angiography and ureteral contrast studies (antegrade or retrograde pyelography) are the most valuable diagnostic tools. Treatment of AUF via endovascular approach using covered stents is effective and safe, and is becoming the reference treatment in AUFs. PMID- 29228872 TI - The in vivo pharmacokinetics, tissue distribution and excretion investigation of mesaconine in rats and its in vitro intestinal absorption study using UPLC-MS/MS. AB - 1. Mesaconine, an ingredient from Aconitum carmichaelii Debx., has been proven to have cardiac effect. For further development and better pharmacological elucidation, the in vivo process and intestinal absorptive behavior of mesaconine should be investigated comprehensively. 2. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitation of mesaconine in rat plasma, tissue homogenates, urine and feces to investigate the in vivo pharmacokinetic profiles, tissue distribution and excretion. The intestinal absorptive behavior of mesaconine was investigated using in vitro everted rat gut sac model. 3. Mesaconine was well distributed in tissues and a mass of unchanged form was detected in feces. It was difficultly absorbed into blood circulatory system after oral administration. The insufficient oral bioavailability of mesaconine may be mainly attributed to its low intestinal permeability due to a lack of lipophilicity. The absorption of mesaconine in rat's intestine is a first-order process with the passive diffusion mechanism. PMID- 29228873 TI - Dehydroacetic acid in cheese and cheese coating, results of official control in Italy. AB - This paper reports the occurrence of dehydroacetic acid in cheese and cheese coatings collected in Italy during Agricultural Ministry Official control. Dehydroacetic acid is an antimicrobial substance not allowed to be used in EU countries as a food additive, with unknown effects on human health. Dehydroacetic acid was measured by a validated HPLC method according to Commission Decision 2002/657/EC criteria in terms of specificity, linearity, precision and accuracy, limit of detection, and limit of quantification. The method was successfully applied to 129 samples of commercial cheese coatings and related treated cheeses collected in Italy during 2017. The overall results demonstrated that about 40% of the investigated cheese coatings contained dehydroacetic acid, ranging from 0.010% to 2.5% w/w, evidencing illicit employment of this substance. Moreover, about 25% of treated cheeses contained dehydroacetic acid, from 5 to 250 mg/Kg, proving transfer of this substance from crust to cheese. PMID- 29228874 TI - iMidwife: midwifery students' use of smartphone technology as a mediated educational tool in clinical environments. AB - BACKGROUND: The increasing use of smartphone technology in health care provides midwifery students with unprecedented access to online resources that facilitates the optimal care of women and supports ongoing learning. PROBLEM: A small pilot study was conducted in Western Australia, with 29 undergraduate and postgraduate midwifery students to explore the use of smartphone technology whilst in clinical practice. AIM: This study aimed to define the impact of smartphones in clinical decision-making and learning whilst in clinical areas, by midwifery students at the point of care. METHODS: An online survey was used to collect data. FINDINGS: Five consistent themes were identified from the results. Smartphone technology encourages self-directed learning, consolidation of theory, engagement through blended learning, complements online education in clinical practice and is a trend in the future of midwifery curriculum. CONCLUSION: Smartphones enhance the learning and mobility of supportive resources that consolidate midwifery students' clinical experience in workplace environments. PMID- 29228875 TI - Comparison of open surgery and endovascular procedures as a therapeutic choice for visceral artery aneurysms. AB - Objectives Visceral arterial aneurysms may be treated using open surgery or endovascular repair, but the best approach remains controversial. This was a retrospective study aiming to compare open surgery and endovascular treatment strategies for visceral arterial aneurysms. Methods The study included all 93 patients who were admitted with visceral artery aneurysms between January 2001 and January 2011 at the Department of Vascular Surgery, Changhai Hospital, Shanghai, China. All cases underwent either open or endovascular procedures. Overall survival and adverse events were compared between the groups. Success rate, blood loss, length of surgery, and length of hospital stay were also compared. The patients were followed up at three, six, and 12 months then every year until April 2014. Results Open surgery was performed on 34 patients and endovascular procedures on 59. There were no differences in characteristics of the patients between the open surgery and endovascular groups. The perioperative complication rate was 52.9 and 13.6% in the open surgery and endovascular groups, respectively. Mean follow-up was 36.8 months (range: 11 months to 10 years). The one- and five-year survival rates were 100 and 60.6%, respectively, in the open surgery group, compared to 100 and 84.5% in the endovascular group. Multivariate analysis for factors related to overall survival showed that there was a significant relationship with the treatment approach (HR = 0.479, 95%CI: 0.278 0.825; P = 0.008) and the presence of false aneurysm (HR = 2.929, 95%CI: 1.388 6.180, P = 0.005). Conclusions Endovascular repair could be considered as an effective method for visceral artery aneurysm. Endovascular repair showed lower perioperative complication rates and better long-term survival. PMID- 29228876 TI - Crossing professional cultures: A qualitative study of nurses working in a medical school. AB - BACKGROUND: Leaving the nursing workforce is often seen as a loss. Some nurses maintain a current nursing registration and work within university schools of medicine. Little is known about their work. AIM: To explore and describe the experiences of nurses who work in a New Zealand medical school. DESIGN: Qualitative descriptive informed by autoethnography. METHODS: Interviews with 14 nurses over a 12-month period in 2015. Data were inductively analysed. RESULTS: The nurses were mid-to-late career with prior clinical experience and all held postgraduate qualifications. Five themes emerged. CONCLUSIONS: Nurses chose to work in a medical school for a variety of reasons. They sought to maintain their nursing identity but the nursing profession often did not recognise them as nurses. Although individual colleagues recognised their value, organisationally, limited attention was afforded to the specific orientation, mentorship and development of nurses' careers within this setting. PMID- 29228877 TI - Homogenization techniques for population dynamics in strongly heterogeneous landscapes. AB - An important problem in spatial ecology is to understand how population-scale patterns emerge from individual-level birth, death, and movement processes. These processes, which depend on local landscape characteristics, vary spatially and may exhibit sharp transitions through behavioural responses to habitat edges, leading to discontinuous population densities. Such systems can be modelled using reaction-diffusion equations with interface conditions that capture local behaviour at patch boundaries. In this work we develop a novel homogenization technique to approximate the large-scale dynamics of the system. We illustrate our approach, which also generalizes to multiple species, with an example of logistic growth within a periodic environment. We find that population persistence and the large-scale population carrying capacity is influenced by patch residence times that depend on patch preference, as well as movement rates in adjacent patches. The forms of the homogenized coefficients yield key theoretical insights into how large-scale dynamics arise from the small-scale features. PMID- 29228878 TI - Quality assessment in Belgian ST elevation myocardial infarction patients: results from the Belgian STEMI database. AB - The present report describes the quality of care, including in hospital mortality for more than 22.000 STEMI patients admitted in 60 Belgian hospitals for the period 2008-2016. We found a strong increase in the use of primary PCI over time, particularly for patients that were admitted first in a non-PCI capable hospital, reaching a penetration rate of >95%. The transition of thrombolysis to transfer for pPCI in the setting of a STEMI network was, however, associated with an increase of the proportion of patients with prolonged (>120 min) diagnosis-to balloon time (from 16 to 22%), suggesting still suboptimal interhospital transfer. The in-hospital mortality of the total study population was 6.5%. For non-cardiac arrest patients in-hospital mortality decreased from 5.1% to 3.7%, while it increased for cardiac arrest patients from 29 to 37%. The observation that quality indicators (QI's), such as modalities and timing of reperfusion therapy, were associated with lower levels of mortality, underscores the potential of QIs for STEMI to improve care and reduce unwarranted variation and premature death from STEMI. PMID- 29228880 TI - A Recurrence of Bilateral Diffuse Sclerosing Lobular Hyperplasia of Breast: A Case Report. AB - Mammary sclerosing lobular hyperplasia is an uncommon benign fibroproliferative lesion of adolescent and young women, often of African American heritage with an incidence of ~3%. Patients generally complain of a palpable, painless, or slightly tender and well-defined lump in breast. Very rarely, this lesion may be bilateral and diffuse. The definitive diagnosis of sclerosing lobular hyperplasia requires histopathologic evaluation. Here, we describe a case of diffuse sclerosing lobular hyperplasia in a 29-year-old African American woman that required bilateral mastectomy and recurred bilaterally requiring second resections. This appears to be the first report of this phenomenon. PMID- 29228879 TI - Greenhouse gas contribution of municipal solid waste collection: A case study in the city of Istanbul, Turkey. AB - This article estimates greenhouse gas emissions and global warming factors resulting from collection of municipal solid waste to the transfer stations or landfills in Istanbul for the year of 2015. The aim of this study is to quantify and compare diesel fuel consumption and estimate the greenhouse gas emissions and global warming factors associated with municipal solid waste collection of the 39 districts of Istanbul. Each district's greenhouse gas emissions resulting from the provision and combustion of diesel fuel was estimated by considering the number of collection trips and distances to municipal solid waste facilities. The estimated greenhouse gases and global warming factors for the districts varied from 61.2 to 2759.1 t CO2-eq and from 4.60 to 15.20 kg CO2-eq t-1, respectively. The total greenhouse gas emission was estimated as 46.4E3 t CO2-eq. Lastly, the collection data from the districts was used to parameterise a collection model that can be used to estimate fuel consumption associated with municipal solid waste collection. This mechanistic model can then be used to predict future fuel consumption and greenhouse gas emissions associated with municipal solid waste collection based on projected population, waste generation, and distance to transfer stations and landfills. The greenhouse gas emissions can be reduced by decreasing the trip numbers and trip distances, building more transfer stations around the city, and making sure that the collection trucks are full in each trip. PMID- 29228881 TI - Unravelling novel congeners from acetyllysine mimicking ligand targeting a lysine acetyltransferase PCAF bromodomain. AB - p300/CBP Associated Factor (PCAF) bromodomain (BRD), a lysine acetyltransferases, has emerged as a promising drug target as its dysfunction is linked to onset and progression of several diseases like cancer, diabetes, AIDS, etc. In this study, a three featured E-Pharmacophore (ARR) was generated based on acetyllysine mimicking inhibitor of PCAF BRD which is available as co-crystal structure (PDB ID: 5FDZ). It was used for filtering small molecule databases followed by molecular docking and consequently validated using enrichment calculation. The resulted hits were found to be congeners which show the predictive power of E Pharmacophore hypothesis. Further, Induced Fit Docking method, Binding energy calculation, ADME prediction, Single Point Energy calculation and Molecular Dynamics simulation were performed to find better hits against PCAF BRD. Based on the results, it was concluded that Asn803, Tyr809 and Tyr802 along with a water molecule (HOH1001) plays crucial role in binding with inhibitor. It is also proposed that four hits from Life Chemicals database namely, F2276-0099, F2276 0008, F2276-0104 and F2276-0106 could act as potent drug molecules for PCAF BRD. Thus, the present study is strongly believed to have bright impact on rational drug design of potent and novel congeners of PCAF BRD inhibitors. PMID- 29228882 TI - Medical education and human trafficking: using simulation. AB - : Healthcare providers have the potential to play a crucial role in human trafficking prevention, identification, and intervention. However, trafficked patients are often unidentified due to lack of education and preparation available to healthcare professionals at all levels of training and practice. To increase victim identification in healthcare settings, providers need to be educated about the issue of trafficking and its clinical presentations in an interactive format that maximizes learning and ultimately patient-centered outcomes. In 2014, University of Louisville School of Medicine created a simulation-based medical education (SBME) curriculum to prepare students to recognize victims and intervene on their behalf. The authors share the factors that influenced the session's development and incorporation into an already full third year medical curriculum and outline the development process. The process included a needs assessment for the education intervention, development of objectives and corresponding assessment, implementation of the curriculum, and finally the next steps of the module as it develops further. Additional alternatives are provided for other medical educators seeking to implement similar modules at their home institution. It is our hope that the description of this process will help others to create similar interactive educational programs and ultimately help trafficking survivors receive the care they need. ABBREVIATIONS: HCP: Healthcare professional; M-SIGHT: Medical student instruction in global human trafficking; SBME: Simulation-based medical education; SP: Standardized patient; TIC: Trauma-informed care. PMID- 29228883 TI - Health-Promoting Behaviors and Their Predictors in Iranian Women of Reproductive Age: A Cross-Sectional Study. AB - Health-promoting behaviors are one of the main determinative components of health in the prevention of many diseases. This cross-sectional study aimed to determine health-promoting behaviors and their relationship to sociodemographic variables on 330 women of reproductive age admitted to the selected primary health-care centers in Qom city (one of the biggest cities in Iran) from March 2016 to July 2016. Data were collected using the health-promoting lifestyle profile II (HPLP II) questionnaire and the sociodemographic characteristics and also were analyzed by one-way analysis of variance, with post hoc (if necessary), and multivariable linear regression. The total HPLP-II mean score of women was 136.64 +/- 22.37. The highest score in the HPLP-II subscales of women was found for interpersonal relations subscale (26.43 +/- 4.21) and the lowest score for physical activity subscale (14.66 +/- 4.62). The educational level and income had significant association with some subscales ( p < .05). PMID- 29228884 TI - Bridging the knowledge-practice gap: a key issue in the prevention of healthcare associated infections. PMID- 29228885 TI - Multiplex analysis of serum hormone and cytokine in patients with cervical cOPLL: towards understanding the potential pathogenic mechanisms. AB - Cervical ossification of the posterior longitudinal ligament (cOPLL) is one of the major causes of myelopathy. However, the mechanism underlying remains elusive. In the present study, using MILLIPLEX magnetic bead panel, we investigated four serum hormones and six serum cytokines in cOPLL patients and healthy subjects. The results showed that tumor necrosis factore-alpha (TNF alpha) were significantly increased, and DDK-1 was significantly decreased in the serum from male and female cOPLL patients compared with those from healthy controls, respectively. Osteopontin (OPN) and fibroblast growth factor-23 (FGF 23) were significantly increased in male cOPLL patients compared with that in healthy male controls. Further analysis showed that FGF-23 and OPN significantly increased, dickkopf-1 (DKK-1) decreased in the extensive cOPLL group. In addition, a significant positive correlation between the OPN and FGF-23 was observed in male cOPLL patients. The results are useful for understanding the mechanism underlying cOPLL. PMID- 29228886 TI - Continuous stimulation with differentiation factors is necessary to enhance osteogenic differentiation of human mesenchymal stem cells in-vitro. AB - Bone defect treatment belongs to the most challenging fields in orthopedic surgery and requires the well-coordinated application of mesenchymal stem cells (MSC) and differentiation factors. MSC isolated from reaming material (RMSC) and iliac crest (BMSC) in combination with bone morphogenetic protein-7 (BMP-7) and insulin-like growth factor-1 (IGF-1) have been used. The short half-life of both factors limit their applications: a burst release of the factor can probably not induce sustainable differentiation. We stimulated MSC in osteogenic differentiation medium with three different concentrations of BMP-7 or IGF-1: Group A was stimulated continuously, group B for 24 h and group C remained without any stimulation. Osteogenic differentiation was measured after seven and 14 days by alizarin red staining and alkaline phosphatase (ALP) activity. Continuous stimulation led to higher levels of osteogenic differentiation than short-term stimulation. This could lead to a reconsideration of established application forms for differentiation factors, aiming to provide a more sustained release. PMID- 29228887 TI - Can whole body vibration exercises affect growth hormone concentration? A systematic review. AB - Whole body vibration (WBV) has been recognized as an effective alternative exercise modality to resistance exercise for its ability in enhancing force and power, generating capacity in skeletal muscle, increasing bone mass and improving cardiovascular function. Since the effect of WBV exercises on growth hormone (GH) levels has been never compared and discussed, the aim of this study was to review systematically the literature to verify the WBV effects on GH concentration. By using PubMed, Scopus and PEDRo databases with the keywords 'growth hormone' or GH and 'whole body vibration' or WBV, we found and analysed 12 papers (182 subjects recruited), verifying their level of evidence (National Health and Medical Research Council hierarchy of evidence) and the methodological quality (PEDRo scale). Although WBV induced GH responses in nine out of 12 publications, caution should be however taken when considering the results due to the markedly different methodologies among these publications. PMID- 29228888 TI - Assessing levels and trends of child health inequality in 88 developing countries: from 2000 to 2014. AB - BACKGROUND: Reducing child mortality was one of the Millennium Development Goals. In the current Sustainable Development Goals era, achieving equity is prioritized as a major aim. OBJECTIVE: This study aims to provide a comprehensive and updated picture of inequalities in child health intervention coverage and child health outcomes by wealth status, as well as their trends between 2000 and 2014. METHODS: Using data from Demographic Health Surveys and Multiple Indicator Cluster Surveys, we adopted three measures of inequality, including one absolute inequality indicator and two relative inequality indicators, to estimate the level and trends of inequalities in three child health outcome variables and 17 intervention coverages in 88 developing countries. RESULTS: While improvements in child health outcomes and coverage of interventions have been observed between 2000 and 2014, large inequalities remain. There was a high level of variation between countries' progress toward reducing child health inequalities, with some countries significantly improving, some deteriorating, and some remaining statistically unchanged. Among child health interventions, the least equitable one was access to improved sanitation (The absolute difference in coverages between the richest quintile and the poorest quintile reached 49.5% [42.7, 56.2]), followed by access to improved water (34.1% [29.5, 38.6]), and skilled birth attendant (SBA) (34.1% [28.8, 39.4]). The most equitable intervention coverage was insecticide-treated bed net for children (1.0% [-3.9, 5.9]), followed by oral rehydration therapy for diarrhea ((8.0% [5.2, 10.8]), and vitamin A supplement (8.4% [5.1, 11.7]). These findings were robust to various inequality measurements. CONCLUSIONS: Although child health outcomes and coverage of interventions have improved largely over the study period for almost all wealth quintiles, insufficient progress was made in reducing child health inequalities between the poorest and richest wealth quintiles. Future efforts should focus on reaching the poorest children by increasing investments toward expanding the coverage of interventions in resource-limited settings. PMID- 29228889 TI - Acute and chronic changes in brain activity with deep brain stimulation for refractory depression. AB - Deep brain stimulation is a potential option for patients with treatment refractory depression. Deep brain stimulation benefits have been reported when targeting either the subgenual cingulate or ventral anterior capsule/nucleus accumbens. However, not all patients respond and optimum stimulation-site is uncertain. We compared deep brain stimulation of the subgenual cingulate and ventral anterior capsule/nucleus accumbens separately and combined in the same seven treatment-refractory depression patients, and investigated regional cerebral blood flow changes associated with acute and chronic deep brain stimulation. Deep brain stimulation-response was defined as reduction in Montgomery-Asberg Depression Rating Scale score from baseline of >=50%, and remission as a Montgomery-Asberg Depression Rating Scale score <=8. Changes in regional cerebral blood flow were assessed using [15O]water positron emission tomography. Remitters had higher relative regional cerebral blood flow in the prefrontal cortex at baseline and all subsequent time-points compared to non remitters and non-responders, with prefrontal cortex regional cerebral blood flow generally increasing with chronic deep brain stimulation. These effects were consistent regardless of stimulation-site. Overall, no significant regional cerebral blood flow changes were apparent when deep brain stimulation was acutely interrupted. Deep brain stimulation improved treatment-refractory depression severity in the majority of patients, with consistent changes in local and distant brain regions regardless of target stimulation. Remission of depression was reached in patients with higher baseline prefrontal regional cerebral blood flow. Because of the small sample size these results are preliminary and further evaluation is necessary to determine whether prefrontal cortex regional cerebral blood flow could be a predictive biomarker of treatment response. PMID- 29228890 TI - Corrigendum. PMID- 29228891 TI - Adherence to asthma treatment in childhood and adolescence - a narrative literature review. AB - OBJECTIVES: We provide a narrative literature review on surveys used to assess the level of medication adherence in children and adolescents with asthma, the attitudes of these patients and their parents toward asthma therapy, and their expectations concerning asthma and available treatment. METHODS: A PubMed search and manual selection of the retrieved papers was conducted to identify studies using surveys or interviews that addressed one of the three topics of interest. RESULTS: Adherence to asthma medication varies across age groups and with the type of measurement used. Levels of 49-71% were observed in children and adolescents by objective measurements. Subjective measurements overestimate the level of adherence compared to objective measurements. A considerable percentage of parents expressed fear of side effects of inhaled corticosteroids, although the impact of these concerns on adherence is unclear. Many adolescents and parents adapt inhaled corticosteroids use according to the prevalence of asthma symptoms, by reducing or eliminating controller medication in the absence of symptoms. Pediatric asthma patients and their parents tend to overestimate the level of asthma control, either by underestimating asthma severity or by assuming that a better control is not possible. The knowledge of parents and adolescents concerning asthma management is suboptimal; moreover, insufficient knowledge about inhaled corticosteroids was linked to poor adherence. CONCLUSION: Medication adherence is crucial for a good control of asthma symptoms. Additional research concerning the triggers of non-adherence is still needed. Educating both the patients and their parents on proper asthma care might improve adherence. PMID- 29228892 TI - Sequence fingerprints distinguish erroneous from correct predictions of intrinsically disordered protein regions. AB - More than 60 prediction methods for intrinsically disordered proteins (IDPs) have been developed over the years, many of which are accessible on the World Wide Web. Nearly, all of these predictors give balanced accuracies in the ~65%-~80% range. Since predictors are not perfect, further studies are required to uncover the role of amino acid residues in native IDP as compared to predicted IDP regions. In the present work, we make use of sequences of 100% predicted IDP regions, false positive disorder predictions, and experimentally determined IDP regions to distinguish the characteristics of native versus predicted IDP regions. A higher occurrence of asparagine is observed in sequences of native IDP regions but not in sequences of false positive predictions of IDP regions. The occurrences of certain combinations of amino acids at the pentapeptide level provide a distinguishing feature in the IDPs with respect to globular proteins. The distinguishing features presented in this paper provide insights into the sequence fingerprints of amino acid residues in experimentally determined as compared to predicted IDP regions. These observations and additional work along these lines should enable the development of improvements in the accuracy of disorder prediction algorithm. PMID- 29228893 TI - P-values, p-values everywhere! PMID- 29228894 TI - Is therapeutic hypothermia during neonatal extracorporeal membrane oxygenation associated with intracranial hemorrhage? AB - INTRODUCTION: The use of therapeutic hypothermia during neonatal extracorporeal membrane oxygenation (ECMO) as a neurologic protective strategy has gained interest among clinicians despite limited data. Our objective is to describe the relationship between the use of therapeutic hypothermia during neonatal ECMO and complications, mortality and functional status among survivors. METHODS: Secondary analysis of data collected by the Collaborative Pediatric Critical Care Research Network between December 2012 and September 2014. Data were collected prospectively from 267 neonates (<30 days) undergoing ECMO at eight clinical sites. Twenty neonates received therapeutic hypothermia. RESULTS: Neonates receiving therapeutic hypothermia were more likely to have intracranial hemorrhage during the first seven days of ECMO than were non-hypothermic neonates (40.0% vs 15.8%, p=0.012). No differences were observed between groups for hospital mortality or functional status at hospital discharge among survivors. Variables independently associated with intracranial hemorrhage in the first seven days of ECMO included therapeutic hypothermia, gestational age at birth, age at initiation of ECMO, fibrinogen concentration and mode of ECMO. CONCLUSION: Therapeutic hypothermia during neonatal ECMO appears to be associated with intracranial hemorrhage. PMID- 29228895 TI - Postcardiotomy refractory ventricular fibrillation: rescue using veno-arterial extracorporeal membrane oxygenation. AB - We present a case of 7-hour ventricular fibrillation with successful use of veno arterial extracorporeal membrane oxygenation as a bridge to recovery in a 30-year old patient with grown-up congenital heart disease who underwent pulmonary valve replacement. PMID- 29228896 TI - Global gene expression in two potato cultivars in response to 'Candidatus Liberibacter solanacearum' infection. AB - BACKGROUND: Transcriptomic analyses were performed to compare the molecular responses of two potato varieties previously shown to differ in the severity of disease symptoms due to infection by "Candidatus Liberibacter solanacearum" (Lso), the causative agent of Zebra Chip in potato. A factorial design utilizing the two varieties and psyllids either harboring Lso or without bacteria was used to discriminate varietal responses to pathogen infection versus psyllid feeding. Plant response was determined from leaf samples 3 weeks after infection. RESULTS: In response to Lso infection, 397 genes were differentially expressed in the variety Atlantic (most susceptible) as compared to 1027 genes in Waneta. Over 80% of the transcriptionally-changed genes were down-regulated in both varieties, including genes involved in photosynthesis or primary and secondary metabolism. Many of the Lso-responsive genes involved in stress responses or hormonal pathways were regulated differently in the two potato varieties. CONCLUSIONS: This study focused on the time point just prior to the onset of symptom development and provides valuable insight into the mechanisms of Liberibacter pathogenicity, especially the widespread suppression of plant gene expression, including genes involved in plant defenses. PMID- 29228897 TI - A new buckwheat dihydroflavonol 4-reductase (DFR), with a unique substrate binding structure, has altered substrate specificity. AB - BACKGROUND: Dihydroflavonol 4-reductase (DFR) is the key enzyme committed to anthocyanin and proanthocyanidin biosynthesis in the flavonoid biosynthetic pathway. DFR proteins can catalyse mainly the three substrates (dihydrokaempferol, dihydroquercetin, and dihydromyricetin), and show different substrate preferences. Although relationships between the substrate preference and amino acids in the region responsible for substrate specificity have been investigated in several plant species, the molecular basis of the substrate preference of DFR is not yet fully understood. RESULTS: By using degenerate primers in a PCR, we isolated two cDNA clones that encoded DFR in buckwheat (Fagopyrum esculentum). Based on sequence similarity, one cDNA clone (FeDFR1a) was identical to the FeDFR in DNA databases (DDBJ/Gen Bank/EMBL). The other cDNA clone, FeDFR2, had a similar sequence to FeDFR1a, but a different exon-intron structure. Linkage analysis in an F2 segregating population showed that the two loci were linked. Unlike common DFR proteins in other plant species, FeDFR2 contained a valine instead of the typical asparagine at the third position and an extra glycine between sites 6 and 7 in the region that determines substrate specificity, and showed less activity against dihydrokaempferol than did FeDFR1a with an asparagine at the third position. Our 3D model suggested that the third residue and its neighbouring residues contribute to substrate specificity. FeDFR1a was expressed in all organs that we investigated, whereas FeDFR2 was preferentially expressed in roots and seeds. CONCLUSIONS: We isolated two buckwheat cDNA clones of DFR genes. FeDFR2 has unique structural and functional features that differ from those of previously reported DFRs in other plants. The 3D model suggested that not only the amino acid at the third position but also its neighbouring residues that are involved in the formation of the substrate binding pocket play important roles in determining substrate preferences. The unique characteristics of FeDFR2 would provide a useful tool for future studies on the substrate specificity and organ-specific expression of DFRs. PMID- 29228899 TI - Use and optimization of different sources of information for genomic prediction. AB - BACKGROUND: Molecular data is now commonly used to predict breeding values (BV). Various methods to calculate genomic relationship matrices (GRM) have been developed, with some studies proposing regression of coefficients back to the reference matrix of pedigree-based relationship coefficients (A). The objective was to compare the utility of two GRM: a matrix based on linkage analysis (LA) and anchored to the pedigree, i.e. [Formula: see text] and a matrix based on linkage disequilibrium (LD), i.e. [Formula: see text], using genomic and phenotypic data collected on 5416 broiler chickens. Furthermore, the effects of regressing the coefficients of [Formula: see text] back to A (LDA) and to [Formula: see text] (LDLA) were evaluated, using a range of weighting factors. The performance of the matrices and their composite products was assessed by the fit of the models to the data, and the empirical accuracy and bias of the BV that they predicted. The sensitivity to marker choice was examined by using two chips of equal density but including different single nucleotide polymorphisms (SNPs). RESULTS: The likelihood of models using GRM and composite matrices exceeded the likelihood of models based on pedigree alone and was highest with intermediate weighting factors for both the LDA and LDLA approaches. For these data, empirical accuracies were not strongly affected by the weighting factors, although they were highest when different sources of information were combined. The optimum weighting factors depended on the type of matrices used, as well as on the choice of SNPs from which the GRM were constructed. Prediction bias was strongly affected by the chip used and less by the form of the GRM. CONCLUSIONS: Our findings provide an empirical comparison of the efficacy of pedigree and genomic predictions in broiler chickens and examine the effects of fitting GRM with coefficients regressed back to a reference anchored to the pedigree, either A or [Formula: see text]. For the analysed dataset, the best results were obtained when [Formula: see text] was combined with relationships in A or [Formula: see text], with optimum weighting factors that depended on the choice of SNPs used. The optimum weighting factor for broiler body weight differed from weighting factors that were based on the density of SNPs and theoretically derived using generalised assumptions. PMID- 29228898 TI - The asymmetric cell division machinery in the spiral-cleaving egg and embryo of the marine annelid Platynereis dumerilii. AB - BACKGROUND: Over one third of all animal phyla utilize a mode of early embryogenesis called 'spiral cleavage' to divide the fertilized egg into embryonic cells with different cell fates. This mode is characterized by a series of invariant, stereotypic, asymmetric cell divisions (ACDs) that generates cells of different size and defined position within the early embryo. Astonishingly, very little is known about the underlying molecular machinery to orchestrate these ACDs in spiral-cleaving embryos. Here we identify, for the first time, cohorts of factors that may contribute to early embryonic ACDs in a spiralian embryo. RESULTS: To do so we analyzed stage-specific transcriptome data in eggs and early embryos of the spiralian annelid Platynereis dumerilii for the expression of over 50 candidate genes that are involved in (1) establishing cortical domains such as the partitioning defective (par) genes, (2) directing spindle orientation, (3) conveying polarity cues including crumbs and scribble, and (4) maintaining cell-cell adhesion between embryonic cells. In general, each of these cohorts of genes are co-expressed exhibiting high levels of transcripts in the oocyte and fertilized single-celled embryo, with progressively lower levels at later stages. Interestingly, a small number of key factors within each ACD module show different expression profiles with increased early zygotic expression suggesting distinct regulatory functions. In addition, our analysis discovered several highly co-expressed genes that have been associated with specialized neural cell-cell recognition functions in the nervous system. The high maternal contribution of these 'neural' adhesion complexes indicates novel general adhesion functions during early embryogenesis. CONCLUSIONS: Spiralian embryos are champions of ACD generating embryonic cells of different size with astonishing accuracy. Our results suggest that the molecular machinery for ACD is already stored as maternal transcripts in the oocyte. Thus, the spiralian egg can be viewed as a totipotent yet highly specialized cell that evolved to execute fast and precise ACDs during spiral cleaving stages. Our survey identifies cohorts of factors in P. dumerilii that are candidates for these molecular mechanisms and their regulation, and sets the stage for a functional dissection of ACD in a spiral-cleaving embryo. PMID- 29228900 TI - Effects of chronic noise on the corticotropin-releasing factor system in the rat hippocampus: relevance to Alzheimer's disease-like tau hyperphosphorylation. AB - BACKGROUND: Chronic noise exposure has been associated with tau hyperphosphorylation and Alzheimer's disease (AD)-like pathological changes, but the underlying mechanism is unknown. In this study, we explored the effects of long-term noise exposure on the corticotropin-releasing factor (CRF) system in the hippocampus and its role in noise-induced tau phosphorylation. METHODS: Sixty four rats were randomly divided into the noise-exposed group and the control group, and rats in the exposure group were exposed to 95 dB SPL white noise for 30 consecutive days. The levels of CRF, CRFR1, CRFR2, and total tau and phosphorylated tau (p-tau) at Ser396 (S396) and Thr205 (T205) in the hippocampus were measured at different time points after the final noise exposure. The co localized distribution of CRF and p-tau (T205) in the hippocampus was evaluated using double-labeling immunofluorescence. RESULTS: Long-term exposure to noise for 30 consecutive days significantly increased the expression of CRF and CRFR1 and their mRNAs levels in the hippocampus, which persisted for 7 days after final exposure. In contrast, CRFR2 was raised for 3-7 days following the last exposure. These alterations were also concomitant with the phosphorylation of tau at S396 and T205. Furthermore, there was co-localization of p-tau and CRF in hippocampal neurons. CONCLUSION: Chronic noise leads to long-lasting increases in the hippocampal CRF system and the hyperphosphorylation of tau in the hippocampus. Our results also provide evidence for the involvement of the CRF system in noise induced AD-like neurodegeneration. PMID- 29228901 TI - The relation between Blastocystis and the intestinal microbiota in Swedish travellers. AB - BACKGROUND: Blastocystis sp. is a unicellular eukaryote that is commonly found in the human intestine. Its ability to cause disease is debated and a subject for ongoing research. In this study, faecal samples from 35 Swedish university students were examined through shotgun metagenomics before and after travel to the Indian peninsula or Central Africa. We aimed at assessing the impact of travel on Blastocystis carriage and seek associations between Blastocystis and the bacterial microbiota. RESULTS: We found a prevalence of Blastocystis of 16/35 (46%) before travel and 15/35 (43%) after travel. The two most commonly Blastocystis subtypes (STs) found were ST3 and ST4, accounting for 20 of the 31 samples positive for Blastocystis. No mixed subtype carriage was detected. All ten individuals with a typable ST before and after travel maintained their initial ST. The composition of the gut bacterial community was not significantly different between Blastocystis-carriers and non-carriers. Interestingly, the presence of Blastocystis was accompanied with higher abundances of the bacterial genera Sporolactobacillus and Candidatus Carsonella. Blastocystis carriage was positively associated with high bacterial genus richness, and negatively correlated to the Bacteroides-driven enterotype. These associations were both largely dependent on ST4 - a subtype commonly described from Europe - while the globally prevalent ST3 did not show such significant relationships. CONCLUSIONS: The high rate of Blastocystis subtype persistence found during travel indicates that long-term carriage of Blastocystis is common. The associations between Blastocystis and the bacterial microbiota found in this study could imply a link between Blastocystis and a healthy microbiota as well as with diets high in vegetables. Whether the associations between Blastocystis and the microbiota are resulting from the presence of Blastocystis, or are a prerequisite for colonization with Blastocystis, are interesting questions for further studies. PMID- 29228902 TI - A methodological consideration for blood lead concentrations obtained from the earlobe in Japanese adults occupationally unexposed to lead. AB - BACKGROUND: Neuropsychological effects of considerably low levels of lead exposure are observed in children, and a reliable and possibly painless technique that can detect such levels is required for the assessment of such exposure. We examined whether the blood lead (BPb) concentrations obtained from the earlobe were as valid and useful as those from the median cubital vein. METHODS: Paired blood samples were collected from the earlobe and cubital vein of 112 Japanese participants occupationally unexposed to lead, and the BPb levels were determined using ICP-MS. RESULTS: The limit of detection of BPb for the ICP-MS method was 0.015 MUg/dL, and there was no participant with a BPb level below this limit. The median values of BPb concentrations were 0.91 (range, 0.41-2.48) MUg/dL for earlobe blood using a 175-MUL capillary tube and 0.85 (0.35-2.39) MUg/dL for venous blood using a 5-mL vacuum tube. There was a significant correlation between the earlobe BPb levels and cubital vein BPb levels (Spearman rank correlation r S = 0.941), though the earlobe BPb levels were significantly higher than the cubital vein BPb levels. Most of the participants regarded earlobe puncture as a painless method. CONCLUSIONS: These data suggest that earlobe BPb levels can be used to assess lead exposure in children. Blood collection using a capillary tube should be done carefully and promptly because slow withdrawal may lead to measurement bias. PMID- 29228903 TI - Couple-kissing flaps for successful repair of severe sacral pressure ulcers in frail elderly patients. AB - BACKGROUND: Surgical repair of severe pressure ulcers (PUs) in elderly patients remains a challenge for clinicians due to the complicated comorbidities and the special physical characteristics of elderly patients. The objective of this study was to evaluate the application of couple-kissing flaps (CKF) in the reconstruction of sacral PUs in these patients. METHODS: Elderly patients (over 70 years) with stage 3 or stage 4 PUs who underwent CKF immediately after radical debridement between July 2012 and December 2015 were enrolled in this retrospective study. Patients' demographics were extracted from the medical records. RESULTS: A total of 12 patients were involved in this study. The average age of the patients was 76.83 years (ranged from 71 to 92 years). The donor site was closed primarily in all cases. All the flaps healed uneventfully without complications. Follow-up observations were conducted for an average of 13.6 months (ranged from 9 months to 2 years). Cosmetic results were satisfactory, with no surgical site breakdown or recurrence of PU in any of the cases. Three representative cases are presented. CONCLUSIONS: The CKF is a reliable and satisfactory option for the reconstruction of severe sacral PUs defects in elderly patients. CKF is associated with an relatively low rate of complications and recurrence. PMID- 29228904 TI - Comparative ribosome profiling uncovers a dominant role for translational control in Toxoplasma gondii. AB - BACKGROUND: The lytic cycle of the protozoan parasite Toxoplasma gondii, which involves a brief sojourn in the extracellular space, is characterized by defined transcriptional profiles. For an obligate intracellular parasite that is shielded from the cytosolic host immune factors by a parasitophorous vacuole, the brief entry into the extracellular space is likely to exert enormous stress. Due to its role in cellular stress response, we hypothesize that translational control plays an important role in regulating gene expression in Toxoplasma during the lytic cycle. Unlike transcriptional profiles, insights into genome-wide translational profiles of Toxoplasma gondii are lacking. METHODS: We have performed genome-wide ribosome profiling, coupled with high throughput RNA sequencing, in intracellular and extracellular Toxoplasma gondii parasites to investigate translational control during the lytic cycle. RESULTS: Although differences in transcript abundance were mostly mirrored at the translational level, we observed significant differences in the abundance of ribosome footprints between the two parasite stages. Furthermore, our data suggest that mRNA translation in the parasite is potentially regulated by mRNA secondary structure and upstream open reading frames. CONCLUSION: We show that most of the Toxoplasma genes that are dysregulated during the lytic cycle are translationally regulated. PMID- 29228905 TI - Evaluation of methods and marker Systems in Genomic Selection of oil palm (Elaeis guineensis Jacq.). AB - BACKGROUND: Genomic selection (GS) uses genome-wide markers as an attempt to accelerate genetic gain in breeding programs of both animals and plants. This approach is particularly useful for perennial crops such as oil palm, which have long breeding cycles, and for which the optimal method for GS is still under debate. In this study, we evaluated the effect of different marker systems and modeling methods for implementing GS in an introgressed dura family derived from a Deli dura x Nigerian dura (Deli x Nigerian) with 112 individuals. This family is an important breeding source for developing new mother palms for superior oil yield and bunch characters. The traits of interest selected for this study were fruit-to-bunch (F/B), shell-to-fruit (S/F), kernel-to-fruit (K/F), mesocarp-to fruit (M/F), oil per palm (O/P) and oil-to-dry mesocarp (O/DM). The marker systems evaluated were simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs). RR-BLUP, Bayesian A, B, Cpi, LASSO, Ridge Regression and two machine learning methods (SVM and Random Forest) were used to evaluate GS accuracy of the traits. RESULTS: The kinship coefficient between individuals in this family ranged from 0.35 to 0.62. S/F and O/DM had the highest genomic heritability, whereas F/B and O/P had the lowest. The accuracies using 135 SSRs were low, with accuracies of the traits around 0.20. The average accuracy of machine learning methods was 0.24, as compared to 0.20 achieved by other methods. The trait with the highest mean accuracy was F/B (0.28), while the lowest were both M/F and O/P (0.18). By using whole genomic SNPs, the accuracies for all traits, especially for O/DM (0.43), S/F (0.39) and M/F (0.30) were improved. The average accuracy of machine learning methods was 0.32, compared to 0.31 achieved by other methods. CONCLUSION: Due to high genomic resolution, the use of whole genome SNPs improved the efficiency of GS dramatically for oil palm and is recommended for dura breeding programs. Machine learning slightly outperformed other methods, but required parameters optimization for GS implementation. PMID- 29228906 TI - Phylogenetic relationship and domain organisation of SET domain proteins of Archaeplastida. AB - BACKGROUND: SET is a conserved protein domain with methyltransferase activity. Several genome and transcriptome data in plant lineage (Archaeplastida) are available but status of SET domain proteins in most of the plant lineage is not comprehensively analysed. RESULTS: In this study phylogeny and domain organisation of 506 computationally identified SET domain proteins from 16 members of plant lineage (Archaeplastida) are presented. SET domain proteins of rice and Arabidopsis are used as references. This analysis revealed conserved as well as unique features of SET domain proteins in Archaeplastida. SET domain proteins of plant lineage can be categorised into five classes- E(z), Ash, Trx, Su(var) and Orphan. Orphan class of SET proteins contain unique domains predominantly in early Archaeplastida. Contrary to previous study, this study shows first appearance of several domains like SRA on SET domain proteins in chlorophyta instead of bryophyta. CONCLUSION: The present study is a framework to experimentally characterize SET domain proteins in plant lineage. PMID- 29228907 TI - Secondary pallidonigral degeneration mimicking recurrent acute stroke in clinical presentation and magnetic resonance imaging: a case report. AB - BACKGROUND: Secondary pallidonigral transneuronal degeneration after a remote primary cerebral infarct can mimic recurrent stroke at clinical presentation. We describe a patient with secondary pallidonigral degeneration following a previous putaminal infarct, which was diagnosed through diffusion-weighted (DWI) and T2 weighted imaging (T2WI). CASE PRESENTATION: A 64-year-old man complained of an acute relapse of right-lower-limb weakness following a cerebral infarction 2 months before presentation. Recurrent cerebral stroke was initially diagnosed in the emergency room. DWI of the brain revealed a subacute to chronic infarct in the left putamen and new acute cytotoxic edema in the left substantia nigra (SN) and globus pallidus while T2WI also showed hyperintensity in the same regions. The SN was outside the aforementioned middle cerebral arterial territory, which includes the putamen. These findings are compatible with the diagnosis of acute pallidonigral injury secondary to striatal infarction. The patient had fully recovered from his right-lower-limb weakness after 1 month. CONCLUSIONS: Secondary pallidonigral degeneration may mimic recurrent stroke. DWI along with T2WI facilitates elucidation of this clinicopathological entity, and thus unnecessary treatment can be avoided. PMID- 29228908 TI - Self-reported dietary adherence, disease-specific symptoms, and quality of life are associated with healthcare provider follow-up in celiac disease. AB - BACKGROUND: The only treatment for celiac disease (CeD) is a lifelong gluten-free diet (GFD). The restrictive nature of the GFD makes adherence a challenge. As an integral part of CeD management, multiple professional organizations recommend regular follow-up with a healthcare provider (HCP). Many CeD patients also participate in patient advocacy groups (PAGs) for education and support. Previous work found that follow-up of CeD patients is highly variable. Here we investigated the self-reported factors associated with HCP follow-up among individuals diagnosed with CeD who participate in a PAG. METHODS: We conducted a survey of members of Beyond Celiac (a PAG), collecting responses from 1832 U.S. adults ages 19-65 who reported having CeD. The survey queried HCP follow-up related to CeD and included validated instruments for dietary adherence (CDAT), disease-specific symptoms (CSI), and quality of life (CD-QOL). RESULTS: Overall, 27% of respondents diagnosed with CeD at least five years ago reported that they had not visited an HCP about CeD in the last five years. The most frequent reason for not visiting an HCP was "doing fine on my own" (47.6%). Using multiple logistic regression, we identified significant associations between whether a respondent reported visiting an HCP about CeD in the last five years and the scores for all three validated instruments. In particular, as disease-specific symptoms and quality of life worsened, the probability of having visited an HCP increased. Conversely, as dietary adherence worsened, the probability decreased. CONCLUSIONS: Our results suggest that many individuals with CeD manage their disease without ongoing support from an HCP. Our results thus emphasize the need for greater access to high quality CeD care, and highlight an opportunity for PAGs to bring together patients and HCPs to improve management of CeD. PMID- 29228909 TI - Adenocarcinoma risk in gastric atrophy and intestinal metaplasia: a systematic review. AB - BACKGROUND: Gastric cancer (GC) has a poor prognosis with wide variation in survival rates across the world. Several studies have shown premalignant lesions gastric atrophy (GA) and intestinal metaplasia (IM) influence gastric cancer risk. This systematic review examines all available evidence of the risk of GC in patients with GA or IM and explores the geographical variation between countries. METHODS: EMBASE, MEDLINE, Web of Science and the Cochrane Library were searched for relevant articles published to June 2016 investigating the risk of GC in individuals with GA or IM. Analysis was performed to determine variation based on geographical location. Study quality was assessed using the Newcastle-Ottawa Scale and heterogeneity between studies was also evaluated. RESULTS: Fifteen relevant articles were identified, in which there were eight studies of GC incidence in GA and nine in IM cohorts (two articles investigated both GA and IM). The incidence rate of GC in patients with GA ranged from 0.53 to 15.24 per 1000 person years, whereas there was more variation in GC incidence in patients with IM (0.38 to 17.08 per 1000 person years). The greatest GC incidence rates were in Asian countries, for patients with GA, and the USA for those with IM (15.24 and 17.08 per 1000 person years, respectively). The largest studies (four over 25,000 person years) had an incidence rate range of 1.0-2.5 per 1000 person years, however, in general, study quality was poor and there was marked heterogeneity. CONCLUSION: Overall there is a wide variation in annual incidence rate of GC from premalignant lesions. With the recent introduction of surveillance guidelines for gastric atrophy and intestinal metaplasia in the Western world, future assessment of this risk should be performed. Furthermore, substantial heterogeneity supports the need for more robust studies in order to pool results and determine the overall incidence rate of gastric cancer for patients with these premalignant lesions. PMID- 29228910 TI - The prognosis of invasive micropapillary carcinoma compared with invasive ductal carcinoma in the breast: a meta-analysis. AB - BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is a rare variant of invasive ductal carcinoma (IDC). The prognosis of IMPC compared with that of IDC remains controversial; we conducted a meta-analysis to evaluate the prognostic difference between IMPC and IDC. METHODS: We searched the PubMed, Cochrane Library, and EMBASE databases for relevant studies comparing overall survival (OS), disease-specific survival (DSS), relapse-free survival (RFS), local-regional recurrence-free survival (LRRFS) or distant metastasis-free survival (DMFS) rates between IMPC and IDC. Fixed-effect and random-effect models were utilized based on the heterogeneity of the eligible studies. Heterogeneity was further evaluated by subgroup and sensitivity analyses. RESULTS: Fourteen studies with 1888 IMPC patients were included in the meta-analysis. The summarized odds ratio (OR) and 95% confidence interval (95% CI) was calculated to estimate the prognostic difference between IMPC and IDC. IMPC patients showed an unfavorable prognosis for RFS (OR; 2.04; 95% CI: 1.63-2.55) and LRRFS (OR: 2.82; 95% CI: 1.90-4.17) compared with IDC. However, no significant difference was observed in OS (OR: 0.93; 95% CI: 0.78-1.10), DSS (OR: 1.16; 95% CI: 0.95-1.40) and DMFS (OR: 0.95; 95% CI: 0.67-1.35) between IMPC and IDC. No obvious statistical heterogeneity was detected, except for DSS. Funnel plots and Egger's tests did not reveal publication bias, except for RFS. CONCLUSIONS: This analysis showed that IMPC patients have a higher rate of loco-regional recurrence than IDC patients. However, OS, DSS and DMFS were not significantly different between IMPC and IDC. These results could help clinicians select therapeutic and follow-up strategies for IMPC patients. PMID- 29228911 TI - Intrapartum factors associated with neonatal hypoxic ischemic encephalopathy: a case-controlled study. AB - BACKGROUND: Neonatal encephalopathy (NE) affects 2-4/1000 live births with outcomes ranging from negligible neurological deficits to severe neuromuscular dysfunction, cerebral palsy and death. Hypoxic ischemic encephalopathy (HIE) is the sub cohort of NE that appears to be driven by intrapartum events. Our objective was to identify antepartum and intrapartum factors associated with the development of neonatal HIE. METHODS: Hospital databases were searched using relevant diagnosis codes to identify infants with neonatal encephalopathy. Cases were infants with encephalopathy and evidence of intrapartum hypoxia. For each hypoxic ischemic encephalopathy case, four controls were randomly selected from all deliveries that occurred within 6 months of the case. RESULTS: Twenty-six cases met criteria for hypoxic ischemic encephalopathy between 2002 and 2014. In multivariate analysis, meconium-stained amniotic fluid (aOR 12.4, 95% CI 2.1 144.8, p = 0.002), prolonged second stage of labor (aOR 9.5, 95% CI 1.0-135.3, p = 0.042), and the occurrence of a sentinel or acute event (aOR 74.9, 95% CI 11.9 infinity, p < 0.001) were significantly associated with hypoxic ischemic encephalopathy. The presence of a category 3 fetal heart rate tracing in any of the four 15-min segments during the hour prior to delivery (28.0% versus 4.0%, p = 0.002) was more common among hypoxic ischemic encephalopathy cases. CONCLUSION: Prolonged second stage of labor and the presence of meconium-stained amniotic fluid are risk factors for the development of HIE. Close scrutiny should be paid to labors that develop these features especially in the presence of an abnormal fetal heart tracing. Acute events also account for a substantial number of HIE cases and health systems should develop programs that can optimize the response to these emergencies. PMID- 29228912 TI - The association between neighbourhood-level deprivation and depression: evidence from the south african national income dynamics study. AB - BACKGROUND: Depression contributes substantially to the burden of disease in South Africa. Little is known about how neighbourhoods affect the mental health of the people living in them. METHODS: Using nationally representative data (N=11,955) from the South African National Income Dynamics Study and the South African Indices of Multiple Deprivation (SAIMD) modelled at small-area level, this study tested associations between neighbourhood-level deprivation and depression, after controlling for individual-level covariates. RESULTS: Results showed a significant positive association between neighbourhood-level deprivation and depression using the composite SAIMD (beta = 0.31 (0.15); p=0.04) as well as the separate deprivation domains. Living environment deprivation (beta =0.53 (0.16); p=0.001) and employment deprivation (beta = 0.38 (0.13); p=0.004), respectively, were the two most salient domains in predicting this relationship. CONCLUSIONS: Findings supported the hypothesis that there is a positive association between living in a more deprived neighbourhood and depression, even after controlling for individual-level covariates. This study suggests that alleviating structural poverty could reduce the burden of depression in South Africa. PMID- 29228913 TI - On the use of the outcome variable "small for gestational age" when gestational age is a potential mediator: a maternal asthma perspective. AB - BACKGROUND: The variable "small for gestational age," frequently defined as birth weight below the 10th percentile in a gestational age and sex-normalized population, is nowadays generally perceived as a more adequate measure than birth weight or low birth weight (birth weight < 2500 g) to capture fetal growth. However, the use of small for gestational age rather than birth weight or low birth weight as an outcome (dependent) variable may have important impacts on the interpretation of analyses aimed at estimating the causal effect of an exposure of interest on infants. We hypothesized potential differences in both types of effects estimated (direct or total) and in ability to control for confounding bias. METHODS: We first examined the use of outcome variables birth weight and small for gestational age to get insights on modeling practices within the field of maternal asthma. Using directed acyclic graph simulations where gestational age was a potential mediator, we then compared estimated exposure effects in regression models for birth weight, low birth weight, and small for gestational age. Graphs with and without confounding were considered. RESULTS: Our simulations showed that the variable small for gestational age captures the direct effect of exposure on birth weight, but not the indirect effect of exposure on birth weight through gestational age. Interestingly, exposure effect estimates from small for gestational age models were found unbiased whenever exposure effect estimates from birth weight models were affected by collider bias due to conditioning on gestational age in the models. CONCLUSIONS: The sole consideration of the outcome small for gestational age in a study may lead to suboptimal understanding and quantification of the underlying effect of an exposure on birth weight-related measures. Instead, our results suggest that both outcome variables (low) birth weight and small for gestational age should minimally be considered in studies investigating perinatal outcomes. PMID- 29228914 TI - Methods to perform systematic reviews of patient preferences: a literature survey. AB - BACKGROUND: Systematic reviews are a commonly used research design in the medical field to synthesize study findings. At present-although several systematic reviews of patient preference studies are published-there is no clear guidance available for researchers to conduct this type of systematic review. The aim of our study was to learn the most current practice of conducting these systematic reviews by conducting a survey of the literature regarding reviews of quantitative patient preference studies. METHODS: Our survey included systematic reviews of studies that used a stated quantitative preference design to elicit patient preferences. We identified eligible reviews through a search of the PubMed database. Two investigators with knowledge of the design of patient preference studies independently screened the titles and abstracts, and where needed, screened the full-text of the reviews to determine eligibility. We developed and pilot-tested a form to extract data on the methods used in each systematic review. RESULTS: Our search and screening identified 29 eligible reviews. A large proportion of the reviews (19/29, 66%) were published in 2014 or after; among them, nine reviews were published in 2016. The median number of databases searched for preference studies was four (interquartile range = 2 to 7). We found that less than half of the reviews (13/29, 45%) clearly reported assessing risk of bias or the methodological quality of the included preference studies; not a single review was able to perform quantitative synthesis (meta analysis) of the data on patient preferences. CONCLUSION: These results suggest that several methodological issues of performing systematic reviews of patient preferences are not yet fully addressed by research and that the methodology may require future development. PMID- 29228915 TI - Qualitative and quantitative evaluation of acute angle-closure mechanisms. AB - BACKGROUND: To evaluate ocular biometric parameters in different subtypes of acute angle closure and compared to fellow eyes of AAC and PACS eyes. METHODS: This is a retrospective chart review study. A total of 167 eyes (96 patients) consisting of 71 AAC eyes, 71 fellow eyes of AAC, and 25 PACS eyes were recruited. All patients underwent ocular examination and biometry. The mechanism of AAC was confirmed by ultrasound biomicroscopy. We then subdivided AAC eyes into four subgroups: crowded-angle (CR), lens subluxation (LS) pupillary block (PB), and plateau iris syndrome (PL). Outcome variables included anterior chamber depth (ACD), lens thickness (LT), vitreal length (VL), axial length (AL), lens position and relative lens position (LP and RLP, respectively), and lens axial length factor (LAF). RESULTS: Among the three groups, ACD was shallower in AAC eyes than fellow eyes of AAC and PACS eyes (p < 0.01 for both) and AAC eyes demonstrated a lesser LP and RLP. The LT, VL, AL, and LAF were not significantly different among the three groups. Among the four subgroups, LS displayed the most shallow ACD (p = 0.01). The lens position in PL was greater than in CR and LS (p < 0.05 and <0.01, respectively). CONCLUSIONS: AAC eyes had a more anterior lens position than fellow eyes and PACS eyes, though lens thickness did not differ among the groups. As such, an anterior lens position may offer more sensitive prognostication regarding future development of AAC compared to lens thickness. PMID- 29228916 TI - Physical and psychosomatic health outcomes in people bereaved by suicide compared to people bereaved by other modes of death: a systematic review. AB - BACKGROUND: Little research has been conducted into the physical health implications of suicide bereavement compared to other causes of death. There is some evidence that suicide bereaved parents have higher morbidity, particularly in terms of chronic illness. This systematic review aims to examine the physical and psychosomatic morbidities of people bereaved by a family member's suicide and compare them with family members bereaved by other modes of death. METHODS: MEDLINE, EMBASE, CINAHL, and PsycINFO were searched from 1985 to February 2016. The search was re-run in March 2017. Peer-reviewed English language articles comparing suicide-bereaved family members to non-suicide bereaved family members on measures of physical or psychosomatic health were eligible for inclusion. Cohort, cross-sectional, case-control and cohort-based register studies were eligible for inclusion. A modified version of the Newcastle Ottawa Scale was used for quality assessment. Results were synthesised using narrative synthesis. RESULTS: The literature search located 24 studies which met the inclusion criteria. Seven studies found statistically significant associations between physical health and suicide bereavement. Five of the studies found that suicide bereaved family members were more likely to experience pain, more physical illnesses and poorer general health. They were also at increased risk of cardiovascular disease, hypertension, diabetes and chronic obstructive pulmonary disease. In contrast, another study in Denmark found that those bereaved by suicide had a lower risk of a number of physical health disorders, including cancers, diabetes, cardiovascular and chronic lower respiratory tract disorders compared to those bereaved by other causes of death. Additionally, a further study conducted in the United States found that suicide-bereaved children visited a GP less frequently than non-suicide bereaved children. CONCLUSIONS: Review findings are relevant for clinicians working with people bereaved by suicide as they highlight that such clients are at increased risk of several adverse physical health outcomes. Future research should examine health risk behaviours of suicide-bereaved and non-suicide bereaved family members as they may confound the association between exposure and outcome. TRIAL REGISTRATIONS: The review protocol has been registered on PROSPERO, registration number CRD42016030007 . PMID- 29228917 TI - Evaluation of the economic burden of leprosy among migrant and resident patients in Guangdong Province, China. AB - BACKGROUND: A lot of time and money was needed during the diagnosis and treatment process of leprosy, the delayed leprosy would also impair the labor capability of patients as well, and these put a heavy burden for the leprosy patients. The migrant leprosy patient is a special group and need more concern. Our goal was to assess the economic burden of leprosy on migrant and resident patient populations in Guangdong province, China. METHODS: We conducted a population-based cross sectional survey from February to July of 2016. A self-designed questionnaire was administered to leprosy patients who: (1) had registered in Leprosy Management Information System in China (LEPMIS) by the end of February 2016, (2) had received multiple drug treatment (MDT) drugs at a local leprosy control institution for three consecutive months or had had at least one physical check in the past half year, and (3) were willing to take part in the investigation and give informed written consent. Demographic characteristics, Financial and disease information, and costs before and after leprosy diagnosis were collected and compared using t-test and chi2 test. RESULTS: A total of 254 participants completed the questionnaires, including 168 males and 86 females. Migrants and residents accounted for 33.9% and 66.1% of patients, respectively. Among migrant patients, the median cost before diagnosis was $131.6 (39.2-450.9), the median yearly cost of leprosy treatment after diagnosis was $300.6 (158.4-868.5), and the median yearly cost of leprosy complications was $69.5 (11-178.4). In comparison, among residents the median yearly costs were $152.4 (30.7-770.9) pre diagnosis, $309.7 (103.2-1016.7) after diagnosis, and $91.9 (32.6-303.1) for leprosy complications. Base on this, we determined that the median yearly total expense after diagnosis amounted to 15% of migrant and 38% of resident patients' annual income. CONCLUSION: Leprosy places a heavy economic burden on both migrant and resident leprosy patients and governmental policies and programs could substantially alleviate this. Measures to implement more active surveillance and early diagnosis would benefit both populations, while labor protection and medical insurance are urgently needed for migrant patients and easier access to medical services and social aids could substantially decrease the burden of leprosy for resident patients. PMID- 29228918 TI - Nevirapine- versus Efavirenz-based antiretroviral therapy regimens in antiretroviral-naive patients with HIV and Tuberculosis infections in India: a multi-centre study. AB - BACKGROUND: According to World Health Organization (WHO) guidelines, which have also been adopted by the National AIDS Control Organization (NACO), India, Efavirenz-based Anti-Retroviral Therapy (ART) is better in Human-Immunodeficiency Virus (HIV)-infected patients who are also being treated with Rifampicin-based Anti-Tuberculous Therapy (ATT). However, Efavirenz is much more expensive. We hypothesize that Nevirapine is a cheaper alternative that possesses equal efficacy as Efavirenz in HIV-Tuberculosis (TB) co-infected patients. METHODS: A parallel open-label randomized clinical trial was conducted at All India Institute of Medical Sciences (AIIMS), New Delhi and National AIDS Research Institute (NARI), Pune. Those who were ART-naive and co-infected with TB were randomized to receive either Nevirapine (Group 1)- or Efavirenz (Group 2)-based ART along with Rifampicin-based ATT. ATT was begun first in ART-naive patients according to the NACO guidelines, with a median of 27 days between ATT and ART in both groups. The primary endpoint was a composite unfavourable outcome (death and/or ART failure) at 96 weeks, and the secondary outcome was successful TB treatment at 48 weeks. RESULTS: A total of 284 patients (mean age 36.7 +/- 8.1 years) were randomized in a 1:1 ratio to receive either Nevirapine (n = 144)- or Efavirenz (n = 140)-based ART after a median ATT-ART gap of 27 days. The median CD4 count was 105 cells/MUl, with a median viral load of 820,200 copies/MUl and no significant difference between the groups. Composite unfavourable outcomes were reported in 49 patients in the Nevirapine group and 51 patients in the Efavirenz group (35.3% vs. 36.9%; hazard ratio, 0.95, 95% confidence interval (CI), 0.63,1.43, adjusted). There was no difference in successful TB treatment outcome between the groups (71.5% vs. 65.6%, 95% CI -3.8,17.9, adjusted). The results were similar, showing no difference between the groups in the two centres of the study after adjusting for disease stage. CONCLUSIONS: Composite unfavourable outcome in HIV-TB co-infected patients who were ART-naive showed no statistically significant difference in the Nevirapine or Efavirenz groups.. Therefore, Nevirapine-based ART is a reasonable alternative to Efavirenz in resource-limited settings. However, multi-centric studies with larger sample sizes are required to confirm these findings. TRIAL REGISTRATION: NCT01805258 (Retrospectively registered on March 6, 2013) Date of registration: March 2013. PMID- 29228919 TI - How effective is the comprehensive approach to rehabilitation (CARe) methodology? A cluster randomized controlled trial. AB - BACKGROUND: The CARe methodology aims to improve the quality of life of people with severe mental illness by supporting them in realizing their goals, handling their vulnerability and improving the quality of their social environment. This study aims to investigate the effectiveness of the CARe methodology for people with severe mental illness on their quality of life, personal recovery, participation, hope, empowerment, self-efficacy beliefs and unmet needs. METHODS: A cluster Randomized Controlled Trial (RCT) was conducted in 14 teams of three organizations for sheltered and supported housing in the Netherlands. Teams in the intervention group received training in the CARe methodology. Teams in the control group continued working according to care as usual. Questionnaires were filled out at baseline, after 10 months and after 20 months. A total of 263 clients participated in the study. RESULTS: Quality of life increased in both groups, however, no differences between the intervention and control group were found. Recovery and social functioning did not change over time. Regarding the secondary outcomes, the number of unmet needs decreased in both groups. All intervention teams received the complete training program. The model fidelity at T1 was 53.4% for the intervention group and 33.4% for the control group. At T2 this was 50.6% for the intervention group and 37.2% for the control group. CONCLUSION: All clients improved in quality of life. However we did not find significant differences between the clients of the both conditions on any outcome measure. Possible explanations of these results are: the difficulty to implement rehabilitation-supporting practice, the content of the methodology and the difficulty to improve the lives of a group of people with longstanding and severe impairments in a relatively short period. More research is needed on how to improve effects of rehabilitation trainings in practice and on outcome level. TRIAL REGISTRATION: ISRCTN77355880 , retrospectively registered (05/07/2013). PMID- 29228921 TI - Testing of the assisting software for radiologists analysing head CT images: lessons learned. AB - BACKGROUND: Assessing a plan for user testing and evaluation of the assisting software developed for radiologists. METHODS: Test plan was assessed in experimental testing, where users performed reporting on head computed tomography studies with the aid of the software developed. The user testing included usability tests, questionnaires, and interviews. In addition, search relevance was assessed on the basis of user opinions. RESULTS: The testing demonstrated weaknesses in the initial plan and enabled improvements. Results showed that the software has acceptable usability level but some minor fixes are needed before larger-scale pilot testing. The research also proved that it is possible even for radiologists with under a year's experience to perform reporting of non-obvious cases when assisted by the software developed. Due to the small number of test users, it was impossible to assess effects on diagnosis quality. CONCLUSIONS: The results of the tests performed showed that the test plan designed is useful, and answers to the key research questions should be forthcoming after testing with more radiologists. The preliminary testing revealed opportunities to improve test plan and flow, thereby illustrating that arranging preliminary test sessions prior to any complex scenarios is beneficial. PMID- 29228920 TI - Comparison of outcomes between emergent-start and planned-start peritoneal dialysis in incident ESRD patients: a prospective observational study. AB - BACKGROUND: The clinical consequences of starting chronic peritoneal dialysis (PD) after emergent dialysis via a temporary hemodialysis (HD) catheter has rarely been evaluated within a full spectrum of treated end-stage renal disease (ESRD). We investigated the longer-term outcomes of patients undergoing emergent start PD in comparison with that of other practices of PD or HD in a prospective cohort of new-onset ESRD. METHODS: This was a 2-year prospective observational study. We enrolled 507 incident ESRD patients, among them 111 chose PD (43 planned-start, 68 emergent-start) and 396 chose HD (116 planned-start, 280 emergent-start) as the long-term dialysis modality. The logistic regression model was used to identify variables associated with emergent-start dialysis. The Kaplan-Meier survival analysis was used to determine patient survival and technique failure. The propensity score-adjusted Cox regression model was used to identify factors associated with patient outcomes. RESULTS: During the 2-year follow-up, we observed 5 (4.5%) deaths, 15 (13.5%) death-censored technique failures (transfer to HD) and 3 (2.7%) renal transplantations occurring in the PD population. Lack of predialysis education, lower predialysis estimated glomerular filtration rate and serum albumin were predictors of being assigned to emergent dialysis initiation. The emergent starters of PD displayed similar risks of patient survival, technique failure and overall hospitalization, compared with the planned-start counterparts. By contrast, the concurrent planned-start and emergent-start HD patients with an arteriovenous fistula or graft were protected from early overall death and access infection-related mortality, compared with the emergent HD starters using a central venous catheter. CONCLUSIONS: In late referred chronic kidney disease patients who have initiated emergent dialysis via a temporary HD catheter, post-initiation PD can be a safe and effective long-term treatment option. Nevertheless, due to the potential complications and cost concerns, such practice of PD initiation would better be replaced with a planned start mode by employing more effective predialysis therapeutic education and timely catheter placement. PMID- 29228923 TI - CDKN2BAS gene polymorphisms and the risk of intracranial aneurysm in the Chinese population. AB - BACKGROUND: CDKN2BAS gene polymorphisms has been shown to correlation with intracranial aneurysm(IA) in the study of foreign people. The study, the author selected the Chinese people as the research object to explore whether CDKN2BAS gene polymorphisms associated with Chinese patients with IA. METHODS: We selected 200 patients(52.69 +/- 11.50) with sporadic IA as experimental group, 200 participants(49.99 +/- 13.00) over the same period to the hospital without cerebrovascular diseases as control group. Extraction of peripheral blood DNA, applying polymerase chain reaction(PCR)-ligase detection reaction (LDR) identified CDKN2BAS Single nucleotide polymorphism(SNP) locus genotype: rs6475606, rs1333040, rs10757272, rs3217992, rs974336, rs3217986, rs1063192. The differences in allelic and genotype frequencies between the patient and control groups were evaluated by the chi-square test or Fisher's exact tests. RESULTS: The genotype of rs1333040 and rs6475606 shown association with sporadic IA(X2 = 8.545, P = 0.014; X2 = 10.961, P = 0.004; respectively);the C allele of rs6475606 showed reduction the occurrence of IA; the rs1333040 and rs6475606 associated with hemorrhage, the C allele of rs1333040 could lower the risk of hemorrhage, and rs6475606 will not, rs1333040 also associated with aneurysm size. CONCLUSION: Our research shows that variant rs1333040 and rs6475606 of CDKN2BAS related to the Chinese han population of sporadic IAs occurs. This study confirms the association between CDKN2BAS and IAs. PMID- 29228922 TI - Effect of siRNA-silencing of SALL2 gene on growth, migration and invasion of human ovarian carcinoma A2780 cells. AB - BACKGROUND: The role of Spalt-like gene-2 (SALL2) in tumorigenesis remains incompletely elucidated. This study investigated the effects of SALL2 on human ovarian carcinoma (OC) A2780 cells and the probable mechanism. METHODS: Expression of SALL2 in human OC cell lines were detected by reverse transcription PCR (RT-PCR) and Western blot analysis. A2780 cells were transfected with small interfering ribonucleic acid (siRNA) to silence SALL2. SALL2 expression was detected by RT-PCR, Western blot analysis and immunofluorescence assay. Cell proliferation was measured by CCK-8 assay and flow cytometry (FCM). Apoptosis was measured by FCM. Cell migration was detected by real-time cell analysis. Cell invasion was detected by transwell assay. mRNA expression of p21 was detected by quantitative real-time PCR. Western blot analysis was used to determine the expression of matrix metalloproteinase (MMP)2, MMP9, protein kinase B (PKB, also called Akt), and phosphorylated-Akt (p-Akt). RESULTS: SALL2 was expressed in six OC cell lines, and the expression was the highest in A2780 cells. Compared with that in the Scramble group, SALL2 expression in A2780 was downregulated after transfection with siRNA-2 and siRNA-3 for 48 h. Compared with that in the Scramble group, proliferation of A2780 cells in the siRNA-2 group increased after transfection for 24, 48 and 72 h. In the siRNA-2 group, the proportion of A2780 cells decreased in the G0/G1 phase, and cell apoptosis decreased after transfection for 48 h. Compared with that in the Scramble group, the cell migration and invasion abilities of A2780 cells increased. Compared with that in the Scramble group, p21 mRNA expression in A2780 cells decreased after transfection with siRNA2. When SALL2 was silenced, the expression of MMP2/9 and p Akt in A2780 cells increased. Furthermore, the PI3K inhibitor LY294002 could effectively reversed SALL2 siRNA-induced phosphorylation of Akt, migration and invasion of A2780 cells. CONCLUSION: Transient silencing of SALL2 promotes cell proliferation, migration, and invasion, and inhibits apoptosis of A2780 cells. In SALL2 siRNA-silenced cells, p21 expression was decreased. SALL2 knockdown by siRNA induces the migration and invasion of A2780 cells; this phenomenon is possibly associated with the increased expression of MMP2/9 and the activation of the PI3K/Akt signalling pathway. PMID- 29228924 TI - The photosynthetic and structural differences between leaves and siliques of Brassica napus exposed to potassium deficiency. AB - BACKGROUND: Most studies of photosynthesis in chlorenchymas under potassium (K) deficiency focus exclusively on leaves; however, little information is available on the physiological role of K on reproductive structures, which play a critical role in plant carbon gain. Brassica napus L., a natural organ-succession species, was used to compare the morphological, anatomical and photo-physiological differences between leaves and siliques exposed to K-deficiency. RESULTS: Compared to leaves, siliques displayed considerably lower CO2 assimilation rates (A) under K-deficient (-K) or sufficient conditions (+K), limited by decreased stomatal conductance (g s), apparent quantum yield (alpha) and carboxylation efficiency (CE), as well as the ratio of the maximum rate of electron transport (J max) and the maximum rate of ribulose 1,5-bisphosphate (RuBP) carboxylation (V cmax). The estimated J max, V cmax and alpha of siliques were considerably lower than the theoretical value calculated on the basis of a similar ratio between these parameters and chlorophyll concentration (i.e. J max/Chl, V cmax/Chl and alpha/Chl) to leaves, of which the gaps between estimated- and theoretical-J max was the largest. In addition, the average ratio of J max to V cmax was 16.1% lower than that of leaves, indicating that the weakened electron transport was insufficient to meet the requirements for carbon assimilation. Siliques contained larger but fewer stoma, tightly packed cross-section with larger cells and fewer intercellular air spaces, fewer and smaller chloroplasts and thin grana lamellae, which might be linked to the reduction in light capture and CO2 diffusion. K deficiency significantly decreased leaf and silique A under the combination of down-regulated stomatal size and g s, chloroplast number, alpha, V cmax and J max, while the CO2 diffusion distance between chloroplast and cell wall (D chl cw) was enhanced. Siliques were more sensitive than leaves to K-starvation, exhibiting smaller reductions in tissue K and parameters such as g s, V cmax, J max and D chl-cw. CONCLUSION: Siliques had substantially smaller A than leaves, which was attributed to less efficient functioning of the photosynthetic apparatus, especially the integrated limitations of biochemical processes (J max and V cmax) and alpha; however, siliques were slightly less sensitive to K deficiency. PMID- 29228925 TI - Daily activity patterns influence retinal morphology, signatures of selection, and spectral tuning of opsin genes in colubrid snakes. AB - BACKGROUND: Morphological divergences of snake retinal structure point to complex evolutionary processes and adaptations. The Colubridae family has a remarkable variety of retinal structure that can range from all-cone and all-rod to duplex (cone/rod) retinas. To explore whether nocturnal versus diurnal activity is responsible for constraints on molecular evolution and plays a role in visual opsin spectral tuning of colubrids, we carried out molecular evolution analyses of the visual opsin genes LWS, RH1, and SWS1 from 17 species and performed morphological analyses. RESULTS: Phylogenetic reconstructions of the RH1 and LWS recovered major clades characterized by primarily diurnal or primarily nocturnal activity patterns, in contrast with the topology for SWS1, which is very similar to the species tree. We found stronger signals of purifying selection along diurnal and nocturnal lineages for RH1 and SWS1, respectively. A blue-shift of the RH1 spectral peak is associated with diurnal habits. Spectral tuning of cone opsins did not differ among diurnal and nocturnal species. Retinas of nocturnal colubrids had many rows of photoreceptor nuclei, with large numbers of rods, labeled by wheat germ agglutinin (WGA), and two types of cones: large cones sensitive to long/medium wavelengths (L/M) and small cones sensitive to ultra violet/violet wavelengths (UV/VS). In contrast, retinas of diurnal species had only one row of photoreceptor nuclei, with four types of cones: large and double L/M cones, small UV/VS cones, and a second group of small cones, labeled by WGA. CONCLUSIONS: For LWS gene, selection tests did not confirm different constraints related to activity pattern. For SWS1, stronger purifying selection in nocturnal lineages indicates divergent evolutionary pressures related to the activity pattern, and the importance of the short wavelength sensitivity at low light condition. Activity pattern has a clear influence on the signatures of selection and spectral tuning of RH1, with stronger purifying selection in diurnal lineages, which indicates selective pressure to preserve rhodopsin structure and function in pure-cone retinas. We suggest that the presence of four cone types in primarily diurnal colubrids might be related to the gain of color discrimination capacity. PMID- 29228926 TI - Factors affecting the achievement of fertility intentions in urban Nigeria: analysis of longitudinal data. AB - BACKGROUND: Maternal mortality ratio in Nigeria is among the highest in the world with an estimated 160 women dying every day of complications related to pregnancy and childbirth. In addition to appropriate management of complications related to pregnancy and childbirth, preventing unwanted pregnancies is an effective way to reduce maternal deaths. Identifying potentially modifiable factors associated with the achievement of fertility intentions is critical for developing behavior change interventions that will contribute to reducing maternal mortality. METHODS: The data analyzed came from a longitudinal design with data collected in 2010/2011 and 2014 from the same group of women of reproductive age in six Nigerian cities. The data were collected as part of efforts to evaluate the effects of the Nigerian Urban Reproductive Health Initiative (NURHI). A total of 10,672 women were interviewed at the two points in time but the analyses in this manuscript were limited to 1921 in-union women who reported that they desired no more children at baseline in 2010/2011. The principal analytic method was multivariable regression adjusted for clustering at the enumeration area level. The analysis controlled for socio-demographic and household variables, ideational characteristics, and contraceptive use at baseline. RESULTS: About two thirds of the women who desired no more children at baseline have neither had any children nor were pregnant at endline. The strongest predictors of the achievement of fertility intentions include parity, age, religion, residence, spousal communication about family size, perceived severity of another pregnancy, and spousal agreement about family size. CONCLUSION: A comprehensive strategy to help women avoid unwanted pregnancies should include efforts to increase women's understanding about effective ways to prevent unplanned pregnancies and strengthen self-efficacy for contraceptive use. Promoting spousal communication about reproductive issues, engaging men, promoting smaller family sizes and changing pronatalist attitudes should also be part of such a strategy. PMID- 29228927 TI - Treatment with Botulinum toxin A in a total population of children with cerebral palsy - a retrospective cohort registry study. AB - BACKGROUND: Botulinum toxin A (BTX-A) has been used to reduce spasticity in children with cerebral palsy (CP) for decades. The purpose of this study was to analyze to what extent BTX-A treatment was used to treat spasticity in a total population of children with CP. We investigated 1) the use of BTX-A in relation to age, sex, and Gross Motor Function Classification System (GMFCS) level, 2) the most common muscle groups treated with BTX-A in relation to the same variables, and 3) changes in the proportions of children treated with BTX-A between two time points (2010 and 2015). METHODS: The study was based on data from CPUP, a combined Swedish follow-up program and national healthcare registry, comprising >95% of all children with CP in Sweden. The participants (N = 3028) were born in 2000 or later. Potential BTX-A treatment and treated muscle groups were included from all CPUP assessments recorded in the registry in 2014-2015. In Aim 3, BTX-A administration in 3-5 year-olds at two time points was assessed. Crosstabs and 95% confidence intervals (CIs) for binominal proportions were calculated and logistic regression was used to regress age, sex, and GMFCS level on BTX-A treatment. Muscle groups treated with BTX-A were assessed using crosstabs and 95% CIs. Proportional change in BTX-A treatment over a 5-year period was analyzed using chi-square. RESULTS: We included 3028 children (57% boys; median age 7 years) of whom 26% received BTX-A. Significantly more boys (28%) than girls (23%) received BTX-A (OR = 1.25, [95% CI 1.05-1.48]). Significant differences were found for age and GMFCS levels; 4-6 year-olds and those at GMFCS III-IV were more likely to receive BTX-A. BTX-A treatment in the gastrocnemius muscle was most common in the 4-6 year-olds and at GMFCS I-III, whereas treatment of the hamstring and adductor muscles was more common in older children and at GMFCS IV V. No significant change in the proportion of BTX-A administered in 2010 and 2015 was demonstrated. CONCLUSIONS: BTX-A treatment differed based on age, sex, and GMFCS level. Proportion of BTX-A treatment in Sweden has remained stable during the past five years. PMID- 29228928 TI - Association between high-density lipoprotein cholesterol level and pulmonary function in healthy Korean adolescents: the JS high school study. AB - BACKGROUND: Accumulating evidence suggests that high-density lipoprotein (HDL) cholesterol is associated with pulmonary function and pulmonary disorders. The aim of this study was to evaluate the association between HDL cholesterol and pulmonary function in healthy adolescents. METHODS: This cross-sectional study was based on data collected for the JS High School study. The analysis included 644 adolescents (318 male and 326 female) aged 15-16 years old and free from asthma or chronic obstructive pulmonary disease. Fasting blood samples were collected for hematologic and biochemical assessment. Forced vital capacity volume (FVC) and forced expiratory volume in the 1 s (FEV1) were measured using dry-rolling-seal spirometry. The associations between HDL cholesterol and pulmonary function were analyzed using multiple linear regression models. RESULTS: Among male adolescents, an increase of 1.0 mg/dL in HDL cholesterol was associated with 10 mL decrease in FVC (p = 0.013) and FEV1 (p = 0.013) after adjusting for age, height, weight, alcohol drinking, smoking, physical activity, systolic blood pressure, total cholesterol, triglyceride, and monthly household income. Percent predicted values of FVC (p = 0.036) and FEV1 (p = 0.017) were also inversely associated with HDL cholesterol. However, among female adolescents, HDL cholesterol level was not significantly associated with absolute or percent predictive value of FVC and FEV1. CONCLUSIONS: Higher HDL cholesterol level may be associated with decreased pulmonary function among healthy male adolescents. The sex differences observed in the association between HDL cholesterol and pulmonary function need further investigation. PMID- 29228929 TI - Virtual bronchoscopic navigation without X-ray fluoroscopy to diagnose peripheral pulmonary lesions: a randomized trial. AB - BACKGROUND: Transbronchial biopsy for peripheral pulmonary lesions is generally performed under X-ray fluoroscopy. Virtual bronchoscopic navigation (VBN) is a method in which virtual images of the bronchial route to the lesion are produced based on CT images obtained before VBN, and the bronchoscope is guided using these virtual images, improving the diagnostic yield of peripheral pulmonary lesions. VBN has the possibility of eliminating the need for X-ray fluoroscopy in the bronchoscopic diagnosis of peripheral lesions. To determine whether VBN can be a substitute for X-ray fluoroscopy, a randomized multicenter trial (non inferiority trial) was performed in VBN and X-ray fluoroscopy (XRF) -assisted groups. METHODS: The non-inferiority margin in the VBN-assisted group compared with the XRF-assisted group was set at 15%. The subjects consisted of 140 patients with peripheral pulmonary lesions with a mean diameter > 3 cm. In the VBN-assisted group, the bronchoscope was guided to the lesion using a VBN system without X-ray fluoroscopy. In the XRF-assisted group, the same bronchoscope was guided to the lesion under X-ray fluoroscopy. Subsequently, in both groups, the lesion was visualized using endobronchial ultrasonography with a guide sheath (EBUS/GS), and biopsy was performed. In this serial procedure, X-ray fluoroscopy was not used in the VBNA group. RESULTS: The subjects of analysis consisted of 129 patients. The diagnostic yield was 76.9% (50/65) in the VBN-assisted group and 85.9% (55/64) in the XRF-assisted group. The difference in the diagnostic yield between the two groups was -9.0% (95% confidence interval: -22.3% ~ 4.3%). The non-inferiority of the VBN-assisted group could not be confirmed. The rate of visualizing lesions by EBUS was 95.4% (62/65) in the VBN-assisted group and 96.9% (62/64) in the XRF-assisted group, being high in both groups. CONCLUSIONS: On EBUS/GS, a bronchoscope and biopsy instruments may be guided to the lesions using VBN without X-ray fluoroscopy, but X-ray fluoroscopy is necessary to improve the accuracy of sample collection from lesions. During transbronchial biopsy for peripheral pulmonary lesions, VBN cannot be a substitute for X-ray fluoroscopy. TRIAL REGISTRATION: UMIN-CTR (UMIN000001710); registered 16 February 2009. PMID- 29228931 TI - Research protocol: Cisplatin-associated ototoxicity amongst patients receiving cancer chemotherapy and the feasibility of an audiological monitoring program. AB - BACKGROUND: Cisplatin is an anti-cancer chemotherapy drug classified as an alkylating agent. It is used for the treatment of a variety of cancers such as cervical, breast, stomach, prostate, bladder and oesophageal, to name a few. However due to its expansive toxicity profile, patients receiving cisplatin can experience high frequency hearing loss, a side effect known as ototoxicity. The dearth of information on the extent and severity of cisplatin-associated ototoxicity in South Africa prevents the implementation of a context-specific audiological monitoring programme. METHODS: This study aims to determine the extent and severity of ototoxicity amongst patients with cervical cancer, receiving cisplatin-based chemotherapy and hence the feasibility of an ototoxicity monitoring program in the province of KwaZulu-Natal, South Africa. A concurrent mixed methods design will be employed in the study. This longitudinal study will involve interviewing oncology nurses, oncologists, pharmacists and audiologists to assess the level of awareness to ototoxicity, as well as conducting diagnostic audiological evaluations at regular intervals on 78 patients with cervical cancer to ascertain the progression of hearing loss during and after chemotherapy. The feasibility of the monitoring program will be assessed as a parallel process to the audiological evaluations, where patient outcomes and cost implications to the patient and the health sector will be considered. Data will be subjected to statistical analyses so as to strengthen knowledge in the field and inform appropriate policies, and healthcare providers. DISCUSSION: This study is the first longitudinal study in South Africa to determine the ototoxic effects of cisplatin therapy on patients diagnosed with cervical cancer. Thus, the results generated from this study is likely to bring novel information to the fore using an evidence-based approach that will influence policy and clinical practice which can vastly improve the quality of life of patients undergoing chemotherapy. Mitigation of any further loss in the quality of life of affected patients is of paramount importance and the data generated from this project can lay the basis for further effective dialogue towards policy formulation on an ototoxic monitoring programme and the resultant strengthening of health systems in limited resource settings. PMID- 29228930 TI - Gene expression analysis in asthma using a targeted multiplex array. AB - BACKGROUND: Gene expression changes in the structural cells of the airways are thought to play a role in the development of asthma and airway hyperresponsiveness. This includes changes to smooth muscle contractile machinery and epithelial barrier integrity genes. We used a targeted gene expression arrays to identify changes in the expression and co-expression of genes important in asthma pathology. METHODS: RNA was isolated from the airways of donor lungs from 12 patients with asthma (8 fatal) and 12 non-asthmatics controls and analyzed using a multiplexed, hypothesis-directed platform to detect differences in gene expression. Genes were grouped according to their role in airway dysfunction: airway smooth muscle contraction, cytoskeleton structure and regulation, epithelial barrier function, innate and adaptive immunity, fibrosis and remodeling, and epigenetics. RESULTS: Differential gene expression and gene co expression analyses were used to identify disease associated changes in the airways of asthmatics. There was significantly decreased abundance of integrin beta 6 and Ras-Related C3 Botulinum Toxin Substrate 1 (RAC1) in the airways of asthmatics, genes which are known to play an important role in barrier function. Significantly elevated levels of Collagen Type 1 Alpha 1 (COL1A1) and COL3A1 which have been shown to modulate cell proliferation and inflammation, were found in asthmatic airways. Additionally, we identified patterns of differentially co expressed genes related to pathways involved in virus recognition and regulation of interferon production. 7 of 8 pairs of differentially co-expressed genes were found to contain CCCTC-binding factor (CTCF) motifs in their upstream promoters. CONCLUSIONS: Changes in the abundance of genes involved in cell-cell and cell matrix interactions could play an important role in regulating inflammation and remodeling in asthma. Additionally, our results suggest that alterations to the binding site of the transcriptional regulator CTCF could drive changes in gene expression in asthmatic airways. Several asthma susceptibility loci are known to contain CTCF motifs and so understanding the role of this transcription factor may expand our understanding of asthma pathophysiology and therapeutic options. PMID- 29228932 TI - Narratives of community engagement: a systematic review-derived conceptual framework for public health interventions. AB - BACKGROUND: Government policy increasingly supports engaging communities to promote health. It is critical to consider whether such strategies are effective, for whom, and under what circumstances. However, 'community engagement' is defined in diverse ways and employed for different reasons. Considering the theory and context we developed a conceptual framework which informs understanding about what makes an effective (or ineffective) community engagement intervention. METHODS: We conducted a systematic review of community engagement in public health interventions using: stakeholder involvement; searching, screening, appraisal and coding of research literature; and iterative thematic syntheses and meta-analysis. A conceptual framework of community engagement was refined, following interactions between the framework and each review stage. RESULTS: From 335 included reports, three products emerged: (1) two strong theoretical 'meta-narratives': one, concerning the theory and practice of empowerment/engagement as an independent objective; and a more utilitarian perspective optimally configuring health services to achieve defined outcomes. These informed (2) models that were operationalized in subsequent meta-analysis. Both refined (3) the final conceptual framework. This identified multiple dimensions by which community engagement interventions may differ. Diverse combinations of intervention purpose, theory and implementation were noted, including: ways of defining communities and health needs; initial motivations for community engagement; types of participation; conditions and actions necessary for engagement; and potential issues influencing impact. Some dimensions consistently co-occurred, leading to three overarching models of effective engagement which either: utilised peer-led delivery; employed varying degrees of collaboration between communities and health services; or built on empowerment philosophies. CONCLUSIONS: Our conceptual framework and models are useful tools for considering appropriate and effective approaches to community engagement. These should be tested and adapted to facilitate intervention design and evaluation. Using this framework may disentangle the relative effectiveness of different models of community engagement, promoting effective, sustainable and appropriate initiatives. PMID- 29228933 TI - Pulmonary exacerbations and clinical outcomes in a longitudinal cohort of infants and preschool children with cystic fibrosis. AB - BACKGROUND: Pulmonary exacerbations (PEx) in school aged children and adults with cystic fibrosis (CF) lead to increased morbidity and lung function decline. However, the effect of exacerbations in young children with CF is not fully understood. We sought to characterize the frequency and clinical impact of PEx in a pilot study of infants and pre-school aged children with CF. METHODS: Thirty young children with CF [median (range) 1.5 years (0.2-4.9)] were prospectively followed for 2 years. Exacerbation frequency (hospitalizations and outpatient antibiotic use) was determined. Chest radiographs were performed at enrollment and study completion and assigned a Brasfield score. Lung function at age 7 years was assessed in a subset of children. The association between PEx frequency, chest radiograph score, and lung function was determined using Spearman correlation coefficients and corresponding 95% confidence intervals. Correlations with an absolute magnitude of 0.3 or greater were considered clinically significant. RESULTS: Over 2 years, participants experienced a median of two PEx (range 0-13). Chest radiograph scores at enrollment and study completion were inversely associated with PEx frequency (R = -0.48 and R = -0.44, respectively). The association between frequency of PEx and lung function [forced expiratory volume in 1 s (FEV1)] at age 7 years was small (R = 0.20). Higher forced vital capacity (FVC) at 7 years was associated with more frequent PEx during the study (R = 0.44). CONCLUSIONS: Children with worse chest radiograph scores had more frequent PEx over the subsequent 2 years, suggesting a group of patients at higher risk for PEx. Frequent PEx in infants and young children with CF were not associated with lower FEV1 and FVC at 7 years, although spirometry in this age group may not be a sensitive marker of mild lung disease and disease progression. PMID- 29228934 TI - A pilot study to assess the utility of a freely downloadable mobile application simulator for undergraduate clinical skills training: a single-blinded, randomised controlled trial. AB - BACKGROUND: Medical simulators offer an invaluable educational resource for medical trainees. However, owing to cost and portability restrictions, they have traditionally been limited to simulation centres. With the advent of sophisticated mobile technology, simulators have become cheaper and more accessible. Touch Surgery is one such freely downloadable mobile application simulator (MAS) used by over one million healthcare professionals worldwide. Nevertheless, to date, it has never been formally validated as an adjunct in undergraduate medical education. METHODS: Medical students in the final 3 years of their programme were recruited and randomised to one of three revision interventions: 1) no formal revision resources, 2) traditional revision resources, or 3) MAS. Students completed pre-test questionnaires and were then assessed on their ability to complete an undisclosed male urinary catheterisation scenario. Following a one-hour quarantined revision period, all students repeated the scenario. Both attempts were scored by allocation-blinded examiners against an objective 46-point mark scheme. RESULTS: A total of 27 medical students were randomised (n = 9 per group). Mean scores improved between baseline and post revision attempts by 8.7% (p = 0.003), 19.8% (p = 0.0001), and 15.9% (p = 0.001) for no resources, traditional resources, and MAS, respectively. However, when comparing mean score improvements between groups there were no significant differences. CONCLUSIONS: Mobile simulators offer an unconventional, yet potentially useful adjunct to enhance undergraduate clinical skills education. Our results indicate that MAS's perform comparably to current gold-standard revision resources; however, they may confer significant advantages in terms of cost-effectiveness and practice flexibility. TRIAL REGISTRATION: Not applicable. PMID- 29228935 TI - Dosimetrically administered nebulized morphine for breathlessness in very severe chronic obstructive pulmonary disease: a randomized, controlled trial. AB - BACKGROUND: Systemic morphine has evidence to support its use for reducing breathlessness in patients with severe chronic obstructive pulmonary disease (COPD). The effectiveness of the nebulized route, however, has not yet been confirmed. Recent studies have shown that opioid receptors are localized within epithelium of human trachea and large bronchi, a target site for a dosimetric nebulizer. The aim of this study was to compare any clinical or statistical differences in breathlessness intensity between nebulized 2.0% morphine and 0,9% NaCl in patients with very severe COPD. METHODS: The study was a double-blind, controlled, cross-over trial. Participants received morphine or NaCl during two 4 day periods. Sequence of periods was randomized. The primary outcome measure was reduction of breathlessness intensity now by >=20 mm using a 100 mm visual analogue scale (VAS) at baseline, 15, 30, 60, 120, 180 and 240 min after daily administration, during normal activities. RESULTS: Ten of 11 patients included completed the study protocol. All patients experienced clinically and statistically significant (p < 0.0001) breathlessness reduction during morphine nebulization. Mean VAS changes for morphine and 0.9% NaCl periods were 25.4 mm (standard deviation (SD): 9.0; median: 23,0; range: 14.0 to 41,5; confidence interval (CI): 95%) and 6.3 mm (SD: 7.8; median: 6.8; range: -11,5 to 19,5; CI: 95%), respectively. No treatment emergent adverse effects were noted. DISCUSSION: Our study showed superiority of dosimetrically administered nebulized morphine compared to NaCl in reducing breathlessness. This may have been achieved through morphine's direct action on receptors in large airways, although a systemic effect from absorption through the lungs cannot be excluded. TRIAL REGISTRATION: Retrospectively registered (07.03.2017), ISRCTN14865597. PMID- 29228936 TI - Inter-day reliability of surface electromyography recordings of the lumbar part of erector spinae longissimus and trapezius descendens during box lifting. AB - BACKGROUND: Low back pain and neck-shoulder pain are the most reported types of work-related musculoskeletal disorders, and performing heavy lifting at work and working with trunk rotation increase the risk of developing work-related musculoskeletal disorders. Surface electromyography (sEMG) provides information about the electrical activity of muscles. Thus it has the potential to retrieve indirect information about the physical exposure of specific muscles of workers during their actual work. This study aimed to investigate the inter-day reliability of absolute and normalized amplitude of sEMG measurements obtained during repeated standardized reference lifts. METHODS: The inter-day reliability of sEMG of the erector spinae longissimus and trapezius descendens muscles was tested during standardized box lifts. The lifts were performed with loads of 3, 15 and 30 kg from floor to table and from table to table in three conditions, i.e., forearm length (short reaching distance), 3/4 arm length (long reaching distance) and forearm length with trunk rotation. Absolute and normalized root mean square (absRMS and normRMS) values were extracted. In line with the guidelines for reporting reliability and agreement studies, we reported relative and absolute reliability estimated by intra class correlation (ICC3,K), standard error of measurement (SEM) and minimal detectable change in percent (MDC). RESULTS: The ICC3,K was higher for absRMS compared with normRMS while SEM and maximal voluntary contraction (MVC) were similar. A total of 50 out of 56, i.e., 89%, and 41 out of 56, i.e., 73%, of the lifting situations were in the range from moderate to almost perfect for absRMS and normRMS, respectively. The SEM and MDC shoved more variation in the lifting situations performed from floor to table and in the trapezius descendens muscle than in the erector spinae longissimus muscle. CONCLUSION: This reliability study showed that maximum absRMS and normRMS were found to have a fair to substantial relative inter-day reliability for most lifts but were more reliable when lifting from table to table than from floor to table for both trapezius descendens and erector spinae muscles. The relative inter-day reliability was higher for absolute compared with normalized sEMG amplitudes while the absolute reliability was similar. PMID- 29228937 TI - Do objective neighbourhood characteristics relate to residents' preferences for certain sports locations? A cross-sectional study using a discrete choice modelling approach. AB - BACKGROUND: The number of sports facilities, sports clubs, or city parks in a residential neighbourhood may affect the likelihood that people participate in sports and their preferences for a certain sports location. This study aimed to assess whether objective physical and socio-spatial neighbourhood characteristics relate to sports participation and preferences for sports locations. METHODS: Data from Dutch adults (N = 1201) on sports participation, their most-used sports location, and socio-demographic characteristics were collected using an online survey. Objective land-use data and the number of sports facilities were gathered for each participant using a 2000-m buffer around their home locations, whereas socio-spatial neighbourhood characteristics (i.e., density, socio-economic status, and safety) were determined at the neighbourhood level. A discrete choice modelling framework (multinomial probit model) was used to model the associations between neighbourhood characteristics and sports participation and location. RESULTS: Higher proportions of green space, blue space, and the number of sports facilities were positively associated with sports participation in public space, at sports clubs, and at other sports facilities. Higher degrees of urbanization were negatively associated with sports participation at public spaces, sports clubs, and other sports facilities. CONCLUSIONS: Those with more green space, blue space or sports facilities in their residential neighbourhood were more likely to participate in sports, but these factors did not affect their preference for a certain sports location. Longitudinal study designs are necessary to assess causality: do active people choose to live in sports facilitating neighbourhoods, or do neighbourhood characteristics affect sports participation? PMID- 29228938 TI - Habitat modification by invasive crayfish can facilitate its growth through enhanced food accessibility. AB - BACKGROUND: Invasive ecosystem engineers can facilitate their invasions by modifying the physical environment to improve their own performance, but this positive feedback process has rarely been tested empirically except in sessile organisms. The invasive crayfish Procambarus clarkii is an ecosystem engineer that destroys aquatic macrophytes, which provide a physical refuge for animal prey, and this destruction is likely to enhance vulnerability to predators. Using two series of mesocosm experiments, we tested the hypothesis that the invasive crayfish increases its feeding efficiency on animal prey by reducing submerged macrophytes, thus increasing its individual growth rate in a positive density dependent manner. RESULTS: In the first experiment, increasing crayfish density reduced both macrophytes and animal prey (dragonfly and chironomid larvae) and, importantly, increased the growth rate of individual crayfish, in accordance with our expectation. In the second experiment, we used artificial macrophytes to clarify whether the physical architecture of macrophytes itself protects animal prey and limits crayfish growth rate. Increasing the artificial macrophyte quantity not only increased the survival of animal prey, but also retarded the crayfish growth rate. CONCLUSIONS: We conclude that macrophytes strengthen bottom up control of crayfish, but this effect can be relaxed by increasing the density of crayfish via reduction in macrophytes. This positive feedback process may explain the crayfish outbreaks and regime shifts occasionally observed in invaded freshwater ecosystems. PMID- 29228939 TI - The ethics of caring for hospital-dependent patients. AB - BACKGROUND: Hospital-dependent patients are individuals who are repeatedly readmitted to the hospital because their acute medical needs cannot be met elsewhere. Unlike the chronically critically ill, these patients do not have a continuous need for life-sustaining equipment and can experience periods of relative stability where they have a good quality of life. However, some end up spending months or even years in the hospital receiving resource-intensive care because they are unable to be safely discharged, despite an initial optimistic prognosis. It is hard to reliably identify these patients on admission and more research is needed to better understand the unique medical needs of this population. But the inability to safely discharge these patients to their home or to a skilled nursing facility without rapid readmissions also creates ethical implications for the physicians who care for them. The aim of this paper is to clarify some of the ethical considerations involved in caring for hospital dependent patients. MAIN BODY: Among physicians, the care of hospital-dependent patients is likely to disproportionately affect hospitalists and intensivists, whose care is often evaluated in terms of reducing patient length of stay and readmissions. Because hospital-dependent patients' medical needs thwart the traditional goal of safe discharge, both clinical ethics and physicians' professional obligations are implicated by their care. The inability to reliably identify these patients early can complicate discussions about treatment goals and informed consent. Similarly, the tremendous dedication of limited resources to these patients without safe discharge back to the community may raise concerns about the just allocation of healthcare resources. CONCLUSION: Our current acute care hospitals are not designed to provide long-term care for hospital-dependent patients. Unfortunately, safe discharge options remain elusive for these patients. Further research and support of this population is needed to more reliably identify hospital-dependent patients on admission, better inform the discussions of short- and long-term treatment goals, and more wisely allocate resources both within our acute care hospitals and larger healthcare system. PMID- 29228940 TI - Communicating wisely: teaching residents to communicate effectively with patients and caregivers about unnecessary tests. AB - BACKGROUND: With rising healthcare costs and a focus on quality, there is a growing need to promote resource stewardship in medical education. Physicians need to be able to communicate effectively with patients/caregivers seeking tests and treatments that are unnecessary. This study aimed to evaluate the impact of an interactive workshop on residents' knowledge of resource stewardship and communication skills when counseling patients/caregivers about requests for unnecessary testing. METHODS: Participants were 83 Internal Medicine and Pediatrics residents at the University of Toronto in 2014-15. The evaluation compared resource stewardship knowledge and communication skills of 57 (69%) residents that attended the resource stewardship workshop to 26 residents (31%) who did not. Knowledge and communication skills assessment consisted of a written test and a structured assessment using standardized patient raters, respectively. A linear regression was applied to determine predictors of overall communication skills performance. RESULTS: Workshop attendance resulted in better performance on the knowledge test (4.3 +/- 1.9 vs. 3.1 +/- 1.7 out of 8, p = 0.01), but not better performance on the communication skills assessment (4.1 +/- 0.8 vs. 4.0 +/ 0.9 out of 5, p = 0.56). Higher training level (p = 0.01) and knowledge test scores (p = 0.046) were independent predictors of better overall communication skills, after adjusting for gender, training level, workshop attendance, knowledge and self-reported prior feedback on communication skills. CONCLUSIONS: An interactive workshop can improve knowledge of resource stewardship, but improving communication skills with patients/caregivers about unnecessary testing may require additional training or reinforcement in the clinical learning environment. These teaching and assessment approaches can support the integration of education on resource stewardship into medical education. PMID- 29228941 TI - Four years' follow-up changes of physical activity and sedentary time in women undergoing roux-en-Y gastric bypass surgery and appurtenant children. AB - BACKGROUND: Objectively measured levels of physical activity (PA) in patients undergoing Roux-en-Y Gastric Bypass (RYGB) surgery remain essentially unchanged from before to one year after surgery. Effects from RYGB on objectively measured levels of PA among women undergoing RYGB and appurtenant children beyond one year post-surgery are unknown. The aim of the present study was to objectively assess longitudinal changes in PA and sedentary time (ST), among women undergoing RYGB and appurtenant children, from three months before to nine and 48 months after maternal surgery. METHODS: Thirty women undergoing RYGB and 40 children provided anthropometric measures during home visits and valid accelerometer assessed (Actigraph GT3X+) PA data, three months before and nine and 48 months after maternal RYGB surgery. RESULTS: Women undergoing RYGB decreased time spent in moderate to vigorous PA (MVPA) with 2.0 min/day (p = 0.65) and increased ST with 14.4 min/day (p = 0.35), whereas their children decreased time spent in MVPA with 13.2 min/day (p = 0.04) and increased ST with 110.5 min/day (p < 0.001), from three months before to 48 months after maternal surgery. Twenty, 27 and 33% of women, and 60, 68 and 35% of children reached current PA guidelines three months before and nine and 48 months after maternal RYGB, respectively. CONCLUSIONS: Objectively measured PA in women remains unchanged, while appurtenant children decrease time spent in MVPA and increase ST, from three months before through nine and 48 months after maternal RYGB. The majority of both women undergoing RYGB and children are insufficiently active 48 months after maternal RYGB. PMID- 29228942 TI - Multiple breath washout testing in adults with pulmonary disease and healthy controls - can fewer measurements eventually be more? AB - BACKGROUND: Multiple breath washout (MBW) became a valuable research tool assessing ventilation heterogeneity. However, routine clinical application still faces several challenges. Deriving MBW parameters from three technically acceptable measurements according to current recommendations prolongs test times. We therefore aimed to evaluate reporting only duplicate measurements in healthy adults and pulmonary disease. METHODS: One hundred and fifty-three subjects prospectively underwent conventional lung function testing and closed-circuit SF6 MBW. Three technically acceptable MBW-measurements were obtained in 103 subjects. RESULTS: Lung clearance index (LCI) differed significantly among 19 controls (7.4 +/- 0.8), 19 patients with sarcoidosis (8.1 +/- 1.2), 32 with bronchial asthma (9.2 +/- 1.9) and 33 with COPD (10.8 +/- 2.2, p < 0.001). Within-test repeatability was high (coefficient of variation between 2.5% in controls and 3.6% in COPD) and remained unchanged when only including the first two measurements. Likewise, LCI remained stable with mean absolute changes ranging from 0.9 +/- 0.8% in controls to 1.5 +/- 0.9% in COPD (p = 0.1). Mean test time reduction differed significantly between groups reaching 200 s in COPD (p = 0.01). CONCLUSIONS: Duplicate SF6-MBW-measurements are sufficient in adult patients with pulmonary disease and healthy controls. LCI values and intra-test repeatability are not affected reducing total test time statistically significant. Our findings have the potential to further facilitate application of MBW in research and clinical routine. TRIAL REGISTRATION: NCT03176745 , June 2, 2017 retrospectively registered. PMID- 29228943 TI - Reconsidering the prognosis of major depressive disorder across diagnostic boundaries: full recovery is the exception rather than the rule. AB - BACKGROUND: Major depressive disorder (MDD) is often handled as an episodic and isolated disorder, resulting in an optimistic view about its prognosis. Herein, we test the idea that the prognosis of MDD changes if we vary the perspective in terms of (1) a longer time frame and (2) a broader diagnostic conceptualisation including dysthymia, (hypo)mania and anxiety disorders as relevant outcomes. METHODS: Patients with current MDD at baseline (n = 903) and available 2-, 4-, and/or 6-year follow-up assessments were selected from the Netherlands Study of Depression and Anxiety, a psychiatric cohort study. Combining psychiatric DSM-IV based diagnoses and life-chart data, patient course trajectories were classified as (1) recovered (no diagnoses at 2-year follow-up or thereafter), (2) recurrent without chronic episodes, (3) recurrent with chronic episodes or (4) consistently chronic since baseline. A chronic episode was defined as having a current diagnosis at the follow-up assessment and consistent symptoms over 2 years. Proportions of course trajectories were provided moving from a short, narrow perspective (2-year follow-up, considering only MDD diagnosis) to a long, broad perspective (6-year follow-up, including MDD, dysthymia, (hypo)mania and anxiety diagnoses). RESULTS: With the short, narrow perspective, the recovery rate was 58% and 21% had a chronic episode. However, in the long, broad perspective the recovery rate was reduced to 17%, while 55% of the patients experienced chronic episodes. CONCLUSIONS: Results from a long and rigorous follow-up in a large cohort suggests that most MDD patients have an unfavourable prognosis. Longer follow-up and broader diagnostic conceptualisation show that the majority of patients have a disabling and chronic disorder. Conceptualising and handling MDD as a narrowly defined and episodic disorder may underestimate the prognosis of the majority of depressed patients and, consequently, the type of care that is appropriate. PMID- 29228944 TI - Effect of acupuncture on Lipopolysaccharide-induced anxiety-like behavioral changes: involvement of serotonin system in dorsal Raphe nucleus. AB - BACKGROUND: Acupuncture has been used as a common therapeutic tool in many disorders including anxiety and depression. Serotonin transporter (SERT) plays an important role in the pathology of anxiety and other mood disorders. The aim of this study was to evaluate the effects of acupuncture on lipopolysaccharide (LPS) induced anxiety-like behaviors and SERT in the dorsal raphe nuclei (DRN). METHODS: Rats were given acupuncture at ST41 (Jiexi), LI11 (Quchi) or SI3 (Houxi) acupoint in LPS-treated rats. Anxiety-like behaviors of elevated plus maze (EPM) and open field test (OFT) were measured and expressions of SERT and/or c-Fos were also examined in the DRN using immunohistochemistry. RESULTS: The results showed that 1) acupuncture at ST41 acupoint, but neither LI11 nor SI3, significantly attenuated LPS-induced anxiety-like behaviors in EPM and OFT, 2) acupuncture at ST41 decreased SERT expression increased by LPS in the DRN. CONCLUSIONS: Our results suggest that acupuncture can ameliorate anxiety-like behaviors, possibly through regulation of SERT in the DRN. PMID- 29228945 TI - Trends in incidence of proximal humerus fractures, surgical procedures and outcomes among elderly hospitalized patients with and without type 2 diabetes in Spain (2001-2013). AB - BACKGROUND: Several studies have reported that diabetic persons have an increased risk for fractures than non-diabetes patients. The association between proximal humerus fractures and type 2 diabetes (T2DM) is unclear and some studies point to insulin treatment, hypoglycaemic episodes consequently to inadequate control of diabetes or, more recently, to an alteration of trabecular bone. We examined trends in the incidence of proximal humerus fractures, surgical procedures and outcomes among hospitalized patients aged >=65 years, with and without T2DM in Spain, 2001-2013. METHODS: This retrospective, observational study was conducted using the Spanish National Hospital Discharge Database to select all hospital admissions with proximal humerus fracture. We calculated incidences overall and stratified by diabetes status, year and sex. We analyzed surgical procedures, comorbidities, length of stay, in-hospital complications and in-hospital mortality. RESULTS: We identified 43,872 patients with proximal humerus fracture (18.3% had a T2DM diagnosis). Age-adjusted incidence rates elevated steadily over the study period for men and women with and without T2DM, independently of diabetes status, although we found a stable trend in the later years. Patients with T2DM had lower relative risk of proximal humeral fracture incidence: 0.87 (95%IC 0.82-0.93) for men and 0.97 (95%IC 0.95-1.00) for women. In-hospital complications were 4.0% of diabetic men vs. 2.6% in non-diabetic (p < 0.001) and 2.9% among T2DM women vs. 1.7% in those without (p < 0.05). The use of open reduction of fracture with internal fixation and arthroplasty is increasing overtime and closed reduction with internal fixation is decreasing. Presence of T2DM in women was associated with higher in-hospital mortality (OR 1.67; 95%CI 1.29-2.15). Comorbidities, in-hospital complications and older age were predictors of higher in-hospital mortality in both sexes. CONCLUSIONS: The incidence of proximal humerus fractures seems to be increasing in Spain. The incidence is lower among men with than without T2DM. T2DM is associated to higher in-hospital complications in both sexes. The use of open reduction of fracture with internal fixation and arthroplasty is increasing overtime beside diabetes status. Women with T2DM have higher in-hospital mortality than those without the disease. PMID- 29228946 TI - A school-based intervention improved dietary intake outcomes and reduced waist circumference in adolescents: a cluster randomized controlled trial. AB - BACKGROUND: In Ecuador, adolescents' food intake does not comply with guidelines for a healthy diet. Together with abdominal obesity adolescent's inadequate diets are risk factors for non-communicable diseases. We report the effectiveness of a school-based intervention on the dietary intake and waist circumference among Ecuadorian adolescents. METHODS: A pair-matched cluster randomized controlled trial including 1430 adolescents (12-14 years old) was conducted. The program aimed at improving the nutritional value of dietary intake, physical activity (primary outcomes), body mass index, waist circumference and blood pressure (secondary outcomes). This paper reports: (i) the effect on fruit and vegetable intake, added sugar intake, unhealthy snacking (consumption of unhealthy food items that are not in line with the dietary guidelines eaten during snack time; i.e. table sugar, sweets, salty snacks, fast food, soft drinks and packaged food), breakfast intake and waist circumference; and, (ii) dose and reach of the intervention. Dietary outcomes were estimated by means of two 24-h recall at baseline, after the first 17-months (stage one) and after the last 11-months (stage two) of implementation. Dose and reach were evaluated using field notes and attendance forms. Educational toolkits and healthy eating workshops with parents and food kiosks staff in the schools were implemented in two different stages. The overall effect was assessed using linear mixed models and regression spline mixed effect models were applied to evaluate the effect after each stage. RESULTS: Data from 1046 adolescents in 20 schools were analyzed. Participants from the intervention group consumed lower quantities of unhealthy snacks (-23.32 g; 95% CI: -45.25,-1.37) and less added sugar (-5.66 g; 95% CI: -9.63,-1.65) at the end of the trial. Daily fruit and vegetable intake decreased in both the intervention and control groups compared to baseline, albeit this decrease was 23.88 g (95% CI: 7.36, 40.40) lower in the intervention group. Waist circumference (-0.84 cm; 95% CI: -1.68, 0.28) was lower in the intervention group at the end of the program; the effect was mainly observed at stage one. Dose and reach were also higher at stage one. CONCLUSIONS: The trial had positive effects on risk factors for non-communicable diseases, i.e. decreased consumption of unhealthy snacks. The program strategies must be implemented at the national level through collaboration between the academia and policy makers to assure impact at larger scale. TRIAL REGISTRATION: ClinicalTrial.gov-NCT01004367 . PMID- 29228947 TI - Estimating prevalence of chronic obstructive pulmonary disease in the Southern Cone of Latin America: how different spirometric criteria may affect disease burden and health policies. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide. The study aimed to determine and compare the prevalence of COPD in the general population aged 45-74 years old according to fixed ratio and lower limit of normal (LLN) thresholds in four cities in the Southern Cone of Latin America. METHODS: The Pulmonary Risk in South America (PRISA) study used a 4-stage stratified sampling method to select 5814 participants from 4 cities in the Southern Cone of Latin America (Bariloche and Marcos Paz, Argentina; Temuco, Chile; and Pando-Barros Blancos, Uruguay). Data on demographic information, medical history, risk factors, pre-bronchodilator and post-bronchodilator spirometry were obtained using a standard protocol. According to GOLD, COPD was defined as a post-bronchodilator ratio of forced expiratory volume in one second (FEV1) over forced vital capacity (FVC) less than 70%. The LLN threshold was defined as the lower fifth percentile for predicted FEV1/FVC, and was evaluated as an alternative COPD definition. RESULTS: Overall COPD prevalence was 9.3% (95% CI 8.4, 10.2%), and men had a higher prevalence [11.8% (95% CI 10.3, 13.3%)] than women [7.3% (95% CI 6.2, 8.3%)] with the fixed ratio. Overall COPD prevalence using LLN was 4.7% (95% CI 4.1, 5.3%), higher in men: 5.8% (95% CI 4.7, 6.8%) than women: 3.9% (95% CI 3.1, 4.7%). COPD prevalence was significantly higher among those who were older, had =1 exacerbation in the preceding year. METHODS: A previously published and validated patient-level simulation model was adapted using clinical data from the FLAME trial and real-world cost data from the ARCTIC study. Costs (total monetary costs comprising drug, maintenance, exacerbation, and pneumonia costs) and health outcomes (life-years (LYs), quality-adjusted life years (QALYs)) were projected over various time horizons (1, 5, 10 years, and lifetime) from the Swedish payer's perspective and were discounted at 3% annually. Uncertainty in model input values was studied through one-way and probabilistic sensitivity analyses. Subgroup analyses were also performed. RESULTS: IND/GLY was associated with lower costs and better outcomes compared with SFC over all the analysed time horizons. Use of IND/GLY resulted in additional 0.192 LYs and 0.134 QALYs with cost savings of ?1211 compared with SFC over lifetime. The net monetary benefit (NMB) was estimated to be ?8560 based on a willingness-to-pay threshold of ?55,000/QALY. The NMB was higher in the following subgroups: severe (GOLD 3), high risk and more symptoms (GOLD D), females, and current smokers. CONCLUSION: IND/GLY is a cost-effective treatment compared with SFC in COPD patients with mMRC dyspnea grade >= 2, moderate to very severe airflow limitation, and >=1 exacerbation in the preceding year. PMID- 29228951 TI - Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. AB - BACKGROUND: Vitamin C is an essential water-soluble nutrient which cannot be synthesised or stored by humans. It is a potent antioxidant with anti inflammatory and immune-supportive roles. Previous research has indicated that vitamin C levels are depleted in critically ill patients. In this study we have assessed plasma vitamin C concentrations in critically ill patients relative to infection status (septic shock or non-septic) and level of inflammation (C reactive protein concentrations). Vitamin C status was also assessed relative to daily enteral and parenteral intakes to determine if standard intensive care unit (ICU) nutritional support is adequate to meet the vitamin C needs of critically ill patients. METHODS: Forty-four critically ill patients (24 with septic shock, 17 non-septic, 3 uncategorised) were recruited from the Christchurch Hospital Intensive Care Unit. We measured concentrations of plasma vitamin C and a pro inflammatory biomarker (C-reactive protein) daily over 4 days and calculated patients' daily vitamin C intake from the enteral or total parenteral nutrition they received. We compared plasma vitamin C and C-reactive protein concentrations between septic shock and non-septic patients over 4 days using a mixed effects statistical model, and we compared the vitamin C status of the critically ill patients with known vitamin C bioavailability data using a four-parameter log logistic response model. RESULTS: Overall, the critically ill patients exhibited hypovitaminosis C (i.e., < 23 MUmol/L), with a mean plasma vitamin C concentration of 17.8 +/- 8.7 MUmol/L; of these, one-third had vitamin C deficiency (i.e., < 11 MUmol/L). Patients with hypovitaminosis C had elevated inflammation (C-reactive protein levels; P < 0.05). The patients with septic shock had lower vitamin C concentrations and higher C-reactive protein concentrations than the non-septic patients (P < 0.05). Nearly 40% of the septic shock patients were deficient in vitamin C, compared with 25% of the non-septic patients. These low vitamin C levels were apparent despite receiving recommended intakes via enteral and/or parenteral nutritional therapy (mean 125 mg/d). CONCLUSIONS: Critically ill patients have low vitamin C concentrations despite receiving standard ICU nutrition. Septic shock patients have significantly depleted vitamin C levels compared with non-septic patients, likely resulting from increased metabolism due to the enhanced inflammatory response observed in septic shock. PMID- 29228952 TI - Association between left ventricular mechanics and diffuse myocardial fibrosis in patients with repaired Tetralogy of Fallot: a cross-sectional study. AB - BACKGROUND: Patients with repaired tetralogy of Fallot (TOF) have progressive, adverse biventricular remodeling, leading to abnormal contractile mechanics. Defining the mechanisms underlying this dysfunction, such as diffuse myocardial fibrosis, may provide insights into poor long-term outcomes. We hypothesized that left ventricular (LV) diffuse fibrosis is related to impaired LV mechanics. METHODS: Patients with TOF were evaluated with cardiac magnetic resonance in which modified Look-Locker (MOLLI) T1-mapping and spiral cine Displacement encoding (DENSE) sequences were acquired at three LV short-axis positions. Linear mixed modeling was used to define the association between regional LV mechanics from DENSE based on regional T1-derived diffuse fibrosis measures, such as extracellular volume fraction (ECV). RESULTS: Forty patients (26 +/- 11 years) were included. LV ECV was generally within normal range (0.24 +/- 0.05). For LV mechanics, peak circumferential strains (-15 +/- 3%) and dyssynchrony indices (16 +/- 8 ms) were moderately impaired, while peak radial strains (29 +/- 8%) were generally normal. After adjusting for patient age, sex, and regional LV differences, ECV was associated with log-adjusted LV dyssynchrony index (beta = 0.67) and peak LV radial strain (beta = -0.36), but not LV circumferential strain. Moreover, post-contrast T1 was associated with log-adjusted LV diastolic circumferential strain rate (beta = 0.37). CONCLUSIONS: We observed several moderate associations between measures of fibrosis and impaired mechanics, particularly the LV dyssynchrony index and peak radial strain. Diffuse fibrosis may therefore be a causal factor in some ventricular dysfunction in TOF. PMID- 29228953 TI - A simple and accurate rule-based modeling framework for simulation of autocrine/paracrine stimulation of glioblastoma cell motility and proliferation by L1CAM in 2-D culture. AB - BACKGROUND: Glioblastoma multiforme (GBM) is a devastating brain cancer for which there is no known cure. Its malignancy is due to rapid cell division along with high motility and invasiveness of cells into the brain tissue. Simple 2 dimensional laboratory assays (e.g., a scratch assay) commonly are used to measure the effects of various experimental perturbations, such as treatment with chemical inhibitors. Several mathematical models have been developed to aid the understanding of the motile behavior and proliferation of GBM cells. However, many are mathematically complicated, look at multiple interdependent phenomena, and/or use modeling software not freely available to the research community. These attributes make the adoption of models and simulations of even simple 2 dimensional cell behavior an uncommon practice by cancer cell biologists. RESULTS: Herein, we developed an accurate, yet simple, rule-based modeling framework to describe the in vitro behavior of GBM cells that are stimulated by the L1CAM protein using freely available NetLogo software. In our model L1CAM is released by cells to act through two cell surface receptors and a point of signaling convergence to increase cell motility and proliferation. A simple graphical interface is provided so that changes can be made easily to several parameters controlling cell behavior, and behavior of the cells is viewed both pictorially and with dedicated graphs. We fully describe the hierarchical rule based modeling framework, show simulation results under several settings, describe the accuracy compared to experimental data, and discuss the potential usefulness for predicting future experimental outcomes and for use as a teaching tool for cell biology students. CONCLUSIONS: It is concluded that this simple modeling framework and its simulations accurately reflect much of the GBM cell motility behavior observed experimentally in vitro in the laboratory. Our framework can be modified easily to suit the needs of investigators interested in other similar intrinsic or extrinsic stimuli that influence cancer or other cell behavior. This modeling framework of a commonly used experimental motility assay (scratch assay) should be useful to both researchers of cell motility and students in a cell biology teaching laboratory. PMID- 29228955 TI - High-efficiency generation of induced pluripotent stem cells from human foreskin fibroblast cells using the Sagunja-tang herbal formula. AB - BACKGROUND: Sagunja-Tang (SGT-4) is a traditional herbal formula in Korean medicine that is used to treat anti-metabolic syndrome, and has antioxidant activity. In this study, we evaluated the effects of SGT-4 on the formation efficiency of induced pluripotent stem cells (iPSCs) from human foreskin fibroblasts (HFFs) by four reprogramming transcription factors: Oct4, Sox2, KIf4, and c-Myc (OSKM). METHODS: SGT-4 contained four different herbal medicines that are composed of Ginseng Radix, Glycyrrhizae Radix et Rhizoma, Atractylodis Rhizoma Alba, and Poria Sclerotium. The composition of SGT-4 was analyzed by high performance liquid chromatography (HPLC). HFFs were transfected with episomal vectors contained by four OSKM. Western blotting, RT-PCR, immunofluroescence, and in vitro differentiation were used to assess the pluripotency of the iPSC cells. RESULTS: SGT-4 exhibited antioxidant activity against the generation of intracellular reactive oxygen species (ROS) as well as promoted the activation of superoxide dismutase 1 (SOD1), catalase, gluthathione peroxidase 1 (GPX1), and glutathione (GSH). Moreover, the ATP level was not significantly fluctuated depending on the concentration of SGT-4 in the hiPSCs. CONCLUSION: Our results indicate that the SGT-4, herbal formula significantly increases the efficiency of human iPSC generation via the transcription factors (Oct4, Sox2, KIf4, and c Myc). PMID- 29228954 TI - Combination of berberine and evodiamine inhibits intestinal cholesterol absorption in high fat diet induced hyperlipidemic rats. AB - BACKGROUND: Hyperlipidemia characterized of elevated serum lipid levels is a prevalent disease frequently resulting in cardiovascular disease (CVD). Berberine and evodiamine are herbal products of traditional Chinese herb Coptis chinensis and Evodia rutaecarpa, which are indicated to exert regulation of lipid metabolism. Therefore, the objective of this study was to investigate the lipid lowering effect of berberine and evodiamine combination in hyperlipidemic rats. METHOD: The rat model of hyperlipidemia was established by providing high-fat diet (HFD) for 4 weeks. Berberine (BB), evodiamine (EV), and their combination (BB + EV) were orally administered to HFD induced rats for 4 weeks. Body weight, food utilization, histopathology of liver tissues, lipid profiles of serum and liver were measured. Gas chromatography (GC) analysis was applied to examine the level of plasma total cholesterol and beta- Sitosterol (BS) to estimate cholesterol absorption activity. Furthermore, intestinal NPC1L1, ACAT2, and ApoB48 protein expressions were evaluated by immunohistochemical assay. RESULT: According to the results, decreased levels of serum cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C), as well as hepatic TC were showed in hyperlipidemic rats treated by combination of berberine and evodiamine. GC analysis indicated that the elevated plasma BS was significantly ameliorated by BB, EV, and BB + EV. In addition, immunohistochemical analysis revealed that BB + EV treatment down-regulated the expressions of intestinal NPC1L1 and ACAT2, and ApoB48 in HFD induced rats. CONCLUSION: Based on the above results, combination of berberine and evodiamine exerted a promising preventive effect on hyperlipidemia, partially through inhibiting intestinal absorption of cholesterol. PMID- 29228957 TI - Evaluation of the effect of D-amino acid incorporation into amyloid-reactive peptides. AB - BACKGROUND: Systemic amyloidoses comprise diseases characterized by the deposition of proteinaceous material known as amyloid. Currently, without performing multiple biopsies, there is no way to ascertain the extent of amyloid deposition in patients-a critical piece of information that informs prognosis and therapeutic strategies. We have developed pan-amyloid-targeting peptides for imaging amyloid and recently have adapted these for use as pre-targeting agents in conjunction with immunotherapy. Incorporation of D-amino acids in these peptides may enhance serum half-life, which is an important characteristic of effective peptide therapeutics. Herein, we assess the effects of partial incorporation of D-amino acids into the amyloidophilic peptide p5 on in vivo amyloid reactivity. METHODS: Peptides, referred to as AQAp5 (d) , aqap5, and AQAp5, were radiolabeled with iodine-125 and the tissue biodistribution (% injected dose/gram) measured in healthy mice at multiple time points post injection. Microscopic distribution of the peptides was further visualized using microautoradiography (ARG). Peptides aqap5 and AQAp5 were injected into healthy and amyloid-laden mice and evaluated by using SPECT/CT imaging at 1, 4 and 24 h post injection. RESULTS: Biodistribution data and ARG revealed persistent retention of [125I]AQAp5 (d) in the liver and kidneys of healthy mice for at least 24 h. In contrast, peptides [125I]aqap5 and [125I]AQAp5 did not bind these organs and was significantly lower than [125I]AQAp5 (d) at 24 h post injection (p < 0.0001). SPECT/CT imaging of amyloid-laden mice revealed accumulation of both [125I]aqap5 and [125I]AQAp5 in amyloid-affected organs; whereas, in healthy mice, [125I]aqap5 was observed in the kidneys and liver at early time points, and free radioiodide liberated during catabolism of [125I]AQAp5 was seen in the stomach and thyroid. Autoradiography confirmed that both [125I]aqap5 and [125I]AQAp5 peptides specifically bound amyloid with no off-target binding to healthy organs. CONCLUSION: Incorporation of D-amino acids in amyloid-binding regions of amyloidophilic peptides resulted in off-target binding; however, N-terminus placement retained amyloid-specificity and evasion of deiodinases. Peptide aqap5, or similar reagents, may prove useful in novel immunotherapy strategies as well as for imaging renal, gastric and pancreatic amyloidosis. PMID- 29228956 TI - Analysis of bearing wear, whole blood and synovial fluid metal ion concentrations and histopathological findings in patients with failed ASR hip resurfacings. AB - BACKGROUND: Adverse Reaction to Metal Debris (ARMD) is still a major reason for revision surgeries in patients with metal-on-metal (MoM) hip replacements. ARMD consists of a wide range of alterations in periprosthetic tissues, most important of which are metallosis, inflammation, pseudotumors and necrosis. Studies investigating histopathological findings and their association to implant wear or indirect measures of wear have yielded inconsistent results. Therefore, we aimed to investigate bearing surface wear volume, whole blood and synovial fluid metal ion concentrations, histopathological findings in periprosthetic tissues and their associations. METHODS: Seventy-eight patients with 85 hips revised for ARMD were included in the study. Prior to revision surgery, all patients had whole blood chromium and cobalt ion levels assessed. In revision surgery, a synovial fluid sample was taken and analyzed for chromium and cobalt. Periprosthetic tissue samples were taken and analyzed for histopathological findings. Explanted implants were analyzed for bearing wear volume of both acetabular cup and femoral head components. RESULTS: Volumetric wear of the failed components was highly variable. The total wear volume of the head and cup had a strong correlation with whole blood chromium and cobalt ion concentrations (Cr: rho = 0.80, p < 0.001 and Co: rho = 0.84, p < 0.001) and a bit weaker correlation with fluid chromium and cobalt ion concentrations (Cr: rho = 0.50, p < 0.01 and Co: rho = 0.41, p = 0.027). Most tissues displayed only low-to-moderate amounts of macrophages and lymphocytes. Total wear volume correlated with macrophage sheet thickness (rho = 0.25, p = 0.020) and necrosis (rho = 0.35, p < 0.01). Whole blood chromium and cobalt ion concentrations had similar correlations. Lymphocyte cuff thickness did not correlate with either total wear volume or whole blood metal ion concentrations, but correlated with the grade of necrosis. CONCLUSIONS: Bearing wear volume correlated with blood metal ion levels and the degree of necrosis and macrophage infiltration in periprosthetic tissues suggesting a dose-response relationship. Whole blood metal ion levels are a useful tool for clinician to estimate bearing wear and subsequent tissue response. PMID- 29228958 TI - Sero-prevalence, risk factors and distribution of sheep and goat pox in Amhara Region, Ethiopia. AB - BACKGROUND: Sheep pox and goat pox are contagious viral diseases of sheep and goats, respectively. The diseases result in substantial economic losses due to decreased milk and meat production, damage to hides and wool, and possible trade restriction. A study was undertaken in Amhara region of Ethiopia. A cross sectional study design was used to estimate the sero-prevalence and identify associated risk factors, while retrospective study design was used to assess the temporal and spatial distribution of the disease. A total of 672 serum samples were collected from 30 Kebeles and tested using virus neutralization test. RESULTS: From a total of 672 sera tested, 104 (15.5%) were positive for sheep and goat pox virus antibody; from which 56 (17%) were sheep and 48 (14%) were goats. The diseases were prevalent in all study zones, the highest sero-prevalence was observed in South Gondar (20.9%) and the lowest in North Gondar and West Gojjam zones (11.9% each). From the potential risk factors considered (species, sex, age, agro-ecology and location); only sex and age were significantly associated (p < 0.05) with the diseases in multivariable logistic regression. Female and young animals were at higher risk than their counterparts. From January 2010 to December 2014, a total of 366 outbreaks, 12,822 cases and 1480 deaths due to SP and 182 outbreaks, 10,066 cases and 997 deaths due to GP were recorded in Amhara National Regional State. CONCLUSION: Both the serological and the outbreak data revealed that sheep and goat pox is one of the most prevalent and widespread diseases of sheep and goats in the study area. Hence, annual mass vaccination program must be implemented for economic and viable control of sheep and goat pox diseases in the Amhara region in particular and at a national level in general. PMID- 29228959 TI - Micro-structural bone changes in early rheumatoid arthritis persist over 1-year despite use of disease modifying anti-rheumatic drug therapy. AB - BACKGROUND: We used High Resolution - peripheral Quantitative CT (HR-pQCT) imaging to examine peri-articular bone quality in early rheumatoid arthritis (RA) and explore whether bone quality improved over 12-months in individuals receiving care consistent with practice guidelines. METHODS: A 1-year longitudinal cohort study (Baseline and 12-months) evaluating individuals with early RA compared to age/sex-matched peers. Personal demographic and health and lifestyle information were collected for all. Whereas, active joint count (AJC28), functional limitation, and RA medications were also collected for RA participants. HR-pQCT imaging analyses quantified bone density and microstructure in the Metacarpal Head (MH) and Ultra-Ultra-Distal (UUD) radius at baseline and 12-months. Analyses included a General Linear Modelling repeated measures analyses examined main effects for disease, time, and interaction on bone quality. RESULTS: Participants (n = 60, 30 RA/30 NRA); 80% female, mean age 53 (varying from 21 to 74 years). At baseline, RA participants were on average 7.7 months since diagnosis, presenting with few active joints (AJC28: 30% none, remaining 70% Median 4 active joints) and minimal self-reported functional limitation (mHAQ-DI0-3: 0.56). At baseline, 29 of 30 RA participants had received one or more non-biologic disease-modifying anti-rheumatic drugs (DMARD);13 in combination with glucocorticoid and 1 in combination with a biologic medication. One participant only received glucocorticoid medication. Four RA participants withdrew leaving 26 pairs (n = 52) at 12-months; 23 pairs (n = 46) with UUD and 22 pairs (n = 44) with MH baseline and 12-month images to compare. Notable RA/NRA differences (p < 0.05) in bone quality at all three sites included lower trabecular bone density and volume, more rod-like trabeculae, and larger and more variable spaces between trabeculae; fewer trabeculae at the UUD and MH2 sites; and lower cortical bone density and volume in the MH sites. Rate of change over 12-months did not differ between RA/NRA participants which meant there was also no improvement over the year in RA bone quality. CONCLUSIONS: Early changes in peri-articular bone density and microstructure seen in RA are consistent with changes more commonly seen in aging bone and are slow or resistant to recover despite well controlled inflammatory joint symptoms with early DMARD therapy. PMID- 29228960 TI - Cross-sectional survey on the use and impact of the Danish national antibiotic use guidelines for companion animal practice. AB - BACKGROUND: The Danish antibiotic use guidelines for companion animal practice were published by the Danish Veterinary Association in 2012. Since then, national surveillance data indicate a 10% reduction in the total use of antibiotics for companion animals, particularly a marked reduction in the use of third generation cephalosporins. The aim of the study was to assess if and how the guidelines have impacted diagnostic and antibiotic prescription habits of the users, and to identify user perceived barriers to implementation. RESULTS: An online questionnaire was sent to all 882 members of the Danish Small Animal Veterinary Association in October 2015. The survey was completed by 151 veterinarians. Respondents most frequently consulted the recommendations on skin and urinary tract infections (UTI), and users generally reported a high degree of adherence to the recommendations. Sixty-five per cent indicated that the guidelines had influenced their habits in one or more of the areas being investigated, i.e. perioperative use of antibiotics, use of first line antibiotics for the treatment of pyoderma or UTI, and/or use of microbiological diagnostics. Perioperative use of antibiotics for clean surgeries was uncommon, irrespective of whether respondents had consulted the relevant recommendations or not. On the contrary, significant differences in the prescribing habits between guideline users and non users were observed for pyoderma and UTI, suggesting an impact of the guidelines towards more prudent antimicrobial use. The diagnostic habits were examined in a subgroup of 63 guideline users. Of those, 19 and 39% reported frequent use of culture and susceptibility (C&S) testing prior to treating pyoderma and UTI respectively, whereas 68-84% reported C&S testing in the event of poor response to treatment or recurrence of infections. The main barriers for implementation of therapeutic recommendations were confidence in old prescribing practices and unavailability of recommended drugs. The main barriers for C&S testing were good experience with empiric treatment, and the owners' financial situation. CONCLUSIONS: The findings suggest a positive influence of the national antibiotic guidelines on prescription patterns among companion animal practitioners in Denmark. Sustained campaign activity is encouraged and should include promotion of bacteriological testing. PMID- 29228961 TI - Does the edge effect impact on the measure of spatial accessibility to healthcare providers? AB - BACKGROUND: Spatial accessibility indices are increasingly applied when investigating inequalities in health. Although most studies are making mentions of potential errors caused by the edge effect, many acknowledge having neglected to consider this concern by establishing spatial analyses within a finite region, settling for hypothesizing that accessibility to facilities will be under reported. Our study seeks to assess the effect of edge on the accuracy of defining healthcare provider access by comparing healthcare provider accessibility accounting or not for the edge effect, in a real-world application. METHODS: This study was carried out in the department of Nord, France. The statistical unit we use is the French census block known as 'IRIS' (Ilot Regroupe pour l'Information Statistique), defined by the National Institute of Statistics and Economic Studies. The geographical accessibility indicator used is the "Index of Spatial Accessibility" (ISA), based on the E2SFCA algorithm. We calculated ISA for the pregnant women population by selecting three types of healthcare providers: general practitioners, gynecologists and midwives. We compared ISA variation when accounting or not edge effect in urban and rural zones. The GIS method was then employed to determine global and local autocorrelation. Lastly, we compared the relationship between socioeconomic distress index and ISA, when accounting or not for the edge effect, to fully evaluate its impact. RESULTS: The results revealed that on average ISA when offer and demand beyond the boundary were included is slightly below ISA when not accounting for the edge effect, and we found that the IRIS value was more likely to deteriorate than improve. Moreover, edge effect impact can vary widely by health provider type. There is greater variability within the rural IRIS group than within the urban IRIS group. We found a positive correlation between socioeconomic distress variables and composite ISA. Spatial analysis results (such as Moran's spatial autocorrelation index and local indicators of spatial autocorrelation) are not really impacted. CONCLUSION: Our research has revealed minor accessibility variation when edge effect has been considered in a French context. No general statement can be set up because intensity of impact varies according to healthcare provider type, territorial organization and methodology used to measure the accessibility to healthcare. Additional researches are required in order to distinguish what findings are specific to a territory and others common to different countries. It constitute a promising direction to determine more precisely healthcare shortage areas and then to fight against social health inequalities. PMID- 29228962 TI - Decision-making on therapeutic futility in Mexican adolescents with cancer: a qualitative study. AB - BACKGROUND: The world literature shows that empirical research regarding the process of decision-making when cancer in adolescents is no longer curable has been conducted in High-income, English speaking countries. The objective of the current study was to explore in-depth and to explain the decision-making process from the perspective of Mexican oncologists, parents, and affected adolescents and to identify the ethical principles that guide such decision-making. METHODS: Purposive, qualitative design based on individual, fact-to-face, semi-structured, in-depth interviews. The participants were thirteen paediatric oncologists, 13 parents or primary carers, and six adolescents with incurable cancer. The participants were recruited from the paediatric oncology services of three national tertiary-care medical centres in Mexico City. RESULTS: The oncologists stated that they broach the subject of palliative management when they have determined that curative treatment has failed. Respect for autonomy was understood as the assent of the parent/adolescent to what the oncologist determined to be in the best interest of the adolescent. The oncologists thought that the adolescent should be involved in the decision-making. They also identified the ability to count on a palliative care clinic or service as an urgent need. For the parents, it was essential that the oncologist be truly interested in their adolescent child. The parents did not consider it necessary to inform the child about impending death. The adolescents stated that the honesty of their oncologists was important; however, several of them opted for a passive role in the decision-making process. CONCLUSION: The findings of this study evidence that to achieve good medical practice in low-middle income countries, like Mexico, it is urgent to begin effective implementation of palliative care, together with appropriate training and continuing education in the ethics of clinical practice. PMID- 29228963 TI - The influence of frequently consumed beverages and snacks on dental erosion among preschool children in Saudi Arabia. AB - BACKGROUND: To determine the prevalence of dental erosion and its association to commonly used beverages and snacks among 3 to 5 year old preschool children in Riyadh, Saudi Arabia. METHODS: Three hundred eighty-eight preschool children between 3 and 5 years old were selected from 10 different schools using a cluster random sample selection; there were 184 (47%) boys and 204 (53%) girls. The surfaces of each tooth were examined for erosion, and the level of tooth wear was recorded. Data on the frequently used beverages and snacks were obtained by questionnaires completed by the parents of the preschool children. RESULTS: Among the 388 children examined, 47% exhibited low erosion, 10% exhibited moderate erosion and 4% exhibited severe erosion. There was no statistically significant difference between boys and girls in terms of the prevalence of erosion. Sixty percent of the children regularly consumed juice drinks. Among daily consumers, 84% of children showed erosion prevalence with strongly significant association (p < 0.005). Holding the drink in the mouth also showed a significant association with erosion (p < 0.02). CONCLUSION: It was concluded that an association was found between the prevalence of dental erosion and the frequency of citrus and carbonated juice consumed by the preschool children in Saudi Arabia. PMID- 29228964 TI - Effects of a multi-strain probiotic supplement for 12 weeks in circulating endotoxin levels and cardiometabolic profiles of medication naive T2DM patients: a randomized clinical trial. AB - BACKGROUND: The present randomized clinical trial characterized the beneficial effects of a multi-strain probiotics supplementation on improving circulating endotoxin levels (primary endpoint) and other cardiometabolic biomarkers (secondary endpoint) in patients with T2DM. METHODS: A total of 78 adult Saudi T2DM patients (naive and without co-morbidities) participated in this clinical trial and were randomized to receive twice daily placebo or probiotics [(2.5 * 109 cfu/g) containing the following bacterial strains: Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, Lactococcus lactis W19 and Lactococcus lactis W58 (Ecologic(r)Barrier)] in a double-blind manner for 12 weeks. Anthropometrics and cardiometabolic profiles were obtained at baseline and after 12/13 weeks of treatment. RESULTS: After 12/13 weeks of intervention and using intention-to-treat analysis, no difference was noted in endotoxin levels between groups [Placebo - 9.5% vs. Probiotics - 52.2%; (CI - 0.05 to 0.36; p = 0.15)]. Compared with the placebo group however, participants in the probiotics groups had a significant but modest improvement in WHR [Placebo 0.0% vs. Probiotics 1.11%; (CI - 0.12 to - 0.01; p = 0.02)] as well as a clinically significant improvement in HOMA-IR [Placebo - 12.2% vs. Probiotics - 60.4%; (CI - 0.34 to - 0.01; p = 0.04)]. CONCLUSION: Using a multi-strain probiotic supplement daily for 12/13 weeks significantly improved HOMA-IR and modestly reduced abdominal adiposity among medication naive T2DM patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01765517 , Registered January 10, 2013. PMID- 29228965 TI - Genetic polymorphism in ATG16L1 gene is associated with adalimumab use in inflammatory bowel disease. AB - BACKGROUND: The role of single nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease (IBD) is gaining interest. With the advent of novel therapies, personalized treatment in IBD is a future goal. We wondered whether IBD-associated SNPs are able to predict response to anti-TNFalpha treatment. METHODS: Data on treatment use and primary response, loss of response and side effects to anti-TNFalpha treatments were retrieved for 570 IBD patients. rs13361189 (IRGM), rs10210302 (ATG16L1), rs2066844, rs2066845, rs2066847 (NOD2), rs35873774 (XBP1), rs11175593 (LRRK2), rs11465804 (IL23R), rs2301436 (CCR6), rs744166 (STAT3) and rs4821544 (NCF4) SNP status were determined. RESULTS: No associations were found between genetic variants of the LRRK2, CCR6, IL23R and NCF4 genes and response to anti-TNFalpha. For NOD2 and XBP1 associations were found, however, these associations were not strong enough to survive multiple testing corrections. Strikingly, patients carrying the ATG16L1 T300A variant were more likely to be treated with adalimumab, even after correction for disease phenotype, disease behavior and age (p = 0.004, OR 2.8, CI 1.6-5.0). CONCLUSIONS: Genetic polymorphisms in the known IBD-associated gene ATG16L1 correlate with requirement of treatment, suggesting a different IBD disease phenotype in these patients. Further investigation will need to elucidate the implications of these findings and identify the underlying disease characteristics. PMID- 29228966 TI - Estimating the prevalence of infectious diseases from under-reported age dependent compulsorily notification databases. AB - BACKGROUND: National or local laws, norms or regulations (sometimes and in some countries) require medical providers to report notifiable diseases to public health authorities. Reporting, however, is almost always incomplete. This is due to a variety of reasons, ranging from not recognizing the diseased to failures in the technical or administrative steps leading to the final official register in the disease notification system. The reported fraction varies from 9 to 99% and is strongly associated with the disease being reported. METHODS: In this paper we propose a method to approximately estimate the full prevalence (and any other variable or parameter related to transmission intensity) of infectious diseases. The model assumes incomplete notification of incidence and allows the estimation of the non-notified number of infections and it is illustrated by the case of hepatitis C in Brazil. The method has the advantage that it can be corrected iteratively by comparing its findings with empirical results. RESULTS: The application of the model for the case of hepatitis C in Brazil resulted in a prevalence of notified cases that varied between 163,902 and 169,382 cases; a prevalence of non-notified cases that varied between 1,433,638 and 1,446,771; and a total prevalence of infections that varied between 1,597,540 and 1,616,153 cases. CONCLUSIONS: We conclude that the model proposed can be useful for estimation of the actual magnitude of endemic states of infectious diseases, particularly for those where the number of notified cases is only the tip of the iceberg. In addition, the method can be applied to other situations, such as the well-known underreported incidence of criminality (for example rape), among others. PMID- 29228967 TI - "Best practices in risk reducing bilateral salpingo-oophorectomy: the influence of surgical specialty". AB - BACKGROUND: Risk-reducing bilateral salpingo-oophorectomy (RRBSO) increases survival in patients at high risk of developing ovarian cancer. While many general gynecologists perform this procedure, some argue it should be performed exclusively by specialists. In this retrospective observational study, we identified how often optimal techniques were used and whether surgeons' training impacted implementation. METHODS: We used the ACOG guidelines highlighting various aspects of the procedure to determine which elements were consistent with best practices to maximize surgical prophylaxis. All cases of RRBSO from 2006 to 2010 were identified. We abstracted data from the operative and pathology reports to review the techniques employed. Fisher's exact test and chi-square were utilized to compare differences between groups (InStat, La Jolla, CA). RESULTS: Among 263 RRBSOs, 22 were performed by general gynecologists and 241 by gynecologic oncologists. Gynecologic oncologists were more likely to perform pelvic washings-217/241 vs. 10/22 (p < .0001). They were more likely to include a description of the upper abdomen-220/241 vs. 12/22 (p < .0001). Oncologists were more likely to utilize a retroperitoneal approach to skeletonize the infundibulopelvic ligaments-157/241 vs. 3/22 (p < .0001). When operations were performed by oncologists, the specimens were more often completely sectioned 217/241 vs. 16/22 (p = .003). The use of a retroperitoneal approach among gynecologic oncologists increased over the study period (chi-square for trend, p < .0001). There was no visible trend in performance improvement in any other area when looking at either group. CONCLUSION: Gynecologic oncologists are more likely to adhere to best practice techniques when performing RRBSO, though there was room for improvement for both groups. PMID- 29228968 TI - Feces and liver tissue metabonomics studies on the regulatory effect of aspirin eugenol eater in hyperlipidemic rats. AB - BACKGROUND: Based on the pro-drug principle, aspirin and eugenol were esterified to synthesize aspirin eugenol ester (AEE). The anti-hyperlipidemia effect of aspirin eugenol ester has been confirmed in hyperlipidemic rat induced by high fat diet (HFD). However, its effect on liver and feces metabonomic profiles remains unknown. METHODS: Suspension of AEE was prepared in 5% carboxymethyl cellulose sodium (CMC-Na). Thirty rats were divided into control, model and AEE groups. The control and model rats were fed with normal diet or HFD for 13 weeks, respectively. Rats in AEE-treated group were fed with HFD for 8 weeks to induce hyperlipidemia, and then given AEE once daily by oral gavage for 5 weeks at the dosage of 54 mg/kg body weight. After drug intervention, lipid profile analysis and oil red O staining were carried out to confirm the lipid accumulation in liver tissue. UPLC-Q-TOF/MS-based liver and feces metabonomics coupled with pathway analysis were conducted to evaluate the changes of metabolic profile and endogenous metabolites. RESULTS: In liver tissue, oral administration of AEE significantly reduced lipid droplets and the levels of triglyceride (TG) and low density lipoprotein (LDL). Using principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA), distinct changes in metabolite patterns in feces and liver were observed. Liver and feces samples in control, model and AEE groups were scattered in PLS-DA score plots. 28 metabolites in liver and 22 in feces were identified as potential biomarkers related to hyperlipidemia. As possible drug targets, the perturbations of those biomarkers can be regulated by administration of AEE. CONCLUSION: Anti-hyperlipidemia effect of AEE was confirmed by lipid analysis, oil red O staining and metabolomics analysis. The mechanism of AEE might be associated with the changes in the metabolism of glycerophospholipid, amino acid, fatty acid, sphingolipid, purine, bile acid and glutathione. PMID- 29228969 TI - Race-associated biological differences among luminal A and basal-like breast cancers in the Carolina Breast Cancer Study. AB - BACKGROUND: We examined racial differences in the expression of eight genes and their associations with risk of recurrence among 478 white and 495 black women who participated in the Carolina Breast Cancer Study Phase 3. METHODS: Breast tumor samples were analyzed for PAM50 subtype and for eight genes previously found to be differentially expressed by race and associated with breast cancer survival: ACOX2, MUC1, FAM177A1, GSTT2, PSPH, PSPHL, SQLE, and TYMS. The expression of these genes according to race was assessed using linear regression and each gene was evaluated in association with recurrence using Cox regression. RESULTS: Compared to white women, black women had lower expression of MUC1, a suspected good prognosis gene, and higher expression of GSTT2, PSPHL, SQLE, and TYMS, suspected poor prognosis genes, after adjustment for age and PAM50 subtype. High expression (greater than median versus less than or equal to median) of FAM177A1 and PSPH was associated with a 63% increase (hazard ratio (HR) = 1.63, 95% confidence interval (CI) = 1.09-2.46) and 76% increase (HR = 1.76, 95% CI = 1.15-2.68), respectively, in risk of recurrence after adjustment for age, race, PAM50 subtype, and ROR-PT score. Log2-transformed SQLE expression was associated with a 20% increase (HR = 1.20, 95% CI = 1.03-1.41) in recurrence risk after adjustment. A continuous multi-gene score comprised of eight genes was also associated with increased risk of recurrence among all women (HR = 1.11, 95% CI = 1.04-1.19) and among white (HR = 1.14, 95% CI = 1.03-1.27) and black (HR = 1.11, 95% CI = 1.02-1.20) women. CONCLUSIONS: Racial differences in gene expression may contribute to the survival disparity observed between black and white women diagnosed with breast cancer. PMID- 29228970 TI - Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus. AB - BACKGROUND: Neuroinflammation has been implicated in the pathophysiology of post hemorrhagic hydrocephalus (PHH) of prematurity, but no comprehensive analysis of signaling molecules has been performed using human cerebrospinal fluid (CSF). METHODS: Lumbar CSF levels of key cytokines (IL-1alpha, IL-1beta, IL-4, IL-6, IL 8, IL-10, IL-12, TNF-alpha, TGF-beta1, IFN-gamma) and chemokines (XCL-1, CCL-2, CCL-3, CCL-19, CXCL-10, CXCL-11, CXCL-12) were measured using conventional and multiplexed Enzyme-linked Immunosorbent Assays and compared between preterm infants with PHH and those with no known neurological injury. The relationships between individual biomarker levels and specific CSF cell counts were examined. RESULTS: Total protein (TP) CSF levels were elevated in the PHH subjects compared to controls. CSF levels of IL-1alpha, IL-4, IL-6, IL-12, TNF-alpha, CCL-3, CCL 19, and CXCL-10 were significantly increased in PHH whereas XCL-1 was significantly decreased in PHH. When normalizing by TP, IL-1alpha, IL-1beta, IL 10, IL-12, CCL-3, and CCL-19 levels were significantly elevated compared to controls, while XCL-1 levels remained significantly decreased. Among those with significantly different levels in both absolute and normalized levels, only absolute CCL-19 levels showed a significant correlation with CSF nucleated cells, neutrophils, and lymphocytes. IL-1beta and CXCL-10 also were correlated with total cell count, nucleated cells, red blood cells, and neutrophils. CONCLUSIONS: Neuroinflammation is likely to be an important process in the pathophysiology of PHH. To our knowledge, this is the first study to investigate CSF levels of chemokines in PHH as well as the only one to show XCL-1 selectively decreased in a diseased state. Additionally, CCL-19 was the only analyte studied that showed significant differences between groups and had significant correlation with cell count analysis. The selectivity of CCL-19 and XCL-1 should be further investigated. Future studies will further delineate the role of these cytokines and chemokines in PHH. PMID- 29228971 TI - Alpha-synuclein oligomer-selective antibodies reduce intracellular accumulation and mitochondrial impairment in alpha-synuclein exposed astrocytes. AB - BACKGROUND: Due to its neurotoxic properties, oligomeric alpha-synuclein (alpha syn) has been suggested as an attractive target for passive immunization against Parkinson's disease (PD). In mouse models of PD, antibody treatment has been shown to lower the levels of pathogenic alpha-syn species, including oligomers, although the mechanisms of action remain unknown. We have previously shown that astrocytes rapidly engulf alpha-syn oligomers that are intracellularly stored, rather than degraded, resulting in impaired mitochondria. METHODS: The aim of the present study was to investigate if the accumulation of alpha-syn in astrocytes can be affected by alpha-syn oligomer-selective antibodies. Co-cultures of astrocytes, neurons, and oligodendrocytes were derived from embryonic mouse cortex and exposed to alpha-syn oligomers or oligomers pre-incubated with oligomer-selective antibodies. RESULTS: In the presence of antibodies, the astrocytes displayed an increased clearance of the exogenously added alpha-syn, and consequently, the alpha-syn accumulation in the culture was markedly reduced. Moreover, the addition of antibodies rescued the astrocytes from the oligomer induced mitochondrial impairment. CONCLUSIONS: Our results demonstrate that oligomer-selective antibodies can prevent alpha-syn accumulation and mitochondrial dysfunction in cultured astrocytes. PMID- 29228973 TI - Cohort profile: the Saskatchewan Rural Health Study-adult component. AB - OBJECTIVES: Less is known about the respiratory health of general farming and non framing populations. A longitudinal Saskatchewan Rural Health Study (SRHS) was conducted to explore the association between individual and contextual factors with respiratory health outcomes in these populations. Hence, the objectives are to: (i) describe the updated methodology of longitudinal SRHS-an extension of baseline survey methodology published earlier; (ii) compare baseline characteristics and the prevalences of respiratory health outcomes between drops outs and completers; and (iii) summarize key findings based on baseline survey data. RESULTS: The SRHS was a prospective cohort study conducted in two phases: baseline survey in 2010 and a follow-up in 2014. Each survey consisted of two components, self-administered questionnaire and clinical assessments. At baseline, 8261 participants (>= 18 years) (4624 households) and at follow-up, 4867 participants (2797 households) completed the questionnaires. Clinical assessments on lung functions and/or allergies were conducted among a sub-group of participants from both the surveys. To date, we published 15 peer-reviewed manuscripts and 40 abstracts in conference proceedings. Findings from the study will improve the knowledge of respiratory disease etiology and assist in the development and targeting of prevention programs for rural populations in Saskatchewan, Canada. PMID- 29228974 TI - Central nervous system transcriptome of Biomphalaria alexandrina, an intermediate host for schistosomiasis. AB - OBJECTIVE: Globally, more than 200 million people live at risk of the neglected tropical disease schistosomiasis (or snail fever). Larval schistosomes require the presence of specific snail species that act as intermediate hosts, supporting their multiplication and transformation into forms that can infect humans. This project was designed to generate a transcriptome from the central nervous system (CNS) of Biomphalaria alexandrina, the major intermediate host for Schistosoma mansoni in Egypt. RESULTS: A transcriptome was generated from five pooled central nervous systems dissected from uninfected specimens of B. alexandrina. Raw Illumina RNA-seq data (~ 20.3 million paired end reads of 150 base pairs length each) generated a transcriptome consisting of 144,213 transcript elements with an N50 contig size of 716 base pairs. Orthologs of 15,246 transcripts and homologs for an additional 16,810 transcripts were identified in the UniProtKB/Swiss-Prot database. The B. alexandrina CNS transcriptome provides a resource for future research exploring parasite-host interactions in a simpler nervous system. Moreover, increased understanding of the neural signaling mechanisms involved in the response of B. alexandrina to infection by S. mansoni larvae could lead to novel and highly specific strategies for the control of snail populations. PMID- 29228972 TI - Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth. AB - BACKGROUND: Identification of factors that influence the neonatal gut microbiome is urgently needed to guide clinical practices that support growth of healthy preterm infants. Here, we examined the influence of nutrition and common practices on the gut microbiota and growth in a cohort of preterm infants. RESULTS: With weekly gut microbiota samples spanning postmenstrual age (PMA) 24 to 46 weeks, we developed two models to test associations between the microbiota, nutrition and growth: a categorical model with three successive microbiota phases (P1, P2, and P3) and a model with two periods (early and late PMA) defined by microbiota composition and PMA, respectively. The more significant associations with phase led us to use a phase-based framework for the majority of our analyses. Phase transitions were characterized by rapid shifts in the microbiota, with transition out of P1 occurring nearly simultaneously with the change from meconium to normal stool. The rate of phase progression was positively associated with gestational age at birth, and delayed transition to a P3 microbiota was associated with growth failure. We found distinct bacterial metabolic functions in P1-3 and significant associations between nutrition, microbiota phase, and infant growth. CONCLUSION: The phase-dependent impact of nutrition on infant growth along with phase-specific metabolic functions suggests a pioneering potential for improving growth outcomes by tailoring nutrient intake to microbiota phase. PMID- 29228975 TI - Prediabetes and cardiovascular complications study (PACCS): international collaboration 4 years' summary and future direction. AB - OBJECTIVE: The prediabetes and cardiovascular complications studies proposes to develop a screening protocol for diabetes cardiovascular risk, and strategies for holistic management amongst others. Over 500 participants were recruited in the first 2 years of rural community research screening. Specific for this report, various published findings were reviewed. The objective is to summarize research outcomes and itemize limitations as they constitute basis of future directions. RESULTS: Affordability and availability are major confounding behavioural change wheel factors in the rural community. 4.9% prevalence of prediabetes, which may be lower or non-significantly different in urban areas. Hyperglycaemia co morbidity with dyslipidaemia (5.0%), obesity (3.1%) and hypertension (1.8%) were observed. Limitation of the study includes participants being mostly over 60 years old, which has created impetus for the Global Alliance on Chronic Diseases agenda on vulnerability of older adults to diabetes being a new direction of the collaboration. Other directions in Australia and Nepal focus on patients with chronic kidney disease with or without cardiovascular complications. This report highlights the need to translational research. PMID- 29228976 TI - Support for research towards understanding the population health vulnerabilities to vector-borne diseases: increasing resilience under climate change conditions in Africa. AB - BACKGROUND: Diseases transmitted to humans by vectors account for 17% of all infectious diseases and remain significant public health problems. Through the years, great strides have been taken towards combatting vector-borne diseases (VBDs), most notably through large scale and coordinated control programmes, which have contributed to the decline of the global mortality attributed to VBDs. However, with environmental changes, including climate change, the impact on VBDs is anticipated to be significant, in terms of VBD-related hazards, vulnerabilities and exposure. While there is growing awareness on the vulnerability of the African continent to VBDs in the context of climate change, there is still a paucity of research being undertaken in this area, and impeding the formulation of evidence-based health policy change. MAIN BODY: One way in which the gap in knowledge and evidence can be filled is for donor institutions to support research in this area. The collaboration between the WHO Special Programme for Research and Training in Tropical Diseases (TDR) and the International Centre for Research and Development (IDRC) builds on more than 10 years of partnership in research capacity-building in the field of tropical diseases. From this partnership was born yet another research initiative on VBDs and the impact of climate change in the Sahel and sub-Saharan Africa. This paper lists the projects supported under this research initiative and provides a brief on some of the policy and good practice recommendations emerging from the ongoing implementation of the research projects. CONCLUSION: Data generated from the research initiative are expected to be uptaken by stakeholders (including communities, policy makers, public health practitioners and other relevant partners) to contribute to a better understanding of the impacts of social, environmental and climate change on VBDs(i.e. the nature of the hazard, vulnerabilities, exposure), and improve the ability of African countries to adapt to and reduce the effects of these changes in ways that benefit their most vulnerable populations. PMID- 29228977 TI - A systematic review of the application of Wilson and Cleary health-related quality of life model in chronic diseases. AB - BACKGROUND: A conceptual model approach to clarify the elements of health-related quality of life (HRQL), their determinants and causal pathways is needed to aid researchers, health practitioners and policy makers in their bid to improve HRQL outcomes in patients. The aim of this systematic review was to appraise empirical evidence on the performance of the Wilson and Cleary Model of HRQL. METHODS: We conducted a search of MEDLINE, Science Direct, PsyARTICLES and CINAHL databases to identify articles that used Wilson and Cleary model to examine HRQL in chronic diseases. A narrative synthesis was employed in the review of the articles. RESULTS: Evidence supports linkages between adjacent concepts and between non adjacent concepts of the Wilson and Cleary model indicating that in practice there is a need to examine relationships among constructs - or to consider interventions in terms of - both with and without mediators. Symptoms status has the highest magnitude of relative impact on health-related quality of life. CONCLUSION: The Wilson and Cleary model demonstrated good features suitable for evaluating health-related quality of life in chronic diseases. PMID- 29228978 TI - Asiatic acid attenuates methamphetamine-induced neuroinflammation and neurotoxicity through blocking of NF-kB/STAT3/ERK and mitochondria-mediated apoptosis pathway. AB - BACKGROUND: Methamphetamine (METH) is a commonly abused drug that may result in neurotoxic effects. Recent studies have suggested that involvement of neuroinflammatory processes in brain dysfunction is induced by misuse of this drug. However, the mechanism underlying METH-induced inflammation and neurotoxicity in neurons is still unclear. In this study, we investigated whether asiatic acid (AA) effected METH-mediated neuroinflammation and neurotoxicity in dopaminergic neuronal cells. And we further determined whether the effect involved in the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK) pathway. METHODS: We used the human dopaminergic neuroblastoma SH-SY5Y cell line, murine microglial BV2 cell line, and primary culture of rat embryo mesencephalic neurons. Pro-inflammatory cytokine production was monitored by ELISA and RT/real-time PCR. The cell cycle distribution and mitochondrial membrane integrity was analyzed by flow cytometry. We used immunoblotting, DNA-binding activity, and immunofluorescence staining to analyze the effect of AA on activation of the NF-kappaB, STAT3, MAPK-ERK, and apoptosis signaling pathways. RESULTS: METH induced TNF receptor (TNFR) expression and led to morphological changes of cells. Additionally, this drug increased pro-inflammatory cytokine (TNFalpha and IL-6) expression. AA significantly suppressed METH-induced TNFR expression in concentration dependent. Increased secretion of TNFalpha and IL-6 was inhibited in METH-stimulated neuronal cells by AA administration. AA showed significant protection against METH-induced translocation of NF-kappaB/STAT3 and ERK phosphorylation. AA inhibited METH-induced proteolytic fragmentation of caspase-3 and PARP. The pro apoptotic protein Bax was significantly decreased, while the anti-apoptotic protein Bcl-xL was increased by AA treatment in METH-stimulated cells. A similar protective effect of AA on mitochondrial membrane integrity was also confirmed by flow cytometry and immunofluorescence staining. CONCLUSIONS: Based on the literatures and our findings, AA is a promising candidate for an anti-neurotoxic agent, and it can potentially be used for the prevention and treatment of various neurological disorders. PMID- 29228979 TI - Contrasting effect of the latency-reversing agents bryostatin-1 and JQ1 on astrocyte-mediated neuroinflammation and brain neutrophil invasion. AB - BACKGROUND: Despite effectiveness of the combined antiretroviral therapy, HIV-1 persists in long-lived latently infected cells. Consequently, new therapeutic approaches aimed at eliminating this latent reservoir are currently being developed. A "shock and kill" strategy using latency-reversing agents (LRA) to reactivate HIV-1 has been proposed. However, the impact of LRA on the central nervous system (CNS) remains elusive. METHODS: We used human fetal astrocytes and investigated the effects of several LRA on their functional and secretory activities. Astrocytes were infected with VSV-G-pseudotyped HIV-1 before treatment with various blood-brain barrier (BBB)-permeable LRA at subcytotoxic doses, which allow HIV-1 reactivation based on previous in vitro and clinical studies. Cells and supernatants were then used to evaluate effects of infection and LRA on (i) viability and metabolic activity of astrocytes using a colorimetric MTS assay; (ii) chemokines and proinflammatory cytokines secretion and gene expression by astrocytes using ELISA and RT-qPCR, respectively; (iii) expression of complement component 3 (C3), a proxy for astrogliosis, by RT-qPCR; (iv) glutamate uptake capacity by a fluorometric assay; and (v) modulation of neutrophil transmigration across an in vitro BBB model. RESULTS: We demonstrate that bryostatin-1 induces secretion of chemokines CCL2 and IL-8 and proinflammatory cytokines IL-6 and GM-CSF, whereas their production is repressed by JQ1. Bryostatin-1 also increases expression of complement component 3 and perturbs astrocyte glutamate homeostasis. Lastly, bryostatin-1 enhances transmigration of neutrophils across an in vitro blood-brain barrier model and induces formation of neutrophil extracellular traps. CONCLUSIONS: These observations highlight the need to carefully assess the potential harmful effect to the CNS when selecting LRA for HIV-1 reactivation strategies. PMID- 29228980 TI - Lipoxin A4 reverses mesenchymal phenotypes to attenuate invasion and metastasis via the inhibition of autocrine TGF-beta1 signaling in pancreatic cancer. AB - BACKGROUND: Pancreatic cancer is a lethal disease in part because of its potential for aggressive invasion and metastasis. Lipoxin A4 (LXA4) is one of the metabolites that is derived from arachidonic acid and that is catalyzed by 15 lipoxygenase (15-LOX), and it has recently been reported to exhibit anti-cancer effects. However, the role of LXA4 in pancreatic cancer remains to be elucidated. METHODS: Pancreatic cell lines were treated with vehicle or LXA4, and the invasive capacity was then assessed by Transwell assays. The expression of epithelial and mesenchymal markers was determined by western blotting and immunofluorescence. Anti-TGF-beta1 neutralizing antibody and exogenous recombinant human TGF-beta1 (rhTGF-beta1) were used to study the effect of LXA4 on the TGF-beta signaling. A liver metastasis model was applied to investigate the effect of LXA4 in vivo. The correlation between the Lipoxin effect score (LES) and the clinical-pathological features of pancreatic cancer was also analyzed. RESULTS: We found that in patients with pancreatic cancer, low LES was correlated with aggressive metastatic potential. The LXA4 activity, which was mediated by the LXA4 receptor FPRL1, could significantly suppress invasion capacity and mesenchymal phenotypes. The expression and autocrine signaling pathway activity of TGF-beta1 were also downregulated by LXA4. In the liver metastasis model in nude mice, the stable analog of LXA4, BML-111, could inhibit the metastasis of pancreatic cancer cells. CONCLUSION: Our results demonstrated that LXA4 could reverse mesenchymal phenotypes, which attenuated invasion and metastasis via the inhibition of autocrine TGF-beta1 signaling in pancreatic cancer, which may provide a new strategy to prevent the metastasis of pancreatic cancer. PMID- 29228981 TI - Composite neuroendocrine tumor and adenocarcinoma of the rectum. AB - BACKGROUND: Although adenocarcinomas showing neuroendocrine differentiation or those mixed with high-grade neuroendocrine carcinoma (NEC) are sometimes encountered, composite tumors comprising neuroendocrine tumor (NET) Grade 1 and adenocarcinoma are exceedingly rare. CASE PRESENTATION: A 64-year-old male presented after testing positive for fecal occult blood at a medical check-up. A biopsy demonstrated the presence of a NET and endoscopic submucosal dissection was undertaken. Histologic examination revealed that a well differentiated tubular adenocarcinoma was present in addition to the NET. Furthermore, histological transition between the two tumors was evident. Accordingly, this case was considered to be a composite tumor comprising NET and adenocarcinoma. CONCLUSION: Composite tumors consisting of NET Grade 1 and adenocarcinoma are exceedingly rare, and only a few examples have been reported hitherto. PMID- 29228982 TI - Electroconvulsive therapy for manic state with mixed and psychotic features in a teenager with bipolar disorder and comorbid episodic obsessive-compulsive disorder: a case report. AB - BACKGROUND: Comorbidity of bipolar disorder and obsessive-compulsive disorder is common in adolescence. Obsessive-compulsive disorder symptoms may be episodic and secondary to alterations in mood, and display specific features. Management of pediatric bipolar disorder-obsessive-compulsive disorder is challenging, as pharmacotherapy of obsessive-compulsive disorder may induce or exacerbate manic episodes and there is limited evidence of treatment efficacy. Electroconvulsive therapy is sparsely used in children and adolescents, but is documented to be a safe and efficacious intervention in adults with bipolar disorder. In view of the severity of symptoms in juvenile mania, studies on treatment strategies are warranted. We report a case of an adolescent with bipolar disorder-obsessive compulsive disorder who was successfully treated with electroconvulsive therapy during an episode of severe mania. CASE PRESENTATION: A 16-year-old girl of Middle East origin first presented to us with depressed mood, irritability, and increased obsessive-compulsive disorder symptoms, which were initially interpreted in the context of acute stress secondary to migration. She had been diagnosed with bipolar disorder and obsessive-compulsive disorder in her previous home country, but had difficulties in accounting for earlier psychiatric history. During hospitalization her mood switched to a manic state with mixed and psychotic features, at times showing aggression toward others. Interruption in her lithium treatment for a short period and possibly the introduction of an atypical antipsychotic could in part have been triggering factors. After 8 weeks of in-patient care and psychotropic drug trials, electroconvulsive therapy was initiated and administered every second or third day for 4 weeks, with marked positive response. No apparent side effects were reported. CONCLUSIONS: This case demonstrates the need for a detailed medical history, taking special note of periodicity and character of obsessive-compulsive disorder symptoms, in adolescents with mood disorders. When treating culturally diverse patients, extra consideration should be taken. Special concerns in the pharmacological treatment to avoid the patient's condition from worsening must be addressed, including giving priority to mood stabilization before obsessive-compulsive disorder symptoms. There are potential benefits in considering electroconvulsive therapy in young patients with severe mania where first-line treatment options have failed. PMID- 29228984 TI - Note on the PCR threshold standard curve. AB - OBJECTIVE: The PCR threshold standard curve is based on an exponential model of the initial phase of a PCR run where template replication efficiency is constant cycle to cycle. As such it requires that a threshold is at a level of amplified template not higher than where replication efficiency falls from its initial value. A second requirement is that all amplification profiles, both calibration and test, have the same initial efficiency. However, whether these requirements are met may not be checked, and there seems an apparent awareness that thresholds can be set higher than where efficiency has dropped from the initial value without compromising result validity. The objective of this study is to reconcile using the method without satisfying the requirement that amplification is exponential at threshold level. RESULTS: Substituting the more general requirement that profile shapes be congruent to threshold level, except for translation along the cycle axis, and a derivation of the standard curve that includes cycles beyond the exponential phase accomplishes the objective without affecting usage of the method or any prior results and enables a practicable way to verify that the second requirement for same initial efficiency is satisfied. PMID- 29228983 TI - Characterization of interactions between hepatitis C virus NS5B polymerase, annexin A2 and RNA - effects on NS5B catalysis and allosteric inhibition. AB - BACKGROUND: Direct acting antivirals (DAAs) provide efficient hepatitis C virus (HCV) therapy and clearance for a majority of patients, but are not available or effective for all patients. They risk developing HCV-induced hepatocellular carcinoma (HCC), for which the mechanism remains obscure and therapy is missing. Annexin A2 (AnxA2) has been reported to co-precipitate with the non-structural (NS) HCV proteins NS5B and NS3/NS4A, indicating a role in HCC tumorigenesis and effect on DAA therapy. METHODS: Surface plasmon resonance biosensor technology was used to characterize direct interactions between AnxA2 and HCV NS5B, NS3/NS4 and RNA, and the subsequent effects on catalysis and inhibition. RESULTS: No direct interaction between AnxA2 and NS3/NS4A was detected, while AnxA2 formed a slowly dissociating, high affinity (K D = 30 nM), complex with NS5B, decreasing its catalytic activity and affinity for the allosteric inhibitor filibuvir. The RNA binding of the two proteins was independent and AnxA2 and NS5B interacted with different RNAs in ternary complexes of AnxA2:NS5B:RNA, indicating specific preferences. CONCLUSIONS: The complex interplay revealed between NS5B, AnxA2, RNA and filibuvir, suggests that AnxA2 may have an important role for the progression and treatment of HCV infections and the development of HCC, which should be considered also when designing new allosteric inhibitors. PMID- 29228985 TI - Investigating the burden of antibiotic resistance in ethnic minority groups in high-income countries: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Antibiotic resistance (ABR) is an urgent problem globally, with overuse and misuse of antibiotics being one of the main drivers of antibiotic resistant infections. There is increasing evidence that the burden of community acquired infections such as urinary tract infections and bloodstream infections (both susceptible and resistant) may differ by ethnicity, although the reasons behind this relationship are not well defined. It has been demonstrated that socioeconomic status and ethnicity are often highly correlated with each other; however, it is not yet known whether accounting for deprivation completely explains any discrepancy seen in infection risk. There have currently been no systematic reviews summarising the evidence for the relationship between ethnicity and antibiotic resistance or prescribing. METHODS: This protocol will outline how we will conduct this systematic literature review and meta-analysis investigating whether there is an association between patient ethnicity and (1) risk of antibiotic-resistant infections or (2) levels of antibiotic prescribing in high-income countries. We will search PubMed/MEDLINE, EMBASE, Global Health, Scopus and CINAHL using MESH terms where applicable. Two reviewers will conduct title/abstract screening, data extraction and quality assessment independently. The Critical Appraisal Skills Programme (CASP) checklist will be used for cohort and case-control studies, and the Cochrane collaboration's risk of bias tool will be used for randomised control trials, if they are included. Meta-analyses will be performed by calculating the minority ethnic group to majority ethnic group odds ratios or risk ratios for each study and presenting an overall pooled odds ratio for the two outcomes. The Grading of Recommendations, Assessments, Development and Evaluation (GRADE) approach will be used to assess the overall quality of the body of evidence. DISCUSSION: In this systematic review and meta analysis, we will aim to collate the available evidence of whether there is a difference in rates of AMR and/or antibiotic prescribing in minority vs. majority ethnic groups in high-income countries. Additionally, this review will highlight areas where more research needs to be conducted and may provide insight into what may cause differences in this relationship, should they be seen. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ( CRD42016051533 ). PMID- 29228987 TI - Patients' attitudes regarding characteristics of physicians in ophthalmology. AB - OBJECTIVE: This retrospective cross-sectional study was performed to assess patient perceptions and attitudes towards physicians' physical appearance and education in the Vitreoretinal Specialist clinic setting. 295 consecutive patients from Retina Consultants of Alabama, a Vitreoretinal Specialty practice at UAB Hospital, completed a questionnaire assessing preferences regarding physicians' appearance and education. The main outcome measure was to determine if physical attributes and education are factors in patient preference for their Vitreoretinal Specialist. RESULTS: There were no significant desirable or undesirable physical characteristics for a Vitreoretinal Specialist in a clinical setting. However, the data indicated trends in patient preferences for Vitreoretinal Specialist attire [209 (71%) of 295 patients prefer casual dress], physical appearance [212 (72%) and 240 (81%) of 295 patients had no preference with regards to long hair and facial hair], and medical education [171 (58%) of 298 patients preferred their Specialist to be involved in research and education]. Gender, race, and age were not significantly associated with patients' perceptions toward the Vitreoretinal Specialist's physical appearance and education. In conclusion, Vitreoretinal Specialist's clothing and physical attributes do not significantly influence patients' opinion of the care they receive, although patients prefer their Specialist to be involved in research and continuing education. PMID- 29228986 TI - Addressing vulnerability, building resilience: community-based adaptation to vector-borne diseases in the context of global change. AB - BACKGROUND: The threat of a rapidly changing planet - of coupled social, environmental and climatic change - pose new conceptual and practical challenges in responding to vector-borne diseases. These include non-linear and uncertain spatial-temporal change dynamics associated with climate, animals, land, water, food, settlement, conflict, ecology and human socio-cultural, economic and political-institutional systems. To date, research efforts have been dominated by disease modeling, which has provided limited practical advice to policymakers and practitioners in developing policies and programmes on the ground. MAIN BODY: In this paper, we provide an alternative biosocial perspective grounded in social science insights, drawing upon concepts of vulnerability, resilience, participation and community-based adaptation. Our analysis was informed by a realist review (provided in the Additional file 2) focused on seven major climate sensitive vector-borne diseases: malaria, schistosomiasis, dengue, leishmaniasis, sleeping sickness, chagas disease, and rift valley fever. Here, we situate our analysis of existing community-based interventions within the context of global change processes and the wider social science literature. We identify and discuss best practices and conceptual principles that should guide future community-based efforts to mitigate human vulnerability to vector-borne diseases. We argue that more focused attention and investments are needed in meaningful public participation, appropriate technologies, the strengthening of health systems, sustainable development, wider institutional changes and attention to the social determinants of health, including the drivers of co-infection. CONCLUSION: In order to respond effectively to uncertain future scenarios for vector-borne disease in a changing world, more attention needs to be given to building resilient and equitable systems in the present. PMID- 29228988 TI - A VP24-truncated isolate of white spot syndrome virus is inefficient in per os infection. AB - White spot syndrome virus (WSSV) is a major pathogen of penaeid shrimp. Here we identified a new WSSV strain, WSSV-CN04, from naturally infected Marsupenaeus japonicus. Whole genomic sequencing results indicate that the WSSV-CN04 genome was 281 054 bp in length, and encoded 157 hypothetic proteins. The genome sequence of WSSV-CN04 was most closely related to the low-virulent strain WSSV CN03, sharing 97.5% sequence identity. Notably, in WSSV-CN04, the major envelop protein VP24 was not only truncated but also absent in the virions. Since VP24 was previously reported to be essential for WSSV per os infection by mediating WSSV-chitin interaction, we further analyzed the peroral infection of WSSV-CN03 and -CN04 in Litopenaeus vannamei, and show that the infectivity of WSSV-CN04 was significantly lower than that of WSSV-CN03. When compared with WSSV-CN03-infected shrimp, fewer virions were detected in the digestive tract tissues of WSSV-CN04 infected shrimp at 4 hours post-infection (hpi), and the viral titers in the animals at 24 hpi were much lower. Moreover, a peptide corresponding to VP24 chitin-binding domain reduced the amount of WSSV-CN03 in the midgut to a level similar to that of WSSV-CN04 at 4 hpi. These findings indicate that the truncation of VP24 may attenuate the peroral infectivity of WSSV-CN04, and therefore verify the important role of VP24 in WSSV per os infection. PMID- 29228989 TI - Physicians' lack of knowledge - a possible reason for red blood cell transfusion overuse? AB - BACKGROUND: A significant percentage of red blood cell transfusions are inappropriately overused. This study investigated physicians from the western Galilee in terms of their knowledge of transfusion medicine as a potential reason for red blood cell overuse, and assessed the influence of personal background characteristics on their knowledge. METHODS: Data were collected via anonymous questionnaires. The questionnaires included a personal background section and a professional section. Study participants were grouped according to field of specialty, seniority, and location of medical school graduation, in order to correlate participant characteristics with knowledge. RESULTS: Scores were calculated on a 0-100 scale. The overall knowledge of the study population was low (mean score 47.8 +/- 18.6). Knowledge regarding basic physiology of red blood cell transfusion was also low. Internal medicine physicians and senior physicians had significantly greater overall knowledge scores and were more familiar with a restrictive blood management policy than were surgeons and residents, respectively. Comparing knowledge scores, no difference was found regarding indications for transfusion. CONCLUSION: General and fundamental knowledge in transfusion medicine is lacking among physicians in the non-operating room setting, which may play a role in red blood cell transfusion overuse. Field of specialty and professional status influenced knowledge of transfusion medicine. Educational programs and increased physicians' awareness might help decrease unnecessary transfusions. TRIAL REGISTRATION: Not applicable. PMID- 29228990 TI - Mannitol and the blood-labyrinth barrier. AB - BACKGROUND: Characterization of the blood labyrinth barrier (BLB) is extremely important to determine whether the BLB can be manipulated pharmacologically. However, experiments to investigate the BLB are technically difficult to perform. In this report, we demonstrated a unique method of controlling the BLB, and established the pharmacokinetics of gentamicin in perilymph, cerebrospinal fluid (CSF) and blood with and without mannitol. STUDY DESIGN: Controlled animal research project. METHODS: Permeability of the BLB and the blood brain barrier (BBB) to gentamicin with and without mannitol was studied by collecting 175 samples from 44 guinea pigs using concentrations relevant to human clinical situations. Samples were taken from two groups of 22 animals, with each animal undergoing sampling at a different time after administration of either 10 mg/ml gentamicin (4 mg/kg) (Gardena, CA) alone or gentamicin with 20% mannitol (250 mg/kg) (Mallinckrodt Inc., KY). The sample times varied from 0.5 to 17.5 h post infusion. Samples were also taken from 4 animals as negative controls after administration of normal saline. Our goal was to simultaneously assess the pharmacokinetics of gentamicin in each of three different fluid samples in the same animal. Thus at the pre-determined post-infusion sampling time, each animal was sampled once for perilymph, CSF, and blood before being euthanized. Each animal contributed to a single time point on the subsequent pharmacokinetic curves with more than one animal per time point. RESULTS: Mannitol increased the rate of entry and egress of gentamicin through BLB significantly (p = 0.0044) but the effects on the BBB did not reach statistical significance (p = 0.581). Mannitol did not alter renal clearance of gentamicin from the blood (p = 0.433). The concentration of gentamicin in perilymph and CSF was always significantly lower than in blood. CONCLUSIONS: Mannitol administration transiently increases the permeability of the BLB. Potential clinical benefits may accrue from selected timing of administration of osmotic agents such as mannitol augmenting the rate of entry and egress of compounds such as gentamicin into and out of perilymph. PMID- 29228992 TI - Maccabi proactive Telecare Center for chronic conditions - the care of frail elderly patients. AB - BACKGROUND: In 2012, Maccabi Healthcare Services founded Maccabi Telecare Center (MTC), a multi-disciplinary healthcare service providing telemedical care to complex chronic patients. The current paper describes the establishment and operation of the MTC center, from the identification of the need for the service, through the design of its solution elements, to outcomes in several areas of care. We analyze the effects of the program on elderly frail patients, a growing population with complex and costly needs. METHODS: Observational quasi experimental analyses using propensity score matching was used to assess the effect of MTC's operation on utilization outcomes including direct costs. RESULTS: Results for frail elderly patients with complex chronic conditions show significant reductions in hospitalization days and hospitalization costs. MTC interventions also entailed lower overall average monthly costs in frail patients. CONCLUSION: We conclude that a proactive telehealth service for complex chronic patients using education, empowerment to self-management, and coordination of care is a cost-effective means of improving quality care and health outcomes in frail elderly patients. PMID- 29228991 TI - The rumen microbiome as a reservoir of antimicrobial resistance and pathogenicity genes is directly affected by diet in beef cattle. AB - BACKGROUND: The emergence and spread of antimicrobial resistance is the most urgent current threat to human and animal health. An improved understanding of the abundance of antimicrobial resistance genes and genes associated with microbial colonisation and pathogenicity in the animal gut will have a major role in reducing the contribution of animal production to this problem. Here, the influence of diet on the ruminal resistome and abundance of pathogenicity genes was assessed in ruminal digesta samples taken from 50 antibiotic-free beef cattle, comprising four cattle breeds receiving two diets containing different proportions of concentrate. RESULTS: Two hundred and four genes associated with antimicrobial resistance (AMR), colonisation, communication or pathogenicity functions were identified from 4966 metagenomic genes using KEGG identification. Both the diversity and abundance of these genes were higher in concentrate-fed animals. Chloramphenicol and microcin resistance genes were dominant in samples from forage-fed animals (P < 0.001), while aminoglycoside and streptomycin resistances were enriched in concentrate-fed animals. The concentrate-based diet also increased the relative abundance of Proteobacteria, which includes many animal and zoonotic pathogens. A high ratio of Proteobacteria to (Firmicutes + Bacteroidetes) was confirmed as a good indicator for rumen dysbiosis, with eight cases all from concentrate-fed animals. Finally, network analysis demonstrated that the resistance/pathogenicity genes are potentially useful as biomarkers for health risk assessment of the ruminal microbiome. CONCLUSIONS: Diet has important effects on the complement of AMR genes in the rumen microbial community, with potential implications for human and animal health. PMID- 29228993 TI - Programmed cell death 5 transgenic mice attenuates adjuvant induced arthritis by 2 modifying the T lymphocytes balance. AB - BACKGROUND: Programmed cell death 5 (PDCD5) is an apoptosis-related gene cloned from TF-1 cells whose primary biological functions are to promote apoptosis and immune regulation. The effects and mechanisms exerted by key mediators of arthritic inflammation remain unclear in PDCD5 transgenic (PDCD5 tg) mice. RESULTS: In the current study, PDCD5 tg mice inhibited the progression of adjuvant-induced arthritis, specifically decreasing clinical signs and histological damage, compared with arthritis control mice. Additionally, the ratio of CD4+IFN-gamma+ cells (Th1) and CD4+IL-17A+ cells (Th17), as well as the mRNA expression of the pro-inflammatory mediators IFN-gamma, IL-6, IL-17A and TNF alpha, were decreased in PDCD5 tg mice, while CD4+CD25+Foxp3+ regulatory T (Treg) cells and the anti-inflammatory mediators IL-4 and IL-10 were increased. Furthermore, PDCD5 tg mice demonstrated reduced serum levels of IFN-gamma, IL-6, IL-17A and TNF-alpha and increased levels of IL-4. CONCLUSIONS: Based on our data, PDCD5 exerts anti-inflammatory effects by modifying the T lymphocytes balance, inhibiting the production of pro-inflammatory mediators and promoting the secretion of anti-inflammatory cytokines, validating PDCD5 protein as a possible treatment for RA. PMID- 29228994 TI - Survival and prognostic factors of non-small cell lung cancer patients with postoperative locoregional recurrence treated with radical radiotherapy. AB - BACKGROUND: Locoregional recurrence remains the challenge for long-term survival of non-small cell lung cancer (NSCLC) patients after radical surgery, and curative-intent radiotherapy could be a treatment choice. This study aimed to assess the survival and prognostic factors of patients with postoperative locoregionally recurrent NSCLC treated with radical radiotherapy. METHODS: We reviewed medical records of 74 NSCLC patients with postoperative locoregional recurrence who received radical radiotherapy between April 2012 and February 2016 at Sun Yat-sen University Cancer Center (Guangzhou, China). The efficacy and safety of radical radiotherapy were analyzed. The probability of survival was estimated using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used to identify prognostic factors. RESULTS: Grade 3/4 adverse events included neutropenia (8 cases, 10.8%), esophagitis (7 cases, 9.5%), pneumonitis (1 case, 1.4%), and vomiting (1 case, 1.4%). The 2-year overall survival, progression-free survival, local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rates of all patients were 84.2, 42.5, 70.0, and 50.9%, respectively. Univariate and multivariate analyses showed that a higher biological effective dose (BED) of radiation was associated with longer LRFS [hazard ratios (HR) = 0.317, 95% confidence interval (CI) = 0.112-0.899, P = 0.016] and that wild-type epidermal growth factor receptor (EGFR) was associated with longer DMFS compared with EGFR mutation (HR = 0.383, 95% CI = 0.171-0.855, P = 0.019). CONCLUSIONS: Radical radiotherapy is effective and well-tolerated in NSCLC patients with postoperative locoregional recurrence. High BED is a predictor for long LRFS, and the presence of wild-type EGFR is a predictor for long DMFS. PMID- 29228995 TI - Correcting the predictive validity of a selection test for the effect of indirect range restriction. AB - BACKGROUND: The validity of selection tests is underestimated if it is determined by simply calculating the predictor-outcome correlation found in the admitted group. This correlation is usually attenuated by two factors: (1) the combination of selection variables which can compensate for each other and (2) range restriction in predictor and outcome due to the absence of outcome measures for rejected applicants. METHODS: Here we demonstrate the logic of these artifacts in a situation typical for student selection tests and compare four different methods for their correction: two formulas for the correction of direct and indirect range restriction, expectation maximization algorithm (EM) and multiple imputation by chained equations (MICE). First we show with simulated data how a realistic estimation of predictive validity could be achieved; second we apply the same methods to empirical data from one medical school. RESULTS: The results of the four methods are very similar except for the direct range restriction formula which underestimated validity. CONCLUSION: For practical purposes Thorndike's case C formula is a relatively straightforward solution to the range restriction problem, provided distributional assumptions are met. With EM and MICE more precision is obtained when distributional requirements are not met, but access to a sophisticated statistical package such as R is needed. The use of true score correlation has its own problems and does not seem to provide a better correction than other methods. PMID- 29228996 TI - Factors associated with gender equality among church-going young men in Kinshasa, Democratic Republic of Congo: a cross-sectional study. AB - BACKGROUND: While women and girls are made vulnerable by inequitable and violent versions of masculinities, there is increasing evidence that gender equality will not be achieved without partnering with men. The aim of this study was to assess gender-equitable norms and their determinants among church-going young men in Kinshasa, the Democratic Republic of Congo. METHOD: A cross-sectional study was carried out among 289 church-going young men, aged 18-24 years, residing in three disadvantaged communes of Kinshasa. Variables included sociodemographic characteristics, attitudes towards gender equality and responses to issues related to the Gender-Equitable Men (GEM) scale. Logistic regression was applied to identify the associations between sociodemographic characteristics, attitudes and the GEM scale. RESULTS: The findings provide evidence of attitudes and beliefs that act as barriers to gender equality. For instance, the majority of church-going young men (83.74%) agreed that a man is the only decision maker in the home and about half (50.87%) of the respondents supported the statement "There are times a woman deserves to be beaten". Similarly, around half of the participants agreed with the idea of men's uncontrollable sex drive (50.87%) and men's toughness (50.17%). Close to half of the participants (44.29%) agreed that it is women's responsibility to prevent pregnancy. These attitudes co-existed with a few gender-equitable norms as 82.70% agreed on the importance of joint decisions concerning family planning. An association between education, certain places of residence, being single or separated, and supportive attitudes towards gender equality was found with higher scores for the GEM. CONCLUSION: Our study findings indicate that a high proportion of church-going young men do not endorse gender-equitable norms. Therefore, churches urgently need comprehensive gender equality and masculinity policies and programmes to influence young men's attitudes and behaviours. The promotion of gender equality in schools and the wider community also need to be encouraged. PMID- 29228997 TI - Toxoplasma gondii seroprevalence in breeding pigs in Estonia. AB - BACKGROUND: Toxoplasma gondii is a widespread occurring parasite infecting warm blooded animals, including pigs and humans. The aims of this study were to estimate the prevalence of anti-T. gondii antibodies and to evaluate risk factors for T. gondii seropositivity in breeding pigs raised in Estonia. Sera from 382 pigs were tested with a commercial direct agglutination test, using a cut-off titer of 40 for seropositivity, for the presence of anti-T. gondii immunoglobulin G antibodies. RESULTS: Twenty-two (5.8%) of the 382 pigs tested seropositive for T. gondii, and 6 of the 14 herds had at least one seropositive pig. The proportion of seropositive pigs within the herds ranged between 0 and 43%. Gender appeared as a significant factor, with sows having 5.6 times higher odds to be seropositive to T. gondii than boars. Seroprevalence did not increase with age. CONCLUSIONS: Anti-T. gondii antibodies were present in a substantial proportion of breeding pig herds in Estonia. On the other hand, the presence of herds without seropositive pigs illustrates that porcine T. gondii infections can be avoided even in a country where the parasite is endemic and common in several other host species. PMID- 29228999 TI - The influence of early research experience in medical school on the decision to intercalate and future career in clinical academia: a questionnaire study. AB - BACKGROUND: Currently, only one in three UK medical students undertake an intercalated degree. This has often been implicated as a result of financial obstacles or a lack of interest in research due to inadequate exposure to academic medicine. The aims of this study were to determine whether exposure to research early in medical school, through the initiation of an early years clinical academic training programme has a positive influence on the decision making related to intercalating and a career long interest in research. This study also aims to evaluate the perceived views of the recipients of such a scholarship programme. METHODS: All previous recipients of the Aberdeen Summer Research Scholarship (ASRS) (n = 117) since its inception in 2010 until 2015 were invited via email in June 2016, to take part in the survey. Data were analysed using SPSS for quantitative data and a thematic approach was used to derive themes from free text. RESULTS: The overall response rate was 56% (66/117). Of the respondents, seven received the scholarship twice. Seventy-three percent were still at medical school and 26% were foundation doctors. One respondent indicated that they were currently not in training. Seventy percent of respondents have continued to be involved in research since completing the scholarship. Fifty percent embarked on an intercalated degree following the ASRS. Furthermore, two thirds of the respondents who were undecided about undertaking an intercalated degree before the scholarship, chose to intercalate after completing the programme. ASRS was generally thought of as a positive, influential programme, yet the success of individual ASRS projects was dependent on the allocated supervisors and the resources available for specific projects. CONCLUSIONS: Our findings indicate that early research exposure in medical school can provide students with a positive influence on involvement in research and allows students to make an informed decision about embarking on an intercalated degree. We therefore recommend the encouragement of similar programmes in medical schools to promote clinical academia at an early stage for medical students. PMID- 29228998 TI - Capturing health and eating status through a nutritional perception screening questionnaire (NPSQ9) in a randomised internet-based personalised nutrition intervention: the Food4Me study. AB - BACKGROUND: National guidelines emphasize healthy eating to promote wellbeing and prevention of non-communicable diseases. The perceived healthiness of food is determined by many factors affecting food intake. A positive perception of healthy eating has been shown to be associated with greater diet quality. Internet-based methodologies allow contact with large populations. Our present study aims to design and evaluate a short nutritional perception questionnaire, to be used as a screening tool for assessing nutritional status, and to predict an optimal level of personalisation in nutritional advice delivered via the Internet. METHODS: Data from all participants who were screened and then enrolled into the Food4Me proof-of-principle study (n = 2369) were used to determine the optimal items for inclusion in a novel screening tool, the Nutritional Perception Screening Questionnaire-9 (NPSQ9). Exploratory and confirmatory factor analyses were performed on anthropometric and biochemical data and on dietary indices acquired from participants who had completed the Food4Me dietary intervention (n = 1153). Baseline and intervention data were analysed using linear regression and linear mixed regression, respectively. RESULTS: A final model with 9 NPSQ items was validated against the dietary intervention data. NPSQ9 scores were inversely associated with BMI (beta = -0.181, p < 0.001) and waist circumference (Beta = 0.155, p < 0.001), and positively associated with total carotenoids (beta = 0.198, p < 0.001), omega-3 fatty acid index (beta = 0.155, p < 0.001), Healthy Eating Index (HEI) (beta = 0.299, p < 0.001) and Mediterranean Diet Score (MDS) (beta = 0. 279, p < 0.001). Findings from the longitudinal intervention study showed a greater reduction in BMI and improved dietary indices among participants with lower NPSQ9 scores. CONCLUSIONS: Healthy eating perceptions and dietary habits captured by the NPSQ9 score, based on nine questionnaire items, were associated with reduced body weight and improved diet quality. Likewise, participants with a lower score achieved greater health improvements than those with higher scores, in response to personalised advice, suggesting that NPSQ9 may be used for early evaluation of nutritional status and to tailor nutritional advice. TRIAL REGISTRATION: NCT01530139 . PMID- 29229000 TI - Changes in Specific Substance Involvement Scores among SBIRT recipients in an HIV primary care setting. AB - BACKGROUND: Substance use is common among people living with HIV (PLHIV) and is associated with worse outcomes along the HIV care continuum. One potentially effective clinic-based approach to addressing unhealthy substance use is screening, brief intervention, and referral to treatment (SBIRT). METHODS: We conducted a two-arm randomized trial to examine the effects of a self administered, computerized SBIRT intervention compared to a clinician administered SBIRT intervention in an HIV primary clinic. Patients were surveyed before receiving the intervention and again at 1, 3, and 6 months. We administered the WHO Alcohol, Smoking and Substance Involvement Screening Test to determine Specific Substance Involvement Scores (SSIS) and to assign participants to categories of lower, moderate, or high risk to health and other problems for each substance. We collapsed moderate or severe risk responses into a single moderate-high risk category. Based on low rates of participation in the computerized arm, we conducted an "as treated" analysis to examine 6-month changes in mean SSIS among SBIRT intervention participants. RESULTS: For the overall sample (n = 208), baseline mean SSIS were in the moderate risk category for alcohol, tobacco, cannabis, cocaine, amphetamine, sedatives and opioids. Of those enrolled, 134 (64.4%) received the intervention, and 109 (52.4%) completed the 6-month follow up. There was a statistically significant decline in mean SSIS for all substances except tobacco and cannabis among participants who were at moderate-high risk at baseline. We also observed a statistically significant increase in mean SSIS for all substances except amphetamines and sedatives among participants who were at lower risk at baseline. CONCLUSIONS: Substance use among patients in this urban, safety-net, HIV primary care clinic was near universal, and moderate risk substance use was common. Among participants who received the SBIRT intervention, mean SSISs decreased among those at moderate-high risk at baseline, but increased among those at lower risk at baseline over the 6-month study period. Additional research should examine the clinical significance of SSIS changes for PLHIV, which SBIRT components drive changes in substance use scores, and what other interventions might support those patients at lower risk to maintain health and engagement along the HIV care continuum. Trial registration ClinicalTrials.gov study NCT01300806. PMID- 29229001 TI - A novel mutation of HOXA11 in a patient with septate uterus. AB - BACKGROUND: The etiology of Mullerian duct anomalies (MDAs) is poorly understood at present. The HOXA11 gene is crucial for the development of the Mullerian duct. The objective of this study is to report a unique case of MDAs with a novel mutation in HOXA11. RESULTS: We identified a potential disease-causing mutation (p. E255K) in a patient with a septate uterus. The mutation was not detected in 169 control subjects or listed in any databases of variations. Bioinformatic predictions and functional studies showed that the mutation reduces the DNA binding affinity and disrupts transactivation ability of HOXA11. CONCLUSION: In conclusion, this is the first report to describe a HOXA11 mutation in Chinese women with MDAs. The results demonstrated that mutation in HOXA11 can contribute to the etiology of MDAs, especially the septate uterus, but might not be a common cause. PMID- 29229002 TI - Comprehensive analysis of ectopic mandibular third molar: a rare clinical entity revisited. AB - BACKGROUND: Ectopic mandibular third molar is a rare clinical entity with incompletely known etiology. Here, we sought to delineate its epidemiological, clinical and radiographic characteristics, and therapy by integrating and analyzing the cases treated in our institution together with previously reported cases. METHOD: A new definition and classification for ectopic mandibular third molar was proposed based on its anatomic location on panoramic images. Thirty eight ectopic mandibular third molars in 37 patients and 51 teeth in 49 patients were identified in our disease registry and from literature (1990-2016), respectively. These cases were further categorized and compared according to our classification protocol. The demographic, clinicopathological and radiographic data were collected and analyzed. RESULTS: These ectopic teeth were categorized into four levels, 33 in level I(upper ramus), 32 in level II (middle ramus), 15 in level III (mandibular angle) and 9 in level IV (mandibular body). The common clinical presentations included pain, swelling and limited mouth opening, although sometimes asymptomatic. Most teeth were associated with pathological lesions. Treatments included clinical monitor and surgical removal by intra- or extraoral approach with favorable outcomes. Clinical presentations and treatment options for these teeth were significantly associated with their ectopic locations as we classified. CONCLUSIONS: Ectopic mandibular third molars are usually found in patients with middle ages and in upper and middle ramus of mandible. Surgery is preferred to remove these ectopic teeth and associated pathologies when possible. PMID- 29229004 TI - Environmental Cleaning of Outpatient Exam Rooms: How Frequent is Enough? PMID- 29229003 TI - Comparative binding properties of the tau PET tracers THK5117, THK5351, PBB3, and T807 in postmortem Alzheimer brains. AB - BACKGROUND: The aim of this study was to compare the binding properties of several tau positron emission tomography tracers-THK5117, THK5351, T807 (also known as AV1451; flortaucipir), and PBB3-head to head in the same human brain tissue. METHODS: Binding assays were performed to compare the regional distribution of 3H-THK5117 and 3H-THK5351 in postmortem tissue from three Alzheimer's disease (AD) cases and three control subjects in frontal and temporal cortices as well as in the hippocampus. Competition binding assays between THK5351, THK5117, PBB3, and T807, as well as off-target binding of THK5117 and T807 toward monoamine oxidase B (MAO-B), were performed using binding assays in brain homogenates and autoradiography of three AD cases. RESULTS: Regional binding of 3H-THK5117 and 3H-THK5351 was similar, except in the temporal cortex, which showed higher 3H-THK5117 binding. Saturation studies demonstrated two binding sites for 3H-THK5351 (K d1 = 5.6 nM, Bmax = 76 pmol/g; K d2 = 1 nM, Bmax = 40 pmol/g). Competition studies in the hippocampus between 3H-THK5351 and unlabeled THK5351, THK5117, and T807 revealed super-high-affinity sites for all three tracers (THK5351 K i = 0.1 pM; THK5117 K i = 0.3 pM; T807 K i = 0.2 pM) and an additional high-affinity site (THK5351 K i = 16 nM; THK5117 K i = 20 nM; T807 K i = 78nM). 18F-T807, 11C-THK5351, and 11C-PBB3 autoradiography of large frozen sections from three AD brains showed similar regional binding for the three tracers, with lower binding intensity for 11C-PBB3. Unlabeled THK5351 and T807 displaced 11C-THK5351 to a similar extent and a lower extent, respectively, compared with 11C-PBB3. Competition with the MAO-B inhibitor 3H-L-deprenyl was observed for THK5117 and T807 in the hippocampus (THK5117 K i = 286 nM; T807 K i = 227 nM) and the putamen (THK5117 K i = 148 nM; T807 K i = 135 nM). 3H-THK5351 binding was displaced using autoradiography competition with unlabeled THK5351 and T807 in cortical areas by 70-80% and 60-77%, respectively, in the basal ganglia, whereas unlabeled deprenyl displaced 3H-THK5351 binding by 40% in the frontal cortex and 50% in the basal ganglia. CONCLUSIONS: THK5351, THK5117, and T807 seem to target similar binding sites, but with different affinities, whereas PBB3 seems to target its own binding site. Both THK5117 and T807 demonstrated off target binding in the hippocampus and putamen with a ten times lower binding affinity to the MAO-B inhibitor deprenyl compared with 3H-THK5351. PMID- 29229005 TI - Neural responses to monetary incentives among self-injuring adolescent girls CORRIGENDUM. PMID- 29229007 TI - De novo synthesis of thiamine (vitamin B1) is the ancestral state in Plasmodium parasites - evidence from avian haemosporidians. AB - Parasites often have reduced genomes as their own genes become redundant when utilizing their host as a source of metabolites, thus losing their own de novo production of metabolites. Primate malaria parasites can synthesize vitamin B1 (thiamine) de novo but rodent malaria and other genome-sequenced apicomplexans cannot, as the three essential genes responsible for this pathway are absent in their genomes. The unique presence of functional thiamine synthesis genes in primate malaria parasites and their sequence similarities to bacterial orthologues, have led to speculations that this pathway was horizontally acquired from bacteria. Here we show that the genes essential for the de novo synthesis of thiamine are found also in avian Plasmodium species. Importantly, they are also present in species phylogenetically basal to all mammalian and avian Plasmodium parasites, i.e. Haemoproteus. Furthermore, we found that these genes are expressed during the blood stage of the avian malaria infection, indicating that this metabolic pathway is actively transcribed. We conclude that the ability to synthesize thiamine is widespread among haemosporidians, with a recent loss in the rodent malaria species. PMID- 29229006 TI - Children of parents with a history of depression: The impact of a preventive intervention on youth social problems through reductions in internalizing problems. AB - The current investigation examined if changes in youth internalizing problems as a result of a family group cognitive behavioral (FGCB) preventive intervention for families with a parent with a history of depression had a cascade effect on youth social problems over 24 months and the bidirectional nature of these effects. One hundred eighty families with a parent with a history of major depressive disorder (M age = 41.96; 88.9% mothers) and a youth age 9 to 15 years (49.4% females; M age = 11.46) participated. Findings from a panel model indicated that, compared to a minimum intervention condition, the FGCB intervention significantly reduced youth internalizing problems at 12 months that in turn were associated with lower levels of social problems at 18 months. Similarly, the FGCB intervention reduced internalizing problems at 18 months, which were associated with fewer social problems at 24 months. Changes in social problems were not related to reductions in subsequent internalizing problems. The findings suggest that reductions in youth internalizing problems can lead to lower levels of social problems. Youth social problems are difficult to change; therefore, targeting internalizing problems may be an effective way to reduce the social problems of children of parents with a history of depression. PMID- 29229008 TI - A minimalist macroparasite diversity in the round goby of the Upper Rhine reduced to an exotic acanthocephalan lineage. AB - The round goby, Neogobius melanostomus, is a Ponto-Caspian fish considered as an invasive species in a wide range of aquatic ecosystems. To understand the role that parasites may play in its successful invasion across Western Europe, we investigated the parasitic diversity of the round goby along its invasion corridor, from the Danube to the Upper Rhine rivers, using data from literature and a molecular barcoding approach, respectively. Among 1666 parasites extracted from 179 gobies of the Upper Rhine, all of the 248 parasites barcoded on the c oxidase subunit I gene were identified as Pomphorhynchus laevis. This lack of macroparasite diversity was interpreted as a loss of parasites along its invasion corridor without spillback compensation. The genetic diversity of P. laevis was represented by 33 haplotypes corresponding to a haplotype diversity of 0.65 +/- 0.032, but a weak nucleotide diversity of 0.0018 +/- 0.00015. Eight of these haplotypes were found in 88.4% of the 248 parasites. These haplotypes belong to a single lineage so far restricted to the Danube, Vistula and Volga rivers (Eastern Europe). This result underlines the exotic status of this Ponto-Caspian lineage in the Upper Rhine, putatively disseminated by the round goby along its invasion corridor. PMID- 29229009 TI - The unwelcome houseguest: secondary household transmission of norovirus. AB - Norovirus is the leading cause of acute gastroenteritis in the USA. Although secondary household transmission of norovirus is frequently reported in outbreaks, little is known about specific risk factors for susceptibility and infectiousness in the household. Three norovirus outbreaks were investigated and data were collected on individuals exposed in the primary outbreak setting and their household members. Potential individual- and household-level risk factors for susceptibility and infectiousness were assessed using univariate and multivariate generalised linear mixed models. In the univariate models, the secondary attack rate (SAR) was significantly higher when living in a household with two or more primary cases (incidence rate ratio (IRR) = 2.1; 95% confidence interval (CI) 1.37-3.29), more than one primary case with vomiting (IRR = 1.9; CI 1.11-3.37), and at least one primary case with diarrhoea (IRR = 3.0; CI 1.46 6.01). After controlling for other risk factors in the multivariate models, the SAR was significantly higher among those living in a household with two or more primary cases (adjusted IRR = 2.0; CI 1.17-3.47) and at least one primary case with diarrhoea (adjusted IRR = 2.8; CI 1.35-5.93). These findings underscore the importance of maintaining proper hygiene and isolating ill household members to prevent norovirus transmission in the household. PMID- 29229011 TI - Making sense of loss through spirituality: Perspectives of African American family members who have experienced the death of a close family member to cancer. AB - OBJECTIVE: Among African Americans, spirituality is meaning or purpose in life and a faith in God who is in control of health and there to provide support and guidance in illness situations. Using qualitative methods, we explored the use of spirituality to make sense of the end-of-life and bereavement experiences among family members of a deceased cancer patient. METHOD: Data in this report come from 19 African Americans who experienced the loss of a family member to cancer. A qualitative descriptive design was used with criterion sampling, open-ended semistructured interviews, and qualitative content analysis. RESULTS: Participants made sense of the death of their loved one using the following five themes: Ready for life after death; I was there; I live to honor their memory; God's wisdom is infinite; and God prepares you and brings you through. These five themes are grounded in conceptualizations of spirituality as connectedness to God, self, and others. Significance of results Our findings support the results that even during bereavement, spirituality is important in the lives of African Americans. African American family members might struggle with issues related to life after death, their ability to be physically present during end-of-life care, and disentangling beliefs around God's control over the beginning and ending of life. The findings in this report can be used to inform healthcare providers to better support and address the needs for support of African American family members during end-of-life and bereavement experiences. PMID- 29229010 TI - Relative importance of phosphatidylinositol-3 kinase (PI3K)/Akt and mitogen activated protein kinase (MAPK3/1) signaling during maturational steroid-induced meiotic G2-M1 transition in zebrafish oocytes. AB - Participation and relative importance of phosphatidylinositol-3 kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling, either alone or in combination, have been investigated during 17alpha,20beta-dihydroxy-4-pregnen-3 one (DHP)-induced meiotic G2-M1 transition in denuded zebrafish oocyte. Results demonstrate that concomitant with rapid phosphorylation (activation) of Akt (Ser473) and MAPK (ERK1/2) at as early as 15 min of incubation, DHP stimulation promotes enhanced an GVBD response and histone H1 kinase activation between 1 and 5 h in full-grown oocytes in vitro. While p-Akt reaches its peak at 60 to 90 min and undergoes downregulation to the basal level by 240 min, ERK1/2 phosphorylation (activation) increases gradually until 120 min and remains high thereafter. Although, priming with MEK1/2 inhibitor U0126 is without effect, PI3K inhibitors, wortmannin or LY294002, delay the GVBD response significantly (P < 0.001) until 3 h but not at 5 h of incubation. Interestingly, blocking PI3K and MEK function together could abrogate steroid-induced oocyte maturation at all time points tested. While DHP stimulation promotes phospho-PKA catalytic (p-PKAc) dephosphorylation (inactivation) between 30-120 min of incubation, simultaneous inhibition of PI3K and MEK1/2 kinases abrogates DHP action. Conversely, elevated intra-oocyte cAMP, through priming with either adenylyl cyclase (AC) activator forskolin (FK) or dibutyryl cAMP (db-cAMP), abrogates steroid-induced Akt and ERK1/2 phosphorylation. Taken together, these results suggest that DHP-induced Akt and ERK activation precedes the onset of meiosis (GVBD response) in a cAMP sensitive manner and PI3K/Akt and MEK/MAPK pathways together have a pivotal influence in the downregulation of PKA and resumption of meiotic maturation in zebrafish oocytes in vitro. PMID- 29229012 TI - Mixed-methods quantitative-qualitative study of 29 nonagenarians and centenarians in rural Southern Italy: focus on positive psychological traits. AB - OBJECTIVE: This was a study of positive psychological traits in a group of rural Italians aged 90 to 101 years, and their children or other family members. DESIGN: Mixed-methods quantitative (standardized rating scales) and qualitative (semi-structured interviews) study. SETTING: Study participants' homes in nine villages in the Cilento region of southern Italy. PARTICIPANTS: Twenty-nine nonagenarians and centenarians and 51 family members aged 51-75 years, selected by their general practitioners as a part of a larger study called CIAO (Cilento Initiative on Aging Outcomes). METHODS: We used published rating scales of mental and physical well-being, resilience, optimism, anxiety, depression, and perceived stress. Qualitative interviews gathered personal narratives of the oldest-old individuals, including migrations, traumatic events, and beliefs. Family members described their impressions about the personality traits of their older relative. RESULTS: Participants age >=90 years had worse physical health but better mental well-being than their younger family members. Mental well-being correlated negatively with levels of depression and anxiety in both the groups. The main themes that emerged from qualitative interviews included positivity (resilience and optimism), working hard, and bond with family and religion, as described in previously published studies of the oldest old, but also a need for control and love of the land, which appeared to be unique features of this rural population. CONCLUSIONS: Exceptional longevity was characterized by a balance between acceptance of and grit to overcome adversities along with a positive attitude and close ties to family, religion, and land, providing purpose in life. PMID- 29229013 TI - Attachment security moderates the link between adverse childhood experiences and cellular aging. AB - Exposure to childhood adversity has been linked to accelerated telomere shortening, a marker of cellular aging and an indicator of physical health risk. In the current study, we examined whether adult attachment representation moderated the association between childhood adversity and telomere length. Participants included 78 young adults (M age = 20.46, SD = 1.57), who reported on their exposure to adverse childhood experiences (ACE) and were administered the Adult Attachment Interview, which was coded for attachment state of mind. Relative telomere length was assayed from buccal cells. Multiple regression analyses revealed a significant interaction between attachment state of mind and ACE in predicting telomere length. Whereas the association between number of ACE and telomere length was nonsignificant for secure-autonomous, r (50) = -.15, p = .31, and insecure-preoccupied young adults, r (9) = -.15, p = .71, there was a strong negative association between number of ACE and telomere length for insecure-dismissing young adults, r (19) = -.59, p = .007. This study is novel in demonstrating that attachment may affect biological resilience following childhood adversity, contributing to the growing literature about the role of the quality of early caregiving experiences and their representations in shaping biological processes and physical health. PMID- 29229014 TI - Effects of pre- and postnatal maternal stress on infant temperament and autonomic nervous system reactivity and regulation in a diverse, low-income population CORRIGENDUM. PMID- 29229015 TI - Risk factors for acquisition of multidrug-resistant Escherichia coli and development of community-acquired urinary tract infections. AB - We examined risk factors associated with the intestinal acquisition of antimicrobial-resistant extraintestinal pathogenic Escherichia coli (ExPEC) and development of community-acquired urinary tract infection (UTI) in a case-control study of young women across Canada. A total of 399 women were recruited; 164 women had a UTI caused by E. coli resistant to ?1 antimicrobial classes and 98 had a UTI caused by E. coli resistant to ?3 antimicrobial classes. After adjustment for age, student health service (region of Canada) and either prior antibiotic use or UTI history, consumption of processed or ground chicken, cooked or raw shellfish, street foods and any organic fruit; as well as, contact with chickens, dogs and pet treats; and travel to Asia, were associated with an increased risk of UTI caused by antimicrobial resistant E. coli. A decreased risk of antimicrobial resistant UTI was associated with consumption of apples, nectarines, peppers, fresh herbs, peanuts and cooked beef. Drug-resistant UTI linked to foodborne and environmental exposures may be a significant public health concern and understanding the risk factors for intestinal acquisition of existing or newly emerging lineages of drug-resistant ExPEC is important for epidemiology, antimicrobial stewardship and prevention efforts. PMID- 29229016 TI - Sequences of maladaptation: Preadolescent self-regulation, adolescent negative social interactions, and young adult psychopathology. AB - This study aims to test whether adolescent negative social interactions mediate the relation between early adolescent self-regulatory capacities and young adult psychopathology, using a fully prospective mediation model. Data were derived from the Tracking Adolescents' Individual Lives Survey, a large population cohort of Dutch adolescents (n = 962). At age 11, three indicators of self-regulation were assessed: low frustration, high effortful control, and high response inhibition. Negative social interactions between ages 11 and 22 were captured twice using the Event History Calendar. Psychopathology (i.e., internalizing and externalizing problems) was assessed at ages 11 and 22. Findings indicate that adolescents' frustration and effortful control but not response inhibition assessed at age 11 are related to both internalizing and externalizing problems at age 22, after controlling for psychopathology at age 11, sex, and socioeconomic status. These associations were partly (about 22%) mediated by the negative social interactions adolescents experienced. Effect sizes were all modest. This study shows that self-regulation is related to subsequent psychopathology in part through its effect on negative social interactions, providing evidence for sequences of self-regulatory capacities, life experiences, and developmental outcomes. PMID- 29229017 TI - Adolescence effortful control as a mediator between family ecology and problematic substance use in early adulthood: A 16-year prospective study. AB - This study examined the mediated effect of early adolescence familial context on early adulthood problematic substance use through effortful control in late adolescence. The sample consisted of a community sample of 311 adolescents and their families comprising the control group within a randomized trial intervention. Parental monitoring and parent-child relationship quality (P-C RQ) were measured annually from ages 11 to 13. Effortful control was measured by self reports and parent and teacher reports at ages 16 to 17. Self-reports of problematic tobacco, alcohol, and marijuana use were measured at ages 18 to 19, 21 to 22, 23 to 24, and 26 to 27. Structural equation modeling was employed to test hypothesized models. Only P-C RQ was found to be significantly associated with adolescent effortful control. As expected, higher levels of adolescent effortful control were associated with lower problematic substance use through early adulthood, controlling for previous substance use levels. Mediation analyses showed that effortful control significantly mediated the relationship between P-C RQ and problematic substance use. Higher relationship quality between youth and parents in early adolescence is associated with higher effortful control, which in turn relates to a lower level of problematic substance use in early adulthood. PMID- 29229019 TI - Clostridium difficile: Epidemiology, Pathogenicity, and an Update on the Limitations of and Challenges in Its Diagnosis. AB - The bacterium originally named Bacillus difficilis was later renamed Clostridium difficile because of the difficulty associated with its isolation in the laboratory. C. difficile causes human-associated diarrhea, which is now known as C. difficile infection (CDI), a major cause of nosocomial infection mainly occurring in developed countries. Changes in antibiotic patterns in its strains produce toxins that are responsible for the high mortality rates associated with CDI; therefore, the epidemiology and severity of CDI have recently changed. Apart from CDI, C. difficile also causes opportunistic infections of the human gut usually when the normal gut flora are disrupted by broad-spectrum antibiotics. By disrupting normal gut flora, spores of C. difficile germinate and traverse the gut mucosa through flagellar binding to the mucosal epithelium where several proteins are involved in the binding of C. difficile. Proper diagnostic techniques have to be applied to ensure early identification of CDI and prompt treatment administered because false results may lead to inappropriate treatment and increase risk of cross-infection. This review discusses the epidemiology and pathogenicity of this bacterium with concern for its changing pattern over the years. Further details on the diagnosis of CDI are elaborated upon, mainly focusing on the limits of and challenges in molecular diagnosis. PMID- 29229023 TI - Editorial. PMID- 29229020 TI - Normalization of Elevated Tumor Marker CA27-29 After Bilateral Lung Transplantation in a Patient With Breast Cancer and Idiopathic Pulmonary Fibrosis. AB - Solid tumors involving glandular organs express mucin glycoprotein that is eventually shed into the circulation. As a result, these proteins can easily be measured in the serum and be used as potential tumor markers. The most commonly used tumor markers for breast cancer are CA27-29 and CA15-3, which both measure the glycoprotein product of the mucin-1 (MUC1) gene. CA27-29 has been approved by the US Food and Drug Administration for monitoring disease activity in breast cancer patients. Most oncology clinical practice guidelines do not recommend the use of tumor markers for routine surveillance of early stage disease but recognize their utility in the metastatic setting. We present a patient with stage IIIA breast cancer and preexisting hypersensitivity pneumonitis who was found to have an elevated serum tumor marker CA27-29. After successful curative intent treatment of her early stage breast cancer, she developed gradual and progressive worsening of her lung disease with eventual development of severe pulmonary fibrosis requiring bilateral lung transplantation. As part of the pretransplant evaluation, she was found to have an elevation of serum tumor marker CA27-29. While the diagnostic evaluation, including imaging studies, was negative for the presence of recurrent disease, the serial serum tumor marker CA27-29 levels remained persistently elevated. The decision was made for her to undergo bilateral lung transplantation. Shortly after surgery, her CA27-29 tumor marker level returned to normal range, and it has continued to remain in the normal range with no evidence of breast cancer recurrence. PMID- 29229027 TI - Climate change and adaptation for health and social services. PMID- 29229030 TI - From organisations to people: improving the prevention and management of long term conditions in Australian primary health care. PMID- 29229018 TI - Prenatal influences on temperament development: The role of environmental epigenetics. AB - This review summarizes current knowledge and outlines future directions relevant to questions concerning environmental epigenetics and the processes that contribute to temperament development. Links between prenatal adversity, epigenetic programming, and early manifestations of temperament are important in their own right, also informing our understanding of biological foundations for social-emotional development. In addition, infant temperament attributes represent key etiological factors in the onset of developmental psychopathology, and studies elucidating their prenatal foundations expand our understanding of developmental origins of health and disease. Prenatal adversity can take many forms, and this overview is focused on the environmental effects of stress, toxicants, substance use/psychotropic medication, and nutrition. Dysregulation associated with attention-deficit/hyperactivity-disruptive disorders was noted in the context of maternal substance use and toxicant exposures during gestation, as well as stress. Although these links can be made based on the existing literature, currently few studies directly connect environmental influences, epigenetic programming, and changes in brain development/behavior. The chain of events starting with environmental inputs and resulting in alterations to gene expression, physiology, and behavior of the organism is driven by epigenetics. Epigenetics provides the molecular mechanism of how environmental factors impact development and subsequent health and disease, including early brain and temperament development. PMID- 29229032 TI - Challenges in China's health system reform: lessons from other countries. AB - We are very pleased to have been invited to edit the inaugural virtual special issue for the Australian Journal of Primary Health. This virtual issue will present a set of recently published papers from the Australian Journal of Primary Health that have been selected for their relevance to issues faced in China. It will be launched on 11 September 2017. We have written this Editorial to set the scene for the special issue, and as a general overview of issues affecting one of our most influential neighbours in the region. PMID- 29229036 TI - The Human Right to Health. PMID- 29229038 TI - The Opportunities and Limitations of Minimally Invasive Cardiac Surgery. AB - BACKGROUND: Over the past two decades, minimally invasive techniques for classic heart valve surgery and isolated bypass surgery have been developed that enable access to the heart via partial sternotomy for most aortic valve procedures and via sternotomy-free mini-thoracotomy for other procedures. METHODS: We review the current evidence on minimally invasive cardiac surgery on the basis of pertinent randomized studies and database studies retrieved by a selective search in the MEDLINE and PubMed Central databases, as well as by the Google Scholar search engine. RESULTS: A PubMed search employing the search term "minimally invasive cardiac surgery" yielded nearly 10 000 hits, among which there were 7 prospective, randomized, controlled trials (RCTs) on aortic valve replacement, with a total of 477 patients, and 3 RCTs on mitral valve surgery, with a total of 340 patients. Only limited reports of specified centers are currently available for multiple valvular procedures and multiple coronary artery bypass procedures. The RCTs reveal that the minimally invasive techniques are associated with fewer wound infections and faster mobilization, without any difference in survival. Minimally invasive procedures are technically demanding and have certain anatomical prerequisites, such as appropriate coronary morphology for multiple bypass operations and the position of the aorta in the chest for sternotomy-free aortic valve procedures. The articles reviewed here were presumably affected by selection bias, in that patients in the published studies were preselected, and there may have been negative studies that were not published at all. CONCLUSION: Specialized surgeons and centers can now carry out many cardiac valvular and bypass operations via minithoracotomy rather than sternotomy. According to current evidence, these minimally invasive techniques yield results that are at least as good as classic open-heart surgery. PMID- 29229040 TI - Persistent Retrosternal Pain in a 72-Year-Old Woman. PMID- 29229041 TI - Continuity and Innovation. PMID- 29229039 TI - Analgesia in Patients with Trauma in Emergency Medicine. AB - BACKGROUND: Suitable analgesic drugs and techniques are needed for the acute care of the approximately 18 200-18 400 seriously injured patients in Germany each year. METHODS: This systematic review and meta-analysis of analgesia in trauma patients was carried out on the basis of randomized, controlled trials and observational studies. A systematic search of the literature over the 10-year period ending in February 2016 was carried out in the PubMed, Google Scholar, and Springer Link Library databases. Some of the considered trials and studies were included in a meta-analysis. Mean differences (MD) of pain reduction or pain outcome as measured on the Numeric Rating Scale were taken as a summarizing measure of treatment efficacy. RESULTS: Out of 685 studies, 41 studies were considered and 10 studies were included in the meta-analysis. Among the drugs and drug combinations studied, none was clearly superior to another with respect to pain relief. Neither fentanyl versus morphine (MD -0.10 with a 95% confidence interval of [-0.58; 0.39], p = 0.70) nor ketamine versus morphine (MD -1.27 [ 3.71; 1.16], p = 0.31), or the combination of ketamine and morphine versus morphine alone (MD -1.23 [-2.29; -0.18], p = 0.02) showed clear superiority regarding analgesia. CONCLUSION: Ketamine, fentanyl, and morphine are suitable for analgesia in spontaneously breathing trauma patients. Fentanyl and ketamine have a rapid onset of action and a strong analgesic effect. Our quantitative meta analysis revealed no evidence for the superiority of any of the three substances over the others. Suitable monitoring equipment, and expertise in emergency procedures are prerequisites for safe and effective analgesia by healthcare professionals.. PMID- 29229042 TI - Economic Pressure in Hospitals. PMID- 29229043 TI - Seizure or Syncope? PMID- 29229044 TI - The Commercialization of Patient-Related Decision Making in Hospitals. AB - BACKGROUND: Hospitals must make a profit to ensure their continued existence. The observed rises in case numbers and case-mix indices lead us to suspect that the admission, treatment, and discharge of patients are now being influenced not just by purely medical factors, but also by economic considerations with a view toward making a profit-i.e., that decision-making has become partially commercialized. In this study, we investigated whether doctors and hospital chief executive officers (CEOs) share this perception of their professional environment. METHODS: In a qualitative study, doctors and hospital CEOs were interviewed. The survey was carried out in two waves over the period 2013-2016. 22 pilot interviews, 41 guided interviews, 3 focus groups, 1 written expert questionnaire and 1 workshop discussion were conducted. Responses were evaluated according to the "grounded theory" of the social sciences. RESULTS: Some of the doctors' and CEOs' perceptions of the patient-care situation differed markedly from each other. The CEOs mentioned the need for a profit orientation and stressed that they obeyed the legal requirement not to have any direct influence on medical decision making, while acknowledging that physicians' actions might be influenced indirectly. The doctors, on the other hand, reported feeling increasing pressure to consider the economic interests of the hospital when making decisions about patient care, leading not only to overtreatment, undertreatment, and incorrect treatment, but also to ethical conflicts, stressful situations, and personal frustration. CONCLUSION: The doctors' responses indicate that the current economic framework conditions and the managers of hospitals are currently influencing medical care to the detriment of the patients, physicians, and nurses. It is important to acknowledge that economic pressure on hospitals can undermine the independence of medical decision-making. The dilemmas facing doctors and hospital CEOs should be openly discussed. The economic framework conditions and steering concepts should be changed as suggested by these findings. PMID- 29229045 TI - Accidental Thumb Injection With an Epinephrine Autoinjector. PMID- 29229047 TI - ? PMID- 29229046 TI - Unemployment Following Childhood Cancer. AB - BACKGROUND: Childhood cancer survivors are at risk of physical and mental long term sequelae that may interfere with their employment situation in adulthood. We updated a systematic review from 2006 and assessed unemployment in adult childhood cancer survivors compared to the general population, and its predictors. METHODS: Systematic literature searches for articles published between February 2006 and August 2016 were performed in CINAHL, EMBASE, PubMed, PsycINFO, and SocINDEX. We extracted unemployment rates in studies with and without population controls (controlled /uncontrolled studies). Unemployment in controlled studies was evaluated using a meta-analytic approach. RESULTS: We included 56 studies, of which 27 were controlled studies. Approximately one in six survivors was unemployed. The overall meta-analysis of controlled studies showed that survivors were more likely to be unemployed than controls (Odds Ratio [OR] = 1.48, 95% confidence interval [CI]: [1.14; 1.93]). Elevated odds were found in survivors in the US and Canada (OR = 1.86, 95% CI: [1.26; 2.75]), as well as in Europe (OR = 1.39, 95% CI: [0.97; 1.97]). Survivors of brain tumors in particular were more likely to be unemployed (OR = 4.62, 95% CI: [2.56; 8.31]). Narrative synthesis across all included studies revealed younger age at study and diagnosis, female sex, radiotherapy, and physical late effects as further predictors of unemployment. CONCLUSION: Childhood cancer survivors are at considerable risk of unemployment in adulthood. They may benefit from psycho social care services along the cancer trajectory to support labor market integration. PMID- 29229048 TI - ? PMID- 29229049 TI - ? PMID- 29229050 TI - ? PMID- 29229051 TI - ? PMID- 29229052 TI - Functional Magnetic Resonance Imaging of Cerebral Hemodynamic Responses to Pain Following Thoracic Thrust Manipulation in Individuals With Neck Pain: A Randomized Trial. AB - OBJECTIVE: The purpose of this study was to examine whether cerebral activation in response to noxious mechanical stimuli varies with thrust manipulation (TM) when compared with sham manipulation (SM) as measured by blood oxygenation level dependent functional magnetic resonance imaging. METHODS: Twenty-four volunteers (67% female) with complaints of acute or subacute mechanical (nontraumatic) neck pain satisfied eligibility requirements and agreed to participate. Participants were randomized to receive TM to the thoracic spine or SM, and then underwent functional magnetic resonance scanning while receiving noxious stimuli before and after TM or SM. An 11-point numeric pain rating scale was administered pre- and postmanipulation for neck pain and to determine perceptions of pain intensity with respect to neck pain and mechanical stimuli. Blood oxygenation level dependent functional magnetic resonance imaging recorded the cerebral hemodynamic response to the mechanical stimuli. RESULTS: Imaging revealed significant group differences, with those individuals in the manipulation group exhibiting increased areas of activation (postmanipulation) in the insular and somatosensory cortices and individuals in the sham group exhibiting greater areas of activation in the precentral gyrus, supplementary motor area, and cingulate cortices (P < .05). However, between-group differences on the numeric pain rating scale for mechanical stimuli and for self-reported neck pain were not statistically significant. CONCLUSIONS: This study provides preliminary level 2b evidence suggesting cortical responses in patients with nontraumatic neck pain may vary between thoracic TM and a sham comparator. PMID- 29229053 TI - Management of Back Pain-related Disorders in a Community With Limited Access to Health Care Services: A Description of Integration of Chiropractors as Service Providers. AB - OBJECTIVE: The purpose of this study was to evaluate a chiropractic service for back pain patients integrated within a publicly funded, multidisciplinary, primary care community health center in Cambridge, Ontario, Canada. METHODS: Patients consulting for back pain of any duration were referred by their medical doctor or nurse practitioner for chiropractic treatment at the community health center. Patients completed questionnaires at baseline and at discharge from the service. Data were collected prospectively on consecutive patients between January 2014 and January 2016. RESULTS: Questionnaire data were obtained from 93 patients. The mean age of the sample was 49.0 +/- 16.27 years, and 66% were unemployed. More than three-quarters (77%) had had their back pain for more than a month, and 68% described it as constant. According to the Bournemouth Questionnaire, Bothersomeness, and global improvement scales, a majority (63%, 74%, and 93%, respectively) reported improvement at discharge, and most (82%) reported a significant reduction in pain medication. More than three-quarters (77%) did not visit their primary care provider while under chiropractic care, and almost all (93%) were satisfied with the service. According to the EuroQol 5 Domain questionnaire, more than one-third of patients (39%) also reported improvement in their general health state at discharge. CONCLUSION: Implementation of an integrated chiropractic service was associated with high levels of improvement and patient satisfaction in a sample of patients of low socioeconomic status with subacute and chronic back pain. PMID- 29229054 TI - Relationship Between Subjective Experience of Individuals, Practitioner Seniority, Cavitation Occurrence, and 3-Dimensional Kinematics During Cervical Spine Manipulation. AB - OBJECTIVE: The purpose of this study was to assess individual subjective experience (ISE) of the recipients of a cervical manipulation and to analyze the influence of kinematics, cavitation occurrence, and practitioner seniority on individual experience. METHODS: Practitioners with different seniority (years of experience) manipulated 20 asymptomatic volunteers at C3 and C5 on both sides. Kinematics were recorded using a 3-dimensional electrogoniometer, and ISE data were gathered through a questionnaire to explore the subjects' experiences of manipulation in terms of tactile sensations, relaxation, perception of the task, and therapist handling. Kinematics, occurrence of cavitation, practitioner's seniority, and ISE data were analyzed concurrently. RESULTS: Motion parameters obtained during manipulation were found to be influenced by cavitation occurrence and differences between practitioners. Data analysis indicated that ISE could be grouped into 2 factors. The first revolved around grip firmness and range and speed of practitioner's gesture. The second factor represented patient's relaxation and the precision of handling. Also, most ISE data correlated with kinematics, although a subjective measurement did not always correlate the highest with its objective counterpart. When cavitation occurred, ISE ratings were higher, suggesting that participants may associate cavitation with the success of manipulations. Higher practitioner seniority (more years of experience) induced feelings of higher speed, amplitude, firmness, and precision. CONCLUSIONS: Recipients of cervical manipulation experienced different subjective feelings that can be expressed in 2 dimensions. These feelings are influenced by cavitation occurrence and practitioner's seniority. A better understanding of an individual's subjective experience related to cervical manipulation could increase confidence and improve the patient-therapist relationship, and it may provide further therapeutic perspectives for the practitioners. PMID- 29229056 TI - Determining Predictive Outcome Factors for a Multimodal Treatment Program in Low Back Pain Patients: A Retrospective Cohort Study. AB - OBJECTIVE: The purpose of this study was to determine the factors predictive of outcomes in a multifaceted rehabilitation program for acute and chronic low back pain (LBP) patients. METHODS: A retrospective cohort study was performed on 565 LBP patients (153 acute and 412 chronic) who participated in a multimodal treatment program at an outpatient clinic in Belgium between 2007 and 2010. The predictive value of several factors, including age, sex, body mass index, fat percentage, Oswestry Disability Index score, Beck Depression Index score, Numeric Pain Rating Scale score for back and leg pain intensity, and Tampa Scale for Kinesiophobia score on favorable treatment outcomes was examined using logistic regression analysis. RESULTS: The results from the multivariate regression indicated that a higher score on the Tampa Scale for Kinesiophobia (odds ratio [OR] = 0.92) decreases the odds of a favorable outcome following a multimodal treatment program in acute LBP. Older age (OR = 0.97), low LBP intensity (OR = 1.191), and higher scores on the Beck Depression Index (OR = 0.96) and the Oswestry LBP Disability Index (OR = 0.93) decreased the odds of a favorable treatment outcome in chronic LBP. CONCLUSIONS: The findings of this study indicate that factors predictive of a (un)favorable treatment outcome differ between acute and chronic LBP. Specifically, kinesiophobia is predictive of poor treatment outcome in acute LBP. In chronic LBP, older age, low LBP intensity, and higher degrees of depression and LBP-related disability are predictive of poor treatment outcome. Therapists should consider assessing these predictive factors at intake to tailor the content of the multimodal treatment program to individual patient needs. PMID- 29229055 TI - Immediate Effects of Upper Cervical Translatoric Mobilization on Cervical Mobility and Pressure Pain Threshold in Patients With Cervicogenic Headache: A Randomized Controlled Trial. AB - OBJECTIVE: The purpose of this study was to evaluate the immediate effects of upper cervical translatoric spinal mobilization (UC-TSM) on cervical mobility and pressure pain threshold in subjects with cervicogenic headache (CEH). METHODS: Eighty-two volunteers (41.54 +/- 15.29 years, 20 male and 62 female) with CEH participated in the study and were randomly divided into the control and treatment groups. The treatment group received UC-TSM and the control group remained in the same position for the same time as the UC-TSM group, but received no treatment. Cervical mobility (active cervical mobility and flexion-rotation test), pressure pain thresholds over upper trapezius muscles, C2-3 zygapophyseal joints and suboccipital muscles, and current headache intensity (visual analog scale) were measured before and immediately after the intervention by 2 blinded investigators. RESULTS: After the intervention, UC-TSM group exhibited significant increases in total cervical mobility (P = .002, d = 0.16) and the flexion-rotation test (P < .001, d = 0.81-0.85). No significant difference in cervical pressure pain thresholds were observed between groups (P > .05). Nevertheless, there was a significantly lower intensity of headache in the UC-TSM group (P = .039, d = 0.57). CONCLUSIONS: Upper cervical translatoric spinal mobilization intervention increased upper, and exhibited a tendency to improve general, cervical range of motion and induce immediate headache relief in subjects with CEH. PMID- 29229057 TI - Functional Limitations in Adults Who Utilize Chiropractic or Osteopathic Manipulation in the United States: Analysis of the 2012 National Health Interview Survey. AB - OBJECTIVES: The goals of this study were to identify self-reported differences in function, comorbidities, and medical service utilization among adults who reported using chiropractic and/or osteopathic manipulation in the 2012 National Health Interview Survey, and to compare these between older and younger adults. METHODS: We conducted a descriptive study of adults aged 18 or older who were included in the 2012 National Health Interview Survey and the Alternative Medicine Questionnaire. We included those who reported using chiropractic and/or osteopathic manipulation in the past 12 months. Responses were analyzed using SAS software. Weighted estimates were reported as percentages of chiropractic/osteopathic users overall and by age group (<65 years vs >=65 years). RESULTS: Among the 8.5% of US adults who reported receiving manipulation, 97.6% saw chiropractors. Most adults were under age 65 (83.7%), female (56.6%), and white (85.1%). Except for sitting tolerance, functional limitations were significantly higher among older manipulation users compared with younger manipulation users (all P < .001). Older (vs younger) chiropractic/osteopathic users more often reported functional limitations (65.7% vs 37.2%), had difficulty walking without equipment (14.7% vs 2.8%), found it very difficult or were unable to walk one-quarter mile (15.7% vs 3.8%) or climb 10 steps (11.4% vs 2.5%), and needed help with instrumental activities of daily living (6.9% vs 2.0%). Comorbidities differed by age: cardiovascular events/conditions, cancer, diabetes, and arthritis were more common among older adults, and headaches, neck pain, and depression were more frequent in younger adults. Similar proportions of older and younger adults had emergency room visits (23.0% vs 21.7%); older adults reported more surgeries (26.1% vs 15.4%). CONCLUSIONS: Notable differences exist in functional limitations and comorbidities between older and younger chiropractic and osteopathic manipulation users. This information could inform clinical practice, education, and policy. PMID- 29229058 TI - Expectations of Qigong and Exercise Therapy in Patients With Long-term Neck Pain: An Analysis of a Prospective Randomized Study. AB - OBJECTIVE: The aim of the present study was to study differences in treatment expectations after participating in qigong and exercise therapy among participants with long-term neck pain, the impact of total group expectations on treatment outcomes, and the relationship between these treatment expectations and pain and disability. METHOD: Reliable questionnaires were used. Differences between qigong and exercise was studied in a randomized, controlled, multicenter trial (n = 122). The impact of total group expectations on treatment outcomes and the association between these treatment expectations and pain and disability were studied with nonparametric statistical analysis and Spearman's correlation coefficient. RESULTS: The exercise group had higher expectations than the qigong group before the intervention on how logical treatment seemed to be and after the intervention on treatment credibility (ie, that the treatment would reduce/eliminate neck pain). The exercise group was also more confident that the treatment could reduce neck pain and significantly increased their expectations of reduced neck pain over the 3-month intervention period. Both treatment groups had high expectations of the assigned treatment. Those with high expectations had better treatment outcomes in pain and disability. The relationship between treatment expectations and credibility, pain, and disability was weak. CONCLUSIONS: The current findings support the role of assessment of expectation/credibility for positive treatment results. An understanding of each patient's treatment expectations may be helpful in guiding patients with respect to appropriate interventions and as an indication of risk of poor outcome. PMID- 29229059 TI - The Reliability of Standing Sagittal Measurements of Spinal Curvature and Range of Motion in Older Women With and Without Hyperkyphosis Using a Skin-Surface Device. AB - OBJECTIVE: The purpose of this study was to investigate the intrarater reliability of a skin-surface instrument (Spinal Mouse, Idiag, Voletswil, Switzerland) in measuring standing sagittal curvature and global mobility of the spine in older women with and without hyperkyphosis. METHODS: Measurements were made in 19 women with hyperkyphosis (thoracic kyphosis angle >=50 degrees ), mean age 67 +/- 5 years, and 14 women without hyperkyphosis (thoracic kyphosis angle <50 degrees ), mean age 63 +/- 6 years. Sagittal thoracic and lumbar curvature and mobility of the spine were assessed with the Spinal Mouse during neutral standing, full spinal flexion, and full spinal extension. Tests were performed by the same examiner on 2 days with a 72-hour interval. The intrarater reliability of the measurements was analyzed using the intraclass correlation coefficient, standard error of measurement and minimal detectable change. RESULTS: Intraclass correlation coefficients ranged from 0.89 to 0.99 in both groups. The standard errors of measurement ranged from 1.02 degrees to 2.06 degrees in the hyperkyphosis group and from 1.15 degrees to 2.22 degrees in the normal group. The minimal detectable change ranged from 2.85 degrees to 5.73 degrees in the hyperkyphosis group and from 3.20 degrees to 6.17 degrees in the normal group. CONCLUSIONS: Our results indicated that the Spinal Mouse has excellent intrarater reliability for the measurement of sagittal thoracic and lumbar curvature and mobility of the spine in older women. PMID- 29229060 TI - Development and Validation of Prediction Equations for Spinal Curve Angles Based on Skin Surface Measurements. AB - OBJECTIVE: The purpose of this study was to develop, assess the reliability of, and validate prediction equations that estimate the sagittal curves of the spine from the skin surface. METHODS: Forty digital panoramic radiographs were used to develop the prediction equation, and 59 radiographs were used to assess reliability and validate the equations. For evaluation of the thoracic and lumbar curves, anatomical reference points were marked on the vertebral body, spinous process, and skin surface at the C6, C7, T2, T4, T6, T8, T10, T12, L2, L4, and S2 vertebrae. Three third-degree polynomials were obtained, estimated with the least squares method: inner curves from the centroid of the vertebral bodies and from the apex of the spinous processes and external curve from the skin surface. The magnitude of the curves of each region was estimated based on the angle between tangent lines at several vertebral levels. Prediction equations were obtained (simple linear regression) for the vertebral levels that had the best correlation between the inner and surface curves. The validation of the prediction equations was confirmed using Pearson's correlation (r), Student t test, and root mean square error. The reliability of the method was confirmed using the intraclass correlation coefficient, standard error of measurement, and minimal detectable change (alpha = 0.05). RESULTS: The best correlations were obtained between the T4-T12 (thoracic) and T10-S2 (lumbar) levels (r > 0.85). For the intrarater and interrater reliability, the correlation was higher than 0.965 and higher than 0.896, respectively. There was a significant and strong correlation between estimated and actual values for the thoracic and lumbar curves, which was confirmed by the t-test results and by the root mean square error inferior to 1 degrees . CONCLUSION: Prediction equations can precisely and accurately estimate the angles of the internal sagittal curves of the spine from the skin surface. PMID- 29229061 TI - Accuracy of a Radiological Evaluation Method for Thoracic and Lumbar Spinal Curvatures Using Spinous Processes. AB - OBJECTIVE: The purpose of this study was to assess a radiographic method for spinal curvature evaluation in children, based on spinous processes, and identify its normality limits. METHODS: The sample consisted of 90 radiographic examinations of the spines of children in the sagittal plane. Thoracic and lumbar curvatures were evaluated using angular (apex angle [AA]) and linear (sagittal arrow [SA]) measurements based on the spinous processes. The same curvatures were also evaluated using the Cobb angle (CA) method, which is considered the gold standard. For concurrent validity (AA vs CA), Pearson's product-moment correlation coefficient, root-mean-square error, Pitman- Morgan test, and Bland Altman analysis were used. For reproducibility (AA, SA, and CA), the intraclass correlation coefficient, standard error of measurement, and minimal detectable change measurements were used. RESULTS: A significant correlation was found between CA and AA measurements, as was a low root-mean-square error. The mean difference between the measurements was 0 degrees for thoracic and lumbar curvatures, and the mean standard deviations of the differences were +/-5.9 degrees and 6.9 degrees , respectively. The intraclass correlation coefficients of AA and SA were similar to or higher than the gold standard (CA). The standard error of measurement and minimal detectable change of the AA were always lower than the CA. CONCLUSION: This study determined the concurrent validity, as well as intra- and interrater reproducibility, of the radiographic measurements of kyphosis and lordosis in children. PMID- 29229063 TI - An overview of nonhuman primates' communication and social abilities through behavioral and neuroscientific approaches. PMID- 29229062 TI - Serum GH concentrations must now be expressed in mass units in France...as in the rest of the world. PMID- 29229064 TI - What is a gesture? A meaning-based approach to defining gestural repertoires. AB - Current systems of categorising ape gestures are typically subjective, relying on human intuition. We have systematised the features on which categorization depends (movement; body part; one/both limbs; use of detached object; rhythmic repetition; contact with recipient), showing that a potential repertoire of over 1000 gestures is physically possible, as large as the lexicon of some languages. In contrast, little more than a tenth of these gestures is used in chimpanzee communication. The striking overlaps in repertoire found between populations and even species of great ape are evidently not a result of a restricted set of possible gestures. Using the reactions of signallers to identify which gestures are intended to be different by the apes themselves, we revised the current classification, making some new distinctions and abolishing others previously considered important, giving a final repertoire of 81. A small number of gestures are used deictically, such that the recipient must pay attention to specific locations to satisfy the signaller; raising the possibility of a stepping-stone to the evolution of reference. PMID- 29229065 TI - Environmental Health and Resources That We Need. PMID- 29229066 TI - Management of Childhood Functional Constipation. PMID- 29229067 TI - Practice Guidelines for Peanut Allergies. AB - This article reviews the latest recommendations and clinical practice guidelines for peanut allergies among the pediatric population. Recommendations in this paper were compiled using information collected from a variety of publications of accredited professional organizations. Peanut allergies are the body's response to what it sees to be an unwanted substance in the body. This article focuses on the causes, signs and symptoms, prevention, diagnosis, and management of peanut allergies. PMID- 29229068 TI - Letter from the Editor. PMID- 29229069 TI - The use of an iced cotton bud as an effective pre-cooling method for palatal anaesthesia: A technical note. AB - The palatal injection of anaesthesia is more painful for the patient when compared to other sites of the oral cavity. Pre-cooling (cyro anaesthesia) is a well-known method practiced to reduce pain, with the use of ice or refrigerant spray on the affected site. The already known methods of ice application to the palatal site have few practical drawbacks. Therefore, this technical note highlights the use of an iced cotton bud as a novel way of providing effective pre-cooling for palatal anaesthesia. Commercially available cotton buds were dipped in clean water and then placed in the freezer. Next the frozen cotton bud was placed on the proposed anaesthetic site for one minute and anaesthesia less than 0.5CC local anaesthetic solution was delivered at a slow pace while maintaining pressure using the iced-cotton cotton bud. All patients tested showed a 0 pain response to a visual analogue scale of 0-10. This technique can be valuable to dental practitioners who are aiming for a pain free anaesthetic experience for their patients. There is potential for further research and evaluation of this technique. PMID- 29229070 TI - Infective endocarditis - An update for dental surgeons. AB - Infective endocarditis (IE) is associated with significant morbidity and mortality. The prevention of infective endocarditis, for many years, has involved the identification of at risk patients undergoing medical or dental procedures and the use of pre-procedural antibiotic prophylaxis. However, evidence regarding the effectiveness of such measures is lacking while evidence is mounting for the adverse effects of inappropriate antibiotic use. International guidelines for antibiotic prophylaxis were amended, radically in some cases to reflect this. Subsequent epidemiological observations of IE have shown mixed results, strengthening calls for well conducted randomised control trials, now that there is genuine clinical equipoise among clinicians about this question. PMID- 29229071 TI - Branching of mandibular canal on cone beam computed tomography images. AB - BACKGROUND: Mandibular neurovascular canal contents may be vulnerable to damage during mandibular surgical procedures. Greater knowledge of the location and configuration of the mandibular canal can help in the safe performance of these procedures in the dental clinic. Cross-sectional CBCT imaging is a good modality for studying the course, location, configuration and accessory branches of the mandibular canal. The aim of this study was to observe the branching of the mandibular canal at different segments of the mandible and mandibular tooth groups. METHODS: CBCT images of 116 mandibular halves were included in this study. The presence of secondary branching of the mandibular canal in the ramus, retromolar area, molar and premolar teeth as well as the length, diameter and angle of these branches were observed. RESULTS: sixty nine mandibular halves (59.5%), had a main canal with no branching, There were 36 IAC (31%) with one, 8 (6.9%) with two, 2 (1.7%) with three and 1(0.9%) with 5 accessory branches. Of these secondary branches, 16 (25.4%) were in the ramus, 16(25.4%) in the retromolar, and 31(49.2%) in the molar regions. CONCLUSION: Advanced cross sectional imaging modalities especially CBCT is a suitable tool for observing anatomic characteristics of mandibular canal to preserve this vital structure in surgical procedures. PMID- 29229072 TI - The role of subepithelial connective tissue graft for reconstruction of interdental papilla: Clinical study. AB - BACKGROUND: The ideal goal of periodontal therapy is regeneration of the lost periodontium. However regeneration of the lost interdental papilla has been elusive. Therefore the ability of rebuilding lost papillae in the maxillary segment has become one of the major challenges in periodontal plastic surgery. OBJECTIVES OF THE STUDY: To evaluate the success and predictability of surgical technique using a sub epithelial connective tissue graft interposed in a coronally displaced flap to reconstruct the lost interdental papillae. METHODS: The purpose of this study is to evaluate the success and predictability of a surgical technique using a subepithelial connective tissue graft from the palate with coronally displaced flap to regenerate the lost interdental papilla in 11 systemically healthy patients. RESULTS: Post treatment follow up show statistically significant results from baseline to 3months and 6 months. CONCLUSION: The present study attempted a single surgical procedure to reconstruct the lost interdental papilla using subepithelial connective tissue graft interposed in coronally displaced flap in 11 patients with Tarnow's class II papillary recessions. At the end of 6 months it was found that the sites demonstrated significantly superior results as determined by percentage of reduction in the area of the black triangle both clinically (60.26%) and on the model (54.29%). CLINICAL IMPLICATIONS: Although complete regeneration of interdental papilla was not achieved, the results of this study demonstrate that a predictable and an esthetically pleasing surgical outcome can be achieved in one attempt for class II papillary recessions. PMID- 29229073 TI - Disinfection of dentinal tubules with 2% Chlorhexidine gel, Calcium hydroxide and herbal intracanal medicaments against Enterococcus faecalis: An in-vitro study. AB - AIM: This in vitro study was conducted to evaluate the disinfection of dentinal tubules using 2% Chlorhexidine gel, Honey, Aloe vera gel, Curcuma longa, Propolis gel and Calcium hydroxide against Enterococcus faecalis. MATERIALS AND METHOD: Two hundred and ten human mandibular first premolars were infected with Enterococcus faecalis for 21 days. Samples were divided into 7 groups. Group I- Saline (negative control), Group II- 2% Chlorhexidine gel(CHX), Group III- honey, Group IV- Aloe vera gel, Group V- 20% Curcuma longa gel, Group VI- Propolis gel and Group VII -Calcium hydroxide (CH). At the end of 1, 3 and 5 days, the antimicrobial efficacy of medicaments against E.faecalis was assessed at the depths of 200um and 400um. RESULTS: 2% Chlorhexidine gel was most effective followed by Propolis and Curcuma longa. CONCLUSION: 2% Chlorhexidine gel gave the best results. Among the herbal extracts Propolis and Curcuma longa hold a promising future but to implement their use as sole intracanal medicaments clinically, further in vivo and long term studies are warranted. PMID- 29229074 TI - Factors associated with faculty participation in research activities in dental schools. AB - BACKGROUND: To quantify participation in dental research activities in Malaysia, and investigate its association with socio-demographic and professional characteristics, and perceptions of research and development (R&D) culture. MATERIALS AND METHODS: Dental academics in Malaysian dental schools were invited to complete a questionnaire by email and post. The survey comprised questions on research activities in the past 12 months, socio-demographic and professional characteristics, and the R&D Culture Index. Principal components factor analysis was carried out to confirm the factor structure of the R&D Culture Index. Chi square test was used to identify association of research activities with R&D culture, and socio-demographic and professional characteristics. Binary logistic regression was carried to identify predicators of research activities. RESULTS: Of 256 potential participants contacted, 128 (50%) useable responses were returned. Three R&D Culture factors accounting for 57.4% of variance were extracted. More positive perception of R&D Support was associated with Malaysians (0.025) and those employed in Government schools (0.017). R&D Skills and Aptitude were associated with older respondents (0.050), PhD qualification (0.014) and more years in academia (0.014). R&D Intention was associated with any of the socio-demographic characteristics. Thirty (23.4%) respondents reported a peer review research publication in the past 12 months, which was associated with having a PhD (OR 12.79, CI 1.28-127.96), after adjustment in regression analyses. DISCUSSION: Postgraduate research training should be encouraged to promote participation in research activities. R&D culture did not appear to impact on research productivity. Other factors such as individual attitudinal interests should be studied. PMID- 29229075 TI - Does periodontal inflammation affect glycosylated haemoglobin level in otherwise systemically healthy individuals? - A hospital based study. AB - BACKGROUND AND OBJECTIVES: Microbial biofilm and host susceptibility play an important role in the initiation and progression of periodontitis. Periodontitis is considered the sixth complication of diabetes mellitus and a bidirectional relationship exists between diabetes and periodontitis. This cross-sectional observational study was undertaken to evaluate the glycosylated haemoglobin (HbA1c) level in chronic periodontitis. METHODS: The study involved 100 subjects. The case group consisted of 50 subjects with chronic periodontitis and the control group consisted of 50 periodontally healthy subjects. Periodontal parameters including plaque index, oral hygiene index, modified gingival index, probing pocket depth, and clinical attachment level were measured and recorded. Systemic parameters like Body Mass Index (BMI), Waist Hip Ratio (WHR), C- Reactive Protein (CRP), Glycosylated haemoglobin (HbA1c), lipid profile, fasting blood sugar, post prandial blood sugar and serum albumin were assessed in all subjects. RESULTS: The mean HbA1C for the case group was 6.27+/-1.5 and for the control was 5.36+/-0.4 and the difference was statistically significant (p = 0.001). The mean FBS, PPBS, LDL, WHR, CRP was statistically significant between groups (p <=0.05). Periodontal parameters like PI, OHI, MGI, PD and CAL were significantly higher in the case group than the control group (p value <= 0.05). The multivariate linear regression model with the dependent variable HbA1c showed chronic periodontitis was significantly associated with HbA1c level. CONCLUSION: In chronic periodontitis patients (otherwise systemically healthy) the presence of periodontal inflammation affected the glycosylated haemoglobin level and they were in prediabetes stage. Therefore, it is plausible that the prediabetes stage might be reduced via appropriate periodontal therapy. PMID- 29229076 TI - The use of 3D models to improve sinus augmentation outcomes - A case report. AB - Sinus augmentation is a predictable procedure that is often required when restoring the posterior maxilla with dental implants. Even with high success rates, careful pre-surgical planning is crucial. A 3D model is a valuable aid for the clinician as it allows for pre-operative simulation, which can reduce surgical time, reduce the risk of intra-operative complications and decrease the potential for error. The aim of this case report is to focus on how such a model is useful when undertaking a sinus augmentation procedure with simultaneous implant placement. PMID- 29229077 TI - Occlusal characteristics and ethnic variations in Malaysian orthodontic patients. PMID- 29229078 TI - Management of peri-implantitis - A contemporary synopsis. AB - Prevalence of peri-implant complication is expected to be on the rise with the increased number of implants being placed. Depending on the degree of osseous involvement, the clinician needs to decide if the treatment goal is to arrest the disease progression, regeneration or explantation and replacement. Host's medical status, defect configuration, aesthetic outcome, ability to access for plaque control post-treatment, and the patient's wishes are key factors to consider. The purpose of this review is to provide a contemporary synopsis on the management of peri-implantitis with emphasis on explantation. Guidance on the identification of factors/situations where salvaging an implant may be less favourable is discussed and the various techniques to remove a fractured, or peri-implantitis-affected non-mobile implant are described. PMID- 29229079 TI - City housing atmospheric pollutant impact on emergency visit for asthma: A classification and regression tree approach. AB - INTRODUCTION: Particulate matter, nitrogen dioxide (NO2) and ozone are recognized as the three pollutants that most significantly affect human health. Asthma is a multifactorial disease. However, the place of residence has rarely been investigated. We compared the impact of air pollution, measured near patients' homes, on emergency department (ED) visits for asthma or trauma (controls) within the Provence-Alpes-Cote-d'Azur region. METHODS: Variables were selected using classification and regression trees on asthmatic and control population, 3-99 years, visiting ED from January 1 to December 31, 2013. Then in a nested case control study, randomization was based on the day of ED visit and on defined age groups. Pollution, meteorological, pollens and viral data measured that day were linked to the patient's ZIP code. RESULTS: A total of 794,884 visits were reported including 6250 for asthma and 278,192 for trauma. Factors associated with an excess risk of emergency visit for asthma included short-term exposure to NO2, female gender, high viral load and a combination of low temperature and high humidity. CONCLUSION: Short-term exposures to high NO2 concentrations, as assessed close to the homes of the patients, were significantly associated with asthma-related ED visits in children and adults. PMID- 29229080 TI - Association of adiposity with pulmonary function in older Chinese: Guangzhou Biobank Cohort Study. AB - OBJECTIVE: We examined the association between different adiposity indices and pulmonary function in Chinese adults in the Guangzhou Biobank Cohort Study (GBCS). METHODS: Participants with body mass index (BMI) < 18.5 (underweight) were excluded. Adiposity indices including BMI, waist circumference (WC), waist hip ratio, waist height ratio and body fat percentage were measured. Lung function was assessed by spirometry using a turbine flowmeter. We analyzed percent predicted for forced expiratory volume in 1 s (FEV1%), forced vital capacity (FVC %) and restrictive respiratory defect (FEV1/FVC ratio > low limits of normal and FVC % <0.80). RESULTS: Of 16186 participants (mean age 61.4 +/- 7.2 years; 74.0% women), 116 (0.7%) had only general obesity (BMI >=28 kg/m2), 4079 (25.2%) had only central obesity (WC: >=90 cm in men, >=80 cm in women) and 1591 (9.8%) had both central obesity and general obesity. Comparing to those with neither central nor general obesity, those with only central adiposity and with both central and general obesity had lower pulmonary function (adjusted beta range from -2.85 to -6.02 for FEV1% and FVC%, adjusted OR range from 1.14 to 1.70, all P < 0.05). But those with only general obesity had better but non significant pulmonary function. (Crude beta range from 1.46 to 2.92 for FEV1% and FVC%, crude OR range from 0.68 to 0.93, all P > 0.05). Both FEV1% and FVC% decreased per standard deviation increase in obesity indices (adjusted beta from 0.46 to -3.17, all P < 0.002). A positive association of central or general obesity with restrictive respiratory defect was observed (adjusted odds ratio (AOR) from 1.50 to 2.04, all P < 0.002). Further adjustment for WC reversed the inverse association between BMI and pulmonary function (adjusted beta from 1.93 to 6.22, all P < 0.001) and restrictive respiratory defect (adjusted AOR from 0.72 to 0.80, all P < 0.001). CONCLUSION: Central adiposity and its indices, but not general adiposity and BMI, were independently associated with lower pulmonary function and higher risk of restrictive respiratory defect in older Chinese. PMID- 29229081 TI - Diversity of methacholine dose-response curves among asymptomatic non-asthmatics. PMID- 29229082 TI - Asthma is associated with endometriosis: A retrospective population-based cohort study. AB - BACKGROUND: Evidence regarding the association between asthma and endometriosis is limited and inconsistent. The goal of the study was to investigate whether women diagnosed as having asthma were at a greater risk of endometriosis than age matched unaffected women. METHODS: We conducted a nationwide population-based retrospective study by using data retrieved from the Taiwan National Health Insurance Research Database during the period of 2000-2005 with follow-up through 2013. The current analysis included 7337 women aged 12-50 years with newly diagnosed asthma and using asthma-related medications and 29,348 age-matched women without asthma. A Cox proportional hazards regression model was used to estimate the risks of endometriosis in women with asthma as compared with those without asthma. RESULTS: The overall risk of endometriosis in the asthma group was 1.50-fold higher (95% confidence interval = 1.33-1.70) than that in the nonasthma group. A stratified analysis by age further revealed that patients with asthma were associated with a higher risk of endometriosis in age groups of 21-50 years. CONCLUSION: Compared with women without asthma, women with asthma of reproductive age are at a higher risk of endometriosis. Additional studies are warranted to elucidate the mechanism(s) underlying the association between asthma and a higher risk of endometriosis. PMID- 29229083 TI - Thoracic involvement in IgG4-related disease in a UK-based patient cohort. AB - IgG4-related disease (IgG4-RD) is a multi-system fibro-inflammatory disorder with classical histopathological findings, often in the context of elevated serum IgG4 levels. The thoracic manifestations of IgG4-RD are numerous and can mimic several common and better known conditions. The objective of this study was to outline the frequency and nature of thoracic involvement in a prospective cohort of IgG4 RD patients who met defined diagnostic criteria. Over 40% of IgG4-RD patients had clinicoradiological and/or histological evidence of thoracic involvement, predominantly mediastinal lymphadenopathy, the majority associated with multi system disease outside the chest. Thoracic involvement was associated with a higher serum IgG4 level, potentially representing greater disease activity or spread. Our data highlight the diverse nature of thoracic IgG4-RD, and the importance of knowledge and recognition of the condition among respiratory physicians who are likely to encounter this disease entity on an increasing basis. PMID- 29229084 TI - Serological study of Bordetella Pertussis, Mycoplasma Pneumonia and Chlamydia Pneumonia in Iranian hajj pilgrims with prolonged cough illnesses: A follow-up study. AB - INTRODUCTION: Hajj pilgrimage is the biggest and longest mass gathering in the Muslim world. Annually, about 50% of more than 2.5 million pilgrims participating in this ritual get involved in severe devastating coughs. Most coughs continue, so the pilgrims turn back home and transmit them to family members and other people. Despite the high prevalence of coughs for many years, what causes them remains unknown. Considering the pertussis-like clinical picture of the so-called "hajj coughs", the researchers conducted a study to measure antibodies against three known common atypical bacteria, namely Bordetella Pertussis, Chlamydia Pneumonia and Mycoplasma Pneumonia. PATIENTS AND METHODS: The study was done on three out of eleven groups of pilgrims from Yazd province, central Iran. The sample was selected randomly and consisted of 202 pilgrims who completed an informed consent. Their blood samples were taken, and the plasma was separated and then stored at -70 degrees C. After turning back from the journey, the pilgrims had their second blood samples taken. As many as 52 pilgrims failed to come for the second sampling, and two samples were broken during transportation. The final analysis was performed on the remaining 148 pairs of samples. RESULTS: Antibodies were already elevated in many pilgrims before the journey probably due to their old age (causing more exposure to pathogens) or unplanned pertussis vaccination. After their return, antibody elevation was only mild, again probably due to the old age of the participants (i.e. due to their weaker immune systems). Some antibodies even fell down without any known reason. In this study, previous hajj journey was assumed as a prophylactic factor, due to acquisition of immunity. Coughs with a prolonged pertussis-like picture were also presumed to be more related than other types of coughs to atypical pathogens. Statistical tests showed that the history of previous journeys had no prophylactic effect. Also, no correlation was found between the clinical pictures of coughs and infection with atypical bacteria. CONCLUSION: Even though some rises and falls occurred in the antibodies titer, the variations could hardly be attributed to coughs in this study. Indeed, the variation of antibodies had no meaningful relationship with clinical factors. In this regard, further studies are needed to clarify the reason for the so-called "hajj coughs", but epidemiological studies will be difficult to do until easier and more reliable methods become available for accurate diagnosis. PMID- 29229085 TI - Prevalence of comorbidities in COPD patients by disease severity in a German population. AB - : Chronic obstructive pulmonary disease (COPD) is commonly associated with multiple comorbidities. Our objective was to assess the prevalence of comorbidities in patients with COPD and to relate their prevalence to the severity of the disease by using a large German health care database. Based on the retrospective analysis of a two-year (2013-2014) database from the German Statutory Health Insurance system, we obtained a representative sample of 4,075,493 german insurants. This sample included 146,141 patients with COPD (age: >=35 years). To these patients, we matched 1:1 by age and gender randomly selected non-COPD controls. We assessed the comorbidities and the use of cardiovascular drugs, and examined COPD subgroups according to lung function (ICD 10-coded FEV1) and the treatment with long-acting inhaled bronchodilators. Compared to non-COPD, patients with COPD had a higher prevalence of hypertension, congestive heart failure, diabetes, gastroesophageal reflux disease, chronic kidney disease, osteoporosis, psychiatric disease and lung cancer, and used more cardiovascular-related drugs. However, the prevalence of comorbidities did not correlate to the severity of airflow limitation. The results of this sizeable nationwide survey support the concept that individuals with COPD need careful evaluation regarding comorbidities. This can already be of relevance in patients with mild to moderate airflow limitation. TAKE HOME MESSAGE: Comorbidities in COPD have a complex relationship with disease severity, requiring a comprehensive therapy approach. PMID- 29229086 TI - Effects of ground-based walking training on daily physical activity in people with COPD: A randomised controlled trial. AB - This study explored the effects of ground-based walking training on physical activity (PA) and sedentary time (ST) in people with chronic obstructive pulmonary disease (COPD). Participants were randomised to a walk group (WG) [supervised, ground-based walking training, two or three times per week for 8-10 weeks] or a control group (CG) [usual medical care]. Before and after the intervention period, PA and ST were measured using the SenseWear(r) Pro3 Armband. Of the 143 participants randomised, 101 (71%) had sufficient data for the primary analysis; 62 were from the WG (mean [SD] age 69 [8] years, FEV1 42 [15] % predicted) and 39 were from the CG (age 68 [9] years, FEV1 43 [15] % predicted). No between-group differences were demonstrated in any measure of PA or ST (all p > 0.05). Secondary analyses (n = 44) revealed that, compared to the CG, the proportion of waking hours spent in moderate intensity PA accumulated in uninterrupted bouts of between 30 and 60 min, increased in the WG by 0.8% (95% CI = 0.4 to 1.3). This study demonstrated that, in people with COPD, ground-based walking training alone had little, if any clinically important effect on daily PA and no effect on ST. PMID- 29229087 TI - Who's at risk of thunderstorm asthma? The ryegrass pollen trifecta and lessons learnt from the Melbourne thunderstorm epidemic. AB - The Melbourne thunderstorm asthma epidemic in November 2016 was unprecedented in scale and impact. We systematically reviewed our hospital's patients with thunderstorm asthma to identify key risk factors. Of 85 adult patients assessed, the majority (60%) had no prior diagnosis of asthma. However, allergic rhinitis during the grass pollen season was almost universal (99%), as were ryegrass pollen sensitization (100%) and exposure to the outdoor environment during the thunderstorm (94%). Airborne pollen levels on the thunderstorm day were extreme. We conclude that ryegrass pollen sensitization, clinical allergic rhinitis, and acute allergen exposure constitute a risk-factor 'trifecta' for thunderstorm asthma. PMID- 29229088 TI - Correlation of serum vascular adhesion protein-1 with airflow limitation and quality of life in stable chronic obstructive pulmonary disease. AB - OBJECTIVE: The serum vascular adhesion protein-1 (VAP-1) level increases in chronic inflammatory diseases. The present study aimed to examine serum VAP-1 level in patients with stable chronic obstructive pulmonary disease (COPD) and the correlation of this marker with airflow limitation and health-related quality of life using the COPD Assessment Test (CAT). MATERIALS AND METHODS: We measured serum VAP-1 level in 43 patients with stable COPD and 30 control subjects and compared them with airflow limitation according to the COPD stage in the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) criteria, peripheral O2 saturation (SpO2), and CAT score. We also tested the association of serum VAP 1 level with COPD patients' clinical parameters. RESULTS: Serum VAP-1 level increased with increasing severity of COPD according to the GOLD classification (P = 0.007). It also increased in patients with high CAT groups and high values on the modified Medical Research Council dyspnea scale (P = 0.012 and P = 0.015, respectively). In addition, there was a significant positive correlation between serum VAP-1 level and both SpO2 and CAT score (r = -0.404, P = 0.007; r = 0.482, P = 0.001, respectively). CONCLUSION: The study showed that serum VAP-1 level increased with an increasing severity of obstruction in patients with stable COPD. This increase was associated with a reduced quality of life and increased severity of hypoxia. These results suggest that inhibiting serum VAP-1 level in COPD patients may be useful in managing the disease. PMID- 29229089 TI - Annual progression of endothelial dysfunction in patients with COPD. AB - BACKGROUND: The risk to die from cardiovascular disease is particularly high in patients with COPD. This longitudinal study aims to evaluate changes of endothelial function over time and identify underlying mechanisms in COPD patients. METHODS: In stable COPD patients we performed annual assessments of endothelial function by flow-mediated dilatation (FMD), lung function, systemic inflammation and cholesterol, sympathetic activation, oxygenation, physical activity and exercise capacity. Associations between annual changes of potential predictors and FMD were investigated in mixed analysis. RESULTS: 76 patients (41% GOLD stage 1/2, 30% 3, 29% 4) were included. Endothelial function significantly decreased annually by -0.14% (95%CI -0.25/-0.04), equal to a relative decrease of -5.6%. Yearly change in 6-min walking distance was significantly associated with FMD in univariable analysis (Coef. -0.00, p = 0.045). Progressive airway obstruction and increase in level of total cholesterol were borderline significant with a greater decrease in FMD (Coeff. -0.02, p = 0.097 and Coeff. 0.16, p = 0.080, respectively). In multivariable analysis a greater annual decline in FEV1 tends to be independently associated with a decrease in FMD (p = 0.085). CONCLUSION: The findings of this study demonstrated that COPD patients experience a significant decrease in endothelial function over time. A greater annual decline in lung function tends to be associated with greater decrease in FMD. However, no other independent predictors for endothelial dysfunction could be identified. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT01527773. PMID- 29229090 TI - Health-related quality of life in asthma patients - A comparison of two cohorts from 2005 and 2015. AB - INTRODUCTION: The aim was to investigate temporal variation in Health-Related Quality of Life (HRQL) and factors influencing low HRQL, in patients with asthma. MATERIAL AND METHODS: Questionnaire data on patient characteristics and the mini Asthma Quality of Life Questionnaire (mini-AQLQ) scores from two separate cohorts of randomly selected Swedish primary and secondary care asthma patients, in 2005 (n = 1034) and 2015 (n = 1126). Student's t-test and analysis of covariance with adjustment for confounders compared mini-AQLQ total and domain scores in 2005 and 2015. Multivariable linear regression analyzed associations with mini-AQLQ scores. RESULTS: The mean Mini-AQLQ scores were unchanged between 2005 and 2015 (adjusted means (95% CI) 2005: 5.39 (5.27-5.33) and in 2015: 5.44 (95% CI 5.32 to 5.38), p = 0.26). Overweight (regression coefficient 95% CI) (0.21 (-0.36 to 0.07)), obesity (-0.34 (-0,50 to -0.18)), one or more exacerbations during the previous six months (-0.64 (-0.79 to -0.50)), self-rated moderate/severe disease (-1.02 (-1.15 to -0.89)), heart disease (-0.42 (-0.68 to -0.16)), anxiety/depression (-0.31 (-0.48 to -0.13)) and rhinitis (-0.25 (-0.42 to -0.08)) were associated with lower HRQL. Higher educational level (0.32 (0.19-0.46)) and self-reported knowledge of self-management of exacerbations (0.35 (0.19-0.51)) were associated with higher HRQL. CONCLUSIONS: HRQL in Swedish patients with asthma is generally good and unchanged during the last decade. Overweight, obesity, exacerbations, self-rated moderate/severe disease, heart disease, depression/anxiety and rhinitis were associated with lower HRQL, and high educational level and knowledge on self-management with higher HRQL. PMID- 29229091 TI - Frequent sauna bathing may reduce the risk of pneumonia in middle-aged Caucasian men: The KIHD prospective cohort study. AB - OBJECTIVE: Emerging evidence suggests sauna bathing to be linked with numerous health benefits. Having frequent sauna baths has been found to be associated with reduced risk of acute and chronic disease conditions. Sauna bathing may reduce the risk of respiratory diseases; however, the evidence is uncertain. We aimed to assess the association of frequency of sauna bathing with risk of pneumonia. METHODS: Baseline sauna bathing habits were assessed by administration of questionnaires in a prospective cohort of 2210 men aged 42-61 years. RESULTS: During a median follow-up of 25.6 years, 375 hospital diagnosed cases of pneumonia were recorded. In age-adjusted analyses, the hazard ratios (HRs) 95% confidence intervals (CIs) of pneumonia were 0.67 (0.53-0.83) and 0.53 (0.34 0.84) for participants who had 2-3 and >=4 sauna sessions per week respectively compared with participants who had <= 1 sauna session per week. After further adjustment for several major risk factors, the HRs were 0.69 (0.55-0.86) and 0.56 (0.35-0.88) respectively. The associations remained on additional adjustment for total energy intake, socioeconomic status, physical activity, and C-reactive protein, 0.72 (0.57-0.90) and 0.63 (0.39-1.00) respectively. CONCLUSIONS: Frequent sauna baths is associated with reduced pneumonia risk in a middle-aged male Caucasian population. PMID- 29229092 TI - Predictors of smoking cessation: A longitudinal study in a large cohort of smokers. AB - BACKGROUND: There are few studies on predictors of smoking cessation in general populations. We studied the smoking cessation rate in relation to several potential predictors, with special focus on respiratory and cardiovascular disease. METHODS: Smokers (n = 4636) from seven centres in Northern Europe, born between 1945 and 1973, who answered a questionnaire in 1999-2001 (the RHINE study) were followed up with a new questionnaire in 2010-2012. Altogether 2564 answered the questionnaire and provided complete data on smoking. Cox regression analyses were performed to calculate hazard ratios (HRs). RESULTS: A total of 999 subjects (39%) stopped smoking during the study period. The smoking cessation rate was 44.9/1000 person-years. Smoking cessation was more common with increasing age, higher education and fewer years of smoking. Asthma, wheeze, hay fever, chronic bronchitis, diabetes and hypertension did not significantly predict smoking cessation, but smokers hospitalized for ischaemic heart disease during the study period were more prone to stopping smoking (HR 3.75 [2.62 5.37]). CONCLUSIONS: Successful smoking cessation is common in middle-aged smokers, and is associated with few smoking years and higher education. A diagnosis of respiratory disease does not appear to motivate people to quit smoking, nor do known cardiovascular risk factors; however, an acute episode of ischaemic heart disease encouraged smoking cessation in our study population. PMID- 29229094 TI - No genetic association detected with mepolizumab efficacy in severe asthma. AB - BACKGROUND AND OBJECTIVES: Treatment with mepolizumab, a humanized monoclonal antibody to interleukin-5, reduces the rate of asthma exacerbations and the requirement for systemic glucocorticoids while maintaining asthma control. Treatment decisions are guided by predictors of response, including blood eosinophil thresholds in patients with frequent exacerbations despite intensive anti-inflammatory and controller treatment. Identification of additional predictors of response could aid treatment decisions. We investigated genetic associations that may predict response to mepolizumab-treatment. METHODS: In this post hoc analysis of DREAM and MENSA, association of genetic markers was tested in patients with severe asthma treated with mepolizumab who provided consent for pharmacogenetic research. Association was tested in a tiered approach with alpha spend differing for candidate genetic markers selected for prior history of association with relevant traits or pathways and in a genome-wide analyses (p < 4.7 * 10-4 and p < 5 * 10-8, respectively). Efficacy endpoints included: clinically significant exacerbation rate (tested using a negative binomial model), time to first exacerbation (tested with a Cox proportional hazards model), change in exacerbation rate, change in eosinophil count, and change in IgE level (tested by linear regression). RESULTS: No genetic marker was significantly associated with the primary endpoint, clinically significant exacerbation rate. One genetic marker was associated with time to first clinically significant exacerbation, but this association was driven by the DREAM data and was not supported in additional sensitivity analyses by treatment regimen/dose. CONCLUSION: No genetic effect on mepolizumab-treatment response was identified in this population on intensive asthma treatment, with history of frequent exacerbations and pre-selected for airway eosinophilia. PMID- 29229093 TI - Bronchopulmonary dysplasia: A review of pathogenesis and pathophysiology. AB - Bronchopulmonary dysplasia (BPD) is a chronic lung disease of primarily premature infants that results from an imbalance between lung injury and repair in the developing lung. BPD is the most common respiratory morbidity in preterm infants, which affects nearly 10, 000 neonates each year in the United States. Over the last two decades, the incidence of BPD has largely been unchanged; however, the pathophysiology has changed with the substantial improvement in the respiratory management of extremely low birth weight (ELBW) infants. Here we have attempted to comprehensively review and summarize the current literature on the pathogenesis and pathophysiology of BPD. Our goal is to provide insight to help further progress in preventing and managing severe BPD in the ELBW infants. PMID- 29229095 TI - Primary immune deficiency diseases as unrecognized causes of chronic respiratory disease. AB - BACKGROUND: More than half of all primary immune deficiency diseases (PIDD) affect antibody production and are well known as causes of recurrent sinusitis and lung infections. Chronic and recurrent infections of the upper and/or lower airways can contribute to inflammatory and obstructive processes in the lower airways which are initially reversible and considered "asthma", but can eventually cause irreversible remodeling and chronic obstructive pulmonary disease (COPD). Conversely, several lines of evidence suggest that many patients who present with a diagnosis of asthma have an increased incidence of infection, suggesting underlying host-defense defects. Asthma and respiratory infections in the first decades of life are recognized as risk factors for development of COPD, but when patients present with COPD as adults, underlying primary immune deficiency disease may be unrecognized. MAIN FINDINGS AND CONCLUSIONS: Detection of PIDD as a potentially treatable underlying contributor to recurrent/acute exacerbations and morbidity of COPD, and provision of immunoglobulin (Ig) G replacement therapy, when appropriate, may decrease the progression of COPD. Decreasing the severity and rate of exacerbations and admissions should improve the quality of life and longevity of an important subset of patients with COPD, while decreasing costs. Major steps toward achieving these goals include developing a high index of suspicion, more frequent use and appropriate interpretation of screening tests such as quantitative immunoglobulins and vaccine responses, and prompt institution of IgG replacement therapy when antibody deficiency has been diagnosed. PMID- 29229097 TI - Polypharmacy, chronic kidney disease, and benign prostatic hyperplasia in patients with chronic obstructive pulmonary disease newly treated with long acting anticholinergics. PMID- 29229096 TI - Clinical characteristics of patients with anti-aminoacyl-tRNA synthetase antibody positive idiopathic interstitial pneumonia. AB - BACKGROUND: Anti-aminoacyl-tRNA synthetase (ARS) antibodies have been detected in patients with polymyositis/dermatomyositis (PM/DM) and are especially correlated with interstitial lung disease (ILD). The aim of this study was to clarify the clinical features of patients with anti-ARS antibody positive idiopathic interstitial pneumonias (IIPs). METHODS: Patients were classified into three groups: 1) IIP with anti-ARS antibodies (ARS(+)IIP), 2) IIP without anti-ARS antibodies (ARS(-)IIP), and 3) PM/DM-associated ILD with anti-ARS antibodies (ARS(+)PM/DM-ILD). Clinical characteristics were compared retrospectively between the ARS(+)IIP group and the ARS(-)IIP group or ARS(+)PM/DM-ILD group. RESULTS: Eighteen ARS(+)IIP, 284 ARS(-)IIP, and 20 ARS(+)PM/DM-ILD patients were enrolled. The ARS(+)IIP group was significantly older and the male sex was predominant, had a lower prevalence of signs of connective tissue disease, differences in HRCT findings and patterns, and higher KL-6 levels compared to the ARS(+)PM/DM-ILD group. The findings in the bronchoalveolar lavage fluid (BALF) showing lymphocytosis and a lower CD4/CD8 ratio were similar between the two groups. However, the ARS(+)IIP group had significantly lower percentage of sputum, higher prevalence of mechanic's hand, higher KL-6 levels, lower percentage of vital capacity in the pulmonary function test, and lower CD4/CD8 ratio in BALF, compared to the ARS(-)IIP group. CONCLUSIONS: The present study demonstrated that features of pulmonary involvement were similar to those in the ARS(+)PM/DM-ILD group; however, some differences including HRCT findings and higher KL-6 levels suggest that ARS(+)IIP has severe ILD compared with ARS(+)PM/DM-ILD. Further prospective studies with a larger number of patients will elucidate the exact role of anti-ARS antibodies in IIPs. PMID- 29229098 TI - Pulmonary veno-occlusive disease: An important consideration in patients with pulmonary hypertension. AB - Pulmonary veno-occlusive disease is a rare subcategory of pulmonary arterial hypertension (WHO Group 1). The disease is poorly understood and difficult to diagnose; it has no definitive cure to date. These patients present with nonspecific symptoms, including dyspnea, exercise intolerance, and weakness. Chest x-rays sometimes differ from idiopathic pulmonary arterial hypertension and may demonstrate alveolar infiltrates and pleural effusions. High resolution computed tomography scans reveal ground glass opacities, interlobular septal thickening, and lymphadenopathy. Echocardiography can estimate the level of pulmonary artery pressures; right heart catheterization is needed for complete hemodynamic characterization of these patients. Lung biopsies demonstrate remodeling of the venules and small veins with intimal and adventitial fibrosis. This can result in total venous occlusion and subsequent recanalization. Similar changes occur in the small arteries and arterioles but are less pronounced than the venous changes. There is no effective medical therapy for these patients, and treatment with the pulmonary arterial hypertension specific medications often causes acute deterioration with pulmonary edema. The recent discovery of the biallelic mutations of the EIF2AK4 gene as an etiology for heritable form of pulmonary veno-occlusive disease increases our understanding of the disease pathogenesis and potentially identifies a future approach to treatment. Without definitive treatment, the prognosis is very poor, and the life expectancy of these patients is much shorter than patients with pulmonary arterial hypertension. These patients need early referral to transplantation centers. PMID- 29229099 TI - A systematic review of school-based interventions that include inhaler technique education. AB - BACKGROUND: Proper use of inhaled medication is essential for the successful treatment of childhood asthma; yet, improper inhaler technique among school-aged children is common. There are many schoolbased asthma education programs, but the extent to which these programs teach inhaler technique is unknown. METHODS: We systematically reviewed the literature to identify schoolbased asthma interventions that included inhaler technique instruction. We searched several databases, including PubMed, for relevant articles. Studies were included if they were asthma interventions of any type (programs, curriculums, education) conducted at kindergarten through twelfth grade schools that taught inhaler technique and included inhaler technique as an outcome measure. Of the 285 citations identified, the final nine studies (selected from 71 full-text articles) met the inclusion criteria. RESULTS: Findings from this systematic review identified a very small number of school-based interventions that evaluated improvements in students' inhaler technique. Two of the nine studies (22%) used a validated measure of inhaler technique. Inhaler technique instruction varied in length, from 15 min to 1 h and nurses implemented inhaler technique instruction in six of the nine (67%) interventions. Existing studies offer mixed evidence for sustained technique improvements up to a 12-month follow up period. CONCLUSIONS: Evidence suggests that students benefit from school-based inhaler technique education; however, inconsistencies in how technique was measured limit our ability to draw firm conclusions regarding the effectiveness of inhaler technique education on student outcomes. Future studies are needed to identify the most appropriate and feasible inhaler technique education components for use in comprehensive asthma self management interventions. PMID- 29229100 TI - Sleep related respiratory events during non-invasive ventilation of patients with chronic hypoventilation. AB - BACKGROUND: Non-invasive ventilation (NIV) is increasingly used in the treatment of patients with chronic hypercapnic respiratory failure (CRF). Residual sleep related respiratory events under NIV such as obstructive or central apnea/hypopnea (AH), or patient-ventilator asynchrony (PVA), may compromise treatment efficacy and/or comfort. AIMS OF STUDY: 1/to quantify the frequency and describe the types of both AH and PVA in a large group of stable patients with CRF during night-time NIV; 2/to analyze the influence of these events on overnight pulse oximetry and transcutaneous CO2 and 3/to assess interrater agreement in identifying and quantifying AH and PVA. METHODS: We quantified AH and PVA by performing sleep polygraphy in 67 patients during elective follow-up visits. Traces were scored by two trained physicians. RESULTS: Residual AH were frequent: 34% of the patients had an AH Index >5/hour, with obstructive hypopnea being the most frequent event. In addition, 21% of the patients had PVA >10% of total recording time. No correlation was found between respiratory events and overnight hypercapnia. The intraclass correlation coefficients for scoring AHI and time with PVA were 0.97 (0.94-0.98) and 0.85 (0.75-0.91) respectively. CONCLUSIONS: Residual respiratory events are common in patients treated with long term NIV for chronic hypercapnic respiratory failure and can be scored with a very high interobserver agreement. However, these events were not associated with persistent nocturnal hypercapnia; thus, their clinical relevance has yet to be clarified. CLINICALTRIALS.GOV REGISTRATION N degrees : NCT01845233. PMID- 29229101 TI - The prevalence of COPD in England: An ontological approach to case detection in primary care. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality in England, however estimates of its prevalence vary considerably. Routinely collected and coded primary care data can be used to monitor disease prevalence, however reliance upon diagnostic codes alone is likely to miss cases. METHODS: We devised an ontological approach to COPD case detection and implemented it in a large primary care database to identify definite and probable cases of COPD. We used this to estimate the prevalence of COPD in England. RESULTS: Use of this approach to detect definite COPD cases yielded a prevalence of 2.57% (95% CI 2.55-2.60) in the total population, 4.56% (95%CI 4.52-4.61) in those aged >= 35 and 5.41% (95% CI 5.36-5.47) in ex or current smokers. The ontological approach identified an additional 10,543 definite cases compared with using diagnostic codes alone. Prevalence estimates were higher than the 1.9% prevalence currently reported by the UK primary care pay for performance (P4P) disease register. COPD prevalence when definite and probable cases were combined was 3.02% (95% CI 3.0-3.05) in the total population, 5.38% (95% CI 5.33-5.42) in those aged >= 35 and 6.46% (95% CI 6.46-6.40-6.56) in ex or current smokers. CONCLUSIONS: We demonstrate a robust reproducible method for COPD case detection in routinely collected primary care data. Our calculated prevalence differed significantly from current estimates based upon P4P data, suggesting that the burden of COPD in England is greater than currently predicted. PMID- 29229102 TI - Clubbing in patients with fibrotic interstitial lung diseases. AB - BACKGROUND: Clubbing is associated with poor prognosis and is variably present in patients with idiopathic pulmonary fibrosis (IPF), but is also seen in other fibrotic interstitial lung diseases (ILDs). Little is known about the best methodology to assess clubbing in ILDs and, hence, the prevalence and clinical utility and clinical significance of clubbing. We therefore aimed to evaluate the agreement between different clubbing assessment methods in patients with fibrotic ILDs. Additionally, we assessed the prevalence of clubbing in different fibrotic ILDs and related clubbing to disease severity and quality of life. METHODS: Consecutive outpatients with fibrotic ILDs of two tertiary referral centers were included. Clubbing was assessed with the phalangeal depth ratio, the digital index, the Schamroth sign test, and by the treating physicians and investigator. RESULTS: We included 153 patients (100 men), mean age 65 (range 33-88), mean FVC 79% (25-145%), mean TLCOc 50% (16-104%). Different methods for assessment of clubbing had poor correlation, and as a result, clubbing prevalence varied according to the method used, ranging from 7 to 42% in the total group of patients and 7-52% in IPF. The degree of clubbing did not correlate with FVC or TLCOc (p > 0.2) or with quality of life scores, but lower mean TLCOc scores were seen in patients with clubbing than in those without. CONCLUSION: Clubbing was present in 7-42% of our fibrotic ILD cohort and showed no correlation with disease severity. Although considered an important clinical feature, assessment methods for clubbing showed no to poor agreement. Further studies are therefore needed to gain more insight into measuring clubbing reliably and the possible prognostic value and evolution of clubbing. PMID- 29229103 TI - Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: The 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study. AB - BACKGROUND: Prevention of exacerbations is a primary goal for chronic obstructive pulmonary disease (COPD) therapy. This randomized, double-blind, double-dummy, parallel-group, multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus formoterol dry powder inhaler (DPI) on reducing COPD exacerbations. METHODS: 1219 patients aged >=40 years with moderate-to-very-severe COPD (per lung function) and a history of >=1 COPD exacerbation received budesonide/formoterol pMDI 320/9 MUg twice daily (BID) during a 4-week run-in. Patients were then randomized 1:1 to receive budesonide/formoterol pMDI 320/9 MUg BID (n = 606) or formoterol DPI 9 MUg BID (n = 613) for 26 weeks. Exacerbations were identified using predefined criteria for symptom worsening and treatment with systemic corticosteroids and/or antibiotics and/or hospitalization. The primary endpoint was annual rate of exacerbations. RESULTS: Budesonide/formoterol pMDI resulted in a 24% reduction in annual rate of exacerbations (0.85 vs 1.12; rate ratio: 0.76 [95% CI: 0.62, 0.92]; P = 0.006), and a significant risk reduction for time to first exacerbation (hazard ratio: 0.78 [95% CI: 0.64, 0.96]; P = 0.016) versus formoterol DPI. The most commonly reported adverse events (AEs; >=3%) in budesonide/formoterol and formoterol groups were COPD (4.5% vs 8.6%) and nasopharyngitis (5.0% vs 5.2%). Pneumonia AEs were reported in 0.5% and 1.0% of budesonide/formoterol-treated and formoterol treated patients, respectively. CONCLUSIONS: Budesonide/formoterol pMDI is an effective treatment option for reducing exacerbation rates in COPD patients with moderate-to-very-severe airflow limitation and history of exacerbations. No increase in pneumonia was observed with budesonide/formoterol; safety data were consistent with its established profile. PMID- 29229104 TI - Heart rate and risk of death among patients with Pulmonary Hypertension: A 12 lead ECG analysis. AB - BACKGROUND: Despite the emergence of new therapies, Pulmonary Hypertension (PH) still has a high mortality. Several clinical, echocardiographic, biological or hemodynamic prognostic factors have been identified but are of limited predictive value for survival. We aimed to assess whether heart rate (HR) and all ECG abnormalities measured on a 12-lead ECG may help to better identify patients at high risk of death in this population. METHODS AND RESULTS: 296 patients followed in a registry were included with all types of PH, except group 2 of the WHO clinical classification. After a median follow-up of 10 years, age, male sex, NYHA III/IV status and, among all ECG parameters, HR and corrected QT interval were associated with mortality. In multivariate analysis, HR, age and male sex remained significant independent predictors of mortality. HR has a higher predictive value in the 238 patients in sinus rhythm. In addition, only HR was significantly correlated with clinical and hemodynamic PH prognostic factors. CONCLUSION: HR measured on a 12-lead ECG at the time of the diagnosis is a strong independent predictor of mortality in PH patients. PMID- 29229105 TI - Pulmonary function and diffusion capacity are associated with pulmonary arterial systolic pressure in the general population: The Rotterdam Study. AB - BACKGROUND: Pulmonary hypertension is a progressive heterogeneous syndrome, characterized by elevated pulmonary arterial pressure which can lead to right ventricular failure. Although the presence of elevated pulmonary arterial systolic pressure (PASP) in patients with a lung disease is a well-known occurrence, little is known about the association between pulmonary function and PASP in the general population. We hypothesized that pulmonary function and PASP are associated, irrespective of airflow limitation. METHODS: This study was performed within the Rotterdam Study, a prospective population-based cohort. We included 1660 participants with spirometry, performed and interpreted according to ATS/ERS-guidelines, and echocardiography performed according to the ASE/EAE/CSE-guidelines. We analyzed the association of Forced Expiratory Volume in 1 s (FEV1), Forced Vital Capacity (FVC), FEV1/FVC and diffusion capacity (DLCO) with estimated PASP (ePASP). Furthermore, we investigated the association between spirometry measures, COPD, and echocardiographic pulmonary hypertension. RESULTS: A 10% absolute decrease in FEV1 was associated with an ePASP increase of 0.46 mmHg (95%CI: 0.31; 0.61). Similarly, per absolute 10% decrease, FVC was significantly associated with an increased ePASP of 0.42 mmHg (95%CI: 0.25; 0.59). FEV1/FVC showed an association of 1.01 mmHg (95%CI: 0.58; 1.45) increase in ePASP per 10% absolute decrease. A decrease in DLCO (in mL/min/kPa) was associated with an increased ePASP (0.46 mmHg, 95%CI: 0.17; 0.76). We found significant associations for FEV1 and FVC with echocardiographic pulmonary hypertension. Importantly, an increased ePASP was significantly associated with mortality (Hazard Ratio: 1.042 per mmHg [95%CI: 1.023-1.062; p < 0.001]). CONCLUSION: We observed a clearly graded association between pulmonary function and ePASP and pulmonary hypertension, even in individuals without airflow limitation. PMID- 29229106 TI - Cardiovascular benefits from standard pulmonary rehabilitation are related to baseline exercise tolerance levels in chronic obstructive pulmonary disease. AB - BACKGROUND: Heightened arterial stiffness is a marker of cardiovascular risk and is elevated in chronic obstructive pulmonary disease (COPD). Physical activity has been shown to reduce arterial stiffness, and our previous work has shown that arterial stiffness is related to physical activity and exercise tolerance in COPD. The purpose of this study was to evaluate whether baseline physical activity and exercise tolerance influence the cardiovascular benefits associated with standard COPD outpatient pulmonary rehabilitation (PR). METHODS: A total of 66 patients with COPD were recruited from the G.F. MacDonald Centre for Lung Health, Edmonton, Alberta, prior to entering PR. Another 23 COPD patients not attending the PR program were recruited as time controls (TC). Arterial stiffness (carotid-radial pulse wave velocity, PWV), physical activity (steps taken over three days), and 6-min walk distance (6MWD) were assessed before and after PR, or before and after six weeks of standard care. RESULTS: Thirty-nine PR and 11 TC completed all parts of the study. Following PR, there was no overall change in PWV. However, changes in arterial stiffness with PR were dependent on baseline exercise tolerance, with those patients with a 6MWD <350 m showing a significant reduction in PWV following PR (6MWD >350 m: 8.2 +/- 1.6 to 8.5 +/- 1.7 versus 6MWD <350 m: 9.2 +/- 0.6 to 7.3 +/- 2.0 m/s, p < 0.05). The PWV response to PR was not influenced by baseline physical activity levels. CONCLUSION: COPD patients with low exercise tolerance appear to derive the greatest cardiovascular benefits from PR. PMID- 29229107 TI - Clinical characterization of 52 patients with immunoglobulin G4-related disease in a single tertiary center in Japan: Special reference to lung disease in thoracic high-resolution computed tomography. AB - BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a rare multi-organ disorder. Physicians rarely encounter patients with IgG4-RD and its range of symptoms. METHODS: To elucidate the clinical characterization of IgG4-RD, along with the clinical significance of lung involvement, we retrospectively reviewed the medical records of patients who satisfied the comprehensive diagnostic criteria for IgG4-RD. RESULTS: We identified 52 patients with IgG4-RD. Of these, 32 patients underwent tissue biopsies, resulting in categorization as definite (n = 23) or possible (n = 9) IgG4-RD cases. Among the 23 definite IgG4-RD cases, those with positive lung involvement (n = 8) had significantly higher values of serum LDH (median 220 IU/L, interquartile range (IQR) 175-378 vs. median 184, IQR 136-249, p = 0.039), IgG (median 2769 mg/dL, IQR 2028-7807 vs. median 2048, IQR 1168-4376, p = 0.009), and soluble interleukin-2 receptors (median 1620 U/mL, IQR 871-2250 vs. median 733, IQR 271-1600, p = 0.003) than those with negative lung involvement (n = 15). Similarly, a significant number of patients with positive lung involvement were positive for rheumatoid factor (71.4% vs. 23.1%, p = 0.041) or hypocomplementemia (50% vs. 0%, p = 0.036). Sixteen patients also showed lung involvement (definite n = 8, possible n = 8); thoracic computed tomography (CT) of these patients revealed mediastinal lymphadenopathies (n = 14, 87.5%), ground glass opacity (n = 11, 68.8%), consolidation (n = 8, 50%), thickening of the bronchovascular bundles (n = 7, 43.8%), small nodules (n = 5, 31.3%), bronchiectasis (n = 4, 25%), and reticular shadows (n = 4, 25%), and pulmonary function tests, using a standard technique involving a single breath, revealed decreased diffusion capacity for carbon monoxide. CONCLUSIONS: IgG4-RD is associated with diverse thoracic CT findings and a decreased diffusion capacity, and careful multidisciplinary assessment is needed to enable differentiation of IgG4-RD from lymphoproliferative disorders. PMID- 29229109 TI - Evaluation and quantification of treatment preferences for patients with asthma or COPD using discrete choice experiment surveys. AB - INTRODUCTION: To investigate treatment preferences of patients with asthma or chronic obstructive pulmonary disease (COPD), previously identified influential treatment factors were used to develop a discrete choice experiment (DCE) survey. METHODS: An internet-based survey was conducted with UK-resident adults (recruited using a commercial panel) who were currently receiving asthma/COPD treatment and had not taken part in the previous phase of this study (qualitative interviews to understand patient burden, life impact and treatment preferences). Participants ranked treatment attributes from 0 (extremely important) to 8 (not at all important) and chose between hypothetical treatments for asthma/COPD with differing attributes. Preferences for each condition were assessed separately using a mixed logit regression model. RESULTS: Most of the 302 participants had not well-controlled asthma (Asthma Control TestTM scores <=19/25) or experienced a high impact of COPD (COPD Assessment TestTM scores >20/40). Participant views were generally similar for both conditions; having well-controlled symptoms all day was considered most important. All treatment attributes significantly influenced preferences; the most preferred were no sleep disturbance (versus waking up often) and low cost. Subsequent preferences (with some variation between asthma/COPD) were for treatments with easy/convenient use, no flare ups/exacerbations, that enabled desired physical activities, well-controlled symptoms all day, that enabled desired social activities, and low medication frequency. CONCLUSIONS: These eight treatment attributes, valued by patients with asthma or COPD, are important for healthcare professionals to consider regarding treatment options and for future therapy development. Our DCE results broadly reinforce the findings from qualitative interviews in the first study phase. PMID- 29229110 TI - Effects of two types of equal-intensity inspiratory muscle training in stable patients with chronic obstructive pulmonary disease: A randomised controlled trial. AB - PURPOSE: We conducted a randomised controlled trial to assess the effects of daily breathing pattern changes to stable patients with COPD excluding the confounding factors of inspiratory muscle mobilization, by ensuring the load intensities of two inspiratory training devices were equal. PATIENTS AND METHODS: Sixty patients with COPD were randomised to three groups: resistive-IMT group (T IMT, 21 patients), threshold-IMT (R-IMT, 19 patients), and a control group (20 patients). Inspiratory load intensity for both methods was set at 60% of maximal inspiratory pressure (MIP), a measure of inspiratory muscle strength, which, along with health-related quality of life (HRQoL), degree of dyspnoea, and exercise capacity, were conducted before and after 8 weeks of daily IMT. RESULTS: At 8 weeks, there was no significantly difference of MIP between the R- and T-IMT groups (P > 0.05). Chronic Respiratory Disease Questionnaire and Transition Dyspnea Index scores improved significantly after each training program compared with controls (P < 0.05), and R-IMT was significant better (P < 0.05). R-IMT was better than T-IMT in performance of exercise (P < 0.05). CONCLUSIONS: In summary, in clinically stable patients with COPD, 8 weeks of R-IMT was superior to 8 weeks of equal-intensity T-IMT in improving HRQoL, degree of dyspnoea, and exercise capacity. PMID- 29229108 TI - Infection control, genetic assessment of drug resistance and drug susceptibility testing in the current management of multidrug/extensively-resistant tuberculosis (M/XDR-TB) in Europe: A tuberculosis network European Trialsgroup (TBNET) study. AB - AIM: Europe has the highest documented caseload and greatest increase in multidrug and extensively drug-resistant tuberculosis (M/XDR-TB) of all World Health Organization (WHO) regions. This survey examines how recommendations for M/XDR-TB management are being implemented. METHODS: TBNET is a pan-European clinical research collaboration for tuberculosis. An email survey of TBNET members collected data in relation to infection control, access to molecular tests and basic microbiology with drug sensitivity testing. RESULTS: 68/105 responses gave valid information and were from countries within the WHO European Region. Inpatient beds matched demand, but single rooms with negative pressure were only available in low incidence countries; ultraviolet decontamination was used in 5 sites, all with >10 patients with M/XDR-TB per year. Molecular tests for mutations associated with rifampicin resistance were widely available (88%), even in lower income and especially in high incidence countries. Molecular tests for other first line and second line drugs were less accessible (76 and 52% respectively). A third of physicians considered that drug susceptibility results were delayed by > 2 months. CONCLUSION: Infection control for inpatients with M/XDR-TB remains a problem in high incidence countries. Rifampicin resistance is readily detected, but tests to plan regimens tailored to the drug susceptibilities of the strain of Mycobacterium tuberculosis are significantly delayed, allowing for further drug resistance to develop. PMID- 29229111 TI - Toxicity risk from glucocorticoids in sarcoidosis patients. AB - BACKGROUND: Glucocorticoids (GC) are considered first-line therapy for treating sarcoidosis, but there are few data about the adverse consequences of GC. Although there are several steroid-sparing medications available for treatment, a large proportion of patients are treated with prolonged courses of GC. The toxicities of GC in sarcoidosis populations have not been carefully evaluated. METHODS: We performed a retrospective cohort study of all newly diagnosed sarcoidosis patients who had the entirety of their medical care in a single health system. We analyzed the time to development of a composite toxicity end point, including diabetes, hypertension, weight gain, hyperlipidemia, low bone density and ocular complications of GC using Cox proportional hazards analysis. RESULTS: One hundred and five patients were ever treated with GC, whereas 49 were not treated during a median follow-up of 101 months. GC-treated patients developed 1.3 +/- 1.1 toxicities during therapy, versus 0.6 +/- 1.0 in the non treated group. After adjustment for age, gender, race and preexisting conditions, the hazard ratio for ever-treated patients was 2.37 (1.34-4.17) for the composite end-point. Age and the presence of preexisting conditions also were associated with reaching the end-point. Similar effects were seen when analyzed for cumulative GC dose and for duration of GC use. For individual end-points, weight gain (HR 2.04) and new hypertension (HR 3.36) were associated with any use of GC. CONCLUSIONS: Our data suggest that GC are associated with clinically important toxicities in sarcoidosis patients, associated with both the cumulative dose and duration of treatment. PMID- 29229112 TI - Disease marker combination enhances patient characterization in the Finnish sarcoidosis patients. AB - Sarcoidosis is an inflammatory disease of unknown etiology and multiple clinical phenotypes. Clinical manifestations range from asymptomatic disease to severe loss-of-function leading to the hypothesis that sarcoidosis might not be just one disease, but consists of several distinct disease entities each with potentially distinct genetic associations. We have previously demonstrated that in our series HLADRB1* 03:01 and haplotype HLA-DRB1*04:01-DPB1*04:01 are associated with good prognosis sarcoidosis. In our recent work, we found a novel SNP (rs9905945) in the 5'upstream region of the ACE gene to be associated with favorable disease prognosis as well. The main objective of this study was to expand the previous results and analyse combined influence of the found ACE SNP rs9905945 with the protective HLA markers HLADRB1* 03:01 and HLA-DRB1*04:01-DPB1*04:01 in 188 Finnish sarcoidosis patients (resolved disease, n = 90; persistent disease, n = 98). When combining the frequencies of the rs9905945 and of the HLA markers, the strongest association was found for a combination of either/or both HLA markers and rs9905945 for good disease prognosis (37.1% in resolved vs. 11.3% in persistent, p < 0.001, OR = 4.61, (95%CI 2.15-9.86)). In conclusion, we discovered that a combination of the ACE SNP rs9905945 and HLA markers enhance the accuracy for predicting disease course in Finnish sarcoidosis patients further characterizing genetic differences between Finnish sarcoidosis patients with different prognosis. PMID- 29229113 TI - Measuring voluntary and reflexive cough strength in healthy individuals. AB - BACKGROUND: Cough reflex testing is a validated tool for identifying patients at risk of silent aspiration. However, inter- and intra-rater reliabilities of perceptual judgements of cough strength are sub-optimal. Although there are clinically established methods for measuring volitional cough strength, no similar methods are identified for reflexive cough strength. This study evaluated three measurement methods of voluntary and suppressed reflexive cough strength. METHODS: Fifty-three healthy subjects (>=50 years) participated in this study. Participants produced 'strong' and 'weak' voluntary coughs and suppressed reflexive coughs to incremental doses of citric acid. Peak and area under the curve (AUC) measurements were taken of pressure, airflow, and acoustics. RESULTS: There was no dose effect of citric acid on measures of reflexive cough strength. Strong voluntary coughs were stronger than reflexive coughs for all measures (p < 0.001) and weak voluntary coughs were stronger than reflexive coughs for two measures (AUC pressure: p < 0.020; peak flow: p < 0.004). AUC pressure and peak flow had the highest correlations and effect sizes. Correlations were low between voluntary and reflexive cough strength for all measures (r <= 0.46). CONCLUSION: Assessing strength of reflexive cough, rather than voluntary cough, is highly desirable in the dysphagic population. Pressure and flow provide the most useful objective measurements. PMID- 29229114 TI - Estradiol mediates the long-lasting lung inflammation induced by intestinal ischemia and reperfusion. AB - BACKGROUND: Lung inflammation is one of the main consequences of intestinal ischemia reperfusion (intestinal IR) and, in severe cases, can lead to acute respiratory distress syndrome and death. We have previously demonstrated that estradiol exerts a protective effect on lung edema and cytokine release caused by intestinal IR in male rats. MATERIALS AND METHODS: We investigated the role of estradiol on the generation of interleukin (IL)-1beta, IL-10, vascular endothelial growth factor (VEGF), and cytokine-induced neutrophil chemoattractant 1 (CINC-1) in a female rat model of intestinal IR. Blood and bone marrow leukocytes were also quantified. Seven-days-ovariectomized rats were subjected to intestinal IR by occlusion of the superior mesenteric artery for 45 min. After reperfusion of the tissue for 2 h, the rats were sacrificed. Lung tissue was collected, cultured for 24 h and assayed. RESULTS: We observed a significant increase in serum levels of IL-10, CINC-1, uric acid and circulating, but not bone marrow, leukocyte numbers. In addition, intestinal IR induced a significant increase in the ex-vivo lung levels of IL-1beta, IL-10, and VEGF. Treatment with 17beta-estradiol before the induction of intestinal IR prevented the systemic release of IL-10, CINC-1, and uric acid, but it did not affect the leukocytosis. In addition, 17beta-estradiol significantly prevented the ex-vivo release of IL 1beta and VEGF from lung tissue. CONCLUSIONS: We demonstrated that intestinal IR interferes with lung homeostasis, priming the tissue to generate proinflammatory mediators for at least 24 h postischemia. Furthermore, our data confirm that the inflammatory responses caused by intestinal IR are estradiol mediated. PMID- 29229115 TI - Cell-specific regulation of iNOS by AMP-activated protein kinase in primary rat hepatocytes. AB - BACKGROUND: AMP-activated protein kinase (AMPK) regulates several metabolic pathways in hepatocytes that are critical to the hepatic response to sepsis and shock. Induction of nitric oxide synthesis is an important response to sepsis, inflammation and shock and many of the stimuli that upregulate inducible nitric oxide synthase (iNOS) also activate AMPK. AMPK inhibits nitric oxide (NO) production in skeletal and cardiac muscle cells, but the role of AMPK in regulating iNOS expression in hepatocytes has not been determined. MATERIALS AND METHODS: Primary cultured rat hepatocytes were preincubated with an AMPK inhibitor, AMPK activators, or transfected with AMPK siRNA before being treated with the proinflammatory cytokines interleukin-1beta (IL-1beta) and interferon gamma (IFNgamma). The hepatocyte cell lysate and culture supernatants were collected for Western blot analysis and Griess assay. RESULTS: IL-1beta and IFNgamma markedly upregulated iNOS expression and AMPK phosphorylation. IL-1beta + IFNgamma-induced NO production and iNOS expression were significantly decreased in hepatocytes treated with the AMPK inhibitor compound C and AMPK knockdown by AMPK siRNA. Cytokine-induced iNOS expression was increased by AMPK activators 1 oxo-2-(2H-pyrrolium-1-yl)-1H-inden-3-olate, AMPK signaling activator III and AICA riboside. Compound C upregulated Akt and c-Jun N-terminal kinase phosphorylation but decreased IkappaBalpha phosphorylation. AICA-riboside exerted opposite effects on these signaling pathways in hepatocytes. CONCLUSIONS: In contrast to other cell types, AMPK increased IL-1beta + IFNgamma-induced NO production and iNOS expression through the Akt, c-Jun N-terminal kinase, and NF-kappaBeta signaling pathways in primary hepatocytes. These data suggest that AMPK-altering medications used clinically may have subsequent effects on iNOS expression and proinflammatory signaling pathways. PMID- 29229116 TI - "No zone" approach in penetrating neck trauma reduces unnecessary computed tomography angiography and negative explorations. AB - BACKGROUND: The most recent management guidelines advocate computed tomography angiography (CTA) for any suspected vascular or aero-digestive injuries in all zones and give zone II injuries special consideration. We hypothesized that physical examination can safely guide CTA use in a "no zone" approach. METHODS: An 8-year retrospective analysis of all adult trauma patients with penetrating neck trauma (PNT) was performed. We included all patients in whom the platysma was violated. Patients were classified into three groups as follows: hard signs, soft signs, and asymptomatic. CTA use, positive CTA (contrast extravasation, dissection, or intimal flap) and operative details were reported. Primary outcomes were positive CTA and therapeutic neck exploration (TNE) (defined by repair of major vascular or aero-digestive injuries). RESULTS: A total of 337 patients with PNT met the inclusion criteria. Eighty-two patients had hard signs and all of them went to the operating room, of which 59 (72%) had TNE. One hundred fifty-six patients had soft signs, of which CTA was performed in 121 (78%), with positive findings in 12 (10%) patients. The remaining 35 (22%) underwent initial neck exploration, of which 14 (40%) were therapeutic yielding a high rate of negative exploration. Ninty-nine patients were asymptomatic, of which CTA was performed in 79 (80%), with positive findings in 3 (4%), however, none of these patients required TNE. On sub analysis based on symptoms, there was no difference in the rate of TNE between the neck zones in patients with hard signs (P = 0.23) or soft signs (P = 0.51). Regardless of the zone of injury, asymptomatic patients did not require a TNE. CONCLUSIONS: Physical examination regardless of the zone of injury should be the primary guide to CTA or TNE in patients with PNT. Following traditional zone-based guidelines can result in unnecessary negative explorations in patients with soft signs and may need rethinking. PMID- 29229117 TI - Outcomes of fetuses with primary hydrothorax that undergo prenatal intervention (prenatal intervention for hydrothorax). AB - BACKGROUND: Primary hydrothorax is a congenital anomaly affecting 1 in 10,000 15,000 pregnancies. The natural history of this condition is variable with some fetuses having spontaneous resolution and others showing progression. The associated pulmonary hypoplasia leads to increased perinatal morbidity and mortality. Optimal prenatal intervention remains controversial. METHODS: After obtaining the Institutional Review Board approval, a retrospective review of all patients evaluated for a fetal pleural effusion in the Fetal Diagnosis and Treatment Center at The University of Michigan, between 2006 and 2016 was performed. Cases with secondary etiologies for an effusion or when families decided to pursue elective termination were excluded. RESULTS: Pleural effusions were identified in 175 patients. Primary hydrothorax was diagnosed in 15 patients (8%). The effusions were bilateral in 13/15 cases (86%) and 10/15 (66%) had hydrops at presentation. All 15 patients with primary hydrothorax underwent prenatal intervention. Thoracentesis was performed in 14/15 cases (93%). Shunt placement was performed in 10/15 cases (66%). Shunt migration was seen in four patients (40%) and all of these underwent prenatal shunt replacement. Overall survival was 76%. The rates of prematurity and preterm premature rupture of membranes were 69% and 35%, respectively. CONCLUSIONS: Fetal intervention for the treatment of primary hydrothorax is effective, and it appears to confer a survival advantage. Both the fetuses and the mothers tolerated the procedures well. Preterm labor and preterm premature rupture of membranes remain an unsolved problem. Further studies are needed to understand the mechanisms behind the development of fetal hydrothorax. PMID- 29229118 TI - Clinical predictors of lymph node metastasis and survival rate in papillary thyroid microcarcinoma: analysis of 3607 patients at a single institution. AB - BACKGROUND: The treatment of papillary thyroid microcarcinoma (PTMC) patients is controversial, as PTMC is often found incidentally and its prognosis is quite good. Because lymph node metastasis (LNM) is one of the main predictors of recurrence and impacts the survival rate of PTMC patients, this study aims to retrospectively identify the clinical factors that increase the risk of LNM and/or recurrence and can then be used to separate clinically unfavorable PTMCs from the rest and to help guide their treatment accordingly. METHODS: Clinical and pathologic data were collected from 3607 patients diagnosed with PTMC at Shanghai Renji Hospital between 2005 and 2015. Univariate and multivariate analyses were performed to identify the clinical predictors of LNM and survival rates were calculated by using the Kaplan-Meier method. RESULTS: Our univariate and multivariate analyses show that age of <45 y (P < 0.01), gender of male (P < 0.01), tumor diameter >0.7 cm (P < 0.01), and multifocality (P < 0.01) significantly increase the risk of central LNM. However, clinical factors, such as LNM, age, gender, multifocality, and operation range, do not affect the 10-y disease-free survival rate (P > 0.05). CONCLUSIONS: Clinical factors, such as gender of male, age of <45 y, multifocality, and tumor size >0.7 cm, suggest a higher risk of LNM; however, they do not affect PTMC patients' 10-y disease-free survival rate. We recommend ipsilateral lobectomy to PTMC patients. For PTMC patients with higher LNM risk, preoperative central and lateral cervical lymph node imaging examination should be emphasized, and lymph node dissection is recommended. The range of dissection should be determined based on the imaging results. PMID- 29229119 TI - Weaker gun state laws are associated with higher rates of suicide secondary to firearms. AB - BACKGROUND: Firearm-related suicides comprise over two-thirds of gun-related violence in the United States, and gun laws and policies remain under scrutiny, with many advocating for revision of the regulatory map for lawful gun ownership, aiming at restricting access and distribution of these weapons. However, the quantitative relationship between how strict gun laws are and the incidence of firearm violence with their associated mortality is largely unknown. We therefore, sought to explore the impact of firearm law patterns among states on the incidence and outcomes of firearm-related suicide attempts, utilizing established objective criteria. METHODS: The National Inpatient Sample for the years 1998-2011 was queried for all firearm-related suicides. Discharge facilities were stratified into five categories (A, B, C, D, and F, with A representing states with the most strict and F representing states with the least strict laws) based on the Brady Campaign to prevent Gun Violence that assigns scorecards for every state. The primary outcomes were suicide attempts and in hospital mortality per 100,000 populations by Brady state grade. RESULTS: During the 14-year study period, 34,994 subjects met inclusion criteria. The mean age was 42.0 years and 80.1% were male. A handgun was utilized by 51.8% of patients. The overall mortality was 33.3%. Overall, 22.0% had reported psychoses and 19.3% reported depression. After adjusting for confounding factors and using group A as reference, there were higher adjusted odds for suicide attempts for patients admitted in group C, D, and F category states (1.73, 2.09, and 1.65, respectively, all P < 0.001). CONCLUSIONS: Firearm-related suicide attempt injuries are more common in states with less strict gun laws, and these injuries tend to be associated with a higher mortality. Efforts aimed at nationwide standardization of firearm state laws are warranted, particularly for young adults and suicide-prone populations. LEVEL OF EVIDENCE: III. STUDY TYPE: Trauma Outcomes study. PMID- 29229120 TI - Susceptibility of ePTFE vascular grafts and bioengineered human acellular vessels to infection. AB - BACKGROUND: Synthetic expanded polytetrafluorethylene (ePTFE) grafts are routinely used for vascular repair and reconstruction but prone to sustained bacterial infections. Investigational bioengineered human acellular vessels (HAVs) have shown clinical success and may confer lower susceptibility to infection. Here we directly compared the susceptibility of ePTFE grafts and HAV to bacterial contamination in a preclinical model of infection. MATERIALS AND METHODS: Sections (1 cm2) of ePTFE (n = 42) or HAV (n = 42) were inserted within bilateral subcutaneous pockets on the dorsum of rats and inoculated with Staphylococcus aureus (107 CFU/0.25 mL) or Escherichia coli (108 CFU/0.25 mL) before wound closure. Two weeks later, the implant sites were scored for abscess formation and explanted materials were halved for quantification of microbial recovery and histological analyses. RESULTS: The ePTFE implants had significantly higher abscess formation scores for both S. aureus and E. coli inoculations compared to that of HAV. In addition, significantly more bacteria were recovered from explanted ePTFE compared to HAV. Gram staining of explanted tissue sections revealed interstitial bacterial contamination within ePTFE, whereas no bacteria were identified in HAV tissue sections. Numerous CD45+ leukocytes, predominantly neutrophils, were found surrounding the ePTFE implants but minimal intact neutrophils were observed within the ePTFE matrix. The host cells surrounding and infiltrating the HAV explants were primarily nonleukocytes (CD45-). CONCLUSIONS: In an established animal model of infection, HAV was significantly less susceptible to bacterial colonization and abscess formation than ePTFE. The preclinical findings presented in this manuscript, combined with previously published clinical observations, suggest that bioengineered HAV may exhibit low rates of infection. PMID- 29229121 TI - Efficacy of completion pancreatectomy for recurrence of adenocarcinoma in the remnant pancreas. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, with a high rate of recurrence even after complete surgical resection. The aim of this study was to investigate the impact of completion pancreatectomy (CP) on the clinical course of patients with recurrent PDAC in the remnant pancreas. MATERIALS AND METHODS: Between January 2008 and December 2014, 194 patients underwent curative-intent surgical resection (initial pancreatectomy [IP]) for PDAC at our institution. The treatment and survival outcomes were evaluated according to the patterns of recurrence. RESULTS: Among 194 patients with IP, 127 patients (65.5%) developed recurrence. Of them, 11 patients (8.7%) developed recurrence in the remnant pancreas and were treated by CP. They showed a significantly longer median survival after the recurrence than the 28 patients who developed unresectable local recurrence and were treated by systemic chemotherapy (44 mo versus 11 mo, P = 0.014) or the 66 patients who developed distant metastasis and were treated by systemic chemotherapy (44 mo versus 13 mo, P = 0.024). Moreover, the median survival after CP was longer in the patients who received adjuvant chemotherapy after CP than in those who did not receive adjuvant chemotherapy (44 mo versus 14 mo, P = 0.002). CONCLUSIONS: This study demonstrated that PDAC patients with resectable local recurrence in the remnant pancreas, who were treated by CP, had better survival outcomes than those with other patterns of recurrence. CP combined with adjuvant chemotherapy appeared to yield greater survival benefit. PMID- 29229122 TI - Use of imaging during symptomatic follow-up after resection of pancreatic ductal adenocarcinoma. AB - BACKGROUND: Controversy exists whether follow-up after resection of pancreatic ductal adenocarcinoma (PDAC) should include standardized imaging for the detection of disease recurrence. The purpose of this study was to evaluate how often patients undergo imaging in a setting where routine imaging is not performed. Secondly, the pattern, timing, and treatment of recurrent PDAC were assessed. MATERIALS AND METHODS: This was a post hoc analysis of a prospective database of all consecutive patients undergoing pancreatic resection of PDAC between January 2011 and January 2015. Data on imaging procedures during follow up, recurrence location, and treatment for recurrence were extracted and analyzed. Associations between clinical characteristics and post-recurrence survival were assessed with the log-rank test and Cox univariable and multivariable proportional hazards models. RESULTS: A total of 85 patients were included. Seventy-four patients (87%) underwent imaging procedures during follow up at least once, with a mean amount of 3.1 +/- 1.9 imaging procedures during the entire follow-up period. Sixty-eight patients (80%) were diagnosed with recurrence, 58 (85%) of whom after the manifestation of clinical symptoms. Additional tumor-specific treatment was administered in 17 of 68 patients (25%) with recurrence. Patients with isolated local recurrence, treatment after recurrence, and a recurrence-free survival >10 mo had longer post-recurrence survival. CONCLUSIONS: Even though a symptomatic follow-up strategy does not include routine imaging, the majority of patients with resected PDAC underwent additional imaging procedures during their follow-up period. Further prospective studies are needed to determine the actual clinical value, psychosocial implications, and cost-effectiveness of different forms of follow-up after resection of PDAC. PMID- 29229123 TI - Sarcopenia is a risk factor for complications and an independent predictor of hospital length of stay in trauma patients. AB - BACKGROUND: Sarcopenia is an independent risk factor for adverse outcomes in critically ill patients. The impact of sarcopenia on morbidity and length of stay in a trauma population has not been completely defined. This project evaluated the influence of sarcopenia on patients admitted to the trauma service. MATERIALS AND METHODS: A retrospective review of 778 patients presenting as a trauma alert at a single institution from 2012-2014 was completed. Records were abstracted for comorbidities and hospital complications. The Hounsfield Unit Area Calculation was collected from admission computed tomography scans. Criteria for sarcopenia were based on the lowest 25th percentile of muscle density measurements. Relationships to patient outcomes were evaluated by univariate and multivariable regression or analyses of variance, when applicable. RESULTS: A total of 432 (55.6%) patients suffered a complication. Sarcopenia was associated with overall complications (P < 0.0001, relative risk 2.54, confidence interval 1.78-3.61) and was an independent risk factor for catheter-associated urinary tract infections (P = 0.011), wound infections (P = 0.011), need for reintubation (P = 0.0062), and length of hospitalization (P = 0.0007). Incorporating sarcopenia into a novel length of stay calculator showed increased prognostic ability for prolonged length of stay over Abbreviated Injury Scale alone (P = 0.0002). CONCLUSIONS: Sarcopenia is an independent risk factor for adverse outcomes and increased length of stay in trauma patients. Prognostic algorithms incorporating sarcopenia better predict hospital length of stay. Identification of patients at risk may allow for targeted interventions early in the patient's hospital course. PMID- 29229124 TI - Mortality after emergency Hartmann's procedure in octogenarians: a propensity score-matched analysis. AB - BACKGROUND: Complicated diverticulitis is associated with a postoperative mortality rate of 20%. We hypothesized that age >=80 was an independent risk factor for mortality after Hartmann's procedure for diverticular disease when controlling for baseline comorbidities. METHODS: Patients who underwent an urgent or emergent Hartmann's procedure (Current Procedural Terminology codes 44143 and 44206) for diverticular disease (International Classification of Diseases 9:562.xx) were identified using the American College of Surgeons National Surgical Quality Improvement Project 2005-2013 user file. Using propensity score matching to control for baseline comorbidities, a group of patients >=80 years old was matched to a group of those <80 years old. Univariate and multivariable logistic regression were performed. A P value <0.05 was considered statistically significant with a confidence interval (CI) of 95%. RESULTS: From a total of 2986 patients, 464 patients (15.5%) were >=80 years old. Two groups of 284 patients in each study arm were matched using propensity-matching. The mean age of the >=80 group and <80 group was 84.4 +/- 3.3 versus 63.77 +/- 911.8; P < 0.0001, respectively. There was no statistical difference in baseline comorbidities or operative time between the groups. There was a significant difference in mortality with 19% and 9.2% in the >80 group versus <80 groups, respectively (P = 0.001). Factors associated with mortality included ascites (odds ratio [OR] 4.95, confidence interval [CI] 1.64-14.93, P = 0.005), previous cardiac surgery (OR 3.68, CI 1.46-9.26, P = 0.006), partially dependent or fully dependent functional status (OR 2.51, CI 1.12-5.56, P = 0.02), albumin <3 (OR 2.49, CI 1.18-5.29, P = 0.01), and American Society of Anesthesiologist class >3 (OR 2.10, CI 1.10-4.46, P = 0.05). CONCLUSIONS: Octogenarians presenting with complicated diverticulitis requiring an emergent Hartmann's procedure have a higher mortality rate compared to those <80, even after controlling for baseline comorbidities. STUDY TYPE: This is a retrospective, descriptive study. PMID- 29229125 TI - Efficacy of the dual controlled release of HGF and bFGF impregnated with a collagen/gelatin scaffold. AB - BACKGROUND: We previously developed collagen/gelatin sponges (CGS) able to sustain and release basic fibroblast growth factor (bFGF) and reported that this CGS impregnated with bFGF promoted dermis-like tissue formation. We herein confirmed the single-sustained release of hepatocyte growth factor (HGF) and the dual sustained release of HGF and bFGF from CGSs, and explored its efficacy using a murine model of skin defects. MATERIALS AND METHODS: The sustained release of HGF alone and both HGF and bFGF from CGSs were evaluated in vitro. CGSs (8 mm in diameter) impregnated with normal saline solution (NSS) (NSS group), HGF solution (10 or 50 MUg/cm2) (HGF-L or HGF-H group), bFGF solution (7 MUg/cm2) (bFGF group), or HGF (10 MUg/cm2) and bFGF (7 MUg/cm2) solution (HGF + bFGF group) were implanted into full-thickness skin defects on the backs of mice. The wound area, neoepithelium length, dermis-like tissue formation and newly formed capillaries were evaluated. RESULTS: The single release of HGF and the dual release of HGF and bFGF from CGSs were confirmed. At week 1, the wound closure and neoepithelium length were promoted in the HGF-L group compared with the NSS group. At week 2, the wound closure, neoepithelium length, dermis-like tissue formation and newly formed capillary formation were promoted in the bFGF and HGF + bFGF groups compared with the NSS and HGF-H groups. Newly formed capillary formation was superior in the HGF + bFGF group compared with the bFGF group. CONCLUSIONS: The dual release of HGF and bFGF from CGS was a promising treatment for full thickness skin defects. PMID- 29229126 TI - Prophylactic enoxaparin doses may be inadequate in patients undergoing abdominal cancer surgery. AB - BACKGROUND: The incidence of venous thromboembolism has increased in patients following cancer surgery despite the increased use of prophylactic anticoagulants, suggesting standard doses may be inadequate. We sought to determine the adequacy of enoxaparin prophylaxis in patients undergoing abdominal cancer surgery. METHODS: Peak and trough anti-Xa levels were measured in patients receiving enoxaparin thromboprophylaxis (40 mg daily or 30 mg twice daily, at the surgeon's discretion) after undergoing open abdominal cancer surgery at a single institution. RESULTS: Fifty-five patients received enoxaparin 40 mg daily (group 1), 18 received 30 mg twice daily (group 2; total n = 73). There were no significant differences in gender, age, body mass index, creatinine clearance, diagnosis, or procedure between the two groups. Thirty-nine patients (53.4%) had inadequate peak anti-Xa levels (<0.2 IU/mL) and 69 patients (94.5%) had inadequate trough levels (<=0.1 IU/mL). Group 2 had lower mean peak levels (0.14 +/- 0.02 IU/mL) than group 1 (0.22 +/- 0.01, P = 0.003), and higher mean trough levels (0.06 +/- 0.017) than group 1 (0.02 +/- 0.004, P = 0.033). Group 2 had lower incidence of adequate peak anti-Xa levels than group 1 when adjusting for gender, age, body mass index, and preoperative creatinine clearance (OR 0.23, P = 0.039). CONCLUSIONS: The majority of patients had inadequate anti-Xa levels following abdominal cancer surgery, calling into question standard prophylactic enoxaparin dosing. PMID- 29229127 TI - Platonin mitigates vascular hyporeactivity of thoracic aorta in septic rats. AB - BACKGROUND: Vascular hyporeactivity contributes to hemodynamic alterations and circulatory failure in severe sepsis. Among the identified mechanisms, inflammation and oxidative stress are the most crucial ones in mediating the development of vascular hyporeactivity induced by sepsis. Platonin, a photosensitive dye and an antioxidant, possesses potent antiinflammation effects. We elucidated whether platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats. MATERIAL AND METHODS: Adult male Sprague-Dawley rats were randomized to receive sham operation (Sham), Sham plus platonin (100 MUg/kg), cecal ligation and puncture (CLP), or CLP plus platonin (10, 50, or 100 MUg/kg) and designated as the Sham, P, CLP, CLP + P(10), CLP + P(50), and CLP + P(100) group, respectively (n = 6 in each group). After maintaining for 12 hours, surviving rats were euthanized and thoracic aorta was isolated and vascular reactivity of aortic rings was determined. RESULTS: Vascular reactivity induced by vasoconstrictors phenylephrine and angiotensin II of the Sham and the P groups (n = 6 in both groups) were similar, whereas vascular reactivity of the CLP group (n = 5) were significantly lower than those of the Sham group (both P < 0.001). Of note, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(10) group (n = 5) and the CLP group were not significantly different. In contrast, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(50) and the CLP + P(100) groups (n = 6 in both groups) were significantly higher than those of the CLP group (phenylephrine: P = 0.024 and 0.017; angiotensin II: P = 0.031 and 0.036). CONCLUSION: Platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats. PMID- 29229128 TI - Thirty-day readmission and mortality among Medicare beneficiaries discharged to skilled nursing facilities after vascular surgery. AB - BACKGROUND: Readmission within 30 d of an acute hospital stay is frequent, costly, and increasingly subject to penalties. Early readmission is most common after vascular surgery; these patients are often discharged to skilled nursing facilities (SNFs), making postacute care an essential partner in reducing readmissions. We characterize 30-day readmissions among vascular surgery patients discharged to SNF to provide evidence for this understudied segment of readmission after specialty surgery. METHODS: We utilize the Centers for Medicare & Medicaid Services Chronic Conditions Warehouse, a longitudinal 5% national random sample of Medicare beneficiaries to study 30-day readmission or death after discharge to SNF following abdominal aortic aneurysm repair or lower extremity revascularization from 2005-2009. Descriptive statistics and logistic regression with Least Adaptive Shrinkage and Selection Operator were used for analysis. RESULTS: Two thousand one hundred ninety-seven patients underwent an abdominal aortic aneurysm procedure or lower extremity revascularization at 686 hospitals and discharged to 1714 SNFs. Eight hundred (36%) were readmitted or had died at 30 d. In adjusted analysis, predictors of readmission or death at 30 d included SNF for-profit status (OR [odds ratio] = 1.2; P = 0.032), number of hospitalizations in the previous year (OR = 1.06; P = 0.011), number of comorbidities (OR = 1.06; P = 0.004), emergent procedure (OR = 1.69; P < 0.001), renal complication (OR = 1.38; P = 0.003), respiratory complication (OR = 1.45; P < 0.001), thromboembolic complication (OR = 1.57; P = 0.019), and wound complication (OR = 0.70; P = 0.017). CONCLUSIONS: Patients discharged to SNF following vascular surgery have exceptionally high rates of readmission or death at 30 d. Many factors predicting readmission or death potentially modify decision making around discharge, making early detection, discharge planning, and matching patient needs to SNF capabilities essential to improving outcomes. PMID- 29229129 TI - Hospital safety-net burden does not predict differences in rectal cancer treatment and outcomes. AB - BACKGROUND: Safety-net hospitals have been shown to have inferior short-term surgical outcomes. The aim of this study was to compare rectal cancer management and survival across hospitals stratified by payer mix. MATERIALS AND METHODS: Rectal cancer patients (n = 296,068) were identified using the 1998-2010 National Cancer Data Base. Hospitals were grouped into safety-net burden categories, according to the proportion of patients with Medicaid or no health insurance, as follows: low-, medium-, and high-burden hospitals (HBHs). Patient and tumor characteristics, processes of care, and outcomes were evaluated, and regression analysis was used to investigate correlations between hospital safety-net burden on patient survival. RESULTS: HBH encountered patients with more advanced disease (P < 0.001). Despite this, stage I-III patients at HBH had equal likelihood of receiving surgery and guideline-appropriate radiation and chemotherapy (all P > 0.05). The 30-day readmissions and mortality were also similar across safety-net groups (all P > 0.05). Multivariate analysis showed no difference in survival between HBH and low-burden hospital (P = 0.164). CONCLUSIONS: Hospital payer mix may not adversely influence management of rectal cancer. This study highlights potential areas to improve cancer care for vulnerable patient populations. PMID- 29229130 TI - Single incision laparoscopic proficiency correlates with residency training level. AB - BACKGROUND: With experience, certain psychomotor skills should translate from standard laparoscopy to single-incision laparoscopy (SIL). We proposed to compare all surgical postgraduate year (PGY) levels and determine if experience translated to improved SIL skills. METHODS: Surgical residents of all PGY levels (1-5) at our institution were included. Baseline surveys were obtained to determine resident level of exposure to both SIL and standard laparoscopic cases. Participants performed the following tasks: running of the bowel, endoloop placement, extracorporeal suture tying, and intracorporeal suture tying. Tasks were performed on a commercially provided simulated inanimate organ model. Participants were given 5 min to complete each task. Data were collected and analyzed by an impartial-certified Fundamentals of Laparoscopic Surgery proctor. RESULTS: A total of 31 residents participated in the study. Overall, there was minimal SIL exposure among all residents. As expected, PGY level correlated with increased ability to complete assigned tasks within the allotted time. There was a statistically significant difference in the number of individuals able to complete a task based on PGY level for all given tasks (P = 0.005). With increased difficulty, the percentage of higher level residents able to complete the task decreased (100% PGY5 completed running of bowel versus 0% intracorporeal knot tying). CONCLUSIONS: Certain psychomotor skills did appear to translate to SIL skills. However, further dedicated SIL training may help to better develop certain laparoscopic skills devoted to SIL. PMID- 29229131 TI - Racial disparities in the cost of surgical care for parathyroidectomy. AB - BACKGROUND: Parathyroidectomy is the only curative therapy for hyperparathyroidism, but its cost and variation in use among different racial and ethnic groups are largely unexamined. The purpose of this study was to examine the association between race and ethnicity and the total hospital cost of parathyroidectomy. METHODS: This retrospective study included 899 consecutive complete parathyroidectomies in our institution between September 2011 and July 2016. Total length of stay and cost were primary outcomes. Nonparametric and chi square tests were used for analysis. RESULTS: The study population was 66.4% Caucasian, 31.4% African American, 0.7% Hispanic, and 0.3% Asian. Total hospital costs were greater for African-American patients ($6154.87 +/- 389.18) compared to Caucasian patients ($5253.28 +/- $91.74). Mean length of stay was 0.99 +/- 0.18 for African-American patients and 0.44 +/- 0.05 for Caucasian patients. African-American patients were more likely than Caucasian patients to be readmitted (4.6% versus 1.2%). Among African Americans, males had a more expensive hospital cost, higher incidence of cases that cost greater than $10,000, and longer length of stay compared to females. CONCLUSIONS: African American race was associated with higher hospital costs for parathyroidectomy compared to Caucasian patients, especially male patients. The increased cost could be explained in part by longer length of stay. More detailed efforts are needed to reduce racial disparity in the management of parathyroidectomy patients. PMID- 29229132 TI - Do not underestimate the tricuspid valve. PMID- 29229133 TI - Risk factors associated with perioperative morbidity and mortality following isolated tricuspid valve replacement. AB - BACKGROUND: Reports of isolated tricuspid valve replacement (iTVR) are relatively rare. The present study aimed to evaluate independent risk factors of perioperative morbidity and mortality after iTVR. MATERIALS AND METHODS: We retrospectively reviewed 118 consecutive patients (42 males; mean age, 49.1 +/- 12.9 y) who underwent iTVR from May 2003 to April 2016 in our center. The multivariate logistic regression model was used to analyze the independent risk factors associated with perioperative morbidity and mortality following iTVR. RESULTS: One hundred one patients (85.6%) were classified as New York Heart Association functional class III or IV preoperatively. The overall perioperative mortality was 11.8% (14/118), and a significant difference was observed between the nonreoperative group and the reoperative group (6.7% versus 18.3%, P = 0.047). The multivariate logistic regression analyses identified that preoperative New York Heart Association functional class IV (OR [odds ratio] = 15.43, 95% CI [confidence interval] = 3.46-68.83, P = 0.000) and ascites (OR = 4.88, 95% CI = 1.24-19.27, P = 0.024) were independent risk factors of perioperative deaths. The previous cardiac surgery (OR = 3.28, 95% CI = 1.41 7.62, P = 0.006) was independently associated with perioperative major adverse events. CONCLUSIONS: The present study revealed that iTVR has relatively high mortality and morbidity rates. Timely surgery may be recommended for this high risk cohort of patients before the development of severe heart and end-organ failure. PMID- 29229134 TI - Animal models in plastic and reconstructive surgery simulation-a review. AB - BACKGROUND: The use of live and cadaveric animal models in surgical training is well established as a means of teaching and improving surgical skill in a controlled setting. We aim to review, evaluate, and summarize the models published in the literature that are applicable to Plastic Surgery training. MATERIALS AND METHODS: A PubMed search for keywords relating to animal models in Plastic Surgery and the associated procedures was conducted. Animal models that had cross over between specialties such as microsurgery with Neurosurgery and pinnaplasty with ear, nose, and throat surgery were included as they were deemed to be relevant to our training curriculum. A level of evidence and recommendation assessment was then given to each surgical model. RESULTS: Our review found animal models applicable to plastic surgery training in four major categories namely-microsurgery training, flap raising, facial surgery, and hand surgery. Twenty-four separate articles described various methods of practicing microsurgical techniques on different types of animals. Fourteen different articles each described various methods of conducting flap-based procedures which consisted of either local or perforator flap dissection. Eight articles described different models for practicing hand surgery techniques. Finally, eight articles described animal models that were used for head and neck procedures. CONCLUSIONS: A comprehensive summary of animal models related to plastic surgery training has been compiled. Cadaveric animal models provide a readily available introduction to many procedures and ought to be used instead of live models when feasible. PMID- 29229135 TI - Intraoperative factors associated with postoperative complications in body contouring surgery. AB - BACKGROUND: Several preoperative factors have been shown to influence outcome of body contouring surgeries. The effect of intraoperative features, including fluid volume administered, hemodynamic and respiratory parameters, and body temperature on postoperative complication, has not been reported to date. MATERIALS AND METHODS: All subsequent patients undergoing body contouring surgery in the Tel Aviv Medical Center between 2007 and 2012 were enrolled. Demographic and intraoperative data were collected and analyzed for possible associations with postoperative complications, including formation of seroma, hematoma/bleeding, other surgical site complications (infection, adhesiolysis, or need for debridement), formation of a hypertrophic scar, any documented, infection or a composite outcome of any of the previously mentioned. RESULTS: Data of 218 patients were assessed. Mean (standard deviation) age of patients was 41(14) y. Intraoperative administration of higher volumes of fluids was significantly associated with formation of seroma (P = 0.01), hematoma/bleeding (P = 0.03), hypertrophic scar (P = 0.01), surgical site complications (P = 0.01), and a composite outcome (P < 0.001). Development of hematoma/bleeding was associated with longer periods of low (<35.6 degrees C) intraoperative core temperature (72% versus 50% of surgery duration in patients who did not develop this complication, P < 0.05). Surgical site complications were associated with longer periods of intraoperative oxygen desaturation (saturation <=92%, 4.2% versus 0.9% of surgery duration in patients who did not develop surgical site complications, P < 0.01). CONCLUSIONS: Intraoperative moderate hypothermia, hypoxemia, and liberal fluid administration are associated with worse surgical outcome in patients undergoing body contouring surgery. Increased awareness of the potential adverse effects of these factors in body contouring surgery will enhance interventions aimed at avoiding and promptly treating such events. PMID- 29229136 TI - The gut-liver axis: impact of a mouse model of small-bowel bacterial overgrowth. AB - BACKGROUND: The mechanisms by which intestinal bacteria impact liver diseases remain poorly understood. The aim of this study was to develop a mouse model of small-bowel bacterial overgrowth and to determine its impact on hepatobiliary injury. MATERIALS AND METHODS: A jejunal self-filling blind loop (SFBL) was created in C57BL/6 mice. Three weeks after surgery, the mice were euthanized, and bacterial cultures of luminal content of the loop and extraintestinal tissues were performed. Liver and jejunum were collected for histological grading of inflammation and injury. Serum liver biochemistry assays were performed. Hepatobiliary transporter mRNA expression in liver was measured by quantitative real-time polymerase chain reaction. Bile and blood were collected for measurement of total bile acids, phospholipid, and cholesterol. Mice undergoing jejunal transection and reanastomosis and laparotomy only served as control groups. RESULTS: SFBL induced a dramatic increase in intraluminal bacterial counts, mesenteric lymph node bacterial translocation, and evidence of jejunal and hepatobiliary injury. Significant reductions in hepatic expression of hepatobiliary transporters involved in biliary canalicular export and basolateral uptake were observed in SFBL mice. SFBL resulted in a significant increase in biliary total bile acid concentration, decreases in bile phospholipid and cholesterol output, and an increase in the bile acid/phospholipid ratio. CONCLUSIONS: We have developed a reproducible mouse model of small-bowel bacterial overgrowth with evidence of liver inflammation, altered hepatobiliary transporter expression, and alterations in bile composition. This model may help to elucidate the mechanisms by which gut-derived bacterial factors impact the liver and contribute to the exacerbation of liver diseases and biliary injury. PMID- 29229137 TI - Effects of MgSO4 on inhibiting Nod-like receptor protein 3 inflammasome involve decreasing intracellular calcium. AB - BACKGROUND: Nod-like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex composed of NLRP3, caspase-1, and apoptosis-associated speck-like protein containing a caspase recruitment domain. Activation of NLRP3 inflammasome leads to interleukin-1beta (IL-1beta) upregulation and pyroptosis, a proinflammatory cell death characterized by increased cell size. Of note, calcium signaling is crucial for NLRP3 inflammasome activation. This study elucidated the effects of magnesium sulfate (MgSO4), a potent calcium antagonist, on modulating NLRP3 inflammasome. MATERIALS AND METHODS: THP-1 cells, the human monocytic leukemia cell line, were treated with lipopolysaccharide (LPS, 1 MUg/ml) plus nigericin (5 MUM) (the LPS + Nig group) and LPS plus nigericin plus MgSO4 (20 mM) [the LPS + Nig + M(20)] to facilitate investigations. Levels of IL-1beta, pyroptosis, and NLRP3 inflammasome induction as well as intracellular calcium were assayed. RESULTS: IL-1beta concentration of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.001). Cell size of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P < 0.001). Level of pyroptotic cell death of the LPS + Nig + M(20) group was significantly lower than the LPS + Nig group (P = 0.004). NLRP3 mRNA and protein concentrations of the LPS + Nig + M(20) group were also significantly lower than the LPS + Nig group (P = 0.021 and P < 0.001). Similarly, apoptosis-associated speck-like protein containing a caspase recruitment domain speck formation ratio and caspase-1 concentration of the LPS + Nig + M(20) group were significantly lower than the LPS + Nig group (both P < 0.001). The change in intracellular calcium level of the LPS + Nig + M(20) group was significantly smaller than the LPS + Nig group (P = 0.001). CONCLUSIONS: MgSO4 inhibits NLRP3 inflammasome, IL-1beta upregulation, and pyroptosis. The mechanism is consistent with decreased intracellular calcium levels. PMID- 29229138 TI - Abdominal wall reconstruction after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: Cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improve survival and decrease recurrence of peritoneal metastasis in a select population of patients. Abdominal wall resection is often needed to achieve complete CRS and the extent of abdominal wall resection may necessitate abdominal wall reconstruction (AWR). We sought to investigate if postoperative morbidity and mortality was increased in patients who underwent AWR with CRS-HIPEC (AWR group) compared to CRS-HIPEC without AWR (non-AWR group) and to identify if patient, tumor, and operative risk factors were associated with poor outcomes following AWR. We postulate that AWR is a safe and viable treatment option in appropriately selected patients with peritoneal disease. METHODS: A retrospective chart review was conducted from 2012 to 2015. Demographics, comorbidities, intraoperative variables, and postoperative outcomes were analyzed and compared between the non-AWR group and the AWR group. RESULTS: A total of 30 patients underwent CRS-HIPEC at our institution; 19 recruited in non-AWR group and 11 in the AWR arm. Median follow-up was 19.1 mo for the non-AWR group and 15.6 mo for AWR. Overall survival and complications were not significantly different between groups. Six patients in the non-AWR group and three patients in AWR group died during the follow-up period (32% versus 27%, P = 0.75). Grade III/IV Clavien-Dindo complications were similar in AWR compared to non-AWR group (64% versus 50%, P = 0.46) however estimated blood loss (1000 mL versus 450 mL, P = 0.01) and operative time (663 min versus 510 min, P = 0.02) were significantly increased in the AWR group. CONCLUSIONS: The results of this study demonstrate that AWR is a safe and viable option and can improve wound closure and strength in select patient populations undergoing CRS-HIPEC. AWR is not associated with an increase in mortality or complication rate. Future studies will need larger sample sizes and randomization to identify patient and operative factors that increase morbidity with AWR and identify the ideal timing of AWR. PMID- 29229139 TI - Comparison of the Lund and Browder table to computed tomography scan three dimensional surface area measurement for a pediatric cohort. AB - BACKGROUND: Treating burns effectively requires accurately assessing the percentage of the total body surface area (%TBSA) affected by burns. Current methods for estimating %TBSA, such as Lund and Browder (L&B) tables, rely on historic body statistics. An increasingly obese population has been blamed for increasing errors in %TBSA estimates. However, this assumption has not been experimentally validated. We hypothesized that errors in %TBSA estimates using L&B were due to differences in the physical proportions of today's children compared with children in the early 1940s when the chart was developed and that these differences would appear as body mass index (BMI)-associated systematic errors in the L&B values versus actual body surface areas. MATERIALS AND METHODS: We measured the TBSA of human pediatric cadavers using computed tomography scans. Subjects ranged from 9 mo to 15 y in age. We chose outliers of the BMI distribution (from the 31st percentile at the low through the 99th percentile at the high). We examined surface area proportions corresponding to L&B regions. RESULTS: Measured regional proportions based on computed tomography scans were in reasonable agreement with L&B, even with subjects in the tails of the BMI range. The largest deviation was 3.4%, significantly less than the error seen in real world %TBSA estimates. CONCLUSIONS: While today's population is more obese than those studied by L&B, their body region proportions scale surprisingly well. The primary error in %TBSA estimation is not due to changing physical proportions of today's children and may instead lie in the application of the L&B table. PMID- 29229140 TI - A novel pilot animal model for the surgical prevention of lymphedema: the power of optical imaging. AB - BACKGROUND: Breast cancer-related lymphedema affects more than 400,000 survivors in the United States. In 2009, lymphatic microsurgical preventive healing approach (LYMPHA) was first described as a surgical technique to prevent lymphedema by bypassing divided arm lymphatics into adjacent veins at the time of an axillary lymph node dissection. We describe the first animal model of LYMPHA. METHODS: In Yorkshire pigs, each distal hind limb lymphatic system was cannulated and injected with a different fluorophore (human serum albumin-conjugated indocyanine green or Evans Blue). Fluorescence-assisted resection and exploration imaging system was used to map the respective lymphangiosomes to the groin. Baseline lymphatic clearance of each hind limb lymphangiosome was obtained by measuring the fluorescence of each dye from centrally obtained blood samples. A lymphadenectomy versus lymphadenectomy with LYMPHA was then performed. The injections were then repeated to obtain clearance rates that were compared against baseline values. RESULTS: Human serum albumin-conjugated indocyanine green and Evans Blue allowed for precise lymphatic mapping of each respective hind limb using fluorescence-assisted resection and exploration imaging. Lymphatic clearance from the distal hind limb dropped 68% when comparing baseline clearance versus after a groin lymphadenectomy. In comparison, lymphatic clearance dropped only 21% when comparing baseline clearance versus a lymphadenectomy with LYMPHA. CONCLUSIONS: We describe the first animal model for LYMPHA, which will enable future studies to further evaluate the efficacy and potential limitations of this technique. Of equal importance, we demonstrate the power of optical imaging to provide real-time lymphatic clearance rates for each hind limb. PMID- 29229141 TI - Neurodevelopment impact of CO2-pneumoperitoneum in neonates: experimental study in a rat model. AB - BACKGROUND: Laparoscopy is becoming more common in neonates. However, concerns remain about the impact of the carbon-dioxide (CO2)-insufflation over the neonatal brain. We aim to evaluate the peripheral (serum) and central (cerebrospinal fluid [CSF]) cytokine response after neonatal CO2-pneumoperitoneum and its impact over neurodevelopmental milestones acquisition and long-term behavioral outcomes. MATERIALS AND METHODS: Rats were subjected to a systematic assessment of neurodevelopmental milestones between postnatal day 1 (PND 1) and PND 21. At PND 10, neonatal rats were anesthetized, mechanically ventilated, and exposed to different pressures and times of abdominal CO2-insufflation. Immediately after pneumoperitoneum, corticosterone was analyzed in serum. Twenty four hours after intervention, serum and CSF were collected to assess inflammatory response (interleukin [IL]-10, IL-1beta, tumor necrosis factor [TNF] alpha, and interferon [IFN]-gamma). In adulthood, animals from each group were submitted to several tests to assess different behavioral domains (locomotion, anxiety, mood, and cognition). RESULTS: The antiinflammatory cytokine IL-10 was significantly increased in CSF in CO2-insufflated groups, with no other significant changes in the other biomarkers. Acquisition of neurodevelopmental milestones was maintained in all studied groups. No significant differences were observed in adult behavior in the different CO2-insufflation conditions. CONCLUSIONS: Neonatal CO2-pneumoperitoneum does not seem to have any negative impact on neurodevelopment or induce behavioral alterations in adulthood. Minimally invasive surgery results in a central antiinflammatory profile, and further studies on the functional consequences of these phenomena are needed. PMID- 29229142 TI - Improvement of consistency in delineating breast lumpectomy cavity using surgical clips. AB - BACKGROUND: Delineation of lumpectomy cavity for whole breast radiation therapy after breast conserving surgery can be challenging because of poor visualization of the cavity. The use of surgical clips on lumpectomy cavity walls has been suggested as an effective and low-cost method to improve the accuracy and consistency of lumpectomy cavity delineation. MATERIALS AND METHODS: Twenty-three eligible female breast cancer patients who were treated with lumpectomy and adjuvant radiation therapy were recruited for this study. During breast conserving surgery, four surgical clips were placed on the superior, inferior, lateral, and medial walls of the lumpectomy cavity. Patients were imaged prior and during radiation treatment. Software was developed to anonymize the image sets and digitally remove the clips from the computed tomography images. Three radiation oncologists contoured the lumpectomy cavity volume, with and without presence of clips. Contoured image sets were analyzed with regard to cavity volume, dimensions, and concordance index. Statistical analysis was performed using a paired t-test. RESULTS: The presence of clips significantly increased the average lumpectomy cavity volumes from 23.50 cc to 26.42 cc (P < 0.0001). The presence of clips also significantly increased the mean craniocaudal, anteroposterior, and mediolateral dimensions by 6.8, 2.3, and 2.9 mm, respectively (all P < 0.01). In addition, the presence of surgical clips improved the consistency in delineation in CC dimension by significantly decreasing the standard deviation (P < 0.006). CONCLUSIONS: The presence of surgical clips improves the accuracy of lumpectomy cavity delineation. However, consistency is only improved in CC dimension. PMID- 29229143 TI - Myocardial functional changes in transfemoral versus transapical aortic valve replacement. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) has greatly expanded the treatment options available for patients with severe aortic stenosis at high surgical risk. MATERIALS AND METHODS: We compared changes in myocardial function in TAVR with a transfemoral (TF) versus a transapical (TA) approach at a major tertiary hospital from 2012-2016. Traditional echocardiographic measures of cardiac structure and function were tracked, alongside the use of two-dimensional speckle tracking echocardiography to measure myocardial strain and strain rates. RESULTS: For the entire cohort with complete data at all time points (n = 42), between the pre-TAVR baseline (mean: 20.1 d) and the post-TAVR 1-mo follow-up (mean: 32.7 d), global longitudinal strain significantly increased (from -15.6% to -18.2%, P < 0.001). When comparing the TF (n = 31) and TA (n = 11) groups, TA patients showed persistently impaired apical longitudinal strain at the 1-mo follow-up (-15.9% versus -22.3%, P < 0.05). In terms of clinical outcomes, both groups (n = 131 for TF, n = 53 for TA) were similar in terms of 30-d mortality, readmission rate, and risk of post-TAVR acute kidney injury. However, TA patients experienced significantly longer length of hospitalization (7.58 versus 3.92 d, P = 0.02), intensive care unit hours (105.4 versus 47.1 h, P = 0.02), and were at a greater risk of long-term (>72 h) intensive care unit stay (45% versus 25%, P = 0.01). CONCLUSIONS: Patients undergoing TA-TAVR exhibit impaired apical longitudinal strain, although global myocardial function is similar to TF-TAVR otherwise. Myocardial strain measured by two-dimensional speckle tracking echocardiography appears to be a sensitive method to detect subtle cardiac remodeling after TAVR. PMID- 29229145 TI - Transparency and the outcomes conversation. PMID- 29229144 TI - Postoperative neonatal mortality prediction using superlearning. AB - BACKGROUND: The variable risks associated with neonatal surgery present a challenge to accurate mortality prediction. We aimed to apply superlearning, an ensemble machine learning method, to the prediction of 30-day neonatal postoperative mortality. MATERIALS AND METHODS: We included neonates in the 2012 2014 National Surgical Quality Improvement Program Pediatric. Patients treated in 2012-13 were used in model development (n = 6499), and patients treated in 2014 formed the validation sample (n = 3552). Our superlearner algorithm included 14 regression and machine learning algorithms and included all preoperative patient demographic and clinical characteristics, including indicator variables for surgical procedures. Performance was evaluated using mean squared error and measures of discrimination and calibration. RESULTS: The superlearner out performed all individual algorithms with regard to cross-validated mean squared error. It showed excellent discrimination, with an area under the receiver operating characteristic curve of 0.91 in development and 0.87 in validation. The superlearner showed good calibration in development but not in validation (Cox calibration test P = 0.06 and P < 0.001, respectively). Performance was improved when the superlearner was fit using only variables strongly associated with mortality in bivariate analysis (area under the receiver-operating characteristic curve 0.89, calibration test P = 0.63 in validation). CONCLUSIONS: Superlearning provided improved or equivalent performance compared with individual regression and machine learning algorithms for predicting neonatal surgical mortality. This method should be considered for prediction in large data sets whenever complex mechanisms make parametric modeling assumptions unrealistic. PMID- 29229146 TI - Procedure-based postoperative risk prediction using NSQIP data. AB - BACKGROUND: The National Surgical Quality Improvement Program (NSQIP) has proposed using procedure-based hierarchical models to predict adverse outcomes, but it is not clear whether this approach was used to develop the NSQIP "Surgical Risk Calculator". We therefore wished to demonstrate how procedure-based hierarchical models can be constructed and to describe their results. METHODS: NSQIP data from 2015 were used to construct statistical models predicting 30-day postoperative mortality and morbidity, using two-level logistic regression with preoperative patient-level variables as fixed effects and procedure-specific codes as a random intercept. Model performance was validated using NSQIP data from 2014. RESULTS: NSQIP for 2015 contained records for 885,502 patients, of whom 8986 died (1.0%) and 104,836 suffered a complication (11.8%). Complete model specifications and results are presented, including odds ratios for patient-level variable effects and random procedure effects. Most comorbidities were associated with increased morbidity and mortality, but overweight and obesity were associated with lower risk. Odds ratios for individual procedures ranged from 0.117 to 10.85 for mortality and from 0.615 to 8.09 for morbidity. Validation C statistics were 0.940 for the mortality model and 0.833 for the morbidity model; Brier Scores were 0.0086 and 0.085, respectively. Graphs for 20 quantiles showed good conformity of observed and predicted risk. CONCLUSIONS: Procedure-based hierarchical logistic regression models of NSQIP outcomes had satisfactory overall performance statistics. Model specifications and results are provided for criticism and improvement, and several possible refinements are suggested. PMID- 29229147 TI - Effects of dermal wounding on distal primary tumor immunobiology in mice. AB - BACKGROUND: Before primary oral tumors are treated, various prophylactic procedures that require tissue repair are often necessary (e.g. biopsies, tooth extractions, radiation, and tracheotomies). Wound healing and tumor growth harness similar immune/inflammatory mechanisms. Our previous work indicates that tumors impair wound healing, although the extent to which tissue repair conversely influences tumor growth is poorly understood. Here, we test the hypothesis that dermal wound healing exacerbates primary tumor growth and influences tumor immunobiology. MATERIALS AND METHODS: Female, immunocompetent mice were inoculated subcutaneously with murine oral cancer cells (AT-84) to induce flank tumors. Half of the mice received dermal excisional wounds (4 * 3.5 mm diameter) on their dorsum 16 days later, whereas the skin of controls remained intact. Tumor and blood tissues were harvested 1 and 5 days post wounding, and tumor myeloid cell populations and inflammatory gene expression were measured. Circulating myeloid cells, cytokines, and corticosterone were also quantified. RESULTS: Wounding increased tumor mass, early tumor infiltration of macrophages, and tumor inflammatory gene expression. While wounding attenuated tumor growth induced increases in circulating myeloid cells, no effects of wounding on circulating cytokine/endocrine measures were observed. CONCLUSIONS: These results indicate that modest skin immune/inflammatory processes can enhance distal tumor growth and alter innate tumor immunity. The implication for this work is that, in the presence of a tumor, the benefits of tissue-damaging procedures that occur clinically must be weighed against the potential consequences for tumor biology. PMID- 29229148 TI - Are we missing the near misses in the OR?-underreporting of safety incidents in pediatric surgery. AB - BACKGROUND: Electronic hospital variance reporting systems used to report near misses and adverse events are plagued by underreporting. The purpose of this study is to prospectively evaluate directly observed variances that occur in our pediatric operating room and to correlate these with the two established variance reporting systems in our hospital. MATERIALS AND METHODS: Trained individuals directly observed pediatric perioperative patient care for 6 wk to identify near misses and adverse events. These direct observations were compared to the established handwritten perioperative variance cards and the electronic hospital variance reporting system. All observations were analyzed and categorized into an additional six safety domains and five variance categories. The chi-square test was used, and P-values < 0.05 were considered statistically significant. RESULTS: Out of 830 surgical cases, 211 were audited by the safety observers. During this period, 137 (64%) near misses were identified by direct observation, while 57 (7%) handwritten and 8 (1%) electronic variance were reported. Only 1 of 137 observed events was reported in the handwritten variance system. Five directly observed adverse events were not reported in either of the two variance reporting systems. Safety observers were more likely to recognize time-out and equipment variances (P < 0.001). Both variance reporting systems and direct observation identified numerous policy and process issues. CONCLUSIONS: Despite multiple reporting systems, near misses and adverse events remain underreported. Identifying near misses may help address system and process issues before an adverse event occurs. Efforts need to be made to lessen barriers to reporting in order to improve patient safety. PMID- 29229149 TI - Transfusion of ethylene carbodiimide-fixed donor splenocytes prolongs survival of vascularized skin allografts. AB - BACKGROUND: Allograft rejection is a major obstacle to the widespread clinical application of vascularized composite allotransplantation. Recent studies revealed a noncytoreductive strategy to protect allografts by the transfusion of ethylene carbodiimide-fixed donor splenocytes (ECDI-SPs). To determine whether this approach offers advantages in protecting skin allografts, we examined the immunological protection of infusing ECDI-SPs with a 30-d administration of rapamycin on the skin allografts of mice. MATERIALS AND METHODS: C57BL/6 recipient mice received BALB/c donor full-thickness skin or vascularized skin transplants at day 0, along with the infusion of donor ECDI-SPs 7 d before and 1 d after allotransplantation and a 30-d course of rapamycin. Recipients received ECDI-untreated splenocytes or C3H allografts as controls. In vitro allostimulatory activity of ECDI-SPs and donor-specific ex vivo hyporesponsiveness were tested. Production of related cytokines (TGF-beta, IL-10, IL-1beta, and TNF-alpha) and expression of CD4+Foxp3+ regulatory T cells (Tregs) were also examined. RESULTS: Transfusion of ECDI-SPs combined with rapamycin significantly prolonged survival of full-thickness skin (median survival time [MST]: 28 d) and full-thickness skin allografts (MST: 71 d) compared with untreated splenocytes (MSTs: 11 d and 30 d) or C3H allografts (MSTs: 11 d and 38 d). This effect was accompanied by increased production of IL-10 and TGF-beta, decreased production of IL-1beta and TNF-alpha, and expansion of Tregs in vitro and in vivo. CONCLUSIONS: ECDI-SP infusion combined with short-term rapamycin administration provides a promising approach to prolong the skin allograft survival. PMID- 29229150 TI - Echocardiography allows for analysis of pulmonary arterial flow in mice with congenital diaphragmatic hernia. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is a structural birth defect associated with pulmonary hypoplasia and pulmonary arterial hypertension (PAH). We hypothesize that echocardiography provides a method to assess real-time right ventricle (RV) function, remodeling, and pulmonary artery (PA) flow. MATERIALS AND METHODS: Slit3 wild-type (WT) (n = 6) and knockout (KO) (n = 5) mice were analyzed at 2-3 months of age. Mice were anesthetized using isoflurane. Echocardiography was performed to analyze left and right ventricular wall thickness, internal diameter (ID), and function. Color Doppler was used to analyze flow in the PA and across the tricuspid valve. RESULTS: There was significant RV dilation in the KO mice versus WT, with an average RVID of 1.99 mm versus 1.26 mm, respectively (P = 0.007). Flow in the PA of KO mice was altered compared to WT, with elevated PA velocity time indices, 30.68 mm versus 22.13 mm (P = 0.012), elevated PA peak velocities, 952.61 mm/s versus 628.73 mm/s (P = 0.003), and decreased pulmonary acceleration times, 8.94 ms versus 16.18 ms (P = 0.002), respectively. Pulmonary vascular resistance, calculated by measuring tricuspid regurgitation peak velocity and right ventricular outflow tract velocity time index, was increased in KO versus WT mice, 17.61 mm2/s versus 8.91 mm2/s (P = 0.003), respectively. CONCLUSIONS: Slit3 KO mice with CDH show evidence of PAH and resultant RV dilation. Using direct cardiac puncture, elevated RV systolic pressures have been demonstrated in KO mice as evidence of PAH. Echocardiography allows direct analysis of the PA and real-time RV function without sacrifice of the mouse. This mode of evaluation allows longitudinal study in mice with PAH and CDH. PMID- 29229151 TI - Ketorolac use may increase risk of postoperative pancreatic fistula after pancreaticoduodenectomy. AB - BACKGROUND: Ketorolac (Toradol), a commonly used nonselective nonsteroidal anti inflammatory drug (NSAID) in the postoperative period, has been associated with increased risk of anastomotic leak after colon resection. The effect of postoperative NSAID and ketorolac use on postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) is unknown. METHODS: Retrospective review of consecutive PDs at a high-volume pancreas center from 2012 to 2015. POPF was identified and graded using International Study Group on Pancreatic Fistula criteria. Demographics, operative variables and 30-d postoperative NSAID use, dosage, and timing (early = postoperative day [POD] 0-5, late > POD 5) were collected. Univariate and multivariate logistic regressions were used to identify predictors of POPF. RESULTS: Four hundred twenty-three PDs were analyzed (mean age 66 y, 47% female), and 60% received NSAIDs postoperatively. Ketorolac (median POD 0-5 cumulative dose = 90 mg, interquartile range 60-165) was used in 35.7% (n = 151). POPF occurred in 90 patients (21.3%). Early (POD 0-5) ketorolac use was associated with increased POPF, especially grade A (odds ratio [OR] 2.16, P = 0.036). Each 25 mg incremental increase in ketorolac use was associated with a 10% increase in the incidence of POPF (OR 1.10, P = 0.021), whereas a cumulative dose of >150 mg was associated with a 44% increased risk of POPF (OR 1.44, 95% confidence interval 1.03-2.01, P = 0.035). A multivariate regression model identified estimated blood loss, soft gland, pancreatic duct diameter, body mass index, and cumulative ketorolac dose >150 mg as independent predictors of POPF (P < 0.0001, pseudo R2 = 0.149). CONCLUSIONS: Increasing doses of ketorolac in the early postoperative period are associated with increased risk of POPF, whereas a cumulative dose of >150 mg is an independent predictor of POPF after PD. PMID- 29229152 TI - Omission of radiotherapy after breast conservation surgery in the postneoadjuvant setting. AB - BACKGROUND: Breast conservation therapy (BCT) consists of breast conservation surgery (BCS) and radiotherapy (RT). Neoadjuvant chemotherapy (NACT) can downstage tumors, broadening BCS eligibility in patients requiring mastectomy. However, tumor downstaging does not obviate need for RT. This study evaluated factors that predict RT omission after NACT and BCS. METHODS: The National Cancer Database was queried for women with unilateral, clinical stage II-III breast cancer, treated with NACT and BCS between 2008 and 2012. Patients not receiving RT after NACT and BCS were identified. A subgroup analysis was performed eliminating patients for whom RT was recommended but not received. RESULTS: Among 10,220 patients meeting study eligibility, 974 (9.53%) did not receive RT after BCS. Predictors of RT omission included older age, insurance status, facility type, facility region, more recent year of diagnosis, receptor status unknown, human epidermal growth factor receptor 2 status positive or unknown, and positive margins. Factors increasing the likelihood of RT receipt included cN3 disease, receptor positivity, and primary downstaging. Race, Hispanicity, education, income, comorbidities, rural versus urban setting, histology, grade, and nodal stage change were not associated with RT omission. When excluding the 314 patients for whom RT was recommended but not received, age, Medicaid insurance, facility type, facility region, receptor status unknown, human epidermal growth factor receptor 2 status unknown, and positive margins were predictors of RT omission. CONCLUSIONS: Race, comorbidities, and socioeconomic status were not predictors of RT omission. It remains unclear whether omission of RT in some cases is due to lack of physician knowledge. Further efforts are needed to ensure that physicians and patients recognize that RT is a vital and required part of BCT, even after NACT. PMID- 29229153 TI - Prophylactic retention suture for surgical site infection: a retrospective cohort study. AB - BACKGROUND: Surgical site infection (SSI) is a common complication of gastrointestinal surgery. Because retention suture is known to prevent abdominal wound dehiscence, it is only considered indicated in high-risk patients. At present, there are no clear indications for retention suture. The purpose of this study was to analyze the effect of prophylactic retention suture and to determine what situations indicate prophylactic retention suture against SSI. MATERIAL AND METHODS: Between January 2014 and January 2016, 135 patients who underwent midline laparotomy in our hospital were analyzed. Inclusion criteria for this study were patients with American Society Anesthesiologists' physical status classification system (ASA-PS score) >= 3 or emergent surgery. RESULTS: Of the 135 patients, 30 (22.2%) received prophylactic retention suture. Diabetes mellitus, surgical wound classification, large incision, and retention suture were associated with SSI in multivariate analysis. In subgroup analysis, SSI risk factors were analyzed in each surgical wound classification. Only in surgical wound classification class II and III did retention suture significantly reduce the risk of SSI (odds ratio = 0.100 [0.012-0.837], P = 0.034). In class IV, however, half the patients developed SSI, regardless of retention suture. Table 3 summarizes the results of the subgroup analysis. CONCLUSIONS: The present data suggest that prophylactic retention suture reduces SSI for surgical wound classification class II or III. For class IV operations, however, other methods to prevent SSI are necessary. PMID- 29229154 TI - Morphofunctional evaluation of end-to-side neurorrhaphy through video system magnification. AB - BACKGROUND: The surgical microscope is an essential tool for microsurgery. Nonetheless, several promising alternatives are being developed, including endoscopes and laparoscopes with video systems. However, these alternatives have only been used for arterial anastomoses so far. The aim of this study was to evaluate the use of a low-cost video-assisted magnification system in end-to-side neurorrhaphy in rats. MATERIALS AND METHODS: Forty rats were randomly divided into four matched groups: (1) normality (sciatic nerve was exposed but was kept intact); (2) denervation (fibular nerve was sectioned, and the proximal and distal stumps were sutured-transection without repair); (3) microscope; and (4) video system (fibular nerve was sectioned; the proximal stump was buried inside the adjacent musculature, and the distal stump was sutured to the tibial nerve). Microsurgical procedures were performed with guidance from a microscope or video system. We analyzed weight, nerve caliber, number of stitches, times required to perform the neurorrhaphy, muscle mass, peroneal functional indices, latency and amplitude, and numbers of axons. RESULTS: There were no significant differences in weight, nerve caliber, number of stitches, muscle mass, peroneal functional indices, or latency between microscope and video system groups. Neurorrhaphy took longer using the video system (P < 0.05). The amplitude was higher in the microscope group than in the video group. CONCLUSIONS: It is possible to perform an end-to-side neurorrhaphy in rats through video system magnification. The success rate is satisfactory and comparable with that of procedures performed under surgical microscopes. PMID- 29229155 TI - Use of Game Theory to model patient engagement after surgery: a qualitative analysis. AB - BACKGROUND: Patient engagement is challenging to define and operationalize. Qualitative analysis allows us to explore patient perspectives on this topic and establish themes. A game theoretic signaling model also provides a framework through which to further explore engagement. METHODS: Over a 6-mo period, thirty eight interviews were conducted within 6 wk of discharge in patients undergoing thyroid, parathyroid, or colorectal surgery. Interviews were transcribed, anonymized, and analyzed using the NVivo 11 platform. A signaling model was then developed depicting the doctor-patient interaction surrounding the patient's choice to reach out to their physician with postoperative concerns based upon the patient's perspective of the doctor's availability. This was defined as "engagement". We applied the model to the qualitative data to determine possible causations for a patient's engagement or lack thereof. A private hospital's and a safety net hospital's populations were contrasted. RESULTS: The private patient population was more likely to engage than their safety-net counterparts. Using our model in conjunction with patient data, we determined possible etiologies for this engagement to be due to the private patient's perceived probability of dealing with an available doctor and apparent signals from the doctor indicating so. For the safety-net population, decreased access to care caused them to be less willing to engage with a doctor perceived as possibly unavailable. CONCLUSIONS: A physician who understands these Game Theory concepts may be able to alter their interactions with their patients, tailoring responses and demeanor to fit the patient's circumstances and possible barriers to engagement. PMID- 29229156 TI - Standardized ultrasound templates for diagnosing appendicitis reduce annual imaging costs. AB - BACKGROUND: Ultrasound is preferred over computed tomography (CT) for diagnosing appendicitis in children to avoid undue radiation exposure. We previously reported our experience in instituting a standardized appendicitis ultrasound template, which decreased CT rates by 67.3%. In this analysis, we demonstrate the ongoing cost savings associated with using this template. METHODS: Retrospective chart review for the time period preceding template implementation (June 2012 September 2012) was combined with prospective review through December 2015 for all patients in the emergency department receiving diagnostic imaging for appendicitis. The type of imaging was recorded, and imaging rates and ultrasound test statistics were calculated. Estimated annual imaging costs based on pretemplate ultrasound and CT utilization rates were compared with post-template annual costs to calculate annual and cumulative savings. RESULTS: In the pretemplate period, ultrasound and CT rates were 80.2% and 44.3%, respectively, resulting in a combined annual cost of $300,527.70. Similar calculations were performed for each succeeding year, accounting for changes in patient volume. Using pretemplate rates, our projected 2015 imaging cost was $371,402.86; however, our ultrasound rate had increased to 98.3%, whereas the CT rate declined to 9.6%, yielding an annual estimated cost of $224,853.00 and a savings of $146,549.86. Since implementation, annual savings have steadily increased for a cumulative cost savings of $336,683.83. CONCLUSIONS: Standardizing ultrasound reports for appendicitis not only reduces the use of CT scans and the associated radiation exposure but also decreases annual imaging costs despite increased numbers of imaging studies. Continued cost reduction may be possible by using diagnostic algorithms. PMID- 29229157 TI - Long-term outcomes of sigmoid diverticulitis: a single-center experience. AB - BACKGROUND: During the last decade, guidelines for the treatment of sigmoid diverticulitis have dramatically changed. The aim of this study is to report the long-term outcomes of patients treated for diverticulitis at a nonspecialized single center. MATERIALS AND METHODS: After obtaining institutional review board approval, medical records of all patients admitted to our institution with the diagnosis of sigmoid diverticulitis between 1998 and 2008 were reviewed. A follow up of at least 5 years was required. RESULTS: During the study period, 266 patients were admitted to our hospital due to sigmoid diverticulitis with a mean follow-up period of 120 +/- 2 months. Of the entire cohort, 249 patients (93.5%) were treated conservatively and 17 (6.5%) patients required emergent surgery on initial presentation. Patients treated conservatively (n = 249) encountered a median of two recurrent episodes (range 0-4). During follow-up, none of these patients required emergent surgery, and 27 patients (11%) underwent elective surgery for recurrent episodes (n = 24), chronic smoldering disease (n = 2), and fistula (n = 1). Minor and major complication rates after elective surgery were 18.5% and 30%, respectively. Specifically, four patients (15%) suffered an anastomotic leak (AL). Late complications after elective surgery occurred in 33% of patients including incisional hernias (11%), bowel obstruction (3.7%), anastomotic stenosis (3.7%), and recurrent diverticulitis (15%). CONCLUSIONS: Patients treated conservatively during their index admission for sigmoid diverticulitis do not require emergent surgery during long-term follow-up and the majority of patients (89%) do not require elective surgery. Elective sigmoidectomy at nonspecialized centers may result in high rates of recurrent diverticulitis (15%) and anastomotic leak (15%). PMID- 29229158 TI - Risk of appendicitis in patients with incidentally discovered appendicoliths. AB - BACKGROUND: An appendicolith-related appendiceal obstruction leading to appendicitis is a commonly encountered surgical emergency that has clear evidence based management plans. However, there is no consensus on management of asymptomatic patients when appendicoliths are found incidentally. The objective of this study was to determine the risk of appendicitis in patients with an incidental finding of the appendicolith. METHODS: A retrospective matched cohort study of patients with appendicolith discovered incidentally on computed tomographic scan from January 2008 to December 2014 at our institution was completed. The size and position of the appendicolith were ascertained. The study group was matched by age and gender to a control group. Both groups were contacted and interviewed regarding development of appendicitis. RESULTS: In total, 111 patients with appendicolith were successfully contacted and included in the study. Mean age was found to be 38 +/- 15 y with 36 (32%) of the study population being females. Mean length of appendix was 66 +/- 16 mm, and mean width was 5.8 +/- 0.9 mm. Mean size of the appendicolith was 3.6 +/- 1.1 mm (1.4 7.8 mm). Fifty-eight percent of appendicoliths was located at the proximal end or whole of appendix, 31% at mid area, and 11% at the distal end of appendix. All patients of the study and control groups were contacted, and at a mean follow-up of 4.0 +/- 1.7 y, there was no occurrence of acute appendicitis in either group. CONCLUSIONS: Patients with incidentally discovered appendicolith on radiological imaging did not develop appendicitis. Hence, the risk of developing acute appendicitis for these patients does not seem higher than the general population. PMID- 29229159 TI - Socioeconomic factors as predictors of organ donation. AB - BACKGROUND: Despite numerous initiatives to increase solid organs for transplant, the gap between donors and recipients widens. There is little in the literature identifying socioeconomic predictors for donation. We evaluate the correlation between socioeconomic factors and familial authorization for donation. METHODS: A retrospective analysis of adult potential donor referrals between 2007 and 2012 to our organ procurement organization (OPO) was performed. Potential donor information was obtained from the OPO database, death certificates, and the US Census Report. Data on demographics, education, residence, income, registry status, cause and manner of death, as well as OPO assessments and approach for donation were collected. End point was familial authorization for donation. RESULTS: A total of 1059 potential donors were included, with an overall authorization rate of 47%. The majority was not on the donor registry (73%). Younger donors (18-39 y: odds ratio [OR] = 4.9, P < 0.001; 40-60 y: OR = 2.1, P < 0.001), higher levels of education (college: OR = 2.5, P = 0.005; graduate studies: OR = 3.9, P = 0.002), prior listing on the donor registry (OR = 10.3, P < 0.001), and residence in counties with lower poverty rates than the US rates (OR = 1.7, P = 0.02) were independently associated with higher authorization rates. Decoupling (OR = 3.1, P < 0.001) and donation first mentioned by the local health care provider (OR = 1.8, P = 0.01) were also independently associated with higher authorization rates. CONCLUSIONS: Donor registration correlated most strongly with the highest authorization rates. These results indicate that public educational efforts in populations with unfavorable socioeconomic considerations may be beneficial in improving donor registration. Collaborations with local providers as well as OPO in-hospital assessments and approach techniques can help with improving authorization rates. PMID- 29229160 TI - Postoperative anti-PD-1 antibody treatment to reduce recurrence in a cancer ablation surgical wound. AB - BACKGROUND: Postoperative radiation and chemotherapy are routinely applied for microscopic residual diseases; however, treatment outcomes are not optimal, and patients frequently suffer from treatment-related toxicities. To search for an effective and less-toxic adjuvant treatment for patients with high risk of recurrence, the preventive effect of anti-programmed cell death protein 1 (PD-1) treatment was evaluated in an in vivo animal model of post-surgical tumor recurrence. MATERIALS AND METHODS: An animal model of postsurgical tumor recurrence (SCCVII tumors in C3H mice) was established by reinoculating tumor cells (105 cells) into surgical wound of primary tumor resection. Initial and recurrent tumors were compared by an immunohistochemistry and complementary DNA microarray. Using this in vivo model, tumor recurrence rates were evaluated in the animals receiving anti-PD-1 treatments. Animals were rechallenged with tumor cells, and interferon gamma secretion from spleen cells was analyzed to determine tumor-specific antitumor immunity. RESULTS: FoxP3high cell population was significantly elevated in recurrent tumors compared with that in primary tumors. Some immune response-related factors (granzyme F, neuronal leucine-rich repeat protein 1, myosin heavy chain 3, and transmembrane protein 8C) showed significant differences between primary and recurrent tumors. In this animal model, anti-PD-1 treatments significantly suppressed tumor recurrence. Importantly, tumor induction was significantly reduced when anti-PD-1-treated mice were rechallenged with tumor cells. Tumor cell-specific interferon gamma production was increased in these animals. CONCLUSIONS: Postoperative anti-PD-1 treatment significantly reduced recurrence in a cancer ablation surgical wound in an in vivo model of tumor recurrence. Our data lay the preclinical groundwork for the future clinical validation of adjuvant anti-PD-1 treatments in patients. PMID- 29229161 TI - Use of immune-deficient hosts to study human development and pathogenesis. PMID- 29229162 TI - [Erratum of "Optimizing post-operative pain management in Latin America"]. PMID- 29229163 TI - Learning From Kids. PMID- 29229164 TI - When Kidneys Grow up. PMID- 29229166 TI - Holding Water: Congenital Anomalies of the Kidney and Urinary Tract, CKD, and the Ongoing Role of Excellence in Plumbing. AB - Congenital anomalies of the kidneys and urinary tracts can result in diminished natal kidney function, possibly through common embryologic pathway disruption or as a result of development taking place in the face of disordered 'post-renal' drainage. Impaired conduit and reservoir function present potential for an ongoing assault leading to further deterioration and progression of chronic kidney disease, a risk that extends to adults with these conditions, even after "correction". The drainage and storage aspects of the urinary system that can impact kidney function are reviewed with attention to correctable or manageable problems including: Bladder dysfunction wherein the low pressure storage of urine is compromised requiring the kidney to work against a pressure gradient, the classic post renal failure problem. The kidney in the aftermath of obstruction which may have lost concentrating capacity leading to a tendency to dehydration ('pre-renal' failure) and through polyuria which exacerbates bladder pressure problems. Further there is an added challenge in evaluation for ongoing or reemergent obstruction in a significantly dilated system where the capacious system leads to slow turnover of urine often requiring a ureteral stent or nephrostomy to clearly establish clinical significance of delayed drainage. Stasis where slow urine flow leads to buildup of debris (stone) or potentiates infection. Vessicoureteral reflux which allows for introduction of lower urinary tract bacteria to the kidney and can lead to pyelonephritis. Conditions which combine problems such as posterior urethral valves where the bladder outlet obstruction compromises kidney function potentially impairing concentrating ability, creates bladder compromise often reducing emptying efficiency or elevating bladder storage pressures, as well as dilating the system potentially promoting stasis. Cognizance of the potential for plumbing problems to further kidney deterioration as patients with congenital urinary tract anomalies, even after they have been repaired is incumbent on those caring for these patients as they age. Thoughtful evaluation of those patients in whom kidney compromise maybe aggravated by drainage and storage disorder will optimize native renal function. PMID- 29229165 TI - Measurement and Estimation of Glomerular Filtration Rate in Children. AB - Rapid, accurate, and precise measures of kidney function are essential for daily management of patients. While plasma and urinary clearances provide the greatest accuracy for assessing glomerular filtration rate (GFR), these are often impractical particularly for the care of children. Serum creatinine, the most commonly used endogenous marker, is simple, convenient, and practical but less accurate because of the influence of non-GFR determinants such as muscle mass, which increases with age in children. GFR estimating equations have been developed for adults and children to improve the accuracy of endogenous biomarkers, such as creatinine and cystatin C, by accounting for some of the non GFR determinants, thus enhancing the practitioner's ability to assess GFR. In the steady state, when height is used as a surrogate for growth, there is a strong correlation between height/SCr and GFR. Current national guidelines recommend routine reporting of the estimated GFR alongside the serum creatinine value for adults using the Chronic Kidney Disease Epidemiology Collaboration creatinine based formula and the updated Schwartz "bedside" formula (CKiD 2009) for children. PMID- 29229167 TI - Glomerular Diseases in Children. AB - Unique challenges exist in the diagnosis and treatment of glomerular diseases with their onset during childhood. Mounting evidence supports the notion that earlier onset cases occur due to larger numbers of genetic risk alleles. Nearly all causes of adult-onset glomerulonephritis, nephrotic syndrome, and thrombotic microangiopathy have also been described in children, although the prevalence of specific causes differs. Postinfectious glomerulonephritis, Henoch-Schonlein purpura nephritis, and minimal change disease remain the most common causes of glomerular disease in younger children in the United States and can be diagnosed clinically without need for biopsy. IgA nephropathy is the most common pediatric glomerular disease diagnosed by kidney biopsy and is considered the most common chronic glomerulopathy worldwide. In both developing and developed countries, there is a strong relationship between infectious diseases and nephritis onset or relapse. Although research has led to a better understanding of how to classify and manage glomerular diseases in children, the need for disease-specific biomarkers of activity and chronicity remains a hurdle. The strength of the immune system and the growth and maturation that occurs during adolescence are unique and require age-specific approaches to disease management. PMID- 29229168 TI - Monogenic Hypertension in Children: A Review With Emphasis on Genetics. AB - Hypertension (HT) is a public health problem in children particularly related to the epidemic of overweight and obesity. Monogenic forms of HT are important in the differential diagnosis in children presenting with severe or refractory HT, who have a family history of early-onset HT, unusual physical examination findings, and/or characteristic hormonal and biochemical abnormalities. Most genetic defects in these disorders ultimately result in increased sodium transport in the distal nephron resulting in volume expansion and HT. Genetic testing, which is increasingly available, has diagnostic, therapeutic, and predictive implications for families affected by these rare conditions. PMID- 29229169 TI - Acute Kidney Injury in Children. AB - Acute kidney injury (AKI) has become one of the more common complications seen among hospitalized children. The development of a consensus definition has helped refine the epidemiology of pediatric AKI, and we now have a far better understanding of its incidence, risk factors, and outcomes. Strategies for diagnosing AKI have extended beyond serum creatinine, and the most current data underscore the diagnostic importance of oliguria as well as introduce the concept of urinary biomarkers of kidney injury. As AKI has become more widespread, we have seen that it is associated with a number of adverse consequences including longer lengths of stay and greater mortality. Though effective treatments do not currently exist for AKI once it develops, we hope that the diagnostic and definitional strides seen recently translate to the testing and development of more effective interventions. PMID- 29229170 TI - Care of the Pediatric Patient on Chronic Dialysis. AB - Optimal care of the pediatric end-stage renal disease (ESRD) patient on chronic dialysis is complex and requires multidisciplinary care as well as patient/caregiver involvement. The dialysis team, along with the family and patient, should all play a role in choosing the dialysis modality which best meets the patient's needs, taking into account special considerations and management issues that may be particularly pertinent to children who receive peritoneal dialysis or hemodialysis. Meticulous attention to dialysis adequacy in terms of solute and fluid removal, as well as to a variety of clinical manifestations of ESRD, including anemia, growth and nutrition, chronic kidney disease-mineral bone disorder, cardiovascular health, and neurocognitive development, is essential. This review highlights current recommendations and advances in the care of children on dialysis with a particular focus on preventive measures to minimize ESRD-associated morbidity and mortality. Advances in dialysis care and prevention of complications related to ESRD and dialysis have led to better survival for pediatric patients on dialysis. PMID- 29229171 TI - Special Considerations in Pediatric Kidney Transplantation. AB - Universally accepted as the treatment of choice for children needing renal replacement therapy, kidney transplantation affords children the opportunity for an improved quality of life over dialysis therapy. Immunologic and surgical advances over the last 15 years have improved the pediatric patient and kidney graft survival. Unique to pediatrics, congenital genitourinary anomalies are the most common primary diseases leading to kidney failure, many with urological issues. Early urological evaluation for post-transplant bladder dysfunction and emphasis on immunization adherence are the mainstays of pediatric pretransplant and post-transplant evaluations. A child's height can be challenging, sometimes requiring an intra-abdominally placed graft, particularly if the patient is <20 kg. Maintenance immunosuppression regimens are similar to adult kidney graft recipients, although distinctive pharmacokinetics may change dosing intervals in children from twice a day to thrice a day. Viral infections and secondary malignancies are problematic for children relative to adults. Current trends to reduce/remove corticosteroid therapy from post-transplant protocols have produced improved linear growth with less steroid toxicity; although these studies are still ongoing, graft function and survival are considered acceptable. Finally, all children with a kidney transplant need a smooth transition to adult clinics. Future research in pertinent psychosocial aspects and continued technological advances will only serve to optimize the transition process. Although some aspects of kidney transplantation are similar in children and adults, for instance immunosuppression and immunosuppressive regimens, and rejection mechanisms and their diagnosis using the Banff criteria, there are important differences this review will focus on and which continue to drive innovation. PMID- 29229172 TI - Self-Management and Health Care Transition Among Adolescents and Young Adults With Chronic Kidney Disease: Medical and Psychosocial Considerations. AB - Health care transition (HCT) is a process that requires preparation as a continuum from pediatric- to adult-focused services. For adolescents and young adults with chronic or ESRD, this process can be prolonged due to their physical, psychological, family, or ecological factors. HCT preparation is a matter of patient safety and patient rights as the consequences of poor preparation at the time of transfer to adult-focused services are great, including rejection of organs, disease relapse, or even death. We present a case to illustrate important points of HCT preparation, with suggestions for intervention by the interdisciplinary team members who serve (and will serve) these survivors of pediatric-onset health conditions. To monitor the HCT process, yearly measurements of skill mastery need to take place guide interventions. PMID- 29229173 TI - Opioid withdrawal and takotsubo syndrome: how can we study further the underpinnings of their connection? PMID- 29229174 TI - Osman Sankoh: better data for better health. PMID- 29229175 TI - Umbilical cord hemangioma: Sonographic features by HDlive Flow. PMID- 29229176 TI - Use of Concomitant Androgen Deprivation Therapy in Patients Treated with Early Salvage Radiotherapy for Biochemical Recurrence After Radical Prostatectomy: Long term Results from a Large, Multi-institutional Series. AB - BACKGROUND: Hormonal manipulation concomitant to salvage radiotherapy (SRT) given for biochemical recurrence (BCR) after radical prostatectomy (RP) improved outcomes in two randomized trials. However, neither of these studies focused on men treated at low prostate-specific antigen (PSA) levels. OBJECTIVE: To test if the impact of androgen deprivation therapy (ADT) on metastasis in patients undergoing early SRT varies according to prostate cancer (PCa) features. DESIGN, SETTING, AND PARTICIPANTS: A total of 525 patients received SRT at PSA levels <=2ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Multivariable Cox regression analyses assessed factors associated with metastasis. We tested the hypothesis that the impact of ADT varied according to the risk of metastasis. An interaction with groups (concomitant ADT vs no ADT) and the probability of distant metastasis according to a newly developed model was tested. A nonparametric curve explored the relationship between the risk of metastasis and 10-yr metastasis rates according to ADT. RESULTS AND LIMITATIONS: Median PSA and radiotherapy dose were 0.42ng/ml and 66Gy, respectively. Overall, 178 (34%) patients received ADT. At a median follow-up of 104 mo, 71 patients experienced metastasis. Grade group >=4 (hazard ratio [HR]: 1.66; 95% confidence interval [CI]: 1.01-3.30), pT3b/4 (HR: 2.61; 95% CI: 1.51-4.52), and dose (HR: 0.82; 95% CI: 0.76-0.89) were associated with metastasis. The impact of ADT differed according to the risk of metastasis calculated using a multivariable model (p=0.01). This was confirmed when considering patients treated with early SRT (p=0.046), where ADT was associated with a reduction in the rate of metastasis only in eSRT; patients with more aggressive characteristics (ie, pT3b/4 and grade group >=4, or pT3b/4 and PSA at eSRT >=0.4ng/ml). CONCLUSIONS: The beneficial effect of ADT concomitant to eSRT varied significantly according to disease characteristics, such that only men with more aggressive PCa features benefit from ADT in the eSRT setting for BCR after RP. PATIENT SUMMARY: The oncological benefits of concomitant androgen deprivation therapy (ADT) in patients undergoing salvage radiotherapy (SRT) vary according to pathological characteristics. Only patients with more aggressive disease characteristics seemed to benefit from the use of hormonal manipulation at the time of early SRT. Conversely, the potential side effects of ADT could be spared in patients with low prostate-specific antigen levels and favorable pathological features. PMID- 29229177 TI - Re: Assessing the effects of manual dexterity and playing computer games on catheter-wire manipulation for inexperienced operators. PMID- 29229178 TI - Cervical spine clearance in adults following blunt trauma: a national survey across major trauma centres in England. AB - AIM: To assess current practice in cervical spine clearance across major trauma centres in England and review current guidelines. MATERIALS AND METHODS: An electronic survey was sent to lead trauma clinicians at 22 major trauma centres in England. This assessed the clinical decision tools used, the choice of initial imaging technique, and the methods used to clear the cervical spine in alert and obtunded patients without focal neurology, and where initial imaging was normal. British Orthopaedic Association Standards for Trauma (BOAST) 2 and Eastern Association for Surgery for Trauma (EAST) guidelines were used as standards. RESULTS: Eighteen out of the 22 (82%) centres responded by completing the survey. Most (71%) centres used the Canadian C-Spine Rule for clearing the cervical spine clinically. Seventy-two percent of centres preferred computed tomography (CT) as the first-line imaging technique, the choice based on age of patient and mechanism of injury. If the initial CT imaging was normal, magnetic resonance imaging (MRI) was performed in 52% of centres to clear the cervical spine, with half of these centres stating that they would discuss further imaging with a radiologist first. The practice across centres was highly variable for the obtunded patient, with most centres preferring continuing immobilisation or MRI to clear the cervical spine, with a small minority removing spinal precautions when a high-quality multidetector CT was normal. CONCLUSION: Multidetector CT is the preferred initial imaging technique across most major trauma centres in England when blunt cervical spine trauma is suspected. There is widespread reliance on MRI to clear the cervical spine in both alert and obtunded patients, if initial CT imaging is normal and there is no focal neurology on clinical assessment. This calls for greater awareness of the reliability of a high-quality normal multidetector CT examination in clearing the cervical spine in the absence of focal neurology. PMID- 29229179 TI - Clinical role of breast MRI now and going forward. AB - Magnetic resonance imaging (MRI) is a well-established method in breast imaging, with manifold clinical applications, including the non-invasive differentiation between benign and malignant breast lesions, preoperative staging, detection of scar versus recurrence, implant assessment, and the evaluation of high-risk patients. At present, dynamic contrast-enhanced MRI is the most sensitive imaging technique for breast cancer diagnosis, and provides excellent morphological and to some extent also functional information. To compensate for the limited functional information, and to increase the specificity of MRI while preserving its sensitivity, additional functional parameters such as diffusion-weighted imaging and apparent diffusion coefficient mapping, and MR spectroscopic imaging have been investigated and implemented into the clinical routine. Several additional MRI parameters to capture breast cancer biology are still under investigation. MRI at high and ultra-high field strength and advances in hard- and software may also further improve this imaging technique. This article will review the current clinical role of breast MRI, including multiparametric MRI and abbreviated protocols, and provide an outlook on the future of this technique. In addition, the predictive and prognostic value of MRI as well as the evolving field of radiogenomics will be discussed. PMID- 29229180 TI - Copper slag as a catalyst for mercury oxidation in coal combustion flue gas. AB - Copper slag is a byproduct of the pyrometallurgical smelting of copper concentrate. It was used in this study to catalyze elemental mercury (Hg0) oxidation in simulated coal combustion flue gas. The copper slag exhibited excellent catalytic performance in Hg0 oxidation at temperatures between 200 degrees C and 300 degrees C. At the most optimal temperature of 250 degrees C, a Hg0 oxidation efficiency of 93.8% was achieved under simulated coal combustion flue gas with both a high Hg0 concentration and a high gas hourly space velocity of 128,000 h-1. Hydrogen chloride (HCl) was the flue gas component responsible for Hg0 oxidation over the copper slag. The transition metal oxides, including iron oxides and copper oxide in the copper slag, exhibited significant catalytic activities in the surface-mediated oxidation of Hg0 in the presence of HCl. It is proposed that the Hg0 oxidation over the copper slag followed the Langmuir Hinshelwood mechanism whereby reactive chlorine species that originated from HCl reacted with the physically adsorbed Hg0 to form oxidized mercury. This study demonstrated the possibility of reusing copper slag as a catalyst for Hg0 oxidation and revealed the mechanisms involved in the process and the key factors in the performance. This knowledge has fundamental importance in simultaneously reducing industrial waste and controlling mercury emissions from coal-fired power plants. PMID- 29229181 TI - Economic evaluation of an electrochemical process for the recovery of metals from electronic waste. AB - As the market of electronic devices continues to evolve, the waste stream generated from antiquated technology is increasingly view as an alternative to substitute primary sources of critical a value metals. Nevertheless, the sustainable recovery of materials can only be achieved by environmentally friendly processes that are economically competitive with the extraction from mineral ores. Hence, This paper presents the techno-economic assessment for a comprehensive process for the recovery of metals and critical materials from e waste, which is based in an electrochemical recovery (ER) technology. Economic comparison is performed with the treatment of e-waste via smelting, which is currently the primary route for recycling metals from electronics. Results indicate that the electrochemical recovery process is a competitive alternative for the recovery of value from electronic waste when compared with the traditional black Cu smelting process. A significantly lower capital investment, 2.9 kg e-waste per dollar of capital investment, can be achieved with the ER process vs. 1.3 kg per dollar in the black Cu smelting process. PMID- 29229183 TI - The elaboration of motor programs for the automation of letter production. AB - We investigated how children learn to write letters. Letter writing evolves from stroke-by-stroke to whole-letter programming. Children of ages 6 to 9 (N=98) wrote letters of varying complexity on a digitizer. At ages 6 and 7 movement duration, dysfluency and trajectory increased with stroke number. This indicates that the motor program they activated mainly coded information on stroke production. Stroke number affected the older children's production much less, suggesting that they programmed stroke chunks or the whole letter. The fact that movement duration and dysfluency decreased from ages 6 to 8, and remained stable at ages 8 and 9 suggests that automation of letter writing begins at age 8. Automation seems to require the elaboration of stroke chunks and/or letter-sized motor programs. PMID- 29229182 TI - Exploiting Metabolic Vulnerabilities of Cancer with Precision and Accuracy. AB - Links between oncogenic drivers and cancer cell metabolism have emerged over the past several decades, indicating that constitutive oncogenic growth signaling can render cancers susceptible to metabolic interventions. While significant progress has been achieved in the identification of metabolic vulnerabilities of cancer cells, the complexity of the tumor microenvironment (TME) and the dynamic nature of organismal circadian metabolism challenge the precision of targeting cancer metabolism. Here current progress in the areas of cancer metabolism and TME metabolism is reviewed, highlighting how cancer metabolism can be accurately and precisely targeted. PMID- 29229184 TI - DNA Bends the Knee to Transcription Factors. PMID- 29229185 TI - Stimpson's hard clam Mercenaria stimpsoni; A multi-decadal climate recorder for the northwest Pacific coast. AB - A sclerochronological and radiocarbon-based study of life history traits of Stimpson's hard clam (Mercenaria stimpsoni), collected alive from Funakoshi Bay, northeast Japan, showed the lifespan of the species to be at least 92 years (determined from annual growth line counts). Three M. stimpsoni specimens exhibited the following synchronous growth pattern, suggestive of environmental control; annual increment width increasing after 1955 to a maximum value between 1970 and 1980, subsequently decreasing gradually until 2000, and thereafter remaining constant or increasing slightly. Variations on annual growth patterns, as well as standardized growth indices chronology, were relatively closely linked to the Atlantic Multidecadal Oscillation (AMO), but less so to Pacific Decadal Oscillation (PDO). Carbonate samples collected from ontogenetically younger shell portions, estimated from growth line counts to have been deposited before 1950, contained no nuclear bomb-test radiocarbon, thereby supporting the accuracy of annual growth line counts (versus overcounting from ventral margin). Together with the synchronous annual increment width patterns, this indicated that age and annual growth rate estimations for M. stimpsoni based on growth line counts were reliable and applicable to high-resolution sclerochronological analyses, which should contribute to a deeper understanding of multi-decadal northwest Pacific climate variability. PMID- 29229186 TI - The impact of artificial surfaces on marine bacterial and eukaryotic biofouling assemblages: A high-throughput sequencing analysis. AB - Vessel hulls and underwater infrastructure can be severely impacted by marine biofouling. Knowledge on which abiotic conditions of artificial structures influence bacterial and eukaryotic community composition is limited. In this study, settlement plates with differing surface texture, orientation and copper based anti-fouling coatings were deployed in a marina. After three months, biofouling samples were collected and bacterial and eukaryotic communities characterised using DNA metabarcoding. The copper anti-fouling coating treatments incurred the most significant compositional changes (p <= 0.001) within both domains. Bacterial diversity decreased, with Gammaproteobacteria becoming the dominant phylum. In contrast, protist diversity increased as well as opportunist nematodes and bryozoans; urochordates and molluscs became less abundant. Network analyses displayed complex relationships on untreated plates, while revealing a simpler, but disturbed and unstable community composition on the anti-fouling coated plates. These networks of copper treatments displayed opportunist taxa that appeared as key organisms in structuring the bacterial and eukaryotic communities. PMID- 29229187 TI - Plant Volatiles as Mate-Finding Cues for Insects. AB - Plant volatiles are used not only by herbivorous insects to find their host plants, but also by the natural enemies of the herbivores to find their prey. There is also increasing evidence that plant volatiles, in addition to species specific pheromones, help these insects to find mating partners. Plant structures such as flowers, fruit, and leaves are frequently rendezvous sites for mate seeking insects. Here we propose that the combined use of plant volatiles and pheromones can efficiently guide insects to these sites, where they will have access to both mates and food. This notion is supported by the fact that plant volatiles can stimulate the release of sex pheromones and can render various insects more receptive to potential mates. PMID- 29229189 TI - Immunoproteasome inhibition prevents chronic antibody-mediated allograft rejection in renal transplantation. AB - Chronic antibody-mediated rejection is the major cause of fading allograft function and loss after renal transplantation. Currently, pharmacological agents for the suppression of chronic antibody-mediated rejection are lacking. Non selective proteasome inhibitors suppress antibody-mediated allograft rejection. However, extensive adverse side effects of these inhibitors severely limit their application. In contrast, immunoproteasome inhibition is effective in preclinical models of autoimmune diseases and was applied over weeks without obvious adverse side effects. ONX 0914, an immunoproteasome subunit LMP7 (beta5i)-selective inhibitor, impeded the chronic rejection of kidneys transplanted from Fischer to allogeneic Lewis rats. ONX 0914 inhibited immunoproteasome induction both in immune organs and renal allografts. Selective immunoproteasome inhibition reduced the numbers of B and plasma cells, and suppressed donor-specific alloantibody production. The infiltration of T cells, B cells and macrophages as well as interferon-gamma, interleukin-17, IgG and complement deposition were reduced in renal allografts of ONX 0914-treated recipients. Chronic nephropathy was ameliorated and renal allograft function preserved, enabling long-term survival of recipients. Thus, our studies define a critical role of the immunoproteasome in chronic kidney allograft rejection and suggest immunoproteasome inhibition as a promising therapeutic approach to suppress chronic antibody-mediated rejection. PMID- 29229190 TI - [Syphilitic rupia still alive and well...]. PMID- 29229188 TI - Plasmodium P47: a key gene for malaria transmission by mosquito vectors. AB - Malaria is caused by infection with Plasmodium parasites that have a complex life cycle. The parasite protein P47 is critical for disease transmission. P47 mediates mosquito immune evasion in both Plasmodium berghei (Pbs47) and Plasmodium falciparum (Pfs47), and has been shown to be important for optimal female gamete fertility in P. berghei. Pfs47 presents strong geographic structure in natural P. falciparum populations, consistent with natural selection of Pfs47 haplotypes by the mosquito immune system as the parasite adapted to new vector species worldwide. These key functions make Plasmodium P47 an attractive target to disrupt malaria transmission. PMID- 29229191 TI - [What future for dermatology in university hospitals?] PMID- 29229192 TI - [Late-onset systemic sclerosis: A retrospective study of 27 patients diagnosed after the age of 70]. AB - BACKGROUND: The aim of this study was to describe special features of patients with systemic sclerosis (SSc) diagnosed after the age of 70. PATIENTS AND METHODS: This is a retrospective study of patients aged above 70 years at the time of diagnosis of SSc and followed at an internal medicine unit between 2000 and 2015. Co-morbidities and clinical characteristics were analyzed, as well as survival at 1, 2 and 3 years. RESULTS: Of 246 patients, 27 (11%) were included (89% women, 96% Caucasians, age 78.3+/-4.5 years). Synchronous cancer was noted in 3 patients. SSc was mostly limited cutaneous only (24/27), with telangiectasia (63%), gastroesophageal reflux (59%) and digital ulcers (22%), and was associated with anti-centromere antibody (69%). Interstitial lung disease was not frequent (29%). Pulmonary arterial hypertension (PAH) was suspected at diagnosis of SSc in 14 cases (52%), but only 5 patients had undergone heart catheterization, with severe PAH in 3 cases. Survival at 1 and 3 years was 85.2% and 66.7%, and was worse in the case of suspected PAH, at 78.6% and 57.1% respectively. CONCLUSION: Cases of SSc diagnosed after 70 years are mostly limited cutaneous forms. Suspicion of PAH is frequent, and PAH may be the main initial sign of the disease for patients at this age. There may be association with synchronous cancer. Survival is poor. PMID- 29229193 TI - Novel role of Vpmas as major adhesins of Mycoplasma agalactiae mediating differential cell adhesion and invasion of Vpma expression variants. AB - Mycoplasma agalactiae exhibits antigenic variation by switching the expression of multiple surface lipoproteins called Vpmas. Although implicated to have a significant influence on the pathogenicity, their exact role in pathogen-host interactions has not been investigated so far. Initial attachment to host cells is regarded as one of the most important steps for colonization but this pathogen lacks the typical mycoplasma attachment organelle. The aim of this study was to determine the role of Vpmas in adhesion of M. agalactiae to host cells. 'Phase Locked' Mutants (PLMs) steadily expressing single well-characterized Vpma lipoproteins served as ideal tools to evaluate the role of each of the six Vpmas in cytadhesion, which was otherwise not possible due to the high-frequency switching of Vpmas in the wildtype strain PG2. Using in vitro adhesion assays with HeLa and sheep mammary epithelial (MECs) and stromal (MSCs) cells, we could demonstrate differences in the adhesion capabilities of each of the six PLMs compared to the wildtype strain. The PLMV mutant expressing VpmaV exhibited the highest adhesion rate, whereas PLMU, which expresses VpmaU showed the lowest adhesion values explaining the reduced in vivo fitness of PLMU in sheep during experimental intramammary and conjunctival infections. Furthermore, adhesion inhibition assays using Vpma-specific polyclonal antisera were performed to confirm the role of Vpmas in M. agalactiae cytadhesion. This led to a significant decrease (p<0.05) in the adhesion percentage of each PLM. Immunofluorescence staining of TX-114 phase proteins extracted from each PLM showed binding of the respective Vpma to HeLa cells and MECs proving the direct role of Vpmas in cytadhesion. Furthermore, as adhesion is a prerequisite for cell invasion, the ability of the six PLMs to invade HeLa cells was also evaluated using the gentamicin protection assay. The results showed a strong correlation between the adhesion rates and invasion frequencies of the individual PLMs. This is the first report that describes a novel function of Vpma proteins in cell adhesion and invasion. Besides the variability of these proteins causing surface antigenic variation, the newly identified phenotypes are likely to play critical roles in the pathogenicity potential of this ruminant pathogen. PMID- 29229195 TI - A comparison of two different fluid resuscitation management protocols for pediatric burn patients: A retrospective study. AB - OBJECTIVE: Pediatric burn patients are more susceptible to burn shock than adults, and an effective fluid management protocol is critical to successful resuscitation. Our research aim was to investigate the safety and efficacy of two protocols for pediatric burn patients for use within the first 24h. METHODS: A total of 113 pediatric burn patients were enrolled from January 2007 to October 2012. Of those patients, 57 received fluid titration regimens of alternating crystalloids and colloids once within 2h in the first 24h after burn (Group A), whereas the remaining patients received regimens of alternating crystalloids and colloids once within 1h in the first 24h after burn (Group B). The safety, fluid volume infused and urine output were recorded and compared. RESULTS: All the patients survived in the first 24h after burn. There were no significant differences between Group A and Group B in lactic acid (LA) level and base excess (BE). The water infused in Group A were greater than that of Group B in the first 24h (P=0.024). No significant differences were found in total volume intake and hourly urine output between the 2 groups in the first 24h. CONCLUSION: The implementation of fluid resuscitation using either protocol A or protocol B is safe and effective for pediatric burn patients in the first 24h. The total fluid infused were similar between two protocols. But using protocol A may be more convenient and labor-saving for nurses. PMID- 29229194 TI - [Gender identity, a factor of inequality forgotten by Spanish health information systems]. AB - The Spanish Health Information System (HIS) collects health information. Trans people have poorer health status. This paper aimed to assess the adequacy of the HIS to collect the health data on trans individuals. The HIS sources available in the Statistical Portal of the National Health System were reviewed. The sources containing population health data were selected. The variables "sex" and "gender identity" were searched. Nineteen sources were identified. In all of them the variable "sex" was found, whereas "gender identify" did not appear in any of the 19. In two sources, the variable "sex" allowed values of "transsexual". The SIS contains little information regarding gender identity. This leads to the invisibility of trans people in Spanish health statistics. Obtaining this information would allow for a better understanding of the barriers to health care access, and the health needs of one of the most discriminated groups in our society. PMID- 29229196 TI - Impact of allergy on phenotypic and endotypic profiles of nasal polyposis. AB - OBJECTIVES: To assess the impact of allergy on clinical presentations (phenotypes) and inflammatory patterns (endotypes) of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: A single-center prospective study was conducted over an 18-month period. Fifty-seven patients with refractory CRSwNP were included. The diagnosis of allergy was based on concordant skin prick tests and symptoms. Phenotypes were determined on symptom severity score, polyp size classification and Lund-Mackay CT staging. Inflammatory endotypes were determined on biomarker analysis (IgE, IgA, IL-5, IL-9, ECP, EDN) in blood and nasal secretions. Eosinophil counts were obtained in blood, nasal secretions and polyps. RESULTS: Phenotype and endotype profiles were comparable in patients with (n=15) or without (n=42) allergy. Only asthma with high total IgE blood concentration showed association with allergy. CONCLUSIONS: The present results suggest that allergy is not directly involved in the clinical expression and specific inflammatory pathways of CRSwNP. New therapies target inflammation signaling pathways, and identifying accurate blood and tissue biomarkers will be the line of research most likely to improve treatment of CRSwNP. PMID- 29229197 TI - Cardiovascular risk and severity factors in patients admitted to hospital for spontaneous epistaxis. AB - OBJECTIVES: To assess the role of cardiovascular risk factors, intake of drugs altering hemostasis and severity signs in patients admitted with spontaneous epistaxis. MATERIAL AND METHODS: A single-center retrospective study covering a 7 year period in a university hospital center included 205 patients admitted with spontaneous epistaxis. Study variables comprised: cardiovascular risk factors (cardiovascular disease or history of cardiovascular disease with hemorrhagic or thromboembolic risk, high blood pressure, type-2 diabetes, dyslipidemia), intake of drugs altering hemostasis, blood pressure and minimum hemoglobin level during hospital stay. Groups of serious and non-serious epistaxis were distinguished. RESULTS: There were no significant inter-group differences for mean age, sex ratio, history of high blood pressure or number of cardiovascular risk factors. Serious epistaxis was associated with significantly lower blood pressure and hemoglobinemia. Number of cardiovascular risk factors correlated with probability of blood transfusion. CONCLUSION: The real influence of the various study factors, including severity factors, on onset of spontaneous epistaxis remains to be elucidated. PMID- 29229198 TI - Combined Raloxifene and Letrozole for Breast Cancer Patients. AB - Raloxifene, an anti-osteoporotic drug, is recently approved for prevention of breast cancer in postmenopausal women and thus the drug may be employed to combat the bony adverse effects of letrozole, another anticancer drug. However, the cytotoxic effect of their combination on human breast cancer (MCF-7) and human embryonic kidney (HEK) cell lines is not known. MCF-7 and HEK cell lines were treated with different graded doses of letrozole, raloxifene and their combination, then incubated for 24-48 h. MTT assay was performed to check the cytotoxicity of the drugs. The study indicates that the combination of letrozole and raloxifene possess additive effect in terms of cytotoxicity of cancer cell lines (MCF-7) and negligible effects in normal cell lines (HEK). Our study indicates that the addition of raloxifene doesn't interfere with anticancer efficacy of letrozole rather the combination acted additively for the treatment of breast cancer. PMID- 29229199 TI - Microbiota and Aging. A Review and Commentary. AB - Although there is a consensus that the dominant species that make up the adult microbiota remains unchanged in elderly people, it has been reported that there are significant alterations in the proportion and composition of the different taxa, leading to reduced microbiota diversity, as well as an increase of enteropathogens that may lead to chronic inflammation. The ageing of mucosal immune and motor systems also contributes to these changes. As the individual ages, there is a loss in the number of Peyer's patches, an altered local capacity of T and B cell functions as well as chronic macrophage activation. Also, environment, diet, place of residence and biogeography are regulatory factors of the microbiota. Communication in the gut-brain-axis is regulated by many intermediaries including diverse metabolites of the microbiota. Microbial changes have been observed in several geriatric diseases, like Parkinson's and Alzheimer's. In addition, evidence has shown that individuals with high frailty scores had a significant reduction on lactobacilli species when compared to non frail individuals. Oral microbiota may be also especially important because of the opportunities for access to the brain through the olfactory nerve at the roof of the nose or through the abundant innervations of the oral cavity by the trigeminal and other cranial nerves. Also, there are an increasing number of reports that have suggested potential mechanisms by which the microbiota promote human health span and aging. The study of the microbiota represents an important advance in the understanding of the aging process. PMID- 29229200 TI - Waste-based alternative adsorbents for the remediation of pharmaceutical contaminated waters: Has a step forward already been taken? AB - When adsorption is considered for water treatment, commercial activated carbon is usually the chosen adsorbent for the removal of pollutants from the aqueous phase, particularly pharmaceuticals. In order to decrease costs and save natural resources, attempts have been made to use wastes as raw materials for the production of alternative carbon adsorbents. This approach intends to increase efficiency, cost-effectiveness, and also to propose an alternative and sustainable way for the valorization/management of residues. This review aims to provide an overview on waste-based adsorbents used on pharmaceuticals' adsorption. Experimental facts related to the adsorption behaviour of each adsorbent/pharmaceutical pair and some key factors were addressed. Also, research gaps that subsist in this research area, as well as future needs, were identified. Simultaneously, this review aims to clarify the current status of the research on pharmaceuticals' adsorption by waste-based adsorbents in order to recognize if the right direction is being taken. PMID- 29229201 TI - Recent advances in degradation of chloronitrophenols. AB - Chloronitrophenols (CNPs) constitute a group of environmental pollutants that are widely distributed in our surrounding environment due to human based activities. This group of chemicals is highly toxic to living beings due to its mutagenic and carcinogenic nature. Examples include 2-chloro-4-nitrophenol, 4-chloro-2 nitrophenol, 2-chloro-5-nitrophenol, 4-chloro-3-nitrophenol and 2,6-dichloro-4 nitrophenol. Several methods including advanced oxidation processes, adsorption and bacterial degradation have been used for degradation of CNPs. Among, bacterial degradation is an eco-friendly and effective way to degrade CNPs. Several bacterial metabolic pathways have been proposed for degradation of CNPs and their genes and enzymes have been identified in bacteria. These bacteria were able to degrade CNPs in broth culture and soil. Therefore, CNPs-degrading bacteria are suitable candidates for bioremediation of CNPs-contaminated sites. Few CNP-degrading bacteria exhibited chemotaxis towards CNPs to enhance their biodegradation. The present review summarizes recent progress in degradation of CNPs. PMID- 29229202 TI - [Endobronchial ultrasound for peripheral pulmonary lesions]. PMID- 29229204 TI - Aging of the body and the brain in schizophrenia. PMID- 29229205 TI - Cytotoxic quinazoline alkaloids from the seeds of Peganum harmala. AB - Seventeen quinazoline alkaloids and derivatives, containing two pairs of new epimers, named as (S)- and (R)-1-(2-aminobenzyl)-3-hydroxypyrrolidin-2-one beta-d glucopyranosyl-(1 -> 6)-beta-d-glucopyranoside (1, 2), (S)- and (R)-vasicinone beta-d-glucopyranosyl-(1 -> 6)-beta-d-glucopyranoside (3, 4), and a new enantiomer (12b), together with six known ones (5-8, 10, and 12a), and three pairs of known enantiomers (9, 11, and 13), were isolated from the ethanol extracts of the seeds of Peganum harmala L.. Their structures including the absolute configuration were elucidated by using 1D and 2D NMR, and ECD calculation approaches. The cytotoxic activities of all isolated compounds were evaluated. 11 showed moderate cytotoxicity against PC-3 cells with an IC50 value of 15.41 MUM. PMID- 29229207 TI - About quick look.... PMID- 29229208 TI - Assessment and treatment at a pain clinic: A one-year follow-up of patients with chronic pain. AB - BACKGROUND AND AIMS: Pain is one of the most common reasons for patients to seek primary health care. Pain relief is likely to be achieved for patients suffering from acute pain, but for individuals with chronic pain it is more likely that the condition will persist. These patients have the option of being referred to specialised pain clinics. However, the complexity surrounding chronic pain patients is not well studied in these settings. This study aimed to describe patients with chronic pain referred to a pain clinic by using the information submitted during their first visit and one year later and also to identify associations between baseline characteristics and improvements in health-related quality of life in the follow-up. METHODS: This was a longitudinal observational study of a sample consisting of 318 patients referred to a pain clinic. One group of patients containing 271 individuals (median age 48, 64% females) was assessed and received conventional pain treatment (CPT group) and a second group of 47 patients (median age 53, 64% females) was assessed by a pain specialist and referred back to their physician with a treatment recommendation (assessment only, AO group). Patient-reported outcome measures in health-related quality of life (EQ-5D), pain intensity (VAS), mental health (HADS), insomnia (ISI), pain related disability (PDI), kinesiophobia (TSK) and sense of coherence (SOC) were collected at the first visit and one year later. RESULTS: At baseline, the CPT group reported a low EQ-5D Index (median (md) 0.157) and EQ VAS (md 40) as well as considerable high, current pain intensity VAS (md 58), HADS anxiety (md 8), ISI (md 17), PDI (md 36) and TSK (md 39). The AO group showed similar problems (no significant differences compared to the CPT group), except for ISI, where the AO group reported less severe problems. At the one-year follow-up, the CPT group had a statistically significant improvement in EQ-5D, VAS, ISI, PDI and TSK. In the AO group no significant changes were observed. In the CPT group there was an association between a high ISI level at baseline and an improved EQ-5D Index in the follow-up. CONCLUSIONS: The study describes rarely explored groups of patients with chronic pain at a pain clinic. Severe pain problems were present in both groups at their first visit. A statistically significant improvement could be seen in the group that was conventionally treated while this was not the case among those subjects who were assessed and referred. The results imply, that relatively limited treatment strategies were helpful for the patients' health related quality of life. Despite these improvements, the patients were not fully recovered, pointing to the chronicity of pain conditions and the need of support for many patients. IMPLICATIONS: Increased knowledge about assessment, selection and treatment at pain clinics is important to improve the quality of the work performed at these clinics. Despite limited resources, further efforts should be made to collect comparable, valid data on a regular base from pain clinics in order to develop recommendation models. PMID- 29229209 TI - Randomized, double-blind, placebo-controlled, dose-escalation study: Investigation of the safety, pharmacokinetics, and antihyperalgesic activity of l 4-chlorokynurenine in healthy volunteers. AB - BACKGROUND AND AIMS: Neuropathic pain is a significant medical problem needing more effective treatments with fewer side effects. Overactive glutamatergic transmission via N-methyl-d-aspartate receptors (NMDARs) are known to play a role in central sensitization and neuropathic pain. Although ketamine, a NMDAR channel blocking antagonist, is often used for neuropathic pain, its side-effect profile and abusive potential has prompted the search for a safer effective oral analgesic. A novel oral prodrug, AV-101 (l-4 chlorokynurenine), which, in the brain, is converted into one of the most potent and selective GlyB site antagonists of the NMDAR, has been demonstrated to be active in animal models of neuropathic pain. The two Phase 1 studies reported herein were designed to assess the safety and pharmacokinetics of AV-101, over a wide dose range, after daily dosing for 14-days. As secondary endpoints, AV-101 was evaluated in the capsaicin induced pain model. METHODS: The Phase 1A study was a single-site, randomized, double-blind, placebo-controlled, single oral ascending dose (30-1800mg) study involving 36 normal healthy volunteers. The Phase 1B study was a single-site randomized, double-blind, placebo-controlled, study of multiple ascending doses (360, 1080, and 1440mg/day) of AV-101 involving 50 normal healthy volunteers, to whom AV-101 or placebo were administered orally daily for 14 consecutive days. Subjects underwent PK blood analyses, laboratory assessments, physical examination, 12-lead ECG, ophthalmological examination, and various neurocognitive assessments. The effect of AV-101 was evaluated in the intradermally capsaicin-induced pain model (ClinicalTrials.gov Identifier: NCT01483846). RESULTS: Two Phase 1, with an aggregate of 86 subjects, demonstrated that up to 14 days of oral AV-101, up to 1440mg per day, was safe and very well tolerated with AEs quantitively and qualitatively like those observed with placebo. Mean half-life values of AV-101 were consistent across doses, ranging with an average of 1.73h, with the highest Cmax (64.4MUg/mL) and AUC0-t (196MUgh/mL) values for AV-101 occurring in the 1440-mg dose group. In the capsaicin induce-pain model, there was no significant change in the area under the pain time curve (AUPC) for the spontaneous pain assessment between the treatment and the placebo groups on Day 1 or 14 (the primary endpoint). In contrast, there were consistent reductions at 60-180min on Day 1 after dosing for allodynia, mechanical hyperalgesia, heat hyperalgesia, and spontaneous pain, and on Day 14 after dosing for heat hyperalgesia. CONCLUSIONS: Although, AV-101 did not reach statistical significance in reducing pain, there were consistent reductions, for allodynia pain and mechanical and heat hyperalgesia. Given the excellent safety profile and PK characteristics demonstrated by this study, future clinical trials of AV-101 in neuropathic pain are justified. IMPLICATIONS: This article presents the safety and PK of AV-101, a novel oral prodrug producing a potent and selective GlyB site antagonist of the NMDA receptor. These data indicate that AV-101 has excellent safety and PK characteristics providing support for advancing AV-101 into Phase 2 studies in neuropathic pain, and even provides data suggesting that AV-101 may have a role in treating depression. PMID- 29229206 TI - Frontal Cortex and the Hierarchical Control of Behavior. AB - The frontal lobes are important for cognitive control, yet their functional organization remains controversial. An influential class of theory proposes that the frontal lobes are organized along their rostrocaudal axis to support hierarchical cognitive control. Here, we take an updated look at the literature on hierarchical control, with particular focus on the functional organization of lateral frontal cortex. Our review of the evidence supports neither a unitary model of lateral frontal function nor a unidimensional abstraction gradient. Rather, separate frontal networks interact via local and global hierarchical structure to support diverse task demands. PMID- 29229210 TI - Prevalence and characteristics of chronic pain: Experience of Niger. AB - INTRODUCTION: Chronic pain is a major health problem, considered as a disease in its own right. The prevalence of chronic pain is estimated to be between 2% and 40% in adult populations. In Niger, there are no data on chronic pain. AIMS: This study was designed to provide the demographic, clinical and etiological profile of chronic pain in patients from Niger in order to create a database on chronic pain in Niger. PATIENTS AND METHODS: Our study is prospectively conducted at the department of external consultation of the Hopital National de Niamey over a period of 10 months from 31 May 2016 to 30 January 2017 collecting all cases of chronic pain. The demographic, clinical and etiological characteristics of all patients were collected and analyzed. RESULTS: During the period of the study, 1927 patients consulted at the department of external consultation of the Hopital National de Niamey, among which 411 patients had chronic pain (21.33% [95% CI: 19.53% and 23.13%]). The average age was 48.28 years (+/-12.84) with 51.6% of patients aged over 50 years. The male sex was predominant (61.8%). The most common sites of chronic pain were legs (25.5%), back (14.4%), neck (13.6%), knees (13.4%) and feet (13.1%). Osteoarthritis was the most common cause of chronic pain (35.5%), followed by herniated disc (22.2%), spondylodiscitis (14.6%) and migraine (4.1%). Significantly patients aged 50-59 years suffered from neck and legs pain (p value<0.001). Significantly chronic headaches and rheumatoid arthritis were more common in women while osteoarthritis, herniated disc and spondylodiscite were more common in men (p value=0.001). Significantly osteoarthritis and herniated disc were more common in patients older than 40 years (p value<0.001). CONCLUSION: Our study provides demographic, clinical and etiological data of chronic pain in patients from Niger, and shows that chronic pain is a common reason for consultation in Niger concerning 1 in 5 patients with a high prevalence among men and patients aged over 40 years. PMID- 29229211 TI - The use of rapid onset fentanyl in children and young people for breakthrough cancer pain. AB - BACKGROUND AND AIMS: No published studies have looked at the dosing and use of rapid onset fentanyl preparations in children. The primary aim of this study was to assess whether there is a correlation between effective dose of rapid onset fentanyl and background oral morphine equivalent analgesia in children less than 18 years old. Secondary objectives included establishing whether there is a correlation between effective dose of rapid onset fentanyl and age and weight. Reported side effects were also reviewed. METHODS: This study is a retrospective case note review of all children less than 18 years old who received rapid onset fentanyl products in a tertiary paediatric oncology centre in England between 2010 and 2015. Correlations were analysed using Spearman's correlation coefficient as data was non-parametric. RESULTS: Data on 26 children (5-17 yrs; 13-100kg) was analysed. The most common diagnosis in children being given rapid onset fentanyl products was a solid tumour (84.6%). Eleven children used sublingual tablets, 17 used lozenges and one used a fentanyl nasal spray (three patients used two different preparations). The only significant correlation found was between dose of fentanyl lozenge and weight (rs=0.81, p<0.001). Very few side effects were reported with the most frequent being nausea (8%) and sleepiness (8%). CONCLUSIONS: Fentanyl lozenges seem to be safe and well tolerated in children as young as five years old, weighing as little as 13kg. Results suggest that children should always be started on the lowest available dose of chosen preparation and that this dose should be titrated according to response. This study demonstrates that there is no correlation between background opioid dose and effective dose of rapid onset fentanyl in children. This mirrors findings of similar studies in adults. There was a strong correlation between effective dose of fentanyl lozenge and weight. This may be in part due to clinicians being more inclined to increase fentanyl lozenge doses as the child is in control of when they have had enough medication. In contrast, buccal tablets are absorbed quickly and the child always receives the full dose, making clinicians more reluctant to titrate the dose. IMPLICATIONS: This article presents initial evidence for feasibility and tolerability of fentanyl lozenges in children as young as five years old, who are on relatively low doses of background opioids. This could be of interest to clinicians who are looking for alternatives to oral opioids to manage breakthrough pain in children with cancer. PMID- 29229212 TI - Acid-induced experimental muscle pain and hyperalgesia with single and repeated infusion in human forearm. AB - BACKGROUND AND PURPOSE: Acid has long been thought to play an important role in the pain process. Animal study showed that repeated acid stimulation induced central sensitization. The purpose of the study is to investigate muscle pain and hyperalgesia evoked by intramuscular infusion of saline at different pH levels, and to compare the effect of a single versus repeated acid infusions. METHODS: Twenty healthy subjects received infusions of buffered saline (pH 5.0, 6.0, and 7.4) into the brachioradialis muscle in a randomized order. Twelve of the subjects received repeated infusions. The subjects rated the pain intensity on visual analogue scale (VAS). Thermal pain sensitivity, and pressure pain threshold (PPT) were assessed in both arm before, during, immediately after, one hour after, and one day after the infusion. A McGill Pain Questionnaire and pain mapping were completed after each infusion. RESULTS: The pH 5 solution caused significantly higher pain and larger areas than pH 6.0 or 7.4. The local PPTs were significantly decreased (hyperalgesia) during and immediately after infusion of all three solutions. No significant differences were detected between the first and second infusion. CONCLUSIONS: The intensity of acid-induced muscle pain is pH-dependent. All three solutions induced pressure hyperalgesia at the infusion site. Repeated infusions did not induce increased pain or prolonged hyperalgesia as compared with a single injection. Human intramuscular acidic saline infusion could not produce chronic pain model. IMPLICATIONS: The acid induced pain model may reflect the early stage responses to tissue injury of clinical conditions. Repeated intramuscular acidic saline injection model of prolonged hyperalgesia in rodents could not be translated into a human for modelling chronic musculoskeletal pain. PMID- 29229213 TI - Swearing as a response to pain: A cross-cultural comparison of British and Japanese participants. AB - BACKGROUND AND AIMS: Research suggests swearing can moderate pain perception. The present study assessed whether changes in pain perception due to swearing reflect a "scripting" effect by comparing swearing as a response to pain in native English and Japanese speakers. Cognitive psychology denotes a 'script' to be a sequence of learnt behaviours expected for given situations. Japanese participants were included as they rarely, if ever, swear as a response to pain and therefore do not possess an available script for swearing in the context of pain. It was hypothesised that Japanese participants would demonstrate less tolerance and more sensitivity to pain than English participants, and - due to a lack of an available script of swearing in response to pain - that Japanese participants would not experience swearword mediated hypoalgesia. METHODS: Fifty six native English (mean age=23 years) and 39 Japanese (mean age=21) speakers completed a cold-pressor task whilst repeating either a swear on control word. A 2 (culture; Japanese, British)*2 (word; swear; non-swear) design explored whether Japanese participants showed the same increase in pain tolerance and experienced similar levels of perceived pain when a swearing intervention was used as British participants. Pain tolerance was assessed by the number of seconds participants could endure of cold-pressor exposure and self-report pain measurements. Levels of perceived pain were assessed using a 120-mm horizontal visual analogue scale anchored by descriptors in the participant's native language of "no pain" (left) and "terrible pain" (right). The participant was asked to mark a 10mm vertical line to indicate overall pain intensity. The score was measured from the zero anchor to the participant's mark. RESULTS: Japanese participants reported higher levels of pain (p<0.005) and displayed lower pain tolerance than British participants (p<0.05). Pain tolerance increased in swearers regardless of cultural background (p<0.001) and no interaction was found between word group and culture (p=0.96), thereby suggesting that swearing had no differential effect related to the cultural group of the participant. CONCLUSIONS: The results replicate previous findings that swearing increases pain tolerance and that individuals from an Asian ethnic background experience greater levels of perceived pain than those from a Caucasian ethnic background. However, these results do not support the idea of pain perception modification due to a "scripting" effect. This is evidenced as swearword mediated hypoalgesia occurs irrespective of participant cultural background. Rather, it is suggested that modulation of pain perception may occur through activation of descending inhibitory neural pain mechanisms. IMPLICATIONS: As swearing can increase pain tolerance in both Japanese and British people, it may be suggested that swearword mediated hypoalgesia is a universal phenomenon that transcends socio-cultural learnt behaviours. Furthermore, swearing could be encouraged as an intervention to help people cope with acute painful stimuli. PMID- 29229215 TI - Atrial fibrillation: Neurogenic or myogenic? AB - A 55-year-old hypertensive patient presents atrial fibrillation after vasovagal syncope. Non-invasive cardiac workup is normal. Without antiarrhythmic therapy, the patient has no recurrence for the next 3years, then presents with a stroke. Echocardiography eventually reveals left atrial dilation. This sequence of events illustrates the well-known links between age, arterial hypertension, atrial fibrillation, atrial neuromyopathy and stroke. A frequently neglected common denominator in this equation is impaired sympathovagal balance. Contrary to what is often stated, autonomic imbalance is not a simple modulation factor of atrial fibrillation; both the trigger and the substrate of atrial fibrillation can be influenced by abnormal cardiac innervation. Here, we review the neurogenic theory of atrial fibrillation, based on literature and original data. We also provide evidence that this concept may help to improve atrial fibrillation prediction, early diagnosis and therapy. PMID- 29229214 TI - Targeting cytokines for treatment of neuropathic pain. AB - BACKGROUND: Neuropathic pain is a challenging condition often refractory to existing therapies. An increasing number of studies have indicated that the immune system plays a crucial role in the mediation of neuropathic pain. Exploration of the various functions of individual cytokines in neuropathic pain will provide greater insight into the mechanisms of neuropathic pain and suggest potential opportunities to expand the repertoire of treatment options. METHODS: A literature review was performed to assess the role of pro-inflammatory and anti inflammatory cytokines in the development of neuropathic pain. Both direct and indirect therapeutic approaches that target various cytokines for pain were reviewed. The current understanding based on preclinical and clinical studies is summarized. RESULTS AND CONCLUSIONS: In both human and animal studies, neuropathic pain has been associated with a pro-inflammatory state. Analgesic therapies involving direct manipulation of various cytokines and indirect methods to alter the balance of the immune system have been explored, although there have been few large-scale clinical trials evaluating the efficacy of immune modulators in the treatment of neuropathic pain. TNF-alpha is perhaps the widely studied pro inflammatory cytokine in the context of neuropathic pain, but other pro inflammatory (IL-1beta, IL-6, and IL-17) and anti-inflammatory (IL-4, IL-10, TGF beta) signaling molecules are garnering increased interest. With better appreciation and understanding of the interaction between the immune system and neuropathic pain, novel therapies may be developed to target this condition. PMID- 29229216 TI - Immediate complete revascularization in patients with ST-segment elevation myocardial infarction and multivessel disease treated by primary percutaneous coronary intervention: Insights from the ORBI registry. AB - BACKGROUND: Recent studies demonstrated the superiority of complete revascularization (CR) in patients treated by primary percutaneous coronary intervention (pPCI) in ST-elevation myocardial infarction (STEMI). AIM: To evaluate whether immediate CR improves in-hospital outcomes in patients with STEMI with multivessel disease. METHODS: Data from a prospective multicentre registry including 9365 patients with STEMI were analysed. Patients with multivessel disease and treated with pPCI (n=3412) were included and separated into two groups according to whether immediate CR was performed during the index procedure. The primary endpoint was in-hospital major adverse cardiovascular events (MACE), defined as a composite of all-cause death, non-fatal myocardial infarction, stroke and definite stent thrombosis. Secondary endpoints were individual components of MACE and major bleeding. Multivariable Cox regression and propensity-score adjustment were performed to account for confounders. RESULTS: Immediate CR was performed in 98 patients (2.9%), whereas 3314 patients (97.1%) were incompletely revascularized. The prevalence of severe heart failure (Killip class III or IV) and significant lesions of the left main coronary artery were higher in the immediate CR group (21.6% vs. 13.5% and 24.5% vs. 6.7%, respectively; P<0.001 for both). After adjustment, immediate CR was not associated with reduced rates of MACE (hazard ratio [HR] 0.64, 95% confidence interval [CI]: 0.31-1.35; P=0.24) or all-cause death (HR: 0.52, 95% CI: 0.23 1.16; P=0.11), but with increased risks of definite stent thrombosis (HR: 3.93, 95% CI: 1.12-13.75; P=0.03) and major bleeding (HR: 17.46, 95% CI: 2.29-133.17; P=0.006). CONCLUSION: Immediate CR did not improve in-hospital outcomes of patients with STEMI with multivessel disease in this analysis. Randomized studies are warranted to elucidate the optimal timing of CR in patients with STEMI. PMID- 29229217 TI - Non-cancer drug consumption during the early trajectory of lymphoma survivorship. AB - PURPOSE: This study explored the use of non-cancer drugs in lymphoma survivors during the early trajectory (0 to 2 years) of cancer survivorship and determined the factors that influenced this consumption. METHODS: Between January and March 2014, a cross-sectional survey was conducted to assess drug consumption in adult lymphoma survivors at the Toulouse University Hospital. This study was based on a questionnaire consisting of ten open questions related to medical prescription and/or self-medication occurring within the last 3 months. RESULTS: A total of 83/103 lymphoma survivors returned the questionnaire. This study showed that 91.6% of patients were drug consumers (about twice more than the general French population). Twenty percent of patients were treated with>=5 drugs. Overall drug consumption mainly concerned analgesics, anti-inflammatory drugs and psychotropics. The presence of comorbidity, urban residence and female gender were associated with overall drug consumption. Moreover, half of survivors required at least one self-medication. Finally, only seven survivors (8.4%) reported no use of any medication. CONCLUSION: This study shows that, at least during the early trajectory of cancer survivorship, lymphoma patients are heavily treated with non-cancer drug therapy. This drug consumption profile may have serious implications in terms of safety, overall benefit and health economics. PMID- 29229218 TI - A controlled study of plasma fatty acids in Indian patients with depressive episode. AB - AIM: To study the plasma omega 3 and omega 6 fatty acid levels in patients with depressive episode and in matched healthy controls. METHOD: Thirty patients with first episode depression and thirty healthy matched control subjects were recruited from a tertiary care hospital setting. We measured plasma omega-3 and omega-6 fatty acid levels of the study and the control group. RESULT: There were no significant differences in plasma omega 3 fatty acid levels between study group and control group. The plasma omega 6 fatty acid levels of study group were significantly less than that of control group. CONCLUSIONS: The present study is an initial attempt to investigate the link between fatty acids and depression in a clinical setting in India. This comparative study with normal controls did not etiologically link these polyunsaturated fatty acids in this sample of depressive disorder. PMID- 29229219 TI - Computer-assisted navigation for intramedullary nail fixation of intertrochanteric femur fractures: A randomized, controlled trial. AB - INTRODUCTION: Lag screw cutout is one of the most commonly reported complications following intramedullary nail fixation of intertrochanteric femur fractures. However, its occurrence can be minimized by a well-positioned implant, with a short Tip-to-Apex Distance (TAD). Computer-assisted navigation systems provide surgeons with the ability to track screw placement in real-time. This could allow for improved lag screw placement and potentially reduce radiation exposure to the patient and surgeon. METHODS: Between Oct 2014 and Jan 2016, patients with intertrochanteric femur fractures being treated with intramedullary nail fixation by one of three fellowship-trained orthopaedic traumatologists were enrolled. Inclusion criteria were low-energy mechanism of injury and fracture class 31 A1/A2. Open fractures and patients with multiple injuries to the lower extremity were excluded. Patients were randomly assigned to computer-assisted navigation or a conventional fluoroscopic technique for lag screw placement. The primary outcomes were TAD, measured by postoperative anteroposterior and lateral x-rays by an independent reviewer, and radiation exposure measured in seconds of fluoroscopy time. Surgical time was also recorded. RESULTS: 50 patients were randomized, 26 to the computer-assisted navigation group and 24 to the control group. The mean manually-measured TAD in the computer-assisted navigation group was 14.1mm+/-3.2 and in the control group was 14.9mm+/-3.0 (p=0.394). There was no difference between groups in total radiation time (navigation: 58.8 s+/-23.6, control: 56.5 s+/-28.5, p=0.337) or radiation time during lag screw placement (navigation: 19.4 s+/-8.8, control: 18.8 s+/-8.0, p=0.522). The surgical time was significantly longer in the computer-assisted navigation group with a mean surgical time of 45.8min+/-9.8 compared to 38.4min+/-9.3 in the control group (p=0.009). CONCLUSIONS: Computer-assisted navigation consistently produced excellent TADs, however it was not significantly better than conventional methods when done by fellowship-trained orthopaedic traumatologists. Surgeons with a lower volume trauma practice could potentially benefit from computer-assisted navigation to obtain better TAD. PMID- 29229220 TI - Relationship between attachment style and symptom severity across the psychosis spectrum: A meta-analysis. AB - There is growing evidence for the role of attachment in psychosis, however, to date there has been no quantitative review of the prevalence of insecure attachment in psychosis. The current study sought to systematically appraise studies investigating the prevalence of insecure attachment and the association with psychosis-spectrum experiences using meta-analytic techniques. A systematic search of studies carried out between January 1980 and 30th November 2015 found 25 papers eligible for inclusion. The meta-analysis showed that the prevalence of insecure attachment style was significantly higher in individuals with psychosis (76%) than in non-clinical samples (38%), with fearful attachment being the most prevalent. Across the continuum, there was a small but significant relationship between positive symptom severity and insecure attachment and a significant relationship between negative symptom severity and insecure attachment in the non clinical analysis. This relationship was not found in the clinical group. The prevalence of insecure attachment appears to be high in psychosis, however, the relationship between symptom severity and attachment is small. Attachment theory may provide greater understanding of the development of positive symptoms than previously thought, however, research needs to include more at-risk samples and longitudinal research to fully understand the dynamics of this relationship. PMID- 29229221 TI - Intravesical Electromotive Botulinum Toxin Type "A" Administration for Management of Urinary Incontinence Secondary to Neuropathic Detrusor Overactivity in Children: Long-term Follow-up. AB - OBJECTIVE: To investigate the long-term efficacy and success rate of intravesical electromotive botulinum toxin type A (BoNTA) "Dysport" administration in patients with myelomeningocele who had urinary incontinence due to neuropathic detrusor overactivity (NDO). MATERIALS AND METHODS: Twenty-four patients with myelomeningocele (mean age: 9 +/- 3.6 years, range: 3-16) were included in the study and followed up for 6 years. Using an electrode bladder catheter, 10 IU/kg of Dysport (BoNTA) was inserted into the bladder for electromotive drug administration (EMDA) without anesthesia on outpatient basis. The EMDA equipment was connected to the electrode of an indwelling catheter and 2 dispersive electrodes, and a pulsed current generator delivered 10 mA for 20 minutes. The preliminary assessments were voiding diary, urodynamic study, kidney and bladder ultrasounds which were also performed annually. RESULTS: Prior to the treatment, all patients had NDO and urinary incontinence. During the follow-up, 18 of 24 (75%), 11 of 24 (45.5%), 9 of 24 (37.5%), 8 of 24 (33%), and 7 of 24 (29.1%) of the patients were completely dry between 2 consecutive clean intermittent catheterizations after once BoNTA-EMDA treatment at 1, 2, 3, 5, and 6 years of follow-up, respectively. The mean maximum detrusor pressure significantly decreased and mean maximal cystometric capacity significantly increased at follow ups (P <.05). CONCLUSION: The results of the present study have shown that BoNTA EMDA is a feasible, safe, reproducible, cost-effective, long-lasting, and pain free method on an outpatient basis, with long-term duration of effects without anesthesia or cystoscopy procedure. This novel delivery system resulted in considerable improvement in urinary incontinence and urodynamic study parameters in patients with refractory NDO. PMID- 29229222 TI - Two degree of freedom internal model control-PID design for LFC of power systems via logarithmic approximations. AB - Load frequency controller has been designed for reduced order model of single area and two-area reheat hydro-thermal power system through internal model control - proportional integral derivative (IMC-PID) control techniques. The controller design method is based on two degree of freedom (2DOF) internal model control which combines with model order reduction technique. Here, in spite of taking full order system model a reduced order model has been considered for 2DOF IMC-PID design and the designed controller is directly applied to full order system model. The Logarithmic based model order reduction technique is proposed to reduce the single and two-area high order power systems for the application of controller design.The proposed IMC-PID design of reduced order model achieves good dynamic response and robustness against load disturbance with the original high order system. PMID- 29229223 TI - Genders and Individual Treatment Progress in (Non-)Binary Trans Individuals. AB - BACKGROUND: Health care for transgender and transsexual (ie, trans) individuals has long been based on a binary understanding of gender (ie, feminine vs masculine). However, the existence of non-binary or genderqueer (NBGQ) genders is increasingly recognized by academic and/or health care professionals. AIM: To gain insight into the individual health care experiences and needs of binary and NBGQ individuals to improve their health care outcomes and experience. METHODS: Data were collected using an online survey study on experiences with trans health care. The non-clinical sample consisted of 415 trans individuals. An individual treatment progress score was calculated to report and compare participants' individual progress toward treatment completion and consider the individual treatment needs and definitions of completed treatment (ie, amount and types of different treatments needed to complete one's medical transition). OUTCOMES: Main outcome measures were (i) general and trans-related sociodemographic data and (ii) received and planned treatments. RESULTS: Participants reported binary (81.7%) and different NBGQ (18.3%) genders. The 2 groups differed significantly in basic demographic data (eg, mean age; P < .05). NBGQ participants reported significantly fewer received treatments compared with binary participants. For planned treatments, binary participants reported more treatments related to primary sex characteristics only. Binary participants required more treatments for a completed treatment than NBGQ participants (6.0 vs 4.0). There were no differences with regard to individual treatment progress score. CLINICAL TRANSLATION: Because traditional binary-focused treatment practice could have hindered NBGQ individuals from accessing trans health care or sufficiently articulating their needs, health care professionals are encouraged to provide a holistic and individual treatment approach and acknowledge genders outside the gender binary to address their needs appropriately. STRENGTHS AND LIMITATIONS: Because the study was made inclusive for non-patients and individuals who decided against trans health care, bias from a participant-patient double role was prevented, which is the reason the results are likely to have a higher level of validity than a clinical sample. However, because of the anonymity of an online survey, it remains unclear whether NBGQ individuals live according to their gender identity in their everyday life. CONCLUSION: The study highlights the broad spectrum of genders in trans-individuals and associated health care needs and provides a novel approach to measure individual treatment progress in trans individuals. Koehler A, Eyssel J, Nieder TO. Genders and Individual Treatment Progress in (Non-)Binary Trans Individuals. J Sex Med 2018;15:102-113. PMID- 29229224 TI - Studies on interactions of carbazole derivatives with DNA, cell image, and cytotoxicity. AB - DNA-binding agents have been considered as an established opportunity for the development of anticancer drugs and DNA fluorescence probes. This work reported the synthesis of two novel carbazole derivatives (1 and 2) and investigated their DNA binding properties, living cell image, and cytotoxicity. The results demonstrated that both compounds presented the higher binding affinity to G quadruplex than to duplex DNA by means of UV-Vis absorption titration and fluorescent intercalator displacement. Continuous variation analysis indicated that their binding stoichiometries of the compound/G-quadruplex were near 2 except the compound/bcl-2. Circular dichroism spectra showed that both compounds had no influence on the conformation of G-quadruplexes. Fluorescence titrations indicated that 2 had the potential to be a G-quadruplex selective fluorescent probe, while 1 could be used as a fluorescent probe for duplex DNA. Confocal fluorescence images indicated that both compounds could enter the living HepG2 cells, and 1 mainly located in nucleus whereas 2 mainly distributed in cytoplasm. DNase and RNase digest tests indicated that both compounds could enter into the nucleus and interact with duplex DNA, especially, 2 could interact with RNA and/or G-quadruplex DNA. They also exhibited an obvious antiproliferative activity to HepG2 by using MTT assays, with IC50 values of 2.7 and 9.5 MUM for 1 and 2, respectively. PMID- 29229225 TI - Design, synthesis and pharmacological evaluation of new acyl sulfonamides as potent and selective Bcl-2 inhibitors. AB - The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity. PMID- 29229226 TI - Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB1 receptor ligand antagonists. AB - A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (Ki values of 44.6 nM for CB1 receptors and >40 MUM for CB2 receptors, respectively). The N-isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB1 receptors with Ki values of 75.5 and 73.2 nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB1 receptor in the [35S]-GTPgammaS binding assays, and none showed adequate predictive blood-brain barrier permeation, exhibiting low estimated LD50. However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist. PMID- 29229229 TI - Is Low-Dose Ketamine an Effective Alternative to Opioids for the Treatment of Acute Pain in the Emergency Department? PMID- 29229228 TI - Factors Influencing Norvancomycin Concentration in Plasma and Cerebrospinal Fluid in Patients After Craniotomy and Dosing Guideline: A Population Approach. AB - PURPOSE: Antibacterial spectrum and activity of norvancomycin are comparable with vancomycin, and it has been widely used in China. Norvancomycin can penetrate into the cerebrospinal fluid (CSF) through the damaged blood-brain barrier in patients after craniotomy. Because higher inter-individual variability was observed, we aimed to identify factors related to drug concentration to guide clinicians with norvancomycin dosing. METHODS: After craniotomy, patients with an indwelling catheter in the operational area/ventricle were intravenously administered norvancomycin. Venous blood and CSF specimens were collected at a scheduled time for measuring drug concentrations. Blood and CSF data were fitted simultaneously with the use of the nonlinear fixed-effects modeling method to develop the population pharmacokinetic model. Covariate analysis was applied to select candidate factors associated with pharmacokinetic parameters. A model based simulation was performed to find optimized regimens for different subgroups of patients. FINDINGS: A 3-compartmental model (central, peripheral, and CSF compartments) with 2 elimination pathways (drug elimination from the kidney and CSF outflow) was developed to characterize the in vivo process of norvancomycin. The covariate analysis identified that weight and drainage amount were strongly associated with the central volume and the drug clearance from CSF, respectively. Goodness-of-fit and model validation suggested that the proposed model was acceptable. A dosage regimen table was created for specific patient populations with different weights and drainage amounts to facilitate clinical application. IMPLICATIONS: We identified 2 clinical markers associated with plasma and CSF concentrations. The proposed simulation may be useful to clinicians for norvancomycin dosing in this specific population with normal kidney function. PMID- 29229227 TI - The importance of the circadian system & sleep for bone health. AB - Adequate sleep timed appropriately during the circadian night is important for numerous biological processes and systems. New evidence suggests that both sleep timing and duration may be important for optimal bone health as well. This review examines the diurnal variation of bone turnover markers (BTMs) and the importance of circadian clock genes in regulating bone mass. In addition, this review explores the evidence for a link between shift work (and its associated disturbances in sleep duration/quality and circadian alignment) and alterations in bone metabolism and bone health. Finally, we review how commonly used medications and over-the-counter substances (e.g. caffeine, melatonin) complicate the relationship between sleep and circadian disorders and bone health. PMID- 29229230 TI - A Not Uncommon Cause of Stroke Mimicker in Children. PMID- 29229231 TI - Associations Between Social Functioning, ADHD Symptomatology, and Emotion Functioning in Children With Autism Spectrum Disorder and Williams Syndrome. PMID- 29229233 TI - Mosquito-Borne Diseases: Advances in Modelling Climate-Change Impacts. AB - Vector-borne diseases are on the rise globally. As the consequences of climate change are becoming evident, climate-based models of disease risk are of growing importance. Here, we review the current state-of-the-art in both mechanistic and correlative disease modelling, the data driving these models, the vectors and diseases covered, and climate models applied to assess future risk. We find that modelling techniques have advanced considerably, especially in terms of using ensembles of climate models and scenarios. Effects of extreme events, precipitation regimes, and seasonality on diseases are still poorly studied. Thorough validation of models is still a challenge and is complicated by a lack of field and laboratory data. On a larger scale, the main challenges today lie in cross-disciplinary and cross-sectoral transfer of data and methods. PMID- 29229234 TI - Trans-resveratrol mitigates type 1 diabetes-induced oxidative DNA damage and accumulation of advanced glycation end products in glomeruli and tubules of rat kidneys. AB - Hyperglycemia induces the formation of advanced glycation end products (AGEs) and their receptors (RAGEs), which alter several intracellular signaling mechanisms leading to the onset and progression of diabetic nephropathy. The present study focused on, i) modulatory effects of trans-resveratrol (3,5,4'-trihydroxy-trans stilbene) on structural changes, AGE (NE-carboxymethyl-lysine), RAGE, oxidative stress and DNA damage, and apoptosis, and ii) localization of fibrotic changes, AGE, RAGE, 8-oxo-dG and 4-hydroxynonenal (4-HNE) in diabetic rat kidneys. Resveratrol (5mg/kg; po, administered during last 45days of 90-day-long hyperglycemic period) administration to streptozotocin-induced type 1 diabetic male Wistar rats reduced renal hypertrophy and structural changes (tubular atrophy, mesangial expansion or shrinkage, diffuse glomerulonephritis, and fibrosis), AGE accumulation, oxidative stress and DNA damage (8-oxo-dG), 4-HNE, caspase-3, and cleaved-caspase-3, but not the RAGE expression. The AGE accumulated in the mesangium, vascular endothelium, and proximal convoluted tubules and less intensely in distal convoluted tubules of diabetic rat kidneys. The RAGE expression increased in the convoluted tubules and collecting ducts of diabetic rat kidneys, but not in the mesangium. Diabetes increased the expression of 8-oxo-dG in nuclei and cytoplasm of renal cells, and 4-HNE in glomeruli, convoluted tubules, the loops of Henle and collecting ducts. Hyperglycemia induced AGE-RAGE axis and oxidative stress in turn induced apoptosis in diabetic kidneys. Resveratrol mitigated all diabetic effects except the RAGE expression. In conclusion, Resveratrol significantly alleviates diabetes-induced glycation, oxidative damage, and apoptosis to inhibit the progression of diabetic nephropathy. Resveratrol supplementation may be useful to hinder the onset and progression of diabetic kidney diseases. PMID- 29229232 TI - Dyslipidemia in Children With Arterial Ischemic Stroke: Prevalence and Risk Factors. AB - BACKGROUND: Risk factors for pediatric stroke are poorly understood and require study to improve prevention. Total cholesterol and triglyceride values peak to near-adult levels before puberty, a period of increased stroke incidence. The role of lipids in childhood arterial ischemic stroke has been minimally investigated. METHODS: We performed a cross-sectional analysis of lipid and Lp(a) concentrations in children with arterial ischemic stroke in the International Pediatric Stroke Study to compare the prevalence of dyslipidemia and high- or low ranking lipid values in our dataset with reported population values. We analyzed sex, body mass index, race, ethnicity, family history, and stroke risk factors for associations with dyslipidemia, high non-high-density lipoprotein cholesterol, and hypertriglyceridemia. RESULTS: Compared with the National Health and Nutrition Examination Survey, a higher proportion of children >=5 years with arterial ischemic stroke had dyslipidemia (38.4% versus 21%), high total cholesterol (10.6% versus 7.4%), high non-high-density lipoprotein cholesterol (23.1% versus 8.4%), and low high-density lipoprotein cholesterol (39.8% versus 13.4%). The lipid values that corresponded to one standard deviation above the mean (84th percentile) in multiple published national studies generally corresponded to a lower ranking percentile in children aged five years or older with arterial ischemic stroke. Dyslipidemia was more likely associated with an underweight, overweight, or obese body mass index compared with a healthy weight. Ethnic background and an acute systemic illness were also associated with abnormal lipids. CONCLUSIONS: Dyslipidemia and hypertriglyceridemia may be more prevalent in children with arterial ischemic stroke compared with stroke-free children. PMID- 29229235 TI - Valproic acid disrupts the oscillatory expression of core circadian rhythm transcription factors. AB - Valproic acid (VPA) is a well-established therapeutic used in treatment of seizure and mood disorders as well as migraines and a known hepatotoxicant. About 50% of VPA users experience metabolic disruptions, including weight gain, hyperlipidemia, and hyperinsulinemia, among others. Several of these metabolic abnormalities are similar to the effects of circadian rhythm disruption. In the current study, we examine the effect of VPA exposure on the expression of core circadian transcription factors that drive the circadian clock via a transcription-translation feedback loop. In cells with an unsynchronized clock, VPA simultaneously upregulated the expression of genes encoding core circadian transcription factors that regulate the positive and negative limbs of the feedback loop. Using low dose glucocorticoid, we synchronized cultured fibroblast cells to a circadian oscillatory pattern. Whether VPA was added at the time of synchronization or 12h later at CT12, we found that VPA disrupted the oscillatory expression of multiple genes encoding essential transcription factors that regulate circadian rhythm. Therefore, we conclude that VPA has a potent effect on the circadian rhythm transcription-translation feedback loop that may be linked to negative VPA side effects in humans. Furthermore, our study suggests potential chronopharmacology implications of VPA usage. PMID- 29229236 TI - Ultrastructural analysis of early toxic effects produced by bee venom phospholipase A2 and melittin in Sertoli cells in rats. AB - In this study, we aimed to investigate the testicular toxicity of two molecules derived from bee venom (BV): phospholipase A2 (PlA2) and melittin (Mlt). Ultrastructural effects of purified BV PlA2 and Mlt were assessed consecutive to repeated dose (30 days) and acute toxicity studies. For the subchronic treatment, PlA2 and Mlt were injected in daily doses equivalent to those released by a bee sting (105 MUg PlA2/kg/day and 350 MUg Mlt/kg/day), while in the acute treatment their doses corresponded to those released by 100 bee stings (9.3 mg PlA2/kg and 31 mg Mlt/kg). Both PlA2 and Mlt affected the Leydig cells and the cells in seminiferous tubules, the Sertoli cells first of all. PlA2 injection resulted in detachment of the Sertoli cells from the surrounding cells, and extracellular vacuolations, cytoplasmic vacuolations in their basal region and in branches as well, detachment of spermatids, residual bodies and sometimes even spermatocytes into the lumen, changes that had a higher magnitude after the acute treatment. Mlt injection induced similar ultrastructural alterations, but more severe, including degeneration of cellular organelles and cellular necrosis, resulting into rarefaction of the seminiferous epithelium; the ultrastructural changes had a higher magnitude after the 30 repeated dose treatment. We concluded that either of the two molecules tested here, PlA2 and Mlt, were Sertoli cells toxicants at the used doses, and they participated both in the BV testicular toxicity. We consider the observed changes as part of a preceding mechanism of the more severe alterations produced by the BV. It also remains possible that these early unspecific changes reported here could represent the response of the SCs not only to the components of bee venom, but to molecules of other venoms as well. The Sertoli cells were the primary target of PlA2 and Mlt in the spermatogenic epithelium, and their alteration led to further degenerative changes of the germ cells. Since the exposure to PlA2 and Mlt caused severe alteration, including cell death and detachment of immature germ cells into the lumen, we may also conclude that the bee venom molecules had a potential to interfere with normal progression of spermatogenesis. All the degenerative changes observed in the Sertoli cells were accompanied with changes of the Leydig cells. PMID- 29229237 TI - Accumulation and transformation of azaspiracids in scallops (Chlamys farreri) and mussels (Mytilus galloprovincialis) fed with Azadinium poporum, and response of antioxidant enzymes. AB - Azaspiracid (AZA) producing microalgae have been reported internationally and could potentially impact a variety of seafood. Scallops (Chlamys farreri) and mussels (Mytilus galloprovincialis) from China were fed with the AZA2 producer, Azadinium poporum, to study uptake, metabolism and oxidative stress in the shellfish. LC-MS/MS showed significant accumulation and differential metabolism of AZA2 in the scallops and mussels. In mussels AZA2 was metabolized to AZA19, with subsequent decarboxylation to AZA6. In scallops no AZA19 or AZA6 was observed, however, a novel AZA metabolite was formed that is isobaric with AZA19 ([M+H]+, m/z 886), but elutes at a different retention time. In addition it was noted that the scallop metabolite was stable during heating, while AZA19 has been shown to decarboxylate. Concentrations of reactive oxygen species (ROS) and activities of antioxidant enzymes were monitored. ROS levels increased slightly in the meat of scallops and mussels due to starvation in the acclimation and depuration periods, but reduced in the feeding periods with non-toxic Isochrysis galbana or toxic A. poporum. No obvious variations were found in activities for a range of antioxidant enzymes. These results provide new insights on the potential for accumulation and metabolism of AZAs in bivalve species relevant to this area of China, which is of importance considering the recent finding of AZA producing microalgae in the region. PMID- 29229238 TI - Effectiveness of an Automated Digital Remote Guidance and Telemonitoring Platform on Costs, Readmissions, and Complications After Hip and Knee Arthroplasties. AB - BACKGROUND: The impact of a new class of automated digital patient engagement (DPE) platforms on potentially avoidable costs, hospital admissions, and complications after discharge following hip and knee arthroplasties has not been established. METHODS: We conducted a multicenter observational cohort study comparing claims data for potentially avoidable costs, hospital admissions, and complications for 90 days after discharge following hip and knee arthroplasties at 10 practice sites in CA and NV. One hundred eighty-six patients, enrolled between 2014 and 2016 on an automated DPE platform receiving guidance and remote monitoring perioperatively, were compared with 372 patients who underwent the same procedures from the same physicians within 3 years immediately preceding platform implementation. The primary end point was the proportion of patients with $0.00 in 90-day target costs because of potentially avoidable utilization within the platform's influence. Secondary end points included rates of potentially avoidable 90-day hospital admissions and composite complications. RESULTS: Ninety-three percent and 84.7% of the study and baseline cohorts, respectively, had $0.00 in target costs (P = .004), with a mean savings of $656.52/patient (P = .006). The baseline and study cohorts had 3.0% and 1.6% 90 day hospital admission rates (relative risk 0.545; 0.154, 1.931, P = .40), and 15.3% and 7.0% composite complication rates, respectively (relative risk 0.456; 0.256, 0.812, P = .004). CONCLUSION: Patients enrolled on an automated DPE platform after hip and knee arthroplasties demonstrated a significant reduction in potentially avoidable 90-day costs, a 45.4% nonsignificant relative reduction in 90-day hospital admissions, and a 54.4% significant relative reduction in 90 day complications. PMID- 29229239 TI - In-vivo postoperative motion analysis of metal and ceramic bipolar hip hemiarthroplasty. AB - BACKGROUND: We hypothesized that ceramic bipolar shows less impingement between stem neck and outer head compared to metal bipolar, because of its low coefficient of friction with the acetabulum cartilage. In this paper, a three dimensional (3D) postoperative motion analysis has been used to assess the different motion characteristics of metal and ceramic bipolar hip hemiarthroplasty systems. METHODS: This study was conducted on 40 patients divided in two matched cohorts: 20 patients with metal bipolar and 20 patients with the ceramic bipolar. We obtained motion pictures from standing position to maximum abduction in flexion by fluoroscopy then analyzed by 2D-3D image matching method. The motion range of the "Outer head angle", "Stem neck angle" and the "Stem neck and outer head angle" was compared between the metal bipolar group and the ceramic bipolar group. RESULTS: The metal bipolar group's inner head's range of movement was greater than the ceramic bipolar group. Impingement between stem neck and outer head occurred in 30% of metal group patients. There were no impingement cases for the ceramic bipolar group. CONCLUSIONS: The ceramic bipolar shows less impingement between stem neck and outer head compared to the metal bipolar. Ceramic bipolar may reduce the typical bipolar related complication and exert less effect on the acetabular cartilage due to less surface coefficient of friction. PMID- 29229240 TI - Brain functional and perfusional alterations in schizophrenia: an arterial spin labeling study. AB - Schizophrenia is a severe mental disorder that affects the anatomy and function of the brain, with an impact on one's thoughts, feelings, and behavior. The purpose of the study was to investigate cerebral blood flow (CBF) and brain connectivity in a group of patients with schizophrenia. Pseudo-continuous arterial spin labeling (pCASL) images were acquired from 28 patients in treatment and 28 age-matched healthy controls. Mean CBF and connectivity patterns were assessed. Schizophrenia patients had decreased CBF in the bilateral frontal pole and superior frontal gyrus, right medial frontal gyrus, triangular and opercular parts of the inferior frontal gyrus, posterior division of the left supramarginal gyrus, superior and inferior divisions of the left lateral occipital cortex, and bilateral occipital pole. Moreover, through different methods to assess connectivity, our results showed abnormal connectivity patterns in regions involved in motor, sensorial, and cognitive functions. Using pCASL, a non invasive technique, we found CBF deficits and altered functional organization of the brain in schizophrenia patients that are associated with the symptoms and characteristics of the disorder. PMID- 29229241 TI - Intelligent poly (vinyl alcohol)-chitosan nanoparticles-mulberry extracts films capable of monitoring pH variations. AB - The aim of this study was to prepare a visually responsive intelligent film based on poly (vinyl alcohol) (PVA), chitosan nanoparticles (CHNPs) and mulberry extracts (MBE). CHNPs were first prepared by using ionotropic gelation method to enhance the mechanical properties of PVA based films. The morphology, particle size, zeta potential and crystallinity of CHNPs were measured. The resultant CHNPs were spherical with a diameter of 381.2nm, with high stability and a zeta potential of 49.1+/-1.33mV. The film with 6% CHNPs (P-C6) had the highest tensile strength (~73.43MPa). MBE was incorporated into the P-C6 film. The film containing 20% MBE had the highest tensile strength and showed visible color responses to variations across pH 1-13. The film was tested by monitoring the spoilage of fish. The color of the film changed from red to green as the fish spoiled. Therefore, the pH responsive intelligent film developed here can be used as a package label to detect food spoilage. PMID- 29229242 TI - Synthesis, characterisation and biomedical applications of curcumin conjugated chitosan microspheres. AB - Curcumin is a diaryl heptanoid of curcuminoids class obtained from Curcuma longa. It possesses various biological activities like anti-inflammatory, hypoglycemic, antioxidant, wound-healing, and antimicrobial activities. Chitosan is a biocompatible, biodegradable and non-toxic natural polymer which enhances the adhesive property of the skin. Chemical conjugation will leads to sustained release action and to enhance the bioavailability. This study aims to synthesis and characterize biocompatible curcumin conjugated chitosan microspheres for bio medical applications. The Schiff base reaction was carried out for the preparation of curcumin conjugated chitosan by microwave method and it was characterised using FTIR and NMR. Curcumin conjugated chitosan microspheres (CCCMs) were prepared by wet milling solvent evaporation method. SEM analysis showed these CCCMs were 2-5MUm spherical particles. The antibacterial activities of the prepared CCCMs were studied against Staphylococcus aureus and Escherichia coli, the zone of inhibition was 28mm and 23mm respectively. Antioxidant activity of the prepared CCCMs was also studied by DPPH and H2O2 method it showed IC50 esteem value of 216MUg/ml and 228MUg/ml, and anti-inflammatory activity results showed that CCCMs having IC50 value of 45MUg/ml. The results conclude that the CCCMs having a good antibacterial, antioxidant and anti-inflammatory activities. This, the prepared CCCMs have potential application in preventing skin infections. PMID- 29229243 TI - Nano-composites chitosan-curcumin synergistically inhibits the oxidative stress induced by toxic metal cadmium. AB - The present study intends to compare the influence of pre-treatment with nanoparticles of curcumin (Cr-NPS), chitosan (Ch-NPS) and nanocomposites chitosan curcumin (CC-NPS) on cadmium (Cd)-induced oxidative damage in the liver, kidneys, and blood indices in Swiss strain adult male mice. The pretreated mice with Cr NPS, Ch-NPS, and CC-NPS were exposed to Cd (10mg/kg) for three weeks. The non enzymatic Oxidative Stress (OS) indices like lipid peroxides (TBARS), reduced total glutathione (GSH), enzymatic OS indices like catalase (CAT), glutathione S transferase (GST) and superoxide dismutase (SOD) were estimated together with some blood indices. Cadmium was able to induce a significant increase in TBARS and a significant decrease in GSH, GST, CAT and SOD levels in all the tissues, which were pretreated with nanocomposite. Furthermore, the blood indices like counts of red and white blood cells, platelets, hemoglobin and packed cell volume were also depleted due to Cd exposure but remained unaffected and kept under normal levels in pretreated mice group. The results indicate that Cr-NPS, Ch-NPS, and CC-NPS may act as natural antioxidants and when compared among the three, CC NPS appears to be the best antioxidant. PMID- 29229244 TI - The functional properties and structural characteristics of deamidated and succinylated wheat gluten. AB - Wheat gluten protein (WGP) was modified by deamidation and succinylation to improve its functional properties. The properties of deamidated and succinylated WGP were compared with those of unmodified WGP, deamidated WGP and succinylated WGP. Structural analysis was carried out with FTIR. Surface visualization was carried out with SEM and the thermal stability was determined by DSC. The results showed that an acylation level of 73.64% produced the optimal properties for modified WGP. After modification, its functional properties were significantly improved. Modification did not significantly change the alpha-helical content, but there was a significant decrease in its beta-turn content and significant increases in beta-sheet and random coil content. According to SEM images, the modified WGP exhibited a smooth and evenly distributed sheet-like structure. The thermal stability of WGP was slightly decreased by modification. These results provide important information for the use of modified WGP in novel products. For example, adding deamidated and succinylated WGP to pound cake may reduce the amount of butter needed by up to 20%. PMID- 29229245 TI - Fabrication of fluorescent labeled ginseng polysaccharide nanoparticles for bioimaging and their immunomodulatory activity on macrophage cell lines. AB - Polysaccharides are a major active component of American ginseng root showing various biological activities including anti-carcinogenic, anti-aging, immunostimulatory and antioxidant effects. Although their biological activity has been reported by several groups, no research has explored their cellular uptake and biodistribution, owing to the lack of suitable detection techniques in living cells. This work examines a novel, simple and efficient fluorescent labeling procedure of ginseng polysaccharides (PS), in order to examine their cellular distribution using confocal microscopy. This procedure utilized a one-pot strategy with fluorescein-5-thiosemicarbazide (FTSC) to introduce a thiosemicarbazide group onto the aldehyde group at the reducing saccharide end to form a stable amino derivative through reductive amination. This polysaccharide FTSC derivative was then characterized by GPC, UV, FTIR, photoluminescence and fluorescence microscopy to confirm attachment and any structural changes. The results demonstrated that the labeled ginseng PS nanostructure showed high fluorescence with minimal changes in PS molecular weight. The labeled PS exhibited almost no cytotoxicity effect against tumor induced macrophage cell lines (RAW 264.7) while retaining high immunostimulating activity similar to the non-labeled ginseng PS. Therefore, the developed approach provides a convenient and highly efficient fluorescent labeling procedure for understanding the mechanism of ginseng PS uptake in macrophage cell lines. PMID- 29229246 TI - Microencapsulation of saffron anthocyanins using beta glucan and beta cyclodextrin: Microcapsule characterization, release behaviour & antioxidant potential during in-vitro digestion. AB - In the present study, the saffron anthocyanins were encapsulated in beta-glucan and beta-cyclodextrin by spray drying technique to achieve their stability under adverse gastro-environmental conditions. The microcapsules were subjected to simulated gastric conditions and release behavior of monomeric anthocyanins, antioxidants and phenols were studied. The structural properties of microcapsules were analyzed by SEM and ATR-FTIR spectroscopy. The particle size distribution, density, color, encapsulation efficiency and powder yield of samples were also evaluated. A characteristic band at 1700 cm-1 by FTIR and specific enclosed particles in the cavities of wall material were observed from the micrographs of SEM that confirmed the incorporation of anthocyanins in the microcapsules. The higher content of anthocyanins, antioxidants and phenols in the intestinal conditions revealed the protection of core material from adverse conditions of stomach by encapsulation. Further studies are suggested to investigate the stability of encapsulated anthocyanins in different environmental and processing conditions. PMID- 29229247 TI - Analysis of lecithin treatment effects on the structural transformation of wool fiber using vibrational spectroscopy. AB - The keratin macromolecule in wool fiber may be found in alpha-helix or beta-sheet conformations besides a disordered portion. The physical and chemical treatments may cause transformations between alpha-helix and beta-sheet conformations. The aim of this study was to investigate the influence of lecithin treatment on the wool fiber using the micro-Raman spectroscopy and Fourier transform infrared spectroscopy. Characteristic bands found in the FTIR spectra of wool fibers including the amide A, amide B and amide I-III, which are assigned to the peptide bonds of wool keratin and arise from the amide bonds that link the amino acids. The lecithin treatment didn't affect the peak position of amide bands and only slightly influenced their intensity. It means that the lecithin treatment didn't change the chemical structure of wool fibers. The amide I and III regions, CC skeletal vibration region, and SS bonds vibration regions were analyzed with the Raman microscope. The results indicated the peak area of alpha-conformation increased gradually by lecithin treatment of the wool fiber, while the peak area of beta-conformation decreased. Therefore, it seems that lecithin treatment of the wool fiber resulted in transformation of beta-sheet to alpha-helix. PMID- 29229248 TI - Physicochemical properties, production, and biological functionality of poly gamma-d-glutamic acid with constant molecular weight from halotolerant Bacillus sp. SJ-10. AB - Poly-gamma-glutamic acid (gamma-PGA) is an unusual anionic homopolyamide that is biodegradable, edible, and nontoxic. It has a wide variety of industrial applications depending on its combined cations, and molecular weight. In this study, extracellular viscous gamma-PGA produced by halotolerant Bacillus sp. SJ 10 isolated from a traditional Korean salted-fermented seafood was purified and characterized. The physicochemical analysis indicated that the gamma-PGA produced by Bacillus sp. SJ-10 consists primarily of d-glutamic acid residues combined with sodium cations. When batch fermentation was performed with 8% NaCl for 3 d, Bacillus sp. SJ-10 produced approximately 24.7g/L gamma-PGA with a molecular weight of approximately 400 kilodaltons (kDa). Under fermentation conditions with 6% NaCl, the maximum yield was 26.2g/L regardless of the molecular weight. The gamma-PGA sodium salt with a molecular weight of 400kDa exhibited antioxidant activity by scavenging 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) radicals and reducing molybdenum, with maximal scavenging activity at 0.5mg/mL and reducing activity at 1mg/mL (20MUg ascorbic acid-equivalent), respectively. These results suggest the potential use of gamma-PGA in the food, cosmetic, and biomedical industries for its antioxidant qualities. Our results also provide an economical method for controlling the molecular weight of the gamma-PGA produced. PMID- 29229249 TI - Enzyme-mediated tissue adhesive hydrogels for meniscus repair. AB - Meniscus tissues have limited regenerative capacity once damaged. The treatment options for the meniscus tissue regeneration have been limited to arthroscopic meniscectomy or surgical interventions. The injectable hydrogels based system would provide an alternative to the conventional meniscus therapy by providing a minimally invasive treatment alternative. Here we utilized enzyme-based approaches to fabricate tissue adhesive hydrogels for meniscus repair. Tyramine (TA) conjugated hyaluronic acid (TA-HA) and gelatin are susceptible to tyrosinase (TYR)-mediated crosslinking in vitro and in vivo. Importantly, mechanical properties and degradation kinetics are modulated by the TA substitution and TYR concentrations. In addition, TYR -mediated crosslinking displayed tissue-adhesive properties. Furthermore, fibrochondrocyte-laden and TYR-crosslinked hydrogels demonstrated strong biocompatibility and resulted in enhancement of cartilage specific gene expression and matrix synthesis. Overall, this represents a potential application of enzyme-mediated crosslinking hydrogels for meniscus tissue engineering. PMID- 29229251 TI - Reply to "Is There Any Link Among C-Reactive Protein, Right Ventricular Function, and Postoperative Atrial Fibrillation?" PMID- 29229250 TI - Genome-wide transcriptomics analysis identifies sox7 and sox18 as specifically regulated by gata4 in cardiomyogenesis. AB - The transcription factors GATA4, GATA5 and GATA6 are important regulators of heart muscle differentiation (cardiomyogenesis), which function in a partially redundant manner. We identified genes specifically regulated by individual cardiogenic GATA factors in a genome-wide transcriptomics analysis. The genes regulated by gata4 are particularly interesting because GATA4 is able to induce differentiation of beating cardiomyocytes in Xenopus and in mammalian systems. Among the specifically gata4-regulated transcripts we identified two SoxF family members, sox7 and sox18. Experimental reinstatement of gata4 restores sox7 and sox18 expression, and loss of cardiomyocyte differentiation due to gata4 knockdown is partially restored by reinstating sox7 or sox18 expression, while (as previously reported) knockdown of sox7 or sox18 interferes with heart muscle formation. In order to test for conservation in mammalian cardiomyogenesis, we confirmed in mouse embryonic stem cells (ESCs) undergoing cardiomyogenesis that knockdown of Gata4 leads to reduced Sox7 (and Sox18) expression and that Gata4 is also uniquely capable of promptly inducing Sox7 expression. Taken together, we identify an important and conserved gene regulatory axis from gata4 to the SoxF paralogs sox7 and sox18 and further to heart muscle cell differentiation. PMID- 29229252 TI - Implementation of an Early Extubation Protocol in Cardiac Surgical Patients Decreased Ventilator Time But Not Intensive Care Unit or Hospital Length of Stay. AB - OBJECTIVE: The optimal timing of extubation following cardiac surgery is currently unknown. Protocols implemented in order to achieve a rapid extubation may achieve this goal, but not prove beneficial in terms of outcomes. DESIGN: A prospective clinical trial. SETTING: Tertiary care cardiac surgical intensive care unit. PARTICIPANTS: Adult cardiac surgical patients. INTERVENTIONS: Implementation of an 8-tier multidisciplinary rapid weaning protocol. MEASUREMENTS AND MAIN RESULTS: Ventilator times 6 months prior to and 6 months after implementation of the protocol were measured. Outcomes associated with ventilator times were measured by dividing the patients into tertiles (<6 hours, 6-12 hours, >12 hours). Primary outcomes were intensive care unit (ICU) and hospital length of stay. Secondary outcomes included mortality at 30 days and other major morbidities. In all, 459 patients were included in the study. With implementation of the protocol, median ventilation times decreased from 7.4 hours (interquartile range, IQR = 3rd quartile - 1st quartil e= 6.72 hours) to 5.73 hours (IQR = 5.51 hours) (p < 0.0001). However, median ICU length of stay in patients who achieved extubation within 6 hours increased to 49.45 hours (IQR = 44.4) from 40.3 (IQR = 25.6) (p = 0.0017). Median hospital length of stay was not significantly changed due to the protocol in any ventilation tertile (p = 0.650). CONCLUSIONS: Decreasing intubation times to <6 hours in postsurgical cardiac patients is obtainable with implementation of a multidisciplinary rapid weaning protocol. However, patients extubated within 6 hours had increased ICU length of stay and no difference in hospital length of stay with this intervention. PMID- 29229253 TI - Can Transesophageal Echocardiography Be Performed Safely Using a Laryngeal Mask Airway During Atrial Fibrillation Ablation? AB - OBJECTIVE: To investigate the feasibility and safety of using a laryngeal mask airway (LMA) compared with a cuffed oral endotracheal tube (COETT) for atrial fibrillation (AF) ablation with transesophageal echocardiography (TEE). DESIGN: Prospective, cohort study. SETTING: A single-center inner-city hospital. PARTICIPANTS: The study comprised adult patients undergoing elective AF ablation with periprocedural TEE over a 3-year period. INTERVENTIONS: Patients were treated with either an LMA or a COETT before undergoing a standardized protocol for TEE and AF ablation. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the need for conversion from an LMA to a COETT. Between January 2014 and January 2017, 346 patients underwent AF ablation. Of those, 126 procedures were performed with a COETT (36.4%) and 220 (63.6%) with an LMA. There were no differences between groups in terms of baseline characteristics, including age, sex, body mass index, and American Society of Anesthesiologists grade. An adequate airway seal was unable to be maintained in 3 patients in the LMA group (1.4%), and those patients were converted to a COETT. No episodes of airway complications occurred in either group. No difference was found in mean propofol (2%) dose between COETT and LMA (385 mg/h v 374 mg/h; p = 0.127). However, the mean remifentanil dose (100 ug/mL) was reduced significantly in the LMA group compared with the COETT group at 355 ug/h and 939 ug/h, respectively (p < 0.001). CONCLUSIONS: LMA use is safe and feasible in the vast majority of patients undergoing AF ablation with TEE and is an acceptable alternative to COETT. A significantly reduced rate of remifentanil was required to maintain anesthesia in the LMA group. PMID- 29229254 TI - Is There Any Link Among C-Reactive Protein, Right Ventricular Function, and Postoperative Atrial Fibrillation? PMID- 29229255 TI - Role of the Pulmonary Artery Catheter in Integrated Management of Renal Cell Carcinoma With Significant Caval Extension of Tumor Thrombus. PMID- 29229256 TI - Unrecognized Esophageal Perforation After Liver Transplantation. PMID- 29229257 TI - Factors Related to the Severity of Early Postoperative Infection After Heart Transplantation in Patients Surviving Prolonged Mechanical Support Periods: Experience at a Single University. AB - OBJECTIVE: The authors examined the effect of prolonged support with continuous flow ventricular assist devices (CF-VADs) and other related factors on the severity of infections within 30 days of heart transplantation (HTx). DESIGN: A retrospective analysis of consecutive HTx procedures. SETTING: University hospital, between 2010 and 2016. PARTICIPANTS: A cohort of 53 heart transplantation recipients (median age, 38.5 yr; interquartile range [IQR], 30.3 49.2 yr; women, 34%). INTERVENTIONS: Forty-nine patients required CF-VAD support (median duration, 946 d; IQR, 600-1,132 d). MEASUREMENTS AND MAIN RESULTS: Severity of postoperative infections was categorized as follows: no infection, minor infection (resolved within 14 days), major infection (resolved after >14 days), and severe infection (septic shock). Results were expressed as number (frequency) and median with IQR. Potential risk factors for increased infection severity were expressed as odds ratio (OR) with 95% confidence interval (CI). Postoperatively, no infection, minor infection, major infection, and severe infection occurred in 32 (60.4%), 8 (15.1%), 8 (15.1%), and 5 patients (9.4%), respectively. Active ventricular assist device (VAD)-specific infections at the time of HTx occurred in 37.7% of patients. Moderate-to-severe primary graft dysfunction occurred in 26.4% of the patients. Multivariable analysis indicated that risk factors for increased infection severity included active VAD-specific infection (OR 4.8; 95% CI 2.3-11.2) and moderate-to-severe primary graft dysfunction (OR 8.8; 95% CI 2.1-42.5) but not duration of CF-VAD support (OR 1.0; 95% CI 1.0-1.0). CONCLUSION: Active VAD-specific infection and poor graft function likely contribute to the severity of early postoperative infections after HTx. PMID- 29229259 TI - Effects of Positive Airway Pressure and Mechanical Ventilation of the Lungs During Cardiopulmonary Bypass on Pulmonary Adverse Events After Cardiac Surgery: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To investigate whether different ventilation strategies during cardiopulmonary bypass (CPB) can improve outcomes in adult cardiac surgery patients. DESIGN: Systematic review of randomized controlled trials with meta analyses. SETTING: Clinical trials for human studies up to July 2016 were obtained from electronic databases (Medline, Embase, PubMed, and the Cochrane Central Register of Controlled Trials) and reference lists of relevant randomized trials and review articles. PARTICIPANTS: Adult patients undergoing cardiac surgery. INTERVENTIONS: Patients who underwent cardiac surgery with CPB and ventilation or continuous positive airway pressure (CPAP). MEASUREMENTS AND MAIN RESULTS: Fifteen randomized controlled trials with 748 patients were analyzed. In cardiac surgery, CPAP use during CPB was associated with an improved alveolar arterial oxygen gradient difference compared with no CPAP (weighted mean difference [WMD] = 4.11 kPa; 95% confidence interval [CI] = 0.85-7.37; I2 = 28.8%). Ventilation during CPB did not improve the postoperative hypoxemia score (WMD = 30.94; 95% CI = -20.76 to 82.63; I2 = 61%) or diffusion capacity compared with the apnea group (WMD = 2.59 kPa; 95% CI = -2.49 to 7.67; I2 = 81.3%). Neither CPAP nor ventilation during CPB was associated with a shorter mechanical ventilation time or hospital stay. CONCLUSIONS: CPAP during CPB improved the alveolar-arterial oxygen gradient difference compared with apnea, but ventilation during CPB did not. Neither CPAP nor ventilation during CPB demonstrated evidence of improving clinical outcomes in low- or intermediate-risk patients for elective cardiac surgery. The findings are inconclusive because of heterogeneity and small sample sizes. PMID- 29229260 TI - TAPSE: A Red Herring After Cardiac Surgery. PMID- 29229258 TI - Perioperative Information Systems: Opportunities to Improve Delivery of Care and Clinical Outcomes in Cardiac and Vascular Surgery. AB - A variety of existing perioperative informatics tools offer clinicians and researchers the opportunity to improve the delivery of care and clinical outcomes for patients undergoing cardiac and vascular surgery. Many of these tools can be used to improve the reliability of the care delivery process through the application of clinical decision support tools and/or quality improvement methodologies at a number of junctures. In this review, the authors will offer a concise overview of the existing perioperative informatics literature, with a focus on tools considered to be of utility in confronting the unique challenges inherent to cardiac and vascular surgery. The authors also highlight areas that they believe are of interest for future targeted inquiry. PMID- 29229262 TI - Heart Transplantation in Patients >60 Years: Importance of Relative Pulmonary Hypertension and Right Ventricular Failure on Midterm Survival. AB - OBJECTIVES: To determine the impact of recipient age and perioperative risk factors on midterm survival after orthotopic heart transplantation (OHT). The authors hypothesized that perioperative variables are more important as predictors of mortality than is a recipient's age. DESIGN: Retrospective study. SETTING: Tertiary care university hospital. PARTICIPANTS: The study comprised 126 consecutive adults who underwent OHT. INTERVENTIONS: After Institutional Review Board approval, the authors analyzed 126 consecutive adult patients who underwent OHT between January 2009 and December 2015 and followed-up with them up until June 2016. Patients were divided into the following 2 groups according to the recipient's age at the time of transplantation: older group (>=60 y old) and younger group (18 to 59 y). MEASUREMENTS AND MAIN RESULTS: Actuarial survival rates for all patients were 88.1%, 78.6%, and 72.2% at 30 days, 1 year, and after a median follow-up of 18.9 months (midterm survival) (1st quartile: 8.1; 3rd quartile: 37.4), respectively. In the unadjusted analysis, the older group demonstrated a significant increase in 1-year mortality (p = 0.005) and a trend toward worse midterm mortality (p = 0.087). Multivariable analysis was performed using Cox proportional hazards regression analysis. Independent risk factors related to midterm mortality after OHT were as follows: preoperative relative pulmonary hypertension using the mean arterial-to-mean pulmonary artery pressure ratio <=3 (hazard ratio [HR] 5.39, 95% confidence interval [CI] 1.64-17.74, p = 0.006); cardiopulmonary bypass duration (per each 10-min increment) (HR 1.14, 95% CI 1.08-1.22, p < 0.001); and postoperative right ventricular dysfunction (HR 3.50, 95% CI 1.52-8.05, p = 0.003). Neither recipients >=60 years old (HR 2.15, 95% CI 0.98-4.67, p = 0.054) nor donor/recipient body surface area ratio (HR 1.01, 95% CI 0.98-1.04, p = 0.463) was an independent risk factor for midterm mortality. CONCLUSIONS: In patients undergoing heart transplantation, survival was related more to preoperative relative pulmonary hypertension, cardiopulmonary bypass duration, and postoperative right ventricular failure than to recipient age. Older patients should be selected for OHT carefully, taking into consideration preoperative factors other than age. PMID- 29229261 TI - Preliminary Experience in Combined Somatic and Cerebral Oximetry Monitoring in Liver Transplantation. AB - OBJECTIVE: The use of cerebral near-infrared spectroscopy (NIRS) has become widespread in cardiac surgery after research demonstrated an association between perioperative cerebral desaturations and postoperative complications. Somatic NIRS desaturation also is associated with an increased risk of postoperative complications and mortality. The objective of this study was to explore the trends of both somatic and cerebral NIRS during liver transplantation. DESIGN: A prospective, single-site, observational case series. SETTING: Tertiary care center. PARTICIPANTS: The study comprised 10 patients undergoing liver transplantation. INTERVENTIONS: NIRS sensors were placed on the forehead (cerebral regional oxygen saturation [rSO2]) and on the right arm and right leg (somatic rSO2) to measure tissue perfusion. Desaturation was defined as a 20% decrease of baseline values for 15 seconds. MEASUREMENTS AND MAIN RESULTS: In all patients, parallel changes in both cerebral and somatic rSO2 values were observed during phlebotomy, bleeding, transfusion, portal vein clamping, and the use of vasoactive agents. Induction of anesthesia increased cerebral rSO2 more than it did somatic values. However, ascites removal, abdominal manipulation, and clamping of the inferior vena cava (IVC) were associated with nonparallel changes in cerebral and somatic rSO2. Ascites removal was associated with increased somatic leg rSO2, and IVC clamping and abdominal hypertension were associated with a significant reduction in somatic leg rSO2. Somatic leg desaturation instead of arm or cerebral desaturation was associated with more postoperative complications. CONCLUSIONS: The use of combined NIRS monitoring allows for the identification of the source of somatic or cerebral desaturation. Compromised venous flow from the IVC from clamping or abdominal compartment syndrome typically is associated with the appearance of more pronounced leg than arm desaturation. PMID- 29229264 TI - Towards a General Theory of Immunity? AB - Theories are indispensable to organize immunological data into coherent, explanatory, and predictive frameworks. We propose to combine different models to develop a unifying theory of immunity which situates immunology in the wider context of physiology. We believe that the immune system will be increasingly understood as a central component of a network of partner physiological systems that interconnect to maintain homeostasis. PMID- 29229263 TI - The Hemodynamic Effects of Different Pacing Modalities After Cardiopulmonary Bypass in Patients With Reduced Left Ventricular Function. AB - OBJECTIVES: Patients with decreased left ventricular function undergoing cardiac surgery have a greater chance of difficult weaning from cardiopulmonary bypass and a poorer clinical outcome. Directly after weaning, interventricular dyssynchrony, paradoxical septal motion, and even temporary bundle-branch block might be observed. In this study, the authors measured arterial dP/dtmax, mean arterial pressure (MAP), and cardiac index using transpulmonary thermodilution, pulse contour analysis, and femoral artery catheter and compared the effects between right ventricular (A-RV) and biventricular (A-BiV) pacing on these parameters. DESIGN: Prospective study. SETTING: Single-center study. PARTICIPANTS: The study comprised 17 patients with a normal or prolonged QRS duration and a left ventricular ejection fraction <=35% who underwent coronary artery bypass grafting with or without valve replacement. INTERVENTIONS: Temporary pacing wires were placed on the right atrium and both ventricles. Different pacing modalities were used in a standardized order. MEASUREMENTS AND MAIN RESULTS: A-BiV pacing compared with A-RV pacing demonstrated higher arterial dP/dtmax values (846 +/- 646 mmHg/s v 800 +/- 587 mmHg/s, p = 0.023) and higher MAP values (77 +/- 19 mmHg v 71 +/- 18 mmHg, p = 0.036). CONCLUSION: In patients with preoperative decreased left ventricular function undergoing coronary artery bypass grafting, A-BiV pacing improve the arterial dP/dtmax and MAP in patients with both normal and prolonged QRS duration compared with standard A-RV pacing. In addition, arterial dP/dtmax and MAP can be used to evaluate the effect of intraoperative pacing. In contrast to previous studies using more invasive techniques, transpulmonary thermodilution is easy to apply in the perioperative clinical setting. PMID- 29229265 TI - Mapping Organism-wide Immune Responses. AB - Immune responses are often dissected at the molecular or cellular level, but rarely are they investigated at the scale of the whole organism. Here, Chevrier and colleagues reveal that an interconnected web of protective immunity exists between organs, which safeguards the host from systemic viral spread. PMID- 29229266 TI - Comment on 'Clinical impact of non-antibiotic recommendations by a multi disciplinary antimicrobial stewardship team'. PMID- 29229267 TI - Intracavitary Contrast-Enhanced Ultrasound in the Management of Post-Surgical Gastrointestinal Fistulas. AB - The goal of this study was to investigate intracavitary contrast-enhanced ultrasound (IC-CEUS) measures in the management of post-surgical gastrointestinal (GI) fistula throughout detection, treatment and follow-up. From June 2010 to August 2016, patients who were administered ultrasound contrast agent (UCA) via a drainage tube for IC-CEUS were enrolled and retrospectively analyzed. They were suspected of having GI anastomotic fistulas or had been found to have fluid collections with ultrasound that were accompanied by abdominal pain or fever after surgical procedures. Forty-two patients met the inclusion criteria and were enrolled into this study. Twenty-two were confirmed to have GI fistulas confirmed by standard references. None were detected by conventional ultrasound. Although IC-CEUS successfully detected GI fistulas in 16 patients, it missed GI fistulas in 6 patients. One patient was misdiagnosed with a GI fistula. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the diagnosis of GI fistulas by IC-CEUS were 72.7% (16/22), 95.0% (19/20), 94.1% (16/17), 76.0% (19/25) and 83.3% (35/42), respectively. Twenty peritoneal fluid collections in 14 patients were related to fistulas by IC-CEUS based on the distribution of ultrasound contrast agents. Additional drainage was performed in 14 fistula-related fluid collections. Eight GI fistulas were judged to be cured after IC-CEUS re-evaluation, and the drainage tubes were removed from these patients. In conclusion, IC-CEUS can greatly improve the ability to diagnose post surgical GI fistulas and may also play an important role in interventional treatment and follow-up. PMID- 29229268 TI - Acoustic Characterization of Echogenic Polymersomes Prepared From Amphiphilic Block Copolymers. AB - Polymersomes are a class of artificial vesicles prepared from amphiphilic polymers. Like lipid vesicles (liposomes), they too can encapsulate hydrophilic and hydrophobic drug molecules in the aqueous core and the hydrophobic bilayer respectively, but are more stable than liposomes. Although echogenic liposomes have been widely investigated for simultaneous ultrasound imaging and controlled drug delivery, the potential of the polymersomes remains unexplored. We prepared two different echogenic polymersomes from the amphiphilic copolymers polyethylene glycol-poly-DL-lactic acid (PEG-PLA) and polyethylene glycol-poly-L-lactic acid (PEG-PLLA), incorporating multiple freeze-dry cycles in the synthesis protocol to ensure their echogenicity. We investigated acoustic behavior with potential applications in biomedical imaging. We characterized the polymeric vesicles acoustically with three different excitation frequencies of 2.25, 5 and 10 MHz at 500 kPa. The polymersomes exhibited strong echogenicity at all three excitation frequencies (about 50- and 25-dB enhancements in fundamental and subharmonic, respectively, at 5-MHz excitation from 20 ug/mL polymers in solution). Unlike echogenic liposomes, they emitted strong subharmonic responses. The scattering results indicated their potential as contrast agents, which was also confirmed by clinical ultrasound imaging. PMID- 29229269 TI - The impact of screening method on HLA antibody detection before and after lung transplantation: A prospective pilot study. PMID- 29229270 TI - Intratracheal instillation of alveolar type II cells enhances recovery from acute lung injury in rats. AB - BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by excess production of inflammatory factors. Alveolar type II (ATII) cells help repair damaged lung tissue, rapidly proliferating and differentiating into alveolar type I cells after epithelial cell injury. In ALI, the lack of viable ATII favors progression to more severe lung injury. ATII cells regulate the immune response by synthesizing surfactant and other anti inflammatory proteins and lipids. Cross-talk between ATII and other cells such as macrophages may also be part of the ATII function. The aim of this study was to test the anti-inflammatory and reparative effects of ATII cells in an experimental model of ALI. METHODS: In this study ATII cells (2.5 * 106 cells/animal) were intratracheally instilled in rats with HCl and lipopolysaccharide (LPS)-induced ALI and in healthy animals to check for side effects. The specific effect of ATII cells was compared with fibroblast transplantation. RESULTS: ATII cell transplantation promoted recovery of lung function, decrease mortality and lung inflammation of the animals with ALI. The primary mechanisms for benefit were paracrine effects of prostaglandin E2 (PGE2) and surfactant protein A (SPA) released from ATII cells that modulate alveolar macrophages to an anti-inflammatory phenotype. To our knowledge, these data are the first to provide evidence that ATII cells secrete PGE2 and SPA, reducing pro inflammatory macrophage activation and ALI. CONCLUSION: ATII cells and their secreted molecules have shown an ability to resolve ALI, thereby highlighting a potential novel therapeutic target. PMID- 29229271 TI - Using Metabolic Equivalents in Clinical Practice. AB - Metabolic equivalents, or METs, are routinely employed as a guide to exercise training and activity prescription and to categorize cardiorespiratory fitness (CRF). There are, however, inherent limitations to the concept, as well as common misapplications. CRF and the patient's capacity for physical activity are often overestimated and underestimated, respectively. Moreover, frequently cited fitness thresholds associated with the highest and lowest mortality rates may be misleading, as these are influenced by several factors, including age and gender. The conventional assumption that 1 MET = 3.5 mL O2/kg/min has been challenged in numerous studies that indicate a significant overestimation of actual resting energy expenditure in some populations, including coronary patients, the morbidly obese, and individuals taking beta-blockers. These data have implications for classifying relative energy expenditure at submaximal and peak exercise. Heart rate may be used to approximate activity METs, resulting in a promising new fitness metric termed the "personal activity intelligence" or PAI score. Despite some limitations, the MET concept provides a useful method to quantitate CRF and define a repertoire of physical activities that are likely to be safe and therapeutic. In conclusion, for previously inactive adults, moderate-to-vigorous physical activity, which corresponds to >=3 METs, may increase MET capacity and decrease the risk of future cardiac events. PMID- 29229272 TI - Effect of different resistance-training protocols on the extracellular matrix of the calcaneal tendon of rats. AB - The calcaneal tendon extracellular matrix (ECM) is composed of collagen, non collagenous glycoproteins and proteoglycans, and able to adapt to various biomechanical stimuli. The objective of this study was to analyze the response of different resistance-training protocols, such as hypertrophy, strength and resistance, on the organization of the calcaneal tendon after training. Wistar rats were divided into four groups: untrained (UT), resistance training (RT), hypertrophy training (HT), and strength training (ST). The protocol in a vertical climbing platform was performed thrice per week over twelve weeks. For biochemical study, the tendons of each group were minced and analyzed for gelatinases, quantification of non-collagenous proteins, sulfated glycosaminoglycans, and hydroxyproline. For morphological analysis, sections were stained with HE and toluidine blue. Non-stained sections were used for birefringence analysis under polarization microscopy. The highest hydroxyproline concentrations were found in HT (154.8+/-14.2) and RT (173.6+/-25.2) compared with UT (122.4+/-27.0). A higher concentration of non-collagenous proteins was detected in the RT group (14.98mg/g) compared with the other groups. In polarization microscopy, major birefringence was observed in HT and the lowest in ST compared with UT, indicating higher organization of collagen bundles in HT. In analysis for zymography, the presence of latent MMP-9 was more prominent in the ST group and the active MMP-9 more prominent in the HT group. For MMP-2, significant differences in the latent isoform between the HT (184,867+/-6765) and UT (173,018+/-9696) groups were found. In sections stained with toluidine blue (TB), higher metachromasia was observed in the tendon's distal region in HT and RT groups, indicating a greater amount of proteoglycans. We conclude that the different training protocols produced different responses in the ECM. The remarkable presence of MMP-2 and -9 in the hypertrophy training group may be related to the highest organization of collagen bundles and possibly a more efficient remodeling process, observed in that group, as demonstrated by images and measurements of birefringence. PMID- 29229273 TI - Mannose-functionalized solid lipid nanoparticles are effective in targeting alveolar macrophages. AB - Mannose receptor is highly expressed on alveolar macrophages, being a potential target to promote the specific local drug delivery of anti-tuberculosis agents through the use of functionalized nanocarriers. In this work, isoniazid (Isn) loaded solid lipid nanoparticles (SLN), reinforced with stearylamine (SA) were produced by double emulsion technique and further surface-functionalized with mannose in a straightforward chemical approach. Upon pre-formulation assessment, SLN close to 500 nm average size, positively charged and with association efficiency of ISN close to 50% were obtained. Functionalization with mannose was performed after SLN production and confirmed by Fourier transform infrared spectroscopy (FTIR). Both functionalized and non-functionalized SLN demonstrated to devoid of toxicity when tested in human lung epithelial cell line (NCI-H441) and differentiated THP-1 (dTHP-1), reducing the intrinsic cytotoxicity of Isn when incorporated into SLN. Uptake studies were conducted on same macrophage-like cells and the results showed that fluorescent mannosylated SLN (M-SLN) were more efficient in be internalized comparatively to SLN. Moreover, the uptake of M-SLN was reduced when cells were pre-incubated with mannose, demonstrating the receptor-dependence internalization of functionalized SLN. These functionalized nanocarriers may represent a useful platform to target alveolar macrophages for delivering anti-infective drugs. PMID- 29229274 TI - Team approach to manage difficult-to-treat TB cases: Experiences in Europe and beyond. AB - As recommended by the World Health Organization (WHO), optimal management of MDR TB cases can be ensured by a multi-speciality consultation body known as 'TB Consilium'. This body usually includes different medical specialities, competences and perspectives (e.g., clinical expertise both for adults and children; surgical, radiological and public health expertise; psychological background and nursing experience, among others), thus lowering the risk of making mistakes - or managing the patients inappropriately, in order to improve their clinical outcomes. At present, several high MDR-TB burden countries in the different WHO regions (and beyond) have introduced TB Consilium-like bodies at the national or subnational level to reach consensus on the best treatment approach for their patients affected by TB. In addition, in countries/settings where a formal system of consultation does not exist, specialized staff from MDR TB reference centres or international organizations usually spend a considerable amount of their working time responding to phone or e-mail clinical queries on how to manage M/XDR-TB cases. The aim of this manuscript is to describe the different experiences with the TB Consilia both at the international level (European Respiratory Society - ERS/WHO TB Consilium) and in some of the countries where this experience operates successfully in Europe and beyond. The Consilium experiences are described around the following topics: (1) history, aims and focus; (2) management and funding; (3) technical functioning and structure; (4) results achieved. In addition a comparative analysis of the TB Consilia in the different countries has been performed. PMID- 29229275 TI - Frequency of Treponema pallidum invasion into cerebrospinal fluid in primary or secondary early-stage syphilis. AB - Frequency of Treponema pallidum invasion into cerebrospinal fluid (CSF) has not been clear at this present. Since it is impossible to culture T. pallidum in vitro at this present, we need molecular based-approach to detect it in CSF. Additionally, neurosyphilis is usually a late sequela, however it might result in asymptomatic neurosyphilis even at primary or secondary syphilis. This study was to reveal the frequency of T. pallidum invasion into CSF especially at primary or secondary syphilis with polymerase chain reaction (PCR) test. All patients were visited the Aichi Medical University Hospital or Izumi ladies' clinic between 2016 and 2017. Clinical CSF samples were collected from patients with early and late stages of syphilis. The PCR was done using primers targeting the tpN47gene. CSF samples were collected from 9 patients (4 patients with primary syphilis, 3 with secondary syphilis, and 1 early latent syphilis and 1 with late latent syphilis). PCR showed positive reaction in 2 of 7 (28.6%) primary and secondary syphilis patients, in 1 of 1 (100%) early latent syphilis patients, and in 1 of 1 (100%) late latent syphilis patients. Despite its lack of sensitivity for use alone as a diagnostic test, this PCR test should be preferred for the diagnosis of neurosyphilis. Because, T. pallidum was detected in the 28.6% CSF of patients at primary and secondary syphilis, which indicated that they invade the central nervous system from the early stages of infection. However, studies in a larger population are required to confirm these preliminary results. PMID- 29229276 TI - Corrigendum to "HIPS: A new hippocampus subfield segmentation method" [NeuroImage 163 (2017) 286-295]. PMID- 29229277 TI - Discussion. PMID- 29229278 TI - The impact of hoist sling fabrics on interface pressure whilst sitting in healthy volunteers and wheelchair users: A comparative study. AB - AIM OF THE STUDY: To evaluate the effect of three sling fabrics on gluteal interface pressure whilst sitting in a population of wheelchair users and to compare these to data previously collected in a pilot study with a healthy population. MATERIALS AND METHODS: A repeated measures experimental design was used with 32 adult wheelchair users (15 women, 17 men). Healthy population pilot study consisted of 61 participants (51 women, 10 men) recruited from staff and students at The University of Salford. METHODS: Gluteal pressures at six pressure zones were recorded using the X-sensor PX100 pressure sensor at 30 s intervals for 10 min. Data were collected in 4 conditions with participants seated in a standardised chair, followed by the chair with slings made of three different fabrics. RESULTS: The spacer fabric reduced the mean gluteal pressure more effectively than slipfit and polyester (p = 0.014 and p = 0.01 respectively, 95%CI) and reduced peak pressure at the left ischial tuberosity and coccyx when compared to the slipfit (p = 0.003 and p = 0.005) with the wheelchair users. When comparing data with the pilot study, the mean gluteal pressure and peak pressures at the ischial tuberosities and coccyx were significantly higher in the wheelchair user group (p < 0.005). CONCLUSION: The fabric identified as the most effective in reducing mean and peak pressures in both groups was the spacer fabric, suggesting that a spacer fabric sling is more likely to reduce the risk of pressure ulcer development. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. PMID- 29229279 TI - Outcomes of Spontaneous Isolated Superior Mesenteric Artery Dissection Without Antithrombotic Use. AB - OBJECTIVES: This study aimed to show the intention to treat results of treatment for spontaneous isolated superior mesenteric artery dissection (SISMAD) without anticoagulation or antiplatelet agents and the follow-up results of SISMAD according to the configuration on computed tomography (CT) scans. DESIGN: Retrospective, observational single centre study METHODS: All cases of SISMAD were enrolled consecutively from 2006 onwards. There were 25 symptomatic and four asymptomatic patients in whom SISMAD was found incidentally. The SISMAD patients were treated using a consistent therapeutic strategy without antithrombotics. SISMAD was categorized into four types based on the configuration on CT scans by Yun's classification. Follow-up CT was performed at 3 months, 6 months, and yearly thereafter. RESULTS: The median follow-up duration was 57 months (13-129 months). Improvement or complete resolution on CT scans, with no symptom recurrence, was seen in 27 patients. The non-invasive approach failed in three cases and two patients underwent further intervention. No patient died during the follow-up. CONCLUSIONS: Weighing the risks versus benefits of antithrombotics and considering the benign nature of SISMAD, conservative treatment without antithrombotics might be sufficient in patients without evidence of bowel ischaemia or infarction on initial CT scan. PMID- 29229280 TI - Antimicrobial susceptibility of Neisseria gonorrhoeae isolates in Vientiane, Lao PDR. AB - OBJECTIVES: The aim of this study was to determine the antimicrobial susceptibility of Neisseria gonorrhoeae isolates in the Lao People's Democratic Republic (Laos). METHODS: A total of 165 gonococcal isolates (1.3%) were obtained from 12 281 genital samples routinely submitted to a diagnostic laboratory in Vientiane, Laos, between 2011 and 2015. Susceptibility to five antibiotics was determined by the standard disk diffusion method for 158 of the isolates. RESULTS: Rates of resistance to penicillin (by beta-lactamase production), tetracycline and ciprofloxacin were 89.9%, 99.4% and 84.8%, respectively. All isolates were susceptible to ceftriaxone and spectinomycin. CONCLUSIONS: The situation in Laos is similar to that in neighbouring countries; this fortunately means that the latest Lao national guidelines for treating gonorrhoea should still be effective. PMID- 29229281 TI - Potential of real-time PCR threshold cycle (CT) to predict presence of free toxin and clinically relevant C. difficile infection (CDI) in patients with cancer. AB - OBJECTIVES: Clostridium difficile infection (CDI) is a toxin-mediated disease. Oncology patients are at increased risk for developing CDI. Diagnosis of CDI by PCR has led to misclassification of some C. difficile carriers as CDI cases. We determined if an optimized C. difficile PCR cycle threshold value (CT) could reliably predict presence of free toxin, and in turn improve the utility of PCR in detecting clinically relevant CDI in oncology patients. METHODS: 183 consecutive patients positive for C. difficile by the Xpert C. difficile were additionally tested using the cell culture cytotoxicity neutralization assay (CYT) and enzyme immunoassays (EIA). CT values at diagnosis and relevant clinical information were recorded. Receiver operating characteristic (ROC) curve was used to assess predictive validity and to find optimal CT for CYT positive cases. Severity of CDI was assessed by blinded charts review. RESULTS: Using CYT as the reference, ROC-derived Youden cut-off CT of 28.0 predicted 77% cytotoxin positive cases, and 91% and 100% of severe and complicated CDI episodes respectively. The median CT values for non-severe, severe, and complicated CDI episodes were 28.0, 24.5 and 22.5 respectively (p = 0.005). CONCLUSIONS: Lower CT value of the Xpert C. difficile PCR was associated with the presence of toxin and increased CDI severity. CT values may be beneficial in interpreting positive C. difficile PCR results. PMID- 29229282 TI - What is the optimal duration of human chorionic gonadotrophin surveillance following evacuation of a molar pregnancy? A retrospective analysis on over 20,000 consecutive patients. AB - OBJECTIVE: To quantify the risk of developing post-molar gestational trophoblastic neoplasia (pGTN) beyond the first normal human chorionic gonadotrophin (hCG) in women who have had a complete (CHM) or partial molar pregnancy (PHM) and to re-evaluate the current UK Hydatidiform mole hCG surveillance guidelines. METHODS: The Charing Cross Hospital Trophoblast Disease Centre database was screened to identify all registered cases of hydatidiform mole (HM) between 1980 and 2009. RESULTS: We identified 20,144 cases of HM, comprising 8400 CHM, 9586 PHM, and 2158 cases of unclassified hydatidiform mole (UHM). Twenty-nine cases (20 CHM, 3 PHM and 6 UHM) developed pGTN after the first normal hCG. For CHM the risk of pGTN at the point of hCG normalisation was 1 in 406, and fell rapidly in the first six months of monitoring. For PHM the risk of pGTN at the point of hCG normalisation was 1 in 3195. Women with CHM where hCG normalisation occurred beyond 56days after uterine evacuation of molar tissue were found to have a 3.8-fold higher risk of pGTN. CONCLUSIONS: Our results show that pGTN can occur after hCG normalisation following PHM but the risk is extremely low. Women with CHM have a comparatively higher risk of pGTN after hCG normalisation. Those with CHM where hCG normalises within 56days have a lower risk of pGTN. We have revised the current UK hCG surveillance protocol for PHM to a single additional confirmatory normal urine hCG measurement one month after first normalisation. The protocol for CHM remains unchanged. PMID- 29229283 TI - Pediatric bicycle helmet legislation and crash-related traumatic brain injury in Illinois, 1999-2009. AB - BACKGROUND: Bicycling is one of the most popular forms of play and exercise for children in the US. However, over 200,000 children per year are injured in bicycle crashes, and an estimated 22,000 pediatric bicycle-related traumatic brain injuries (TBIs) occur annually. Bicycle helmets are known to decrease the risk of head injury, but efficacy and magnitude of the effect of helmet legislation have not been fully elucidated. METHODS: This was a retrospective, observational study of children aged <18, who presented after a bicycle crash in Illinois from 1999 to 2009. Demographic information, injury types, injury severity, helmet usage, and location of injury data were collected. Multiple logistic regression analysis was used to quantify the independent effects of helmet usage on TBI. Data were compared between communities with and without helmet legislation. RESULTS: A total of 3080 pediatric bicycle-related crashes were identified. Children wearing helmets were less likely to sustain a TBI, odds ratio [OR] = 0.56 (95% confidence interval [CI] 0.37-0.84, P < 0.001). Overall 5.0% of patients were noted as wearing helmets. Black and Hispanic children were less likely to wear helmets, OR = 0.24 (95% CI 0.09-0.68, P < 0.001) and OR = 0.10 (95% CI 0.02-0.42, P < 0.001), respectively. There was no significant change in helmet usage between before and after legislation in helmet legislation areas or over time in non-helmet legislation areas. DISCUSSION: Helmet use was protective against TBI, but socioeconomic and racial disparities exist in usage. Local legislation did not appear to impact helmet usage or admissions for bicycle related TBIs in these areas. PMID- 29229284 TI - Primary care and survival among American Indian patients with diabetes in the Southwest United States: Evaluation of a cohort study at Gallup Indian Medical Center, 2009-2016. AB - OBJECTIVES: To evaluate the role of primary care healthcare delivery on survival for American Indian patients with diabetes in the southwest United States. METHODS: Data from patients with diabetes admitted to Gallup Indian Medical Center between 2009 and 2016 were analyzed using a log-rank test and Cox Proportional Hazards analyses. RESULTS: Of the 2661 patients included in analysis, 286 patients died during the study period. Having visited a primary care provider in the year prior to first admission of the study period was protective against all-cause mortality in unadjusted analysis (HR (95% CI)=0.47 (0.31, 0.73)), and after adjustment. The log-rank test indicated there is a significant difference in overall survival by primary care engagement history prior to admission (p<0.001). The median survival time for patients who had seen a primary care provider was 2322days versus 2158days for those who had not seen a primary care provider. CONCLUSIONS: Compared with those who did not see a primary care provider in the year prior to admission, having seen a primary care provider was associated with improved survival after admission. PMID- 29229285 TI - SVEPM 2017-Recent developments and contemporary foci in veterinary epidemiology and economics, Society of Veterinary Epidemiology and Preventive Medicine conference Inverness, Scotland 29-31 March 2017. PMID- 29229286 TI - Whole length myosin binding protein C stabilizes myosin S2 as measured by gravitational force spectroscopy. AB - The mechanical stability of the myosin subfragment-2 (S2) was tested with simulated force spectroscopy (SFS) and gravitational force spectroscopy (GFS). Experiments examined unzipping S2, since it required less force than stretching parallel to the coiled coil. Both GFS and SFS demonstrated that the force required to destabilize the light meromyosin (LMM) was greater than the force required to destabilize the coiled coil at each of three different locations along S2. GFS data also conveyed that the mechanical stability of the S2 region is independent from its association with the myosin thick filament using cofilaments of myosin tail and a single intact myosin. The C-terminal end of myosin binding protein C (MyBPC) binds to LMM and the N-terminal end can bind either S2 or actin. The force required to destabilize the myosin coiled coil molecule was 3 times greater in the presence of MyBPC than in its absence. Furthermore, the in vitro motility assay with full length slow skeletal MyBPC slowed down the actin filament sliding over myosin thick filaments. This study demonstrates that skeletal MyBPC both enhanced the mechanical stability of the S2 coiled coil and reduced the sliding velocity of actin filaments over polymerized myosin filaments. PMID- 29229287 TI - [Craniometrical study of the species complex of Meriones shawii-grandis (Mammalia: Rodentia) in Morocco, in Algeria and in Tunisia]. AB - In North Africa, the rodents of the species complex Meriones shawii-grandis have a considerable ecological, economic and epidemiological importance. Until now, the systematics of these species was subject to discussion due to the presence of populations displaying high morphological variability. By means of an approach of traditional morphometrics based on cranial distances and by using the method of the log shape-ratio, we attempt to characterize morphologically these two taxa. The results show significant differences in size and shape between the specimens of Morocco, on the one hand, and those of Algeria and Tunisia, on the other hand. The samples of Morocco that have been molecularly typed and attributed to M. grandis have larger tooth rows and narrower skulls, as well as relatively small tympanic bullae. On the other hand, those of Algeria and Tunisia assigned to M. shawii are characterized by small tooth rows and wide skulls with well-developed tympanic bullae. The morphological distance is relatively strong between both clades (79.5%), which corresponds to the molecular distance. However, the discriminant analysis performed after molecularly-typed specimens allows the correct classification of only 91.8% of the individuals. PMID- 29229288 TI - Chronification of low back pain: getting to the spine of the problem. PMID- 29229289 TI - Expression of fibronectin-binding protein of L. acidophilus NCFM and in vitro refolding to adhesion capable native-like protein from inclusion bodies. AB - The ability of Lactobacilli to adhere to host epithelial surface and intestinal tracts is important for colonization and persistence of bacteria in the host gut. Extracellular matrix components like fibronectin, mucin, collagen and other adhesion molecules serve as substratum for attachment of bacteria. However, the precise structure, function and mechanism of binding of microbial surface adhesion proteins such as Fibronectin-binding protein (FBP) with host molecules remains unclear. This is primarily due to limitations in high expression of these proteins in biologically active form. To study adhesion of its FBP (64 kDa), the fbp gene of L. acidophilus NCFM was cloned and expressed in E. coli. However, the fibronectin-binding protein expressed in soluble form could not be purified by Ni NTA affinity chromatography possibly because of partially buried Histidine tag in the recombinant fusion protein. Therefore, the protein was expressed as inclusion bodies (IBs) at 37 degrees C and solubilized in urea followed by purification in denatured form by Ni-NTA affinity chromatography. The purified denatured protein was refolded in vitro to structurally stable and biologically active form. The conformational properties of the refolded protein were studied by circular dichroism, which showed prominence of alpha+ beta structural element. The refolded FBP also showed significant binding to human intestinal tissue sections. Our optimized refolding protocol from IBs of this recombinant probiotic FBP led into high amounts of biologically active protein. Our results help in increasing understanding of structure-function relation of surface adhesion proteins and host-microbial interactions. PMID- 29229291 TI - Primary intraosseous squamous cell carcinoma of the mandible: locoregional control and survival is significantly reduced if the tumour is more than 4cm in size. AB - To establish the prognostic factors for primary intraosseous squamous cell carcinoma we designed a retrospective study of patients treated in the head and neck department of a tertiary referral centre in China from 2010-2015. We collected clinical, radiological, and histopathological data from 36 patients treated during the given time period, among which 34 were followed up. There were 22 male and 12 female patients, 13 of whom gave a history of smoking tobacco and four who drank alcohol. All 34 patients were treated by segmental mandibulectomy and neck dissection. Nine had cervical lymph node metastases on histopathological examination, and none had invaded surgical margins. Twenty-eight were treated with radiotherapy postoperatively. During follow up nine died of locoregional recurrence or metastases. Specific factors such as cervical lymph node metastases were related to a greater likelihood of locoregional recurrence. Patients who drank alcohol were also more likely to develop metastases postoperatively. Tumours more than 4cm in size were significantly associated with reductions in locoregional control and survival. PMID- 29229290 TI - Simple Detection of Telomere Fusions in Pancreatic Cancer, Intraductal Papillary Mucinous Neoplasm, and Pancreatic Cyst Fluid. AB - Telomere end-to-end fusions are an important source of chromosomal instability that arise in cells with critically shortened telomeres. We developed a nested real-time quantitative PCR method for telomere fusion detection in pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and IPMN cyst fluids. Ninety-one pancreatic cancer cell lines and xenograft samples, 93 IPMNs, and 93 surgically aspirated IPMN cyst fluid samples were analyzed. The association between telomere shortening, telomerase activity, and telomere fusion detection was evaluated. Telomere fusions were detected in 56 of 91 pancreatic cancers (61.5%). Telomere fusion-positive cell lines had significantly shorter telomere lengths than fusion-negative lines (P = 0.003). Telomere fusions were undetectable in normal pancreas or IPMNs with low-grade dysplasia (0.0%) and were detected in IPMN with high-grade dysplasia (HGD; 48.0%) (P < 0.001). In IPMN cyst fluids, telomere fusions were more frequent in IPMNs with HGD (26.9%) or associated invasive cancer (42.9%) than IPMN with intermediate-grade dysplasia (15.4%) or low-grade dysplasia (0%) (P = 0.025). Telomerase activity levels were higher in cyst fluids with fusions than in those without (P = 0.0414). Cyst fluid telomere fusion status was an independent predictor of HGD/invasive cancer by multivariate analysis (odds ratio, 6.23; 95% CI, 1.61-28.0). Telomere fusions are detected in later stages of IPMN progression and can serve as a marker for predicting the presence of HGD and/or invasive cancer. PMID- 29229292 TI - Shoe Lifts for Leg Length Discrepancy in Adults With Common Painful Musculoskeletal Conditions: A Systematic Review of the Literature. AB - OBJECTIVE: To determine whether shoe lifts effectively treat leg length discrepancy (LLD)-associated morbidities in adults with common painful musculoskeletal conditions. DATA SOURCES: Trip database, Cochrane Central Register of Controlled Trials database, PubMed database, Physiotherapy Evidence Database, and National Guideline Clearinghouse database. The search was performed in September 2017, was limited to English only, and had no time constraints. STUDY SELECTION: Two reviewers independently determined study eligibility. Inclusion criteria were (1) participants >=18 years old with musculoskeletal related complaints and LLD; (2) a shoe lift intervention was used; and (3) the study reported on pain, function, range of motion, patient satisfaction, quality of life, or adverse events. Randomized controlled trials (RCTs) and controlled intervention, cohort, before-and-after, case series, and case report studies were included. Three-hundred and nineteen articles were screened, and 9 guidelines were reviewed. DATA EXTRACTION: We extracted data pertaining to participant demographic characteristics, study setting, recruitment, randomization, method of LLD measurement, shoe lift characteristics, treatment duration, and outcome measures. We included 10 studies, including 1 RCT. DATA SYNTHESIS: LLD was associated with low back pain, scoliosis, and osteoarthritis of the hip and knee. Description of LLD correction strategy was often inadequate. Study quality was very low or poor. In non-RCT studies reporting on the proportion of participants who improved with a shoe lift, 88%+/-3% of 349 participants treated had partial or complete pain relief (effect size range, 66.7%-100%). All 22 RCT participants receiving treatment experienced pain relief (mean pain reduction, 27+/-9mm on a 150-mm visual analog scale). Two of 9 guidelines recommended shoe lift use based on consensus and were of moderate-to-high quality. CONCLUSIONS: There is low quality evidence that shoe lifts reduce pain and improve function in patients with LLD and common painful musculoskeletal conditions. High-quality research evaluating a threshold LLD to correct and a strategy to do so is necessary. Developing an appropriate comparison group to test clinically relevant outcome measures would make a valuable contribution in this regard. PMID- 29229293 TI - Validation of EN ISO method 15216 - Part 1 - Quantification of hepatitis A virus and norovirus in food matrices. AB - Hepatitis A virus (HAV) and norovirus are important agents of food-borne human viral illness, with common vehicles including bivalve molluscan shellfish, soft fruit and various vegetables. Outbreaks of viral illness due to contamination of the surfaces of foods, or food preparation surfaces by for example infected food handlers are also common. Virus analysis of food matrices can contribute towards risk management for these hazards and a two-part technical specification for determination of Hepatitis A virus and norovirus in food matrices (ISO/TS 15216:2013) was published jointly by the European Committee for Standardisation and the International Organization for Standardization in 2013. As part of the European Mandate No. M381 to validate 15 standards in the field of food microbiology, an international validation study involving 18 laboratories from 11 countries in Europe was conducted between 2012 and 2014. This study aimed to generate method characteristics including limit of detection, limit of quantification, repeatability and reproducibility for ISO 15216 - Part 1, the method for quantification, in seven food matrices. The organization and results of this study, including observations that led to improvements in the standard method are presented here. After its conclusion, the method characteristics generated were added to the revised international standard, ISO 15216-1:2017, published in March 2017. PMID- 29229295 TI - The role of the internist in the patient blood management program. PMID- 29229294 TI - Impact of DHA intake in a mouse model of synucleinopathy. AB - Polyunsaturated fatty acids omega-3 (n-3 PUFA), such as docosahexaenoic acid (DHA), have been shown to prevent, and partially reverse, neurotoxin-induced nigrostriatal denervation in animal models of Parkinson's disease (PD). However, the accumulation of alpha-synuclein (alphaSyn) in cerebral tissues is equally important to the pathophysiology. To determine whether DHA intake improves various aspects related to synucleinopathy, ninety male mice overexpressing human alphaSyn under the Thy-1 promoter (Thy1-alphaSyn) were fed one of three diets (specially formulated control, low n-3 PUFA or high DHA) and compared to non transgenic C57/BL6 littermate mice exposed to a control diet. Thy1-alphaSyn mice displayed impaired motor skills, lower dopaminergic neuronal counts within the substantia nigra (-13%) in parallel to decreased levels of the striatal dopamine transporter (DAT) (-24%), as well as reduced NeuN (-41%) and synaptic proteins PSD-95 (-51%), synaptophysin (-80%) and vesicular acetylcholine transporter (VChAT) (-40%) in the cerebral cortex compared to C57/BL6 mice. However, no significant difference in dopamine concentrations was observed by HPLC analysis between Thy1-alphaSyn and non-transgenic C57/BL6 littermates under the control diet. The most striking finding was a favorable effect of DHA on the survival/longevity of Thy1-alphaSyn mice (+51% survival rate at 12months of age). However, dietary DHA supplementation did not have a significant effect on other parameters examined in this study, despite increased striatal dopamine concentrations. While human alphaSyn monomers and oligomers were detected in the cortex of Thy1-alphaSyn mice, the effects of the diets were limited to a small increase of 42kDa oligomers in insoluble protein fractions upon n-3 PUFA deprivation. Overall, our data indicate that a diet rich in n-3 PUFA has a beneficial effect on the longevity of a murine model of alpha-synucleinopathy without a major impact on the dopamine system and motor impairments, nor alphaSyn levels. PMID- 29229296 TI - Association between melanoma, lymphoma and thyroid cancer. Case report and review of the literature. PMID- 29229297 TI - Prevalence of smoking in pregnancy: Optimization of the diagnosis. PMID- 29229298 TI - Empyema necessitatis 17 years after a pneumonectomy. PMID- 29229299 TI - Diffusion MRI of white matter microstructure development in childhood and adolescence: Methods, challenges and progress. AB - Diffusion magnetic resonance imaging (dMRI) continues to grow in popularity as a useful neuroimaging method to study brain development, and longitudinal studies that track the same individuals over time are emerging. Over the last decade, seminal work using dMRI has provided new insights into the development of brain white matter (WM) microstructure, connections and networks throughout childhood and adolescence. This review provides an introduction to dMRI, both diffusion tensor imaging (DTI) and other dMRI models, as well as common acquisition and analysis approaches. We highlight the difficulties associated with ascribing these imaging measurements and their changes over time to specific underlying cellular and molecular events. We also discuss selected methodological challenges that are of particular relevance for studies of development, including critical choices related to image acquisition, image analysis, quality control assessment, and the within-subject and longitudinal reliability of dMRI measurements. Next, we review the exciting progress in the characterization and understanding of brain development that has resulted from dMRI studies in childhood and adolescence, including brief overviews and discussions of studies focusing on sex and individual differences. Finally, we outline future directions that will be beneficial to the field. PMID- 29229301 TI - Earlier Initiation of Community-Based Palliative Care Is Associated With Fewer Unplanned Hospitalizations and Emergency Department Presentations in the Final Months of Life: A Population-Based Study Among Cancer Decedents. AB - CONTEXT: Although community-based palliative care (CPC) is associated with decreased acute care use in the lead up to death, it is unclear how the timing of CPC initiation affects this association. OBJECTIVES: We aimed to explore the association between timing of CPC initiation and hospital use, over the final one, three, six, and 12 months of life. METHODS: We conducted a retrospective, population-based study in Perth, Western Australia. Linked administrative data including cancer registry, mortality, hospital admissions, emergency department (ED), and CPC records were obtained for cancer decedents from 1 January, 2001 to 31 December, 2011. The exposure was month of CPC initiation; outcomes were unplanned hospitalizations, ED presentations, and associated costs. RESULTS: Of 28,331 decedents residing in the CPC catchment area, 16,439 (58%) accessed CPC, mostly (64%) in the last three months of life. Initiation of CPC before the last six months of life was associated with a lower mean rate of unplanned hospitalizations in the last six months of life (1.4 vs. 1.7 for initiation within six months of death); associated costs were also lower ($(A2012) 12,976 vs. $13,959, comparing the same groups). However, those initiating CPC earlier did show a trend toward longer time in hospital when admitted, compared to those initiating in the final month of life. CONCLUSIONS: When viewed at a population level, these results argue against temporally restricting access to CPC, as earlier initiation may pay dividends in the final few months of life in terms of fewer unplanned hospitalizations and ED presentations. PMID- 29229300 TI - c-MYC G-quadruplex binding by the RNA polymerase I inhibitor BMH-21 and analogues revealed by a combined NMR and biochemical Approach. AB - BACKGROUND: Pyridoquinazolinecarboxamides have been reported as RNA polymerase I inhibitors and represent a novel class of potential antitumor agents. BMH-21, was reported to intercalate with GC-rich rDNA, resulting in nucleolar stress as a primary mechanism of cytotoxicity. METHODS: The interaction of BMH-21 and analogues with DNA G-quadruplex structures was studied by NMR and molecular modelling. The cellular response was investigated in a panel of human tumor cell lines and protein expression was examined by Western Blot analysis. RESULTS AND CONCLUSIONS: We explored the ability of BMH-21 and its analogue 2 to bind to G quadruplex present in the c-MYC promoter, by NMR and molecular modelling studies. We provide evidence that both compounds are not typical DNA intercalators but are effective binders of the tested G-quadruplex. The interaction with c-MYC G quadruplex was reflected in down-regulation of c-Myc expression in human tumor cells. The inhibitory effect was almost complete in lymphoma cells SUDHL4 characterized by overexpression of c-Myc protein. This downregulation reflected an early and persistent modulation of cMyc mRNA. Given the relevance of c-MYC in regulation of ribosome biogenesis, it is conceivable that the inhibition of c-MYC contributes to the perturbation of nuclear functions and RNA polymerase I activity. Similar experiments with CX-5461, another RNA polymerase I transcription inhibitor, indicate the same behaviour in G-quadruplex stabilization. GENERAL SIGNIFICANCE: Our results support the hypothesis that BMH 21 and analogue compounds share the same mechanism, i.e. G-quadruplex binding as a primary event of a cascade leading to inhibition of RNA polymerase I and apoptosis. PMID- 29229302 TI - Doctors' Attitudes to Palliation and Palliative Care in Patients With Advanced Chronic Obstructive Pulmonary Disease. PMID- 29229303 TI - Pretransplant coronary artery disease is a predictor for myocardial infarction and cardiac death after liver transplantation. AB - BACKGROUND: Cardiovascular disease is a serious problem of liver transplant (LT) recipients because of increased cardiovascular risk due to immunosuppressive therapy, higher age, intraoperative risk and comorbidities (such as diabetes and nicotine abuse). Reported frequency of cardiovascular events after LT shows a high variability between different LT cohorts. Our aim was to analyze a cohort of LT recipients from a single center in Germany to evaluate frequency of the cardiovascular endpoints (CVE) myocardial infarction and/or cardiac death after LT and to investigate correlations of CVE post LT with pretransplant patient characteristics. PATIENTS: In total, data from 352 LT patients were analyzed. Patients were identified from an administrative transplant database, and all data were retrieved from patients' charts and reports. RESULTS: During the median follow-up of 4.0 (0-13) years, 10 cases of CVE were documented (six myocardial infarctions and four coronary deaths). The frequency of CVE did not differ according to classic cardiovascular risk factors such as body mass index (p=0.071), total cholesterol (p=0.533), hypertension (p=0.747), smoking (p=1.000) and pretransplant diabetes mellitus (p=0.146). In patients with pretransplant coronary heart disease (n=24; 6.8%) CVE were found more frequently (p=0.024). CONCLUSION: In summary, we found a rate of 2.8% CVE after LT in a German transplant cohort. Pretransplant CHD was the only risk factor for CVE, but showed no significant impact on overall survival. PMID- 29229304 TI - Functional characterization of the G162R and D216H genetic variants of human CYP17A1. AB - Cytochrome P450 17A1 (CYP17A1) is a dual-function enzyme catalyzing reactions necessary for cortisol and androgen biosynthesis. CYP17A1 is a validated drug target for prostate cancer as CYP17A1 inhibition significantly reduces circulating androgens and improves survival in castration-resistant prostate cancer. Germline CYP17A1 genetic variants with altered CYP17A1 activity manifesting as various endocrinopathies are extremely rare; however, characterizing these variants provides critical insights into CYP17A1 protein structure and function. By querying the dbSNP online database and publically available data from the 1000 genomes project (http://browser.1000genomes.org), we identified two CYP17A1 nonsynonymous genetic variants with unknown consequences for enzymatic activity and stability. We hypothesized that the resultant amino acid changes would alter CYP17A1 stability or activity. To test this hypothesis, we utilized a HEK-293T cell-based expression system to characterize the functional consequences of two CYP17A1 variants, D216H (rs200063521) and G162R (rs141821705). Cells transiently expressing the D216H variant demonstrate a selective impairment of 16alpha-hydroxyprogesterone synthesis by 2.1-fold compared to wild-type (WT) CYP17A1, while no effect on 17alpha hydroxyprogesterone synthesis was observed. These data suggest that substrate orientations in the active site might be altered with this amino acid substitution. In contrast, the G162R substitution exhibits decreased CYP17A1 protein stability compared to WT with a near 70% reduction in protein levels as determined by immunoblot analysis. This variant is preferentially ubiquitinated and degraded prematurely, with an enzyme half-life calculated to be ~2.5 h, and proteasome inhibitor treatment recovers G162R protein expression to WT levels. Together, these data provide new insights into CYP17A1 structure-function and stability mechanisms. PMID- 29229305 TI - Expression and shedding of CD44 in the endometrium of women with endometriosis and modulating effects of vitamin D: A randomized exploratory trial. AB - Endometriosis is an estrogen-dependent disease. The impaired estrogen and progesterone signaling over-activates the Wnt/beta-catenin pathway in endometriosis patients, which can explain the increased invasion potency of endometrial cells derived from the endometrium of women with endometriosis. The regulatory effects of vitamin D on Wnt/beta-catenin pathway were demonstrated by previous studies. According to gene prioritization method, among Wnt target genes, CD44 was in high ranking in relation to endometriosis. The aim of this study is to investigate the expression of CD44 in the endometrium of women with endometriosis and to study the effects of vitamin D on its expression. This prospective study was performed, during a 12 months period from December 2015 to November 2016, on healthy women as the control group (n = 14) and endometriosis patients (n = 34). The endometriosis patients randomly divided into two groups: One group treated according to the routine protocol and the other group, alongside the routine protocol, took 50,000 IU vitamin D weekly for 12-14 weeks. Blood, endometrial fluid, and endometrial tissue samples were obtained from the control group and endometriosis groups before and after the intervention. We used in silico gene prioritization to study the relevance of CD44. The expression of CD44 was evaluated using the techniques of Western blot, real-time polymerase chain reaction, and ELISA. The eutopic endometrium of women with endometriosis in mid-secretory phase expressed significantly higher levels of CD44s, CD44V, and CD44v6. The concentration of soluble CD44 in the serum and endometrial fluid of endometriosis patients was higher than of healthy women. The expression level of CD44s, CD44V, and CD44v6 in the eutopic endometrium as well as the concentration of soluble CD44 in the endometrial fluid was decreased after modification of the circulating levels of 25(OH)D. It seems that the increased expression and extensive shedding of CD44 in eutopic endometrium play a role in the pathogenesis of endometriosis. Vitamin D can control and modify this process at least in part. We suggest more in vivo investigations on the therapeutic potency of vitamin D in endometriosis. PMID- 29229307 TI - Localizing implanted fiducial markers using undersampled co-RASOR MR imaging. AB - The goal of this work was to use an undersampled, dual-plane centre-out radial sampling acquisition pulse sequence, with off-resonance reception, to localize fiducial markers with reduced acquisition time. Two iterative reconstruction techniques, conjugate gradient CG-SENSE and the variational penalty Total Generalized Variation (TGV), were investigated to minimize the undersampling artifacts in off-resonant radial imaging. Simulations of a field perturber were performed at sub-millimeter resolution and reconstructed to display signal pileups that can be radially compressed towards the geometric centre of the perturber for high contrast visualization, but contrast is non-recoverable as the echo time increases. A cylindrical platinum fiducial marker, placed in a phantom parallel and perpendicular to the B0-field was imaged with a short-TE half-echo readout. Contrast-to-Noise (CNR) between the signal of the fiducial its adjacent surrounding shell and half-maximum area were used to compare reconstruction methods and undersampling factors. For single slice acquisitions centred about the fiducial, each slice can be performed in as little as 2.8s. The total acquisition time to localize the fiducial marker in a phantom was reduced to 73s by undersampling (R=8) 37 axial and 15 coronal slices, effectively encoding 1.4s/slice. The noise present in undersampled images, for both scan planes and fiducial orientations, decreased significantly using TGV and CG-SENSE reconstructions, with TGV displaying better spatial resolution from reduced half maximum area. PMID- 29229306 TI - Pseudo continuous arterial spin labeling quantification in anemic subjects with hyperemic cerebral blood flow. AB - PURPOSE: To investigate possible sources of quantification errors in global cerebral blood flow (CBF) measurements by comparing pseudo continuous arterial spin labeling (PCASL) and phase contrast (PC) MRI in anemic, hyperemic subjects. METHODS: All studies were performed on a Philips 3T Achieva MRI scanner. PC and PCASL CBF examinations were performed in 10 healthy, young adult subjects and 18 young adults with chronic anemia syndromes including sickle cell disease and thalassemia. CBF estimates from single and two compartment ASL kinetic models were compared. Numerical simulation and flow phantom experiments were used to explore the effects of blood velocity and B1+ on CBF quantification and labeling efficiency. RESULTS: PCASL CBF underestimated PC in both populations using a single compartment model (30.1+/-9.2% control, 45.2+/-17.2% anemia). Agreement substantially improved using a two-compartment model (-8.0+/-6.0% control, 11.7+/ 12.3% anemia). Four of the anemic subjects exhibited venous outflow of ASL signal, suggestive of cerebrovascular shunt, possibly confounding PC-PCASL comparisons. Additionally, sub-study experiments demonstrated that B1+ was diminished at the labeling plane (82.9+/-5.1%), resulting in suboptimal labeling efficiency. Correcting labeling efficiency for diminished B1+, PCASL slightly overestimated PC CBF in controls (-15.4+/-6.8%) and resulted in better matching of CBF estimates in anemic subjects (0.7+/-10.0% without outflow, 10.5+/-9.4% with outflow). CONCLUSIONS: This work demonstrates that a two-compartment model is critical for PCASL quantification in hyperemic subjects. Venous outflow and B1+ under-excitation may also contribute to flow underestimation, but further study of these effects is required. PMID- 29229309 TI - Interaction of margin status and tumour burden determines survival after resection of colorectal liver metastases: A retrospective cohort study. AB - PURPOSE: We sought to determine the impact of surgical margin status on overall survival (OS) and recurrence pattern stratified by tumor burden. MATERIALS AND METHODS: Data were collected from patients undergoing resection for colorectal liver metastases (CRLM). Tumor burden was calculated according to a newly proposed Tumor Burden Score (TBS) system, defined as the distance from the origin on a Cartesian plane that incorporated maximum tumor size and number of liver lesions. Patients were divided into low tumor burden group and high tumor burden group accordingly, and the impact of resection margin on overall survival was examined. RESULTS: A total of 286 patients were available, among which R1 resection was observed in 88 patients. The median TBS for the entire cohort was 3.84. Metastases in the R1 group were characterized by more advanced disease and more complex resections. Compared with a R0 resection, a R1 resection offered an lower 5-year overall survival rate (46.8% vs. 22.1%, p = 0.001). Multivariate analysis identified R1 resection (p = 0.03), high TBS (p = 0.002), lymph nodes metastases (p = 0.003) and lymphovascular invasion (p = 0.03) of the primary colorectal tumor as the factors independently associated with worse survival. The survival benefit associated with negative margins was greater in patients with low TBS (55.7% vs. 21.7%, p = 0.021) than in patients with high TBS (31.8% vs. 24.5%, p = 0.116). R1 resection was associated with an increased true margin recurrence rate in patients with low TBS (32.3% vs. 13.4%; p = 0.014) and an increased risk of new intrahepatic metastases in patients with high TBS (43.9% vs. 26.7%; p = 0.034). CONCLUSIONS: Negative margin is an important determinant of survival. The impact of positive margins is more pronounced in patients with low tumor burden. PMID- 29229308 TI - Lymphocyte-Dominant Encephalitis and Meningitis in Simian Immunodeficiency Virus Infected Macaques Receiving Antiretroviral Therapy. AB - A retrospective neuropathologic review of 30 SIV-infected pigtailed macaques receiving combination antiretroviral therapy (cART) was conducted. Seventeen animals with lymphocyte-dominant inflammation in the brain and/or meninges that clearly was morphologically distinct from prototypic SIV encephalitis and human immunodeficiency virus encephalitis were identified. Central nervous system (CNS) infiltrates in cART-treated macaques primarily comprised CD20+ B cells and CD3+ T cells with fewer CD68+ macrophages. Inflammation was associated with low levels of SIV RNA in the brain as shown by in situ hybridization, and generally was observed in animals with episodes of cerebrospinal fluid (CSF) viral rebound or sustained plasma and CSF viremia during treatment. Although the lymphocytic CNS inflammation in these macaques shared morphologic characteristics with uncommon immune-mediated neurologic disorders reported in treated HIV patients, including CNS immune reconstitution inflammatory syndrome and neurosymptomatic CSF escape, the high prevalence of CNS lesions in macaques suggests that persistent adaptive immune responses in the CNS also may develop in neuroasymptomatic or mildly impaired HIV patients yet remain unrecognized given the lack of access to CNS tissue for histopathologic evaluation. Continued investigation into the mechanisms and outcomes of CNS inflammation in cART-treated, SIV-infected macaques will advance our understanding of the consequences of residual CNS HIV replication in patients on cART, including the possible contribution of adaptive immune responses to HIV-associated neurocognitive disorders. PMID- 29229310 TI - Tumor volume predicts local recurrence in early rectal cancer treated with radical resection: A retrospective observational study of 270 patients. AB - OBJECTIVE: Radical resection is regarded as the primary treatment for early rectal cancer, and tumor volume is an independent predictor of many other types of cancer. The purpose of the present study is to assess the effect of tumor volume on the survival of patients with early rectal cancer treated with radical surgery. METHODS: A total of 270 patients with histologically confirmed stage T1/2 N0 rectal cancer who underwent radical resection between September 2006 and September 2014 were enrolled in this study. The tumor volume was measured based on the preoperative pelvic MRI. The clinical significance of tumor volume with respect to patients' outcomes was evaluated, and the multivariate Cox proportional regression model was used to analyse the risk factors for survival of these patients. RESULTS: The median follow-up period was 57.6 months. The tumor volume was significantly correlated with preoperative Hb, CEA level and number of retrieved lymph nodes (all p < 0.05). The large tumor group had a lower disease-free survival (DFS) rate than the small tumor group (5-year DFS rate: 80.4% vs 89.6%, p = 0.042), whereas there was no difference in the overall survival rate. The 5-year local recurrence rates for patients in the large and small tumor groups were 10.5% and 3.0%, respectively (p = 0.030). Additionally, the tumor volume was an independent clinical predictor for both DFS and local recurrence-free survival (LRFS). CONCLUSION: In conclusion, the tumor volume is significantly associated with DFS and LRFS of patients with stage T1/2 N0 rectal cancer who underwent radical resection alone. Tumor volume may be considered an important indicator for neoadjuvant or adjuvant therapeutic interventions. PMID- 29229311 TI - An extra priming dose of hepatitis A vaccine to adult patients with rheumatoid arthritis and drug induced immunosuppression - A prospective, open-label, multi center study. AB - BACKGROUND: Previous studies have indicated that a pre-travel single dose of hepatitis A vaccine is not sufficient as protection against hepatitis A in immunocompromised travelers. We evaluated if an extra dose of hepatitis A vaccine given shortly prior to traveling ensures seroconversion. METHOD: Patients with rheumatoid arthritis (n = 69, median age = 55 years) treated with Tumor Necrosis Factor inhibitor(TNFi) and/or Methotrexate (MTX) were immunized with two doses of hepatitis A vaccine, either as double dose or four weeks apart, followed by a booster dose at six months. Furthermore, 48 healthy individuals, median age = 60 years were immunized with two doses, six months apart. Anti-hepatitis A antibodies were measured at 0, 1, 2, 6, 7 and 12 months. RESULTS: Two months after the initial vaccination, 84% of the RA patients had protective antibodies, compared to 85% of the healthy individuals. There was no significant difference between the two vaccine schedules. At twelve months, 99% of RA patients and 100% of healthy individuals had seroprotective antibodies. CONCLUSION: An extra priming dos of hepatitis A vaccine prior to traveling offered an acceptable protection in individuals treated with TNFi and/or MTX. This constitutes an attractive pre-travel solution to this vulnerable group of patients. PMID- 29229312 TI - [Anemia of chronic kidney disease: Protocol of study, management and referral to Nephrology]. AB - The objective of this protocol is to know which test are needed to study an anaemia in a patient with chronic kidney disease, the differential diagnosis of renal anaemia, to know and correct other deficiency anaemias, and the criteria for referral to Nephrology or other specialties of the anaemic patient with chronic kidney disease. PMID- 29229313 TI - Emerging Role of Adipocytokines in Type 2 Diabetes as Mediators of Insulin Resistance and Cardiovascular Disease. AB - Adipose tissue is an enormously active endocrine organ, secreting various hormones, such as adiponectin, leptin, resistin and visfatin, together with classical cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). All these adipocytokines play significant roles in the regulation of energy metabolism, glucose and lipid metabolism, reproduction, cardiovascular function and immunity. Adipocytokines are significantly regulated by nutritional status and can directly influence other organ systems, including brain, liver and skeletal muscle. Adiponectin plays a key role as an anti inflammatory hormone. Upregulated expression of resistin, vaspin, apelin and TNF alpha plays a significant role in induction of insulin resistance linked with obesity and type 2 diabetes. Ghrelin, the circulating peptide, has been found to stimulate appetite and regulate energy balance. Thus, it can be considered 1 of the candidate genes for obesity and type 2 diabetes. Omentin is a novel adipokine produced by visceral adipose tissue. Circulating levels of omentin are decreased in insulin-resistant states, for example, in obesity and diabetes. IL-6 plays a vital role in regulating the accumulation of lipids intramyocardially. Based on the biologic relevance of these adipocytokines, they can no longer be considered as energy storage sites alone but must also be considered in metabolic control. Hence, the present review summarizes the regulatory roles of adipocytokines in diabetes linked with obesity. PMID- 29229314 TI - An atypical odontogenic myxoma. AB - INTRODUCTION: Odontogenic myxoma is an uncommon tumor of the jaws, benign but locally invasive. It arises from the mesenchymal portion of the tooth germ. It has a variable non-specific clinical and radiological appearance, and may be confused with other lesions of the jaws. CASE REPORT: A patient aged 50 presented for a periodontal treatment. After routine retroalveolar X-rays, we noted a small limited radiolucency between the left mandibular canine and the left mandibular first premolar. There were no clinical symptoms. Histology after enucleation of the lesion revealed the diagnosis of odontogenic myxoma. DISCUSSION: Odontogenic myxoma is a relatively rare benign neoplasia. It is locally aggressive, inducing important facial deformation and tooth displacement. The lesion often grows without symptoms and presents as a painless swelling. The radiographic features are variable, it appears as a unilocular or multilocular radiolucency, and the diagnosis is therefore not easy. The case reported is an atypical presentation of odontogenic myxoma because of the small size of the lesion, the radiographic features, and the early detection and management. PMID- 29229315 TI - Discussion. PMID- 29229316 TI - Risk-adjusted hospital outcomes in elective carotid artery surgery in patients with Medicare. AB - BACKGROUND: The risk-adjusted outcomes by hospital of elective carotid endarterectomy that is inclusive of inpatient and 90-day postdischarge adverse outcomes have not been studied. METHODS: We studied Medicare inpatients to identify hospitals with 25 or more qualifying carotid endarterectomy cases between 2012-2014. Risk-adjusted prediction models were designed for adverse outcomes of inpatient deaths, 3-sigma prolonged duration-of-stay outliers, 90-day postdischarge deaths without readmission, and 90-day postdischarge associated readmissions. Standard deviations of predicted overall adverse outcomes were computed for each hospital. Hospital-specific z scores and risk-adjusted adverse outcomes were calculated. RESULTS: There were 77,086 carotid endarterectomy patients from 960 hospitals complicated by 191 inpatient deaths (0.25%), 4,436 prolonged duration of stay (5.8%), 457 90-day postdischarge deaths (0.6%), and 7,956 90-day postdischarge associated readmissions (10.3%). In the 90-day postdischarge associated readmission patients, an additional 561 patients died after readmission, for total deaths of 1,209 (1.6%) for the study period, and 11,928 (15.5%) patients had one or more adverse outcomes. There were 29 best performing hospitals (3.0%) with z scores of -2.0 or less (P < .05) with a median rate of risk-adjusted adverse outcomes of 7.1%. A total of 61 suboptimal performers (6.3%) had z scores of +2.0 or greater (P < .05) with a median rate of risk-adjusted adverse outcome rate of 26.4%. CONCLUSION: Hospital risk-adjusted adverse outcome rates for carotid endarterectomy are highly variable. Comparisons of hospital performance define the opportunity for improvement. PMID- 29229317 TI - Team-based simulations for new surgeons: Does early and often make a difference? AB - BACKGROUND: Current work hour restrictions and the expansion of requirements for surgery residents has led to decreased time on high-acuity rotations such as trauma and acute care surgery. In an effort to improve resident competency, we examined the efficacy of a new team-based trauma curriculum for postgraduate year 1 (PGY1) residents. METHODS: After completing required Advanced Trauma Life Support certification, PGY1s participated in a series of trauma simulations in 3 person teams from June to August. Scenarios were created to develop skills related to trauma management, teamwork, and communication. Each simulation was followed by video-based debriefing with a faculty facilitator. Clinical performance on a 1-month trauma rotation during the year was assessed by trauma faculty using a 24-item evaluation assessing management of acutely ill patients, leadership, communication, cooperation, and professionalism on a 1 (poor) to 5 (very effective) scale. Performance metrics of this intern class were compared with 2 years of previous cohorts who had not participated in any trauma-focused simulation curricula. One-way analysis of variance was used to examine differences in performance ratings across groups. RESULTS: The 2015 intern class (n = 30) each participated in 6 scenarios during their first 2 months in residency. Trauma as intended specialty and performance on preinternship Advanced Trauma Life Support course were similar across 2013, 2014, and 2015 cohorts. Average performance on the trauma rotation was 3.55 +/- 0.56 for the 2013 cohort (n = 11), 3.50 +/- 0.57 for the 2014 cohort (n = 11), and 4.35 +/- 0.68 for the 2015 cohort (n = 12). Post hoc analyses indicated no difference between means of the 2013 and 2014 cohort. However, the mean of the 2015 cohort was statistically significantly better than both the 2013 cohort (P < .01) and the 2014 cohort (P < .01). CONCLUSION: Trauma-focused simulation improved PGY1 faculty ratings of performance in the clinical setting compared with previous cohorts with no such simulation experience. Adoption of these curricula is both feasible and beneficial. PMID- 29229318 TI - Low dose chemotherapy combined with attenuated Salmonella decreases tumor burden and is less toxic than high dose chemotherapy in an autochthonous murine model of breast cancer. AB - BACKGROUND: Immunotherapies for cancer treatment have demonstrated substantial promise even though toxicities and development of tumor resistance limit their effectiveness. A combinatorial approach using immunotherapy with other treatment modalities may decrease side effects while maintaining maximal therapeutic effect. We aimed to determine if bacterial immunotherapy in combination with a chemotherapeutic would be efficacious and less toxic than conventional chemotherapy in an established, preclinical, autochthonous tumor model. METHODS: BALB-neuT mice develop autochthonous mammary neoplasms that resemble closely the aggressive Her2-driven cancer found in human patients. Virulence-attenuated S. Typhimurium was used for bacterial immunotherapy. Doxorubicin was the chemotherapeutic agent used at the maximum tolerated dose (5 mg/kg) and low dose (1.25 mg/kg). S. Typhimurium was administered intravenously on day 0 and doxorubicin on days 0, 7, and 14. Experiments concluded on day 35. Mammary pad tumors were measured weekly to ascertain efficacy, and mice were weighed weekly to evaluate toxicity. RESULTS: Mice administered maximum tolerated dose doxorubicin (5 mg/kg) demonstrated a 1.4-fold increase in tumor size by day 35 and showed a nearly 25% weight loss by day 14 revealing severe toxicity. When mice were administered a single dose of S. Typhimurium combined with a low dose of doxorubicin (1.25 mg/kg), tumors increased <3-fold by day 35, and mice showed only 5% weight loss, indicating no clinically relevant toxicity. CONCLUSION: Bacterial immunotherapy combined with low dose chemotherapy decreased the tumor burden when compared with low dose chemotherapy alone and was less toxic than maximum tolerated dose chemotherapy in an established, autochthonous murine model of breast cancer. PMID- 29229319 TI - Discussion. PMID- 29229320 TI - Vaccine-mismatched influenza B/Yamagata lineage viruses in Cuba, 2012-2013 season. AB - Annual trivalent influenza vaccines contain one of influenza B lineages; influenza B/Victoria-lineage or influenza B/Yamagata viruses. Theoretically, these vaccines should protect against viruses expected to circulate in the next influenza season. The National Influenza Centers, based on surveillance data from National Reference Laboratories, selects the strains composing each annual trivalent or tetravalent vaccine. Nevertheless, in some epidemics, vaccine strains do not match genetically with circulating strains. The aim of the present study is to compare the HA1-domain of 42 influenza B viruses circulating in Cuba during the 2012-2013 season with the vaccine strain B/Wisconsin/01/2010-like virus from the B/Yamagata lineage, included in the 2012-2013 Northern-Hemisphere Influenza vaccine. The efficacy of the influenza vaccine was also estimated. The analysis of the present study indicates that the B/Victoria and B/Yamagata lineages co-circulated in Cuba in the 2012-2013 season. In 2012-2013 season, according to the sequences analysis, trivalent vaccine did not match with the circulating strains. The present study also detected amino acid substitutions which could have altered the antigenic properties of HA gene. The results presented here suggest the need to consider a possible introduction of tetravalent influenza vaccine in Cuba, as has been recommended by the WHO to ensure higher levels of protection. PMID- 29229321 TI - The role of aspirin, heparin, and other interventions in the prevention and treatment of fetal growth restriction. AB - Fetal growth restriction and related placental pathologies such as preeclampsia, stillbirth, and placental abruption are believed to arise in early pregnancy when inadequate remodeling of the maternal spiral arteries leads to persistent high resistance and low-flow uteroplacental circulation. The consequent placental ischaemia, reperfusion injury, and oxidative stress are associated with an imbalance in angiogenic/antiangiogenic factors. Many interventions have centered on the prevention and/or treatment of preeclampsia with results pertaining to fetal growth restriction and small-for-gestational-age pregnancy often included as secondary outcomes because of the common pathophysiology. This renders the study findings less reliable for determining clinical significance. For the prevention of fetal growth restriction, a recent large-study level meta-analysis and individual patient data meta-analysis confirm that aspirin modestly reduces small-for-gestational-age pregnancy in women at high risk (relative risk, 0.90, 95% confidence interval, 0.81-1.00) and that a dose of >=100 mg should be recommended and to start at or before 16 weeks of gestation. These findings support national clinical practice guidelines. In vitro and in vivo studies suggest that low-molecular-weight heparin may prevent fetal growth restriction; however, evidence from randomized control trials is inconsistent. A meta-analysis of multicenter trial data does not demonstrate any positive preventative effect of low-molecular-weight heparin on a primary composite outcome of placenta mediated complications including fetal growth restriction (18% vs 18%; absolute risk difference, 0.6%; 95% confidence interval, 10.4-9.2); use of low-molecular weight heparin for the prevention of fetal growth restriction should remain in the research setting. There are even fewer treatment options once fetal growth restriction is diagnosed. At present the only management option if the risk of hypoxia, acidosis, and intrauterine death is high is iatrogenic preterm birth, with the use of peripartum maternal administration of magnesium sulphate for neuroprotection and corticosteroids for fetal lung maturity, to prevent adverse neonatal outcomes. The pipeline of potential therapies use different strategies, many aiming to increase fetal growth by improving poor placentation and uterine blood flow. Phosphodiesterase type 5 inhibitors that potentiate nitric oxide availability such as sildenafil citrate have been extensively researched both in preclinical and clinical studies; results from the Sildenafil Therapy In Dismal Prognosis Early-Onset Intrauterine Growth Restriction consortium of randomized control clinical trials are keenly awaited. Targeting the uteroplacental circulation with novel therapeutics is another approach, the most advanced being maternal vascular endothelial growth factor gene therapy, which is being translated into the clinic via the doEs Vascular endothelial growth factor gene therapy safEly impRove outcome in seveRe Early-onset fetal growth reSTriction consortium. Other targeting approaches include nanoparticles and microRNAs to deliver drugs locally to the uterine arterial endothelium or trophoblast. In vitro and in vivo studies and animal models have demonstrated effects of nitric oxide donors, dietary nitrate, hydrogen sulphide donors, statins, and proton pump inhibitors on maternal blood pressure, uteroplacental resistance indices, and angiogenic/antiangiogenic factors. Data from human pregnancies and, in particular, pregnancies with fetal growth restriction remain very limited. Early research into melatonin, creatine, and N-acetyl cysteine supplementation in pregnancy suggests they may have potential as neuro- and cardioprotective agents in fetal growth restriction. PMID- 29229322 TI - [Study of correlation between radiological aspect of pulmonary hydatid cyst and postoperative course]. AB - : Pulmonary Hydatid Cyst (PHC) may represent a real therapeutic challenge. Surgery remains the treatment of choice and postoperative course may be complicated in some cases. Several factors can be involved like the cyst's size and location. We aimed to study the existence of correlation between the radiological aspect of the PHC and the postoperative course through a retrospective study including 267 patients. Different radiological aspect of PHC found on the X-ray and/or computed tomography of the chest were classified according to Zidi et al. CLASSIFICATION: Analytical study showed that there is minor chance to have complications with simple cyst (P<0.05 and OR<1), while type VI cyst were more likely to cause complications (P=0.007 and OR=2.6). Considering these results, more attention should be paid to type VI of PHC to prevent postoperative complications. A multicentric study will be more precise to study correlation between different characteristics of the PHC and postoperative course. PMID- 29229323 TI - MRI-based Assessment of 3D Intrafractional Motion of Head and Neck Cancer for Radiation Therapy. AB - PURPOSE: To determine the 3-dimensional (3D) intrafractional motion of head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS: Dynamic contrast enhanced magnetic resonance images from 56 patients with HNSCC in the treatment position were analyzed. Dynamic contrast-enhanced magnetic resonance imaging consisted of 3D images acquired every 2.9 seconds for 4 minutes 50 seconds. Intrafractional tumor motion was studied in the 3 minutes 43 seconds of images obtained after initial contrast enhancement. To assess tumor motion, rigid registration (translations only) was performed using a region of interest (ROI) mask around the tumor. The results were compared with bulk body motion from registration to all voxels. Motion was split into systematic motion and random motion. Correlations between the tumor site and random motion were tested. The within-subject coefficient of variation was determined from 8 patients with repeated baseline measures. Random motion was also assessed at the end of the first week (38 patients) and second week (25 patients) of radiation therapy to investigate trends of motion. RESULTS: Tumors showed irregular occasional rapid motion (eg, swallowing or coughing), periodic intermediate motion (respiration), and slower systematic drifts throughout treatment. For 95% of the patients, displacements due to systematic and random motion were <1.4 mm and <2.1 mm, respectively, 95% of the time. The motion without an ROI mask was significantly (P<.0001, Wilcoxon signed rank test) less than the motion with an ROI mask, indicating that tumors can move independently from the bony anatomy. Tumor motion was significantly (P=.005, Mann-Whitney U test) larger in the hypopharynx and larynx than in the oropharynx. The within-subject coefficient of variation for random motion was 0.33. The average random tumor motion did not increase notably during the first 2 weeks of treatment. CONCLUSIONS: The 3D intrafractional tumor motion of HNSCC is small, with systematic motion <1.4 mm and random motion <2.1 mm 95% of the time. PMID- 29229324 TI - Comparison of 36 Gy, 20 Gy, or No Radiation Therapy After 6 Cycles of EBVP Chemotherapy and Complete Remission in Early-Stage Hodgkin Lymphoma Without Risk Factors: Results of the EORT-GELA H9-F Intergroup Randomized Trial. AB - PURPOSE: While patients with early-stage Hodgkin lymphoma (HL) have an excellent outcome with combined treatment, the radiation therapy (RT) dose and treatment with chemotherapy alone remain questionable. This noninferiority trial evaluates the feasibility of reducing the dose or omitting RT after chemotherapy. METHODS AND MATERIALS: Patients with untreated supradiaphragmatic HL without risk factors (age >= 50 years, 4 to 5 nodal areas involved, mediastinum-thoracic ratio >= 0.35, and erythrocyte sedimentation rate >= 50 mm in first hour without B symptoms or erythrocyte sedimentation rate >= 30 mm in first hour with B symptoms) were eligible for the trial. Patients in complete remission after chemotherapy were randomized to no RT, low-dose RT (20 Gy in 10 fractions), or standard-dose involved-field RT (36 Gy in 18 fractions). The limit of noninferiority was 10% for the difference between 5-year relapse-free survival (RFS) estimates. From September 1998 to May 2004, 783 patients received 6 cycles of epirubicin, bleomycin, vinblastine, and prednisone; 592 achieved complete remission or unconfirmed complete remission, of whom 578 were randomized to receive 36 Gy (n=239), 20 Gy of involved-field RT (n=209), or no RT (n=130). RESULTS: Randomization to the no-RT arm was prematurely stopped (>=20% rate of inacceptable events: toxicity, treatment modification, early relapse, or death). Results in the 20-Gy arm (5-year RFS, 84.2%) were not inferior to those in the 36 Gy arm (5-year RFS, 88.6%) (difference, 4.4%; 90% confidence interval [CI] -1.2% to 9.9%). A difference of 16.5% (90% CI 8.0%-25.0%) in 5-year RFS estimates was observed between the no-RT arm (69.8%) and the 36-Gy arm (86.3%); the hazard ratio was 2.55 (95% CI 1.44-4.53; P<.001). The 5-year overall survival estimates ranged from 97% to 99%. CONCLUSIONS: In adult patients with early-stage HL without risk factors in complete remission after epirubicin, bleomycin, vinblastine, and prednisone chemotherapy, the RT dose may be limited to 20 Gy without compromising disease control. Omitting RT in these patients may jeopardize the treatment outcome. PMID- 29229325 TI - Prospective Phase 2 Trial of Permanent Seed Implantation Prostate Brachytherapy for Intermediate-Risk Localized Prostate Cancer: Efficacy, Toxicity, and Quality of Life Outcomes. AB - PURPOSE: To report the efficacy, physician-reported toxicity, and patient reported outcomes of men with intermediate-risk prostate cancer after brachytherapy in a prospective phase 2 trial. METHODS AND MATERIALS: This prospective phase 2 trial involved 300 patients with previously untreated prostate cancer treated from 2006 through 2013. Eligible patients had <=cT2b (T3 excluded according to magnetic resonance imaging), Gleason score (GS) 6 with prostate-specific antigen (PSA) level 10-15 ng/mL, or GS 7 with PSA <10 ng/mL, and were treated with prostate brachytherapy (without hormonal therapy). RESULTS: Median patient age was 64.9 years; 3.7% had GS 6, 78.7% had GS 7 (3+4), and 17.7% had GS 7 (4+3). Median follow-up time was 5.1 years. Median PSA at 5 years was 0.01 ng/mL (range, 0-6.0 ng/mL). Ten biochemical failures occurred, for a 5-year freedom from biochemical failure rate of 97.3% (95% confidence interval [CI], 95.1-99.5), and 16 patients died, only 1 from prostate cancer, for 5-year rates of overall and biochemical progression-free survival of 94.9% (95% CI, 92.1-97.9) and 92.7% (95% CI, 89.3-96.2%). Four patients had late grade 3 genitourinary toxicity, and 2 patients had late grade 3 rectal toxicity; no grade 4 or 5 toxicity was observed. Rates of "moderate or big problems" at 4 years were 7.4% for urinary (vs 0.4% at baseline), 2.9% bowel (vs 0.4%), and 29.7% sexual function (vs 19.7%). Most men were "satisfied or extremely satisfied" (91% at 2 years after treatment and 93% at 4 years). CONCLUSIONS: Brachytherapy monotherapy is safe and effective and leads to good quality of life for some men with localized intermediate-risk prostate cancer. PMID- 29229326 TI - Quantifying the Effect of 3T Magnetic Resonance Imaging Residual System Distortions and Patient-Induced Susceptibility Distortions on Radiation Therapy Treatment Planning for Prostate Cancer. AB - PURPOSE: To investigate the effect of magnetic resonance system- and patient induced susceptibility distortions from a 3T scanner on dose distributions for prostate cancers. METHODS AND MATERIALS: Combined displacement fields from the residual system and patient-induced susceptibility distortions were used to distort 17 prostate patient CT images. VMAT dose plans were initially optimized on distorted CT images and the plan parameters transferred to the original patient CT images to calculate a new dose distribution. RESULTS: Maximum residual mean distortions of 3.19 mm at a radial distance of 25 cm and maximum mean patient-induced susceptibility shifts of 5.8 mm were found using the lowest bandwidth of 122 Hz per pixel. There was a dose difference of <0.5% between distorted and undistorted treatment plans. The 90% confidence intervals of the mean difference between the dCT and CT treatment plans were all within an equivalence interval of (-0.5, 0.5) for all investigated plan quality measures. CONCLUSIONS: Patient-induced susceptibility distortions at high field strengths in closed bore magnetic resonance scanners are larger than residual system distortions after using vendor-supplied 3-dimensional correction for the delineated regions studied. However, errors in dose due to disturbed patient outline and shifts caused by patient-induced susceptibility effects are below 0.5%. PMID- 29229327 TI - Dose Escalation Using Contact X-ray Brachytherapy After External Beam Radiotherapy as Nonsurgical Treatment Option for Rectal Cancer: Outcomes From a Single-Center Experience. AB - PURPOSE: To review the outcomes of rectal cancer patients treated with a nonsurgical approach using contact x-ray brachytherapy (CXB) when suspicious residual disease (<=3 cm) was present after external beam chemoradiation therapy/radiation therapy (EBCRT/EBRT). METHODS AND MATERIALS: Outcome data for rectal cancer patients referred to our institution from 2003 to 2012 were retrieved from an institutional database. These patients were referred after initial local multidisciplinary team discussion because they were not suitable for, or had refused, surgery. All selected patients received a CXB boost after EBCRT/EBRT. Most patients received a total of 90 Gy of CXB delivered in 3 fractions over 4 weeks. RESULTS: The median follow-up period was 2.5 years (range 1.2-8.3). Of 345 consecutive patients with rectal cancer referred to us, 83 with suspicious residual disease (<=3 cm) after EBCRT/EBRT were identified for a CXB boost. Their median age was 72 years (range 36-87), and 58 (69.9%) were men. The initial tumor stages were cT2 (n = 28) and cT3 (n = 55), and 54.2% were node positive. A clinical complete response (cCR) was achieved in 53 patients (63.8%) after the CXB boost that followed EBCRT/EBRT. Of these 53 patients, 7 (13.2%) developed a relapse after achieving a cCR, and the 6 patients (11.6%) with nonmetastatic regrowth underwent salvage surgery (100%). At the end of the study period, 69 of 83 patients (83.1%) were cancer free. CONCLUSIONS: Our data suggest that a CXB boost for selected patients with suspicious residual disease (<=3 cm) after EBCRT/EBRT can be offered as an alternative to radical surgery. In our series, patients with a sustained cCR had a low rate of local regrowth, and those with nonmetastatic regrowth could be salvaged successfully. This approach could provide an alternative treatment option for elderly or comorbid patients who are not suitable for surgery and those with rectal cancer who wish to avoid surgery. PMID- 29229328 TI - Outcomes After Reirradiation for Recurrent Pediatric Intracranial Ependymoma. AB - PURPOSE: To determine the long-term outcomes and the optimal dose and volume for reirradiation of recurrent pediatric ependymoma. METHODS AND MATERIALS: Patients with recurrent ependymoma treated with a second course of fractionated radiation therapy (RT2) were reviewed retrospectively. Eligible patients had localized, intracranial ependymoma at initial diagnosis that was treated with focal radiation (RT1) without craniospinal irradiation (CSI) and were aged <=21 years at the time of RT2. The median doses of RT1, focal RT2, and CSI-RT2 were 59.4, 54, and 39.6 Gy, respectively. The primary endpoint, overall survival (OS), was measured from the first day of RT2. RESULTS: We included 101 patients in the study. The median interval between RT1 and RT2 was 26.8 months (interquartile range, 18.0-43.1). The median durations of OS and freedom from progression (FFP) were 75.1 and 27.3 months, respectively. Male sex and anaplastic histology at recurrence were associated with decreased OS and FFP on multivariate analysis. Distant-only failure treated with CSI-RT2 was independently associated with improved OS compared with individuals with local failure treated with focal RT2 (hazard ratio 0.37; 95% confidence interval 0.16-0.87). Among individuals experiencing any distant failure after RT1, gain of chromosome 1q was adversely associated with poorer OS (hazard ratio 3.5; 95% confidence interval 1.1-10.6). No distant-only failures were observed in individuals with RT1 local failure who received CSI-RT2 (n=10). The 10-year cumulative incidence of grade >=3 radiation necrosis after RT2 was 7.9%. CONCLUSIONS: Reirradiation for relapsed pediatric ependymoma was well tolerated by most patients and resulted in long-term survival in a subset of patients. The best results were observed in patients who experienced distant-only failure after RT1 and were treated with CSI as part of RT2, without anaplasia at recurrence. The option of reirradiation should be discussed with patients who develop recurrent ependymoma. PMID- 29229329 TI - Prognostic Value of c-MET Expression in Patients With Pancreatic Cancer Receiving Adjuvant and Neoadjuvant Chemoradiation Therapy. AB - PURPOSE: To determine the prognostic significance of c-MET expression and develop a predictor of distant failure in patients with resectable pancreatic cancer treated with chemoradiation. METHODS AND MATERIALS: We used a tissue microarray to study protein expression by immunohistochemistry in 102 patients treated surgically for pancreatic cancer. Two cores per patient were blindly scored from 0 (no staining) to 3 (strong staining) by a single pathologist. The Kaplan-Meier method was used to determine time to local and distant failure, overall survival, and progression-free survival. P values were calculated with the log-rank test. RESULTS: High tumor expression of c-MET was associated with a shorter time to distant failure in patients receiving neoadjuvant (n=23) or neoadjuvant therapy (n=73) (median 8.9 months vs 22.0 months, P=.0010). We then examined the ability of incorporating 2 known biomarkers, thymidylate synthase and DPC4 (SMAD4), with c-MET to risk-stratify patients. This multi-protein predictor divided our cohort into groups of similar numbers and was predictive of distant failure (median 13.4 months vs 24.2 months, P=.0094) but not of local control. CONCLUSION: c-MET is potentially predictive of distant failure. Using c-MET, DPC4, and thymidylate synthase, we developed a multi-protein predictor that could be used to risk stratify patients and guide decisions regarding the sequencing of locoregional and systemic therapies in pancreatic cancer. PMID- 29229330 TI - Detection and confirmation of alpha-cobratoxin in equine plasma by solid-phase extraction and liquid chromatography coupled to mass spectrometry. AB - alpha-Cobratoxin (CTX) is a large peptide (71 amino acids) with strong analgesic effect and may be misused in sports such as horse racing. To prevent such misuse, a sensitive method is required for detection and confirmation of the toxin in equine samples. CTX was extracted from equine plasma using an optimized mixed mode solid-phase extraction (SPE) procedure. Extracted CTX was reduced with dithiothreitol and alkylated with iodoacetamide, and then was digested by trypsin at 56 degrees C for 30min. The digest was analysed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), and tryptic peptides T2 (3CFITPDITSK12) and T4 (24TWCDAFCSIR33) were monitored for detection and confirmation of CTX. The limit of detection (LOD) was 0.05ng/mL for CTX in plasma, and the limit of confirmation (LOC) 0.2ng/mL. Unlike small peptides consisting of the 20 canonical amino acids, CTX was stable in equine plasma at ambient temperature for at least 24h. The developed analytical method was successfully applied to analysis of incurred plasma samples; CTX was detected in plasma collected 15min through 36h post subcutaneous administration of CTX (2.0mg dose) to a research horse, and confirmed 30min through 24h. Additionally, an approach named "reliable targeted SEQUEST search" has been proposed for assessing the specificity of T2 at product ion spectrum level for confirmation of CTX. T2 is uniquely specific for CTX, as evaluated with this approach and BLAST search. Furthermore, the effect of dimethyl sulfoxide (DMSO) as a mobile phase additive on electrospray (ESI) response of T2 and T4, background noise level and signal to noise ratio (S/N) was examined; DMSO increased signal intensity of T2 and T4 by a factor of less than 2. It is the first report that DMSO raised background noise level and did not improve S/N for the peptides, to the authors' knowledge. The developed analytical method may be applicable for analysis of CTX in plasma from other species such as greyhound dogs or even human beings. PMID- 29229331 TI - An integrated precipitation and ion-exchange chromatography process for antibody manufacturing: Process development strategy and continuous chromatography exploration. AB - In the past decades, research was carried out to find cost-efficient alternatives to Protein A chromatography as a capture step in monoclonal antibody (mAb) purification processes. In this work, polyethylene glycol (PEG) precipitation has shown promising results in the case of mAb yield and purity. Especially with respect to continuous processing, PEG precipitation has many advantages, like low cost of goods, simple setup, easy scalability, and the option to handle perfusion reactors. Nevertheless, replacing Protein A has the disadvantage of renouncing a platform unit operation as well. Furthermore, PEG precipitation is not capable of reducing high molecular weight impurities (HMW) like aggregates or DNA. To overcome these challenges, an integrated process strategy combining PEG precipitation with cation-exchange chromatography (CEX) for purification of a mAb is presented. This work discusses the process strategy as well as the associated fast, easy, and material-saving process development platform. These were implemented through the combination of high-throughput methods with empirical and mechanistic modeling. The strategy allows the development of a common batch process. Additionally, it is feasible to develop a continuous process. In the presented case study, a mAb provided from cell culture fluid (HCCF) was purified. The precipitation and resolubilization conditions as well as the chromatography method were optimized, and the mutual influence of all steps was investigated. A mAb yield of over 95.0% and a host cell protein (HCP) reduction of over 99.0% could be shown. At the same time, the aggregate level was reduced from 3.12% to 1.20% and the DNA level was reduced by five orders of magnitude. Furthermore, the mAb was concentrated three times to a final concentration of 11.9mg/mL. PMID- 29229332 TI - Determination of household and industrial chemicals, personal care products and hormones in leafy and root vegetables by liquid chromatography-tandem mass spectrometry. AB - A multiresidue method has been developed for the determination of emerging pollutants in leafy and root vegetables. Selected compounds were 6 perfluoroalkyl compounds (5 perfluorocarboxylic acids and perfluorooctanesulfonic acid), 3 non ionic surfactants (nonylphenol and nonylphenolethoxylates), 8 anionic surfactants (4 alkylsulfates and 4 linear alkylbenzene sulfonates), 4 preservatives (parabens), 2 biocides (triclosan and triclocarban), 2 plasticizers (bisphenol A and di-(2-ethylhexyl)phthalate), 6 UV-filters (benzophenones) and 4 hormones. The method is based on ultrasound-assisted extraction, clean-up by dispersive solid phase extraction (d-SPE) and liquid chromatography-tandem mass spectrometry analysis. Due to the diversity of the physico-chemical properties of the target compounds, and to better evaluate the influence of sample treatment variables in extraction efficiencies, Box-Behnken design was applied to optimize extraction solvent volume, number of extraction cycles and d-SPE sorbent amount. Linearity (R2) higher than 0.992, accuracy (expressed as relative recoveries) in the range from 81 to 126%, precision (expressed as relative standard deviation) lower than 19% and limits of detection between 0.025 and 12.5ngg-1 dry weight were achieved. The method was applied to leafy vegetables (lettuce, spinach and chard) and root vegetables (carrot, turnip and potato) from a local market. The highest concentrations corresponded to the surfactants reaching levels up to 114ngg-1 (dry weight), in one of the lettuce samples analyzed. PMID- 29229333 TI - Simultaneous determination of 12 vitamin D compounds in human serum using online sample preparation and liquid chromatography-tandem mass spectrometry. AB - The development and validation of a method to simultaneously quantify 12 vitamin D compounds in human serum by LC-MS/MS is described. The main challenge was that of extracting and chromatographing vitamin D compounds with a range of polarities, both lipophilic and hydrophilic, in a single analytical procedure. The extractions of all 12 vitamin D compounds were achieved by an optimised protein precipitation method using acetonitrile as the precipitant, and the separation was accomplished by using a pentafluorophenyl (PFP) column. The sensitivity was increased by minimising matrix effects in MS detector rather than using a lengthy derivatisation procedure; an online solid phase extraction (SPE) using a PFP guard column was used for cleanup. Detection limits for all compounds were in the picomole range when using a 500MUL sample volume. Recovery percentages ranged from 92% to 99%. LC-MS/MS resolution of all 12 vitamin D compounds, including the chromatographic separation of 25(OH)D3 from the isomer 3 epi-25(OH)D3 was achieved. Stable isotope labelled vitamin D compounds were used as internal standards for the quantification of all 12 vitamin D compounds. This is a simple yet accurate, selective, and sensitive method for the quantification of 12 major vitamin D compounds, including the sulfated forms, in human serum. The method is sufficiently robust to offer potential for use in routine analysis in a pathology laboratory setting. PMID- 29229334 TI - Broad range chemical profiling of natural deep eutectic solvent extracts using a high performance thin layer chromatography-based method. AB - Natural deep eutectic solvents (NADES) made mainly with abundant primary metabolites are being increasingly applied in green chemistry. The advantages of NADES as green solvents have led to their use in novel green products for the food, cosmetics and pharma markets. However, one of the main difficulties encountered in the development of novel products and their quality control arises from their low vapour pressure and high viscosity. These features create the need for the development of new analytical methods suited to this type of sample. In this study, such a method was developed and applied to analyse the efficiency of a diverse set of NADES for the extraction of compounds of interest from two model plants, Ginkgo biloba and Panax ginseng. The method uses high-performance thin layer chromatography (HPTLC) coupled with multivariate data analysis (MVDA). It was successfully applied to the comparative quali- and quantitative analysis of very chemically diverse metabolites (e.g., phenolics, terpenoids, phenolic acids and saponins) that are present in the extracts obtained from the plants using six different NADES. The composition of each NADES was a combination of two or three compounds mixed in defined molar ratios; malic acid-choline chloride (1:1), malic acid-glucose (1:1), choline chloride-glucose (5:2), malic acid-proline (1:1), glucose-fructose-sucrose (1:1:1) and glycerol-proline-sucrose (9:4:1). Of these mixtures, malic acid-choline chloride (1:1) and glycerol-proline-sucrose (1:1:1) for G. biloba leaves, and malic acid-choline chloride (1:1) and malic acid glucose (1:1) for P. ginseng leaves and stems showed the highest yields of the target compounds. Interestingly, none of the NADES extracted ginkgolic acids as much as the conventional organic solvents. As these compounds are considered to be toxic, the fact that these NADES produce virtually ginkgolic acid-free extracts is extremely useful. The effect of adding different volumes of water to the most efficient NADES was also evaluated and the results revealed that there is a great influence exerted by the water content, with maximum yields of ginkgolides, phenolics and ginsenosides being obtained with approximately 20% water (w/w). PMID- 29229335 TI - Determination of organophosphorus flame retardants in fish by freezing-lipid precipitation, solid-phase extraction and gas chromatography-mass spectrometry. AB - An analytical method has been developed for measuring 12 organophosphorus flame retardants (PFRs) in fish tissue samples. After the Soxhlet extraction of PFRs with dichloromethane. The experimental parameters of the clean-up were systematically optimized. Methanol was found to be a more effective solvent than acetonitrile used in freezing-lipid precipitation. Methanol (5%) in ultrapure water, was finally selected to perform solid-phase extraction (SPE, Oasis HLB cartridge), with mean lipid removal efficiency of 94% after freezing-lipid precipitation. Further purification followed by 200mg of Z-Sep and C18 dispersant to eliminate the remaining interferences. Quantification was performed using gas chromatography-mass spectrometry in selective ion monitoring mode. The recovery, precision, and the method detection limits (MDLs) were verified by spiking experiments. All chemicals except triethyl phosphate (TEP) showed satisfactory recoveries in the range of 73-107% and 56-108% in the spiked blanks samples and spiked fish tissue samples, respectively. MDLs for PFRs in the biological samples ranged from 0.004 to 0.059ng/g. The proposed method successfully applied to the determination of PFRs in real fish samples with recoveries of four internal standards varying from 75 to 97%. The results demonstrated that the proposed method is highly effective for analyzing PFRs in fish samples. PMID- 29229336 TI - Determination of heavy polycyclic aromatic hydrocarbons by non-aqueous reversed phase liquid chromatography: Application and limitation in refining streams. AB - The heavy polycyclic aromatic hydrocarbons (HPAHs) cause detrimental effects to hydrocracker operations by deactivating the catalysts and depositing in the downstream of the reactor/ exchangers. Therefore, it is essential to continuously monitor the accumulation of HPAHs in a hydrocracker unit. To accurately measure the concentration of HPAHs, the development of a fast and reliable analytical method is inevitable. In this work, an analytical method based on non-aqueous reversed phase chromatography in combination with high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) was developed. As a first step, five different types of stationary phases were evaluated for the separation of HPAHs in non-aqueous mode and the best suited phase was further used for the fractionation of HPAHs in a fractionator bottom sample obtained from a refinery hydrocracker unit. The eight major fractions or peaks obtained from the separation were further characterized by UV spectroscopy and FT-ICR MS and the compounds in the fractions were tentatively confirmed as benzoperylene, coronene, methylcoronene, naphthenocoronene, benzocoronene, dibenzoperylene, naphthocoronene and ovalene. The developed liquid chromatography method can be easily adapted in a refinery laboratory for the quantitation of HPAHs in hydrocracking products. The method was further tested to check the interference of sulfur aromatics and/or large alkylated aromatic hydrocarbons on the determination of HPAHs in hydrocracking products. PMID- 29229337 TI - Receptor protein of Lysinibacillus sphaericus mosquito-larvicidal toxin displays amylomaltase activity. AB - The activated binary toxin (BinAB) from Lysinibacillus sphaericus binds to surface receptor protein (Cqm1) on the midgut cell membrane and kills Culex quinquefasciatus larvae on internalization. Cqm1 is attached to cells via a glycosyl-phosphatidylinositol (GPI) anchor. It has been classified as a member of glycoside hydrolase family 13 of the CAZy database. Here, we report characterization of the ordered domain (residues 23-560) of Cqm1. Gene expressing Cqm1 of BinAB susceptible mosquito was chemically synthesized and the protein was purified using E. coli expression system. Values for the Michaelis-Menten kinetics parameters towards 4-nitrophenyl alpha-D-glucopyranoside (alpha-pNPG) substrate were estimated to be 0.44 mM (Km) and 1.9 s-1 (kcat). Thin layer chromatography experiments established Cqm1 as alpha-glucosidase competent to cleave alpha-1,4-glycosidic bonds of maltose and maltotriose with high glycosyltransferase activity to form glucose-oligomers. The observed hydrolysis and synthesis of glucose-oligomers is consistent with open and accessible active site in the structural model. The protein also hydrolyses glycogen and sucrose. These activities suggest that Cqm1 may be involved in carbohydrate metabolism in mosquitoes. Further, toxic BinA component does not inhibit alpha-glucosidase activity of Cqm1, while BinB reduced the activity by nearly 50%. The surface plasmon resonance study reveals strong binding of BinB with Cqm1 (Kd, 9.8 nM). BinA interaction with Cqm1 however, is 1000-fold weaker. Notably the estimated Kd values match well with dissociation constants reported earlier with larvae brush border membrane fractions. The Cqm1 protein forms a stable dimer that is consistent with its apical localization in lipid rafts. Its melting temperature (Tm) as observed by thermofluor-shift assay is 51.5 degrees C and Ca2+ provides structural stability to the protein. PMID- 29229338 TI - Delayed Occurrence of Diabetes Insipidus After Transsphenoidal Surgery with Radiologic Evaluation of the Pituitary Stalk on Magnetic Resonance Imaging. AB - BACKGROUND: Diabetes insipidus (DI) is a major complication of transsphenoidal surgery (TSS). DI usually occurs within a couple of days after TSS. Delayed occurrence of postoperative DI is rarely observed and its developing mechanisms remain unknown. METHODS: Six patients were identified as having postoperative delayed DI, which was defined as DI that first occurred 2 or more weeks after TSS. They consisted of 1 male and 5 females, and their mean age was 38.3 years (range, 10-76 years). Five patients were histologically diagnosed with Rathke cleft cyst (RCC), and one had RCC coexisting with prolactin-secreting adenoma. Sequential T1-weighted magnetic resonance imaging was evaluated for hyperintensity (HI) in the pituitary stalk and the posterior lobe, indicating the location of antidiuretic hormone. RESULTS: No patients had any DI before TSS. Delayed DI occurred 2 weeks to 3 months after TSS and persisted for 2 weeks to 5 months. T1-weighted magnetic resonance imaging showed that the HI in the posterior lobe became faint but did not disappear after DI occurrence, and their intensities increased with recovery from DI. In contrast, the HI in the pituitary stalk was found faintly preoperatively and turned clear postoperatively and decreased with recovery from DI. The morphologic patterns were dependent on DI duration. CONCLUSIONS: In the delayed occurrence of DI, it was suggested that preoperative antidiuretic hormone transport was mildly congested yet not completely blocked when DI manifested postoperatively. Gradual spreading of inflammation to the infundibulum after RCC removal was considered as 1 possible mechanism of this delayed DI development. PMID- 29229339 TI - Hemangioblastomas of the Posterior Cranial Fossa in Adults: Demographics, Clinical, Morphologic, Pathologic, Surgical Features, and Outcomes. A Systematic Review. AB - BACKGROUND: Posterior cranial fossa (PCF) hemangioblastomas are benign, highly vascularized, and well-differentiated tumors with well-described histopathologic features. Although relatively rare, this tumor is the most prevalent primary tumor of the cerebellum in adults. OBJECTIVE: Because the demographics of patients with such a tumor (as well as the clinical, morphologic, pathologic, surgical features, and outcomes) are not fully understood, we systematized characteristic patient and tumor features. METHODS: We undertook a systematic review of the English-language literature in PubMed for PCF hemangioblastomas in adults published in the past 31 years. We analyzed geographic distribution and year of publication of articles; demographic data of patients; presenting symptoms and clinical signs; tumor location and morphology; histopathologic features, extent of tumor resection, perioperative blood loss, and postoperative complications; length of hospital stay; and outcomes. RESULTS: We reviewed 207 articles describing 1759 infratentorial hemangioblastomas in a cohort of 1515 adult patients. We found female predominance in patients with Von Hippel-Lindau disease (VHLD) compared with male predominance in the general patient group. Symptoms of intracranial hypertension were more common in the VHLD group compared with the general group of patients. The cerebellar location was more common in the VHLD group and solid (parenchymatous) tumor was the most common type. Most patients underwent total resection but rate of resection did not differ between the general and VHLD groups. Most patients had a favorable outcome. CONCLUSIONS: The literature of adult PCF hemangioblastomas is limited and general surgical experience with such tumors is scarce because of their rarity. Rates of postoperative complications and mortality remain higher than expected. However, prognosis and surgical outcomes are generally favorable. Nevertheless, surgery of adult PCF hemangioblastomas is a demanding and challenging task. PMID- 29229340 TI - An Unusual Case of Ureteral Perforation in Minimally Invasive Pedicle Screw Instrumentation: Case Report and Review of the Literature. AB - BACKGROUND: Injury of the ureter is a potentially devastating complication most often reported in gynecologic, colorectal, or vascular pelvic surgery or endoscopic procedures for ureteric diseases. We report a rare case of ureteral rupture occurring as a complication of percutaneous pedicle screw placement. CASE DESCRIPTION: A 60-year-old man reported unbearable abdominal pain on the day after right L4-L5 transforaminal intervertebral fusion and percutaneous pedicle screw placement. A computer tomography workup showed contrast media extravasation outside the excretory system consistent with a left ureteral traumatic perforation. The patient underwent left nephrostomy and a double-J stent insertion and subsequently fully recovered. The ureter completely healed, enabling stent removal 5 months later. METHODS: PubMed and EMBASE were screened for ureteral injury caused by posterior lumbar surgery. RESULTS: We found 27 other reports with only 1 other case after minimally invasive transforaminal lumbar interbody. CONCLUSIONS: Complications of minimally invasive pedicle screw placement are often described as dural tear of neurologic impairment. This report shows that unexpected side effects are still possible and spine surgeons should be aware especially when performing minimally invasive procedures, in which, by definition, pedicles are concealed from direct visualization. PMID- 29229341 TI - Diagnostic Performance of Increased Signal Intensity Within the Resection Cavity on Fluid-Attenuated Inversion Recovery Sequences for Detection of Progression in Patients with Glioma. AB - OBJECTIVE: To systematically evaluate the diagnostic performance of increased signal intensity within the resection cavity on fluid-attenuated inversion recovery (FLAIR) sequences for detection of progression in patients with glioma through performing a meta-analysis. METHODS: PubMed, Web of Science, Embase, Cochrane Library, and China National Knowledge Infrastructure were searched for potentially relevant literature. The study characteristics and relevant data were extracted. We estimated the pooled sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, and diagnostic odds ratio and constructed summary receiver operating characteristics curves to identify the diagnostic value of FLAIR signal increase for detection of glioma progression. RESULTS: A total of 4 studies with 438 patients were included. The pooled sensitivity and specificity of increased signal intensity in FLAIR sequences in the resection cavity for detection of glioma progression were 0.36 (95% confidence interval 0.31-0.42) and 0.93 (95% confidence interval 0.86-0.97), respectively. The area under the curve was 0.7505. Subgroup analyses also were performed according to different patient sources, tumor grades, and definitions of progression. No significant publication bias was found in the meta-analysis (P = 0.85). CONCLUSIONS: Our results suggested that increased signal intensity within the resection cavity on FLAIR sequences could indicate tumor progression early with high specificity in patients with glioma. This readily accessible sign could implicate closer monitoring and could be crucial for therapeutic decisions and outcome. However, because of the limited number of studies, more well-designed studies are warranted to further verify our results and elucidate the underlining mechanisms. PMID- 29229342 TI - Parahippocampectomy as a New Surgical Approach to Mesial Temporal Lobe Epilepsy Caused By Hippocampal Sclerosis: A Pilot Randomized Comparative Clinical Trial. AB - BACKGROUND AND OBJECTIVE: The parahippocampal gyrus plays an important role in the epileptogenic pathways of mesial temporal lobe epilepsy caused by hippocampal sclerosis (mTLE-HS); its resection could prevent epileptic seizures with fewer complications. This study evaluates the initial efficacy and safety of anterior temporal lobectomy (ATL), selective amygdalohipppocampectomy (SAH), and parahippocampectomy (PHC) surgical approaches in mTLE-HS. METHODS: A randomized comparative pilot clinical trial (2008-2011) was performed that included patients with mTLE-HS who underwent ATL, trans-T3 SAH, and trans-T3 PHC. Their sociodemographic characteristics, visual field profiles, verbal and visual memory profiles, and Engel scale outcome at baseline and at 1 and 5 years are described, using descriptive statistics along with parametric and nonparametric tests. RESULTS: Forty-three patients with a mean age of 35.2 years (18-56 years), 65% female, were analyzed: 14 underwent PHC, 14 ATL, and 15 SAH. The following percentages refer to those patients who were seizure free (Engel class IA) at 1 year and 5-year follow-up, respectively: 42.9% PHC, 71.4% ATL, and 60% SAH (P = 0.304); 28.6% PHC, 50% ATL, and 53.3% SAH (P = 0.353). Postoperative visual field deficits were 0% PHC, 85.7% ATL, and 46.7% SAH (P = 0.001). Verbal and/or visual memory worsening were present in 21.3% PHC, 42.8% ATL, and 33.4% SAH (P = 0.488) and preoperative and postoperative visual memory scores were significantly different in the SAH group only (P = 0.046). CONCLUSIONS: PHC, ALT, and SAH show a preliminary similar efficacy in short-term seizure-free rates in patients with mTLE-HS. However, PHC efficacy in the long-term decreases compared with the other surgical techniques. PHC does not produce postoperative visual field deficits. PMID- 29229343 TI - Heat Generation During Bony Decompression of Lumbar Spinal Stenosis Using a High Speed Diamond Drill with or without Automated Irrigation and an Ultrasonic Bone Cutting Knife: A Single-Blinded Prospective Randomized Controlled Study. AB - OBJECTIVE: The main objective of the present prospective, randomized, single blinded controlled study was to measure heat during bony decompression of lumbar spinal stenosis with high-speed drills and an ultrasonic bone-cutting knife. METHODS: Ninety patients diagnosed with lumbar spinal stenosis were included in this study and randomized for lumbar spinal canal decompression using either a high-speed drill with automatic irrigation, high-speed drill with manual irrigation, or an ultrasonic bone-cutting knife with automatic irrigation (USBCD). For evaluation of group homogeneity, a visual analog scale pain score and neurologic findings were measured preoperatively and postoperatively. Temperatures during bony decompression were measured using a forward-looking infrared camera system. RESULTS: Clinical results among the 3 groups did not differ in pain reduction, improvement of neurologic findings, or the rate of complications. However, significantly lower values were found for absolute and mean maximal temperatures during bony decompression in the USBCD group compared with the groups of patients who received the high-speed drill with automatic irrigation and the high-speed drill with manual irrigation, indicating this technique to be less aggressive in terms of thermal induction of bone necrosis. USBCD allows more precise bone removal compared with high-speed drills, and despite increased device time, no significant difference in the overall decompression time was observed. CONCLUSIONS: All methods examined produced short temperature peaks with possible, at least temporary, damage to bone and neural tissue. Automatic irrigation was associated with lower heat development compared with manual irrigation. Despite evidence of critical temperatures, no clinical correlation (e.g., neurologic deficits) was encountered in this study. Clinically, all 3 methods presented equally good results. PMID- 29229344 TI - Cavernous Sinus Hemangioma: Rare Vascular Tumor of Cavernous Sinus. AB - Cavernous sinus hemangiomas (CSHs) are rare vascular tumors, which are infrequently encountered in everyday neurosurgical practice. Attempted resection of this lesion without preoperative planning carries a high risk for significant blood loss and cranial neuropathies. Radiation treatments can provide an alternative and safe treatment modality for these lesions. Therefore an increased awareness is warranted for their clinical suspicion. We reported on a patient who presented with visual deficits and a mass in the sellar, suprasellar, and middle fossa regions. Given the high suspicion for a CSH due to characteristic radiologic findings, a keyhole craniotomy approach was safely used for an open biopsy. The final pathology was consistent with a CSH, and the patient subsequently underwent radiation therapy without complications. PMID- 29229346 TI - Building Healthcare Capacity in Pediatric Neurosurgery and Psychiatry in a Post Soviet System: Ukraine. AB - OBJECTIVE: Many academic centers in North America are initiating global partnerships to build physician capacity in resource-poor countries. An opportunity arose to develop a pediatric program (Ukraine Paediatric Fellowship Program, UPFP) in Ukraine, a large European country in transition from a Soviet/communist political and social system. This entailed dealing with a centralized and rigid healthcare system based on the Semashko model of the former Soviet Union. METHODS: Our capacity-building model has several key features: endowed philanthropic funding for sustainability, bilateral exchange of knowledge, a focus primarily on pediatric brain disorders, and team building. Centers for partnering are selected on the basis of need, receptivity to change, and participants' fluency in English. Ukrainian physicians attend month-long observerships in Toronto, and biannual teaching visits are conducted by Canadian clinicians. RESULTS: Over 5 years, 7 teaching visits have taken place, and 20 physicians have trained at SickKids Hospital in Toronto. Six Ukrainian children's hospitals are now collaborating with UPFP. New surgical procedures have been introduced, such as endoscopic ventriculostomy and corpus callosotomy. Patient referrals to regional institutions have increased, and new projects that affect fetal and infant neurodevelopment have been initiated (e.g., treatment of perinatal maternal depression and folic acid fortification of flour). Ukrainian participants rate the program highly in their evaluations. CONCLUSIONS: In a short time, UPFP has had considerable success in increasing physician capacity for improved pediatric care in regions of Ukraine. The keys to success have included focusing locally, selecting trustable partners, building incrementally, and creating interspecialty synergies. PMID- 29229345 TI - Comparison of Outcomes in 3 Surgical Approaches for Dystrophic Cervical Kyphosis in Patients with Neurofibromatosis 1. AB - OBJECTIVE: To compare outcomes of anterior-only (AO), posterior-only (PO), and anteroposterior (AP) surgical approaches for treatment of dystrophic cervical kyphosis in patients with neurofibromatosis 1 (NF1). METHODS: This retrospective observational study included 81 patients with dystrophic cervical kyphosis secondary to NF1. Length of kyphosis, duration of halo traction, Cobb angle, C2-7 sagittal vertical axis (SVA), T1 slope, Neck Disability Index score, and postoperative complications were evaluated before and, if possible, after each surgical approach. RESULTS: AP approach provided the best outcomes (average spinal Cobb angle was corrected from 61.2 +/- 9.1 degrees to 5.7 +/- 3.2 degrees , P < 0.05); there was no significant difference between AO and PO approaches (P > 0.05). With regard to cervical sagittal balance, AP approach had the most improvements of C2-7-SVA (mean C2-7-SVA was corrected from 3.2 +/- 9.2 mm to 12.8 +/- 2.6 mm, P < 0.05); the difference between AO and PO approaches was not significant (P > 0.05). T1 slope results were similar to C2-7-SVA. Neck Disability Index score of all patients improved significantly after surgery (P < 0.05); specifically, patients who had an AP approach constituted the largest portion of the satisfied patient group. Postoperative junctional kyphosis occurred in 11 patients (1 AP approach, 6 AO approach, 4 PO approach); these findings correlated with patients with <=5 fused segments. CONCLUSIONS: AP approach surgery provided the best correction of dystrophic cervical kyphosis and sagittal balance for patients with NF1. Patients undergoing an AP approach were more satisfied with their outcomes. Junctional kyphosis can be prevented effectively using an AP approach in patients with >5 fused segments. PMID- 29229347 TI - Postoperative Stridor and Acute Respiratory Failure After Parkinson Disease Deep Brain Stimulator Placement: Case Report and Review of Literature. AB - BACKGROUND: Parkinson disease (PD), a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra of the midbrain, is commonly thought of as a motion disorder, but it can have significant effect on the respiratory system. Respiratory failure is the most common cause of death in these patients, but it can also affect laryngeal function causing dysphonia, dysphagia, and dysarthric speech. Acute upper airway obstruction is a rare finding in PD, especially in the perioperative settings. In this article we report a PD patient who developed upper respiratory obstruction postoperatively. We also review the literature and highlight the importance of preoperative evaluation to identify patients who may be at risk of this complication. CASE DESCRIPTION: We describe a PD patient presenting for brain stimulation electrode implantation under general anesthesia, who postoperatively developed stridor and near complete upper airway obstruction despite maintenance of oral anti-Parkinson medication regimen intraoperatively. The patient was reintubated in post anesthesia-care unit, and tracheostomy was performed after 1 week due to persistent vocal cord dysfunction. CONCLUSIONS: Baseline vocal cord impairment in PD patients can be acutely aggravated perioperatively. Symptoms such as dysphagia and dysarthria, which can indicate susceptibility to postoperative upper airway obstruction, may not be well recognized by the patient and family. Surgical candidates should be carefully interviewed preoperatively, and watchful monitoring of respiratory function intraoperatively and postoperatively is of paramount importance. Neurosurgical and neuroanesthesia team should be aware of, and prepared to manage, this potentially life-threatening airway obstruction in PD patients. PMID- 29229348 TI - Bone Morphogenetic Protein Usage in Anterior Lumbar Interbody Fusion: What Else Can Go Wrong? AB - BACKGROUND: Bone morphogenetic protein (BMP) graft showed promising outcome during early phases of its use. However, unreported adverse events and off-label use shattered its safe profile and raised concerns regarding its indication. In 2008 the U.S. Food and Drug Administration prohibited its use in anterior cervical spine procedures due to the possibility of edema, hematoma, and need to intubate. At the molecular level, BMPs act as multifactorial growth factors playing a role in cartilage, heart, and bone formation. However, its unfavorable effect on bone overgrowth or heterotopic ossification post spine surgeries has been described. Reported cases in the literature were limited to epidural bone formation. CASE DESCRIPTION: We present a rare and interesting case of a 59-year old female, in whom BMP caused intradural bone growth several years after an anterior lumbar interbody fusion surgery. CONCLUSION: Caution must be exercised while using BMPs because of inadvertent complications. PMID- 29229349 TI - Surgical Management of Ruptured Isolated Aneurysm of Artery of Adamkiewicz: Interesting Report and Overview of Literature. AB - BACKGROUND: Spinal subarachnoid hemorrhage due to rupture of an isolated spinal aneurysm is extremely rare. Patients usually present with symptoms and signs resulting from spinal cord compression. No standard guidelines are available for the treatment of this condition. CASE ILLUSTRATION: In this report we present the case of a 78-year-old Caucasian male who presented with sudden-onset back pain and bilateral lower extremity weakness. Spinal angiogram revealed an isolated aneurysm of the artery of Adamkiewicz. The aneurysm was successfully managed by surgical clipping, and the patient recovered well with rehabilitation. At 46 months' follow-up, the patient was able to ambulate and perform activities of daily living independently. CONCLUSION: Our case is the first description of surgical clipping of a ruptured isolated spinal aneurysm of the artery of Adamkiewicz with a long-term successful outcome and shows that it is a safe and feasible option in carefully selected patients. PMID- 29229350 TI - Predictors of Readmissions and Reoperations Related to Venous Thromboembolic Events After Spine Surgery: A Single-Institution Experience with 6869 Patients. AB - BACKGROUND: Readmission and reoperation are used as hospital and surgeon quality metrics. Venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism (PE), are a major cause of readmission, morbidity, and mortality after spine surgery. Specific procedural, perioperative, and patient characteristics may be associated with these outcomes. METHODS: We retrospectively examined records from 6869 consecutive spine surgeries at our institution. We collected data on patient demographics, surgery, hospital course, and 30-day rates of VTE, readmission, reoperation, and epidural hematoma. Stepwise multivariable logistic regression was used to identify independent predictors of each outcome. RESULTS: Factors associated with VTE within 30 days of surgery include a history of VTE (odds ratio [OR] 3.92 [confidence interval 1.83-8.36], P < 0.001), estimated blood loss (EBL; OR 1.017 [1.005-1.029], P = 0.004), fracture (OR 5.42 [2.09-14.05], P = 0.001), history of PE (OR 4.04 [1.22 13.42], P = 0.023), and transfusion (OR 2.26 [1.07-4.77], P = 0.033). Factors associated with readmission were a history of PE (OR 3.27 [1.07-9.97], P = 0.038), PE (OR 8.07 [2.26-28.8], P = 0.001), transfusion (OR 2.54 [1.55-4.17], P < 0.001), comorbid disease burden (OR 1.35 [1.01-1.80], P = 0.041), and tumor surgery (OR 2.84 [1.32-6.10], P = 0.007). Factors associated with reoperation were EBL (OR 1.024 [1.006-1.042], P = 0.008), transfusion (OR 3.86 [1.38-10.79], P = 0.01), and PE (OR 6.05 [1.03-35.62], P = 0.046). Transfusion was associated with epidural hematoma within 30 days (OR 7.38 [1.37-39.83], P = 0.02). CONCLUSIONS: Transfusion and EBL are associated with numerous negative outcomes. Transfusion is an independent predictor of VTE, readmission, reoperation, and epidural hematoma requiring evacuation. Specific pathologies were associated with specific negative outcomes. PMID- 29229351 TI - Evaluation of Measuring Methods of Spinal Canal Occupation Rate in Thoracic Ossification of Ligamentum Flavum. AB - OBJECTIVE: The degree of hypertrophy of thoracic ossification of ligamentum flavum (TOLF) is related to the severity of the myelopathy. There is no uniform measuring method to calculate the spinal canal occupation ratio (COR) of TOLF simply and effectively. The study was to determine an appropriate measuring method to calculate the COR of TOLF. METHODS: A total of 37 computed tomography cross-sectional imaging scans (bone window) from 22 patients were analyzed retrospectively in this study. The ventral side of the lamina or superior facet was selected as bottom in Method 1, and a line perpendicular to the anteroposterior diameter and on the dorsal side of the spinal canal was selected as bottom in Method 2. The maximum thickness of the bilateral ossified mass to the bottom is d1 and d2. The maximum distance from the anterior wall of the spinal canal to the bottom is d. COR of Method 1 or 2 was (d1 + d2)/2d * 100%. Standard COR values calculated by software served as controls. RESULTS: The standard COR values were <50% in 10 images, 51%-60% in 9 images, 61%-70% in 10 images, and >71% in 8 images. There was no significant difference between COR1 and COR in every range. There were significant differences between COR2 and COR in the <=50%, 51%-60%, and 61%-70% groups but they were not statistically significant in the >70% group. CONCLUSIONS: Method 1 is a convenient and practical method to measure the COR of ossification in patients with TOLF. PMID- 29229353 TI - Novel 1,4-benzothazines obliterate COX-2 mediated JAK-2/STAT-3 signals with potential regulation of oxidative and metabolic stress during colorectal cancer. AB - 1,4-benzothiazines have ameliorative effects through inhibition of COX-2 mediated STAT-3 pathways at G-protein couple receptor site. As per this scenario, we recently prepared and tested novel 1,4-benzothiazine derivatives against HT-29 human colon cancer cell line. Two compounds namely AR13 and AR15 showed higher inhibitions among all the synthesized compounds. In the present context, we conducted the in vivo antiproliferative action and identified the molecular mechanism associated to cytotoxic action of AR13 and AR15 in dimethylhydrazine (DMH) induced colorectal carcinoma (CRC) model. Various physiological, oxidative stress, histopathology, ELISA, qRT-PCR, western blot and NMR-based metabolomics were accomplished to evaluate the anticancer effect of titled compounds. Both compounds were subjected to histological and biochemical tests to observe the protective action of the compounds. ELISA showed potential role of these compounds to normalize increased levels of IL-2, IL-6 and COX-2 mediators. This action was more pronounced for COX-2 rather than IL-2 and IL-6. Gene expression analyses further revealed that both of them attenuated the over-expressed COX-2 gene. Furthermore, it was confirmed that these compounds exerted antitumor potential via preventing COX-2 induced JAK-2 and STAT-3 phosphorylation. This action was substansiated by immunohistochemistry using JAK2, p-JAK2, STAT3 and p STAT3 targets in colon tissue. Finally, score plots of PLS-DA models exhibited significant metabolic discriminations between the treated and CRC groups, and both compounds showed ability to restore the imbalance of multiple metabolites during CRC. In conclusion, our study provided the evidence towards better antiproliferative effect of AR13 and AR15 in DMH-induced CRC through the blockade of COX-2/JAK-2/STAT-3 signal transduction pathway and could be demonstrated as useful anti-CRC candidate molecules for future anticancer therapy. PMID- 29229354 TI - Comparative clinical trial of the variability factors of the exposure indices used for the drug monitoring of two tacrolimus formulations in kidney transplant recipients. AB - BACKGROUND: Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics. METHODS: 45 adult kidney transplant recipients were randomized to receive either Tac OD or Tac BID. On days 8+/-1 (D8) and 90+/-3 (month 3, M3), blood samples were collected over 24h in both groups. Tacrolimus concentrations were determined using HPLC-MS/MS and common CYP3A5, CYP3A4 and ABCB1 genotypes characterized using allelic discrimination assays. Tacrolimus population pharmacokinetics was studied in the two patient groups using the Iterative Two Stage (ITS) technique, considering a one-compartment model with two gamma laws to describe the absorption phase. Bayesian estimation based on the C0, C1h and C3h concentrations was employed to estimate individual Tac AUC0-12h and AUC12-24h (for Tac BID), or AUC0-24h (for Tac OD). Multiple linear regression was used to evaluate the influence of Tac formulation, post-transplantation period, recipient gender, existing glucose metabolism disorders, and CYP3A5, CYP3A4 and ABCB1 genotypes on C0, AUC0-24h and the AUC-to-trough concentration ratios. RESULTS: The Full Analysis Set comprised 22 patients on Tac OD and 20 on Tac BID. Tac exposure indices as well as their time evolution were similar in the two groups. Multi-linear modeling analysis showed that the Tac dose was higher with Tac-OD than Tac-BID, on D8 than at M3 and in CYP3A5 expressors (p<0.0001 for all). No such influence was found on C0 or C24h, while the AUC0-24h was significantly higher on D8 than at M3. The AUC0 24h/C0 ratio was not affected by the drug formulation and the polymorphisms studied, but it was significantly lower on D8 than at M3 (p=7.8*10-5). In contrast, both the post-transplantation period (p=1.53*10-4), and CYP3A5 expression (p=0.003) had a significant influence on the AUC0-24h/C24h ratio, explaining 19% and 12% of its variability, respectively. Consistently, for both Tac formulations, the AUC0-24h was better correlated with C24h than C0, and for Tac-BID the AUC0-12h was better correlated with C12h than C0. CONCLUSIONS: This study confirms that the precisely timed 12h- or 24h-post-dose blood concentration (as opposed to the vaguely defined 'trough level') is a convenient surrogate of the 24h-AUC of tacrolimus for the two TAC formulations over the first 3 months post-transplantation. Still, for a given C24h value, AUC0-24h was higher on D8 and in CYP3A5 expressors. Bayesian estimation of AUC0-12h for TAC BID and AUC0 24h for TAC OD is feasible using only 3 time points within the first 3h, thus giving access to the actual overall exposure. PMID- 29229355 TI - Effects of biflavonoids from Garcinia madruno on a triple transgenic mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is pathologically characterized by the deposition of beta-amyloid (betaA) peptides in senile plaques and neurofibrillary tangles in the brain. Flavonoids have recently been used to prevent and treat a variety of neurodegenerative diseases, but little is known about bioflavonoids. In this study, we evaluate whether a biflavonoid fraction (BF) exerts neuroprotective effects on an aged triple transgenic mouse mode of AD (3xTg-AD). Then, 21-24-month-old 3xTg AD mice were i.p. injected with 25mg/kg of a BF from Garcinia madruno composed of morelloflavone (65%), volkensiflavone (12%), GB 2a (11%), fukugiside (6%) and amentoflavone (0.4%) every 48h for 3 months. The BF treatment reduced betaA deposition in different regions of the brain (the hippocampus, entorhinal cortex and amygdala), reduced betaA1-40 and betaA1-42 levels, BACE1-mediated cleavage of APP (CTFbeta), tau pathology, astrogliosis and microgliosis in the brains of aged 3xTg-AD mice. Although the BF treatment weakly improved learning, animals treated with BF spent more time in the open arms of the elevated plus maze test and displayed greater risk assessment behavior than the control groups. In summary, the BF reverses histopathological hallmarks and reduces emotional disorders in the 3xTg-AD mouse model, suggesting that the biflavonoids from G. madruno represent a potential natural therapeutic option for AD if its bioavailability is improved. PMID- 29229356 TI - Double inferior vena cava with double left renal vein. PMID- 29229357 TI - Obstructive uropathy in a patient with double district ureter. PMID- 29229352 TI - The Outcome of Severe Traumatic Brain Injury in Latin America. AB - BACKGROUND: Traumatic brain injury (TBI) disproportionately affects lower- and middle-income countries (LMIC). The factors influencing outcomes in LMIC have not been examined as rigorously as in higher-income countries. METHODS: This study was conducted to examine clinical and demographic factors influencing TBI outcomes in Latin American LMIC. Data were prospectively collected during a randomized trial of intracranial pressure monitoring in severe TBI and a companion observational study. Participants were aged >=13 years and admitted to study hospitals with Glasgow Coma Scale score <=8. The primary outcome was Glasgow Outcome Scale, Extended (GOS-E) score at 6 months. Predictors were analyzed using a multivariable proportional odds model created by forward stepwise selection. RESULTS: A total of 550 patients were identified. Six-month outcomes were available for 88%, of whom 37% had died and 44% had achieved a GOS E score of 5-8. In multivariable proportional odds modeling, higher Glasgow Coma Scale motor score (odds ratio [OR], 1.41 per point; 95% confidence interval [CI], 1.23-1.61) and epidural hematoma (OR, 1.83; 95% CI, 1.17-2.86) were significant predictors of higher GOS-E score, whereas advanced age (OR, 0.65 per 10 years; 95% CI, 0.57-0.73) and cisternal effacement (P < 0.001) were associated with lower GOS-E score. Study site (P < 0.001) and race (P = 0.004) significantly predicted outcome, outweighing clinical variables such as hypotension and pupillary examination. CONCLUSIONS: Mortality from severe TBI is high in Latin American LMIC, although the rate of favorable recovery is similar to that of high income countries. Demographic factors such as race and study site played an outsized role in predicting outcome; further research is required to understand these associations. PMID- 29229358 TI - Thigh Necrotizing Fasciitis Secondary to Perforated Sigmoid Diverticulitis. PMID- 29229359 TI - Pelvic exenteration with rectal resection for different types of malignancies at two tertiary referral centres. AB - INTRODUCTION: Pelvic exenteration (PE) offers the best chance of cure for locally advanced primary or recurrent pelvic organ malignancies invading adjacent organs. The aims of this study were to analyse results for any pelvic exenteration that includes rectal resection and the analysis of results of fecal and urinary reconstruction. METHOD: From January 2000 to April 2014, 111 PE with rectal resection for any pelvic cancer were analysed retrospectively at two national tertiary referral centers. RESULTS: Thirty-six colorectal anastomosis were performed. Urologic reconstructions performed were 30 double barrelled wet colostomy (DBWC), 14 Bricker ileal conduit (BIC), and 2 ureterocutaneostomies. Postoperative complications occurred in 71 patients (64%). Six deaths (5.4%) occurred within 30 postoperative days. Five-year overall survival following R0 resection was 62.6%; R1: 42.7%; R2: 24.2% (P=.018). The resection margin status was associated with overall survival, local recurrence and distant recurrence. CONCLUSION: Pelvic exenterations for any cause need to be performed in referral centers and by specialized surgeons. Anastomosis after modified supralevator pelvic exenteration for ovarian cancer, is safe. DBWC can be considered a valid option for urologic reconstruction. The most important prognostic factor after pelvic exenteration for malignant pelvic tumors is the status of surgical margins. PMID- 29229360 TI - Peri-aortic lymphoma simulating an acute aortic syndrome. PMID- 29229361 TI - An updated literature review on maternal-fetal and reproductive disorders of Toxoplasma gondii infection. AB - BACKGROUND: Toxoplasma gondii infection is one of the most prevalent infectious disease with worldwide distribution. Congenital toxoplasmosis is annually responsible for 1.20 million disability-adjusted life years around the world, but often it is overlooked many countries. METHODS: We performed an updated review to summarize the current researches on fetal, neonatal and maternal consequences of T. gondii infection and also adverse effects of toxoplasmosis on women reproductive organs. RESULTS: T. gondii infection could be cause of several abnormalities from hydrocephalus, microcephaly, deafness, abortion and still birth in fetal to psychomotor retardation, intellectual disability, hearing loss, slower postnatal motor development during the first year of life; and chorioretinitis, cryptogenic epilepsy and autism spectrum disorders in newborns. Moreover, this infection is related with neuropsychiatric disorders such as anxiety, schizophrenia spectrum disorders, depression, decreased weight, autoimmune thyroid diseases, self-directed violence, violent suicide attempts in mothers. This literature review emphasized that toxoplasmosis could be an important neglected factor endometritis, ovarian dysfunction, impaired folliculogenesis, ovarian and uterine atrophy, decrease in reproductive organs weight and reproductive performance in women. We reviewed role of the immunological profile such as pro-infiammatory cytokines and hormonal changes as main potential mechanisms related to this infection and development of maternal fetal and reproductive disorders. CONCLUSION: T. gondii is associated with several brain related disorders in both mothers and newborns, and also it is cause of several abnormalities in reproductive organs. Early diagnosis and treatment of the infection could be effective to significantly improve the clinical outcome. PMID- 29229362 TI - French validation and adaptation of the Grobman nomogram for prediction of vaginal birth after cesarean delivery. AB - OBJECTIVE: To validate Grobman nomogram for predicting vaginal birth after cesarean delivery (VBAC) in a French population and adapt it. STUDY DESIGN: Multicenter retrospective study of maternal and obstetric factors associated with VBAC between May 2012 and May 2013 in 6 maternity units. External validation and adaptation of the prenatal and intrapartum Grobman nomograms for vaginal birth prediction after cesarean delivery in a French cohort. RESULTS: The study included 523 women with previous cesarean deliveries; 70% underwent a trial of labor for a subsequent delivery (n=367) with a success rate of 65% (n=240). In the univariate analysis, 5 factors were associated with successful VBAC: previous vaginal delivery before the cesarean (P<0.001), the number of previous vaginal deliveries (P<0.001), and a favorable cervix at delivery room admission, cervical effacement (P=0.035), or cervical dilatation at least 3cm (P<0.001), or a Bishop score >6 (P=0.03). A potentially recurrent indication (defined as arrest of dilation or descent as the indication for the previous cesarean) (P=0.039), a hypertensive disorder during pregnancy (P=0.05), and labor induction (P=0.017) were each associated with failed VBAC. External validation of the prenatal and intrapartum Grobman nomograms showed an area under the ROC curve of 69% (95% CI: 0.638, 0.736) and 65% (95% CI: 0.599, 0.700) respectively. Adaptation of the nomogram to the French cohort resulted in the inclusion of the following factors: maternal age, body mass index at last prenatal visit, hypertensive disorder, gestational age at delivery, recurring indication, cervical dilatation, and induction of labor. Its area under the curve to predict successful VBAC was 78% (95% CI: 0.738, 0.825). CONCLUSION: The nomogram to predict VBAC developed by Grobman et al. is validated in the French population. Adaptation to the French population, by excluding ethnicity, appeared to improve its performance. Impact of the nomogram use on the caesarean section rate has to be validated in a randomized control trial. PMID- 29229363 TI - Comparison of the effects of flaxseed oil and sunflower seed oil consumption on serum glucose, lipid profile, blood pressure, and lipid peroxidation in patients with metabolic syndrome. AB - BACKGROUND: Metabolic syndrome (MetSyn) increases the risk of type II diabetes and morbidity and mortality due to cardiovascular diseases. Flaxseed oil (FO), as a functional food, is one of the major vegetal sources of essential omega-3 fatty acids. OBJECTIVE: This study aimed to compare the effects of consumption of FO and sunflower seed oil (SO) on lipid peroxidation and other symptoms of MetSyn. METHODS: This randomized controlled interventional trial was conducted on 60 volunteers aged 30 to 60 years who were diagnosed with MetSyn in Shiraz, Iran. The participants who fulfilled the inclusion criteria were randomly assigned to SO (n = 30, receiving 25 mL/d SO) and FO (n = 30, receiving 25 ml/d FO) groups using block randomization. The diets were identical for all the participants. Blood pressure (BP), serum lipid, fasting blood sugar, and malondialdehyde were measured at baseline and at the end of week 7. RESULT: The results showed no significant difference between the 2 groups regarding blood lipid levels and fasting blood sugar at the end of the study. However, significant reductions in total cholesterol, low-density lipoprotein cholesterol (5.6% in FO and 10.8% in SO), and triglyceride levels were seen within each group after treatment with FO and SO (P < .05). Nonetheless, between-group changes were significant (<0.05) for systolic BP (mean [+/-standard deviation {SD}] changes were -14.0 +/- 22.41 in the FO group [P = .004] and 0.92 +/- 8.70 in the SO group [P = .594]) and diastolic BP (mean [+/-SD] changes were -4.26 +/- 7.44 in the FO group [P = .007] and 1.30 +/- 6.91 in the SO group [P = .344]), but marginally significant (P = .053) for malondialdehyde level (mean [+/-SD] changes were -1.29 +/- 1.48 in the FO group [P < .001] and -0.52 +/- 1.34 in the SO group [P = .52]). A significant decrease in weight was also found in both groups. However, waist circumference decreased significantly only in the FO group at the end of the study (P < .05). CONCLUSION: Our results indicated that dietary FO could be effective in amelioration of some symptoms of MetSyn and decrease BP and lipid peroxidation. PMID- 29229364 TI - Pathology and management of masses in the accessory parotid gland region: 24-year experience at a single institution. AB - PURPOSE: Masses in the accessory parotid gland (APG) region are clinically rare and their management can lead to conflicts between the need for tumor resection and facial cosmesis. The aim of this study was to analyze the pathological classifications and management of APG lesions in our hospital. MATERIALS AND METHODS: From January 1993 to March 2017, 130 patients with primary tumors in the APG region who underwent surgical treatment were enrolled. Follow-up surveys after surgery were then carried out. RESULTS: Among the 130 patients, 53.8% of lesions were benign (n = 70), 23.8% were malignant (n = 31), 14.6% were vascular malformations (n = 19), 6.15% were sialadenitis (n = 8), and 1.65% were cysts (n = 2). Pleomorphic adenoma accounted for 67.1% of the benign tumors (n = 47). Lymphoma, lymphoepithelial carcinoma, and acinar cell carcinoma topped the list of malignant tumors (5 cases in each group). Surgery and surgery plus radio chemotherapy were performed for benign and aggressive malignant lesions, respectively. At the time of follow-up, 5-year overall survival was 88.1%; mean follow-up was 139 months (range 3-281 months). CONCLUSIONS: Masses in the APG region have complicated pathological types. Perfect preoperative preparation, with fine-needle aspiration biopsy and imaging examinations, would contribute to identifying characteristics. Treatment schedules and surgical approaches should be determined according to the cytology reports and frozen-section examinations before and during operation. PMID- 29229365 TI - Repair of maxillary cystic bone defects with mesenchymal stem cells seeded on a cross-linked serum scaffold. AB - : Tissue engineering combining cross-linked serum scaffolds with bone-derived mesenchymal stem cells has displayed excellent results for repair of maxillofacial bone defects in animal models, but it had not been tested in humans yet. We present here a pilot clinical trial using autologous bone-derived mesenchymal stem cells (H-MSV) grown in a serum cross-linked scaffold (BioMax) for treatment of maxillary cysts in 9 patients. Cells obtained from alveolar bone were seeded in the BioMax scaffold prepared from autologous serum, expanded under GMP conditions, and subjected to osteogenic differentiation for 3-4 weeks before application. Evolution of the cystic cavity was followed by computerized tomography (CT) for 7 months. There was no inflammation or other adverse effects, and the CT density of the cyst interior increased significantly after the treatment. The ratio of the CT values after/before treatment was (mean +/- SE) 2.52 +/- 0.45; in contrast, the density of the contralateral control area of spongy alveolar bone without treatment did not change (ratio after/before, 0.99 +/- 0.14). In conclusion, cell therapy with BioMax could be considered as an alternative therapy for maxillary bone defects and other losses of bone substance. Further research with allogeneic cells would be useful for reducing costs and improving logistics. CLINICAL TRIAL REGISTRATION NUMBERS: EudraCT 2010 024246-30 and NCT01389661. PMID- 29229366 TI - Chondromalacia as pathological finding in arthroscopy of the temporomandibular joint: A retrospective study. AB - OBJECTIVE: The objective of this study was to describe the arthroscopic findings of chondromalacia and its relation with the internal derangement of the temporomandibular joint (TMJ). PATIENTS AND METHODS: A total of 161 patients (299 TMJs) who underwent arthroscopy were included in the study. The TMJs were evaluated objectively under arthroscopic vision, and 4 groups of patients were established according to the degree of involvement, degree I, II, III and IV. Statistical analyses were conducted using logistic regression models (P < 0.05). RESULTS: It was observed that 95 patients (59%) had no sign of chondromalacia and 66 (41%) in 88 joints exhibited some degree of chondromalacia (44 patients unilaterally and 22 bilaterally). Of the 88 joints with chondromalacia, 14 (15.9%) had chondromalacia degree I, 12 (13.6%) chondromalacia degree II, 20 (22.7%) chondromalacia degree III and 42 (47.7%) chondromalacia degree IV. The chondromalacia was more significantly found in patients with ADDwR and discal perforation (P < 0.05), even as a common finding in patients without any internal deragement. Chondromalacia degree IV was a significant finding in cases of ADDwoR (P = 0.000619). CONCLUSIONS: Chondromalacia of the TMJ is a common finding in patients with internal derangement even at the early stages. PMID- 29229367 TI - The Energy Cost of Steady State Physical Activity in Acute Stroke. AB - OBJECTIVE: Cardiorespiratory fitness levels are very low after stroke, indicating that the majority of stroke survivors are unable to independently perform daily activities. Physical fitness training improves exercise capacity poststroke; however, the optimal timing and intensity of training is unclear. Understanding the energy cost of steady-state activity is necessary to guide training prescription early poststroke. We aimed to determine if acute stroke survivors can reach steady state (oxygen-uptake variability <=2.0 mL O2/kg/min) during physical activity and if the energy cost of steady state activity differs from healthy controls. MATERIAL AND METHODS: We recruited 23 stroke survivors less than 2 weeks poststroke. Thirteen were able to walk independently and performed a 6-minute walk (median age 78 years, interquartile range [IQR] 70-85), and 7 who were unable to walk independently performed 6 minutes of continuous sit-to-stands (median age 78 years, IQR 74-79) and we recruited 10 healthy controls (median age 73 years, IQR 70-77) who performed both 6 minutes of walking and sit-to-stands. Our primary outcome was energy cost (oxygen-uptake) during steady state activity (i.e., walking and continuous) sit-to-stands, measured by a mobile metabolic cart. RESULTS: All stroke survivors were able to reach steady state. Energy costs of walking was higher in stroke than in controls (mean difference .10 mL O2/kg/m, P = .02); the difference in energy costs during sit-to-stands was not significant (mean difference .11 mL O2/kg/sts, P = .45). CONCLUSIONS: Acute stroke survivors can reach a steady state during activity, indicating they are able to perform cardiorespiratory exercise. Acute stroke survivors require more energy per meter walked than controls. PMID- 29229368 TI - Pharmacodynamic evaluation of self micro-emulsifying formulation of standardized extract of Lagerstroemia speciosa for antidiabetic activity. AB - BACKGROUND: Lagerstroemia speciosa (SEL) leaves are a popular folk medicine for diabetes treatment due to presence of corosolic acid. It has low water solubility resulting poor absorption after oral administration. Self micro-emulsified drug delivery system is the way by which we can improve the oral absorption of drug. OBJECTIVE: The objective of this study was to develop the self micro-emulsifying formulation of standardized extract of SEL leaves and evaluate its pharmacodynamic performance for antidiabetic activity. MATERIALS AND METHODS: The SME formulation was prepared by using sefsol-218 as oil, cremophor-EL as surfactant and transcutol-P as co-surfactant. The ratio of surfactant and co surfactant was determined by pseudoternary phase diagram. SME formulations were characterized for dilution at different pH, self emulsification, optical clarity, globule size and thermodynamic stability. Pharmacodynamic evaluation of formulations was assessed in Wistar rats by using parameters viz. blood glucose level and serum lipid profile. RESULTS: SEL loaded SME formulation was successfully developed by using sefsol-218, cremophor-EL and transcutol-P with a droplet size 23.53 nm. Pharmacodynamic results showed a higher reduction in blood glucose by SME formulation than SEL without SMES respectively at 50 mg/kg dose while reduction produced at dose of 100 mg/kg was found significant and better on 15th day of study. The percentage reduction produced by SME formulation on serum lipid profile was also significant and was more prominent than SEL. CONCLUSION: This study confirms that the formulation elevates the pharmacodynamic performance of SEL approximately two fold. PMID- 29229369 TI - Dielectric study of Clove oil. AB - Dielectric properties of clove oil were determined using an impedance gain phase analyzer (HP 4194 A) at discrete frequencies between 10 kHz and 3 MHz and a range of temperature between 25 degrees C and 45 degrees C. A micro processor controller based temperature controller (Julabo F-25) was used for keeping the temperature of clove oil constant. Dielectric constant of the sample is found to decrease with increase in frequency and temperature, while dielectric loss decreases with increase in frequency but increases with increase in temperature. Penetration depth has been calculated with the help of dielectric data and is found to decrease with increase in frequency. PMID- 29229370 TI - Differences in signal peptide processing between GP3 glycoproteins of Arteriviridae. AB - We reported previously that carbohydrate attachment to an overlapping glycosylation site adjacent to the signal peptide of GP3 from equine arteritis virus (EAV) prevents cleavage. Here we investigated whether this unusual processing scheme is a feature of GP3s of other Arteriviridae, which all contain a glycosylation site at a similar position. Expression of GP3 from type-1 and type-2 porcine reproductive and respiratory syndrome virus (PRRSV) and from lactate dehydrogenase-elevating virus (LDV) revealed that the first glycosylation site is used, but has no effect on signal peptide cleavage. Comparison of the SDS PAGE mobility of deglycosylated GP3 from PRRSV and LDV with mutants having or not having a signal peptide showed that GP3's signal peptide is cleaved. Swapping the signal peptides between GP3 of EAV and PRRSV revealed that the information for co translational processing is not encoded in the signal peptide, but in the remaining part of GP3. PMID- 29229371 TI - Measuring NO production rate from l-arginine in MELAS by mass spectrometry-based approaches: GC-MS or LC-MS/MS? PMID- 29229372 TI - Invasive and noninvasive hemodynamic assessment in adults with Fontan palliation. AB - BACKGROUND/OBJECTIVES: Although echocardiographic-Doppler cardiac index (CI) assessment is widely used to guide heart failure management in patients with biventricular circulation, this application has not been studied in the Fontan population. The objective of this study was to: (1) determine the correlation between Doppler and cardiac catheterization CI calculation; (2) determine the association between Doppler CI and the occurrence of Fontan failure. METHODS: Retrospective review of adult Fontan patients followed at Mayo Clinic Adult Congenital Heart Disease program, 1994-2015. Inclusion criteria were: systemic left ventricle and echocardiogram and cardiac catheterization performed within the same week. Fontan failure was defined as a composite of all-cause mortality, heart transplantation listing, and palliative care. RESULTS: 59 patients (age 29+/-6years; men 32[54%]) underwent 97 studies. Of the 59, 41[69%] had atriopulmonary Fontan and 12 (20%) had cirrhosis. Compared to patients without cirrhosis, patients with cirrhosis had higher Doppler CI (3.6+/-0.6 vs 2.8+/ 0.4L/min*m2, p=0.039); Fick CI (3.3 [2.5-3.7] vs 2.4 [1.6-3.1] L/min/m2, p=0.028); lower systemic vascular resistance (20+/-3 vs 25+/-4 WU*m2, p=0.04). There was a positive correlation between Doppler and Fick CI (r=0.52; p<0.0001). Fontan failure occurred in 13 patients (22%) within 7.5+/-2.1years. In patients without cirrhosis, Fick CI and Doppler CI <2.5L/min/m2 were associated with Fontan failure (odds ratio [OR] 1.58, p=0.046) and (OR 1.43, p=0.051) respectively. CONCLUSIONS: Doppler CI assessment in feasible in a selected group of Fontan patients and it is predictive of clinical outcomes. The application of this concept in systemic right ventricles deserves further research. PMID- 29229373 TI - Paper-based detection of HIV-1 drug resistance using isothermal amplification and an oligonucleotide ligation assay. AB - Regular HIV-1 viral load monitoring is the standard of care to assess antiretroviral therapy effectiveness in resource-rich settings. Persistently elevated viral loads indicate virologic failure (VF), which warrants HIV drug resistance testing (HIVDRT) to allow individualized regimen switches. However, in settings lacking access to HIVDRT, clinical decisions are often made based on symptoms, leading to unnecessary therapy switches and increased costs of care. This work presents a proof-of-concept assay to detect M184V, the most common drug resistance mutation after first-line antiretroviral therapy failure, in a paper format. The first step isothermally amplifies a section of HIV-1 reverse transcriptase containing M184V using a recombinase polymerase amplification (RPA) assay. Then, an oligonucleotide ligation assay (OLA) is used to selectively label the mutant and wild type amplified sequences. Finally, a lateral flow enzyme linked immunosorbent assay (ELISA) differentiates between OLA-labeled products with or without M184V. Our method shows 100% specificity and 100% sensitivity when tested with samples that contained 200 copies of mutant DNA and 800 copies of wild type DNA prior to amplification. When integrated with sample preparation, this method may detect HIV-1 drug resistance at a low cost and at a rural hospital laboratory. PMID- 29229374 TI - Genetic therapies for spinal muscular atrophy type 1. PMID- 29229375 TI - The pathophysiology of migraine: implications for clinical management. AB - The understanding of migraine pathophysiology is advancing rapidly. Improved characterisation and diagnosis of its clinical features have led to the view of migraine as a complex, variable disorder of nervous system function rather than simply a vascular headache. Recent studies have provided important new insights into its genetic causes, anatomical and physiological features, and pharmacological mechanisms. The identification of new migraine-associated genes, the visualisation of brain regions that are activated at the earliest stages of a migraine attack, a greater appreciation of the potential role of the cervical nerves, and the recognition of the crucial role for neuropeptides are among the advances that have led to novel targets for migraine therapy. Future management of migraine will have the capacity to tailor treatments based on the distinct mechanisms of migraine that affect individual patients. PMID- 29229376 TI - Combat-related guilt and the mechanisms of exposure therapy. AB - Exposure therapy (EXP) is one of the most widely used and empirically supported treatments for PTSD; however, some researchers have questioned its efficacy with specific populations and in targeting specific symptoms. One such symptom, guilt, has garnered increased attention in the PTSD treatment literature, as it is associated with worse symptomatology and outcomes. The current study examined cognitive changes in guilt in response to Intensive (3-week) and Standard (17 week) Trauma Management Therapy (TMT), and the potential mechanisms underlying TMT treatment. TMT is an exposure based intervention that does not include an emotional processing component after the imaginal exposure session. A portion of the sample completed measures of guilt. As a result, sample size for these analyses ranged from 39 to 102 and varied by the domain and measure. Of the 102 individuals that completed the PTSD Checklist- Military Version, 42 completed the Trauma Related Guilt Inventory, and 39 completed the Clinician Administered PTSD Scale supplemental guilt items. Participants reported significant reductions in trauma-related guilt symptoms over the course of the TMT interventions. Greater reductions in avoidance and prior session general arousal predicted the reduction of guilt symptoms. Exposure therapy may be effective in reducing trauma-related guilt even in the absence of the emotional processing component of treatment. PMID- 29229377 TI - Dosimetric effects of saline- versus water-filled balloon applicators for IORT using the model S700 electronic brachytherapy source. AB - PURPOSE: The Xoft Axxent Electronic Brachytherapy System (Xoft, Inc., San Jose, CA) is a viable option for intraoperative radiation therapy (IORT) treatment of early-stage breast cancer. The low-energy (50-kVp) X-ray source simplifies shielding and increases relative biological effectiveness but increases dose distribution sensitivity to medium composition. Treatment planning systems typically assume homogenous water for brachytherapy dose calculations, including precalculated atlas plans for Xoft IORT. However, Xoft recommends saline for balloon applicator filling. This study investigates dosimetric differences due to increased effective atomic number (Zeff) for saline (Zeff = 7.56) versus water (Zeff = 7.42). METHODS: Balloon applicator diameters range from 3 to 6 cm. Monte Carlo N-Particle software is used to calculate dose at the surface (Ds) of and 1 cm away (D1cm) from the water-/saline-filled balloon applicator using a single dwell at the applicator center as a simple estimation of the dosimetry and multiple dwells simulating the clinical dose distributions for the atlas plans. RESULTS: Single-dwell plans show a 4.4-6.1% decrease in Ds for the 3- to 6-cm diameter applicators due to the saline. Multidwell plans show similar results: 4.9% and 6.4% Ds decrease, for 4-cm and 6-cm diameter applicators, respectively. For the single-dwell plans, D1cm decreases 3.6-5.2% for the 3- to 6-cm diameter applicators. For the multidwell plans, D1cm decreases 3.3% and 5.3% for the 4-cm and 6-cm applicators, respectively. CONCLUSIONS: The dosimetric effect introduced by saline versus water filling for Xoft balloon applicator-based IORT treatments is ~5%. Users should be aware of this in the context of both treatment planning and patient outcome studies. PMID- 29229378 TI - Geriatrics training for nurses in a skilled nursing facility: a GWEP feasibility study. AB - Geriatrics knowledge and expertise is critical to the care of older adults in skilled nursing facilities. However, opportunities for ongoing geriatrics training for nurses working in skilled nursing facilities are often scarce or nonexistent. This feasibility study describes a mixed-methods analysis of nurses' educational needs and barriers to continuing education in a for-profit skilled nursing facility in an underserved, urban environment. Potential mechanisms to overcome barriers are proposed. PMID- 29229379 TI - Improving diagnosis in healthcare: Local versus national adoption of recommended guidelines for the clinical breast examination. AB - BACKGROUND: This study explores the long-term effectiveness of a newly developed clinical skills curriculum. METHODS: Students (N = 40) were exposed to a newly developed, simulation-based, clinical breast exam (CBE) curriculum. The same students returned one year later to perform the CBE and were compared to a convenience sample of medical students (N = 15) attending a national conferences. All students were given a clinical vignette and performed the CBE. CBE techniques were video recorded. Chi-squared tests were used to assess differences in CBE technique. RESULTS: Students exposed to a structured curriculum performed physical examination techniques more consistent with national guidelines than the random, national student sample. Structured curriculum students were more organized, likely to use two hands, a linear search pattern, and include the nipple-areolar complex during the CBE compared to national sample (p < 0.01). CONCLUSIONS: Students exposed to a structured skills curriculum more consistently performed the CBE according to national guidelines. The variability in technique compared with the national sample of students calls for major improvements in adoption and implementation of structured skills curricula. PMID- 29229380 TI - Analysis of retracted articles in the surgical literature. AB - BACKGROUND: Retractions of scientific articles represent attempts to correct the literature. Our goal was to examine retracted surgical papers. METHODS: NCBI PubMed database was queried using the search terms "surgery," "surg," or "surgical" and "retracted" or "retraction." Article details were recorded. RESULTS: There were 184 retracted surgical articles identified from 1991 through 2015. Average retraction time was 3.6 years. General (26%), Cardiac (22%), and Orthopedic (10%) surgery were most common. Reasons for retraction were duplication (35.3%), Institutional Review Board violations (18.5%), falsified data (14.7%), data errors (9.8%), author dispute (8.2%), plagiarism (7.6%), copyright violations (2.2%), financial disclosure violations (0.5%), and consent (0.5%). No reason for retraction was given in 8.7% of cases. Median IF was higher for administrative than content-related retraction reasons (3.0 vs. 2.0, P < 0.01). A paywall, requiring a subscription to read, restricted access to 23.4% of retraction notices. CONCLUSIONS: Article retractions occur across all fields of surgery for various reasons, both administrative and content-related. The majority of surgical retraction notices have a reason for retraction listed and do not require payment to read. PMID- 29229381 TI - Factors associated with morbidity and in-hospital mortality after surgery beyond the age of 90: Comparison with outcome results of younger patients matched for treatment. AB - BACKGROUND: Surgical outcome to extremes of age is understudied. The purpose of this study was to evaluate the patient characteristics and incidence of postoperative morbidity and in-hospital mortality among patients aged 90 years and older who underwent surgery in comparison to younger controls. METHODS: Patients aged 90 years or older (n = 80; mean age, 92.36 +/- 2.37) were matched for surgical treatment with patients aged 79 years or younger (n = 80; mean age, 55.98 +/- 15.95) taken from the same cohort. RESULTS: The overall morbidity and mortality rates were 57.5% and 31.3% in the elderly vs. 47.5% and 23.1% in the younger group respectively. Patient groups aged 90 years or older and 79 years or younger each had 4 and 6 predictive factors for morbidity and 10 and 9 predictive factors for mortality respectively. CONCLUSION: while advanced age carries an increased risk of morbidity and mortality, it seems that age in itself is no barrier to surgery. Despite the comparably high prevalence of chronic disease, elderly patients in this study fared quite well. PMID- 29229382 TI - Is incident type 2 diabetes associated with cumulative excess weight and abdominal adiposity? Tehran Lipid and Glucose Study. AB - AIMS: To examine the association of the risk of incident type 2 diabetes (T2D) with cumulative excess weight (CEW) and cumulative excess waist circumference (CEWC) scores. METHODS: Adults participants without T2D (n = 4635) aged >=20 years were included in the study. The differences between the body mass index (BMI) and waist circumference (WC) values and their normal references were calculated until the incident T2D. The CEW and CEWC scores represent the accumulation of BMI and WC deviations from normal values over time, i.e. (kg/m2 * years and cm * years, respectively). Time-dependent Cox models, adjusting for confounders were used to examine the association between CEW/CEWC and the risk of T2D. Further multivariate analyses were performed to examine the association of CEW and CEWC with incident diabetes in baseline BMI and WC strata. RESULTS: There were 503 incident cases of T2D over a median follow-up 9.38 years. The multivariate sex adjusted hazard ratios (HR) per one standard deviation (SD) increase in CEW and CEWC were 1.23 (95% CI: 1.15-1.32) and 1.41 (1.25-1.59), respectively. After further adjustment for baseline BMI and WC, no significant association was observed for CEW (1.02: 0.84-1.23) and CEWC (1.09: 0.93-1.28) and incident T2D. A strong association was found between CEW and CEWC with incident diabetes among overweight (2.12: 1.20-3.74) and centrally obese individuals (1.29: 1.10-1.51), respectively. CONCLUSIONS: Generally, CEW and CEWC were not associated with risk of T2D, independent of baseline values for BMI and WC, respectively. Moreover, CEW and CEWC highlighted an increased risk among overweight and centrally obese participants for T2D. PMID- 29229383 TI - Short-term culture with IL-2 is beneficial for potent memory chimeric antigen receptor T cell production. AB - Interleukin-2 (IL-2) has been extensively used to boost the body's immune cells, especially T cells. IL-2 is a cytokine that for many years was used to activate and amplify T cells. Due to its potent T cell growth-inducing functions in vitro, for many years, IL-2 was used for the culture and expansion of various T cell products, including tumor-infiltrating lymphocytes (TIL), T cell receptors T cells (TCR T), or genetically engineered cells with chimeric antigen receptors T cells (CAR T). Despite its positive effect on T cell production, the side-effect is not well studied. Here, we reported that long-term culture with IL-2 promotes terminal differentiation and impairs rather than boosts the function of chimeric antigen receptor T cells. However, short-term culture with IL-2 predominantly generates memory CAR T cell favorable for cancer treatment. PMID- 29229384 TI - Crystal structure of the chloroplast RNA editing factor MORF2. AB - RNA editing is a post-transcription process that alters the genetic information on RNA molecules. In plastids and mitochondria of flowering plants, the multiple organellar RNA editing factors (MORFs) interact with the PLS-type pentatricopeptide repeat (PPR) proteins and participate in RNA editing of cytidine-to-uridine conversion. The PPR proteins recognize cytidine targets around the editing sites, and the MORF proteins modulate the RNA-binding activity of the PPR proteins. Here, we report the structure of the Arabidopsis thaliana chloroplast MORF2 at 2.4 A resolution. The structure, adopting typical MORF-box fold as observed in mitochondrial MORF1 and chloroplast MORF9, reveals an MORF1 like dimerization mode. The difference between the two dimerization modes can be attributed to F157 (corresponding F162 in MORF1 and W160 in MORF9), which causes a 60 degrees shift upon dimerization. This observation, together with the PPR MORF2 model, suggests a dimer-to-monomer transition during RNA editosome formation. PMID- 29229385 TI - Circular RNA hsa_circ_0001564 regulates osteosarcoma proliferation and apoptosis by acting miRNA sponge. AB - Circular RNAs (circRNAs) is a novel type of non-coding RNAs generated from back splicing, which has been verified to mediate multiple tumorigenesis. However, the role of circRNA in osteosarcoma is still unclear. In the present study, we preliminarily screened the circRNAs expression profiles in osteosarcoma and investigated the potential regulation mechanism. The circRNAs expression profiles in osteosarcoma were screened using circRNA microarray analysis, and results showed that there were 1152 circRNAs up-regulated and 915 circRNAs down-regulated in tumor tissue compared to adjacent tissue. Hsa_circ_0001564, located at 5q35.3 and its associated-gene symbol is CANX, was one of the significantly overexpressed circRNAs in osteosarcoma tissue, as well as in osteosarcoma cell lines. In functional experiments, hsa_circ_001564 knockdown significantly suppressed the proliferation activity, induced cell cycle arrest in G0/G1 phase, and promoted apoptosis in HOS and MG-63 cells. Subsequently, we explored the probable mechanism of hsa_circ_001564, and fortunately, bioinformatics analysis revealed that miR-29c-3p contained the complementary binding region with hsa_circ_0001564, which was confirmed by dual-luciferase reporter assay. Moreover, rescue experiments illustrated that miR-29c-3p could reverse the oncogenesis effect of hsa_circ_001564. Our study discovers that hsa_circ_0001564 acts as miR-29c-3p sponge to mediate the tumorigenicity, which could act as a potential biomarker for the osteosarcoma and provide a novel insight for competing endogenous RNAs (ceRNAs) mechanism in osteosarcoma. PMID- 29229386 TI - The interaction of soybean reticulon homology domain protein (GmRHP) with Soybean mosaic virus encoded P3 contributes to the viral infection. AB - Soybean mosaic virus (SMV), a member of the Potyvirus genus, is a prevalent and devastating viral pathogen in soybean-growing regions worldwide. Potyvirus replication occurs in the 6K2-induced viral replication complex at endoplasmic reticulum exit sites. Potyvirus-encoded P3 is also associated with the endoplasmic reticulum and is as an essential component of the viral replication complex, playing a key role in viral replication. This study provides evidence that the soybean (Glycine max) reticulon homology domain protein (designated as GmRHP) interacts with SMV-P3 by using a two-hybrid yeast system to screen a soybean cDNA library. A bimolecular fluorescence complementation assay further confirmed the interaction, which occurred on the cytomembrane, endoplasmic reticulum and cytoskeleton in Nicotiana benthamiana cells. The transient expression of GmRHP can promote the coupling of Turnip mosaic virus replication and cell-to-cell movement in N. benthamiana. The interaction between the membrane protein SMV-P3 and GmRHP may contribute to the potyvirus infection, and GmRHP may be an essential host factor for P3's involvement in potyvirus replication. PMID- 29229387 TI - miR-124-3p affects the formation of intramuscular fat through alterations in branched chain amino acid consumption in sheep. AB - Intramuscular fat is used to determine meat quality in animals; however, factors affecting branched chain amino acid (BCAA) catabolism, which fuels adipogenesis and lipogenesis, remain unclear. To better understand the post-transcriptional influence on BCAA catabolism during adipogenesis, we investigated the role of miR 124-3p. Stromal vascular fraction (SVF) cells were isolated from skeletal muscle of sheep, and induced to differentiate. We determined the roles of miR-124-3p and its predicted target, branched chain keto acid dehydrogenase E1, alpha polypeptide (BCKDHA), in adipogenic differentiation and lipogenesis of SVFs after overexpressing or inhibiting miR-124-3p or BCKDHA, respectively. miR-124-3p altered the luciferase activity of constructs containing 3'-UTR of BCKDHA and the formation of lipid droplets, along with the adipogenic markers and BCAA consumption. Besides, the adipogenic performance and BCAA consumption in BCKDHA overexpressing or knocked-down SVFs and the expression of adipogenic marker genes were altered. We demonstrate that miR-124-3p is an important factor for adipogenesis and provide insights into the formation of intramuscular fat in animals. PMID- 29229388 TI - LncRNA SNHG12 promotes tumorigenesis and metastasis in osteosarcoma by upregulating Notch2 by sponging miR-195-5p. AB - Osteosarcoma is the most common primary malignant bone tumor and has a high fatality rate in children and adolescents. Recently, an increasing amount of evidence has demonstrated that lncRNAs have crucial roles in regulating biological characteristics in malignant tumors. Therefore, this research was carried out to uncover the biological function and the potential molecular mechanism of SNHG12 in osteosarcoma. In this study, we found that SNHG12 was significantly upregulated in both osteosarcoma tissues and cell lines and osteosarcoma patients with high levels of SNHG12 tended to have a poor prognosis. We evaluated the biological function of SNHG12 in 143B and U2OS cells and show that the downregulation of SNHG12 suppressed cell proliferation by blocking cell cycle progression at the G0/G1 phase and weakened cell invasion and migration abilities. Dual-luciferase reporter and RIP assays were conducted to confirm that SNHG12 functioned as a ceRNA, modulating the expression of Notch2 by sponging miR 195-5p in osteosarcoma. We further demonstrate that Notch2 played a crucial role in activating the Notch signaling pathway. In conclusion, SNHG12 might serve as a valuable biomarker and prognosis factor in osteosarcoma patients. The SNHG12/miR 195-5p/Notch2-Notch signaling pathway axis might become a novel therapeutic for osteosarcoma. PMID- 29229389 TI - Direct evidence that KLK4 is a hydroxyapatite-binding protein. AB - The protease kallikrein 4 (KLK4) plays a pivotal role during dental enamel formation by degrading the major enamel protein, amelogenin, prior to the final steps of enamel hardening. KLK4 dysfunction is known to cause some types of developmental defect in enamel but the mechanisms responsible for transient retention of KLK4 in semi-hardened enamel matrix remain unclear. To address contradictory reports about the affinity of KLK4 for enamel hydroxyapatite-like mineral, we used pure components in quasi-physiological conditions and found that KLK4 binds hydroxyapatite directly. Hypothesising KLK4 self-destructs once amelogenin is degraded, biochemical analyses revealed that KLK4 progressively lost activity, became aggregated, and autofragmented when incubated without substrate in both the presence and absence of reducer. However, with non-ionic detergent present as proxy substrate, KLK4 remained active and intact throughout. These findings prompt a new mechanistic model and line of enquiry into the role of KLK4 in enamel hardening and malformation. PMID- 29229390 TI - Structural insight into a novel indole prenyltransferase in hapalindole-type alkaloid biosynthesis. AB - FamD1 is a novel CloQ/NphB-family indole prenyltransferase which involves in hapalindole-type alkaloid biosynthesis. Here the native FamD1 structure and three protein-ligand complexes are analyzed to investigate the molecular basis of substrate binding and catalysis. FamD1 adopts a typical ABBA architecture of aromatic prenyltransferase, in which the substrate-binding chamber is found in the central beta-barrel. The indole-containing acceptor substrate is bound adjacent to the prenyl donor. Based on the complex structures, a catalytic mechanism of FamD1 is proposed. Functional implications on the sister enzyme FamD2 are also discussed. PMID- 29229392 TI - A novel cold-regulated gene from Phlox subulata, PsCor413im1, enhances low temperature tolerance in Arabidopsis. AB - Low temperature stress adversely affects plant growth, development, and crop productivity. Analysis of the function of genes in the response of plants to low temperature stress is essential for understanding the mechanism of chilling and freezing tolerance. In this study, PsCor413im1, a novel cold-regulated gene isolated from Phlox subulata, was transferred to Arabidopsis to investigate its function under low temperature stress. Real-time quantitative PCR analysis revealed that PsCor413im1 expression was induced by cold and abscisic acid. Subcellular localization revealed that PsCor413im1-GFP fusion protein was localized to the periphery of the chloroplast, consistent with the localization of chloroplast inner membrane protein AtCor413im1, indicating that PsCor413im1 is a chloroplast membrane protein. Furthermore, the N-terminal of PsCor413im1 was determined to be necessary for its localization. Compared to the wild-type plants, transgenic plants showed higher germination and survival rates under cold and freezing stress. Moreover, the expression of AtCor15 in transgenic plants was higher than that in the wild-type plants under cold stress. Taken together, our results suggest that the overexpression of PsCor413im1 enhances low temperature tolerance in Arabidopsis. PMID- 29229391 TI - Hepatocyte-specific clusterin overexpression attenuates diet-induced nonalcoholic steatohepatitis. AB - Clusterin is a multifunctional glycoprotein that plays important roles and is up regulated in liver diseases such as hepatitis and hepatocellular carcinoma. However, little is known about the significance of clusterin in the pathogenesis of non-alcoholic steatohepatitis (NASH). The aim of this study is to examine the role of clusterin in progression of steatohepatitis in mice fed a methionine and choline deficient (MCD) diet. We generated hepatocyte-specific clusterin overexpression (hCLU-tg) mice, and hCLU-tg mice showed lower levels of hepatic triglycerides, less infiltration of macrophages and reduction of TNF-alpha, activation of Nrf-2 than wild-type littermates fed the MCD diet. Also, sustained clusterin expression in liver ameliorated hepatic fibrogenesis by reducing the activation of hepatic stellate cells by MCD diet. Sustained expression of clusterin in liver functioned as a preconditioning stimulus and prevented MCD diet-induced severe steatohepatitis injury via Nrf2 activation. These results demonstrate a novel function of clusterin as an immune preconditioning regulator in various inflammatory diseases including steatohepatitis. PMID- 29229393 TI - A triangular loop of domain D1 of FlgE is essential for hook assembly but not for the mechanical function. AB - The bacterial flagellar hook is a short, curved tubular structure made of FlgE. The hook connects the basal body as a rotary motor and the filament as a helical propeller and functions as a universal joint to smoothly transmit torque produced by the motor to the filament. Salmonella FlgE consists of D0, Dc, D1 and D2 domains. Axial interactions between a triangular loop of domain D1 (D1-loop) and domain D2 are postulated to be responsible for hook supercoiling. In contrast, Bacillus FlgE lacks the D1-loop and domain D2. Here, to clarify the roles of the D1-loop and domain D2 in the mechanical function, we carried out deletion analysis of Salmonella FlgE. A deletion of the D1-loop conferred a loss-of function phenotype whereas that of domain D2 did not. The D1-loop deletion inhibited hook polymerization. Suppressor mutations of the D1-loop deletion was located within FlgD, which acts as the hook cap to promote hook assembly. This suggests a possible interaction between the D1-loop of FlgE and FlgD. Suppressor mutant cells produced straight hooks, but retained the ability to form a flagellar bundle behind a cell body, suggesting that the loop deletion does not affect the bending flexibility of the Salmonella hook. PMID- 29229394 TI - MiR-628-5p decreases the tumorigenicity of epithelial ovarian cancer cells by targeting at FGFR2. AB - Micro RNAs (miRNAs) are small non-coding RNAs which are 19-24 nucleotides in length. MiRNAs play a vital role in the whole process of tumour development, but how they influence the tumourigenecity of epithelial ovarian cancer (EOC)cells is rarely researched. In our study, it was verified that miR-628-5p decreased the stem like cell percentage of EOC cells by inducing their apoptosis. The animal experiments showed that miR-628-5p decreased the tumourigenecity of EOC cells. Besides, we found miR-628-5p targeted at and down-regulated the expression of fibroblast growth factor receptor 2 (FGFR2). FGFR2 expressed higher in ovarian cancer tissues and was correlated with worse prognosis. Our findings indicated that miR-628-5pplays an important role in ovarian cancer stem cell driven tumorigenesis. PMID- 29229395 TI - The effect of shoulder position on motor evoked and maximal muscle compound action potentials of the biceps brachii. AB - The purpose of the study was to assess the effect of shoulder position, 0 degrees versus 90 degrees shoulder flexion, on stimulation intensity and maximal muscle compound action potentials (Mmax) and motor evoked potentials (MEP) of the biceps brachii during both rest and 10% maximum voluntary contraction (MVC). Nine participants completed two experimental sessions with four conditions. During each condition, transcranial magnetic (TMS) and Erb's point stimulation were used to elicit MEPs and Mmax, respectively. During rest, the TMS intensity to elicit a MEP response (p<0.001), was significantly lower by 28.6+/-6.8%, in the 90 degrees compared to the 0 degrees position, but the stimulation intensity to elicit a Mmax was not different. MEP (p<0.001) and Mmax (p<0.001) amplitudes were significantly higher by 212.4+/-43.3% and 86.5+/-38.0%, respectively in the 90 degrees compared to the 0 degrees position. During 10% MVC the Mmax stimulation intensity (p=0.022), but not TMS intensity, was significantly lower by 7.4+/-3.8% in the 90 degrees compared to the 0 degrees position. Mmax (p<0.001) amplitudes were significantly higher by 92.2+/-20.2% in the 90 degrees compared to the 0 degrees position whereas MEP (p<0.001) amplitudes were significantly lower by 24.5+/-6.0% in the 90 degrees compared to the 0 degrees position. In conclusion, TMS intensity and Mmax intensity were both shoulder-position and state-dependent, whereas MEP and Mmax amplitudes were only shoulder position dependent. PMID- 29229396 TI - Albeit nocturnal, rats subjected to traumatic brain injury do not differ in neurobehavioral performance whether tested during the day or night. AB - Behavioral assessments in rats are overwhelmingly conducted during the day, albeit that is when they are least active. This incongruity may preclude optimal performance. Hence, the goal of this study was to determine if differences in neurobehavior exist in traumatic brain injured (TBI) rats when assessed during the day vs. night. The hypothesis was that the night group would perform better than the day group on all behavioral tasks. Anesthetized adult male rats received either a cortical impact or sham injury and then were randomly assigned to either Day (1:00-3:00p.m.) or Night (7:30-9:30p.m.) testing. Motor function (beam balance/walk) was conducted on post-operative days 1-5 and cognitive performance (spatial learning) was assessed on days 14-18. Corticosterone (CORT) levels were quantified at 24h and 21days after TBI. No significant differences were revealed between the TBI rats tested during the Day vs. Night for motor or cognition (p's<0.05). CORT levels were higher in the Night-tested TBI and sham groups at 24h (p<0.05), but returned to baseline and were no longer different by day 21 (p>0.05), suggesting an initial, but transient, stress response that did not affect neurobehavioral outcome. These data suggest that the time rats are tested has no noticeable impact on their performance, which does not support the hypothesis. The finding validates the interpretations from numerous studies conducted when rats were tested during the day vs. their natural active period. PMID- 29229397 TI - Di-acetyl creatine ethyl ester, a new creatine derivative for the possible treatment of creatine transporter deficiency. AB - Creatine is pivotal in energy metabolism of the brain. In primary creatine deficiency syndromes, creatine is missing from the brain. Two of them (AGAT and GAMT deficiency) are due to impaired creatine synthesis, and can be treated by creatine supplementation. By contrast, creatine transporter deficiency cannot be treated by such supplementation, since creatine crossing of biological membranes (plasma membrane and blood-brain barrier) is dependent on its transporter. This problem might be overcome by modifying the creatine molecule to allow it to cross biological membranes independently of its transporter. Thus, we designed and synthesized di-acetyl creatine ethyl ester (DAC), a compound that should cross biological membranes independently of the transporter due to its very high lipophilicity. We investigated its ability to increase intracellular creatine levels even after block of creatine transporter, and to counter cell damage induced by transporter block. In our experiments after block of the creatine transporter, DAC was able both to prevent electrophysiological failure and to increase intracellular creatine. Interestingly, it did so in micromolar concentrations, at variance with all the other creatine derivatives that we know of. PMID- 29229398 TI - Can an aversive, extinction-resistant memory trigger impairments in walking adaptability? An experimental study using adult rats. AB - Cognitive demands can influence the adaptation of walking, a crucial skill to maintain body stability and prevent falls. Whilst previous research has shown emotional load tunes goal-directed movements, little attention has been given to this finding. This study sought to assess the effects of suffering an extinction resistant memory on skilled walking performance in adult rats, as an indicator of walking adaptability. Thus, 36 Wistar rats were divided in a two-part experiment. In the first part (n=16), the aversive, extinction-resistance memory paradigm was established using a fear-conditioning chamber. In the second, rats (n=20) were assessed in a neutral room using the ladder rung walking test before and tree days after inducing an extinction-resistance memory. In addition, the elevated plus-maze test was used to control the influence of the anxiety-like status on gait adaptability. Our results revealed the shock group exhibited worse walking adaptability (lower skilled walking score), when compared to the sham group. Moreover, the immobility time in the ladder rung walking test was similar to the controls, suggesting that gait adaptability performance was not a consequence of the fear generalization. No anxiety-like behavior was observed in the plus maze test. Finally, correlation coefficients also showed the skilled walking performance score was positively correlated with the number of gait cycles and trial time in the ladder rung walking test and the total crossings in the plus maze. Overall, these preliminary findings provide evidence to hypothesize an aversive, extinction-resistant experience might change the emotional load, affecting the ability to adapt walking. PMID- 29229399 TI - The malleus cap: Anatomic description of cartilage of the lateral process of the malleus. AB - PURPOSE: To anatomically describe a cartilaginous cap attached to the lateral process of the malleus. STUDY DESIGN: Histologic and gross anatomic review. METHODS: Twenty temporal bones were histologically reviewed. The anatomical relationship between the tympanic membrane and malleus was then defined at the level of the lateral process of the malleus and the long process of the malleus. Separately, gross evaluation of these levels at the macroscopic level was undertaken through endoscopic imaging in five subjects. RESULTS: All temporal bones reviewed revealed the presence of a cartilaginous cap articulating between the tympanic membrane and the lateral process of the malleus. The cartilaginous cap was also readily identifiable in gross evaluation of the tympanic membrane from views lateral and medial to the tympanic membrane during endoscopic evaluation. CONCLUSION: The cartilaginous cap of the lateral process of the malleus is an important and reliable anatomical structure of the middle ear that has not previously been described. Through knowledge of the structure surgeons may exploit its presence by creating a cleavage plane between the cartilaginous cap and the malleus during tympanoplasty, possibly allowing for safer and more efficient surgery. PMID- 29229402 TI - Full-field strain distribution in multi-vertebra spine segments: An in vitro application of digital image correlation. AB - The biomechanics of the spine is experimentally assessed in terms of range of motion and overall stiffness. Quantification of the surface strain distribution is currently limited either to the vertebrae or the discs, whereas a full-field approach to measure the strain distribution in a multi-vertebra segment is currently missing. The aim of this work was to explore the feasibility of using Digital Image Correlation (DIC) to measure the strain distribution simultaneously on the vertebral bodies and the intervertebral discs of spine segments in different loading configurations. Three porcine spine segments were tested. A white-on-black speckle pattern was prepared which covered the hard and soft tissues. Two different loading configurations (flexion and lateral bending) were reproduced, while two sides of the spine were analyzed with DIC. Measurements were successfully performed on the entire region of interest of all specimens, in both configurations. The DIC analysis highlighted the strain gradients present on the spine segments including tension and compression associated with bending, the direction of principal strains in the different regions, as well as bulging of the discs under compression. Strains of tens of thousands microstrain were measured in the discs, and below 2000 microstrain in the bone. This work showed the feasibility of applying DIC on spine segments including hard and soft tissues. It also highlights the need for a full-field investigation, because of the strain inhomogeneity in the vertebrae and discs. PMID- 29229400 TI - Tumor Necrosis Factor-producing T-regulatory Cells Are Associated With Severe Liver Injury in Patients With Acute Hepatitis A. AB - BACKGROUND AND AIMS: CD4+CD25+Foxp3+ T-regulatory (Treg) cells control immune responses and maintain immune homeostasis. However, under inflammatory conditions, Treg cells produce cytokines that promote inflammation. We investigated production of tumor necrosis factor (TNF) by Treg cells in patients with acute hepatitis A (AHA), and examined the characteristics of these cells and association with clinical factors. METHODS: We analyzed blood samples collected from 63 patients with AHA at the time of hospitalization (and some at later time points) and 19 healthy donors in South Korea. Liver tissues were collected from patients with fulminant AHA during liver transplantation. Peripheral blood mononuclear cells were isolated from whole blood and lymphocytes were isolated from liver tissues and analyzed by flow cytometry. Cytokine production from Treg cells (CD4+CD25+Foxp3+) was measured by immunofluorescence levels following stimulation with anti-CD3 and anti-CD28. Epigenetic stability of Treg cells was determined based on DNA methylation patterns. Phenotypes of Treg cells were analyzed by flow cytometry and an RORgammat inhibitor, ML-209, was used to inhibit TNF production. Treg cell suppression assay was performed by co-culture of Treg-depleted peripheral blood mononuclear cells s and isolated Treg cells. RESULTS: A higher proportion of CD4+CD25+Foxp3+ Treg cells from patients with AHA compared with controls produced TNF upon stimulation with anti-CD3 and anti-CD28 (11.2% vs 2.8%). DNA methylation analysis confirmed the identity of the Treg cells. TNF-producing Treg cells had features of T-helper 17 cells, including up regulation of RORgammat, which was required for TNF production. The Treg cells had reduced suppressive functions compared with Treg cells from controls. The frequency of TNF-producing Treg cells in AHA patients' blood correlated with their serum level of alanine aminotransferase. CONCLUSIONS: Treg cells from patients with AHA have altered functions compared with Treg cells from healthy individuals. Treg cells from patients with AHA produce higher levels of TNF, gain features of T-helper 17 cells, and have reduced suppressive activity. The presence of these cells is associated with severe liver injury in patients with AHA. PMID- 29229403 TI - Detection of ventricular premature beats based on the pressure signals of a hemodialysis machine. AB - Monitoring of ventricular premature beats (VPBs), being abundant in hemodialysis patients, can provide information on cardiovascular instability and electrolyte imbalance. In this paper, we describe a method for VPB detection which explores the signals acquired from the arterial and the venous pressure sensors, located in the extracorporeal blood circuit of a hemodialysis machine. The pressure signals are mainly composed of a pump component and a cardiac component. The cardiac component, severely overshadowed by the pump component, is estimated from the pressure signals using an earlier described iterative method. A set of simple features is extracted, and linear discriminant analysis is performed to classify beats as either normal or ventricular premature. Performance is evaluated on signals from nine hemodialysis treatments, using leave-one-out crossvalidation. The simultaneously recorded and annotated photoplethysmographic signal serves as the reference signal, with a total of 149,686 normal beats and 3574 VPBs. The results show that VPBs can be reliably detected, quantified by a Youden's J statistic of 0.9, for average cardiac pulse pressures exceeding 1 mmHg; for lower pressures, the J statistic drops to 0.55. It is concluded that the cardiac pressure signal is suitable for VPB detection, provided that the average cardiac pulse pressure exceeds 1 mmHg. PMID- 29229401 TI - Regular Use of Aspirin or Non-Aspirin Nonsteroidal Anti-Inflammatory Drugs Is Not Associated With Risk of Incident Pancreatic Cancer in Two Large Cohort Studies. AB - BACKGROUND & AIMS: Use of aspirin and/or non-aspirin nonsteroidal anti inflammatory drugs (NSAIDs) reduces the risk of several cancers, but it is not clear if use of these drugs is associated with risk of pancreatic cancer. METHODS: We evaluated aspirin and non-aspirin NSAID use and risk of pancreatic adenocarcinoma in 141,940 participants from the Health Professionals Follow-up Study and Nurses' Health Study using multivariable-adjusted Cox proportional hazards regression. We considered several exposure classifications to model differing lag times between NSAID exposure and cancer development. We also conducted a nested case-control study of participants from 3 prospective cohorts using conditional logistic regression to evaluate pre-diagnosis levels of plasma salicylurate, a major metabolite of aspirin, in 396 pancreatic cancer cases and 784 matched individuals without pancreatic cancer (controls). RESULTS: In the prospective cohort study, 1122 participants developed pancreatic adenocarcinoma over 4.2 million person-years. Use of aspirin or non-aspirin NSAIDs was not associated with pancreatic cancer risk, even after considering several latency exposure classifications. In a pre-planned subgroup analysis, regular aspirin use was associated with reduced pancreatic cancer risk among participants with diabetes (relative risk, 0.71; 95% CI, 0.54-0.94). In the nested case-control study, pre-diagnosis levels of salicylurate were not associated with pancreatic cancer risk (odds ratio, 1.08; 95% CI, 0.72-1.61; Ptrend 0.81; comparing participants in the highest quintile with those in the lowest quintile of plasma salicylurate). CONCLUSIONS: Regular aspirin or non-aspirin NSAID use was not associated with future risk of pancreatic cancer in participants from several large prospective cohort studies. A possible reduction in risk for pancreatic cancer among people with diabetes who regularly use aspirin should be further examined in preclinical and human studies. PMID- 29229404 TI - Integrated experimental and computational approach to laser machining of structural bone. AB - This study describes the fundamentals of laser-bone interaction during bone machining through an integrated experimental-computational approach. Two groups of laser machining parameters identified the effects of process thermodynamics and kinetics on machining attributes at micro to macro. A continuous wave Yb fiber Nd:YAG laser (wavelength 1070 nm) with fluences in the range of 3.18 J/mm2 8.48 J/mm2 in combination of laser power (300 W-700 W) and machining speed (110 mm/s-250 mm/s) were considered for machining trials. The machining attributes were evaluated through scanning electron microscopy observations and compared with finite element based multiphysics-multicomponent computational model predicted values. For both groups of laser machining parameters, experimentally evaluated and computationally predicted depths and widths increased with increased laser energy input and computationally predicted widths remained higher than experimentally measured widths whereas computationally predicted depths were slightly higher than experimentally measured depths and reversed this trend for the laser fluence >6 J/mm2. While in both groups, the machining rate increased with increased laser fluence, experimentally derived machining rate remained lower than the computationally predicted values for the laser fluences lower than ~4.75 J/mm2 for one group and ~5.8 J/mm2 for other group and reversed in this trend thereafter. The integrated experimental-computational approach identified the physical processes affecting machining attributes. PMID- 29229405 TI - Instrumented socket inserts for sensing interaction at the limb-socket interface. AB - The objective of this research was to investigate a strategy for designing and fabricating computer-manufactured socket inserts that were embedded with sensors for field monitoring of limb-socket interactions of prosthetic users. An instrumented insert was fabricated for a single trans-tibial prosthesis user that contained three sensor types (proximity sensor, force sensing resistor, and inductive sensor), and the system was evaluated through a sequence of laboratory clinical tests and two days of field use. During in-lab tests 3 proximity sensors accurately distinguish between don and doff states; 3 of 4 force sensing resistors measured gradual pressure increases as weight-bearing increased; and the inductive sensor indicated that as prosthetic socks were added the limb moved farther out of the socket and pistoning amplitude decreased. Multiple sensor types were necessary in analysis of field collected data to interpret how sock changes affected limb-socket interactions. Instrumented socket inserts, with sensors selected to match clinical questions of interest, have the potential to provide important insights to improve patient care. PMID- 29229406 TI - Validation of single-plane fluoroscopy and 2D/3D shape-matching for quantifying shoulder complex kinematics. AB - Fluoroscopy and 2D/3D shape-matching has emerged as the standard for non invasively quantifying kinematics. However, its accuracy has not been well established for the shoulder complex when using single-plane fluoroscopy. The purpose of this study was to determine the accuracy of single-plane fluoroscopy and 2D/3D shape-matching for quantifying full shoulder complex kinematics. Tantalum markers were implanted into the clavicle, humerus, and scapula of four cadaveric shoulders. Biplane radiographs were obtained with the shoulder in five humerothoracic elevation positions (arm at the side, 30 degrees , 60 degrees , 90 degrees , maximum). Images from both systems were used to perform marker tracking, while only those images acquired with the primary fluoroscopy system were used to perform 2D/3D shape-matching. Kinematics errors due to shape matching were calculated as the difference between marker tracking and 2D/3D shape-matching and expressed as root mean square (RMS) error, bias, and precision. Overall RMS errors for the glenohumeral joint ranged from 0.7 to 3.3 degrees and 1.2 to 4.2 mm, while errors for the acromioclavicular joint ranged from 1.7 to 3.4 degrees . Errors associated with shape-matching individual bones ranged from 1.2 to 3.2 degrees for the humerus, 0.5 to 1.6 degrees for the scapula, and 0.4 to 3.7 degrees for the clavicle. The results of the study demonstrate that single-plane fluoroscopy and 2D/3D shape-matching can accurately quantify full shoulder complex kinematics in static positions. PMID- 29229407 TI - Inducing targeted failure in cadaveric testing of 3-segment spinal units with and without simulated metastases. AB - We propose an experimental setup and protocol able to induce targeted failure of the middle vertebra in 3-segment spinal units and to capture the specimens' deformation in their post-failure state. Sixteen 3-segment spinal units with and without artificial metastases were destructively tested in axial compression using one of two failure criteria; either: (A) A clear drop in force (>10-15% of peak force) (n = 4); or (B) A minimum displacement of 5 mm (n = 12). Subsequently, the specimens were fully fixated in polymethylmethacrylate (PMMA), thereby preserving their post-failure state. Pre- and post-experiment computed tomography (CT) scans were acquired to determine the occurrence of failure in one of the vertebral bodies. All specimens were successfully fixated in their post failure state. When applying failure criterion A, two specimens showed signs of failure. When applying failure criterion B, all specimens showed signs of failure; in 9 out of 12 specimens this occurred in the middle vertebrae only. In conclusion, this research provides an experimental setup and protocol able to induce targeted failure of 3-segment spinal units and to capture the specimens' deformation in their post-failure state. Furthermore, this study illustrates the importance of an adequate failure criterion for successful simulation of vertebral fractures in an experimental setup. PMID- 29229408 TI - Imbalance in DNA repair machinery is associated with BRAFV600E mutation and tumor aggressiveness in papillary thyroid carcinoma. AB - The involvement of alterations in MLH1, an essential mismatch repair component, in BRAFV600E mutated papillary thyroid carcinoma (PTC) has been suggested to be associated with features of tumor aggressiveness. Thirty-two PTC and surrounding normal thyroid tissues were evaluated for 11 representative DNA repair genes expression. BRAFV600E mutational status assessment and clinicopathological correlations were evaluated for their gene and protein expression. BRAFV600E PTC is associated with lower levels of XPD and MLH1 gene expression. Decrease in MLH1 and XPD mRNA levels in BRAFV600E PTC (but not their protein products) are associated with predictors of poor patient outcomes. Considering the complete subset of patients, MGMT and XRCC2 genes were shown down and upregulated, respectively, in PTC tissues. Low expression of MGMT gene and weak XRCC2 protein expression were correlated with characteristics of tumor aggressiveness. These results suggest that an imbalance in DNA repair gene expression in PTC is associated with aggressive clinicopathological features and BRAFV600E mutation. PMID- 29229409 TI - Postpartum depression screening and pelvic floor symptoms among women referred to a specialty postpartum perineal clinic. AB - BACKGROUND: Postpartum depression and pelvic floor disorders are both common conditions that affect women; however, the association between the 2 has yet to be determined. OBJECTIVE: The aims of our study are to: (1) determine the prevalence of a positive postpartum depression screen in a specialty postpartum perineal clinic, and (2) identify risk factors for postpartum depression in this population. STUDY DESIGN: A retrospective chart review was performed of 294 women referred to a specialty postpartum perineal clinic at the University of Michigan from March 30, 2012, through May 3, 2016. Women who completed a new patient intake form, including the Edinburgh Postnatal Depression Scale, were included. The prevalence of a positive Edinburgh Postnatal Depression Scale screen (>=10) was determined. Bivariate analyses were used to compare demographics, delivery characteristics, referral indications, and postpartum pelvic floor symptoms between women with and without a positive Edinburgh Postnatal Depression Scale screen. Significant variables identified in the analyses were then used to perform logistic regression to identify factors independently associated with a positive Edinburgh Postnatal Depression Scale screen. RESULTS: In all, 15.6% (46/294) of women had a positive postpartum depression screen. Average age was 30.6 +/- 4.8 years, average body mass index was 28.9 +/- 5.06 kg/m2, 68.0% (200/294) were Caucasian, 79.6% (234/294) were primiparous, and 86.0% (245/285) were breast-feeding. Using multivariable logistic regression, women with a positive postpartum depression screen had higher odds of being non-Caucasian (adjusted odds ratio, 2.72; 95% confidence interval, 1.27-5.832; P = .01), having a history of depression and/or anxiety (adjusted odds ratio, 2.77; 95% confidence interval, 1.23-6.24; P = .01), having been referred for pain (adjusted odds ratio, 2.61; 95% confidence interval, 1.24-5.49; P = .01), and reporting urinary incontinence during and after pregnancy (adjusted odds ratio, 3.81; 95% confidence interval, 1.57-9.25; P = .003). CONCLUSION: Urinary incontinence during and after pregnancy and referral for pain were pelvic floor symptoms independently associated with a positive postpartum depression screen in women referred to a specialty perineal clinic. Therefore, consideration should be given to depression screening in women presenting with perinatal urinary incontinence and persistent postpartum pain, as these women may be at increased risk of developing postpartum depression. PMID- 29229410 TI - Pre-weaning maternal separation increases eating later in life in male and female offspring, but increases brainstem dopamine receptor 1a and 2a only in males. AB - Maternal separation stress (MS) is a model of early life stress performed by the separation between dam and pups in the first days of life. This model has been associated with eating behavior and dopaminergic system abnormal phenotypes. This study aims to investigate whether maternal separation in the light or dark phase of the circadian cycle promotes phenotypic adjustments in the eating behavior and the dopamine system in both males and females. Lactating Wistar rats were separated from their litters from postnatal day 1 (PND 1) to PND 14 for 6 h in the light or dark phase of the circadian cycle. The groups of female control (FC), male control (MC), female rat separated in the dark (FSD), male rat separated in the dark (MSD), female rat separated in the light (FSL), and male rat separated in the light (MSL) were composed. The assessment of food intake was performed at the age of 120-150 days and the analysis of brainstem drd1a and drd2a dopamine receptors expression at 180 days of life. Maternal separation promoted higher palatable diet intake independent on sex and circadian cycle. On the other hand, drd1a and drd2a dopamine receptors expression were higher only in males separated in the dark phase of the circadian cycle. These findings demonstrate that maternal separation effects on feeding behavior do not depend on sex and circadian cycle, but the effects on dopamine receptors expression depend on sex and circadian cycle. PMID- 29229411 TI - Disentangling the effects of parental food restriction on child's risk of overweight. AB - The links between parental restriction of food intake, child's eating behaviour and child's adiposity are still unclear. Our aim was to validate a model suggesting an underlying mechanism for the impact of parental restriction on child's adiposity through a broad dimension of child's eating temperament entitled the appetite reactivity (including both appetite arousal and appetite persistence). Using an online questionnaire administered at home to children aged between 8 and 11 years (N = 414) with one or both of their parents, we measured: based on child's reports, the perceived maternal restriction of child's food intake, the appetite reactivity and both the desired and the eaten mean food portion sizes; based on parental reports, the mean food portion size given to the child and the child's BMI. Structural equation modelling was used to test a model linking measured variables. A well-fitting structural model (AGFI = 0.91; RMSEA = 0.07; SRMR = 0.08) was identified, showing that: (i) perceived maternal restriction of child's food intake negatively impacts child's appetite arousal and food portion size but positively influences child's appetite persistence; (ii) the two components of appetite reactivity have a positive effect on child's adiposity which is partly mediated by child's actual food portion size. Results suggest an explanation for the controversy surrounding the links between parental food restriction and child's adiposity: through its negative impact on child's appetite arousal and food portion size, parental control may protect against overweight, but because of its positive effect on appetite persistence, it can also be detrimental. PMID- 29229412 TI - Long-term Voice Outcome Following Radiation Versus Laser Microsurgery in Early Glottic Cancer. AB - OBJECTIVES: Long-term voice outcome (LTVO) after radiation (XRT) or trans-oral laser microsurgery (TLM) is unclear. This study is a multi-modality analysis of LTVO following XRT or TLM in patients with early glottic cancer. We hypothesize that as compared with TLM, LTVO is worse in the XRT group because of progressive fibrosis in the glottic tissue MATERIAL AND METHODS: One hundred and two patients with early glottic carcinoma (carcinoma in situ, T1, T2) were included. Multi modality voice analyses were performed with self-perception using Voice Handicap Index-10, objective analysis using Analysis of Dysphonia in Speech and Voice Software (Cepstral Spectral Index of Dysphonia score for Consensus Auditory Perceptual Evaluation of Voice sentences), and perceptual rating by two blinded speech language pathologists (GRBAS scale). RESULTS: Fifty-five patients received TLM (mean follow-up = 52 months) and 47 patients had XRT (mean follow-up = 65 months). There is no difference between the two groups in sex, age, stage, and follow-up time. Intraclass correlation coefficient between raters was high at 0.94. Controlling for age and stage, XRT increases total GRBAS score by 1.38 points (P = 0.006) and increases Cepstral Spectral Index of Dysphonia score by 13.7 points (P < 0.001) when compared with the TLM group. No significant differences were found in the Voice Handicap Index score between the XRT and the TLM groups. CONCLUSIONS: This is the first multi-modality voice analysis to suggest TLM results in better LTVO than XRT in GRBAS score and objective voice analysis but not in self-perception. These differences may reflect the progressive effects of XRT on glottic tissue. A randomized controlled study is required to confirm our findings. PMID- 29229413 TI - Constant light environment suppresses maturation and reduces complexity of new born neuron processes in the hippocampus and caudal nidopallium of a diurnal corvid: Implication for impairment of the learning and cognitive performance. AB - Periodic day-night environment shapes the temporal pattern in the behaviour and physiology (e.g. 24-h activity-rest and sleep-wake cycles) and the advanced brain function, such as learning, memory and decision making. In a previous study, we showed the abolition of 24-h rhythm in the activity-rest pattern, and an attenuated cognitive performance in diurnal Indian house crows (Corvus splendens) under constant light (no-night; LL) environment. Present study extended this, and investigated LL-induced effects on the neurogenesis (birth, maturation and neurite complexity of new born neurons) in the hippocampus and caudal nidopallium, the brain regions directly associated with learning and cognition in birds. We performed immunohistochemistry of doublecortin (DCX; a neurogenesis marker) and tyrosine hydroxylase (TH, a key enzyme of the dopamine biosynthesis) in the brain section containing hippocampus or caudal nidopallium of Indian house crows exposed for 2 weeks to LL, with controls maintained under 12L:12D. As expected, crows showed arrhythmicity with a significantly reduced rest period in the 24-h activity-rest pattern, and a decreased cognitive performance when tested for the spatial and pattern association learning tasks under LL. Importantly, there was a significant decrease in DCX-immunoreactive (ir) cells and, as shown by Sholl analysis, in the complexity of DCX-ir neurites in both, the hippocampus and caudal nidopallium of crows under LL, as compared to those under 12L:12D. The anatomical proximity of DCX-ir neurons with TH-ir fibers suggested a functional association of the new born hippocampal and caudal nidopallial neurons with the learning, and perhaps cognition in Indian house crows. These results give insights into possible impact of the loss of night on brain health and functions in an emerging ecosystem in which other diurnal species including humans may be inadvertently exposed to an illuminated night, such as in an overly lighted metropolitan urban habitat. PMID- 29229414 TI - Lipid droplets induced by secreted phospholipase A2 and unsaturated fatty acids protect breast cancer cells from nutrient and lipotoxic stress. AB - Cancer cells driven by the Ras oncogene scavenge unsaturated fatty acids (FAs) from their environment to counter nutrient stress. The human group X secreted phospholipase A2 (hGX sPLA2) releases FAs from membrane phospholipids, stimulates lipid droplet (LD) biogenesis in Ras-driven triple-negative breast cancer (TNBC) cells and enables their survival during starvation. Here we examined the role of LDs, induced by hGX sPLA2 and unsaturated FAs, in protection of TNBC cells against nutrient stress. We found that hGX sPLA2 releases a mixture of unsaturated FAs, including omega-3 and omega-6 polyunsaturated FAs (PUFAs), from TNBC cells. Starvation-induced breakdown of LDs induced by low micromolar concentrations of unsaturated FAs, including PUFAs, was associated with protection from cell death. Interestingly, adipose triglyceride lipase (ATGL) contributed to LD breakdown during starvation, but it was not required for the pro-survival effects of hGX sPLA2 and unsaturated FAs. High micromolar concentrations of PUFAs, but not OA, induced oxidative stress-dependent cell death in TNBC cells. Inhibition of triacylglycerol (TAG) synthesis suppressed LD biogenesis and potentiated PUFA-induced cell damage. On the contrary, stimulation of LD biogenesis by hGX sPLA2 and suppression of LD breakdown by ATGL depletion reduced PUFA-induced oxidative stress and cell death. Finally, lipidomic analyses revealed that sequestration of PUFAs in LDs by sPLA2-induced TAG remodelling and retention of PUFAs in LDs by inhibition of ATGL-mediated TAG lipolysis protect from PUFA lipotoxicity. LDs are thus antioxidant and pro-survival organelles that guard TNBC cells against nutrient and lipotoxic stress and emerge as attractive targets for novel therapeutic interventions. PMID- 29229415 TI - Return to Sports After Tibial Tubercle Osteotomy for Patellofemoral Pain and Osteoarthritis. AB - PURPOSE: To determine the rate of return to sports and clinical outcomes after anteromedialization (AMZ) tibial tubercle osteotomy (TTO) for patients with patellofemoral pain and/or osteoarthritis. METHODS: This study is a retrospective case series of consecutive patients who underwent unilateral or staged bilateral AMZ TTO for a primary diagnosis of patellofemoral pain or arthritis. Included were all patients with minimum 1-year follow-up. The indication for surgery was failure of at least 6 months of nonoperative treatment. Simultaneous tubercle distalization or proximal-medial soft-tissue procedures were excluded; however, prior patellar instability procedures did not prohibit inclusion if there was no recurrence. A diagnostic arthroscopy was performed to evaluate the cartilage surfaces; AMZ TTO was performed by use of a freehand technique and two 4.5-mm fully threaded screws for fixation. A gradual return to activities was permitted at 6 months; however, contact sports were prohibited until 9 months postoperatively. Patients were evaluated retrospectively for participation in sports using a questionnaire about the level of participation, return to sporting activities, and Kujala score. Statistical analysis included 1-way analysis of variance and chi2 or Fisher exact and paired t tests. RESULTS: Forty-eight patients played sports within 3 years before surgery. The majority were female patients (84.2%). The average age at surgery was 29.6 years, with an average follow-up period of 4.6 years. The average Kujala score improved from 51.2 to 82.6 (P < .0001); the average pain score improved from 4.1 to 1.8 (P < .001). Of the patients, 83.3% returned to at least 1 sport on average 7.8 months postoperatively. Of these, 77.5% believed they returned to sports at the same level or a higher level. CONCLUSIONS: Patients undergoing AMZ TTO for patellofemoral pain or arthritis had an 83.3% rate of return to 1 or more sporting activities at an average of 7.8 months after surgery, with many patients returning at the same level or a higher level of intensity compared with their preoperative state. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29229416 TI - Comparison of Arthroscopic and Conservative Treatments for Knee Osteoarthritis: A 5-Year Retrospective Comparative Study. AB - PURPOSE: To compare the effectiveness of arthroscopic and conservative treatments in patients with knee osteoarthritis (KOA) with 5 years of follow-up. METHODS: Patients diagnosed with Kellgren-Lawrence grade 2 to 4 KOA who underwent arthroscopic or conservative treatment from May 2005 to May 2012 were included. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score was collected 1, 2, 3, 4, and 5 years after the initial treatment, and the number of patients who underwent total knee arthroplasty (TKA) at every time point was recorded. RESULTS: Three hundred eighty-two patients (168 in the conservative group and 214 in the arthroscopy group) were included. Five years after the initial treatment, 32 of the 214 patients who underwent arthroscopy (15.0%) compared with 30 of the 168 patients in the conservative treatment group (17.9%) ultimately underwent TKA, with no statistically significant difference between groups (P = .20). The WOMAC score was significantly lower in the arthroscopy group than in the conservative group at year 1 (24.33 +/- 21.56 vs 36.43 +/- 16.22, respectively) and year 2 (26.31 +/- 17.84 vs 35.41 +/- 19.21, respectively). There were no significant between-group differences at years 3, 4, and 5. CONCLUSIONS: Compared with conservative treatment, arthroscopy provided no benefit in decreasing or delaying arthroplasty surgery. However, arthroscopy had a greater ability to relieve symptoms at 1 and 2 years. Our results suggest that arthroscopy can relieve symptoms up to 2 years without elevating the risk of arthroplasty. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29229417 TI - Diagnostic Value of Computed Tomography and Risk Factors for Lateral Hinge Fracture in the Open Wedge High Tibial Osteotomy. AB - PURPOSE: The purposes of this study were to evaluate (1) the disparity of detection of lateral hinge fracture (LHF) between postoperative simple radiography and high-resolution computed tomography (CT) and affecting factors of LHF and (2) whether generally recommended postoperative rehabilitation protocols are appropriate according to the type of LHF. METHODS: From 2014 to 2015, patients who underwent primary open wedge high tibial osteotomy (OWHTO) for isolated medial compartment osteoarthritis of the knee joint were retrospectively enrolled. The patients with minimum 1-year follow-up were included. The incidence of LHF after OWHTO based on simple radiographs was compared with its incidence based on CT scans. In the stable type of LHF and the non-LHF group, early weight bearing was encouraged immediately after OWHTO. In unstable LHF (types II and III), weight bearing was delayed until 2 weeks postoperatively. RESULTS: Twenty three cases (24.5%) of LHF after 94 OWHTOs were detected (15 cases on simple radiographs, 8 cases on CT scan). The coronal osteotomy slope and the osteotomy gap were significantly larger in the LHF group than in the non-LHF group (coronal osteotomy slope, 20.3 degrees +/- 5.1 degrees vs 16.7 degrees +/- 4.2 degrees , P = .001; anterior osteotomy gap, 7.9 mm +/- 2.1 mm vs 6.7 mm +/- 1.8 mm, P = .008; posterior osteotomy gap, 12.7 mm +/- 3.7 mm vs 11.2 mm +/- 3.2 mm, P = .048). The correction loss of the hip-knee-ankle angle and the medial proximal tibial angle in the LHF group was significantly larger than those in the non-LHF group (1.3 degrees +/- 1.8 degrees vs 0.4 degrees +/- 1.4 degrees , P < .001; 1.3 degrees +/- 1.1 degrees vs 0.7 degrees +/- 0.9 degrees , P = .009, respectively). CONCLUSIONS: Further evaluation with CT scanning is highly valuable immediately after all OWHTO because of its higher detection rate (24.5%) of LHF compared with simple radiographs (16%). In addition, the coronal osteotomy slope was steeper and the opening gap was larger in the LHF group than in the non LHF group. Finally, the LHF should be managed conservatively in order to prevent postoperative correction loss. LEVEL OF EVIDENCE: Level III, case-control study. PMID- 29229418 TI - A Biomechanical Evaluation of Various Double Krackow Suture Techniques for Soft Tissue Graft Fixation. AB - PURPOSE: The purpose of this study was to compare the biomechanical properties among the different double Krackow suture techniques for tendon graft fixation. METHODS: Thirty porcine flexor profundus tendons were randomly divided into 3 groups of 10 specimens each. Three different double Krackow suture techniques were evaluated, namely, the McKeon's double Krackow (MDK) suture, Wilson's double Krackow (WDK) suture, and Ostrander's modified Krackow (OMK) suture. All suture configurations were completed with a braided nonabsorbable suture. Each suture tendon construct was pretensioned to 100 N for 3 cycles, cyclically loaded from 50 to 200 N for 200 cycles, and then finally loaded to failure. Elongation after cyclic loading, ultimate load to failure, and the mode of failure were recorded for each specimen. RESULTS: There were significant differences in elongation after cyclic loading among the MDK suture (7.9 +/- 3.6 mm, 14% +/- 6%), WDK suture (11.6 +/- 2.2 mm, 22% +/- 3%), and OMK suture (9.6 +/- 3.3 mm, 17% +/- 6%; P = .018). In addition, although the post hoc analysis showed that elongation after cyclic loading in the MDK suture was significantly less than the WDK suture (P = .004), ultimate failure load and cross-sectional area were not significantly different across the 3 groups. CONCLUSIONS: In this porcine in vitro biomechanical study, the MDK suture had significantly smaller elongation after cyclic loading than the WDK suture; however, high elongation values may have a potential for risk of clinical laxity. The ultimate failure load was not different across the MDK, WDK, and OMK sutures. CLINICAL RELEVANCE: Smaller elongation during cyclic loading in a suture-tendon construct represents a lower possibility of tendon graft loosening after ligament reconstruction surgery. The double Krackow suture techniques are attractive options for tendon graft fixation in ligament reconstruction, and the MDK suture could possibly be the optimal choice among the double Krackow suture techniques. PMID- 29229419 TI - Capillary electrophoresis as a fast and efficient alternative for the analysis of Urceola rosea leaf extracts. AB - Urceola rosea, a plant whose leaves are used as food and for medical purposes, is a climbing liana found in many south-east Asian countries. Main polar compounds are flavonoids (kaempferol and quercetin glycosides) and phenolic acids. As an alternative to the established HPLC method their analysis by capillary electrophoresis is described for the first time. It was possible in <8min with a 25mM sodium tetraborate decahydrate solution with pH8.5, at a capillary temperature of 40 degrees C and an applied voltage of 25kV. Up to five compounds could be quantified in different methanolic U. rosea extracts, which showed to be of variable composition; e.g. the content of total flavonoids ranged from 0.29 to 1.08%. In respect to quantitative results as well as validation parameters (e.g. R2>=0.994, recovery rates from 95.5 to 103.6%, inter-day precision<=4.5%) the CE method was well comparable to HPLC. However, in terms of required analysis time and environmental sustainability capillary electrophoresis is definitely advantageous. PMID- 29229420 TI - ROS-mediated oligomerization of VDAC2 is associated with quinocetone-induced apoptotic cell death. AB - Quinocetone (QCT) has been approved and widely used as an animal feed additive in China since 2003. However, investigations indicate that QCT shows potential toxicity both in vitro and in vivo. Although voltage dependent anion channel 1 (VDAC1) involved in regulating QCT-induced apoptotic cell death has been established, the role of voltage dependent anion channel 2 (VDAC2) in QCT-induced toxicity remains unclear. In this study, we showed that QCT-induced cell death was coupled to VDAC2 oligomerization. Moreover, VDAC inhibitor 4, 4' diisothiocyano stilbene-2, 2'-disulfonic acid (DIDS) alleviated QCT-induced cell death and VDAC2 oligomerization. Meanwhile, overexpression VDAC2 aggravated QCT induced VDAC2 oligomerization. In addition, caspase inhibitor Z-VAD-FMK and reactive oxidative species (ROS) scavenger N-acetyl-l-cysteine (NAC) apparently blocked QCT-induced cell death and VDAC2 oligomerization. Finally, overexpression N-terminal truncated VDAC2 attenuated QCT-induced VDAC2 oligomerization but had no influence on its localization to mitochondria when comparing to the full length of VDAC2. Taken together, our results reveal that ROS-mediated VDAC2 oligomerization is associated with QCT-induced apoptotic cell death. The N terminal region of VDAC2 is required for QCT-induced VDAC2 oligomerization. PMID- 29229422 TI - Split-sciatic nerve surgery: A new microsurgical model in experimental nerve repair. AB - INTRODUCTION: Sciatic experimental surgery in rat often leads to hindlimb autophagy, with considerable ethical and research issues. In this work, the distal part of the sciatic nerve was split following the natural bifurcation between tibial and peroneal branches, before applying regenerative stem cells in a fibrin conduit on the peroneal segment. The new microsurgical model was tested in terms of animal morbidity and consistency of research outcomes, particularly comparing to the standard total sciatic axotomy procedure. MATERIALS AND METHODS: After dissection of sciatic the nerve, the tibial and peroneal fibres were split upwards and a total axotomy was performed in the peroneal side. The 1 cm nerve gap between the proximal sciatic nerve and peroneal nerve was crossed using fibrin conduits. The tibial nerve was not included. Experimental groups involved either empty or fibrin conduit seeded with Schwann cell-like differentiated adipose derived stem cells (dASC) (Fib + dASC). Autografts and sham rats were used as controls (total n = 20). At 12 weeks post-implantation, an extensive histomorphometric analysis was performed. Functional aspects of regeneration were analysed by walking track analysis. RESULTS: No major autophagy occurred using the split-sciatic technique. A detailed histomorphometric analysis showed consistent results with previous literature using fibrin conduits in a full sciatic axotomy experimental setting. Walking track analysis reflected the histological regeneration pattern, displaying superior regeneration in both autograft and dASC groups. CONCLUSION: Split-Sciatic nerve surgery reduced animal morbidity, while being representative of the whole nerve as regeneration outcomes were consistent with previous data obtained on the whole sciatic nerve. The decreased autophagy rate allowed for a more efficient functional evaluation. PMID- 29229421 TI - The amino analogue of beta-boswellic acid efficiently attenuates the release of pro-inflammatory mediators than its parent compound through the suppression of NF kappaB/IkappaBalpha signalling axis. AB - Natural product derivatives have proven to be cutting edge window for drug discovery and development. BA-25 (3-alpha-o-acetoxy-4beta-amino-11-oxo-24-norurs 12-ene) an amino analogue of beta-boswellic acid exhibited inhibition of TNF alpha and IL-6 in THP-1 cells as demonstrated previously, however, the effect on principal inflammatory mediators such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and the pathways that mediate this function remains unknown. This study was designed to examine the comparative anti-inflammatory activity of BA-25 with its parent compound, beta boswellic acid both in vitro and in vivo. The effect of BA and BA-25 on suppression of NO, PGE2, LTB4, COX-2 in LPS-stimulated RAW 264.7 cells was determined by ELISA, RT-PCR and ROS by flow cytometry. Phosphorylation of NF-kBp65, IKB degradation was determined by western blotting and also the nuclear localization of NF-kBp65 was assessed by immunofluorescence. Furthermore, this study was extended on Carrageenan induced paw oedema modelled BALB/c mice. A novel derivative BA-25, reported first time notably decreased the LPS (1 MUg/mL) induced upregulation in the transcription of TNF-alpha, IL-6, iNOS and COX-2. Also the protein expression of iNOS and COX-2 as well as their downstream products NO and PGE2 respectively, were also decreased efficiently at a concentration of 10 MUM than BA. Moreover, LPS upregulated NF-kB p65 expression and IkappaB degradation was significantly decreased after BA-25 treatment. In addition, the treatment of BA-25 also restored the paw oedema and decreased the magnitude of histopathological alterations. Our data together suggested that BA-25 might be regarded as prospective therapeutic anti inflammatory alternative and demands further investigation in pharmacological studies. PMID- 29229423 TI - Effect of carpal tunnel release on median nerve epineurial flux. PMID- 29229424 TI - Analysis of the correlation between deformational plagiocephaly and neurodevelopment delay: Methodological issues. PMID- 29229425 TI - Dynamic analysis on the calcium oscillation model considering the influences of mitochondria. AB - Based on the model considering the influences of mitochondria, a further theoretical study on the dynamic behaviors of calcium signals is made. First of all, the reason for the generation and disappearance of calcium oscillations is verified in theory. Second, an analysis on the model considering the influences of mitochondria and the model neglecting the influences of mitochondria is carried out. Third, beta (representing calcium leak) is introduced and it can be found that with the increase of beta, the Hopf bifurcation points of system move towards the decreasing direction of MU (representing stimulus intensity) and calcium oscillations region gradually decreases. Forth, the study on tauh (representing relaxation time) indicates that with the increase of tauh, the second Hopf bifurcation point of system moves towards the increasing direction of MU and calcium oscillations region gradually increases. Under certain stimulus intensity, when relaxation time increases, calcium oscillation peak rises rapidly and the period increases obviously. Fifth, two-parameter bifurcation diagram of Vm1 (representing mitochondria activity) and MU contains three regions: stable region, oscillation region and unstable region. When the parameters fall in the unstable region Ca2+ gather towards mitochondria and further lead to cell apoptosis. With the increase of Vm1, calcium oscillations region shrinks gradually. Vm1 and MU both play a key role in regulating cell apoptosis. Only when Vm1 and MU are high enough can cells enter into programmed cell death and the higher Vm1 is, the lower the stimulus intensity required by cell apoptosis is. PMID- 29229426 TI - CBX4 exhibits oncogenic activities in breast cancer via Notch1 signaling. AB - Polycomb chromobox (CBX) proteins are involved in gene silencing to function as oncogenes or tumor suppressors through the polycomb repressive complex (PRC1). CBX4 has been implicated in the progression of human cancers, but its role and clinical significance in breast cancer remain unclear. Here, we show that CBX4 is up-regulated in breast cancer and exerts oncogenic activities via miR-137 mediated activation of Notch1 signaling pathway. CBX4 expression was increased in breast cancer, compared with the nontumorous tissues. High CBX4 expression was closely correlated with tumor metastasis, advanced clinical stage and poor overall survival in a cohort of 179 patients with breast cancer. In vitro studies demonstrated that CBX4 overexpression enhanced, whereas CBX4 knockdown inhibited cell growth and migration. Mechanistically, in a PRC1-dependent manner, CBX4 inhibited the promoter activity of miR-137 and suppressed its expression. miR-137 decreased the expression of Notch1, Jag1 and Hey2 via targeting their 3'-UTRs. The suppression of Notch1 by siRNA or overexpression of miR-137 markedly attenuated CBX4-promoted phenotypes. Collectively, these findings indicate that CBX4 promotes breast cancer via miR-137-mediated Notch1 signaling. Our data, therefore, suggest that CBX4 serve as a prognostic biomarker and that targeting CBX4/miR-137 axis may provide therapeutic potent in the treatment of breast cancer. PMID- 29229427 TI - Cost-effectiveness of dengue vaccination in ten endemic countries. AB - Following publication of results from two phase-3 clinical trials in 10 countries or territories, endemic countries began licensing the first dengue vaccine in 2015. Using a published mathematical model, we evaluated the cost-effectiveness of dengue vaccination in populations similar to those at the trial sites in those same Latin American and Asian countries. Our main scenarios (30-year horizon, 80% coverage) entailed 3-dose routine vaccinations costing US$20/dose beginning at age 9, potentially supplemented by catch-up programs of 4- or 8-year cohorts. We obtained illness costs per case, dengue mortality, vaccine wastage, and vaccine administration costs from the literature. We estimated that routine vaccination would reduce yearly direct and indirect illness cost per capita by 22% (from US$10.51 to US$8.17) in the Latin American countries and by 23% (from US$5.78 to US$4.44) in the Asian countries. Using a health system perspective, the incremental cost-effectiveness ratio (ICER) averaged US$4,216/disability-adjusted life year (DALY) averted in the five Latin American countries (range: US$666/DALY in Puerto Rico to US$5,865/DALY in Mexico). In the five Asian countries, the ICER averaged US$3,751/DALY (range: US$1,935/DALY in Malaysia to US$5,101/DALY in the Philippines). From a health system perspective, the vaccine proved to be highly cost effective (ICER under one times the per capita GDP) in seven countries and cost effective (ICER 1-3 times the per capita GDP) in the remaining three countries. From a societal perspective, routine vaccination proved cost-saving in three countries. Including catch-up campaigns gave similar ICERs. Thus, this vaccine could have a favorable economic value in sites similar to those in the trials. PMID- 29229428 TI - Not all HPV nucleic acid tests are equal: only those calibrated to detect high grade lesions matter for cervical screening: Response to 'Concordant testing results between various human papillomavirus assays in primary cervical cancer screening: systematic review' by de Thurah, Bonde, Uyen, Lam and Rebolj. Published 27 May, 2017. PMID- 29229429 TI - Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations. AB - BACKGROUND: Deriving suitable dosing regimens for antibiotic combination therapy poses several challenges as the drug interaction can be highly complex, the traditional pharmacokinetic-pharmacodynamic (PKPD) index methodology cannot be applied straightforwardly, and exploring all possible dose combinations is unfeasible. Therefore, semi-mechanistic PKPD models developed based on in vitro single and combination experiments can be valuable to suggest suitable combination dosing regimens. AIMS: To outline how the interaction between two antibiotics has been characterized in semi-mechanistic PKPD models. We also explain how such models can be applied to support dosing regimens and design future studies. SOURCES: PubMed search for published semi-mechanistic PKPD models of antibiotic drug combinations. CONTENT: Thirteen publications were identified where ten had applied subpopulation synergy to characterize the combined effect, i.e. independent killing rates for each drug and bacterial subpopulation. We report the various types of interaction functions that have been used to describe the combined drug effects and that characterized potential deviations from additivity under the PKPD model. Simulations from the models had commonly been performed to compare single versus combined dosing regimens and/or to propose improved dosing regimens. IMPLICATIONS: Semi-mechanistic PKPD models allow for integration of knowledge on the interaction between antibiotics for various PK and PD profiles, and can account for associated variability within the population as well as parameter uncertainty. Decisions on suitable combination regimens can thereby be facilitated. We find the application of semi-mechanistic PKPD models to be essential for efficient development of antibiotic combination regimens that optimize bacterial killing and/or suppress resistance development. PMID- 29229430 TI - Self-Guided Online Cognitive Behavioral Strategies for Chemotherapy-Induced Peripheral Neuropathy: A Multicenter, Pilot, Randomized, Wait-List Controlled Trial. AB - : The purpose of this pilot, parallel, randomized controlled trial was to examine the efficacy of a self-guided online cognitive and behaviorally-based pain management intervention (Proactive Self-Management Program for Effects of Cancer Treatment [PROSPECT]) to reduce "worst" pain for individuals with chronic painful chemotherapy-induced peripheral neuropathy (CIPN). Secondary outcomes included "average" pain, nonpainful CIPN symptom severity, impression of change, and pain interference. Sixty patients with chronic painful CIPN were recruited from 5 outpatient academic and community cancer centers. Patients were randomized in a 1:1 ratio to receive either 8 weeks of PROSPECT or usual care. A 7-day electronic "worst" pain intensity diary and standardized measures of pain interference, nonpainful CIPN symptom severity, impression of change, and "average" pain were administered pre/post intervention. Postintervention mean scores were evaluated between groups using analysis of covariance adjusting for baseline. Individuals who received the PROSPECT intervention (n = 19) had significantly greater improvements in "worst pain" compared with individuals receiving usual care (n = 19; P = .046, d = .58). There were no significant differences in mean scores between groups for the secondary outcomes (n = 42). A larger, adequately powered study testing the PROSPECT intervention is needed to determine if improvements in pain may be sustained, evaluate the effect of the intervention on the secondary outcomes, and identify mediators of pain intensity-related improvement. PERSPECTIVE: This study explores the efficacy of an 8-week online cognitive behavioral pain management intervention for chronic painful CIPN. Intervention use resulted in greater improvements in "worst" pain than usual care alone. The findings provide preliminary support for the efficacy of a nonpharmacological intervention for chronic painful CIPN. PMID- 29229431 TI - Altered Neurocognitive Processing of Tactile Stimuli in Patients with Complex Regional Pain Syndrome. AB - : Chronic pain in complex regional pain syndrome (CRPS) has been linked to tactile misperceptions and deficits in somatotopic representation of the affected limb. In this study, we identify altered cognitive processing of tactile stimuli in CRPS patients that we propose marks heterogeneity in tactile decision-making mechanisms. In a case-control design, we compared middle- and late-latency somatosensory evoked potentials in response to pseudorandomized mechanical stimulation of the digits of both hands (including CRPS-affected and nonaffected sides) between 13 CRPS patients and 13 matched healthy controls. During a task to discriminate the digit simulated, patients (compared with controls) had significantly lower accuracy and slowed response times but with high between subject variability. At middle latencies (124-132 ms), tactile processing in patients relative to controls showed decrements in superior parietal lobe and precuneus (that were independent of task demands) but enhanced activity in superior frontal lobe (that were task-dependent). At late latencies, patients showed an augmented P300-like response under task demands that localized to the supplementary motor area. Source activity in the supplementary motor area correlated with slowed response times, although its scalp representation intriguingly correlated with better functioning of the affected limb, suggesting a compensatory mechanism. Future research should investigate the clinical utility of these putative markers of tactile decision-making mechanisms in CRPS. PERSPECTIVE: We present evidence of altered but highly variable cognitive processing (124-268 ms latency) in response to mechanical tactile stimuli in patients with CRPS compared with healthy controls. Such mid- to late-latency responses could potentially provide convenient and robust biomarkers of abnormal perceptual decision-making mechanisms in CRPS to aid in clinical detection and treatment. PMID- 29229432 TI - Correspondence: Training opportunities in renal replacement access. PMID- 29229433 TI - Establishment of integration-free induced pluripotent stem cells from human recessive dystrophic epidermolysis bullosa keratinocytes. AB - BACKGROUND: Induced pluripotent stem cell (iPSC) technology enables patient specific pluripotent stem cells to be derived from adult somatic cells without the use of an embryonic cell source. To date, recessive dystrophic epidermolysis bullosa (RDEB)-specific iPSCs have been generated from patients using integrating retroviral vectors. However, vector integration into the host genome can endanger the biosafety and differentiation propensities of iPSCs. Although various integration-free reprogramming systems have been reported, their utility in reprogramming somatic cells from patients remains largely undetermined. OBJECTIVE: Our study aims to establish safe iPSCs from keratinocytes of RDEB patients using non-integration vector. METHOD: We optimized and infected non integrating Sendai viral vectors to reprogram keratinocytes from healthy volunteers and RDEB patients. RESULTS: Sendai vector infection led to the reproducible generation of genomic modification-free iPSCs from these keratinocytes, which was proved by immunohistochemistry, reverse transcription polymerase chain reaction, methylation assay, teratoma assay and embryoid body formation assay. Furthermore, we confirmed that these iPSCs have the potential to differentiate into dermal fibroblasts and epidermal keratinocytes. CONCLUSION: This is the first report to prove that the Sendai vector system facilitates the reliable reprogramming of patient keratinocytes into transgene-free iPSCs, providing another pluripotent platform for personalized diagnostic and therapeutic approaches to RDEB. PMID- 29229434 TI - Homozygous acceptor splice site mutation in DSG1 disrupts plakoglobin localization and results in keratoderma and skin fragility. PMID- 29229435 TI - Developmental and cytogenetic assessments of preimplantation embryos derived from in-vivo or in-vitro matured human oocytes. AB - Aneuploidy is of great relevance to embryo selection, as it represents one of the important causes of implantation failure. Furthermore, immature oocytes, retrieved during gonadotrophin-stimulated IVF cycles, are generally discarded in clinics; whereas, there was no detectable comprehensive evidence on higher rates of aneuploidy based on maturity status on the day of oocyte retrieval. As well, the correlation between embryo morphology on aneuploidy remains unclear. The aim was to evaluate the developmental and genetic integrity of human preimplantation embryos from rescue in-vitro matured MII stage oocytes as well as in vivo matured oocytes. 541 rescue in-vitro matured oocytes as case as well as 659 in-vivo matured oocytes as control were used for the developmental assay. Finally, 121 cleaved embryos with good quality were analyzed by FISH technique for the detection of chromosomes X, Y, 13, 15, 16, 18, 21 and 22. The fertilization rates were 61.62% and 61.76% in case and control groups, respectively. Also, embryo formation rates of 89.1% vs. 92.2% were recorded for case and control groups, respectively. Good quality embryos on day 3 were 62.54% in case and 68.36% in control groups. There were insignificant differences in fertilization, embryo formation and quality between the groups. Total abnormality in 35 of the 60 embryos was 58.5% in case and 62.3% in control (p < 0.05). There were significant differences between aneuploidy rates of embryos using only sex chromosome preimplantation genetic screening (PGS) and sex chromosome in combination with autosomal chromosomes PGS in case (58.5% vs 28.3%, p = 0.000) and control groups (62.3% vs 21.3%; p = 0.000). The results demonstrated that a high proportion of good quality embryos were aneuploid in both patient groups with no obvious increase in aneuploidies as a result of rescue IVM application. Furthermore, the morphological characteristics of embryos do not completely consistent with chromosomal content. Despite the Rescue IVM is currently not a routine procedure in association with IVF, our finding suggested a viable option for young infertile women facing cancellation of their IVF treatment due to ovarian over response or resistance factors as well as patients with low functional ovarian reserve considering good quality of embryos from rescue IVM-MII oocytes. PMID- 29229437 TI - The epidemiology of hip fractures across western Victoria, Australia. AB - BACKGROUND: Hip fractures are associated with considerable morbidity and mortality. Hip fracture incidence varies across different levels of accessibility/remoteness and socioeconomic status (SES). As part of the Ageing, Chronic Disease and Injury Study, we aimed to map the pattern of hip fractures across the western region of the Australian state of Victoria, which contains a range of remoteness levels and SES. METHODS: Data on hip fractures resulting in hospital admission were extracted from the Victorian Admitted Episodes Dataset (VAED) for men and women aged 40+years during 2010-2013 inclusive. An age adjusted incidence rate (per 10,000population/year) was calculated for the entire region. Crude incidence rates and length of acute care hospital stay (excluding rehabilitation) were calculated for each Local Government Area (LGA). The impact of aggregated age, accessibility/remoteness index of Australia (ARIA) and SES on hip fracture rates aggregated across LGAs was determined using Poisson regression. RESULTS: For men, the age-standardised rate of hospitalisations for hip fracture across the whole region was 19.2 per 10,000population/year (95%CI 18.0-20.4) and for women, 40.0 (95%CI 38.3-41.7). The highest incidence rates for both sexes occurred in the less accessible LGAs of Yarriambiack and Hindmarsh, as well as the LGA with the lowest SES, Central Goldfields. In both sexes, approximately two thirds of individuals were discharged from acute hospital care within 14days. Increasing age, higher remoteness and lower SES were all associated with higher hip fracture rates. CONCLUSION: Crude incidence rates varied by location. Given that a high proportion of patients had acute hospital care of <=14days, and accessibility and SES were associated with hip fracture rates, these results can inform policy and provide a model for other groups to conduct similar research in their local environment. PMID- 29229436 TI - A Longitudinal Analysis of Allostatic Load among a Multi-Ethnic Sample of Midlife Women: Findings from the Study of Women's Health Across the Nation. AB - OBJECTIVES: We examined longitudinal patterns and sociodemographic correlates of allostatic load (AL), a measure of cumulative biological risk and aging, in a sample of midlife women consisting of non-Hispanic White, African American, Chinese, and Japanese women. METHODS: Longitudinal cohort data from the Study of Women's Health Across the Nation were used to examine AL patterns in midlife women ages 42-53 (n = 1,932). AL measures were created using 10 biomarkers representing cardiovascular, inflammatory, neuroendocrine, and metabolic system functioning. We used longitudinal random effects Poisson regression models to assess change in AL over the 7-year follow-up period and associations between sociodemographic factors and AL. RESULTS: On average, a woman's AL score increased 2% each year over the course of the study. Baseline measures of African American race, low family income, older age, and ability to read and speak only in English were significantly associated with higher levels of AL over the study period. We did not observe significant differences in rates of change in AL by race/ethnicity or socioeconomic status. CONCLUSIONS: This study demonstrates that AL increases in a cumulative manner as women age. Midlife is an especially important time in women's life course with respect to health maintenance and healthy aging. AL can be an early warning indicator of subsequent disease burden, pointing to subclinical conditions and the need for implementation of medical and public health interventions earlier in the disease process. PMID- 29229438 TI - Pulsed electromagnetic fields (PEMF) attenuate changes in vertebral bone mass, architecture and strength in ovariectomized mice. AB - Pulsed electromagnetic fields (PEMF) has been investigated as a noninvasive alternative method to prevent bone loss for postmenopausal osteoporosis (OP), and the bone tissue involved in these studies are usually long bones such as femur and tibia in OP patients or rat models. However, few studies have investigated the effects of PEMF on the vertebral bone in mice with OP. This study aimed to investigate whether PEMF preserve lumbar vertebral bone mass, microarchitecture and strength in ovariectomized (OVX) mouse model of OP and its associated mechanisms. Thirty 3-month-old female BALB/c mice were randomly divided into three groups (n=10): sham-operated control (Sham), ovariectomy (OVX), and ovariectomy with PEMF treatment (OVX+PEMF). The OVX+PEMF group was exposed to 15Hz, 1.6 mT PEMF for 8h/day, 7days/week. After 8weeks, the mice were sacrificed. The OVX+PEMF group showed lower body weight gain of mice induced by estrogen deficiency compared with OVX group. Biochemical analysis of serum demonstrated that serum bone formation markers including bone specific alkaline phosphatase (BALP), serum osteocalcin (OCN), osteoprotegerin (OPG) and N-terminal propeptide of type I procollagen (P1NP) were markedly higher in OVX+PEMF group compared with OVX group. Besides, serum bone resorption markers including tartrate-resistant acid phosphatase 5b (TRAP-5b) and C-terminal crosslinked telopeptides of type I collagen (CTX-I) were markedly lower in OVX+PEMF group compared with OVX group. Biomechanical test observed that OVX+PEMF group showed higher compressive maximum load and stiffness of the lumbar vertebrae compared with OVX group. Micro computed tomography (MUCT) and histological analysis of lumbar vertebrae revealed that PEMF partially prevented OVX-induced decrease of trabecular bone mass and deterioration of trabecular bone microarchitecture in lumbar vertebrae. Real-time PCR showed that the canonical Wnt signaling pathway of the lumbar vertebrae, including Wnt3a, LRP5 and beta-catenin were markedly up-regulated in OVX+PEMF group compared with OVX group. Moreover, the mRNA expressions of RANKL and OPG were markedly up-regulated in OVX+PEMF group compared with OVX group, whereas no statistical difference in RANKL/OPG mRNA ratio was found between OVX+PEMF group and OVX group. Besides, our study also found that the RANK mRNA expression was down-regulated in OVX+PEMF group compared with OVX group. Taken together, we reported that long-term stimulation with PEMF treatment was able to alleviate lumbar vertebral OP in postmenopausal mice through a combination of increased bone formation and suppressed bone resorption related to regulating the skeletal gene expressions of Wnt3a/LRP5/beta-catenin and OPG/RANKL/RANK signaling pathways. PMID- 29229439 TI - Doxycycline post-exposure prophylaxis: let the debate begin. PMID- 29229441 TI - Does dietary insect meal affect the fish immune system? The case of mealworm, Tenebrio molitor on European sea bass, Dicentrarchus labrax. AB - Feeding small European sea bass, Dicentrarchus labrax, for 6 weeks with Tenebrio molitor larval meal showed significant anti-inflammatory responses (ceruloplasmin, myeloperoxidase and nitric oxide). Serum bacteriolytic activity against a Gram negative bacterium was not significantly affected by dietary Tenebrio, while both lysozyme antibacterial activity and serum trypsin inhibition usually linked to the anti-parasite activity of the fish, were significantly enhanced. The latter may be due to the similarities in the composition of the exoskeleton of parasites and insects that may therefore act as an immunostimulant potentially increasing the anti-parasitic activity. The addition of exogenous proteases significantly decreased both trypsin-inhibition and serum bacteriolytic activity probably through direct inhibition of the proteins responsible for these immune functions. Further investigation involving bacterial or parasitic challenges will be necessary to assess if the effects of dietary mealworm meal on the immune system observed in the present study are translated into an improved resistance to diseases. PMID- 29229440 TI - Post-exposure prophylaxis with doxycycline to prevent sexually transmitted infections in men who have sex with men: an open-label randomised substudy of the ANRS IPERGAY trial. AB - BACKGROUND: Increased rates of sexually transmitted infections (STIs) have been reported among men who have sex with men. We aimed to assess whether post exposure prophylaxis (PEP) with doxycycline could reduce the incidence of STIs. METHODS: All participants attending their scheduled visit in the open-label extension of the ANRS IPERGAY trial in France (men aged 18 years or older having condomless sex with men and using pre-exposure prophylaxis for HIV with tenofovir disoproxil fumarate plus emtricitabine) were eligible for inclusion in this open label randomised study. Participants were randomly assigned (1:1) at a central site to take a single oral dose of 200 mg doxycycline PEP within 24 h after sex or no prophylaxis. The primary endpoint was the occurrence of a first STI (gonorrhoea, chlamydia, or syphilis) during the 10-month follow-up. The cumulative probability of occurrence of the primary endpoint was estimated in each group with the Kaplan-Meier method and compared with the log-rank test. The primary efficacy analysis was done on the intention-to-treat population, comprising all randomised participants. All participants received risk-reduction counselling and condoms, and were tested regularly for HIV. This trial is registered with ClinicalTrials.gov number, NCT01473472. FINDINGS: Between July 20, 2015, and Jan 21, 2016, we randomly assigned 232 participants (n=116 in the doxycycline PEP group and n=116 in the no-PEP group) who were followed up for a median of 8.7 months (IQR 7.8-9.7). Participants in the PEP group used a median of 680 mg doxycycline per month (IQR 280-1450). 73 participants presented with a new STI during follow-up, 28 in the PEP group (9-month probability 22%, 95% CI 15 32) and 45 in the no-PEP group (42%, 33-53; log-rank test p=0.007). The occurrence of a first STI in participants taking PEP was lower than in those not taking PEP (hazard ratio [HR] 0.53; 95% CI 0.33-0.85; p=0.008). Similar results were observed for the occurrence of a first episode of chlamydia (HR 0.30; 95% CI 0.13-0.70; p=0.006) and of syphilis (0.27; 0.07-0.98; p=0.047); for a first episode of gonorrhoea the results did not differ significantly (HR 0.83; 0.47 1.47; p=0.52). No HIV seroconversion was observed, and 72 (71%) of all 102 STIs were asymptomatic. Rates of serious adverse events were similar in the two study groups. Gastrointestinal adverse events were reported in 62 (53%) participants in the PEP group and 47 (41%) in the no-PEP group (p=0.05). INTERPRETATION: Doxycycline PEP reduced the occurrence of a first episode of bacterial STI in high-risk men who have sex with men. FUNDING: France Recherche Nord & Sud Sida HIV Hepatites (ANRS) and Bill & Melinda Gates Foundation. PMID- 29229442 TI - Quantitative analysis of TNF-alpha, IL-4, and IL-10 expression, nitric oxide response, and apoptosis in Encephalitozoon cuniculi-infected rabbits. AB - The expression of tumor necrosis factor (TNF) -alpha, interleukin (IL) -4 and IL 10, as well as apoptosis and nitric oxide (NO) levels were measured in the brain and kidneys of immunocompetent and immunosuppressed New Zealand White rabbits infected with Encephalitozoon cuniculi. All of the animals had clinical signs histopathological lesions compatible with encephalitozoonosis and were E. cuniculi-positive by using a carbon immunoassay test. Encephalitozoon cuniculi infection promoted the expression of TNF-alpha and NO production in the kidneys of infected rabbits, and a synergic effect was observed in animal treated with dexamethasone. The IL-4 expression was similar in the brain and kidneys of infected rabbits, regardless of their immunologic status. The IL-10 mRNA expression in the brain of infected immunosuppressed rabbits was elevated when compared with positive controls. Apoptosis of granuloma mononuclear-like cells was detected in immunocompetent E. cuniculi-infected rabbits, but it was more evident in infected-immunosuppressed animals. Nitric oxide levels were elevated both in immunocompetent and immunosuppressed infected animals, but it was more apparent in the kidneys. These data suggest that modulation of the immune response by E. cuniculi could contribute to the survival of the parasite within phagocytic cells in granulomas via an as yet undetermined mechanism. PMID- 29229443 TI - Immune functions of insect betaGRPs and their potential application. AB - Insects rely completely on the innate immune system to sense the foreign bodies and to mount the immune responses. Germ-line encoded pattern recognition receptors play crucial roles in recognizing pathogen-associated molecular patterns. Among them, beta-1,3-glucan recognition proteins (betaGRPs) and gram negative bacteria-binding proteins (GNBPs) belong to the same pattern recognition receptor family, which can recognize beta-1,3-glucans. Typical insect betaGRPs are comprised of a tandem carbohydrate-binding module in the N-terminal and a glucanase-like domain in the C-terminal. The former can recognize triple-helical beta-1,3-glucans, whereas the latter, which normally lacks the enzymatic activity, can recruit adapter proteins to initiate the protease cascade. According to studies, insect betaGRPs possess at least three types of functions. Firstly, some betaGRPs cooperate with peptidoglycan recognition proteins to recognize the lysine-type peptidoglycans upstream of the Toll pathway. Secondly, some directly recognize fungal beta-1,3-glucans to activate the Toll pathway and melanization. Thirdly, some form the 'attack complexes' with other immune effectors to promote the antifungal defenses. The current review will focus on the discovery of insect betaGRPs, functions of some well-characterized members, structure-function studies and their potential application. PMID- 29229445 TI - Optical coherence tomography angiography. AB - Optical coherence tomography (OCT) was one of the biggest advances in ophthalmic imaging. Building on that platform, OCT angiography (OCTA) provides depth resolved images of blood flow in the retina and choroid with levels of detail far exceeding that obtained with older forms of imaging. This new modality is challenging because of the need for new equipment and processing techniques, current limitations of imaging capability, and rapid advancements in both imaging and in our understanding of the imaging and applicable pathophysiology of the retina and choroid. These factors lead to a steep learning curve, even for those with a working understanding dye-based ocular angiography. All for a method of imaging that is a little more than 10 years old. This review begins with a historical account of the development of OCTA, and the methods used in OCTA, including signal processing, image generation, and display techniques. This forms the basis to understand what OCTA images show as well as how image artifacts arise. The anatomy and imaging of specific vascular layers of the eye are reviewed. The integration of OCTA in multimodal imaging in the evaluation of retinal vascular occlusive diseases, diabetic retinopathy, uveitis, inherited diseases, age-related macular degeneration, and disorders of the optic nerve is presented. OCTA is an exciting, disruptive technology. Its use is rapidly expanding in clinical practice as well as for research into the pathophysiology of diseases of the posterior pole. PMID- 29229446 TI - Clinical utility of decorin in follicular fluid as a biomarker of oocyte potential. AB - This study investigated the concentration of decorin (DCN) in mature follicular fluid and the existence in the granulosa cells. It also investigated whether DCN is useful as a biomarker for outcomes of assisted reproductive technology (ART). A retrospective cohort study was performed involving 130 oocytes of 88 patients treated with ART because of unexplained infertility. The concentration of DCN in the follicular fluid (F-DCN) was 39.26ng/ml (median value); it was higher than that in serum. F-DCN of the oocytes fertilized by intracytoplasmic sperm injection (ICSI) was significantly lower than that of oocytes that were not fertilized (33.24ng/ml vs 40.18ng/ml; P=0.043). When a cut-off level of 34.5ng/ml was set according to the receiver-operating characteristic curve, the fertilization rate of the oocytes from the follicles in which F-DCN was lower than the cut-off level tended to be good compared to that of the oocytes with F DCN higher than the cut-off level (P=0.052). DCN is less likely to be produced by the granulosa cells (GCs), because it was not detected in GCs by immunostaining and Western blot analysis. F-DCN has a possibility to be a biomarker indicating the quality of oocytes collected from the corresponding follicle. PMID- 29229447 TI - hnRNP A1 promotes keratinocyte cell survival post UVB radiation through PI3K/Akt/mTOR pathway. AB - hnRNP A1 acts as a critical splicing factor in regulating many alternative splicing events in various physiological and pathophysiological progressions. hnRNP A1 is capable of regulating UVB-induced hdm2 gene alternative splicing according to our previous study. However, the biological function and underlying molecular mechanism of hnRNP A1 in cell survival and cell cycle in response to UVB irradiation are still unclear. In this study, silencing hnRNP A1 expression by siRNA transfection led to decreased cell survival after UVB treatment, while promoting hnRNP A1 by lentiviruse vector resulted in increased cell survival. hnRNP A1 remarkably enhanced PI3K/Akt/mTOR signaling pathway by increasing phosphorylation of Akt, mTOR and P70S6 protein. Inhibition of PI3K/Akt signaling by LY294002 suppressed the expression of hnRNP A1. While mTOR signaling inhibitors, rapamycin and AZD8055, did not influence hnRNP A1 expression in HaCaT cells, suggesting that hnRNP A1 may be an upstream mediator of mTOR signaling. Furthermore, hnRNP A1 could alleviate UVB-provoked cell cycle arrest at G0/G1 phase and promoted cell cycle progression at G2/M phase. Our results indicate that hnRNP A1 promotes cell survival and cell cycle progression following UVB radiation. PMID- 29229448 TI - Characteristics and Disease Course in a Cohort of Children With PFAPA Syndrome in the Community of Madrid, Spain. AB - INTRODUCTION: PFAPA syndrome is an autoinflammatory disease whose diagnosis is mainly clinical. Several treatments have been proposed; among them, tonsillectomy could be an effective one. MATERIAL AND METHODS: Retrospective multicenter study. Patients included were diagnosed with PFAPA syndrome, according to the Thomas criteria, in 3 hospitals in Madrid between 2009-2013. RESULTS: Thirty-two cases were included. Median age at onset and at diagnosis were 32 months (IQR 24-44) and 47.5 months (IQR 37-60), respectively. There were increases in leukocytes (13,580/MUL [IQR 8,200-16,600] vs. 8,300/MUL [IQR 7,130-9,650], P=.005), neutrophils (9,340/MUL [IQR 5,900-11,620] vs. 3,660/MUL [IQR 2,950-4,580], P=.002) and C-reactive protein (11.0mg/dL [IQR 6.6-12.7] vs. 0.2mg/dL [IQR 0.1 0.6], P=.003) during febrile episodes. In all, 80.8% of patients reported remission of symptoms within 24h after oral corticosteroid therapy. Fourteen patients were tonsillectomized. In 11, the febrile episodes stopped while, in 3, the frequency was reduced; there were 2 cases of postoperative bleeding. The disease was resolved in 56.3% of the patients, at a median age of 60 months (IQR 47-95), with similar duration in patients who were tonsillectomized and those who were not. CONCLUSIONS: We present a large cohort of children with PFAPA syndrome, with clinical and analytical features similar to those described in the literature, and a good response to corticosteroids and a high resolution rate of symptoms after tonsillectomy. PMID- 29229449 TI - Treatment of Persistent Cutaneous Atrophy After Corticosteroid Injection With Fat Graft. AB - Subcutaneous fat atrophy and hypopigmentation are potential adverse side effects of local corticosteroid injection that may resolve spontaneously within 1-2 years. This report shows that fat grafting provides a simple, effective and safe correction of corticosteroid induced cutaneous atrophy with very satisfying esthetic and functional results. PMID- 29229450 TI - Gastric Emptying Time, Esophageal pH-Impedance Parameters, Quality of Life, and Gastrointestinal Comorbidity in Obese Children and Adolescents. AB - OBJECTIVES: To provide further evidence regarding the relationship between obesity and gastroesophageal reflux disease (GERD) in children, through the use of 13C-octanoic acid breath test for gastric emptying time (GET) assessment and esophageal multichannel intraluminal impedance pH-testing (MII-pH). STUDY DESIGN: Obese children aged 4-17 years completed a questionnaire investigating reflux symptoms, the presence of functional gastrointestinal disorders, and quality of life. A subgroup of obese patients with and without GERD symptoms were asked to undergo 13C-octanoic acid breath test. Symptomatic patients were also required to undergo MII-pH. Age- and sex- matched asymptomatic nonobese children were enrolled as a comparison group. RESULTS: Of 113 enrolled patients, 44 (38.9%) reported reflux symptoms; 22 of the 44 underwent MII-pH. Their mean reflux index was 14.6%, and their mean number of daily reflux episodes was 51.8. The mean T1/2 GET of symptomatic was 107.6 minutes vs 116.5 minutes in asymptomatic obese children. Healthy nonobese children had a mean T1/2 GET of 100.1 minutes. The mean GET of symptomatic obese patients having >70 daily reflux events was 121.8 vs 87.6 minutes of patients with <70 daily reflux events (P <.05). Both symptomatic and asymptomatic obese patients had a worse quality of life than nonobese (P = 0.003 and P = 0.0002, respectively); a narrow waist circumference was directly related to GET (P = 0.01). CONCLUSIONS: A high percentage of obese children and adolescents experience GERD symptoms. GET was directly related to the narrow waist circumference of obese children with GERD and was significantly delayed in obese children with increased reflux events. Both symptomatic and asymptomatic obese patients had a worse quality of life compared with nonobese healthy patients. PMID- 29229451 TI - More Clinical Mimics of Infant Botulism. AB - OBJECTIVE: To ascertain the actual diagnoses of 76 patients (2005-2015) whose clinical presentations so closely resembled infant botulism that the patients were treated with Human Botulism Immune Globulin Intravenous (BIG-IV; BabyBIG), but whose illnesses subsequently were not laboratory confirmed as infant botulism ("clinical mimics" of infant botulism). STUDY DESIGN: The California Department of Public Health produces BIG-IV and distributes it nationwide as a public service (ie, not-for-profit) orphan drug to treat patients hospitalized with suspected infant botulism. During the study period, admission records and discharge summaries for all patients treated with BIG-IV but who lacked a laboratory-confirmed diagnosis of infant botulism were collected and abstracted. The patients' discharge diagnoses were identified, categorized, and compared with previously reported clinical mimics categories for 32 patients (1992-2005). RESULTS: From 2005 to 2015, 76 clinical mimic illnesses were identified. These illnesses were distributed into the 5 categories previously reported of (1) probable infant botulism lacking confirmatory testing (26.3%); (2) spinal muscular atrophy (19.7%); (3) miscellaneous (15.8%); (4) metabolic disorders (11.8%); and (5) other infectious diseases (10.6%). Of the 76 clinical mimic illnesses, 15.8% had no alternate diagnosis established and were therefore categorized as undetermined. CONCLUSIONS: Over the 23 years 1992-2015, patients presenting with illnesses so clinically similar to infant botulism that they were treated with BIG-IV had actual diagnoses that were distributed into 5 main categories. These categories and their individual components constitute a working bedside differential diagnosis of infant botulism. PMID- 29229452 TI - Efficacy of Human Botulism Immune Globulin for the Treatment of Infant Botulism: The First 12 Years Post Licensure. AB - OBJECTIVES: To report the efficacy of Human Botulism Immune Globulin Intravenous (BIG-IV) in the first 12 years following its licensure in 2003 and to characterize its use nationwide in treating patients with infant botulism. STUDY DESIGN: Medical records and billing information were collected for US patients treated with BIG-IV from 2003 to 2015. Length of hospital stay (LOS) and hospital charge information for treated patients were compared with the BIG-IV Pivotal Clinical Trial Placebo Group to quantify decreases in LOS and hospital charges. RESULTS: The use of BIG-IV reduced mean LOS from 5.7 to 2.2 weeks. This shortened hospital stay resulted in a mean decrease in hospital charges of $88 900 per patient. For all US patients 2003-2015, total decreases in LOS and hospital charges were 66.9 years and $86.2 million, respectively. The decrease in mean LOS was time dependent: BIG-IV treatment on hospital days 0-3 reduced mean LOS by 3.7 weeks (P <.001 vs the BIG-IV Pivotal Clinical Trial Placebo Group), on hospital days 4-7 by 2.6 weeks (P <.001 vs the BIG-IV Pivotal Clinical Trial Placebo Group) and on hospital days 8-10 by just 1 week (P = NS). Since licensure, 1192 patients in 48 states and Washington, DC, have been treated with BIG-IV. CONCLUSIONS: The use of BIG-IV since its licensure in 2003 treated approximately 93% of US patients with laboratory-confirmed infant botulism, and prevented >65 years in hospital stay and >$85 million in hospital charges from occurring. The greatest LOS reduction was achieved when BIG-IV was administered soon after hospital admission. Effective and appropriate use of BIG-IV in the US has continued in the postlicensure period. PMID- 29229453 TI - Efficacy of Ultrasound Doppler Flowmetry in Assessing Pulp Vitality of Traumatized Teeth: A Propensity Score Matching Analysis. AB - INTRODUCTION: This retrospective study aimed to evaluate and compare the efficacy of ultrasound Doppler flowmetry (UDF) with that of electric pulp testing (EPT) in assessing pulp vitality in traumatized teeth. METHODS: A total of 246 teeth from 78 patients who visited the authors' hospital with histories of dental trauma between February 2012 and May 2015 were included. Patients were divided into 2 groups based on the diagnostic method used to determine pulp vitality during the follow-up visits. In the control group, EPT alone was used to assess pulp vitality, whereas both UDF and EPT were used in the UDF group. Kaplan-Meier survival analysis and the log-rank test were performed after propensity score matching. Survival was defined as the tooth not having to undergo root canal treatment. Additionally, the McNemar test was used to compare the results of UDF with those of EPT in the UDF group. RESULTS: After propensity score matching, 69 teeth were included in each group. The pulp survival rates at 1 year were 74% and 90% in the control and UDF groups, respectively, a difference that was statistically significant (P < .01). In the UDF group, there was a significant difference between the UDF and EPT results at all follow-up evaluations (P < .001). CONCLUSIONS: Within the limitations of this study, UDF appeared to be more sensitive in assessing pulp vitality in traumatized teeth. PMID- 29229444 TI - Neural control of choroidal blood flow. AB - The choroid is richly innervated by parasympathetic, sympathetic and trigeminal sensory nerve fibers that regulate choroidal blood flow in birds and mammals, and presumably other vertebrate classes as well. The parasympathetic innervation has been shown to vasodilate and increase choroidal blood flow, the sympathetic input has been shown to vasoconstrict and decrease choroidal blood flow, and the sensory input has been shown to both convey pain and thermal information centrally and act locally to vasodilate and increase choroidal blood flow. As the choroid lies behind the retina and cannot respond readily to retinal metabolic signals, its innervation is important for adjustments in flow required by either retinal activity, by fluctuations in the systemic blood pressure driving choroidal perfusion, and possibly by retinal temperature. The former two appear to be mediated by the sympathetic and parasympathetic nervous systems, via central circuits responsive to retinal activity and systemic blood pressure, but adjustments for ocular perfusion pressure also appear to be influenced by local autoregulatory myogenic mechanisms. Adaptive choroidal responses to temperature may be mediated by trigeminal sensory fibers. Impairments in the neural control of choroidal blood flow occur with aging, and various ocular or systemic diseases such as glaucoma, age-related macular degeneration (AMD), hypertension, and diabetes, and may contribute to retinal pathology and dysfunction in these conditions, or in the case of AMD be a precondition. The present manuscript reviews findings in birds and mammals that contribute to the above-summarized understanding of the roles of the autonomic and sensory innervation of the choroid in controlling choroidal blood flow, and in the importance of such regulation for maintaining retinal health. PMID- 29229454 TI - Impact of Cone-beam Computed Tomography on Treatment Planning for External Cervical Resorption and a Novel Axial Slice-based Classification System. AB - INTRODUCTION: The aim of this study was to compare treatment plans for external cervical resorption (ECR) developed from periapical (PA) radiographs and cone beam computed tomographic (CBCT) imaging. The secondary aim of this study was to test a new classification system for ECR based on CBCT axial slice analysis. METHODS: ECR was identified in 56 teeth (47 patients) from a database of 928 CBCT images. Strict exclusion criteria resulted in a sample of 30 ECR teeth (25 patients) and 10 ECR-free control teeth. Six examiners evaluated CBCT and matched PA images in separate sessions. Examiners classified ECR according to the Heithersay classification system and the novel Rohde classification system and provided a treatment plan. RESULTS: All 30 ECR cases were identified by CBCT imaging and 29 by PA radiography. Interrater agreement was uniformly higher with CBCT imaging, and treatment plans developed from CBCT scans differed from those developed with PA radiographs in 56.7% of the cases. Examiners recommended ECR repair in the majority of cases (59.8% of CBCT images and 56.7% of PA radiographs). The Heithersay classification was dependent on the method of imaging with a greater prevalence of class 4 reported with CBCT imaging (P = .0016). The Rohde classification system significantly predicted the recommended treatment plan (P = .002 for Rohde class 2 and P = .043 for Rohde class 3). All Heithersay classifications failed to statistically predict treatment plans. CONCLUSIONS: Treatment plans changed between PA and CBCT imaging in the majority of cases evaluated. If CBCT imaging is available, the Rohde classification system may help guide treatment planning for cases of ECR. PMID- 29229455 TI - Evaluation of 3 Different Retreatment Techniques in Maxillary Molar Teeth by Using Micro-computed Tomography. AB - INTRODUCTION: Nonsurgical retreatment procedure involves the complete removal of the previous filling material to allow thorough instrumentation, disinfection, and refilling of root canal system. We aimed to determine the residuals of the root-filling material by using 3 different retreatment techniques with the aid of micro-computed tomography. METHODS: Thirty extracted human maxillary molar teeth were included. All root canals were also obturated with F2 ProTaper single cones and AH Plus sealer. The following retreatment techniques were performed: group 1, ProTaper retreatment files; group 2, Mtwo retreatment files; and group 3, ProFile files. For the assessment of residual filling material, preoperative and postoperative micro-computed tomography scans were compared with each other, and the working time was recorded. One-way analysis of variance was used to analyze the differences between the groups. The significance level was set at P < .05. RESULTS: None of the retreatment techniques were capable of removing the whole filling material. The percentages of the residual filling materials for groups 1, 2, and 3 were 34.45, 45.43, and 23.63, respectively. There was a statistically significant difference between groups 2 and 3 (P < .05). ProTaper and ProFile instruments required less time for the removal of filling materials when compared with Mtwo instrument. CONCLUSIONS: ProFile files revealed the best results for endodontic retreatment in terms of both removing capacity and time requirement. PMID- 29229456 TI - Survival Rates of Teeth with Primary Endodontic Treatment after Core/Post and Crown Placement. AB - INTRODUCTION: The objective of this study was to determine the effect of delayed placement of the core/post and crown on the outcomes of nonsurgical root canal therapy (NSRCT). METHODS: According to the Delta Dental of Wisconsin claims database, 160,040 NSRCTs were completed with a core/post and a crown placed before the end of the continuous coverage period or occurrence of an untoward event. Untoward events were defined as a retreatment, apicoectomy, or extraction as defined by the Code on Dental Procedures and Nomenclature. Statistical analysis was performed by using a multivariable Cox proportional hazards model. RESULTS: The survival rate from the time of crown placement to an untoward event was 99.1% at 1 year, 96.0% at 3 years, 92.3% at 5 years, and 83.8% at 10 years. Failure rates were greater when a core/post was placed more than 60 days after the NSRCT (adjusted hazard ratio, 1.08) and when the crown was placed more than 60 days after the core/post placement (adjusted hazard ratio, 1.14). Overall, the survival rates of NSRCT were greater when performed by an endodontist versus other providers. CONCLUSIONS: On the basis of the information available from insurance claims data, this study shows that the long-term survival rates of initial endodontic therapy are adversely affected by the delayed placement of the final restoration and full coverage crown. PMID- 29229457 TI - "Ferrule Comes First. Post Is Second!" Fake News and Alternative Facts? A Systematic Review. AB - INTRODUCTION: Both the role of an endodontic post and the ferrule effect have been discussed for decades. The clinical impact of endodontic posts compared with post-free restoration with or without ferrule support was not systematically reviewed so far. It was assumed that the effect of an endodontic post compared with a post-free restoration can be evaluated only when at the same time a ferrule or no-ferrule situation was clinically compared. METHODS: The specific PICO question was as follows: Patient: adults with sufficient endodontic treatment needing a core or post; Intervention: post-endodontic treatment using posts with or without ferrule; Comparison: post-endodontic treatment without posts with or without ferrule; Outcomes: failure rates of post/core complexes with or without ferrule support. A Medline search was performed via PubMed in June 2017 using relevant electronic databases. Additionally, hand search was performed. Only prospective clinical studies in humans comparing the success/survival of teeth restored with or without posts over a minimum time of observation of 5 years were included. RESULTS: In total, 7 randomized controlled trials and 1 prospective clinical trial met inclusion criteria. Cochrane rating showed high risk of bias in 5 studies. Two of 3 studies support the ferrule effect concept. Seven of 8 show no post effect. Clinical evidence regarding the influence of tooth location on its survival is scarce. CONCLUSION: Ferrule effect and maintaining cavity walls are the predominant factors with regard to tooth and restoration survival of endodontically treated teeth. Most studies do not confirm a positive effect of post placement. PMID- 29229458 TI - The Effects of Irrigants on the Survival of Human Stem Cells of the Apical Papilla, Including Endocyn. AB - INTRODUCTION: Endocyn, a pH-neutral solution of hypochlorous acid and hypochlorite has been developed for use as an endodontic irrigant. The purpose of this study was to evaluate the effect of Endocyn on human periodontal ligament (PDL) fibroblasts, rat osteosarcoma cells (UMR-106), and stem cells of the apical papilla (SCAP) compared with other commonly used endodontic irrigants. METHODS: To determine cytotoxicity, cells were exposed to various concentrations of Endocyn, 6% sodium hypochlorite (NaOCl), 17% EDTA, and 2% chlorhexidine for 10 minutes, 1 hour, or 24 hours. Cell survival was measured fluorescently using calcein AM. Endocyn also was tested for its ability to inhibit SCAP proliferation and alkaline phosphatase activity. Finally, SCAP transcript expression was examined via reverse-transcriptase polymerase chain reaction. RESULTS: Endocyn was no more toxic to PDL and UMR cells than water for up to 24 hours. Endocyn concentrations of 50% were toxic to SCAP after 1 hour of exposure. Endocyn concentrations of >20% inhibited SCAP proliferation, whereas concentrations of >=10% inhibited alkaline phosphatase activity. Exposure of SCAP to 10% Endocyn for 3 days did not alter most transcript expression, but did significantly reduce the expression of alkaline phosphatase, fibromodulin, and osteomodulin. CONCLUSION: Endocyn was significantly less cytotoxic to PDL, UMR-106, and SCAP cells compared with other commonly used endodontic irrigants. High concentrations of Endocyn did inhibit some transcript expression and alkaline phosphatase activity, indicating a potential reduction in the osteogenic potential of stems cells exposed to Endocyn. PMID- 29229459 TI - Regenerative Endodontic Procedures among Endodontists: A Web-based Survey. AB - INTRODUCTION: The protocols that endodontists implement for regenerative endodontic procedures (REPs) are unknown. The aim of this study was to examine current REP protocols among practicing endodontists in the United States. METHODS: A Web-based survey was sent to 4060 active members of the American Association of Endodontists (AAE). A total of 850 participants completed the survey, representing a 20.9% response rate. RESULTS: Responses indicated 60% reported having performed REPs; most performed 1 to 3 per year. The most commonly selected source (60.8%) for the clinical protocol was the "AAE Clinical Considerations for a Regenerative Procedure." Time constraints were the most common reason why 92.4% of respondents did not report their REP cases to the AAE.org database; additionally, 15.5% were unaware of it. Almost half (49.8%) of the participants reported they would attempt an REP on a patient of any age. The most commonly used irrigants were >3% sodium hypochlorite at the first appointment and EDTA at the scaffold formation appointment. As the intracanal medicament, 52.2% used calcium hydroxide, whereas 23.5% used triple antibiotic paste. At the scaffold formation appointment, 77.1% used a local anesthetic without a vasoconstrictor, and 94.3% used a blood clot as the scaffold. Mineral trioxide aggregate was the coronal barrier most often selected. Considering factors most likely to encourage the use of REPs in the future, 79.8% reported the availability of good candidates followed by 40.1% who desired better evidence. CONCLUSIONS: Based on the results of this survey, REP protocols appear to be heterogeneous and do not strictly conform to the "AAE Clinical Considerations for a Regenerative Procedure." PMID- 29229460 TI - Effect of Low-surface Tension EDTA Solutions on the Bond Strength of Resin-based Sealer to Young and Old Root Canal Dentin. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of low-surface tension EDTA solutions on the push-out bond strength of resin-based sealer to young and old root canal dentin. METHODS: Root canals from 64 (n = 32 age <30 years old and n = 32 >60 years old) extracted, decoronized, single-rooted human teeth were prepared with ProTaper rotary instruments (Dentsply Maillefer, Ballaigues, Switzerland) up to size F4 using 3 mL 2.5% sodium hypochlorite (NaOCl) between each file. Each group was divided into 4 subgroups as follows: 3 mL EDTA, REDTA (17% EDTA + 0.84 g cetyltrimethylammonium bromide; Sigma-Aldrich, St Louis, MO), EDTA-T (17% EDTA + 1.25% sodium lauryl ether sulfate, Sigma Aldrich), and saline as the control (n = 8). The final irrigation was completed with 3 mL saline after 3 mL NaOCl in the experimental groups and 3 mL saline in the control group. After root canal filling with gutta-percha (GP) cones/AH Plus sealer (Dentsply, Petropolis, RJ, Brazil), samples were stored at 37 degrees C and 100% humidity for 2 weeks. One-millimeter-thick horizontal sections from the coronal and midthirds of each root were sliced, and push-out bond strength values were measured using a universal testing machine. Data were analyzed using 2-way analysis of variance followed by the Bonferroni test (P < .05). RESULTS: EDTA-T, REDTA, and EDTA significantly increased the bond strength values of GP/AH Plus to the root canal dentin compared with saline in both young and old groups (P < .05). EDTA-T treatment provided higher bond strength values in young dentin compared with EDTA and EDTA-T-treated old dentin (P < .05). CONCLUSIONS: The bond strength values of GP/AH Plus could be altered depending on age and the type of EDTA compounds. PMID- 29229461 TI - Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. AB - The critical role of angiogenesis in promoting tumor growth and metastasis has been well established scientifically, and consequently blocking this pathway as a therapeutic strategy has demonstrated great clinical success for the treatment of cancer. The holy grail however, has been the identification of patients who derive significant survival benefit from this class of agents. Here we attempt to delineate the diverse mechanisms related to anti-VEGF including its role as an anti-vascular, anti-angiogenic or an anti-permeability factor and review the most promising predictive biomarkers interrogated in large clinical trials, that identify patients who may derive significant survival advantage with VEGF inhibition. Lastly, we describe the function of VEGF as an immunomodulator and illustrate the evidence for anti-VEGF in reprogramming the tumor milieu from an immunosuppressive to an immune permissive microenvironment in human cancers, thus elucidating the role of anti-VEGF as an optimal combination partner for immune checkpoint inhibitors. PMID- 29229462 TI - Regular Physical Activity and Educational Outcomes in Youth: A Longitudinal Study. AB - PURPOSE: The objectives of this study were to determine whether longitudinal changes in accelerometer-assessed moderate-to-vigorous physical activity (MVPA) were associated with changes in educational outcomes (i.e., academic performance and mathematics engagement) and to examine whether the association was nonlinear. METHODS: Longitudinal data were collected from 2,194 Australian adolescents (mean age = 13.40 years, standard deviation = .73) at two time points (Term 1, 2014, and Term 2, 2015). To measure the total MVPA, the adolescents wore an accelerometer for seven consecutive days. The participants responded to a questionnaire to measure mathematics engagement and completed a nationally administered numeracy test to assess academic performance. RESULTS: Latent change score models indicated that increases in MVPA had a positive quadratic association with National Assessment Program-Literacy and Numeracy (NAPLAN) scores in girls (beta = .39, p < .001) but not boys. In comparison, cross sectional regression analyses indicated that MVPA had a positive quadratic association with NAPLAN scores in grade 7 (beta = .92, p = .04) boys and in grade 9 boys (beta = .60, p = .06), but not in girls. There was also a positive quadratic association between MVPA and school engagement in grade 9 boys (beta = .77, p = .03). CONCLUSIONS: Cross-sectional evidence indicated that boys who were more physically active had better educational outcomes than their less active peers, and girls who increased their regular physical activity showed improvements in academic performance. All students need to increase their physical activity levels for health and educational benefits, without compromising the time spent on study and homework. PMID- 29229463 TI - Circulating epithelial cells as potential biomarkers for detection of recurrence in patients of papillary thyroid carcinoma with positive serum anti-thyroglobulin antibody. AB - BACKGROUND: Serum thyroglobulin (Tg) is not a reliable tumor marker for monitoring disease status after treatment in patients with papillary thyroid carcinoma (PTC) with positive anti-thyroglobulin antibody (TgAb). The aim of this study was to evaluate the clinical role of circulating epithelial cells (CECs) in PTC patients with positive serum TgAb and undetectable serum Tg. METHODS: A pilot study was performed to evaluate CECs in 25 PTC patients with positive serum TgAb and undetectable serum Tg. CECs were isolated and enriched from peripheral blood with a negative selection system PowerMag. Immunofluorescence staining with anti epithelial cell adhesion molecule (anti-EpCAM) and anti-thyroid stimulating hormone receptor (anti-TSHR) antibodies were used to define EpCAM+-CECs and TSHR+ CECs. After CECs testing, 25 patients were classified into two groups: recurrence group (n=7) and remission group (n=18) based on biopsy or imaging studies. The diagnostic accuracy and cutoff points of EpCAM+-CECs and TSHR+-CECs were evaluated using receiver operating characteristic (ROC) curves. The optimal cut off values of CECs were determined by the Youden index (sensitivity+specificity 1). RESULTS: The median numbers of EpCAM+-CECs (72.5 vs. 10.75) and TSHR+-CECs (54 vs. 5.25) were significantly increased in recurrence group compared to remission group. The area under the curve (AUC) showed good performance of EpCAM+ CECs (0.937) and TSHR+-CECs (0.825) to discriminate between recurrence and remission. The cut-off value for EpCAM+-CECs and TSHR+-CECs were set at 48cells/ml and 10cells/ml, respectively and showed a sensitivity (EpCAM+-CECs: 85.7%; TSHR+-CECs: 85.7%) and a specificity (EpCAM+-CECs: 100%; TSHR+-CECs: 77.8%) in predicting the recurrence. CONCLUSIONS: Our study suggests CECs testing could be a potential biomarker to identify recurrence in PTC patients with positive serum TgAb and undetectable serum Tg. PMID- 29229464 TI - Complications and retrieval characteristics of Celect Platinum inferior vena cava filters. AB - BACKGROUND: The purpose of this study was to retrospectively assess the retrieval characteristics and rate of filter-related complications associated with use of the Celect Platinum (Cook Medical, Bloomington, Ind) inferior vena cava filter (IVCF). METHODS: A single-center, retrospective review was conducted to identify patients who received a Celect Platinum IVCF between June 2013 and February 2016. The patients' charts and imaging records (computed tomography [CT] and cavography) associated with filter placement, follow-up, and filter retrieval procedures were assessed for attempted and successful retrieval rates and filter related complications. RESULTS: During the review period, 562 Celect Platinum filters were placed in 556 patients. Outcome and evaluable imaging data (CT and cavography) were available from 335 patients, with median CT follow-up time of 45 days (average, 126 days) and median cavography follow-up time of 90 days (average, 102 days). IVCF leg perforation of the inferior vena cava wall >3 mm was identified in 65 cases (19.4%) on follow-up imaging (64 cases). In addition, filter tilt >15 degrees was identified in 4 filters (1.2%), filter migration >2 cm in 1 filter (0.3%), and occlusive filter or inferior vena cava or iliac vein thrombus in 11 filters; no filter fracture was observed. One case of breakthrough pulmonary embolism and two additional indeterminate cases were identified on follow-up CT pulmonary angiography (2.6%-7.7%). Retrieval was successful in 155 of 155 patients (median indwell time, 90 days; range, 1-445 days); an advanced retrieval technique was used in 11 retrievals. CONCLUSIONS: The outcomes for the Celect Platinum filter were comparable to those previously reported for the first generation Celect filter in all categories assessed. PMID- 29229465 TI - Diverse management of isolated calf deep venous thrombosis in a university hospital. AB - BACKGROUND: The management of patients with isolated deep venous thrombosis (DVT) is controversial, leading to overtreatment and undertreatment with several complications and increased cost. The aim of this study was to describe the management of isolated calf DVT (ICDVT) in a university hospital. METHODS: Data on patients with acute DVT in our hospital are prospectively entered in a database through our venous thromboembolism team. All patients had an objective diagnosis with duplex ultrasound (DU) in our accredited vascular laboratory. A retrospective analysis was performed on patients with ICDVT from July 2015 to June 2016. Patients with proximal DVT were excluded. The management of the patients was assessed for use of different types of anticoagulation, use of sequential compression devices, serial follow-up with ultrasound, or any combination. Patients' demographic information, risk factors, calf DVT anatomic location, DVT extension into calf deep veins, DVT propagation to proximal deep veins, and pulmonary embolism were collected as well. RESULTS: There were 159 patients diagnosed with ICDVT in 1 year, of whom 52% were female with a mean age of 59 years. Nearly half of the patients were smokers (48%), 62% had limited or no mobility, 36% had surgery within the past 30 days, and 23% were considered readmissions. Anticoagulation was given to 121 patients who received seven different types of treatment varying from prophylactic dosing to thrombin inhibitors. In the rest of the 38 patients, 28 had a contraindication to anticoagulation and two had an inferior vena cava filter placed. Eighty-six patients had one DU follow-up study, 39 patients had two follow-up studies, and 21 had three follow-up studies. In the 86 patients with one DU study, seven propagated within the calf (8.1%) and two to the proximal veins (2.3%). Two patients developed nonfatal pulmonary embolism (1.2%). Sequential compression devices were applied in 75 patients despite that the majority were receiving anticoagulation and having serial DU examinations. CONCLUSIONS: Significant variation in the management of ICDVT was found on the basis of the physician's preference. The type of treatment overall did not follow a plan based on the patient's risk. Such an approach may increase the cost in the management of these patients without ensuring benefit. PMID- 29229466 TI - Prospective, double-blind, randomized controlled trial comparing electrocoagulation and radiofrequency in the treatment of patients with great saphenous vein insufficiency and lower limb varicose veins. AB - OBJECTIVE: Thermoablation has been replacing conventional surgery in the surgical treatment of great saphenous vein (GSV) reflux in patients with lower limb varicose veins; however, thermoablation is expensive. Intravenous electrocoagulation (EC) may, selectively and safely, cause necrosis of the GSV wall, but the clinical results have never been studied. The objective of this study was to compare EC and radiofrequency ablation (RFA) in the treatment of GSV insufficiency, considering efficacy, complications, and effect on quality of life. METHODS: This was a prospective, double-blind, randomized clinical trial. Patients with lower limb varicose veins and GSV reflux confirmed by duplex ultrasound were randomized into two treatment groups: EC and RFA. Patients were followed up at 1 week, 3 months, and 6 months after the procedure. Occlusion of the GSV confirmed by duplex ultrasound was considered the primary outcome, and the rate of complications and improvement in quality of life, using the Aberdeen Varicose Vein Questionnaire score, were the secondary outcomes. RESULTS: Fifty seven patients were included, with a total of 85 treated GSVs; 43 were treated with RFA and 42 with EC. There was no statistically significant difference between the groups regarding age (P = .264), sex (P = .612), Aberdeen Varicose Vein Questionnaire score (P = .054), and diameter (P = .880) and depth (P = .763) of the treated GSV. In the intraoperative period, immediately after thermoablation, all GSVs treated with EC presented no flow and incompressibility in the treated segment, whereas 12 limbs still had flow in the treated GSV (P < .001) and 9 veins showed compressibility (P < .001) when treated with RFA. The main postoperative complication was paresthesia; however, there was no statistical significance between the groups (P = .320) regarding its presence. Time to return to routine activities was lower in the EC group than in the RFA group (P = .026). There was no difference between the groups at the 3-month (P = .157) and 6-month (P = .157) follow-up in occlusion of the GSV and improvement of the quality of life score (P = .786 and P = .401, respectively). CONCLUSIONS: EC has been shown to be an effective method for ablation of the GSV, with venous occlusion rate, occurrence of complications, and effect on quality of life similar to those with RFA. PMID- 29229467 TI - Renal involvement in PMM2-CDG, a mini-review. AB - Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-linked glycosylation disorder. The majority of patients present with a multisystem phenotype, including central nervous system involvement, hepatopathy, gastrointestinal and cardiac symptoms, endocrine dysfunction and abnormal coagulation. Renal abnormalities including congenital malformations and altered renal function are part of the multisystem manifestations of congenital disorders of glycosylation. We reviewed the literature on 933 patients with molecularly and/or enzymatically confirmed PMM2 deficiency to evaluate the incidence of renal involvement in PMM2-CDG. Renal abnormalities were reported in 56 patients. Congenital abnormalities were present in 41 out of these 55. Cystic kidney and mild proteinuria were the most common findings. One of the most severe renal manifestations, congenital nephrotic syndrome, was detected in 6 children. Renal manifestations were not associated with the presence of specific PMM2 alleles. This review summarizes the reported renal abnormalities in PMM2-CDG and draws attention to the pathophysiological impact of abnormal glycosylation on kidney structure and function. PMID- 29229468 TI - Senator McCain and Our Shared Humanity. PMID- 29229469 TI - Colonic Anisakiasis. PMID- 29229470 TI - How Pure is PURE? Dietary Lessons Learned and Not Learned From the PURE Trials. PMID- 29229471 TI - Patent Foramen Ovale Closure for Secondary Prevention of Cryptogenic Stroke: Updated Meta-Analysis of Randomized Clinical Trials. AB - BACKGROUND: Patent foramen ovale closure represents a potential secondary prevention strategy for cryptogenic stroke, but available trials have varied by size, device studied, and follow-up. METHODS: We conducted a systematic search of published randomized clinical trials evaluating patent foramen ovale closure versus medical therapy in patients with recent stroke or transient ischemic attack using PubMED, EMBASE, and Cochrane through September 2017. Weighting was by random effects models. RESULTS: Of 480 studies screened, we included 5 randomized clinical trials in the meta-analysis in which 3440 patients were randomized to patent foramen ovale closure (n = 1829) or medical therapy (n = 1611) and followed for an average of 2.0 to 5.9 years. Index stroke/transient ischemic attack occurred within 6 to 9 months of randomization. The primary end point was composite stroke/transient ischemic attack and death (in 3 trials) or stroke alone (in 2 trials). Patent foramen ovale closure reduced the primary end point (0.70 vs 1.48 events per 100 patient-years; risk ratio [RR], 0.52 [0.29 0.91]; I2 = 55.0%) and stroke/transient ischemic attack (1.04 vs 2.00 events per 100 patient-years; RR, 0.55 [0.37-0.82]; I2 = 42.2%) with modest heterogeneity compared with medical therapy. Procedural bleeding was not different between study arms (1.8% vs 1.8%; RR, 0.94 [0.49-1.83]; I2 = 29.2%), but new-onset atrial fibrillation/flutter was increased with patent foramen ovale closure (6.6% vs 0.7%; RR, 4.69 [2.17-10.12]; I2 = 29.3%). CONCLUSIONS: In patients with recent cryptogenic stroke, patent foramen ovale closure reduces recurrent stroke/transient ischemic attack compared with medical therapy, but is associated with a higher risk of new-onset atrial fibrillation/flutter. PMID- 29229472 TI - Cardiac Tamponade: An Unusual Presentation of Systemic Lupus Erythematosus. PMID- 29229473 TI - Cystic fibrosis research topics featured at the 14th ECFS Basic Science Conference: Chairman's summary. AB - In recent years, tremendous progress has been made in the development of novel drugs targeting the basic defect in patients with cystic fibrosis (CF). This breakthrough is based on a solid foundation of knowledge on CFTR's function in health and how mutations in CFTR cause CF multi-organ disease. This knowledge has been collected and continuously expanded by an active and persistent CF research community and has paved the way for precision medicine for CF. Since 2004, the European Cystic Fibrosis Society (ECFS) has held an annual Basic Science Conference that has evolved as an international forum for interdisciplinary discussion of hot topics and unsolved questions related to CF research. This Special Issue reviews CF research topics featured at the 14th ECFS Basic Science Conference and provides an up-to-date overview of recent progress in our understanding of CFTR structure and function, disease mechanisms implicated in airway mucus plugging, inflammation and abnormal host-pathogen interactions, and advancements with enhanced cell and animal model systems and breakthrough therapies directed at mutant CFTR or alternative targets. In addition, this Special Issue also identifies a number of fundamental questions and hurdles that still have to be overcome to realize the full potential of precision medicine and develop transformative therapies for all patients with CF. PMID- 29229474 TI - Accuracy of a New Algorithm to Identify Asthma-COPD Overlap (ACO) Patients in a Cohort of Patients with Chronic Obstructive Airway Disease. AB - OBJECTIVES: We aimed to characterize the clinical, functional and inflammatory features of patients diagnosed diagnosed with ACO according to a new algorithm and to compare them with those of other chronic obstructive airway disease (COAD) categories (asthma and COPD). METHODS: ACO was diagnosed in a cohort of COAD patients in those patients with COPD who were either diagnosed with current asthma or showed significant blood eosinophilia (>=300cells/MUl) and/or a very positive bronchodilator response (>400ml and >15% in FEV1). RESULTS: Eighty-seven (29.8%) out of 292 patients fulfilled the ACO diagnostic criteria (12.8% asthmatics who smoked <20 pack-years, 100% of asthmatics who smoked >=20 pack years, 47.7% of COPD with >200eosinophils/MUl in blood and none with non eosinophilic COPD). ACO, asthma and COPD patients showed no differences in symptoms or exacerbation rate. Mean pre-bronchodilator FEV1 in ACO and asthma were similar (1741 vs 1771ml), higher than in COPD (1431ml, p<0.05). DLCO was lower in ACO than in asthma (68.1 vs 84.1%) and similar to COPD (64.5%). Mean blood eosinophil count was similar in ACO and asthma (360 vs 305cells/MUl) and higher than in COPD (170cells/MUl). Periostin levels were similar in ACO to COPD (36.6 and 36.5IU/ml) and lower than in asthma (41.5IU/ml, p<0.05), whereas FeNO levels in ACO were intermediate. CONCLUSION: This algorithm classifies as ACO all smoking asthmatics with non-fully reversible airway obstruction and a considerable proportion of e-COPD patients, highlighting those who can benefit from inhaled corticosteroids. PMID- 29229475 TI - A Huge Mass in a Boy's Chest: An Unusual Case of Mesenchymal Chondrosarcoma. PMID- 29229476 TI - Recurrent Chylothorax Due To Secondary Superior Vena Cava Obstruction. PMID- 29229478 TI - Gastric teratoma: Our 17 year experience. AB - BACKGROUND: Teratomas originating from the stomach are extremely rare and account for less than 1% of all cases of teratomas. This site of occurrence has unique diagnostic and management issues. METHODS: A single centre case-record review of gastric teratomas presenting between January 2000 and April 2017 was performed. RESULTS: Thirteen children were found to have gastric teratomas. Presenting features were abdominal distension in 12 (92%) and palpable abdominal mass in 9 (69%). At operation, 8 (61%) were exogastric tumors. The tumor was excised with partial gastrectomy (n=7, 54%), total gastrectomy (n=1, 8%), partial gastrectomy and limited transverse colectomy (n=2, 15%), and excision of small part of serosa (mucosal sparing) (n=3, 23%). Histopathologically, these were identified as mature gastric teratomas in 8 (61%). Three (23%) children died postoperatively. CONCLUSION: Gastric teratomas are rare, with the majority described as exogastric. Partial gastrectomy is always needed, but occasionally complete gastrectomy is necessary. Overall survival is >75% in our experience. LEVEL OF EVIDENCE: IV. PMID- 29229477 TI - PUMA dependent mitophagy by Abrus agglutinin contributes to apoptosis through ceramide generation. AB - PUMA, a BH3-only pro-apoptotic Bcl2 family protein, is known to translocate from the cytosol into the mitochondria in order to induce apoptosis. Interestingly, the induction of PUMA by p53 plays a critical role in DNA damage-induced apoptosis. In this study, we reported mitophagy inducing potential of PUMA triggered by phytolectin Abrus agglutinin (AGG) in U87MG glioblastoma cells and established AGG-induced ceramide acts as the chief mediator of mitophagy dependent cell death through activation of both mitochondrial ROS as well as ER stress. Importantly, AGG upregulates PUMA expression in U87MG cells with the generation of dysfunctional mitochondria, with gain and loss of function of PUMA is shown to alter mitophagy induction. At the molecular level, our study identified that the LC3 interacting region (LIR) located at the C-terminal end of PUMA interacts with LC3 in order to stimulate mitophagy. In addition, AGG is also found to trigger ubiquitination of PUMA which in turn interacted with p62 for prompting mitophagy suggesting that AGG turns on PUMA-mediated mitophagy in U87MG cells in both p62-dependent as well as in p62-independent manner. Interestingly, AGG-triggered ceramide production through activation of ceramide synthase-1 leads to induction of ER stress and ROS accumulation to promote mitochondrial damage as well as mitophagy. Further, upon pre-treatment with Mdivi-1, DRP1 inhibitor, AGG exposure results in suppression of apoptosis in U87MG cells indicating AGG induced mitophagy switches to apoptosis that can be exploited for better cancer therapeutics. PMID- 29229479 TI - Defining normal neonatal abdominal wall musculature with ultrasonography. AB - INTRODUCTION: The development of new surgical approaches for the management of congenital abdominal wall defects may be facilitated by using an animal model. However, because the anatomy of the neonatal abdominal wall has not been described, a suitable model is yet to be identified. We aimed to evaluate and define the neonatal abdominal wall musculature using ultrasound, to be used as a reference to identify an appropriate animal model for the neonatal abdominal wall in the future. METHODS: Infants with a postconceptual age of less than one month weighing between 2 and 3 kg were eligible. With ethical approval, ultrasonography of three abdominal wall locations bilaterally was performed. The depth of the skin to external oblique and the thickness of the three abdominal wall muscles, external oblique (EO), internal oblique (IO) and transversus abdominis (TA), were measured. RESULTS: Ten males and seven females were recruited with median postconceptual age of 36 weeks (IQR 36-38), median postnatal age of 8 days (IQR 3 30) and median weight of 2.35kg (IQR 2.26-2.56). The mean depth of EO from skin was 2.06 mm (+/- 0.44). The mean thicknesses of the muscles were: EO 1.02 mm (+/- 0.33), IO 1.16 mm (+/- 0.39) and TA 1.02 mm (+/- 0.37). There was no statistical difference between the thickness of EO, IO or TA (p= 0.43). CONCLUSIONS: It is possible to consistently identify and measure the components of the neonatal abdominal wall musculature with ultrasonography. We hope this can aid in developing an appropriate animal model, with the ultimate aim of facilitating innovation in surgical management of neonatal abdominal wall pathology. LEVELS OF EVIDENCE: Study of Diagnostic test, Level IV. PMID- 29229480 TI - Liver transplantation for deterioration in native liver function after portoenterostomy for biliary atresia in Japan: Short- versus long-term survivors. AB - PURPOSE: We reviewed our post-Kasai portoenterostomy biliary atresia (BA) patients who required liver transplantation (LTx) for deterioration in native liver (NL) function to investigate mortality in relation to age at LTx. METHODS: BA patients indicated for LTx when less than 18years old (U18; n=17) and when 18 or older (18+; n=13) were compared. All achieved jaundice clearance postoperatively (TBil <=1.2mg/dL (~20MUmol/L)). RESULTS: In U18, living-donor (LD) LTxs were performed at a median of 6.1years (range: 0.5-16.7; n=14) and cadaveric (CD) LTxs at a median of 1.3years (1.1-1.5; n=3). In 18+, LDLTxs were performed at a median of 28years (18-37; n=8), and 1 case died from graft versus host disease. CDLTxs were indicated in 5, but 4 died at a median of 30years (26 32), a mean of 1.4years (0.7-1.8) after NL deterioration commenced. One case is awaiting CDLTx. At the time of review, all U18 and 7 LDLTx cases in 18+ were clinically stable. Mortality rates were 0% in U18 and 38% in 18+ (P=.006). CONCLUSION: Our results highlight the extremely grave prognosis for long-term BA patients requiring LTx when 18 or older because of poor donor availability in Japan. LEVEL OF EVIDENCE: Level III. PMID- 29229481 TI - Feasibility of laparoscopic tumour nephrectomy in children. AB - AIMS: The laparoscopic approach to tumour nephrectomy in children is controversial. We therefore reviewed our institution's cases of tumour nephrectomy (laparoscopic, open, and converted) to better understand which is suitable for this approach, what factors prevent it, and whether one can excise tumours greater than the CCLG recommendation of 300 ml. METHODS: All tumour nephrectomies performed between 2002 and 2016 were identified using our surgical database. Further data were gathered from radiology and pathology databases. Those with nonrenal tumours or having a partial nephrectomy were excluded. Tumour maximum diameters, volumes, and ratios to contralateral kidneys were calculated. A Mann-Whitney U was used to compare the groups. RESULTS: Forty-three cases were included. Fifteen procedures were completed laparoscopically (35%), and a further 3 converted. The median age at surgery was 2.5 years (range 0-10) in the laparoscopic group and 2 years (range 0-15) in the open group. There was a significant difference (P < 0.05) between the laparoscopic and open groups for: median maximum diameter (10cm vs 12.25cm), median volume (155 ml vs 459 ml), maximum diameter ratio (1.22 vs 1.75), and volume ratio (3.8 vs 11.2). CONCLUSION: Tumours in the laparoscopic group were significantly smaller, but it was possible to excise tumours more than 300 ml. Difficulties in excision related to tumour size relative to the abdomen. Therefore, a ratio of tumour to contralateral kidney may be a better guide to safe excision than an overall volume cutoff. From our series, the laparoscopic approach is likely to be achievable if the volume ratio is <= 8.1. LEVEL OF EVIDENCE: Level 3. PMID- 29229482 TI - Selective intraoperative cholangiography during laparoscopic cholecystectomy in children is justified. AB - AIMS: Intraoperative cholangiograms (IOC) during laparoscopic cholecystectomy have been advocated to detect biliary anomalies and intraductal calculi. However, IOC increases operative time and patient irradiation, and therefore is not universally used. We hypothesise selective IOC may be a valuable tool in children. METHODS: A retrospective case note review was performed of all children who underwent laparoscopic cholecystectomy at a single institution by a single surgeon between January 2011 and March 2017. Demographics, radiological imaging, indications for surgery and IOC, and clinical outcomes were collected. Chi Squared and Wilcoxon Rank Sum tests were used for comparisons. RESULTS: Sixty-two patients were reviewed. Median follow-up was 2 months (0.1-60), and 53 (85%) had complete symptom resolution following surgery. Twenty-two patients underwent IOC. Six (27%) had anomalies undetected by preoperative imaging. IOC identified common bile duct (CBD) stones in 2 patients which were cleared at laparoscopy. One patient required subsequent ERCP for impacted stones. One patient has a long common channel and pancreatitis. Two patients have CBD strictures. These last 3 are awaiting biliary reconstruction. Presence of CBD dilatation or ductal stones on preoperative ultrasound were significantly associated with positive findings at IOC. No complications resulted from IOC. Patients who did not undergo IOC did not represent with missed anomalies. CONCLUSIONS: Despite using multimodal preoperative imaging, IOC detected biliary anomalies requiring further treatment in 6/62 (10%) of patients undergoing laparoscopic cholecystectomy. Our data support the use of IOC in selective patients with CBD dilatation or suspicion of ductal stones on preoperative imaging. LEVEL OF EVIDENCE: Study of Diagnostic Test: Level III. PMID- 29229483 TI - Outcomes of fundoplication in oesophageal atresia associated gastrooesophageal reflux disease. AB - AIM OF THE STUDY: Conservative management of gastrooesophageal reflux (GORD) in oesophageal atresia (OA) is sometimes inefficient, and fundoplication is required. We assessed the outcomes of fundoplication among OA patients from 1980 to 2016. METHODS: After ethical consent, hospital records of 290 patients, including 22 referred patients, were reviewed. Included were 262 patients with end-to-end repair. Excluded were patients who underwent oesophageal reconstruction (n=23) or no repair (n=5). Primary outcome measures included survival, retaining the native oesophagus, resolution of GGORD symptoms, failure of fundoplication, and long-term endoscopic results. MAIN RESULTS: Gross types of OA in 262 patients were A (n=12), B (n=2), C (n=217), D (n=10), E (n=19), and F (n=2). Eighty-six (33%) patients, type A (n=12, 100%), B (n=2, 100%), C (n=69, 31%), D (n=3, 30%), and F (n=1, 50%), underwent fundoplication at the median age of 5.4 (IQR 3.1-16) months. Main indications included recalcitrant anastomotic stenosis (RAS) in 41 (48%), respiratory symptoms in 16 (19%), and acute life threatening events (ALTE) in 15 (17%) of patients. Associated tracheomalacia in 25 (29%) patients were treated with aortopexy. Median follow-up was 7.5 (IQR 1.8 15) years. RAS resolved in 30 (73%) patients, whereas 11 (27%) with unresolved RAS underwent oesophageal resection (n=8) or replacement (n=3). Six (7%) patients died of heart failure (n=4), bolus impaction (n=1), and ALTE (n=1). Fundoplication failed in 27 (31%) patients, and 13 (15%) underwent redo fundoplication. Fundoplication failure was predicted by long-gap OA RR=3.8 (95%CI=1.1-13), P=0.04. In total GORD associated symptoms persisted in 7 (8%) patients, including one with permanent feeding jejunostomy. Latest endoscopy showed moderate or severe oesophagitis in 7% of fundoplicated and in 3% nonfundoplicated patients and intestinal metaplasia in 3% and 1% (p=0.20-0.29). CONCLUSION: Fundoplication provided a safe and relatively effective control of OA associated symptomatic GORD and oesophagitis. The failure rate of fundoplication was high in those with long-gap OA. TYPE OF STUDY: Treatment study. LEVEL OF EVIDENCE: IV. PMID- 29229485 TI - The position of the anal dimple in newborns and infants with anorectal malformations and its correlation with the normal anal position. AB - BACKGROUND/PURPOSE: The anal position index (API) defines the normal anal position as the ratio of fourchette-anal distance to fourchette-coccyx distance for females and the scrotum-anal distance to scrotum-coccyx distance for males. In this study, measurement of the API in newborns and infants with anorectal malformations (ARM), using the center of the midline anal dimple (AD) to represent the center of the proposed neoanus, was performed to assess whether or not the AD was located in a significantly abnormal position as correlated with the normal anal position. METHODS: The cases comprised 65 consecutive newborn and infants with ARM, divided into 2 age-based groups (Group A: 1st day to 1month; Group B: 1-12months), without sacral or significant perineal abnormalities. Controls included an equal number of age and gender matched patients admitted for other conditions. The characteristics of the AD ('well developed' or 'moderately developed') as well as those of the midline perineal raphe in males and the perineal groove in females were also recorded. RESULTS: Combining both age groups, the mean API+/-SD was 0.41+/-0.012 in male cases and 0.53+/-0.07 in male controls (p value 0.003). The corresponding values for female cases and controls were 0.31+/-0.09 and 0.36+/-0.07 respectively (p = 0.040). In male newborns, the API in cases was significantly lower than the API in controls (p<0.001). Combining both males and female newborns, the differences between the API in cases and controls was also statistically significant (p<0.001). In older boys as well as in girls from both age groups, apart from cases of persistent cloaca, the API was lower in cases than in controls, especially in boys, although the difference was not statistically significant. On comparing the API in individual male ARM with that in male controls, cases of rectobulbar urethral fistula (RBUF) and rectovesical fistula had a statistically significant lower API (p<0.001). In the 4 cases of persistent cloaca, the mean API (0.40+/-0.1) was higher than the mean API in female controls and the AD was well developed with a well-delineated, narrow perineal groove. The majority (53/65; 81.53%) of patients had a 'well developed' AD. Twelve patients (18.47%) had a 'moderately developed' AD including 10 females and 2 males. There were 15 patients with a depressed AD (anal fossette); of these 12 (80%) were females. All boys had a well delineated perineal raphe in contrast to 10 girls (29.4% of total female ARM) who had a poorly delineated midline perineal groove. CONCLUSIONS: During definitive surgery for ARM, if the AD is taken as the site of the proposed neoanus, the neoanal position is likely to be anterior to the normal anal position in both males and females and especially so in males. Overall, girls with ARM appear to be more likely to have a relatively poorly developed and/ or depressed AD and a poorly delineated perineal groove. TYPE OF STUDY: Clinical Research. LEVEL OF EVIDENCE: Level III. PMID- 29229484 TI - Prenatal growth characteristics and pre/postnatal management of bronchopulmonary sequestrations. AB - PURPOSE: The prenatal natural history of intralobar and extralobar bronchopulmonary sequestrations (BPSs), including lesion growth patterns and need for prenatal intervention, have not been fully characterized. We review our series of BPSs to determine their natural history and outcomes in the context of the need for prenatal intervention. METHODS: A retrospective review of the pre/postnatal course of 103 fetuses with an intralobar (n=44) or extralobar BPS (n=59) managed at a single institution between 2008 and 2015 was performed. Outcomes included prenatal lesion growth trajectory, presence of hydrops, need for prenatal intervention, survival, and postnatal surgical management. RESULTS: Most extralobar (71%) and intralobar BPSs (94%) decreased in size or became isoechoic from initial to final evaluation. Peak lesion size occurred at 26 28weeks gestation. Eight fetuses developed hydrothorax, four of which (all extralobar BPSs) also developed hydrops. All four hydropic fetuses received maternal betamethasone, and three hydropic fetuses underwent thoracentesis and/or thoracoamniotic shunt placement with subsequent hydrops resolution. All fetuses survived. Forty-one intralobar (93%) and 35 extralobar BPSs (59%) were resected after birth. CONCLUSIONS: BPSs tend to decrease in size after 26-28weeks gestation and rarely require fetal intervention. Lesions resulting in hydrothorax +/- hydrops can be effectively managed with maternal steroids and/or drainage of the hydrothorax. LEVEL OF EVIDENCE: IV. PMID- 29229486 TI - Screening for spontaneous preterm birth and resultant therapies to reduce neonatal morbidity and mortality: A review. AB - Despite considerable effort aimed at decreasing the incidence of spontaneous preterm birth, it remains the leading cause of perinatal morbidity and mortality. Screening strategies are imperfect. Approaches used to identify women considered by historical factors to be low risk for preterm delivery (generally considered to be women with singleton pregnancies without a history of a previous preterm birth) as well as those at high risk for preterm birth (those with a previous preterm birth, short cervix, or multiple gestation) continue to evolve. Herein, we review the current evidence and approaches to screening women for preterm birth, and examine future directions for clinical practice. Further research is necessary to better identify at-risk women and provide evidence-based management. PMID- 29229487 TI - Proteomics reveals key proteins participating in growth difference between fall dormant and non-dormant alfalfa in terminal buds. AB - : To explore the molecular mechanism of growth differences between fall dormant (FD) and non-FD alfalfa, we conducted iTRAQ-based quantitative proteomics on terminal buds of Maverick (FD) and Cuf101 (non-FD) cultivars, identified differential abundance protein species (DAPS) and verified expression profiling of certain corresponding mRNA by qRT-PCR. A total of 3872 protein species were annotated. Of the 90 DAPS, 56 and 34 were respectively up- and down-accumulated in Maverick, compared to Cuf101. They were grouped into 35 functional categories and enriched in seven pathways. Of which, auxin polar transport was up-regulated, while phenylpropanoid biosynthesis, pyruvate metabolism and transportation, vitamin B1 synthesis process and flavonoid biosynthesis were down-regulated in Maverick, comparing with Cuf101. In Maverick, mRNA abundances of l-asparaginase, chalcone and stilbene synthase family protein, cinnamyl alcohol dehydrogenase like protein, thiazole biosynthetic enzyme, pyruvate dehydrogenase E1 beta subunit, and aldo/keto reductase family oxidoreductase were significantly lower at FD than at other stages, and lower than in Cuf101. We also observed opposite mRNA profiles of thiazole biosynthetic enzyme, chalcone and stilbene synthase family protein, pyruvate dehydrogenase E1 beta subunit in both cultivars from summer to autumn. Our results suggest that these DAPS could play important roles in growth difference between FD and non-FD alfalfa. BIOLOGICAL SIGNIFICANCE: Up to now, as far as we know, currently the proteins related with the growth differences between FD and non-FD alfalfa cultivars in autumn have not yet been identified in terminal buds. This study identified the protein species expressed in alfalfa terminal buds, selected differentially abundant protein species in terminal buds between Maverick (FD) and Cuf101 (non-FD) cultivars in autumn and identified the important protein species participated in the growth differences. This study lays a foundation for further investigation of the molecular mechanism of the growth differences between FD and non-FD alfalfa and the cultivation of advanced alfalfa cultivars. PMID- 29229489 TI - State of the art on Mycobacterium chimaera research: a bibliometric analysis. PMID- 29229488 TI - A preliminary molecular phylogeny of shield-bearer moths (Lepidoptera: Adeloidea: Heliozelidae) highlights rich undescribed diversity. AB - Heliozelidae are a widespread, evolutionarily early diverging family of small, day-flying monotrysian moths, for which a comprehensive phylogeny is lacking. We generated the first molecular phylogeny of the family using DNA sequences of two mitochondrial genes (COI and COII) and two nuclear genes (H3 and 28S) from 130 Heliozelidae specimens, including eight of the twelve known genera: Antispila, Antispilina, Coptodisca, Heliozela, Holocacista, Hoplophanes, Pseliastis, and Tyriozela. Our results provide strong support for five major Heliozelidae clades: (i) a large widespread clade containing the leaf-mining genera Antispilina, Coptodisca and Holocacista and some species of Antispila, (ii) a clade containing most of the described Antispila, (iii) a clade containing the leaf-mining genus Heliozela and the monotypic genus Tyriozela, (iv) an Australian clade containing Pseliastis and (v) an Australian clade containing Hoplophanes. Each clade includes several new species and potentially new genera. Collectively, our data uncover a rich and undescribed diversity that appears to be especially prevalent in Australia. Our work highlights the need for a major taxonomic revision of the family and for generating a robust molecular phylogeny using multi-gene approaches in order to resolve the relationships among clades. PMID- 29229491 TI - Could cannabis liberalisation lead to wider changes in drug policies and outcomes? AB - Cannabis policies are changing in some countries. This may have consequences that extend beyond cannabis-specific outcomes, such as an impact on the consumption patterns of other substances. Changes in cannabis policies may also influence policy responses to other drugs, as countries re-assess the balance between law enforcement and public health objectives. If this happens, it could have important health and social consequences, especially in those countries where a 'war on drugs' policy perspective has inhibited investment in evidence based responses in areas such as treatment and harm reduction. The burden of disease associated with opioid use for example is large and this is an area in which treatment and harm reduction have been shown to deliver benefits. Thus if the changes in cannabis policies result in a greater willingness to invest in effective interventions for other drugs, the potential net health gains could be considerable. On the other hand, if cannabis policy changes are associated with an increase in health risk behaviours, such as driving under the influence or increased use of harmful substances such as tobacco, then significant increased health costs could result. To date most attention has been focused on recent cannabis sales liberalisation in the Americas, but experiences from elsewhere are also informative. In Europe, for example, moves towards decriminalisation of drug possession are resulting in lower rates of incarceration and arguably have reduced barriers to treatment uptake. Robust monitoring and assessment of the impact of these different policy changes is crucial to evaluating and understanding their results. It is important that such monitoring is international in scope, is not limited to issues around the use of cannabis only, and considers the interactions that may exist between cannabis policies and the approaches taken to other substances. PMID- 29229492 TI - Programming Morphogenesis through Systems and Synthetic Biology. AB - Mammalian tissue development is an intricate, spatiotemporal process of self organization that emerges from gene regulatory networks of differentiating stem cells. A major goal in stem cell biology is to gain a sufficient understanding of gene regulatory networks and cell-cell interactions to enable the reliable and robust engineering of morphogenesis. Here, we review advances in synthetic biology, single cell genomics, and multiscale modeling, which, when synthesized, provide a framework to achieve the ambitious goal of programming morphogenesis in complex tissues and organoids. PMID- 29229490 TI - Pseudomonas aeruginosa intensive care unit outbreak: winnowing of transmissions with molecular and genomic typing. AB - BACKGROUND: Pseudomonas aeruginosa healthcare outbreaks can be time consuming and difficult to investigate. Guidance does not specify which typing technique is most practical for decision-making. AIM: To explore the usefulness of whole genome sequencing (WGS) in the investigation of a P. aeruginosa outbreak, describing how it compares with pulsed-field gel electrophoresis (PFGE) and variable number tandem repeat (VNTR) analysis. METHODS: Six patient isolates and six environmental samples from an intensive care unit (ICU) positive for P. aeruginosa over two years underwent VNTR, PFGE and WGS. FINDINGS: VNTR and PFGE were required to fully determine the potential source of infection and rule out others. WGS results unambiguously distinguished linked isolates, giving greater assurance of the transmission route between wash-hand basin water and two patients, supporting the control measures employed. CONCLUSION: WGS provided detailed information without the need for further typing. When allied to epidemiological information, WGS can be used to understand outbreak situations rapidly and with certainty. Implementation of WGS in real-time would be a major advance in day-to-day practice. It could become a standard of care as it becomes more widespread due to its reproducibility and lower costs. PMID- 29229493 TI - Intervendor Consistency and Accuracy of Left Ventricular Volume Measurements Using Three-Dimensional Echocardiography. AB - BACKGROUND: Intervendor consistency of left ventricular (LV) volume measurements using three-dimensional transthoracic echocardiography (3DTTE) has never been reported. Accordingly, we designed a prospective study to (1) compare head-to head the accuracy of three three-dimensional echocardiography (3DE) systems in measuring LV volumes and ejection fraction (EF) against cardiac magnetic resonance (CMR); (2) assess the intervendor variability of LV volumes and EF; and (3) compare the accuracy of fully automated versus semiautomated (i.e., manually corrected) methods of LV endocardial delineation against CMR. METHODS: We studied 92 patients (64% males, 52 years [95% CI, 20-83]) with a wide range of end diastolic volumes (from 87 to 446 mL) and EFs (from 16% to 77%) using three different 3DE platforms (iE33; Vivid E9; Acuson SC2000) during the same echo study. CMR was performed within 3 +/- 5 hours from the 3DE study in 35 patients. RESULTS: LV volumes provided by the three 3DE systems correlated with CMR volumes: end-diastolic volume (iE33: R2 = 0.93; E9: R2 = 0.94; SC2000: R2 = 0.94), end-systolic volume (iE33: R2 = 0.93; E9: R2 = 0.95; SC2000: R2 = 0.94), and EF (iE33: R2 = 0.79; E9: R2 = 0.80; SC2000: R2 = 0.77). In the 92 patients studied, LV volumes and EFs measured with the three systems were similar. Use of fully automated endocardial border detection algorithms significantly underestimated LV volumes, and the degree of underestimation was higher with larger LV volumes. CONCLUSIONS: LV volumes and EFs measured with the three 3DE systems are consistent. Fully automated algorithms underestimated LV volumes. Our findings may help in the clinical interpretation of LV parameters obtained using different 3DE systems and encourage the clinical use of 3DTTE. PMID- 29229494 TI - Classic-Pattern Dyssynchrony in Adolescents and Adults With a Fontan Circulation. AB - BACKGROUND: Previous studies have suggested the presence of dyssynchrony in the functionally single ventricle. The aim of this study was to investigate the presence of classic-pattern dyssynchrony (CPD), characterized by typical early and late deformation of opposite walls, and its relation to QRS duration and myocardial function in patients with single-ventricle physiology after Fontan palliation. METHODS: In a retrospective cross-sectional study, 101 adolescent and adult patients with single-ventricle physiology after the Fontan procedure were investigated. Strain curves were visually assessed for the presence of CPD. Systolic and diastolic function were assessed using echocardiography. RESULTS: One hundred one patients were included, with varying anatomic morphology: two sizable ventricular components (n = 21), right dominant (n = 21), left dominant (n = 49), and undefined anatomy (n = 10). Fifteen of 101 Fontan patients had CPD. Forty-three percent of patients with two sizable ventricular masses displayed CPD, mostly with prolonged QRS, while the number of patients with CPD with right dominant (9%) and left-dominant (6%) morphology was significantly lower (P = .016). Those with CPD displayed significantly (P < .05) larger QRS widths (142 +/ 22 vs 112 +/- 24 msec), lower ejection fractions (31 +/- 14% vs 45 +/- 14%), lower global early diastolic strain rates (0.7 +/- 0.5 vs 1.2 +/- 0.8 sec-1), and global systolic circumferential (-10 +/- 5% vs -16 +/- 7%) and longitudinal (-9 +/- 5% vs -14 +/- 5%) strain, respectively. CONCLUSIONS: CPD is present in a proportion of adolescent and adult patients after Fontan palliation. The presence of CPD is associated with reduced systolic and diastolic function compared with Fontan patients without CPD. Because the presence of CPD appears to be a promising predictor for response to cardiac resynchronization therapy in patients with biventricular circulation, these findings may have important potential for prospective evaluation of cardiac resynchronization therapy in patients with univentricular circulation. PMID- 29229495 TI - Pulmonary Hypertension and Pulmonary Artery Acceleration Time: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Measuring mean pulmonary artery pressure by right-heart catheterization is the gold standard for pulmonary hypertension (PH) diagnosis. However, its invasiveness and complication leads to its limited use. The aim of this study was to determine whether echocardiography-derived pulmonary artery acceleration time (PAAT) possesses adequate diagnostic performance for PH, using right-heart catheterization as a reference standard. METHODS: MEDLINE, Embase, PubMed, and the Cochrane Central Register of Controlled Trials were searched through July 2016 for studies evaluating PAAT for the diagnosis of PH. Methodologic quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. For each study, the sensitivity, specificity, and diagnostic odds ratio, along with 95% CIs, were calculated to determine the diagnostic accuracy of PAAT. Meta-regression was conducted to evaluate the impact of potential confounding factors. RESULTS: Of 430 articles, 21 studies (1,280 patients) were identified, including three studies that used transesophageal echocardiography and 18 studies that used transthoracic echocardiography. The pooled sensitivity across studies was 0.84 (95% CI, 0.75-0.90), the pooled specificity was 0.84 (95% CI, 0.78-0.89), and the pooled diagnostic odds ratio was 28 (95% CI, 16-49). The arrhythmia ratio in the population did not affect the specificity of PAAT's diagnostic performance and increased the sensitivity of PH detection. CONCLUSIONS: The results of this study suggest that PAAT is useful for PH detection. PMID- 29229496 TI - Turning back the clock on adrenal insufficiency. PMID- 29229497 TI - Advanced neuroendocrine tumours of the small intestine and pancreas: clinical developments, controversies, and future strategies. AB - In this Review, we discuss clinical developments and controversies in the treatment of neuroendocrine tumours (NETs) that are relevant for clinicians and clinical researchers. We describe advances in genetics, blood-based biomarkers, functional imaging, and systemic therapy of advanced NETs and discuss results of recent phase 3 studies, systemic treatment of advanced disease with peptide receptor radionuclide therapy, biotherapy, chemotherapy, and molecularly targeted therapy, and the potential role of immunotherapy in the treatment of NETs. Suggested treatment algorithms for NETs of ileal or jejunal origin and of pancreatic origin are presented. PMID- 29229498 TI - Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial. AB - BACKGROUND: Conventional treatment of patients with adrenal insufficiency involves administration of glucocorticoids multiple times a day and has been associated with weight gain and metabolic impairment. The optimal glucocorticoid replacement therapy for these patients is highly debated because of the scarcity of evidence from randomised trials. We aimed to establish whether the timing and pharmacokinetics of glucocorticoid replacement therapy affect the metabolism and immune system of patients with adrenal insufficiency. METHODS: We did a single blind randomised controlled trial at two reference university hospitals in Italy. Eligible patients (aged 18-80 years) with adrenal insufficiency were on conventional glucocorticoid therapy and had been stable for at least 3 months before enrolment. Patients were randomly assigned (1:1) with a computer-generated random sequence stratified by type of adrenal insufficiency and BMI to continue conventional glucocorticoid therapy (standard treatment group) or to switch to an equivalent dose of once-daily, modified-release oral hydrocortisone (switch treatment group). Outcome assessors were masked to treatment allocation. The primary outcome was bodyweight change from baseline to 24 weeks. Secondary outcomes included immune cell profiles, susceptibility to infections, and quality of life. Efficacy analyses included all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02277587. FINDINGS: Between March 1, 2014, and June 30, 2016, 89 patients with adrenal insufficiency were randomly assigned to continue standard glucocorticoid therapy (n=43) or to switch to once-daily, modified-release hydrocortisone (n=46). At 24 weeks, bodyweight reduction was superior in patients in the once-daily hydrocortisone group compared with those in the standard treatment group (-2.1 kg [95% CI -4.0 to -0.3] vs 1.9 kg [-0.1 to 3.9]; treatment difference -4.0 kg, 95% CI -6.9 to -1.1; p=0.008). Additionally, patients in the once-daily hydrocortisone group had more normal immune cell profiles, reduced susceptibility to infections, and improved quality of life compared with the standard glucocorticoid therapy group. We observed no difference in frequency or severity of adverse events between the two intervention groups, although a lower cumulative number of recurrent upper respiratory tract infections was observed with once-daily hydrocortisone than with standard treatment (17 vs 38; p=0.016). Most adverse events were mild; three serious adverse events occurred in each group, of which one adverse advent (arthritis) in the switch treatment group could be considered drug related. INTERPRETATION: Patients with adrenal insufficiency on conventional glucocorticoid replacement therapy multiple times a day exhibit a pro-inflammatory state and weakened immune defence. Restoration of a more physiological circadian glucocorticoid rhythm by switching to a once daily, modified-release regimen reduces bodyweight, normalises the immune cell profile, reduces recurrent infections, and improves the quality of life of patients with adrenal insufficiency. FUNDING: Italian Ministry of University and Research. PMID- 29229499 TI - Molecular diagnosis of suspected tuberculosis from archived smear slides from the Balimo region, Papua New Guinea. AB - BACKGROUND: Tuberculosis (TB) is a serious health problem in Papua New Guinea (PNG) with an estimated 30000 new cases and 3800 deaths each year. In the Balimo region of the Western Province, diagnosis relies on clinical manifestations and on the microscopic detection of acid-fast bacilli (AFB) in sputum smears, a technique with limited sensitivity. METHODS: A molecular diagnosis assay targeting DNA extracted from archived sputum smear slides collected from the Balimo region (2012-2014) was conducted, without the need for a viable culture. The presence of Mycobacterium sp on 1162 slides prepared from 345 sputum samples was assessed using a real-time PCR (qPCR) approach. RESULTS: The qPCR technique identified the presence of mycobacteria in 35.4% of the smear slides and 59.7% of the tested sputum samples. Poor agreement was observed between the two diagnosis methods (smear AFB microscopy versus qPCR), with 100 AFB-positive sputum samples compared to 206 qPCR-positive sputum samples overall. Treatment was initiated in 90.2% of the smear-positive cases. Unnecessary treatment of 'false-positive' TB cases (AFB-negative/qPCR-negative) was very low (8.6%) and was even lower when the nine patients diagnosed with extrapulmonary TB were excluded from the analysis. However, the prevalence of false-negatives (AFB-negative/qPCR-positive) was high (28.5%). CONCLUSIONS: Undetected smear-negative TB is occurring in the Balimo region of PNG, as well as some unnecessary empirical treatment. Molecular methods of diagnosis could greatly reduce the frequency of inappropriate clinical assessment, as well as providing point-of-care diagnosis. This may provide substantial patient and programmatic benefits, including lowering the economic burden on patients from rural areas seeking medical diagnosis in Balimo. PMID- 29229500 TI - Diagnostic value of circulating cell-free DNA levels for hepatocellular carcinoma. AB - OBJECTIVES: Circulating cell-free DNA (cfDNA) is a potential biomarker for tumor diagnosis. Hepatocyte damage is a characteristic component of the pathobiology of hepatocellular carcinoma (HCC), which would be expected to result in substantial leakage of cfDNA into the circulation. However, the diagnostic value of cfDNA levels for HCC remains unclear. METHODS: Plasma samples were collected from 24 HCC patients and 62 hepatitis B virus-related liver fibrosis patients. Plasma cfDNA levels were quantified by Qubit method. RESULTS: Plasma cfDNA levels were associated with the degree of liver inflammation, body mass index, and alpha fetoprotein (AFP) level, but were not associated with fibrosis stages. Plasma cfDNA levels were significantly higher in HCC patients than in non-HCC patients. Multivariate analysis revealed that age and cfDNA, rather than AFP, were independent predictors of HCC. The HCC index, a combination model including age, cfDNA, and AFP, had an area of 0.98 (95% confidence interval 0.92-1.00) under the receiver operating characteristics curve for the diagnosis of HCC at the cut-off value of 0.61, with 87.0% sensitivity and 100% specificity. The diagnostic power of the HCC index was superior to that of cfDNA alone and AFP alone. CONCLUSIONS: These results suggest that the combination of cfDNA with age and AFP could improve the diagnostic performance for HCC. PMID- 29229501 TI - Proceedings of the 2017 Santa Fe Bone Symposium: Insights and Emerging Concepts in the Management of Osteoporosis. AB - The 18th Annual Santa Fe Bone Symposium was held on August 4-5, 2017, in Santa Fe, New Mexico, USA. The symposium convenes health-care providers and clinical researchers to present and discuss clinical applications of recent advances in research of skeletal diseases. The program includes lectures, oral presentations by endocrinology fellows, case-based panel discussions, and breakout sessions on topics of interest, with emphasis on participation and interaction of all participants. Topics included the evaluation and treatment of adult survivors with pediatric bone diseases, risk assessment and management of atypical femur fractures, nonpharmacologic strategies in the care of osteoporosis, and skeletal effects of parathyroid hormone with opportunities for therapeutic intervention. Management of skeletal complications of rheumatic diseases was discussed. Insights into sequential and combined use of antiresorptive agents were presented. Individualization of patient treatment decisions when clinical practice guidelines may not be applicable was covered. Challenges and opportunities with osteoporosis drug development were discussed. There was an update on progress of Bone Health TeleECHO (Bone Health Extension for Community Healthcare Outcomes), a teleconferencing strategy for sharing knowledge and expanding capacity to deliver best-practice skeletal health care. PMID- 29229502 TI - Sodium butyrate abolishes lipopolysaccharide-induced depression-like behaviors and hippocampal microglial activation in mice. AB - Patients with major depressive disorder have elevated peripheral inflammation; the degree of this increase correlates with the severity of the disorder. Chronic psychological stress increases pro-inflammatory cytokines and promotes microglial activation, leading to stress vulnerability. Epigenetics, including DNA methylation and histone modification, are also related to the pathophysiology of major depressive disorder. Sodium butyrate (SB), a histone deacetylase inhibitor, exerts an antidepressant effect by altering gene expression in the hippocampus. In this study, we investigated whether lipopolysaccharide (LPS)-induced depressive-like behaviors in mice are affected by the repeated treatment with SB. Intraperitoneal injection of LPS (5 mg/kg) induced cytokines and ionized calcium binding adaptor molecule 1(Iba1), a marker of microglial activation, in the hippocampus. It also increased the immobility time in a forced swim test, without changing locomotion. Repeated treatment with SB reduced LPS-induced alterations. These findings suggested that epigenetic regulation exist in hippocampal microglial activation, and is involved in depressive-like behaviors associated with neuro-inflammation. Further, using cDNA microarray analyses, we examined whether LPS and SB treatment affected the microglial gene profiles. Our results indicated 64 overlapping genes, between LPS-increased genes and SB-decreased genes. Among these genes, EF hand calcium binding domain 1 was a particularly distinct candidate gene. Altogether, our findings indicated that microglial activation mediated through epigenetic regulation may be involved in depressive like behaviors. In addition, we demonstrated the effect of SB on gene information in hippocampal microglia under neuroinflammatory conditions. PMID- 29229504 TI - An inhibitory action of chitosan nanoparticles against pathogenic bacteria and fungi and their potential applications as biocompatible antioxidants. AB - Chitosan is the second most abundant polymer obtained from the byproduct of seafood. Chitosan and its derivatives and chitosan loaded drugs are the recent area of interest against microbial pathogenesis. The cationic chitosan nanoparticles (ChNPs) interact with the anionic surfaces of the microbial cell membrane, which promotes antimicrobial activity. Although, ChNPs are potential against pathogenic microbes, selection of adaptable, suitable and cost effective synthesis method is much important. In the present study, ChNPs were synthesized adopting ionic gelation using sodium tripolyphosphate as a cross linking agent and characterized by FTIR, DLS, SEM and TEM analysis. ChNPs were investigated for antimicrobial activity against bacterial (Escherichia coli and Staphylococcus aureus) and fungal (Candida albicans) pathogens. ChNPs showed bactericidal activity at the lower minimum inhibitory concentration of about 40-80 MUg mL-1. Interestingly, ChNPs exhibits biocompatible antioxidant property by inhibiting DPPH free radicals at 76% and also proven to be a potential candidate against the microbial pathogenesis with an inevitable applications in biomedicine. PMID- 29229503 TI - Characterization of early-onset motor deficits in the Pink1-/- mouse model of Parkinson disease. AB - In Parkinson disease (PD), a complex neurodegenerative disorder that affects nearly 10 million people worldwide, motor skills are significantly impaired. However, onset and progression of motor deficits and the neural correlates of these deficits are poorly understood. We used a genetic mouse model of PD (Pink1 /-), with phenotypic similarities to human PD, to investigate the manifestation of early-onset sensorimotor deficits. We hypothesized this mouse model would show early vocalization and gross motor dysfunction that would be progressive in nature. Pink1-/- mice, compared to wild type (WT) controls, were evaluated at 2, 3, 4, 5, and 6 months of age. To quantify deficit progression, ultrasonic vocalizations and spontaneous locomotor activity (cylinder test and pole test) were analyzed. Although somewhat variable, in general, Pink1-/- mice produced significantly more simple calls with reduced intensity as well as a larger percentage of cycle calls compared to WT counterparts. However, there were no significant differences in duration, bandwidth, or peak frequency for any of the ultrasonic call types between genotypes. Pink1-/- mice showed a significant impairment in limb motor skills with fewer hindlimb steps, forelimb steps, and rears and lands in the cylinder test compared to WT. Additionally, Pink1-/- mice took significantly longer to turn and traverse during the pole test. Immunohistochemical staining showed no significant difference in the number of tyrosine hydroxylase (TH) positive cells in the substantia nigra or density of TH staining in the striatum between genotypes. These data suggest the Pink1-/- mouse model may be instrumental in defining early motor biomarkers of PD in the absence of nigrostriatal dopamine loss. PMID- 29229505 TI - Action mechanism of naphthofuranquinones against fluconazole-resistant Candida tropicalis strains evidenced by proteomic analysis: The role of increased endogenous ROS. AB - The increased incidence of candidemia in terciary hospitals worldwide and the cross-resistance frequency require the new therapeutic strategies development. Recently, our research group demonstrated three semi-synthetic naphthofuranquinones (NFQs) with a significant antifungal activity in a fluconazole-resistant (FLC) C. tropicalis strain. The current study aimed to investigate the action's preliminary mechanisms of NFQs by several standardized methods such as proteomic and flow cytometry analyzes, comet assay, immunohistochemistry and confocal microscopy evaluation. Our data showed C. tropicalis 24 h treated with all NFQs induced an expression's increase of proteins involved in the metabolic response to stress, energy metabolism, glycolysis, nucleosome assembly and translation process. Some aspects of proteomic analysis are in consonance with our flow cytometry analysis which indicated an augmentation of intracellular ROS, mitochondrial dysfunction and DNA strand breaks (neutral comet assay and gamma-H2AX detection). In conclusion, our data highlights the great contribution of ROS as a key event, probably not the one, associated to anti-candida properties of studied NFQs. PMID- 29229506 TI - The population benefit of evidence-based radiotherapy: 5-Year local control and overall survival benefits. AB - BACKGROUND: To describe the population benefit of radiotherapy in a high-income setting if evidence-based guidelines were routinely followed. METHODS: Australian decision tree models were utilized. Radiotherapy alone (RT) benefit was defined as the absolute proportional benefit of radiotherapy compared with no treatment for radical indications, and of radiotherapy over surgery alone for adjuvant indications. Chemoradiotherapy (CRT) benefit was the absolute incremental benefit of concurrent chemoradiotherapy over RT. Five-year local control (LC) and overall survival (OS) benefits were measured. Citation databases were systematically queried for benefit data. Meta-analysis and sensitivity analysis were performed. FINDINGS: 48% of all cancer patients have indications for radiotherapy, 34% curative and 14% palliative. RT provides 5-year LC benefit in 10.4% of all cancer patients (95% Confidence Interval 9.3, 11.8) and 5-year OS benefit in 2.4% (2.1, 2.7). CRT provides 5-year LC benefit in an additional 0.6% of all cancer patients (0.5, 0.6), and 5-year OS benefit for an additional 0.3% (0.2, 0.4). RT benefit was greatest for head and neck (LC 32%, OS 16%), and cervix (LC 33%, OS 18%). CRT LC benefit was greatest for rectum (6%) and OS for cervix (3%) and brain (3%). Sensitivity analysis confirmed a robust model. INTERPRETATION: Radiotherapy provides significant 5-year LC and OS benefits as part of evidence-based cancer care. CRT provides modest additional benefits. PMID- 29229508 TI - Outcomes of type 2 endoleaks detected on venous phase CT arteriography. AB - PURPOSE: The majority of type 2 endoleaks (T2EL) are identified on computed tomography angiography (CTA) both on arterial and venous phase. There is a subset of T2EL that are demonstrated only on venous phase CTA. This study was done to report the outcomes of T2EL detected only on venous phase CTA. MATERIALS AND METHODS: A total of 261 consecutive T2EL treated via embolization were reviewed for the presence of endoleak demonstrated only on venous phase CTA. A group of 16 patients (12 men, 4 women; mean age, 80.1 years) was identified who had pre embolization venous phase T2EL. Patients were evaluated for presence of T2EL after embolization, change in aneurysm diameter, and need for further intervention. RESULTS: The prevalence of venous phase T2EL was 6.1% (16/261; 95%CI: 3.2%-9.0%). On post-embolization CTA, the rate of successful embolization at 6 months was 2/12 (17%; 95%CI: 0%-38%). At 6-month follow-up, mean change in aneurysm diameter was +2.3mm (n=12; 95%CI: -0.5mm to +5.0mm). In total, 4/16 (25%; 95%CI: 4%-46%) underwent re-embolization and 4/16 (25%, 95%CI: 4%-46%) underwent conversion to open repair. There was one aneurysm rupture, which was successfully treated surgically. CONCLUSION: These results suggest that venous phase T2EL are not as responsive to embolization as standard T2EL and emphasize the need to follow patients with venous phase T2EL closely. PMID- 29229509 TI - Diagnosis of congenital abnormalities with post-mortem ultrasound in perinatal death. AB - PURPOSE: To determine the sensitivity and specificity of post-mortem ultrasound in the diagnosis of major congenital abnormalities of fetuses using conventional autopsy as the standard of reference. MATERIAL AND METHODS: All fetuses coming from terminations of pregnancy or intrauterine fetal deaths in a single institution were included. A total of 75 fetuses were included during the study period. The results of post-mortem ultrasound examinations were compared to those of conventional autopsy that served as standard of reference. RESULTS: Gestational age of the fetuses ranged from 15 to 38 weeks gestation. A complete post-mortem ultrasound assessment was possible in all fetuses. Regarding detection of brain abnormalities, post-mortem ultrasound had a sensitivity of 81.5% or 4/5 (95% CI: 63.3-91.8%), and a specificity of 97.9% (95% CI: 89.1 99.6%). Specificities for the diagnosis of thoracic, cardiac, urinary tract, spinal and bone abnormalities were 100%. CONCLUSION: Post-mortem ultrasound shows high sensitivity and specificity for the diagnosis of congenital structural abnormalities as compared to conventional autopsy, with the exception of congenital cardiac diseases. PMID- 29229507 TI - Patient reported dry mouth: Instrument comparison and model performance for correlation with quality of life in head and neck cancer survivors. AB - PURPOSE: To identify a clinically meaningful cut-point for the single item dry mouth question of the MD Anderson Symptom Inventory-Head and Neck module (MDASI HN). METHODS: Head and neck cancer survivors who had received radiation therapy (RT) completed the MDASI-HN, the University of Michigan Hospital Xerostomia Questionnaire (XQ), and the health visual analog scale (VAS) of the EuroQol Five Dimension Questionnaire (EQ-5D). The Bayesian information criteria (BIC) were used to test the prediction power of each tool for EQ-5D VAS. The modified Breiman recursive partitioning analysis (RPA) was used to identify a cut point of the MDASI-HN dry mouth score (MDASI-HN-DM) with EQ-5D VAS, using a ROC-based approach; regression analysis was used to confirm the threshold effect size. RESULTS: Two-hundred seven respondents formed the cohort. Median follow-up from the end of RT to questionnaire completion was 88 months. The single item MDASI-HN DM score showed a linear relationship with the XQ composite score (rho = 0.80, p < 0.001). The MDASI-HN-DM displayed improved model performance for association with EQ-5D VAS as compared to XQ (BIC of 1803.7 vs. 2016.9, respectively). RPA showed that an MDASI-HN-DM score of >=6 correlated with EQ-5D VAS decline (LogWorth 5.5). CONCLUSION: The single item MDASI-HN-DM correlated with the multi item XQ and performed favorably in the prediction of QOL. A MDASI-HN-DM cut point of >=6 correlated with decline in QOL. PMID- 29229510 TI - Opacification of nondilated bile ducts through the gallbladder as an aid to percutaneous transhepatic biliary drainage. AB - PURPOSE: The purpose of this study was to retrospectively assess the potential of percutaneous transhepatic biliary drainage (PTBD) in patients with nondilated bile ducts (NDBD) using a transgallbladder opacification of the bile ducts. PATIENTS AND METHODS: Eight patients with NDBD (7 men, 1 women; median age, 65 years; Q1-Q3, 35-69 years; range, 22-77 years) who underwent PTBD after opacification of the bile ducts through the gallbladder were evaluated. Opacification of NDBD was performed using a retrograde injection of contrast material through the gallbladder. The opacified peripheral NDBD was punctured percutaneously and a drainage catheter was introduced under fluoroscopy guidance. The success and safety of the procedure were assessed. RESULTS: PTBD could be achieved in 6/8 patients (75%) and no significant complications were observed. The biliary tree opacification was attempted but could not be achieved due to biliary sludge that obstructed the cystic duct in 2/8 patients (25%). Two minor complications in two different patients were observed consisting of transient hemobilia and chills. CONCLUSION: Opacification of the bile ducts using a transgallbladder approach appears to be a safe and successful procedure for PTBD in patients with NDBD. PMID- 29229511 TI - Real time release testing of tablet content and content uniformity. AB - A comprehensive commercial control strategy for tablet content and content uniformity focussed on the unit operation of compression is presented and is proposed to enable real time release for these critical quality attributes. The control strategy is based on process understanding, process control through compaction force weight control on the tablet press, periodic checks of mean and individual tablet weight combined with at-line testing of tablet content by near infrared (NIR). The application of the at-line NIR tablet content method is discussed and an acceptance criteria based on a parametric tolerance interval test (PTIT) is proposed. Sample handling limitations and spectral acquisition time for the NIR content method limit the sample size, however the chosen PTIT assures an appropriate level of batch coverage. Data are presented for ten commercial-scale batches that demonstrates the control strategy delivered the quality standard for content and content uniformity. PMID- 29229512 TI - Efficiency of resveratrol-loaded sericin nanoparticles: Promising bionanocarriers for drug delivery. AB - Sericin protein nanoparticles are a biocompatible, bio-viable class of nanocarriers gaining prominence in drug delivery system. This research aimed to investigate the suitability fabrication of silk protein (SP) nanoparticles for loading with resveratrol (RSV) via a solventless precipitation technique. The addition of 0.5% (w/v) pluronic surfactant proved optimal for SP nanoparticle fabrication, with obtained nanoparticles being spherical, mono-dispersed and having mean size of approximately 200-400 nm. All exhibited negative surface charges, the extent of which being dependent on the SP concentration, and were non-toxic to normal skin fibroblasts (CRL-2522). Loading of RSV, a promising which poorly soluble multi-targeted anti-oxidative and anti-inflammatory natural polyphenol, into SP nanoparticles proved feasible, with encapsulation levels of 71-75% for 0.6% and 1.0% (w/v) nanoparticle formulations, respectively. Resveratrol-loaded SP nanoparticles strongly inhibited growth of colorectal adenocarcinoma (Caco-2) cells although proved non-cytotoxic to skin fibroblasts, as indicated by cell viability assays. Cellular internalization of SP nanoparticles proved facile and dependent on incubation time; transfection of these carriers, in vitro results indicating sustained release of RSV (over 72 h), and drug solubility enhancements on encapsulation highlight their potential in therapeutic and pharmaceutical applications. Thus, SP nanoparticles is a promising approach to be potential bio-nanocarrier for drug delivery system. PMID- 29229513 TI - Modelling drug release from polymer-free coronary stents with microporous surfaces. AB - Traditional coronary drug-eluting stents (DES) are made from metal and are coated with a permanent polymer film containing an anti-proliferative drug. Subsequent to stent deployment in a diseased coronary artery, the drug releases into the artery wall and helps prevent restenosis by inhibiting the proliferation of smooth muscle cells. Although this technology has proven to be remarkably successful, there are ongoing concerns that the presence of a polymer in the artery can lead to deleterious medical complications, such as late stent thrombosis. Polymer-free DES may help overcome such shortcomings. However, the absence of a rate-controlling polymer layer makes optimisation of the drug release profile a particular challenge. The use of microporous stent surfaces to modulate the drug release rate is an approach that has recently shown particularly promising clinical results. In this study, we develop a mathematical model to describe drug release from such stents. In particular, we develop a mathematical model to describe drug release from microporous surfaces. The model predicts a two-stage release profile, with a relatively rapid initial release of most of the drug, followed by a slower release of the remaining drug. In the model, the slow release phase is accounted for by an adsorption/desorption mechanism close to the stent surface. The theoretical predictions are compared with experimental release data obtained in our laboratory, and good agreement is found. The valuable insights provided by our model will serve as a useful guide for designing the enhanced polymer-free stents of the future. PMID- 29229514 TI - How obstetricians and pregnant women decide mode of birth in light of a recent regulation in Brazil. AB - BACKGROUND: In Brazil, 88% of births among women with private insurance are caesarean sections, even though a caesarean rate above 15% is associated with greater maternal and child morbidity and mortality. Aiming to reduce unnecessary caesarean sections in the private sector, in July 2015 the Brazilian government enacted Resolucao Normativa 368, a regulation requiring the use of partograms, pre-natal cards to document pregnancies, and consent forms for elective caesareans, and recommending that obstetricians provide women with an informational letter about birth. AIMS: This study aimed to describe Brazilian women's experiences deciding their mode of birth and obstetricians' roles in this decision-making process after Resolucao Normativa 368's enactment. METHODS: Interviews were conducted with obstetricians (n=8) and women who had recently given birth (n=19) in Pelotas, Brazil, and the constant comparative method was used to identify emergent themes. FINDINGS: Resolucao Normativa 368's provisions do not appear to affect decision-making about birth mode. Reportedly, consent forms were rarely used, and were viewed as bureaucratic formalities. Obstetricians described consistent use of pre-natal cards and partograms, but all participants were unaware of informational letters about birth. Moreover, women viewed caesarean sections as a way to avoid pain, and obstetricians felt that vaginal birth's long duration, unpredictability, and low remuneration contribute to high caesarean section rates. CONCLUSIONS: Improved enforcement of Resolucao Normativa 368, accompanied by structural changes like an on-call schedule and higher compensation for vaginal births in the private sector, could better inform patients about modes of birth and incentivise physicians to encourage vaginal birth. PMID- 29229515 TI - OxyR of Haemophilus parasuis is a global transcriptional regulator important in oxidative stress resistance and growth. AB - Haemophilus parasuis is an opportunistic pathogen and the causative agent of Glasser's disease in swine. This disease has high morbidity and mortality rates in swine populations, and is responsible for major economic losses worldwide. Survival of H. parasuis within the host requires mechanisms for coping with oxidative stress conditions. In many bacteria, OxyR is known to mediate protection against oxidative stress; however, little is known about the role of OxyR in H. parasuis. In the current study, an oxyR mutant strain was constructed in H. parasuis strain SC1401 and designated H. parasuis SC1401?oxyR. The oxyR mutant strain had a slower growth rate and impaired biofilm formation compared to the wild type strain. Complementation restored the growth-associated phenotypes to wild type levels. Oxidative stress susceptibility testing, using a range of concentrations of H2O2, indicated that H. parasuis SC1401?oxyR was more sensitive to oxidative stress than the wild type strain. RNA sequencing transcriptome analysis comparing H. parasuis SC1401 with H. parasuis SC1401?oxyR identified 466 differentially expressed genes. These genes were involved in a wide range of biological processes, including: oxidative stress, transcriptional regulation, and DNA replication, recombination, and repair. These findings provide a foundation for future research to examine the role of OxyR as a global transcriptional regulator and to better define its role in oxidative stress resistance in H. parasuis. PMID- 29229516 TI - Dissimilar substitution rates between two strands of DNA influence codon usage pattern in some human genes. AB - We illustrated the descriptive aspects of codon usage of some important human genes and their expression potential in E. coli. By comparing the results of various codon usage parameters, effects that are due to selection and mutational pressures have been deciphered. The variation in GC3s explains a significant proportion of the variation in codon usage patterns. The codons CGC, CGG, CTG and GCG showed strong positive correlation with GC3, which suggested that codon usage had been influenced by GC bias. We also found that ACC (Thr, RSCU-1.77), GCC (Ala, RSCU-1.67), CCC (Pro, RSCU-1.54), TCC (Ser, RSCU-1.47) were frequently used which signified that C was common at 2nd and 3rd codon positions. Correspondence analysis revealed that F1 axis had significant correlation with various GC contents suggesting that compositional properties under mutation pressure might affect codon usage bias. Nc-GC3 plot analysis suggested that both mutation pressure and natural selection might affect the codon usage bias which is also supported by neutrality plot analysis. The dinucleotide CT, TG and AG were significantly over-represented and CG, TA, AT, TT, and GT were underrepresented due to high rate of spontaneous mutation resulting from cytosine deamination. PMID- 29229517 TI - Defibrillation threshold testing in hypertrophic cardiomyopathy: As SIMPLE as possible but not simpler. PMID- 29229518 TI - Reply to the editor- The cost of cardiac resynchronization therapy generator replacement? PMID- 29229519 TI - Leptin injection into the left stellate ganglion augments ischemia-related ventricular arrhythmias via sympathetic nerve activation. AB - BACKGROUND: Leptin is a peptide hormone produced by adipose tissue whose basic function is regulating energy balance and sympathetic outflow. Previous studies have shown that increased nerve activity of the left stellate ganglion (LSG) promotes ventricular arrhythmia (VA). OBJECTIVE: The purpose of this study was to investigate whether leptin could facilitate VA through activation of the LSG. METHODS: Sixteen pentobarbital-anesthetized dogs were divided into a control group (saline; n = 8) and a leptin group (leptin; n = 8). Microinjections of either 0.1 mL saline or leptin (18 MUg) were injected into the LSG. Action potential duration (APD) of the myocyte and the function and neural activity of the LSG were measured at different time points. VA induced by occlusion of the left anterior descending branch was continuously measured for 1 hour. At the end of the experiment, the LSG tissues were collected for molecular detections. RESULTS: Compared with the control group, leptin microinjection resulted in (1) significant enhancement in the incidence of VA; (2) significant decrease in APD and increase in APD dispersion; and (3) significant increase in the function and neural activity of the LSG. Mechanistically, the leptin receptor was found in the LSG, and its signaling was significantly activated in the leptin-injected group. Additionally, leptin microinjection markedly increased the expression of proinflammatory cytokines. CONCLUSION: LSG activation induced by leptin microinjection promotes ischemia-induced VAs. Activated leptin receptor signaling and up-regulation of proinflammatory cytokines in the LSG may be responsible for these effects. PMID- 29229520 TI - To the Editor- The cost of cardiac resynchronization therapy generator replacement? PMID- 29229521 TI - Repolarization tremors: Do they predict arrhythmic earthquakes? PMID- 29229522 TI - Transcatheter/leadless pacing. PMID- 29229523 TI - Inference in population genetics using forward and backward, discrete and continuous time processes. AB - A central aim of population genetics is the inference of the evolutionary history of a population. To this end, the underlying process can be represented by a model of the evolution of allele frequencies parametrized by e.g., the population size, mutation rates and selection coefficients. A large class of models use forward-in-time models, such as the discrete Wright-Fisher and Moran models and the continuous forward diffusion, to obtain distributions of population allele frequencies, conditional on an ancestral initial allele frequency distribution. Backward-in-time diffusion processes have been rarely used in the context of parameter inference. Here, we demonstrate how forward and backward diffusion processes can be combined to efficiently calculate the exact joint probability distribution of sample and population allele frequencies at all times in the past, for both discrete and continuous population genetics models. This procedure is analogous to the forward-backward algorithm of hidden Markov models. While the efficiency of discrete models is limited by the population size, for continuous models it suffices to expand the transition density in orthogonal polynomials of the order of the sample size to infer marginal likelihoods of population genetic parameters. Additionally, conditional allele trajectories and marginal likelihoods of samples from single populations or from multiple populations that split in the past can be obtained. The described approaches allow for efficient maximum likelihood inference of population genetic parameters in a wide variety of demographic scenarios. PMID- 29229524 TI - Toxic responses of Sox2 gene in the regeneration of the earthworm Eisenia foetida exposed to Retnoic acid. AB - Exogenous retinoic acid delays and disturbs the regeneration of Eisenia foetida. The stem cell pluripotency factor, Sox2, can play a crucial role in cell reprogramming and dedifferentiation. In this study, we compared the regeneration of Eisenia foetida in different segments after amputation and the effects of retinoic acid on the regeneration of different segments. The results showed that the regeneration speed of the head and tail was slightly faster than the middle part, and retinoic acid disrupted and delayed the regeneration of the earthworm. The qRT-PCR and Western blot analysis showed that the expression of the Sox2 gene and Sox2 protein was highest on the seventh day in different segments (p<0.05). After treatment with retinoic acid, the expression level of the Sox2 gene and Sox2 protein was significantly reduced (p<0.05). The results indicated that the regeneration of earthworms and the formation of blastema are related to the expression of the Sox2 gene and protein. Retinoic acid delays and interferes with the regeneration of the earthworm by affecting the expression levels of the Sox2 gene and protein. PMID- 29229525 TI - Examining water in model membranes by near infrared spectroscopy and multivariate analysis. AB - By exploiting the sensitivity of the NIR spectrum, particularly the first overtone of water, to the number and strength of hydrogen bonds, the hydrogen bond network and water polymerization in membranes of DMPA (1,2-dimyristoyl-sn glycero-3-phosphate) and DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) was investigated as a function of the temperature and the presence of this two phospholipids having the same tail but different polar head. Principal components analysis performed on the spectra was used to disclose subtle spectral changes that mirror the alteration of the vibrational energy of the water O-H bonds, as a measure of the H-bond network. Temperature showed a dominating effect on the H bond network. Increasing temperatures diminished the number of strongly H-bonded water molecules and increased the number of weakly H-bonded waters. This main effect of temperature was missing after the subtraction of the pure water spectra from the lipid-containing ones. An intriguing secondary effect of temperature was also revealed. Phospholipids exhibited an effect qualitatively similar to that of the temperature. DMPA, and particularly DMPC, disrupted the H-bond network in the neighboring lipid-water interface, reducing water polymerization and strengthening the water O-H bonds. The type of the polar head affects the H-bonds more than duplicate the concentration of the lipid. A connection between head group structure and the effect on the H-bonds network, and the existence of two populations of water molecules are discussed. PMID- 29229526 TI - An oligothiophene compound neutralized influenza A viruses by interfering with hemagglutinin. AB - BACKGROUND AND OBJECTIVES: Recently influenza pandemic outbreaks were caused by emerging H5N1, H7N9 and H1N1 viruses. However, virucidal disinfectants are mainly unspecific and toxic. It is tactical to discover specific virucidal compounds. METHODS: The inhibitory potency was determined in H5N1 pseudovirus system; Interactions of compounds with hemagglutinin (HA) were detected with surface plasmon resonance (SPR) and further calculated with molecular docking. Virucidal effect was also estimated in influenza virus A/Puerto Rico/8/34(H1N1). Prevention efficacy was further estimated in mice model. RESULTS: Oligothiophene compound 4sc was potently virucidal against H5N1 pseudovirus with selective index>1169 (IC50=0.17+/-0.01MUM). Pseudovirus assay revealed 4sc may interact with HA. However, HA inhibition test indicated 4sc did not interact with receptor pocket in HA. SPR detection revealed 4sc interacted directly with HA and its HA2 subunits. Molecular docking analysis revealed that 4sc interacted with the cavity of HA2 stem region and HA1-HA2 interface which consist of 7 residues: L22, K262, G472 and F1102 in HA2; M241, E251 and N271 in HA1. 4sc also potently and irreversibly neutralized PR8 (H1N1) virus, causing 105.06+/-0.26 fold decrease of virus titer after exposure for 10min. 4sc blocked PR8 transmission to MDCK cells. Amazingly, virucidal effect of 4sc was not significantly reduced even at 4 degrees C. Furthermore, 4sc blocked viral transmission to mice. CONCLUSION: Oligothiophene compound 4sc is a novel selective virucide of influenza virus, which blocks entry by interfering viral hemagglutinin. Due to promising safety profile and stable virucidal effect at 4 degrees C, 4sc may be useful in disinfecting H5N1 and H1N1 influenza virus. PMID- 29229528 TI - Palmitoyl ceramide promotes milk sphingomyelin gel phase domains formation and affects the mechanical properties of the fluid phase in milk-SM/DOPC supported membranes. AB - Ceramides are minor structural components of membranes involved in biological functions. In the milk fat globule membrane (MFGM), ceramides are susceptible to affect the lateral packing of polar lipids, especially the milk sphingomyelin (MSM). To investigate this, palmitoylceramide (PCer) was added to MSM/DOPC (dioleoylphosphatidylcholine) in order to form hydrated lipid bilayers. Differential scanning calorimetry evidenced interactions of PCer with the MSM in the solid-ordered phase to form MSM/PCer structures with a higher thermostability than MSM. Atomic force microscopy revealed that PCer modified lipid packing in both the liquid-disordered DOPC phase where it increased thickness and mechanical stability, and the solid-ordered MSM phase where it recruited MSM molecules yet initially in the liquid phase at 26 degrees C and then increased the area of the MSM/PCer domains. The effect of PCer on the mechanical properties of the MSM-rich domains remains to be elucidated. These results bring new insights on the role of ceramides in the control of biophysical and biological properties of the MFGM. They also open perspectives for the design of emulsions and liposomes, using milk polar lipids as food-grade ingredients. PMID- 29229527 TI - Surface proteins and the formation of biofilms by Staphylococcus aureus. AB - Staphylococcus aureus biofilms pose a serious clinical threat as reservoirs for persistent infections. Despite this clinical significance, the composition and mechanism of formation of S. aureus biofilms are unknown. To address these problems, we used solid-state NMR to examine S. aureus (SA113), a strong biofilm forming strain. We labeled whole cells and cell walls of planktonic cells, young biofilms formed for 12-24h after stationary phase, and more mature biofilms formed for up to 60h after stationary phase. All samples were labeled either by (i) [15N]glycine and l-[1-13C]threonine, or in separate experiments, by (ii) l-[2 13C,15N]leucine. We then measured 13C-15N direct bonds by C{N} rotational-echo double resonance (REDOR). The increase in peptidoglycan stems that have bridges connected to a surface protein was determined directly by a cell-wall double difference (biofilm REDOR difference minus planktonic REDOR difference). This procedure eliminates errors arising from differences in 15N isotopic enrichments and from the routing of 13C label from threonine degradation to glycine. For both planktonic cells and the mature biofilm, 20% of pentaglycyl bridges are not cross linked and are potential surface-protein attachment sites. None of these sites has a surface protein attached in the planktonic cells, but one-fourth have a surface protein attached in the mature biofilm. Moreover, the leucine-label shows that the concentration of beta-strands in leucine-rich regions doubles in the mature biofilm. Thus, a primary event in establishing a S. aureus biofilm is extensive decoration of the cell surface with surface proteins that are linked covalently to the cell wall and promote cell-cell adhesion. PMID- 29229529 TI - Evaluation of root-knot nematode disease control and plant growth promotion potential of biofertilizer Ning shield on Trichosanthes kirilowii in the field. AB - Biofertilizer Ning shield was composed of different strains of plant growth promotion bacteria. In this study, the plant growth promotion and root-knot nematode disease control potential on Trichosanthes kirilowii in the field were evaluated. The application of Ning shield significantly reduced the diseases severity caused by Meloidogyne incognita, the biocontrol efficacy could reached up to 51.08%. Ning shield could also promote the growth of T. kirilowii in the field by increasing seedling emergence, height and the root weight. The results showed that the Ning shield could enhance the production yield up to 36.26%. Ning shield could also promote the plant growth by increasing the contents of available nitrogen, phosphorus, potassium and organic matter, and increasing the contents of leaf chlorophyll and carotenoid pigment. Moreover, Ning shield could efficiently enhance the medicinal compositions of Trichosanthes, referring to the polysaccharides and trichosanthin. Therefore, Ning shield is a promising biofertilizer, which can offer beneficial effects to T. kirilowii growers, including the plant growth promotion, the biological control of root-knot disease and enhancement of the yield and the medicinal quality. PMID- 29229530 TI - Trichoderma harzianum MTCC 5179 impacts the population and functional dynamics of microbial community in the rhizosphere of black pepper (Piper nigrum L.). AB - Employing Illumina Hiseq whole genome metagenome sequencing approach, we studied the impact of Trichoderma harzianum on altering the microbial community and its functional dynamics in the rhizhosphere soil of black pepper (Piper nigrum L.). The metagenomic datasets from the rhizosphere with (treatment) and without (control) T. harzianum inoculation were annotated using dual approach, i.e., stand alone and MG-RAST. The probiotic application of T. harzianum in the rhizhosphere soil of black pepper impacted the population dynamics of rhizosphere bacteria, archae, eukaryote as reflected through the selective recruitment of bacteria [Acidobacteriaceae bacterium (p=1.24e-12), Candidatus koribacter versatilis (p=2.66e-10)] and fungi [(Fusarium oxysporum (p=0.013), Talaromyces stipitatus (p=0.219) and Pestalotiopsis fici (p=0.443)] in terms of abundance in population and bacterial chemotaxis (p=0.012), iron metabolism (p=2.97e-5) with the reduction in abundance for pathogenicity islands (p=7.30e-3), phages and prophages (p=7.30e-3) with regard to functional abundance. Interestingly, it was found that the enriched functional metagenomic signatures on phytoremediation such as benzoate transport and degradation (p=2.34e-4), and degradation of heterocyclic aromatic compounds (p=3.59e-13) in the treatment influenced the rhizosphere micro ecosystem favoring growth and health of pepper plant. The population dynamics and functional richness of rhizosphere ecosystem in black pepper influenced by the treatment with T. harzianum provides the ecological importance of T. harzianum in the cultivation of black pepper. PMID- 29229531 TI - Eriodictyol stimulates insulin secretion through cAMP/PKA signaling pathway in mice islets. AB - Eriodictyol, a flavonoid isolated from Lyonia ovalifolia, was found to be the most potent insulin secretagogue in our preliminary studies. Here, we explored mechanism(s) of insulin secretory activity of eriodictyol in vitro and in vivo. Mice islets and MIN6 cells were incubated in basal and stimulatory glucose containing eriodictyol with or without agonist/antagonist. Secreted insulin and cAMP contents were measured using ELISA kits. K+- and Ca2+-channels currents were recorded with patch-clamp technique. Oral glucose tolerance test and plasma insulin was evaluated in non-diabetic and diabetic rats. Eriodictyol stimulated insulin secretion from mice islets and MIN6 cells only at stimulatory glucose concentrations with maximum effect at 200MUM. Eriodictyol showed no pronounced effect on inward rectifying K+ and Ca2+ currents. Furthermore, in KCl depolarized islets, in the presence of diazoxide, insulin secretory ability of eriodictyol was enhanced. IBMX, a phosphodiesterase inhibitor, significantly (P<0.001) enhanced eriodictyol-induced insulin secretion at 16.7mM glucose in comparison to eriodictyol or IBMX alone. The cAMP content after eriodictyol exposure was also increased. Eriodictyol-induced insulin secretion was partially inhibited by adenylate cyclase inhibitor (SQ22536) and completely inhibited by PKA inhibitor (H-89), suggesting that the eriodictyol effect is more on PKA. Molecular docking studies showed the best binding affinities of eriodictyol with PKA. Eriodictyol improved glucose tolerance and enhanced plasma insulin in non-diabetic and diabetic rats. Eriodictyol also lowered blood glucose in diabetic rats upon chronic treatment. Taken together, it can be concluded that eriodictyol, a novel insulin secretagogue, exerts an exclusive glucose-dependent insulinotropic effect through cAMP/PKA pathway. PMID- 29229532 TI - Inflammation and renal fibrosis: Recent developments on key signaling molecules as potential therapeutic targets. AB - Chronic kidney disease (CKD) is a major public health issue. At the histological level, renal fibrosis is the final common pathway of progressive kidney disease irrespective of the initial injury. Considerable evidence now indicates that renal inflammation plays a central role in the initiation and progression of CKD. Some of the inflammatory signaling molecules involved in CKD include: monocyte chemoattractant protein-1 (MCP-1), bradykinin B1 receptor (B1R), nuclear factor kappaB (NF-kappaB), tumor necrosis factor-alpha (TNFalpha), transforming growth factor beta (TGF-beta), and platelet-derived growth factor (PDGF). Multiple antifibrotic factors, such as interleukin-10 (IL-10), interferon-gamma (IFN gamma), bone morphogenetic protein-7 (BMP-7), hepatocyte growth factor (HGF) are also downregulated in CKD. Therefore, restoration of the proper balance between pro- and antifibrotic signaling pathways could serve as a guiding principle for the design of new antifibrotic strategies that simultaneously target many pathways. The purpose of this review is to summarize the existing body of knowledge regarding activation of cytokine pathways and infiltration of inflammatory cells as a starting point for developing novel antifibrotic therapies to prevent progression of CKD. PMID- 29229533 TI - Xanthoceraside attenuates amyloid beta peptide1-42-induced memory impairments by reducing neuroinflammatory responses in mice. AB - Xanthoceraside, a novel triterpenoid saponin extracted from the husks of Xanthoceras sorbifolia Bunge, has neuroprotective effects in vivo and anti inflammatory properties in vitro. However, the exact mechanism of xanthoceraside on anti-amyloid beta (Abeta)-induced neuroinflammatory responses has not been elucidated. Therefore, we used intracerebroventricular injection of amyloid 1-42 (Abeta1-42) to establish a mouse model to test the effects of xanthoceraside on Abeta-induced cognitive impairments and the TLR2/NF-kappaB and MAPK pathways. The mice received xanthoceraside (0.02, 0.08 or 0.32mg/kg) or vehicle from the day of Abeta1-42 injection. The Morris water maze test was performed 4 days after Abeta1 42 injection. The levels of inflammatory cytokines (interleukin (IL)-6 and IL-4) were measured by enzyme-linked immunosorbent assay (ELISA). The expression levels of glial fibrillary acidic protein (GFAP) and cluster of differentiation 11b (CD11b) in the hippocampus were determined with an immunohistochemistry assay. Inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) were analysed by Western blotting; iNOS, COX-2 and Toll-like receptor 2 (TLR2) mRNA expression levels were measured by reverse transcription-polymerase chain reaction (RT-PCR). Here, we observed that xanthoceraside at doses of 0.08 and 0.32mg/kg significantly improved learning and memory impairments and significantly inhibited GFAP and CD11b overexpression induced by Abeta1-42 in mice. ELISA results revealed that xanthoceraside suppressed IL-6 release and increased IL-4 levels. Western blotting results showed that xanthoceraside reduced iNOS and COX 2 protein levels in hippocampus; xanthoceraside also inhibited translocation of NF-kappaB p50 and p65 into the nucleus and phosphorylation of extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38. RT-PCR confirmed that xanthoceraside decreased iNOS, COX-2 and TLR2 mRNA levels. These results suggest that xanthoceraside inhibition of the TLR2 pathway and down regulation of MAPK and NF-kappaB activities may be related to the improvement in learning and memory impairments. PMID- 29229534 TI - A novel compound DT-010 protects against doxorubicin-induced cardiotoxicity in zebrafish and H9c2 cells by inhibiting reactive oxygen species-mediated apoptotic and autophagic pathways. AB - Doxorubicin (Dox) is an effective anti-cancer agent but limited by its cardiotoxicity, thus the search for pharmacological agents for enhancing anti cancer activities and protecting against cardiotoxicity has been a subject of great interest. We have previously reported the synergistic anti-cancer effects of a novel compound DT-010. In the present study, we further investigated the cardioprotective effects of DT-010 in zebrafish embryos in vivo and the molecular underlying mechanisms in H9c2 cardiomyocytes in vitro. We showed that DT-010 prevented the Dox-induced morphological distortions in the zebrafish heart and the associated cardiac impairments, and especially improved ventricular functions. By using H9c2 cells model, we showed that DT-010 directly inhibited the generation of reactive oxygen species by Dox and protected cell death and cellular damage. We further observed that DT-010 protected against Dox-induced myocardiopathy via inhibiting downstream molecular pathways in response to oxidative stress, including reactive oxygen species-mediated MAPK signaling pathways ERK and JNK, and apoptotic pathways involving the activation of caspase 3, caspase 7, and PARP signaling. Recent studies also suggest the importance of alterations in cardiac autophagy in Dox cardiotoxicity. We further showed that DT 010 could inhibit the induction of autophagosomes formation by Dox via regulating the upstream Akt/AMPK/mTOR signaling. Since Dox-induced cardiotoxicity is multifactorial, our results suggest that multi-functional agent such as DT-010 might be an effective therapeutic agent for combating cardiotoxicity associated with chemotherapeutic agents such as Dox. PMID- 29229535 TI - In reply: Ketamine is an important therapy for prehospital agitation - Its exact role and side effect profile are still undefined. PMID- 29229536 TI - Is there an association between trichomoniasis and other sexually transmitted infections in adolescent ED patients? PMID- 29229537 TI - Think twice before applying non-invasive ventilation in patients with CAP requiring vasopressor in the ED. PMID- 29229538 TI - Association of prehospital intubation with decreased survival among pediatric trauma patients in Iraq and Afghanistan. AB - INTRODUCTION: Airway compromise is the second leading cause of preventable death on the battlefield among US military casualties. Airway management is an important component of pediatric trauma care. Yet, intubation is a challenging skill with which many prehospital providers have limited pediatric experience. We compare mortality among pediatric trauma patients undergoing intubation in the prehospital setting versus a fixed-facility emergency department. METHODS: We queried the Department of Defense Trauma Registry (DODTR) for all pediatric encounters in Iraq and Afghanistan from January 2007 to January 2016. We compared outcomes of pediatric subjects undergoing intubation in the prehospital setting versus the emergency department (ED) setting. RESULTS: During this period, there were 3439 pediatric encounters (8.0% of DODTR encounters during this time). Of those, 802 (23.3%) underwent intubation (prehospital=211, ED=591). Compared to patients undergoing ED intubation, patients undergoing prehospital intubation had higher median composite injury severity scores (17 versus 16) and lower survival rates (66.8% versus 79.9%, p<0.001). On univariable logistic regression analysis, prehospital intubation increased mortality odds (OR 1.97, 95% CI 1.39-2.79). After adjusting for confounders, the association between prehospital intubation and death remained significant (OR 2.03, 95% CI 1.35-3.06). CONCLUSIONS: Pediatric trauma subjects intubated in the prehospital setting had worse outcomes than those intubated in the ED. This finding persisted after controlling for measurable confounders. PMID- 29229539 TI - Bisphenol A (BPA) and cell signaling pathways. AB - Bisphenol A (BPA; 4,4'-isopropylidenediphenol) is an endocrine disruptor that is used as a material for the production of phenol resins, polyacrylates, polyesters, epoxy resins, and polycarbonate plastics. Endocrine-disruptive or toxic effects of BPA on living organisms through a number of cell signaling pathways have been reported. BPA induces carcinogenesis, reproductive toxicity, abnormal inflammatory or immune response, and developmental disorders of brain or nervous system through various cell signaling pathways. This review considers the literature concerning BPA and its association with cancer-related cell signaling pathways, reproductive toxicity-related cell signaling pathways, inflammatory or immune response-related cell signaling pathways, and brain and nervous system related cell signaling pathways. PMID- 29229540 TI - In vivo confirmation of the reliability of the dorsal tangential view of the wrist. AB - : The purpose of the study was to evaluate the reliability of the dorsal tangential view (DTV) of the wrist using direct visualization of the extensor compartments in vivo. Twelve patients with extensor tendon complications [nine patients with extensor synovitis, two patients with isolated extensor pollicis longus (EPL) rupture, one patient with EPL and extensor indicis proprius rupture] after volar plating of a distal radius fracture were enrolled in the study. We obtained DTVs in the operating room before implant removal and explored the extensor compartments during synovectomy or tendon reconstruction to confirm suspected screw penetration. We confirmed screw penetration on 10 patients during exploration of the extensor compartments. DTV was able to detect seven of these dorsal cortex breaches. There were no false positive results, which we had defined as a screw penetrating an extensor compartment preoperatively, but not visible on the DTV. Of these seven breaches, one was in the second compartment, four were in the third compartment, and the remaining two were in the fourth compartment. The DTV is sufficiently reliable to be used routinely to reduce postoperative extensor tendon complications during volar plating of the distal radius. LEVEL OF EVIDENCE: 4 (case series) diagnostic. PMID- 29229541 TI - Results of percutaneous fixation and distal radius core decompression in scaphoid waist non-unions treated without grafting. AB - : Scaphoid non-union management is still a challenge in clinical practice for orthopaedic surgeons. Though several treatment methods have been described, there is an ongoing debate about optimum management. Based on new concepts about avascular conditions, promising results were reported with metaphyseal decompression of the distal radius by increasing the vascularization of the radial column of the carpus. We aimed to evaluate the clinical, radiological, and functional outcomes of distal radius core decompression and fixation with palmar percutaneous cannulated compression screws without grafting in patients with scaphoid waist fracture non-union. Twenty-nine patients with scaphoid non-union were included in this prospective study. There were 27 male and 2 female patients with an average age of 29 years (range 18-45 years). Mean time from the injury to surgery was 18.3 months. The Slade and Geissler classification was used to classify the non-unions. Wrist range of motion (ROM), pain based on a visual analog scale (VAS), and the Mayo wrist score were used to assess the clinical outcomes. Postoperative radiographs and CT-scans were reviewed to assess fracture union, carpal alignment and screw position. The average clinical follow-up was 76 weeks (range: 74-87 weeks) postoperatively. Mean time to union was 11 weeks (range: 7-18 weeks). There was no humpback/no DISI in any of the cases. Twenty six patients healed successfully with no additional procedures. Three patients with failed union underwent revision surgery with grafting. At the final follow up, average wrist ROM was 61 degrees (range: 30-80) in extension and 61 degrees (range: 35-80) in flexion, the average Mayo wrist score was 66+/-20 (range: 20 90), and the mean VAS was 2+/-2 (range: 0-7). Percutaneous fixation without grafting associated with distal radius core decompression can provide satisfactory outcomes in surgical management of scaphoid non-unions. LEVEL OF EVIDENCE: II. PMID- 29229542 TI - Random knock-in expression system for high yield production of heterologous protein in Bacillus subtilis. AB - Chromosome-integrated recombinant protein expression in bacteria has advantages for the stable maintenance of genes without any use of antibiotics during large scale fermentation. Even though different levels of gene expression were reported, depending upon their chromosomal position in bacterial species, only a limited number of integration sites have been used in B. subtilis. In this study, we randomly integrated the GFP and AprE expression cassettes into the B. subtilis genome to determine integration sites that can produce a high yield of heterologous protein expression. Our mariner transposon-based expression cassette integration system was able to find integration sites, which can produce up to 2.9-fold and 1.5-fold increased expression of intracellular GFP and extracellular AprE, respectively, compared to the common integration site amyE. By analyzing the location of integration sites, we observed an adjacent promoter effect, gene dosage effect, and gene knock-out effect all complexly contributing to the increased level of integrated gene expression. Besides obtaining a high yield of heterologous protein expression, our system can also provide a wide-range of expression to expand the systematic application for steady-state metabolic protein production. PMID- 29229543 TI - The complete genome sequence of Lactobacillus plantarum LPL-1, a novel antibacterial probiotic producing class IIa bacteriocin. AB - Bacteriocins are antibacterial proteins or peptides synthesized by ribosomes to inhibit or kill both closely related and non-related bacterium. Class IIa bacteriocins possess high activity against foodborne pathogen Listeria monocytogenes. A novel strain Lactobacillus plantarum LPL-1 was isolated from fermented fish and considered as a bacteriocin producing probiotic with great antibacterial activity against Listeria monocytogenes 54002. The complete genome of L. plantarum LPL-1 contains one circular chromosome and plasmid. According to the genome, biosynthetic genes of bacteriocin including precursor, immunity protein,accessory protein and transporter protein were identified; and biosynthetic mechanism of class IIa bacteriocin was also further analyzed. The antibacterial activity of purified bacteriocin against L.monocytogenes54002 was determined and the diameter of inhibition zone was about 16.6 mm by vernier caliper. This work provided the complete genome information of L. plantarum LPL-1 that could benefit for understanding the biosynthetic mechanism of class IIa bacteriocin as well as the potential application of L. plantarum LPL-1 in nutraceutical and pharmaceutical. PMID- 29229544 TI - A new textured polyphosphazene biomaterial with improved blood coagulation and microbial infection responses. AB - : A new poly[bis(octafluoropentoxy) phosphazene] (OFP) was synthesized for the purpose of blood contacting medical devices. OFP was further either developed into crosslinkable polyphosphazene (X-OFP) or blended with polyurethane (PU) as the mixture (OFP/PU) for improvement of mechanical property of polyphosphazene polymers. All the materials were fabricated as smooth films or further textured with submicron pillars for the assay of antimicrobial and antithrombotic properties. Results showed that crosslinkable OFP (X-OFP) and blends of OFP/PU successfully improved the mechanical strength of OFP and fewer defects of pillars were found on the textured polyphosphazene surfaces. The antithrombotic experiments showed that polyphosphazene OFP materials reduced human Factor XII activation and platelet adhesion, thereby being resistant to plasma coagulation and thrombosis. The bacterial adhesion and biofilm experiments demonstrated that OFP materials inhibited staphylococcal bacterial adhesion and biofilm formation. The surface texturing further reduced the platelet adhesion and bacterial adhesion, and inhibited biofilm formation up to 23 days. The data suggested that textured OFP materials may provide a practical approach to improve the biocompatibility of current biomaterials in the application of blood contacting medical devices with significant reduction in risk of pathogenic infection and thrombosis. STATEMENT OF SIGNIFICANCE: The thromboembolic events and microbial infection have been the significant barriers for the long term use of biomaterials in blood-contacting medical devices. The development of new materials with multiple functions including anti-thrombosis and antibacterial surfaces is a high research priority. This study synthesized new biostable and biocompatible polyphosphazene polymers, poly[bis(octafluoropentoxy)phosphazene] (OFP) and crosslinkable OFP, and successfully improved the mechanical strength of polyphosphazenes. Polymers were fabricated into textured films with submicron pillars on the surfaces. The antimicrobial and antithrombotic assays demonstrated that new materials combined with surface physical modification have significant reduction in risk of pathogenic infection and thrombosis, and improve the biocompatibility of current biomaterials in the application of blood-contacting medical devices. It would be interest to biomaterials and bioengineering related communities. PMID- 29229545 TI - Fabrication of hybrid crosslinked network with buffering capabilities and autonomous strengthening characteristics for dental adhesives. AB - : Ingress of bacteria and fluids at the interfacial gaps between the restorative composite biomaterial and the tooth structure contribute to recurrent decay and failure of the composite restoration. The inability of the material to increase the pH at the composite/tooth interface facilitates the outgrowth of bacteria. Neutralizing the microenvironment at the tooth/composite interface offers promise for reducing the damage provoked by cariogenic and aciduric bacteria. We address this problem by designing a dental adhesive composed of hybrid network to provide buffering and autonomous strengthening simultaneously. Two amino functional silanes, 2-hydroxy-3-morpholinopropyl (3-(triethoxysilyl)propyl) carbamate and 2 hydroxy-3-morpholinopropyl (3-(trimethoxysilyl)propyl) carbamate were synthesized and used as co-monomers. Combining free radical initiated polymerization (polymethacrylate-based network) and photoacid-induced sol-gel reaction (polysiloxane) results in the hybrid network formation. Resulting formulations were characterized with regard to real-time photo-polymerization, water sorption, leached species, neutralization, and mechanical properties. Results from real time FTIR spectroscopic studies indicated that ethoxy was less reactive than methoxy substituent. The neutralization results demonstrated that the methoxy containing adhesives have acute and delayed buffering capabilities. The mechanical properties of synthetic copolymers tested in dry conditions were improved via condensation reaction of the hydrolyzed organosilanes. The leaching from methoxy containing copolymers was significantly reduced. The sol-gel reaction provided a chronic and persistent reaction in wet condition-performance that offers potential for reducing secondary decay and increasing the functional lifetime of dental adhesives. STATEMENT OF SIGNIFICANCE: The interfacial gaps between the restorative composite biomaterial and the tooth structure contributes to recurrent decay and failure of the composite restoration. The inability of the material to increase the pH at the composite/tooth interface facilitates the outgrowth of more cariogenic and aciduric bacteria. This paper reports a novel, synthetic resin that provides buffering capability and autonomous strengthening characteristics. In this work, two amino functional silanes were synthesized and the effect of alkoxy substitutions on the photoacid-induced sol-gel reaction was investigated. We evaluated the neutralization capability (monitoring the pH of lactic acid solution) and the autonomous strengthening property (monitoring the mechanical properties of the hybrid copolymers under wet conditions and quantitatively analyzing the leachable species by HPLC). The novel resin investigated in this study offers the potential benefits of reducing the risk of recurrent decay and prolonging the functional lifetime of dental adhesives. PMID- 29229546 TI - Changes in cognition and dendritic complexity following intrathecal methotrexate and cytarabine treatment in a juvenile murine model. AB - Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and accounts for 26.8% of cancer diagnoses among children, worldwide-approximately 3000 children each year. While advancements in treating ALL have led to a remission rate of more than 90%, many survivors experience adverse neurocognitive and/or neurobehavioral effects as a result of intrathecal chemotherapy. Methotrexate (MTX) is commonly administered with cytosine arabinoside (AraC, cytarabine) during intrathecal chemotherapy for ALL. To date, few studies exist that test the cognitive effects of intrathecal injections of MTX/AraC on juvenile populations. The purpose of our study was to investigate the combined effects of MTX/AraC on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty, 21-day-old male C57BL/6 mice were used in this study; 10 mice received intrathecal MTX/AraC treatment, and 10 were given intrathecal saline injections. Five weeks after injections, we tested the animals' hippocampus dependent cognitive performance in the Morris water maze. After the first day of hidden-platform training, we observed that the mice that received MTX/AraC treatment showed signs of significant impairment in spatial memory retention. MTX/AraC treatment significantly compromised the dendritic architecture and reduced mushroom spine density in the dorsal ganglion (DG), CA1, and CA3 areas of the hippocampus. The present data provided evidence that MTX/AraC compromised the dendritic architecture and impaired hippocampal dependent cognition. This could provide insight into chemotherapy-induced cognitive decline in juvenile patients treated for ALL. PMID- 29229548 TI - Tongue protrusions modify the syntax of skilled reaching for food by the mouse: Evidence for flexibility in action selection and shared hand/mouth central modulation of action. AB - Skilled reaching for food by the laboratory mouse has the appearance of an action pattern with a distinctive syntax in which ten submovements occur in an orderly sequence. A mouse locates the food by Sniffing, Lifts, Aims, Advances, and Shapes the hand to Pronate it over a food target that it Grasps, Retracts, and Withdraws to Release to its mouth for eating. The structure of the individual actions in the chain are useful for the study of the mouse motor system and contribute to the use of the mouse as a model of human neurological conditions. The present study describes tongue protrusions that modify the syntax of reaching by occurring at the point of the reaching action at which the hand is at the Aim position. Tongue protrusions were not related to reaching success and were not influenced by training. Tongue protrusions were more likely to occur in the presence of a food target than with reaches made when food was absent. There were vast individual differences; some mice always make tongue protrusions while other mice never make tongue protrusions. That the syntax of reaching can be altered by the insertion of a surrogate (co-occurring) movement adds to a growing body of evidence that skilled reaching is assembled from a number of relatively independent actions, each with its own sensorimotor control that are subject to central modulation. That tongue and hand reaching movements can co-occur suggests a privileged relation between neural mechanisms that control movements of the tongue and hand. PMID- 29229547 TI - Role of angiotensin system modulation on progression of cognitive impairment and brain MRI changes in aged hypertensive animals - A randomized double- blind pre clinical study. AB - Growing evidence suggests that renin angiotensin system (RAS) modulators support cognitive function in various animal models. However, little is known about their long-term effects on the brain structure in aged hypertensive animals with chronic cerebral hypoperfusion as well as which specific domains of cognition are most affected. Therefore, in the current study we examined the effects of Candesartan and Compound 21 (C21) (RAS modulators) on aspects of cognition known to diminish with advanced age and accelerate with hypertension and vascular disease. Outcome measures for sensorimotor and cognitive function were performed using a sequence of tests, all blindly conducted and assessed at baseline and after 4 and 8 weeks of chronic hypoxic hypoperfusion and treatment. Magnetic resonance imaging (MRI) was performed at the end of the 8 week study period followed by animal sacrifice and tissue collection. Both Candesartan and C21 effectively preserved cognitive function and prevented progression of vascular cognitive impairment (VCI) but only candesartan prevented loss of brain volume in aged hypertensive animals. Collectively, our findings demonstrate that delayed administration of RAS modulators effectively preserve cognitive function and prevent the development / progression of VCI in aged hypertensive animals with chronic cerebral hypoperfusion. PMID- 29229549 TI - What do primary immunodeficiencies tell us about the essentiality/redundancy of immune responses? AB - Advances in genomics and medicine have enabled the identification of (currently) 346 primary immunodeficiencies (PIDs) caused by mutations in 336 different genes. Most of these PIDs are monogenic conditions with Mendelian inheritance. Given this large number, it is possible to analyze the distribution of PIDs associated with infections and/or immunopathology according to the nature of the defect - even though this exercise can be challenging and arguable because of the pleiotropic nature of some gene products. The results of this analysis nevertheless strongly suggests that innate immune responses (mediated by pattern recognition receptor (PRR) engagement) are largely redundant, whereas adaptive immune responses are essential. Conversely, gain of function is more frequent in PRR-mediated immune responses than in adaptive immune responses - suggesting that robust innate immune pathways are less stringently regulated than energetically costly and potentially harmful adaptive immune responses. PMID- 29229551 TI - Modulation of reactive oxygen species via ERK and STAT3 dependent signalling are involved in the response of mesothelioma cells to exemestane. AB - Pleural mesothelioma is a deadly form of cancer. The prognosis is extremely poor due to the limited treatment modalities. Uptake of asbestos fibres, the leading cause of mesothelioma, lead to the accumulation of reactive-oxygen-species (ROS). Interestingly, increasing ROS production by using ROS-generating drugs may offer a strategy to selectively trigger cell death. Exemestane, an aromatase inhibitor, has previously shown anti-tumor properties in mesothelioma preclinical models suggesting a role of G protein-coupled receptor 30 (GPR30) in the drug response. As exemestane, in addition to blocking estrogen biosynthesis, generates ROS that are able to arrest the growth of breast cancer, we explored the role of ROS, antioxidant defense system, and ROS-induced signalling pathways in mesothelioma cells during exemestane response. Here we report that exemestane treatment reduced cell proliferation with an increase in ROS production and reduction of cyclic adenosine monophosphate (cAMP) levels in MSTO-H211, Ist-Mes1, Ist-Mes2 and MPP89 exemestane-sensitive mesothelioma cell lines, but not in NCI-H2452 exemestane-insensitive mesothelioma cells. Exemestane induced a significant antioxidant response in NCI-H2452 cells, as highlighted by an increase in gamma glutamylcysteine levels, catalase (Cat), superoxide-dismutase and (SOD) and glutathione-peroxidase (GSH-Px) activity and nuclear factor E2-related factor 2 (Nrf2) activation, responsible for drug insensitivity. Conversely, exemestane elevated ROS levels along with increased ERK phosphorylation and a reduction of p STA3 in exemestane-sensitive mesothelioma cells. ROS generation was the crucial event of exemestane action because ROS inhibitor N-acetyl-L-cysteine (NAC) abrogated p-ERK and p-STAT3 modulation and cellular death. Exemestane also modulates ERK and STAT3 signalling via GPR30. Results indicate an essential role of ROS in the antiproliferative action of exemestane in mesothelioma cells. It is likely that the additional oxidative insults induced by exemestane results in the lethal effects of mesothelioma cells by increasing ROS production. As such, manipulating ROS levels with exemestane seems to be a feasible strategy to selectively kill mesothelioma cells with less toxicity to normal cells by regulating ERK and STAT3 activity. PMID- 29229550 TI - Cardiovascular disease risk factors and oxidative stress among premenopausal women. AB - Oxidative stress is one hypothesized mechanism linking anthropometric, behavioral, and medical risk factors with cardiovascular disease (CVD). We evaluated cross-sectional associations between CVD risk factors and biomarkers of oxidative stress, and investigated these biomarkers as predictors of incident diabetes and hypertension among premenopausal women. F2-isoprostane (F2-IsoP) and metabolite (15-F2t-IsoP-M), reliable biomarkers of oxidative stress, were measured in urine samples collected at enrollment from 897 premenopausal women (ages 35-54) enrolled in the Sister Study cohort without a CVD history. Blood pressure, waist circumference, and body mass index (BMI) were measured at enrollment by trained study personnel. Diabetes and cigarette smoking were self reported via enrollment questionnaires. Over a maximum follow-up of 11.5 years, participants self-reported incident diabetes and hypertension diagnoses on mailed questionnaires. In cross-sectional analyses, both F2-IsoP and 15-F2t-IsoP-M were positively associated with BMI, waist circumference, diastolic blood pressure, and current smoking. F2-IsoP was elevated among those with diabetes, and 15-F2t IsoP-M increased with higher systolic blood pressure. Prospective analyses suggested an increased hypertension risk among those with elevated 15-F2t-IsoP-M (highest vs. lowest quartile: hazard ratio=2.34; 95% CI: 1.20-4.56). Our results suggest that urinary F2-IsoP and 15-F2t-IsoP-M are positively associated with adiposity measures, blood pressure, and cigarette smoking. Further investigation is warranted to evaluate 15-F2t-IsoP-M as a predictor of hypertension. PMID- 29229552 TI - Caspase-6 is a Dispensable Enabler of Adult Mammalian Axonal Degeneration. AB - The progress of axonal degeneration (AxD) following injury or insult impacts both recovery from axonal transection and protection of axons from diverse insults, or axonopathy. Here we provide evidence that increases in capase-6 (Casp6) expression and action contribute to the progression of AxD. The expression of Casp6 protein and mRNA in distal branches of sensory axons undergoing AxD was confirmed. We developed and utilized a new model of axonopathy in live mice by serially visualizing the viability of cutaneous axons in the ear pinna that expressed an axonal YFP transgene, in response to capasaicin-induced AxD. Both specific pharmacological inhibition of caspase-6 and local knockdown offered early but subtle and mild attenuation of axonopathy. To evaluate an axon autonomous role of Casp6, we examined axon integrity following transection ex vivo, and analyzed the serial morphological fragmentation of neurofilament expression as a structural index of AxD. Adding a specific Casp6 inhibitor to the preparation delayed neurofilament fragmentation. Intact motor axons of Casp6 null mice had normal electrophysiological properties but, as tested serially during AxD, there was attenuated loss of excitability. Following transection, morphological features of AxD were evident in both wild type and Casp6-/- mice but the latter had evidence of slowed progression. Taken together, our findings suggest a subtle but dispensable enabling role of local Casp6 expression in axons undergoing AxD. Serial analysis of cutaneous ear pinna axons in live mice provides a useful and novel model of axonal integrity. PMID- 29229554 TI - The Effect of Complex Acoustic Environment during Early Development on the Responses of Auditory Cortex Neurons in Rats. AB - Acoustical environment plays an important role during the maturation of the auditory system. It has been shown that the sensory inputs to the developing centres influence the development of the structure of projections, neuronal responsiveness, excitatory-inhibitory balance, or tonotopical arrangement, throughout the auditory pathway. Our previous study (Bures et al., 2014) showed that rats reared in a complex acoustic environment (spectrally and temporally modulated sound reinforced by an active behavioural paradigm with a positive feedback) exhibit permanently improved response characteristics of the inferior colliculus (IC) neurons. Extending these results, the current work provides evidence that the changes occur also at the level of auditory cortex (AC). In particular, the enriched animals have lower excitatory thresholds, sharper frequency selectivity, and a lower proportion of non-monotonic rate-intensity functions. In contrast to the changes observed in the IC, the cortical neurons of enriched animals have lower response magnitudes. In addition, the enrichment changed the AC responsiveness to frequency-modulated and also to a lesser extent, amplitude-modulated stimuli. Significantly, the alterations span the entire hearing range and may be regarded as general and not directly linked to the characteristics of the acoustical stimulation. Furthermore, these developmentally induced changes are permanent and detectable in adulthood. The findings indicate that an acoustically enriched environment during the critical period of postnatal development influences basic properties of neuronal receptive fields in the AC, which may have implications for the ability to detect and discriminate sounds. PMID- 29229553 TI - Human vs. Mouse Nociceptors - Similarities and Differences. AB - The somatosensory system allows us to detect a diverse range of physical and chemical stimuli including noxious ones, which can initiate protective reflexes to prevent tissue damage. However, the sensation of pain can - under pathological circumstances - outlive its usefulness and perpetrate ongoing suffering. Rodent model systems have been tremendously useful to help understand basic mechanisms of pain perception. Unfortunately, the translation of this knowledge into novel therapies has been challenging. We have investigated similarities and differences of human and mouse peptidergic (TRKA expressing) nociceptors using dual-color fluorescence in situ hybridization of dorsal root ganglia. By comparing the transcripts of a selected group of well-established nociceptive markers, we observed significant differences for some of them. We found co-expression of Trpv1, a key player for sensitization and inflammatory pain, with TrkA in a larger population in humans compared to mice. Similar results could be obtained for Nav1.8 and Nav1.9, two voltage gated sodium channels implicated in pathological forms of pain. Additionally, co-expression of Ret and TrkA was also found to be more abundant in human neurons. Moreover, the neurofilament heavy polypeptide was detected in all human sensory DRG neurons compared to a more selective expression pattern observed in rodents. To our knowledge, this is the first time that such detailed comparative analysis has been performed and we believe that our findings will direct future experimentation geared to understand the difficulties we face in translating findings from rodent models to humans. PMID- 29229555 TI - Reduced Cerebrovascular Reactivity and Increased Resting Cerebral Perfusion in Rats Exposed to a Cafeteria Diet. AB - To better understand the effects of a diet high in fat, sugar, and sodium on cerebrovascular function, Sprague Dawley rats were chronically exposed to a Cafeteria diet. Resting cerebral perfusion and cerebrovascular reactivity was quantified using continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI). In addition, structural changes to the cerebrovasculature and susceptibility to ischemic lesion were examined. Compared to control animals fed standard chow (SD), Cafeteria diet (CAF) rats exhibited increased resting brain perfusion in the hippocampus and reduced cerebrovascular reactivity in response to 10% inspired CO2 challenges in both the hippocampus and the neocortex. CAF rats switched to chow for one month (SWT) exhibited improved resting perfusion in the hippocampus as well as improved cerebrovascular reactivity in the neocortex. However, the diet switch did not correct cerebrovascular reactivity in the hippocampus. These changes were not accompanied by alterations in the structural integrity of the cerebral microvasculature, examined using rat endothelial cell antigen-1 (RECA-1) and immunoglobulin G (IgG) immunostaining. Also, the extent of tissue damage induced by endothelin-1 injection into sensorimotor cortex was not affected by the Cafeteria diet. These results demonstrate that short-term consumption of an ultra-processed diet reduces cerebrovascular reactivity. This effect persists after dietary normalization despite recovery of peripheral symptomatology. PMID- 29229556 TI - Experimental and Clinical Strategies for Treating Spinocerebellar Ataxia Type 3. AB - Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is an autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine (polyQ) tract in the ataxin-3 protein. To date, there is no effective therapy available to prevent progression of this disease. However, clinical strategies for alleviating various symptoms are imperative to promote a better quality of life for SCA3/MJD patients. Furthermore, experimental therapeutic strategies, including gene silencing or mutant protein clearance, mutant polyQ protein modification, stabilizing the native protein conformation, rescue of cellular dysfunction and neuromodulation to slow the progression of SCA3/MJD, have been developed. In this study, based on the current knowledge, I detail the clinical and experimental therapeutic strategies for treating SCA3/MJD, paying particular attention to drug discovery. PMID- 29229558 TI - Enhanced Activities of delta Subunit-containing GABAA Receptors Blocked Spinal Long-term Potentiation and Attenuated Formalin-induced Spontaneous Pain. AB - The delta subunit-containing gamma-Aminobutyric acid type A receptors (delta GABAARs) are located at extrasynaptic sites and persistently active in the control of neuronal excitability. Here we recorded primary afferent C fiber evoked field potentials in the superficial dorsal horn of rat spinal cords in vivo and investigated the possible influence of delta-GABAARs activities on nociceptive synaptic transmission. We found that delta-GABAARs-preferring agonist 4,5,6,7-tetrahydroisoxazolol [4,5-c] pyridine-3-ol (THIP), when topically applied onto spinal cord dorsum, inhibited the basal synaptic responses in a dose dependent manner. Low-frequency stimulation (LFS) of sciatic nerves elicited long term potentiation (LTP) of C fiber transmission, a synaptic correlate of central sensitization. Pretreatment with THIP before LFS delivery blocked the induction of LTP. When applied at 30 min and 180 min post-LFS, THIP reduced the magnitudes of established LTP. Intraplantar injection of formalin naturally evoked LTP in anesthetized rats. Spinal administration of THIP not only reversed formalin induced LTP, but alleviated the spontaneous painful behaviors and mechanical hyperalgesia. Biochemical analysis demonstrated that delta-GABAARs activation by THIP decreased the synaptic expression and phosphorylation of AMPA receptor GluA1 subunit in formalin-injected rats, and meanwhile, increased synaptic GluA2 content, allowing the switch of GluA2-lacking AMPA receptors to GluA2-containing ones at synapses. THIP also suppressed the synaptic accumulation and phosphorylation of NMDA receptor GluN1 subunit in formalin-injected rats. Our data suggested that enhanced delta-GABAARs activities blunted the initiation and maintenance of spinal LTP, which correlated with the amelioration of central sensitization of nociceptive behaviors. PMID- 29229557 TI - alpha1b-Adrenergic Receptor Localization and Relationship to the D1-Dopamine Receptor in the Rat Nucleus Accumbens. AB - The alpha1-adrenergic receptors (alpha1ARs) have been implicated in numerous actions of the brain, including attention and wakefulness. Additionally, they have been identified as contributing to disorders of the brain, such as drug addiction, and recent work has shown a role of these receptors in relapse to psychostimulants. While some functionality is known, the actual subcellular localization of the subtypes of the alpha1ARs remains to be elucidated. Further, their anatomical relationship to receptors for other neurotransmitters, such as dopamine (DA), remains unclear. Therefore, using immunohistochemistry and electron microscopy techniques, this study describes the subcellular localization of the alpha1b-adrenergic receptor (alpha1bAR), the subtype most tied to relapse behaviors, as well as its relationship to the D1-dopamine receptor (D1R) in both the shell and core of the rat nucleus accumbens (NAc). Overall, alpha1bARs were found in unmyelinated axons and axon terminals with some labeling in dendrites. In accordance with other studies of the striatum, the D1R was found mainly in dendrites and spines; therefore, colocalization of the D1R with the alpha1bAR was rare postsynaptically. However, in the NAc shell, when the receptors were co expressed in the same neuronal elements there was a trend for both receptors to be found on the plasma membrane, as opposed to the intracellular compartment. This study provides valuable anatomical information about the alpha1bAR and its relationship to the D1R and the regulation of DA and norepinephrine (NE) neurotransmission in the brain which have been examined previously. PMID- 29229559 TI - Axons of Individual Dorsal Horn Neurons Bifurcated to Project in Both the Anterolateral and the Postsynaptic Dorsal Column Systems. AB - Sensory information stimulates receptors of somatosensory system neurons generating a signal that codifies the characteristics of peripheral stimulation. This information reaches the spinal cord and is relayed to supra-spinal structures through two main systems: the postsynaptic dorsal column-medial lemniscal (DC-ML) and the anterolateral (AL) systems. From the classical point of view, the DC-ML has an ipsilateral ascending pathway to the Gracilis (GRA) or Cuneate (CUN) nuclei and the AL has a contralateral ascending pathway to the ventral posterolateral (VPL) thalamic nucleus. These two systems have been the subject of multiple studies that established their independence and interactions. To analyze the ascending projections of L1-L5 spinal dorsal horn neurons in the rat, two retrograde neuronal tracers were injected into the GRA and the VPL. Additionally, an electrophysiological study was performed by applying electrical stimulation at the GRA or VPL and recording antidromic evoked activity in single unit spinal cord cells. Importantly, a subset of spinal dorsal horn neurons exhibited double staining, indicating that these neurons projected to both the GRA and the VPL. These double-stained neurons were located on both sides of the dorsal horn of the spinal cord. The spinal dorsal horn neurons exhibited antidromic and collision activities in response to both GRA and VPL electrical activation. These results show spinal cord neurons with bifurcated bilateral projections to both the DC-ML and AL systems. Based on these results, we named these neurons bilateral and bifurcated cells. PMID- 29229560 TI - First steps towards Echinometra lucunter embryo cryopreservation. AB - We have studied the sensitivity to cryoprotecting agents of different embryos of the local sea urchin, Echinometra lucunter which is the species used for embryo larval bioassays in Brazil. We have located significant differences between both species sensitivity to cryoprotecting agents; while for P. lividus propylene glycol was the less toxic compound for most development stages, whereas for E. lucunter is was the most toxic and the least toxic was Dimethyl sulfoxide. There is a significant difference between development stages as well; in the case of P. lividus, the blastula embryo was the most resistant to the cryoprotecting agents, meanwhile for E. lucunter, it was the fertilized oocyte. This is a very promising result, a really early embryo that is not extremely sensitive to Me2SO. Our next aim is to develop a cryopreservation protocol for E. lucunter early embryos and test them in an embryo-larval bioassay. PMID- 29229561 TI - Effect of trehalose- and sucrose-based extenders on equine sperm quality after vitrification: Preliminary results. AB - There has been a lack of research into equine sperm vitrification to date, but studies of other species suggest it may have significant potential. To evaluate the impact of various cryoprotectant agents (CPA) and vitrification on equine sperm quality, a controlled study was carried out. A total of 12 ejaculates were subjected to exposure to CPA and vitrification. Sperm was diluted in a range of CPA: fresh, control (BSA), sucrose (0.15M, 0.3M and 0.5M), trehalose (0.15M, 0.3M and 0.5M) and the combination of sucrose and trehalose (M1: 0.15M sucrose+0.5M trehalose; M2: 0.5M sucrose+0.15M trehalose). Sperm motility, viability, acrosome integrity and DNA fragmentation were assessed at the time of CPA exposure and after vitrification. The exposure of spermatozoa to various concentrations of sucrose and/or trehalose significantly reduced sperm motility, with lower concentrations resulting in higher sperm motility. Sperm viability and DNA fragmentation did not vary after exposure to CPA, but acrosome integrity fell significantly when spermatozoa were exposed to CPA with high osmolality. When spermatozoa were vitrified, motility values were significantly higher than those obtained during the exposure. Low concentrations of sucrose (0.15M and 0.3M) and trehalose (0.15M) showed the best progressive sperm motility. The vitrification warmed procedure significantly reduced sperm viability and acrosome integrity, but DNA did not vary with any of CPA used. Equine sperm vitrification demonstrates a low capacity for preserving sperm motility, and extenders containing trehalose or sucrose at lower concentrations are associated with a better protective effect on sperm motility. After vitrification, acrosome and plasma membranes were severely impaired, while the DNA structure was maintained. Equine spermatozoa partially recover the motility after vitrification, but there is a need for further studies into the preservation of sperm membranes. PMID- 29229562 TI - Electromechanical properties of human osteoarthritic and asymptomatic articular cartilage are sensitive and early detectors of degeneration. AB - OBJECTIVE: To evaluate cross-correlations of ex vivo electromechanical properties with cartilage and subchondral bone plate thickness, as well as their sensitivity and specificity regarding early cartilage degeneration in human tibial plateau. METHOD: Six pairs of tibial plateaus were assessed ex vivo using an electromechanical probe (Arthro-BST) which measures a quantitative parameter (QP) reflecting articular cartilage compression-induced streaming potentials. Cartilage thickness was then measured with an automated thickness mapping technique using Mach-1 multiaxial mechanical tester. Subsequently, a visual assessment was performed by an experienced orthopedic surgeon using the International Cartilage Repair Society (ICRS) grading system. Each tibial plateau was finally evaluated with MUCT scanner to determine the subchondral-bone plate thickness over the entire surface. RESULTS: Cross-correlations between assessments decreased with increasing degeneration level. Moreover, electromechanical QP and subchondral-bone plate thickness increased strongly with ICRS grade (rho = 0.86 and rho = 0.54 respectively), while cartilage thickness slightly increased (rho = 0.27). Sensitivity and specificity analysis revealed that the electromechanical QP is the most performant to distinguish between different early degeneration stages, followed by subchondral-bone plate thickness and then cartilage thickness. Lastly, effect sizes of cartilage and subchondral bone properties were established to evaluate whether cartilage or bone showed the most noticeable changes between normal (ICRS 0) and each early degenerative stage. Thus, the effect sizes of cartilage electromechanical QP were almost twice those of the subchondral-bone plate thickness, indicating greater sensitivity of electromechanical measurements to detect early osteoarthritis. CONCLUSION: The potential of electromechanical properties for the diagnosis of early human cartilage degeneration was highlighted and supported by cartilage thickness and MUCT assessments. PMID- 29229564 TI - Alternative MyPlate Menus: Effects of Ultra-Processed Foods on Saturated Fat, Sugar, and Sodium Content. AB - OBJECTIVE: Compare saturated fat, sugar, and sodium in the US Department of Agriculture sample menu with a version in which menu items were replaced with comparable ultra-processed foods. DESIGN AND SETTING: The authors modified 7 days of a US Department of Agriculture sample menu providing approximately 2,000 kcal/d by replacing foods with comparable ultra-processed alternatives and then visited 2 chain supermarkets in San Luis Obispo, CA (August, 2016) to locate shopping list items for the 2 menu versions. Product-specific bar codes were entered into an application for recording dietary intake and analyzing nutrient content. VARIABLES MEASURED/ANALYSIS: Paired t tests (with Bonferroni correction, alpha = .003) were performed to compare the menus' percent energy from saturated fat and sugar, and energy and sodium content. RESULTS: Mean energy was lower (1,618 vs 1,892 kcal/d; P = .002) whereas percent energy from sugar (24.9% vs 21.4%; P <= .001) and sodium content (2,784 vs 2,101 mg/d; P = .001) were higher in the ultra-processed vs original menu. In secondary analyses, mean cost of the ultra-processed version exceeded that of the original menu by $36.87. CONCLUSIONS AND IMPLICATIONS: In a sample menu developed to meet US Dietary Guidelines, substituting items with ultra-processed foods provided fewer calories but more sugar and sodium. Distinguishing ultra-processed from less processed foods may help consumers make healthier choices when using MyPlate tools, particularly in a food environment that presents a wide range of alternatives. PMID- 29229563 TI - Osteoarthritis year in review 2017: clinical. AB - This review is based on a systematic review of the literature relevant to clinical topics in osteoarthritis (OA) performed for the time period February 22, 2016 to April 1, 2017. A PubMed search using the terms "osteoarthritis" and "treatment or epidemiology" returned over 800 papers, of which 57 are reviewed here, with inclusion primarily based on relevance to clinical OA. Epidemiologic studies in this time frame focused on the incidence and prevalence of OA, comorbidities and mortality in relation to OA (particularly obesity and cardiovascular disease), and multiple joint involvement. Papers on therapeutic approaches to OA considered: non-pharmacologic options, a number of topical, oral, and intra-articular therapies, as well as the cost-effectiveness of some OA treatments. There an enormous need to identify novel strategies to reduce the impact of this highly prevalent and debilitating condition. PMID- 29229565 TI - GM-CSF producing autoreactive CD4+ T cells in type 1 diabetes. AB - The phenotype of autoreactive T cells in type 1 diabetes is described as Th1, Th17 and/or Th21, but is largely uncharacterized. We combined multi-parameter cytokine profiling and proliferation, and identified GM-CSF producing cells as a component of the response to beta cell autoantigens proinsulin and GAD65. Overall cytokine profiles of CD4+ T cell were not altered in type 1 diabetes. In contrast, patients with recent onset type 1 diabetes had increased frequencies of proinsulin-responsive CD4+CD45RA- T cells producing GM-CSF (p=0.002), IFNgamma (p=0.004), IL-17A (p=0.008), IL-21 (p=0.011), and IL-22 (p=0.007), and GAD65 responsive CD4+CD45RA- T cells producing IL-21 (p=0.039). CD4+ T cells with a GM CSF+IFNgamma-IL-17A-IL-21-IL-22- phenotype were increased in patients for responses to both proinsulin (p=0.006) and GAD65 (p=0.037). GM-CSF producing T cells are a novel phenotype in the repertoire of T helper cells in type 1 diabetes and consolidate a Th1/Th17 pro-inflammatory pathogenesis in the disease. PMID- 29229566 TI - Agreement Between Parent Proxy Report and Child Self-Report of Pain Intensity and Health-Related Quality of Life After Surgery. AB - OBJECTIVES: Monitoring patient-centered health outcomes after hospital discharge is important for identifying patients experiencing poor recovery after surgery. Utilizing parent reports may improve the feasibility of monitoring recovery when children are not available to provide self-report. We therefore aimed to examine agreement between parent and child reports of child pain and health-related quality of life (HRQOL) in children after hospital discharge from inpatient surgery. METHODS: A total of 295 children aged 8 to 18 years and their parents reported on child pain intensity using an 11-point numerical rating scale and on HRQOL using the 0- to 100-point Pediatric Quality of Life Inventory Version 4.0 Generic Core Scales by phone or online, 4 to 8 weeks after surgery. Agreement between parent and child ratings was assessed by absolute discrepancy scores, Pearson product-moment correlations, 2-way mixed effects intraclass correlation coefficient models, and linear regression models. RESULTS: We found good to excellent agreement between child and parent reports of pain intensity and HRQOL. Average absolute discrepancy scores of pain intensity and HRQOL were 0.6 and 7.8 points, respectively. Pearson product-moment correlation coefficients were 0.74 and 0.80, and intraclass correlation coefficients were 0.72 and 0.79, for pain intensity and HRQOL, respectively. Regression coefficients for models examining pain intensity and HRQOL were 0.93 to 0.98 and 1.0, respectively. CONCLUSIONS: Although child and parent reports may both contribute important information, parent report is a valid proxy for child self-reported pain intensity and HRQOL after discharge from inpatient pediatric surgery, which may prove important for better understanding pain experiences and intervention needs. PMID- 29229567 TI - Rice Stripe Virus Interferes with S-acylation of Remorin and Induces Its Autophagic Degradation to Facilitate Virus Infection. AB - Remorins are plant-specific membrane-associated proteins and were proposed to play crucial roles in plant-pathogen interactions. However, little is known about how pathogens counter remorin-mediated host responses. In this study, by quantitative whole-proteome analysis we found that the remorin protein (NbREM1) is downregulated early in Rice stripe virus (RSV) infection. We further discovered that the turnover of NbREM1 is regulated by S-acylation modification and its degradation is mediated mainly through the autophagy pathway. Interestingly, RSV can interfere with the S-acylation of NbREM1, which is required to negatively regulate RSV infection by restricting virus cell-to-cell trafficking. The disruption of NbREM1 S-acylation affects its targeting to the plasma membrane microdomain, and the resulting accumulation of non-targeted NbREM1 is subjected to autophagic degradation, causing downregulation of NbREM1. Moreover, we found that RSV-encoded movement protein, NSvc4, alone can interfere with NbREM1 S-acylation through binding with the C-terminal domain of NbREM1 the S-acylation of OsREM1.4, the homologous remorin of NbREM1, and thus remorin mediated defense against RSV in rice, the original host of RSV, indicating that downregulation of the remorin protein level by interfering with its S-acylation is a common strategy adopted by RSV to overcome remorin-mediated inhibition of virus movement. PMID- 29229568 TI - Trans-Kingdom RNA Silencing in Plant-Fungal Pathogen Interactions. AB - Fungal pathogens represent a major group of plant invaders that are the causative agents of many notorious plant diseases. Large quantities of RNAs, especially small RNAs involved in gene silencing, have been found to transmit bidirectionally between fungal pathogens and their hosts. Although host-induced gene silencing (HIGS) technology has been developed and applied to protect crops from fungal infections, the mechanisms of RNA transmission, especially small RNAs regulating trans-kingdom RNA silencing in plant immunity, are largely unknown. In this review, we summarize and discuss recent important findings regarding trans kingdom sRNAs and RNA silencing in plant-fungal pathogen interactions compared with the well-known RNAi mechanisms in plants and fungi. We focus on the interactions between plant and fungal pathogens with broad hosts, represented by the vascular pathogen Verticillium dahliae and non-vascular pathogen Botrytis cinerea, and discuss the known instances of natural RNAi transmission between fungal pathogens and host plants. Given that HIGS has been developed and recently applied in controlling Verticillium wilt diseases, we propose an ideal research system exploiting plant vasculature-Verticillium interaction to further study trans-kingdom RNA silencing. PMID- 29229569 TI - The Hardy Rubber Tree Genome Provides Insights into the Evolution of Polyisoprene Biosynthesis. AB - Eucommia ulmoides, also called hardy rubber tree, is an economically important tree; however, the lack of its genome sequence restricts the fundamental biological research and applied studies of this plant species. Here, we present a high-quality assembly of its ~1.2-Gb genome (scaffold N50 = 1.88 Mb) with at least 26 723 predicted genes for E. ulmoides, the first sequenced genome of the order Garryales, which was obtained using an integrated strategy combining Illumina sequencing, PacBio sequencing, and BioNano mapping. As a sister taxon to lamiids and campanulids, E. ulmoides underwent an ancient genome triplication shared by core eudicots but no further whole-genome duplication in the last ~125 million years. E. ulmoides exhibits high expression levels and/or gene number expansion for multiple genes involved in stress responses and the biosynthesis of secondary metabolites, which may account for its considerable environmental adaptability. In contrast to the rubber tree (Hevea brasiliensis), which produces cis-polyisoprene, E. ulmoides has evolved to synthesize long-chain trans polyisoprene via farnesyl diphosphate synthases (FPSs). Moreover, FPS and rubber elongation factor/small rubber particle protein gene families were expanded independently from the H. brasiliensis lineage. These results provide new insights into the biology of E. ulmoides and the origin of polyisoprene biosynthesis. PMID- 29229570 TI - Medicinal plants used for hypertension treatment by folk healers in Songkhla province, Thailand. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hypertension is the most dominant risk factor for the development of cardiovascular, kidney, and eye diseases. In Thailand, illness and hospitalisation in the modern public health system due to high blood pressure is increasing. However, some Thai people have turned their attention to the use of herbal medicines for healthcare. Therefore, this study aimed (1) to study the folk knowledge of hypertension treatment and (2) to study plant utilisation in the treatment of high blood pressure by Songkhla folk healers. MATERIALS AND METHODS: Field surveys and semi-structured interviews about theories of disease, principles of healing, and herbal usage (plant species, parts used, preparation, and application methods) were gathered. The data were analysed by descriptive statistics. The literatures regarding medicinal plants used in any traditional medicine, antihypertension activity, and toxicity was reviewed. RESULTS: Most healers believed that hypertension was caused by the disorder of fire and wind elements in the body. The medicinal plants containing hot and mild tastes, which had the potential for treating problems in the wind element, were applied. A total of 62 species were used for hypertension treatment. Most plants were in the Asteraceae, Piperaceae, Rutaceae, or Zingiberaceae family (4 species each). Herbal medicines were preferred to be prepared by boiling (78%) and consumed by drinking 1 teacup before 3 meals each day (26%). Piper retrofractum and Cleome viscosa had the greatest Frequency of Citation (FC = 6, n = 14). Thirty-seven species have been reported for use in traditional medicine. Twenty-four and 46 species have already been investigated for antihypertension activity and toxicity, respectively. CONCLUSION: Identifying medicinal plants that have been tested by experienced folk doctors would provide an opportunity for people to choose and consume local herbs that are easy to access in their local area. However, the remaining plants that have not been studied for antihypertension activity and toxicity should be further analysed to confirm their efficacy. PMID- 29229571 TI - Potential engagement of pathways of the resolution of inflammation as mechanism of action for plants on animal models. PMID- 29229572 TI - Comparison of elliptical excision versus punch incision for the treatment of epidermal inclusion cysts: A prospective, randomized study. PMID- 29229574 TI - Merkel cell carcinoma: An update and review: Pathogenesis, diagnosis, and staging. AB - Merkel cell carcinoma (MCC) is an uncommon primary cutaneous neuroendocrine cancer. It most commonly presents as an indurated plaque or nodule on sun-damaged skin in elderly patients and is characterized by high rates of local recurrence and nodal metastasis. Survival at 5 years is 51% for local disease and as low as 14% for distant disease, which underscores the aggressive nature of this tumor and challenges in management. Advances in immunology and molecular genetics have broadened our understanding of the pathophysiology of MCC and expanded our therapeutic arsenal. With this comprehensive review, we provide an update of MCC epidemiology, pathogenesis, clinical presentation, diagnostic evaluation and prognostic markers. The second article in this continuing medical education series explores the evolving landscape in MCC management. PMID- 29229573 TI - Merkel cell carcinoma: An update and review: Current and future therapy. AB - Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin associated with a high risk of local recurrence and distant metastases. It most commonly occurs on sun-exposed areas of white patients >65 years of age. The Merkel cell polyomavirus (MCV) is thought to be responsible for malignant transformation in approximately 80% of cases in the northern hemisphere, while ultraviolet radiation-induced DNA damage is implicated in MCV-negative tumors. The overall incidence of MCC is low, with approximately 1600 cases diagnosed annually in the United States. The rate is much higher in patients with lymphoproliferative malignancies, solid organ transplants, and HIV infection. The low overall incidence of this tumor makes it challenging to conduct prospective clinical trials with sufficient power. As a result, most management recommendations are based on case series, retrospective reviews, and expert opinion. The pathogenesis, diagnosis, and staging of MCC was discussed in the first article in this continuing medical education series. This article focuses on current management guidelines and promising new therapies in development. Because of the complexity, aggressive nature, and individuality of each case, MCC is best treated by a multidisciplinary team. PMID- 29229575 TI - Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis: A concise review with an emphasis on distinctive clinical features. AB - Melanoma differentiation-associated gene 5 (MDA5) is a recently described autoantigen target in a subset of patients with dermatomyositis. Anti-MDA5 dermatomyositis is characterized by a unique mucocutaneous and systemic phenotype that includes cutaneous and oral ulceration, painful palmar papules, alopecia, panniculitis, arthritis, a lower incidence of myositis, and, importantly, an elevated risk of interstitial lung disease with a potentially fatal course. Because the clinical features can differ substantially from those typically observed in cutaneous dermatomyositis, the diagnosis is often overlooked, which might negatively affect patient outcomes. This review aims to familiarize the clinician with the distinctive clinical features of anti-MDA5 dermatomyositis in order to enhance its recognition and to facilitate an appropriate screening and management strategy. PMID- 29229576 TI - Intralesional drainage injection of triamcinolone acetonide for epidermal cyst. PMID- 29229577 TI - Dermoscopy as an evolving tool to assess vitiligo activity. PMID- 29229578 TI - Left Lateral Endosurgical Extraperitoneal Total Hysterectomy with Para-Aortic and Pelvic Lymphadenectomy: A Novel Approach for the Obese Patient with Endometrial Cancer. AB - STUDY OBJECTIVE: To describe the left lateral extraperitoneal approach to perform complete para-aortic and pelvic lymphadenectomy and transverse total hysterectomy from left to right as a novel approach to treat obese patients with endometrial cancer. Laparoscopic management of obese patients represents a challenge for the gynecologic surgeon. The extraperitoneal approach is technically easier in the obese patient because it naturally creates a bowel-free operative field. DESIGN: A prospective pilot bicentric and descriptive study (Canadian Task Force classification III) evaluating the feasibility and reproducibility of the transverse total hysterectomy and complete lymphadenectomy through left endoscopic extraperitoneal approach in obese patients with endometrial cancer. SETTING: A comprehensive cancer center in Toulouse and a teaching university hospital in Madrid. PATIENTS: Sixteen consecutive overweight or obese patients (body mass index > 25 kg/m2) with high-risk endometrial cancer. INTERVENTIONS: Currently, the left extraperitoneal approach is routinely used to perform complete para-aortic and pelvic lymphadenectomy. It provides direct access to the left ureter and uterine pedicle. This access can be extended to the right side when performing a transverse extrafascial hysterectomy from left to right. The procedure starts from the left extraperitoneal space, where the left uterine artery is sectioned and the vesicovaginal and rectovaginal septa are developed, without opening the peritoneum. Colpotomy is performed from the left to the right side. Once the right ureter is identified, the right uterine artery can be safely transected. Alternatively, the right uterine artery can be sealed and sectioned during the right pelvic lymphadenectomy. At the end of the procedure the peritoneum is opened to complete the surgery. MEASUREMENTS AND MAIN RESULTS: Between May 2015 and February 2016, 16 consecutive obese patients were successfully treated using this technique. Median patient age was 62 years (range, 44-78), and median body mass index was 32.5 kg/m2 (range, 26-42). In 3 cases the right uterine artery was sealed during the right pelvic lymphadenectomy, in 11 cases after completing vaginal opening, and in 2 cases after peritoneal opening. The median operative time was 137.5 minutes (range, 66 260). The median blood loss was 85 mL (range, 0-260), and no blood transfusion was required in any of our 16 patients. No significant complications occurred. CONCLUSION: The full extraperitoneal approach represents an interesting alternative strategy for the surgical treatment of obese patients with high-risk endometrial cancer. PMID- 29229579 TI - Investigation of the pulsatility of cerebrospinal fluid using cardiac-gated Intravoxel Incoherent Motion imaging. AB - The quantitative and non-invasive monitoring of cerebrospinal fluid (CSF) dynamics and composition may have high clinical relevance in the management of CSF disorders. In this study, we propose the use of the Intravoxel Incoherent Motion (IVIM) MRI for obtaining simultaneous measurements of CSF self-diffusion and fluid circulation. The rationale for this study was that turbulent fluid and mesoscopic fluid fluctuations can be modeled in a first approximation as a fast diffusion process. In this case, we expect that the fast fluid circulation and slower molecular diffusion dynamics can be quantified, assuming a bi-exponential attenuation pattern of the diffusion-weighted signal in MRI. IVIM indexes of fast and slow diffusion measured at different sites of the CSF system were systematically evaluated depending on both the phase of the heart cycle and the direction of the diffusion-encoding. The IVIM measurements were compared to dynamic measurements of fluid circulation performed by phase-contrast MRI. Concerning the dependence on the diffusion/flow-encoding direction, similar patterns were found both in the fraction of fast diffusion, f, and in the fluid velocity. Generally, we observed a moderate to high correlation between the fraction of fast diffusion and the maximum fluid velocity along the high-flow directions. Exploratory data analysis detected similarities in the dependency of the fraction of fast diffusion and of the velocity from the phase of the cardiac cycle. However, no significant differences were found between parameters measured during different phases of the cardiac cycle. Our results suggest that the fraction of fast diffusion may reflect CSF circulation. The bi-exponential IVIM model potentially allows us to disentangle the two diffusion components of the CSF dynamics by providing measurements of fluid cellularity (via the slow diffusion coefficient) and circulation (via the fraction of fast-diffusion index). PMID- 29229580 TI - Detecting white matter activity using conventional 3 Tesla fMRI: An evaluation of standard field strength and hemodynamic response function. AB - Detection of functional magnetic resonance imaging (fMRI) activation in white matter has been increasingly reported despite historically being controversial. Much of the development work to-date has used high-field 4 T MRI and specialized pulse sequences. In the current study, we utilized conventional 3 T MRI and a commonly applied gradient-echo-planar imaging sequence to evaluate white matter (WM) fMRI sensitivity within a common framework. Functional WM activity was replicated in target regions of interest within the corpus callosum, at the group and individual levels. As expected there was a reduction in overall WM activation sensitivity. Individual analyses revealed that 8 of the 13 individuals showed white matter activation, showing a lower percentage of individuals with WM activation detected. Importantly, WM activation results were sensitive to analyses that applied alternate hemodynamic response functions, with an increase in the group level cluster when hemodynamic response function (HRF) onset slope was reduced. The findings supported the growing evidence that WM activation is detectable, with activation levels are closer to thresholds used for routine 3T MRI studies. Optimization factors, such as the HRF model, appear to be important to further enhance the characterization of WM activity in fMRI. PMID- 29229581 TI - Balancing cellular redox metabolism in microbial electrosynthesis and electro fermentation - A chance for metabolic engineering. AB - More and more microbes are discovered that are capable of extracellular electron transfer, a process in which they use external electrodes as electron donors or acceptors for metabolic reactions. This feature can be used to overcome cellular redox limitations and thus optimizing microbial production. The technologies, termed microbial electrosynthesis and electro-fermentation, have the potential to open novel bio-electro production platforms from sustainable energy and carbon sources. However, the performance of reported systems is currently limited by low electron transport rates between microbes and electrodes and our limited ability for targeted engineering of these systems due to remaining knowledge gaps about the underlying fundamental processes. Metabolic engineering offers many opportunities to optimize these processes, for instance by genetic engineering of pathways for electron transfer on the one hand and target product synthesis on the other hand. With this review, we summarize the status quo of knowledge and engineering attempts around chemical production in bio-electrochemical systems from a microbe perspective. Challenges associated with the introduction or enhancement of extracellular electron transfer capabilities into production hosts versus the engineering of target compound synthesis pathways in natural exoelectrogens are discussed. Recent advances of the research community in both directions are examined critically. Further, systems biology approaches, for instance using metabolic modelling, are examined for their potential to provide insight into fundamental processes and to identify targets for metabolic engineering. PMID- 29229582 TI - Survival after Cytoreductive Nephrectomy in Metastatic Non-clear Cell Renal Cell Carcinoma Patients: A Population-based Study. AB - BACKGROUND: The benefit of cytoreductive nephrectomy (CNT) for cancer-specific mortality (CSM)-free survival is unclear in contemporary metastatic non-clear cell renal cell carcinoma (non-ccmRCC) patients. OBJECTIVE: To assess the role of CNT in non-ccmRCC patients. DESIGN, SETTING, AND PARTICIPANTS: Within Surveillance, Epidemiology, and End Results registry (2001-2014), we identified patients with non-ccmRCC. INTERVENTION: CNT versus no CNT in non-ccmRCC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable logistic regression, cumulative incidence, competing-risks regression models, incremental survival benefit (ISB), conditional survival, and landmark analyses were performed. Sensitivity analyses focused on histological subtypes and most contemporary patients (2010-2014). RESULTS AND LIMITATIONS: Of 851 patients with non-ccmRCC, 67.6% underwent CNT. In multivariable logistic regression, year of diagnosis in contemporary (p<0.001) and intermediate (p=0.008) tertiles, as well as age >=75 yr (p<0.001) yielded lower CNT rates. Cumulative incidence showed 2-yr CSM of 52.6% versus 77.7%, respectively, after CNT versus no CNT. CSM after CNT versus no CNT was invariably lower in all histologic subtypes and in contemporary patients. Multivariable competing-risks regression models predicting CSM favored CNT (hazard ratio [HR]: 0.38, confidence interval: 0.30-0.47, p<0.001) in all patients and in all subgroups defined by histologic subtypes (HR: 0.14-0.43, all p<=0.02), as well as in contemporary patients (HR: 0.32, p<0.001). The ISB analyses yielded statistically significant and clinically meaningful CSM-free survival benefit of +3 mo after CNT versus no CNT in individuals with observed CSM-free survival <=24 mo. The 2-yr CSM-free survival increased from baseline of 46.1% versus 19.4% (Delta=26.7%, p<0.001) to 70.3% versus 54.4% (Delta=15.9%, p=0.005) after CNT versus no CNT, in patients that survived 12 mo, respectively. Landmark analyses rejected bias favoring CNT. Data were retrospective. CONCLUSIONS: CSM is lower after CNT for non-ccmRCC in all histologic subtypes and in contemporary patients except for unproven ISB in collecting duct patients. This observation should encourage greater CNT consideration in non-ccmRCC. PATIENT SUMMARY: Cytoreductive nephrectomy appears to improve survival in metastatic non-clear cell renal cell carcinoma, but it is used infrequently. PMID- 29229583 TI - Integrative Genomic Analysis of Coincident Cancer Foci Implicates CTNNB1 and PTEN Alterations in Ductal Prostate Cancer. AB - BACKGROUND: Ductal adenocarcinoma of the prostate is an aggressive subtype, with high rates of biochemical recurrence and overall poor prognosis. It is frequently found coincident with conventional acinar adenocarcinoma. The genomic features driving evolution to its ductal histology and the biology associated with its poor prognosis remain unknown. OBJECTIVE: To characterize genomic features distinguishing ductal adenocarcinoma from coincident acinar adenocarcinoma foci from the same patient. DESIGN, SETTING, AND PARTICIPANTS: Ten patients with coincident acinar and ductal prostate cancer underwent prostatectomy. Laser microdissection was used to separately isolate acinar and ductal foci. DNA and RNA were extracted, and used for integrative genomic and transcriptomic analyses. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Single nucleotide mutations, small indels, copy number estimates, and expression profiles were identified. Phylogenetic relationships between coincident foci were determined, and characteristics distinguishing ductal from acinar foci were identified. RESULTS AND LIMITATIONS: Exome sequencing, copy number estimates, and fusion genes demonstrated coincident ductal and acinar adenocarcinoma diverged from a common progenitor, yet they harbored distinct alterations unique to each focus. AR expression and activity were similar in both histologies. Nine of 10 cases had mutually exclusive CTNNB1 hotspot mutations or phosphatase and tensin homolog (PTEN) alterations in the ductal component, and these were absent in the acinar foci. These alterations were associated with changes in expression in WNT- and PI3K-pathway genes. CONCLUSIONS: Coincident ductal and acinar histologies typically are clonally related and thus arise from the same cell of origin. Ductal foci are enriched for cases with either a CTNNB1 hotspot mutation or a PTEN alteration, and are associated with WNT- or PI3K-pathway activation. These alterations are mutually exclusive and may represent distinct subtypes. PATIENT SUMMARY: The aggressive subtype ductal adenocarcinoma is closely related to conventional acinar prostate cancer. Ductal foci contain additional alterations, however, leading to frequent activation of two targetable pathways. PMID- 29229584 TI - Eliminating hepatitis C within low-income countries - The need to cure genotypes 4, 5, 6. AB - Around 70 to 100 million people are chronically infected with HCV worldwide. HCV antiviral drug development has revolutionised the treatment of HCV, with several direct-acting antiviral agents offering patients the chance of cure after only 8 12 weeks of treatment. Drug development was initially focussed on HCV genotype 1 (GT1) infection, since this was the most prevalent worldwide, although clinical trials included all genotypes prevalent in the US and Europe. Because the earliest in vitro assays utilised the GT1b and 2 replicons, the initial classes of direct-acting antivirals (protease inhibitors, non-nucleotide polymerase inhibitors) were GT1-specific, albeit they had an effect on other less prevalent genotypes. Epidemiological data has shown the regional importance of other HCV genotypes. More than 50% of all HCV infections around the globe are not with GT1. The prevalence of HCV genotype 4 (GT4), 5 (GT5), and 6 (GT6) is increasing in North America and Europe due to migration from the Middle East, Africa and South East Asia. With the successful development of the multi and pan-genotypic non structural protein 5A inhibitors, second generation protease inhibitors and nucleotide non-structural protein 5B inhibitors comes a unique opportunity to achieve global HCV elimination. The goal of this review is to summarise the available information pertaining to GT4, GT5 and GT6, with a specific focus on direct-acting antiviral agents. PMID- 29229585 TI - Oscillatory fungal cell growth. AB - Cells are dynamic systems, the state of which undergoes constant alteration that results in morphological changes and movement. Many dynamic cellular processes that appear continuous are driven by underlying mechanisms that oscillate with distinct periods. For example eukaryotic cells do not grow continuously, but rather by pulsed extension of the periphery. Stepwise cell extension at the hyphal tips of several filamentous fungi was discovered 20 years ago, but only a few molecular details of the mechanism have been clarified since then. A recent study has provided evidence for correlations among intracellular Ca2+ levels, actin assembly, exocytosis and cell extension in growing hyphal tips. This suggests that pulsed Ca2+ influxes coordinate the temporal control of actin assembly and exocytosis, which results in stepwise cell extension. The coordinated oscillation of these machineries are likely to be ubiquitous among all eukaryotes. Indeed, intracellular Ca2+ levels and/or actin polymerization oscillate in mammalian and plant cells. This review summarizes the mechanisms of oscillation in several systems. PMID- 29229586 TI - Predictors of Playing Augmented Reality Mobile Games While Walking Based on the Theory of Planned Behavior: Web-Based Survey. AB - BACKGROUND: There has been a sharp increase in the number of pedestrians injured while using a mobile phone, but little research has been conducted to explain how and why people use mobile devices while walking. Therefore, we conducted a survey study to explicate the motivations of mobile phone use while walking. OBJECTIVE: The purpose of this study was to identify the critical predictors of behavioral intention to play a popular mobile game, Pokemon Go, while walking, based on the theory of planned behavior (TPB). In addition to the three components of TPB, automaticity, immersion, and enjoyment were added to the model. This study is a theory-based investigation that explores the underlying mechanisms of mobile phone use while walking focusing on a mobile game behavior. METHODS: Participants were recruited from a university (study 1; N=262) and Amazon Mechanical Turk (MTurk) (study 2; N=197) in the United States. Participants completed a Web-based questionnaire, which included measures of attitude, subjective norms, perceived behavioral control (PBC), automaticity, immersion, and enjoyment. Participants also answered questions regarding demographic items. RESULTS: Hierarchical regression analyses were conducted to examine hypotheses. The model we tested explained about 41% (study 1) and 63% (study 2) of people's intention to play Pokemon Go while walking. The following 3 TPB variables were significant predictors of intention to play Pokemon Go while walking in study 1 and study 2: attitude (P<.001), subjective norms (P<.001), and PBC (P=.007 in study 1; P<.001 in study 2). Automaticity tendency (P<.001), immersion (P=.02), and enjoyment (P=.04) were significant predictors in study 1, whereas enjoyment was the only significant predictor in study 2 (P=.01). CONCLUSIONS: Findings from this study demonstrated the utility of TPB in predicting a new behavioral domain-mobile use while walking. To sum up, younger users who are habitual, impulsive, and less immersed players are more likely to intend to play a mobile game while walking. PMID- 29229587 TI - MyVoice National Text Message Survey of Youth Aged 14 to 24 Years: Study Protocol. AB - BACKGROUND: There has been little progress in adolescent health outcomes in recent decades. Researchers and youth-serving organizations struggle to accurately elicit youth voice and translate youth perspectives into health care policy. OBJECTIVE: Our aim is to describe the protocol of the MyVoice Project, a longitudinal mixed methods study designed to engage youth, particularly those not typically included in research. Text messaging surveys are collected, analyzed, and disseminated in real time to leverage youth perspectives to impact policy. METHODS: Youth aged 14 to 24 years are recruited to receive weekly text message surveys on a variety of policy and health topics. The research team, including academic researchers, methodologists, and youth, develop questions through an iterative writing and piloting process. Question topics are elicited from community organizations, researchers, and policy makers to inform salient policies. A youth-centered interactive platform has been developed that automatically sends confidential weekly surveys and incentives to participants. Parental consent is not required because the survey is of minimal risk to participants. Recruitment occurs online (eg, Facebook, Instagram, university health research website) and in person at community events. Weekly surveys collect both quantitative and qualitative data. Quantitative data are analyzed using descriptive statistics. Qualitative data are quickly analyzed using natural language processing and traditional qualitative methods. Mixed methods integration and analysis supports a more in-depth understanding of the research questions. RESULTS: We are currently recruiting and enrolling participants through in-person and online strategies. Question development, weekly data collection, data analysis, and dissemination are in progress. CONCLUSIONS: MyVoice quickly ascertains the thoughts and opinions of youth in real time using a widespread, readily available technology-text messaging. Results are disseminated to researchers, policy makers, and youth-serving organizations through a variety of methods. Policy makers and organizations also share their priority areas with the research team to develop additional question sets to inform important policy decisions. Youth-serving organizations can use results to make decisions to promote youth well-being. PMID- 29229588 TI - Reporting of Telehealth-Delivered Dietary Intervention Trials in Chronic Disease: Systematic Review. AB - BACKGROUND: Telehealth-delivered dietary interventions are effective for chronic disease management and are an emerging area of clinical practice. However, to apply interventions from the research setting in clinical practice, health professionals need details of each intervention component. OBJECTIVE: The aim of this study was to evaluate the completeness of intervention reporting in published dietary chronic disease management trials that used telehealth delivery methods. METHODS: Eligible randomized controlled trial publications were identified through a systematic review. The completeness of reporting of experimental and comparison interventions was assessed by two independent assessors using the Template for Intervention Description and Replication (TIDieR) checklist that consists of 12 items including intervention rationale, materials used, procedures, providers, delivery mode, location, when and how much intervention delivered, intervention tailoring, intervention modifications, and fidelity. Where reporting was incomplete, further information was sought from additional published material and through email correspondence with trial authors. RESULTS: Within the 37 eligible trials, there were 49 experimental interventions and 37 comparison interventions. One trial reported every TIDieR item for their experimental intervention. No publications reported every item for the comparison intervention. For the experimental interventions, the most commonly reported items were location (96%), mode of delivery (98%), and rationale for the essential intervention elements (96%). Least reported items for experimental interventions were modifications (2%) and intervention material descriptions (39%) and where to access them (20%). Of the 37 authors, 14 responded with further information, and 8 could not be contacted. CONCLUSIONS: Many details of the experimental and comparison interventions in telehealth delivered dietary chronic disease management trials are incompletely reported. This prevents accurate interpretation of trial results and implementation of effective interventions in clinical practice. PMID- 29229589 TI - The Effect of Group Support Psychotherapy Delivered by Trained Lay Health Workers for Depression Treatment Among People with HIV in Uganda: Protocol of a Pragmatic, Cluster Randomized Trial. AB - BACKGROUND: There is limited information on the effectiveness of task shifting of mental health services in populations with HIV. OBJECTIVE: This trial aims to evaluate the effectiveness of group support psychotherapy delivered by trained lay health workers to persons living with HIV (PLWH) with depression in primary care. METHODS: Thirty eligible primary care health centers across three districts were randomly allocated to have their lay health workers trained to deliver group support psychotherapy (intervention arm) or group HIV education and treatment as usual (control arm) to PLWH with depression. Treated PLWH will be evaluated at baseline, after the end of treatment, and at 6-month intervals thereafter for 2 years. Primary outcomes will be the difference in follow-up proportions of participants with Mini International Neuropsychiatric Interview criteria for major depression and difference in follow-up function scores of participants in the intervention and control arms 6 months after the end of treatment. Secondary outcomes will include measures of self-esteem, posttraumatic stress symptoms, social support, stigma, adherence to antiretroviral therapy, viral load, and number of disability days, asset possession indices, and cost-effectiveness data. Primary and secondary outcomes as well as subgroup analyses will be conducted at the individual level using multilevel random effects regression analyses adjusting for clustering in health centers. A process evaluation using mixed methods to assess acceptability, feasibility, fidelity, causal mediating processes, and contextual influences in the trial will be conducted. RESULTS: The trial has been approved by the Makerere College of Health Sciences School of Health Sciences Research Ethics Committee, the AIDS Support Organization, and the Uganda National Council of Science and Technology. A data and safety monitoring board has been put in place to monitor trial progress. A total of 1140 persons living with HIV have been recruited to the trial. An analysis of baseline and 6 month data is in progress. The results of this trial will not only be presented at national and international conferences but also submitted for publication in peer-reviewed journals and as a report to the funding agencies. CONCLUSIONS: This cluster randomized trial will provide critical evidence to support culturally sensitive group-based psychotherapy for depression treatment in sub-Saharan Africa. Process evaluation outcomes will provide contextual information that health care and public health stakeholders can use to guide implementation decisions for their particular setting. TRIAL REGISTRATION: Pan African Clinical Trials Registry (PACTR): 201608001738234; http://www.pactr.org/ATMWeb/ appmanager/atm/atmregistry?dar=true&tNo=PACTR201608001738234 (Archived by WebCite at http://www.webcitation.org/ 6vUAgAQlj). PMID- 29229590 TI - The Swedish Web Version of the Quality of Recovery Scale Adapted for Use in a Mobile App: Prospective Psychometric Evaluation Study. AB - BACKGROUND: The 40-item Quality of Recovery (QoR-40) questionnaire is well validated for measuring self-assessed postoperative recovery. The Swedish version of the 40-item Quality of Recovery (QoR-40) has been developed into a Web-based questionnaire, the Swedish Web version of the Quality of Recovery (SwQoR) questionnaire, adapted for use in a mobile app, Recovery Assessment by Phone Points, or RAPP. OBJECTIVE: The aim of this study was to test the validity, reliability, responsiveness, and clinical acceptability and feasibility of SwQoR. METHODS: We conducted a prospective psychometric evaluation study including 494 patients aged >=18 years undergoing day surgery at 4 different day-surgery departments in Sweden. SwQoR was completed daily on postoperative days 1 to 14. RESULTS: All a priori hypotheses were confirmed, supporting convergent validity. There was excellent internal consistency (Cronbach alpha range .91-.93), split half reliability (coefficient range .87-.93), and stability (ri=.99, 95% CI .96 .99; P<.001). Cohen d effect size was 1.00, with a standardized response mean of 1.2 and a percentage change from baseline of 59.1%. An exploratory factor analysis found 5 components explaining 57.8% of the total variance. We noted a floor effect only on postoperative day 14; we found no ceiling effect. CONCLUSIONS: SwQoR is valid, has excellent reliability and high responsiveness, and is clinically feasible for the systematic follow-up of patients' postoperative recovery. PMID- 29229591 TI - Clinic Versus Online Social Network-Delivered Lifestyle Interventions: Protocol for the Get Social Noninferiority Randomized Controlled Trial. AB - BACKGROUND: Online social networks may be a promising modality to deliver lifestyle interventions by reducing cost and burden. Although online social networks have been integrated as one component of multimodality lifestyle interventions, no randomized trials to date have compared a lifestyle intervention delivered entirely via online social network with a traditional clinic-delivered intervention. OBJECTIVE: This paper describes the design and methods of a noninferiority randomized controlled trial, testing (1) whether a lifestyle intervention delivered entirely through an online social network would produce weight loss that would not be appreciably worse than that induced by a traditional clinic-based lifestyle intervention among overweight and obese adults and (2) whether the former would do so at a lower cost. METHODS: Adults with body mass index (BMI) between 27 and 45 kg/m2 (N=328) will be recruited from the communities in central Massachusetts. These overweight or obese adults will be randomized to two conditions: a lifestyle intervention delivered entirely via the online social network Twitter (Get Social condition) and an in-person group-based lifestyle intervention (Traditional condition) among overweight and obese adults. Measures will be obtained at baseline, 6 months, and 12 months after randomization. The primary noninferiority outcome is percentage weight loss at 12 months. Secondary noninferiority outcomes include dietary intake and moderate intensity physical activity at 12 months. Our secondary aim is to compare the conditions on cost. Exploratory outcomes include treatment retention, acceptability, and burden. Finally, we will explore predictors of weight loss in the online social network condition. RESULTS: The final wave of data collection is expected to conclude in June 2019. Data analysis will take place in the months following and is expected to be complete in September 2019. CONCLUSIONS: Findings will extend the literature by revealing whether delivering a lifestyle intervention via an online social network is an effective alternative to the traditional modality of clinic visits, given the former might be more scalable and feasible to implement in settings that cannot support clinic-based models. TRIAL REGISTRATION: ClinicalTrials.gov NCT02646618; https://clinicaltrials.gov/ct2/show/NCT02646618 (Archived by WebCite at http://www.webcitation.org/6v20waTFW). PMID- 29229592 TI - A Human-Centered Platform for HIV Infection Reduction in New York: Development and Usage Analysis of the Ending the Epidemic (ETE) Dashboard. AB - BACKGROUND: Dashboards have been increasingly used in clinic-based interventions, such as clinical performance improvement and monitoring risk of hospital readmissions, and are now gaining traction in population-based interventions, especially in disease assessment. OBJECTIVE: We describe the design, development, and usage analysis of a geovisualization dashboard, the Ending the Epidemic (ETE) Dashboard. The ETE dashboard is a tool developed to track New York's progress towards achieving the goal of its ETE Initiative, to reduce new HIV infections from 3000 per year to 750 per year by the end of 2020. METHODS: The ETE dashboard was adapted from an existing human-centered geovisualization platform, SanaViz, an Internet-enabled, interactive app incorporating principles of human-centered design and cognitive fit theory to enhance visual exploration of population health data. Usage evaluation of the ETE geovisualization dashboard was conducted using Google Analytics over a 4-week period from March 19 to April 18, 2016. The aim was to monitor user activity and analyze traffic on the ETE dashboard using evidence-based metrics that can provide adequate feedback to enhance its utilization. Usage was characterized based on three metrics: (1) number of unique visits to each page, (2) average time on each page in seconds, and (3) page bounce rate (ie, percentage of visits where user left the site immediately after viewing just a single page). Further analysis was also conducted by cross tabulating specific usage metrics. RESULTS: Of 860 sessions, 324 sessions were initiated by unique users (37.7%). The most common acquisition channels included direct source (353/860, 41.0%); followed by referral traffic (340/860, 39.5%) and organic search (134/860, 15.5%). Usage statistics indicate that for the 860 sessions initiated by both new and returning users, the average viewing time was 8 minutes, 51 seconds, and the bounce rate was 46%. These statistics reflect positive results given that prior literature estimates an average session duration of 10-20 seconds and a bounce rate of 40-60% for most websites. Key findings from our study showed that the highest bounce rates were seen for the "About" page of the ETE website (65%), which describes the ETE initiative. The lowest bounce rates were seen for the ETE blog page (17%), consistent with prior research on website usage metrics that indicate that blog pages are often the most frequently viewed pages on Web portals. CONCLUSIONS: Our findings reveal the potential of Google Analytics as a tool to enhance user traffic and performance of the ETE geovisualization platform by using feedback from regular monitoring of key parameters including page bounce rates and average time on page. It also identifies the need for a follow-up usability assessment of the system. PMID- 29229593 TI - Acute rotator cuff tears. PMID- 29229595 TI - Single-board hematology fellowship track: a 10-year institutional experience. PMID- 29229594 TI - Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. AB - In this phase 1/2 study, brentuximab vedotin (BV) and nivolumab (Nivo) administered in combination were evaluated as initial salvage therapy in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). Patients received up to 4 cycles of combination treatment, with BV administered on day 1 and Nivo on day 8 of the first cycle. For cycles 2 to 4, BV and Nivo were both administered on day 1. After study treatment, responses were evaluated by investigators per the 2014 Lugano classification, and patients could proceed to autologous stem cell transplantation (ASCT). Sixty-two patients were enrolled; the complete response rate among all treated patients (n = 61) was 61%, with an objective response rate of 82%. Before ASCT, adverse events (AEs) occurred in 98% of patients, mostly grades 1 and 2. Infusion-related reactions (IRRs) occurred in 44% of patients overall, with 41% of patients experiencing an IRR during at least 1 infusion of BV. Five patients (8%) were treated with systemic steroids for immune-related AEs. A reduction of peripheral T-cell subsets including regulatory T cells was observed after the first dose of BV, and reduced serum levels of thymus- and activation-regulated chemokine concurrent with an increase in proinflammatory cytokines and chemokines were seen after the first BV plus Nivo infusions. The combination of BV plus Nivo was an active and well-tolerated first salvage regimen, potentially providing patients with R/R HL an alternative to traditional chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT02572167. PMID- 29229596 TI - No evidence that CD33 splicing SNP impacts the response to GO in younger adults with AML treated on UK MRC/NCRI trials. PMID- 29229597 TI - Nkx2-2as Suppression Contributes to the Pathogenesis of Sonic Hedgehog Medulloblastoma. AB - Aberrant Hedgehog signaling and excessive activation of the Gli family of transcriptional activators are key drivers of medulloblastoma (MB), the most common human pediatric brain malignancy. MB originates mainly from cerebellar granule neuron progenitors (CGNP), but the mechanisms underlying CGNP transformation remain largely obscure. In this study, we found that suppression of the noncoding RNA Nkx2-2as promoted Sonic Hedgehog (Shh)-potentiated MB development. Nkx2-2as functioned as a competing endogenous RNA against miR-103 and miR-107, sequestering them and thereby derepressing their tumor suppressive targets BTG2 and LATS1 and impeding cell division and migration. We also found that Nkx2-2as tethered miR-548m and abrogated its LATS2 targeting activity. Shh signaling impaired Nkx2-2as expression by upregulating the transcriptional repressor FoxD1. In clinical specimens of Shh-subgroup MB, we validated coordinated expression of the aforementioned proteins. Notably, exogenous expression of Nkx2-2as suppressed tumorigenesis and prolonged animal survival in MB mouse models. Our findings illuminate the role of noncoding RNAs in Hedgehog signaling and MB occurrence, with implications for identifying candidate therapeutic targets for MB treatment.Significance: These findings illuminate the role of noncoding RNAs in Hedgehog signaling and an interplay between the Hedgehog and Hippo pathways in medulloblastoma pathogenesis. Cancer Res; 78(4); 962-73. (c)2017 AACR. PMID- 29229599 TI - Downregulating Neuropilin-2 Triggers a Novel Mechanism Enabling EGFR-Dependent Resistance to Oncogene-Targeted Therapies. AB - Neuropilins are a class of cell surface proteins implicated in cell migration and angiogenesis, with aberrant expression in human tumors. Here, we show that the expression of Neuropilin-2 (NRP2) controls EGFR protein levels, thereby impinging on intracellular signaling, viability, and response to targeted therapies of oncogene-addicted cells. Notably, increased NRP2 expression in EGFR-addicted tumor cells led to downregulation of EGFR protein and tumor cell growth inhibition. NRP2 also blunted upregulation of an EGFR "rescue" pathway induced by targeted therapy in Met-addicted carcinoma cells. Cancer cells acquiring resistance to MET oncogene-targeted drugs invariably underwent NRP2 loss, a step required for EGFR upregulation. Mechanistic investigations revealed that NRP2 loss activated NFkB and upregulated the EGFR-associated protein KIAA1199/CEMIP, which is known to oppose the degradation of activated EGFR kinase. Notably, KIAA1199 silencing in oncogene-addicted tumor cells improved therapeutic responses and counteracted acquired drug resistance. Our findings define NRP2 as the pivotal switch of a novel broad-acting and actionable pathway controlling EGFR signaling, and driving resistance to therapies targeting oncogene addiction.Significance: These important findings identify the cell surface molecule Nrp2 as the pivotal switch of a novel, actionable pathway driving EGFR upregulation and resistance to oncogene- targeted therapies. Cancer Res; 78(4); 1058-68. (c)2017 AACR. PMID- 29229598 TI - CDKN2A/p16 Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition. AB - Checkpoint kinase inhibitors (CHKi) exhibit striking single-agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of CHK1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity. To explore genomic underpinnings of CHKi hypersensitivity, comparative genomic analysis was performed between hypersensitive cells and cells categorized as least sensitive because they showed drug IC50 value greater than the cell panel median and lacked early S-phase arrest. Novel association between CDKN2A/p16 copy number loss, CDK2 activation, replication stress, and hypersensitivity of HNSCC cells to CHKi monotherapy was found. Restoring p16 in cell lines harboring CDKN2A/p16 genomic deletions alleviated CDK2 activation and replication stress, attenuating CHKi hypersensitivity. Taken together, our results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from CHKi therapy.Significance: These results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from therapy with CHK inhibitors. Cancer Res; 78(3); 781-97. (c)2017 AACR. PMID- 29229600 TI - Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Resensitization to Platinum Drugs. AB - DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients.Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. Cancer Res; 78(3); 631-44. (c)2017 AACR. PMID- 29229601 TI - A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment. AB - Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs antitumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK-cell specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays. Moreover, targeting A2AR specifically on NK cells also improved tumor control and delayed tumor initiation. Taken together, our results establish A2AR-mediated adenosine signaling as an intrinsic negative regulator of NK-cell maturation and antitumor immune responses. On the basis of these findings, we propose that administering A2AR antagonists concurrently with NK cell-based therapies may heighten therapeutic benefits by augmenting NK cell-mediated antitumor immunity.Significance: Ablating adenosine signaling is found to promote natural killer cell maturation and antitumor immunity and reduce tumor growth. Cancer Res; 78(4); 1003-16. (c)2017 AACR. PMID- 29229602 TI - VEGFR2-Mediated Reprogramming of Mitochondrial Metabolism Regulates the Sensitivity of Acute Myeloid Leukemia to Chemotherapy. AB - Metabolic reprogramming is central to tumorigenesis, but whether chemotherapy induces metabolic features promoting recurrence remains unknown. We established a mouse xenograft model of human acute myeloid leukemia (AML) that enabled chemotherapy-induced regressions of established disease followed by lethal regrowth of more aggressive tumor cells. Human AML cells from terminally ill mice treated with chemotherapy (chemoAML) had higher lipid content, increased lactate production and ATP levels, reduced expression of peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha), and fewer mitochondria than controls from untreated AML animals. These changes were linked to increased VEGFR2 signaling that counteracted chemotherapy-driven cell death; blocking of VEGFR2 sensitized chemoAML to chemotherapy (re-)treatment and induced a mitochondrial biogenesis program with increased mitochondrial mass and oxidative stress. Accordingly, depletion of PGC-1alpha in chemoAML cells abolished such induction of mitochondrial metabolism and chemosensitization in response to VEGFR2 inhibition. Collectively, this reveals a mitochondrial metabolic vulnerability with potential therapeutic applications against chemotherapy resistant AML.Significance: These findings reveal a mitochondrial metabolic vulnerability that might be exploited to kill chemotherapy-resistant acute myeloid leukemia cells. Cancer Res; 78(3); 731-41. (c)2017 AACR. PMID- 29229603 TI - LNMICC Promotes Nodal Metastasis of Cervical Cancer by Reprogramming Fatty Acid Metabolism. AB - Cancer spread to lymph nodes predicts poor survival but underlying mechanisms remain little understood. In this study, we show that overexpression of the long noncoding RNA LNMICC associates with lymph node metastasis of primary cervical cancer, where it serves as an independent high-risk factor in patient survival. Functional investigations demonstrated that LNMICC promoted lymph node metastasis by reprogramming fatty acid metabolism, by recruiting the nuclear factor NPM1 to the promoter of the fatty acid binding protein FABP5. We also found that the prometastatic effects of LNMICC were directly targeted and suppressed by miR-190. Our results establish a new mechanism of lymph node metastasis and highlight LNMICC as a candidate prognostic biomarker and therapeutic target in cervical cancer.Significance: These results establish the role of a novel long noncoding RNA in lymph node metastasis, with implications as a candidate prognostic biomarker and therapeutic target in cervical cancer. Cancer Res; 78(4); 877-90. (c)2017 AACR. PMID- 29229604 TI - Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer. AB - Transcriptional dysregulation induced by aberrant transcription factors (TF) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here, we infer the transcriptional activity of 127 TFs through analysis of RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey a total of 1,056 cancer cell lines and 9,250 primary tumors. Predicted TF activities are supported by their agreement with independent shRNA essentiality profiles and homozygous gene deletions, and recapitulate mutant-specific mechanisms of transcriptional dysregulation in cancer. By analyzing cell line responses to 265 compounds, we uncovered numerous TFs whose activity interacts with anticancer drugs. Importantly, combining existing pharmacogenomic markers with TF activities often improves the stratification of cell lines in response to drug treatment. Our results, which can be queried freely at dorothea.opentargets.io, offer a broad foundation for discovering opportunities to refine personalized cancer therapies.Significance: Systematic analysis of transcriptional dysregulation in cancer cell lines and patient tumor specimens offers a publicly searchable foundation to discover new opportunities to refine personalized cancer therapies. Cancer Res; 78(3); 769-80. (c)2017 AACR. PMID- 29229605 TI - miR-204-5p and miR-211-5p Contribute to BRAF Inhibitor Resistance in Melanoma. AB - Melanoma treatment with the BRAF V600E inhibitor vemurafenib provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to vemurafenib with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in vemurafenib-resistant cells was determined to impact vemurafenib response. Their expression was rapidly affected by vemurafenib treatment through RNA stabilization. Similar effects were elicited by MEK and ERK inhibitors but not AKT or Rac inhibitors. Ectopic expression of both miRNA in drug-naive human melanoma cells was sufficient to confer vemurafenib resistance and more robust tumor growth in vivo Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after vemurafenib exposure. Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following vemurafenib treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve vemurafenib responses.Significance: Identification of miRNAs that enable resistance to BRAF inhibitors in melanoma suggests a mechanism-based strategy to limit resistance and improve clinical outcomes. Cancer Res; 78(4); 1017-30. (c)2017 AACR. PMID- 29229606 TI - Coactivation of Estrogen Receptor and IKKbeta Induces a Dormant Metastatic Phenotype in ER-Positive Breast Cancer. AB - A growing body of evidence suggests that the inflammatory NFkappaB pathway is associated with the progression of ER+ tumors to more aggressive stages. However, it is unknown whether NFkappaB is a driver or a consequence of aggressive ER+ disease. To investigate this question, we developed breast cancer cell lines expressing an inducible, constitutively active form of IkappaB kinase beta (CA IKKbeta), a key kinase in the canonical NFkappaB pathway. We found that CA IKKbeta blocked E2-dependent cell proliferation in vitro and tumor growth in vivo in a reversible manner, suggesting that IKKbeta may contribute to tumor dormancy and recurrence of ER+ disease. Moreover, coactivation of ER and IKKbeta promoted cell migration and invasion in vitro and drove experimental metastasis in vivo Gene expression profiling revealed a strong association between ER and CA-IKKbeta driven gene expression and clinically relevant invasion and metastasis gene signatures. Mechanistically, the invasive phenotype appeared to be driven by an expansion of a basal/stem-like cell population rather than EMT. Taken together, our findings suggest that coactivation of ER and the canonical NFkappaB pathway promotes a dormant, metastatic phenotype in ER+ breast cancer and implicates IKKbeta as a driver of certain features of aggressive ER+ breast cancer.Significance: The canonical NFkappaB pathway promotes expansion of stem/basal-like cells and a dormant, metastatic phenotype in ER+ breast cancer cells. Cancer Res; 78(4); 974-84. (c)2017 AACR. PMID- 29229607 TI - Race Disparities in the Contribution of miRNA Isoforms and tRNA-Derived Fragments to Triple-Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) is a breast cancer subtype characterized by marked differences between White and Black/African-American women. We performed a systems-level analysis on datasets from The Cancer Genome Atlas to elucidate how the expression patterns of mRNAs are shaped by regulatory noncoding RNAs (ncRNA). Specifically, we studied isomiRs, that is, isoforms of miRNAs, and tRNA-derived fragments (tRF). In normal breast tissue, we observed a marked cohesiveness in both the ncRNA and mRNA layers and the associations between them. This cohesiveness was widely disrupted in TNBC. Many mRNAs become either differentially expressed or differentially wired between normal breast and TNBC in tandem with isomiR or tRF dysregulation. The affected pathways included energy metabolism, cell signaling, and immune responses. Within TNBC, the wiring of the affected pathways with isomiRs and tRFs differed in each race. Multiple isomiRs and tRFs arising from specific miRNA loci (e.g., miR-200c, miR-21, the miR-17/92 cluster, the miR-183/96/182 cluster) and from specific tRNA loci (e.g., the nuclear tRNAGly and tRNALeu, the mitochondrial tRNAVal and tRNAPro) were strongly associated with the observed race disparities in TNBC. We highlight the race specific aspects of transcriptome wiring by discussing in detail the metastasis related MAPK and the Wnt/beta-catenin signaling pathways, two of the many key pathways that were found differentially wired. In conclusion, by employing a data and knowledge-driven approach, we comprehensively analyzed the normal and cancer transcriptomes to uncover novel key contributors to the race-based disparities of TNBC.Significance: This big data-driven study comparing normal and cancer transcriptomes uncovers RNA expression differences between Caucasian and African American patients with triple-negative breast cancer that might help explain disparities in incidence and aggressive character. Cancer Res; 78(5); 1140-54. (c)2017 AACR. PMID- 29229608 TI - Statin-Induced Cancer Cell Death Can Be Mechanistically Uncoupled from Prenylation of RAS Family Proteins. AB - The statin family of drugs preferentially triggers tumor cell apoptosis by depleting mevalonate pathway metabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are used for protein prenylation, including the oncoproteins of the RAS superfamily. However, accumulating data indicate that activation of the RAS superfamily are poor biomarkers of statin sensitivity, and the mechanism of statin-induced tumor-specific apoptosis remains unclear. Here we demonstrate that cancer cell death triggered by statins can be uncoupled from prenylation of the RAS superfamily of oncoproteins. Ectopic expression of different members of the RAS superfamily did not uniformly sensitize cells to fluvastatin, indicating that increased cellular demand for protein prenylation cannot explain increased statin sensitivity. Although ectopic expression of HRAS increased statin sensitivity, expression of myristoylated HRAS did not rescue this effect. HRAS-induced epithelial-to-mesenchymal transition (EMT) through activation of zinc finger E-box binding homeobox 1 (ZEB1) sensitized tumor cells to the antiproliferative activity of statins, and induction of EMT by ZEB1 was sufficient to phenocopy the increase in fluvastatin sensitivity; knocking out ZEB1 reversed this effect. Publicly available gene expression and statin sensitivity data indicated that enrichment of EMT features was associated with increased sensitivity to statins in a large panel of cancer cell lines across multiple cancer types. These results indicate that the anticancer effect of statins is independent from prenylation of RAS family proteins and is associated with a cancer cell EMT phenotype.Significance: The use of statins to target cancer cell EMT may be useful as a therapy to block cancer progression. Cancer Res; 78(5); 1347-57. (c)2017 AACR. PMID- 29229609 TI - Recent advances in pre-exposure prophylaxis for HIV. AB - Although pre-exposure prophylaxis (PrEP)-the use of antiretroviral drugs by non infected people to prevent the acquisition of HIV-is a promising preventive option, important public health questions remain. Daily oral emtricitabine (FTC) tenofovir disoproxil fumarate (TDF) is highly efficacious in preventing the acquisition of HIV in people at risk as a result of a range of different types of sexual exposure. There is good evidence of efficacy in women and men, and when men who have sex with men use event based dosing. Studies have been conducted in several countries and epidemics. Because adherence to this treatment varies greatly there are questions about its public health benefit. Oral FTC-TDF is extremely safe, with minimal impact on kidney, bone, or pregnancy outcomes, and there is no evidence that its effectiveness has been reduced by risk compensation during open label and programmatic follow-up. It is too early to assess the impact of this treatment on the incidence of sexually transmitted infections (STIs) at a population level. Many challenges remain. Access to pre-exposure prophylaxis is limited and disparities exist, including those governed by race and sex. Different pricing and access models need to be explored to avoid further widening inequalities. The optimal combination prevention program needs to be defined, and this will depend on local epidemiology, service provision, and cost effectiveness. This review updates the evidence base for pre-exposure prophylaxis regarding its effectiveness, safety, and risk compensation. PMID- 29229610 TI - Follow-up imaging after nephrectomy for cancer in Canada: urologists' compliance with guidelines. An observational study. AB - BACKGROUND: Surgical tumour removal remains the preferred treatment for most patients with renal cell carcinoma, and many medical associations have proposed guidelines for the optimal surveillance of patients following surgery. This study evaluated the adherence of Canadian urologists to the follow-up guidelines proposed by the Canadian Urological Association (CUA) in 2009. METHODS: The study cohort was identified from the Canadian Kidney Cancer Information System, a prospectively populated database from 15 academic institutions in 6 Canadian provinces: British Colombia, Alberta, Manitoba, Ontario, Quebec and Nova Scotia. A total of 1982 patients who underwent radical or partial nephrectomy for stage pT1-3N0M0 renal cancer between January 2011 and June 2016 were included in the cohort. Numbers of abdominal and chest imaging tests performed during the follow up period were captured and compared with the 2009 CUA guidelines. The level of compliance was measured by means of weighted kappa and Pearson correlation statistics. Multivariate logistic regression was used to evaluate factors associated with noncompliance (under- or overtesting) in the postoperative surveillance period. RESULTS: Of the 1982 patients, 1380 had stage pT1 disease, 164 had stage pT2 disease, and 438 had stage pT3 disease. There was incongruent adherence to the CUA surveillance guidelines, with a ratio of observed to recommended tests of 0.71 and 2.27 for chest and abdominal imaging, respectively. Overall, moderate correlation between observed and recommended tests was observed, with the highest value found for abdominal imaging in the pT3 group (kappa = 0.59 [95% confidence interval 0.52-0.66]). Patients who underwent radical nephrectomy and those who presented with a higher stage of the disease were less likely to receive fewer chest imaging tests than recommended, and those with stage pT2 disease, those with stage pT3 disease, those with conventional clear cell renal cell carcinoma and those with a low-risk histologic type had an increased risk of undertesting. INTERPRETATION: In the 6 Canadian provinces, there are large differences between guidelines and clinical practice in imaging surveillance after nephrectomy for renal cell carcinoma. Better adherence to clinical guidelines could improve optimization of health care services. PMID- 29229611 TI - Opposing Actions of Fibroblast and Cardiomyocyte Smad3 Signaling in the Infarcted Myocardium. AB - BACKGROUND: Transforming growth factor-betas regulate a wide range of cellular responses by activating Smad-dependent and Smad-independent cascades. In the infarcted heart, Smad3 signaling is activated in both cardiomyocytes and interstitial cells. We hypothesized that cell-specific actions of Smad3 regulate repair and remodeling in the infarcted myocardium. METHODS: To dissect cell specific Smad3 actions in myocardial infarction, we generated mice with Smad3 loss in activated fibroblasts or cardiomyocytes. Cardiac function was assessed after reperfused or nonreperfused infarction using echocardiography. The effects of cell-specific Smad3 loss on the infarcted heart were studied using histological studies, assessment of protein, and gene expression levels. In vitro, we studied Smad-dependent and Smad-independent actions in isolated cardiac fibroblasts. RESULTS: Mice with fibroblast-specific Smad3 loss had accentuated adverse remodeling after reperfused infarction and exhibited an increased incidence of late rupture after nonreperfused infarction. The consequences of fibroblast-specific Smad3 loss were not a result of effects on acute infarct size but were associated with unrestrained fibroblast proliferation, impaired scar remodeling, reduced fibroblast-derived collagen synthesis, and perturbed alignment of myofibroblast arrays in the infarct. Polarized light microscopy in Sirius red-stained sections demonstrated that the changes in fibroblast morphology were associated with perturbed organization of the collagenous matrix in the infarcted area. In contrast, alpha-smooth muscle actin expression by infarct myofibroblasts was not affected by Smad3 loss. Smad3 critically regulated fibroblast function, activating integrin-mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2) expression. Smad3 loss in cardiomyocytes attenuated remodeling and dysfunction after infarction. Cardiomyocyte-specific Smad3 loss did not affect acute infarct size but was associated with attenuated cardiomyocyte apoptosis in the remodeling myocardium, accompanied by decreased myocardial NOX-2 levels, reduced nitrosative stress, and lower matrix metalloproteinase-2 expression. CONCLUSIONS: In healing myocardial infarction, myofibroblast- and cardiomyocyte-specific activation of Smad3 has contrasting functional outcomes that may involve activation of an integrin/reactive oxygen axis. PMID- 29229612 TI - Targeting Transmembrane BAX Inhibitor Motif Containing 1 Alleviates Pathological Cardiac Hypertrophy. AB - BACKGROUND: Cardiac hypertrophy and its resultant heart failure are among the most common causes of mortality worldwide. Abnormal protein degradation, especially the impaired lysosomal degradation of large organelles and membrane proteins, is involved in the progression of cardiac hypertrophy. However, the underlying mechanisms have not been fully elucidated. METHODS: We investigated cardiac transmembrane BAX inhibitor motif containing 1 (TMBIM1) mRNA and protein expression levels in samples from patients with heart failure and mice with aortic banding (AB)-induced cardiac hypertrophy. We generated cardiac-specific Tmbim1 knockout mice and cardiac-specific Tmbim1-overexpressing transgenic mice and then challenged them with AB surgery. We used microarray, confocal image, and coimmunoprecipitation analyses to identify the downstream targets of TMBIM1 in cardiac hypertrophy. Tmbim1/Tlr4 double-knockout mice were generated to investigate whether the effects of TMBIM1 on cardiac hypertrophy were Toll-like receptor 4 (TLR4) dependent. Finally, lentivirus-mediated TMBIM1 overexpression in a monkey AB model was performed to evaluate the therapeutic potential of TMBIM1. RESULTS: TMBIM1 expression was significantly downregulated on hypertrophic stimuli in both human and mice heart samples. Silencing cardiac Tmbim1 aggravated AB-induced cardiac hypertrophy. This effect was blunted by Tmbim1 overexpression. Transcriptome profiling revealed that the TLR4 signaling pathway was disrupted dramatically by manipulation of Tmbim1. The effects of TMBIM1 on cardiac hypertrophy were shown to be dependent on TLR4 in double knockout mice. Fluorescent staining indicated that TMBIM1 promoted the lysosome mediated degradation of activated TLR4. Coimmunoprecipitation assays confirmed that TMBIM1 directly interacted with tumor susceptibility gene 101 via a PTAP motif and accelerated the formation of multivesicular bodies that delivered TLR4 to the lysosomes. Finally, lentivirus-mediated TMBIM1 overexpression reversed AB induced cardiac hypertrophy in monkeys. CONCLUSIONS: TMBIM1 protects against pathological cardiac hypertrophy through promoting the lysosomal degradation of activated TLR4. Our findings reveal the central role of TMBIM1 as a multivesicular body regulator in the progression of pathological cardiac hypertrophy, as well as the role of vesicle trafficking in signaling regulation during cardiac hypertrophy. Moreover, targeting TMBIM1 could be a novel therapeutic strategy for treating cardiac hypertrophy and heart failure. PMID- 29229613 TI - Acupuncture with or without combined auricular acupuncture for insomnia: a randomised, waitlist-controlled trial. AB - BACKGROUND: Few high-quality, large-scale, controlled trials comparing the effectiveness and safety of acupuncture, auricular acupuncture and combined acupuncture treatment for insomnia are available. OBJECTIVE: To carry out a randomised, assessor-blinded, waitlist-controlled trial to test the superiority of combination treatment. METHODS: After in-person and polysomnography screening, 224 subjects (mean age 53.4 years; 75.4% female) with DSM-5 insomnia disorder, who were free from major psychiatric disorders and with sleep-diary-derived sleep efficiency averaged over 1 week of <85%, were randomised to acupuncture alone, acupuncture plus auricular acupuncture (combination treatment), or a waitlist in a 3:3:1 ratio. Standardised acupuncture and combination treatment were provided three times weekly for 3 weeks. The primary outcome was sleep-diary-derived sleep efficiency. Secondary outcomes included wrist actigraphy and self-reported scales on insomnia, anxiety and depression, fatigue, sleepiness and functioning. Assessments were conducted at baseline, 1 week, 4 weeks and 13 weeks after treatment. Participants on the waitlist were re-randomised to receive acupuncture or combination treatment after the second post-baseline assessment. RESULTS: There was no significant difference between acupuncture and combination treatment in the primary outcome and most secondary outcomes at all time points. However, both treatments were better than waitlist in reducing insomnia, anxiety/depressive symptoms and fatigue, and improving function. Within-group improvements were maintained at 13 weeks after treatment. Of 260 adverse events, 243 were mild (93.5%). Discontinuation due to adverse events was 2.1% and 3.1% for acupuncture and combination treatment, respectively. CONCLUSIONS: Limited by short-term treatment and follow-up, the attempt to augment acupuncture by auricular acupuncture was not supported. Acupuncture and combination treatment were safe and had mild hypnotic effects, which lasted for at least 13 weeks. TRIAL REGISTRATION NUMBER: NCT01891097; Results. PMID- 29229614 TI - Does pride really come before a fall? Longitudinal analysis of older English adults. AB - OBJECTIVE: To test whether high levels of reported pride are associated with subsequent falls. DESIGN: Secondary analysis of the English Longitudinal Study of Ageing (ELSA) dataset. SETTING: Multi-wave longitudinal sample of non institutionalised older English adults. PARTICIPANTS: ELSA cohort of 6415 participants at wave 5 (baseline, 2010/11), of whom 4964 were available for follow-up at wave 7 (follow-up, 2014/15). MAIN OUTCOME MEASURES: Self reported pride at baseline (low/moderate/high) and whether the participant had reported having fallen during the two years before follow-up. RESULTS: The findings did not support the contention that "pride comes before a fall." Unadjusted estimates indicate that the odds of reported falls were significantly lower for people with high pride levels compared with those who had low pride (odds ratio 0.69, 95% confidence interval 0.58 to 0.81, P<0.001). This association remained after adjustment for age, sex, household wealth, and history of falls (odds ratio 0.81, 0.68 to 0.97, P<0.05). It was partially attenuated after further adjustment for mobility problems, eyesight problems, the presence of a limiting long term illness, a diagnosis of arthritis or osteoporosis, medication use, cognitive function, and pain and depression (odds ratio 0.86, 0.72 to 1.03, P<0.1). Because the confidence interval exceeded 1 in the final model, it remains possible that pride may not be an independent predictor of falls when known risk factors are considered. People with moderate pride did not have lower odds of having fallen than those with low pride in adjusted models. Participants lost to follow-up did not differ from those retained in terms of key variables, and weighting the analyses to account for selective attrition did not produce different results. CONCLUSIONS: Contrary to the well known saying "pride comes before a fall," these findings suggest that pride may actually be a protective factor against falling in older adults. Future studies may seek to investigate the mechanisms underpinning this relation. PMID- 29229615 TI - Defective Amplifying Pathway of beta-Cell Secretory Response to Glucose in Type 2 Diabetes: Integrated Modeling of In Vitro and In Vivo Evidence. AB - In vivo studies have investigated the role of beta-cell dysfunction in type 2 diabetes (T2D), whereas in vitro research on islets has elucidated key mechanisms that control the insulin secretion rate. However, the relevance of the cellular mechanisms identified in vitro (i.e., the triggering and amplifying pathways) has not been established in vivo. Furthermore, the mechanisms underpinning beta-cell dysfunction in T2D remain undetermined. We propose a unifying explanation of several characteristic features of insulin secretion both in vitro and in vivo by using a mathematical model. The model describes the triggering and amplifying pathways and reproduces a variety of in vitro and in vivo tests in subjects with and without T2D, identifies the mechanisms modulating first-phase insulin secretion rate in response to basal hyperglycemia or insulin resistance, and shows that beta-cell dysfunction in T2D can be explained by an impaired amplifying pathway with no need to postulate defects in intracellular calcium handling. PMID- 29229618 TI - Recent Evolution of the Treatment of Coronary Artery Disease in China: A Conversation With Ya-Ling Han, MD, PhD. PMID- 29229616 TI - Glutamine-Elicited Secretion of Glucagon-Like Peptide 1 Is Governed by an Activated Glutamate Dehydrogenase. AB - Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from beta-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo in mice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo. PMID- 29229617 TI - Is Instantaneous Wave-Free Ratio a New Standard of Care for Physiologic Assessment of Coronary Lesions? More Questions Than Answers. PMID- 29229619 TI - Optimizing Systems of Care for Endovascular Thrombectomy in Ischemic Stroke: Drip and Ship Versus Mothership. PMID- 29229620 TI - Cardioprotection Is Alive But Remains Enigmatic: The Nitric Oxide-Protein Kinases Mitochondria Signaling Axis. PMID- 29229622 TI - Regular Tachycardia With Abnormal QRS Axis. PMID- 29229621 TI - Stem Cell Therapy for Congenital Heart Disease: A Systematic Review. AB - BACKGROUND: Congenital heart disease (CHD) constitutes the most prevalent and heterogeneous group of congenital anomalies. Although surgery remains the gold standard treatment modality, stem cell therapy has been gaining ground as a complimentary or alternative treatment option in certain types of CHD. The aim of this study was to present the existing published evidence and ongoing research efforts on the implementation of stem cell-based therapeutic strategies in CHD. METHODS: A systematic review was conducted by searching Medline, ClinicalTrials.gov, and the Cochrane library, along with reference lists of the included studies through April 23, 2017. RESULTS: Nineteen studies were included in this review (8 preclinical, 6 clinical, and 5 ongoing trials). Various routes of cardiac stem cell delivery have been reported, including intracoronary, intramyocardial, intravenous, and epicardial. Depending on their origin and level of differentiation at which they are harvested, stem cells may exhibit different properties. Preclinical studies have mostly focused on modeling right ventricle dysfunction or failure and pulmonary artery hypertension by using pressure or volume overload in vitro or in vivo. Only a limited number of clinical trials on patients with CHD exist, and these primarily focus on hypoplastic left heart syndrome. Cell-based tissue engineering has recently been introduced, and research currently is focusing on developing cell-seeded grafts and patches that could potentially grow in parallel with whole body growth once implanted in the heart. CONCLUSIONS: It seems that stem cell delivery to the diseased heart as an adjunct to surgical palliation may provide some benefits over surgery alone in terms of cardiac function, somatic growth, and quality of life. Despite encouraging preliminary results, stem cell therapies for patients with CHD should only be considered in the setting of well-designed clinical trials. More wet laboratory research experience is needed, and translation of promising findings to large clinical studies is warranted to clearly define the efficacy and safety profile of this alternative and potentially groundbreaking therapeutic approach. PMID- 29229623 TI - Letter by Jin-Shan and Xue-Bin Regarding Article, "Fractional Flow Reserve and Cardiac Events in Coronary Artery Disease: Data From a Prospective IRIS-FFR Registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve)". PMID- 29229624 TI - Response by Ahn and Park to Letter Regarding Article, "Fractional Flow Reserve and Cardiac Events in Coronary Artery Disease: Data From a Prospective IRIS-FFR Registry (Interventional Cardiology Research Incooperation Society Fractional Flow Reserve)". PMID- 29229625 TI - Letter by Triantafyllou and Straub Regarding Article, "Thresholds for Ambulatory Blood Pressure Among African Americans in the Jackson Heart Study". PMID- 29229626 TI - Letter by Chi and Marszalek Regarding Article, "Composite End Points in Clinical Research: A Time for Reappraisal". PMID- 29229627 TI - Late-Breaking Science Abstracts From the American Heart Association's Scientific Sessions 2017 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2017. PMID- 29229629 TI - Student who died from anorexia was failed by NHS, review finds. PMID- 29229628 TI - Nationwide multicenter study on the management of pulmonary neuroendocrine (carcinoid) tumors. AB - BACKGROUND AND AIM: To analyze the management and outcome of patients with primary typical (TC) and atypical lung carcinoids (AC) in Switzerland. METHODS: Retrospective analysis of patients selected from a neuroendocrine tumor (NET) registry. Patients were divided into TC and AC according to pathology reports, and surgical procedures were grouped as wedge/segmentectomy, lobectomy/bilobectomy and pneumectomy. Survival analysis was performed using the Kaplan-Meier method and log-rank test. RESULTS: Over 7 years, 113 pulmonary carcinoids (61.9% females, mean age 59.4 years) were included from 19 hospitals, with pathology data on Ki67 and necrosis incomplete in 16 cases. Eighty-three TC and 14 AC underwent surgical resection with a primary tumor size of median 14.5 (range 1-80) mm and diagnosis was established in 55.8% at surgery. Mean follow-up was 30.2 +/- 23.1 months. Lobectomy was performed in 54.2% and wedge resection in 17.7% of cases. Six patients received additional systemic therapy. There was a trend for larger primary lesion size and a significantly higher rate of N2-N3 status in AC. Mean survival tended to be increased in patients with TC compared to AC (86.1 vs 48.4 months, P = 0.06) and mean disease-free interval after surgical resection was 74.1 and 48.3 months for TC and AC, respectively (P = 0.74). CONCLUSION: AC of the lung has a more malignant behavior and a trend to a worse outcome. The results of this registry reinforce the need for standardized histological diagnosis and inter-disciplinary therapeutic decision making to improve the quality of care of patients with TC and AC. PMID- 29229631 TI - Update on Electronic Dental Record and Clinical Computing Adoption Among Dental Practices in the United States. AB - This study sought to re-characterize trends and factors affecting electronic dental record (EDR) and technologies adoption by dental practices and the impact of the Health Information Technology for Economic and Clinical Health (HITECH) act on adoption rates through 2012. A 39-question survey was disseminated nationally over 3 months using a novel, statistically-modeled approach informed by early response rates to achieve a predetermined sample. EDR adoption rate for clinical support was 52%. Adoption rates were higher among: (1) younger dentists; (2) dentists <= 15 years in practice; (3) females; and (4) group practices. Top barriers to adoption were EDR cost/expense, cost-benefit ratio, electronic format conversion, and poor EDR usability. Awareness of the Federal HITECH incentive program was low. The rate of chairside computer implementation was 72%. Adoption of EDR in dental offices in the United States was higher in 2012 than electronic health record adoption rates in medical offices and was not driven by the HITECH program. Patient portal adoption among dental practices in the United States remained low. PMID- 29229630 TI - The Role of Moisturizers in Addressing Various Kinds of Dermatitis: A Review. AB - Moisturizer is a major component of basic daily skin care, particularly in presence of epidermal barrier alteration and reduced epidermal water content. It is an important part of a dermatologist's strategy to maintain skin health as well as treating various dermatoses which co-exist with skin dryness and are linked to impaired skin barrier function, such as in atopic disorders as well as other types of dermatitis. Mastering the knowledge regarding mechanism of action, application, dosage, adverse effects as well as specific clinical usage of moisturizers is a must for a dermatologist in order to support their use, particularly for evidence-based, therapeutic purposes. This review discusses the use of moisturizer both for skin health maintenance as well as a definitive or adjuvant therapy for many kinds of dermatitis. PMID- 29229632 TI - Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non-Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling. AB - Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified.Experimental Design: AhR expression in non small cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms.Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized EGFR tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacologic and molecular approaches rendered EGFR-mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2-Src interaction, which does not require the canonical transcriptional activity of AhR.Conclusions: Our results reveal a transcription independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR activated NSCLC. Clin Cancer Res; 24(5); 1227-39. (c)2017 AACR. PMID- 29229633 TI - Correction: Anti-TNF treatment blocks the induction of T cell-dependent humoral responses. PMID- 29229634 TI - Genomic Insights into Colistin-Resistant Klebsiella pneumoniae from a Tunisian Teaching Hospital. AB - The emergence of colistin-resistant Klebsiella pneumoniae (CoRKp) is a public health concern, since this antibiotic has become the last line of treatment for infections caused by multidrug-resistant (MDR) Gram negatives. In this study, we have investigated the molecular basis of colistin resistance in 13 MDR K. pneumoniae strains isolated from 12 patients in a teaching hospital in Sousse, Tunisia. Whole-genome sequencing (WGS) was used to decipher the molecular mechanism of colistin resistance and to identify the resistome of these CoRKp isolates. It revealed a genome of ca. 5.5 Mbp in size with a G+C content of 57%, corresponding to that commonly observed for K. pneumoniae These isolates belonged to the 5 different sequence types (ST11, ST15, ST101, ST147, and ST392), and their resistome was composed of acquired beta-lactamases, including extended spectrum beta-lactamase and carbapenemase genes (blaCTX-M-15, blaOXA-204, blaOXA 48, and blaNDM-1 genes), aminoglycoside resistance genes [aac(6')Ib-cr, aph(3") Ib, aph(6)-Id, and aac(3)-IIa], and fosfomycin (fosA), fluoroquinolone (qnr like), chloramphenicol, trimethoprim, and tetracycline resistance genes. All of the isolates were identified as having a mutated mgrB gene. Mapping reads with reference sequences of the most common genes involved in colistin resistance revealed several modifications in mgrB, pmr, and pho operons (deletions, insertions, and substitutions) likely affecting the function of these proteins. It is worth noting that among the 12 patients, 10 were treated with colistin before the isolation of CoRKp No plasmid encoding mcr-1 to mcr-5 genes was found in these isolates. This study corresponds to the first molecular characterization of a collection of CoRKp strains in Tunisia and highlights that the small transmembrane protein MgrB is a main mechanism for colistin resistance in K. pneumoniae. PMID- 29229635 TI - Plasmodium falciparum Recrudescence Two Years after Treatment of an Uncomplicated Infection without Return to an Area Where Malaria Is Endemic. AB - We report evidence, confirmed by the lack of travel activity outside of France and genetic diversity analysis using polymorphic microsatellite markers, that Plasmodium falciparum malaria infection effectively treated with an artemisinin based combination can remain dormant and relapse during pregnancy at least 2 years after treatment. PMID- 29229636 TI - Topical Antibiotic Use Coselects for the Carriage of Mobile Genetic Elements Conferring Resistance to Unrelated Antimicrobials in Staphylococcus aureus. AB - Topical antibiotics, such as mupirocin and fusidic acid, are commonly used in the prevention and treatment of skin infections, particularly those caused by staphylococci. However, the widespread use of these agents is associated with increased resistance to these agents, potentially limiting their efficacy. Of particular concern is the observation that resistance to topical antibiotics is often associated with multidrug resistance, suggesting that topical antibiotics may play a role in the emergence of multidrug-resistant (MDR) strains. New Zealand (NZ) has some of the highest globally recorded rates of topical antibiotic usage and resistance. Using a combination of Pacific Biosciences single-molecule real-time (SMRT) whole-genome sequencing, Illumina short-read sequencing, and Bayesian phylogenomic modeling on 118 new multilocus sequence type 1 (ST1) community Staphylococcus aureus isolates from New Zealand and 61 publically available international ST1 genome sequences, we demonstrate a strong correlation between the clinical introduction of topical antibiotics and the emergence of MDR ST1 S. aureus We also provide in vitro experimental evidence showing that exposure to topical antibiotics can lead to the rapid selection of MDR S. aureus isolates carrying plasmids that confer resistance to multiple unrelated antibiotics, from within a mixed population of competitor strains. These findings have important implications regarding the impact of the indiscriminate use of topical antibiotics. PMID- 29229637 TI - Elucidating the Pharmacokinetics/Pharmacodynamics of Aerosolized Colistin against Multidrug-Resistant Acinetobacter baumannii and Klebsiella pneumoniae in a Mouse Lung Infection Model. AB - The pharmacokinetics/pharmacodynamics (PK/PD) of aerosolized colistin was investigated against Acinetobacter baumannii and Klebsiella pneumoniae over 24 h in a neutropenic mouse lung infection model. Dose fractionation studies were performed over 2.64 to 23.8 mg/kg/day, and the data were fitted to a sigmoid inhibitory model. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC) in the epithelial lining fluid was the most predictive PK/PD index for aerosolized colistin against both pathogens. Our study provides important pharmacological information for optimizing aerosolized colistin. PMID- 29229638 TI - Sequencing of FKS Hot Spot 1 from Saprochaete capitata To Search for a Relationship to Reduced Echinocandin Susceptibility. AB - Saprochaete capitata, formerly known as Geotrichum capitatum, is an emerging fungal pathogen with low susceptibility to echinocandins. Here, we report the nucleotide sequence of the S. capitata hot spot 1 region of the FKS gene (FKS HS1), which codifies for the catalytic subunit of beta-1,3-d-glucan synthase, the target of echinocandins. For that purpose, we first designed degenerated oligonucleotide primers derived from conserved flanking regions of the FKS1 HS1 segment of 12 different fungal species. Interestingly, analysis of the translated FKS HS1 sequences of 12 isolates of S. capitata revealed that all of them exhibited the same F-to-L substitution in a position that is highly related to reduced echinocandin susceptibility. PMID- 29229639 TI - Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular. AB - Several key antituberculosis drugs, including pyrazinamide, with a molecular mass of 123.1 g/mol, are smaller than the usual drug-like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular masses centered around 400 to 500 g/mol. Fragment (molecular mass < 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1,000 fragments, present in the Maybridge Ro3 library, for whole-cell activity against Mycobacterium tuberculosis Twenty-nine primary hits showed dose-dependent growth inhibition equal to or better than that of pyrazinamide. The most potent hit, indole propionic acid [IPA; 3-(1H-indol-3 yl)propanoic acid], a metabolite produced by the gut microbiota, was profiled in vivo The molecule was well tolerated in mice and showed adequate pharmacokinetic properties. In a mouse model of acute M. tuberculosis infection, IPA reduced the bacterial load in the spleen 7-fold. Our results suggest that IPA should be evaluated as an add-on to current regimens and that fragment libraries should be further explored to identify antimycobacterial lead candidates. PMID- 29229640 TI - Adverse Effects of Intravenous Vancomycin-Based Prophylaxis during Therapy for Pediatric Acute Myeloid Leukemia. AB - Children and adolescents with acute myeloid leukemia (AML) are at risk of life threatening bacterial infections, especially with viridans group streptococci. Primary antibacterial prophylaxis with vancomycin-based regimens reduces this risk but might increase the risks of renal or liver toxicity or Clostridium difficile infection (CDI). A retrospective review of data for patients treated for newly diagnosed AML at St. Jude Children's Research Hospital between 2002 and 2008 was conducted. Nephrotoxicity was classified according to pediatric risk, injury, failure, loss, and end-stage renal disease (pRIFLE) criteria and hepatotoxicity according to Common Terminology Criteria for Adverse Events (CTCAE) criteria. The risks of nephrotoxicity, hepatotoxicity, and CDI were compared between patients receiving vancomycin-based prophylaxis, no intravenous prophylaxis, or other prophylaxis. Generalized linear mixed models were used to address potential confounding. A total of 392 chemotherapy courses (108 with no intravenous prophylaxis, 218 with vancomycin-based prophylaxis, and 66 with other prophylaxis) for 111 patients were included. Development of pRIFLE risk, injury, and failure occurred in 190, 44, and 2 courses, respectively. Increases of at least one, two, and three grades for hepatotoxicity occurred in 189, 52, and 19 courses, respectively. After adjustment for confounders, vancomycin-based prophylaxis was not associated with nephrotoxicity or hepatotoxicity and reduced the risk of CDI, compared to no intravenous prophylaxis (0.9% versus 6.5%; P = 0.007) or other prophylactic regimens (0.9% versus 3.0%; P = 0.23). Despite concerns about vancomycin toxicity, vancomycin-based prophylaxis in pediatric patients with AML did not increase the risk of nephrotoxicity or hepatotoxicity and reduced the risk of CDI. Caution is advised to avoid contributing to antibiotic resistance. PMID- 29229641 TI - Hyperbaric Oxygen Reduces Aspergillus fumigatus Proliferation In Vitro and Influences In Vivo Disease Outcomes. AB - Recent estimates suggest that more than 3 million people have chronic or invasive fungal infections, causing more than 600,000 deaths every year. Aspergillus fumigatus causes invasive pulmonary aspergillosis (IPA) in patients with compromised immune systems and is a primary contributor to increases in human fungal infections. Thus, the development of new clinical modalities as stand alone or adjunctive therapy for improving IPA patient outcomes is critically needed. Here we tested the in vitro and in vivo impacts of hyperbaric oxygen (HBO) (100% oxygen, >1 atmosphere absolute [ATA]) on A. fumigatus proliferation and murine IPA outcomes. Our findings indicate that HBO reduces established fungal biofilm proliferation in vitro by over 50%. The effect of HBO under the treatment conditions was transient and fungistatic, with A. fumigatus metabolic activity rebounding within 6 h of HBO treatment being removed. In vivo, daily HBO provides a dose-dependent but modest improvement in murine IPA disease outcomes as measured by survival analysis. Intriguingly, no synergy was observed between subtherapeutic voriconazole or amphotericin B and HBO in vitro or in vivo with daily HBO dosing, though the loss of fungal superoxide dismutase genes enhanced HBO antifungal activity. Further studies are needed to optimize the HBO treatment regimen and better understand the effects of HBO on both the host and the pathogen during a pulmonary invasive fungal infection. PMID- 29229642 TI - Suppression of Reactive Oxygen Species Accumulation Accounts for Paradoxical Bacterial Survival at High Quinolone Concentration. AB - When bacterial cells are exposed to increasing concentrations of quinolone-class antibacterials, survival drops, reaches a minimum, and then recovers, sometimes to 100%. Despite decades of study, events underlying this paradoxical high concentration survival remain obscure. Since reactive oxygen species (ROS) have been implicated in antimicrobial lethality, conditions generating paradoxical survival were examined for diminished ROS accumulation. Escherichia coli cultures were treated with various concentrations of nalidixic acid, followed by measurements of survival, rate of protein synthesis, and ROS accumulation. The last measurement used a dye (carboxy-H2DCFDA) that fluoresces in the presence of ROS; fluorescence was assessed by microscopy (individual cells) and flow cytometry (batch cultures). High, nonlethal concentrations of nalidixic acid induced lower levels of ROS than moderate, lethal concentrations. Sublethal doses of exogenous hydrogen peroxide became lethal and eliminated the nalidixic acid associated paradoxical survival. Thus, quinolone-mediated lesions needed for ROS executed killing persist at high, nonlethal quinolone concentrations, thereby implicating ROS as a key factor in cell death. Chloramphenicol suppressed nalidixic acid-induced ROS accumulation and blocked lethality, further supporting a role for ROS in killing. Nalidixic acid also inhibited protein synthesis, with extensive inhibition at high concentrations correlating with lower ROS accumulation and paradoxical survival. A catalase deficiency, which elevated ROS levels, overcame the inhibitory effect of chloramphenicol on nalidixic acid mediated killing, emphasizing the importance of ROS. The data collectively indicate that ROS play a dominant role in the lethal action of narrow-spectrum quinolone-class compounds; a drop in ROS levels accounted for the quinolone tolerance observed at very high concentrations. PMID- 29229644 TI - Narrative approach in understanding the drivers for resilience of military combat medics. AB - INTRODUCTION: Qualitative insights may demonstrate how combat medics (CM) deal with stressors and identify how resilience can potentially develop. Yet, qualitative research is scant in comparison to the many quantitative studies of health outcomes associated with military service. METHOD: Semistructured qualitative interviews were used to collect personal narratives of US Army CMs who had previously served in Iraq or Afghanistan. RESULTS: Thematic analysis revealed three key driving forces for how resilience develops in the context of combat and war. The first was patriotism, which captures loyalty and full commitment to the military and its missions. The second was commitment to their family, reflecting the balance of responsibility to family of origin with the obligation one feels towards their military family. The last driving force was faith, or the drive to reach towards the transcendent to provide a moral compass and develop empathy in the face of difficult situations. CONCLUSIONS: An individual's commitment to country, military family and faith strengthens their resilience, and this can be used to inform future research efforts as well as current clinical practice. PMID- 29229643 TI - Cystatins 9 and C as a Novel Immunotherapy Treatment That Protects against Multidrug-Resistant New Delhi Metallo-Beta-Lactamase-1-Producing Klebsiella pneumoniae. AB - Multidrug-resistant (MDR) bacterial pneumonia can induce dysregulated pulmonary and systemic inflammation leading to morbidity and mortality. Antibiotics to treat MDR pathogens do not function to modulate the extent and intensity of inflammation and can have serious side effects. Here we evaluate the efficacy of two human cysteine proteinase inhibitors, cystatin 9 (CST9) and cystatin C (CSTC), as a novel immunotherapeutic treatment to combat MDR New Delhi metallo beta-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae Our results showed that mice infected intranasally (i.n.) with a 90% lethal dose (LD90) challenge of NDM 1 K. pneumoniae and then treated with the combination of human recombinant CST9 (rCST9) and rCSTC (rCSTs; 50 pg of each i.n. at 1 h postinfection [p.i.] and/or 500 pg of each intraperitoneally [i.p.] at 3 days p.i.) had significantly improved survival compared to that of infected mice alone or infected mice treated with individual rCSTs (P < 0.05). Results showed that both of our optimal rCST treatment regimens modulated pulmonary and systemic proinflammatory cytokine secretion in the serum, lungs, liver, and spleen in infected mice (P < 0.05). Treatment also significantly decreased the bacterial burden (P < 0.05) while preserving lung integrity, with reduced inflammatory cell accumulation compared to that in infected mice. Further, rCST treatment regimens reduced lipid peroxidation and cell apoptosis in the lungs of infected mice. Additionally, in vitro studies showed that rCSTs (50 or 500 pg of each) directly decreased the viability of NDM-1 K. pneumoniae In conclusion, the data showed that rCST9/rCSTC worked synergistically to modulate host inflammation against MDR NDM-1 K. pneumoniae pneumonia, which significantly improved survival. Therefore, rCST9/rCSTC is a promising therapeutic candidate for the treatment of bacterial pneumonia. PMID- 29229645 TI - The incidence of military training-related injuries in Chinese new recruits: a systematic review and meta-analysis. AB - INTRODUCTION: Training-related injuries are the main reason for disability, long term rehabilitation, functional impairment and premature discharge from military service. The aim of this study was to identify the incidence of injuries in the training of Chinese new recruits via a systematic review of the literature. METHOD: A systematic review and meta-analysis was conducted to evaluate the combined incidence of military training-related injuries in Chinese new recruits. The electronic databases of full-text journals were searched, and the Loney criteria were used to assess the quality of eligible articles. Summary estimates were obtained using random-effects models. Subgroup analyses and publication bias tests were performed. RESULTS: Fifty-five eligible articles representing 109 611 Chinese new recruits met the inclusion criteria, of which 21 253 recruits were clinically diagnosed with military training-related injuries. The combined incidence of military training-related injuries in Chinese new recruits was found to be 21.04%. CONCLUSIONS: An increased incidence of training injuries was found in more recent years, underscoring the need for further research on the risk factors associated with their causation. PMID- 29229646 TI - NHE- and diffusion-dependent proton fluxes across the tubular system membranes of fast-twitch muscle fibers of the rat. AB - The complex membrane structure of the tubular system (t-system) in skeletal muscle fibers is open to the extracellular environment, which prevents measurements of H+ movement across its interface with the cytoplasm by conventional methods. Consequently, little is known about the t-system's role in the regulation of cytoplasmic pH, which is different from extracellular pH. Here we describe a novel approach to measure H+-flux measurements across the t-system of fast-twitch fibers under different conditions. The approach involves loading the t-system of intact rat fast-twitch fibers with a strong pH buffer (20 mM HEPES) and pH-sensitive fluorescent probe (10 mM HPTS) before the t-system is sealed off. The pH changes in the t-system are then tracked by confocal microscopy after rapid changes in cytoplasmic ionic conditions. T-system sealing is achieved by removing the sarcolemma by microdissection (mechanical skinning), which causes the tubules to pinch off and seal tight. After this procedure, the t system repolarizes to physiological levels and can be electrically stimulated when placed in K+-based solutions of cytosolic-like ionic composition. Using this approach, we show that the t-system of fast-twitch skeletal fibers displays amiloride-sensitive Na+/H+ exchange (NHE), which decreases markedly at alkaline cytosolic pH and has properties similar to that in mammalian cardiac myocytes. We observed mean values for NHE density and proton permeability coefficient of 339 pmol/m2 of t-system membrane and 158 um/s, respectively. We conclude that the cytosolic pH in intact resting muscle can be quantitatively explained with respect to extracellular pH by assuming that these values apply to the t-system membrane and the sarcolemma. PMID- 29229647 TI - TAB1-Induced Autoactivation of p38alpha Mitogen-Activated Protein Kinase Is Crucially Dependent on Threonine 185. AB - p38alpha mitogen-activated protein kinase is essential to cellular homeostasis. Two principal mechanisms to activate p38alpha exist. The first relies on dedicated dual-specificity kinases such as mitogen-activated protein kinase kinase (MAP2K) 3 (MKK3) or 6 (MKK6), which activate p38alpha by phosphorylating Thr180 and Tyr182 within the activation segment. The second is by autophosphorylation of Thr180 and Tyr182 in cis, mediated by p38alpha binding the scaffold protein TAB1. The second mechanism occurs during myocardial ischemia, where it aggravates myocardial infarction. Based on the crystal structure of the p38alpha-TAB1 complex we replaced threonine 185 of p38alpha with glycine (T185G) to prevent an intramolecular hydrogen bond with Asp150 from being formed. This mutation did not interfere with TAB1 binding to p38alpha. However, it disrupted the consequent long-range effect of this binding event on the distal activation segment, releasing the constraint on Thr180 that oriented its hydroxyl for phosphotransfer. Based on assays performed in vitro and in vivo, the autoactivation of p38alpha(T185G) was disabled, while its ability to be activated by upstream MAP2Ks and to phosphorylate downstream substrates remained intact. Furthermore, myocardial cells expressing p38alpha(T185G) were resistant to injury. These findings reveal a mechanism to selectively disable p38alpha autoactivation and its consequences, which may ultimately circumvent the toxicity associated with strategies that inhibit p38alpha kinase activity under all circumstances, such as with ATP-competitive inhibitors. PMID- 29229648 TI - Phosphorylation of the Unique C-terminal Tail of the Alpha Isoform of the Scaffold Protein SH2B1 Controls the Ability of SH2B1alpha to Enhance Nerve Growth Factor Function. AB - The scaffold protein SH2B1, a major regulator of body weight, is recruited to the receptors of multiple cytokines and growth factors, including nerve growth factor (NGF). The beta isoform, but not the alpha isoform, of SH2B1 greatly enhances NGF dependent neurite outgrowth of PC12 cells. Here we asked how the unique C terminal tails of the alpha and beta isoforms modulate SH2B1 function. We compared the actions of SH2B1alpha and SH2B1beta to those of the N-terminal 631 amino acids shared by both isoforms. In contrast to the beta-tail, the alpha-tail inhibited the ability of SH2B1 to both cycle through the nucleus and enhance NGF mediated neurite outgrowth, gene expression, phosphorylation of Akt and PLCgamma and autophosphorylation of the NGF receptor TrkA. These functions were restored when Tyr753 in the alpha-tail was mutated to phenylalanine. We provide evidence that TrkA phosphorylates Tyr753 in SH2B1alpha, as well as tyrosines 439 and 55 in both SH2B1alpha and SH2B1beta. Finally, co-expression of SH2B1alpha, but not SH2B1alpha Y753F, inhibited the ability of SH2B1beta to enhance neurite outgrowth. These results suggest that the C-terminal tails of SH2B1 isoforms are key determinants of the cellular role of SH2B1. Furthermore, the function of SH2B1alpha is regulated by phosphorylation of the alpha-tail. PMID- 29229649 TI - Isolated tricuspid regurgitation: outcomes and therapeutic interventions. AB - Isolated tricuspid regurgitation (TR) can be caused by primary valvular abnormalities such as flail leaflet or secondary annular dilation as is seen in atrial fibrillation, pulmonary hypertension and left heart disease. There is an increasing recognition of a subgroup of patients with isolated TR in the absence of other associated cardiac abnormalities. Left untreated isolated TR significantly worsens survival. Stand-alone surgery for isolated TR is rarely performed due to an average operative mortality of 8%-10% and a paucity of data demonstrating improved survival. When surgery is performed, valve repair may be preferred over replacement; however, there is a risk of significant recurrent regurgitation after repair. Existing society guidelines do not fully address the management of isolated TR. We propose that patients at low operative risk with symptomatic severe isolated TR and no reversible cause undergo surgery prior to the onset of right ventricular dysfunction and end-organ damage. For patients at increased surgical risk novel percutaneous interventions may offer an alternative treatment but further research is needed. Significant knowledge gaps remain and future research is needed to define operative outcomes and provide comparative data for medical and surgical therapy. PMID- 29229650 TI - Improving Contraceptive Access, Use, and Method Mix by Task Sharing Implanon Insertion to Frontline Health Workers: The Experience of the Integrated Family Health Program in Ethiopia. AB - In 2009, the Ethiopian Federal Ministry of Health launched an Implanon scale-up program with the goal of improving the availability of long-acting reversible contraceptive (LARC) methods at the community level. The Integrated Family Health Program (IFHP) supported the ministry to train Health Extension Workers (HEWs), a cadre of frontline health workers, on Implanon insertion. Prior to this task sharing initiative, HEWs were only permitted to provide short-acting contraceptive methods; Implanon insertion services were only available at higher level health facilities, such as health centers and above. To train HEWs on Implanon insertion, IFHP followed a phase-based approach, which consisted of a learning phase (July to September 2009) that transitioned into a scale-up phase (December 2009 to December 2015). Training began with a series of service delivery-based training of trainers (TOT) sessions for clinical care providers selected from health centers followed by rollout trainings on Implanon insertion for HEWs selected from health posts. Immediately after the Implanon rollout trainings, each trained HEW was provided with consumables and Implanon implants to enable them to initiate the Implanon services at their respective health post. To reinforce knowledge and skills, we conducted mentoring visits and performance review meetings. From July 2009 to September 2015, 98 TOT sessions trained 2,328 clinicians and 320 rollout trainings reached 8,436 HEWs. A total of 1,382,318 women received contraceptive services through any IFHP-supported service delivery point, 1,273,990 of whom received an Implanon implant. The IFHP approach proved to be a successful model for increasing access to contraceptive methods in the community, and the program supported the integration of Implanon services into the existing public health service delivery system. PMID- 29229651 TI - In situ measurements of Saturn's ionosphere show that it is dynamic and interacts with the rings. AB - The ionized upper layer of Saturn's atmosphere, its ionosphere, provides a closure of currents mediated by the magnetic field to other electrically charged regions (for example, rings) and hosts ion-molecule chemistry. In 2017, the Cassini spacecraft passed inside the planet's rings, allowing in situ measurements of the ionosphere. The Radio and Plasma Wave Science instrument detected a cold, dense, and dynamic ionosphere at Saturn that interacts with the rings. Plasma densities reached up to 1000 cubic centimeters, and electron temperatures were below 1160 kelvin near closest approach. The density varied between orbits by up to two orders of magnitude. Saturn's A- and B-rings cast a shadow on the planet that reduced ionization in the upper atmosphere, causing a north-south asymmetry. PMID- 29229652 TI - Protocol for the specialist supervised individualised multifactorial treatment of new clinically diagnosed type 2 diabetes in general practice (IDA): a prospective controlled multicentre open-label intervention study. AB - INTRODUCTION: We present the protocol for a multifactorial intervention study designed to test whether individualised treatment, based on pathophysiological phenotyping and individualised treatment goals, improves type 2 diabetes (T2D) outcomes. METHODS AND ANALYSIS: We will conduct a prospective controlled multicentre open-label intervention study, drawing on the longitudinal cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2). New clinically diagnosed patients with T2D in the intervention group will be assigned to receive individualised treatment by their general practitioner. Intervention patients will be compared with a matched control cohort of DD2 patients receiving routine clinical care. Among intervention patients, we will first do pathophysiological phenotyping to classify patients into WHO-defined T2D or other specific types of diabetes (monogenic diabetes, secondary diabetes etc). Patients with WHO-defined T2D will then be further subcharacterised by their beta-cell function (BCF) and insulin sensitivity (IS), using the revised homeostatic assessment model, as having either insulinopaenic T2D (high IS and low BCF), classical T2D (low IS and low BCF) or hyperinsulinaemic T2D (low IS and high BCF). For each subtype, a specific treatment algorithm will target the primary pathophysiological defect. Similarly, antihypertensive treatment will be targeted at the specific underlying pathophysiology, characterised by impedance cardiography (relative importance of vascular resistance, intravascular volume and cardiac inotropy). All treatment goals will be based on individual patient assessment of expected positive versus adverse effects. Web-based and face-to-face individualised lifestyle intervention will also be implemented to empower patients to make a sustainable improvement in daily physical activity and to change to a low-carbohydrate diet. ETHICS AND DISSEMINATION: The study will use well-known pharmacological agents according to their labels; patient safety is therefore considered high. Study results will be published in international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02015130; Pre-results. PMID- 29229653 TI - Investigation of time to first presentation and extrahospital factors in the treatment of neovascular age-related macular degeneration: a retrospective cross sectional study. AB - OBJECTIVES: To assess the time from symptom onset to treatment for neovascular age-related macular degeneration (nvAMD) and to measure the awareness of AMD in Southeast Scotland. DESIGN: Retrospective cross-sectional study. SETTING: Secondary care, Southeast of Scotland. METHODS: Patients treated with intravitreal therapy (IVT) for nvAMD in Southeast Scotland between 2013 and 2015 were identified using a treatment register. Notes were retrospectively reviewed. We measured time from: (A) symptom onset to first presentation at primary care, (B) referral to ophthalmic clinic appointment and (C) ophthalmic clinic appointment to first IVT treatment. To investigate AMD awareness, we performed a cluster random sample survey of patients visiting non-AMD ophthalmic clinics using a previously validated 12-item questionnaire. RESULTS: 195 patients (mean age 78 years) were included in the study. The mean delays between the different stages-A, B and C-were 54.2 (95% CI +/-13), 28.2 (95% CI +/-4.0) and 31.5 (95% CI +/-3.6) days, respectively. There was an additional mean delay of 7.5 (95% CI +/ 1.6) days when patients were indirectly referred by optometrists via general practitioners (P<0.05). 140 patients (mean age 78) participated in the awareness survey; 62.1% reported being 'aware' of AMD but only 37.3% described AMD symptoms correctly. CONCLUSIONS: There was a significant delay at every step of the nvAMD care pathway. The causes for this were multifactorial and included delays in first presentation to a healthcare provider, referral from primary care and initiation of secondary care treatment. Our data are likely to underestimate prehospital delays as a large number of cases are likely to have undefined symptoms and onset. We also identified suboptimal awareness of AMD which could account for a substantial delay in presentation from symptom onset. These findings highlight the need to address AMD awareness and the need for urgent treatment to prevent avoidable vision loss resulting from nvAMD. PMID- 29229654 TI - Protocol for developing a Database of Zoonotic disease Research in India (DoZooRI). AB - INTRODUCTION: Zoonotic and emerging infectious diseases (EIDs) represent a public health threat that has been acknowledged only recently although they have been on the rise for the past several decades. On an average, every year since the Second World War, one pathogen has emerged or re-emerged on a global scale. Low/middle income countries such as India bear a significant burden of zoonotic and EIDs. We propose that the creation of a database of published, peer-reviewed research will open up avenues for evidence-based policymaking for targeted prevention and control of zoonoses. METHODS AND ANALYSIS: A large-scale systematic mapping of the published peer-reviewed research conducted in India will be undertaken. All published research will be included in the database, without any prejudice for quality screening, to broaden the scope of included studies. Structured search strategies will be developed for priority zoonotic diseases (leptospirosis, rabies, anthrax, brucellosis, cysticercosis, salmonellosis, bovine tuberculosis, Japanese encephalitis and rickettsial infections), and multiple databases will be searched for studies conducted in India. The database will be managed and hosted on a cloud-based platform called Rayyan. Individual studies will be tagged based on key preidentified parameters (disease, study design, study type, location, randomisation status and interventions, host involvement and others, as applicable). ETHICS AND DISSEMINATION: The database will incorporate already published studies, obviating the need for additional ethical clearances. The database will be made available online, and in collaboration with multisectoral teams, domains of enquiries will be identified and subsequent research questions will be raised. The database will be queried for these and resulting evidence will be analysed and published in peer-reviewed journals. PMID- 29229655 TI - New Zealand policy experts' appraisal of interventions to reduce smoking in young adults: a qualitative investigation. AB - OBJECTIVES: Reducing smoking in young adults, particularly young Maori and Pacific, is vital for reducing tobacco harm and health inequalities in New Zealand (NZ). We investigated how NZ policy experts appraised the feasibility and likely effectiveness of interventions designed to reduce smoking prevalence among 18-24 year olds. DESIGN: We used a qualitative design, conducting semistructured interviews and applying thematic analysis. PARTICIPANTS: We interviewed 15 key informants, including politicians, senior policy analysts and leading tobacco control advocates. Participant selection was based on seniority and expertise and ensuring diverse perspectives were represented. INTERVENTIONS: We examined nine interventions that could either promote greater mindfulness or introduce barriers impeding smoking uptake: smoke-free outdoor dining and bars; no tobacco sales where alcohol is sold; social marketing campaigns; real life stories (testimonials); life skills training; raise purchase age to 21; tobacco-free generation; smokers' licence; make tobacco retail premises R18. RESULTS: The policies perceived as more effective denormalised tobacco; made it less convenient to access and use; highlighted immediate disadvantages (eg, impact on fitness); aligned with young people's values; and addressed the underlying causes of smoking (eg, stress). Participants highlighted some political barriers and noted concerns that some interventions might widen ethnic disparities. Exceptions were social marketing campaigns and extending smoke-free regulations to include outdoor areas of cafes and bars, which participants saw as politically feasible and likely to be effective. CONCLUSIONS: Our findings suggest the merit of an approach that combines social marketing with regulation that makes accessing and using tobacco less convenient for young adults; however, political barriers may limit the regulatory options available in the short term. Strategies to support self-determination and address the underlying causes of smoking in young people warrant further investigation. Determining policy acceptability to Maori and Pacific, and likely effectiveness for these populations, should be key priorities. PMID- 29229656 TI - Informing future research for carriage of multiresistant Gram-negative bacteria: problems with recruiting to an English stool sample community prevalence study. AB - OBJECTIVES: This study aims to highlight problems with recruiting to an English stool sample community prevalence study. It was part of a larger cross-sectional research to determine the risk factors for the presence of extended-spectrum beta lactamase and carbapenemase-producing coliforms in stool samples of the asymptomatic general English population. SETTING: Four National Health Service primary care trusts (PCTs) of England representing a different section of the population of England: Newham PCT; Heart of Birmingham Teaching PCT; Shropshire County PCT; and Southampton City PCT. PARTICIPANTS: Sixteen general practices across the four PCTs were purposefully selected. After stratification of GP lists by age, ethnicity and antibiotic use, 58 337 randomly selected patients were sent a postal invitation.Patients who had died, moved to a different surgery, were deemed too ill by their General Practitioner or hospitalised at the time of mailing were excluded. RESULTS: Stool and questionnaire returns varied by area, age, gender and ethnicity; the highest return rate of 27.3% was in Shropshire in the age group of over 60 years; the lowest, 0.6%, was in Birmingham in the age group of 18-39 years. Whereas only 3.9%(2296) returned a completed questionnaire and stool sample, 94.9% of participants gave permission for their sample and data to be used in future research. CONCLUSION: Researchers should consider the low stool specimen return rate and wide variation by ethnicity and age when planning future studies involving stool specimen collection. This is particularly pertinent if the study has no health benefit to participants. Further research is needed to explore how to improve recruitment in multicultural communities and in younger people. PMID- 29229657 TI - Adapting the emergency first aid responder course for Zambia through curriculum mapping and blueprinting. AB - OBJECTIVES: Community members are often the first to witness and respond to medical and traumatic emergencies, making them an essential first link to emergency care systems. The Emergency First Aid Responder (EFAR) programme is short course originally developed to help South Africans manage emergencies at the community level, pending arrival of formal care providers. EFAR was implemented in two rural regions of Zambia in 2015, but no changes were originally made to tailor the course to the new setting. We undertook this study to identify potential refinements in the original EFAR curriculum, and to adapt it to the local context in Zambia. DESIGN: The EFAR curriculum was mapped against available chief complaint data. An expert group used information from the map, in tandem with personal knowledge, to rank each course topic for potential impact on patient outcomes and frequency of use in practice. Individual blueprints were compiled to generate a refined EFAR curriculum, the time breakdown of which reflects the relative weight of each topic. SETTING: This study was conducted based on data collected in Kasama, a rural region of Zambia's Northern Province. PARTICIPANTS: An expert group of five physicians practising emergency medicine was selected; all reviewers have expertise in the Zambian context, EFAR programme and/or curriculum development. RESULTS: The range of emergencies that Zambian EFARs encounter indicates that the course must be broad in scope. The refined curriculum covers 54 topics (seven new) and 25 practical skills (five new). Practical and didactic time devoted to general patient care and scene management increased significantly, while time devoted to most other clinical, presentation based categories (eg, trauma care) decreased. CONCLUSIONS: Discrepancies between original and refined curricula highlight a mismatch between the external curriculum and local context. Even with limited data and resources, curriculum mapping and blueprinting are possible means of resolving these contextual issues. PMID- 29229658 TI - Effectiveness of acupuncture for cancer pain: protocol for an umbrella review and meta-analyses of controlled trials. AB - INTRODUCTION: The National Comprehensive Cancer Network guidelines for adult cancer pain indicate that acupuncture and related therapies may be valuable additions to pharmacological interventions for pain management. Of the systematic reviews related to this topic, some concluded that acupuncture was promising for alleviating cancer pain, while others argued that the evidence was insufficient to support its effectiveness. METHODS AND ANALYSIS: This review will consist of three components: (1) synthesis of findings from existing systematic reviews; (2) updated meta-analyses of randomised clinical trials and (3) analyses of results of other types of clinical studies. We will search six English and four Chinese biomedical databases, dissertations and grey literature to identify systematic reviews and primary clinical studies. Two reviewers will screen results of the literature searches independently to identify included reviews and studies. Data from included articles will be abstracted for assessment, analysis and summary. Two assessors will appraise the quality of systematic reviews using Assessment of Multiple Systematic Reviews; assess the randomised controlled trials using the Cochrane Collaboration's risk of bias tool and other types of studies according to the Newcastle-Ottawa Scale. We will use 'summary of evidence' tables to present evidence from existing systematic reviews and meta-analyses. Using the primary clinical studies, we will conduct meta-analysis for each outcome, by grouping studies based on the type of acupuncture, the comparator and the specific type of pain. Sensitivity analyses are planned according to clinical factors, acupuncture method, methodological characteristics and presence of statistical heterogeneity as applicable. For the non-randomised studies, we will tabulate the characteristics, outcome measures and the reported results of each study. Consistencies and inconsistencies in evidence will be investigated and discussed. Finally, we will use the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate the quality of the overall evidence. ETHICS AND DISSEMINATION: There are no ethical considerations associated with this review. The findings will be disseminated in peer-reviewed journals or conference presentations. PROSPERO REGISTRATION NUMBER: CRD42017064113. PMID- 29229659 TI - A smoking prevention photoageing intervention for secondary schools in Brazil delivered by medical students: protocol for a randomised trial. AB - INTRODUCTION: Most smokers start smoking during their early adolescence, often with the idea that smoking is glamorous; the dramatic health consequences are too far in the future to fathom. We recently designed and tested an intervention that takes advantage of the broad availability of mobile phones as well as adolescents' interest in their appearance. A free photoageing mobile app (Smokerface) was implemented by medical students in secondary schools via a novel method called mirroring. The pupils' altered three-dimensional selfies on tablets were 'mirrored' via a projector in front of their whole grade. This is the first randomised trial to measure the effectiveness of the mirroring approach on smoking behaviour in secondary schools. METHODS AND ANALYSIS: The mirroring intervention, which lasts 45 min, is implemented by Brazilian medical students in at least 35 secondary school classes with 21 participants each (at least 35 classes with 21 participants for control) in February 2018 in the city of Itauna, Brazil. External block randomisation via computer is performed on the class level with a 1:1 allocation. In addition to sociodemographic data, smoking behaviour is measured via a paper-pencil questionnaire before, 3 and 6 months postintervention plus a random carbon monoxide breathing test at baseline and end line. The primary outcome is cigarette smoking in the past week at 6 months follow-up. Smoking behaviour (smoking onset, quitting) and effects on the different genders are studied as secondary outcomes. Analysis is by intention to treat. ETHICS AND DISSEMINATION: Ethical approval is obtained from the ethics committee of the University of Itauna in Brazil. Results will be disseminated at conferences, in peer-reviewed journals, throughout the Education Against Tobacco network social media channels and on our websites. TRIAL REGISTRATION NUMBER: NCT03178227. PMID- 29229661 TI - Women's recall of requirements for oral contraception prescription in Italy. PMID- 29229660 TI - Rationale and design of GENEiUS: a prospective observational study on the genetic and environmental determinants of body mass index evolution in Canadian undergraduate students. AB - INTRODUCTION: Obesity is a global epidemic and is a risk factor for developing other comorbidities. Young adulthood is a critical period for body weight change and establishing healthy lifestyle behaviours. The 'Freshman 15' suggests that undergraduate students gain 15 lbs (6.8 kg) during their first year of university, although evidence estimates a more modest weight gain of approximately 3-5 lbs (1.4-2.3 kg). Previous studies have only investigated weight change in the first year and do not study potential risk factors. Genetic and EnviroNmental Effects on weight in University Students (GENEiUS) is a prospective observational study which will investigate the environmental and biological determinants of weight change in undergraduate students over 4 years. METHODS AND ANALYSIS: The GENEiUS study will recruit 2500 multiethnic undergraduates aged 17-25 years at McMaster University at the start of their first year and will follow them every 6 months for 4 years. Primary outcomes are obesity traits: body mass index, waist circumference, waist-to-hip ratio, body fat mass and body fat percentage. The contribution of well-established and novel genetic variants for obesity traits and heritability values will be derived from whole-genome single-nucleotide polymorphism genotyping arrays. Civil status, age, sex, ethnicity, length of residence in Canada, religiosity, energy intake, physical activity, exercise motivation, electronic screen time, sleep patterns, history of assault, smoking status, alcohol consumption, medication and drug use, stress, impulsivity, body image perception, self-esteem, anxiety, eating disorders and depression will be investigated for their effect on obesity traits. The findings of the GENEiUS study will be used to help design obesity prevention programme in North American universities with multiethnic populations. ETHICS AND DISSEMINATION: Ethical approval of the study protocol has been obtained from the Hamilton Integrated Research Ethics Board. Study results will be disseminated through scientific publications, scholarly meetings, and collaborative meetings with university administration and student groups. PMID- 29229662 TI - Does Peppa Pig encourage inappropriate use of primary care resources? PMID- 29229663 TI - The science behind "man flu". PMID- 29229664 TI - Metabolic Vulnerabilities of Prostate Cancer: Diagnostic and Therapeutic Opportunities. AB - Cancer cells hijack metabolic pathways to support bioenergetics and biosynthetic requirements for their uncontrolled growth. Thus, cancer can be considered as a metabolic disease. In this review, we discuss the main metabolic features of prostate cancer with a particular focus on the link between oncogene-directed cancer metabolic regulation, metabolism rewiring, and epigenetic regulation. The potential of using metabolic profiling as a means to predict disease behavior and to identify novel therapeutic targets and new diagnostic markers will be addressed as well as the current challenges in metabolomics analyses. Finally, diagnostic and prognostic metabolic imaging approaches, including positron emission tomography, mass spectrometry, nuclear magnetic resonance, and their translational applications, will be discussed. Here, we emphasize how targeting metabolic vulnerabilities in prostate cancer may pave the way for novel personalized diagnostic and therapeutic interventions. PMID- 29229665 TI - Ras and the Plasma Membrane: A Complicated Relationship. AB - The primary site of Ras signal transduction is the plasma membrane (PM). On the PM, the ubiquitously expressed Ras isoforms, H-, N-, and K-Ras, spatially segregate to nonoverlapping nanometer-sized domains, called nanoclusters, with further lateral segregation into nonoverlapping guanosine triphosphate (GTP) bound and guanosine diphosphate (GDP)-bound nanoclusters. Effector binding and activation is restricted to GTP nanoclusters, rendering the underlying assembly mechanism essential to Ras signaling. Ras nanoclusters have distinct lipid compositions as a result of lipid-sorting specificity encoded in each Ras carboxy terminal membrane anchor. The role of the G-domain in regulating anchor-membrane interactions is becoming clearer. Ras G-domains undergo significant conformational orientation changes on guanine nucleotide switch, leading to differential direct contacts between the G-domain and reorganization of the membrane anchor. Ras G-domains also contain weak dimer interfaces, resulting in homodimerization, which is an obligate step of nanoclustering. Modulating the formation of Ras dimers, the lipid composition of the PM or lateral dynamics of key PM phospholipids represent novel mechanisms whereby the extent of Ras nanoclustering can be regulated to tune the gain in Ras signaling circuits. PMID- 29229666 TI - Prostate Cancer Disparities by Race and Ethnicity: From Nucleotide to Neighborhood. AB - Prostate cancer (CaP) incidence, morbidity, and mortality rates vary substantially by race and ethnicity, with African American men experiencing among the highest CaP rates in the world. The causes of these disparities are multifactorial and complex, and likely involve differences in access to screening and treatment, exposure to CaP risk factors, variation in genomic susceptibility, and other biological factors. To date, the proportion of CaP that can be explained by environmental exposures is small and differences in the role factors play by race or ethnicity is poorly understood. In the absence of additional data, it is likely that environmental factors do not contribute greatly to CaP disparities. In contrast, CaP has one of the highest heritabilities of all major cancers and many CaP susceptibility genes have been identified. Some CaP loci, including the risk loci found at chromosome 8q24, have consistent effects in all racial/ethnic groups studied to date. However, replication of many susceptibility loci across race or ethnicity remains limited. It is likely that inequities in health care access strongly influences CaP disparities. CaP is a disease with a complex multifactorial etiology, and therefore any approach attempting to address racial/ethnic disparities in CaP must consider the many sources that influence risk, outcomes, and disparities. PMID- 29229667 TI - Prostate Organogenesis. AB - The prostate is a male exocrine gland that secretes components of the seminal fluid. In men, prostate tumors are one of the most prevalent cancers. Studies on the development of the prostate have given a better understanding of the processes and genes that are important in the formation of this organ and have provided insights into the mechanisms of prostate tumorigenesis. These developmental studies have provided evidence that some of the genes and signaling pathways involved in development are reactivated or deregulated during prostate cancer. The prostate goes through a number of different stages during organogenesis, which include organ specification, epithelial budding, branching morphogenesis, canalization, and cytodifferentiation. During development, these processes are tightly regulated, many of which are controlled by the male hormone androgens. The majority of prostate tumors remain hormone regulated, and antiandrogen therapy is a first-line therapy, highlighting the important link between prostate organogenesis and cancer. In this review, we describe some of the data on genes that have important roles during prostate development that also have strong evidence linking them to prostate cancer. PMID- 29229668 TI - Multiple Myeloma and Bone: The Fatal Interaction. AB - Multiple myeloma (MM) is the second-most-common hematologic malignancy and the most frequent cancer to involve bone. MM bone disease (MMBD) has devastating consequences for patients, including dramatic bone loss, severe bone pain, and pathological fractures that markedly decrease the quality of life and impact survival of MM patients. MMBD results from excessive osteoclastic bone resorption and persistent suppressed osteoblastic bone formation, causing lytic lesions that do not heal, even when patients are in complete and prolonged remission. This review discusses the cellular and molecular mechanisms that regulate the uncoupling of bone remodeling in MM, the effects of MMBD on tumor growth, and potential therapeutic approaches that may prevent severe bone loss and repair damaged bone in MM patients. PMID- 29229670 TI - Kras and Tumor Immunity: Friend or Foe? AB - With the recent breakthroughs in immunotherapy as curative treatments in certain tumor types, there has been renewed interest in the relationship between immunity and tumor growth. Although we are gaining a greater understanding of the complex interplay of immune modulating components in the tumor microenvironment, the specific role that tumor cells play in shaping the immune milieu is still not well characterized. In this review, we focus on how mutant Kras tumor cells contribute to tumor immunity, with a specific focus on processes induced directly or indirectly by the oncogene. PMID- 29229669 TI - KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer. AB - RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in human cancer. With the highest RAS mutation frequencies seen with the top three causes of cancer deaths in the United States (lung, colorectal, and pancreatic cancer), the development of anti-RAS therapies is a major priority for cancer research. Despite more than three decades of intense effort, no effective RAS inhibitors have yet to reach the cancer patient. With bitter lessons learned from past failures and with new ideas and strategies, there is renewed hope that undruggable RAS may finally be conquered. With the KRAS isoform mutated in 84% of all RAS-mutant cancers, we focus on KRAS. With a near 100% KRAS mutation frequency, pancreatic ductal adenocarcinoma (PDAC) is considered the most RAS addicted of all cancers. We review the role of KRAS as a driver and therapeutic target in PDAC. PMID- 29229671 TI - H3S10ph broadly marks early-replicating domains in interphase ESCs and shows reciprocal antagonism with H3K9me2. AB - Phosphorylation of histone H3 at serine 10 (H3S10ph) by Aurora kinases plays an important role in mitosis; however, H3S10ph also marks regulatory regions of inducible genes in interphase mammalian cells, implicating mitosis-independent functions. Using the fluorescent ubiquitin-mediated cell cycle indicator (FUCCI), we found that 30% of the genome in interphase mouse embryonic stem cells (ESCs) is marked with H3S10ph. H3S10ph broadly demarcates gene-rich regions in G1 and is positively correlated with domains of early DNA replication timing (RT) but negatively correlated with H3K9me2 and lamin-associated domains (LADs). Consistent with mitosis-independent kinase activity, this pattern was preserved in ESCs treated with Hesperadin, a potent inhibitor of Aurora B/C kinases. Disruption of H3S10ph by expression of nonphosphorylatable H3.3S10A results in ectopic spreading of H3K9me2 into adjacent euchromatic regions, mimicking the phenotype observed in Drosophila JIL-1 kinase mutants. Conversely, interphase H3S10ph domains expand in Ehmt1 (also known as Glp) null ESCs, revealing that H3S10ph deposition is restricted by H3K9me2. Strikingly, spreading of H3S10ph at RT transition regions (TTRs) is accompanied by aberrant transcription initiation of genes co-oriented with the replication fork in Ehmt1-/- and Ehmt2-/- ESCs, indicating that establishment of repressive chromatin on the leading strand following DNA synthesis may depend upon these lysine methyltransferases. H3S10ph is also anti-correlated with H3K9me2 in interphase murine embryonic fibroblasts (MEFs) and is restricted to intragenic regions of actively transcribing genes by EHMT2. Taken together, these observations reveal that H3S10ph may play a general role in restricting the spreading of repressive chromatin in interphase mammalian cells. PMID- 29229673 TI - LncRNA GAS5 suppresses ovarian cancer by inducing inflammasome formation. AB - OBJECTIVE: Long non-coding RNA growth arrest-specific transcript 5 (lncRNA GAS5) is involved in various kinds of cancer. However, the role of lncGAS5 in the development of ovarian cancer remains unclear. In the current study, we explored the cellular mechanism and clinical value of lncRNA GAS5 in ovarian cancer. METHODS: Quantitative real-time PCR was used to detect mRNA level of LncRNA GAS5 in 20 ovarian cancer tissues. The effect of lncRNA GAS5 on cell proliferation was performed using CCK-8 assay. Cell apoptosis was evaluated by flow cytometry. Western blotting was used to detect the protein level of lncRNA GAS5 potential target. Standard sandwich ELISA was used to quantify the level of inflammatory cytokines. The cells with stable expression of lncRNA GAS5 were injected into nude mice to study the effect of lncRNA GAS5 on tumorigenesis in vivo. Results: The expression of lncRNA GAS5 was significantly decreased in ovarian cancer tissues. Decrease in lncRNA GAS5 expression resulted in increased cell proliferation and colony formation and reduced ovarian cancer cell apoptosis. In contrast, exogenous overexpression of lncRNA GAS5 in ovarian cancer cells inhibited proliferation, colony formation and apoptosis in ovarian cancer cells. In addition, the role of lncRNA GAS5 in ovarian cancer was associated with inflammasome formation and pyroptosis. CONCLUSION: These results suggested that lncRNA GAS5 acts as tumor suppressor and could be used as a potential treatment target for diagnosis and therapy of ovarian cancer. PMID- 29229672 TI - Detecting differential copy number variation between groups of samples. AB - We present a method to detect copy number variants (CNVs) that are differentially present between two groups of sequenced samples. We use a finite-state transducer where the emitted read depth is conditioned on the mappability and GC-content of all reads that occur at a given base position. In this model, the read depth within a region is a mixture of binomials, which in simulations matches the read depth more closely than the often-used negative binomial distribution. The method analyzes all samples simultaneously, preserving uncertainty as to the breakpoints and magnitude of CNVs present in an individual when it identifies CNVs differentially present between the two groups. We apply this method to identify CNVs that are recurrently associated with postglacial adaptation of marine threespine stickleback (Gasterosteus aculeatus) to freshwater. We identify 6664 regions of the stickleback genome, totaling 1.7 Mbp, which show consistent copy number differences between marine and freshwater populations. These deletions and duplications affect both protein-coding genes and cis-regulatory elements, including a noncoding intronic telencephalon enhancer of DCHS1 The functions of the genes near or included within the 6664 CNVs are enriched for immunity and muscle development, as well as head and limb morphology. Although freshwater stickleback have repeatedly evolved from marine populations, we show that freshwater stickleback also act as reservoirs for ancient ancestral sequences that are highly conserved among distantly related teleosts, but largely missing from marine stickleback due to recent selective sweeps in marine populations. PMID- 29229674 TI - Efficacy and safety of linezolid compared with other treatments for skin and soft tissue infections: a meta-analysis. AB - Linezolid with other treatments for skin and soft tissue infections (SSTIs) has been evaluated in several studies. However, the conclusions remain controversial. By searching PubMed, EMBASE, and Cochrane library databases, we conducted a meta analysis to evaluate linezolid and other treatments for skin and soft tissue infections. The study was summarized, and the risk ratio (RR) and its 95% confidence interval (CI) were calculated. Eleven related articles were included in the meta-analysis. Our results revealed that linezolid was associated with a significantly better clinical (RR = 1.09, 95% CI: 1.02-1.16, Pheterogeneity = 0.326, I2 = 13.0%) and microbiological cure rates (RR = 1.08, 95% CI: 1.01-1.16, Pheterogeneity = 0.089, I2 = 41.7%) when comparing with vancomycin. There was no significant difference in the incidence of anemia, nausea, and mortality; however, the incidence of vomiting, diarrhea, and thrombocytopenia in patients treated with linezolid is significantly higher than that with other treatments. Our study confirmed that linezolid seems to be more effective than vancomycin for treating people with SSTIs. It is recommended that linezolid be monitored for thrombocytopenia, vomiting, and diarrhea. Further studies with larger dataset and well-designed models are required to validate our findings. PMID- 29229676 TI - Teleost-Specific TLR19 Localizes to Endosome, Recognizes dsRNA, Recruits TRIF, Triggers both IFN and NF-kappaB Pathways, and Protects Cells from Grass Carp Reovirus Infection. AB - TLRs are pivotal pattern recognition receptors in initiating innate immunity and triggering adaptive immunity. TLR pathways have been comprehensively investigated in mammals. However, the teleost-specific TLR19 pathway remains largely unknown. In this study, we identified TLR19 from grass carp (Ctenopharyngodon idella), and explored the ligand, adaptor, and signaling pathways. Pathogen-associated molecular pattern binding and luciferase activity assays indicate that TLR19 recognizes and responds to dsRNA analog (polyinosinic:polycytidylic acid). Confocal fluorescence microscopy demonstrates that TLR19 is synthesized in ribosomes not binding on endoplasmic reticulum, then transfers to early endosome post-polyinosinic:polycytidylic acid stimulation. Fluorescence colocalization and immunoprecipitation experiments confirm TLR19 interacts with adaptor TRIF, not MyD88, TIRAP, or SARM1. TLR19 facilitates protein and phosphorylation levels of IRF3, inhibits phosphorylation of IRF7. TLR19 enhances the promoter activities and mRNA expressions of major IFNs and NF-kappaBs; in contrast, grass carp TLR3 just significantly motivates IFN1 expression post-grass carp reovirus (GCRV) infection. Further investigations reveal that TLR19 inhibits GCRV replication by overexpression, knockdown, Western blotting techniques and virus titer assays, and protects cells from GCRV infection by flow cytometry and MTT method. Collectively, these results demonstrate that teleost-specific TLR19 recognizes dsRNA, recruits adaptor molecule TRIF, enhances IRF3 protein and phosphorylation levels, triggers both IFN and NF-kappaB pathways, and prevents viral proliferation. This is the first attempt to systematically clarify the TLR19 signaling pathway, which is the third TLR member recognizing dsRNA. The results will serve the antiviral immune mechanisms in teleost and evolutionary immunology. PMID- 29229675 TI - Evaluation of METase-pemetrexed-loaded PEG-PLGA nanoparticles modified with anti CD133-scFV for treatment of gastric carcinoma. AB - PEG-PLGA nanoparticles (NPs) modified with anti-CD133 and tumor-targeting single chain antibody fragment (scFV-NPs) for systemic delivery of methioninase (METase) and pemetrexed for gastric carcinoma were successfully formulated. The structure characterization and biological functions of METase-pemetrexed-loaded scFV-PEG PLGA NPs (scFV-METase/pemetrexed-NPs) in vitro were investigated. Functional scFV PEG-PLGA NPs or PEG-PLGA NPs present low cell cytoxicity in CD133+ SGC7901 cells. scFV-METase/pemetrexed-NPs (scFv-M/P-NP) was more effective in inhibiting tumor growth (including cell growth and migration ability) in CD133 positive expressed gastric cancer cells than METase/pemetrexed-NPs (M/P-NP). Moreover, METase enhanced the inhibitory effect of pemetrexed on thymidylate synthase (TS) synthesis and cell apoptosis. We have demonstrated the application of scFV targeted PEG-PLGA NPs as a new potential strategy to enhance treatment benefits for gastric carcinoma. PMID- 29229677 TI - Apoptotic Cancer Cells Suppress 5-Lipoxygenase in Tumor-Associated Macrophages. AB - The enzyme 5-lipoxygenase (5-LO) is key in the synthesis of leukotrienes, which are potent proinflammatory lipid mediators involved in chronic inflammatory diseases including cancer. 5-LO is expressed in immune cells but also found in cancer cells. Although the role of 5-LO in tumor cells is beginning to emerge, with the notion that tumor-promoting functions are attributed to its products, the function of 5-LO in the tumor microenvironment remains unclear. To understand the role of 5-LO and its products in the tumor microenvironment, we analyzed its expression and function in tumor-associated macrophages (TAMs). TAMs were generated by coculturing primary human macrophages (MPhi) with human MCF-7 breast carcinoma cells, which caused cell death of cancer cells followed by phagocytosis of cell debris by MPhi. Expression and activity of 5-LO in TAMs were reduced upon coculture with cancer cells. Downregulation of 5-LO in TAMs required tumor cell death and the direct contact between MPhi and dying cancer cells via Mer tyrosine kinase. Subsequently, upregulation of proto-oncogene c-Myb in TAMs induced a stable transcriptional repression of 5-LO. Reduced 5-LO expression in TAMs was mechanistically coupled to an attenuated T cell recruitment. In primary TAMs from human and murine breast tumors, 5-LO expression was absent or low when compared with monocyte-derived MPhi. Our data reveal that 5-LO, which is required for leukotriene production and subsequent T cell recruitment, is downregulated in TAMs through Mer tyrosine kinase-dependent recognition of apoptotic cancer cells. Mechanistically, we noticed transcriptional repression of 5-LO by proto-oncogene c-Myb and conclude that loss of stromal 5-LO expression favors tumor progression. PMID- 29229680 TI - Prenatal Paternal Selective Serotonin Reuptake Inhibitors Use and Risk of ADHD in Offspring. AB - OBJECTIVES: It has been shown that maternal prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) may be a risk factor for attention deficit/hyperactivity disorder (ADHD) in offspring. Our goal was to examine whether paternal SSRI use before conception increases the risk of ADHD in offspring. METHODS: On the basis of Danish national registers, we conducted a cohort study of 781 470 singletons born between 1996 and 2008 with follow-up throughout 2013. The children whose fathers used SSRIs during the last 3 months before conception were identified as the exposed. Cox regression was used to estimate the hazard ratio (HR) of ADHD. RESULTS: A total of 7216 children (0.92%) were born to fathers who had used SSRIs during the last 3 months before conception. There were 12 520 children diagnosed with ADHD. Compared with unexposed children, the exposed had a 26% increased risk of ADHD (HR = 1.26, 95% confidence interval [CI]: 1.06-1.51) after adjusting for potential confounders. When extending the exposure window to 1 year before conception, paternal use of SSRIs only during the period of 12 to 3 months before conception was associated with the HR of 1.35 (95% CI: 1.10-1.66), whereas paternal use of SSRIs only during the last 3 months before conception was associated with a similarly increased risk of ADHD (adjusted HR = 1.31, 95% CI: 0.95-1.82). CONCLUSIONS: The mildly increased risk of ADHD in offspring associated with paternal SSRI use before conception could probably be due to the underlying indications related to SSRI use. PMID- 29229681 TI - Toward Better Understanding of How Fathers Contribute to Their Offspring's Health. PMID- 29229679 TI - Epigenetic and Posttranscriptional Regulation of CD16 Expression during Human NK Cell Development. AB - The surface receptor FcgammaRIIIA (CD16a) is encoded by the FCGR3A gene and is acquired by human NK cells during maturation. NK cells bind the Fc portion of IgG via CD16a and execute Ab-dependent cell-mediated cytotoxicity, which is critical for the effectiveness of several antitumor mAb therapies. The role of epigenetic regulatory mechanisms controlling transcriptional and posttranscriptional CD16 expression in NK cells is unknown. In this study, we compared specific patterns of DNA methylation and expression of FCGR3A with FCGR3B, which differ in cell type-specific expression despite displaying nearly identical genomic sequences. We identified a sequence within the FCGR3A promoter that selectively exhibits reduced methylation in CD16a+ NK cells versus CD16a- NK cells and neutrophils. This region contained the transcriptional start site of the most highly expressed CD16a isoform in NK cells. Luciferase assays revealed remarkable cell-type specificity and methylation-dependent activity of FCGR3A- versus FCGR3B-derived sequences. Genomic differences between FCGR3A and FCGR3B are enriched at CpG dinucleotides, and mutation of variant CpGs reversed cell-type specificity. We further identified miR-218 as a posttranscriptional negative regulator of CD16a in NK cells. Forced overexpression of miR-218 in NK cells knocked down CD16a mRNA and protein expression. Moreover, miR-218 was highly expressed in CD16a- NK cells compared with CD16a+ NK cells. Taken together, we propose a system of FCGR3A regulation in human NK cells in which CpG dinucleotide sequences and concurrent DNA methylation confer developmental and cell type-specific transcriptional regulation, whereas miR-218 provides an additional layer of posttranscriptional regulation during the maturation process. PMID- 29229682 TI - Pediatric Injuries Related to Window Blinds, Shades, and Cords. AB - OBJECTIVES: To provide an epidemiologic description of fatal and nonfatal window blind-related injuries among US children younger than 6 years of age. METHODS: Data from the Consumer Product Safety Commission's National Electronic Injury Surveillance System and In-Depth Investigation (IDI) databases were retrospectively analyzed. RESULTS: From 1990 to 2015, there were an estimated 16 827 (95% confidence interval: 13 732-19 922) window blind-related injuries among children younger than 6 years of age treated in emergency departments in the United States, corresponding to an injury rate of 2.7 per 100 000 children. The most common mechanism of injury was "struck by" (48.8%). Entanglement injuries accounted for 11.9% of all cases, and among this subgroup, 98.9% involved blind cords, and 80.7% were to the neck. Overall, most injuries (93.4%) were treated and released. In IDI reports for 1996 through 2012, we identified 231 window blind cord entanglement incidents among children <6 years of age, and 98.7% involved the child's neck; entanglements with the window blind's operating cords (76.4%) or inner cords (22.1%) were the most common. Two-thirds of entanglement incidents included in the IDI database resulted in death (67.1%). CONCLUSIONS: Despite existing voluntary safety standards for window blinds, these products continue to pose an injury risk to young children. Although many of the injuries in this study were nonfatal and resulted in minor injuries, cases involving window blind cord entanglements frequently resulted in hospitalization or death. A mandatory safety standard that eliminates accessible window blind cords should be adopted. PMID- 29229678 TI - Epitope Mapping of SERCA2a Identifies an Antigenic Determinant That Induces Mainly Atrial Myocarditis in A/J Mice. AB - Sarcoplasmic/endoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA)2a, a critical regulator of calcium homeostasis, is known to be decreased in heart failure. Patients with myocarditis or dilated cardiomyopathy develop autoantibodies to SERCA2a suggesting that they may have pathogenetic significance. In this report, we describe epitope mapping analysis of SERCA2a in A/J mice that leads us to make five observations: 1) SERCA2a contains multiple T cell epitopes that induce varying degrees of myocarditis. One epitope, SERCA2a 971-990, induces widespread atrial inflammation without affecting noncardiac tissues; the cardiac abnormalities could be noninvasively captured by echocardiography, electrocardiography, and magnetic resonance microscopy imaging. 2) SERCA2a 971-990-induced disease was associated with the induction of CD4 T cell responses and the epitope preferentially binds MHC class II/IAk rather than IEk By creating IAk/and IEk/SERCA2a 971-990 dextramers, the T cell responses were determined by flow cytometry to be Ag specific. 3) SERCA2a 971-990-sensitized T cells produce both Th1 and Th17 cytokines. 4) Animals immunized with SERCA2a 971 990 showed Ag-specific Abs with enhanced production of IgG2a and IgG2b isotypes, suggesting that SERCA2a 971-990 can potentially act as a common epitope for both T cells and B cells. 5) Finally, SERCA2a 971-990-sensitized T cells were able to transfer disease to naive recipients. Together, these data indicate that SERCA2a is a critical autoantigen in the mediation of atrial inflammation in mice and that our model may be helpful to study the inflammatory events that underlie the development of conditions such as atrial fibrillation in humans. PMID- 29229683 TI - Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue-engineered constructs via activating CXCR2-Src-PKL/Vav2-Rac1. AB - Tissue-engineered constructs (TECs) hold great promise for treating large bone defects. Incorporated mesenchymal stem cells (MSCs) can facilitate the vascularization of TECs. Nevertheless, the underlying mechanism remains ambiguous. Here we analyzed the roles of C-X-C chemokine receptor 2 (CXCR2) and its downstream signal pathways in MSC-induced endothelial progenitor cell (EPC) migration. Transwell assays and immunofluorescence staining were performed for cell migration analysis in vitro and in vivo, respectively. A series of signal inhibitors and short hairpin RNA was used for screening essential signaling molecules. We found that blockade of CXCR2 abolished the migration of EPCs toward MSCs as well as subsequent vascularization and bone repair in TECs. Moreover, screening results suggested that steroid receptor coactivator (Src) acted as a predominant downstream effector of CXCR2. Further molecular biologic and histomorphological experiments revealed that the action of Src required the phosphorylation of ras-related C3 botulinum toxin substrate 1 (Rac1), which was pivotal for the development of lamellipodia and filopodia. The phosphorylation and colocalization of paxillin kinase linker (PKL) and vav guanine nucleotide exchange factor 2 (Vav2) were essential for the activation of Rac1. Therefore, we demonstrated that MSCs promoted EPC migration via activating CXCR2 and its downstream Src-PKL/Vav2-Rac1 signaling pathway. These findings unveiled the molecular mechanism in the vascularization of TECs and were expected to provide novel targets for efficacy improvement.-Li, Z., Yang, A., Yin, X., Dong, S., Luo, F., Dou, C., Lan, X., Xie, Z., Hou, T., Xu, J., Xing, J. Mesenchymal stem cells promote endothelial progenitor cell migration, vascularization, and bone repair in tissue-engineered constructs via activating CXCR2-Src-PKL/Vav2-Rac1. PMID- 29229684 TI - C-peptide prevents NF-kappaB from recruiting p300 and binding to the inos promoter in diabetic nephropathy. AB - C-peptide (CP) has demonstrated unique beneficial effects in diabetic nephropathy (DN), but whether and how CP regulates NF-kappaB and its coactivator, p300, to suppress inducible iNOS and antagonize DN are unknown. iNOS expression, NF-kappaB nuclear translocation, colocalization and binding of NF-kappaB to p300, binding of NF-kappaB to the inos promoter, and the bound NF-kappaB, p300, and histone 3 lysine 9 acetylation (H3K9ac) at binding sites were measured in high glucose stimulated mesangial cells. We evaluated pathologic changes, iNOS expression, NF kappaB, and p300 contents in diabetic rats. We found that CP inhibited iNOS expression and notably prevented colocalization and binding of NF-kappaB and p300. CP prevented NF-kappaB from binding to the inos promoter, especially at the distal site, and reduced bound NF-kappaB, p300, and H3K9ac. N-terminal plus middle fragment could mostly mimic the antagonizing effects of CP against the pathologic changes of DN and equally suppresses renal iNOS expression as CP. In conclusion, CP prevented NF-kappaB from recruiting p300 and binding to the inos promoter, and decreased H3K9ac at the binding sites to suppress iNOS expression and antagonize DN, with the effect region identified as N-terminal plus middle fragment.-Li, Y., Li, X., He, K., Li, B., Liu, K., Qi, J., Wang, H., Wang, Y., Luo, W. C-peptide prevents NF-kappaB from recruiting p300 and binding to the inos promoter in diabetic nephropathy. PMID- 29229685 TI - The essential role of phospho-T38 CPI-17 in the maintenance of physiological blood pressure using genetically modified mice. AB - PKC-potentiated phosphorylation-dependent inhibitory protein of protein phosphatase 1 (CPI-17), an endogenous myosin phosphatase inhibitory protein, is considered a key molecule for Ca2+ sensitization of the contractile apparatus. Here, we have used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 to generate CPI-17-deficient [knockout (KO)] and threonine 38 (T38)-phospho-resistant mice [threonine mutant into alanine (TA)], and then effects of CPI-17 on vascular contractility in vitro and mean blood pressure (MBP) in vivo were investigated. In isolated thoracic aorta, phorbol 12, 13-dibutyrate induced a sustained contraction of wild-type (WT) mice, whereas no contraction showed from TA or KO mice. A high concentration of KCl solution-induced contraction was not different between transgenic and WT mice. In contrast, phenylephrine (PE)-induced contractions in both mutant strains were significantly smaller than those of WT mice in association with a low level of myosin phosphorylation, suggesting that at least part of PE-induced contraction is regulated by phosphorylation of CPI-17 at T38. Finally, the physiologic role of CPI-17 in the regulation of blood pressure was investigated using radio telemetry. MBP was decreased significantly in both transgenic mice, even with a compensatory increase in heart rate. In summary, we generated KO and constitutively phospho-resistant mouse models of CPI-17 for the first time. p-CPI 17 at T38, possibly by PKC, could be important to maintain vascular contractility and blood pressure in vivo. -Yang, Q., Fujii, W., Kaji, N., Kakuta, S., Kada, K., Kuwahara, M., Tsubone, H., Ozaki, H., Hori, M. The essential role of phospho-T38 CPI-17 in the maintenance of physiological blood pressure using genetically modified mice. PMID- 29229687 TI - Letter re: Hospital safety among neurologic patients: A population-based cohort study of adverse events. PMID- 29229686 TI - Editors' Note. PMID- 29229688 TI - Letter re: Hospital safety among neurologic patients: A population-based cohort study of adverse events. PMID- 29229689 TI - Author response: Hospital safety among neurologic patients: A population-based cohort study of adverse events. PMID- 29229690 TI - Clinical Reasoning: Monocular vision loss, ophthalmoplegia, and strokes in a 61 year-old man with diabetes mellitus. PMID- 29229691 TI - Opinion and Special Articles: Neurology education at US osteopathic medical schools. AB - Osteopathic medical schools have a longstanding tradition of training primary care physicians (PCP). Neurologic symptoms are common in the PCP's office and there is an undersupply of neurologists in the United States. It is therefore crucial for osteopathic medical students to have a strong foundation in clinical neurology. Despite the importance, a mere 6% of osteopathic medical schools have required neurology clerkships. Furthermore, exposure to neurology in medical school through required clerkships has been correlated with matching into neurology residency. As osteopathic medical schools continue to expand, it will become increasingly important to emphasize the American Academy Neurology's published guidelines for a core clerkship curriculum. Practicing neurologists should take an active role in encouraging osteopathic medical schools to adopt these guidelines. PMID- 29229692 TI - Residency Training: The need for an integrated diversity curriculum for neurology residency. AB - BACKGROUND: Providing culturally responsive care to an increasingly multicultural population is essential and requires formal cultural humility training for residents. We sought to understand the current prevalence and need for this type of training within neurology programs and to pilot an integrated curriculum locally. NEEDS ASSESSMENT: We surveyed via email all program directors of academic neurology programs nationally regarding the prevalence of and need for formal cultural responsiveness training. Forty-seven program directors (36%) responded to the survey. The majority of respondents did not have a formalized diversity curriculum in their program (65%), but most (85%) believed that training in cultural responsiveness was important. PROGRAM DESCRIPTION: We developed locally an integrated diversity curriculum as a proof of concept. The curriculum covered topics of diversity in language, religion, sexual orientation, gender identity/expression, and socioeconomic status designed to focus on the needs of the local community. Program evaluation included a pre and post survey of the learner attitudes toward cultural diversity. FUTURE DIRECTIONS: There is an unmet need for cultural responsiveness training within neurology residencies, and integrating this curriculum is both feasible and efficacious. When adapted to address cultural issues of the local community, this curriculum can be generalizable to both academic and community organizations. PMID- 29229693 TI - Teaching NeuroImages: A protruding asymmetrical belly. PMID- 29229694 TI - Teaching Video NeuroImages: Trigeminal neuralgia due to compression by the superior cerebellar artery. PMID- 29229695 TI - Finite Element Modeling of Shape Changes in Plant Cells. PMID- 29229696 TI - The SlCBL10 Calcineurin B-Like Protein Ensures Plant Growth under Salt Stress by Regulating Na+ and Ca2+ Homeostasis. AB - Characterization of a new tomato (Solanum lycopersicum) T-DNA mutant allowed for the isolation of the CALCINEURIN B-LIKE PROTEIN 10 (SlCBL10) gene whose lack of function was responsible for the severe alterations observed in the shoot apex and reproductive organs under salinity conditions. Physiological studies proved that SlCBL10 gene is required to maintain a proper low Na+/Ca2+ ratio in growing tissues allowing tomato growth under salt stress. Expression analysis of the main responsible genes for Na+ compartmentalization (i.e. Na+/H+ EXCHANGERs, SALT OVERLY SENSITIVE, HIGH-AFFINITY K+ TRANSPORTER 1;2, H+-pyrophosphatase AVP1 [SlAVP1] and V-ATPase [SlVHA-A1]) supported a reduced capacity to accumulate Na+ in Slcbl10 mutant leaves, which resulted in a lower uploading of Na+ from xylem, allowing the toxic ion to reach apex and flowers. Likewise, the tomato CATION EXCHANGER 1 and TWO-PORE CHANNEL 1 (SlTPC1), key genes for Ca2+ fluxes to the vacuole, showed abnormal expression in Slcbl10 plants indicating an impaired Ca2+ release from vacuole. Additionally, complementation assay revealed that SlCBL10 is a true ortholog of the Arabidopsis (Arabidopsis thaliana) CBL10 gene, supporting that the essential function of CBL10 is conserved in Arabidopsis and tomato. Together, the findings obtained in this study provide new insights into the function of SlCBL10 in salt stress tolerance. Thus, it is proposed that SlCBL10 mediates salt tolerance by regulating Na+ and Ca2+ fluxes in the vacuole, cooperating with the vacuolar cation channel SlTPC1 and the two vacuolar H+ pumps, SlAVP1 and SlVHA-A1, which in turn are revealed as potential targets of SlCBL10. PMID- 29229697 TI - Temporal Proteomics of Inducible RNAi Lines of Clp Protease Subunits Identifies Putative Protease Substrates. AB - The Clp protease in the chloroplasts of plant cells is a large complex composed of at least 13 nucleus-encoded subunits and one plastid-encoded subunit, which are arranged in several ring-like structures. The proteolytic P-ring and the structurally similar R-ring form the core complex that contains the proteolytic chamber. Chaperones of the HSP100 family help with substrate unfolding, and additional accessory proteins are believed to assist with Clp complex assembly and/or to promote complex stability. Although the structure and function of the Clp protease have been studied in great detail in both bacteria and chloroplasts, the identification of bona fide protease substrates has been very challenging. Knockout mutants of genes for protease subunits are of limited value, due to their often pleiotropic phenotypes and the difficulties with distinguishing primary effects (i.e. overaccumulation of proteins that represent genuine protease substrates) from secondary effects (proteins overaccumulating for other reasons). Here, we have developed a new strategy for the identification of candidate substrates of plant proteases. By combining ethanol-inducible knockdown of protease subunits with time-resolved analysis of changes in the proteome, proteins that respond immediately to reduced protease activity can be identified. In this way, secondary effects are minimized and putative protease substrates can be identified. We have applied this strategy to the Clp protease complex of tobacco (Nicotiana tabacum) and identified a set of chloroplast proteins that are likely degraded by Clp. These include several metabolic enzymes but also a small number of proteins involved in photosynthesis. PMID- 29229698 TI - Laccase GhLac1 Modulates Broad-Spectrum Biotic Stress Tolerance via Manipulating Phenylpropanoid Pathway and Jasmonic Acid Synthesis. AB - Plants are constantly challenged by a multitude of pathogens and pests, which causes massive yield and quality losses annually. A promising approach to reduce such losses is to enhance the immune system of plants through genetic engineering. Previous work has shown that laccases (p-diphenol:dioxygen oxidoreductase, EC 1.10.3.2) function as lignin polymerization enzymes. Here we demonstrate that transgenic manipulation of the expression of the laccase gene GhLac1 in cotton (Gossypium hirsutum) can confer an enhanced defense response to both pathogens and pests. Overexpression of GhLac1 leads to increased lignification, associated with increased tolerance to the fungal pathogen Verticillium dahliae and to the insect pests cotton bollworm (Helicoverpa armigera) and cotton aphid (Aphis gosypii). Suppression of GhLac1 expression leads to a redirection of metabolic flux in the phenylpropanoid pathway, causing the accumulation of JA and secondary metabolites that confer resistance to V. dahliae and cotton bollworm; it also leads to increased susceptibility to cotton aphid. Plant laccases therefore provide a new molecular tool to engineer pest and pathogen resistance in crops. PMID- 29229699 TI - The Nitrogen Regulatory PII Protein (GlnB) and N-Acetylglucosamine 6-Phosphate Epimerase (NanE) Allosterically Activate Glucosamine 6-Phosphate Deaminase (NagB) in Escherichia coli. AB - Amino sugars are good sources of both ammonia and fructose-6-phosphate, produced by the glucosamine 6-phosphate deaminase, NagB. NagB is known to be allosterically regulated by N-acetylglucosamine 6-phosphate (GlcNAc-6P) and the phosphocarrier protein of the bacterial phosphotransferase system, HPr, in Escherichia coli We provide evidence that NanE, GlcNAc-6P epimerase, and the uridylylated PII protein (U-PII) also allosterically activate NagB by direct protein-protein interactions. NanE is essential for neuraminic acid (NANA) and N acetylmannosamine (ManNAc) utilization, and PII is known to be a central metabolic nitrogen regulator. We demonstrate that uridylylated PII (but not underivatized PII) activates NagB >10-fold at low concentrations of substrate, whereas NanE increases NagB activity >2-fold. NanE activates NagB in the absence or presence of GlcNAc-6P, but HPr and U-PII activation requires the presence of GlcNAc-6P. Activation of NagB by HPr and uridylylated PII, as well as by NanE and HPr (but not by NanE and U-PII), is synergistic, and the modeling, which suggests specific residues involved in complex formation, provides possible explanations. Specific physiological functions for the regulation of NagB by its three protein activators are proposed. Each regulatory agent is suggested to mediate signal transduction in response to a different stimulus.IMPORTANCE The regulation of amino sugar utilization is important for the survival of bacteria in a competitive environment. NagB, a glucosamine 6-phosphate deaminase in Escherichia coli, is essential for amino sugar utilization and is known to be allosterically regulated by N-acetylglucosamine 6-phosphate (GlcNAc-6P) and the histidine phosphorylatable phosphocarrier protein, HPr. We provide evidence here that NanE, GlcNAc-6P epimerase, and the uridylylated PII protein allosterically activate NagB by direct protein-protein interactions. NanE is essential for N acetylneuraminic acid (NANA) and N-acetylmannosamine (ManNAc) utilization, and the PII protein is known to be a central metabolic nitrogen regulator. Regulatory links between carbon and nitrogen metabolism are important for adaptation of metabolism to different growth conditions. PMID- 29229700 TI - Flexible Hinges in Bacterial Chemoreceptors. AB - Transmembrane bacterial chemoreceptors are extended, rod-shaped homodimers with ligand-binding sites at one end and interaction sites for signaling complex formation and histidine kinase control at the other. There are atomic-resolution structures of chemoreceptor fragments but not of intact, membrane-inserted receptors. Electron tomography of in vivo signaling complex arrays lack distinct densities for chemoreceptor rods away from the well-ordered base plate region, implying structural heterogeneity. We used negative staining, transmission electron microscopy, and image analysis to characterize the molecular shapes of intact homodimers of the Escherichia coli aspartate receptor Tar rendered functional by insertion into nanodisc-provided E. coli lipid bilayers. Single particle analysis plus tomography of particles in a three-dimensional matrix revealed two bend loci in the chemoreceptor cytoplasmic domain, (i) a short, two strand gap between the membrane-proximal, four-helix-bundle HAMP (histidine kinases, adenylyl cyclases, methyl-accepting chemoreceptors, and phosphatases) domain and the membrane-distal, four-helix coiled coil and (ii) aligned glycines in the extended, four-helix coiled coil, the position of a bend noted in the previous X-ray structure of a receptor fragment. Our images showed HAMP bends from 0 degrees to ~13 degrees and glycine bends from 0 degrees to ~20 degrees , suggesting that the loci are flexible hinges. Variable hinge bending explains indistinct densities for receptor rods outside the base plate region in subvolume averages of chemotaxis arrays. Bending at flexible hinges was not correlated with the chemoreceptor signaling state. However, our analyses showed that chemoreceptor bending avoided what would otherwise be steric clashes between neighboring receptors that would block the formation of core signaling complexes and chemoreceptor arrays.IMPORTANCE This work provides new information about the shape of transmembrane bacterial chemoreceptors, crucial components in the molecular machinery of bacterial chemotaxis. We found that intact, lipid-bilayer inserted, and thus functional homodimers of the Escherichia coli chemoreceptor Tar exhibited bends at two flexible hinges along their ~200-A, rod-like, cytoplasmic domains. One hinge was at the short, two-strand gap between the membrane-proximal, four-helix-bundle HAMP (histidine kinases, adenylyl cyclases, methyl-accepting chemoreceptors, and phosphatases) domain and the membrane distal, four-helix coiled coil. The other hinge was at aligned glycines in the extended, four-helix coiled coil, where a bend had been identified in the X-ray structure of a chemoreceptor fragment. Our analyses showed that flexible hinge bending avoided structural clashes in chemotaxis core complexes and their arrays. PMID- 29229701 TI - CodY-Mediated c-di-GMP-Dependent Inhibition of Mammalian Cell Invasion in Listeria monocytogenes. AB - Elevated levels of the second messenger c-di-GMP suppress virulence in diverse pathogenic bacteria, yet mechanisms are poorly characterized. In the foodborne pathogen Listeria monocytogenes, high c-di-GMP levels inhibit mammalian cell invasion. Here, we show that invasion is impaired because of the decreased expression levels of internalin genes whose products are involved in invasion. We further show that at high c-di-GMP levels, the expression of the entire virulence regulon is suppressed, and so is the expression of the prfA gene encoding the master activator of the virulence regulon. Analysis of mechanisms controlling prfA expression pointed to the transcription factor CodY as a c-di-GMP-sensitive component. In high-c-di-GMP strains, codY gene expression is decreased, apparently due to the lower activity of CodY, which functions as an activator of codY transcription. We found that listerial CodY does not bind c-di-GMP in vitro and therefore investigated whether c-di-GMP levels affect two known cofactors of listerial CodY, branched-chain amino acids and GTP. Our manipulation of branched chain amino acid levels did not perturb the c-di-GMP effect; however, our replacement of listerial CodY with the streptococcal CodY homolog, whose activity is GTP independent, abolished the c-di-GMP effect. The results of this study suggest that elevated c-di-GMP levels decrease the activity of the coordinator of metabolism and virulence, CodY, possibly via lower GTP levels, and that decreased CodY activity suppresses L. monocytogenes virulence by the decreased expression of the PrfA virulence regulon.IMPORTANCEListeria monocytogenes is a pathogen causing listeriosis, a disease responsible for the highest mortality rate among foodborne diseases. Understanding how the virulence of this pathogen is regulated is important for developing treatments to decrease the frequency of listerial infections in susceptible populations. In this study, we describe the mechanism through which elevated levels of the second messenger c-di-GMP inhibit listerial invasion in mammalian cells. Inhibition is caused by the decreased activity of the transcription factor CodY that coordinates metabolism and virulence. PMID- 29229702 TI - Galactosylation of the Secondary Cell Wall Polysaccharide of Bacillus anthracis and Its Contribution to Anthrax Pathogenesis. AB - Bacillus anthracis, the causative agent of anthrax disease, elaborates a secondary cell wall polysaccharide (SCWP) that is essential for bacterial growth and cell division. B. anthracis SCWP is comprised of trisaccharide repeats with the structure, [->4)-beta-ManNAc-(1->4)-beta-GlcNAc(O3-alpha-Gal)-(1->6)-alpha GlcNAc(O3-alpha-Gal, O4-beta-Gal)-(1->]6-12 The genes whose products promote the galactosylation of B. anthracis SCWP are not yet known. We show here that the expression of galE1, encoding a UDP-glucose 4-epimerase necessary for the synthesis of UDP-galactose, is required for B. anthracis SCWP galactosylation. The galE1 mutant assembles surface (S) layer and S layer-associated proteins that associate with ketal-pyruvylated SCWP via their S layer homology domains similarly to wild-type B. anthracis, but the mutant displays a defect in gamma phage murein hydrolase binding to SCWP. Furthermore, deletion of galE1 diminishes the capsulation of B. anthracis with poly-d-gamma-glutamic acid (PDGA) and causes a reduction in bacterial virulence. These data suggest that SCWP galactosylation is required for the physiologic assembly of the B. anthracis cell wall envelope and for the pathogenesis of anthrax disease.IMPORTANCE Unlike virulent Bacillus anthracis isolates, B. anthracis strain CDC684 synthesizes secondary cell wall polysaccharide (SCWP) trisaccharide repeats without galactosyl modification, exhibits diminished growth in vitro in broth cultures, and is severely attenuated in an animal model of anthrax. To examine whether SCWP galactosylation is a requirement for anthrax disease, we generated variants of B. anthracis strains Sterne 34F2 and Ames lacking UDP-glucose 4-epimerase by mutating the genes galE1 and galE2 We identified galE1 as necessary for SCWP galactosylation. Deletion of galE1 decreased the poly-d-gamma-glutamic acid (PDGA) capsulation of the vegetative form of B. anthracis and increased the bacterial inoculum required to produce lethal disease in mice, indicating that SCWP galactosylation is indeed a determinant of anthrax disease. PMID- 29229703 TI - Orai1 Plays a Crucial Role in Central Sensitization by Modulating Neuronal Excitability. AB - Pathological pain is a common and debilitating condition that is often poorly managed. Central sensitization is an important mechanism underlying pathological pain. However, candidate molecules involved in central sensitization remain unclear. Store-operated calcium channels (SOCs) mediate important calcium signals in nonexcitable and excitable cells. SOCs have been implicated in a wide variety of human pathophysiological conditions, including immunodeficiency, occlusive vascular diseases, and cancer. However, the role of SOCs in CNS disorders has been relatively unexplored. Orai1, a key component of SOCs, is expressed in the human and rodent spinal cord dorsal horn, but its functional significance in dorsal horn neurons is poorly understood. Here we sought to explore a potential role of Orai1 in the modulation of neuronal excitability and A-type potassium channels involved in pain plasticity. Using both male and female Orai1 knock-out mice, we found that activation of Orai1 increased neuronal excitability and reduced A-type potassium channels via the protein kinase C-extracellular signal regulated protein kinase (PKC-ERK) pathway in dorsal horn neurons. Orai1 deficiency significantly decreased acute pain induced by noxious stimuli, nearly eliminated the second phase of formalin-induced nociceptive response, markedly attenuated carrageenan-induced ipsilateral pain hypersensitivity and abolished carrageenan-induced contralateral mechanical allodynia. Consistently, carrageenan induced increase in neuronal excitability was abolished in the dorsal horn from Orai1 mutant mice. These findings uncover a novel signaling pathway involved in the pain process and central sensitization. Our study also reveals a novel link among Orai1, ERK, A-type potassium channels, and neuronal excitability.SIGNIFICANCE STATEMENT Orai1 is a key component of store-operated calcium channels (SOCs) in many cell types. It has been implicated in such pathological conditions as immunodeficiency, autoimmunity, and cancer. However, the role of Orai1 in CNS disorders remains poorly understood. The functional significance of Orai1 in neurons is elusive. Here we demonstrate that activation of Orai1 modulates neuronal excitability and Kv4-containing A-type potassium channels via the protein kinase C-extracellular signal-regulated protein kinase (PKC-ERK) pathway. Genetic knock-out of Orai1 nearly eliminates the second phase of formalin-induced pain and markedly attenuates carrageenan-induced pain hypersensitivity and neuronal excitability. These findings reveal a novel link between Orai1 and neuronal excitability and advance our understanding of central sensitization. PMID- 29229704 TI - A Unifying Motif for Spatial and Directional Surround Suppression. AB - In the visual system, the response to a stimulus in a neuron's receptive field can be modulated by stimulus context, and the strength of these contextual influences vary with stimulus intensity. Recent work has shown how a theoretical model, the stabilized supralinear network (SSN), can account for such modulatory influences, using a small set of computational mechanisms. Although the predictions of the SSN have been confirmed in primary visual cortex (V1), its computational principles apply with equal validity to any cortical structure. We have therefore tested the generality of the SSN by examining modulatory influences in the middle temporal area (MT) of the macaque visual cortex, using electrophysiological recordings and pharmacological manipulations. We developed a novel stimulus that can be adjusted parametrically to be larger or smaller in the space of all possible motion directions. We found, as predicted by the SSN, that MT neurons integrate across motion directions for low-contrast stimuli, but that they exhibit suppression by the same stimuli when they are high in contrast. These results are analogous to those found in visual cortex when stimulus size is varied in the space domain. We further tested the mechanisms of inhibition using pharmacological manipulations of inhibitory efficacy. As predicted by the SSN, local manipulation of inhibitory strength altered firing rates, but did not change the strength of surround suppression. These results are consistent with the idea that the SSN can account for modulatory influences along different stimulus dimensions and in different cortical areas.SIGNIFICANCE STATEMENT Visual neurons are selective for specific stimulus features in a region of visual space known as the receptive field, but can be modulated by stimuli outside of the receptive field. The SSN model has been proposed to account for these and other modulatory influences, and tested in V1. As this model is not specific to any particular stimulus feature or brain region, we wondered whether similar modulatory influences might be observed for other stimulus dimensions and other regions. We tested for specific patterns of modulatory influences in the domain of motion direction, using electrophysiological recordings from MT. Our data confirm the predictions of the SSN in MT, suggesting that the SSN computations might be a generic feature of sensory cortex. PMID- 29229705 TI - Proteolytic Processing of Neurexins by Presenilins Sustains Synaptic Vesicle Release. AB - Proteolytic processing of synaptic adhesion components can accommodate the function of synapses to activity-dependent changes. The adhesion system formed by neurexins (Nrxns) and neuroligins (Nlgns) bidirectionally orchestrate the function of presynaptic and postsynaptic terminals. Previous studies have shown that presenilins (PS), components of the gamma-secretase complex frequently mutated in familial Alzheimer's disease, clear from glutamatergic terminals the accumulation of Nrxn C-terminal fragments (Nrxn-CTF) generated by ectodomain shedding. Here, we characterized the synaptic consequences of the proteolytic processing of Nrxns in cultured hippocampal neurons from mice and rats of both sexes. We show that activation of presynaptic Nrxns with postsynaptic Nlgn1 or inhibition of ectodomain shedding in axonal Nrxn1-beta increases presynaptic release at individual terminals, likely reflecting an increase in the number of functional release sites. Importantly, inactivation of PS inhibits presynaptic release downstream of Nrxn activation, leaving synaptic vesicle recruitment unaltered. Glutamate-receptor signaling initiates the activity-dependent generation of Nrxn-CTF, which accumulate at presynaptic terminals lacking PS function. The sole expression of Nrxn-CTF decreases presynaptic release and calcium flux, recapitulating the deficits due to loss of PS function. Our data indicate that inhibition of Nrxn processing by PS is deleterious to glutamatergic function.SIGNIFICANCE STATEMENT To gain insight into the role of presenilins (PS) in excitatory synaptic function, we address the relevance of the proteolytic processing of presynaptic neurexins (Nrxns) in glutamatergic differentiation. Using synaptic fluorescence probes in cultured hippocampal neurons, we report that trans-synaptic activation of Nrxns produces a robust increase in presynaptic calcium levels and neurotransmitter release at individual glutamatergic terminals by a mechanism that depends on normal PS activity. Abnormal accumulation of Nrxn C-terminal fragments resulting from impaired PS activity inhibits presynaptic calcium signal and neurotransmitter release, assigning synaptic defects to Nrxns as a specific PS substrate. These data may provide links into how loss of PS activity inhibits glutamatergic synaptic function in Alzheimer's disease patients. PMID- 29229707 TI - The Primary Role of Flow Processing in the Identification of Scene-Relative Object Movement. AB - Retinal image motion could be due to the movement of the observer through space or an object relative to the scene. Optic flow, form, and change of position cues all provide information that could be used to separate out retinal motion due to object movement from retinal motion due to observer movement. In Experiment 1, we used a minimal display to examine the contribution of optic flow and form cues. Human participants indicated the direction of movement of a probe object presented against a background of radially moving pairs of dots. By independently controlling the orientation of each dot pair, we were able to put flow cues to self-movement direction (the point from which all the motion radiated) and form cues to self-movement direction (the point toward which all the dot pairs were oriented) in conflict. We found that only flow cues influenced perceived probe movement. In Experiment 2, we switched to a rich stereo display composed of 3D objects to examine the contribution of flow and position cues. We moved the scene objects to simulate a lateral translation and counter-rotation of gaze. By changing the polarity of the scene objects (from light to dark and vice versa) between frames, we placed flow cues to self-movement direction in opposition to change of position cues. We found that again flow cues dominated the perceived probe movement relative to the scene. Together, these experiments indicate the neural network that processes optic flow has a primary role in the identification of scene-relative object movement.SIGNIFICANCE STATEMENT Motion of an object in the retinal image indicates relative movement between the observer and the object, but it does not indicate its cause: movement of an object in the scene; movement of the observer; or both. To isolate retinal motion due to movement of a scene object, the brain must parse out the retinal motion due to movement of the eye ("flow parsing"). Optic flow, form, and position cues all have potential roles in this process. We pitted the cues against each other and assessed their influence. We found that flow parsing relies on optic flow alone. These results indicate the primary role of the neural network that processes optic flow in the identification of scene-relative object movement. PMID- 29229708 TI - Neuronal Glutamate Transporters Control Dopaminergic Signaling and Compulsive Behaviors. AB - There is an ongoing debate on the contribution of the neuronal glutamate transporter EAAC1 to the onset of compulsive behaviors. Here, we used behavioral, electrophysiological, molecular, and viral approaches in male and female mice to identify the molecular and cellular mechanisms by which EAAC1 controls the execution of repeated motor behaviors. Our findings show that, in the striatum, a brain region implicated with movement execution, EAAC1 limits group I metabotropic glutamate receptor (mGluRI) activation, facilitates D1 dopamine receptor (D1R) expression, and ensures long-term synaptic plasticity. Blocking mGluRI in slices from mice lacking EAAC1 restores D1R expression and synaptic plasticity. Conversely, activation of intracellular signaling pathways coupled to mGluRI in D1R-containing striatal neurons of mice expressing EAAC1 leads to reduced D1R protein level and increased stereotyped movement execution. These findings identify new molecular mechanisms by which EAAC1 can shape glutamatergic and dopaminergic signals and control repeated movement execution.SIGNIFICANCE STATEMENT Genetic studies implicate Slc1a1, a gene encoding the neuronal glutamate transporter EAAC1, with obsessive-compulsive disorder (OCD). EAAC1 is abundantly expressed in the striatum, a brain region that is hyperactive in OCD. What remains unknown is how EAAC1 shapes synaptic function in the striatum. Our findings show that EAAC1 limits activation of metabotropic glutamate receptors (mGluRIs) in the striatum and, by doing so, promotes D1 dopamine receptor (D1R) expression. Targeted activation of signaling cascades coupled to mGluRIs in mice expressing EAAC1 reduces D1R expression and triggers repeated motor behaviors. These findings provide new information on the molecular basis of OCD and suggest new avenues for its treatment. PMID- 29229706 TI - Causal Evidence for Learning-Dependent Frontal Lobe Contributions to Cognitive Control. AB - The lateral prefrontal cortex (LPFC) plays a central role in the prioritization of sensory input based on task relevance. Such top-down control of perception is of fundamental importance in goal-directed behavior, but can also be costly when deployed excessively, necessitating a mechanism that regulates control engagement to align it with changing environmental demands. We have recently introduced the "flexible control model" (FCM), which explains this regulation as resulting from a self-adjusting reinforcement-learning mechanism that infers latent statistical structure in dynamic task environments to predict forthcoming states. From this perspective, LPFC-based control is engaged as a function of anticipated cognitive demand, a notion for which we previously obtained correlative neuroimaging evidence. Here, we put this hypothesis to a rigorous, causal test by combining the FCM with a transcranial magnetic stimulation (TMS) intervention that transiently perturbed the LPFC. Human participants (male and female) completed a nonstationary version of the Stroop task with dynamically changing probabilities of conflict between task-relevant and task-irrelevant stimulus features. TMS was given on each trial before stimulus onset either over the LPFC or over a control site. In the control condition, we observed adaptive performance fluctuations consistent with demand predictions that were inferred from recent and remote trial history and effectively captured by our model. Critically, TMS over the LPFC eliminated these fluctuations while leaving basic cognitive and motor functions intact. These results provide causal evidence for a learning-based account of cognitive control and delineate the nature of the signals that regulate top-down biases over stimulus processing.SIGNIFICANCE STATEMENT A core function of the human prefrontal cortex is to control the signal flow in sensory brain regions to prioritize processing of task-relevant information. Abundant work suggests that such control is flexibly recruited to accommodate dynamically changing environmental demands, yet the nature of the signals that serve to engage control remains unknown. Here, we combined computational modeling with noninvasive brain stimulation to show that changes in control engagement are captured by a self-adjusting reinforcement-learning mechanism that tracks changing environmental statistics to predict forthcoming processing demands and that transient perturbation of the prefrontal cortex abolishes these adjustments. These findings delineate the learning signals that underpin adaptive engagement of prefrontal control functions and provide causal evidence for their relevance in behavioral control. PMID- 29229709 TI - Health services research: a special CMAJ focus. PMID- 29229710 TI - Financial incentives for physicians to improve health care. PMID- 29229711 TI - Physician retirement: gender, geography, flexibility and pensions. PMID- 29229712 TI - Payment incentives for community-based psychiatric care in Ontario, Canada. AB - BACKGROUND: In September 2011, the government of Ontario implemented payment incentives to encourage the delivery of community-based psychiatric care to patients after discharge from a psychiatric hospital admission and to those with a recent suicide attempt. We evaluated whether these incentives affected supply of psychiatric services and access to care. METHODS: We used administrative data to capture monthly observations for all psychiatrists who practised in Ontario between September 2009 and August 2014. We conducted interrupted time-series analyses of psychiatrist-level and patient-level data to evaluate whether the incentives affected the quantity of eligible outpatient services delivered and the likelihood of receiving follow-up care. RESULTS: Among 1921 psychiatrists evaluated, implementation of the incentive payments was not associated with increased provision of follow-up visits after discharge from a psychiatric hospital admission (mean change in visits per month per psychiatrist 0.0099, 95% confidence interval [CI] -0.0989 to 0.1206; change in trend 0.0032, 95% CI 0.0035 to 0.0095) or after a suicide attempt (mean change -0.0910, 95% CI -0.1885 to 0.0026; change in trend 0.0102, 95% CI 0.0045 to 0.0159). There was also no change in the probability that patients received follow-up care after discharge (change in level -0.0079, 95% CI -0.0223 to 0.0061; change in trend 0.0007, 95% CI -0.0003 to 0.0016) or after a suicide attempt (change in level 0.0074, 95% CI 0.0094 to 0.0366; change in trend 0.0006, 95% CI -0.0007 to 0.0022). INTERPRETATION: Our results suggest that implementation of the incentives did not increase access to follow-up care for patients after discharge from a psychiatric hospital admission or after a suicide attempt, and the incentives had no effect on supply of psychiatric services. Further research to guide design and implementation of more effective incentives is warranted. PMID- 29229714 TI - Testing and treatment for obstructive sleep apnea in Canada: funding models must change. PMID- 29229713 TI - Patterns of physician retirement and pre-retirement activity: a population-based cohort study. AB - BACKGROUND: Knowing when physicians retire and how they practise in the pre retirement years is important information for health human resource planning. We identified patterns of retirement for physicians in British Columbia and the determinants of when and how physicians retire. METHODS: For this population based retrospective cohort study, we used administrative data to examine activity levels and to identify retirements among BC's practising physicians. We included all physicians who were at least 50 years of age as of March 2006 and who had received payments for clinical services in at least 1 year between 2005/06 and 2011/12. We defined retirement as a permanent drop in monthly payments to less than $1667/month ($20 000/yr). We examined the patterns and timing of retirement by age, sex, specialty and location using linear and logistic regression models. RESULTS: Of the 4572 physicians who met the inclusion criteria, 1717 (37.6%) retired during the study period. The average age at retirement was 65.1 (standard deviation 7.8) years. Controlling for other demographic and practice characteristics, we found that women and physicians working in rural areas retired earlier, by 4.1 (95% confidence interval [CI] -4.9 to -3.2) years and 2.3 (95% CI -3.4 to -1.1) years, respectively. We found no difference in retirement age by specialty. We identified 4 patterns of pre-retirement activity: slow decline, rapid decline, maintenance and increasing activity. About 40% of physicians (440/1107) reduced their activity levels by at least 10% in the 3 years preceding retirement. INTERPRETATION: During the study period, physicians in BC - particularly women and those in rural areas - retired earlier than indicated by licensure and survey data. Many physicians reduced their practice activity in the pre-retirement years. These trends indicate that forecasts relying on licensure "head counts" are likely overestimating current and future physician supply. PMID- 29229715 TI - A 15-year-old boy with sickle cell disease, chest pain and respiratory distress. PMID- 29229716 TI - Disseminated blastomycosis in a 57-year-old man working in construction. PMID- 29229717 TI - Generic drug names: no art, no science, just enhanced safety. PMID- 29229718 TI - Smoking is the first cause of morbidity and death in psychiatric settings. PMID- 29229719 TI - New association for health humanities coming in 2018. PMID- 29229720 TI - Medication costs driving seniors to food banks. PMID- 29229721 TI - Opioid prescriptions still rising but for smaller quantities. PMID- 29229722 TI - Doctor who supported tax reforms removed from board of Doctors Nova Scotia. PMID- 29229723 TI - Prospective Study of Fasting Blood Glucose and Intracerebral Hemorrhagic Risk. AB - BACKGROUND AND PURPOSE: Although diabetes mellitus is an established independent risk factor for ischemic stroke, the association between fasting blood glucose and intracerebral hemorrhage (ICH) is limited and inconsistent. The objective of the current study was to examine the potential impact of long-term fasting blood glucose concentration on subsequent risk of ICH. METHODS: This prospective study included 96 110 participants of the Kailuan study, living in Kailuan community, Tangshan city, China, who were free of cardiovascular diseases and cancer at baseline (2006). Fasting blood glucose concentration was measured in 2006, 2008, 2010, and 2012. Updated cumulative average fasting blood glucose concentration was used as primary exposure of the current study. Incident ICH from 2006 to 2015 was confirmed by review of medical records. RESULTS: During 817 531 person-years of follow-up, we identified 755 incident ICH cases. The nadir risk of ICH was observed at fasting blood glucose concentration of 5.3 mmol/L. The adjusted hazard ratios and their 95% confidence intervals (CIs) of ICH were 1.59 (95% CI, 1.26-2.02) for diabetes mellitus or fasting blood glucose >=7.00 mmol/L, 1.31 (95% CI, 1.02-1.69) for impaired fasting blood glucose (fasting blood glucose, 6.10-6.99 mmol/L), 0.98 (95% CI, 0.78-1.22) for fasting blood glucose 5.60 to 6.09 mmol/L, and 2.04 (95% CI, 1.23-3.38) for hypoglycemia (fasting blood glucose, <4.00 mmol/L), comparing with normal fasting blood glucose 4.00 to 5.59 mmol/L. The results persisted after excluding individuals who used hypoglycemic, aspirin, antihypertensive agents, or anticoagulants, and those with intracerebral hemorrhagic cases occurred in the first 2 years of follow-up. CONCLUSIONS: In this large community-based cohort, low (<4.0 mmol/L) and high (>=6.1 mmol/L) fasting blood glucose concentrations were associated with higher risk of incident ICH, relative to fasting blood glucose concentrations of 4.00 to 6.09 mmol/L. PMID- 29229724 TI - Serum Galectin-3 and Poor Outcomes Among Patients With Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Elevated galectin-3 has been associated with atherosclerosis and poor outcomes in patients with heart failure. However, it remains unclear whether galectin-3 has any effect on the poor outcomes of ischemic stroke. The aim of the present study was to examine the association between galectin-3 with poor outcomes among patients with acute ischemic stroke. METHODS: Serum galectin-3 was measured in 3082 patients with acute ischemic stroke. The primary outcome was a combination of death or major disability (modified Rankin Scale score, >=3) at 3 months after stroke. RESULTS: Compared with the lowest quartile of galectin-3, multivariate adjusted odds ratios (95% confidence intervals) for the highest quartile of galectin-3 were 1.55 (1.15 2.09) for composite outcome, 2.10 (0.89-4.95) for death, and 1.43 (1.05-1.93) for major disability. The addition of galectin-3 to the conventional risk factors significantly improved prediction of the combined outcome of death or major disability in patients with ischemic stroke (net reclassification index, 18.9%; P<0.001; integrated discrimination improvement, 0.4%; P=0.001). CONCLUSIONS: Higher levels of serum galectin-3 were independently associated with increased risk of death or major disability after stroke onset, suggesting that galectin-3 may have prognostic value in poor outcomes of ischemic stroke. PMID- 29229725 TI - Ambient Temperature and Stroke Risk: Evidence Supporting a Short-Term Effect at a Population Level From Acute Environmental Exposures. PMID- 29229726 TI - Prognostic Significance of Blood Pressure Variability on Beat-to-Beat Monitoring After Transient Ischemic Attack and Stroke. AB - BACKGROUND AND PURPOSE: Visit-to-visit and day-to-day blood pressure (BP) variability (BPV) predict an increased risk of cardiovascular events but only reflect 1 form of BPV. Beat-to-beat BPV can be rapidly assessed and might also be predictive. METHODS: In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (Oxford Vascular Study), BPV (coefficient of variation) was measured beat-to-beat for 5 minutes (Finometer), day-to-day for 1 week on home monitoring (3 readings, 3* daily), and on awake ambulatory BP monitoring. BPV after 1-month standard treatment was related (Cox proportional hazards) to recurrent stroke and cardiovascular events for 2 to 5 years, adjusted for mean systolic BP. RESULTS: Among 520 patients, 26 had inadequate beat-to-beat recordings, and 22 patients were in atrial fibrillation. Four hundred five patients had all forms of monitoring. Beat-to-beat BPV predicted recurrent stroke and cardiovascular events independently of mean systolic BP (hazard ratio per group SD, stroke: 1.47 [1.12-1.91]; P=0.005; cardiovascular events: 1.41 [1.08 1.83]; P=0.01), including after adjustment for age and sex (stroke: 1.47 [1.12 1.92]; P=0.005) and all risk factors (1.40 [1.00-1.94]; P=0.047). Day-to-day BPV was less strongly associated with stroke (adjusted hazard ratio, 1.29 [0.97 1.71]; P=0.08) but similarly with cardiovascular events (1.41 [1.09-1.83]; P=0.009). BPV on awake ambulatory BP monitoring was nonpredictive (stroke: 0.89 [0.59-1.35]; P=0.59; cardiovascular events: 1.08 [0.77-1.52]; P=0.65). Despite a weak correlation (r=0.119; P=0.02), beat-to-beat BPV was associated with risk of recurrent stroke independently of day-to-day BPV (1.41 [1.05-1.90]; P=0.02). CONCLUSIONS: Beat-to-beat BPV predicted recurrent stroke and cardiovascular events, independently of mean systolic BP and risk factors but short-term BPV on ambulatory BP monitoring did not. Beat-to-beat BPV may be a useful additional marker of cardiovascular risk. PMID- 29229727 TI - High-Salt Conditions Alter Transcription of Helicobacter pylori Genes Encoding Outer Membrane Proteins. AB - Helicobacter pylori infection and high dietary salt intake are risk factors for the development of gastric adenocarcinoma. One possible mechanism by which a high salt diet could influence gastric cancer risk is by modulating H. pylori gene expression. In this study, we utilized transcriptome sequencing (RNA-seq) methodology to compare the transcriptional profiles of H. pylori grown in media containing different concentrations of sodium chloride. We identified 118 differentially expressed genes (65 upregulated and 53 downregulated in response to high-salt conditions), including multiple members of 14 operons. Twenty-nine of the differentially expressed genes encode proteins previously shown to undergo salt-responsive changes in abundance, based on proteomic analyses. Real-time reverse transcription (RT)-PCR analyses validated differential expression of multiple genes encoding outer membrane proteins, including adhesins (SabA and HopQ) and proteins involved in iron acquisition (FecA2 and FecA3). Transcript levels of sabA, hopA, and hopQ are increased under high-salt conditions, whereas transcript levels of fecA2 and fecA3 are decreased under high-salt conditions. Transcription of sabA, hopA, hopQ, and fecA3 is derepressed in an arsS mutant strain, but salt-responsive transcription of these genes is not mediated by the ArsRS two-component system, and the CrdRS and FlgRS two-component systems do not have any detectable effects on transcription of these genes. In summary, these data provide a comprehensive view of H. pylori transcriptional alterations that occur in response to high-salt environmental conditions. PMID- 29229728 TI - cas9 Enhances Bacterial Virulence by Repressing the regR Transcriptional Regulator in Streptococcus agalactiae. AB - Clustered regularly interspaced palindromic repeats (CRISPR) and their associated cas genes have been demonstrated to regulate self-genes and virulence in many pathogens. In this study, we found that inactivation of cas9 caused reduced adhesion and intracellular survival of the piscine Streptococcus agalactiae strain GD201008-001 and significantly decreased the virulence of this strain in zebrafish and mice. Further investigation indicated that the regR transcriptional regulator was upregulated in the Deltacas9 mutant. As regR mediates the repression of hyaluronidase, a critical factor involved in opening the blood brain barrier (BBB) in mice, cas9-mediated repression of regR transcription is important for S. agalactiae to open the BBB and thereby cause meningitis in animals. This study expands our understanding of endogenous gene regulation mediated by CRISPR-Cas systems in bacteria. PMID- 29229729 TI - CdtC-Induced Processing of Membrane-Bound CdtA Is a Crucial Step in Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Holotoxin Formation. AB - Aggregatibacter actinomycetemcomitans is an oral pathogen causing periodontal disease and bacterial endocarditis. It produces cytolethal distending toxin (CDT) that could damage mammalian cells and tissues. CDT is a tripartite protein toxin composed of CdtA, CdtB, and CdtC. We have previously indicated that CdtA is a lipoprotein and that the proteolytic processing of CdtA is important for biogenesis and secretion of CDT holotoxin. Here, we established an in vitro processing assay of CdtA and investigated the interactions of CdtA with other Cdt subunits. This assay demonstrated that incubation of membrane-bound CdtA (MCdtA), CdtB, and CdtC immediately generated a processed form of CdtA (CdtA'), which is recovered from the soluble fraction. In contrast, incubation of soluble membrane unbound CdtA with CdtB and CdtC did not yield any CdtA'. Furthermore, incubation of CdtC with MCdtA was enough to induce rapid processing of MCdtA, whereas CdtB alone was unable to induce the processing. Coimmunoprecipitation demonstrated that CdtA' and CdtC formed a complex. Furthermore, subsequent addition of CdtB to this reaction mixture resulted in complete CDT holotoxin complex. The cytolethal distending activity assay demonstrated that CDT complex containing CdtA' showed far stronger cytotoxicity than that containing CdtA. Collectively, our data suggest that CDT holotoxin formation in vivo is a sequential event: interaction of MCdtA and CdtC induces proteolytic processing of MCdtA, and the released CdtA' forms a complex with CdtC. Subsequent binding of CdtB to the CdtA'/CdtC complex results in CDT holotoxin formation. PMID- 29229730 TI - Role of Ethanolamine Utilization Genes in Host Colonization during Urinary Tract Infection. AB - Urinary tract infection (UTI) is the second most common infection in humans, making it a global health priority. Nearly half of all women will experience a symptomatic UTI, with uropathogenic Escherichia coli (UPEC) being the major causative agent of the infection. Although there has been extensive research on UPEC virulence determinants, the importance of host-specific metabolism remains understudied. We report here that UPEC upregulates the expression of ethanolamine utilization genes during uncomplicated UTIs in humans. We further show that UPEC ethanolamine metabolism is required for effective bladder colonization in the mouse model of ascending UTI and is dispensable for bladder colonization in an immunocompromised mouse model of UTI. We demonstrate that although ethanolamine metabolism mutants do not show increased susceptibility to antimicrobial responses of neutrophils, this metabolic pathway is important for surviving the innate immune system during UTI. This study reveals a novel aspect of UPEC metabolism in the host and provides evidence for an underappreciated link between bacterial metabolism and the host immune response. PMID- 29229731 TI - Activation of Porcine Alveolar Macrophages by Actinobacillus pleuropneumoniae Lipopolysaccharide via the Toll-Like Receptor 4/NF-kappaB-Mediated Pathway. AB - Actinobacillus pleuropneumoniae is the causative agent of porcine contagious pleuropneumonia. Overproduction of proinflammatory cytokines, like interleukin 1beta (IL-1beta), IL-6, tumor necrosis factor alpha, and resistin, in the lung is an important feature of A. pleuropneumoniae infection. These proinflammatory cytokines enhance inflammatory and immunological responses. However, the mechanism that leads to cytokine production remains unclear. As a major virulence factor of A. pleuropneumoniae, lipopolysaccharide (LPS) may act as a potent stimulator of Toll-like receptor 4 (TLR4), triggering a number of intracellular signaling pathways that lead to the synthesis of proinflammatory cytokines. Porcine alveolar macrophages (PAMs) are the first line of defense against pathogenic microbes during pathogen invasion. The results of the present study demonstrate that A. pleuropneumoniae LPS induces PAMs to produce inflammatory cytokines in time- and dose-dependent manners. Moreover, PAMs were activated by A. pleuropneumoniae LPS, resulting in upregulation of signaling molecules, including TLR4, MyD88, TRIF-related adaptor molecule, and NF-kappaB. In contrast, the activation effects of A. pleuropneumoniae LPS on PAMs could be suppressed by specific inhibitors, like small interfering RNA and Bay11-7082. Taken together, our data indicate that A. pleuropneumoniae LPS can induce PAMs to produce proinflammatory cytokines via the TLR4/NF-kappaB-mediated pathway. These findings partially reveal the mechanism of the overproduction of proinflammatory cytokines in the lungs of swine with A. pleuropneumoniae infection and may provide targets for the prevention of A. pleuropneumoniae-induced pneumonia. All the data could be used as a reference for the pathogenesis of respiratory infection. PMID- 29229732 TI - Utilization of Variant and Fusion Proteins To Functionally Map the Aggregatibacter actinomycetemcomitans Trimeric Autotransporter Protein ApiA. AB - The Gram-negative bacterium Aggregatibacter actinomycetemcomitans is a causative agent of localized aggressive periodontitis. Critical to its infection process is the first and essential step of attachment, which is related to the coordinated functions of surface components comprised of proteins and extracellular polysaccharides. One such protein is the outer membrane trimeric autotransporter protein ApiA, a versatile virulence factor with numerous functions, including cell binding, invasion, serum resistance, autoaggregation, and induction of cytokine release. Here we report on the use of Escherichia coli strains expressing protein variants to define the separate functions ascribed to the N terminus and those related to the C terminus. Importantly, a hybrid protein that comprised the N terminus of trimeric ApiA and the beta-barrel domain of monomeric autotransporter Aae was constructed, which allowed the expression of a monomer surface-exposed domain of ApiA. Functional and phenotypic analyses demonstrated that the C terminus of ApiA forms an independent domain that is crucial for general stability and trimer formation, which appears to be associated with autoaggregation, biofilm formation, and surface expression. Importantly, the results show that the monomeric form of the N-terminal passenger domain of ApiA, while surface exposed, is sufficient for binding to buccal epithelial cells; however, it is not sufficient to allow aggregation and biofilm formation, strengthening the importance of the role of trimerization in these phenotypes. PMID- 29229733 TI - Expression of Toll-Like Receptor 2 by Dendritic Cells Is Essential for the DnaJ DeltaA146Ply-Mediated Th1 Immune Response against Streptococcus pneumoniae. AB - The fusion protein DnaJ-DeltaA146Ply could induce cross-protective immunity against pneumococcal infection via mucosal and subcutaneous immunization in mice in the absence of additional adjuvants. DnaJ and Ply are both Toll-like receptor 4 (TLR4) but not TLR2 ligands. However, we found that TLR2-/- mice immunized subcutaneously with DnaJ-DeltaA146Ply showed significantly lower survival rates and higher bacterial loads in nasal washes than did wild-type (WT) mice after being challenged with pneumococcal strain D39 or 19F. The gamma interferon (IFN gamma) level in splenocytes decreased in TLR2-/- mice, indicating that Th1 immunity elicited by DnaJ-DeltaA146Ply was impaired in these mice. We explored the mechanism of protective immunity conferred by DnaJ-DeltaA146Ply and the role of TLR2 in this process. DnaJ-DeltaA146Ply effectively promoted dendritic cell (DC) maturation via TLR4 but not the TLR2 signaling pathway. In a DnaJ DeltaA146Ply-treated DC and naive CD4+ T cell coculture system, the deficiency of TLR2 in DCs resulted in a significant decline of IFN-gamma production and Th1 subset differentiation. The same effect was observed in adoptive-transfer experiments. In addition, TLR2-/- DCs showed remarkably lower levels of the Th1 polarizing cytokine IL-12p70 than did WT DCs, suggesting that TLR2 was indispensable for DnaJ-DeltaA146Ply-induced IL-12 production and Th1 proliferation. Thus, our findings illustrate that dendritic cell expression of TLR2 is essential for optimal Th1 immune response against pneumococci in mice immunized subcutaneously with DnaJ-DeltaA146Ply. PMID- 29229734 TI - Macrophage Polarization Alters Postphagocytosis Survivability of the Commensal Streptococcus gordonii. AB - Oral streptococci are generally considered commensal organisms; however, they are becoming recognized as important associate pathogens during the development of periodontal disease as well as being associated with several systemic diseases, including as a causative agent of infective endocarditis. An important virulence determinant of these bacteria is an ability to evade destruction by phagocytic cells, yet how this subversion occurs is mostly unknown. Using Streptococcus gordonii as a model commensal oral streptococcus that is also associated with disease, we find that resistance to reactive oxygen species (ROS) with an active ability to damage phagosomes allows the bacterium to avoid destruction within macrophages. This ability to survive relies not only on the ROS resistance capabilities of the bacterium but also on ROS production by macrophages, with both being required for maximal survival of internalized bacteria. Importantly, we also show that this dependence on ROS production by macrophages for resistance has functional significance: S. gordonii intracellular survival increases when macrophages are polarized toward an activated (M1) profile, which is known to result in prolonged phagosomal ROS production compared to that of alternatively (M2) polarized macrophages. We additionally find evidence of the bacterium being capable of both delaying the maturation of and damaging phagosomes. Taken together, these results provide essential insights regarding the mechanisms through which normally commensal oral bacteria can contribute to both local and systemic inflammatory disease. PMID- 29229735 TI - Oral Application of Recombinant Bacillus subtilis Spores to Dogs Results in a Humoral Response against Specific Echinococcus granulosus Paramyosin and Tropomyosin Antigens. AB - Bacillus subtilis is known as an endospore- and biofilm-forming bacterium with probiotic properties. We have recently developed a method for displaying heterologous proteins on the surface of B. subtilis biofilms by introducing the coding sequences of the protein of interest into the bacterial genome to generate a fusion protein linked to the C terminus of the biofilm matrix protein TasA. Although B. subtilis is a regular component of the gut microflora, we constructed a series of recombinant B. subtilis strains that were tested for their ability to be used to immunize dogs following oral application of the spores. Specifically, we tested recombinant spores of B. subtilis carrying either the fluorescent protein mCherry or else selected antigenic peptides (tropomyosin and paramyosin) from Echinococcus granulosus, a zoonotic intestinal tapeworm of dogs and other carnivores. The application of the recombinant B. subtilis spores led to the colonization of the gut with recombinant B. subtilis but did not cause any adverse effect on the health of the animals. As measured by enzyme-linked immunosorbent assay and immunoblotting, the dogs were able to develop a humoral immune response against mCherry as well as against E. granulosus antigenic peptides. Interestingly, the sera of dogs obtained after immunization with recombinant spores of E. granulosus peptides were able to recognize E. granulosus protoscoleces, which represent the infective form of the head of the tapeworms. These results represent an essential step toward the establishment of B. subtilis as an enteric vaccine agent. PMID- 29229736 TI - Comparison of Salmonella enterica Serovars Typhi and Typhimurium Reveals Typhoidal Serovar-Specific Responses to Bile. AB - Salmonella enterica serovars Typhi and Typhimurium cause typhoid fever and gastroenteritis, respectively. A unique feature of typhoid infection is asymptomatic carriage within the gallbladder, which is linked with S Typhi transmission. Despite this, S Typhi responses to bile have been poorly studied. Transcriptome sequencing (RNA-Seq) of S Typhi Ty2 and a clinical S Typhi isolate belonging to the globally dominant H58 lineage (strain 129-0238), as well as S Typhimurium 14028, revealed that 249, 389, and 453 genes, respectively, were differentially expressed in the presence of 3% bile compared to control cultures lacking bile. fad genes, the actP-acs operon, and putative sialic acid uptake and metabolism genes (t1787 to t1790) were upregulated in all strains following bile exposure, which may represent adaptation to the small intestine environment. Genes within the Salmonella pathogenicity island 1 (SPI-1), those encoding a type IIII secretion system (T3SS), and motility genes were significantly upregulated in both S Typhi strains in bile but downregulated in S Typhimurium. Western blots of the SPI-1 proteins SipC, SipD, SopB, and SopE validated the gene expression data. Consistent with this, bile significantly increased S Typhi HeLa cell invasion, while S Typhimurium invasion was significantly repressed. Protein stability assays demonstrated that in S Typhi the half-life of HilD, the dominant regulator of SPI-1, is three times longer in the presence of bile; this increase in stability was independent of the acetyltransferase Pat. Overall, we found that S Typhi exhibits a specific response to bile, especially with regard to virulence gene expression, which could impact pathogenesis and transmission. PMID- 29229737 TI - The Superantigen Toxic Shock Syndrome Toxin-1 Alters Human Aortic Endothelial Cell Function. AB - Staphylococcus aureus infective endocarditis (IE) is a fast-progressing and tissue destructive infection of the cardiac endothelium. The superantigens (SAgs) toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxin C (SEC), and the enterotoxin gene cluster (egc) play a novel and essential role in the etiology of S. aureus IE. Recent studies indicate that SAgs act at the infection site to cause tissue pathology and promote vegetation growth. The underlying mechanism of SAg involvement has not been clearly defined. In SAg-mediated responses, immune cell priming is considered a primary triggering event leading to endothelial cell activation and altered function. Utilizing immortalized human aortic endothelial cells (iHAECs), we demonstrate that TSST-1 directly activates iHAECs, as documented by upregulation of vascular and intercellular adhesion molecules (VCAM-1 and ICAM-1). TSST-1-mediated activation results in increased monolayer permeability and defects in vascular re-endothelialization. Yet, stimulation of iHAECs with TSST-1 fails to induce IL-8 and IL-6 production. Furthermore, simultaneous stimulation of iHAECs with TSST-1 and LPS inhibits LPS mediated IL-8 and IL-6 secretion, even after pre-treatment with the pro inflammatory cytokines TNFalpha or IL-1beta. IL-8 suppression is not mediated by TSST-1 binding to its canonical receptor MHC-II, supporting current evidence for a non-hematopoietic interacting site on SAgs. Altogether the data suggest that TSST-1 differentially regulates cell-bound and secreted markers of endothelial cell activation that may result in dysregulated innate immune responses during S. aureus IE. Endothelial changes resulting from the action of SAgs can therefore directly contribute to the aggressive nature of S. aureus IE and development of life-threatening complications. PMID- 29229738 TI - HDAC5 integrates ER stress and fasting signals to regulate hepatic fatty acid oxidation. AB - Disregulation of fatty acid oxidation, one of the major mechanisms for maintaining hepatic lipid homeostasis under fasting conditions, leads to hepatic steatosis. Although obesity and type 2 diabetes-induced endoplasmic reticulum (ER) stress contribute to hepatic steatosis, it is largely unknown how ER stress regulates fatty acid oxidation. Here we show that fasting glucagon stimulates the dephosphorylation and nuclear translocation of histone deacetylase 5 (HDAC5), where it interacts with PPARalpha and promotes transcriptional activity of PPARalpha. As a result, overexpression of HDAC5 but not PPARalpha binding deficient HDAC5 in liver improves lipid homeostasis, whereas RNAi-mediated knockdown of HDAC5 deteriorates hepatic steatosis. ER stress inhibits fatty acid oxidation gene expression via calcium/calmodulin-dependent protein kinase II mediated phosphorylation of HDAC5. Most important, hepatic overexpression of a phosphorylation-deficient mutant HDAC5 2SA promotes hepatic fatty acid oxidation gene expression and protects against hepatic steatosis in mice fed a high-fat diet. We have identified HDAC5 as a novel mediator of hepatic fatty acid oxidation by fasting and ER stress signals, and strategies to promote HDAC5 dephosphorylation could serve as new tools for the treatment of obesity associated hepatic steatosis. PMID- 29229739 TI - Complete assessment of whole-body n-3 and n-6 PUFA synthesis-secretion kinetics and DHA turnover in a rodent model. AB - Previous assessments of the PUFA biosynthesis pathway have focused on DHA and arachidonic acid synthesis. Here, we determined whole-body synthesis-secretion kinetics for all downstream products of PUFA metabolism, including direct measurements of DHA and n-6 docosapentaenoic acid (DPAn-6, 22:5n-6) turnover, and compared n-6 and n-3 homolog kinetics. We infused labeled alpha-linolenic acid (ALA, 18:3n-3), linoleic acid (LNA, 18:2n-6), DHA, and DPAn-6 as 2H5-ALA, 13C18 LNA, 13C22-DHA, and 13C22-DPAn-6. Eight 11-week-old Long Evans rats fed a 10% fat diet were infused with the labeled PUFAs over 3 h, and plasma enrichment of labeled products was measured every 30 min. The DHA synthesis-secretion rate (94 +/- 34 nmol/day) did not differ from other PUFA products (range, 21.8 +/- 4.3 nmol/day to 408 +/- 116 nmol/day). Synthesis-secretion rates of n-6 and n-3 PUFA homologs were similar, except 22:4n-6 and DPAn-6 had lower synthesis rates. However, daily turnover from newly synthesized DHA (0.067 +/- 0.023%) was 56-fold to 556-fold slower than all other PUFA turnover and was 130-fold slower than that determined directly from the total plasma unesterified DHA pool. In conclusion, n 6 and n-3 PUFA synthesis-secretion kinetics suggest that differences in turnover, not in synthesis-secretion rates, primarily determine PUFA plasma levels. PMID- 29229740 TI - Bone marrow-derived cPLA2alpha contributes to renal fibrosis progression. AB - The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2alpha) enzyme directs a complex "eicosanoid storm" that accompanies the tissue response to injury. cPLA2alpha and its downstream eicosanoid mediators are also implicated in the pathogenesis of fibrosis in many organs, including the kidney. We aimed to determine the role of cPLA2alpha in bone marrow-derived cells in a murine model of renal fibrosis, unilateral ureteral obstruction (UUO). WT C57BL/6J mice were irradiated and engrafted with donor bone marrow from either WT mice [WT-bone marrow transplant (BMT)] or mice deficient in cPLA2alpha (KO-BMT). After full engraftment, mice underwent UUO and kidneys were collected 3, 7, and 14 days after injury. Using picrosirius red, collagen-3, and smooth muscle alpha actin staining, we determined that renal fibrosis was significantly attenuated in KO BMT animals as compared with WT-BMT animals. Lipidomic analysis of homogenized kidneys demonstrated a time-dependent upregulation of pro-inflammatory eicosanoids after UUO; KO-BMT animals had lower levels of many of these eicosanoids. KO-BMT animals also had fewer infiltrating pro-inflammatory CD45+CD11b+Ly6Chi macrophages and reduced message levels of pro-inflammatory cytokines. Our results indicate that cPLA2alpha and/or its downstream mediators, produced by bone marrow-derived cells, play a major role in eicosanoid production after renal injury and in renal fibrinogenesis. PMID- 29229742 TI - Adrenal Vein Sampling Is the Preferred Method to Select Patients With Primary Aldosteronism for Adrenalectomy: Pro Side of the Argument. PMID- 29229743 TI - Meta-Analysis and Systematic Review to Assess the Role of Soluble FMS-Like Tyrosine Kinase-1 and Placenta Growth Factor Ratio in Prediction of Preeclampsia: The SaPPPhirE Study. AB - Preeclampsia is a major cause of morbidity and mortality worldwide. Numerous candidate biomarkers have been proposed for diagnosis and prediction of preeclampsia. Measurement of maternal circulating angiogenesis biomarker as the ratio of sFlt-1 (soluble FMS-like tyrosine kinase-1; an antiangiogenic factor)/PlGF (placental growth factor; an angiogenic factor) reflects the antiangiogenic balance that characterizes incipient or overt preeclampsia. The ratio increases before the onset of the disease and thus may help in predicting preeclampsia. We conducted a meta-analysis to explore the predictive accuracy of sFlt-1/PlGF ratio in preeclampsia. We included 15 studies with 534 cases with preeclampsia and 19 587 controls. The ratio has a pooled sensitivity of 80% (95% confidence interval, 0.68-0.88), specificity of 92% (95% confidence interval, 0.87-0.96), positive likelihood ratio of 10.5 (95% confidence interval, 6.2 18.0), and a negative likelihood ratio of 0.22 (95% confidence interval, 0.13 0.35) in predicting preeclampsia in both high- and low-risk patients. Most of the studies have not made a distinction between early- and late-onset disease, and therefore, the analysis for it could not be done. It can prove to be a valuable screening tool for preeclampsia and may also help in decision-making, treatment stratification, and better resource allocation. PMID- 29229741 TI - Accuracy of Blood Pressure Measurement Devices in Pregnancy: A Systematic Review of Validation Studies. AB - The accurate measurement of blood pressure (BP) in pregnancy is essential to guide medical decision making that affects both mother and fetus. The aim of this systematic review was to determine the accuracy of ambulatory, home, and clinic BP measurement devices in pregnant women. We searched Ovid MEDLINE, The Cochrane Library, EMBASE, CINAHL EBSCO, ClinicalTrials.gov, International Clinical Trials Registry Platform, and dabl from inception through August 3, 2017 for articles that assessed the validity of an upper arm BP measurement device against a mercury sphygmomanometer in pregnant women. Two independent investigators determined eligibility, extracted data, and adjudicated protocol violations. From 1798 potential articles identified, 41, that assessed 28 devices, met the inclusion criteria. Most articles (n=32) followed a standard or modified American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization, British Hypertension Society, or European Society of Hypertension validation protocol. Several articles described the results of validation studies performed on >1 device (n=7) or in >1 population of pregnant women (n=12), comprising 64 pairwise validity assessments. The device was validated in 61% (32 of 52) of studies which used a standard or modified protocol. Only 34% (11 of 32) of the studies wherein the device was successfully validated were performed without a protocol violation. Given the implications of inaccurate BP measurement in pregnant women, healthcare providers should be aware of and try to use the BP measurement devices which have been properly validated in this population. PMID- 29229744 TI - Three Reportedly Unrelated Families With Liddle Syndrome Inherited From a Common Ancestor. AB - Liddle syndrome is considered a rare Mendelian hypertension. We have previously described 3 reportedly unrelated families, native of an Italian area around the Strait of Messina, carrying the same mutation (betaP617L) of the epithelial sodium channel. The aims of our study were (1) to evaluate whether a close genomic relationship exists between the 3 families through the analysis of mitochondrial DNA and Y chromosome; and (2) to quantify the genomic relatedness between the patients with Liddle syndrome belonging to the 3 families and assess the hypothesis of a mutation shared through identity by descent. HVRI (the hypervariable region I) of the mitochondrial DNA genome and the Y chromosome short tandem repeats profiles were analyzed in individuals of the 3 families. Genotyping 542 585 genome-wide single nucleotide polymorphisms was performed in all the patients with Liddle syndrome of the 3 families and some of their relatives. A panel of 780 healthy Italian adult samples typed for the same set of markers was used as controls. espite different lineages between the 3 families based on the analysis of mitochondrial DNA and Y chromosome, the 3 probands and their 6 affected relatives share the same ~5 Mbp long haplotype which encompasses the mutant allele. Using an approach based on coalescent theory, we estimate that the 3 families inherited the mutant allele from a common ancestor ~13 generations ago and that such an ancestor may have left ~20 carriers alive today. The prevalence of Liddle syndrome in the region of origin of the 3 families may be much higher than that estimated worldwide. PMID- 29229745 TI - Aging and Adrenal Aldosterone Production. PMID- 29229746 TI - Inhibition of NADPH Oxidase-Dependent Oxidative Stress in the Rostral Ventrolateral Medulla Mediates the Antihypertensive Effects of Acupuncture in Spontaneously Hypertensive Rats. AB - Oxidative stress in the rostral ventrolateral medulla (RVLM), where the sympathetic nervous control center is located, contributes to neural mechanisms of hypertension. Acupuncture was previously reported to favorably affect high blood pressure. However, little is known about the effect of acupuncture on oxidative stress-modulated mechanisms in hypertension. This study was designed to evaluate the hypothesis that acupuncture exerts an antihypertensive effect via ameliorating oxidative stress and the redox-sensitive pathway in the RVLM of spontaneously hypertensive rats. Two weeks of acupuncture reduced blood pressure and sympathetic nervous system activity in spontaneously hypertensive rats. Oxidative stress in the RVLM was alleviated by acupuncture, accompanied by a decrease in nicotinamide adenine dinucleotide phosphate oxidase activity and expression of its subunits. Acupuncture significantly altered the mitogen activated protein kinases signaling pathway as assessed by pathway enrichment analysis in a gene chip assay. The phosphorylation of p38 mitogen-activated protein kinases and extracellular signal-regulated protein kinase 1/2, but not Jun N-terminal kinase, was downregulated by acupuncture. Microinjection bilaterally of the superoxide dismutase mimetic tempol, nicotinamide adenine dinucleotide phosphate oxidase inhibitor apocynin, or diphenyleneiodonium chloride into the RVLM mimicked the antihypertensive effect of acupuncture. In contrast, the nicotinamide adenine dinucleotide phosphate oxidase agonist tetrabromocinnamic acid abolished the beneficial effects of acupuncture. Furthermore, injection of capsaicin or surgical sectioning of the sciatic nerve abolished the antihypertensive effect of acupuncture. We conclude that acupuncture decreases high blood pressure and nicotinamide adenine dinucleotide phosphate oxidase in the RVLM of spontaneously hypertensive rats. The mitogen activated protein kinases and the sciatic nerve are involved in the mechanism of acupuncture's amelioration of hypertension. PMID- 29229747 TI - The Eye of the Needle: Redox Mechanisms of Acupuncture Effects in Hypertension. PMID- 29229748 TI - Adrenal Vein Sampling Is the Preferred Method to Select Patients With Primary Aldosteronism for Adrenalectomy: Con Side of the Argument. PMID- 29229749 TI - Brutalist medicine: a reflection on the architecture of healthcare. PMID- 29229752 TI - Ribociclib Extends Survival in HR+ Breast Cancer. AB - Adding the CDK4/6 inhibitor ribociclib to standard first-line endocrine therapy significantly prolonged survival in premenopausal and perimenopausal women with advanced HR-positive, HER2-negative breast cancer enrolled in the MONALEESA-7 trial. This is the first definitive evidence that CDK4/6 inhibitor-based therapy is effective for first-line treatment of premenopausal and perimenopausal women. PMID- 29229750 TI - Profiling of Accessible Chromatin Regions across Multiple Plant Species and Cell Types Reveals Common Gene Regulatory Principles and New Control Modules. AB - The transcriptional regulatory structure of plant genomes remains poorly defined relative to animals. It is unclear how many cis-regulatory elements exist, where these elements lie relative to promoters, and how these features are conserved across plant species. We employed the assay for transposase-accessible chromatin (ATAC-seq) in four plant species (Arabidopsis thaliana, Medicago truncatula, Solanum lycopersicum, and Oryza sativa) to delineate open chromatin regions and transcription factor (TF) binding sites across each genome. Despite 10-fold variation in intergenic space among species, the majority of open chromatin regions lie within 3 kb upstream of a transcription start site in all species. We find a common set of four TFs that appear to regulate conserved gene sets in the root tips of all four species, suggesting that TF-gene networks are generally conserved. Comparative ATAC-seq profiling of Arabidopsis root hair and non-hair cell types revealed extensive similarity as well as many cell-type-specific differences. Analyzing TF binding sites in differentially accessible regions identified a MYB-driven regulatory module unique to the hair cell, which appears to control both cell fate regulators and abiotic stress responses. Our analyses revealed common regulatory principles among species and shed light on the mechanisms producing cell-type-specific transcriptomes during development. PMID- 29229753 TI - Fusobacterium Travels with Colorectal Cancer Cells. AB - Fusobacterium is enriched in colorectal cancer, but until now it has been unclear whether these bacteria drive tumorigenesis. A recent study shows that colorectal cancer cells take their microbiomes with them as they metastasize-and that targeting Fusobacterium with antibiotics reduces tumor growth in mice xenografts. PMID- 29229751 TI - SUV420H2 is an epigenetic regulator of epithelial/mesenchymal states in pancreatic cancer. AB - Epithelial-to-mesenchymal transition is implicated in metastasis, where carcinoma cells lose sessile epithelial traits and acquire mesenchymal migratory potential. The mesenchymal state is also associated with cancer stem cells and resistance to chemotherapy. It might therefore be therapeutically beneficial to promote epithelial identity in cancer. Because large-scale cell identity shifts are often orchestrated on an epigenetic level, we screened for candidate epigenetic factors and identified the histone methyltransferase SUV420H2 (KMT5C) as favoring the mesenchymal identity in pancreatic cancer cell lines. Through its repressive mark H4K20me3, SUV420H2 silences several key drivers of the epithelial state. Its knockdown elicited mesenchymal-to-epithelial transition on a molecular and functional level, and cells displayed decreased stemness and increased drug sensitivity. An analysis of human pancreatic cancer biopsies was concordant with these findings, because high levels of SUV420H2 correlated with a loss of epithelial characteristics in progressively invasive cancer. Together, these data indicate that SUV420H2 is an upstream epigenetic regulator of epithelial/mesenchymal state control. PMID- 29229754 TI - From app developer to WhatsApp queen-stereotypes of 21st century doctors. PMID- 29229755 TI - The full moon and motorcycle related mortality: population based double control study. AB - OBJECTIVE: To test whether a full moon contributes to motorcycle related deaths. DESIGN: Population based, individual level, double control, cross sectional analysis. SETTING: Nighttime (4 pm to 8 am), United States. PARTICIPANTS: 13 029 motorcycle fatalities throughout the United States, 1975 to 2014 (40 years). MAIN OUTCOME MEASURE: Motorcycle fatalities during a full moon. RESULTS: 13 029 motorcyclists were in fatal crashes during 1482 relevant nights. The typical motorcyclist was a middle aged man (mean age 32 years) riding a street motorcycle with a large engine in a rural location who experienced a head-on frontal impact and was not wearing a helmet. 4494 fatal crashes occurred on the 494 nights with a full moon (9.10/night) and 8535 on the 988 control nights without a full moon (8.64/night). Comparisons yielded a relative risk of 1.05 associated with the full moon (95% confidence interval 1.02 to 1.09, P=0.005), a conditional odds ratio of 1.26 (95% confidence interval 1.17 to 1.37, P<0.001), and an absolute increase of 226 additional deaths over the study interval. The increase extended to diverse types of motorcyclists, vehicles, and crashes; was accentuated during a supermoon; and replicated in analyses from the United Kingdom, Canada, and Australia. CONCLUSION: The full moon is associated with an increased risk of fatal motorcycle crashes, although potential confounders cannot be excluded. An awareness of the risk might encourage motorcyclists to ride with extra care during a full moon and, more generally, to appreciate the power of seemingly minor distractions at all times. PMID- 29229756 TI - Decoding the molecular switches of natriuretic peptides which differentiate its vascular and renal functions. AB - Heart failure (HF) is associated with high morbidity and mortality. Dysfunction of blood pressure and/or volume homeostatic processes result in lower perfusion and/or congestion. Treatment strategies exerting differential effects on pressure and volume mechanisms are critical in handling patients with HF. Atrial natriuretic peptides (ANPs) are a key hormone in maintaining circulation. It binds to NP receptor-A (NPR-A) on vasculature, kidneys and nervous system to lowers blood pressure and volume. It exerts a concentration-dependent pharmacological activity, and only increased renal excretion of water and sodium at low doses and vasodilation along with renal effects at slightly higher doses. Recently, we showed that K-Ring (conserved ring of krait venom NP) elicited only vasodilatory properties despite its ability to evoke NPR-A. Through systematic analysis of the structure-function relationships of K-Ring, we have delineated the molecular switches that control vasodilatory and diuretic properties of NPs in anesthetized rats. In the process, we have identified residues that - (a) differentiate vascular and renal functions, (b) affect heart rate and pulse pressure, (c) exhibit sustained effect on vasodilatory function and (d) forceful diuresis switches. Furthermore, we have shown these residues to have equivalent effects on ANP scaffold, thereby introducing modularity in designing function based ANP analogs. By comparing the ability of designed NPs to evoke cGMP levels, we propose a hypothetical mechanism for the observed tissue-specific effects. The present study opens new avenues in the development of suitable therapeutic agents for personalized care for HF patients. PMID- 29229757 TI - Structure and activity of ChiX: a peptidoglycan hydrolase required for chitinase secretion by Serratia marcescens. AB - The Gram-negative bacterium Serratia marcescens secretes many proteins that are involved in extracellular chitin degradation. This so-called chitinolytic machinery includes three types of chitinase enzymes and a lytic polysaccharide monooxygenase. An operon has been identified in S. marcescens, chiWXYZ, that is thought to be involved in the secretion of the chitinolytic machinery. Genetic evidence points to the ChiX protein being a key player in the secretion mechanism, since deletion of the chiX gene in S. marcescens led to a mutant strain blocked for secretion of all members of the chitinolytic machinery. In this work, a detailed structural and biochemical characterisation of ChiX is presented. The high-resolution crystal structure of ChiX reveals the protein to be a member of the LAS family of peptidases. ChiX is shown to be a zinc containing metalloenzyme, and in vitro assays demonstrate that ChiX is an l-Ala d Glu endopeptidase that cleaves the cross-links in bacterial peptidoglycan. This catalytic activity is shown to be intimately linked with the secretion of the chitinolytic machinery, since substitution of the ChiX Asp-120 residue results in a variant protein that is both unable to digest peptidoglycan and cannot rescue the phenoytype of a chiX mutant strain. PMID- 29229758 TI - The stress sigma factor of RNA polymerase RpoS/sigmaS is a solvent-exposed open molecule in solution. AB - In bacteria, one primary and multiple alternative sigma (sigma) factors associate with the RNA polymerase core enzyme (E) to form holoenzymes (Esigma) with different promoter recognition specificities. The alternative sigma factor RpoS/sigmaS is produced in stationary phase and under stress conditions and reprograms global gene expression to promote bacterial survival. To date, the three-dimensional structure of a full-length free sigma factor remains elusive. The current model suggests that extensive interdomain contacts in a free sigma factor result in a compact conformation that masks the DNA-binding determinants of sigma, explaining why a free sigma factor does not bind double-stranded promoter DNA efficiently. Here, we explored the solution conformation of sigmaS using amide hydrogen/deuterium exchange coupled with mass spectrometry, NMR, analytical ultracentrifugation and molecular dynamics. Our data strongly argue against a compact conformation of free sigmaS Instead, we show that sigmaS adopts an open conformation in solution in which the folded sigma2 and sigma4 domains are interspersed by domains with a high degree of disorder. These findings suggest that E binding induces major changes in both the folding and domain arrangement of sigmaS and provide insights into the possible mechanisms of regulation of sigmaS activity by its chaperone Crl. PMID- 29229759 TI - JMJD6 induces HOTAIR, an oncogenic lincRNA, by physically interacting with its proximal promoter. AB - Using microarray analysis, we found that HOX transcript antisense intergenic RNA (HOTAIR) is up-regulated by Jumonji domain containing-6 (JMJD6), a bifunctional lysyl hydroxylase and arginine demethylase. In breast cancer, both JMJD6 and HOTAIR RNAs increase tumor growth and associate with poor prognosis but no molecular relationship between them is known. We show that overexpression of JMJD6 increased HOTAIR expression and JMJD6 siRNAs suppressed it in ER+ MCF-7, triple negative MDA-MB-231 and non-breast cancer HEK 293 cells. Therefore, JMJD6 regulates HOTAIR independent of ER status. Using various deletion constructs spanning (-1874 to +50) of the HOTAIR promoter, we identified pHP216 (-216 to +50 bp) as the smallest construct that retained maximal JMJD6 responsiveness. In ChIP assays, JMJD6 bound this region suggesting that JMJD6 may be directly recruited to the HOTAIR promoter. Mutant JMJD6H187A that is devoid of enzymatic activity could bind this site but failed to induce transcription. ChIP and electromobility shift assays identified a JMJD6 interaction region from (-123 to -103 bp) within the HOTAIR promoter. In tumor samples but not normal breast tissue, the expression of JMJD6 linearly correlated with HOTAIR suggesting that JMJD6 mediated up-regulation may occur specifically in tumors. Further, concurrent high expression of both genes correlated with poor survival when individual expression of either gene showed no significant association in TCGA datasets. We propose that high JMJD6 expression may achieve higher levels of HOTAIR in breast tumors. Further, since high levels of HOTAIR promote metastasis and death, blocking JMJD6 may be useful in preventing such events. PMID- 29229760 TI - Functional characterization of the Ca2+-ATPase SMA1 from Schistosoma mansoni. AB - Schistosoma mansoni is a parasite that causes bilharzia, a neglected tropical disease affecting hundreds of millions of people each year worldwide. In 2012, S. mansoni had been identified as the only invertebrate possessing two SERCA-type Ca2+-ATPases, SMA1 and SMA2. However, our analysis of recent genomic data shows that the presence of two SERCA pumps is rather frequent in parasitic flatworms. To understand the reasons of this redundancy in S. mansoni, we compared SMA1 and SMA2 at different levels. In terms of sequence and organization, the genes SMA1 and SMA2 are similar, suggesting that they might be the result of a duplication event. At the protein level, SMA1 and SMA2 only slightly differ in length and in the sequence of the nucleotide-binding domain. To get functional information on SMA1, we produced it in an active form in Saccharomyces cerevisiae, as previously done for SMA2. Using phosphorylation assays from ATP, we demonstrated that like SMA2, SMA1 bound calcium in a cooperative mode with an apparent affinity in the micromolar range. We also showed that SMA1 and SMA2 had close sensitivities to cyclopiazonic acid but different sensitivities to thapsigargin, two specific inhibitors of SERCA pumps. On the basis of transcriptomic data available in GeneDB, we hypothesize that SMA1 is a housekeeping Ca2+-ATPase, whereas SMA2 might be required in particular striated-like muscles like those present the tail of the cercariae, the infecting form of the parasite. PMID- 29229761 TI - An unusual diphosphatase from the PhnP family cleaves reactive FAD photoproducts. AB - Flavins are notoriously photolabile, but while the photoproducts derived from the iso-alloxazine ring are well known the other photoproducts are not. In the case of FAD, typically the main cellular flavin, the other photoproducts are predicted to include four- and five-carbon sugars linked to ADP. These FAD photoproducts were shown to be potent glycating agents, more so than ADP-ribose. Such toxic compounds would require disposal via an ADP-sugar diphosphatase or other route. Comparative analysis of bacterial genomes uncovered a candidate disposal gene that is chromosomally clustered with genes for FAD synthesis or transport and is predicted to encode a protein of the PhnP cyclic phosphodiesterase family. The representative PhnP family enzyme from Koribacter versatilis (here named Fpd, FAD photoproduct diphosphatase) was found to have high, Mn2+-dependent diphosphatase activity against FAD photoproducts, FAD, and ADP-ribose, but almost no phosphodiesterase activity against riboflavin 4',5'-cyclic phosphate, a chemical breakdown product of FAD. To provide a structural basis of the unique Fpd activity, the crystal structure of K. versatilis Fpd was determined. The results place Fpd in the broad metallo-beta-lactamase-like family of hydrolases, a diverse family commonly using two metals for hydrolytic catalysis. The active site of Fpd contains two Mn2+ ions and a bound phosphate, consistent with a diphosphatase mechanism. Our results characterize the first PhnP family member that is a diphosphatase rather than a cyclic phosphodiesterase and suggest its involvement in a cellular damage-control system that efficiently hydrolyzes the reactive, ADP-ribose-like products of FAD photodegradation. PMID- 29229764 TI - Clusters Not Classifications: Making Sense of Complement-Mediated Kidney Injury. PMID- 29229762 TI - Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239. AB - OXA-239 is a class D carbapenemase isolated from an Acinetobacter baumannii strain found in Mexico. This enzyme is a variant of OXA-23 with three amino acid substitutions in or near the active site. These substitutions cause OXA-239 to hydrolyze late-generation cephalosporins and the monobactam aztreonam with greater efficiency than OXA-23. OXA-239 activity against the carbapenems doripenem and imipenem is reduced ~3-fold and 20-fold, respectively. Further analysis demonstrated that two of the substitutions (P225S and D222N) are largely responsible for the observed alteration of kinetic parameters, while the third (S109L) may serve to stabilize the protein. Structures of OXA-239 with cefotaxime, doripenem and imipenem bound as acyl-intermediates were determined. These structures reveal that OXA-239 has increased flexibility in a loop that contains P225S and D222N. When carbapenems are bound, the conformation of this loop is essentially identical with that observed previously for OXA-23, with a narrow active site that makes extensive contacts to the ligand. When cefotaxime is bound, the loop can adopt a different conformation that widens the active site to allow binding of that bulky drug. This alternate conformation is made possible by P225S and further stabilized by D222N. Taken together, these results suggest that the three substitutions were selected to expand the substrate specificity profile of OXA-23 to cephalosporins and monobactams. The loss of activity against imipenem, however, suggests that there may be limits to the plasticity of class D enzymes with regard to evolving active sites that can effectively bind multiple classes of beta-lactam drugs. PMID- 29229765 TI - Renal Dendritic Cells: The Long and Winding Road. PMID- 29229763 TI - Assaying kinase activity of the TPL-2/NF-kappaB1 p105/ABIN-2 complex using an optimal peptide substrate. AB - The MKK1/2 kinase tumour progression locus 2 (TPL-2) is critical for the production of tumour necrosis factor alpha (TNFalpha) in innate immune responses and a potential anti-inflammatory drug target. Several earlier pharmaceutical company screens with the isolated TPL-2 kinase domain have identified small molecule inhibitors that specifically block TPL-2 signalling in cells, but none of these have progressed to clinical development. We have previously shown that TPL-2 catalytic activity regulates TNF production by macrophages while associated with NF-kappaB1 p105 and ABIN-2, independently of MKK1/2 phosphorylation via an unknown downstream substrate. In the present study, we used a positional scanning peptide library to determine the optimal substrate specificity of a complex of TPL-2, NF-kappaB1 p105 and ABIN-2. Using an optimal peptide substrate based on this screen and a high-throughput mass spectrometry assay to monitor kinase activity, we found that the TPL-2 complex has significantly altered sensitivities versus existing ATP-competitive TPL-2 inhibitors than the isolated TPL-2 kinase domain. These results imply that screens with the more physiologically relevant TPL-2/NF-kappaB1 p105/ABIN-2 complex have the potential to deliver novel TPL-2 chemical series; both ATP-competitive and allosteric inhibitors could emerge with significantly improved prospects for development as anti-inflammatory drugs. PMID- 29229766 TI - Mesenchymal Stromal Cells for AKI after Cardiac Surgery. PMID- 29229767 TI - NHS England throws down challenge to government. PMID- 29229768 TI - Revealing age-related changes of adult hippocampal neurogenesis using mathematical models. AB - New neurons are continuously generated in the dentate gyrus of the adult hippocampus. This continuous supply of newborn neurons is important to modulate cognitive functions. Yet the number of newborn neurons declines with age. Increasing Wnt activity upon loss of dickkopf 1 can counteract both the decline of newborn neurons and the age-related cognitive decline. However, the precise cellular changes underlying the age-related decline or its rescue are fundamentally not understood. The present study combines a mathematical model and experimental data to address features controlling neural stem cell (NSC) dynamics. We show that available experimental data fit a model in which quiescent NSCs may either become activated to divide or may undergo depletion events, such as astrocytic transformation and apoptosis. Additionally, we demonstrate that old NSCs remain quiescent longer and have a higher probability of becoming re activated than depleted. Finally, our model explains that high NSC-Wnt activity leads to longer time in quiescence while enhancing the probability of activation. Altogether, our study shows that modulation of the quiescent state is crucial to regulate the pool of stem cells throughout the life of an animal. PMID- 29229769 TI - Cytoplasmic polyadenylation-mediated translational control of maternal mRNAs directs maternal-to-zygotic transition. AB - In the earliest stages of animal development following fertilization, maternally deposited mRNAs direct biological processes to the point of zygotic genome activation (ZGA). These maternal mRNAs undergo cytoplasmic polyadenylation (CPA), suggesting translational control of their activation. To elucidate the biological role of CPA during embryogenesis, we performed genome-wide polysome profiling at several stages of zebrafish development. Our analysis revealed a correlation between CPA and polysome-association dynamics, demonstrating a coupling of translation to the CPA of maternal mRNAs. Pan-embryonic CPA inhibition disrupted the maternal-to-zygotic transition (MZT), causing a failure of developmental progression beyond the mid-blastula transition and changes in global gene expression that indicated a failure of ZGA and maternal mRNA clearance. Among the genes that were differentially expressed were those encoding chromatin modifiers and key transcription factors involved in ZGA, including nanog, pou5f3 and sox19b, which have distinct CPA dynamics. Our results establish the necessity of CPA for ensuring progression of the MZT. The RNA-seq data generated in this study represent a valuable zebrafish resource for the discovery of novel elements of the early embryonic transcriptome. PMID- 29229770 TI - Retinoblastoma 1 protects T cell maturation from premature apoptosis by inhibiting E2F1. AB - T lymphocytes are key cellular components of an acquired immune system and play essential roles in cell-mediated immunity. T cell development occurs in the thymus where 95% of immature thymocytes are eliminated via apoptosis. It is known that mutation of Zeb1, one of the retinoblastoma 1 (Rb1) target genes, results in a decrease in the number of immature T cells in mice. E2F1, an RB1-interacting protein, has been shown to regulate mature T cell development by interfering with thymocyte apoptosis. However, whether Rb1 regulates thymocyte development in vivo still needs to be further investigated. Here, we use a zebrafish model to investigate the role of Rb1 in T cell development. We show that Rb1-deficient fish exhibit a significant reduction in T cell number during early development that it is attributed to the accelerated apoptosis of immature T cells in a caspase-dependent manner. We further show that E2F1 overexpression could mimic the reduced T lymphocytes phenotype of Rb1 mutants, and E2F1 knockdown could rescue the phenotype in Rb1-deficient mutants. Collectively, our data indicate that the Rb1-E2F1-caspase axis is crucial for protecting immature T cells from apoptosis during early T lymphocyte maturation. PMID- 29229771 TI - Drosophila female-specific Ilp7 motoneurons are generated by Fruitless-dependent cell death in males and by a double-assurance survival role for Transformer in females. AB - Female-specific Ilp7 neuropeptide-expressing motoneurons (FS-Ilp7 motoneurons) are required in Drosophila for oviduct function in egg laying. Here, we uncover cellular and genetic mechanisms underlying their female-specific generation. We demonstrate that programmed cell death (PCD) eliminates FS-Ilp7 motoneurons in males, and that this requires male-specific splicing of the sex-determination gene fruitless (fru) into the FruMC isoform. However, in females, fru alleles that only generate FruM isoforms failed to kill FS-Ilp7 motoneurons. This blockade of FruM-dependent PCD was not attributable to doublesex gene function but to a non-canonical role for transformer (tra), a gene encoding the RNA splicing activator that regulates female-specific splicing of fru and dsx transcripts. In both sexes, we show that Tra prevents PCD even when the FruM isoform is expressed. In addition, we found that FruMC eliminated FS-Ilp7 motoneurons in both sexes, but only when Tra was absent. Thus, FruMC-dependent PCD eliminates female-specific neurons in males, and Tra plays a double-assurance function in females to establish and reinforce the decision to generate female specific neurons. PMID- 29229772 TI - Hierarchical genetic interactions between FOXG1 and LHX2 regulate the formation of the cortical hem in the developing telencephalon. AB - During forebrain development, a telencephalic organizer called the cortical hem is crucial for inducing hippocampal fate in adjacent cortical neuroepithelium. How the hem is restricted to its medial position is therefore a fundamental patterning issue. Here, we demonstrate that Foxg1-Lhx2 interactions are crucial for the formation of the hem. Loss of either gene causes a region of the cortical neuroepithelium to transform into hem. We show that FOXG1 regulates Lhx2 expression in the cortical primordium. In the absence of Foxg1, the presence of Lhx2 is sufficient to suppress hem fate, and hippocampal markers appear selectively in Lhx2-expressing regions. FOXG1 also restricts the temporal window in which loss of Lhx2 results in a transformation of cortical primordium into hem. Therefore, Foxg1 and Lhx2 form a genetic hierarchy in the spatiotemporal regulation of cortical hem specification and positioning, and together ensure the normal development of this hippocampal organizer. PMID- 29229774 TI - Ethical considerations for the design and implementation of child injury prevention interventions: the example of delivering and installing safety equipment into the home. AB - INTRODUCTION: Public health ethics is a growing field of academic interest but ethical discussion of injury prevention seems to have received limited attention. Interventions that promise to be effective are not necessarily-without explicit justification-'good' and 'right' interventions in every sense. This paper explores public health ethics in the context of child injury prevention with the objective to initiate interdisciplinary dialogue on the ethics of child safety interventions. METHOD: A framework of seven public health ethics principles (non maleficence, health maximisation, beneficence, respect for autonomy, justice, efficiency and proportionality) were applied to an intervention to promote child safety in the home. RESULTS: Preventing child injury in the home is ethically challenging due to the requirement for the state to intervene in the private sphere. Non-maleficence and beneficence are difficult to judge within this intervention as these are likely to be highly dependent on the nature of intervention delivery, in particular, the quality of communication. Respect for autonomy is challenged by an intervention occurring in the home. The socioeconomic gradient in child injury risk is an important factor but a nuanced approach could help to avoid exacerbating inequalities or stigmatisation. Equally, a nuanced approach may be necessary to accommodate the principles of proportionality and efficiency within the local context. CONCLUSION: We conclude that this intervention is justifiable from an ethical perspective but that this type of reflection loop is helpful to identify the impact of interventions beyond effectiveness. PMID- 29229773 TI - AP-2alpha and AP-2beta cooperatively orchestrate homeobox gene expression during branchial arch patterning. AB - The evolution of a hinged moveable jaw with variable morphology is considered a major factor behind the successful expansion of the vertebrates. DLX homeobox transcription factors are crucial for establishing the positional code that patterns the mandible, maxilla and intervening hinge domain, but how the genes encoding these proteins are regulated remains unclear. Herein, we demonstrate that the concerted action of the AP-2alpha and AP-2beta transcription factors within the mouse neural crest is essential for jaw patterning. In the absence of these two proteins, the hinge domain is lost and there are alterations in the size and patterning of the jaws correlating with dysregulation of homeobox gene expression, with reduced levels of Emx, Msx and Dlx paralogs accompanied by an expansion of Six1 expression. Moreover, detailed analysis of morphological features and gene expression changes indicate significant overlap with various compound Dlx gene mutants. Together, these findings reveal that the AP-2 genes have a major function in mammalian neural crest development, influencing patterning of the craniofacial skeleton via the DLX code, an effect that has implications for vertebrate facial evolution, as well as for human craniofacial disorders. PMID- 29229776 TI - Positive charge in the n-region of the signal peptide contributes to efficient post-translational translocation of small secretory preproteins. AB - Increasing evidence indicates that many small secretory preproteins can undergo post-translational translocation across the membrane of the endoplasmic reticulum. Although the cellular machinery involved in post-translational translocation of small secretory preproteins has begun to be elucidated, the intrinsic signals contained within these small secretory preproteins that contribute to their efficient post-translational translocation remain unknown. Here, we analyzed the eukaryotic secretory proteome and discovered the small secretory preproteins tend to have a higher probability to harbor the positive charge in the n-region of the signal peptide (SP). Eliminating the positive charge of the n-region blocked post-translational translocation of newly synthesized preproteins and selectively impaired translocation efficiency of small secretory preproteins. The pathophysiological significance of the positive charge in the n-region of SP was underscored by recently identified preproinsulin SP mutations that impair translocation of preproinsulin and cause maturity onset diabetes of youth (MODY). Remarkably, we have found that slowing the polypeptide elongation rate of small secretory preproteins could alleviate the translocation defect caused by loss of the n-region positive charge of the signal peptide. Together, these data reveal not only a previously unrecognized role of the n region's positive charge in ensuring efficient post-translational translocation of small secretory preproteins, but they also highlight the molecular contribution of defects in this process to the pathogenesis of genetic disorders such as MODY. PMID- 29229775 TI - Molecular characterization of DXCF cyanobacteriochromes from the cyanobacterium Acaryochloris marina identifies a blue-light power sensor. AB - Cyanobacteriochromes (CBCRs) are linear tetrapyrrole-binding photoreceptors that sense a wide range of wavelengths from ultraviolet to far-red. The primary photoreaction in these reactions is a Z/E isomerization of the double bond between rings C and D. After this isomerization, various color-tuning events establish distinct spectral properties of the CBCRs. Among the various CBCRs, the DXCF CBCR lineage is widely distributed among cyanobacteria. Because the DXCF CBCRs from the cyanobacterium Acaryochloris marina vary widely in sequence, we focused on these CBCRs in this study. We identified seven DXCF CBCRs in A. marina and analyzed them after isolation from Escherichia coli that produces phycocyanobilin, a main chromophore for the CBCRs. We found that six of these CBCRs covalently bound a chromophore and exhibited variable properties, including blue/green, blue/teal, green/teal, and blue/orange reversible photoconversions. Notably, one CBCR, AM1_1870g4, displayed unidirectional photoconversion in response to blue-light illumination, with a rapid dark reversion that was temperature-dependent. Furthermore, the photoconversion took place without Z/E isomerization. This observation indicated that AM1_1870g4 likely functions as a blue-light power sensor, whereas typical CBCRs reversibly sense two light qualities. We also found that AM1_1870g4 possesses a GDCF motif in which the Asp residue is swapped with the next Gly residue within the DXCF motif. Site-directed mutagenesis revealed that this swap is essential for the light power-sensing function of AM1_1870g4. This is the first report of a blue-light power sensor from the CBCR superfamily and of photoperception without Z/E isomerization among the bilin-based photoreceptors. PMID- 29229777 TI - Crystal structure of the FliF-FliG complex from Helicobacter pylori yields insight into the assembly of the motor MS-C ring in the bacterial flagellum. AB - The bacterial flagellar motor is a self-assembling supramolecular nanodevice. Its spontaneous biosynthesis is initiated by the insertion of the MS ring protein FliF into the inner membrane, followed by attachment of the switch protein FliG. Assembly of this multiprotein complex is tightly regulated to avoid nonspecific aggregation, but the molecular mechanisms governing flagellar assembly are unclear. Here, we present the crystal structure of the cytoplasmic domain of FliF complexed with the N-terminal domain of FliG (FliF C -FliG N ) from the bacterium Helicobacter pylori Within this complex, FliF C interacted with FliG N through extensive hydrophobic contacts similar to those observed in the FliF C -FliG N structure from the thermophile Thermotoga maritima, indicating conservation of the FliF C -FliG N interaction across bacterial species. Analysis of the crystal lattice revealed that the heterodimeric complex packs as a linear superhelix via stacking of the armadillo repeat-like motifs (ARM) of FliG N Notably, this linear helix was similar to that observed for the assembly of the FliG middle domain. We validated the in vivo relevance of the FliG N stacking by complementation studies in Escherichia coli Furthermore, structural comparison with apo FliG from the thermophile Aquifex aeolicus indicated that FliF regulates the conformational transition of FliG and exposes the complementary ARM-like motifs of FliG N , containing conserved hydrophobic residues. FliF apparently both provides a template for FliG polymerization and spatiotemporally controls subunit interactions within FliG. Our findings reveal that a small protein fold can serve as a versatile building block to assemble into a multiprotein machinery of distinct shapes for specific functions. PMID- 29229778 TI - Structural and functional insights into the role of BamD and BamE within the beta barrel assembly machinery in Neisseria gonorrhoeae. AB - The beta-barrel assembly machinery (BAM) is a conserved multicomponent protein complex responsible for the biogenesis of beta-barrel outer membrane proteins (OMPs) in Gram-negative bacteria. Given its role in the production of OMPs for survival and pathogenesis, BAM represents an attractive target for the development of therapeutic interventions, including drugs and vaccines against multidrug-resistant bacteria such as Neisseria gonorrhoeae The first structure of BamA, the central component of BAM, was from N. gonorrhoeae, the etiological agent of the sexually transmitted disease gonorrhea. To aid in pharmaceutical targeting of BAM, we expanded our studies to BamD and BamE within BAM of this clinically relevant human pathogen. We found that the presence of BamD, but not BamE, is essential for gonococcal viability. However, BamE, but not BamD, was cell-surface-displayed under native conditions; however, in the absence of BamE, BamD indeed becomes surface-exposed. Loss of BamE altered cell envelope composition, leading to slower growth and an increase in both antibiotic susceptibility and formation of membrane vesicles containing greater amounts of vaccine antigens. Both BamD and BamE are expressed in diverse gonococcal isolates, under host-relevant conditions, and throughout different phases of growth. The solved structures of Neisseria BamD and BamE share overall folds with Escherichia coli proteins but contain differences that may be important for function. Together, these studies highlight that, although BAM is conserved across Gram-negative bacteria, structural and functional differences do exist across species, which may be leveraged in the development of species-specific therapeutics in the effort to combat multidrug resistance. PMID- 29229779 TI - Subtle changes at the variable domain interface of the T-cell receptor can strongly increase affinity. AB - Most affinity-maturation campaigns for antibodies and T-cell receptors (TCRs) operate on the residues at the binding site, located within the loops known as complementarity-determining regions (CDRs). Accordingly, mutations in contact residues, or so-called "second shell" residues, that increase affinity are typically identified by directed evolution involving combinatorial libraries. To determine the impact of residues located at a distance from the binding site, here we used single-codon libraries of both CDR and non-CDR residues to generate a deep mutational scan of a human TCR against the cancer antigen MART-1.HLA-A2. Non-CDR residues included those at the interface of the TCR variable domains (Valpha and Vbeta) and surface-exposed framework residues. Mutational analyses showed that both Valpha/Vbeta interface and CDR residues were important in maintaining binding to MART-1.HLA-A2, probably due to either structural requirements for proper Valpha/Vbeta association or direct contact with the ligand. More surprisingly, many Valpha/Vbeta interface substitutions yielded improved binding to MART-1.HLA-A2. To further explore this finding, we constructed interface libraries and selected them for improved stability or affinity. Among the variants identified, one conservative substitution (F45betaY) was most prevalent. Further analysis of F45betaY showed that it enhanced thermostability and increased affinity by 60-fold. Thus, introducing a single hydroxyl group at the Valpha/Vbeta interface, at a significant distance from the TCR.peptide.MHC-binding site, remarkably affected ligand binding. The variant retained a high degree of specificity for MART-1.HLA-A2, indicating that our approach provides a general strategy for engineering improvements in either soluble or cell-based TCRs for therapeutic purposes. PMID- 29229780 TI - Cathepsin D regulates cathepsin B activation and disease severity predominantly in inflammatory cells during experimental pancreatitis. AB - Acute pancreatitis is a complex disorder involving both premature intracellular protease activation and inflammatory cell invasion. An initiating event is the intracellular activation of trypsinogen by cathepsin B (CTSB), which can be induced directly via G protein-coupled receptors on acinar cells or through inflammatory cells. Here, we studied CTSB regulation by another lysosomal hydrolase, cathepsin D (CTSD), using mice with a complete (CTSD-/-) or pancreas specific conditional CTSD knockout (KO) (CTSDf/f/p48Cre/+). We induced acute pancreatitis by repeated caerulein injections and isolated acinar and bone marrow cells for ex vivo studies. Supramaximal caerulein stimulation induced subcellular redistribution of CTSD from the lysosomal to the zymogen-containing subcellular compartment of acinar cells and activation of CTSD, CTSB, and trypsinogen. Of note, the CTSD KO greatly reduced CTSB and trypsinogen activation in acinar cells, and CTSD directly activated CTSB but not trypsinogen in vitro During pancreatitis in pancreas-specific CTSDf/f/p48Cre/+ animals, markers of severity were reduced only at 1 h, whereas in the complete KO, this effect also included the late disease phase (8 h), indicating an important effect of extra-acinar CTSD on course of the disease. CTSD-/- leukocytes exhibited reduced cytokine release after lipopolysaccharide (LPS) stimulation, and CTSD KO also reduced caspase-3 activation and apoptosis in acinar cells stimulated with the intestinal hormone cholecystokinin. In summary, CTSD is expressed in pancreatic acinar and inflammatory cells, undergoes subcellular redistribution and activation during experimental pancreatitis, and regulates disease severity by potently activating CTSB. Its impact is only minimal and transient in the early, acinar cell dependent phase of pancreatitis and much greater in the later, inflammatory cell dependent phase of the disease. PMID- 29229782 TI - Innate Lymphoid Cells (ILCs): Cytokine Hubs Regulating Immunity and Tissue Homeostasis. AB - Innate lymphoid cells (ILCs) have emerged as an expanding family of effector cells particularly enriched in the mucosal barriers. ILCs are promptly activated by stress signals and multiple epithelial- and myeloid-cell-derived cytokines. In response, ILCs rapidly secrete effector cytokines, which allow them to survey and maintain the mucosal integrity. Uncontrolled action of ILCs might contribute to tissue damage, chronic inflammation, metabolic diseases, autoimmunity, and cancer. Here we discuss the recent advances in our understanding of the cytokine network that modulate ILC immune responses: stimulating cytokines, signature cytokines secreted by ILC subsets, autocrine cytokines, and cytokines that induce cell plasticity. PMID- 29229781 TI - Differential control of Toll-like receptor 4-induced interleukin-10 induction in macrophages and B cells reveals a role for p90 ribosomal S6 kinases. AB - Increasing evidence has linked dysregulated interleukin (IL)-10 production by IL 10+ve B cells to autoimmunity, highlighting the importance of improving the understanding of the regulation of IL-10 production in these cells. In both B cells and myeloid cells, IL-10 can be produced in response to Toll-like receptor (TLR) agonists. In macrophages, previous studies have established that mitogen- and stress-activated protein kinases (MSKs) regulate IL-10 production via the phosphorylation of cAMP response element-binding (CREB) protein on the IL-10 promoter. We found here that although MSKs are activated in peritoneal B cells in response to TLR4 agonists, neither MSKs nor CREB are required for IL-10 production in these cells. Using a combination of chemical inhibitors and knockout mice, we found that IL-10 induction in B cells was regulated by an ERK1/2- and p90 ribosomal S6 kinase-dependent mechanism, unlike in macrophages in which p90 ribosomal S6 kinase was not required. This observation highlights fundamental differences in the signaling controlling IL-10 production in B cells and macrophages, even though these two cell types respond to a common TLR stimulus. PMID- 29229783 TI - Heartbeat: What is the best emergency treatment for decompensated severe aortic stenosis? PMID- 29229784 TI - Oral anticoagulants and liver injury: the threat of uncontrolled confounding. PMID- 29229785 TI - The chemokine receptor CX3CR1 coordinates monocyte recruitment and endothelial regeneration after arterial injury. AB - Regeneration of arterial endothelium after injury is critical for the maintenance of normal blood flow, cell trafficking, and vascular function. Using mouse models of carotid injury, we show that the transition from a static to a dynamic phase of endothelial regeneration is marked by a strong increase in endothelial proliferation, which is accompanied by induction of the chemokine CX3CL1 in endothelial cells near the wound edge, leading to progressive recruitment of Ly6Clo monocytes expressing high levels of the cognate CX3CR1 chemokine receptor. In Cx3cr1-deficient mice recruitment of Ly6Clo monocytes, endothelial proliferation and regeneration of the endothelial monolayer after carotid injury are impaired, which is rescued by acute transfer of normal Ly6Clo monocytes. Furthermore, human non-classical monocytes induce proliferation of endothelial cells in co-culture experiments in a VEGFA-dependent manner, and monocyte transfer following carotid injury promotes endothelial wound closure in a hybrid mouse model in vivo Thus, CX3CR1 coordinates recruitment of specific monocyte subsets to sites of endothelial regeneration, which promote endothelial proliferation and arterial regeneration. PMID- 29229787 TI - Wave height estimates from pressure and velocity data at an intermediate depth in the presence of uniform currents. AB - Bounds on estimates of wave heights (valid for large amplitudes) from pressure and flow measurements at an arbitrary intermediate depth have been provided. Two dimensional irrotational steady water waves over a flat bed with a finite depth in the presence of underlying uniform currents have been considered in the analysis. Five different upper bounds based on a combination of pressure and velocity field measurements have been derived, though there is only one available lower bound on the wave height in the case of the speed of current greater than or less than the wave speed.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229786 TI - Seed-induced Abeta deposition is modulated by microglia under environmental enrichment in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by severe neuronal loss as well as the accumulation of amyloid-beta (Abeta), which ultimately leads to plaque formation. Although there is now a general agreement that the aggregation of Abeta can be initiated by prion-like seeding, the impact and functional consequences of induced Abeta deposits (Abeta seeding) on neurons still remain open questions. Here, we find that Abeta seeding, representing early stages of plaque formation, leads to a dramatic decrease in proliferation and neurogenesis in two APP transgenic mouse models. We further demonstrate that neuronal cell death occurs primarily in the vicinity of induced Abeta deposits culminating in electrophysiological abnormalities. Notably, environmental enrichment and voluntary exercise not only revives adult neurogenesis and reverses memory deficits but, most importantly, prevents Abeta seeding by activated, phagocytic microglia cells. Our work expands the current knowledge regarding Abeta seeding and the consequences thereof and attributes microglia an important role in diminishing Abeta seeding by environmental enrichment. PMID- 29229788 TI - On three-dimensional Gerstner-like equatorial water waves. AB - This paper reviews some recent mathematical research activity in the field of nonlinear geophysical water waves. In particular, we survey a number of exact Gerstner-like solutions which have been derived to model various geophysical oceanic waves, and wave-current interactions, in the equatorial region. These solutions are nonlinear, three-dimensional and explicit in terms of Lagrangian variables.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229789 TI - Recent advances on the global regularity for irrotational water waves. AB - We review recent progress on the long-time regularity of solutions of the Cauchy problem for the water waves equations, in two and three dimensions. We begin by introducing the free boundary Euler equations and discussing the local existence of solutions using the paradifferential approach. We then describe in a unified framework, using the Eulerian formulation, global existence results for three- and two-dimensional gravity waves, and our joint result (with Deng and Pausader) on global regularity for the gravity-capillary model in three dimensions. We conclude this review with a short discussion about the formation of singularities and give a few additional references to other interesting topics in the theory.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229790 TI - On the short-wavelength stabilities of some geophysical flows. AB - This paper is a survey of the short-wavelength stability method for rotating flows. Additional complications such as stratification in the flow or the presence of non-conservative body forces are considered too. This method is applied to the specific study of some exact geophysical flows. For Gerstner-like geophysical flows one can identify perturbations in certain directions as a source of instabilities with an exponentially growing amplitude, the growth rate of the instabilities depending on the steepness of the travelling wave profile. On the other hand, for certain physically realistic velocity profiles, steady flows moving only in the azimuthal direction, with no variation in this direction, are locally stable to the short-wavelength perturbations.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229791 TI - Hamiltonian models for the propagation of irrotational surface gravity waves over a variable bottom. AB - A single incompressible, inviscid, irrotational fluid medium bounded by a free surface and varying bottom is considered. The Hamiltonian of the system is expressed in terms of the so-called Dirichlet-Neumann operators. The equations for the surface waves are presented in Hamiltonian form. Specific scaling of the variables is selected which leads to approximations of Boussinesq and Korteweg-de Vries (KdV) types, taking into account the effect of the slowly varying bottom. The arising KdV equation with variable coefficients is studied numerically when the initial condition is in the form of the one-soliton solution for the initial depth.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229792 TI - Application of the ideas and techniques of classical fluid mechanics to some problems in physical oceanography. AB - This review makes a case for describing many of the flows observed in our oceans, simply based on the Euler equation, with (piecewise) constant density and with suitable boundary conditions. The analyses start from the Euler and mass conservation equations, expressed in a rotating, spherical coordinate system (but the f-plane and beta-plane approximations are also mentioned); five examples are discussed. For three of them, a suitable non-dimensionalization is introduced, and a single small parameter is identified in each case. These three examples lead straightforwardly and directly to new results for: waves on the Pacific Equatorial Undercurrent (EUC) with a thermocline (in the f-plane); a nonlinear, three-dimensional model for EUC-type flows (in the beta-plane); and a detailed model for large gyres. The other two examples are exact solutions of the complete system: a flow which corresponds to the underlying structure of the Pacific EUC; and a flow based on the necessary requirement to use a non-conservative body force, which produces the type of flow observed in the Antarctic Circumpolar Current. (All these examples have been discussed in detail in the references cited.) This review concludes with a few comments on how these solutions can be extended and expanded.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229793 TI - Analytical approximation and numerical simulations for periodic travelling water waves. AB - We present recent analytical and numerical results for two-dimensional periodic travelling water waves with constant vorticity. The analytical approach is based on novel asymptotic expansions. We obtain numerical results in two different ways: the first is based on the solution of a constrained optimization problem, and the second is realized as a numerical continuation algorithm. Both methods are applied on some examples of non-constant vorticity.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229794 TI - Existence and amplitude bounds for irrotational water waves in finite depth. AB - We prove the existence of solutions to the irrotational water-wave problem in finite depth and derive an explicit upper bound on the amplitude of the nonlinear solutions in terms of the wavenumber, the total hydraulic head, the wave speed and the relative mass flux. Our approach relies upon a reformulation of the water wave problem as a one-dimensional pseudo-differential equation and the Newton Kantorovich iteration for Banach spaces.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229795 TI - The dynamic pressure in deep-water extreme Stokes waves. AB - In this paper, we consider the dynamic pressure in a deep-water extreme Stokes wave. While the presence of stagnation points introduces a number of mathematical complications, maximum principles are applied to analyse the dynamic pressure in the fluid body by means of an excision process. It is shown that the dynamic pressure attains its maximum value beneath the wave crest and its minimum beneath the wave trough, while it decreases in moving away from the crest line along any streamline.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229796 TI - On periodic geophysical water flows with discontinuous vorticity in the equatorial f-plane approximation. AB - We are concerned here with geophysical water waves arising as the free surface of water flows governed by the f-plane approximation. Allowing for an arbitrary bounded discontinuous vorticity, we prove the existence of steady periodic two dimensional waves of small amplitude. We illustrate the local bifurcation result by means of an analysis of the dispersion relation for a two-layered fluid consisting of a layer of constant non-zero vorticity gamma1 adjacent to the surface situated above another layer of constant non-zero vorticity gamma2?gamma1 adjacent to the bed. For certain vorticities gamma1,gamma2, we also provide estimates for the wave speed c in terms of the speed at the surface of the bifurcation inducing laminar flows.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229797 TI - Capturing the flow beneath water waves. AB - Recently, the authors presented two numerical studies for capturing the flow structure beneath water waves (Nachbin and Ribeiro-Junior 2014 Disc. Cont. Dyn. Syst. A34, 3135-3153 (doi:10.3934/dcds.2014.34.3135); Ribeiro-Junior et al. 2017 J. Fluid Mech.812, 792-814 (doi:10.1017/jfm.2016.820)). Closed orbits for irrotational waves with an opposing current and stagnation points for rotational waves were some of the issues addressed. This paper summarizes the numerical strategies adopted for capturing the flow beneath irrotational and rotational water waves. It also presents new preliminary results for particle trajectories, due to irrotational waves, in the presence of a bottom topography.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229798 TI - Solitary interfacial hydroelastic waves. AB - Solitary waves travelling along an elastic plate present between two fluids with different densities are computed in this paper. Different two-dimensional configurations are considered: the upper fluid can be of infinite extent, bounded by a rigid wall or under a second elastic plate. The dispersion relation is obtained for each case and numerical codes based on integro-differential formulations for the full nonlinear problem are derived.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229799 TI - Shallow water equations for equatorial tsunami waves. AB - We present derivations of shallow water model equations of Korteweg-de Vries and Boussinesq type for equatorial tsunami waves in the f-plane approximation and discuss their applicability.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229800 TI - Evolution of statistically inhomogeneous degenerate water wave quartets. AB - A discretized equation for the evolution of random surface wave fields on deep water is derived from Zakharov's equation, allowing for a general treatment of the stability and long-time behaviour of broad-banded sea states. It is investigated for the simple case of degenerate four-wave interaction, and the instability of statistically homogeneous states to small inhomogeneous disturbances is demonstrated. Furthermore, the long-time evolution is studied for several cases and shown to lead to a complex spatio-temporal energy distribution. The possible impact of this evolution on the statistics of freak wave occurrence is explored.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229801 TI - Prediction of the free-surface elevation for rotational water waves using the recovery of pressure at the bed. AB - This paper considers the pressure-streamfunction relationship for a train of regular water waves propagating on a steady current, which may possess an arbitrary distribution of vorticity, in two dimensions. The application of such work is to both near shore and offshore environments, and in particular, for linear waves we provide a description of the role which the pressure function on the seabed plays in determining the free-surface profile elevation. Our approach is shown to provide a good approximation for a range of current conditions.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229802 TI - Dynamic-pressure distributions under Stokes waves with and without a current. AB - To investigate changes in the instability of Stokes waves prior to wave breaking in shallow water, pressure data were recorded vertically over the entire water depth, except in the near-surface layer (from 0 cm to -3 cm), in a recirculating channel. In addition, we checked the pressure asymmetry under several conditions. The phase-averaged dynamic-pressure values for the wave-current motion appear to increase compared with those for the wave-alone motion; however, they scatter in the experimental range. The measured vertical distributions of the dynamic pressure were plotted over one wave cycle and compared to the corresponding predictions on the basis of third-order Stokes wave theory. The dynamic-pressure pattern was not the same during the acceleration and deceleration periods. Spatially, the dynamic pressure varies according to the faces of the wave, i.e. the pressure on the front face is lower than that on the rear face. The direction of wave propagation with respect to the current directly influences the essential features of the resulting dynamic pressure. The results demonstrate that interactions between travelling waves and a current lead more quickly to asymmetry.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229803 TI - Stokes drift. AB - During its periodic motion, a particle floating at the free surface of a water wave experiences a net drift velocity in the direction of wave propagation, known as the Stokes drift (Stokes 1847 Trans. Camb. Philos. Soc.8, 441-455). More generally, the Stokes drift velocity is the difference between the average Lagrangian flow velocity of a fluid parcel and the average Eulerian flow velocity of the fluid. This paper reviews progress in fundamental and applied research on the induced mean flow associated with surface gravity waves since the first description of the Stokes drift, now 170 years ago. After briefly reviewing the fundamental physical processes, most of which have been established for decades, the review addresses progress in laboratory and field observations of the Stokes drift. Despite more than a century of experimental studies, laboratory studies of the mean circulation set up by waves in a laboratory flume remain somewhat contentious. In the field, rapid advances are expected due to increasingly small and cheap sensors and transmitters, making widespread use of small surface following drifters possible. We also discuss remote sensing of the Stokes drift from high-frequency radar. Finally, the paper discusses the three main areas of application of the Stokes drift: in the coastal zone, in Eulerian models of the upper ocean layer and in the modelling of tracer transport, such as oil and plastic pollution. Future climate models will probably involve full coupling of ocean and atmosphere systems, in which the wave model provides consistent forcing on the ocean surface boundary layer. Together with the advent of new space-borne instruments that can measure surface Stokes drift, such models hold the promise of quantifying the impact of wave effects on the global atmosphere-ocean system and hopefully contribute to improved climate projections.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229804 TI - New exact relations for steady irrotational two-dimensional gravity and capillary surface waves. AB - Steady two-dimensional surface capillary-gravity waves in irrotational motion are considered on constant depth. By exploiting the holomorphic properties in the physical plane and introducing some transformations of the boundary conditions at the free surface, new exact relations and equations for the free surface only are derived. In particular, a physical plane counterpart of the Babenko equation is obtained.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229805 TI - Nonlinear water waves: introduction and overview. AB - For more than two centuries progress in the study of water waves proved to be interdependent with innovative and deep developments in theoretical and experimental directions of investigation. In recent years, considerable progress has been achieved towards the understanding of waves of large amplitude. Within this setting one cannot rely on linear theory as nonlinearity becomes an essential feature. Various analytic methods have been developed and adapted to come to terms with the challenges encountered in settings where approximations (such as those provided by linear or weakly nonlinear theory) are ineffective. Without relying on simpler models, progress becomes contingent upon the discovery of structural properties, the exploitation of which requires a combination of creative ideas and state-of-the-art technical tools. The successful quest for structure often reveals unexpected patterns and confers aesthetic value on some of these studies. The topics covered in this issue are both multi-disciplinary and interdisciplinary: there is a strong interplay between mathematical analysis, numerical computation and experimental/field data, interacting with each other via mutual stimulation and feedback. This theme issue reflects some of the new important developments that were discussed during the programme 'Nonlinear water waves' that took place at the Isaac Newton Institute for Mathematical Sciences (Cambridge, UK) from 31st July to 25th August 2017. A cross-section of the experts in the study of water waves who participated in the programme authored the collected papers. These papers illustrate the diversity, intensity and interconnectivity of the current research activity in this area. They offer new insight, present emerging theoretical methodologies and computational approaches, and describe sophisticated experimental results.This article is part of the theme issue 'Nonlinear water waves'. PMID- 29229806 TI - How reduced excitonic coupling enhances light harvesting in the main photosynthetic antennae of diatoms. AB - Strong excitonic interactions are a key design strategy in photosynthetic light harvesting, expanding the spectral cross-section for light absorption and creating considerably faster and more robust excitation energy transfer. These molecular excitons are a direct result of exceptionally densely packed pigments in photosynthetic proteins. The main light-harvesting complexes of diatoms, known as fucoxanthin-chlorophyll proteins (FCPs), are an exception, displaying surprisingly weak excitonic coupling between their chlorophyll (Chl) a's, despite a high pigment density. Here, we show, using single-molecule spectroscopy, that the FCP complexes of Cyclotella meneghiniana switch frequently into stable, strongly emissive states shifted 4-10 nm toward the red. A few percent of isolated FCPa complexes and ~20% of isolated FCPb complexes, on average, were observed to populate these previously unobserved states, percentages that agree with the steady-state fluorescence spectra of FCP ensembles. Thus, the complexes use their enhanced sensitivity to static disorder to increase their light harvesting capability in a number of ways. A disordered exciton model based on the structure of the main plant light-harvesting complex explains the red-shifted emission by strong localization of the excitation energy on a single Chl a pigment in the terminal emitter domain due to very specific pigment orientations. We suggest that the specific construction of FCP gives the complex a unique strategy to ensure that its light-harvesting function remains robust in the fluctuating protein environment despite limited excitonic interactions. PMID- 29229807 TI - Sclerostin influences body composition by regulating catabolic and anabolic metabolism in adipocytes. AB - Sclerostin has traditionally been thought of as a local inhibitor of bone acquisition that antagonizes the profound osteoanabolic capacity of activated Wnt/beta-catenin signaling, but serum sclerostin levels in humans exhibit a correlation with impairments in several metabolic parameters. These data, together with the increased production of sclerostin in mouse models of type 2 diabetes, suggest an endocrine function. To determine whether sclerostin contributes to the coordination of whole-body metabolism, we examined body composition, glucose homeostasis, and fatty acid metabolism in Sost-/- mice as well as mice that overproduce sclerostin as a result of adeno-associated virus expression from the liver. Here, we show that in addition to dramatic increases in bone volume, Sost-/- mice exhibit a reduction in adipose tissue accumulation in association with increased insulin sensitivity. Sclerostin overproduction results in the opposite metabolic phenotype due to adipocyte hypertrophy. Additionally, Sost-/- mice and those administered a sclerostin-neutralizing antibody are resistant to obesogenic diet-induced disturbances in metabolism. This effect appears to be the result of sclerostin's effects on Wnt signaling and metabolism in white adipose tissue. Since adipocytes do not produce sclerostin, these findings suggest an unexplored endocrine function for sclerostin that facilitates communication between the skeleton and adipose tissue. PMID- 29229808 TI - Impact of insecticide resistance in Anopheles arabiensis on malaria incidence and prevalence in Sudan and the costs of mitigation. AB - Insecticide-based interventions have contributed to ~78% of the reduction in the malaria burden in sub-Saharan Africa since 2000. Insecticide resistance in malaria vectors could presage a catastrophic rebound in disease incidence and mortality. A major impediment to the implementation of insecticide resistance management strategies is that evidence of the impact of resistance on malaria disease burden is limited. A cluster randomized trial was conducted in Sudan with pyrethroid-resistant and carbamate-susceptible malaria vectors. Clusters were randomly allocated to receive either long-lasting insecticidal nets (LLINs) alone or LLINs in combination with indoor residual spraying (IRS) with a pyrethroid (deltamethrin) insecticide in the first year and a carbamate (bendiocarb) insecticide in the two subsequent years. Malaria incidence was monitored for 3 y through active case detection in cohorts of children aged 1 to <10 y. When deltamethrin was used for IRS, incidence rates in the LLIN + IRS arm and the LLIN only arm were similar, with the IRS providing no additional protection [incidence rate ratio (IRR) = 1.0 (95% confidence interval [CI]: 0.36-3.0; P = 0.96)]. When bendiocarb was used for IRS, there was some evidence of additional protection [interaction IRR = 0.55 (95% CI: 0.40-0.76; P < 0.001)]. In conclusion, pyrethroid resistance may have had an impact on pyrethroid-based IRS. The study was not designed to assess whether resistance had an impact on LLINs. These data alone should not be used as the basis for any policy change in vector control interventions. PMID- 29229809 TI - Proteasomes tether to two distinct sites at the nuclear pore complex. AB - The partitioning of cellular components between the nucleus and cytoplasm is the defining feature of eukaryotic life. The nuclear pore complex (NPC) selectively gates the transport of macromolecules between these compartments, but it is unknown whether surveillance mechanisms exist to reinforce this function. By leveraging in situ cryo-electron tomography to image the native cellular environment of Chlamydomonas reinhardtii, we observed that nuclear 26S proteasomes crowd around NPCs. Through a combination of subtomogram averaging and nanometer-precision localization, we identified two classes of proteasomes tethered via their Rpn9 subunits to two specific NPC locations: binding sites on the NPC basket that reflect its eightfold symmetry and more abundant binding sites at the inner nuclear membrane that encircle the NPC. These basket-tethered and membrane-tethered proteasomes, which have similar substrate-processing state frequencies as proteasomes elsewhere in the cell, are ideally positioned to regulate transcription and perform quality control of both soluble and membrane proteins transiting the NPC. PMID- 29229811 TI - Correction for Giang et al., Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. PMID- 29229812 TI - Perception and misperception of surface opacity. AB - A fundamental problem in extracting scene structure is distinguishing different physical sources of image structure. Light reflected by an opaque surface covaries with local surface orientation, whereas light transported through the body of a translucent material does not. This suggests the possibility that the visual system may use the covariation of local surface orientation and intensity as a cue to the opacity of surfaces. We tested this hypothesis by manipulating the contrast of luminance gradients and the surface geometries to which they belonged and assessed how these manipulations affected the perception of surface opacity/translucency. We show that (i) identical luminance gradients can appear either translucent or opaque depending on the relationship between luminance and perceived 3D surface orientation, (ii) illusory percepts of translucency can be induced by embedding opaque surfaces in diffuse light fields that eliminate the covariation between surface orientation and intensity, and (iii) illusory percepts of opacity can be generated when transparent materials are embedded in a light field that generates images where surface orientation and intensity covary. Our results provide insight into how the visual system distinguishes opaque surfaces and light-permeable materials and why discrepancies arise between the perception and physics of opacity and translucency. These results suggest that the most significant information used to compute the perceived opacity and translucency of surfaces arise at a level of representation where 3D shape is made explicit. PMID- 29229810 TI - Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1. AB - X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease associated with an antisense insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within an intron of TAF1 This unique insertion coincides with six additional noncoding sequence changes in TAF1, the gene that encodes TATA-binding protein-associated factor-1, which appear to be inherited together as an identical haplotype in all reported cases. Here we examined the sequence of this SVA in XDP patients (n = 140) and detected polymorphic variation in the length of a hexanucleotide repeat domain, (CCCTCT)n The number of repeats in these cases ranged from 35 to 52 and showed a highly significant inverse correlation with age at disease onset. Because other SVAs exhibit intrinsic promoter activity that depends in part on the hexameric domain, we assayed the transcriptional regulatory effects of varying hexameric lengths found in the unique XDP SVA retrotransposon using luciferase reporter constructs. When inserted sense or antisense to the luciferase reading frame, the XDP variants repressed or enhanced transcription, respectively, to an extent that appeared to vary with length of the hexamer. Further in silico analysis of this SVA sequence revealed multiple motifs predicted to form G-quadruplexes, with the greatest potential detected for the hexameric repeat domain. These data directly link sequence variation within the XDP-specific SVA sequence to phenotypic variability in clinical disease manifestation and provide insight into potential mechanisms by which this intronic retroelement may induce transcriptional interference in TAF1 expression. PMID- 29229814 TI - SE2 reaction in noncarbon system: Metal-halide catalysis for dehydrogenation of ammonia borane. AB - An electrophilic substitution (SE) reaction of BN isosteres has been investigated for the dehydrogenation of ammonia borane (AB) by metal chlorides (MCl2) using various ab initio calculations. In contrast to the typical SE reaction occurring at the carbon atom, the nitrogen atom in AB serves as the reaction center for the SE reaction with the boron moiety as the leaving group when the MCl2 approaches the AB. The SE2 backside reaction is favored as a trigger step for the dehydrogenation of AB by the MCl2 The SE2 reaction is found for 3d-transition metal chlorides (e.g., FeCl2, CoCl2, NiCl2, CuCl2, and ZnCl2), while PdCl2 leads to the dehydrogenation of AB by a direct B-H sigma-bond activation, similar to most organometallic catalysts. Interestingly, the polymerization of AB promoted by MCl2 can be explained with the similar SE2 mechanism, and the dehydrogenation of the BN derivative 3-methyl-1,2-BN-cyclopentane (CBN) bearing a carbon backbone ring also follows the SE2 reaction. In particular, the experimental observation that the use of metal-chloride catalysis decreases the by-products obtained during the hydrogenation of AB can be explained by our mechanism involving the SE2 reaction. This work is helpful for the development of novel metal-halide catalysts for practical hydrogen storage materials, including the BN moiety. PMID- 29229813 TI - Human genetic variation alters CRISPR-Cas9 on- and off-targeting specificity at therapeutically implicated loci. AB - The CRISPR-Cas9 nuclease system holds enormous potential for therapeutic genome editing of a wide spectrum of diseases. Large efforts have been made to further understanding of on- and off-target activity to assist the design of CRISPR-based therapies with optimized efficacy and safety. However, current efforts have largely focused on the reference genome or the genome of cell lines to evaluate guide RNA (gRNA) efficiency, safety, and toxicity. Here, we examine the effect of human genetic variation on both on- and off-target specificity. Specifically, we utilize 7,444 whole-genome sequences to examine the effect of variants on the targeting specificity of ~3,000 gRNAs across 30 therapeutically implicated loci. We demonstrate that human genetic variation can alter the off-target landscape genome-wide including creating and destroying protospacer adjacent motifs (PAMs). Furthermore, single-nucleotide polymorphisms (SNPs) and insertions/deletions (indels) can result in altered on-target sites and novel potent off-target sites, which can predispose patients to treatment failure and adverse effects, respectively; however, these events are rare. Taken together, these data highlight the importance of considering individual genomes for therapeutic genome editing applications for the design and evaluation of CRISPR-based therapies to minimize risk of treatment failure and/or adverse outcomes. PMID- 29229815 TI - De novo reconstitution reveals the proteins required for skeletal muscle voltage induced Ca2+ release. AB - Skeletal muscle contraction is triggered by Ca2+ release from the sarcoplasmic reticulum (SR) in response to plasma membrane (PM) excitation. In vertebrates, this depends on activation of the RyR1 Ca2+ pore in the SR, under control of conformational changes of CaV1.1, located ~12 nm away in the PM. Over the last ~30 y, gene knockouts have revealed that CaV1.1/RyR1 coupling requires additional proteins, but leave open the possibility that currently untested proteins are also necessary. Here, we demonstrate the reconstitution of conformational coupling in tsA201 cells by expression of CaV1.1, beta1a, Stac3, RyR1, and junctophilin2. As in muscle, depolarization evokes Ca2+ transients independent of external Ca2+ entry and having amplitude with a saturating dependence on voltage. Moreover, freeze-fracture electron microscopy indicates that the five identified proteins are sufficient to establish physical links between CaV1.1 and RyR1. Thus, these proteins constitute the key elements essential for excitation contraction coupling in skeletal muscle. PMID- 29229816 TI - Correction for Possner and Caldeira, Geophysical potential for wind energy over the open oceans. PMID- 29229818 TI - Accelerating fishes increase propulsive efficiency by modulating vortex ring geometry. AB - Swimming animals need to generate propulsive force to overcome drag, regardless of whether they swim steadily or accelerate forward. While locomotion strategies for steady swimming are well characterized, far less is known about acceleration. Animals exhibit many different ways to swim steadily, but we show here that this behavioral diversity collapses into a single swimming pattern during acceleration regardless of the body size, morphology, and ecology of the animal. We draw on the fields of biomechanics, fluid dynamics, and robotics to demonstrate that there is a fundamental difference between steady swimming and forward acceleration. We provide empirical evidence that the tail of accelerating fishes can increase propulsive efficiency by enhancing thrust through the alteration of vortex ring geometry. Our study provides insight into how propulsion can be altered without increasing vortex ring size and represents a fundamental departure from our current understanding of the hydrodynamic mechanisms of acceleration. Our findings reveal a unifying hydrodynamic principle that is likely conserved in all aquatic, undulatory vertebrates. PMID- 29229817 TI - Comparative transcriptomics as a guide to natural product discovery and biosynthetic gene cluster functionality. AB - Bacterial natural products remain an important source of new medicines. DNA sequencing has revealed that a majority of natural product biosynthetic gene clusters (BGCs) maintained in bacterial genomes have yet to be linked to the small molecules whose biosynthesis they encode. Efforts to discover the products of these orphan BGCs are driving the development of genome mining techniques based on the premise that many are transcriptionally silent during normal laboratory cultivation. Here, we employ comparative transcriptomics to assess BGC expression among four closely related strains of marine bacteria belonging to the genus Salinispora The results reveal that slightly more than half of the BGCs are expressed at levels that should facilitate product detection. By comparing the expression profiles of similar gene clusters in different strains, we identified regulatory genes whose inactivation appears linked to cluster silencing. The significance of these subtle differences between expressed and silent BGCs could not have been predicted a priori and was only revealed by comparative transcriptomics. Evidence for the conservation of silent clusters among a larger number of strains for which genome sequences are available suggests they may be under different regulatory control from the expressed forms or that silencing may represent an underappreciated mechanism of gene cluster evolution. Coupling gene expression and metabolomics data established a bioinformatic link between the salinipostins and their associated BGC, while genetic manipulation established the genetic basis for this series of compounds, which were previously unknown from Salinispora pacifica. PMID- 29229819 TI - Discovery of the leinamycin family of natural products by mining actinobacterial genomes. AB - Nature's ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF-SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF-SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature's rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature's biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity. PMID- 29229820 TI - Beta oscillations reflect supramodal information during perceptual judgment. AB - Previous work on perceptual decision making in the sensorimotor system has shown population dynamics in the beta band, corresponding to the encoding of stimulus properties and the final decision outcome. Here, we asked how oscillatory dynamics in the medial premotor cortex (MPC) contribute to supramodal perceptual decision making. We recorded local field potentials (LFPs) and spikes in two monkeys trained to perform a tactile-acoustic frequency discrimination task, including both unimodal and crossmodal conditions. We studied the role of oscillatory activity as a function of stimulus properties (frequency and sensory modality), as well as decision outcome. We found that beta-band power correlated with relevant stimulus properties: there was a significant modulation by stimulus frequency during the working-memory (WM) retention interval, as well as modulation by stimulus modality-the latter was observed only in the case of a purely unimodal task, where modality information was relevant to prepare for the upcoming second stimulus. Furthermore, we found a significant modulation of beta power during the comparison and decision period, which was predictive of decision outcome. Finally, beta-band spike-field coherence (SFC) matched these LFP observations. In conclusion, we demonstrate that beta power in MPC is reflective of stimulus features in a supramodal, context-dependent manner, and additionally reflects the decision outcome. We propose that these beta modulations are a signature of the recruitment of functional neuronal ensembles, which encode task relevant information. PMID- 29229822 TI - Chemical physics of water. PMID- 29229821 TI - Critical dynamics in population vaccinating behavior. AB - Vaccine refusal can lead to renewed outbreaks of previously eliminated diseases and even delay global eradication. Vaccinating decisions exemplify a complex, coupled system where vaccinating behavior and disease dynamics influence one another. Such systems often exhibit critical phenomena-special dynamics close to a tipping point leading to a new dynamical regime. For instance, critical slowing down (declining rate of recovery from small perturbations) may emerge as a tipping point is approached. Here, we collected and geocoded tweets about measles mumps-rubella vaccine and classified their sentiment using machine-learning algorithms. We also extracted data on measles-related Google searches. We find critical slowing down in the data at the level of California and the United States in the years before and after the 2014-2015 Disneyland, California measles outbreak. Critical slowing down starts growing appreciably several years before the Disneyland outbreak as vaccine uptake declines and the population approaches the tipping point. However, due to the adaptive nature of coupled behavior disease systems, the population responds to the outbreak by moving away from the tipping point, causing "critical speeding up" whereby resilience to perturbations increases. A mathematical model of measles transmission and vaccine sentiment predicts the same qualitative patterns in the neighborhood of a tipping point to greatly reduced vaccine uptake and large epidemics. These results support the hypothesis that population vaccinating behavior near the disease elimination threshold is a critical phenomenon. Developing new analytical tools to detect these patterns in digital social data might help us identify populations at heightened risk of widespread vaccine refusal. PMID- 29229823 TI - Sex determination of human remains from peptides in tooth enamel. AB - The assignment of biological sex to archaeological human skeletons is a fundamental requirement for the reconstruction of the human past. It is conventionally and routinely performed on adults using metric analysis and morphological traits arising from postpubertal sexual dimorphism. A maximum accuracy of ~95% is possible if both the cranium and os coxae are present and intact, but this is seldom achievable for all skeletons. Furthermore, for infants and juveniles, there are no reliable morphological methods for sex determination without resorting to DNA analysis, which requires good DNA survival and is time consuming. Consequently, sex determination of juvenile remains is rarely undertaken, and a dependable and expedient method that can correctly assign biological sex to human remains of any age is highly desirable. Here we present a method for sex determination of human remains by means of a minimally destructive surface acid etching of tooth enamel and subsequent identification of sex chromosome-linked isoforms of amelogenin, an enamel-forming protein, by nanoflow liquid chromatography mass spectrometry. Tooth enamel is the hardest tissue in the human body and survives burial exceptionally well, even when the rest of the skeleton or DNA in the organic fraction has decayed. Our method can reliably determine the biological sex of humans of any age using a body tissue that is difficult to cross-contaminate and is most likely to survive. The application of this method will make sex determination of adults and, for the first time, juveniles a reliable and routine activity in future bioarcheological and medico legal science contexts. PMID- 29229824 TI - Molecular mechanism for the subversion of the retromer coat by the Legionella effector RidL. AB - Microbial pathogens employ sophisticated virulence strategies to cause infections in humans. The intracellular pathogen Legionella pneumophila encodes RidL to hijack the host scaffold protein VPS29, a component of retromer and retriever complexes critical for endosomal cargo recycling. Here, we determined the crystal structure of L. pneumophila RidL in complex with the human VPS29-VPS35 retromer subcomplex. A hairpin loop protruding from RidL inserts into a conserved pocket on VPS29 that is also used by cellular ligands, such as Tre-2/Bub2/Cdc16 domain family member 5 (TBC1D5) and VPS9-ankyrin repeat protein for VPS29 binding. Consistent with the idea of molecular mimicry in protein interactions, RidL outcompeted TBC1D5 for binding to VPS29. Furthermore, the interaction of RidL with retromer did not interfere with retromer dimerization but was essential for association of RidL with retromer-coated vacuolar and tubular endosomes. Our work thus provides structural and mechanistic evidence into how RidL is targeted to endosomal membranes. PMID- 29229825 TI - Network analysis identifies chromosome intermingling regions as regulatory hotspots for transcription. AB - The 3D structure of the genome plays a key role in regulatory control of the cell. Experimental methods such as high-throughput chromosome conformation capture (Hi-C) have been developed to probe the 3D structure of the genome. However, it remains a challenge to deduce from these data chromosome regions that are colocalized and coregulated. Here, we present an integrative approach that leverages 1D functional genomic features (e.g., epigenetic marks) with 3D interactions from Hi-C data to identify functional interchromosomal interactions. We construct a weighted network with 250-kb genomic regions as nodes and Hi-C interactions as edges, where the edge weights are given by the correlation between 1D genomic features. Individual interacting clusters are determined using weighted correlation clustering on the network. We show that intermingling regions generally fall into either active or inactive clusters based on the enrichment for RNA polymerase II (RNAPII) and H3K9me3, respectively. We show that active clusters are hotspots for transcription factor binding sites. We also validate our predictions experimentally by 3D fluorescence in situ hybridization (FISH) experiments and show that active RNAPII is enriched in predicted active clusters. Our method provides a general quantitative framework that couples 1D genomic features with 3D interactions from Hi-C to probe the guiding principles that link the spatial organization of the genome with regulatory control. PMID- 29229827 TI - Correction for Matthews et al., Optimal nutrient exchange and immune responses operate in partner specificity in the cnidarian-dinoflagellate symbiosis. PMID- 29229826 TI - Identification of cancer genes that are independent of dominant proliferation and lineage programs. AB - Large, multidimensional cancer datasets provide a resource that can be mined to identify candidate therapeutic targets for specific subgroups of tumors. Here, we analyzed human breast cancer data to identify transcriptional programs associated with tumors bearing specific genetic driver alterations. Using an unbiased approach, we identified thousands of genes whose expression was enriched in tumors with specific genetic alterations. However, expression of the vast majority of these genes was not enriched if associations were analyzed within individual breast tumor molecular subtypes, across multiple tumor types, or after gene expression was normalized to account for differences in proliferation or tumor lineage. Together with linear modeling results, these findings suggest that most transcriptional programs associated with specific genetic alterations in oncogenes and tumor suppressors are highly context-dependent and are predominantly linked to differences in proliferation programs between distinct breast cancer subtypes. We demonstrate that such proliferation-dependent gene expression dominates tumor transcriptional programs relative to matched normal tissues. However, we also identified a relatively small group of cancer associated genes that are both proliferation- and lineage-independent. A subset of these genes are attractive candidate targets for combination therapy because they are essential in breast cancer cell lines, druggable, enriched in stem-like breast cancer cells, and resistant to chemotherapy-induced down-regulation. PMID- 29229830 TI - Correction for Gerth et al., Intersectin associates with synapsin and regulates its nanoscale localization and function. PMID- 29229828 TI - Dispersal limitation promotes the diversification of the mammalian gut microbiota. AB - The gut bacterial communities of mammals have profound effects on host fitness, but the processes that generate and maintain gut bacterial diversity remain poorly understood. We mapped compositional variation (i.e., beta-diversity) in the gut microbiotas of 136 pairs of wild mammalian species living throughout the Americas to assess how the distribution of mammals across geographic space influences the diversification of their gut bacteria. Comparing the gut microbiotas of sympatric and allopatric mammalian populations provided insights into the flow of gut bacteria within and between mammalian communities, revealing that spatial limits on bacterial dispersal promote beta-diversity between the gut microbiotas of mammalian species. Each geographic locale displayed a unique gut microbiota composition that could not be fully explained by the diets and phylogenetic histories of the resident mammalian hosts, indicating that some gut bacteria are geographically restricted. Across the western hemisphere, the compositional overlap between the gut microbiotas of allopatric mammalian populations decayed exponentially with the geographic distance separating the hosts. The relationship between geographic distances among hosts and compositional differences among their gut microbiotas was independent of dietary and phylogenetic divergence among hosts. Within mammalian communities, we observed widespread sharing of gut bacteria between predator-prey host-species pairs, indicating horizontal transfer of gut bacteria through mammalian food chains. Collectively, these results indicate that compositional differences between the gut microbiotas of mammalian taxa are generated and maintained by limits to bacterial dispersal imposed by physical distance between hosts. PMID- 29229829 TI - PSMA-targeted polyinosine/polycytosine vector induces prostate tumor regression and invokes an antitumor immune response in mice. AB - There is an urgent need for an effective treatment for metastatic prostate cancer (PC). Prostate tumors invariably overexpress prostate surface membrane antigen (PSMA). We designed a nonviral vector, PEI-PEG-DUPA (PPD), comprising polyethylenimine-polyethyleneglycol (PEI-PEG) tethered to the PSMA ligand, 2-[3 (1, 3-dicarboxy propyl)ureido] pentanedioic acid (DUPA), to treat PC. The purpose of PEI is to bind polyinosinic/polycytosinic acid (polyIC) and allow endosomal release, while DUPA targets PC cells. PolyIC activates multiple pathways that lead to tumor cell death and to the activation of bystander effects that harness the immune system against the tumor, attacking nontargeted neighboring tumor cells and reducing the probability of acquired resistance and disease recurrence. Targeting polyIC directly to tumor cells avoids the toxicity associated with systemic delivery. PPD selectively delivered polyIC into PSMA-overexpressing PC cells, inducing apoptosis, cytokine secretion, and the recruitment of human peripheral blood mononuclear cells (PBMCs). PSMA-overexpressing tumors in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with partially reconstituted immune systems were significantly shrunken following PPD/polyIC treatment, in all cases. Half of the tumors showed complete regression. PPD/polyIC invokes antitumor immunity, but unlike many immunotherapies does not need to be personalized for each patient. The potent antitumor effects of PPD/polyIC should spur its development for clinical use. PMID- 29229831 TI - Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11beta-hydroxysteroid dehydrogenase type 2 deficiency. AB - Mutations in 11beta-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) cause an extraordinarily rare autosomal recessive disorder, apparent mineralocorticoid excess (AME). AME is a form of low renin hypertension that is potentially fatal if untreated. Mutations in the HSD11B2 gene result either in severe AME or a milder phenotype (type 2 AME). To date, ~40 causative mutations have been identified. As part of the International Consortium for Rare Steroid Disorders, we have diagnosed and followed the largest single worldwide cohort of 36 AME patients. Here, we present the genotype and clinical phenotype of these patients, prominently from consanguineous marriages in the Middle East, who display profound hypertension and hypokalemic alkalosis. To correlate mutations with phenotypic severity, we constructed a computational model of the HSD11B2 protein. Having used a similar strategy for the in silico evaluation of 150 mutations of CYP21A2, the disease-causing gene in congenital adrenal hyperplasia, we now provide a full structural explanation for the clinical severity of AME resulting from each known HSD11B2 missense mutation. We find that mutations that allow the formation of an inactive dimer, alter substrate/coenzyme binding, or impair structural stability of HSD11B2 yield severe AME. In contrast, mutations that cause an indirect disruption of substrate binding or mildly alter intramolecular interactions result in type 2 AME. A simple in silico evaluation of novel missense mutations could help predict the often-diverse phenotypes of an extremely rare monogenic disorder. PMID- 29229832 TI - FKBP12 contributes to alpha-synuclein toxicity by regulating the calcineurin dependent phosphoproteome. AB - Calcineurin is an essential Ca2+-dependent phosphatase. Increased calcineurin activity is associated with alpha-synuclein (alpha-syn) toxicity, a protein implicated in Parkinson's Disease (PD) and other neurodegenerative diseases. Calcineurin can be inhibited with Tacrolimus through the recruitment and inhibition of the 12-kDa cis-trans proline isomerase FK506-binding protein (FKBP12). Whether calcineurin/FKBP12 represents a native physiologically relevant assembly that occurs in the absence of pharmacological perturbation has remained elusive. We leveraged alpha-syn as a model to interrogate whether FKBP12 plays a role in regulating calcineurin activity in the absence of Tacrolimus. We show that FKBP12 profoundly affects the calcineurin-dependent phosphoproteome, promoting the dephosphorylation of a subset of proteins that contributes to alpha syn toxicity. Using a rat model of PD, partial elimination of the functional interaction between FKBP12 and calcineurin, with low doses of the Food and Drug Administration (FDA)-approved compound Tacrolimus, blocks calcineurin's activity toward those proteins and protects against the toxic hallmarks of alpha-syn pathology. Thus, FKBP12 can endogenously regulate calcineurin activity with therapeutic implications for the treatment of PD. PMID- 29229833 TI - Kinetics of drug-ribosome interactions defines the cidality of macrolide antibiotics. AB - Antibiotics can cause dormancy (bacteriostasis) or induce death (cidality) of the targeted bacteria. The bactericidal capacity is one of the most important properties of antibacterial agents. However, the understanding of the fundamental differences in the mode of action of bacteriostatic or bactericidal antibiotics, especially those belonging to the same chemical class, is very rudimentary. Here, by examining the activity and binding properties of chemically distinct macrolide inhibitors of translation, we have identified a key difference in their interaction with the ribosome, which correlates with their ability to cause cell death. While bacteriostatic and bactericidal macrolides bind in the nascent peptide exit tunnel of the large ribosomal subunit with comparable affinities, the bactericidal antibiotics dissociate from the ribosome with significantly slower rates. The sluggish dissociation of bactericidal macrolides correlates with the presence in their structure of an extended alkyl-aryl side chain, which establishes idiosyncratic interactions with the ribosomal RNA. Mutations or chemical alterations of the rRNA nucleotides in the drug binding site can protect cells from macrolide-induced killing, even with inhibitor concentrations that significantly exceed those required for cell growth arrest. We propose that the increased translation downtime due to slow dissociation of the antibiotic may damage cells beyond the point where growth can be reinitiated upon the removal of the drug due to depletion of critical components of the gene-expression pathway. PMID- 29229835 TI - O-GlcNAcylation destabilizes the active tetrameric PKM2 to promote the Warburg effect. AB - The Warburg effect, characterized by increased glucose uptake and lactate production, is a well-known universal across cancer cells and other proliferating cells. PKM2, a splice isoform of the pyruvate kinase (PK) specifically expressed in these cells, serves as a major regulator of this metabolic reprogramming with an adjustable activity subjected to numerous allosteric effectors and posttranslational modifications. Here, we have identified a posttranslational modification on PKM2, O-GlcNAcylation, which specifically targets Thr405 and Ser406, residues of the region encoded by the alternatively spliced exon 10 in cancer cells. We show that PKM2 O-GlcNAcylation is up-regulated in various types of human tumor cells and patient tumor tissues. The modification destabilized the active tetrameric PKM2, reduced PK activity, and led to nuclear translocation of PKM2. We also observed that the modification was associated with an increased glucose consumption and lactate production and enhanced level of lipid and DNA synthesis, indicating that O-GlcNAcylation promotes the Warburg effect. In vivo experiments showed that blocking PKM2 O-GlcNAcylation attenuated tumor growth. Thus, we demonstrate that O-GlcNAcylation is a regulatory mechanism for PKM2 in cancer cells and serves as a bridge between PKM2 and metabolic reprogramming typical of the Warburg effect. PMID- 29229834 TI - Rapid, direct activity assays for Smoothened reveal Hedgehog pathway regulation by membrane cholesterol and extracellular sodium. AB - Hedgehog signaling specifies tissue patterning and renewal, and pathway components are commonly mutated in certain malignancies. Although central to ensuring appropriate pathway activity in all Hedgehog-responsive cells, how the transporter-like receptor Patched1 regulates the seven-transmembrane protein Smoothened remains mysterious, partially due to limitations in existing tools and experimental systems. Here we employ direct, real-time, biochemical and physiology-based approaches to monitor Smoothened activity in cellular and in vitro contexts. Patched1-Smoothened coupling is rapid, dynamic, and can be recapitulated without cilium-specific proteins or lipids. By reconstituting purified Smoothened in vitro, we show that cholesterol within the bilayer is sufficient for constitutive Smoothened activation. Cholesterol effects occur independently of the lipid-binding Smoothened extracellular domain, a region that is dispensable for Patched1-Smoothened coupling. Finally, we show that Patched1 specifically requires extracellular Na+ to regulate Smoothened in our assays, raising the possibility that a Na+ gradient provides the energy source for Patched1 catalytic activity. Our work suggests a hypothesis wherein Patched1, chemiosmotically driven by the transmembrane Na+ gradient common to metazoans, regulates Smoothened by shielding its heptahelical domain from cholesterol, or by providing an inhibitor that overrides this cholesterol activation. PMID- 29229836 TI - Single-cell analysis resolves the cell state transition and signaling dynamics associated with melanoma drug-induced resistance. AB - Continuous BRAF inhibition of BRAF mutant melanomas triggers a series of cell state changes that lead to therapy resistance and escape from immune control before establishing acquired resistance genetically. We used genome-wide transcriptomics and single-cell phenotyping to explore the response kinetics to BRAF inhibition for a panel of patient-derived BRAFV600 -mutant melanoma cell lines. A subset of plastic cell lines, which followed a trajectory covering multiple known cell state transitions, provided models for more detailed biophysical investigations. Markov modeling revealed that the cell state transitions were reversible and mediated by both Lamarckian induction and nongenetic Darwinian selection of drug-tolerant states. Single-cell functional proteomics revealed activation of certain signaling networks shortly after BRAF inhibition, and before the appearance of drug-resistant phenotypes. Drug targeting those networks, in combination with BRAF inhibition, halted the adaptive transition and led to prolonged growth inhibition in multiple patient derived cell lines. PMID- 29229837 TI - Early endosome as a pathogenic target for antiphosphatidylethanolamine antibodies. AB - Phosphatidylethanolamine (PE) is a major phospholipid species with important roles in membrane trafficking and reorganization. Accumulating clinical data indicate that the presence of circulating antibodies against PE is positively correlated with the symptoms of antiphospholipid syndromes (APS), including thrombosis and repeated pregnancy loss. However, PE is generally sequestered inside a normal resting cell, and the mechanism by which circulating anti-PE antibodies access cellular PE remains unknown. The studies presented here were conducted with synthetic PE-binding agents, plasma samples from patients with anti-PE autoimmunity, and purified anti-PE antibodies. The results suggest that the cellular vulnerability to anti-PE antibodies may be mediated by the binding of PE molecules in the membrane of the early endosome. Endosomal PE binding led to functional changes in endothelial cells, including declines in proliferation and increases in the production of reactive oxygen species, as well as the expression of inflammatory molecules. Collectively, our findings provide insight into the etiology of anti-PE autoimmunity and, because endosomes are of central importance in almost all types of cells, could have important implications for a wide range of biological processes. PMID- 29229839 TI - Correction for Roehr, Core Concept: Tissue resident memory cells emerging as key player in health and disease. PMID- 29229838 TI - Architecture of the human PI4KIIIalpha lipid kinase complex. AB - Plasma membrane (PM) phosphoinositides play essential roles in cell physiology, serving as both markers of membrane identity and signaling molecules central to the cell's interaction with its environment. The first step in PM phosphoinositide synthesis is the conversion of phosphatidylinositol (PI) to PI4P, the precursor of PI(4,5)P2 and PI(3,4,5)P3 This conversion is catalyzed by the PI4KIIIalpha complex, comprising a lipid kinase, PI4KIIIalpha, and two regulatory subunits, TTC7 and FAM126. We here report the structure of this complex at 3.6-A resolution, determined by cryo-electron microscopy. The proteins form an obligate ~700-kDa superassembly with a broad surface suitable for membrane interaction, toward which the kinase active sites are oriented. The structural complexity of the assembly highlights PI4P synthesis as a major regulatory junction in PM phosphoinositide homeostasis. Our studies provide a framework for further exploring the mechanisms underlying PM phosphoinositide regulation. PMID- 29229841 TI - Predicting glycosaminoglycan surface protein interactions and implications for studying axonal growth. AB - Cell-surface carbohydrates play important roles in numerous biological processes through their interactions with various protein-binding partners. These interactions are made possible by the vast structural diversity of carbohydrates and the diverse array of carbohydrate presentations on the cell surface. Among the most complex and important carbohydrates are glycosaminoglycans (GAGs), which display varied stereochemistry, chain lengths, and patterns of sulfation. GAG protein interactions participate in neuronal development, angiogenesis, spinal cord injury, viral invasion, and immune response. Unfortunately, little structural information is available for these complexes; indeed, for the highly sulfated chondroitin sulfate motifs, CS-E and CS-D, there are no structural data. We describe here the development and validation of the GAG-Dock computational method to predict accurately the binding poses of protein-bound GAGs. We validate that GAG-Dock reproduces accurately (<1-A rmsd) the crystal structure poses for four known heparin-protein structures. Further, we predict the pose of heparin and chondroitin sulfate derivatives bound to the axon guidance proteins, protein tyrosine phosphatase sigma (RPTPsigma), and Nogo receptors 1-3 (NgR1-3). Such predictions should be useful in understanding and interpreting the role of GAGs in neural development and axonal regeneration after CNS injury. PMID- 29229840 TI - Structural changes of tailless bacteriophage PhiX174 during penetration of bacterial cell walls. AB - Unlike tailed bacteriophages, which use a preformed tail for transporting their genomes into a host bacterium, the ssDNA bacteriophage PhiX174 is tailless. Using cryo-electron microscopy and time-resolved small-angle X-ray scattering, we show that lipopolysaccharides (LPS) form bilayers that interact with PhiX174 at an icosahedral fivefold vertex and induce single-stranded (ss) DNA genome ejection. The structures of PhiX174 complexed with LPS have been determined for the pre- and post-ssDNA ejection states. The ejection is initiated by the loss of the G protein spike that encounters the LPS, followed by conformational changes of two polypeptide loops on the major capsid F proteins. One of these loops mediates viral attachment, and the other participates in making the fivefold channel at the vertex contacting the LPS. PMID- 29229842 TI - Male homosexuality and maternal immune responsivity to the Y-linked protein NLGN4Y. AB - We conducted a direct test of an immunological explanation of the finding that gay men have a greater number of older brothers than do heterosexual men. This explanation posits that some mothers develop antibodies against a Y-linked protein important in male brain development, and that this effect becomes increasingly likely with each male gestation, altering brain structures underlying sexual orientation in their later-born sons. Immune assays targeting two Y-linked proteins important in brain development-protocadherin 11 Y-linked (PCDH11Y) and neuroligin 4 Y-linked (NLGN4Y; isoforms 1 and 2)-were developed. Plasma from mothers of sons, about half of whom had a gay son, along with additional controls (women with no sons, men) was analyzed for male protein specific antibodies. Results indicated women had significantly higher anti-NLGN4Y levels than men. In addition, after statistically controlling for number of pregnancies, mothers of gay sons, particularly those with older brothers, had significantly higher anti-NLGN4Y levels than did the control samples of women, including mothers of heterosexual sons. The results suggest an association between a maternal immune response to NLGN4Y and subsequent sexual orientation in male offspring. PMID- 29229843 TI - Machine learning shows association between genetic variability in PPARG and cerebral connectivity in preterm infants. AB - Preterm infants show abnormal structural and functional brain development, and have a high risk of long-term neurocognitive problems. The molecular and cellular mechanisms involved are poorly understood, but novel methods now make it possible to address them by examining the relationship between common genetic variability and brain endophenotype. We addressed the hypothesis that variability in the Peroxisome Proliferator Activated Receptor (PPAR) pathway would be related to brain development. We employed machine learning in an unsupervised, unbiased, combined analysis of whole-brain diffusion tractography together with genomewide, single-nucleotide polymorphism (SNP)-based genotypes from a cohort of 272 preterm infants, using Sparse Reduced Rank Regression (sRRR) and correcting for ethnicity and age at birth and imaging. Empirical selection frequencies for SNPs associated with cerebral connectivity ranged from 0.663 to zero, with multiple highly selected SNPs mapping to genes for PPARG (six SNPs), ITGA6 (four SNPs), and FXR1 (two SNPs). SNPs in PPARG were significantly overrepresented (ranked 7-11 and 67 of 556,000 SNPs; P < 2.2 * 10-7), and were mostly in introns or regulatory regions with predicted effects including protein coding and nonsense-mediated decay. Edge-centric graph-theoretic analysis showed that highly selected white matter tracts were consistent across the group and important for information transfer (P < 2.2 * 10-17); they most often connected to the insula (P < 6 * 10 17). These results suggest that the inhibited brain development seen in humans exposed to the stress of a premature extrauterine environment is modulated by genetic factors, and that PPARG signaling has a previously unrecognized role in cerebral development. PMID- 29229844 TI - Cytokine signaling through Drosophila Mthl10 ties lifespan to environmental stress. AB - A systems-level understanding of cytokine-mediated, intertissue signaling is one of the keys to developing fundamental insight into the links between aging and inflammation. Here, we employed Drosophila, a routine model for analysis of cytokine signaling pathways in higher animals, to identify a receptor for the growth-blocking peptide (GBP) cytokine. Having previously established that the phospholipase C/Ca2+ signaling pathway mediates innate immune responses to GBP, we conducted a dsRNA library screen for genes that modulate Ca2+ mobilization in Drosophila S3 cells. A hitherto orphan G protein coupled receptor, Methuselah like receptor-10 (Mthl10), was a significant hit. Secondary screening confirmed specific binding of fluorophore-tagged GBP to both S3 cells and recombinant Mthl10-ectodomain. We discovered that the metabolic, immunological, and stress protecting roles of GBP all interconnect through Mthl10. This we established by Mthl10 knockdown in three fly model systems: in hemocyte-like Drosophila S2 cells, Mthl10 knockdown decreases GBP-mediated innate immune responses; in larvae, Mthl10 knockdown decreases expression of antimicrobial peptides in response to low temperature; in adult flies, Mthl10 knockdown increases mortality rate following infection with Micrococcus luteus and reduces GBP-mediated secretion of insulin-like peptides. We further report that organismal fitness pays a price for the utilization of Mthl10 to integrate all of these various homeostatic attributes of GBP: We found that elevated GBP expression reduces lifespan. Conversely, Mthl10 knockdown extended lifespan. We describe how our data offer opportunities for further molecular interrogation of yin and yang between homeostasis and longevity. PMID- 29229846 TI - Understanding the mechanisms of amorphous creep through molecular simulation. AB - Molecular processes of creep in metallic glass thin films are simulated at experimental timescales using a metadynamics-based atomistic method. Space-time evolutions of the atomic strains and nonaffine atom displacements are analyzed to reveal details of the atomic-level deformation and flow processes of amorphous creep in response to stress and thermal activations. From the simulation results, resolved spatially on the nanoscale and temporally over time increments of fractions of a second, we derive a mechanistic explanation of the well-known variation of creep rate with stress. We also construct a deformation map delineating the predominant regimes of diffusional creep at low stress and high temperature and deformational creep at high stress. Our findings validate the relevance of two original models of the mechanisms of amorphous plasticity: one focusing on atomic diffusion via free volume and the other focusing on stress induced shear deformation. These processes are found to be nonlinearly coupled through dynamically heterogeneous fluctuations that characterize the slow dynamics of systems out of equilibrium. PMID- 29229845 TI - Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases. AB - The neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD. PMID- 29229847 TI - Population is the main driver of war group size and conflict casualties. AB - The proportions of individuals involved in intergroup coalitional conflict, measured by war group size (W), conflict casualties (C), and overall group conflict deaths (G), have declined with respect to growing populations, implying that states are less violent than small-scale societies. We argue that these trends are better explained by scaling laws shared by both past and contemporary societies regardless of social organization, where group population (P) directly determines W and indirectly determines C and G. W is shown to be a power law function of P with scaling exponent X [demographic conflict investment (DCI)]. C is shown to be a power law function of W with scaling exponent Y [conflict lethality (CL)]. G is shown to be a power law function of P with scaling exponent Z [group conflict mortality (GCM)]. Results show that, while W/P and G/P decrease as expected with increasing P, C/W increases with growing W. Small-scale societies show higher but more variance in DCI and CL than contemporary states. We find no significant differences in DCI or CL between small-scale societies and contemporary states undergoing drafts or conflict, after accounting for variance and scale. We calculate relative measures of DCI and CL applicable to all societies that can be tracked over time for one or multiple actors. In light of the recent global emergence of populist, nationalist, and sectarian violence, our comparison-focused approach to DCI and CL will enable better models and analysis of the landscapes of violence in the 21st century. PMID- 29229848 TI - Three tRNAs on the ribosome slow translation elongation. AB - During protein synthesis, the ribosome simultaneously binds up to three different transfer RNA (tRNA) molecules. Among the three tRNA binding sites, the regulatory role of the exit (E) site, where deacylated tRNA spontaneously dissociates from the translational complex, has remained elusive. Here we use two donor-quencher pairs to observe and correlate both the conformation of ribosomes and tRNAs as well as tRNA occupancy. Our results reveal a partially rotated state of the ribosome wherein all three tRNA sites are occupied during translation elongation. The appearance and lifetime of this state depend on the E-site tRNA dissociation kinetics, which may vary among tRNA species and depends on temperature and ionic strength. The 3-tRNA partially rotated state is not a proper substrate for elongation factor G (EF-G), thus inhibiting translocation until the E-site tRNA dissociates. Our result presents two parallel kinetic pathways during translation elongation, underscoring the ability of E-site codons to modulate the dynamics of protein synthesis. PMID- 29229849 TI - Obligatory role of hypothalamic neuroestradiol during the estrogen-induced LH surge in female ovariectomized rhesus monkeys. AB - Negative and positive feedback effects of ovarian 17beta-estradiol (E2) regulating release of gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) are pivotal events in female reproductive function. While ovarian feedback on hypothalamo-pituitary function is a well-established concept, the present study shows that neuroestradiol, locally synthesized in the hypothalamus, is a part of estrogen's positive feedback loop. In experiment 1, E2 benzoate induced LH surges in ovariectomized female monkeys were severely attenuated by systemic administration of the aromatase inhibitor, letrozole. Aromatase is the enzyme responsible for synthesis of E2 from androgens. In experiment 2, using microdialysis, GnRH and kisspeptin surges induced by E2 benzoate were similarly attenuated by infusion of letrozole into the median eminence of the hypothalamus. Therefore, neuroestradiol is an integral part of the hypothalamic engagement in response to elevated circulating E2 Collectively, we will need to modify the concept of estrogen's positive feedback mechanism. PMID- 29229850 TI - Human presence diminishes the importance of climate in driving fire activity across the United States. AB - Growing human and ecological costs due to increasing wildfire are an urgent concern in policy and management, particularly given projections of worsening fire conditions under climate change. Thus, understanding the relationship between climatic variation and fire activity is a critically important scientific question. Different factors limit fire behavior in different places and times, but most fire-climate analyses are conducted across broad spatial extents that mask geographical variation. This could result in overly broad or inappropriate management and policy decisions that neglect to account for regionally specific or other important factors driving fire activity. We developed statistical models relating seasonal temperature and precipitation variables to historical annual fire activity for 37 different regions across the continental United States and asked whether and how fire-climate relationships vary geographically, and why climate is more important in some regions than in others. Climatic variation played a significant role in explaining annual fire activity in some regions, but the relative importance of seasonal temperature or precipitation, in addition to the overall importance of climate, varied substantially depending on geographical context. Human presence was the primary reason that climate explained less fire activity in some regions than in others. That is, where human presence was more prominent, climate was less important. This means that humans may not only influence fire regimes but their presence can actually override, or swamp out, the effect of climate. Thus, geographical context as well as human influence should be considered alongside climate in national wildfire policy and management. PMID- 29229851 TI - Structure-based prediction of ligand-protein interactions on a genome-wide scale. AB - We report a template-based method, LT-scanner, which scans the human proteome using protein structural alignment to identify proteins that are likely to bind ligands that are present in experimentally determined complexes. A scoring function that rapidly accounts for binding site similarities between the template and the proteins being scanned is a crucial feature of the method. The overall approach is first tested based on its ability to predict the residues on the surface of a protein that are likely to bind small-molecule ligands. The algorithm that we present, LBias, is shown to compare very favorably to existing algorithms for binding site residue prediction. LT-scanner's performance is evaluated based on its ability to identify known targets of Food and Drug Administration (FDA)-approved drugs and it too proves to be highly effective. The specificity of the scoring function that we use is demonstrated by the ability of LT-scanner to identify the known targets of FDA-approved kinase inhibitors based on templates involving other kinases. Combining sequence with structural information further improves LT-scanner performance. The approach we describe is extendable to the more general problem of identifying binding partners of known ligands even if they do not appear in a structurally determined complex, although this will require the integration of methods that combine protein structure and chemical compound databases. PMID- 29229852 TI - Regulatory networks specifying cortical interneurons from human embryonic stem cells reveal roles for CHD2 in interneuron development. AB - Cortical interneurons (cINs) modulate excitatory neuronal activity by providing local inhibition. During fetal development, several cIN subtypes derive from the medial ganglionic eminence (MGE), a transient ventral telencephalic structure. While altered cIN development contributes to neurodevelopmental disorders, the inaccessibility of human fetal brain tissue during development has hampered efforts to define molecular networks controlling this process. Here, we modified protocols for directed differentiation of human embryonic stem cells, obtaining efficient, accelerated production of MGE-like progenitors and MGE-derived cIN subtypes with the expected electrophysiological properties. We defined transcriptome changes accompanying this process and integrated these data with direct transcriptional targets of NKX2-1, a transcription factor controlling MGE specification. This analysis defined NKX2-1-associated genes with enriched expression during MGE specification and cIN differentiation, including known and previously unreported transcription factor targets with likely roles in MGE specification, and other target classes regulating cIN migration and function. NKX2-1-associated peaks were enriched for consensus binding motifs for NKX2-1, LHX, and SOX transcription factors, suggesting roles in coregulating MGE gene expression. Among the NKX2-1 direct target genes with cIN-enriched expression was CHD2, which encodes a chromatin remodeling protein mutated to cause human epilepsies. Accordingly, CHD2 deficiency impaired cIN specification and altered later electrophysiological function, while CHD2 coassociated with NKX2-1 at cis regulatory elements and was required for their transactivation by NKX2-1 in MGE like progenitors. This analysis identified several aspects of gene-regulatory networks underlying human MGE specification and suggested mechanisms by which NKX2-1 acts with chromatin remodeling activities to regulate gene expression programs underlying cIN development. PMID- 29229853 TI - Designing flexible 2D transition metal carbides with strain-controllable lithium storage. AB - Efficient flexible energy storage systems have received tremendous attention due to their enormous potential applications in self-powering portable electronic devices, including roll-up displays, electronic paper, and "smart" garments outfitted with piezoelectric patches to harvest energy from body movement. Unfortunately, the further development of these technologies faces great challenges due to a lack of ideal electrode materials with the right electrochemical behavior and mechanical properties. MXenes, which exhibit outstanding mechanical properties, hydrophilic surfaces, and high conductivities, have been identified as promising electrode material candidates. In this work, taking 2D transition metal carbides (TMCs) as representatives, we systematically explored several influencing factors, including transition metal species, layer thickness, functional group, and strain on their mechanical properties (e.g., stiffness, flexibility, and strength) and their electrochemical properties (e.g., ionic mobility, equilibrium voltage, and theoretical capacity). Considering potential charge-transfer polarization, we employed a charged electrode model to simulate ionic mobility and found that ionic mobility has a unique dependence on the surface atomic configuration influenced by bond length, valence electron number, functional groups, and strain. Under multiaxial loadings, electrical conductivity, high ionic mobility, low equilibrium voltage with good stability, excellent flexibility, and high theoretical capacity indicate that the bare 2D TMCs have potential to be ideal flexible anode materials, whereas the surface functionalization degrades the transport mobility and increases the equilibrium voltage due to bonding between the nonmetals and Li. These results provide valuable insights for experimental explorations of flexible anode candidates based on 2D TMCs. PMID- 29229854 TI - Interferon-beta represses cancer stem cell properties in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC), the deadliest form of this disease, lacks a targeted therapy. TNBC tumors that fail to respond to chemotherapy are characterized by a repressed IFN/signal transducer and activator of transcription (IFN/STAT) gene signature and are often enriched for cancer stem cells (CSCs). We have found that human mammary epithelial cells that undergo an epithelial-to mesenchymal transition (EMT) following transformation acquire CSC properties. These mesenchymal/CSCs have a significantly repressed IFN/STAT gene expression signature and an enhanced ability to migrate and form tumor spheres. Treatment with IFN-beta (IFN-beta) led to a less aggressive epithelial/non-CSC-like state, with repressed expression of mesenchymal proteins (VIMENTIN, SLUG), reduced migration and tumor sphere formation, and reexpression of CD24 (a surface marker for non-CSCs), concomitant with an epithelium-like morphology. The CSC-like properties were correlated with high levels of unphosphorylated IFN-stimulated gene factor 3 (U-ISGF3), which was previously linked to resistance to DNA damage. Inhibiting the expression of IRF9 (the DNA-binding component of U-ISGF3) reduced the migration of mesenchymal/CSCs. Here we report a positive translational role for IFN-beta, as gene expression profiling of patient-derived TNBC tumors demonstrates that an IFN-beta metagene signature correlates with improved patient survival, an immune response linked with tumor-infiltrating lymphocytes (TILs), and a repressed CSC metagene signature. Taken together, our findings indicate that repressed IFN signaling in TNBCs with CSC-like properties is due to high levels of U-ISGF3 and that treatment with IFN-beta reduces CSC properties, suggesting a therapeutic strategy to treat drug-resistant, highly aggressive TNBC tumors. PMID- 29229855 TI - Distinct roles of N- and O-glycans in cellulase activity and stability. AB - In nature, many microbes secrete mixtures of glycoside hydrolases, oxidoreductases, and accessory enzymes to deconstruct polysaccharides and lignin in plants. These enzymes are often decorated with N- and O-glycosylation, the roles of which have been broadly attributed to protection from proteolysis, as the extracellular milieu is an aggressive environment. Glycosylation has been shown to sometimes affect activity, but these effects are not fully understood. Here, we examine N- and O-glycosylation on a model, multimodular glycoside hydrolase family 7 cellobiohydrolase (Cel7A), which exhibits an O-glycosylated carbohydrate-binding module (CBM) and an O-glycosylated linker connected to an N- and O-glycosylated catalytic domain (CD)-a domain architecture common to many biomass-degrading enzymes. We report consensus maps for Cel7A glycosylation that include glycan sites and motifs. Additionally, we examine the roles of glycans on activity, substrate binding, and thermal and proteolytic stability. N-glycan knockouts on the CD demonstrate that N-glycosylation has little impact on cellulose conversion or binding, but does have major stability impacts. O-glycans on the CBM have little impact on binding, proteolysis, or activity in the whole enzyme context. However, linker O-glycans greatly impact cellulose conversion via their contribution to proteolysis resistance. Molecular simulations predict an additional role for linker O-glycans, namely that they are responsible for maintaining separation between ordered domains when Cel7A is engaged on cellulose, as models predict alpha-helix formation and decreased cellulose interaction for the nonglycosylated linker. Overall, this study reveals key roles for N- and O-glycosylation that are likely broadly applicable to other plant cell wall-degrading enzymes. PMID- 29229856 TI - Global biogeochemical cycle of vanadium. AB - Synthesizing published data, we provide a quantitative summary of the global biogeochemical cycle of vanadium (V), including both human-derived and natural fluxes. Through mining of V ores (130 * 109 g V/y) and extraction and combustion of fossil fuels (600 * 109 g V/y), humans are the predominant force in the geochemical cycle of V at Earth's surface. Human emissions of V to the atmosphere are now likely to exceed background emissions by as much as a factor of 1.7, and, presumably, we have altered the deposition of V from the atmosphere by a similar amount. Excessive V in air and water has potential, but poorly documented, consequences for human health. Much of the atmospheric flux probably derives from emissions from the combustion of fossil fuels, but the magnitude of this flux depends on the type of fuel, with relatively low emissions from coal and higher contributions from heavy crude oils, tar sands bitumen, and petroleum coke. Increasing interest in petroleum derived from unconventional deposits is likely to lead to greater emissions of V to the atmosphere in the near future. Our analysis further suggests that the flux of V in rivers has been incremented by about 15% from human activities. Overall, the budget of dissolved V in the oceans is remarkably well balanced-with about 40 * 109 g V/y to 50 * 109 g V/y inputs and outputs, and a mean residence time for dissolved V in seawater of about 130,000 y with respect to inputs from rivers. PMID- 29229857 TI - Effect of oil palm sustainability certification on deforestation and fire in Indonesia. AB - Many major corporations and countries have made commitments to purchase or produce only "sustainable" palm oil, a commodity responsible for substantial tropical forest loss. Sustainability certification is the tool most used to fulfill these procurement policies, and around 20% of global palm oil production was certified by the Roundtable on Sustainable Palm Oil (RSPO) in 2017. However, the effect of certification on deforestation in oil palm plantations remains unclear. Here, we use a comprehensive dataset of RSPO-certified and noncertified oil palm plantations (~188,000 km2) in Indonesia, the leading producer of palm oil, as well as annual remotely sensed metrics of tree cover loss and fire occurrence, to evaluate the impact of certification on deforestation and fire from 2001 to 2015. While forest loss and fire continued after RSPO certification, certified palm oil was associated with reduced deforestation. Certification lowered deforestation by 33% from a counterfactual of 9.8 to 6.6% y-1 Nevertheless, most plantations contained little residual forest when they received certification. As a result, by 2015, certified areas held less than 1% of forests remaining within Indonesian oil palm plantations. Moreover, certification had no causal impact on forest loss in peatlands or active fire detection rates. Broader adoption of certification in forested regions, strict requirements to avoid all peat, and routine monitoring of clearly defined forest cover loss in certified and RSPO member-held plantations appear necessary if the RSPO is to yield conservation and climate benefits from reductions in tropical deforestation. PMID- 29229858 TI - Zooplankton can actively adjust their motility to turbulent flow. AB - Calanoid copepods are among the most abundant metazoans in the ocean and constitute a vital trophic link within marine food webs. They possess relatively narrow swimming capabilities, yet are capable of significant self-locomotion under strong hydrodynamic conditions. Here we provide evidence for an active adaptation that allows these small organisms to adjust their motility in response to background flow. We track simultaneously and in three dimensions the motion of flow tracers and planktonic copepods swimming freely at several intensities of quasi-homogeneous, isotropic turbulence. We show that copepods synchronize the frequency of their relocation jumps with the frequency of small-scale turbulence by performing frequent relocation jumps of low amplitude that seem unrelated to localized hydrodynamic signals. We develop a model of plankton motion in turbulence that shows excellent quantitative agreement with our measurements when turbulence is significant. We find that, compared with passive tracers, active motion enhances the diffusion of organisms at low turbulence intensity whereas it dampens diffusion at higher turbulence levels. The existence of frequent jumps in a motion that is otherwise dominated by turbulent transport allows for the possibility of active locomotion and hence to transition from being passively advected to being capable of controlling diffusion. This behavioral response provides zooplankton with the capability to retain the benefits of self locomotion despite turbulence advection and may help these organisms to actively control their distribution in dynamic environments. Our study reveals an active adaptation that carries strong fitness advantages and provides a realistic model of plankton motion in turbulence. PMID- 29229859 TI - Ultrafast rotation in an amphidynamic crystalline metal organic framework. AB - Amphidynamic crystals are an emergent class of condensed phase matter designed with a combination of lattice-forming elements linked to components that display engineered dynamics in the solid state. Here, we address the design of a crystalline array of molecular rotors with inertial diffusional rotation at the nanoscale, characterized by the absence of steric or electronic barriers. We solved this challenge with 1,4-bicyclo[2.2.2]octane dicarboxylic acid (BODCA) MOF, a metal-organic framework (MOF) built with a high-symmetry bicyclo[2.2.2]octane dicarboxylate linker in a Zn4O cubic lattice. Using spin lattice relaxation 1H solid-state NMR at 29.49 and 13.87 MHz in the temperature range of 2.3-80 K, we showed that internal rotation occurs in a potential with energy barriers of 0.185 kcal mol-1 These results were confirmed with 2H solid state NMR line-shape analysis and spin-lattice relaxation at 76.78 MHz obtained between 6 and 298 K, which, combined with molecular dynamics simulations, indicate that inertial diffusional rotation is characterized by a broad range of angular displacements with no residence time at any given site. The ambient temperature rotation of the bicyclo[2.2.2]octane (BCO) group in BODCA-MOF constitutes an example where engineered rotational dynamics in the solid state are as fast as they would be in a high-density gas or in a low-density liquid phase. PMID- 29229860 TI - Autocatalytic surface reduction and its role in controlling seed-mediated growth of colloidal metal nanocrystals. AB - The growth of colloidal metal nanocrystals typically involves an autocatalytic process, in which the salt precursor adsorbs onto the surface of a growing nanocrystal, followed by chemical reduction to atoms for their incorporation into the nanocrystal. Despite its universal role in the synthesis of colloidal nanocrystals, it is still poorly understood and controlled in terms of kinetics. Through the use of well-defined nanocrystals as seeds, including those with different types of facets, sizes, and internal twin structure, here we quantitatively analyze the kinetics of autocatalytic surface reduction in an effort to control the evolution of nanocrystals into predictable shapes. Our kinetic measurements demonstrate that the activation energy barrier to autocatalytic surface reduction is highly dependent on both the type of facet and the presence of twin boundary, corresponding to distinctive growth patterns and products. Interestingly, the autocatalytic process is effective not only in eliminating homogeneous nucleation but also in activating and sustaining the growth of octahedral nanocrystals. This work represents a major step forward toward achieving a quantitative understanding and control of the autocatalytic process involved in the synthesis of colloidal metal nanocrystals. PMID- 29229861 TI - Appetite suppressive role of medial septal glutamatergic neurons. AB - Feeding behavior is controlled by diverse neurons and neural circuits primarily concentrated in the hypothalamus and hindbrain in mammals. In this study, by using chemo/optogenetic techniques along with feeding assays, we investigate how neurons within the medial septal complex (MSc), a brain area implicated in emotion and cognition, contribute to food intake. We find that chemo/optogenetic activation of MSc glutamatergic neurons profoundly reduces food intake during both light and dark periods of the rodent light cycle. Furthermore, we find that selective activation of MSc glutamatergic projections in paraventricular hypothalamus (PVH) reduces food intake, suggesting that MSc glutamatergic neurons suppress feeding by activating downstream neurons in the PVH. Open-field behavioral assays reveal that these neurons do not overtly affect anxiety levels and locomotion. Collectively, our findings demonstrate that septal glutamatergic neurons exert anorexigenic effects by projecting to the PVH without affecting anxiety and physical activities. PMID- 29229862 TI - A small-molecule activator of kinesin-1 drives remodeling of the microtubule network. AB - The microtubule motor kinesin-1 interacts via its cargo-binding domain with both microtubules and organelles, and hence plays an important role in controlling organelle transport and microtubule dynamics. In the absence of cargo, kinesin-1 is found in an autoinhibited conformation. The molecular basis of how cargo engagement affects the balance between kinesin-1's active and inactive conformations and roles in microtubule dynamics and organelle transport is not well understood. Here we describe the discovery of kinesore, a small molecule that in vitro inhibits kinesin-1 interactions with short linear peptide motifs found in organelle-specific cargo adaptors, yet activates kinesin-1's function of controlling microtubule dynamics in cells, demonstrating that these functions are mechanistically coupled. We establish a proof-of-concept that a microtubule motor cargo interface and associated autoregulatory mechanism can be manipulated using a small molecule, and define a target for the modulation of microtubule dynamics. PMID- 29229863 TI - Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. AB - Thyroid hormone (TH) and TH receptors (TRs) alpha and beta act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRalpha and TRbeta, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding-defective TRbeta leads to disruption of the hypothalamic-pituitary-thyroid axis with resistance to TH, while mutation of TRalpha causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level. PMID- 29229864 TI - Cytoplasmic Cl- couples membrane remodeling to epithelial morphogenesis. AB - Chloride is the major free anion in the extracellular space (>100 mM) and within the cytoplasm in eukaryotes (10 ~ 20 mM). Cytoplasmic Cl- level is dynamically regulated by Cl- channels and transporters. It is well established that movement of Cl- across the cell membrane is coupled with cell excitability through changes in membrane potential and with water secretion. However, whether cytoplasmic Cl- plays additional roles in animal development and tissue homeostasis is unknown. Here we use genetics, cell biological and pharmacological tools to demonstrate that TMEM16A, an evolutionarily conserved calcium-activated chloride channel (CaCC), regulates cytoplasmic Cl- homeostasis and promotes plasma membrane remodeling required for mammalian epithelial morphogenesis. We demonstrate that TMEM16A-mediated control of cytoplasmic Cl- regulates the organization of the major phosphoinositide species PtdIns(4,5)P2 into microdomains on the plasma membrane, analogous to processes that cluster soluble and membrane proteins into phase-separated droplets. We further show that an adequate cytoplasmic Cl- level is required for proper endocytic trafficking and membrane supply during early stages of ciliogenesis and adherens junction remodeling. Our study thus uncovers a critical function of CaCC-mediated cytoplasmic Cl- homeostasis in controlling the organization of PtdIns(4,5)P2 microdomains and membrane remodeling. This newly defined role of cytoplasmic Cl- may shed light on the mechanisms of intracellular Cl- signaling events crucial for regulating tissue architecture and organelle biogenesis during animal development. PMID- 29229865 TI - Daple coordinates organ-wide and cell-intrinsic polarity to pattern inner-ear hair bundles. AB - The establishment of planar polarization by mammalian cells necessitates the integration of diverse signaling pathways. In the inner ear, at least two systems regulate the planar polarity of sensory hair bundles. The core planar cell polarity (PCP) proteins coordinate the orientations of hair cells across the epithelial plane. The cell-intrinsic patterning of hair bundles is implemented independently by the G protein complex classically known for orienting the mitotic spindle. Although the primary cilium also participates in each of these pathways, its role and the integration of the two systems are poorly understood. We show that Dishevelled-associating protein with a high frequency of leucine residues (Daple) interacts with PCP and cell-intrinsic signals. Regulated by the cell-intrinsic pathway, Daple is required to maintain the polarized distribution of the core PCP protein Dishevelled and to position the primary cilium at the abneural edge of the apical surface. Our results suggest that the primary cilium or an associated structure influences the domain of cell-intrinsic signals that shape the hair bundle. Daple is therefore essential to orient and pattern sensory hair bundles. PMID- 29229866 TI - Allosteric histidine switch for regulation of intracellular zinc(II) fluctuation. AB - Metalloregulators allosterically control transcriptional activity through metal binding-induced reorganization of ligand residues and/or hydrogen bonding networks, while the coordination atoms on the same ligand residues remain seldom changed. Here we show that the MarR-type zinc transcriptional regulator ZitR switches one of its histidine nitrogen atoms for zinc coordination during the allosteric control of DNA binding. The Zn(II)-coordination nitrogen on histidine 42 within ZitR's high-affinity zinc site (site 1) switches from Nepsilon2 to Ndelta1 upon Zn(II) binding to its low-affinity zinc site (site 2), which facilitates ZitR's conversion from the nonoptimal to the optimal DNA-binding conformation. This histidine switch-mediated cooperation between site 1 and site 2 enables ZitR to adjust its DNA-binding affinity in response to a broad range of zinc fluctuation, which may allow the fine tuning of transcriptional regulation. PMID- 29229867 TI - Intracranial pulsatility in patients with cerebral small vessel disease: a systematic review. AB - Growing evidence suggests that increased intracranial pulsatility is associated with cerebral small vessel disease (SVD). We systematically reviewed papers that assessed intracranial pulsatility in subjects with SVD. We included 27 cross sectional studies (n=3356): 20 used Doppler ultrasound and 7 used phase-contrast MRI. Most studies measured pulsatility in the internal carotid or middle cerebral arteries (ICA, MCA), whereas few assessed veins or cerebrospinal fluid (CSF). Methods to reduce bias and risk factor adjustment were poorly reported. Substantial variation between studies in assessment of SVD and of pulsatility indices precluded a formal meta-analysis. Eight studies compared pulsatility by SVD severity (n=26-159, median = 74.5): arterial pulsatility index was generally higher in more severe SVD (e.g. MCA: standardized mean difference = 3.24, 95% confidence interval [2.40, 4.07]), although most did not match for age. Seventeen studies (n=9-700; median = 110) performed regression or correlation analysis, of which most showed that increased pulsatility was associated with SVD after adjustment for age. In conclusion, most studies support a cross-sectional association between higher pulsatility in large intracranial arteries and SVD. Future studies should minimize bias, adjust for potential confounders, include pulsatility in veins and CSF, and examine longitudinal relationship between pulsatility and SVD. Agreement on reliable measures of intracranial pulsatility would be helpful. PMID- 29229868 TI - Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury. AB - A sexual dimorphism in liver inflammation and repair was previously demonstrated. Its cellular dissection in the course of acute liver injury (ALI) was explored. BALB/c mice were treated with carbon tetrachloride (CCl4) by intraperitoneal injection and killed after 3, 5, and 8 days. Histological and hepatic cell population analyses were performed. The correlation between androgen receptor (AR) expression and liver recruited inflammatory cells was investigated by treatment with the AR antagonist flutamide. Additionally, patients with a diagnosis of drug induced liver injury (DILI) were included in the study, with a particular focus on gender dimorphism in circulating monocytes. A delayed resolution of necrotic damage and a higher expression of proinflammatory cytokines were apparent in male mice along with a slower recruitment of inflammatory monocytes. F4/80+CD11b+ macrophages and CD11bhighGr-1high monocytes expressed AR and were recruited later in male compared with female livers after CCl4 treatment. Moreover, CD11bhighAR+Gr-1high recruitment was negatively modulated by flutamide in males. Analysis of DILI patients showed overall a significant reduction in circulating mature monocytes compared with healthy subjects. More interestingly, male patients had higher numbers of immature monocytes compared with female patients.A stronger cytotoxic tissue response was correlated with an impaired recruitment of CD11bhighAR+Gr-1high cells and F4/80+CD11b+ macrophages in the early inflammatory phase under AR signaling. During DILI, a dimorphic immune response was apparent, characterized by a massive recruitment of monocytes to the liver both in males and females, but only in males was this recruitment sustained by a turnover of immature monocytes. PMID- 29229869 TI - Irregular designs and Darwinism in biology: Genomes as the test case. PMID- 29229870 TI - What history tells us XLIV: The construction of the zinc finger nucleases. PMID- 29229871 TI - Antifolate drug resistance: Novel mutations and haplotype distribution in dhps and dhfr from Northeast India. AB - Malaria is a major public health concern in Northeast India with a preponderance of drug-resistant strains. Until recently the partner drug for artemisinin combination therapy (ACT) was sulphadoxine pyrimethamine (SP). Antifolate drug resistance has been associated with the mutations at dihydropteroate synthase (dhps) and dihydrofolatereductase (dhfr) genes. This study investigated antifolate drug resistance at the molecular level. A total of 249 fever cases from Arunachal Pradesh, NE India, were screened for malaria, and of these, 75 were found to be positive for Plasmodium falciparum. Samples were sequenced and analysed with the help of BioEdit and ClustalW. Three novel point mutations were found in the dhps gene with 10 haplotypes along with the already reported mutations. A single haplotype having quadruple mutation was found in the dhfr gene. The study reports higher degree of antifolate drug resistance as evidenced by the presence of multiple point mutations in dhps and dhfr genes. The findings of this study strongly discourage the use SP as a partner drug in ACT. PMID- 29229872 TI - Specific mutation of transglutaminase gene from Streptomyces hygroscopicus H197 and characterization of microbial transglutaminase. AB - Microbial transglutaminase (MTG) gene (mtg) from Streptomyces hygroscopicus H197 strain was cloned by PCR and mutated by deleting a specific 84 bp fragment using overlapping extension PCR. The mutant MTG and the wild MTG genes expressed by recombinant plasmid pET32a+- mutant mtg and pET32a+ -mtg, respectively, and were harvested by alternating freeze-thaw steps and purified by Ni column. The purified mutant MTG and the wild MTG exhibited 0.22 U/mg and 0.16 U/mg activity, respectively, and 0.69 U/mg and 0.54 U/mg activity, respectively, after activated by trypsin. The molecular weight of mutant MTG was estimated as 67 kDa by SDS PAGE. Both MTGs showed optimum activity at pH 6-8 for hydroxamate formation from N-CBZ-Gln-Gly and hydroxylamine, and exhibited higher stability at 40 degrees C and 1-3% salinity. The two types of MTG were not stable in the presence of Zn(II), Cu(II), Hg(II), Pb(II), Fe(III), and Ag(I), suggesting that they could possess a thiol group. In addition, the mutant MTG and the wild MTG were strongly affected by ethanol. Furthermore, the mutant MTG was obviously (P less than 0.05 or P less than 0.01) more stable than the wild MTG at 50 degrees C and 60 degrees C, at pH 4, 5, and 9, at 7 % and 9 % salinity, 30 % and 35 % ethanol concentration, and in the presence of Li(I) and Ag(I). The polyhydroxy compounds as protein stabilizers could elevate MTG stability. PMID- 29229873 TI - Thymoquinone induces cytotoxicity and reprogramming of EMT in gastric cancer cells by targeting PI3K/Akt/mTOR pathway. AB - Gastric cancer is one of the lethal causes of cancer-related deaths worldwide. The incidence and mortality rates of this disease is comparatively higher in China. In the current study, we evaluated the anticancer effects of Thymoquinone (TQ) against gastric cancer cells (MGC80-3 and SGC-7901) and normal noncancerous GES-1 cells and attempted to investigate the underlying mechanism. Our results indicated that TQ exhibited significant growth inhibitory effects on gastric cancer cells (MGC80-3 and SGC-7901). However, lower cytotoxicity was observed against normal GES-1 cells. Moreover, TQ could inhibit the colony formation potential of MGC80-3 and SGC-7901 cells in a dose-dependent manner. TQ also inhibited cell migration ability of the gastric cancer cells and down-regulated the expression of the mesenchymal genes such as N-cadherin, Vimentin, and TWIST. However, the epithelial markers such as E-cadherin and cytokeratin-19 were distinctly up-regulated in TQ-treated gastric cancer cells. Since PI3K/Akt/ mTOR plays an important role in progression and tumorigenesis, we also investigated the effect of TQ on PI3K/Akt/mTOR signalling pathway in gastric cancer cells. It was observed that TQ down-regulated the expression of some of the key proteins of this pathway. Taken together, we conclude that TQ may prove lead molecule for the treatment of gastric cancer. PMID- 29229874 TI - Induction of morphological and functional differentiation of human neuroblastoma cells by miR-124. AB - Neuroblastoma is the most common extracranial solid tumour in children, and differentiation is considered its most appropriate therapy. In this work, we studied effects of miR-124 overexpression on differentiation in M17 cell line as a model of neuroblastoma cancer. Influence of miR-124 overexpression on differentiation in M17 cells was studied. M17 cells were infected with lentivirus that contained miR-124 precursor sequence and followed for 2 weeks to differentiate. Ectopic expression of miR-124 in M17 cells changed the shape of spherical undifferentiated cells to cells with extended neurites that formed neuronal networks. Overexpression of MiR-124 respectively increased the expression level of markers of beta-Tubulin III, MAP2, SYN, NF-M and Nestin by 16 , 5-, 4-, 2.3- and 2-folds at the messenger RNA level. MiR-124 overexpression also increased the protein levels of beta-Tubulin III and MAP2. Moreover, exogenous expression of miR-124 significantly increased the intracellular calcium in differentiated M17 cells. Since miR-124 is naturally expressed in neuronal cells and is downregulated in neuroblastoma cancer cells, differentiation with this type of microRNA can be a novel treatment for neuroblastoma cancer. PMID- 29229875 TI - Re-engineering the two-component systems as light-regulated in Escherichia coli. AB - Bacteria live in environments with dynamic changes. To sense and respond to different external stimuli, bacteria make use of various sensor-response circuits, called two-component systems (TCSs). A TCS comprises a histidine protein kinase (HK) sensing environmental stimuli and a response regulator protein (RR) regulating downstream genes. The two components are coupled via a phosphorylation control mechanism. In a recent study, we adopted an optogenetics approach to re-engineer the sensor HKs in Escherichia coli as a light-sensing fusion protein. We constructed a light-controllable HK by replacing the original signal-specific sensing domain of HK with the light-sensing domain of Cph1 from Cyanobacteria Synechocystis, so that HK can be investigated by red light. Here, we extended the study to other 16 HK-RR TCSs and constructed a library of light responsible HK-Cph1 chimeras. By taking the NarX-NarL system as an example, we demonstrated the light responsiveness of the constructed chimera and investigated the frequency response of the NarXNarL system. The constructed library serves as a toolkit for future TCS study using optogenetics approach. PMID- 29229876 TI - MicroRNA-486-5p suppresses TGF-beta2-induced proliferation, invasion and epithelial-mesenchymal transition of lens epithelial cells by targeting Smad2. AB - The pathological development of lens epithelial cells (LECs) leads to posterior capsular opacification (PCO). This study was undertaken to investigate the effects of microRNA-486-5p (miR-486-5p) on TGF-beta2-induced proliferation, invasion and epithelial-mesenchymal transition (EMT) in the lens epithelial cell line SRA01/04, and to explore the underlying molecular mechanisms. The expression of miR-486-5p in TGF-beta2-induced SRA01/04 cells was down-regulated, and the expression of Smad2, p-Smad2 and p-Smad3 was up-regulated. A dual-luciferase reporter assay revealed that miR-486-5p directly targets the 30'-UTR of Smad2. MiR-486-5p mimic transfection markedly down-regulated the expression levels of Smad2, thus inhibiting the expression of p-Smad2 and p-Smad3. MiR-486-5p overexpression in SRA01/04 cells markedly suppressed TGF-beta2-induced proliferation and invasion, inhibited protein expression of CDK2 and CDK4, down regulated fibronectin, alpha-SMA and vimentin and up-regulated E-cadherin; these effects were partly reversed by Smad2 overexpression. In short, these data show that miR-486-5p overexpression can inhibit TGF-beta2-induced proliferation, invasion and EMT in SRA01/04 cells by repressing Smad2/Smad3 signalling, implying that miR-486-5p may be an effective target to interfere in the progression of PCO. PMID- 29229878 TI - Uptake of phenolic compounds from plant foods in human intestinal Caco-2 cells. AB - In continuation of our studies on the bioaccessibility of phenolic compounds from food grains as influenced by domestic processing, we examined the uptake of phenolics from native/sprouted finger millet (Eleucine coracana) and green gram (Vigna radiata) and native/heat-processed onion (Allium cepa) in human Caco-2 cells. Absorption of pure phenolic compounds, as well as the uptake of phenolic compounds from finger millet, green gram, and onion, was investigated in Caco-2 monolayer model. Transport of individual phenolic compounds from apical compartment to the basolateral compartment across Caco-2 monolayer was also investigated. Sprouting enhanced the uptake of syringic acid from both these grains. Open-pan boiling reduced the uptake of quercetin from the onion. Among pure phenolic compounds, syringic acid was maximally absorbed, while the flavonoid isovitexin was least absorbed. Apparent permeability coefficient P(app) of phenolic compounds from their standard solutions was 2.02 x 10-6cm/s to 8.94 x 10-6cm/s. Sprouting of grains enhanced the uptake of syringic acid by the Caco-2 cells. Open-pan boiling drastically reduced the uptake of quercetin from the onion. The permeability of phenolic acids across Caco-2 monolayer was higher than those of flavonoids. PMID- 29229877 TI - Fermentative metabolism impedes p53-dependent apoptosis in a Crabtree-positive but not in Crabtree-negative yeast. AB - Tumour cells distinguish from normal cells by fermenting glucose to lactate in presence of sufficient oxygen and functional mitochondria (Warburg effect). Crabtree effect was invoked to explain the biochemical basis of Warburg effect by suggesting that excess glucose suppresses mitochondrial respiration. It is known that the Warburg effect and Crabtree effect are displayed by Saccharomyces cerevisiae, during growth on abundant glucose. Beyond this similarity, it was also demonstrated that expression of human pro-apoptotic proteins in S. cerevisiae such as Bax and p53 caused apoptosis. Here, we demonstrate that p53 expression in S. cerevisiae (Crabtree-positive yeast) causes increase in ROS levels and apoptosis when cells are growing on non-fermentable carbon sources but not on fermentable carbon sources, a feature similar to tumour cells. In contrast, in Kluyveromyces lactis (Crabtree-negative yeast) p53 causes increase in ROS levels and apoptosis regardless of the carbon source. Interestingly, the increased ROS levels and apoptosis are correlated to increased oxygen uptake in both S. cerevisiae and K. lactis. Based on these results, we suggest that at least in yeast, fermentation per se does not prevent the escape from apoptosis. Rather, the Crabtree effect plays a crucial role in determining whether the cells should undergo apoptosis or not. PMID- 29229879 TI - Small phosphatidate phosphatase (TtPAH2) of Tetrahymena complements respiratory function and not membrane biogenesis function of yeast PAH1. AB - Phosphatidate phosphatases (PAH) play a central role in lipid metabolism and intracellular signaling. Herein, we report the presence of a low-molecular-weight PAH homolog in the single-celled ciliate Tetrahymena thermophila. In vitro phosphatase assay showed that TtPAH2 belongs to the magnesium-dependent phosphatidate phosphatase (PAP1) family. Loss of function of TtPAH2 did not affect the growth of Tetrahymena. Unlike other known PAH homologs, TtPAH2 did not regulate lipid droplet number and ER morphology. TtPAH2 did not rescue growth and ER/nuclear membrane defects of the pah1Delta yeast cells, suggesting that the phosphatidate phosphatase activity of the protein is not sufficient to perform these cellular functions. Surprisingly, TtPAH2 complemented the respiratory defect in the pah1Delta yeast cells indicating a specific role of TtPAH2 in respiration. Overall, our results indicate that TtPAH2 possesses the minimal function of PAH protein family in respiration. We suggest that the amino acid sequences absent from TtPAH2 but present in all other known PAH homologs are critical for lipid homeostasis and membrane biogenesis. PMID- 29229880 TI - Klebsiella pneumoniae antibiotic resistance identified by atomic force microscopy. AB - In the last decade the detection of the resistance of bacteria to antibiotics treatment, developed by different kind of bacteria, is becoming a huge problem. We hereby present a different approach to the current problem of detection of bacteria resistance to antibiotics. Our aims were to use the atomic force microscopy (AFM) to investigate bacteria morphological changes in response to antibiotics treatment and explore the possibility of reducing the time required to obtain information on their resistance. In particular, we studied Klebsiella pneumoniae bacteria provided by the Lavagna Hospital ASL4 Liguria (Italy), where there are cases linked with antibiotics resistance of the Klebsiella pneumoniae. By comparing AFM images of bacteria strains treated with different antibiotics is possible to identify unambiguously the Klebsiella pneumoniae strains resistant to antibiotics. In fact, the analysis of the AFM images of the antibiotic-sensitive bacteria shows clearly the presence of morphological alterations in the cell wall. While in the case of the antibiotic-resistant bacteria morphological alterations are not present. This approach is based on an easy and potentially rapid AFM analysis. PMID- 29229881 TI - MicroRNA-146 protects A549 and H1975 cells from LPS-induced apoptosis and inflammation injury. AB - Pneumonia is an inflammatory condition affecting the lungs, in which pro inflammatory cytokines are secreted. It has been shown that microRNA-146 (miR 146) is involved in the regulation of immune and inflammatory responses. The present study explored the protective effects of miR-146 overexpression on lipopolysaccharide (LPS)-mediated injury in A549 and H1975 cells. In this study, A549 and H1975 cells were transfected with miR-146 mimic or inhibitor, and then were subjected with LPS. Thereafter, cell viability, colony formation capacity, apoptosis, the release of proinflammatory factors, Sirt1 expression, and the expression of NF-kappaB and Notch pathway proteins were respectively assessed. As a result, miR- 146 overexpression exerted protective functions on LPS-damaged A549 and H1975 cells, as evidenced by the increases in cell viability and colony number, the decrease in apoptotic cell rate, as well as the down-regulations of IL-1, IL-6, and TNF-alpha. Sirt1 can be positively regulated by miR-146. Furthermore, miR-146 overexpression blocked NF-kappaB and Notch pathways, while these blocking effects were abolished when Sirt1 was silenced. The findings in the current study indicated that miR-146 protected A549 and H1975 cells from LPS induced apoptosis and inflammation injury. miR-146 exerted protective functions might be via up-regulation of Sirt1 and thereby blocking NF-kappaB and Notch pathways. PMID- 29229882 TI - IGF1 stimulates differentiation of primary follicles and their growth in ovarian explants of zebrafish (Danio rerio) cultured in vitro. AB - The present study is an attempt to elucidate the involvement of insulin-like growth factor (IGF1) in the differentiation and growth of primary follicles in ovarian explant cultures of zebrafish. Ovaries from adult females were cultured in triplicate sets/treatment group for 15 days at 22 degrees in the laboratory. Culture medium was supplemented with either insulin (1 ng/mL) or IGF1 (1 ng/mL) or insulin + IGF1 (Experiment 1) or 0.1 or 1.0 or 10 ng/mL of IGF1 (Experiment 2). Ovaries cultured in medium alone served as controls and those fixed at the beginning of the culture as initial controls. Experiments were repeated. On the 16th day ovarian explants were fixed in Bouin's fluid and processed for paraffin embedding, sections (3 MU m) were cut and stained with hematoxylin-eosin. Follicles were classified into 6 stages and atretic follicles (AF). Previtellogenic, vitellogenic and total follicle number was calculated. At the start of the culture, ovaries contained all stages of growing and degenerating follicles. In in vitro cultured control ovaries, vitellogenic follicles underwent atresia, while, primary follicles remained unaffected. Insulin or insulin + IGF1 treated ovaries did not differ significantly while IGF1 exposed ovarian explants had greater (P less than 0.05) number of primary follicles compared to controls. IGF1 also caused an increase in the number and growth of primary follicles in a dose dependent manner although; cultures were not supplemented with gonadotrophic hormones. Results suggest that locally derived intra-ovarian IGF1 may have a role in the differentiation and growth of primary follicles in zebrafish ovary. PMID- 29229883 TI - In vitro leishmanicidal, antibacterial and antitumour potential of anhydrocochlioquinone A obtained from the fungus Cochliobolus sp. AB - The bioassay-guided fractionation of the ethyl acetate extract of the fungus Cochliobolus sp. highlighted leishmanicidal activity and allowed for anhydrocochlioquinone A (ANDC-A) isolation. MS, 1D and 2D NMR spectra of this compound were in agreement with those published in the literature. ANDC-A exhibited leishmanicidal activity with EC 50 value of 22.4 microgram/mL (44 mu M) and, when submitted to the microdilution assay against Gram-ositive and Gram negative bacteria, showed a minimal inhibitory concentration against Staphylococcus aureus ATCC 25295 of 128 microgram/mL (248.7 mu M). It was also active against five human cancer cell lines, showing IC50 values from 5.4 to 20.3 mu M. ANDC-A demonstrated a differential selectivity for HL-60 (SI 5.5) and THP-1 (SI 4.3) cell lines in comparison with Vero cells and was more selective than cisplatin and doxorubicin against MCF-7 cell line in comparison with human peripheral blood mononuclear cells. ANDC-A was able to eradicate clonogenic tumour cells at concentrations of 20 and 50 mu M and induced apoptosis in all tumour cell lines at 20 mu M. These results suggest that ANDC-A might be used as a biochemical tool in the study of tumour cells biochemistry as well as an anticancer agent with durable effects on tumours. PMID- 29229884 TI - Enthalpy-entropy compensation and the isokinetic temperature in enzyme catalysis. AB - Enthalpy-entropy compensation supposes that differences in activation enthalpy DeltaH++ for different reactions (or, typically in biochemistry, the same reaction catalysed by enzymes obtained from different species) may be compensated for by differences in activation entropy DeltaS++. At the isokinetic temperature the compensation is exact, so that all samples have the same activity. These ideas have been controversial for several decades, but examples are still frequently reported as evidence of a real phenomenon, nearly all of the reports ignoring or discounting the possibility of a statistical artefact. Even for measurements in pure chemistry artefacts occur often, and they are almost inescapable in enzyme kinetics and other fields that involve biological macromolecules, on account of limited stability and the fact that kinetic equations are normally valid only over a restricted range of temperature. Here I review the current status and correct an error in a recent book chapter. PMID- 29229885 TI - MiR-876-5p suppresses epithelial-mesenchymal transition of lung cancer by directly down-regulating bone morphogenetic protein 4. AB - Lung cancer is the leading cause of cancer-related death throughout the world. We aimed to investigate the role of a novel microRNA-876-5p and its potential molecular target bone morphogenetic protein 4 (BMP-4), in the epithelial mesenchymal transition (EMT) of lung cancer. Expressions of microRNA-876-5p and its potential target BMP-4 were analysed in lung cancer cells and patient tissues. Luciferase activity assay was conducted to verify direct targeting of microRNA- 876-5p to the 3'-UTR of BMP-4 mRNA. Migration, invasion capacities of lung cancer cells expressing microRNA-876-5p were analysed, and characteristics of lung cancer EMT protein markers were also evaluated. A xenograft tumour mouse model was established to address the roles of microRNA-876-5p and BMP-4 in lung cancer EMT in vivo. MicroRNA-876- 5p was decreased while BMP-4 was increased in lung cancer cells and tissues. MicroRNA-876-5p directly targeted 3'-UTR of BMP-4 mRNA to inhibit its expression. MicroRNA-876-5p expression significantly inhibited the migration, invasion and EMT of lung cancer cells in vitro, as well as metastasis in vivo, which required BMP-4 expression. MicroRNA-876-5p suppresses EMT of lung cancer by directly down-regulating BMP-4, both of which could serve as potential therapeutic targets in the treatment of lung cancer. PMID- 29229886 TI - Criticality in cell differentiation. AB - Cell differentiation is an important process in living organisms. Differentiation is mostly based on binary decisions with the progenitor cells choosing between two specific lineages. The differentiation dynamics have both deterministic and stochastic components. Several theoretical studies suggest that cell differentiation is a bifurcation phenomenon, well-known in dynamical systems theory. The bifurcation point has the character of a critical point with the system dynamics exhibiting specific features in its vicinity. These include the critical slowing down, rising variance and lag-1 autocorrelation function, strong correlations between the fluctuations of key variables and non-Gaussianity in the distribution of fluctuations. Recent experimental studies provide considerable support to the idea of criticality in cell differentiation and in other biological processes like the development of the fruit fly embryo. In this review, an elementary introduction is given to the concept of criticality in cell differentiation. The correspondence between the signatures of criticality and experimental observations on blood cell differentiation in mice is further highlighted. PMID- 29229888 TI - The association between body mass index and frequency of emergency department visits and hospitalization for asthma exacerbation in a pediatric population. AB - BACKGROUND: The prevalence of both asthma and obesity are increasing. Although some studies suggest an association between body mass index (BMI) and frequency of emergency department (ED) visits and hospitalization for asthma exacerbation, any association remains unproven. OBJECTIVE: Estimate the frequency of asthma exacerbation in obese children, and identify any relationship between BMI and frequency of ED visits and hospitalization for asthma exacerbation. DESIGN: Retrospective review of medical records. SETTINGS: Tertiary children's hospital, Riyadh. SUBJECTS AND METHODS: All children aged 2-15 years who attended the ED for asthma exacerbation between January 2015 and January 2016 were included. Children with comorbidities or undocumented asthma were excluded. The Centers for Disease Control and Prevention BMI-for-age growth charts for boys and girls aged 2 to 20 years were used to classify underweight, normal, overweight, and obese. MAIN OUTCOME MEASURES: The frequency of ED visits and the rate, frequency, and duration of hospitalization. RESULTS: Of the 1000 cases reviewed, 64.6% were boys and the mean age (standard deviation) of all sub.jects was 5.6 (3.3) years. The proportions of overweight and obese children was 11.8% and 12.1%, respectively. There was no association between increased BMI and frequency of ED visits for asthma exacerbation (P=.84), duration of hospitalization (P=.41) or frequency of hospitalization (P=.89). CONCLUSION: There was no evidence of an association between BMI and frequency of ED visits and hospitalization for asthma exacerbation among children. LIMITATIONS: This study included patients as young as 2 years, while asthma is only well-defined in children > 5 years. Asthma triggers that can cause exacerbation despite body weight were not included. We included only frequency of ED visits and hospitalization, which may be inadequate to measure asthma severity. PMID- 29229889 TI - Admission of term infants to the neonatal intensive care unit in a Saudi tertiary teaching hospital: cumulative incidence and risk factors. AB - BACKGROUND: An increasing number of term infants of appropriate birthweight receive care in neonatal intensive care units (NICUs). OBJECTIVES: This study assessed the prevalence, patterns, and risk factors for admission of term infants to a NICU to identify areas for quality improvement. DESIGN: Cross-sectional analytical study. SETTING: An academic and referral center in Jeddah, Saudi Arabia. PATIENTS AND METHODS: The cases were all term infants (>=37 weeks gestational age) admitted to the NICU between 1 January and 31 December 2015. The controls were term infants who were not admitted to the NICU. Cases and controls were matched in a 1:1 ratio according to the date of birth (within one day). MAIN OUTCOME MEASURES: Prevalence, pattern, and risk factors for admission of term infants to the NICU. RESULTS: The rate of admission of term infants to the NICU during the study period was 4.1% (142 of 3314 live births in that year). Respiratory complications accounted for 36.6% (52/142) of admissions, followed by hypoglycemia (23/142, 16.2%) and jaundice (11/142, 7.7%). Premature membrane rupture and non-Saudi national status were the risk factors that remained significant after adjusting for confounders. CONCLUSION: A growing number of term infants are admitted unexpectedly to the NICU. The risk factors and pattern of admission of term infants to the NICU should receive more attention in quality improvement and management agendas. LIMITATIONS: This was a single-center study with limited access to information about unbooked mothers and details of the hospital stay of the admitted neonates. PMID- 29229887 TI - Multiple oncogenic roles of nuclear beta-catenin. AB - beta-Catenin is essential for embryonic development and required for cell renewal/regeneration in adult life. Cellular beta-catenin exists in three different pools: membranous, cytoplasmic and nuclear. In this review, we focus on functions of the nuclear pool in relation to tumorigenesis. In the nucleus, beta catenin functions as both activator and repressor of transcription in a context dependent manner. It promotes cell proliferation and supports tumour growth by enhancing angiogenesis. beta-Catenin-mediated signalling regulates cancer cell metabolism and is associated with tumour-initiating cells in multiple malignancies. In addition, it functions as both pro- and anti-apoptotic factor besides acting to inhibit recruitment of inflammatory anti-tumour T-cells. Thus, beta-catenin appears to possess a multifaceted nuclear function that may significantly impact tumour initiation and progression. PMID- 29229890 TI - Q192R polymorphism in the PON1 gene and familial hypercholesterolemia in a Saudi population. AB - BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant condition characterized by abnormal levels of low-density lipoprotein (LDL) in the blood. FH is a risk factor for atherosclerosis and cardiovascular disease. The relationship between the paraoxonase 1 (PON1) gene, atherosclerosis and coronary artery disease has not been studied in Saudi patients. OBJECTIVE: To investigate the genetic associations of the Q192R polymorphism in the PON1 gene with FH in Saudi patients. DESIGN: Case-control study. SETTING: Tertiary care center, Riyadh. METHODS: Two hundred Saudi patients were enrolled in this study, including 100 patients with FH and 100 healthy controls, during the period from January 2012 to March 2013. Serum was separated from coagulated blood (3 mL) and used for analysis of lipid profiles. Genomic DNA was isolated from anticoagulant treated blood (2 mL). Genotyping for the Q192R polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism analysis, followed by 3% agarose gel electrophoresis. MAIN OUTCOME MEASURE: The strength of association between the Q192R polymorphism and FH in the Saudi population. RESULTS: We confirmed that QR versus QQ (odds ratio [OR]: 1.55; 95% confidence interval [CI]: 1.05-3.43; P=.03), QR+RR versus QQ (OR: 1.98; 95% CI: 1.13-3.49; P=.01), and R versus Q (OR: 1.68; 95% CI: 1.09- 2.59; P=.01) in the Q192R polymorphism were associated with FH in the Saudi population. CONCLUSION: In conclusion, the Q192R polymorphism in the PON1 gene is associated with FH in the Saudi population. Our results confirmed that the R allele, QR, and dominant model genotypes were associated with FH. LIMITATION: Only a single variant (Q192R) was analyzed, and the medical and family histories of the patients were not known. PMID- 29229891 TI - Cost-effectiveness of oral agents in relapsing-remitting multiple sclerosis compared to interferon-based therapy in Saudi Arabia. AB - BACKGROUND: Promising clinical and humanistic outcomes are associated with the use of new oral agents in the treatment of relapsing-remitting multiple sclerosis (RRMS). This is the first cost-effectiveness study comparing these medications in Saudi Arabia. OBJECTIVES: We aimed to compare the cost-effectiveness of fingolimod, teriflunomide, dimethyl fumarate, and interferon (IFN)-b1a products (Avonex and Rebif) as first-line therapies in the treatment of patients with RRMS from a Saudi payer perspective. DESIGN: Cohort Simulation Model (Markov Model). SETTING: Tertiary care hospital. METHODS: A hypothetical cohort of 1000 RRMS Saudi patients was assumed to enter a Markov model model with a time horizon of 20 years and an annual cycle length. The model was developed based on an expanded disability status scale (EDSS) to evaluate the cost-effectiveness of the five disease-modifying drugs (DMDs) from a healthcare system perspective. Data on EDSS progression and relapse rates were obtained from the literature; cost data were obtained from King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Results were expressed as incremental cost-effectiveness ratios (ICERs) and net monetary benefits (NMB) in Saudi Riyals and converted to equivalent $US. The base-case willingness-to-pay (WTP) threshold was assumed to be $100000 (SAR375000). One-way sensitivity analysis and probabilistic sensitivity analysis were conducted to test the robustness of the model. MAIN OUTCOME MEASURES: ICERs and NMB. RESULTS: The base-case analysis results showed Rebif as the optimal therapy at a WTP threshold of $100000. Avonex had the lowest ICER value of $337282/QALY when compared to Rebif. One-way sensitivity analysis demonstrated that the results were sensitive to utility weights of health state three and four and the cost of Rebif. CONCLUSION: None of the DMDs were found to be cost effective in the treatment of RRMS at a WTP threshold of $100000 in this analysis. The DMDs would only be cost-effective at a WTP above $300000. LIMITATIONS: The current analysis did not reflect the Saudi population preference in valuation of health states and did not consider the societal perspective in terms of cost. PMID- 29229892 TI - Influence of body mass index on severity of dental caries: cross-sectional study in healthy adults. AB - BACKGROUND: The relationship between body mass index (BMI) and dental caries is still undetermined. OBJECTIVE: This study aimed to assess the relationship between the dental status by decayed, missed, filled teeth index (DMFT), and BMI by age and gender among healthy adults. DESIGN: Analytical, cross-sectional study. SETTINGS: University dental hospital in Riyadh. SUBJECTS AND METHODS: Healthy adults aged between 18 and 35 years were recruited during the 10-month period from March 2015 to December 2015. Dental caries severity was estimated using the DMFT index. MAIN OUTCOME MEASURE: The prevalence of overweight/obesity and the association of BMI category with the DMFT index. RESULTS: The mean age of 502 subjects was 24.3 (4.9) years. The caries severity of the study population was considered moderate according to the WHO caries severity scale (mean [standard deviation] DMFT 13.3 [3.8]). The mean (SD) DMFT of male and female subjects was 13.1 (4.0) and 13.36 (3.7), respectively. No significant association was seen between dental caries and BMI. Logistic regression analysis showed that males had two times more risk of developing dental caries compared to females. In addition, the risk of caries development was increased by about 5 times for every year of age. CONCLUSION: Dental caries was not associated with BMI but age significantly influenced the DMFT index and gender was associated with more missing teeth. Further longitudinal studies with larger cohorts from several geographic regions are warranted. LIMITATION: Convenience sampling and recruitment from a single dental center may have some impact on the generalization of data. PMID- 29229893 TI - Prognostic factors for epilepsy following first febrile seizure in Saudi children. AB - BACKGROUND: Febrile seizure is the most common convulsive event during childhood, but it is generally considered benign. OBJECTIVES: To estimate the rate of epilepsy after first presentation of febrile seizure and to describe factors that can predispose children to have subsequent epilepsy after their first febrile seizure. DESIGN: Retrospective chart review. SETTING: A tertiary care center in Riyadh. PATIENTS AND METHODS: All children whose first febrile seizure developed between 2009-2012, and who were admitted to the pediatric wards. MAIN OUTCOME MEASURES: The rate of epilepsy and prognostic factors for epilepsy following first febrile seizure. RESULTS: Of 109 febrile seizure patients, 6 (5.5%, 95% CI: 2.1% - 11.6%) were diagnosed with subsequent epilepsy 5 to 46 months after their first febrile seizure. The risk of having subsequent epilepsy was higher in children who were convulsing at a low-grade fever during their first febrile convulsion (P=.02). Moreover, delayed vaccination status (P=.03), prolonged duration of the first convulsion (P=.04), frequent febrile seizures (P=.01), and fever without documented infection (P=.03) during the first febrile convulsion were associated with epilepsy. CONCLUSION: The rate of epilepsy following first febrile seizure in Saudi children is within the range of values reported in different populations. Although most childhood febrile seizures are self limiting, careful observation is needed, particularly for children who exhibit factors associated with epilepsy. LIMITATIONS: Conducted at a single center in Saudi Arabia, which may limit generalizability. PMID- 29229894 TI - Retrospective review of pediatric status epilepticus in 116 Saudi patients: predictors of outcome. AB - BACKGROUND: Status epilepticus (SE) is a common, life-threatening condition. Multiple factors are used to predict its outcome and evaluate its risks, and there have been only a few studies in Saudi Arabia. OBJECTIVES: Investigate predictors of SE outcome. DESIGN: Retrospective chart review study. SETTING: Tertiary center, Riyadh. PATIENTS AND METHODS: We reviewed all pediatric cases (age 14 years or younger) of SE admitted between January 2005 and December 2015, collecting data on age, sex, date of birth, developmental status, pre-existing neurological diseases, SE etiology, Glasgow Outcome Scale (GOS) scores, and electroencephalogram (EEG) findings. The outcome was categorized as poor based on any decrease in baseline GOS score or moderate-to-severe developmental delay in young children; otherwise outcome was considered good. MAIN OUTCOME MEASURE: Outcome of SE. RESULTS: One hundred and sixteen patients (54% boys) with ages from 1 month to 10 years were included in the analysis. Fifty-five (47.4%) had a poor outcome. The overall mortality rate related to SE was 2.6%. Four patients had an SE duration of more than 24 hours. Univariate and multivariate analysis revealed that poor outcome was related to symptomatic SE etiology and a history of epilepsy. Age, sex, SE duration, and EEG findings were not predictors of poor outcome. CONCLUSION: Pediatric status epilepticus is highly associated with neurological morbidity. The main pre.dictor of outcome is underlying symptomatic etiology of SE and to a lesser degree the presence of a history of epilepsy. Duration does not seem to play a major role. LIMITATIONS: The main limitation is the retrospective chart review nature of the study with possible bias. PMID- 29229895 TI - Prevalence and predictors of myocardial ischemia by preoperative myocardial perfusion single photon emission computed tomography in patients undergoing noncardiac surgery. AB - BACKGROUND: The prevalence and predictors of myocardial ischemia before noncardiac surgery are unknown. In addition the predictive value of myocardial perfusion single-photon emission computed tomography (SPECT) before noncardiac in individual patients is uncertain. OBJECTIVE: Evaluate the prevalence and predictors of myocardial ischemia before noncardiac surgery, and determine the postoperative cardiac outcome based on results of myocardial perfusion SPECT. DESIGN: Retrospective. SETTING: Single tertiary care center. PATIENTS AND METHODS: We reviewed the records of adult patients diagnosed with myocardial ischemia by myocardial perfusion SPECT who were undergoing noncardiac surgery. Myocardial perfusion SPECT had been performed within 4 weeks prior to noncardiac surgery requiring general anesthesia. MAIN OUTCOME MEASURES: Prevalence of abnormal myocardial perfusion SPECT results on preoperative evaluation; abnormal myocardial perfusion SPECT results as a predictor for postoperative cardiac events such as cardiac death, nonfatal myocardial infarction, and unstable angina. RESULTS: Of 131 patients who underwent noncardiac surgery from February 2015 to April 2016, 84 (64%) patients were female and the mean (SD) age was 64.1 (13.6) years. The prevalence of abnormal myocardial perfusion SPECT was 18% (24 of 131). Normal myocardial perfusion SPECT was highly predictive (up to 100%), but a positive myocardial perfusion SPECT had low positive predictive value (4%). Variables associated with an abnormal myocardial perfusion SPECT included ischemic heart disease, congestive heart failure, ASA score of 3 or more, limited exercise capacity (less than 4 METs), male sex, hypercholesterolemia, hypertension, smoking, and abnormal ECG. In a multivariable analysis, history of ischemic heart disease and history of smoking were significant predictors of abnormal myocardial perfusion SPECT (P=.001, and .029, respectively). CONCLUSIONS: Because of the low positive predictive value of myocardial perfusion SPECT, utilization of the technique in the workup of cardiac patients undergoing noncardiac surgery has been inappropriate. Myocardial perfusion SPECT should be restricted to only clearly defined appropriate use criteria. LIMITATIONS: Relatively small number of patients and retrospective design. PMID- 29229896 TI - Recurrence of malignant melanoma presenting as black-colored pyopneumothorax: a rare entity. AB - : We report a 63-year-old patient with black-colored pus (pyopneumothorax) resulting from an infected pleural effusion associated with metastatic malignant melanoma of the skin. The patient was also positive for Pseudomonas, so the color was unexpected. Although rare, malignant melanoma can present as a black pleural effusion due to the presence of melanocytes in the pleural fluid. Black pleural fluid should raise the suspicion of malignant melanoma. SIMILAR CASES PUBLISHED: Nine cases of black pleural effusion due to different causes have been reported.1,2 Three cases of black pleural effusion due to metastatic malignant melanoma are published.2,6,7. PMID- 29229897 TI - Integrative Analysis to Identify Common Genetic Markers of Metabolic Syndrome, Dementia, and Diabetes. AB - BACKGROUND Emerging data have established links between systemic metabolic dysfunction, such as diabetes and metabolic syndrome (MetS), with neurocognitive impairment, including dementia. The common gene signature and the associated signaling pathways of MetS, diabetes, and dementia have not been widely studied. MATERIAL AND METHODS We exploited the translational bioinformatics approach to choose the common gene signatures for both dementia and MetS. For this we employed "DisGeNET discovery platform". RESULTS Gene mining analysis revealed that a total of 173 genes (86 genes common to all three diseases) which comprised a proportion of 43% of the total genes associated with dementia. The gene enrichment analysis showed that these genes were involved in dysregulation in the neurological system (23.2%) and the central nervous system (20.8%) phenotype processes. The network analysis revealed APOE, APP, PARK2, CEPBP, PARP1, MT-CO2, CXCR4, IGFIR, CCR5, and PIK3CD as important nodes with significant interacting partners. The meta-regression analysis showed modest association of APOE with dementia and metabolic complications. The directionality of effects of the variants on Alzheimer disease is generally consistent with previous observations and did not differ by race/ethnicity (p>0.05), although our study had low power for this test. CONCLUSIONS Our novel approach showed APOE as a common gene signature with a link to dementia, MetS, and diabetes. Future gene association studies should focus on the association of gene polymorphisms with multiple disease models to identify novel putative drug targets. PMID- 29229898 TI - A Multicenter Phase III Study to Evaluate the Efficacy and Safety of Hepabulin, a New Hepatitis B Immunoglobulin, in Liver Transplantation Recipients with Hepatitis B. AB - BACKGROUND This study was performed to evaluate the effects and stability of the new hepatitis B immunoglobulin (HBIG), Hepabulin, in patients undergoing liver transplantation for hepatitis B. MATERIAL AND METHODS A total of 87 patients undergoing liver transplantation for hepatitis B-related liver disease were enrolled in this multicenter, phase III, open-label, single-arm study. Seventy (80.5%) of the 87 enrolled patients completed the study during the 52-week study period. Hepabulin (10,000 units) was intravenously injected intraoperatively, daily for 1 week, weekly for 1 month, and then once per month. Hepabulin was used as monotherapy without antiviral agents. Hepatitis B recurrence was defined as conversion from negativity for surface antigen after HBIG administration to positivity. RESULTS There were no cases of hepatitis B recurrence during the 52 week observation period. A total of 876 adverse events (AEs) that occurred during the study period were observed in 83 (95.4%) of 87 patients, and serious AEs were seen in 119 cases in 44 (50.6%) of the 87 patients. None of the AEs showed a relationship with this drug. Hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) rapidly disappeared within 1 week after HBIG administration, but hepatitis B virus (HBV) DNA persisted for up to 8 weeks after surgery, which was related to HBV viral load. Hepatitis B surface antibody (HBsAb) was correlated with HBIG (Hepabulin) dose. CONCLUSIONS The new HBIG, Hepabulin, was shown to be safe and effective in preventing the recurrence of HBV after liver transplantation. PMID- 29229899 TI - Phenotypic Variation in Patients with Homozygous c.1678G>T Mutation in EVC Gene: Report of Two Mexican Families with Ellis-van Creveld Syndrome. AB - BACKGROUND Ellis-van Creveld syndrome is an autosomal recessive chondro ectodermal dysplasia characterized by disproportionate short stature, limb shortening, narrow chest, postaxial polydactyly and dysplastic nails and teeth. In addition, 60% of cases present congenital heart defects. Ellis-van Creveld syndrome is predominantly caused by mutations in the EVC or EVC2 (4p16) genes, with only a few cases caused by mutations in WDR35. CASE REPORT Here, we report on two Mexican families with patients diagnosed with Ellis-van Creveld syndrome. Family 1 includes four patients: three females of 15, 18, and 23 years of age and a 7-year old male. Family 2 has only one affected newborn male. All patients exhibited multiple features including hypodontia, dysplastic teeth, extra frenula, mild short stature, distal limb shortening, postaxial polydactyly of hands and feet, nail dystrophy, and knee joint abnormalities. Only two patients had an atrial septal defect. In all cases, molecular analysis by Sanger sequencing identified the same homozygous mutation in exon 12 of EVC, c.1678G>T, which leads to a premature stop codon. CONCLUSIONS The mutation c.1678G>T has been previously reported in another Mexican patient and it appears to be a recurrent mutation in Mexico which could represent a founder mutation. The large number of patients in this case allows the clinical variability and spectrum of manifestations present in individuals with Ellis-van Creveld syndrome even if they carry the same homozygous mutation in a same family. PMID- 29229900 TI - Post-transcriptional 3'-UTR cleavage of mRNA transcripts generates thousands of stable uncapped autonomous RNA fragments. AB - The majority of mammalian genes contain one or more alternative polyadenylation sites. Choice of polyadenylation sites was suggested as one of the underlying mechanisms for generating longer/shorter transcript isoforms. Here, we demonstrate that mature mRNA transcripts can undergo additional cleavage and polyadenylation at a proximal internal site in the 3'-UTR, resulting in two stable, autonomous, RNA fragments: a coding sequence with a shorter 3'-UTR (body) and an uncapped 3'-UTR sequence downstream of the cleavage point (tail). Analyses of the human transcriptome has revealed thousands of such cleavage positions, suggesting a widespread post-transcriptional phenomenon producing thousands of stable 3'-UTR RNA tails that exist alongside their transcripts of origin. By analyzing the impact of microRNAs, we observed a significantly stronger effect for microRNA regulation at the body compared to the tail fragments. Our findings open a variety of future research prospects and call for a new perspective on 3' UTR-dependent gene regulation. PMID- 29229901 TI - Functional reduction in pollination through herbivore-induced pollinator limitation and its potential in mutualist communities. AB - Plant-pollinator interactions are complex because they are affected by both interactors' phenotypes and external variables. Herbivory is one external variable that can have divergent effects on the individual and the population levels depending on specific phenotypic plastic responses of a plant to herbivory. In the wild tomato, Solanum peruvianum, herbivory limits pollinator visits, which reduces individual plant fitness due to herbivore-induced chemical defenses and signaling on pollinators (herbivore-induced pollinator limitation). We showed these herbivory-induced decreases in pollination to individual plants best match a Type II functional-response curve. We then developed a general model that shows these individual fitness reductions from herbivore-induced changes in plant metabolism can indirectly benefit overall populations and community resilience. These results introduce mechanisms of persistence in antagonized mutualistic communities that were previously found prone to extinction in theoretical models. Results also imply that emergent ecological dynamics of individual fitness reductions may be more complex than previously thought. PMID- 29229902 TI - Mapping the ecological networks of microbial communities. AB - Mapping the ecological networks of microbial communities is a necessary step toward understanding their assembly rules and predicting their temporal behavior. However, existing methods require assuming a particular population dynamics model, which is not known a priori. Moreover, those methods require fitting longitudinal abundance data, which are often not informative enough for reliable inference. To overcome these limitations, here we develop a new method based on steady-state abundance data. Our method can infer the network topology and inter taxa interaction types without assuming any particular population dynamics model. Additionally, when the population dynamics is assumed to follow the classic Generalized Lotka-Volterra model, our method can infer the inter-taxa interaction strengths and intrinsic growth rates. We systematically validate our method using simulated data, and then apply it to four experimental data sets. Our method represents a key step towards reliable modeling of complex, real-world microbial communities, such as the human gut microbiota. PMID- 29229903 TI - Loss of PBRM1 rescues VHL dependent replication stress to promote renal carcinogenesis. AB - Inactivation of the VHL (Von Hippel Lindau) tumour suppressor has long been recognised as necessary for the pathogenesis of clear cell renal cancer (ccRCC); however, the molecular mechanisms underlying transformation and the requirement for additional genetic hits remain unclear. Here, we show that loss of VHL alone results in DNA replication stress and damage accumulation, effects that constrain cellular growth and transformation. By contrast, concomitant loss of the chromatin remodelling factor PBRM1 (mutated in 40% of ccRCC) rescues VHL-induced replication stress, maintaining cellular fitness and allowing proliferation. In line with these data we demonstrate that combined deletion of Vhl and Pbrm1 in the mouse kidney is sufficient for the development of fully-penetrant, multifocal carcinomas, closely mimicking human ccRCC. Our results illustrate how VHL and PBRM1 co-operate to drive renal transformation and uncover replication stress as an underlying vulnerability of all VHL mutated renal cancers that could be therapeutically exploited. PMID- 29229904 TI - Sporadic low-velocity volumes spatially correlate with shallow very low frequency earthquake clusters. AB - A low-velocity zone (LVZ) has been detected by seismic exploration surveys within the Nankai accretionary prism toe off the Kii Peninsula, southwestern Japan, and is considered to be a mechanically weak volume at depth. Such mechanical heterogeneities potentially influence seismic and tsunamigenic slips on megathrust earthquakes in the subduction zone. However, the spatial distribution of the LVZ along the trough-parallel direction is still elusive. Here we show sporadic LVZs in the prism toe from one-dimensional shear wave velocity (Vs) profiles obtained at 49 cabled ocean bottom stations, which were estimated by a nonlinear inversion technique, simulated annealing, using the displacement pressure ratios of the Rayleigh wave. The estimated distribution of LVZs along the trough widely correlates with the epicentres of shallow very low frequency earthquakes (sVLFEs), which suggests that sVLFEs are activated in the sporadically distributed low-velocity and mechanically weak volumes where fluids significantly reduce the shear strength of faults. PMID- 29229905 TI - Single-cell RNA-sequencing uncovers transcriptional states and fate decisions in haematopoiesis. AB - The success of marker-based approaches for dissecting haematopoiesis in mouse and human is reliant on the presence of well-defined cell surface markers specific for diverse progenitor populations. An inherent problem with this approach is that the presence of specific cell surface markers does not directly reflect the transcriptional state of a cell. Here, we used a marker-free approach to computationally reconstruct the blood lineage tree in zebrafish and order cells along their differentiation trajectory, based on their global transcriptional differences. Within the population of transcriptionally similar stem and progenitor cells, our analysis reveals considerable cell-to-cell differences in their probability to transition to another committed state. Once fate decision is executed, the suppression of transcription of ribosomal genes and upregulation of lineage-specific factors coordinately controls lineage differentiation. Evolutionary analysis further demonstrates that this haematopoietic programme is highly conserved between zebrafish and higher vertebrates. PMID- 29229906 TI - Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration. AB - Integrin alphabeta heterodimer cell surface receptors mediate adhesive interactions that provide traction for cell migration. Here, we test whether the integrin, when engaged to an extracellular ligand and the cytoskeleton, adopts a specific orientation dictated by the direction of actin flow on the surface of migrating cells. We insert GFP into the rigid, ligand-binding head of the integrin, model with Rosetta the orientation of GFP and its transition dipole relative to the integrin head, and measure orientation with fluorescence polarization microscopy. Cytoskeleton and ligand-bound integrins orient in the same direction as retrograde actin flow with their cytoskeleton-binding beta subunits tilted by applied force. The measurements demonstrate that intracellular forces can orient cell surface integrins and support a molecular model of integrin activation by cytoskeletal force. Our results place atomic, A-scale structures of cell surface receptors in the context of functional and cellular, MUm-scale measurements. PMID- 29229907 TI - Live bearing promotes the evolution of sociality in reptiles. AB - Identifying factors responsible for the emergence and evolution of social complexity is an outstanding challenge in evolutionary biology. Here we report results from a phylogenetic comparative analysis of over 1000 species of squamate reptile, nearly 100 of which exhibit facultative forms of group living, including prolonged parent-offspring associations. We show that the evolution of social groupings among adults and juveniles is overwhelmingly preceded by the evolution of live birth across multiple independent origins of both traits. Furthermore, the results suggest that live bearing has facilitated the emergence of social groups that remain stable across years, similar to forms of sociality observed in other vertebrates. These results suggest that live bearing has been a fundamentally important precursor in the evolutionary origins of group living in the squamates. PMID- 29229909 TI - Pseudogap phase of cuprate superconductors confined by Fermi surface topology. AB - The properties of cuprate high-temperature superconductors are largely shaped by competing phases whose nature is often a mystery. Chiefly among them is the pseudogap phase, which sets in at a doping p* that is material-dependent. What determines p* is currently an open question. Here we show that the pseudogap cannot open on an electron-like Fermi surface, and can only exist below the doping p FS at which the large Fermi surface goes from hole-like to electron like, so that p* <= p FS. We derive this result from high-magnetic-field transport measurements in La1.6-x Nd0.4Sr x CuO4 under pressure, which reveal a large and unexpected shift of p* with pressure, driven by a corresponding shift in p FS. This necessary condition for pseudogap formation, imposed by details of the Fermi surface, is a strong constraint for theories of the pseudogap phase. Our finding that p* can be tuned with a modest pressure opens a new route for experimental studies of the pseudogap. PMID- 29229908 TI - Identification of regulatory targets for the bacterial Nus factor complex. AB - Nus factors are broadly conserved across bacterial species, and are often essential for viability. A complex of five Nus factors (NusB, NusE, NusA, NusG and SuhB) is considered to be a dedicated regulator of ribosomal RNA folding, and has been shown to prevent Rho-dependent transcription termination. Here, we identify an additional cellular function for the Nus factor complex in Escherichia coli: repression of the Nus factor-encoding gene, suhB. This repression occurs primarily by translation inhibition, followed by Rho-dependent transcription termination. Thus, the Nus factor complex can prevent or promote Rho activity depending on the gene context. Conservation of putative NusB/E binding sites upstream of Nus factor genes suggests that Nus factor autoregulation occurs in many bacterial species. Additionally, many putative NusB/E binding sites are also found upstream of other genes in diverse species, and we demonstrate Nus factor regulation of one such gene in Citrobacter koseri. We conclude that Nus factors have an evolutionarily widespread regulatory function beyond ribosomal RNA, and that they are often autoregulatory. PMID- 29229910 TI - A mechanistic theory for aquatic food chain length. AB - Multiple hypotheses propose an ostensibly disparate array of drivers of food chain length (FCL), with contradictory support from natural settings. Here we posit that the magnitude of vertical energy flux in food webs underlies several drivers of FCL. We show that rising energy flux fuels top-heavy biomass pyramids, promoting omnivory, thereby reducing FCL. We link this theory to commonly evaluated hypotheses for environmental drivers of FCL (productivity, ecosystem size) and demonstrate that effects of these drivers should be context-dependent. We evaluate support for this theory in lake and marine ecosystems and demonstrate that ecosystem size is the most important driver of FCL in low-productivity ecosystems (positive relationship) while productivity is most important in large and high-productivity ecosystems (negative relationship). This work stands in contrast to classical hypotheses, which predict a positive effect of productivity on FCL, and may help reconcile the contradictory nature of published results for drivers of FCL. PMID- 29229911 TI - Comparative genome analysis of the vineyard weed endophyte Pseudomonas viridiflava CDRTc14 showing selective herbicidal activity. AB - Microbes produce a variety of secondary metabolites to be explored for herbicidal activities. We investigated an endophyte Pseudomonas viridiflava CDRTc14, which impacted growth of its host Lepidium draba L., to better understand the possible genetic determinants for herbicidal and host-interaction traits. Inoculation tests with a variety of target plants revealed that CDRTc14 shows plant-specific effects ranging from beneficial to negative. Its herbicidal effect appeared to be dose-dependent and resembled phenotypically the germination arrest factor of Pseudomonas fluorescens WH6. CDRTc14 shares 183 genes with the herbicidal strain WH6 but the formylaminooxyvinylglycine (FVG) biosynthetic genes responsible for germination arrest of WH6 was not detected. CDRTc14 showed phosphate solubilizing ability, indole acetic acid and siderophores production in vitro and harbors genes for these functions. Moreover, genes for quorum sensing, hydrogen cyanide and ACC deaminase production were also found in this strain. Although, CDRTc14 is related to plant pathogens, we neither found a complete pathogenicity island in the genome, nor pathogenicity symptoms on susceptible plant species upon CDRTc14 inoculation. Comparison with other related genomes showed several unique genes involved in abiotic stress tolerance in CDRTc14 like genes responsible for heavy metal and herbicide resistance indicating recent adaptation to plant protection measures applied in vineyards. PMID- 29229912 TI - Understanding population structure and historical demography of Litsea auriculata (Lauraceae), an endangered species in east China. AB - Detecting how historical and contemporary factors contribute to genetic divergence and genetic structure is a central question in ecology and evolution. We examine this question by intergrating population genetics with ecological niche modelling of Litsea auriculata (Lauraceae), which is endangered and native to east China. Geographical and environmental factors including climatic fluctuations since the last glacial maximum (LGM) have also contribute to population demography and patterns of genetic structure. L. auriculata populations underwent expansion after divergence and dramatically decreased to the current small size with relative population bottlenecks due to climate changes. Populations separated by physical geographical barrier including geographic distance and Yangtze River, as a result contemporary gene flow among L. auriculata populations showed drastic declines in comparison with historical gene flow, resulting in a high level of population divergence. Thus, patterns of genetic structure of L. auriculata can result from both geographic and environmental factors including climate changes. This information is helpful in forming conservation strategies for L. auriculata in China. PMID- 29229913 TI - A metagenome-derived thermostable beta-glucanase with an unusual module architecture which defines the new glycoside hydrolase family GH148. AB - The discovery of novel and robust enzymes for the breakdown of plant biomass bears tremendous potential for the development of sustainable production processes in the rapidly evolving new bioeconomy. By functional screening of a metagenomic library from a volcano soil sample a novel thermostable endo-beta glucanase (EngU) which is unusual with regard to its module architecture and cleavage specificity was identified. Various recombinant EngU variants were characterized. Assignment of EngU to an existing glycoside hydrolase (GH) family was not possible. Two regions of EngU showed weak sequence similarity to proteins of the GH clan GH-A, and acidic residues crucial for catalytic activity of EngU were identified by mutation. Unusual, a carbohydrate-binding module (CBM4) which displayed binding affinity for beta-glucan, lichenin and carboxymethyl-cellulose was found as an insertion between these two regions. EngU hydrolyzed beta-1,4 linkages in carboxymethyl-cellulose, but displayed its highest activity with mixed linkage (beta-1,3-/beta-1,4-) glucans such as barley beta-glucan and lichenin, where in contrast to characterized lichenases cleavage occurred predominantly at the beta-1,3 linkages of C4-substituted glucose residues. EngU and numerous related enzymes with previously unknown function represent a new GH family of biomass-degrading enzymes within the GH-A clan. The name assigned to the new GH family is GH148. PMID- 29229914 TI - Magnetostriction-polarization coupling in multiferroic Mn2MnWO6. AB - Double corundum-related polar magnets are promising materials for multiferroic and magnetoelectric applications in spintronics. However, their design and synthesis is a challenge, and magnetoelectric coupling has only been observed in Ni3TeO6 among the known double corundum compounds to date. Here we address the high-pressure synthesis of a new polar and antiferromagnetic corundum derivative Mn2MnWO6, which adopts the Ni3TeO6-type structure with low temperature first order field-induced metamagnetic phase transitions (T N = 58 K) and high spontaneous polarization (~ 63.3 MUC.cm-2). The magnetostriction-polarization coupling in Mn2MnWO6 is evidenced by second harmonic generation effect, and corroborated by magnetic-field-dependent pyroresponse behavior, which together with the magnetic-field-dependent polarization and dielectric measurements, qualitatively indicate magnetoelectric coupling. Piezoresponse force microscopy imaging and spectroscopy studies on Mn2MnWO6 show switchable polarization, which motivates further exploration on magnetoelectric effect in single crystal/thin film specimens. PMID- 29229915 TI - Skeletal fluorosis in relation to drinking water in rural areas of West Azerbaijan, Iran. AB - Skeletal fluorosis resulting from high fluoride level in drinking water is a major public health problem. The present study evaluated the association between exposures to drinking water fluoride and skeletal fluorosis in 5 villages of Poldasht County, Iran. All the data and information on the prevalence of bone diseases were obtained from the Health Record Department, Poldasht Health Centre. To obtain the odds ratio of bone disease problem in different risk factors, when considering the cluster effect of rural area, logistic regression in a multilevel model was used. Results showed that skeletal fluorosis of people who live in areas with high fluoride concentration is 18.1% higher than that of individuals who live in areas with low fluoride concentration. Skeletal fluorosis (54.5%) was observed in the age group of 71 years and above, and was more commonly found in females than males. According to Unadjusted, individuals who consume <=3 unit milk and dairy products per week have almost the same level of bone diseases as compared to those that consume more than 3 units. This study indicated that, skeletal fluorosis is a general health problem in these rural areas because the results revealed that high percentage of the studied population had symptoms of skeletal fluorosis. PMID- 29229916 TI - Calcination does not remove all carbon from colloidal nanocrystal assemblies. AB - Removing organics from hybrid nanostructures is a crucial step in many bottom-up materials fabrication approaches. It is usually assumed that calcination is an effective solution to this problem, especially for thin films. This assumption has led to its application in thousands of papers. We here show that this general assumption is incorrect by using a relevant and highly controlled model system consisting of thin films of ligand-capped ZrO2 nanocrystals. After calcination at 800 degrees C for 12 h, while Raman spectroscopy fails to detect the ligands after calcination, elastic backscattering spectrometry characterization demonstrates that ~18% of the original carbon atoms are still present in the film. By comparison plasma processing successfully removes the ligands. Our growth kinetic analysis shows that the calcined materials have significantly different interfacial properties than the plasma-processed counterparts. Calcination is not a reliable strategy for the production of single-phase all inorganic materials from colloidal nanoparticles. PMID- 29229917 TI - Whole-genome sequencing and SNV genotyping of 'Nebbiolo' (Vitis vinifera L.) clones. AB - 'Nebbiolo' (Vitis vinifera) is among the most ancient and prestigious wine grape varieties characterised by a wide genetic variability exhibited by a high number of clones (vegetatively propagated lines of selected mother plants). However, limited information is available for this cultivar at the molecular and genomic levels. The whole-genomes of three 'Nebbiolo' clones (CVT 71, CVT 185 and CVT 423) were re-sequenced and a de novo transcriptome assembly was produced. Important remarks about the genetic peculiarities of 'Nebbiolo' and its intra varietal variability useful for clonal identification were reported. In particular, several varietal transcripts identified for the first time in 'Nebbiolo' were disease resistance genes and single-nucleotide variants (SNVs) identified in 'Nebbiolo', but not in other cultivars, were associated with genes involved in the stress response. Ten newly discovered SNVs were successfully employed to identify some periclinal chimeras and to classify 98 'Nebbiolo' clones in seven main genotypes, which resulted to be linked to the geographical origin of accessions. In addition, for the first time it was possible to discriminate some 'Nebbiolo' clones from the others. PMID- 29229918 TI - Negative regulation of TGF-beta1-induced MKK6-p38 and MEK-ERK signalling and epithelial-mesenchymal transition by Rac1b. AB - Prompted by earlier findings that the Rac1-related isoform Rac1b inhibits transforming growth factor (TGF)-beta1-induced canonical Smad signalling, we studied here whether Rac1b also impacts TGF-beta1-dependent non-Smad signalling such as the MKK6-p38 and MEK-ERK mitogen-activated protein kinase (MAPK) pathways and epithelial-mesenchymal transition (EMT). Transient depletion of Rac1b protein in pancreatic cancer cells by RNA interference increased the extent and duration of TGF-beta1-induced phosphorylation of p38 MAPK in a Smad4-independent manner. Rac1b depletion also strongly increased basal ERK activation - independent of the kinase function of the TGF-beta type I receptor ALK5 - and sensitised cells towards further upregulation of phospho-ERK levels by TGF-beta1, while ectopic overexpression of Rac1b had the reverse effect. Rac1b depletion increased an EMT phenotype as evidenced by cell morphology, gene expression of EMT markers, cell migration and growth inhibition. Inhibition of MKK6-p38 or MEK-ERK signalling partially relieved the Rac1b depletion-dependent increase in TGF-beta1-induced gene expression and cell migration. Rac1b depletion also enhanced TGF-beta1 autoinduction of crucial TGF-beta pathway components and decreased that of TGF beta pathway inhibitors. Our results show that Rac1b antagonises TGF-beta1 dependent EMT by inhibiting MKK6-p38 and MEK-ERK signalling and by controlling gene expression in a way that favors attenuation of TGF-beta signalling. PMID- 29229920 TI - Integration of neurogenesis and angiogenesis models for constructing a neurovascular tissue. AB - Neurovascular unit (NVU) is a basic unit in the brain, including neurons, glial cells, blood vessels and extracellular matrix. This concept implies the importance of a three-dimensional (3D) culture model including these cell types for investigating brain functions. However, little is known about the construction of an in vitro 3D NVU model. In the present study, we aimed at constructing 3D neurovascular tissues by combining in vitro neurogenesis and angiogenesis models using a microfluidic platform, which is a critical step toward the NVU construction in vitro. Three gel conditions, which were fibrin gel, fibrin-Matrigel mixed gel and fibrin-hyaluronan mixed gel, were investigated to optimize the gel components in terms of neurogenesis and angiogenesis. First, fibrin-Matrigel mixed gel was found to promote neural stem cell (NSC) differentiation into neurons and neurite extension. In particular, 3D neural networks were constructed in 2-8 mg/ml fibrin-Matrigel mixed gel. Second, we found that capillary-like structures were also formed in the fibrin-Matrigel mixed gel by coculturing brain microvascular endothelial cells (BMECs) and human mesenchymal stem cells (MSCs). Finally, we combined both neural and vascular culture models and succeeded in constructing 3D neurovascular tissues with an optimized seeding condition of NSCs, BMECs and MSCs. PMID- 29229919 TI - Migratory dendritic cells acquire and present lymphatic endothelial cell-archived antigens during lymph node contraction. AB - Antigens derived from viral infection or vaccination can persist within a host for many weeks after resolution of the infection or vaccine responses. We previously identified lymphatic endothelial cells (LEC) as the repository for this antigen archival, yet LECs are unable to present their archived antigens to CD8+ T cells, and instead transfer their antigens to CD11c+ antigen-presenting cells (APC). Here we show that the exchange of archived antigens between LECs and APCs is mediated by migratory dendritic cells (DC). After vaccination, both migratory basic leucine zipper ATF-like transcription factor 3 (BatF3)-dependent and BatF3-independent DCs are responsible for antigen exchange and cross presentation. However, exchange of archived viral antigens is mediated only by BatF3-dependent migratory DCs potentially acquiring apoptotic LECs. In conclusion, LEC-archived antigens are exchanged with migratory DCs, both directly and through LEC apoptosis, to cross-present archived antigens to circulating T cells. PMID- 29229921 TI - Phenotypic plasticity promotes recombination and gene clustering in periodic environments. AB - While theory offers clear predictions for when recombination will evolve in changing environments, it is unclear what natural scenarios can generate the necessary conditions. The Red Queen hypothesis provides one such scenario, but it requires antagonistic host-parasite interactions. Here we present a novel scenario for the evolution of recombination in finite populations: the genomic storage effect due to phenotypic plasticity. Using analytic approximations and Monte-Carlo simulations, we demonstrate that balanced polymorphism and recombination evolve between a target locus that codes for a seasonally selected trait and a plasticity modifier locus that modulates the effects of target-locus alleles. Furthermore, we show that selection suppresses recombination among multiple co-modulated target loci, in the absence of epistasis among them, which produces a cluster of linked selected loci. These results provide a novel biological scenario for the evolution of recombination and supergenes. PMID- 29229922 TI - Comparison of electrohysterogram signal measured by surface electrodes with different designs: A computational study with dipole band and abdomen models. AB - Non-invasive measurement of uterine activity using electrohysterogram (EHG) surface electrodes has been attempted to monitor uterine contraction. This study aimed to computationally compare the performance of acquiring EHG signals using monopolar electrode and three types of Laplacian concentric ring electrodes (bipolar, quasi-bipolar and tri-polar). With the implementation of dipole band model and abdomen model, the performances of four electrodes in terms of the local sensitivity were quantified by potential attenuation. Furthermore, the effects of fat and muscle thickness on potential attenuation were evaluated using the bipolar and tri-polar electrodes with different radius. The results showed that all the four types of electrodes detected the simulated EHG signals with consistency. That the bipolar and tri-polar electrodes had greater attenuations than the others, and the shorter distance between the origin and location of dipole band at 20 dB attenuation, indicating that they had relatively better local sensitivity. In addition, ANOVA analysis showed that, for all the electrodes with different outer ring radius, the effects of fat and muscle on potential attenuation were significant (all p < 0.01). It is therefore concluded that the bipolar and tri-polar electrodes had higher local sensitivity than the others, indicating that they can be applied to detect EHG effectively. PMID- 29229924 TI - Solution-phase synthesis of Al13- using a dendrimer template. AB - Superatoms, clusters that mimic the properties of elements different to those of which they are composed, have the potential to serve as building blocks for unprecedented materials with tunable properties. The development of a method for the solution-phase synthesis of superatoms would be an indispensable achievement for the future progress of this research field. Here we report the fabrication of aluminum clusters in solution using a dendrimer template, producing Al13-, which is the most well-known superatom. The Al13- cluster is identified using mass spectrometry and scanning transmission electron microscopy, and X-ray photoelectron spectroscopy is used to measure the binding energies. The superatomic stability of Al13- is demonstrated by evaluating its tendency toward oxidation. In addition, the synthesis of Al13- in solution enables electrochemical measurements, the results of which suggest oxidation of Al13-. This solution-phase synthesis of Al13- superatoms has a significant role for the experimental development of cluster science. PMID- 29229923 TI - Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex. AB - The ventricular zone (VZ) of the developing cerebral cortex is a pseudostratified epithelium that contains progenitors undergoing precisely regulated divisions at its most apical side, the ventricular lining (VL). Mitotic perturbations can contribute to pathological mechanisms leading to cortical malformations. The HeCo mutant mouse exhibits subcortical band heterotopia (SBH), likely to be initiated by progenitor delamination from the VZ early during corticogenesis. The causes for this are however, currently unknown. Eml1, a microtubule (MT)-associated protein of the EMAP family, is impaired in these mice. We first show that MT dynamics are perturbed in mutant progenitor cells in vitro. These may influence interphase and mitotic MT mechanisms and indeed, centrosome and primary cilia were altered and spindles were found to be abnormally long in HeCo progenitors. Consistently, MT and spindle length regulators were identified in EML1 pulldowns from embryonic brain extracts. Finally, we found that mitotic cell shape is also abnormal in the mutant VZ. These previously unidentified VZ characteristics suggest altered cell constraints which may contribute to cell delamination. PMID- 29229925 TI - Publisher Correction: Nonlinear Bayesian filtering and learning: a neuronal dynamics for perception. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29229927 TI - Activation of non-canonical WNT signaling in human visceral adipose tissue contributes to local and systemic inflammation. AB - The accumulation of visceral adiposity is strongly associated with systemic inflammation and increased cardiometabolic risk. WNT5A, a non-canonical WNT ligand, has been shown to promote adipose tissue inflammation and insulin resistance in animal studies. Among other non-canonical pathways, WNT5A activates planar cell polarity (PCP) signaling. The current study investigated the potential contribution of non-canonical WNT5A/PCP signaling to visceral adipose tissue (VAT) inflammation and associated metabolic dysfunction in individuals with obesity. VAT and subcutaneous adipose tissue (SAT) samples obtained from subjects undergoing bariatric surgery were analyzed by qRT-PCR for expression of WNT/PCP genes. In vitro experiments were conducted with preadipocytes isolated from VAT and SAT biopsies. The expression of 23 out of 33 PCP genes was enriched in VAT compared to SAT. Strong positive expression correlations of individual PCP genes were observed in VAT. WNT5A expression in VAT, but not in SAT, correlated with indexes of JNK signaling activity, IL6, waist-to-hip ratio and hsCRP. In vitro, WNT5A promoted the expression of IL6 in human preadipocytes. In conclusion, elevated non-canonical WNT5A signaling in VAT contributes to the exacerbated IL-6 production in this depot and the low-grade systemic inflammation typically associated with visceral adiposity. PMID- 29229928 TI - Author Correction: Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29229926 TI - Cell cycle-dependent phosphorylation regulates RECQL4 pathway choice and ubiquitination in DNA double-strand break repair. AB - Pathway choice within DNA double-strand break (DSB) repair is a tightly regulated process to maintain genome integrity. RECQL4, deficient in Rothmund-Thomson Syndrome, promotes the two major DSB repair pathways, non-homologous end joining (NHEJ) and homologous recombination (HR). Here we report that RECQL4 promotes and coordinates NHEJ and HR in different cell cycle phases. RECQL4 interacts with Ku70 to promote NHEJ in G1 when overall cyclin-dependent kinase (CDK) activity is low. During S/G2 phases, CDK1 and CDK2 (CDK1/2) phosphorylate RECQL4 on serines 89 and 251, enhancing MRE11/RECQL4 interaction and RECQL4 recruitment to DSBs. After phosphorylation, RECQL4 is ubiquitinated by the DDB1-CUL4A E3 ubiquitin ligase, which facilitates its accumulation at DSBs. Phosphorylation of RECQL4 stimulates its helicase activity, promotes DNA end resection, increases HR and cell survival after ionizing radiation, and prevents cellular senescence. Collectively, we propose that RECQL4 modulates the pathway choice of NHEJ and HR in a cell cycle-dependent manner. PMID- 29229929 TI - Oestrogen Receptor-alpha binds the FOXP3 promoter and modulates regulatory T-cell function in human cervical cancer. AB - Oestrogen controls Foxp3 expression in regulatory T cells (Treg cells) via a mechanism thought to involve oestrogen receptor alpha (ERalpha), but the molecular basis and functional impact of ERalpha signalling in Treg cells remain unclear. We report that ERalpha ligand oestradiol (E2) is significantly increased in human cervical cancer (CxCa) tissues and tumour-infiltrating Treg cells (CD4+CD25hiCD127low), whereas blocking ERalpha with the antagonist ICI 182,780 abolishes FOXP3 expression and impairs the function of CxCa infiltrating Treg cells. Using a novel approach of co-immunoprecipitation with antibodies to E2 for capture, we identified binding of E2:ERalpha complexes to FOXP3 protein in CxCa derived Treg cells. Chromatin immunoprecipitation analyses of male blood Treg cells revealed ERalpha occupancy at the FOXP3 promoter and conserved non-coding DNA elements 2 and 3. Accordingly, computational analyses of the enriched regions uncovered eight putative oestrogen response elements predicted to form a loop that can activate the FOXP3 promoter. Together, these data suggest that E2 mediated ERalpha signalling is critical for the sustenance of FOXP3 expression and Treg cell function in human CxCa via direct interaction of ERalpha with FOXP3 promoter. Overall, our work gives a molecular insight into ERalpha signalling and highlights a fundamental role of E2 in controlling human Treg cell physiology. PMID- 29229931 TI - Brain gene expression signature on primate genomic sequence evolution. AB - Considering the overwhelming changes that occurred during primate evolution in brain structure and function, one might expect corresponding changes at the molecular level. Surprisingly, a relatively constrained gene expression pattern is observed in brain compared with other tissues among primates, an observation that calls for reassessment of RNA expression influence on primate genome evolution. We built phylogenetic trees based on genomic sequences of functional genomic regions and tissue-specific RNA expression in eight tissue types for six primate species. Comparisons of the phylogenetic trees from brain tissues revealed that DNA- and RNA-based trees were significantly similar. The similarity was specific for promoter regions and cerebellum and frontal cortex expression, suggesting a major impact of gene regulation in the brain on genome shaping along the primate branch. PMID- 29229930 TI - Controllable Plasmonic Nanostructures induced by Dual-wavelength Femtosecond Laser Irradiation. AB - We demonstrated an abnormal double-peak (annular shaped) energy deposition through dual-wavelength synthesis of the fundamental frequency (omega) and the second-harmonic frequency (2omega) of a femtosecond (fs) Ti:sapphire laser. The annular shaped distribution of the dual-wavelength fs laser was confirmed through real beam shape detection. This uniquely simple and flexible technique enables the formation of functional plasmonic nanostructures. We applied this double-peak fs-laser-induced dewetting effect to the controlled fabrication and precise deposition of Au nanostructures, by using a simple, lithography-free, and single step process. In this process, the double-peak energy-shaped fs laser pulse induces surface patterning of a thin film followed by nanoscale hydrodynamic instability, which is highly controllable under specific irradiation conditions. Nanostructure morphology (shape, size, and distribution) modulation can be achieved by adjusting the laser irradiation parameters, and the subsequent ion beam polishing enables further dimensional reduction and removal of the surrounding film. The unique optical properties of the resulting nanostructure are highly sensitive to the shape and size of the nanostructure. In contrast to a nanoparticle, the resonance-scattering spectrum of an Au nanobump exhibites two resonance peaks. These suggest that the dual-wavelength fs laser-based dewetting of thin films can be an effective means for the scalable manufacturing of patterned-functional nanostructures. PMID- 29229932 TI - Neutral fitness outcomes contradict inferences of sexual 'coercion' derived from male's damaging mating tactic in a widow spider. AB - Sexual conflict over mating frequency has driven the evolution of morphological and behavioural traits across taxa. Interactions may be termed 'coercive' and assumed to arise from conflict when male mating behaviours cause physical injury to females and females appear to resist injurious matings.However, coercion per se occurs only if the behaviour reduces female fitness; and such outcomes are rarely measured. Here we show that a damaging mating tactic, apparently adaptive for males, is not coercive for females. Adult male Latrodectus spiders mate with immature females after tearing the exoskeleton covering the female's recently developed reproductive tract, which can cause haemolymph bleeding. We show that, relative to pairings with adult females, males use reduced courtship displays when approaching immature females, which in some cases respond with elevated deterrent behavioural responses. Nevertheless, we found no reproductive cost for immature-mated females in terms of longevity, fertility or fecundity. Moreover, most immature-mated females did not produce sex pheromones as adults, so did not seek additional matings. Thus, despite the appearance of conflict there is no evidence that immature-mating is coercive. These results show it is critical to measure fitness outcomes, in addition to behavioural responses, to test for coercion. PMID- 29229933 TI - Evaluation of serum epidermal growth factor receptor (EGFR) in correlation to circulating tumor cells in patients with metastatic breast cancer. AB - Overexpression of epidermal growth factor receptor in breast cancer is associated with estrogen receptor negativity, higher histological grade and larger tumors. The aim of the present study was to evaluate the clinical significance of serum EGFR (sEGFR) in relation to circulating tumor cells (CTCs) in metastatic breast cancer. 252 patients were enrolled in this prospective multicentre study. Blood was drawn before start of a new line of therapy. sEGFR was determined using a sandwich-type ELISA. CTCs were detected using CellSearch. sEGFR was determined in 48 healthy controls and 252 patients, with no significant differences between the two groups. Clinical-pathological parameters did not correlate with sEGFR, irrespective of the cutoff chosen. Patients with sEGFR levels above the 50th and 75th percentile were more likely to present with <5 CTCs per 7.5 ml blood (p = 0.007; p = 0.003). Patients with sEGFR >=73 ng/ml had significantly longer overall survival than those with sEGFR <73 ng/ml (19.7 vs. 15.2 months; p = 0.007). In the multivariate analysis, presence of >=5 CTCs, higher grading and higher line of therapy remained independent predictors of shorter OS, while only higher line of therapy and presence of >=5 CTCs were independent predictors of shorter PFS. PMID- 29229934 TI - Bis(monoacylglycero)phosphate lipids in the retinal pigment epithelium implicate lysosomal/endosomal dysfunction in a model of Stargardt disease and human retinas. AB - Stargardt disease is a juvenile onset retinal degeneration, associated with elevated levels of lipofuscin and its bis-retinoid components, such as N retinylidene-N-retinylethanolamine (A2E). However, the pathogenesis of Stargardt is still poorly understood and targeted treatments are not available. Utilizing high spatial and high mass resolution matrix assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS), we determined alterations of lipid profiles specifically localized to the retinal pigment epithelium (RPE) in Abca4 /- Stargardt model mice compared to their relevant background strain. Extensive analysis by LC-MS/MS in both positive and negative ion mode was required to accurately confirm the identity of one highly expressed lipid class, bis(monoacylgylercoro)phosphate (BMP) lipids, and to distinguish them from isobaric species. The same BMP lipids were also detected in the RPE of healthy human retina. BMP lipids have been previously associated with the endosomal/lysosomal storage diseases Niemann-Pick and neuronal ceroid lipofuscinosis and have been reported to regulate cholesterol levels in endosomes. These results suggest that perturbations in lipid metabolism associated with late endosomal/lysosomal dysfunction may play a role in the pathogenesis of Stargardt disease and is evidenced in human retinas. PMID- 29229935 TI - Two-dimensional semiconductors ZrNCl and HfNCl: Stability, electric transport, and thermoelectric properties. AB - Searching for novel two-dimensional (2D) semiconducting materials is a challenging issue. We investigate novel 2D semiconductors ZrNCl and HfNCl which would be isolated to single layers from van der Waals layered bulk materials, i.e., ternary transition-metal nitride halides. Their isolations are unquestionably supported through an investigation of their cleavage energies as well as their thermodynamic stability based on the ab initio molecular dynamics and phonon dispersion calculations. Strain engineering is found to be available for both single-layer (1L) ZrNCl and 1L-HfNCl, where a transition from an indirect to direct band gap is attained under a tensile strain. It is also found that 1L-ZrNCl has an excellent electron mobility of about 1.2 * 103 cm2 V-1 s-1, which is significantly higher than that of 1L-MoS2. Lastly, it is indicated that these systems have good thermoelectric properties, i.e., high Seebeck coefficient and high power factor. With these findings, 1L-ZrNCl and 1L-HfNCl would be novel promising 2D materials for a wide range of optoelectronic and thermoelectric applications. PMID- 29229936 TI - Identification of a gene signature for discriminating metastatic from primary melanoma using a molecular interaction network approach. AB - Understanding the biological factors that are characteristic of metastasis in melanoma remains a key approach to improving treatment. In this study, we seek to identify a gene signature of metastatic melanoma. We configured a new network based computational pipeline, combined with a machine learning method, to mine publicly available transcriptomic data from melanoma patient samples. Our method is unbiased and scans a genome-wide protein-protein interaction network using a novel formulation for network scoring. Using this, we identify the most influential, differentially expressed nodes in metastatic as compared to primary melanoma. We evaluated the shortlisted genes by a machine learning method to rank them by their discriminatory capacities. From this, we identified a panel of 6 genes, ALDH1A1, HSP90AB1, KIT, KRT16, SPRR3 and TMEM45B whose expression values discriminated metastatic from primary melanoma (87% classification accuracy). In an independent transcriptomic data set derived from 703 primary melanomas, we showed that all six genes were significant in predicting melanoma specific survival (MSS) in a univariate analysis, which was also consistent with AJCC staging. Further, 3 of these genes, HSP90AB1, SPRR3 and KRT16 remained significant predictors of MSS in a joint analysis (HR = 2.3, P = 0.03) although, HSP90AB1 (HR = 1.9, P = 2 * 10-4) alone remained predictive after adjusting for clinical predictors. PMID- 29229938 TI - Exploiting Anopheles responses to thermal, odour and visual stimuli to improve surveillance and control of malaria. AB - Mosquito surveillance and control are at the heart of efforts to eliminate malaria, however, there remain significant gaps in our understanding of mosquito behaviour that impede innovation. We hypothesised that a combination of human associated stimuli could be used to attract and kill malaria vectors more successfully than individual stimuli, and at least as well as a real human. To test this in the field, we quantified Anopheles responses to olfactory, visual and thermal stimuli in Burkina Faso using a simple adhesive trap. Traps baited with human odour plus high contrast visual stimuli caught more Anopheles than traps with odour alone, showing that despite their nocturnal habit, malaria vectors make use of visual cues in host-seeking. The best performing traps, however, combined odour and visual stimuli with a thermal signature in the range equivalent to human body temperature. When tested against a human landing catch during peak mosquito abundance, this "host decoy" trap caught nearly ten times the number of Anopheles mosquitoes caught by a human collector. Exploiting the behavioural responses of mosquitoes to the entire suite of host stimuli promises to revolutionise vector surveillance and provide new paradigms in disease control. PMID- 29229937 TI - CpG-oligodeoxynucleotides developed for grouper toll-like receptor (TLR) 21s effectively activate mouse and human TLR9s mediated immune responses. AB - Synthetic phosphorothiolate-modified CpG-oligodeoxynucleotides (CpG-ODNs) are potent immune stimuli. Toll-like receptor (TLR) 9 and TLR21 are their cellular receptors in different species. The structural requirements for CpG-ODN to strongly activate TLR9 have been relatively well studied, but studies on TLR21 are in their infancy. Therefore, in this study, we investigated the interaction between CpG-ODNs and TLR21s from groupers (Epinephelus spp.), which are economically important fish species. We cloned the cDNA of giant grouper (E. lanceolatus) TLR21, and compared its sequence with orange-spotted grouper (E. coioides) TLR21A and TLR21B. These three receptors were activated by CpG-ODNs containing the GTCGTT motif but not by those containing the GACGTT motif. We developed two CpG-ODNs that contained 19 phosphorothiolated deoxynucleotides with one or two GTCGTT motifs. These CpG-ODNs had better activity on grouper TLR21s than currently developed CpG-ODNs, and produced similar immune stimulatory profiles when applied to cells isolated from orange-spotted grouper. The developed CpG-ODNs also effectively activated both human and mouse TLR9-mediated NF-kappaB activation and cytokine productions. These findings suggest that the GTCGTT motif is required for CpG-ODNs to activate grouper TLR21s, and that the CpG-ODNs that were developed for grouper TLR21s contain structures that effectively activate human and mouse TLR9s. PMID- 29229939 TI - Synaesthesia-type associations and perceptual changes induced by hypnotic suggestion. AB - Are synaesthetic experiences congenital and so hard-wired, or can a functional analogue be created? We induced an equivalent of form-colour synaesthesia using hypnotic suggestions in which symbols in an array (circles, crosses, squares) were suggested always to have a certain colour. In a Stroop type-naming task, three of the four highly hypnotizable participants showed a strong synaesthesia type association between symbol and colour. This was verified both by their subjective reports and objective eye-movement behaviour. Two resembled a projector- and one an associator-type synaesthete. Participant interviews revealed that subjective experiences differed somewhat from typical (congenital) synaesthesia. Control participants who mimicked the task using cognitive strategies showed a very different response pattern. Overall, the results show that the targeted, preconsciously triggered associations and perceptual changes seen in association with congenital synaesthesia can rapidly be induced by hypnosis. They suggest that each participant's subjective experience of the task should be carefully evaluated, especially when studying hypnotic hallucinations. Studying such experiences can increase understanding of perception, automaticity, and awareness and open unique opportunities in cognitive neuroscience and consciousness research. PMID- 29229940 TI - Single Crystal Organic Nanoflowers. AB - Nano-flowers reported so far were mostly constituted of inorganic or hybrid materials. We have synthesized and crystallized a new organic compound, 1, 2 bis(tritylthio)ethane forming an organic nano-flower consisting of single crystalline petals. Crystal structure at nano and micro level indicates that pi pi stacking interactions between aromatic systems is the principal factor governing molecular recognition and assembly. Single crystal X-ray Diffraction (S XRD) supported by Selective Area Electron Diffraction (SAED) experiments indicate the single crystalline nature of the flower-like assembly even at the nanoscale. In order to fabricate the nanoflower as a potential stimulus responsive material; the 'petals' were coated with magnetite nanoparticles, verified by Energy dispersive X-ray spectroscopic (EDX) analysis. Herein, we have further tested the potential utility of the hybrid material in water remediation as a nano-based adsorbent for removal of heavy metals like chromium. PMID- 29229941 TI - Urinary endotrophin predicts disease progression in patients with chronic kidney disease. AB - Renal fibrosis is the central pathogenic process in progression of chronic kidney disease (CKD). Collagen type VI (COL VI) is upregulated in renal fibrosis. Endotrophin is released from COL VI and promotes pleiotropic pro-fibrotic effects. Kidney disease severity varies considerably and accurate information regarding CKD progression may improve clinical decisions. We tested the hypothesis that urinary endotrophin derived during COL VI deposition in fibrotic human kidneys is a marker for progression of CKD in the Renal Impairment in Secondary Care (RIISC) cohort, a prospective observational study of 499 CKD patients. Endotrophin localised to areas of increased COL VI deposition in fibrotic kidneys but was not present in histologically normal kidneys. The third and fourth quartiles of urinary endotrophin:creatinine ratio (ECR) were independently associated with one-year disease progression after adjustment for traditional risk factors (OR (95%CI) 3.68 (1.06-12.83) and 8.65 (2.46-30.49), respectively). Addition of ECR quartiles to the model for disease progression increased prediction as seen by an increase in category-free net reclassification improvement (0.45, 95% CI 0.16-0.74, p = 0.002) and integrated discrimination improvement (0.04, 95% CI 0.02-0.06, p < 0.001). ECR was associated with development of end-stage renal disease (ESRD). It is concluded that ECR predicts disease progression of CKD patients. PMID- 29229942 TI - A neuronal signature of accurate imitative learning in wild-caught songbirds (swamp sparrows, Melospiza georgiana). AB - In humans and other animals, behavioural variation in learning has been associated with variation in neural features like morphology and myelination. By contrast, it is essentially unknown whether cognitive performance scales with electrophysiological properties of individual neurons. Birdsong learning offers a rich system to investigate this topic as song acquisition is similar to human language learning. Here, we address the interface between behavioural learning and neurophysiology in a cohort of wild-caught, hand-reared songbirds (swamp sparrows, Melospiza georgiana). We report the discovery in the forebrain HVC of sensorimotor 'bridge' neurons that simultaneously and selectively represent two critical learning-related schemas: the bird's own song, and the specific tutor model from which that song was copied. Furthermore, the prevalence and response properties of bridge neurons correlate with learning ability - males that copied tutor songs more accurately had more bridge neurons. Our results are consistent with the hypothesis that accurate imitative learning depends on a successful bridge, within single cortical neurons, between the representation of learning models and their sensorimotor copies. Whether such bridge neurons are a necessary mechanism for accurate learning or an outcome of learning accuracy is unknown at this stage, but can now be addressed in future developmental studies. PMID- 29229943 TI - Visible emission from bismuth-doped yttrium oxide thin films for lighting and display applications. AB - Due to the great development of light sources for several applications from displays to lighting, great efforts are devoted to find stable and efficient visible emitting materials. Moreover, the requirement of Si compatibility could enlarge the range of applications inside microelectronic chips. In this scenario, we have studied the emission properties of bismuth doped yttrium oxide thin films grown on crystalline silicon. Under optical pumping at room temperature a stable and strong visible luminescence has been observed. In particular, by the involvement of Bi ions in the two available lattice sites, the emission can be tuned from violet to green by changing the excitation wavelength. Moreover, under electron beam at low accelerating voltages (3 keV) a blue emission with high efficiency and excellent stability has been recorded. The color is generated by the involvement of Bi ions in both the lattice sites. These peculiarities make this material interesting as a luminescent medium for applications in light emitting devices and field emission displays by opening new perspectives for the realization of silicon-technology compatible light sources operating at room temperature. PMID- 29229944 TI - Author Correction: Evolutionary morphology of the lizard chemosensory system. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29229945 TI - Molecular thresholds of ITS2 and their implications for molecular evolution and species identification in seed plants. AB - Although molecular data have revealed huge amounts of plant diversity, interpreting genetic diversity into entities corresponding to species is still challenging. Taxonomic ranking based on genetic distance has been used extensively, but the results have been open to dispute, while the application of the strategy to plants has been restricted to a small number of cases. Here, levels of internal transcribed spacer 2 (ITS2) sequence variation were examined from 17,203 sequences, representing 5,439 species in 113 genera of seed plants, to ascertain the association between species status and their molecular divergence. Our results showed that, although the average genetic distances of sister species (AGDS) varied among angiosperms, the mean value was 3.98% and seemed not to be influenced by higher-level hierarchical classification or life history. AGDS was also stable within the major lineages of the gymnosperms but at approximately half the value of angiosperms, except for the Gnetidae, where the AGDS almost equaled that of angiosperms. We found that these AGDS discrepancies, associated with the rates of molecular evolution, cannot simply be attributed to generation-time differences, and highlight the complex life histories of plants. Our results provide general ITS2 thresholds in seed plants, and suggest their use in species identification. PMID- 29229946 TI - Find_tfSBP: find thermodynamics-feasible and smallest balanced pathways with high yield from large-scale metabolic networks. AB - Biologically meaningful metabolic pathways are important references in the design of industrial bacterium. At present, constraint-based method is the only way to model and simulate a genome-scale metabolic network under steady-state criteria. Due to the inadequate assumption of the relationship in gene-enzyme-reaction as one-to-one unique association, computational difficulty or ignoring the yield from substrate to product, previous pathway finding approaches can't be effectively applied to find out the high yield pathways that are mass balanced in stoichiometry. In addition, the shortest pathways may not be the pathways with high yield. At the same time, a pathway, which exists in stoichiometry, may not be feasible in thermodynamics. By using mixed integer programming strategy, we put forward an algorithm to identify all the smallest balanced pathways which convert the source compound to the target compound in large-scale metabolic networks. The resulting pathways by our method can finely satisfy the stoichiometric constraints and non-decomposability condition. Especially, the functions of high yield and thermodynamics feasibility have been considered in our approach. This tool is tailored to direct the metabolic engineering practice to enlarge the metabolic potentials of industrial strains by integrating the extensive metabolic network information built from systems biology dataset. PMID- 29229948 TI - Assessment of Lipid and Metabolite Changes in Obese Calf Muscle Using Multi-Echo Echo-planar Correlated Spectroscopic Imaging. AB - Obesity-related conditions including heart disease, stroke, and type 2 diabetes are leading causes of preventable death. Recent evidence suggests that altered myocellular lipid metabolism in obesity may lead to increased insulin resistance (IR) that predisposes to these disorders. To test the hypothesis that muscles rich in type I vs. type II muscle fibers would exhibit similar changes in intramyocellular lipid (IMCL) and extramyocellular lipid (EMCL) content in obesity, we utilized a new four-dimensional multi echo echo-planar correlated spectroscopic imaging technique that allows separate determination of IMCL and EMCL content in individual calf muscles in obese vs. normal healthy human subjects. Calf muscles were scanned in 32 obese and 11 healthy subjects using a 3T MRI/MRS scanner, and IR in the obese subjects was documented by glucose tolerance testing. In obese subjects, elevation of both IMCL and EMCL content was observed in the gastrocnemius and tibialis anterior muscles (with mixed type I and II fiber content), while a significant increase in only IMCL content (+48%, p < 0.001) was observed in the soleus muscle (predominantly type I fibers). These observations indicate unexpected differences in changes in myolipid metabolism in type I vs. type II rich muscle regions in obesity, perhaps related to IR, and warrant further investigation. PMID- 29229947 TI - Recombinant human osteopontin expressed in Nicotiana benthamiana stimulates osteogenesis related genes in human periodontal ligament cells. AB - Tissue engineering aims to utilise biologic mediators to facilitate tissue regeneration. Several recombinant proteins have potential to mediate induction of bone production, however, the high production cost of mammalian cell expression impedes patient access to such treatments. The aim of this study is to produce recombinant human osteopontin (hOPN) in plants for inducing dental bone regeneration. The expression host was Nicotiana benthamiana using a geminiviral vector for transient expression. OPN expression was confirmed by Western blot and ELISA, and OPN was purified using Ni affinity chromatography. Structural analysis indicated that plant-produced hOPN had a structure similar to commercial HEK cell produced hOPN. Biological function of the plant-produced hOPN was also examined. Human periodontal ligament stem cells were seeded on an OPN-coated surface. The results indicated that cells could grow normally on plant-produced hOPN as compared to commercial HEK cell-produced hOPN determined by MTT assay. Interestingly, increased expression of osteogenic differentiation-related genes, including OSX, DMP1, and Wnt3a, was observed by realtime PCR. These results show the potential of plant-produced OPN to induce osteogenic differentiation of stem cells from periodontal ligament in vitro, and suggest a therapeutic strategy for bone regeneration in the future. PMID- 29229949 TI - Investigations of the Optical Properties of GaNAs Alloys by First-Principle. AB - We present a Density Functional Theory (DFT) analysis of the optical properties of dilute-As GaN1-xAsx alloys with arsenic (As) content ranging from 0% up to 12.5%. The real and imaginary parts of the dielectric function are investigated, and the results are compared to experimental and theoretical values for GaN. The analysis extends to present the complex refractive index and the normal-incidence reflectivity. The refractive index difference between GaN and GaNAs alloys can be engineered to be up to ~0.35 in the visible regime by inserting relatively low amounts of As-content into the GaN system. Thus, the analysis elucidates on the birefringence of the dilute-As GaNAs alloys and comparison to other experimentally characterized III-nitride systems is drawn. Our findings indicate the potential of GaNAs alloys for III-nitride based waveguide and photonic circuit design applications. PMID- 29229950 TI - Aneurysm Severity is Increased by Combined Mmp-7 Deletion and N-cadherin Mimetic (EC4-Fc) Over-Expression. AB - There is an unmet need for treatments to reduce abdominal aortic aneurysm (AAA) progression. Vascular smooth muscle cell (VSMC) apoptosis precipitates AAA formation, whereas VSMC proliferation repairs the vessel wall. We previously demonstrated that over-expression of EC4-Fc (truncated N-cadherin), or deletion of matrix-metalloproteinase-7 (Mmp-7) reduced VSMC apoptosis in mouse atherosclerotic plaques. Additionally, MMP-7 promotes VSMC apoptosis by cleavage of N-cadherin. We investigated their combined effect on AAA formation. Increased apoptosis and proliferation were observed in human AAA (HAAA) sections compared to normal aortae (HA). This coincided with increased MMP-7 activity and reduced N cadherin protein levels in HAAA sections compared to HA. Using a mouse model of aneurysm formation, we showed that the combination of Mmp-7 deletion and EC4-Fc overexpression significantly increased AAA severity. Medial apoptosis and proliferation were both significantly reduced in these mice compared to control mice. In vitro, MMP-7 inhibition and EC4-Fc administration significantly supressed human aortic VSMC apoptosis (via activation of PI-3 kinase/Akt signalling) and proliferation. In conclusion, combined Mmp-7 deletion and systemic over-expression of EC4-Fc reduced both proliferation and apoptosis. Reduced proliferation-mediated repair over-rides any benefit of reduced apoptosis, increasing aneurysm severity. Future studies should therefore focus on retarding VSMC apoptosis whilst promoting VSMC proliferation. PMID- 29229951 TI - A new high-pressure form of Mg2SiO4 highlighting diffusionless phase transitions of olivine. AB - High-pressure polymorphism of olivine (alpha-phase of Mg2SiO4) is of particular interest for geophysicists aiming to understand the structure and dynamics of the Earth's interior because of olivine's prominent abundance in the upper mantle. Therefore, natural and synthetic olivine polymorphs have been actively studied in the past half century. Here, we report a new high-pressure polymorph, the epsilon*-phase, which was discovered in a heavily shocked meteorite. It occurs as nanoscale lamellae and has a topotaxial relationship with the host ringwoodite (gamma-phase of Mg2SiO4). Olivine in the host rock entrapped in a shock-induced melt vein initially transformed into polycrystalline ringwoodite through a nucleation and growth mechanism. The ringwoodite grains then coherently converted into the epsilon*-phase by shear transformation during subsequent pressure release. This intermediate metastable phase can be formed by all Mg2SiO4 polymorphs via a shear transformation mechanism. Here, we propose high-pressure transformations of olivine that are enhanced by diffusionless processes, not only in shocked meteorites but also in thick and cold lithosphere subducting into the deep Earth. PMID- 29229952 TI - Ultra-bright gamma-ray emission and dense positron production from two laser driven colliding foils. AB - Matter can be transferred into energy and the opposite transformation is also possible by use of high-power lasers. A laser pulse in plasma can convert its energy into gamma-rays and then e - e + pairs via the multi-photon Breit-Wheeler process. Production of dense positrons at GeV energies is very challenging since extremely high laser intensity ~1024 Wcm-2 is required. Here we propose an all optical scheme for ultra-bright gamma-ray emission and dense positron production with lasers at intensity of 1022-23 Wcm-2. By irradiating two colliding elliptically-polarized lasers onto two diamondlike carbon foils, electrons in the focal region of one foil are rapidly accelerated by the laser radiation pressure and interact with the other intense laser pulse which penetrates through the second foil due to relativistically induced foil transparency. This symmetric configuration enables efficient Compton back-scattering and results in ultra bright gamma-photon emission with brightness of ~1025 photons/s/mm2/mrad2/0.1%BW at 15 MeV and intensity of 5 * 1023 Wcm-2. Our first three-dimensional simulation with quantum-electrodynamics incorporated shows that a GeV positron beam with density of 2.5 * 1022 cm-3 and flux of 1.6 * 1010/shot is achieved. Collective effects of the pair plasma may be also triggered, offering a window on investigating laboratory astrophysics at PW laser facilities. PMID- 29229953 TI - Dual-specificity phosphatase 5 acts as an anti-inflammatory regulator by inhibiting the ERK and NF-kappaB signaling pathways. AB - Although dual-specificity phosphatase 5 (DUSP5), which inactivates extracellular signal-regulated kinase (ERK), suppresses tumors in several types of cancer, its functional roles remain largely unknown. Here, we show that DUSP5 is induced during lipopolysaccharide (LPS)-mediated inflammation and inhibits nuclear factor kappaB (NF-kappaB) activity. DUSP5 mRNA and protein expression increased transiently in LPS-stimulated RAW 264.7 cells and then returned to basal levels. DUSP5 overexpression in RAW 264.7 cells suppressed the production of pro inflammatory tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), whereas knockdown of DUSP5 increased their expression. Investigation of two major inflammatory signaling pathways, mitogen-activated protein kinase (MAPK) and NF kappaB, using activator protein-1 (AP-1) and NF-kappaB reporter plasmids, respectively, showed that NF-kappaB transcription activity was downregulated by DUSP5 in a phosphatase activity-independent manner whereas AP-1 activity was inhibited by DUSP5 phosphatase activity towards ERK,. Further investigation showed that DUSP5 directly interacts with transforming growth factor beta activated kinase 1 (TAK1) and inhibitor of kappaB (IkappaB) kinases (IKKs) but not with IkappaBalpha. DUSP5 binding to IKKs interfered with the association of TAK1 with IKKs, suggesting that DUSP5 might act as a competitive inhibitor of TAK1-IKKs association. Therefore, we propose that DUSP5 negatively regulates ERK and NF-kappaB in a phosphatase activity-dependent and -independent manner, respectively. PMID- 29229954 TI - Recent evolution in use and effectiveness in mainland China of thoracic endovascular aortic repair of type B aortic dissection. AB - A meta-analysis was performed on 175 studies selected among those published in mainland China between 2008 and 2015 on thoracic endovascular aortic repair (TEVAR) for type B aortic dissection (AD). Most TEVAR were performed in Shanghai, Beijing, Hubei and Guangdong in patients with mean age of 53.9 years, and acute (70%) or chronic (30%) type B AD. Procedural success rate was 99.1 +/- 0.8%. Major complication rate was 1.7 +/- 2.3%, with paraplegia in 0.4 +/- 0.0%. Overall in-hospital mortality rate was 1.6 +/- 0.9% with AD rupture in 30% (about 40% during first postoperative day); follow-up mortality rate was 2.3 +/- 1.1%, with AD rupture in 39.2% (50% within first year). Compared with 2001-2007 data from China, there appeared to be improvement in rates of major complications, paraplegia and in-hospital mortality. Compared with 1999-2004 Western data, rates of procedural success, stroke, and paraplegia appeared similar, while those for major complications, in-hospital mortality, retrograde type A dissection and follow-up mortality appeared lower. Compared with more recent Western data (2006 2013) on acute complicated type B AD, stroke, paraplegia, in-hospital mortality and follow-up mortality appeared lower. Therefore, in mainland China, safety for TEVAR of type B AD appeared better between 2008 and 2015 than in previous periods in China or Western countries. PMID- 29229955 TI - Effect of whole milk compared with skimmed milk on fasting blood lipids in healthy adults: a 3-week randomized crossover study. AB - BACKGROUND/OBJECTIVES: Dietary guidelines have for decades recommended choosing low-fat dairy products due to the high content of saturated fat in dairy known to increase blood concentration of LDL cholesterol. However, meta-analyses including observational studies show no association between overall dairy intake and risk of cardiovascular disease and even point to an inverse association with type 2 diabetes. The objective was to compare the effects of whole milk (3.5% fat) with skimmed milk (0.1% fat) on fasting serum blood lipids, insulin, and plasma glucose in healthy subjects. SUBJECT/METHODS: A randomized, controlled 2 * 3-week crossover dietary intervention in 18 healthy adults randomly assigned to a sequence of treatments consisting of 0.5 L/d of whole milk and skimmed milk as part of their habitual diet. A total of 17 subjects completed the intervention. RESULTS: Whole milk increased HDL cholesterol concentrations significantly compared to skimmed milk (P < 0.05). There were no significant differences between whole milk and skimmed milk in effects on total and LDL cholesterol, triacylglycerol, insulin, and glucose concentrations. CONCLUSIONS: Intake of 0.5 L/d of whole milk did not adversely affect fasting blood lipids, glucose, or insulin compared to skimmed milk. Moreover, intake of whole milk increased HDL cholesterol concentration compared to skimmed milk. These findings suggest that if the higher energy content is taken into account, whole milk might be considered a part of a healthy diet among the normocholesterolemic population. PMID- 29229956 TI - Response to letter to the editor 'Mortality due to refeeding syndrome? You only find what you look for, and you only look for what you know'. PMID- 29229957 TI - Plants increase CO2 uptake by assimilating nitrogen via the photorespiratory pathway. AB - Photorespiration is a major bioengineering target for increasing crop yields as it is often considered a wasteful process. Photorespiratory metabolism is integrated into leaf metabolism and thus may have certain benefits. Here, we show that plants can increase their rate of photosynthetic CO2 uptake when assimilating nitrogen de novo via the photorespiratory pathway by fixing carbon as amino acids in addition to carbohydrates. Plants fed NO3- had higher rates of CO2 assimilation under photorespiratory than low-photorespiratory conditions, while plants lacking NO3- nutrition exhibited lower stimulation of CO2 uptake. We modified the widely used Farquhar, von Caemmerer and Berry photosynthesis model to include the carbon and electron requirements for nitrogen assimilation via the photorespiratory pathway. Our modified model improves predictions of photosynthetic CO2 uptake and of rates of photosynthetic electron transport. The results highlight how photorespiration can improve photosynthetic performance despite reducing the efficiency of Rubisco carboxylation. PMID- 29229959 TI - Insulin-like peptide 3 expressed in the silkworm possesses intrinsic disulfide bonds and full biological activity. AB - Insulin-like peptide 3 (INSL3) is a member of the relaxin/insulin superfamily and is expressed in testicular Leydig cells. Essential for fetal testis descent, INSL3 has been implicated in testicular and sperm function in adult males via interaction with relaxin/insulin-like family peptide receptor 2 (RXFP2). The INSL3 is typically prepared using chemical synthesis or overexpression in Escherichia coli followed by oxidative refolding and proteolysis. Here, we expressed and purified full-length porcine INSL3 (pINSL3) using a silkworm-based Bombyx mori nucleopolyhedrovirus bacmid expression system. Biophysical measurements and proteomic analysis revealed that this recombinant pINSL3 exhibited the correct conformation, with the three critical disulfide bonds observed in native pINSL3, although partial cleavage occurred. In cAMP stimulation assays using RXFP2-expressing HEK293 cells, the recombinant pINSL3 possessed full biological activity. This is the first report concerning the production of fully active pINSL3 without post-expression treatments and provides an efficient production platform for expressing relaxin/insulin superfamily peptides. PMID- 29229960 TI - How costly punishment, diversity, and density of connectivity influence cooperation in a biological network. AB - It has been an old unsolved puzzle to evolutionary theorists on which mechanisms would increase large-scale cooperation in human societies. Thus, how such mechanisms operate in a biological network is still not well understood. This study addresses these questions with empirical evidence from agent-based models designed to understand these network interactions. Repeated Prisoner's Dilemma games were designed to study how costly punishment, diversity, and density of connectivity interact to influence cooperation in a biological network. There were 1000 rounds in each game made up of 18 players engaged in pairwise relationship with their neighbors. This study shows three important interactions. (1) Introducing diversity to costly punishment favors both cooperation and defection, but not vice versa. Introducing costly punishment to diversity disfavors defection but favors cooperation. (2) Costly Punishment, alone, disfavors defection but decreases average payoff. Decreasing the density of connectivity, D c , when there is no costly punishment applied, increases average payoff. (3) A synergy of diversity and decreasing density of connectivity favors cooperation in a biological network. Furthermore, this study also suggests a likelihood from empirical findings that spatial structures may not be favoring cooperation, as is the widely-accepted notion, but rather disfavoring defection in the global scale. PMID- 29229958 TI - EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer. AB - Transport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin beta family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output. Focal deletions of the RanBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM) and silencing of RanBP6 promoted glioma growth in vivo. Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway. PMID- 29229961 TI - Laser-induced blurring of molecular structure information in high harmonic spectroscopy. AB - High harmonic spectroscopy gives access to molecular structure with Angstrom resolution. Such information is encoded in the destructive interferences occurring between the harmonic emissions from the different parts of the molecule. By solving the time-dependent Schrodinger equation, either numerically or with the molecular strong-field approximation, we show that the electron dynamics in the emission process generally results in a strong spectral smoothing of the interferences, blurring the structural information. However we identify specific generation conditions where they are unaffected. These findings have important consequences for molecular imaging and orbital tomography using high harmonic spectroscopy. PMID- 29229962 TI - Reference and Influential Factors of Serum Bone Markers in Chinese Adolescents. AB - This study aimed to establish reference ranges of bone markers in Chinese adolescents between the age of 12 and 16, and to search these markers' characteristics and influential factors. Personal information and fasting blood samples were collected from 174 healthy adolescents in Northeast China. Serum levels of PINP, ALP, beta-CrossLaps, calcium, phosphate, PTH, 25(OH)D and TSH were measured. Reference ranges were established for PINP [(85.55 2,028.75)ng/ml], ALP [(53.88-463.63)U/L], beta-CrossLaps [(0.16-1.19)ng/ml], calcium [(2.35-2.70)mmol/L], phosphate [(1.17-2.06)mmol/L] and PTH [(2.64 43.36)MUg/L] in this population. We observed that bone formation markers PINP and ALP levels were evidently higher when compared to kit references for adults. Reference ranges for calcium, phosphate and PTH also differed from those provided by kit manuals. Serum ALP, PINP, phosphate and PTH changed with age (all P < 0.005), and were significantly higher in boys than in girls (all P < 0.05). Serum 25(OH)D and TSH levels didn't correlate with PINP, ALP and beta-CrossLaps (all P > 0.05). In conclusion, unique reference ranges should be provided for adolescents. BMI, sex and age independently influence certain serum bone markers in adolescents. Vitamin D deficiency is widespread. Serum levels of vitamin D and TSH may not influence bone turnover markers in this population. PMID- 29229963 TI - Mineral surface chemistry control for origin of prebiotic peptides. AB - Some seventy years ago, John Desmond Bernal proposed a role for clays in the origin of life. While much research has since been dedicated to the study of silicate clays, layered double hydroxides, believed to be common on the early Earth, have received only limited attention. Here we examine the role that layered hydroxides could have played in prebiotic peptide formation. We demonstrate how these minerals can concentrate, align and act as adsorption templates for amino acids, and during wetting-drying cycles, promote peptide bond formation. This enables us to propose a testable mechanism for the growth of peptides at layered double hydroxide interfaces in an early Earth environment. Our results provide insights into the potential role of mineral surfaces in mimicking aspects of biochemical reaction pathways. PMID- 29229964 TI - Aerosols cause intraseasonal short-term suppression of Indian monsoon rainfall. AB - Aerosol abundance over South Asia during the summer monsoon season, includes dust and sea-salt, as well as, anthropogenic pollution particles. Using observations during 2000-2009, here we uncover repeated short-term rainfall suppression caused by coincident aerosols, acting through atmospheric stabilization, reduction in convection and increased moisture divergence, leading to the aggravation of monsoon break conditions. In high aerosol-low rainfall regions extending across India, both in deficient and normal monsoon years, enhancements in aerosols levels, estimated as aerosol optical depth and absorbing aerosol index, acted to suppress daily rainfall anomaly, several times in a season, with lags of a few days. A higher frequency of prolonged rainfall breaks, longer than seven days, occurred in these regions. Previous studies point to monsoon rainfall weakening linked to an asymmetric inter-hemispheric energy balance change attributed to aerosols, and short-term rainfall enhancement from radiative effects of aerosols. In contrast, this study uncovers intraseasonal short-term rainfall suppression, from coincident aerosol forcing over the monsoon region, leading to aggravation of monsoon break spells. Prolonged and intense breaks in the monsoon in India are associated with rainfall deficits, which have been linked to reduced food grain production in the latter half of the twentieth century. PMID- 29229965 TI - Transfer of Minibeam Radiation Therapy into a cost-effective equipment for radiobiological studies: a proof of concept. AB - Minibeam radiation therapy (MBRT) is an innovative synchrotron radiotherapy technique able to shift the normal tissue complication probability curves to significantly higher doses. However, its exploration was hindered due to the limited and expensive beamtime at synchrotrons. The aim of this work was to develop a cost-effective equipment to perform systematic radiobiological studies in view of MBRT. Tumor control for various tumor entities will be addressable as well as studies to unravel the distinct biological mechanisms involved in normal and tumor tissues responses when applying MBRT. With that aim, a series of modifications of a small animal irradiator were performed to make it suitable for MBRT experiments. In addition, the brains of two groups of rats were irradiated. Half of the animals received a standard irradiation, the other half, MBRT. The animals were followed-up for 6.5 months. Substantial brain damage was observed in the group receiving standard RT, in contrast to the MBRT group, where no significant lesions were observed. This work proves the feasibility of the transfer of MBRT outside synchrotron sources towards a small animal irradiator. PMID- 29229966 TI - Energy harvesting efficiency of piezoelectric polymer film with graphene and metal electrodes. AB - In this study, we investigated an energy harvesting effect of tensile stress using piezoelectric polymers and flexible electrodes. A chemical-vapor-deposition grown graphene film was transferred onto both sides of the PVDF and P(VDF-TrFE) films simultaneously by means of a conventional wet chemical method. Output voltage induced by sound waves was measured and analyzed when a mechanical tension was applied to the device. Another energy harvester was made with a metallic electrode, where Al and Ag were deposited by using an electron-beam evaporator. When acoustic vibrations (105 dB) were applied to the graphene/PVDF/graphene device, an induced voltage of 7.6 Vpp was measured with a tensile stress of 1.75 MPa, and this was increased up to 9.1 Vpp with a stress of 2.18 MPa for the metal/P(VDF-TrFE)/metal device. The 9 metal/PVDF/metal layers were stacked as an energy harvester, and tension was applied by using springs. Also, we fabricated a full-wave rectifying circuit to store the electrical energy in a 100 MUF capacitor, and external vibration generated the electrical charges. As a result, the stored voltage at the capacitor, obtained from the harvester via a bridge diode rectifier, was saturated to ~7.04 V after 180 s charging time. PMID- 29229967 TI - Electrical synapses convey orientation selectivity in the mouse retina. AB - Sensory neurons downstream of primary receptors are selective for specific stimulus features, and they derive their selectivity both from excitatory and inhibitory synaptic inputs from other neurons and from their own intrinsic properties. Electrical synapses, formed by gap junctions, modulate sensory circuits. Retinal ganglion cells (RGCs) are diverse feature detectors carrying visual information to the brain, and receive excitatory input from bipolar cells and inhibitory input from amacrine cells (ACs). Here we describe a RGC that relies on gap junctions, rather than chemical synapses, to convey its selectivity for the orientation of a visual stimulus. This represents both a new functional role of electrical synapses as the primary drivers of feature selectivity and a new circuit mechanism for orientation selectivity in the retina. PMID- 29229968 TI - Individual differences in empathy are associated with apathy-motivation. AB - Empathy - the capacity to understand and resonate with the experiences of other people - is considered an essential aspect of social cognition. However, although empathy is often thought to be automatic, recent theories have argued that there is a key role for motivation in modulating empathic experiences. Here we administered self-report measures of empathy and apathy-motivation to a large sample of healthy people (n = 378) to test whether people who are more empathic are also more motivated. We then sought to replicate our findings in an independent sample (n = 198) that also completed a behavioural task to measure state affective empathy and emotion recognition. Cognitive empathy was associated with higher levels of motivation generally across behavioural, social and emotional domains. In contrast, affective empathy was associated with lower levels of behavioural motivation, but higher levels of emotional motivation. Factor analyses showed that empathy and apathy are distinct constructs, but that affective empathy and emotional motivation are underpinned by the same latent factor. These results have potentially important clinical applications for disorders associated with reduced empathy and motivation as well as the understanding of these processes in healthy people. PMID- 29229969 TI - Transcriptome and metabolome profiling of Narcissus pseudonarcissus 'King Alfred' reveal components of Amaryllidaceae alkaloid metabolism. AB - Amaryllidaceae alkaloids (AAs) represent a diverse class of plant specialized metabolites and many display potent pharmacological activities. The AA metabolic pathway is poorly understood and resources are minimal. To enable AA pathway elucidation and novel biosynthetic enzymes discovery, we generated comprehensive metabolomic and corresponding transcriptomic datasets from different tissues of Narcissus pseudonarcissus 'King Alfred'. In this study, we performed untargeted UPLC-QTOF-MS metabolite analysis from different tissues, which generated exhaustive list of compounds, including several AAs, most predominant and diverse in bulbs. RNA sequencing of N. pseudonarcissus 'King Alfred' bulbs yielded 195,347 transcripts, after assembly. Top expressed genes belong to process like metabolism, survival, and defense including alkaloid biosynthetic genes. The transcriptome contained complete sequences for all proposed genes encoding AA biosynthetic enzymes such as tyrosine decarboxylase (TYDC1 and TYDC2), phenylalanine ammonia-lyase (PAL1 and PAL2) and phenolic acids hydroxylases (C4H and C3H) to name a few. Furthermore, transcriptome data were validated using RT qPCR analysis and expression study in different tissues of N. pseudonarcissus 'King Alfred' was performed. Here, we present the first comprehensive metabolome and transcriptome study from N. pseudonarcissus 'King Alfred' providing invaluable resources for metabolic engineering and biotechnological applications. PMID- 29229970 TI - Regression to the mean, apparent data errors and biologically extraordinary results: letter regarding 'changes in telomere length 3-5 years after gastric bypass surgery'. PMID- 29229971 TI - Development of Decision Forest Models for Prediction of Drug-Induced Liver Injury in Humans Using A Large Set of FDA-approved Drugs. AB - Drug-induced liver injury (DILI) presents a significant challenge to drug development and regulatory science. The FDA's Liver Toxicity Knowledge Base (LTKB) evaluated >1000 drugs for their likelihood of causing DILI in humans, of which >700 drugs were classified into three categories (most-DILI, less-DILI, and no-DILI). Based on this dataset, we developed and compared 2-class and 3-class DILI prediction models using the machine learning algorithm of Decision Forest (DF) with Mold2 structural descriptors. The models were evaluated through 1000 iterations of 5-fold cross-validations, 1000 bootstrapping validations and 1000 permutation tests (that assessed the chance correlation). Furthermore, prediction confidence analysis was conducted, which provides an additional parameter for proper interpretation of prediction results. We revealed that the 3-class model not only had a higher resolution to estimate DILI risk but also showed an improved capability to differentiate most-DILI drugs from no-DILI drugs in comparison with the 2-class DILI model. We demonstrated the utility of the models for drug ingredients with warnings very recently issued by the FDA. Moreover, we identified informative molecular features important for assessing DILI risk. Our results suggested that the 3-class model presents a better option than the binary model (which most publications are focused on) for drug safety evaluation. PMID- 29229972 TI - Tunable liquid crystal multifocal microlens array. AB - A novel liquid crystal microlens array with tunable multifocal capability, high optical power and fill-factor is proposed and experimentally demonstrated. A specific hole pattern design produces a multifocal array with only one voltage control. Three operations modes are possible, "Off", "Tunable Multifocal" and "Unifocal". The design is patterned in both substrates. Then, the substrates are arranged in symmetrical configuration. The result is a high optical power in comparison with typical hole patterned structures. Besides, it is proposed a hexagonal pattern that produces a high fill factor, specially indicated for some applications as Integral Imaging. The array has several useful characteristics for this type of application: tunability for the loss of resolution; multifocal for extended DOF; high fill factor for increase the number of views; and low power consumption for integration in portable devices. Moreover, the optical characteristics of the proposed device could bring new applications in other fields. PMID- 29229973 TI - Resensitization of Akt Induced Docetaxel Resistance in Breast Cancer by 'Iturin A' a Lipopeptide Molecule from Marine Bacteria Bacillus megaterium. AB - Development of the resistance is the major problem in cancer therapy. Docetaxel is a taxol alkaloid that is frequently used in metastatic breast cancer. However, resistance often limits the usefulness of this drug in many breast cancer patients. Manipulation of resistant cells to re-sensitize to the therapeutic effect of docetaxel is current strategy to overcome this problem. Here, we have introduced 'Iturin A' as a potent chemosensitizer in docetaxel resistant breast cancer cells. Combination of Iturin A and docetaxel treatment significantly hampered the proliferation of docetaxel resistant MDA-MB-231 and MDA-MB-468 breast cancer cells. Cell cycle analysis also showed massive amount of apoptotic population (Sub G0/G1) in combination therapy. A number of apoptotic and anti apoptotic proteins were significantly altered in dual drug treated groups. Caspase 3 dependent cell death was observed in dual treatment. Molecular mechanism study showed that over-expression of Akt and its downstream signaling pathway was associated with docetaxel resistance. Iturin A significantly reduced Akt signaling pathway in resistant cells. This mechanistic action might be the reason behind the chemo-sensitization effect of Iturin A in docetaxel resistant breast cancer cells. In conclusion, Iturin A resensitized the resistant breast cancer cells to docetaxel therapy by inhibiting Akt activity. PMID- 29229974 TI - Ensemble Modeling Approach Targeting Heterogeneous RNA-Seq data: Application to Melanoma Pseudogenes. AB - We studied the transcriptome landscape of skin cutaneous melanoma (SKCM) using 103 primary tumor samples from TCGA, and measured the expression levels of both protein coding genes and non-coding RNAs (ncRNAs). In particular, we emphasized pseudogenes potentially relevant to this cancer. While cataloguing the profiles based on the known biotypes, all the employed RNA-Seq methods generated just a small consensus of significant biotypes. We thus designed an approach to reconcile the profiles from all methods following a simple strategy: we selected genes that were confirmed as differentially expressed by the ensemble predictions obtained in a regression model. The main advantages of this approach are: 1) Selection of a high-confidence gene set identifying relevant pathways; 2) Use of a regression model whose covariates embed all method-driven outcomes to predict an averaged profile; 3) Method-specific assessment of prediction power and significance. Furthermore, the approach can be generalized to any biological system for which noisy RNA-Seq profiles are computed. As our analyses concerned bio-annotations of both high-quality protein coding genes and ncRNAs, we considered the associations between pseudogenes and parental genes (targets). Among the candidate targets that were validated, we identified PINK1, which is studied in patients with Parkinson and cancer (especially melanoma). PMID- 29229975 TI - Design of plasmonic Ag-TiO2/H3PW12O40 composite film with enhanced sunlight photocatalytic activity towards o-chlorophenol degradation. AB - A series of plasmonic Ag-TiO2/H3PW12O40 composite films were fabricated and immobilized by validated preparation technique. The chemical composition and phase, optical, SPR effect and pore-structure properties together with the morphology of as-prepared composite film are well-characterized. The multi synergies of as-prepared composite films were gained by combined action of electron-capture action via H3PW12O40, visible-response induced by Ag, and Schottky-junction formed between TiO2-Ag. Under simulated sunlight, the maximal K app of o-chlorophenol (o-CP) reached 0.0075 min-1 which was 3.95-fold larger than that of TiO2 film, while it was restrained obviously under acid condition. In the photocatalytic degradation process, .OH and .O2- attacked preferentially ortho and para position of o-CP molecule, and accordingly the specific degradation pathways were speculated. The novel composite film exhibited an excellent applicability due to self-regeneration of H3PW12O40, well-protection of metal Ag degrees and favorable immobilization. PMID- 29229976 TI - A novel Tn1696-like composite transposon (Tn6404) harboring bla IMP-4 in a Klebsiella pneumoniae isolate carrying a rare ESBL gene bla SFO-1. AB - Genetic determinants of a clinical Klebsiella pneumoniae isolate (KP1814) coproducing IMP-4 and a rare ESBL gene SFO-1 was investigated. KP1814 belongs to a novel sequence type (ST) assigned to ST2270. WGS identified four circular DNA sequences in KP1814, including two multidrug-resistance (MDR) plasmids, one virulence plasmid, and one circular form. The MDR plasmid pKP1814-1 (299.9 Kb) is untypeable, and carries two large mosaic multiresistance regions (MRRs). bla SFO 1 and bla IMP-4 co-exists on MRR1, and bla SFO-1 is associated with an IS/Tn independent genetic context. bla IMP-4 is carried by a novel In804-like integron (intlI-bla IMP-4-Kl.pn.I3-qacG2-aacA4-catB3?) associated with a novel Tn1696-like transposon (designed Tn6404) flanked by IS5075. The other MDR plasmid pKP1814-3 is a 95,701-bp IncFII plasmid, and is a hybrid of a Shigella flexneri plasmid pSF07201 and an E. coli plasmid pCA08. All resistance genes of pKP1814-3 were detected in a ~16-kb IS26-flanked composite transposon carried by a Tn5396 transposon. The circular form (18.3 Kb) was composed of two parts belonging to pKP1814-1 and pKP1814-3, respectively. The plasmid pKP1814-2, carrying multiple virulence factors, encodes IncFIBK and IncFIIK replicons with a size of 187,349 bp. The coexistence of MDR and virulence plasmids largely enhances the bacterial fitness in the host and environment. PMID- 29229978 TI - Manipulation of dangling bonds of interfacial states coupled in GeTe-rich GeTe/Sb2Te3 superlattices. AB - Superlattices consisting of stacked nano-sized GeTe and Sb2Te3 blocks have attracted considerable attention owing to their potential for an efficient non melting switching mechanism, associated with complex bonding between blocks. Here, we propose possible atomic models for the superlattices, characterized by different interfacial bonding types. Based on interplanar distances extracted from ab initio calculations and electron diffraction measurements, we reveal possible intercalation of dangling bonds as the GeTe content in the superlattice increases. The dangling bonds were further confirmed by X-ray photoelectron spectroscopy, anisotropic temperature dependent resistivity measurements down to 2 K and magnetotransport analysis. Changes of partially coherent decoupled topological surfaces states upon dangling bonds varying contributed to the switching mechanism. Furthermore, the topological surface states controlled by changing the bonding between stacking blocks may be optimized for multi functional applications. PMID- 29229979 TI - Near-Infrared Plasmonic Assemblies of Gold Nanoparticles with Multimodal Function for Targeted Cancer Theragnosis. AB - Here we report a novel assembly structure of near-infrared plasmonic gold nanoparticles (AuNPs), possessing both photoacoustic (PA) and photothermal (PT) properties. The template for the plasmonic AuNP assembly is a bioconjugate between short double-strand DNA (sh-dsDNA) and human methyl binding domain protein 1 (MBD1). MBD1 binds to methylated cytosine-guanine dinucleotides (mCGs) within the sequence of sh-dsDNA. Hexahistidine peptides on the engineered MBD1 function as a nucleation site for AuNP synthesis, allowing the construction of hybrid conjugates, sh-dsDNA-MBD1-AuNPs (named DMAs). By varying the length of sh dsDNA backbone and the spacer between two adjacent mCGs, we synthesized three different DMAs (DMA_5mCG, DMA_9mCG, and DMA_21mCG), among which DMA_21mCG exhibited a comparable photothermal and surprisingly a higher photoacoustic signals, compared to a plasmonic gold nanorod. Further, epidermal growth factor receptor I (EGFR)-binding peptides are genetically attached to the MBD1 of DMA_21mCG, enabling its efficient endocytosis into EGFR-overexpressing cancer cells. Notably, the denaturation of MBD1 disassembled the DMA and accordingly released the individual small AuNPs (<5 nm) that can be easily cleared from the body through renal excretion without causing accumulation/toxicity problems. This DMA-based novel approach offers a promising platform for targeted cancer theragnosis based on simultaneous PA imaging and PT therapy. PMID- 29229980 TI - Molecular cloning of novel transcripts of human kallikrein-related peptidases 5, 6, 7, 8 and 9 (KLK5 - KLK9), using Next-generation sequencing. AB - Alternative splicing of cancer-related genes is a common cellular mechanism accounting for cancer cell transcriptome complexity and affecting cell cycle control, proliferation, apoptosis, angiogenesis, invasion, and metastasis. In this study, we describe the discovery and molecular cloning of thirty novel transcripts of the human KLK5, KLK6, KLK7, KLK8 and KLK9 genes, using 3' rapid amplification of cDNA ends (3' RACE) and NGS technology, as well as their expression analysis in many established cell lines, originating from several distinct cancerous and normal tissues. Extensive bioinformatic analysis revealed novel splice variants of these five members of the KLK family, comprising entirely new exons, previously unknown boundaries of the already annotated exons (extensions and truncations) as well as alternative splicing events between these exons. Nested RT-PCR in a panel of human cell lines originating from seventeen cancerous and two normal tissues with the use of variant-specific pairs of primers was carried out for expression analysis of these novel splice variants, and Sanger sequencing of the respective amplicons confirmed our NGS results. Given that some splice variants of KLK family members possess clinical value, novel alternatively spliced transcripts appear as new candidate biomarkers for diagnostic and/or prognostic purposes and as targets for therapeutic strategies. PMID- 29229981 TI - The mating type locus protein MAT1-2-1 of Trichoderma reesei interacts with Xyr1 and regulates cellulase gene expression in response to light. AB - Cellulase production in the model cellulolytic fungus Trichoderma reesei is subject to a variety of environmental and physiological conditions involving an intricate regulatory network with multiple transcription factors. Here, we identified the mating type locus protein MAT1-2-1 as an interacting partner for the key transcriptional activator Xyr1 of T. reesei cellulase genes. Yeast two hybrid and GST pulldown analyses revealed that MAT1-2-1 directly interacted with the putative transcription activation domain (AD, 767~940 aa) and the middle homology region (MHR2, 314~632 aa) of Xyr1. Disruption of the mat1-2-1 gene compromised the induced expression of cellulase genes with Avicel in response to light or with lactose. Chromatin immunoprecipitation (ChIP) demonstrated that MAT1-2-1 was recruited to the cbh1 (cellobiohydrolase 1-encoding) gene promoter in a Xyr1-dependent manner. These results strongly support an important role of MAT1-2-1 as a physiological cofactor of Xyr1, and suggest that MAT1-2-1 represents another regulatory node that integrates the light response with carbon source signaling to fine tune cellulase gene transcription. PMID- 29229982 TI - Myosin-X knockout is semi-lethal and demonstrates that myosin-X functions in neural tube closure, pigmentation, hyaloid vasculature regression, and filopodia formation. AB - Myosin-X (Myo10) is an unconventional myosin best known for its striking localization to the tips of filopodia. Despite the broad expression of Myo10 in vertebrate tissues, its functions at the organismal level remain largely unknown. We report here the generation of KO-first (Myo10 tm1a/tm1a ), floxed (Myo10 tm1c/tm1c ), and KO mice (Myo10 tm1d/tm1d ). Complete knockout of Myo10 is semi lethal, with over half of homozygous KO embryos exhibiting exencephaly, a severe defect in neural tube closure. All Myo10 KO mice that survive birth exhibit a white belly spot, all have persistent fetal vasculature in the eye, and ~50% have webbed digits. Myo10 KO mice that survive birth can breed and produce litters of KO embryos, demonstrating that Myo10 is not absolutely essential for mitosis, meiosis, adult survival, or fertility. KO-first mice and an independent spontaneous deletion (Myo10 m1J/m1J ) exhibit the same core phenotypes. During retinal angiogenesis, KO mice exhibit a ~50% decrease in endothelial filopodia, demonstrating that Myo10 is required to form normal numbers of filopodia in vivo. The Myo10 mice generated here demonstrate that Myo10 has important functions in mammalian development and provide key tools for defining the functions of Myo10 in vivo. PMID- 29229983 TI - Annotation-free quantification of RNA splicing using LeafCutter. AB - The excision of introns from pre-mRNA is an essential step in mRNA processing. We developed LeafCutter to study sample and population variation in intron splicing. LeafCutter identifies variable splicing events from short-read RNA-seq data and finds events of high complexity. Our approach obviates the need for transcript annotations and circumvents the challenges in estimating relative isoform or exon usage in complex splicing events. LeafCutter can be used both to detect differential splicing between sample groups and to map splicing quantitative trait loci (sQTLs). Compared with contemporary methods, our approach identified 1.4-2.1 times more sQTLs, many of which helped us ascribe molecular effects to disease-associated variants. Transcriptome-wide associations between LeafCutter intron quantifications and 40 complex traits increased the number of associated disease genes at a 5% false discovery rate by an average of 2.1-fold compared with that detected through the use of gene expression levels alone. LeafCutter is fast, scalable, easy to use, and available online. PMID- 29229984 TI - Molecular and functional variation in iPSC-derived sensory neurons. AB - Induced pluripotent stem cells (iPSCs), and cells derived from them, have become key tools for modeling biological processes, particularly in cell types that are difficult to obtain from living donors. Here we present a map of regulatory variants in iPSC-derived neurons, based on 123 differentiations of iPSCs to a sensory neuronal fate. Gene expression was more variable across cultures than in primary dorsal root ganglion, particularly for genes related to nervous system development. Using single-cell RNA-sequencing, we found that the number of neuronal versus contaminating cells was influenced by iPSC culture conditions before differentiation. Despite high differentiation-induced variability, our allele-specific method detected thousands of quantitative trait loci (QTLs) that influenced gene expression, chromatin accessibility, and RNA splicing. On the basis of these detected QTLs, we estimate that recall-by-genotype studies that use iPSC-derived cells will require cells from at least 20-80 individuals to detect the effects of regulatory variants with moderately large effect sizes. PMID- 29229985 TI - Circulating CCL20 as a New Biomarker of Abdominal Aortic Aneurysm. AB - Autoimmunity appears to play a role in abdominal aortic aneurysm (AAA) pathology. Although the chemokine CCL20 has been involved in autoimmune diseases, its relationship with the pathogenesis of AAA is unclear. We investigated CCL20 expression in AAA and evaluated it as a potential biomarker for AAA. CCL20 was measured in plasma of AAA patients (n = 96), atherosclerotic disease (AD) patients (n = 28) and controls (n = 45). AAA presence was associated with higher plasma levels of CCL20 after adjustments for confounders in the linear regression analysis. Diagnostic performance of plasma CCL20 was assessed by ROC curve analysis, AUC 0.768 (CI:0.678-0.858; p<0.001). Classification and regression tree analysis classified patients into two CCL20 plasma level groups. The high-CCL20 group had a higher number of AAA than the low-CCL20 group (91% vs 54.3%, p< 0.001). mRNA of CCL20 and its receptor CCR6 were higher in AAA (n = 89) than in control aortas (n = 17, p<0.001). A positive correlation was found between both mRNA in controls (R = 0674; p = 0.003), but not in AAA. Immunohistochemistry showed that CCR6 and CCL20 colocalized in the media and endothelial cells. Infiltrating leukocytes immunostained for both proteins but only colocalized in some of them. Our data shows that CCL20 is increased in AAA and circulating CCL20 is a high sensitive biomarker of AAA. PMID- 29229986 TI - High-fat diet-induced obesity impairs insulin signaling in lungs of allergen challenged mice: Improvement by resveratrol. AB - Insulin resistance plays an important role in obesity-associated asthma exacerbations. Using a murine model of allergic airway inflammation, we evaluated the insulin signaling transmission in lungs of obese compared with lean mice. We further evaluated the effects of the polyphenol resveratrol in the pulmonary insulin signaling. In lean mice, insulin stimulation significantly increased phosphorylations of AKT, insulin receptor substrate 1 (IRS-1) and insulin receptor beta (IRbeta) in lung tissue and isolated bronchi (p < 0.05), which were impaired in obese group. Instead, obese mice displayed increased tyrosine nitrations of AKT, IRbeta and IRS-1 (p < 0.05). Two-week therapy of obese mice with resveratrol (100 mg/kg/day) restored insulin-stimulated AKT, IRS-1 and IRbeta phosphorylations, and simultaneously blunted the tyrosine nitration of these proteins. Additionally, the c-Jun N-terminal kinase (JNK) and inhibitor of NF-kappaB Kinase (IkappaK) phosphorylations were significantly increased in obese group, an effect normalized by resveratrol. In separate experiments, the inducible nitric oxide synthase (iNOS) inhibitor aminoguanidine (20 mg/kg/day, three weeks) mimicked the protective effects exerted by resveratrol in lungs of obese mice. Lungs of obese mice display nitrosative-associated impairment of insulin signaling, which is reversed by resveratrol. Polyphenols may be putative drugs to attenuate asthma exacerbations in obese individuals. PMID- 29229987 TI - Identification of ARNT-regulated BIRC3 as the target factor in cadmium renal toxicity. AB - Cadmium (Cd) is an environmental contaminant that exhibits renal toxicity. The target transcription factors involved in Cd renal toxicity are still unknown. In this study, we demonstrated that Cd decreased the activity of the ARNT transcription factor, and knockdown of ARNT significantly decreased the viability of human proximal tubular HK-2 cells. Microarray analysis in ARNT knockdown cells revealed a decrease in the expression of a number of genes, including a known apoptosis inhibitor, BIRC3, whose gene and protein expression level was also decreased by Cd treatment. Although the BIRC family consists of 8 members, Cd suppressed only BIRC3 gene expression. BIRC3 is known to suppress apoptosis through the inhibition effect on caspase-3. Knockdown of BIRC3 by siRNA as well as Cd treatment increased the level of active caspase-3. Moreover, knockdown of BIRC3 not only triggered cell toxicity and apoptosis but also strengthened Cd toxicity in HK-2 cells. Meanwhile, the activation of caspase-3 by suppression of BIRC3 gene expression was mostly specific to Cd and to proximal tubular cells. These results suggest that Cd induces apoptosis through the inhibition of ARNT regulated BIRC3 in human proximal tubular cells. PMID- 29229988 TI - Dietary Habits and Cooking Methods Could Reduce Avoidable Exposure to PCBs in Maternal and Cord Sera. AB - Polychlorinated biphenyls (PCBs), like other persistent organic pollutants, are accumulating throughout the food chain and pose health threats to humans, especially children and foetuses. There is no protocol for reducing the contamination levels of the PCBs in humans. This study identified food items and cooking methods that reduce serum PCB levels by analysing data collected from the Chiba Study of Mother and Child Health. The sample size was 194 subjects. Serum PCB levels were measured using gas chromatography-electron capture negative ionization quadrupole mass spectrometry. Information on dietary habits was obtained from a brief diet history questionnaire that included questions about food items and cooking methods. Food items were categorized into food groups, and nutrient levels were calculated based on food item consumption. Principal component analysis and lasso regression were used as statistical methods. The analyses of food items and nutrients suggested that food items rich in dietary fibre reduce avoidable exposure to PCBs, as could grilling and deep frying of food, which could reduce avoidable exposure to serum PCBs in mothers and foetuses. (174 words). PMID- 29229989 TI - Necroptotic signaling is primed in Mycobacterium tuberculosis-infected macrophages, but its pathophysiological consequence in disease is restricted. AB - Mixed lineage kinase domain-like (MLKL)-dependent necroptosis is thought to be implicated in the death of mycobacteria-infected macrophages, reportedly allowing escape and dissemination of the microorganism. Given the consequent interest in developing inhibitors of necroptosis to treat Mycobacterium tuberculosis (Mtb) infection, we used human pharmacologic and murine genetic models to definitively establish the pathophysiological role of necroptosis in Mtb infection. We observed that Mtb infection of macrophages remodeled the intracellular signaling landscape by upregulating MLKL, TNFR1, and ZBP1, whilst downregulating cIAP1, thereby establishing a strong pro-necroptotic milieu. However, blocking necroptosis either by deleting Mlkl or inhibiting RIPK1 had no effect on the survival of infected human or murine macrophages. Consistent with this, MLKL deficiency or treatment of humanized mice with the RIPK1 inhibitor Nec-1s did not impact on disease outcomes in vivo, with mice displaying lung histopathology and bacterial burdens indistinguishable from controls. Therefore, although the necroptotic pathway is primed by Mtb infection, macrophage necroptosis is ultimately restricted to mitigate disease pathogenesis. We identified cFLIP upregulation that may promote caspase 8-mediated degradation of CYLD, and other necrosome components, as a possible mechanism abrogating Mtb's capacity to coopt necroptotic signaling. Variability in the capacity of these mechanisms to interfere with necroptosis may influence disease severity and could explain the heterogeneity of Mtb infection and disease. PMID- 29229990 TI - Tumor suppressor p53 links ceramide metabolism to DNA damage response through alkaline ceramidase 2. AB - p53 mediates the DNA damage response (DDR) by regulating the expression of genes implicated in cell cycle arrest, senescence, programmed cell death (PCD), and metabolism. Herein we demonstrate that human alkaline ceramidase 2 (ACER2) is a novel transcriptional target of p53 and that its transactivation by p53 mediates the DDR. We found that p53 overexpression or its activation by ionizing radiation (IR) upregulated ACER2 in cells. Two putative p53 responsive elements (p53REs) were found in its first intron of the ACER2 gene, and Chromatin Immunoprecipitation (ChIP) assays in combination with promoter activity assays demonstrated that these p53REs are the bona fide p53 binding sites that mediate ACER2 transactivation by p53. As ACER2 catalyzes the hydrolysis of ceramides into sphingosine, which in turn is phosphorylated to form sphingosine-1-phosphate (S1P), ACER2 upregulation increased the levels of both sphingosine and S1P while decreasing the levels of ceramides in cells. A moderate upregulation of ACER2 inhibited cell cycle arrest and cellular senescence in response to low-level expression of p53 or low-dose IR by elevating S1P, a pro-proliferative and pro survival bioactive lipid, and/or decreasing ceramides whereas its robust upregulation mediated PCD in response to high-level expression of p53 or high dose IR likely by accumulating cellular sphingosine, a pro-death bioactive lipid. ACER2 is frequently inactivated in various cancers due to its deletion or mutations, and restoring its expression inhibited the growth of tumor xenografts in mice. These results suggest that p53 mediates DDR and exerts its tumor suppressive role in part by regulating the expression of ACER2, which in turn regulates the bioactive sphingolipid lipids. PMID- 29229991 TI - BOK promotes chemical-induced hepatocarcinogenesis in mice. AB - BCL-2-related ovarian killer (BOK) is a conserved and widely expressed BCL-2 family member with sequence homology to pro-apoptotic BAX and BAK, but with poorly understood pathophysiological function. Since several members of the BCL-2 family are critically involved in the regulation of hepatocellular apoptosis and carcinogenesis we aimed to establish whether loss of BOK affects diethylnitrosamine (DEN)-induced hepatocarcinogenesis in mice. Short-term exposure to DEN lead to upregulation of BOK mRNA and protein in the liver. Of note, induction of CHOP and the pro-apoptotic BH3-only proteins PUMA and BIM by DEN was strongly reduced in the absence of BOK. Accordingly, Bok -/- mice were significantly protected from DEN-induced acute hepatocellular apoptosis and associated inflammation. As a consequence, Bok -/- animals were partially protected against chemical-induced hepatocarcinogenesis showing fewer and, surprisingly, also smaller tumors than WT controls. Gene expression profiling revealed that downregulation of BOK results in upregulation of genes involved in cell cycle arrest. Bok -/- hepatocellular carcinoma (HCC) displayed higher expression levels of the cyclin kinase inhibitors p19INK4d and p21cip1. Accordingly, hepatocellular carcinoma in Bok -/- animals, BOK-deficient human HCC cell lines, as well as non-transformed cells, showed significantly less proliferation than BOK-proficient controls. We conclude that BOK is induced by DEN, contributes to DEN-induced hepatocellular apoptosis and resulting hepatocarcinogenesis. In line with its previously reported predominant localization at the endoplasmic reticulum, our findings support a role of BOK that links the cell cycle and cell death machineries upstream of mitochondrial damage. PMID- 29229992 TI - miRNA-21 ablation protects against liver injury and necroptosis in cholestasis. AB - Inhibition of microRNA-21 (miR-21) prevents necroptosis in the mouse pancreas. Necroptosis contributes to hepatic necro-inflammation in the common bile duct ligation (BDL) murine model. We aimed to evaluate the role of miR-21 in mediating deleterious processes associated with cholestasis. Mechanistic studies established a functional link between miR-21 and necroptosis through cyclin dependent kinase 2-associated protein 1 (CDK2AP1). miR-21 expression increased in the liver of primary biliary cholangitis (PBC) patients and BDL wild-type (WT) mice at both 3 and 14 days. Notably, under BDL, miR-21 -/- mice displayed decreased liver injury markers in serum compared with WT mice, accompanied by reduced hepatocellular degeneration, oxidative stress and fibrosis. Hallmarks of necroptosis were decreased in the liver of BDL miR-21 -/- mice, via relieved repression of CDK2AP1. Further, miR-21 -/- mice displayed improved adaptive response of bile acid homeostasis. In conclusion, miR-21 ablation ameliorates liver damage and necroptosis in BDL mice. Inhibition of miR-21 should arise as a promising approach to treat cholestasis. PMID- 29229993 TI - Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL/Greatwall in breast cancer. AB - PP2A is a major tumor suppressor whose inactivation is frequently found in a wide spectrum of human tumors. In particular, deletion or epigenetic silencing of genes encoding the B55 family of PP2A regulatory subunits is a common feature of breast cancer cells. A key player in the regulation of PP2A/B55 phosphatase complexes is the cell cycle kinase MASTL (also known as Greatwall). During cell division, inhibition of PP2A-B55 by MASTL is required to maintain the mitotic state, whereas inactivation of MASTL and PP2A reactivation is required for mitotic exit. Despite its critical role in cell cycle progression in multiple organisms, its relevance as a therapeutic target in human cancer and its dependence of PP2A activity is mostly unknown. Here we show that MASTL overexpression predicts poor survival and shows prognostic value in breast cancer patients. MASTL knockdown or knockout using RNA interference or CRISPR/Cas9 systems impairs proliferation of a subset of breast cancer cells. The proliferative function of MASTL in these tumor cells requires its kinase activity and the presence of PP2A-B55 complexes. By using a new inducible CRISPR/Cas9 system in breast cancer cells, we show that genetic ablation of MASTL displays a significant therapeutic effect in vivo. All together, these data suggest that the PP2A inhibitory kinase MASTL may have both prognostic and therapeutic value in human breast cancer. PMID- 29229994 TI - Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion. AB - Cells undergoing Bax/Bak-mediated apoptosis exhibit signs of autophagy, but how it is activated and its significance is unknown. By directly activating Bax/Bak with BH3-only proteins or BH3 mimetic compounds, we demonstrate that mitochondrial damage correlated with a rapid increase in intracellular [AMP]/[ATP], phosphorylation of 5' AMP-activated protein kinase (AMPK), and activation of unc-51 like autophagy activating kinase 1 (ULK1). Consequently, autophagic flux was triggered early in the apoptotic pathway, as activation of the apoptosome and caspases were not necessary for its induction. Bax/Bak triggered autophagy resulted in the clearance of damaged mitochondria in an ATG5/7-dependent manner that did not require Parkin. Importantly, Bax/Bak mediated autophagy inhibited the secretion of the pro-inflammatory cytokine interferon-beta (IFN-beta) produced in response to mitochondrial damage, but not another cytokine interleukin-6 (IL-6). These findings show that Bax/Bak stimulated autophagy is essential for ensuring immunological silence during apoptosis. PMID- 29229995 TI - Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability. AB - Lysyl oxidase-like 3 (LOXL3) is a member of the lysyl oxidase family comprising multifunctional enzymes with depicted roles in extracellular matrix maturation, tumorigenesis, and metastasis. In silico expression analyses followed by experimental validation in a comprehensive cohort of human cell lines revealed a significant upregulation of LOXL3 in human melanoma. We show that LOXL3 silencing impairs cell proliferation and triggers apoptosis in various melanoma cell lines. Further supporting a pro-oncogenic role in melanoma, LOXL3 favors tumor growth in vivo and cooperates with oncogenic BRAF in melanocyte transformation. Upon LOXL3 depletion, melanoma cells display a faulty DNA damage response (DDR), characterized by ATM checkpoint activation and inefficient ATR activation leading to the accumulation of double-strand breaks (DSBs) and aberrant mitosis. Consistent with these findings, LOXL3 binds to proteins involved in the maintenance of genome integrity, in particular BRCA2 and MSH2, whose levels dramatically decrease upon LOXL3 depletion. Moreover, LOXL3 is required for efficient DSB repair in melanoma cells. Our results reveal an unexpected role for LOXL3 in the control of genome stability and melanoma progression, exposing its potential as a novel therapeutic target in malignant melanoma, a very aggressive condition yet in need for more effective treatment options. PMID- 29229996 TI - RAB37 interacts directly with ATG5 and promotes autophagosome formation via regulating ATG5-12-16 complex assembly. AB - Intracellular membrane trafficking is essential for eukaryotic cell existence. Here, we show that RAB37 activation through GTP binding recruits ATG5-12 to isolation membrane and promotes autophagosome formation through the ATG5-ATG12 ATG16L1 complex. RAB37 is localized on the isolation membrane. It can bind directly with ATG5 and promotes formation of the ATG5-12-16 complex. Mutation analysis reveals that GTP-bound RAB37 exhibits an enhanced interaction with ATG5 12 and GDP-stabilised mutation impairs the interaction. RAB37 promotes ATG5-12 interaction with ATG16L1, thus facilitates lipidation of LC3B in a GTP-dependent manner to enhance autophagy. Notably, ablation of RAB37 expression affects the complex formation and decreases autophagy, whereas forced RAB37 expression promotes autophagy and also suppresses cell proliferation. Our results demonstrate a role of RAB37 in autophagosome formation through a molecular connection of RAB37, ATG5-12, ATG16L1 up to LC3B, suggesting an organiser role of RAB37 during autophagosomal membrane biogenesis. These findings have broad implications for understanding the role of RAB vesicle transport in autophagy and cancer. PMID- 29229997 TI - SPLICS: a split green fluorescent protein-based contact site sensor for narrow and wide heterotypic organelle juxtaposition. AB - Contact sites are discrete areas of organelle proximity that coordinate essential physiological processes across membranes, including Ca2+ signaling, lipid biosynthesis, apoptosis, and autophagy. However, tools to easily image inter organelle proximity over a range of distances in living cells and in vivo are lacking. Here we report a split-GFP-based contact site sensor (SPLICS) engineered to fluoresce when organelles are in proximity. Two SPLICS versions efficiently measured narrow (8-10 nm) and wide (40-50 nm) juxtapositions between endoplasmic reticulum and mitochondria, documenting the existence of at least two types of contact sites in human cells. Narrow and wide ER-mitochondria contact sites responded differently to starvation, ER stress, mitochondrial shape modifications, and changes in the levels of modulators of ER-mitochondria juxtaposition. SPLICS detected contact sites in soma and axons of D. rerio Rohon Beard (RB) sensory neurons in vivo, extending its use to analyses of organelle juxtaposition in the whole animal. PMID- 29229999 TI - Heme accumulation in endothelial cells impairs angiogenesis by triggering paraptosis. AB - Heme is required for cell respiration and survival. Nevertheless, its intracellular levels need to be finely regulated to avoid heme excess, which may catalyze the production of reactive oxygen species (ROS) and promote cell death. Here, we show that alteration of heme homeostasis in endothelial cells due to the loss of the heme exporter FLVCR1a, results in impaired angiogenesis. In vitro, FLVCR1a silencing in endothelial cells causes defective tubulogenesis and poor viability due to intracellular heme accumulation. Consistently, endothelial specific Flvcr1a knockout mice show aberrant angiogenesis responsible for hemorrhages and embryonic lethality. Importantly, we demonstrate that impaired heme export leads to endothelial cell death by paraptosis and provide evidence that endoplasmic reticulum (ER) stress precedes heme-induced paraptosis. These findings highlight a crucial role for the cytosolic heme pool in the control of endothelial cell survival and in the regulation of the angiogenic process. Interfering with endothelial heme export represents a valuable model for a deeper understanding of the molecular mechanisms underlying heme-triggered paraptosis and, in the future, might provide a novel tool for the modulation of angiogenesis in pathophysiologic conditions. PMID- 29230000 TI - Snail mediates crosstalk between TGFbeta and LXRalpha in hepatocellular carcinoma. AB - Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor beta (TGFbeta) and liver X receptor alpha (LXRalpha) pathways. TGFbeta is known to promote cytostatic and pro-apoptotic responses in HCC, and to facilitate mesenchymal differentiation. We here demonstrate that stimulation of the nuclear LXRalpha receptor system by physiological and clinically useful agonists controls the HCC response to TGFbeta. Specifically, LXRalpha activation antagonizes the mesenchymal, reactive oxygen species and pro-apoptotic responses to TGFbeta and the mesenchymal transcription factor Snail mediates this crosstalk. In contrast, LXRalpha activation and TGFbeta cooperate in enforcing cytostasis in HCC, which preserves their epithelial features. LXRalpha influences Snail expression transcriptionally, acting on the Snail promoter. These findings propose that clinically used LXR agonists may find further application to the treatment of aggressive, mesenchymal HCCs, whose progression is chronically dependent on autocrine or paracrine TGFbeta. PMID- 29230001 TI - Diacylglycerol triggers Rim101 pathway-dependent necrosis in yeast: a model for lipotoxicity. AB - The loss of lipid homeostasis can lead to lipid overload and is associated with a variety of disease states. However, little is known as to how the disruption of lipid regulation or lipid overload affects cell survival. In this study we investigated how excess diacylglycerol (DG), a cardinal metabolite suspected to mediate lipotoxicity, compromises the survival of yeast cells. We reveal that increased DG achieved by either genetic manipulation or pharmacological administration of 1,2-dioctanoyl-sn-glycerol (DOG) triggers necrotic cell death. The toxic effects of DG are linked to glucose metabolism and require a functional Rim101 signaling cascade involving the Rim21-dependent sensing complex and the activation of a calpain-like protease. The Rim101 cascade is an established pathway that triggers a transcriptional response to alkaline or lipid stress. We propose that the Rim101 pathway senses DG-induced lipid perturbation and conducts a signaling response that either facilitates cellular adaptation or triggers lipotoxic cell death. Using established models of lipotoxicity, i.e., high-fat diet in Drosophila and palmitic acid administration in cultured human endothelial cells, we present evidence that the core mechanism underlying this calpain dependent lipotoxic cell death pathway is phylogenetically conserved. PMID- 29230002 TI - Deficiency in interferon type 1 receptor improves definitive erythropoiesis in Klf1 null mice. AB - A key regulatory gene in definitive erythropoiesis is the transcription factor Kruppel-like factor 1 (Klf1). Klf1 null mice die in utero by day 15.5 (E15.5) due to impaired definitive erythropoiesis and severe anemia. Definitive erythropoiesis takes place in erythroblastic islands in mammals. Erythroblastic islands are formed by a central macrophage (Central Macrophage of Erythroblastic Island, CMEI) surrounded by maturating erythroblasts. Interferon-beta (IFN-beta) is activated in the fetal liver's CMEI of Klf1 null mice. The inhibitory effect of IFN-beta on erythropoiesis is known and, therefore, we speculated that IFN beta could have contributed to the impairment of definitive erythropoiesis in Klf1 knockout (KO) mice fetal liver. To validate this hypothesis, in this work we determined whether the inactivation of type I interferon receptor (Ifnar1) would ameliorate the phenotype of Klf1 KO mice by improving the lethal anemia. Our results show a prolonged survival of Klf1/Ifnar1 double KO embryos, with an improvement of the definitive erythropoiesis and erythroblast enucleation, together with a longer lifespan of CMEI in the fetal liver and also a restoration of the apoptotic program. Our data indicate that the cytotoxic effect of IFN-beta activation in CMEI contribute to the impairment of definitive erythropoiesis associated with Klf1 deprivation. PMID- 29230003 TI - Pulse pressure, arterial stiffening, and the efficacy of renin-angiotensin system inhibitor combinations. PMID- 29229998 TI - Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases. AB - Neurodegenerative diseases are a spectrum of chronic, debilitating disorders characterised by the progressive degeneration and death of neurons. Mitochondrial dysfunction has been implicated in most neurodegenerative diseases, but in many instances it is unclear whether such dysfunction is a cause or an effect of the underlying pathology, and whether it represents a viable therapeutic target. It is therefore imperative to utilise and optimise cellular models and experimental techniques appropriate to determine the contribution of mitochondrial dysfunction to neurodegenerative disease phenotypes. In this consensus article, we collate details on and discuss pitfalls of existing experimental approaches to assess mitochondrial function in in vitro cellular models of neurodegenerative diseases, including specific protocols for the measurement of oxygen consumption rate in primary neuron cultures, and single-neuron, time-lapse fluorescence imaging of the mitochondrial membrane potential and mitochondrial NAD(P)H. As part of the Cellular Bioenergetics of Neurodegenerative Diseases (CeBioND) consortium ( www.cebiond.org ), we are performing cross-disease analyses to identify common and distinct molecular mechanisms involved in mitochondrial bioenergetic dysfunction in cellular models of Alzheimer's, Parkinson's, and Huntington's diseases. Here we provide detailed guidelines and protocols as standardised across the five collaborating laboratories of the CeBioND consortium, with additional contributions from other experts in the field. PMID- 29230004 TI - Prognostic impact of baseline urinary albumin excretion rate in patients with resistant hypertension: a prospective cohort study. AB - Moderately increased albuminuria, defined as urinary albumin excretion rate (UAER) between 30 and 300-mg/24-h is a well-known cardiovascular risk factor, especially in diabetic and hypertensive patients. This study aim to analyze the prognostic value of baseline UAER in a still understudied group, patients with resistant hypertension (RHT). This is a prospective observational study, which had enrolled 1048 outpatients with RHT, who were submitted to a clinical laboratory assessment and ambulatory blood pressure monitoring (ABPM) during the follow-up. Primary endpoints were a composite of fatal and non-fatal cardiovascular events, all-cause mortality and cardiovascular mortality. Survival analysis by multiple Cox regression assessed the associations among endpoints, baseline UAER, glomerular filtration rate (GFR), and ABPM control. After a mean 7.5 years follow-up, 233 patients died, 120 from cardiac death; 215 cardiovascular events occurred, 90 strokes and 116 coronary diseases. UAER above 30-mg/24-h increased above 40% the risk of fatal and non-fatal cardiovascular events, and of all-cause mortality. At these UAER levels, secondary outcomes were associated to increased risk of stroke and risk of end-stage renal disease, but did not affect coronary events. Both the GFR below 60-mL/min and uncontrolled ABPM were related to nearly two-fold raised risk of fatal and non-fatal cardiovascular events, when coupled with UAER above 30-mg/24-h. In conclusion, moderately increased albuminuria predicts cardiovascular events and all-cause mortality in RHT, and its prognostic impact is enhanced in association with a GFR under 60-mL/min and uncontrolled baseline ABPM. PMID- 29230005 TI - Prevalence, treatment patterns, and risk factors of hypertension and pre hypertension among Bangladeshi adults. AB - In Bangladesh, morbidity and mortality due to non-communicable diseases (NCDs) has increased over the last few decades. Hypertension is an important risk factor for NCDs, specifically cardiovascular disease. The objective of this study was to assess prevalence and risk factors for hypertension and pre-hypertension among adults in Bangladesh. Data for this analysis were collected during the national NCD Risk Factor Survey of Bangladesh conducted in 2010 from a representative sample of men and women, aged 25 years or above. The survey adopted a multistage, geographically clustered, probability-based sampling approach. WHO STEPS questionnaire was used to collect data on demographics, behavioral risk factors, and physical measurements. Overall, 20% of the study population were hypertensive at study measurement. The prevalence of hypertension increased with age and body mass index (BMI). Twelve percent of the population were previously diagnosed with hypertension. Among these individuals, nearly half were not taking any medications to control their hypertension. Additionally, the prevalence of pre hypertension was 43%, with higher levels among males, older age groups, and those with higher education, higher wealth index and high BMI. Predictors of hypertension, included older age, high BMI, and diabetes comorbidity. Based on this study, we estimate that 1 out of 5 Bangladeshi adults have hypertension. The risk of hypertension increases with older age and high BMI. Additionally, prevalence of pre-hypertension is high in Bangladesh in both rural and urban areas. Findings from this study can be used to inform public health programming to control the spread of NCDs in Bangladesh. PMID- 29230006 TI - Platinum sensitivity in metastatic prostate cancer: does histology matter? AB - BACKGROUND: Platinum-based chemotherapy is effective in men with neuroendocrine prostate cancer (NEPC), but it is unclear whether histology (adenocarcinoma vs. non-adenocarcinoma NEPC variants) is predictive of platinum sensitivity. Given that NEPC exists as a spectrum, there may be men with adenocarcinoma who might benefit from platinum chemotherapy, particularly those men with DNA repair defects. METHODS: This was a retrospective study of all of the men seen at Duke University since 2005 who had metastatic castration-resistant prostate cancer (mCRPC) and were treated with a platinum agent. Data surrounding clinical features, histology, imaging, safety, and neuroendocrine transformation were collected. Scans were re-reviewed using RECIST v1.1 criteria to estimate responses as well as calculate radiographic progression-free survival (rPFS). RESULTS: A database search identified 73 men with mCRPC treated with cisplatin, carboplatin, or oxaliplatin. There were three men with primary NEPC and small cell prostate cancer, and 14 with a NEPC transformation. In the first-line setting, 10 (63%) men with NEPC had a partial response (PR) compared with 14 (29%) of the men with adenocarcinoma (p = 0.017), with a median rPFS of 5.1 mo (3.1-7.8) and 4.3 mo (3.0-5.2 mo), respectively. The median overall survival was 8.5 mo (6.4-20.1 mo) for men with NEPC compared to 10.0 mo (8.0-14.4) in men with adenocarcinoma. Prostate-specific antigen (PSA) declines meeting >30%, >50%, and >90% criteria from baseline were observed in 64/57/29% of NEPC patients (n = 14) treated with platinum chemotherapy vs. 48/30/14% of men with prostate adenocarcinoma (n = 50), respectively. CONCLUSIONS: This study suggests that NEPC histology enriches for platinum sensitivity, but that an important minority group (20-30%) of men with adenocarcinoma have a clinical benefit with platinum-based chemotherapy. Molecular predictors, such as germline or somatic mutations in DNA repair enzymes, should be evaluated for platinum responsiveness. PMID- 29230007 TI - Elevated preoperative neutrophil-lymphocyte ratio predicts upgrading at radical prostatectomy. AB - BACKGROUND: Neutrophil-lymphocyte ratio (NLR) is a widely used, representative marker of systemic inflammatory response within the body. NLR can be calculated from simple, inexpensive peripheral blood samples. High NLR is a negative prognostic factor in a variety of malignancies including urological tumors. In this study, we aim to assess the prognostic value of preoperative neutrophil- lymphocyte ratio (NLR) in patients treated with radical prostatectomy (RP) for localized prostate cancer (PCa). MATERIALS AND METHODS: Records of 7426 patients were retrospectively analyzed from prospectively collected datasets. A cut-off point of 3 was taken for NLR based on ROC analyses and previous literature. RESULTS: 23% (n = 1707) of patients had an NLR of >=3. Patients with NLR >=3 were more likely to harbor unfavorable pathological features such as higher biopsy Gleason score (GS), higher RP GS, higher rates of extra capsular extension, nodal involvement (all p < 0.001) and positive surgical margins (p = 0.002). On multivariable analyses, NLR >= 3 was associated with higher RP GS (OR 2.32; p < 0.001), seminal vesicle invasion (OR 1.60; p < 0.001) and nodal involvement (OR 1.43; p < 0.001). On multivariable analyses, NLR >= 3 was significantly associated with GS upgrading at RP (OR 1.39 p < 0.001). During a median follow up of 45 months, NLR >= 3 was associated with higher risk of BCR (p = 0.001). However, on multivariable Cox regression analysis such association was not shown (HR 0.86; p = 0.4). CONCLUSION: Preoperative NLR >= 3 was associated with aggressive PCa, such as upgrading at RP. Even though its effect on clinical decision making seems to be limited when all clinical and pathological confounders are taken into account, preoperative NLR may still be useful in selected patients to identify aggressive PCa helping patient selection for active surveillance protocols. Conversely, it does not predict BCR when adjusted for the effect of pathological features. PMID- 29230008 TI - Positive margin length and highest Gleason grade of tumor at the margin predict for biochemical recurrence after radical prostatectomy in patients with organ confined prostate cancer. AB - BACKGROUND: To evaluate the pathologic features after radical prostatectomy to determine if the length of positive surgical margin (PSM) and the highest Gleason grade within the tumor at the PSM could risk stratify patients for biochemical recurrence (BCR). METHODS: We performed a retrospective, matched, cohort study to identify patients with pathologically organ-confined (pT2) tumors and negative nodes (pN0/Nx), receiving no adjuvant therapy. Specimens underwent single pathologist review. BCR-free survival was estimated using the Kaplan-Meier method and compared between subgroups using two-sided log-rank test. Using Classification and Regression Tree analysis (CART), we identified an optimal cutoff for the PSM length which differentiated risk for BCR. Cox proportional hazards regression models were fit to assess the association between variables and BCR-free survival. RESULTS: Two-hundred PSM patients were matched to 200 patients with negative surgical margins (NSM). Median follow-up was 64 months. 5 year BCR-free survival was 90% (95% CI 84-97%) in the NSM group and 70% (95% CI 63-79%) in the PSM group. There was an increased risk of BCR with any PSM. Multivariable analysis demonstrated an association with length of PSM ( > 1 mm vs. <= 1 mm, HR 2.29; 95% CI 1.2-4.5) and having a highest Gleason grade of the cancer focus at the margin >= 4 (HR 6.8; 95% CI 1.6-29). CONCLUSIONS: We demonstrated that patients with pathologic T2 tumors with PSM > 1 mm or a Gleason grade of tumor focus at the margin >= 4 are at elevated risk for BCR. However, this study suggests that patients with pT2 tumors with positive surgical margins have a relatively low risk of biochemical recurrence and adjuvant radiation may be over treating this sub population. The subsets at greatest risk for BCR may benefit from more frequent PSA monitoring to direct salvage therapies. PMID- 29230009 TI - The use of PET/CT in prostate cancer. AB - BACKGROUND: Positron emission tomography/computed tomography (PET/CT) has recently emerged as a promising diagnostic imaging platform for prostate cancer. Several radiolabelled tracers have demonstrated efficacy for cancer detection in various clinical settings. In this review, we aim to illustrate the diverse use of PET/CT with different tracers for the detection of prostate cancer. METHODS: We searched MEDLINE using the terms 'prostate cancer', 'PET', 'PET/CT' and 'PET/MR'). The current review was limited to 18F-NaF PET/CT, choline-based PET/CT, fluciclovine PET/CT and PSMA-targeted PET/CT, as these modalities have been the most widely adopted. RESULTS: NaF PET/CT has shown efficacy in detecting bone metastases with high sensitivity, but relatively low specificity. Currently, choline PET/CT has been the most extensively studied modality. Although having superior specificity, choline PET/CT suffers from low sensitivity, especially at low PSA levels. Nevertheless, choline PET/CT was found to significantly improve upon conventional imaging modalities (CIM) in the detection of metastatic lesions at biochemical recurrence (BCR). Newer methods using fluciclovine and PSMA targeted radiotracers have preliminarily demonstrated great promise in primary and recurrent staging of prostate cancer. However, their superior efficacy awaits confirmation in larger series. CONCLUSIONS: PET/CT has emerged as a promising staging modality for both primary and recurrent prostate cancer. Newer tracers have increased detection accuracies for small, incipient metastatic foci. The clinical implications of these occult PET/CT detected disease foci require organized evaluation. Efforts should be aimed at defining their natural history as well as responsiveness and impact of metastasis-directed therapy. PMID- 29230010 TI - Serotype and virulence genes of Klebsiella pneumoniae isolated from mink and its pathogenesis in mice and mink. AB - In the study, 15 K. pneumoniae strains were isolated from the mink experiencing respiratory distress in mideastern Shandong province, China, and the prevalence of K. pneumoniae in the sampled mink was 11.9% (15/126). Fourteen (93.33%) of the 15 K. pneumoniae isolates were identified as serotype K2 and hypermucoviscosity phenotype. The 12 virulence-associated genes of the K. pneumoniae isolates were tested. The prevalence of the wabG gene for the isolates were 100% (15/15), the ureA gene 100% (15/15), the rmpA gene 93.33% (14/15), the aerobactin gene 93.33% (14/15), the uge gene 93.33% (14/15), the IucB gene 80% (12/15) and the ybtA gene 13.33% (2/15). But the other five genes, fim, iroNB, wcaG, alls and kfuBC, gave a negative PCR reaction in the 15 isolates, respectively. The animal experiments using K. pneumoniae-SD-12 and K. pneumoniae-SD-21 demonstrated that the serotype K2 was high virulence for mice and mink. These finding implied there exist potential threat that K. pneumoniae pathogens could transmit to human, especially the fur animal farm workers and residents lived near the fur animal farms. Therefore, the etiology and epidemiological surveillance of K. pneumoniae in mink should be strengthened for people's public health. PMID- 29230011 TI - Pairing sound with vagus nerve stimulation modulates cortical synchrony and phase coherence in tinnitus: An exploratory retrospective study. AB - Recent research has shown that vagus nerve stimulation (VNS) paired with tones or with rehabilitative training can help patients to achieve reductions in tinnitus perception or to expedite motor rehabilitation after suffering an ischemic stroke. The rationale behind this treatment is that VNS paired with experience can drive neural plasticity in a controlled and therapeutic direction. Since previous studies observed that gamma activity in the auditory cortex is correlated with tinnitus loudness, we assessed resting-state source-localized EEG before and after one to three months of VNS-tone pairing in chronic tinnitus patients. VNS-tone pairing reduced gamma band activity in left auditory cortex. VNS-tone pairing also reduced the phase coherence between the auditory cortex and areas associated with tinnitus distress, including the cingulate cortex. These results support the hypothesis that VNS-tone pairing can direct therapeutic neural plasticity. Targeted plasticity therapy might also be adapted to treat other conditions characterized by hypersynchronous neural activity. PMID- 29230012 TI - Estimation of immune cell content in tumour tissue using single-cell RNA-seq data. AB - As interactions between the immune system and tumour cells are governed by a complex network of cell-cell interactions, knowing the specific immune cell composition of a solid tumour may be essential to predict a patient's response to immunotherapy. Here, we analyse in depth how to derive the cellular composition of a solid tumour from bulk gene expression data by mathematical deconvolution, using indication-specific and cell type-specific reference gene expression profiles (RGEPs) from tumour-derived single-cell RNA sequencing data. We demonstrate that tumour-derived RGEPs are essential for the successful deconvolution and that RGEPs from peripheral blood are insufficient. We distinguish nine major cell types, as well as three T cell subtypes. Using the tumour-derived RGEPs, we can estimate the content of many tumours associated immune and stromal cell types, their therapeutically relevant ratios, as well as an improved gene expression profile of the malignant cells. PMID- 29230014 TI - Putting gene essentiality into context. PMID- 29230013 TI - Artemisia annua extract prevents ovariectomy-induced bone loss by blocking receptor activator of nuclear factor kappa-B ligand-induced differentiation of osteoclasts. AB - The activities of osteoclasts and osteoblasts are balanced to maintain normal bone density. Many pathological conditions cause osteoclastic bone resorption in excess of osteoblastic bone formation, resulting in osteoporosis. We found that oral administration of Artemisia annua ethanol extract (AaE) or major components, artemisinin and arteannuin B, to ovariectomized (OVX) mice prevented bone loss, as verified by examining three-dimensional images and bone morphometric parameters derived from microcomputed tomography analysis, as well as serum levels of bone turnover markers and proinflammatory cytokines. The administered doses were not toxic to the liver or kidney and showed promising effects that were comparable to those of 17beta-estradiol treatment. At non-cytotoxic concentrations, AaE and active components, artemisinin, artemisinic acid, and arteannuin B, potently inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis and the formation of osteoclast mediated resorption pits. Furthermore, AaE, artemisinin, and arteannuin B remarkably reduced the expression of the c-Fos and NFATc1 transcription factors, which play critical roles in RANKL-induced osteoclast differentiation. Taken together, the in vivo anti-osteoporotic activity of AaE may be derived from the anti-osteoclastic and anti-bone resorptive activities of its active components. AaE has beneficial applications for the prevention and inhibition of osteoporosis and osteoclast-mediated bone diseases. PMID- 29230015 TI - A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival. AB - The unfolded protein response (UPR) is a stress-activated signalling pathway that regulates cell proliferation, metabolism and survival. The circadian clock coordinates metabolism and signal transduction with light/dark cycles. We explore how UPR signalling interfaces with the circadian clock. UPR activation induces a 10 h phase shift in circadian oscillations through induction of miR-211, a PERK inducible microRNA that transiently suppresses both Bmal1 and Clock, core circadian regulators. Molecular investigation reveals that miR-211 directly regulates Bmal1 and Clock via distinct mechanisms. Suppression of Bmal1 and Clock has the anticipated impact on expression of select circadian genes, but we also find that repression of Bmal1 is essential for UPR-dependent inhibition of protein synthesis and cell adaptation to stresses that disrupt endoplasmic reticulum homeostasis. Our data demonstrate that c-Myc-dependent activation of the UPR inhibits Bmal1 in Burkitt's lymphoma, thereby suppressing both circadian oscillation and ongoing protein synthesis to facilitate tumour progression. PMID- 29230016 TI - Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification. AB - To establish and maintain organ structure and function, tissues need to balance stem cell proliferation and differentiation rates and coordinate cell fate with position. By quantifying and modelling tissue stress and deformation in the mammalian epidermis, we find that this balance is coordinated through local mechanical forces generated by cell division and delamination. Proliferation within the basal stem/progenitor layer, which displays features of a jammed, solid-like state, leads to crowding, thereby locally distorting cell shape and stress distribution. The resulting decrease in cortical tension and increased cell-cell adhesion trigger differentiation and subsequent delamination, reinstating basal cell layer density. After delamination, cells establish a high tension state as they increase myosin II activity and convert to E-cadherin dominated adhesion, thereby reinforcing the boundary between basal and suprabasal layers. Our results uncover how biomechanical signalling integrates single-cell behaviours to couple proliferation, cell fate and positioning to generate a multilayered tissue. PMID- 29230017 TI - Systematic analysis of ribophagy in human cells reveals bystander flux during selective autophagy. AB - Ribosomes are abundant cellular machines 1,2 that are regulated by assembly, supernumerary subunit turnover and nascent chain quality control mechanisms 1-5 . Moreover, nitrogen starvation in yeast has been reported to promote selective ribosome delivery to the vacuole in an autophagy conjugation system dependent manner, a process called 'ribophagy' 6,7 . However, whether ribophagy in mammals is selective or regulated is unclear. Using Ribo-Keima flux reporters, we find that starvation or mTOR inhibition promotes VPS34-dependent ribophagic flux, which, unlike yeast, is largely independent of ATG8 conjugation and occurs concomitantly with other cytosolic protein autophagic flux reporters 8,9 . Ribophagic flux was not induced upon inhibition of translational elongation or nascent chain uncoupling, but was induced in a comparatively selective manner under proteotoxic stress induced by arsenite 10 or chromosome mis-segregation 11 , dependent upon VPS34 and ATG8 conjugation. Unexpectedly, agents typically used to induce selective autophagy also promoted increased ribosome and cytosolic protein reporter flux, suggesting significant bulk or 'bystander' autophagy during what is often considered selective autophagy 12,13 . These results emphasize the importance of monitoring non-specific cargo flux when assessing selective autophagy pathways. PMID- 29230018 TI - A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells. AB - CD8+ memory T (Tm) cells are fundamental for protective immunity against infections and cancers 1-5 . Metabolic activities are crucial in controlling memory T-cell homeostasis, but mechanisms linking metabolic signals to memory formation and survival remain elusive. Here we show that CD8+ Tm cells markedly upregulate cytosolic phosphoenolpyruvate carboxykinase (Pck1), the hub molecule regulating glycolysis, tricarboxylic acid cycle and gluconeogenesis, to increase glycogenesis via gluconeogenesis. The resultant glycogen is then channelled to glycogenolysis to generate glucose-6-phosphate and the subsequent pentose phosphate pathway (PPP) that generates abundant NADPH, ensuring high levels of reduced glutathione in Tm cells. Abrogation of Pck1-glycogen-PPP decreases GSH/GSSG ratios and increases levels of reactive oxygen species (ROS), leading to impairment of CD8+ Tm formation and maintenance. Importantly, this metabolic regulatory mechanism could be readily translated into more efficient T-cell immunotherapy in mouse tumour models. PMID- 29230019 TI - Metabolic profiling of zebrafish (Danio rerio) embryos by NMR spectroscopy reveals multifaceted toxicity of beta-methylamino-L-alanine (BMAA). AB - beta-methylamino-L-alanine (BMAA) has been linked to several interrelated neurodegenerative diseases. Despite considerable research, specific contributions of BMAA toxicity to neurodegenerative diseases remain to be fully resolved. In the present study, we utilized state-of-the-art high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR), applied to intact zebrafish (Danio rerio) embryos, as a model of vertebrate development, to elucidate changes in metabolic profiles associated with BMAA exposure. Complemented by several alternative analytical approaches (i.e., in vivo visualization and in vitro assay), HRMAS NMR identified robust and dose-dependent effect of BMAA on several relevant metabolic pathways suggesting a multifaceted toxicity of BMAA including: (1) localized production of reactive oxygen species (ROS), in the developing brain, consistent with excitotoxicity; (2) decreased protective capacity against excitotoxicity and oxidative stress including reduced taurine and glutathione; (3) inhibition of several developmentally stereotypical energetic and metabolic transitions, i.e., metabolic reprogramming; and (4) inhibition of lipid biosynthetic pathways. Matrix-assisted laser desorption time-of-flight (MALDI ToF) mass spectrometry further identified specific effects on phospholipids linked to both neural development and neurodegeneration. Taken together, a unified model of the neurodevelopmental toxicity of BMAA in the zebrafish embryo is presented in relation to the potential contribution of BMAA to neurodegenerative disease. PMID- 29230020 TI - SNP co-association and network analyses identify E2F3, KDM5A and BACH2 as key regulators of the bovine milk fatty acid profile. AB - The fatty acid (FA) profile has a considerable impact on the nutritional and technological quality of milk and dairy products. The molecular mechanism underlying the regulation of fat metabolism in bovine mammary gland have been not completely elucidated. We conducted genome-wide association studies (GWAS) across 65 milk FAs and fat percentage in 1,152 Brown Swiss cows. In total, we identified 175 significant single nucleotide polymorphism (SNPs) spanning all chromosomes. Pathway analyses revealed that 12:0 was associated with the greatest number of overrepresented categories/pathways (e.g. mitogen-activated protein kinase (MAPK) activity and protein phosphorylation), suggesting that it might play an important biological role in controlling milk fat composition. An Associated Weight Matrix approach based on SNP co-associations predicted a network of 791 genes related to the milk FA profile, which were involved in several connected molecular pathways (e.g., MAPK, lipid metabolism and hormone signalling) and undetectable through standard GWAS. Analysis of transcription factors and their putative target genes within the network identified BACH2, E2F3 and KDM5A as key regulators of milk FA metabolism. These findings contribute to increasing knowledge of FA metabolism and mammary gland functionality in dairy cows and may be useful in developing targeted breeding practices to improve milk quality. PMID- 29230023 TI - Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD. AB - Stimulant medication has long been effective in treating attention deficit/hyperactivity disorder (ADHD) and is currently the first-line pharmacological treatment for children. Both methylphenidate and amphetamine modulate extracellular catecholamine levels through interaction with dopaminergic, adrenergic and serotonergic system components; it is therefore likely that catecholaminergic molecular components influence the effects of ADHD treatment. Using meta-analysis, we sought to identify predictors of pharmacotherapy to further the clinical implementation of personalized medicine. We identified 36 studies (3647 children) linking the effectiveness of methylphenidate treatment with DNA variants. Pooled-data revealed a statistically significant association between single nucleotide polymorphisms (SNPs) rs1800544 ADRA2A (odds ratio: 1.69; confidence interval: 1.12-2.55), rs4680 COMT (odds ratio (OR): 1.40; confidence interval: 1.04-1.87), rs5569 SLC6A2 (odds ratio: 1.73; confidence interval: 1.26-2.37) and rs28386840 SLC6A2 (odds ratio: 2.93; confidence interval: 1.76-4.90), and, repeat variants variable number tandem repeat (VNTR) 4 DRD4 (odds ratio: 1.66; confidence interval: 1.16-2.37) and VNTR 10 SLC6A3 (odds ratio: 0.74; confidence interval: 0.60-0.90), whereas the following variants were not statistically significant: rs1947274 LPHN3 (odds ratio: 0.95; confidence interval: 0.71-1.26), rs5661665 LPHN3 (odds ratio: 1.07; confidence interval: 0.84-1.37) and VNTR 7 DRD4 (odds ratio: 0.68; confidence interval: 0.47-1.00). Funnel plot asymmetry among SLC6A3 studies was identified and attributed largely to small study effects. Egger's regression test and Duval and Tweedie's 'trim and fill' were used to examine and correct for publication bias. These findings have major implications for advancing our therapeutic approach to childhood ADHD treatment. PMID- 29230022 TI - Trained innate immunity: a salient factor in the pathogenesis of neuroimmune psychiatric disorders. AB - Historically, only cells of the adaptive immune system have been considered capable of retaining memory for infectious challenges. Recently, however, cells of the innate immune system have been shown to be capable of displaying long-term functional memory following a single immunostimulatory challenge, leading to enhanced production of proinflammatory molecules upon other subsequent, and temporally distant, immunostimulatory challenges. This effect has been termed 'trained innate immunity', and is underwritten by stable epigenetic changes in immune and metabolic pathways. Importantly, the long-term training of innate immune cells can occur as a result of infectious as well as and non-infectious challenges, including stress. Given the role that both stress and an activated immune system have in neuropathology, innate immune training has important implications for our understanding and treatment of neuropsychiatric disorders. This review focuses on the evidence for trained innate immunity and highlights some insights into its relevance for psychiatric diseases. PMID- 29230024 TI - Forest extent and deforestation in tropical Africa since 1900. AB - Accurate estimates of historical forest extent and associated deforestation rates are crucial for quantifying tropical carbon cycles and formulating conservation policy. In Africa, data-driven estimates of historical closed-canopy forest extent and deforestation at the continental scale are lacking, and existing modelled estimates diverge substantially. Here, we synthesize available palaeo proxies and historical maps to reconstruct forest extent in tropical Africa around 1900, when European colonization accelerated markedly, and compare these historical estimates with modern forest extent to estimate deforestation. We find that forests were less extensive in 1900 than bioclimatic models predict. Resultantly, across tropical Africa, ~ 21.7% of forests have been deforested, yielding substantially slower deforestation than previous estimates (35-55%). However, deforestation was heterogeneous: West and East African forests have undergone almost complete decline (~ 83.3 and 93.0%, respectively), while Central African forests have expanded at the expense of savannahs (~ 1.4% net forest expansion, with ~ 135,270 km2 of savannahs encroached). These results suggest that climate alone does not determine savannah and forest distributions and that many savannahs hitherto considered to be degraded forests are instead relatively old. These data-driven reconstructions of historical biome distributions will inform tropical carbon cycle estimates, carbon mitigation initiatives and conservation planning in both forest and savannah systems. PMID- 29230025 TI - Regulated hunting re-shapes the life history of brown bears. AB - Management of large carnivores is among the most controversial topics in natural resource administration. Regulated hunting is a centrepiece of many carnivore management programmes and, although a number of hunting effects on population dynamics, body-size distributions and life history in other wildlife have been observed, its effects on life history and demography of large carnivores remain poorly documented. We report results from a 30-year study of brown bears (Ursus arctos) analysed using an integrated hierarchical approach. Our study revealed that regulated hunting has severely disrupted the interplay between age-specific survival and environmental factors, altered the consequences of reproductive strategies, and changed reproductive values and life expectancy in a population of the world's largest terrestrial carnivore. Protection and sustainable management have led to numerical recovery of several populations of large carnivores, but managers and policymakers should be aware of the extent to which regulated hunting may be influencing vital rates, thereby reshaping the life history of apex predators. PMID- 29230026 TI - Homogenization of lake cyanobacterial communities over a century of climate change and eutrophication. AB - Human impacts on biodiversity are well recognized, but uncertainties remain regarding patterns of diversity change at different spatial and temporal scales. Changes in microbial assemblages are, in particular, not well understood, partly due to the lack of community composition data over relevant scales of space and time. Here, we investigate biodiversity patterns in cyanobacterial assemblages over one century of eutrophication and climate change by sequencing DNA preserved in the sediments of ten European peri-Alpine lakes. We found species losses and gains at the lake scale, while species richness increased at the regional scale over approximately the past 100 years. Our data show a clear signal for beta diversity loss, with the composition and phylogenetic structure of assemblages becoming more similar across sites in the most recent decades, as have the general environmental conditions in and around the lakes. We attribute patterns of change in community composition to raised temperatures affecting the strength of the thermal stratification and, as a consequence, nutrient fluctuations, which favoured cyanobacterial taxa able to regulate buoyancy. Our results reinforce previous reports of human-induced homogenization of natural communities and reveal how potentially toxic and bloom-forming cyanobacteria have widened their geographic distribution in the European temperate region. PMID- 29230021 TI - Markers of microglia in post-mortem brain samples from patients with Alzheimer's disease: a systematic review. AB - Neuroinflammation is proposed as one of the mechanisms by which Alzheimer's disease pathology, including amyloid-beta plaques, leads to neuronal death and dysfunction. Increases in the expression of markers of microglia, the main neuroinmmune cell, are widely reported in brains from patients with Alzheimer's disease, but the literature has not yet been systematically reviewed to determine whether this is a consistent pathological feature. A systematic search was conducted in Medline, Embase and PsychINFO for articles published up to 23 February 2017. Papers were included if they quantitatively compared microglia markers in post-mortem brain samples from patients with Alzheimer's disease and aged controls without neurological disease. A total of 113 relevant articles were identified. Consistent increases in markers related to activation, such as major histocompatibility complex II (36/43 studies) and cluster of differentiation 68 (17/21 studies), were identified relative to nonneurological aged controls, whereas other common markers that stain both resting and activated microglia, such as ionized calcium-binding adaptor molecule 1 (10/20 studies) and cluster of differentiation 11b (2/5 studies), were not consistently elevated. Studies of ionized calcium-binding adaptor molecule 1 that used cell counts almost uniformly identified no difference relative to control, indicating that increases in activation occurred without an expansion of the total number of microglia. White matter and cerebellum appeared to be more resistant to these increases than other brain regions. Nine studies were identified that included high pathology controls, patients who remained free of dementia despite Alzheimer's disease pathology. The majority (5/9) of these studies reported higher levels of microglial markers in Alzheimer's disease relative to controls, suggesting that these increases are not solely a consequence of Alzheimer's disease pathology. These results show that increased markers of microglia are a consistent feature of Alzheimer's disease, though this seems to be driven primarily by increases in activation-associated markers, as opposed to markers of all microglia. PMID- 29230027 TI - Genome of the Tasmanian tiger provides insights into the evolution and demography of an extinct marsupial carnivore. AB - The Tasmanian tiger or thylacine (Thylacinus cynocephalus) was the largest carnivorous Australian marsupial to survive into the modern era. Despite last sharing a common ancestor with the eutherian canids ~160 million years ago, their phenotypic resemblance is considered the most striking example of convergent evolution in mammals. The last known thylacine died in captivity in 1936 and many aspects of the evolutionary history of this unique marsupial apex predator remain unknown. Here we have sequenced the genome of a preserved thylacine pouch young specimen to clarify the phylogenetic position of the thylacine within the carnivorous marsupials, reconstruct its historical demography and examine the genetic basis of its convergence with canids. Retroposon insertion patterns placed the thylacine as the basal lineage in Dasyuromorphia and suggest incomplete lineage sorting in early dasyuromorphs. Demographic analysis indicated a long-term decline in genetic diversity starting well before the arrival of humans in Australia. In spite of their extraordinary phenotypic convergence, comparative genomic analyses demonstrated that amino acid homoplasies between the thylacine and canids are largely consistent with neutral evolution. Furthermore, the genes and pathways targeted by positive selection differ markedly between these species. Together, these findings support models of adaptive convergence driven primarily by cis-regulatory evolution. PMID- 29230028 TI - Abundance and richness of key Antarctic seafloor fauna correlates with modelled food availability. AB - Most seafloor communities at depths below the photosynthesis zone rely on food that sinks through the water column. However, the nature and strength of this pelagic-benthic coupling and its influence on the structure and diversity of seafloor communities is unclear, especially around Antarctica where ecological data are sparse. Here we show that the strength of pelagic-benthic coupling along the East Antarctic shelf depends on both physical processes and the types of benthic organisms considered. In an approach based on modelling food availability, we combine remotely sensed sea-surface chlorophyll-a, a regional ocean model and diatom abundances from sediment grabs with particle tracking and show that fluctuating seabed currents are crucial in the redistribution of surface productivity at the seafloor. The estimated availability of suspended food near the seafloor correlates strongly with the abundance of benthic suspension feeders, while the deposition of food particles correlates with decreasing suspension feeder richness and more abundant deposit feeders. The modelling framework, which can be modified for other regions, has broad applications in conservation and management, as it enables spatial predictions of key components of seafloor biodiversity over vast regions around Antarctica. PMID- 29230029 TI - Publisher Correction: Social polymorphism is favoured by the co-evolution of dispersal with social behaviour. AB - Owing to a technical error, some text was missing in the originally published version of this Article. In the last paragraph of the Discussion section, the second sentence should have read "Yet, the selection that associates dispersal and social behaviour in our model will influence evolution under most ecological settings because it depends only on kin structure, which, due to limited dispersal and the spatial scale of social interactions, is ubiquitous in nature47." This error has now been corrected in all versions of the Article. PMID- 29230030 TI - Silica inhalation altered telomere length and gene expression of telomere regulatory proteins in lung tissue of rats. AB - Exposure to silica can cause lung fibrosis and cancer. Identification of molecular targets is important for the intervention and/or prevention of silica induced lung diseases. Telomeres consist of tandem repeats of DNA sequences at the end of chromosomes, preventing chromosomal fusion and degradation. Regulator of telomere length-1 (RTEL1) and telomerase reverse transcriptase (TERT), genes involved in telomere regulation and function, play important roles in maintaining telomere integrity and length. The goal of this study was to assess the effect of silica inhalation on telomere length and the regulation of RTEL1 and TERT. Lung tissues and blood samples were collected from rats at 4, 32, and 44 wk after exposure to 15 mg/m3 of silica * 6 h/d * 5 d. Controls were exposed to air. At all-time points, RTEL1 expression was significantly decreased in lung tissue of the silica-exposed animals compared to controls. Also, significant increases in telomere length and TERT were observed in the silica group at 4 and 32 wk. Telomere length, RTEL1 and TERT expression may serve as potential biomarkers related to silica exposure and may offer insight into the molecular mechanism of silica-induced lung disease and tumorigeneses. PMID- 29230031 TI - Two-dimensional topological superconductivity in Pb/Co/Si(111). AB - Just like insulators can present topological phases characterized by Dirac edge states, superconductors can exhibit topological phases characterized by Majorana edge states. In particular, one-dimensional topological superconductors are predicted to host zero-energy Majorana fermions at their extremities. By contrast, two-dimensional superconductors have a one-dimensional boundary which would naturally lead to propagating Majorana edge states characterized by a Dirac like dispersion. In this paper we present evidences of one-dimensional dispersive in-gap edge states surrounding a two-dimensional topological superconducting domain consisting of a monolayer of Pb covering magnetic Co-Si islands grown on Si(111). We interpret the measured dispersive in-gap states as a spatial topological transition with a gap closure. Our method could in principle be generalized to a large variety of heterostructures combining a Rashba superconductor with a magnetic layer in order to be used as a platform for engineering topological quantum phases. PMID- 29230032 TI - Carmen Keith Conners. PMID- 29230033 TI - Decrease in the AP-2 DNA-Binding Activity and in the Protein Expression of AP-2 a and AP-2 b in Frontal Cortex of Rats Treated with Lithium for 6 Weeks. AB - This corrects the article DOI: 10.1038/ajg.2016.125. PMID- 29230034 TI - Telomere Length and Bipolar Disorder. AB - This corrects the article DOI: 10.1038/npp.2017.125. PMID- 29230035 TI - A Dilatometric Study of Tempering Complemented by Mossbauer Spectroscopy and other Characterization Techniques. AB - A new approach for non-isothermal tempering analysis utilizing dilatometry is proposed and was carried out on a medium carbon steel with high silicon and additions of Mo and V for secondary hardening. The method includes a second non isothermal step performed with the same heating rate (2 degrees C/min) used for the first step in order to create a baseline for analysis. The results were correlated with several other characterization techniques. Mossbauer spectroscopy confirmed the formation of transition carbides by auto-tempering as well as the presence of retained austenite decomposition (stage II) and cementite precipitation (stage III), which demonstrated significant overlap. Electrical resistivity measurements were correlated with dislocation densities obtained through X-ray diffraction analysis. Transmission electron microscopy dark field images confirmed the secondary hardening assessment from dilatometry. PMID- 29230037 TI - Author Correction: FAM46C is critical for the anti-proliferation and pro apoptotic effects of norcantharidin in hepatocellular carcinoma cells. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29230036 TI - Negative charge and membrane-tethered viral 3B cooperate to recruit viral RNA dependent RNA polymerase 3D pol. AB - Most single stranded plus RNA viruses hijack phosphatidylinositol 4-kinases (PI4Ks) to generate membranes highly enriched in phosphatidylinositol 4-phosphate (PI4P). These membranous compartments known as webs, replication factories or replication organelles are essential for viral replication because they provide protection from the innate intracellular immune response while serving as platforms for viral replication. Using purified recombinant proteins and biomimetic model membranes we show that the nonstructural viral 3A protein is sufficient to promote membrane hyper-phosphorylation given the proper intracellular cofactors (PI4KB and ACBD3). However, our bio-mimetic in vitro reconstitution assay revealed that rather than the presence of PI4P specifically, negative charge alone is sufficient for the recruitment of 3Dpol enzymes to the surface of the lipid bilayer. Additionally, we show that membrane tethered viral 3B protein (also known as Vpg) works in combination with the negative charge to increase the efficiency of membrane recruitment of 3Dpol. PMID- 29230038 TI - The LPS-inducible lncRNA Mirt2 is a negative regulator of inflammation. AB - Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRR) with a crucial function in innate immune responses. Activation of TLR4 signaling at the plasma membrane by lipopolysaccharide (LPS) stimulates proinflammatory signaling pathways dependent on the E3 ubiquitin ligase TRAF6. Here we show the LPS-induced long non-coding RNA (lncRNA) Mirt2 functions as a checkpoint to prevent aberrant activation of inflammation, and is a potential regulator of macrophage polarization. Mirt2 associates with, and attenuates Lys63 (K63)-linked ubiquitination of, TRAF6, thus inhibiting activation of NF-kappaB and MAPK pathways and limiting production of proinflammatory cytokines. Adenovirus mediated gene transfer of Mirt2 protects mice from endotoxemia induced fatality and multi-organ dysfunction. These findings identify lncRNA Mirt2 as a negative feedback regulator of excessive inflammation. PMID- 29230039 TI - Gli1 identifies osteogenic progenitors for bone formation and fracture repair. AB - Bone formation in mammals requires continuous production of osteoblasts throughout life. A common molecular marker for all osteogenic mesenchymal progenitors has not been identified. Here, by lineage-tracing experiments in fetal or postnatal mice, we discover that Gli1+ cells progressively produce osteoblasts in all skeletal sites. Most notably, in postnatal growing mice, the Gli1+ cells residing immediately beneath the growth plate, termed here "metaphyseal mesenchymal progenitors" (MMPs), are essential for cancellous bone formation. Besides osteoblasts, MMPs also give rise to bone marrow adipocytes and stromal cells in vivo. RNA-seq reveals that MMPs express a number of marker genes previously assigned to mesenchymal stem/progenitor cells, including CD146/Mcam, CD44, CD106/Vcam1, Pdgfra, and Lepr. Genetic disruption of Hh signaling impairs proliferation and osteoblast differentiation of MMPs. Removal of beta-catenin causes MMPs to favor adipogenesis, resulting in osteopenia coupled with increased marrow adiposity. Finally, postnatal Gli1+ cells contribute to both chondrocytes and osteoblasts during bone fracture healing. Thus Gli1 marks mesenchymal progenitors responsible for both normal bone formation and fracture repair. PMID- 29230040 TI - Congenital embryonal rhabdomyosarcoma caused by heterozygous concomitant PTCH1 and PTCH2 germline mutations. AB - The sonic hedgehog (SHH) signaling pathway has been shown to play important roles in embryogenesis, cell proliferation as well as in cell differentiation. It is aberrantly activated in various common cancers in adults, but also in pediatric neoplasms, such as rhabdomyosarcoma (RMS) and atypical teratoid/rhabdoid tumors (AT/RTs). Dysregulation and germline mutation in PATCHED1 (PTCH1), a receptor for SHH, is responsible for the Gorlin Syndrome, a familial cancer predisposing syndrome including RMS. Here, we report a newborn diagnosed with congenital embryonal RMS. Whole-exome sequencing (WES) identified the presence of two heterozygous germline mutations in two target genes of the SHH signaling pathway. The PTCH1 mutation p.(Gly38Glu) is inherited from the mother, whereas the PTCH2 p.(His622Tyr) mutation is transmitted from the father. Quantitative RT-PCR expression analysis of GLI and SMO, key players of the SHH pathway, showed significantly increase in the tumor tissue of the patient and also enrichment in the germline sample in comparison to the parents indicating activation of the SHH pathway in the patient. These findings demonstrate that SHH pathway activity seems to play a role in eRMS as evidenced by high expression levels of GLI1 RNA transcripts. We speculate that PTCH2 modulates tumorigenesis linked to the PTCH1 mutation and is likely associated with the congenital onset of the RMS observed in our patient. PMID- 29230041 TI - Efficient dissolved organic carbon production and export in the oligotrophic ocean. AB - Biologically fixed carbon is transferred from the surface to deep ocean as sinking particles or dissolved organic carbon (DOC). DOC is estimated to account for ~20% of global export production, but the degree to which this varies regionally has not been assessed at a global scale. Here we present the first observationally based global-scale assessment of DOC production and export, obtained by combining an artificial neural network estimate of the global DOC distribution, and a data-constrained ocean circulation model. Our results demonstrate that the efficiency of DOC production and export varies more than threefold across oceanographic regions. DOC production and export display a pronounced peak in the oligotrophic subtropical oceans, where DOC accounts for roughly half of the total organic carbon export. These stratified nutrient depleted regions are expected to expand with future warming, amplifying the role of DOC in the biological pump, and magnifying the need to improve DOC cycling in climate models. PMID- 29230042 TI - Direct-current triboelectricity generation by a sliding Schottky nanocontact on MoS2 multilayers. AB - The direct conversion of mechanical energy into electricity by nanomaterial-based devices offers potential for green energy harvesting 1-3 . A conventional triboelectric nanogenerator converts frictional energy into electricity by producing alternating current (a.c.) triboelectricity. However, this approach is limited by low current density and the need for rectification 2 . Here, we show that continuous direct-current (d.c.) with a maximum density of 106 A m-2 can be directly generated by a sliding Schottky nanocontact without the application of an external voltage. We demonstrate this by sliding a conductive-atomic force microscope tip on a thin film of molybdenum disulfide (MoS2). Finite element simulation reveals that the anomalously high current density can be attributed to the non-equilibrium carrier transport phenomenon enhanced by the strong local electrical field (105-106 V m-2) at the conductive nanoscale tip 4 . We hypothesize that the charge transport may be induced by electronic excitation under friction, and the nanoscale current-voltage spectra analysis indicates that the rectifying Schottky barrier at the tip-sample interface plays a critical role in efficient d.c. energy harvesting. This concept is scalable when combined with microfabricated or contact surface modified electrodes, which makes it promising for efficient d.c. triboelectricity generation. PMID- 29230045 TI - Bridging the gap with hot electrons. PMID- 29230044 TI - Reactive tunnel junctions in electrically driven plasmonic nanorod metamaterials. AB - Non-equilibrium hot carriers formed near the interfaces of semiconductors or metals play a crucial role in chemical catalysis and optoelectronic processes. In addition to optical illumination, an efficient way to generate hot carriers is by excitation with tunnelling electrons. Here, we show that the generation of hot electrons makes the nanoscale tunnel junctions highly reactive and facilitates strongly confined chemical reactions that can, in turn, modulate the tunnelling processes. We designed a device containing an array of electrically driven plasmonic nanorods with up to 1011 tunnel junctions per square centimetre, which demonstrates hot-electron activation of oxidation and reduction reactions in the junctions, induced by the presence of O2 and H2 molecules, respectively. The kinetics of the reactions can be monitored in situ following the radiative decay of tunnelling-induced surface plasmons. This electrically driven plasmonic nanorod metamaterial platform can be useful for the development of nanoscale chemical and optoelectronic devices based on electron tunnelling. PMID- 29230043 TI - Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression. AB - Nanotechnology offers many benefits, and here we report an advantage of applying RNA nanotechnology for directional control. The orientation of arrow-shaped RNA was altered to control ligand display on extracellular vesicle membranes for specific cell targeting, or to regulate intracellular trafficking of small interfering RNA (siRNA) or microRNA (miRNA). Placing membrane-anchoring cholesterol at the tail of the arrow results in display of RNA aptamer or folate on the outer surface of the extracellular vesicle. In contrast, placing the cholesterol at the arrowhead results in partial loading of RNA nanoparticles into the extracellular vesicles. Taking advantage of the RNA ligand for specific targeting and extracellular vesicles for efficient membrane fusion, the resulting ligand-displaying extracellular vesicles were capable of specific delivery of siRNA to cells, and efficiently blocked tumour growth in three cancer models. Extracellular vesicles displaying an aptamer that binds to prostate-specific membrane antigen, and loaded with survivin siRNA, inhibited prostate cancer xenograft. The same extracellular vesicle instead displaying epidermal growth factor receptor aptamer inhibited orthotopic breast cancer models. Likewise, survivin siRNA-loaded and folate-displaying extracellular vesicles inhibited patient-derived colorectal cancer xenograft. PMID- 29230046 TI - Bullying incidences identification within an immersive environment using HD EEG based analysis: A Swarm Decomposition and Deep Learning approach. AB - Bullying is an everlasting phenomenon and the first, yet difficult, step towards the solution is its detection. Conventional approaches for bullying incidence identification include questionnaires, conversations and psychological tests. Here, unlike the conventional approaches, two experiments are proposed that involve visual stimuli with cases of bullying- and non-bullying- related ones, set within a 2D (simple video preview) and a Virtual Reality (VR) (immersive video preview) context. In both experimental settings, brain activity is recorded using high density (HD) (256 channels) electroencephalogram (EEG), and analyzed to identify the bullying stimuli type (bullying/non-bullying) and context (2D/VR). The proposed classification analysis uses a convolutional neural network (CNN), applying deep learning on the oscillatory modes (OCMs) embedded within the raw HD EEG data. The extraction of OCMs from the HD EEG data is achieved with swarm decomposition (SWD), which efficiently accounts for the non-stationarity and noise contamination of the raw HD EEG data. Experimental results from 17 subjects indicate that the new SWD/CNN approach achieves high discrimination accuracy (AUC = 0.987 between bullying/non-bullying stimuli type; AUC = 0.975, between bullying/non-bullying stimuli type and 2D/VR context), paving the way for better understanding of how brain's responses could act as indicators of bullying experience within immersive environments. PMID- 29230048 TI - Author Correction: An in planta biolistic method for stable wheat transformation. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29230047 TI - Three-dimensional (3D) culture of adult murine colon as an in vitro model of cryptosporidiosis: Proof of concept. AB - Cryptosporidium parvum is a major cause of diarrheal illness and was recently potentially associated with digestive carcinogenesis. Despite its impact on human health, Cryptosporidium pathogenesis remains poorly known, mainly due to the lack of a long-term culture method for this parasite. Thus, the aim of the present study was to develop a three-dimensional (3D) culture model from adult murine colon allowing biological investigations of the host-parasite interactions in an in vivo-like environment and, in particular, the development of parasite-induced neoplasia. Colonic explants were cultured and preserved ex vivo for 35 days and co-culturing was performed with C. parvum. Strikingly, the resulting system allowed the reproduction of neoplastic lesions in vitro at 27 days post-infection (PI), providing new evidence of the role of the parasite in the induction of carcinogenesis. This promising model could facilitate the study of host-pathogen interactions and the investigation of the process involved in Cryptosporidium induced cell transformation. PMID- 29230049 TI - Insights into substrate binding of ferulic acid esterases by arabinose and methyl hydroxycinnamate esters and molecular docking. AB - Ferulic acid esterases (FAE, EC 3.1.1.73) cleave the arabinose hydroxycinnamate ester in plant hemicellulose and other related substrates. FAE are commonly categorised as type A-D based on catalytic activities towards model, short alkyl chain esters of hydroxycinnamates. However, this system correlates poorly with sequence and structural features of the enzymes. In this study, we investigated the basis of the type A categorisation of an FAE from Aspergillus niger, AnFaeA, by comparing its activity toward methyl and arabinose hydroxycinnamate esters. kcat/Km ratios revealed that AnFaeA hydrolysed arabinose ferulate 1600-fold, and arabinose caffeate 6.5 times more efficiently than their methyl ester counterparts. Furthermore, small docking studies showed that while all substrates adopted a catalytic orientation with requisite proximity to the catalytic serine, methyl caffeate and methyl p-coumarate preferentially formed alternative non catalytic conformations that were energetically favoured. Arabinose ferulate was unable to adopt the alternative conformation while arabinose caffeate preferred the catalytic orientation. This study demonstrates that use of short alkyl chain hydroxycinnnamate esters can result in activity misclassification. The findings of this study provide a basis for developing a robust classification system for FAE and form the basis of sequence-function relationships for this class. PMID- 29230050 TI - Synaptic weight set by Munc13-1 supramolecular assemblies. AB - The weight of synaptic connections, which is controlled not only postsynaptically but also presynaptically, is a key determinant in neuronal network dynamics. The mechanisms controlling synaptic weight, especially on the presynaptic side, remain elusive. Using single-synapse imaging of the neurotransmitter glutamate combined with super-resolution imaging of presynaptic proteins, we identify a presynaptic mechanism for setting weight in central glutamatergic synapses. In the presynaptic terminal, Munc13-1 molecules form multiple and discrete supramolecular self-assemblies that serve as independent vesicular release sites by recruiting syntaxin-1, a soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) protein essential for synaptic vesicle exocytosis. The multiplicity of these Munc13-1 assemblies affords multiple stable states conferring presynaptic weight, potentially encoding several bits of information at individual synapses. Supramolecular assembling enables a stable synaptic weight, which confers robustness of synaptic computation on neuronal circuits and may be a general mechanism by which biological processes operate despite the presence of molecular noise. PMID- 29230051 TI - Integration of grid maps in merged environments. AB - Natural environments are represented by local maps of grid cells and place cells that are stitched together. The manner by which transitions between map fragments are generated is unknown. We recorded grid cells while rats were trained in two rectangular compartments, A and B (each 1 m * 2 m), separated by a wall. Once distinct grid maps were established in each environment, we removed the partition and allowed the rat to explore the merged environment (2 m * 2 m). The grid patterns were largely retained along the distal walls of the box. Nearer the former partition line, individual grid fields changed location, resulting almost immediately in local spatial periodicity and continuity between the two original maps. Grid cells belonging to the same grid module retained phase relationships during the transformation. Thus, when environments are merged, grid fields reorganize rapidly to establish spatial periodicity in the area where the environments meet. PMID- 29230052 TI - Regulation of developing myelin sheath elongation by oligodendrocyte calcium transients in vivo. AB - How action potentials regulate myelination by oligodendrocytes is uncertain. We show that neuronal activity raises [Ca2+]i in developing oligodendrocytes in vivo and that myelin sheath elongation is promoted by a high frequency of [Ca2+]i transients and prevented by [Ca2+]i buffering. Sheath elongation occurs ~1 h after [Ca2+]i elevation. Sheath shortening is associated with a low frequency of [Ca2+]i transients but with longer duration [Ca2+]i bursts. Thus, [Ca2+]i controls myelin sheath development. PMID- 29230053 TI - Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly. AB - Accumulating evidence support a causal link between Zika virus (ZIKV) infection during gestation and congenital microcephaly. However, the mechanism of ZIKV associated microcephaly remains unclear. We combined analyses of ZIKV-infected human fetuses, cultured human neural stem cells and mouse embryos to understand how ZIKV induces microcephaly. We show that ZIKV triggers endoplasmic reticulum stress and unfolded protein response in the cerebral cortex of infected postmortem human fetuses as well as in cultured human neural stem cells. After intracerebral and intraplacental inoculation of ZIKV in mouse embryos, we show that it triggers endoplasmic reticulum stress in embryonic brains in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that controls neurogenesis. Thus, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex, whereupon sustained endoplasmic reticulum stress leads to apoptosis. Furthermore, we demonstrate that administration of pharmacological inhibitors of unfolded protein response counteracts these pathophysiological mechanisms and prevents microcephaly in ZIKV-infected mouse embryos. Such defects are specific to ZIKV, as they are not observed upon intraplacental injection of other related flaviviruses in mice. PMID- 29230055 TI - Impaired path integration in mice with disrupted grid cell firing. AB - Path integration (PI) is a highly conserved, self-motion-based navigation strategy. Since the discovery of grid cells in the medial entorhinal cortex, neurophysiological data and computational models have suggested that these neurons serve PI. However, more direct empirical evidence supporting this hypothesis has been missing due to a lack of selective manipulations of grid cell activity and suitable behavioral assessments. Here we report that selective disruption of grid cell activity in mice can be achieved by removing NMDA glutamate receptors from the retro-hippocampal region and that disrupted grid cell firing accounts for impaired PI performance. Notably, the genetic manipulation did not affect the activity of other spatially selective cells in the medial entorhinal cortex and the hippocampus. By directly linking grid cell activity to PI, these results contribute to a better understanding of how grid cells support navigation and spatial memory. PMID- 29230054 TI - Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex. AB - Activity-dependent transcriptional responses shape cortical function. However, a comprehensive understanding of the diversity of these responses across the full range of cortical cell types, and how these changes contribute to neuronal plasticity and disease, is lacking. To investigate the breadth of transcriptional changes that occur across cell types in the mouse visual cortex after exposure to light, we applied high-throughput single-cell RNA sequencing. We identified significant and divergent transcriptional responses to stimulation in each of the 30 cell types characterized, thus revealing 611 stimulus-responsive genes. Excitatory pyramidal neurons exhibited inter- and intralaminar heterogeneity in the induction of stimulus-responsive genes. Non-neuronal cells showed clear transcriptional responses that may regulate experience-dependent changes in neurovascular coupling and myelination. Together, these results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders. PMID- 29230056 TI - The C-terminal tails of endogenous GluA1 and GluA2 differentially contribute to hippocampal synaptic plasticity and learning. AB - Long-term potentiation (LTP) and depression (LTD) at glutamatergic synapses are intensively investigated processes for understanding the synaptic basis for learning and memory, but the underlying molecular mechanisms remain poorly understood. We have made three mouse lines where the C-terminal domains (CTDs) of endogenous AMPA receptors (AMPARs), the principal mediators of fast excitatory synaptic transmission, are specifically exchanged. These mice display profound deficits in synaptic plasticity without any effects on basal synaptic transmission. Our study reveals that the CTDs of GluA1 and GluA2, the key subunits of AMPARs, are necessary and sufficient to drive NMDA receptor-dependent LTP and LTD, respectively. In addition, these domains exert differential effects on spatial and contextual learning and memory. These results establish dominant roles of AMPARs in governing bidirectional synaptic and behavioral plasticity in the CNS. PMID- 29230057 TI - Synaptotagmin-1 drives synchronous Ca2+-triggered fusion by C2B-domain-mediated synaptic-vesicle-membrane attachment. AB - The synaptic vesicle (SV) protein synaptotagmin-1 (Syt1) is the Ca2+ sensor for fast synchronous release. Biochemical and structural data suggest that Syt1 interacts with phospholipids and SNARE complex, but the manner in which these interactions translate into SV fusion remains poorly understood. Using flash-and freeze electron microscopy, which triggers action potentials with light and coordinately arrests synaptic structures with rapid freezing, we found that synchronous-release-impairing mutations in the Syt1 C2B domain (K325, 327; R398, 399) also disrupt SV-active-zone plasma-membrane attachment. Single action potential induction rescued membrane attachment in these mutants within less than 10 ms through activation of the Syt1 Ca2+-binding site. The rapid SV membrane translocation temporarily correlates with resynchronization of release and paired pulse facilitation. On the basis of these findings, we redefine the role of Syt1 as part of the Ca2+-dependent vesicle translocation machinery and propose that Syt1 enables fast neurotransmitter release by means of its dynamic membrane attachment activities. PMID- 29230058 TI - Ca 2+ activity signatures of myelin sheath formation and growth in vivo. AB - During myelination, individual oligodendrocytes initially over-produce short myelin sheaths, which are either retracted or stabilized. By live-imaging oligodendrocyte Ca2+ activity in vivo, we find that high-amplitude, long-duration Ca2+ transients in sheaths prefigure retractions, mediated by calpain. Following stabilization, myelin sheaths grow along axons, and we find that higher-frequency Ca2+ transient activity in sheaths precedes faster elongation. Our data implicate local Ca2+ signaling in regulating distinct stages of myelination. PMID- 29230059 TI - Genome-wide association study of delay discounting in 23,217 adult research participants of European ancestry. AB - Delay discounting (DD), the tendency to discount the value of delayed versus current rewards, is elevated in a constellation of diseases and behavioral conditions. We performed a genome-wide association study of DD using 23,127 research participants of European ancestry. The most significantly associated single-nucleotide polymorphism was rs6528024 (P = 2.40 * 10-8), which is located in an intron of the gene GPM6B. We also showed that 12% of the variance in DD was accounted for by genotype and that the genetic signature of DD overlapped with attention-deficit/hyperactivity disorder, schizophrenia, major depression, smoking, personality, cognition and body weight. PMID- 29230060 TI - Natural Erosion of Sandstone as Shape Optimisation. AB - Natural arches, pillars and other exotic sandstone formations have always been attracting attention for their unusual shapes and amazing mechanical balance that leave a strong impression of intelligent design rather than the result of a stochastic process. It has been recently demonstrated that these shapes could have been the result of the negative feedback between stress and erosion that originates in fundamental laws of friction between the rock's constituent particles. Here we present a deeper analysis of this idea and bridge it with the approaches utilized in shape and topology optimisation. It appears that the processes of natural erosion, driven by stochastic surface forces and Mohr Coulomb law of dry friction, can be viewed within the framework of local optimisation for minimum elastic strain energy. Our hypothesis is confirmed by numerical simulations of the erosion using the topological-shape optimisation model. Our work contributes to a better understanding of stochastic erosion and feasible landscape formations that could be found on Earth and beyond. PMID- 29230061 TI - Boosting with recombinant MVA expressing M. tuberculosis alpha-crystallin antigen augments the protection imparted by BCG against tuberculosis in guinea pigs. AB - Tuberculosis (TB) is one of the major causes of mortality all over the globe. BCG, the only vaccine available against this disease has been successful in preventing the severe forms of childhood TB. However, the unsatisfactory performance of BCG in controlling the adult pulmonary tuberculosis has made the development of an effective vaccine against M. tuberculosis a prime objective of the TB research. In this study, a genetically stable, marker-free recombinant MVA expressing alpha-crystallin of M. tuberculosis (rMVA.acr) was generated which was further evaluated for its ability to impart protection as a booster vaccine against tuberculosis in a heterologous prime boost approach. Our results demonstrated that intradermal delivery of rMVA.acr was able to efficiently boost the BCG induced protection against M. tuberculosis infection in guinea pigs by significantly reducing the pulmonary bacillary load (1.27 log10 fewer bacilli) in comparison to BCG vaccination alone. In addition, boosting BCG vaccinated animals with intramuscular delivery of rMVA.acr resulted in significantly superior protective efficacy in both lungs and spleen with 0.83 log10 and 0.74 log10 CFU fewer bacilli, respectively, when compared to animals vaccinated with BCG only. These findings establish the promise of this prime-boost strategy involving rMVA.acr in enhancing the efficacy of BCG. PMID- 29230062 TI - Continuous Radar Tracking Illustrates the Development of Multi-destination Routes of Bumblebees. AB - Animals that visit multiple foraging sites face a problem, analogous to the Travelling Salesman Problem, of finding an efficient route. We explored bumblebees' route development on an array of five artificial flowers in which minimising travel distances between individual feeders conflicted with minimising overall distance. No previous study of bee spatial navigation has been able to follow animals' movement during learning; we tracked bumblebee foragers continuously, using harmonic radar, and examined the process of route formation in detail for a small number of selected individuals. On our array, bees did not settle on visit sequences that gave the shortest overall path, but prioritised movements to nearby feeders. Nonetheless, flight distance and duration reduced with experience. This increased efficiency was attributable mainly to experienced bees reducing exploration beyond the feeder array and flights becoming straighter with experience, rather than improvements in the sequence of feeder visits. Flight paths of all legs of a flight stabilised at similar rates, whereas the first few feeder visits became fixed early while bees continued to experiment with the order of later visits. Stabilising early sections of a route and prioritising travel between nearby destinations may reduce the search space, allowing rapid adoption of efficient routes. PMID- 29230063 TI - Multiple gene genealogy reveals high genetic diversity and evidence for multiple origins of Chinese Plasmopara viticola population. AB - Downy mildew caused by Plasmopara viticola is one of the most devastating diseases of grapevines worldwide. So far, the genetic diversity and origin of the Chinese P. viticola population are unclear. In the present study, 103 P. viticola isolates were sequenced at four gene regions: internal transcribed spacer one (ITS), large subunit of ribosomal RNA (LSU), actin gene (ACT) and beta-tubulin (TUB). The sequences were analyzed to obtain polymorphism and diversity information of the Chinese population as well as to infer the relationships between Chinese and American isolates. High genetic diversity was observed for the Chinese population, with evidence of sub-structuring based on climate. Phylogenetic analysis and haplotype networks showed evidence of close relationships between some American and Chinese isolates, consistent with recent introduction from America to China via planting materials. However, there is also evidence for endemic Chinese P. viticola isolates. Our results suggest that the current Chinese Plasmopara viticola population is an admixture of endemic and introduced isolates. PMID- 29230064 TI - Social learning may lead to population level conformity without individual level frequency bias. AB - A requirement of culture, whether animal or human, is some degree of conformity of behavior within populations. Researchers of gene-culture coevolution have suggested that population level conformity may result from frequency-biased social learning: individuals sampling multiple role models and preferentially adopting the majority behavior in the sample. When learning from a single role model, frequency-bias is not possible. We show why a population-level trend, either conformist or anticonformist, may nonetheless be almost inevitable in a population of individuals that learn through social enhancement, that is, using observations of others' behavior to update their own probability of using a behavior in the future. The exact specification of individuals' updating rule determines the direction of the trend. These results offer a new interpretation of previous findings from simulations of social enhancement in combination with reinforcement learning, and demonstrate how results of dynamical models may strongly depend on seemingly innocuous choices of model specifications, and how important it is to obtain empirical data on which to base such choices. PMID- 29230065 TI - The Toll-Like Receptor 2/6 Agonist, FSL-1 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome. AB - Risks of radiation exposure from nuclear incidents and cancer radiotherapy are undeniable realities. These dangers urgently compel the development of agents for ameliorating radiation-induced injuries. Biologic pathways mediated by myeloid differentiation primary response gene 88 (MyD88), the common adaptor for toll like receptor (TLR) and Interleukin-1 receptor signaling, are critical for radioprotection. Treating with agonists prior to radiation enhances survival by activating TLR signaling, whereas radiomitigating TLR-activating therapeutics given after exposure are less defined. We examine the radiomitigation capability of TLR agonists and identify one that is superior for its efficacy and reduced toxic consequences compared to other tested agonists. We demonstrate that the synthetic TLR2/6 ligand Fibroblast-stimulating lipopeptide (FSL-1) substantially prolongs survival in both male and female mice when administered 24 hours after radiation and shows MyD88-dependent function. FSL-1 treatment results in accelerated hematopoiesis in bone marrow, spleen and periphery, and augments systemic levels of hematopoiesis-stimulating factors. The ability of FSL-1 to stimulate hematopoiesis is critical, as hematopoietic dysfunction results from a range of ionizing radiation doses. The efficacy of a single FSL-1 dose for alleviating radiation injury while protecting against adverse effects reveals a viable radiation countermeasures agent. PMID- 29230066 TI - Functional and evolutionary analysis of Korean bob-tailed native dog using whole genome sequencing data. AB - Rapid and cost effective production of large-scale genome data through next generation sequencing has enabled population-level studies of various organisms to identify their genotypic differences and phenotypic consequences. This is also used to study indigenous animals with historical and economical values, although they are less studied than model organisms. The objective of this study was to perform functional and evolutionary analysis of Korean bob-tailed native dog Donggyeong with distinct tail and agility phenotype using whole-genome sequencing data by using population and comparative genomics approaches. Based on the uniqueness of non-synonymous single nucleotide polymorphisms obtained from next generation sequencing data, Donggyeong dog-specific genes/proteins and their functions were identified by comparison with 12 other dog breeds and six other related species. These proteins were further divided into subpopulation-specific ones with different tail length and protein interaction-level signatures were investigated. Finally, the trajectory of shaping protein interactions of subpopulation-specific proteins during evolution was uncovered. This study expands our knowledge of Korean native dogs. Our results also provide a good example of using whole-genome sequencing data for population-level analysis in closely related species. PMID- 29230068 TI - Measurement and Correlation of the Thermal Conductivity of trans-1-Chloro-3,3,3 trifluoropropene (R1233zd(E)). AB - New experimental data on the thermal conductivity of trans-1-chloro-3,3,3 trifluoropropene (R1233zd(E)) are reported that allow the development of wide range correlations. These new experimental data, covering a temperature range of 204 K to 453 K at pressures from 0.1 MPa to 67 MPa, are used to develop a correlation for the thermal conductivity. The experimental data reported here have an uncertainty of (1 - 1.5) % for liquid measurements and for gas at pressures above 1 MPa, increasing to (3 - 4) % for gas at low pressures (less than 1 MPa) and near the gas-liquid critical point. Based on the uncertainty of and comparisons with the present data, the thermal-conductivity correlation for R1233zd(E) is estimated to have a relative expanded uncertainty ranging at a 95 % confidence level from 1 % to 4 % depending on the temperature and pressure, with larger uncertainties in the critical region. PMID- 29230067 TI - Salient Cues and Wayfinding in Alzheimer's Disease within a Virtual Senior Residence. AB - Wayfinding is a problem for persons with Alzheimer's disease (AD), especially in complex environments such as senior residential communities. In this study, persons with AD or mild cognitive impairment (MCI) and a control group of older adults were asked to navigate a virtual reality simulation of a senior residential community. Subjects had to find their way repeatedly over multiple trials for two consecutive days in standard (no extra cues) and salient (colorful, memorable cues placed at key decision points) cue conditions. The results showed that all subjects found their way faster and more effectively in the salient cue condition than in the standard cue condition. Those in the AD/MCI group were significantly more impaired in wayfinding ability compared with those in the control group. Persons with impaired wayfinding ability due to AD and MCI can find their way more effectively in virtual environments enhanced with salient environmental cues. PMID- 29230069 TI - Value-Based Standards Guide Sexism Inferences for Self and Others. AB - People often disagree about what constitutes sexism, and these disagreements can be both socially and legally consequential. It is unclear, however, why or how people come to different conclusions about whether something or someone is sexist. Previous research on judgments about sexism has focused on the perceiver's gender and attitudes, but neither of these variables identifies comparative standards that people use to determine whether any given behavior (or person) is sexist. Extending Devine and colleagues' values framework (Devine, Monteith, Zuwerink, & Elliot, 1991; Plant & Devine, 1998), we argue that, when evaluating others' behavior, perceivers rely on the morally-prescriptive values that guide their own behavior toward women. In a series of 3 studies we demonstrate that (1) people's personal standards for sexism in their own and others' behavior are each related to their values regarding sexism, (2) these values predict how much behavioral evidence people need to infer sexism, and (3) people with stringent, but not lenient, value-based standards get angry and try to regulate a sexist perpetrator's behavior to reduce sexism. Furthermore, these personal values are related to all outcomes in the present work above and beyond other person characteristics previously used to predict sexism inferences. We discuss the implications of differing value-based standards for explaining and reconciling disputes over what constitutes sexist behavior. PMID- 29230070 TI - ASSESSING CLIMATE CHANGE IMPACTS ON THE STABILITY OF SMALL TIDAL INLETS: Part 2- DATA RICH ENVIRONMENTS. AB - Climate change (CC) is likely to affect the thousands of bar-built or barrier estuaries (here referred to as Small tidal inlets - STIs) around the world. Any such CC impacts on the stability of STIs, which governs the dynamics of STIs as well as that of the inlet-adjacent coastline, can result in significant socio economic consequences due to the heavy human utilisation of these systems and their surrounds. This article demonstrates the application of a process based snap-shot modelling approach, using the coastal morphodynamic model Delft3D, to 3 case study sites representing the 3 main STI types; Permanently open, locationally stable inlets (Type 1), Permanently open, alongshore migrating inlets (Type 2) and Seasonally/Intermittently open, locationally stable inlets (Type 3). The 3 case study sites (Negombo lagoon - Type 1, Kalutara lagoon - Type 2, and Maha Oya river - Type 3) are all located along the southwest coast of Sri Lanka. After successful hydrodynamic and morphodynamic model validation at the 3 case study sites, CC impact assessment are undertaken for a high end greenhouse gas emission scenario. Future CC modified wave and riverflow conditions are derived from a regional scale application of spectral wave models (WaveWatch III and SWAN) and catchment scale applications of a hydrologic model (CLSM) respectively, both of which are forced with IPCC Global Climate Model output dynamically downscaled to ~ 50 km resolution over the study area with the stretched grid Conformal Cubic Atmospheric Model CCAM. Results show that while all 3 case study STIs will experience significant CC driven variations in their level of stability, none of them will change Type by the year 2100. Specifically, the level of stability of the Type 1 inlet will decrease from 'Good' to 'Fair to poor' by 2100, while the level of (locational) stability of the Type 2 inlet will also decrease with a doubling of the annual migration distance. Conversely, the stability of the Type 3 inlet will increase, with the time till inlet closure increasing by ~75%. The main contributor to the overall CC effect on the stability of all 3 STIs is CC driven variations in wave conditions and resulting changes in longshore sediment transport, not Sea level rise as commonly believed. PMID- 29230071 TI - West Hollywood is Not That Big on Anything But White People: Constructing "Gay Men of Color". AB - Rather than a defined endpoint that is waiting to be discovered or developed, racial and sexual identities can be considered social identities which are fluid, malleable, and socially created through a social process that defines what it means to be a member of a social group. This paper expands the work on how social identities are constructed by examining personal anecdotes used by gay men of color to discuss how they come to see themselves as "gay men of color." In doing so, we find that gay men of color use a number of cultural tropes that provide them the framework necessary to structure their experiences within a larger social context of a largely white, heterosexual society. Drawing on these cultural tropes, gay men of color create a social identity that is simultaneously raced and sexed through the use of shared cultural tropes that define what it means to be a member of this group. PMID- 29230072 TI - Synthesis of cananodine by intramolecular epoxide opening. AB - Cananodine is a guaipyridine alkaloid with activity against liver cancer. Cananodine was synthesized using a remarkable intramolecular opening of a trisubstituted epoxide as the key step in construction of the seven-membered carbocycle of the target. The epoxide opening strategy allows all four stereoisomers of cananodine to be prepared. PMID- 29230073 TI - Selective alkylation/oxidation of N-substituted isoindolinone derivatives: synthesis of N-phthaloylated natural and unnatural alpha-amino acid analogues. AB - The interchangeability of the isoindolinone group as a nitrogen protecting group for amino acid intermediates is demonstrated by the preparation of several natural and unnatural alpha-amino acid derivatives using a two-carbon N isoindolinone (phthalimidine) scaffold. Using a selective benzylic oxidation, the N-isoindolinone group is then converted to the N-phthaloyl group for convenient removal (65-98%). For preparation of the isoindolinone products which were to be the substrates for benzylic oxidation, a range of side chains were installed on the isoindolinone-protected glycine equivalent on deprotonation to demonstrate the utility of the N-protected isoindolinone synthon (51-93%). While the ensuing benzylic oxidation is employed successfully for converting the N-isoindolinone group to the N-phthaloyl group in simple substrates, substrates bearing unsaturated or electron-rich side chains respond poorly to the oxidation. PMID- 29230074 TI - Reference Correlations for the Viscosity and Thermal Conductivity of n-Undecane. AB - This paper presents new wide-ranging correlations for the viscosity and thermal conductivity of n-undecane based on critically evaluated experimental data. The correlations are designed to be used with a recently published equation of state that is valid from the triple point to 700 K, at pressures up to 500 MPa, with densities below 776.86 kg m-3. The estimated uncertainty for the dilute-gas viscosity is 2.4%, and the estimated uncertainty for viscosity in the liquid phase for pressures up to 60 MPa over the temperature range 260 K to 520 K is 5%. The estimated uncertainty is 3% for the thermal conductivity of the low-density gas, and 3% for the liquid over the temperature range from 284 K to 677 K at pressures up to 400 MPa. Both correlations behave in a physically reasonable manner when extrapolated to the full range of the equation of state, however care should be taken when using the correlations outside of the validated range. The uncertainties will be larger outside of the validated range, and also in the critical region. PMID- 29230075 TI - Personality Predicts Mortality Risk: An Integrative Data Analysis of 15 International Longitudinal Studies. AB - This study examined the Big Five personality traits as predictors of mortality risk, and smoking as a mediator of that association. Replication was built into the fabric of our design: we used a Coordinated Analysis with 15 international datasets, representing 44,094 participants. We found that high neuroticism and low conscientiousness, extraversion, and agreeableness were consistent predictors of mortality across studies. Smoking had a small mediating effect for neuroticism. Country and baseline age explained variation in effects: studies with older baseline age showed a pattern of protective effects (HR<1.00) for openness, and U.S. studies showed a pattern of protective effects for extraversion. This study demonstrated coordinated analysis as a powerful approach to enhance replicability and reproducibility, especially for aging-related longitudinal research. PMID- 29230076 TI - Cohort-Sequential Study of Conflict Inhibition during Middle Childhood. AB - This longitudinal study examined developmental changes in conflict inhibition and error correction in three cohorts of children (5, 7, and 9 years of age). At each point of assessment children completed three levels of Luria's tapping task (1980), which requires the inhibition of a dominant response and maintenance of task rules in working memory. Findings suggest that both conflict inhibition and error detection and correction improve significantly during middle childhood. When cognitive demands were high, conflict inhibition, as shown by initial response accuracy, improved steadily across middle childhood. In contrast, the ability to detect and correct for errors improved between 5 and 6 years of age. Further, variability in conflict inhibition decreased with age and individual differences in conflict inhibition were stable across the one-year period in 7- and 9-year-old, but not 5-year-old children. These findings are discussed in relation to previous research on the development of inhibition. PMID- 29230077 TI - Spanish Instruction in Head Start and Dual Language Learners' Academic Achievement. AB - Data from the Head Start Impact Study (N = 1,141) and the Head Start Family and Child Experiences Survey, 2009 Cohort (N = 825) were used to investigate whether Spanish instruction in Head Start differentially increased Spanish-speaking Dual Language Learners' (DLLs) academic achievement. Although hypothesized that Spanish instruction would be beneficial for DLLs' early literacy and math skills, results from residualized growth models showed there were no such positive associations. Somewhat surprisingly, DLL children instructed in Spanish had higher English receptive vocabulary skills at the end of the Head Start year than those not instructed, with children randomly assigned to Head Start and instructed in Spanish having the highest scores. Policy implications for Head Start-eligible Spanish-speaking DLLs are discussed. PMID- 29230079 TI - Development of a food composition database to monitor changes in packaged foods and beverages. AB - In order to monitor nutritional changes in the US food supply and assess potential impact on individual dietary intake, an approach was developed to enhance existing standard food composition tables with time-varying product- and brand-specific information for barcoded packaged foods. A "Crosswalk" was formed between barcoded products and USDA foodcodes in a time-specific manner, such that sales-weighted average nutritional profiles were generated for each foodcode based on corresponding products (275,000 to 350,000 per 2-year cycle). This Crosswalk-enhanced food composition table was applied to dietary intake data from the National Health and Nutrition Examination Survey (cycles 2007-2008, 2009 2010, and 2011-2012). Total energy density of foods consumed by Americans from stores/vending was stable over time and differed by <5 kcal/100g using the Crosswalk-enhanced vs standard database. However, changes in the energy density of food groups were found utilizing the Crosswalk that were not detected using the standard database. Likewise, significant declines in energy intake from beverages among children (288+/-7.3 to 258+/-6.8 kcal/d) were found using the Crosswalk-enhanced database but were non-significant using the standard database. The Crosswalk approach can potentially augment national nutrition surveys by utilizing commercial food purchase and nutrient databases to capture changes in the nutrient content of packaged foods. PMID- 29230078 TI - X-ray excited luminescent chemical imaging (XELCI) for non-invasive imaging of implant infections. AB - X-ray excited luminescent chemical imaging (XELCI) uses a combination of X-ray excitation to provide high resolution and optical detection to provide chemical sensing. A key application is to detect and study implant-associated infection. The implant is coated with a layer of X-ray scintillators which generate visible near infrared light when irradiated with an X-ray beam. This light first passes through a pH indicator dye-loaded film placed over the scintillator film in order to modulate the luminescence spectrum according to pH. The light then passes through tissue is collected and the spectral ratio measured to determine pH. A focused X-ray beam irradiates a point in the scintillator film, and a pH image is formed point-by-point by scanning the beam across the sample. The sensor and scanning system are described along with preliminary results showing images in rabbit models. PMID- 29230080 TI - Cancer Victim Identity for Individuals with Histories of Cancer and Childhood Sexual Abuse. AB - Identifying as a 'cancer victim' has been linked to adverse psychosocial sequelae in individuals who have been diagnosed with cancer. Being a childhood sexual abuse (CSA) survivor may predispose individuals towards a "victim" identity in general. The aim of this study was to determine the prevalence of identifying as a 'cancer victim' among CSA survivors who were diagnosed with cancer as adults, and to explore psychological factors associated with identification as a cancer victim. 105 adults reporting both a history of CSA and of having been diagnosed with cancer as an adult were recruited through Amazon Mechanical Turk. Variables assessed included CSA severity, abuse-related powerlessness, general mastery, and cancer victim identity. Fifty-one percent of the sample endorsed a cancer victim identity. Path analysis revealed that abuse-related powerlessness was related to decreased feelings of general mastery, which was in turn associated with cancer victim identification (x2 = .12, DF = 1, p < .73; RMSEA = .00; SRMR = .01: Bentler CFI = 1.0). From a clinical perspective, the results suggest that increasing general mastery in CSA survivors in the cancer setting may be an important mechanism for attenuating the risk for developing a cancer victim identity and, presumably, for downstream adverse psychosocial sequelae. PMID- 29230083 TI - Temperature Measurement and Damage Detection in Concrete Beams Exposed to Fire Using PPP-BOTDA Based Fiber Optic Sensors. AB - In this study, distributed fiber optic sensors based on pulse pre-pump Brillouin optical time domain analysis (PPP-BODTA) are characterized and deployed to measure spatially-distributed temperatures in reinforced concrete specimens exposed to fire. Four beams were tested to failure in a natural gas fueled compartment fire, each instrumented with one fused silica, single-mode optical fiber as a distributed sensor and four thermocouples. Prior to concrete cracking, the distributed temperature was validated at locations of the thermocouples by a relative difference of less than 9 %. The cracks in concrete can be identified as sharp peaks in the temperature distribution since the cracks are locally filled with hot air. Concrete cracking did not affect the sensitivity of the distributed sensor but concrete spalling broke the optical fiber loop required for PPP-BOTDA measurements. PMID- 29230084 TI - Ionizing radiation processing and its potential in advancing biorefining and nanocellulose composite materials manufacturing. AB - Nanocellulose is a high value material that has gained increasing attention because of its high strength, stiffness, unique photonic and piezoelectric properties, high stability and uniform structure. Through utilization of a biorefinery concept, nanocellulose can be produced in large volumes from wood at relatively low cost via ionizing radiation processing. Ionizing radiation causes significant break down of the polysaccharide and leads to the production of potentially useful gaseous products such as H2 and CO. The application of radiation processing to the production of nanocellulose from woody and non-wood sources, such as field grasses, bio-refining byproducts, industrial pulp waste, and agricultural surplus materials remains an open field, ripe for innovation and application. Elucidating the mechanisms of the radiolytic decomposition of cellulose and the mass generation of nanocellulose by radiation processing is key to tapping into this source of nanocelluose for the growth of nanocellulostic product development. More importantly, understanding the structural break-up of the cell walls as a function of radiation exposure is a key goal and only through careful, detailed characterization and dimensional metrology can this be achieved at the level of detail that is needed to further the growth of large scale radiation processing of plant materials. This work is resulting from strong collaborations between NIST and its academic partners who are pursuing the unique demonstration of applied ionizing radiation processing to plant materials as well as the development of manufacturing metrology for novel nanomaterials. PMID- 29230081 TI - Hand Rehabilitation Robotics on Poststroke Motor Recovery. AB - The recovery of hand function is one of the most challenging topics in stroke rehabilitation. Although the robot-assisted therapy has got some good results in the latest decades, the development of hand rehabilitation robotics is left behind. Existing reviews of hand rehabilitation robotics focus either on the mechanical design on designers' view or on the training paradigms on the clinicians' view, while these two parts are interconnected and both important for designers and clinicians. In this review, we explore the current literature surrounding hand rehabilitation robots, to help designers make better choices among varied components and thus promoting the application of hand rehabilitation robots. An overview of hand rehabilitation robotics is provided in this paper firstly, to give a general view of the relationship between subjects, rehabilitation theories, hand rehabilitation robots, and its evaluation. Secondly, the state of the art hand rehabilitation robotics is introduced in detail according to the classification of the hardware system and the training paradigm. As a result, the discussion gives available arguments behind the classification and comprehensive overview of hand rehabilitation robotics. PMID- 29230085 TI - Finding Pure Sub-Models for Improved Differentiation of Bi-Factor and Second Order Models. AB - Several studies have indicated that bi-factor models fit a broad range of psychometric data better than alternative multidimensional models such as second order models, e.g Rodriguez, Reise and Haviland (2016), Gignac (2016), and Carnivez (2016). Murray and Johnson (2013) and Gignac (2016) argue that this phenomenon is partially due to un-modeled complexities (e.g. un-modeled cross factor loadings) that induce a bias in standard statistical measures that favors bi-factor models over second-order models. We extend the Murray and Johnson simulation studies to show how the ability to distinguish second-order and bi factor models diminishes as the amount of un-modeled complexity increases. By using theorems about rank constraints on the covariance matrix to find sub-models of measurement models that have less un-modeled complexity, we are able to reduce the statistical bias in favor of bi-factor models; this allows researchers to reliably distinguish between bi-factor and second-order models. PMID- 29230086 TI - Psychometric Study of the Pain Drawing. AB - Purpose: The objectives of the study were to (1) assess the extent to which interrater reliability of pain drawing location and dispersion scoring methods are similar across pain disciplines in a sample of patients with cancer treatment induced neuropathic pain (N = 56) and (2) investigate indicators of validity of the pain drawing in this unique sample. Methods: Patients undergoing cancer therapy completed the Brief Pain Inventory Body Map, the MD Anderson Symptom Inventory, and the McGill Pain Questionnaire. Results: Intraclass correlation coefficients among medical and psychology professionals ranged from .93-.99. Correlations between pain drawing score and symptom burden severity ranged from .29-.39; correlations between pain drawing score and symptom burden interference ranged from .28-.34. Patients who endorsed pain in the hands and feet more often described their pain as electric, numb, and shooting than patients without pain in the hands and feet. They also endorsed significantly more descriptors of neuropathic pain. Conclusions: Results suggest a similar understanding among members of a multidisciplinary pain team as to the location and dispersion of pain as represented by patients' pain drawings. In addition, pain drawing scores were related to symptom burden severity and interference and descriptors of neuropathic pain in expected ways. PMID- 29230082 TI - Recent Advances in ADAM17 Research: A Promising Target for Cancer and Inflammation. AB - Since its discovery, ADAM17, also known as TNFalpha converting enzyme or TACE, is now known to process over 80 different substrates. Many of these substrates are mediators of cancer and inflammation. The field of ADAM metalloproteinases is at a crossroad with many of the new potential therapeutic agents for ADAM17 advancing into the clinic. Researchers have now developed potential drugs for ADAM17 that are selective and do not have the side effects which were seen in earlier chemical entities that targeted this enzyme. ADAM17 inhibitors have broad therapeutic potential, with properties ranging from tumor immunosurveillance and overcoming drug and radiation resistance in cancer, as treatments for cardiac hypertrophy and inflammatory conditions such as inflammatory bowel disease and rheumatoid arthritis. This review focuses on substrates and inhibitors identified more recently for ADAM17 and their role in cancer and inflammation. PMID- 29230087 TI - Nest design in a changing world: great tit Parus major nests from a Mediterranean city environment as a case study. AB - Investigations of urbanization effects on birds have focused mainly on breeding traits expressed after the nest-building stage (e.g. first-egg date, clutch size, breeding success, and offspring characteristics). Urban studies largely ignored how and why the aspects of nest building might be associated with the degree of urbanization. As urban environments are expected to present novel environmental changes relative to rural environments, it is important to evaluate how nest building behavior is impacted by vegetation modifications associated with urbanization. To examine nest design in a Mediterranean city environment, we allowed urban great tits (Parus major) to breed in nest boxes in areas that differed in local vegetation cover. We found that different measures of nest size or mass were not associated with vegetation cover. In particular, nests located adjacent to streets with lower vegetation cover were not smaller or lighter than nests in parks with higher vegetation cover. Nests adjacent to streets contained more pine needles than nests in parks. In addition, in nests adjacent to streets, nests from boxes attached to pine trees contained more pine needles than nests from boxes attached to other trees. We suggest that urban-related alterations in vegetation cover do not directly impose physical limits on nest size in species that are opportunistic in the selection of nesting material. However, nest composition as reflected in the use of pine needles was clearly affected by habitat type and the planted tree species present, which implies that rapid habitat change impacts nest composition. We do not exclude that urbanization might impact other aspects of nest building behaviour not covered in our study (e.g. costs of searching for nest material), and that the strengths of the associations between urbanization and nest structures might differ among study populations or species. PMID- 29230088 TI - Measurement of Neighborhood Context in an Urban Cohort of HIV-infected or at risk Low-Income Women. AB - The study of neighborhood disadvantage and health relies on census socioeconomic data but would benefit from reliable survey measures of factors that influence health within low income communities. The Perceptions of Neighborhood Environment Scale (PNES) was developed for use in the general U.S. population, and its measurement properties in a cohort of low-income urban women living with or at risk for HIV are described. The scale and all but one subscale have good psychometric and ecometric reliability, as well as convergent, construct, and concurrent validity, and are not collinear with household and community area income in low-income urban neighborhoods. PMID- 29230089 TI - Study on Effects of Titanium Surface Microporous Coatings Containing Zinc on Osteoblast Adhesion and Its Antibacterial Activity. AB - Metal surface structure/biomedical function integration is the current research focus. In previous studies, we have successfully prepared the microporous coatings containing zinc on the pure titanium surface by MAO. In the study, osteoblasts were seeded on the surface of the microporous coatings containing zinc and the adhesion of osteoblasts were evaluated, and the antibacterial activity of the microporous coatings containing zinc is observed through in vitro bacterial experiments. The result indicates that the adhesion ability of osteoblasts on the surface of microporous coatings containing zinc was very good, and the coatings could obviously inhibit the growth of Staphylococcus aureus and had good antibacterial activity. In conclusion, the microporous coatings containing zinc on titanium surface have good osteogenic and antibacterial properties and have good application prospect. PMID- 29230090 TI - Calcium Dynamics and Cardiac Arrhythmia. AB - This Special Collection will gather all studies highlighting recent advances in theoretical and experimental studies of arrhythmia, with a specific focus on research seeking to elucidate links between calcium homeostasis in cardiac cells and organ-scale disruption of heart rhythm. PMID- 29230091 TI - Spatiotemporal multivariate mixture models for Bayesian model selection in disease mapping. AB - It is often the case that researchers wish to simultaneously explore the behavior of and estimate overall risk for multiple, related diseases with varying rarity while accounting for potential spatial and/or temporal correlation. In this paper, we propose a flexible class of multivariate spatio-temporal mixture models to fill this role. Further, these models offer flexibility with the potential for model selection as well as the ability to accommodate lifestyle, socio-economic, and physical environmental variables with spatial, temporal, or both structures. Here, we explore the capability of this approach via a large scale simulation study and examine a motivating data example involving three cancers in South Carolina. The results which are focused on four model variants suggest that all models possess the ability to recover simulation ground truth and display improved model fit over two baseline Knorr-Held spatio-temporal interaction model variants in a real data application. PMID- 29230093 TI - TLD and OSLD dosimetry systems for remote audits of radiotherapy external beam calibration. AB - The Imaging and Radiation Oncology Core QA Center in Houston (IROC-H) performs remote dosimetry audits of more than 20,000 megavoltage photon and electron beams each year. Both a thermoluminescent dosimeter (TLD-100) and optically stimulated luminescent dosimeter (OSLD; nanoDot) system are commissioned for this task, with the OSLD system being predominant due to the more time-efficient read-out process. The measurement apparatus includes 3 TLD or 2 OSLD in an acrylic mini phantom, which are irradiated by the institution under reference geometry. Dosimetry systems are calibrated based on the signal-to-dose conversion established with reference dosimeters irradiated in a Co-60 beam, using a reference dose of 300 cGy for TLD and 100 cGy for OSLD. The uncertainty in the dose determination is 1.3% for TLD and 1.6% for OSLD at the one sigma level. This accuracy allows for a tolerance of +/-5% to be used. PMID- 29230092 TI - Fetomaternal and Pediatric Toxoplasmosis. AB - Toxoplasmosis is one of the most important causes of foodborne illnesses and inflammatory complications, as well as congenital disorders. Promiscuous Toxoplasma is transmitted by contaminated food and animal produce, water, vegetations, fruits and sexually through semen. Toxoplasma infects nucleated cells with a unique tropism for muscles and central nervous system and a mind bugging malicious effect. Pregnant women with acute or reactivated toxoplasmosis can transmit Toxoplasma via transplacental to the fetus. The severity of congenital toxoplasmosis depends on the gestation period, as infection in early pregnancy causes more severe consequences. Congenital toxoplasmosis complications include miscarriage, encephalitis, neurological retardation, mental illnesses, auditory and visual inflammatory disorders, cardiovascular abnormalities, and pains. Current therapies are inefficient for congenital and chronic toxoplasmosis or have severe side effects with life threatening complications. There is an urgent need for effective and safe therapeutic modalities to treat complications of toxoplasmosis and effective vaccines to eliminate the infectious agent. This investigation will discuss pathogenesis of feto-maternal, congenital and pediatric toxoplasmosis, the current available therapies in practice, and explore those therapeutic modalities in experimental stages for promising future trials. PMID- 29230094 TI - Application of Finite Element, Phase-field, and CALPHAD-based Methods to Additive Manufacturing of Ni-based Superalloys. AB - Numerical simulations are used in this work to investigate aspects of microstructure and microseg-regation during rapid solidification of a Ni-based superalloy in a laser powder bed fusion additive manufacturing process. Thermal modeling by finite element analysis simulates the laser melt pool, with surface temperatures in agreement with in situ thermographic measurements on Inconel 625. Geometric and thermal features of the simulated melt pools are extracted and used in subsequent mesoscale simulations. Solidification in the melt pool is simulated on two length scales. For the multicomponent alloy Inconel 625, microsegregation between dendrite arms is calculated using the Scheil-Gulliver solidification model and DICTRA software. Phase-field simulations, using Ni-Nb as a binary analogue to Inconel 625, produced microstructures with primary cellular/dendritic arm spacings in agreement with measured spacings in experimentally observed microstructures and a lesser extent of microsegregation than predicted by DICTRA simulations. The composition profiles are used to compare thermodynamic driving forces for nucleation against experimentally observed precipitates identified by electron and X-ray diffraction analyses. Our analysis lists the precipitates that may form from FCC phase of enriched interdendritic compositions and compares these against experimentally observed phases from 1 h heat treatments at two temperatures: stress relief at 1143 K (870 degrees C) or homogenization at 1423 K (1150 degrees C). PMID- 29230095 TI - CRISPR-offinder: a CRISPR guide RNA design and off-target searching tool for user defined protospacer adjacent motif. AB - Designing efficient and specific CRISPR single-guide RNAs (sgRNAs) is vital for the successful application of CRISPR technology. Currently, a growing number of new RNA-guided endonucleases with a different protospacer adjacent motif (PAM) have been discovered, suggesting the necessity to develop a versatile tool for designing sgRNA to meet the requirement of different RNA-guided DNA endonucleases. Here, we report the development of a flexible sgRNA design program named "CRISPR-offinder". Support for user-defined PAM and sgRNA length was provided to increase the targeting range and specificity. Additionally, evaluation of on- and off-target scoring algorithms was integrated into the CRISPR-offinder. The CRISPR-offinder has provided the bench biologist a rapid and efficient tool for identification of high quality target sites, and it is freely available at https://sourceforge.net/projects/crispr-offinder-v1-2/ or http://www.biootools.com. PMID- 29230097 TI - The Molecular Mechanisms of Regulation on USP2's Alternative Splicing and the Significance of Its Products. AB - Ubiquitin-specific protease 2 (USP2) has a regulatory function in cell growth or death and is involved in the pathogenesis of various diseases. USP2 gene can generate 7 splicing variants through alternative splicing, and 5 variants respectively as USP2-201, USP2-202, USP2-204, USP2-205, USP2-206 can encode proteins. The influence of circadian rhythm, nutrition and androgen on specific signaling molecules or cytokines can regulate the alternative splicing of USP2. Specifically, PKC activator, IL-1beta, TNF-alpha, PDGF-BB, TGF-beta1 are all regulatory factors for USP2's alternative splicing. USP2-201 plays a crucial role in cell cycle progression, and is also of great significance in EGFR recycling. USP2-202 can activate apoptosis signaling pathway to participate in cell apoptosis, and USP2-204 can induce cell anti-virus reaction to decrease. In general, we collect and summarize the factors involved in the alternative splicing of USP2 in this review to further understand the mechanism behind the USP2's alternative splicing. PMID- 29230096 TI - Fibroblast Growth Factor Receptor 2 (FGFR2) Mutation Related Syndromic Craniosynostosis. AB - Craniosynostosis results from the premature fusion of cranial sutures, with an incidence of 1 in 2,100-2,500 live births. The majority of cases are non syndromic and involve single suture fusion, whereas syndromic cases often involve complex multiple suture fusion. The fibroblast growth factor receptor 2 (FGFR2) gene is perhaps the most extensively studied gene that is mutated in various craniosynostotic syndromes including Crouzon, Apert, Pfeiffer, Antley-Bixler, Beare-Stevenson cutis gyrata, Jackson-Weiss, Bent Bone Dysplasia, and Seathre Chotzen-like syndromes. The majority of these mutations are missense mutations that result in constitutive activation of the receptor and downstream molecular pathways. Treatment involves a multidisciplinary approach with ultimate surgical fixation of the cranial deformity to prevent further sequelae. Understanding the molecular mechanisms has allowed for the investigation of different therapeutic agents that can potentially be used to prevent the disorders. Further research efforts are need to better understand screening and effective methods of early intervention and prevention. Herein, the authors provide a comprehensive update on FGFR2-related syndromic craniosynostosis. PMID- 29230098 TI - Circular RNAs: A novel type of non-coding RNA and their potential implications in antiviral immunity. AB - Circular RNAs (circRNAs), a novel type of non-coding RNAs (ncRNAs), are ubiquitously expressed in eukaryotic cells during post-transcriptional processes. Unlike linear RNAs, circRNAs form covalent-closed continuous loops without 5' to 3' polarities and poly (A) tails. With advances in high-throughput sequencing technology, numerous circRNAs have been identified in plants, animals and humans. Notably, circRNAs display cell-type, tissue-type and developmental-stage specific expression patterns in eukaryotic transcriptome, which reveals their significant regulatory functions in gene expression. More importantly, circRNAs serve as microRNA (miRNA) sponges and crucial regulators of gene expression. Additionally, circRNAs modulate pre-mRNA alternative splicing and possess protein-coding capacity. CircRNAs exhibit altered expression under pathological conditions and are strongly associated with the development of various human diseases. Interestingly, circRNAs can also induce antiviral immune responses. A recent study found that the delivery of circRNAs generated in vitro activates RIG-I mediated innate immune responses and provides protection against viral infection. The antiviral dsRNA-binding proteins, NF90/NF110, act as key regulators in circRNA biogenesis. NF90/NF110 are also functional in inhibiting viral replication through binding to viral mRNAs. In this review, we provide a comprehensive overview on the classification, biogenesis and functions of circRNAs. We also discuss the critical role of circRNAs in eliciting antiviral immunity, providing evidence for the potential implications of circRNAs in antiviral therapies. PMID- 29230099 TI - The effect of co-transplantation of nerve fibroblasts and Schwann cells on peripheral nerve repair. AB - Combinations of fibroblasts (Fbs) and corresponding epithelial cells have been widely used in many tissues, such as the skin and breast tissues, to augment tissue repair and remodeling. Recently, a large amount of new data has indicated that nerve Fbs play critical roles in Schwann cells (SCs) and axons in vitro. However, little is known regarding the effects of co-transplanting nerve Fbs and SCs on peripheral nerve repair in vivo. The aim of this study was to investigate the effect of co-transplanting sciatic nerve Fbs (SN-Fbs) and sciatic nerve SCs (SN-SCs) on nerve regeneration. We developed a 5 mm nerve-defect model in mice using a polyurethane (PUR) catheter and then injected one of four different mixtures of cells into the catheters to form the following four groups: pure Matrigel (Control group), SN-Fbs alone (SN-Fb group), SN-Fbs combined with SN-SCs at a ratio of 1:2 (Fb&SC group) and SN-SCs alone (SN-SC group). Histological and functional analyses were performed 3 months later. The results indicated that in vitro, the expression levels of NGF, BDNF and GDNF were significantly higher, and in vivo, a more moderate amount of extracellular matrix was produced in the Fb&SC group than in the SN-SC group. Compared to the other groups, co-transplanting SN Fbs with SCs at a 1:2 ratio had significantly positive effects on nerve regeneration and functional recovery. PMID- 29230100 TI - Dl-3-n-butylphthalide prevents the disruption of blood-spinal cord barrier via inhibiting endoplasmic reticulum stress following spinal cord injury. AB - After spinal cord injury (SCI), the destruction of blood-spinal cord barrier (BSCB) is shown to accelerate gathering of noxious blood-derived components in the nervous system, leading to secondary neurodegenerative damages. SCI activates endoplasmic reticulum stress (ER stress), which is considered to evoke secondary damages of neurons and glia. Recent evidence indicates that Dl-3-n-butylphthalide (NBP) has the neuroprotective effect in ischaemic brain injury, but whether it has protective effects on SCI or not is largely unclear. Here, we show that NBP prevented BSCB disruption after SCI via inhibition of ER stress. Following a moderate contusion injury of the T9 level of spinal cord, NBP was administered by oral gavage and further treated once a day. NBP significantly attenuated BSCB permeability and breakdown of adherens junction (AJ) and tight junction (TJ) proteins, then improved locomotion recovery following SCI. The protective role of NBP on BSCB disruption is associated with the restrain of ER stress caused by SCI. Furthermore, NBP considerably constrained the expression of ER stress associated proteins and degradation of TJ and AJ in human brain microvascular endothelial cells (HBMECs) treated with TG. In conclusion, our results indicate that ER stress is associated with the disruption of BSCB integrity after injury, NBP attenuates BSCB disruption via inhibiting ER stress and improve functional recovery following SCI. PMID- 29230101 TI - Azadirachtin induced apoptosis in the prothoracic gland in Bombyx mori and a pronounced Ca2+ release effect in Sf9 cells. AB - Azadirachtin is a bio-rational insecticide used as an antifeedant and growth disruption agent against many insect species. However, recent studies have shown that there is a potential risk of this compound harming some beneficial insects. In such cases its application does not normally lead to death, but it may result in altered developmental regulation. Therefore, it is essential to obtain toxicological data to understand the mechanism of such sub-lethal effects, especially where they relate to important beneficial insects. Here, we found that azadirachtin could regulate growth and cocooning in silkworms, which may be associated with induced apoptotic effect on the prothoracic gland. However, azadirachtin treatment could not induce apoptosis in the prothoracic gland in vitro, in contrast to the effect of 20-hydroxyecdysone in vitro, which suggesting that the apoptosis might not be direct effect of azadirachtin. Then we examined the activity of Ca2+-Mg2+-ATPase and found that azadirachtin could trigger a significant increase in intracellular Ca2+ release in the Sf9 cell line, which suggested that the calcium signaling pathway might be involved in the process of apoptosis in prothoracic gland and growth regulation in vivo silkworms. Although more evidence is needed to fully understand the mechanism of azadirachtin in perturbing the growth of silkworms, this study provides some toxicological information and highlights the potential risks of azadirachtin in relation to silkworms. PMID- 29230102 TI - Specific Deletion of beta-Catenin in Col2-Expressing Cells Leads to Defects in Epiphyseal Bone. AB - The role of canonical Wnt/beta-catenin signaling in postnatal bone growth has not been fully defined. In the present studies, we generated beta-catenin conditional knockout (KO) mice and deleted beta-catenin in Col2-expressing chondrocytes and mesenchymal progenitor cells. Findings from analyzing the beta-cateninCol2CreER KO mice revealed severe bone destruction and bone loss phenotype in epiphyseal bone, probably due to the increase in osteoclast formation and the accumulation of adipocytes in this area. In addition, we also found bone destruction and bone loss phenotype in vertebral bone in beta-cateninCol2CreER KO mice. These findings indicate that beta-catenin signaling plays a critical role in postnatal bone remodeling. Our study provides new insights into the regulation of epiphyseal bone homeostasis at postnatal stage. PMID- 29230103 TI - Oxygen Supplementation Ameliorates Tibial Development via Stimulating Vascularization in Tibetan Chickens at High Altitudes. AB - Tibetan chickens (TBCs) living in high-altitude hypoxic environment, are characterized by delayed growth and small size as compared to low-altitude broiler chickens. Increasing evidences signify the beneficial effect of oxygen (O2) supplementation in animal's body for regulating their body growth and organ development. However, it is still unclear that whether O2 supplementation has an ameliorative and protective role in TBCs living at high altitude. In this study, we first found that O2 supplementation not only increased the survival rate but also promoted the growth of TBCs associated with bone development. Importantly, we observed that the increase of vascular distribution in the tibial hypertrophic zone could contribute to promote growth and development of the tibia, which is highly correlated with the up-regulated expression level of vascular endothelial growth factor (VEGF)-A and VEGF receptor-1 (VEGFR1). Additionally, hypoxia inducible factor (HIF)-1alpha also has a stimulative elevation by O2 supplementation. These results were confirmed by histology, immunohistochemistry, qRT-PCR and Western blotting techniques. Altogether, these findings demonstrated that the up-regulation of VEGFA and its receptors are accompanied by proangiogeneic factor (HIF-1alpha) expression, which were required for angiogenesis to meliorate tibia development of TBCs in hypoxia-induced bone suppression that occurred during O2 supplementation. Thus, O2 supplementation may serve as a good applicant for promoting and meliorating bone development in juvenile high-altitude animals. PMID- 29230106 TI - From The Editor's Desk: A Focus on Cancer Services. PMID- 29230104 TI - Metformin Sensitizes Non-small Cell Lung Cancer Cells to an Epigallocatechin-3 Gallate (EGCG) Treatment by Suppressing the Nrf2/HO-1 Signaling Pathway. AB - Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. (-) Epigallocatechin-3-gallate (EGCG), a major polyphenol in green tea, is widely studied as a cancer chemopreventive agent with potential anti-cancer effects. The NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway is considered to mediate cellular resistance to EGCG. Metformin, a classical antidiabetic drug, has been shown to prevent cancer progression. Researchers have not reported whether metformin potentiates the anti-cancer efficacy of EGCG. In this study, metformin inhibited HO-1 expression and augmented the anti-tumor effect of EGCG. Metformin also enhanced ROS (reactive oxygen species) generation induced by EGCG (100 MUM), subsequently resulting in apoptosis. Based on the results of the in vivo study, size of xenografts treated with the combination of metformin and EGCG was smaller than other groups. Mechanistically, metformin modulated the EGCG-activated Nrf2/HO-1 pathway through Sirtuin 1 (SIRT1) dependent deacetylation of Nrf2. Moreover, metformin upregulated SIRT1 expression partially through the NF-kB pathway. Comparatively, the combination of EGCG and metformin showed little impact on normal lung epithelial BEAS-2B cells. Based on our findings, metformin sensitized NSCLC cells to the EGCG treatment by suppressing the Nrf2/HO-1 signaling pathway. PMID- 29230107 TI - From the Guest Editor: The Rapidly Changing Field of Cancer Treatment. PMID- 29230105 TI - Growth Characteristics of Methanomassiliicoccus luminyensis and Expression of Methyltransferase Encoding Genes. AB - DNA sequence analysis of the human gut revealed the presence a seventh order of methanogens referred to as Methanomassiliicoccales. Methanomassiliicoccus luminyensis is the only member of this order that grows in pure culture. Here, we show that the organism has a doubling time of 1.8 d with methanol + H2 and a growth yield of 2.4 g dry weight/mol CH4. M. luminyensis also uses methylamines + H2 (monomethylamine, dimethylamine, and trimethylamine) with doubling times of 2.1-2.3 d. Similar cell yields were obtained with equimolar concentrations of methanol and methylamines with respect to their methyl group contents. The transcript levels of genes encoding proteins involved in substrate utilization indicated increased amounts of mRNA from the mtaBC2 gene cluster in methanol grown cells. When methylamines were used as substrates, mRNA of the mtb/mtt operon and of the mtmBC1 cluster were found in high abundance. The transcript level of mtaC2 was almost identical in methanol- and methylamine-grown cells, indicating that genes for methanol utilization were constitutively expressed in high amounts. The same observation was made with resting cells where methanol always yielded the highest CH4 production rate independently from the growth substrate. Hence, M. luminyensis is adapted to habitats that provide methanol + H2 as substrates. PMID- 29230108 TI - Letter To The Editor: Ertapenem-Induced Acute Pancreatitis in a Cirrhotic Patient. PMID- 29230109 TI - Letter To The Editor: Reply to Polio Eradication in Pakistan: Call for Alliance. PMID- 29230110 TI - Letter To The Editor: Management of Aortic Root Thrombosis After Implantation of a Continuous-Flow Left Ventricular Assist Device: A Real Conundrum. PMID- 29230111 TI - Letter To The Editor: Catheter Track Metastasis With Indwelling Pleural Catheter. PMID- 29230112 TI - Clinical Images: Transjugular Intrahepatic Portosystemic Shunt Reduction for Management of Recurrent Hepatic Encephalopathy. PMID- 29230113 TI - Bioethics In Practice: Understanding Understood Consent. PMID- 29230114 TI - Building a Phase 1 Cancer Research Program: Lessons Learned and Progress Made. PMID- 29230115 TI - Interval Colorectal Cancers at Ochsner Medical Center: Where Do We Stand? AB - Background: An interval colorectal cancer is a cancer diagnosed prior to the recommended follow-up time from a previously negative colonoscopy. These cancers are thought to arise from a rapidly growing cancer, missed cancer, or incompletely resected adenomas. Our study aimed to identify interval cancers diagnosed during a 4-year period and to identify any potential risk factors associated with these cancers. Secondly, we compared our interval colorectal cancer rate with other published rates. Methods: Our population included all patients who underwent colonoscopy for any indication between August 1, 2010 and July 31, 2014 (n=28,794), excluding individuals <18 years and patients with a history of inflammatory bowel disease, previously diagnosed colorectal cancer, or known hereditary cancer syndrome. Using a retrospective review of our institution's electronic medical record and data from the Louisiana Tumor Registry, we identified patients who were diagnosed with colorectal cancer. From these individuals, we reviewed and selected those who met the criteria for interval cancers. Results: We identified 20 interval cancers during the 4-year study period. Based on the total number of index colonoscopies performed during the time period, our overall incidence rate was 0.07%. Approximately 1 interval cancer was diagnosed per 1,400 colonoscopy examinations. Our occurrence rate of 0.28 cases per 1,000 person-years of observation was less than or similar to the rates reported in other studies. Conclusion: Our study demonstrated that our institution has a low incidence of interval cancers, supporting the effectiveness of our cancer screening program. To further minimize interval colorectal cancers, we recommend the documentation and reporting of endoscopy quality measures, as well as close follow-up intervals or alternate examinations for patients who have poor bowel preparation or incomplete/difficult examinations. PMID- 29230116 TI - Overall Survival Associated With Ileostomy Closure in Patients With Rectal Cancer Before and After Adjuvant Therapy. AB - Background: A diverting loop ileostomy is commonly constructed to protect a distal anastomosis after proctectomy for rectal cancer. Little data are available on whether closing the ileostomy before or after adjuvant chemotherapy affects survival. Methods: We conducted a retrospective review of patients with rectal cancer who underwent a low anterior resection with diverting loop ileostomy followed by adjuvant chemotherapy at Ochsner Medical Center. The primary outcome was the long-term survival in patients who had their loop ileostomies closed before chemotherapy (BC) vs after chemotherapy (AC). Results: Seventy-two patients were identified (22 in the BC group vs 50 in the AC group). No difference in mean age (BC 59.5 +/- 9.8 vs AC 59.2 +/- 12.6, P=0.9) or preoperative clinical stage was seen between study groups. The mean interval from ileostomy creation to closure was significantly shorter in the BC group vs AC group (16.9 +/- 14.5 weeks vs 33.6 +/- 18.1 weeks, P=0.0001). Follow-up data revealed a similar mean duration from surgery to last contact (BC 50.6 +/- 23.6 months vs AC 43.5 +/- 22.1 months, P=0.23) and similar overall survival (BC 86% vs AC 70%, P=0.23) between groups. Conclusion: Long-term survival was similar in patients who underwent ileostomy closure before and after adjuvant therapy following low anterior resection for rectal cancer. While this study was underpowered, it adds additional insight to an area of surgery lacking significant data. The timing of ileostomy closure should be individualized for each patient. PMID- 29230117 TI - Outcomes of Patients With Late-Relapse Metastatic Renal Cell Carcinoma Treated With Targeted Therapies: A Single Institution Experience. AB - Background: Late relapse with presentation of metastatic disease >5 years after nephrectomy with curative intent is a known behavior of renal cell carcinoma (RCC), but data on outcomes, especially regarding targeted therapies, are limited. In this study, we analyze clinicopathologic features and response to targeted therapy in patients with late-relapse metastatic RCC (mRCC). Methods: We retrospectively reviewed clinical data on consecutive patients treated with targeted therapy for mRCC diagnosed >5 years after nephrectomy with curative intent. Results: A total of 24 patients (100% clear cell histology, median age 72 years, 83% males, all with prior nephrectomies) met inclusion criteria; 71% had favorable risk, and 25% had intermediate risk by International Metastatic Renal Cell Carcinoma Database Consortium criteria. The estimated median overall survival for all patients was 60.5 months, and the 3-year overall survival rate was 71.78% (95% confidence interval, 47.98%-84.77%). All patients were treated with targeted therapy; first-line treatments included pazopanib (46%), sorafenib (25%), sunitinib (17%), and cytokine (13%), with no significant difference in time to treatment failure between therapies. Median time on first-line therapy was 19.7 months; 67% of patients received second-line treatment. Metastases were detected at considerable rates in sites considered historically uncommon, such as the pancreas, adrenal glands, and soft tissue. Conclusion: Patients with late relapse mRCC treated with targeted therapy had prolonged survival that compared favorably to historical controls, and metastases in uncommon sites were noted. PMID- 29230118 TI - Prognostic Factors in Typical and Atypical Pulmonary Carcinoids. AB - Background: Typical and atypical carcinoids represent approximately 2% of all lung tumors. Survival of patients with typical bronchial carcinoids, unlike the survival of patients with most lung tumors, is generally long but dependent on stage. We report the findings of the Ochsner Medical Center/Louisiana State University (LSU) Health Sciences Center neuroendocrine tumor (NET) program. Methods: A database with all patients seen at the Ochsner Medical Center/LSU NET program was queried for patients with bronchopulmonary NET. We included patients who had confirmed pathologic bronchopulmonary carcinoid and who had at least 1 clinic visit. Patients with large or small cell NETs or diffuse idiopathic pulmonary neuroendocrine cell hyperplasia were excluded. Results: A total of 169 patients seen from January 1996 to March 2015 met the inclusion criteria. The mean age at diagnosis was 53 years. Of the tumors, 51% percent (86/169) were well differentiated, 12% (21/169) were moderately differentiated, and 85% and 53% were positive on positron emission tomography and octreotide scanning, respectively. The 5- and 10-year survival rates were 88% and 81% for well-differentiated tumors and 80% and 42% for moderately differentiated tumors, respectively. The 10-year survival rates stratified by Ki-67 index ranges 0-2%, >2%-10%, and >10% were 90%, 72%, and 44%, respectively (P<0.05). Conclusion: Overall, patients with bronchial carcinoids have long 5- and 10-year survival rates. We found significant survival differences between nodal status, differentiation status, and carcinoid phenotype. Interestingly, the difference in survival stratified by Ki-67 indices was statistically significant despite its absence in the World Health Organization grading system. As with gastroenteropancreatic NETs, Ki-67 index could become a valuable prognostic indicator for bronchial carcinoids. PMID- 29230119 TI - A Potential Additional Variable to Consider in the Surgical Treatment of Ductal Carcinoma in Situ. AB - Background: HER2/neu is a potentially interesting variable that has been demonstrated to have a profound impact on the management of invasive breast carcinoma, and we performed this study to evaluate the differences between HER2 positive and HER2-negative ductal carcinoma in situ. The impetus for this study was our poor recruitment to the National Surgical Adjuvant Breast and Bowel Project Protocol B-43 trial that was designed to evaluate the potential role of trastuzumab in breast conservation therapy for patients with HER2-positive ductal carcinoma in situ. Methods: All patients with ductal carcinoma in situ and an assessment for the HER2/neu receptor were identified. Patients with HER2-positive and HER2-negative ductal carcinoma in situ were compared to determine differences in demographic, hormone receptor status, nuclear grade, presence of necrosis, surgical procedure (lumpectomy or mastectomy), tumor size, and extent of margins. Quantitative variables were analyzed with t test, and nominal variables were assessed by chi square analysis. Results: A total of 177 patients were identified with a mean age of 61.0 years. A total of 101 patients (57.1%) were treated with lumpectomy, and 76 had mastectomy (42.9%). Forty-four (24.9%) patients were positive, and 133 (75.1%) were negative for the HER2/neu receptor. HER2-positive tumors were larger (23.6 vs 13.8 mm, P=0.001) and more likely to undergo mastectomy (61.4% vs 36.8%, P=0.01). Conclusion: Based on these results, an HER2 positive ductal carcinoma in situ is likely to be larger than an HER2-negative tumor, leading to more frequent use of mastectomy. This finding would explain our poor recruitment to the National Surgical Adjuvant Breast and Bowel Project Protocol B-43 trial. PMID- 29230120 TI - The Relationship Between Regional Anesthesia and Cancer: A Metaanalysis. AB - Background: Some studies have suggested using epidural analgesia after cancer surgery to reduce metastasis. This article examines the relationship between regional anesthesia (RA) and cancer metastasis in an array of cancers. Methods: We conducted a review of the literature using PubMed and included 67,577 patients across 28 studies in a metaanalysis, evaluating the hazard ratios (HRs) of overall survival, recurrence-free survival, and biochemical recurrence-free survival. Results: We found no benefit to RA as it relates to cancer. The HR was 0.92 for overall survival, 1.06 for recurrence-free survival, and 1.05 for biochemical recurrence-free survival. Despite the overall analysis showing no benefit, we found some benefit when we evaluated only the randomized trials. However, we found no significant benefit of RA when we evaluated the cancers (gastrointestinal, prostate, breast, and ovarian) individually. Conclusion: This metaanalysis shows that RA has no overall survival, recurrence-free survival, or biochemical recurrence-free survival benefit. However, some individual studies have shown significant benefit in terms of cancer recurrence. Further, RA reduces the use of opioids, which has led to some secondary benefits. Further studies are needed to establish the benefits of RA as it relates to cancer. PMID- 29230122 TI - The Role of Checkpoint Inhibition in Non-Small Cell Lung Cancer. AB - Background: The development of immune checkpoint inhibitors has revolutionized the treatment of cancer. Their use in non-small cell lung cancer (NSCLC) remains in its infancy, but rapid progress has been made in treating metastatic NSCLC. Methods: This article outlines the role of immune checkpoint inhibitors in the treatment of malignancy and reviews clinical trials of novel immunotherapies in the setting of metastatic NSCLC. Results: Traditional chemotherapy with a platinum-based doublet has long been the backbone in the treatment of metastatic NSCLC. While the treatment of NSCLC can be targeted to specific mutations such as epidermal growth factor receptor, these subgroups are rare. The development of immunotherapy has expanded the treatment options for patients who have failed initial chemotherapy. Additionally, new studies have shown positive results for the use of immunotherapy in the first-line setting under certain conditions, allowing pembrolizumab to become the first immunotherapy to be approved in the first-line setting. Conclusion: Treatment of NSCLC is constantly changing, and new immune checkpoint inhibitors have shown promising results. Clinical trials are examining their use in the adjuvant setting and in combination with other therapies, and these combination therapies have the potential to show even greater benefits and broader applications than the individual drugs themselves. PMID- 29230121 TI - Leptomeningeal Disease and the Evolving Role of Molecular Targeted Therapy and Immunotherapy. AB - Background: Leptomeningeal disease (LMD) is a complication that results from solid tumor metastasis. Prognosis is extremely poor. As therapeutic options for solid tumors improve, the rate of LMD continues to increase. Until recently, treatment has been limited to radiation therapy, intrathecal chemotherapy, and systemic chemotherapy, with an overall survival of 2-3 months. Targeted molecular therapy and immunotherapies are promising new options for increasing overall survival and clinical improvement; however, optimal clinical management remains unknown. Methods: In this review, we discuss targeted molecular therapy and immunotherapy treatment options for LMD resulting from primary lung, breast, and melanoma tumors. In addition, we summarize dosing strategies, overall survival, clinical outcomes, and novel approaches to treatment. Results: Our review indicates a deficiency in the current literature. Presently, intrathecal trastuzumab administration may be an effective option for patients with HER2 positive breast cancer. BRAF inhibitors and cytotoxic T lymphocyte-associated antigen-4 targets have shown promising results in LMD resulting from melanoma. Finally, tyrosine kinase inhibitors may increase overall survival in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Pulsatile drug administration or dual therapy may be beneficial for patients who progress to LMD while being treated with EGFR targets for their primary malignancy. Conclusion: Targeted molecular therapy and immunotherapy in LMD may provide favorable treatment options. Current literature is lacking in safety, efficacy, and overall response rates from the use of targeted therapy. Research is needed to draw significant conclusions about the most appropriate therapy for patients with LMD. PMID- 29230123 TI - Molecular Targets in Non-Small Cell Lung Cancer. AB - Background: Lung cancer is the second most common cancer in the United States among men and women, and it is the most common cause of cancer-related death. Non small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases. Historically, patients with metastatic NSCLC received similar cytotoxic chemotherapy regimens. Genotyping studies have revealed genetic/molecular abnormalities in lung cancer. These driver mutations render a cancer dependent on that specific mutation's biochemical pathway for its growth and survival. With the development of tyrosine kinase inhibitors and antibodies against specific driver mutations, the landscape of lung cancer treatment has changed from treatment based on histologic subtype to treatment based on molecularly defined subtypes. Methods: In this article, we review the current molecular-targeted therapies in lung cancer. Results: We review landmark trials that have led to approval of molecular-targeted therapies against epidermal growth factor receptor, anaplastic lymphoma kinase, and ROS1. We also explore less common mutations/molecular abnormalities and review data on the use of targeted therapies against them. Finally, we offer a treatment algorithm for patients with metastatic NSCLC that harbors actionable mutations. Conclusion: Patients with advanced NSCLC should undergo mutational testing to evaluate for actionable mutations. If such a mutation is discovered, targeted therapy should be considered for first-line treatment. PMID- 29230124 TI - Oncology and Palliative Medicine: Providing Comprehensive Care for Patients With Cancer. AB - Background: Despite the evidence for the fundamental need for palliative medicine services in the practice of oncology, integration of these medical specialties remains a clinical challenge. Methods: We reviewed the current literature regarding the practice of palliative medicine in the field of oncology, examining randomized clinical trials of palliative medicine services in advanced cancer, models of palliative medicine delivery, studies of cost effectiveness, and national palliative medicine practice and referral guidelines. In this review, we describe the role of palliative medicine in oncology, including the timing of palliative medicine consultation, models of care delivery, and improvements in patient outcomes. Results: Randomized controlled trials and national guidelines support early referral of patients with cancer to palliative medicine. Palliative medicine has a fundamental role in symptom management, distress relief, family and caregiver support, and advance care planning. Integration of palliative medicine in oncology improves patient outcomes and decreases healthcare costs. Early involvement of palliative medicine after the cancer diagnosis is supported by national guidelines, but barriers include variable referral patterns among oncologists and the need for an expanded palliative medicine workforce. Conclusion: Palliative medicine has a wide-ranging role in the spectrum of comprehensive cancer care-from patient diagnosis to survivorship. The entire multidisciplinary care team has a role in providing palliative care in inpatient and outpatient settings. An effective palliative medicine and oncology collaboration improves patient care and quality of life, has broad research and guideline support, and is cost effective. PMID- 29230126 TI - Endocrine Therapy for Early Breast Cancer: Updated Review. AB - Background: Although breast cancer is still the second most common cause of cancer-related deaths, breast cancer mortality has been declining because of advances in the use of adjuvant therapies. Methods: We summarize clinical trials involving endocrine therapies used to treat early breast cancer and discuss their inception and recent advances. Results: Endocrine therapies such as tamoxifen have revolutionized the treatment of breast cancer, resulting in significant decreases in cancer-related mortality. Aromatase inhibitors such as anastrozole and letrozole have further improved breast cancer survival. Conclusion: With the implementation of such therapies resulting in decreased mortality, patients with breast cancer are living longer than ever before. The focus of research is now directed toward the length of treatment and prediction models for recurrence. PMID- 29230125 TI - Older Patients With Acute Myeloid Leukemia: Treatment Challenges and Future Directions. AB - Background: Even though acute myeloid leukemia (AML) occurs most commonly in adults >=60 years, the treatment of AML in older patients remains a significant challenge. Methods: We reviewed the current literature regarding patient assessment tools, treatment options, and current therapies in clinical trial for patients with AML who are >=60 years. Results: Our approach to the older patient with AML is evolving with better understanding of the unique disease epidemiology in this population and the development of tools to assess individual patient functional status, including grading systems for comorbidities, geriatric assessment tools, and measurements of frailty. Almost all older patients will benefit from therapy, whether intensive curative therapy, such as allogeneic stem cell transplant that should be considered whenever possible, or low-intensity therapy that should be offered with concurrent palliative care at diagnosis to improve patient survival and quality of life. To achieve the improved survival demonstrated in younger adults, older patients should also be considered for clinical trial enrollment as more studies are being designed to specifically target this unique patient population. Conclusion: Older patients with AML are candidates for and benefit from the entire spectrum of AML therapy, including intense chemotherapy, allogeneic stem cell transplant, and clinical trial participation after thorough patient assessment. Older patients with AML would benefit from increased clinical trial enrollment and early inclusion of palliative medicine. PMID- 29230127 TI - Intraarterial Liver-Directed Therapies: The Role of Interventional Oncology. AB - Background: Since the early 1990s, the minimally invasive image-guided therapies used in interventional oncology to treat hepatocellular carcinoma have continued to evolve. Additionally, the range of applications has been expanded to the treatment of hepatic metastases from colorectal cancer, neuroendocrine tumors, cholangiocarcinoma, breast cancer, melanoma, and sarcoma. Methods: We searched the literature to identify publications from 1990 to the present on various image guided intraarterial therapies and their efficacy, as well as their role in the management of primary and secondary liver malignancies. Results: Chemoembolization and radioembolization are considered a standard of care in treating, delaying progression of disease, and downstaging to bridge to liver transplantation. Progression-free survival and overall survival outcomes are promising in patients with colorectal cancer and neuroendocrine tumors with liver metastases. Applications in the treatment of hepatic metastases from cholangiocarcinoma, breast cancer, melanoma, and sarcoma also show potential. Conclusion: Interventional oncology and its image-guided intraarterial therapies continue to gain recognition as treatment options for primary and secondary liver cancers. Growing evidence supports their role as a standard of care alongside medical oncology, surgery, and radiation oncology. PMID- 29230128 TI - Sigmoid Colonic Polyp as Initial Presentation of Metastatic Papillary Renal Cell Carcinoma. AB - Background: Upon initial presentation, 25%-30% of patients with renal cell carcinoma have metastatic disease. Metastasis to the gastrointestinal tract is rare, but when it occurs, the large bowel is the least common site. Case Report: A 75-year-old white male presented with vague abdominal symptoms and worsening hemoglobin and hematocrit levels. Colonoscopy revealed a polyp in the distal portion of the sigmoid colon. Histologic and immunohistochemical analysis suggested metastatic papillary renal cell carcinoma. Conclusion: To the best of our knowledge, this patient had a rare case of metastatic papillary renal cell carcinoma that metastasized to the colon and presented as a colon polyp. PMID- 29230129 TI - Paraneoplastic Cardiac Involvement in Renal Cell Carcinoma With Dermatomyositis Sine Dermatitis. AB - Background: Dermatomyositis is an idiopathic inflammatory myopathy that has been established as one of the many paraneoplastic phenomena. Cardiac involvement can occur with dermatomyositis but has rarely been reported in the literature because symptoms are usually subclinical. Case Report: A 72-year-old female presented with generalized weakness for 1 month after a recent diagnosis of renal cell carcinoma. Her weakness was attributed to a myopathic process that was identified as dermatomyositis after muscle biopsy. Laboratory tests revealed persistently elevated cardiac troponin I despite the absence of cardiac symptoms and a subsequent negative ischemic workup. After administration of intravenous steroids and treatment of the underlying renal cell carcinoma, the patient's cardiac enzymes normalized, suggesting a paraneoplastic etiology of her cardiac manifestations. Conclusion: Cardiac involvement as a paraneoplastic process is a rare entity and can present with elevated troponin as shown in our case. Its underlying mechanism has not been clearly elucidated, but this case may shed some light on a new or unknown myocardial manifestation related to malignancy. PMID- 29230130 TI - Periampullary Carcinoma: Unusual Sites of Metastasis. AB - Background: Periampullary neoplasms include carcinomas of the duodenum, ampulla of Vater, distal common bile duct, and pancreas. The aggressive course of these neoplasms is attributable to the delay in diagnosis, as patients have no symptoms until advanced stages of the disease. More than half of patients have distant metastasis at the time of diagnosis. The most frequent sites of metastasis are the liver, lymph nodes, peritoneum, lung, bone, kidney, and, rarely the skin. Case Report: We report the case of a 45-year-old female patient with adenocarcinoma of the ampulla of Vater metastasizing to the right parietal skull with overlying cutaneous involvement 1 year after a Whipple procedure. Conclusion: Cutaneous and skull metastasis of periampullary neoplasms is unusual, but early recognition of such metastatic disease is important because it indicates a poor prognosis for the patient. PMID- 29230131 TI - Body Art Confounding a Case of Breast Cancer. AB - Background: Heavy metals in tattoo ink can be deposited in axillary lymph nodes, mimicking malignant calcifications. High-density foci in axillary lymph nodes can be the sequelae of a benign or malignant process. Case Report: A 34-year-old female presented with left breast discomfort. Mammography showed suspicious left breast calcifications for which biopsy revealed multicentric ductal carcinoma in situ. Imaging also showed high-density foci in her left axillary lymph nodes suspicious for nodal metastases; however, biopsy of the lymph nodes found the high-density foci to be pigment-laden histiocytes from tattoo ink metallic deposits. Conclusion: High-density foci in axillary lymph nodes on mammography can be evidence of calcifications or metal deposits and can be the manifestation of a benign or malignant process. Thus, this finding may warrant additional diagnostic workup (including mammography, ultrasound, and possibly biopsy) and correlation with clinical history. PMID- 29230132 TI - Primary Undifferentiated Pleomorphic Sarcoma of the Penis. AB - Background: Primary penile sarcoma is a rare disease that affects men of all ages. Different subtypes of primary penile sarcoma exist, with the rarest being pleomorphic sarcoma. Delays in presentation and diagnosis of primary penile sarcoma have been reported because of its benign-appearing presenting features and rarity. If penile sarcoma is left untreated, the clinical consequence is metastasis that is fatal in most cases. Case Report: We report an extremely rare case of undifferentiated pleomorphic sarcoma of the penis in a 59-year-old patient who initially presented with a slow-growing penile nodule. The tumor was surgically excised, but the patient experienced local recurrence and, despite receiving chemotherapy and surgery, died of metastatic disease 15 months after initial presentation. Conclusion: Vigilance regarding biopsy and intervention for penile nodules may lead to early diagnosis and improved clinical outcomes. PMID- 29230133 TI - Invasive Insular Thyroid Carcinoma Presenting as Nonparalytic Dysphonia. AB - Background: Patients with suspected thyroid malignancy often undergo preoperative laryngeal examination with a focus on vocal fold mobility. We present the unique case of a patient with invasive thyroid carcinoma who presented with dysphonia despite intact vocal fold motion. Case Report: A 73-year-old female with a remote thyroid lobectomy presented with dysphonia. Thyroid ultrasound and fine-needle aspiration revealed a 1.1-cm nodule consistent with a colloid cyst. Videostroboscopy demonstrated mild laryngeal stenosis at the glottis and infraglottis with no evidence of paralysis. After failed medical therapy, the patient underwent microlaryngoscopy with biopsy of her infraglottic fullness, with histopathology reporting squamous epithelium without nucelar atypia. After several weeks of worsening dysphonia and persistent infraglottic fullness, she underwent repeat microlaryngoscopy with biopsy. On postoperative day 1, she developed dyspnea and stridor refractory to maximal medical management. To secure the airway, she underwent an awake tracheostomy, during which the thyroid isthmus was found to be densely adherent to the larynx. Histopathology identified insular thyroid carcinoma. Subsequent imaging confirmed a large, invasive thyroid tumor. Further workup revealed metastases to the bone and liver. The patient underwent a successful palliative resection of the thyroid followed by neck radiation and received palliative spinal surgery with adjuvant radiation. A clinical trial of vandetanib was initiated but withdrawn because of myelosuppression. She deferred any further treatment and was alive with few symptoms despite persistent disease 1.5 years after initial diagnosis. Conclusion: Physicians should consider the diagnosis of invasive thyroid carcinoma in a dysphonic patient with an infiltrative endolaryngeal process despite intact vocal fold mobility. PMID- 29230135 TI - Fall Conferences. PMID- 29230134 TI - Guiding Elastic Rods With a Robot-Manipulated Magnet for Medical Applications. AB - Magnet-tipped, elastic rods can be steered by an external magnetic field to perform surgical tasks. Such rods could be useful for a range of new medical applications because they do not require either pull wires or other bulky mechanisms that are problematic in small anatomical regions. However, current magnetic rod steering systems are large and expensive. Here, we describe a method to guide a rod using a robot-manipulated magnet located near a patient. We solve for rod deflections by combining permanent-magnet models with a Kirchhoff elastic rod model and use a resolved-rate approach to compute trajectories. Experiments show that three-dimensional trajectories can be executed accurately without feedback and that the system's redundancy can be exploited to avoid obstacles. PMID- 29230136 TI - Managing the Adult Patient With Short Bowel Syndrome. AB - Short bowel syndrome (SBS) is a malabsorptive disorder associated with significant morbidity and mortality, reduced quality of life, and high health care costs. Managing the patient with SBS requires an understanding of gastrointestinal anatomy and physiology; a dedicated multidisciplinary team; and the coordination of dietary, fluid, pharmacologic, and comorbid disease management. This article provides an overview of the current state of management of SBS, including a practical approach to optimizing the care and quality of life of the adult patient with SBS. PMID- 29230137 TI - Hybrid Argon Plasma Coagulation in Patients With Barrett Esophagus. PMID- 29230138 TI - Introduction to Biosimilar Use in Patients With Inflammatory Bowel Disease. PMID- 29230139 TI - The Use of Nonselective Beta Blockers for Treatment of Portal Hypertension. PMID- 29230140 TI - The Past, Present, and Future of Endoscopic Retrograde Cholangiopancreatography. PMID- 29230142 TI - GASTRO-HEP News. PMID- 29230141 TI - Current Status of Sorafenib Use for Treatment of Hepatocellular Carcinoma. PMID- 29230143 TI - Postoperative Recurrence of Crohn's Disease. PMID- 29230144 TI - Risk Stratification for Prevention of Recurrence of Postoperative Crohn's Disease. AB - Although there have been significant advances in medical therapies to treat Crohn's disease, an estimated 50% of patients will require surgery within the first decade of disease duration. Of these patients, a substantial number will develop recurrent symptoms within the first postoperative year. To prevent disease recurrence, many physicians use postoperative prophylactic therapy. Randomized, controlled trials, although limited in number, have demonstrated that a prophylactic postoperative strategy is effective at reducing recurrence (both clinical and endoscopic) in high-risk patients. This article reviews the frequency of and risk factors for postoperative Crohn's disease recurrence and the current evidence in favor of postoperative Crohn's disease management strategies. Future studies must be conducted to establish a gold standard as to who should receive postoperative prophylaxis and which therapies and time course are ideal. PMID- 29230145 TI - Practical Issues in the Management of Overt Hepatic Encephalopathy. AB - Hepatic encephalopathy (HE) is a condition that encompasses a range of neuropsychiatric abnormalities in patients with significant liver disease. Overt HE occurs in approximately 30% to 45% of patients with cirrhosis. This article discusses practical issues in the management of patients with overt HE and cirrhosis, including a recently developed 4-pronged approach that consists of identifying and correcting precipitating factors, recognizing and treating concomitant medical conditions, commencing empiric treatment, and caring for the unconscious patient. Following recovery from overt HE, a plan of action should be developed to prevent readmissions. PMID- 29230147 TI - Training in Advanced Endoscopy. PMID- 29230148 TI - Recent Research on Joint Pain and Arthritis in Patients With Inflammatory Bowel Disease. PMID- 29230146 TI - Microscopic Colitis: A Review of Collagenous and Lymphocytic Colitis. AB - Microscopic colitis (MC) is a chronic inflammatory bowel disease characterized by chronic watery diarrhea and diagnosed with the histologic hallmarks of disease despite a macroscopically normal large bowel. Although 2 distinct disease phenotypes exist, their clinical presentations and epidemiologic characteristics have overlapping features. This article summarizes evidence regarding the pathogenesis of MC, mechanisms of diarrhea in this cohort, and associations with medications. In addition, currently recommended and novel therapeutic approaches to achieving remission in this patient population are reviewed. PMID- 29230149 TI - Improving the Treatment of Irritable Bowel Syndrome With the Rome IV Multidimensional Clinical Profile. PMID- 29230150 TI - Nonmedical Switching of Biosimilars in Patients With Inflammatory Bowel Disease. PMID- 29230151 TI - Integrating a 19F MRI Tracer Agent into the Clinical Scale Manufacturing of a T Cell Immunotherapy. AB - Leukocyte immunotherapies have made great progress in the treatment of cancer. Recent reports on the treatment of B-cell malignancies using Chimeric Antigen Receptor and affinity enhanced T-Cell Receptor therapies have demonstrated encouraging clinical results. As investigators begin to explore the treatment of solid tumors with these cells, the hurdle of evaluating T-cell homing to and persistence at the site of disease remain. Significant challenges regarding the GMP manufacture and administration of a therapeutic dose of millions to billions of transduced T-cells remain. Here we report on the application of a clinically authorized 19F MRI tracer agent to human T-cells, employing state-of-the-art methods and equipment in the manufacture of a cellular therapy. Using a general T cell expansion protocol and clinical scale industrial bioreactors, we show 19F labeling without detriment to the product +/- cryopreservation. While the incorporation of the 19F tracer is not trivial, it is just one of the many steps that can aid in progression of a therapeutic to and though the clinic. Combining the MRI tracking capabilities, safety profiles, and clinical sensitivity of this method, this application demonstrates the ability of 19F MRI to be used in industrial scale applications to visualize the spatial fate of cellular therapeutics. PMID- 29230152 TI - Development of a Mixed Methods Investigation of Process and Outcomes of Community Based Participatory Research. AB - This article describes a mixed methods study of community-based participatory research (CBPR) partnership practices and the links between these practices and changes in health status and disparities outcomes. Directed by a CBPR conceptual model and grounded in indigenous-transformative theory, our nation-wide, cross site study showcases the value of a mixed methods approach for better understanding the complexity of CBPR partnerships across diverse community and research contexts. The article then provides examples of how an iterative, integrated approach to our mixed methods analysis yielded enriched understandings of two key constructs of the model: trust and governance. Implications and lessons learned while using mixed methods to study CBPR are provided. PMID- 29230153 TI - Synthesis of Diarylated 4-Pyridylmethyl Ethers via Palladium-Catalyzed Cross Coupling Reactions. AB - The direct arylation of weakly acidic sp3-hybridized C-H bonds via deprotonated cross-coupling processes (DCCP) is a challenge. Herein, a Pd(NIXANTPHOS)-based catalyst for the mono arylation of 4-pyridylmethyl 2-aryl ethers to generate diarylated 4-pyridyl methyl ethers is introduced. Furthermore, under similar conditions, the diarylation of 4-pyridylmethyl ethers with aryl bromides has been developed. These methods enable the synthesis of new pyridine derivatives, which are common in medicinally active compounds and in application in materials science. PMID- 29230154 TI - The influence of isomer purity on trap states and performance of organic thin film transistors. AB - Organic field-effect transistor (OFET) performance is dictated by its composition and geometry, as well as the quality of the organic semiconductor (OSC) film, which strongly depends on purity and microstructure. When present, impurities and defects give rise to trap states in the bandgap of the OSC, lowering device performance. Here, 2,8-difluoro-5,11-bis(triethylsilylethynyl)-anthradithiophene is used as a model system to study the mechanism responsible for performance degradation in OFETs due to isomer coexistence. The density of trapping states is evaluated through temperature dependent current-voltage measurements, and it is discovered that OFETs containing a mixture of syn- and anti-isomers exhibit a discrete trapping state detected as a peak located at ~ 0.4 eV above the valence band edge, which is absent in the samples fabricated on single-isomer films. Ultraviolet photoelectron spectroscopy measurements and density functional theory calculations do not point to a significant difference in electronic band structure between individual isomers. Instead, it is proposed that the dipole moment of the syn-isomer present in the host crystal of the anti-isomer locally polarizes the neighboring molecules, inducing energetic disorder. The isomers can be separated by applying gentle mechanical vibrations during film crystallization, as confirmed by the suppression of the peak and improvement in device performance. PMID- 29230155 TI - Methodological considerations in a pilot study on the effects of a berry enriched smoothie on children's performance in school. AB - Berries contain bioactive compounds that may affect children's cognitive function positively, while hunger and thirst during lessons before lunch affect academic performance negatively. This pilot study addresses methodological challenges in studying if a berry smoothie, offered to schoolchildren as a mid-morning beverage, affects academic performance. The objective was to investigate if a cross-over design can be used to study these effects in a school setting. Therefore, in order to investigate assay sensitivity, 236 Swedish children aged 10-12 years were administered either a berry smoothie (active) or a fruit-based control beverage after their mid-morning break. Both beverages provided 5% of child daily energy intake. In total, 91% of participants completed the study. Academic performance was assessed using the d2 test of attention. Statistical analyses were performed using the Wilcoxon signed rank test in StatXact v 10.3. The results showed that the children consumed less of the active berry smoothie than the control (154 g vs. 246 g). Both beverages increased attention span and concentration significantly (p = 0.000). However, as there was no significant difference (p = 0.938) in the magnitude of this effect between the active and control beverages, the assay sensitivity of the study design was not proven. The effect of the beverages on academic performance was attributed the supplementation of water and energy. Despite careful design, the active smoothie was less accepted than the control. This could be explained by un-familiar sensory characteristics and peer influence, stressing the importance of sensory similarity and challenges to perform a study in school settings. The employed cross-over design did not reveal any effects of bioactive compound consumption on academic performance. In future studies, the experimental set up should be modified or replaced by e.g. the parallel study design, in order to provide conclusive results. PMID- 29230156 TI - Neocentromeres to the Rescue of Acentric Chromosome Fragments. PMID- 29230157 TI - Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening. AB - STIL (SCL/TAL1 interrupting locus) is a core component of the centriole duplication process. STIL mutations have been associated with both autosomal recessive primary microcephaly (MCPH) and holoprosencephaly. In this report, we describe a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum. Whole exome sequencing allowed us to identify novel compound heterozygous mutations in STIL. The mutations lie, respectively, in the CPAP/CENPJ and the hsSAS6 interacting domains of STIL. M-phase synchronized amniocytes from both affected fetuses did not display an aberrant number of centrioles, as shown previously for either STIL-depleted or overexpressing cells. However, we observed an elongation of at least 1 centriole for each duplicated centrosome. These preliminary results may point to a novel mechanism causing MCPH and embryonic lethality in humans. PMID- 29230158 TI - Significant Improvement of Clinical Symptoms, Bone Lesions, and Bone Turnover after Long-Term Zoledronic Acid Treatment in Patients with a Severe Form of Camurati-Engelmann Disease. AB - Camurati-Engelmann disease (CED) is an ultrarare autosomal dominant bone dysplasia. Cortical thickening of the diaphyses of the long bones with narrowing of the medullary cavity are associated with bone pain, waddling gait, muscular weakness, easy fatigability, and a marfanoid body habitus. There is no specific treatment for CED. Nonsteroidal anti-inflammatory drugs or glucocorticoids are ineffective in improving bone lesions. A family with a mild to severe form of CED is described. Two patients received long-term bisphosphonate treatment: the 19 year-old female proband was treated with zoledronic acid for 2.2 years; the 4 year-old male proband was treated with neridronic acid for 16 months and with zoledronic acid for an additional 18 months. In both probands, zoledronic acid treatment significantly improved the clinical symptoms, bone lesions, ambulation, and body habitus. Before treatment, both probands showed a marked increase in serum levels of osteocalcin, procollagen type I N-terminal propeptide, and cross linked carboxyterminal telopeptide of type I collagen, reflecting an increased bone turnover. Bone marker levels returned to their normal values during treatment. Zoledronic acid treatment may be an important therapeutic option in patients with severe CED. Biochemical markers of bone turnover could be considered as surrogate indexes of CED activity. PMID- 29230159 TI - Spondyloepimetaphysial Dysplasia with Joint Laxity in Three Siblings with B3GALT6 Mutations. AB - Spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMDJL1) is a rare entity with a recessive inheritance. In this report, we describe 3 affected members of the same family who present with short stature, hyperlaxity with secondary spinal malalignment, ulnar subluxation, developmental dysplasia of the hips, and craniofacial alterations; one member also had learning difficulties. DNA analysis showed compound heterozygous variants in the B3GALT6 gene (c.901_921dup, c.511C>T) in all 3 patients, inherited from the parents. This family demonstrates the clinical variability of SEMDJL1. PMID- 29230160 TI - Whole-Exome Sequencing Identifies a de novo AHDC1 Mutation in a Colombian Patient with Xia-Gibbs Syndrome. AB - Xia-Gibbs syndrome is an autosomal dominant multisystem developmental disorder characterized by global developmental delay, hypotonia, obstructive sleep apnea, seizures, retrocerebellar cysts, delayed myelination, micrognathia, and mild dysmorphic features. Using whole-exome sequencing, we identified a de novo AHDC1 frameshift mutation c.2030_2030delG (p.G677Afs*52) in a Colombian patient, which was absent in both parents. Furthermore, we summarized the phenotypes of patients reported in the literature. PMID- 29230161 TI - A Homozygous Missense Variant in INPP5E Associated with Joubert Syndrome and Related Disorders. AB - Joubert syndrome and related disorders (JSRD; ORPHA 140874) is a complex set of neurodevelopmental disorders with multiple organ involvement. JSRD is a type of ciliopathy which is caused by the presence of defective primary cilia in an individual. JSRD is commonly inherited in an autosomal recessive pattern, and more than 23 genes are known to be associated with JSRD. We report a novel homozygous mutation identified in the INPP5E gene, c.1303C>T, which leads to a change of an amino acid from arginine to tryptophan at residue 435 in the protein chain. In silico analysis indicates that p.Arg435Trp substitution affects the functionality of the protein product of the gene. Our result adds to the growing body of evidences that underlines the clinical utility of next-generation sequencing in the diagnosis of a genetic disorder when clinical features are inconclusive. PMID- 29230162 TI - A Novel de novo FZD2 Mutation in a Patient with Autosomal Dominant Omodysplasia. AB - We described a heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits. The findings of our patient were compared to an autosomal dominant omodysplasia (OMOD2) family with FZD2 mutation reported in the literature. OMOD2 is a rare skeletal dysplasia and characterized by facial dysmorphism and shortness of the upper extremities and first metacarpal bones. This is the second report which supports the findings of the first family described and points out that heterozygous FZD2 mutations may be disease-causing for OMOD2. PMID- 29230163 TI - Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1. AB - We report a 3-generation family in which 2 Xp copy number variations (CNVs) co segregate. The proband presented with syndromic intellectual disability. The CNV had been revealed by conventional karyotyping, identifying a large Xp22 duplication causing an Xp functional disomy. Family studies found that this duplication was inherited from the proband's mother and was also present in one of his sisters. This sister had conventional karyotyping performed during pregnancy with a normal result. Postnatally, her child, the proband's nephew, presented with autism spectrum disorders. aCGH revealed a 339-kb IL1RAPL1 duplication. Overall, the proband, his mother, and one of his sisters all harboured both CNVs, while his other sister and the 2 sons of each sister only carried the IL1RAPL1 intragenic duplication. As seen in this family, we emphasise the importance of small CNV detection, the pathogenicity of IL1RAPL1 exonic duplications in male carriers, and the difficulties for genetic counselling with the risk of double diagnosis in a single patient. PMID- 29230164 TI - A Sub-millimeter, Inductively Powered Neural Stimulator. AB - Wireless neural stimulators are being developed to address problems associated with traditional lead-based implants. However, designing wireless stimulators on the sub-millimeter scale (<1 mm3) is challenging. As device size shrinks, it becomes difficult to deliver sufficient wireless power to operate the device. Here, we present a sub-millimeter, inductively powered neural stimulator consisting only of a coil to receive power, a capacitor to tune the resonant frequency of the receiver, and a diode to rectify the radio-frequency signal to produce neural excitation. By replacing any complex receiver circuitry with a simple rectifier, we have reduced the required voltage levels that are needed to operate the device from 0.5 to 1 V (e.g., for CMOS) to ~0.25-0.5 V. This reduced voltage allows the use of smaller receive antennas for power, resulting in a device volume of 0.3-0.5 mm3. The device was encapsulated in epoxy, and successfully passed accelerated lifetime tests in 80 degrees C saline for 2 weeks. We demonstrate a basic proof-of-concept using stimulation with tens of microamps of current delivered to the sciatic nerve in rat to produce a motor response. PMID- 29230166 TI - The Therapeutic Potential of Monocyte/Macrophage Manipulation in the Treatment of Chemotherapy-Induced Painful Neuropathy. AB - In cancer treatments a dose-limiting side-effect of chemotherapeutic agents is the development of neuropathic pain, which is poorly managed by clinically available drugs at present. Chemotherapy-induced painful neuropathy (CIPN) is a major cause of premature cessation of treatment and so a greater understanding of the underlying mechanisms and the development of novel, more effective therapies, is greatly needed. In some cases, only a weak correlation between chemotherapy induced pain and neuronal damage is observed both clinically and preclinically. As such, a critical role for non-neuronal cells, such as immune cells, and their communication with neurons in CIPN has recently been appreciated. In this mini review, we will discuss preclinical evidence for the role of monocytes/macrophages in the periphery in CIPN, with a focus on that which is associated with the chemotherapeutic agents vincristine and paclitaxel. In addition we will discuss the potential mechanisms that regulate monocyte/macrophage-neuron crosstalk in this context. Informed by preclinical data, we will also consider the value of monocytes/macrophages as therapeutic targets for the treatment of CIPN clinically. Approaches that manipulate the signaling pathways discussed in this review show both promise and potential pitfalls. Nonetheless, they are emerging as innovative therapeutic targets with CX3CL1/R1-regulation of monocyte/macrophage-neuron communication currently emerging as a promising front-runner. PMID- 29230165 TI - Fear Conditioning Downregulates Rac1 Activity in the Basolateral Amygdala Astrocytes to Facilitate the Formation of Fear Memory. AB - Astrocytes are well known to scale synaptic structural and functional plasticity, while the role in learning and memory, such as conditioned fear memory, is poorly elucidated. Here, using pharmacological approach, we find that fluorocitrate (FC) significantly inhibits the acquisition of fear memory, suggesting that astrocyte activity is required for fear memory formation. We further demonstrate that fear conditioning downregulates astrocytic Rac1 activity in basolateral amygdala (BLA) in mice and promotes astrocyte structural plasticity. Ablation of astrocytic Rac1 in BLA promotes fear memory acquisition, while overexpression or constitutive activation of astrocytic Rac1 attenuates fear memory acquisition. Furthermore, temporal activation of Rac1 by photoactivatable Rac1 (Rac1-PA) induces structural alterations in astrocytes and in vivo activation of Rac1 in BLA astrocytes during fear conditioning attenuates the formation of fear memory. Taken together, our study demonstrates that fear conditioning-induced suppression of BLA astrocytic Rac1 activity, associated with astrocyte structural plasticity, is required for the formation of conditioned fear memory. PMID- 29230167 TI - Changes in the Cholinergic, Catecholaminergic, Orexinergic and Serotonergic Structures Forming Part of the Sleep Systems of Adult Mice Exposed to Intrauterine Alcohol. AB - We examined the effect of chronic prenatal alcohol exposure on certain neuronal systems involved with the sleep-wake cycle of C57BL/6J mice exposed to prenatal alcohol once they had reached 56 days post-natal. Pregnant mice were exposed to alcohol, through oral gavage, on gestational days 7-16, with recorded blood alcohol concentration (BAC)s averaging 1.84 mg/ml (chronic alcohol group, CA). Two control groups, an oral gavage sucrose control group (chronic alcohol control group, CAc) and a non-treated control group (NTc), were also examined. At 56 days post-natal, the pups from each group were sacrificed and the whole brain sectioned in a coronal plane and immunolabeled for cholineacetyltransferase (ChAT), tyrosine hydroxylase (TH), serotonin (5HT) and orexin-A (OxA) which labels cholinergic, catecholaminergic, serotonergic and orexinergic structures respectively. The overall nuclear organization and neuronal morphology were identical in all three groups studied, and resemble that previously reported for laboratory rodents. Quantification of the estimated numbers of ChAT immunopositive (+) neurons of the pons, the TH+ neurons of the pons and the OxA+ neurons of the hypothalamus showed no statistically significant difference between the three experimental groups. The stereologically estimated areas and volumes of OxA+ neurons in the CA group were statistically significantly larger than the groups not exposed to prenatal alcohol, but the ChAT+ neurons in the CA group were statistically significantly smaller. The density of orexinergic boutons in the anterior cingulate cortex was lower in the CA group than the other groups. No statistically significant difference was found in the area and volume of TH+ neurons between the three experimental groups. These differences are discussed in relation to the sleep disorders recorded in children with fetal alcohol spectrum disorder (FASD). PMID- 29230168 TI - A Novel Dopamine Transporter Inhibitor CE-123 Improves Cognitive Flexibility and Maintains Impulsivity in Healthy Male Rats. AB - Reduced cognitive abilities are often characterized by an impairment of flexibility, i.e., the ability to switch from learned rules or categories that were important in certain contexts to different new modalities that rule the task. Drugs targeting the dopamine transporter (DAT) are widely used for their potential to enhance cognitive abilities. However, commercially available drugs are of limited specificity for DAT, blocking also noradrenaline and serotonine transporters, that can lead to unwanted side effects in healthy subjects. Therefore, we tested a newly synthetized compound (CE-123) with higher specificity for DAT in male rats in an attentional set-shifting task (ASST), that proves for cognitive flexibility and a 5-choice serial-reaction time task (5 CSRTT) assessing visuospatial attention and impulsivity. Treated rats at a dose of 0.3 and 1.0 but not 0.1 mg/kg bodyweight showed reduced extra-dimensional shifts in the ASST compared to controls indicating increased cognitive flexibility. Rats treated with R-Modafinil, a commercially available DAT inhibitor at a dose of 10 mg/kg bodyweight showed increased premature responses, an indicator of increased impulsivity, during a 10 s but not a 2.5, 5, or 7.5 s intertrial interval when compared to vehicle-treated rats in the 5-CSRTT. This was not found in rats treated with CE-123 at the same dose as for R-Modafinil. Visuospatial attention, except premature responses, did not differ between R Modafinil and CE-123-treated rats and their respective controls. Thus, CE-123 increased cognitive flexibility with diminished impulsivity. PMID- 29230169 TI - Eye Gaze and Aging: Selective and Combined Effects of Working Memory and Inhibitory Control. AB - Eye-tracking is increasingly studied as a cognitive and biological marker for the early signs of neuropsychological and psychiatric disorders. However, in order to make further progress, a more comprehensive understanding of the age-related effects on eye-tracking is essential. The antisaccade task requires participants to make saccadic eye movements away from a prepotent stimulus. Speculation on the cause of the observed age-related differences in the antisaccade task largely centers around two sources of cognitive dysfunction: inhibitory control (IC) and working memory (WM). The IC account views cognitive slowing and task errors as a direct result of the decline of inhibitory cognitive mechanisms. An alternative theory considers that a deterioration of WM is the cause of these age-related effects on behavior. The current study assessed IC and WM processes underpinning saccadic eye movements in young and older participants. This was achieved with three experimental conditions that systematically varied the extent to which WM and IC were taxed in the antisaccade task: a memory-guided task was used to explore the effect of increasing the WM load; a Go/No-Go task was used to explore the effect of increasing the inhibitory load; a 'standard' antisaccade task retained the standard WM and inhibitory loads. Saccadic eye movements were also examined in a control condition: the standard prosaccade task where the load of WM and IC were minimal or absent. Saccade latencies, error rates and the spatial accuracy of saccades of older participants were compared to the same measures in healthy young controls across the conditions. The results revealed that aging is associated with changes in both IC and WM. Increasing the inhibitory load was associated with increased reaction times in the older group, while the increased WM load and the inhibitory load contributed to an increase in the antisaccade errors. These results reveal that aging is associated with changes in both IC and WM. PMID- 29230171 TI - Spatial-Temporal Feature Analysis on Single-Trial Event Related Potential for Rapid Face Identification. AB - The event-related potential (ERP) is the brain response measured in electroencephalography (EEG), which reflects the process of human cognitive activity. ERP has been introduced into brain computer interfaces (BCIs) to communicate the computer with the subject's intention. Due to the low signal-to noise ratio of EEG, most ERP studies are based on grand-averaging over many trials. Recently single-trial ERP detection attracts more attention, which enables real time processing tasks as rapid face identification. All the targets needed to be retrieved may appear only once, and there is no knowledge of target label for averaging. More interestingly, how the features contribute temporally and spatially to single-trial ERP detection has not been fully investigated. In this paper, we propose to implement a local-learning-based (LLB) feature extraction method to investigate the importance of spatial-temporal components of ERP in a task of rapid face identification using single-trial detection. Comparing to previous methods, LLB method preserves the nonlinear structure of EEG signal distribution, and analyze the importance of original spatial-temporal components via optimization in feature space. As a data-driven methods, the weighting of the spatial-temporal component does not depend on the ERP detection method. The importance weights are optimized by making the targets more different from non-targets in feature space, and regularization penalty is introduced in optimization for sparse weights. This spatial-temporal feature extraction method is evaluated on the EEG data of 15 participants in performing a face identification task using rapid serial visual presentation paradigm. Comparing with other methods, the proposed spatial-temporal analysis method uses sparser (only 10% of the total) features, and could achieve comparable performance (98%) of single-trial ERP detection as the whole features across different detection methods. The interesting finding is that the N250 is the earliest temporal component that contributes to single-trial ERP detection in face identification. And the importance of N250 components is more laterally distributed toward the left hemisphere. We show that using only the left N250 component over-performs the right N250 in the face identification task using single-trial ERP detection. The finding is also important in building a fast and efficient (fewer electrodes) BCI system for rapid face identification. PMID- 29230170 TI - The Dancing Brain: Structural and Functional Signatures of Expert Dance Training. AB - Dance - as a ritual, therapy, and leisure activity - has been known for thousands of years. Today, dance is increasingly used as therapy for cognitive and neurological disorders such as dementia and Parkinson's disease. Surprisingly, the effects of dance training on the healthy young brain are not well understood despite the necessity of such information for planning successful clinical interventions. Therefore, this study examined actively performing, expert-level trained college students as a model of long-term exposure to dance training. To study the long-term effects of dance training on the human brain, we compared 20 young expert female Dancers with normal body mass index with 20 age- and education-matched Non-Dancers with respect to brain structure and function. We used diffusion tensor, morphometric, resting state and task-related functional MRI, a broad cognitive assessment, and objective measures of selected dance skill (Dance Central video game and a balance task). Dancers showed superior performance in the Dance Central video game and balance task, but showed no differences in cognitive abilities. We found little evidence for training-related differences in brain volume in Dancers. Dancers had lower anisotropy in the corticospinal tract. They also activated the action observation network (AON) to greater extent than Non-Dancers when viewing dance sequences. Dancers showed altered functional connectivity of the AON, and of the general motor learning network. These functional connectivity differences were related to dance skill and balance and training-induced structural characteristics. Our findings have the potential to inform future study designs aiming to monitor dance training induced plasticity in clinical populations. PMID- 29230172 TI - Sensor-Motor Maps for Describing Linear Reflex Composition in Hopping. AB - In human and animal motor control several sensory organs contribute to a network of sensory pathways modulating the motion depending on the task and the phase of execution to generate daily motor tasks such as locomotion. To better understand the individual and joint contribution of reflex pathways in locomotor tasks, we developed a neuromuscular model that describes hopping movements. In this model, we consider the influence of proprioceptive length (LFB), velocity (VFB) and force feedback (FFB) pathways of a leg extensor muscle on hopping stability, performance and efficiency (metabolic effort). Therefore, we explore the space describing the blending of the monosynaptic reflex pathway gains. We call this reflex parameter space a sensor-motor map. The sensor-motor maps are used to visualize the functional contribution of sensory pathways in multisensory integration. We further evaluate the robustness of these sensor-motor maps to changes in tendon elasticity, body mass, segment length and ground compliance. The model predicted that different reflex pathway compositions selectively optimize specific hopping characteristics (e.g., performance and efficiency). Both FFB and LFB were pathways that enable hopping. FFB resulted in the largest hopping heights, LFB enhanced hopping efficiency and VFB had the ability to disable hopping. For the tested case, the topology of the sensor-motor maps as well as the location of functionally optimal compositions were invariant to changes in system designs (tendon elasticity, body mass, segment length) or environmental parameters (ground compliance). Our results indicate that different feedback pathway compositions may serve different functional roles. The topology of the sensor-motor map was predicted to be robust against changes in the mechanical system design indicating that the reflex system can use different morphological designs, which does not apply for most robotic systems (for which the control often follows a specific design). Consequently, variations in body mechanics are permitted with consistent compositions of sensory feedback pathways. Given the variability in human body morphology, such variations are highly relevant for human motor control. PMID- 29230173 TI - Blueberry Phenolics Reduce Gastrointestinal Infection of Patients with Cerebral Venous Thrombosis by Improving Depressant-Induced Autoimmune Disorder via miR-155 Mediated Brain-Derived Neurotrophic Factor. AB - Cerebral venous thrombosis (CVT) often causes human depression, whereas depression-induced low immunity makes the patients susceptible to gastrointestinal infection. Blueberry possesses antidepressant properties which may improve autoimmunity and reduce gastrointestinal infection. Brain-derived neurotrophic factor (BDNF) performs antidepressant function and can be regulated by miR-155, which may be affected by blueberry. To explore the possible molecular mechanism, blueberry compounds were analyzed by high-performance liquid chromatography. Activity of compounds was tested by using HT22 cells. The present study tested 124 patients with CVT-induced mild-to-moderate depressive symptoms (Center for Epidemiologic Studies-Depression Scale [CES-D] >=16) and gastrointestinal infection. Patients were randomly assigned to blueberry extract group (BG, received 10 mg blueberry extract daily) and placebo group (PG, received 10 mg placebo daily). After 3 months, depression, gastrointestinal infection and lipid profiles were investigated. Serum miR-155 and BDNF were measured using real-time quantitative polymerase chain reaction and or Western Blot. Blueberry treatment improved depressive symptoms and lipid profiles, and also reduced gastrointestinal infection in the BG group (P < 0.05) but those of the PG group (P = 1). These changes were paralleled by increase in serum levels of BDNF and miR-155 (P < 0.05). HPLC analysis showed that blueberry extracts were the main phenolic acids with 0.18, 0.85, 0.26, 0.72, 0.66, 0.4,1, and 1.92 mg/g of gentisic acid, chlorogenic acid, [2]-epicatechin, p-coumaric acid, benzoic acid, p-anisic acid, and quercetin in blueberry extracts, respectively. Phenolics in blueberry are possible causal agents in improving antidepressant activity and reducing gastrointestinal infection. Administration of blueberry increased BDNF expression and miR-155. Blueberry cannot affect BDNF level when miR-155 is overexpressed or inhibited. Phenolics from blueberry reduced gastrointestinal infection of patients with CVT by improving antidepressant activity via upregulation of miR-155-mediated BDNF. PMID- 29230175 TI - The Combined Use of in Silico, in Vitro, and in Vivo Analyses to Assess Anti cancerous Potential of a Bioactive Compound from Cyanobacterium Nostoc sp. MGL001. AB - Escalating incidences of cancer, especially in developed and developing countries, demand evaluation of potential unexplored natural drug resources. Here, anticancer potential of 9-Ethyliminomethyl-12-(morpholin-4-ylmethoxy) 5,8,13,16-tetraaza -hexacene-2,3-dicarboxylic acid (EMTAHDCA) isolated from fresh water cyanobacterium Nostoc sp. MGL001 was screened through in silico, in vitro, and in vivo studies. For in silico analysis, EMTAHDCA was selected as ligand and 11 cancer related proteins (Protein Data Bank ID: 1BIX, 1NOW, 1TE6, 2RCW, 2UVL, 2VCJ, 3CRY, 3HQU, 3NMQ, 5P21, and 4B7P) which are common targets of various anticancer drugs were selected as receptors. The results obtained from in silico analysis showed that EMTAHDCA has strong binding affinity for all the 11 target protein receptors. The ability of EMTAHDCA to bind active sites of cancer protein targets indicated that it is functionally similar to commercially available anticancer drugs. For assessing cellular metabolic activities, in vitro studies were performed by using calorimetric assay viz. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT). Results showed that EMTAHDCA induced significant cytotoxic response against Dalton's lymphoma ascites (DLA) cells in a dose and time dependent manner with an inhibitory concentration (IC50) value of 372.4 ng/mL after 24 h of incubation. However, in case of normal bone marrow cells, the EMTAHDCA did not induce cytotoxicity as the IC50 value was not obtained even with higher dose of 1,000 ng/mL EMTAHDCA. Further, in vivo studies revealed that the median life span/survival days of tumor bearing mice treated with EMTAHDCA increased significantly with a fold change of ~1.9 and 1.81 corresponding to doses of 5 and 10 mg/kg body weight (B.W.) of EMTAHDCA respectively, as compared to the DL group. Our results suggest that 5 mg/kg B.W. is effective since the dose of 10 mg/kg B.W. did not show any significant difference as compared to 5 mg/kg B.W. Taken together, our findings based on in silico, in vitro, and in vivo analyses suggest that EMTAHDCA has potential anticancer effects, and thus, can be considered for cancer treatment. PMID- 29230174 TI - Pelargonidin Modulates Keap1/Nrf2 Pathway Gene Expression and Ameliorates Citrinin-Induced Oxidative Stress in HepG2 Cells. AB - Pelargonidin chloride (PC) is one of the major anthocyanin found in berries, radish and other natural foods. Many natural chemopreventive compounds have been shown to be potent inducers of phase II detoxification genes and its up regulation is important for oxidative stress related disorders. In the present study, we investigated the effect of PC in ameliorating citrinin (CTN) induced cytotoxicity and oxidative stress. The cytotoxicity of CTN was evaluated by treating HepG2 (Human hepatocellular carcinoma) cells with CTN (0-150 MUM) in a dose dependent manner for 24 h, and the IC50 was determined to be 96.16 MUM. CTN increased lactate dehydrogenase leakage (59%), elevated reactive oxygen species (2.5-fold), depolarized mitochondrial membrane potential as confirmed by JC-1 monomers and arrested cell cycle at G2/M phase. Further, apoptotic and necrotic analysis revealed significant changes followed by DNA damage. To overcome these toxicological effects, PC was pretreated for 2 h followed by CTN exposure for 24 h. Pretreatment with PC resulted in significant increase in cell viability (84.5%), restored membrane integrity, reactive oxygen species level were maintained and cell cycle phases were normal. PC significantly up-regulated the activity of detoxification enzymes: heme oxygenase 1 (HO-1), glutathione transferase, glutathione peroxidase, superoxide dismutase and quinone reductase. Nrf2 translocation into the nucleus was also observed by immunocytochemistry analysis. These data demonstrate the protective effect of PC against CTN-induced oxidative stress in HepG2 cells and up-regulated the activity of detoxification enzyme levels through Keap1/Nrf2 signaling pathway. PMID- 29230176 TI - Editorial: Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function. PMID- 29230177 TI - Effect of Morinda citrifolia (Noni)-Enriched Diet on Hepatic Heat Shock Protein and Lipid Metabolism-Related Genes in Heat Stressed Broiler Chickens. AB - Heat stress (HS) has been reported to alter fat deposition in broilers, however the underlying molecular mechanisms are not well-defined. The objectives of the current study were, therefore: (1) to determine the effects of acute (2 h) and chronic (3 weeks) HS on the expression of key molecular signatures involved in hepatic lipogenic and lipolytic programs, and (2) to assess if diet supplementation with dried Noni medicinal plant (0.2% of the diet) modulates these effects. Broilers (480 males, 1 d) were randomly assigned to 12 environmental chambers, subjected to two environmental conditions (heat stress, HS, 35 degrees C vs. thermoneutral condition, TN, 24 degrees C) and fed two diets (control vs. Noni) in a 2 * 2 factorial design. Feed intake and body weights were recorded, and blood and liver samples were collected at 2 h and 3 weeks post-heat exposure. HS depressed feed intake, reduced body weight, and up regulated the hepatic expression of heat shock protein HSP60, HSP70, HSP90 as well as key lipogenic proteins (fatty acid synthase, FASN; acetyl co-A carboxylase alpha, ACCalpha and ATP citrate lyase, ACLY). HS down regulated the hepatic expression of lipoprotein lipase (LPL) and hepatic triacylglycerol lipase (LIPC), but up regulated ATGL. Although it did not affect growth performance, Noni supplementation regulated the hepatic expression of lipogenic proteins in a time- and gene-specific manner. Prior to HS, Noni increased ACLY and FASN in the acute and chronic experimental conditions, respectively. During acute HS, Noni increased ACCalpha, but reduced FASN and ACLY expression. Under chronic HS, Noni up regulated ACCalpha and FASN but it down regulated ACLY. In vitro studies, using chicken hepatocyte cell lines, showed that HS down-regulated the expression of ACCalpha, FASN, and ACLY. Treatment with quercetin, one bioactive ingredient in Noni, up-regulated the expression of ACCalpha, FASN, and ACLY under TN conditions, but it appeared to down-regulate ACCalpha and increase ACLY levels under HS exposure. In conclusion, our findings indicate that HS induces hepatic lipogenesis in chickens and this effect is probably mediated via HSPs. The modulation of hepatic HSP expression suggest also that Noni might be involved in modulating the stress response in chicken liver. PMID- 29230178 TI - Human Cardiac 31P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise. AB - Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is a unique non-invasive imaging modality for probing in vivo high-energy phosphate metabolism in the human heart. We investigated whether current 31P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized 31P-MRS methods [3D image-selected in vivo spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans (n = 8) at rest were determined on a clinical 3 Tesla MR system. Numerical simulations of myocardial energy homeostasis in response to increased cardiac work rates were performed using a biophysical model of myocardial oxidative metabolism. Hypertrophic cardiomyopathy was modeled by either inefficient sarcomere ATP utilization or decreased mitochondrial ATP synthesis. The effect of creatine depletion on myocardial energy homeostasis was explored for both conditions. The mean in vivo myocardial PCr/ATP ratio measured with 3D ISIS was 1.57 +/- 0.17 with a large repeatability coefficient of 40.4%. For 1D CSI in a 1D ISIS-selected slice perpendicular to the surface coil, the PCr/ATP ratio was 2.78 +/- 0.50 (repeatability 42.5%). With 1D CSI in a 1D ISIS-selected slice parallel to the surface coil, the PCr/ATP ratio was 1.70 +/- 0.56 (repeatability 43.7%). The model predicted a PCr/ATP ratio reduction of only 10% at the maximal cardiac work rate in normal myocardium. Hypertrophic cardiomyopathy led to lower PCr/ATP ratios for high cardiac work rates, which was exacerbated by creatine depletion. Simulations illustrated that when conducting cardiac 31P-MRS exercise stress testing with large measurement error margins, results obtained under pathophysiologic conditions may still lie well within the 95% confidence interval of normal myocardial PCr/ATP dynamics. Current measurement precision of localized 31P-MRS for quantification of the myocardial PCr/ATP ratio precludes the detection of the changes predicted by computational modeling. This hampers clinical employment of 31P-MRS for diagnostic testing and risk stratification, and warrants developments in cardiac 31P-MRS exercise stress testing methodology. PMID- 29230180 TI - Immediate/Early vs. Delayed Invasive Strategy for Patients with Non-ST-Segment Elevation Acute Coronary Syndromes: A Systematic Review and Meta-Analysis. AB - Invasive coronary revascularization has been shown to improve prognoses in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), but the optimal timing of intervention remains unclear. This meta-analysis is to evaluate the outcomes in immediate (<2 h), early (<24 h), and delayed invasive group and find out which is the optimal timing of intervention in NSTE-ACS patients. Studies were identified through electronic literature search of Medline, PubMed Central, Embase, the Cochrane Library, and CNKI. Data were extracted for populations, interventions, outcomes, and risk of bias. All-cause mortality was the pre-specified primary end point. The longest follow-up available in each study was chosen. The odds ratio (OR) with 95% CI was the effect measure. The fixed or random effect pooled measure was selected based on the heterogeneity test among studies. In the comparison between early and delayed intervention, we found that early intervention led to a statistical significant decrease in mortality rate (n = 6,624; OR 0.78, 95% CI: 0.61-0.99) and refractory ischemia (n = 6,127; OR 0.50, 95% CI: 0.40-0.62) and a non-significant decrease in myocardial infarction (MI), major bleeding and revascularization. In the analysis comparing immediate and delayed invasive approach, we found that immediate intervention significantly reduced major bleeding (n = 1,217; OR 0.46, 95% CI: 0.23-0.93) but led to a non-significant decrease in mortality rate, refractory ischemia and revascularization and a non-significant increase in MI. In conclusion, early invasive strategy may lead to a lower mortality rate and reduce the risk of refractory ischemia, while immediate invasive therapy shows a benefit in reducing the risk of major bleeding. PMID- 29230179 TI - Transplacental Nutrient Transport Mechanisms of Intrauterine Growth Restriction in Rodent Models and Humans. AB - Although the causes of intrauterine growth restriction (IUGR) have been intensively investigated, important information is still lacking about the role of the placenta as a link from adverse maternal environment to adverse pregnancy outcomes of IUGR and preterm birth. IUGR is associated with an increased risk of cardiovascular, metabolic, and neurological diseases later in life. Determination of the most important pathways that regulate transplacental transport systems is necessary for identifying marker genes as diagnostic tools and for developing drugs that target the molecular pathways. Besides oxygen, the main nutrients required for appropriate fetal development and growth are glucose, amino acids, and fatty acids. Dysfunction in transplacental transport is caused by impairments in both placental morphology and blood flow, as well as by factors such as alterations in the expression of insulin-like growth factors and changes in the mTOR signaling pathway leading to a change in nutrient transport. Animal models are important tools for systematically studying such complex events. Debate centers on whether the rodent placenta is an appropriate tool for investigating the alterations in the human placenta that result in IUGR. This review provides an overview of the alterations in expression and activity of nutrient transporters and alterations in signaling associated with IUGR and compares these findings in rodents and humans. In general, the data obtained by studies of the various types of rodent and human nutrient transporters are similar. However, direct comparison is complicated by the fact that the results of such studies are controversial even within the same species, making the interpretation of the results challenging. This difficulty could be due to the absence of guidelines of the experimental design and, especially in humans, the use of trophoblast cell culture studies instead of clinical trials. Nonetheless, developing new therapy concepts for IUGR will require the use of animal models for gathering robust data about mechanisms leading to IUGR and for testing the effectiveness and safety of the intervention among pregnant women. PMID- 29230181 TI - Calvarial Suture-Derived Stem Cells and Their Contribution to Cranial Bone Repair. AB - In addition to the natural turnover during life, the bones in the skeleton possess the ability to self-repair in response to injury or disease-related bone loss. Based on studies of bone defect models, both processes are largely supported by resident stem cells. In the long bones, the source of skeletal stem cells has been widely investigated over the years, where the major stem cell population is thought to reside in the perivascular niche of the bone marrow. In contrast, we have very limited knowledge about the stem cells contributing to the repair of calvarial bones. In fact, until recently, the presence of specific stem cells in adult craniofacial bones was uncertain. These flat bones are mainly formed via intramembranous rather than endochondral ossification and thus contain minimal bone marrow space. It has been previously proposed that the overlying periosteum and underlying dura mater provide osteoprogenitors for calvarial bone repair. Nonetheless, recent studies have identified a major stem cell population within the suture mesenchyme with multiple differentiation abilities and intrinsic reparative potential. Here we provide an updated review of calvarial stem cells and potential mechanisms of regulation in the context of skull injury repair. PMID- 29230182 TI - A Network Model to Explore the Effect of the Micro-environment on Endothelial Cell Behavior during Angiogenesis. AB - Angiogenesis is an important adaptation mechanism of the blood vessels to the changing requirements of the body during development, aging, and wound healing. Angiogenesis allows existing blood vessels to form new connections or to reabsorb existing ones. Blood vessels are composed of a layer of endothelial cells (ECs) covered by one or more layers of mural cells (smooth muscle cells or pericytes). We constructed a computational Boolean model of the molecular regulatory network involved in the control of angiogenesis. Our model includes the ANG/TIE, HIF, AMPK/mTOR, VEGF, IGF, FGF, PLCgamma/Calcium, PI3K/AKT, NO, NOTCH, and WNT signaling pathways, as well as the mechanosensory components of the cytoskeleton. The dynamical behavior of our model recovers the patterns of molecular activation observed in Phalanx, Tip, and Stalk ECs. Furthermore, our model is able to describe the modulation of EC behavior due to extracellular micro-environments, as well as the effect due to loss- and gain-of-function mutations. These properties make our model a suitable platform for the understanding of the molecular mechanisms underlying some pathologies. For example, it is possible to follow the changes in the activation patterns caused by mutations that promote Tip EC behavior and inhibit Phalanx EC behavior, that lead to the conditions associated with retinal vascular disorders and tumor vascularization. Moreover, the model describes how mutations that promote Phalanx EC behavior are associated with the development of arteriovenous and venous malformations. These results suggest that the network model that we propose has the potential to be used in the study of how the modulation of the EC extracellular micro-environment may improve the outcome of vascular disease treatments. PMID- 29230183 TI - Corrigendum: Optimization of an In silico Cardiac Cell Model for Proarrhythmia Risk Assessment. AB - [This corrects the article on p. 616 in vol. 8, PMID: 28878692.]. PMID- 29230184 TI - Neuroligin 2 R215H Mutant Mice Manifest Anxiety, Increased Prepulse Inhibition, and Impaired Spatial Learning and Memory. AB - Neuroligin 2 (NLGN2) is a postsynaptic adhesion protein that plays an essential role in synaptogenesis and function of inhibitory neuron. We previously identified a missense mutation R215H of the NLGN2 in a patient with schizophrenia. This missense mutation was shown to be pathogenic in several cell based assays. The objective of this study was to better understand the behavioral consequences of this mutation in vivo. We generated a line of transgenic mice carrying this mutation using a recombinant-based method. The mice were subjected to a battery of behavioral tests including open field locomotor activity assay, prepulse inhibition (PPI) assay, accelerated rotarod test, novel location and novel recognition tests, elevated plus-maze (EPM) test, and Morris water maze test. The transgenic animals were viable and fertile, but the Nlgn2 R215H knock in (KI) homozygous mice showed growth retardation, anxiety-like behavior, increased PPI, and impaired spatial learning and memory. There was no significant interaction between sex and genotype in most behavioral tests; however, we observed a significant interaction between sex and genotype in EPM test in this study. Also, we found that the Nlgn2 R215H homozygous KI mice did not express the NLGN2 protein, resembling Nlgn2 knockout mice. Our results demonstrate that Nlgn2 R215H KI homozygous mice manifest several behavioral abnormalities similar to those found in psychiatric patients carrying NLGN2 mutations, indicating that dysfunction of NLGN2 contributes to the pathogenesis of certain psychiatric symptoms commonly present in various mental disorders, not limited to schizophrenia. PMID- 29230185 TI - The Relationship between the Brexit Vote and Individual Predictors of Prejudice: Collective Narcissism, Right Wing Authoritarianism, Social Dominance Orientation. AB - The Leave campaign in the U.K., which advocated exiting the European Union, emphasized anxiety over immigration and the need to take control of the U.K.'s borders. Citizens who expressed concerns about immigration to the U.K. were more likely to vote to leave. Two correlational studies examined the previously unexplored question of whether the Brexit vote and support for the outcome of the E.U. referendum were linked to individual predictors of prejudice toward foreigners: British collective narcissism (a belief in national greatness), right wing authoritarianism, and social dominance orientation. The results converged to indicate that all three variables were independently related to the perceived threat of immigrants and, via this variable, to the Brexit vote and a support for the outcome of the E.U. referendum. These variables explained the variance in the perceived threat of immigrants and support for the Brexit vote over and above other previously examined predictors such as age, education, or ethnicity, as well as, national identification and national attachment. PMID- 29230186 TI - Preschool Phonological and Morphological Awareness As Longitudinal Predictors of Early Reading and Spelling Development in Greek. AB - Different language skills are considered fundamental for successful reading and spelling acquisition. Extensive evidence has highlighted the central role of phonological awareness in early literacy experiences. However, many orthographic systems also require the contribution of morphological awareness. The goal of this study was to examine the morphological and phonological awareness skills of preschool children as longitudinal predictors of reading and spelling ability by the end of first grade, controlling for the effects of receptive and expressive vocabulary skills. At Time 1 preschool children from kindergartens in the Greek regions of Attika, Crete, Macedonia, and Thessaly were assessed on tasks tapping receptive and expressive vocabulary, phonological awareness (syllable and phoneme), and morphological awareness (inflectional and derivational). Tasks were administered through an Android application for mobile devices (tablets) featuring automatic application of ceiling rules. At Time 2 one year later the same children attending first grade were assessed on measures of word and pseudoword reading, text reading fluency, text reading comprehension, and spelling. Complete data from 104 children are available. Hierarchical linear regression and commonality analyses were conducted for each outcome variable. Reading accuracy for both words and pseudowords was predicted not only by phonological awareness, as expected, but also by morphological awareness, suggesting that understanding the functional role of word parts supports the developing phonology-orthography mappings. However, only phonological awareness predicted text reading fluency at this age. Longitudinal prediction of reading comprehension by both receptive vocabulary and morphological awareness was already evident at this age, as expected. Finally, spelling was predicted by preschool phonological awareness, as expected, as well as by morphological awareness, the contribution of which is expected to increase due to the spelling demands of Greek inflectional and derivational suffixes introduced at later grades. PMID- 29230187 TI - Long-Term Memory Updating: The Reset-of-Encoding Hypothesis in List-Method Directed Forgetting. AB - People's memory for new information can be enhanced by cuing them to forget older information, as is shown in list-method directed forgetting (LMDF). In this task, people are cued to forget a previously studied list of items (list 1) and to learn a new list of items (list 2) instead. Such cuing typically enhances memory for the list 2 items and reduces memory for the list 1 items, which reflects effective long-term memory updating. This review focuses on the reset-of-encoding (ROE) hypothesis as a theoretical explanation of the list 2 enhancement effect in LMDF. The ROE hypothesis is based on the finding that encoding efficacy typically decreases with number of encoded items and assumes that providing a forget cue after study of some items (e.g., list 1) resets the encoding process and makes encoding of subsequent items (e.g., early list 2 items) as effective as encoding of previously studied (e.g., early list 1) items. The review provides an overview of current evidence for the ROE hypothesis. The evidence arose from recent behavioral, neuroscientific, and modeling studies that examined LMDF on both an item and a list level basis. The findings support the view that ROE plays a critical role for the list 2 enhancement effect in LMDF. Alternative explanations of the effect and the generalizability of ROE to other experimental tasks are discussed. PMID- 29230188 TI - Control of Rest:Activity by a Dopaminergic Ultradian Oscillator and the Circadian Clock. AB - There is long-standing evidence for rhythms in locomotor activity, as well as various other aspects of physiology, with periods substantially shorter than 24 h in organisms ranging from fruit flies to humans. These ultradian oscillations, whose periods frequently fall between 2 and 6 h, are normally well integrated with circadian rhythms; however, they often lack the period stability and expression robustness of the latter. An adaptive advantage of ultradian rhythms has been clearly demonstrated for the common vole, suggesting that they may have evolved to confer social synchrony. The cellular substrate and mechanism of ultradian rhythm generation have remained elusive so far, however recent findings the subject of this review-now indicate that ultradian locomotor rhythms rely on an oscillator based on dopamine, dubbed the dopaminergic ultradian oscillator (DUO). These findings also reveal that the DUO period can be lengthened from <4 to >48 h by methamphetamine treatment, suggesting that the previously described methamphetamine-sensitive (circadian) oscillator represents a long-period manifestation of the DUO. PMID- 29230189 TI - Structural Covariance of Sensory Networks, the Cerebellum, and Amygdala in Autism Spectrum Disorder. AB - Sensory dysfunction is a core symptom of autism spectrum disorder (ASD), and abnormalities with sensory responsivity and processing can be extremely debilitating to ASD patients and their families. However, relatively little is known about the underlying neuroanatomical and neurophysiological factors that lead to sensory abnormalities in ASD. Investigation into these aspects of ASD could lead to significant advancements in our general knowledge about ASD, as well as provide targets for treatment and inform diagnostic procedures. Thus, the current study aimed to measure the covariation of volumes of brain structures (i.e., structural magnetic resonance imaging) that may be involved in abnormal sensory processing, in order to infer connectivity of these brain regions. Specifically, we quantified the structural covariation of sensory-related cerebral cortical structures, in addition to the cerebellum and amygdala by computing partial correlations between the structural volumes of these structures. These analyses were performed in participants with ASD (n = 36), as well as typically developing peers (n = 32). Results showed decreased structural covariation between sensory-related cortical structures, especially between the left and right cerebral hemispheres, in participants with ASD. In contrast, these same participants presented with increased structural covariation of structures in the right cerebral hemisphere. Additionally, sensory-related cerebral structures exhibited decreased structural covariation with functionally identified cerebellar networks. Also, the left amygdala showed significantly increased structural covariation with cerebral structures related to visual processing. Taken together, these results may suggest several patterns of altered connectivity both within and between cerebral cortices and other brain structures that may be related to sensory processing. PMID- 29230190 TI - Daith Piercing in a Case of Chronic Migraine: A Possible Vagal Modulation. AB - Daith piercing is an ear piercing located at the crus of the helix, bilaterally. It is getting great consent on social media as alternative treatment in chronic migraine. No data about its efficacy and action are available in scientific literature so far. We present the case of a 54-year-old male patient suffering from refractory chronic migraine with medication-overuse, who substantially improved after bilateral ear daith piercing. His migraine was refractory to symptomatic as well as prophylactic therapies. He used to treat headaches with up to five symptomatic drugs per attack and had attempted several pharmacological preventive therapies, including Onabotulinumtoxin A. He also underwent detoxification treatments with intravenous steroids and diazepam, without durable benefit. At the time of daith piercing, the headache-related disability measures showed a HIT-6 score of 64, a MIDAS-score of 70, and a 11-point Box scale of 5. On his own free will, he decided to get a "daith piercing." After that, he experienced a reduction of migraine attacks, which became very rare, and infrequent, less disabling episodes of tension-type headache (HIT-6 score of 56; MIDAS score of 27, 11-point Box scale of 3). Painkiller assumption has much decreased: he takes only one tablet of indomethacin 50 mg to treat tensive headaches, about four times per month. Beyond a placebo effect, we can speculate a vagal modulation as the action mechanism of daith piercing: a nociceptive sensory stimulus applied to trigeminal and vagal areas of the ear can activate ear vagal afferents, which can modulate pain pathways by means of projections to the caudal trigeminal nucleus, to the locus coeruleus and to the nucleus raphe magnus. Currently, daith piercing cannot be recommended as migraine treatment because of the lack of scientific evidence, the unquantified rate of failure and the associated risks with insertion. However, given the increasing but anecdotal evidence, we think that the mechanism needs testing by means of a controlled clinical trial in a population of chronic migraineurs. PMID- 29230191 TI - The Reticulospinal Pathway Does Not Increase Its Contribution to the Strength of Contralesional Muscles in Stroke Survivors as Compared to Ipsilesional Side or Healthy Controls. AB - Objective: Startling acoustic stimulation (SAS), via activation of reticulospinal (RS) pathways, has shown to increase muscle strength in healthy subjects. We hypothesized that, given RS hyperexcitability in stroke survivors, SAS could increase muscle strength in stroke survivors. The objective was to quantify the effect of SAS on maximal and sub-maximal voluntary elbow flexion on the contralesional (impaired) side in stroke survivors as compared to ipsilesional (non-impaired) side and healthy controls. Design: Thirteen hemiparetic stroke survivors and 12 healthy subjects volunteered for this investigation. Acoustic stimulation was given at rest, during ballistic maximal and sustained sub-maximal isometric elbow contractions using low (80 dB) and high intensity sound (105 dB). The effect of acoustic stimuli was evaluated from EMG and force recordings. Results: Prevalence of acoustic startle reflex with shorter latency in the impaired biceps was greater as compared to the response in the non-impaired side of stroke subjects and in healthy subjects. Delivery of SAS resulted in earlier initiation of elbow flexion and greater peak torque in healthy subjects and in stroke subjects with spastic hemiplegia during maximal voluntary elbow flexion tasks. During sub-maximal elbow flexion tasks, SAS-induced force responses were slightly greater on the impaired side than the non-impaired side. However, no statistically significant difference was found in SAS-induced responses between impaired and non-impaired sides at maximal and sub-maximal elbow flexion tasks. Conclusion: The findings suggest RS hyperexcitability in stroke survivors with spastic hemiplegia. The results of similar SAS-induced responses between healthy and stroke subjects indicate that RS projections via acoustic stimulation are not likely to contribute to muscle strength for stroke survivors to a significant extent. PMID- 29230192 TI - External Validity of Randomized Controlled Trials on Alzheimer's Disease: The Biases of Frailty and Biological Aging. AB - To date, the external validity of randomized controlled trials (RCTs) on Alzheimer's disease (AD) has been assessed only considering monodimensional variables. Nevertheless, looking at isolated and single characteristics cannot guarantee a sufficient level of appreciation of the AD patients' complexity. The only way to understand whether the two worlds (i.e., research and clinics) deal with the same type of patients is to adopt multidimensional approaches more holistically reflecting the biological age of the individual. In the present study, we compared measures of frailty/biological aging [assessed by a Frailty Index (FI)] of a sample of patients with AD resulted eligible and subsequently included in phase III RCTs compared to patients referring to the same clinical service, but not considered for inclusion. The "RCT sample" and the "real world sample" were found to be statistically similar for all the considered sociodemographic and clinical variables. Nevertheless, the "real world sample" was found to be significantly frailer compared to the "RCT sample," as indicated by higher FI scores [0.28 (SD 0.1) vs. 0.17 (SD 0.1); p < 0.001, respectively]. Moreover, when assessing the relationship between FI and age, we found that the correlation was almost null in the "RCT sample" (Spearman's r = 0.01; p = 0.98), while it was statistically significant in the "real world sample" (r = 0.49; p = 0.02). The application of too rigid designs may result in the poor representativeness of RCT samples. It may even imply the study of a condition biologically different from that observed in the "real world." The adoption of multidimensional measures capable to capture the individual's biological age may facilitate evaluating the external validity of clinical studies, implicitly improving the interpretation of the results and their translation in the clinical arena. PMID- 29230193 TI - Editorial: Non-Coding RNAs in Neurodevelopmental Disorders. PMID- 29230194 TI - Acute Flaccid Paralysis by Enterovirus D68 Infection: First Italian Description in Adult Patient and Role of Electrophysiology. AB - A Peruvian woman was admitted to the Emergency Department, due to an acute flaccid paralysis (AFP) of the upper limbs that progressively involved also lower limbs and respiratory muscles. She previously suffered from non-Hodgkin's lymphoma and had to undergo hematopoietic stem cell transplantation. A magnetic resonance imaging showed a T2 hyperintensity in the anterior and central region of the cervical segment with an elective involvement of gray matter. This finding, combined with other clinical, laboratory, and electrophysiological data, led to a diagnosis of AFP. Enterovirus D68 was isolated in the patient's cerebrospinal fluid, plasma, and throat swab. To our knowledge, this is the first Italian case of AFP by Enterovirus D68 infection in an adult. The diagnostic assessment and management of AFP by Enterovirus D68 are discussed. PMID- 29230195 TI - Content Analysis of Mobile Health Applications on Diabetes Mellitus. AB - Diabetes self-management offers an opportunity to patients to be actively involved in managing their conditions and modifying lifestyle behaviors to attain positive health outcomes. With the unprecedented growth of mobile technology, smartphone plays a role in supporting diabetes self-management. Nonetheless, selecting appropriate mobile applications (apps) is challenging for patients. Thus, this study aimed to evaluate and compare the contents and features of mobile medical apps for diabetes self-management. Of 346 commercial apps, 16 (16%) and 19 (7.72%) of the diabetes apps found in Apple and Google Play stores, respectively, were included based on the selection criteria and individually scored for the availability of 8 main features of diabetes self-management. The apps supported self-management by offering features such as free installation, less than 50 MB space used, offline use, automated data entry, data export and sharing, educational tool, and advice. Of the 8 evaluated features, only 11 (31.4%) apps had a score of 5 whereas 7 (20%) apps scored the lowest, with a score of 3. The majority of apps were free, required no Internet connectivity to use and were less than 50 MB in size. Our findings showed that the design of diabetes mobile apps focused on reporting and setting reminders, rather than providing personalized education or therapeutic support. In the future, the design of apps could be improved to integrate patients' needs, usability for disease management, and lifestyle modifications. PMID- 29230196 TI - Saxagliptin Induces beta-Cell Proliferation through Increasing Stromal Cell Derived Factor-1alpha In Vivo and In Vitro. AB - Dipeptidyl peptidase-4 inhibitors, such as saxagliptin, have been reported to have beneficial effects on beta-cell function, but the specific underlying mechanism remains unclear. Stromal cell-derived factor-1alpha (SDF-1alpha), a chemokine produced in multiple organs, has been considered as a crucial regulator in promoting beta-cell survival. Here, we speculate that SDF-1alpha might mediate the effect of saxagliptin on improving beta-cell function. After 12-week saxagliptin treatment in high-fat diet/streptozotocin-induced diabetic rats, significant improvement in pancreas insulin secretion capacity evaluated by hyperglycemia clamp and increased beta-cell to alpha-cell areas ratio were observed. Saxagliptin significantly induced beta-cell proliferation and upregulated the expression of proliferation-related factors including c-myc and cyclind D1 determined with western blotting from the isolated islets. The expression/activity of DPP-4 was significantly reduced and paralleled with the restoration of SDF-1alpha levels in the saxagliptin-treated diabetic rats, subsequently the key WNT-signaling regulators, beta-catenin, and AKT were activated. However, the effect of saxagliptin inducing beta-cell proliferation was attenuated when we silenced the SDF-1alpha receptor (CXCR4) with RNAi in INS cell lines. Collectively, our data indicate that SDF-1alpha mediates the protective effect of saxagliptin on beta-cell proliferation, suggesting that DPP 4 inhibitors have the potential role on delaying beta-cell failure and SDF-1alpha could be a therapeutic target of beta-cell regeneration. PMID- 29230197 TI - Exosome-Mediated Genetic Information Transfer, a Missing Piece of Osteoblast Osteoclast Communication Puzzle. AB - The skeletal system functions and maintains itself based on communication between cells of diverse origins, especially between osteoblasts (OBs) and osteoclasts (OCs), accounting for bone formation and resorption, respectively. Previously, protein-level information exchange has been the research focus, and this has been discussed in detail. The regulative effects of microRNAs (miRNAs) on OB and OC ignite the question as to whether genetic information could be transferred between bone cells. Exosomes, extracellular membrane vesicles 30-100 nm in diameter, have recently been demonstrated to transfer functional proteins, mRNAs, and miRNAs, and serve as mediators of intercellular communication. By reviewing the distinguishing features of exosomes, a hypothesis was formulated and evaluated in this article that exosome-mediated genetic information transfer may represent a novel strategy for OB-OC communication. The exosomes may coordinately regulate these two cells under certain physiological conditions by transferring genetic information. Further research in exosome-shuttered miRNAs in OB-OC communication may add a missing piece to the bone cells communication "puzzle." PMID- 29230198 TI - Commentary: Rifabutin Resistance Associated with Double Mutations in rpoB Gene in Mycobacterium tuberculosis Isolates. PMID- 29230199 TI - Resource Legacies of Organic and Conventional Management Differentiate Soil Microbial Carbon Use. AB - Long-term contrasts in agricultural management can shift soil resource availability with potential consequences to microbial carbon (C) use efficiency (CUE) and the fate of C in soils. Isothermal calorimetry was combined with 13C labeled glucose stable isotope probing (SIP) of 16S rRNA genes to test the hypothesis that organically managed soils would support microbial communities with greater thermodynamic efficiency compared to conventional soils due to a legacy of lower resource availability and a resultant shift toward communities supportive of more oligotrophic taxa. Resource availability was greater in conventionally managed soils, with 3.5 times higher available phosphorus, 5% more nitrate, and 36% more dissolved organic C. The two management systems harbored distinct glucose-utilizing populations of Proteobacteria and Actinobacteria, with a higher Proteobacteria:Actinobacteria ratio (2.4 vs. 0.7) in conventional soils. Organically managed soils also harbored notable activity of Firmicutes. Thermodynamic efficiency indices were similar between soils, indicating that glucose was metabolized at similar energetic cost. However, differentially abundant glucose utilizers in organically managed soils were positively correlated with soil organic matter (SOM) priming and negatively correlated to soil nutrient and carbon availability, respiration, and heat production. These correlation patterns were strongly reversed in the conventionally managed soils indicating clear differentiation of microbial functioning related to soil resource availability. Fresh C addition caused proportionally more priming of SOM decomposition (57 vs. 51%) in organically managed soils likely due to mineralization of organic nutrients to satisfy microbial demands during glucose utilization in these more resource deprived soils. The additional heat released from SOM oxidation may explain the similar community level thermodynamic efficiencies between management systems. Restoring fertility to soils with a legacy of nutrient limitation requires a balanced supply of both nutrients and energy to protect stable SOM from microbial degradation. These results highlight the need to consider managing C for the energy it provides to icritical biological processes that underpin soil health. PMID- 29230201 TI - Differential Metabolism of a Two-Carbon Substrate by Members of the Paracoccidioides Genus. AB - The genus Paracoccidioides comprises known fungal pathogens of humans and can be isolated from different infection sites. Metabolic peculiarities in different members of the Paracoccidioides led us to perform proteomic studies in the presence of the two-carbon molecule acetate, which predominates in the nutrient poor environment of the phagosome. To investigate the expression rates of proteins of different members of Paracoccidioides, including one isolate of P. lutzii (Pb01) and three isolates of P. brasiliensis (Pb03, Pb339, and PbEPM83), using sodium acetate as a carbon source, proteins were quantified using label free and data-independent liquid chromatography-mass spectrometry. Protein profiles of the isolates were statistically analyzed, revealing proteins that were differentially expressed when the fungus was cultivated in a non preferential carbon source rather than glucose. A total of 1,160, 1,211, 1,280, and 1,462 proteins were reproducibly identified and relatively quantified in P. lutzii and the P. brasiliensis isolates Pb03, Pb339, and PbEPM83, respectively. Notably, 526, 435, 744, and 747 proteins were differentially expressed among P. lutzii and the P. brasiliensis isolates Pb03, Pb339, and PbEPM83, respectively, with a fold-change equal to or higher than 1.5. This analysis revealed that reorganization of metabolism occurred through the induction of proteins related to gluconeogenesis, glyoxylic/glyoxylate cycle, response to stress, and degradation of amino acids in the four isolates. The following differences were observed among the isolates: higher increases in the expression levels of proteins belonging to the TCA and respiratory chain in PbEPM83 and Pb01; increase in ethanol production in Pb01; utilization of cell wall components for gluconeogenesis in Pb03 and PbEPM83; and increased beta-oxidation and methylcitrate cycle proteins in Pb01and PbEPM83. Proteomic profiles indicated that the four isolates reorganized their metabolism in different manners to use acetate as a carbon source. PMID- 29230202 TI - Development of a Novel Escherichia coli-Kocuria Shuttle Vector Using the Cryptic pKPAL3 Plasmid from K. palustris IPUFS-1 and Its Utilization in Producing Enantiopure (S)-Styrene Oxide. AB - The novel cryptic pKPAL3 plasmid was isolated from the Gram-positive microorganism Kocuria palustris IPUFS-1 and characterized in detail. pKPAL3 is a circular plasmid that is 4,443 bp in length. Open reading frame (ORF) and homology search analyses indicated that pKPAL3 possesses four ORFs; however, there were no replication protein coding genes predicted in the plasmid. Instead, there were two nucleotide sequence regions that showed significant identities with untranslated regions of K. rhizophila DC2201 (NBRC 103217) genomic sequences, and these sequences were essential for autonomous replication of pKPAL3 in Kocuria cells. Based on these findings, we constructed the novel Escherichia coli-Kocuria shuttle vectors pKITE301 (kanamycin resistant) and pKITE303 (thiostrepton resistant) from pKPAL3. The copy numbers of the constructed shuttle vectors were estimated to be 20 per cell, and they exhibited low segregation stability in Kocuria transformant cells in the absence of antibiotics. Moreover, constructed vectors showed compatibility with the other K. rhizophila shuttle vector pKITE103. We successfully expressed multiple heterologous genes, including the styrene monooxygenase gene from Rhodococcus sp. ST-10 (rhsmo) and alcohol dehydrogenase gene from Leifsonia sp. S749 (lsadh), in K. rhizophila DC2201 using the pKITE301P and pKITE103P vectors under the control of the glyceraldehyde 3-phosphate dehydrogenase (gapdh) promotor. The RhSMO-LSADH co-expressing K. rhizophila was used as a biocatalyst in an organic solvent-water biphasic reaction system to efficiently convert styrene into (S)-styrene oxide with 99% ee in the presence of 2-propanol as a hydrogen donor. The product concentration of the reaction in the organic solvent reached 235 mM after 30 h under optimum conditions. Thus, we demonstrated that this novel shuttle vector is useful for developing biocatalysts based on organic solvent-tolerant Kocuria cells. PMID- 29230200 TI - From Genes to Ecosystems in Microbiology: Modeling Approaches and the Importance of Individuality. AB - Models are important tools in microbial ecology. They can be used to advance understanding by helping to interpret observations and test hypotheses, and to predict the effects of ecosystem management actions or a different climate. Over the past decades, biological knowledge and ecosystem observations have advanced to the molecular and in particular gene level. However, microbial ecology models have changed less and a current challenge is to make them utilize the knowledge and observations at the genetic level. We review published models that explicitly consider genes and make predictions at the population or ecosystem level. The models can be grouped into three general approaches, i.e., metabolic flux, gene centric and agent-based. We describe and contrast these approaches by applying them to a hypothetical ecosystem and discuss their strengths and weaknesses. An important distinguishing feature is how variation between individual cells (individuality) is handled. In microbial ecosystems, individual heterogeneity is generated by a number of mechanisms including stochastic interactions of molecules (e.g., gene expression), stochastic and deterministic cell division asymmetry, small-scale environmental heterogeneity, and differential transport in a heterogeneous environment. This heterogeneity can then be amplified and transferred to other cell properties by several mechanisms, including nutrient uptake, metabolism and growth, cell cycle asynchronicity and the effects of age and damage. For example, stochastic gene expression may lead to heterogeneity in nutrient uptake enzyme levels, which in turn results in heterogeneity in intracellular nutrient levels. Individuality can have important ecological consequences, including division of labor, bet hedging, aging and sub-optimality. Understanding the importance of individuality and the mechanism(s) underlying it for the specific microbial system and question investigated is essential for selecting the optimal modeling strategy. PMID- 29230203 TI - Ibalizumab Targeting CD4 Receptors, An Emerging Molecule in HIV Therapy. AB - The HIV infection is responsible for the most devastating global pandemic of the last century. More than 39 million people have died of HIV/AIDS since 1981. The development of the antiretroviral (ARV) treatment begins with the discovery of zidovudine a nucleoside reverse transcriptase inhibitor. This breakthrough was followed by other ARV drug classes and representatives. Presently, HIV treatment employs 27 ARV representatives belonging to five different classes. Despite the proven benefits of ARV treatment and its long-term control of the HIV infection, there is an increasing concern about the numerous adverse effects and resistance to current ARV drugs. Therefore, the new HIV treatment strategies focus on the development of new ARV agents with a high genetic barrier to resistance and low toxicity. Monoclonal antibodies (MAbs) belong to a new drug class with encouraging results in the treatment of cancer, autoimmune disorders and most recently against HIV infection. The advantages of using MAbs for HIV treatment are related to their antiviral effect, lack of toxicity, good resistance profile, additional synergy with other ARV drug classes and ability to restore CD4 T-cell responses. The current article is a short summary of ibalizumab, an anti-CD4 monoclonal antibody that interferes with HIV viral entry. Current studies on ibalizumab have underlined its antiviral potential, minimal adverse effects, and lack of crossed resistance with other ARV agents thus supporting its further therapeutic use in multidrug resistant HIV-infected patients. PMID- 29230205 TI - Bacterial Genetic Architecture of Ecological Interactions in Co-culture by GWAS Taking Escherichia coli and Staphylococcus aureus as an Example. AB - How a species responds to such a biotic environment in the community, ultimately leading to its evolution, has been a topic of intense interest to ecological evolutionary biologists. Until recently, limited knowledge was available regarding the genotypic changes that underlie phenotypic changes. Our study implemented GWAS (Genome-Wide Association Studies) to illustrate the genetic architecture of ecological interactions that take place in microbial populations. By choosing 45 such interspecific pairs of Escherichia coli and Staphylococcus aureus strains that were all genotyped throughout the entire genome, we employed Q-ROADTRIPS to analyze the association between single SNPs and microbial abundance measured at each time point for bacterial populations reared in monoculture and co-culture, respectively. We identified a large number of SNPs and indels across the genomes (35.69 G clean data of E. coli and 50.41 G of S. aureus). We reported 66 and 111 SNPs that were associated with interaction in E. coli and S. aureus, respectively. 23 out of 66 polymorphic changes resulted in amino acid alterations.12 significant genes, such as murE, treA, argS, and relA, which were also identified in previous evolutionary studies. In S. aureus, 111 SNPs detected in coding sequences could be divided into 35 non-synonymous and 76 synonymous SNPs. Our study illustrated the potential of genome-wide association methods for studying rapidly evolving traits in bacteria. Genetic association study methods will facilitate the identification of genetic elements likely to cause phenotypes of interest and provide targets for further laboratory investigation. PMID- 29230204 TI - A Comprehensive Overview of Online Resources to Identify and Predict Bacterial Essential Genes. AB - Genes critical for the survival or reproduction of an organism in certain circumstances are classified as essential genes. Essential genes play a significant role in deciphering the survival mechanism of life. They may be greatly applied to pharmaceutics and synthetic biology. The continuous progress of experimental method for essential gene identification has accelerated the accumulation of gene essentiality data which facilitates the study of essential genes in silico. In this article, we present some available online resources related to gene essentiality, including bioinformatic software tools for transposon sequencing (Tn-seq) analysis, essential gene databases and online services to predict bacterial essential genes. We review several computational approaches that have been used to predict essential genes, and summarize the features used for gene essentiality prediction. In addition, we evaluate the available online bacterial essential gene prediction servers based on the experimentally validated essential gene sets of 30 bacteria from DEG. This article is intended to be a quick reference guide for the microbiologists interested in the essential genes. PMID- 29230206 TI - Anaerobic Corrosion of 304 Stainless Steel Caused by the Pseudomonas aeruginosa Biofilm. AB - Pseudomonas aeruginosa is a ubiquitous bacterium capable of forming problematic biofilms in many environments. They cause biocorrosion of medical implants and industrial equipment and infrastructure. Aerobic corrosion of P. aeruginosa against stainless steels has been reported by some researchers while there is a lack of reports on anaerobic P. aeruginosa corrosion in the literature. In this work, the corrosion by a wild-type P. aeruginosa (strain PAO1) biofilm against 304 stainless steel (304 SS) was investigated under strictly anaerobic condition for up to 14 days. The anaerobic corrosion of 304 SS by P. aeruginosa was reported for the first time. Results showed that the average sessile cell counts on 304 SS coupons after 7- and 14-day incubations were 4.8 * 107 and 6.2 * 107 cells/cm2, respectively. Scanning electron microscopy and confocal laser scanning microscopy corroborated the sessile cell counts. The X-ray diffraction analysis identified the corrosion product as iron nitride, confirming that the corrosion was caused by the nitrate reducing biofilm. The largest pit depths on 304 SS surfaces after the 7- and 14-day incubations with P. aeruginosa were 3.9 and 7.4 MUm, respectively. Electrochemical tests corroborated the pitting data. PMID- 29230207 TI - Targeting the Bacterial Orisome in the Search for New Antibiotics. AB - There is an urgent need for new antibiotics to combat drug resistant bacteria. Existing antibiotics act on only a small number of proteins and pathways in bacterial cells, and it seems logical that expansion of the target set could lead to development of novel antimicrobial agents. One essential process, not yet exploited for antibiotic discovery, is the initiation stage of chromosome replication, mediated by the bacterial orisome. In all bacteria, orisomes assemble when the initiator protein, DnaA, as well as accessory proteins, bind to a DNA scaffold called the origin of replication (oriC). Orisomes perform the essential tasks of unwinding oriC and loading the replicative helicase, and orisome assembly is tightly regulated in the cell cycle to ensure chromosome replication begins only once. Only a few bacterial orisomes have been fully characterized, and while this lack of information complicates identification of all features that could be targeted, examination of assembly stages and orisome regulatory mechanisms may provide direction for some effective inhibitory strategies. In this perspective, we review current knowledge about orisome assembly and regulation, and identify potential targets that, when inhibited pharmacologically, would prevent bacterial chromosome replication. PMID- 29230209 TI - The Mechanism of Synchronous Precise Regulation of Two Shrimp White Spot Syndrome Virus Targets by a Viral MicroRNA. AB - MicroRNAs (miRNAs), important factors in animal innate immunity, suppress the expressions of their target genes by binding to target mRNA's 3' untranslated regions (3'UTRs). However, the mechanism of synchronous regulation of multiple targets by a single miRNA remains unclear. In this study, the interaction between a white spot syndrome virus (WSSV) miRNA (WSSV-miR-N32) and its two viral targets (wsv459 and wsv322) was characterized in WSSV-infected shrimp. The outcomes indicated that WSSV-encoded miRNA (WSSV-miR-N32) significantly inhibited virus infection by simultaneously targeting wsv459 and wsv322. The silencing of wsv459 or wsv322 by siRNA led to significant decrease of WSSV copies in shrimp, showing that the two viral genes were required for WSSV infection. WSSV-miR-N32 could mediate 5'-3' exonucleolytic digestion of its target mRNAs, which stopped at the sites of target mRNA 3'UTRs close to the sequence complementary to the miRNA seed sequence. The complementary bases (to the target mRNA sequence) of a miRNA 9th 18th non-seed sequence were essential for the miRNA targeting. Therefore, our findings presented novel insights into the mechanism of miRNA-mediated suppression of target gene expressions, which would be helpful for understanding the roles of miRNAs in innate immunity of invertebrate. PMID- 29230208 TI - Ramadan Fasting Exerts Immunomodulatory Effects: Insights from a Systematic Review. AB - Ramadan is the ninth month of the Islamic lunar calendar and is observed by Muslims as a month of fasting. All Muslim adults are expected to fast; nevertheless certain subgroups, including sick, frail subjects, and pregnant women, among others, are exempted. Ramadan fasting has been shown to impact on body systems in different manners. The influence of Ramadan fasting on immune system regulation remains elusive; however, immune system changes, such as the modulation of body response to various infectious, stressful, and other harmful events, are of great interest during fasting. In this paper, we performed an extensive systematic literature review of different scholarly databases (ISI/Web of Science, Scopus, PubMed,/MEDLINE, Google Scholar, Directory of Open Access Journals, EbscoHOST, Scirus, Science Direct, the Cochrane Library, and ProQuest), using the following key words: "fasting," "Ramadan," "Islam," and "immunity." Conclusions drawn from these findings included: (1) Ramadan fasting has been shown to only mildly influence the immune system and the alterations induced are transient, returning to basal pre-Ramadan status shortly afterward. (2) Ramadan fasting during the second trimester of pregnancy was shown to be safe and did not result in negative fetal outcomes, or maternal oxidative status alterations. (3) In cardiac patients, Ramadan fasting can have beneficial effects including lipid profile improvement and alleviation of oxidative stress. (4) In asthmatic patients as well as in patients with human immunodeficiency virus/acquired immunodeficiency syndrome and autoimmune disorders, fasting was safe. (5) In psychiatric patients, such as those suffering from schizophrenia, fasting could increase immunologic markers. (6) Fasting Muslim athletes who maintain intensive training schedule during Ramadan showed fluctuations of immunologic markers. PMID- 29230210 TI - Checkpoint Blockade Toxicity and Immune Homeostasis in the Gastrointestinal Tract. AB - Monoclonal antibodies targeting the regulatory immune "checkpoint" receptors CTLA 4, PD-1, and PD-L1 are now standard therapy for diverse malignancies including melanoma, lung cancer, and renal cell carcinoma. Although effective in many patients and able to induce cures in some, targeting these regulatory pathways has led to a new class of immune-related adverse events. In many respects, these immune toxicities resemble idiopathic autoimmune diseases, such as inflammatory bowel disease, autoimmune hepatitis, rheumatoid arthritis, and vitiligo. Understanding the pathogenesis of these immune toxicities will have implications not only for care of patients receiving checkpoint blockade but may also provide critical insights into autoimmune disease. The gastrointestinal (GI) mucosa is arguably the most complex barrier in the body, host to a diverse commensal microflora and constantly challenged by ingested foreign proteins both of which must be tolerated. At the same time, the GI mucosa must defend against pathogenic microorganisms while maintaining sufficient permeability to absorb nutrients. For these reasons, regulatory cells and receptors are likely to play a central role in maintaining the gut barrier and GI toxicities, such as colitis and hepatitis are indeed among the most common side effects of CTLA-4 blockade and to a lesser extent blockade of PD-1 and PD-L1. High-dose corticosteroids are typically effective for management of both checkpoint colitis and hepatitis, although a fraction of patients will require additional immune suppression such as infliximab. Prompt recognition and treatment of these toxicities is essential to prevent more serious complications. PMID- 29230211 TI - Evaluation of Aggregated Ag85B Antigen for Its Biophysical Properties, Immunogenicity, and Vaccination Potential in a Murine Model of Tuberculosis Infection. AB - Protein aggregates have been reported to act as a reservoir that can release biologically active, native form of precursor protein. Keeping this fact into consideration, it is tempting to exploit protein aggregate-based antigen delivery system as a functional vaccine to expand desirable immunological response in the host. Herein, we explored the capacity of aggregated Ag85B of Mycobacterium tuberculosis (Mtb) to act as a prophylactic vaccine system that releases the precursor antigen in slow and sustained manner. Being particulate system with exposed hydrophobic residues, aggregated Ag85B is likely to be avidly taken up by both phagocytosis as well as fusion with plasma membrane of antigen presenting cells, leading to its direct delivery to their cytosol. Its unique ability to access cytosol of target cells is further evident from the fact that immunization with aggregated Ag85B led to the induction of Th1-dominant immune response along with upregulated expression of qualitatively superior polyfunctional T cells in the mice. Antibodies generated following immunization with aggregated antigen recognized both native and monomeric Ag85B released from protein aggregate. The implicated immunization strategy offers protection at par to that of established BCG vaccine with desirable central and effector memory responses against subsequent Mtb aerosol challenge. The study highlights the potential of aggregated Ag85B as promising antigen delivery system and paves the way to design better prophylactic regimes against various intracellular pathogens including Mtb. PMID- 29230212 TI - A Novel Function for the Streptococcus pneumoniae Aminopeptidase N: Inhibition of T Cell Effector Function through Regulation of TCR Signaling. AB - Streptococcus pneumoniae (Spn) causes a variety of disease states including fatal bacterial pneumonia. Our previous finding that introduction of Spn into an animal with ongoing influenza virus infection resulted in a CD8+ T cell population with reduced effector function gave rise to the possibility of direct regulation by pneumococcal components. Here, we show that treatment of effector T cells with lysate derived from Spn resulted in inhibition of IFNgamma and tumor necrosis factor alpha production as well as of cytolytic granule release. Spn aminopeptidase N (PepN) was identified as the inhibitory bacterial component and surprisingly, this property was independent of the peptidase activity found in this family of proteins. Inhibitory activity was associated with reduced activation of ZAP-70, ERK1/2, c-Jun N-terminal kinase, and p38, demonstrating the ability of PepN to negatively regulate TCR signaling at multiple points in the cascade. These results reveal a novel immune regulatory function for a bacterial aminopeptidase. PMID- 29230214 TI - Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency. AB - Primary immunodeficiency disorders (PIDs) render patients vulnerable to infection with a wide range of microorganisms and thus provide good in vivo models for the assessment of immune responses during infectious challenges. Priming of the immune system, especially in infancy, depends on different environmental exposures and medical practices. This may determine the timing and phenotype of clinical appearance of immune deficits as exemplified with early exposure to Bacillus Calmette-Guerin (BCG) vaccination and dissemination in combined immunodeficiencies. Varied phenotype expression poses a challenge to identification of the putative immune deficit. Without the availability of genomic diagnosis and data analysis resources and with limited capacity for functional definition of immune pathways, it is difficult to establish a definitive diagnosis and to decide on appropriate treatment. This study describes the use of exome sequencing to identify a homozygous recessive variant in MAP3K14, NIKVal345Met, in a patient with combined immunodeficiency, disseminated BCG-osis, and paradoxically elevated lymphocytes. Laboratory testing confirmed hypogammaglobulinemia with normal CD19, but failed to confirm a definitive diagnosis for targeted treatment decisions. NIKVal345Met is predicted to be deleterious and pathogenic by two in silico prediction tools and is situated in a gene crucial for effective functioning of the non-canonical nuclear factor-kappa B signaling pathway. Functional analysis of NIKVal345Met- versus NIKWT transfected human embryonic kidney-293T cells showed that this mutation significantly affects the kinase activity of NIK leading to decreased levels of phosphorylated IkappaB kinase-alpha (IKKalpha), the target of NIK. BCG-stimulated RAW264.7 cells transfected with NIKVal345Met also presented with reduced levels of phosphorylated IKKalpha, significantly increased p100 levels and significantly decreased p52 levels compared to cells transfected with NIKWT. Ideally, these experiments would have been conducted in patient-derived immune cells, but we were unable to source these cells from the patient. The functional analysis described in this paper supports previous illustrations of the importance of NIK in human immune responses and demonstrates the involvement of function-altering mutations in MAP3K14 in PIDs. The genomic approach used for this patient demonstrates its value in the diagnosis of an unusual PID and as a tool for detecting rarer mutations to help guide treatment approaches. PMID- 29230213 TI - Transcription Factor C/EBP Homologous Protein in Health and Diseases. AB - C/EBP homologous protein (CHOP), known also as DNA damage-inducible transcript 3 and as growth arrest and DNA damage-inducible protein 153 (GADD153), is induced in response to certain stressors. CHOP is universally acknowledged as a main conduit to endoplasmic reticulum stress-induced apoptosis. Ongoing research established the existence of CHOP-mediated apoptosis signaling networks, for which novel downstream targets are still being determined. However, there are studies that contradict this notion and assert that apoptosis is not the only mechanism by which CHOP plays in the development of pathologies. In this review, insights into the roles of CHOP in pathophysiology are summarized at the molecular and cellular levels. We further focus on the newest advances that implicate CHOP in human diseases including cancer, diabetes, neurodegenerative disorders, and notably, fibrosis. PMID- 29230215 TI - Potential Effects of Horizontal Gene Exchange in the Human Gut. AB - Many essential functions of the human body are dependent on the symbiotic microbiota, which is present at especially high numbers and diversity in the gut. This intricate host-microbe relationship is a result of the long-term coevolution between the two. While the inheritance of mutational changes in the host evolution is almost exclusively vertical, the main mechanism of bacterial evolution is horizontal gene exchange. The gut conditions, with stable temperature, continuous food supply, constant physicochemical conditions, extremely high concentration of microbial cells and phages, and plenty of opportunities for conjugation on the surfaces of food particles and host tissues, represent one of the most favorable ecological niches for horizontal gene exchange. Thus, the gut microbial system genetically is very dynamic and capable of rapid response, at the genetic level, to selection, for example, by antibiotics. There are many other factors to which the microbiota may dynamically respond including lifestyle, therapy, diet, refined food, food additives, consumption of pre- and probiotics, and many others. The impact of the changing selective pressures on gut microbiota, however, is poorly understood. Presumably, the gut microbiome responds to these changes by genetic restructuring of gut populations, driven mainly via horizontal gene exchange. Thus, our main goal is to reveal the role played by horizontal gene exchange in the changing landscape of the gastrointestinal microbiome and potential effect of these changes on human health in general and autoimmune diseases in particular. PMID- 29230216 TI - Metabolism Controls the Balance of Th17/T-Regulatory Cells. AB - Accumulating evidence indicates that metabolism reprogramming is critically important to T cell differentiation, and manipulating metabolic pathways in T cells can shape their fate and function. During T cell differentiation, metabolism provides T cells with energy as well as precursors for various biological processes. Some key metabolic reactions, such as glycolysis, oxidative phosphorylation and fatty acid oxidation, are also considered to play important roles in T cell activation and differentiation. In this review, we will explain why cellular metabolism is important for the Th17/T-regulatory (Treg) cell balance and how metabolism reprogramming impacts this balance. Moreover, we will also discuss some important metabolic sensors, such as mammalian target of rapamycin, AMP-activated protein kinase, and some nuclear receptors. In addition, we will review specific small molecular compounds, which can shift the Th17/Treg cell balance and, therefore, have promising therapeutic roles. Finally, potential methods of manipulating Th17 cell metabolism for treating Th17-associated diseases will be discussed. PMID- 29230217 TI - Type I Interferons in the Pathogenesis of Tuberculosis: Molecular Drivers and Immunological Consequences. AB - Tuberculosis (TB) remains a major global health threat. Urgent needs in the fight against TB include improved and innovative treatment options for drug-sensitive and -resistant TB as well as reliable biological indicators that discriminate active from latent disease and enable monitoring of treatment success or failure. Prominent interferon (IFN) inducible gene signatures in TB patients and animal models of Mycobacterium tuberculosis infection have drawn significant attention to the roles of type I IFNs in the host response to mycobacterial infections. Here, we review recent developments in the understanding of the innate immune pathways that drive type I IFN responses in mycobacteria-infected host cells and the functional consequences for the host defense against M. tuberculosis, with a view that such insights might be exploited for the development of targeted host directed immunotherapies and development of reliable biomarkers. PMID- 29230218 TI - Endogenous Antimicrobial Peptide Expression in Response to Bacterial Epidermal Colonization. AB - Bacterial commensal colonization of human skin is vital for the training and maintenance of the skin's innate and adaptive immune functions. In addition to its physical barrier against pathogen colonization, the skin expresses a variety of antimicrobial peptides (AMPs) which are expressed constitutively and induced in response to pathogenic microbial stimuli. These AMPs are differentially effective against a suite of microbial skin colonizers, including both bacterial and fungal residents of the skin. We review the breadth of microorganism-induced cutaneous AMP expression studies and their complementary findings on the efficacy of skin AMPs against different bacterial and fungal species. We suggest further directions for skin AMP research based on emerging skin microbiome knowledge in an effort to advance our understanding of the nuanced host-microbe balance on human skin. Such advances should enable the scientific community to bridge the gap between descriptive disease-state AMP studies and experimental single-species in vitro studies, thereby enabling research endeavors that more closely mimic the natural skin environs. PMID- 29230220 TI - Induction of Human Lung Mast Cell Apoptosis by Granule Permeabilization: A Novel Approach for Targeting Mast Cells. AB - Mast cells are implicated as detrimental players in inflammatory lung diseases, particularly asthma. Mast cells respond to activating stimuli by releasing a wide panel of pro-inflammatory compounds that can contribute profoundly to the pathology, and there is currently an unmet need for strategies that efficiently ameliorate harmful effects of mast cells under such conditions. Here, we sought to evaluate a novel concept for targeting human lung mast cells, by assessing the possibility of selectively depleting the lung mast cells by induction of apoptosis. For this purpose, we used lysosomotropic agents, i.e., compounds that are known to permeabilize the secretory granules of mast cells, thereby releasing the contents of the granules into the cytosol. Either intact human lung tissue, purified human lung mast cells or mixed populations of human lung cells were incubated with the lysosomotropic agents mefloquine or siramesine, followed by measurement of apoptosis, reactive oxygen species (ROS) production, and release of cytokines. We show that human lung mast cells were highly susceptible to apoptosis induced by this strategy, whereas other cell populations of the lung were largely refractory. Moreover, we demonstrate that apoptosis induced by this mode is dependent on the production of ROS and that the treatment of lung tissue with lysosomotropic agents causes a decrease in the release of pathogenic cytokines. We conclude that selective apoptosis of human lung mast cells can be accomplished by administration of lysosomotropic agents, thus introducing the possibility of using such drugs as novel therapeutics in the treatment of inflammatory lung disorders such as asthma. PMID- 29230221 TI - Editorial: Immune Control of JC Virus Infection and Immune Failure during Progressive Multifocal Leukoencephalopathy. PMID- 29230219 TI - Functional Impairment of Mononuclear Phagocyte System by the Human Respiratory Syncytial Virus. AB - The mononuclear phagocyte system (MPS) comprises of monocytes, macrophages (MPhi), and dendritic cells (DCs). MPS is part of the first line of immune defense against a wide range of pathogens, including viruses, such as the human respiratory syncytial virus (hRSV). The hRSV is an enveloped virus that belongs to the Pneumoviridae family, Orthopneumovirus genus. This virus is the main etiological agent causing severe acute lower respiratory tract infection, especially in infants, children and the elderly. Human RSV can cause bronchiolitis and pneumonia and it has also been implicated in the development of recurrent wheezing and asthma. Monocytes, MPhi, and DCs significantly contribute to acute inflammation during hRSV-induced bronchiolitis and asthma exacerbation. Furthermore, these cells seem to be an important component for the association between hRSV and reactive airway disease. After hRSV infection, the first cells encountered by the virus are respiratory epithelial cells, alveolar macrophages (AMs), DCs, and monocytes in the airways. Because AMs constitute the predominant cell population at the alveolar space in healthy subjects, these cells work as major innate sentinels for the recognition of pathogens. Although adaptive immunity is crucial for viral clearance, AMs are required for the early immune response against hRSV, promoting viral clearance and controlling immunopathology. Furthermore, exposure to hRSV may affect the phagocytic and microbicidal capacity of monocytes and MPhis against other infectious agents. Finally, different studies have addressed the roles of different DC subsets during infection by hRSV. In this review article, we discuss the role of the lung MPS during hRSV infection and their involvement in the development of bronchiolitis. PMID- 29230222 TI - Single Dose of Consensus Hemagglutinin-Based Virus-Like Particles Vaccine Protects Chickens against Divergent H5 Subtype Influenza Viruses. AB - The H5 subtype highly pathogenic avian influenza (HPAI) virus is one of the greatest threats to global poultry industry. To develop broadly protective H5 subunit vaccine, a recombinant consensus HA sequence (rHA) was constructed and expressed in virus-like particles (rHA VLPs) in the baculovirus-insect cell system. The efficacy of the rHA VLPs vaccine with or without immunopotentiator (CVCVA5) was assessed in chickens. Compared to the commercial Re6 or Re6-CVCVA5 vaccines, single dose immunization of chickens with rHA VLPs or rHA-CVCVA5 vaccines induced higher levels of serum hemagglutinin inhibition titers and neutralization titers, mucosal antibodies, IFN-gamma and IL-4 cytokines in sera, and cytotoxic T lymphocyte responses. The rHA VLPs vaccine was superior to the commercial Re6 vaccine in conferring cross-protection against different clades of H5 subtype viruses. This study reports that H5 subtype consensus HA VLP single dose vaccination provides broad protection against HPAI virus in chickens. PMID- 29230223 TI - Glutaraldehyde Cross-linking of HIV-1 Env Trimers Skews the Antibody Subclass Response in Mice. AB - Well-ordered soluble HIV-1 envelope glycoprotein (Env) spike mimetics such as Native Flexibly Linked (NFL) trimers display high homogeneity, desired antigenicity, and high in vitro stability compared to previous generation soluble HIV-1 Env trimers. Glutaraldehyde (GLA) cross-linking was shown to further increase the thermostability of clade C 16055 NFL trimers and enhance the induction of tier 2 autologous neutralizing antibodies in guinea pigs. Here, we investigated if GLA fixation affected other aspects of the Env-specific immune response by performing a comparative immunogenicity study in C57BL/6 mice with non-fixed and GLA-fixed 16055 NFL trimers administered in AbISCO-100 adjuvant. We detected lower Env-specific binding antibody titers and increased skewing toward Th2 responses in mice immunized with GLA-fixed trimers compared to mice immunized with unfixed trimers, as shown by a higher Env-specific IgG1:IgG2b antibody subclass ratio. These results suggest that the presence of GLA adducts on Env influences the quality of the induced antibody response. PMID- 29230224 TI - Lipoarabinomannan Decreases Galectin-9 Expression and Tumor Necrosis Factor Pathway in Macrophages Favoring Mycobacterium tuberculosis Intracellular Growth. AB - Lipoarabinomannan (LAM) is a lipid virulent factor secreted by Mycobacterium tuberculosis (Mtb). LAM can be found in the sputum and urine of patients with active tuberculosis. When human monocytes are differentiated into macrophages [monocyte-derived macrophages (MDM)] in the presence of LAM, MDM are poorly functional which may limit the immune response to Mtb infection. Our previous studies have shown that TIM3 and galectin (GAL)9 interaction induces anti mycobacterial activity, and the expression levels of TIM3 and GAL9 are downregulated during Mtb infection. We postulated that LAM affects GAL9/TIM3 pathway, and, in consequence, the ability of the macrophage to control bacterial growth could be affected. In this work, we have generated MDM in the presence of LAM and observed that the expression of TIM3 was not affected; in contrast, GAL9 expression was downregulated at the transcriptional and protein levels. We observed that the cell surface and the soluble form of tumor necrosis factor (TNF) receptor 2 were decreased. We also found that when LAM-exposed MDM were activated with LPS, they produced less TNF, and the transcription factor proteinase-activated receptor-2 (PAR2), which is involved in host immune responses to infection, was not induced. Our data show that LAM-exposed MDM were deficient in the control of intracellular growth of Mtb. In conclusion, LAM exposed MDM leads to MDM with impaired intracellular signal activation affecting GAL9, TNF, and PAR2 pathways, which are important to restrict Mtb growth. PMID- 29230225 TI - Sensing Lipids with Mincle: Structure and Function. AB - Mincle is a C-type lectin receptor that has emerged as an important player in innate immunity through its capacity to recognize a wide range of lipidic species derived from damaged/altered self and foreign microorganisms. Self-ligands include sterols (e.g., cholesterol), and beta-glucosylceramides, and the protein SAP130, which is released upon cell death. Foreign lipids comprise those from both microbial pathogens and commensals and include glycerol, glucose and trehalose mycolates, and glycosyl diglycerides. A large effort has focused on structural variation of these ligands to illuminate the structure-activity relationships required for the agonism of signaling though Mincle and has helped identify key differences in ligand recognition between human and rodent Mincle. These studies in turn have helped identify new Mincle ligands, further broadening our understanding of the diversity of organisms and lipidic species recognized by Mincle. Finally, progress toward the development of Mincle agonists as vaccine adjuvants providing humoral and cell-mediated immunity with reduced toxicity is discussed. PMID- 29230227 TI - Anti-idiotypic Antibodies against BP-IgG Prevent Type XVII Collagen Depletion. AB - Bullous pemphigoid (BP) mainly targets type XVII collagen (COL17). Intravenous immunoglobulin (IVIg) is used to treat numerous autoimmune diseases, including BP. The major mechanism of action for IVIG is thought to be its immunomodulatory effect. However, little is known about the precise mechanisms of IVIg in BP. We investigate the cellular effects of IVIg, toward treatments for BP. Keratinocytes were treated with IgG from BP patients (BP-IgG) and with IVIg, and then the COL17 expression was detected by Western blotting. Cell adhesion and ex vivo dermal epidermal separation were also investigated for the condition with BP-IgG and IVIg. BP-IgG targeting the non-collagenous 16A domain induces the depletion of COL17 in cultured keratinocytes (DJM-1 cells). The COL17 levels in DJM-1 cells were decreased by 50% after 4 h of BP-IgG stimulation as determined by Western blotting. By contrast, BP-IgG with IVIg was found to result in 70-90% increases in COL17 and to restore adhesion to the plate. Interestingly, IVIg significantly inhibited the binding of BP-IgG to the COL17-enzyme-linked immunosorbent assay plate, and this was due to anti-idiotypic antibodies against BP-IgG. When anti idiotypic antibodies against BP-IgG in 0.02% of IVIg were depleted from IVIg, those antibodies did not exhibit inhibitory effects on COL17 depletion. When cryosections of human skin were incubated with BP-IgG in the presence of leukocytes, dermal-epidermal separation was observed. BP-IgG treatment with IVIg or anti-idiotypic antibodies did not induce such separation. These findings strongly suggest the presence of anti-idiotypic antibodies against anti-COL17 IgG in IVIg. This mechanism of IVIg could be a target for therapies against BP. PMID- 29230226 TI - Cholesterol Metabolism in T Cells. AB - Compartmentalization and spatial control of biochemical reactions is the foundation of cell-based life on earth. The lipid bilayer system employed by eukaryote cells not only keeps them separate from the environment but also provides a platform for key receptors to sense and interact with outside factors. Arguably one of the cell types most reliant on interactions of this kind, immune cells depend on their membrane to keep functioning properly. In this review, the influence of variation in cholesterol levels, a key component of lipid bilayer stability, on T cells will be discussed in detail. In comparison to other cells, T cells must be able to undergo rapid activation followed by proliferation. Furthermore, receptor colocalization is an important mechanism in this activation process. The impact of cholesterol availability on the processes of T cell proliferation and receptor sensitivity, as well as its potential for immunomodulation in disease treatment will be considered. PMID- 29230228 TI - Overexpression of SmMYC2 Increases the Production of Phenolic Acids in Salvia miltiorrhiza. AB - MYC2 is a core transcription factor in the plant response to jasmonates. It also functions in secondary metabolism and various processes for growth and development. However, the knowledge about its role in Salvia miltiorrhiza is still very limited. We determined that the biosynthesis of salvianolic acid B (Sal B) was strongly induced in 2-month-old transgenic plants that over-expressed SmMYC2. In the roots of transgenic line 12 that over-expressed SmMYC2 (OEM-12), the Sal B concentration was as high as 5.95 +/- 0.07 mg g-1, a level that was 1.88-fold higher than that in control plants that had been transformed with an empty vector. Neither tanshinone IIA nor cryptotanshinone was detected by high performance liquid chromatography in any of the genotypes. Global transcriptomic analysis using RNA sequencing revealed that most enzyme-encoding genes for the phenylpropanoid biosynthesis pathway were up-regulated in the overexpression lines. Furthermore, both the phenylalanine and tyrosine biosynthesis pathways were activated in those transgenics. Our data demonstrate that overexpression of SmMYC2 promotes the production of phenolic acids by simultaneously activating both primary and secondary pathways for metabolism in S. miltiorrhiza. PMID- 29230229 TI - High-Throughput Phenotyping of Plant Height: Comparing Unmanned Aerial Vehicles and Ground LiDAR Estimates. AB - The capacity of LiDAR and Unmanned Aerial Vehicles (UAVs) to provide plant height estimates as a high-throughput plant phenotyping trait was explored. An experiment over wheat genotypes conducted under well watered and water stress modalities was conducted. Frequent LiDAR measurements were performed along the growth cycle using a phenomobile unmanned ground vehicle. UAV equipped with a high resolution RGB camera was flying the experiment several times to retrieve the digital surface model from structure from motion techniques. Both techniques provide a 3D dense point cloud from which the plant height can be estimated. Plant height first defined as the z-value for which 99.5% of the points of the dense cloud are below. This provides good consistency with manual measurements of plant height (RMSE = 3.5 cm) while minimizing the variability along each microplot. Results show that LiDAR and structure from motion plant height values are always consistent. However, a slight under-estimation is observed for structure from motion techniques, in relation with the coarser spatial resolution of UAV imagery and the limited penetration capacity of structure from motion as compared to LiDAR. Very high heritability values (H2> 0.90) were found for both techniques when lodging was not present. The dynamics of plant height shows that it carries pertinent information regarding the period and magnitude of the plant stress. Further, the date when the maximum plant height is reached was found to be very heritable (H2> 0.88) and a good proxy of the flowering stage. Finally, the capacity of plant height as a proxy for total above ground biomass and yield is discussed. PMID- 29230230 TI - Comparative Performance of Ground vs. Aerially Assessed RGB and Multispectral Indices for Early-Growth Evaluation of Maize Performance under Phosphorus Fertilization. AB - Low soil fertility is one of the factors most limiting agricultural production, with phosphorus deficiency being among the main factors, particularly in developing countries. To deal with such environmental constraints, remote sensing measurements can be used to rapidly assess crop performance and to phenotype a large number of plots in a rapid and cost-effective way. We evaluated the performance of a set of remote sensing indices derived from Red-Green-Blue (RGB) images and multispectral (visible and infrared) data as phenotypic traits and crop monitoring tools for early assessment of maize performance under phosphorus fertilization. Thus, a set of 26 maize hybrids grown under field conditions in Zimbabwe was assayed under contrasting phosphorus fertilization conditions. Remote sensing measurements were conducted in seedlings at two different levels: at the ground and from an aerial platform. Within a particular phosphorus level, some of the RGB indices strongly correlated with grain yield. In general, RGB indices assessed at both ground and aerial levels correlated in a comparable way with grain yield except for indices a* and u*, which correlated better when assessed at the aerial level than at ground level and Greener Area (GGA) which had the opposite correlation. The Normalized Difference Vegetation Index (NDVI) evaluated at ground level with an active sensor also correlated better with grain yield than the NDVI derived from the multispectral camera mounted in the aerial platform. Other multispectral indices like the Soil Adjusted Vegetation Index (SAVI) performed very similarly to NDVI assessed at the aerial level but overall, they correlated in a weaker manner with grain yield than the best RGB indices. This study clearly illustrates the advantage of RGB-derived indices over the more costly and time-consuming multispectral indices. Moreover, the indices best correlated with GY were in general those best correlated with leaf phosphorous content. However, these correlations were clearly weaker than against grain yield and only under low phosphorous conditions. This work reinforces the effectiveness of canopy remote sensing for plant phenotyping and crop management of maize under different phosphorus nutrient conditions and suggests that the RGB indices are the best option. PMID- 29230231 TI - Activation of the LRR Receptor-Like Kinase PSY1R Requires Transphosphorylation of Residues in the Activation Loop. AB - PSY1R is a leucine-rich repeat (LRR) receptor-like kinase (RLK) previously shown to act as receptor for the plant peptide hormone PSY1 (peptide containing sulfated tyrosine 1) and to regulate cell expansion. PSY1R phosphorylates and thereby regulates the activity of plasma membrane-localized H+-ATPases. While this mechanism has been studied in detail, little is known about how PSY1R itself is activated. Here we studied the activation mechanism of PSY1R. We show that full-length PSY1R interacts with members of the SERK co-receptor family in planta. We identified seven in vitro autophosphorylation sites on serine and threonine residues within the kinase domain of PSY1R using mass spectrometry. We furthermore show that PSY1R autophosphorylation occurs in trans and that the initial transphosphorylation takes place within the activation loop at residues Ser951, Thr959, and Thr963. While Thr959 and Thr963 are conserved among other related plant LRR RLKs, Ser951 is unique to PSY1R. Based on homology modeling we propose that phosphorylation of Ser951 stabilize the inactive conformation of PSY1R. PMID- 29230232 TI - Chemosensitization of Fusarium graminearum to Chemical Fungicides Using Cyclic Lipopeptides Produced by Bacillus amyloliquefaciens Strain JCK-12. AB - Fusarium head blight (FHB) caused by infection with Fusarium graminearum leads to enormous losses to crop growers, and may contaminate grains with a number of Fusarium mycotoxins that pose serious risks to human and animal health. Antagonistic bacteria that are used to prevent FHB offer attractive alternatives or supplements to synthetic fungicides for controlling FHB without the negative effects of chemical management. Out of 500 bacterial strains isolated from soil, Bacillus amyloliquefaciens JCK-12 showed strong antifungal activity and was considered a potential source for control strategies to reduce FHB. B. amyloliquefaciens JCK-12 produces several cyclic lipopeptides (CLPs) including iturin A, fengycin, and surfactin. Iturin A inhibits spore germination of F. graminearum. Fengycin or surfactin alone did not display any inhibitory activity against spore germination at concentrations less than 30 MUg/ml, but a mixture of iturin A, fengycin, and surfactin showed a remarkable synergistic inhibitory effect on F. graminearum spore germination. The fermentation broth and formulation of B. amyloliquefaciens JCK-12 strain reduced the disease incidence of FHB in wheat. Furthermore, co-application of B. amyloliquefaciens JCK-12 and chemical fungicides resulted in synergistic in vitro antifungal effects and significant disease control efficacy against FHB under greenhouse and field conditions, suggesting that B. amyloliquefaciens JCK-12 has a strong chemosensitizing effect. The synergistic antifungal effect of B. amyloliquefaciens JCK-12 and chemical fungicides in combination may result from the cell wall damage and altered cell membrane permeability in the phytopathogenic fungi caused by the CLP mixtures and subsequent increased sensitivity of F. graminearum to fungicides. In addition, B. amyloliquefaciens JCK-12 showed the potential to reduce trichothecenes mycotoxin production. The results of this study indicate that B. amyloliquefaciens JCK-12 could be used as an available biocontrol agent or as a chemosensitizer to chemical fungicides for controlling FHB disease and as a strategy for preventing the contamination of harvested crops with mycotoxins. PMID- 29230233 TI - Whole Genome Sequencing of Fusarium fujikuroi Provides Insight into the Role of Secretory Proteins and Cell Wall Degrading Enzymes in Causing Bakanae Disease of Rice. AB - Fusarium fujikuroi causing bakanae disease has emerged as one of the major pathogen of rice across the world. The study aims to comparative genomic analysis of Fusarium fujikuroi isolates and identification of the secretary proteins of the fungus involved in rice pathogenesis. In the present study, F. fujikuroi isolate "F250" was sequenced with an assembly size of 42.47 Mb providing coverage of 96.89% on reference IMI58289 genome. A total of 13,603 protein-coding genes were predicted from genome assembly. The average gene density in the F. fujikuroi genome was 315.10 genes per Mb with an average gene length of 1.67 kb. Additionally, 134,374 single nucleotide polymorphisms (SNPs) are identified against IMI58289 isolate, with an average SNP density of 3.11 per kb of genome. Repetitive elements represent approximately 270,550 bp, which is 0.63% of the total genome. In total, 3,109 simple sequence repeats (SSRs), including 302 compound SSRs are identified in the 8,656 scaffolds. Comparative analysis of the isolates of F. fujikuroi revealed that they shared a total of 12,240 common clusters with F250 showing higher similarity with IMI58289. A total of 1,194 secretory proteins were identified in its genome among which there were 356 genes encoding carbohydrate active enzymes (CAZymes) capable for degradation of complex polysaccharides. Out of them glycoside hydrolase (GH) families were most prevalent (41%) followed by carbohydrate esterase (CE). Out of them CE8 (4 genes), PL1 (10 genes), PL3 (5 genes), and GH28 (8 genes) were prominent plant cell wall degrading enzymes families in F250 secretome. Besides this, 585 genes essential for the pathogen-host interactions were also identified. Selected genes were validated through quantitative real-time PCR analyses in resistant and susceptible genotypes of rice at different days of inoculation. The data offers a better understanding of F. fujikuroi genome and will help us enhance our knowledge on Fusarium fujikuroi-rice interactions. PMID- 29230234 TI - The Epigenetic Cytocrin Pathway to the Nucleus. Epigenetic Factors, Epigenetic Mediators, and Epigenetic Traits. A Biochemist Perspective. AB - A single word, Epigenetics, underlies one exciting subject in today's Science, with different sides and with interactions with philosophy. The apparent trivial description includes everything in between genotype and phenotype that occurs for a given unique DNA sequence/genome. This Perspective article first presents an historical overview and the reasons for the lack of consensus in the field, which derives from different interpretations of the diverse operative definitions of Epigenetics. In an attempt to reconcile the different views, we propose a novel concept, the "cytocrin system." Secondly, the article questions the inheritability requirement and makes emphasis in the epigenetic mechanisms, known or to be discovered, that provide hope for combating human diseases. Hopes in cancer are at present in deep need of deciphering mechanisms to support ad hoc therapeutic approaches. Better perspectives are for diseases of the central nervous system, in particular to combat neurodegeneration and/or cognitive deficits in Alzheimer's disease. Neurons are post-mitotic cells and, therefore, epigenetic targets to prevent neurodegeneration should operate in non-dividing diseased cells. Accordingly, epigenetic-based human therapy may not need to count much on transmissible potential. PMID- 29230235 TI - Editorial: Ubiquitin and Ubiquitin-Relative SUMO in DNA Damage Response. PMID- 29230236 TI - Post-transcriptional Regulation of PCSK9 by miR-191, miR-222, and miR-224. AB - Since proprotein convertase subtilisin kexin 9 (PCSK9) discovery, a gene involved in LDL metabolism regulation and cardiovascular diseases (CVD), many therapeutic strategies have been introduced for direct targeting of PCSK9. The main goal of these strategies has been to reduce PCSK9 protein level either by application of antibodies or inhibition of its production. In this study, we have tried to discover microRNAs (miRNAs) which can target, and hence regulate, PCSK9 expression. Using bioinformatics tools, we selected three microRNAs with binding sites on 3'-UTR of PCSK9. The expression level of these miRNAs was examined in three different cell lines using real-time RT-PCR. We observed a reciprocal expression pattern between expression level of miR-191, miR-222, and miR-224 with that of PCSK9. Accordingly, the expression levels were highest in Huh7 cells which expressed the lowest level of PCSK9, compared to HepG2 and A549 cell lines. PCSK9 mRNA level also showed a significant decline in HepG2 cells transfected with the vectors overexpressing the aforementioned miRNAs. Furthermore, the miRNAs target sites were cloned in psiCHECK-2 vector, and a direct interaction of the miRNAs and the PCSK9 3'-UTR putative target sites was investigated by means of luciferase assay. Our findings revealed that miR-191, miR-222, and miR-224 can directly interact with PCSK9 3'-UTR and regulate its expression. In conclusion, our data introduces a role for miRNAs to regulate PCSK9 expression. PMID- 29230237 TI - RNA-Seq of Plant-Parasitic Nematode Meloidogyne incognita at Various Stages of Its Development. PMID- 29230238 TI - Fluid Retention Caused by Rosiglitazone Is Related to Increases in AQP2 and alphaENaC Membrane Expression. AB - Peroxisome proliferator activated receptor-gamma (PPARgamma) is a ligand activated transcription factor of the nuclear hormone receptor superfamily. The decreased phosphorylation of PPARgamma due to rosiglitazone (ROS) is the main reason for the increased insulin sensitivity caused by this antidiabetic drug. However, there is no clear evidence whether the nuclear translocation of p PPARgamma stimulated by ROS is related to fluid retention. It is also unclear whether the translocation of p-PPARgamma is associated with the change of aquaporin-2 (AQP2) and epithelial sodium channel alpha subunit (alphaENaC) in membranes, cytoplasm, and nucleus. Our experiments indicate that ROS significantly downregulates nuclear p-PPARgamma and increases membrane AQP2 and alphaENaC; however, SR1664 (a nonagonist PPARgamma ligand) reduces p-PPARgamma and has no effect on AQP2 and alphaENaC. Therefore, we conclude that in vitro the fluid retention caused by ROS is associated with the increases in membrane alphaENaC and AQP2 but has little relevance to the phosphorylation of PPARgamma. PMID- 29230239 TI - A Comparison Study on Multidomain EEG Features for Sleep Stage Classification. AB - Feature extraction from physiological signals of EEG (electroencephalogram) is an essential part for sleep staging. In this study, multidomain feature extraction was investigated based on time domain analysis, nonlinear analysis, and frequency domain analysis. Unlike the traditional feature calculation in time domain, a sequence merging method was developed as a preprocessing procedure. The objective is to eliminate the clutter waveform and highlight the characteristic waveform for further analysis. The numbers of the characteristic activities were extracted as the features from time domain. The contributions of features from different domains to the sleep stages were compared. The effectiveness was further analyzed by automatic sleep stage classification and compared with the visual inspection. The overnight clinical sleep EEG recordings of 3 patients after the treatment of Continuous Positive Airway Pressure (CPAP) were tested. The obtained results showed that the developed method can highlight the characteristic activity which is useful for both automatic sleep staging and visual inspection. Furthermore, it can be a training tool for better understanding the appearance of characteristic waveforms from raw sleep EEG which is mixed and complex in time domain. PMID- 29230240 TI - Utility of Endoscopic Examination in the Diagnosis of Acute Graft-versus-Host Disease in the Lower Gastrointestinal Tract. AB - Background and Aims: We retrospectively investigated the incidence of acute graft versus-host disease (GVHD) in the lower gastrointestinal (GI) tract and the diagnostic accuracy of endoscopy. Methods: Of 1231 patients who underwent allogeneic hematopoietic stem cell transplantation between January 2005 and December 2014, 186 of whom underwent colonoscopy and biopsy and had no cytomegalovirus infection. The endoscopic findings and histologic diagnosis from these 186 patients were retrospectively analyzed. Results: Based on the histopathological findings, 171 patients were diagnosed with GVHD, accounting for 13.9% of all transplant recipients. Useful endoscopic findings for the diagnosis of GVHD were atrophy of the ileocecal valve and villous atrophy in the terminal ileum and tortoise shell-like mucosae, edema, and low vascular permeability in the colon. Even when no mucosal abnormality was observed, the incidence of GVHD was 78.9% in the terminal ileum and 75.0% in the colon. Furthermore, patients with mucosal exfoliation, although infrequent, were all diagnosed with grade 3/4 GVHD. Conclusions: It is important to perform endoscopy proactively for the early diagnosis of GVHD, and biopsy should be performed even when no abnormality is observed. In addition, because patients with mucosal exfoliation are extremely likely to have grade 3/4 GVHD, early treatment should be initiated. PMID- 29230241 TI - Detection Rate and Clinical Relevance of Ink Tattooing during Balloon-Assisted Enteroscopy. AB - Background and Aims: Balloon-assisted enteroscopy (BAE) is a well-established tool in the diagnosis and therapy of small bowel diseases. Ink tattooing of the small bowel is used to mark pathologic lesions or the depth of small bowel insertion. The purpose of this study was to determine the safety, the detection rate, and the clinical relevance of ink tattooing during BAE. Methods: We performed a retrospective analysis of all 81 patients who received an ink tattooing during BAE between 2010 and 2015. Results: In all patients, ink tattooing was performed with no complications. 26 patients received a capsule endoscopy after BAE. The tattoo could be detected via capsule endoscopy in 19 of these 26 patients. The tattoo of the previous BAE could be detected via opposite BAE in 2 of 11 patients. In 9 patients, ink tattooing influenced the choice of approach for reenteroscopy. In 7 patients, the tattoo was used for intraoperative localization and in 3 patients for intraoperative localization as well as for reenteroscopy. The intraoperative detection rate of the tattoo was 100%. Conclusion: Ink tattooing of the small intestine is a safe endoscopic procedure to mark the depth of scope insertion or a pathologic lesion during balloon assisted enteroscopy. PMID- 29230243 TI - Type 2 Diabetes Mellitus and Macrovascular Complications. PMID- 29230242 TI - Families Living with Blood-Borne Viruses: The Case for Extending the Concept of "Serodiscordance". AB - The concept of "serodiscordance" (mixed infection status) is primarily associated with epidemiological concerns about HIV transmission risk in couples. We make the case for extending this concept to include families with mixed HIV and viral hepatitis status. Social research on couples with mixed HIV and hepatitis C status has laid an important foundation for illuminating how experiences of serodiscordance within intimate partnerships are much broader than concerns about risk. This body of work attests to serodiscordance holding promise as a valuable concept for understanding viral infections as socially situated and intensely relational phenomena. However, serodiscordance is still limited as a concept because of its near universal focus on couples. It is rarely applied to wider relationships, including family networks beyond the couple. Despite evidence in the literature that families are affected by blood-borne viruses in multiple social, emotional, financial, and generational ways, the concept of serodiscordance does not capture these broader dynamics. Making serodiscordance more inclusive is an important step in recognising the diverse ways families' everyday lives, relationships, and futures can be entangled with HIV, hepatitis C, and hepatitis B, and for understanding how today's era of effective treatment options might shape the "family life" of viral infections. PMID- 29230244 TI - Tumor Lysis Syndrome in Patients with Hematological Malignancies. AB - Tumor lysis syndrome is a metabolic complication that may follow the initiation of cancer therapy. It commonly occurs in hematological malignant patients particularly non-Hodgkin's lymphoma and acute leukemia due to chemotherapy or spontaneously. It is characterized by a biochemical abnormality such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia and its clinical outcome is directly related to these biochemical abnormalities. Prevention and treatment of tumor lysis syndrome depend on immediate recognition of patients at risk. Therefore, identifying patients at risk and prophylactic measures are important to minimize the clinical consequences of tumor lysis syndrome. Patients with low risk should receive hydration and allopurinol. On the other hand patients with high risk should receive hydration and rasburicase in an inpatient setting. It is important to start therapy immediately, to correct all parameters before cancer treatment, to assess risk level of patients for TLS, and to select treatment options based on the risk level. In this review a comprehensive search of literatures was performed using MEDLINE/PubMed, Hinari, the Cochrane library, and Google Scholar to summarize diagnostic criteria, incidence, predicting factors, prevention, and treatment options for tumor lysis syndrome in patients with hematological malignancies. PMID- 29230245 TI - Adaptation and Molecular Characterization of Two Malaysian Very Virulent Infectious Bursal Disease Virus Isolates Adapted in BGM-70 Cell Line. AB - Two Malaysian very virulent infectious bursal disease virus (vvIBDV) strains UPM0081 and UPM190 (also known as UPMB00/81 and UPM04/190, respectively) isolated from local IBD outbreaks were serially passaged 12 times (EP12) in specific pathogen free (SPF) chicken embryonated eggs (CEE) by chorioallantoic membrane (CAM) route. The EP12 isolate was further adapted and serially propagated in BGM 70 cell line up to 20 passages (P20). Characteristic cytopathic effects (CPEs) were subtly observed at P1 in both isolates 72 hours postinoculation (pi). The CPE became prominent at P5 with cell rounding, cytoplasmic vacuoles, granulation, and detachment from flask starting from day 3 pi, up to 7 days pi with titers of 109.50 TCID50/mL and log109.80 TCID50/mL for UPM0081 and UPM190, respectively. The CPE became subtle at P17 and disappeared by P18 and P19 for UPM0081 and UPM190, respectively. However, the presence of IBDV was confirmed by immunoperoxidase, immunofluorescence, and RT-PCR techniques. Phylogenetic analysis showed that these two isolates were of the vvIBDV. It appears that a single mutation of UPM190 and UPM0081 IBDV isolates at D279N could facilitate vvIBDV strain adaptability in CEE and BGM-70 cultures. PMID- 29230246 TI - Usefulness of Endoscopic Managements in Patients with Ceftriaxone-Induced Pseudolithiasis Causing Biliary Obstruction. AB - Ceftriaxone (CTRX) is known to cause reversible biliary stones/sludge, which is called biliary pseudolithiasis. We report two rare cases of biliary obstruction by pseudolithiasis shortly after completing CTRX treatment. Stones and sludge, which had not been detected before CTRX administration, appeared in the gallbladder and common bile duct and led to biliary obstruction and acute cholangitis. The obstructions were successfully treated with endoscopic retrograde biliary drainage and endoscopic sphincterotomy. CTRX-induced biliary pseudolithiasis has been reported mainly in children and adolescents but is also seen in adults with similar incidence rate. Although CTRX-induced biliary pseudolithiasis is usually asymptomatic and disappears spontaneously after discontinuing the drug, some patients develop biliary obstruction. Endoscopic managements should be considered in such cases. PMID- 29230247 TI - Wireless Neuromodulation for Chronic Back Pain: Delivery of High-Frequency Dorsal Root Ganglion Stimulation by a Minimally Invasive Technique. AB - Objective: To evaluate the analgesic effect of a dorsal root ganglion (DRG) stimulation technology utilizing high-frequency pulse rates to treat intractable chronic back and leg pain. Methods: This case study presents the outcomes, with a novel, wireless, minimally invasive miniature neurostimulator system in a case of chronic back pain. The subject was implanted bilaterally with a Freedom 4A quadripolar electrode array at the L2 dorsal root ganglion. Stimulation was applied using 10 kHz pulse rate and 30 MUs pulse width. A VAS pain-rating scale, Oswestry Disability Index (ODI), EQ-5D-5L Quality of Life Questionnaire 5 dimensions, and Patients' Global Impression of Change (PGIC) scale were evaluated at 12 weeks and 6 months post implantation. Results: VAS pain scores for back pain reduced from 91 to 31 mms and 80 to 35 mms for leg pain. Additionally, while stimulation remained paresthesia-free, there were a marked decrease in pain medications and an increase in quality of life. Also, an increase in functionality from crippled to moderate was reported. There were no adverse reactions related to the procedure or device. Conclusion: The minimally invasive, wireless approach to deliver high-frequency, paresthesia-free DRG stimulation for treatment of chronic back and leg pain associated with FBSS was effective and encouraging. PMID- 29230248 TI - A Concise Review on the Use of Mesenchymal Stem Cells in Cell Sheet-Based Tissue Engineering with Special Emphasis on Bone Tissue Regeneration. AB - The integration of stem cell technology and cell sheet engineering improved the potential use of cell sheet products in regenerative medicine. This review will discuss the use of mesenchymal stem cells (MSCs) in cell sheet-based tissue engineering. Besides their adhesiveness to plastic surfaces and their extensive differentiation potential in vitro, MSCs are easily accessible, expandable in vitro with acceptable genomic stability, and few ethical issues. With all these advantages, they are extremely well suited for cell sheet-based tissue engineering. This review will focus on the use of MSC sheets in osteogenic tissue engineering. Potential application techniques with or without scaffolds and/or grafts will be discussed. Finally, the importance of osteogenic induction of these MSC sheets in orthopaedic applications will be demonstrated. PMID- 29230249 TI - The Impact of GFP Reporter Gene Transduction and Expression on Metabolomics of Placental Mesenchymal Stem Cells Determined by UHPLC-Q/TOF-MS. AB - Introduction: Green fluorescent protein (GFP) is widely used as a reporter gene in regenerative medicine research to label and track stem cells. Here, we examined whether expressing GFP gene may impact the metabolism of human placental mesenchymal stem cells (hPMSCs). Methods: The GFP gene was transduced into hPMSCs using lentiviral-based infection to establish GFP+hPMSCs. A sensitive 13C/12C dansyl labeling LC-MS method targeting the amine/phenol submetabolome was used for in-depth cell metabolome profiling. Results: A total of 1151 peak pairs or metabolites were detected from 12 LC-MS runs. Principal component analysis and partial least squares discriminant analysis showed poor separation, and the volcano plots demonstrated that most of the metabolites were not significantly changed when hPMSCs were tagged with GFP. Overall, 739 metabolites were positively or putatively identified. Only 11 metabolites showed significant changes. Metabolic pathway analyses indicated that three of the identified metabolites were involved in nine pathways. However, these metabolites are unlikely to have a large impact on the metabolic pathways due to their nonessential roles and limited hits in pathway analysis. Conclusion: This study indicated that the expression of ectopic GFP reporter gene did not significantly alter the metabolomics pathways covered by the amine/phenol submetabolome. PMID- 29230250 TI - Mesenchymal Stromal Cells Are More Immunosuppressive In Vitro If They Are Derived from Endometriotic Lesions than from Eutopic Endometrium. AB - Endometriosis is an inflammatory disease with predominance of immunosuppressive M2 macrophages in the pelvic cavity that could be involved in the pathology through support and immune escape of ectopic lesions. Mesenchymal stromal cells (MSC) are found in ectopic lesions, and MSC from nonendometriosis sources are known to induce M2 macrophages. Therefore, MSC were hypothesized to play a role in the pathology of endometriosis. The aim was to characterize the functional phenotype of MSC in ectopic and eutopic endometrium from women with endometriosis. Stromal cells from endometriotic ovarian cysts (ESCcyst) and endometrium (ESCendo) were examined if they exhibited a MSC phenotype. Then, ESC were phenotypically examined for protein and gene expression of immunosuppressive and immunostimulatory molecules. Finally, ESC were functionally examined for their effects on monocyte differentiation into macrophages. ESCcyst and ESCendo expressed MSC markers, formed colonies, and differentiated into osteoblasts and adipocytes. Phenotypically, ESCcyst were more immunosuppressive, with significantly higher expression of immunosuppressive molecules. Functionally, ESCcyst induced more spindle-shaped macrophages, with significantly higher expression of CD14 and CD163, both features of M2 macrophages. The results suggest that ESCcyst may be more immunosuppressive than ESCendo and may promote immunosuppressive M2 macrophages that may support growth and reduce immunosurveillance of ectopic lesions. PMID- 29230251 TI - Establishment of Novel Limbus-Derived, Highly Proliferative ABCG2+/ABCB5+ Limbal Epithelial Stem Cell Cultures. AB - Homeostasis and regeneration of corneal epithelia are sustained by limbal epithelial stem cells (LESCs); thus, an LESC deficiency is a major cause of blindness worldwide. Despite the generally promising results of cultivated LESC transplantation, it has been limited by variations in long-term success rates, the use of xenogeneic and undefined culture components, and a scarcity of donor tissues. In this study, we identified the culture conditions required to expand LESCs in vitro and established human limbus-derived highly proliferative ABCG2+/ABCB5+ double-positive LESCs. These LESCs exhibited the LESC marker profile and differentiated into corneal epithelial cells. In addition, cultured LESCs expressed high levels of the stem cell markers Sox2, Oct4, c-Myc, and Klf4, had high telomerase activity, and had stable, normal genomes. These results suggest that our novel cultivation protocol affects the phenotype and differentiation capacity of LESCs. From the limbus, which contains a heterogenous cell population, we have derived highly proliferative ABCG2+/ABCB5+ double positive cells with the ability to differentiate into corneal epithelial cells. This study opens a new avenue for investigation of the molecular mechanism of LESC maintenance and expansion in vitro and may impact the treatment of corneal disease, particularly corneal blindness due to an LESC deficiency. PMID- 29230252 TI - Evaluation of the Utility of Point-of-Care HIV Testing on a Canadian Internal Medicine Inpatient Unit. AB - Point-of-care (POC) HIV testing has been shown to be an acceptable method for increasing HIV testing uptake. To date, no studies have examined the use of POC testing for routine HIV screening on the medicine inpatient unit. A prospective cross-sectional study was conducted over a three-month period in July, August, and October 2016 to evaluate the prevalence of undiagnosed HIV and the attitudes towards routine POC HIV testing. Patients admitted directly to medicine inpatient teaching units at a tertiary hospital in Winnipeg, Canada, were approached for participation. The POC HIV test was administered at the bedside. Reactive and indeterminate tests were confirmed with standard serological HIV testing. Participants were given a questionnaire regarding their attitudes towards POC testing on the unit. Although no cases of previously undiagnosed HIV were identified during the study period, only 35% of participants were found to have ever had HIV testing previously. The majority of participants were satisfied with the POC testing experience and would choose to have the POC testing again. Overall, the low rate of outpatient testing highlights the need for routine HIV testing on an inpatient basis. PMID- 29230253 TI - Barriers to clinical adoption of next-generation sequencing: a policy Delphi panel's solutions. AB - Aim: Identify solutions to the most important policy barriers to the clinical adoption of next-generation sequencing. Materials & methods: Four-round modified policy Delphi with a multistakeholder panel of 48 experts. The panel deliberated policy solutions to (previously reported) challenges deemed most important to address. Results: The group advocated using consensus panels to promote consistency in payer policies and to standardize test reporting, and favored making genomic data-sharing a condition of regulatory clearance, certification, or accreditation processes. They were split on the role of US FDA. Conclusion: Panelists found common ground on solutions for health plan coverage policy consistency, data-sharing, and standardizing reporting, but were sharply divided on the role of the FDA in mitigating risks to patients. PMID- 29230254 TI - A Cross-Lingual Mobile Medical Communication System Prototype for Foreigners and Subjects with Speech, Hearing, and Mental Disabilities Based on Pictograms. AB - People with speech, hearing, or mental impairment require special communication assistance, especially for medical purposes. Automatic solutions for speech recognition and voice synthesis from text are poor fits for communication in the medical domain because they are dependent on error-prone statistical models. Systems dependent on manual text input are insufficient. Recently introduced systems for automatic sign language recognition are dependent on statistical models as well as on image and gesture quality. Such systems remain in early development and are based mostly on minimal hand gestures unsuitable for medical purposes. Furthermore, solutions that rely on the Internet cannot be used after disasters that require humanitarian aid. We propose a high-speed, intuitive, Internet-free, voice-free, and text-free tool suited for emergency medical communication. Our solution is a pictogram-based application that provides easy communication for individuals who have speech or hearing impairment or mental health issues that impair communication, as well as foreigners who do not speak the local language. It provides support and clarification in communication by using intuitive icons and interactive symbols that are easy to use on a mobile device. Such pictogram-based communication can be quite effective and ultimately make people's lives happier, easier, and safer. PMID- 29230255 TI - Control of cell proliferation by a porous chitosan scaffold with multiple releasing capabilities. AB - The aim of this study was to develop a porous chitosan scaffold with long-acting drug release as an artificial dressing to promote skin wound healing. The dressing was fabricated by pre-freezing at different temperatures (-20 and -80 degrees C) for different periods of time, followed by freeze-drying to form porous chitosan scaffolds with different pore sizes. The chitosan scaffolds were then used to investigate the effect of the controlled release of fibroblast growth factor-basic (bFGF) and transforming growth factor-beta1 (TGFbeta1) on mouse fibroblast cells (L929) and bovine carotid endothelial cells (BEC). The biocompatibility of the prepared chitosan scaffold was confirmed with WST-1 proliferation and viability assay, which demonstrated that the material is suitable for cell growth. The results of this study show that the pore sizes of the porous scaffolds prepared by freeze-drying can change depending on the pre freezing temperature and time via the formation of ice crystals. In this study, the scaffolds with the largest pore size were found to be 153 +/- 32 MUm and scaffolds with the smallest pores to be 34 +/- 9 MUm. Through cell culture analysis, it was found that the concentration that increased proliferation of L929 cells for bFGF was 0.005 to 0.1 ng/mL, and the concentration for TGFbeta1 was 0.005 to 1 ng/mL. The cell culture of the chitosan scaffold and growth factors shows that 3.75 ng of bFGF in scaffolds with pore sizes of 153 +/- 32 MUm can promote L929 cell proliferation, while 400 pg of TGFbeta1 in scaffolds with pore size of 34 +/- 9 MUm can enhance the proliferation of L929 cells, but also inhibit BEC proliferation. It is proposed that the prepared chitosan scaffolds can form a multi-drug (bFGF and TGFbeta1) release dressing that has the ability to control wound healing via regulating the proliferation of different cell types. PMID- 29230256 TI - Design and Evaluation of a Robotic Device for Automated Tail Vein Cannulations in Rodent Models. AB - Preclinical testing in rodent models is a ubiquitous part of modern biomedical research and commonly involves accessing the venous bloodstream for blood sampling and drug delivery. Manual tail vein cannulation is a time-consuming process and requires significant skill and training, particularly since improperly inserted needles can affect the experimental results and study outcomes. In this paper, we present a miniaturized, robotic medical device for automated, image-guided tail vein cannulations in rodent models. The device is composed of an actuated three degrees-of-freedom (DOFs) needle manipulator, three dimensional (3D) near-infrared (NIR) stereo cameras, and an animal holding platform. Evaluating the system through a series of workspace simulations and free-space positioning tests, the device exhibited a sufficient work volume for the needle insertion task and submillimeter accuracy over the calibration targets. The results indicate that the device is capable of cannulating tail veins in rodent models as small as 0.3 mm in diameter, the smallest diameter vein required to target. PMID- 29230257 TI - Nanotribological Properties of Graphite Intercalation Compounds: AFM Studies. AB - Tetraalkylammonium salts have larger ions than metal ions, which can greatly change the interlayer space and energy, and then potentially tune the properties of graphite. In this work, various graphite intercalation compounds (GICs) have been synthesized by intercalating tetraoctylammonium bromide (TOAB) ions into graphite through electrochemical interactions under different reduction potentials. Different degrees of expansion between graphite layers as well as their corresponding structures and topographies have been characterized by different analytical techniques. The nanoscale friction and wear properties of these GICs have been investigated by AFM-based nanofrictional and scratch tests. The results show that electrochemical intercalation using tetraalkylammonium salts with different interaction potentials can tune the friction and wear properties of graphite. Under relatively large applied loads of AFM tips, friction increase and wear can be easier to occur with the increase of the intercalation potential. It is inferred that the increases of both the interlayer space of graphite and the number of ions on the surface give rise to puckered effect and formation of rougher surfaces. This work gives us deep insight into the friction and wear properties of GICs as composite lubrication materials, which would be of great help for material design and preparation. PMID- 29230258 TI - Osgood-schlatter disease: risk of a disease deemed banal. PMID- 29230259 TI - [Nosocomial urinary tract and surgical site infection rates in the Maternity Ward at the General Referral Hospital in Katuba, Lubumbashi, Democratic Republic of the Congo]. AB - Introduction: In Intertropical Africa hospitalized patients are exposed to a risk of nosocomial infections. The dearth of published data on this subject limits the descriptive analysis of the situation. This study aimed to determine the incidence, the germs responsible for these infections and the risk factors of nosocomial infections in the Maternity Ward at the General Referral Hospital in Katuba, Lubumbashi, Democratic Republic of the Congo. Methods: We conducted a descriptive, longitudinal study from 1 October 2014 to 1 January 2015. Our study population consisted of 207 women who had been hospitalized in the Maternity Ward at the General Referral Hospital in Katuba. We carried out a comprehensive data collection. Results: Nosocomial infection rate accounted for 15.5%. Parturient women who had been hospitalized for more than three days were three times more likely to develop a nosocomial infection (p=0.003), while those who had had a complicated delivery were four times more likely to be at risk of developing nosocomial infection (p = 0.000). Escherichia coli was the most isolated causative agent (38.1%), followed by Citrobacter freundi (23.8%), Acinobacter baumani (.18, 2%), Staphylococcus aureus (18.2%), Enterococcus aureus (14.3%) and Pseudomonas aeroginosa (9.1%). Ampicillin was the most prescribed antibiotic, to which isolated microbes were resistant. Conclusion: It is necessary to improve hospital hygiene and to conduct further study to examine the similarity between germs strains in the environment and those in biological fluids. PMID- 29230260 TI - [Epidemiological features of cardiorenal syndrome: a study of 36 cases in the Cardiology Department in Dakar]. AB - Introduction: Cardiorenal syndrome (CRS) is a pathophysiologic disorder of the heart and the kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. In Africa, particularly in Senegal, the incidence of cardiorenal syndrome is not accurately known. This study aimed to assess the prevalence of CRS in the Cardiology Department. Methods: We conducted a retrospective study including all patients with heart failure associated with alteration of renal function, hospitalized in the Cardiology Department between April 2010 and April 2011. Data were analyzed with the statistical software Epi-Info 3.5.3. Results: 36 patients were included in the study. The prevalence rate was 3.7% with male predominance (sex-ratio 1.77) and an average age of 56.9 years [30-92]. Patients' medical history was dominated by high blood pressure (52.77%) and diabetes (19.4%). The main etiologies were hypertensive cardiomyopathy (39%) and coronary heart disease (19.44%). The symptomatology was dominated by dyspnoea (69.4%) and edema (50%). 17 patients had anemia. The mean measured clearance (MDRD) was 46 ml/min. Doppler echocardiography showed mainly kinetic disorders (89.3%) and left ventricular systolic dysfunction (71%). The three renal ultrasound examinations were normal. Six deaths (16.7%) were recorded. Conclusion: Cardiorenal syndrome is a reality and marks a turning point in the evolution of heart and kidney diseases. In Senegal, its prevalence in the Cardiology Department is low. Prospective multicentric studies should be conducted in order to better evaluate this syndrome in Senegal. PMID- 29230261 TI - Early experience with open heart surgery in a pioneer private hospital in West Africa: the Biket medical centre experience. AB - Introduction: More than forty years after the first open heart surgery in Nigeria, all open heart surgeries were carried out in government-owned hospitals before the introduction of such surgeries in 2013 at Biket Medical Centre, a privately owned hospital in Osogbo, South-western Nigeria. The aim of this paper is to review our initial experience with open heart surgery in this private hospital. Methods: All patients who underwent open heart surgery between August 2013 and January 2014 were included in this prospective study. The medical records of the patients were examined and data on age, sex, diagnosis, type of surgery, cardiopulmonary bypass details, complications and length of hospital stay were extracted and the data was analysed using SPSS version 16. Results: Eighteen patients comprising of 12 males and 6 females with ages ranging between 8 months and 52 years (mean= of 15.7 +/- 15 years) were studied. Pericardial patch closure of isolated ventricular septal defect was done in 7 patients (38.9%) while total correction of isolated tetralogy of Fallot was carried out in 5 patients (27.8%). Two patients had mitral valve repair for rheumatic mitral regurgitation. Sixty day mortality was 0%. Conclusion: Safe conduct of open heart surgery in the private hospital setting is feasible in Nigeria. It may be our only guarantee of hitch free and sustainable cardiac surgery. PMID- 29230262 TI - [Cavernous metastasis from blader tumor]. AB - The incidence of cavernous metastases after radical treatment for bladder tumor is exceptional and is approximately 1%. The mean time between surgery and the occurrence of metastases is 8 months. In some cases they occur after 10 years. Diagnosis is confirmed by biopsy, which shows their urothelial origin. Here we report the case of 56-year old patient, with a history of smoking, having undergone total cystoprostatectomy in January 2017, who presented 2 months later with induratio penis plastica with no other sign associated. Priapism and gangrene of the penis of infectious origin have been suspected but, given the patient's clinical condition, the more likely diagnosis was cavernous metastasis. On two occasions the patient refused biopsy: during two consultations at 15 days interval (A, B). The patient accepted to undergo biopsy during the 3th consultation (C, D). Biopsy confirmed the diagnosis of cavernous metastasis. PMID- 29230263 TI - [Kaposi's sarcoma of the penis in a HIV-seronegative patient]. AB - Sarcomas of the penis account for less than 5% of all tumors of the penis. They are dominated by Kaposi's sarcoma that mainly affects HIV-positive patients. However, recent studies have shown a relationship between Kaposi's sarcoma and HHV-8 infection (Human herpes virus-8), which explains why this sarcoma occurs in non-immunocompromised and HIV-seronegative patients. We here report the case of a 72-year old patient, with no previous medical history, reporting of gradual onset of tumor-like granulation tissue of 3 years duration at the level of the gland, without secondary location. Given the patient's clinical condition, epidermoid carcinoma or sarcomatoid carcinoma of the penis were suspected. Initial biopsy was negative, the second was in favor of Kaposi's sarcoma, confirmed by immunohistochemistry. The patient underwent chemotherapy. PMID- 29230264 TI - Prevalence and risk factors of intra-dialytic hypotension: a 5 year retrospective report from a single Nigerian Centre. AB - Introduction: Intra-dialytic hypotension (IDH) is a common complication of haemodialysis that impacts negatively on the patient's quality of life and can induce serious cardiovascular events. Methods: Records of all adults who had haemodialysis treatments from Jan 2012-Jan 2016 were reviewed. Socio-demographic data, health status of patient, aetiology of renal disease, clinical and biochemical parameters such as systolic and diastolic blood pressures (SBP and DBP), packed cell volume, were collated using Microsoft Excel. Results: The overall prevalence of intra-dialytic hypotension was 8.6%. Of all haemodialysis patients, 45.7% experienced a drop in SBP > 20mmHg, 28.5% required nurses' intervention and 8.6% had symptoms. Diagnosis of obstructive nephropathy (OR: 3.1, CI:1.43-6.60, p = < 0.004) and sepsis (OR: 3.57, CI: 1.31- 9.75, P = 0.013) increased the odds of experiencing IDH. Only 5% of patients with predialysis SBP < 100mmHg developed IDH (OR: 0.12, CI: 0.02-0.93, P = 0.04). Conclusion: IDH was common among the patients studied. It was more prevalent among patients with obstructive nephropathy and sepsis; however other traditional risk factors of IDH such as older age and anaemia, were not found to be significantly associated with IDH. Surprisingly, prevalence of IDH was significantly less among patients with pre-dialysis hypotension compared to those without. PMID- 29230265 TI - [Juvenile myasthenia gravis in sub-Saharan Africa: a case study of two consanguine sisters born from consanguinity in Togo]. AB - Myasthenia gravis is a rare acquired autoimmune pathology causing neuromuscular transmission impairment. Juvenile onset of myasthenia gravis is often characterized by ocular involvement. We report two cases of ocular juvenile myasthenia gravis (JMG) in two siblings. They were two young girls, XA and XB, aged 11 and 9 years, of Malian origin, residing in Togo, born from first-degree of consanguinity presenting to Ophthalmology due to progressive decrease in visual acuity. XA showed visual acuity 8/10 on both eyes while XB showed improvement in visual acuity from 3/10 to 7/10 using a pinhole occluder, suggesting ametropia. XA had a 2-year history of bilateral ptosis lifting the upper eyelid of 7 mm, while XB had a 3-year history of bilateral ptosis with no lifting of the upper eyelid. Ice pack test was strongly positive in both patients. They had Cogan's lid twitch with paresis of the oculomotor nerve without diplopia. The dosage of acetylcholine receptor autoantibodies was normal. The diagnosis of JMG associated with ametropia was suspected. Ametropia was corrected by glasses and a specific treatment with pyridostigmine was initiated, but both patients were lost to follow-up. Autoimmune myasthenia gravis with inaugural ophthalmologic manifestation is rare but it can occur among children living in sub-Saharan Africa. Studies should be conducted to establish the features of this disease. PMID- 29230266 TI - [Shoulder tumor of startling appearance]. AB - Chondrosarcoma is a malignant tumor of bone of mesenchymal origin which usually occurs in people after age 40 at the level of the pelvis and the shoulder. We report the case of a 65-year old female patient, with no particular past medical history, with impaired general condition, hospitalized for exploration of a large tumor of the right shoulder, evolving over 3 years. Clinical examination showed giant, humpbacked, hard, adherent tumor measuring 44 * 32 cm along its longer axis, with inflammatory signs associated with signs of vasculo-nervous compression. Radiological evaluation showed expansive, epiphyseal, metaphyseal, diaphyseal, heterogeneou, multilobulated, poorly differentiated, calcified tumoral process with complete destruction of the glenohumeral joint that extensively invaded the soft tissues with loco-regional extension. Histological examination of a deep biopsy specimen was in favor of poorly differentiated chondrosarcoma. Staging evaluation objectified bilateral axillary lymphadenopathies and multiple metastatic subpleural and hepatic nodules. The patient died after 2 months. This study highlights the role of awareness campaigns for early diagnosis and management. PMID- 29230267 TI - Presenting signs of retinoblastoma at a tertiary level teaching hospital in Ethiopia. AB - Introduction: Retinoblastoma is a primary malignant intraocular neoplasm that arise from immature retinoblasts with in developing retina. The commonest presenting sign in developing country is proptosis which is the late presenting sign. We report presenting signs of retinoblastoma in Ethiopian children seen at a tertiary level teaching hospitals in Ethiopia. Methods: Prospective case series study was done on children who presented with retinoblastoma between May 1, 2005 and September 1, 2006. This study was done as part of requirement for partial fulfilment of certificate of specialty study in ophthalmology during the year 2005 to 2006. SPSS 11 statistical package was used to analyse the data. Results: Among 41 patients seen during the study period, 24 (58.5%) were males and 17(41%) were females. Unilateral retinoblastoma was found in 32 (78%) patients and bilateral cases were found in 9(22%). Mean age of onset for right eye was 27.5 months and left eye 33.7 months. The mean ages of presentation at time of diagnosis for right and left eye were 34.4 and 40.2 months, respectively .In bilateral retinoblastoma mean age of presentation was 33.3 months. The commonest presenting sign was proptosis 22(53.7%) followed by leucocorea nine (22%),ocular inflammation four (9.0 %), strabismus three (7.3%), glaucoma one (2.4%), loss of vision one (2.4%)and hyphemaone (2.4%). Conclusion: The commonest presenting signs of retinoblastoma in our set up were Proptosis followed by leucocorea. This is due to late presentation of patient and late referral by medical professionals. Health education to the public and health professionals will help early detection of retinoblastoma. PMID- 29230268 TI - An Alginate/Cyclodextrin Spray Drying Matrix to Improve Shelf Life and Antioxidant Efficiency of a Blood Orange By-Product Extract Rich in Polyphenols: MMPs Inhibition and Antiglycation Activity in Dysmetabolic Diseases. AB - Alginate and beta-cyclodextrin were used to produce easily dosable and spray dried microsystems of a dried blood orange extract with antidysmetabolic properties, obtained from a by-product fluid extract. The spray-dried applied conditions were able to obtain a concentrate dried extract without the loss of AOA and with TPC and TMA values of 35-40% higher than that of the starting material. They were also effective in producing microparticles with 80-100% of encapsulation efficiency. The 2% sodium alginate was capable of improving the extract shelf life, while the beta-cyclodextrin (1 : 1 molar ratio with dried extract) prolonged the extract antioxidant efficiency by 6 hours. The good inhibition effect of the dried extract on the AGE formation and the MMP-2 and MMP 9 activity is presumably due to a synergic effect exerted by both anthocyanin and bioflavonoid extract compounds and was improved by the use of alginate and cyclodextrin. PMID- 29230269 TI - Extracellular Vesicles from Adipose-Derived Mesenchymal Stem Cells Downregulate Senescence Features in Osteoarthritic Osteoblasts. AB - Osteoarthritis (OA) affects all articular tissues leading to pain and disability. The dysregulation of bone metabolism may contribute to the progression of this condition. Adipose-derived mesenchymal stem cells (ASC) are attractive candidates in the search of novel strategies for OA treatment and exert anti-inflammatory and cytoprotective effects on cartilage. Chronic inflammation in OA is a relevant factor in the development of cellular senescence and joint degradation. In this study, we extend our previous observations of ASC paracrine effects to study the influence of conditioned medium and extracellular vesicles from ASC on senescence induced by inflammatory stress in OA osteoblasts. Our results in cells stimulated with interleukin- (IL-) 1beta indicate that conditioned medium, microvesicles, and exosomes from ASC downregulate senescence-associated beta-galactosidase activity and the accumulation of gammaH2AX foci. In addition, they reduced the production of inflammatory mediators, with the highest effect on IL-6 and prostaglandin E2. The control of mitochondrial membrane alterations and oxidative stress may provide a mechanism for the protective effects of ASC in OA osteoblasts. We have also shown that microvesicles and exosomes mediate the paracrine effects of ASC. Our study suggests that correction of abnormal osteoblast metabolism by ASC products may contribute to their protective effects. PMID- 29230270 TI - Activation of NLRP3 Inflammasome by Advanced Glycation End Products Promotes Pancreatic Islet Damage. AB - Accumulation of advanced glycation end products (AGEs) contributes to ageing and age-related diseases, especially type 2 diabetes. The NLRP3 inflammasome, as a vital component of the innate immune system, is implicated in the pathogenesis of type 2 diabetes. However, the role of the NLRP3 inflammasome in AGE-induced pancreatic islet damage remains largely unclear. Results showed that administration of AGEs (120 mg/kg for 6 weeks) in C57BL/6J mice induced an abnormal response to glucose (as measured by glucose tolerance and insulin release), pancreatic beta-cell ultrastructural lesion, and cell death. These effects were associated with an excessive superoxide anion level, significant increased protein expression levels for NADPH oxidase 2 (NOX2), thioredoxin interacting protein (TXNIP), NLRP3, and cleaved IL-1beta, enhanced caspase-1 activity, and a significant increase in the levels of TXNIP-NLRP3 protein interaction. Ablation of the NLRP3 inflammasome or treatment with antioxidant N acetyl-cysteine (NAC) clearly ameliorated these effects. In conclusion, our results reveal a possible mechanism for AGE-induced pancreatic islet damage upon NLRP3 inflammasome activation. PMID- 29230271 TI - The Role of Oxidative Stress in Decreased Acetylcholinesterase Activity at the Neuromuscular Junction of the Diaphragm during Sepsis. AB - Our recent study demonstrated that acetylcholinesterase (AChE) activity at the neuromuscular junction (NMJ) of the diaphragm decreased during sepsis. However, the mechanisms were not clearly identified. In this study, we aimed to investigate whether the decreased AChE activity was related to oxidative stress by observing AChE activity in different grades of sepsis induced by caecal ligation and puncture (CLP). At 24 h after surgery, an assay of thiobarbituric acid reactive species (TBARS) and protein carbonyls, as well as the myeloperoxidase (MPO), superoxide dismutase (SOD), and catalase (CAT) activity, was conducted. AChE activity was measured by biochemical and histological detection. AChE and CAT activity in the diaphragm decreased, while the contents of TBARS and protein carbonyls, the activity of MPO and SOD, and the SOD/CAT ratios increased. The above changes were much more significant in the mid-grade septic group than in the low-grade septic group. The colour of the AChE activity staining at the NMJ gradually lightened from the sham surgery group to the mid grade septic group. AChE activity was significantly negatively correlated with the levels of TBARS and protein carbonyls. We consider that oxidative stress might be responsible for decreased AChE activity in the diaphragms of rats induced with sepsis. PMID- 29230272 TI - The role of guilt in Posttraumatic Stress Disorder. AB - Background: A growing body of evidence supports the notion that the emotional profile of Posttraumatic Stress Disorder (PTSD) may be more diverse than traditional accounts presume. PTSD's image as an anxiety-based disorder is undergoing change as the significance of other emotions in its development becomes more evident. Experimental research is needed in order to expand the understanding of underlying processes driving the development of PTSD. Objective: Experimentally test the influence of stressor-related guilt on the occurrence of PTSD symptomatology. Method: A non-clinical student sample faced an analogue trauma, a stressor in the form of a computer crash and related loss of data. We either personally blamed participants for causing the incident (blame group) or told them that it was a technical failure and therefore not their fault (no-blame group). Levels of guilt before and after the incident as well as number and associated distress of incident-related intrusions were assessed using a one-day diary and compared between groups. Results: The guilt manipulation was successful: feelings of guilt significantly increased in the blame group but not in the no-blame group. Furthermore, the blame group showed a significantly higher number of intrusions and associated distress compared to the no-blame group at one-day follow-up. Conclusions: These laboratory findings indicate that feelings of guilt may lead to increased PTSD symptomatology, supporting the view that guilt experienced in reaction to a traumatic event may be part of a causal mechanism driving the development of PTSD. PMID- 29230273 TI - Is your lunch salad safe to eat? Occurrence of bacterial pathogens and potential for pathogen growth in pre-packed ready-to-eat mixed-ingredient salads. AB - As part of a trend toward healthy convenience foods, ready-to-eat (RTE) mixed ingredient salads have become popular products among consumers. A mixed ingredient salad contains combinations of raw (e.g. leafy vegetables and tomatoes) and processed (e.g. chicken, salmon, ham, pasta and couscous) ingredients. Contamination of leafy vegetables can occur during any step in the production chain and, since there is no step that kills pathogens, a completely safe final product can never be guaranteed. Meat ingredients, for example poultry meat and ham, are generally heat-treated before preparation, but may be contaminated after this treatment, e.g. when diced or sliced. When several ingredients are mixed together, cross-contamination may occur. Preparation of mixed-ingredient salads requires human handling, which presents an additional risk of bacterial contamination. With high-protein ingredients, e.g. cooked meat, the mixed-ingredient salad represents an excellent substrate for bacterial growth. This article reviews current knowledge regarding human bacterial pathogen prevalence in mixed-ingredient salads and the potential for pathogen growth in this product during storage. PMID- 29230274 TI - Factors influencing pharmacological treatment in COPD: a comparison of 2005 and 2014. AB - Introduction: The aim was to investigate how the pattern of pharmacological treatment in Swedish patients with chronic obstructive pulmonary disease (COPD) has changed over a decade, and to identify factors associated with treatment. Methods: Data on patient characteristics and pharmacological treatment were collected using questionnaires from two separate cohorts of randomly selected primary and secondary care patients with a doctor's diagnosis of COPD in central Sweden, in 2005 (n = 1111) and 2014 (n = 1329). Cross-tabulations and chi-square tests were used to compare maintenance treatment in 2005 and 2014, and to investigate the distribution of treatment by the 2017 Global Initiative for Obstructive Lung Disease (GOLD) ABCD groups. Multinomial logistic regression was used to analyze associations with the major types of recommended treatments: bronchodilator therapy, combined long-acting beta-2-antagonists (LABA) + inhaled corticosteroids (ICS), and triple inhaled therapy. Results: The proportion of patients with no maintenance treatment, with only LABA + ICS, and with sole ICS statistically significantly decreased (36 vs. 31%, 16 vs. 12% and 5 vs. 2%, respectively), and the proportion with triple inhaled therapy statistically significantly increased (29 vs. 40%). In 2014, triple inhaled therapy was the most common treatment in all GOLD groups except group A. In 2014, previous frequent exacerbations [OR (95% CI) 2.34 (1.62 to 3.36)], worse COPD Assessment Test score [1.07 (1.05 to 1.09)], female sex [2.13 (1.56 to 2.91)], and access to a specific responsible doctor [1.95 (1.41 to 2.69)] were associated with triple inhaled therapy. Current smoking [0.40 (0.28 to 0.57)] and overweight [0.62 (0.41 to 0.93)] were inversely associated with triple inhaled therapy. Conclusions: Over the last decade, triple inhaled therapy has increased, and no maintenance treatment, ICS, or LABA + ICS has decreased. Triple inhaled therapy is the most common treatment and is associated with previous exacerbations, higher symptom level, female sex, and having a specific responsible doctor. PMID- 29230275 TI - The Efficacy of a Haptic-Enhanced Virtual Reality System for Precision Grasp Acquisition in Stroke Rehabilitation. AB - Stroke is a leading cause of long-term disability, and virtual reality- (VR-) based stroke rehabilitation is effective in increasing motivation and the functional performance. Although much of the functional reach and grasp capabilities of the upper extremities were regained, the pinch movement remains impaired following stroke. In this study, we developed a haptic-enhanced VR system to simulate haptic pinch tasks to assist the recovery of upper-extremity fine motor function. We recruited 16 adults with stroke to verify the efficacy of this new VR system. Each patient received 30 min VR training sessions 3 times per week for 8 weeks. Outcome measures, Fugl-Meyer assessment (FMA), Test Evaluant les Membres superieurs des Personnes Agees (TEMPA), Wolf motor function test (WMFT), Box and Block test (BBT), and Jamar grip dynamometer, showed statistically significant progress from pretest to posttest and follow-up, indicating that the proposed system effectively promoted fine motor recovery of function. Additionally, our evidence suggests that this system was also effective under certain challenging conditions such as being in the chronic stroke phase or a coside of lesion and dominant hand (nondominant hand impaired). System usability assessment indicated that the participants strongly intended to continue using this VR-based system in rehabilitation. PMID- 29230276 TI - Seasonal Changes in Color Preferences Are Linked to Variations in Environmental Colors: A Longitudinal Study of Fall. AB - People form associations between colors and entities, which influence their evaluations of the world. These evaluations are dynamic, as specific associations become more or less active in people's minds over time. We investigated how evaluations of colors (color preferences) changed over the course of fall, as color-associated fall entities became more prevalent in the environment. Participants judged their preferences for the same set of colors during nine testing sessions over 11 weeks during fall. We categorized the colors as Leaf and Non-Leaf Colors by matching them to leaves collected during the same period. Changes in preferences for Leaf Colors followed a quadratic pattern, peaking around when the leaves were most colorful and declining as winter approached. Preferences for Non-Leaf Colors did not significantly change. Individual differences in these changes could be explained by preferences for seasonal entities, as predicted by the differential activation hypothesis within the Ecological Valence Theory. The more a given individual liked fall-associated entities, the more their preference for Leaf Colors increased during fall. No analogous relations existed with winter-associated entities or Non-Leaf Colors. These results demonstrate the importance of studying temporal and individual differences for understanding preferences. PMID- 29230277 TI - The Sense of Being Watched Is Modulated by Arousal and Duration of the Perceptual Episode. AB - The mere presence of a depiction of eyes can elicit a sense of being watched in the perceiver. To this date, the factors affecting the intensity of this sense of being watched, however, have not been investigated. In the present experiment, we tested the impact of two potentially relevant variables: arousal (manipulated using specific musical pieces) and duration of the perceptual episode (manipulated using presentation times of 200 ms and 10 s, respectively). We asked participants to report how intensely they felt being watched while we exposed them to various observation cues ranging from human eyes to surveillance cameras. We found that, on average, reported intensities were higher if participants were in a state of relatively higher arousal and if the perceptual episode during which the respective observation cues were presented lasted long enough (10 s) to allow more than a first glance. Scientific and practical implications are briefly discussed. PMID- 29230278 TI - Laparoscopic repair of a right diaphragmatic hernia in a post-partum lady. AB - Traumatic diaphragmatic injuries (TDI) are often challenging to diagnose. Research suggests that no single diagnostic study is sensitive or specific enough to identify such an injury, unless there is established herniation of intrabdominal contents. It is a rare cause of small bowel obstruction, which carries a substantial mortality rate. This report describes a case of a 41-year old pregnant female who presented with irretractable vomiting and abdominal pain secondary to a delayed presentation of right-sided TDI. The most accepted mechanism regarding TDI is due to sudden elevation in the pleuroperitoneal pressure gradient. This case is unusual given its mechanism of injury during pregnancy and its right-sided location. She underwent laparoscopy which facilitated successful reduction of the hernial and closure of the defect. Postoperatively, she made an excellent recovery and was discharged within a few days. This report aims to increase the awareness amongst surgeons. PMID- 29230279 TI - Elasto fibroma Dorsi: a case report of bilateral tumours and excision of the symptomatic lesion in a male patient. AB - Elasto fibroma dorsi is a rare tumour of the shoulder girdle that usually arises at the infra scapular area. We present a 57-year-old male with a soft tissue swelling on his right infra scapular area of 6 months duration. It was a painless lesion which caused him discomfort while sleeping. Preoperative imaging revealed bilateral tumours but the left tumour was impalpable. The surgery itself was uneventful but post-operatively he developed a haematoma which was managed conservatively Elasto fibroma is a benign pseudo tumour of the shoulder girdle. It's aetiology is tied in to repetitive trauma of the shoulder girdle resulting in a pseudo tumour at the infra scapular area. Magnetic resonance imaging is the diagnostic modality of choice and is pathognomic in the presence of bilateral infra scapular tumours. Treatment is usually conservative and tissue diagnosis is essential as it can mimic a soft tissue sarcoma radiologically. PMID- 29230280 TI - A case of Mirizzi syndrome that was successfully treated by laparoscopic choledochoplasty using a gallbladder patch. AB - The use of laparoscopic surgery in the treatment of Mirizzi syndrome is considered controversial due to the degree of technical difficulty. We herein describe the case of a 36-year-old woman who was admitted to our hospital due to appetite loss, nausea and back pain. Endoscopic retrograde cholangiography revealed a round-shaped filling defect at the confluence of the bile duct. The patient was diagnosed with Mirizzi syndrome Type II according to the Csendes classification. Before surgery, an endoscopic nasobiliary drainage tube was placed for intraoperative cholangiography. Based on the intraoperative findings, the anterior wall of Hartmann's pouch was excised to remove the impacted gallstone. The neck portion of the gallbladder wall was then used to make a gallbladder patch, which was sutured to cover the anterior wall of the common hepatic bile duct. Laparoscopic choledochoplasty using a gallbladder patch was a technically feasible treatment for Mirizzi syndrome Type II. PMID- 29230281 TI - Colon adenocarcinoma after jejunoileal bypass for morbid obesity. AB - Jejunoileal bypass (JIB) was developed as a surgical treatment for morbid obesity in the early 1950s. However, this procedure is now known to be associated with multiple metabolic complications and has subsequently been abandoned as a viable bariatric procedure. Some of these known complications include renal stone formation, liver failure, migratory arthritis, fat-soluble deficiencies, blind loop syndrome and severe diarrhea. Additionally, there have been animal models suggesting colon dysplasia after JIB. To our knowledge however, in humans, no colon cancers have been attributed to JIB in the literature. Here we report a 63 year-old morbidly obese female who had a JIB surgery in 1973 and subsequently was found to have numerous sessile colonic polyps throughout her colon and adenocarcinoma of the ascending colon without any family history of colonic polyposis syndromes or colon cancer. PMID- 29230282 TI - Giant splenic hemangioma in a 10-year-old boy treated with a spleen saving surgery. AB - Tumors of spleen are rare. The most common benign tumor of spleen is hemangioma. Most splenic hemangiomas (SH) tend to be discovered in mid-30s to mid-50s. SH are discovered incidentally in most of the cases as they are usually asymptomatic. Small asymptomatic SH can be managed with observation. The treatment options for large hemangiomas are embolization of the splenic arterial branch, splenectomy by laparotomy or laparoscopy. Partial splenectomy can be done if the lesion is small and located at the poles of the spleen. We present a rare case of splenic hemangioma in a 10-year-old boy who presented with a painless palpable mass in the left upper abdomen. On CT scan-A large well-defined cystic lesion with few thin enhancing septa within it is seen involving the spleen. Laparotomy was done followed by Partial splenectomy. The histopathology report was suggestive of Cavernous Hemangioma of spleen. PMID- 29230283 TI - Repair of giant inguinoscrotal hernia with loss of domain. AB - A massive inguinoscrotal hernia extending below the midpoint of the inner thigh, in a standing position, constitute a 'giant' inguinoscrotal hernia. A 74-year-old male presented with giant left sided inguinal hernia for the last 30 years. Patient underwent open repair under general anesthesia after perioperative respiratory exercise. Standard hernia repair identified a sliding hernia containing entire omentum, small and large bowel, and the appendix. Giant hernias pose a challenging problem because reduction of the hernia contents inside the abdominal cavity may increase intra-abdominal and thoracic pressures. Recurrence remains an issue for these patients after successful meshoplasty and debulking of abdominal contents. We describe a simple reduction with biological mesh repair, omentectomy, small bowel resection and sigmoidopexy as a viable technique for patients with greater than 50% of abdominal contents in the inguinoscrotal region with complete loss of domain. PMID- 29230284 TI - Acute appendicitis presenting as a complicated inguinal hernia: a case of left sided Amyand's hernia in an elderly man. AB - Amyand's hernia (AH) is characterized by the presence of the vermiform appendix in an inguinal hernia sac. Typically presenting on the right side and with manifestations similar to those seen in complicated hernias, it presents a diagnostic challenge and is frequently only diagnosed intraoperatively. We present the case of a left-sided AH on a 75-year-old man treated with appendicectomy, orchidectomy and hernioplasty without mesh. PMID- 29230285 TI - Cellular senescence associated immune responses in liver cancer. AB - Cellular senescence is a stress-induced cell-cycle arrest program that prevents malignant transformation of senescent cells following oncogenic pathway activation and DNA damage. Senescent cells are metabolically active and secrete cytokines and chemokines that shape the function and composition of their microenvironment. These cytokines can recruit immune cells such as lymphocytes and myeloid cells that depending on the context can either promote or inhibit liver tumor development and progression. Accordingly, pharmacologically targeting of secreted cytokines or reprogramming the expression of these cytokines in senescent cells represents a promising approach to skew senescence-associated immune responses toward cancer cell killing. PMID- 29230286 TI - Asthma mimic: Case report and literature review of vocal cord nodule associated with wheezing. AB - Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. Various clinical conditions can mimic asthma, such as foreign body aspiration, subglottic stenosis, congestive heart failure, diffuse panbronchiolitis, aortic arch anomalies, reactive airway dysfunction syndrome, chronic obstructive pulmonary disease, retrosternal goiter, vocal cord tumors, other airway tumors, and vocal cord dysfunction. Upper airway obstruction can be a life-threatening emergency. Here, we present the case of a 58-year-old female with recurrent hospital visits for wheezing and exacerbations of asthma, who was later found to have a vocal cord nodule confirmed to be squamous cell carcinoma, which was mimicking like asthma. PMID- 29230287 TI - Kyphoplasty for the treatment of an atypical osteoporotic vertebral compression fracture of the lumbar spine: A case report. AB - Vertebral augmentation is a minimally invasive but sometimes technically challenging intervention typically reserved for the treatment of older patients with painful vertebral compression fractures due to osteoporosis or neoplasms. We report the successful treatment of osteoporotic vertebral compression fractures of the first lumbar vertebral body (L1) using kyphoplasty in a paraplegic young patient with multiple comorbidities. Despite the unusual and complicated clinical scenario, kyphoplasty was nonetheless performed with immediate and lasting pain relief. PMID- 29230288 TI - Embryonal tumor with multilayered rosettes, C19MC-altered: Report of an extremely rare malignant pediatric central nervous system neoplasm. AB - The 2016 update of the WHO Classification of Tumours of the Central Nervous System has redefined a number of tumors. Embryonal tumor with multilayered rosettes, C19MC-altered is one such tumor entity which has been newly defined on the basis of a characteristic molecular alteration. We report, to our knowledge, the first case of this rare pediatric brain neoplasm in the Pakistani population. An 8-month-old girl was presented with vomiting and left-sided ptosis, and magnetic resonance imaging scan showed a cerebellar tumor. Histologically, a highly cellular population of primitive cells was seen alternating with hypocellular neuropil-rich regions containing multilayered true rosettes and cells with glial and neuronal differentiation. Amplification of 19q13. 42 chromosome region on fluorescence in situ hybridization analysis confirmed the diagnosis. Post-operative radiological examination revealed widespread central nervous system involvement. Adjuvant treatment was not offered due to complications. Patient expired a week after diagnosis. PMID- 29230289 TI - Accessory anterolateral talar facet impingement with tibialis spastic varus foot. AB - In recent years, some authors have reported accessory anterolateral talar facet impingement with flatfoot including peroneal spastic flatfoot. Conversely, to our knowledge, no case report has been published about accessory anterolateral talar facet impingement with tibialis spastic varus foot. We report the first case in a 22-year-old man with intellectual disability, bilateral cleft hands and type 1 diabetes mellitus. Since spraining his left ankle over a year earlier, he experienced left sinus tarsi pain while standing and walking. Physical examination revealed that his left foot was in the varus position with spasm of the anterior tibial muscle, tenderness in the sinus tarsi and lateral hindfoot pain upon attempted passive hindfoot eversion. He could not stand on his left toes. His pain decreased after lying down and receiving a massage on his anterolateral lower leg at night. Radiographs and computed tomography scans revealed the absence of tarsal coalition and the presence of accessory anterolateral talar facet in both feet. Magnetic resonance imaging demonstrated abutting bone marrow edema between the talus and calcaneus around the accessory anterolateral talar facet. We diagnosed the patient with accessory anterolateral talar facet impingement and tibialis spastic varus foot. After conservative treatment failed, resection of accessory anterolateral talar facet achieved good results with short-term follow-up. PMID- 29230290 TI - Delayed severe anaphylactoid reaction following retrograde pyelogram: A case report. AB - Retrograde pyelography is used to evaluate upper collecting system in patients with hematuria who have contrast allergy. Reported here is a patient who developed severe, late-onset anaphylactoid reaction after retrograde pyelography. Premedication is commonly used to reduce risk of allergic reaction but has limited evidence to support its efficacy. Caution should be used when evaluating microhematuria with retrograde pyelography in patients with prior anaphylactoid reaction to intravenous contrast. PMID- 29230291 TI - Multifunctional Cu39S28 Hollow Nanopeanuts for In Vivo Targeted Photothermal Chemotherapy. AB - Actively targeted hollow nanoparticles may play key roles in precise anti-cancer therapy. Here, unique Cu39S28 hollow nanopeanuts (HNPs) were synthesized via a facile one-step method and the formation mechanism was illustrated. The as synthesized Cu39S28 HNPs exhibit outstanding photothermal conversion efficiency (41.1%) and drug storage capacity (DOX, 99.5 %). At the same time, the DOX drug loading nanocomposites have shown great sensitive response of release to either pH value or near infrared ray (NIR). In particular, the folic acid (FA) can easily conjugate with the synthesized Cu39S28 HNPs without further modification to get a targeted effect. The FA modified Cu39S28 HNPs showed an efficiently targeting effect in vitro and could considerably enhance the tumor-targeting effect more than 10 times in vivo. Moreover, the synthetical hyperthermia and drug release from Cu39S28 HNPs when under 808 nm laser could significantly improve the therapeutic efficacy compared with photothermal or chemotherapy alone both in vitro and in vivo. The histological studies in main organs also proved the well biocompatibility, while the tumor sites were in seriously destruction due to the accumulation of the nanocomposites and the combined photothermal chemo therapy effect. Therefore, the multi-functional nanocomposites is excellent antitumor agents due to their superb therapy effect in breast cancer. PMID- 29230292 TI - Multiple steroid and thyroid hormones detected in baleen from eight whale species. AB - Recent studies have demonstrated that some hormones are present in baleen powder from bowhead (Balaena mysticetus) and North Atlantic right (Eubalaena glacialis) whales. To test the potential generalizability of this technique for studies of stress and reproduction in large whales, we sought to determine whether all major classes of steroid and thyroid hormones are detectable in baleen, and whether these hormones are detectable in other mysticetes. Powdered baleen samples were recovered from single specimens of North Atlantic right, bowhead, blue (Balaenoptera [B.]musculus), sei (B. borealis), minke (B. acutorostrata), fin (B. physalus), humpback (Megaptera novaeangliae) and gray (Eschrichtius robustus) whales. Hormones were extracted with a methanol vortex method, after which we tested all species with commercial enzyme immunoassays (EIAs, Arbor Assays) for progesterone, testosterone, 17beta-estradiol, cortisol, corticosterone, aldosterone, thyroxine and tri-iodothyronine, representing a wide array of steroid and thyroid hormones of interest for whale physiology research. In total, 64 parallelism tests (8 species * 8 hormones) were evaluated to verify good binding affinity of the assay antibodies to hormones in baleen. We also tested assay accuracy, although available sample volume limited this test to progesterone, testosterone and cortisol. All tested hormones were detectable in baleen powder of all species, and all assays passed parallelism and accuracy tests. Although only single individuals were tested, the consistent detectability of all hormones in all species indicates that baleen hormone analysis is likely applicable to a broad range of mysticetes, and that the EIA kits tested here perform well with baleen extract. Quantification of hormones in baleen may be a suitable technique with which to explore questions that have historically been difficult to address in large whales, including pregnancy and inter-calving interval, age of sexual maturation, timing and duration of seasonal reproductive cycles, adrenal physiology and metabolic rate. PMID- 29230293 TI - Semen collection and ejaculate characteristics of the Leopard Tortoise (Stigmochelys pardalis). AB - The preservation of spermatozoa is an important tool used in conservation programs to increase the genetic diversity of threatened and endangered species. Although routinely used to manage conservation programs for higher vertebrates, there have been limited attempts to establish reproductive assistance programs for tortoises. The purpose of this study was to develop a model for collecting and characterizing semen in Testudinidae. Semen was collected from 13/16 (81.2%, 95% CI: 62-100) adult male leopard tortoises (Stigmochelys pardalis) via electroejaculation under propofol anesthesia. Semen samples were collected most frequently after the second series of electrostimulations (6/13, 46.1%), with fewer animals producing semen after the first (5/13, 38.5%) or third (2/13, 15.4%) electrostimulations. The average volume of a semen sample in the tortoises was 0.26 ml (standard deviation: 0.16, minimum-maximum: 0.1-0.6), the average spermatozoal concentration was 101.62 * 106/ml, and the average motility at time of collection was 57.3%. A rapid decrease in motility was observed in refrigerated samples over 24 h resulting in a median motility of 0% at 24 h post collection. The results of this study suggest that electroejaculation is a safe and efficient method for collecting semen from leopard tortoises. PMID- 29230294 TI - Right whale poo: the key to conserving an endangered species? PMID- 29230296 TI - Intestinal autotransplantation. AB - Most abdominal neoplasms involving the root of the superior mesenteric artery and/or celiac artery are difficult to manage with conventional operative techniques because of limited intestinal ischemia times and poor accessibility to the tumor region. Ex vivo surgery followed by intestinal autotransplantation (IATx) is a relatively novel surgical strategy to offer chances for complete resection in such hopeless circumstances. This review aims to assess potential surgical indications, operative techniques and clinical outcomes after IATx. Currently the main indications reported for IATx broadly include pancreatic, mesenteric and retroperitoneal neoplasms closely involving the superior mesenteric vessels. The preliminary results show that radical resection can be effectively achieved in carefully selective patients. Although perioperative morbidity and mortality are relatively high, there are several long-term survivors, particularly after complete resection of benign and low-grade tumor. Early tumor recurrence, however, remains a major problem in patients with high grade tumor, particularly pancreatic ductal carcinoma. In conclusion, IATx allows patients with selected abdominal neoplasms involving the major mesenteric vessels to be completely resected. However, this aggressive approach is associated with a considerable operative risk, and should only be performed at experienced centers. Additional and adjunctive treatment therapies are required to improve the efficacy of this treatment. PMID- 29230297 TI - From genetics and epigenetics to the future of precision treatment for obesity. AB - Obesity has become a major global health problem, epitomized by excess accumulation of body fat resulting from an imbalance between energy intake and expenditure. The treatments for obesity range from modified nutrition and additional physical activity, to drugs or surgery. But the curative effect of each method seems to vary between individuals. With progress in the genetics and epigenetics of obesity, personalization of the clinical management of obesity may be at our doorstep. This review presents an overview of our current understanding of the genetics and epigenetics of obesity and how these findings influence responses to treatments. As bariatric surgery is the most effective long-term treatment for morbid obesity, we pay special attention to the association between genetic factors and clinical outcomes of bariatric surgery. Finally, we discuss the prospects for precision obesity treatment. PMID- 29230298 TI - Hepatic paragonimiasis: a single-center retrospective analysis of 32 cases in Mainland China. AB - Background: In paragonimiasis, the lungs and pleural cavity are the major target organs, and the central nervous system can also be affected. The liver is an organ in which ectopic paragonimiasis rarely occurs. Because the symptoms and examinations in hepatic paragonimiasis (HP) are not typical, the disease is often misdiagnosed in the clinic. Methods: From February 2008 to March 2015, our department accepted 32 patients who presented with a liver mass upon ultrasound and computed tomography imaging and in whom the source of the mass could not be identified upon numerous further diagnostic tests. We ultimately obtained surgical biopsies of their lesions for pathological examination. We analysed the clinical data of these cases, along with their disease characteristics, the diagnostic strategies employed and their treatment experiences. Additionally, we performed patient follow-up for a period of 6-12 months. Results: All patients underwent half/partial hepatectomy and were diagnosed with HP upon pathological examination. They recovered well after surgery and their original symptoms were markedly improved without recurrence. The liver functions of the patients reached normal levels before discharge and no additional liver lesions were found upon diagnostic imaging. Conclusion: The diagnosis of HP based on clinical manifestations, laboratory tests or image examination is difficult and only pathologic analysis of biopsies could confirm HP. Surgical treatment not only removes lesions, but also allows for pathologic biopsy. This study encompasses the largest number of HP patients to date, but the surgical outcomes require further research and long-term follow-up. PMID- 29230295 TI - Modulating protein amyloid aggregation with nanomaterials. AB - Direct exposure or intake of nanopaticles (NPs) to the human body can invoke a series of biological responses, some of which are deleterious, and as such the role of NPs in vivo requires thorough examination. Over the past decade, it has been established that biomolecules such as proteins can bind NPs to form a 'corona', where the structures and dynamics of NP-associated proteins can assign new functionality, systemic distribution and toxicity. However, the behavior and fate of NPs in biological systems are still far from being fully understood. Growing evidence has shown that some natural or artificial NPs could either up- or down-regulate protein amyloid aggregation, which is associated with neurodegenerative diseases like Alzheimer's and Parkinson's diseases, as well as metabolic diseases such as type 2 diabetes. These effects can be either indirect (e.g., through a crowding effect) or direct, depending on the NP composition, size, shape and surface chemistry. However, efforts to design anti-amyloid NPs for biomedical applications have been largely hindered by insufficient understanding of the complex processes, even though proof-of-concept experiments have been conducted. Therefore, exploring the general mechanisms of NP-meditated protein aggregation marks an emerging field in bio-nano research and a new stage of handling nanotechnology that not only aids in elucidating the origin of nanotoxicity, but also provides a foundation for engineering de novo anti-amyloid nanomedicines. In this review, we summarize research on NP-mediated protein amyloid aggregation, with the goal of contributing to sustained nanotechnology and safe nanomedicine against amyloid diseases. PMID- 29230299 TI - Predictors of acute gastrointestinal bleeding in diabetic ketoacidosis: a retrospective observational study in minority population. AB - Background: Diabetic ketoacidosis (DKA) is a common acute complication of diabetes mellitus requiring aggressive medical management. We attempted to study the incidence and various clinical and laboratory variables associated with acute gastrointestinal bleeding (AGIB) and acute upper AGIB (AUGIB) in patients with DKA. Methods: We conducted a retrospective chart review of all the patients admitted to our hospital with DKA between January 2010 and December 2015. We collected demographic, clinical, laboratory, endoscopy and hospitalization details using an electronic medical-record database. Patients were divided into two groups based on the occurrence of gastrointestinal bleeding. Results: A total of 234 patients with DKA were admitted during this period, of which 27 (11.5%) patients had documented AGIB. The majority of patients had hematemesis (n=22, 9.4%) except two had rectal and three had occult bleeding. We did not notice any difference in age, gender and ethnicity distribution between the two groups. There was no difference in the serum levels of electrolytes, anion gap, pH and hemoglobin A1C between the two groups. However, patients with AGIB had significantly higher initial blood glucose levels (738 vs 613 mg/dL, p =0.014). There was also increased mortality (7.4% vs 4.8%) in patients with AGIB, but this did not reach statistical significance. Conclusion: We conclude that higher initial serum blood glucose was associated with increased incidence of AGIB in patients admitted with DKA. We also noted increased in-patient mortality in patients with DKA who had AGIB, even though statistically insignificant. More aggressive measures to correct blood glucose levels may result in decreased incidence of AGIB, thereby reducing mortality during hospitalization in patients with DKA. PMID- 29230301 TI - Localized herpes zoster infection: a rare cause of syndrome of inappropriate secretion of antidiuretic hormone. AB - Hyponatremia is the most common electrolyte abnormality observed in clinical practice and syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is diagnosed in nearly 40% of the hospitalized hyponatremic patients. We present a case report of herpes zoster infection causing a severe hyponatremia/hypokalemia. This rare association between SIADH and varicella zoster virus infection is described in only few case in the literature. In our case report, the associated hypokalemia was not related to the use of diuretics but, probably, dependent on the frank serum hyposmolality able to induce an aldosterone release. PMID- 29230300 TI - Preoperative hypoalbuminemia is associated with an increased risk for intra abdominal septic complications after primary anastomosis for Crohn's disease. AB - Objective: The aim of this study was to evaluate the impact of preoperative hypoalbuminemia on the development of intra-abdominal septic complications (IASCs) after primary anastomosis for patients with Crohn's disease (CD). Methods: All CD patients undergoing bowel resection with a primary anastomosis during the study period from 2007 to 2015 were enrolled. The association of preoperative hypoalbuminemia (<30 g/L) with the risk for IASCs were assessed using both univariate and multivariate analyses. Results: A total of 124 eligible patients were included, 117 (94.4%) of whom had available preoperative albumin level. Preoperative hypoalbuminemia occurred in 13 (11.7%) patients. The duration from diagnosis to surgery was longer for patients with preoperative hypoalbuminemia than those without (p = 0.012). Patients with preoperative hypoalbuminemia were more likely to have a history of preoperative use of 5 aminosalicylic acid (p = 0.013) and have an intraoperative finding of small bowel obstruction (p = 0.015). Of all patients, 24 (19.4%) developed postoperative IASCs. Univariate analysis showed that patients with preoperative hypoalbuminemia had an increased risk for IASCs (p = 0.012). Multivariate analysis confirmed the association between preoperative hypoalbuminemia and IASCs (odds ratio 4.67, 95% confidence interval: 1.28-17.04, p = 0.02). Similar findings were also obtained when preoperative albumin level was analysed as a continuous variable (p = 0.019). Conclusions: Preoperative hypoalbuminemia is a significant predictor for the development of postoperative IASCs in CD patients after bowel resection with a primary anastomosis. Favorable preoperative nutrition status might lessen the risk for IASCs. PMID- 29230302 TI - Letrozole-induced hepatitis with autoimmune features: a rare adverse drug reaction with review of the relevant literature. AB - While aromatase inhibitors (AIs) have been known to cause minor elevations in liver enzymes, severe hepatotoxicity is rare. To the best of our knowledge, this is the first reported case of Letrozole-induced hepatitis with autoimmune features. A 70-year-old female with estrogen positive, invasive ductal carcinoma of the breast, presented with jaundice 3 months after starting letrozole. Hepatic transaminases were markedly elevated and her ANA and anti-smooth muscle antibody was positive. Liver biopsy featured drug-induced hepatitis. After stopping letrozole, liver tests trended back to normal within 3 weeks. She scored 9 for Roussel-Uclaf Causality Assessment Method (RUCAM). Over the last 10 years, there have been reported cases of drug-induced hepatitis secondary to AIs. We anticipate that there will be more widespread use of AIs based on recommendations from the TEXT, SOFT and extended AI trials. Therefore, physicians must be aware of this rare but life-threatening complication. PMID- 29230303 TI - Case series of paragonimiasis from Nepal. AB - Paragonimiasis is an important food-borne parasitic zoonosis caused by trematodes of genus Paragonimus. We report case series of paragonimiasis with common symptoms of cough with blood tinged sputum, shortness of breath, chest pain with occasional fever, eosinophilia and radiological findings mimicking pulmonary tuberculosis and had taken anti-tubercular drug despite all investigation negative for tuberculosis without improvement. They all had common history of consumption of raw/undercooked crab. There is a local belief in remote villages of Nepal that eating raw crab helps in healing bone fracture and cure jaundice. Microscopic examination of sputum sample revealed the ova of Paragonimus species. All patients were treated with praziquantel and got improved. Pulmonary paragonimiasis is endemic in Southeast Asia including Nepal. So, it has to be differentiated from pulmonary tuberculosis in the patient with symptoms of cough, chest pain and hemoptysis with eosinophilia and having history of consumption of raw/undercooked crabs or crayfish. PMID- 29230304 TI - Coil embolization for intrahepatic haemorrhage following liver biopsy in a patient with hepatitis C virus infection and hepatic microaneurysms. AB - Intrahepatic bleeding secondary to rupture of hepatic microaneurysms is an uncommon clinical entity more frequently associated with polyarteritis nodosa (PAN) or rarely with other vasculitis or autoimmune disease. Hepatic vasculitis is reported in chronic hepatitis C virus (HCV) infection and an association between hepatitis C and PAN is described. The current report presents the case of a middle-aged female patient with a medical history remarkable for HCV infection who underwent a percutaneous liver biopsy, which was complicated by severe intrahepatic and perihepatic haemorrhage. Computed tomography angiography revealed innumerous microaneurysms. She underwent transcatheter angiography and coil embolization of a peripheral branch of the right hepatic artery which controlled the bleeding. Subsequently, she was empirically treated with a course of Prednisolone. Follow-up imaging showed a good response to treatment. PMID- 29230305 TI - Changes needed to medicine in the UK before senior UK-trained doctors, working outside the UK, will return: questionnaire surveys undertaken between 2004 and 2015. AB - Objective: To report the changes to UK medicine which doctors who have emigrated tell us would increase their likelihood of returning to a career in UK medicine. Design: Questionnaire survey. Setting: UK-trained medical graduates. Participants: Questionnaires were sent 11 years after graduation to 7158 doctors who qualified in 1993 and 1996 in the UK: 4763 questionnaires were returned. Questionnaires were sent 17 and 19 years after graduation to the same cohorts: 4554 questionnaires were returned. Main outcome measures: Comments from doctors working abroad about changes needed to UK medicine before they would return. Results: Eleven years after graduation, 290 (6%) of respondents were working in medicine abroad; 277 (6%) were doing so 17/19 years after graduation. Eleven years after graduation, 53% of doctors working abroad indicated that they did not intend to return, and 71% did so 17/19 years after graduation. These respondents reported a number of changes which would need to be made to UK medicine in order to increase the likelihood of them returning. The most frequently mentioned changes cited concerned 'politics/management/funding', 'pay/pension', 'posts/security/opportunities', 'working conditions/hours', and 'factors outside medicine'. Conclusions: Policy attention to factors including funding, pay, management and particularly the clinical-political interface, working hours, and work-life balance may pay dividends for all, both in terms of persuading some established doctors to return and, perhaps more importantly, encouraging other, younger doctors to believe that the UK and the National Health Service can offer them a satisfying and rewarding career. PMID- 29230306 TI - Cultural shift in mental illness: a comparison of stress responses in World War I and the Vietnam War. AB - Objectives: Post-traumatic stress disorder is an established diagnostic category. In particular, over the past 20 years, there has been an interest in culture as a fundamental factor in post-traumatic stress disorder symptom manifestation. However, only a very limited portion of this literature studies the historical variability of post-traumatic stress within a particular culture. Design: Therefore, this study examines whether stress responses to violence associated with armed conflicts have been a culturally stable reaction in Western troops. Setting: We have compared historical records from World War I to those of the Vietnam War. Reference is also made to observations of combat trauma reactions in pre-World War I conflicts, World War II, the Korean War, the Falklands War, and the First Gulf War. Participants: The data set consisted of literature that was published during and after these armed conflicts. Main outcome measures: Accounts of World War I Shell Shock that describe symptom presentation, incidence (both acute and delayed), and prognosis were compared to the observations made of Vietnam War post-traumatic stress disorder victims. Results: Results suggest that the conditions observed in Vietnam veterans were not the same as those which were observed in World War I trauma victims. Conclusions: The paper argues that the concept of post-traumatic stress disorder cannot be stretched to cover the typical battle trauma reactions of World War I. It is suggested that relatively subtle changes in culture, over little more than a generation, have had a profound effect on how mental illness forms, manifests itself, and is effectively treated. We add new evidence to the argument that post-traumatic stress disorder in its current conceptualisation does not adequately account, not only for ethnocultural variation but also for historical variation in stress responses within the same culture. PMID- 29230307 TI - WHO Parents Skills Training (PST) programme for children with developmental disorders and delays delivered by Family Volunteers in rural Pakistan: study protocol for effectiveness implementation hybrid cluster randomized controlled trial. AB - Background: Development disorders and delays are recognised as a public health priority and included in the WHO mental health gap action programme (mhGAP). Parents Skills Training (PST) is recommended as a key intervention for such conditions under the WHO mhGAP intervention guide. However, sustainable and scalable delivery of such evidence based interventions remains a challenge. This study aims to evaluate the effectiveness and scaled-up implementation of locally adapted WHO PST programme delivered by family volunteers in rural Pakistan. Methods: The study is a two arm single-blind effectiveness implementation-hybrid cluster randomised controlled trial. WHO PST programme will be delivered by 'family volunteers' to the caregivers of children with developmental disorders and delays in community-based settings. The intervention consists of the WHO PST along with the WHO mhGAP intervention for developmental disorders adapted for delivery using the android application on a tablet device. A total of 540 parent child dyads will be recruited from 30 clusters. The primary outcome is child's functioning, measured by WHO Disability Assessment Schedule - child version (WHODAS-Child) at 6 months post intervention. Secondary outcomes include children's social communication and joint engagement with their caregiver, social emotional well-being, parental health related quality of life, family empowerment and stigmatizing experiences. Mixed method will be used to collect data on implementation outcomes. Trial has been retrospectively registered at ClinicalTrials.gov (NCT02792894). Discussion: This study addresses implementation challenges in the real world by incorporating evidence-based intervention strategies with social, technological and business innovations. If proven effective, the study will contribute to scaled-up implementation of evidence based packages for public mental health in low resource settings. Trial registration: Registered with ClinicalTrials.gov as Family Networks (FaNs) for Children with Developmental Disorders and Delays. Identifier: NCT02792894 Registered on 6 July 2016. PMID- 29230308 TI - Subjective well-being among young people in five Eastern European countries. AB - Background: Subjective well-being incorporates elements of life satisfaction, happiness and optimism. It is increasingly relevant in the assessment of population health and economic development. There are strong continuities in well being from youth into later life. Despite its significance, few global surveys capture subjective well-being. This paper describes patterns of well-being among young people in five Eastern European countries [Belarus, Bosnia and Herzegovina (BiH), the Former Yugoslav Republic of Macedonia, Serbia and Ukraine] and investigates association between demographic factors and well-being. Methods: Nationally representative household surveys, including large Roma population samples, were conducted as part of UNICEF's Multiple Indicator Cluster Survey programme. Young people aged 15-24 years (N = 11 944) indicated their satisfaction with life, happiness and expectations about the future. Multilevel logistic regressions were conducted to determine the impact of individual-level predictors while accounting for country- and cluster-level variability. Results: Around 40% of young people considered themselves very happy or very satisfied with their life overall. Three quarters reported optimism. Yet well-being varied greatly between countries, with youth in BiH and Ukraine reporting lowest levels of well-being. Current marriage, increasing wealth, higher education, rural residence and not having children were associated with greater well-being. Conclusions: Patterns of well-being in youth vary substantially between countries and are only partly accounted for by standard demographic characteristics. Despite higher rates of adolescent marriage and childbearing, and lower levels of educational attainment and employment, Roma youth had similar levels of well being to the general population. PMID- 29230309 TI - Alcohol use and intimate partner violence among women and their partners in sub Saharan Africa. AB - Background: Alcohol use is a well-documented risk factor for intimate partner violence (IPV); however, the majority of research comes from high-income countries. Methods: Using nationally representative data from 86 024 women that participated in the Demographic and Health Surveys, we evaluated the relationship between male partner alcohol use and experiencing IPV in 14 countries in sub Saharan Africa (SSA). Using multilevel mixed-effects models, we calculated the within-country, between-country, and contextual effects of alcohol use on IPV. Results: Prevalence of partner alcohol use and IPV ranged substantially across countries (3-62 and 11-60%, respectively). Partner alcohol use was associated with a significant increase in the odds of reporting IPV for all 14 countries included in this analysis. Furthermore, the relationship between alcohol use and IPV, although largely explained by partner alcohol use, was also attributable to overall prevalence of alcohol use in a given country. The partner alcohol use-IPV relationship was moderated by socioeconomic status (SES): among women with a partner who used alcohol those with lower SES had higher odds of experiencing IPV than women with higher SES. Conclusions: Results of this study suggest that partner alcohol use is a robust correlate of IPV in SSA; however, drinking norms may independently relate to IPV and confound the relationship between partner alcohol use and IPV. These findings motivate future research employing experimental and longitudinal designs to examine alcohol use as a modifiable risk factor of IPV and as a novel target for treatment and prevention research to reduce IPV in SSA. PMID- 29230310 TI - Applying systems thinking to task shifting for mental health using lay providers: a review of the evidence. AB - Objective: This paper seeks to review the available evidence to determine whether a systems approach is employed in the implementation and evaluation of task shifting for mental health using lay providers in low- and middle-income countries, and to highlight system-wide effects of task-shifting strategies in order to better inform efforts to strength community mental health systems. Methods: Pubmed, CINAHL, and Cochrane Library databases were searched. Articles were screened by two independent reviewers with a third reviewer resolving discrepancies. Two stages of screens were done to ensure sensitivity. Studies were analysed using the World Health Organization's building blocks framework with the addition of a community building block, and systems thinking characteristics to determine the extent to which system-wide effects had been considered. Results: Thirty studies were included. Almost all studies displayed positive findings on mental health using task shifting. One study showed no effect. No studies explicitly employed systems thinking tools, but some demonstrated systems thinking characteristics, such as exploring various stakeholder perspectives, capturing unintended consequences, and looking across sectors for system-wide impact. Twenty-five of the 30 studies captured elements other than the most directly relevant building blocks of service delivery and health workforce. Conclusions: There is a lack of systematic approaches to exploring complexity in the evaluation of task-shifting interventions. Systems thinking tools should support evidence-informed decision making for a more complete understanding of community-based systems strengthening interventions for mental health. PMID- 29230311 TI - Household water insecurity, missed schooling, and the mediating role of caregiver depression in rural Uganda. AB - Background: School attendance rates in sub-Saharan Africa are among the lowest worldwide, placing children at heightened risk for poor educational and economic outcomes. One understudied risk factor for missed schooling is household water insecurity, which is linked to depression among women and may increase children's water-fetching burden at the expense of educational activities, particularly among children of depressed caregivers. In this study conducted in rural Uganda, we assessed the association between household water insecurity and child school participation and the mediating pathways behind these associations. Method: We conducted a population-based, cross-sectional study of female household heads (N = 257) and their children ages 5-17 (N = 551) in the rural regions surrounding the town of Mbarara, in southwestern Uganda. We used multivariable linear regressions to estimate the association between water insecurity and missed schooling. We then assessed the extent to which the association was mediated by caregiver depression. Results: Among children, water insecurity had a statistically significant association with the number of missed school days (a standard deviation increase in water insecurity resulted in 0.30 more missed school days in the last week). The estimated association was partially mediated by caregiver depression. When stratified by sex, this mediating pathway remained significant for boys, but not among girls. Conclusions: Water insecurity is a risk factor for missed schooling among children in rural Uganda. Caregiver depression partially mediated this relationship. Also addressing caregiver mental health in water insecure families may more fully address the needs of sub-Saharan African families and promote educational participation among youth. PMID- 29230312 TI - Internet and mobile technologies: addressing the mental health of trauma survivors in less resourced communities. AB - Internet and mobile technologies offer potentially critical ways of delivering mental health support in low-resource settings. Much evidence indicates an enormous negative impact of mental health problems in low- and middle-income countries (LMICs), and many of these problems are caused, or worsened, by exposure to wars, conflicts, natural and human-caused disasters, and other traumatic events. Though specific mental health treatments have been found to be efficacious and cost-effective for low-resource settings, most individuals living in these areas do not have access to them. Low-intensity task-sharing interventions will help, but there is a limit to the scalability and sustainability of human resources in these settings. To address the needs of trauma survivors, it will be important to develop and implement Internet and mobile technology resources to help reduce the scarcity, inequity, and inefficiency of current mental health services in LMICs. Mobile and Internet resources are experiencing a rapid growth in LMICs and can help address time, stigma, and cost barriers and connect those who have been socially isolated by traumatic events. This review discusses current research in technological interventions in low-resource settings and outlines key issues and future challenges and opportunities. Though formidable challenges exist for large-scale deployment of mobile and Internet mental health technologies, work to date indicates that these technologies are indeed feasible to develop, evaluate, and deliver to those in need of mental health services, and that they can be effective. PMID- 29230313 TI - Development and cross-cultural testing of the International Depression Symptom Scale (IDSS): a measurement instrument designed to represent global presentations of depression. AB - Background: Self-report measurement instruments are commonly used to screen for mental health disorders in Low and Middle-Income Countries (LMIC). The Western origins of most depression instruments may constitute a bias when used globally. Western measures based on the DSM, do not fully capture the expression of depression globally. We developed a self-report scale design to address this limitation, the International Depression Symptom Scale-General version (IDSS-G), based on empirical evidence of the signs and symptoms of depression reported across cultures. This paper describes the rationale and process of its development and the results of an initial test among a non-Western population. Methods: We evaluated internal consistency reliability, test-retest reliability and inter-rater reliability of the IDSS-G in a sample N = 147 male and female attendees of primary health clinics in Yangon, Myanmar. For criterion validity, IDSS-G scores were compared with diagnosis by local psychiatrists using the Structured Clinical Interview for DSM (SCID). Construct validity was evaluated by investigating associations between the IDSS-G and the Patient Health Questionnaire (PHQ), impaired function, and suicidal ideation. Results: The IDSS G showed high internal consistency reliability (alpha = 0.92), test-retest reliability (r = 0.87), and inter-rater reliability (ICC = 0.90). Strong correlations between the IDSS-G and PHQ-9, functioning, and suicidal ideation supported construct validity. Criterion validity was supported for use of the IDSS-G to identify people with a SCID diagnosed depressive disorder (major depression/dysthymia). The IDSS-G also demonstrated incremental validity by predicting functional impairment beyond that predicted by the PHQ-9. Results suggest that the IDSS-G accurately assesses depression in this population. Future testing in other populations will follow. PMID- 29230315 TI - Latent class analysis of violence against adolescents and psychosocial outcomes in refugee settings in Uganda and Rwanda. AB - Background: Little is known about violence against children in refugee camps and settlements, and the evidence-base concerning mental health outcomes of youth in refugee settings in low and middle-income countries is similarly small. Evidence is needed to understand patterns of violence against children in refugee camps, and associations with adverse mental health outcomes. Methods: Surveys were conducted with adolescent refugees (aged 13-17) in two refugee contexts - Kiziba Camp, Rwanda (n = 129) (refugees from Democratic Republic of Congo) and Adjumani and Kiryandongo refugee settlements, Uganda (n = 471) (refugees from South Sudan). Latent Class Analysis was utilized to identify classes of violence exposure (including exposure to witnessing household violence, verbal abuse, physical violence and sexual violence). Logistic regressions explored the association between latent class of violence exposure and symptoms of depression and anxiety. Results: In Rwanda, a two-class solution was identified, with Class 1 (n = 33) representing high levels of exposure to violence and Class 2 (n = 96) representing low levels of exposure. In Uganda, a three-class solution was identified: Class 1 (high violence; n = 53), Class 2 (low violence, n = 100) and Class 3 (no violence, n = 317). Logistic regression analyses indicated that latent violence class was associated with increased odds of high anxiety symptoms in Rwanda (AOR 3.56, 95% CI 1.16-0.95), and high v. no violence class was associated with depression (AOR 3.97, 95% CI 1.07-7.61) and anxiety symptoms (AOR 2.04, 95% CI 1.05-3.96) in Uganda. Conclusions: The present results support the existing evidence-base concerning the association between violence and adverse mental health outcomes, while identifying differences in patterns and associations between refugee youth in two different contexts. PMID- 29230314 TI - Testing the effectiveness of a transdiagnostic treatment approach in reducing violence and alcohol abuse among families in Zambia: study protocol of the Violence and Alcohol Treatment (VATU) trial. AB - Background: Violence against women and girls (VAWG) is an urgent global health problem. Root causes for VAWG include the individual- and family-level factors of alcohol abuse, mental health problems, violence exposure, and related adverse experiences. Few studies in low- and middle-income countries (LMIC) have assessed the effectiveness of psychological interventions for reducing VAWG. This randomized controlled trial, part of the What Works to Prevent Violence Against Women and Girls consortium, examines the effectiveness of a common elements treatment approach (CETA) for reducing VAWG and comorbid alcohol abuse among families in Zambia. Methods/design: Study participants are families consisting of three persons: an adult woman, her male husband or partner, and one of her children aged 8-17 (if available). Eligibility criteria include experience of moderate-to-severe intimate partner violence by the woman and hazardous alcohol use by her male partner. Family units are randomized to receive CETA or treatment as usual. The primary outcome is VAWG as measured by the Severity of Violence Against Women Scale, assessed along with secondary outcomes at 24 months post baseline. Interim assessments are also conducted at 4-5 months (following CETA completion) and 12 months post-baseline. Conclusions: This ongoing trial is one of the first in sub-Saharan Africa to evaluate the use of an evidence-based common elements approach for reducing VAWG by targeting a range of individual- and family-level factors, including alcohol abuse. Results of this trial will inform policy on what interventions work to prevent VAWG in LMIC with local perspectives on scale up and wider implementation. PMID- 29230317 TI - Feasibility and acceptability of a universal screening and referral protocol for gender-based violence with women seeking care in health clinics in Dadaab refugee camps in Kenya. AB - Background: Gender-based violence (GBV) is both a global public health problem and violation of human rights. Refugees and internally displaced persons experience an increased risk of GBV and health outcomes associated with GBV are often exacerbated in conflict settings. Methods: A mixed methods study to examine the feasibility and acceptability of universal screening for GBV in a refugee population in the Dadaab refugee camp of Kenya, using the ASIST-GBV from January to July 2015. Results: Of 9366 women offered screening at International Rescue Committee health clinics, about 89% (n = 8369) female refugees consented to participate. Only 15% of the potentially eligible population could participate in GBV screening because of the ongoing struggle to identify private space in the clinics. Over 85% of women reported being 'willing' or 'very willing' to participate in GBV screening; 96% felt they had a good or very good experience with the screening protocol. Qualitative findings stressed the importance of securing a room/space in the busy clinic is critical to universal screening with referral to safe and confidential services for survivors. Conclusions: The findings suggest that the evidence-based ASIST-GBV is both feasible to implement and acceptable to both providers and women seeking care. Universal GBV screening and referral is an effective way for health care and service providers in humanitarian settings to assist survivors of GBV. PMID- 29230316 TI - Converging on child mental health - toward shared global action for child development. AB - We are a group of researchers and clinicians with collective experience in child survival, nutrition, cognitive and social development, and treatment of common mental conditions. We join together to welcome an expanded definition of child development to guide global approaches to child health and overall social development. We call for resolve to integrate maternal and child mental health with child health, nutrition, and development services and policies, and see this as fundamental to the health and sustainable development of societies. We suggest specific steps toward achieving this objective, with associated global organizational and resource commitments. In particular, we call for a Global Planning Summit to establish a much needed Global Alliance for Child Development and Mental Health in all Policies. PMID- 29230318 TI - Reducing PTSD symptoms through a gender norms and economic empowerment intervention to reduce intimate partner violence: a randomized controlled pilot study in Cote D'Ivoire. AB - Background: Women living in war-affected contexts face high levels of gender based violence, including intimate partner violence (Stark & Ager, 2011). Despite well-documented negative consequences, including posttraumatic stress disorder (PTSD) (Garcia-Moreno et al. 2006; Steel et al. 2009), evidence remains thin regarding intervention effectiveness to mitigate consequences in these settings. Methods: This study used a two-armed parallel pilot randomized controlled trial to compare the impact of a group savings only (control) to gender dialogue groups added to group savings (treatment) on women's symptoms of PTSD in northwestern Cote d'Ivoire. Eligible Ivorian women (18+ years, no prior experience with group savings) were invited to participate and 1198 were randomized into treatment groups. Results: In the ITT analyses, women in the treatment arm had significantly fewer PTSD symptoms relative to the control arm (beta: -0.12; 95% CI: -0.20 to -0.03; p = 0.005). Partnered women in the treatment arm who had not experienced intimate partner violence (IPV) at baseline had significantly fewer PTSD symptoms than the control arm (beta = -0.12; 95% CI: -0.21 to -0.03; p = 0.008), while those who had experienced IPV did not show significant differences between treatment and control arms (beta = -0.09; 95% CI: -0.29 to 0.11; p = 0.40). Conclusions: Adding a couples gender discussion group to a women's savings group significantly reduced women's PTSD symptoms overall. Different patterns emerge for women who experienced IPV at baseline v. those who did not. More research is needed on interventions to improve mental health symptoms for women with and without IPV experiences in settings affected by conflict. PMID- 29230319 TI - Knowledge gaps in implementing global mental health activities. PMID- 29230320 TI - Factors promoting and inhibiting sustained impact of a mental health task shifting program for HIV providers in Ethiopia. AB - Background: Task-shifting mental health into general medical care requires more than brief provider training. Generalists need long-term support to master new skills and changes to work context are required to sustain change in the face of competing priorities. We examined program and context factors promoting sustainability of a mental health task-shifting training for hospital-based HIV providers in Ethiopia. Methods: Convergent mixed-methods quasi-experimental study. Sustained impact was measured by trained/not-trained provider differences in case detection and management 16 months following the end of formal support. Factors related to sustainability were examined through interviews with trained providers. Results: Extent of sustained impact: Trained providers demonstrated modest but better agreement with standardized screeners (greater sensitivity with similar specificity). They were more likely to request that patients with mental health problems return to see them v. making a referral. Factors promoting sustainability (reported in semi-structured interviews): provider belief that the treatments they had learned were effective. New interactions with on-site mental health staff were a source of ongoing learning and encouragement. Factors diminishing sustainability: providers feelings of isolation when mental health partners left for work elsewhere, failure to incorporate mental health indicators into administrative data, to re-stock staff education materials, and to build formal mechanisms for generalist-mental health staff interaction. Conclusions: An intervention seen as feasible and effective, and promotion of relationships across professional lines, helped generalists sustain new skills. Failure to address key system context issues made use of the skills unsustainable as external supports ended. PMID- 29230321 TI - The Management of Retinal Detachment: Techniques and Perspectives. PMID- 29230322 TI - Macular Retinal Vessel Oxygen Saturation Elevation in Chinese Central Serous Chorioretinopathy. AB - Purpose: To evaluate the retinal vessel oxygen saturation in central serous chorioretinopathy (CSC) cases among the Chinese. Methods: Relative oxygen saturation of retinal blood vessels was measured in 33 Chinese patients with single-eye CSC using the Oxymap T1 retinal oximeter. The contralateral eyes were the control. The mean saturation of the retinal arteriole (AS) and venule (VS), arteriovenous difference (AVS), and arteriole and venule diameters (AD, VD) was analyzed in the optic disc area and macular region. Results: In the optic disc area, the inferotemporal quadrant (TI) AS (93.2 +/- 10.2%) and inferonasal quadrant (NI) VS (61.3 +/- 7.3%) were higher in the affected eyes than in the contralateral eyes (88.7 +/- 7.7% and 56.9 +/- 6.5%) and AVS in NI (36.7 +/- 10.4%) decreased compared to the contralateral eyes (41.5 +/- 11.2%). The VD in TI was expanded (19.9 +/- 2.5 pixels versus 18.1 +/- 3.4 pixels). Around the macular region, AS was 93.6 +/- 7.6%, higher than in the contralateral eyes (89.5 +/- 6.3%). No other significant changes were found. Conclusions: AS increased in the TI, and VS decreased in the NI in the eyes with CSC. In addition, AS also increased around the macular region, suggesting that these are contributors to CSC pathophysiology. PMID- 29230324 TI - On the Helical Structure of Guanosine 5'-Monophosphate Formed at pH 5: Is It Left or Right-Handed? AB - Early X-ray fiber diffraction studies have established that the spontaneous gel formation of guanosine 5'-monophosphate (5'-GMP) under slightly acidic conditions (e.g., pH 5) results from self-assembly of 5'-GMP into a helical structure in which hydrogen-bonded guanine bases form a continuous helix with 15 nucleotides per 4 turns. For more than five decades, the sense of this helix is believed to be left-handed. Using multinuclear solid-state NMR and IR spectroscopic methods, we have finally determined the long-missing structural details of this helix. First, we found that this 5'-GMP helix is right-handed containing exclusive C3' endo sugar puckers. Second, we showed that the central channel of this helix is free of Na+ ions, which is in sharp contrast to the helix formed by 5'-GMP at pH 8 where the central channel is filled with Na+ ions. PMID- 29230323 TI - Baseline Oxidative Stress Is Associated with Memory Changes in Omega-3 Fatty Acid Treated Coronary Artery Disease Patients. AB - Objective: This study investigated whether pretreatment oxidative stress, measured by lipid hydroperoxides (LPH), 4-hydroxy-2-nonenal (4-HNE), 8 isoprostane (8-ISO), and malondialdehyde (MDA), was associated with improvement in immediate recall among n-3 PUFA-treated coronary artery disease patients. Methods: This was a secondary analysis of the CAROTID trial (NCT00981383). Composite immediate recall, measured using the California Verbal Learning Test, Second Edition, and the Brief Visuospatial Memory Test-Revised, was assessed. LPH, 4-HNE, 8-ISO, MDA, and n-3 PUFA concentrations were analysed from fasting blood. Patients then received either n-3 PUFA treatment or placebo for 12 weeks, after which composite immediate recall was reassessed. Linear regression was used to investigate relationships between lipid peroxidation markers and changes in composite immediate recall in each treatment group. Results: Eighty-five patients (age = 61.1 +/- 8.5, 77% male, mean years of education = 15.3 +/- 3.4) were included (n = 46 placebo, n = 39 n-3 PUFA). After adjusting for multiple comparisons and potential confounders, greater baseline concentrations of LPH (beta = 0.45, p = .002) and 4-HNE (beta = 0.38, p = .005) were associated with greater improvement in composite immediate recall among n-3 PUFA-treated patients. No other associations were observed. Conclusions: N-3 PUFA treatment may be more likely to improve immediate recall in patients with greater oxidative stress. PMID- 29230325 TI - A Study on Knowledge, Awareness, and Medication Adherence in Patients with Hypertension from a Tertiary Care Centre from Northern Sri Lanka. AB - Objective: To assess the patient's knowledge and awareness about hypertension and adherence to antihypertensive medication among hypertensive patients with validated Morisky questionnaires in a tertiary care centre of northern Sri Lanka. Methods: A cross-sectional descriptive comparative study was carried out at Teaching Hospital Jaffna, from January 2017 to April 2017. Hypertensive patients were recruited by systematic randomized controlled sampling and interviewed with validated Morisky questionnaires to assess their knowledge about hypertension. Data were analyzed using SPSS (version 21) analytical package. Results: 73 of 303 patients were males. 69.9% of patients had adequate knowledge about hypertension. 40.5% of patients were unaware of their disease status. 75.8% of patients could not recall their blood pressure values at the time of diagnosis. 72.3% of patients were unaware of their values of blood pressure during their last outpatient clinic visit. 48.2% of patients had awareness of target organ damage due to hypertension (kidney, 72, 23.7%; heart, 128, 42.2%; brain, 140, 46.7%; eye, 42, 13.8%). Most of the patients had poor drug compliance. The most common reasons for nonadherence were forgetfulness (70, 23.1%) and interruptions of daily routine (53, 17.5%). Conclusion: The knowledge about hypertension among majority of patients was reasonable. But they were unaware of their disease status. The drug compliance among them was poor. Forgetfulness and interruptions of daily routine were common reasons attributed for nonadherence. PMID- 29230326 TI - Tuberculosis Treatment Adherence of Patients in Kosovo. AB - Setting: The poor patient adherence in tuberculosis (TB) treatment is considered to be one of the most serious challenges which reflect the decrease of treatment success and emerging of the Multidrug Resistance-TB (MDR-TB). To our knowledge, the data about patients' adherence to anti-TB treatment in our country are missing. Objective: This study was aimed to investigate the anti-TB treatment adherence rate and to identify factors related to eventual nonadherence among Kosovo TB patients. Design: This study was conducted during 12 months, and the survey was a descriptive study using the standardized questionnaires with total 324 patients. Results: The overall nonadherence for TB patient cohort was 14.5%, 95% CI (0.109-0.188). Age and place of residence are shown to have an effect on treatment adherence. Moreover, the knowledge of the treatment prognosis, daily dosage, side effects, and length of treatment also play a role. This was also reflected in knowledge regarding compliance with regular administration of TB drugs, satisfaction with the treatment, interruption of TB therapy, and the professional monitoring in the administration of TB drugs. Conclusion: The level of nonadherence TB treatment in Kosovar patients is not satisfying, and more health care worker's commitments need to be addressed for improvement. PMID- 29230327 TI - Corrigendum to "Impaired Fertility Associated with Subclinical Hypothyroidism and Thyroid Autoimmunity: The Danish General Suburban Population Study". AB - [This corrects the article DOI: 10.1155/2015/132718.]. PMID- 29230331 TI - The Successful Treatment of a Case of Linear Psoriasis with Ixekizumab. AB - Linear psoriasis is an unusual clinical variation of psoriasis that manifests segmentally along the lines of Blaschko. A major differential diagnosis is inflammatory linear verrucous epidermal nevus (ILVEN). The treatment of linear psoriasis is often challenging, with inadequate response to biological agents reported in the literature. We report a case of a 25-year-old African-American female who presented with asymptomatic hyperkeratotic papules along the lines of Blaschko and was subsequently diagnosed with linear psoriasis. After failing conventional treatment regimens, the patient received a trial of ixekizumab with complete resolution of cutaneous lesions reported after 4 months and only 8 doses of the anti-IL-17 biologic agent. PMID- 29230329 TI - Regionally Specific Regulation of Sensorimotor Network Connectivity Following Tactile Improvement. AB - Correlations between inherent, task-free low-frequency fluctuations in the blood oxygenation level-dependent (BOLD) signals of the brain provide a potent tool to delineate its functional architecture in terms of intrinsic functional connectivity (iFC). Still, it remains unclear how iFC is modulated during learning. We employed whole-brain resting-state magnetic resonance imaging prior to and after training-independent repetitive sensory stimulation (rSS), which is known to induce somatosensory cortical reorganization. We investigated which areas in the sensorimotor network are susceptible to neural plasticity (i.e., where changes in functional connectivity occurred) and where iFC might be indicative of enhanced tactile performance. We hypothesized iFC to increase in those brain regions primarily receiving the afferent tactile input. Strengthened intrinsic connectivity within the sensorimotor network after rSS was found not only in the postcentral gyrus contralateral to the stimulated hand, but also in associative brain regions, where iFC correlated positively with tactile performance or learning. We also observed that rSS led to attenuation of the network at higher cortical levels, which possibly promotes facilitation of tactile discrimination. We found that resting-state BOLD fluctuations are linked to behavioral performance and sensory learning, indicating that network fluctuations at rest are predictive of behavioral changes and neuroplasticity. PMID- 29230330 TI - Calcifying Acne: An Unusual Extraoral Radiographic Finding. AB - Calcinosis cutis is a condition of accumulation of calcium salts within the dermis leading to the formation of a calcified mass. This complication has been reported in acne vulgaris and other systemic metabolic disorders. This paper presents a rare case of calcinosis cutis in a 14-year-old male which was found at a routine orthodontic assessment. PMID- 29230332 TI - Mechanisms Involving Myocardial Injury in Tropical Stings and Bites. AB - It is known that a number of toxic substances produce myocardial injury by several mechanisms involving interruption of coronary blood flow due to stimulation of clotting mechanism and coronary vasospasm. Number of toxic substances may cause direct myocardial toxicity independent of coronary blood flow. Acute myocardial injury due to stings and bites is a rare entity and not well understood. Here we illustrate a case of myocardial injury due to Russell's viper envenomation. PMID- 29230333 TI - Celiac Disease in Patients with Cystic Fibrosis-Related Bone Disease. AB - Both cystic fibrosis (CF) and celiac disease can cause low bone mineral density (BMD) and fractures. Celiac disease may occur at a higher frequency in patients with CF than the general population, and symptoms of these conditions may overlap. We report on two patients presenting with CF-related bone disease in the past year who were subsequently found to have concurrent celiac disease. Because adherence to a gluten-free diet may improve BMD in patients with celiac disease, this could have important implications for treatment. Clinicians should consider screening for celiac disease in patients with CF who have low BMD, worsening BMD in the absence of other risk factors, and/or difficult to treat vitamin D deficiency. PMID- 29230334 TI - Thyrotoxicosis Associated with a Hypopharyngeal Toxic Nodular Thyroid. AB - Ectopic thyroid is a rare developmental anomaly which may be either asymptomatic or present with thyroid dysfunction as well as pressure symptoms. Here we present a novel case of thyrotoxicosis associated with a hypopharyngeal multinodular thyroid in a female. Removal of the ectopic thyroid led to normalization of the thyroid status. PMID- 29230335 TI - A Case of Ignatzschineria indica Bacteremia following Maggot Colonization. AB - Ignatzschineria indica is a Gram-negative bacterium that is commonly associated with the larvae of flesh flies. I. indica is difficult to isolate in routine laboratory procedures but has been associated with neglected wounds infested with maggots, fever, elevated white blood count and C-reactive protein, and polymicrobial culture results. Other specific hematological/immunological changes are not known. We present a case of I. indica bacteremia and polymicrobial osteomyelitis resulting from infected decubitus ulcers. The patient improved after treatment with cefepime followed by levofloxacin. PMID- 29230336 TI - Metastatic Spinal Cord Compression Secondary to Liver Cancer. AB - Metastatic spinal cord compression (MSCC) is a medical emergency that requires rapid diagnosis and treatment to reduce pain, to preserve neurological functioning, and to prolong survival. The diagnosis of liver cancer is often neglected in the differential diagnosis of MSCC. Treatment is usually palliative and evolution is often fatal. This is a case report of a 28-year-old patient living in Mauritania hospitalized in November 2014 at the neurology department of Fann national teaching hospital in Dakar, for the management of a chronic dorsal spinal cord compression. The radiological and laboratory investigations done revealed the metastatic compression originating from a liver cancer with elevated alpha-fetoprotein and aspartate transaminase, positive hepatitis B surface antigen, and multiple metastasis in the lungs, mediastinum, ribs, iliac, and peritoneum. The hip joint X-ray showed a spontaneous fracture of the right femoral neck. The multidisciplinary treatment was palliative and the evolution was fatal within the month of hospitalization. Earlier diagnosis and treatment of MSCC may not have saved the life of the patient but may have prevented much suffering and would likely have prolonged the life of a young man. PMID- 29230328 TI - Circadian Rhythm Disturbances in Mood Disorders: Insights into the Role of the Suprachiasmatic Nucleus. AB - Circadian rhythm disturbances are a common symptom among individuals with mood disorders. The suprachiasmatic nucleus (SCN), in the ventral part of the anterior hypothalamus, orchestrates physiological and behavioral circadian rhythms. The SCN consists of self-sustaining oscillators and receives photic and nonphotic cues, which entrain the SCN to the external environment. In turn, through synaptic and hormonal mechanisms, the SCN can drive and synchronize circadian rhythms in extra-SCN brain regions and peripheral tissues. Thus, genetic or environmental perturbations of SCN rhythms could disrupt brain regions more closely related to mood regulation and cause mood disturbances. Here, we review clinical and preclinical studies that provide evidence both for and against a causal role for the SCN in mood disorders. PMID- 29230337 TI - Prenatal Diagnosis of a Segmental Small Bowel Volvulus with Threatened Premature Labor. AB - Fetal primary small bowel volvulus is extremely rare but represents a serious life-threatening condition needing emergency neonatal surgical management to avoid severe digestive consequences. We report a case of primary small bowel volvulus with meconium peritonitis prenatally diagnosed at 27 weeks and 4 days of gestation during threatened premature labor with reduced fetal movements. Ultrasound showed a small bowel mildly dilated with thickened and hyperechogenic intestinal wall, with a typical whirlpool configuration. Normal fetal development allowed continuation of pregnancy with ultrasound follow-up. Induction of labor was decided at 37 weeks and 2 days of gestation because of a significant aggravation of intestinal dilatation appearing more extensive with peritoneal calcifications leading to the suspicion of meconium peritonitis, associated with reduced fetal movements and reduced fetal heart rate variability, for neonatal surgical management with a good outcome. PMID- 29230338 TI - Optical Coherence Tomography Angiography of Punctate Inner Choroidopathy. AB - Purpose: To report a case of bilateral choroidal neovascularization (CNV) in punctate inner choroidopathy (PIC) visualized utilizing optical coherence tomography angiography (OCT-A). Methods: Case report. Results: A 29-year-old woman presented with new visual symptoms in both eyes. Fundoscopic exam revealed bilateral multifocal, small, well-defined lesions consistent with PIC. Optical coherence tomography demonstrated subretinal fluid and retinal pigment epithelium detachments (RPEDs) in both eyes. OCT-A revealed bilateral abnormal increased flow within the RPEDs consistent with CNV. Fluorescein angiography confirmed the presence of bilateral CNV. Conclusion: CNV secondary to PIC may be identified using noninvasive optical coherence tomography angiography. PMID- 29230339 TI - Nodular Lymphocyte Predominant Hodgkin Lymphoma of the Ileum. AB - Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma derived from germinal center B lymphocytes that typically presents with localized lymph node involvement and can mimic a variety of both reactive and other neoplastic conditions. Extranodal involvement is uncommon in NLPHL and typically occurs in the context of previously documented or synchronous nodal disease. Involvement of the gastrointestinal tract is exceedingly rare. Here, we present the first case to our knowledge of NLPHL involving the ileum that was discovered incidentally on routine screening colonoscopy in an asymptomatic patient. An awareness of the spectrum of clinical presentations, careful morphologic evaluation, and a comprehensive panel of immunohistochemical stains are essential for correct diagnosis of NLPHL presenting in unusual anatomic sites. PMID- 29230340 TI - Primary Esophageal Melanoma with Aberrant CD56 Expression: A Potential Diagnostic Pitfall. AB - Primary esophageal malignant melanoma (MM) is rare and extremely aggressive. For pathologists, it can be challenging to diagnose and differentiate from other poorly differentiated malignant neoplasms in the esophagus. Complicating this fact, MM can have divergent differentiation and express nonmelanocytic immunohistochemical markers including epithelial markers (cytokeratins) and rarely neuroendocrine markers. Lack of awareness of this fact by a pathologist can lead to an erroneous diagnosis and delay treatment for an already aggressive disease. Herein, we report a case of primary esophageal malignant melanoma with aberrant CD56 expression without accompanying synaptophysin or chromogranin expression. PMID- 29230341 TI - Pancreatic Laceration in a Pediatric Patient: An Unexpected Diagnosis. AB - Pediatric pancreatic injuries are rare. We present an atypical case that occurred in a 4-year-old male. The child presented with a twenty-four-hour history of vomiting that had progressed to right lower quadrant abdominal pain on examination in the emergency department. The initial differential was gastroenteritis versus appendicitis. An abnormality on the ultrasonography and an elevated lipase level eventually led to an MRI showing a complete transection through the posterior margin of the pancreas. The patient was admitted to pediatric surgery and underwent a successful distal pancreatectomy with preservation of the spleen. On further inquiry specific to trauma, the child disclosed that his older brother had punched him in his abdomen the night before. The child's parents were separated due to intimate partner violence, and this older sibling recently had been very stressed. The sibling was referred for mental health evaluation and counseling, and the case reported to the county children and youth investigative services system. A low threshold for considering trauma and child abuse in the pediatric population is recommended when significant intra-abdominal injury is diagnosed. PMID- 29230342 TI - The Treatment of Clozapine-Withdrawal Delirium with Electroconvulsive Therapy. AB - Clozapine, a commonly used atypical antipsychotic, can precipitate a severe withdrawal syndrome. In this report, we describe a case of delirium with catatonic features emerging after the immediate cessation of clozapine subsequent to concerns of developing neuroleptic malignant syndrome. After multiple treatments were found to be inefficacious, electroconvulsive therapy (ECT) was initiated, resulting in significant improvement. A literature search revealed six previous cases of clozapine-withdrawal syndromes of varied symptomatology treated with ECT. To our knowledge, the present case represents the first reported clozapine-withdrawal delirium treated successfully with ECT. PMID- 29230343 TI - Unusual Pathology in a Kidney from a Heart-Transplant Patient. AB - Acute kidney injury (AKI) is often observed after heart transplantation. In this setting, acute tubular necrosis is the main histological finding on kidneys. We report the unusual pathology found in a kidney from a heart-transplant patient. The patient experienced several hemodynamic insults, massive transfusion, and implantation of a mechanical circulatory-support device before heart transplantation: there was prolonged AKI after transplantation. A kidney biopsy revealed acute tubular necrosis and renal hemosiderosis, which was probably related to the transfusion and to mechanical circulatory-support device-induced intravascular hemolysis. Assessment of iron during resuscitation could have prevented, at least partly, AKI. PMID- 29230344 TI - Cystic Adventitial Disease of Popliteal Artery with Venous Aneurysm of Popliteal Vein: Two-Year Follow-Up after Surgery. AB - We report a rare case of cystic adventitial disease of popliteal artery with venous aneurysm of popliteal vein. A 46-year-old woman had sudden-onset intermittent claudication and coldness in her right leg. The right-sided ankle brachial pressure index (ABI) was 1.01, but peripheral arterial pulsation was decreased at knee venting position. Computed tomography revealed simple cystic lesion of the popliteal artery and stenosis of the arterial lumen in this lesion. The patient was treated by complete resection of the cystic adventitial layer of popliteal artery. A venous aneurysm of popliteal vein was revealed by intraoperative echo and was simply ligated. The patient had uneventful postoperative course and no symptoms of relevance during the two years of follow up. PMID- 29230345 TI - New Trends for the Evaluation of Heat Treatments of Milk. AB - Milk is generally very rich in nutrients and this may lead it to be an ideal growth environment for many microorganisms, including pathogens, so effective measurements aiming to ensure total microbiological safety of milk and minimize the risk to human health are needed. Milk heat treatments are the most common practices carried out to inhibit the microbial growth; therefore it is necessary to have analytical procedures that are more and more up-to-date and capable of detecting the effectiveness of the heat treatments. Most of the reference and official methods to assess heat treatment in milk are based on the evaluation of the modifications of some milk components following the thermal process, such as the determination of enzyme activities (alkaline phosphatase and lactoperoxidase), whey proteins, Maillard reaction compounds (generally furosine), and lactulose. Besides the most common techniques (liquid and gas chromatography, capillary electrophoresis, or spectroscopy) used for the detection of single thermal indicators, new approaches, such as chemometric studies or more recent techniques, including size-exclusion chromatography with online electrospray mass spectrometry or stable isotope ratio mass spectrometry, are discussed in this review in order to evaluate heat treatment in milk. PMID- 29230346 TI - Solid-State Kinetic Investigations of Nonisothermal Reduction of Iron Species Supported on SBA-15. AB - Iron oxide catalysts supported on nanostructured silica SBA-15 were synthesized with various iron loadings using two different precursors. Structural characterization of the as-prepared Fe x O y /SBA-15 samples was performed by nitrogen physisorption, X-ray diffraction, DR-UV-Vis spectroscopy, and Mossbauer spectroscopy. An increasing size of the resulting iron species correlated with an increasing iron loading. Significantly smaller iron species were obtained from (Fe(III), NH4)-citrate precursors compared to Fe(III)-nitrate precursors. Moreover, smaller iron species resulted in a smoother surface of the support material. Temperature-programmed reduction (TPR) of the Fe x O y /SBA-15 samples with H2 revealed better reducibility of the samples originating from Fe(III) nitrate precursors. Varying the iron loading led to a change in reduction mechanism. TPR traces were analyzed by model-independent Kissinger method, Ozawa, Flynn, and Wall (OFW) method, and model-dependent Coats-Redfern method. JMAK kinetic analysis afforded a one-dimensional reduction process for the Fe x O y /SBA-15 samples. The Kissinger method yielded the lowest apparent activation energy for the lowest loaded citrate sample (Ea ~ 39 kJ/mol). Conversely, the lowest loaded nitrate sample possessed the highest apparent activation energy (Ea ~ 88 kJ/mol). For samples obtained from Fe(III)-nitrate precursors, Ea decreased with increasing iron loading. Apparent activation energies from model-independent analysis methods agreed well with those from model-dependent methods. Nucleation as rate-determining step in the reduction of the iron oxide species was consistent with the Mampel solid-state reaction model. PMID- 29230347 TI - Induction of Reactive Intermediates and Autophagy-Related Proteins upon Infection of Macrophages with Rhodococcus equi. AB - Rhodococcus equi (R. equi) is an intracellular macrophage-tropic pathogen with potential for causing fatal pyogranulomatous pneumonia in foals between 1 and 6 months of age. In this study, we sought to determine whether infection of macrophages with R. equi could lead to the induction of autophagy. Murine bone marrow derived macrophages (BMDM) were infected with R. equi for various time intervals and analyzed for upregulation of autophagy proteins and accumulation of autophagosomes relative to uninfected controls. Western blot analysis showed a progressive increase in LC3-II and Beclin1 levels in a time-dependent manner. The functional accumulation of autophagosomes detected with monodansylcadaverine further supported the enhanced induction of autophagy in BMDM infected with R. equi. In addition, infection of BMDM with R. equi induced generation of reactive oxygen species (ROS) in a time-dependent manner. These data are consistent with reports documenting the role of ROS in induction of autophagy and indicate that the infection of macrophages by R. equi elicits innate host defense mechanisms. PMID- 29230348 TI - A Randomized, Two-Way Crossover Study to Evaluate the Pharmacokinetics of Caffeine Delivered Using Caffeinated Chewing Gum Versus a Marketed Caffeinated Beverage in Healthy Adult Volunteers. AB - Background: This study was conducted to compare the pharmacokinetics of caffeine delivered using caffeinated chewing gum to that delivered using a marketed caffeinated beverage (instant coffee) in 16 healthy adult volunteers. Materials and Methods: This was a controlled open-label, randomized, two-period crossover study. Caffeinated chewing gum and a serving of instant coffee, each containing ~50 mg caffeine, were administered with blood samples collected before and up to 24 hours after administration starts. Plasma caffeine levels were analyzed using validated liquid chromatography coupled with tandem mass spectrometry methodology. Results: There were no statistical differences between the two caffeine products in tmax (p = 0.3308) and ka (p = 0.3894). Although formulated at ~50 mg caffeine each, mean dose released from chewing gum was ~18% less than beverage. Dose-normalized area under the concentration-time curve (AUC)0-t, AUC0 infinity, and Cmax was similar between products. Although the criteria were not set a priori and the study was not powered for concluding bioequivalence, the 90% confidence intervals fell within the bioequivalence limit of 80% to 125%. Conclusions: Existing scientific literature on caffeine, based mostly on data from caffeinated beverages, can be leveraged to support the safety of caffeine delivered by chewing gum and current maximum safe caffeine dose advice should be applicable irrespective of delivery method. PMID- 29230349 TI - Reinforcing Value of Caffeinated and Noncaffeinated Beverages After Acute Exposure in Children and Adolescents. AB - Background: When caffeine is added to beverages, it increases beverage liking and the relative reinforcing value (RRV) of these beverages after repeated exposure. The purpose of this study was to test the hypothesis that a single acute exposure to caffeine increases liking and motivation to consume sugar-sweetened beverages (SSBs) relative to placebo. Methods: Participants were children ages 8-9 years (n = 36) and adolescents ages 15-17 years (n = 41) with an approximately equal number of boys and girls. A double-blind, placebo-controlled crossover study was conducted where participants sampled a SSB containing caffeine (1 and 2 mg/kg) on one visit and placebo (quinine 0.01 and 0.02 mg/kg) on a second visit day and then, on a third visit, played a computer game to earn points for the beverages and rated liking and taste sensations. They returned to the laboratory after a 1 week washout and had the alternate dose combination. Results: Acute exposure to the higher dose of caffeine increased the RRV of the SSB relative to placebo, but only when that dose was presented in the first week and only in female participants. The liking of the caffeine-containing SSB at the higher dose was lower than the placebo at all time points. Conclusions: These data suggest that a single exposure to a caffeinated SSB can impact its RRV and liking, but only under certain conditions and only in females. This supports previous work suggesting that caffeine can increase desire to consume SSB. PMID- 29230350 TI - Spatially graded hydrogels for preclinical testing of glioblastoma anticancer therapeutics. AB - While preclinical models such as orthotopic tumors generated in mice from patient derived specimens are widely used to predict sensitivity or therapeutic interventions for cancer, such xenografts can be slow, require extensive infrastructure, and can make in situ assessment difficult. Such concerns are heightened in highly aggressive cancers, such as glioblastoma (GBM), that display genetic diversity and short mean survival. Biomimetic biomaterial technologies offer an approach to create ex vivo models that reflect biophysical features of the tumor microenvironment (TME). We describe a microfluidic templating approach to generate spatially graded hydrogels containing patient-derived GBM cells to explore drug efficacy and resistance mechanisms. PMID- 29230352 TI - Interpopulational and seasonal variation in the chemical signals of the lizard Gallotia galloti. AB - Communicative traits are strikingly diverse and may vary among populations of the same species. Within a population, these traits may also display seasonal variation. Chemical signals play a key role in the communication of many taxa. However, we still know far too little about chemical communication in some vertebrate groups. In lizards, only a few studies have examined interpopulational variation in the composition of chemical cues and signals and only one study has explored the seasonal effects. Here we sampled three subspecies of the Tenerife lizards (Gallotia galloti) and analyze the lipophilic fraction of their femoral gland secretions to characterize the potential interpopulational variation in the chemical signals. In addition, we assessed whether composition of these secretions differed between the reproductive and the non-reproductive season. We analyzed variations in both the overall chemical profile and the abundance of the two main compounds (cholesterol and vitamin E). Our results show interpopulational and seasonal differences in G. gallotia chemical profiles. These findings are in accordance with the high interpopulational variability of compounds observed in lizard chemical signals and show that their composition is not only shaped by selective factors linked to reproductive season. PMID- 29230353 TI - A Cdk1 phosphomimic mutant of MCAK impairs microtubule end recognition. AB - The microtubule depolymerising kinesin-13, MCAK, is phosphorylated at residue T537 by Cdk1. This is the only known phosphorylation site within MCAK's motor domain. To understand the impact of phosphorylation by Cdk1 on microtubule depolymerisation activity, we have investigated the molecular mechanism of the phosphomimic mutant T537E. This mutant significantly impairs microtubule depolymerisation activity and when transfected into cells causes metaphase arrest and misaligned chromosomes. We show that the molecular mechanism underlying the reduced depolymerisation activity of this phosphomimic mutant is an inability to recognise the microtubule end. The microtubule-end residence time is reduced relative to wild-type MCAK, whereas the lattice residence time is unchanged by the phosphomimic mutation. Further, the microtubule-end specific stimulation of ADP dissociation, characteristic of MCAK, is abolished by this mutation. Our data shows that T537E is unable to distinguish between the microtubule end and the microtubule lattice. PMID- 29230351 TI - Collision skin lesions-results of a multicenter study of the International Dermoscopy Society (IDS). AB - Background: Collision lesions as two independent and unrelated skin tumors often manifest an atypical morphology. Objective: To determine the combinations of collision skin lesions (CSLs). Methods: Twenty-one pigmented lesion clinics in nine countries included 77 histopathologically proven CSLs in this retrospective observational study. Results: Seventy-seven CSLs from 75 patients (median age 59.8 years) were analyzed; 24.7% of CSLs were located on the head and neck area, 5.2% on the upper extremities, 48.1% on the trunk, and 11.7% on the lower extremities; 40.3% revealed a melanocytic component (median age 54.7 years), followed by 45.5% with a basal cell carcinoma (BCC) (median age 62.4 years) and 11.7% with a seborrheic keratosis (median age 64.7 years). CSLs with a BCC component were more often found on the head and neck area compared to tumors with a melanocytic component (34.3% versus 16.1%). Lesions with a melanocytic component were more often detected on the trunk compared to lesions with a BCC (64.5% versus 37.1%). Patients with CSLs with epidermal-epidermal cell combination were older than patients with epidermal-dermal cell combination (63 versus 55.2 years), were more often male than female (63% versus 43.3%), more often had the lesion on the head and neck area (32.6% versus 13.3%), and less often on the upper (2.2 % versus 10%) or lower extremities (8.7% versus 16.6%). Conclusions: CSLs consist of a heterogeneous group of lesions of varying cell types. They are associated with advancing age and cumulative UV-exposure. CSLs manifest a complex morphology making it challenging to diagnose correctly. PMID- 29230354 TI - Ecomorphological inferences in early vertebrates: reconstructing Dunkleosteus terrelli (Arthrodira, Placodermi) caudal fin from palaeoecological data. AB - Our knowledge about the body morphology of many extinct early vertebrates is very limited, especially in regard to their post-thoracic region. The prompt disarticulation of the dermo-skeletal elements due to taphonomic processes and the lack of a well-ossified endoskeleton in a large number of groups hinder the preservation of complete specimens. Previous reconstructions of most early vertebrates known from partial remains have been wholly based on phylogenetically closely related taxa. However, body design of fishes is determined, to a large extent, by their swimming mode and feeding niche, making it possible to recognise different morphological traits that have evolved several times in non-closely related groups with similar lifestyles. Based on this well-known ecomorphological correlation, here we propose a useful comparative framework established on extant taxa for predicting some anatomical aspects in extinct aquatic vertebrates from palaeoecological data and vice versa. For this, we have assessed the relationship between the locomotory patterns and the morphological variability of the caudal region in extant sharks by means of geometric morphometrics and allometric regression analysis. Multivariate analyses reveal a strong morphological convergence in non-closely related shark species that share similar modes of life, enabling the characterization of the caudal fin morphology of different ecological subgroups. In addition, interspecific positive allometry, affecting mainly the caudal fin span, has been detected. This phenomenon seems to be stronger in sharks with more pelagic habits, supporting its role as a compensation mechanism for the loss of hydrodynamic lift associated with the increase in body size, as previously suggested for many other living and extinct aquatic vertebrates. The quantification of shape change per unit size in each ecological subgroup has allowed us to establish a basis for inferring not only qualitative aspects of the caudal fin morphology of extinct early vertebrates but also to predict absolute values of other variables such as the fin span or the hypocercal and heterocercal angles. The application of this ecomorphological approach to the specific case of Dunkleosteus terrelli has led to a new reconstruction of this emblematic placoderm. Our proposal suggests a caudal fin with a well-developed ventral lobe, narrow peduncle and wide span, in contrast to classical reconstructions founded on the phylogenetic proximity with much smaller placoderms known from complete specimens. Interestingly, this prediction gains support with the recent discovery of fin distal elements (ceratotrichia) in a well preserved D. terrelli, which suggests a possible greater morphological variability in placoderm caudal fins than previously thought. PMID- 29230355 TI - Relationships between consumption of ultra-processed foods, gestational weight gain and neonatal outcomes in a sample of US pregnant women. AB - Background: An increasingly large share of diet comes from ultra-processed foods (UPFs), which are assemblages of food substances designed to create durable, convenient and palatable ready-to-eat products. There is increasing evidence that high UPF consumption is indicative of poor diet and is associated with obesity and metabolic disorders. This study sought to examine the relationship between percent of energy intake from ultra-processed foods (PEI-UPF) during pregnancy and maternal gestational weight gain, maternal lipids and glycemia, and neonatal body composition. We also compared the PEI-UPF indicator against the US government's Healthy Eating Index-2010 (HEI-2010). Methods: Data were used from a longitudinal study performed in 2013-2014 at the Women's Health Center and Obstetrics & Gynecology Clinic in St. Louis, MO, USA. Subjects were pregnant women in the normal and obese weight ranges, as well as their newborns (n = 45). PEI-UPF and the Healthy Eating Index-2010 (HEI-2010) were calculated for each subject from a one-month food frequency questionnaire (FFQ). Multiple regression (ANCOVA-like) analysis was used to analyze the relationship between PEI-UPF or HEI-2010 and various clinical outcomes. The ability of these dietary indices to predict clinical outcomes was also compared with the predictive abilities of total energy intake and total fat intake. Results: An average of 54.4 +/- 13.2% of energy intake was derived from UPFs. A 1%-point increase in PEI-UPF was associated with a 1.33 kg increase in gestational weight gain (p = 0.016). Similarly, a 1%-point increase in PEI-UPF was associated with a 0.22 mm increase in thigh skinfold (p = 0.045), 0.14 mm in subscapular skinfold (p = 0.026), and 0.62 percentage points of total body adiposity (p = 0.037) in the neonate. Discussion: PEI-UPF (percent of energy intake from ultra-processed foods) was associated with and may be a useful predictor of increased gestational weight gain and neonatal body fat. PEI-UPF was a better predictor of all tested outcomes than either total energy or fat intake, and a better predictor of the three infant body fat measures than HEI-2010. UPF consumption should be limited during pregnancy and diet quality should be maximized in order to improve maternal and neonatal health. PMID- 29230356 TI - SDMtoolbox 2.0: the next generation Python-based GIS toolkit for landscape genetic, biogeographic and species distribution model analyses. AB - SDMtoolbox 2.0 is a software package for spatial studies of ecology, evolution, and genetics. The release of SDMtoolbox 2.0 allows researchers to use the most current ArcGIS software and MaxEnt software, and reduces the amount of time that would be spent developing common solutions. The central aim of this software is to automate complicated and repetitive spatial analyses in an intuitive graphical user interface. One core tenant facilitates careful parameterization of species distribution models (SDMs) to maximize each model's discriminatory ability and minimize overfitting. This includes carefully processing of occurrence data, environmental data, and model parameterization. This program directly interfaces with MaxEnt, one of the most powerful and widely used species distribution modeling software programs, although SDMtoolbox 2.0 is not limited to species distribution modeling or restricted to modeling in MaxEnt. Many of the SDM pre- and post-processing tools have 'universal' analogs for use with any modeling software. The current version contains a total of 79 scripts that harness the power of ArcGIS for macroecology, landscape genetics, and evolutionary studies. For example, these tools allow for biodiversity quantification (such as species richness or corrected weighted endemism), generation of least-cost paths and corridors among shared haplotypes, assessment of the significance of spatial randomizations, and enforcement of dispersal limitations of SDMs projected into future climates-to only name a few functions contained in SDMtoolbox 2.0. Lastly, dozens of generalized tools exists for batch processing and conversion of GIS data types or formats, which are broadly useful to any ArcMap user. PMID- 29230357 TI - Comparative analyses of putative toxin gene homologs from an Old World viper, Daboia russelii. AB - Availability of snake genome sequences has opened up exciting areas of research on comparative genomics and gene diversity. One of the challenges in studying snake genomes is the acquisition of biological material from live animals, especially from the venomous ones, making the process cumbersome and time consuming. Here, we report comparative sequence analyses of putative toxin gene homologs from Russell's viper (Daboia russelii) using whole-genome sequencing data obtained from shed skin. When compared with the major venom proteins in Russell's viper studied previously, we found 45-100% sequence similarity between the venom proteins and their putative homologs in the skin. Additionally, comparative analyses of 20 putative toxin gene family homologs provided evidence of unique sequence motifs in nerve growth factor (NGF), platelet derived growth factor (PDGF), Kunitz/Bovine pancreatic trypsin inhibitor (Kunitz BPTI), cysteine rich secretory proteins, antigen 5, andpathogenesis-related1 proteins (CAP) and cysteine-rich secretory protein (CRISP). In those derived proteins, we identified V11 and T35 in the NGF domain; F23 and A29 in the PDGF domain; N69, K2 and A5 in the CAP domain; and Q17 in the CRISP domain to be responsible for differences in the largest pockets across the protein domain structures in crotalines, viperines and elapids from the in silico structure-based analysis. Similarly, residues F10, Y11 and E20 appear to play an important role in the protein structures across the kunitz protein domain of viperids and elapids. Our study highlights the usefulness of shed skin in obtaining good quality high-molecular weight DNA for comparative genomic studies, and provides evidence towards the unique features and evolution of putative venom gene homologs in vipers. PMID- 29230358 TI - Neither slim nor fat: estimating the mass of the dodo (Raphus cucullatus, Aves, Columbiformes) based on the largest sample of dodo bones to date. AB - The dodo (Raphus cucullatus) might be the most enigmatic bird of all times. It is, therefore, highly remarkable that no consensus has yet been reached on its body mass; previous scientific estimates of its mass vary by more than 100%. Until now, the vast amount of bones stored at the Natural History Museum in Mauritius has not yet been studied morphometrically nor in relation to body mass. Here, a new estimate of the dodo's mass is presented based on the largest sample of dodo femora ever measured (n = 174). In order to do this, we have used the regression method and chosen our variables based on biological, mathematical and physical arguments. The results indicate that the mean mass of the dodo was circa 12 kg, which is approximately five times as heavy as the largest living Columbidae (pigeons and doves), the clade to which the dodo belongs. PMID- 29230359 TI - Genetic differentiation and phylogeography of Mediterranean-North Eastern Atlantic blue shark (Prionace glauca, L. 1758) using mitochondrial DNA: panmixia or complex stock structure? AB - Background: The blue shark (Prionace glauca, Linnaeus 1758) is one of the most abundant epipelagic shark inhabiting all the oceans except the poles, including the Mediterranean Sea, but its genetic structure has not been confirmed at basin and interoceanic distances. Past tagging programs in the Atlantic Ocean failed to find evidence of migration of blue sharks between the Mediterranean and the adjacent Atlantic, despite the extreme vagility of the species. Although the high rate of by-catch in the Mediterranean basin, to date no genetic study on Mediterranean blue shark was carried out, which constitutes a significant knowledge gap, considering that this population is classified as "Critically Endangered", unlike its open-ocean counterpart. Methods: Blue shark phylogeography and demography in the Mediterranean Sea and North-Eastern Atlantic Ocean were inferred using two mitochondrial genes (Cytb and control region) amplified from 207 and 170 individuals respectively, collected from six localities across the Mediterranean and two from the North-Eastern Atlantic. Results: Although no obvious pattern of geographical differentiation was apparent from the haplotype network, Phist analyses indicated significant genetic structure among four geographical groups. Demographic analyses suggest that these populations have experienced a constant population expansion in the last 0.4-0.1 million of years. Discussion: The weak, but significant, differences in Mediterranean and adjacent North-eastern Atlantic blue sharks revealed a complex phylogeographic structure, which appears to reject the assumption of panmixia across the study area, but also supports a certain degree of population connectivity across the Strait of Gibraltar, despite the lack of evidence of migratory movements observed by tagging data. Analyses of spatial genetic structure in relation to sex-ratio and size could indicate some level of sex/stage biased migratory behaviour. PMID- 29230360 TI - Skin temperature and reproductive condition in wild female chimpanzees. AB - Infrared thermal imaging has emerged as a valuable tool in veterinary medicine, in particular for evaluating reproductive processes. Here, we explored differences in skin temperature of twenty female chimpanzees in Budongo Forest, Uganda, four of which were pregnant during data collection. Based on previous literature in other mammals, we predicted increased skin temperature of maximally swollen reproductive organs of non-pregnant females when approaching peak fertility. For pregnant females, we made the same prediction because it has been argued that female chimpanzees have evolved mechanisms to conceal pregnancy, including swellings of the reproductive organs, conspicuous copulation calling, and solicitation of male mating behaviour, to decrease the infanticidal tendencies of resident males by confusing paternity. For non-pregnant females, we found slight temperature increases towards the end of the swelling cycles but no significant change between the fertile and non-fertile phases. Despite their different reproductive state, pregnant females had very similar skin temperature patterns compared to non-pregnant females, suggesting little potential for males to use skin temperature to recognise pregnancies, especially during maximal swelling, when ovulation is most likely to occur in non-pregnant females. We discuss this pattern in light of the concealment hypothesis, i.e., that female chimpanzees have evolved physiological means to conceal their reproductive state during pregnancy. PMID- 29230361 TI - Changes of arthropod diversity across an altitudinal ecoregional zonation in Northwestern Argentina. AB - This study examined arthropod community patterns over an altitudinal ecoregional zonation that extended through three ecoregions (Yungas, Monte de Sierras y Bolsones, and Puna) and two ecotones (Yungas-Monte and Prepuna) of Northwestern Argentina (altitudinal range of 2,500 m), and evaluated the abiotic and biotic factors and the geographical distance that could influence them. Pitfall trap and suction samples were taken seasonally in 15 sampling sites (1,500-4,000 m a.s.l) during one year. In addition to climatic variables, several soil and vegetation variables were measured in the field. Values obtained for species richness between ecoregions and ecotones and by sampling sites were compared statistically and by interpolation-extrapolation analysis based on individuals at the same sample coverage level. Effects of predictor variables and the similarity of arthropods were shown using non-metric multidimensional scaling, and the resulting groups were evaluated using a multi-response permutation procedure. Polynomial regression was used to evaluate the relationship between altitude with total species richness and those of hyperdiverse/abundant higher taxa and the latter taxa with each predictor variable. The species richness pattern displayed a decrease in species diversity as the elevation increased at the bottom wet part (Yungas) of our altitudinal zonation until the Monte, and a unimodal pattern of diversity in the top dry part (Monte, Puna). Each ecoregion and ecotonal zone evidenced a particular species richness and assemblage of arthropods, but the latter ones displayed a high percentage of species shared with the adjacent ecoregions. The arthropod elevational pattern and the changes of the assemblages were explained by the environmental gradient (especially the climate) in addition to a geographic gradient (the distance of decay of similarity), demonstrating that the species turnover is important to explain the beta diversity along the elevational gradient. This suggests that patterns of diversity and distribution of arthropods are regulated by the dissimilarity of ecoregional environments that establish a wide range of geographic and environmental barriers, coupled with a limitation of species dispersal. Therefore, the arthropods of higher taxa respond differently to the altitudinal ecoregional zonation. PMID- 29230362 TI - Cytochrome c oxidase barcodes for aquatic oligochaete identification: development of a Swiss reference database. AB - Introduction: Aquatic oligochaetes represent valuable indicators of the quality of sediments of watercourses and lakes, but their difficult identification based on morphological criteria compromises their more common use for eco-diagnostic analyses. This issue could be overcome by using DNA barcodes for species identification. A 10% threshold of cytochrome c oxidase (COI) divergence was proposed for differentiating between oligochaete species based on molecular and morphological data. A Swiss database of COI sequences of aquatic oligochaetes was initiated in 2012. The aim of this study is to complement the Swiss oligochaete database of COI sequences and to confirm the relevance of this threshold for species delimitation. Methods: We sequenced the COI sequence of 216 specimens collected in different regions of Switzerland and ITS2 region of some lineages whose delimitation with COI data was doubtful. Results: We distinguished 53 lineages, among which 34 were new for Switzerland and 17 sequenced for the first time. All the lineages were separated by more than 10% of COI variation, with the exception of some species within Nais and Uncinais. In these two genera, the threshold was lowered to 8% to be congruent with the morphological analysis. The total number of lineages reported so far for Switzerland is 75, including 59 morphospecies or unidentified species and 16 cryptic species. Discussion: Our study shows that the threshold of 10% of COI divergence is generally appropriate to distinguish aquatic oligochaete lineages, but that it must be adjusted for some species. The database reported here will be complemented in the future in parallel to the development of genetic oligochaete indices. PMID- 29230363 TI - Genome-wide identification of ABA receptor PYL family and expression analysis of PYLs in response to ABA and osmotic stress in Gossypium. AB - Abscisic acid (ABA) receptor pyrabactin resistance1/PYR1-like/regulatory components of ABA receptor (PYR1/PYL/RCAR) (named PYLs for simplicity) are core regulators of ABA signaling, and have been well studied in Arabidopsis and rice. However, knowledge is limited about the PYL family regarding genome organization, gene structure, phylogenesis, gene expression and protein interaction with downstream targets in Gossypium. A comprehensive analysis of the Gossypium PYL family was carried out, and 21, 20, 40 and 39 PYL genes were identified in the genomes from the diploid progenitor G. arboretum, G. raimondii and the tetraploid G. hirsutum and G. barbadense, respectively. Characterization of the physical properties, chromosomal locations, structures and phylogeny of these family members revealed that Gossypium PYLs were quite conservative among the surveyed cotton species. Segmental duplication might be the main force promoting the expansion of PYLs, and the majority of the PYLs underwent evolution under purifying selection in Gossypium. Additionally, the expression profiles of GhPYL genes were specific in tissues. Transcriptions of many GhPYL genes were inhibited by ABA treatments and induced by osmotic stress. A number of GhPYLs can interact with GhABI1A or GhABID in the presence and/or absence of ABA by the yeast-two hybrid method in cotton. PMID- 29230364 TI - Complete genome sequence and comparative genomics of the golden pompano (Trachinotus ovatus) pathogen, Vibrio harveyi strain QT520. AB - Vibrio harveyi is a Gram-negative, halophilic bacterium that is an opportunistic pathogen of commercially farmed marine vertebrate species. To understand the pathogenicity of this species, the genome of V. harveyi QT520 was analyzed and compared to that of other strains. The results showed the genome of QT520 has two unique circular chromosomes and three endogenous plasmids, totaling 6,070,846 bp with a 45% GC content, 5,701 predicted ORFs, 134 tRNAs and 37 rRNAs. Common virulence factors, including ACF, IlpA, OmpU, Flagellin, Cya, Hemolysin and MARTX, were detected in the genome, which are likely responsible for the virulence of QT520. The results of genomes comparisons with strains ATCC 33843 (392 (MAV)) and ATCC 43516 showed that greater numbers genes associated with types I, II, III, IV and VI secretion systems were detected in QT520 than in other strains, suggesting that QT520 is a highly virulent strain. In addition, three plasmids were only observed in the complete genome sequence of strain QT520. In plasmid p1 of QT520, specific virulence factors (cyaB, hlyB and rtxA) were identified, suggesting that the pathogenicity of this strain is plasmid associated. Phylogenetic analysis of 12 complete Vibrio sp. genomes using ANI values, core genes and MLST revealed that QT520 was most closely related to ATCC 33843 (392 (MAV)) and ATCC 43516, suggesting that QT520 belongs to the species V. harveyi. This report is the first to describe the complete genome sequence of a V. harveyi strain isolated from an outbreak in a fish species in China. In addition, to the best of our knowledge, this report is the first to compare the V. harveyi genomes of several strains. The results of this study will expand our understanding of the genome, genetic characteristics, and virulence factors of V. harveyi, setting the stage for studies of pathogenesis, diagnostics, and disease prevention. PMID- 29230365 TI - Identification and characterization of a novel zebrafish (Danio rerio) pentraxin carbonic anhydrase. AB - Background: Carbonic anhydrases (CAs) are ubiquitous, essential enzymes which catalyze the conversion of carbon dioxide and water to bicarbonate and H+ ions. Vertebrate genomes generally contain gene loci for 15-21 different CA isoforms, three of which are enzymatically inactive. CA VI is the only secretory protein of the enzymatically active isoforms. We discovered that non-mammalian CA VI contains a C-terminal pentraxin (PTX) domain, a novel combination for both CAs and PTXs. Methods: We isolated and sequenced zebrafish (Danio rerio) CA VI cDNA, complete with the sequence coding for the PTX domain, and produced the recombinant CA VI-PTX protein. Enzymatic activity and kinetic parameters were measured with a stopped-flow instrument. Mass spectrometry, analytical gel filtration and dynamic light scattering were used for biophysical characterization. Sequence analyses and Bayesian phylogenetics were used in generating hypotheses of protein structure and CA VI gene evolution. A CA VI-PTX antiserum was produced, and the expression of CA VI protein was studied by immunohistochemistry. A knock-down zebrafish model was constructed, and larvae were observed up to five days post-fertilization (dpf). The expression of ca6 mRNA was quantitated by qRT-PCR in different developmental times in morphant and wild-type larvae and in different adult fish tissues. Finally, the swimming behavior of the morphant fish was compared to that of wild-type fish. Results: The recombinant enzyme has a very high carbonate dehydratase activity. Sequencing confirms a 530-residue protein identical to one of the predicted proteins in the Ensembl database (ensembl.org). The protein is pentameric in solution, as studied by gel filtration and light scattering, presumably joined by the PTX domains. Mass spectrometry confirms the predicted signal peptide cleavage and disulfides, and N-glycosylation in two of the four observed glycosylation motifs. Molecular modeling of the pentamer is consistent with the modifications observed in mass spectrometry. Phylogenetics and sequence analyses provide a consistent hypothesis of the evolutionary history of domains associated with CA VI in mammals and non mammals. Briefly, the evidence suggests that ancestral CA VI was a transmembrane protein, the exon coding for the cytoplasmic domain was replaced by one coding for PTX domain, and finally, in the therian lineage, the PTX-coding exon was lost. We knocked down CA VI expression in zebrafish embryos with antisense morpholino oligonucleotides, resulting in phenotype features of decreased buoyancy and swim bladder deflation in 4 dpf larvae. Discussion: These findings provide novel insights into the evolution, structure, and function of this unique CA form. PMID- 29230366 TI - Comparison between radial artery tonometry pulse analyzer and pulsed-Doppler echocardiography derived hemodynamic parameters in cardiac surgery patients: a pilot study. AB - Background: Bedside non-invasive techniques, such as radial artery tonometry, to estimate hemodynamic parameters have gained increased relevance as an attractive alternative and efficient method to measure hemodynamics in outpatient departments. For our pilot study, we sought to compare cardiac output (CO), and stroke volume (SV) estimated from a radial artery tonometry blood pressure pulse analyzer (BPPA) (DMP-Life, DAEYOMEDI Co., Gyeonggi-do, South Korea) to pulsed wave Doppler (PWD) echocardiography derived parameters. Methods: From January 2015 to December 2016, all patients scheduled for coronary artery bypass (CABG) surgery at our department were screened. Exclusion criteria were, inter alia, moderate to severe aortic- or Mitral valve disease and peripheral arterial disease (PAD) > stage II. One hundred and seven patients were included (mean age 66.1 +/- 9.9, 15 females, mean BMI 27.2 +/- 4.1 kg/m2). All patients had pre operative transthoracic echocardiography (TTE). We measured the hemodynamic parameters with the BPPA from the radial artery, randomly before or after TTE. For the comparison between the measurement methods we used the Bland-Altman test and Pearson correlation. Results: Mean TTE-CO was 5.1 +/- 0.96 L/min, and the mean BPPA-CO was 5.2 +/- 0.85 L/min. The Bland-Altman analysis for CO revealed a bias of -0.13 L/min and SD of 0.90 L/min with upper and lower limits of agreement of -1.91 and +1.64 L/min. The correlation of CO measurements between DMP-life and TTE was poor (r = 0.501, p < 0.0001). The mean TTE-SV was 71.3 +/- 16.2 mL and the mean BPPA-SV was 73.8 +/- 19.2 mL. SV measurements correlated very well between the two methods (r = 0.900, p < 0.0001). The Bland-Altman analysis for SV revealed a bias of -2.54 mL and SD of +/-8.42 mL and upper and lower limits of agreement of -19.05 and +13.96 mL, respectively. Conclusion: Our study shows for the first time that the DMP-life tonometry device measures SV and CO with reasonable accuracy and precision of agreement compared with TTE in preoperative cardiothoracic surgery patients. Tonometry BPPA are relatively quick and simple measuring devices, which facilitate the collection of cardiac and hemodynamic information. Further studies with a larger number of patients and with repeated measurements are in progress to test the reliability and repeatability of DMP Life system. PMID- 29230367 TI - A novel approach for human whole transcriptome analysis based on absolute gene expression of microarray data. AB - Background: In spite of the emergence of RNA sequencing (RNA-seq), microarrays remain in widespread use for gene expression analysis in the clinic. There are over 767,000 RNA microarrays from human samples in public repositories, which are an invaluable resource for biomedical research and personalized medicine. The absolute gene expression analysis allows the transcriptome profiling of all expressed genes under a specific biological condition without the need of a reference sample. However, the background fluorescence represents a challenge to determine the absolute gene expression in microarrays. Given that the Y chromosome is absent in female subjects, we used it as a new approach for absolute gene expression analysis in which the fluorescence of the Y chromosome genes of female subjects was used as the background fluorescence for all the probes in the microarray. This fluorescence was used to establish an absolute gene expression threshold, allowing the differentiation between expressed and non expressed genes in microarrays. Methods: We extracted the RNA from 16 children leukocyte samples (nine males and seven females, ages 6-10 years). An Affymetrix Gene Chip Human Gene 1.0 ST Array was carried out for each sample and the fluorescence of 124 genes of the Y chromosome was used to calculate the absolute gene expression threshold. After that, several expressed and non-expressed genes according to our absolute gene expression threshold were compared against the expression obtained using real-time quantitative polymerase chain reaction (RT qPCR). Results: From the 124 genes of the Y chromosome, three genes (DDX3Y, TXLNG2P and EIF1AY) that displayed significant differences between sexes were used to calculate the absolute gene expression threshold. Using this threshold, we selected 13 expressed and non-expressed genes and confirmed their expression level by RT-qPCR. Then, we selected the top 5% most expressed genes and found that several KEGG pathways were significantly enriched. Interestingly, these pathways were related to the typical functions of leukocytes cells, such as antigen processing and presentation and natural killer cell mediated cytotoxicity. We also applied this method to obtain the absolute gene expression threshold in already published microarray data of liver cells, where the top 5% expressed genes showed an enrichment of typical KEGG pathways for liver cells. Our results suggest that the three selected genes of the Y chromosome can be used to calculate an absolute gene expression threshold, allowing a transcriptome profiling of microarray data without the need of an additional reference experiment. Discussion: Our approach based on the establishment of a threshold for absolute gene expression analysis will allow a new way to analyze thousands of microarrays from public databases. This allows the study of different human diseases without the need of having additional samples for relative expression experiments. PMID- 29230368 TI - Stem-loop structure preference for site-specific RNA editing by APOBEC3A and APOBEC3G. AB - APOBEC3A and APOBEC3G cytidine deaminases inhibit viruses and endogenous retrotransposons. We recently demonstrated the novel cellular C-to-U RNA editing function of APOBEC3A and APOBEC3G. Both enzymes deaminate single-stranded DNAs at multiple TC or CC nucleotide sequences, but edit only a select set of RNAs, often at a single TC or CC nucleotide sequence. To examine the specific site preference for APOBEC3A and -3G-mediated RNA editing, we performed mutagenesis studies of the endogenous cellular RNA substrates of both proteins. We demonstrate that both enzymes prefer RNA substrates that have a predicted stem-loop with the reactive C at the 3'-end of the loop. The size of the loop, the nucleotides immediately 5' to the target cytosine and stability of the stem have a major impact on the level of RNA editing. Our findings show that both sequence and secondary structure are preferred for RNA editing by APOBEC3A and -3G, and suggest an explanation for substrate and site-specificity of RNA editing by APOBEC3A and -3G enzymes. PMID- 29230369 TI - Microcos magnifica (Sparrmanniaceae) a new species of cloudforest tree from Cameroon. AB - Background: Although many new species to science have been discovered from thousands of specimens resulting from botanical inventories to support conservation management in Cameroon in recent years, additional species remain to be formally evaluated taxonomically and described. These include species from genera which have been taxonomically neglected for many decades in Africa, such as Microcos. Methods: This study is based mainly on herbarium specimens and field observations made in Cameroon during a series of botanical surveys. Herbarium material was examined with a Leica Wild M8 dissecting binocular microscope fitted with an eyepiece graticule. Principal Findings: Microcos magnifica Cheek (Malvaceae-Grewioideae or Sparrmanniaceae) is described as an Endangered (EN B2 ab(iii)) new tree species from the submontane forests of Cameroon. It is illustrated and described, and its conservation status and taxonomic affinities are assessed. It is the first new Microcos described from Africa in more than 90 years and is unique on the continent in having sculptured fruits. Discussion: A systematic revision, with a molecular phylogenetic study, of Microcos Burm. ex L. in Africa is necessary if the affinities of the species, including M. magnifica, are to be reliably established. PMID- 29230370 TI - Cell wall composition and lignin biosynthetic gene expression along a developmental gradient in an Australian sugarcane cultivar. AB - Sugarcane bagasse is an abundant source of lignocellulosic material for bioethanol production. Utilisation of bagasse for biofuel production would be environmentally and economically beneficial, but the recalcitrance of lignin continues to provide a challenge. Further understanding of lignin production in specific cultivars will provide a basis for modification of genomes for the production of phenotypes with improved processing characteristics. Here we evaluated the expression profile of lignin biosynthetic genes and the cell wall composition along a developmental gradient in KQ228 sugarcane. The expression levels of nine lignin biosynthesis genes were quantified in five stem sections of increasing maturity and in root tissue. Two distinct expression patterns were seen. The first saw highest gene expression in the youngest tissue, with expression decreasing as tissue matured. The second pattern saw little to no change in transcription levels across the developmental gradient. Cell wall compositional analysis of the stem sections showed total lignin content to be significantly higher in more mature tissue than in the youngest section assessed. There were no changes in structural carbohydrates across developmental sections. These gene expression and cell wall compositional patterns can be used, along with other work in grasses, to inform biotechnological approaches to crop improvement for lignocellulosic biofuel production. PMID- 29230371 TI - Mass marking of juvenile Schizothorax wangchiachii (Fang) with alizarin red S and evaluation of stock enhancement in the Jinping area of the Yalong River. AB - Schizothorax wangchiachii is a key fish species in the stock enhancement program of the Yalong River hydropower project, China. Alizarin red S (ARS) was used to mark large numbers of juvenile S. wangchiachii in the Jinping Hatchery and later used to evaluate stock enhancement in the Jinping area of the Yalong River. In a small-scale pilot study, 7,000 juveniles of the 2014 cohort were successfully marked by immersion in ARS solution, and no mortality was recorded during the marking process. The ARS mark in the fish otoliths remained visible 20 months later. In the large-scale marking study, approximately 600,000 juveniles of the 2015 cohort were successfully marked. Mortalities of both marked and unmarked juveniles were very low and did not differ significantly. Total length, wet mass and condition factor did not differ significantly between unmarked and marked individuals after three months. On 24 July 2015, about 840,000 Jinping Hatchery produced young S. wangchiachii, including 400,000 marked individuals, were released at two sites in the Jinping area. Recapture surveys showed that (1) marked and unmarked S. wangchiachii did not differ significantly in total length, wet mass and condition factor; (2) stocked individuals became an important part of recruitment of the 2015 cohort; (3) instantaneous growth rate of marked individuals tended to slightly increase; and (4) most stocked individuals were distributed along a 10-15 km stretch near the release sites. These results suggest that the ARS method is a cost-efficient way to mass mark juvenile S. wangchiachii and that releasing juveniles is an effective means of stock recruitment. PMID- 29230372 TI - Integrated downstream regulation by the quorum-sensing controlled transcription factors LrhA and RcsA impacts phenotypic outputs associated with virulence in the phytopathogen Pantoea stewartii subsp. stewartii. AB - Pantoea stewartii subsp. stewartii is a Gram-negative proteobacterium that causes leaf blight and Stewart's wilt disease in corn. Quorum sensing (QS) controls bacterial exopolysaccharide production that blocks water transport in the plant xylem at high bacterial densities during the later stage of the infection, resulting in wilt. At low cell density the key master QS regulator in P. stewartii, EsaR, directly represses rcsA, encoding an activator of capsule biosynthesis genes, but activates lrhA, encoding a transcription factor that regulates surface motility. Both RcsA and LrhA have been shown to play a role in plant virulence. In this study, additional information about the downstream targets of LrhA and its interaction with RcsA was determined. A transcriptional fusion assay revealed autorepression of LrhA in P. stewartii and electrophoretic mobility shift assays (EMSA) using purified LrhA confirmed that LrhA binds to its own promoter. In addition, LrhA binds to the promoter for the RcsA gene, as well as those for putative fimbrial subunits and biosurfactant production enzymes in P. stewartii, but not to the flhDC promoter, which is the main direct target of LrhA in Escherichia coli. This work led to a reexamination of the physiological function of RcsA in P. stewartii and the discovery that it also plays a role in surface motility. These findings are broadening our understanding of the coordinated regulatory cascades utilized in the phytopathogen P. stewartii. PMID- 29230374 TI - The tetrapod fauna of the upper Permian Naobaogou Formation of China: 1. Shiguaignathus wangi gen. et sp. nov., the first akidnognathid therocephalian from China. AB - The Permian from China has a well-known terrestrial record where approximately 30 tetrapod taxa, including several therapsids, have been described. However, the record of therocephalians in China has remained elusive. Shiguaignathus wangi gen. et sp. nov., discovered in the Member III of the Naobaogou Formation, Nei Mongol, China, is here described. This is the first therocephalian recovered from this fauna and only the second from the Permian of China. It is represented by a well-preserved robust snout of a medium-sized animal. This is the first akidnognathid reported from the Chinese Permian and only the second genus from Laurasia as one genus is known from Russia whereas the remaining members of the group are from the South African Karoo Basin. A phylogenetic analysis of therocephalians supports a basal position of S. wangi within Akidnognathidae, followed by the Russian Annatherapsidus. Akidnognathidae is the latest major group of therocephalian appearing in the fossil record, and one of the few that does not have species from South Africa representing its most basal members. PMID- 29230373 TI - Epigenetic considerations in aquaculture. AB - Epigenetics has attracted considerable attention with respect to its potential value in many areas of agricultural production, particularly under conditions where the environment can be manipulated or natural variation exists. Here we introduce key concepts and definitions of epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNA, review the current understanding of epigenetics in both fish and shellfish, and propose key areas of aquaculture where epigenetics could be applied. The first key area is environmental manipulation, where the intention is to induce an 'epigenetic memory' either within or between generations to produce a desired phenotype. The second key area is epigenetic selection, which, alone or combined with genetic selection, may increase the reliability of producing animals with desired phenotypes. Based on aspects of life history and husbandry practices in aquaculture species, the application of epigenetic knowledge could significantly affect the productivity and sustainability of aquaculture practices. Conversely, clarifying the role of epigenetic mechanisms in aquaculture species may upend traditional assumptions about selection practices. Ultimately, there are still many unanswered questions regarding how epigenetic mechanisms might be leveraged in aquaculture. PMID- 29230375 TI - The impact of choosing words carefully: an online investigation into imaging reporting strategies and best practice care for low back pain. AB - Background: Low back pain clinical practice guidelines consistently recommend against the routine ordering of spinal imaging; however, imaging is frequently requested in primary care, without evidence of benefit. Imaging reports frequently identify degenerative features which are likely to be interpreted as 'abnormal', despite their high prevalence in symptom-free individuals. The aim of this study was to investigate whether post-imaging back-related perceptions are influenced by providing prior information about normal findings, and to compare the effect of receiving imaging results with best practice care (without imaging). The impact of introducing novel, 'enhanced' reporting strategies was also explored. Methods: This study was a simulated-patient, randomised, multiple arm experiment. Patient scenarios were presented to volunteer healthy adult participants via an online survey. In the scenarios, 'virtual' patients with low back pain were randomised to one of three groups. Group 1 received imaging and was pre-informed about normal findings. Group 2 received imaging (without pre information). Group 3 received best practice care: quality information without imaging. Group 1 was further divided to receive either a standard report, or an 'enhanced' report (containing altered terminology and epidemiological information). The primary outcome was back-related perceptions (BRP), a composite score derived from three numeric rating scale scores exploring perceptions of spinal condition, recovery concerns and planned activity. The secondary outcomes were satisfaction and kinesiophobia. Results: Full data were available from 660 participants (68% female). Analysis of covariance revealed a significant effect of group after controlling for baseline BRP scores [Formula: see text]. Pairwise comparisons indicated that receiving best practice care resulted in more positive BRPs than receiving imaging results, and receiving prior information about normal findings had no impact. Enhanced reporting strategies also positively impacted BRPs [Formula: see text]. Significant relationships between group allocation and both satisfaction [Formula: see text] and kinaesiophobia [Formula: see text] were found, with statistically significant pairwise comparisions again in favour of best-practice care. Conclusion: Intervention strategies such as enhanced reporting methods and the provision of quality information (without imaging) have the potential to improve the outcome of patients with recent-onset LBP and should be further considered by primary care providers. PMID- 29230376 TI - Population structure and phenotypic variation of Sclerotinia sclerotiorum from dry bean (Phaseolus vulgaris) in the United States. AB - The ascomycete pathogen Sclerotinia sclerotiorum is a necrotrophic pathogen on over 400 known host plants, and is the causal agent of white mold on dry bean. Currently, there are no known cultivars of dry bean with complete resistance to white mold. For more than 20 years, bean breeders have been using white mold screening nurseries (wmn) with natural populations of S. sclerotiorum to screen new cultivars for resistance. It is thus important to know if the genetic diversity in populations of S. sclerotiorum within these nurseries (a) reflect the genetic diversity of the populations in the surrounding region and (b) are stable over time. Furthermore, previous studies have investigated the correlation between mycelial compatibility groups (MCG) and multilocus haplotypes (MLH), but none have formally tested these patterns. We genotyped 366 isolates of S. sclerotiorum from producer fields and wmn surveyed over 10 years in 2003-2012 representing 11 states in the United States of America, Australia, France, and Mexico at 11 microsatellite loci resulting in 165 MLHs. Populations were loosely structured over space and time based on analysis of molecular variance and discriminant analysis of principal components, but not by cultivar, aggressiveness, or field source. Of all the regions tested, only Mexico (n = 18) shared no MLHs with any other region. Using a bipartite network-based approach, we found no evidence that the MCGs accurately represent MLHs. Our study suggests that breeders should continue to test dry bean lines in several wmn across the United States to account for both the phenotypic and genotypic variation that exists across regions. PMID- 29230377 TI - Clinical significance of circulating immune cells in left- and right-sided colon cancer. AB - Background: Left-sided and right-sided colon cancers (LCCs and RCCs, respectively) differ in their epidemiology, pathogenesis, genetic and epigenetic alterations, molecular pathways and prognosis. Notably, immune response gene expression profiles have been shown to differ between patients with LCC and patients with RCC. The immune system plays an important role in tumor immunosurveillance, and there is increasing evidence that peripheral blood immune cells have a profound influence on tumor prognosis. This study aimed to determine the clinical significance of circulating immune cells with respect to colon tumor locations. Methods: Different types of circulating immune cells were separated and analysed based on their surface markers by flow cytometry. We compared the numbers of dendritic cells (DCs) and T cell subsets in the peripheral blood of 94 patients with RCC or LCC and analysed the proportions of these immune cells in relation to tumor stage, tumor differentiation and lymphatic metastasis. Results: We show that at later tumor stages, patients with LCC had higher levels of circulating myeloid DCs (P = 0.049) and plasmacytoid DCs (P = 0.018) than patients with RCC. In poorly differentiated tumors, LCC patients had significantly higher amount of plasmacytoid DCs (P = 0.036), CD4+ memory T (Tm) cells (P = 0.012), CD4+ T cells (P = 0.028), Tm cells (P = 0.014), and regulatory T cells (P = 0.001) than RCC patients. The levels of circulating CD4+ T cells, Tm cells and CD4+ Tm cells were significantly elevated at later stages in patients with LCC or RCC, while these cells decreased in poorly differentiated tumors in patients with RCC. Moreover, CD4+ Tm cell and CD4+ T cell levels are significantly associated with lymph node metastasis in patients with LCC and RCC. Discussion: Circulating immune cells were associated with tumor location, tumor stage and tumor differentiation, and can be used to predict lymphatic metastasis in patients with colon cancer. This variation in systemic immunity could contribute to the differential prognosis of patients with colon cancer. PMID- 29230378 TI - Species diversity and drivers of arbuscular mycorrhizal fungal communities in a semi-arid mountain in China. AB - Arbuscular mycorrhizal fungi (AMF) play an essential role in complex ecosystems. However, the species diversity and composition of AMF communities remain unclear in semi-arid mountains. Further, it is not well understood if the characteristics of AMF community assemblies differ for different habitat types, e.g., agricultural arable land, artificial forest land, natural grassland, and bush/wood land. Here, using the high-throughput technology by Illumina sequencing on the MiSeq platform, we explored the species diversity and composition of soil AMF communities among different habitat types in a semi-arid mountain (Taihang Mountain, Mid-western region of China). Then, we analyzed the effect of nutrient composition and soil texture on AMF community assembly. Our results showed that members of the Glomus genera were predominated in all soil types. The distance based redundancy analysis indicated that the content of water, available phosphorus, and available potassium were the most crucial geochemical factors that significantly affected AMF communities (p < 0.05). The analysis of the soil texture confirmed that AMF diversity was negatively correlated with soil clay content. The comparison of AMF diversity among the various habitat types revealed that the artificial forest land had the lowest AMF diversity in comparison with other land types. Our findings suggest that there were differences in species diversity and composition of soil AMF communities among different habitat types. These findings shed new light on the characteristics of community structure and drivers of community assembly in AMF in semi-arid mountains, and point to the potential importance of different habitat types on AMF communities. PMID- 29230379 TI - Cross-cultural and hemispheric laterality effects on the ensemble coding of emotion in facial crowds. AB - In many social situations, we make a snap judgment about crowds of people relying on their overall mood (termed "crowd emotion"). Although reading crowd emotion is critical for interpersonal dynamics, the sociocultural aspects of this process have not been explored. The current study examined how culture modulates the processing of crowd emotion in Korean and American observers. Korean and American (non-East Asian) participants were briefly presented with two groups of faces that were individually varying in emotional expressions and asked to choose which group between the two they would rather avoid. We found that Korean participants were more accurate than American participants overall, in line with the framework on cultural viewpoints: Holistic versus analytic processing in East Asians versus Westerners. Moreover, we found a speed advantage for other-race crowds in both cultural groups. Finally, we found different hemispheric lateralization patterns: American participants were more accurate to perceive the facial crowd to be avoided when it was presented in the left visual field than the right visual field, indicating a right hemisphere advantage for processing crowd emotion of both European American and Korean facial crowds. However, Korean participants showed weak or nonexistent laterality effects, with a slight right hemisphere advantage for European American facial crowds and no advantage in perceiving Korean facial crowds. Instead, Korean participants showed positive emotion bias for own-race faces. This work suggests that culture plays a role in modulating our crowd emotion perception of groups of faces and responses to them. PMID- 29230380 TI - The Axolotl Limb Regeneration Model as a Discovery Tool for Engineering the Stem Cell Niche. AB - Purpose of review: Recent advances in genomics and gene editing have expanded the range of model organisms to include those with interesting biological capabilities such as regeneration. Among these are the classic models of regeneration biology, the salamander. Although stimulating endogenous regeneration in humans likely is many years away, with advances in stem cell biology and biomedical engineering (e.g. bio-inspired materials), it is evident that there is great potential to enhance regenerative outcomes by approaching the problem from an engineering perspective. The question at this point is what do we need to engineer? Recent findings: The value of regeneration models is that they show us how regeneration works, which then can guide efforts to mimic these developmental processes therapeutically. Among these models, the Accessory Limb Model (ALM) was developed in the axolotl as a gain-of-function assay for the sequential steps that are required for successful regeneration. To date, this model has identified a number of proregenerative signals, including growth factor signaling associated with nerves, and signals associated with the extracellular matrix (ECM) that induce pattern formation. Summary: Identification of these signals through the use of models in highly regenerative vertebrates (e.g. the axolotl) offers a wide range of possible modifications for engineering bio inspired, biomimetic materials to create a dynamic stem cell niche for regeneration and scar-free repair. PMID- 29230381 TI - Exploring process variables through which acceptance-based behavioral interventions may improve weight loss maintenance. AB - Objective: A previously published randomized trial with individuals reporting high internal disinhibition showed significant differences in post-treatment weight change favoring Acceptance-Based Behavioral Intervention (ABBI) when compared to standard behavioral treatment (SBT). This paper examines process variables that might contribute to the observed differences in weight change. Methods: Participants were 162 adults with overweight or obesity (mean BMI 37.6) randomly assigned to ABBI or SBT. Both interventions provided the same calorie intake target, exercise goal, and self-monitoring skills training. SBT incorporated current best practice interventions for addressing problematic thoughts and emotions. ABBI utilized acceptance-based techniques based on Acceptance and Commitment Therapy. ABBI and SBT were compared on process measures hypothesized to be related to outcome in ABBI and SBT and their association with weight loss outcomes using linear and non-linear mixed models methods and exploratory correlational analyses. Results: Both the SBT and the ABBI groups showed significant changes over time on all process variables. The only significant between group difference was for values consistent behavior, with the ABBI group improving more as compared to SBT (t=2.45, p=.016); however, changes in values consistent behavior did not mediate weight change. Exploratory analyses suggest the possibility that changes in process variables were less associated with weight change in ABBI than in SBT after treatment was discontinued. Conclusions: Both conditions produced significant changes in process variables, however there was little difference between groups. Thus, the results do not provide an adequate process account for the observed weight change differences between ABBI and SBT, leaving important questions that need to be addressed by future research. PMID- 29230382 TI - Light Rail Leads to More Walking Around Station Areas. AB - Areas around Light Rail Transit (LRT) stations offer ideal conditions for Transit Oriented Development (TOD). Relatively dense, mixed-use neighborhoods can have positive impacts on mobility, health, and perceptions of neighborhood safety among nearby residents, primarily through walking activity for both transit and other purposes. To examine how station areas may attract new activity, this study analyzed changes in walking around station areas among people living close to an LRT station before and after the opening of a new transit system. This study examined walking behavior among the subset of 214 participants living within one mile of one of 13 LRT stations from among a sample of residents living close or further away from a new LRT line in Seattle. They completed a survey and a travel log and wore an accelerometer and a GPS for 7 days both before (2008) and after the opening of the Seattle area LRT (2010). Walking bouts were derived using a previously developed algorithm. The main outcome was the individual-level change in the proportion of daily walking within one quarter Euclidean mile of an LRT station. Overall walking decreased from before to after the LRT opening while station area walking did not change significantly, indicating a shift in walking activity to the station areas after the introduction of LRT. Increases in the proportion of station area walking were negatively related to participants' distance between home and the nearest LRT station, peaking at <0.25 mile and decaying beyond >0.75 mile. Male gender, college education, normal weight status, less access to cars, and frequent LRT use were also significantly associated with greater positive changes in the proportion of station area walking. The shift in walking to station areas after the completion of light rail provides evidence that the local proximate population is attracted to station areas, which may potentially benefit both transit use and TOD area economic activity. The residential catchment area for the shift in LRT area walking was < 0.75 mile of the LRT stations. PMID- 29230383 TI - Solitary Extramedullary Plasmacytoma of the Cricoid Cartilage-Case Report. AB - Solitary plasmacytoma (SP) is an extremely rare form of hematologic malignancy that can be classified as solitary bone plasmacytoma or solitary extramedullary plasmacytoma. Here, we report a patient who presented with progressive shortness of breath and foreign body sensation in his throat. Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) demonstrated an abnormal FDG-avid soft tissue mass arising from the larynx involving the cricoid cartilage without additional suspicious lesions. Histology revealed an abundance of plasma cells; immunohistochemistry was positive for CD138 expression and lambda chains, and negative for CD20. Comprehensive imaging studies and panendoscopy of the ENT tract confirmed solitary disease involvement. Following additional systemic work up, a diagnosis of extramedullary plasmacytoma was rendered. The patient underwent definitive radiotherapy using intensity-modulated radiation therapy (total dose of 46 Gy, divided in 23 fractions of 200 cGy). Serial PET/CT showed the stepwise resolution of abnormal FDG uptake and resolution of the cricoid cartilage lesion. With 22 months of follow-up, the patient remains free of disease. We describe the rare case of SP presenting as a FDG-avid hypermetabolic soft tissue mass in the cricoid cartilage, which should be considered in the differential diagnosis of laryngeal tumors. Of note, SP is radiosensitive; favorable outcome can be expected once treated with doses of 40-50 Gy. FDG PET/CT is helpful in diagnosis and response assessment for this disease. PMID- 29230384 TI - Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer. AB - Hypoxia-inducible factor 1 alpha (HIF-1alpha) orchestrates cellular adaptation to low oxygen and nutrient-deprived environment and drives progression to malignancy in human solid cancers. Its canonical regulation involves prolyl hydroxylases (PHDs), which in normoxia induce degradation, whereas in hypoxia allow stabilization of HIF-1alpha. However, in certain circumstances, HIF-1alpha regulation goes beyond the actual external oxygen levels and involves PHD independent mechanisms. Here, we gather and discuss the evidence on the non canonical HIF-1alpha regulation, focusing in particular on the consequences of mitochondrial respiratory complexes damage on stabilization of this pleiotropic transcription factor. PMID- 29230386 TI - Three-dimensional surgical simulation for facial asymmetry: soft tissue-, skeleton-, and occlusion-based planning. PMID- 29230385 TI - Urinary Microbiome and Psychological Factors in Women with Overactive Bladder. AB - Objectives: Emerging evidence indicates that alterations to the urinary microbiome are related to lower urinary tract symptoms. Overactive bladder (OAB) is a common disorder with complex etiologies and usually accompanied by psychological diseases. More information concerning the urinary microbiome and psychological factors in OAB is required. The aim of this study was to characterize the female urinary microbiome associated with OAB and investigate the relationships between urinary microbiome and psychological factors. Methods: Thirty women with OAB and 25 asymptomatic controls were recruited and asked to finish the Overactive Bladder Symptom Score, Self-Rating Anxiety Scale and Self Rating Depression Scale. Urine specimens were collected by transurethral catheterization and processed for 16S rRNA gene sequencing using Illumina MiSeq. Sequencing reads were processed using QIIME. LEfSe revealed significant differences in bacterial genera between controls and OAB patients. The relationships between the diversity of the urinary microbiome and psychological scores were identified by Pearson's correlation coefficient. Results: We found that bacterial diversity (Simpson index) and richness (Chao1) were lower in OAB samples compared to controls (P both = 0.038). OAB and control bacterial communities were significantly different (based on weighted UniFrac distance metric, R = 0.064, P = 0.037). LEfSe demonstrated that 7 genera were increased (e.g., Proteus and Aerococcus) and 13 were reduced (e.g., Lactobacillus and Prevotella) in OAB group compared to controls. There were negative correlations between scores on Self-Rating Depression Scale and both richness (Chao1, r = 0.458, P = 0.011) and diversity (Shannon index, r = -0.516, P = 0.003) of urinary microbiome in OAB group. Some bacterial genera of OAB women with anxiety or depression were significantly different from those without. Conclusions: The aberrant urinary microbiome with decreased diversity and richness may have strong implications in pathogenesis and treatment of OAB. Psychological conditions were correlated with characteristics of urinary microbiome in women with OAB. Further research is needed to understand the connection between central nervous system and urinary microbiome. PMID- 29230387 TI - Hyperpigmentation of the hard palate mucosa in a patient with chronic myeloid leukaemia taking imatinib. AB - Background: Imatinib mesylate is an inhibitor of the tyrosine kinase Bcr-Abl and a first-line treatment for Philadelphia chromosome-positive chronic myeloid leukaemia (CML). Dermatological side effects include superficial oedema, pustular eruption, lichenoid reactions, erythroderma, and skin rash. Depigmentation of the skin and/or mucosa is uncommon, and hyperpigmentation is rare. Case presentation: We present the case of a 63-year-old Caucasian male with widespread hyperpigmentation of the hard palate associated with a 9-year history of imatinib therapy to treat CML. He did not complain of any symptoms. Clinical examination did not reveal any abnormal pigmentation of the skin or other region of the oral mucosa. He did not smoke cigarettes or drink alcohol. His medication regimen was a proton pump inhibitor, a beta-blocker, cardioaspirin, atorvastatin, and imatinib 400 mg/day. Histopathologically, melanin and haemosiderin deposits were evident in the lamina propria. The lesion persisted, with no clinical change, through several follow-ups. We reviewed the literature to explore the possible relationship between oral hyperpigmentation and long-term imatinib mesylate treatment. Conclusions: We diagnosed oral pigmentation associated with imatinib intake based on the medical history and clinical features of the pigmented macules. Oral pigmentation may have a variety of causes, and differential diagnosis requires nodal analysis. Clinicians should be aware of possible oral mucosal hyperpigmentation in patients taking imatinib mesylate. Such pigmentation is benign and no treatment is needed, but surveillance is advisable. PMID- 29230388 TI - Blood/Body Fluid Exposure and Needle Stick/Sharp Injury among Nurses Working in Public Hospitals; Southwest Ethiopia. AB - Background: Every health professional around the world is at risk of blood/body fluid exposure and needle stick/sharp injury as a result of exposure to blood or body fluids and needle or sharp injuries. However, the extent of these hazards and their driving forces are not well documented in Ethiopia. Thus, the aim of this study was to assess determinants of blood/body fluid exposure and needle stick/sharp injury among nurses working in Jimma zone, southwest Ethiopia. Methods: An institution-based census was conducted among 318 nurses working in Jimma zone public hospitals from March 10 to 30, 2016. Data were collected by using pretested self-administered questionnaire. Epi info and SPSS were used for data entry and analysis, respectively. Descriptive statistics were done. Bivariate and inter multivariate logistic regression analysis was also carried out to identify predictors of occupational hazards. Results: The overall prevalence of blood/body fluid exposure and needle stick/sharp injury was found to be 249 (78.3%). Blood/body fluid exposure and needle stick/sharp injury incidents were reported by 62.6 and 58.8% of respondents, respectively. Majority of the hazards occurred during morning shift. Being male [AOR: 2.20, 95% confidence interval (CI): 1.09, 4.4], being single (AOR: 2.26, 95% CI: 1.09, 4.69), and having no training on infection prevention (AOR: 5.99, 95% CI: 3.14, 11.41) were positively associated with blood/body fluid exposure and needle stick/sharp injury; while working in chronic illness follow-up clinic (AOR: 0.19, 95% CI: 0.05, 0.71) showed negative association at p value of 0.05. Conclusion: Prevalence of blood/body fluid exposure and needle stick/sharp injury was high among the nurses. The safety of nurses depends directly on the degree to which nurses can identify and control the varied occupational hazards specific to jobs. Thus, working unit specific safety precautions and basic infection prevention in service training might improve nurses' safety practice and thereby decrease the on job hazard. PMID- 29230389 TI - Cyclic Tensile Strain Can Play a Role in Directing both Intramembranous and Endochondral Ossification of Mesenchymal Stem Cells. AB - Successfully regenerating damaged or diseased bone and other joint tissues will require a detailed understanding of how joint specific environmental cues regulate the fate of progenitor cells that are recruited or delivered to the site of injury. The goal of this study was to explore the role of cyclic tensile strain (CTS) in regulating the initiation of mesenchymal stem cell/multipotent stromal cell (MSC) differentiation, and specifically their progression along the endochondral pathway. To this end, we first explored the influence of CTS on the differentiation of MSCs in the absence of any specific growth factor, and secondly, we examined the influence of the long-term application of this mechanical stimulus on markers of endochondral ossification in MSCs maintained in chondrogenic culture conditions. A custom bioreactor was developed to apply uniaxial tensile deformation to bone marrow-derived MSCs encapsulated within physiological relevant 3D fibrin hydrogels. Mechanical loading, applied in the absence of soluble differentiation factors, was found to enhance the expression of both tenogenic (COL1A1) and osteogenic markers (BMP2, RUNX2, and ALPL), while suppressing markers of adipogenesis. No evidence of chondrogenesis was observed, suggesting that CTS can play a role in initiating direct intramembranous ossification. During long-term culture in the presence of a chondrogenic growth factor, CTS was shown to induce MSC re-organization and alignment, increase proteoglycan and collagen production, and to enhance the expression of markers associated with endochondral ossification (BMP2, RUNX2, ALPL, OPN, and COL10A1) in a strain magnitude-dependent manner. Taken together, these findings indicate that tensile loading may play a key role in promoting both intramembranous and endochondral ossification of MSCs in a context-dependent manner. In both cases, this loading-induced promotion of osteogenesis was correlated with an increase in the expression of the osteogenic growth factor BMP2. The results of this study demonstrate the potent role that extrinsic mechanical loading plays in guiding stem cell fate, which must be carefully considered when designing cell and tissue engineering therapies if they are to realize their clinical potential. PMID- 29230390 TI - HER2 Overexpression in Retinoblastoma: A Potential Therapeutic Target? AB - Background: Retinoblastoma (RB) is the most common primary intraocular malignancy. Current therapies are associated with high morbidity in the short- and long-term. Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein detected in 15-30% of breast cancers, but it has also been described in other malignancies. Recently, it has been claimed that a truncated version of this protein is expressed in RB, responsive to directed therapies in vitro. We scored HER2 overexpression in RB tissue samples and discussed its potential clinical utility. Methods: HER2 overexpression was investigated using immunohistochemistry; the overexpression was evaluated with a score ranging from 0 to 3+ according to the membranous staining pattern in archival formalin-fixed, paraffin-embedded RBs. Results: A total of 60 RB cases and a RB cell line (Y79) were considered. The mean age at enucleation was 31.6 +/- 31.5 months. The mean time from diagnosis to enucleation was 11.8 +/- 11.2 months (range 1-44). Five (8%) cases were multifocal. HER2 overexpression was negative in all RB cases (49 cases scored 0 and 11 scored 1+) and in the Y79 cell line. Conclusions: Overall, we were not able to demonstrate the overexpression of HER2. Further studies should clarify and better elucidate the potential role of HER2-targeted therapies in RB. PMID- 29230391 TI - Uterine Histone Secretion Likely Fosters Early Embryo Development So Efforts to Mitigate Histone Cytotoxicity Should Be Cautious. PMID- 29230392 TI - Non-Invasive Monitoring of Cardiac Output in Critical Care Medicine. AB - Critically ill patients require close hemodynamic monitoring to titrate treatment on a regular basis. It allows administering fluid with parsimony and adjusting inotropes and vasoactive drugs when necessary. Although invasive monitoring is considered as the reference method, non-invasive monitoring presents the obvious advantage of being associated with fewer complications, at the expanse of accuracy, precision, and step-response change. A great many methods and devices are now used over the world, and this article focuses on several of them, providing with a brief review of related underlying physical principles and validation articles analysis. Reviewed methods include electrical bioimpedance and bioreactance, respiratory-derived cardiac output (CO) monitoring technique, pulse wave transit time, ultrasound CO monitoring, multimodal algorithmic estimation, and inductance thoracocardiography. Quality criteria with which devices were reviewed included: accuracy (closeness of agreement between a measurement value and a true value of the measured), precision (closeness of agreement between replicate measurements on the same or similar objects under specified conditions), and step response change (delay between physiological change and its indication). Our conclusion is that the offer of non-invasive monitoring has improved in the past few years, even though further developments are needed to provide clinicians with sufficiently accurate devices for routine use, as alternative to invasive monitoring devices. PMID- 29230393 TI - Commentary: Hernia, Mesh, and Topical Antibiotics, Especially Gentamycin: Seeking the Evidence for the Perfect Outcome.... PMID- 29230395 TI - THC Treatment Alters Glutamate Receptor Gene Expression in Human Stem Cell Derived Neurons. AB - Given the cognitive and behavioral effects following in utero Delta9 tetrahydrocannabinol (THC) exposure that have been reported in humans and rodents, it is critical to understand the precise consequences of THC on developing human neurons. Here, we utilize excitatory neurons derived from human induced pluripotent stem cells (hiPSCs), and report that in vitro THC exposure reduced expression of glutamate receptor subunit genes (GRIA1, GRIA2, GRIN2A, and GRIN2B). By expanding these studies across hiPSC-derived neurons from individuals with a variety of genotypes, we believe that a hiPSC-based model will facilitate studies of the interaction of THC exposure and the genetic risk factors underlying neuropsychiatric disease vulnerability. PMID- 29230394 TI - Acetylome of Acinetobacter baumannii SK17 Reveals a Highly-Conserved Modification of Histone-Like Protein HU. AB - Lysine acetylation is a prevalent post-translational modification in both eukaryotes and prokaryotes. Whereas this modification is known to play pivotal roles in eukaryotes, the function and extent of this modification in prokaryotic cells remain largely unexplored. Here we report the acetylome of a pair of antibiotic-sensitive and -resistant nosocomial pathogen Acinetobacter baumannii SK17-S and SK17-R. A total of 145 lysine acetylation sites on 125 proteins was identified, and there are 23 acetylated proteins found in both strains, including histone-like protein HU which was found to be acetylated at Lys13. HU is a dimeric DNA-binding protein critical for maintaining chromosomal architecture and other DNA-dependent functions. To analyze the effects of site-specific acetylation, homogenously Lys13-acetylated HU protein, HU(K13ac) was prepared by genetic code expansion. Whilst not exerting an obvious effect on the oligomeric state, Lys13 acetylation alters both the thermal stability and DNA binding kinetics of HU. Accordingly, this modification likely destabilizes the chromosome structure and regulates bacterial gene transcription. This work indicates that acetyllysine plays an important role in bacterial epigenetics. PMID- 29230396 TI - Altered Expression of Endoplasmic Reticulum Stress-Related Genes in the Middle Frontal Cortex of Subjects with Autism Spectrum Disorder. AB - The endoplasmic reticulum (ER) is an important organelle responsible for the folding and sorting of proteins. Disturbances in ER homeostasis can trigger a cellular response known as the unfolded protein response, leading to accumulation of unfolded or misfolded proteins in the ER lumen called ER stress. A number of recent studies suggest that mutations in autism spectrum disorder (ASD) susceptible synaptic genes induce ER stress. However, it is not known whether ER stress-related genes are altered in the brain of ASD subjects. In the present study, we investigated the mRNA expression of ER stress-related genes (ATF4, ATF6, PERK, XBP1, sXBP1, CHOP, and IRE1) in the postmortem middle frontal gyrus of ASD and control subjects. RT-PCR analysis showed significant increases in the mRNA levels of ATF4, ATF6, PERK, XBP1, CHOP, and IRE1 in the middle frontal gyrus of ASD subjects. In addition, we found a significant positive association of mRNA levels of ER stress genes with the diagnostic score for stereotyped behavior in ASD subjects. These results, for the first time, provide the evidence of the dysregulation of ER stress genes in the brain of subjects with ASD. PMID- 29230397 TI - Circuitry-Based Human Neuroanatomy for the Next Generation in Psychiatry and Neuroscience. PMID- 29230398 TI - Insulin Signaling Deficiency Produces Immobility in Caenorhabditis elegans That Models Diminished Motivation States in Man and Responds to Antidepressants. AB - Defects in insulin signaling have been reported in schizophrenia and major depressive disorder, which also share certain negative symptoms such as avolition, anhedonia, and apathy. These symptoms reflect diminished motivational states, which have been modeled in rodents as increased immobility in the forced swimming test. We have discovered that loss-of-function mutations in the insulin receptor (daf-2) and syntaxin (unc-64) genes in Caenorhabditis elegans, brief food deprivation, and exposure to DMSO produce immobility and avolition in non dauer adults. The animals remain responsive to external stimuli; however, they fail to forage and will remain in place for >12 days or until they die. Their immobility can be prevented with drugs used to treat depression and schizophrenia and that reduce immobility in the forced swimming test. This includes amitriptyline, amoxapine, clozapine, and olanzapine, but not benzodiazepines and haloperidol. Recovery experiments confirm that immobility is induced and maintained by excessive signaling via serotonergic and muscarinic cholinergic pathways. The immobility response described here represents a potential protophenotype for avolition/anhedonia in man. This work may provide clues about why there is a significant increase in depression in patients with diabetes and suggest new therapeutic pathways for disorders featuring diminished motivation as a prominent symptom. PMID- 29230400 TI - Perspectives of Post-Acute Transition of Care for Cardiac Surgery Patients. AB - Post-acute care (PAC) facilities improve patient recovery, as measured by activities of daily living, rehabilitation, hospital readmission, and survival rates. Seamless transitions between discharge and PAC settings continue to be challenges that hamper patient outcomes, specifically problems with effective communication and coordination between hospitals and PAC facilities at patient discharge, patient adherence and access to cardiac rehabilitation (CR) services, caregiver burden, and the financial impact of care. The objective of this review is to examine existing models of cardiac transitional care, identify major challenges and social factors that affect PAC, and analyze the impact of current transitional care efforts and strategies implemented to improve health outcomes in this patient population. We intend to discuss successful methods to address the following aspects: hospital-PAC linkages, improved discharge planning, caregiver burden, and CR access and utilization through patient-centered programs. Regular home visits by healthcare providers result in decreased hospital readmission rates for patients utilizing home healthcare while improved hospital-PAC linkages reduced hospital readmissions by 25%. We conclude that widespread adoption of improvements in transitional care will play a key role in patient recovery and decrease hospital readmission, morbidity, and mortality. PMID- 29230399 TI - Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature. AB - Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD. PMID- 29230401 TI - Shiga Toxin-Producing Escherichia coli O157 Shedding Dynamics in an Australian Beef Herd. AB - Shiga toxin-producing Escherichia coli (STEC) O157 is an important foodborne pathogen that can be transmitted to humans both directly and indirectly from the feces of beef cattle, its primary reservoir. Numerous studies have investigated the shedding dynamics of E. coli O157 by beef cattle; however, the spatiotemporal trends of shedding are still not well understood. Molecular tools can increase the resolution through the use of strain typing to explore transmission dynamics within and between herds and identify strain-specific characteristics that may influence pathogenicity and spread. Previously, the shedding dynamics and molecular diversity, through the use of multilocus variable number of tandem repeat analysis (MLVA) of STEC O157, were separately investigated in an Australian beef herd over a 9-month study period. Variation in shedding was observed over time, and 33 MLVA types were identified. The study presented here combines the two datasets previously published with an aim to clarify the relationship between epidemiological variables and strain types. Three major genetic clusters (GCs) were identified that were significantly associated with the location of the cattle in different paddocks. No significant association between GCs and individual cow was observed. Results from this molecular epidemiological study provide evidence for herd-level clonal replacement over time that may have been triggered by movement to a new paddock. In conclusion, this study has provided further insight into STEC O157 shedding dynamics and pathogen transmission. Knowledge gaps remain regarding the relationship of strain types and the shedding dynamics of STEC O157 by beef cattle that could be further clarified through the use of whole-genome sequencing. PMID- 29230402 TI - Animal Health Surveillance in Scotland in 2030: Using Scenario Planning to Develop Strategies in the Context of "Brexit". AB - Animal health surveillance is necessary to protect human and animal health, rural economies, and the environment from the consequences of large-scale disease outbreaks. In Scotland, since the Kinnaird review in 2011, efforts have been made to engage with stakeholders to ensure that the strategic goals of surveillance are better aligned with the needs of the end-users and other beneficiaries. The aims of this study were to engage with Scottish surveillance stakeholders and multidisciplinary experts to inform the future long-term strategy for animal health surveillance in Scotland. In this paper, we describe the use of scenario planning as an effective tool for the creation and exploration of five plausible long-term futures; we describe prioritization of critical drivers of change (i.e., international trade policy, data-sharing philosophies, and public versus private resourcing of surveillance capacity) that will unpredictably influence the future implementation of animal health surveillance activities. We present 10 participant-developed strategies to support 3 long-term visions to improve future resilience of animal health surveillance and contingency planning for animal and zoonotic disease outbreaks in Scotland. In the absence of any certainty about the nature of post-Brexit trade agreements for agriculture, participants considered the best investments for long-term resilience to include data collection strategies to improve animal health benchmarking, user-benefit strategies to improve digital literacy in farming communities, and investment strategies to increase veterinary and scientific research capacity in rural areas. This is the first scenario planning study to explore stakeholder beliefs and perceptions about important environmental, technological, societal, political, and legal drivers (in addition to epidemiological "risk factors") and effective strategies to manage future uncertainties for both the Scottish livestock industry and animal health surveillance after Brexit. This insight from stakeholders is important to improve uptake and implementation of animal heath surveillance activities and the future resilience of the livestock industry. The conclusions drawn from this study are applicable not only to Scotland but to other countries and international organizations involved in global animal health surveillance activities. PMID- 29230403 TI - Farmer and Veterinarian Attitudes towards the Bovine Tuberculosis Eradication Programme in Spain: What Is Going on in the Field? AB - The effectiveness of health interventions against bovine tuberculosis (bTB) is influenced by several "non-biological" factors that may hamper bTB detection and control. Although the engagement of stakeholders is a key factor for the eradication programme's success, social factors have been often ignored in the control programmes of animal diseases, especially in developed countries. In this study, we used a qualitative approach to investigate perceptions, opinions, attitudes, and beliefs of farmers, and veterinarians who may influence the effectiveness of the Spanish bTB eradication programme. The study was carried out in two phases. First, 13 key representatives of different groups involved in the programme were interviewed through exploratory interviews to identify most relevant themes circulating in the population. Interviews focused on strong and weak points of the programme; reasons for failure to achieve eradication; benefits of being disease free; future perspectives, and proposed changes to the programme. Based on these results, a thematic guide was developed and detailed information was gained through face-to-face in-depth interviews conducted on a purposive sample of 39 farmers and veterinarians. Data were analysed following an ethnographic methodology. Main results suggested that the bTB programme is perceived as a law enforcement duty without an adequate motivation of some stakeholders and a general feeling of distrust arose. The complexity of bTB epidemiology combined with gaps in knowledge and weak communication throughout stakeholders contributed to causing disbeliefs, which in turn generated different kinds of guesses and interpretations. Low reliability in the routine skin test for bTB screening was expressed and the level of confidence on test results interpretation was linked with skills and experience of public and private veterinarians in the field. Lack of training for farmers and pressure faced by veterinarians during field activities also emerged. Few benefits of being bTB free were perceived and comparative grievances referred to wildlife and other domestic reservoirs, sector-specific legislation for bullfighting farms, and the absence of specific health legislation for game hunting farms were reported. Understanding reasons for demotivation and scepticism may help institutions to ensure stakeholders' collaboration and increase the acceptability of control measures leading to an earlier achievement of eradication. PMID- 29230404 TI - Experimental Gait Analysis to Study Stress Distribution of the Human Foot. AB - Researchers and clinicians are increasingly using plantar pressure and force measurement system to evaluate foot functions. This research evaluates the quality and reliability of a Tekscan HR mat to study the plantar pressures and forces acting during walking, running, jumping, and standing of healthy subjects. The following regions of the foot were investigated: heel, mid foot, metatarsophalangeal joint, hallux, and the toes. The arches of both feet of the three healthy subjects in the gait analysis were presented which addresses the balancing issues of the body during locomotion. The results indicated that the peaks at the big toe (79.4 +/- 8.5 N/cm2, p = 0.0001) were the maximum compared to forefoot (40.3 +/- 3.3 N/cm2, p = 0.001), to midfoot (7.5 +/- 1.3 N/cm2, p = 0.001), and to heel (27.8 +/- 3.9 N/cm2, p = 0.0002) for jump activity. The running activity demonstrated similar results as jump where the maximum peak pressures were absorbed at the big toe region. The heel region during running (86.3 +/- 12.6 N/cm2, p = 0.001) showed three times the pressure peak compared to the jump land (27.8 +/- 3.9 N/cm2, p = 0.0002) activity. The measurement system proved to be highly capable of detecting heel strike and toe-off moments. PMID- 29230405 TI - Variability of Chemical Compositions and Antimicrobial and Antioxidant Activities of Ruta chalepensis Leaf Essential Oils from Three Palestinian Regions. AB - Introduction: Interest in essential oils was recently revived with their popularity increasing in medicine, pharmacy, and aromatherapy. This study was performed to identify the chemical compositions of the essential oil of Ruta chalepensis growing wildly in three regions in Palestine and to assess and compare their antimicrobial and antioxidant activities. Methods: Identification of the essential oil was performed by gas chromatography coupled with mass spectrometry (GC-MS). Antimicrobial activity was tested against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Methicillin-Resistant Staphylococcus aureus, and Candida albicans by using minimum inhibitory concentration (MIC) assay, while antioxidant activity was analyzed by using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method. Results: The essential oils of R. chalepensis from Jerusalem and Hebron regions have almost identical components; the major compounds identified were linalyl acetate and beta-linalool; these essential oils exerted potential antioxidant and antibacterial activities. On the other hand, the major components of the plant essential oil from Jenin region were 2-undecanone and 2-nonanone, which exhibited potential antifungal activity. Conclusions: The phytoconstituents and antioxidant and antimicrobial properties of the essential oil of R. chalepensis from different regions in Palestine were established in this study. The obtained results indicate possible applications for R. chalepensis in the treatment of various infectious and noninfectious diseases. PMID- 29230406 TI - Intraoperative Myelography in Transpsoas Lateral Lumbar Interbody Fusion for Degenerative Lumbar Spinal Stenosis: A Preliminary Prospective Study. AB - Aim: To investigate the feasibility and effectiveness of intraoperative myelography in determining adequacy of indirect spinal canal decompression during transpsoas lateral lumbar interbody fusion (LLIF). Methods: Seven patients diagnosed with degenerative lumbar spinal stenosis (DLSS) were prospectively included to this study. All patients underwent LLIF and subsequently received intraoperative myelography to determine the effect of indirect spinal canal decompression, which was visualized in both anterior-posterior and lateral images. Those patients with insufficient indirect canal decompression were further resolved by microendoscopic canal decompression (MECD). Radiological parameters, including stenosis ratio and dural sac area of operated levels, were measured and compared before and after operation. Besides, all patients were followed up for at least one year using visual analogue scale (VAS) for back and leg, Japanese Orthopaedic Association score (JOA), and Oswestry disability index (ODI). Results: Seven patients with 8 operated levels underwent LLIF safely and demonstrated significant symptom relief postoperatively. Five operated levels showed adequate indirect canal decompression intraoperatively, while the remaining three levels did not achieve the adequacy, and their residual stenosis was resolved following MECD. Radiological parameters were improved statistically when compared with preoperation (P < 0.05). Furthermore, neurological symptoms of all patients were also improved significantly (P < 0.05), shown by improved VAS (back and leg), JOA, and ODI at both two-week and one-year follow-up. Conclusions: Intraoperative myelography during LLIF is able to assess adequacy of indirect canal decompression for DLSS, thus promising favorable clinical outcomes. PMID- 29230408 TI - Fungicidal, Corrosive, and Mutational Effects of Polyhexamethylene Biguanide Combined with 1-Bromo-3-chloro-5,5-dimethylimidazolidine-2,4-dione. AB - Background: The disinfectants polyhexamethylene biguanide (PHMB) and 1-bromo-3 chloro-5,5-dimethylimidazolidine-2,4-dione (BCDMH) each have limitations. So far, their combined usage has not been examined. In this study, the fungicidal activity of combined disinfectant using PHMB and BCDMH, named PB, against Candida albicans was evaluated. Methods: Suspension quantitative fungicidal test and viable fungi count were used to test fungicidal effects against C. albicans. Coupon corrosion testing was used to evaluate disinfectants' corrosive effects on stainless steel, copper, and aluminum. The mouse lymphoma assay was used to detect mutations induced by PB. Results and Discussion: Fungicidal activity of the combination of 40 mg/L PHMB and 40 mg/L BCDMH was comparable to, or even better than, those of 600 mg/L PHMB or 640 mg/L BCDMH alone. The combination of 400 mg/L PHMB and 400 mg/L BCDMH exhibited good fungicidal effects in field applications. The combination of 100 mg/L PHMB and 100 mg/L BCDMH did not have corrosive effects on stainless steel and no mutagenic effect was observed under the test conditions. Conclusions: The combination of PHMB and BCDMH has strong fungicidal effects and little metal corrosive and mutagenic effect and can be used as one suitable fungicide for wide household and industrial applications, including shipping containers. PMID- 29230407 TI - Comparison of the Effect of Low-Frequency Repetitive Transcranial Magnetic Stimulation with That of Theta Burst Stimulation on Upper Limb Motor Function in Poststroke Patients. AB - Background: The purpose of this study was to evaluate the difference between the therapeutic effect of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) and that of continuous theta burst stimulation (cTBS), when each is combined with intensive occupational therapy (OT), in poststroke patients with upper limb hemiparesis. Materials and Methods: The study subjects were 103 poststroke patients with upper limb hemiparesis, who were divided into two groups: the LF-rTMS group (n = 71) and the cTBS group (three pulse bursts at 50 Hz) (n = 32). Each subject received 12 sessions of repetitive transcranial magnetic stimulation of 2,400 pulses applied to the nonlesional hemisphere and 240-min intensive OT (two 60-min one-to-one training sessions and two 60-min self training exercises) daily for 15 days. Motor function was evaluated using the Fugl-Meyer Assessment (FMA) and the performance time of the Wolf motor function test (WMFT) was determined on the days of admission and discharge. Results: Both groups showed a significant increase in the FMA score and a short log performance time of the WMFT (p < 0.001), but the increase in the FMA score was higher in the LF-rTMS group than the cTBS group (p < 0.05). Conclusion: We recommend the use of 2400 pulses of LF-rTMS/OT for 2 weeks as treatment for hemiparetic patients. PMID- 29230409 TI - Relationship of Obstructive Sleep Apnoea with Diabetic Retinopathy: A Meta Analysis. AB - Until now, the relationship of obstructive sleep apnoea (OSA) with diabetic retinopathy (DR) was controversial. This meta-analysis was performed to obtain definitive conclusion on this topic. Relevant articles were searched on databases of Pubmed, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI). The articles were selected according to inclusion and exclusion criteria. Odds ratio (OR) with 95% confidence interval (CI) was used to evaluate the relationship of OSA with risk of DR. I2 and P value were used to assess the presence of heterogeneity. I2 >= 50% or P < 0.05 indicated significant heterogeneity. Sensitivity analysis was performed to evaluate the robustness of pooled results. Begg's funnel plot and Egger's regression analysis were adopted to assess publication bias. 6 eligible studies were selected in the present meta analysis. The pooled results indicated that OSA was significantly associated with increased risk of DR (OR = 2.01, 95% CI = 1.49-2.72). Subgroup analysis based on type of diabetes mellitus suggested that OSA was related to DR in both Type 1 and Type 2 diabetes mellitus. Sensitivity analysis demonstrated that pooled results were robust. No significant publication bias was observed (P = 0.128). The results indicate that OSA is related to increased risk of DR. PMID- 29230410 TI - Sera from Visceral Leishmaniasis Patients Display Oxidative Activity and Affect the TNF-alpha Production by Macrophages In Vitro. AB - Mammalian protection against leishmanial infection depends on the development of an effective immune response. Zoonotic visceral leishmaniasis (ZVL) patients are usually unable to mount an effective immune response against the parasite and indeed appear to be severely immunosuppressed. This suppression has strong nonspecific and specific components mediated by serum factors and leishmanicidal activity of infected macrophages, respectively. The lipid profile has been shown to be altered in ZVL patients' sera. This work aimed at (i) determining the HDL, Apo A1, LDL, and VLDL concentrations in ZVL patients' sera; (ii) investigating the oxidative effect of ZVL patients' sera on the beta-carotene matrix; (iii) measuring IL-10, IL-6, IL-12p40, and tumour necrosis factor-alpha (TNF-alpha) concentrations in the macrophage cultures, to which 10% of ZVL patients' serum had been added. Levels of HDL, LDL fraction, and apolipoprotein A1 in ZVL patients' sera were lower than those of healthy individuals' sera, except for the mean level of VLDL. The matrix of beta-carotene and linoleic acid system was oxidized in the presence of ZLV patients' sera. The presence of ZVL patients' sera did not modify the cytokine production of IL-6, IL-12p40, and IL-10 by human macrophages in vitro but TNF-alpha production was altered, probably due to lack of macrophage stimulation by lipoprotein. PMID- 29230411 TI - Rapid Analyses of Polyetheretherketone Wear Characteristics by Accelerated Wear Testing with Microfabricated Surfaces for Artificial Joint Systems. AB - Wear particle-induced biological responses are the major factors resulting in the loosening and then failure of total joint arthroplasties. It is feasible to improve the lubrication and reduce the wear of artificial joint system. Polyetheretherketone (PEEK) is considered as a potential bearing material due to its mechanical characteristics of resistance to fatigue strain. The PEEK wear particles have been indicated to be involved in biological responses in vitro, and further studies regarding the wear phenomena and wear particle generation are needed. In this study, we have established an accelerated wear testing system with microfabricated surfaces. Various contact pressures and lubricants have been utilized in the accelerated wear tests. Our results showed that increasing contact pressure resulted in an increase of wear particle sizes and wear rate, and the size of PEEK wear particles can be controlled by the feature size of microfabricated surfaces. These results provided the information rapidly about factors that affect the morphology and amount of PEEK wear particles and can be applied in the future for application of PEEK on the biological articulation system. PMID- 29230412 TI - Corrigendum to "Topography Prediction of Helical Transmembrane Proteins by a New Modification of the Sliding Window Method". AB - [This corrects the article DOI: 10.1155/2014/921218.]. PMID- 29230413 TI - Establishment and Application of Prostate Cancer Circulating Tumor Cells in the Era of Precision Medicine. AB - Prostate cancer (PC) is the second most common cancer in men and is the fifth leading cause of cancer-related deaths worldwide. Additionally, there is concern for overdiagnosis and overtreatment of PC. Thus, selection of an appropriate candidate for active surveillance as well as more accurate and less invasive tools for monitoring advanced PC is required. Circulating tumor cells (CTCs) have emerged as a liquid biopsy tool; there have been several reports on its role, technologies, and applications to various cancers, including PC. Liquid biopsy using CTCs has been gaining attention as a minimal invasive tool for investigation of biomarkers and for prognosis and assessment of response to therapies in patients with PC. Because of the lower invasiveness of liquid biopsy using CTCs, it can be performed more frequently; accordingly, personalized disease status can be successively determined at serial time points. CTC analysis enables detection of genomic alterations, which is drug-targetable, and it is a potential tool for monitoring response to therapeutic agents in patients with PC. This review focuses on the characteristics, technologies for analysis, and advantages and disadvantages of CTCs as a liquid biopsy tool and their application in PC. Finally, we propose future directions of CTCs. PMID- 29230414 TI - Analysis of the Ocular Refractive State in Fighting Bulls: Astigmatism Prevalence. AB - The purpose of this study was to describe the ocular refractive state (ORS) of fighting bulls. The study consisted of 90 ophthalmological healthy animals (85 in post-mortem and 5 in living conditions, resp.). The ORS of the eyes (2 per animal) was determined using streak retinoscopy. In vivo animals were assessed at a fighting bull farm facility. Post-mortem measurements were carried out at a local arena. The ORS along the horizontal meridian ranged between -1.00 and +2.50 diopters (D), with a mean of +0.66 +/- 0.85 D in post-mortem animals. Values for in vivo conditions were similar (+0.75 +/- 0.46 D). Left and right eyes were highly correlated in both sets (p < 0.001). A fairly good correlation was also observed when comparing living and post-mortem eyes in the same animals. Anisometropia >= 1.00 D was diagnosed in 3 animals. Astigmatism (>=+0.5 D) was detected in 93% of the eyes. To our knowledge, the ORS of the fighting bull has been reported for the first time. Although values vary among individuals, all eyes presented a marked astigmatism. Whereas the horizontal meridian was slightly hyperopic, the vertical meridian was always closer to emmetropia. These results represent a starting point to understand the ocular optics of this kind of animals, which might benefit the selection of animals at the farm before being sent to the bullfighting arena. PMID- 29230415 TI - Hypoxia Induces Apoptosis through HIF-1alpha Signaling Pathway in Human Uterosacral Ligaments of Pelvic Organ Prolapse. AB - The purpose of this study is to evaluate the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in women uterosacral ligament tissues with pelvic organ prolapse and women with normal uterine support structures and illuminate its relationship with apoptosis. Samples were collected from 38 women with pelvic organ prolapse and 31 age matched controls. The expression levels of HIF-1alpha and BNIP3 in the uterosacral ligaments were measured using immunohistochemistry, qRT-PCR, and Western blot. To assess apoptosis we performed TUNEL assay and Western blot analyses. Lastly, the short form of the Pelvic Floor Impact Questionnaire-7 (PFIQ-7) was used to evaluate prognosis of surgical patients and twenty patients finished the follow-up. The expressions of HIF-1alpha and BNIP3 in the uterosacral ligaments were significantly higher in patients with pelvic organ prolapse than in control group. Pearson's correlation test revealed significant positive correlations between HIF-1alpha and apoptosis index. Similarly, Western blot analysis showed the expression of proapoptosis proteins (Bax and Bad), Cytochrome-c, cleaved caspase-3, and caspase-9 in patients with pelvic organ prolapse was upregulated. The PFIQ-7 scores were higher in HIF 1alpha positive group than in the negative group. Hypoxia may contribute to the pathological process of pelvic organ prolapse by increasing apoptosis via activating HIF-1alpha signaling pathway. PMID- 29230416 TI - Legume Consumption and All-Cause and Cardiovascular Disease Mortality. AB - Background: Legume consumption is suggested to have protective effects against cardiovascular disease (CVD) mortality in the general population, but the results have been equivocal. We conducted a meta-analysis of prospective cohort studies to assess the association between legume consumption and risk of CVD mortality and all-cause mortality. Methods and Results: Medline (via Ovid) and EMBASE (via Ovid) databases were searched through April 2017 to identify eligible studies. The two authors independently extracted the data and the adjusted relative risks (RRs) and 95% confidence intervals (CIs) were pooled by using a random-effects model. A total of 6 studies were identified, including the sizes of participants ranging from 23,601 to 59,485 with a sum of 21,8997. Comparing the highest category with the lowest, the pooled RR (95% CI) was 0.96 (0.86-1.06) for CVD mortality and 0.93 (0.87-0.99) for all-cause mortality. Conclusions: Results from the current study show that high legume intakes are associated with lower risk of all-cause mortality. In consideration of the small number of studies, the evidence for assessing relationship between legumes intake and risk of all-cause mortality remains inclusive and warrants further study in the future. Further, consuming legumes does not increase the risk of CVD mortality. PMID- 29230417 TI - Discussion on the Timing of Balloon Occlusion of the Abdominal Aorta during a Caesarean Section in Patients with Pernicious Placenta Previa Complicated with Placenta Accreta. AB - Objective: This paper is aimed at investigating the role and value of the timing of balloon occlusion of the abdominal aorta during caesarean section in patients with pernicious placenta previa complicated with placenta accreta. Methods: 79 cases admitted to the Second Affiliated Hospital of Zhengzhou University from September 2015 to December 2016 were treated with ultrasound mediated abdominal aortic balloon occlusion. Among them, 42 cases, whose balloon occlusion time was selected before the delivery and transverse incision was taken, were group A. The other 37 cases were group B, whose timing of balloon occlusion was selected after the delivery and the uterine incision made trying to avoid the placenta or double incisions. The intraoperative blood loss, utilization of blood, and other indicators were compared between the two groups. Results: The intraoperative blood loss in groups A and B was 413.8 +/- 105.9 ml and 810.3 +/- 180.3 ml, and the utilization of blood products in groups A and B was 30.23% and 89.2%. The total hysterectomy rate was 2.53% (2/79), with no hysterectomies in groups A and 2 cases in group B. Conclusion: The balloon occlusion of the abdominal aorta before the delivery combined with a transverse incision is more effective. PMID- 29230418 TI - An Overview of the Biological Effects of Some Mediterranean Essential Oils on Human Health. AB - Essential oils (EOs), extracted from aromatic plants, are interesting natural products and represent an important part of the traditional pharmacopeia. The use of some EOs as alternative antimicrobial and pharmaceutical agents has attracted considerable interest recently. Most of the EOs and their single constituents have been reported to inhibit several phytopathogens, human pathogens, and insects as well as their effective uses in food and pharmaceutical industries. The current review discussed the chemical composition and bioactivity of some important EOs extracted from some Mediterranean plants and their principal bioactive single constituents. Information has been furnished on the mechanisms, mode of actions, and factors affecting the bioactivity of some single constituents from different Mediterranean plant EOs. The current review gives an insight into some common plant EOs belonging to Lamiaceae, Apiaceae, Rutaceae, and Verbenaceae families commonly growing in Mediterranean region. Further information has been provided about the medical uses of some EOs for several human diseases covering the pharmacological effects (anti-inflammatory, antioxidant, and anticarcinogenic). The antimicrobial effects have been also considered in the current review. Although plant EOs are considered promising natural alternatives for many chemical drugs, they still need more specific research for wide application especially in food and pharmaceutical industries. PMID- 29230419 TI - Proteobacteria: A Common Factor in Human Diseases. AB - Microbiota represents the entire microbial community present in the gut host. It serves several functions establishing a mutualistic relation with the host. Latest years have seen a burst in the number of studies focusing on this topic, in particular on intestinal diseases. In this scenario, Proteobacteria are one of the most abundant phyla, comprising several known human pathogens. This review highlights the latest findings on the role of Proteobacteria not only in intestinal but also in extraintestinal diseases. Indeed, an increasing amount of data identifies Proteobacteria as a possible microbial signature of disease. Several studies demonstrate an increased abundance of members belonging to this phylum in such conditions. Major evidences currently involve metabolic disorders and inflammatory bowel disease. However, more recent studies suggest a role also in lung diseases, such as asthma and chronic obstructive pulmonary disease, but evidences are still scant. Notably, all these conditions are sustained by various degree of inflammation, which thus represents a core aspect of Proteobacteria related diseases. PMID- 29230420 TI - Glycaemic Control after Metformin Discontinuation in Diabetic Patients with a Declining Renal Function. AB - Metformin is contraindicated in diabetic patients with declining renal function. This study examined the glycaemic control in diabetic patients with chronic kidney disease when metformin was discontinued. This was a retrospective study. We screened 2032 diabetic patients who attended the Diabetes Clinic at a tertiary hospital between 1 September 2014 and 30 September 2015. We analyzed the data on 69 patients whom metformin was discontinued due to declining renal function and had a complete 6-month follow-up. There was no significant difference in the HbA1c and body weight at 6-month follow-up compared to baseline after metformin discontinuation. The eGFR was significantly lower at 6-month follow-up compared to baseline. Upon metformin discontinuation, the majority of patients had their diabetes medication uptitrated (in particular insulin or sulphonylurea). Patients with an improved glycaemia at 6-month follow-up had further declined in eGFR compared to patients with worsened glycaemia. 17% of the study patients experienced hypoglycaemia. Upon metformin discontinuation, glycaemic control could be optimised with uptitration but should be balanced against the risk of hypoglycaemia. Further improvement in the glycaemic control might indicate further deterioration in the renal function. PMID- 29230421 TI - Association of Vitamin D Deficiency and Degree of Coronary Artery Disease in Cardiac Patients with Type 2 Diabetes. AB - Several modifiable factors may influence cardiac function in diabetic patients. The aim of the study was to evaluate the influence of vitamin D level on the stage of coronary atherosclerosis in cardiac patients diagnosed with type 2 diabetes. The study was performed in 337 consecutive patients undergoing coronarography. The stage of atherosclerosis was evaluated using Coronary Artery Surgery Study Score. The plasma 25(OH)D concentration was determined by an electrochemiluminescence method. Patients without significant lesions in coronary arteries presented the highest 25(OH)D level, significantly higher than patients with one-, two-, and three-vessel coronary artery disease (CAD) (p < 0.01). Significantly lower level of the 25(OH)D was observed in patients hospitalized due to acute coronary syndrome (ACS) in comparison to patients hospitalized due to stable CAD (p < 0.001). Lower 25(OH)D levels were observed in patients with the history of myocardial infarction (MI) in comparison to patients without previous MI (p < 0.001). In cardiac patients with diabetes, the higher number of stenotic coronary arteries is associated with lower values of the 25(OH)D. A group of male cardiac patients with diabetes with significant stenosis in three coronary arteries, hospitalized due to acute coronary syndrome, with a history of previous MI and hyperlipidemia presented the lowest vitamin D level. PMID- 29230422 TI - Novel Semiquantitative Bone Marrow Oedema Score and Fracture Score for the Magnetic Resonance Imaging Assessment of the Active Charcot Foot in Diabetes. AB - There are no accepted methods to grade bone marrow oedema (BMO) and fracture on magnetic resonance imaging (MRI) scans in Charcot osteoarthropathy. The aim was to devise semiquantitative BMO and fracture scores on foot and ankle MRI scans in diabetic patients with active osteoarthropathy and to assess the agreement in using these scores. Three radiologists assessed 45 scans (Siemens Avanto 1.5T, dedicated foot and ankle coil) and scored independently twenty-two bones (proximal phalanges, medial and lateral sesamoids, metatarsals, tarsals, distal tibial plafond, and medial and lateral malleoli) for BMO (0-no oedema, 1-oedema < 50% of bone volume, and 2-oedema > 50% of bone volume) and fracture (0-no fracture, 1-fracture, and 2-collapse/fragmentation). Interobserver agreement and intraobserver agreement were measured using multilevel modelling and intraclass correlation (ICC). The interobserver agreement for the total BMO and fracture scores was very good (ICC = 0.83, 95% confidence intervals (CI) 0.76, 0.91) and good (ICC = 0.62; 95% CI 0.48, 0.76), respectively. The intraobserver agreement for the total BMO and fracture scores was good (ICC = 0.78, 95% CI 0.6, 0.95) and fair to moderate (ICC = 0.44; 95% CI 0.14, 0.74), respectively. The proposed BMO and fracture scores are reliable and can be used to grade the extent of bone damage in the active Charcot foot. PMID- 29230423 TI - Immune Dysfunction in HIV: A Possible Role for Pro- and Anti-Inflammatory Cytokines in HIV Staging. AB - HIV infection is a chronic infection that almost inevitably progresses to AIDS. The infection is characterized by the deterioration in the immune function leading to opportunistic infections and malignancies. Additionally, there is an associated immune dysfunction characterized by a persistent inflammatory state and unhealthy elaboration of both pro- and anti-inflammatory cytokines. The CD4+ T cell count has been used as a surrogate for the level of immune dysfunction that exists in patients with HIV infection. Eighty-eight (88) patients with HIV infection, forty-four (44) of whom were treatment naive patients and forty-four (44) who were treatment-experienced patients, were recruited. The serum concentrations of cytokines IL-6 and IL-10 were carried out using R&D human Quantikine ELISA kits, while patients' CD4+ T cell counts were evaluated using the Partec easy count kit. The serum IL-6 and IL-10 concentrations were significantly higher among the AR-naive participants compared to the ART experienced group. Additionally, the IL-6 and IL-10 concentrations were higher in patients with lower CD4+ T cell count compared to those with higher cell counts though this was not statistically significant. Also, both IL-6 and IL-10 concentrations were higher in patients with higher WHO clinical staging of disease, significantly so for IL-6. PMID- 29230424 TI - Comparison of Myeloid Cells in Circulation and in the Tumor Microenvironment of Patients with Colorectal and Breast Cancers. AB - We have previously reported levels of myeloid cells in the periphery and in the tumor microenvironment (TME) of patients with primary breast cancer (PBC) and colorectal cancer (CRC). We found that both PBC and CRC patients have significantly higher levels of granulocytic and immature myeloid cells in the TME. Additionally, we reported an expansion of circulating granulocytic myeloid cells in CRC patients, but not in PBC patients. In this report, we compared levels of myeloid cells between these two common cancers and have added data from more cancer patients. We also investigated associations between clinical stage/histological grade of tumors and levels of myeloid cells in cancer patients. We found that although granulocytic myeloid cells were expanded in the TME of both PBC and CRC patients, the levels of these cells were significantly higher in the TME of CRC patients. Moreover, our results indicate that increased levels of circulating granulocytic myeloid cells are associated with poorly differentiated tumors in CRC patients. Taken together, this work suggests that CRC patients may benefit more from the development of therapeutic agents to promote myeloid cell differentiation or inhibition for the reversal of immune suppression. PMID- 29230425 TI - Neuroprotective Potential of Gentongping in Rat Model of Cervical Spondylotic Radiculopathy Targeting PPAR-gamma Pathway. AB - Cervical spondylotic radiculopathy (CSR) is the most general form of spinal degenerative disease and is characterized by pain and numbness of the neck and arm. Gentongping (GTP) granule, as a classical Chinese patent medicine, has been widely used in curing CSR, whereas the underlying mechanism remains unclear. Therefore, the aim of this study is to explore the pharmacological mechanisms of GTP on CSR. The rat model of CSR was induced by spinal cord injury (SCI). Our results showed that GTP could significantly alleviate spontaneous pain as well as ameliorate gait. The HE staining and Western blot results showed that GTP could increase the quantity of motoneuron and enhance the activation of peroxisome proliferator-activated receptor gamma (PPAR-gamma) in the spinal cord tissues. Meanwhile, immunofluorescence staining analysis indicated that GTP could reduce the expression of TNF-alpha in the spinal cord tissues. Furthermore, the protein level of Bax was decreased whereas the protein levels of Bcl-2 and NF200 were increased after the GTP treatment. These findings demonstrated that GTP might modulate the PPAR-gamma pathway by inhibiting the inflammatory response and apoptosis as well as by protecting the cytoskeletal integrity of the spinal cord, ultimately play a neuroprotective role in CSR. PMID- 29230426 TI - Lateral Patellofemoral Ligament: An Anatomic Study. AB - Background: Medial instability of the patellofemoral joint is a rare but known phenomenon that may result from an incompetent lateral patellofemoral ligament (LPFL). Surgical reconstruction of the LPFL has been described. However, anatomic details of the ligament have not been the subject of scrutiny. Purpose: To describe the anatomic origin and insertion of the LPFL. Study Design: Descriptive laboratory study. Methods: Ten fresh-frozen, unpaired human cadaveric knees (mean age, 57 years) were dissected to identify the LPFL. The dissection was carried out by elevating the iliotibial band to expose the deep capsular layer of the knee joint, followed by a medial parapatellar approach to the knee. Then the quadriceps and patellar tendons were sectioned, and the LPFL was isolated by visualization and palpation. The LPFL was dissected to reveal its origin and insertion; these were measured with respect to the lateral epicondyle and the superior-inferior axis of the lateral patella, respectively. Results: On average, the LPFL had a variable point of origin in location as well as width about the lateral epicondyle. The LPFL originated, on average, 2.6 mm distal (range, 13.1 mm proximal to 11.4 mm distal) and 10.8 mm anterior (range, 7.3 mm posterior to 14.9 mm anterior) to the lateral epicondyle. The LPFL insertion on the patella was more reliably found to be about 45% (range, 23.7%-58.4%) of its lateral articular surface. The insertion on the patella was found to be in the middle third of the lateral patella. Conclusion: The LPFL has an origin that is variable but, on average, was found to be distal and anterior to the lateral epicondyle. The patella insertion was more reliably found to be in the middle third of the lateral patella. These anatomic relationships can help the surgeon reconstruct the LPFL in a more anatomic fashion. Clinical Relevance: Surgeons who are tasked with reconstruction of the LPFL of a patient with idiopathic medial instability or a previous aggressive lateral release of the knee may reference this article to perform an anatomic reconstruction of the LPFL. We hope that having anatomic landmarks for the reconstruction of this ligament permits the surgeon to operate in an efficient manner that allows for the optimal outcome. This is a rare surgical issue, and no studies are available that provide this information. The little information present in the literature does not provide measurements for anatomic reconstruction; rather, it is limited to descriptions of reconstruction techniques that indirectly provide stability on the lateral aspect of the knee. PMID- 29230427 TI - Biomechanical Comparison of Single- Versus Double-Row Capsulolabral Repair for Shoulder Instability: A Review. AB - Background: The glenohumeral joint is the most commonly dislocated joint in the body. Failure rates of capsulolabral repair have been reported to be approximately 8%. Recent focus has been on restoration of the capsulolabral complex by a double-row capsulolabral repair technique in an effort to decrease redislocation rates after arthroscopic capsulolabral repair. Purpose: To present a review of the biomechanical literature comparing single- versus double-row capsulolabral repairs and discuss the previous case series of double-row fixation. Study Design: Narrative review. Methods: A simple review of the literature was performed by PubMed search. Only biomechanical studies comparing single- versus double-row capsulolabral repair were included for review. Only those case series and descriptive techniques with clinical results for double-row repair were included in the discussion. Results: Biomechanical comparisons evaluating the native footprint of the labrum demonstrated significantly superior restoration of the footprint through double-row capsulolabral repair compared with single-row repair. Biomechanical comparisons of contact pressure at the repair interface, fracture displacement in bony Bankart lesion, load to failure, and decreased external rotation (suggestive of increased load to failure) were also significantly in favor of double- versus single-row repair. Recent descriptive techniques and case series of double-row fixation have demonstrated good clinical outcomes; however, no comparative clinical studies between single- and double-row repair have assessed functional outcomes. Conclusion: The superiority of double-row capsulolabral repair versus single-row repair remains uncertain because comparative studies assessing clinical outcomes have yet to be performed. PMID- 29230428 TI - An account from the inside: Examining the emotional impact of qualitative research through the lens of "insider" research. AB - The benefits and challenges of insider positionality have been much written about in relation to qualitative research. However, the specific emotional implications of insider research have been little explored. In this manuscript, I aim to bring the literature on insider positionality to the study of emotion in qualitative research through a reflection on my experiences as a "total insider" conducting interviews for a longitudinal qualitative study examining mental health during the transition to parenthood among sexual minority women. On the basis of this experience, I highlight emotion-related benefits and challenges of my insider positionality, as they pertain both to the quality of the research and to my personal experiences as a qualitative researcher. In particular, I examine the potential benefits of my insider positioning for establishing rapport and my capacity for empathy, and the personal emotional growth and learning that my insider positioning made possible for me. With respect to challenges, I examine how my emotional investment in the researcher-participant relationship influenced my role as a research instrument, and discuss the difficulties I encountered in managing appropriately boundaried relationships and making decisions about self disclosure. I close by highlighting promising avenues for further exploration of the emotional implications of insider research, from the perspectives of both researchers and participants. PMID- 29230429 TI - Cost-Effectiveness Analysis of Probiotic Use to Prevent Clostridium difficile Infection in Hospitalized Adults Receiving Antibiotics. AB - Background: Systematic reviews with meta-analyses and meta-regression suggest that timely probiotic use can prevent Clostridium difficile infection (CDI) in hospitalized adults receiving antibiotics, but the cost effectiveness is unknown. We sought to evaluate the cost effectiveness of probiotic use for prevention of CDI versus no probiotic use in the United States. Methods: We programmed a decision analytic model using published literature and national databases with a 1-year time horizon. The base case was modeled as a hypothetical cohort of hospitalized adults (mean age 68) receiving antibiotics with and without concurrent probiotic administration. Projected outcomes included quality-adjusted life-years (QALYs), costs (2013 US dollars), incremental cost-effectiveness ratios (ICERs; $/QALY), and cost per infection avoided. One-way, two-way, and probabilistic sensitivity analyses were conducted, and scenarios of different age cohorts were considered. The ICERs less than $100000 per QALY were considered cost effective. Results: Probiotic use dominated (more effective and less costly) no probiotic use. Results were sensitive to probiotic efficacy (relative risk <0.73), the baseline risk of CDI (>1.6%), the risk of probiotic-associated bactermia/fungemia (<0.26%), probiotic cost (<$130), and age (>65). In probabilistic sensitivity analysis, at a willingness-to-pay threshold of $100000/QALY, probiotics were the optimal strategy in 69.4% of simulations. Conclusions: Our findings suggest that probiotic use may be a cost-effective strategy to prevent CDI in hospitalized adults receiving antibiotics age 65 or older or when the baseline risk of CDI exceeds 1.6%. PMID- 29230430 TI - Triethylene glycol dimethacrylate: adjuvant properties and effect on cytokine production. AB - Objective: Leakage of monomers from dental fillings due to incomplete curing is very common. The objective of the present study was to examine the cytokine profile in cells exposed to triethyleneglycol dimethacrylate (TEGDMA) and the adjuvant properties of TEGDMA. Materials and methods: Human peripheral blood mononuclear cells were exposed to TEGDMA (500 and 1000 MUM) for 24 h in vitro. Bio-Plex ProTM assays were used for analysis and detection of cytokines. In vivo, BALB/c mice were immunized subcutaneously in the base of the tail with TEGDMA in combination with ovalbumin (OVA). Results: The cytokine levels of IL-8, IL-18, GRO-alpha and MCP-1 were significantly increased for both concentrations. IL 1beta, IL-6 and TNF-alpha was only significantly increased in cultures exposed to 500 MUM TEGDMA. The concentration of TNF-alpha was significantly decreased in cultures exposed to 1000 MUM TEGDMA. Animals immunized with OVA co-administrated with TEGDMA had a significantly higher IgE and IgG anti-OVA antibody levels in blood than animals immunized with OVA only. Conclusions: TEGDMA affects production of proinflammatory cytokines IL-1beta, IL-6, IL-8, IL-18 and TNF alpha. This inflammatogenic capacity renders TEGDMAs adjuvant properties, which may interfere with the homeostasis between the immune system and the indigenous microflora in the oral cavity. PMID- 29230431 TI - Initial Experience and Usage Patterns With the Owlet Smart Sock Monitor in 47,495 Newborns. AB - We report the largest experience, to our knowledge, of home cardiorespiratory monitoring in 47,495 newborns using the novel Owlet Smart Sock (OSS) technology (October 2015 to May 2017). On average, 47,495 newborns were monitored for 6 months, 4.5 d/wk, 9.9 h/d. Continuous readings of oxygen saturation and heart rate were obtained from 39,626 full-term newborns. OSS users were likely first time parents in their 30s with at least a college degree; 37% had a healthcare professional in the family; and 28% were at or below median income level per the US Census Bureau. "Peace of mind" was the reason to own an OSS in 75%, and 82% of parents followed Safe Sleep Guidelines. A total of 94% of parents reported a better quality of sleep. The fast and continuous pace of device adoption and reported experience suggest excellent parental acceptance of the OSS. Prospective studies are warranted to further evaluate its applications in the high-risk newborn population. PMID- 29230432 TI - Case Report of an Adolescent Male With Unexplained Pancytopenia: GATA2-Associated Bone Marrow Failure and Genetic Testing. PMID- 29230434 TI - Compressive 3D ultrasound imaging using a single sensor. AB - Three-dimensional ultrasound is a powerful imaging technique, but it requires thousands of sensors and complex hardware. Very recently, the discovery of compressive sensing has shown that the signal structure can be exploited to reduce the burden posed by traditional sensing requirements. In this spirit, we have designed a simple ultrasound imaging device that can perform three dimensional imaging using just a single ultrasound sensor. Our device makes a compressed measurement of the spatial ultrasound field using a plastic aperture mask placed in front of the ultrasound sensor. The aperture mask ensures that every pixel in the image is uniquely identifiable in the compressed measurement. We demonstrate that this device can successfully image two structured objects placed in water. The need for just one sensor instead of thousands paves the way for cheaper, faster, simpler, and smaller sensing devices and possible new clinical applications. PMID- 29230433 TI - Proangiogenic Activity of Endometrial Epithelial and Stromal Cells in Response to Estradiol in Gelatin Hydrogels. AB - Biomaterial vascularization remains a major focus in the field of tissue engineering. Biomaterial culture of endometrial cells is described as a platform to inform the design of proangiogenic biomaterials. The endometrium undergoes rapid growth and shedding of dense vascular networks during each menstrual cycle mediated via estradiol and progesterone in vivo. Cocultures of endometrial epithelial and stromal cells encapsulated within a methacrylamide-functionalized gelatin hydrogel are employed. It is reported that proangiogenic gene expression profiles and vascular endothelial growth factor production are hormone dependent in endometrial epithelial cells, but that hormone signals have no effect on human telomerase reverse transcriptase (hTERT)-immortalized endometrial stromal cells. This study subsequently examines whether the magnitude of epithelial cell response is sufficient to induce changes in human umbilical vein endothelial cell network formation. Incorporation of endometrial stromal cells improves vessel formation, but co-culture with endometrial epithelial cells leads to a decrease in vascular formation, suggesting the need for stratified cocultures of endometrial epithelial and stromal cells with endothelial cells. Given the transience of hormonal signals within 3D biomaterials, the inclusion of sex hormone binding globulin (SHBG) to alter the bioavailability of estradiol within the hydrogel is reported, demonstrating a strategy to reduce diffusive losses via SHBG-mediated estradiol sequestration. PMID- 29230435 TI - Ultralong relaxation times in bistable hybrid quantum systems. AB - Nonlinear systems, whose outputs are not directly proportional to their inputs, are well known to exhibit many interesting and important phenomena that have profoundly changed our technological landscape over the last 50 years. Recently, the ability to engineer quantum metamaterials through hybridization has allowed us to explore these nonlinear effects in systems with no natural analog. We investigate amplitude bistability, which is one of the most fundamental nonlinear phenomena, in a hybrid system composed of a superconducting resonator inductively coupled to an ensemble of nitrogen-vacancy centers. One of the exciting properties of this spin system is its long spin lifetime, which is many orders of magnitude longer than other relevant time scales of the hybrid system. This allows us to dynamically explore this nonlinear regime of cavity quantum electrodynamics and demonstrate a critical slowing down of the cavity population on the order of several tens of thousands of seconds-a time scale much longer than observed so far for this effect. Our results provide a foundation for future quantum technologies based on nonlinear phenomena. PMID- 29230437 TI - One-step volumetric additive manufacturing of complex polymer structures. AB - Two limitations of additive manufacturing methods that arise from layer-based fabrication are slow speed and geometric constraints (which include poor surface quality). Both limitations are overcome in the work reported here, introducing a new volumetric additive fabrication paradigm that produces photopolymer structures with complex nonperiodic three-dimensional geometries on a time scale of seconds. We implement this approach using holographic patterning of light fields, demonstrate the fabrication of a variety of structures, and study the properties of the light patterns and photosensitive resins required for this fabrication approach. The results indicate that low-absorbing resins containing ~0.1% photoinitiator, illuminated at modest powers (~10 to 100 mW), may be successfully used to build full structures in ~1 to 10 s. PMID- 29230436 TI - Magnetic flux tailoring through Lenz lenses for ultrasmall samples: A new pathway to high-pressure nuclear magnetic resonance. AB - A new pathway to nuclear magnetic resonance (NMR) spectroscopy for picoliter sized samples (including those kept in harsh and extreme environments, particularly in diamond anvil cells) is introduced, using inductively coupled broadband passive electromagnetic lenses, to locally amplify the magnetic field at the isolated sample, leading to an increase in sensitivity. The lenses are adopted for the geometrical restrictions imposed by a toroidal diamond indenter cell and yield signal-to-noise ratios at pressures as high as 72 GPa at initial sample volumes of only 230 pl. The corresponding levels of detection are found to be up to four orders of magnitude lower compared to formerly used solenoidal microcoils. Two-dimensional nutation experiments on long-chained alkanes, CnH2n+2 (n = 16 to 24), as well as homonuclear correlation spectroscopy on thymine, C5H6N2O2, were used to demonstrate the feasibility of this approach for higher dimensional NMR experiments, with a spectral resolution of at least 2 parts per million. This approach opens up the field of ultrahigh-pressure sciences to one of the most versatile spectroscopic methods available in a pressure range unprecedented up to now. PMID- 29230438 TI - A Programmable Optical Stimulator for the Drosophila Eye. AB - A programmable optical stimulator for Drosophila eyes is presented. The target application of the stimulator is to induce retinal degeneration in fly photoreceptor cells by exposing them to light in a controlled manner. The goal of this work is to obtain a reproducible system for studying age-related changes in susceptibility to environmental ocular stress. The stimulator uses light emitting diodes and an embedded computer to control illuminance, color (blue or red) and duration in two independent chambers. Further, the stimulator is equipped with per-chamber light and temperature sensors and a fan to monitor light intensity and to control temperature. An ON/OFF temperature control implemented on the embedded computer keeps the temperature from reaching levels that will induce the heat shock stress response in the flies. A custom enclosure was fabricated to house the electronic components of the stimulator. The enclosure provides a light impermeable environment that allows air flow and lets users easily load and unload fly vials. Characterization results show that the fabricated stimulator can produce light at illuminances ranging from 0 to 16000 lux and power density levels from 0 to 7.2 mW/cm2 for blue light. For red light the maximum illuminance is 8000 lux which corresponds to a power density of 3.54 mW/cm2. The fans and the ON/OFF temperature control are able to keep the temperature inside the chambers below 28.17 degrees C. Experiments with white-eye male flies were performed to assess the ability of the fabricated simulator to induce blue light-dependent retinal degeneration. Retinal degeneration is observed in flies exposed to 8 hours of blue light at 7949 lux. Flies in a control experiment with no light exposure show no retinal degeneration. Flies exposed to red light for the similar duration and light intensity (8 hours and 7994 lux) do not show retinal degeneration either. Hence, the fabricated stimulator can be used to create environmental ocular stress using blue light. PMID- 29230439 TI - Ex vivo detection and quantification of gold nanoparticles in human seminal and follicular fluids. AB - Increasing consumption of engineered nanoparticles and occupational exposure to novel, ultrafine airborne particles during the last decades has coincided with deterioration of sperm parameters and delayed fecundity. In order to prevent possible adverse health effects and ensure a sustainable growth for the nanoparticle industry, the ability to investigate the nanosized, mineralogical load of human reproductive systems is becoming a real clinical need. Toward this goal, the current study proposes two methods for the detection and quantification of engineered nanoparticles in human follicular and seminal fluid, developed with the use of well-defined 60 nm Au particles. Despite the complexity of these biological fluids, simple physical and chemical treatments allow for the precise quantification of more than 50 and 70% wt of the spiked Au nanoparticles at low MUg ml-1 levels in follicular and seminal fluids, respectively. The use of electron microscopy for the detailed observation of the detected analytes is also enabled. The proposed method is applied on a small patient cohort in order to demonstrate its clinical applicability by exploring the differences in the metal and particulate content between patients with normal and low sperm count. PMID- 29230440 TI - N-Gemini peptides: cytosolic protease resistance via N-terminal dimerization of unstructured peptides. AB - Herein we describe a synthetically simple strategy for increasing the lifetime of unstructured peptides in cytosolic environment via dimerization at the N-terminus to block threading into the catalytic cleft of cytosolic proteases. We establish this approach with kinase substrates, allowing for phosphorylation in cells as a demonstration of protease resistance. PMID- 29230441 TI - Detection of Abeta plaque-associated astrogliosis in Alzheimer's disease brain by spectroscopic imaging and immunohistochemistry. AB - Recent work using micro-Fourier transform infrared (MUFTIR) imaging has revealed that a lipid-rich layer surrounds many plaques in post-mortem Alzheimer's brain. However, the origin of this lipid layer is not known, nor is its role in the pathogenesis of Alzheimer's disease (AD). Here, we studied the biochemistry of plaques in situ using a model of AD. We combined FTIR, Raman and immunofluorescence images, showing that astrocyte processes co-localise with the lipid ring surrounding many plaques. We used MUFTIR imaging to rapidly measure chemical signatures of plaques over large fields of view, and selected plaques for higher resolution analysis with Raman microscopy. Raman maps showed similar lipid rings and dense protein cores as in FTIR images, but also revealed cell bodies. We confirmed the presence of plaques using amylo-glo staining, and detected astrocytes using immunohistochemistry, revealing astrocyte co localisation with lipid rings. This work is important because it correlates biochemical changes surrounding the plaque with the biological process of astrogliosis. PMID- 29230449 TI - Conducting nanofibres of solvatofluorochromic cyclohexanetrione-dithiolylidene based C3 symmetric molecule. AB - We report a novel set of easily tailorable C3 symmetric molecules with a pi extended core and adorned with different thioalkyl groups, exhibiting solvatofluorochromic and amphoteric redox behaviour. The nearly planar core exhibits intermolecular face-to-face pi-stacking, SS and intramolecular SO interactions. Current-sensing atomic force microscopy studies revealed a high conductivity of ~0.15 mS cm-1 in the undoped J-aggregate nanofibres of the thiopropyl appended gelator. PMID- 29230450 TI - Charge evolution during the unfolding of a single DNA i-motif. AB - The effective charge and evolution of single chains of a DNA i-motif during its unfolding process are investigated at the single molecule level. Using fluorescence correlation spectroscopy and photon counting histograms, the single chain dimensions and electrical potential of cytosine-rich human telomeric oligonucleotides are monitored, during their unfolding from the i-motif to the random coil state. It is discovered that the effective charge density of the DNA chain is very sensitive to conformation changes and the results remarkably expose the existence of an intermediate state of the unfolding process. A huge difference in pH value exists in the vicinity of the DNA chain and the bulk solution, depending on the salt concentration, as reflected by a down-shift in the pH value of unfolding. The presence of an external salt in the solution helps to stabilize the i-motif structure at low pH values due to the reduction of the effective charge density. It can also destabilize the folded structure in the pH range of the conformation transition due to the elevation of the local pH value, encouraging the deprotonation of the cytosine groups. These results provide new information for understanding the structure and stability of i-motif DNA, and its biological function, as well as the building blocks for smart nanomaterials. PMID- 29230451 TI - Energy transfer and charge separation dynamics in photoexcited pyrene-bodipy molecular dyads. AB - The photophysical properties of two pyrene-bodipy molecular dyads, composed of a phenyl-pyrene (Py-Ph) linked to the meso position of a bodipy (BD) molecule with either H-atoms (BD1) or ethyl groups (BD2) at the 2,6 positions, are investigated by stationary, nanosecond and femtosecond spectroscopy. The properties of these dyads (Py-Ph-BD1 and Py-Ph-BD2) are compared to those of their constituent chromophores in two solvents namely 1,2-dichloroethane (DCE) and acetonitrile (ACN). Stationary spectroscopy reveals a weak coupling among the subunits in both dyads. Excitation of the pyrene (Py) subunit leads to emission that is totally governed by the BD subunits in both dyads pointing to excitation energy transfer (EET) from the Py to BD chromophore. Femtosecond fluorescence and transient absorption spectroscopy reveal that EET takes place within 0.3-0.5 ps and is mostly independent of the solvent and the type of the BD subunit. The EET lifetime is in reasonable agreement with that predicted by Forster theory. After EET has taken place, Py-Ph-BD1 in DCE and Py-Ph-BD2 in both solvents decay mainly radiatively to the ground state with 3.5-5.0 ns lifetimes which are similar to those of the individual BD chromophores. However, the excited state of Py-Ph-BD1 in ACN is quenched having a lifetime of 1 ns. This points to the opening of an additional non-radiative channel of the excited state of Py-Ph-BD1 in this solvent, most probably charge separation (CS). Target analysis of the TA spectra has shown that the CS follows inverted kinetics and is substantially slower than the recombination of the charge-separated state. Occurrence of CS with Py-Ph-BD1 in ACN is also supported by energetic considerations. The above results indicate that only a small change in the structure of the BD units incorporated in the dyads significantly affects the excited state dynamics leading either to a dyad with long lifetime and high fluorescence quantum yield or to a dyad with ability to undergo CS. PMID- 29230453 TI - An organoferroelasticity driven by molecular conformational change. AB - A single crystal of adipic acid shows twinning ferroelasticity by the reversible molecular conformational change. The flexible nature of components in molecular solids raises the efficiency of energy dissipation using organoferroelasticity. PMID- 29230454 TI - Homogeneous electrocatalytic water oxidation at neutral pH by a robust trinuclear copper(ii)-substituted polyoxometalate. AB - [(alpha-SbW9O33)2Cu3(H2O)3]12- (1) was tested as the first copper-containing polyoxometalate catalyst for O2 production via electrocatalytic water oxidation at a neutral pH. Multiple lines of experimental evidence confirm that catalytic water oxidation by 1 takes place in the absence of any heterogeneous species generated in situ. The catalytic capabilities of 1 and equal amounts of CuCl2 are completely different for electrocatalytic water oxidation behavior. PMID- 29230455 TI - Mixed ether-based solvents provide a long cycle life with high rate capability to graphite anodes for Na-ion batteries. AB - Energy storage devices using sodium ions have great potential in terms of their low cost, high power, and long life. In particular, there could be a significant cost reduction, because of the abundant resource of sodium. Recently, electro chemical sodium storage performance has been demonstrated in graphite anodes using ether-based solvents. However, the high power and long life were not compatible in the same ether solution. Here, we demonstrated using mixed ether based solvents that a long cycle life and high rate capability can coexist in the graphite anodes for sodium-ion batteries. The cycle performance indicated that the discharge capacity retention ratio after 10 000 cycles was more than 90% and the capability of 4 A g-1/0.2 A g-1 (40C/2C) was more than 75%. These results could advance the development of sodium storage devices for practical use. PMID- 29230456 TI - The role of charge and proton transfer in fragmentation of hydrogen-bonded nanosystems: the breakup of ammonia clusters upon single photon multi-ionization. AB - The charge and proton dynamics in hydrogen-bonded networks are investigated using ammonia as a model system. The fragmentation dynamics of medium-sized clusters (1 2 nm) upon single photon multi-ionization is studied, by analyzing the momenta of small ionic fragments. The observed fragmentation pattern of the doubly- and triply-charged clusters reveals a spatial anisotropy of emission between fragments (back-to-back). Protonated fragments exhibit a distinct kinematic correlation, indicating a delay between ionization and fragmentation (fission). The different kinematics observed for channels containing protonated and unprotonated species provides possible insights into the prime mechanisms of charge and proton transfer, as well as proton hopping, in such a nanoscale system. PMID- 29230457 TI - Influence of macroscopic defects on the corrosion behavior of U-0.79 wt%Ti alloy in sodium chloride solution. AB - Uranium alloys containing a low concentration of titanium have received wide attention due to their greatly enhanced corrosion resistance and outstanding mechanical performances. Herein, we investigated the effect of macroscopic defects on the corrosion behavior of U-0.79 wt%Ti (denoted as U-Ti) alloy in 0.01 M NaCl solution using traditional electrochemical testing technologies and a novel scanning electrochemical composite probe (SECP). The results demonstrate that pitting corrosion occurs rapidly on the alloy surface due to macroscopic defects. Moreover, macroscopic defects led to a decrease in corrosion potential and polarization resistance, and an increase in corrosion current density. Furthermore, the potential and pH value distributions were detected in the same region using the composite probe. The results show that the region around the macroscopic defects become corrosion-active positions and the potential difference (vs. the average potential of the alloy surface) in this area is significantly higher than that at positions without macroscopic defects, while the opposite was observed for the pH value distribution. In addition, the distribution of the vertical direction (Z) potential at the active point was clearly different from that at the inactive point. A possible reason for this could lie in the difference in the electric field distribution and electrode reaction type between the active point and inactive point on the alloy surface. PMID- 29230458 TI - Three Pd-decavanadates with a controllable molar ratio of Pd to decavanadate and their heterogeneous aerobic oxidation of benzylic C-H bonds. AB - By the combination of Pd-complexes and [V10O28]6-, three Pd-decavanadate compounds [Pd(NH3)4]3[V10O28].8H2O (1), [Pd(deta)(H2O)]2(NH4)2[V10O28].2H2O (2) (deta = diethylenetriamine) and [Pd(dpa)2](Hdpa)2(Et3NH)2[V10O28].2H2O (3) (dpa = 2,2'-dipyridylamine) have been successfully synthesized and thoroughly characterized using single X-ray diffraction (SXRD), powder X-ray diffraction (PXRD), infrared spectroscopy (FT-IR) and elemental analyses (EA). Interestingly, in the three compounds, the molar ratios of Pd to decavanadate vary from 3 : 1 to 1 : 1 by changing N-ligands. The three Pd-decavanadates as heterogeneous catalysts are active in the aerobic oxidation of benzylic hydrocarbons under solvent-free conditions without adding any additives and co-catalysts. Moreover, compound 1 can be reused three times without losing its activity. PMID- 29230460 TI - Bis-meridional Fe2+ spincrossover complexes of phenyl and pyridyl substituted 2 (pyridin-2-yl)-1,10-phenanthrolines. AB - A series of Fe2+ SCO complexes of substituted 2-(pyridin-2-yl)-1,10 phenanthrolines 2 was prepared and the SCO (spincrossover) properties were characterized in the solid state (X-ray crystallography, SQUID magnetometry) and in solution (VT-1H NMR spectroscopy), augmented by theoretical modelling. Bis meridional coordination of the tridendate 2a-c and tetradentate 2d ligands gives octahedral and distorted trigonal-dodecahedral complexes [Fe(2)2]2+, respectively, which were identified as SCO complexes with the transition temperature T1/2 below room temperature. SCO in the solid state is limited to bromo-substituted [Fe(2a)2]2+ (Dalton Trans., 2017, 46, 6218-6229) and [Fe(2b)2]2+ with a pyridine-appended phenyl group, whereas solution state NMR studies reveal SCO behaviour for all complexes, which is in agreement with DFT derived results. As anticipated from its N6(+2) coordination in the HS state, DFT structure modelling of [Fe(2d)2]2+ identified deviation from a structure conserving SCO reaction coordinate; that is, Fe-N breathing is accompanied by a change in the coordination number. Accordingly, a remarkably slow SCO is observed in [Fe(2d)2]2+, owing to an extended coordinate. De-novo defined characteristic temperatures T(tauHSLS) are introduced as structure-dependent parameters deemed to define the onset of phenomenological "slow" SCO. The rich phenomenology of the NMR spectra of [Fe(2)2]2+ is identified to be largely controlled by the dynamics of spin-state exchange and a qualitative illustration of the NMR-reporters of SCO is suggested. PMID- 29230461 TI - Formation of new polymorphs and control of crystallization in molecular glass formers by electric field. AB - Static electric fields were observed to modify the crystallization behavior in a simple supercooled liquid, leading to a new crystal polymorph that could not be obtained in the absence of a field, even under high-pressure conditions. Using different thermal protocols and field amplitudes in the range from 40 to 200 kV cm-1, changes in both nucleation and crystal growth rates of 4-vinyl-propylene carbonate (vinyl-PC) are revealed. Remarkably, all field-induced changes in the crystallization behaviour were found to be fully reversible and do not affect dynamics of the tested liquid. Because vinyl-PC is a simple polar molecule, these field induced features are expected to occur in many other materials having permanent dipole moments. Our results highlight the important role of an external electric field as an additional control variable to influence the crystallization tendency of molecular glass-formers, and provide new opportunities in pharmaceutical science or organic electronics. PMID- 29230462 TI - Synthesis of M-UiO-66 (M = Zr, Ce or Hf) employing 2,5-pyridinedicarboxylic acid as a linker: defect chemistry, framework hydrophilisation and sorption properties. AB - Metal-organic frameworks of general composition [M6(OH)4(O)4(PDC)6 x(Cl)2x(H2O)2x] with M = Zr, Ce, Hf; PDC2- = 2,5-pyridinedicarboxylate and 0 <= x <= 2 were obtained under reflux using formic, nitric or acetic acid as an additive. Rietveld refinements carried out using a fixed occupancy of the linker molecules according to the results of thermogravimetric measurements confirmed that the MOFs crystallize in the UiO-66 type structure and demonstrate that the structural models describe the data well. Further characterization was carried out by NMR spectroscopy, thermogravimetric analysis, Zr K-edge EXAFS- and Ce L3 edge XANES measurements. To highlight the influence of the additional nitrogen atom of the pyridine ring, luminescence and vapour sorption measurements were carried out. The hydrophilisation of the MOFs was shown by the adsorption of water at lower p/p0 (<0.2) values compared to the corresponding BDC-MOFs (0.3). For water and methanol stability cycling adsorption experiments were carried out to evaluate the MOFs as potential adsorbents in heat transformation applications. PMID- 29230463 TI - Real-time two-photon lithography in controlled flow to create a single microparticle array and particle-cluster array for optofluidic imaging. AB - Microarray technology provides an excellent platform for biomedical and biochemical research including basic scientific studies, drug discovery, and diagnostics. Here, we develop a novel method referred to as real-time two-photon lithography in a controlled flow in which femtosecond laser two-photon lithography is performed in situ in the sequential mode stopping and flowing the flow of liquid resin containing microparticles to achieve 100% trapping on a one bead-to-one-trap basis. Polydisperse particles can be all trapped to form a desired array by freely designing trap structures, resulting in an unprecedentedly high capture efficiency of ~100%. No persistent pressure is needed after trapping which reduces the complexity of the system. In addition, trapping of particle-cluster arrays with a controlled number of particles is also achieved via this method. The trapped particles inside the microchip are successfully applied as microlenses for high quality imaging. The present technology marks an essential step towards a versatile platform for the integration of bead-based assays and paves the way for developing innovative microfluidics, optofluidics, micro-optics and single-cell analysis devices. PMID- 29230464 TI - Do protocells preferentially retain macromolecular solutes upon division/fragmentation? A study based on the extrusion of POPC giant vesicles. AB - A key process of protocell behaviour is their recursive growth and division. In order to be sustainable, the latter must be characterized by an even and homogeneous partition of the solute molecules initially present in the parent protocell among the daughter ones. Here we have investigated, by means of an artificial division model (extrusion of giant lipid vesicles) and confocal microscopy, the fate of solutes when a large vesicle fragments into many smaller vesicles. Solutes of low- and high-molecular weight such as pyranine, calcein, albumin-FITC, dextran-FITC and carbonic anhydrase have been employed. Although the vesicle extrusion brings about a release of their inner content in the environment, the results shown in this initial report indicate that macromolecules can be partially retained when compared with low-molecular weight ones. Results are discussed from the viewpoint of the life cycle of primitive cells. In particular, the findings suggest that a similar mechanism operating during the critical step of vesicle growth-division could have contributed to primitive evolution. PMID- 29230465 TI - Metal binding properties of zinc fingers with a naturally altered metal binding site. AB - Zinc fingers (ZFs) are among the most abundant motifs found in proteins, and are commonly known for their structural role. Classical ZFs (CCHH) are part of the transcription factors that participate in DNA binding. Although biochemical studies of classical ZFs have a long history, there is limited knowledge about the sequential and structural diversity of ZFs. We have found that classical ZFs, with metal binding sites consisting of amino acids other than conserved Cys or His residues, are frequently encoded in the human genome, and we refer to these peptides as ZFs with a naturally altered metal binding site. The biological role of the altered ZFs remains undiscovered. In this study, we characterized nine natural XCHH, CXHH, CCXH and CCHX ZFs in terms of their Zn(ii) and Co(ii) binding properties, such as complex stoichiometry, spectroscopic properties and metal-to peptide affinity. We revealed that XCHH and CXHH ZFs form ML complexes that are 4 5 orders of magnitude weaker in comparison to CCHH ZFs. Nevertheless, spectroscopic studies demonstrate that, depending on the altered position, they may adopt an open coordination geometry with one or two water molecules bound to a central metal ion, which has not been demonstrated in natural ZFs before. Stability data show that both CCXH and CCHX peptides have high Zn(ii) affinity (with a Kd of 10-9 to 10-11 M), suggesting their potential biological function. This study is a comprehensive overview of the relationship between the sequence, structure, and stability of ZFs. PMID- 29230466 TI - Synthesis and reactions of 4H-1,4-telluraborine. AB - The B(C6F5)3-catalyzed reaction of the 1,4-telluraborine, Te(PhC[double bond, length as m-dash]C(C6F5))2BOCH2Ph 2 with PhSiH3 gives Te(PhC[double bond, length as m-dash]C(C6F5))2BH 3. Compound 3 acts as a synthetic precursor to Te(PhC[double bond, length as m-dash]C(C6F5))2BCl 4 and Te(PhC[double bond, length as m-dash]C(C6F5))2B(THF)(O3SCF3) 5. In addition, 3 undergoes reactions with alkenes, alkynes, ketones and aldehydes to give a series of hydroboration products, 6-16. PMID- 29230467 TI - In situ synthesis of magnesium hydroxides modified with tripodal ligands in an organic medium. AB - Layered magnesium hydroxides modified organically with tris(hydroxymethyl)aminomethane (Tris-NH2) were directly synthesized from magnesium chloride dissolved in a polar organic solvent, like dimethyl sulfoxide (DMSO), containing a small amount of water. Tris-NH2 acted as a base for precipitating magnesium hydroxides as well as an organic modifier. In contrast to the case of an aqueous solution, the use of organic solvents substantially increased the degree of modification of layered magnesium hydroxides with Tris NH2 owing to the formation of bidentate Mg-O-C linkages by Tris-NH2 in addition to its tridentate bonding mode. Bidentate linkages, hydrolyzed readily in water, are stable in the organic media. Pentaerythritol (Tris-CH2OH), trimethylolethane (Tris-CH3), and trimethylolpropane (Tris-C2H5) were also successfully used for the synthesis of organically-modified layered magnesium hydroxides by the addition of tetrabutylammonium hydroxide as a base with DMSO as the solvent. The synthesis of hybrid magnesium hydroxides in organic solvents is expected to expand the chemistry of organically modified layered metal hydroxides with various metallic species and a wide variety of organic functional groups. PMID- 29230468 TI - Chlorogermylenes and -stannylenes stabilized by diimidosulfinate ligands: synthesis, structures, and reactivity. AB - The reaction of the lithium salt of N,N'-di-tert-butyldiimidosulfinate ([PhS(NtBu)2]Li) having a phenyl group on the sulphur atom with ECl2.(dioxane) (E = Ge, Sn) afforded the corresponding chlorogermylene [PhS(NtBu)2]GeCl 1 and stannylene [PhS(NtBu)2]SnCl 2, respectively. In contrast, treatment of the N,N' bis(trimethylsilyl)diimidosulfinate ion ([PhS(NSiMe3)2]-) with ECl2.(dioxane) resulted in the unexpected formations of six-membered 1,3-bis(chlorogermylene) [PhS(NSiMe3)2(eta1-eta1-GeCl)2[MU-NSPh(NHSiMe3)] 7 and -stannylene [PhS(NSiMe3)2(eta1-eta1-SnCl)2[MU-NSPh(NHSiMe3)] 8. The structures of these chlorometallylene derivatives were fully characterized on the basis of their NMR spectroscopic data and X-ray diffraction. In the crystalline states of 1 and 2, the diimidosulfinate ligands chelate to the metal centre to form slightly hinged four-membered EN2S rings. On the other hand, X-ray analyses of 7 and 8 revealed that the central six-membered E2N3S rings adopt a distorted boat-conformation, and one diimidosulfinate ligand coordinates to the metal centre in a bridging monodentate MU-eta1-eta1-fashion. As the reactivity of 1 and 2, the oxidation of 1 with elemental chalcogen (S8 or Se) afforded the corresponding tetra coordinated germanium compounds [PhS(NtBu)2]Ge([double bond, length as m dash]Ch)Cl 3 (Ch[double bond, length as m-dash]S) and 4 (Ch[double bond, length as m-dash]Se). In sharp contrast, the reactions of 2 with elemental chalcogen resulted in the formation of four-membered Sn2Ch2 ring compounds, 1,3,2,4 dichalcogenadistannetanes {(PhS(NtBu)2)SnCl(MU-Ch)}25 (Ch[double bond, length as m-dash]S) and 6 (Ch[double bond, length as m-dash]Se). PMID- 29230470 TI - Bridged cyclometalated diruthenium complexes for fundamental electron transfer studies and multi-stage redox switching. AB - Four bridged cyclometalated diruthenium systems are highlighted in this Frontier article, including strongly-coupled diruthenium complexes with a short phen-1,4 diyl or a planar pyren-2,7-diyl bridge, redox asymmetric diruthenium complexes characterized by different terminal ligands on the two ends, diruthenium complexes with a urea bridge that allows modulating the degree of electronic coupling, and those with a redox-active amine bridge with varying electronic structures. These complexes posess redox couples with low potentials and intense intervalence charge transfer absorptions in the near-infrared region in the one electron-oxidized mixed-valent state. They are appealing not only for providing a platform for fundamental electron transfer studies but also as molecular materials with multi-stage redox switching properties. PMID- 29230469 TI - Controlling with light the interaction between trans-tetrapyridyl ruthenium complexes and an oligonucleotide. AB - Three new trans-ruthenium(ii) complexes coordinated to tetrapyridyl ligands, namely [Ru(bapbpy)(dmso)Cl]Cl ([2]Cl), [Ru(bapbpy)(Hmte)2](PF6)2 ([3](PF6)2), and [Ru(biqbpy)(Hmte)2](PF6)2 ([4](PF6)2), were prepared as analogues of [Ru(biqbpy)(dmso)Cl]Cl ([1]Cl), a recently described photoactivated chemotherapy agent. The new complexes were characterized, and their crystal structures showed the distorted coordination octahedron typical of this family of complexes. Their photoreactivity in solution was analyzed by spectrophotometry and mass spectrometry, which showed that the sulfur ligand was substituted upon blue light irradiation. The binding of the ruthenium complexes to a reference single stranded oligonucleotide (s(5'CTACGGTTTCAC3')) was explored both in the dark and under light irradiation by gel electrophoresis and high-resolution mass spectrometry. While adduct formation in the dark was negligible for the four complexes, light irradiation led to the formation of adducts with one or two ruthenium centers per oligonucleotide. The absence of interactions in the dark and the presence of complex-oligonucleotide adducts demonstrate that visible light controls the interaction of these ruthenium complexes with nucleic acids. PMID- 29230471 TI - Transport to the Emergency Department for Assisted Living Residents Who Fall. PMID- 29230473 TI - Improving Care for Ground-Level Falls in Assisted Living. PMID- 29230474 TI - Cost-Effectiveness of Individualized Management of Diabetes Among U.S. Adults. PMID- 29230472 TI - Individualized Glycemic Control for U.S. Adults With Type 2 Diabetes: A Cost Effectiveness Analysis. AB - Background: Intensive glycemic control in type 2 diabetes (glycated hemoglobin [HbA1c] level <7%) is an established, cost-effective standard of care. However, guidelines recommend individualizing goals on the basis of age, comorbidity, diabetes duration, and complications. Objective: To estimate the cost effectiveness of individualized control versus uniform intensive control (HbA1c level <7%) for the U.S. population with type 2 diabetes. Design: Patient-level Monte Carlo-based Markov model. Data Sources: National Health and Nutrition Examination Survey 2011-2012. Target Population: The approximately 17.3 million persons in the United States with diabetes diagnosed at age 30 years or older. Time Horizon: Lifetime. Perspective: Health care sector. Intervention: Individualized versus uniform intensive glycemic control. Outcome Measures: Average lifetime costs, life-years, and quality-adjusted life-years (QALYs). Results of Base-Case Analysis: Individualized control saved $13 547 per patient compared with uniform intensive control ($105 307 vs. $118 854), primarily due to lower medication costs ($34 521 vs. $48 763). Individualized control decreased life expectancy (20.63 vs. 20.73 years) due to an increase in complications but produced more QALYs (16.68 vs. 16.58) due to fewer hypoglycemic events and fewer medications. Results of Sensitivity Analysis: Individualized control was cost saving and generated more QALYs compared with uniform intensive control, except in analyses where the disutility associated with receiving diabetes medications was decreased by at least 60%. Limitation: The model did not account for effects of early versus later intensive glycemic control. Conclusion: Health policies and clinical programs that encourage an individualized approach to glycemic control for U.S. adults with type 2 diabetes reduce costs and increase quality of life compared with uniform intensive control. Additional research is needed to confirm the risks and benefits of this strategy. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases. PMID- 29230475 TI - Improving Decisions About Transport to the Emergency Department for Assisted Living Residents Who Fall. AB - Background: Residents of assisted living facilities who fall may not be seriously ill or injured, but policies often require immediate transport to an emergency department regardless of the patient's condition. Objective: To determine whether unnecessary transport can be avoided. Design: Prospective cohort study. Setting: One large county with a single system of emergency medical services. Participants: Convenience sample of residents in 22 assisted living facilities served by 1 group of primary care physicians. Intervention: Paramedics providing emergency medical services followed a protocol that included consulting with a physician by telephone. Measurements: The number of transports after a fall and the number of time-sensitive conditions in nontransported patients. Results: Of the 1473 eligible residents, 953 consented to participate in the study (mean age, 86 years; 76% female) and 359 had 840 falls in 43 months. The protocol recommended nontransport after 553 falls. Eleven of these patients had a time sensitive condition. At least 7 of them received appropriate care: 4 requested and received transport despite the protocol recommendation, and 3 had minor injuries that were successfully managed on site. Three additional patients had fractures that were diagnosed by outpatient radiography. The final patient developed vomiting and diarrhea, started palliative care, and died 60 hours after the fall. At least 549 of the 553 patients (99.3% [95% CI, 98.2% to 99.8%]) with a protocol recommendation for nontransport received appropriate care. Limitation: The resources required for this program will preclude use in some locations. Conclusion: Shared decision making between paramedics and primary care physicians can prevent transport to the emergency department for many residents of assisted living facilities who fall. Primary Funding Source: None. PMID- 29230476 TI - Is the Role of External Feedback in Auditory Skill Learning Age Dependent? AB - Purpose: The purpose of this study is to investigate the role of external feedback in auditory perceptual learning of school-age children as compared with that of adults. Method: Forty-eight children (7-9 years of age) and 64 adults (20 35 years of age) conducted a training session using an auditory frequency discrimination (difference limen for frequency) task, with external feedback (EF) provided for half of them. Results: Data supported the following findings: (a) Children learned the difference limen for frequency task only when EF was provided. (b) The ability of the children to benefit from EF was associated with better cognitive skills. (c) Adults showed significant learning whether EF was provided or not. (d) In children, within-session learning following training was dependent on the provision of feedback, whereas between-sessions learning occurred irrespective of feedback. Conclusions: EF was found beneficial for auditory skill learning of 7-9-year-old children but not for young adults. The data support the supervised Hebbian model for auditory skill learning, suggesting combined bottom-up internal neural feedback controlled by top-down monitoring. In the case of immature executive functions, EF enhanced auditory skill learning. This study has implications for the design of training protocols in the auditory modality for different age groups, as well as for special populations. PMID- 29230477 TI - Interleukin-1 Inhibitors and Dacryoadenitis in Adult-Onset Still Disease. PMID- 29230478 TI - Testicular Cancer in Monozygotic Twin Brothers with Urticaria Pigmentosa. PMID- 29230480 TI - [On the new Editor-in-Chief of Der Urologe]. PMID- 29230479 TI - Effects of a Hybrid Education Programme for Korean Mothers of Children with Atopic Dermatitis. AB - Atopic dermatitis (AD), a common childhood skin disorder, can limit a child's learning and physical activities. South Korean mothers, as primary caregivers, experience anxiety and helplessness when caring for their ill children. The aim of this study was to develop a hybrid AD education programme (consisting of a face-to-face session followed by 8 online sessions) and evaluate its effects on anxiety, caregiving efficacy and caregiving behaviour among mothers of children with AD. Twenty mothers of patients with AD treated in a South Korean hospital received one on-site session and 8 weekly online modules. After the intervention, mothers' mean+/-standard deviation anxiety reduced (from 50.3 +/- 14.2 to 31.7 +/ 6.3 points, t = 5.75, p < 0.001). Their caregiving efficacy and caregiving behaviour improved significantly, from 18.3 +/- 3.5 to 29.4 +/- 3.2 points (t = 9.64, p < 0.001) and from 47.7 +/- 7.7 to 78.8 +/- 4.9 points (t = -14.4, p < 0.001), respectively. The effects of the hybrid education programme for this population were significant. Healthcare providers should consider examining the programme nationwide, including in rural areas, while investigating its long-term effects. PMID- 29230481 TI - Biological Responses in Brook Trout (Salvelinus fontinalis) Caged Downstream from Municipal Wastewater Treatment Plants in the Credit River, ON, Canada. AB - To determine whether discharges of contaminants from municipal wastewater treatment plants (WWTPs) may be contributing to the decline in populations of brook trout (Salvelinus fontinalis) in the watershed of the Credit River in ON, Canada, we caged juvenile brook trout upstream and downstream of the WWTPs of the small communities of Acton and Orangeville. Levels of vitellogenin were significantly elevated in liver tissue of trout caged downstream of both WWTPs, indicating exposure to estrogenic substances. Levels of thiobarbituric acid reactive substances indicative of oxidation of lipids were elevated in the gill tissue of brook trout caged downstream of the Orangeville WWTP, and levels of total glutathione were significantly lower in the gills of brook trout caged downstream of the Acton WWTP. Both biomarkers are indicative of oxidative stress, although many constituents of wastewater could be responsible for these responses. More work is needed to determine whether discharges of wastewater are contributing to the decline of brook trout in the Credit River and other cold water streams in the Lake Ontario catchment basin. PMID- 29230482 TI - Photoenhanced Toxicity of Weathered Crude Oil in Sediment and Water to Larval Zebrafish. AB - Solar radiation exposure can increase the toxicity of bioaccumulated oil compounds in a diversity of aquatic species. We investigated the photoenhanced toxicity of weathered South Louisiana crude oil in sediment and water accommodated fractions (WAF) to larval zebrafish. Larvae were first exposed for 24 h to one of six treatments: no oil (sediment or water), 7.5 g oil/kg sediment, oil-only WAF, oil WAF plus the dispersant Corexit 9500A, or dispersant alone. Larvae were then exposed to high or low levels of sunlight in control water for 3 or 3.5 h. Hydrocarbon concentrations were measured in exposure media, including alkanes, polycyclic aromatic compounds and total petroleum hydrocarbons. Significant phototoxicity was observed in larvae exposed to oiled sediment, oil only WAF, and oil plus dispersant WAF. The results indicated that petroleum from the northern Gulf of Mexico can be phototoxic to larval fish exposed to oil in either the water column or sediment. PMID- 29230483 TI - Evaluation of Mercury Uptake and Distribution in Rice (Oryza sativa L.). AB - Mercury (Hg) contamination in soil-rice systems from industry, mining and agriculture has received increasing attention recently in China. Pot experiments were conducted to research the Hg accumulation capacity of rice under exogenous Hg in the soil and study the major soil factors affecting translocation of Hg from soil to plant. Soil treated with 2 mg kg-1 Hg decreased rice grain yield and inhibited the growth of rice plants. With increased Hg contamination of the rice, the enrichment rate of Hg was significantly higher in the rice grain than that in the stalk and leaf. Soil pH and cation exchange capacity are the key factors controlling Hg bioavailability in soils. PMID- 29230484 TI - [Vaccination in advanced age]. AB - Infectious diseases are responsible for up to 5% of fatalities even in developed countries. In addition, there is an increasing susceptibility for infections in elderly people due to physiological aging of the immune system. The principles of vaccination are based on a targeted activation of the human immune system. Principally, a distinction is made between passive immunization, i.e. the application of specific antibodies against a pathogen and active immunization. In active immunization, i.e. vaccination, weakened (attenuated) or dead pathogens or components of pathogens (antigens) are administered. After a latency period that depends on the vaccine, complete immune protection is achieved and immunity is maintained for a certain period of time. In contrast to dead vaccines, by the use of live vaccines there is always a risk for infection with the administered vaccine. In passive immunization antibodies are administered. As a rule passive immunization is carried out in persons who have had contact with an infected person and in whom no or uncertain immunity against the corresponding disease is present. Based on the recommendations of the Standing Committee on Vaccination (STIKO), influenza, pneumococcal, herpes zoster, early summer meningoencephalitis (FSME) and travel vaccines are described. PMID- 29230485 TI - [Importance of functional diagnostics in gastroenterology]. AB - In this review article important and frequently used investigation methods for gastrointestinal functional diagnostics are presented. Some other rarely used special investigations are also explained. The hydrogen breath test is simple to carry out, ubiquitously available and enables the detection of lactose, fructose and sorbitol malabsorption. Furthermore, by the application of glucose, the test can be carried out when there is a suspicion of abnormal intestinal bacterial colonization and using lactulose for measuring small intestinal transit time. The 13C urea breath test is applied for non-invasive determination of Helicobacter pylori infections and assessment of gastrointestinal transit time, liver and exocrine pancreas functions. The secretin cholecystokinin test was the gold standard for the detection of exocrine pancreas insufficiency. However, measurement of pancreatic elastase in stool is less invasive but also less sensitive. Scintigraphy and capsule investigations with pH and temperature probes constitute important methods for determination of gastric emptying, intestinal and colon transit times. For evaluation of constipation panoramic abdominal images are taken after intake of radiologically opaque markers (Hinton test). For the diagnosis of functional esophageal diseases manometry is indispensable. In addition, manometry is only occasionally used for diagnosing a dysfunction of the sphincter of Oddi, due to the danger of inducing pancreatitis. A 24 h pH-metry is applied for the detection of non-erosive gastroesophageal reflux disease and, if necessary, with impedance measurements. Recent investigation procedures, e. g. specific MRI sequences, sonographic determination of gall bladder ejection fraction, analysis of gastric accomodation or real-time lumen imaging, require further evaluation prior to clinical application. PMID- 29230486 TI - Update to 'Re: Tarazona et al. (2017): glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC. doi: 10.1007/s00204-017-1962-5'. PMID- 29230487 TI - [Osteoporosis in private accident insurance]. AB - Osteoporosis is a multifactorial disease resulting in reduced bone strength and increased bone fragility. The cause of osteoporosis is underexplored. The manifestation of osteoporosis makes a significant contribution to the development of bone fractures. In the medical assessment, the question arises to what extent osteoporosis is considered to be a previous disability or in particular as a contributory factor. In particular, there are some uncertainties relating to the degree of possible participation, as there are only insufficient scientific evaluation systems. From the authors' point of view no valid assessment of the degree of participation exists on the basis of technical examinations or even the severity of the trauma. At the current time there is no possibility to indicate the level of contribution in 10% or 20% steps. Taking the total picture, including clinical and radiological findings into consideration, it seems possible to assess the contribution only in larger percentage steps (e.g. 0%, 50% or >=80%). The mere diagnosis of osteoporosis does not justify a participation rate unless its effects can be pathomorphologically proven. PMID- 29230488 TI - Surgical treatment of compressive spinal hemangioma : A case series of three patients and literature review. AB - PURPOSE: In this article we describe the treatment of compressive vertebral hemangioma. METHODS: Our case series comprised three patients with aggressive hemangioma. We performed a combination of posterior decompression and vertebroplasty for the two patients with a sacral hemangioma and a thoracic hemangioma, and en bloc resection for the third patient, who also had a thoracic lesion. RESULTS: Surgical intervention is indicated in cases of rapidly progressive tumors or severe myelopathy. All three patients had good clinical results. The follow-up period ranged from 8 to 56 months. The mean blood loss was around 700 ml, and mean surgical time was 2.1 h. Blood loss for the en bloc procedure was around 1,200 ml, and surgical time was 2.3 h. CONCLUSION: A combination of posterior decompression, vertebroplasty, and posterior fixation for aggressive hemangioma can reduce blood loss during surgery. For patients with hemangioma and with incomplete paralysis, total en bloc spondylectomy should be considered. Adjuvant radiotherapy can reduce the recurrence of cavernous vertebral hemangiomas. PMID- 29230489 TI - [Potential of allogeneic bone grafts as antibiotic carriers : Effect of different preparation processes on efficacy]. AB - BACKGROUND: The rising number of primary joint replacements worldwide is causing an increase of endoprosthetic revision surgery due bacterial infection. Revision surgery using non-cemented implants seems beneficial for the long-term outcome, and the use of antibiotic-impregnated bone grafts might control the infection and provide a good support for the implant. In this study, we evaluated the release of antibiotics from fresh-frozen and lyophilized allogeneic bone grafts. METHODS: Heat-treated, lyophilized and fresh frozen cryopreserved bone chips were impregnated with gentamicin sulphate, gentamicin palmitate and vancomycin, and calcium carbonate/calcium sulphate treated with antibiotics. The efficacy of each preparation was measured by drug release tests and bacterial susceptibility using B. subtilis, S. aureus and methicillin-resistant Staphylococcus aureus. RESULTS: The release of gentamicin from lyophilized bone was similar to the release rate from fresh frozen bone during the entire experiment. This might be related to the similar porosity and microstructure of the bone chips. The release of gentamicin from lyophilized and fresh frozen bone was high on the first and second days, then decreased and stayed at a low rate until the end of the second week. CONCLUSION: Depending on the surgical strategy, either polymethylmethacrylate or allogeneic bone are able to deliver sufficient concentrations of gentamicin to achieve bacterial inhibition within 2 weeks after surgery. In the case of uncemented revision of joint replacements, allogeneic bone can deliver therapeutic doses of gentamicin and peak levels immediately and a fortnight after implantation. PMID- 29230491 TI - [Treatment effect of liver resection vs. RFA or TACE in hepatocellular carcinoma]. PMID- 29230490 TI - Pharmacokinetic study of tianeptine and its active metabolite MC5 in rats following different routes of administration using a novel liquid chromatography tandem mass spectrometry analytical method. AB - Tianeptine is an atypical antidepressant with a unique mechanism of action and recently it has been also reported that its major metabolite, compound MC5, possesses pharmacological activity similar to that of the parent drug. The current study aims to investigate the pharmacokinetics (PK) of both tianeptine and MC5 after intravenous or intraperitoneal administration of the parent drug as well as the metabolic ratio of MC5 in rats. To achieve these goals an LC-MS/MS method using the small sample volume for the quantitation of tianeptine and its active metabolite MC5 in rat plasma and liver perfusate has been developed and validated. Following an intravenous administration of tianeptine pharmacokinetic parameters were calculated by non-compartmental analysis. The average tianeptine volume of distribution at steady state was 2.03 L/kg and the systemic clearance equaled 1.84 L/h/kg. The mean elimination half-lives of tianeptine and MC5 metabolite were 1.16 and 7.53 h, respectively. The hepatic clearance of tianeptine determined in the isolated rat liver perfusion studies was similar to the perfusate flow rate despite the low metabolic ratio of MC5. Mass spectrometric analysis of rat bile indicated that tianeptine and MC5 metabolite are eliminated with bile as glucuronide and glutamine conjugates. Bioavailability of tianeptine after its intraperitoneal administration was 69%. The PK model with a metabolite compartment developed in this study for both tianeptine and MC5 metabolite after two routes of administration may facilitate tianeptine dosage selection for the prospective pharmacological experiments. PMID- 29230492 TI - UPLC-MS/MS analysis of antibiotics in pharmaceutical effluent in Tunisia: ecotoxicological impact and multi-resistant bacteria dissemination. AB - The UPLC MS/MS analysis showed the presence of the two antibiotics in the pharmaceutical industry discharges during 3 months; norfloxacin and spiramycin which were quantified with the mean concentrations of 226.7 and 84.2 ng mL-1, respectively. Sixteen resistant isolates were obtained from the pharmaceutical effluent and identified by sequencing. These isolates belong to different genera, namely Citrobacter, Acinetobacter, Pseudomonas, Delftia, Shewanella, and Rheinheimera. The antibiotic resistance phenotypes of these isolates were determined (27 tested antibiotics-discs). All the studied isolates were found resistant to amoxicillin and gentamicin, and 83.33% of isolates were resistant to ciprofloxacin. Multiple antibiotic resistances were revealed against beta lactams, quinolones, and aminoglycosides families. Our overall results suggest that the obtained bacterial isolates may constitute potential candidates for bioremediation and can be useful for biotechnological applications. Genotoxic effects were assessed by a battery of biotests; the pharmaceutical wastewater was genotoxic according to the bacterial Vitotox test and micronuclei test. Genotoxicity was also evaluated by the comet test; the tail DNA damages reached 38 and 22% for concentrated sample (10*) and non-concentrated sample (1*), respectively. However, the histological sections of kidney and liver's mice treated by pharmaceutical effluent showed normal histology and no visible structural effects or alterations as cytolysis, edema, or ulcerative necrosis were observed. Residual antibiotics can reach water environment through wastewater and provoke dissemination of the antibiotics resistance and induce genotoxic effects. PMID- 29230493 TI - The limitations of some European healthcare databases for monitoring the effectiveness of pregnancy prevention programmes as risk minimisation measures. AB - PURPOSE: Pregnancy prevention programmes (PPPs) exist for some medicines known to be highly teratogenic. It is increasingly recognised that the impact of these risk minimisation measures requires periodic evaluation. This study aimed to assess the extent to which some of the data needed to monitor the effectiveness of PPPs may be present in European healthcare databases. METHODS: An inventory was completed for databases contributing to EUROmediCAT capturing pregnancy and prescription data in Denmark, Norway, the Netherlands, Italy (Tuscany/Emilia Romagna), Wales and the rest of the UK, to determine the extent of data collected that could be used to evaluate the impact of PPPs. RESULTS: Data availability varied between databases. All databases could be used to identify the frequency and duration of prescriptions to women of childbearing age from primary care, but there were specific issues with availability of data from secondary care and private care. To estimate the frequency of exposed pregnancies, all databases could be linked to pregnancy data, but the accuracy of timing of the start of pregnancy was variable, and data on pregnancies ending in induced abortions were often not available. Data availability on contraception to estimate compliance with contraception requirements was variable and no data were available on pregnancy tests. CONCLUSION: Current electronic healthcare databases do not contain all the data necessary to fully monitor the effectiveness of PPP implementation, and thus, special data collection measures need to be instituted. PMID- 29230494 TI - Association of polymorphisms in TNF and GRN genes with ankylosing spondylitis in a Chinese Han population. AB - The aim of this study is to investigate the association of the polymorphisms in tumor necrosis factor (TNF) and granulin (GRN) with ankylosing spondylitis (AS) in a Chinese Han population. Five single nucleotide polymorphisms (SNPs) covering TNF and six SNPs covering GRN were investigated in 861 Chinese Han AS patients and 864 healthy controls. For rs1799964, the C allele was linked to reduced risk of AS (p < 0.0001, OR = 0.60, 95% CI = 0.50-0.71). The carriers of the C/C homozygote showed a significantly lower risk of AS compared with the TT homozygote and the C/T heterozygote under the recessive model (p < 0.0001, OR = 0.23, 95% CI = 0.12-0.45). For rs1800629, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.54, 95% CI = 0.39-0.74). For rs1800630, the A allele was also linked to reduced risk of AS (p < 0.0001, OR = 0.59, 95% CI = 0.48-0.72). The carriers of the A/A homozygote showed a significantly lower risk of AS compared with the C/C homozygote and the A/C heterozygote under the recessive model (p < 0.0001, OR = 0.18, 95% CI = 0.07-0.47). For rs769178, the T allele was linked to increased risk of AS (p < 0.0001, OR = 2.59, 95% CI = 2.18 3.09). The carriers of the T/T homozygote showed a significantly higher risk of AS compared with the GG homozygote and the G/T heterozygote under the recessive model (p < 0.0001, OR = 3.34, 95 %CI = 1.95-5.72). There was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs361525. For GRN, there was no significant difference between the AS patients and the controls in the genotype or allele frequencies of rs25646, rs3760365, rs3785817, rs4792939, rs5848, rs850713 (p > 0.05). This study indicates that polymorphisms in TNF are related to AS, but polymorphisms in GRN are not related to AS susceptibility in a Chinese Han population. PMID- 29230497 TI - Triple In Situ Antegrade Laser Fenestration of Aortic Stent-Graft Extension Using Fusion Imaging for Urgent Treatment of Symptomatic Abdominal Aneurysm with Type 1 Endoleak. AB - The present report describes the management of massive proximal type 1 endoleak with an enlarged symptomatic aneurysmal sac. Urgent treatment was performed using in situ laser fenestration of an aortic proximal extension facing renovisceral ostia. Image fusion was obtained intraoperatively. For each target vessel (superior mesenteric and two renal arteries), an Aptus HeliFX steerable sheath (Medtronic) inserted through femoral access was curved to face the vessel's ostium marker. A laser catheter (Spectranetics) was used to traverse the stent graft and insert a 0.014" guidewire in the vessel. The fenestration was enlarged using a 2.5-mm-diameter cutting balloon, followed by a 4-mm-diameter balloon angioplasty and a V12 I Cast/Advanta covered stent implantation. Final angiogram demonstrated aneurysm exclusion and patent target vessels. The postoperative course and 7 months follow-up were uneventful. Level of evidence Level 4. PMID- 29230495 TI - Comparison of readmission and short-term mortality rates between different types of urinary diversion in patients undergoing radical cystectomy. AB - PURPOSE: To analyze the impact of urinary diversion type following radical cystectomy (RC) on readmission and short-term mortality rates. METHODS: Patients who underwent RC for bladder cancer in the National Cancer Data Base were grouped based on the type of urinary diversion performed: non-continent [ileal conduit (IC)] or two continent techniques [continent pouch (CP) and orthotopic neobladder (NB)]. We used propensity score matching and multivariable logistic regression models to compare 30-day readmission and 30- and 90-day mortality between the different types of urinary diversion. RESULTS: Among 11,933 patients who underwent RC, we identified 10,197 (85.5%) IC, 1044 (8.7%) CP, and 692 (5.8%) NB. Patients who received IC were significantly older and had more comorbidities (p < 0.0001). Continent diversions were more likely to be performed at an academic center (p < 0.0001). Surgery performed at a non-academic center was an independent predictor of 30-day readmission (OR 1.19, p = 0.010) and 30-day mortality (OR 1.27, p = 0.043). Patients undergoing NB had an increased likelihood of being readmitted (OR 1.41, p = 0.010). There was no significant difference in short-term mortality between groups. CONCLUSIONS: Patients undergoing NB had marginally increased rates of readmission compared to IC. Surgery performed at a non-academic center was associated with higher readmission and 30-day mortality. Similar short-term mortality rates were observed among the different types of urinary diversion. PMID- 29230496 TI - Testicle-sparing surgery versus radical orchiectomy in the management of Leydig cell tumors: results from a multicenter study. AB - OBJECTIVE: To compare the oncological outcomes of testicle-sparing surgery (TSS) and radical orchiectomy (RO) in patients with Leydig cell tumor (LCT) of the testis. PATIENTS AND METHODS: A multicenter retrospective clinical study was conducted in 12 centers in France. All the patients with histologically proven LCT were included and analyzed according to treatment (organ-sparing surgery or radical orchiectomy). Patients underwent preoperative clinical, biological and imaging assessment. Demographic, clinical, and pathological variables were collected at baseline and compared between groups according to surgical treatment. Follow-up was calculated using the reverse Kaplan-Meier estimation and was updated at the end of 2015. RESULTS: Between 1986 and 2014, 56 patients presented with LCT were identified and included in the study. Twenty-one patients (37.5%) underwent TSS and 35 (62.5%) RO. Demographics and tumor characteristics were not significantly different between the groups. Median follow-up was 62 months after TSS, but only 35 months after RO. Two patients (9.5%) developed local recurrence 15 and 34 months after TSS and underwent secondary RO. No local recurrence or metastasis was observed after complementary treatment. No recurrence was observed after RO. Disease-free survival did not differ between the groups (95.2% in TSS versus 77.1% in the RO group, p = 0.23). No patient died in the TSS group, but three patients (8.6%) in the RO group died from other diseases without evidence of relapse. One patient (4.8%) in the TSS group versus five (14.3%) in the RO group were lost to follow-up. CONCLUSION: Long-term follow up suggests that testicle-sparing surgery does not compromise relapse-free survival in the treatment of Leydig cell tumor of the testis. PMID- 29230498 TI - Trans-rectal Ultrasound-Guided Autologous Blood Injection in the Interprostatorectal Space Prior to Percutaneous MRI-Guided Cryoablation of the Prostate. AB - OBJECTIVE: To report a novel technique of ultrasound-guided injection of autologous blood in the interprostatorectal space, in an attempt to facilitate ablative prostatic procedures by widening durably the space between the rectum and the prostate. MATERIALS AND METHODS: Between April and November 2016, four consecutive patients underwent the haemoprotection injection technique. For each patient, we recorded the time to perform the technique, the amount of injected blood, the achieved distances between the rectum and the prostate post-injection at fixed defined points (apex, middle, and base of prostate at the midline, left, and right sides of the gland), the extension of the ice ball outside the prostate capsule at those fixed points, and whether any residual blood was present on 1 month follow-up MRI. RESULTS: Mean time to perform haemoprotection injection was 54 min, with an average blood volume of 103 cc. Mean distance achieved at the apex, middle, and base of the prostate, respectively, was 12, 13, and 16 mm in the midline; 8, 10, and 13 mm on the left side; and 9, 10, and 13 mm on the right side. The mean extension distance of the ice ball beyond the capsule was 4, 6, and 6 mm in the midline; 4, 5, and 6 mm on the left side; and 1, 3, and 3 mm on the right side. No residual blood was present on 1-month follow-up MRI in all patients. No rectal fistula occurred. CONCLUSION: Haemoprotection may create a safe and effective virtual space between the prostate and rectum. PMID- 29230499 TI - [Fulminant sepsis after Capnocytophaga canimorsus infection]. AB - Capnocytophaga canimorsus is a Gram-negative bacterium present in the oral cavities of cats and dogs. It is known for its capability to cause life threatening sepsis following a dog bite, especially in immunocompromised patients. We report the case of a 67-year-old man who suffered from septic shock and multiorgan failure presumably following contamination of a pre-existing minor skin lesion by canine saliva. The purpose of this report is to raise awareness of Capnocytophaga canimorsus among physicians when faced with a patient presenting with fulminant septic shock and Gram-negative bacteremia, who has been exposed to dogs. PMID- 29230500 TI - [Analysis and options for optimization of preoperative assessment for anesthesia at a university hospital]. AB - BACKGROUND: Risk assessment prior to elective surgery is an important tool in the context of perioperative patient care; however, only a few studies have been carried out to address the processes and problems during preoperative assessment for anesthesia. AIM: Over a period of several weeks all preoperative anesthesia evaluations prior to elective surgery were prospectively recorded in order to generate a data pool with a view to identifying options for process optimization. MATERIAL AND METHODS: All preoperative evaluations over a period of 38 working days at the University Medical Center Regensburg were recorded and analyzed with respect to waiting time for the patient and the duration of the preoperative consultation on medication. Also documented were the patient age, ASA score, the faculty carrying out the operation, type and risk of surgery, planned time of surgery, professional experience of the anesthesiologist and the approval status for surgery. In addition, all problems which occurred during the preoperative anesthesia evaluation were documented using a questionnaire. RESULTS: Overall 2233 preoperative assessments for anesthesia were recorded and analyzed. The number of patients attending the preoperative assessment clinic differed markedly in the course of a day and was lower at the end of the week. Approval for surgery with no reservations was given more frequently by anesthesiologists with more than 5 years professional experience and consultants compared to younger colleagues. The main reason for approval with reservations or no approval was the lack of patient records and test results, which should have been presented according to the in-house standard for preoperative assessment for anesthesia. The mean waiting time was 58.6 +/- 30.3 min, the mean duration of the patient documentation review and physician-patient consultation together was 33.6 +/- 16.3 min. Anesthesiologists with 2-5 years professional experience needed significantly less time for patient documentation reviews and physician-patient consultations than younger and more experienced colleagues. The duration of the preoperative assessment for anesthesia correlated with the ASA score and risks of surgery. CONCLUSION: The analysis of processes and problems in the context of preoperative assessment for anesthesia revealed several options for optimization. Major efforts should be the implementation of an appointment system for the preoperative assessment clinic in order to generate a homogeneous distribution of patients during the course of a day. Furthermore, surgeons and case managers should be requested to refer patients to the preoperative assessment clinic only with complete records and test results according to the in-house standard. PMID- 29230501 TI - [Development of ground-based physician-staffed emergency missions in the city of Leipzig from 2003 to 2013]. AB - BACKGROUND: The annual number of physician-based emergency missions reported is continuously increasing. Data from large cities concerning this development over long periods is sparse. MATERIAL AND METHODS: In this retrospective study the charts of all ground-based physician-staffed emergency missions in the city of Leipzig for the first quarters of 2003 and 2013 were analyzed. Patient characteristics, injury and illness severities, mission location, hospital admission rate, as well as emergency interventions were collated. The emergency mission rate was calculated as rescue missions per 1000 inhabitants per year. RESULTS: The number of physician-staffed emergency missions increased by approximately 24% between 2003 and 2013 (6030 vs. 7470, respectively). The emergency mission rate was 48 vs. 58 in the 2 study periods. The median patient age increased from 66 to 70 years. The number of geriatric patients (age >= 85 years: n = 650 (11%) vs. n = 1161 (16%), p < 0.01) also increased. The corresponding number of emergency missions in nursing homes showed a fourfold (n = 175, 3% vs. n = 750, 10%, p < 0.01). The percentage of hospital admissions also increased (n = 3049, 51% vs. n = 4738, 66%, p < 0.01). A change in patient distribution to level I hospitals was noticed (n = 1742, 29% vs. n = 3436, 46%, p < 0.01). CONCLUSION: The findings suggest that the necessity for the high number of physician-staffed emergency missions should be verified, especially in the context of strained emergency healthcare resources. The basis of an optimized use of resources could be a better inclusion of alternative, especially ambulant, healthcare structures and the implementation of a structured emergency call questionnaire accompanied by a more efficient disposition of the operating resources, not least in view of the economic aspects. Taking the concentrated patient allocation to level 1 hospitals into consideration, there is a need for optimized patient distribution strategies to minimize the overload of individual institutions and thereby improve the general quality of care at the interface between preclinical and clinical emergency medicine. PMID- 29230502 TI - [Acceptance of post-mortem organ donation in Germany : Representative cross sectional study]. AB - BACKGROUND: The German post-mortem organ donation rate has dropped by one third since 2010. Furthermore, 958 patients died in 2015 in Germany while waiting for an organ. To decrease organ shortage, an amendment of the transplantation law was established in 2012. An information package including an organ donor card is sent to all German citizens via the postal service. A voluntary national transplantation register was introduced in 2016 to improve transparency in the organ donation process. The influence of several transplantation scandals starting in 2012 on organ donation rates is in question. Therefore, the objective of this article is to discuss approval and objections to post-mortem organ donation among the next of kin of potential donors and the general public in Germany. METHODS: Binary logistic regression of data from the 2014 survey by the Federal Centre for Health Education on attitudes towards organ and tissue donation in Germany was conducted, aiming to identify influencing factors on the likelihood of organ donor card possession. Additionally, data of the German Organ Transplantation Foundation on post-mortem organ donations in Germany in 2014 were studied to highlight reasons for approval and objections by next of kin of potential and explanted post-mortem organ donors. Methods of documentation of the deceased's will according to data of the German Organ Transplantation Foundation were analyzed. RESULTS: Male gender and lack of knowledge about organ donation decrease the likelihood of having an organ donor card. Of the respondents in the survey of the Federal Centre for Health Education 71.0% would donate their own organs, whereas only one third possess an organ donor card. Health insurances and physicians are the most important providers of organ donor cards in Germany. An increase in the percentage of organ donor card possession following the amendment of the transplantation law could not be observed by 2016. Fear of organ trade and unjust organ allocation are the main reasons for rejecting organ donation among the general public. Previous transplantation scandals are a primary reason for a negative change in attitudes. Main reasons for objection among the next of kin of potential organ donors are known objections of the deceased and the lack of knowledge about the will of the deceased. In addition, only 58.1% of all explanted organ donors documented their will in written or verbal form. CONCLUSION: Education on organ donation can be a means to increase organ donation rates. The effects of the change in legislation and the establishment of the transplant register need to be evaluated. Further research regarding the influence of religion, especially among religious minorities, on organ donation rates in Germany needs to be conducted to identify possible obstacles. Moreover, the use of social networks to address potential organ donors has proven to increase registration numbers and could easily be implemented in Germany. PMID- 29230503 TI - Concordance between the response evaluation criteria in solid tumors version 1.1 and the immune-related response criteria in patients with non-small cell lung cancer treated with nivolumab: a multicenter retrospective cohort study. AB - PURPOSE: The immune-related response criteria (irRC) were proposed to incorporate pseudo-progression. However, the association between the irRC and overall survival (OS) has yet to be evaluated in non-small cell lung cancer (NSCLC). Therefore, the purpose of this study is to evaluate the concordance between the response evaluation criteria in solid tumors (RECIST) version 1.1 and the irRC in patients with NSCLC treated with nivolumab, as well as, to determine the relationship between these two response criteria and OS. METHODS: We conducted a retrospective cohort study of 143 patients at three tertiary care hospitals in Japan between January and December 2016 (UMIN000022014). RESULTS: The weighted kappa statistic for the two response criteria was 0.72 (95% confidence interval (CI) 0.66-0.76). The Harrell's C-index was 0.74 (95% CI 0.68-0.80) for the RECIST and 0.74 (95% CI 0.68-0.80) for the irRC, respectively. The difference between the two criteria was - 0.002 (95% CI - 0.05 to 0.04). The Moreau, O'Quigley, and Lellouch statistic was 0.03 for the RECIST and 0.17 for the irRC, respectively. CONCLUSION: We demonstrated a good concordance between the RECIST and the irRC for predicting OS in patients with NSCLC treated with nivolumab. PMID- 29230504 TI - Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD): syndactyly type IX. PMID- 29230505 TI - Polymorphisms and expression of inflammasome genes are associated with the development and severity of rheumatoid arthritis in Brazilian patients. AB - OBJECTIVE: In the present study, we analyzed the possible association of inflammasome gene variants and expression to rheumatoid arthritis (RA)'s development and severity in the Brazilian population. MATERIALS AND METHODS: Thirteen single nucleotide polymorphisms within six inflammasome genes (NLRP1, NLRP3, NLRC4, AIM2, CARD8, CASP1) as well as IL1B and IL18 genes in two different Brazilian populations (from Northeast and Southeast Brazil) were analyzed. We also evaluated inflammasome gene expression profile in resting and LPS + ATP treated monocytes from RA patients and healthy individuals. For genetic association study, 218 patients and 307 healthy controls were genotyped. For gene expression study, inflammasome genes mRNA levels of 12 patients and ten healthy individuals were assessed by qPCR. RESULTS: Our results showed that rs10754558 NLRP3 and rs2043211 CARD8 polymorphisms are associated with RA development (p value = 0.044, OR = 1.77, statistical power = 0.999) and severity measured by Health Assessment Questionnaire (HAQ) (p value = 0.03), respectively. Gene expression analyses showed that RA patients display activation of CASP1, IL1B and IL1R genes independently of LPS + ATP activation. In LPS + ATP-treated monocytes, NLRP3 and NLRC4 expressions were also significantly higher in patients compared with controls. CONCLUSIONS: The first reported results in Brazilian populations support the role of inflammasome in the development of RA. PMID- 29230509 TI - Laudation on Prof. Alexander Berghaus. PMID- 29230508 TI - [Quality of life and vertigo after bilateral cochlear implantation : Questionnaires as tools for quality assurance]. AB - BACKGROUND: Persistent dizziness symptoms after cochlear implantation have an impact on quality of life. In this study, the effects of bilateral cochlear implants (CI) on quality of life as well as on subjective dizziness complaints are analyzed using questionnaires, some of which have never been applied before in these patient collectives. OBJECTIVE: In this article, questionnaires for the assessment of dizziness symptoms and quality of life are introduced in order to realize quality assurance. MATERIALS AND METHODS: A total of 32 patients with bilateral CI were questioned regarding dizziness symptoms and quality of life. The Nijmegen Cochlear Implant Questionnaire (NCIQ) was used. In the case of reported regular dizziness, the Vertigo Handicap Questionnaire (VHQ) and the Vertigo Symptom Scale (VSS) were also assessed. RESULTS: Persistent dizziness symptoms were shown in 8 of 32 patients. Quality of life was measured with the NCIQ and was improved significantly (p < 0.001) by 23.7% after the second CI. The dizziness symptoms changed slightly (VHQ -11.2%; VSS +16.4%) after the second implantation. CONCLUSION: The results show that the questionnaires are valid instruments for documenting quality of life and dizziness symptoms for quality assurance. These questionnaires may be applied as a complement or an alternative to device-based measurements of peripheral vestibular dysfunction. PMID- 29230506 TI - The isoprenoid end product N6-isopentenyladenosine reduces inflammatory response through the inhibition of the NFkappaB and STAT3 pathways in cystic fibrosis cells. AB - OBJECTIVE: N6-isopentenyladenosine (iPA) is an intermediate of the mevalonate pathway that exhibits various anti-cancer effects. However, studies on its anti inflammatory activity are scarce and underlying molecular mechanisms are unknown. Therefore, we aimed to investigate the ability of iPA to exert anti-inflammatory effects in the human cystic fibrosis (CF) cell model of exacerbated inflammation. MATERIALS AND METHODS: TNFalpha-stimulated CF cells CuFi-1 and its normal counterpart NuLi-1 were pre-treated with increasing concentrations of iPA and cell viability and proliferation were assessed by MTT and BrdU assays. The effect of iPA on IL-8 and RANTES secretion was determined by ELISA, and the activation and expression of signaling molecules and selenoproteins were studied by Western blot. To assess the direct effect of iPA on NFkappaB activity, luciferase assay was performed on TNFalpha-stimulated HEK293/T cells transfected with a NFkappaB reporter plasmid. RESULTS: We demonstrated for the first time that iPA prevents IL-8 and RANTES release in TNFalpha-stimulated CF cells and this effect is mediated by increasing the expression of the direct NFkappaB inhibitor IkappaBalpha and decreasing the levels of STAT3. Consistent with this, we showed that iPA inhibited TNFalpha-mediated NFkappaB activation in HEK/293T cells. Finally, we also found that iPA improved the levels of glutathione peroxidase 1 and thioredoxin reductase 1 only in CF cells suggesting its ability to maintain sufficient expression of these anti-oxidant selenoproteins. CONCLUSIONS: Our findings indicate that iPA can exert anti-inflammatory activity especially in the cases of excessive inflammatory response as in CF. PMID- 29230507 TI - Evidence for regional hippocampal damage in patients with schizophrenia. AB - PURPOSE: Schizophrenia patients show cognitive and mood impairments, including memory loss and depression, suggesting damage in the brain regions. The hippocampus is a brain structure that is significantly involved in memory and mood function and shows impairment in schizophrenia. In the present study, we examined the regional hippocampal changes in schizophrenia patients using voxel based morphometry (VBM), Freesurfer, and proton magnetic resonance spectroscopy (1H MRS) procedures. METHODS: 1H MRS and high-resolution T1-weighted magnetic resonance imaging were collected in both healthy control subjects (N = 28) and schizophrenia patients (N = 28) using 3-Tesla whole body MRI system. Regional hippocampal volume was analyzed using VBM and Freesufer procedures. The relative ratios of the neurometabolites were calculated using linear combination model (LCModel). RESULTS: Compared to controls, schizophrenia patients showed significantly decreased gray matter volume in the hippocampus. Schizophrenia patients also showed significantly reduced glutamate (Glu) and myo-inositol (mI) ratios in the hippocampus. Additionally, significant positive correlation between gray matter volume and Glu/tCr was also observed in the hippocampus in schizophrenia. CONCLUSION: Our findings provide an evidence for a possible association between structural deficits and metabolic alterations in schizophrenia patients. PMID- 29230510 TI - Manfred Eigen: the realization of his vision of Biophysical Chemistry. AB - Manfred Eigen turned 90 on May 9th, 2017. He celebrated with a small group of colleagues and friends on behalf of the many inspired by him over his lifetime whether scientists, artists, or philosophers. A small group of friends, because many-who by their breakthroughs have changed the face of science in different research areas-have already died. But it was a special day, devoted to the many genius facets of Manfred Eigen's oeuvre, and a day to highlight the way in which he continues to exude a great, vital and unbroken passion for science as well as an insatiable curiosity beyond his own scientific interests. He continues to dismiss arguments such as, that scientific problems cannot be solved because of a current lack of appropriate tools, or because of the persuasion of the community that certain things are immeasurable. He has lived up to and accepted only the highest scientific standards with his fundamental contributions in widely differing research fields, for which he has received numerous prizes and honorary doctorates, including the Nobel Prize for Chemistry in 1967. Some of his outstanding contributions to science and technology are honored in the following chapters. Here, we will report some characteristic traits of Manfred Eigen, and his personal development. We highlight his visionary foresight regarding how multidisciplinary science should combine to study the complex processes of life and its evolution in establishing an institute that applied biological, chemical, and physical methods, and how his vision became sustained reality. PMID- 29230512 TI - Rebound-associated vertebral fractures after discontinuation of denosumab for the treatment of maxillitis. AB - We reported a 69-year-old female who discontinued denosumab due to dental treatment and subsequently suffered rebound-associated vertebral fractures 10 months after the last injection. This case raised an alarm regarding the discontinuation of denosumab for dental treatment. Denosumab, a human monoclonal antibody administered by subcutaneous injection, to the best of our knowledge, is the only fully investigated inhibitor of receptor activator of nuclear factor kappa B ligand. Discontinuation of denosumab leads to bone turnover rebound and rapid bone mineral density loss. Several studies have reported rebound-associated vertebral fractures after discontinuation of denosumab. We report on a new case of rebound-associated vertebral fractures after discontinuation of denosumab. A 69-year-old female, who withdrew from denosumab treatment after 3 years due to maxillitis, presented to our hospital with severe low back pain without any history of trauma. Ten months had passed since the last injection. Magnetic resonance imaging showed five acute vertebral fractures, which appeared to be rebound-associated vertebral fractures caused by discontinuation of denosumab due to dental treatment. This case clearly demonstrates the risk of discontinuation of denosumab for dental treatment. PMID- 29230511 TI - Quality of life for up to 18 months after low-energy hip, vertebral, and distal forearm fractures-results from the ICUROS. AB - : This study used data from the International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) to estimate the quality of life (QoL) impact of fracture. Hip, vertebral, and distal forearm fractures incur substantial QoL losses. Hip and vertebral fracture results in markedly impaired QoL for at least 18 months. INTRODUCTION: The International Costs and Utilities Related to Osteoporotic fractures Study (ICUROS) is a multinational observational study that aims to describe costs and quality of life (QoL) consequences of osteoporotic fractures. To date, 11 countries have participated in the study: Australia, Austria, Estonia, France, Italy, Lithuania, Mexico, Russia, Spain, the UK, and the USA. The objective of this paper is to describe the QoL impact of hip, vertebral, and distal forearm fracture. METHODS: Data were collected at four time-points for five QoL point estimates: within 2 weeks after fracture (including pre-fracture recall) and at 4, 12, and 18 months after fracture. Quality of life was measured as health state utility values (HSUVs) derived from the EQ-5D-3L. Complete case analysis was conducted as the base case with available case and multiple imputation performed as sensitivity analyses. Multivariate analysis was performed to explore predictors of QoL impact of fracture. RESULTS: Among 5456 patients enrolled using convenience sampling, 3021 patients were eligible for the base case analysis (1415 hip, 1047 distal forearm, and 559 vertebral fractures). The mean (SD) difference between HSUV before and after fracture for hip, vertebral, and distal forearm fracture was estimated at 0.89 (0.40), 0.67 (0.45), and 0.48 (0.34), respectively (p < 0.001 for all fracture types). Eighteen months after fracture, mean HSUVs were lower than before the fracture in patients with hip fracture (0.66 vs. 0.77 p < 0.001) and vertebral fracture (0.70 vs. 0.83 p < 0.001). Hospitalization and higher recalled pre-fracture QoL were associated with increased QoL impact for all fracture types. CONCLUSIONS: Hip, vertebral, and distal forearm fractures incur substantial loss in QoL and for patients with hip or vertebral fracture, QoL is markedly impaired for at least 18 months. PMID- 29230513 TI - [Interprofessional approaches in undergraduate medical education]. AB - Social change and the subsequent increase in the complexity of patient care create new challenges for all health care professionals that can only be met by close collaboration. Good cooperation between professionals from all healthcare backgrounds has proven to be essential and should therefore play a larger role in educational and study contexts.It is for this reason that over the past few years more and more countries are requiring cooperative skills and competencies in formal medical training and consequently implementing this training in their healthcare systems. This is certainly true in countries such as Sweden, Canada, England, and most recently Switzerland, where interprofessional teaching is being systematically introduced into medical training.The current situation in Germany is demonstrated by the selected projects from the Robert Bosch Foundation's support program "Operation Team." The existing need for interprofessional qualification opportunities and advanced training programs for teaching staff, the need for exam content for medical state examinations, as well as to establish a structural framework and research structure in the area of interprofessional education and competence development are outlined and discussed. PMID- 29230514 TI - [Guideline recommendations and quality indicators for invasive treatment of peripheral arterial disease in Germany : The IDOMENEO study for quality improvement and research in vascular medicine]. AB - Due to the paucity of independent trials, practical guidelines for the diagnosis and treatment of peripheral arterial disease (PAD) contain several recommendations developed by expert consensus. Furthermore, there is a lack of commonly defined quality indicators and valid data on real world treatment. Therefore, it remains challenging to scrutinize if treatment reality is conforming to guideline recommendations. This article aims to give a short overview on existing guideline recommendations. It further aims to introduce the multistage multimethodological IDOMENEO study, utilizing primary registry data (GermanVasc) and health insurance claims data (BARMER) in PAD treatment. PMID- 29230515 TI - [Competence-based assessment in the national licensing examination in Germany]. AB - In Germany, future physicians have to pass a national licensing examination at the end of their medical studies. Passing this examination is the requirement for the license to practice medicine. The Masterplan Medizinstudium 2020 with its 41 measures aims to shift the paradigm in medical education and medical licensing examinations.The main goals of the Masterplan include the development towards competency-based and practical medical education and examination as well as the strengthening of general medicine. The healthcare policy takes into account social developments, which are very important for the medical education and licensing examination.Seven measures of the Masterplan relate to the realignment of the licensing examinations. Their function to drive learning should better support students in achieving the study goal defined in the German Medical Licensure Act: to educate a medical doctor scientifically and practically who is qualified for autonomous and independent professional practice, postgraduate education and continuous training. PMID- 29230516 TI - [The distribution of cardiovascular risk factors in employees from small- and medium-sized enterprises in Germany]. AB - BACKGROUND: The German Prevention Act, the main parts of which came into force on 25 July 2015, encourages health promotion and prevention programs for people in their living environment. Through this act, preventive measures could reach employees at work that hardly seek medical services. This is of importance since employees with a low occupational position often show risk factors that increase morbidity and mortality. METHODS: In this study, clinical data from n = 2280 employees from small and medium sized enterprises (SME) were analyzed for economic sector, sex, socioeconomic position (SEP), economic sector cardiovascular risk factors, musculoskeletal and psychological diseases. The socioeconomic position was categorized using the European Socioeconomic Classification into an intermediate/high and a low SEP category. RESULTS: Male employees showed a significantly higher occurrence of risk factors, such as smoking, diabetes or hypertension in comparison to female employees. In the manufacturing industry, male employees with a low SEP showed a higher prevalence of diabetes (2.3 vs. 5.9%), smoking (27.4 vs. 46.5%), and physical inactivity (sports: 55.0 vs. 37.1%) in comparison to employees with an intermediate/high SEP. Male employees with a low SEP from health and social services reported psychiatric disorders more frequently in comparison to those with an intermediate/high SEP (0.7 vs. 5.9%). CONCLUSION: Male employees with a low SEP should be given special consideration in the implementation of preventive measures at work within the framework of the Prevention Act. PMID- 29230517 TI - [Mentoring for medical students : Description and evaluation of a differentiated mentoring program at a medical school]. AB - In recent years, mentoring programs for medical students have been increasingly implemented in medical schools in Germany. This article describes a voluntary mentoring program for students, which is differentiated into a common mentoring program (AP), a mentoring program for excellent students (EP) and a mentoring plus program (PP) for students with academic difficulties, and its evaluation.The evaluation is based on annual evaluation surveys among the participating mentees, who evaluate the mentoring relationship as well as the impact on their studies.The three student groups differ significantly with regard to sociodemographic variables. The satisfaction with the mentoring program is generally high: 84-94% are mentored by their preferred mentor, the majority assesses the conversational atmosphere as open (78-91%), and 89-98% would recommend participation in the program to others. The programs differ with regard to specific aspects. While PP mentees report the highest ratings on the mentor's accessibility, trustworthiness and feedback, EP mentees report the highest ratings on the mentor's competence as well as increased identification with the faculty and early career promotion through the mentoring program.The different assessments of the three programs as well as the generally high acceptance and satisfaction ratings indicate that such a differentiated mentoring program provides a framework of individual support, which is highly appreciated by most students. PMID- 29230518 TI - Analysis of mirror neuron system activation during action observation alone and action observation with motor imagery tasks. AB - This study aimed to explore the relationship between action observation (AO) related corticomotor excitability changes and phases of observed action and to explore the effects of pure AO and concurrent AO and motor imagery (MI) state on corticomotor excitability using TMS. It was also investigated whether the mirror neuron system activity is muscle-specific. Fourteen healthy volunteers were enrolled in the study. EMG recordings were taken from the right first dorsal interosseous and the abductor digiti minimi muscles. There was a significant main effect of TMS timing (after the beginning of the movement, at the beginning of motor output state, and during black screen) on the mean motor evoked potential (MEP) amplitude. Mean MEP amplitudes for AO combined with MI were significantly higher than pure AO session. There was a significant interaction between session and TMS timing. There was no significant main effect of muscle on MEP amplitude. The results indicate that corticomotor excitability is modulated by different phases of the observed motor movement and this modulation is not muscle-specific. Simultaneous MI and AO enhance corticomotor excitability significantly compared to pure AO. PMID- 29230519 TI - Temperature influences perception of the length of a wielded object via effortful touch. AB - Individuals can perceive the properties of an attached or grasped object by wielding it through muscular effort-an ability referred to as dynamic or effortful touch. Sensitivity to the forces required to move such objects and to the resulting global patterns of tissue deformation underlies such perception. Given that perception via dynamic touch is movement-based, we hypothesized that manipulations that affect the ability to produce and control muscular movements might affect perception via dynamic touch. Cooling muscles from 40 to 10 degrees C impedes the development and transmission of muscular force and diminishes muscle stretch-reflex sensitivity. Accordingly, we anticipated that changes in hand temperature would alter the ability to detect patterns of tissue deformation and thus perception of the properties of wielded objects. In two experiments, participants wielded dowels with different lengths and rotational inertias (Experiment 1) and objects with identical lengths and different rotational inertias (Experiment 2). They reported perceived lengths of these objects, in the absence of vision, in cool (~ 10 degrees C), neutral (~ 30 degrees C), and warm temperature conditions (~ 40 degrees C). Actual length predicted perceived length of the dowels (Experiment 1), and rotational inertia predicted perceived length of the objects (Experiment 2); perceived lengths were longer in the warm condition than in the cool condition. In consideration of known temperature induced changes in tissue structure and function, our results support the hypothesis that comparable processes underlie the control of movement and perception via dynamic touch. PMID- 29230520 TI - Ipsilesional functional recruitment within lower mu band in children with unilateral cerebral palsy, an event-related desynchronization study. AB - Cerebral palsy (CP) is a group of non-progressive developmental movement disorders inducing a strong brain reorganization in primary and secondary motor areas. Nevertheless, few studies have been dedicated to quantify brain pattern changes and correlate them with motor characteristics in CP children. In this context, it is very important to identify feasible and complementary tools able to enrich the description of motor impairments by considering their neural correlates. To this aim, we recorded the electroencephalographic activity and the corresponding event-related desynchronization (ERD) of a group of mild-to moderate affected unilateral CP children while performing unilateral reach-to grasp movements with both their paretic and non-paretic arms. During paretic arm movement execution, we found a reduced ERD in the upper u band (10-12.5 Hz) over central electrodes, preceded by an increased fronto-central ERD in the lower u band (7.5-10 Hz) during movement preparation. These changes positively correlated, respectively, with the Modified House Classification scale and the Manual Ability Classification System. The fronto-central activation likely represents an ipsilesional plastic compensatory reorganization, confirming that in not-severely affected CP, the lesioned hemisphere is able to compensate part of the damage effects. These results highlight the importance of analyzing different sub-bands within the classical mu band and suggest that in similar CP population, the lesioned hemisphere should be the target of specific intensive rehabilitation programs. PMID- 29230521 TI - Correction to: Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials. AB - Owing to an oversight by the authors, all the figures in the last column of Table 2 (upper section: Number needed to treat; lower section: Number needed to harm) in this article were given without the final digit 0 and are thus 10 times too small. PMID- 29230522 TI - Airway pressure release ventilation: a step forward? PMID- 29230523 TI - Adjuvant therapies in critical care: steroids to treat infectious diseases. PMID- 29230524 TI - One-view digital breast tomosynthesis as a stand-alone modality for breast cancer detection: do we need more? AB - PURPOSE: To compare the performance of one-view digital breast tomosynthesis (1v DBT) to that of three other protocols combining DBT and mammography (DM) for breast cancer detection. MATERIALS AND METHODS: Six radiologists, three experienced with 1v-DBT in screening, retrospectively reviewed 181 cases (76 malignant, 50 benign, 55 normal) in two sessions. First, they scored sequentially: 1v-DBT (medio-lateral oblique, MLO), 1v-DBT (MLO) + 1v-DM (cranio caudal, CC) and two-view DM + DBT (2v-DM+2v-DBT). The second session involved only 2v-DM. Lesions were scored using BI-RADS(r) and level of suspiciousness (1 10). Sensitivity, specificity, receiver operating characteristic (ROC) and jack knife alternative free-response ROC (JAFROC) were computed. RESULTS: On average, 1v-DBT was non-inferior to any of the other protocols in terms of JAFROC figure of-merit, area under ROC curve, sensitivity or specificity (p>0.391). While readers inexperienced with 1v-DBT screening improved their sensitivity when adding more images (69-79 %, p=0.019), experienced readers showed similar sensitivity (76 %) and specificity (70 %) between 1v-DBT and 2v-DM+2v-DBT (p=0.482). Subanalysis by lesion type and breast density showed no difference among modalities. CONCLUSION: Detection performance with 1v-DBT is not statistically inferior to 2v-DM or to 2v-DM+2v-DBT; its use as a stand-alone modality might be sufficient for readers experienced with this protocol. KEY POINTS: * One-view breast tomosynthesis is not inferior to two-view digital mammography. * One-view DBT is not inferior to 2-view DM plus 2-view DBT. * Training may lead to 1v-DBT being sufficient for screening. PMID- 29230525 TI - Diagnostic accuracy of prospective application of the Liver Imaging Reporting and Data System (LI-RADS) in gadoxetate-enhanced MRI. AB - OBJECTIVES: To evaluate the diagnostic performance of the LI-RADS (v2014) on gadoxetate-enhanced MRI prospectively applied in actual practice. METHODS: We retrospectively reviewed the prospectively written radiology reports of 143 treatment-naive at-risk patients who underwent gadoxetate-enhanced liver MRI from January to December 2014, and identified 202 hepatic observations categorized using the LI-RADS. The diagnostic performances of LI-RADS categories for hepatocellular carcinoma (HCC) and hepatic malignancy were calculated. RESULTS: Twenty (69.0 %) of 29 LR-4, 73 (97.3 %) of 75 LR-5, and all of five (100 %) LR-5V observations were HCCs. The remaining two (2.7 %) LR-5 observations were combined hepatocellular-cholangiocarcinomas, while 10 (76.9 %) of 13 LR-M observations were HCCs. The sensitivity and specificity of LR-5/5V for HCC were 60.5 % and 97.3 %, respectively. Including LR-M in the diagnostic criteria for HCC increased sensitivity (68.2 %, p = 0.002) but decreased specificity without statistical significance (93.2 %, p = 0.154). LR-5/5V/M yielded sensitivity of 68.9 % and specificity of 100.0 % for hepatic malignancy. CONCLUSIONS: LI-RADS v2014 was successfully applied on gadoxetate-enhanced MRI in clinical practice. LR-5/5V was the most specific diagnostic measure for HCC, but most LR-M observations were HCCs and a considerable portion of non-HCC malignancies were categorized as LR-4 or LR-5. KEY POINTS: * LR-5/5V provided a highly specific diagnosis for HCC. * Half of non-HCC malignancies were categorized as LR-4 or LR-5. * The majority of LR-M observations were finally diagnosed as HCCs. * More sensitive diagnosis of HCC was feasible with LR-5/5V/M on gadoxetate-enhanced MRI. * Observations in either LR-5/5V or LR-M categories were definitely malignant. PMID- 29230526 TI - Peripheral nerve diffusion tensor imaging (DTI): normal values and demographic determinants in a cohort of 60 healthy individuals. AB - OBJECTIVE: To identify demographic determinants of peripheral nerve diffusion tensor imaging (DTI) and to establish normal values for fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). METHODS: Sixty subjects were examined at 3 Tesla by single-shot DTI. FA, AD, RD, and MD were collected for the sciatic, tibial, median, ulnar, and radial nerve and were correlated with demographic variables. RESULTS: Mean FA of all nerves declined with increasing age (r = -0.77), which could be explained by RD increasing (r = 0.56) and AD declining (r = -0.40) with age. Moreover, FA was inversely associated with height (r = -0.28), weight (r = -0.38) and BMI (r = 0.35). Although FA tended to be lower in men than women (p = 0.052), this difference became completely negligible after adjustment to body weight. A multiple linear regression model for FA was calculated with age and weight as predictors (defined by backward variable selection), yielding an R 2 = 0.71 and providing a correction formula to adjust FA for age and weight. CONCLUSION: Peripheral nerve DTI parameters depend on demographic variables. The most important determinants age and weight should be considered in all studies employing peripheral nerve DTI. KEY POINTS: * Peripheral nerve diffusion tensor imaging (DTI) parameters depend on demographic variables. * Fractional anisotropy (FA) declines with increasing age and weight. * Gender does not systematically affect peripheral nerve DTI. * The formula presented here allows adjustment of FA for demographic variables. PMID- 29230528 TI - Cofactor F430 as a biomarker for methanogenic activity: application to an anaerobic bioreactor system. AB - Over the last decades, anaerobic bioreactor technology proved to be a competitive technology for purifying wastewater while producing biogas. Methanogens perform the crucial final step in methane production, and monitoring their activity is of paramount importance for system understanding and management. Cofactor F430 is an essential prosthetic group of the methyl-coenzyme M reductase (MCR) enzyme catalysing this final step. This research investigates whether the quantification of cofactor F430 in bioreactor systems is a viable intermediate-complexity monitoring tool in comparison to the conventional biogas and volatile fatty acid (VFA) concentration follow-up and molecular genetic techniques targeting the mcrA gene encoding the MCR protein or its transcripts. Cofactor F430 was quantified in a lab-scale anaerobic membrane bioreactor (AnMBR) using liquid chromatography. The system was subjected to two organic loading rate shocks, and the F430 content of the sludge was followed up alongside mcrA gene copy and transcript numbers and classical performance monitoring tools. The research showed for the first time the combined mcrA gene transcript and F430 content dynamics in an anaerobic bioreactor system and reveals their significant positive correlation with in situ methane production rate. The main difference between the two monitoring methods relates to the cofactor's slower degradation kinetics. The work introduces the use of cofactor F430 as a biomarker for methanogenic activity and, hence, as a monitoring tool that can be quantified within half a working day, yielding information directly related to in situ methanogenic activity in methanogenic reactors. PMID- 29230527 TI - LEFTY2 inhibits endometrial receptivity by downregulating Orai1 expression and store-operated Ca2+ entry. AB - : Early embryo development and endometrial differentiation are initially independent processes, and synchronization, imposed by a limited window of implantation, is critical for reproductive success. A putative negative regulator of endometrial receptivity is LEFTY2, a member of the transforming growth factor (TGF)-beta family. LEFTY2 is highly expressed in decidualizing human endometrial stromal cells (HESCs) during the late luteal phase of the menstrual cycle, coinciding with the closure of the window of implantation. Here, we show that flushing of the uterine lumen in mice with recombinant LEFTY2 inhibits the expression of key receptivity genes, including Cox2, Bmp2, and Wnt4, and blocks embryo implantation. In Ishikawa cells, a human endometrial epithelial cell line, LEFTY2 downregulated the expression of calcium release-activated calcium channel protein 1, encoded by ORAI1, and inhibited store-operated Ca2+ entry (SOCE). Furthermore, LEFTY2 and the Orai1 blockers 2-APB, MRS-1845, as well as YM-58483, inhibited, whereas the Ca2+ ionophore, ionomycin, strongly upregulated COX2, BMP2 and WNT4 expression in decidualizing HESCs. These findings suggest that LEFTY2 closes the implantation window, at least in part, by downregulating Orai1, which in turn limits SOCE and antagonizes expression of Ca2+-sensitive receptivity genes. KEY MESSAGES: *Endometrial receptivity is negatively regulated by LEFTY2. *LEFTY2 inhibits the expression of key murine receptivity genes, including Cox2, Bmp2 and Wnt4, and blocks embryo implantation. *LEFTY2 downregulates the expression of Orai1 and inhibits SOCE. *LEFTY2 and the Orai1 blockers 2-APB, MRS 1845, and YM-58483 inhibit COX2, BMP2, and WNT4 expression in endometrial cells. *Targeting LEFTY2 and Orai1 may represent a novel approach for treating unexplained infertility. PMID- 29230529 TI - Sexual Maturity and Life Stage Influences Toxic Metal Accumulation in Croatian Brown Bears. AB - The influence of reproductive and (early) life stages on toxic metal levels was investigated in the brown bear (Ursus arctos), the largest mammalian predator species in Croatia. The purpose was to examine critical clusters in a population that might be at a higher risk of adverse health effects caused by metals as environmental contaminants. Levels of cadmium, mercury and lead in muscle, liver and kidney cortex of 325 male and 139 female bears, quantified by inductively coupled plasma mass spectrometry, were analysed according to distinct bear life stages (young: cub, yearling, subadult; mature: adult). Metal levels did not differ among sexes in young animals (< 4 years), except for mercury in muscles (higher in females), and adult females had higher cadmium and mercury. A trend of renal cadmium accumulation with age in immature male animals disappeared once they reached maturity, whereas for females this trend has only slowly declined in mature compared to immature bears. In early life stage (< 1 year), bear cubs had lower cadmium, comparable mercury, and higher lead in the kidneys than the bears of the following age category (yearlings). Due to a higher proportion of renal lead transfer from the mother to the cub compared with cadmium, it may be that the high burden of cadmium found in kidneys of older females has lower toxicological concern for their cubs than the lead content. Sex, reproductive, and life stages of bears were confirmed as important in assessing toxic metal burden. PMID- 29230530 TI - Typical Endocrine Disrupting Compounds in Rivers of Northeast China: Occurrence, Partitioning, and Risk Assessment. AB - Liao River Basin (LRB), located in northeast China, is one of seven largest river basins in China. The Daliao River Watershed (DLRW) is severely disturbed by human activities in the LRB. In this study, three rivers within the DLRW-Xi River (XR), Hun River (HR), and Daliao River (DLR)-were selected as sampling locations. The distribution, partitioning, and risk assessment of four endocrine-disrupting compounds (EDCs), e.g., bisphenol A (BPA), 17beta-estradiol (E2), estrone (E1), and 17alpha-ethinyl estradiol (EE2), in the rivers were investigated. The results showed that the concentration of BPA was generally higher than those of the other three steroidal estrogens in the sampling locations. The estrogen levels in the XR were greater than those in the HR and DLR. As a result of a decreasing river flow rate during the frozen season and irregular wastewater discharge from human domestic activities and manufacture processing, the total concentration of selected EDCs in the frozen season was much greater than those in nonfrozen season with the highest concentration in surface water of the XR at 1131.0 ng/L for BPA, 1235.0 ng/L for E1, 1253.5 ng/L for E2, and 17,111.5 ng/L for EE2, respectively. Based on the field-measured BPA concentrations in the sediment and water, the organic carbon-normalized partition coefficient (K oc) of BPA were calculated with the values of 2884-45,031 L/kg; the concentration of BPA in sediment was positive correlated with the content of OC (R 2 = 0.932). The risk assessment made by estradiol equivalent (EEQ) and risk quotient (RQ) showed that 64.7% of sampling sites were exposed to high estrogenic activity (?EEQ > 1) and high risk in surface water, whereas the RQ values of all selected estrogens in sediment were in medium or minimal risk. Both EE2 and E1 were the major contributors to the total estrogenic activity and risk quotient in surface water. PMID- 29230531 TI - Risk factors and the associated cutoff values for failure of corticosteroid injection in treatment of Morton's neuroma. AB - BACKGROUND: Understanding the risk factors that predict the prognosis of Morton's neuroma after corticosteroid injection would help clinicians determine the appropriate treatment protocol. However, the cut-off values for the risk factors are unknown. The aim of this study was to identify the risk factors and cut-off values that predict failure of corticosteroid injection in treatment of Morton's neuroma. METHOD: Among 201 patients who had corticosteroid injection for Morton's neuroma, 40 underwent further treatment after injections. Injection was performed with ultrasound guidance following ultrasound confirmation of the diagnosis. We compared demographic information, size of the neuroma, and other comorbidities between the patients who did and did not undergo further treatment after injection in order to determine the risk factors of failure. Receiver operating characteristic (ROC) curves were constructed to determine optimal cutoff values for each risk factor. RESULTS: Stepwise logistic regression analysis showed that larger neuromas (p < 0.001) and younger patients (p = 0.026) predicted the failure of corticosteroid injection. The optimal cutoff value for the size of the neuroma was 6.3 mm (sensitivity, 81%; specificity, 95%; positive predictive value, 84%; negative predictive value, 88%) for predicting the failure of corticosteroid injection. Age was not associated with a specific cutoff value. CONCLUSIONS: This study found that, with a cut-off value of 6.3 mm, larger Morton's neuromas were associated with failure of corticosteroid injection. PMID- 29230532 TI - RNA-mediated transgenerational inheritance in ciliates and plants. AB - In the age of next-generation sequencing (NGS) and with the availability of whole sequenced genomes and epigenomes, some attention has shifted from purely sequence based studies to those of heritable epigenetic modifications. Transgenerational inheritance can be defined as heritable changes to the state of DNA that may be passed on to subsequent generations without alterations to the underlying DNA sequence. Although this phenomenon has been extensively studied in many systems, studies of transgenerational inheritance in mammals and other higher-level eukaryotes may be complicated by the fact that many epigenetic marks are reprogrammed during sexual reproduction. This, by definition, may obscure our interpretation of what is in fact truly transgenerational. Therefore, in this mini review, we discuss what is currently known in the field about transgenerational epigenetic inheritance in ciliates and plants, with a particular emphasis on RNA-mediated processes and changes in chromatin states. PMID- 29230535 TI - A new method for non-invasive biomass determination based on stereo photogrammetry. AB - A novel, non-destructive method for the biomass estimation of biological samples on culture dishes was developed. To achieve this, a photogrammetric system, which consists of a digital single-lens reflex camera (DSLR), an illuminated platform where the culture dishes are positioned and an Arduino board which controls the capturing process, was constructed. The camera was mounted on a holder which set the camera at different title angles and the platform rotated, to capture images from different directions. A software, based on stereo photogrammetry, was developed for the three-dimensional (3D) reconstruction of the samples. The proof of-concept was demonstrated in a series of experiments with plant tissue cultures and specifically with calli cultures of Salvia fruticosa and Ocimum basilicum. For a period of 14 days images of these cultures were acquired and 3D reconstructions and volumetric data were obtained. The volumetric data correlated well with the experimental measurements and made the calculation of the specific growth rate, u max, possible. The u max value for S. fruticosa samples was 0.14 day-1 and for O. basilicum 0.16 day-1. The developed method demonstrated the high potential of this photogrammetric approach in the biological sciences. PMID- 29230534 TI - The Burden of Comorbidity and Complexity in Sarcoidosis: Impact of Associated Chronic Diseases. AB - PURPOSE: To evaluate comorbidity, complexity and poor outcomes in patients with sarcoidosis and to compare those scores with a control group. METHODS: 218 consecutive patients were diagnosed with sarcoidosis according to the ATS/ERS/WASOG criteria; extrathoracic involvement was evaluated using the 2014 WASOG organ assessment instrument. Sarcoidosis patients were compared with an age and gender-matched control group of primary care outpatients without sarcoidosis. Comorbidities were assessed retrospectively using the Charlson Comorbidity Index (CCI); complexity was evaluated according to the classification into Clinical Risk Groups (CRG) and severity levels. RESULTS: The cohort included 142 women and 76 men; the mean age was 47.1 years at diagnosis of sarcoidosis and 55.9 years at the last visit. Patients with a CCI > 1 had a higher frequency of calcium/vitamin D abnormalities (p < 0.001), kidney involvement (p = 0.005) and a higher mortality rate (p < 0.001) compared with patients with a CCI <= 1. Patients with a CRG >= 6 had a higher frequency of extrathoracic involvement (p = 0.039), calcium/vitamin D abnormalities (p = 0.019) and treatment with glucocorticoids (p = 0.032) compared with patients with a CRG < 6. 11% patients died after a mean follow-up of 102.3 months. Country of birth, kidney involvement and extrathoracic disease were significantly associated with death. Patients with sarcoidosis had a higher frequency of liver (p < 0.001), pulmonary (p = 0.002) and autoimmune disease (p = 0.011) and cancer (p = 0.007) compared with the control group. CONCLUSION: We found higher rates of comorbidity and complexity in patients with sarcoidosis compared with a control group. Liver, pulmonary, autoimmune and neoplastic diseases were the main comorbidities found in patients with sarcoidosis. PMID- 29230533 TI - Regulation of type I collagen expression by microRNA-29 following ionizing radiation. AB - Radiation-induced fibrosis (RIF) is thought to involve the excessive accumulation of collagen and other extracellular matrix components; previously, we reported that ionizing radiation increased the type I collagen expression and that transforming growth factor (TGF)-beta was involved in this increase through activating its downstream mediator, Smad3. A recent study found that microRNAs (miRNAs)-small, noncoding sequences approximately 20 nucleotides long-negatively regulate the gene expression posttranscriptionally, and it has been suggested that miRNAs play essential roles in cellular processes, including fibrosis. However, their role in the development of RIF remains unexplored. In the present study, we examined the effects of miRNA on the expression of type I collagen induced by ionizing radiation and the mechanisms underlying the miRNA expression observed following ionizing radiation. We analyzed the regulation of miRNA following ionizing radiation by an miRNA real-time PCR, and found that miR-29 family members were downregulated in irradiated mouse fibroblasts and directly targeted type I collagen genes by specifically binding to the 3' untranslated region. We also found that the overexpression of miR-29 inhibited the ionizing radiation-induced expression of type I collagen, whereas the knockdown of miR-29 enhanced it. In addition, TGF-beta/Smad-signaling significantly decreased the transcription of miR-29, whereas the inhibition of this signaling pathway cancelled this decrease. In conclusion, miR-29 was involved in the regulation of type I collagen expression through the TGF-beta/Smad-signaling pathway in irradiated cells, suggesting that miR-29 may be an important regulator of RIF. PMID- 29230536 TI - Development of nitrogen supply strategy for Scenedesmus rubescens attached cultivation toward growth and lipid accumulation. AB - In this study, the microalgae Scenedesmus rubescens were cultivated under the following nitrogen sources, nitrogen concentrations, and nitrogen feeding times (NFTs). This was to help assess biomass and lipid productivity. Scenedesmus rubescens can grow well by adhering to the cellulose acetate membrane in five kinds of nitrogen medium: KNO3, urea, NaNO3, (NH4)2CO3, and NH4NO3. Under the criteria of bio-productivity and lipid productivity, urea was the optimal nitrogen source. Among different urea concentrates, biomass productivity and lipid content of S. rubescens cultivated in 0.27 g/L urea medium were optimized at 8.8 g/(m2 day) and 31.1%, respectively. With attached cultivation, the highest biomass of 9.4 g/m2 was obtained at NFTs of 4 days. These results showed that culturing S. rubescens using urea as sole nitrogen source by improving nitrogen uptake with attached cultivation is more efficient. PMID- 29230537 TI - What is the net effect of introducing vitrification for cryopreservation of surplus 2PN oocytes in an IVF program? AB - PURPOSE: The aim of this study was to accurately describe outcome differences (cryo-survival, pregnancy rate and live birth rate, both per ET and cumulatively), between the vitrification method and slow-freezing method of surplus 2PN oocytes in an IVF program. METHODS: In 2004, the freezing method for 2PN oocytes was changed from slow-cooling to vitrification. The data of 711 patients (timespan: 1/1999-7/2011; 410 vitrification and 301 slow-cooling events) undergoing a first IVF/ICSI cycles with freezing of 2PN oocytes were retrospectively analyzed. The outcome of one, the first, IVF cycle per patient was explored. The data were analyzed per freezing-thawing attempt as well as cumulatively per one complete IVF cycle, taking pregnancy occurrence after a fresh embryo transfer preceding the cryo-cycle(s) and other confounders (such as female age, elective vs. surplus 2PN cryopreservation) into account by means of exploratory regression analyses. RESULTS: In the vitrification and slow-cooling group, 756 and 376, respectively, attempts of thawing 2PN oocytes were recorded. Each attempt of thawing 2PN oocytes showed statistically significantly higher mean cryo-survival rates after vitrification (effect size approximately 30-40%, with vitrification cryo-survival consistently above 90% in all thawing attempts). Furthermore, the incidence of "zero survival" was lower after vitrification (0.5 vs. 7.3%, p < 0.01). It is estimated that the odds of achieving a live birth per one IVF cycle (fresh and frozen transfers combined) with vitrification of 2PN oocytes is increased approximately 1.4-fold (OR of 1.405, 95% CI 0.968-2.038; p = 0.07); however, statistical significance was not achieved due to sample size. Female age and elective cryopreservation of all 2PN oocytes without a fresh transfer (e.g., hyperresponders) were found to be negatively and positively, respectively, associated with the chance of achieving a live birth. CONCLUSIONS: The introduction of vitrification has a measurable impact on the efficacy of an IVF program. However, this effect is not large despite the impressively higher cryo-survival rates with vitrification. The "true" net efficacy effect of introducing 2PN vitrification in an IVF program will, in real life, be lower due to patients not having surplus 2PN oocytes available for freezing and later transfer. PMID- 29230538 TI - A robotic shower system : Acceptance and ethical issues. AB - BACKGROUND: Being able to maintain personal hygiene plays a crucial role for independent living in old age or when suffering from disabilities. Within the European project ICT Supported Bath Robots (I-SUPPORT) an intelligent robotic shower system is being developed, which enables patients to shower independently at home or in institutionalized settings. OBJECTIVE: The aim of this contribution is the identification of ethical issues in the development of a robotic shower system utilizing the model for the ethical evaluation of socio-technical arrangements (MEESTAR). MATERIAL AND METHODS: In I-SUPPORT a variety of concepts and methods are implemented in order to achieve technology acceptance such as user-centered requirements analysis, usability-tests and analysis of sociocultural and ethical aspects. This article reports the analysis of focus groups with 14 older adults and 9 professional caregivers utilizing MEESTAR as a heuristic approach for analyzing sociotechnical arrangements and identifying ethical problems. RESULTS AND DISCUSSION: The MEESTAR procedure was adapted to the research question and client groups and implemented as a discursive method. This gave an insight into the meaning and background of ethical aspects and also a deeper insight into nursing processes as well as the requirements which the system should fulfil. Shortcomings are that the ethical dimensions are not everyday language and the time restrictions. In the next step a standardized assessment instrument will be developed and piloted. PMID- 29230539 TI - Use of methylene blue and near-infrared fluorescence in thyroid and parathyroid surgery. AB - PURPOSE: Intraoperative localisation and preservation of parathyroid glands improves outcomes following thyroid and parathyroid surgery. This can be facilitated by fluorescent imaging and methylene blue; a fluorophore is thought to be taken up avidly by parathyroid glands. This preliminary study aims to identify the optimum dose of methylene blue (MB), fluorescent patterns of thyroid and parathyroid glands and develop a protocol for the use of intravenous MB emitted fluorescence to enable parathyroid identification. METHODS: This is a phase 1b, interventional study (NCT02089542) involving 41 patients undergoing thyroid and/or parathyroid surgery. After exposure of the thyroid and/or parathyroid gland(s), intravenous boluses of between 0.05 and 0.5 mg/kg of MB were injected. Fluobeam(r) (a hand held fluorescence real-time imager) was used to record fluorescence from the operating field prior and up to 10 min following administration. RESULTS: The optimum dose of MB to visualise thyroid and parathyroid glands was 0.4 mg/kg body weight. The median time to onset of fluorescence was 23 and 22 s and the median time to peak fluorescence was 41.5 and 40 s, respectively. The peak fluorescence for thyroid and parathyroid glands compared to muscle were 2.6 and 4.3, respectively. Parathyroid auto-fluorescence prior to methylene blue injection was commonly observed. CONCLUSIONS: A clinical protocol for detection of fluorescence from MB during thyroid and parathyroid surgery is presented. Parathyroids (especially enlarged glands) fluoresce more intensely than thyroid glands. Auto-fluorescence may aid parathyroid detection, but MB fluorescence is needed to demonstrate viability. PMID- 29230540 TI - Preventing future fractures: effectiveness of an orthogeriatric fracture liaison service compared to an outpatient fracture liaison service and the standard management in patients with hip fracture. AB - : An observational study was carried out in two hospitals in patients > 65 years admitted for hip fracture. At 6 months, 15% of patients in the hospital with orthogeriatric standard care and 75% in the hospital with fracture liaison service were receiving bisphosphonates. PURPOSE: Many patients with fractures are discharged without preventive therapy against further fractures. We sought to compare the effectiveness of an orthogeriatric fracture liaison service (FLS), outpatient FLS, and the standard care after hip fractures in prevention of future fractures. METHODS: An observational study was carried out in two hospitals in patients > 65 years of age, admitted between March and July 2016 for fractures. The Candelaria hospital (HUNSC) has no specific protocol for secondary prevention, while at the Negrin Hospital (HUGCDN), an FLS nurse visits the inpatients, gathers metabolic history, instructs regarding the diet, exercises, and fall prevention, and completes a discharge report regarding osteoporosis treatment. The prescription rate of osteoporosis treatment was analyzed at admission, discharge, and 6 months after discharge. We also analyzed the data of patients with hip fractures who attended the outpatient FLS before March 2016. RESULTS: We included a total of 185 inpatients with a mean age of 82 years and 73% were women. At admission, 8% of the patients in HUNSC and 10% in HUGCDN were receiving bisphosphonates. At discharge, the percentages were 8 and 96%, while at 6 months they were 15 and 75%, respectively (p < 0.001). The outpatient FLS recorded 206 hip fractures (27% of discharges for fractures), with 77% adherence to treatment at 6 months. CONCLUSIONS: Compared with the conventional management, the FLS model for inpatients with hip fractures achieved a fivefold increase in the adherence to treatment at 6 months, similar to the rates of outpatient FLS. PMID- 29230541 TI - Theoretical and experimental investigation into a eutectic system of 3,4 dinitropyrazole and 1-methyl-3,4,5-trinitropyrazole. AB - Eutectic mixtures of 3,4-dinitropyrazole (DNP) and 1-methyl-3,4,5 trinitropyrazole (MTNP) were investigated by theoretical and experimental methods. The mass ratio of DNP and MTNP ranged from 0:100 to 100:0. Melting points of the mixtures were predicted through observing the inflection point of a specific volume vs. temperature in molecular dynamics (MD) simulation. The results are in good agreement with experimental results obtained from the differential scanning calorimeter (DSC) study. The binding energy of a 50/50 DNP/MTNP eutectic mixture is lower than those of other mixtures, in accordance with the common sense that the melting point of materials is linked to the strength of intermolecular interactions. There are definitely hydrogen bonds and dispersion interactions between DNP and MTNP based on the analyses of interaction energy, atom in molecules (AIM), and reduced density gradient (RDG). The eutectic mixture would be encouraged to be used in melt-cast explosives because of the favorable sensitivity to heat and impact, great detonation performances, acceptable vacuum stability and excellent compatibility with high explosives. Graphical abstract The eutectic mixture of DNP and MTNP were investigated through molecular dynamics (MD) simulation and quantum chemistry calculations. The predicted melting points of mixtures are in good agreement with the experimental data. The eutectic mixture shows good stability. PMID- 29230542 TI - Secondary intracranial hypertension (pseudotumor cerebri) presenting as post traumatic headache in mild traumatic brain injury: a case series. AB - BACKGROUND: Cerebral edema peaks 36-72 h after moderate traumatic brain injury but thought to be uncommon after mild traumatic brain injury. Post-traumatic headache can develop 48-72 h post-injury, perhaps reflecting the developing cerebral edema. Pseudotumor cerebri can result from various causes, including cerebral edema, and is characterized by increased intracranial pressure, headache, visual, and other common symptoms. Our objective was to report a phenotypically identifiable post-traumatic headache subtype. CASE SERIES PRESENTATION: This case series of six pediatric patients with post-traumatic pseudotumor cerebri was assessed at 48-120 h post-primary injury with new or a change in symptoms such as headache, vision, auditory, balance, and cognition. Clinical findings included slight fever, neck/head pain, papilledema or cranial nerve deficit (6th), and lack of coordination. Elevated cerebral spinal fluid pressure was documented by lumbar puncture, with no infection. Symptoms improved with treatment specific to post-traumatic headache subtype (lumbar puncture, topiramate, or acetazolamide). CONCLUSIONS: Recognition of specific post traumatic headache subtypes after mild traumatic brain injury will expedite treatment intervention to lower intracranial pressure and resolve symptoms. PMID- 29230543 TI - The contents and distributions of cadmium, mercury, and lead in Usnea antarctica lichens from Solorina Valley, James Ross Island (Antarctica). AB - Lichens are efficient and cost-effective biomonitors of the environment. Their geographic distribution together with their slow growth rate enable investigation of the deposition patterns of various elements and substances. In this research, levels of cadmium, lead, and mercury in Usnea antarctica lichens in the area of James Ross Island, Antarctica, were investigated. The lichens were microwave digested, and the metals were determined by means of atomic absorption spectrometry with graphite furnace and a direct mercury analyzer. Median total contents of Cd, Hg, and Pb were 0.04, 0.47, and 1.6 mg/kg in whole lichens, respectively. The bottom-up distributions of these metals in the fruticose lichen thalli were investigated, and it was revealed that the accumulation patterns for mercury and lead were opposite to that for cadmium. The probable reason for this phenomenon may lie in the inner structure of thalli. The total contents of metals were comparable with those published for other unpolluted areas of maritime Antarctica. However, this finding was not expected for mercury, since the sampling locality was close to an area with some of the highest mercury contents published for Antarctic lichens. In short, lichens proved their usability as biological monitors, even in harsh conditions. However, the findings emphasize the need to take into account the distributions of elements both in the environment and in the lichen itself. PMID- 29230544 TI - Size discrimination in barn owls as compared to humans. AB - We tested how well barn owls can discriminate objects of different sizes. This ability may be important for the owls when catching prey. We performed a quantitative experiment in the laboratory and trained owls in a task in which the owls had to discriminate whether two rhombi presented simultaneously on a computer monitor were of the same or of different sizes. We obtained full data sets with two experienced owls and one data point with a third owl. For objects being sufficiently larger than the spatial resolution of the barn owl, the angular threshold was related to object size, implying that the discrimination followed Weber's law. The range of Weber fractions we determined was between 0.026 and 0.09. For object sizes close to the spatial resolution, performance degraded. We conducted similar experiments with human subjects. Human thresholds showed the same dependence on object size, albeit down to smaller object sizes. Human performance resulted in a range of Weber fractions extending from 0.025 to 0.036. The differences between owls and humans could be explained by the much higher spatial acuity of humans compared with owls. PMID- 29230545 TI - Influence of different types of light on the response of the pulp tissue in dental bleaching: a systematic review. AB - OBJECTIVES: This systematic review (PROSPERO register: CRD42016053140) investigated the influence of different types of light on the pulp tissue during dental bleaching. MATERIALS AND METHODS: Two independent authors conducted a systematic search and risk of bias evaluations. An electronic search was undertaken (PubMed/Medline, Embase, The Cochrane Library, and other databases) until May 2017. The population, intervention, comparison, outcomes (PICO) question was: "Does the light in dental bleaching change the response of the pulp to the bleaching procedure?" The intervention involved pulp tissue/cells after bleaching with light, while the comparison involved pulp tissue/cells after bleaching without light. The primary outcome was the inflammation/cytotoxicity observed in pulp after bleaching. RESULTS: Out of 2210 articles found, 12 articles were included in the review; four were in vivo studies (one study in dogs/others in human), and eight were in vitro studies (cell culture/with artificial pulp chamber or not). The light source used was halogen, light emitting diode (LED), and laser. Only one in vivo study that used heat to simulate light effects showed significant pulp inflammation. Only two in vitro studies demonstrated that light influenced cell metabolism; one using halogen light indicated negative effects, and the other using laser therapy indicated positive effects. Given that animal and in vitro studies have been identified, there remain some limitations for extrapolation to the human situation. Furthermore, different light parameters were used. CONCLUSIONS: The effects of dental bleaching on the pulp are not influenced by different types of light, but different light parameters can influence these properties. CLINICAL RELEVANCE: There is insufficient evidence about the influence of different types of light on inflammation/cytotoxicity of the pulp. PMID- 29230546 TI - Management and predictors of outcome in unselected patients with cardiogenic shock complicating acute ST-segment elevation myocardial infarction: results from the Bremen STEMI Registry. AB - INTRODUCTION: Patients with ST-segment elevation myocardial infarction (STEMI) and consecutive cardiogenic shock (CS) represent a challenge in clinical practice. Only few 'real-world' data on therapeutic management and outcome exist. METHODS: The present analysis focuses on changes of clinical management of STEMI patients with CS and analyzes predictors of outcome using the Bremen-STEMI registry. RESULTS: Out of 7865 patients with STEMI, 981 patients (13%) presented with CS. Most CS patients (88%) underwent an early percutaneous intervention (PCI). Intraaortic balloon pumps (IABP) were less implanted since 2013 (p < 0.001), the rate of drug-eluting stents and periprocedural prasugrel or ticagrelor therapy increased over the years. Overall in-hospital mortality of patients with CS was 37%, 1 year mortality was 50%. A significantly reduced 1 year mortality (2006-2009: 55%, 2010-2013: 50%; 2014-2015: 43%, p = 0.027) was observed. In a multivariate analysis significant predictors of an increased 1 year mortality were acute renal failure (OR 3.6; 95% CI 1.9-7.0), atrial fibrillation (OR 2.8; 95% CI 1.3-6.0), three-vessel disease (OR 2.5; 95% CI 1.3 4.7), age >= 75 years (OR 2.4, 95% CI 1.3-4.4) and anemia (OR 1.9; 95% CI 1.1 3.3). A successful performed PCI (OR 0.5, 95% CI 0.2-0.9) was associated with a significantly reduced 1-year mortality. CONCLUSION: management of patients with CS changed with a steep decrease of IABP implantations. Mortality of patients with CS decreased over the last 10 years. Especially, performance of successful PCI was associated with a reduction of mortality, indicating the crucial role of early revascularization to improve prognosis in this high-risk cohort of STEMI patients. PMID- 29230547 TI - Novel fluorochromes label tonoplast in living plant cells and reveal changes in vacuolar organization after treatment with protein phosphatase inhibitors. AB - The recently synthesized isocyanonaphtalene derivatives ACAIN and CACAIN are fluorochromes excitable at wavelengths of around 366 nm and bind cysteine-rich proteins with hydrophobic motifs. We show that these compounds preferentially label tonoplasts in living Arabidopsis and tobacco (Nicotiana tabacum SR1) cells. ACAIN-labeled membranes co-localized with the GFP signal in plants expressing GFP delta-TIP (TIP2;1) (a tonoplast aquaporin) fusion protein. ACAIN preserved the dynamics of vacuolar structures. tip2;1 and triple tip1;1-tip1;2-tip2;1 knockout mutants showed weaker ACAIN signal in tonoplasts. The fluorochrome is also suitable for the labeling and detection of specific (cysteine-rich, hydrophobic) proteins from crude cell protein extracts following SDS-PAGE and TIP mutants show altered labeling patterns; however, it appears that ACAIN labels a large variety of tonoplast proteins. ACAIN/CACAIN could be used for the detection of altered vacuolar organization induced by the heptapeptide natural toxin microcystin-LR (MCY-LR), a potent inhibitor of both type 1 and 2A protein phosphatases and a ROS inducer. As revealed both in plants with GFP-TIP2;1 fusions and in wild-type (Columbia) plants labeled with ACAIN/CACAIN, MCY-LR induces the formation of small vesicles, concomitantly with the absence of the large vegetative vacuoles characteristic for differentiated cells. TEM studies of MCY-LR-treated Arabidopsis cells proved the presence of multimembrane vesicles, with characteristics of lytic vacuoles or autophagosomes. Moreover, MCY-LR is a stronger inducer of small vesicle formation than okadaic acid (which inhibits preferentially PP2A) and tautomycin (which inhibits preferentially PP1). ACAIN and CACAIN emerge as useful novel tools to study plant vacuole biogenesis and programmed cell death. PMID- 29230548 TI - Quality of life of patients with locally advanced head and neck cancer treated with induction chemotherapy followed by cisplatin-containing chemoradiotherapy in the Dutch CONDOR study: a randomized controlled trial. AB - PURPOSE: The CONDOR study showed that docetaxel/cisplatin/5-fluorouracil (TPF) followed by conventional radiotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 (cis100 + RT; n = 27)) versus accelerated radiotherapy with cisplatin weekly 40 mg/m2 (cis40 + ART; n = 29) in locally advanced head and neck cancer (LAHNC) patients was not feasible. Here, we report the analysis of health-related quality of life (HRQOL) of the patients entered in this study. METHODS: HRQOL was assessed at baseline, after two TPF, before start of chemoradiotherapy, and 1, 4, 8, 12, and 24 months after completion of chemoradiotherapy using the EORTC-QLQ C30 and QLQ-H&N35 in 62 patients. RESULTS: Compliance with the QOL questionnaires was 94% (59/62) at baseline and 61% (30/49) at 12 months, respectively. HRQOL decreased after TPF and further decreased during chemoradiohteray in both arms equally. Pain and swallowing dysfunction improved significantly during TPF but deteriorated below baseline levels during chemoradiotherapy, cis40 + ART > cis100 + RT (p < 0.05). HRQOL and symptoms restored to baseline within 12 months in both arms and remained at that level until 24 months. CONCLUSIONS: After TPF, cis40 + ART had a larger negative impact on symptoms than cis100 + RT, probably due to the ART. HRQOL and symptoms restored to baseline levels within 12 months after end of treatment in both arms, which is an important perspective for patients during the phase of most serious acute side effects of treatment. TRIAL REGISTRATION: NCT00774319. PMID- 29230549 TI - A nationwide survey of incidence rates and risk factors of inguinal hernia in preterm children. AB - PURPOSE: Clinical observations showed a higher incidence rate of inguinal hernia (IH) in preterm infants. In this study, we calculated the incidence rate of preterm IH from the National Health Insurance Research Database (NHIRD) of Taiwan. METHODS: From NHIRD, 92,308 subjects born in the year of 1997-2005 were randomly selected as the study cohort. The medical claims of these subjects from birth to 6th year of age were analyzed. Preterm births were defined using ICD code 765.1*. Risk factors such as birth weight, lung disorders, and ventilator supports before IH repairs were investigated. The risk of incarceration and bowel resection were also evaluated. RESULTS: From 92,308 subjects, 2560 preterm births were identified. IH was repaired in 231 preterm (9.02%) and 3650 term subjects (4.07%). Male (preterm 13.3% and non-preterm 6.3%) had more hernia repairs than female (preterm 3.8% and non-preterm 1.6%). The incidence rate of IH is 13.7% for those under 1500 g, 8.2% for those 1500-1999 g, 7.7% for those 2000-2499 g, and 6.3% for those above 2500 g. The incidence rate of IH in preterms with past history of lung disorders and ventilation supports is 8.7 and 13.6%, respectively. There was no significant difference in the incidences of incarceration and bowel resection between preterms and non-preterms. CONCLUSIONS: Birth weight under 2500 g is a significant risk factor for IH repairs. Other risk factors are male gender, past history of lung diseases, and ventilator supports. PMID- 29230550 TI - [Acupuncture covered by statutory health insurance in Germany : An observational study based on claims data]. AB - BACKGROUND: The coverage for acupuncture for chronic lower back or knee pain by the statutory health insurance was introduced in 2007. The aim of this study was to investigate characteristics of patients and providers of acupuncture and temporal and regional trends in the utilization of acupuncture. METHODS: This retrospective observational study used anonymized statutory health insurance claims data from a sample of roughly four million subjects. The sample is representative of the German population regarding age and gender in 2013. RESULTS: Lower back pain was the most common coded indication (86%) for billing acupuncture. Women were more often treated with acupuncture than men; the mean age was 61.1 years. For 63% acupuncture was billed in 2014 for the first time, 37% already had an acupuncture treatment in 2012 or 2013. Premature termination (<6 sessions) was observed in 14% of all insurants receiving acupuncture for the first time in 2014 for knee pain and in 21% of those with back pain. Overall there was a statistically significant decrease in the utilization of acupuncture from 2008 to 2015. Regional differences between East and West Germany and city states were observed. Half of all acupuncture treatments in 2014 were provided by 11% of all physicians who billed acupuncture at least once. DISCUSSION: Higher utilization of acupuncture by women reflects the epidemiology of back and knee pain and their preference for alternative complementary medicine. On the one hand, the large proportion of patients treated repeatedly with acupuncture suggests perceived benefits. On the other hand, provision of acupuncture services is decreasing continuously and a relevant proportion of subjects are terminating treatment prematurely. PMID- 29230551 TI - [Pain and poverty]. AB - BACKGROUND: Poverty is an important problem in Germany. The health effects of poverty can lead to a higher risk of disease and the arising of chronic affections. On the other hand chronic illness may support the development and continuance of poverty. The context of chronic pain and poverty has not been analyzed so far. OBJECTIVES: We investigated the correlation between chronic pain and poverty. MATERIALS AND METHODS: In a prospective manner we interviewed 20 patients with pain syndromes during our consultation hour regarding their household income. Further, data from the German Federal Statistical Office were analyzed with respect to the correlation between the incidence of a chronic pain diagnosis and household income. RESULTS: At 1546 ?, the average household income of the patients studied was below the poverty level. The analyzed data showed that women suffered from chronic pain more often than men did and also had a lower income. Another economic inequality was found between Eastern and Western Germany. There was a statistically significant correlation between income and the incidence of the diagnostic codes for chronic pain (R52.1, 2, 9) for men. CONCLUSION: Our investigation showed the correlation between chronic pain and poverty. A commitment and cooperation of German medical associations and federal politics is necessary to overcome this sociopolitical issue. PMID- 29230552 TI - Identification of clustered phosphorylation sites in PKD2L1: how PKD2L1 channel activation is regulated by cyclic adenosine monophosphate signaling pathway. AB - Polycystic kidney disease 2-like-1 (PKD2L1), or polycystin-L or TRPP2, formerly TRPP3, is a transient receptor potential (TRP) superfamily member. It is a calcium-permeable non-selective cation channel that regulates intracellular calcium concentration and thereby calcium signaling. PKD2L1 has been reported to take part in hedgehog signaling in renal primary cilia and sour tasting coupling with PKD1L3. In addition to the previous reports, PKD2L1 is recently found to play a crucial role in localization with beta2-adrenergic receptor (beta2AR) on the neuronal primary cilia. The disruption of PKD2L1 leads to the loss of beta2AR on the primary cilia and reduction in intracellular concentration of cyclic adenosine monophosphate (cAMP). Since the role of cAMP and PKA is frequently mentioned in the studies of PKD diseases, we investigated on the mechanism of cAMP regulation in relation to the function of PKD2L1 channel. In this study, we observed the activity of PKD2L1 channel increased by the downstream cascades of beta2AR and found the clustered phosphorylation sites, Ser-682, Ser-685, and Ser 686 that are significant in the channel regulation by phosphorylation. PMID- 29230553 TI - Correction to: Letter to the editor. AB - The original version of this article unfortunately contained a mistake. There was an error in the last sentence of the article. It should read as "Therefore, we propose to incorporate the current LR-M category into LR-4 and LR-5 using the suffix "M," as LR-4M or LR-5M categories, to indicate the probability of non-HCC malignancy in each category". PMID- 29230554 TI - Correction to: Differentiating focal nodular hyperplasia from hepatocellular adenoma: Is hepatobiliary phase MRI (HBP-MRI) using linear gadolinium chelates always useful? AB - The original version of this article unfortunately contained a mistake. There was an error in the last sentence of the summary and the last sentence of the discussion. It should read as "On HBP, all FNH appeared hyper- or iso-intense compared to adjacent liver while close to 97% of HCA appeared hypointense". PMID- 29230555 TI - Non-visualization of the ovary on CT or ultrasound in the ED setting: utility of immediate follow-up imaging. AB - PURPOSE: In the setting of female patients in the ED receiving both a CT scan and ultrasound of the pelvis, we compared the studies to assess the diagnostic value of non-visualization of the ovary in predicting the absence of ovarian disease. METHODS: A retrospective review of the electronic medical record identified adult female non-pregnant patients who received both a CT abdomen and pelvis and a transabdominal and transvaginal pelvic ultrasound within a 48-h period through the emergency department. The imaging studies were blindly reviewed to evaluate the ovaries on each CT and US independently. Ovaries were characterized as normal, non-visualized, or abnormal requiring follow-up. All cases of non visualized ovaries were compared to the appearance on the corresponding exam for each patient, and assessed for agreement (normal or non-visualized) or disagreement (abnormal). Subsequently, the electronic medical record was used as a reference standard to assess the presence or absence of ovarian pathology over the subsequent ninety days. Statistical analysis was performed utilizing a McNemar test with a 95% confidence interval. RESULTS: A total of 181 patients were included in the study (age range 18-75). Of these, 36 patients had non visualization of one ovary (21 patients) or both ovaries (15 patients) on either study. On CT, 18 ovaries were non-visualized, with no cases of disagreement on ultrasound or subsequent short-term follow-up (NPV 100%). On ultrasound, 39 ovaries were non-visualized, with three of these adnexae appearing abnormal on CT (NPV 92%): one with an enlarged ovary and two with hydrosalpinx. No ovarian abnormalities were evident on chart follow-up. Significant correlation of agreement between normal and non-visualized pairs on CT and US was observed (p = 0.025, McNemar). There was a combined NPV of 94% regardless of modality for the absence of ovarian pathology in the case of non-visualization. The most common abnormal imaging findings associated with non-visualized ovaries were uterine fibroids and hemoperitoneum. CONCLUSION: The absence of detection of the ovary on pelvic US or CT is highly predictive of the lack of ovarian abnormality on short term follow-up, and does not typically require additional imaging to exclude ovarian disease. PMID- 29230556 TI - Liver-directed therapy for hepatocellular carcinoma. AB - Liver-directed therapy is a critical component of treatment strategies for hepatocellular carcinoma. These therapies included percutaneous image-guided ablation, transarterial chemoembolization, and transarterial radioembolization, and are administered by interventional radiologists. Depending on the stage of disease, a particular treatment modality, or a combination thereof, is expected to be most efficacious in achieving the goals of treatment for a particular patient. This article seeks to review the various liver-directed treatment modalities for treatment of hepatocellular carcinoma, with attention to their efficacy and patient selection criteria. PMID- 29230557 TI - Seasonal variation of serum vitamin D levels in Romania. AB - : We measured serum vitamin D in 8024 Romanian subjects and found a marked seasonal variation with highest levels in September and lowest levels in March. The seasonal variation (early autumn vs. early spring) persisted in all age and sex groups. The prevalence of vitamin D deficiency was very high. PURPOSE: Romania is located in Eastern Europe, roughly between 44 degrees N and 48 degrees N latitude. Seasonal variation of serum vitamin D in Romanian subjects is unknown. We assessed the seasonal variation of 25-hydroxy vitamin D [25(OH)D] in Romanian population. METHODS: We retrieved from our endocrinology center database all 25(OH)D measurements between 2012 and 2016. We also evaluated age, sex, diagnosis, and date of blood sampling. The 25(OH)D was measured by two different chemiluminescence or electrochemiluminescence assays. RESULTS: There were 8024 subjects (median age 50 (37, 62); 1429 men (17.8%)) without a diagnosis of low bone mass (osteopenia or osteoporosis). The median serum 25(OH)D was 18.6 (12.7, 25.4) ng/mL. Of the subjects, 0.73, 14.4, 55.6, and 86.1% had a serum 25(OH)D level below 4, 10, 20, and 30 ng/mL, respectively. Serum 25(OH)D showed a marked seasonal variation with highest levels in September (24.1 [18.3, 30.3] ng/mL) and lowest levels in March (13.5 [9.4, 19.6] ng/mL) (p < 0.001). The seasonal variation (early autumn vs. early spring) persisted in all age and sex groups and was maximal for 21-40 years of age (26.5 (20.8, 33.1) vs. 12.9 (9.7, 17.9) ng/mL) and minimal for >65 years of age (18.6 (13.0, 27.2) vs. 12.7 (7.8, 19.7) ng/mL). Men and women showed similar amplitude of serum 25(OH)D variation. CONCLUSION: The prevalence of vitamin D deficiency is high, particularly in the elderly. The data show a strong seasonal variation of serum 25(OH)D in all subgroups of our Romanian population with highest levels in September and lowest levels in March. PMID- 29230558 TI - Psychiatric comorbidity and intimate partner violence among women who inject drugs in Europe: a cross-sectional study. AB - Women who inject drugs (WWID) are an especially vulnerable group of drug users. This study determined the prevalence of psychiatric comorbidity and intimate partrner violence (IPV), and factors associated with psychiatric comorbidity among WWID recruited from drug treatment services (67%) and harm reduction services in five European regions in Austria, Catalonia, Italy, Poland, and Scotland. Psychiatric comorbidity was assessed among 226 WWID using the Dual Diagnosis Screening Instrument. IPV was assessed using the Composite Abuse Scale and injecting and sexual risk behaviors were assessed using a battery of questionnaires adapted and developed for the study. Eighty-seven percent met criteria for at least one lifetime psychiatric disorder. The most common disorders were depression (76%), panic (54%), and post-traumatic stress (52%). WWID recruited in drug treatment services were almost three times as likely (OR 2.90 95% CI 1.30-6.43; p = 0.007) to meet criteria for a lifetime psychiatric disorder than those recruited from harm reduction services, specifically dysthymia (OR 5.32 95% CI 2.27-12.48; p = 0.000) and post-traumatic stress disorder (OR 1.83 95% CI 1.02-3.27; p = 0.040). WWID who reported sharing needles and syringes were almost three times as likely to meet criteria for lifetime psychiatric comorbidity than those who did not (OR 2.65 95% CI 1.07-6.56). Compared to WWID who had not experienced IPV, victims (70%) were almost two times more likely to meet criteria for post-traumatic stress disorder (OR 1.95 95% CI 1.10-3.48). Psychiatric comorbidity and IPV among WWID are common. Drug treatment and harm reduction services should address psychiatric comorbidity and IPV to improve treatment outcomes. PMID- 29230560 TI - Non-functionalized soft alginate hydrogel promotes locomotor recovery after spinal cord injury in a rat hemimyelonectomy model. AB - BACKGROUND: Spinal cord injury (SCI) and the consecutive devastating neurological sequelae have an enormous individual and economic impact. Implantation of functionalized hydrogels is a promising approach, because they can serve as a matrix for the regenerating tissue, carry and release bioactive molecules and various cell types. We already demonstrated that non-functionalized soft alginate hydrogel supported axonal outgrowth and protected neurons against oxidative stress in vitro. Here, we investigated the effects of such soft alginate hydrogels on locomotor recovery in small and large spinal cord lesions. METHOD: Hemimyelonectomy of 2 mm or 4 mm length was performed in rats and soft alginate hydrogel was implanted. Functional recovery of the hindlimbs was assessed in the open field [Batto Beattie Bresnahan (BBB) score] and using swimming test [Louisville Swim score (LSS)] for 140 days post injury (DPI). Reference histology was performed. RESULTS: Rats that received an alginate implant into 2 mm spinal cord lesions demonstrated significantly improved locomotor recovery compared to controls detectable already at 10 DPI. At 140 DPI, they reached higher LSS and BBB scores in swimming and open field tests, respectively. However, this beneficial effect of alginate was lacking in animals with larger (4 mm) lesions. Histological examination suggested that fibrous scarring in the spinal cord was reduced after alginate implantation in comparison to controls. CONCLUSIONS: Implantation of soft alginate hydrogel in small spinal cord lesions improved functional recovery. Possible underlying mechanisms include the mechanical stabilization of the wound, reduction of secondary damage and inhibition of fibrous scarring. PMID- 29230559 TI - Increased histopathological yield for granulomatosis with polyangiitis based on nasal endoscopy of suspected active lesions. AB - PURPOSE: To present the results of an endoscopic and histopathologic evaluation of suspected nasal active granulomatosis with polyangiits (GPA) lesions, describe them as seen by the ENT specialist, and propose a guide for tissue sampling of the nasal cavity to improve the yield of confirmatory histology. METHODS: Randomly selected patients seen from December 1997-October 2007 had a thorough endoscopic nasal evaluation, preceded by careful cleansing of the nasal cavity. Endoscopic lesions were described; sensitivities, specificities, and predictive values of the composites of endoscopic and histological activity were determined. RESULTS: Six lesions, some not previously described in detail, were observed: white submucosal nodules, mucosal swelling, polypoid nodules, vascular submucosal dilatations, bloody submucosal patches, and ulcers. Of these, polypoid nodules (PPV 100%), persistent white submucosal nodules (PPV 81%), and bloody submucosal patches (PPV 93%) had the better diagnostic performance with confirmed histological diagnosis. CONCLUSIONS: Careful nasal cavity preparation, observation, and description of the nasal mucosa can guide tissue sampling documenting active GPA. This can lead to a better histological yield when definitive proof of the disease is needed. PMID- 29230561 TI - Neurophysiological variability masks differences in functional neuroanatomical networks and their effectiveness to modulate response inhibition between children and adults. AB - Executive functions are well-known to undergo developmental changes from childhood to adulthood. Considerable efforts have been made to elucidate the affected system neurophysiological mechanisms. But while it is well-known that developmental changes affect intra-individual variability, this potential bias has largely been neglected when investigating the neurophysiology underlying developmental differences between children and adults. We hypothesize that due to differences in intra-individual variability of neural processes between children and adults, reliable group differences will only be evident after accounting for intra-individual variability in neurophysiological processes. We, therefore, investigate response-inhibition processes as an important instance of executive control in children (between 10 and 14 years) and adults (between 20 and 29 years) and decompose EEG data on the basis of the latency and temporal variability. This was combined with source localization. Children showed more impulsive behavior than adults. Importantly, a reliable match between the neurophysiological and behavioral data could only be found when accounting for intra-individual variability in the EEG data. These decomposed data showed that children and adults use similar neurophysiological mechanisms at the response selection level to accomplish inhibitory control, but seem to engage different neuroanatomical structures to do so according to source localization results: In adults, these processes were related to the medial frontal cortex. In children, the same processes were reflected in a shift of the scalp topography and related to the superior parietal cortex. These shifts in neural networks were associated with lower effectiveness in exerting inhibitory control. However, these differences in the functional neuroanatomical architecture can only be seen when intra-individual variability is taken into account. PMID- 29230562 TI - Risks of bleeding and thrombosis in intensive care unit patients with haematological malignancies. AB - BACKGROUND: Patients with malignant haematological disease and especially those who require intensive care have an increased risk of bleeding and thrombosis, but none of these data were obtained in ICU patients only. We assessed the incidence of bleeding and thrombotic complications, use of blood products and risk factors for bleeding in an adult population of ICU patients with haematological malignancies. METHODS: We screened all patients with acute leukaemia and myelodysplastic syndrome admitted to a university hospital ICU during 2008-2012. Bleeding in ICU was scored according to the WHO grading system, and risk factors were evaluated using unadjusted and adjusted analyses. RESULTS: In total, 116 of 129 ICU patients were included; their median length of stay was 7 (IQR 2-16) days. Of these, 66 patients (57%) had at least one bleeding episode in ICU; they bled for 3 (2-6) days and most often from lower and upper airways and upper GI tract. Thirty-nine (59%) of the 66 patients had severe or debilitating (WHO grade 3 or 4) bleeding. The median platelet count on the day of grade 3 or 4 bleeding was 23 * 109 per litre (IQR 13-39). Nine patients (8%) died in ICU following a bleeding episode; five of these had intra-cerebral haemorrhage. Platelet count on admission was associated with subsequent bleeding (adjusted odds ratio 1.18 (95% CI 1.03-1.35) for every 10 * 109 per litre drop in platelet count, p = 0.016). Eleven of the 116 patients (9%) developed a clinically significant thrombosis in ICU, which was the cause of death in four patients. The median platelet count was 20 * 109 per litre (15-48) at the time of thrombosis. The patients received a median of 6 units of red blood cells, 1 unit of fresh frozen plasma and 8 units of platelet concentrates in ICU. CONCLUSIONS: Severe and debilitating bleeding complications were frequent in our ICU patients with haematological malignancies, but thrombosis also occurred in spite of low platelet counts. Platelet count on ICU admission was associated with subsequent bleeding. PMID- 29230563 TI - Self-assembly of smart mesoscopic objects. AB - Self-assembly due to capillary forces is a common method for generating 2D mesoscale structures made of identical particles floating at some liquid-air interface. We show herein how to create soft entities that deform or not the liquid interface as a function of the strength of some applied magnetic field. These smart floating objects self-assemble or not depending on the application of an external field. Moreover, we show that the self-assembling process can be reversed opening ways to rearrange structures. PMID- 29230564 TI - Adsorptive filtration systems for effective removal of blood amyloid beta: a potential therapy for Alzheimer's disease. AB - Accumulation of amyloid-beta protein (Abeta) in the brain causes cognitive impairment in Alzheimer's disease. We hypothesized that an extracorporeal system that rapidly removed Abeta from the blood may accelerate Abeta drainage from the brain. We previously reported that dialyzers remove blood Abetas effectively, mainly by adsorption on the inner surfaces of the hollow fibers, resulting in lower Abeta accumulation in the brains of patients undergoing hemodialysis than the controls without hemodialysis. The aim of the present study was to create a more convenient and effective blood Abeta removal system using adsorptive filtration, in which the filtrate returned to the body. Filtration from inside to outside of the fibers may enhance the adsorption of plasma Abetas on the surface of micropores inside the hollow fiber walls. Hence, pool solutions of 4 ng/mL synthetic Abeta1-40 and Abeta1-42 peptides (300 mL) or human plasma (1000 mL of 250-346 pg/mL Abeta1-40 and 30-48 pg/mL Abeta1-42) were circulated through polysulfone dialyzers at a flow rate of 50 mL/min to evaluate an adsorptive filtration system. The rates of Abeta reduction from the pool solutions significantly increased along with the filtration rates. A filtration rate of > 1 mL/min, preferably 5-10 mL/min resulted in an 80-100% reduction of Abetas within 30 min of circulation. The rates of Abetas passing through the membrane walls were maintained around 0% for plasma Abetas during circulation. Thus, our adsorptive filtration systems may be useful for removing blood Abetas for patients with Alzheimer's disease. PMID- 29230565 TI - Correction to: The influence of surface type on the absorbed radiation by a human under hot, dry conditions. AB - The original article contains mistakes in Eqs. 12 and 13. PMID- 29230566 TI - A Rate-Reduced Neuron Model for Complex Spiking Behavior. AB - We present a simple rate-reduced neuron model that captures a wide range of complex, biologically plausible, and physiologically relevant spiking behavior. This includes spike-frequency adaptation, postinhibitory rebound, phasic spiking and accommodation, first-spike latency, and inhibition-induced spiking. Furthermore, the model can mimic different neuronal filter properties. It can be used to extend existing neural field models, adding more biological realism and yielding a richer dynamical structure. The model is based on a slight variation of the Rulkov map. PMID- 29230567 TI - Cancer nanomedicine: a review of recent success in drug delivery. AB - Cancer continues to be one of the most difficult global healthcare problems. Although there is a large library of drugs that can be used in cancer treatment, the problem is selectively killing all the cancer cells while reducing collateral toxicity to healthy cells. There are several biological barriers to effective drug delivery in cancer such as renal, hepatic, or immune clearance. Nanoparticles loaded with drugs can be designed to overcome these biological barriers to improve efficacy while reducing morbidity. Nanomedicine has ushered in a new era for drug delivery by improving the therapeutic indices of the active pharmaceutical ingredients engineered within nanoparticles. First generation nanomedicines have received widespread clinical approval over the past two decades, from Doxil(r) (liposomal doxorubicin) in 1995 to Onivyde(r) (liposomal irinotecan) in 2015. This review highlights the biological barriers to effective drug delivery in cancer, emphasizing the need for nanoparticles for improving therapeutic outcomes. A summary of different nanoparticles used for drug delivery applications in cancer are presented. The review summarizes recent successes in cancer nanomedicine in the clinic. The clinical trials of Onivyde leading to its approval in 2015 by the Food and Drug Adminstration are highlighted as a case study in the recent clinical success of nanomedicine against cancer. Next generation nanomedicines need to be better targeted to specifically destroy cancerous tissue, but face several obstacles in their clinical development, including identification of appropriate biomarkers to target, scale-up of synthesis, and reproducible characterization. These hurdles need to be overcome through multidisciplinary collaborations across academia, pharmaceutical industry, and regulatory agencies in order to achieve the goal of eradicating cancer. This review discusses the current use of clinically approved nanomedicines, the investigation of nanomedicines in clinical trials, and the challenges that may hinder development of the nanomedicines for cancer treatment. PMID- 29230568 TI - Ankle-brachial pressure index as a predictor of the 2-year outcome after transcatheter aortic valve replacement: data from the Japanese OCEAN-TAVI Registry. AB - Peripheral artery disease plays a pivotal role for access site selection in transcatheter aortic valve replacement (TAVR). Abnormal ankle-brachial index (ABI) is a generalized mortality marker in many cardiovascular scenarios. However, the long-term outcomes in high-risk TAVR populations remain unclear. We investigated the association between low ABI and 2-year outcome after TAVR. Of 1613 patients enrolled in the OCEAN-TAVI registry, 1458 (90.4%) who underwent ABI before TAVR were divided into groups: patients with (1) ABI >= 0.9 in both legs and (2) ABI < 0.9 in either leg. Primary endpoint was all-cause death within 2 years. ABI < 0.9 was noted in 304 patients (20.8%). ABI < 0.9-group had more frequent and severe comorbidities. Primary endpoint in ABI < 0.9-group was significantly higher than that in ABI >= 0.9-group (15.8 vs. 8.7%, p < 0.001). This trend continued in the transfemoral (TF)-approach (14.9 vs. 7.5%, p < 0.001), but not in the alternative approach (17.2 vs. 15.8%, p = 0.815). Within 30 days, ABI < 0.9-group had a higher cardiac death rate (3.1 vs. 1.0%, p = 0.033), whereas between 31 days and 2 years, non-cardiovascular death was more frequently observed (9.2 vs. 5.1%, p = 0.003). In ABI < 0.9-group, in-hospital vascular complications (11.9 vs. 4.9%, p < 0.001) and acute kidney injury (10.8 vs, 5.7%, p = 0.009) were more frequently found when using the transfemoral approach. In multivariate analysis, ABI < 0.9 was an independent predictor of 2 year mortality (adjusted hazard ratio 1.495, 95% CI 1.007-2.220, p = 0.046). Pre procedure ABI < 0.9 is a useful prognostic marker for all-cause mortality, even in high-risk TAVR populations. PMID- 29230569 TI - A proctoring system to manage the learning curve associated with the introduction of transcatheter aortic valve implantation in Japan. AB - As transcatheter aortic valve implantation (TAVI) requires multidisciplinary collaboration, operators and the entire heart team must overcome a steep learning curve. A web-based screening and traditional on-site proctoring system were developed for the introduction of TAVI in Japan. To assess the learning curve involved with the introduction of TAVI under the supervision of a novel proctoring system. We divided 749 consecutive patients enrolled in the OCEAN-TAVI study between October 2013 and August 2015 into the trans-femoral (TF, n = 608) and transapical (TA, n = 141) approach groups to compare outcomes in patients who underwent TAVI during the early proctoring period (proctoring group) and after the procedures began to be performed independently (independent group). The primary endpoint was the rate of composite events regarding early safety (at 30 days) according to the valve academic research consortium-2 criteria. For TF TAVI, the logistic EuroSCORE and the rate of peripheral artery disease were significantly lower during the independent period. The rate of device success significantly increased during the independent period (90.5 vs. 81.8%, p = 0.005). The rate of the primary endpoint was significantly reduced during the independent period compared to that during the proctoring period for TA-TAVI (21.3 vs. 37.9%, p = 0.031); however, no difference was observed for TF-TAVI (16.8 vs. 13.1%, p = 0.283). No deaths occurred within 30 days during the proctoring period for TF-TAVI. After adjustment using propensity score matching, the procedure time for TF-TAVI (88 +/- 43 vs. 102 +/- 36 min, p = 0.004) and the rate of life-threatening bleeding for TA-TAVI (3.6 vs. 25%, p = 0.026) reduced during the independent period compared to the values during the proctoring period. During the introduction of TAVI under the supervision of a new proctoring system in Japan, clinical outcomes and technical aspects improved significantly. There are differences in the steepness of the learning curve between TF-TAVI and TA-TAVI. PMID- 29230570 TI - The relationship between systolic vector flow mapping parameters and left ventricular cardiac function in healthy dogs. AB - Vector flow mapping (VFM) is a novel echocardiographic technology that shows blood flow vectors and vortexes, enabled the hydrokinetic evaluation of hemodynamics within the left ventricle. VFM provides several unique parameters: circulation, vorticity, vortex area, and energy loss. The present study aims to reveal a relationship between VFM parameters and cardiac function. Five healthy Beagle dogs were anesthetized and administered with dobutamine (0, 2, 4, 8, 12 ug/kg/min). Pressure-volume diagrams were acquired to assess cardiac function using pressure-volume conductance catheter. Systolic maximum circulation, vorticity, vortex area, and energy loss were measured using VFM. The systolic maximum circulation, systolic vorticity, systolic vortex area, and systolic energy loss were increased by dobutamine administration. There was a strongly significant correlation between the systolic maximum circulation and ejection fraction (r = 0.76), maximal positive left ventricular (LV) pressure derivatives (dP/dt max) (r = 0.80), and end-systolic LV elastance (r = 0.73). Systolic vorticity and systolic vortex area were strongly correlated with ejection fraction (r = 0.76, 0.68) and dP/dt max (r = 0.76, 0.69), and end-systolic LV elastance (r = 0.62, 0.74), respectively. Systolic energy loss was strongly correlated with dP/dt max (r = 0.78), systolic maximum circulation (r = 0.81), and systolic vorticity (r = 0.82). The present study revealed that systolic VFM parameters are associated with the LV contractility. Furthermore, systolic energy loss was susceptible to the systolic vortex parameters such as systolic vorticity and systolic maximum circulation. Systolic VFM parameters are new hydrokinetic indices reflecting LV contractility. PMID- 29230572 TI - Responsiveness of internal thoracic arteries to nitroglycerin in patients with renal failure. AB - Nitroglycerin is commonly used as an antispasmodic for treating spasm of coronary artery bypass grafts. This study investigated whether the presence of renal failure affects reactivity to nitroglycerin in internal thoracic arteries obtained from patients undergoing coronary bypass surgery. The patients were divided into three groups according to estimated glomerular filtration rate (eGFR, mL/min/1.73 m2): without renal failure (60 <= eGFR, n = 13), with moderate renal failure (30 <= eGFR < 60, n = 10), and with severe renal failure (eGFR < 30, n = 10). Organ chamber technique was used to evaluate concentration-related responses of isolated internal thoracic arteries to vasodilators. Nitroglycerin induced a concentration-dependent relaxation, which was significantly augmented in patients with severe but not moderate renal failure than in those without renal failure. In addition, there was a negative correlation between eGFR and the relaxant efficacy of nitroglycerin (P = 0.016). On the other hand, relaxant responses to BAY 60-2770 (which enhances cGMP generation as with nitroglycerin) were similar among three grades of renal function. An inverse relationship of eGFR to the relaxant efficacy of BAY 60-2770 was not observed, either (P = 0.314). These findings suggest that severe renal failure specifically potentiates nitroglycerin-induced relaxation in internal thoracic artery grafts. PMID- 29230571 TI - Correlation of left ventricular dyssynchrony on gated myocardial perfusion SPECT analysis with extent of late gadolinium enhancement on cardiac magnetic resonance imaging in hypertrophic cardiomyopathy. AB - Myocardial perfusion-single-photon emission computed tomography (MP-SPECT) is used to evaluate microvascular dysfunction and coexisting coronary artery disease in patients with hypertrophic cardiomyopathy (HCM). Phase analysis in gated MP SPECT can provide additional information on left ventricular (LV) dyssynchrony, while the extent of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging is an important prognostic factor in patients with HCM. We, therefore, sought to investigate the relationship of dyssynchrony by phase analysis on gated MP-SPECT and LGE on CMR imaging in 22 patients with HCM who underwent both stress/rest-gated MP-SPECT and contrast-enhanced CMR imaging. LV dyssynchrony parameters [phase standard deviation (SD) and histogram bandwidth] from gated MP-SPECT were compared with LGE parameters from CMR imaging [L/C contrast and %LGE calculated, respectively, as LGE intensity/LV cavity intensity and (LGE volume/myocardial volume) * 100]. Phase SD and histogram bandwidth showed strong correlation with %LGE (r = 0.73, p < 0.0001 and r = 0.73, p < 0.0001, respectively), although they did not significantly correlate with L/C contrast (r = 0.30, p = 0.17 and r = 0.26, p < 0.25, respectively). The LV dyssynchrony derived from gated MP-SPECT strongly correlated with the extent of LGE on CMR imaging. In conclusion, our investigation suggests that gated MP-SPECT may be useful not only for the assessment of myocardial ischemia but also the extent of myocardial replacement fibrosis. PMID- 29230573 TI - Incidence of perioperative stroke in clampless aortic anastomosis during off-pump coronary artery bypass grafting. AB - This study aimed to assess if clampless off-pump coronary artery bypass grafting (OPCAB) decreases the incidence of perioperative stroke (POS) rate and in hospital mortality. The secondary aim was to evaluate 12-year rates of overall mortality. Between January 2003 to December 2015, data of 645 consecutive patients undergoing isolated CABG were retrospectively collected. 363 underwent aortic no-touch OPCAB (No-touch group) and 282 underwent OPCAB with the Heartstring device (HS group). In-hospital mortality and perioperative stroke rate as primary endpoint, as well as long-term follow-up outcome were analysed. In-hospital mortality was lower into No-touch group compared with HS group but without significant statistical difference (1.7 vs. 3.2%, p = 0.19, respectively); the rate of postoperative stroke was higher in No-touch group compared with HS group, although this difference did not reach statistically significance. Delirium was reported with higher presentation rate in HS group (3.9 vs. 0.8%, p = 0.01). Blood transfusions rate was higher in HS subjects (23.4 vs. 16.1%, p = 0.01). Intubation time, ICU, and hospital length of stay were increased in the HS group (p = 0.008, p = 0.001 and p = 0.003, respectively). Over a 12-year follow-up period, survival probabilities at 1, 5, and 10 years were 93.6 +/- 1.3 vs. 93.2 +/- 1.5, 80.4 +/- 2.6 vs. 80.3 +/- 2.2, and 57.9 +/- 5 vs. 58.4 +/- 3.8% in the No-touch and HS group, respectively (p = 0.97). In this retrospective study, clampless off-pump CABG lowers perioperative stroke rate whose incidence is, however, not inferior compared with No-touch technique, and no statistically significance was detected. Delirium has a higher presentation rate in clampless off-pump CABG. PMID- 29230574 TI - Pigeons (Columba livia) know when they will need hints: prospective metacognition for reference memory? AB - Despite their impressive cognitive abilities, avian species have shown less evidence for metacognition than mammals. We suspect that commonly used tasks such as matching to sample might be too demanding to allow metacognitive processing within birds' working memory. Here, we examined whether pigeons could control their behavior as a function of knowledge levels on a three-item sequence learning task, a reference memory task supposedly requiring fewer working memory resources. The experiment used two types of lists differing in familiarity. One was familiar to the pigeons through repeated exposure, whereas the other was novel in every new session. In test sessions, pigeons could choose between a trial with a hint specifying the next item to peck and one with no hint. However, successful responses in trials with a hint resulted in lowered rates of primary reinforcement: .60 in the first test and .75 in the second. Results showed that two of four pigeons chose the trial with a hint significantly more often before receiving a novel list than the familiar list in the four sessions of the first test, and three did so in the second test. Impressively, one bird showed robust evidence in the very first sessions in both tests. These results suggest that pigeons may monitor their long-term knowledge states and thereby control their environment before starting to solve a task. PMID- 29230575 TI - Global Curriculum in Research Literacy for the Surgical Oncologist. AB - BACKGROUND: The ability to provide optimal care to cancer patients depends on awareness of current evidence-based practices emanating from research or involvement in research where circumstances permit. The significant global variations in cancer-related research activity and its correlation to cancer specific outcomes may have an influence on the care provided to cancer patients and their outcomes. The aim of this project is to develop a global curriculum in research literacy for the surgical oncologist. MATERIALS AND METHODS: The leadership of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in research literacy for the Surgical Oncologist. RESULTS: A global curriculum in research literacy is developed to incorporate the required domains considered to be essential to interpret the published research or become involved in research activity where circumstances permit. The purpose of this curriculum is to promote research literacy for the surgical oncologist, wherever they are based. It does not mandate direct research participation which may not be feasible due to restrictions within the local health-care delivery environment, socio-economic priorities and the educational environment of the individual institution where they work. CONCLUSIONS: A global curriculum in research literacy is proposed which may promote research literacy or encourage involvement in research activity where circumstances permit. It is hoped that this will enhance cancer-related research activity, promote awareness of optimal evidence-based practices and improve outcomes for cancer patients globally. PMID- 29230576 TI - Global Variations in the Level of Cancer-Related Research Activity and Correlation to Cancer-Specific Mortality: Proposal for a Global Curriculum. AB - INTRODUCTION: The aim of this study was to analyze global variations in the level of cancer-related research activity and correlate this with cancer-specific mortality. METHODS: The SCOPUS database was explored to obtain data relating to the number of cancer-related publications per country. Cancer-specific mortality rates were obtained from the World Health Organization. Global variations in the level of scholarly activity were analyzed and correlated with variations in cancer-specific mortality. RESULTS: Data for 142 countries were obtained and significant variations in the level of research activity was noted. The level of research activity increased with rising socio-economic status. The United States was the most prolific country with 222,300 publications followed by Japan and Germany. Several countries in different regions of the world had a low level of research activity. An inverse relationship between the level of research activity and cancer-specific mortality was noted. This relationship persisted even in countries with a low level of research activity. The socioeconomic status of a nation and geographic location (continent) had a mixed influence with an overall apparent correlation with cancer-related research activity. CONCLUSION: This study demonstrates significant global variation in the level of cancer-related research activity and a correlation with cancer-specific mortality. The presence of a minimum set of standards for research literacy, as proposed by the European Society of Surgical Oncology and the Society of Surgical Oncology may contribute to enhanced research activity and improve outcomes for cancer patients worldwide. PMID- 29230577 TI - Long-term adaptation of Escherichia coli to methanogenic co-culture enhanced succinate production from crude glycerol. AB - Escherichia coli can hardly grow anaerobically on glycerol without exogenous electron acceptor. The formate-consuming methanogen Methanobacterium formicicum plays a role as a living electron acceptor in glycerol fermentation of E. coli. Wild-type and mutant E. coli strains were screened for succinate production using glycerol in a co-culture with M. formicicum. Subsequently, E. coli was adapted to glycerol fermentation over 39 rounds (273 days) by successive co-culture with M. formicicum. The adapted E. coli (19.9 mM) produced twice as much succinate as non adapted E. coli (9.7 mM) and 62% more methane. This study demonstrated improved succinate production from waste glycerol using an adapted wild-type strain of E. coli with wild-type M. formicicum, which is more useful than genetically modified strains. Crude glycerol, an economical feedstock, was used for the cultivation. Furthermore, the increase in methane production by M. formicicum during co culture with adapted E. coli illustrated the possibility of energy-saving effects for the fermentation process. PMID- 29230578 TI - Reduced methanol input induces increased protein output by AOX1 promoter in a trans-acting elements engineered Pichia pastoris. AB - High oxygen consumption and heat release caused by methanol catabolism usually bring difficulties to industrial scale-up and cost for protein expression driven by methanol-induced AOX1 promoter in Pichia pastoris. Here, reduced methanol feeding levels were investigated for expression of insulin precursor in a trans acting elements engineered P. pastoris strain MF1-IP. Insulin precursor expression level reached 6.69 g/(L supernatant) at the methanol feeding rate of 6.67 mL/(h.L broth), which was 59% higher than that in the wild-type strain WT-IP at the methanol feeding rate of 12 mL/(h.L broth). Correspondingly, the insulin precursor expression level in fermentation broth and maximum specific insulin precursor production rate was 137 and 77% higher than the WT-IP, respectively. However, oxygen consumption and heat evolution were reduced, and the highest oxygen consumption rate and heat evolution rate of the MF1-IP were 18.0 and 37.7% lower than the WT-IP, respectively. PMID- 29230579 TI - Prevalence of cysticercosis in Estonian pigs and cattle. AB - Taenia solium has been ranked as the most important foodborne parasite and Taenia saginata as the most commonly found human Taenia tapeworm worldwide. The last official reports of taeniosis from Estonia were in 2003 for T. solium and 2012 for T. saginata. By law, all animal cases of cysticercosis must be registered and reported when found. Our aim was to estimate the prevalence of cysticercosis in Estonia caused by T. solium in pigs and T. saginata in cattle. The four slaughterhouses participating in the study slaughter between them approximately 80% of pigs and cattle in Estonia annually. Sampling spanned from February to April 2014, visiting the slaughterhouses five times per week. Visual inspection, palpation, and incisions at predilection sites were used to find cysts in both species. The sites inspected in both species were the external masseter, tongue, heart, and diaphragm. In addition, the internal masseter in pigs was examined, and the internal pterygoid muscle and esophagus in cattle. DNA was extracted from the cysts and used for PCR amplification of the cox1-gene for Taenia genus and species identification. A total of 564 cattle and 1217 pigs were examined. Cysts were found in 0.36% (n = 2; CI 0.06-1.17) of cattle and in 0.08% (n = 1; CI 0.004 0.40) of pigs. Cestode PCR was negative from all cysts. Results should be considered taking into account the low sensitivity and specificity of finding cysts. Results reflect the situation in larger slaughterhouses, and the possibility that the situation in smaller slaughterhouses is different should not be excluded. PMID- 29230580 TI - In vivo studies of the effectiveness of novel N-halomethylated and non halomethylated quaternary ammonium salts in the topical treatment of cutaneous leishmaniasis. AB - The physicochemical properties of four N-halomethylated and one non halomethylated ammonium salts, with proven in vitro antileishmanial activity, were determined according to pharmaceutical standard procedures. The effectiveness and toxicity of these compounds were assessed in hamsters infected with Leishmania (Viannia) braziliensis and compared to that showed by meglumine antimoniate. Animals were followed during 90 days after the completion of treatment. Therapeutic response was determined according to the reduction of size of skin lesions. Toxicity was determined by the effect of compounds on body weight changes and serum levels of renal and hepatic metabolites. The effectiveness of compound 4 was similar to that showed by intralesional administration of meglumine antimoniate and better than that of the other ammonium salts. Levels of creatinine, alanine amino transferase, and blood urea nitrogen in serum were not significantly different between treatment groups, including healthy or untreated hamsters. Results imply that compound 4 has potential as a pharmaceutical active ingredient in the development of new and better formulations for the treatment of cutaneous leishmaniasis. PMID- 29230581 TI - A new species of Eimeria Schneider, 1875 from the Serra dos Orgaos National Park, Rio de Janeiro, Brazil, with notes on its endogenous development in the montane grass mouse, Akodon montensis Thomas, 1913 (Rodentia: Sigmodontinae). AB - A total of 53 specimens of the montane grass mouse, Akodon montensis Thomas, 1913 were collected in the Serra dos Orgaos National Park (SONP) in November 2014 and July 2015. The fecal material was analyzed, and a prevalence of 7.5% was recorded for a new coccidian species of the genus Eimeria Schneider, 1875, with part of its endogenous development recorded in the small intestine. The oocysts of a new coccidian species of genus Eimeria are ellipsoidal to subspherical. The wall is bi-layered, c. 1.5 MUm (1.3-1.6 MUm) thick, outer layer rough. Oocyst (n = 126) mean length is 25.3 MUm (21.0-28.0 MUm), with a width of 20.2 MUm (17.0-22.0 MUm) and mean length/width (L:W) ratio of 1.3 (1.2-1.4). Polar granule is present, with the oocyst residuum as a large spherical to subspherical globule. Sporocyst shape (n = 126) is ellipsoidal, with a mean length of 11.8 MUm (9.3-14.4 MUm), width of 7.9 MUm (6.7-9.3 MUm), and mean L:W ratio of 1.5 (1.4-1.7). Sporocysts with nipple-like Stieda body and sub-Stieda body are absent. A sporocyst residuum formed by several globules, usually along the sporocyst wall. This is the first record of Eimeria in the montane grass mouse from Brazil. PMID- 29230582 TI - A new monozoic tapeworm, Parabreviscolex niepini n. g., n. sp. (Cestoda: Caryophyllidea), from schizothoracine fishes (Cyprinidae: Schizothoracinae) in Tibet, China. AB - A new monozoic cestode, Parabreviscolex niepini n. gen. and n. sp. (Cestoda: Caryophyllidea), is described from the type-host Schizopygopsis younghusbandi Regan, 1905 (Cyprinidae: Schizothoracinae) and Schizothorax waltoni Regan, 1905 (Cyprinidae: Schizothoracinae) in the Yarlung Tsangpo River, the upper tributary of the Brahmaputra River on the Tibetan Plateau. The new genus is placed in the Capingentidae because the vitellarium is situated partly in the medullary and cortical parenchyma, i.e., neither completely external nor internal to inner longitudinal muscles. Parabreviscolex n. gen. is characterized by possessing an afossate and cuneiform scolex; numerous vitelline follicles and testes present immediately after the scolex, and spread backward near the cirrus sac; the uterus does not loop anterior to the cirrus sac; genital pores separate, opening to the common genital atrium; the pre-ovarian vitelline follicles lateral and median, post-ovarian vitelline follicles present; ovary H-shaped, compact, and ovarian arms long, anteriorly reaching the cirrus sac. Homology search by the basic local alignment search tool (BLAST) showed that the partial 18S rDNA and complete mtDNA cox-1 sequences obtained in this report were not consistent with any sequences available in GenBank, and molecular phylogenetic analyses revealed Parabreviscolex formed a separated long branch within the caryophyllideans from cyprinids. PMID- 29230583 TI - Mutation screening of Chinese Treacher Collins syndrome patients identified novel TCOF1 mutations. AB - Treacher Collins syndrome (TCS) (OMIM 154500) is a rare congenital craniofacial disorder with an autosomal dominant manner of inheritance in most cases. To date, three pathogenic genes (TCOF1, POLR1D and POLR1C) have been identified. In this study, we conducted mutational analysis on Chinese TCS patients to reveal a mutational spectrum of known causative genes and show phenotype-genotype data to provide more information for gene counselling and future studies on the pathogenesis of TCS. Twenty-two TCS patients were recruited from two tertiary referral centres, and Sanger sequencing for the coding exons and exon-intron boundaries of TCOF1, POLR1D and POLR1C was performed. For patients without small variants, further copy number variations (CNVs) analysis was conducted using high density SNP array platforms. The Sanger sequencing overall mutation detection rate was as high as 86.3% (19/22) for our cohort. Fifteen TCOF1 pathogenic variants, including ten novel mutations, were identified in nineteen patients. No causative mutations in POLR1D and POLR1C genes and no CNVs mutations were detected. A suspected autosomal dominant inheritance case that implies germinal mosaicism was described. Our study confirmed that TCOF1 was the main disease causing gene for the Chinese TCS population and revealed its mutation spectrum. We also addressed the need for more studies of mosaicism in TCS cases, which could explain the mechanism of autosomal dominant inheritance in TCS cases and benefit the prevention of TCS. PMID- 29230584 TI - Mapping of a major quantitative trait locus for bakanae disease resistance in rice by genome resequencing. AB - Bakanae disease (BD) has emerged as a serious threat in almost all rice cultivation regions worldwide. Nampyeong is a Korean japonica rice variety known to be resistant to BD. In this study, quantitative trait locus (QTL) mapping was performed with F2 and F3 plants derived from a cross between the Nampyeong variety and a susceptible Korean japonica line, DongjinAD. First, resequencing of Nampyeong and DongjinAD was performed, which identified 171,035 single nucleotide polymorphisms (SNPs) between the two parental varieties. Using these SNPs, 161 cleaved amplified polymorphic sequence (CAPS) markers and six derived CAPS markers were developed; then, a genetic map was constructed from the genotypes of 180 plants from the DongjinAD/Nampyeong F2 plants. The total length of the constructed genetic map was 1386 cM, with an average interval of 8.9 cM between markers. The BD mortality rates of each F3 family were measured by testing 40 F3 progenies using in vitro seedling screening method. QTL analysis based on the genetic map and mortality rate data revealed a major QTL, qFfR1, on rice chromosome 1. qFfR1 was located at 89.8 cM with a logarithm of the odds (LOD) score of 22.7. Further, there were three markers at this point: JNS01033, JNS01037, and JNS01041. A total of 15 genes were identified with annotations related to defense against plant diseases among the 179 genes in the qFfR1 interval at 95% probability, thereby providing potential candidate genes for qFfR1. qFfR1 and its closely linked markers will be useful in breeding rice varieties resistant to BD. PMID- 29230586 TI - Comparison of the diagnostic efficacy and perioperative outcomes of limited versus extended pelvic lymphadenectomy during robot-assisted radical prostatectomy: a multi-institutional retrospective study in Japan. AB - BACKGROUND: We conducted a retrospective study to compare the perioperative course and lymph node (LN) counts of patients undergoing limited pelvic lymphadenectomy (lPLND) or extended pelvic lymphadenectomy (ePLND) during robot assisted radical prostatectomy in an initial Japanese series. METHODS: The cohort included 1333 patients who underwent either lPLND (n = 902) or ePLND (n = 431) during robot-assisted radical prostatectomy at five institutions in Japan. All complications within 28 days of surgery were recorded, and clinical data were collected retrospectively. The outcomes and complications were compared relative to the extent of lymphadenectomy, and we conducted univariate and multivariate logistic regression analyses to assess the predictors of the major complications. RESULTS: On multivariate analysis for evaluating the associations between major complications and perioperative characteristics, console time (p = 0.001) was significantly associated with major complications, although the extent of lymphadenectomy (p = 0.272) was not significantly associated with major complications. In the distribution of positive LNs removed in the extended pelvic lymphadenectomy cohort, 60.4% of patients had positive LNs only in the obturator/internal iliac region. However, 22.6% of the patients with positive LNs had no positive LNs in the obturator/internal iliac region, but only in the external/common iliac region. CONCLUSIONS: ePLND, which significantly increased the console time and blood loss but nearly quadrupled the lymph node yield, is considered a relatively safe and acceptable procedure. Moreover, the results of this study suggest that ePLND improves staging and removes a greater number of metastatic nodes. PMID- 29230585 TI - Identification of novel genes significantly affecting growth in catfish through GWAS analysis. AB - Growth is the most important economic trait in aquaculture. Improvements in growth-related traits can enhance production, reduce costs and time to produce market-size fish. Catfish is the major aquaculture species in the United States, accounting for 65% of the US finfish production. However, the genes underlying growth traits in catfish were not well studied. Currently, the majority of the US catfish industry uses hybrid catfish derived from channel catfish female mated with blue catfish male. Interestingly, channel catfish and blue catfish exhibit differences in growth-related traits, and therefore the backcross progenies provide an efficient system for QTL analysis. In this study, we conducted a genome-wide association study for catfish body weight using the 250 K SNP array with 556 backcross progenies generated from backcross of male F1 hybrid (female channel catfish * male blue catfish) with female channel catfish. A genomic region of approximately 1 Mb on linkage group 5 was found to be significantly associated with body weight. In addition, four suggestively associated QTL regions were identified on linkage groups 1, 2, 23 and 24. Most candidate genes in the associated regions are known to be involved in muscle growth and bone development, some of which were reported to be associated with obesity in humans and pigs, suggesting that the functions of these genes may be evolutionarily conserved in controlling growth. Additional fine mapping or functional studies should allow identification of the causal genes for fast growth in catfish, and elucidation of molecular mechanisms of regulation of growth in fish. PMID- 29230587 TI - Arterial wall hypertrophy is ameliorated by alpha2-adrenergic receptor antagonist or aliskiren in kidneys of angiotensinogen-knockout mice. AB - BACKGROUND: Arterial hypertrophy and interstitial fibrosis are important characteristics in kidneys of angiotensinogen-knockout (Atg -/-) mice. In these mice, which exhibit polyuria and hypotension, sympathetic nerve signaling is estimated to be compensatorily hyperactive. Furthermore, transforming growth factor (TGF)-beta1 is overexpressed in mice kidneys. To determine whether sympathetic nerve signaling and TGF-beta1 exacerbate arterial hypertrophy and interstitial fibrosis, intervention studies of such signaling are required. METHODS: We performed renal denervation and administered the alpha2-adrenergic receptor (AR) antagonist, atipamezole, to Atg -/- mice. A renin inhibitor, aliskiren, which was preliminarily confirmed to reduce TGF-beta1 gene expression in kidneys of the mice, was additionally administered to assess the effect on the arterial hypertrophy and interstitial fibrosis. RESULTS: Norepinephrine content in kidneys of Atg -/- mice was three times higher than in kidneys of wild-type mice. Interventions by renal denervation and atipamezole resulted in amelioration of the histological findings. Overexpression of TGF-beta1 gene in kidneys of Atg /- mice was altered in a manner linked to the histological findings. Surprisingly, aliskiren reduced alpha2-AR gene expression, interstitial fibrosis, and arterial hypertrophy in kidneys of Atg -/- mice, which lack renin substrate. CONCLUSIONS: Alpha2-AR signaling is one of the causes of persistent renal arterial hypertrophy in Atg -/- mice. Aliskiren also angiotensinogen independently reduces the extent of renal arterial hypertrophy, partly thorough downregulation of alpha2-ARs. Although renal arterial hypertrophy in Atg -/- mice appears to be of multifactorial origin, TGF-beta1 may play a key role in the persistence of such hypertrophy. PMID- 29230588 TI - The impact of advanced age on short-term outcomes following gastric cancer resection: an ACS-NSQIP analysis. AB - BACKGROUND: Evidence on short-term outcomes for GC resection in elderly patients is limited by small samples from single-institutions. This study sought to examine the association between advanced age and short-term outcomes of gastrectomy for gastric cancer (GC). METHODS: Using ACS-NSQIP data, patients undergoing gastrectomy for GC (2007-2013) were identified. Primary outcome was 30 day major morbidity. Outcomes were compared across age categories (<65, 65-70, 71 75, 76-80, >80 years old). Univariable and multivariable regression was used to estimate the morbidity risk associated with age. RESULTS: Of 3637 patients, 60.6% were >=65 years old. Major morbidity increased with age, from 16.3% (<65 years old) to 21.5% (76-80 years old), and 24.1% (>80 years old) (p < 0.001), driven by higher respiratory and infectious events. Perioperative 30-day mortality increased from 1.2% (<65years old) to 6.5% (>80 years old) (p < 0.0001). After adjustments, age was independently associated with morbidity for 76-80 years of age (RR 1.31, 95% CI, 1.08-1.60) and >80 years old (RR 1.49, 95% CI, 1.23-1.81). Predicted morbidity increased by 18.6% in those 75-80 years old and 27.5% in those >80 years old (compared to <65 years old) for total gastrectomy, and by 11.6% and 17.2% for subtotal gastrectomy, for worst case scenario. Morbidity increased by 5.1% in those 75-80 years old and 7.6% in those >80 years old for total gastrectomy, and by 3.1% and 4.7% for subtotal gastrectomy, for best case scenario. CONCLUSIONS: Advanced age, defined as more than 75 years, was independently associated with increased morbidity after GC resection. The magnitude of this impact is further modulated by clinical scenarios. Increased risk in elderly GC patient should be recognized and considered in indications for resection. PMID- 29230589 TI - Physical parameter estimation from porcine ex vivo vocal fold dynamics in an inverse problem framework. AB - This study presents a framework for a direct comparison of experimental vocal fold dynamics data to a numerical two-mass-model (2MM) by solving the corresponding inverse problem of which parameters lead to similar model behavior. The introduced 2MM features improvements such as a variable stiffness and a modified collision force. A set of physiologically sensible degrees of freedom is presented, and three optimization algorithms are compared on synthetic vocal fold trajectories. Finally, a total of 288 high-speed video recordings of six excised porcine larynges were optimized to validate the proposed framework. Particular focus lay on the subglottal pressure, as the experimental subglottal pressure is directly comparable to the model subglottal pressure. Fundamental frequency, amplitude and objective function values were also investigated. The employed 2MM is able to replicate the behavior of the porcine vocal folds very well. The model trajectories' fundamental frequency matches the one of the experimental trajectories in [Formula: see text] of the recordings. The relative error of the model trajectory amplitudes is on average [Formula: see text]. The experiments feature a mean subglottal pressure of 10.16 (SD [Formula: see text]) [Formula: see text]; in the model, it was on average 7.61 (SD [Formula: see text]) [Formula: see text]. A tendency of the model to underestimate the subglottal pressure is found, but the model is capable of inferring trends in the subglottal pressure. The average absolute error between the subglottal pressure in the model and the experiment is 2.90 (SD [Formula: see text]) [Formula: see text] or [Formula: see text]. A detailed analysis of the factors affecting the accuracy in matching the subglottal pressure is presented. PMID- 29230590 TI - Author Correction: Research Priorities for the Intersection of Alcohol and HIV/AIDS in Low and Middle Income Countries: A Priority Setting Exercise. AB - The original version of this article unfortunately contained an error in the co authors name. The co-author names should be Sarah Gordon and Charles Parry instead of Sara Gordon and Charles Perry. PMID- 29230592 TI - Correction to: Soil respiration patterns and rates at three Taiwanese forest plantations: dependence on elevation, temperature, precipitation, and litterfall. AB - Unfortunately, the original article (Huang et al. 2017) contained some errors. The Fig. 4 displayed incorrectly. The correct figure can be found below. PMID- 29230591 TI - Intraoperative use of ICG fluorescence imaging to reduce the risk of anastomotic leakage in colorectal surgery: a systematic review and meta-analysis. AB - BACKGROUND: Indocyanine green (ICG) fluorescence imaging has been proven to be an effective tool to assess anastomotic perfusion. The aim of this systematic review and meta-analysis was to evaluate its efficacy in reducing the anastomotic leakage (AL) rate after colorectal surgery. METHODS: PubMed, Scopus, WOS, Google Scholar and Cochrane Library were searched up to January 2017 for studies comparing fluorescence imaging with standard care. ClinicalTrials.gov register was searched for ongoing trials. The primary outcome measure was AL rate with at least 1 month of follow-up. ROBINS-I tool was used for quality assessment. A meta analysis with random-effects model was performed to calculate odds ratios (ORs) from the original data. RESULTS: One thousand three hundred and two patients from 5 non-randomized studies were included. Fluorescence imaging significantly reduced the AL rate in patients undergoing surgery for colorectal cancer (OR 0.34; CI 0.16-0.74; p = 0.006). Low AL rates were shown in rectal cancer surgery (ICG 1.1% vs non-ICG 6.1%; p = 0.02). There was no significant decrease in the AL rate when colorectal procedures for benign and malignant disease were combined. To date, there are no published randomized control trials (RCTs) on this subject, though 3 ongoing RCTs were identified. CONCLUSIONS: ICG fluorescence imaging seems to reduce AL rates following colorectal surgery for cancer. However, the inherent bias of the non-randomized studies included, and their differences in AL definition and diagnosis could have influenced results. Large well-designed RCTs are needed to provide evidence for its routine use in colorectal surgery. PMID- 29230593 TI - Effects of alpha-ketoglutarate (AKG) on growth performance and non-specific immunity of juvenile red drum fed diets with low or adequate phosphorus levels. AB - This study evaluated the effects of alpha-ketoglutarate (AKG) on the growth performance, body, and skeletal composition, as well as non-specific immunity of juvenile red drum (Sciaenops ocellatus) fed adequate or low-phosphorus diets. A 2 * 2 factorial design was arranged with two levels of total phosphorus (1.0 or 1.6%) and two levels (0 or 1%) of AKG. Each diet was fed to red drum in four replicate 110-L aquaria (15 fish/aquarium) twice daily for 7 weeks. The results indicated that the low-P diets significantly (P < 0.05) decreased weight gain, feed efficiency, and condition factor of red drum, but increased moisture content and decreased ash content of whole body, as well as decreased ash content of skeletal tissue and decreased plasma lysozyme. Supplementation of AKG significantly improved the fillet yield and plasma lysozyme and tended to improve neutrophil oxidative radical production (P = 0.097). Based on these results, phosphorus level had the greatest effect on growth performance and non-specific immunity of red drum, while AKG supplementation had limited positive effects on immunological responses and fillet yield of juvenile red drum. PMID- 29230594 TI - Molecular evolution of myoglobin in the Tibetan Plateau endemic schizothoracine fish (Cyprinidae, Teleostei) and tissue-specific expression changes under hypoxia. AB - Myoglobin (Mb) is an oxygen-binding hemoprotein that was once thought to be exclusively expressed in oxidative myocytes of skeletal and cardiac muscle where it serves in oxygen storage and facilitates intracellular oxygen diffusion. In this study, we cloned the coding sequence of the Mb gene from four species, representing three groups, of the schizothoracine fish endemic to the Qinghai Tibetan Plateau (QTP), then conducted molecular evolution analyses. We also investigated tissue expression patterns of Mb and the expression response to moderate and severe hypoxia at the mRNA and protein levels in a representative of the highly specialized schizothoracine fish species, Schizopygopsis pylzovi. Molecular evolution analyses showed that Mb from the highly specialized schizothoracine fish have undergone positive selection and one positively selected residue (81L) was identified, which is located in the F helix, close to or in contact with the heme. We present tentative evidence that the Mb duplication event occurred in the ancestor of the schizothoracine and Cyprininae fish (common carp and goldfish), and that the Mb2 paralog was subsequently lost in the schizothoracine fish. In S. pylzovi, Mb mRNA is expressed in various tissues with the exception of the intestine and gill, but all such tissues, including the liver, muscle, kidney, brain, eye, and skin, expressed very low levels of Mb mRNA (< 8.0%) relative to that of the heart. The trace levels of Mb expression in non-muscle tissues are perhaps the major reason why non-muscle Mb remained undiscovered for so long. The expression response of the Mb gene to hypoxia at the mRNA and protein levels was strikingly different in S. pylzovi compared to that found in the common carp, medaka, zebrafish, and goldfish, suggesting that the hypoxia response of Mb in fish may be species and tissue specific. Notably, severe hypoxia induced significant expression of Mb at the mRNA and protein levels in the S. pylzovi heart, which suggests Mb has a major role in the supply of oxygen to the heart of Tibetan Plateau fish. PMID- 29230595 TI - An optimized technique of endoscopic third ventriculocisternostomy (ETV) for children with occlusive hydrocephalus. AB - In this article, we present an optimized minimally invasive technique of ETV for children with occlusive hydrocephalus. The study comprises of 64 consecutive pediatric cases (34 boys and 30 girls aged from 1 month to 5 years) of occlusive hydrocephalus from various etiologies, which were treated with a modified technique of ETV. Mean clinical follow-up period after ETV was 24.2 +/- 3.8 months. Application of the new technique made it possible to significantly reduce the length of the soft tissue incision for access, and the use of upgraded instruments allowed to perform a twist drill hole in the skull to less than half a usual size. Access to the brain and lateral ventricle was performed by blunt trephination of the dura without the need for significant corticectomy or coagulation, and yielded minimal damage to the brain, which is very important in patients of young age. Continued endoscopic control during the approach down to the lateral ventricle increases safety and decreases risk of injury, and can be performed in cases of pathologies affecting the anatomical relationships of the lateral and third ventricle. Mortality in our cohort was 0%, and there were no postoperative neurological, endocrinological, or infectious complications. Patency rates of the first ETV performed was 78%, with the remaining patients requiring additional surgical procedures for complicated settings. This new technique of minimally invasive ETV placement in pediatric patients is an effective and safe method to treat occlusive hydrocephalus and can be recommended for extensive clinical use. PMID- 29230596 TI - Distribution of potential eye and tissue donors within an Australian teaching hospital. AB - Eye and Tissue donation has the capacity to transform lives, yet the vast majority of potential in-hospital donors are not recognised. Studies which describe the relative importance of specific units or wards in determining the size of the donor pool are limited. The aim of this study was to map the distribution of potential Eye and Tissue donors within the study hospital. A 12 month retrospective analysis of all patient deaths at the study hospital was undertaken. The ability to donate corneal, heart valve, bone and skin tissue was investigated. Patients were classified as potential donors if they met specific age criteria and had an absence of contraindications based on electronic database search. There were 985 deaths during the study period. Deaths occurred under the care of 26 separate clinical units, and within 28 unique wards and treatment spaces. Four hundred and forty nine (45.6%) patients were identified as potential eye or tissue donors. The majority of potential donors occurred in ICU, Emergency and palliative care units. Of the subset of 328 deaths <= 70 years, the frequency of potential tissue donors was 55% (n = 181). ED and ICU had significantly higher frequencies of potential donor than other wards (86 and 77%, p < 0.01). The current study has identified the ED, ICU and PCUs are being important sites for potential Eye and Tissue Donors within our hospital. These will provide an important focus for future interventions to improve the rate of eye and tissue donation. PMID- 29230597 TI - Presence of post-systolic shortening is an independent predictor of heart failure in patients following ST-segment elevation myocardial infarction. AB - Following an ischemic event post systolic shortening (PSS) may occur. We investigated the association between PSS in patients with ST-segment elevation myocardial infarction (STEMI) following primary percutaneous coronary intervention (pPCI) and occurrence of cardiovascular events at follow-up. A total of 373 patients admitted with STEMI and treated with pPCI were prospectively included in the study cohort. All patients were examined by echocardiography a median of 2 days after admission (interquartile range, 1-3 days). PSS was measured by color tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE) in six myocardial walls from all three apical projections. During a median follow-up period of 5.4 years (interquartile range, 4.1-6.0 years), 180 events occurred: 59 deaths, 70 heart failures (HF) and 51 new myocardial infarctions (MI). In multivariable analysis adjusting for: age, sex, peak troponin, left ventricle ejection fraction, TIMI flow grade, left ventricle mass index, hypertension and diabetes, presence of PSS by TDI in the culprit region was associated with a nearly twofold increased risk of HF (HR 1.90, 95% CI 1.02-3.53, P = 0.043) and the risk of HF increased incrementally with increasing numbers of walls displaying PSS. The increased risk of HF was confirmed when assessing the post-systolic index by STE (HR 1.29 95% CI 1.09-1.53, P = 0.003, per 1% increase). A regional analysis showed that PSS by TDI in the septal wall was the strongest predictor of HF (HR 1.77, 95% CI 1.08-2.92, P = 0.024). Presence of PSS was not associated with increased risk of death or MI. In patients with STEMI treated with pPCI, the presence of PSS examined by TDI and STE provides prognostic information on development of HF. Presence of PSS in the septal wall is the strongest predictor of HF. PMID- 29230599 TI - Erratum to: Nitrogen detected TROSY at high field yields high resolution and sensitivity for protein NMR. AB - The authors regret a mistake appeared in the supplement of this paper. PMID- 29230598 TI - Multi-view approach for the diagnosis of pulmonary hypertension using transthoracic echocardiography. AB - Pulmonary hypertension (PH) is a disease with severe morbidity and mortality. Echocardiography plays an essential role in the screening of PH. The quality of the acquired continuous wave Doppler signal is the major limitation of the method and can greatly affect the accuracy of estimated pulmonary pressures. The aim of this study was to evaluate the clinical need to image from multiple ultrasound windows in patients with suspected pulmonary hypertension. We prospectively evaluated 65 patients (43% male, mean age 67.2 years) with echocardiography and right heart catheterization. 17% had invasively normal pulmonary pressures, 83% had pulmonary hypertension. Peak tricuspid regurgitation (TR) velocity was imaged in five echocardiographic views. Sufficient Doppler signal was recorded in 94% of the patients. Correlation for overall peak TR velocity with invasively measured systolic pulmonary artery pressure was r = 0.83 (p < 0.001). Considering all five imaging windows resulted in a sensitivity of 87%, and a specificity of 91% for correct diagnosis of PH with an AUC of 0.89, which was significantly better as compared to sole imaging from the right ventricular modified apical four-chamber view (AUC 0.85, p = 0.0395). Additional imaging from atypical views changed the overall peak TR velocity in 32% of the patients. A multiple-view approach changed the echocardiographic diagnosis of PH in 11% of the patients as opposed to sole imaging from an apical four-chamber view. This study comprehensively assessed the impact on clinical decision making when evaluating patients with an echocardiographic multiplane approach for suspected PH. This approach substantially increased sensitivity without a decrease in specificity. PMID- 29230600 TI - Inaugural Editorial. PMID- 29230601 TI - Deer Mates: A Quantitative Study of Heterospecific Sexual Behaviors Performed by Japanese Macaques Toward Sika Deer. AB - This is the first quantitative study of heterospecific sexual behavior between a non-human primate and a non-primate species. We observed multiple occurrences of free-ranging adolescent female Japanese macaques (Macaca fuscata) performing mounts and sexual solicitations toward sika deer (Cervus nippon) at Minoo, central Japan. Our comparative description of monkey-deer versus monkey-monkey interactions supported the "heterospecific sexual behavior" hypothesis: the mounts and demonstrative solicitations performed by adolescent female Japanese macaques toward sika deer were sexual in nature. In line with our previous research on the development of homospecific sexual behavior in immature female Japanese macaques, this study will allow us to test other hypotheses in the future, such as the "practice for homospecific sex," the "safe sex," the "homospecific sex deprivation," the "developmental by-product," and the "cultural heterospecific sex" hypotheses. Further research will be necessary to ascertain whether this group-specific sexual behavior was a short-lived fad or an incipient cultural phenomenon and may also contribute to better understanding the proximate and ultimate causes of reproductive interference. PMID- 29230602 TI - Butch-Femme Identity and Visuospatial Performance Among Lesbian and Bisexual Women in China. AB - Lesbian and bisexual women who self-identify as "butch" show a masculine profile with regard to gender roles, gender nonconformity, and systemizing cognitive style, whereas lesbian and bisexual women who self-identify as "femme" show a corresponding feminine profile and those who self-identify as "androgynes" show an intermediate profile. This study examined the association between butch or femme lesbian or bisexual identity and visuospatial ability among 323 lesbian and bisexual women, compared to heterosexual women (n = 207) and men (n = 125), from multiple cities in China. Visuospatial ability was assessed using a Shepard and Metzler-type mental rotation task and Judgment of Line Angle and Position (JLAP) test on the Internet. Heterosexual men outperformed heterosexual women on both mental rotation and JLAP tasks. Lesbian and bisexual women outperformed heterosexual women on mental rotation, but not on JLAP. There were significant differences in mental rotation performance among women, with butch- and androgyne identified lesbian/bisexual women outperforming femme-identified and heterosexual women. There were also significant differences in JLAP performance among women, with butch- and androgyne-identified lesbian/bisexual women and heterosexual women outperforming femme-identified lesbian/bisexual women. The butch-femme differences in visuospatial ability indicated an association between cognitive ability and butch-femme identity and suggest that neurobiological underpinnings may contribute to butch-femme identity although alternative explanations exist. PMID- 29230603 TI - AMP-activated protein kinase activation in mediating phenylalanine-induced neurotoxicity in experimental models of phenylketonuria. AB - Phenylketonuria (PKU), one of the most prevalent autosomal recessive disorders of amino acid metabolism, is characterized by abnormal accumulation of phenylalanine, which can lead to intellectual disability. The main pathologic changes in the central nervous system of untreated phenylketonuric patients are reductions in the number of axons, dendrites, and synapses in the brain. Such alterations are thought to be mainly associated with the toxic effects caused by phenylalanine. However, the underlying molecular mechanisms have not been fully elucidated. The present study shows that a high concentration of phenylalanine remarkably inhibited neuronal neurite formation in vitro. Interestingly, AMP activated protein kinase (AMPK), the energy status sensor, was activated in cultured cerebral cortical neurons upon phenylalanine treatment. Pretreatment with an AMPK inhibitor ameliorated the reduction of neurite formation caused by phenylalanine. In addition, the levels of the phosphorylated AMPK, the active form of AMPK, were significantly higher in the cerebral cortices of PKU mice with elevated phenylalanine levels in this brain region compared to those in wild-type control mice, whereas the density of dendritic spines on basal secondary dendrites of pyramidal neurons in prefrontal cortices of PKU mice was significantly decreased. Collectively, these findings indicate that AMPK activation is a key event in impaired neuronal dendritic development in PKU and consequently, a potential therapeutic target for developing neuroprotective strategies against phenylalanine-evoked brain injury in PKU. PMID- 29230604 TI - Do inborn errors of metabolism confer or impede the risk of diabetes? PMID- 29230605 TI - The Persian Version of the "Life Satisfaction Scale": Construct Validity and Test Re-Test Reliability among Iranian Older Adults. AB - After forward-backward translation, the LSS was administered to 334 Persian speaking, cognitively healthy elderly aged 60 years and over recruited through convenience sampling. To analyze the validity of the model's constructs and the relationships between the constructs, a confirmatory factor analysis followed by PLS analysis was performed. The Construct validity was further investigated by calculating the correlations between the LSS and the "Short Form Health Survey" (SF-36) subscales measuring similar and dissimilar constructs. The LSS was re administered to 50 participants a month later to assess the reliability. For the eight-factor model of the life satisfaction construct, adequate goodness of fit between the hypothesized model and the model derived from the sample data was attained (positive and statistically significant beta coefficients, good R squares and acceptable GoF). Construct validity was supported by convergent and discriminant validity, and correlations between the LSS and SF-36 subscales. Minimum Intraclass Correlation Coefficient level of 0.60 was exceeded by all subscales. Minimum level of reliability indices (Cronbach's alpha, composite reliability and indicator reliability) was exceeded by all subscales. The Persian version of the Life Satisfaction Scale is a reliable and valid instrument, with psychometric properties which are consistent with the original version. PMID- 29230606 TI - Agreement and Discrepancy Between Supervisor and Clinician Alliance: Associations with Clinicians' Perceptions of Psychological Climate and Emotional Exhaustion. AB - Despite increasing interest in supervision as a leverage point for bolstering public mental health services, the potential influence of supervisory alliance on organizations and direct service providers remains understudied, particularly in the context of supporting evidence-based treatment (EBT) use. This study examined agreement and discrepancy between supervisor and clinician ratings of alliance associated with clinicians' perceptions of psychological climate and emotional exhaustion. Results indicated that discrepancies in alliance ratings were common and associated with clinicians' perceptions of psychological climate. These findings have important implications for collaboration among supervisors and clinicians within a community mental health organizational context and the provision of EBTs. PMID- 29230607 TI - The effect of high count rates on cardiac perfusion quantification in a simultaneous PET-MR system using a cardiac perfusion phantom. AB - BACKGROUND: PET-MRI is under investigation as a new strategy for quantitative myocardial perfusion imaging. Consideration is required as to the maximum scanner count rate in order to limit dead-time losses resulting from administered activity in the scanner field of view during the first pass of the radiotracer. RESULTS: We performed a decaying-source experiment to investigate the high count rate performance of a PET-MR system (Siemens mMR) over the expected range of activities during a clinical study. We also performed imaging of a cardiac perfusion phantom, which provides an experimental simulation of clinical transit of a simultaneous radiotracer (phantom injected activities range 252 to 997 MBq) and gadolinium-based contrast agent (GBCA). Time-activity and time-intensity curves of the aorta and myocardium compartments from PET and MR images were determined, and quantification of perfusion was then performed using a standard cardiac kinetic model. The decaying-source experiment showed a maximum noise equivalent count rate (NECRmax) of 286 kcps at a singles rate of 47.1 Mcps. NECR was maintained within 5% (NECR95%) of the NECRmax with a singles rate of 34.1 Mcps, corresponding to 310 MBq in the phantom. Count-rate performance was degraded above the singles rate of 64.9 Mcps due to the number of detection events impacting the quantitative accuracy of reconstructed images. A 10% bias in image activity concentration was observed between singles rates of 78.2 and 82.9 Mcps. Perfusion phantom experiments showed that image-based activity concentration and quantified values of perfusion were affected by count losses when the total singles rate was greater than 64.9 Mcps. This occurred during the peak arterial input function (AIF) phase of imaging for injected activities to the phantom of 600 MBq and greater. CONCLUSIONS: Care should be taken to avoid high count-rate losses in simultaneous PET-MRI studies. Based on our results in phantoms, bias in reconstructed images should be avoided by adhering to a singles rate lower than 64.9 Mcps on the mMR system. Quantification of perfusion values using singles rates higher than 64.9 Mcps on this system may be compromised and should be avoided. PMID- 29230608 TI - Combinatorial therapy with two pro-coagulants and one osmotic agent reduces the extent of the lesion in the acute phase of spinal cord injury in the rat. AB - BACKGROUND: Spinal cord injury (SCI) is a complex disease that leads to a motor, sensitive, and vegetative impairment. So far, single therapies are ineffective for treating SCI in humans and a multifactorial therapeutic approach may be required. The aim of this work was to assess the effect of a triple therapy (TT) associating two pro-coagulant therapies (tranexamic acid and fibrinogen) with an anti-edema therapy (hypertonic saline solution), on the extent of the lesion 24 h post-injury. METHODS: The design of this study is a randomized controlled study. The setting of this study is an experimental study. Male Wistar rats were assigned to receive saline solution for the control group or one of the treatment, or a combination of two treatments or the three treatments (triple therapy group (TT)). Animals were anesthetized and received a weight-drop SCI induced at the level of the 12th thoracic vertebra (Th12). They were treated by single therapies, double therapies, or TT started 5 min after the SCI. RESULTS: The extent of the lesion was assessed 24 h after injury by spectrophotometry (quantification of parenchymal hemorrhage and blood-spinal cord barrier disruption) and by histology (quantification of spared neuronal tissue). As compared with the control group, the TT significantly reduced parenchymal hemorrhage (p < 0.05) and improved the total amount of intact neural tissue, measured 24 h later (p = 0.003). CONCLUSIONS: Combinatorial therapy associating two pro-coagulants (tranexamic acid and fibrinogen) with an anti-edema therapy (hypertonic saline solution) reduces the extent of the lesion in the acute phase of spinal cord injury in the rat. PMID- 29230610 TI - Predictive value of vascular endothelial growth factor receptor type 2 in triple negative breast cancer patients treated with neoadjuvant chemotherapy. AB - The identification of informative biomarkers that could predict the treatment response is particularly important in the triple-negative (TN) breast cancer, which is characterized by biological diversity. The aim of this study was to investigate the impact of vascular endothelial growth factor receptor (VEGFR2) expression and its gene polymorphisms on pathologic complete response (pCR) to neoadjuvant chemotherapy (NCT) in Russian patients with TN breast cancer. We performed a retrospective analysis of 70 women with operable TN breast cancer, who underwent NCT with 5-fluorouracil, adriamycin, and cyclophosphamide (FAC) or cyclophosphamide, adriamycin, and capecitabine (CAX) between 2007 and 2013. VEGFR2 expression was evaluated before NCT by immunohistochemistry. TaqMan SNP assays were used for genotyping KDR - 604T>C (rs2071559) and KDR 1192G>A (rs2305948) polymorphisms. The pCR was used as an end-point in the treatment efficacy analysis. In the univariate analysis, the pCR rate was strongly associated with young age (P = 0.004), high Ki67 expression (P = 0.012), lymph node negativity (P = 0.023) as well as with positive VEGFR2 expression (P = 0.019) and the CAX regimen (P = 0.005). In the multivariate analysis, only patient's age (P = 0.005) and pre-NCT VEGFR2 expression (P = 0.048) remained significant predictors of pCR. The pCR rate was higher in the CAX-treated patients than that in the FAC-treated patients (P = 0.005). Our results revealed that - 604TT genotype of rs2071559 and age < 50 years were correlated with a pCR in the CAX-treated patients. VEGFR2 expression in pre-NCT tumors and KDR gene polymorphism can be considered as additional predictive molecular markers of pCR in Russian TN breast cancer patients treated with NCT. PMID- 29230609 TI - Comparative assessment of chloroplast transcriptional responses highlights conserved and unique patterns across Triticeae members under salt stress. AB - Chloroplast functional genomics, in particular understanding the chloroplast transcriptional response is of immense importance mainly due to its role in oxygenic photosynthesis. As a photosynthetic unit, its efficiency and transcriptional activity is directly regulated by reactive oxygen species during abiotic and biotic stress and subsequently affects carbon assimilation, and plant biomass. In crops, understanding photosynthesis is crucial for crop domestication by identifying the traits that could be exploited for crop improvement. Transcriptionally and translationally active chloroplast plays a key role by regulating the PSI and PSII photo-reaction centres, which ubiquitously affects the light harvesting. Using a comparative transcriptomics mapping approach, we identified differential regulation of key chloroplast genes during salt stress across Triticeae members with potential genes involved in photosynthesis and electron transport system such as CytB6f. Apart from differentially regulated genes involved in PSI and PSII, we found widespread evidence of intron splicing events, specifically uniquely spliced petB and petD in Triticum aestivum and high proportion of RNA editing in ndh genes across the Triticeae members during salt stress. We also highlight the role and differential regulation of ATP synthase as member of CF0CF1 and also revealed the effect of salt stress on the water splitting complex under salt stress. It is worthwhile to mention that the observed conserved down-regulation of psbJ across the Triticeae is limiting the assembly of water-splitting complexes and thus making the BEP clade Triticeae members more vulnerable to high light during the salt stress. Comparative understanding of the chloroplast transcriptional dynamics and photosynthetic regulation will improve the approaches for improved crop domestication. PMID- 29230611 TI - One-pot synthesis of novel 1-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2 a]pyrazine derivatives via an Ugi-azide 4CR process. AB - A facile one-pot method has been developed for the synthesis of novel pyrrolo[2,1 a]pyrazine scaffolds. A variety of 1-(1H-tetrazol-5-yl)-1,2,3,4 tetrahydropyrrolo[1,2-a]pyrazine derivatives were obtained in moderate to high yields in methanol using a one-pot four-component condensation of 1-(2 bromoethyl)-1H-pyrrole-2-carbaldehyde, amine, isocyanide and sodium azide at room temperature. These reactions presumably proceed via a domino imine formation, intramolecular annulation and Ugi-azide reaction. Unambiguous assignment of the molecular structures was carried out by single-crystal X-ray diffraction. PMID- 29230613 TI - Impacts of Pathogen Introduction Risk on Importer Behavior and Gains from Trade in the Livestock Industry. AB - Trade eliminates geographic barriers, allowing for novel exchange of goods and services, but also creates pathways for the unintentional spread of infectious pathogens such as foot and mouth disease. In the absence of trade regulation, a producer's choice of import origin depends on relative prices and costs associated with trading partners. This paper develops a framework for exploring importer behavior in a non-regulated economy, allowing for price and risk heterogeneity among potential import sources. In the model, importers determine the risk of introducing foot and mouth disease to home soil and choose import volumes using risk and market data. When importers consider the possibility of unreported or undetected outbreaks, they choose to import from multiple sources to minimize risk and simultaneously create gains from trade over the regulated outcome. Our results have implications for the development of import and inspection policies that could be specifically designed to target highest risk imports of livestock. PMID- 29230612 TI - Antibiotic-Resistant Escherichia coli in Migratory Birds Inhabiting Remote Alaska. AB - We explored the abundance of antibiotic-resistant Escherichia coli among migratory birds at remote sites in Alaska and used a comparative approach to speculate on plausible explanations for differences in detection among species. At a remote island site, we detected antibiotic-resistant E. coli phenotypes in samples collected from glaucous-winged gulls (Larus glaucescens), a species often associated with foraging at landfills, but not in samples collected from black legged kittiwakes (Rissa tridactyla), a more pelagic gull that typically inhabits remote areas year-round. We did not find evidence for antibiotic-resistant E. coli among 347 samples collected primarily from waterfowl at a second remote site in western Alaska. Our results provide evidence that glaucous-winged gulls may be more likely to be infected with antibiotic-resistant E. coli at remote breeding sites as compared to sympatric black-legged kittiwakes. This could be a function of the tendency of glaucous-winged gulls to forage at landfills where antibiotic resistant bacterial infections may be acquired and subsequently dispersed. The low overall detection of antibiotic-resistant E. coli in migratory birds sampled at remote sites in Alaska is consistent with the premise that anthropogenic inputs into the local environment or the relative lack thereof influences the prevalence of antibiotic-resistant bacteria among birds inhabiting the area. PMID- 29230615 TI - Association of -604G/A and -501A/C Ghrelin and Obestatin Prepropeptide Gene Polymorphisms with Polycystic Ovary Syndrome. AB - Ghrelin hormone has an important role in a wide range of metabolic and non metabolic processes. Polymorphisms of ghrelin gene could be associated with a large number of diseases. The aim of this study was to evaluate the association of -604G/A and -501A/C polymorphisms in ghrelin and obestatin prepropeptide gene (GHRL) with polycystic ovary syndrome (PCOS) in a sample of Iranian women. One hundred and fifty-two women with PCOS and 162 age-matched apparently healthy women as control group were enrolled in this study. The study subjects were genotyped for polymorphisms in the ghrelin gene using polymerase chain reaction restriction fragment length polymorphism-based methods. Biochemical parameters, serum prolactin, luteinizing hormone, follicle stimulating hormone, estradiol, and testosterone were estimated by chemiluminescence assay. Serum lipids and lipoproteins were determined by standard enzymatic methods. The association between the risk of PCOS and ghrelin gene polymorphisms was examined using Multivariate analysis. The frequency of the -604G/A and -501A/C polymorphisms was not statistically different between patients and the control group of women (p = 0.12 and p = 0.21, respectively). A significantly higher level of LDL-C was found in the wild-type AA genotype compared with CC genotype of -501A/C polymorphism (p = 0.02). Our findings indicate that neither -604G/A and nor -501A/C polymorphisms of ghrelin gene are associated with PCOS, but suggest a relation between the presence of polymorphic allele of -501A/C polymorphism and LDL-C level in a sample of Iranian women. PMID- 29230614 TI - Translating Predictions of Zoonotic Viruses for Policymakers. AB - Recent outbreaks of Ebola virus disease and Zika virus disease highlight the need for disseminating accurate predictions of emerging zoonotic viruses to national governments for disease surveillance and response. Although there are published maps for many emerging zoonotic viruses, it is unknown if there is agreement among different models or if they are concordant with national expert opinion. Therefore, we reviewed existing predictions for five high priority emerging zoonotic viruses with national experts in Cameroon to investigate these issues and determine how to make predictions more useful for national policymakers. Predictive maps relied primarily on environmental parameters and species distribution models. Rift Valley fever virus and Crimean-Congo hemorrhagic fever virus predictions differed from national expert opinion, potentially because of local livestock movements. Our findings reveal that involving national experts could elicit additional data to improve predictions of emerging pathogens as well as help repackage predictions for policymakers. PMID- 29230616 TI - Elevated inflammation in association with alcohol abuse among Blacks but not Whites: results from the MIDUS biomarker study. AB - Some studies document racial disparities in self-reported health associated with alcohol use and abuse. However, few studies examined biomarkers that underlie the onset of alcohol-related chronic diseases. We investigated whether the association between alcohol abuse and five biomarkers of inflammation (CRP, IL-6, fibrinogen, E-selectin, sICAM-1) vary between Black and White Americans aged 35 to 84 (n = 1173) from the Midlife in the United States Biomarker Study. Multivariable Ordinary Least Squares regressions were used to assess Black-White differences in the association between alcohol abuse and the biomarkers. Race moderated the association between alcohol abuse and CRP (b = 0.56, SE = 0.28, p = 0.048), IL-6 (b = 0.65, SE = 0.22, p = 0.004), and a composite inflammation score (b = 0.014, SE = 0.07, p = 0.041). These findings potentially shed light for why alcohol has a stronger negative association with poorer health for Blacks compared to Whites. Analysis should be replicated in larger prospective cohorts. PMID- 29230617 TI - Retrospective review on the outcome and safety of transscleral diode laser cyclophotocoagulation in refractory glaucoma in Chinese patients. AB - PURPOSE: Transscleral cyclodiode laser cyclophotocoagulation (TSCP) is often reserved for treatment of refractory glaucoma. This retrospective study investigates the safety and efficacy of TSCP among the Chinese population. METHODS: A retrospective review was performed on electronic patient records of all patients receiving TSCP between years 2009 to year 2016. Patient demographics, indication for laser, success and response rate, change in intraocular pressure (IOP), number of treatment sessions, laser energy, glaucoma medication, visual acuity, pain symptoms and complication rate were documented. RESULTS: The study included 126 patients: 81 patients were male and 45 were female, and the mean age was 66.6 +/- 14.3 years old and the mean follow-up was 22.7 +/- 14.1 months. The mean number of treatment sessions was 1.5 +/- 0.8. The success rate was 67.3%. The mean IOP before TSCP was 67 +/- 38.6 mmHg and 22.8 +/ 14.2 mmHg after TSCP, the mean IOP reduction was 38.4%, which was statistically significant (P value < 0.001, Wilcoxon signed rank test). The mean laser energy used per eye was 72.7 +/- 56.6 and 49.2 +/- 22.9 J per individual treatment session. The mean number of laser shots was 15.0 +/- 6.1. 71% of patients were able to reduce their glaucoma medication after TSCP, (P value < 0.01, Wilcoxon signed rank test). 86.1% of patients had improvement in pain symptoms after TSCP. The overall complication rate was 7.1%. CONCLUSION: TSCP was found to be safe and effective among the Chinese population, with comparably low laser energy setting and complication rate. It was found to be most effective in treatment of glaucoma due to trauma, acute angle closure, uveitis and chronic angle closure. PMID- 29230618 TI - Visits for Depression to Physician Assistants and Nurse Practitioners in the USA. PMID- 29230620 TI - Long non-coding RNAs in metastasis. AB - Long non-coding RNA (lncRNA) genes have recently been discovered as key regulators of developmental, physiological, and pathological processes in humans. Recent studies indicate that lncRNAs regulate every step of gene expression, and their aberrant expression can be found in the majority of cancer types. Particularly, lncRNAs were found to function in tumor development and metastasis, which is the major cause of cancer-related death. Thus, exploring key roles of lncRNAs in metastasis is predicted to enhance our knowledge of metastasis, and uncover novel therapeutic targets and biomarkers of this process. In this review, we discuss the molecular mechanisms of lncRNAs in gene expression regulation and their function in metastasis. PMID- 29230619 TI - Neuroanatomical and molecular correlates of cognitive and behavioural outcomes in hypogonadal males. AB - Robust epidemiological, clinical and laboratory evidence supports emerging roles for the sex steroids in such domains as neurodevelopment, behaviour, learning and cognition. Regions of the mammalian brain that are involved in cognitive development and memory do not only express the classical nuclear androgen receptor, but also the non-genomic membrane receptor, which is a G protein coupled receptor that mediates some rapid effects of the androgens on neurogenesis and synaptic plasticity. Under physiological conditions, hippocampal neurons do express the enzyme aromatase, and therefore actively aromatize testosterone to oestradiol. Although glial expression of the aromatase enzyme is minimal, increased expression following injury suggests a role for sex steroids in neuroprotection. It is therefore plausible to deduce that low levels of circulating androgens in males would perturb neuronal functions in relation to cognition and memory, as well as neural repair following injury. The present review is an overview of some roles of the sex steroids on cognitive function in males, and the neuroanatomical and molecular underpinnings of some behavioural and cognitive deficits characteristic of such genetic disorders noted for low androgen levels, including Klinefelter syndrome, Bardet-Biedl syndrome, Kallman syndrome and Prader-Willi syndrome. Recent literature in relation to some behavioural and cognitive changes secondary to surgical and pharmacological castration are also appraised. PMID- 29230621 TI - Electroacupuncture Stimulation of Language-Implicated Acupoint Tongli (HT 5) in Healthy Subjects: An fMRI Evaluation Study. AB - OBJECTIVE: To explore brain activations associated with electroacupuncture simulation at Tongli (HT 5) and its comparison with brain activations during picture-naming task. METHODS: Twenty healthy subjects were enrolled in this study. Half of them received electroacupuncture stimulation at HT 5 (ACUP group) and the other half of them received stimulation at a nonmeridian sham acupoint (SHAM group). All subjects performed picture-naming task. Each subject finished two runs of functional magnetic resonance imaging examinations in one session and picture-naming task was performed before electroacupuncture stimulation. Subjective brain activations were obtained using generalized linear model and inter-group analyses were performed after that. RESULTS: The electroacupuncture stimulation at HT 5 induced significant brain activations in both the anterior and posterior language regions, including the left inferior frontal gyrus, which was in consistent with activations induced during picture-naming task. Group analysis showed a tendency of increased activation of ACUP group in left inferior frontal gyrus compared with SHAM group (P<0.05 FDR corrected). CONCLUSIONS: Electroacupuncture treatment at the acupoint HT 5 has modulation effect on typical language-implicated brain regions in healthy subjects, which provides supporting evidence for beneficial effects of needling at HT 5 for recovery of language function in aphasia. PMID- 29230622 TI - Detecting Bile Reflux-the Enigma of Bariatric Surgery. AB - Duodeno-gastro-esophageal reflux, or bile reflux, is a condition for which there is no diagnostic gold standard, and it remains controversial in terms of carcinoma risk. This is pertinent in the context of an increasingly overweight population who are undergoing weight-loss operations that theoretically further increase the risk of bile reflux. This article reviews investigations for bile reflux based on efficacy, patient tolerability, cost, and infrastructure requirements. At this time, whilst no gold standard exists, hepatobiliary scintigraphy is the least invasive investigation with good-patient tolerability, sensitivity, and reproducibility to be considered first-line for diagnosis of bile reflux. This review will guide clinicians investigating bile reflux. PMID- 29230624 TI - An observational study of the optimal placement of a cerebral oximeter probe to avoid the frontal sinus in children. AB - The frontal sinus is an airspace behind the brow ridge in the skull and can affect the accuracy of the regional cerebral oxygen saturation measurements. We evaluated the optimal location for placement of a cerebral oximeter probe while avoiding the frontal sinus in pediatric patients. This retrospective observational study included 203 pediatric patients aged 3-17 years who had undergone brain computed tomography from November 2010 to December 2015. The patients were divided into five subgroups based on their age. The frontal sinus height was measured from the superior orbital rim. Pneumatization of the frontal sinus was not visible in 78% (3-5 years) and 22% (6-8 years) of the patients. The mean (SD) of the frontal sinus height was 5.9 (3.4), 9.5 (4.1), 14.0 (6.2) 18.6 (8.4), and 21.1 (7.9) mm in the 3-5, 6-8, 9-11, 12-14, and 15-17 year age-groups, respectively. Age was positively correlated with the frontal sinus height (r = 0.61, P < 0.001, 95% confidence interval [CI] 0.513-0.688). A frontal sinus height shorter than 1, 2, and 3 cm were seen in 10 of 11 (91%), 69 of 74 (94%), and 108 of 118 (90%) patients aged 3-5, 6-10, and 11-17 years, respectively. When oximeter probes are applied in pediatric patients, placement based on age can help avoid the frontal sinus. PMID- 29230623 TI - Depression and Anxiety: Lack of Associations with an Inadequate Diet in a Sample of Pregnant Women with a History of Bariatric Surgery-a Multicenter Prospective Controlled Cohort Study. AB - BACKGROUND: Anxiety and depression levels are higher in obese compared to those in normal weight pregnant women. The aims of this study are to examine anxiety and depression in pregnancy following bariatric surgery and to compare with obese pregnant controls considering the dietary intake of polyunsaturated fatty acids (PUFA), folate, and vitamin B12. METHODS: Anxiety (State-Trait Anxiety Inventory) and depression (Edinburgh Postnatal Depression Scale) were examined in the first (T1) and third (T3) pregnancy trimester in 54 women with bariatric surgery and 25 obese. T1 and T3 dietary intake of PUFA, folate, and vitamin B12 intake was assessed using a 3-day food record. Mixed models with a compound symmetry covariance structure and regression models were applied. RESULTS: About half of the women with surgery had high state and trait anxiety scores (>= 40), which did not significantly change during pregnancy. Every 10-kg postoperative weight loss was associated with an increase in T1 state and trait anxiety with respectively 2.7 and 2.3 points. A smoking woman had a 8.6-point higher state anxiety score than a non-smoking woman in T1. In T3, every additional hour of sleep was associated with a decrease in trait anxiety score with 1.59 points. Anxiety and depression scores were not associated with and could not be explained by inadequate PUFAs, folate, and vitamin B12 intakes. Anxiety scores were higher following surgery than those in untreated obesity at both time points. CONCLUSION: Pregnancy following bariatric surgery induces high levels of anxiety that are not associated with an inadequate maternal diet. PMID- 29230625 TI - Systemic lupus erythematosus and the risk of perioperative major adverse cardiovascular events. AB - Systemic lupus erythematosus (SLE) is a significant risk factor for cardiovascular disease. The relationship between SLE and perioperative cardiovascular risks following non-cardiac surgery is uncertain. We investigated associations between a diagnosis of SLE and outcomes following major non-cardiac surgery in a large national database from the United States. Patients age >= 18 years requiring major non-cardiac surgery were identified from Healthcare Cost and Utilization Project's National Inpatient Sample data from 2004 to 2014. Systemic lupus erythematosus and perioperative major adverse cardiovascular events (MACE; myocardial infarction, ischemic stroke or death) were defined by ICD-9 diagnosis codes. Perioperative MACE were reported for SLE patients stratified by age and sex. From 2004 to 2014, a total of 17,853,194 hospitalizations for major non-cardiac surgery met study inclusion criteria. SLE was identified in 70,578 (0.4%) hospitalizations. Overall, the frequency of perioperative MACE was higher in patients with vs. without SLE [2.4 vs. 2.0%, p < 0.001; adjusted OR (aOR) 1.25; 95% CI 1.18-1.31]. Perioperative MACE associated with SLE was largely driven by increased death (aOR 1.58 95% CI 1.40-1.77) and myocardial infarction (aOR 1.32; 95% CI 1.05-1.66) in younger patients with SLE. The increased risk of perioperative MACE associated with SLE in younger patients was attenuated with increasing age. A diagnosis of SLE is associated with increased risk of perioperative MACE, particularly among younger patients. Efforts to improve the perioperative management and outcomes of patients with SLE are needed. PMID- 29230626 TI - Efficient One-Step Fusion PCR Based on Dual-Asymmetric Primers and Two-Step Annealing. AB - Gene splicing by fusion PCR is a versatile and widely used methodology, especially in synthetic biology. We here describe a rapid method for splicing two fragments by one-round fusion PCR with a dual-asymmetric primers and two-step annealing (ODT) method. During the process, the asymmetric intermediate fragments were generated in the early stage. Thereafter, they were hybridized in the subsequent cycles to serve as template for the target full-length product. The process parameters such as primer ratio, elongation temperature and cycle numbers were optimized. In addition, the fusion products produced with this method were successfully applied in seamless genome editing. The fusion of two fragments by this method takes less than 0.5 day. The method is expected to facilitate various kinds of complex genetic engineering projects with enhanced efficiency. PMID- 29230627 TI - Effect of pollen extract supplementation on the varroatosis tolerance of honey bee (Apis mellifera) larvae reared in vitro. AB - As the main source of lipids and proteins in honey bees, pollen is a major nutrient provider involved in development and health and has been studied for tolerance stimulation against pathogens and parasites. In the case of Varroa destructor Anderson & Trueman (Acari, Mesostigmata: Varroidae) parasitization, the lack of a complete laboratory system to rear both the bee larva and the acarian parasite limited the studies concerning larval nutrition effects on the bee tolerance and resistance against varroatosis. Due to the development of this complete rearing protocol, we managed to feed young honey bee larvae with pollen supplemented solutions and to study the effect on their later development under parasitism conditions. In our experimental conditions, pollen influences neither the deformity rate, nor the survival of bees both parasitized and unparasitized. However, pollen extract supplementation seems to significantly impact the weight of the spinning bee larvae without having an effect on the physiological weight loss during pupation, so the differences found at the larval stage remain the same as at emergence. Varroa has a deleterious effect on bee pupae and led to a steady increase of the physiological weight loss experienced during metamorphosis. Interestingly, this ponderal loss associated with Varroa parasitization seems to be reduced in the polyfloral pollen supplementation condition. Altogether, this work is to our knowledge the first to study in laboratory conditions the impact of larval nutrition on the tolerance to parasitism. A diverse pollen diet may be beneficial to the bees' tolerance against V. destructor parasitism. PMID- 29230629 TI - Finding the needle in the haystack. PMID- 29230628 TI - Blacks' Diminished Health Return of Family Structure and Socioeconomic Status; 15 Years of Follow-up of a National Urban Sample of Youth. AB - The protective effect of family structure and socioeconomic status (SES) on physical and mental health is well established. There are reports, however, documenting a smaller return of SES among Blacks compared to Whites, also known as Blacks' diminished return. Using a national sample, this study investigated race by gender differences in the effects of family structure and family SES on subsequent body mass index (BMI) over a 15-year period. This 15-year longitudinal study used data from the Fragile Families and Child Wellbeing Study (FFCWS), in home survey. This study followed 1781 youth from birth to age 15. The sample was composed of White males (n = 241, 13.5%), White females (n = 224, 12.6%), Black males (n = 667, 37.5%), and Black females (n = 649, 36.4%). Family structure and family SES (maternal education and income to need ratio) at birth were the independent variables. BMI at age 15 was the outcome. Race and gender were the moderators. Linear regression models were run in the pooled sample, in addition to race by gender groups. In the pooled sample, married parents, more maternal education, and income to need ratio were all protective against high BMI of youth at 15 years of age. Race interacted with family structure, maternal education, and income to need ratio on BMI, indicating smaller effects for Blacks compared to Whites. Gender did not interact with SES indicators on BMI. Race by gender stratified regressions showed the most consistent associations between family SES and future BMI for White females followed by White males. Family structure, maternal education, and income to need ratio were not associated with lower BMI in Black males or females. The health gain received from family economic resources over time is smaller for male and female Black youth than for male and female White youth. Equalizing access to economic resources may not be enough to eliminate health disparities in obesity. Policies should address qualitative differences in the lives of Whites and Blacks which result in diminished health returns with similar SES resources. Policies should address structural and societal barriers that hold Blacks against translation of their SES resources to health outcomes. PMID- 29230630 TI - Phytochemical study and evaluation of cytotoxicity, mutagenicity, cell cycle kinetics and gene expression of Bauhinia holophylla (Bong.) Steud. in HepG2 cells in vitro. AB - Bauhinia holophylla (Bong.) Steud. (Fabaceae) is a plant used in Brazilian folk medicine to treat diabetes and inflammation. This study evaluated the phytochemical properties, cytotoxic, apoptotic, mutagenic/antimutagenic effects and alterations in gene expression (RNAm) in HepG2 cells treated with the B. holophylla extract. The phytochemical profile highlight the presence of flavonoids isorhamentin and quercetin derivates. The MTT assay was used to evaluate the cytotoxicity of different concentrations for different treatment times. Three concentrations (7.5, 15, 30 ug/mL) were chosen for assessment of apoptosis (AO/EB), mutagenicity (micronucleus), and cell cycle kinetics (flow cytometry). Thereafter, the concentration of 7.5 ug/mL was chosen to evaluate the protective effects against DNA damage induced by benzo[a]pyrene (B[a]P). At concentrations higher than 7.5 ug/mL (between 10 and 50 ug/mL), the extract was cytotoxic, induced apoptosis, and caused antiproliferative effects. However, it did not induce micronucleus and a reduction of apoptotic and micronucleated cells was observed in treatments that included the extract and B[a]P. The protective effect is attributable to the presence of flavonoids, described as antioxidants, inhibitors of DNA adduct and activators of detoxifying enzymes. The results of the present study such as absence of cytotoxic and mutagenic effects and protective effects against known carcinogens suggest that B. holophylla has potential for use soon as herbal medicine. PMID- 29230631 TI - The investigation of ceranib-2 on apoptosis and drug interaction with carboplatin in human non small cell lung cancer cells in vitro. AB - Ceramide is found to be involved in inhibition of cell division and induction of apoptosis in certain tumour cells. Ceranib-2 is an agent that increases ceramide levels by inhibiting ceramidase in cancer cells. Therefore, we aimed to investigate the effects of ceranib-2 on cell survival, apoptosis and interaction with carboplatin in human non-small cell lung cancer cells. The cytotoxic effect of ceranib-2 (1-100 uM) was determined by MTT assay in human lung adenocarcinoma (A549) and large cell lung carcinoma (H460) cells. Carboplatin (1-100 uM) and lung bronchial epithelial cells (BEAS-2B) were used as positive controls. Morphological and ultrastructural changes were analysed by light microscope and TEM. Apoptotic/necrotic cell death and acid ceramidase activity were analysed by ELISA. Combination effects of ceranib-2 and carboplatin were investigated by MTT. The expression levels of CASP3, CASP9, BAX and BCL-2 were examined by qRT-PCR. The IC50 of ceranib-2 was determined as 22 MUM in A549 cells and 8 MUM in H460 cells for 24 h. Morphological changes and induction of DNA fragmentation have revealed apoptotic effects of ceranib-2 in both cell lines. Ceranib-2 and carboplatin has shown synergism in combined treatment at 10 and 25 MUM doses in H460 cells for 24 h. Ceranib-2 inhibited acid ceramidase activity by 44% at 25 uM in H460 cells. Finally, CASP3, CASP9 and BAX expressions were increased while BCL 2 expression was reduced in both cells. Our results obtained some preliminary results about the cytotoxic and apoptotic effects of ceranib-2 for the first time in NSCLC cell lines. PMID- 29230632 TI - Ghrelin accelerates the cartilagic differentiation of rabbit mesenchymal stem cells through the ERK1/2 pathway. AB - Mesenchymal stem cells (MSCs) can differentiate into chondroblasts, adipocytes, or cartilage under appropriate stimulation. Identifying a mechanism triggering the differentiation of MSCs into cartilage may help develop novel therapeutic approaches for treating heterotopic ossification, the pathological formation of lamellar bone in soft tissue outside the skeleton that can lead to debilitating immobility. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, stimulates growth hormone secretion, and has both orexigenic and adipogenic effects. This study sought to understand the potential involvement of the ERK1/2 signaling pathway in the ghrelin-induced growth of rat MSCs (rMSCs). We applied various concentrations of ghrelin to cultured rMSCs by observing the changes in the phosphorylation state of ERK1/2, p38, JNK as well as the type II collagen expression levels by western blot. The highest expression level for both type II collagen was obtained with 600 ng/mL ghrelin at 24 h. We found that the ghrelin-induced differentiation of rMSCs into cartilage was promoted primarily by the ERK1/2 pathway. Our study suggests that ghrelin induced differentiation of rMSCs into cartilage primarily through the ERK1/2 pathway. PMID- 29230634 TI - [Primary care reforms in Austria : Is there potential in the region of Tyrol?] AB - Within the Austrian health care reform, a new policy is generally proposed to strengthen primary care (PC). The aim of this study was to illustrate the status quo in the Tyrolean PC system and to provide the opportunity to examine the reform feasibility. Therefore, a prospective cross-sectional study was performed among licensed GPs in Tyrol, using an online questionnaire. The results of the survey among 87 GPs show that only 20% of Tyrolean PC settings already fulfill the coreteam availabilty described in the reformplans. However, there are differences between urban and rural areas. The highest dissatisfaction was detected in the fields of administration, financing and appreciation of PC. Primarily there is a request by the GPs for implementation of group practices. Only few concerns about the proposed PC centers were noticed. It seems necessary to improve availability, especially outside the core times and during the night. PMID- 29230633 TI - Alteration of the PAC1 Receptor Expression in the Basal Ganglia of MPTP-Induced Parkinsonian Macaque Monkeys. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-known neuropeptide with strong neurotrophic and neuroprotective effects. PACAP exerts its protective actions via three G protein-coupled receptors: the specific Pac1 receptor (Pac1R) and the Vpac1/Vpac2 receptors, the neuroprotective effects being mainly mediated by the Pac1R. The protective role of PACAP in models of Parkinson's disease and other neurodegenerative diseases is now well-established in both in vitro and in vivo studies. PACAP and its receptors occur in the mammalian brain, including regions associated with Parkinson's disease. PACAP receptor upregulation or downregulation has been reported in several injury models or human diseases, but no data are available on alterations of receptor expression in Parkinson's disease. The model closest to the human disease is the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced macaque model. Therefore, our present aim was to evaluate changes in Pac1R expression in basal ganglia related to Parkinson's disease in a macaque model. Monkeys were rendered parkinsonian with MPTP, and striatum, pallidum, and cortex were evaluated for Pac1R immunostaining. We found that Pac1R immunosignal was markedly reduced in the caudate nucleus, putamen, and internal and external parts of the globus pallidus, while the immunoreactivity remained unchanged in the cortex of MPTP treated parkinsonian monkey brains. This decrease was attenuated in some brain areas in monkeys treated with L-DOPA. The strong, specific decrease of the PACAP receptor immunosignal in the basal ganglia of parkinsonian macaque monkey brains suggests that the PACAP/Pac1R system may play an important role in the development/progression of the disease. PMID- 29230635 TI - Quality of life and growth after childhood craniopharyngioma: results of the multinational trial KRANIOPHARYNGEOM 2007. AB - CONTEXT: Quality of life (QoL) after childhood-onset craniopharyngioma (CP) is frequently impaired due to tumor and/or treatment-related factors such as endocrine deficits and hypothalamic involvement/lesions. PATIENTS AND METHODS: In a multinational trial, we prospectively analyzed parental and self-assessment of CP patient QoL at 3 months, 1 and 3 years after CP diagnosis related to growth hormone (GH) substitution. 47 of 194 CP recruited between 2007 and 2015 in KRANIOPHARYNGEOM 2007 were analyzed for QoL 1 and 3 years after CP diagnosis. QoL was assessed by Pediatric Quality of Life (PEDQOL) questionnaire and PEDQOL scores of parental and self-assessed QoL during 3 years follow-up after CP diagnosis were analyzed. RESULTS: Parents estimated QoL of their children worse than patients did themselves. GH substitution had no relevant effect on short term weight and height development. CP patients GH-treated at 3 years follow-up presented at baseline (1 year after diagnosis, before GH substitution) with reduced self-assessed QoL when compared with GH non-treated CP. QoL stabilized during 1-3 years of follow-up in GH-treated patients, whereas non GH-treated patients experienced decreases in autonomy (p = 0.03), cognition (p = 0.01), and physical function (p = 0.04). CONCLUSIONS: Parents assess QoL in CP survivors worse than their children. GH substitution should be considered as a therapeutic option to ameliorate imminent impairments of QoL after CP. PMID- 29230636 TI - Predictors of improvement in bone mineral density after celiac disease diagnosis. AB - PURPOSE: Low bone density is frequently found in patients newly diagnosed with celiac disease (CD), and improvement is variable. This study was performed to assess changes in bone mineral density (BMD) by dual x-ray absorptiometry (DXA) at the lumbar spine, hip, and distal one-third radius as well as clinical predictors of BMD changes after the diagnosis and treatment of CD. METHODS: Adult CD patients who had serial DXA at the Celiac Disease Center at Columbia University Medical Center were included (N = 103). We assessed within-person changes in BMD with paired t-tests. Multiple regression was utilized to assess baseline clinical and laboratory predictors of BMD improvement after diagnosis and treatment. RESULTS: The mean age of our sample was 45.6 years (+/-SD 15.1) and 60% were female. After a median follow-up of 21 months, lumbar spine BMD increased by 1.7 +/- 5.5% (p = 0.006) after CD diagnosis. There was a similar trend at the total hip (1.6 +/- 6.3%, p = 0.06), but no change at the femoral neck or distal one-third radius. Lower baseline serum calcium predicted a greater increase in lumber spine BMD (beta = -0.0470 g/cm2, p = 0.002). At the hip, higher baseline creatinine clearance (beta = 0.005, p = 0.02) was associated with greater gains in BMD. CONCLUSION: BMD increases at the lumbar spine after the diagnosis of CD and greater BMD improvement is associated with lower baseline serum calcium. This suggests that those with the lowest calcium, which is likely a surrogate for the greatest malabsorption, may have the greatest potential for improvement in skeletal health after treatment of CD. PMID- 29230637 TI - Conception and validation of a protocol for reuse of non-irrigated electrophysiology catheters in a Brazilian teaching hospital. AB - PURPOSE: Since the Brazilian current legislation permits the reuse of single-use devices under a validated processing protocol, the main purpose of our study was to develop and validate a method for reusing non-irrigated electrophysiology catheter (EC). METHODS: Manual and mechanical processing by ultrasonic washer was associated with the use of enzymatic solution and hydrogen peroxide with a final rinse with filtered water. Validation of the cleaning process, as well as catheter integrity, was done by observing the ECs in stereoscopic microscope at *60 magnification, followed by HemoCheck-S(r) (HCS) test to monitor the presence of residual blood on their surfaces. Ethylene oxide (EO) was used for sterilization, and the final validations of the processing were performed by assays of sterility, pyrogenicity, and EO residuals. Lastly, a cost-minimization study was performed. RESULTS: Cleaning process demonstrated absence of organic material detectable by HCS at the surfaces of the ECs. Assays for sterility were negative, and assays of EO residuals and endotoxins showed levels under established standards. The number of reuses was settled to a maximum of seven uses for the ECs with handle and ten uses for ECS without handle. The cost minimization study showed an 84% savings, when considering seven reuses. CONCLUSIONS: Processing of ECs was validated at all stages. Therefore, reuse of ECs under the conditions that we designed was considered safe for patients and cost-effective for our institution. PMID- 29230638 TI - Application of the sodium hyaluronate-CNTF scaffolds in repairing adult rat spinal cord injury and facilitating neural network formation. AB - The present study aimed to explore the potential of the sodium hyaluronate-CNTF (ciliary neurotrophic factor) scaffold in activating endogenous neurogenesis and facilitating neural network re-formation after the adult rat spinal cord injury (SCI). After completely cutting and removing a 5-mm adult rat T8 segment, a sodium hyaluronate-CNTF scaffold was implanted into the lesion area. Dil tracing and immunofluorescence staining were used to observe the proliferation, differentiation and integration of neural stem cells (NSCs) after SCI. A planar multielectrode dish system (MED64) was used to test the electrophysiological characteristics of the regenerated neural network in the lesioned area. Electrophysiology and behavior evaluation were used to evaluate functional recovery of paraplegic rat hindlimbs. The Dil tracing and immunofluorescence results suggest that the sodium hyaluronate-CNTF scaffold could activate the NSCs originating from the spinal cord ependymal, and facilitate their migration to the lesion area and differentiation into mature neurons, which were capable of forming synaptic contact and receiving glutamatergic excitatory synaptic input. The MED64 results suggest that functional synapsis could be established among regenerated neurons as well as between regenerated neurons and the host tissue, which has been evidenced to be glutamatergic excitatory synapsis. The electrophysiology and behavior evaluation results indicate that the paraplegic rats' sensory and motor functions were recovered in some degree. Collectively, this study may shed light on paraplegia treatment in clinics. PMID- 29230639 TI - Conserved peptides enhance immune efficiency of inactive vaccines against emerging avian influenza viruses in chicken. AB - Avian influenza viruses (AIVs) such as H5N1 and H7N9 are a great threat to poultry economics and public health. Vaccination can effectively inhibit the spread of AIV in poultry, which is also a viable strategy for controlling virus transmission from poultry to human. Adjuvants that are commonly used in current inactivated vaccines to provide stronger anti-AIV immune responses are often limited in their capacity to quantitatively induce both humoral and cellular immune responses. Herein, we assessed the levels of immune responses generated by a vaccine formulation comprising inactivated H5N1 antigen and synthetic peptides covering conserved CD4+, CD8+ T cell, and B cell epitopes. We found that the synthetic peptides enhanced the antibody responses against conserved influenza virus antigen M2e. Notably, the hemagglutination inhibition test results indicated that the peptides significantly augmented the antibody responses of inactivated H5N1 antigen even in the 1/10 or 1/5 dose group, in the identical antibody level as antigen alone used at the full dose. This indicates that the peptide can significantly reduce the use of inactivated virus, lowering the cost of the vaccine. Moreover, the peptides increased the transcript levels of interleukin-4 and interferon-gamma cytokines in chicken peripheral blood mononuclear cells, which may facilitate both humoral and cellular immune responses. Our data suggest that this peptide combined with inactivated H5N1 antigen enhances both the humoral and cellular immune responses, which may benefit the prediction and design of synthetic peptide-based adjuvants for vaccines in chicken. PMID- 29230640 TI - New class of reduced computationally efficient neuronal models for large-scale simulations of brain dynamics. AB - During slow-wave sleep, brain electrical activity is dominated by the slow (< 1 Hz) electroencephalogram (EEG) oscillations characterized by the periodic transitions between active (or Up) and silent (or Down) states in the membrane voltage of the cortical and thalamic neurons. Sleep slow oscillation is believed to play critical role in consolidation of recent memories. Past computational studies, based on the Hodgkin-Huxley type neuronal models, revealed possible intracellular and network mechanisms of the neuronal activity during sleep, however, they failed to explore the large-scale cortical network dynamics depending on collective behavior in the large populations of neurons. In this new study, we developed a novel class of reduced discrete time spiking neuron models for large-scale network simulations of wake and sleep dynamics. In addition to the spiking mechanism, the new model implemented nonlinearities capturing effects of the leak current, the Ca2+ dependent K+ current and the persistent Na+ current that were found to be critical for transitions between Up and Down states of the slow oscillation. We applied the new model to study large-scale two-dimensional cortical network activity during slow-wave sleep. Our study explained traveling wave dynamics and characteristic synchronization properties of transitions between Up and Down states of the slow oscillation as observed in vivo in recordings from cats. We further predict a critical role of synaptic noise and slow adaptive currents for spike sequence replay as found during sleep related memory consolidation. PMID- 29230641 TI - Associations between left ventricular diastolic function and right ventricular function in patients with and without preserved left ventricular ejection fraction. AB - BACKGROUND: The purpose of this study was to investigate associations between right ventricular (RV) function and left ventricular (LV) diastolic function in patients with reduced LV ejection fraction (LVEF) and preserved LVEF. METHODS: A total of 139 patients who had undergone echocardiography were recruited. LV diastolic function was determined as the ratio of mitral inflow E to mitral e' lateral annular velocities (E/e'). RV function was determined as the RV index of myocardial performance (RIMP). Patients were divided into two groups: the preserved LVEF group (n = 100, LVEF >= 50%) and the reduced LVEF group (n = 39, LVEF < 50%). RESULTS: Associations between RV function and LV diastolic function in patients with reduced LVEF and preserved LVEF differed significantly. RIMP correlated significantly with E/e' in patients with reduced LVEF (r = 0.47, p = 0.003), but not in those with preserved LVEF (r = 0.04, p = 0.68). An important finding of the multivariate regression analysis showed that RIMP was the only independent determinant of E/e' in patients with reduced LVEF, whereas age and gender (not RIMP) was the independent determinant of E/e' in patients with preserved LVEF. CONCLUSIONS: Associations between RV function and LV diastolic function in patients with reduced LVEF and preserved LVEF differed significantly, and RV function showed a close correlation with LV diastolic function in patients with reduced LVEF, but not in those with preserved LVEF. Thus, these findings may well have clinical implications for better management of patients with reduced LVEF. PMID- 29230642 TI - A case of a protruded lesion formed by a poorly differentiated intramucosal adenocarcinoma of the stomach: an immunohistochemical analysis. AB - A 70-year-old woman underwent upper gastrointestinal endoscopy and was found to have a 25-mm protruded lesion in the gastric body. A biopsy revealed malignant cells. Endoscopic submucosal dissection was performed. Histopathologically, the tumor was mainly composed of poorly differentiated adenocarcinoma (PDA), while moderately differentiated adenocarcinoma was observed on its superficial layer. The tumor was located within the mucosal layer. PDAs rarely form a protruded lesion. Here, the presence of a moderately differentiated adenocarcinoma element in the superficial layer of the tumor might have protected the tumor cells from erosion, and solid proliferation of the PDA also contributed to its outward growth. PMID- 29230643 TI - Measuring Fear of Physical Activity in Patients with Heart Failure. AB - PURPOSE: Fear of physical activity (FoPA) has been suggested as a psychological barrier to exercise-based cardiac rehabilitation and everyday physical activity (PA) in patients with heart failure (HF). We evaluated the recently developed Fear of Activity in Situations-Heart Failure (FActS-HF) questionnaire that assesses affective/cognitive fear reactions to situations of varying PA intensities. METHODS: The FActS-HF was given to 132 ambulatory patients with stable HF (67 +/- 12 years, 80% men). In 121 participants with valid FActS-HF data, the questionnaire's dimensionality was investigated. Psychometric properties were determined in terms of reliability and validity. We assessed convergent and discriminant correlations of FoPA with anxiety, kinesiophobia, and depression. External validation criteria encompassed clinical variables and objectively assessed accelerometer measures of everyday PA in a subsample of 61 participants. RESULTS: The FActS-HF measures a unidimensional construct (i.e., FoPA) based on items presenting varying PA intensities (i.e., the more intense the PA, the stronger the fear response). The scale demonstrated good 2-week stability (r tt = 0.82) and excellent internal consistency reliability (alpha = 0.97). FoPA was moderately to strongly associated with anxiety and kinesiophobia, and weakly to moderately associated with state/trait depression, supporting convergent and discriminant validity, respectively. High FoPA was associated with feeling uninformed about HF, comorbidities, non participitation to cardio fitness groups, and less stair climbing, as measured by accelerometry. CONCLUSION: The FActS-HF is a reliable and valid instrument to measure FoPA in patients with HF and provides a promising tool for further research and practice. PMID- 29230644 TI - Effects of organochlorine pesticides on plant growth-promoting traits of phosphate-solubilizing rhizobacterium, Paenibacillus sp. IITISM08. AB - The study aimed to identify an effective phosphate-solubilizing and organochlorine pesticide-tolerant bacterial strain(s). A total of 50 phosphate solubilizing bacterial (PSB) strains were isolated from pesticide-stressed soil. Ten isolates showing higher solubilization were selected for organochlorine pesticides (endosulfan, aldrin, and lindane) tolerance. The strain IITISM08 showed the maximum potential of phosphorous solubilization in Pikovaskya agar medium (solubilization index = 3.2) and in broth medium (348 +/- 2 MUg mL-1) and tolerated up to 250 MUg mL-1 of organochlorine pesticides. During phosphorous solubilization, the presence of functional group and organic acid production were also observed using FT-IR and HPLC. The plant growth-promoting (PGP) traits of the strain IITISM08 was highly inhibited in presence of endosulfan among the three organochlroine pesticides. The strain IITISM08 degraded aldrin (79%), lindane (68%), and endosulfan (51%) at a concentration of 50 MUg mL-1. The strain IITISM08 was identified using 16S rDNA gene sequencing as Paenibacillus sp. (IITISM08). The study revealed that the strain IITISM08 can be used as PGP candidate even under organochlorine pesticide-stressed condition. PMID- 29230645 TI - Pollution evaluation of total and acid-leachable trace elements in surface sediments of Hooghly River Estuary and Sundarban Mangrove Wetland (India). AB - The present work investigated the spatial distribution and ecological risk assessment of total and mild acid-leachable trace elements in surface sediments (top 0-10 cm; grain size <= 63 MUm) along the Hooghly (Ganges) River Estuary and Sundarban Mangrove Wetland, India. The trace elements, analyzed by ICPMS, showed wide range of variations with the following descending order (mean values expressed in milligrams per kilogram): Fe (25,050 +/- 4918) > Al (16,992 +/- 4172) > Mn (517 +/- 102) > Zn (53 +/- 18) > Cu (33 +/- 11) > Cr (29 +/- 7) > Ni (27 +/- 6) > Pb (14 +/- 3) > As (5 +/- 1) > Se (0.37 +/- 0.10) > Cd (0.17 +/- 0.13) > Ag (0.16 +/- 0.19) > Hg (0.05 +/- 0.10). In the acid-leachable fraction, Cd (92%) is dominated followed by Pb (81%), Mn (77%), Cu (70%), and Se (58%) indicating their high mobility, imposing negative impact on the adjacent benthos. The sediment pollution indices (both enrichment factor and contamination factor) suggested severe pollution by Ag at the sampling site Sajnekhali, a wildlife sanctuary in Sundarban. The mean probable effect level quotient indicated that surface sediments in the vicinity of the studied region have 21% probability of toxicity to biota. The result of multivariate analyses affirms lithogenic sources (e.g., weathering parent rocks, dry deposition) for As, Pb, Cr, Cu, and Ni, whereas Cd and Hg originated from anthropogenic activities (such as urban and industrial activities). Both human-induced stresses and natural processes controlled trace element accumulation and distribution in the estuarine system, and remedial measures are required to mitigate the potential impacts of these hazardous trace elements. PMID- 29230647 TI - Validating a continental-scale groundwater diffuse pollution model using regional datasets. AB - In this study, we assess the validity of an African-scale groundwater pollution model for nitrates. In a previous study, we identified a statistical continental scale groundwater pollution model for nitrate. The model was identified using a pan-African meta-analysis of available nitrate groundwater pollution studies. The model was implemented in both Random Forest (RF) and multiple regression formats. For both approaches, we collected as predictors a comprehensive GIS database of 13 spatial attributes, related to land use, soil type, hydrogeology, topography, climatology, region typology, nitrogen fertiliser application rate, and population density. In this paper, we validate the continental-scale model of groundwater contamination by using a nitrate measurement dataset from three African countries. We discuss the issue of data availability, and quality and scale issues, as challenges in validation. Notwithstanding that the modelling procedure exhibited very good success using a continental-scale dataset (e.g. R 2 = 0.97 in the RF format using a cross-validation approach), the continental-scale model could not be used without recalibration to predict nitrate pollution at the country scale using regional data. In addition, when recalibrating the model using country-scale datasets, the order of model exploratory factors changes. This suggests that the structure and the parameters of a statistical spatially distributed groundwater degradation model for the African continent are strongly scale dependent. PMID- 29230646 TI - Abundance of Naegleria fowleri in roof-harvested rainwater tank samples from two continents. AB - Roof-harvested rainwater (RHRW) has been used as an alternative source of water in water scarce regions of many countries. The microbiological and chemical quality of RHRW has been questioned due to the presence of bacterial and protozoan pathogens. However, information on the occurrence of pathogenic amoeba in RHRW tank samples is needed due to their health risk potential and known associations with opportunistic pathogens. Therefore, this study aims to determine the quantitative occurrence of Naegleria fowleri in RHRW tank samples from Southeast Queensland (SEQ), Australia (AU), and the Kleinmond Housing Scheme located in Kleinmond, South Africa (SA). In all, 134 and 80 RHRW tank samples were collected from SEQ, and the Kleinmond Housing Scheme, Western Cape, SA, respectively. Quantitative PCR (qPCR) assays were used to measure the concentrations of N. fowleri, and culture-based methods were used to measure fecal indicator bacteria (FIB) Escherichia coli (E. coli) and Enterococcus spp. Of the 134 tank water samples tested from AU, 69 and 62.7% were positive for E. coli, and Enterococcus spp., respectively. For the SA tank water samples, FIB analysis was conducted for samples SA-T41 to SA-T80 (n = 40). Of the 40 samples analyzed from SA, 95 and 35% were positive for E. coli and Enterococcus spp., respectively. Of the 134 water samples tested in AU, 15 (11.2%) water samples were positive for N. fowleri, and the concentrations ranged from 1.7 * 102 to 3.6 * 104 gene copies per 100 mL of water. Of the 80 SA tank water samples screened for N. fowleri, 15 (18.8%) tank water samples were positive for N. fowleri and the concentrations ranged from 2.1 * 101 to 7.8 * 104 gene copies per 100 mL of tank water. The prevalence of N. fowleri in RHRW tank samples from AU and SA thus warrants further development of dose-response models for N. fowleri and a quantitative microbial risk assessment (QMRA) to inform and prioritize strategies for reducing associated public health risks. PMID- 29230648 TI - Risk perception of aquatic pollution originated from chemical industry clusters in the coastal area of Jiangsu province, China. AB - According to "the Layout Scheme of the Chemical Industry in Jiangsu Province From 2016 to 2030" and "the Development Planning in the Coastal Area of Jiangsu Province, China," several chemical industry clusters will be located in the coastal area of Jiangsu province, China, and the risk of surface water pollution will be inevitably higher in the densely populated region. To get to know the risk acceptance level of the residents near the clusters, public perception was analyzed from the five risk factors: the basic knowledge about the pollution, the negative effects on aquatic environment imposed by the clusters, the positive effects brought by the clusters, the trust of controlling aquatic pollution, and the acceptance of the clusters. Twenty-four statements were screened out to describe the five factors, and about 600 residents were covered in three typical clusters surveyed. On the whole, the youth showed a higher interest on the survey, and middle-aged people were likely to be more concerned about aquatic pollution incident. There was no significant difference on risk perception of the three clusters. The respondents investigated had good knowledge background on aquatic pollution and the residents identified with the benefits brought by the clusters. They were weak in risk awareness of pollution originated from the chemical enterprises' groups. Although the respondents regarded that chemical industry clusters did not expose all points of pollutants' generation to the public, they inclined to trust the administration agencies on controlling the pollution and welcome the construction of chemical clusters in their dwelling cities. Besides, risk perception showed obvious spatial distribution. The closer were the samples' sites to the clusters and the rivers receiving pollutants, the higher were the residents' perceived risk, benefit, and trust. However, there was no identical spatial difference on risk acceptance, which might be comprehensively influenced by various factors. Demographic variables on diverse risk acceptance levels were further illustrated, and some useful conclusions might be provided for managing the response of residents to aquatic pollution and helping identify effective precautionary measures in the vicinity of chemical industry clusters. PMID- 29230649 TI - Investigating monsoon and post-monsoon variabilities of bacterioplankton communities in a mangrove ecosystem. AB - In mangrove environments, bacterioplankton communities constitute an important component of aquatic biota and play a major role in ecosystem processes. Variability of bacterioplankton communities from Sundarbans mangrove, located in the Indian subcontinent in South Asia and sits on the apex of Bay of Bengal, was investigated over monsoon and post-monsoon seasons. The study was undertaken in two stations in Sundarbans using 16S rRNA clone library and Illumina MiSeq approaches with focus on the functionally important members that participate in coastal biogeochemical cycling. Out of 544 sequenced clones, Proteobacteria dominated the study area (373 sequences) with persistence of two major classes, namely, Gammaproteobacteria and Alphaproteobacteria across both monsoon and post monsoon seasons in both stations. Several sequences belonging to Sphingomonadales, Chromatiales, Alteromonadales, Oceanospirillales, and Bacteroidetes were encountered that are known to play important roles in coastal carbon cycling. Some sequences showed identity with published uncultured Planctomycetes and Chloroflexi highlighting their role in nitrogen cycling. The detection of two novel clades highlighted the existence of indigenous group of bacterioplankton that may play important roles in this ecosystem. The eubacterial V3-V4 region from environmental DNA extracted from the above two stations, followed by sequencing in Illumina MiSeq system, was also targeted in the study. A congruency between the clone library and Illumina approaches was observed. Strong variability in bacterioplankton community structure was encountered at a seasonal scale in link with precipitation. Drastic increase in sediment associated bacteria such as members of Firmicutes and Desulfovibrio was found in monsoon hinting possible resuspension of sediment-dwelling bacteria into the overlying water column. Principal component analysis (PCA) revealed dissolved ammonium and dissolved nitrate to account for maximum variation observed in the bacterioplankton community structure. Overall, the study showed that a strong interplay exists between environmental parameters and observed variability in bacterioplankton communities as a result of precipitation which can ultimately influence processes and rates linked to coastal biogeochemical cycles. PMID- 29230650 TI - Available forms of nutrients and heavy metals control the distribution of microbial phospholipid fatty acids in sediments of the Three Gorges Reservoir, China. AB - The construction of the Three Gorges Reservoir (TGR) as well as the development of local industry and agriculture not only had tremendous impacts on the environment but also affected human health. Although water, soil, and air in the TGR have been well studied for environmental risk assessment, very little information is available on benthic sediments and microorganisms. In this study, sedimentary samples were collected along the main stream of the TGR to examine microbial phospholipid fatty acids (PLFA) and relevant variables (e.g., nutrients and heavy metals) after the full operation of the TGR. The results showed that there were prominent trends (increase or decrease) of sedimentary PLFAs and properties from downstream to upstream. Bacteria-specific PLFA decreased toward the dam, while fungi-specific PLFA did not show any significant trend. The PLFA ratio of fungi to bacteria (F/B) increased along the mainstream. The total PLFA concentration, which represents the microbial biomass, decreased significantly toward the dam. Upstream and downstream sampling points were clearly distinguished by PLFA ordination in the redundancy analysis (RDA). That finding showed microbial PLFAs to have an obvious distribution pattern (increase or decrease) in the TGR. The PLFA distribution was markedly controlled by nutrients and heavy metals, but nutrients were more important. Moreover, among nutrients, Bio-P, NH4+-N, NO3--N, and DOC were more important than TP, TN, TOC, and pH in controlling PLFA distribution. For heavy metals, Tl, V, Mo, and Ni were more important than Zn, Cu, Cd, and Pb. These findings suggested that Tl, V, Mo, and Ni should not be ignored to guard against their pollution in the TGR, and we should pay attention to them and make them our first priority. This study highlighted that the construction of the TGR changed riverine environments and altered microbial communities in sediments by affecting sedimentary properties. It is a reminder that the microbial ecology of sediment as an indicator should be considered in assessing the eco-risk of the TGR. PMID- 29230651 TI - Preparation and assessment of carboxylate polyelectrolyte as draw solute for forward osmosis. AB - Reverse draw solute diffusion not only reduces the water flux in forward osmosis (FO), but also contaminates the feed solution and eventually increases the regeneration cost of draw solution. In the present study, a new polyelectrolyte was synthesized as FO draw solute to address this problem. Acrylic acid and sodium p-styrenesulfonate monomers with hydrophilic group were used to fabricate carboxylate polyelectrolyte through free radical polymerization reaction. Results demonstrated that the osmotic pressure of carboxylate polyelectrolyte solution had a good linear relationship with concentration, and the viscosity of 0.18 g/mL solution was less than 5.4 cP. Active layer facing draw solution produced the initial water flux of 11.77 LMH and active layer facing feed solution yielded the initial water flux of 6.68 LMH when the concentration of draw solution was 0.18 g/mL. The reverse solute flux was around 1 gMH, and specific reverse solute flux of 0.18 g/mL carboxylate polyelectrolyte draw solution was 0.11 g/L which was much lower than that of traditional inorganic salts. Finally, diluted draw solution was regenerated via ultrafiltration, and the recovery efficiency of 94.78% was achieved. So, carboxylate polyelectrolyte can be suitable draw solute for FO. PMID- 29230652 TI - Response of energy microalgae Chlamydomonas reinhardtii to nitrogen and phosphorus stress. AB - Microalgae can effectively absorb nitrogen (N) and phosphorus (P) in wastewater, while growth characteristics can be affected by such nutrients. The influences of the N and P concentration on growth, biomass yield, protein yield, and cell ultrastructure of Chlamydomonas reinhardtii (C. reinhardtii) were investigated in this study. The results showed that, in the optimum conditions (24-72 mg/L for N and 4.5-13.5 mg/L for P), the final biomass and protein content of C. reinhardtii could reach maximum value, and the cell organelles (chloroplast, mitochondria,etc.) showed good structures with larger chloroplasts, and more and neater thylakoids. However, if the concentration of nutrients was much higher or lower than the optimal value, it would cause adverse effects on the growth of C. reinhardtii, especially in high nitrogen (1000 mg/L) and low phosphorus (0.5 mg/L) conditions. Under these extreme conditions, the ultrastructure of the cells was also damaged significantly as follows: the majority of the organelles were deformed, the chloroplast membrane became shrunken, and the mitochondria became swollen, even partial disintegrated (differing slightly under high-N and low-P conditions); furthermore, it is found that C. reinhardtii was more sensitive to low-P stress. On the basis of these results, our findings have general implications in the application of wastewater treatment. PMID- 29230653 TI - Environmental exposure to cadmium-a risk for health of the general population in industrialized countries and preventive strategies. AB - Cadmium (Cd) is a heavy metal belonging to the group of the main chemical pollutants of the natural and occupational environment in economically developed countries. The forecasts indicate that contamination of the environment with this toxic metal, and thus the exposure of the general population, will increase. Food (particularly plant products) is the main source of the general population exposure to this element. Moreover, an important, and often the main, source of intoxication with Cd is habitual tobacco smoking. Recent epidemiological studies have provided numerous evidence that even low-level environmental exposure to this toxic metal, nowadays occurring in numerous economically developed countries, creates a risk for health of the general population. The low-level lifetime exposure to this metal may lead to the damage to the kidneys, liver, skeletal system, and cardiovascular system, as well as to the deterioration of the sight and hearing. Moreover, it has been suggested that environmental exposure to this xenobiotic may contribute to the development of cancer of the lung, breast, prostate, pancreas, urinary bladder, and nasopharynx. Taking the above into account, the aim of this review article is to draw more attention to Cd as an environmental risk factor for the health of the general population and the need to undertake preventive actions allowing to reduce the risk of health damage due to a lifetime exposure to this toxic metal. PMID- 29230654 TI - Fertilizer effects of composted materials from different sources on cultivating Impatiens balsamina L. in municipal solid waste management. AB - At different stages of municipal solid waste management, several technologies such as home composting, industrial composting, and landfill mining could be used to recycle organic matters. Assessing the quality of composted material is crucial for determining where and how for recycling the organic fractions of municipal solid waste (OFMSW). Current studies mainly focused on comparing their biochemical characteristics and environmental impacts; however, comprehensive effects on cultivating plants were rarely compared with composted materials from different sources. Here, the final composting products from home composting (HC), industrial composting (IC), and landfill mining (LM), with different mixing ratios between OFMSW and soil (25, 50, 75, and 100%), were applied for cultivating Impatiens balsamina L. to examine the growing and flowering features under 195 days of observation. We found that all types of composted materials showed positive effects on growth of impatiens; however, their individual profiles were significant different. Generally, compost from HC showed the best comprehensive effects on the plant. Impatiens' dry weight biomass and maximum number of leaves and flowers of HC were1.5 and 2.8 times, 1.1 and 1.6 times, and 1.8 and 4.2 times than those of IC and LM, respectively. Compost from IC was superior in prolonging leaf-growing phase and increasing photosynthesis pigment contents of impatiens. Although comprehensive effect of fine fraction from landfill mining was much lower than HC and IC compost, it still improved impatiens growth and flowering compared to normal sandy soil. The results suggest that direct comprehensive effect on plants growth, flowering, and physiological influences could be introduced as an indicator when we compare different approach to recycle organics from MSW. Comprehensive effect on plants growth, flowering, and physiological influences could be introduced as a direct indicator for assessing organic waste recycling. PMID- 29230655 TI - Elegant grapheme-phoneme correspondence: a periodic chart and singularity generalization unify decoding. AB - The accompanying article introduces highly transparent grapheme-phoneme relationships embodied within a Periodic table of decoding cells, which arguably presents the quintessential transparent decoding elements. The study then folds these cells into one highly transparent but simply stated singularity generalization-this generalization unifies the decoding cells (97% transparency). Deeper, the periodic table and singularity generalization together highlight the connectivity of the periodic cells. Moreover, these interrelated cells, coupled with the singularity generalization, clarify teaching targets and enable efficient learning of the letter-sound code. This singularity generalization, in turn, serves as a model for creating unified but easily stated subordinate generalizations for any one of the transparent cells or groups of cells shown within the tables. The article then expands the periodic cells into two tables of teacher-ready sample word lists-one table includes sample words for the basic and phonogram vowel cells, and the other table embraces word samples for the transparent consonant cells. The paper concludes with suggestions for teaching the cellular transparency embedded within reoccurring isolated words and running text to promote decoding automaticity of the periodic cells. PMID- 29230656 TI - Development of GATE Monte Carlo simulation for a CsI pixelated gamma camera dedicated to high resolution animal SPECT. AB - GATE is currently considered in scintigraphic imaging as a powerful tool to develop, design and optimize nuclear medicine modalities. This paper describes the GATE simulation of a pixelated gamma camera which is dedicated to high resolution of small animals imaging. It consists of a CsI(Na) crystal array coupled to position sensitive photomultiplier tube. The simulation model includes photon tracking through low energy high resolution hexagonal parallel holes collimator, CsI(Na) pixelated crystal, back-compartment, and camera shielding. Simulations were compared with experimental results by some criteria such as energy spectrum, energy resolution, spatial resolution, sensitivity and count profiles obtained from line and point sources imaging. The acquired energy resolution show good agreement with measured spectra. Difference between calculated and experimental values is about 0.3% for absolute sensitivity measurement. The result of the image uniformity is more consistent after implementation of non-uniformity correction. These values were about 1.3 and 1.2% for experimental and simulation study in the central field of view, respectively. Measurements showed that the spatial resolutions differences at the head surface along the long dimensions of gamma camera for simulation and experimental differed by no more than 4%.Differences along the short axis were about 6%. The FWHMs of images of point and line sources show good consistency between experimental images and corresponding simulated ones. The difference between experimental and simulated system parameters was within 11%. Our results demonstrate the ability and flexibility of the Monte Carlo simulation for modeling pixelated gamma camera with position sensitive detector by selecting the appropriate parameters for digitizer chain and collimator position on the detector surface. PMID- 29230657 TI - A quick glance at selected topics in this issue. AB - A quick glance at selected topics in this issue aims to highlight contents of the Journal and provide a quick review to the readers. PMID- 29230658 TI - Guidelines in review: Comparison of the 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes and the 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. AB - In this Guidelines in Review, we review side-by-side the recommendations provided by the 2014 AHA/ACC Guideline for the management of patients with non-ST elevation acute coronary syndromes and the 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. We review the recommendations for imaging in the evaluation of patients with possible ACS followed by the diagnostic evaluation of patients with proven NSTE-ACS, based on their risk for adverse clinical events. PMID- 29230661 TI - Weak circadian rhythm increases neutropenia risk among breast cancer patients undergoing adjuvant chemotherapy. AB - PURPOSE: Severe neutropenia is a common dose-limiting side effect of adjuvant breast cancer chemotherapy. We aimed to test the hypothesis that weak circadian rhythm is associated with an increased risk of neutropenia using a cohort study. METHODS: We consecutively recruited 193 breast cancer patients who received adjuvant chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide followed by docetaxel; doxorubicin and cyclophosphamide; docetaxel and cyclophosphamide). Participants wore a wrist actigraph continuously for 168 h at the beginning of chemotherapy. Values of percent rhythm and double amplitude below medians represented weak circadian rhythm. Mesor measured the mean activity level and acrophase symboled the peak time of the rhythm. We used Cox proportional hazard regression model to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of grade 4 neutropenia and febrile neutropenia in relation to actigraphy derived parameters. RESULTS: Low levels of percent rhythm (HR:2.59, 95% CI 1.50 4.72), double amplitude (HR:2.70, 95% CI 1.51-4.85), and mesor (HR: 2.48, 95% CI 1.44-4.29) were positively associated with the risk of grade 4 neutropenia during chemotherapy. Low levels of percent rhythm (HR: 2.41, 95% CI 1.02-5.69) and double amplitude (HR:2.49, 95% CI 1.05-5.90) were also associated with increased risks of febrile neutropenia. The HRs for acrophase were not statistically significant. CONCLUSIONS: This study provides the first epidemiological evidence that increased risks of grade 4 neutropenia and febrile neutropenia are associated with weak circadian rhythm among adjuvant breast cancer patients. The results suggest that circadian rhythm might be one potential target for the prevention of chemotherapy-induced neutropenia among cancer patients. PMID- 29230660 TI - Dietary intake of soy and cruciferous vegetables and treatment-related symptoms in Chinese-American and non-Hispanic White breast cancer survivors. AB - PURPOSE: This project was undertaken to examine the association between dietary intake of soy or cruciferous vegetables and breast cancer treatment-related symptoms among Chinese-American (CA) and Non-Hispanic White (NHW) breast cancer survivors. METHODS: This cross-sectional study included 192 CA and 173 NHW female breast cancer survivors (stages 0-III, diagnosed between 2006 and 2012) recruited from two California cancer registries, who had completed primary treatment. Patient-reported data on treatment-related symptoms and potential covariates were collected via telephone interviews. Dietary data were ascertained by mailed questionnaires. The outcomes evaluated were menopausal symptoms (hot flashes, night sweats, vaginal dryness, vaginal discharge), joint problems, fatigue, hair thinning/loss, and memory problems. Associations between soy and cruciferous vegetables and symptoms were assessed using logistic regression. Analyses were further stratified by race/ethnicity and endocrine therapy usage (non-user, tamoxifen, aromatase inhibitors). RESULTS: Soy food and cruciferous vegetable intake ranged from no intake to 431 and 865 g/day, respectively, and was higher in CA survivors. Higher soy food intake was associated with lower odds of menopausal symptoms (>= 24.0 vs. 0 g/day, OR 0.51, 95% CI 0.25, 1.03), and fatigue (>= 24.0 vs. 0 g/day, OR 0.43, 95% CI 0.22, 0.84). However, when stratified by race/ethnicity, associations were statistically significant in NHW survivors only. Compared with low intake, higher cruciferous vegetable intake was associated with lower odds of experiencing menopausal symptoms (>= 70.8 vs. < 33.0 g/day, OR 0.50, 95% CI 0.25, 0.97) in the overall population. CONCLUSIONS: In this population of breast cancer survivors, higher soy and cruciferous vegetable intake was associated with less treatment-related menopausal symptoms and fatigue. PMID- 29230662 TI - Relationship of histologic grade and histologic subtype with oncotype Dx recurrence score; retrospective review of 863 breast cancer oncotype Dx results. AB - PURPOSE: Oncotype Dx (ODx) is a multigene assay that is prognostic and predictive in estrogen receptor (ER) positive early breast cancer. ODx recurrence score (RS) is reported to be histologic grade dependent. Relationship of RS with breast cancer histologic subtypes is unknown. This study was designed to assess the relationship of histologic subtype with RS. Histologic grade dependence of RS was also investigated. METHODS: Results of consecutive ODx tests (1/2007-7/2016) from two institutions were reviewed. Histologic subtypes (in: Lakhani et al., WHO classification, IARC Press, Lyon, 2012), combined Nottingham histologic grade, age and tumor size were recorded from pathology reports. Univariate and multivariate analysis was performed to investigate the relationship between RS and ODx risk categories and histologic subtypes, grade, age and tumor size. RESULTS: RS was grade dependent. RS of grade 1 and grade 2 tumors were significantly lower than grade 3 tumors. There was no high-risk grade 1 tumor. In favorable histologic subtypes there was no high-risk tumor. Mean RS of grade 1 lobular tumors was significantly higher than grade 1 ductal tumors. Using newer ODx cut-offs, 5 grade 1 tumors were reclassified as high risk (RS > 25) and grade 3 lobular tumors showed significantly higher rate of reclassification as high risk than grade 3 ductal tumors. In a multivariate analysis, only grade showed a significant positive correlation with RS. Adding dichotomous histologic subtyping (favorable vs. non-favorable) to grade further improved correlation with RS. CONCLUSIONS: The Oncotype Dx result is impacted by histologic grade and histologic subtype. Tumors with favorable histologic subtypes and histologic grade 1 tumors do not have high-risk RS. High RS in a grade 1 tumor or in a tumor with favorable histology is unusual that warrants further investigation. Invasive lobular carcinomas rarely show high-risk RS. Histologic grade and histologic subtype should be considered while ordering ODx testing. PMID- 29230663 TI - Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study. AB - BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 ug/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 ug/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 ug/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 ug/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy. PMID- 29230664 TI - CD14+ HLA-DR-/low MDSCs are elevated in the periphery of early-stage breast cancer patients and suppress autologous T cell proliferation. AB - PURPOSE: Despite the recent expansion in the use of immunotherapy for many cancer types, it is still not a standard treatment for breast cancer. Identifying differences in the immune systems of breast cancer patients compared to healthy women might provide insight into potential targets for immunotherapy and thus may assist its clinical implementation. METHODS: Multi-colour flow cytometry was used to investigate myeloid and lymphoid populations in the peripheral blood of breast cancer patients (n = 40) and in the blood of healthy age-matched women (n = 25). We additionally performed functional testing to identify immune suppressive mechanisms used by circulating CD14+ myeloid cells from breast cancer patients. RESULTS: Our results show that breast cancer patients have significantly elevated frequencies of cells with the monocytic myeloid-derived suppressor cell (mMDSC) phenotype CD14+ HLA-DR-/low compared with healthy women (p < 0.01). We also observed higher levels of earlier differentiated T cells and correspondingly lower levels of T cells in later stages of differentiation (p < 0.05). These disease-associated differences could already be detected in early-stage breast cancer patients in stages 1 and 2 (n = 33 of 40) (p < 0.05). Levels of circulating T cells correlated with certain clinical features and with patient age (p < 0.05). Functional tests showed that CD14+ myeloid cells from breast cancer patients more potently suppressed autologous T cell proliferation than CD14+ cells from healthy women (p < 0.01). Subsequent investigation determined that suppression was mediated in part by reactive oxygen species, because inhibiting this pathway partially restored T cell proliferation (p < 0.01). CONCLUSION: Our results highlight the potential importance of cells with mMDSC phenotypes in breast cancer, identifiable already at early stages of disease. This may provide a basis for identifying possible new therapeutic targets to enhance anti-cancer immunity. PMID- 29230665 TI - Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer. AB - PURPOSE: For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy. METHODS: In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node negative and node-positive patients using Kaplan Meier and Cox regression survival analyses. RESULTS: In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47-0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38-0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13-1.06), although this additional analysis was underpowered for definite conclusions. CONCLUSIONS: This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up. PMID- 29230666 TI - Granuloma Annulare: A Focused Review of Therapeutic Options. AB - Granuloma annulare (GA) is a benign inflammatory disease associated with many conditions such as malignancy, trauma, thyroid disease, diabetes mellitus, and HIV infection. Common clinical subtypes include localized GA, generalized GA, subcutaneous GA, perforating GA, and patch GA. There exists an abundance of literature on GA, yet we know relatively little about its exact etiology and even less about its treatment. The paucity of conclusive data on effective treatment options is largely because the majority of published studies are limited to small case reports, case series, and retrospective studies. As such, there does not yet exist a gold standard of care to guide clinical management. Depending on the clinical subtype, the clinical prognosis for GA can vary. The localized variant generally self-resolves within 2 years without treatment, whereas the generalized form is more chronic and less responsive to treatment. This focused up-to-date review serves to summarize the latest therapeutic options available for GA. PMID- 29230667 TI - Impact of musculoskeletal pain on balance and concerns of falling in mobility limited, community-dwelling Danes over 75 years of age: a cross-sectional study. AB - BACKGROUND: In older adults, musculoskeletal pain is associated with increased concerns of falling, reduced balance and increased occurrence of falls. In younger adults, the intensity of neck pain and low back pain is associated with increased postural sway. It is not known if pain further impairs balance and concerns of falling in mobility-limited older adults, and if so, whether this is associated with different intensities of pain. OBJECTIVE: This study examined whether mobility-limited older adults with mild or intense neck pain and/or low back pain have significantly increased postural sway as measured by centre of pressure (COP) changes and concerns of falling compared to those without pain. METHODS: 48 older adults with a gait speed of < 0.9 m/s from Odense, Denmark were recruited through the public health service. Self-reported neck pain, low back pain, and concerns of falling were recorded on questionnaires. Sway range, velocity and area were recorded on a force plate in a comfortable standing stance. Pain intensity was rated on an 11 point numerical rating scale (0-10). Participants were sub-grouped into mild (0-4) and intense (> 5) neck pain or low back pain. RESULTS: Intense neck pain was associated with increased anterior posterior sway range and area of sway. Intense low back pain was associated with increased concerns of falling. CONCLUSION: Intense neck pain in mobility-limited older adults is associated with significant changes in postural balance, and intense low back pain is associated with significantly higher concerns of falling. PMID- 29230668 TI - Regional specificity of 1p/19q co-deletion combined with radiological features for predicting the survival outcomes of anaplastic oligodendroglial tumor patients. AB - In this study we aimed to identify the anatomic features of 1p/19q co-deletion and investigate the predictive values of tumor location and radiological characteristics for the survival of anaplastic oligodendroglial (AO) glioma patients. Voxel-based lesion-symptom mapping (VLSM) analysis was applied to define the brain regions associated with occurrence of 1p/19q co-deletion in a cohort of 206 AO tumor patients (discovery set) treated between May 2009 and September 2013. Retrospectively, the acquired clusters and radiological features were subjected to Kaplan-Meier survival analysis using data from the Chinese Glioma Genome Atlas (validation set) to evaluate their prognostic role in AO patients. The institutional review board approved this study. The right frontal lobe and right anterior insular lobe were specifically associated with high occurrence of 1p/19q co-deletion. For AO tumors not involving these areas, the absence of contrast enhancement predicted longer progression-free (p = 0.018) and overall survival (p = 0.020); moreover, in patients with contrast enhancement, edema could stratify the survival outcome (p = 0.013 for progression-free survival, p = 0.016 for overall survival). For AO tumors located in the VLSM identified regions, edema was also able to stratify the survival outcome of patients without contrast enhancement (p = 0.025 for progression-free survival, p = 0.028 for overall survival). The 1p/19q co-deletion showed predilection for specific brain regions. According to the tumor involvement of VLSM-identified regions associated with 1p/19q co-deletion, radiological features were predictive for AO patient survival outcomes. PMID- 29230669 TI - P21Waf1/Cip1 and p27Kip1 are correlated with the development and invasion of prolactinoma. AB - Cell cycle control can prevent excessive proliferative response in the pituitary homeostasis. Cyclin dependent kinases (Cdks) are modulated by cyclins or Cdk inhibitors, such as p21 and p27, which can regulate cell cycle progression from the G1 to S phases. This study was conducted to evaluate the levels and the promoter region methylation status of p21 and p27 in prolactinomas (PRL) and analyze their association with clinicopathologic features. We found high-p21 level cases were featured by 5/23 and H-scores 142.3 +/- 23.7 in invasive-PRL specimens, and 19/25 and 221.3 +/- 45.4 in non-invasive specimens (x2 = 14.11, p = 0.000), while high-p27 level cases were featured by 6/23 and H-scores 129.8 +/- 31.1 in invasive-PRL specimens, and 18/25 and 197.1 +/- 46.6 in non-invasive specimens (x2 = 10.11, p = 0.001). A similar trend was also observed for p21 and p27 protein levels in PRL specimens through western-blot (P < 0.01, respectively). The Ki-67 index was much higher in invasive specimens than in non invasive specimens (x2 = 10.10, p = 0.001). Average 33 CpG sites per sample were analyzed by using MALDI-TOF Mass array, and 7/33 CpG sites methylation levels of p27 were higher than 50%. There existed significant differences in 4 CpG sites between invasive specimens and non-invasive specimens (p < 0.01). We found that D2 receptor was closely correlated with p21 levels (P < 0.05, r = 0.567) and p27 levels (P < 0.05, r = 0.591). In PRL, the deficiency in p21 and p27 contributed to the tumor proliferation and migration and Cdk inhibitors may be used as a new therapeutic approach. PMID- 29230670 TI - Double somatic SMARCB1 and NF2 mutations in sporadic spinal schwannoma. AB - In sporadic schwannomas, inactivation of both copies of the NF2 tumor suppressor gene on 22q is common. Constitutional mutations of SMARCB1 are responsible of schwannomatosis, an inherited tumor predisposition syndrome, characterized by the development of multiple schwannomas. We analysed the frequency of copy number changes on chromosome 22 and the mutation of NF2 and SMARCB1 in 26 sporadic schwannomas. We found two spinal schwannomas with an identical somatic missense mutation in SMARCB1 exon 9: p.(Arg377His). Both SMARCB1 mutated schwannomas had LOH of 22q and one of them harbored an inactivating mutation of NF2. The p.(Arg377His) change was not found in a series of 28 vestibular schwannomas. Our data indicate that mutations affecting SMARCB1 play a role in the development or progression of a small subset of spinal schwannomas and that biallelic inactivation of SMARCB1 may cooperate with deficiency of NF2 function in schwannoma tumorigenesis according to the "four-hit/three events" mechanism of tumorigenesis that we demonstrated in schwannomatosis-associated schwannomas. PMID- 29230671 TI - Incorporating DNA Methyltransferase Inhibitors (DNMTis) in the Treatment of Genitourinary Malignancies: A Systematic Review. AB - Inhibition of DNA methyltransferases (DNMTs) has emerged as a novel treatment strategy in solid tumors. Aberrant hypermethylation in promoters of critical tumor suppressor genes is the basis for the idea that treatment with hypomethylating agents may lead to the restoration of a "normal" epigenome and produce clinically meaningful therapeutic outcomes. The aim of this review article is to summarize the current state of knowledge of DNMT inhibitors in the treatment of genitourinary malignancies. The efficacy of these agents in genitourinary malignancies was reported in a number of studies and suggests a role of induced DNA hypomethylation in overcoming resistance to conventional cytotoxic treatments. The clinical significance of these findings should be further investigated. PMID- 29230672 TI - The Role of B-Cell Maturation Antigen in the Biology and Management of, and as a Potential Therapeutic Target in, Multiple Myeloma. AB - B-cell maturation antigen (BCMA) was originally identified as a cell membrane receptor, expressed exclusively on late stage B-cells and plasma cells (PCs). Investigations of BCMA as a target for therapeutic intervention in multiple myeloma (MM) were initiated in 2007, using cSG1 as a naked antibody (Ab) as well as an Ab-drug conjugate (ADC) targeting BCMA, ultimately leading to ongoing clinical studies for previously treated MM patients. Since then, multiple companies have developed anti-BCMA-directed ADCs. Additionally, there are now three bispecific antibodies in development, which bind to both BCMA and CD3epsilon on T-cells. This latter binding results in T-cell recruitment and activation, causing target cell lysis. More recently, T-cells have been genetically engineered to recognize BCMA-expressing cells and, in 2013, the first report of anti-BCMA-chimeric antigen receptor T-cells showed that these killed MM cell lines and human MM xenografts in mice. BCMA is also solubilized in the blood (soluble BCMA [sBCMA]) and MM patients with progressive disease have significantly higher sBCMA levels than those responding to treatment. sBCMA circulating in the blood may limit the efficacy of these anti-BCMA-directed therapies. When sBCMA binds to B-cell activating factor (BAFF), BAFF is unable to perform its major biological function of inducing B-cell proliferation and differentiation into Ab-secreting PC. However, the use of gamma-secretase inhibitors, which prevent shedding of BCMA from PCs, may improve the efficacy of these BCMA-directed therapies. PMID- 29230673 TI - Rejecting salient distractors: Generalization from experience. AB - Distraction impairs performance of many important, everyday tasks. Attentional control limits distraction by preferentially selecting important items for limited-capacity cognitive operations. Research in attentional control has typically investigated the degree to which selection of items is stimulus-driven versus goal-driven. Recent work finds that when observers initially learn a task, the selection is based on stimulus-driven factors, but through experience, goal driven factors have an increasing influence. The modulation of selection by goals has been studied within the paradigm of learned distractor rejection, in which experience over a sequence of trials enables individuals eventually to ignore a perceptually salient distractor. The experiments presented examine whether observers can generalize learned distractor rejection to novel distractors. Observers searched for a target and ignored a salient color-singleton distractor that appeared in half of the trials. In Experiment 1, observers who learned distractor rejection in a variable environment rejected a novel distractor more effectively than observers who learned distractor rejection in a less variable, homogeneous environment, demonstrating that variable, heterogeneous stimulus environments encourage generalizable learned distractor rejection. Experiments 2 and 3 investigated the time course of learned distractor rejection across the experiment and found that after experiencing four color-singleton distractors in different blocks, observers could effectively reject subsequent novel color singleton distractors. These results suggest that the optimization of attentional control to the task environment can be interpreted as a form of learning, demonstrating experience's critical role in attentional control. PMID- 29230674 TI - Diet and activity patterns of Arsi geladas in low-elevation disturbed habitat south of the Rift Valley at Indetu, Ethiopia. AB - Understanding the basic natural history of threatened primate taxa is crucial to developing and implementing successful conservation strategies for them. Data on feeding ecology and activity patterns are particularly important for identifying the strategies through which primates invest time and foraging effort towards survival and reproduction at a given locale. Here, we report the results of the first study of the diet and activity budget of Arsi geladas, a population of < 1000 individuals endemic to a heavily disturbed region of the southern Ethiopian Highlands and believed to represent a new taxon of geladas. We conducted our research on a band of 34 individuals belonging to five, one-male units at Indetu, eastern Arsi, Ethiopia, from August 2010 to May 2011 (excluding March 2011). Feeding accounted for 41.7% of total scans, followed by moving (20.3%), resting (19.0%), and social behavior (19.0%). Feeding and moving increased and resting and socializing decreased during the dry season when food availability was probably lower than during the wet season. Geladas ate mostly graminoid leaves (51.7% of feeding scans) though they also consumed graminoid rhizomes (24.4%), forb tubers (7.1%), forb leaves (7.1%), cactus, shrub, and tree fruits (3.6%), graminoid corms (1.7%), forb roots (1.6%), and unidentified items (3.0%). Underground foods (corms, rhizomes, roots, and tubers) accounted for 22-47% (mean = 35%) of the monthly (n = 9) diet and were eaten slightly more during the wet season than during the dry season. Contributions of human crops to the gelada diet could not be quantified without creating conflict between farmers and researchers, though we did note that geladas visited farms on 5-10% of study days. Threats from farmers, children, and dogs limited the geladas' access to crops once they entered the farms. Further research involving questionnaire surveys of farmers, direct observation of crop damage by geladas, and DNA metabarcoding of gelada feces are crucial to the development of strategies to mitigate human-gelada conflict in the densely populated Arsi Zone of Ethiopia. PMID- 29230675 TI - Clozapine and Gastrointestinal Hypomotility. AB - Gastrointestinal hypomotility (GIH) is an under-reported but highly prevalent and potentially dangerous side effect of clozapine. In a comprehensive meta-analysis of clozapine-treated patients, the prevalence of GIH was 32%. In general, GIH has consistently been reported to have a negative impact on quality of life, and there is no reason to believe this will be different in clozapine-treated patients with therapy-resistant schizophrenia. GIH is dangerous; in a comparative review of lethal side effects of clozapine, the mortality of agranulocytosis was 2.2-4.2% compared with 15.0-27.5% for GIH. The mortality rate in our review of all published case reports of ileus was 43.7%. (Co-)Prescription of anticholinergic drugs in patients treated with clozapine should be avoided as anticholinergics are associated with increased incidence and fatality of ileus. Prevention of GIH can best be obtained by frequent and targeted questioning by the mental healthcare providers of the patients' defecation pattern and this is therefore strongly recommended for timely detection and treatment of treatment emergent GIH throughout clozapine treatment. Treatment approaches can be either preventive laxative prescription with every clozapine prescription in all clozapine-treated patients or targeted treatment of treatment-emergent GIH. First line treatments of GIH are the osmotic laxative macrogol, stool softener docusate and bowel stimulant senna. As the occurrence of severe cases of GIH is not restricted to a certain treatment duration, alertness for and/or treatment of GIH is required for the whole duration of clozapine treatment. PMID- 29230677 TI - Neocosmocercella fisherae n. sp. (Nematoda: Cosmocercidae), a parasite of the large intestine of Phyllomedusa bicolor (Boddaert) (Anura: Phyllomedusidae) from the Brazilian Amazon. AB - Neocosmocercella fisherae n. sp. is the first nematode species found parasitising Phyllomedusa bicolor from the Brazilian Amazon Region. The new species has a triangular oral opening, with bi-lobed lips, and is distinguished from N. bakeri (triangular oral opening with simple lips), and from N. paraguayensis (hexagonal oral opening with bi-lobed lips). Additionally, the new species has ciliated cephalic papillae, which are absent in the other species of the genus. The reduced uterine sac and the presence of a single egg in the uterus in females are the main morphological characters that differentiate the new species from its congeners N. bakeri (8-10 eggs) and N. paraguayensis (10 eggs, based on the allotype). Additionally, the new species differs from the other two species of the genus by morphometric characters such as the size of spicules and gubernaculum in males and the vagina in females. Until now, phyllomedusid anurans are the only known hosts for the nematodes of this genus. The present work describes the third species of the genus and the first species of nematode parasitising P. bicolor. PMID- 29230676 TI - Gut microbial balance and liver transplantation: alteration, management, and prediction. AB - Liver transplantation is a conventional treatment for terminal stage liver diseases. However, several complications still hinder the survival rate. Intestinal barrier destruction is widely observed among patients receiving liver transplant and suffering from ischemia-reperfusion or rejection injuries because of the relationship between the intestine and the liver, both in anatomy and function. Importantly, the resulting alteration of gut microbiota aggravates graft dysfunctions during the process. This article reviews the research progress for gut microbial alterations and liver transplantation. Especially, this work also evaluates research on the management of gut microbial alteration and the prediction of possible injuries utilizing microbial alteration during liver transplantation. In addition, we propose possible directions for research on gut microbial alteration during liver transplantation and offer a hypothesis on the utilization of microbial alteration in liver transplantation. The aim is not only to predict perioperative injuries but also to function as a method of treatment or even inhibit the rejection of liver transplantation. PMID- 29230678 TI - Fractal-based radiomic approach to predict complete pathological response after chemo-radiotherapy in rectal cancer. AB - The aim of this study was to propose a methodology to investigate the tumour heterogeneity and evaluate its ability to predict pathologically complete response (pCR) after chemo-radiotherapy (CRT) in locally advanced rectal cancer (LARC). This approach consisted in normalising the pixel intensities of the tumour and identifying the different sub-regions using an intensity-based thresholding. The spatial organisation of these subpopulations was quantified using the fractal dimension (FD). This approach was implemented in a radiomic workflow and applied to 198 T2-weighted pre-treatment magnetic resonance (MR) images of LARC patients. Three types of features were extracted from the gross tumour volume (GTV): morphological, statistical and fractal features. Feature selection was performed using the Wilcoxon test and a logistic regression model was calculated to predict the pCR probability after CRT. The model was elaborated considering the patients treated in two institutions: Fondazione Policlinico Universitario "Agostino Gemelli" of Rome (173 cases, training set) and University Medical Centre of Maastricht (25 cases, validation set). The results obtained showed that the fractal parameters of the subpopulations have the highest performance in predicting pCR. The predictive model elaborated had an area under the curve (AUC) equal to 0.77 +/- 0.07. The model reliability was confirmed by the validation set (AUC = 0.79 +/- 0.09). This study suggests that the fractal analysis can play an important role in radiomics, providing valuable information not only about the GTV structure, but also about its inner subpopulations. PMID- 29230679 TI - Short tau inversion recovery in breast diffusion-weighted imaging: signal-to noise ratio and apparent diffusion coefficients using a breast phantom in comparison with spectral attenuated inversion recovery. AB - OBJECTIVE: This study aimed to compare the signal-to-noise ratios (SNRs) and apparent diffusion coefficients (ADCs) obtained using two fat suppression techniques in breast diffusion-weighted imaging (DWI) of a phantom. MATERIALS AND METHODS: The breast phantom comprised agar gels with four different concentrations of granulated sugar (samples 1, 2, 3, and 4). DWI with short tau inversion recovery (STIR-DWI) and that with spectral attenuated inversion recovery (SPAIR-DWI) were performed using 3.0-T magnetic resonance imaging, and the obtained SNRs and ADCs were compared. ADCs were also compared between the right and left breast phantoms. RESULTS: For samples 3 and 4, SNRs obtained using STIR-DWI were lower than those obtained using SPAIR-DWI. For samples 2, 3, and 4, overall ADCs obtained using STIR-DWI were significantly higher than those obtained using SPAIR-DWI (p < 0.001 for all), although no significant difference was observed for sample 1 (p = 0.62). STIR-DWI shows a positive bias and wide limits of agreement in Bland-Altman plot. The coefficients of variance of overall ADCs were good in STIR-DWI and SPAIR-DWI. For all samples, STIR-DWI demonstrated slightly larger percentage differences in ADCs between the right and left phantoms than SPAIR-DWI. CONCLUSION: SNRs and ADCs obtained using STIR-DWI are influenced by the T 1 value; a shorter T 1 value decreases SNRs, overestimates ADCs, and induces the measurement error in ADCs. STIR-DWI showed a larger difference in ADCs between the right and left phantoms than SPAIR-DWI. PMID- 29230681 TI - The metagenomic approach to characterization of the microbial community shift during the long-term cultivation of anammox-enriched granular sludge. AB - A metagenomic approach was used to investigate how the microbial community composition changes when an anammox-based granular sludge reactor is seeded with nitritation-anammox biomass from a wastewater treatment plant. In the seed sample, the abundance of Candidatus Kuenenia stuttgartiensis was similar to Candidatus Jettenia caeni (12.63 vs. 11.68%). This biomass was typical in terms of microbial nitrogen conversion; both ammonia (Nitrosomonas sp.) and nitrite (Nitrospira sp.) oxidizing bacteria were detected. In the lab-scale reactor, Candidatus Kuenenia stuttgartiensis and Candidatus Jettenia caeni bacteria were also present in equal proportions (18.57 vs. 20.89%). On the contrary, Candidatus Nitrospira defluvii bacteria were highly abundant in this reactor, but no known ammonia-oxidizing bacteria were detected. In light of recent studies showing that Nitrospira sp. are capable of complete nitrification, the results presented here may well indicate that both stages of nitrification in the anammox-based granular sludge reactor were performed by this bacteria. PMID- 29230680 TI - Structured reporting for fibrosing lung disease: a model shared by radiologist and pulmonologist. AB - OBJECTIVES: To apply the Delphi exercise with iterative involvement of radiologists and pulmonologists with the aim of defining a structured reporting template for high-resolution computed tomography (HRCT) of patients with fibrosing lung disease (FLD). METHODS: The writing committee selected the HRCT criteria-the Delphi items-for rating from both radiology panelists (RP) and pulmonology panelists (PP). The Delphi items were first rated by RPs as "essential", "optional", or "not relevant". The items rated "essential" by < 80% of the RP were selected for the PP rating. The format of reporting was rated by both RP and PP. RESULTS: A total of 42 RPs and 12 PPs participated to the survey. In both Delphi round 1 and 2, 10/27 (37.7%) items were rated "essential" by more than 80% of RP. The remaining 17/27 (63.3%) items were rated by the PP in round 3, with 2/17 items (11.7%) rated "essential" by the PP. PP proposed additional items for conclusion domain, which were rated by RPs in the fourth round. Poor consensus was observed for the format of reporting. CONCLUSIONS: This study provides a template for structured report of FLD that features essential items as agreed by expert thoracic radiologists and pulmonologists. PMID- 29230683 TI - Primary Esophagogastric Neuroendocrine Carcinoma: a Retrospective Study from the Nottingham Upper Gastrointestinal Cancer Center. PMID- 29230682 TI - Association of functional markers with flowering time in lentil. AB - In the present study, a diverse panel of 96 accessions of lentil germplasm was used to study flowering time over environments and to identify simple sequence repeat markers associated with flowering time through association mapping. The study showed high broad sense heritability estimate (h 2 bs=0.93) for flowering time in lentil. Screening of 534 SSR markers resulted in an identification of 75 SSR polymorphic markers (13.9%) across studied genotypes. These markers amplified 266 loci and generated 697 alleles ranging from two to 16 alleles per locus. Model-based cluster analysis used for the determination of population structure resulted in the identification of two distinct subpopulations. Distribution of flowering time was ranged from 40 to 70 days in subpopulation I and from 54 to 69 days in subpopulation II and did not skew either late or early flowering time within a subpopulation. No admixture was observed within the subpopulations. Use of the most accepted maximum likelihood model (P3D mixed linear model with optimum compression) of MTA analysis showed significant association of 26 SSR markers with flowering time at <0.05 probability. The percent of phenotypic explained by each associated marker with flowering time ranged from 2.1 to 21.8% and identified QTLs for flowering time explaining high phenotypic variation across the environments (10.7-21.8%) or in a particular environment (10.2-21.4%). In the present study, 13 EST-SSR showed significant association with flowering time and explained large phenotypic variation (2.3-21.8%) compared to genomic SSR markers (2.1-10.2%). Hence, these markers can be used as functional markers in the lentil breeding program to develop short duration cultivars. PMID- 29230686 TI - Impact of a Breast Cancer Educational Program on Female University Students' Knowledge, Attitudes, and Practices. AB - Breast cancer (BC) is a worldwide fatal cancer among females. Efforts fighting against this disease should start with females at younger ages. This study evaluated the effectiveness a BC educational program in promoting female university students' knowledge and attitudes towards BC and practices of breast self-examination (BSE). A pre- and post-test design was used in two phases; pre- and post-intervention phase. A 1-day educational program was conducted with theoretical and practical educational sessions. Participants were evaluated twice (before and 2 weeks after the intervention) for the following variables: knowledge regarding BC warning signs, BC risk factors and knowledge in regard to BSE, in addition to their attitudes and practices of BSE. A total of 110 participants were randomized into either intervention (n = 64, 58.2%) or control group (n = 46, 41.8%). Analysis revealed that participants in both groups had relatively low level of knowledge, negative attitudes, and poor practice towards BC and BSE before attending the intervention. Analysis of the post test revealed that participants in the interventional group had significant improvement in knowledge, positive attitudes, and more practice of BSE compared to participants in the control group. The implementation of a BC awareness program had positive effects on the female university students' knowledge, attitudes, and practices regarding BC and BSE. Findings from this study strengthen and reinforce the importance of conducting such awareness programs for this young age group. PMID- 29230687 TI - Effectiveness of Online Cancer Education for Nurses and Allied Health Professionals; a Systematic Review Using Kirkpatrick Evaluation Framework. AB - Embedding online learning within higher education can provide engaging, cost effective, interactive and flexible education. By evaluating the impact, outcomes and pedagogical influence of online cancer and education, future curricula can be shaped and delivered by higher education providers to better meet learner, health care provider and educational commissioners' requirements for enhanced patient care and service delivery needs. Using the Kirkpatrick's four-level model of educational evaluation, a systematic review of the effectiveness of online cancer education for nurses and allied health professionals was conducted. From 101 articles, 30 papers were included in the review. Educational theory is not always employed. There is an absence of longitudinal studies to examine impact; an absence of reliability and/or validity testing of measures, limited experimental designs taking account of power and few attempts to mitigate bias. There is, however, an emerging innovative use of mobile/spaced learning techniques. Evidence for clinical and educational effectiveness is weak offering insights into experiences and participant perceptions rather than concrete quantitative data and patient-reported outcomes. More pedagogical research is merited to inform effective evaluation of online cancer education, which incorporates and demonstrates a longer-term impact. PMID- 29230685 TI - Calcitriol Reverses the Down-Regulation Pattern of Tuberous Sclerosis Complex Genes in an In Vitro Calcification Model. AB - Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with autosomal dominant inheritance, and most of the cases are related to loss of function of the TSC1 and TSC2 genes. TSC may occur with a wide range of clinical findings and skin, kidney, brain, and heart are the most commonly affected organs. Brain calcifications in TSC are also described and reported as diffuse and without pattern of symmetry or bilaterality. Recently, a new discovery opened the possibility of using vitamin D (VitD) for treating cerebral calcifications. Calcitriol, the active form of VitD, was able to reduce the calcification in an in vitro model, increasing expression of a gene related to primary familial brain calcification. We show that in the same experimental model, calcitriol was also able to restore and even increase expression of genes related to TSC. This article discusses the use of calcitriol supplementation in patients with TSC, which can be a very interesting strategy due to its low cost and because it is already used in various therapies. PMID- 29230684 TI - Imipenem-Relebactam and Meropenem-Vaborbactam: Two Novel Carbapenem-beta Lactamase Inhibitor Combinations. AB - Relebactam (formerly known as MK-7655) is a non-beta-lactam, bicyclic diazabicyclooctane, beta-lactamase inhibitor that is structurally related to avibactam, differing by the addition of a piperidine ring to the 2-position carbonyl group. Vaborbactam (formerly known as RPX7009) is a non-beta-lactam, cyclic, boronic acid-based, beta-lactamase inhibitor. The structure of vaborbactam is unlike any other currently marketed beta-lactamase inhibitor. Both inhibitors display activity against Ambler class A [including extended-spectrum beta-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)] and class C beta-lactamases (AmpC). Little is known about the potential for relebactam or vaborbactam to select for resistance; however, inactivation of the porin protein OmpK36 in K. pneumoniae has been reported to confer resistance to both imipenem relebactam and meropenem-vaborbactam. The addition of relebactam significantly improves the activity of imipenem against most species of Enterobacteriaceae [by lowering the minimum inhibitory concentration (MIC) by 2- to 128-fold] depending on the presence or absence of beta-lactamase enzymes. Against Pseudomonas aeruginosa, the addition of relebactam also improves the activity of imipenem (MIC reduced eightfold). Based on the data available, the addition of relebactam does not improve the activity of imipenem against Acinetobacter baumannii, Stenotrophomonas maltophilia and most anaerobes. Similar to imipenem-relebactam, the addition of vaborbactam significantly (2- to > 1024-fold MIC reduction) improves the activity of meropenem against most species of Enterobacteriaceae depending on the presence or absence of beta-lactamase enzymes. Limited data suggest that the addition of vaborbactam does not improve the activity of meropenem against A. baumannii, P. aeruginosa, or S. maltophilia. The pharmacokinetics of both relebactam and vaborbactam are described by a two compartment, linear model and do not appear to be altered by the co administration of imipenem and meropenem, respectively. Relebactam's approximate volume of distribution (V d) and elimination half-life (t 1/2) of ~ 18 L and 1.2 2.1 h, respectively, are similar to imipenem. Likewise, vaborbactam's V d and t1/2 of ~ 18 L and 1.3-2.0 h, respectively, are comparable to meropenem. Like imipenem and meropenem, relebactam and vaborbactam are both primarily renally excreted, and clearance correlates with creatinine clearance. In vitro and in vivo pharmacodynamic studies have reported bactericidal activity for imipenem relebactam and meropenem-vaborbactam against various Gram-negative beta-lactamase producing bacilli that are not inhibited by their respective carbapenems alone. These data also suggest that pharmacokinetic-pharmacodynamic parameters correlating with efficacy include time above the MIC for the carbapenems and overall exposure for their companion beta-lactamase inhibitors. Phase II clinical trials to date have reported that imipenem-relebactam is as effective as imipenem alone for treatment of complicated intra-abdominal infections and complicated urinary tract infections, including acute pyelonephritis. Imipenem-relebactam is currently in two phase III clinical trials for the treatment of imipenem resistant bacterial infections, as well as hospital-associated bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). A phase III clinical trial has reported superiority of meropenem-vaborbactam over piperacillin-tazobactam for the treatment of complicated urinary tract infections, including acute pyelonephritis. Meropenem-vaborbactam has recently demonstrated higher clinical cure rates versus best available therapy for the treatment of carbapenem-resistant Enterobacteriaceae (CRE), as well as for HABP and VABP. The safety and tolerability of imipenem-relebactam and meropenem vaborbactam has been reported in various phase I pharmacokinetic studies and phase II and III clinical trials. Both combinations appear to be well tolerated in healthy subjects and hospitalized patients, with few serious drug-related treatment-emergent adverse events reported to date. In conclusion, relebactam and vaborbactam serve to broaden the spectrum of imipenem and meropenem, respectively, against beta-lactamase-producing Gram-negative bacilli. The exact roles for imipenem-relebactam and meropenem-vaborbactam will be defined by efficacy and safety data from further clinical trials. Potential roles in therapy for these agents include the treatment of suspected or documented infections caused by resistant Gram-negative bacilli-producing ESBL, KPC, and/or AmpC beta lactamases. The usage of these agents in patients with CRE infections will likely become the standard of care. Finally, increased activity of imipenem-relebactam against P. aeruginosa may be of clinical benefit to patients with suspected or documented P. aeruginosa infections. PMID- 29230688 TI - Therapeutic effects of histone deacetylase inhibitors on kidney disease. AB - Increasing evidence has shown the involvement of histone deacetylases (HDACs) in the development and progression of various renal diseases, highlighting its inhibition as a promising therapeutic strategy to prevent kidney diseases. Accordingly, numerous studies have shown that HDAC inhibitors protect the kidneys from various diseases through their effects on multiple pathways, such as suppression of transforming growth factor-beta signaling pathway and nuclear factor-kappaB signaling pathways, augmentation of apoptosis, and inhibition of angiogenesis. To develop more effective and less toxic isoform-selective HDAC inhibitors and further improve clinical outcomes, it is necessary to identify and understand the mechanisms involved in the pathogenesis and progression of renal diseases. This review focuses on the roles of HDAC inhibitors and the mechanisms involved in their therapeutic effects in experimental models of kidney diseases including glomerulosclerosis, tubulointerstitial fibrosis, glomerular and tubulointerstitial inflammation, lupus nephritis, polycystic kidney disease, and renal cell carcinoma (RCC). PMID- 29230689 TI - The combination of curcumin and 5-fluorouracil in cancer therapy. AB - 5-Fluorouracil (5-FU) alone or in combination with other therapeutic drugs has been widely used for clinical treatment of various cancers. However, 5-FU-based chemotherapy has limited anticancer efficacy in clinic due to multidrug resistance and dose-limiting cytotoxicity. Some molecules and genes in cancer cells, such as nuclear factor kappa B, insulin-like growth factor-1 receptor, epidermal growth factor receptor, cyclooxygenase-2, signal transducer and activator of transcription 3, phosphatase and tensin homolog deleted on chromosome ten and Bcl-2 etc. are related to the chemoresistance and sensitivity of cancer cells to 5-FU. The activation of these molecules and genes expressions in cancer cells will be increased or decreased with long-term exposure of 5-FU. Curcumin has been found to be able to negatively regulate these processes. In order to overcome the problems of 5-FU, curcumin has been used to combine with 5 FU in cancer therapy. PMID- 29230690 TI - Dihydroxanthyletin-type coumarins from Angelica decursiva that inhibits the formation of advanced glycation end products and human recombinant aldose reductase. AB - The formation of advanced glycation end-products (AGE) and aldose reductase activity have been implicated in the development of diabetic complications. The present study was aimed to evaluate human recombinant aldose reductase (HRAR) and AGE inhibitory activity of seven natural dihydroxanthyletin-type coumarins, 4 hydroxy Pd-C-III (1), 4'-methoxy Pd-C-I (2), Pd-C-I (3), Pd-C-II (4), Pd-C-III (5), decursidin (6), and (+)-trans-decursidinol (7) from Angelica decursiva. Coumarins 1-7 showed potent HRAR and AGE inhibitory activities with ranges of IC50 values of 1.03-21.31 and 0.41-5.56 uM, respectively. In the kinetic study for HRAR enzyme inhibition, coumarins 1, 3, 4, and 7 were competitive-type inhibitors, 6 was a mixed-type inhibitor, whereas 2 and 5 were noncompetitive type inhibitors. Furthermore, we also predicted the docking interactions of HRAR with coumarins 1-7 using AutoDock Vina, and as a result, the simulated enzyme inhibitor complexes exhibited negative binding energies (Autodock Vina = - 9.6 to - 8.1 kcal/mol for HRAR), indicating a high affinity and tight binding capacity for the HRAR active site. Our results clearly indicate the potential HRAR and AGE formation inhibitory activities of dihydroxanthyletin-type coumarins, which could be further explored to develop therapeutic modalities for the treatment of diabetes and related complications. PMID- 29230691 TI - Beta-Blocker Use in Pregnancy and Risk of Specific Congenital Anomalies: A European Case-Malformed Control Study. AB - INTRODUCTION: The prevalence of chronic hypertension is increasing in pregnant women. Beta-blockers are among the most prevalent anti-hypertensive agents used in early pregnancy. OBJECTIVE: The objective of this study was to investigate whether first-trimester use of beta-blockers increases the risk of specific congenital anomalies in offspring. METHODS: A population-based case-malformed control study was conducted in 117,122 registrations of congenital anomalies from 17 European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registries participating in EUROmediCAT with data for all or part of the period between 1995 and 2013. Associations previously reported in the literature (signals) were tested and an exploratory analysis was performed to identify new signals. Odds ratios of exposure to any beta-blocker or to a beta-blocker subgroup were calculated for each signal anomaly compared with two control groups (non-chromosomal, non-signal anomalies and chromosomal anomalies). The exploratory analyses were performed for each non-signal anomaly compared with all the other non-signal anomalies. RESULTS: The signals from the literature (congenital heart defects, oral clefts, neural tube defects and hypospadias) were not confirmed. Our exploratory analysis revealed that multi-cystic renal dysplasia had significantly increased odds of occurring after maternal exposure to combined alpha- and beta-blockers (adjusted odds ratio 3.8; 95% confidence interval 1.3-11.0). CONCLUSION: Beta-blocker use in the first trimester of pregnancy was not found to be associated with a higher risk of specific congenital anomalies in the offspring, but a new signal between alpha- and beta blockers and multi-cystic renal dysplasia was found. Future large epidemiological studies are needed to confirm or refute our findings. PMID- 29230692 TI - SEOM clinical guideline on unknown primary cancer (2017). AB - Cancer of unknown primary site is a histologically confirmed cancer that manifests in advanced stage, with no identifiable primary site following standard diagnostic procedures. Patients are initially categorized based on the findings of the initial biopsy: adenocarcinoma, squamous-cell carcinoma, neuroendocrine carcinoma, and poorly differentiated carcinoma. Appropriate patient management requires understanding several clinical and pathological features that aid in identifying several subsets of patients with more responsive tumors. PMID- 29230693 TI - Clinical implications of the deregulated TP73 isoforms expression in cancer. AB - TP73 is a member of the TP53 family whose expression has been observed altered in most human cancers and associated with the prognosis. TP73 translates into a complex number of isoforms with both oncogenic and tumour-suppressor functions and presents a complex cross-talk with other members of the family (TP53 and TP63). In this revision, we focus on the evidence that may support TP73 variants as prognostic markers in cancer. Nowadays, most publications in this topic highlight the association between overexpression of the oncogenic variants and failure to respond to chemotherapy and/or shorter survival. In addition, we comment on the putative possibilities that the detection through a liquid biopsy of TP73 variants may provide, and finally, the significance of determining the value of the combined alteration of the TP53 family members in the clinical setting. PMID- 29230694 TI - Anthropometric Changes in Patients with Pancreatic Cancer Undergoing Preoperative Therapy and Pancreatoduodenectomy. AB - BACKGROUND: The changes in body composition that occur in response to therapy for localized pancreatic ductal adenocarcinoma (PDAC) and during the early survivorship period, as well as their clinical significance, are poorly understood. METHODS: One hundred twenty-seven consecutive patients with PDAC who received preoperative therapy followed by pancreatoduodenectomy (PD) at a single institution between 2009 and 2012 were longitudinally evaluated. Changes in skeletal muscle (SKM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were measured on serial computed tomography images obtained upon presentation, prior to pancreatectomy, and approximately 3 and 12 months after surgery. RESULTS: Prior to therapy, patients' mean baseline BMI was 26.5 +/- 4.7 kg/m2 and 63.0% met radiographic criteria for sarcopenia. During a mean 5.4 +/- 2.3 months of preoperative therapy, minimal changes in SKM (- 0.5 +/- 7.8%, p > 0.05), VAT (- 1.8 +/- 62.6%, p < 0.001), and SAT (- 4.8 +/- 27.7%, p < 0.001) were observed. In contrast, clinically significant changes were observed on postoperative CT compared to baseline anthropometry: SKM - 4.1 +/- 10.7%, VAT - 38.7 +/- 30.2%, and SAT - 24.1 +/- 22.6% (all p < 0.001) and these changes persisted at one year following PD. While anthropometric changes during preoperative therapy were not independently associated with survival, SKM gain between the postoperative period and one-year follow-up was associated with improved overall survival (OR 0.50, 95% CI 0.29-0.87). CONCLUSIONS: In contrast to the minor changes that occur during preoperative therapy for PDAC, significant losses in key anthropometric parameters tend to occur over the first year following PD. Ongoing SKM loss in the postoperative period may represent an early marker for worse outcomes. PMID- 29230696 TI - An Exploration of the Protective Effects of Investigators' Ethical Awareness upon Subjects of Drug Clinical Trials in China. AB - Up till now, China has not enacted any legal mechanisms governing certification or supervision for ethics committees. This article analyses deficiencies in the protection of subjects in clinical drug trials under China's current laws and regulations; it emphasizes that investigators, as practitioners who have direct contact with subjects, play significant roles in protecting and safeguarding subjects' rights and interests. The paper compares the status quo in China in this area to that of other countries and discusses ways China might enhance the protection of rights and interests of trial subjects, such as enhancing the ethical awareness of investigators through training, improving laws and regulations, and strengthening the communication between investigators and ethics committees. PMID- 29230695 TI - Oyster Contamination with Human Noroviruses Impacted by Urban Drainage and Seasonal Flooding in Vietnam. AB - This study investigated the level of norovirus contamination in oysters collected at a lagoon receiving urban drainage from Hue City for 17 months (August 2015 December 2016). We also investigated the genetic diversity of norovirus GI and GII in oyster and wastewater samples by using pyrosequencing to evaluate the effect of urban drainage on norovirus contamination of oysters. A total of 34 oyster samples were collected at two sampling sites (stations A and B) in a lagoon. Norovirus GI was more frequently detected than GII (positive rate 79 vs. 41%). Maximum concentrations of GI and GII were 2.4 * 105 and 2.3 * 104 copies/g, respectively. Co-contamination with GI and GII was observed in 35% of samples. Norovirus GII concentration was higher at station A in the flood season than in the dry season (P = 0.04, Wilcoxon signed-rank test). Six genotypes (GI.2, GI.3, GI.5, GII.2, GII.3, and GII.4) were identified in both wastewater and oyster samples, and genetically similar or identical sequences were obtained from the two types of samples. These observations suggest that urban drainage and seasonal flooding contribute to norovirus contamination of oysters in the study area. PMID- 29230697 TI - Knowing, Anticipating, Even Facilitating but Still not Intending: Another Challenge to Double Effect Reasoning. AB - A recent administrative law decision in Victoria, Australia, applied double effect reasoning in a novel way. Double effect reasoning has hitherto been used to legitimate treatments which may shorten life but where the intent of treatment is pain relief. The situation reviewed by the Victorian tribunal went further, supporting actions where a doctor agrees to provide pentobarbitone (Nembutal) to a patient at some time in the future if the patient feels at that time that his pain is unbearable and he wants to end his life. The offer to provide the drug was described as a palliative treatment in that it gave reassurance and comfort to the patient. Double effect reasoning was extended in this instance to encompass potentially facilitating a patient's death. This extension further muddies the murky double effect reasoning waters and creates another challenge to this concept. PMID- 29230698 TI - Mode 2 Knowledge Production in the Context of Medical Research: A Call for Further Clarifications. AB - The traditional researcher-driven environment of medical knowledge production is losing its dominance with the expansion of, for instance, community-based participatory or participant-led medical research. Over the past few decades, sociologists of science have debated a shift in the production of knowledge from traditional discipline-based (Mode 1) to more socially embedded and transdisciplinary frameworks (Mode 2). Recently, scholars have tried to show the relevance of Mode 2 knowledge production to medical research. However, the existing literature lacks detailed clarifications on how a model of Mode 2 knowledge production can be constructed in the context of medical research. This paper calls for such further clarifications. As a heuristic means, the advocacy for a controversial experimental stem cell therapy (Stamina) is examined. It is discussed that the example cannot be considered a step towards Mode 2 medical knowledge production. Nonetheless, the example brings to the fore some complexities of medical knowledge production that need to be further examined including: (1) the shifting landscape of defining and addressing vulnerability of research participants, (2) the emerging overlap between research and practice, and (3) public health implications of revising the standard notions of quality control and accountability. PMID- 29230699 TI - Predictive Psychiatric Genetic Testing in Minors: An Exploration of the Non Medical Benefits. AB - Predictive genetic testing for susceptibility to psychiatric conditions is likely to become part of standard practice. Because the onset of most psychiatric diseases is in late adolescence or early adulthood, testing minors could lead to early identification that may prevent or delay the development of these disorders. However, due to their complex aetiology, psychiatric genetic testing does not provide the immediate medical benefits that current guidelines require for testing minors. While several authors have argued non-medical benefits may play a crucial role in favour of predictive testing for other conditions, little research has explored such a role in psychiatric disorders. This paper outlines the potential non-medical benefits and harms of psychiatric genetic testing in minors in order to consider whether the non-medical benefits could ever make such testing appropriate. Five non-medical themes arise in the literature: psychological impacts, autonomy/self-determination, implications of the biomedical approach, use of financial and intellectual resources, and discrimination. Non-medical benefits were prominent in all of them, suggesting that psychiatric genetic testing in minors may be appropriate in some circumstances. Further research needs to empirically assess these potential non medical benefits, incorporate minors in the debate, and include normative reflection to evaluate the very purposes and motivations of psychiatric genetic testing in minors. PMID- 29230700 TI - Disclosure is Inadequate as a Solution to Managing Conflicts of Interest in Human Research. AB - Disclosure is a common response to conflicts of interest; it is intended to expose the conflict to scrutiny and enable it to be appropriately managed. For disclosure to be effective the receiver of the disclosure needs to be able to use the information to assess how the conflict may impact on their interests and then implement a suitable response. The act of disclosure also creates an expectation of self-regulation, as the person with the conflicting interests will be mindful of their own potential biases and aware that their decisions may be monitored. This article discusses some of the problems of relying on disclosure as a solution to address conflicts of interest in research, including the added complexities around institutional conflicts of interest. The case of Dan Markingson illustrates these issues and highlights the vulnerable position relying on disclosure as a solution leaves research participants in. PMID- 29230701 TI - Estimating Intermittent Individual Spawning Behavior via Disaggregating Group Data. AB - In order to understand fish biology and reproduction, it is important to know the fecundity patterns of individual fish, as frequently established by recording the output of mixed-sex groups of fish in a laboratory setting. However, for understanding individual reproductive health and modeling purposes it is important to estimate individual fecundity from group fecundity. We created a multistage method that disaggregates group-level data into estimates for individual-level clutch size and spawning interval distributions. The first stage of the method develops estimates of the daily spawning probability of fish. Daily spawning probabilities are then used to calculate the log likelihood of candidate distributions of clutch size. Selecting the best candidate distribution for clutch size allows for a Monte Carlo resampling of annotations of the original data which state how many fish spawned on which day. We verify this disaggregation technique by combining data from fathead minnow pairs, and checking that the disaggregation method reproduced the original clutch sizes and spawning intervals. This method will allow scientists to estimate individual clutch size and spawning interval distributions from group spawning data without specialized or elaborate experimental designs. PMID- 29230702 TI - Quantitative PET Imaging in Drug Development: Estimation of Target Occupancy. AB - Positron emission tomography, an imaging tool using radiolabeled tracers in humans and preclinical species, has been widely used in recent years in drug development, particularly in the central nervous system. One important goal of PET in drug development is assessing the occupancy of various molecular targets (e.g., receptors, transporters, enzymes) by exogenous drugs. The current linear mathematical approaches used to determine occupancy using PET imaging experiments are presented. These algorithms use results from multiple regions with different target content in two scans, a baseline (pre-drug) scan and a post-drug scan. New mathematical estimation approaches to determine target occupancy, using maximum likelihood, are presented. A major challenge in these methods is the proper definition of the covariance matrix of the regional binding measures, accounting for different variance of the individual regional measures and their nonzero covariance, factors that have been ignored by conventional methods. The novel methods are compared to standard methods using simulation and real human occupancy data. The simulation data showed the expected reduction in variance and bias using the proper maximum likelihood methods, when the assumptions of the estimation method matched those in simulation. Between-method differences for data from human occupancy studies were less obvious, in part due to small dataset sizes. These maximum likelihood methods form the basis for development of improved PET covariance models, in order to minimize bias and variance in PET occupancy studies. PMID- 29230703 TI - Combinatorics of Contacts in Protein Contact Maps. AB - Contacts play a fundamental role in the study of protein structure and folding problems. The contact map of a protein can be represented by arranging its amino acids on a horizontal line and drawing an arc between two residues if they form a contact. In this paper, we are mainly concerned with the combinatorial enumeration of the arcs in m-regular linear stack, an elementary structure of the protein contact map, which was introduced by Chen et al. (J Comput Biol 21(12):915-935, 2014). We modify the generating function for m-regular linear stacks by introducing a new variable y regarding to the number of arcs and obtain an equation satisfied by the generating function for m-regular linear stacks with n vertices and k arcs. Consequently, we also derive an equation satisfied by the generating function of the overall number of arcs in m-regular linear stacks with n vertices. PMID- 29230704 TI - Emodin ameliorates renal fibrosis in rats via TGF-beta1/Smad signaling pathway and function study of Smurf 2. AB - BACKGROUND: Emodin is a natural active component extracted from Chinese herbs. In this study, we investigated the therapeutic effect of emodin on surgery-induced renal fibrosis in rat. Moreover, the function of Smad ubiquitination regulatory factor 2 (Smurf 2) was further studied in vitro. METHODS: The renal fibrosis rat model was established via 5/6 renal mass reduction. The histopathological abnormalities of renal tissues in rats were tested via staining method and microscopic examination. Renal function indicators, the serum creatinine, blood urea nitrogen and total urinary protein were measured via spectrophotometric method. The renal tissues were tested via Western blotting and real-time quantitative PCR. Moreover, Smurf 2 protein expression under different conditions and its regulatory function in vitro was measured via Western blotting. RESULTS: Our results showed that the histopathological abnormalities, the decrease in rat body weight and the abnormal renal function caused by renal fibrosis were improved by emodin. Further, mRNA expression of TGF-beta1 was decreased by emodin. Furthermore, extracellular matrix (ECM) components as well as TGF beta1/Smad signaling-related Smurf 2 were decreased by emodin both in vivo and in vitro. The protein level of mothers against decapentaplegic homolog 7 (Smad7) was up-regulated. In addition, ECM components were increased by Smurf 2 over expression and these effects were weakened by emodin co-treatment in vitro. CONCLUSION: Emodin showed an anti-fibrosis effect in surgery-induced renal fibrotic rats. And this effect was potentially achieved via down-regulating expressions of TGF-beta1 and Smurf 2 and up-regulating Smad7 expression. PMID- 29230705 TI - Crosstalk between TLR4 and Notch1 signaling in the IgA nephropathy during inflammatory response. AB - PURPOSE: IgA nephropathy (IgAN) is an immune complex-mediated disease involved in the kidney disease. Recent studies have revealed that Notch signaling-related genes are aberrantly expressed in various cell types and maybe associate with inflammation-induced carcinogenesis. The aim of our study was to investigate the function of Notch1 in the inflammatory response of IgAN. METHODS: The expression of Notch1, Jagged1 and NICD1 in 52 IgAN renal tissues and 20 control renal tissues was first determined using quantitative real-time PCR and Western blot. ELISA was then used to estimate the inflammatory response of human podocytes to LPS. NF-kappaB activity was measured using dual-luciferase reporter assay. Activation of Notch1 and NF-kappaB signaling pathway was assessed using Western blot. RESULTS: The expression of Notch1, NICD1 and Jagged1 was significantly higher in IgAN renal tissues than control renal tissues (P < 0.05). LPS treatment resulted in an obvious increase of MCP-1, IL-8 and phosphorylated NF-kappaB p65 in podocytes polymeric IgA (pIgA) IgAN group compared to control group (P < 0.05 for all). Activated Notch1 and its target genes, Hes1 and Hey1 were also enhanced upon LPS stimulation. Silencing of Notch1 signaling with inhibitor DAPT, NF kappaB activation and LPS-induced inflammatory response were obviously attenuated, whereas Notch1 activator Jagged1 could markedly restore NF-kappaB activity and LPS-induced inflammatory response (P < 0.05 for all). CONCLUSIONS: Crosstalk between TLR4 and Notch1 signaling regulates the inflammatory response in the IgAN and maybe plays an important role in the progression of IgAN. PMID- 29230706 TI - Differential diagnosis of the small renal masses: role of the apparent diffusion coefficient of the diffusion-weighted MRI. AB - INTRODUCTION: Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and more than 90% of neoplasms arising from the kidney. Uninformative percutaneous kidney biopsies vary from 10 to 23%. As a result, 7.5 33.6% of partial nephrectomies in patients with small renal masses (SRM) are performed on benign renal tumors. The aim of this study was to assess the feasibility of the apparent diffusion coefficient (ADC) of the diffusion-weighted imaging (DWI) of MRI, as RCC imaging biomarker for differentiation of SRM. METHOD: Adult patients (n = 158) with 170 SRM were enrolled into this study. The control group were healthy volunteers with normal clinical and radiologic findings (n = 15). All participants underwent MRI with DWI sequence included. RESULTS: Mean ADC values of solid RCC (1.65 +/- 0.38 * 10-3 mm2/s) were lower than healthy renal parenchyma (2.47 +/- 0.12 * 10-3 mm2/s, p < 0.05). There was no difference between mean ADC values of ccRCC, pRCC and chRCC (1.82 +/- 0.22 * 10-3 vs 1.61 +/- 0.07 * 10-3 vs 1.46 +/- 0.09 * 10-3 mm2/s, respectively, p = ns). An inverse relationship between mean ADC values and Fuhrman grade of nuclear atypia of solid ccRCCs was observed: grade I-1.92 +/- 0.11 * 10-3 mm2/s, grade II 1.84 +/- 0.14 * 10-3 mm2/s, grade III-1.79 +/- 0.10 * 10-3 mm2/s, grade IV-1.72 +/- 0.06 * 10-3 mm2/s. This was significant (p < 0.05) only between tumors of I and IV grades. Significant difference (p < 0.05) between mean ADC values of solid RCCs, benign renal tumors and renal cysts was observed (1.65 +/- 0.38 * 10-3 vs 2.23 +/- 0.18 * 10-3 vs 3.15 +/- 0.51 * 10-3 mm2/s, respectively). In addition, there was a significant difference (p < 0.05) in mean ADC values between benign cysts and cystic RCC (3.36 +/- 0.35 * 10-3 vs 2.83 +/- 0.21 * 10-3 mm2/s, respectively). CONCLUSION: ADC maps with b values of 0 and 800 s/mm2 can be used as an imaging biomarker, to differentiate benign SRM from malignant SRM. Using ADC value threshold of 1.75 * 10-3 mm2/s allows to differentiate solid RCC from solid benign kidney tumors with 91% sensitivity and 89% specificity; ADC value threshold of 2.96 * 10-3 mm2/s distinguishes cystic RCC from benign renal cysts with 90% sensitivity and 88% specificity. However, the possibility of differentiation between ccRCC histologic subtypes and grades, utilizing ADC values, is limited. PMID- 29230707 TI - Acute kidney injury after abdominal aortic aneurysm repair: current epidemiology and potential prevention. AB - PURPOSE: Acute kidney injury (AKI) is a severe complication after infrarenal abdominal aortic aneurysm (iAAA) repair. Little data are available whether endovascular aneurysm (EVAR) or open aortic repair (OAR) differs with respect to AKI frequency and severity, consecutive development of chronic kidney disease (CKD) and potentially preventable and modifiable risk factors of AKI. PATIENTS AND METHODS: We assessed AKI rates, AKI stages and CKD applying current, complete definitions from the kidney disease improving global outcomes initiative in propensity-score-matched cohorts of all patients with elective and urgent iAAA repair at our institution from 2007 to 2011. Risk factors were analysed using multivariate logistic regression analyses. RESULTS: From 268 patients, we identified 91 matched pairs who had undergone either EVAR or OAR. The AKI rate was 13.2% with EVAR versus 41.8% with OAR (P < 0.001). AKI was significantly less severe in EVAR. OAR patients lost more glomerular filtration rate (- 11.3 vs. - 6.5%; P = 0.02) and developed more frequently CKD (14.3 vs. 3.2%; P < 0.001) 3 months after iAAA repair. EVAR, circulatory shock, radiocontrast media, rhabdomyolysis and sepsis were identified as potentially preventable or modifiable risk factors of AKI. CONCLUSIONS: AKI is significantly less frequent and severe in iAAA patients after EVAR as compared to OAR. Furthermore OAR patients demonstrate a higher CKD rate. The identified risk factors may be prevented or modified as a bundle of measures especially in patients with pre existing CKD to reduce AKI and its severity after iAAA repair. PMID- 29230708 TI - Changes in Gut Microbiota Linked to a Reduction in Systolic Blood Pressure in Spontaneously Hypertensive Rats Fed an Extra Virgin Olive Oil-Enriched Diet. AB - Fat type in diet is responsible for specific changes in gut microbiota (GM). Extra virgin olive oil (EVOO) has been shown to be beneficial for blood pressure and to produce effects on GM. To analyze the cause-effect relationship between intestinal microbial changes and blood pressure, we studied the effect of EVOO on fecal microbiota and systolic blood pressure (SBP) levels in spontaneously hypertensive rats (SHR). SHR were fed either an enriched EVOO diet or a standard diet for a period of 12 weeks. At the end of the experimental period, the microbial profiles in the feces were studied in both groups by using PCR denaturing gradient gel electrophoresis. Real-time PCR was used to quantify the selected bacterial groups. The results demonstrated significant differences when using Lactobacillus (p<0.05), clostridia XIV (p<0.01) and universal (p<0.05) primers. A significant (r=-0.475; p=0.04) inverse correlation between the abundance of clostridia XIV and SBP, which depends on the type of diet, was also observed. Finally, the results suggested an increase in the microbial diversity of the feces of the animals fed the EVOO diet. These results strongly connect the pattern of GM in SHR fed a diet enriched with EVOO to the lower levels of SBP observed in these animals at the end of the feeding period. PMID- 29230709 TI - Point-of-care gastric ultrasound and aspiration risk assessment: a narrative review. AB - This narrative review summarizes the current knowledge on point-of-care ultrasound (POCUS) of gastric contents in order to inform an assessment of aspiration risk and guide anesthetic management at the bedside. An I-AIM framework (Indication, Acquisition, Interpretation, and Medical decision-making) is used to summarize and organize the content areas. This narrative review spans the breadth of the literature on pediatric and adult subjects as well as on special patient populations such as obstetric and severely obese individuals. Areas that need further investigation include the diagnostic accuracy of gastric POCUS from a Bayesian perspective and the impact of POCUS on patient outcomes, healthcare economics, and educational curricula. PMID- 29230710 TI - A case report of proliferative glomerulonephritis with monoclonal immunoglobulin M-kappa deposits without associated lymphoproliferative disorder or detectable paraproteinemia. AB - A 53-year-old man presented with proteinuria and hematuria. No significant abnormality was detected in his physical examination or laboratory tests, including evidence of paraprotein in serum and urine. Renal biopsy revealed mesangial proliferation, thickened glomerular basement membranes, and spike formation. Immunofluorescence revealed deposition of immunoglobulin (Ig) M heavy chain, kappa (kappa) light chain, and complement component C3 along capillary walls in the glomeruli. Light chain staining indicated significant restriction, because only kappa chain, not lambda chain, was present in glomeruli. Aggregated electron dense deposits were observed in the subepithelial area and within the lamina densa on electron-microscopic examination. Cryoglobulinemia and amyloidosis were ruled out. Clinically, steroid therapy was not initiated due to patient preference, and the only prescribed medication was an angiotensin II receptor blocker. At the approximately 3-year follow-up, estimated glomerular filtration rate had decreased very mildly. The present case demonstrates that deposition of monoclonal IgM-kappa may be associated with membranoproliferative glomerulonephritis-like changes in the glomeruli. Although no underlying hematological abnormality or paraproteinemia was observed in this case within the range of limited clinical examination, the patient's condition is consistent with proliferative glomerulonephritis with monoclonal IgM deposits, similar to the recently established proliferative glomerulonephritis with monoclonal IgG deposits. Further elucidation of the pathophysiology and effective treatments of the disorder should be expected in the future through the accumulation of similar cases. PMID- 29230711 TI - Hospital-wide education committees and high-quality residency training : A qualitative study. AB - INTRODUCTION: High-quality residency training is of utmost importance for residents to become competent medical specialists. Hospital-wide education committees have been adopted by several healthcare systems to govern postgraduate medical education and to support continuous quality improvement of residency training. To understand the functioning and potential of such committees, this study examined the mechanisms through which hospital-wide education committees strive to enable continuous quality improvement in residency training. METHODS: Focus group studies with a constructivist grounded theory approach were performed between April 2015 and August 2016. A purposeful sample of hospital-wide education committees led to seven focus groups. RESULTS: Hospital-wide education committees strived to enable continuous quality improvement of residency training by the following mechanisms: creating an organization-wide quality culture, an organization-wide quality structure and by collaborating with external stakeholders. However, the committees were first and foremost eager to claim a strategic position within the organization they represent. All identified mechanisms were interdependent and ongoing. DISCUSSION: From a governance perspective, the position of hospital-wide education committees in the Netherlands is uniquely contributing to the call for institutional accountability for the quality of residency training. When implementing hospital-wide education committees, shared responsibility of the committees and the departments that actually provide residency training should be addressed. Although committees vary in the strategies they use to impact continuous quality improvement of residency training, they increasingly have the ability to undertake supporting actions and are working step by step to contribute to high-quality postgraduate medical education. PMID- 29230712 TI - Sensitivity of the Medication Possession Ratio to Modelling Decisions in Large Claims Databases. AB - OBJECTIVES: When preparing administrative medical and pharmacy claims data for analysis, decisions about data clean up and analytical approach need to be made. However, information about the effects of various modelling decisions on adherence measures such as the medication possession ratio (MPR) is limited. We address this gap with this study. METHODS: We utilized cross-sectional administrative claims data for commercially insured members filling at least two prescriptions for drugs within five classes of hypertension medication between 2008 and 2010. We divided nine modelling decisions into three categories: data scrubbing, study design, and MPR definition/calculations. We defined the base case settings with commonly used values, varied each modelling decision singly and in combination, and measured the effects on the MPR. RESULTS: Claims data for 358,418 individuals were available for analysis. Two modelling decisions were found to be highly influential, each yielding a difference of over 25 percentage points from the base case: the decision of whether to use interval- or prescription-based study periods, and the decision of how to handle overlapping prescription claims. The effect of other decisions was smaller, with a difference of 1-9 percentage points from the base case. CONCLUSIONS: Some of the decisions considered had a large impact on the MPR. Therefore, it is important for researchers to standardize approaches for study period length and overlapping prescription claims. We also conclude that transparent reporting of modelling decisions will facilitate the interpretation of results and comparisons across studies. PMID- 29230713 TI - Obesity: focus on ongoing multidisciplinary and comprehensive research. PMID- 29230715 TI - Chronic lymphocytic thyroiditis (CLT) has a positive prognostic value in papillary thyroid cancer (PTC) patients: the potential key role of Foxp3+ T lymphocytes. AB - BACKGROUND: An impact of chronic lymphocytic thyroiditis (CLT) on papillary thyroid cancer (PTC) outcome has long been advocated but it is still controversial. PURPOSE: The aim of this study was to evaluate the prognostic value of CLT in a retrospective cohort of PTC patients and to characterize the lymphocytic subpopulations and infiltrate (LI). MATERIALS AND METHODS: We assessed 375 PTC patients, aged 45.2 +/- 16.4 years, and treated with thyroidectomy and radioiodine remnant ablation, with a mean follow-up of 6.28 +/- 3.86 years. In a subgroup of patients (n = 81) tissue sections were reviewed for the presence of CLT or lymphocytes associated with tumor in absence of background thyroiditis (TAL); cytotoxic CD8+/regulatory Foxp3+ T lymphocyte (CD8+/Foxp3+) ratio was characterized by immunohistochemistry: a low ratio is suggestive of a less effective anti tumor immune response. RESULTS: Seventy-five/375 patients (20%) had a histological diagnosis of CLT and showed at the last follow-up a significantly better outcome compared to those with no CLT (cure rate: 91.8 versus 76.3%, p = 0.003). LI was characterized in 81 PTC patients (24 with CLT and 57 with TAL): the peri-tumoral CD8+/Foxp3+ ratio was lower in patients not cured at the final evaluation. CONCLUSIONS: Our data suggest that concurrent CLT has a protective effect on PTC outcome and that the imbalance between cytotoxic and regulatory T lymphocytes in the peri-tumoral TAL may affect the tumor specific immune response favoring a more aggressive behavior of cancer. PMID- 29230714 TI - Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. AB - Obesity, defined as excess fat mass, increases risks for multiple chronic diseases, such as type 2 diabetes, cardiovascular disease, and several types of cancer. Beyond adiposity per se, the pattern of fat distribution, android or truncal as compared to gynoid or peripheral, has a profound influence on systemic metabolism and hence risk for obesity complications. Not only factors as genetics, environment, gender, and age account for the apparent compartmentalization of white adipose tissue (WAT) in the body. Indeed, the heterogeneity among different anatomical depots also appears to stem from their intrinsic diversity, including cellular developmental origin, proliferative capacity, glucose and lipid metabolism, insulin sensitivity, cytokine pattern, thermogenic ability, and vascularization. Under the obese condition, these depot specific differences translate into specific WAT distribution patterns, giving rise to different cardiometabolic consequences. This review summarizes the clinical and mechanistic evidence for the depot-specific differences and the phenotypic characteristics of different WAT depots that link their depot-specific biology to obesity-specific complications. PMID- 29230716 TI - Efficacy and tolerability of a spray formulation containing Visnadine in women self-reporting sexual symptoms: a randomized double-blind placebo-controlled pilot study. AB - PURPOSE: The aim of this pilot, double-blind, randomized, placebo-controlled study, was to evaluate both the efficacy and the tolerability of a formulation for vulvar application containing Visnadine, a natural extractive substance with vasoactive properties, (ReFeel(r) spray, IDI Integratori Dietetici Italiani S.r.l., Italy) in women self-reporting sexual symptoms. METHODS: Sixty women (age range 18-60 years) volunteered to test the product against placebo (PL): Two puffs in the vulvar area, 10 min before sexual stimulation, for 30 days and for a minimum of six times. The main outcome measure was the improvement of the Female Sexual Function Index (FSFI) score (cut-off <= 26.55 for female sexual dysfunction [FSD]). Secondary outcomes were sexual satisfaction and tolerability with the product. RESULTS: PL group (n = 28) and Visnadine group (n = 30) were comparable for age, sexual function and rate of FSD at baseline (T0). After 1 month (T1), women in Visnadine group scored from 25.0 +/- 3.8 to 27.9 +/- 2.4 (p < 0.001), whereas no changes were evident in PL group (from 25.4 +/- 5.0 to 25.6 +/- 4.7). Statistically significant differences at T1 were reported in women with a positive (p < 0.001) or a negative FSD diagnosis (p < 0.01) using active treatment. Women with FSD reported significantly more improvement in satisfaction with their sexual function when treated with Visnadine spray compared to PL (p < 0.001), as well as more excitation (p < 0.001), pleasure (p < 0.001) and less time to reach orgasm (p < 0.003). No significant side effects were evident in both groups. CONCLUSIONS: On demand, 1-month use of Visnadine spray displayed positive effects on sexual function in women with and without FSD and it was well tolerated. Topical Visnadine may not only be part of multimodal strategies to manage clinically relevant sexual symptoms but also simply to help women to enhance their subjective impaired perception of sexual response. PMID- 29230717 TI - Utility of 2-Pyridine Aldoxime Methyl Chloride (2-PAM) for Acute Organophosphate Poisoning: A Systematic Review and Meta-Analysis. AB - Organophosphates (OP) account for the majority of pesticide-related unintentional or intentional poisonings in lower- and middle-income countries. The therapeutic role of atropine is well-established for patients with acute OP poisoning. The benefit of adding 2-pyridine aldoxime methyl chloride (2-PAM), however, is controversial. We performed a systematic review and meta-analysis of available randomized controlled trials (RCT) to compare 2-PAM plus atropine in comparison to atropine alone for acute OP poisoning. We searched PubMed, EMBASE, and SCOPUS up to March 2017. The Cochrane review handbook was used to assess the risk of bias. Data were abstracted and risk ratios (RR) were calculated for mortality, rate of intubation, duration of intubation, intermediate syndrome, and complications such as hospital-acquired infections, dysrhythmias, and pulmonary edema. We found five studies comprising 586 patients with varying risks of bias. The risk of death (RR = 1.5, 95% CI 0.9-2.5); intubation (RR = 1.3, 95% CI 1.0 1.6); intermediate syndrome (RR = 1.6, 95% CI 1.0-2.6); complications (RR = 1.2, 95% CI 0.8-1.8); and the duration of intubation (mean difference 0.0, 95% CI - 1.6-1.6) were not significantly different between the atropine plus 2-PAM and atropine alone. Based on our meta-analysis of the available RCTs, 2-PAM was not shown to improve outcomes in patients with acute OP poisoning. PMID- 29230718 TI - Anemhupehins A-C, Podocarpane Diterpenoids from Anemone hupehensis. AB - Three new podocarpane diterpenoids, namely anemhupehins A-C (1-3), together with four known analogues (4-7), have been isolated from aerial parts of Anemone hupehensis. Their structures were characterized based on extensive spectroscopic data. Compounds 1 and 4 showed certain cytotoxicities against human cancer cell lines. PMID- 29230720 TI - Erratum to: Robust, Cost-Effective Profiling of RNA Binding Protein Targets with Single-end Enhanced Crosslinking and Immunoprecipitation (seCLIP). PMID- 29230719 TI - Resveratrol and/or exercise training counteract aging-associated decline of physical endurance in aged mice; targeting mitochondrial biogenesis and function. AB - Mitochondrial dysfunction and decreased mitochondrial content are hallmarks of aging that leads to decreased physical endurance. Our aim was to explore the anti aging effect of resveratrol (RSVT) supplementation, a polyphenol, and/or exercise training, started at an older age, on improving physical activity, therefore, help in frailty avoidance and promotion of healthy aging in elderly. Eighteen month-old aged mice received RSVT (15 mg/kg/day) and/or exercise trained for 4 weeks showed significant longer time to exhaustion with decreased blood lactate and free fatty acids levels associated with improved oxidative stress evidenced by decreased gastrocnemius muscle lipid peroxidation and increased antioxidant enzymes activities, catalase and superoxide dismutase, when compared to aged mice control group. These changes were accompanied by over-expression of skeletal muscle peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC 1alpha) mRNA, the master regulator of mitochondrial biogenesis, and increased muscle citrate synthase activity, a marker for mitochondrial function. These findings may provide evidence for improved physical endurance by RSVT supplementation or exercise training with better results of their combination, even at an older age, through increasing mitochondrial biogenesis and function. Increased muscle PGC-1alpha mRNA expression and citrate synthase enzyme activity in addition to improved aging-associated oxidative damage were among the mechanisms involved in this protection. PMID- 29230721 TI - ? PMID- 29230722 TI - ? PMID- 29230723 TI - Erratum to: Cognitive-Behavioral Therapy. PMID- 29230724 TI - ? PMID- 29230725 TI - ? PMID- 29230727 TI - ? PMID- 29230726 TI - [It's still time to get the Flu vaccine for this season]. PMID- 29230728 TI - ? PMID- 29230729 TI - ? PMID- 29230730 TI - ? PMID- 29230731 TI - ? PMID- 29230732 TI - ? PMID- 29230734 TI - ? PMID- 29230733 TI - ? PMID- 29230735 TI - ? PMID- 29230736 TI - ? PMID- 29230737 TI - ? PMID- 29230738 TI - ? PMID- 29230739 TI - ? PMID- 29230740 TI - [Peroneal nerve entrapment syndrome]. PMID- 29230741 TI - [Severe emergencies in patients with diabetes]. PMID- 29230743 TI - ? PMID- 29230744 TI - [Breast cancer in male]. PMID- 29230745 TI - ? PMID- 29230746 TI - [Music learning and music performance in patients with diabetes mellitus]. PMID- 29230747 TI - [Performing arts medicine and pain management in musicians in Germany]. PMID- 29230748 TI - ? PMID- 29230749 TI - ? PMID- 29230750 TI - ? PMID- 29230751 TI - ? PMID- 29230752 TI - ? PMID- 29230753 TI - ? PMID- 29230754 TI - ? PMID- 29230755 TI - ? PMID- 29230757 TI - ? PMID- 29230756 TI - ? PMID- 29230758 TI - ? PMID- 29230759 TI - ? PMID- 29230760 TI - ? PMID- 29230761 TI - ? PMID- 29230762 TI - ? PMID- 29230763 TI - ? PMID- 29230764 TI - ? PMID- 29230765 TI - ? PMID- 29230766 TI - ? PMID- 29230767 TI - ? PMID- 29230769 TI - ? PMID- 29230768 TI - ? PMID- 29230770 TI - ? PMID- 29230771 TI - ? PMID- 29230772 TI - ? PMID- 29230773 TI - ? PMID- 29230774 TI - ? PMID- 29230775 TI - ? PMID- 29230777 TI - ? PMID- 29230776 TI - ? PMID- 29230778 TI - ? PMID- 29230779 TI - ? PMID- 29230780 TI - ? PMID- 29230781 TI - ? PMID- 29230782 TI - ? PMID- 29230783 TI - ? PMID- 29230784 TI - ? PMID- 29230785 TI - ? PMID- 29230786 TI - ? PMID- 29230787 TI - ? PMID- 29230788 TI - ? PMID- 29230789 TI - ? PMID- 29230790 TI - ? PMID- 29230792 TI - ? PMID- 29230793 TI - ? PMID- 29230794 TI - ? PMID- 29230795 TI - ? PMID- 29230796 TI - ? PMID- 29230797 TI - The association of pre-operative home accelerometry with cardiopulmonary exercise variables. AB - We investigated the association of pre-operative activity, reported by the Duke Activity Score Index, Short Form-12 and measured by an accelerometer worn at home, with five cardiopulmonary exercise variables: peak power; peak oxygen consumption; anaerobic threshold; and ventilatory equivalents for oxygen and carbon dioxide. Fifty patients scheduled for major surgery underwent a standard pre-operative cardiopulmonary exercise test and wore a chest-mounted triaxial accelerometer for a mean (SD) duration of 3.2 (0.4) days. The Duke Activity Score Index and six accelerometer variables were significantly correlated with all five cardiopulmonary exercise variables, Pearson correlation coefficients 0.5-0.7, p = 0.02 to p < 0.001. Our results can guide future studies that measure physical activity for pre-operative assessment and interventions. PMID- 29230798 TI - Botulinum toxin type A therapy for cervical dystonia. AB - BACKGROUND: This is an update of a Cochrane Review first published in 2005. Cervical dystonia is the most common form of focal dystonia and is a highly disabling movement disorder characterised by involuntary, usually painful, head posturing. Currently, botulinum toxin type A (BtA) is considered the first line therapy for this condition. OBJECTIVES: To compare the efficacy, safety, and tolerability of botulinum toxin type A (BtA) versus placebo in people with cervical dystonia. SEARCH METHODS: To identify studies for this review we searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of articles and conference proceedings. All elements of the search, with no language restrictions, were run in October 2016. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third review author. We performed meta-analyses using a random-effects model for the comparison of BtA versus placebo to estimate pooled effects and corresponding 95% confidence intervals (95% CI). In addition, we performed preplanned subgroup analyses according to BtA dose used, the BtA formulation used, and the use or not of guidance for BtA injection. The primary efficacy outcome was improvement in cervical dystonia-specific impairment. The primary safety outcome was the proportion of participants with any adverse event. MAIN RESULTS: We included eight RCTs of moderate overall risk of bias, including 1010 participants with cervical dystonia. Six studies excluded participants with poorer responses to BtA treatment, therefore including an enriched population with a higher probability of benefiting from this therapy. Only one trial was independently funded. All RCTs evaluated the effect of a single BtA treatment session, using doses from 150 U to 236 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of abobotulinumtoxinA (Dysport).BtA was associated with a moderate-to-large improvement in the participant's baseline clinical status as assessed by investigators, with reduction of 8.06 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS total score) at week 4 after injection (95% CI 6.08 to 10.05; I2 = 0%) compared to placebo, corresponding on average to a 18.7% improvement from baseline. The mean difference (MD) in TWSTRS pain subscore at week 4 was 2.11 (95% CI 1.38 to 2.83; I2 = 0%). Overall, both participants and clinicians reported an improvement of subjective clinical status. There were no differences between groups regarding withdrawals due to adverse events. However, BtA treatment was associated with an increased risk of experiencing an adverse event (risk ratio (RR) 1.19; 95% CI 1.03 to 1.36; I2 = 16%). Dysphagia (9%) and diffuse weakness/tiredness (10%) were the most common treatment-related adverse events (dysphagia: RR 3.04; 95% CI 1.68 to 5.50; I2 = 0%; diffuse weakness/tiredness: RR 1.78; 95% CI 1.08 to 2.94; I2 = 0%). Treatment with BtA was associated with a decreased risk of participants withdrawing from trials. We have moderate certainty in the evidence across all of the aforementioned outcomes.We found no evidence supporting the existence of a clear dose-response relationship with BtA, nor a difference between BtA formulations, nor a difference with use of EMG-guided injection.Due to clinical heterogeneity, we did not pool data regarding health-related quality of life, duration of clinical effect, or the development of secondary non-responsiveness. AUTHORS' CONCLUSIONS: We have moderate certainty in the evidence that a single BtA treatment session is associated with a significant and clinically relevant reduction of cervical dystonia-specific impairment, including severity, disability, and pain, and that it is well tolerated, when compared with placebo. There is also moderate certainty in the evidence that people treated with BtA are at an increased risk of developing adverse events, most notably dysphagia and diffuse weakness. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals and doses, usefulness of guidance techniques for injection, the impact on quality of life, or the duration of treatment effect. PMID- 29230799 TI - A retrospective study on the management of patients with rituximab refractory follicular lymphoma. AB - Given that there are currently no clear recommendations regarding therapeutic options for rituximab refractory/relapsed follicular lymphoma patients, this study aimed to describe the real-life management of patients with refractory follicular lymphoma after systemic rituximab-containing regimens (rFL), and rFL patient characteristics. In this retrospective, national, multicentre study, descriptive analyses were mainly performed according to rituximab-containing regimen at rFL diagnosis [rituximab monotherapy (R-MONO), rituximab + chemotherapy (R-COMBO), and ongoing rituximab maintenance (R-MAINTAIN)]. The 459 analysed patients experienced rituximab-refractoriness between October 2013 and September 2015: R-MONO: 58 (13%), R-COMBO: 197 (43%), R-MAINTAIN: 204 (44%). Post refractoriness strategies were heterogeneous: idelalisib +/- rituximab (22%), without anti-lymphoma treatment (21%), rituximab-chemotherapy (21%) and stem cell transplantation (18%). Rituximab was continued in combination in 41% of cases. Chosen strategies varied according to patient age (without anti-lymphoma treatment: 28% of patients if >=65 years vs. 12% if <65 years old; stem-cell transplantation: 4% vs. 38%), treatment line at rFL, FL International Prognostic Index score and prior treatment. This French retrospective study, the first one conducted in a large cohort of rFL patients, showed that further strategies were highly heterogeneous, depending notably on patient characteristics and previous treatment. These data are the basis for a better understanding of rFL management and for the design of clinical trials in these patients. PMID- 29230800 TI - Negotiating quality standards for effective delivery of labor and childbirth care in Nigeria and Uganda. AB - OBJECTIVE: "Negotiated standards" describe a level of quality of care that is acceptable and achievable within a specific health system, based on consensus between key stakeholders. This paper presents the development of negotiated standards for effective labor and childbirth care in selected hospitals and communities in Nigeria and Uganda. METHODS: A four-step development process involving different methodologies. The process included: (1) review and synthesis of internationally recognized intrapartum clinical principles and practices; (2) primary qualitative research to assess values and preferences of women and healthcare providers, and practices that align with these preferences; (3) draft contextualization of effective and ineffective behaviors to reflect values and preferences; and (4) WHO-mediated negotiations between relevant stakeholders, including community members, providers, and administrators. RESULTS: The primary outcomes of this process were a comprehensive set of effective behaviors and clinical practices covering the main domains of quality of care, which are practical and easy to communicate, implement, and audit across all levels of healthcare delivery. CONCLUSION: The process demonstrates that health facilities and providers can be motivated to adopt standards of care that uphold the values and preferences of both service users and providers, while adhering to international best practices. PMID- 29230801 TI - Medicaid Expansion and Health Plan Quality in Medicaid Managed Care. AB - OBJECTIVE: To assess the effect of the 2014 Medicaid expansion on Medicaid managed care plan quality. DATA SOURCES: Three composite measures of plan-level quality constructed from the Health Care Effectiveness Data and Information Set. STUDY SETTING: One hundred and sixty-three plans in 27 Medicaid expansion states and 100 plans in 14 nonexpansion states. STUDY DESIGN: Quasi-experimental difference-in-differences (DID) analysis, comparing quality before (2011-13) and after (2014-15) Medicaid expansion in states that elected to expand Medicaid eligibility and those that did not. PRINCIPAL FINDINGS: Mean plan enrollment increased from 130,533 to 274,259 in expansion states and from 105,449 to 148,194 in nonexpansion states. The proportion of enrollees receiving recommended preventive care increased from 62.6 to 65.2 percent in expansion states and from 59.3 to 62.5 percent in nonexpansion states (adjusted DID: -0.7 percentage points [95% CI -2.2, 0.7]). The proportion of enrollees receiving recommended chronic disease care management increased from 65.4 to 66.0 percent in expansion states and from 62.5 to 63.1 percent in nonexpansion states (adjusted DID: 1.1 percentage points [95% CI -0.5, 2.6]). We observed similar patterns for the receipt of recommended maternity care. CONCLUSIONS: Medicaid expansion increased enrollment in managed care plans, but it did not result in erosion of quality. PMID- 29230802 TI - Measurement properties of instruments that assess participation in young people with autism spectrum disorder: a systematic review. AB - AIM: To systematically review the measurement properties of instruments assessing participation in young people with autism spectrum disorder (ASD). METHOD: A search was performed in MEDLINE, PsycINFO, and PubMed combining three constructs ('ASD', 'test of participation', 'measurement properties'). Results were restricted to articles including people aged 6 to 29 years. The 2539 identified articles were independently screened by two reviewers. For the included articles, data were extracted using standard forms and their risk of bias was assessed. RESULTS: Nine studies (8 cross-sectional) met the inclusion criteria, providing information on seven different instruments. The total sample included 634 participants, with sex available for 600 (males=494; females=106) and age available for 570, with mean age for these participants 140.58 months (SD=9.11; range=36-624). Included instruments were the school function assessment, vocational index, children's assessment of participation and enjoyment/preferences for activities of children, experience sampling method, Pediatric Evaluation of Disability Inventory, Computer Adaptive Test, adolescent and young adult activity card sort, and Patient-Reported Outcomes Measurement Information System parent-proxy peer relationships. Seven studies assessed reliability and validity; good properties were reported for half of the instruments considered. Most studies (n=6) had high risk of bias. Overall the quality of the evidence for each tool was limited. INTERPRETATION: Validation of these instruments, or others that comprehensively assess participation, is needed. Future studies should follow recommended methodological standards. WHAT THIS PAPER ADDS: Seven instruments have been used to assess participation in young people with autism. One instrument, with excellent measurement properties in one study, does not comprehensively assess participation. Studies of three instruments that incorporate a more comprehensive assessment of participation have methodological limitations. Overall, limited evidence exists regarding measurement properties of participation assessments for young people with autism. PMID- 29230803 TI - Peri-operative management of patients with type-2 diabetes mellitus undergoing non-cardiac surgery using liraglutide, glucose-insulin-potassium infusion or intravenous insulin bolus regimens: a randomised controlled trial. AB - In this open-label multicentre randomised controlled trial, we investigated three peri-operative treatment strategies to lower glucose and reduce the need for rescue insulin in patients aged 18-75 years with type-2 diabetes mellitus undergoing non-cardiac surgery. Patients were randomly allocated using a web based randomisation program to premedication with liraglutide (liraglutide group), glucose-insulin-potassium infusion (insulin infusion group) or insulin bolus regimen (insulin bolus group), targeting a glucose < 8.0 mmol.l-1 . The primary outcome was the between group difference in median glucose levels 1 h after surgery. We analysed 150 patients (liraglutide group n = 44, insulin infusion group n = 53, insulin bolus group n = 53) according to the intention-to treat principle. Median (IQR [range]) plasma glucose 1 h postoperatively was lower in the liraglutide group compared with the insulin infusion and insulin bolus groups (6.6 (5.6-7.7 [4.2-13.5]) mmol.l-1 vs. 7.5 (6.4-8.3 [3.9-16.6]) mmol.l-1 (p = 0.026) and 7.6 (6.4-8.9 [4.7-13.2]) mmol.l-1 ) p = 0.006, respectively). The incidence of hypoglycaemia and postoperative complications did not differ between the groups. Six patients had pre-operative nausea in the liraglutide group, of which two had severe nausea, compared with no patients in the insulin infusion and insulin bolus groups (p = 0.007). The pre-operative administration of liraglutide stabilised peri-operative plasma glucose levels and reduced peri-operative insulin requirements, at the expense of increased pre operative nausea rates. PMID- 29230804 TI - Egg viability decreases rapidly with time since ovulation in the rainbow darter Etheostoma caeruleum: implications for the costs of choosiness. AB - Egg viability in the rainbow darter Etheostoma caeruleum, a fish apparently lacking female mate choice, was found to decline rapidly after ovulation. It was observed that the majority of a female's clutch may fail to hatch if she is prevented from mating for as little as 6 h. These data suggest that exercising female mate preferences may be selectively disfavoured in E. caeruleum due to the high cost of delaying mating. PMID- 29230805 TI - USPIO-labeling in M1 and M2-polarized macrophages: An in vitro study using a clinical magnetic resonance scanner. AB - Aim of the study was to evaluate USPIO labeling in different macrophage populations using a clinical 3.0T MR unit with optical and electron microscopy as the gold standard. Human monocytic cell line THP-1 cells were differentiated into macrophages. Afterwards, M0 macrophages were incubated with IL-4 and IL-13 in order to obtain M2 polarized macrophages or with IFN-gamma and LPS for classical macrophage activation (M1). These groups were incubated with USPIO-MR contrast agent (P904) for 36 hr; M0, M0 + P904, M1 + P904, and M2 + P904 were analyzed in gel phantoms with a 3.0T MR scanner. m-RNA of M1 and M2 markers confirmed the polarization of THP-1-derived macrophages. M2 + P904 showed a much higher T1 signal (p < 0.0001), a significantly lower (p < 0.0001) T2* signal, and significantly higher R* (p < 0.0001) compared to the other populations. Hystological analysis confirmed higher iron content in the M2-polarized population compared to both M1-polarized (p = 0.04) and M0-P904 (p = 0.003). Ultrastructure analysis demonstrated ubiquitous localization of P904 within the cellular compartments. Our results demonstrate that a selective USPIO-labeling of different macrophage populations can be detected in vitro using the 3.0T clinical scanner. PMID- 29230806 TI - Comparing the characteristics and outcomes of parent- and teacher-reported oppositional defiant disorder: findings from a national sample. AB - BACKGROUND: Parents and teachers often disagree on the presence of Oppositional Defiant Disorder (ODD) in children. It has been argued that ODD should be treated as an informant-specific disorder. This study compared the characteristics of children identified with ODD by parent- and teacher report. METHODS: We used the 1999 British Child and Adolescent Mental Health Survey, including more than 10,000 observations aged 5-15 years, to investigate symptom profiles, risk factors, comorbidities and three-year outcomes of parent- and teacher-reported ODD. RESULTS: Parents and teachers poorly agreed on ODD diagnosis. Parent reported ODD was more strongly associated with a concurrent anxiety disorder at time1 and a successive diagnosis of ODD at time2 . Beyond these differences, parent- and teacher- reported ODD showed similar symptom profiles, risk factors, comorbidities, and outcomes. CONCLUSIONS: Children identified by parent report and teacher report share more similarities than differences in the characteristics of their disorder. This does not support the formation of informant-specific ODD disorders. PMID- 29230807 TI - A comparative study of the neural stem cell niche in the adult hypothalamus of human, mouse, rat and gray mouse lemur (Microcebus murinus). AB - The adult brain contains niches of neural stem cells that continuously add new neurons to selected circuits throughout life. Two niches have been extensively studied in various mammalian species including humans, the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus. Recently, studies conducted mainly in rodents have identified a third neurogenic niche in the adult hypothalamus. In order to evaluate whether a neural stem cell niche also exists in the adult hypothalamus in humans, we performed multiple immunofluorescence labeling to assess the expression of a panel of neural stem/progenitor cell (NPC) markers (Sox2, nestin, vimentin, GLAST, GFAP) in the human hypothalamus and compared them with the mouse, rat and a non-human primate species, the gray mouse lemur (Microcebus murinus). Our results show that the adult human hypothalamus contains four distinct populations of cells that express the five NPC markers: (a) a ribbon of small stellate cells that lines the third ventricular wall behind a hypocellular gap, similar to that found along the lateral ventricles, (b) ependymal cells, (c) tanycytes, which line the floor of the third ventricle in the tuberal region, and (d) a population of small stellate cells in the suprachiasmatic nucleus. In the mouse, rat and mouse lemur hypothalamus, co-expression of NPC markers is primarily restricted to tanycytes, and these species lack a ventricular ribbon. Our work thus identifies four cell populations with the antigenic profile of NPCs in the adult human hypothalamus, of which three appear specific to humans. PMID- 29230809 TI - The RSPO3 gene as genetic markers for bone mass assessed by quantitative ultrasound in a population of young adults. AB - Ultrasound bone mass measurement has been postulated as a valuable bone-health assessment tool for primary care. The aim of this study was to analyse the possible relationship between the SPTBN1, RSPO3, CCDC170, DKK1, GPATCH1, and TMEM135 genes, with calcaneal quantitative ultrasound (QUS) in a population of young adults. These genes were first associated with broadband ultrasound attenuation (BUA) in the GEFOS/GENOMOS study. A cross-sectional study was conducted on 575 individuals (mean age 20.41 +/- 2.69). Bone mass at the right calcaneus was estimated by QUS. Six single-nucleotide polymorphisms (SNPs) in SPTBN1 (rs11898505), RSPO3 (rs7741021), CCDC170 (rs4869739), DKK1 (rs7902708), TMEM135 (rs597319), and GPATCH1 (rs10416265) were selected as genetic markers based on their previous association with calcaneal QUS. After adjusting for multiple confounding factors, the only significant association with QUS in our population was found for the rs7741021 SNP in the RSPO3 gene (P = 0.006) using the dominant model of inheritance. This suggests the possible implication of the RSPO3 gene in bone mass acquisition during early adulthood. PMID- 29230808 TI - Dopamine drives left-hemispheric lateralization of neural networks during human speech. AB - Although the concept of left-hemispheric lateralization of neural processes during speech production has been known since the times of Broca, its physiological underpinnings still remain elusive. We sought to assess the modulatory influences of a major neurotransmitter, dopamine, on hemispheric lateralization during real-life speaking using a multimodal analysis of functional MRI, intracranial EEG recordings, and large-scale neural population simulations based on diffusion-weighted MRI. We demonstrate that speech-induced phasic dopamine release into the dorsal striatum and speech motor cortex exerts direct modulation of neuronal activity in these regions and drives left hemispheric lateralization of speech production network. Dopamine-induced lateralization of functional activity and networks during speaking is not dependent on lateralization of structural nigro-striatal and nigro-motocortical pathways. Our findings provide the first mechanistic explanation for left hemispheric lateralization of human speech that is due to left-lateralized dopaminergic modulation of brain activity and functional networks. PMID- 29230811 TI - Whole-exome sequencing of oral mucosal melanoma reveals mutational profile and therapeutic targets. AB - Oral mucosal melanoma (OMM) is a rare and aggressive subtype of melanoma with little known about its pathogenesis or carcinogenesis. We therefore performed whole-exome sequencing (WES) on 19 matched OMM tumor/normal pairs in order to gain insight into potential genetic drivers of tumor formation. For the first time, we describe the comprehensive mutational profile of OMM. Our data suggest that the genetic background of OMM differs from those of other melanoma subtypes. We identified recurrent mutations involving KIT, POLE, PTPRD, PTCHD2, and DMXL2. Notably, copy number analysis revealed recurrently amplified regions of 12q14 (57.9%, containing CDK4) and 5p15 (47.4%, containing TERT). CNV analysis in a separate cohort of 15 samples validated the frequent CNV in CDK4 and TERT. We also observed that the melanocyte development and pigmentation signaling pathway is frequently altered in OMM. Furthermore, our data suggest several altered genes that may be amenable for targeted therapy. We identified one patient with metastatic OMM in our cohort who was identified to harbor a targetable KIT mutation using our WES results. This patient was able to achieve complete remission following implementation of KIT-targeted therapy. These findings provide further insight into the genetic underpinnings of OMM development and suggest that patients with OMM may benefit from WES analysis to identify potential targetable genetic mutations. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29230810 TI - Trauma exposure interacts with the genetic risk of bipolar disorder in alcohol misuse of US soldiers. AB - OBJECTIVE: To investigate whether trauma exposure moderates the genetic correlation between substance use disorders and psychiatric disorders, we tested whether trauma exposure modifies the association of genetic risks for mental disorders with alcohol misuse and nicotine dependence (ND) symptoms. METHODS: High-resolution polygenic risk scores (PRSs) were calculated for 10 732 US Army soldiers (8346 trauma-exposed and 2386 trauma-unexposed) based on genome-wide association studies of bipolar disorder (BD), major depressive disorder, and schizophrenia. RESULTS: The main finding was a significant BD PRS-by-trauma interaction with respect to alcohol misuse (P = 6.07 * 10-3 ). We observed a positive correlation between BD PRS and alcohol misuse in trauma-exposed soldiers (r = 0.029, P = 7.5 * 10-3 ) and a negative correlation in trauma-unexposed soldiers (r = -0.071, P = 5.61 * 10-4 ). Consistent (nominally significant) result with concordant effect, directions were observed in the schizophrenia PRS by-trauma interaction analysis. The variants included in the BD PRS-by-trauma interaction showed significant enrichments for gene ontologies related to high voltage-gated calcium channel activity (GO:0008331, P = 1.51 * 10-5 ; GO:1990454, P = 4.49 * 10-6 ; GO:0030315, P = 2.07 * 10-6 ) and for Beta1/Beta2 adrenergic receptor signaling pathways (P = 2.61 * 10-4 ). CONCLUSIONS: These results indicate that the genetic overlap between alcohol misuse and BD is significantly moderated by trauma exposure. This provides molecular insight into the complex mechanisms that link substance abuse, psychiatric disorders, and trauma exposure. PMID- 29230812 TI - The gut microbiota: An emerging risk factor for cardiovascular and cerebrovascular disease. AB - Commensal gut microbiota have recently been implicated in cardiovascular disease (CVD) and cerebrovascular disease. Atherosclerotic plaque formation depends on the colonization status of the host. In addition to host nutrition and the related microbiota-dependent metabolic changes, activation of innate immune pathways triggers the development of atherosclerosis and supports arterial thrombosis. Gnotobiotic mouse models have uncovered that activation of Toll-like receptor-2 by gut microbial ligands supports von Willebrand factor-integrin mediated platelet deposition to the site of vascular injury. Depending on nutritional factors, the microbiota-derived choline-metabolite trimethylamine N oxide (TMAO) increases atherosclerotic plaque size, triggers prothrombotic platelet function and promotes arterial thrombus growth. Hence, the composition of the commensal microbiota is an emerging risk factor for CVD. Here, we provide an overview on microbiota-dependent pathomechanisms that drive the development of CVD and arterial thrombosis. PMID- 29230813 TI - Editorial on the history of the Journal of Fish Biology, 1969 to 2017. PMID- 29230814 TI - Nigella sativa L. as an alternative antibiotic feed supplement and effect on growth performance in weanling pigs. AB - BACKGROUND: Nigella sativa L. (NS) is a plant containing bioactive constituents such as thymoquinone. Extracts of NS improve performance and reduce enteropathogen colonization in poultry and small ruminants, but studies with swine are lacking. In two different studies oral administration of NS extracts at doses equivalent to 0, 1.5 and 4.5 g kg-1 diet was assessed on piglet performance and intestinal carriage of wildtype Escherichia coli and Campylobacter, and Salmonella Typhimurium. RESULTS: Wildtype E. coli populations in the jejunal and rectal content collected 9 days after treatment began were decreased (P <= 0.05). Populations recovered from pigs treated with extract at 1.5 and 4.5 g kg-1 diet were 0.72-1.31 log10 units lower than the controls (ranging from 6.05 to 6.61 log10 CFU g-1 ). Wildtype Campylobacter and Salmonella Typhimurium were unaffected by NS treatment. Feed efficiency over the 9 days improved linearly (P < 0.05) from 3.88 with 0 NS-treated pigs to 1.47 and 1.41 with pigs treated with NS at 1.5 and 4.5 g kg-1 diet, respectively, possibly due to high glutamine/glutamic acid content of the NS extract. CONCLUSION: NS supplementation of weanling pigs improved feed efficiency and helped control intestinal E. coli during this vulnerable production phase. (c) 2017 Society of Chemical Industry. PMID- 29230815 TI - Topographies of 'care pathways' and 'healthscapes': reconsidering the multiple journeys of people with a brain tumour. AB - People diagnosed with brain tumours enter new and unfamiliar worlds in which they must make complex and previously unimaginable decisions about care, treatment and how to live their lives. While decisions are increasingly based around care pathways, these are embedded in values that often fail to accord with those of patients. In this article, we examine the cases of people with a brain tumour and how they, their families and healthcare professionals navigate and intervene in the course of life-threatening disease. We use ethnographic data (2014-16) and modified social theory to highlight: (1) patients' interpretations of disease and care and how they might differ from dominant biomedical logics; (2) complexity and contingency in care decisions; (3) rapid and unanticipated change owing to disease and bodily change; and (4) how people find ways through a world that is continually in motion and which comes into being through the combined action of human and non-human agencies. Our modified 'healthscapes' approach provides an analytic that emphasises the constant precariousness of life with a brain tumour. It helps to explain the times when patients' feel bumped off the pathway and moments when they themselves step away to make new spaces for choice. PMID- 29230816 TI - How grinding level and brewing method (Espresso, American, Turkish) could affect the antioxidant activity and bioactive compounds in a coffee cup. AB - BACKGROUND: Depending on geographical origin and cultural traditions, different brewing procedures are used all over the world to prepare a cup of coffee. In this work, we explored how three grinding levels of coffee powder and three coffee preparation methods - filtration (American), boiling (Turkish) and extraction under pressure (Espresso) - affect healthy compounds and physicochemical attributes in coffee served to consumers. RESULTS: Grinding level slightly affected the quality of coffee, whereas the preparation method significantly influenced all in-cup attributes. When the content per cup was compared, the American coffee presented higher values of antioxidant activity and total phenol content than espresso and Turkish coffees. Caffeine content was 316, 112 and 64 mg for the American, Turkish and espresso coffee cup, respectively. CONCLUSION: One American, three Turkish and five Espresso coffee cups contain similar amount of caffeine of 316, 336 and 320 mg, respectively which are below the maximum daily consumption (400 mg per day) suggested by the European Food Safety Authority. The extraction method affects the intake of bioactive and antioxidant substances with specific properties. (c) 2017 Society of Chemical Industry. PMID- 29230818 TI - Relationship between carbohydrate composition and fungal deterioration of functional strawberry juices preserved using non-thermal treatments. AB - BACKGROUND: The quantification of the main carbohydrates present in strawberry juices enriched with inulin and fructo-oligosaccharides (FOS) and preserved by non-thermal techniques (vanillin and ultrasound) was conducted, in addition to an investigation of the evolution of these compounds and their relationship with fungal deterioration over 14 days of refrigerated storage. RESULTS: A simple and environmentally friendly analytical approach based on high-performance liquid chromatography with a reflection index detector was developed for simultaneous determination of inulin, FOS and mono- and disaccharides present in the juices. When analyzing the evolution of carbohydrates during storage, a direct relationship between the consumption of sucrose and the growth of yeasts and molds (main spoilage flora in strawberry) was observed, especially in untreated samples (control). By contrast, no sucrose consumption was observed during storage of the treated sample, thus demonstrating the efficiency of the non thermal treatments for controlling yeasts and mold growth. In turn, inulin and FOS added to juices were not degraded during storage. CONCLUSION: The results obtained in the present study demonstrate that non-thermal treatments are adequate for preventing the growth of deteriorative flora in strawberry juices and that the addition of inulin and FOS can be a good strategy for functionalizing them, as well as improving their nutritional properties. (c) 2017 Society of Chemical Industry. PMID- 29230817 TI - EBV-encoded miRNAs target ATM-mediated response in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein-Barr virus (EBV) infection. In NPC, miR-BARTs, the EBV encoded miRNAs derived from BamH1-A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV-encoded miRNAs in a panel of NPC patient-derived xenografts and an EBV positive NPC cell line by small RNA sequencing. Among the 40 miR-BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV-miRNAs, BART5-5p, BART7-3p, BART9-3p, and BART14-3p could negatively regulate the expression of a key DNA double-strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'-UTR. Notably, the expression of these four miR-BARTs represented more than 10% of all EBV-encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT-PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5-5p, BART7-3p, BART9-3p, and BART14-3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR-BARTs in EBV-positive NPC cells, we further demonstrated the novel function of miR-BARTs in inhibiting Zta-induced lytic reactivation. These findings imply that the four viral miRNAs work co-operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. (c) 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29230819 TI - Genetic inheritance of pulp colour and selected traits of cassava (Manihot esculenta Crantz) at early generation selection. AB - BACKGROUND: The early generation selection of cassava quantitative and qualitative traits saves breeding resources as it can shorten breeding schemes. Inheritance analysis provides important breeding information for developing new improved varieties. This study aimed at developing an F1 segregating cassava population and determining mode of gene action of pulp colour and selected traits at early generation selection (F1 seedling and clones). RESULTS: The 15 families exhibited significant (P < 0.05) phenotypic variation between offspring. The general combining ability (GCA) was significant for all traits except cassava brown streak disease on leaves, whereas specific combining ability (SCA) was significant for all evaluated traits. The Garukansubire and Gitamisi genotypes were the best general combiners for improving fresh storage root yield, while G1 and G2 were the best general combiners for improved carotenoid (yellow/orange pulp colour) and delayed physiological postharvest deterioration. The pulp colour had the highest GCA/SCA ratio and percent sum of squares due to GCA. CONCLUSION: The 15 F1 families exhibited essential genetic diversity for cassava improvement. The expression of most cassava traits was controlled by both additive and non additive gene action. The study elucidated the role of dominance effects over the additive effects for the evaluated traits. However, the pulp colour was predominantly controlled by additive gene action. This implies the possibility of improving cassava through conventional breeding using recurrent selection for most traits. (c) 2017 Society of Chemical Industry. PMID- 29230821 TI - Tibial plateau levelling osteotomy locking-compression plates for stabilisation of canine and feline ilial body fractures. AB - OBJECTIVES: To evaluate the clinical and radiographic outcomes following surgical stabilisation of ilial fractures in dogs and cats using a laterally applied Synthes TPLO locking compression plate. MATERIALS AND METHODS: Medical records and radiographs of seven dogs and two cats which had undergone surgical repair of an ilial body fracture with a TPLO locking compression plate were reviewed. Long term clinical follow-up was obtained from an owner or referring veterinarian questionnaire. RESULTS: Fracture reduction was anatomic in six of nine ilia and near-anatomic in three of nine. All but one fracture achieved osseous union by 6 weeks after surgery. No screw loosening or implant-related complications occurred in any patient. There was pelvic canal narrowing in six of nine patients (median reduction in pelvic canal diameter was 4.9%). No intraoperative or postoperative complications were reported. CLINICAL SIGNIFICANCE: Lateral plating of canine and feline ilial fractures with a Synthes TPLO locking compression plate was associated with a low complication rate and satisfactory radiographic and clinical outcomes in this small case series. PMID- 29230820 TI - Tree age affects physicochemical, functional quality and storability of Amrapali mango (Mangifera indica L.) fruits. AB - BACKGROUND: The effect of tree age on physicochemical quality attributes and storage behaviour of Amrapali mango fruit was evaluated. Physiologically mature fruits were harvested from 6-, 18- and 30-year-old trees and kept for ripening under ambient conditions (temperature 35 +/- 3 degrees C, relative humidity 60 +/- 5%). Observations were recorded at 3-day intervals. RESULTS: Highest total soluble solids and total sugars were found in the fruit sourced from 18-year-old trees. At the end of storage, least titratable acidity (0.17%) and higher carotenoids (10.86 mg 100 g-1 ) were found in 30-year-old tree fruits during the last day of storage. Highest total phenols (TP) (251.33 MUg gallic acid g-1 ), antioxidant capacity (AC) (5.63 MUmol Trolox g-1 ) and ascorbic acid (AA) (31.13 mg 100 g-1 ) were reported in fruits from younger trees of 6 years old. Maximum respiratory and ethylene evolution peak was observed in fruits obtained from oldest trees, whereas least activities of pectin methyl esterase (0.31 MUmol min 1 g-1 fresh weight) and polygalacturonase (53.67 MUg galacturonic acid g-1 h-1 ) were observed in 6-year-old tree fruits at the end of the 9-day storage period. CONCLUSION: Higher total soluble solids and total sugars were found in fruit harvested from middle-age-group (18-year-old) trees during the entire storage period of 9 days. Most of the functional parameters, such as TP, AC and AA, were observed to be higher in fruits from younger (6-year-old) trees. The obtained results revealed that produce from middle-age-group (18-year-old) Amrapali mango orchards suit consumers' and processors' requirements. (c) 2017 Society of Chemical Industry. PMID- 29230822 TI - Rapid prediction of stem cell mobilization using volume and conductivity data from automated hematology analyzers. AB - BACKGROUND: Rapid analytics to predict circulating hematopoietic stem cells are valuable for optimal management of mobilization, particularly for the use of newer and costly mobilization agents such as plerixafor. STUDY DESIGN AND METHODS: We used stepwise, linear multiple regression modeling applied to cell population data collected by routine hematology analyzers (Beckman Coulter DxH 800) on patients undergoing autologous stem cell collection (n = 131). Beta coefficients were used to derive a formula for a stem cell index (SCI). We then tested the correlation of SCI with stem cell counts and performance of the SCI as a predictor of poor mobilization with external validation in a separate cohort (n = 183). RESULTS: The SCI correlated strongly with CD34 counts by flow cytometry (r = 0.8372 in the development cohort, r = 0.8332 in the external validation cohort) and compares favorably with other rapid stem cell enumerating technologies. In the external validation cohort, the SCI performed well as a predictor (receiver operating characteristic area under the curve, 0.9336) of poor mobilization (CD34 count < 10), with a sensitivity of 72% and a specificity of 93%. When prevalence of poor mobilization was 33%, this resulted in a positive predictive value of 83% and a negative predictive value of 87%. The SCI also showed promise in tracking responses to plerixafor administration. CONCLUSION: The findings demonstrate the utility of the cell population data collected by hematology analyzers to provide rapid data beyond standard complete blood counts, particularly for stem cell count prediction, requiring no additional reagents, specimen, or instrumentation. PMID- 29230823 TI - Decreasing fructose-1,6-bisphosphate aldolase activity reduces plant growth and tolerance to chilling stress in tomato seedlings. AB - In northern China, low temperature is the most common abiotic stresses for tomato plants cultivated in solar-greenhouse in winter. We recently found that the expression and enzyme activity of fructose-1,6-bisphosphate aldolases (FBAs) in tomato, which are important enzymes in the Calvin-Benson cycle (CBC), were significantly altered in tomato seedlings subjected to heat/cold stresses. In order to study the role of FBA in photosynthesis and in regulating cold stress responses of tomato seedlings (Solanum lycopersicum), we transformed a tomato inbred line (FF) with RNA interference (RNAi) vector containing SlFBA7 reverse tandem repeat sequence. We found that the decreased SlFBA7 expression led to the decreased activities of FBA, as well as the activities of other main enzymes in the CBC. We also noticed a decrease in net photosynthetic rate, ribulose-1,5 bisphosphate and soluble sugar content, stem diameter, dry weight and seed size in RNAi SlFBA7 plants compared to wild-type. However, there are no changes in starch contents in the RNAi transgenic plants. RNAi SlFBA7 plants showed a decreased germination rate, and an increased levels of superoxide anions (O2.- ) and hydrogen peroxide (H2 O2 ) under low temperature (8/5 degrees C) and low light intensity (100 MUmol m-2 s-1 photon flux density) growth conditions. These findings demonstrated the important role of SlFBA7 in regulating growth and chilling tolerance of tomato seedlings, and suggested that the catalytic activity of FBA in the CBC is sensitive to temperature. PMID- 29230824 TI - Effects of medium-chain triacylglycerols on Maillard reaction in bread baking. AB - BACKGROUND: To investigate the relationship between the fatty acid composition of medium-chain triacylglycerols (MCTs) and the Maillard reaction induced during bread baking, a comparison with various fatty acids was conducted. RESULTS: Saturated fatty acids had a remarkable inhibitory effect on the amount of advanced glycation end products (AGEs) generated from the Maillard reaction in bread baking compared to unsaturated fatty acids. The amount of AGEs produced by each fatty acid (mg kg-1 ) was as follows: C18:0, 18.7; C12:0, 35.2; C16:0, 21.4; C18:0, 38.2; C18:1, 68.7; C18:2, 80.1; C20:4, 80.8; C22:4, 89.8. Saturated fatty acids were possibly involved in the Maillard reaction and, as a result, acted to inhibit it. In the case of unsaturated fatty acids, amounts of AGEs during the Maillard reaction in baking tended to increase as the degree of unsaturation increased. In other words, there was a positive correlation between the degree of unsaturation and the amount of AGEs. It was also confirmed that the air pore distribution in baked bread was closely related to AGEs. CONCLUSION: These results led us to conclude that the fatty acid composition of the added lipids also influences properties that determine the tastiness of bread. (c) 2017 Society of Chemical Industry. PMID- 29230825 TI - Introduction special dermatology plastic surgery issue January 2018. PMID- 29230826 TI - Evolution of Biventricular Loading Condition in Pediatric LVAD Patient: A Prospective and Observational Study. AB - The aim of this study was to describe the echocardiographic trend of left ventricular (LV) and right ventricular (RV) function after implantation of a pulsatile flow left ventricular assist device (LVAD) in children. From 2013 to 2016, we prospectively evaluated 13 consecutive pediatric Berlin Heart EXCOR LVAD patients. Clinical and echocardiographic data were collected at baseline, within 24 h after implantation and monthly until LVAD explant. Median age and weight at the implantation was 8 (4-23) months and 5 (4.6-8.3) kg at the time of implantation, respectively. All were affected by dilated cardiomyopathy. Average LVAD support time was 226.2 +/- 121.2 days. Nine (70%) were transplanted, 4 (30%) died. LV end-systolic and end-diastolic volumes were reduced until the follow up of two months (P = 0.019 and P = 0.001). A progressive increase in RV dimensions was observed. After 4 months of follow up, RV fractional area change worsening was statistically related with the deterioration of LV unloading (P = 0.0036). Four patients needed prolonged inotropic support for RV failure. Pulsatile LVAD in pediatrics is followed by an early and mid-term LV unloading, as expressed by a decrease in LV volumes and diameters at echocardiogram. The effects of unloading do not remain stable at long term follow up. RV function improved in the acute phase, but a progressive dilatation of RV was noted over time. In some patients, RV failure might lead to the need of an increase of inotropic support at long term follow up. PMID- 29230827 TI - Occurrence of variable levels of health-promoting fruit compounds in horn-shaped Italian sweet pepper varieties assessed by a comprehensive approach. AB - BACKGROUND: Cultivated pepper is a rich source of diverse bioactive compounds with potential properties related to the prevention of major degenerative and proliferative diseases. In the present study, 15 sweet pepper varieties, highly appreciated on the Italian market, were assessed for variation in the content of ascorbic acid, isoprenoids and flavonoids, as well as morpho-agronomic performances and molecular diversity. RESULTS: The collection under study showed a wide variability for all traits considered. Traditional cultivars, although less productive, were characterized by a high content of beta-carotene and ascorbic acid, reaching maximum concentrations of 230.5 mg kg-1 fresh weight (fw) and 2750 mg kg-1 fw, respectively. Strong correlations were demonstrated between neoxanthin and luteolins. Fruit weight was positively correlated with alpha tocopherol content and negatively correlated with luteolins content. The genotyping by sequencing platform allowed the identification of 1833 single nucleotide polymorphism, which better defined the relationships among cultivars, based on provenance and improvement rate. CONCLUSIONS: The present study provides an overview of the variability in the expression of fruit nutritional traits in a collection of horn-shaped pepper cultivars, integrating agronomic and molecular data. The impact for breeding and consumers is discussed. (c) 2017 Society of Chemical Industry. PMID- 29230828 TI - Synthesis, stability and bioavailability of astaxanthin succinate diester. AB - BACKGROUND: We synthesized astaxanthin succinate diester (ASD), a novel astaxanthin (AST) derivate, with succinic anhydride and free AST. ASD was purified and characterized using silica gel column chromatography and spectrometry, respectively. RESULTS: The ASD final synthesis rate was 82.63%. A stability test revealed a high AST and ASD retention rate at pH 5.0-7.0. ASD showed better stability than did AST under acidic conditions. Both sample ions showed lower retention rates under Fe2+ and Fe3+ states. The ASD metabolic curve showed serum and liver area under the curve from 0 h to time t (AUC0-t ) values of 45.05 +/- 4.58 and 120.38 +/- 23.66 ug h-1 mL-1 , respectively. The long-term accumulation was significantly higher in the ASD group than in the AST group, which showed higher accumulation in the heart, muscle and spleen than in other tissues in vivo. CONCLUSION: The thermal stability and bioavailability of ASD were higher than that of the non-esterified free AST and common free AST, respectively. Additionally, AST accumulation in different tissues of the ASD group was multifold higher than that of free AST. These results prove that ASD may serve as a better source of AST for human nutrition than does free AST. (c) 2017 Society of Chemical Industry. PMID- 29230829 TI - Pathology of retroperitoneal sarcomas: A brief review. AB - Sarcomas represent a highly heterogeneous group of tumors as reflected in the significant overlap between their histologic phenotypes between the different types, posing diagnostic challenges for the pathologist. Definitive tumor classification is increasingly important because of prognostication and emergence of targeted therapies for some of the sarcoma types. In this review, we highlight pertinent pathologic and molecular aspects of sarcomas common in the retroperitoneum, relevant to the surgical oncologist. PMID- 29230830 TI - In vitro bioaccessibility of individual carotenoids from persimmon (Diospyros kaki, cv. Rojo Brillante) used as an ingredient in a model dairy food. AB - BACKGROUND: Addition of persimmon fruit, which is highly rich in carotenoids, to dairy products represents an alternative to obtain functional foods. However, carotenoid bioaccessibility is strongly influenced by fat content and food composition. That is why in vitro bioaccessibility of individual carotenoids was evaluated in persimmon-based dairy products formulated with whole (3.6% fat) or skimmed milk (0.25% fat) and different freeze-dried persimmon tissues. RESULTS: Unambiguous identification of seven xanthophylls (neoxanthin, violaxanthin, antheraxanthin, lutein, zeaxanthin, lutein epoxide and beta-cryptoxanthin) and three hydrocarbon carotenes (alpha-carotene, beta-carotene and lycopene) was achieved using high-performance liquid chromatography with a reverse-phase C-30 column. Total carotenoid content declined up 71% through the digestion process. In vitro bioaccessibility of carotenoids was significantly higher in dairy products formulated with whole milk than those with skimmed milk, representing a difference of more than 21% (in the formulation using persimmon whole fruit as ingredient). Furthermore, addition of whole milk to any type of persimmon tissue significantly improved the bioaccessibility of total provitamin A carotenoids, reaching the highest values (38%) with whole fruit and whole milk. CONCLUSION: The higher fat content in whole milk exerted a significant influence on carotenoid bioaccessibility, especially when using freeze-dried persimmon whole fruit. (c) 2017 Society of Chemical Industry. PMID- 29230831 TI - Genotype * environment interaction on tocochromanol and plastochromanol-8 content in seeds of doubled haploids obtained from F1 hybrid black * yellow seeds of winter oilseed rape (Brassica napus L.). AB - BACKGROUND: The aim of the study was to determine the effect of genotype * environment interaction on the levels of alpha-, beta-, gamma- and delta tocopherol (alpha-T, beta-T, gamma-T and delta-T, respectively) and plastochromanol-8 (PC-8) in seeds of 17 doubled haploids (DHs) obtained from the F1 hybrid derived from crossing black (DH H2 -26) * yellow (DH Z-114) seeds of winter oilseed rape. RESULTS: The content of tocopherols in the tested DH lines ranged from 415.6 to 540.1 mg kg-1 seeds, while PC-8 content ranged from 56.3 to 89.0 mg kg-1 seeds. The alpha-T/gamma-T ratio reached a level of 0.78-1.29. Studies have shown that heritability for alpha-T, beta-T, gamma-T, total-T and PC 8 is mainly due to genotypic variation. For the delta-T homologue the level was dependent on environmental effect. CONCLUSION: The obtained DH lines population of oilseed rape is characterized by high heritability coefficients for alpha-T, beta-T, gamma-T, total-T and PC-8 levels, which indicates a greater influence of genotype than the environment on the content of these compounds. Among all studied doubled haploids, seven DHs were selected which were characterized by stable contents of alpha-T, beta-T, gamma-T, delta-T and total-T with the simultaneous stable content of PC-8. (c) 2017 Society of Chemical Industry. PMID- 29230832 TI - Management of chronic myeloid leukemia in the setting of pregnancy: when is leukocytapheresis appropriate? A case report and review of the literature. AB - BACKGROUND: Chronic myeloid leukemia (CML) is a common hematologic malignancy; however, its occurrence during pregnancy is unusual due to its low prevalence in females of childbearing age. There are conflicting reports of how to best manage CML in pregnancy, particularly in the setting of leukocytosis. HEMAPHERESIS: A 30 year-old female was diagnosed with CML at 18 weeks' estimated gestational age. On initial presentation she reported fatigue, night sweats, and early satiety, and was found to have a white blood cell (WBC) count of 69.3 * 109 /L and platelet count of 366 * 109 /L. Her disease was managed during pregnancy using interferon alpha alone despite persistent leukocytosis. CONCLUSION: CML may be effectively managed during pregnancy, even in the setting of leukocytosis, without the application of leukocytapheresis. Management relies not only upon the coordination of drug therapy and fetal monitoring, but requires close communication between multiple medical disciplines. Leukocytapheresis has been safely performed during pregnancy and may be a suitable adjunct management strategy in pregnant patients diagnosed with CML with specific clinical presentations, such as hyperleukocytosis (WBC count > 150 * 109 /L) and/or symptomatic leukostasis. PMID- 29230833 TI - Causes of iron overload in blood donors - a clinical study. AB - BACKGROUND AND OBJECTIVES: Despite the obligate iron loss from blood donation, some donors present with hyperferritinaemia that can result from a wide range of acute and chronic conditions including hereditary haemochromatosis (HH). The objective of our study was to investigate the causes of hyperferritinaemia in the blood donor population and explore the value of extensive HH mutational analyses. MATERIALS AND METHODS: Forty-nine consecutive donors (f = 6, m = 43) were included prospectively from the Capital Regional Blood Center. Inclusion criteria were a single ferritin value >1000 MUg/l or repeated hyperferritinaemia with at least one value >500 MUg/l. All donors were questioned about their medical history and underwent a physical examination, biochemical investigations and next generation sequencing of HH-related genes, including the HFE gene, the haemojuvelin gene (HFE2/HJV), the hepcidin gene (HAMP), the ferroportin 1 gene (SLC40A1) and the transferrin receptor 2 gene (TFR2). RESULTS: Forty of 49 donors were mutation positive with a combined 69 mutations, 54 of which were located in the HFE gene. There were 11 mutations in the TFR2 gene, two mutations in the HFE2 gene and two mutations in the HAMP gene. Only four donors had apparent alternative causes of hyperferritinaemia. CONCLUSION: HH-related mutations were the most frequent cause of hyperferritinaemia in a Danish blood donor population, and it appears that several different HH-genotypes can contribute to hyperferritinaemia. HH screening in blood donors with high ferritin levels could be warranted. HH-related iron overload should not in itself result in donor ineligibility. PMID- 29230835 TI - Genetic contributions to precocity traits in racing Thoroughbreds. AB - Adaptation to early training and racing (i.e. precocity), which is highly variable in racing Thoroughbreds, has implications for the selection and training of horses. We hypothesised that precocity in Thoroughbred racehorses is heritable. Age at first sprint training session (work day), age at first race and age at best race were used as phenotypes to quantify precocity. Using high density SNP array data, additive SNP heritability (hSNP2) was estimated to be 0.17, 0.14 and 0.17 for the three traits respectively. In genome-wide association studies (GWAS) for age at first race and age at best race, a 1.98-Mb region on equine chromosome 18 (ECA18) was identified. The most significant association was with the myostatin (MSTN) g.66493737C>T SNP (P = 5.46 * 10-12 and P = 1.89 * 10 14 respectively). In addition, two SNPs on ECA1 (g.37770220G>A and g.37770305T>C) within the first intron of the serotonin receptor gene HTR7 were significantly associated with age at first race and age at best race. Although no significant associations were identified for age at first work day, the MSTN:g.66493737C>T SNP was among the top 20 SNPs in the GWAS (P = 3.98 * 10-5 ). Here we have identified variants with potential roles in early adaptation to training. Although there was an overlap in genes associated with precocity and distance aptitude (i.e. MSTN), the HTR7 variants were more strongly associated with precocity than with distance. Because HTR7 is closely related to the HTR1A gene, previously implicated in tractability in young Thoroughbreds, this suggests that behavioural traits may influence precocity. PMID- 29230834 TI - Quantitative examination of isometric tongue protrusion forces in children with oro-facial dysfunctions or myofunctional disorders. AB - Oro-facial dysfunctions (OFD) or oro-facial myofunctional disorders in children lead to severe problems in teeth and jaw position, articulation, chewing and swallowing. The forces of the tongue, the central muscle for articulation, chewing and swallowing are focused on in several studies. In this examination, isometric tongue protrusion forces (TPF) of children with OFD and controls were compared. Thirty participants with OFD and 30 controls were presented a target force level as a straight line on a monitor that they were supposed to match by generating an isometric tongue force for different target levels (0.25 N and 0.5 N). Correlations of the severity of OFD (symptom score) with the capacities of the TPF 0.25 N and 0.5 N were calculated. Statistical differences were obvious in TPF variability and the accuracy, depending on the weight. Tongue contact time, expressed as per cent (TCT, total contact: 100%), was significantly lower in children with OFD (P = .005). Mean and median TPF was not different between groups. The predictive value of TPF for OFD revealed a level of 58.6% for TPF 0.25 N and 74.5% for TPF 0.5 N. Correlations of the severity of OFD were seen for some parameters. Subjects with OFD show significantly lower competencies in accuracy and endurance of tongue protrusion forces. This may have a high impact on phenotyping children with OFD and influence therapeutical approaches. PMID- 29230836 TI - Dynamic prediction in functional concurrent regression with an application to child growth. AB - In many studies, it is of interest to predict the future trajectory of subjects based on their historical data, referred to as dynamic prediction. Mixed effects models have traditionally been used for dynamic prediction. However, the commonly used random intercept and slope model is often not sufficiently flexible for modeling subject-specific trajectories. In addition, there may be useful exposures/predictors of interest that are measured concurrently with the outcome, complicating dynamic prediction. To address these problems, we propose a dynamic functional concurrent regression model to handle the case where both the functional response and the functional predictors are irregularly measured. Currently, such a model cannot be fit by existing software. We apply the model to dynamically predict children's length conditional on prior length, weight, and baseline covariates. Inference on model parameters and subject-specific trajectories is conducted using the mixed effects representation of the proposed model. An extensive simulation study shows that the dynamic functional regression model provides more accurate estimation and inference than existing methods. Methods are supported by fast, flexible, open source software that uses heavily tested smoothing techniques. PMID- 29230837 TI - Alterations in DNA methylation patterns and gene expression in spermatozoa of subfertile males. AB - This study was designed to evaluate the DNA methylation patterns and gene expression in spermatozoa from subfertile males. Thirty samples were subjected to 450K arrays as a screening study to evaluate the variation in sperm DNA methylation levels between cases and controls groups, and then three CpG sites (cg07227024, cg05813498 and cg23081194) have the highest difference in methylation levels and located within ALS2CR12, GAA and UBE2G2 genes respectively; these were selected for further analysis using deep bisulphite sequencing and qPCR in 136 samples (64 proven fertile males "controls" and 72 subfertile males "cases"). A significant difference in the methylation level was found between cases and controls at two CpGs, six CpGs and three CpGs in ALS2CR12, GAA and UBE2G2 gene-related amplicon respectively. Besides, the qPCR results showed a significant change in the expression levels of GAA, UBE2G2 and ALS2CR12 gene in cases compared to the controls (p <= .00001). In conclusion, the methylation levels at CpGs in GAA, UBE2G2 and ALS2CR12 gene amplicons were significantly different in subfertile compared to proven fertile males. In addition, a significantly different was showed in the expression levels of GAA, UBE2G2 and ALS2CR12 genes in subfertile males compared to proven fertile males. PMID- 29230838 TI - Carnosine prevents testicular oxidative stress and advanced glycation end product formation in D-galactose-induced aged rats. AB - D-Galactose is shown to mimic natural ageing in rodents by exacerbating oxidative stress and glycation. Steroid production and having a poor antioxidant system make testis vulnerable to galactose-induced ageing. Antioxidation and antiglycating actions of carnosine may be intriguing for prevention of testicular ageing. In this study, male Wistar rats were applied D-galactose (300 mg/kg; subcutaneously 5 days a week) and carnosine (250 mg/kg; intraperitoneally 5 days a week) along with D-galactose for 2 months. D-Galactose treatment increased testicular reactive oxygen species, thiobarbituric acid reactive substances, diene conjugates, protein carbonyls, advanced oxidation products of proteins and advanced glycation end products. Carnosine was capable of repelling oxidative stress and glycation produced by D-galactose. Johnsen's score, which describes histopathological evaluation, was also significantly improved with preserved spermatogenesis by carnosine. It appears that carnosine deters the testicular oxidative stress due to galactose-induced ageing directly by its antioxidative and antiglycating properties. PMID- 29230839 TI - Prevalence estimation when disease status is verified only among test positives: Applications in HIV screening programs. AB - The first goal of the United Nations' 90-90-90 HIV/AIDS elimination strategy is to ensure that, by 2020, 90% of HIV-positive people know their HIV status. Estimating the prevalence of HIV among people eligible for screening allows assessment of the number of additional cases that might be diagnosed through continued screening efforts in this group. Here, we present methods for estimating prevalence when HIV status is verified by a gold standard only among those who test positive on an initial, imperfect screening test with known sensitivity and specificity. We develop maximum likelihood estimators and asymptotic confidence intervals for use in 2 scenarios: when the total number of test negatives is known (Scenario 1) and unknown (Scenario 2). We derive Bayesian prevalence estimators to account for non-negligible uncertainty in previous estimates of the sensitivity and specificity. The Scenario 1 estimator consistently outperformed the Scenario 2 estimator in simulations, demonstrating the use of recording the number of test negatives in public health screening programs. For less accurate tests (sensitivity and specificity < 90%), the performance of the 2 estimators was comparable, suggesting that, under these circumstances, prevalence can still be estimated with adequate precision when the number of test negatives is unknown. However, use of the Bayesian approach to account for uncertainty in the sensitivity and specificity is especially recommended for the Scenario 2 estimator, which was particularly sensitive to misspecification of these values. R code for implementing these methods is available at hsph.harvard.edu/donna-spiegelman/software. PMID- 29230840 TI - Correlation of biochemical constituents of seminal plasma with semen quality in Teddy goat (Capra hircus) bucks. AB - This study was planned to determine the relationship between semen quality parameters and the levels of biochemical constituents of seminal plasma of Teddy (Capra hircus) buck semen. For this purpose, semen ejaculates were collected from five mature healthy Teddy bucks. All the experimental bucks were kept under natural environmental conditions. Semen was collected twice in a week for the duration of 6 weeks by Artificial Vagina (AV) in the breeding season (February April). Two successive ejaculates of single buck were pooled at time of collection, and a total of 60 semen samples were processed for semen analysis. Sperm per cent motility, sperm concentration, dead sperm percentage, morphological abnormal spermatozoa, plasma membrane integrity were correlated with biochemical constituents of seminal plasma. The mean per cent motility (89.18% +/- 0.37%), sperm concentration (1.86 +/- 0.04 * 109 /ml), dead sperm percentage (8.08% +/- 0.29%), morphological abnormal spermatozoa (6.05% +/- 0.29%) and plasma membrane integrity (88.22% +/- 0.34%) were recorded. The seminal plasma contained Na+ (144.12 +/- 1.59 mEq/L), K+ (27.38 +/- 0.49 mEq/L), Cl- (65.73 +/- 0.45 mEq/L), Ca++ (9.34 +/- 0.22 mg/dl), P (19.32 +/- 0.97 mg/dl), aspartate aminotransferase (AST; 26.48 +/- 1.30 IU/L), alanine aminotransferase (ALT; 168.47 +/- 5.18 IU/L), lactate dehydrogenase (LDH; 215.98 +/- 6.06 IU/L), albumin (1.90 +/- 0.10 g/dl), globulins (2.08 +/- 0.11 g/dl) and total protein (3.98 +/- 0.20 g/dl). The collected data were analysed by applying Pearson's correlation coefficients. Dead sperm percentage had negative correlation with sodium (r = -.278, p < .05), albumin (r = -.294, p < .05), globulin (r = -.266, p < .05) and total protein (r = -.295, p < .05). Phosphorus was negatively associated with sperm concentration (r = -.262, p < .05). AST was negatively correlated with plasma membrane integrity (r = -.292, p < .05). It was concluded that most of the semen quality parameters of Teddy bucks were positively correlated with biochemical constituents, but opposite trends were found in case of dead sperm percentage. The seminal biochemical constituents dynamically interact with each other. PMID- 29230841 TI - Photoaggravated allergic contact dermatitis and transient photosensitivity caused by methylisothiazolinone. AB - BACKGROUND: Photoaggravated allergic contact dermatitis caused by methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) and MI has been reported. OBJECTIVES: To describe the clinical characteristics and results of (photo)patch tests and photo-tests of 10 patients in Belgium and France suffering from photoaggravated contact dermatitis caused by MI. PATIENTS AND METHODS: Five men and five women, with a median age of 49.5 years, were investigated between January 2012 and February 2017 because of suspected photoaggravated contact dermatitis. Patch tests, photopatch tests and/or photo-tests were performed. RESULTS: Seven patients had positive patch test reactions to both MCI/MI and MI, whereas 3 patients had positive patch test reactions only to MI. In most cases, MI was the (strong) primary sensitizer. Photopatch tests with MCI/MI and/or MI gave stronger reactions than patch tests with these derivatives, indicating photoaggravation. Sensitization probably took place from cosmetics and work related biocides, whereas elicitation of dermatitis was remarkably often related to airborne exposure to MI present in paints or industrial biocides. Four patients suffered from transient photosensitivity. CONCLUSION: Photoaggravated allergic contact dermatitis and transient photosensitivity caused by MI is a peculiar clinical presentation of allergic contact dermatitis caused by this preservative, and should be considered in daily clinical practice. PMID- 29230842 TI - Use of Ultrasound Contrast Agents in Relation to Percutaneous Interventional Procedures: A Systematic Review and Pictorial Essay. AB - The aim of this article is to provide an inventory of the use of contrast enhanced ultrasound (CEUS) in relation to percutaneous interventional procedures. The article is structured into a systematic literature review followed by a clinical part relating to percutaneous CEUS-guided procedures. A literature search identified 3109 records. After abstract screening, 55 articles were analyzed and supplemented with pictorial material to explain the techniques. In conclusion, the best-evidenced indications for CEUS-guided interventions are biopsy and ablation of inconspicuous or B-mode-invisible tumors, intraprocedural ablation control and follow-up, as well as percutaneous transhepatic cholangiography and drainage procedures. PMID- 29230844 TI - Cyclophilin D promotes tubular cell damage and the development of interstitial fibrosis in the obstructed kidney. AB - Cyclophilin D (CypD) is an important component in mitochondrial-dependent tubular cell death in acute kidney injury. However, it is not known whether CypD contributes to tubular cell damage in chronic interstitial fibrosis. We investigated this question in the unilateral ureter obstruction (UUO) model of renal interstitial fibrosis. Groups of CypD-/- and wild type (WT) mice were killed 7 or 12 days after UUO surgery. The significant tubular cell apoptosis seen in WT UUO was significantly reduced in CypD-/- UUO based on TUNEL and cleaved caspase 3 staining. Other markers of tubular cell damage; loss of E cadherin and AQP1 expression, were also reduced in the CypD-/- UUO kidney. This reduced tubular damage was associated with less inflammation and a partial protection against loss of peritubular capillaries. The prominent accumulation of alpha-SMA+ myofibroblasts and interstitial collagen deposition seen in WT UUO was significantly reduced in CypD-/- UUO on day 12, but not day 7. Activation of several pro-fibrotic signalling pathways (p38 MAPK, JNK and Smad3) was unaltered in CypD-/- UUO, arguing that CypD acts independently to promote renal fibrosis. CypD deletion in cultured tubular cells attenuated oxidative stress-induced pro inflammatory, pro-fibrotic and apoptotic responses; however, responses to angiotensin II and LPS were unaffected. In contrast, CypD deletion in cultured renal fibroblasts did not affect PDGF-induced proliferation or TGF-beta1-induced collagen I expression, suggesting no direct role of CypD in the fibroblast response. In conclusion, we have identified a role for CypD in chronic tubular cell damage and in the development of renal interstitial fibrosis. PMID- 29230843 TI - Cardiac function in paediatric patients with congenital adrenal hyperplasia due to 21 hydroxylase deficiency. AB - BACKGROUND: Hyperandrogenism and exogenous glucocorticoid excess may cause unfavourable changes in the cardiovascular risk profile of patients with congenital adrenal hyperplasia (CAH). OBJECTIVE: To evaluate the cardiac function in paediatric patients with CAH. PATIENTS AND METHODS: Twenty-seven paediatric patients with CAH, aged 8-16 years, were evaluated by physical examination, electrocardiogram (ECG), conventional echocardiography, tissue Doppler imaging and two-dimensional (2D) myocardial strain (rate) imaging. Results were compared to 27 age- and gender- matched healthy controls. RESULTS: No signs of left ventricular hypertrophy or dilatation were detected on echocardiography. ECG revealed a high prevalence (25.9%) of incomplete right bundle branch block. Left ventricular posterior wall thickness in diastole (LVPWd) was significantly lower in patients with CAH compared to controls (5.55 vs 6.53 mm; P = .009). The LVPWd Z-score was significantly lower in patients with CAH yet within the normal range (-1.12 vs -0.35; P = .002). Isovolumetric relaxation time was significantly lower in patients with CAH (49 vs 62 ms; P = .003). Global longitudinal, radial and circumferential strain was not significantly different compared to controls. Global radial strain rate was significantly higher compared to healthy controls (2.58 vs 2.06 1/s; P = .046). Global longitudinal strain was negatively correlated with 24-hour blood pressure parameters. CONCLUSION: Cardiac evaluation of paediatric patients with CAH showed no signs of left ventricular hypertrophy or ventricular dilatation. LVPWd was lower in patients with CAH than in controls but within the normal range. A shorter isovolumetric relaxation time in patients with CAH may be a sign of mild left ventricular diastolic dysfunction. PMID- 29230845 TI - The Relative Citation Ratio: Measuring Impact of Publications From an International Conference With a New NIH Metric. PMID- 29230847 TI - Electrochemotherapy Treatment of Canine Transmissible Venereal Tumors. PMID- 29230849 TI - Temporary Biventricular Assist Device to Bridge a Patient With Cardiogenic Shock Due to AL Amyloidosis to Heart Transplantation. PMID- 29230848 TI - Challenges in the Field of Biomedical Devices: A Multidisciplinary Perspective. PMID- 29230851 TI - A novel case-control subsampling approach for rapid model exploration of large clustered binary data. AB - In many settings, an analysis goal is the identification of a factor, or set of factors associated with an event or outcome. Often, these associations are then used for inference and prediction. Unfortunately, in the big data era, the model building and exploration phases of analysis can be time-consuming, especially if constrained by computing power (ie, a typical corporate workstation). To speed up this model development, we propose a novel subsampling scheme to enable rapid model exploration of clustered binary data using flexible yet complex model set ups (GLMMs with additive smoothing splines). By reframing the binary response prospective cohort study into a case-control-type design, and using our knowledge of sampling fractions, we show one can approximate the model estimates as would be calculated from a full cohort analysis. This idea is extended to derive cluster-specific sampling fractions and thereby incorporate cluster variation into an analysis. Importantly, we demonstrate that previously computationally prohibitive analyses can be conducted in a timely manner on a typical workstation. The approach is applied to analysing risk factors associated with adverse reactions relating to blood donation. PMID- 29230852 TI - Data-generating models of dichotomous outcomes: Heterogeneity in simulation studies for a random-effects meta-analysis. AB - Simulation studies to evaluate performance of statistical methods require a well specified data-generating model. Details of these models are essential to interpret the results and arrive at proper conclusions. A case in point is random effects meta-analysis of dichotomous outcomes. We reviewed a number of simulation studies that evaluated approximate normal models for meta-analysis of dichotomous outcomes, and we assessed the data-generating models that were used to generate events for a series of (heterogeneous) trials. We demonstrate that the performance of the statistical methods, as assessed by simulation, differs between these 3 alternative data-generating models, with larger differences apparent in the small population setting. Our findings are relevant to multilevel binomial models in general. PMID- 29230853 TI - Coexistence of pemphigus herpetiformis with extramammary Paget disease. PMID- 29230854 TI - Adjuvant potential of virgin coconut oil extract on antiretroviral therapy induced testicular toxicity: An ultrastructural study. AB - The effects of Virgin coconut oil as an adjuvant to highly active antiretroviral therapy (HAART) were investigated on the testicular ultrastructure and biochemical markers in rats. Twenty male Sprague-Dawley rats, weighing 153-169 g were divided into four groups and treated as follows: control A (distilled water), B (HAART), C (HAART+Virgin coconut oil 10 ml/kg) and D (Virgin coconut oil [VCO] 10 ml/kg). Testicular segments were evaluated using transmission electron microscopy. Serum was assayed for testosterone, luteinising hormone, follicle stimulating hormone and testicular tissue for malondialdehyde and glutathione. Ultrastructure of basement membrane (Bm), mitochondria and spermatocytes was normal in the control group. HAART-treated group showed significant increase (p < .01) in Bm thickness with significant decrease in Leydig cell nuclear diameter (p < .05) and volume (p < .01) when compared with control group. Mitochondrial cristae appear collapsed, and Sertoli cells showed cytoplasmic vacuolations. HAART+VCO group showed improved ultrastructural details in Bm, and Sertoli cell and Leydig cells show abundant lipid droplets. Virgin coconut oil-treated group showed thinning of Bm with otherwise normal ultrastructural features of organelles. HAART-treated group showed significant increase (p < .01) in testosterone levels. There was no significant effect on malondialdehyde and glutathione levels. Virgin coconut oil improved testicular morphology and reversed HAART-induced ultrastructural alterations. Further studies on putative mechanism are required. PMID- 29230855 TI - A role for autophagy in long-term spatial memory formation in male rodents. AB - A hallmark of long-term memory formation is the requirement for protein synthesis. Administration of protein synthesis inhibitors impairs long-term memory formation without influencing short-term memory. Rapamycin is a specific inhibitor of target of rapamycin complex 1 (TORC1) that has been shown to block protein synthesis and impair long-term memory. In addition to regulating protein synthesis, TORC1 also phosphorylates Unc-51-like autophagy activating kinase-1 (Ulk-1) to suppress autophagy. As autophagy can be activated by rapamycin (and rapamycin inhibits long-term memory), our aim was to test the hypothesis that autophagy inhibitors would enhance long-term memory. To examine if learning alters autophagosome number, we used male reporter mice carrying the GFP-LC3 transgene. Using these mice, we observed that training in the Morris water maze task increases the number of autophagosomes, a finding contrary to our expectations. For learning and memory studies, male Long Evans rats were used due to their relatively larger size (compared to mice), making it easier to perform intrahippocampal infusions in awake, moving animals. When the autophagy inhibitors 3-methyladenine (3-MA) or Spautin-1 were administered bilaterally into the hippocampii prior to training in the Morris water maze task, the drugs did not alter learning. In contrast, when memory was tested 24 hours later by a probe trial, significant impairments were observed. In addition, intrahippocampal infusion of an autophagy activator peptide (TAT-Beclin-1) improved long-term memory. These results indicate that autophagy is not necessary for learning, but is required for long-term memory formation. PMID- 29230856 TI - The role of the assessment policy in the relation between learning and performance. AB - CONTEXT: Optimising student learning and academic performance is a continuous challenge for medical schools. The assessment policy may influence both learning and performance. Previously, the joint contribution of self-regulated learning (SRL) and participation in scheduled learning activities towards academic performance has been reported. However, little is known about the relationships between SRL, participation and academic performance under different assessment policies. OBJECTIVES: The goal of this study was to investigate differences in average scores of SRL, participation and academic performance of students under two assessment policies: (i) a conjunctive lower stakes, lower performance standard (old) assessment policy and (ii) a compensatory higher stakes, higher performance standard (new) assessment policy. In addition, this research investigated whether the relationships between academic performance, SRL and participation are similar across both assessment policies. METHODS: Year-1 medical students (i) under the old assessment policy (n = 648) and (ii) under the new assessment policy (n = 529) completed the Motivated Strategies for Learning Questionnaire on SRL, and additional items on participation. Year-1 performance was operationalised as students' average Year-1 course examination grades. manova and structural equation modelling were used for analyses. RESULTS: Generally, students under the new assessment policy showed significantly higher Year-1 performance, SRL and participation, compared with students under the old assessment policy. The relationships between Year-1 performance, SRL and participation were similar across assessment policies. CONCLUSIONS: This study indicates that the higher academic performance under a compensatory higher stakes, higher performance standard assessment policy, results from higher SRL and participation, but not from altered relationships between SRL, participation and performance. In sum, assessment policies have the potential to optimise student learning and performance. PMID- 29230858 TI - Score and shave technique with freehand scalpel for harvesting small split thickness skin grafts in dermatological surgery. PMID- 29230857 TI - Chemical aspects of metal ion chelation in the synthesis and application antibody based radiotracers. AB - Radiometals are becoming increasingly accessible and are utilized frequently in the design of radiotracers for imaging and therapy. Nuclear properties ranging from the emission of gamma-rays and beta+ -particles (imaging) to Auger electron and beta- and alpha-particles (therapy) in combination with long half-lives are ideally matched with the relatively long biological half-life of monoclonal antibodies in vivo. Radiometal labeling of antibodies requires the incorporation of a metal chelate onto the monoclonal antibody. This chelate must coordinate the metal under mild conditions required for the handling of antibodies, as well as provide high kinetic, thermodynamic, and metabolic stability once the metal ion is coordinated to prevent release of the radionuclide before the target site is reached in vivo. Herein, we review the role of different radiometals that have found applications of the design of radiolabeled antibodies for imaging and radioimmunotherapy. Each radionuclide is described regarding its nuclear synthesis, coordinative preference, and radiolabeling properties with commonly used and novel chelates, as well as examples of their preclinical and clinical applications. An overview of recent trends in antibody-based radiopharmaceuticals is provided to spur continued development of the chemistry and application of radiometals for imaging and therapy. PMID- 29230859 TI - Placenta microstructure and microcirculation imaging with diffusion MRI. AB - PURPOSE: To assess which microstructural models best explain the diffusion weighted MRI signal in the human placenta. METHODS: The placentas of nine healthy pregnant subjects were scanned with a multishell, multidirectional diffusion protocol at 3T. A range of multicompartment biophysical models were fit to the data, and ranked using the Bayesian information criterion. RESULTS: Anisotropic extensions to the intravoxel incoherent motion model, which consider the effect of coherent orientation in both microvascular structure and tissue microstructure, consistently had the lowest Bayesian information criterion values. Model parameter maps and model selection results were consistent with the physiology of the placenta and surrounding tissue. CONCLUSION: Anisotropic intravoxel incoherent motion models explain the placental diffusion signal better than apparent diffusion coefficient, intravoxel incoherent motion, and diffusion tensor models, in information theoretic terms, when using this protocol. Future work will aim to determine if model-derived parameters are sensitive to placental pathologies associated with disorders, such as fetal growth restriction and early onset pre-eclampsia. Magn Reson Med 80:756-766, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 29230860 TI - Cardiac gating using scattering of an 8-channel parallel transmit coil at 7T. AB - PURPOSE: To establish a cardiac signal from scattering matrix or scattering coefficient measurements made on a 7T 8-channel parallel transmit (pTx) system, and to evaluate its use for cardiac gating. METHODS: Measurements of the scattering matrix and scattering coefficients were acquired using a monitoring pulse sequence and during a standard cine acquisition, respectively. Postprocessing used an independent component analysis and gating feature identification. The effect of the phase of the excitation radiofrequency (RF) field ( B1+ shim) on the cardiac signal was simulated for multiple B1+ shim configurations, and cine images were reconstructed from both the scattering coefficients and electrocardiogram (ECG). RESULTS: The cardiac motion signal was successfully identified in all subjects with a mean signal-to-noise ratio of 33.1 and 5.7 using the scattering matrix and scattering coefficient measurements, respectively. The dominant gating feature in the cardiac signal was a peak aligned with end-systole that occurred on average at 311 and 391 ms after the ECG trigger, with a mean standard deviation of 13.4 and 18.1 ms relative to ECG when using the scattering matrix and scattering coefficients measurements, respectively. The scattering coefficients showed a dependence on B1+ shim with some shim configurations not showing any cardiac signal. Cine images were successfully reconstructed using the scattering coefficients with minimal differences compared to those using ECG. CONCLUSION: We have shown that the scattering of a pTx RF coil can be used to estimate a cardiac signal, and that scattering matrix and coefficients can be used to cardiac gate MRI acquisitions with the scattering matrix providing a superior cardiac signal. Magn Reson Med 80:633-640, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 29230861 TI - An uncommon cause of panniculitis. PMID- 29230862 TI - Patient perspectives on loss of local obstetrical services in rural northern Minnesota. AB - BACKGROUND: Obstetrical care has been declining in rural communities. We examined patient choices and perspectives from two rural northern Minnesota communities who lost their local obstetrical services in July 2015. Our purpose was to characterize obstetrical use patterns through the years leading to and following the closure and to explore the effects of the closure on these communities. METHODS: Information introducing the project and providing access to the survey was mailed to women who received prenatal care in the communities of interest. Responses were analyzed quantitatively and qualitatively. FINDINGS: Two hundred and one participants completed the survey with 356 deliveries reported from 1990 to 2016. Before the closure, there was a trend toward an increasing percentage of women electing regional delivery (P < .001); however, women were still 1.6 times more likely to choose local (62%) than regional (38%) delivery. Reasons for choosing delivery location changed over the decades. While birth experiences remained positive or extremely positive, anxiety about getting to the hospital rose 10-fold from 1990 to 2016 (5%-51%, P < .001). Women voiced substantial concern about the lack of local obstetrical services. Qualitative analysis revealed significant negative emotional reactions and concerns for the consequences of this loss for the viability of their rural communities. CONCLUSIONS: Choices and opinions about obstetric care have significantly changed from 1990 to 2016 in rural Minnesota. Understanding these changes can help address shifting risks and costs to rural communities here and elsewhere in an effort to support and sustain healthy, viable rural communities. PMID- 29230863 TI - Characterization of a Nilaparvata lugens (Stal) brummer gene and analysis of its role in lipid metabolism. AB - The brummer (bmm) genes encode the lipid storage droplet-associated triacylglycerols (TAG) lipases, which belong to the Brummer/Nutrin subfamily. These enzymes hydrolyze the ester bonds in TAG in lipid metabolism and act in insect energy homeostasis. Exposure to some agricultural chemicals leads to increased fecundity, which necessarily involves lipid metabolism, in some planthopper species. However, the biological roles of bmm in planthopper lipid storage and mobilization have not been investigated. Here, the open reading frame (ORF) of bmm (Nlbmm) was cloned and sequenced from the brown planthopper (BPH; Nilaparvata lugens). The ORF is 1014 bp encoding 338 amino acid residues. Nlbmm contained patatin domains and shared considerable evolutionary conservation with other insect bmms. Nlbmm is highly expressed in the fat body, consistent with its roles in lipid metabolism. Injection with Nlbmm double-stranded RNA (dsNlbmm) led to reduced Nlbmm mRNA accumulation, but did not influence expression of several genes related to lipid synthesis including acyl-CoA-binding protein (ACBP), acetyl-CoA carboxylase (ACC), and a lipophorin receptor (LpR). Nlbmm knockdown led to increased TAG contents in whole bodies, accumulation of total fat body lipid, and decreased hemolymph lipid content. Nlbmm knockdown did not influence the synthesis and distribution of glycerol. We infer that Nlbmm acts in TAG breakdown and fat metabolism in N. lugens. PMID- 29230864 TI - Complete magnetic field dependence of SABRE-derived polarization. AB - Signal amplification by reversible exchange (SABRE) is a promising hyperpolarization technique, which makes use of spin-order transfer from parahydrogen (the H2 molecule in its singlet spin state) to a to-be-polarized substrate in a transient organometallic complex, termed the SABRE complex. In this work, we present an experimental method for measuring the magnetic field dependence of the SABRE effect over an ultrawide field range, namely, from 10 nT to 10 T. This approach gives a way to determine the complete magnetic field dependence of SABRE-derived polarization. Here, we focus on SABRE polarization of spin-1/2 hetero-nuclei, such as 13 C and 15 N and measure their polarization in the entire accessible field range; experimental studies are supported by calculations of polarization. Features of the field dependence of polarization can be attributed to level anticrossings in the spin system of the SABRE complex. Features at magnetic fields of the order of 100 nT-1 MUT correspond to "strong coupling" of protons and hetero-nuclei, whereas features found in the mT field range stem from "strong coupling" of the proton system. Our approach gives a way to measuring and analyzing the complete SABRE field dependence, to probing NMR parameters of SABRE complexes and to optimizing the polarization value. PMID- 29230866 TI - Utility of HbA1c and fasting plasma glucose for screening of Type 2 diabetes: a meta-analysis of full ROC curves. AB - AIMS: There is still debate on the optimal threshold for population-based screening of diabetes (diagnosed by the oral glucose tolerance test) using tests like HbA1c or fasting plasma glucose. Meta-analyses provide meaningful input in such situations. The aim of this article is to perform a meta-analysis that includes the complete information reported in the individual studies of two existing systematic reviews. METHODS: We screened the individual studies from two systematic reviews and reconstructed the full four-fold tables for every reported threshold. Using a recently proposed meta-analysis model for the comparison of two diagnostic tests, we compared HbA1c with fasting plasma glucose, and estimated meta-analytic receiver operating characteristic curves for both tests using the 11.1 mmol/l threshold of the 2-h post-challenge glucose level (2 h-PG) as the gold standard. RESULTS: We included nine studies from two existing systematic reviews in our analysis. Based on our data set, the optimal threshold lies between 42 and 44 mmol/mol (6.0-6.2%) for HbA1c , and 6.2-6.4 mmol/l for fasting plasma glucose choosing the Youden index as the technical criterion. In addition, we found that there is no relevant difference in the performance of HbA1c and fasting plasma glucose. CONCLUSIONS: In our meta-analysis, we found that the optimal threshold with reference to the 2 h-PG should be chosen between 42 and 44 mmol/mol (6.0-6.2%) for HbA1c , and 6.2-6.4 mmol/l for fasting plasma glucose on the basis of maximal sensitivity and specificity. PMID- 29230867 TI - Sleep patterns and problems in infants and young children in Ireland. AB - BACKGROUND: There is an increasing recognition that sleep is an important aspect of health and well-being, and this is particularly the case in infancy and early childhood where sleep behaviours and patterns can result in substantial problems. METHODS: This paper draws on Wave 1, 2, and 3 data from Growing Up in Ireland, the national longitudinal study of children in Ireland to provide an overview of sleep patterns in a population of children aged 9 months (n = 11,112), 3 years (n = 9,790), and 5 years (n = 8,996). The anonymised data made available through the Irish Social Science Data Archive were analysed using descriptive statistics. RESULTS: Findings from the analysis show that about two thirds of infants (66.9%; n = 7,433) and just under 3 quarters of children aged 3 years (72.8%; n = 7,127) go to sleep between 7:00 p.m. and 9:00 p.m. and about 3 quarters (78.6%; n = 7,070) of 5-year-old children are in bed by 9:00 p.m. Just under half of infants (48.5%; n = 5,000) wake up between 7:00 a.m. and 8:00 a.m. and 13.5% (n = 1,500) wake up between 6:00 a.m. and 7:00 a.m. More than 80% (n = 8,889) of mothers report their 9-month-old infant wakes up at least occasionally and 13.8% report it happens every night. Almost all infants nap during the daytime, with the majority (56.0%; n = 6,222) doing so for between 1 and 2 hours. About one third (65.4%; n = 6,402) of 3-year-olds take daytime naps, but only 5.0% (n = 449) of 5 year-olds do so. Substantial proportions of mothers report children's sleep patterns are at least a small problem for them (ranging from about 30% (n = 3,333) in infancy to 22% (n = 2,444) at 3 years and 12% (n = 1,079) at 5 years). CONCLUSIONS: These findings highlight a substantial unmet need, and it is suggested that public health nurses and health visitors have a key role to play in supporting positive sleep patterns in early childhood. PMID- 29230865 TI - Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy. AB - Epileptogenesis is the process of developing an epileptic condition and/or its progression once it is established. The molecules that initiate, promote, and propagate remarkable changes in the brain during epileptogenesis are emerging as targets for prevention/treatment of epilepsy. Epileptogenesis is a continuous process that follows immediately after status epilepticus (SE) in animal models of acquired temporal lobe epilepsy (TLE). Both SE and epileptogenesis are potential therapeutic targets for the discovery of anticonvulsants and antiepileptogenic or disease-modifying agents. For translational studies, SE targets are appropriate for screening anticonvulsive drugs prior to their advancement as therapeutic agents, while targets of epileptogenesis are relevant for identification and development of therapeutic agents that can either prevent or modify the disease or its onset. The acute seizure models do not reveal antiepileptogenic properties of anticonvulsive drugs. This review highlights the important components of epileptogenesis and the long-term impact of intervening one of these components, nitric oxide (NO), in rat and mouse kainate models of TLE. NO is a putative pleotropic gaseous neurotransmitter and an important contributor of nitro-oxidative stress that coexists with neuroinflammation and epileptogenesis. The long-term impact of inhibiting the glial source of NO during early epileptogenesis in the rat model of TLE is reviewed. The importance of sex as a biological variable in disease modification strategies in epilepsy is also briefly discussed. PMID- 29230868 TI - Frequency distribution of osteochondral fragmentation of the dorsoproximal articular surface of the proximal phalanx in racing Thoroughbreds in the UK. AB - BACKGROUND: Osteochondral fragmentation of the dorsoproximal margin of the proximal phalanx is commonly recognised in racing Thoroughbreds. Frequency distribution has been documented in racing Thoroughbreds and Quarter Horses in the USA and in European Warmbloods but no data have been published from the UK. Concurrent intra-articular soft tissue lesions and radiographic accuracy of fragment distribution in racing Thoroughbreds have not previously been reported. OBJECTIVES: To document frequency distribution of dorsoproximal fragmentation of the proximal phalanx in a UK population of racing Thoroughbreds and to compare this with published data. To document concurrent intra-articular lesions identified arthroscopically and radiographic accuracy of fragment distribution. STUDY DESIGN: A retrospective single centre-based, observational study. METHODS: Surgical reports and radiographs of all racing Thoroughbreds that underwent arthroscopic surgery for removal of fragmentation from the dorsoproximal margin of the proximal phalanx at Newmarket Equine Hospital between 2011 and 2015 were reviewed. RESULTS: Two hundred and forty-two (85.8%) horses were in or being prepared for flat racing. Osteochondral fragmentation of the dorsoproximal aspect of the proximal phalanx was present in 428 fetlock joints of 282 horses, consisting of 194 (45.3%) left and 188 (43.9%) right metacarpophalangeal joints, and 20 (4.7%) left and 26 (6.1%) right metatarsophalangeal joints. Fragmentation was located dorsomedially in 316 (73.8%), dorsolaterally in 32 (7.5%) and biaxially in 80 (18.7%) joints. Concurrent soft tissue lesions were identified in 168 (39.3%) joints. Radiographic evidence of fragmentation was visible in 320 joints (74.8%). MAIN LIMITATIONS: Limited numbers preclude conclusions with respect to yearlings and horses in jump race training. CONCLUSION: Dorsoproximal fragmentation of the proximal phalanx occurred most frequently medially and in the forelimbs. Sidedness was not demonstrated. Although similar to previously reported data, variance in limb distribution is evident. Further research is required to determine whether concurrent intra-articular soft tissue lesions are aetiopathogenic or an additional result of the pathological changes leading to fragmentation. Fragmentation site was not always accurately identified radiographically. The Summary is available in Spanish - see Supporting information. PMID- 29230869 TI - Microvascular replantation of a composite facial avulsion in a 24-month-old child after dog bite. AB - Dog bite injuries are common sources of morbidity with an estimated incidence of 4.5 million bites per year with over 350,000 requiring treatment in the emergency room. Children under the age of 14 are most likely to be affected with a peak age of 5-9 years old. We report a case of a 24-month-old female who sustained a large composite facial avulsion injury from a pit bull dog bite. The avulsed tissue involved a substantial portion of the patient's mid-face, including the entire soft tissue of the nose, upper lip, part of the left cheek, and left oral commissure. Artery-only microvascular replantation was performed because no recipient vein could be identified from the facial defect. Medicinal leech therapy was used for eight days postoperatively to prevent venous congestion. The patient experienced significant blood loss due to leech therapy and required nearly 29 L of blood product replacement. At the last follow up of 8 months postoperatively, the patient was recovering well with significant improvement in function and cosmesis of the mid-face. This case describes a successful artery only replantation of an avulsive bite injury to the face of a young child. Despite the technical difficulty of cases such as this one, microvascular replantation should be attempted because when successful it provides a superior cosmetic and functional result to other reconstructive techniques. PMID- 29230870 TI - Orchestrated approaches using pure shift NMR: Extraction of spectral parameters, ultra-high resolution, and sensitivity enhancement. AB - The limited chemical shift range of protons and pairwise interaction among all the abundant nuclear spins of a molecule makes 1 H spectrum too complicated. As a consequence, the straightforward analysis and the accurate extraction of their interaction strengths from the 1 H spectrum of a complex spin system are formidably difficult or often impossible. This problem persists in the determination of scalar couplings be it between two abundant homonuclear spins or between 1 H and an abundant heteronuclear spin (viz., 19 F and 31 P). Such problems are encountered in many situations where the determination of homonuclear and heteronuclear couplings is challenging. The several pure shift based one-dimensional and two-dimensional NMR strategies recently developed in our laboratory for the straightforward extraction of homonuclear and heteronuclear interaction parameters in diverse situations are discussed. Initially, the unique application of pure shift technique that paves the way for easy and straightforward extraction of magnitudes of heteronuclear couplings, namely, n JHX (where X stands for 19 F, 31 P, etc.), is discussed. Subsequently, several pure shift edited one-dimensional and two-dimensional NMR strategies that are developed for the direct extraction of homonuclear and heteronuclear couplings and for achieving ultra-high-resolved 1 H spectra with complete eradication of zero frequency peaks and the evolution of unwanted couplings. The enhancement in the sensitivity has also been achieved in the slice-selective pure shift experiments by the rapid acquisition of proton spectrum where the polarization from the adjacent protons is transferred to the selectively excited proton. PMID- 29230872 TI - Ageing in India: Financial hardship from health expenditures. AB - India's rapidly ageing population raises concerns about the burden of health care payments among older individuals who may have both limited income and greater health care needs. Using a nationally representative household survey, we investigate the association between age and financial hardship due to health expenditures. We find that both the probability of experiencing health problems and mean total out-of-pocket health expenditures increase with age. Second, the probability of households experiencing catastrophic health expenditures increases with each additional member aged 60 and above-33% of households with one 60+ member and 38% of households with 2 or more 60+ members experienced catastrophic health expenditures, compared to only 20% in households with all members under the age of 60 years. Lastly, we show that individuals aged 60 and above had a much higher probability of becoming impoverished as a result of health expenditures-the probability of impoverishment for 60+ individuals was 3 percentage points higher than for individuals under the age of 60. Overall, around 4.8% of the older population, representing 4.1 million people, fell into poverty. The results suggest that there is an urgent need for public investments in financial protection programs for older people in India. PMID- 29230871 TI - Prospective motion correction enables highest resolution time-of-flight angiography at 7T. AB - PURPOSE: Higher magnetic field strengths enable time-of-flight (TOF) angiography with higher resolution to depict small-vessel pathologies. However, this potential is limited by the subject's ability to remain motionless. Even small scale, involuntary motion can degrade vessel depiction, thus limiting the effective resolution. The aim of this study was to overcome this resolution limit by deploying prospectively motion-corrected (PMC) TOF. METHODS: An optical, marker-based, in-bore tracking system was used to update the imaging volume prospectively according to the subject's head motion. PMC TOF was evaluated in 12 healthy, cooperative subjects at isotropic resolution of up to 150 MUm. Image quality was assessed qualitatively through reader rating and quantitatively with the average edge-strength metric. RESULTS: PMC significantly increased the average edge strength and qualitatively improved the vessel depiction in nine out of 11 cases. Image quality was never degraded by motion correction. PMC also enabled acquisition of the highest resolution human brain in vivo TOF angiography to date. CONCLUSION: With PMC enabled, high-resolution TOF is able to visualize brain vasculature beyond the effective resolution limit. Magn Reson Med 80:248 258, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29230873 TI - Noncoded amino acids in protein engineering: Structure-activity relationship studies of hirudin-thrombin interaction. AB - The advent of recombinant DNA technology allowed to site-specifically insert, delete, or mutate almost any amino acid in a given protein, significantly improving our knowledge of protein structure, stability, and function. Nevertheless, a quantitative description of the physical and chemical basis that makes a polypeptide chain to efficiently fold into a stable and functionally active conformation is still elusive. This mainly originates from the fact that nature combined, in a yet unknown manner, different properties (i.e., hydrophobicity, conformational propensity, polarizability, and hydrogen bonding capability) into the 20 standard natural amino acids, thus making difficult, if not impossible, to univocally relate the change in protein stability or function to the alteration of physicochemical properties caused by amino acid exchange(s). In this view, incorporation of noncoded amino acids with tailored side chains, allowing to finely tune the structure at a protein site, would facilitate to dissect the effects of a given mutation in terms of one or a few physicochemical properties, thus much expanding the scope of physical organic chemistry in the study of proteins. In this review, relevant applications from our laboratory will be presented on the use of noncoded amino acids in structure-activity relationships studies of hirudin binding to thrombin. PMID- 29230874 TI - Symmetric Dimethylarginine in Cats with Hypertrophic Cardiomyopathy and Diabetes Mellitus. AB - BACKGROUND: Symmetric dimethylarginine (SDMA) has been increasingly used as a marker of early chronic kidney disease (CKD) in cats, but little is known about the influence of comorbidities on SDMA in this species. HYPOTHESIS: Hypertrophic cardiomyopathy (HCM) and diabetes mellitus (DM), independently of CKD, are associated with changes in serum SDMA. ANIMALS: Ninety-four cats (17 with CKD, 40 with HCM, 17 with DM, and 20 healthy controls). METHODS: Case-control study. Clinical examination, echocardiography, ECG, blood pressure, CBC, biochemistry, thyroxine, and SDMA measurement were performed. Urinalysis was performed in controls and cats with CKD and DM. Analysis of variance was used to compare overall differences in the log-transformed SDMA data among groups. A random forest algorithm was applied to explore which clinical and other factors influenced serum SDMA. RESULTS: Median (range) serum SDMA for the renal group (positive control) was 19 (10-93) MUg/dL, whereas for the control group (negative control), it was 10 (5-15) MUg/dL. For the cardiac and diabetic groups, serum SDMA was 9 (4-24) MUg/dL and 7 (3-11) MUg/dL, respectively. The renal group had significantly higher SDMA concentrations and the diabetic group significantly lower SDMA concentrations compared to all other groups. CONCLUSIONS AND CLINICAL IMPORTANCE: Serum SDMA concentrations in cats with HCM were not significantly different from those of healthy control cats. Cats with DM, however, had significantly lower SDMA concentrations than controls, a finding that needs further investigation and should be kept in mind when evaluating renal function of cats with this endocrinopathy. PMID- 29230876 TI - On individual-specific prediction of hidden inbreeding depression load. AB - Inbreeding depression is caused by increased homozygosity in the genome and merges two genetic mechanisms, a higher impact from recessive mutations and the waste of overdominance contributions. It is of major concern for the conservation of endangered populations of plants and animals, as major abnormalities are more frequent in inbred families than in outcrosses. Nevertheless, we lack appropriate analytical methods to estimate the hidden inbreeding depression load (IDL) in the genome of each individual. Here, a new mixed linear model approach has been developed to account for the inbreeding depression-related background of each individual in the pedigree. Within this context, inbred descendants contributed relevant information to predict the IDL contained in the genome of a given ancestor; moreover, known relationships spread these predictions to the remaining individuals in the pedigree, even if not contributing inbred offspring. Results obtained from the analysis of weaning weight in the MARET rabbit population demonstrated that the genetic background of inbreeding depression distributed heterogeneously across individuals and inherited generation by generation. Moreover, this approach was clearly preferred in terms of model fit and complexity when compared with classical approaches to inbreeding depression. This methodology must be viewed as a new tool for a better understanding of inbreeding in domestic and wild populations. PMID- 29230875 TI - Kinetics of Plasma Cell-Free DNA and Creatine Kinase in a Canine Model of Tissue Injury. AB - BACKGROUND: Cell-free DNA (cfDNA) comprises short, double-stranded circulating DNA sequences released from damaged cells. In people, cfDNA concentrations correlate well with disease severity and tissue damage. No reports are available regarding cfDNA kinetics in dogs. OBJECTIVES/HYPOTHESIS: Cell-free DNA will have a short biological half-life and would be able to stratify mild, moderate, and severe tissue injury. Our study aims were to determine the kinetics and biological half-life of cfDNA and to contrast them with those of creatine kinase (CK). ANIMALS: Three groups of 10 dogs undergoing open ovariohysterectomy, surgery for cranial cruciate ligament rupture (CCLR), or hemilaminectomy. METHODS: Plasma for cfDNA and CK analysis was collected at admission, at induction of anesthesia, postsurgery (time 0) and at 6, 12, 24, 36, 48, 60, and 72 hours after surgery. RESULTS: The biological half-life of plasma cfDNA and CK were 5.64 hours (95% confidence interval [CI 95], 4.36-7.98 hours) and 28.7 hours (CI95, 25.3-33.3 hours), respectively. In the hemilaminectomy group, cfDNA concentrations differed significantly from admission at 6-12 hours after surgery. Creatine kinase activity differed among the surgical groups and reached a peak 6 hours after surgery. In the ovariohysterectomy and CCLR groups, plasma CK activity 72 hours after surgery did not differ from admission activity of the ovariohysterectomy group. In contrast, in the hemilaminectomy group, plasma CK activity after 72 hours did not return to the ovariohysterectomy group admission activity. CONCLUSIONS AND CLINICAL IMPORTANCE: Plasma CK activity has a longer biological half-life than previously thought. In contrast to plasma CK activity, cfDNA has a short half-life and could be a useful marker for peracute severe tissue injury. PMID- 29230877 TI - Neonatal mouse cortical but not isogenic human astrocyte feeder layers enhance the functional maturation of induced pluripotent stem cell-derived neurons in culture. AB - Human induced pluripotent stem (iPS) cell-derived neurons and astrocytes are attractive cellular tools for nervous system disease modeling and drug screening. Optimal utilization of these tools requires differentiation protocols that efficiently generate functional cell phenotypes in vitro. As nervous system function is dependent on networked neuronal activity involving both neuronal and astrocytic synaptic functions, we examined astrocyte effects on the functional maturation of neurons from human iPS cell-derived neural stem cells (NSCs). We first demonstrate human iPS cell-derived NSCs can be rapidly differentiated in culture to either neurons or astrocytes with characteristic cellular, molecular and physiological features. Although differentiated neurons were capable of firing multiple action potentials (APs), few cells developed spontaneous electrical activity in culture. We show spontaneous electrical activity was significantly increased by neuronal differentiation of human NSCs on feeder layers of neonatal mouse cortical astrocytes. In contrast, co-culture on feeder layers of isogenic human iPS cell-derived astrocytes had no positive effect on spontaneous neuronal activity. Spontaneous electrical activity was dependent on glutamate receptor-channel function and occurred without changes in INa , IK , Vm , and AP properties of iPS cell-derived neurons. These data demonstrate co culture with neonatal mouse cortical astrocytes but not human isogenic iPS cell derived astrocytes stimulates glutamatergic synaptic transmission between iPS cell-derived neurons in culture. We present RNA-sequencing data for an immature, fetal-like status of our human iPS cell-derived astrocytes as one possible explanation for their failure to enhance synaptic activity in our co-culture system. PMID- 29230879 TI - MicroRNA 143-5p regulates alpaca melanocyte migration, proliferation and melanogenesis. AB - microRNAs (miRNAs) have been shown to be closely involved in the control of melanogenesis and hair colour in mammals. Previous data also indicate that miR 143 regulates cell growth in melanoma. Here, we aimed to investigate the role of miR-143-5p in alpaca melanocytes. We found that miR-143-5p was highly expressed in the cytoplasm of alpaca melanocytes as demonstrated by an in situ hybridization assay. Prediction analysis revealed that miR-143-5p could regulate TGF-beta-activated kinase 1 (TAK1) expression, which we confirmed by luciferase reporter assay, indicating that miR-143-5p controls TAK1 expression by directly targeting its 3' untranslated region (UTR). miR-143-5p overexpression decreased TAK1 expression, which led to increased melanocyte migration and proliferation, and downregulation of microphthalmia-associated transcription factor (MITF), which regulates melanin production. These results support a functional role for miR-143-5p in regulating alpaca melanocyte migration, proliferation and melanogenesis through direct targeting of TAK1. PMID- 29230878 TI - A randomized controlled pilot study of continuous glucose monitoring and flash glucose monitoring in people with Type 1 diabetes and impaired awareness of hypoglycaemia. AB - AIM: Hypoglycaemia in Type 1 diabetes is associated with mortality and morbidity, especially where awareness of hypoglycaemia is impaired. Clinical pathways for access to continuous glucose monitoring (CGM) and flash glucose monitoring technologies are unclear. We assessed the impact of CGM and flash glucose monitoring in a high-risk group of people with Type 1 diabetes. METHODS: A randomized, non-masked parallel group study was undertaken. Adults with Type 1 diabetes using a multiple-dose insulin-injection regimen with a Gold score of >= 4 or recent severe hypoglycaemia were recruited. Following 2 weeks of blinded CGM, they were randomly assigned to CGM (Dexcom G5) or flash glucose monitoring (Abbott Freestyle Libre) for 8 weeks. The primary outcome was the difference in time spent in hypoglycaemia (below 3.3 mmol/l) from baseline to endpoint with CGM versus flash glucose monitoring. RESULTS: Some 40 participants were randomized to CGM (n = 20) or flash glucose monitoring (n = 20). The participants (24 men, 16 women) had a median (IQR) age of 49.6 (37.5-63.5) years, duration of diabetes of 30.0 (21.0-36.5) years and HbA1c of 56 (48-63) mmol/mol [7.3 (6.5-7.8)%]. The baseline median percentage time < 3.3 mmol/l was 4.5% in the CGM group and 6.7% in the flash glucose monitoring. At the end-point the percentage time < 3.3 mmol/l was 2.4%, and 6.8% respectively (median between group difference -4.3%, P = 0.006). Time spent in hypoglycaemia at all thresholds, and hypoglycaemia fear, were different between groups, favouring CGM. CONCLUSION: CGM more effectively reduces time spent in hypoglycaemia in people with Type 1 diabetes and impaired awareness of hypoglycaemia compared with flash glucose monitoring. (Clinical Trial Registry No: NCT03028220). PMID- 29230880 TI - Angiosarcoma of the right atrium and right ventricle. PMID- 29230881 TI - Variance component analysis to assess protein quantification in biomarker discovery. Application to MALDI-TOF mass spectrometry. AB - Controlling the technological variability on an analytical chain is critical for biomarker discovery. The sources of technological variability should be modeled, which calls for specific experimental design, signal processing, and statistical analysis. Furthermore, with unbalanced data, the various components of variability cannot be estimated with the sequential or adjusted sums of squares of usual software programs. We propose a novel approach to variance component analysis with application to the matrix-assisted laser desorption/ionization time of-flight (MALDI-TOF) technology and use this approach for protein quantification by a classical signal processing algorithm and two more recent ones (BHI-PRO 1 and 2). Given the high technological variability, the quantification failed to restitute the known quantities of five out of nine proteins present in a controlled solution. There was a linear relationship between protein quantities and peak intensities for four out of nine peaks with all algorithms. The biological component of the variance was higher with BHI-PRO than with the classical algorithm (80-95% with BHI-PRO 1, 79-95% with BHI-PRO 2 vs. 56-90%); thus, BHI-PRO were more efficient in protein quantification. The technological component of the variance was higher with the classical algorithm than with BHI PRO (6-25% vs. 2.5-9.6% with BHI-PRO 1 and 3.5-11.9% with BHI-PRO 2). The chemical component was also higher with the classical algorithm (3.6-18.7% vs. < 3.5%). Thus, BHI-PRO were better in removing noise from signal when the expected peaks are detected. Overall, either BHI-PRO algorithm may reduce the technological variance from 25 to 10% and thus improve protein quantification and biomarker validation. PMID- 29230883 TI - Real-time homonuclear broadband decoupled pure shift COSY. AB - The present manuscript reports development and applications of real-time homonuclear broadband decoupled pure shift version of in-phase zero-quantum filtered COSY (PS-IPZF-COSY) and clean in-phase COSY (PS-CLIP-COSY) pulse schemes. In contrast to the conventional COSY schemes, these pure shift versions provide enhanced spectral resolution and simplify the chemical shift correlation analysis of scalar coupled spins in complex organic molecules, which are exemplified for erythromycin A, estradiol, and a mixture of estradiol and testosterone. PMID- 29230884 TI - Stereoselective Ring-Opening of gem-Difluorocyclopropanes: An Entry to Stereo defined (E,E)- and (E,Z)-Conjugated Fluorodienes. AB - The ring-opening of gem-difluorocyclopropyl acetaldehydes producing selectively (E,E)- and (E,Z)-conjugated fluorodienals is described. Two stereo-divergent methods are presented to access both stereoisomers from a common precursor, in high yield and selectivity. The mechanistic aspect of these transformations is discussed. PMID- 29230882 TI - Molecular profiling and genome-wide analysis based on somatic copy number alterations in advanced colorectal cancers. AB - To characterize somatic alterations in colorectal cancer (CRC), we conducted a genome-scale analysis of 106 CRC specimens. We assessed comprehensive somatic copy number alterations (SCNAs) in these CRC specimens. In addition, we examined microsatellite instability (MSI; low and high), genetic mutations (KRAS, BRAF, TP53, and PIK3CA), and DNA methylation status (classified into low, intermediate, and high type). We stratified molecular alterations in the CRCs using a hierarchical cluster analysis. The examined CRCs could be categorized into three subgroups using hierarchical cluster analysis. Tumors in subgroup 1 were characterized by a low frequency of SCNAs and a high frequency of MSI-high status, whereas tumors in subgroups 2 and 3 were closely associated with a high frequency of SCNAs. Tumors in subgroup 1 were preferentially present in the right sided colon and showed frequent MSI-high status. Subgroup 3 was distinguished by specific alterations, including gains at 1q23-44, 1p11-36, 10q11-26, 10p11-13, 12q24-24, and 13q33-33. In contrast, tumors in subgroup 2 were characterized by copy-neutral LOH at 12p12-13, 1q24-25, and 10q22. In addition, KRAS mutations were more frequently found in subgroup 3 than in subgroup 1. TP53 mutations and intermediate levels of DNA methylation were common alterations in the three subgroups. SCNAs contributed to sporadic CRC, and there were three subgroups based on SCNAs that played a different role in driving the development of this disease. PMID- 29230886 TI - Carbothermal Reduction Induced Ti3+ Self-Doped TiO2 /GQD Nanohybrids for High Performance Visible Light Photocatalysis. AB - A facile calcination method is developed for the in situ synthesis of nanohybrids of Ti3+ self-doped TiO2 /graphene quantum dot nanosheets (Ti3+ -TiO2 /GQD NSs). Ti3+ sites are formed on the surface of the TiO2 nanosheets through carbothermal reduction by GQDs, using citric acid as a carbon source. Such heterojunctions exhibit enhanced visible-light absorption properties, large photocurrent current densities, and low recombination of photoinduced carriers. The methylene blue (MB) and rhodamine B (RhB) photodegradation result demonstrates a higher visible light photocatalysis performance than that of the original TiO2 . On one hand, inducing Ti3+ sites is efficient for the separation of photogenerated charge carriers and for reducing electron-hole pair recombination. On the other hand, GQDs are beneficial for generating more photocurrent carriers and facilitating the charge transfer across the TiO2 surface. It is proposed that Ti3+ sites and GQDs induced in TiO2 nanosheets have a synergistic effect, leading to excellent photocatalysis properties. Finally, a theoretical calculation is provided of the carbothermal reduction for the formation mechanism of the Ti3+ defect sites. PMID- 29230885 TI - Intercellular Transfer of Microvesicles from Young Mesenchymal Stromal Cells Rejuvenates Aged Murine Hematopoietic Stem Cells. AB - Donor age is one of the major concerns in bone marrow transplantation, as the aged hematopoietic stem cells (HSCs) fail to engraft efficiently. Here, using murine system, we show that a brief interaction of aged HSCs with young mesenchymal stromal cells (MSCs) rejuvenates them and restores their functionality via inter-cellular transfer of microvesicles (MVs) containing autophagy-related mRNAs. Importantly, we show that MSCs gain activated AKT signaling as a function of aging. Activated AKT reduces the levels of autophagy related mRNAs in their MVs, and partitions miR-17 and miR-34a into their exosomes, which upon transfer into HSCs downregulate their autophagy-inducing mRNAs. Our data identify previously unknown mechanisms operative in the niche mediated aging of HSCs. Inhibition of AKT in aged MSCs increases the levels of autophagy-related mRNAs in their MVs and reduces the levels of miR-17 and miR-34a in their exosomes. Interestingly, transplantation experiments showed that the rejuvenating power of these "rescued" MVs is even better than that of the young MVs. We demonstrate that such ex vivo rejuvenation of aged HSCs could expand donor cohort and improve transplantation efficacy. Stem Cells 2018;36:420-433. PMID- 29230887 TI - Integration of molecular dynamics simulation and hotspot residues grafting for de novo scFv design against Salmonella Typhi TolC protein. AB - With the development of de novo binders for protein targets from non-related scaffolds, many possibilities for therapeutics and diagnostics have been created. In this study, we described the use of de novo design approach to create single chain fragment variable (scFv) for Salmonella enterica subspecies enterica serovar Typhi TolC protein. Typhoid fever is a global health concern in developing and underdeveloped countries. Rapid typhoid diagnostics will improve disease management and therapy. In this work, molecular dynamics simulation was first performed on a homology model of TolC protein in POPE membrane bilayer to obtain the central structure that was subsequently used as the target for scFv design. Potential hotspot residues capable of anchoring the binders to the target were identified by docking "disembodied" amino acid residues against TolC surface. Next, scFv scaffolds were selected from Protein Data Bank to harbor the computed hotspot residues. The hotspot residues were then incorporated into the scFv scaffold complementarity determining regions. The designs recapitulated binding energy, shape complementarity, and interface surface area of natural protein-antibody interfaces. This approach has yielded 5 designs with high binding affinity against TolC that may be beneficial for the future development of antigen-based detection agents for typhoid diagnostics. PMID- 29230888 TI - The status of support for cannabis regulation in Uruguay 4 years after reform: Evidence from public opinion surveys. AB - INTRODUCTION AND AIMS: The objective of this study was to measure the public support for marijuana legalisation in Uruguay, both overall and in its provisions, in nearly 4 years after its implementation. DESIGN AND METHODS: Three separate cross-national surveys were conducted in early 2014, late 2015 and mid 2017 with national representative samples of adults. The first study was carried out during the initial months of implementation of the law and used face-to-face interviews (N = 1490); the second survey was conducted using a computer-assisted telephone interviewing system (N = 703); and the third study (N = 1515), using face-to-face interviews, was completed just before the implementation of pharmacy sales. RESULTS: About 60.7% of respondents in 2014 were against marijuana legalisation; in 2017, 54.1% remained opposed to the marijuana law. In 2015, half of the people interviewed (49.9%) supported access to marijuana through self cultivation, while 38.6% favoured the provision of cannabis clubs and 33.1% agreed with the pharmacy retail provision. Support for medical cannabis was high in 2015, with 74.5% favouring it. DISCUSSION AND CONCLUSIONS: This study shows a change in the public opinion toward legalisation of marijuana although most people still remain opposed to the law. However, the data do not provide indication of a significant change in its use. Results suggest that opposition to legalisation may be focused on the pharmacy retail provision. PMID- 29230889 TI - Use of personal protective equipment in a radiology room at a veterinary teaching hospital. AB - The use of personal protective equipment by veterinary workers during radiographic imaging is inconsistent. While the self-reported use of leaded aprons and thyroid shields approaches 100% in some studies, the use of leaded gloves and eyeglasses is much lower. Previous studies describing personal protective equipment use are based on self-reporting. Objectives of this prospective, observational study were to describe use of leaded personal protective equipment during radiographic imaging by veterinary workers, and to compare observed use with self-reported use. Use of leaded personal protective equipment during radiographic imaging by veterinary workers was observed over a 10 week period using two motion-triggered video cameras, and a questionnaire was then completed by workers on their use of personal protective equipment. Workers restrained the animal during 91.8% (753/820) of exposures. An apron and a securely closed thyroid shield were worn for >99% of studies. Gloves were used correctly for 43.6% (156/358) of radiographic studies. Leaded eyeglasses were worn for 1.7% (6/358) of studies. Correct glove use was more frequent during regular working hours than after-hours for both veterinarians (odds ratio 32.7, P = 0.001) and veterinary students (odds ratio 75.1, P < 0.001). The number of workers in the room was lower when animals were sedated (P = 0.002) or anesthetized (P = 0.017). Workers overestimated their frequency of glove use (P <0.001). In conclusion, workers use personal protective equipment less frequently in an unsupervised environment, and overestimate their use of personal protective equipment. Use of sedation or anesthesia decreases worker exposure to ionizing radiation. PMID- 29230891 TI - Linking individual-level data on diagnoses and dispensing for research on antibiotic use: Evaluation of a novel data source from English secondary care. AB - PURPOSE: There has been a focus on stewardship programmes to curb inappropriate antibiotic prescribing and reduce antimicrobial resistance. In-hospital, patient level prescribing linked to indication is needed to support surveillance, evaluation of stewardship initiatives, as well as other antibiotic research. We evaluated whether a novel dataset linking hospital pharmacy records to Hospital Episode Statistics data can be used for antibiotic research. METHODS: Using the Hospital Treatment Insights (HTI) database, which links Hospital Episode Statistics to pharmacy records from 43 out of 153 hospital trusts in England, we estimated the proportion of missed linkage and identified characteristics associated with missing data. RESULTS: Linkage of antibiotics to patients was inconsistent and dependent on drug type and clinical setting, so that linkage for some specific antibiotics was high (80-100%), but overall, only 27.6% (CI: 27.4% 27.8%) for all antibiotics dispensed. Linkage was best for quinolones (62.6%; CI: 61.8%-63.8%), but only 21.1% (CI: 21.1%-21.2%) for penicillins. Linkage was lower for common antibiotics and in emergency departments; however, 80% linkage was achieved for individual drugs like clindamycin, especially on wards with reduced ward stock use. CONCLUSIONS: For those antibiotics with high linkage, HTI might be used to study associations between indication, dispensing, and outcomes. However, the majority of common antibiotics had insufficient linkage, likely due to extensive use of ward stocks. Therefore, HTI in its current form is not suitable for general antibiotic surveillance or evaluation of stewardship initiatives. For drugs in HTI other than antibiotics, linkage should be similarly evaluated before a study is conducted. PMID- 29230890 TI - Effects of analgesics on bone mineral density: A longitudinal analysis of the prospective SWAN cohort with three-group matching weights. AB - PURPOSE: To examine the effects of analgesics on bone mineral density (BMD), which have not been examined in a longitudinal study with multiple measurements. METHODS: We investigated changes in BMD associated with new use of analgesics in a prospective longitudinal cohort of mid-life women. BMD and medication use were measured annually. We compared BMD among new users of acetaminophen, NSAIDs, and opioids. Adjustment for baseline covariates was conducted through propensity score matching weights. On-treatment analysis was conducted with inverse probability of censoring weights. Analysis based on the initial treatment group was also conducted to provide insights into selection bias. Repeated BMD measurements were examined with generalized estimating equations. RESULTS: We identified 71 acetaminophen new users, 659 NSAID new users, and 84 opioid new users among 2365 participants. In the on-treatment analysis, the opioid group in comparison to the acetaminophen group had an additional average BMD decline of 0.06% [-1.24, 1.11] per year in the spine and -0.45% [-1.51, 0.61] per year in the femoral neck. BMD mean trajectories over time suggested a fifth-year decline in the opioid persistent users compared with other 2 groups. In the initial treatment group analysis, all 3 groups showed similar trajectories. CONCLUSION: The BMD decline over time was similar among the 3 groups. However, 5 years of continuous opioid use may be associated with a greater BMD decline than 5 years on other analgesics. Further studies examining the relationship between very long term persistent opioid use and BMD are warranted. PMID- 29230892 TI - Stable ZnI -Containing MOFs with Large [Zn70 ] Nanocages from Assembly of ZnII Ions and Aromatic [ZnI8 ] Clusters. AB - Two unique ZnI -containing MOFs {[ZnI8 ZnII3 (H2 O)x (HL)12 ](OH)2 ?13 H2 O}n (x=6, 1; x=2, 2) (HL=tetrazole monoanion) with high-nuclearity Zn-cages were prepared successfully. These Zn-cages are constructed from [ZnI8 ] clusters with multi-centered ZnI -ZnI bonds and ZnII ions. [ZnI8 ] clusters in 1 and 2 display Oh and D4h symmetry, respectively. Importantly, eight [ZnI8 ] clusters and six ZnII ions form a large [Zn70 ] nanocage in 1. To our knowledge, this is the first MOF based on polynuclear Zn-cages consisting of ZnI and ZnII ions. Compared with reported ZnI -species, 1 and 2 display high thermal and solvent stabilities. Theoretical investigations based on DFT calculations uncover that effective 4s-4s orbital overlap and electron delocalization through these a1g +t1u molecular orbitals on [ZnI8 ] clusters lead to considerable aromatic stabilization, which can explain well the intrinsic stability of 1 and 2. Interestingly, 1 can behave as a luminescent probe to detect the toxic CrVI ions in aqueous. PMID- 29230894 TI - Vouchers for primary healthcare services in an ageing world? The perspectives of elderly voucher recipients in Hong Kong. AB - Considering the ageing population in economically advanced regions across the world, measures are necessary to enhance the health of the older population as well as contain public healthcare spending. Hong Kong implements the Elderly Health Care Voucher Scheme (EHCVS), providing older people aged 65 or above an annual subsidy of visiting private healthcare service providers for chronic disease prevention and management. The services also aim at reallocating demand from the public to private sector as well as improve quality of services. This qualitative study explored the experiences of EHCVS recipients (n = 55, aged 61 94) with eight focus group interviews in Hong Kong in the year 2016. Convenience sampling was used. Research questions were: (1) Why do older people choose not to use EHCVS for preventive as well as disease management services among older people in Hong Kong? (2) What are the barriers to reallocating demand from the public to private sector? (3) In what ways did EHCVS improve the quality of primary care services for older people? Using a deductive and inductive approach, eight qualitative themes were identified. Findings suggested that the non targeted services and inadequate knowledge on EHCVS deterred older people from using the vouchers for disease management and prevention. The relatively expensive private services, lack of trust in the private sector, low public clinic fees and good services quality of the public sector, together with inadequate private practitioners in the healthcare market were barriers that hinder demand reallocation. Nevertheless, the quality of primary care services had been improved after the implementation of EHCVS with shortened wait times and opportunities to discuss health-related issues with private practitioners. Findings were discussed with practice, policy and research implications. PMID- 29230893 TI - Microbial communities exhibit host species distinguishability and phylosymbiosis along the length of the gastrointestinal tract. AB - Host-associated microbial communities consist of stable and transient members that can assemble through purely stochastic processes associated with the environment or by interactions with the host. Phylosymbiosis predicts that if host-microbiota interactions impact assembly patterns, then one conceivable outcome is concordance between host evolutionary histories (phylogeny) and the ecological similarities in microbial community structures (microbiota dendrogram). This assembly pattern has been demonstrated in several clades of animal hosts in laboratory and natural populations, but in vertebrates, it has only been investigated using samples from faeces or the distal colon. Here, we collected the contents of five gut regions from seven rodent species and inventoried the bacterial communities by sequencing the 16S rRNA gene. We investigated how community structures varied across gut regions and whether the pattern of phylosymbiosis was present along the length of the gut. Gut communities varied by host species and gut region, with Oscillospira and Ruminococcus being more abundant in the stomach and hindgut regions. Gut microbial communities were highly distinguishable by host species across all gut regions, with the strength of the discrimination increasing along the length of the gut. Last, the pattern of phylosymbiosis was found in all five gut regions, as well as faeces. Aspects of the gut environment, such as oxygen levels, production of antimicrobials or other factors, may shift microbial communities across gut regions. However, regardless of these differences, host species maintain distinguishable, phylosymbiotic assemblages of microbes that may have functional impacts for the host. PMID- 29230895 TI - Dissecting and analyzing key residues in protein-DNA complexes. AB - Protein-DNA interactions are involved in various fundamental biological processes such as replication, transcription, DNA repair, and gene regulation. To understand the interaction in protein-DNA complexes, the integrative study of binding and stabilizing residues is important. In the present study, we have identified key residues that play a dual role in both binding and stability from a nonredundant dataset of 319 protein-DNA complexes. We observed that key residues are identified in very less number of complexes (29%) and only about 4% of stabilizing/binding residues are identified as key residues. Specifically, stabilizing residues have higher preference to be key residues than binding residues. These key residues include polar, nonpolar, aliphatic, aromatic, and charged amino acids. Moreover, we have analyzed and discussed the key residues in different protein-DNA complexes, which are classified based on protein structural class, function, DNA strand, and their conformations. Especially, Ser, Thr, Tyr, Arg, and Lys residues are commonly found in most of the subclasses of protein-DNA complexes. Further, we analyzed atomic contacts, which show that polar-nonpolar is more enriched than other types of contacts. In addition, the charged contacts are highly preferred in protein-DNA complexes compared with protein-protein and protein-RNA complexes. Finally, we have discussed the sequence and structural features of key residues such as conservation score, surrounding hydrophobicity, solvent accessibility, secondary structure, and long-range order. This study will be helpful to understand the recognition mechanism and structural and functional aspects of protein-DNA complexes. PMID- 29230896 TI - Neurogenomics - towards a more rigorous science. PMID- 29230897 TI - Screen-time matters. PMID- 29230898 TI - Molecular Characterization of Enterocytozoon bieneusi in Wild Carnivores in Spain. AB - Microsporidia comprises a diverse group of obligate intracellular parasites that infect a broad range of invertebrates and vertebrates. Among Microsporidia, Enterocytozoon bieneusi is the most frequently detected species in humans and animals worldwide bringing into question the possible role of animal reservoirs in the epidemiology of this pathogen. Although E. bieneusi is an emerging zoonotic pathogen able to infect many domestic and wild mammals that could act as reservoir of infection for humans and other animals, only few studies have documented its occurrence in wild carnivores. To determine the occurrence of E. bieneusi in wild carnivores, we examined 190 wild carnivores collected from different locations in Spain. Twenty-five fecal samples (13.2%) from three host species (European badger, beech marten, and red fox) were E. bieneusi-positive by PCR. Nucleotide sequence analysis of the ITS region revealed a high degree of genetic diversity with a total of eight distinct genotypes including four known (PtEbIX, S5, S9, and WildBoar3) and four novel (EbCar1-EbCar4) genotypes identified. Phylogenetic analysis showed that the four novel genotypes (EbCar1 EbCar4), S5, S9, and WildBoar3 clustered within the previously designated zoonotic Group 1. Our results demonstrate that human-pathogenic genotypes are present in wild carnivores, corroborating their potential role as a source of human infection and environmental contamination. PMID- 29230899 TI - A survey of the blood supply in China during 2012-2014. AB - OBJECTIVES: The aim of this study was to identify the status of the blood supply in China during 2012-2014. BACKGROUND: China is a middle-income country, which contains more than 20% of the world population. Increasing the blood supply in China, along with increased healthcare coverage, involves many challenges. METHODS: A survey questionnaire regarding blood centre activities was sent to all of the blood centres in 32 provinces via the Internet. The data were collected from the responses and analysed using Microsoft Excel 2013. RESULTS: The total supply of whole blood and red blood cells (RBCs) in 2012 was 18 644 700 units; in 2013, 18 985 800 units; and in 2014, 19 658 800 units. A similar trend of the total platelet supply was also observed during the same period of 2012-2014, as follows: 1 019 100 units in 2012, 1 168 400 units in 2013 and 1 276 200 units in 2014. Similarly, the plasma supply was 27 529 300 units in 2012 and 27 657 600 units in 2013, which rose to 28 307 500 units in 2014. The total cryoprecipitate supply was 1 653 900, 1 891 300 and 2 366 500 units in 2012, 2013 and 2014, respectively. When the blood supply was analysed according to the geographic regional population, large differences in the rates of blood supply between regions were evident. CONCLUSIONS: The blood product supply in China is steadily increasing. Blood centres in China continue to face challenges regarding their ability to provide a sufficient blood supply in the future. PMID- 29230900 TI - Expression of a carotenoid-modifying gene and evolution of red coloration in weaverbirds (Ploceidae). AB - Red carotenoid colours in birds are widely assumed to be sexually selected quality indicators, but this rests on a very incomplete understanding of genetic mechanisms and honesty-mediating costs. Recent progress was made by the implication of the gene CYP2J19 as an avian carotenoid ketolase, catalysing the synthesis of red C4-ketocarotenoids from yellow dietary precursors, and potentially a major mechanism behind red coloration in birds. Here, we investigate the role of CYP2J19 in the spectacular colour diversification of African weaverbirds (Ploceidae), represented by five genera and 16 species: eight red, seven yellow and one without carotenoid coloration. All species had a single copy of CYP2J19, unlike the duplication found in the zebra finch, with high expression in the retina, confirming its function in colouring red oil droplets. Expression was weak or undetected in skin and follicles of pigment-depositing feather buds, as well as in beaks and tarsi, including those of the red-billed quelea. In contrast, the hepatic (liver) expression of CYP2J19 was consistently higher (>14-fold) in seven species with C4-ketocarotenoid coloration than in species without (including one red species), an association strongly supported by a phylogenetic comparative analysis. The results suggest a critical role of the candidate ketolase, CYP2J19, in the evolution of red C4-ketocarotenoid colour variation in ploceids. As ancestral state reconstruction suggests that ketocarotenoid coloration has evolved twice in this group (once in Euplectes and once in the Quelea/Foudia clade), we argue that while CYP2J19 has retained its ancestral role in the retina, it has likely been co-opted for red coloration independently in the two lineages, via increased hepatic expression. PMID- 29230901 TI - Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. PMID- 29230902 TI - The evolutionary fate of heterogeneous gene duplications: A precarious overdominant equilibrium between environment, sublethality and complementation. AB - Gene duplications occur at a high rate. Although most appear detrimental, some homogeneous duplications (identical gene copies) can be selected for beneficial increase in produced proteins. Heterogeneous duplications, which combine divergent alleles of a single locus, are seldom studied due to the paucity of empirical data. We investigated their role in an ongoing adaptive process at the ace-1 locus in Culex pipiens mosquitoes. We assessed the worldwide diversity of the ace-1 alleles (single-copy, susceptible S and insecticide-resistant R, and duplicated D that pair one S and one R copy), analysed their phylogeography and measured their fitness to understand their early dynamics using population genetics models. It provides a coherent and comprehensive evolutionary scenario. We show that D alleles are present in most resistant populations and display a higher diversity than R alleles (27 vs. 4). Most appear to result from independent unequal crossing-overs between local single-copy alleles, suggesting a recurrent process. Most duplicated alleles have a limited geographic distribution, probably resulting from their homozygous sublethality (HS phenotype). In addition, heterozygotes carrying different HS D alleles showed complementation, indicating different recessive lethal mutations. Due to mosaic insecticide control practices, balancing selection (overdominance) plays a key role in the early dynamics of heterogeneous duplicated alleles; it also favours a high local polymorphism of HS D alleles in natural populations (overdominance reinforced by complementation). Overall, our study shows that the evolutionary fate of heterogeneous duplications (and their long-term role) depends on finely balanced selective pressures due to the environment and to their genomic structure. PMID- 29230903 TI - Nurse manager succession planning: A cost-benefit analysis. AB - AIM: This commentary presents a cost-benefit analysis to advocate for the use of succession planning to mitigate the problems ensuing from nurse manager turnover. BACKGROUND: An estimated 75% of nurse managers will leave the workforce by 2020. Many benefits are associated with proactively identifying and developing internal candidates. Fewer than 7% of health care organisations have implemented formal leadership succession planning programmes. EVALUATION: A cost-benefit analysis of a formal succession-planning programme from one hospital illustrates the benefits of the programme in their organisation and can be replicated easily. KEY ISSUES: Assumptions of nursing manager succession planning cost-benefit analysis are identified and discussed. The succession planning exemplar demonstrates the integration of cost-benefit analysis principles. CONCLUSION: Comparing the costs of a formal nurse manager succession planning strategy with the status quo results in a positive cost-benefit ratio. IMPLICATIONS FOR NURSING MANAGEMENT: The implementation of a formal nurse manager succession planning programme effectively reduces replacement costs and time to transition into the new role. This programme provides an internal pipeline of future leaders who will be more successful than external candidates. Using an actual cost-benefit analysis equips nurse managers with valuable evidence depicting succession planning as a viable business strategy. PMID- 29230904 TI - Impacts of climate change on rice production in Africa and causes of simulated yield changes. AB - This study is the first of its kind to quantify possible effects of climate change on rice production in Africa. We simulated impacts on rice in irrigated systems (dry season and wet season) and rainfed systems (upland and lowland). We simulated the use of rice varieties with a higher temperature sum as adaptation option. We simulated rice yields for 4 RCP climate change scenarios and identified causes of yield declines. Without adaptation, shortening of the growing period due to higher temperatures had a negative impact on yields (-24% in RCP 8.5 in 2070 compared with the baseline year 2000). With varieties that have a high temperature sum, the length of the growing period would remain the same as under the baseline conditions. With this adaptation option rainfed rice yields would increase slightly (+8%) but they remain subject to water availability constraints. Irrigated rice yields in East Africa would increase (+25%) due to more favourable temperatures and due to CO2 fertilization. Wet season irrigated rice yields in West Africa were projected to change by -21% or +7% (without/with adaptation). Without adaptation irrigated rice yields in West Africa in the dry season would decrease by -45% with adaptation they would decrease significantly less (-15%). The main cause of this decline was reduced photosynthesis at extremely high temperatures. Simulated heat sterility hardly increased and was not found a major cause for yield decline. The implications for these findings are as follows. For East Africa to benefit from climate change, improved water and nutrient management will be needed to benefit fully from the more favourable temperatures and increased CO2 concentrations. For West Africa, more research is needed on photosynthesis processes at extreme temperatures and on adaptation options such as shifting sowing dates. PMID- 29230906 TI - Arterial stiffness in junior high school students: Longitudinal observations. AB - BACKGROUND: Early atherosclerotic change is found even in childhood, and there is an urgent need to clarify the factors causing childhood atherosclerosis and take preventive measures. Early detection of the contributing risk factors is crucial to facilitate preventive measures. Pulse wave velocity (PWV) is a widely used technique for the assessment of atherosclerosis in children. METHODS: Lifestyle questionnaire, brachio-ankle PWV (baPWV) and anthropometric data were obtained from junior high school students in an urban area of Japan between 2006 and 2008, from seventh to ninth grades. RESULTS: Mean baPWV increased from 867.4 +/- 99.5 m/s to 944.5 +/- 117.5 m/s in boys, and from 864.0 +/- 99.5 m/s to 923.0 +/- 101.3 m/s in girls. Obese students had higher baPWV than non-obese students in both genders across each grade. On logistic regression analysis of ninth grade student data, high baPWV was dependent on systolic blood pressure (SBP), time watching television (TV) and symptoms of depression and anxiety, whereas low baPWV was dependent on time playing video games, light exercise, sleep and indoor play, as well as good friendship and motivation. CONCLUSION: Systolic blood pressure, time watching TV, and symptoms of depression and anxiety may contribute to arterial stiffness and be related to obesity in junior high school students. PMID- 29230907 TI - Comparative evaluation of GPR versus APRI and FIB-4 in predicting different levels of liver fibrosis of chronic hepatitis B. AB - It is of great significance to develop and evaluate noninvasive indexes predicting the level of liver fibrosis. The aim of this study was to comparatively evaluate gamma-glutamyl transpeptidase-to-platelet ratio (GPR) versus aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on 4 factors (FIB-4) in predicting different levels of liver fibrosis of chronic hepatitis B (CHB) within the framework of HBeAg-positive and HBeAg negative patients. A total of 1157 HBeAg-positive and 859 HBeAg-negative CHB patients were enrolled, among whom the pathological stage >=S2, >=S3, >=S4 were defined as significant fibrosis, extensive fibrosis and cirrhosis, respectively. Receiver operating characteristic (ROC) curves were used to evaluate the performance of GPR, APRI and FIB-4 in predicting different levels of liver fibrosis. In HBeAg-positive patients, the area under ROC curves (AUROCs) of GPR in predicting extensive fibrosis and cirrhosis were both significantly larger than those of APRI (P = .0001 and P < .0001). In HBeAg-negative patients, the AUROCs of GPR in predicting significant fibrosis and cirrhosis were significantly larger than those of FIB-4 (P = .0006 and P = .0041). The AUROC of GPR in predicting extensive fibrosis was significantly larger than that of APRI and FIB 4 (P = .0320 and P = .0018). Using a cut-off of GPR > 0.500 as standard, the sensitivities and specificities of GPR in predicting significant fibrosis in HBeAg-positive patients were 59.6% and 81.2%, and for cirrhosis 80.9% and 63.8%, respectively; and those of HBeAg-negative patients were 60.3% and 78.3%, 84.5% and 66.1%, respectively. Regardless of HBeAg-positive or HBeAg-negative status, GPR had the best performance in predicting different levels of liver fibrosis. PMID- 29230908 TI - Desktop NMR and Its Applications From Materials Science To Organic Chemistry. AB - NMR spectroscopy is an indispensable method of analysis in chemistry, which until recently suffered from high demands for space, high costs for acquisition and maintenance, and operational complexity. This has changed with the introduction of compact NMR spectrometers suitable for small-molecule analysis on the chemical workbench. These spectrometers contain permanent magnets giving rise to proton NMR frequencies between 40 and 80 MHz. The enabling technology is to make small permanent magnets with homogeneous fields. Tabletop instruments with inhomogeneous fields have been in use for over 40 years for characterizing food and hydrogen-containing materials by relaxation and diffusion measurements. Related NMR instruments measure these parameters in the stray field outside the magnet. They are used to inspect the borehole walls of oil wells and to test objects nondestructively. The state-of-the-art of NMR spectroscopy, imaging and relaxometry with compact instruments is reviewed. PMID- 29230909 TI - Histatins, wound healing, and cell migration. AB - Wounds in the oral mucosa heal faster and more efficiently than those in the skin, although the mechanisms underlying these differences are not completely clear. In the last 10 years, a group of salivary peptides, the histatins, has gained attention on behalf of their ability to improve several phases of the wound-healing process. In addition to their roles as anti-microbial agents and in enamel maintenance, histatins elicit other biological effects, namely by promoting the migration of different cell types contained in the oral mucosa and in non-oral tissues. Histatins, and specifically histatin-1, promote cell adhesion and migration in oral keratinocytes, gingival and dermal fibroblasts, non-oral epithelial cells, and endothelial cells. This is particularly relevant, as histatin-1 promotes the re-epithelialization phase and the angiogenic responses by increasing epithelial and endothelial cell migration. Although the molecular mechanisms associated with histatin-dependent cell migration remain poorly understood, recent studies have pointed to the control of signaling endosomes and the balance of small GTPases. This review aimed to update the literature on the effects of histatins in cell migration, with a focus on wound healing. We will also discuss the consequences that this increasing field will have in disease and therapy design. PMID- 29230905 TI - Muscle Control and Non-specific Chronic Low Back Pain. AB - OBJECTIVES: Chronic low back pain (CLBP) is the most prevalent of the painful musculoskeletal conditions. CLBP is a heterogeneous condition with many causes and diagnoses, but there are few established therapies with strong evidence of effectiveness (or cost effectiveness). CLBP for which it is not possible to identify any specific cause is often referred to as non-specific chronic LBP (NSCLBP). One type of NSCLBP is continuing and recurrent primarily nociceptive CLBP due to vertebral joint overload subsequent to functional instability of the lumbar spine. This condition may occur due to disruption of the motor control system to the key stabilizing muscles in the lumbar spine, particularly the lumbar multifidus muscle (MF). METHODS: This review presents the evidence for MF involvement in CLBP, mechanisms of action of disruption of control of the MF, and options for restoring control of the MF as a treatment for NSCLBP. RESULTS: Imaging assessment of motor control dysfunction of the MF in individual patients is fraught with difficulty. MRI or ultrasound imaging techniques, while reliable, have limited diagnostic or predictive utility. For some patients, restoration of motor control to the MF with specific exercises can be effective, but population results are not persuasive since most patients are unable to voluntarily contract the MF and may be inhibited from doing so due to arthrogenic muscle inhibition. CONCLUSIONS: Targeting MF control with restorative neurostimulation promises a new treatment option. PMID- 29230910 TI - Estimating causal effects for survival (time-to-event) outcomes by combining classification tree analysis and propensity score weighting. AB - RATIONALE, AIMS AND OBJECTIVES: A common approach to assessing treatment effects in nonrandomized studies with time-to-event outcomes is to estimate propensity scores and compute weights using logistic regression, test for covariate balance, and then estimate treatment effects using Cox regression. A machine-learning alternative-classification tree analysis (CTA)-used to generate propensity scores and to estimate treatment effects in time-to-event data may identify complex relationships between covariates not found using conventional regression-based approaches. METHOD: Using empirical data, we identify all statistically valid CTA propensity score models and then use them to compute strata-specific, observation level propensity score weights that are subsequently applied in outcomes analyses. We compare findings obtained using this framework to the conventional method, by evaluating covariate balance and treatment effect estimates obtained using Cox regression and a weighted CTA outcomes model. RESULTS: All models had some imbalanced covariates. Nevertheless, treatment effect estimates were generally consistent across all weighted models. CONCLUSIONS: In the study sample, given that all approaches elicited similar results, using CTA increased confidence that bias could not be reduced any further. Because the CTA algorithm identifies all statistically valid propensity score models for a sample, it is most likely to identify a correctly specified propensity score model-and therefore should be used either to confirm results using traditional methods, or to reveal biases that may be missed by traditional methods. Moreover, given that the true treatment effect is never known in observational data, CTA should be considered for estimating outcomes because no statistical assumptions are required. PMID- 29230911 TI - Social dimensions of health across the life course: Narratives of Arab immigrant women ageing in Canada. AB - The increase in ethnically and linguistically diverse older adults in Canada necessitates attention to their experiences and needs for healthy ageing. Arab immigrant women often report challenges in maintaining health, but little is known about their ageing experiences. This interpretive descriptive study uses a transnational life course framework to understand Arab Muslim immigrant women's experiences of engaging in health-promoting practices as they age in Canada. Women's stories highlight social dimensions of health such social connectedness, social roles and social support that are constructed and maintained within different migration contexts across the life course. Barriers and facilitators to healthy ageing in this population centred around five themes: (i) the necessity of staying strong, (ii) caring for self while caring for others, (iii) double jeopardy of chronic illnesses and loneliness, (iv) inadequate support within large social networks and (v) navigating access to health-supporting resources. The findings point to transnational connections and post-migration social support as major influencers in creating facilitators and barriers to healthy ageing for Arab Muslim immigrant women. PMID- 29230912 TI - Factors associated with the delay of diagnosis of leprosy in north-eastern Colombia: a quantitative analysis. AB - OBJECTIVES: To determine the average time in months between the beginning of symptoms and the diagnostic confirmation of leprosy by the health system and to investigate factors associated with diagnostic delay. METHODS: A total of 249 patients older than 15 years diagnosed with leprosy between 2011 and 2015, in 20 endemic municipalities of north-eastern Colombia, provided informed consent and were interviewed face-to-face. Clinical histories from health centres or hospitals where study participants were treated for leprosy were also reviewed. RESULTS: The mean delay in diagnosis of leprosy was 33.5 months. About 14.9% of patients showed a visible deformity or damage (disability grade 2, DG2) at the time of diagnosis. In multivariable regression analysis, five or more consultancies required to confirm the diagnosis and not seeking care immediately after noticing first symptoms were associated with longer diagnostic delay. CONCLUSIONS: Our study found a significant delay in diagnosis of leprosy in north eastern Colombia, which might explain the continuously high rate of DG2 among new cases being notified in the country. Both patient- and health system-related factors were associated with longer diagnostic delay. Interventions to increase awareness of disease among the general population and timely referral to a specialised health professional are urgently needed in our study setting. PMID- 29230914 TI - Delta-Like 4 Activates Notch 3 to Regulate Self-Renewal in Skeletal Muscle Stem Cells. AB - Notch signaling is essential to maintain skeletal muscle stem cells in quiescence. However, the precise roles of different Notch receptors are incompletely defined. Here, we demonstrate a role for Notch3 (N3) in the self renewal of muscle stem cells. We found that N3 is active in quiescent C2C12 reserve cells (RCs), and N3 over-expression and knockdown studies in C2C12 and primary satellite cells reveal a role in self-renewal. The Notch ligand Delta like 4 (Dll4) is expressed by newly formed myotubes and interaction with this ligand is sufficient to maintain N3 activity in quiescent C2C12 RCs to prevent activation and progression into the cell cycle. Thus, our data suggest a model whereby during regeneration, expression of Dll4 by nascent muscle fibers triggers N3 signaling in associated muscle stem cells to recruit them to quiescence, thereby renewing the stem cell pool. Stem Cells 2018;36:458-466. PMID- 29230913 TI - A Novel Approach to Single Cell RNA-Sequence Analysis Facilitates In Silico Gene Reporting of Human Pluripotent Stem Cell-Derived Retinal Cell Types. AB - Cell type-specific investigations commonly use gene reporters or single-cell analytical techniques. However, reporter line development is arduous and generally limited to a single gene of interest, while single-cell RNA (scRNA) sequencing (seq) frequently yields equivocal results that preclude definitive cell identification. To examine gene expression profiles of multiple retinal cell types derived from human pluripotent stem cells (hPSCs), we performed scRNA-seq on optic vesicle (OV)-like structures cultured under cGMP-compatible conditions. However, efforts to apply traditional scRNA-seq analytical methods based on unbiased algorithms were unrevealing. Therefore, we developed a simple, versatile, and universally applicable approach that generates gene expression data akin to those obtained from reporter lines. This method ranks single cells by expression level of a bait gene and searches the transcriptome for genes whose cell-to-cell rank order expression most closely matches that of the bait. Moreover, multiple bait genes can be combined to refine datasets. Using this approach, we provide further evidence for the authenticity of hPSC-derived retinal cell types. Stem Cells 2018;36:313-324. PMID- 29230915 TI - Periapical infection may affect birth outcomes via systemic inflammation. AB - OBJECTIVES: Maternal dental periapical infections are associated with preterm birth and intrauterine growth restriction. This study investigates whether the association is mediated through bacterial spread from periapical lesions to placenta (direct pathway) or systemic inflammatory reaction (indirect pathway). MATERIALS AND METHODS: We compared birth outcomes in Malawian mothers with and without periapical infection. As markers of a direct pathway, we identified placental bacteria using a 16S rDNA approach and assessed histological evidence of inflammation in the placenta and amniotic membranes. We measured C-reactive protein, alpha-1-acid glycoprotein, and salivary cortisol as markers of an indirect pathway. We used regression models to associate the predictor variables with duration of pregnancy and newborn size. RESULTS: Of 1,024 women, 23.5% had periapical infection. There was no association of periapical infection with either bacterial DNA or histological inflammation in placenta or membranes. Periapical infection was associated with C-reactive protein, alpha-1-acid glycoprotein, and cortisol concentrations in a dose-dependent manner at 36 weeks. Addition of alpha-1-acid glycoprotein or cortisol concentration into regression models attenuated the association between periapical infection and pregnancy outcomes. CONCLUSION: There was no evidence of direct spread of periapical bacteria to the placenta. Periapical infections and adverse pregnancy outcomes are in part mediated through systemic inflammation. PMID- 29230916 TI - The relationship between emotional experience with dyslexia and work self efficacy among adults with dyslexia. AB - This study responds to a call for more research on working adults with dyslexia investigating how employment-related factors affect and relate to one another. Two important work-related factors are self-efficacy and emotional experience with dyslexia. Work self-efficacy is viewed one of the most vital intrapersonal capacities in the work environment. It can be viewed as a subjective indicator of work success and is conceptualized as a multidimensional construct. Research speaks to a unique emotional experience stemming from living with an often misunderstood and stereotyped learning difference. The participants were 173 working adults with dyslexia (average age = 43.5 years, females = 56.6%) who participated in a web-based survey. Hierarchical multiple regression analyses revealed that more negative or uncomfortable emotions emanating from living with dyslexia predicted lower levels of total work self-efficacy, work attributes, work competency, and work anxiety over and beyond background contextual variables. Implications of these findings are discussed. PMID- 29230917 TI - Interfacial Nanoprecipitation toward Stable and Responsive Microbubbles and Their Use as a Resuscitative Fluid. AB - A new approach has been developed to prepare stable microbubbles (MBs) by interfacial nanoprecipitation of bioabsorbable polymers at air/liquid interfaces. This facile method offers robust control over the morphology and chemophysical properties of MBs by simple chemical modifications. This approach is amenable to large-scale manufacturing, and is useful to develop functional MBs for advanced biomedical applications. To demonstrate this, a MB-based intravenous oxygen carrier was created that undergoes pH-triggered self-elimination. Intravenous injection of previous MBs increased the risk of pulmonary vascular obstruction. However, we show, for the first time, that our current design is superior, as they 1) yielded no evidence of acute risks in rodents, and 2) improved the survival in a disease model of asphyxial cardiac arrest (from 0 to 100 %), a condition that affects more than 100 000 in-hospital patients, and carries a mortality of about 90 %. PMID- 29230919 TI - Parents' pain medication underdosing is associated with more emergency department visits in sickle cell disease. AB - OBJECTIVE: To determine the association between health literacy, medication knowledge, and pain treatment skills with emergency department (ED) use of parents of children with sickle cell disease (SCD). METHODS: Parents of children 1- to 12-years-old with SCD were enrolled. Health literacy was assessed using the Newest Vital Sign. Parents completed a structured interview assessing knowledge of the dosage and frequency of home pain medications and an applied skills task requiring them to dose a prescribed pain medication. Underdosage was defined by too small a dose (dosage error) or too infrequent a dose (frequency error). The association between medication knowledge and applied skills with ED visits for pain over the past year was evaluated using Poisson regression adjusting for genotype. RESULTS: One hundred parent/child pairs were included; 50% of parents had low health literacy. Low health literacy was associated with more underdose frequency errors (38% vs. 19%, P = 0.02) on the skills task. On medication knowledge, underdose dosage errors (adjusted incidence rate ratio [aIRR] 2.0, 95% confidence interval [CI] 1.3-3.0) and underdose frequency errors (aIRR, 1.7, 95% CI 1.2-2.6) were associated with a higher rate of ED visits for pain. On the skills task, underdose dosage errors (aIRR 1.6, 95% CI 1.1-2-.4) and underdose frequency errors were associated with more ED visits (aIRR 1.5, 95% CI 1.1-2.1). CONCLUSIONS: For medication knowledge and skills tasks, children of parents who underdosed pain medication had a higher rate of ED visits for pain. Health literate strategies to improve parents' medication skills may improve pain treatment at home and decrease healthcare utilization. PMID- 29230918 TI - Poor continuity of care for TB diagnosis and treatment in Zambian Prisons: a situation analysis. AB - OBJECTIVES: Prisons act as infectious disease reservoirs. We aimed to explore the challenges of TB control and continuity of care in prisons in Zambia. METHODS: We evaluated treatment outcomes for a cohort of inmates diagnosed with TB during a TB REACH funded screening programme initiated by the Zambia Prisons Service and the Centre for Infectious Disease Research in Zambia. RESULTS: Between October 2010 and September 2011, 6282 inmates from six prisons were screened for TB, of whom 374 (6.0%) were diagnosed. TB treatment was initiated in 345 of 374 (92%) inmates. Of those, 66% were cured or completed treatment, 5% died and 29% were lost to follow-up. Among those lost to follow-up, 11% were released into the community and 13% were transferred to other prisons. CONCLUSIONS: Weak health systems within the Zambian prison service currently undermines continuity of care, despite intensive TB screening and case-finding interventions. To prevent TB transmission and the development of drug resistance, we need sufficient numbers of competent staff for health care, reliable health information systems including electronic record keeping for prison facilities, and standard operating procedures to guide surveillance, case-finding and timely treatment initiation and completion. PMID- 29230920 TI - Kin competition accelerates experimental range expansion in an arthropod herbivore. AB - With ongoing global change, life is continuously forced to move to novel areas, which leads to dynamically changing species ranges. As dispersal is central to range dynamics, factors promoting fast and distant dispersal are key to understanding and predicting species ranges. During range expansions, genetic variation is depleted at the expanding front. Such conditions should reduce evolutionary potential, while increasing kin competition. Organisms able to recognise relatives may be able to assess increased levels of relatedness at expanding range margins and to increase their dispersal in a plastic manner. Using individual-based simulations and experimental range expansions of a spider mite, we demonstrate that plastic responses to kin structure can be at least as important as evolution in driving range expansion speed. Because recognition of kin or kind is increasingly documented across the tree of life, we anticipate it to be a highly important but neglected driver of range expansions. PMID- 29230921 TI - Global grass (Poaceae) success underpinned by traits facilitating colonization, persistence and habitat transformation. AB - Poaceae (the grasses) is arguably the most successful plant family, in terms of its global occurrence in (almost) all ecosystems with angiosperms, its ecological dominance in many ecosystems, and high species richness. We suggest that the success of grasses is best understood in context of their capacity to colonize, persist, and transform environments (the "Viking syndrome"). This results from combining effective long-distance dispersal, efficacious establishment biology, ecological flexibility, resilience to disturbance and the capacity to modify environments by changing the nature of fire and mammalian herbivory. We identify a diverse set of functional traits linked to dispersal, establishment and competitive abilities. Enhanced long-distance dispersal is determined by anemochory, epizoochory and endozoochory and is facilitated via the spikelet (and especially the awned lemma) which functions as the dispersal unit. Establishment success could be a consequence of the precocious embryo and large starch reserves, which may underpin the extremely short generation times in grasses. Post-establishment genetic bottlenecks may be mitigated by wind pollination and the widespread occurrence of polyploidy, in combination with gametic self incompatibility. The ecological competitiveness of grasses is corroborated by their dominance across the range of environmental extremes tolerated by angiosperms, facilitated by both C3 and C4 photosynthesis, well-developed frost tolerance in several clades, and a sympodial growth form that enabled the evolution of both annual and long-lived life forms. Finally, absence of investment in wood (except in bamboos), and the presence of persistent buds at or below ground level, provides tolerance of repeated defoliation (whether by fire, frost, drought or herbivores). Biotic modification of environments via feedbacks with herbivory or fire reinforce grass dominance leading to open ecosystems. Grasses can be both palatable and productive, fostering high biomass and diversity of mammalian herbivores. Many grasses have a suite of architectural and functional traits that facilitate frequent fire, including a tufted growth form, and tannin-like substances in leaves which slow decomposition. We mapped these traits over the phylogeny of the Poales, spanning the grasses and their relatives, and demonstrated the accumulation of traits since monocots originated in the mid-Cretaceous. Although the sympodial growth form is a monocot trait, tillering resulting in the tufted growth form most likely evolved within the grasses. Similarly, although an ovary apparently constructed of a single carpel evolved in the most recent grass ancestor, spikelets and the awned lemma dispersal units evolved within the grasses. Frost tolerance and C4 photosynthesis evolved relatively late (late Palaeogene), and the last significant trait to evolve was probably the production of tannins, associated with pyrophytic savannas. This fits palaeobotanical data, suggesting several phases in the grass success story: from a late Cretaceous origin, to occasional tropical grassland patches in the later Palaeogene, to extensive C3 grassy woodlands in the early middle Miocene, to the dramatic expansion of the tropical C4 grass savannas and grasslands in the Pliocene, and the C3 steppe grasslands during the Pleistocene glacial periods. Modern grasslands depend heavily on strongly seasonal climates, making them sensitive to climate change. PMID- 29230922 TI - Synthetic Cancer-Targeting Innate Immune Stimulators Give Insights into Avidity Effects. AB - Multispecific and multivalent antibodies are seen as promising cancer therapeutics, and numerous antibody fragments and derivatives have been developed to exploit avidity effects that result in increased selectivity. Most of these multispecific and multivalent antibody strategies make use of recombinant expression of antigen-binding modules. In contrast, chemical synthesis and chemoselective ligations can be used to generate a variety of molecules with different numbers and combinations of binding moieties in a modular and homogeneous fashion. In this study we synthesized a series of targeted immune system engagers (ISErs) by using solid-phase peptide synthesis and chemoselective ligations. To explore avidity effects, we constructed molecules bearing different numbers and combinations of two "binder" peptides that target ephrin A2 and integrin alpha3 receptors and an "effector" peptide that binds to formyl peptide receptors and stimulates an immune response. We investigated various strategies for generating multivalent and multispecific targeted innate immune stimulators and studied their activities in terms of binding to cancer cells and stimulation of immune cells. This study gives insights into the influence that multivalency and receptor density have on avidity effects and is useful for the design of potential anticancer therapeutics. PMID- 29230923 TI - Primary antifungal prophylaxis: decrease of invasive fungal disease incidence and reduction of risk factors in haematological patients in a 5-year retrospective study. AB - BACKGROUND: Invasive fungal disease (IFD) is a major cause of morbidity and mortality in patients with haematological malignancies. AIM: To evaluate the efficacy and rationality of primary antifungal prophylaxis (PAP) in a 5-year real life setting and choose an appropriate PAP strategy. METHODS: Clinical data of patients were retrospectively reviewed and IFD was diagnosed using the revised diagnostic criteria. The efficacy of PAP and the risk factors for IFD, especially the rationality of PAP, were evaluated. RESULTS: Of the 1340 patients enrolled, 749 patients received PAP (55.9%), and IFD occurred in 157 patients: 51 (6.8%) in the PAP group and 106 (17.9%) in the non-PAP group (P = 0.000). The IFD-related mortality was 10.1 and 29.7% in the PAP group and non-PAP group (P = 0.000) respectively. PAP was an independent protective factor for IFD (odds ratio = 0.183, 95% confidence interval: 0.122-0.274, P = 0.000) and could reduce the effect of risk factors, such as allogeneic haemopoietic stem cell transplantation, prolonged neutropenia and corticosteroid. The IFD incidence was not significantly different among different PAP regimens and PAP start time subgroups, and it was lowest (4.2%) when PAP started after a short period of neutropenia (1-10 days). CONCLUSION: PAP is necessary and efficient to prevent IFD in haematological patients, and the real-life PAP strategy is reasonable. Different drugs can be chosen, and it is better to start PAP as soon as neutropenia begins. PMID- 29230924 TI - Response in a child with a BRAF V600E mutated desmoplastic infantile astrocytoma upon retreatment with vemurafenib. AB - Infants with low-grade glioma (LGG) and diencephalic syndrome have a poor outcome. The patient described here had a desmoplastic infantile astrocytoma harboring a BRAF V600E mutation. After relapse following initial standard chemotherapy treatment, he was successfully treated with the BRAF V600E inhibitor vemurafenib at the age of 3 years 11 months and 5 years 0 months. A rapid response was observed on both occasions. This illustrates the possibility of continuous oncogenic addiction and the therapeutic potential of BRAF V600E inhibitor monotherapy in LGG, even in very young severely compromised children. BRAF V600E inhibition in LGG and possible (re-)treatment regimens are briefly discussed. PMID- 29230925 TI - Novel pressure sensors and bioreporters in the synthetic biology era. PMID- 29230926 TI - Economic strain and support in couple: The mediating role of positive emotions. AB - This study examined positive emotions as mediating mechanisms in the association between economic strain and spouses' supportive behaviour. Data were collected from 295 married couples living in Romania. Results from the Actor-Partner Mediator Model indicated that economic strain had a negative indirect effect on spouses' supportive dyadic coping due to its negative association with partners' positive emotions (joy, contentment, and pride). For both partners, positive emotions decreased when they experienced economic strain, which in turn reduced supportive dyadic coping in couples. These findings have theoretical implications in explaining the association of economic strain with partners' positive emotions and behaviours and also clinical implications for practitioners working with couples experiencing economic strain. PMID- 29230927 TI - Copper-Catalyzed Enantioselective Markovnikov Protoboration of alpha-Olefins Enabled by a Buttressed N-Heterocyclic Carbene Ligand. AB - Reported is a highly enantioselective copper-catalyzed Markovnikov protoboration of unactivated terminal alkenes. A variety of simple and abundant feedstock alpha olefins bearing a diverse array of functional groups and heterocyclic substituents can be used as substrates, and the reaction proceeds under mild reaction conditions at ambient temperature to provide expedient access to enantioenriched alkylboronic esters in good regioselectivity and with excellent enantiocontrol. Critical to the success of the protocol was the development and application of a novel, sterically hindered N-heterocyclic carbene, (R,R,R,R) ANIPE, as the ligand for copper. PMID- 29230928 TI - Audiological monitoring in Swiss childhood cancer patients. AB - BACKGROUND: Full audiological monitoring is the best strategy to detect hearing loss early and to provide timely intervention in the absence of a clinical method of otoprotection. Full monitoring requires audiological evaluation before, and then during and after ototoxic cancer treatment. In a worldwide context of monitoring protocols that vary substantially, we analyzed the audiological monitoring of childhood cancer patients over the last decade across treatment centers in Switzerland. PROCEDURE: We retrospectively searched for audiological evaluations in all nine Swiss Pediatric Oncology Centers. We analyzed proportions of patients who had audiological monitoring and described type and timing of monitoring. We determined predictors of audiological monitoring using multivariable logistic regression and described time trends. RESULTS: We included 185 patients from the Swiss Childhood Cancer Registry diagnosed from 2005 to 2013 who had platinum chemotherapy and/or cranial radiation >=30 Gray and who were alive at time of study. Less than half of children, 43%, had full audiological monitoring (before, during, and after treatment), while 72% were tested after cancer treatment. Nonstudy patients were less likely to have had monitoring in all phases of cancer treatment. Patients who received treatment with cisplatin or both platinum chemotherapy and cranial radiation were more likely to have had monitoring after treatment. Monitoring during and after treatment increased over the study period, but monitoring before treatment was insufficient in all time periods. CONCLUSIONS: Our population-based study indicates that audiological monitoring is insufficient in Switzerland, particularly for nonstudy patients. Clinicians must become more aware of the importance of full audiological monitoring. PMID- 29230930 TI - Respectful maternity care needs to be the standard for all women worldwide. PMID- 29230931 TI - Temporal changes in glycaemic thresholds for treatment intensification in type 2 diabetes in an urban Australian setting: the Fremantle Diabetes Study. AB - BACKGROUND: Pharmacotherapy and supportive care for diabetes in Australia are improving, with potential beneficial effects on therapeutic procrastination. AIM: To determine whether glycaemic thresholds for therapeutic intensification in type 2 diabetes changed over the 15 years between phases of the community-based Fremantle Diabetes Study (FDS). METHODS: We studied 531 Phase 1 participants (mean age 62.4 years, 54.2% males, median diabetes duration 3.0 years) with valid data from baseline assessment and five subsequent annual reviews between 1993 and 2001 and 930 Phase 2 participants (mean age 65.3 years, 53.8% males, median diabetes duration 8.0 years) with valid data from baseline and two subsequent biennial reviews between 2008 and 2015. The main outcome measure was HbA1c at assessments before and after change in blood glucose-lowering therapy (average 6 months in Phase 1, 12 months in Phase 2). RESULTS: Ninety-seven participants in Phase 1 and 84 in Phase 2 progressed from diet-based management to oral hypoglycaemic agents (OHA) and 45 and 85 participants, respectively, progressed from diet/OHA to insulin. The median HbA1c was 7.5% (58 mmol/mol) and 6.9% (52 mmol/mol) before OHA initiation in Phases 1 and 2, respectively, and 9.1% (76 mmol/mol) and 7.8% (62 mmol/mol), respectively, before insulin initiation. There were median HbA1c falls of 0.3% (3 mmol/mol) and 1.5% (16 mmol/mol) after OHA and insulin initiation in Phase 1, but no statistically significant changes in Phase 2. CONCLUSIONS: HbA1c thresholds triggering treatment intensification fell between FDS phases, suggesting a more proactive approach to management of glycaemia over time. PMID- 29230929 TI - Application of protoplast technology to CRISPR/Cas9 mutagenesis: from single-cell mutation detection to mutant plant regeneration. AB - Plant protoplasts are useful for assessing the efficiency of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) mutagenesis. We improved the process of protoplast isolation and transfection of several plant species. We also developed a method to isolate and regenerate single mutagenized Nicotianna tabacum protoplasts into mature plants. Following transfection of protoplasts with constructs encoding Cas9 and sgRNAs, target gene DNA could be amplified for further analysis to determine mutagenesis efficiency. We investigated N. tabacum protoplasts and derived regenerated plants for targeted mutagenesis of the phytoene desaturase (NtPDS) gene. Genotyping of albino regenerants indicated that all four NtPDS alleles were mutated in amphidiploid tobacco, and no Cas9 DNA could be detected in most regenerated plants. PMID- 29230932 TI - A multi-modality tracking, navigation and calibration for a flexible robotic drill system for total hip arthroplasty. AB - BACKGROUND: This paper presents a novel multi-modality tracking and navigation system that provides a unique capability to guild a flexible drill tip inside the bone with accurate curved tunnelling. METHODS: As the flexible drill tip cannot be tracked optically inside the bone, this research focuses on developing a hybrid tracking and navigation system for tracking a flexible drill tip by using both optical and kinematic tracking. The tracking information is used to guide the THA (total hip arthroplasty) procedure, providing a real-time virtual model of the flexible drill. RESULTS: The flexible and steerable drill tip system is then tested on total hip arthroplasty followed by evaluation of the positioning and orientation of femoral stem placement by femoral milling. CONCLUSIONS: Based on this study, we conclude that the tracking and navigation system is able to guide the flexible drill to mill inside femoral canal. PMID- 29230933 TI - Biology and pathological implications of brown adipose tissue: promises and caveats for the control of obesity and its associated complications. AB - The discovery of metabolically active brown adipose tissue (BAT) in adult humans has fuelled the research of diverse aspects of this previously neglected tissue. BAT is solely present in mammals and its clearest physiological role is non shivering thermogenesis, owing to the capacity of brown adipocytes to dissipate metabolic energy as heat. Recently, a number of other possible functions have been proposed, including direct regulation of glucose and lipid homeostasis and the secretion of a number of factors with diverse regulatory actions. Herein, we review recent advances in general biological knowledge of BAT and discuss the possible implications of this tissue in human metabolic health. In particular, we confront the claimed thermogenic potential of BAT for human energy balance and body mass regulation, mostly based on animal studies, with the most recent quantifications of human BAT. PMID- 29230934 TI - Adult children of parents with mental illness: Dehumanization of a parent - 'She wasn't the wreck in those years that she was to become later'. AB - Children who have lived with parental mental illness experience long-standing reduced health and social outcomes, alongside ongoing personal distress. While there has been some dialogue regarding interventions to support children who are living with parental mental illness, there remains a paucity of knowledge regarding adult children's experiences and potential needs. Given this, the aim of the present study was to establish parenting narratives of adult children who had experienced childhood parental mental illness. This included their experiences of being parented alongside their own subsequent parenting roles. Three men and 10 women, ranging from 30 to 78 years old, met individually with a researcher to tell their stories. Narratives were thematically analysed to establish themes. The findings of the study demonstrated that individuals who have lived with childhood parental mental illness dehumanized their parent with mental illness. The authors argue that all mental health services should be underpinned with a whole of family assessment and care philosophy. There is also a need for all mental health services to consider how policies and procedures might inadvertently dehumanize clients who are parents, which could contribute to familial dehumanization. This could prevent the dehumanization of parents who experience mental illness to preserve parental and child relationships. PMID- 29230935 TI - Optimization and characterization of biosurfactant from Streptomyces griseoplanus NRRL-ISP5009 (MS1). AB - AIMS: This work aimed to study, isolate, characterize and stabilize the biosurfactant isolated from actinomycetes found in petroleum contaminated soil. METHODS AND RESULTS: Optimized production of the biosurfactant from Streptomyces griseoplanus NRRL-ISP5009, SM1 was obtained on day 6 at 30 degrees C, pH 7, 150 rev min-1 , in glycerol yeast extract broth medium supplemented with cellulose, yeast extract and 1% NaCl. The stability of the biosurfactant produced was studied at different temperatures, pH and different concentrations of NaCl. The produced biosurfactant was extracted and purified. CONCLUSION: Streptomyces griseoplanus NRRL-ISP5009, SM1 isolated from oil contaminated soil produced a biosurfactant exhibiting emulsification activity. The produced biosurfactant is a mixture of carbohydrate, lipid and protein. It has promising characteristics, including a higher stability at alkaline pH than at acidic pH, a salinity of 1-3% and stable in the temperature range from 0 and 100 degrees C. Also, the potential antimicrobial activity of the purified biosurfactant was recorded. SIGNIFICANCE AND IMPACT OF THE STUDY: The research was focused on the isolation of a novel source of biosurfactants that have great importance in the manufacture of food, detergent, pharmaceutical and cosmetics. PMID- 29230936 TI - Evidence for declining forest resilience to wildfires under climate change. AB - Forest resilience to climate change is a global concern given the potential effects of increased disturbance activity, warming temperatures and increased moisture stress on plants. We used a multi-regional dataset of 1485 sites across 52 wildfires from the US Rocky Mountains to ask if and how changing climate over the last several decades impacted post-fire tree regeneration, a key indicator of forest resilience. Results highlight significant decreases in tree regeneration in the 21st century. Annual moisture deficits were significantly greater from 2000 to 2015 as compared to 1985-1999, suggesting increasingly unfavourable post fire growing conditions, corresponding to significantly lower seedling densities and increased regeneration failure. Dry forests that already occur at the edge of their climatic tolerance are most prone to conversion to non-forests after wildfires. Major climate-induced reduction in forest density and extent has important consequences for a myriad of ecosystem services now and in the future. PMID- 29230938 TI - Normal aPTT in children with mild factor XI deficiency. AB - It has been suggested that persons with factor XI deficiency can have a normal activated partial thromboplastin time (aPTT). This notion is based on limited data, especially in children. Because of the central role the aPTT plays in diagnostic algorithms for bleeding disorders, it is important to know if a normal aPTT eliminates the need for factor XI activity testing. Our institutional database contains seven children with factor XI deficiency, of whom four have a normal aPTT. This supports the hypothesis that children with factor XI deficiency can have a normal aPTT. Clinicians may wish to consider this evidence when evaluating children with abnormal bleeding. PMID- 29230937 TI - Chrysanthemum CmHSFA4 gene positively regulates salt stress tolerance in transgenic chrysanthemum. AB - Salinity-induced Na+ toxicity and oxidative stress hamper plant growth. Here, we showed that expression of the chrysanthemum CmHSFA4, a homologue of the heat shock factor AtHSFA4a, is inducible by salt and localizes to the nucleus. It is a transcription activator binding with HSE. Chrysanthemum overexpressing CmHSFA4 displayed enhanced salinity tolerance by limiting Na+ accumulation while maintaining K+ concentration, which is consistent with the up-regulation of ion transporters CmSOS1 and CmHKT2. Additionally, the transgenic plants reduced H2 O2 and O2?- accumulation under salinity, which could be due to up-regulation of ROS scavenger activities such as SOD, APX and CAT as well as CmHSP70, CmHSP90. Together, these results suggest that CmHSFA4 conferred salinity tolerance in chrysanthemum as a consequence of Na+ /K+ ion and ROS homeostasis. PMID- 29230939 TI - Normative values and factors affecting water-perfused esophageal high-resolution impedance manometry for a Chinese population. AB - BACKGROUND: Combined esophageal high-resolution impedance manometry (HRIM) measures multiple pressures and bolus transit simultaneously, facilitating detailed assessment of esophageal motility. Currently, normative values for water perfused HRIM systems for Chinese populations are lacking. METHODS: Healthy volunteers were enrolled for comprehensive anthropometric measures, blood biochemistry tests, and an HRIM study using 22 water-perfused pressure sensors and 12 impedance channels. Ten 5-mL liquid swallows of saline at 30-second intervals were conducted. The following parameters were calculated: distal contractile integral (DCI), distal latency (DL), lower esophageal sphincter (LES) basal pressure, 4-second integrated relaxation pressure (IRP-4s), and complete bolus transit percentage. Normal values were established based on the 5th and 95th percentiles. KEY RESULTS: All 66 participants (34 male, 32 female, aged 21 64 years) completed the study and tolerated the HRIM procedure well. The upper normal limit (95th percentile) of IRP-4 second was 20 mmHg. The 5th-95th percentile range for DCI, DL, and complete bolus transit was 99-2186 mmHg?s?cm, 6.2-11.3 second, and 50%-100%, respectively. Age was negatively correlated with DL. Females had significantly higher upper limits for IRP-4s and median DCI than males. Multivariate analyses confirmed that IRP-4s was higher in females, and that higher body mass index and waist circumference were associated with reduced DL and better bolus transit, respectively. CONCLUSIONS AND INFERENCES: We established normative values for the water-perfused HRIM system for a Chinese population. Gender and anthropometric factors may affect various major HRIM parameters and should be taken into account when interpreting HRIM results in clinical practice. PMID- 29230940 TI - The effects of recreational ketamine cystitis on urinary tract reconstruction - a surgical challenge. AB - OBJECTIVES: To identify the rate of postoperative complications in patients who require surgical reconstruction for ketamine-induced urinary tract dysfunction and to identify any predictors for poor postoperative outcome with subsequent management strategies. PATIENTS AND METHODS: A retrospective review of data collected between 2007 and 2017 of all patients with ketamine-induced urinary tract disease was performed. Evaluation included computed tomography urogram, cystoscopy, and biopsy. Indications and outcomes for surgical intervention were assessed. RESULTS: In all, 44 patients were identified of which 68% were male. The mean (range) age at presentation was 31 (23-55) years. All bladder biopsies confirmed an eosinophilic inflammatory infiltrate. A significant proportion of patients (81.8%) were found to have reduced cystoscopic bladder capacity of <300 mL (mean 196, range 25-550 mL). In all, 29 patients were treated conservatively with a view to symptom resolution. Two patients underwent dilatation for urethral strictures. Four patients underwent repeated intra-detrusor onabotulinum toxin injection with minimal subjective symptom relief. Two of these patients proceeded to have major reconstruction. Indications for urinary tract reconstruction included intractable symptoms, high-pressure compliance loss with renal compromise and ureteric obstruction. Patients were advised to abstain from ketamine use for a minimum of 6 months prior to consideration of surgical intervention. A total of 14 patients underwent major reconstruction. Surgical intervention included ileal conduit urinary diversion, augmentation cystoplasty with or without Mitrofanoff channels, ureteric re-implantation, and cystectomy with neobladders. Complications included anastomotic leaks, ureteric strictures, adhesional small bowel obstruction, renal failure, and sepsis. Overall, complications occurred in 10/14 patients. CONCLUSION: In a tertiary high-volume reconstructive unit, ketamine patients were at high risk of significant perioperative complications. There did not appear to be any other common factor apart from their use of ketamine, and the significant inflammatory change associated with this. We recommend meticulous preoperative evaluation and multidisciplinary consultation for all patients to determine optimal treatment strategies. PMID- 29230941 TI - A child with Myhre syndrome presenting with corectopia and tetralogy of Fallot. AB - Myhre syndrome is a rare autosomal dominant disorder caused by a narrow spectrum of missense mutations in the SMAD4 gene. Typical features of this disorder are distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, short hands and feet, compact build, joint stiffness, and skeletal anomalies. The clinical features generally appear during childhood and become more evident in older patients. Therefore, the diagnosis of this syndrome in the first years of life is challenging. We report a 2-year-old girl diagnosed with Myhre syndrome by whole exome sequencing (WES) that revealed the recurrent p.Ile500Val mutation in the SMAD4 gene. Our patient presented with growth deficiency, dysmorphic features, tetralogy of Fallot, and corectopia (also known as ectopia pupillae). The girl we described is the youngest patient with Myhre syndrome. Moreover, corectopia and tetralogy of Fallot have not been previously reported in this disorder. PMID- 29230942 TI - Visualization of Heterogeneous Oxygen Storage Behavior in Platinum-Supported Cerium-Zirconium Oxide Three-Way Catalyst Particles by Hard X-ray Spectro Ptychography. AB - The cerium density and valence in micrometer-size platinum-supported cerium zirconium oxide Pt/Ce2 Zr2 Ox (x=7-8) three-way catalyst particles were successfully mapped by hard X-ray spectro-ptychography (ptychographic-X-ray absorption fine structure, XAFS). The analysis of correlation between the Ce density and valence in ptychographic-XAFS images suggested the existence of several oxidation behaviors in the oxygen storage process in the Ce2 Zr2 Ox particles. Ptychographic-XAFS will open up the nanoscale chemical imaging and structural analysis of heterogeneous catalysts. PMID- 29230943 TI - Clinical information seeking in traumatic brain injury: a survey of Veterans Health Administration polytrauma care team members. AB - BACKGROUND: The polytraumatic nature of traumatic brain injury (TBI) makes diagnosis and treatment difficult. OBJECTIVES: To (1) characterise information needs among Veterans Health Administration (VHA) polytrauma care team members engaged in the diagnosis and treatment of TBI; (2) identify sources used for TBI related information; and (3) identify barriers to accessing TBI related information. METHODS: Cross-sectional online survey of 236 VHA polytrauma care team members. RESULTS: Most respondents (95.8%) keep at least somewhat current regarding TBI, but 31.5% need more knowledge on diagnosing TBI and 51.3% need more knowledge on treating TBI. Respondents use VHA affiliated sources for information, including local colleagues (81.7%), VHA offsite conferences/meetings (78.3%) and onsite VHA educational offerings (73.6%); however, limited time due to administrative responsibilities (50.9%), limited financial resources (50.4%) and patient care (50.4%) were prominent barriers. DISCUSSION: Medical librarians are in a unique position to develop information services, resources and other electronic tools that reflect the clinical context in which polytrauma care team members practice, and the different tasks they perform. CONCLUSION: Polytrauma care team members could benefit from additional information regarding the diagnosis and treatment of TBI. Addressing their information needs and supporting their information seeking requires a mulit-pronged approach to time and financial constraints. PMID- 29230945 TI - A novel peer feedback programme of family-centred rounds. AB - BACKGROUND: Family-centred rounds (FCRs) are becoming standard practice in in patient paediatrics. Few faculty development programmes to train doctors in how to lead FCRs have been described in the literature, yet recent studies of peer feedback of in-patient rounds in internal medicine suggest benefits to teaching practices. Peer feedback may be useful as a faculty development method for FCRs. The study objective was to describe the experience of paediatric hospitalists participating in a peer feedback programme based on direct observation of FCRs. METHODS: This was a qualitative study of 13 paediatric hospitalists at an academic centre, who participated in individual semi-structured interviews about their experience with the programme of peer feedback of FCRs. Interviews were transcribed and the data were analysed by coding statements of interest. Like content was categorised into over-arching themes. RESULTS: The resultant themes included: (1) comfort is key for participation; (2) initial trepidation fades; (3) seniority has an effect; and (4) peer feedback of FCRs has value. Several specific elements of feedback were provided to improve teaching behaviours. Recent studies of peer feedback of in-patient rounds in internal medicine suggest benefits to teaching practices DISCUSSION: This faculty development programme of peer feedback based on direct observation of FCRs was endorsed by participants at our institution. Our findings serve to inform other programmes interested in peer feedback or in faculty development opportunities for FCRs. PMID- 29230944 TI - Long term (4 years) improved insulin sensitivity following islet cell transplant in type 1 diabetes. AB - BACKGROUND: Impaired insulin sensitivity (IS) predicts complications and mortality in type 1 diabetes (T1D). Insulin sensitivity improves shortly after islet cell transplant for T1D, yet long-term changes in IS and associated factors such as patient characteristics, transplant factors, clinical management, and IS related biomarkers are unknown. METHODS: Up to 9 years (mean 4) of longitudinal data were available on 22 adults (18 female) with T1D who received 1 to 3 transplants in Phase 1/2 or 3 clinical trials (2004-2014). Metabolic testing posttransplant estimated IS by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR; 111 observations) and the Simple Index of Insulin Sensitivity (SIis ; 95 observations). RESULTS: Simple Index of Insulin Sensitivity significantly increased the first year posttransplant (P = .02), then stabilized (P = .39); HOMA-IR remained stable posttransplant (P = .92). Adjusting for age and BMI, higher SIis was associated with lower HbA1c following transplant (P = .03). Greater IS as measured by lower HOMA-IR and higher SIis was associated with lower fasting C-peptide (both P <= .04) and also with higher exenatide dose (both P <= .01). More islets transplanted were associated with higher SIis (P < .0001). Lower leptin at transplant predicted lower HOMA-IR and higher SIis after transplant, and lower bone marker receptor activator of nuclear factor kappa-B ligand predicted lower HOMA-IR (all P <= .01). CONCLUSIONS: Insulin sensitivity measured by SIis was improved several years following transplant, while IS measured by HOMA-IR did not worsen. Higher exenatide dose, more islets transplanted, and diet and exercise (lowering leptin and receptor activator of nuclear factor kappa-B ligand) may improve IS, which may enhance glycaemic control and lower metabolic demand on transplanted islets. Long-term clamp studies are needed to confirm these results. PMID- 29230946 TI - Direct HPLC separation of carnosine enantiomers with two chiral stationary phases based on penicillamine and teicoplanin derivatives. AB - Carnosine is present in high concentrations in specific human tissues such as the skeletal muscle, and among its biological functions, the remarkable scavenging activity toward reactive carbonyl species is noteworthy. Although the two enantiomers show almost identical scavenging reactivity toward reactive carbonyl species, only d-carnosine is poorly adsorbed at the gastrointestinal level and is stable in human plasma. Direct methods for the enantioselective analysis of carnosine are still missing even though they could find more effective applications in the analysis of complex matrices. In the present study, the use of two different chiral stationary phases is presented. A chiral ligand-exchange chromatography stationary phase based on N,S-dioctyl-d-penicillamine resulted in the direct enantioseparation of carnosine. Indeed, running the analysis at 25 degrees C and 1.0 mL/min with a 1.5 mM copper(II) sulfate concentration allowed us to obtain separation and resolution factors of 3.37 and 12.34, respectively. However, the use of a copper(II)-containing eluent renders it hardly compatible with mass spectrometry detectors. With the teicoplanin-based stationary phase, a mass spectrometry compatible method was successfully developed. Indeed, a water/methanol 60:40 v/v pH 3.1 eluent flowed at 1.0 mL/min and with a 25 degrees C column temperature produced separation and resolution factors of 2.60 and 4.16, respectively. PMID- 29230947 TI - Dietary Slowly Digestible Starch Triggers the Gut-Brain Axis in Obese Rats with Accompanied Reduced Food Intake. AB - SCOPE: Slowly digestible starch (SDS), as a functional carbohydrate providing a slow and sustained glucose release, may be able to modulate food intake through activation of the gut-brain axis. METHODS AND RESULTS: Diet-induced obese rats were used to test the effect on feeding behavior of high-fat (HF) diets containing an SDS, fabricated to digest into the ileum, as compared to rapidly digestible starch (RDS). Ingestion of the HF-SDS diet over an 11-week period reduced daily food intake, through smaller meal size, to the same level as a lean body control group, while the group consuming the HF-RDS diet remained at a high food intake. Expression levels (mRNA) of the hypothalamic orexigenic neuropeptide Y (NPY) and Agouti-related peptide (AgRP) were significantly reduced, and the anorexigenic corticotropin-releasing hormone (CRH) was increased, in the HF-SDS fed group compared to the HF-RDS group, and to the level of the lean control group. CONCLUSION: SDS with digestion into the ileum reduced daily food intake and paralleled suppressed expression of appetite-stimulating neuropeptide genes associated with the gut-brain axis. This novel finding suggests further exploration involving a clinical study and potential development of SDS-based functional foods as an approach to obesity control. PMID- 29230948 TI - Three-dimensional printed model of bilateral Wilms tumor: A useful tool for planning nephron sparing surgery. AB - Nephron sparing surgery (NSS) is increasingly utilized to treat patients with bilateral Wilms tumor. We present a case of NSS planning using a three dimensional computerized and printed model of both kidneys with anatomical structures of interest (parenchyma, renal pelvis, major calyx, renal artery, renal vein, and tumor). This model allowed a better understanding of the anatomic relation between the tumor and the normal kidney on each side, improving the surgical planning and the preoperative discussion with the patient's family. PMID- 29230949 TI - Glucocorticoid receptor activation is associated with increased resistance to heat-induced hyperthermia and injury. AB - AIM: Anti-inflammatory mediators likely play a key role in maintaining thermal homeostasis and providing protection against heat stress. The aim of this study was to investigate the association between activation of the glucocorticoid receptor (GR) and resistance to heat-induced hyperthermia and injury. METHODS: Effects of heat exposure on core body temperature, muscle GR phosphorylation status and subcellular expression were examined in control mice and thermal acclimation (TA)-exposed mice. In addition, effects of TA and corticosterone on C2C12 mouse myoblast viability and subcellular GR were assessed during heat exposure. RESULTS: Phosphorylated, nuclear and mitochondrial GR levels were significantly higher in the gastrocnemius muscles of mice with mild hyperthermia (tolerant), compared to mice with severe hyperthermia (intolerant) during a heat exposure test. Similar changes were found in mice after TA, compared to non-TA exposed controls. Additional groups of TA and non-TA-exposed mice underwent a heat exposure test. TA mice presented a significantly lower hyperthermic response during heat exposure than non-TA-exposed control. C2C12 cells exposed to TA incubation had higher viability against heat shock and showed higher GR levels in their mitochondria and nuclei detected by Western blot analysis and fluorescence microscopy, compared to cells exposed to normal incubation. Furthermore, pre incubation with 0.1 MUM corticosterone increased C2C12 cell viability during heat exposure and mitochondrial and nuclear GR expression. CONCLUSION: The results of these in vivo and in vitro studies suggest that GR activation is associated with increased resistance against heat-induced hyperthermia and injury. PMID- 29230950 TI - Converging and Integrating Our Knowledge to Sustain Humanity. AB - "Science must ever progress and expand, but the scientific community must not allow unbridled splintering into narrow categories. Our community will lose its trust if we cannot discard outdated perceptions, and if we allow ourselves to fossilize into a rigid academic system of small, narrow-minded specialist groups." Read more thoughts on the role of science and technology in order to sustain human civilization in the Editorial by Ryoji Noyori, who steps down from his position as board chairman of the journal. PMID- 29230951 TI - The artefacts of death: CT post-mortem findings. AB - Post-mortem CT is an increasingly used tool for investigating cause of death. While sharing many similarities with pre-mortem imaging, a number of unique artefacts occur at post-mortem CT, and these have the potential to mask underlying disease processes. It is vital that the artefacts associated with the process of dying and decompositional changes are recognised to avoid misdiagnosis. The following pictorial review discusses and illustrates the important and common post-mortem changes. PMID- 29230952 TI - Children tolerate intradialytic oral nutrition. AB - BACKGROUND: People undergoing haemodialysis (HD) often have poor nutrition, which in turn can contribute to worse outcomes. Inadequate nutrition has a particularly deleterious effect on growth and neurocognitive development, as well as mortality, in children and adolescents. Nutritional supplementation can improve outcomes but can be difficult to administer. OBJECTIVE: Determine the tolerability of intradialytic oral nutrition in children and adolescents. DESIGN: A cross-sectional quality improvement study in an outpatient paediatric HD unit. Intervention was intradialytic oral nutritional supplementation provided as protein bars and/or meals. SUBJECTS: Children and adolescents undergoing outpatient HD who were able to participate in surveys and eat by mouth. MEASUREMENTS: Adverse effects and symptoms on nurse- and patient-reported surveys, respectively. Relationships between the predictor variables and the outcomes were assessed using generalised estimating equations. RESULTS: The majority of children felt better after eating on dialysis (72%) with no adverse effects (80%). On unadjusted analyses and confirmed with generalised estimating equation modelling, children who reported being hungry felt better after eating on dialysis, despite being more likely to have adverse effects. CONCLUSION: The study demonstrates that our children and adolescents feel better after eating on HD with minimal adverse effects. The finding that hungry patients are more likely to feel better despite having a higher likelihood of an adverse effect demonstrates the tolerability of eating on HD. Intradialytic oral nutrition could be a safe and well-tolerated opportunity to provide supplemental nutrition to paediatric HD patients and improve outcomes. PMID- 29230954 TI - Association between vitamin D receptor polymorphisms and systemic lupus erythematosus in an Indian cohort. AB - AIM: Systemic lupus erythematosus (SLE) is an autoimmune disorder with various clinical manifestations. Susceptibility to development of SLE has been linked to several factors, such as genetic, environmental and hormonal. Vitamin D appears to have a regulatory role on disease manifestation and activity. Vitamin D exerts its effect through vitamin D receptors (VDR). Several studies have demonstrated an association between VDR polymorphisms and susceptibility to SLE in different populations, although the results are still inconclusive. In the present study, we investigated the association of VDR polymorphisms with SLE in a cohort of patients from Odisha, India. METHODS: Female SLE patients (n = 331) who fulfilled the revised American College of Rheumatology classification criteria were enrolled along with 282 healthy controls from similar geographical areas. VDR polymorphisms (BsmI, ApaI, TaqI and FokI) were typed by polymerase chain reaction followed by restriction fragment length polymorphism. Plasma level of 25-OH vitamin D was quantified by enzyme-linked immunosorbent assay. RESULTS: Prevalence of FokI (Ff) and TaqI (Tt) heterozygotes were significantly higher in SLE patients compared to healthy controls (Ff: P < 0.0001, odds ratio [OR] = 2.80, 95%CI = 1.99-3.95; Tt: P < 0.0001, OR = 2.07, 95%CI = 1.49-2.89). Furthermore, the minor alleles of FokI (f) and TaqI (t) polymorphisms were also more frequent in SLE patients than healthy controls (f: P < 0.0001, OR = 1.96, 95%CI = 1.52-2.52; t: P = 0.0002, OR = 1.60, 95%CI = 1.25-2.09). CONCLUSIONS: FokI and TaqI variants are significantly associated with SLE in an eastern Indian cohort. The cause-effect relationship can be assessed from the combined analyses of VDR polymorphism, plasma vitamin D levels and clinical manifestations. PMID- 29230955 TI - Diagnostic value of cell bound and circulating neutrophil antibody detection in pediatric neutropenia. AB - BACKGROUND: Chronic benign neutropenia of infancy includes primary autoimmune neutropenia (pAIN) and chronic idiopathic neutropenia (CIN). A diagnosis of CIN is supported by the absence of free and/or cell-bound neutrophil autoantibodies, which can be detected by flow cytometry with the indirect-granulocyte immunofluorescence test (I-GIFT) and direct-granulocyte immunofluorescence test (D-GIFT), respectively. Conclusive evidence is lacking on the diagnostic value of the D-GIFT, whose performance requires specific laboratory expertise, may be logistically difficult, and hampered by very low neutrophil count in patient samples. This study investigated whether the evaluation of D-GIFT improves the diagnostic accuracy of pediatric neutropenia. PROCEDURE: I-GIFT and D-GIFT were performed in 174 pAIN, 162 CIN, 81 secondary AIN, 51 postinfection neutropenic, and 65 nonautoimmune neutropenic children referred to this laboratory during 2002 2014. RESULTS: Using 90% specific median fluorescence intensity cut-off values calculated by receiver operating characteristic curves, D-GIFT was positive in 49% of CIN patients, who showed similar clinical features as those with pAIN. In 44 (27%) of 162 CIN patients, I-GIFT was repeated two to three times in a year, resulting positive in 12 and two patients at second and third screening, respectively. Interestingly, 10 of the latter 14 patients showed a positive D GIFT at the first serological screening. False positive D-GIFT was shown by 12% and 22% of nonneutropenic and nonautoimmune neutropenic patients, respectively. CONCLUSIONS: D-GIFT evaluation improves the diagnostic accuracy of pediatric neutropenia, but improvement of cell-bound antibody detection is needed to decrease false positive results. PMID- 29230953 TI - Predictors of CD4 cell recovery following initiation of antiretroviral therapy among HIV-1 positive patients with well-estimated dates of seroconversion. AB - OBJECTIVES: To investigate factors that predict speed of recovery and long-term CD4 cell count in HIV-1 seroconverters initiating combination antiretroviral therapy (cART), and to quantify the influence of very early treatment initiation. We make use of all pre-treatment CD4 counts, because analyses using only a single observation at initiation may be subject to biases. METHODS: We used data from the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) multinational cohort collaboration of HIV-1 seroconverters. We analysed pre- and post-treatment data of patients with seroconversion dates estimated January 2003 March 2014 (n = 7600 for primary analysis) using a statistical model in which the characteristics of recovery in CD4 counts are determined by multiple predictive factors. Secondary analyses were performed incorporating uncertainty in the exact timing of seroconversion to allow more precise estimation of the benefit of very early treatment initiation. RESULTS: 'True' CD4 count at cART initiation was the strongest predictor of CD4 count beyond 3 years on cART. Allowing for lack of complete certainty in the date of seroconversion, CD4 recovery was more rapid for patients in whom treatment was initiated within 4 months. For a given CD4 count, higher viral load (VL) at initiation was strongly associated with higher post treatment CD4 recovery. For other patient and drug characteristics, associations with recovery were statistically significant but small in magnitude. CONCLUSIONS: CD4 count at cART initiation is the most important factor in predicting post treatment recovery, but VL provides substantial additional information. If cART is initiated in the first 4 months following seroconversion, recovery of CD4 counts appears to be more rapid. PMID- 29230956 TI - Prevalence of non 18 F-fluorodeoxyglucose-avid incidental findings of clinical significance on whole body positron emission tomography/computed tomography: A review of 500 consecutive cases. AB - INTRODUCTION: The prevalence of incidental 18 F-fluorodeoxyglucose (FDG)-avid findings on positron emission tomography-computed tomography (PET/CT) has been extensively described. Few studies, however, have assessed the prevalence and significance of non-FDG-avid findings; pathology that is identified on review of the low-dose, non-contrast CT. The aim of this study was to determine the overall prevalence of non FDG-avid incidental findings on PET/CT and the prevalence of 'clinically significant' non FDG-avid pathology. METHODS: Five hundred consecutive whole body PET/CT studies performed in 2016 at a university affiliated tertiary hospital were retrospectively reviewed by two radiologists experienced in reporting PET/CT. Findings were categorized according to potential clinical relevance, and a targeted follow-up of clinically significant incidental findings was performed. RESULTS: Incidental findings were encountered in 463 of 500 (92.6%) patients. In 226 patients, these findings had been detected on previous imaging studies, with unknown incidental findings present in 237 of 500 (47.4%) patients. 113 of 500 (22.6%) patients had non-avid incidental findings of potentially major clinical significance, and in 35 patients (7.0%) these findings were considered previously unknown. The most common non-avid findings of potentially major significance were pulmonary nodules (6 mm or larger), moderate or large size pleural effusions, and vascular aneurysms. Unknown incidental findings of potentially major clinical significance were significantly higher in patients imaged for melanoma staging (P= 0.004). CONCLUSION: The prevalence of incidental findings of clinical significance that do not accumulate FDG in PET/CT is not insignificant. Routine systematic review of the low-dose CT is required to avoid missing potentially clinically important findings, in particular pleural effusions, vascular aneurysms and metastatic pulmonary nodules. PMID- 29230957 TI - An implementation algorithm to improve skin-to-skin practice in the first hour after birth. AB - Evidence supporting the practice of skin-to-skin contact and breastfeeding soon after birth points to physiologic, social, and psychological benefits for both mother and baby. The 2009 revision of Step 4 of the WHO/UNICEF "Ten Steps to Successful Breastfeeding" elaborated on the practice of skin-to-skin contact between the mother and her newly born baby indicating that the practice should be "immediate" and "without separation" unless documented medically justifiable reasons for delayed contact or interruption exist. While in immediate, continuous, uninterrupted skin-to-skin contact with mother in the first hour after birth, babies progress through 9 instinctive, complex, distinct, and observable stages including self-attachment and suckling. However, the most recent Cochrane review of early skin-to-skin contact cites inconsistencies in the practice; the authors found "inadequate evidence with respect to details ... such as timing of initiation and dose." This paper introduces a novel algorithm to analyse the practice of skin to skin in the first hour using two data sets and suggests opportunities for practice improvement. The algorithm considers the mother's Robson criteria, skin-to-skin experience, and Widstrom's 9 Stages. Using data from vaginal births in Japan and caesarean births in Australia, the algorithm utilizes data in a new way to highlight challenges to best practice. The use of a tool to analyse the implementation of skin-to-skin care in the first hour after birth illuminates the successes, barriers, and opportunities for improvement to achieving the standard of care for babies. Future application should involve more diverse facilities and Robson's classifications. PMID- 29230959 TI - Fishing for histamine H3 receptor functions. PMID- 29230958 TI - Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia. AB - BACKGROUND: Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment-related toxicity impacts survival. PROCEDURE: In this retrospective population-based study, we described the causes of death and estimated the risk for treatment-related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL-92 and ALL-2000 trials. RESULTS: Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment-related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment-related mortality were as follows: high-risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3-3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3-9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17-9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment-related causes. CONCLUSIONS: Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL. PMID- 29230960 TI - CIQ, a positive allosteric modulator of GluN2C/D-containing N-methyl-d-aspartate receptors, rescues striatal synaptic plasticity deficit in a mouse model of Parkinson's disease. AB - AIMS: To investigate if CIQ, a positive allosteric modulator of N-methyl-d aspartate receptors (NMDARs) containing GluN2C/D subunits, rescues the loss of long-term potentiation (LTP) and forelimb-use asymmetry in a mouse model of Parkinson's disease (PD). METHODS: We have used electrophysiology in brain slices and the cylinder test to examine the effect of CIQ on glutamatergic synaptic transmission, synaptic plasticity, and forelimb-use in the unilateral 6 hydroxydopamine-lesion mouse model of PD. RESULTS: CIQ, applied in the perfusion solution, reversibly reduced glutamatergic synaptic transmission in the dopamine depleted striatum and had no effect in the dopamine-intact striatum. LTP, a dopamine- and NMDAR-dependent form of synaptic plasticity, was induced in the dopamine-intact striatum but was lost in the dopamine-depleted striatum. This impaired LTP was restored in the presence of CIQ applied in the perfusion solution. This treatment, however, prevented LTP induction in control slices. In brain slices from mice which received single and chronic intraperitoneal injections of CIQ, LTP was restored in the dopamine-depleted striatum and unaffected in the dopamine-intact striatum. Forelimb-use asymmetry, a test which assesses deficits in paw usage in the unilateral lesion model of PD, was reversed by systemic chronic treatment with CIQ. CONCLUSION: A positive allosteric modulator of GluN2C/D-containing NMDARs rescues LTP and forelimb-use asymmetry in a mouse model of PD. This study proposes GluN2D as a potential candidate for therapeutic intervention in PD. PMID- 29230961 TI - Health and social factors associated with a delayed discharge amongst inpatients in acute geriatric wards: A retrospective observational study. AB - AIM: In the English National Health Service there is an increasing interest in understanding the factors associated with delayed discharges in older hospitalized adults. The present study sought to analyze whether clinical frailty was a significant and independent risk factor for having a delayed discharge when the data were controlled for potential health and social confounders. METHODS: This was a retrospective observational study in an English National Health Service teaching hospital. We analyzed all first hospitalization episodes to the Department of Medicine for the Elderly between 1 May 2016 and 31 July 2016. A delayed discharge was operationally defined as a patient being discharged more than 24 h after his/her last recorded clinically fit date. RESULTS: A total of 924 cases were analyzed. The independent risk factors for having a delayed discharge were: needing a new package of care (OR 4.05, 95% CI 2.68-6.10), new institutionalization (OR 2.78, 95% CI:1.67-4.62), living alone (OR 1.98, 95% CI 1.40-2.81), delirium (OR 1.79, 95% CI 1.17-2.74) and frailty (i.e. >=5 on the Clinical Frailty Scale, OR 1.74, 95% CI 1.15-2.63). CONCLUSIONS: The present results are consistent with previous reports that delayed discharges in older hospitalized patients are mainly related to new formal social care requirements in survivors of acute illness. Frailty was an independent risk factor for delay, but its effect might have been confounded by the unmeasured variable of informal care requirements. Our operational definition of delayed discharge does not mirror the legal definition of delayed transfer of care in England, and the results are not externally valid. Geriatr Gerontol Int 2018; 18: 530-537. PMID- 29230962 TI - Hypogammaglobulinemia due to CAR T-cell therapy. PMID- 29230963 TI - Unravelling current sexual care in chronic kidney disease: perspective of social workers. AB - BACKGROUND: Fifty to eighty percent of patients suffering from chronic kidney disease (CKD) experience a form of sexual dysfunction (SD), even after renal transplantation. Despite this, inquiring about SD is often not included in the daily practice of renal care providers. OBJECTIVES: This paper explores the perspectives of renal social workers regarding sexual care for patients and evaluates their practice, attitude towards responsibility and knowledge of SD. DESIGN: A cross-sectional study was conducted using a 41-item online survey. PARTICIPANTS: Seventy-nine members of the Dutch Federation of Social Workers Nephrology. RESULTS: It was revealed that 60% of respondents discussed SD with a fifth of their patients. Frequency of discussion was associated with experience (p = 0.049), knowledge (p = 0.001), supplementary education (p = 0.006), and the availability of protocols on sexual care (p = 0.007). Main barriers towards discussing SD consisted of 'culture and religion' (51.9%), 'language and ethnicity' (49.4%), and 'presence of a third person' (45.6%). Sufficient knowledge of SD was present in 28% of respondents. The responsibility for discussion was 96% nephrologists and 81% social workers. CONCLUSION: This study provides evidence that a part of Dutch nephrology social workers do not provide sexual care regularly, due to insufficient experience and sexual knowledge, absence of privacy and protocols and barriers based on cultural diversity. According to the respondents the responsibility for this aspect of care should be multidisciplinary. Recommendations include a need for further education on the topic, private opportunities to discuss SD and multidisciplinary guidelines on sexual care. PMID- 29230964 TI - Preventive effect of diverting stoma on anastomotic leakage after laparoscopic low anterior resection with double stapling technique reconstruction applied based on risk stratification. AB - INTRODUCTION: During laparoscopic low anterior resection with double stapling technique reconstruction, it is necessary to securely implement rectal transection and anastomosis to prevent anastomotic leakage (AL). However, risk factors and preventive measures for AL are not known sufficiently. Therefore, this study aimed to elucidate risk factors associated with AL and to clarify strategies to prevent it. METHODS: We analyzed a total of 296 cases with rectal cancer who had undergone laparoscopic low anterior resection with double stapling technique reconstruction at the National Cancer Center Hospital East. The relationship between AL and patient, tumor, and treatment characteristics were retrospectively investigated. RESULTS: There were 186 male and 110 female patients with a median age of 62. Overall, AL occurred in 24 cases (8.1%). Being a man, having an anal verge distance <=7 cm, and undergoing neoadjuvant chemotherapy were associated with an elevated risk for AL (P = 0.0005, 0.0034, and 0.0222, respectively). Neither an anal drainage tube nor diverting stoma creation correlated with incidence of AL. Multivariate analysis demonstrated that being a man (odds ratio = 18.0; 95% confidence interval: 2.4-138) and having an anal verge distance <=7 cm (odds ratio = 3.8; 95% confidence interval: 1.5-9.4) were significant risk factors. These two factors were present in 61 cases, including 14 who developed AL (23.0%). In this high-risk group, diverting stoma creation significantly reduced the occurrence of AL (P = 0.0363), but an anal drainage tube had no effect on incidence of AL (P = 0.3399). CONCLUSION: We identified the high-risk population for AL after laparoscopic low anterior resection with double stapling technique reconstruction based on two factors. This will enable surgeons to appropriately recommend diverting stoma creation. PMID- 29230966 TI - Transcriptome analysis and anaerobic C4 -dicarboxylate transport in Actinobacillus succinogenes. AB - A global transcriptome analysis of the natural succinate producer Actinobacillus succinogenes revealed that 353 genes were differentially expressed when grown on various carbon and energy sources, which were categorized into six functional groups. We then analyzed the expression pattern of 37 potential C4 -dicarboxylate transporters in detail. A total of six transporters were considered potential fumarate transporters: three transporters, Asuc_1999 (Dcu), Asuc_0304 (DASS), and Asuc_0270-0273 (TRAP), were constitutively expressed, whereas three others, Asuc_1568 (DASS), Asuc_1482 (DASS), and Asuc_0142 (Dcu), were differentially expressed during growth on fumarate. Transport assays under anaerobic conditions with [14 C]fumarate and [14 C]succinate were performed to experimentally verify that A. succinogenes possesses multiple C4 -dicarboxlayte transport systems with different substrate affinities. Upon uptake of 5 mmol/L fumarate, the systems had substrate specificity for fumarate, oxaloacetate, and malate, but not for succinate. Uptake was optimal at pH 7, and was dependent on both proton and sodium gradients. Asuc_1999 was suspected to be a major C4 -dicarboxylate transporter because of its noticeably high and constitutive expression. An Asuc_1999 deletion (?1999) decreased fumarate uptake significantly at approximately 5 mmol/L fumarate, which was complemented by the introduction of Asuc_1999. Asuc_1999 expressed in Escherichia coli catalyzed fumarate uptake at a level of 21.6 MUmol.gDW-1 .min-1 . These results suggest that C4 -dicarboxylate transport in A. succinogenes is mediated by multiple transporters, which transport various types and concentrations of C4 -dicarboxylates. PMID- 29230967 TI - The Obesity Factor: How Cardiorespiratory Fitness is Estimated More Accurately in People with Obesity. AB - OBJECTIVE: Cardiopulmonary exercise testing is clinically used to estimate cardiorespiratory fitness (CRF). The relation to total body mass (TBM) leads to an underestimation of CRF in people with obesity and to inappropriate prognostic and therapeutic decisions. This study aimed to determine body composition-derived bias in the estimation of CRF in people with obesity. METHODS: Two hundred eleven participants (58.8% women; mean BMI 35.7 kg/m2 [+/- 6.94; 20.7-58.6]) were clinically examined, and body composition (InBody720; InBody Co., Ltd., Seoul, South Korea) and spiroergometrical peak oxygen consumption (VO2 peak) were assessed. The impacts of TBM, lean body mass (LBM), and skeletal muscle mass (SMM) on CRF estimates were analyzed by the application of respective weight models. Linear regression and plotting of residuals against BMI were performed on the whole study population and two subgroups (BMI < 30 kg/m2 and BMI >= 30 kg/m2 ). RESULTS: For every weight model, Deltamean VO2 peak (expected - measured) was positive. LBM and SMM had a considerable impact on VO2 peak demand (P = 0.001; DeltaR2 = 2.3%; adjusted R2 = 56% and P = 0.001; DeltaR2 = 2.7%; adjusted R2 = 56%), whereas TBM did not. Confounding of body composition on VO2 peak did not differ in LBM and SMM. CONCLUSIONS: TBM-adjusted overestimation of relative VO2 demand is much higher in people with obesity than in those without. LBM or SMM adjustment may be superior alternatives, although small residual body composition derived bias remains. PMID- 29230965 TI - Prevention of chemotherapy-induced cachexia by ACVR2B ligand blocking has different effects on heart and skeletal muscle. AB - BACKGROUND: Toxicity of chemotherapy on skeletal muscles and the heart may significantly contribute to cancer cachexia, mortality, and decreased quality of life. Doxorubicin (DOX) is an effective cytostatic agent, which unfortunately has toxic effects on many healthy tissues. Blocking of activin receptor type IIB (ACVR2B) ligands is an often used strategy to prevent skeletal muscle loss, but its effects on the heart are relatively unknown. METHODS: The effects of DOX treatment with or without pre-treatment with soluble ACVR2B-Fc (sACVR2B-Fc) were investigated. The mice were randomly assigned into one of the three groups: (1) vehicle (PBS)-treated controls, (2) DOX-treated mice (DOX), and (3) DOX-treated mice administered with sACVR2B-Fc during the experiment (DOX + sACVR2B-Fc). DOX was administered with a cumulative dose of 24 mg/kg during 2 weeks to investigate cachexia outcome in the heart and skeletal muscle. To understand similarities and differences between skeletal and cardiac muscles in their responses to chemotherapy, the tissues were collected 20 h after a single DOX (15 mg/kg) injection and analysed with genome-wide transcriptomics and mRNA and protein analyses. The combination group was pre-treated with sACVR2B-Fc 48 h before DOX administration. Major findings were also studied in mice receiving only sACVR2B Fc. RESULTS: The DOX treatment induced similar (~10%) wasting in skeletal muscle and the heart. However, transcriptional changes in response to DOX were much greater in skeletal muscle. Pathway analysis and unbiased transcription factor analysis showed that p53-p21-REDD1 is the main common pathway activated by DOX in both skeletal and cardiac muscles. These changes were attenuated by blocking ACVR2B ligands especially in skeletal muscle. Tceal7 (3-fold to 5-fold increase), transferrin receptor (1.5-fold increase), and Ccl21 (0.6-fold to 0.9-fold decrease) were identified as novel genes responsive to blocking ACVR2B ligands. Overall, at the transcriptome level, ACVR2B ligand blocking had only minor influence in the heart while it had marked effects in skeletal muscle. The same was also true for the effects on tissue wasting. This may be explained in part by about 18-fold higher gene expression of myostatin in skeletal muscle compared with the heart. CONCLUSIONS: Cardiac and skeletal muscles display similar atrophy after DOX treatment, but the mechanisms for this may differ between the tissues. The present results suggest that p53-p21-REDD1 signalling is the main common DOX activated pathway in these tissues and that blocking activin receptor ligands attenuates this response, especially in skeletal muscle supporting the overall stronger effects of this treatment in skeletal muscles. PMID- 29230968 TI - Attenuated first-rank symptoms and conversion to psychosis in a clinical high risk cohort. AB - AIM: We sought to examine attenuated first-rank symptoms (FRS) and subcomponents of the Unusual Thought Content (P.1.) section of the Structured Interview for Psychosis-Risk Syndromes (SIPS) to investigate the robust relationship between total P.1. and conversion. We hypothesized that attenuated FRS would drive the association and, additionally, be most predictive of a schizophrenia diagnosis. METHOD: We assessed 189 clinical high-risk participants. Two independent raters separately scored attenuated FRS and each subcomponent of P.1. as if each were the only symptom reported. Total P.1. was also scored. Participants were evaluated for conversion up to 2 years. RESULTS: While total P.1. score significantly predicted conversion in the 54 converters, attenuated FRS, which were relatively uncommon in this sample, nor any subcomponent of P.1., was independently predictive. FRS did not predict conversion to schizophrenia among 35 subjects. CONCLUSION: Although attenuated FRS, and subcomponents of P.1. of the SIPS, did not significantly predict transition to psychosis, our results support previous research affirming the value of total P.1. score as a tool for predicting conversion to psychosis. PMID- 29230969 TI - Laparoscopic colectomy after self-expanding metallic stent placement through the ileocecal valve for right-sided malignant colonic obstruction: A case report. AB - A 78-year-old man with a history of open sigmoidectomy for sigmoid cancer presented with abdominal pain and vomiting. Abdominal multi-detector CT revealed an obstructive ileocecal tumor with distended small bowel on the oral side. We performed emergency drainage using a transnasal decompression tube, and 2 days later, we conducted a colonoscopic examination, which lead to a provisional diagnosis of obstruction with a malignant tumor invading the ileocecal valve. We then placed a self-expanding metallic stent (SEMS) through the ileocecal valve. We confirmed patency of the ileocecal valve and removed the transnasal decompression tube 2 days after SEMS placement. We then performed elective laparoscopic colectomy 8 days after SEMS placement. To the best of our knowledge, there has been only one previous report of laparoscopic colectomy after decompression with SEMS placement through the ileocecal valve for right-sided malignant colonic obstruction. PMID- 29230971 TI - Electroless-coated magnetic three-dimensional graphene with silver nanoparticles used for the determination of pesticides in fruit samples. AB - A new type of adsorbent composed of magnetic three-dimensional graphene coated with silver nanoparticles was synthesized by an electroless technique and used in the magnetic solid-phase extraction of selected pesticides (fenitrothion, chlorpyrifos, and hexaconazole) before gas chromatography with a micro-electron capture detector. The adsorbent was characterized using Fourier-transform infrared spectroscopy, X-ray diffraction, vibrating sample magnetometry, and field-emission scanning electron microscopy. The important extraction parameters such as pH, adsorbent dose, extraction time, and desorption conditions were investigated. Under the optimal conditions, the analytical figures of merit were obtained as: linear dynamic range of 0.1-5 ng/g with determination coefficients of 0.991-0.996; limit of detection of 0.07-0.13 ng/g; limit of quantification of 0.242-0.448 ng/g; and the intraday and interday relative standard deviations (C = 5 ng/g, n = 3) were 3.8-8.7 and 6.6-8.9%, respectively. The developed method was successfully applied for analysis of the selected pesticides in tomato and grape with extraction recoveries in the range of 72.8-109.6%. PMID- 29230970 TI - The DNABII family of proteins is comprised of the only nucleoid associated proteins required for nontypeable Haemophilus influenzae biofilm structure. AB - Biofilms play a central role in the pathobiology of otitis media (OM), bronchitis, sinusitis, conjunctivitis, and pneumonia caused by nontypeable Haemophilus influenzae (NTHI). Our previous studies show that extracellular DNA (eDNA) and DNABII proteins are essential components of biofilms formed by NTHI. The DNABII protein family includes integration host factor (IHF) and the histone like protein HU and plays a central role in NTHI biofilm structural integrity. We demonstrated that immunological targeting of these proteins during NTHI-induced experimental OM in a chinchilla model caused rapid clearance of biofilms from the middle ear. Given the essential role of DNABII proteins in maintaining the structure of an NTHI biofilm, we investigated whether any of the other nucleoid associated proteins (NAPs) expressed by NTHI might play a similar role, thereby serving as additional target(s) for intervention. We demonstrated that although several NAPs including H-NS, CbpA, HfQ and Dps are present within the biofilm extracellular matrix, only the DNABII family of proteins is critical for the structural integrity of the biofilms formed by NTHI. We have also demonstrated that IHF and HU are located at distinct regions within the extracellular matrix of NTHI biofilms formed in vitro, indicative of independent functions of these two proteins. PMID- 29230972 TI - The CHOICE pilot project: Challenges of implementing a combined peer work and shared decision-making programme in an early intervention service. AB - AIM: Youth participation is central to early intervention policy and quality frameworks. There is good evidence for peer support (individuals with lived experience helping other consumers) and shared decision making (involving consumers in making decisions about their own care) in adult settings. However, youth programs are rarely tested or described in detail. This report aims to fill this gap by describing a consumer focused intervention in an early intervention service. METHODS: This paper describes the development process, intervention content and implementation challenges of the Choices about Healthcare Options Informed by Client Experiences and Expectations (CHOICE) Pilot Project. This highly novel and innovative project combined both youth peer work and youth shared decision making. RESULTS: Eight peer workers were employed to deliver an online shared decision-making tool at a youth mental health service in New South Wales, Australia. The intervention development involved best practice principles, including international standards and elements of co-design. The implementation of the peer workforce in the service involved a number of targeted strategies designed to support this new service model. However, several implementation challenges were experienced which resulted in critical learning about how best to deliver these types of interventions. CONCLUSIONS: Delivering peer work and shared decision making within an early intervention service is feasible, but not without challenges. Providing adequate detail about interventions and implementation strategies fills a critical gap in the literature. Understanding optimal youth involvement strategies assists others to deliver acceptable and effective services to young people who experience mental ill health. PMID- 29230973 TI - Sensitivity, specificity and predictive probability values of serum agglutination test titres for the diagnosis of Salmonella Dublin culture-positive bovine abortion and stillbirth. AB - The objective of this study was to determine the diagnostic value of maternal serology for the diagnosis of Salmonella Dublin bovine abortion and stillbirth. A retrospective, unmatched, case-control study was carried out using twenty year's data (1989-2009) from bovine foetal submissions to an Irish government veterinary laboratory. Cases (n = 214) were defined as submissions with a S. Dublin culture positive foetus from a S. Dublin unvaccinated dam where results of maternal S. Dublin serology were available. Controls (n = 415) were defined as submissions where an alternative diagnosis other than S. Dublin was made in a foetus from an S. Dublin unvaccinated dam where the results of maternal S. Dublin serology were available. A logistic regression model was fitted to the data: the dichotomous dependent variable was the S. Dublin foetal culture result, and the independent variables were the maternal serum agglutination test (SAT) titre results. Salmonella serology correctly classified 87% of S. Dublin culture-positive foetuses at a predicted probability threshold of 0.44 (cut-off at which sensitivity and specificity are at a maximum, J = 0.67). The sensitivity of the SAT at the same threshold was 73.8% (95% CI: 67.4%-79.5%), and the specificity was 93.2% (95% CI: 90.3%-95.4%). The positive and negative predictive values were 84.9% (95% CI: 79.3%-88.6%) and 87.3% (95% CI: 83.5%-91.3%), respectively. This study illustrates that the use of predicted probability values, rather than the traditional arbitrary breakpoints of negative, inconclusive and positive, increases the diagnostic value of the maternal SAT. Veterinary laboratory diagnosticians and veterinary practitioners can recover from the test results, information previously categorized, particularly from those results declared to be inconclusive. PMID- 29230974 TI - Diagnostic yield and accuracy of a new cytology brush design compared to standard brush cytology for evaluation of biliary strictures. AB - BACKGROUND: The sensitivity of brush cytology for biliary strictures has typically been low, usually 30%-60%. We compared the cellular yield and diagnostic accuracy using a new cytology brush (n = 16) versus standard biliary brushings (n = 16) in 32 patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) with brushings for evaluation of a biliary stricture for malignancy. METHODS: We performed retrospective chart reviews of 16 consecutive ERCPs with brushings performed for the cytologic evaluation of a biliary stricture for malignancy using the new cytology brush between January 2016 and February 2017 at our institution. Our control cohort was 16 consecutive ERCP cases performed for the same indication directly preceding the availability of the new cytology brush. RESULTS: The biliary brushing cases performed using the new cytology brush demonstrated a significantly increased number of total cell clusters per representative *20 field compared with cases using the standard brush (mean 24.6 versus 14.4, P = .03). This trend continued when assessing large (>50 cells) clusters (mean 5.8 vs. 3.3, P = .02) and medium (6-49 cells) clusters (11.1 vs. 5.8, P = .03). Nonetheless, there were no statistically significant differences with regards to diagnostic accuracy for the new cytology brush versus standard biliary brushings. CONCLUSION: We found that the Infinity brush significantly increased diagnostic yield with regards to total cell clusters, large (>50 cells) clusters, and medium (6-49 cells) clusters, however, this did not lead to increased diagnostic accuracy overall. Further studies of this and other brush designs are warranted to optimize biliary brushing specimens. PMID- 29230975 TI - Negative Pap tests in women with high-grade cervical lesions on follow-up biopsies: Contributing factors and role of human papillomavirus genotyping. AB - BACKGROUND: Previous studies have indicated that negative Papanicolaou (Pap) tests can precede high-grade cervical lesions (HGCL) on biopsy. This study aims to determine the contributing factors for cytologic discrepancy and the potential role of human papilloma virus (HPV) testing in risk evaluation of women with negative Pap tests. METHODS: Of 42,797 Pap tests interpreted as negative for intraepithelial lesion or malignancy (NILM) from March 1, 2013 to December 30, 2014, 426 had available HPV testing and follow-up biopsy. The NILM Pap tests with biopsy-confirmed HGCL were reviewed. RESULTS: Among 426 cytology-negative cases, the biopsies showed benign histology in 243 (57%), low-grade squamous intraepithelial lesion in 157 (37%), HGCL in 22 (5%), and endometrial adenocarcinoma in 4 (1%) cases. The sensitivity/specificity/positive predictive values (PPV) of high-risk HPV (hrHPV) and HPV16/18 tests in predicting HGCL was 91%/45%/8% and 55%/76%/11%, respectively. Upon review of NILM Pap tests with biopsy-confirmed HGCL, the contributing factors to negative cytology included absence of abnormal cells (12/21, 57%) or diagnostic high-grade cells (6/21, 29%), unsatisfactory samples (2/21, 10%), and interpretation variances (1/21, 5%). Interpretation variances in three high-risk lesions (1 HSIL, 2 ASC-H) were influenced by marked obscuring inflammation. CONCLUSIONS: Our study demonstrated that 5% of women underwent co-testing with negative Pap tests had HGCL on follow up biopsy. Absence of diagnostic cells was the leading cause for cytology discrepancy and interpretation variances were influenced by marked obscuring inflammation. HPV testing and genotyping had limited value in risk stratification due to extremely low PPV. Focused rescreening of hrHPV-positive NILM with obscuring factors may help reduce interpretation variances. PMID- 29230976 TI - Efficacy and Safety of a Large Conjunctival Autograft for Recurrent Pterygium. AB - PURPOSE: To evaluate the efficacy and safety of pterygium excision using a large conjunctival autograft for the treatment of recurrent pterygium. METHODS: The medical records of 120 patients (126 eyes) with recurrent pterygium were reviewed. For each affected eye, pterygium excision with a large conjunctival autograft was performed. The graft was harvested from the superior bulbar area and measured more than 8 * 10 mm in size. Only patients who completed at least six months of follow-up were included. Postoperative clinical outcomes, recurrence rate, and complications were analyzed. Patients with any evidence of recurrence after surgery received a subconjunctival bevacizumab injection. RESULTS: The average patient age was 56.5 +/- 10.2 years, and 45 out of 120 patients were male. The mean study follow-up period was 17.7 +/- 17.6 months. Most patients were satisfied with the cosmetic outcome. Postoperative visual acuity improved from 0.69 to 0.75 (p < 0.05). Postoperative refractive astigmatism and corneal astigmatism decreased by 0.55 and 2.73 diopters, respectively (p < 0.05). The postoperative recurrence rate was 4.0%, and the average recurrence period was 7.4 +/- 0.6 weeks. A subconjunctival injection of 5 mg bevacizumab was performed in cases of recurrence; no progression of the pterygium was observed following the injection. Postoperative complications included 2 cases of conjunctival graft edema in 2 eyes, 5 donor site scars in 5 eyes, 13 pyogenic granulomas in 13 eyes, and a conjunctival epithelial inclusion cyst in 7 eyes. CONCLUSIONS: Pterygium excision with a large conjunctival autograft for the treatment of recurrent pterygium produced an excellent cosmetic outcome, a low recurrence rate, and minimal complications. A subconjunctival bevacizumab injection given in cases of recurrence following surgery might be effective in preventing progression of the pterygium. PMID- 29230977 TI - Scleral Buckling Using a Non-contact Wide-Angle Viewing System with a 25-Gauge Chandelier Endoilluminator. AB - PURPOSE: To report the outcome of scleral buckling using a non-contact wide-angle viewing system with a 25-gauge chandelier endoilluminator. METHODS: Retrospective analyses of medical records were performed for 17 eyes of 16 patients with primary rhegmatogenous retinal detachment (RRD) without proliferative vitreoretinopathy who had undergone conventional scleral buckling with cryoretinopexy using the combination of a non-contact wide-angle viewing system and chandelier endoillumination. RESULTS: The patients were eight males and five females with a mean age of 26.8 +/- 10.2 (range, 11 to 47) years. The mean follow up period was 7.3 +/- 3.1 months. Baseline best-corrected visual acuity was 0.23 +/- 0.28 logarithm of the minimum angle of resolution units. Best-corrected visual acuity at the final visit showed improvement (0.20 +/- 0.25 logarithm of the minimum angle of resolution units), but the improvement was not statistically significant (p = 0.722). As a surgery-related complication, there was vitreous loss at the end of surgery in one eye. As a postoperative complication, increased intraocular pressure (four cases) and herpes simplex epithelial keratitis (one case) were controlled postoperatively with eye drops. One case of persistent RRD after primary surgery needed additional vitrectomy, and the retina was postoperatively attached. CONCLUSIONS: Scleral buckling with chandelier illumination as a surgical technique for RRD has the advantages of relieving the surgeon's neck pain from prolonged use of the indirect ophthalmoscope and sharing the surgical procedure with another surgical team member. In addition, fine retinal breaks that are hard to identify using an indirect ophthalmoscope can be easily found under the microscope by direct endoillumination. PMID- 29230978 TI - Alternating and Relapsing Migratory Orbital Myositis. PMID- 29230979 TI - Blindness in Sweet's Syndrome. PMID- 29230980 TI - Spontaneous Resolution of Macular Hole with Retinal Detachment in a Highly Myopic Eye. PMID- 29230981 TI - Management of Anterior Chamber Migration of Dexamethasone Intravitreal Implant. PMID- 29230982 TI - [The Role of CBS in Injury Time Estimation after Brain Contusion]. AB - OBJECTIVES: To observe the changes of cystathionine beta-synthase (CBS) expression in the cerebral cortex after brain contusion at different times. METHODS: An experimental model of traumatic brain injury (TBI) in mice was established by an improved weight-drop device. Then Western blotting and immunohistochemical examination were used to detect the CBS expression in cerebral cortex around injury at different time points (1 h, 6 h, 12 h, 1 d, 2 d, 3 d, 7 d). RESULTS: The results of Western blotting revealed that the expression level of CBS was down-regulated and reached its lowest level at the 3rd days after injury, and then restored to normal level after 7 days. The results of immunohistochemistry showed that CBS was present in the normal brain cortex. CBS expression gradually decreased at the 3rd days after injury, and then restored to normal level after 7 days. CONCLUSIONS: CBS has the potential to be a reference index for time estimation after brain contusion in forensic practice. PMID- 29230983 TI - [The Changes of HIF-1alpha and VEGF-A in Myocardial Tissue of Rats with Arrhythmias]. AB - OBJECTIVES: To observe the expression changes of hypoxia inducible factor 1alpha(HIF-1alpha) and vascular endothelial growth factor-A (VEGF-A) in rats with arrhythmias, and to explore the differences of the expression pattern in the two indicators of acute myocardial ischemia caused by arrhythmias and coronary insufficiency. METHODS: The arrhythmia was induced by CaCl2, and the expression changes of HIF-1alpha and VEGF-A were detected by immunohistochemistry, Western blotting and real-time PCR within 6 h after the arrhythmia in rats. RESULTS: The expression of HIF-1alpha and VEGF-A showed diffuse in the myocardial tissue of rats died from arrhythmias. Both of them increased in the early arrhythmia, then decreased. Extensive myocardial ischemia happened at the beginning of arrhythmia occurrence and its range didn't expand with time. CONCLUSIONS: The expressions of HIF-1alpha and VEGF-A in myocardium of the rats with arrhythmia can provide evidence for the differential diagnosis of acute myocardial ischemia caused by fatal arrhythmia and coronary insufficiency. PMID- 29230984 TI - [Forensic Application of Objective Assessment on Visual Acuity by ERP]. AB - OBJECTIVES: To explore the composition characteristic of event related potential (ERP) in different visual acuity levels, and to provide theoretical basis for the objective assessment of visual acuity. METHODS: Monocular stimulus was performed on 16 selected subjects. The subjects were required to look straight at the screen ahead and count the amount of stimuli from different directions. The pictures of optotype stimulus which corresponding to three different visual acuity levels were showed in the center of the screen. The ERP results were recorded separately. RESULTS: (1) The P1 amplitudes of match stimuli recorded under the supra-threshold visual acuity level were higher than that of match stimuli recorded under the threshold and sub-threshold visual acuity levels. There was no significant difference between the P1 amplitudes of match stimuli recorded under the threshold and sub-threshold visual acuity levels. The tendency of conflict stimuli was similar to that of match stimuli under three visual acuity levels. (2) In the 340-500 ms post-stimulus range, P300 component was found under supra-threshold and threshold visual acuity levels; no P300 component was found in corresponding time window under sub-threshold visual acuity. The differences of P300 amplitudes among three visual acuity levels were statistically significant. The amplitudes from high to low were the supra threshold, threshold and sub-threshold visual acuity levels. CONCLUSIONS: ERP can be a potential new method for the objective assessment of visual acuity in forensic medicine. PMID- 29230985 TI - [Adult Stature Estimation by Multiple Parameters of Body Torso Segment]. AB - OBJECTIVES: To promote the further research on body stature estimation and the innovative applications based on the distances between the anatomical landmarks on body torso surface. METHODS: A specification for the collection of distances between the anatomical landmarks on body torso surface was established. The data of 933 cases of adult population in Yangtze River Delta region were collected. Multiple linear regression method was used to statistical analyse and establish the regression equation of stature estimation. RESULTS: A regression equation about 5 variables including gender (x1), cervical vertebrae-coccyx line (x2), sterna-pubis line (x3), distance between acromion and iliospinale anterius (x4) and shoulder breadth (x5), and stature (y) was established, y=105.406+5.414 x1+0.436 x2+0.286 x3+0.225 x4+ 0.193 x5. CONCLUSIONS: The method is suitable for the rapid, simple and accurate estimation of stature for the forensic experts. PMID- 29230986 TI - [Sixty-six Biallelic Genetic Markers on Y chromosome by MALDI-TOF-MS]. AB - OBJECTIVES: To analyse the genetic polymorphisms of 66 biallelic genetic markers on Y chromosome in Eastern Chinese Han population, and evaluate their values in forensic application. METHODS: Genotyping of 66 biallelic genetic markers on Y chromosome was studied in 205 unrelated males of Eastern Chinese Han population by multiplex PCR combined matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS). The allele frequencies on the loci to be tested were calculated by direct counting method, and the gene diversity (GD) and haplotype diversity (HD) were calculated by corresponding formulas. The haplotypes of this system were tested by software Arlequin v3.5.2.2 and the comparison of population genetics were analyzed. RESULTS: A total of 60 biallelic genetic markers on Y chromosome were polymorphic in males of Eastern Chinese Han population, and the ranges of GD were from 0.038 5 to 0.501 9. Eighty-five different haplotypes were observed and the HD was 0.970 3. The differences of partial SNP loci between the Han population of Eastern China and that of Xinjiang and Guangdong were statistically significance. CONCLUSIONS: Sixty biallelic genetic markers and the detection system can complementally provide genetic information in kinship testing and individual identification. The MALDI-TOF-MS technology is able to type biallelic genetic markers. PMID- 29230987 TI - [Comparison of Criminal Characteristics in Depression Patients and Schizophrenics with Homicide Behavior]. AB - OBJECTIVES: To explore the criminal characteristics of forensic psychiatry expertise in depression patients and schizophrenics with homicide behavior. METHODS: A total of 40 depression (depressive episode) patients and 50 schizophrenics with homicide behavior were randomly assigned into the study group and control group, respectively. Data of demographic and criminal characteristic of the two groups were collected by a self-designed questionnaire, and then were compared. RESULTS: There were no statistical differences in age, education level and career between study and control groups (P>0.05). Compared with the control group, the victims in the study group were mainly the patient's children and parents, and most offenders had suicidal behavior after homicide (70%). In study group, the motives of crime were mainly extended suicide and indirect suicide, and most offenders had attempted suicide (85%) and diminished capacity of criminal responsibility (70%), which in control group had no capacity of criminal responsibility (56%). Except for criminal site, there were statistical differences in other criminal characteristics between two groups (P<0.05). CONCLUSIONS: There are different criminal characteristics between depression patients and schizophrenics with homicide behavior in forensic psychiatry, and these characteristics should be considered when these two diagnoses are distinguished in forensic psychiatry expertise. PMID- 29230988 TI - [Evaluation of Brodifacoum-induced Toxicity by Metabonomics Approach Based on HPLC-TOF-MS]. AB - OBJECTIVES: To analyse the metabolic changes in urine of rats with brodifacoum intoxication, and to reveal the molecular mechanism of brodifacoum-induced toxicity on rats. METHODS: By establishing a brodifacoum poisoning rats model, the urine metabolic profiling data of rats were acquired using high performance liquid chromatography-time of flight mass spectrometry (HPLC-TOF-MS). The orthogonal partial least squares analysis-discrimination analysis (OPLS-DA) was applied for the multivariate statistics and the discovery of differential metabolites closely related to toxicity of brodifacoum. RESULTS: OPLS-DA score plot showed that the urinary metabolic at different time points before and after drug administration had good similarity within time period and presented clustering phenomenon. Comparing the urine samples of rats before drug administration with which after drug administration, twenty-two metabolites related to brodifacoum-induced toxicity were selected. CONCLUSIONS: The toxic effect of brodifacoum worked by disturbing the metabolic pathways in rats such as tricarboxylic cycle, glycolysis, sphingolipid metabolism and tryptophan metabolism, and the toxicity of brodifacoum is characterized of accumulation effect. The metabonomic method based on urine HPLC-TOF-MS can provide a novel insight into the study on molecular mechanism of brodifacoum-induced toxicity. PMID- 29230989 TI - [The Role of Segmental Analysis of Clonazepam in Hair in Drug Facilitated Cases]. AB - OBJECTIVES: To infer the frequency of dosage and medication history investigate of the victims in drug facilitated cases by the segmental analysis of clonazepam in hair. METHODS: Freezing milling under liquid nitrogen environment combined with ultrasonic bath was used as sample pretreatment in this study, and liquid chromatography-tandem mass spectrometry was used for the segmental analysis of the hair samples collected from 6 victims in different cases. The concentrations of clonazepam and 7-aminoclonazepam were detected in each hair section. RESULTS: Clonazepam and its metabolite 7-aminoclonazepam were detected in parts of hair sections from the 6 victims. The occurrence time of drug peak concentration was consistent with the intake timing provided by victims. CONCLUSIONS: Segmental analysis of hair can provide the information of frequency of dosage and intake timing, which shows an unique evidential value in drug facilitated crimes. PMID- 29230990 TI - [Analysis of Forensic Identification on 32 Cases of Lumbar Spondylolysis]. AB - OBJECTIVES: To explore the casual relationship and the significance of identification among the injury, disease and damage consequence in the disability evaluation of lumbar spondylolysis by the standard for identifying grading of disability caused by work-related injuries. METHODS: The general data, injury manner, clinical treatment and the imaging examination of 32 lumbar spondylolysis cases were collected and retrospectively analyzed. According to the degree of participation in the injury and damage consequence, the identification and assessment of casual relationship was made, and the grading of disability was assessed. RESULTS: For 32 cases, injury had no effect on damage consequence in 7 cases, slight effect in 5 cases, secondary effect in 13 cases, equivalent effect in 4 cases, and complete effect in 3 cases. According to the related items in the standard for identifying grading of disability caused by work-related injuries, 3 cases were rated level 7, 5 cases were level 8, 6 cases were level 9, 11 cases were level 11 among the cases which existed causal relationship. CONCLUSIONS: The formation of lumbar spondylolysis is connected to the factors of age, anatomy, occupation and injury manner etc. The degree of disability should be accessed comprehensively after the analysis of the casual relationship among the injury, disease and damage consequence. PMID- 29230991 TI - [Mutation Analysis of 19 STR Loci in 20 723 Cases of Paternity Testing]. AB - OBJECTIVES: To observe and analyze the confirmed cases of paternity testing, and to explore the mutation rules of STR loci. METHODS: The mutant STR loci were screened from 20 723 confirmed cases of paternity testing by Goldeneye 20A system.The mutation rates, and the sources, fragment length, steps and increased or decreased repeat sequences of mutant alleles were counted for the analysis of the characteristics of mutation-related factors. RESULTS: A total of 548 mutations were found on 19 STR loci, and 557 mutation events were observed. The loci mutation rate was 0.070/00-2.230/00. The ratio of paternal to maternal mutant events was 3.06:1. One step mutation was the main mutation, and the number of the increased repeat sequences was almost the same as the decreased repeat sequences. The repeat sequences were more likely to decrease in two steps mutation and above. Mutation mainly occurred in the medium allele, and the number of the increased repeat sequences was almost the same as the decreased repeat sequences. In long allele mutations, the decreased repeat sequences were significantly more than the increased repeat sequences. The number of the increased repeat sequences was almost the same as the decreased repeat sequences in paternal mutation, while the decreased repeat sequences were more than the increased in maternal mutation. CONCLUSIONS: There are significant differences in the mutation rate of each locus. When one or two loci do not conform to the genetic law, other detection system should be added, and PI value should be calculated combined with the information of the mutate STR loci in order to further clarify the identification opinions. PMID- 29230992 TI - [Investigation of the Necrophagous Flies in Beijing]. AB - OBJECTIVES: To explore the number of necrophagous flies and seasonal distribution of common necrophagous flies at present in Beijing. METHODS: The specimens of necrophagous flies were collected by the methods of animal carcass, trapping and feeding. And the specimens were observed and counted after the classification and preservation. RESULTS: The necrophagous flies in Beijing belonged to 4 families, 9 subfamilies, 21 genera and 46 species, and 12 species of them were the first records in Beijing. The necrophagous flies had the characteristics of regional and seasonal distribution. CONCLUSIONS: The data of seasonal distribution of necrophagous flies and common necrophagous flies in Beijing can provide reference for related research. PMID- 29230993 TI - [Genetic Polymorphisms of 30 InDel Loci in Ewenki Ethnic Group from Inner Mongolia]. AB - OBJECTIVES: To study the genetic polymorphisms of 30 insertion/deletion (InDel) loci and evaluate their forensic application in Ewenki ethnic group from Inner Mongolia. METHODS: Peripheral blood samples were collected from 87 unrelated healthy individuals in Ewenki ethnic group. Genomic DNA were extracted, and 30 InDel loci of the samples were multiplex amplified and genotyped. Hardy-Weinberg balance tests were preformed for all loci and genetic parameters were calculated by modified PowerStats v1.2 software. The linkage disequilibrium between loci were tested by SNPAnalyzer v2.0 software. Based on the allele frequencies of 30 InDel loci, the genetic relationships between Ewenki ethnic group and other populations were evaluated by analysis of molecular variance, principal component analysis and phylogenetic reconstruction. RESULTS: After correction, 30 InDel loci conformed to Hardy-Weinberg equilibrium. It was found that the pairwise InDel loci were in linkage equilibrium after Bonferroni correction. The results of population genetics indicated that Ewenki ethnic group had close genetic relationships with Henan Han and Beijing Han populations; whereas it was significantly different from several populations in Europe and Mexico. CONCLUSIONS: There are relatively high genetic polymorphisms on 30 InDel loci of Ewenki ethnic group from Inner Mongolia, which can be used as a helpful supplement application for STR detection system. PMID- 29230994 TI - [Genotyping of ABO Blood Group in Partial Population of Yunnan Province by SNaPshot Technology]. AB - OBJECTIVES: To detect the genotype of ABO blood group by SNaPshot technology. METHODS: DNA were extracted from the peripheral blood samples with known blood groups (obtained by serology) of 107 unrelated individuals in Yunnan. Six SNP loci of the 261th, 297th, 681th, 703th, 802th, and 803th nucleotide positions were detected by SNaPshot Multiplex kit, and relevant genetics parameters were calculated. RESULTS: In 107 blood samples, the allele frequencies of types A, B, OA, and OG were 0.355 1, 0.168 2, 0.230 0 and 0.247 6, respectively, while that of types AG and cis AB were not detected. The genotyping results of ABO blood group were consistent with that of serologic testing. CONCLUSIONS: SNaPshot technology can be adapted for genotyping of ABO blood group. PMID- 29230995 TI - [Individual Identification of Cartilage by Direct Amplification in Mass Disasters]. AB - OBJECTIVES: To explore the effectiveness of direct amplification for the STR analysis of cartilage, and to accelerate the effectiveness of disaster victim identification. METHODS: Eighty-eight cartilage samples were directly amplified by PowerPle(r) 21 kit, and the results of genotyping were compared with that obtained by the magnetic beads method. RESULTS: In 88 cartilage samples, the STR genotypes were successfully detected from 84 samples by direct amplification and magnetic beads method, and both the results of genotyping by two method were consistent. CONCLUSIONS: Direct amplification with PowerPlex(r) 21 kit can be used for STR genotyping of cartilages. This method is operated easily and promptly, which has a potential application in the individual identification of mass disasters. PMID- 29230996 TI - [Research Progress of the Correlation between Caveolin and Unexpected Sudden Cardiac Death]. AB - Due to the negative autopsy and without cardiac structural abnormalities, unexpected sudden cardiac death (USCD) is always a tough issue for forensic pathological expertise. USCD may be associated with parts of fatal arrhythmic diseases. These arrhythmic diseases may be caused by disorders of cardiac ion channels or channel-related proteins. Caveolin can combine with multiple myocardial ion channel proteins through its scaffolding regions and plays an important role in maintaining the depolarization and repolarization of cardiac action potential. When the structure and function of caveolin are affected by gene mutations or abnormal protein expression, the functions of the regulated ion channels are correspondingly impaired, which leads to the occurrence of multiple channelopathies, arrhythmia or even sudden cardiac death. It is important to study the effects of caveolin on the functions of ion channels for exploring the mechanisms of malignant arrhythmia and sudden cardiac death. PMID- 29230997 TI - [Research Progress of the Relationship between the Expression of TAR DNA-binding Domain Protein 43 and Brain Injury]. AB - TAR DNA-binding domain protein 43 (TDP-43) is a highly conserved and widely expressed nuclear protein. Nowadays, the expression of TDP-43 can be found in most neurodegenerative diseases such as Alzheimer's disease, which makes it become a neurodegenerative disease associated marker protein. From the current research status at homeland and abroad, and around the relationship between the expression of TDP-43 and brain injury, this article emphatically probes into the specific expression and function of TDP-43 in acute and chronic brain injury based on the knowledge of its biological characteristics, which aims to explore the feasibility for determining the cause of death and the injury and disability situations by TDP-43 in forensic pathology. PMID- 29230998 TI - [Research Progress on the Detection Method of DNA Methylation and Its Application in Forensic Science]. AB - As an important part of epigenetic marker, DNA methylation involves in the gene regulation and attracts a wide spread attention in biological auxology, geratology and oncology fields. In forensic science, because of the relative stable, heritable, abundant, and age-related characteristics, DNA methylation is considered to be a useful complement to the classic genetic markers for age prediction, tissue-identification, and monozygotic twins' discrimination. Various methods for DNA methylation detection have been validated based on methylation sensitive restriction endonuclease, bisulfite modification and methylation-CpG binding protein. In recent years, it is reported that the third generation sequencing method can be used to detect DNA methylation. This paper aims to make a review on the detection method of DNA methylation and its applications in forensic science. PMID- 29230999 TI - [Comparison of the Skin and Skeletal Muscle Contusion in Rats Induced by Blunt Force with Different Heights]. AB - OBJECTIVES: To explore the differences in the repair process of skin and skeletal muscle after contusion caused by blunt force attack with different heights. METHODS: Three degrees of contusion were performed on SD rats' right hind limbs by a designed free-dropping device falling from 15, 30 and 50 cm heights, which as a main consideration factor for degree of injury. The repair process of skin and skeletal muscle at 6 h, 24 h, 3 d, 7 d and 13 d after contusion were observed using routine histological methods. RESULTS: Hematoma within skin and/or muscle was found in the rats' hind limbs after contusion with three different heights. The repair processes were similar at 24 h after contusion. However, with the increase of height, the display degree was more obvious. At 3 d after contusion, the RBC of the hemorrhagic region would be decomposed and elapsed in 15 cm contusion group, but for 30 cm contusion group, it delayed to 7 d. At 13 d after contusion, the similar result was found in 15 cm and 30 cm contusion groups, in contrast, the 50 cm contusion group was still in the proliferative phase. CONCLUSIONS: With the increase of height, the occurring rate of hematoma within skin and muscle at the same time increases, and the more serious histological appearance after contusion, including inflammation and proliferation, the longer healing process are observed. According to the results of present study and considering forensic application, the contusion model with 50 cm height (2.58 J/cm2) is recommended as the experimental animal model for the future study of wound age estimation on contusion. PMID- 29231000 TI - Time-dependent Expression of MT1A mRNA and MT2A mRNA in the Contused Skeletal Muscle of Rats. AB - OBJECTIVES: To investigate the time-dependent expression of metallothionein (MT) 1A mRNA and MT2A mRNA in contused skeletal muscle of rats. METHODS: A total of 54 Sprague-Dawley rats were used in this study. The rats were divided into two parts: control group (n=6) and contusion groups (0.5, 1, 6, 12, 18, 24, 30, and 36 h after contusion, n=6). Total RNA was extracted from skeletal muscle. The expression levels of MT1A mRNA and MT2A mRNA were detected by SYBR Green I real time PCR. RESULTS: The expression trends of the two potential marker genes were related to wound age. In addition to 0.5 h, there were significant contrasts between the control group and contused group (P<0.05), about the expression levels of MT1A mRNA and MT2A mRNA in different phases. As the extension of wound age, the relative expression of MT1A mRNA and MT2A mRNA at 1 h, 6 h, 12 h and 18 h after contusion demonstrated upgrade tendency until its expression levels in 18 h peak with 239.41+/-15.20 and 717.42+/-50.76, respectively. When time extends to 24 h after injury, the expression of above two marks decreased, respectively. The MT1A mRNA and MT2A mRNA expression levels increased at 30 h and then decreased. CONCLUSIONS: Determination of MT1A mRNA and MT2A mRNA levels by real-time PCR may be useful for the estimation of wound age. PMID- 29231001 TI - [Metabolic Characteristics of Lethal Bradycardia Induced by Myocardial Ischemia]. AB - OBJECTIVES: To explore the metabolic characteristics of lethal bradycardia induced by myocardial ischemia in rat's serum. METHODS: A rat myocardial ischemia bradycardia-sudden cardiac death (MI-B-SCD) model was established, which was compared with the sham-operation group. The metabolic profile of postmortem serum was analyzed by gas chromatography-mass spectrometry (GC-MS), coupled with the analysis of serum metabolic characteristics using metabolomics strategies. RESULTS: The serum metabolic profiles were significantly different between the MI B-SCD rats and the control rats. Compared to the control rats, the MI-B-SCD rats had significantly higher levels of lysine, ornithine, purine, serine, alanine, urea and lactic acid; and significantly lower levels of succinate, hexadecanoic acid, 2-ketoadipic acid, glyceraldehyde, hexendioic acid and octanedioic acid in the serum. There were some correlations among different metabolites. CONCLUSIONS: There is obvious metabolic alterations in the serum of MI-B-SCD rat. Both lysine and purine have a high value in diagnosing MI-B-SCD. The results are expected to provide references for forensic and clinical applications of prevention and control of sudden cardiac death. PMID- 29231002 TI - [Relationship between Electrical Conductivity and Decomposition Rate of Rat Postmortem Skeletal Muscle]. AB - OBJECTIVES: To analyze the relationship among electrical conductivity (EC), total volatile basic nitrogen (TVB-N), which is an index of decomposition rate for meat production, and postmortem interval (PMI). To explore the feasibility of EC as an index of cadaveric skeletal muscle decomposition rate and lay the foundation for PMI estimation. METHODS: Healthy Sprague-Dawley rats were sacrificed by cervical vertebrae dislocation and kept at 28 C. Muscle of rear limbs was removed at different PMI, homogenized in deionized water and then skeletal extraction liquid of mass concentration 0.1 g/mL was prepared. EC and TVB-N of extraction liquid were separately determined. The correlation between EC (x1) and TVB-N (x2) was analyzed, and their regression function was established. The relationship between PMI (y) and these two parameters were studied, and their regression functions were separately established. RESULTS: The change trends of EC and TVB-N of skeletal extraction liquid at different PMI were almost the same, and there was a linear positive correlation between them. The regression equation was x2=0.14x1 164.91(R2=0.982). EC and TVB-N of skeletal muscle changed significantly with PMI, and the regression functions were y=19.38x13-370.68x12+2 526.03 x1 717.06(R2=0.994), and y=2.56x23-48.39x22+330.60x2-255.04(R2=0.997), respectively. CONCLUSIONS: EC and TVB-N of rat postmortem skeletal muscle show similar change trends, which can be used as an index for decomposition rate of cadaveric skeletal muscle and provide a method for further study of late PMI estimation. PMID- 29231003 TI - [Contrast Visual Evoked Potentials under Pattern Stimulus in Ocular Trauma]. AB - OBJECTIVES: To study the characteristic of contrast visual evoked potentials (CVEP) in patients with ocular trauma. METHODS: Sixty patients defined as ocular trauma by forensic clinical examination in our center were selected, and split into 0.2-0.3 (Group A), 0.3-0.5 (Group B) and >=0.5 (Group C) according to the best corrected visual acuity. The variation characteristics of wave amplitude and latency of CVEP under 100%, 25% and 10% contrast were observed and analyzed statistically. RESULTS: (1) Under the same contrast, the wave amplitude of P100 decreased with the decrease of stimulus perspective. (2) Under the same stimulus perspective, the wave amplitude of P100 decreased with the decrease of contrast (P<0.05). (3) Under the contrast of 100% and 25% with the same stimulus perspective (except 100% 7' perspective stimulus), the difference between group A and group B had no statistical significance (P>0.05). Between group A and group C, group B and group C, the wave amplitude of P100 gradually increased with the increase of vision (P<0.05). Under the contrast of 10% with 15' stimulus perspective, the wave amplitude of P100 increased with the increase of vision (P<0.05). (4) Under the same contrast with the same stimulation perspective, the latency of P100 wave shortened with the increase of vision, while the difference had no statistical significance (P>0.05). Under the same stimulus perspective, the latency of P100 wave was prolonged with the decrease of contrast (P>0.05). CONCLUSIONS: CVEP may become one of the possible methods for the evaluation of contrast visual acuity. PMID- 29231004 TI - [Establishment of Automation System for Detection of Alcohol in Blood]. AB - OBJECTIVES: To establish an automation system for detection of alcohol content in blood. METHODS: The determination was performed by automated workstation of extraction-headspace gas chromatography (HS-GC). The blood collection with negative pressure, sealing time of headspace bottle and sample needle were checked and optimized in the abstraction of automation system. The automatic sampling was compared with the manual sampling. RESULTS: The quantitative data obtained by the automated workstation of extraction-HS-GC for alcohol was stable. The relative differences of two parallel samples were less than 5%. The automated extraction was superior to the manual extraction. A good linear relationship was obtained at the alcohol concentration range of 0.1-3.0 mg/mL (r>=0.999) with good repeatability. CONCLUSIONS: The method is simple and quick, with more standard experiment process and accurate experimental data. It eliminates the error from the experimenter and has good repeatability, which can be applied to the qualitative and quantitative detections of alcohol in blood. PMID- 29231005 TI - [Application of MOAS for Evaluating of Violence Risk in the Inpatients with Mental Disorders]. AB - OBJECTIVES: To explore the value of Modified Overt Aggression Scale (MOAS) on predicting serious aggressive behavior in the inpatients with mental disorders and to provide theoretical basis for violence risk assessments in the inpatients with mental disorders. METHODS: Total 918 inpatients in a psychiatric hospital were evaluated by trained medical workers using MOAS in September 2009, and their serious violent behavior were followed up for 2 years. The value of MOAS on predicting violence in the inpatients with mental disorders was analyzed by SPSS 21.0. RESULTS: (1) Compared to the patients without serious aggressive behaviors, the patients with serious aggressive behavior within 2 years showed significantly higher scores (P<0.05) on verbal aggression, aggression against property, physical aggression and total weighted score of MOAS; (2) Significant correlation was found between the score of verbal aggression and the serious acts of violence within 2 years (P<0.05); (3) Scores of verbal aggression, physical aggression and total weighted score of MOAS had predictive value on serious aggressive behaviors within 2 years. CONCLUSIONS: MOAS has certain value on predicting the serious aggressive behaviors of patients with mental disorders within 2 years. PMID- 29231006 TI - [Characteristics of Schizophrenia Patients' Homicide Behaviors and Their Correlations with Criminal Capacity]. AB - OBJECTIVES: To explore the characteristics of schizophrenia patients' homicide behaviors and the influences of the assessments of criminal capacity. METHODS: Indicators such as demographic and clinical data, characteristics of criminal behaviors and criminal capacity from the suspects whom were diagnosed by forensic psychiatry as schizophrenia (n=110) and normal mental (n=70) with homicide behavior, were collected by self-made investigation form and compared. The influences of the assessments of criminal capacity on the suspects diagnosed as schizophrenia were also analyzed using logistic regression analysis. RESULTS: There were no significant statistical differences between the schizophrenic group and the normal mental group concerning age, gender, education and marital status (P>0.05). There were significant statistical differences between the two groups concerning thought disorder, emotion state and social function before crime (P<0.05) and there were significant statistical differences in some characteristics of the case such as aggressive history (P<0.05), cue, trigger, plan, criminal incentives, object of crime, circumstance cognition and self protection (P<0.05). Multivariate logistic regression analysis suggested that thought disorder, emotion state, social function, criminal incentives, plan and self-protection before crime of the schizophrenic group were positively correlated with the criminal capacity (P<0.05). CONCLUSIONS: The relevant influences of psychopathology and crime characteristics should be considered comprehensively for improving the accuracy of the criminal capacity evaluation on the suspects diagnosed as schizophrenia with homicide behavior. PMID- 29231007 TI - [Automobile Traffic Accident Death Case Analysis of Characteristics of Driver Injury]. AB - OBJECTIVES: To distinguish the injury characteristic changes on the drivers between the injuries of drivers and passengers in traffic accidents, and to provide scientific evidence for confirming the identity of driver in traffic accidents. METHODS: Data of 126 automobile traffic accident death cases in the reclamation areas of Heilongjiang province from 2006-2014 were retrospectively studied. The injury characteristics on the drivers of automobile traffic accident death cases were analyzed and the forensic identification problem in the injuries of drivers and passengers were discussed. RESULTS: Injuries were frequently observed on driver's neck, chest and abdomen. The characteristic injuries caused by auto parts were also found, which appeared at the places of passenger's head, face and limbs contacted with automobile. Such characteristic injuries were not found at other places. CONCLUSIONS: The location and type of injury are associated with the identity of the deceased. PMID- 29231008 TI - [Significance of Hypoxia-related microRNA for Estimating the Cause of Mechanical Asphyxia Death]. AB - Under hypoxia condition, microRNA (miRNA) can interact with transcription factors for regulating the cell metabolism, angiogenesis, erythropoiesis, cellular proliferation, differentiation and apoptosis. The biological processes above may play an important role in mechanical asphyxia death. This article reviews the regulating function of miRNA under hypoxia condition and the influence of hypoxia to biosynthesis of miRNA, which may provide some new ideas to the research of miRNA on determining the cause of mechanical asphyxia death in the field of forensic medicine. PMID- 29231009 TI - [Research Progress on Diagnosis of Drowning]. AB - These external and internal signs of drowning are non-specific. Therefore, diagnosis of drowning is always one of the most difficult tasks in forensic pathology. This paper meticulously and comprehensively reviews research progress on the diagnosis of drowning in pathological signs, laboratory examination, immunohistochemistry test and virtopsy technology, and it also prospects the research direction of diagnosis of drowning. PMID- 29231010 TI - [Advance of Forensic Research in Insulin Poisoning]. AB - Insulin as a common clinical hypoglycemic agent can effectively control serves to lower the concentration of blood glucose. However, insulin overdose can lead to death. In the whole fatal cases of insulin overdose, medical accident is the most common, followed by suicide. Though insulin homicide is extremely rare, it deserves great attention. Though there are some researches about insulin poisoning on forensic toxicology and pathology, it is still a difficult task in forensic practice. In this paper, the mechanism of death, pathological changes, detection methods and diagnose criteria of insulin overdose will be discussed in the view of forensic toxicology and pathology. We hope that this paper could enhance relative knowledges of insulin poisoning for medical examiners. PMID- 29231011 TI - [Research Progress of the Relationship between SUNDS and OSAHS]. AB - Sudden unexplained nocturnal death syndrome (SUNDS) is always a difficulty in forensic medicine researches. Although the development of molecular genetics promotes the etiologic study of SUNDS, the pathogenesis of most such cases is still unclear. Sleep apnea syndrome (SAS) is one of the common forms of sleep disorders, and obstructive sleep apnea hypopnea syndrome (OSAHS) is the most common. In recent years, some domestic and international researches show that OSAHS is related to the development of cardiovascular disease, which may cause cardiac arrhythmia, even sudden death. This article reviews the relationship between SUNDS and OSAHS and aims to provide new ideas for the pathogenesis of SUNDS. PMID- 29231012 TI - [Progress in Application of Measuring Skeleton by CT in Forensic Anthropology Research]. AB - Individual identification by measuring the human skeleton is an important research in the field of forensic anthropology. Computed tomography (CT) technology can provide high-resolution image of skeleton. Skeleton image can be reformed by software in the post-processing workstation. Different skeleton measurement indexes of anthropology, such as diameter, angle, area and volume, can be measured on section and reformative images. Measurement process is barely affected by human factors. This paper reviews the literatures at home and abroad about the application of measuring skeleton by CT in forensic anthropology research for individual identification in four aspects, including sex determination, height infer, facial soft tissue thickness measurement and age estimation. The major technology and the application of CT in forensic anthropology research are compared and discussed, respectively. PMID- 29231013 TI - [Diagnostic Value of Postmortem CT Angiography in Coronary Atherosclerosis]. AB - OBJECTIVES: To explore the application value of postmortem computed tomography (CT) angiography on diagnosis of coronary atherosclerotic stenosis degree. METHODS: Based on the previous experimental results, the postmortem CT angiography device of human isolated heart was improved. Different coronary atherosclerotic stenosis degree of sudden death cases was selected. Before the cardiac anatomy, hearts were removed out completely and CT angiography was performed immediately. The CT angiography results were compared with histopathological findings. Meanwhile, the advantages and disadvantages of the angiography device before and after improvement were compared. RESULTS: The improved angiography device of isolated heart could get better imaging results. The postmortem CT angiography results had high consistency with the histopathological findings on diagnosis of coronary atherosclerotic stenosis degree. And the coronary artery lesions could be revealed more objectively and vividly by 3D reconstruction technology. However, CT angiography could only be used to examine the pathological changes of blood vessels, which might have some limitations on the diagnosis of cause of death. CONCLUSIONS: Postmortem CT angiography can be used as an additional method for the conventional autopsy in the cases of coronary atherosclerosis. PMID- 29231014 TI - [Correlation between Genetic Variants and Polymorphism of Caveolin and Sudden Unexplained Death]. AB - OBJECTIVES: To explore the genetic variation sites of caveolin (CAV) and their correlation with sudden unexplained death (SUD). METHODS: The blood samples were collected from SUD group (71 cases), coronary artery disease (CAD) group (62 cases) and control group (60 cases), respectively. The genome DNA were extracted and sequencing was performed directly by amplifying gene coding region and exon intron splicing region of CAV1 and CAV3 using PCR. The type of heritable variation of CVA was confirmed and statistical analysis was performed. RESULTS: A total of 4 variation sites that maybe significative were identified in SUD group, and two were newfound which were CAV1: c.45C>T (T15T) and CAV1:c.512G>A (R171H), and two were SNP loci which were CAV1:c.246C>T (rs35242077) and CAV3:c.99C>T (rs1008642) and had significant difference (P<0.05) in allele and genotype frequencies between SUD and control groups. Forementioned variation sites were not found in CAD group. CONCLUSIONS: The variants of CAV1 and CAV3 may be correlated with a part of SUD group. PMID- 29231015 TI - [Relationship between the Change Rules of Volatile Organic Compounds in Rat Muscle and Postmortem Interval]. AB - OBJECTIVES: To explore the relationship between the change rules of volatile organic compounds (VOCs) in rat muscle and postmortem interval (PMI). METHODS: A total of 120 healthy rats were divided randomly into 12 groups (10 for each group). After the rats were sacrificed by cervical dislocation, the bodies were kept at (25+/-1) C. Rat muscle samples were separately obtained at 12 PMI points, including 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 d. The VOCs in rat muscles were collected, detected and analyzed by headspace solid-phase microextraction (HS-SPME) coupled to gas chromatography-mass spectrometer (GC-MS). RESULTS: In total, 15 species of VOCs were identified, including 9 aromatic compounds, 3 sulfur compounds, 2 aliphatic acids and 1 heterocyclic compound. The species of VOCs increased with PMI: no species were detected within 1 day, 3 species were detected on day 2, 9 on day 3, 11 on day 4, 14 from day 5 to 7, and 15 from day 8 to 10. Total peak area of 15 species of VOCs was significantly correlated to PMI (adjusted R2=0.15-0.96): the regression function was y=-17.05 x2+ 164.36 x-246.36 (adjusted R2=0.96) from day 2 to 5, and y=2.24 x+101.13 (adjusted R2=0.97) from day 6 to 10. CONCLUSIONS: The change rules of VOCs in rat muscle are helpful for PMI estimation. PMID- 29231016 TI - [Effect of Different Attentional Conditions on ERP Detection of Visual Acuity]. AB - OBJECTIVES: To study the effect of different attentional conditions on the event related potential (ERP) components generated by the visual information stimuli related to visual acuity, and provide a theoretical reference for clinical forensic visual objective evaluation. METHODS: With visual acuity optotypes as normal form of visual information stimuli, 15 volunteers as study subjects were supposed to account the visual acuity optotypes under the attentional condition of visual stimuli. Furthermore, the subjects were required to listen to the storytelling carefully under the non-attentional condition of visual stimuli, and after the examination, they needed to answer the story-related questions. All the EEG results of two different attentional conditions from the subjects were recorded by 32 channel ERP system. RESULTS: Under two attentional conditions, P1 and P300 components were evoked by the visual acuity optotypes on supra-threshold and threshold visual acuity levels, while only P1 component were evoked by the visual acuity optotypes on sub-threshold levels. In the ERP waveforms evoked by the visual acuity optotypes on supra-threshold, P1 and P300 amplitudes under attentional condition were larger than that under non-attentional condition. CONCLUSIONS: Attentional conditions can influence the detection of visual acuity. P300 component can be used to distinguish the visual acuity levels with supra threshold and sub-threshold under non-attentional condition. PMID- 29231017 TI - [Forensic Application of HuaxiaTM Platinum Kit]. AB - OBJECTIVES: To investigate the genetic polymorphism of 23 autosomal STR loci of HuaxiaTM Platinum kit in Chinese Han population, and to evaluate the forensic efficiency of HuaxiaTM Platinum kit. METHODS: A total of 500 unrelated healthy individuals from Han population were genotyped with HuaxiaTM Platinum kit. The frequency distribution and the parameter of population genetics of STR loci were analysed statistically. HuaxiaTM Platinum kit was compared with other 7 commercial STR kits commonly seen at home and abroad in the number of STR loci, interior label, fluorescent mark, total number of alleles in Ladder and system effectiveness. RESULTS: All the 23 autosomal STR loci were consistent with Hardy Weinberg equilibrium (P>0.05). The discrimination power was 0.791 5-0.986 2. The polymorphism information content (PIC) was 0.559 0-0.914 0. The combined discrimination power (CDP) was 1-4.1*10-28, while combined probability of paternity exclusion in trio (CPET) and in duo (CPED) were 1-4.1*10-10 and 1 8.4*10-7, respectively. Compared with other 7 kits, HuaxiaTM Platinum kit contained the most number of alleles within the Ladder. CONCLUSIONS: All the 23 autosomal STR loci of HuaxiaTM Platinum kit with highly polymorphic in Han population can be used for paternity testing and individual identification. Compared with other 7 kits, it appears that HuaxiaTM Platinum kit can provide more genetic information. PMID- 29231018 TI - [Full Sibling Identification by IBS Scoring Method and Establishment of the Query Table of Its Critical Value]. AB - OBJECTIVES: To establish a query table of IBS critical value and identification power for the detection systems with different numbers of STR loci under different false judgment standards. METHODS: Samples of 267 pairs of full siblings and 360 pairs of unrelated individuals were collected and 19 autosomal STR loci were genotyped by GoldeneyeTM 20A system. The full siblings were determined using IBS scoring method according to the 'Regulation for biological full sibling testing'. The critical values and identification power for the detection systems with different numbers of STR loci under different false judgment standards were calculated by theoretical methods. RESULTS: According to the formal IBS scoring criteria, the identification power of full siblings and unrelated individuals was 0.764 0 and the rate of false judgment was 0. The results of theoretical calculation were consistent with that of sample observation. The query table of IBS critical value for identification of full sibling detection systems with different numbers of STR loci was successfully established. CONCLUSIONS: The IBS scoring method defined by the regulation has high detection efficiency and low false judgment rate, which provides a relatively conservative result. The query table of IBS critical value for identification of full sibling detection systems with different numbers of STR loci provides an important reference data for the result judgment of full sibling testing and owns a considerable practical value. PMID- 29231019 TI - [Simultaneous Quantitative Analysis of Koumine, Gelsemine and Gelsenicine in Biological Samples by LC-MS/MS]. AB - OBJECTIVES: To establish a LC-MS/MS method which is accurate and sensitive for determination of koumine, gelsemine, and gelsenicine in biological samples and to verify the method. METHODS: Strychnine was used as internal standard. Analytes in blood, urine and liver with 1% sodium hydroxide solution were extracted by ethyl acetate. Chromatographic separation was achieved on a ZORBAX SB-C18 column (150 mm*2.1 mm, 5 MUm), and gradient elution was performed with the buffer solution of methanol-20 mmol/L ammonium acetate (including 0.1% formic acid and 5% acetonitrile) as mobile phase. Qualitative and quantitative analysis was performed in the multiple reaction monitoring mode coupled with an electrospray ionization source under positive ion mode(ESI+). RESULTS: The linearity of koumine, gelsemine and gelsenicine in blood, urine and liver was good within corresponding linear limitation and the correlation coefficients (r)>0.995 0. The limits of detection were 0.1 ng/mL (0.1 ng/g), 0.1 ng/mL (0.1 ng/g) and 0.01 ng/mL (0.01 ng/g), respectively. The extraction recovery and accuracy of the alkaloids ranged from 61.9% to 114.6% and 92.4% to 114.3%, respectively. The relative standard deviations of the intra-day and inter-day precisions were not more than 11.0%. CONCLUSIONS: The method is selective, sensitive and suitable for simultaneous determination of koumine, gelsemine and gelsenicine in body fluids and tissues, which offering technical support for clinical diagnosis and treatment and forensic toxicological analysis of Gelsemium elegans poisoning. PMID- 29231020 TI - [Determination of Sulfide Ion in Blood from Hydrogen Sulfide Poisoning Cases]. AB - OBJECTIVES: To establish a gas chromatography-mass spectrometry (GC-MS) method for the determination of sulfide ion in blood and apply it to the practical cases. METHODS: The 1, 3, 5-tribromobenzene was selected as an internal standard, and 0.2 mL blood sample was collected and analyzed using GC-MS after alpha-Bromo 2, 3, 4, 5, 6-pentafluorobenzyl bromide derivatization. RESULTS: The mass concentration of sulfide ion in blood had good linearity in the range of 0.2-40 MUg/mL with a limit of detection (LOD) of 0.05 MUg/mL. The mass concentration of sulfide ion was less than 0.05 MUg/mL in blank blood from different sources such as healthy subjects and dead cases. In 3 sulfide poisoning cases, sulfide ion was detected in the blood samples of 6 victims, and the mass concentration range was 1.02-3.13 MUg/mL. CONCLUSIONS: This study establishes a method for investigation of sulfide ion in blood which has been applied successfully to the cases of fatal sulfide poisonings. PMID- 29231021 TI - [Eye Movement Characteristics of Cooperation Degree during Image Completion Test in Psychiatric Impairment Assessment]. AB - OBJECTIVES: To explore the difference of eye movement characteristics between uncooperative and cooperative subjects with mental disorder after cerebral trauma. METHODS: Thirty-nine subjects which needed psychiatric impairment assessment were selected. According to the binomial forced-choice digit memory test (BFDMT), all subjects were divided into cooperative and uncooperative groups. The subjects were asked to take the image completion test from Wechsler adult intelligence scale. Meanwhile, the data of eye movement track, fixation, saccade, pupil and blink were recorded by the track system of eye movement. RESULTS: There were significantly differences (P<0.05) in the data of saccade between cooperative (10 cases) and uncooperative groups (29 cases). The frequency, time, amplitude, acceleration of saccadic in uncooperative group were significantly higher than cooperation group. The saccade latencies of cooperation group increased more than uncooperative group. There was a significant difference (P<0.05) in total discrete distance, average distance and total time of fixation between two groups, while the average duration time, number and frequency of fixation had no significantly difference (P>0.05) between two groups. And the blink frequency of cooperation group was higher than uncooperative group. CONCLUSIONS: Eye movement can be an objective index for the primary judgment of cooperation level. PMID- 29231022 TI - [Forensic Psychiatric Assessment for Organic Personality Disorders after Craniocerebral Trauma]. AB - OBJECTIVES: To explore the occurrence and the differences of clinical manifestations of organic personality disorder with varying degrees of craniocerebral trauma. METHODS: According to the International Classification of Diseases-10, 396 subjects with craniocerebral trauma caused by traffic accidents were diagnosed, and the degrees of craniocerebral trauma were graded. The personality characteristics of all patients were evaluated using the simplified Neuroticism Extraversion Openness Five-Factor Inventory (NEO-FFI). RESULTS: The occurrence rate of organic personality disorder was 34.6% while it was 34.9% and 49.5% in the patients with moderate and severe craniocerebral trauma, respectively, which significantly higher than that in the patients (18.7%) of mild craniocerebral trauma (P<0.05). Compared with the patients without personality disorder, the neuroticism, extraversion and agreeableness scores all showed significantly differences (P<0.05) in the patients of mild craniocerebral trauma with personality disorder; the neuroticism, extraversion, agreeableness and conscientiousness scores showed significantly differences ( P>0.05) in the patients of moderate and severe craniocerebral trauma with personality disorder. The agreeableness and conscientiousness scores in the patients of moderate and severe craniocerebral trauma with personality disorder were significantly lower than that of mild craniocerebral trauma, and the patients of severe craniocerebral trauma had a lower score in extraversion than in the patients of mild craniocerebral trauma. CONCLUSIONS: The severity of craniocerebral trauma is closely related to the incidence of organic personality disorder, and it also affects the clinical features of the latter, which provides a certain significance and help for forensic psychiatric assessment. PMID- 29231023 TI - [Analysis on the Injury Mechanism and Characteristics of Ox Horn]. AB - OBJECTIVES: To study the morphological characteristics of the injury caused by ox horn on human body and its injury mechanism, and to discuss the rules and characteristics of injury by ox horn and provide forensic evidences for identification of such cases. METHODS: The comparative analysis of position and morphological characteristics were performed by summarizing the data of 100 victims gored by ox accepted by Heilongjiang agricultural areas public security bureau during 2004-2014. RESULTS: The specific injuries only could be found at the contact positions such as thorax and abdomen, lower back and limbs of the victims gored by ox horn. Most of the skin wounds had the characteristics of sharp injuries, the bar-type injury by club which called "rail way bruise" was an obvious characteristic appeared on the soft tissue. CONCLUSIONS: Ox horn can cause non-specific injuries on thorax and abdomen, lower back and limbs of human body, which are similar with the characteristics of sharp injury and injury by club. Careful analyzation and identification should be performed on such injury in daily work. PMID- 29231024 TI - [Diatom Detection Using Enzyme Combined with Strong Acid Digestion Method]. AB - OBJECTIVES: To detect diatom in the organs of drowners by enzyme combined with strong acid digestion method, and evaluate its application value. METHODS: A total of 40 cases which have been identified as drowning in local region were collected. Samples of the lung, liver, kidney, and the water of the scene were also gathered from each case. Strong acid digestion method, enzyme combined with strong acid digestion method, and enzymic digestion method were respectively performed to detect the diatom in the samples. The comparative analysis was made on digestion time, digestive power and detection rate of diatom, etc. RESULTS: Enzyme combined with strong acid digestion method was significantly better than enzymic digestion method on digestion time and digestive power; enzyme combined with strong acid digestion method were obviously superior to strong acid digestion method on the detection rate of diatom. CONCLUSIONS: Enzyme combined with strong acid digestion method combines the advantages of strong acid digestion method and enzymic digestion method. It has the characters of operation safety with little pollution to environment, which is worthy of further popularization and practice. PMID- 29231025 TI - [Comparison of MPure-12 Automatic Nucleic Acid Purification and Chelex-100 Method]. AB - OBJECTIVES: To explore the forensic application value of MPure-12 automatic nucleic acid purification (MPure-12 Method) for DNA extraction by extracting and typing DNA from bloodstains and various kinds of biological samples with different DNA contents. METHODS: Nine types of biological samples, such as bloodstains, semen stains, and saliva were collected. DNA were extracted using MPure-12 method and Chelex-100 method, followed by PCR amplification and electrophoresis for obtaining STR-profiles. RESULTS: The samples such as hair root, chutty, butt, muscular tissue, saliva stain, bloodstain and semen stain were typed successfully by MPure-12 method. Partial alleles were lacked in the samples of saliva, and the genotyping of contact swabs was unsatisfactory. Additional, all of the bloodstains (20 MUL, 15 MUL, 10 MUL, 5 MUL, 1 MUL) showed good typing results using Chelex-100 method. But the loss of alleles occurred in 1 MUL blood volume by MPure-12 method. CONCLUSIONS: MPure-12 method is suitable for DNA extraction of a certain concentration blood samples.Chelex-100 method may be better for the extraction of trace blood samples.This instrument used in nucleic acid extraction has the advantages of simplicity of operator, rapidity, high extraction efficiency, high rate of reportable STR-profiles and lower man made pollution. PMID- 29231026 TI - [Impact of Myocardial Infarction and Abnormalities of Cardiac Conduction System on Sudden Cardiac Death]. AB - Sudden cardiac death (SCD), most commonly seen in coronary heart disease, is a kind of sudden death caused by series of cardiac parameters, which usually combines with myocardial infarction. However, some SCDs (including early myocardial infarction) happen suddenly and cause death in a very short time. In these circumstances, typical morphological changes are lack in macroscopic or microscopic fields, which make such SCDs become the emphasis and difficulty in the present research. SCD caused by myocardial infarction and abnormalities of cardiac conduction system (CCS) is related to atherosclerosis of coronary artery closely. This paper reviews cardiac dysfunction caused by myocardial infarction and diseases of CCS from morphology and molecular biology, and explores potential relationship between them. This paper aims to provide clues to the mechanism of myocardial infarction related sudden death and possible assistance for forensic diagnosis of SCD. PMID- 29231027 TI - [Research Progress on Forensic Dentistry]. AB - Forensic dentistry is an interdiscipline of forensic medicine and stomatology, which provides legal information by collecting, testing and assessing the dental evidence scientifically. In this review, the present application of forensic dentistry has been described, such as the estimation of age, sex, species, occupation and living habit, as well as the identification of individual, domestic violence or abuse, which aims to enrich and improve forensic dentistry for making it be more useful in forensic medicine even in juridical practice. PMID- 29231028 TI - [Confirming Indicators of Qualitative Results by Chromatography-mass Spectrometry in Biological Samples]. AB - Because of the exist of complex matrix, the confirming indicators of qualitative results for toxic substances in biological samples by chromatography-mass spectrometry are different from that in non-biological samples. Even in biological samples, the confirming indicators are different in various application areas. This paper reviews the similarities and differences of confirming indicators for the analyte in biological samples by chromatography mass spectrometry in the field of forensic toxicological analysis and other application areas. These confirming indicators include retention time (RT), relative retention time (RRT), signal to noise (S/N), characteristic ions, relative abundance of characteristic ions, parent ion-daughter ion pair and abundance ratio of ion pair, etc. PMID- 29231029 TI - The Technology Boom Continues. PMID- 29231030 TI - Opportunities and Challenges of a Small Group Practice. PMID- 29231031 TI - Focus on: In-office Technologies. PMID- 29231032 TI - Digital Technologies: A Roundtable Discussion on Changing the Face of Dentistry. PMID- 29231033 TI - Proper Preparation for Prosthetically Driven Implants: CBCT Diagnosing and Surgical Protocol. PMID- 29231034 TI - Failure Followed by a Successful Outcome. PMID- 29231035 TI - An Asymmetric Dehydrogenative Diels-Alder Reaction for the Synthesis of Chiral Tetrahydrocarbazole Derivatives. AB - An asymmetric dehydrogenative Diels-Alder reaction of 2-methyl-3 phenylmethylindoles and alpha,beta-unsaturated aldehydes has been established. The successful in situ generation of the indole ortho-quinodimethane intermediate and the iminium activation of enals are the keys to success, providing various tetrahydrocarbazole derivatives with up to >99% ee. PMID- 29231037 TI - Energy envelope maintenance among patients with myalgic encephalomyelitis and chronic fatigue syndrome: Implications of limited energy reserves. AB - Objective The Energy Envelope Theory of myalgic encephalomyelitis and chronic fatigue syndrome postulates that individuals with myalgic encephalomyelitis and chronic fatigue syndrome may experience some increase in functioning if their level of exertion consistently remains within the limits of their available energy. Findings of several studies support this theory; however, the current study is the first to explore how an individual's initial level of available energy may influence the relation between energy envelope maintenance and level of functioning. Method The functioning, activity, and symptomatology of six groups of individuals with myalgic encephalomyelitis and chronic fatigue syndrome were compared. Groups were created based upon level of available energy (higher or lower) and energy envelope adherence (underextended, within, overextended). Results Results indicate that, as expected, individuals with myalgic encephalomyelitis and chronic fatigue syndrome who had higher available energy also had better functioning than individuals with lower available energy; however, this relation was less pronounced for individuals who were overexerting themselves. Discussion These results are consistent with the Energy Envelope Theory, and they suggest that overexertion was particularly impactful for individuals with higher levels of available energy. PMID- 29231036 TI - Mucoepidermoid carcinoma mimicking a mucocele (ranula) in the floor of the mouth. AB - Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. The submandibular gland is rarely involved, about less than 10% of all other major salivary glands. We report a case of a 49-year-old female who presented with a mass on the left side of the floor of the mouth. She was complaining of neck pain for the last 2-3 days and had noticed the mass growing in size and becoming tender to palpation. There was no exacerbation of pain during eating, drinking, or opening of mouth. A multidetector CT scan was made. The radiographic examination revealed a mostly well-defined hypodense area suggestive of mucocele (ranula), which was thought to be corroborated by the clinical findings. The treatment of choice was the complete excision of the mucocele and the left submandibular salivary gland. The histopathological examination surprisingly revealed a low-grade MEC. No further treatment was recommended; however, a follow up was scheduled in 4 months. This atypical location of MEC in the floor of the mouth simulated the clinical and radiographic features of a mucocele. This case highlights the value and importance of using all the available diagnostic tools and modalities for optimal patient management, as the histopathological analysis played an important role to confirm the diagnosis. PMID- 29231038 TI - Examining the Impact of Alcohol and Other Drug Education Exposure on Student Alcohol Consumption. AB - This investigation examined the association between alcohol and other drug (AOD) prevention/education programs and drinking behaviors among students aged 12 to 17 years. We conducted a secondary analysis of the 2013 National Survey on Drug Use and Health ( N = 17,736). AOD prevention/education was assessed in three school settings: special class, regular class, and outside regular class. Outcome variables included past year alcohol use and current heavy episodic drinking. Associations were assessed via one-way analyses of variance and multiple regression models. There was a significant effect of program exposure on alcohol use ( p<.001) and heavy episodic drinking ( p = .002). Regression results found AOD prevention/education exposure ( p = .004) was significant, indicating that exposure decreased past year use. No difference was found based on heavy episodic drinking. Increasing exposure to AOD prevention/education programs is warranted and encouraged. PMID- 29231039 TI - Alcohol Service Practices: A Survey of Bar and Restaurant Managers. AB - Excessive alcohol consumption can result from illegal sales to intoxicated patrons at bars and restaurants. We surveyed bar/restaurant managers about their practices in reducing illegal sales to intoxicated patrons. We found that managers were confident that they could refuse service to intoxicated customers but were less likely to have communicated necessary information to their staff on how to refuse such sales. Managers who agreed that a business in their community would be cited for overservice were more likely to be confident that they could handle customers who had been cut off from alcohol service. Our study suggests that bar/restaurant managers may need training to improve their communication with staff and that increased enforcement may lead to an increase in manager confidence in handling intoxicated patrons. PMID- 29231040 TI - Differentiation between phyllodes tumours and fibroadenomas using intravoxel incoherent motion magnetic resonance imaging: comparison with conventional diffusion-weighted imaging. AB - OBJECTIVE: To investigate whether the parameters derived from intravoxel incoherent motion (IVIM) MRI could differentiate phyllodes tumours (PTs) from fibroadenomas (FAs) by comparing the apparent diffusion coefficient (ADC) values. METHODS: This retrospective study included 7 FAs, 10 benign PTs (BPTs), 4 borderline PTs, and one malignant PT. Biexponential analyses of IVIM were performed using a 3 T MRI scanner. Quantitative IVIM parameters [pure diffusion coefficient (D), perfusion-related diffusion coefficient (D*), and fraction (f)] were calculated. The ADC was also calculated using monoexponential fitting. RESULTS: The D and ADC values showed an increasing tendency in the order of FA, BPT, and borderline or malignant PT (BMPT). No significant difference was found in the D value among the three groups. The ADC value of the BMPT group was significantly higher than that of the FA group (p = 0.048). The D* value showed an increasing tendency in the order of BMPT, BPT, and FA, and the D* value of the BMPT group was significantly lower than that of the FA group (p = 0.048). CONCLUSION: The D* derived from IVIM and the ADC were helpful for differentiating between FA and BMPT. Advances in knowledge: IVIM MRI examination showed that the perfusion-related diffusion coefficient is lower in borderline and malignant PTs than in FAs and the opposite is true for the ADC. PMID- 29231041 TI - Using Trial Vocal Fold Injection to Select Vocal Fold Scar Patients Who May Benefit From More Durable Augmentation. AB - OBJECTIVES: Clinical indications for vocal fold injection augmentation (VFI) are expanding. Prior studies demonstrate the benefit of trial VFI for select causes of glottic insufficiency. No studies have examined trial VFI for glottic insufficiency resulting from true vocal fold (TVF) scar. METHODS: Retrospective chart review of patients who underwent trial VFI for a dominant pathology of TVF scar causing dysphonia. Patients who subsequently underwent durable augmentation were identified. The primary study outcome was the difference in Voice Handicap Index-10 (VHI-10) score from pretrial VFI to post-durable augmentation. RESULTS: Twenty-eight patients underwent trial VFI for TVF scar, 22 of whom reported a positive response. Fifteen of 22 subjects who underwent durable augmentation had viable data for analysis. Mean VHI-10 improved from 26.9 to 18.6 ( P < .05), for a delta VHI-10 of 8.3, or 30.9% improvement. Twelve of the 15 (80%) showed a clinically significant improvement (delta VHI-10 >5). CONCLUSIONS: A trial VFI is a potentially useful, low-risk procedure that appears to help the patient and clinician identify when global augmentation might improve the voice when vocal fold scar is present. Patients who reported successful trial VFI often demonstrated significant improvement in their VHI-10 after subsequent durable augmentation. PMID- 29231042 TI - Perceptions of Harm From Substance Use and Social Self-Efficacy Among Early Adolescents. AB - Researchers examined the association between perceptions of harm from substance use and social self-efficacy (SSE) in a sample of early adolescents in public middle schools ( n = 4,122). One-way analysis of covariance and post hoc tests were used to assess the relationships between perceptions of harm from tobacco, alcohol, marijuana, and cocaine use and SSE while controlling for the effects of grade, sex, race, and socioeconomic status. Effect sizes were calculated from the post hoc comparisons to estimate practical importance. Results suggest that lower perceptions of harm from each examined substance were significantly associated with lower SSE ( p < .0001). Effect sizes were of medium practical importance. Enhancing SSE in early adolescents may be an effective component of interventions designed to reduce perceptions of harm associated and subsequent substance use. PMID- 29231043 TI - Understanding Student Drinking Patterns: Does Shame Proneness Matter? AB - This study ( N = 202; mean age = 19.52 years, SD = 1.36 years; 66.5% female) analyzed three structural equation models to determine whether ruminative brooding and negative affect, moderated by shame proneness, explained college student drinking behaviors more than a model without shame proneness. Results indicated a model including shame proneness fit the data best; however, the moderated variables were not significantly associated with other variables in the retained model. Results are discussed alongside clinical recommendations within a university counseling center framework. PMID- 29231044 TI - A systematic review of exercise and psychosocial rehabilitation interventions to improve health-related outcomes in patients with bladder cancer undergoing radical cystectomy. AB - OBJECTIVE: Summarizing the evidence on the effects of pre- and postoperative exercise and psychosocial rehabilitation interventions on patient-reported outcomes (PROs) and physical fitness in bladder cancer patients undergoing radical cystectomy. DATA SOURCES: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Web of Science and the Physiotherapy Evidence Database were searched independently by two authors from inception until 10 November 2017. Cited references of the studies and citing references retrieved via Web of Science were also checked. REVIEW METHODS: Randomized controlled trials (RCTs) and non-randomized studies assessing effects of exercise and psychosocial interventions in bladder cancer patients undergoing radical cystectomy were eligible. Primary outcome measures were PROs and physical fitness. Risk of bias was assessed using the Cochrane Collaboration tool and the Newcastle-Ottawa Scale. RESULTS: Five RCTs (three exercise and two psychosocial studies) and one non-randomized psychosocial study comprising 317 bladder cancer patients were included. Timing of the intervention was preoperative ( n = 2), postoperative ( n = 2) or both pre- and postoperative ( n = 2). Positive effects of exercise were found for physical fitness ( n = 3), some health-related quality-of-life (HRQoL) domains ( n = 2), personal activities in daily living ( n = 1) and muscle strength ( n = 1). Psychosocial interventions showed positive effects on anxiety ( n = 1), fatigue ( n = 1), depression ( n = 1), HRQoL ( n = 1) and posttraumatic growth ( n = 1). Quality assessment showed most shortcomings with sample sizes and strong heterogeneity was observed between studies. CONCLUSION: The evidence relating to the effects of exercise in bladder cancer is very limited and is even less for psychosocial interventions. PMID- 29231045 TI - Let's Get Involved! The Impact of Service Learning on Drinking Perceptions, Alcohol Use, and Protective Behaviors in College Students. AB - While there is mounting support for the efficacy of alcohol-based curriculum infusion (CI) programs, studies have yielded mixed results. Insufficient attention has been given to nuances in the types of CI. Using a two-group pretest posttest quasi-experimental design, this study assessed two forms of CI, information-only (IO) and service learning (SL), on drinking perceptions, drinking behavior, and protective behaviors. When the entire sample was considered, CI significantly improved participants' drinking perceptions and behavior. SL was more effective than IO for one measure of drinking behavior and for protective behaviors. Interestingly, there was a greater decrease in men's drinking behavior and increase in women's protective behaviors in the SL group. This study may help guide health professionals, educators, and faculty members interested in developing alcohol-focused CI programs. PMID- 29231046 TI - An Assessment of the Effects of Hydrotherapy During the Active Phase of Labor on the Labor Process and Parenting Behavior. AB - This study was conducted to assess the effect on labor process and parenting behavior of hydrotherapy applied during the active phase of labor. This quasi experimental study was conducted by using an equivalent comparison group ( n = 40). The participants in the experimental group whose cervical dilation was 5 cm were taken to the hydrotherapy tub. This application continued until cervical dilation reached 10 cm. The Participants Questionnaire, The Birth Follow-up Questionnaire, The Postpartum ]collection tools. The duration of the active phase and second stage of labor was extremely short in the experimental group in comparison with the equivalent comparison group ( p = .001). The Visual Analogue Scale (VAS) scores of the experimental group were lower than those of the equivalent comparison group when cervical dilation was 6 cm and 10 cm ( p = .001). The experimental group also displayed more positive parenting behavior and positive labor feeling ( p = .001). PMID- 29231047 TI - Cost-effectiveness analysis of treatments involving radioembolization in intermediate-stage hepatocellular carcinoma. AB - AIM: We evaluated two treatment sequences, transarterial radioembolization followed by transarterial chemoembolization and possibly sorafenib (=TTS) versus transarterial radioembolization followed by sorafenib alone (=TS), to identify the most cost-effective pathway to treat intermediate-stage hepatocellular carcinoma from the Italian healthcare system perspective. MATERIALS & METHODS: A Markov model was developed to project costs and health outcomes for TTS and TS over a lifetime horizon. Data available at three hospitals in Italy were collected. Healthcare resource utilization was derived from standard clinical protocols. Costs were obtained from official regional tariffs. RESULTS & CONCLUSION: Taking into consideration 16 patients for TTS and 22 patients for TS pathways, the TTS sequence provided a dominant strategy in comparison to TS. Further evidence is desirable to confirm these results. PMID- 29231048 TI - Development of a Computerized Adaptive Test for Anxiety Based on the Dutch Flemish Version of the PROMIS Item Bank. AB - We used the Dutch-Flemish version of the USA PROMIS adult V1.0 item bank for Anxiety as input for developing a computerized adaptive test (CAT) to measure the entire latent anxiety continuum. First, psychometric analysis of a combined clinical and general population sample ( N = 2,010) showed that the 29-item bank has psychometric properties that are required for a CAT administration. Second, a post hoc CAT simulation showed efficient and highly precise measurement, with an average number of 8.64 items for the clinical sample, and 9.48 items for the general population sample. Furthermore, the accuracy of our CAT version was highly similar to that of the full item bank administration, both in final score estimates and in distinguishing clinical subjects from persons without a mental health disorder. We discuss the future directions and limitations of CAT development with the Dutch-Flemish version of the PROMIS Anxiety item bank. PMID- 29231049 TI - Heart Rate Recovery and Cancer Risk: Prospective Cohort Study. AB - This study aims to determine the association between 2-minute heart rate recovery (HRR) and cancer risk. Each participant (5379 women; 8485 men) provided HRR obtained from treadmill tests. The outcome was site-specific cancer. Over 9 years of follow-up, 630 cancer events (258 women) were accrued. Slower HRR was associated with increased thyroid cancer risk in women ( P for trend = .0121) and colorectal cancer risk in men ( P for trend = .0034). The lowest HRR (<13 bpm) had higher hazards of thyroid cancer (hazard ratio [HR] = 2.20; 95% CI = 1.28 3.77) in women and colorectal cancer (HR = 3.08; 95% CI = 1.32-7.15) in men. In women, slower HRR and lower proportions of heart rate recovery (PHRR) were associated with higher hazards of thyroid cancer in women and metabolically related cancers (liver and colorectal) in men. Slower HRR and lower PHRR were independent risk factors for thyroid cancer in women and metabolically related cancers in men. PMID- 29231050 TI - Follow-up interval for probably benign breast lesions on screening ultrasound in women at average risk for breast cancer with dense breasts. AB - Background Women at high risk for breast cancer and women at average risk have different pretest probabilities. Probably benign lesions on screening ultrasound (US) should be assessed and managed differently for these two risk groups. Purpose To evaluate the effectiveness of short-term follow-up for probably benign lesions on screening US in women at average risk for breast cancer with dense breasts. Material and Methods A total of 445 women at average risk for breast cancer with probably benign lesions on screening US, dense breasts, and negative or benign mammography results were included. Women were classified into the six month group (n = 345) or 12-month group (n = 100) according to when the first follow-up was performed (3-9 months or 9-15 months). The cancer detection rate, frequencies of newly developed lesions and progressed lesions, and biopsy rate were compared. Results There were no malignancies from three to 15 months. Three cancers newly developed after 15 months. One was a 3-mm ductal carcinoma in situ and two were 10-mm and 18-mm invasive ductal carcinoma without lymph node metastasis. The frequency of newly developed lesions and progressed lesions and biopsy rate were not significantly different between the six-month and 12-month groups ( P = 0.320, 0.621, and >0.999). Conclusion A follow-up at 12 months can be considered for probably benign lesions on screening US in women at average risk for breast cancer with dense breasts. However, a large series prospective study is needed before clinical application. PMID- 29231051 TI - Midostaurin in Combination With Standard Chemotherapy for Treatment of Newly Diagnosed FMS-Like Tyrosine Kinase 3 (FLT3) Mutation-Positive Acute Myeloid Leukemia. AB - OBJECTIVE: To evaluate the efficacy and safety of midostaurin in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation in newly diagnosed FLT3-mutated acute myeloid leukemia (AML). DATA SOURCE: A literature search of PubMed and MEDLINE (September 2017) was performed using the terms midostaurin, PKC412, FLT3 gene, and acute myeloid leukemia. STUDY SELECTION/DATA EXTRACTION: Clinical trials evaluating the efficacy and safety of midostaurin in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation were reviewed for the treatment of newly diagnosed FLT3-mutated AML. All peer-reviewed articles with clinically relevant information were evaluated for inclusion. DATA SYNTHESIS: Midostaurin is a multikinase inhibitor also targeting FLT3 indicated for the treatment of newly diagnosed FLT3 mutated AML. A phase III trial illustrated that midostaurin in combination with standard chemotherapy improved event-free survival, disease-free survival, and overall survival in patients with newly diagnosed FLT3-mutation-positive AML compared with standard chemotherapy alone. However, midostaurin did not show a difference in the rate of patients who proceeded to receive an allogeneic stem cell transplant compared with placebo. There was no significant difference in toxicity between the midostaurin and placebo groups, except that more patients experienced grade 3 to 5 anemia and rash with midostaurin. CONCLUSIONS: Midostaurin in combination with standard induction and consolidation is safe and efficacious in newly diagnosed FLT3-mutated AML. PMID- 29231052 TI - Efficacy and Safety of Ranolazine in Diabetic Patients: A Systematic Review and Meta-analysis. AB - BACKGROUND: Recent studies have discovered that the antiangina agent ranolazine exerts a glucometabolic effect. OBJECTIVE: This systematic review and meta analysis aimed to further understand the efficacy and safety profile of ranolazine in patients with diabetes. METHODS: Randomized controlled trials (RCTs) were searched in PubMed, Cochrane, and EMBASE databases and in ClinicalTrials.gov up to July 2017. Efficacy end points were defined as the change in hemoglobin A1C (A1C) and fasting serum glucose (FSG) levels. Safety end points included the incidence of hypoglycemia, persistent hyperglycemia, and major adverse cardiovascular events (MACE). Sensitive and subgroup analyses were also conducted. RESULTS: Seven RCTs with 4461 diabetic patients were selected. Compared with placebo, the use of ranolazine significantly reduced the levels of A1C (weighted mean difference [WMD] = -0.49%; 95% CI = -0.58 to -0.40; P < 0.00001) and FSG (WMD = -6.70 mg/dL; 95% CI = -11.87 to -1.52; P = 0.01). No significant differences were observed in the rates of hypoglycemia (relative risk [RR] = 1.17; 95% CI = 0.76 to 1.80; P = 0.47), persistent hyperglycemia (RR = 0.78; 95% CI = 0.47 to 1.31; P = 0.35), and MACE (RR = 0.65; 95% CI = 0.32 to 1.32; P = 0.23). CONCLUSION: Ranolazine exerts a positive effect on glucose control and is a well-tolerated agent for patients with diabetes. PMID- 29231053 TI - The Contribution of Malodour in Quality of Life of Patients With Hidradenitis Suppurativa. AB - BACKGROUND: Malodourous discharge in patients with hidradenitis suppurativa (HS) has a strong psychosocial impact and is often reported as a source of embarrassment, low self-esteem, social stigma, and barriers to interpersonal relationships. Malodour is a maker of bacterial colonization, and its role in HS is understudied. OBJECTIVES: The aim of this study is to assess the relationship between severity of malodourous discharge and quality-of-life impairment in patients with HS. METHODS: This is a cross-sectional study of 51 patients recruited from the Women's College Hospital and the York Dermatology Centre. Quality of life was assessed using both the Dermatology Life Quality Index (DLQI) and the Skindex-29 instruments. RESULTS: Severity of odour significantly predicts the total Skindex score after controlling for disease severity as measured by the Hurley stage and Sartorius score ( R2 = 0.39, F = 8.11, P < .0001). However, odour severity is not a predictor of DLQI ( R2 = 0.17, F = 2.63, P = .064). There was no difference in mean DLQI scores for the low- vs high-odour groups, but patients with high odour had a greater quality of life impairment as measured by the Skindex tool ( t = -4.19, df = 43, P < .0001, mean difference = -18.87). CONCLUSION: Malodour is a common symptom that significantly impairs quality of life in patients with HS. The fact that this effect is captured in Skindex and not the DLQI may be attributed to the nonspecificity of the DLQI in terms of unique disease characteristics. It is important to address odour in the management of patients with HS. PMID- 29231054 TI - Polytobacco Use and the "Customization Generation"-New Perspectives for Tobacco Control. AB - In recent years, the United States observed a significant uptake in concurrent use of multiple tobacco products and alternative nicotine delivery devices among youth-a phenomenon identified as polytobacco use-making tobacco control efforts more complex for clinicians, policy makers, and scientists, alike.The present commentary stimulates new perspectives on tobacco control in the context of polytobacco use and a youth culture of customization. This culture-based value of today's youth may inform current patterns of tobacco use. More specifically, the authors hypothesize a concept of tobacco customization-the concurrent use of multiple tobacco products to create personalized tobacco experience matching lifestyle, culture, values, and addiction levels. With a range of experiences made possible through an ever-increasing menu of tobacco products, flavors, and novel devices, the current youth culture of customization may also translate to tobacco customization. Given the predominance of polytobacco use in youth-tobacco users, tobacco control initiatives must be challenged to new perspectives. Should we discover the viability of tobacco customization, tobacco use strategies that target cultural values, harness popular trends, and culture and provide customizable experiences may have a notable impact on tobacco use in this population. PMID- 29231055 TI - Effect of anatomical region on the formation of metal artefacts produced by dental implants in cone beam computed tomographic images. AB - OBJECTIVES: To quantitatively compare metal artefacts produced by implants in different maxillomandibular regions on cone beam CT (CBCT) images. METHODS: A total of 200 implants selected from CBCT examinations were divided into four groups: Group 1 (n = 50)-implants located in the anterior maxilla; Group 2 (n = 50)-implants located in the posterior maxilla; Group 3 (n = 50)-implants located in the anterior mandible and Group 4 (n = 50)-implants located in the posterior mandible. The implants were further classified as isolated or adjacent to other implants. Three axial reconstructions were selected for each sampled implant (apical, middle and cervical). On each slice, the artefacts produced by the implants were counted. The Mann-Whitney test was used to compare the variables between groups. The Kruskal-Wallis and Student-Newman-Keuls tests were used to compare the axial reconstructions. RESULTS: The mandible showed a greater number of artefacts than the maxilla (apical image: p = 0.0024; middle image: p < 0.0001). The anterior region produced more artefacts than the posterior region (apical image: p = 0.0105; middle image: p < 0.0316). There was no significant difference in the number of artefacts between isolated and adjacent implants, and the cervical image was most affected by artefacts. CONCLUSIONS: Dental implants always produce metal artefacts in CBCT images, and these artefacts are affected by the anatomical location in the dental arch. PMID- 29231056 TI - The application of control charts in regulated bioanalysis for monitoring long term reproducibility. AB - In regulated bioanalysis, the acceptance of results is batch-wise. When during clinical development derived pharmacokinetic or pharmacodynamic results from different studies will be combined or compared, it is recommendable to monitor the long-term reproducibility of bioanalytical assays. Long-term reproducibility can be evaluated by control charts generated from control samples included in each batch. We present a methodology for the implementation, construction and evaluation of control charts next to the regular batch acceptance of bioanalytical results. Decision rules can be set up for a statistical evaluation of the results. Violation of a decision rule may lead to a root-cause investigation and corrective actions to improve assay robustness. Three examples of control charts, for pharmacokinetic and pharmacodynamic analytes are presented. PMID- 29231057 TI - A critical review on ramucirumab in the treatment of advanced urothelial cancer. AB - Advanced urothelial cancer (UC) is a lethal disease despite current advances in systemic therapy, including platinum chemotherapy combinations and immune checkpoint inhibition. Tumor angiogenesis is involved in UC growth and metastatic progression. Proangiogenic signaling through the VEGFR is a key process in UC with prognostic significance. Targeting of VEGFR2 with the monoclonal antibody ramucirumab has been tested in various different tumor types. In this review, we discuss the development of the drug in the context of its preclinical and clinical use with a focus on UC. Improvements in our ability to predict responses and resistance are key for maximizing its efficacy and selecting the most appropriate combinations with other active agents. PMID- 29231058 TI - Efaverinz and nano-gold-loaded mannosylated niosomes: a host cell-targeted topical HIV-1 prophylaxis via thermogel system. AB - Sexual dissemination of Human Immunodeficiency Virus-1 (HIV-1) is the prime mode of its spread. Topical microbicidal approach has gained much attention, but no real success is observed till date, either due to toxicity or resistance of active moieties and the lack of efficient drug delivery approaches. In this research protocol, a unique combination approach of a standard drug moiety, that is, Efaverinz (EFV) and a nanometal, that is, gold nanoparticles (GNPs) was tried. Both these candidates were delivered through a mannosylated niosomal system, to exploit protein (lectins present on HIV host cells) - carbohydrate (oligosaccharides such as mannan present on HIV gp-120 receptor) interaction. GNPs (10.4 nm average size) were entrapped inside the aqueous core, whereas lipophilic EFV was loaded in the bilayer membrane. Results demonstrated a significant increase in antiviral activity when EFV was fired with GNPs. Delivery of this combination via mannosylated niosomes proved to be a perfect approach with exceedingly well potential compared to non liganded niosomal system. A thermosensitive gel vehicle was prepared and the loaded niosomes were dispersed in it to have a nanogel system. The optimized formulation was evaluated for its prophylactic activity and the results showed completely inhibited viral dissemination at folds dilution levels. PMID- 29231059 TI - Association between hand-grip strength and erectile dysfunction in older men. AB - OBJECTIVES: To evaluate the association between handgrip strength and erectile dysfunction (ED) in community-dwelling older men. METHODS: This cross-sectional study included 1771 participants of the Dong-gu Study. Handgrip strength was measured with a handheld dynamometer. ED was assessed with the Korean version of the International Index of Erectile Function (IIEF). ED was categorized as none to mild (IIEF-EF scores of 13-30) and moderate to severe (IIEF-EF scores of 0 12). Multivariable logistic regression was conducted with adjustment for potential confounders. RESULTS: The proportion of men with moderate to severe ED was 48.8%. The age-adjusted ED score increased with increasing quartile of handgrip strength (11.0, 12.4, 13.4, and 14.0 in the lowest, second, third, and highest quartiles, respectively). After adjustment for potential confounders, greater handgrip strength was associated with a lower risk of ED (odds ratio (OR): 0.82 per 5 kg; 95% confidence interval (CI): 0.74-0.90). In addition, a high level of moderate to vigorous physical activity was associated with a lower risk of ED (OR: 0.75; 95% CI: 0.61-0.93). CONCLUSION: In this study, aging men with greater handgrip strength had a lower risk of ED. This result suggests that reduced physical functioning may contribute to ED. PMID- 29231060 TI - Combined effects of ovariectomy and streptozotocin-induced diabetes in the articular cartilage of rats. AB - AIM: To evaluate the combined effects of streptozotocin-induced diabetes (Di) and ovariectomy in the articular cartilage of rats. METHODS: Forty adult female Wistar rats were ovariectomized (OVX) or sham-operated. After recovery from surgery, the animals were assigned randomly into four groups: OVX control (OVX C); OVX treated with 10 ug/kg/day of 17beta-estradiol (OVX-E); sham-operated subjected to Di (Sham-Di); and OVX subjected to Di (OVX-Di). After 60 days of treatment, the animals were euthanized and the distal femurs with articular cartilage were processed for paraffin-embedding. Sections were stained with hematoxylin and eosin for histomorphometry, Picro-Sirius Red for collagen, or Alcian Blue for glycosaminoglycan (GAG) content. To detect apoptosis, sections were stained with an antibody to cleaved caspase-3 (casp-3). RESULTS: Articular cartilage thickness and GAG content were significantly lower (p < 0.05) in the OVX-Di group, which also showed a higher number of casp-3-positive chondrocytes than the other groups. Interestingly, the higher percentage (p < 0.05) of mature collagen fibers was seen in the OVX-Di group, may be as a result of a reduced extracellular matrix remodeling of the articular cartilage. CONCLUSION: Our results indicate that the combination of ovariectomy and streptozotocin-induced diabetes produces more deleterious effects in articular cartilage of rats than either condition alone. PMID- 29231061 TI - The effect of aqueous extract of Rosa damascena on formaldehyde-induced toxicity in mice testes. AB - CONTEXT: Rosa damascena L. (Rosaceae) (RD) essential oil and extracts are commonly used as a flavour in herbal medicine which increase libido. Previous studies have shown inhalation of RD flower's oil increases libido and causes protective effects in formaldehyde (FA)-induced testicular damage. OBJECTIVE: The protective effects of aqueous extract of RD on the male reproductive system of mice were examined following FA-induced damage. MATERIALS AND METHODS: Forty eight adult NMRI male mice were randomly assigned to six groups (n = 8): control (normal saline, 10 mg/kg); RD40 (40 mg/kg, p.o.); FA treated (10 mg/kg of 10%, i.p.) and FA + RD treated at 10, 20 and 40 mg/kg (FA + RD10), (FA + RD20) and (FA + RD40), respectively, for 40 days. At the end of treatment regimes, serum testosterone (T) level and the reproductive activity, viz. body/organ weights, testicular structure and sperm characteristics were studied. RESULTS: Formaldehyde administration significantly decreased serum T level (p < 0.001), testicular weight/volume, tubular diameter and sperm characteristics compared to the control group (p < 0.05). RD (40 mg/kg) administration in FA-treated mice significantly improved serum T level, testicular weight/histological structure, tubular diameter, Leydig cell number and epididymal sperm characteristics in comparison to its lower doses and the control group (p < 0.05). DISCUSSION AND CONCLUSIONS: We may conclude that RD flower extract can withstand effects of FA in the male reproductive system of mice possibly due to its antioxidative properties. PMID- 29231062 TI - Promising immunotherapy for prostate cancer. AB - INTRODUCTION: Sipuleucel-T is the only currently approved immunotherapy for the management of prostate cancer. However, other immunotherapy agents have recently shown activity in prostate cancer and are being developed alone or in combination with other agents. Areas covered: This article provides a review of positive or encouraging clinical trials of agents under development including vaccines, monoclonal antibodies, immune modulators, gene-mediated cytotoxic immunotherapy and chimeric antigen receptor-modified 'designer' T cells in patients with prostate cancer. Expert opinion: Personalized peptide vaccines have been associated with improvements in overall survival in early phase clinical trials of patients with prostate cancer, which may lead to their future adoption into management. While single agent, monoclonal antibody-based immunotherapy trials and PSA-TRICOM's phase III trial have not demonstrated statistically significant improvements in overall survival, combinations of these agents with complementary agents have demonstrated encouraging activity. To improve the development and targeting of these therapies, agent and patient selection/modification needs to occur in the context of a rational model of the immune system's interaction with prostate cancer. In addition, some traditional surrogates of efficacy may need to be reconsidered as multiple trials of immunotherapy in prostate cancer have had conflicting results between progression-free survival and overall survival. PMID- 29231063 TI - Pour Convergence: College Students' Definitions and Free-Poured Volumes of Standard Alcohol Servings. AB - We examined the correspondence between college students' ( N = 192, 71% women) definitions of free-pours and their free-poured volumes of beer, wine, and liquor. Participants' mean beer definitions and free-pours were positively correlated; participants' mean wine and liquor definitions were larger than their free-pours, which were fairly accurate. Contrary to what the aggregate mean values indicated, fewer than half of the participants accurately free-poured a standard volume of beer, wine, or liquor (37.4%, 35.1%, and 22.2%, respectively) or provided an accurate definition of beer (45.8%); similar to the aggregate data, few participants provided accurate definitions of standard serving of wine (12.2%) or liquor (12.8%) Instead, a majority of participants' definitions and free-pours were well over or under a standard serving. For all three types of alcohol, there was little correspondence between each individual participant's definitions and his or her free-poured volumes. These data suggest analyses of individual data points may provide information important for data collection, prevention, and intervention strategies. PMID- 29231064 TI - Pharmacokinetics, pharmacodynamics and clinical efficacy of non-statin treatments for hypercholesterolemia. AB - INTRODUCTION: Hypercholesterolemia is the main modifiable risk factor for atherosclerosis progression and cardiovascular disease (CVD) development. Its pharmacological management is usually based on the prescription of statins, that in some cases are not however fully effective to reach the desired Low-Density Lipoproteins cholesterol (LDL-C) target, or are not tolerated by patients due to side effects. Areas covered: This manuscript summarizes the basic properties of the emerging new classes of lipid-lowering drugs such as ezetimibe, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors, and Microsomal Triglyceride Transfer Protein (MTP) inhibitors, also citing new drugs in development. Our aim is to describe the main pharmacodynamic and pharmacokinetic characteristics, the available efficacy, tolerability and safety data obtained in randomized clinical trials where these drugs were tested. Expert opinion: Non statin lipid-lowering drugs can be considered an excellent strategy to reduce the residual CV risk, also represented by non-target LDL-C values and high lipoprotein(a) serum levels. In particular, the approved PCSK9 inhibitors (Evolocumab and Alirocumab) have been very effective in optimizing plasma LDL-C values and reducing CV event risk. PMID- 29231065 TI - Serum interleukin-6 levels as an indicator of aseptic meningitis among children with enterovirus 71-induced hand, foot and mouth disease. AB - OBJECTIVES: The enterovirus EV71 is a major pathogen of hand, foot, and mouth disease (HFMD) in children. Aseptic meningitis is the most common neurologic complication of EV71-induced HFMD. Lumbar puncture is a crucial procedure in the diagnosis of aseptic meningitis. It is often performed based on physicians' clinical suspicion. A diagnostic method that can aid in deciding whether this procedure should be performed is necessary. Cytokines are speculated to be associated with neurologic complications. In this study, we aimed to find an indicator of the presence of aseptic meningitis in children with EV71-induced HFMD. METHODS: This cross-sectional study included children with EV71-induced HFMD. The children underwent lumbar puncture due to suspected aseptic meningitis. They were categorized into an aseptic meningitis complicated group (n = 54) and uncomplicated group (n = 47) based on the results of cerebrospinal fluid examination. Healthy children were included as controls (n = 51). The sample serum levels of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL) 1beta, IL-2, IL-6, IL-8, IL-10, and IL-13 were detected using multiplexed fluorescent bead-based immunoassays. RESULTS: The levels of all cytokines were significantly higher in children with EV71-induced HFMD complicated with aseptic meningitis than in children with uncomplicated EV71-induced HFMD and controls (p < 0.001). Binary logistic regression analysis demonstrated that IL-6 had the strongest association with aseptic meningitis of all cytokines examined. According to receiver operating characteristic analysis, the optimal cutoff value for IL-6 was 66 pg/mL with maximum sensitivity and specificity. CONCLUSIONS: The results of this study suggest the association between higher production of cytokine and aseptic meningitis among children with EV71-induced HFMD. IL-6 was also suggested as an indicator of aseptic meningitis. Rapid measurement of IL-6 could be useful in deciding whether physicians should perform lumbar puncture on children. PMID- 29231066 TI - Synthesis and characterisation of celastrol derivatives as potential anticancer agents. AB - In the present study, three series of novel celastrol derivatives were designed and synthesised by modifying the carboxylic acid at the 20th position with amino acid, amine, and triazole derivatives. All the synthesised compounds were screened for their anticancer activities using MTT assay against AGS, MGC-803, SGC-7901, HCT-116, A549, HeLa, BEL-7402, and HepG-2 cell lines. Most of the synthesised compounds exhibited potent antiproliferative effects. The most promising compound 3-Hydroxy-9beta,13alpha-dimethyl-2-oxo-24,25,26-trinoroleana 1(10),3,5,7-tetraen-29-oic amide, N-(R)-methyl-3-(1H-indol-2-yl)propanoate (11) showed considerable high anticancer activity against AGS cell lines, with an IC50 value of 0.44 MUM, and considerably higher activities against HCT-116, BEL-7402, and HepG-2 cell lines, with IC50 values of 0.78, 0.63, and 0.76 MUM, respectively. The results of apoptosis tests and molecular docking study of compound 11 binding to Caspase-3 revealed that its mechanism of action with antiproliferative was possibly involved in inducing apoptosis by inducing the activation of caspase-3. PMID- 29231067 TI - In vitro artifact assessment of an MR-compatible, microwave antenna device for percutaneous tumor ablation with fluoroscopic MRI-sequences. AB - OBJECTIVE: To evaluate artifact configuration and diameters of a magnetic resonance (MR) compatible microwave (MW) applicator using near-realtime MR fluoroscopic sequences for percutaneous tumor ablation procedures. MATERIAL AND METHODS: Two MW applicators (14 G and 16 G) were tested in an ex-vivo phantom at 1.5 T with two 3 D fluoroscopic sequences: T1-weighted spoiled Gradient Echo (GRE) and T1/T2-weighted Steady State Free Precession (SSFP) sequence. Applicator orientation to main magnetic field (B0), slice orientation and phase encoding direction (PED) were systematically varied. The influence of these variables was assessed with ANOVA and post-hoc testing. RESULTS: The artifact was homogenous along the whole length of both antennas with all tested parameters. The tip artifact diameter of the 16 G antenna measured 6.9 +/- 1.0 mm, the shaft artifact diameter 8.6 +/- 1.2 mm and the Tip Location Error (TLE) was 1.5 +/- 1.2 mm.The tip artifact diameter of the 14 G antenna measured 7.7 +/- 1.2 mm, the shaft artifact diameter 9.6 +/- 1.5 mm and TLE was 1.6 +/- 1.2 mm. Orientation to B0 had no statistically significant influence on tip artifact diameters (16 G: p = .55; 14 G: p = .07) or TLE (16 G: p = .93; 14 G: p = .26). GRE sequences slightly overestimated the antenna length with TLE(16 G) = 2.6 +/- 0.5 mm and TLE(14 G) = 2.7 +/- 0.7 mm. CONCLUSIONS: The MR-compatible MW applicator's artifact seems adequate with an acceptable TLE for safe applicator positioning during near realtime fluoroscopic MR-guidance. PMID- 29231068 TI - Clinicopathological and prognostic significance of platelet count in patients with ovarian cancer. AB - AIM: Increasing evidence indicates that platelet count is a useful biomarker of long-term outcomes in patients with ovarian cancer. However, the prognostic value of platelet count in patients with ovarian cancer remains controversial. We therefore conducted a meta-analysis aimed to investigate the prognostic role of the platelet count in patients with ovarian cancer. METHOD: A comprehensive search was performed from the databases of PubMed, Embase and the Cochrane Library until June 20, 2017. A total of 18 studies with 6754 patients were included. Hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) and odds ratios and 95% CIs from each study were pooled. RESULTS: The results demonstrated that elevated pretreatment platelet count was significantly related to poor survival from ovarian cancer; the pooled HRs for overall, progression-free and disease-free survival were 1.81 (95% CI 1.52-2.15), 1.48 (95% CI 1.24-1.75) and 1.39 (95% CI 1.19-1.61), respectively. Subgroup analyses were divided by ethnicity, sample size, FIGO stage, cut-off value of the platelet count, analysis method and Newcastle Ottawa Scale score, but the results did not show any significant change in the main results. Increased platelet count was also significantly associated with the FIGO stage, tumor differentiation, ascites, residual tumor mass, CA125 level, recurrence and metastasis. CONCLUSION: This meta-analysis revealed that an elevated platelet count pretreatment denotes a predictive factor of poor prognosis and unfavorable clinicopathological parameters for ovarian cancer patients. PMID- 29231069 TI - Corrigendum. PMID- 29231070 TI - Building the Ontario Surgical Oncology Program. AB - From the 1940s onward the establishment of an increasing number of cancer centres in Ontario concentrated predominantly on radiation and systemic therapy. Increasing attention to the organization of cancer surgery services in Ontario over the last 3 decades through measures led by Cancer Care Ontario has resulted in building a progressive provincial and regional surgical oncology network. These networks are rooted in leadership mobilization and have used quality data and best evidence to promote the elaboration of communities of practice to achieve better outcomes. This article briefly chronicles this journey and points to areas of progress. PMID- 29231071 TI - The mental health of married immigrant women in South Korea and its risk and protective factors: A literature review. AB - BACKGROUND AND AIMS: Married immigrant women in South Korea undergo a wide array of psychosocial challenges in the process of adapting to a new culture and marriage with a Korean husband. For an integrative understanding of women's mental health status and to determine the key risk and protective factors, we systematically reviewed empirical articles about the mental health of married immigrant women. METHODS: We searched and reviewed articles from nine online databases: PubMed, Scopus, PsycINFO, Embase, DBpia, KISS, KMbase, KoreaMed and RISS, which were published up until January 2017. We identified 38 quantitative studies that examined psychiatric symptoms and pertinent factors for this population. RESULTS: The relative risks of psychiatric symptoms among married immigrant women varied across diverse samples. We summarized the associated factors existing prior to and after marriage migration that may moderate their mental health consequences. We identified five key risk factors: acculturative stress, country of origin, family stress, domestic violence and extended family structure, and two protective factors: social support and marriage satisfaction, which were consistently supported by the included studies. CONCLUSION: With the paucity of prospective studies, longitudinal research is needed that addresses the long-term processes of married immigrant women's psychological adaptation and the underlying risk and protective factors at diverse settlement phases. Furthermore, we suggest that future research should focus on how women's personal attributes interact with macro-level, socio-cultural contexts, including familial relationship and the community social-support system. Future evidence-based policy and interventions should comprehensively address married immigrant women's socio-cultural, economic and mental health needs. PMID- 29231072 TI - The Stakeholder Model of voice research: Acknowledging barriers to human rights of all stakeholders in a communicative exchange. AB - The act of communication is a complex, transient and often abstract phenomenon that involves many stakeholders, each of whom has their own perspective: the speaker, the listener, the observer and the researcher. Current research practices in voice disorder are frequently framed through a single lens - that of the researcher/clinician or their participant/patient. This single lens approach risks overlooking significant barriers to the basic human right of freedom of expression for those with a voice disorder as it omits consideration of the impact of voice disorder on the listener, and consideration of the wider impact of the voice in the occupational context. Recent research in the area of voice has developed a multiple lens and subsequent Stakeholder Model that acknowledges the experience and reality of multiple stakeholders viewing the same phenomenon, the voice. This research paradigm is built on Article 19 of the Universal Declaration of Human Rights as it considers the realities of all stakeholders in forming a deeper understanding of the causality, impact and aspects of communication disorder. The Stakeholder Model will be presented as a suggestion for future investigations of communication disorders more widely. PMID- 29231073 TI - Pelargonium sidoides preparation EPs 7630 in COPD: health-related quality-of-life and other patient-reported outcomes in adults receiving add-on therapy. AB - OBJECTIVE: Patient-reported outcomes (PRO) such as health-related quality-of-life (HRQoL) belong to the most important criteria for the evaluation of medical therapies in clinical trials or practice-based benefit assessments. This study, therefore, revisited results of an earlier published clinical trial investigating the effects of the herbal drug preparation from the roots of Pelargonium sidoides EPs 7630, administered as add-on therapy in patients suffering from chronic obstructive pulmonary disease (COPD), with respect to HRQoL and other PRO. METHODS: A total of 199 adults diagnosed with COPD stages II/III and receiving standard treatment according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) were randomly assigned to add-on therapy with EPs 7630 or placebo for 24 weeks. HRQoL (disease-specific St. George's Respiratory Questionnaire, SGRQ; current HRQoL state according to the EuroQuol visual analog scale, EQ VAS) and PRO (Integrative Medicine Outcomes Scale, IMOS; Integrative Medicine Patient Satisfaction Scale, IMPSS; symptom severity score of cough, sputum production and sternal pain while coughing; duration of inability to work) were assessed at each study visit or documented daily by the patient in a patient diary, respectively. RESULTS: At week 24, all HRQoL and PRO measures showed a more pronounced improvement under EPs 7630 than under placebo (EQ VAS, p < .001; SGRQ total score, p < .001; symptom severity score of cough, sputum production, and sternal pain while coughing, p = .021; duration of inability to work, p = .004; two-sided t-test each; IMOS, p < .001, IMPSS, p < .001, two-sided Mantel Haenszel test each). Moreover, the difference seen for the SGRQ exceeded the SGRQ minimal clinically important difference (MCID) threshold of 4 points. CONCLUSIONS: Add-on therapy with EPs 7630 led to an improvement in HRQoL and other PRO in adult patients with COPD compared to placebo while showing a good long-term tolerability. PMID- 29231074 TI - Hybrid response surface methodology-artificial neural network optimization of drying process of banana slices in a forced convective dryer. AB - The aim of the study is to fit models for predicting surfaces using the response surface methodology and the artificial neural network to optimize for obtaining the maximum acceptability using desirability functions methodology in a hot air drying process of banana slices. The drying air temperature, air velocity, and drying time were chosen as independent factors and moisture content, drying rate, energy efficiency, and exergy efficiency were dependent variables or responses in the mentioned drying process. A rotatable central composite design as an adequate method was used to develop models for the responses in the response surface methodology. Moreover, isoresponse contour plots were useful to predict the results by performing only a limited set of experiments. The optimum operating conditions obtained from the artificial neural network models were moisture content 0.14 g/g, drying rate 1.03 g water/g h, energy efficiency 0.61, and exergy efficiency 0.91, when the air temperature, air velocity, and drying time values were equal to -0.42 (74.2 C), 1.00 (1.50 m/s), and -0.17 (2.50 h) in the coded units, respectively. PMID- 29231075 TI - Sea-trial verification of ultrasonic antifouling control. AB - An ultrasonic antifouling treatment was applied to a 96,000 m3 class drill-ship to verify its feasibility through a sea-trial. Soon after the hull cleaning had been performed, six ultrasonic projectors were evenly deployed around the starboard shell plate. Driven by a 23 kHz sinusoidal ultrasound in an intermittent manner, the projectors emitted a high-intensity sound reaching 214 dB at the source level causing cavitation around the adjacent water and eventually deterring the settlement of marine fouling organisms. Underwater photographs acquired after four months showed fairly clean slabs on the starboard side, but heavy fouling on the port side. This experiment revealed that ultrasound treatment is a promising method for inhibiting fouling accumulation, even for large-scale ship applications. PMID- 29231076 TI - Selective autophagy restricts IL-9 secretion from TH9 cells: relevance in cancer growth. PMID- 29231079 TI - ? PMID- 29231078 TI - Do I Really Feel Your Pain? Comparing the Effects of Observed and Personal Ostracism. AB - It has been argued that "we feel the pain of others' ostracism as our own". However, it is unknown whether observed ostracism is as distressing as self experienced ostracism. We conducted two studies to address this lacuna. In Study 1, participants played or observed an online ball-tossing game, in which they or a stranger were ostracized or included by others. In Study 2, participants imagined themselves or someone else being ostracized or included. Across both studies, self-experienced and observed ostracism had the same negative effect on mood. Also, both self-experienced and observed ostracism evoked need threat, but this effect was slightly lower after observed ostracism. In sum, the findings suggest that we do feel the pain of others' ostracism as our own, consistent with the notion that humans are equipped with a system that detects violations of social inclusion norms in the environment. PMID- 29231077 TI - Preventing syndemic Zika virus, HIV/STIs and unintended pregnancy: dual method use and consistent condom use among Brazilian women in marital and civil unions. AB - Syndemic Zika virus, HIV and unintended pregnancy call for an urgent understanding of dual method (condoms with another modern non-barrier contraceptive) and consistent condom use. Multinomial and logistic regression analysis using data from the Pesquisa Nacional de Demografia e Saude da Crianca e da Mulher (PNDS), a nationally representative household survey of reproductive aged women in Brazil, identified the socio-demographic, fertility and relationship context correlates of exclusive non-barrier contraception, dual method use and condom use consistency. Among women in marital and civil unions, half reported dual protection (30% condoms, 20% dual methods). In adjusted models, condom use was associated with older age and living in the northern region of Brazil or in urban areas, whereas dual method use (versus condom use) was associated with younger age, living in the southern region of Brazil, living in non-urban areas and relationship age homogamy. Among condom users, consistent condom use was associated with reporting Afro-religion or other religion, not wanting (more) children and using condoms only (versus dual methods). Findings highlight that integrated STI prevention and family planning services should target young married/in union women, couples not wanting (more) children and heterogamous relationships to increase dual method use and consistent condom use. PMID- 29231081 TI - ? PMID- 29231080 TI - ? PMID- 29231082 TI - ? PMID- 29231083 TI - ? PMID- 29231084 TI - ? PMID- 29231086 TI - ? PMID- 29231085 TI - ? PMID- 29231087 TI - ? PMID- 29231088 TI - ? PMID- 29231089 TI - Erratum. AB - Lambert PR, Silverstein H, LeBel C, Bishop K. OTO-104 in Meniere's disease patients: phase 3 results. Otolaryngol Head Neck Surg. 2017;157:P122-P123. (Original doi: 10.1177/0194599817717251f) This Oral Presentation abstract should have included a note indicating that it was withdrawn during production of the issue. The online version has been updated to include this note. PMID- 29231090 TI - Esophageal Dysmotility in Patients following Total Laryngectomy. AB - Objectives Dysphagia is common in total laryngectomees, with some symptoms suggesting esophageal dysmotility. Tracheoesophageal (TE) phonation requires effective esophagopharyngeal air passage. Hence, esophageal dysmotility may affect deglutition or TE phonation. This study aimed to determine (1) the characteristics of esophageal dysmotility in laryngectomees, (2) whether clinical history is sensitive in detecting esophageal dysmotility, and (3) the relationship between esophageal dysmotility and TE prosthesis dysfunction. Study Design Multidisciplinary cross-sectional study. Setting Tertiary academic hospital. Subjects and Methods For 31 participants undergone total laryngectomy 1 to 12 years prior, clinical histories were taken by a gastroenterologist and a speech pathologist experienced in managing dysphagia. Esophageal high-resolution manometry was performed and analyzed using Chicago Classification v3.0. Results Interpretable manometric studies were obtained in 23 (1 normal manometry). Esophageal dysmotility patterns included achalasia, esophagogastric junction outflow obstruction, diffuse esophageal spasm, and other major (30%) and minor (50%) peristaltic disorders. The sensitivity of predicting any esophageal dysmotility was 28%, but it is noteworthy that patients with achalasia and diffuse esophageal spasm (DES) were predicted. Two of 4 participants with TE puncture leakage had poor esophageal clearance. Of 20 TE speakers, 12 had voice problems, no correlation between poor voice, and any dysmotility pattern. Conclusions Peristaltic and lower esophageal sphincter dysfunction are common in laryngectomees. Clinical history, while not predictive of minor motor abnormalities, predicted correctly cases with treatable spastic motor disorders. Dysmotility was not associated with poor phonation, although TE puncture leakage might be linked to poor esophageal clearance. Esophageal dysmotility should be considered in the laryngectomees with persisting dysphagia or leaking TE puncture. PMID- 29231091 TI - An electronic handoff tool to facilitate transfer of care from anesthesia to nursing in intensive care units. AB - Checklists are commonly used to structure the communication process between anesthesia nursing healthcare providers during the transfer of care, or handoff, of a patient after surgery. However, intraoperative information is often recalled from memory leading to omission of critical data or incomplete information exchange during the patient handoff. We describe the implementation of an electronic anesthesia information transfer tool (T2) for use in the handover of intubated patients to the intensive care unit. A pilot observational study auditing handovers against a pre-existing checklist was performed to evaluate information reporting and attendee participation. There was a modest improvement in information reporting on part of the anesthesia provider, as well as team discussions regarding the current hemodynamic status of the patient. While T2 was well-received, further evaluation of the tool in different handover settings can clarify its potential for decreasing adverse communication-related events. PMID- 29231092 TI - Test-retest reliability of the irrational performance beliefs inventory. AB - The irrational performance beliefs inventory (iPBI) was developed to measure irrational beliefs within performance domains such as sport, academia, business, and the military. Past research indicates that the iPBI has good construct, concurrent, and predictive validity, but the test-retest reliability of the iPBI has not yet been examined. Therefore, in the present study the iPBI was administered to university sport and exercise students (n = 160) and academy soccer athletes (n = 75) at three-time points. Time point two occurred 7 days after time point one, and time point three occurred 21 days after time point two. In addition, social desirability was also measured. Repeated-measures MANCOVAs, intra-class coefficients, and Pearson's (r) correlations demonstrate that the iPBI has good test-retest reliability, with iPBI scores remaining stable across the three-time points. Pearson's correlation coefficients revealed no relationships between the iPBI and social desirability, indicating that the iPBI is not highly susceptible to response bias. The results are discussed with reference to the continued usage and development of the iPBI, and future research recommendations relating to the investigation of irrational performance beliefs are proposed. PMID- 29231093 TI - The Utility of Simulation in the Management of Patients With Congenital Heart Disease: Past, Present, and Future. AB - Significant advancements have been made in the diagnosis and management of congenital heart disease (CHD). As a result, a higher percentage of these patients are surviving to adulthood. Despite this improvement in management, these patients remain at higher risk of morbidity and mortality, particularly in the perioperative setting. One new area of interest in these patients is the implementation of simulation-based medical education. Simulation has demonstrated various benefits across high-acuity scenarios encountered in the hospital. In CHD, simulation has been used in the training of pediatrics residents, assessment of intraoperative complications, echocardiography, and anatomic modeling with 3 dimensional printing. Here, we describe the current state of simulation in CHD, its role in training care providers for the management of this population, and future directions of CHD simulation. PMID- 29231096 TI - Vaginal discharge. AB - Preview A variety of genital pathogens, many of which are sexually transmitted, cause infections of the vagina and cervix. Discharge is often a prominent and telling symptom. Which infectious agents should be suspected when the discharge is accompanied by itching? Vulvar pain? Odor? Which laboratory tests are most helpful in making a diagnosis? The authors answer these and other questions in this overview of genital infections in women. PMID- 29231098 TI - Are invasive procedures .... PMID- 29231097 TI - Genital ulcer disease. AB - Preview What are the main causes of genital ulcer disease in the United States? Why is clinical diagnosis so difficult? What role will molecular diagnostics have in the future? The authors answer these questions and provide a functional approach to successful management of three common types of sexually transmitted genital ulcers. PMID- 29231099 TI - Human papillomavirus infection. AB - Preview Human papillomavirus (HPV) is one of the most common sexually transmitted infections in the United States, and evidence that HPV plays a central role in the development of cervical cancer and its precursors is growing. Recent innovations in detection techniques have permitted progress in HPV epidemiology, which in turn has fueled new clinical controversies. This article outlines some recent advances in technology and the questions that remain concerning management of cervical HPV infection. PMID- 29231095 TI - Thoracic surgeon and patient focus groups on decision-making in early-stage lung cancer surgery. AB - AIM: To investigate medical decision-making from the thoracic surgeons' and patients' perspectives in early-stage lung cancer. PATIENTS & METHODS: We conducted one focus group with thoracic surgeons (n = 15) and one with a group of early-stage lung cancer patients treated with surgery (n = 7). Focus groups were recorded, transcribed and coded for themes. RESULTS: For surgeons, surgical procedure choice was a primary concern, followed by the surgical treatment plan decision-making process. Survivors focused primarily on the physical and mental health-related postsurgical burden for which they felt they were not well prepared and placed less emphasis on surgical decision-making. CONCLUSION: As early-stage lung cancer mortality rates are improving, surgeons and patients can prioritize surgical approaches and postsurgical care that enhance quality of life. PMID- 29231094 TI - Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. AB - BACKGROUND: Low-molecular-weight heparin is the standard treatment for cancer associated venous thromboembolism. The role of treatment with direct oral anticoagulant agents is unclear. METHODS: In this open-label, noninferiority trial, we randomly assigned patients with cancer who had acute symptomatic or incidental venous thromboembolism to receive either low-molecular-weight heparin for at least 5 days followed by oral edoxaban at a dose of 60 mg once daily (edoxaban group) or subcutaneous dalteparin at a dose of 200 IU per kilogram of body weight once daily for 1 month followed by dalteparin at a dose of 150 IU per kilogram once daily (dalteparin group). Treatment was given for at least 6 months and up to 12 months. The primary outcome was a composite of recurrent venous thromboembolism or major bleeding during the 12 months after randomization, regardless of treatment duration. RESULTS: Of the 1050 patients who underwent randomization, 1046 were included in the modified intention-to-treat analysis. A primary-outcome event occurred in 67 of the 522 patients (12.8%) in the edoxaban group as compared with 71 of the 524 patients (13.5%) in the dalteparin group (hazard ratio, 0.97; 95% confidence interval [CI], 0.70 to 1.36; P=0.006 for noninferiority; P=0.87 for superiority). Recurrent venous thromboembolism occurred in 41 patients (7.9%) in the edoxaban group and in 59 patients (11.3%) in the dalteparin group (difference in risk, -3.4 percentage points; 95% CI, -7.0 to 0.2). Major bleeding occurred in 36 patients (6.9%) in the edoxaban group and in 21 patients (4.0%) in the dalteparin group (difference in risk, 2.9 percentage points; 95% CI, 0.1 to 5.6). CONCLUSIONS: Oral edoxaban was noninferior to subcutaneous dalteparin with respect to the composite outcome of recurrent venous thromboembolism or major bleeding. The rate of recurrent venous thromboembolism was lower but the rate of major bleeding was higher with edoxaban than with dalteparin. (Funded by Daiichi Sankyo; Hokusai VTE Cancer ClinicalTrials.gov number, NCT02073682 .). PMID- 29231101 TI - overused in Angina patients? PMID- 29231100 TI - Achilles tendon rupture. AB - Preview A patient limps into your office with ankle pain and a story about a popping sound he heard during a mad dash to the net on a tennis court. After evaluation, you diagnose complete rupture of the Achilles tendon. Do you apply a cast or refer him to an orthopedic surgeon? When are the higher risks and costs associated with surgical repair worth it? The authors take on these and other questions that have arisen in the ongoing debate over treatment of Achilles tendon rupture. PMID- 29231102 TI - When bleeding complicates oral anticoagulant therapy. AB - Preview The risk-benefit ratio of oral anticoagulant therapy is of special concern in the 1990s, because potential uses of these agents are expanding rapidly. A careful review of all aspects of therapy with patients new to anticoagulants may improve compliance and lessen the incidence of bleeding, the major complication. Dr Brigden provides case reports to illustrate risk factors for bleeding, approaches to determining the source, and management of elevated prothrombin time. PMID- 29231103 TI - Acute acalculous cholecystitis. AB - Preview Although it still occurs most often in seriously ill or injured patients, acute acalculous cholecystitis is being diagnosed with increasing frequency in outpatients who have an underlying chronic condition, such as cardiovascular disease or diabetes. As Dr Chung points out, primary care physicians must be aware of this disease, because it can be fatal if not detected and treated promptly, and the population at highest risk-the elderly-is growing. PMID- 29231104 TI - The burgeoning problem of latex sensitivity. AB - Preview Contact dermatitis from the nearly constant use of latex gloves during the workday has become a real problem for many healthcare professionals. Moreover, the patients who come in contact with these gloves or with other latex containing equipment may show reactions. Far worse than skin problems is life threatening anaphylaxis, which can be the first indication a person has latex sensitivity. Fortunately, risk factors have been established, and careful assessment can help minimize the chances of an untoward event. The authors furnish a questionnaire for use in identifying people at risk and describe appropriate steps to take. PMID- 29231105 TI - HIV and sexually transmitted diseases. AB - Preview HIV infection and sexually transmitted diseases (STDs) are common problems encountered in virtually every medical practice. Physicians and other healthcare providers are generally well aware of the management of STD syndromes, but they may be less prepared to prevent infection or reinfection. In this article, Dr Cohen reviews the mechanisms of HIV transmission and discusses preventive strategies already available to healthcare providers. PMID- 29231106 TI - All Gummed Up. PMID- 29231107 TI - Acute exacerbations of chronic bronchitis. AB - Preview Patients with chronic bronchitis already, by definition, have coughing with copious and ongoing mucus production. Acute exacerbations increase the severity of these problems and add to them. Still, most patients can be treated without hospitalization if inflammation and infection are properly managed and adequate tracheobronchial clearance is achieved. Dr Aboussouan summarizes treatment methods to accomplish these goals and also discusses measures to prevent exacerbations. PMID- 29231108 TI - Medical examination of the internationally adopted child. AB - Preview Because of the number of internationally adopted children with undiagnosed disease, a defined set of screening tests for medical evaluation is now recommended. By and large, these tests are directed toward infectious diseases that are more common abroad than in the United States. In this article, the authors examine various aspects of screening and highlight tests that are useful in children from specified areas. They also review developmental issues that are of prime importance to these children and their new families. PMID- 29231109 TI - A modem is your connection to the outside world. PMID- 29231110 TI - Attorneys as Patients. PMID- 29231112 TI - Risk stratification after acute myocardial infarction. AB - Preview The purpose of risk stratification in survivors of acute myocardial infarction is to identify those most likely to have subsequent cardiac events and, if possible, to improve their prognosis with medical therapy, revascularization, or both. Dr Figueredo reviews methods of assessing risk and discusses the merits and limitations of each. PMID- 29231111 TI - Gas gangrene. AB - Preview Clostridial myonecrosis (gas gangrene) is an uncommon sequela of traumatic injury. Because the infection can become rapidly fatal, early recognition and expeditious treatment are critical. In addition to wide surgical debridement and treatment with broad-spectrum antibiotics, hyperbaric oxygen therapy has been shown to have synergistic benefit. Dr Stephens presents an illustrative case and discusses current data regarding effective management. PMID- 29231113 TI - Urinary tract infection. AB - Preview Management approaches to urinary tract infection have changed in recent years as new information has emerged. What are the current recommendations for appropriate diagnostic testing and treatment? Dr Williams discusses the various types of complicated and uncomplicated infection and describes management strategies that reflect the recent developments. PMID- 29231114 TI - Infectious arthritis. AB - Preview Without prompt diagnosis and treatment, infection of the joint space can result in irreversible damage. Antibiotic therapy must be started immediately, before the infectious organism has been identified. In this comprehensive article, Dr Stimmler discusses the clues inherent in the clinical setting that point to specific causes of infectious arthritis and appropriate therapeutic options. PMID- 29231115 TI - Proctalgia fugax. AB - Preview Severe, episodic pain in the rectum may prompt extensive- and expensive- diagnostic testing. If the cause is proctalgia fugax, such testing is unnecessary and wasteful. The author, a gastroenterologist, offers a guide to prompt recognition of the disorder based on patient history and suggests several therapeutic stategies that may help to relieve the pain. PMID- 29231116 TI - Common eye disorders. AB - Preview How is dacryocystitis in infants treated? What are the common causes of conjunctivitis? Why is patients' use of anesthetic eye-drops dangerous? In this article, the authors describe some of the more common eye conditions that can be treated in the primary care office and point out several important ways to avoid potentially serious, even vision-threatening, consequences. PMID- 29231117 TI - The costs of treating hypertension. AB - Preview Hypertension is a common target of cost-containment measures because so many people receive so much medication for it. However, to paraphrase Oscar Wilde's sentiments on being talked about: There is only one thing worse than the cost of treating hypertension, and that may be the cost of not treating hypertension. Dr Elliott describes some reasonable methods of cutting down on drug costs that do not result in insufficient or more costly medical care in the long term. PMID- 29231118 TI - Common eye disorders. AB - Preview Many eye disorders can be diagnosed and treated in the primary care office. While some ocular conditions require in-depth evaluation, others are emergencies and require quick diagnosis and referral. This article offers help in recognizing glaucoma, retinal artery occlusion, and other conditions in which ophthalmologic referral is essential. The authors also provide information on thorough routine eye assessment, including history taking, physical examination, and funduscopic examination. PMID- 29231119 TI - Common eye disorders. PMID- 29231120 TI - Gastroesophageal reflux. AB - Preview Although heartburn is the most common symptom of gastroesophageal reflux, many patients with reflux have other, more obscure manifestations. Recognition of all potential signs and symptoms of reflux is important for expeditious management. This article focuses on these atypical presentations and discusses how treatment can be tailored to the specific pathophysiologic mechanism involved. PMID- 29231121 TI - Vaginal prolapsed. AB - Preview As many as 20% of postmenopausal women may have symptomatic genital prolapse, but often they do not report it because of embarrassment or a belief that it is a natural consequence of aging. Dr Davila discusses predisposing factors in prolapse, associated urinary dysfunction, and conservative treatment approaches. Special attention is paid to the renewed interest in an ancient device- vaginal pessaries. PMID- 29231122 TI - Oral cancer. AB - Preview Even though the oral cavity is one of the most accessible areas for examination, oral cancer is often diagnosed at an advanced stage. Why is this so, and how can this tendency be reversed? In this article, Dr Alvi stresses the importance of education of both physicians and patients in achieving the goal of earlier diagnosis. He also discusses warning signs of cancerous oral lesions, diagnosis, and treatment choices. PMID- 29231124 TI - Unraveling Neuroblastoma Pathogenesis with the Zebrafish. PMID- 29231126 TI - What potential does plasmonics-amplified synergistic immuno photothermal nanotherapy have for treatment of cancer? PMID- 29231125 TI - Attentional Focus and Grip Width Influences on Bench Press Resistance Training. AB - This study evaluated the influence of different attentional foci for varied grip widths in the bench press. Eighteen resistance-trained men were familiarized with the procedure and performed a one-repetition maximum (1RM) test during Session 1. In Session 2, they used three different standardized grip widths (100%, 150%, and 200% of biacromial width distance) in random order at 50% of 1RM while also engaged in three different attention focus conditions (external focus on the bench press, internal focus on pectoralis major muscles, and internal focus on triceps brachii muscles). Surface electromyography (EMG) signals were recorded from the triceps brachii and pectoralis major, and peak EMG of the filtered signals were normalized to maximum EMG of each muscle. Both grip width and focus influenced the muscle activity level, but there were no significant interactions between these variables. Exploratory analyses suggested that an internal focus may slightly (4%-6%) increase pectoralis major activity at wider grip widths and triceps brachii activity at narrower grip widths, but this should be confirmed or rejected in a study with a larger sample size or through a meta-analysis of research to date. PMID- 29231127 TI - View From the Penthouse: Epistemological Bumps and Emergent Metaphors as Method for Team Reflexivity. AB - Research in health care occurs within interdisciplinary teams that include clinician-researchers who have multiple epistemological orientations. Rigor in collaborative projects requires reflexive attention to how the paradigmatic questions raised by diverse epistemological orientations, and the ethical stances of each researcher, shape findings. This methodological article draws on three events during an ethnography of stigma in psychiatry to define and illustrate how we used double hermeneutics in data analysis. This allowed us to examine the metaphors that emerged from what we are conceptualizing as "epistemological bumps." This heightened the team's awareness of the epistemological horizons and mixing that occurred, as well as revealing what mattered to each researcher, during the crafting of our research decisions and findings. We argue that interdisciplinary research on complex processes in health care requires this close examination of team experiences and moral stakes during collaborative analysis, and offer conceptual suggestions for reflexivity and rigor. PMID- 29231123 TI - Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy. AB - Despite recent progress in the development of novel approaches to treat cancer, traditional antineoplastic drugs, such as cisplatin, remain a mainstay of regimens targeting solid tumors. Use of cisplatin is limited by acute kidney injury, which occurs in approximately 30% of patients. Current clinical measures, such as serum creatinine and estimated glomerular filtration rate, are inadequate in their ability to detect acute kidney injury, particularly when there is only a moderate degree of injury. Thus, there is an urgent need for improved diagnostic biomarkers to predict nephrotoxicity. There is also interest by the U.S. Food and Drug Administration to validate and implement new biomarkers to identify clinical and subclinical acute kidney injury in patients during the drug approval process. This minireview provides an overview of the current literature regarding the utility of urinary proteins (albumin, beta-2-microglobulin, N-acetyl-D glucosaminidase, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and cystatin C) as biomarkers for cisplatin-induced AKI. Many of the well-studied urinary proteins (KIM-1, NGAL, B2M, albumin) as well as emerging biomarkers (calbindin, monocyte chemotactic protein-1, and trefoil factor 3) display distinct patterns of time-dependent excretion after cisplatin administration. Implementation of these biomarker proteins in the oncology clinic has been hampered by a lack of validation studies. To address these issues, large head-to-head studies are needed to fully characterize time-dependent responses and establish accurate cutoff values and ranges, particularly in cancer patients. Impact statement There is growing interest in using urinary protein biomarkers to detect acute kidney injury in oncology patients prescribed the nephrotoxic anticancer drug cisplatin. We aim to synthesize and organize the existing literature on biomarkers examined clinically in patients receiving cisplatin containing chemotherapy regimens. This minireview highlights several proteins (kidney injury molecule-1, beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, calbindin, monocyte chemotactic protein-1, trefoil factor 3) with the greatest promise for detecting cisplatin-induced acute kidney injury in humans. A comprehensive review of the existing literature may aid in the design of larger studies needed to implement the clinical use of these urinary proteins as biomarkers of kidney injury. PMID- 29231128 TI - Exploring the Experiences of Persons Who Frequently Visit the Emergency Department for Mental Health-Related Reasons. AB - In this qualitative study, the experiences of persons who frequently visit the emergency department (ED) for mental health-related reasons were explored. Interpretive Description guided the design, and data were collected through interviews with 10 adults who made 12+ ED visits within a 1-year time frame (2015). Thematic analysis was used to analyze data inductively. The participants' experiences were described with the help of three themes emerging from the data: The Experience, The Providers, and Protective Factors. The participants felt compelled to come to hospital. For them, every visit was necessary, and dismissal of their needs by staff was interpreted as disrespect and prejudice. We noted differences in ED utilization patterns according to psychiatric diagnosis, and more research is needed to explore the phenomenon of frequent use by particular patient populations. Furthermore, health care providers implementing interventions designed to improve emergency care should consider tailored approaches rather than a one-size-fits-all strategy. PMID- 29231129 TI - "I Think It's Pretty Much the Same, as It Should Be": Perspectives of Inpatient Care Among Women Veterans. AB - The purpose of this study was to gain a deeper understanding of the inpatient hospitalization experience for women veterans through in-depth interviews. Women veterans who were admitted for inpatient care on medical units within a university-affiliated VA hospital were invited to participate in a semistructured interview that inquired about their hospital experience, interactions with medical providers, and how being a woman veteran might affect this experience. Interviews were transcribed verbatim and analyzed using constant comparative method until thematic saturation was achieved ( n = 25). Three themes, (a) Being a woman and a veteran: Intersecting identities, (b) Expecting equality and equity, and (c) Defining woman-centered inpatient care described the unique perspective and context for Veterans Health Administration (VHA) health care of women veterans. These findings provide insight and guidance to clinical practice and care delivery for women veterans, including training and interpersonal approaches medical providers can take to improve the hospital experience for women. PMID- 29231131 TI - Impact of Accountable Care Organizations on Utilization, Care, and Outcomes: A Systematic Review. AB - Since 2010, more than 900 accountable care organizations (ACOs) have formed payment contracts with public and private insurers in the United States; however, there has not been a systematic evaluation of the evidence studying impacts of ACOs on care and outcomes across payer types. This review evaluates the quality of evidence regarding the association of public and private ACOs with health service use, processes, and outcomes of care. The 42 articles identified studied ACO contracts with Medicare ( N = 24 articles), Medicaid ( N = 5), commercial ( N = 11), and all payers ( N = 2). The most consistent associations between ACO implementation and outcomes across payer types were reduced inpatient use, reduced emergency department visits, and improved measures of preventive care and chronic disease management. The seven studies evaluating patient experience or clinical outcomes of care showed no evidence that ACOs worsen outcomes of care; however, the impact on patient care and outcomes should continue to be monitored. PMID- 29231130 TI - Development and Testing of the Provider and Staff Perceptions of Integrated Care (PSPIC) Survey. AB - This article discusses development and testing of the Provider and Staff Perceptions of Integrated Care Survey, a 21-item questionnaire, informed by Singer and colleagues' seven-construct framework. Questionnaires were sent to 2,936 providers and staff at 100 federally qualified health centers and other safety net clinics in 10 Midwestern U.S. states; 332 were ineligible, leaving 2,604 potential participants. Following 4 mailings, 781 (30%) responded from 97 health centers. Item analyses, exploratory factor analysis, and confirmatory factor analysis were undertaken. Exploratory factor analysis suggests four latent factors: Teams and Care Continuity, Patient Centeredness, Coordination with External Providers, and Coordination with Community Resources. Confirmatory factor analysis confirmed these factor groupings. For the total sample, Cronbach's alpha exceeded 0.7 for each latent factor. Descriptive responses to each of the 21 Provider and Staff Perceptions of Integrated Care questions appear to have potential in identifying areas that providers and staff recognize as care integration strengths, and areas that may warrant improvement. PMID- 29231132 TI - Functional regulation of proteins by 20S proteasome proteolytic processing. PMID- 29231134 TI - Plant-Made Antibodies: Properties and Therapeutic Applications. AB - A cost-effective plant platform for therapeutic monoclonal antibody production is both flexible and scalable. In addition, plant-made antibodies (PMAbs) could be advantageous compared to those produced in animal cells due to the absence of a risk of contamination from nucleic acids or proteins of animal origin. In this review, the various platforms of PMAbs production are described, and the widely used transient expression system based on Agrobacterium-mediated delivery of genetic material into plant cells is discussed in detail. Plants produce less complex and diverse Asn-attached glycans compared to animal cells and contain plant-specific residues. In this review, we examine the features of and approaches to humanizing the Asn297-linked glycan of PMAbs. The prospects for PMAbs in the prevention and treatment of human infectious diseases have been illustrated by promising results with PMAbs against Human immunodeficiency virus, rotavirus infection, Human respiratory syncytial virus, rabies, anthrax and Ebola virus. The pre-clinical and clinical trials of PMAbs against different types of cancer, including lymphoma and breast cancer, are addressed. PMID- 29231135 TI - Preparation, Characterization, Toxicity and Pharmacodynamics of the Inclusion Complex of Brucea javanica Oil with beta-cyclodextrin Polymers. AB - BACKGROUND: The novel water-soluble inclusion complex of Brucea javanica oil (BJO) by beta-cyclodextrin polymers (CDP) was prepared by saturated aqueous method and characterized by SEM, FT-IR and 1H NMR. Compared with BJO, the aqueous solubility of BJO-CDP (77.76%) greatly enhanced due to the water-soluble CDP host. RESULTS: In the acute toxicity test, the value of LD50 of BJO-CDP was 11.94 g/kg, suggesting the lower toxicity of BJO-CDP. Moreover, the pharmacodynamics of BJO-CDP was investigated by evaluating its inhibition effects on human hepatoma SMMC-7721 cells and mice transplantable colon cancer CT- 26 cells. CONCLUSION: It has been revealed that BJO-CDP significantly decreased the toxicity of BJO and enhanced its anti-tumor activity. In conclusion, BJO-CDP could be a new and improved clinical formulation of BJO with higher water solubility, lower toxicity and enhanced anti-tumor activity. PMID- 29231136 TI - Stability of Drugs of Abuse in Urine Samples at Room Temperature by Use of a Salts Mixture. AB - BACKGROUND: It has long been recognized that ensuring analyte stability is of crucial importance in the use of any quantitative bioanalytical method. As analyses are usually not performed directly after collection of the biological samples, but after these have been processed and stored, it is essential that analyte stability can be maintained at storage conditions to ensure that the obtained concentration results adequately reflect those directly after sampling. The conservation of urine samples in refrigerated/ frozen conditions is strongly recommended; but not always feasible. The aim of this study was to assess the stability of some well-known drugs of abuse methamphetamine (MA), 11-nor-9 carboxy-Delta9- tetrahydrocannabinol (THC-COOH), benzoylecgonine (BE), and morphine (MOR) in urine samples kept at room temperature by adding a salt mixture (sodium citrate, sodium ascorbate, borax). METHODS: Two different urine samples were prepared with and without salt mixture, stored at room temperature and then analyzed by gas chromatography-mass spectrometry at 0, 1, 7, 15, and 30 days after collection/preparation to look for eventual analyte degradation. RESULTS: Methamphetamine showed no significant changes with respect to the time of collection/ preparation (T0) up to 7 days later (T7), with or without salt mixture addiction. Then a significant degradation occurred in both salted and non salted urine. BE decrease was observed starting from day 1 after sample collection in salted and not salted samples, respectively. Salt addition seemed to reduce at least the initial BE degradation, with a significant difference (p<0.001) at 7 and 15 days of storage. However, the degradation was not more prevented in salted samples at 30 days of storage. A 20% decrease of MOR concentration was observed starting from day 1 after collection/preparation, both in salted and not salted samples with no subsequent decrease. With regard to THCCOOH, a significant decrease was observed starting from 7 days after collection/preparation, with of without adding the salt mixture. However, when comparing salted versus non salted samples at each time point, a statistically significant difference was observed at 7 and 30 days of storage. CONCLUSION: The results obtained indicate that the degradation of MA, THC-COOH and BE in urine samples kept at room temperature can be slowed by the addition of the salt mixture, whereas it seems to be ineffective in samples containing MOR. This evidence has to be taken into account, in the eventuality of using salted urine to prevent in a certain extent abuse of above-reported drugs of abuse. PMID- 29231137 TI - Therapeutic Role of Harmalol Targeting Nucleic Acids: Biophysical Perspective and in vitro Cytotoxicity. AB - BACKGROUND: Harmalol, a beta carboline alkaloid, shows remarkable importance in the contemporary biomedical research and drug discovery programs. With time, there is emerging interest in search for better anti-cancer drugs of plant origin with high activity and lower toxicity. Most of the chemotherapeutic agents due to their non-specific target and toxicity on active healthy cells, use is often restricted, necessitating search for newer drugs having greater potentiality. OBJECTIVE: The review highlighted the interaction of harmalol with nucleic acids of different motifs as sole target biomolecules and in vitro cytotoxicity of the alkaloid in human cancer cell lines with special emphasis on its apoptotic induction ability. METHODS: Binding study and in vitro cytotoxicity was performed using several biophysical techniques and biochemical assays, respectively. RESULTS: Data from competition dialysis, UV and fluorescence spectroscopic analysis, circular dichroism, viscometry and isothermal calorimetry shows binding and interaction of harmalol with several natural and synthetic nucleic acids, both DNA and RNA, of different motifs. Furthermore, apoptotic hallmarks like internucleosomal DNA fragmentation, membrane blebbing, cell shrinkage, chromatin condensation, change of mitochondrial membrane potential, comet tail formation and ROS (reactive oxygen species) dependent cytotoxicity being analyzed in the harmalol treated cancer cells. CONCLUSION: These results stating the therapeutic role of harmalol, will lead to the interesting knowledge on the cytotoxicity, mode, mechanism, specificity of binding and correlation between structural aspects and energetics enabling a complete set of guidelines for design of new drugs. PMID- 29231138 TI - Cholinesterase Inhibitor 6-Chlorotacrine - In Vivo Toxicological Profile and Behavioural Effects. AB - BACKGROUND: 6-chlorotacrine is a cholinesterase inhibitor showing good inhibitory potential, even better than parent compound tacrine, in vitro. Despite tacrine scaffold is broadly used for design and synthesis of novel compounds with anti Alzheimer's potential, no in vivo effects have been investigated so far. Thus, basic toxicological and behavioural evaluation has been carried out throughout this study. METHODS: Maximum tolerated dose (MTD) and median lethal dose (LD50) were assessed in BALB/c mice and Wistar rats. Behavioural effects were observed in rats performing the multiple T-maze test, the water maze test and the step through passive avoidance test. All outcomes were compared with the effects of parent compound - tacrine. RESULTS: The toxicity of 6-chlorotacrine was increased compared to tacrine with MTD 6.0/5.0 mg.kg-1 (i.m., male/female mice), 6.0/5.0 mg.kg-1 (i.p., male/female rats) and LD50 9.0 mg.kg-1 (male rats). At MTD doses, no histopathological changes and blood biochemistry abnormalities were observed except decreased plasma creatinine levels. 6-chlorotacrine showed good effects in the reversal of quinuclidinyl benzilate-induced amnesia. Best results were achieved at the dose of 1.8 mg.kg-1 (20% LD50) in the water maze test; the pro cognitive effect was stronger than that of tacrine (5.2 mg.kg-1, 20% LD50). Other doses tested (0.9 mg.kg-1 and 2.7 mg.kg-1) showed similar effects as tacrine in the water maze, multiple T-maze and passive avoidance test. CONCLUSION: Observed effects predetermined 6-chlorotacrine as a potent parent compound for the synthesis of novel multifactorial drugs intended to the treatment of Alzheimer's disease. Even though 6- chlorotacrine showed in vivo beneficial effect with no signs of toxicity, further tests on the field of biochemistry and pharmacology are essential to disclose the exact mechanism of action, safety evaluation and the metabolic fate of the compound after the repeated administration. PMID- 29231139 TI - Catechol-O-methyltransferase, Cognition and Alzheimer's Disease. AB - OBJECTIVE: Cognition is a complex trait representing a set of all mental abilities and processes related to knowledge. Although diverse brain regions are involved, most cognitive processes appear to engage cortical regions. The activity of dopaminergic neurons in prefrontal cortex represents a biological substrate underlying cognitive functions. Alzheimer's Disease (AD) is the most frequent dementia associated with cognitive impairments. Cognitive impairment in AD starts slowly with discrete deterioration in memory, language, thinking and reasoning, but it progresses into more severe and debilitating cognitive dysfunction. Cognitive function is affected by the complex interactions between various genetic, epigenetic, developmental and environmental factors. One of the most studied genes, associated with cognitive disturbances, is the gene coding for Catechol-O-methyltransferase (COMT), the enzyme with major role in dopamine metabolism and modulation of different brain functions. Therefore, COMT is studied as a target for many neuropsychiatric disorders, including dementias and AD. The COMT Val158/108Met functional polymorphism affects significantly the enzyme activity and consequently cognitive performance associated with altered dopamine function. The association of COMT Val158/108Met polymorphism with some cognitive domains and psychosis in AD was reported in some but not in all studies. Besides COMT Val158/108Met polymorphism, other risk genotypes or haplotypes should be evaluated to determine the association of COMT with cognitive decline in AD. CONCLUSION: Better understanding of the role of COMT in cognitive processes in AD, as well as integration of neurobiological, genetic, genomic and epigenetic data, might help in developing new potential therapies of cognitive impairments and psychotic symptoms, characteristic features of AD. PMID- 29231141 TI - An Overview on the Importance of Combining Complementary Analytical Platforms in Metabolomic Research. AB - The analytical bias introduced by most of the commonly used techniques in metabolomics considerably hinders the simultaneous detection of all metabolites present in complex biological samples. In order to solve this limitation, the combination of complementary approaches is emerging in recent years as the most suitable strategy in order to maximize metabolite coverage. This review article presents a general overview of the most important analytical techniques usually employed in metabolomics: nuclear magnetic resonance, mass spectrometry and hybrid approaches. Furthermore, we emphasize the potential of integrating various tools in the form of metabolomic multi-platforms in order to get a deeper metabolome characterization, for which a revision of the existing literature in this field is provided. This review is not intended to be exhaustive but, rather, to give a practical and concise guide to readers not familiar with analytical chemistry on the considerations to account for the proper selection of the technique to be used in a metabolomic experiment in biomedical research. PMID- 29231142 TI - CRISPR-Cas in Medicinal Chemistry: Applications and Regulatory Concerns. AB - A rapid search in scientific publication's databases shows how the use of CRISPR Cas genome editions' technique has considerably expanded, and its growing importance, in modern molecular biology. Just in pub-med platform, the search of the term gives more than 3000 results. Specifically, in Drug Discovery, Medicinal Chemistry and Chemical Biology in general CRISPR method may have multiple applications. Some of these applications are: resistance-selection studies of antimalarial lead organic compounds; investigation of druggability; development of animal models for chemical compounds testing, etc. In this paper, we offer a review of the most relevant scientific literature illustrated with specific examples of application of CRISPR technique to medicinal chemistry and chemical biology. We also present a general overview of the main legal and ethical trends regarding this method of genome editing. PMID- 29231133 TI - Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. AB - BACKGROUND: The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival. RESULTS: At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab associated infusion-related reactions occurred in 27.7% of the patients. CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .). PMID- 29231140 TI - Up-regulation of DMN Connectivity in Mild Cognitive Impairment Via Network-based Cognitive Training. AB - BACKGROUND: Previous work designed a network-based protocol of cognitive training. This programme exploits a mechanism of induced task-oriented co activation of multiple regions that are part of the default mode network (DMN), to induce functional rewiring and increased functional connectivity within this network. OBJECTIVE: In this study, the programme was administered to patients with a diagnosis of mild cognitive impairment to test its effects in a clinical sample. METHOD: Twenty-three patients with mild cognitive impairment (mean age: 73.74 years, standard deviation 5.13, female/male ratio 13/10) allocated to the experimental condition, underwent one month of computerised training, while fourteen patients (mean age: 73.14 years, standard deviation 6.16, female/ male ratio 7/7) assigned to the control condition underwent a regime of intense social engagement. Patients were in the prodromal stage of Alzheimer's disease (AD) as confirmed by clinical follow ups for at least two years. The DMN was computed at baseline and retest, together with other, control patterns of connectivity, grey matter maps and neuropsychological profiles. RESULTS: A condition-by-timepoint interaction indicating increased connectivity triggered by the programme was found in left parietal DMN regions. No decreases as well as no changes in the other networks or morphology were found. Although between-condition cognitive changes did not reach statistical significance, they correlated positively with changes in DMN connectivity in the left parietal region, supporting the hypothesis that parietal changes were beneficial. CONCLUSION: This programme of cognitive training up-regulates a pattern of connectivity which is pathologically down-regulated in AD. We argue that, when cognitive interventions are conceptualised as tools to induce co-activation repeatedly, they can lead to clinically relevant improvements in brain functioning, and can be of aid in support of pharmacological and other interventions in the earliest stages of AD. PMID- 29231143 TI - Complex Network Study of the Immune Epitope Database for Parasitic Organisms. AB - BACKGROUND: Complex network approach allows the representation and analysis of complex systems of interacting agents in an ordered and effective manner, thus increasing the probability of discovering significant properties of them. In the present study, we defined and built for the first time a complex network based on data obtained from Immune Epitope Database for parasitic organisms. We then considered the general topology, the node degree distribution, and the local structure (triadic census) of this network. In addition, we calculated 9 node centrality measures for observed network and reported a comparative study of the real network with three theoretical models to detect similarities or deviations from these ideal networks. RESULT: The results obtained corroborate the utility of the complex network approach for handling information and data mining within the database under study. CONCLUSION: They confirm that this type of approach can be considered a valuable tool for preliminary screening of the best experimental conditions to determine whether the amino acid sequences being studied are true epitopes or not. PMID- 29231144 TI - QSAR of Natural Sesquiterpene Lactones as Inhibitors of Myb-dependent Gene Expression. AB - BACKGROUND: Protein c-Myb is a therapeutic target. Some sesquiterpene lactones suppress Myb-dependent gene expression, which results in their potential anti cancer activity. MATERIAL & METHODS: Database ChEMBL is a representative of lactones for physicochemical and physiochemical properties. Data presented for 31 natural lactones are discussed in terms of quantitative structureactivity relationships with the objective to predict inhibitors of Myb-induced gene expression. Several constitutional descriptors are related to structure-activity. alpha-Methylene-gamma-lactone groups enhance while OH functions worsen potency. The latter feature is in agreement with the fact that the more lipophilic the lactone, the greater the cytotoxicity because of the ability to cross lipoidal biomembranes. In general, numbers of π-systems and atoms, and polarizability enhance activity. Linear and nonlinear structure-activity models are developed, between lactones of a great structural diversity, to predict inhibitors of Myb induced gene expression. Four variables (ML, UNC, TCO+OCOR, UNC+UNA) related to ATOM show a positive correlation because of the partial anionic and H-acceptor characters of O-atom. In most, CO group is conjugated. RESULT AND CONCLUSION: Term OH shows negative coefficients because of the partial cationic quality of H atom and because OH forms H-bonds with CO, causing them to be less H-acceptor. s trans-s-trans-Germacranolide structure is the most active. Coefficients standard errors result acceptable in almost all equations. After cross-validation, linear equations for lactones, pseudoguaianolides and germacranolides are the most predictive. Most descriptors are constitutional variables. PMID- 29231146 TI - Comparison of Two Naloxone Regimens in Opioid-dependent Methadoneoverdosed Patients: A Clinical Trial Study. AB - BACKGROUND: Methadone toxicity is one of the major causes of death in opioiddependent individuals. OBJECTIVE: We aimed to compare two different protocols of naloxone administration in terms of reversal of overdose signs and symptoms and frequency of complications in opioid-dependent methadone-intoxicated patients. METHOD: One-hundred opioid-dependent patients with signs/symptoms of methadone overdose were included. The patients were consecutively assigned into Tintinalli (group 1) or Goldfrank regimen protocol (group 2) of naloxone administration. Group 1 received naloxone with the dose 0.1 mg given every two to three minutes while group 2 received naloxone with the initial dose of 0.04 mg increasing to 0.4, 2, and 10 mg every two to three minutes to reverse respiratory depression. They were then compared regarding reversal of toxicity and risk of development of complications. RESULTS: The time to reversal of the overdose signs/symptoms was significantly less in Goldfrank regimen protocol (P<0.001). Frequency of withdrawal syndrome and recurrence of respiratory depression were not significantly different between the two groups. Aspiration pneumonia and intubation were more frequent in group 2, as well. CONCLUSION: It seems that gradual titration of naloxone by Tintinalli protocol can reduce major complications compared to the Goldfrank regimen. However, this protocol was not perfect in opioid-dependent methadone-overdosed patients, either, since it could induce complications, as well. We may need new protocols in overdosed opioid dependent patients. PMID- 29231145 TI - Learning from Multiple Classifier Systems: Perspectives for Improving Decision Making of QSAR Models in Medicinal Chemistry. AB - Quantitative Structure - Activity Relationship (QSAR) modeling has been widely used in medicinal chemistry and computational toxicology for many years. Today, as the amount of chemicals is increasing dramatically, QSAR methods have become pivotal for the purpose of handling the data, identifying a decision, and gathering useful information from data processing. The advances in this field have paved a way for numerous alternative approaches that require deep mathematics in order to enhance the learning capability of QSAR models. One of these directions is the use of Multiple Classifier Systems (MCSs) that potentially provide a means to exploit the advantages of manifold learning through decomposition frameworks, while improving generalization and predictive performance. In this paper, we presented MCS as a next generation of QSAR modeling techniques and discuss the chance to mining the vast number of models already published in the literature. We systematically revisited the theoretical frameworks of MCS as well as current advances in MCS application for QSAR practice. Furthermore, we illustrated our idea by describing ensemble approaches on modeling histone deacetylase (HDACs) inhibitors. We expect that our analysis would contribute to a better understanding about MCS application and its future perspectives for improving the decision making of QSAR models. PMID- 29231147 TI - Neuroendocrine and Metabolic Disorders in Bulimia Nervosa. AB - BACKGROUND AND OBJECTIVE: Bulimia nervosa, is an eating disorder characterized by excessive influence of weight and body shape on the levels of self-esteem, with pervasive feelings of failure and inadequacy. The eating is characterized by the presence of episodes of uncontrolled eating (Binge), during which the person ingests mass wide variety of foods and the feeling of not being able to stop eating. This review focuses on the metabolic and hormonal alterations in the in bulimia nervosa. METHODS: A literature search was conducted using the electronic database Medline and PubMed and with additional hand searches through the reference list obtained from the articles found. Journal were searched up to 2015. Inclusion criteria were: 1) full text available in English; 2) published in a peerreviewed journal and using the following keywords: neurotransmitters (AgRP, BDNF, alphaMSH, NP Y, endocannabinoids, adiponectin, CCK, ghrelin, GLP-1, insulin, leptin, PP, PYY), hormones (FSH, LH, estrogen, progesterone, testosterone) and bulimia nervosa, eating disorders. RESULTS: All data reported in the present review indicated that changes in the central and peripheral neuroendocrine equilibria may favor the onset and influence the course and prognosis of a DA. However, it is still questionable whether the alterations of the peptides and hormones regulating the mechanisms of eating behavior are the cause or consequence of a compromised diet. CONCLUSION: The results of the present review indicate that the altered balance of the various peptides or hormones can be relevant not only for the genesis and / or maintenance of altered dietary behaviors, but also for the development of specific psychopathological aspects in eating disorders. PMID- 29231148 TI - PET Radiopharmaceuticals in Brazil and Belarus: Economic Comparison Using the Case of 18FDG. AB - BACKGROUND: The production of radiopharmaceuticals, especially the PET ones, is a complex combination of economic and social factors. Despite the social aspects, that are essential, the economic issue must be considered and play an important parameter for the implementation and maintenance of producer centers around the world, with especial regards for countries which face economic crisis and/or belongs to aegis of under development countries. OBJECTIVES: In order to evaluate this scenario with carried out this study, comparing a well-established producer center in Brazil and a new on in Belarus. RESULTS: The results showed that the producer center in Brazil face serious economic problems and all the production logistic must be re-done. On the other hand the new producer center in Belarus started following a new model of production and although it has not been profitable, the perspectives seem to be better than the Brazilian producer center. CONCLUSION: The Brazilian model for PET radiopharmaceutical productions should be revised in order to avoid waste and create a new perspective for the research area. PMID- 29231149 TI - Radiopharmaceuticals Labelled with Copper Radionuclides: Clinical Results in Human Beings. AB - BACKGROUND: Positron emission tomography (PET) is an instrumental diagnostic modality developed around the positron-emitting radioisotopes of biologically important elements such as carbon, oxygen and nitrogen (11C, 15O, 13N). Among longer-lived PET radionuclides, 18F is by far the most commonly used radiotracer, extensively used for tumour imaging with FDG ([18F]-fluorodeoxyglucose) and also frequently investigated in the development of novel radiopharmaceuticals. Many other positron- emitting radionuclides with higher atomic numbers and longer half lives have been investigated for both imaging and therapeutic purposes, including the halogens (124I, 120I, 76Br) and a number of metal radionuclides. The radio copper has attracted considerable attention, because they include isotopes which, due to their emission properties, offer themselves as agents of both diagnostic imaging (60Cu, 61Cu, 62Cu, 64Cu) and in vivo targeted radiation therapy (64Cu and 67Cu). OBJECTIVES: Although the use of this radionuclide has grown exponentially over the last decade, academic institutions have largely been responsible for its production and for the development of the vast majority of radiopharmaceutical based on these nuclides. A number of compounds labelled with Cuisotopes have been proposed, not only for imaging purposes but also for therapy. The aim of the present paper is to provide an overview on the clinical results obtained in human beings with copper radionuclides. CONCLUSION: Several preliminary studies and clinical trials evaluated the potential clinical role of copper radioisotopes for diagnostic and therapeutic purposes. 64Cu seems to be the most suitable radioisotope for future clinical applications due to its longer half-life (12.7 h) and its commercial availability. Future clinical applications of copper radioisotopes could be enhanced by the possibility of radioligand therapy with the beta-emitting 67Cu, creating a new "theranostics pair". PMID- 29231150 TI - Quality of reporting and risk of bias in therapeutic otolaryngology publications. AB - BACKGROUND: High-quality trials have the potential to influence clinical practice. METHODS: Ten otolaryngology journals with the highest 2011 impact factors were selected and publications from 2010 were extracted. From all medical journals, the 20 highest impact factor journals were selected, and publications related to otolaryngology for 2010 and 2011 were extracted. For all publications, the reporting quality and risk of bias were assessed. RESULTS: The impact factor was 1.8-2.8 for otolaryngology journals and 6.0-101.8 for medical journals. Of 1500 otolaryngology journal articles, 262 were therapeutic studies; 94 had a high reporting quality and 5 a low risk of bias. Of 10 967 medical journal articles, 76 were therapeutic studies; 57 had a high reporting quality and 8 a low risk of bias. CONCLUSION: Reporting quality was high for 45 per cent of otolaryngology related publications and 9 per cent met quality standards. General journals had higher impact factors than otolaryngology journals. Reporting quality was higher and risk of bias lower in general journals than in otolaryngology journals. Nevertheless, 76 per cent of articles in high impact factor journals carried a high risk of bias. Better reported and designed studies are the goal, with less risk of bias, especially in otolaryngology journals. PMID- 29231151 TI - In vitro effect of various cryoprotectants on the semen quality of endangered Oravka chicken. AB - We aimed to compare the effect of three different permeating cryoprotectants on the post-thaw spermatozoa quality. Pooled semen from Oravka cock line (n = 6) was diluted in Kobidil+ extender and frozen in cryoprotectant solutions containing 8% dimethylsulfoxide (DMSO), 8% ethylene glycol (EG) or 8% glycerol (GL) in liquid nitrogen vapours before being plunged into the liquid nitrogen. Spermatozoa motility parameters were assessed in vitro after freezing-thawing by a computer assisted semen analysis (CASA) system and viability status was examined using fluorescent probes. The lower percentage (P < 0.05) of motile and progressively moving spermatozoa immediately after thawing were obtained in all experimental groups (DMSO, EG, GL) compared with the control. Significant (P < 0.05) differences in total motility and progressive movement between GL and DMSO, EG groups were observed. However, the higher number (P < 0.05) of acrosome damaged spermatozoa was found in the DMSO and EG groups and no significant differences were observed in the GL group compared with the control. Differences (P < 0.05) between experimental groups and the control in the results of spermatozoa necrosis were observed. No significant differences in the percentage of apoptotic spermatozoa were found between control and experimental groups. However, significant differences (P < 0.05) in number of live and necrotic spermatozoa between GL and DMSO, EG groups were examined. The findings of the present study indicate that glycerol seems to be suitable for semen cryopreservation in the gene banks. In addition, fertility evaluation in vivo is needed in order to evaluate the possible contribution for the bank of animal genetic resources. PMID- 29231152 TI - Risk Factors for Human Brucellosis in Northern Tanzania. AB - Little is known about the epidemiology of human brucellosis in sub-Saharan Africa. This hampers prevention and control efforts at the individual and population levels. To evaluate risk factors for brucellosis in northern Tanzania, we conducted a study of patients presenting with fever to two hospitals in Moshi, Tanzania. Serum taken at enrollment and at 4-6 week follow-up was tested by Brucella microagglutination test. Among participants with a clinically compatible illness, confirmed brucellosis cases were defined as having a >= 4-fold rise in agglutination titer between paired sera or a blood culture positive for Brucella spp., and probable brucellosis cases were defined as having a single reciprocal titer >= 160. Controls had reciprocal titers < 20 in paired sera. We collected demographic and clinical information and administered a risk factor questionnaire. Of 562 participants in the analysis, 50 (8.9%) had confirmed or probable brucellosis. Multivariable analysis showed that risk factors for brucellosis included assisting goat or sheep births (Odds ratio [OR] 5.9, 95% confidence interval [CI] 1.4, 24.6) and having contact with cattle (OR 1.2, 95% CI 1.0, 1.4). Consuming boiled or pasteurized dairy products was protective against brucellosis (OR 0.12, 95% CI 0.02, 0.93). No participants received a clinical diagnosis of brucellosis from their healthcare providers. The under recognition of brucellosis by healthcare workers could be addressed with clinician education and better access to brucellosis diagnostic tests. Interventions focused on protecting livestock keepers, especially those who assist goat or sheep births, are needed. PMID- 29231153 TI - Antibiotic susceptibility pattern of Neisseria gonorrhoeae strains isolated from five cities in India during 2013-2016. AB - PURPOSE: Emergence of multidrug resistance in Neisseria gonorrhoeae, an STI of public health significance is the biggest challenge to gonorrhoea control. Monitoring for antimicrobial resistance is essential for the early detection of emergent drug resistance patterns. METHODOLOGY: One hundred and twenty four N. gonorrhoeae strains were isolated between September 2013-August 2016 [82-New Delhi, 3-Pune, 3-Mumbai, 20-Secunderabad and 16-Hyderabad] to determine antimicrobial susceptibility and to compare the CLSI disc diffusion method with Etest for these strains. The results of the two methods were compared by using kappa statistics. RESULTS: Ninety eight percent [CI: 96.2-100] of isolates were resistant to ciprofloxacin, 52 % [CI: 43.2-60.8] to penicillin, 56 % [CI: 47.2 64.7] to tetracycline and 5 % [CI: 1.2-8.8] to azithromycin. All the strains were susceptible to spectinomycin, ceftriaxone and cefixime except for two strains which showed decreased susceptibility to ceftriaxone and cefixime. Kappa scores for penicillin, azithromycin, ciprofloxacin, ceftriaxone and cefixime showed that the CLSI method had high agreement with Etest while tetracycline had substantial agreement. CONCLUSION: Our data suggest that the disc diffusion method which is both cost effective and more feasible, can effectively be used routinely for monitoring antibiotic susceptibility in N. gonorrhoeae, in limited resource countries like India. We demonstrate the emergence of decreased susceptibility to ceftriaxone and cefixime and threshold levels of resistance to azithromycin in India. This underscores the importance of maintaining continued surveillance for antibiotic resistance in N. gonorrhoeae and a potential requirement for strategic change in guidelines in the not so distant future. PMID- 29231154 TI - Enteropathogens and Gut Inflammation in Asymptomatic Infants and Children in Different Environments in Southern India. AB - Children in poor environmental conditions are exposed early and often to enteric pathogens, but within developing countries, heterogeneity in enteropathogen exposure in different settings and communities is rarely addressed. We tested fecal samples from healthy infants and children from two different environments in the same Indian town for gut enteropathogens and biomarkers of gut inflammation. A significantly higher proportion of infants and children from a poor semi-urban neighborhood (93%) had one or more enteropathogens than those from a medical college campus (71.7%). Infants and children from the poor neighborhood had an average of 3.3 (95% confidence interval [CI]: 2.9-3.7) enteropathogens compared with an average of 1.4 (95% CI: 1.0-1.7) enteropathogens in campus infants/children. Viral and bacterial infections, including enteroviruses, adenoviruses, Campylobacter spp., and diarrhegenic Escherichia coli were more common and fecal biomarkers of inflammation were higher in the poor neighborhood. The findings demonstrate significant difference in the asymptomatic carriage of gut enteropathogens and gut inflammatory biomarkers in infants and children from two different environments within the same town in south India. PMID- 29231155 TI - Pedobacter quisquiliarum sp. nov., isolated from activated sludge. AB - A Gram-stain-negative, aerobic, rod-shaped, bacterium, C62-2T, was isolated from activated sludge in Fujian Province, China. Phylogenetic analysis of the 16S rRNA gene sequences showed that it was closely related to Pedobacter duraquae WB 2.1 25T (97.92 %), Pedobacter bambusae THG-G118T (97.40 %), Pedobacter cryoconitis A37T (97.37 %) and Pedobacter caeni LMG 22862T (97.3 %). Cells grew aerobically at 20-37 degrees C (optimum, 30 degrees C), pH 5.0-8.0 (optimum, pH 7.0) and in the presence of 0-3.0 % (w/v) NaCl. Strain C62-2T contained MK-7 as the major menaquinone and the major polar lipid was phosphatidylethanolamine. The major cellular fatty acids were iso-C15 : 0, summed feature 3 (C16 : 1omega6c, C16 : 1omega7c) and iso-C17 : 0 3-OH. The DNA G+C content was 43.2 mol% (Tm) and DNA DNA reassociation values were 35.4 % between strain C62-2T and P. duraquae WB 2.1 25T. On the basis of phenotypic, chemotaxonomic and phylogenetic comparisons with the closely related species and DNA-DNA relatedness values, it was concluded that strain C62-2T represents a novel species within the genus Pedobacter, for which the name Pedobacterquisquiliarum sp. nov. is proposed. The type strain is C62-2T (=CGMCC 1.15343T=NBRC 111767T). PMID- 29231156 TI - Efficient bio-production of citramalate using an engineered Escherichia coli strain. AB - Citramalic acid is a central intermediate in a combined biocatalytic and chemocatalytic route to produce bio-based methylmethacrylate, the monomer used to manufacture Perspex and other high performance materials. We developed an engineered E. coli strain and a fed-batch bioprocess to produce citramalate at concentrations in excess of 80 g l-1 in only 65 h. This exceptional efficiency was achieved by designing the production strain and the fermentation system to operate synergistically. Thus, a single gene encoding a mesophilic variant of citramalate synthase from Methanococcus jannaschii, CimA3.7, was expressed in E. coli to convert acetyl-CoA and pyruvate to citramalate, and the ldhA and pflB genes were deleted. By using a bioprocess with a continuous, growth-limiting feed of glucose, these simple interventions diverted substrate flux directly from central metabolism towards formation of citramalate, without problematic accumulation of acetate. Furthermore, the nutritional requirements of the production strain could be satisfied through the use of a mineral salts medium supplemented only with glucose (172 g l-1 in total) and 1.4 g l-1 yeast extract. Using this system, citramalate accumulated to 82+/-1.5 g l-1, with a productivity of 1.85 g l-1 h-1 and a conversion efficiency of 0.48 gcitramalate g-1glucose. The new bioprocess forms a practical first step for integrated bio- and chemocatalytic production of methylmethacrylate. PMID- 29231158 TI - Halomonas nigrificans sp. nov., isolated from cheese. AB - A Gram-stain-negative, rod-shaped Proteobacteria isolate, MBT G8648T, was obtained from an acid curd cheese called Quargel. The isolate was moderately salt tolerant and motile, with numerous peritrichous flagella. The 16S rRNA gene sequence analysis indicated that the strain belongs to the genus Halomonas, with 98.42 % 16S rRNA gene sequence similarity with Halomonas titanicae BH1T as nearest related neighbour. Further comparative sequence analysis of secA and gyrB genes, as well as physiological and biochemical tests, revealed that this bacterium formed a taxon well-separated from its nearest neighbours and other established Halomonas species. Thus, the strain represents a new species, for which the name Halomonas nigrificans sp. nov. is proposed, with strain MBT G8648T (=LMG 29097T =DSM 105749T) as type strain. PMID- 29231159 TI - Facet-joint injections for non-specific low back pain: a feasibility RCT. AB - BACKGROUND: Pain of lumbar facet-joint origin is a common cause of low back pain in adults and may lead to chronic pain and disability, with associated health and socioeconomic implications. The socioeconomic burden includes an inability to return to work resulting in loss of productivity in addition to direct and indirect health-care utilisation costs. Lumbar facet-joints are paired synovial joints between the superior and inferior articular processes of consecutive lumbar vertebrae and between the fifth lumbar vertebra and the sacrum. Facet joint pain is defined as pain that arises from any structure that is part of the facet-joints, including the fibrous capsule, synovial membrane, hyaline cartilage and bone. This pain may be treated by intra-articular injections with local anaesthetic and steroid, although this treatment is not standardised. At present, there is no definitive research to support the use of targeted lumbar facet-joint injections to manage this pain. Because of the lack of high-quality, robust clinical evidence, the National Institute for Health and Care Excellence (NICE) guidelines on the management of chronic low back pain [NICE. Low Back Pain in Adults: Early Management. Clinical guideline (CG88). London: NICE; 2009] did not recommend the use of spinal injections despite their perceived potential to reduce pain intensity and improve rehabilitation, with NICE calling for further research to be undertaken. The updated guidelines [NICE. Low Back Pain and Sciatica in Over 16s: Assessment and Management. NICE guideline (NG59). London: NICE; 2016] again do not recommend the use of spinal injections. OBJECTIVES: To assess the feasibility of carrying out a definitive study to evaluate the clinical effectiveness and cost-effectiveness of lumbar facet-joint injections compared with a sham procedure in patients with non-specific low back pain of > 3 months' duration. DESIGN: Blinded parallel two-arm pilot randomised controlled trial. SETTING: Initially planned as a multicentre study involving three NHS trusts in the UK, recruitment took place in the pain and spinal orthopaedic clinics at Barts Health NHS Trust only. PARTICIPANTS: Adult patients referred by their GP to the specialist clinics with non-specific low back pain of at least 3 months' duration despite NICE-recommended best non-invasive care (education and one of a physical exercise programme, acupuncture or manual therapy). Patients who had already received lumbar facet-joint injections or who had had previous back surgery were excluded. INTERVENTIONS: Participants who had a positive result following a diagnostic test (single medial branch nerve blocks) were randomised and blinded to receive either intra-articular lumbar facet-joint injections with steroids (intervention group) or a sham procedure (control group). All participants were invited to attend a group-based combined physical and psychological (CPP) programme. MAIN OUTCOME MEASURES: In addition to the primary outcome of feasibility, questionnaires were used to assess a range of pain related (including the Brief Pain Inventory and Short-Form McGill Pain Questionnaire version 2) and disability-related (including the EuroQol-5 Dimensions five-level version and Oswestry Low Back Pain Questionnaire) issues. Health-care utilisation and cost data were also assessed. The questionnaire visits took place at baseline and at 6 weeks, 3 months and 6 months post randomisation. The outcome assessors were blinded to the allocation groups. RESULTS: Of 628 participants screened for eligibility, nine were randomised to receive the study intervention (intervention group, n = 5; sham group, n = 4), six completed the CPP programme and eight completed the study. LIMITATIONS: Failure to achieve our expected recruitment targets led to early closure of the study by the funder. CONCLUSIONS: Because of the small number of participants recruited to the study, we were unable to draw any conclusions about the clinical effectiveness or cost-effectiveness of intra-articular lumbar facet-joint injections in the management of non-specific low back pain. Although we did not achieve the target recruitment rate from the pain clinics, we demonstrated our ability to develop a robust study protocol and deliver the intended interventions safely to all nine randomised participants, thus addressing many of the feasibility objectives. FUTURE WORK: Stronger collaborations with primary care may improve the recruitment of patients earlier in their pain trajectory who are suitable for inclusion in a future trial. TRIAL REGISTRATION: EudraCT 2014-003187 20 and Current Controlled Trials ISRCTN12191542. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 74. See the NIHR Journals Library website for further project information. PMID- 29231160 TI - Oxaliplatin-induced acute tubulointerstitial nephritis: Two case reports?. AB - Oxaliplatin is a platinum compound commonly used in the treatment of advanced colorectal cancer. This report describes two patients who had received repetitive combination chemotherapy including oxaliplatin for the treatment of metastatic colon cancer and who visited the emergency department with acute kidney injury several days after experiencing a hypersensitivity reaction to oxaliplatin. In both cases, the pathologic diagnosis was acute tubulointerstitial nephritis, and corticosteroid therapy resulted in improved renal function. Induction of acute tubulointerstitial nephritis by oxaliplatin has rarely been reported.?. PMID- 29231157 TI - Plant-Produced Subunit Vaccine Candidates against Yellow Fever Induce Virus Neutralizing Antibodies and Confer Protection against Viral Challenge in Animal Models. AB - Yellow fever (YF) is a viral disease transmitted by mosquitoes and endemic mostly in South America and Africa with 20-50% fatality. All current licensed YF vaccines, including YF-Vax(r) (Sanofi-Pasteur, Lyon, France) and 17DD-YFV (Bio Manguinhos, Rio de Janeiro, Brazil), are based on live attenuated virus produced in hens' eggs and have been widely used. The YF vaccines are considered safe and highly effective. However, a recent increase in demand for YF vaccines and reports of rare cases of YF vaccine-associated fatal adverse events have provoked interest in developing a safer YF vaccine that can be easily scaled up to meet this increased global demand. To this point, we have engineered the YF virus envelope protein (YFE) and transiently expressed it in Nicotiana benthamiana as a stand-alone protein (YFE) or as fusion to the bacterial enzyme lichenase (YFE LicKM). Immunogenicity and challenge studies in mice demonstrated that both YFE and YFE-LicKM elicited virus neutralizing (VN) antibodies and protected over 70% of mice from lethal challenge infection. Furthermore, these two YFE-based vaccine candidates induced VN antibody responses with high serum avidity in nonhuman primates and these VN antibody responses were further enhanced after challenge infection with the 17DD strain of YF virus. These results demonstrate partial protective efficacy in mice of YFE-based subunit vaccines expressed in N. benthamiana. However, their efficacy is inferior to that of the live attenuated 17DD vaccine, indicating that formulation development, such as incorporating a more suitable adjuvant, may be required for product development. PMID- 29231161 TI - Pleural and pericardial effusion in a long-term PD patient - a defying diagnosis?. AB - Peritoneopleural shunt is an uncommon complication of peritoneal dialysis (PD) usually presenting early as a right pleural transudate. Peritoneopericardial shunt is an even rarer entity in PD, almost never occurring spontaneously. We present the case of a 37-year-old woman on PD for 24 months exhibiting a left pleural and pericardial effusion following pneumonia. Pleural fluid was initially compatible with an exudate with a high glucose concentration and later with a transudate. In order to clarify the suspicion of an ongoing shunt an abdominal scintigraphy was performed confirming the diagnosis of a peritoneopleuropericardial communication. This case underlines the importance of considering this unusual diagnosis in a patient on long-term PD. Its timely diagnosis is important to stop PD and start hemodialysis.?. PMID- 29231162 TI - Evaluation of clinical outcomes among nonvalvular atrial fibrillation patients treated with rivaroxaban or warfarin, stratified by renal function?. AB - BACKGROUND: Renal dysfunction increases the risk of thromboembolic and bleeding events in patients with nonvalvular atrial fibrillation (NVAF). MATERIALS AND METHODS: Adult NVAF patients with >= 6 months prior to first warfarin or rivaroxaban dispensing were selected from the IMS Health Real-World Data Adjudicated Claims database (05/2011 - 06/2015) with electronic medical records. Ischemic stroke events, thromboembolic events (venous thromboembolism, myocardial infarction, or ischemic stroke), and major bleeding events were compared between patients by renal function identified by 1) relevant ICD-9-CM diagnosis codes and 2) estimated creatinine clearance (eCrCl). Baseline confounders were adjusted using inverse probability of treatment weights. RESULTS: The diagnosis-based analysis included 39,872 rivaroxaban and 48,637 warfarin users (3,572 and 8,230 with renal dysfunction, respectively). The eCrCl-based analysis included 874 rivaroxaban and 1,069 warfarin users (66 and 208 with eCrCl < 60 mL/min, respectively). In the diagnosis-based analysis, rivaroxaban users with renal dysfunction had a significantly lower stroke rate (HR = 0.55, p = 0.0004) compared to warfarin users; rivaroxaban users with and without renal dysfunction had significantly lower thromboembolic event rates (HR = 0.62, p < 0.0001; and HR = 0.64, p < 0.0001, respectively), and similar major bleeding rates to warfarin users. In the eCrCl-based analysis, rivaroxaban users with eCrCl >= 60 mL/min had a significantly lower thromboembolic event rate, but other outcomes were not statistically significant. CONCLUSION: Rivaroxaban-treated NVAF patients with diagnosed renal dysfunction had a significantly lower stroke rate compared to warfarin-treated patients. Regardless of renal dysfunction diagnoses, rivaroxaban users had lower thromboembolic event rates compared to warfarin users, and a similar rate of major bleeding. eCrCl-based analysis was limited by a small sample size.?. PMID- 29231163 TI - Norbuprenorphine and respiratory depression: Exploratory analyses with new lyophilized buprenorphine and sublingual buprenorphine?. AB - OBJECTIVES: To investigate plasma levels of buprenorphine and norbuprenorphine and their relationship to respiratory depression. MATERIALS AND METHODS: Opioid dependent subjects were randomized 2 : 1 to novel lyophilized rapid disintegrating tablet ("bup-lyo") or standard sublingual buprenorphine tablet ("bup-SL"). Measurements included oximetry scores and linked plasma buprenorphine and norbuprenorphine levels. RESULTS: Respiratory depression (cumulative duration of SpO2 < 90% over 30-minute periods) increased with corresponding exposure levels (AUC30 min) of buprenorphine and particularly with norbuprenorphine. A lower buprenorphine/norbuprenorphine ratio was predictive of respiratory depression. The mean (SD) observed ratio was significantly higher for "bup-lyo" (3.4 (2.8)) compared to "bup-SL" (1.7 (0.77)), p < 0.0001. CONCLUSION: Exploratory investigation found respiratory depression more strongly associated with norbuprenorphine than with buprenorphine. This accords with animal studies.?. PMID- 29231165 TI - Polyvalent immunoglobulins with vitamin D3 and vitamin B12 in the treatment of Sjogren's syndrome in a vegetarian with stomatitis, glossodynia, xerostomia, and elevated antinuclear antibodies: Case report?. AB - BACKGROUND: Sjogren's syndrome, involving sicca symptoms with xerostomia, stomatitis, and considerable pain is a difficult-to-treat autoimmune disease where the treatment options are limited and, as in the case of methotrexate, have a low therapeutic index. CASE REPORT: This case report concerns a male patient, aged 75 years and vegetarian, with Sjogren's syndrome subsequently confirmed by salivary gland biopsy. Serum antinuclear antibodies (ANA) were elevated (1 : 320). Low serum vitamin B12 and iron levels could be improved after 20 days using vitamin B12 and iron oral supplements. Despite symptomatic treatment, xerostomia, glossitis, and glossodynia were still present, at times marked, after 12 months when the ANA titer was unchanged. Following treatment with an anti-inflammatory polyvalent immunoglobulin formulation (Lactobin(r)N, 7 g daily), a bovine colostrum concentrate given orally in combination with oral vitamin D3 (2,000 IU daily), sicca symptoms and xerostomia progressively decreased and at day 750 were confined to occasional and minor glossitis of the upper lip. CONCLUSION: This case report demonstrates the satisfactory control of Sjogren's syndrome using oral polyvalent immunoglobulins with vitamin D3. In contrast to treatment options involving antimalarial drugs and methotrexate, there are no safety issues in patients tolerant to milk products.?. PMID- 29231164 TI - Lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer: A systematic review?. AB - OBJECTIVE: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which accounts for 20 - 25% of cases of breast cancers, is highly aggressive. Due to cardiotoxicity and increasing resistance associated with trastuzumab, the first-line treatment, there is a need for effective second-line therapies in treating HER2-positive breast cancer. In this context, there has been increasing interest in the combination of lapatinib plus capecitabine. The aim of this systematic review was to assess the efficacy of lapatinib plus capecitabine for HER2-positive breast cancer after progression with trastuzumab therapy, in comparison with capecitabine monotherapy and other agents such as vinorelbine and trastuzumab emtansine. MATERIALS AND METHODS: We performed a keyword search in five electronic databases (OVID MEDLINE, the Cochrane Library, Web of Science, SCOPUS, and CINAHL; January 2010 to April 2017) for trials in patients with HER2-positive breast cancer that has progressed on trastuzumab. After screening, the relevant studies were assessed for their methodological quality (including selection bias, randomization, control for confounders, and blinding) by two reviewers independently. RESULTS AND DISCUSSION: A total of 50 studies were identified; only 6 of those met the inclusion criteria and were analyzed. Five received a weak rating on the quality assessment tool, and none could be considered as being of high scientific quality after taking the risk of bias and other confounding variables into account. The studies demonstrated that lapatinib plus capecitabine is effective in extending median overall (OS) and progression-free survival (PFS) outcomes, achieving OS of 37.6 - 108.7 weeks and PFS of 21.1 - 30 weeks across studies. However, median OS and PFS for trastuzumab emtansine therapy were found to be considerably better (133.9 weeks and 41.6 weeks, respectively) than for lapatinib plus capecitabine. CONCLUSION: The results suggest that the combination of lapatinib plus capecitabine can improve PFS and OS in patients with HER2-positive breast cancer that has progressed on trastuzumab. However, it appears that trastuzumab emtansine provides better treatment outcomes in this context.?. PMID- 29231166 TI - Effect of polyvalent immunoglobulins on the cytokine cascade in monocytes from colorectal cancer patients: Basis for a new adjuvant therapy?. PMID- 29231167 TI - Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis. AB - The heart switches its energy substrate from glucose to fatty acids at birth, and maternal hyperglycemia is associated with congenital heart disease. However, little is known about how blood glucose impacts heart formation. Using a chemically defined human pluripotent stem-cell-derived cardiomyocyte differentiation system, we found that high glucose inhibits the maturation of cardiomyocytes at genetic, structural, metabolic, electrophysiological, and biomechanical levels by promoting nucleotide biosynthesis through the pentose phosphate pathway. Blood glucose level in embryos is stable in utero during normal pregnancy, but glucose uptake by fetal cardiac tissue is drastically reduced in late gestational stages. In a murine model of diabetic pregnancy, fetal hearts showed cardiomyopathy with increased mitotic activity and decreased maturity. These data suggest that high glucose suppresses cardiac maturation, providing a possible mechanistic basis for congenital heart disease in diabetic pregnancy. PMID- 29231168 TI - Multiple sources of slow activity fluctuations in a bacterial chemosensory network. AB - Cellular networks are intrinsically subject to stochastic fluctuations, but analysis of the resulting noise remained largely limited to gene expression. The pathway controlling chemotaxis of Escherichia coli provides one example where posttranslational signaling noise has been deduced from cellular behavior. This noise was proposed to result from stochasticity in chemoreceptor methylation, and it is believed to enhance environment exploration by bacteria. Here we combined single-cell FRET measurements with analysis based on the fluctuation-dissipation theorem (FDT) to characterize origins of activity fluctuations within the chemotaxis pathway. We observed surprisingly large methylation-independent thermal fluctuations of receptor activity, which contribute to noise comparably to the energy-consuming methylation dynamics. Interactions between clustered receptors involved in amplification of chemotactic signals are also necessary to produce the observed large activity fluctuations. Our work thus shows that the high response sensitivity of this cellular pathway also increases its susceptibility to noise, from thermal and out-of-equilibrium processes. PMID- 29231169 TI - An evolutionarily young defense metabolite influences the root growth of plants via the ancient TOR signaling pathway. AB - To optimize fitness a plant should monitor its metabolism to appropriately control growth and defense. Primary metabolism can be measured by the universally conserved TOR (Target of Rapamycin) pathway to balance growth and development with the available energy and nutrients. Recent work suggests that plants may measure defense metabolites to potentially provide a strategy ensuring fast reallocation of resources to coordinate plant growth and defense. There is little understanding of mechanisms enabling defense metabolite signaling. To identify mechanisms of defense metabolite signaling, we used glucosinolates, an important class of plant defense metabolites. We report novel signaling properties specific to one distinct glucosinolate, 3-hydroxypropylglucosinolate across plants and fungi. This defense metabolite, or derived compounds, reversibly inhibits root growth and development. 3-hydroxypropylglucosinolate signaling functions via genes in the ancient TOR pathway. If this event is not unique, this raises the possibility that other evolutionarily new plant metabolites may link to ancient signaling pathways. PMID- 29231173 TI - Size control mechanism of ZnO nanoparticles obtained in microwave solvothermal synthesis. AB - The aim of the paper is to explain the mechanism of zinc oxide (ZnO) nanoparticle (NP) size control, which enables the size control of ZnO NPs obtained in microwave solvothermal synthesis (MSS) within the size range between circa 20 and 120 nm through the control of water content in the solution of zinc acetate in ethylene glycol. Heavy water was used in the tests. The mechanism of ZnO NPs size control was explained, discussed and experimentally verified. The discovery and investigation of this mechanism was possible by tracking the fate of water molecules during the whole synthesis process. All the synthesis products were identified. It was indicated that the MSS of ZnO NPs proceeded through the formation and conversion of intermediates such as Zn5(OH)8(CH3COO)2 . xH2O. Esters and H2O were the by-products of the MSS reaction of ZnO NPs. We justified that the esterification reaction is the decisive stage that is a prerequisite of the formation of ZnO NPs. The following parameters of the obtained ZnO NPs and of the intermediate were determined: pycnometric density, specific surface area, phase purity, average particles size, particles size distribution and chemical composition. The ZnO NPs morphology and structure were determined using scanning electron microscopy. PMID- 29231172 TI - Cefazolin and coagulation disorders: a case report. AB - We report the case of a 79-year-old patient, admitted to the department of infectious diseases at Bretagne Sud Hospital Center for a right calcaneal osteitis, complicated by a pacemaker leads infectious endocarditis. Meticillin sensitive Staphylococcus aureus was documented by blood culture. Antibiotic treatment was established using intravenous cefazolin for an initial 6 weeks period. Prothrombin time (PT) decreased as well as vitamin K dependent factors, without anticoagulation therapy, at day 7 of cefazolin treatment. After bleeding occurred on calcaneal osteitis, the VAC(r) therapy system was removed and intravenous vitamin K 10 mg (then 5 mg per day for 5 days per os) was administered. Vitamin K allowed PT and vitamin K dependent factors to return to normal values. Literature review does not explicitly mention the effects on vitamin K dependent factors after cefazolin administration. Four severe haemorrhagic episodes under cefazolin have been declared in France so far since February 2017. The goal of this article is to alert clinicians and clinical pathologists from the potential appearance of coagulation disorders in patients treated by cefazolin. PMID- 29231171 TI - Tracing neuronal circuits in transgenic animals by transneuronal control of transcription (TRACT). AB - Understanding the computations that take place in brain circuits requires identifying how neurons in those circuits are connected to one another. We describe a technique called TRACT (TRAnsneuronal Control of Transcription) based on ligand-induced intramembrane proteolysis to reveal monosynaptic connections arising from genetically labeled neurons of interest. In this strategy, neurons expressing an artificial ligand ('donor' neurons) bind to and activate a genetically-engineered artificial receptor on their synaptic partners ('receiver' neurons). Upon ligand-receptor binding at synapses the receptor is cleaved in its transmembrane domain and releases a protein fragment that activates transcription in the synaptic partners. Using TRACT in Drosophila we have confirmed the connectivity between olfactory receptor neurons and their postsynaptic targets, and have discovered potential new connections between neurons in the circadian circuit. Our results demonstrate that the TRACT method can be used to investigate the connectivity of neuronal circuits in the brain. PMID- 29231170 TI - Phenotypic diversity and temporal variability in a bacterial signaling network revealed by single-cell FRET. AB - We present in vivo single-cell FRET measurements in the Escherichia coli chemotaxis system that reveal pervasive signaling variability, both across cells in isogenic populations and within individual cells over time. We quantify cell to-cell variability of adaptation, ligand response, as well as steady-state output level, and analyze the role of network design in shaping this diversity from gene expression noise. In the absence of changes in gene expression, we find that single cells demonstrate strong temporal fluctuations. We provide evidence that such signaling noise can arise from at least two sources: (i) stochastic activities of adaptation enzymes, and (ii) receptor-kinase dynamics in the absence of adaptation. We demonstrate that under certain conditions, (ii) can generate giant fluctuations that drive signaling activity of the entire cell into a stochastic two-state switching regime. Our findings underscore the importance of molecular noise, arising not only in gene expression but also in protein networks. PMID- 29231174 TI - The influence of substrate roughness, patterning, curvature, and compliance in peeling problems. AB - Biological adhesion, in particular the mechanisms by which animals and plants 'stick' to surfaces, has been widely studied in recent years, and some of the structural principles have been successfully applied to bioinspired adhesives. However, modelling of adhesion, such as in single or multiple peeling theories, has in most cases been limited to ideal cases, and due consideration of the role of substrate geometry and mechanical properties has been limited. In this paper, we propose a numerical model to evaluate these effects, including substrate roughness, patterning, curvature, and deformability. The approach is validated by comparing its predictions with classical thin film peeling theoretical results, and is then used to predict the effects of substrate properties. These results can provide deeper insight into experiments, and the developed model can be a useful tool to design and optimize artificial adhesives with tailor-made characteristics. PMID- 29231175 TI - High-pressure oxygen annealing of Al2O3 passivation layer for performance enhancement of graphene field-effect transistors. AB - High-pressure annealing in oxygen ambient at low temperatures (~300 degrees C) was effective in improving the performance of graphene field-effect transistors. The field-effect mobility was improved by 45% and 83% for holes and electrons, respectively. The improvement in the quality of Al2O3 and the reduction in oxygen related charge generation at the Al2O3-graphene interface, are suggested as the reasons for this improvement. This process can be useful for the commercial implementation of graphene-based electronic devices. PMID- 29231176 TI - TensorCalculator: exploring the evolution of mechanical stress in the CCMV capsid. AB - A new computational methodology for the accurate numerical calculation of the Cauchy stress tensor, stress invariants, principal stress components, von Mises and Tresca tensors is developed. The methodology is based on the atomic stress approach which permits the calculation of stress tensors, widely used in continuum mechanics modeling of materials properties, using the output from the MD simulations of discrete atomic and [Formula: see text]-based coarse-grained structural models of biological particles. The methodology mapped into the software package TensorCalculator was successfully applied to the empty cowpea chlorotic mottle virus (CCMV) shell to explore the evolution of mechanical stress in this mechanically-tested specific example of a soft virus capsid. We found an inhomogeneous stress distribution in various portions of the CCMV structure and stress transfer from one portion of the virus structure to another, which also points to the importance of entropic effects, often ignored in finite element analysis and elastic network modeling. We formulate a criterion for elastic deformation using the first principal stress components. Furthermore, we show that von Mises and Tresca stress tensors can be used to predict the onset of a viral capsid's mechanical failure, which leads to total structural collapse. TensorCalculator can be used to study stress evolution and dynamics of defects in viral capsids and other large-size protein assemblies. PMID- 29231177 TI - Hindrances to precise recovery of cellular forces in fibrous biopolymer networks. AB - How cells move through the three-dimensional extracellular matrix (ECM) is of increasing interest in attempts to understand important biological processes such as cancer metastasis. Just as in motion on flat surfaces, it is expected that experimental measurements of cell-generated forces will provide valuable information for uncovering the mechanisms of cell migration. However, the recovery of forces in fibrous biopolymer networks may suffer from large errors. Here, within the framework of lattice-based models, we explore possible issues in force recovery by solving the inverse problem: how can one determine the forces cells exert to their surroundings from the deformation of the ECM? Our results indicate that irregular cell traction patterns, the uncertainty of local fiber stiffness, the non-affine nature of ECM deformations and inadequate knowledge of network topology will all prevent the precise force determination. At the end, we discuss possible ways of overcoming these difficulties. PMID- 29231178 TI - Internal structure and swelling behaviour of in silico microgel particles. AB - Microgels are soft colloids that, by virtue of their polymeric nature, can react to external stimuli such as temperature or pH by changing their size. The resulting swelling/deswelling transition can be exploited in fundamental research as well as for many diverse practical applications, ranging from art restoration to medicine. Such an extraordinary versatility stems from the complex internal structure of the individual microgels, each of which is a crosslinked polymer network. Here we employ a recently-introduced computational method to generate realistic microgel configurations and look at their structural properties, both in real and Fourier space, for several temperatures across the volume phase transition as a function of the crosslinker concentration and of the confining radius employed during the 'in-silico' synthesis. We find that the chain-length distribution of the resulting networks can be analytically predicted by a simple theoretical argument. In addition, we find that our results are well-fitted to the fuzzy-sphere model, which correctly reproduces the density profile of the microgels under study. PMID- 29231179 TI - The influence of amine structures on the stability and catalytic activity of gold nanoparticles stabilized by amine-modified hyperbranched polymers. AB - Amine-modified amphiphilic hyperbranched polymers (MePEG-H104-Nx) were prepared from hyperbranched 2,2-bis(methylol)propionic acid polyester (H104) by decoration with polyethylene glycol monomethyl ether (MePEG) and different classes of oligo(ethylenimine)s. By using the MePEG-H104-Nx polymers as stabilizers, gold nanoparticles (AuNPs) were prepared in an aqueous medium by the reduction of HAuCl4 with NaBH4. The AuNPs were sphere-like with diameters of 2-4 nm, which were dependent on the structure of the amines. Further, the catalytic activity of these AuNPs was evaluated by monitoring the reduction reaction of 4-nitrophenol by sodium borohydride. The results demonstrate that the longer chain length and the branched structure of the amine moieties are beneficial for the stability and catalytic activity of the AuNPs. The AuNPs stabilized by MePEG-H104-N4 and MePEG H104-Nb3 showed high catalytic activity for the reduction of 4-nitrophenol to 4 aminophenol. PMID- 29231180 TI - Realization of synaptic learning and memory functions in Y2O3 based memristive device fabricated by dual ion beam sputtering. AB - Single synaptic device with inherent learning and memory functions is demonstrated based on a forming-free amorphous Y2O3 (yttria) memristor fabricated by dual ion beam sputtering system. Synaptic functions such as nonlinear transmission characteristics, long-term plasticity, short-term plasticity and 'learning behavior (LB)' are achieved using a single synaptic device based on cost-effective metal-insulator-semiconductor (MIS) structure. An 'LB' function is demonstrated, for the first time in the literature, for a yttria based memristor, which bears a resemblance to certain memory functions of biological systems. The realization of key synaptic functions in a cost-effective MIS structure would promote much cheaper synapse for artificial neural network. PMID- 29231182 TI - Effect of drop volume and surface statistics on the superhydrophobicity of randomly rough substrates. AB - In this paper, a simple theoretical approach is developed with the aim of evaluating shape, interfacial pressure, apparent contact angle and contact area of liquid drops gently deposed on randomly rough surfaces. This method can be useful to characterize the superhydrophobic properties of rough substrates, and to investigate the contact behavior of impacting drops. We assume that (i) the size of the apparent liquid-solid contact area is much larger than the micromorphology of the substrate, and (ii) a composite interface is always formed at the microscale. Results show apparent contact angle and liquid-solid area fraction are slightly influenced by the drop volume only at relatively high values of the root mean square roughness h rms, whereas the effect of volume is practically negligible at small h rms. The main statistical quantity affecting the superhydrophobic properties is found to be the Wenzel roughness parameter r W, which depends on the average slope of the surface heights. Moreover, transition from the Cassie-Baxter state to the Wenzel one is observed when r W reduces below a certain critical value, and theoretical predictions are found to be in good agreement with experimental data. Finally, the present method can be conveniently exploited to evaluate the occurrence of pinning phenomena in the case of impacting drops, as the Wenzel critical pressure for liquid penetration gives an estimation of the maximum impact pressure tolerated by the surface without pinning occurring. PMID- 29231181 TI - Automatic two-channel sleep staging using a predictor-corrector method. AB - OBJECTIVE: We developed and implemented two predictor-corrector methods for the classification of two-channel EEG data into sleep stages. APPROACH: The sequence of sleep stages over the night is modeled by a Markov chain of first and second order, resulting in an informative prior distribution for the new state, given the distribution of the current one. The correction step is realized by applying a Bayes classifier using the (preprocessed) data and this prior. The preprocessing step consists of a frequency analysis, a log transformation and a dimensionality reduction via principal component analysis. MAIN RESULTS: The software automatically generates sleep profiles in which it detects wakeful phases as well as the different sleep stages with error rates of 16.5%-31.9% (n = 8, healthy subjects, mean age +/- SD: 39 +/- 8.1 years, five females), where we compared our results to those of a certified polysomnographic technologist, who used a full polysomnograph and rated according to the American Academy of Sleep Medicine (AASM) criteria. SIGNIFICANCE: The method presented relies on considerably less information than visual scoring and is done automatically. Furthermore, the error is comparable to visual scoring, where the inter-rater variability lies around 82%. Therefore, it has the potential to lessen the overheads associated with sleep diagnostics. PMID- 29231183 TI - Metamaterials based on the phase transition of VO2. AB - In this article, we present a comprehensive review on recent research progress in design and fabrication of active tunable metamaterials and devices based on phase transition of VO2. Firstly, we introduce mechanisms of the metal-to-insulator phase transition (MIPT) in VO2 investigated by ultrafast THz spectroscopies. By analyzing the THz spectra, the evolutions of MIPT in VO2 induced by different external excitations are described. The superiorities of using VO2 as building blocks to construct highly tunable metamaterials are discussed. Subsequently, the recently demonstrated metamaterial devices based on VO2 are reviewed. These metamaterials devices are summarized and described in the categories of working frequency. In each working frequency range, representative metamaterials based on VO2 with different architectures and functionalities are reviewed and the contributions of the MIPT of VO2 are emphasized. Finally, we conclude the recent reports and provide a prospect on the strategies of developing future tunable metamaterials based on VO2. PMID- 29231184 TI - Novel approach for improving the performance of Si-based anodes in lithium-ion batteries. AB - Herein, we report successful deposition of aluminum oxide films on the silicon nanowires (SiNWs) to realize core-shell silicon-based lithium-ion battery anodes. By means of reactive ion etching, it has been possible to form an ultra-thin layer of Al2O3 on SiNWs through hydrogen plasma. This deposition technique leads to the formation of tiny holes on the surface of the Al2O3 layer while introducing the pore sites into the inner silicon material without damaging the whole structure. SiNW@Al2O3 core-shell nanostructures were used as the effective anode materials and showed a superior electrochemical performance compared to conventional SiNWs. Our electrode exhibited the high first cycle specific discharge capacity of 3936 mAh g-1 at a rate of C/16 as well as high rate capability. Furthermore, this anode electrode showed less than 6% degradation of specific capacity over 120 cycles at high rate density of 2C and it delivers high reversible capacity of 965 mAh g-1. The improvement in the electrochemical properties of our electrode is achieved due to both a high specific capacity of Si core and the effect of aluminum oxide shell on active material cycling stability. PMID- 29231185 TI - Quantitative evaluation of graded hindlimb ischemia based on pharmacokinetic modelling and hemodynamic analysis of indocyanine green. AB - OBJECTIVE: Accurate evaluation of the degree of hindlimb ischemia is challenging but essential for the diagnosis and treatment of peripheral vascular insufficiency. The aim of the study is to apply a multiparametric method for the quantitative estimation of mouse models with different degrees of hindlimb ischemia based on a dynamic fluorescence imaging-based strategy. APPROACH: An adjustable hydraulic occluder was placed around the thigh root of one hindlimb to induce six different degrees of hindlimb ischemia. Five parameters were extracted to quantitatively evaluate the degree of ischemia, including perfusion rate (PR) and perfusion vascular density (PVD) from a mathematical model of indocyanine green (ICG) pharmacokinetics, rising time (T rise), blood flow index (BFI) and mean fluorescence intensity (MFI) from time-series analysis of ICG hemodynamics. MAIN RESULTS: The results showed that the normalized PR and BFI decreased while the normalized T rise increased progressively with the degree of ischemia. The normalized PVD and MFI first increased and then decreased with the degree of ischemia. High correlation was observed between the degree of ischemia and the arterial oxygen saturation which was measured by an oximeter. SIGNIFICANCE: The results of this work demonstrated that PR, BFI and T rise can be used for the quantitative and comprehensive evaluation of graded hindlimb ischemia. PMID- 29231186 TI - [Psychometric properties of postpartum depression predictors inventory- revised- prenatal version in a sample of spanish pregnant women.] AB - OBJECTIVE: Prenatal depression is a major public health problem, therefore predicting and preventing it is a relevant objective for public health agendas. Consequently, it is important to have adequate screening tools to detect risk factors associated with prenatal depression. The aim of this study was to evaluate the psychometric properties reliability and factor structure of the Spanish version of the Postpartum Depression Predictors Inventory- Revised- Prenatal Version (PDI-R) in pregnant women who attend prenatal care in an urban hospital in Spain. METHODS: The sample was formed of 445 women receiving prenatal care in an obstetrics clinic in an urban public hospital in Madrid, Spain. The internal consistency of PDPI-R was assessed by measuring Cronbach's Alfa index, calculating the COR curve and percentiles for this sample. RESULTS: The PDPI-R showed good internal consistency in this sample (Cronbach's Alfa = 0,855). The area under the COR curve is 0,84 p<=0,001. Sensibility and specificity values were 62,3% and 69,5% respectively, and the cut-off point with greatest sensibility and specificity was 4. CONCLUSIONS: The PDPI-R is reliable and can be used to screen for risk factor for depression during pregnancy. PMID- 29231187 TI - [Emergency Medical Technician profile in Spain]. AB - OBJECTIVE: The emergency medical technician plays a fundamental role and is the most important figure quantitatively in pre-hospital emergencies. The aim was to asses the socio-demographic, work-related, health characteristics and technical skills of an Emergency Medical Technician in Spain. METHODS: Cross-sectional descriptive study. An ad hoc questionnaire was managed using Google Docs(r) that was delivered between April-June 2014 via email and social networks. A total of 705 questionnaires were collected. Statistical analysis was performed with SPSS (r) 20.0 Windows version. A significance level p<=0.05 was used for all analyzes. RESULTS: The data analyzed show that the profile of the Emergency Medical Technician in Spain is an 39 year-old man, married or living as a couple and has a child. The average BMI is 27 kg/m2, does regular exercise, does not smoke. His seniority in the company is 10 years and has the Medium Cycle of Emergency Medical Technician. The analysis for gender shows that men have an average of 40, an average BMI of 27, 5 kg/m2 and work in an advanced life support unit; while women have an average of 36,5 years, an average BMI of 24,7 kg/m2, mainly work in Basic Life Support Unit and her seniority in the company is 6,76 years. CONCLUSIONS: Emergency Medical Technician profile is a overweight men, who refer to practise regular exercise, his seniority in the company is 10 years and is in possession of CMTES; differences were observed according to gender in BMI, resource where they perform their work, seniority and age. PMID- 29231189 TI - The Liver Frailty Index Improves Mortality Prediction of the Subjective Clinician Assessment in Patients With Cirrhosis. AB - OBJECTIVES: Frailty, a critical determinant of health outcomes, is most commonly assessed in patients with cirrhosis by general clinician assessment that is limited by its subjectivity. We aimed to compare the objective Liver Frailty Index (LFI), consisting of three performance-based tests (grip, chair stands, balance), with a subjective hepatologist assessment. METHODS: Outpatients with cirrhosis awaiting liver transplantation (LT) underwent: (1) objective measurement using the LFI and (2) subjective clinician assessment. Spearman's correlation assessed associations between the LFI and clinician assessment; Cox regression with waitlist mortality (death/delisting for sickness); discriminative ability with Concordance(C) statistics. The net reclassification index evaluated the percentage of patients correctly reclassified by adding the LFI to the clinician assessment. RESULTS: Of the 529 patients with cirrhosis, median LFI was 3.8 (range 1.0-7.0) and clinician assessment was 3 (range 0-5). Correlation between LFI and the clinician assessment was modest (rho=0.38) with high variability by hepatologist (rho=0.26-0.70). At a median of 11 months, 102 (19%) died/were delisted. Both the LFI (hazard ratio (HR) 2.2, 95% confidence interval (CI) 1.7-2.9) and clinician assessment (HR 1.6, 95% CI 1.3-1.9) were associated with adjusted waitlist mortality risk (P<0.01). The addition of the LFI to the clinician assessment significantly improved mortality prediction over the clinician assessment alone (0.74 vs. 0.68; P=0.02). Compared with the clinician assessment alone, the addition of the LFI correctly reclassified 34% (95% CI 8 53%) of patients to their correct survival status. CONCLUSION: The subjective clinician assessment can predict waitlist mortality in patients with cirrhosis but is subjective and variable by hepatologist. The addition of the LFI to the subjective clinician assessment significantly improved mortality risk prediction, reclassifying 34% of patients. Our data strongly support the incorporation of the objective LFI to anchor our assessments of patients with cirrhosis to enhance our decision-making. PMID- 29231188 TI - Major Hepatic Complications in Ursodeoxycholic Acid-Treated Patients With Primary Biliary Cholangitis: Risk Factors and Time Trends in Incidence and Outcome. AB - OBJECTIVES: In this era of near universal ursodeoxycholic acid (UDCA) treatment for primary biliary cholangitis (PBC), progression to cirrhosis still occurs in an important proportion of patients. The aim of this study was to describe the incidence of cirrhosis-associated complications in patients with PBC and assess risk factors and impact on survival. METHODS: Cohorts of UDCA-treated patients from 16 European and North-American liver centers were included. We used Cox proportional hazards assumptions and Kaplan-Meier estimates. RESULTS: During 8.1 years' median follow-up, 278 of 3,224 patients developed ascites, variceal bleeding, and/or encephalopathy (incidence rate of 9.7 cases/1,000 patient years). The overall cumulative incidence was 9.1% after 10 years of follow-up, but decreased over time to 5.8% after the year 2000. Earlier calendar year of diagnosis (P<0.001), high aspartate aminotransferase to platelets ratio index (APRI; P<0.001) and biochemical non-response (P<0.001) were independently associated with future complications. Patients with both biochemical non-response and an APRI >0.54 after 12 months of UDCA had a 10-year complication rate of 37.4%, as compared to 3.2% in biochemical responders with an APRI <=0.54. The 10 year transplantation-free survival after a complication was 9% (time-dependent hazard ratio 21.5; 20.1-22.8). Prognosis after variceal bleeding has improved over time. CONCLUSIONS: In this large international cohort, up to 15% of UDCA treated PBC patients developed major non-neoplastic, cirrhosis-associated hepatic complications within 15 years, but cumulative incidence has decreased over time. Biochemical non-response to UDCA and APRI were independent risk factors for these complications. Subsequent long-term outcome after complications is generally poor, but has improved over the past decades. PMID- 29231190 TI - Lesions of All Types Exist in Colon Polyps of All Sizes. AB - OBJECTIVES: Although large polyps are known to harbor more advanced neoplasia than small polyps, the extent of the relationship between size and type is not fully known. The study aim was to establish benchmarks for the prevalence of different histologic polyp types among varying size categories. METHODS: The Miraca Life Sciences Database is an electronic repository of histopathologic patient records from private practices throughout the United States. We extracted the records of 483,998 unique patients who underwent colonoscopy with polypectomy between January 2008 and December 2014. A total of 550,811 polyps were stratified by their endoscopic size measurement. Polyps of each size were further stratified as hyperplastic polyp (HP), tubular adenoma (TA), tubulovillous adenoma (TVA), sessile serrated adenoma/polyp, and adenocarcinoma. RESULTS: Of all 550,811 polyps, 447,343 (81%) were 1-9 mm in size, and 103,517 (19%) were 10 mm or larger. A fraction of 18,591/550,811 polyps (3.4%) harbored histologic features of advanced adenoma, such as TVA, high-grade dysplasia, or cancer. Of these, 4,725/18,591 (25%) occurred in polyps 1-9 mm and 13,868/18,591 (75%) occurred in polyps 10 mm or larger. The fractions of advanced adenoma were 0.6% (0.5-0.6%) in 1-5 mm polyps and 2.1% (2.0-2.2%) in 6-9 mm polyps, as compared to 13.4% (13.2 13.6%) in polyps 10 mm or larger. The frequency of HP significantly decreased with increasing polyp size, whereas the frequency of TA remained largely unaffected by polyp size. CONCLUSIONS: While advanced histopathology was found more frequently in colorectal polyps of larger than smaller size, one quarter of all advanced histopathology existed in polyps of <10 mm. PMID- 29231191 TI - Putting Patients First. PMID- 29231193 TI - Pancreatic cancer: Mass spectrometry indicates malignant potential. PMID- 29231194 TI - Breast cancer in 2017: Spurring science, marking progress, and influencing history. PMID- 29231192 TI - Defining an Optimal Adherence Threshold for Patients Taking Subcutaneous Anti TNFs for Inflammatory Bowel Diseases. AB - OBJECTIVES: In patients with inflammatory bowel disease (IBD) using biological therapy, non-adherence leads to anti-drug antibody formation and reduced effectiveness. Little is known about the optimal level of adherence in IBD patients on biologic therapy. We aimed to identify the association between adherence and disease flare and determine an optimal level of adherence. METHODS: We analyzed claims data for IBD patients prescribed adalimumab (ADA) and certolizumab (CZP) from the Truven Health MarketScan Commercial Claims and Encounters database from 2009 to 2013. Adherence was calculated using the medication possession ratio (MPR) from initiation until flare occurrence. A disease flare was defined as any hospitalization or new steroid prescription>90 days after drug initiation. The optimal MPR was determined using log-rank testing. The association between the optimal MPR and flare was assessed using multivariable Cox-Proportional hazards ratio. RESULTS: There were 6,048 patients who were prescribed ADA (n=5,325) or CZP (n=723) for IBD. The average age was 41 years (+/-15) and 54% were female. The optimal MPR identified was 0.86 for ADA and 0.87 for CZP; 24% of the patients were below this level. Adjusting for age, gender, and concomitant medications at initiation, patients who were adherent above these levels had a 25% lower risk of flare for ADA (HR: 0.75, 95%CI: 0.67 0.83, P<0.01) and 41% lower risk for CZP (HR: 0.59, 95%CI: 0.46-0.76, P<0.01). CONCLUSIONS: Patients who delay refills >2 days on average every 2 weeks of their subcutaneous biologics have significantly increased risk of flare. Further studies to improve adherence among those patients who consistently delay medication use are necessary. PMID- 29231195 TI - HSD3B1 status as a biomarker of androgen deprivation resistance and implications for prostate cancer. AB - Patients with advanced prostate cancer who receive androgen deprivation therapy (ADT) almost invariably develop castration-resistant disease. The mechanism of resistance is largely based on synthesis of intratumoral androgens from adrenal precursors, requiring enzymatic action of 3beta-hydroxysteroid dehydrogenase/Delta5->4 isomerase 1 (3beta-HSD1), encoded by HSD3B1. A nucleotide polymorphism (1245A>C) in HSD3B1 results in a protein variant with increased steady-state levels and subsequently increased androgen synthesis from extragonadal precursors. Multiple clinical studies have shown that patients with the variant allele have significantly worse outcomes after ADT than those without, indicating that HSD3B1 variant status is a predictive biomarker of shortened ADT response. In addition, inheritance of the HSD3B1 variant is associated with extended responses to 17alpha-hydroxylase/17,20-lyase (CYP17A1) inhibition with a nonsteroidal agent, adding to evidence of increased tumour dependence on extragonadal androgens in patients who inherited the HSD3B1 variant. However, steroidal drugs with a 3beta-hydroxyl, Delta5-structure, such as abiraterone, are also metabolized by 3beta-HSD1, and 5alpha-abiraterone, a downstream metabolite, has been shown to activate the androgen receptor, potentially driving cancer progression. These data indicate a potential requirement to modify the treatment framework of patients harbouring variant HSD3B1. PMID- 29231196 TI - Prostate cancer: Damaged good - targeting DNA damage repair in neuroendocrine disease. PMID- 29231197 TI - Prostate cancer: Castration resistance driven by a GI transcriptional circuit. PMID- 29231198 TI - Prostate cancer in 2017: Advances in imaging. PMID- 29231199 TI - Prostate cancer: Enzalutamide-cabazitaxel interactions. PMID- 29231200 TI - Developments in the meiotic analysis of hybrids. I. Review of theory and optimization in triploids. AB - The theory, construction and optimization of a model of chromosome pairing in triploid hybrids are re-examined and the model reconstructed. A new approach to optimization is described that removes a bias in the estimation of x, the measure of relative affinity, by weighting the observed and calculated meiotic figure frequencies by the number of chromosomes in each figure type. The amended analysis is compared with its antecedent and with other models. PMID- 29231201 TI - Enzyme heterozygosity and growth in rainbow trout: genetic and physiological explanations. AB - The possibility of whether the association between enzyme heterozygosity and body size (fork length) is consistent among rainbow trout (Oncorhynchus mykiss) with different degrees of relationship and is affected by fish age was determined. Six month-old full-sibs and progeny groups from five and 13 parents of each sex do not show the positive associations between multilocus heterozygosity and fork length which are detectable in larger pooled gamete matings (25? * 25?). Moreover, the relationship between heterozygosity at single loci and fork length is inconsistent among families. These data suggest that chromosomal segments, marked by the enzyme loci, are responsible for the phenotypic effects (associative overdominance). Fish age affects both the strength and direction of the association between multilocus heterozygosity and fork length; the association is positive in 6-month-old rainbow trout but is weaker, negative, or differs between the sexes in fish at 1 year. Moreover, the strength of the relationship changes over time in repeated measurements on the same fish. A decline in growth of larger and more heterozygous fish, because of precocial sexual maturation, may partially explain the changing relationship between multilocus heterozygosity and fork length. Sexually mature males are significantly more heterozygous than immature males and show significantly reduced recent growth rates as measured by white muscle RNA concentration. However, females, who rarely mature at 1 year, show significantly higher recent growth rates. Thus, heterozygosity is differentially associated with the allocation of energy resources into somatic and reproductive tissue in male and female rainbow trout. PMID- 29231202 TI - Genetic structure of natural populations of the free-living amoeba, Naegleria lovaniensis. Evidence for sexual reproduction. AB - The genetic structure of two populations of Naegleria lovaniensis, comprising 71 isolates collected from the same local geographical area was investigated by isoenzyme analysis. Allelic variation at seven polymorphic enzymatic loci allowed identification of 45 distinctive genotype associations. Analysis of single locus variation reveals that most of them are close to Hardy-Weinberg equilibrium, which indicates segregation and free recombination between alleles. The recovery of a relatively high number of distinct genotypic associations (most of them being unique), and the absence of linkage disequilibrium between genotypes at the different loci also support the existence of recombination. Although we have no idea about the process involved, the results clearly indicate that genetic exchanges occur, at least occasionally, in natural populations of N. lovaniensis. PMID- 29231203 TI - Developments in the meiotic analysis of hybrids. II. Amended models for tetraploids. AB - Amended models of meiotic behaviour in tetraploid species' hybrids have been constructed which better reflect the theory and assumptions about chromosome pairing necessary to conduct such analyses. In particular they correct problems concerning the distribution of chiasmata among and within chromosome configurations inherent in the earlier models of Kimber & Alonso (1981). In general these analyses give similar interpretations to the earlier models but in some cases call the previous conclusions into question. PMID- 29231204 TI - On the developmental theory of ageing. II. The effect of developmental temperature on longevity in relation to adult body size in D. melanogaster. AB - Flies from a wild type strain of Drosophila melanogaster, previously kept at 25 degrees C, were reared at either 20,25 or 29 degrees C. As expected, developmental time and adult body size decreased with increasing temperature. Adult longevity of flies reared at 25 degrees C was slightly greater than that of flies raised at 20 or 29 degrees C when measured at all three temperatures. This may reflect the laboratory history of the strain. On the whole, it appeared that longevity was independent of adult body size. These results support our previous conclusion (Zwaan et al., 1991) that developmental time and body size are not causally related to longevity in 'environmental' studies. It is stressed, that genetic analysis is needed to investigate the reputed correlation between development and ageing. PMID- 29231205 TI - Segregation and fertility in Mus musculus domesticus (wild mice) heterozygous for the Rb(4.12) translocation. AB - Analysis of the progeny of wild mice heterozygous for the Rb(4.12) shows that fertility and segregation are normal. This study, and others with similar results, suggests that our view of the chromosomal evolution of the house mouse should be revised. PMID- 29231206 TI - Identification and evidence for relationships among geographical isolates of Bursaphelenchus spp. (pinewood nematode) using homologous DNA probes. AB - Homologous DNA probes with a variable degree of repetitivity were used to identify the precise relationships between isolates belonging to the pinewood nematodes. Southern blot hybridization patterns obtained with genomic DNA from 13 geographical isolates confirm the existence of a B. xylophilus group and a B. mucronatus group within these pinewood nematodes. With these probes we were also able to discriminate between geographical isolates. The results clearly indicate the existence of three geographical subgroups in the B. xylophilus species: the United States, Canada and Japan with a close relationship between the USA and Japanese isolates. This supports the hypothesis that the B. xylophilus isolate, which was introduced into Japan, originated from the USA. Furthermore, these probes clarify the taxonomic status of a Minnesota isolate found on Abies balsamea and of the French and Norwegian isolates of pinewood nematodes. The nature of the isolated sequences is also discussed. PMID- 29231207 TI - More about the multiplicative model for the analysis of genotype-environment interaction. AB - In this paper various multiplicative models that are often used to analyse genotype-environment interaction are described and some of the statistical relationships between them are explored. It is shown that principal-component analysis can be seen as a natural generalization of the joint regression analysis. A set of maize data is used to exemplify these statistical models. PMID- 29231208 TI - Analysis of mating systems in the schistosome-vector hermaphrodite snail Bulinus globosus by DNA fingerprinting. AB - Bulinus globosus, one of the intermediate hosts for Schistosoma, is a hermaphrodite freshwater snail. Multilocus DNA fingerprinting was applied in order to investigate the mating system of this facultatively self-fertilizing species. By analysing DNA fingerprints of eight broods, we have shown that selfed and outcrossed individuals could be unambiguously distinguished by comparison with their parent fingerprints. First, selfed offspring patterns shared a higher number of bands with their mother than did outcrossed ones. Secondly, at least three paternal bands could be detected per out-crossed offspring pattern. PMID- 29231209 TI - Variation of ribosomal gene spacer length among wild and cultivated banana. AB - The diversity of rDNA spacer length (IGS) of 107 wild and cultivated clones of banana belonging to different genetic groups, was studied using a sulphonated wheat rDNA probe. The length of the rDNA unit was between 10 and 12.6 kb and was highly variable. Fifteen different types of IGS could be observed. IGS diversity within the acuminata complex was greater among the diploid cultivars than among the triploid cultivars. Variation was also found among BB genotypes and confirms the diversity of this species. As opposed to previous studies, based on enzymatic or poly-phenolic markers, there was no obvious relation between the rDNA structure and the classification into genetic groups. More particularly, the IGS variations did not differentiate between the A and B genomes. This analysis, however, indicates a relationship between the geographical origin and the IGS structure of Thai and Indonesian clones. PMID- 29231212 TI - Relationship between pairing frequencies and genome affinity estimations in Aegilops ovata * Triticum aestivum hybrid plants. AB - Meiotic associations at metaphase I have been analysed in Aegilops ovata * Triticum aestivum hybrid plants (genome constitution ABDUM) with low and high homoeologous pairing by using C-banding. Five different types of meiotic associations involving Aegilops and wheat genomes were identified. Pairing affinities between Aegilops and wheat genomes have been analysed from meiotic associations at metaphase I in low and high homoeologous pairing hybrid plants as well as from different meiotic configurations (bivalents and multivalents) in those hybrids with a high pairing mutant (phlb). Those kinds of distinguishable associations revealed the same relative order: AD-UM > A-D > U-M > AD-B > UM-B in both low and high homoeologous pairing hybrids. The mean number of associations per total associations (relative contribution) for the different distinguishable types of pairing was well maintained among hybrids with different levels of pairing (low and high) as well as in different meiotic configurations (bivalents and multivalents) in the high pairing plants. These results seem to indicate that the affinities expressed between the genomes that are in competition for pairing are independent of the meiotic configurations considered and on the level of pairing analysed. PMID- 29231214 TI - Picea omorika is a self-fertile but outcrossing conifer. AB - Outcrossing rates were estimated in a natural Yugoslavian and in a cultivated Finnish population of Serbian spruce [Picea omorika (Pancic) Purk.]. The outcrossing rates in the cultivated stand in two years were 0.98 +/-0.03 and 1.02 +/-0.04, and in the natural stand 0.84 +/-0.05. The relative self-fertility was estimated in seven trees in the cultivated population. The results indicate high self-fertility, which agrees with the earlier information. The high self fertility combined with high outcrossing rate shows that Serbian spruce, in contrast to most other conifers, employs other means than early acting inbreeding depression to avoid selfing. PMID- 29231215 TI - Involvement of FAK-mediated BMP-2/Smad pathway in mediating osteoblast adhesion and differentiation on nano-HA/chitosan composite coated titanium implant under diabetic conditions. AB - Chitosan (CS)-based hydroxyapatite (HA) composites have emerged as a novel strategy for promoting bone regeneration. Here nanophase HA/CS composite coated porous titanium implants (nCT) were fabricated and their biological behavior under diabetic conditions was investigated. We proposed that the focal adhesion kinase (FAK)-mediated BMP-2/Smad pathway played a role in mediating the promotive effect of nCTs on osteoblast adhesion and differentiation under diabetes-induced high reactive oxygen species (ROS) condition. To confirm the hypothesis, rat osteoblasts on bare titanium implants (Ti) and nCT were subjected to normal serum (NS), diabetic serum (DS), DS + NAC (a potent ROS inhibitor) and DS + cytochalasin D (an actin polymerization inhibitor). In vivo on diabetic sheep implanted with Ti or nCT showed that diabetes-induced ROS overproduction impaired osteoblast adhesion, evidenced by immunostaining of F-actin and vinculin and morphological observation through inhibition of FAK phosphorylation, which contributed to suppressed BMP-2-dependent Smad1/5/8 phosphorylation. nCT substrate reactivated the FAK-BMP-2/Smad pathway, thus reversing osteoblast dysfunction, which exerted a similar effect to NAC treatment on Ti. These effects were further confirmed by improved osteointegration within nCT in diabetic sheep, evidenced by micro-CT and histological examinations. Our study demonstrated that reactivation of the FAK-BMP-2/Smad pathway was involved in improving osteoblast adhesion and differentiation by nano-HA/CS composite coating, potentially directing biomaterial modification and biofunctionalization under diabetic conditions. PMID- 29231216 TI - Aronia-citrus juice (polyphenol-rich juice) intake and elite triathlon training: a lipidomic approach using representative oxylipins in urine. AB - In the present study, we examined whether particular urinary oxylipins (isoprostanes (IsoPs), leukotrienes (LTs), prostaglandins (PGs), and thromboxanes (TXs)) in 16 elite triathletes could alter during 145 days of training. Within this time span, 45 days were dedicated to examining the effects of the intake of a beverage rich in polyphenols (one serving: 200 mL per day) supplemented in their diet. The beverage was a mixture of citrus juice (95%) and Aronia melanocarpa juice (5%) (ACJ). Fifty-two oxylipins were analyzed in the urine. The quantification was carried out using solid-phase extraction, liquid chromatography coupled with triple quadrupole mass spectrometry. The physical activity decreased the excretion of some PG, IsoP, TX, and LT metabolites from arachidonic acid, gamma-dihomo-linolenic acid, and eicosapentaenoic acid. The ACJ also reduced the excretion of 2,3-dinor-11beta-PGF2alpha and 11-dehydro-TXB2, although the levels of other metabolites increased after juice supplementation (PGE2, 15-keto-15-F2t-IsoP, 20-OH-PGE2, LTE4, and 15-epi-15-E2t-IsoP), compared to the placebo. The metabolites that increased in abundance have been related to vascular homeostasis and smooth muscle function, suggesting a positive effect on the cardiovascular system. In conclusion, exercise influences mainly the decrease in oxidative stress and the inflammation status in elite triathletes, while ACJ supplementation has a potential benefit regarding the cardiovascular system that is connected in a synergistic manner with elite physical activity. PMID- 29231217 TI - Ultrathin nickel hydroxide on carbon coated 3D-porous copper structures for high performance supercapacitors. AB - An ultrathin nickel hydroxide layer electrodeposited on a carbon-coated three dimensional porous copper structure (3D-C/Cu) is suggested as an additive and binder-free conductive electrode with short electron path distances, large electrochemical active sites, and improved structural stability, for high performance supercapacitors. The 3D-porous copper structure (3D-Cu) provides high electrical conductivity and facilitates electron transport between the Ni(OH)2 active materials and the current collector of the Ni-plate. A carbon coating was applied to the 3D-Cu to prevent the oxidation of Cu, without degrading the electron transport behavior of the 3D-Cu. The 3D-Ni(OH)2/C/Cu exhibited a high specific capacitance of 1860 F g-1 at 1 A g-1, and good cycling performance, with an 86.5% capacitance retention after 10 000 cycles. When tested in a two electrode system, an asymmetric supercapacitor exhibited an energy density of 147.9 W h kg-1 and a power density of 37.0 kW kg-1. These results open a new area of ultrahigh-performance supercapacitors, supported by 3D-Cu electrodes. PMID- 29231218 TI - Metal oxide- and N-codoped carbon nanosheets: facile synthesis derived from MOF nanofibers and their application in oxygen evolution. AB - We successfully developed an approach to synthesize a metal oxide- and N-codoped carbon nanosheet, NC@CoO/CuO, derived from a metal-organic framework nanofiber, Cu(ii)-Asp@Co(II) (Asp = l-aspartate). The use of NC@CoO/CuO as a high performance catalyst for the oxygen evolution reaction in water splitting has also been demonstrated. PMID- 29231219 TI - The mixing effect of organic cations on the structural, electronic and optical properties of FAxMA1-xPbI3 perovskites. AB - Organic-inorganic hybrid perovskites as new emerging functional materials stand out from numerous photovoltaic materials thanks to the unprecedentedly rapid improvement of their power conversion efficiency within a short period. To explore potentially more efficient photovoltaic candidates, the structural and electronic properties of FAxMA1-xPbI3 based on prototype MAPbI3 are investigated for superior performance. Specifically, structural relaxation is performed at the PBE+D2 level and the electronic and optical properties are investigated at the HSE + SOC level. Optical simulations show that significantly improved performance can be successfully achieved by means of the injection of FA cations. Moreover, the calculations of defect formation energies imply that MA-poor ambient conditions are energetically favorable to synthesize a variety of FA-doped pervoskite compounds FAxMA1-xPbI3 of different ratios. It is interesting to find that compared with the prototype MAPbI3, the optical performance of the perovskite series FAxMA1-xPbI3 is effectively improved with an increase in FA content; meanwhile the relative stability of the perovskite series is also efficiently enhanced. Our study not only sheds new light on further understanding perovskite absorbers but also provides the basic rationale for designing new functional materials used for photovoltaics. PMID- 29231220 TI - Plug-and-actuate on demand: multimodal individual addressability of microarray plates using modular hybrid acoustic wave technology. AB - The microarray titre plate remains a fundamental workhorse in genomic, proteomic and cellomic analyses that underpin the drug discovery process. Nevertheless, liquid handling technologies for sample dispensing, processing and transfer have not progressed significantly beyond conventional robotic micropipetting techniques, which are not only at their fundamental sample size limit, but are also prone to mechanical failure and contamination. This is because alternative technologies to date suffer from a number of constraints, mainly their limitation to carry out only a single liquid operation such as dispensing or mixing at a given time, and their inability to address individual wells, particularly at high throughput. Here, we demonstrate the possibility for true sequential or simultaneous single- and multi-well addressability in a 96-well plate using a reconfigurable modular platform from which MHz-order hybrid surface and bulk acoustic waves can be coupled to drive a variety of microfluidic modes including mixing, sample preconcentration and droplet jetting/ejection in individual or multiple wells on demand, thus constituting a highly versatile yet simple setup capable of improving the functionality of existing laboratory protocols and processes. PMID- 29231221 TI - Responsive DNA G-quadruplex micelles. AB - A novel and versatile design of DNA-lipid conjugates is presented. The assembly of the DNA headgroups into G-quadruplex structures is essential for the formation of micelles and their stability. By hybridization with a complementary oligonucleotide the micelles were destabilized, resulting in cargo release. In combination with a hairpin DNA aptamer as complementary strand, the release is obtained selectively by the presence of ATP. PMID- 29231222 TI - Facile synthesis and bridgehead-functionalization of bicyclo[3.3.3]pentasiloxanes. AB - A fascinating but still rare bicyclic siloxane, bicyclo[3.3.3]pentasiloxane, was synthesized by the oxidation of a bicyclic silicon cluster and characterized using a combination of NMR spectroscopy and X-ray diffraction analysis. The bridgehead OSiMe3 groups of the siloxane were selectively and efficiently converted to O-K+ (siloxide) by treating with tBuOK in the presence of 18-crown-6 ether. The resulting siloxides provided various bridgehead-functionalized bicyclo[3.3.3]pentasiloxanes after treatment with electrophiles. PMID- 29231223 TI - Modelling the luminescence of iridium cyclometalated complexes encapsulated in cucurbituril. AB - Iridium(iii) cyclometalated complexes in aqueous solution often display relatively weak luminescence. It has been shown in previous work that this emission can be significantly enhanced (by up to two orders of magnitude) by encapsulation in cucurbit[10]uril (Q[10]). Luminescence lifetime measurements suggest a dynamic self-quenching mechanism is active, possibly due to displacement of an excited guest complex via collision with an unbound complex. We devise a model for the association of a group of iridium(iii) cyclometalated complexes with Q[10]. The model parameters are then fitted to steady-state emission titration curves. The excellent agreement of experimental data with the model provides valuable mechanistic information relating to the way this class of metal complexes interact and associate with the Q[10] host. PMID- 29231224 TI - Controllable one-step double emulsion formation via phase inversion. AB - Double emulsions, the simplest form of multiple emulsion, have been intensively utilized in various industries as well as in fundamental research. A variety of strategies to effectively form double emulsions have been developed, but no simple yet controlled and scalable technique has been achieved yet. Herein, we examine the mechanism of the entire process of double emulsion formation by phase inversion, and we propose a universal one-step strategy for the formation of an oil/water/oil double emulsion using oil soluble polymers and hydrophobic silica nanoparticles. We demonstrate that this new approach enables control of both the fraction and the number of inner small droplets; even high internal phase double emulsions could be achieved. PMID- 29231225 TI - Unusual phonon behavior and ultra-low thermal conductance of monolayer InSe. AB - Monolayer indium selenide (InSe) possesses numerous fascinating properties, such as high electron mobility, quantum Hall effect and anomalous optical response. However, its phonon properties, thermal transport properties and the origin of its structural stability remain unexplored. Using first-principles calculations, we show that the atoms in InSe are highly polarized and such polarization causes strong long-range dipole-dipole interaction (DDI). For acoustic modes, DDI is essential for maintaining its structural stability. For optical modes, DDI causes a significant frequency shift of its out-of-phase vibrations. Surprisingly, we observed that there were two isolated frequency regimes, which were completely separated from other frequency regimes with large frequency gaps. Within each frequency regime, only a single phonon mode exists. We further reveal that InSe possesses the lowest thermal conductance among the known two-dimensional materials due to the low cut-off frequency, low phonon group velocities and the presence of large frequency gaps. These unique behaviors of monolayer InSe can enable the fabrication of novel devices, such as thermoelectric module, single mode phonon channel and phononic laser. PMID- 29231226 TI - Strong magnetic resonances and largely enhanced second-harmonic generation of colloidal MoS2 and ReS2@Au nanoantennas with assembled 2D nanosheets. AB - Colloidal disk-like and sphere-like MoS2 nanoantennas are synthesized. They consist of curly and interlaced 2D nanosheets. The resonance peak of the MoS2 nanoantennas can be tuned from 500 to 900 nm by adjusting the size and shape. The strong magnetic and electric resonances of the dielectric antennas are revealed by theoretical calculations with Mie theory. The second harmonic generation (SHG) of the exfoliated nanosheets and the synthesized nanodisks and nanospheres is investigated and compared by scanning the excitation laser wavelength. SHG enhancement of 52 fold is observed for the spherical nanoantennas at 400 nm, which is attributed to the nanoantenna-enhanced two-photon resonance excitation of the D exciton of MoS2 monolayers. Moreover, ReS2@Au plasmon-dielectric hybrid nanoantennas are also synthesized. The SHG of Au nanoparticles is enhanced 8.5 times by the coupling of the two types of nanoantennas. This new class of optical nanoantennas consisting of 2D materials and exhibiting unique linear and nonlinear optical responses will bring promising applications ranging from nonlinear photonics to photochemistry. PMID- 29231227 TI - Viscoelastic behaviour and relaxation modes of one polyamic acid organogel studied by rheometers and dynamic light scattering. AB - A novel polyamic acid (PAA from BAPMPO-BPDA) organogel was synthesized and characterized via dynamic light scattering (DLS), a classical rheometer, and diffusion wave spectroscopy (DWS). In situ monitoring was performed using a classical rheometer to observe the formation of the PAA organogel. The rheological curves confirm the formation of the PAA gel network and the origin of hydrogen bonding from the -NH- group (donor) and P[double bond, length as m dash]O group (acceptor). The autocorrelation functions of PAA under different conditions (pure gel, gel with NaNO3, gel with formamide) are measured via DLS, and different characteristic times are obtained via the CONTIN method. Three different relaxation modes of the PAA gel, i.e., fast, intermediate and slow modes, are observed. The fast and intermediate modes show a diffusive behaviour (tau ~ q-2), whereas the slow mode did not. When enough formamide is added into the PAA gel, the fast mode disappears; addition of enough salt (NaNO3) leads to disappearance of the slow mode. The relationship between characteristic time and diffusion vector demonstrates that the different decorrelation modes consisted of two homodyne and two heterodyne components. Two single-exponential functions and two stretched exponential functions were used, and the different decorrelation modes of the PAA gel are expressed with a non-linear function, which fits the autocorrelation function very well. And the different decorrelation modes are also discussed. DWS results in the high-frequency region not only demonstrate the formation of a PAA gel network but also indicate that the semiflexible chains of PAA are due to electrostatic interaction. The DWS results at different time scales are analyzed by applying the de Gennes' reptation model. PMID- 29231228 TI - Immunotherapy of AD: Alum Demain? PMID- 29231229 TI - Possible Endpoints in a Prodromal Alzheimer's Disease Trial. PMID- 29231230 TI - Results from a Phase II Study to Assess the Clinical and Immunological Activity of AFFITOPE(r) AD02 in Patients with Early Alzheimer's Disease. AB - OBJECTIVES: The primary objective of this clinical trial was to assess the clinical activity of various doses and formulations of AFFITOPE(r) AD02 following its repeated s.c. administration to patients with early Alzheimer's disease (AD), based on the evaluation of cognitive and functional domains. DESIGN: It was designed as a randomized, placebo-controlled, parallel group, double blind, multicenter phase II trial with 10 regular outpatient visits and 6 telephone interviews. SETTING: The trial was performed at 32 sites in six countries. PARTICIPANTS: A total of 332 patients were enrolled and 265 patients completed the trial in 3 treatment groups with AD02 and 2 control groups with aluminum oxihydroxide, here named IMM-AD04. Patients were randomly assigned to 5 groups: two doses of IMM-AD04, 25ug AD02 (in two different formulations) and 75ug AD02. INTERVENTION: At months 0, 1, 2, 3, 9 and 15, each patient received a single s.c. injection of the corresponding preparations of AFFITOPE(r) AD02 or the control, IMM-AD04. MEASUREMENTS: Co-primary efficacy outcomes included a measure of cognition (adapted AD Assessment Scale cognitive [aADAS cog]), and a measure of function (adapted AD Cooperative Trial Activities of Daily Living [aADCS-ADL]). A primary composite score was the sum of these two scores. RESULTS: Treatments were generally well tolerated and adverse events (AEs) were seen at similar rates across all treatment groups, with the exception that more injection site reactions were seen in the groups with a higher level of adjuvant. None of the AD02 groups showed a benefit over the IMM-AD04 controls for primary or exploratory efficacy outcomes. The control groups differed on aADCS-ADL and therefore couldn't be pooled (p=0.039). Unexpectedly, the 2mg IMM-AD04 showed statistically significant effects over the other groups on several clinical outcomes including: aADAS-cog, aADL, Composite, ADAS-cog, CDR-sb, and QOL-AD Caregiver as well as two biomarker outcomes: right and total hippocampal volume (all p<0.05). 48% of patients in the IMM-AD04 2mg group had no decline in the composite outcome over 18 months compared to 17%-31% in the other groups, which is consistent with historical placebo groups. CONCLUSION: No significant treatment effects were seen for the investigational compound AD02. However, the IMM-AD04 2mg group showed statistically significant effects over all other groups on several clinical outcomes as well as a slowing of decline on right hippocampal volume. The data support further development of IMM-AD04 as a disease modifying agent in line with EMA/FDA definitions. PMID- 29231231 TI - Tea for Alzheimer Prevention. AB - The availability of empirical data from human studies in recent years have lend credence to the old axiomatic wisdom that health benefits of tea drinking extend to the area of cognition. Specifically, there is increasing interest as to whether tea drinking can delay or even prevent the onset of Alzheimer's disease (AD). Data from several cross-sectional studies have consistently shown that tea drinking is associated with better performance on cognitive tests. This association is supported by longitudinal data from the Singapore Longitudinal Aging Study, the Chinese Longitudinal Healthy Longevity Survey and the Cardiovascular Health Study. The only two published longitudinal analyses on clinical outcome reported conflicting results: one study reported that mid-life tea drinking was not associated with risk reduction of Alzheimer's disease in late life while the other one found that green tea consumption reduced the incidence of dementia or mild cognitive impairment. Two small trials from Korea and Japan reported encouraging but preliminary results. While the existing evidence precludes a definite conclusion as to whether tea drinking can be an effective and simple lifestyle preventive measure for AD, further research involving longer-term longitudinal studies and randomized controlled trials is clearly warranted to shed light on this topic of immense public health interest. Biological markers of tea consumption and Alzheimer diseases should be employed in future research to better delineate the underlying mechanisms of tea drinking's protective effect on cognition. PMID- 29231232 TI - Cognitive Rehabilitation in Alzheimer's Disease - A Conceptual and Methodological Review. AB - Within the last 20 years, several standardized cognitive trainings have been developed aiming at the delay of cognitive decline in older people who are at risk of Alzheimer's Disease (AD) or in mild stages of dementia. The transfer of cognitive training effects into activities of daily living was very limited in most previous studies. Therefore, multimodal Cognitive Rehabilitation approaches have been designed that aim to improve the activities of daily living. These approaches also attempt to integrate the patient's psychopathological and behavioral status as well as social relationships into the treatment plan. Contrary to other approaches, CR mainly focuses on compensation rather than restoration of impaired functionality. In this review, we define CR conceptually, and derive specific criteria to evaluate current CR approaches for individuals with mild cognitive impairment (MCI) and AD dementia. In addition, we perform a critical, methodical analysis of available CR studies, reviewing their short- and long-term treatment effects. Findings suggest that CR approaches improve memory performance and competence of activity of daily living (ADL) in mildly cognitively impaired subjects (MCI), when compensatory, integrative, as well as interactive elements and domain specificity are taken into account. Interactive and individual aspects also appear to be relevant to sustain long-term effects. In AD dementia, similar results emerged, although with smaller effect sizes. The efficacy of individualized CR approaches was comparable with theory-based, manual guided concepts as long as promoting interaction was part of the treatment. So far, only few randomized controlled studies of sufficient sample size are available. Future systematic efficacy studies need to consider precisely defined outcome variables. This is necessary before one can draw conclusions of how CR can be used for secondary prevention of AD dementia as well as AD treatment. PMID- 29231233 TI - Access to hepatitis C treatment for patients in drug substitution programmes: the fight is far from over. PMID- 29231234 TI - Feasibility, acceptability and effectiveness of integrated care for COPD patients: a mixed methods evaluation of a pilot community-based programme. AB - QUESTION UNDER STUDY: The aim of this study was to assess the feasibility, acceptability and effectiveness of a pilot COPD integrated care programme implemented in Valais, Switzerland. METHODS: The programme was adapted from the self-management programme Living Well with COPD, and included the following elements: self-management patient-education group sessions, telephone and medical follow-ups, multidisciplinary teams, training of healthcare professionals, and evidence-based COPD care. A process and outcome evaluation of the pilot phase of the programme was conducted by means of qualitative and quantitative methods. Reach (coverage, participation rates), dosage (interventions carried out), fidelity (delivered as intended) and stakeholders' acceptance of the programme were evaluated through data monitoring and conduct of focus groups with patients and healthcare professionals. Effectiveness was assessed with pre-post analyses (before and after the intervention). The primary outcome measures were; (1) generic and disease-specific quality of life (36-Item Short Form Health Survey, Chronic Respiratory Questionnaire); and (2) hospitalisations (all-cause and for acute exacerbations) in the past 12 months. Secondary outcomes included self efficacy, number of exacerbations and exercise capacity. Finally, controlled pre post comparisons were also made with patients from the Swiss COPD Cohort for three common outcome measures (dyspnoea [mMRC score], number of exacerbations and smoking status). RESULTS: During the first 2 years of the programme, eight series of group-based education sessions were delivered to 57 patients with COPD in three different locations of the canton of Valais. Coverage objectives were achieved and attendance rate at the education sessions was high (83.6%). Patients' and healthcare professionals' reported a high degree of satisfaction, except for multidisciplinarity and transfer of information. Exploration of the effectiveness of this pilot programme suggested positive pre-post results at 12 months, with improvements in terms of health-related quality of life, self efficacy, exercise capacity, immunisation coverage and Patient Assessment of Chronic Illness Care score. No other outcome, including the number of hospital admissions, differed significantly after 12 months. We observed no differences from the control group. CONCLUSIONS: The evaluation demonstrated the feasibility and acceptability of the programme and confirmed the relevance of mixed method process evaluation to adjust and improve programme implementation. The introduction of multidisciplinary teams in a context characterised by fragmentation of care was identified as the main challenge in the programme implementation and could not be achieved as expected. Despite this area for improvement, patients' feedback and early effectiveness results confirmed the benefits of COPD integrated care programmes emphasising self-management education. PMID- 29231235 TI - The perioperative use of synthetic and biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. AB - Disease-modifying antirheumatic drugs (DMARDs) have become essential treatments in the management of patients with inflammatory rheumatic diseases. Their use has resulted in a marked improvement of disease control and a limitation of joint damage, although some patients still require subsequent corrective or joint replacement surgery. Due to their immunosuppressive effects, some DMARDs are associated with an increased risk of infection. The aim of this review is to discuss the available literature on the management of DMARDs during the perioperative period, particularly in the case of orthopaedic surgery. Conventional synthetic DMARDs such as methotrexate, sulfasalazine, leflunomide, hydroxychloroquine appear to be safe during the perioperative period. Conflicting results on biological DMARDs, mainly tumour necrosis factor antagonists, are reported in the literature, including both increased and unchanged risk of superimposed infections after surgery. Taking into account the available literature, we included some propositions for the management of patients who will undergo surgical interventions. PMID- 29231236 TI - Relevance of the cerebral collateral circulation in ischaemic stroke: time is brain, but collaterals set the pace. AB - Blood supply to the brain is secured by an extensive collateral circulation system, which can be divided into primary routes, i.e., the Circle of Willis, and secondary routes, e.g., collaterals from the external to the internal carotid artery and leptomeningeal collaterals. Collateral flow is the basis for acute stroke treatment, since neurones will only survive long enough to be rescued with reperfusion therapies if there is sufficient collateral flow. Poor collateral flow is associated with worse outcome and faster growth of larger infarcts in acute stroke treatment. Therapeutic promotion of collateral flow theoretically offers the chance for outcome improvement, but randomised trials are lacking. The extent of collateral flow is highly variable between individuals. As a consequence, the speeds of infarct growth are highly variable, resulting in varying individual treatment time windows until the whole salvageable tissue has become infarcted. An ideal patient selection for reperfusion therapies should be based on imaging of the salvageable tissue, the so called penumbra. The penumbra can be approximately visualised by computed tomography (CT) and magnetic resonance imaging (MRI), but both methods are significantly inaccurate in about 25% of the patients. There is a need for improved penumbra imaging by CT and MRI, and first studies applying machine learning techniques have shown promising results. PMID- 29231237 TI - Unusual cutaneous manifestation of dermatomyositis. PMID- 29231238 TI - Overexpression of S100A7 protein is an integral part of abnormal epidermal differentiation in cornoid lamella of porokeratosis. PMID- 29231240 TI - Syphilis of the pharynx. PMID- 29231239 TI - Female pattern hair loss: a pilot study investigating combination therapy with low-dose oral minoxidil and spironolactone. AB - BACKGROUND: Minoxidil and spironolactone are oral antihypertensives known to stimulate hair growth. OBJECTIVE: To report on a case series of women with pattern hair loss (PHL) treated with once daily minoxidil 0.25 mg and spironolactone 25 mg. METHODS: Women newly diagnosed with a Sinclair stage 2-5 PHL were scored for hair shedding and hair density before and after 12 months of treatment with oral minoxidil 0.25 mg and spironolactone 25 mg. RESULTS: A total of 100 women were included in this observational pilot study. Mean age was 48.44 years (range 18-80). Mean hair loss severity at baseline was Sinclair 2.79 (range 2-5). Mean hair shedding score at baseline was 4.82. Mean duration of diagnosis was 6.5 years (range 0.5-30). Mean reduction in hair loss severity score was 0.85 at 6 months and 1.3 at 12 months. Mean reduction in hair shedding score was 2.3 at 6 months and 2.6 at 12 months. Mean change in blood pressure was -4.52 mmHg systolic and -6.48 mmHg diastolic. Side effects were seen in eight women but were generally mild. No patients developed hyperkalemia or any other blood test abnormality. Six of these women continued treatment, and two women who developed urticaria discontinued treatment. LIMITATIONS: Prospective, uncontrolled, open label observational study. DISCUSSION: Once daily capsules containing minoxidil 0.25 mg and spironolactone 25 mg appear to be safe and effective in the treatment of FPHL. Placebo-controlled studies to investigate this further are warranted. PMID- 29231241 TI - Population-based incidence and melanoma-specific survival of cutaneous malignant melanoma in a Colombian population 2000-2009. AB - BACKGROUND: Demographic, clinical, and morphological characteristics of cutaneous melanoma are unknown for the Colombian population. We aim to provide these characteristics as well as population-based incidence and survival data. METHODS: All patients with an invasive cutaneous melanoma diagnosed in the period 2000 2009 registered in the population-based cancer registry of the metropolitan area of Bucaramanga were included for analysis (n = 169). Age-standardized incidence rates were calculated and melanoma-specific and overall survival estimated with follow-up until June 9, 2016, using Kaplan-Meier methodology, stratifying for gender, anatomical localization, and type of affiliation to the social security system. RESULTS: The age-standardized melanoma incidence rate was 1.7 per 100,000, with lower limbs being the most affected body sites (42.6% of all melanomas). A high proportion of melanomas presented on the plants or palms (16%) and under the nails (7.1%); at least 24.3% of melanomas were ulcerated, and 21.1% had a Breslow thickness more than 2 mm. Melanoma-specific 5-year survival was 79.3%, with worst survival for melanomas localized on the plants (64.6%) and subungual areas (55.6%). Affiliation to the subsidized type of affiliation to the social security system was statistically significantly (P = 0.003) associated with poorer survival (68.8%) compared to the special regimes (95.8%). CONCLUSIONS: Melanoma is a relatively rare cancer in Colombia with mainly the acral sites, high proportion of thick and ulcerated melanomas, and relatively poor survival being distinct features, indicating the need for tailor-made primary and secondary prevention strategies. Better training of pathologists in the difficult field of melanoma would improve precision of available data. PMID- 29231242 TI - A case of heroin linear track hyperpigmentation: histopathology and treatment with Q-switched Nd:YAG 1064nm laser. PMID- 29231243 TI - Neuromuscular electrical stimulation (NMES) for patellofemoral pain syndrome. AB - BACKGROUND: Patellofemoral pain syndrome, now generally referred to as patellofemoral pain (PFP), is one of the most common orthopaedic disorders, characterised by pain in the anterior or retropatellar knee region. Neuromuscular electrical stimulation (NMES) has been proposed generally as a complementary treatment, associated with other interventions such as exercise, or as a single treatment to increase muscle force, reduce knee pain, and improve function. OBJECTIVES: To assess the effects (benefits and harms) of neuromuscular electrical stimulation for people with patellofemoral pain. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PEDro, CINAHL, SPORTDiscus, AMED, LILACS, trial registers, conference abstracts, and reference lists. We carried out the search in May 2017. SELECTION CRITERIA: We included randomised controlled clinical trials that evaluated the use of NMES for people with PFP. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the process of study selection, data extraction, and 'Risk of bias' assessment in duplicate. The primary outcomes were knee pain, knee function, and adverse events. The timing of outcome measurements was up to three months (short term), three to 12 months (medium term), and 12 months and above from trial entry (long term). We calculated risk ratios for dichotomous data and mean differences or standardised mean differences for continuous data. Where appropriate, we pooled data using the fixed-effect model. MAIN RESULTS: We included eight randomised clinical trials, reporting results for 345 participants with PFP. The mean ages of trial populations ranged from 25 to 43 years, and the majority (53% to 100%) of participants were female. There was a wide duration of symptoms, with the minimum duration of symptoms for trial inclusion ranging from one to six months. In addition to the study inclusion criteria, studies varied widely in the characteristics of the NMES and its application, and associated co interventions. We assessed all trials as at high risk of bias in at least one domain, particularly blinding and incomplete outcome data. The results of a laboratory-based trial reporting knee pain immediately after a single 15-minute session of NMES are not reported here as these are of questionable clinical relevance. The seven remaining trials provided evidence for three comparisons. We assessed the overall quality of the evidence, using GRADE, for all primary outcomes for all comparisons as very low, thus we are very unsure of the findings.Four studies compared NMES plus exercise versus exercise alone. Patellar taping was applied as well as exercise to all participants of one study, and patellar taping and ice were also applied in another study. Each trial tested a different multiple-session NMES programme. Pooled data from three studies (118 participants) provided very low-quality evidence that NMES is associated with reduced pain at the end of treatment (ranging from 3 to 12 weeks): mean difference -1.63, 95% confidence interval (CI) -2.23 to -1.02; visual analogue scale (VAS) 0 to 10; higher scores = worse pain. However, this result may not be clinically relevant since the minimal clinically important difference for VAS during activities (1.5 to 2.0, out of 10 points) lies within the 95% CI. We found very low-quality evidence from pooled data from two trials of little effect of NMES on knee function, as measured by two knee function rating systems. We found inconclusive and very low-quality evidence from one trial (29 participants) of little effect of NMES on pain and function at one-year follow-up. None of the four trials reported on adverse effects of treatment.One study (94 participants) compared NMES, applied four hours per day on a daily basis for four weeks, with two types of exercises (isometric and isokinetic). The study did not report on knee pain or adverse events. The study provided very low-quality evidence of no important difference between the two groups in knee function at the end of the four-week treatment. Of note is the potentially onerous NMES schedule in this study, which does not correspond to that typically used in clinical practice.Two studies compared different types of NMES. Simultaneously delivered high-low frequencies NMES was compared with sequentially delivered high-low frequencies NMES in one trial (14 participants) and with fixed frequency NMES in the second trial (64 participants). The studies provided very low-quality evidence of no important differences at the end of the six-week treatment programme between the simultaneous frequencies NMES and the two other NMES programmes in overall knee pain, knee function, or in quadriceps fatigue (an adverse event). AUTHORS' CONCLUSIONS: This review found insufficient and inconclusive evidence from randomised controlled trials to inform on the role of NMES for treating people with PFP in current clinical practice. The very low-quality evidence available means that we are uncertain whether or not a multiple-session programme of NMES combined with exercise over several weeks versus exercise alone results in clinically important differences in knee pain and function at the end of the treatment period or at one year. There were no data on adverse effects such as muscle fatigue and discomfort. High-quality randomised clinical trials are needed to inform on the use of NMES for people with PFP. However, professional and stakeholder consensus is required on prioritisation of the research questions for interventions for treating people with PFP, including on the NMES treatment protocol for trials testing NMES. PMID- 29231244 TI - SIRT7 depletion inhibits cell proliferation, migration, and increases drug sensitivity by activating p38MAPK in breast cancer cells. AB - SIRT7 is a member of the sirtuin family of proteins that are known to be associated with tumor development. However, the functional roles and molecular mechanisms underlying the function of SIRT7 in breast cancer cell survival and tumor development remain unclear. Recent studies demonstrated that SIRT7 is upregulated in breast cancer cells and tissues. In the present study, we systematically explored the roles of SIRT7 in the growth of breast cancer cells and tumors both in vitro and in vivo. Our results showed that SIRT7 plays a major role in facilitating cell survival by promoting cell proliferation and inhibiting apoptosis. SIRT7 depletion significantly inhibited cell invasion and wound healing by blocking cell cycle progression and inducing cell apoptosis. Meanwhile, SIRT7 depletion can increase the sensitivity of breast cancer cells to doxorubicin (DOX). Xenograft model studies showed that stable silencing of SIRT7 inhibited tumor growth and enhanced tumor sensitivity to DOX. Further research revealed that p38MAPK is involved in SIRT7-mediated regulation of breast cancer cell proliferation and tumor growth. Taken together, our results showed that SIRT7 plays a critical role in breast cancer cell survival, migration, and tumor growth, and increased the efficiency of DOX treatment both in vitro and in vivo. Therefore, SIRT7 is a promising therapeutic target in breast cancer treatment. PMID- 29231245 TI - Two cases of human cutaneous anthrax with massive tissue damage, severe edema, and slight injury to the liver. PMID- 29231246 TI - Is Lactobacillus reuteri administration beneficial to oral candida levels? PMID- 29231247 TI - Biocatalysis in radiochemistry: Enzymatic incorporation of PET radionuclides into molecules of biomedical interest. AB - Biocatalysis is emerging as a new approach to radiolabel biologically active molecules with short half-lived positron emitters for their use in positron emission tomography. Despite the golden era of biocatalysis in radiochemistry occurred in the 70s and 80s, advances in enzyme engineering during the last decade have significantly enhanced the toolbox of enzymes available for chemical reactions, which may find application in the context of radiochemistry. In the present review, we intend to give an overview of the biocatalytic approaches that have been reported during the last 4 decades for the synthesis of PET radiotracers using nitrogen-13, carbon-11, and fluorine-18. PMID- 29231248 TI - SLURP-1 is mutated in Mal de Meleda, a potential molecular signature for melanoma and a putative squamous lineage tumor suppressor gene. AB - BACKGROUND: Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by palmoplantar keratoderma (PPK) with transgrediens and caused by mutations in the SLURP1 gene. Uncommonly, cutaneous tumors have been found at PPK sites in MDM patients. OBJECTIVE: To study a Middle Eastern family with MDM with both PPK and skin tumors. METHODS: We studied a Middle Eastern (Palestinian) family with clinical features of MDM and cutaneous tumors. Histopathological analysis was performed on biopsies from skin lesions found in the affected individuals. Direct sequencing of SLURP1 was performed in MDM affected members. In silico analysis of publicly available datasets was used to survey SLURP1 mRNA levels in normal and malignant tissues. Statistical analysis was performed in the R statistical language. RESULTS: Affected members from the Middle Eastern family displayed severe forms of PPK consistent with MDM. Histopathological analysis of the skin lesions revealed that the examined affected members exhibited skin squamous cell carcinomas (SCCs) and melanoma. Sequence analysis revealed homozygous SLURP1 mutations (c.82delT) in the affected members. Following analysis of various publicly available expression datasets, SLURP1 mRNA levels were found to be markedly elevated in tissues of epithelial lineage, relative to tissues of other lineages, and significantly suppressed in malignant tumors of epithelial lineage relative to normal or their premalignant counterparts. There was significant decrease in SLURP-1 expression in melanomas versus melanocytic nevi as well as a highly significant decrease in SLURP-1 expression in metastatic melanomas as compared to primary melanoma. CONCLUSION: Our study underscores cases of Middle Eastern MDM with SLURP1 mutations and skin malignancies at PPK sites. Our findings also highlight a plausible epithelial lineage-specific tumor suppressor role for the SLURP1 gene, as well as a role in the development and metastasis of melanoma and thus a potential molecular signature for melanoma. PMID- 29231250 TI - Synthesis of stable isotope-labeled nasturlexins and potential precursors to probe biosynthetic pathways of cruciferous phytoalexins. AB - The syntheses of perdeuterated phytoalexins nasturlexins A and C, and putative biosynthetic precursors, including phenylethyl isothiocyanates and phenylethyl dithiocarbamates, using commercially available [2,3,4,5,6-D5 ]phenylalanine, [2,3,4,5,6-D5 ]nitrobenzene, and [2,3,4,5,6-D5 ]benzaldehyde are described. In addition, application of an efficient deuterium-hydrogen exchange transformation to nonlabeled starting materials allowed access to new deuterated compounds, including 3-hydroxyphenylethyl glucosinolate. PMID- 29231249 TI - Analysis of the costs of veterinary education and factors associated with financial stress among veterinary students in Australia. AB - OBJECTIVE: To investigate the course-related and other costs involved in obtaining a veterinary education in Australia and how these costs are met. The study also aimed to identify sociodemographic and course-related factors associated with increased financial stress. METHODS: Students from seven Australian veterinary schools were surveyed using an online questionnaire. A total of 443 students participated (response rate 17%). Responses to survey items relating to finances, employment and course-related costs were compared with sociodemographic factors and prior research in the area of student financial stress. RESULTS: Respondents reported spending a median of A$300 per week on living costs and a median of A$2,000 per year on course-related expenses. Over half of respondents received the majority of their income from their parents or Youth Allowance (56%). A similar proportion (55%) reported that they needed to work to meet basic living expenses. Circumstances and sociodemographic factors linked to perceived financial stress included requiring additional finances to meet unexpected costs during the course; sourcing additional finances from external loans; an expected tuition debt at graduation over A$40,000; being 22 years or older; working more than 12 hours per week; living costs above A$300 per week; and being female. CONCLUSION: The costs involved in obtaining a veterinary education in Australia are high and over half of respondents are reliant on parental or Government income support. Respondents with certain sociodemographic profiles are more prone to financial stress. These findings may have implications for the psychological health, diversity and career plans of veterinary students in Australia. PMID- 29231252 TI - LncRNA CCAT1 contributes to the growth and invasion of gastric cancer via targeting miR-219-1. AB - Gastric cancer (GC) is one of the most malignant tumors that seriously threaten to human health. Increased reports indicated that long non-coding RNAs (lncRNAs) were associated with GC. This study aims to investigate the regulatory role of colon cancer associated transcript-1 (CCAT1) in GC. The results exhibited that CCAT1 was higher expressed in 57 GC tissue samples than in 57 paired adjacent normal tissue samples. The expression of CCAT1 was also increased in GC cell lines (MKN45, Hs746T and SGC-7901) compared with gastric epithelial cell line GES 1. Besides, decreased cell proliferation with increased cell apoptosis were detected in SGC-7902 cells transfected with CCAT1 shRNA. At the same time, lower cell invasion ability was measured in SCG-7901 cells transfected with CCAT1 shRNA. In addition, miR-219-1 was predicted and convinced a direct target of CCAT1. The expression of miR-219-1 was declined in GC tissues and GC cell lines. Further studies demonstrated that the roles of CCAT1 on cell proliferation, apoptosis and invasion were inhibited by miR-219-1. At last, the in vivo experiment indicated that tumor growth of GC was suppressed through knockdown of CCAT1. In conclusion, these results suggested that CAT1 promotes the tumorigenesis and progression of GC by negative-regulating miR-219-1. This article is protected by copyright. All rights reserved. PMID- 29231251 TI - Mechanoactivation of the angiotensin II type 1 receptor induces beta-arrestin biased signaling through Galphai coupling. AB - Ligand activation of the angiotensin II type 1 receptor (AT1R), a member of the G protein-coupled receptor (GPCR) family, stimulates intracellular signaling to mediate a variety of physiological responses. The AT1R is also known to be a mechanical sensor. When activated by mechanical stretch, the AT1R can signal via the multifunctional adaptor protein beta-arrestin, rather than through classical heterotrimeric G protein pathways. To date, the AT1R conformation induced by membrane stretch in the absence of ligand was thought to be the same as that induced by beta-arrestin-biased agonists, which selectively engage beta-arrestin thereby preventing G protein coupling. Here, we show that in contrast to the beta arrestin-biased agonists TRV120023 and TRV120026, membrane stretch uniquely promotes the coupling of the inhibitory G protein (Galphai ) to the AT1R to transduce signaling. Stretch-triggered AT1R-Galphai coupling is required for the recruitment of beta-arrestin2 and activation of downstream signaling pathways, such as EGFR transactivation and ERK phosphorylation. Our findings demonstrate additional complexity in the mechanism of receptor bias in which the recruitment of Galphai is required for allosteric mechanoactivation of the AT1R-induced beta arrestin-biased signaling. PMID- 29231253 TI - Internal venous anomalies in patients with a genital venous malformation. AB - BACKGROUND: Cutaneous venous malformation (VM) can be associated with internal vascular anomalies. Our objective was to investigate the frequency of internal vascular anomalies in patients with an isolated genital venous malformation to assess the utility of screening for internal findings. METHODS: We retrospectively reviewed our Vascular Anomalies Center database for patients with a focal genital venous malformation presenting between 1999 and 2016. Abdominal and pelvic imaging reports were reviewed for internal vascular anomalies. Endoscopy reports were also reviewed when available. RESULTS: A focal genital venous malformation was found in 22 patients (14 female, 8 male). Ten (45%) had a venous malformation of at least one internal structure, most commonly the pelvic floor (n = 6), colon (n = 5), urethra (n = 4), and/or bladder (n = 3). Eight experienced hematuria, hematochezia, and/or rectorrhagia secondary to their internal venous malformation. In patients with internal venous malformations, the mean age of symptom presentation was 7.3 years (range 1-22 years). Two patients had malformed inferior mesenteric and portal veins visible using ultrasonography and magnetic resonance imaging. They required surgical intervention to prevent thrombosis and decrease urogenital and gastrointestinal bleeding. CONCLUSION: Nearly half of our patients with a focal genital venous malformation had internal venous anomalies. Physicians should suspect urogenital or gastrointestinal venous malformations in patients with a focal genital venous malformation, especially if they develop hematuria, hematochezia, or rectorrhagia. Significant mesenteric venous trunk anomalies can also occur. Because these require surgical intervention, early recognition is important. We recommend that all patients with a focal genital venous malformation undergo abdominal and pelvic ultrasound to evaluate for internal venous anomalies. PMID- 29231254 TI - Characteristics of pediatric recurrent erythema multiforme. AB - BACKGROUND: Erythema multiforme (EM) is an acute condition characterized by distinctive target lesions of the skin often accompanied by mucosal ulcers. A subset of individuals experience frequent episodes of recurrent EM, which is rare and poorly understood, especially in children. OBJECTIVE: To characterize clinical features, laboratory findings, and treatment responses of pediatric recurrent EM. METHODS: A retrospective chart review was conducted at the Children's Hospital of Wisconsin in Milwaukee, Wisconsin (2000-2015) and the Mayo Clinic in Rochester, Minnesota (1990-2015). Inclusion criterion was a diagnosis before age 18 years with recurrent EM, defined as a symmetrically distributed, fixed eruption, including target lesions, with or without mucous membrane involvement, occurring on at least three occasions. A literature review was conducted to include individuals who met the inclusion criterion. RESULTS: Twenty six patients were included, of whom 16 (62%) were male. The median age of onset was 9.1 years (range 0-15.7 years). Nine patients (35%) required hospitalization. Herpes simplex virus testing was positive in 9 of 17 (65%) patients. Remission was achieved in 5 of 16 (31%) patients while taking suppressive antivirals. Eight patients received continuous anti-inflammatory treatment, two (25%) of whom experienced remission. CONCLUSION: This study of pediatric recurrent EM found a greater male predominance, more hospitalizations, fewer cases caused by herpes simplex virus, and a lower response to immunosuppression in children than in the general population. PMID- 29231255 TI - The structural and functional reliability of Circulins of Chassalia parvifolia for peptide therapeutic scaffolding. AB - Computational methods have refined the mode of peptide drug designing to a new plateau recently. Circulin, a 30 residue natural plant polypeptide acts as a plant defensive peptide. Additional to its antimicrobial activity it also possesses an inhibitory cytopathic effect on the replication of human immunodeficiency virus (HIV). Stable Circulin can be a functionally able template for scaffolding peptide based drugs. Hence, structural stability of Chassalia parvifolia, Circulin A (1BH4), and Circulin B (2ERI) was computationally investigated. From this analysis, the stability favored toward Circulin B which was supported by various parameters such as intra-molecular interactions (61), secondary structure, hydrophobicity (67.34%), root mean square deviation (2.64A), root mean square fluctuation (0.08A), radius of gyration (8.96A), ovality (3.49), angular deviation (73.6%), surface area (both polar and non-polar), hydrogen bond distribution (11.94), and disulphide bond distances. Further, the functional activity calculated in terms of membrane associated free energy (-4.10 kcal/mol) also favored Circulin B. Hence, Circulin B could be proposed as the best template for scaffolding antimicrobial as well as antiviral (HIV) peptide based drug design. The obtained computational data can aid experimental biologists to successfully produce stable therapeutic peptides from natural resources reducing erroneous wastage of monetary sources and time. PMID- 29231256 TI - Chemotherapy-induced eccrine squamous syringometaplasia in an infant. AB - There are few reports of chemotherapy-induced eccrine squamous syringometaplasia in children. We report the first case of an infant developing this condition after treatment with busulfan, fludarabine, and antithymocyte globulin in preparation for bone marrow transplantation. Twenty-eight days after transplantation, the infant developed faintly erythematous papules and plaques on the bilateral axillae, inguinal folds, and sites of adhesives. Punch biopsy revealed eccrine glands with dyskeratotic cells and focal squamous metaplasia consistent with chemotherapy-induced eccrine squamous syringometaplasia. PMID- 29231257 TI - Halofuginone-induced autophagy suppresses the migration and invasion of MCF-7 cells via regulation of STMN1 and p53. AB - Traditional Chinese medicines have been recognized as especially promising anticancer agents in modern anticancer research. Halofuginone (HF), an analog of quinazolinone alkaloid extracted from Dichroa febrifuga, is widely used in traditional medicine. However, whether HF inhibits the growth of breast cancer cells and/or reduces the migration and invasion of MCF-7 human breast cancer cells, as well as the underlying mechanisms in vitro, remains unclear. In this study, we report that an HF extract inhibits the growth of MCF-7 cells and reduces their migration and invasion, an important feature of potential anticancer agents. In addition, HF significantly increases the activation of autophagy, which is closely associated with tumor metastasis. As STMN1 and p53 have been closely implicated in breast cancer progression, we analyzed their expression in the context of HF extract treatment. Western blot analysis showed that HF suppresses STMN1 and p53 expression and activity in an autophagy dependent manner. Collectively, these data indicate that activation of autophagy reduces expression of STMN1 and p53, and the migration and invasion of cancer cells contributes to the anti-cancer effects of the HF. These findings may provide new insight into breast cancer prevention and therapy. PMID- 29231258 TI - Retrospective review of immunocompromised children undergoing skin biopsy for suspected invasive infection: Analysis of factors predictive of invasive mold. AB - OBJECTIVES: Cutaneous lesions are often the first marker of invasive mold infection, which can cause substantial morbidity in immunocompromised children. The purpose of this study was to describe the evaluation and outcomes of immunocompromised children who presented with findings requiring skin biopsy because of concern about invasive infection. In children who were biopsied, we sought to determine the factors predictive of invasive mold infection. METHODS: A retrospective review was conducted at the Children's Hospital of Philadelphia. Patients included in the study were immunocompromised individuals younger than 26 years old who underwent skin biopsy by the inpatient dermatology consultation team between January 1, 2003, and March 15, 2015, because of development of new cutaneous lesions that were suspected of being invasive infection. RESULTS: One hundred five encounters met the inclusion criteria. Fifty (47.6%) biopsied individuals had an infectious pathogen identified on histopathology or culture. Mold was the most common (36%) pathogen, followed by bacteria (32%) and yeast (26%). The presence of a single lesion (P = .001) and prior occlusion at the site of the lesion (P < .001) were associated with mold on biopsy. The combination of a single lesion, history of occlusion, and tissue necrosis on examination was highly predictive for invasive mold infection (86.3% [95% confidence interval 55.1-97.0%]). Of the 18 individuals with confirmed invasive mold infection, 13 (72%) underwent surgical resection, of whom 12 (92%) survived the 30-day follow up period. CONCLUSION: Skin biopsy enabled the detection of a pathogen that informed directed therapeutic interventions in nearly half of participants. Institutions caring for immunocompromised children should ensure adequate staffing of clinical personnel approved to perform skin biopsies. PMID- 29231260 TI - Metformin inhibits tumorigenesis in HBV-induced hepatocellular carcinoma by suppressing HULC overexpression caused by HBX. AB - We aimed to understand whether metformin imposes the inhibitory effect on the HBV associated tumorigenesis by regulating the HULC and its downstream signaling pathway. Luciferase assay, RT-PCR, and Western-blot, MTT and flow cytometry analysis were performed to understand and the mechanism, by which metformin enhance the inhibitory effect on the HBV-associated tumorigenesis by regulating the HULC and its downstream signaling pathway. HBX promoted viability of three types of cell lines, while metformin inhibited apoptosis of above two cells. ZEB1 was a direct downstream of miR-200a, which was further confirmed that miR-200a reduced luciferase activity of wild-type but not mutant ZEB1 3'UTR, and HULC was bound to region of miR-200a-3p using alignment prediction, but can't affect ZEB1 level. HULC transcription ability, HULC, ZEB1, and p18 levels were much higher in cell treated with HBX, while notably lower in cell treated with metformin, furthermore miR-200a level in cell showed an opposite trend as HULC, ZEB1, and p18 levels. HULC siRNA and miR-200a had no effect on HULC transcription ability, but decreased HULC, ZEB1, and p18 levels, and increased miR-200a expression. HBV (+) HCC +metformin exhibited a higher survival ratio and a lower recurrence rates than HBV (+) HCC group, HBV (-) HCC displayed an even higher survival ratio and an even lower recurrence rates than HBV (+) HCC + metformin groups. This study indicated that metformin imposed inhibitory effect on the HBV-associated HCC by negatively regulating the HULC/p18/miR-200a/ZEB1 signaling pathway. PMID- 29231259 TI - Pernio as the presenting sign of blast crisis in acute lymphoblastic leukemia. AB - A previously healthy 5-year-old girl presented with acute onset of blue toes and red spots on the nose and fingers. The striking nature of these lesions, along with the finding of submandibular lymphadenopathy, prompted further evaluation. Laboratory findings were remarkable for anemia, high transaminase levels, and high blast count. Histopathologic findings were consistent with early pernio. Further examination revealed acute B-cell lymphoblastic leukemia. Treatment of the leukemia led to resolution of the pernio. PMID- 29231261 TI - LncRNA AWPPH inhibits SMAD4 via EZH2 to regulate bladder cancer progression. AB - This study aimed to investigate the effect and underlying mechanism of lncRNA AWPPH in bladder cancer (BC). A total of 20 Ta-T1 stage BC tissues, 20 T2-T4 stage BC tissues, and 20 normal bladder tissues, as well as human bladder epithelial cell line SV-HUC-1, human BC cell lines RT4, and T24 were obtained to detect the levels of AWPPH, enhancer of zeste homolog 2 (EZH2) and SMAD4 using RT qPCR or Western blotting. RT4 cells were transfected with pc-AWPPH, pc-EZH2, or pc-control and T24 cells were transfected with si-AWPPH, si-EZH2, si-control, or pc-AWPPH + pc-SMAD4, respectively. Then, cell proliferation, apoptosis, autophagy, and migration, were detected using MTT assay, colony formation assay, Annexin V-FITC/PI method, Western blotting, and Transwell analysis, respectively. The relationship of AWPPH and EZH2 or SMAD4 was evaluated by RNA immunoprecipitation (RIP) assay or Chromatin immunoprecipitation (ChIP) assay. Compared with normal bladder tissues or cells, the levels of AWPPH and EZH2 were overexpressed, while SMAD4 was down-regulated in BC tissues or cells (all P < 0.01). Cell viability, colony number, and migration were significantly increased, while cell apoptosis ratio was reduced in cells with pc-AWPPH compared with cells with pc-control (all P < 0.05), meanwhile, these effects were reversed by the treatment of pc-SMAD4. Then, RIP assay revealed that AWPPH could bind to EZH2 and ChIP assay showed SMAD4 was regulated by EZH2. LncRNA AWPPH can promote cell proliferation, autophagy, and migration, as well as inhibit cell apoptosis in BC by inhibiting SMAD4 via EZH2. PMID- 29231262 TI - miR-24-3p promotes cell migration and proliferation in lung cancer by targeting SOX7. AB - Lung cancer (LC) is one of the leading causes of cancer-related death in the world. miR-24-3p plays critical roles in many cancer types, including LC. In this study, we first investigated whether miR-24-3p promoted LC cell migration and proliferation in vitro. We used three bioinformatics algorithms to predict the miR-24-3p target gene to study the molecular mechanism by which miR-24-3p contributes to LC progression. Then, we used the luciferase reporter assay to identify whether SOX7 was a direct target of miR-24-3p. Moreover, Western blotting and a quantitative real time-polymerase chain reaction analysis showed that miR-24-3p downregulated SOX7 protein expression by a post-transcriptional mechanism. Finally, we determined that SOX7 had opposing effects to those of miR 24-3p on LC cell proliferation and migration, suggesting that miR-24-3p promotes cell proliferation and migration by directly targeting SOX7. Furthermore, miR-24 3p accelerated tumor growth in xenograft mice by targeting SOX7. These results provide the first clue that miR-24-3p could play a role as an oncomiR in LC by regulating SOX7. PMID- 29231263 TI - A prospective controlled trial comparing xenograft/autogenous bone and collagen stabilized xenograft for maxillary sinus augmentation-Complications, patient reported outcomes and volumetric analysis. AB - OBJECTIVE: Compare maxillary sinus augmentation (MSA) using two different materials-anorganic bovine bone mineral (ABBM) + autogenous bone (AB) (control group) vs. collagen-stabilized ABBM (test group) in terms of complications, patient-reported outcome measures (PROMs) and volumetric analysis. MATERIALS AND METHODS: Sixty patients underwent sinus augmentation (30 control + 30 test group). Intra- and postoperative complications were recorded. PROMs measured the impact of grafting on daily activities, pain and morbidity. CT scans were used to measure graft volume, ridge height, material selection and degree of contact of graft-to-surrounding sinus walls. Dental implant placement parameters were also recorded. RESULTS: All complications were minor and did not prevent completion of the augmentation or subsequent implant placement. Schneiderian membrane perforation was the most frequently encountered complication. Both treatment groups reported moderate limitation in the 1st 48 hr post-surgery but little or none by day 3 or 4. Jaw opening, chewing and bruising were significantly higher in the control group. The impact on work and social life was moderate initially but reduced to little or none by the 2nd day. Mild to moderate pain and interference to daily activities were reported for the first 3 days requiring the use of NSAIDs only. A mean graft volume of 1.46 cm3 (+/-0.77) was calculated in the control group and 1.27 cm3 (+/-0.65) in the test group. Extent of contact between graft and surrounding sinus walls had a significant impact on bone volume. Shorter (8 mm) implants were utilized more frequently in the test group, which was also more likely to require additional vertical augmentation, but this was not statistically significant. CONCLUSION: MSA using a lateral wall approach is safe and associated with mild to moderate pain and restrictions to daily activities for 48-72 hr. Patients' reports of morbidity were greater with autogenous bone harvesting. Collagen-stabilized ABBM provides comparable bone volume to AB + ABBM that is sufficient for placement of implants of adequate size with no need for further vertical augmentation. Engaging the surrounding sinus walls had a significant positive impact on graft volume. PMID- 29231264 TI - Abnormally adherent and invasive placenta: a spectrum disorder in need of a name. PMID- 29231265 TI - Kirmse-Doyle- and Stevens-Type Rearrangements of Glutarate-Derived Oxonium Ylides. AB - A novel chemoenzymatic synthetic cascade enables the preparation of densely decorated tetrahydrofuran building blocks. Here, the lipase-catalyzed desymmetrization of 3-alkoxyglutarates renders highly enantioenriched carboxylic acid intermediates, whose subsequent activation and oxonium ylide rearrangement by means of rhodium or copper complexes furnishes functionalized O-heterocycles with excellent diastereoselectivity. The two-step protocol offers a streamlined and flexible synthesis of tetrahydrofuranones bearing different benzylic, allylic or allenylic side chains with full control over multiple stereogenic centers. PMID- 29231266 TI - A case of keratosis circumscripta in a Chinese boy. AB - Keratosis circumscripta is a rare dermatosis occurring in children and adolescents that has been reported in the English literature only in Africans and their descendants. We report here a case of keratosis circumscripta in a 13-year old Chinese boy who presented with pruritic follicular keratotic rashes below both knees. This case indicates that keratosis circumscripta may not occur only in individuals of African descent. PMID- 29231267 TI - Contribution of the two dsRBM motifs to the double-stranded RNA binding and protein interactions of PACT. AB - PACT is a stress-modulated activator of protein kinase PKR (protein kinase, RNA activated), which is involved in antiviral innate immune responses and stress induced apoptosis. Stress-induced phosphorylation of PACT is essential for PACT's increased association with PKR leading to PKR activation, phosphorylation of translation initiation factor eIF2alpha, inhibition of protein synthesis, and apoptosis. PACT-induced PKR activation is negatively regulated by TRBP (transactivation response element RNA-binding protein), which dissociates from PACT after PACT phosphorylation in response to stress signals. The conserved double-stranded RNA binding motifs (dsRBMs) in PKR, PACT, and TRBP mediate protein-protein interactions, and the stress-dependent phosphorylation of PACT changes the relative strengths of PKR-PACT, PACT-TRBP, and PACT-PACT interactions to bring about a timely and transient PKR activation. This regulates the general kinetics as well as level of eIF2alpha phosphorylation, thereby influencing the cellular response to stress either as recovery and survival or elimination by apoptosis. In the present study, we evaluated the effect of specific mutations within PACT's two evolutionarily conserved dsRBMs on dsRNA-binding, and protein protein interactions between PKR, PACT, and TRBP. Our data show that the two motifs contribute to varying extents in dsRNA binding, and protein interactions. These findings indicate that although the dsRBM motifs have high sequence conservation, their functional contribution in the context of the whole proteins needs to be determined by mutational analysis. Furthermore, using a PACT mutant that is deficient in PACT-PACT interaction but competent for PACT-PKR interaction, we demonstrate that PACT-PACT interaction is essential for efficient PKR activation. PMID- 29231269 TI - Lichen planus pigmentosus inversus in children: Case report and updated review of the literature. AB - Lichen planus pigmentosus inversus (LPPI) is a rare variant of lichen planus characterized by slate grey to dark black-brown macules, papules, or patches occurring in the skin folds. We present a case of LPPI in an 11-year-old girl, the second-youngest case and only the third pediatric case. This article also reviews the differential diagnosis and treatment of LPPI. PMID- 29231268 TI - Circadian rhythm in atopic dermatitis-Pathophysiology and implications for chronotherapy. AB - Circadian rhythm is a biological clock that controls a wide range of physiological functions throughout the body, including various skin functions. A 24-h diurnal cycle, governed by an endogenous clock in the brain, largely controls cutaneous diurnal rhythm, which external factors, including temperature, humidity, diet, and stress, also modulate locally. Circadian rhythm influences cutaneous blood flow and properties of skin barrier function, such as transepidermal water loss and capacitance, and has important implications in atopic dermatitis (AD). This review explores how aberrations in circadian rhythm may play a role in the pathogenesis of AD and proposes implementation of chronotherapy to improve treatment outcomes in patients with AD. PMID- 29231270 TI - Profiling and characterization of microRNAs responding to sodium butyrate treatment in A549 cells. AB - Butyrate inhibits growth of lung cancer. However, the molecular mechanism is still unclear. Here we profiled miRNAs that responded to sodium butyrate(NaB) stimulation in A549 cells, a non-small cell lung cancer cell line, using microarray. We found 33 up-regulated microRNAs and 22 down-regulated microRNAs (log2 >=1.5 folds, P-value <0.05). The expression of miR-3935, miR-574-3p, and miR-494-3p was confirmed by realtime qPCR. Then,we explored their potential targets of miR-3935 and miR-494-3p using long noncoding RNA(LncRNA) microarray. Using cell expressing negative microRNA as control, we found 103 up-regulated transcripts (including 69 mRNA and 34 LncRNA), and 36 down-regulated transcripts (including 34 mRNAs and 2 LncRNA), in miR-3935 over-expressing A549 cells; 128 up regulated transcripts (121 mRNAs, 7 LncRNAs) and 180 down-regulated transcripts (169 mRNAs, 11 LncRNAs) in mir-494-3p, respectively (log2 Fold change >= 1 & P < 0.05). The expression of RNF115, NTRK3, SLC39A6, and USB1 was confirmed with qPCR. Immunoblotting was adopted to detect RNF115 expression in miR-3935 overexpressed A549 cells. Then, using a luciferase reporter assay system, we found that miR-3935 overexpression significantly decreased 3UTR of RNF115 mediated luciferase expression .In addition, we also observed that the proliferation and migration of A549 cells was obviously prevented by miR-3935 overexpression. Finally, we showed miR-3935 and miR-494-3p induced interferon stimulated gene 15(ISG15) expression through activating its promoter transcription. Together, we profiled microRNAs that responded to NaB treatment and characterized their biological functions in A549 cells. Those results provided new clue for the future treatment of non small cell lung cancer. PMID- 29231271 TI - A Precisely Assembled Carbon Source to Synthesize Fluorescent Carbon Quantum Dots for Sensing Probes and Bioimaging Agents. AB - A broad range of carbon sources have been used to fabricate varieties of carbon quantum dots (CQDs). However, the majority of these studies concern the influence of primary structures and chemical compositions of precursors on the CQDs; it is still unclear whether or not the superstructures of carbon sources have effects on the physiochemical properties of the synthetic CQDs. In this work, the concept of molecular assembly is first introduced into the design of a new carbon source. Compared with the tropocollagen molecules, the hierarchically assembled collagen scaffolds, as a new carbon source, immobilize functional groups of the precursors through hydrogen bonds, electrostatic attraction, and hydrophobic forces. Moreover, the accumulation of functional groups in collagen self-assembly further promotes the covalent bond formation in the obtained CQDs through a hydrothermal process. Both of these two chemical superiorities give rise to high quality CQDs with enhanced emission. The assembled collagen scaffold-based CQDs with heteroatom doping exhibit superior stability, and could be further applied as effective fluorescent probes for Fe3+ detection and cellular cytosol imaging. These findings open a wealth of possibilities to explore more nanocarbons from precursors with assembled superstructures. PMID- 29231272 TI - Impact of fear of falling and fall history on disability incidence among older adults: Prospective cohort study. AB - OBJECTIVE: Fear of falling (FOF) is a major health problem for older adults, present not just in fallers, but also nonfallers. This study examined the impact of FOF and fall history on disability incidence among community-dwelling older adults from a prospective cohort study. METHODS: A total of 5104 older adults living in community settings participated in baseline assessment and were followed up for about 4 years (median 52 mo, range 49-55 mo). At baseline, participants were assessed the presence of FOF and their fall history, and divided into 4 groups: Fall (-) FOF (-), Fall (+) FOF (-), Fall (-) FOF (+), and Fall (+) FOF (+). Disability incidence was defined as national long-term care insurance certification for personal support or care. RESULTS: During the follow up period, 429 participants (9.9%) were newly certified as having a disability and needing personal support for long-term care insurance. Fall (-) FOF (+) group and Fall (+) FOF (+) group showed a significantly higher risk of disability incidence than Fall (-) FOF (-) group even after adjusting for covariates (Fall ( ) FOF (+): hazard ratio 1.28, 95% confidence interval, 1.01-1.62, Fall (+) FOF (+): hazard ratio 1.44, 95% confidence interval, 1.05-1.98). CONCLUSIONS: Fear of falling could be a simple and useful predictor of disability incidence in community-dwelling older adults. Identifying and decreasing fall risk factors may prevent fall-related injuries, but excessive FOF may be associated with increased risk of disability incidence. PMID- 29231273 TI - The added value of inclusive research. AB - BACKGROUND: The study asks when does inclusive research add value? The authors argue that this is important, given the additional time and cost of co researching with people with intellectual disabilities. The study is situated in debates about a "second generation" of inclusive research which advocates focussing more on outcomes than process. The authors argue that this is premature, rather the authors propose that inclusive research is valuable when it helps to recognize, foster, and above all communicate the contributions people with intellectual disabilities can make. METHOD: The authors conducted a literature review of 52 peer-reviewed journal articles about inclusive research and analysed them.. RESULTS: The authors conclude that inclusive research adds value when there is a distinctive contribution which only co-researchers with intellectual disabilities can make, when it highlights the contributions people with intellectual disabilities make, and when it contributes to better lives for the wider population of people with intellectual disabilities. CONCLUSIONS: The authors propose a revised definition of inclusive research to replace that published by Walmsley and Johnson in 2003. PMID- 29231274 TI - Chiral Bifunctional Phosphine-Carboxylate Ligands for Palladium(0)-Catalyzed Enantioselective C-H Arylation. AB - Previous enantioselective Pd0 -catalyzed C-H activation reactions proceeding via the concerted metalation-deprotonation mechanism employed either a chiral ancillary ligand, a chiral base, or a bimolecular mixture thereof. This study describes the development of new chiral bifunctional ligands based on a binaphthyl scaffold which incorporates both a phosphine and a carboxylic acid moiety. The optimal ligand provided high yields and enantioselectivities for a desymmetrizing C(sp2 )-H arylation leading to 5,6-dihydrophenanthridines, whereas the corresponding monofunctional ligands showed low enantioselectivities. The bifunctional system proved applicable to a range of substituted dihydrophenanthridines, and allowed the parallel kinetic resolution of racemic substrates. PMID- 29231275 TI - Effects of limit-feeding diets with different forage-to-concentrate ratios on nutrient intake, rumination, ruminal fermentation, digestibility, blood parameters and growth in Holstein heifers. AB - The objective of this study was using a wide range of dietary concentrate levels to investigate the major effects of limit-feeding on heifers. Twenty-four Holstein heifers were blocked into six groups and fed with one of four diets containing different levels of concentrate (20%, 40%, 60% and 80% on a dry matter (DM) basis) but with same intakes of metabolizable energy for 28 days. Increasing levels of dietary concentrate caused decreased (P <= 0.02) intakes of dry matter (DMI) and neutral detergent fiber and total rumination time, but increased (P < 0.01) nonfiberous carbohydrates intake, ruminal concentrations of NH3 -N, propionate and butyrate, and digestibility of DM and crude protein. Dietary concentrate levels had no significant effect on most plasma concentrations and body measurements. The corrected average daily gain (CADG) and feed efficency (ADG/DMI, CFE) were linearly increased (P < 0.01) with increasing dietary concentrate levels when gut fill impact was removed. In conclusion, heifers limit fed high concentrate diets increased most ruminal fermentation parameters, CADG and CFE with similar body growth and blood metabolites as heifers fed low concentrate diets, and had the potential to be used as an effective feeding strategy in dairy heifers. PMID- 29231276 TI - Self-Assemblies of Zinc Bacteriochlorophyll-d Analogues Having Amide, Ester, and Urea Groups as Substituents at 17-Position and Observation of Lamellar Supramolecular Nanostructures. AB - Chlorosomes are unique light-harvesting apparatuses in photosynthetic green bacteria. Single chlorosomes contain a large number of bacteriochlorophyll (BChl) c, -d, -e, and -f molecules, which self-assemble without protein assistance. These BChl self-assemblies involving specific intermolecular interactions (Mg???O32 -H???O=C131 and pi-pi stacks of chlorin skeletons) in a chlorosome have been reported to be round-shaped rods (or tubes) with diameters of 5 or 10 nm, or lamellae with a layer spacing of approximately 2 nm. Herein, the self-assembly of synthetic zinc BChl-d analogues having ester, amide, and urea groups in the 17 substituent is reported. Spectroscopic analyses indicate that the zinc BChl-d analogues self-assemble in a nonpolar organic solvent in a similar manner to natural chlorosomal BChls with additional assistance by hydrogen-bonding of secondary amide (or urea) groups (CON-H???O=CNH). Microscopic analyses of the supramolecules of a zinc BChl-d analogue bearing amide and urea groups show round or square-shaped rods with widths of about 65 nm. Cryogenic TEM shows a lamellar arrangement of the zinc chlorin with a layer spacing of 1.5 nm inside the rod. Similar thick rods are also visible in the micrographs of self-assemblies of zinc BChl-d analogues with one or two secondary amide moieties in the 17-substituent. PMID- 29231277 TI - Do individuals with intellectual disability have a lower peak heart rate and maximal oxygen uptake? AB - BACKGROUND: Individuals with intellectual disability (ID) have very low physical activity and low peak oxygen uptake (VO2peak ), potentially explained by physiologically lower peak heart rates (HRpeak ). METHOD: The present authors performed a retrospective analysis of a large data set of individuals with intellectual disability (n = 100), with Down syndrome (DS) (n = 48) and without intellectual disability (n = 224) using multiple linear regression analyses, to determine if individuals with intellectual disability exhibit lower HRpeak and VO2peak than individuals without intellectual disability, controlling for age, sex and body mass index (BMI). RESULTS: Individuals with intellectual disability on average have significantly lower HRpeak and VO2peak than individuals without intellectual disability, even when controlling VO2peak for the lower HRpeak . CONCLUSIONS: This study suggests potential physiological differences in individuals with intellectual disability and warrants further investigation to determine their relevance to physical activity promotion and exercise testing in individuals with intellectual disability. PMID- 29231278 TI - Are obesity and rheumatoid arthritis interrelated? AB - OBJECTIVES: In recent years, both the prevalence of obesity and the incidence of RA have been rising. Our aim was to assess the association between overweight or obesity and rheumatoid arthritis (RA). DESIGN: Patients who were diagnosed with RA were compared with population-based controls, matched for age and sex (by a ratio of 1:5). Body measurements and smoking status were collected from medical records. Body mass index was classified in WHO categories of underweight, normal, overweight and obese (<18.5, 18.5-<25, 25-<30, >=30 kg/m2 ). chi2 and t-tests and logistic regression models were used to compare the study groups and to assess the association between obesity and RA. SETTING: A cross-sectional analysis performed utilizing the database of Clalit Health Services, the largest healthcare provider organisation in Israel. Data were collected from the beginning of computerised database usage (around year 2000) until 2015. PARTICIPANTS: CHS covers over 4.4 million enrollees, of which all RA patients and matched controls were selected. MAIN OUTCOME MEASURES: Proportion of obesity (BMI>=30.0 kg/m2 ) among RA patients and controls. RESULTS: The study included 11 406 patients with RA and 54 701 controls. The proportion of obese subjects among RA patients was higher in comparison with controls, (33.4% vs 31.6%, respectively). In multivariate regression model, smoking and obesity were found to be associated with RA, whereas male gender was found as inversely related to RA. CONCLUSIONS: Our findings demonstrate that obesity is significantly associated with RA. This finding underlines the role that obesity plays in inflammation and autoimmune conditions. PMID- 29231279 TI - Copper sulphate forms in piglet diets: Microbiota, intestinal morphology and enteric nervous system glial cells. AB - The objective of this study was to evaluate dietary supplementation with different copper sulphate (CuSO4 ) forms on small intestine microanatomy and large intestine microbiota. Ninety weaned piglets were divided into three experimental groups: control diet (CTR), with no added CuSO4 and diets supplemented with 150 ppm of CuSO4 in protected (150P) and unprotected form (150UP). After 18 days of dietary treatment, six piglets per treatment were randomly selected and sacrificed. Duodenum villi length and crypt depths were higher (P < 0.001) in the animals fed 150UP than other groups. Glial fibrillary acidic protein (GFAP), a marker for enteric glial cells, was unaffected by dietary treatments. The total bacteria and Enterobacteriaceae bacteria counts were lower (P < 0.05) in cecum of animals fed 150P in comparison with the other two groups. In the colon the Streptococci spp were lower (P < 0.001) in both CuSO4 supplemented groups than controls. The obtained results revealed a modulation of intestinal structure and microbiota exerted by the studied CuSO4 dietary supplementation. The present data show that dietary supplementation with 150UP in the first period post-weaning may assist in restoring the gut morphology, improving duodenal structure. PMID- 29231280 TI - Modeling of a C-end rule peptide adsorbed onto gold nanoparticles. AB - The RPAR peptide, a prototype C-end Rule (CendR) sequence that binds to neuropilin-1 (NRP-1), has potential therapeutic uses as internalization trigger in anticancer nanodevices. Recently, the functionalization of gold nanoparticles with CendR peptides has been proved to be a successful strategy to target the NRP 1 receptor in prostate cancer cells. In this work, we investigate the influence of two gold surface facets, (100) and (111), on the conformational preferences of RPAR using molecular dynamics simulations. Both clustering and conformational analyses revealed that the peptide backbone becomes very rigid upon adsorption onto gold, which is a very fast and favored process, the only flexibility being attributed to the side chains of the two Arg residues. Thus, the different components of RPAR tend to adopt an elongated shape, which is characterized by the pseudo-extended conformation of both the backbone and the Arg side chains. This conformation is very different from the already known bioactive conformation, indicating that RPAR is drastically affected by the substrate. Interestingly, the preferred conformations of the peptide adsorbed onto gold facets are not stabilized by salt bridges and/or specific intramolecular hydrogen bonds, which represent an important difference with respect to the conformations found in other environments (e.g. the peptide in solution and interacting with NRP-1 receptor). However, the conformational changes induced by the substrate are not detrimental for the use of gold nanoparticles as appropriate vehicles for the transport and targeted delivery of the RPAR. Thus, once their high affinity for the NRP-1 receptor induces the targeted delivery of the elongated peptide molecules from the gold nanoparticles, the lack of intramolecular interactions facilitates their evolution towards the bioactive conformation, increasing the therapeutic efficacy of the peptide. PMID- 29231281 TI - Novel 3D Neuron Regeneration Scaffolds Based on Synthetic Polypeptide Containing Neuron Cue. AB - Neural tissue engineering has become a potential technology to restore the functionality of damaged neural tissue with the hope to cure the patients with neural disorder and to improve their quality of life. This paper reports the design and synthesis of polypeptides containing neuron stimulate, glutamic acid, for the fabrication of biomimetic 3D scaffold in neural tissue engineering application. The polypeptides are synthesized by efficient chemical reactions. Monomer gamma-benzyl glutamate-N-carboxyanhydride undergoes ring-opening polymerization to form poly(gamma-benzyl-l-glutamate), then hydrolyzes into poly(gamma-benzyl-l-glutamate)-r-poly(glutamic acid) random copolymer. The glutamic acid amount is controlled by hydrolysis time. The obtained polymer molecular weight is in the range of 200 kDa for good quality of fibers. The fibrous 3D scaffolds of polypeptides are fabricated using electrospinning techniques. The scaffolds are biodegradable and biocompatible. The biocompatibility and length of neurite growth are improved with increasing amount of glutamic acid in scaffold. The 3D scaffold fabricated from aligned fibers can guide anisotropic growth of neurite along the fiber and into 3D domain. Furthermore, the length of neurite outgrowth is longer for scaffold made from aligned fibers as compared with that of isotropic fibers. This new polypeptide has potential for the application in the tissue engineering for neural regeneration. PMID- 29231282 TI - New Insight into the Synthesis and Biological Activity of the Polymeric Materials Consisting of Folic Acid and beta-Cyclodextrin. AB - This work presents a very new look at folate targeting and is focused on synthesizing and assessing the biological activity of folic acid-targeted drug delivery materials based on beta-cyclodextrin. Both folic acid and beta cyclodextrin have been covalently conjugated to branched polyethylenimine as the polymeric vector. Host-guest inclusion of folic acid into a beta-cyclodextrin cavity, demonstrated by means of the spectroscopic methods (2-D NMR, IR, UV-Vis), is found to be of crucial importance for biological activity of nanotherapeutics. This paper describes the very first example of the versatile synthetic approach to create the polymeric biosystems, where folic acid activity is not limited by the inclusion phenomenon. Cytotoxicity of the obtained polymeric materials against Lewis lung carcinoma cells is determined by neutral red uptake assay. Folate receptor-binding studies reveal that the developed synthetic approach enables full exploitation of the potential of folic acid as a targeting ligand. PMID- 29231283 TI - Potent Inhibitors against Newcastle Disease Virus Hemagglutinin-Neuraminidase. AB - Neuraminidase activity is essential for the infection and propagation of paramyxoviruses, including human parainfluenza viruses (hPIVs) and the Newcastle disease virus (NDV). Thus, many inhibitors have been developed based on the 2 deoxy-2,3-didehydro-d-N-acetylneuraminic acid inhibitor (DANA) backbone. Along this line, herein we report a series of neuraminidase inhibitors, having C4 (p toluenesulfonamido and azido substituents) and C5 (N-perfluorinated chains) modifications to the DANA backbone, resulting in compounds with 5- to 15-fold greater potency than the currently most active compound, the N-trifluoroacetyl derivative of DANA (FANA), toward the NDV hemagglutinin-neuraminidase (NDV-HN). Remarkably, these inhibitors were found to be essentially inactive against the human sialidase NEU3, which is present on the outer layer of the cell membrane and is highly affected by the current NDV inhibitor FANA. PMID- 29231285 TI - Co-research with adults with intellectual disability: A systematic review. AB - BACKGROUND: Co-research with people with intellectual disability is a distinct form of patient and public involvement (PPI). This systematic review summarize published studies and protocols to report on the process of co-research in social and healthcare research. METHOD: Relevant studies were identified using electronic searches on ASSIA, PsycInfo and MedLine. Study quality was assessed, and information relevant to the process of working with co-researchers was extracted and thematically analysed. RESULTS: Thirteen studies were retrieved. Data are reported under three themes: (i) challenges of co-research; (ii) facilitators of co-research; (iii) benefits of co-research. Best practice is presented as a model of co-research. Content analysis on 12 research protocols identified four themes related to PPI. CONCLUSIONS: All stakeholders involved in co-research with people with intellectual disability can benefit, providing there is adequate infrastructure to accommodate and empower the co-researchers. Many current intellectual disability research projects still lack systematic involvement of PPI members. PMID- 29231284 TI - The science behind skin care: Cleansers. AB - Two of the most important skin care categories with profound dermatologic implications are cleansers and moisturizers. Cleansers are composed of alkaline soaps or the less barrier-damaging synthetic detergents, known as syndets. The lower skin irritation and dryness found with syndets are related to their reduced tendency to cause protein denaturation due to the charge density of protein-bound micelle-like surfactant aggregates. Many cleansing formulations are available for purchase to meet hygiene needs varying by sex, age, ethnicity, occupation, environment, personal preferences, and the presence or absence of skin disease. This discussion covers the science of skin cleansing. PMID- 29231286 TI - Equally Well. Physical health and mental illness. PMID- 29231287 TI - Using secondments in tertiary health facilities to build paediatric expertise in allied health professionals working in rural New South Wales. AB - OUTLINE OF PROBLEM: Allied health professionals working in rural settings have broad caseloads requiring advanced skills as general specialists. This can include children with specialised needs. DESIGN: Educational secondments were coordinated for allied health professionals to achieve self-nominated learning objectives. Learning objectives were assessed using pre and post evaluations to determine the effect of the educational secondment on knowledge and confidence specific to the nominated learning outcomes. SETTING: Educational secondments were undertaken by allied health professionals from New South Wales Health facilities in regional or rural locations outside of the Sydney metropolitan area. The educational secondments occurred in tertiary-level hospitals or specialist health facilities. KEY MEASURES FOR IMPROVEMENT: Using self-reported questionnaires, allied health secondees' outcomes were assessed prior to the secondment, immediately following and again at 6 months post-secondment, and their managers at 6 months post-secondment. The program aimed to improve the allied health professional's knowledge and confidence around self-selected learning objectives related to the specialised care of children with complex health needs in rural settings. STRATEGIES FOR CHANGE: Allied health professionals reported increased knowledge and confidence immediately following the secondment which was sustained at 6 months. On the basis of this outcome, the secondment program will continue. EFFECTS OF CHANGE: The secondment program resulted in changes to the ongoing clinical practice of participating clinicians as well as other health professionals within the departments where they worked. LESSONS LEARNT: Educational secondments can improve the knowledge and skills of allied health professionals working in rural and remote locations with a view to improving access to equitable health care for children living in rural settings. PMID- 29231288 TI - Affordable, acceptable and appropriate access. PMID- 29231289 TI - A "Cell-Friendly" Window for the Interaction of Cells with Hyaluronic Acid/Poly-l Lysine Multilayers. AB - Polyelectrolyte multilayers assembled from hyaluronic acid (HA) and poly-l-lysine (PLL) are most widely studied showing excellent reservoir characteristics to host molecules of diverse nature; however, thick (HA/PLL)n films are often found cell repellent. By a systematic study of the adhesion and proliferation of various cells as a function of bilayer number "n" a correlation with the mechanical and chemical properties of films is developed. The following cell lines have been studied: mouse 3T3 and L929 fibroblasts, human foreskin primary fibroblasts VH Fib, human embryonic kidney HEK-293, human bone cell line U-2-OS, Chinese hamster ovary CHO-K and mouse embryonic stem cells. All cells adhere and spread well in a narrow "cell-friendly" window identify in the range of n = 12-15. At n < 12, the film is inhomogeneous and at n > 15, the film is cell repellent for all cell lines. Cellular adhesion correlates with the mechanical properties of the films showing that softer films at higher "n" number exhibiting a significant decrease of the Young's modulus below 100 kPa are weakly adherent to cells. This trend cannot be reversed even by coating a strong cell-adhesive protein fibronectin onto the film. This indicates that mechanical cues plays a major role for cell behavior, also in respect to biochemical ones. PMID- 29231291 TI - [Training residents in emergency medicine in Spain]. PMID- 29231290 TI - Cardiovascular magnetic resonance imaging and clinical performance of somatostatin receptor positron emission tomography in cardiac sarcoidosis. AB - AIMS: Cardiac affection constitutes a major limiting condition in systemic sarcoidosis. The primary objective of this study was to investigate the persistence rate of cardiac sarcoid involvement by cardiovascular magnetic resonance (CMR) imaging in patients diagnosed with cardiac sarcoidosis (CS). Moreover, we examined the additional insights into myocardial damage's characteristics gained by somatostatin receptor scintigraphy. METHODS AND RESULTS: In a pilot study, we had previously identified cardiac involvement diagnosed by CMR imaging-to be present in 29 of 188 patients (15.4%) with histologically proven, extra-CS. Out of these initial 29 CS-positive patients, 27 patients (49.9 +/- 11.8 years, 59.3% male) were presently re-examined and underwent a second CMR study and complementary standard clinical testing. Somatostatin receptor scintigraphy using the ligand 68 Ga-DOTATOC was additionally performed when clinically indicated (17 patients). Within a median follow-up period of 2.6 years, none of the initial 29 patients deceased or experienced aborted sudden cardiac death. However, two patients developed third degree atrioventricular block that required device therapy. Among the 27 re examined CS patients, pathological CMR findings persisted in 14 of 27 patients (51.9%). CS remission was primarily due to a resolution of acute inflammatory processes. 68 Ga-DOTATOC positron emission tomography/computed tomography (PET/CT) identified one patient with regions of raised tracer uptake that concorded with acute inflammatory changes, as assessed by CMR; this patient received no immunosuppressive medication at the time of PET/CT execution. CONCLUSIONS: Within follow-up, CS persisted in barely half the patients, and the patients were not afflicted with cardiac death. Additional 68 Ga-DOTATOC PET/CT allowed for visualization of acute myocardial inflammation. PMID- 29231293 TI - [Electroacupuncture for severe acute pancreatitis accompanied with paralytic ileus:a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy differences between electroacupuncture (EA) and regular treatment for severe acute pancreatitis accompanied with paralytic ileus. METHODS: This was a prospective pragmatic randomized controlled trial. A total of 140 cases of severe acute pancreatitis accompanied with paralytic ileus were randomly assigned into an EA group and a regular treatment group, 70 cases in each one. The patients in the regular treatment group were treated with regular treatment, including intensive care, gastrointestinal decompression, fasting, blood capacity supplement, acid suppression treatment, internal environment maintenance, infection prevention, inhibition of pancreatic exocrine secretion, etc. Based on the regular treatment, patients in the EA group were treated with EA at Zusanli (ST 36) and Zhigou (TE 6), 30 min for each treatment, once a day for totally 5 days. The VAS-based abdominal distension severity scale and abdominal pain severity scale were compared before and during treatment in the two groups, moreover, the number of patients who transferred to surgery or ICU was compared. RESULTS: (1) After the 1st EA, the abdominal pain and distension severity scales were both improved in the EA group, which were superior to those of the regular treatment group (all P<0.05); afterwards, the abdominal distension and pain severity scales of each day in the EA group were all significantly superior to those of the regular treatment group (all P<0.05). (2) The number of patients who transferred to surgery or ICU was not significantly different between the two groups (P>0.05). CONCLUSIONS: EA at Zusanli (ST 36) and Zhigou (TE 6) can significantly reduce the abdominal distension and pain severity scales in patients of severe acute pancreatitis accompanied with paralytic ileus, indicating positive clinical significance; in addition, EA is safe and can be recommended to the treatment of severe acute pancreatitis in combination with treatment plan of integrated Chinese and western medicine. PMID- 29231292 TI - [Comparative study on the effects between manual acupuncture and electroacupuncture for hemiplegia after acute ischemic stroke]. AB - OBJECTIVE: To compare the efficacy differences between manual acupuncture (MA) and electroacupuncture (EA) in the treatment of hemiplegia after acute ischemic stroke. METHODS: Sixty-eight patients of hemiplegia after acute ischemic stroke were randomized into a MA group (34 cases) and an EA group (34 cases). The routine western medication and bilateral Dingnieqianxiexian (MS 6) were adopted in the two groups. The needles were retained for 30 min. In the MA group, the even-needling technique was used for 3 times during the needle retaining, 1 min each time. In the EA group, on the basis of manual stimulation, EA therapy was added, with disperse-dense wave, 5 Hz/20 Hz. The treatment was given once every day, 6 treatments a week, totally for 2 weeks. US National Institutes of Health stroke scale (NIHSS) score, the simplified Fugl-Meyer motor function (FMA) score and Barthel index (BI) were observed before and after treatment in the two groups. The clinical efficacy was compared between the two groups. RESULTS: NIHSS score was reduced apparently after treatment in the two groups (both P<0.01). The score in the EA group was lower than that in the MA group (P<0.05). After treatment, FMA score and BI score were all increased apparently in the two groups (all P<0.01) and the scores in the EA group were higher than those in the MA group (both P<0.01). The total effective rate was 94.1% (32/34) in the EA group and was 85.3% (29/34) in the MA group. The efficacy in the EA group was better than that in the MA group (P<0.05). CONCLUSIONS: EA acts on the rehabilitative effect on nerve defect function in the patients of hemiplegia after acute ischemic stroke. It improves limb motor function and the ability ofdaily life activity. The efficacy is better than that of MA. PMID- 29231294 TI - [Acupressure combined with press needles for prevention of gastroscopy-induced nausea and vomiting]. AB - OBJECTIVE: To explore the clinical effects of acupressure at Neiguan (PC 6) combined with press needles for prevention of gastroscopy-induced nausea and vomiting. METHODS: One hundred and twenty patients who were scheduled to gastroscopy for the first time were randomly assigned into an acupressure group and a combined treatment group, 60 cases in each one.The patients in the two groups were treated with acupressure at Neiguan (PC 6) 15 min before gastroscopy; moreover, the patients in the combined treatment group were additionally treated with press needles at Neiguan (PC 6) until the end of gastroscopy. The time of gastroscopy-induced nausea and vomiting, VAS-based nausea and vomiting scale and the state-trait anxiety inventory were compared between the two groups. RESULTS: The time of gastroscopy-induced nausea and vomiting in the combined treatment group was lower than that in the acupressure group (P<0.05); the score of VAS based nausea and vomiting scale in the combined treatment group was lower than that in the acupressure group (P<0.05); the state-trait anxiety inventory was not significantly different between the two groups, before and after gastroscopy (all P>0.05). CONCLUSIONS: Acupressure at Neiguan (PC 6) combined with press needles can relieve gastroscopy-induced nausea and vomiting without increasing anxiety. PMID- 29231295 TI - [Impacts of electroacupucnture at Zusanli (ST 36) and Feishu (BL 13) on the postoperative inflammatory reaction and pulmonary complications in senile patients after radical resection of pulmonary carcinoma]. AB - OBJECTIVE: To observe the impacts of electroacupuncture (EA) at Zusanli (ST 36) and Feishu (BL 13) applied 30 min before the operation till the end of the operation on the postoperative inflammatory reaction and pulmonary complications in the senile patients after radical resection of pulmonary carcinoma. METHODS: Eighty senile patients of pulmonary carcinoma were selected and randomized into an observation group and a control group, 40 cases in each one. In the observation group, EA stimulation at Zusanli (ST 36) and Feishu (BL 13) was used 30 min before the operation till the end of the operation. In the control group, electric stimulation was not used. Separately, before operation (T1, basic state), 12 h after operation (T2) and 24 h after operation (T3), blood sample was collected from the central vein. The concentrations of plasma tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) were detected. Additionally, the radial arterial blood sample was collected at the above time points; oxygen partial pressure (PaO2) was determined; pulmonary alveoli-arterial partial pressure of oxygen (PA-aDO2) and oxygenation index (OI) were calculated. The pulmonary complication in the two days after operation was recorded. RESULTS: Compared with the control group, in the observation group, at T2 and T3, TNF alpha concentration and PA-aDO2 were lower (all P<0.05); plasma IL-10 concentration and OI were higher (all P<0.05). In the observation group, the incidences of postoperative pneumonia and acute pulmonary injury were lower than those in the control group (both P<0.05). CONCLUSIONS: EA reduces the postoperative inflammatory reaction in the senile patients with radical resection of pulmonary carcinoma and decreases the postoperative pulmonary complicattizen. PMID- 29231296 TI - [Penetration moxibustion with different dosage for insomnia of insufficiency of heart and spleen type]. AB - OBJECTIVE: To observe the clinical efficacy differences between acupuncture combined with 40-min penetration moxibustion and 60-min penetration moxibustion at back-shu points for insomnia of insufficiency of heart and spleen type. METHODS: Sixty patients of insomnia with insufficiency of heart and spleen type were randomly assigned into a 40-min group and a 60-min group. The two groups were treated with acupuncture at Jueyinshu (BL 14), Xinshu (BL 15), Geshu (BL 17), Pishu (BL 20), Shendao (GV 11) and Zhiyang (GV 9). With moxibustion box, the penetration moxibustion was applied at the back until sweating and redness on the back. The moxibustion was given for 40 min in the 40-min group and 60 min in the 60-min group. The treatment was given once a day, five days per week. Each session was consisted of 5 treatments, with an interval of 2 days between session and totally 4 consecutive weeks were provided. The Pittsburgh sleep quality index (PSQI), TCM symptom scale were observed and recorded before and after treatment in the two groups. The even temperature at raising period, effective period, reducing period, as well as minimum high temperature, comfortable temperature, minimum cold temperature and medication status were compared; also the effect was compared between the two groups. RESULTS: The total effective rate was 96.6% (28/29) in the 60-min group, which was higher than 89.3% (25/28) in the 40-min group (P<0.05). Compared before treatment, the total score of PSQI and sleep quality, sleep time, sleep efficiency, sleep disorder, daytime dysfunction as well as the total TCM symptom score and its drowsiress in the morning, palpitation, amnesia, appetite were reduced after treatment in the 40-min group (all P<0.05). After treatment, the total score and each score of PSQI as well as total score and each score of TCM symptom scale were reduced after treatment in the 60-min group (all P<0.05). After treatment, the total score and each score of PSQI as well as total score and each score of TCM symptom scale were significantly different between the two groups (all P<0.05). CONCLUSIONS: Acupuncture combined with penetration moxibustion can improve the symptomsof insomnia with insufficiency of heart and spleen type, which is more significant in the 60-min group, indicating prolonged time of penetration moxibustion can improve sleep latency. PMID- 29231297 TI - [Clinical efficacy of warm needling therapy on cervical spondylosis of neck type based on the theory of "treatment both for the neck and lumbus"]. AB - OBJECTIVE: To compare the difference in the short-term and long-term efficacy on cervical spondylosis of neck type between warm needling therapy in the regions of both neck and lumbus and that only in the region of neck. METHODS: Eighty-one patients of cervical spondylosis of neck type were randomized into group A (41 cases) and group B (40 cases), in which 2 cases dropped out. Finally, 40 cases in the group A and 39 cases in the group B accomplished the trial. In the group A, the warm needling therapy was applied to the acupoints in the region of neck and the lumbus. Fengchi (GB 20), Tianzhu (BL 10), Neck-Bailao (EX-HN 15), Wangu (GB 12), Tianyou (TE 16) and ashi (including the tender points and code-like masses on palpation) were selected in the region of neck. Dachangshu (BL 25), Qihaishu (BL 24) and Jiaji (EX-B 2) of L5 were selected in the region of lumbus. The warm needling was applied to Fengchi (GB 20), Tianzhu (BL 10), Dachangshu (BL 25). In the group B, the warm needling therapy was applied only to the acupoints in the neck, which were same as the group A. The treatment was given once every two days, three times a week in the two groups. Separately, before treatment, 1 week after treatment, at the end of 2-week treatment and at the end of 1 month follow up, the score of neck pain questionnaire (NPQ), the score of range of motion (ROM) in the cervical region and the score of the cervical symptoms were recorded. The efficacy at the end of treatment and in the follow-up was evaluated. RESULTS: Compared with those before treatment, the scores at all the observation time points were significantly improved in the two groups after treatment (all P<0.05). In the follow-up, NPQ score, ROM score and the score of cervicalsymptoms were different significantly between the two groups (all P<0.05). The results in the group A were better than those in the group B. At the end of 2-week treatment, the total effective rate was 92.5% (37/40) in the group A and was 87.2% (34/39) in the group B (P>0.05). In the follow-up, the total effective rate was 87.5% (35/40) in the group A, better than 64.1% (25/39) in the group B (P<0.05). CONCLUSIONS: The treatment for both neck and lumbar regions with warm needling therapy and the treatment in the local area all achieve the short-term efficacy on cervical spondylosis of neck type. For the long-term efficacy, the treatment for both neck and lumbar regions achieves the better result as compared with the routine treatment in the region of neck. PMID- 29231298 TI - [Clinical observation of cervical spondylosis of neck type with wind-cold-damp treated with four-hand-needling therapy]. AB - OBJECTIVE: To compare the clinical efficacy between the four-hand-needling therapy and the routine needling therapy at neck-Jiaji (EX-B 2) in the treatment of cervical spondylosis of neck type. METHODS: Eighty patients of cervical spondylosis of neck type were randomized into an observation group and a control group, 40 cases in each one. In the observation group, Sanjian (LI 3), Wailaogong (EX-UE 8), Zhongzhu (TE 3) and Houxi (SI 3) on the affected side were selected. In the control group, the neck-Jiaji (EX-B 2) on bilateral C4, C5 and C6 were selected. The treatment was given once every two days. The score of visual analogue scale (VAS) was observed before treatment, right after the first treatment, in a half of one month of treatment and in one month of treatment separately and the clinical efficacy was observed after 1-month treatment in the two groups. RESULTS: After treatment, VAS score was reduced as compared with that before treatment in the two groups (all P<0.05). The immediate VAS score after treatment in the observation group was reduced much more apparently as compared with that in the control group (P<0.01). The curative rate was 52.5% (21/40) in the observation group and was 32.5% (13/40) in the control group and the total effective rates were 95.0% (38/40) and 82.5% (33/40) respectively. The efficacy in the observation group was better than that in the control group (both P<0.05). CONCLUSIONS: The four-hand-needling therapy and routine acupuncture at neck-Jiaji (EX-B 2) all have the very good efficacy on cervical spondylosis of neck type with wind-cold-damp. The immediate efficacy of the four-hand-needling therapy is much more significant. PMID- 29231299 TI - [Acupuncture assisted by dynamic moxibustion for adult ankylosing spondylitis at early-to-mid stage]. AB - OBJECTIVE: To observe the clinical efficacy differences between acupuncture combined with dynamic moxibustion and acupuncture alone for adult ankylosing spondylitis (AS) at early-to-mid stage based on medication. METHODS: Fifty-five cases of adult AS were randomly divided into an acupuncture-moxibustion group (28 cases) and an acupuncture group (27 cases). The two groups were treated with oral administration of sulfasalazine tablets. In addition, the acupuncture-moxibustion group was treated with acupuncture at Jiaji (EX-B 2), Shenshu (BL 23), Dachangshu (BL 25), Weizhong (BL 40) as well as dynamic moxibustion at the first line of bladder meridian of foot-taiyang and governor vessel from Dazhui (GV 14) to Yaoshu (GV 2). The acupuncture group was treated with acupuncture, the acupoints and manipulation of which were identical to acupuncture-moxibustion group. The treatment was given once a day, five days per week; one session was consisted of one-month treatment, and totally three sessions were given. The bath ankylosing spondylitis functional index (BAFI) and bath ankylosing spondylitis disease activity index (BASDAI) were compared before and after treatment in the two groups; also the clinical effective rates were compared between the two groups. RESULTS: The total effective rate was 96.4% (27/28) in the acupuncture moxibustion group, which was superior to 88.9% (24/27) in the acupuncture group (P<0.05). Compared before treatment, the BASFI and BASDAI were reduced after treatment in the two groups (all P<0.05), which were more significant in the acupuncture-moxibustion group (both P<0.05). CONCLUSIONS: Based on medication, acupuncture combined with dynamic moxibustion could improve the clinical symptoms of AS, which is superior to simple acupuncture. PMID- 29231300 TI - [Flying needling therapy combined with clomiphene for ovulation failure in polycystic ovary syndrome:a randomized controlled trial]. AB - OBJECTIVE: To compare the efficacy among the combined treatment of flying needling therapy and clomiphene, the simple application of flying needling therapy and simple clomiphene in the treatment of ovulation failure in polycystic ovary syndrome (PCOS). METHODS: Ninety patients of PCOS were randomized into a flying needling therapy group, a medication group and a combined treatment group, 30 cases in each one. In the flying needling therapy group, the flying needling therapy was simply applied to Ganshu (BL 18), Shenshu (BL 23), Zhongwan (CV 12), Shuifen (CV 9), Guanyuan (CV 4) and Zhongji (CV 3). The unilateral back-shu points were used alternatively in each treatment. The needles were inserted rapidly with rotation technique and even-needling manipulation. The needles were retained for 30 min. The treatment was given once every two days, 3 times a week. In the medication group, clomiphene was taken orally on the 5th day of menstruation, continuously for 5 days. In the combined treatment group, the flying needling therapy and clomiphene were used in combination. All of the patients were treated for 3 months and followed up for 1 month. The ovulation rates were compared among the three groups. The levels of androgen testosterone were compared before and after treatment. RESULTS: In the combined treatment group, the ovulation rate was 86.2% (100/116), better than 66.7% (80/120) in the flying needling therapy group and 69.6% (78/112) in the medication group (both P<0.05). The efficacy was similar between the fly needling therapy group and the medication group (P>0.05). After treatment, the level of testosterone was reduced in the three groups (all P<0.05). In the combined treatment group, the improvement in androgen level was better than those in the flying needling therapy group and the medication group (both P<0.05). The efficacy was similar between the flying needling therapy group and the medication group (P>0.05). The adverse reactions in the combined treatment group and the flying needling therapy group were lower than those in the medication group (both P<0.05). CONCLUSIONS: The flying needling therapy effectively improves in the ovulation failure of PCOS and its effect is similar to clomiphene. The allied treatment of them apparently improves the clinical efficacy and alleviates the adverse reactions. PMID- 29231301 TI - [Adverse reactions of acupoint embedding and its treatment]. AB - In this paper the adverse reactions of acupoint embedding and its treatment are summarized, including fever, infection, callosity, blood stasis, red swelling, numb swelling, pain, fester, ulcer, etc. It is consi-dered that adverse reactions are induced by the inappropriate operation, special constitution and embedding material. Thus we need to pay attention to standard manipulation, the contraindication, and cautious usage. Symptomatic treatment needs to be implemented timely once adverse reactions occur. PMID- 29231302 TI - [Feasibility and safety assessment of fossa infratemporalis approach for blind needle at sphenopalatine ganglion]. AB - OBJECTIVE: To identify the feasibility and safety of fossa infratemporalis approach for blind-needle at sphenopalatine ganglion so as to provide anatomical evidence for the operation and the prevention of non-immediate adverse reaction. METHODS: The variations of pterygopalatine fossae in sixty dry skulls were observed by selecting measuring points for facial skull width. The brains of six wet skulls were taken out,then acupuncture of fossa infratemporalis approach was applied. Sphenopalatine ganglion was separated accurately with the pterygopalatine segment of maxillary arteria retained in the pterygopalatine fossa after its paries posterior was opened. We detected whether the needle was inserted into pterygopalatine fossa. Measurements showed needle inserted depth, facial skull width,the distance between the needle and sphenopalatine ganglion,the distance between the needle and the pterygopalatine segment of maxillary arteria,the distance between the pterygopalatine segment of maxillary arteria and the crotaphitic nerve in pterygopalatine fossa. RESULTS: The distance between the slight hollow under bilateral arcus superciliaris was selected as skull width, and 3 dry skulls showed the variation of pterygopalatine fossa. Needles were inserted into the pterygopalatine fossae of the wet skulls (12 times). The proportion of the inserting depth to the distance between the slight hollow under bilateral arcus superciliaris was 44%-54%. Only twice did the needle contact sphenopalatine ganglion. The average distances between the sphenopalatine ganglion and the needle were (5.88+/-3.70) mm in the left side and (6.43+/-5.54) mm in the right side. The average distances between the needle and the pterygopalatine segment of maxillary arteria were (2.77+/-3.99) mm left and (2.53+/-3.10) mm right. The average distances between the pterygopalatine segment of maxillary arteria and the crotaphitic nerve in pterygopalatine fossa were (2.83+/-4.05) mm left and (2.67+/-4.95) mm right. The mean data between the two sides had no statistic significance about all the above indices (all P>0.05). CONCLUSIONS: Fossa infratemporalis approach is feasible for blind-needle at sphenopalatine ganglion with less possibility to contact it. The effect of treating nasitis may achieved by little distance to nerve. Pricking at the pterygopalatine segment of maxillary arteria may induce non-immediate adverse reaction. The safety and efficacy should be comprehensively considered. There is a proportional relationship between the width of the skull and the insertion depth of the needle. The inserting depth of 44 percent may appropriate accounted for skull width. PMID- 29231303 TI - [Motion acupuncture for therapeutic target]. AB - Motion acupuncture (MA) refers to a special acupuncture technique where a patient carries out body motions under supervision of doctors with needles inserted and retained in the points. The motions include active movement, allocinesis and load exercise. The technique of MA involves three major procedures,namely target examination (finding target), acupuncture techniques (motion allowed after acupuncture) and motion methods (needle-retaining motion), which are described in detail in this article. The target can be found by examining along meridians, along sinews, along muscles and along fascia. The targets are examined with the techniques of pressing along the points, sliding and pressing, smoothly pushing, grasping, and poking. Common acupuncture needles are used for MA. The needling methods include floating insertion, perpendicular insertion, oblique insertion, single insertion, and multi-insertion. The motions involve the flexion and extension, stretching, and resistance of the affected muscle(s). MA is mainly applied for the treatment of pain and various soft tissue injuries as well as relevant visceral disorders, which shows clinical efficacy. PMID- 29231304 TI - [Impacts on thepregnancy outcome in the mice of controlled ovarian hyperstimulation treated with acupuncture at different time points]. AB - OBJECTIVE: To explore the optimal time of acupuncture intervention in the assisted reproduction. METHODS: One hundred and twenty female mice and 60 male mice were collected. 20 female mice were selected in the natural period group and the rest 100 female mice were prepared as the model of controlled ovarian hyperstimulation (COH). The model mice were randomized into a COH group, a down regulation group, a gonadotropins (Gn) start group, an injection of human chorionic gonadotropin (HCG) group and an embryo culture group, 20 mice in each one. The donor mice and receptor mice were subdivided in each group, 10 mice in each subgroup. One week before the experiment, vas deferens ligature was done in 30 male mice and the other 30 male mice did not receive ligature. In the down regulation group, the Gn start group, the HCG injection group and the embryo culture group, electroacupuncture (EA) was applied to "Guanyuan" (CV 4), "Zhongji" (CV 3) and "Sanyinjiao" (SP 6) at the time points accordingly. EA stimulation was in the condition of continuous wave, 2 Hz and 1 mA. No inter vention was given in the natural period group and the COH group. On the day of HCG injection, the donor mice and the non-ligatured male mice were put in the same cage of each group. The fertilized ovum was collected with the date of fertilization marked and was fostered in the incubator. At the ratio of 1:1, the receptor mice and ligatured mice were put in the same cage in each group. The vaginal plug was examined in the next morning. The pseudopregnancy was marked with the date of plug observed. In the 68th hour of embryo culture, the embryo of the donor was shifted to the receptor on the same day when the plug was observed. The clinical pregnancy rate and embryo imbed site number were observed. RT-PCR assay was adopted to determine the expression of insulin-like growth factor-1 (IGF-1) mRNA in endometrium. RESULTS: In the COH group, the pregnancy rate, average imbed site number and endometrial IGF-1 mRNA expression were all significantly lower than those in the natural period group (all P<0.01). After EA treatment, in the Gn group, the HCG injection group and the embryo culture group, the pregnancy rates were higher significantly than those in the COH group (P<0.05, P<0.01). In the HCG injection group, the average imbed site number and IGF-1 mRNA expression were increased apparently as compared with those in the COH group (both P<0.01), better than those in the Gn group and the embryo culture group (all P<0.01). CONCLUSIONS: In the treatment with acupuncture combined with IVF-ET for infertility, the intervention of acupuncture on the day of HCG injection is the optimal time point. It increases the secretion of endometrial IGF-1 so as to improve the clinical pregnancy rate, the mean imbed site number and the embryo implantation. PMID- 29231305 TI - [Preventive and therapeutic effects of TEAS on rabbits with orthodontic toothache]. AB - OBJECTIVE: To explore the action mechanisms of transcutaneous electrical acupoint stimulation (TEAS) on prevention and treatment of orthodontic toothache. METHODS: Twenty-four male New Zealand rabbits were randomly divided into a blank group, an orthodontic group and a TEAS group, 8 rabbits in each one. The orthodontic model of rabbit was made in orthodontic group and TEAS group by bonding brackets and fixing NI-TI screw with ligature wire. After model establishment, the TEAS group was treated with TEAS at ashi points (skin surface corresponding points to the bilateral upper 1st molars) and "Hegu" (LI 4) with dilatational wave, 20 min per treatment, twice a day, totally 2-day consecutive treatment (4 treatments) was provided. The rabbit general behavior, total food intake and threshold of pain were observed; the contents of serum prostaglandin E2 (PGE2), granulocyte macrophage colony stimulating factor (GM-CSF) as well as endorphin (beta-EP) fluid and cholecystokinin-8 (CCK-8) in cerebrospinal fluid (CSF) were detected. RESULTS: Compared with the orthodontic group, the rabbit general behavior, total food intake and threshold of pain in the TEAS group were significantly improved (P<0.05, P<0.01). The serum PGE2 were significantly reduced (P<0.05), while GM CSF presented reducing trend without statistical significance (P>0.05). The beta EP in the CSF were increased (P<0.05), while CCK-8 in CSF presented reducing trend without statistical significance (P>0.05). CONCLUSIONS: The preventive and therapeutic effects of TEAS on rabbits with orthodontic toothache are achieved by reducing algogenic substance PGE2 in peripheral nervous system selectively, increasing beta-EP in CSF in central nervous system and keeping the level of anti opioid pain maintaining substance CCK-8.Both the central and peripheral nervous systems participate in the analgesic effect of TEAS. PMID- 29231306 TI - [Application of blistering cupping]. AB - Blistering cupping is special as eliminating wind and dampness as well as removing phlegm and blood stasis, and it achieves effects through suction. In this paper we reviewed relevant literature combined with clinical experience so as to summarize its operation attention through exploring the origin, mechanism and application. We divide the progress into the blistering period, the phlegm stasis-eliminating period, and the escharosis period according to the changes of bubble and the things pulled out. Blistering cupping creates ways to eliminate concrete unhealthy influences through smoothing meridians and collaterals, such as phlegm and retained fluid, dampness and blood stasis. Thus chronic diseases are relieved. Also,we propose the rules of "blistering acupoints being related to disease location as well as the nature of acupoints and diseases". The therapy has been used to treat diseases of respiratory system, osteoarticular, skin and subcutaneous tissue, mental and behavioral disorders, and tumor, among which the effects of intractable diseases of respiratory and osteoarticular systems are definite. It deserves to be further explored and promoted. PMID- 29231307 TI - [Construction of the study platform for Meridians and Acupoints and the application in the flipped classroom]. AB - OBJECTIVE: To construct the study platform for meridians and acupoints by analyzing the status and current problems of teaching Meridians and Acupoints and in accordance with the principles as "knowledge fragmentation, game breakthrough and overall assessment" and observe the application effect in the flipped classroom. METHODS: Totally two hundred and five 2014 grade bachelor candidates from four classes of the department of acupuncture-moxibustion and tuina were selected from Hunan Junior College of TCM. They were randomized into an observation group (102 cases) and a control group (103 cases). in the observation group, the flipped classroom was performed by adopting the study platform of meridians and acupoints. Additionally, the team cooperation learning and overall assessment were conducted. In the control group, the traditional teaching system was adopted, in which, the mode of "teacher's demonstration-to-discussion in group-to-teachers' assessment" and the operation check at the end of the semester were applied. The learning effect and the self-learning ability were evaluated at the end of semester in the two groups. The satisfaction survey was conducted in the observation group. RESULTS: In the observation group, the drawing of meridian running course and locating the acupoints, as well as the self-learning ability were better than those in the control group, indicating the significant differences (all P<0.05). The interests in platform, interaction, contribution to knowledge learning and the improvement of the self-learning ability were much more obvious and the satisfaction was quite high, accounting for over 90%. The acceptance to the flipped classroom and the satisfaction of participation were slightly low. CONCLUSIONS: The study platform of learning Meridians and Acupoints was applied in the flipped classroom and has effectively improved the practical manipulation results and self-learning ability. However, the interestingness and interactivity of the platform are expected to be improved. The effective teaching design should be adopted in the flipped classroom to improve the students' desire of participation. PMID- 29231308 TI - [Impacts of collaborative teaching method on the teaching achievement of Acupuncture and Moxibustion]. AB - OBJECTIVE: To explore the impacts of collaborative teaching method on the teaching achievement of Acupuncture and Moxibustion. METHODS: Six classes in Hunan University of CM of 2012 grade Chinese medicine department were randomized into an observation group and a control group, 3 classes in each one. In the observation group, the collaborative teaching method was adopted, in which, different teaching modes were used according to the characteristics of each chapter and the study initiative of students was predominated. In the control group, the traditional teaching method was used, in which, the class teaching was the primary and the practice was the secondary in the section of techniques of acupuncture and moxibustion. The results of each curriculum and the total results were compared between the two groups during the whole semester. RESULTS: Compared with the control group, in the observation group, the total achievements of curriculum and case analysis combined with the total result of the theory examination were apparently improved (both P<0.01). CONCLUSIONS: The collaborative teaching method improves the comprehensive ability of students and provides a new approach to the teaching of Acupuncture and Moxibustion. PMID- 29231309 TI - [Survey and analysis of application of Anhui indigenous and special acupuncture moxibustion techniques]. AB - Based on the survey on Anhui indigenous medicine and the protection for the traditional Chinese medicine knowledge, we made an analysis and summary for the survey result of Anhui indigenous and special acupuncture techniques in terms of area distribution, types, diseases of treatment, etc. The result shows that though acupuncture and moxibustion are widely applied for all kinds of diseases in most areas of Anhui grassroots regions, they mainly concentrat in major cities like Hefei, Wuhu, Anqing, etc. The techniques are mainly used in orthopedics department and neurology department. They have weighted too much on needling skills, but moxibustion and other special techniques are not paid attention to. We propose that special acupuncture-moxibustion techniques should be promoted, and the relevant training for grassroots medical workers should be developed so as to further enhance their ability to serve grassroots people as well as inherit and innovate the techniques. PMID- 29231310 TI - [Characteristics and reasons of the great importance to the techniques in the teaching materials of acupuncture and moxibustion in the Republic of China]. AB - There are the obvious differences in the framework and structure between the teaching materials of acupuncture and moxibustion in the Republic of China and the traditional works, in which, the importance to the techniques is very clear. 1Attaching the great importance to the manipulation elements of acupuncture moxibustion techniques:explaining clearly the preparation and the storage of the device of acupuncture and moxibustion, as well as the manipulation procedures and methods. 2Attaching the great importance to the localization of acupoint and decreasing the consideration to the theory of meridians and collaterals. 3Connecting the principles of acupuncture and moxibustion with the operation procedures and emphasizing the scientific evidences. The changes mentioned above originate from the following profound social and historical factors. 1Influences from the western culture and advanced science and technology, in which, pursuit of scientific and practical value is the mainstream in the time of Republic of China. 2Attaching the great importance to the specific characteristics of acupuncture and moxibustion and the training to the technical personnel, by which, the medical scholars of acupuncture and moxibustion in the Republic of China could enable the science of acupuncture and moxibustion to be survived and then developed in adverse situation. 3The scientific elaboration of the principle of acupuncture and moxibustion is a kind of academic adjustment on the influence of western learning. PMID- 29231311 TI - [Point application in literature of Dunhuang stone chamber and its application]. AB - Acupuncture-moxibustion material found in Dunhuang stone chamber shows academic value on research of acupuncture-moxibustion in Tang Dynasty and before. In the paper we summarize its medical prescriptions and the existing acupoint application contents. It is considered that its acupoint application is widely clinically used in dermatological department, cosmetology department, ophthalmology and otorhinolaryngology departments, paediatrics department, gynaecology department, anorectal department, orthopedics and traumatology department. It achieves remarkable effects in dermatological department, orthopedics and traumatology department. Medical literature of Dunhuang is a treasure of TCM with distinctive feature and it deserves to be further explored so as to serve the clinic and promote the inheritance and development of Dunhuang medicine, such as finding out high effect prescription. PMID- 29231312 TI - [Status of diagnosis and treatment devices of acupuncture based on SooPAT and bibliometrics in China]. AB - OBJECTIVE: To perform a bibliometrics analysis on patent literature regarding diagnosis and treatment devices of acupuncture in China, aiming to provide references for the development of diagnosis and treatment devices of acupuncture. METHODS: Based on SooPAT, a patent database, the patent literature regarding diagnosis and treatment devices of acupuncture in China was collected. With bibliometrics methods, the annual distribution of type, quantity, classification and content of diagnosis and treatment devices of acupuncture were analyzed. RESULTS: The number of acupuncture diagnosis and treatment devices reached its peak in 2012 and 2013 in China. The A61N in patent and utility model patent were the most, which were mainly related to electrotherapy, magnetic therapy, radioactive therapy and ultrasound therapy, etc. The main content was acupuncture treatment devices and meridian treatment devices. The 24-01 in design patent was the most, involving fixation devices used by doctors, hospitals and laboratories, etc. CONCLUSIONS: Currently the majority of diagnosis and treatment devices of acupuncture is therapeutic apparatus, while the acupuncture diagnosis devices are needed. PMID- 29231313 TI - [Exploration of acupoints selection law for post-traumatic stress disorder treated with acupuncture and moxibustion]. AB - To analyze the modern clinical literature on post-traumatic stress disorder(PTSD) treated with acupuncture and moxibustion so as to summarize the acupoints selection law. The related articles from 2005 to 2014 were collected and then the frequencies were statistically analyzed. Finally 16 papers were gathered,while the main acupoints among the 23 acupoints refer to Baihui(GV 20),Sishencong(EX-HN 1),Shenting(GV 24),Fengchi(GB 20),Shenmen(HT 7),Neiguan(PC 6),Taichong(LR 3) and Sanyinjiao(SP 6). It is concluded that the law means taking smoothing liver and governor vessel to regulate the spirit as priority,and assisted by nourishing kidney and supporting yang to peace the spirit,as well as strengthening spleen and helping qi to smooth meridians. PMID- 29231314 TI - [Differences and international standardization between acupuncture as therapy and as specialty]. AB - The purpose of this study is to explore the differences of definition and clinical roles as well as international standardization between acupuncture as therapy and as specialty, which can provide reference evidence for specialization and internationalization of acupuncture. Owing to the clinical efficacy and safety, the credibility and controversy both exist in acupuncture; moreover, there is a lack of fair definition and international precedent regarding acupuncture specialty. Therefore, it is particularly essential to objectively compare the differences of definitions and clinical roles as well as criteria of international standardization for acupuncture as therapy and as specialty. It is believed acupuncture standardization can draw lessons from the international medical standards, evidence-based medicine and acupuncture theory from the following three major projects:acupuncture safety and contraindications; acupuncture indications and treatment guidelines; acupuncture indication classified into 3 levels of evidence-based acupuncture disease spectrum, as objective evidence of indication of acupuncture specialty. PMID- 29231315 TI - [Acupuncture with regulating mind and spleen for diarrhea irritable bowel syndrome and sleep quality:a randomized controlled trial]. AB - OBJECTIVE: To compare the effects between acupuncture with regulating mind and spleen and wes-tern medication for diarrhea irritable bowel syndrome (IBS-D). METHODS: Eighty-one patients were randomly at the ratio of 2 to 1 assigned into an acupuncture group (54 cases) and a western medication group (27 cases). Acupuncture with regulating mind and spleen was applied in the acupuncture group for 6 weeks at Baihui (GV 20), Yintang (GV 29), Tianshu (ST 25), Zusanli (ST 36), Shangjuxu (ST 37), Sanyinjiao (SP 6), and Taichong (LR 3), once every other day, 3 times a week. Pinaverium bromide tablet was used orally in the western medication group for 6 weeks, 50 mg a time, 3 times a day. IBS symptom severity score (IBS-SSS) were observed before and after 1-week, 6-week treatment. Pittsburgh sleep quality index (PSQI) was applied before and after 6-week treatment. Also, clinical efficacy was evaluated in the two groups. RESULTS: Three patients dropped out in the acupuncture group, and 1 in the western medication group. Except abdominal distension score after 1-week treatment in the western medication group, single scores and total scores of IBS-SSS apparently reduced in the two groups after 1-week and 6-week treatment (P<0.01, P<0.05). After 1-week treatment, the abdominal pain score of the acupuncture group was obviously lower than that of the western medication group (P<0.05). After 6-week treatment, with abdominal pain relief advantage, other results including the number of pain days, defecation satisfaction,life disturbance degree and total score of the acupuncture group were obviously lower than those of the wes-tern medication group (P<0.01,P<0.05). After 6-week treatment, the PSQI score and its change before and after treatment in the acupuncture group were superior to those in the western medication group (both P<0.05). The relief rate and relief plus obvious effective rate in the acupuncture group were higher than those in the western medication group[51.0% (26/51) vs 19.2% (5/26), P<0.01; 64.7% (33/51) vs 34.6% (9/26), P<0.05]. CONCLUSIONS: Acupuncture with regulating mind and spleen for diarrhea irritable bowel syndrome can more effectively relieve abdominal pain than pinaverium bromide tablet at the early stage. Its total effect and single effects are better at the later stage on abdominal pain, seizure frequency, defecation satisfaction, life disturbance, and sleep quality. PMID- 29231316 TI - [Resuscitation acupuncture for thalamic pain:a randomized controlled trial]. AB - OBJECTIVE: To compare the effects between resuscitation acupuncture and pregabalin for thalamic pain and their impacts on plasma P substance (SP) and beta-endorphin (beta-EP). METHODS: Sixty-four patients were randomly assigned into an acupuncture group and a western medication group, 32 cases in each one. Based on conventional western methods, pregabalin capsule was used orally in the western medication group, 75 mg a time,twice a day; resuscitation acupuncture was applied in the acupuncture group. The main acupoints were Shuigou (GV 26), Neiguan (PC 6), Sanyinjiao (SP 6). Patients with upper limb pain were attached affected Jiquan (HT 1), Chize (LU 5), and Hegu (LI 4); lower limb pain, affected Weizhong (BL 40), Zusanli (ST 36); hea-dache, bilateral Fengchi (GB 20), Wangu (GB 12), and Yifeng (TE 17), twice a day. Treatment was given 6 d a week for 8 weeks in the two groups. The changes of simplified McGill pain questionnaire (SF MPQ), plasma SP and beta-EP were observed before and after 4-week, 8-week treatment, as well as at follow-up, namely, 3 months after treatment. Also, clinical effects were evaluated. RESULTS: The total effective rate of the acupuncture group was 50.0% (16/32) after 4-week treatment, which was similar to 46.9% (15/32) in the western medication group (P>0.05). While after 8-week treatment and at follow-up, the total effective rates of the acupuncture group were 90.6% (29/32) and 84.4% (27/32), which were better than 65.6% (21/32) and 40.6% (13/32) of the western medication group correspondingly (both P<0.05). After 4-week, 8-week treatment and at follow-up, the pain scores of the acupuncture group were lower than that before treatment (all P<0.05). After 4 week and 8-week treatment, the pain scores of the western medication group were lower than that before treatment (both P<0.05). After 8-week treatment and at follow-up, the pain scores of the acupuncture group were superior to thoseof the western medication group (both P<0.05). After 4-week and 8-week treatment,the contents of plasma SP reduced compared with those before treatment in the two groups (all P<0.05), and plasma beta-EP increased (all P<0.05). After 8-week treatment, SP content of the acupuncture group was apparently lower than that of the western medication group (P<0.05), and beta-EP increased more obviously (P<0.05). CONCLUSIONS: Resuscitation acupuncture can effectively relieve the symptoms of thalamic pain with stable and long-term effect, and it is better than pregabalin. Meanwhile, the acupuncture can increase beta-EP and reduce SP. PMID- 29231317 TI - [Regulation action and nerve electrophysiology mechanism of acupuncture on arousal state in patients of primary insomnia]. AB - OBJECTIVE: To compare the difference between acupuncture and estazolam on arousal state in patients of primary insomnia, and to explore its nerve electrophysiology mechanism. METHODS: Sixty-four patients of primary insomnia were randomized into an acupuncture group (32 cases) and a medication group (32 cases). After 3 patients were excluded, 31 cases in the acupuncture group and 30 cases in the medication group were included. Patients in the acupuncture group were treated with acupuncture at Sishencong (EX-HN 1), Anmian (Extra), Shenmen (HT 7), Sanyinjiao (SP 6), Zhaohai (KI 6), Shenmai (BL 62) as main acupoints, combined with supporting acupoints, once a day, five times per week, continuously for 4 weeks. Patients in the medication group were treated with oral administration of estazolam, once a day, continuously for 4 weeks. The Pittsburgh sleep quality index (PSQI) and mean sleep latency (MSL) of multiple sleep latency test (MSLT) were compared before and after treatment in the two groups; the polysomnography (PSG) was applied to monitor the indices regarding sleep structure. RESULTS: Compared before treatment, PSQI score was reduced after treatment in the two groups (both P<0.01), which was more significant in the acupuncture group (P<0.05). Compared before treatment, sleep onset latency (SOL), number of awakenings (NWAK) and wake after sleep onset (WASO) were reduced, while total sleep time (TST) and sleep efficiency (SE) were significantly increased in the two groups after treatment (all P<0.01). Compared before treatment, the percentage of non-rapid eye movement period 1/2/3 (N1, N2, N3) and the percentage of rapid eye movement period (REM) to TST were not significantly changed after treatment in the medication group (all P>0.05). Compared before treatment, the percentage of N1, N2 to TST was reduced, while the percentage of N3 and REM to TST was increased after treatment in the acupuncture group (P<0.01). The SOL, NWAK, WASO, TST, SE were not statistically changed after treatment in each group (all P>0.05). Compared with the medication group, the percentage of N1 and N2 was reduced while that of N3 and REM was increased after treatment in the acupuncture group (all P<0.01). After treatment, MSL of MSLT were obviously decreased in the two groups (both P<0.01), which were more significant in the acupuncture group (P<0.05). CONCLUSIONS: Acupuncture can more effectively improve sleep quality of primary insomnia than estazolam, and is more beneficial for regulation of hyperarousal state. PMID- 29231318 TI - [Differences of acupuncture and moxibustion on heart rate variability in qi deficiency syndrome:a randomized controlled trial]. AB - OBJECTIVE: To observe the improvement of acupuncture and moxibustion on symptoms of qi-deficiency syndrome as well as their differences on the parameters of heart rate variability (HRV). METHODS: Thirty patients with qi-deficiency syndrome and 15 healthy volunteers were recruited. Thirty patients with qi-deficiency syndrome were randomly assigned into an acupuncture group and a moxibustion group, 15 cases in each one. Fifteen healthy volunteers were allocated as a healthy control group. Patients in the acupuncture group and healthy control group were treated with acupuncture while patients in the moxibustion group were treated with moxibustion. Guanyuan (CV 4) and Zusanli (ST 36) were chosen for treatment, once every other day, for totally 10 times. All the patients were evaluated with qi deficiency assessment scale (QDAS) and HRV parameters before treatment, after 4th treatment and after all treatment. The correlation was analyzed between QDAS and HRV parameters, and HRV parameters were compared among the three groups before treatment, after 4th treatment and after all treatment. RESULTS: Compared before treatment, the scores of QDAS were decreased in the acupuncture group and the moxibustion group after 4th treatment and after all treatment (all P<0.05); after all treatment the score of QDAS in the moxibustion group was lower than that in the acupuncture group (P<0.05). The HRV parameters of qi-deficiency syndrome were significantly lower than those of healthy volunteers with higher correlation with QDAS. Compared before treatment, the mean heart rate was decreased after treatment (P<0.05), while total HRV and low frequency were increased in the moxibustion group (both P<0.05). The mean heart rate in the healthy control group was increased after treatment (P<0.05). The differences of HRV parameters before and after treatment were not significant in the acupuncture group (all P>0.05). CONCLUSIONS: Total HRV can reflect the severity of qi-deficiency syndrome. Both acupuncture and moxibustion can improve symptoms of qi-deficiency patients, which is superior in moxibustion. The possible mechanism is likely to be related with improved sustainable activation of autonomic nervous system. PMID- 29231319 TI - [Efficacy on primary trigeminal neuralgia treated with triple puncture technique and electroacupuncture at trigger points]. AB - OBJECTIVE: To compare the clinical efficacy on primary trigeminal neuralgia between the combined therapy of electroacupuncture and triple puncture and the routine electroacupuncture therapy. METHODS: Thirty-six patients of primary trigeminal neuralgia were randomly assigned into an electroacupuncture and triple puncture group (group A) and a routine electroacupuncture group (group B), 18 cases in each one. In the group A, the triple puncture technique was used at the trigger points (the positive reactive points to trigger facial pain) and stimulated with electricity. In the group B, the regular needling technique was used at the trigger points, stimulated with electricity. The treatment was given once every two days, the treatment for 10 days made one session and two sessions were required. Separately, before treatment, at the end of the first session of treatment and at the end of the second session, the score of comprehensive symptoms, the score of visual analogue scale (VAS) and the cli-nical efficacy were evaluated in the two groups. RESULTS: Compared with those before treatment, the comprehensive symptom score and VAS score were all reduced after treatment in the two groups (P<0.05, P<0.01). The scores were reduced much more apparently in the group A as compared with those in the group B (both P<0.01). The curative and remarkably effective rate was 44.4% (8/18) and the total effective rate was 88.9% (16/18) in the group A, better than 27.8% (5/18) and 66.7% (12/18) in the group B respectively (both P<0.05). CONCLUSIONS: The combined therapy of triple puncture and electroacupuncture at trigger points achieves the better efficacy on primary trigeminal neuralgia as compared with the routine electroacupuncture therapy. PMID- 29231320 TI - [Comparative observation of the efficacy on facial spasm among different therapies]. AB - OBJECTIVE: To compare the differences in the clinical efficacy on facial spasm among auricular acupuncture, acupuncture and western medication. METHODS: Ninety cases of facial spasm were randomized into an auricular acupuncture group, an acupuncture group and a western medication group, 30 cases in each one. In the auricular acupuncture group, yan (LO5), shenmen (TF4), xin (CO15), gan (CO12), pi (CO13), pizhixia (AT4), chuiqian (LO4), and zhen (AT3) were selected. In the acupuncture group, Baihui (GV 20), Fengchi (GB 20), Sibai (ST 2), Xiaguan (ST 7), Chengqi (ST 1), Hegu (LI 4), Taichong (LR 3) and Zusanli (ST 36) were selected. The needling therapy was given once a day in these two groups and 5 treatments as one session. There were 2 days at intervals. Totally two sessions were required. In the western medication group, carbamazepine tablets were prescribed for oral administration, 0.1 g each time, three times a day, for 7 days as one session, and totally 2 sessions were required. The facial spasmodic intensity was observed before and after treatment in the three groups. The effects were compared among the three groups. RESULTS: After treatment, the facial spasmodic intensity was reduced as compared with that before treatment in all of the three groups (all P<0.05). The result in the auricular acupuncture group was better than the other two groups (both P<0.05). The result in the acupuncture group was better than that in the western medication group (P<0.05). The total effective rates were 93.3% (28/30), 80.0% (24/30) and 53.3% (16/30) in the three groups separately. The efficacy in the auricular acupuncture group was better than either the acupuncture group or the western medication group (both P<0.05). The result in the acupuncture group was better than that in the western medication group (P<0.05). The efficacy in the cases with the diseases duration less than 6 months was significantly better than that in the cases with the diseases duration over 6 months (all P<0.05). What's more, the efficacy of the auricular acupuncture group were the best. CONCLUSIONS: The auricular acupuncture is quite optimal in the treatment of facial spasm. Its efficacy is better than that of routine acupuncture and carbamazepine. The efficacy is especially better in the cases with the diseases duration less than 6 months. PMID- 29231321 TI - [Efficacy of acupuncture-moxibustion periodic therapy on follicular maldevelopment differentiated as spleen and kidney yang deficiency]. AB - OBJECTIVE: To observe the clinical efficacy of acupuncture and moxibustion periodic therapy on folli-cular maldevelopment differentiated as spleen and kidney yang deficiency. METHODS: Sixty patients of follicular maldevelopment differentiated as spleen and kidney yang deficiency were randomized as an observation group and a control group, 30 cases in each one. The conventional acupuncture-moxibustion therapy was used in the control group and the acupuncture moxibustion periodic therapy was applied to the observation group. In the control group, the acupoints were selected in terms of spleen and kidney yang deficiency, such as Guanyuan (CV 4), Qihai (CV 6), Zusanli (ST 36), Sanyinjiao (SP 6), Taixi (KI 3), Xuehai (SP 10) and Zigong (EX-CA 1). In the observation group, the acupoints were selected in terms of the physiological characteristics of follicular phase, ovulatory phase, luteal phase and menstrual phase. The main acupoints were Zusanli (ST 36), Sanyinjiao (SP 6), Taixi (KI 3) and Xuehai (SP 10). The acupoints for benefiting kidney yin were added in the follicular phase, such as Guanyuan (CV 4) and Dahe (KI 12), etc. The acupoints for regulating qi and activating blood circulation were added in the ovulatory phase, such as Hegu (LI 4) and Taichong (LR 3), etc. The moxibustion was added for tonifying kidney yang in the luteal phase, such as Qihai (CV 6) and Guanyuan (CV 4). The treatment was discontinued during the menstrual phase in the two groups. In the rest phases, acupuncture and moxibustion were given once every two days, 30 min each time. The overall efficacy, basal body temperature (BBT), follicular development, the average endometrial thickness and morphology as well as TCM syndrome score of spleen and kidney yang deficiency were observed in the patients after 3-month menstrual periods. The adverse reactions were recorded in the two groups. RESULTS: In the observation group, one case gave up the treatment due to the personal reason and another one stopped the treatment due to suffering from another kind of disease. 28 cases were included totally. In the control group, 3 cases were dropped out since attempting to receive in vitro fertilization-embryo transfer (IVF-ET) and 27 cases were finally included. The total effective rate was 92.9% (26/28) in the observation group, better than 85.2% (23/27) in the control group (P<0.05). Except the endometrial morphology in the control group, after treatment, BBT, follicular development, the average endometrial thickness and morphology as well as TCM syndrome score were all improved apparently after treatment in the two groups (all P<0.05). The improvements in follicular development, endometrial morphology and TCM syndrome score in the observation group were more obvious as compared with those in the control group (all P<0.05). The incidence of the adverse reaction was 7.1% (2/28) in the observation group and was 3.7% (1/27) in the control group, indicating mild adverse reaction that could be relieved naturally. CONCLUSIONS: The treatment with acupuncture and moxibustion achieves the significant efficacy on follicular maldevelopment differentiated as spleen and kidney yang deficiency. Compared with conventional acupuncture-moxibustion therapy, the periodic therapy of acupuncture and moxibustion achieves the much better clinical efficacy. PMID- 29231322 TI - [Acupuncture based on nourishing spleen and kidney and dredging the governor vessel for motor function and ADL in children with spastic cerebral palsy]. AB - OBJECTIVE: To compare the effects of acupuncture based on nourishing spleen and kidney and dre-dging the governor vessel (GV) combined with rehabilitation and simple rehabilitation for children with spastic cere-bral palsy. METHODS: One hundred and twenty patients were randomly assigned into an observation group and a control group, 60 cases in each one. Physicotherapeutics and hand function training were used in the control group for 3 sessions with 20 d at the interval, 20 times as one session, once a day. Based on the treatment of the control group, acupuncture of nourishing spleen and kidney and dredging GV was applied in the observation group for 3 sessions with 20 d at the interval, 10 times as one session, once every other day. The acupoints were Baihui (GV 20), Fengfu (GV 16), Shenzhu (GV 12), Zhiyang (GV 9), Jinsuo (GV 8), Yaoyangguan (GV 3), Mingmen (GV 4), Pishu (BL 20), Shenshu (BL 23), Zusanli (ST 36) and Sanyinjiao (SP 6). Gross motor function measure (GMFM), Peabody developmental fine motor scale and activities of daily living (ADL) scale were observed before and after treatment in the two groups. RESULTS: After treatment, the scores of GMFM and Peabody fine motor were apparently improved compared with those before treatment in the two groups (P<0.01, P<0.05), with better results in the observation group (both P<0.05). The total effective rate in the observation group was 76.7% (46/60), which was obviously better than 65.0% (39/60) in the control group (P<0.05). CONCLUSIONS: Acupuncture based on nourishing spleen and kidney and dredging the governor vessel, as an assisted method for children with spastic cerebral palsy, can effectively improve gross and fine moter functions and activities of daily living. PMID- 29231323 TI - [Analysis on mechanism of acupuncture with three needles at Hegu (LI 4) and its clinical application]. AB - Inverted horse acupuncture (acupuncture with three needles) at Hegu (LI 4) is different from triple needling, a traditional needling method. Based on DONG's warming yang and tonifying qi by simultaneous acu-puncture at Linggu (Extra) and Dabai (Extra), we palpate points along the large intestine meridian of hand yangming, and Linggu (Extra), Hegu (LI 4), and Dabai (Extra) are pricked perpendicularly to smooth triple energizer directly. Thus, functions of zangfu organs are holistically adjusted and clinical effect is better. We believe that Hegu (LI 4) is located on the radialis side of the forefinger, and changeable according to the body function states. While Linggu (Extra) and Dabai (Extra), two radialis points of the second metacarpal,are related to Hegu (LI 4) when it is moving pathologically. According to Sizongxuege (a verse about the four general acupoints), Hegu (LI 4) is effective for face and mouth diseases, which reveals the close relationship between the acupoint and head and face. Acupuncture with three needles achieves better long-term effect than simple acupuncture at Hegu (LI 4) for face and mouth diseases, including mimetic convulsion. PMID- 29231324 TI - [Effects of heat-reinforcing acupuncture on urine metabolites in rheumatoid arthritis rabbits]. AB - OBJECTIVE: To compare the effects of different acupuncture methods on urine metabolites in rheumatoid arthritis (RA) rabbits, and to explore the specificity mechanism of heat-reinforcing acupuncture for RA. METHODS: A total of 40 clean purple-blue rabbits were randomly allocated to a normal group, a model group, a mild reinforcing-reducing needling (MRRN) group, a twirling-reinforcing needling (TRN) group and a heat-reinforcing needling (HRN) group, 8 rabbits in each one. Except the normal group, the rabbits in the remaining groups were treated with ovalbumin and freezing to establish RA model. The rabbits in the MRRN group, TRN group and HRN group were treated with MRRN, TRN and HRN at "Zusanli" (ST 36), respectively, 30 min per treatment, once a day for seven days. After treatment, 24-h urine was collected. The rabbits were sacrificed to collect synovial tissues of knee to perform morphology observation; the liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q/TOF-MS) was applied to measure urine metabolites. All the data were analyzed by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). RESULTS: Compared with the normal group, the leucine-related metabolites, as main urine metabolites, were decreased in the model group (P<0.05), while the purine-related metabolites and tryptophane-related metabolites were increased (P<0.05). Compared with the model group, the leucine-related metabolites, as main urine metabolites, were increased in the three needling groups after treatment (P<0.05), while the tryptophan related metabolites andpurine-related metabolites were decreased (P<0.05), moreover, the leucine-related metabolites in the HRN group were obviously higher than those in the MRRN group and TRN gruop (P<0.05). CONCLUSIONS: MRRN, TRN and HRN can regulate the pathway of leucine metabolism (energy metabolism), purine metabolism (oxidative damage) and tryptophane metabolism (immune regulation) for RA, The specificity of HRN for RA focuses on regulation of leucine metabolism (energy metabolism). PMID- 29231325 TI - [Intervention of acupuncture on abnormal spatiotemporal pattern of visual cortex area 17 neuron in monocular deprivation amblyopia rats]. AB - OBJECTIVE: To preliminarily explore the electrophysiological mechanism of acupuncture on plasticity variability of visual cortex. METHODS: Fifty 14-day-old Wistar rats were randomly divided into a blank group, a model group, an early stage acupuncture group, a middle-stage acupuncture group and a late-stage acupuncture group, 10 rats in each one. Except the blank group, the rats in the remaining groups were treated with eyelid suture to establish the model of monocular deprivation amblyopia. After model establishment, the rats in the blank group and model group were grasped without any intervention everyday. The rats in the acupuncture groups were treated with acupuncture at bilateral "Jingming" (BL 1), "Cuanzhu" (BL 2), "Fengchi" (GB 20) and "Guangming" (GB 37) on the 3rd, 12th and 21st days into model establishment. The needles were retained for 10 min, once a day for totally 9 days. After treatment, the M-NEMEA technology was applied to measure the discharge amplitude and power spectral density of visual cortex area 17 neuron of each group. RESULTS: Compared with the blank group, the number of discharged neuron of visual cortex area 17 was reduced, and the amplitude was significantly reduced in the model group (both P<0.05). Compared with the model group, the numbers of discharged neuron were increased, and the amplitudes were significantly increased in the early-stage acupuncture group and middle-stage acupuncture group (all P<0.05). The neuron discharge amplitude in the early-stage acupuncture group was higher than those in the middle-stage acupuncture group and late-stage acupuncture group (both P<0.05); the neuron discharge amplitude in the middle-stage acupuncture group was higher than that in the late-stage acupuncture group (P<0.05). In the 120-second time domain of acquisition, the distribution of power spectral density in the blank group was mainly between -105 dB and -100 dB; compared with the blank group, the power spectral density in the model group was increased and distributed between -132 dB and -124 dB; compared with the model group, the power spectral densities in the acupuncture groups was reduced and distributed between -115 dB and -110 dB in the early-stage acupuncture group, -120 dB and -115 dB in the middle-stage acupuncture group and -129 dB and -122 dB in the late-stage acupuncture group. CONCLUSIONS: There are abnormal changes of spatiotemporal pattern in visual cortex area 17 of monocular deprivation rats, but acupuncture can regulate abnormal spatiotemporal pattern of neuron. Therefore, there is developmental plasticity of visual cortex neuron in the sensitive period, and early treatment is key to superior efficacy. PMID- 29231326 TI - [Huxiang acupuncture and massage academic school with "the combination of five meridians" for post-stroke urinary incontinence]. AB - The theory of "combination of five meridians" focuses on meridians and acupoints as well as compatibility and interrelationship of generation and restriction of five elements. By regulating corresponding meridians to diseased zangfu, the relationship of unbalanced zangfu is balanced, which can regulate body function and effectively treat diseases. Under the guide of theory "the combination of five meridians", according to etiology and pathogenesis of post-stroke urinary incontinence, wind, fire and phlegm, from three aspects of deficiency, excess and deficient root and excessive surface, under the treatment principle of "nourishing the mother if it is deficient, reducing the son if it is excessive", the original meridian, son meridian, mother meridian, conquering meridian and conquered meridian are selected while the methods of nourishing the mother, reducing the son, reinforcing the suppression and developing the weak are applied, so as to discuss the acupuncture treatment for post-stroke urinary incontinence, which can provide new clinical thoughts of acupuncture treatment for post-stroke urinary incontinence. PMID- 29231327 TI - [JIN Bohua's experience of peripheral facial paralysis diagnosed and treated by Yifeng (TE 17)]. AB - To introduce famous TCM doctor JIN Bohua's experience of peripheral facial paralysis diagnosed and treated by Yifeng (TE 17). Based on holism concept of TCM, Doctor JIN refers to modern medicine and takes Yifeng (TE 17) as the main acupoint for its diagnosis, treatment and prognosis. She determines severe degree according to the pressing pain of Yifeng (TE 17) and the significance of positive substances. She inserts the needle at the acupoint to pharynx and larynx, with 60 degrees ~80 degrees from skin. The inserting method is to ensure quick qi arrival and safety. Besides, the manipulations are various according to different stage principles. PMID- 29231328 TI - [The academic characteristics of acupuncture and moxibustion of professor ZHANG Yongshu:a famous acupuncturist in Southern Fujian]. AB - Professor ZHANG Yongshu, who studied from professor LIU Zhangjie, is a famous acupuncturist in Quanzhou of Southern Fujian. The publications authored by professor ZHANG Yongshu were collected in this study to summarize his academic characteristics of acupuncture and moxibustion. The result indicated he highly valued the regulation of yang qi, and established the theory of "developing yang to nourish yin", which proposes to develop yang qi to achieve the effect of culturing yin; he summarized eight methods to regulate the governor vessel and conception vessel, which can condition the body's yin and yang; he paid attention to moxibustion therapy and its dosage, and made the best of direct moxibustion. In addition, he focused on meridian theory with effective application of meridian syndrome differentiation; in clinical treatment, he regulated the hand-yangming meridian to treat diseases by nourishing yang, generating yin and regulating fu. PMID- 29231329 TI - [Definition of ashi point from the view of linguistics]. AB - The definition of ashi point has not been unified yet till now. Likewise, the precise explanation on its connotation has always been an elusive question in acupuncture theory. By collecting diverse definitions on ashi point in the textbooks of Acupuncture and Moxibustion, dictionaries and term standards, several rational elements in definitions with consensus were screened. With the assistance of two important theories of cognitive linguistics, such as figure ground theory and distance iconicity theory, the concept of ashi point was newly defined. Additiona-lly, on the base of the understanding on several similar terms such as "taking the painful site as acupoint", "responding point" and "reactive point", the semanteme analytic method was used to distinguish the difference among them so that the more profound explorations on acupuncture therapy are expounded. PMID- 29231330 TI - [Hypothesis of "sinew-meridian system"]. AB - The author provides the hypothesis on the "sinew-meridian system" in terms of the physiology, pathology, diagnosis and treatment of meridians and sinew-meridians. Meridians are nourished with blood and sinew-meridians are softened with yang qi. Meridians are circulated in linear form and sinew-meridians are distributed in centripetal state. Meridians are communicated externally and internally and sinew meridians are connected with tendons and bones. Meridians pertain to zangfu organs and sinew-meridians stabilize zangfu organs. Meridians nourish five sensory organs and sinew-meridians moisten nine orifices. Meridians are characterized as nourishment and sinew-meridians as solidity. Meridians emphasize the conditions of either deficiency or excess, and sinew-meridians as either cold or heat. The meridian disorder is located deeply and of complex and sinew meridian's is located superficially and of simplicity. The meridian disorder is difficult to treat and with poor therapeutic effect and the sinew-meridian disorder is easy to treat and with rapid therapeutic effect. The "sinew-meridian system" composes of meridian-collateral system and tendon-skin system, in which the meridian-collateral system includes the twelve meridians, eight extra meridians and fifteen collaterals, being relevant with nutrition and blood, acting on transporting qi, blood and message; the tendon-skin system includes twelve sinew-meridians and twelve meridians of cutaneous regions, being relevant with defensive qi, acting on governing the motor function and protecting the body. PMID- 29231331 TI - [Bridge role of Jingming (BL 1) for VDT asthenopia and brainfag based on human instinct]. AB - To explore the bridge role of Jingming (BL 1) for video display terminal (VDT) asthenopia and brainfag. Ancient literature and modern scientific research on the acupoint have been analyzed and summarized so as to explore pressing the acupoint the instinct feedback of brain after asthenopia. It is demonstrated that Jingming (BL 1) is a key channel between eyes, brain and the outside world, and it is one of major feedback points of brain after asthenopia. In this paper we try to establish a new research thinking and ascertain it, namely Jingming (BL 1) reflecting the relationship between asthenopia and brainfag. We hope that it can provide some references for further research on cognizing brain through eye. PMID- 29231332 TI - [Deqi(qi arrival) theory in ancient TCM books]. AB - Acupuncturists in all ages emphasize deqi(qi arrival). We arranged and analyzed contents on deqi and qi arrival electronic texts in 1156 ancient medical books through Chinese Medical Code, the major electronic series of books on TCM, with medical classics as well as acupuncture-moxibustion and tuina parts as the emphasis. It is found that deqi is a standard for traditional acupuncture effect evaluation. Meanwhile, it acts on regulating body cold, heat, insufficiency and excess, guiding reinforce-reducing manipulation, determining needle depth, retaining and withdrawing, as well as prognosis, etc. Deqi takes the priority in clinical and scientific research. PMID- 29231333 TI - [From Bonghan system to primo vascular system:the thought on the substantial study on meridian points]. AB - Through the systematic analysis on the primo vascular system (PVS) in recent years, we believe that in recent years, more and more studies have indicated that PVS is distributed in reticulate structure in every part of body, such as vessels, lymphangions, nerves, brain, spinal cords and internal organs, and it contains a large amount of immunocytes and has involved in the physiological or pathological process of the immunity and circulation in the body. There are the evidences to prove that in morphology and cytobiology. But, nowadays, there is no way to explain its effect characters. On the basis of the study on living matter characteristics, a breakthrough is possibly made through the systematic cooperation even though it is the difficulty to detect the life function effect. It is especially displayed in the substantial study on meridian points. Hence, the study on the law of meridian point effects on the basis of clinical practice has to be focused on in the substantial study on meridian points. PMID- 29231334 TI - [Design of warm-acupuncture technique training evaluation device]. AB - To design a warm-acupuncture teaching instrument to train and evaluate its manipulation. We refer to the principle and technical operation characteristics of traditional warm-acupuncture, as well as the mechanical design and single-chip microcomputer technology. The device is consisted of device noumenon, universal acupoints simulator, vibration reset system and circuit control system, including frame, platform framework, the swing framework, universal acupoints simulator, vibration reset outfit, operation time circuit, acupuncture sensation display, and vibration control circuit, etc. It can be used to train needle inserting with different angles and moxa rubbing and loading. It displays whether a needle point meets the location required. We determine whether the moxa group on a needle handle is easy to fall off through vibration test, and operation time is showed. The device can objectively help warm-acupuncture training and evaluation so as to promote its clinical standardization manipulation. PMID- 29231335 TI - [Review on skin temperature of acupoints]. AB - We retrieve and analyze the articles on body surface temperature of acupoints in the recent 50 years. Surface temperatures have been compared between acupoints and nonacupoints, and among acupoints in different states. The impacts of interventions for acupoint temperature are explored, including acupuncture,moxibustion and cupping, etc. We summarize the features and the rules of acupoint skin temperature. It is considered that there exists distribution rule for healthy people's acupoint skin temperature. That means acupoints have higher surface temperature than nonacupoints. In the same meridian the nearer acupoints close to the head and trunk, the higher the temperature is. The difference in symmetrical acupoints temperatures between the left and right side is about 0.5C. In the different meridians the skin temperatures of adjacent acpoints are similar. The changes of acupoint's skin temperature in illness can be used as the auxiliary diagnosis. Acupuncture, moxibustion and cupping can produce acupoints stimulating, metabolism improving, yin-yang balance, acupoint temperature regulating. Thus,diseases are relieved. The specificity and regularity that acupoint's skin temperature presents may be one of the manifestations of the acupoint specificity, also it is an important starting point of the research on acupoint sensitization. The further studies should consider different diseases and modern biological engineering techniques, so that more rules of acupoints temperature can be found by more sensitive and objective temperature measurements as well as experimental and the mathematical models. PMID- 29231336 TI - [Clinical observation of peptic ulcer treated with acupuncture based on theory of "the compatibility of the five meridians" in Huxiang]. AB - OBJECTIVE: To compare the effects differences for peptic ulcer between acupuncture based on the theory of "the compatibility of the five meridians" in Huxiang and conventional western medication. METHODS: Sixty patients with peptic ulcer of liver-stomach disharmony type (LSDT) and weakness of spleen and stomach type (WSST) were assigned into an observation group and a control group by block randomization according to syndrome differentiation.Finally,28 cases (17 with LSDT and 11 with WSST) in the observation group,29 cases (18 with LSDT and 11 with WSST) in the control group were included.In the observation group,patients with LSDT were treated with acupuncture at Zhongwan (CV 12),Taichong (LR 3),Xingjian (LR 2),Qimen (LR 14),Zusanli (ST 36),Gongsun (SP 4),Shaofu (HT 8),Jingqu (LU 8),Neiguan (PC 6); those with WSST,at Zhongwan (CV 12),Dadu (SP 2),Taibai (SP 3),Yinlingquan (SP 9),Zusanli (ST 36),Shaofu (HT 8), Taichong (LR 3),Yingu (KI 10),Taixi (KI 3),Taiyuan (LU 9) according to the theory of "the compatibility of the five meridians" in Huxiang.Reinforcing and reducing were according to syndrome differentiation.The treatment was given once a day with needle retained for 30 min,5 days a week,2 days at interval.In the control group,the conventional triple drugs (omeprazole,amoxicillin and clarithromycin) were prescribed orally for Hp positive patients,and omeprazole for Hp negative patients.All the patients were treated for 4 weeks.The clinical syndrome score,ulcer healing under gastroscope,anti-Hp infection and Hp negative conversion ratio rate were observed in the two groups before and after treatment as well as 1 month after treatment.The total effects were evaluated. RESULTS: The syndrome scores after treatment and at 1 month ofter treatment decreased in the two groups (all P<0.05),while without significant difference between the two groups (both P>0.05).The scores within the group between the two syndromes showed no significance in the two groups (both P>0.05).The cure rates under gastroscope,anti-Hp infection rates and the total rates had no statistically significant difference between the two groups (all P>0.05).The Hp negative conversion ratio was 22.2%(4/18) in the observation group,which was worse than 52.6%(10/19) in the control group (P<0.05). CONCLUSIONS: Acupuncture based on the theory of "the compatibility of the five meridians" in Huxiang for peptic ulcer can improve clinical symptoms,ulcer coalescence and anti-Hp infection,which is similar to conventional western medication.While the Hp negative conversion ratio is less than that of conventional western medicine. PMID- 29231337 TI - [Migraine without aura treated with balance acupuncture therapy:a randomized controlled trial]. AB - OBJECTIVE: To assess the effect of balance acupuncture for migraine without aura. METHODS: Blind evaluation was conducted. Forty patients with migraine without aura were randomized into an observation group and a control group, 19 cases in each one with 1 patient dropped out respectively. In the observation group, Toutongxue, the middle point was used in the hollow before the 1, 2 metatarsal combination, and in the control group, a sham point was applied in the hollow before the 3, 4 metatarsal combination. The manipulation in the two groups was the same. The treatment was given for 4 weeks, once a day, 5 times a week. The comprehensive score and visual analogue scale (VAS) were used before and after treatment, as well as 4 weeks after treatment. RESULTS: The comprehensive score and VAS score after treatment in the observation group decreased after treatment (both P<0.05), of which the total headache time and attack number for one month were lower than those before treatment (both P<0.05), but at follow-up the VAS score was higher than that after treatment (P<0.05). The above indices in the control group were not significantly different from those before treatment (allP>0.05). All the indices in the observation group after treatment and at follow-up were lower than those in the control group (all P<0.05). The different values for the comprehensive score and VAS score before and after treatment, before treatment and at follow-up in the observation group were better than those in the control group (all P<0.05). The different values after treatment and at follow-up had no significant difference between the two groups (bothP>0.05). CONCLUSIONS: Balance acupuncture at Toutongxue achieves obvious effect for migraine without aura, which can relieve pain. PMID- 29231338 TI - [The third lumbar transverse process syndrome treated with acupuncture at zygapophyseal joint and transverse process:a randomized controlled trial]. AB - OBJECTIVE: To explore the effects differences for the third lumbar transverse process syndrome between acupuncture mainly at zygapophyseal joint and transverse process and conventional acupuncture. METHODS: Eighty cases were randomly assigned into an observation group and a control group, 40 cases in each one. In the observation group, patients were treated with acupuncture at zygapophyseal joint, transverse process, the superior gluteus nerve into the hip point and Weizhong (BL 40), and those in the control group were treated with acupuncture at Qihaishu (BL 24), Jiaji (EX-B 2) of L2-L4, the superior gluteus nerve into the hip point and Weizhong (BL 40). The treatment was given 6 times a week for 2 weeks, once a day. The visual analogue scale (VAS), Japanese Orthopaedic Association (JOA) low back pain score and simplified Chinese Oswestry disability index (SC-ODI) were observed before and after treatment as well as 6 months after treatment, and the clinical effects were evaluated. RESULTS: The total effective rate in the observation group was 95.0% (38/40), which was significantly higher than 82.5% (33/40) in the control group (P<0.05). After treatment and at follow up, the VAS score and SC-ODI score were lower and JOA score was higher than those before treatment in the two groups (all P<0.05), with better results in the observation group (all P<0.05). CONCLUSIONS: Acupuncture mainly at zygapophyseal joint and transverse process for the third lumbar transverse process syndrome achieves good effect, which is better than that of conventional acupuncture on relieving pain, improving lumbar function and life quality. PMID- 29231339 TI - [Efficacy of acupoint catgut embedding combined with ginger-partitioned moxibustion on chronic fatigue syndrome of spleen-kidney yang deficiency syndrome and its effects on T lymphocyte subsets and activity of NK cell]. AB - OBJECTIVE: To observe the efficacy differences between acupoint catgut embedding combined with ginger-partitioned moxibustion and regular acupuncture on chronic fatigue syndrome (CFS) of spleen-kidney yang deficiency syndrome, and to explore its effects on T lymphocyte subsets and activity of NK cell. METHODS: A total of 60 patients with CFS of spleen-kidney yang deficiency syndrome were randomly divided into a catgut embedding combined with ginger-partitioned moxibustion (CECGP) group and a regular acupuncture group, 30 cases in each one. The patients in the CECGP group were treated with acupoint catgut embedding combined with ginger-partitioned moxibustion; the acupoint catgut embedding was applied at Guanyuan (CV 4), Shenshu (BL 23), Pishu (BL 20), Zusanli (ST 36), Qihai (CV 6), once a week, while the ginger-partitioned moxibustion was applied at Guanyuan (CV 4), Qihai (CV 6) and Zusanli (ST 36), once every three days for consecutive one month. The patients in the regular acupuncture group were treated with regular acupuncture at Guanyuan (CV 4), Shenshu (BL 23), Pishu (BL 20), Zusanli (ST 36), Qihai (CV 6), once a day, 6 treatments per week (one day for rest) for consecutive one month. The clinical symptom scores, fatigue scale-14 (FS-14), fatigue assessment instrument (FAI), laboratory test results and total effective rate were compared between the two groups before and after treatment. RESULTS: (1) After treatment, the clinical symptom scores, FS-14 and FAI were reduced in the two groups (all P<0.05); after treatment, the clinical symptom scores, FS-14 and FAI in the CECGP group were significantly lower than those in the regular acupuncture group (all P<0.05). (2) After treatment, the CD4+/CD8+, natural killer cell% (NK%), CD3+%, CD% were all increased in the two groups (all +4 P<0.05); the CD4+/CD8+, CD3+%, CD% in the CECGP group were significantly higher than those in the regular acupuncture group (all P<0.05). (3) After treatment, the total effective rate was 96.7% (29/30) in the CECGP group, which was similar to 93.3% (28/30) in the regular acupuncture group (P>0.05). CONCLUSIONS: The acupoint catgut embedding combined with ginger-partitioned moxibustion, which could effectively relieve the symptoms, regulate T lymphocyte subsets and the activity of NK cell, is an effective method for CFS of spleen-kidney yang deficiency syndrome. PMID- 29231340 TI - [Herb-partitioned moxibustion on navel for anovulatory infertility:a randomized controlled trial]. AB - OBJECTIVE: To observe the efficacy differences between herb-partitioned moxibustion on navel and clomiphene for anovulatory infertility. METHODS: With double-blind double-dummy randomized control method, a total of 40 patients with anovulatory infertility were randomly divided into a moxibustion group and a clomiphene group, 20 cases in each one. Blinding was conducted on both patients and doctors. The patients in the moxibustion group were treated with herb partitioned moxibustion on navel and oral administration of clomiphene placebo, while the patients in the clomiphene group were treated with placebo-partitioned moxibustion on navel and oral administration of clomiphene. The herb-partitioned moxibustion and placebo-partitioned moxibustion were given at the end of menstruation, 1.5 hours per treatment, once a week, and no treatment was given during menstruation. The oral administration of clomiphene and clomiphene placebo were given from 5 days into menstruation, 50 mg, once a day, for consecutive 5 days. One menstrual cycle was taken as one treatment course, and 3 treatment courses were conducted. After 3 treatment courses, the endometrial thickness (ET), maximum follicular diameter (MFD), ovulation rate (OR) and effective rate (ER) were evaluated between the two groups. RESULTS: (1) Compared before treatment, ET was significantly increased after treatment in the two groups (both P<0.05); after treatment, the ET in the moxibustion group was higher than that in the clomiphene group (P<0.05). (2) After treatment, MFD was significantly increased in the moxibustion group (P<0.05) and insignificantly increased in the clomiphene group (P>0.05); the MFD in the moxibustion group was higher than that in the clomiphene group (P<0.05). (3) The OR was 75.0% (15/20) and 65.0% (13/20) in the two groups respectively, which were not significantly different (P>0.05). (4) The total ER in the moxibustion group was 95.0% (19/20), which was superior to 70.0% (14/20) in the clomiphene group (P<0.05). CONCLUSIONS: The clinical efficacy of herb-partitioned moxibustion at navel on anovulatory infertility was superior to that of clomiphene, but their effects on OR was similar. PMID- 29231341 TI - [Effect of polycystic ovary syndrome treated with the periodic therapy of acupuncture]. AB - OBJECTIVE: To observe the effects differences for polycystic ovary syndrome (PCOS) between periodic therapy of acupuncture and diane-35 and to explore its mechanism. METHODS: Sixty patients were randomly assigned into an acupuncture group and a western medication group, 30 cases in each one, 29 patients finally included with one case dropping out respectively. In the acupuncture group, periodic therapy was mainly used at bilateral Sanyinjiao (SP 6), Dahe (KI 12), Guilai (ST 29), Guanyuan (CV 4), Zhongji (CV 3), with different acupoints in the postmenstrual, intermenstrual, premenstrual periods, once every other day, 3 times a week. EA (2 Hz/100 Hz) was used at bilateral Dahe (KI 12) and Guilai (ST 29). If treatment, FSH increased and LH, LH/FSH, T decreased in the two groups (all P<0.05), but T level and the different value before and after treatment in the western medication group were better than those in the acupuncture group (both P<0.05). CONCLUSIONS: Periodic therapy of acupuncture is probably one of the effective methods for PCOS, which can improve patients' clinical symptoms, sex hormone level, and menstrual cycle. there was no discomfort during menstrual period, no treatment was given. In the western medication group, diane-35 was prescribed orally for 21 days as a course, with 7 days at interval, one tablet a day. All the treatment was started on the fifth day of the menstrual circle, for continuously 3 months. The indexes were observed before and after treatment, including the menstrual circle, acne score, body mass index (BMI), serum follicle stimulating hormone (FSH), luteinizing hormone (LH), LH/FSH and testosterone (T). The effects of the two groups were compared. RESULTS: The total effective rate was 75.9% (22/29) in the acupuncture group, which was not significantly different from 79.3% (23/29) in the western medication group (P>0.05). The menstrual cycles were shorter after treatment in the two groups (both P<0.05), with better effect and different value before and after treatment in the acupuncture group (both P<0.05). BMI in the acupuncture group after treatment was lower than that before treatment (P<0.05) and that after treatment in the western medicine group (P<0.01), with better different value before and after treatment in the acupuncture group (P<0.05). The acne scores after treatment decreased in the two groups (both P<0.05), without significant difference after treatment between the two groups (P>0.05). After treatment,FSH increased and LH,LH/FSH,T decreased in the two groups (all P<0.05),but T level and the different value before and after treatment in the western medication group were better than those in the acupuncture group (both P<0.05). Conclusion Periodic therapy of acupuncture is probably one of the effective methods for PCOS,which can improve patients' clinical symptoms,sex hormone level,and menstrual cycle. PMID- 29231342 TI - [The effect of warm needling pretreatment for endometrial receptivity of frozen embryo transfer]. AB - OBJECTIVE: To explore the effect of warming needling pretreatment for endometrial receptivity before frozen-thawed embryo transfer (FET). METHODS: Fifty-six repeatedly embryo transfer (ET) failure patients with ultrasound showing follicular phase endometrium of C type, hysteroscopy examination presenting endometritis were randomly assigned into an observation group (25 cases) and a control group (31 cases). The patients in the observation group three months before ET were treated with antibiotics in the menstrual period, warming needle (once a day) at Zhongwan (CV 12), Tianshu (ST 25), Guanyuan (CV 4), Zhongji (CV 3), Zigong (EX-CA 1), Liangqiu (ST 34), Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39) after menstruation until the ovulation stopped, and oral administration of progesterone was applied after ovulation. The patients in the control group three months before ET were treated with antibiotics in the menstrual period, and oral administration of progesterone was applied after ovulation. Continuous three menstrual periods were carried out for the both groups. The changes of endometrial thickness, type and endometrial blood flow and the outcome of FET were observed. RESULTS: Endometrial morphology and blood flow were improved after treatment in the two groups (all P<0.01), with better results in the observation group (both P<0.01). The embryo transplantation rate and pregnancy rate in the observation group were higher than those in the control group (both P<0.01), and the early abortion rate decreased (P<0.01). CONCLUSIONS: Warm needling may improve endometrial receptivity, embryo transplantation rate and pregnancy rate and decrease early abortion rate by regulating endometrial morphology and blood flow. PMID- 29231343 TI - [Effects of acupoint catgut embedding combined with auricular point pressure on menopausal syndrome of liver-kidney deficiency type and estradiol]. AB - OBJECTIVE: To observe the efficacy differences between acupoint catgut embedding combined with auricular point pressure with beans and nilestriol on menopausal syndrome of liver-kidney deficiency type, and to explore their effects on estradiol (E2). METHODS: Sixty patients with menopausal syndrome of liver-kidney deficiency type were randomly divided into an acupoint stimulation group and a medication group, 30 cases in each group. The patients in the acupoint stimulation group were treated by acupoint catgut embedding at Taixi (KI 3), Sanyinjiao (SP 6), Shenshu (BL 23), Ganshu (BL 18) and Taichong (LR 3), combined with auricular point pressure at Gan (CO12), Shen (CO10), Neifenmi (CO18), Shenmen (TF4), Pizhixia (AT4); the treatment was given once a week for consecutive four weeks. The patients in the medication group were treated with oral administration of nilestriol, 1 mg, once a day, combined with oral administration of oryzanol, 20 mg, three times per day for consecutive four weeks. The clinical symptom score was compared between the two groups before and after treatment as well as in follow-up visit. The level of E2 was obserced before and after treatment, and the clinical effect was compared. RESULTS: (1) Compared before treatment, the clinical symptom score in the two groups was significantly reduced after treatment and in follow-up visit (all P<0.05); In follow-up visit, the clinical symptom score in the acupoint stimulation group was significantly lower than that in the medication group (P<0.05). The different value before treatment and at follow-up in the acupoint stimulation group was better than that in the medication group (P<0.05). (2) Compared before treatment, the level of E2 in the two groups were increased after treatment (both P<0.05); compared before and after treatment, the difference in the treatment group was significantly higher than that in the medication group (P<0.05). (3) After treatment, the total effective rate was 93.33% (28/30) in the acupoint stimulation group, which was similar to 90.00% (27/30) in the medication group (P>0.05). CONCLUSIONS: Compared with nilestriol, acupoint catgut embedding combined with auricular point pressure with beans could better improve clinical symptoms for patients with menopausal syndrome of liver-kidney deficiency type, and increased the level of E2. PMID- 29231344 TI - [The effect of drug oil moxibustion for contents of Zinc and C-reactive protein in succus prostaticus of chronic nonbacterial prostatitis]. AB - OBJECTIVE: To observe the clinical effects differences and partial mechanism for chronic nonbacterial prostatitis (CNP) among drug oil moxibustion, simple moxibustion, and conventional western medicine. METHODS: A total of 120 patients who met the criteria of inclusion were randomly assigned into a drug oil moxibustion group, a moxibustion group and a western medication group, 40 cases in each one. Moxibustion was used at Guanyuan (CV 4), Zhongji (CV 3), Qihai (CV 6) and bilateral Yinlingquan (SP 9), Sanyinjiao (SP 6), Shenshu (BL 23), Mingmen (GV 4), Pangguangshu (BL 28), Ciliao (BL 32), and Zhibian (BL 54), etc. The same moxibustion was used at the same acupoints in the drug oil moxibustion group after external application of medicated oil. Thirty min treatment was used once a day in alternated abdomen and back. In the western medication group, oral tamsulosin hydrochloride capsules were applied once a day, one capsule at a time. All the treatment was given for 30 days. Chronic prostatitis symptom index from National Institutes for Health (NIH-CPSI), the contents of Zinc (Zn) and C reactive protein (CRP), as well as the number of white blood cells (WBC) and density of lecithin bodies were observed before and after treatment and 1 month after treatment. The effects were evaluated after treatment. RESULTS: After treatment, the total effective rate of the drug oil moxibustion group was 90.0% (36/40), which was significantly higher than 72.5% (29/40) of the moxibustion group and 62.5% (25/40) of the western medication group (both P<0.05). After treatment and at follow-up in the three groups, the NIH-CPSI scores were lower than those before treatment (all P<0.05), and those in the drug oil moxibustion group were lower than the results in the moxibustion group and the western medication group (all P<0.05). The contents of Zn in the three groups were higher than those before treatment (all P<0.05), with better results in the drug oil moxibustion group (all P<0.05), and higher Zn contents in the moxibustion group compared with those in the western medication group (both P<0.05). The CRP levels were lower than those before treatment (all P<0.05), and those in the drug oil moxibustion group were better than those in the moxibustion group and western medication group (all P<0.05). The CRP contents in the moxibustion group were lower than those in the western medication group (both P<0.05). The number of WBC were lower than those before treatment (all P<0.05), with better results in the drug oil moxibustion group (all P<0.05). The concentrations of lecithin were higher than those before treatment (all P<0.05), with better results in the drug oil moxibustion group (all P<0.05). CONCLUSIONS: The clinical effect of drug oil moxibustion is better than those of simple moxibustion and western medicine, which has advantages in improving clinical symptoms, Zn, the density of lecithin body and decreasing CRP content and the number of WBC. PMID- 29231345 TI - [Research progress of Shenshu (BL 23)]. AB - In order to accurately understand the location of Shenshu (BL 23) and to improve the efficacy of acupuncture, a discussion is performed in this paper from aspects of acupoint function, anatomical structure, experiment research, clinical application, etc., hoping to provide benefit for future animal experiments and clinical selection of acupoint. The characteristics of rat spine is different from that of human, and the reliability and authenticity of acupoint location would be compromised if the anatomical characteristics of human was inflexibly applied on animals. "Shenshu" (BL 23) belongs to the bladder meridian of foot taiyang, and is located 1.5 cun lateral to the lower border of the spinous process of the second lumbar vertebra. It is close to kidney, therefore deep insertion or repeated lifting and thrusting of needle would damage kidney and causes acupuncture accident. Therefore, to locate "Shenshu" (BL 23) in rat, the 6th lumbar vertebra is located firstly based on tuber coxae of rat, and then 11th thoracic vertebra is located by upward 4 vertebral bodies or locate 9th to 11th thoracic vertebra which are tight, and finally 2nd lumbar vertebra is located by downward 4 vertebral bodies, and "Shenshu" (BL 23) is 5 mm lateral to it. During clinical treatment, the technique should be gentle; oblique and outward insertion of needle is not allowed; the maximum depth of needle insertion is 1.6 cun (approximately 4.30 cm); the vertical or oblique insertion with needle 45 degrees towards spine is appropriate; the depth of 0.8 to 1.2 cun (2.00 to 3.10 cm) is suitable. In cases of too thin or fat patients, the depth of needle insertion should be adjusted for safety. PMID- 29231346 TI - [Discussion on locating of back-shu points]. AB - Back-shu points were firstly discussed in Lingshu (the Miraculous Pivot), and various location methods of back-shu points had been proposed by acupuncturists until conclusive method was made in Song dynasty. In this paper, the different location methods of back-shu points were reviewed; based on this, the reasons of divergences among each theory on location methods were discussed, and the theoretical background and reference of the original establishment of back-shu points were further explored. Therefore, it was proposed that the standardized location of back-shu points should be just considered as the center of possible distribution range, and adjustment should be made during clinical application according to the variability of individual combined with finger pressing. PMID- 29231347 TI - [Study on electroacupuncture along the visual conductive pathway for ocular cell apoptosis in anterior ischemic optic neuropathy]. AB - OBJECTIVE: To study the protective effect of electroacupuncture (EA) along the visual conductive pathway for the optic nerve tissue of anterior ischemic optic neuropathy (AION) in terms of the structure and apoptosis. METHODS: The AION model of right eye was established with laser in 48 New Zealand white ear rabbits. All rabbits were randomly divided into a model group, an acupuncture group and an acupuncture combined with EA group, 16 rabbits in each one. Other 16 normal left eyes were selected as a blank group. Acupuncture and EA of 30 min were used in the corresponding groups for 3 days at the right "Cuanzhu" (BL 2), "Yuyao" (EX-HN 4) and "Qiaomingxue" (Extra), once a day. There was no intervention in the model group and the blank group. The morphological structure and retinal thickness of lining of the optic nerve were detected with HE stain. The expressions of the Bcl-2 and Bax in the retina were detected with immunohistochemistry. And the concentration of tumor necrosis factor-alpha (TNF alpha) in the retina was detected with enzyme linked immunosorbent assay (ELISA). RESULTS: In the model group, the ganglion cell layer revealed hyperplasia and disorder, and the retina ganglion cells revealed loose arrangements, thin inner nuclear layers, and reduction of cell amounts, some long parts missing cells. However, the above structural damages were much weaker in the acupuncture group and acupuncture combined with EA group. The inner layer of the retina in the model group was thinner than that in the blank group (P<0.05). That in the acupuncture combined with EA group showed significant better results than those in the acupuncture and model groups (both P<0.05), which was not statistically different from that in the normal group (P>0.05). The Bcl-2 count in the model group was lower than that in the blank group (P<0.05), and that in the acupuncture combined with EA group was better than those in the acupuncture and model groups (both P<0.05), not significantly different from that in the blank group (P>0.05). The number of Bax in the model group was higher than that in the blank group (P<0.05), and that in the acupuncture combined with EA group was lower than those in the acupuncture and model groups (both P<0.05), and was similar to that in the blank group (P>0.05). Bcl-2/Bax in the model group was lower than that in the blank group (P<0.05). The value in the acupuncture combined with EA group presented better than those in the acupuncture and model groups (both P<0.05), which had no difference from that in the blank group (P>0.05). TNF-alpha in the model group was higher than that in the blank group (P<0.05), and no such differences were detected between other groups and the model group (bothP>0.05). CONCLUSIONS: EA along the visual conductive pathway is protective to some extent for optic nerve tissue, which can increase the expression of Bcl-2 and reduce the expression of Bax so as to restrain ganglion cell apoptosis. PMID- 29231348 TI - [Effects of electroacupuncture on postoperative cognitive dysfunction and AngII/AT1R in the hippocampus in aging rats induced by D-galactose]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) on postoperative cognitive dysfunction (POCD) and AngII/AT1R in the hippocampus in D-galactose induced aging rats which received hepalobectomy, and to explore the possible mechanism of EA on POCD. METHODS: Eighty male Sprague-Dawley rats were randomly divided into a young control group (10 rats), a D-Galactose-induced aged (Da) group (10 rats), a Da+hepatolobectomy group (30 rats) and an EA group (30 rats). The rats in the Da+hepatolobectomy group and EA group were further randomly divided into a 1 d subgroup, 3 d subgroup and a 7 d subgroup, 10 rats in each subgroup. The rats in the EA group were treated with EA at "Baihui" (GV 20) and "Dazhui" (GV 14) with continuous wave (15 Hz in frequency and 1 mA in intensity), and rats in each subgroup were treated for 1 d, 3 d and 7 d, respectively. The rats in the remaining groups were treated with immobilization, once a day. The Y maze was used to observe the behavior change of rats, and ELISA was applied to measure the level of hippocampal AngII, and RT-PCR and immunohistochemistry method were performed to detect AT1R mRNA expressions and AT1R positive expression in the hippocampus. RESULTS: The number of rat initiative avoidance in the Da group was significantly less than that in the young control group (P<0.05), and the mRNA expression and positive percentage of AT1R in the hippocampus in the Da group were significantly higher than those in the young control group (both P<0.01). Compared with the Da group, the number of rat initiative avoidance in each subgroup of Da+hepatolobectomy group and EA group were significantly reduced (all P<0.01), and the expression of AngII, AT1R mRNA and AT1R positive cells percentage in the hippocampus were significantly increased (P<0.05, P<0.01). The number of rat initiative avoidance in each subgroup of EA group was higher than that in the subgroup of Da+hepatolobectomy group (P<0.05, P<0.01); and the expression of AngII, AT1R mRNA, and AT1R positive percentage in the EA group were significantly less than that in the Da+hepatolobectomy group (P<0.05, P<0.01). CONCLUSIONS: EA at "Baihui" (GV 20) and "Dazhui" (GV 14) could improve POCD in D-galactose-induced aging rats which received hepalobectomy, and it is likely to be related with the inhibition of AngII, AT1R positive expression and AT1R mRNA in the hippocampus. PMID- 29231349 TI - [Effect of ear point embedding on plasma and effect site concentrations of propofol-remifentanil in elderly patients after target-controlled induction]. AB - OBJECTIVE: To observe the clinical effect of ear point embedding on plasma and effect site concentrations of propofol-remifentanil in elderly patients who underwent abdominal external hernia surgery at the time of consciousness and pain disappearing by target-controlled infusion (TCI) and bispectral index (BIS). METHODS: Fifty patients who underwent elective abdominal hernia surgery were randomly assigned into an observation group and a control group, 25 cases in each one. In the observation group, 30 minutes before anesthesia induction, Fugugou (Extra), Gan (CO12), Pizhixia (AT4), and Shenmen (TF4) were embedded by auricular needles until the end of surgery, 10 times of counter press each point. In the control group, the same amount of auricular tape was applied until the end of surgery at the same points without stimulation 30 minutes before anesthesia induction. Patients in the two groups were given total intravenous anesthesia, and BIS was monitored by BIS anesthesia depth monitor. Propofol was infused by TCI at a beginning concentration of 1.5MUg/L and increased by 0.3MUg/L every 30s until the patients lost their consciousness. After that, remifentanil was infused by TCI at a beginning concentration of 2.0MUg/L and increased by 0.3MUg/L every 30s until the patients had no body reaction to pain stimulation (orbital reflex). Indices were recorded, including mean arterial pressure (MAP), heart rate (HR) and the BIS values, at the time of T0 (entering into the operation room), T1 (losing consciousness) and T2 (pain relief), the plasma and effect site concentrations of propofol at T1, the plasma and effect site concentrations of remifentanil at T2. After surgery we recorded the total amounts of propofol and remifentanil, surgery time and anesthesia time. RESULTS: At T1 and T2, MAP and HR of the observation group were higher than those of the control group (P<0.05, P<0.01). At T1, the plasma and effect site concentrations of propofol in the observation group were significantly lower than those in the control group (P<0.05, P<0.01). At T2, the plasma and effect site concentrations of remifentanil in the observation group were significantly lower than those in the control group (P<0.05, P<0.01). There was no significant difference in BIS values at T1 and T2 between the two groups (bothP>0.05). There was no significant difference in operation time and anesthesia time between the two groups (bothP>0.05). The total amount of remifentanil in the observation group was significantly lower than that in the control group (P<0.01). There was no significant difference in the total amount of propofol between the two groups (P>0.05). CONCLUSIONS: Ear points embedding combined with propofol-remifentanil TCI could reduce the plasma and effect site concentrations of propofol and remifentanil and the total amount of remifentanil in elderly patients with extra abdominal hernia surgery, and had the effect of assisting sedation and analgesia. PMID- 29231350 TI - [Learning experience of acupuncture technique from professor ZHANG Jin]. AB - As a famous acupuncturist in the world, professor ZHANG Jin believes the key of acupuncture technique is the use of force, and the understanding of the "concentrating the force into needle body" is essential to understand the essence of acupuncture technique. With deep study of Huangdi Neijing (The Inner Canon of Huangdi) and Zhenjiu Dacheng (Compendium of Acupuncture and Moxibustion), the author further learned professor ZHANG Jin's theory and operation specification of "concentrating force into needle body, so the force arriving before and together with needle". The whole-body force should be subtly focused on the tip of needle, and gentle force at tip of needle could get significant reinforcing and reducing effect. In addition, proper timing at tip of needle could start reinforcing and reducing effect, lead qi to disease location, and achieve superior clinical efficacy. PMID- 29231351 TI - [Brief discussion on acupuncture technique "controlling Qihai to regulate blood pressure" proposed by academician SHI Xuemin]. AB - According to Qihai theory, academician SHI Xuemin established the acupuncture technique "controlling Qihai to regulate blood pressure" which focused on Renying (ST 9), and achieved favorable effects in clinical application. In this paper, based on the Qihai theory, from aspects of Yuanqi, Zongqi, Yingqi and Weiqi and relations among qi, blood and veins in TCM, and cardiac output, sympathetic nerve activity and blood vessels in modern medicine, the understanding on hypertension was explained. As a result, both TCM and modern medicine had consistency in the understanding of hypertension, reflecting the scientificity and practicability of this acupuncture technique. Besides, according to Qihai theory and "wind leading to vertigo" theory, academician SHI Xuemin brought forward the key pathogenesis of hypertension was "dysfunction of Qihai", and the acupoint selected Renying (ST 9), Quchi (LI 11), Hegu (LI 4), Zusanli (ST 36) and Taichong (LR 3). At the same time, the operation specification of each acupoint was mainly discussed, and the references of acupoint selection was explained based on TCM theory and modern clinical research. PMID- 29231352 TI - [Acupoint selection thought for post-stroke anxiety disorder in terms of heart and brain differentiation]. AB - To explore the relativity between heart-brain and post-stroke anxiety disorder by analyzing the pathogenesis of post-stroke anxiety disorder combined with the physiology and pathology of organs. The acupoint selection thought was explored by its selection rule according to literature. Post-stroke anxiety belongs to the brain organic anxiety disorder, whose basic pathogenesis is mind injury. The crucial cause is heart and brain disorder at the same time. Thus, Baihui (GV 20), Fengfu (GV 16) for brain and Xinshu (BL 15), Shenmen (HT 7) for heart can improve anxiety disorder according to the theories such as five organ, qijie (qi thoroughfare), sihai (four seas), meridian and collateral. PMID- 29231353 TI - [Efficacy of filiform needle manipulation on primary dysmenorrhea:a systematic review]. AB - The paper is a systematic review on the efficacy of acupuncture manipulation on primary dysmenorrhea. Ten medical literatures database at home and abroad were retrieved, including CNKI, VIP, CBM, WANFANG, MEDLINE, Cochrane, CENTRAL, CINAHL PLUS, EMBASE, AMED and PsycINFO, as well as 6 clinical trial registration platforms. All of randomized controlled trials (RCTs) on primary dysmenorrhea treated with different acupuncture manipulations were collected. The data were extracted by two persons. Finally, RevMa 5.3 software was used for statistical analysis. Totally, 5 148 pieces of literature were retrieved and 8 pieces on RCTs were screened with 644 cases included. According to the results of statistical analysis on the total effective rate and other indicators of pain degree, it was showed that the effects of the manipulation with filiform needle, deep puncture with strong stimulation, and specific reinforcing and reducing needling technique were better than those without manipulation applied or with shallow puncture and weak stimulation and even needling technique in the treatment of primary dysmenorrhea. It is believed initially that acupuncture manipulation contributes to the improvement of the therapeutic effects of primary dysmenorrheal, but much higher quality studies are required for the further confirmation. Protocol registration number:PROSPERO:CRD42016038515. PMID- 29231354 TI - [Top-cited academic articles in acupuncture and moxibustion research]. AB - OBJECTIVE: To identify the 100 top-cited articles published in journals dedicated to acupuncture & moxibustion research and analyze their characteristics so as to explore its academic state. METHODS: All the articles were collected from the China National Knowledge Infrastructure (CNKI, January 1, 1943 to December 25, 2016), Web of Science (January 1, 1950 to December 25, 2016), WANFANG Database (January 1, 1998 to December 25, 2016). The top-cited articles were selected and analyzed with regard to publication year, number of citations, journals, authors, country or region, institution, title, type and subject. RESULTS: One hundred and two articles were included, 43 Chinese articles and 59 English articles, cited between 146 and 505 times, and the average number of citation was 222. Of the 10 articles cited in the top 10, China and the United States had 4 articles respectively. These articles appeared in 44 journals, 24 articles in Chinese Acupuncture & Moxibustion, followed by 8 articles in Pain. All the articles belonged to 9 countries and regions, 47 articles from mainland China and 21 articles from the United State. Of the 14 institutes whose article number ranked at top 10, Tianjing University of TCM had 8 articles. The first authors published most papers were professor HAN Jisheng and Cherkin DC, each of whom had 4 articles. All the articles were categorized into basic science article (n=27), clinical research (n=33) and literature study (n=42). The main topics were pain diseases and brain impairment. CONCLUSIONS: This analysis of high cited articles reveals academic trends and directions of acupuncture and moxibustion. Acupuncture and moxibustion are more and more recognized by mainstream medicine in the world, but the academic dominance of China has been increasingly challenged by the United States, Germany and so on. PMID- 29231355 TI - [A survey on knowledge of acupuncture disease spectrum and expectation of acupuncture treatment in Chengdu residents]. AB - OBJECTIVE: To understand the knowledge of acupuncture disease spectrum, expectation of acupuncture treatment in Chengdu residents. METHODS: A questionnaire regarding the knowledge of acupuncture disease spectrum and expectation of acupuncture treatment in Chengdu residents was established. By field sampling and internet survey, related data were collected and analyzed. RESULTS: Totally 1 548 valid questionnaires were collected, including 1 041 from field survey and 507 from internet survey. The results indicated the knowledge of acupuncture and its disease spectrum were moderate in Chengdu residents; among the disease spectrum of acupuncture, the disease with the highest cognition was insomnia, accounting for 45.0% in field survey and 75.4% in internet survey; while the disease with the lowest cognition was infertility, accounting for 8.3% in field survey and 34.3% in internet survey. CONCLUSIONS: The knowledge of acupuncture in Chengdu residents could be further improved, and the promotion of popular science of acupuncture should be strengthened in future. PMID- 29231356 TI - [Acupuncture for diarrhea-predominant irritable bowel syndrome:a meta-analysis]. AB - OBJECTIVE: To systematically evaluate the efficacy and safety of acupuncture on diarrhea-predominant irritable bowel syndrome (IBS) in the past five years. METHODS: Online databases, including CNKI, VIP, WANFANG, PubMed, CBM, ScienceDirect OnSite, Cochrane Library, etc. were searched for randomized controlled trials (RCTs) of acupuncture for diarrhea-predominant IBS. Retrieval time was from January of 2011 to January of 2016. According to modified Jadad standard, the bias risk and quality assessment of each RCT included were evaluated by two researchers. RevMan 5.3 software was adopted for the meta analysis. RESULTS: Totally 17 RCTs were included with 1 333 patients. The result of meta-analysis indicated the total effective rate of clinical symptoms improvement in the acupuncture group or acupuncture combined with western medicine group was superior to that in the western medicine group (OR=3.92, 95% CI:2.83~5.43, P<0.01), and the funnel plot was basically symmetry. The result of meta-analysis showed 3-month recurrence rate:OR=0.22, 95% CI:0.12~0.41 (P<0.01), indicating the recurrence rate in the acupuncture group was lower than that in the western medicine group in three month. CONCLUSIONS: Acupuncture for diarrhea predominant irritable bowel syndrome is superior to conventional treatment of western medication, which can improve the clinical symptoms and reduce the recurrence rate of patients. PMID- 29231357 TI - [Acupuncture combined with medication for blood-stasis in unstable angina patients with different thrombolysis in myocardial infarction risk stratification]. AB - OBJECTIVE: To observe the intervention effects of acupuncture combined with standardized treatment of western medicine on blood-stasis syndrome in unstable angina (UA) patients with different thrombolysis in myo-cardial infarction (TIMI) risk stratification. METHODS: According to TIMI risk score, a total of 72 UA patients were included, 24 cases in low-risk (0 to 2 points) group, 24 cases in moderate-risk (3 to 4 points) group and 24 cases in high-risk (5 to 7 points) group. Based on routine standardized treatment of western medicine, acupuncture was applied at Xinshu (BL 15), Xuehai (SP 10), Geshu (BL 17), Danzhong (CV 17), Jueyinshu (BL 14), Ximen (PC 4) and Neiguan (PC 6) in three groups. Acupuncture was given once a day, 14 days as a session. After one session, each symptom score and total score of blood stasis syndrome were observed. RESULTS: One patient dropped out respectively, and 23 patients in each group were included in the analysis. After treatment, the score of angina symptom and total score of blood stasis syndrome were significantly improved in three groups (all P<0.01). The improvements of each score and total score of blood stasis syndrome in the high risk group were superior to those in the low-risk group and moderate-risk group (P<0.05, P<0.01). CONCLUSIONS: With the higher TIMI scores, the blood stasis syndrome is aggravated accordingly. Acupuncture combined with standardized treatment of western medicine could effectively intervene blood stasis syndrome, especially for the score of blood stasis syndrome of patients in high-risk group. PMID- 29231359 TI - [Clinical observation of analgesia in delivery treated with acupoint pressure therapy]. AB - OBJECTIVE: To observe the efficacy of acupoint pressure therapy on relieving labor pain in primiparas. METHODS: One hundred and twenty primiparas were randomized into an observation group (60 cases) and a control group (60 cases). In the observation group, Hegu (LI 4), Sanyinjiao (SP 6), Taichong (LR 3), Neiguan (PC 6), Ciliao (BL 32) and Zhongliao (BL 33) on bilateral sides were selected. The acupoint pressure therapy was applied when the uterine orifice was dilated to 2 to 3 cm. In the control group, the acupoint pressure therapy was not used. Separately, when the orifice was dilated as 2 to 3 cm, 5 to 6 cm, 7 to 8 cm and 9 to 10 cm, the pain response grade was assessed (including physician's analgesia score and patient's self-evaluation score of analge-sia). The in labor pain was observed and compared in the puerperas between the two groups. The time of the first, second and third stages of labor, the time of total stage of labor as well as the cesarean section rate were compared in the puerperas between the two groups. RESULTS: (1) Analgesic effect:when the uterine orifice was dilated as 2 to 3 cm, 5 to 6 cm, 7 to 8 cm and 9 to 10 cm, the self-evaluation scores of analgesia in the puerperas of the observation group at each time point were all apparently lower than those in the control groups (all P<0.05). In the observation group, for the physician's analgesia score, 213 person-times presented analgesic effect and 18 person-times no effect. In the control group, 178 person-times presented analgesic effect and 44 person-times no effect. The analgesic effect in the observation group was better than that in the control group (P<0.05). (2) Stages of labor:the differences in the second and third stages of labor were not significant statistically between the two groups (both P>0.05). The time of the first stage of labor and the time of the total stages of labor in the observation group were shorter appa-rently than those in the control group[(8.07+/-2.08)h vs (9.58+/-2.79)h, (8.91+/-2.80)h vs (10.51+/-2.83)h, both P<0.05]. (3) Cesarean section rate:the cesarean section rate in the observation group was lower than that in the control group[5.0% (3/60) vs 10.0% (6/60), P>0.05]. CONCLUSIONS: Acupoint pressure therapy has definite efficacy on relieving labor pain. It shortens the stages of labor and cesarean section rate. PMID- 29231358 TI - [The "regulating conception-governor vessel" acupuncture method for infertility of polycystic ovarian syndrome]. AB - OBJECTIVE: To compare clinical efficacy differences between"regulating conception governor vessel" acupuncture method and clomiphene for infertility of polycystic ovarian syndrome (PCOS). METHODS: One hundred patients of PCOS were randomly assigned into an observation group and a control group, 50 cases in each one. The patients in the observation group were treated with"regulating Conception Governor Vessel" acupuncture method at Zhongwan (CV 12), Guanyuan (CV 4), Qihai (CV 6), Zhongji (CV 3), Mingmen (GV 4), Yaoyangguan (GV 3) and Yaoshu (GV 2). The acupuncture treatment started at the end of menstruation, once every other day; after four treatments, the follicle was tested with B ultrasound; when follicle was longer than 18 mm or above, the acupuncture treatment was given once a day until follicle was discharged and acupuncture treatment finished. The patients in the control group were treated with oral administration of clomiphene from 5 days into menstruation, 50 mg per day for 5 consecutive days. Both groups were treated for three menstruation cycle. The menstrual cycles, endometrial thickness, endometrium types (A, B and C), cervical mucus scores, basal body temperature (BBT), cases of ovulation, cases of pregnancy were observed.The levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), prolactin (PRL), progesterone (P) and testosterone (T) in serum were detected before and after the treatment. RESULTS: After the treatment, the menstrual cycles were shortened (both P<0.05),the endometrial thickness and cervical mucus scores were increased in the two groups (P<0.05, P<0.01); the improvement of endometrial thickness and cervical mucus score in the observation group were higher than those in the control group (both P<0.01). The percentages of type-A endometrium in both groups were higher than those before the treatment (both P<0.05); the number of type-A endometrium in the observation group was higher than that in the control group (P<0.05). The ovulation rate was 88.0% (44/50) in the observation group, which was superior to 70.0% (35/50) in the control group (P<0.05). After treatment, the levels of LH were reduced in the two groups (P<0.05, P<0.01), which was more significant in the observation group (P<0.05). CONCLUSIONS: The"regulating Conception-Governor Vessel" acupuncture method could improve menstrual cycles, increase endomet-rial thickness and promote the development of follicles in PCOS patient; in addition, it could decrease serum LH level, improve the ovarian functions and increase ovulation rate, which is superior to oral administration of clomiphene. PMID- 29231360 TI - [Acupuncture combined with western medicine for CP/CPPS:a randomized controlled trial]. AB - OBJECTIVE: To compare the clinical efficacy differences among acupuncture combined with western medicine, acupuncture alone and western medicine alone for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: Ninety patients were randomly assigned into a needle-medicine group, an acupuncture group and a western medicine group, 30 patients in each group. The patients in the needle-medicine group were treated with acupuncture combined with western medicine; the scalp points included Shenting (GV 24), Xinhui (GV 22), Qianding (GV 21), Baihui (GV 20), Chengguang (BL 6), Tongtian (BL 7), etc. The body points were Zhongji (CV 3), Guanyuan (CV 4), Pangguangshu (BL 28), Ciliao (BL 32), etc. The acupuncture was given 30 min per treatment, once a day. Besides, oral administration of 0.2g levofloxacin (twice per day) and 0.2 mg tamsulosin (once a day) was applied. The patients in the acupuncture group and western medicine group were treated by acupuncture and western medicine respectively. 12-d treatment was taken as one session, and totally 2 sessions were given. The clinical efficacy of the three groups after treatment was compared as well as the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) total score and pain score, self-rating anxiety scale (SAS) and self-rating depression scale (SDS) before and after treatment. RESULTS: During the trial two patients dropped out, as a result, 30 patients in the needle-medicine group, 29 patients in the acupuncture group and 29 patients in the western medicine group were included in the analysis. After treatment, 21 patients were cured, 6 patients were markedly effective, 2 patients were effective and 1 patient failed in the needle-medicine group;12 patients were cured, 10 patients were markedly effective, 5 patients were effective and 2 patients failed in the acupuncture group; 11 patients were cured, 12 patients were markedly effective, 4 patients were effective and 2 patients failed in the medicine group; the efficacy in the needle-medicine group was superior to those in the acupuncture group and medicine group (both P<0.05). Each score was improved after treatment in each group (all P<0.01); the total score of NIH-CPSI as well as SAS and SDS scores in the needle medicine group were superior to those in the acupuncture group and medicine group (P<0.05, P<0.01); the pain scores of NIH-CPSI in needle-medicine group and acupuncture group were superior to that in the medicine group (P<0.05, P<0.01), but the difference between the needle-medicine group and acupuncture group was not significant (P>0.05). CONCLUSIONS: The efficacy of acupuncture combined with western medicine for CP/CPPS is superior to that of acupuncture alone and western medicine alone, which could improve the symptom of prostatitis as well as status of anxiety and depression. PMID- 29231361 TI - [Clinical study on depression differentiated as yang deficiency treated with the combined therapy of ginger-isolated moxibustion and western medicine]. AB - OBJECTIVE: To compare the differences in the clinical efficacy on depression differentiated as yang deficiency between the combined therapy of ginger-isolated moxibustion and escitalopram and the simple application escitalopram. METHODS: Eighty patients of depression differentiated as yang deficiency were randomized into an observation group and a control group, 40 cases in each one. In the control group, escitalopram was prescribed for oral administration, 10 mg a day, after each breakfast. In the observation group, on the basis of the treatment as the control group, the ginger-isolated moxibustion was supplemented at Dazhui (GV 14) and bilateral back-shu points of five zang organs[Xinshu (BL 15), Ganshu (BL 18), Pishu (BL 20), Feishu (BL 13) and Shenshu (BL 23)]. Moxibustion was used 5 times a week. Twenty times of moxibustion were taken as one session and totally 3 sessions were required (totally 84 days). After 3 sessions of treatment, the concentration of serum 5-hydroxytryptamine (5-HT) before and after treatment and clinical efficacy were observed in the two groups. After 3 sessions of treatment, escitalopram was taken continuously, 10 mg a day for 9 months in the two groups and the recurrent rate was observed in a half year after discontinuity of medication in the two groups. RESULTS: The total effective rate was 97.5% (39/40) in the observation group and was 92.5% (37/40) in the control group. The total effective rate was similar between the two groups (both P>0.05). The curative and remarkably effective rate was 82.5% (33/40) in the observation group, better than 62.5% (25/40) in the control group (P<0.05). The serum 5-HT after treatment was increased as compared with that before treatment in the patients of the two groups (both P<0.05), but the diffe-rence was not significant statistically between the two groups (P>0.05). The recurrent rate of depression was 7.7% (3/39) in the observation group, lower than 27.0% (10/37) in the control group (P<0.05). CONCLUSIONS: The combined therapy of ginger-isolated moxibustion and escitalopram achieves the better curative and remarkably effective rate as compared with the simple western medicine and it significantly reduces the recurrence of depression. PMID- 29231362 TI - [Clinical observation of post-infectious cough differentiated as wind-cold retention in the lung treated with scraping therapy and xuanfei zhisou decoction]. AB - OBJECTIVE: To compare the difference in the therapeutic effect on post-infectious cough differentiated as wind-cold retention in the lung between the combined therapy of scraping and xuanfei zhisou decoction and the simple application of xuanfei zhisou decoction. METHODS: Eighty patients were randomized into a combined therapy group and a Chinese herbal medicine group, 40 cases in each one. In the Chinese herbal medicine group, the oral administration of xuanfei zhisou decoction was used. The main ingredients included roasted herba ephedrae, amygdalus communis vas, rhizoma zingiberis recens, platycodon grandiflorum, flos farfarae, pinellia temata, radix stemonae, herba periliae, etc., one dose a day, twice a day. In the combined therapy group, on the basis of the treatment as the Chinese herbal medicine group, scraping therapy was added and applied to the bladder meridian of foot-taiyang, the lung meridian of hand-taiyin, the conception vessel and the governor vessel, focusing on Tiantu (CV 22), Baihui (GV 20), Dazhui (GV 14), Feishu (BL 13), Fengmen (BL 12), Taiyuan (LU 9), Lieque (LU 7) and Fengchi (GB 20), once a week and one-week treatment as one session. Totally, the continuous two sessions were required in the two groups. The cough symptom score, cough remission time, relapse, TCM syndrome score, the score of Leicester cough questionnaire (LCQ), SP concentration in the supernatant of the induced sputum before and after treatment as well as clinical efficacy were observed in the two groups. RESULTS: The cough symptom score, TCM symptom score and SP concentration in the supernatant of the induced sputum were all apparently reduced after treatment in the patients of the two groups (all P<0.01). The scores in the combined therapy group were reduced in the higher amplitude as compared with those in the Chinese herbal medicine group (all P<0.01). The total effective rate was 95.0% (38/40) in the combined therapy group, better than 87.5% (35/40) in the Chinese herbal medicine group (P<0.05). Regarding the cough remission time and relapse rate, the results in the combined therapy group were better than those in the Chinese herbal medicine group[(5.3+/-1.2) d vs (7.4+/ 1.5) d, P<0.01; 0% (0/19) vs 62.5% (5/8), P<0.01]. The scoreo of LCQ was all apparently improved in the patients of the two groups (both P<0.01), and the score in the combined therapy group was higher than that in the Chinese herbal medicine group (P<0.01). CONCLUSIONS: Scraping therapy combined with xuanfei zhisou decoction and the simple application of xuanfei zhisou decoction all relieve the symptoms of post-infectious cough and improves the living quality. The therapeutic effects of the combined therapy are superior to the oral administration of xuanfei zhisou decoction. PMID- 29231363 TI - [Acupuncture with twirling reducing method for tinnitus of excessive liver-fire type:a clinical observation]. AB - OBJECTIVE: To observe the clinical efficacy of acupuncture with twirling reducing method for tinnitus of excessive liver-fire type. METHODS: One hundred and one patients with tinnitus of excessive liver-fire type were randomly divided into a twirling reducing method group (35 cases), a needle retaining group (33 cases) and a physical therapy group (33 cases). The patients in the twirling reducing method group were treated by acupuncture at Tinggong (SI 19), Tinghui (GB 2), Yifeng (TE 17), Zhongzhu (TE 3), Waiguan (TE 5), Xiaxi (GB 43), Taichong (LR 3), Qiuxu (GB 40), while the strong low-frequency twirling reducing method was applied at Xiaxi (GB 43) and Taichong (LR 3); the patients in the needle retaining group were treated with identical acupoints and needle insertion manipulation, but no reducing method was applied after needle insertion. Needles were all retained for 30 min. The patients in the physical therapy group were treated with laser and ultrashort wave. All the treatment was given once a day; one session was consisted of 7 days of treatment, and there was an interval of 2 days between sessions; totally 3 sessions were given. Before and after treatment, the tinnitus severity scale, the tinnitus handicap inventory (THI) and clinical efficacy were compared in the three groups. RESULTS: After treatment, the tinnitus severity scale and THI in the three groups were reduced (all P<0.05), and the scores in the twirling reducing method group were lower than those in the physical therapy group (both P<0.05). After treatment, the cured and markedly effective rate was 71.4% (25/35) in the twirling reducing method group, which was higher than 42.4% (14/33) in the physical therapy group (P<0.05). CONCLUSIONS: The efficacy of acupuncture with twirling reducing method for tinnitus of excessive liver-fire type is superior to that of physical therapy. PMID- 29231364 TI - [Clinical study of the electroacupuncture combined with thunder-fire moxibustion in treatment of degenerative knee osteoarthritis with cold-damp stagnation]. AB - OBJECTIVE: To observe the clinical effect of early degenerative knee osteoarthritis with cold-damp stagnation treated with electroacupuncture (EA) combined with thunder-fire moxibustion and simple EA. METHODS: Eighty cases were randomly assigned into a combination group and an EA group,40 cases in each one. Twenty-five min EA was used in the EA group mainly at ashi points,Neixiyan(EX-LE 4),Zusanli(ST 36),Dubi(ST 35),Yanglingquan(GB 34),Yinlingquan(SP 9) and Liangqiu(ST 34) after deqi (qi arrival),once a day. Based on EA at the same acupoints as the EA group,thunder-fire moxibustion was applied at ashi points,Dubi(ST 35)and Liangqiu(ST 34) by means of 20-minute suspended moxibustion,once a day. Ten-day treatment was seen as one course,and continuous 2 courses were applied. The indices were observed before and after treatment including visual analogue scale(VAS) score,Lequesne index score,Lysholm score of knee joint,serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Clinical effects were also evaluated and 6-month follow-up was implemented to show the recurrence rate. RESULTS: After treatment the total effective rate of the combination group was 95.0%(38/40),which was better than 82.5%(33/40) of the EA group(P<0.05).The Lequesne index score,VAS score,serum CRP and ESR apparently decreased compared with those before treatment in the two groups(all P<0.05),and the four indices in the combination group were obviously lower than those in the EA group(all P<0.05). As for the Lysholm knee joint score,the good rates of the two groups enhanced after treatment(both P<0.05),and the result of the combination group was superior to that of the EA group[87.5%(35/40) vs 72.5%(29/40),P<0.05]. At 6-month follow-up,the recurrence rate of the combination group was lower than that of the EA group[26.7%(4/15) vs 100.0%(9/9),P<0.05]. CONCLUSIONS: EA combined with thunder-fire moxibustion achieve good effect for degenerative knee osteoarthritis with cold-damp stagnation. The combination therapy have advantages in effect duration compared with simple EA. PMID- 29231365 TI - [Discussion of biological effects of moxibustion at Guanyuan (CV 4) and its influence factors]. AB - Moxibustion at Guanyuan (CV 4) can produce biological effects, mainly including local effects, targeting organ effects, systemic effects. The biological effects of moxibustion at Guanyuan (CV 4) are related to stimulation parameters and health or pathological nature of the objects, and the effects show acupoint specificity. Its research of local effects should be attached importance to and the acupoint specificity needs to be ascertained, as well as the relationships between the biological effects and stimulation parameters, and between the effects and health or pathological nature of the objects. PMID- 29231366 TI - [Revelation of angiosome theory in the study of meridian point structure]. AB - Meridian point and angiosome are the concepts in two different medical systems with a thousand year in between. In comparison between the angiosome concept and the meridian point structure characteristics in Huangdi Neijing (Yellow Emperor's Internal Classic), it is found that angiosome and meridian point are distri-buted in the head, face, trunk and four limbs. Both of them are the complex tissues of stereostructure. The essential structure of them is the vessel for blood circulation and the relevant vascular grades are of equity relationship. Both meridian point and angiosome are distributed segmentally and the number of perforator vessels is very near to that of meridian points. It is indicated on the basis of analysis that both of them are of high similarity in terms of human body structure and it is further discovered that the study achievement on angiosome not only benefits the understanding of traditional literature of meridian point, but also contributes to the deep research on the structural morphology of meridian point in terms of modern science and technology. PMID- 29231367 TI - [Experimental study of glucose-lowering effects on electroacupuncture at back-shu points in rats]. AB - OBJECTIVE: To observe the effects of electroacupuncture(EA) at different acupoints for fasting blood glucose(FBG) and oral glucose tolerance in type 2 diabetes rats so as to verify the glucose-lowering effects of EA. METHODS: Total 100 SD male rats were seen as experimental objects,among which 13 were randomly assigned into a blank group. Other rats were fed with high fat and high sugar diet combined with intraperitoneal injection of small dose streptozotocin (STZ) to establish type 2 diabetes model. Sixty diabetic rats were randomly assigned into a model group,a Weiwanxiashu group,a Xinshu group,a Shenshu group and a Housanli group,12 cases in each one. Combined with the improved diet habits and routines,EA (2 Hz and 2 mA) was used at "Weiwanxiashu" (EX-B 3),"Xinshu" (BL 15),"Shenshu" (BL 23) and "Housanli" (ST 36) in the corresponding groups,6 times a week for 4 weeks. There was no treatment in the blank group and in the model group. The observation indexes were the FBG on the 7th,14th,21st,and 28th day of intervention,the instant glucose-lowering effect on the 21st day during treatment,and the area under the curve of oral glucose tolerance test (OGTT) after intervention. Also,the glucose regulation condition was observed. RESULTS: Type 2 diabetes model could be established by high fat and high sugar diet combined with intraperitoneal injection of small dose STZ. Glucose decreased apparently at the end of the 1st week or the 2nd week compared with that before treatment in the Weiwanxiashu,Xinshu and Shenshu groups(P<0.05,P<0.01). The instant FBG of the Weiwanxiashu and Xinshu groups was obviously lower than that of the model and Housanli groups at the end of the 3rd week(all P<0.01). The area under the curve of OGTT of the Weiwanxiashu group was apparently smaller than that of the model group (P<0.05),and the results of the index in the other groups were not significantly different from that of the model group(all P>0.05). CONCLUSIONS: Low frequency EA at "Weiwanxiashu"(EX-B 3),"Xinshu"(BL 15) and "Shenshu"(BL 23) can reduce glucose with different onset times,effects,and durations. And "Weiwanxiashu"(EX-B 3) is more effective. PMID- 29231368 TI - [Repair effects of close-to-bone needing combined with electroacupuncture on extracellular matrix of cartilage in rabbits with knee osteoarthritis]. AB - OBJECTIVE: To observe the effects of close-to-bone needing combined with electroacupuncture (EA) on cartilage collagen type II/discoidin domain receptor/matrix metalloproteinase 13 (collagen type II/DDR2/MMP 13) signaling pathway in rabbits with knee osteoarthritis (KOA), and to explore the possible action mechanism of this method on repair of extracellular matrix of knee cartilage. METHODS: Forty New Zealand white rabbits were randomly assigned into a normal group (10 rabbits) and a model establishing group (30 rabbits). The Hulth Telhag technique was applied to establish the model of KOA, and X-ray was used for outcome assessment. The rabbits with successful modeling were randomly assigned into a model group, a close-to-bone needing group, a regular acupuncture group, 10 rabbits in each one. The rabbits in the close-to-bone needing group were treated with close-to-bone needing and EA; the rabbits in the regular acupuncture group were treated with regular acupuncture and EA. "Neixiyan" (EX-LE 4), "Dubi" (ST 35), "Yinlingquan" (SP 9), "Zusanli" (ST 36) and "Liangqiu" (ST 34) were selected in the two groups. The intervention was given for 20 min, once a day; the intervention of 5 days made 1 session, 2 days as the interval and totally 4 sessions were given. Rabbits in normal and model group were immobilized without any treatment. After the treatment, western blotting method was applied to evaluate the expression of DDR2 and collagen type II; the activity of collagen type II, DDR2 and MMP 13 was assessed by immunohistochemistry method; the mRNA expression of DDR2 and MMP 13 was determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Compared with the normal group, the activity expression of collagen type II were significantly reduced in the other groups (all P<0.01),while the activity and mRNA expression of DDR2 and MMP 13 were notably increased (all P<0.01). Compared with the model group, the activity expression of collagen type II in the close-to-bone needing group and regular acupuncture group were increased (all P<0.01), while the activity and mRNA expression of DDR2 and MMP 13 were reduced (all P<0.01). Compared with the regular acupuncture group, the activity and mRNA expression of MMP 13 and DDR2 in the close-to-bone needing group were reduced (all P<0.01), while the activity expression of collagen type II were increased (P<0.01). CONCLUSIONS: The close-to bone needing combined with EA and regular EA could both promote the repair of knee cartilage, where closing-to-bone needing combined with EA shows a superior efficacy. The mechanism may be associated with the blocking effect of collagen type II/DDR2/MMP13 signaling pathway and the inhibiting effect of degradation in extracellular matrix of cartilage. PMID- 29231369 TI - [Professor SHI Yin's experience of staging, classification and sorting method for polycystic ovary syndrome]. AB - The clinical experience of professor SHI Yin for polycystic ovary syndrome (PCOS) was summarized. According to the main pathogenesis of PCOS, the tonifying kidney should be taken as essence with synchronous treatment on liver, spleen and heart, presenting staging, classification and sorting method for PCOS. In the staging method, the regulation on follicle development should be taken as treatment core to comply with the rules of yin and yang. A four-stage method was proposed, where "regulating method" was suitable in menstrual period, "tonifying method" in follicular phase;"dredging method" in ovulatory period and "adjustment and tonifying " in luteal phase. In the classification and sorting method, attention was paid on individualized treatment, and treatment was based on fat type, thin type and non-fat type as well as childbearing. Besides, psychological counseling and life adjustment for patient was essential, and the unity of body and mind could enhance curative effect. PMID- 29231370 TI - [Experience of professor GUO Chengjie for mammary gland hyperplasia by disease symptom diagnosis and treatment]. AB - To introduce the experience of professor GUO Chengjie for mammary gland hyperplasia by disease-symptom diagnosis and treatment. Under disease-symptom combination and the reference of both Chinese medicine and western medicine,he took priority in diagnosis and then treated diseases by acupuncture and medicine,etc. Meanwhile,he considered the superficiality and origin of diseases and served patients based on individuals,seasons and regions. Also,regulation for mood was applied. As a result, the good effect was achieved. PMID- 29231371 TI - [Educational philosophy of acupuncture and moxibustion of Chengjiang school successor professor HUANG Zongxu]. AB - Based on the historical documents regarding professor HUANG Zongxu, his educational philosophy of acupuncture and moxibustion was summarized. As a result, the following characteristics were found. He focused on the education of acupuncture and moxibustion, which combined the classroom teaching with apprentice teaching; he compiled teaching materials and committed himself to education reform; he started the first acupuncture undergraduate majors in Fujian province; he valued the academic inheritance and practice of acupuncture; he authored publications and proposed arguments to inherit experience. In addition, he valued medical ethics and focused on patients. PMID- 29231372 TI - [Exploration on the treatment of xiaoke in terms of the conception vessel]. AB - Diabetes is in the category of xiaoke in TCM, which is mainly discussed in light of yin deficiency. The conception vessel is the sea of yin meridians, acting on regulating the accumulation and irrigation of qi and blood of twelve meridians and collaterals. The physiological function of the conception vessel is closely related to the pathogenesis of xiaoke, its running course is highly coincident with the location of xiaoke and the symptoms of xiaoke are relevant with the indications of the conception vessel. Hence, harmonizing qi and blood of the conception vessel may be an effective approach to the prevention and treatment of xiaoke. PMID- 29231373 TI - [Early meridian theories on unearthed medical bamboo slips from the Han Tomb in Laoguanshan of Chengdu]. AB - The meridian theories of Meridian Book unearthed from the Han Tomb in Laoguanshan have close relationship with those in ancient meridian literature from Mawangdui. The meridian theories of Meridian Book are different from those of the tomb figure marked with meridians and acupoints unearthed from the same tomb. The two meridian lines in the figure,which are red and white,show different meridian theories. The related content of Death Syndrome of Pulse from Laoguanshan is a reflection for generalization trend of meridian death syndrome and acupoints. PMID- 29231374 TI - [Influential factors and mechanism of non-specific effect in acupuncture]. AB - Even though a large amount of researches showing the clinical effectiveness of acupuncture, there are the researches indicating the absent difference between acupuncture and sham-acupuncture (placebo), which provides the doubts on the specificity of acupuncture. It may be considered that acupuncture intervention is complica-ted and may produce unique non-specific effect, which results in the failure to evaluate effectively the acupuncture efficacy. The influential factors of the non-specific effect of acupuncture include the interaction between physician and patient, expectancy, physician authority, acupuncture treatment experiences, etc. It may be also relevant with the anticipated biological effect, Hawthorne effect, Pavlovian conditioned reflex, etc. PMID- 29231375 TI - [Analysis for contemporary academic study of Experience on Acupuncture and Moxibustion Therapy]. AB - Experience on Acupuncture and Moxibustion Therapy is a profound book by WANG Zhizhong for acupuncture-moxibustion development. Twenty-five articles about arranging the book were analyzed in China National Knowledge Infrastructure(CNKI) from 1980 to 2015. It is considered that the versions spread are clear, and literature quoted is abundant but needed to be further sorted. Also, academic thoughts with value were deeply explored in terms of acupoint, moxibustion, acupuncture-moxibustion case, contraindication and health preserving. However, shortages about contemporary research exist, such as less exploration on historical cultural background of the book, the humanistic spirit of WANG Zhizhong, the rule of acupoint application and the treatment experie-nce. We should pay attention to the above points so as to further systematically study its academic thought. PMID- 29231376 TI - [Analysis of ancient literature on baliao points for pelvic floor diseases]. AB - The relationship between baliao points and pelvis floor diseases was explored based on the ancient literature review on these acupoints' targeted diseases. It is considered that baliao points are applied to treat various pelvis floor diseases and symptoms of different systems. Each point has similar function but with unique feature. Shangliao (BL 31) is mainly used to treat gynecologic diseases;Ciliao (BL 32) and Zhongliao (BL 33),urologic system and reproductive system diseases;Zhongliao (BL 33) and Xialiao (BL 34),reproductive system and anorectal system diseases. PMID- 29231377 TI - [Analysis of analogical function acupoints for mental diseases based on Indications of Acupoints, National Standard]. AB - OBJECTIVE: To summarize the acupoints for mental diseases in Indications of Acupoints,National Standard(GB/T30233-2013) so as to provide theoretical evidence for acupoint compatibility and acupuncture-moxibustion prescription. METHODS: The acupoints for mental diseases in Indications of Acupoints,National Standard were artificially retrieved,and then their frequencies,meridians and locations were analyzed. RESULTS: Eighty acupoints were collected totally. Shenmen (HT 7) was with the highest frequency,and Baihui (GV 20) was followed. The frequently-used meridians in turn were governor vessel (GV),bladder meridian of foot taiyang,small intestine meridian of hand-taiyang and stomach meridian of foot yangming,etc.,among which GV showed the highest number with 17 (21.25%) acupoints. As for the positions of analogical function acupoints,they in turn were head and face,upper limbs,lower lumbs,back and waist,chest and abdomen,with 30 percent acupoints locating at head and face. CONCLUSIONS: Analogical acupoints for mental diseases are focused at head and face,and they are mainly along GV. The treatment is based on syndrome differentiation. PMID- 29231378 TI - [Review and prospect of the standardization of acupuncture and moxibustion in China]. AB - Literature,achievements and other materials on acupuncture-moxibustion standardization research in recent years were collected and summarized domestically and overseas. The process of acupuncture-moxibustion standardization in China was reviewed through two phases. Also,we compared domestic acupuncture moxibustion standardization study with the foreign one. It is considered that its domestic development is sound but challenged by world competition in its internationalization. Going forward,acupuncture-moxibustion standardization system is needed to be completed and become international. Contemporary techniques should be used including big data,artificial intelligence,internet of things,and cloud computing,etc., and its application engineering research will be improved so as to drive Chinese medicine modernization. PMID- 29231379 TI - [Effects of electroacupuncture for visceral fat of simple obesity with stomach and intestinal heat]. AB - OBJECTIVE: To observe the clinical effect of electroacupuncture (EA) for visceral fat of simple obesity with stomach and intestinal heat. METHODS: Forty patients (waistline of male >= 90 cm and female >= 80 cm) were treated with EA at Quchi (LI 11), Zusanli (ST 36), Xiajuxu (ST 39), Shangjuxu (ST 37), Neiting (ST 44), Qiangu (SI 2), Erjian (LI 2), Tianshu (ST 25) and Fenglong (ST 40) for continuous 3 courses (12 treatments as 1 course) once every other day. The observation items before and after treatment were obesity indices[body weight (W), obesity degree (A%), body mass index (BMI), body fat percentage (F%, skinfold thickness me thod)], body circumference indices (chest measurement, waistline, hip circumference, thigh circumference, waist-to-hip ratio) and body composition indices[body fat percentage (F%), body moisture content ratio, visceral fat cross assessment index (VFA)]. Besides, 40 healthy control subjects with similar ages and gender ratio were recruited as control. RESULTS: The total effective rate of the observation group was 97.5% (39/40), with lower W, A%, F%, BMI, chest measurement, waistline, hip circumference, thigh circumference, waist-to-hip ratio and VFA as well as higher body moisture content ratio after treatment (all P<0.01). While there was statistical significance between the two groups for all the indices after treatment (all P<0.01). CONCLUSIONS: EA can induce body weight and visceral fat of simple obesity with stomach and intestinal heat as well as improve body composition. Besides, body moisture ratio increases. PMID- 29231380 TI - ["Dredging governor vessel" for cervical vertigo with deficiency of qi and blood:a randomized controlled trial]. AB - OBJECTIVE: To compare the effect differences of acupuncture of dredging the governor vessel (GV) and conception vessel (CV) for cervical vertigo with deficiency of qi and blood so as to provide Objective evaluation and guide for clinical treatment. METHODS: A total of 60 patients were randomly divided assigned into an observation group and a control group, 30 cases in each one. The acupoints of the observation group were mainly in the GV, namely Shenting (GV 24), Baihui (GV 20), Fengfu (GV 16), Dazhui (GV 14), Shenzhu (GV 12), Jiaji (EX-B 2) of C6 and C7, Zusanli (ST 36) and Sanyinjiao (SP 6). The acupoints of the control group were mainly in the CV, including Danzhong (CV 17), Zhongwan (CV 12), Xiawan (CV 10), Guanyan (CV 4), Qihai (CV 6), Jiaji (EX-B 2) of C6 and C7, Zusanli (ST 36) and Sanyinjiao (SP 6). Acupuncture was given once every other day and 10 treatments were taken as one course. After 2-course treatment, the changes before and after treatment of the scores of symptoms of cervical vertigo and functional evaluation scale, the scores of symptoms of deficiency of qi and blood, the mean blood flow rate of vertebral-basilar artery were observed. Also, the effects were evaluated. RESULTS: (1) The cured and effective rate and total effective rate of the observation group were 76.7% (23/30) and 93.3% (28/30), which were better than 46.7% (14/30) and 70.0% (21/30) of the control group (both P<0.05). (2) As for the scores of symptoms of cervical vertigo and functional evaluation scale and the mean blood flow rate, the results were obviously improved after treatment in the two groups (all P<0.05), with superiority in the observation group (all P<0.01). (3) After treatment,the scores of the symptoms of deficiency of qi and blood were decreased obviously in the two groups (all P<0.05). As to fatigue,facial expression,tongue and pulse condition,there was no statistical significance between the two groups after treatment (all P>0.05),but treatment for palpitation and shortness of breath achieved better effect in the control group(P<0.01). CONCLUSIONS: The effect of dredging the GV for cervical vertigo with deficiency of qi and blood is superior to that of acupuncture mainly in the CV,which can improve the symptoms of cervical vertigo and the mean blood flow rate of vertebral-besilar better. But acupuncture at acupoints both in the GV and CV may be better for the patients with syndrome of deficiency of qi and blood seriously. PMID- 29231382 TI - [Clinical observation of post semicircular canal benign paroxysmal positional vertigo treated with acupuncture at dizzy auditory region plus modified Epley]. AB - OBJECTIVE: To compare the effects between acupuncture mainly at dizzy auditory region combined with modified Epley and simple modified Epley for post semicircular canal benign paroxysmal positional vertigo (PC-BPPV). METHODS: Sixty seven patients were randomly assigned into an observation group (37 cases) and a control group (30 cases). Modified Epley was used in the two groups, and acupuncture was mainly applied at dizzy auditory region, Baihui (GV 20), emotion region and Taiyang (EX-HN 5) for 2 courses (6 days as a course), once a day. Syndrome scores before and after treatment as well as the effects of the two groups were observed. RESULTS: The total effective rate of the observation group was 91.9% (34/37),which was higher than 83.3% (25/30) of the control group, but there was no statistical significance between the two groups (P>0.05). The syndrome scores were improved apparently after treatment in the two groups (both P<0.001), with the better results after 1-course and 2-course treatments in the observation group compared with the corresponding ones in the control group (both P<0.01). CONCLUSIONS: Acupuncture mainly at dizzy auditory region combined with modified Epley for PC-BPPV are better than simple modified Epley. PMID- 29231381 TI - [The influence for success rate of warm acupuncture for tube baby of infertility patients with kidney yang deficiency:a randomized controlled trial]. AB - OBJECTIVE: To observe the success rate of warm acupuncture for tube baby of infertility patients with kidney yang deficiency. METHODS: Sixty patients were randomized assigned into an observation group and a control group, 30 cases in each one. Long-term super ovulation was applied in the two groups. While acupuncture was used at Zhongwan (CV 12), Tianshu (ST 25), Daimai (GB 26), Guanyuan (CV 4), Qihai (CV 6), Zhongji (CV 3), Zigong (EX-CA 1), Xuehai (SP 10), Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3) in the observation group, with warm acupuncture at Zigong (EX-CA 1) and Zusanli (ST 36), once a day, and treatment was implemented monthly from 10 days to 1 day before menstruation and continuously for 3 months. After the accomplishment of treatment or waiting, embryo transplantation was operated in the two groups. The success rates of embryo transplantation, the changes before and after treatment of the symptom and sign scores of kidney yang deficiency, menstrual symptom scores and endometrial types were observed. RESULTS: The pregnancy rate of the observation group was 46.7% (14/30), which was better than 23.3%(7/30) of the control group (P<0.05). After treatment, the symptom and sign scores of kidney yang deficiency and the menstrual symptom scores were improved compared with those before treatment in the two groups (all P<0.05), with the lower ones in the observation group (kidney yang deficiency score:5.6+/-1.8 vs 9.6+/-2.9, menstrual symptom score:4.1+/-0.5 vs 5.6+/-0.9, both P<0.05). After treatment, the endometrial types were superior to those before treatment in the two groups (both P<0.01), with better improvement in the observation group (P<0.05). CONCLUSIONS: Warm acupuncture can improve the success rate of tube baby of infertility patients with kidney yang deficiency, with advantages in symptom and sign of kidney yang deficiency, menstrual and endometrial situations. Its mechanism may be related to the improvement of menstruation and endometrium. PMID- 29231383 TI - [Clinical observation of herb-partition moxibustion at navel for constipation with excess syndrome]. AB - OBJECTIVE: To observe the effect differences between herb-partition moxibustion and starch-partition moxibustion at navel for constipation with excess syndrome. METHODS: Sixty patients were randomly assigned into an herb-partition moxibustion at navel group (herbal group) and a starch-partition moxibustion at navel group (starch group), 30 cases in each one. The acupoint was Shenque (CV 8) in the two groups. The treatment was given once a week and 4 times totally. Scores for constipation degree and quality of life (PAC-QOL) were observed before and after treatment and at follow-up; clinical effects were compared between the two groups as well. RESULTS: After treatment, the scores of constipation degree and QOL were lower than those before treatment in the herbal group (P<0.01,P<0.05), which were better than those of the starch group (P<0.01,P<0.05). Good effects were achieved for heat constipation (84.6%), qi constipation (77.8%) and cold constipation (87.5%) in the herbal group, and the improvements of heat constipation and qi constipation were better than corresponding results in the starch group (both P<0.05). The effective rate of the herbal group was 83.3% (25/30), and it was better than 43.3% (13/30) of the starch group. The two scores at follow-up had no statistical significances compared with those after treatment in the herbal group (both P>0.05), but superior to ones of the starch group (P<0.01,P<0.05); the effective rate of the herbal group was 86.6% (26/30), which was better than 50.0% (15/30) of the starch group (P<0.01). CONCLUSIONS: Herb-partition moxibustion at navel achieves better short-term and long-term effects than starch-partition for constipation with excess syndrome. PMID- 29231384 TI - ["Warming-promotion acupuncture" on knee osteoarthritis:a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy differences between warming-promotion acupuncture, mild reinforcing-reducing acupuncture and acupoint injection for knee osteoarthritis (KOA). METHODS: Ninety cases of KOA were randomly assigned into a warming-promotion acupuncture group (group A), a mild reinforcing-reducing acupuncture group (group B) and a sodium hyaluronate group (group C), 30 cases in each one. Patients in the group A and group B were treated at Xuehai (SP 10), Heding (EX-LE 2), Liangqiu (ST 34), Neixiyan (EX-LE 4), Dubi (ST 35), Xizhong (Extra), Yanglingquan (GB 34), Yinlingquan (SP 9), Zusanli (ST 36), and acupoints could be added or reduced based on syndrome differentiation; warming-promotion acupuncture was applied in the group A and mild reinforcing-reducing method was applied in the group B. Patients in the group C were treated with injection of sodium hyaluronate at any of Neixiyan (EX-LE 4), Dubi (ST 35) or Xizhong (Extra). Treatment was given once a day for group A and group B, and ten days were taken as one course; the injection was given every 5 days, and 2 times were taken as one course. There was an interval of 2 days between courses in the three groups. After three courses, the symptom and sign score and clinical efficacy were observed in the three groups. RESULTS: Compared with the group B and group C, the symptom and sign score was significantly reduced after treatment in the group A (all P<0.05). The total effective rate was 100.00% (30/30) in the group A, which was superior to 90.00% (27/30) in the group B (P<0.05) and 73.33% (22/30) in the group C (P<0.01). CONCLUSIONS: The clinical efficacy of warming-promotion acupuncture on KOA is obviously superior to the mild reinforcing-reducing acupuncture and injection of sodium hyaluronate, indicating its positive efficacy. PMID- 29231385 TI - [Relaxing needling combined with rehabilitation training for medial collateral ligament injury of knee joint]. AB - OBJECTIVE: To compare the clinical efficacy differences between relaxing needling combined with rehabilitation training and rehabilitation training alone for medial collateral ligament (MCL) injury of knee joint. METHODS: Sixty cases of MCL injury were randomly assigned into an observation group (30 cases, one case dropping out) and a control group (30 cases, two cases dropping out). Patients in the control group were treated with rehabilitation training; based on the treatment of control group, patients in the observation group were additionally treated with relaxing needles at ashi points, Heding (EX-LE 2), Neixiyan (EX-LE 4), Dubi (ST 35), Yanglingquan (GB 34), Liangqiu (ST 34), etc. The treatment was given once a day; six treatments were taken as one course, and totally four courses were given. The visual analogue scale (VAS), Lysholm knee function score and clinical efficacy before and after treatment were evaluated; also the safety was evaluated. RESULTS: After treatment, VAS scores were apparently reduced and the Lysholm scores were obviously increased in the two groups (all P<0.001). The improvement of VAS and Lysholm scores in the observation group were superior to that in the control group (both P<0.05). The effective rate was 93.1% (27/29) in the observation group, which was superior to 71.4% (20/28) in the control group (P<0.05). During the treatment, no adverse events occurred in the two groups. CONCLUSIONS: Relaxing needling combined with rehabilitation training can effectively improve the swel-ling, pain and other symptoms of MCL injury, which is superior to rehabilitation training alone. PMID- 29231386 TI - [Clinical observation of moxibustion plus exercise prescription for patella tendinopathy of athlete]. AB - OBJECTIVE: To compare the effects between moxibustion and inflammation therapy apparatus for patella tendinopathy of athlete. METHODS: Eighty patients were randomly assigned into a moxibustion group and a naturopathy group, 40 cases in each one. According to conditions,moxibustion was applied at the pain points of the terminal patellar tendon, Dubi (ST 35), Zusanli (ST 36), Yanglingquan (GB 34), Liangqiu (ST 34) and Xuehai (SP 10), etc., once a day and 30 min a time. Besides, exercise prescription was used, including ice compress, pull relaxation and targeted common strength exercise, etc. While in the naturopathy group, the microwave probe of inflammation therapy apparatus was aimed at the pain points of the terminal patellar tendon, once a day and 20 min a time. Also, the same exercise prescription was implemented as the moxibustion group. Seven treatments were taken as a course and 2 courses were required. Visual analogue scale (VAS) for knee joint pain and clinical effects were observed. RESULTS: After treatment, the VAS scores decreased compared with those before treatment in the two groups (both P<0.01),with more apparent one in the moxibustion group (P<0.05). The total effective rate of the moxibustion group was 97.5%(39/40), which was better than 82.5% (33/40) of the naturopathy group (P<0.05). CONCLUSIONS: Moxibustion combined with exercise prescription can effectively improve the pain induced by patella tendinopathy of the athletes, which is better than inflammation therapy apparatus. PMID- 29231387 TI - [Clinical observation of blood-letting to reduce pressure plus electroacupuncture for acute scapulohumeral periarthritis]. AB - OBJECTIVE: To evaluate the clinical effect of blood-letting to reduce pressure combined with electro-acupuncture for acute scapulohumeral periarthritis and to explore its mechanism. METHODS: Sixty-six patients were randomly assigned into an observation group (34 cases) and a control group (32 cases).Electroacupuncture (EA) was used at Jianyu (LI 15), Jianliao (TE 14), Jianqian (Extra), Jianzhen (SI 9), Quchi (LI 11) and ashi points in the two groups, once a day for 9 days. Besides, blood-letting to reduce pressure was applied at ashi points in the observation group, namely cupping therapy after blood-letting puncture 3 times, 3 10 mL a time,once 3 days. Ibuprofen capsules were prescribed orally for 9 days in the control group, 0.3 g a time,twice a day. 5-hydroxy-tryptamine (5-HT) and prostaglandin E2 (PGE2) of blood in the cups were tested by enzyme linked immunosorbent assay after the first and third blood-letting in the observation group. The changes of numerical rating scale (NRS) grades for pain and shoulder joint movements were observed. The comprehensive effects of the two groups were evaluated. RESULTS: The contents of 5-HT and PGE2 after the third blood-letting apparently decreased compared with those after the first operation in the observation group (both P<0.001). The grades of NRS and shoulder movements were obviously improved after treatment in the two groups (all P<0.001),with better results in the observation group (both P<0.05). The result of 4 cured cases, 20 apparently effective cases, 9 effective cases and 1 noneffective case in the observation group was superior to that of 1, 10, 15, 6 in the control group (P<0.05). CONCLUSIONS: Blood-letting therapy combined with EA can ease pain and improve shoulder joint function of scapulohumeral periarthritis,and the effect is better than that of ibuprofen combined with EA. The mechanism may be related to directly discharging the inflammatory substances in local blood of the affected shoulder. PMID- 29231388 TI - [Introduction to "motion acupuncture" and target points]. AB - Motion Acupuncture (MA) is a novel acupuncture technique characterized by accurate insertion, special needling, and needle-retaining motion. It refers to that patients continuously carry out active or passive motions of the body under supervision of doctors, with needles inserted and retained in the acupuncture points throughout the session. The therapeutic points of MA are pain points, ashi points, pressure points, trigger points and nodules of sinews. MA is mainly to release the subcutaneous fascia by needling; the key point of this therapy is to carry out motions of the body with the needles' retention; and the key technologies are the muscle flexion and extension, stretching and resistance. MA has shown a good efficacy for pain caused by soft tissue injury and relevant visceral disorders. The main mechanism of MA is through the treatment of target points to release the relevant fascial chains, and through the fascial chain transmission to restore the balance of body structures, so as to achieve the purpose of treating diseases. PMID- 29231389 TI - [Effects of acupuncture manipulations for acupoints impedance under the skin clinical report of 60 healthy volunteers]. AB - OBJECTIVE: To explore the effects of acupuncture manipulations for acupoints by their impedance under the skin. METHODS: The retaining,reinforcing and reducing of acupuncture were implemented on 60 healthy volunteers, and the needles were retained for 20 min. Data analysis system for the electrical characteristics of single point was used, with insulation coating needles as the probes. The effects of acupuncture manipulations before, in the middle of and after intervention were observed through the real time dynamic detection for Zusanli (ST 36). RESULTS: 1The impedance during the reducing process was apparently higher than that during the reinforcing (P<0.05), and the reinforcing was obviously higher than that of retaining (P<0.05), namely Rreducing > Rreinforcing > Rretaining. 2After intervention,the three manipulations can decrease the impedance of acupoints than before (all P<0.01). The retaining method reduced about 11.44 kOmega; reinforcing, 11.15 kOmega; reducing,11.12 kOmega. CONCLUSIONS: Acupuncture manipulations can variously and apparently change the impedance of acupoints. PMID- 29231390 TI - [Effects of electroacupuncture combined with dietary control on liver endoplasmic reticulum stress in rats with non-alcoholic fatty liver disease]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) combined with dietary control on liver endoplasmic reticulum stress (ERS) in rats with non alcoholic fatty liver disease (NAFLD), and to explore the action mechanism of EA on NAFLD. METHODS: Sixty male SD rats were randomly divided into a common diet group (15 rats) and a model group (45 rats, fed with high-fat diet to induce NAFLD model). After model establishment, 10 rats in the common diet group were randomly selected as a control group, and 40 rats in model group were randomly divided into a high-fat diet (HFD) group, a low-fat diet (LFD) group, an EA-1 group and an EA-2 group, 10 rats in each one. From the 2nd day of model establishment, rats in the HFD group and EA-1 group were fed with high-fat diet, while rats in the LFD group and EA-2 group were fed with common diet. Rats in the EA-1 group and EA-2 group were treated with acupuncture at unilateral "Zusanli" (ST 36), "Sanyinjiao" (SP 6) and "Taichong" (LR 3), besides,"Zusanli" (ST 36) and "Sanyinjiao" (SP 6) were connected with EA. The treatment was given once a day, and two sides of acupoints were selected alternatively. Each treatment last 20 min for totally 4 weeks. The rats in the remaining groups were treated with identical fixation method. After treatment, the liver tissues of rats in each group were collected and made into ultra-thin slice to perform transmission electron microscope (TEM) on the endoplasmic reticulum morphology; western blot and real-time PCR method were applied to observe the protein and gene expression of the specific ERS protein, glucose-regulated protein 78 (GRP78). RESULTS: Under TEM, plenty of rough endoplasmic reticulum in alignment was observed in the cytoplasm of rats in the control group, accompanied with indistinct adhering ribosome; the rough endoplasmic reticulum in the cytoplasm in the HFD group was in expansion and obvious breakage, presenting small vacuoles in irregular arrangement; the expansion of rough endoplasmic reticulum in the LFD group and EA 1 group was relieved without appa-rent breakage and disarrangement; the rough endoplasmic reticulum in the EA-2 group was in alignment without obvious expansion. The protein expression of GRP78 was little in the control group, while the protein and mRNA expression of GRP78 were obviously increased in the remaining groups (all P<0.01). The protein and mRNA expression of GRP78 in the LFD group and EA-1 group were significantly lower than those in the HFD group (all P<0.01); those in the EA-2 group were lower than those in the LFD group and EA-1 group (all P<0.01). CONCLUSIONS: EA effectively improves the liver ERS in NAFLD rats, which can be one of the action mechanisms of EA on NAFLD. In addition, the efficacy is more significant with diet control. PMID- 29231392 TI - [Brief introduction of ZHENG's "golden hook fishing" technique in acupuncture]. AB - Golden hook fishing technique in acupuncture is one of the characteristics for the inheritance of aca-demic school of ZHENG's acupuncture technique. On the theoretic basis of traditional "lifting and thrusting" technique and "biting hook" sensation, by the coordination of the hands, focusing on the gentle lifting and shaking technique, selecting ashi points, the tendon-knotted sites, the eight influential points and experienced effective points, this special acupuncture technique is used for acute pain disorders and brain disorders in clinical application. PMID- 29231391 TI - [Effects of electroacupuncture on insulin resistance and hypothalamic insulin signal molecule in rats with diet-induced obesity]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) on body weight, insulin resistance (IR) and hypothalamic insulin signal molecule in rats with diet-induced obesity (DIO), and to explore the action mechanism of EA on DIO. METHODS: Fifty SD male rats were randomly divided into a low fat diet (LFD) group (10 rats) and a high fat diet (HFD) group (40 rats). Rats were fed with LFD and HFD, respectively, and the DIO model was established in the HFD group. After the model was established, the rats were randomly divided intoa model group, an EA group and a medication group, ten rats in each one. The rats in the EA group were treated with EA at "Housanli" (ST 36) and "Quchi" (LI 11) for 20 min, once a day for totally 28 days. The rats in the medication group were treated with intragastric administration of orlistat, once a day for 28 days. The rats in the LFD group and model group received no treatment. After treatment, HE staining method was applied to observe the morphological changes of liver; the biochemistry technique and radioimmunoassay method were applied to detect the fasting plasma glucose (FPG) and fasting insulin (FINS); Western blot method was applied to measure the expression of phosphatidylinositol-3 kinase p85 subunit (PI3K-p85) and insulin receptor substrate 2 (IRS2). RESULTS: Under light microscope, compared with the model group, the fatty degenerative cells were below 1/2 in the EA group and the medication group, accompanied with decreased lipid droplet, mild edema and none inflammatory infiltration. The body weight, FPG, FINS, homeostasis model assessment-insulin resistance index (HOMA-IR) and PI3K-p85 in the EA group were significantly lower than those in the model group (P<0.01, P<0.05), but the expression of IRS2 was not significantly different from the model group (P>0.05). The body weight, HOMA-IR and PI3K-p85 in the medication group were lower than those in the model group (P<0.01, P<0.05), but the expression of IRS2 was higher than that in the model group (P<0.05). The differences of each index were not significant between the EA group and the medication group (all P>0.05). In addition, rats in the medication group showed watery defecation, decreased activity, fatigue mentality and yellow hairs, while rats in the EA group showed normal defecation and vivid hair. CONCLUSIONS: EA can decrease the expression of PI3K-p85 to prompt the IR of DIO rats, inhibit the weight body and improve hepatic steatosis, which is probably one of the action mechanisms of EA on DIO. Besides, the adverse effects as the medication group can be avoided. PMID- 29231393 TI - [Professor WANG Yin's academic thoughts and clinical application of acupuncture for spleen-sto-mach care]. AB - Professor WANG Yin's academic thoughts and clinical application for difficult and miscellaneous di-seases, especially acupuncture for spleen-stomach care, are introduced. Based on TCM basic theory and "ten needles for elderly" by WANG Yueting, Professor WANG Yin proposes the acupuncture for spleen-stomach care. In this method, three-element acupoint selection is applied; the conception vessel, spleen meridian of foot taiyin and stomach meridian of foot yangming were selected. The deep and penetration acupuncture with 0.4 mm*100 mm elongated needles is used at Zhongwan (CV 12), Qihai (CV 6) and Zigong (EX-CA 1), and the mild reinforcing-reducing method is used at remaining acupoints. According to the severity of diseases, fire acupuncture combined with blood-letting cupping is applied at Tianshu (ST 25), Xuehai (SP 10) and Yinlingquan (SP 9); gene-rally, two acupoints are selected and 1 to 3 mL blood-letting is appropriate. The modification based on this me-thod can be applied for various difficult and miscellaneous diseases, leading to superior efficacy. PMID- 29231394 TI - [History of acupuncture in India]. AB - India and China are both featured with ancient civilization. During the communication between the two countries, the communication from Indian culture, especially Buddhism, to China was predominant, while communication from Chinese culture to India was rare. So it was with medical communication until the end of 1950s when acupuncture was introduced to India. In this article, the medical communication between India and China as well as the introduction of acupuncture to India were discussed, and the resulting phenomenon was analyzed. The introduction of acupuncture to India proved personnel exchange was not necessary to acupuncture communication, and several invisible factors, such as language, religion and culture tradition might be the reasons for foreign nations to accept acupuncture. Therefore, these factors should be valued in the future international communication of acupuncture. PMID- 29231395 TI - [Superficial-vessel diagnosis and its significance]. AB - Based on Internal Classic,the significant issues related to the superficial vessel diagnosis are discussed from five aspects,namely observing the color and shape of the superficial vessel,making a diagnosis and treatment,observing the development,the reactive diagnosis and special diagnosis. The theoretical and clinical va-lue is analyzed. The new understanding refers to the concept of reactive diagnosis for the superficial vessel and its significance,the diagnosis and development without treatment,special pathogenic factors invading and then staying in meridians until the out-breaking of Bi syndrome. Also,it is proposed that the diagnostic methods of the pulse and the superficial vessel are the basis of qi and blood differentiation in acupuncture and moxibustion. It is considered that the theories of collateral and cutaneous region in ancient time have close relationship with the superficial-vessel diagnosis. PMID- 29231396 TI - [New approach to acupoint prescription:acupoint combination based on Chinese herbal medication]. AB - In the paper, the origins of acupoint combination based on Chinese herbal medication, the characteris-tics and the correspondence of acupoints and Chinese herbal medicines are introduced, referring to meridian tropism, harmonization of acupoints and herbal medicines, ascending or descending action of herbal medicines, four natures of herbal medicines, etc. In clinical application, the Chinese herbal medicine formulas are determined before the acupoint combination in terms of pattern/syndrome differentiation. As a result, the actions of herbal medicines and properties of acupoints are harmonized and mutually affected with each other. PMID- 29231397 TI - [Research of preparation for Principle of the establishment and revision for Standardized Manipu-lation of Acupuncture and Moxibustion,national standard]. AB - During the preparation for Principle of the establishment and revision for Standardized Manipulation of Acupuncture and Moxibustion,a national standard, it is difficult to revise and ascertain the title of the standard, which is finally defined through related literature. The key of the standard presents the selection of standardized manipulation, including the process of work, the basic requirement as well as the structural elements and content requirement. The requirement for content is the priority and difficulty of the standard establishment,which takes great importance to the term and definition as well as the step and requirement of manipulation. Based on the issues and solutions during the study, we conclude that it is better to implement the following measures, such as learning the principle and method of standard establishment, referring to the similar standards, retrieving technique-related literature, taking advices from all aspects and revising the protocol repeatedly. PMID- 29231398 TI - [Comparison of the compilation features of Science of Meridians and Acupoints among different editions]. AB - The compilation features of Jingluo Shuxue Xue (Science of Meridians and Acupoints) among different editions were summarized and analyzed. Jingluo Xue (Science of Meridians) and Shuxue Xue (Science of Acupoints) published by Shanghai Scientific and Technical Publishers in 1984 are the pioneer as the textbook for the education of acupuncture discipline for the bachelor degree, but there is the big controversy for the editions in 1996. These two books were combined as one, titled Science of Meridians and Acupoints, 2013 edition, published by China Press of Traditional Chinese Medicine. It is concise and coherent in content and is regarded as the milestone in the history of textbook compilation. This book was re-edited in 2007 without major changes in content. The one in 2009 was revised a lot on the basis of the original several editions, published by Shanghai Scientific and Technical Publishers. But unfortunately, it did not bring the big impacts in China. The edition in 2012, published by China Press of Traditional Chinese Medicine had made the innovations besides integrating the achievements of the previous editions, characterized as preciseness and conciseness. By contrast, the edition in 2012, published by People's Medical Publishing House was accomplished by simple modification on the basis of the editions in 2003 and in 2007, without great innovation. Regarding the on-going publication of the textbooks in "the 13th five-year plan", it is viewed that the new edition of textbook should maintain the general framework of "the 12th five-year plan", based on which, a few questions should be revised appropriately. Additionally, "less words, more illustration" should be the basic principle for the revision of the new edition. PMID- 29231399 TI - [Exploration of the teaching model of acupuncture in the foreign fair]. AB - The teaching experience is getting enriched during the past 40-year practice in Beijing International Acupuncture Training Center. The new teaching model is explored constantly and enable to adapt to the development and demand in the new era. In the paper, the necessity and feasibility of the reform of acupuncture teaching model are explained in five aspects, named developing teaching materials and promoting traditional culture, brea-king routine sequence and striving to the combination of the dynamic and the static, enhancing clinical case practice and improving practice ability, adjusting teaching time and emphasizing clinical teaching, reforming checking me-thod and increasing practice skills. An acupuncture teaching model in foreign fair is proposed in terms of individual and flexible teaching and practice emphasis. PMID- 29231400 TI - [Origin and exploration of "white tiger shaking the head" technique]. AB - White tiger shaking head technique is one of the four techniques for meridian qi conduction. It is a very complicated technique and has many controversies by medical scholars of dynasties, which results in the difficulties in the normalization of manipulation in teaching and clinical practice. In the paper, in terms of the origins and the statements of medical scholars in different dynasties, it is attempted to explain the original technique, to explore the existing questions in practice and also propose the understanding on this technique. PMID- 29231401 TI - [Literature regarding clinical research of acupuncture for depression in the worldwide:comparison and discussion]. AB - The literature regarding clinical research of acupuncture for depression published in Wanfang database, VIP database, CNKI database and PubMed from January of 2004 to March of 2005 was collected, and the quality of randomized controlled trial (RCT) that met the inclusive criteria was evaluated with Jadad. The research designs (research objective, intervention, effect assessment) were compared and analyzed by using the 2010 version of Consolidated Standards of Reporting Trials (CONSORT) and Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA). As a result, a total of 57 articles were included in the comparative study, 46 of which were RCTs (36 articles were published in China core journals, 6 articles written by China were published in foreign countries, and 4 articles were foreign researches). It was found the literature of Chinese researches attached great importance to the syndrome differentiation of acupuncture, and various types of acupuncture intervention and biological effect indicators were applied; the literature of foreign researches presented advantages on RCT quality, and the baseline evaluation and effect evaluation systems were more comprehensive, in addition, more attention was paid to quantitative design of clinical parameters. It was concluded the differences between Chinese and foreign clinical research of acupuncture for depression were unfavorable for the evidence-based research, and the overall quality of researches was in need of improvement. It was recommended the future researchers should be designed and reported in accord with unified criteria, and the registration of acupuncture clinical trial should be valued, which could promote the integration of research results and improve the overall researches level. In this process, the research model of real world might be introduced to stimulate new development trends of acupuncture clinical research. PMID- 29231402 TI - [Clinical plan of acupuncture for sclerosis]. AB - The literature regarding acupuncture for sclerosis in CNKI database, VIP database and Wanfang database from date of database establishment to April 1st, 2015 was retrieved. As a result, 26 articles of clinical researches and medical cases with significant efficacy were collected. It was found the methods and clinical plan of acu-puncture for sclerosis were various and distinctive, including filiform needle acupuncture, electroacupuncture, bee acupuncture, fire acupuncture, moxibustion, herb moxibustion as well as acupuncture-moxibustion combined with cupping, hot compress, acupoint injection. It was concluded acupuncture moxibustion combined with various methods could complement each other's strengths, and achieve synergistic effect. The efficacy was affirmative and the characteristics of TCM were significant, however, researches regarding the scientific normalization and stan-dardization of the clinical plan were needed. PMID- 29231403 TI - [Post-stroke dysphagia treated with acupuncture of meridian differentiation:a randomized controlled trial]. AB - OBJECTIVE: To observe the effect on post-stroke dysphagia treated with acupuncture of meridian differentiation. METHODS: One hundred and thirty patients of post-stroke dysphagia were randomized into an observation group (67 cases) and a control group (63 cases). Conventional medication and rehabilitation training were applied in the two groups. In the observation group, acupuncture based on meridian differentiation was adopted. The main acupoints were Neiguan (PC 6), Shuigou (GV 26), Sanyinjiao (SP 6), Fengchi (GB 20), Lianquan (CV 23), Jialianquan (Extra), Jinjin (EX-HN 12), Yuye (EX-HN 13), etc. The supplementary points were selected according to different patterns/syndromes. In the control group, the points were selected 5 cm lateral to the acupoints used in the observation groups and stimulated with shallow puncture. The needles were retained for 30 min, once daily, 5 treatments a week and continuously for 6 weeks in the two groups. Separately, before treatment, in 6 weeks after treatment and in follow-up after 3 months, the standardized swallowing assessment (SSA), the video fluoroscopic swallowing study (VFSS), the modified Barthel index (MBI) and the swallowing related quality of life (SWAL-QOL) were observed in the two groups and the efficacy was assessed. RESULTS: In 6 weeks of treatment, the scores of SSA, VFSS, MBI and SWAL-QOL were improved apparently as compared with those before treatment (P<0.01, P<0.05) in the patients of the two groups. The results in the observation group were better apparently than those in the control group (P<0.01, P<0.05). In follow-up after 3 months, the scores of SSA, MBI and SWAL QOL were improved apparently as compared with those before treatment in thepatients of the two groups (all P<0.01), in which, MBI score was improved apparently as compared with that in 6 weeks of treatment in the patients of the two groups (both P<0.05). Those scores in the observation group were improved apparently as compared with those in the control group (P<0.01, P<0.05). In 6 weeks of treatment and in 3 months of follow-up, the effective rates in the observation group were 91.8% (56/61) and 93.4% (57/61), better than 80.0% (44/55) and 85.5% (47/55) in the control group separately, indicating the significant difference (both P<0.05). CONCLUSIONS: The acupuncture of meridian differentiation improves significantly swallowing function and survival quality in patients of stroke. PMID- 29231404 TI - [Acupuncture combined with rehabilitation training for foot drop after stroke]. AB - OBJECTIVE: To compare the clinical efficacy difference between acupuncture combined with rehabilitation and simple rehabilitation for foot drop after stroke. METHODS: Ninety-eight patients were randomly divided into a combination group and a rehabilitation group, 49 cases in each one. Acupuncture and rehabilitation were used in the combination group. The acupoints were Yanglingquan (GB 34), Zusanli (ST 36), Guangming (GB 37), Xuanzhong (GB 39), Sanyinjiao (SP 6), etc., while rehabilitation included training for musculi hippicus strength and musculi triceps surae. Only the same rehabilitation was applied in the rehabilitation group. The treatment was given six times a week for continuous six weeks. Musculi hippicus force, shank triceps spasticity, toe flexion improvement and the maximum integral EMG (iEMG) of the musculi tibialis anterior and caput laterale musculi gastrocnemii were compared between the two groups,and the effects were evaluated. RESULTS: After treatment, the musculi hippicus force, iEMG of musculi tibialis anterior and caput laterale musculi gastrocnemii, the function scores of the lower limbs by Fugl-Meyer of the two groups were better than those before treatment (all P<0.05), with the better effect in the combination group (all P<0.05). And the scores of shank triceps tension were decreased in the two groups (both P<0.05), more apparently for the combination therapy (P<0.05). The improvement rate of toe flexion of the combination group was 87.76% (43/49), which was obviously higher than 69.39% (34/49) of the rehabilitation group (P<0.05). The cured rate of the combination group was 48.98%(24/49), and it was better than 28.57% (14/49) of the rehabilitation group (P<0.05). CONCLUSIONS: Acupuncture combined with rehabilitation achieves better effect than simple rehabilitation for foot drop after stroke. PMID- 29231405 TI - [Active Crohn's disease treated with acupuncture and moxibustion:a randomized controlled trial]. AB - OBJECTIVE: To observe the effects and safety of clinical common symptoms of active Crohn's disease at the mild and moderate stages treated with acupuncture and moxibustion. METHODS: One hundred and two patients were randomly divided into an observation group and a control group, 51 cases in each one. Herb-partition moxibustion and acupuncture were used in the observation group. Herbal cakes with Huanglian (coptis chinensis), Fuzi (radix aconiti carmichaeli), Rougui (cinnamomum cassia), Muxiang (radices saussureae), Honghua (carthamus tinctorious), Danshen (the root of red-rooted salvia) and Danggui (angelica sinensis) as the main ingredients were used on Tianshu (ST 25), Qihai (CV 6) and Zhongwan (CV 12); acupuncture was used at Zusanli (ST 36), Shangjuxu (ST 37), Sanyinjiao (SP 6), Taixi (KI 3), Gongsun (SP 4) and Taichong (LR 3). Bran partition moxibustion and shallow acupuncture were applied in the control group. Wheat bran-partition moxibustion in the shape of cake was implemented on the same acupoints as the observation group; shallow acupuncture was used 1~2 cm next to the acupoints. Treatment was given three times a week for 12 weeks, 36 times totally. Clinical effects of eight symptoms were evaluated by TCM symptom score, and the symptoms included abdominal pain (degree, frequency, time), diarrhoea (number, shape and frequency), fatigue, anorexia, borborygmus andflatus, fear of cold, soreness and weakness of waist and knees, tenesmus. RESULTS: After 12-week treatment, the eight symptoms were improved apparently (all P<0.05), with the scores of abdominal pain (degree, frequency, time), diarrhoea (shape and frequency), fatigue and anorexia in the observation group decreasing more obviously (all P<0.01). There was no statistical significance about the other symptom scores between the two groups (all P>0.05). CONCLUSIONS: Herb-partition moxibustion combined with acupuncture achieve safety and efficacy for mild and moderate Crohn's disease, and can improve the clinical common symptoms. Furthermore, their effects on abdominal pain (degree, frequency, time), diarrhoea (shape and frequency), fatigue and anorexia are better than those of bran partition moxibustion and shallow acupuncture. PMID- 29231406 TI - [Efficacy differences between different position in patients treated with electroacupuncture for lumbar herniated disc]. AB - OBJECTIVE: To observe the clinical efficacy differences between modified lateral position and prone position in patients treated with electroacupuncture (EA) for lumbar herniated disc (LHD). METHODS: Seventy-six patients with LHD were randomly divided into a lateral position group and a prone position group, 38 cases in each one. The acupoint selection and treatment method were identical in the two groups except the position. Mingmen (GV 4), Yaoyangguan (GV 3), Dachangshu (BL 25), Xiaochangshu (BL 27), Zhibian (BL 54) and Huantiao (GB 30) were selected. EA was given three times a week, ten times were taken as one course and totally 20 times were given. The visual analogue scale (VAS) and Japanese orthopaedic association (JOA) scale were taken as efficacy criteria, which were evaluated before and after treatment as well as one month after treatment. RESULTS: After treatment, VAS and JOA were significantly improved in the two groups (lateral position group:JOA 10.60+/-2.60 vs 18.92+/-3.87, VAS 8.13+/-0.99 vs 2.34+/-0.81; prone position group:JOA 10.94+/-2.06 vs 17.02+/-3.96, VAS 8.02+/-1.05 vs 2.86+/ 0.96, all P<0.01); the VAS and JOA in the lateral position group were higher than those in the prone position group (both P<0.05). One month after treatment, VAS and JOA were significantly improved in the two groups (all P<0.01), which was more significant in the lateral position group (both P<0.05). CONCLUSIONS: The treatment position could influence the efficacy of EA for LHD, and lateral position pre-sents certain advantages to prone position group. PMID- 29231407 TI - [Long-snake moxibustion for rheumatoid arthritis:a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy differences among long-snake moxibustion, warm needling and western medication on rheumatoid arthritis and explore its effect mechanism. METHODS: One hundred and twenty patients were randomized into a long-snake moxibustion group, a warm needling group and a western medication group, 40 cases in each one. In the long-snake moxibustion group, the long-snake moxibustion was used. The ginger-isolated moxibustion was applied along the governor vessel, from Dazhui (GV 14) to Yaoshu (GV 2), once a month, for 2 months. In the warm needling group, the main points included Dazhui (GV 14), Ganshu (BL 18), Pishu (BL 20), Shenshu (BL 23), Zhiyang (GV 9), Mingmen (GV 4) and Yaoyangguan (GV 3). The warm needling technique was used at 4 to 5 points each time, and 3 moxa cones were required at each points. The treatment was given once every two days, for 2 months. In the western medication group, methotrexate was prescribed for oral administration, 10 mg each time, once a week. If the joint pain score or joint swelling score was up to 6, diclofenac sodium was combined, 25 mg each time, 3 times a day, for 2 months. The symptom score, physical sign score, the visual analogue scale (VAS) score, levels of rheumatoid factor (RF), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), immunoglobulin M (IgM) and immunoglobulin G (IgG) were observed before and after treatment in the patients of the three groups. RESULTS: The treatments relieved the symptoms and physical signs of rheumatoid arthritis and improved VAS score and the levels of serum RF, ESR, CRP, IgM and IgG in all of the three groups (all P<0.01). The efficacy in the long-snake moxibustion group was significantly better than that in the warm needling group and the western medication group (P<0.05, P<0.01). CONCLUSIONS: The long-snake moxibustion achieves the significant clinical efficacy on rheumatoid arthritis, better than warm needling therapy and methotrexate. This therapy much better reduces immune response and alleviates the sickness. PMID- 29231408 TI - [Rheumatoid arthritis treated with acupoint application of huiyao tongluo dingtong san:a rando-mized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy differences on rheumatoid arthritis treated with acupoint application of huiyao tongluo dingtong san (preparation of Hui medicine), tender point herbal application and leflunomide. METHODS: Ninety six patients were randomized into an acupoint herbal application group, a tender point herbal application group and a leflunomide group, 32 cases in each one. In the acupoint herbal application group, huiyao tongluo dingtong san paste was used at Dazhui (GV 14), Mingmen (GV 4), Zusanli (ST 36) and the local points on the yang meridians around the knee joint. In the tender point herbal application group, the self-prepared Hui medicine was used at tender points, 4 to 6 h each time, at the interval of 7 days. In the leflunomide group, leflunomide was applied for oral administration, 50 mg on each of the first 3 days, once a day; 20 mg each time 3 days later, once a day. The treatment for 1 month made one session in the three groups, and continuous three sessions of treatment were required. The clinical symptoms, laboratory indices such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF) and the total score of symptoms were observed before and after treatment in the patients of three groups. The efficacy was evaluated in the 3 groups. RESULTS: The total effective rate was 87.5% (28/32) in the acupoint herbal application group and was 90.6% (29/32) in the leflunomide group, better than 68.8% (22/32) in the tender point herbal application group (both P<0.05). After treatment, the clinical symptoms, laboratory indices and the total score of symptoms were all improved as compared with those before treatment in the three groups (all P<0.05). Among the three groups, the results of pain, swelling, tenderness and the total score of symptoms as well as ESR and RF in the acupoint herbal application group and the leflunomide group were all better than those in the tender point herbal application group (P<0.05, P<0.01). Blister and pruritus occurred in 2 cases in each of the acupoint herbal application group and the tender point herbal application group. Nausea and poor appetites in 2 cases, dizziness and lassitude in 1 case and skin rashes in 1 case occurred in the leflunomide group. CONCLUSIONS: The improvements in the symptoms of rheumatoid arthritis and laboratory indices in the acupoint herbal application of huiyao tongluo dingtong san are better than those in the treatment with tender point herbal application. The efficacy of it is similar to that of leflunomide, without adverse reactions such as nausea, poor appetite, dizziness and lassitude. PMID- 29231409 TI - [Postmenopausal osteoporosis treated with acupoint injection of salmon calcitonin:a randomized controlled trial]. AB - OBJECTIVE: To verify the clinical efficacy on postmenopausal osteoporosis treated with acupoint injection of salmon calcitonin. METHODS: Ninety patients of postmenopausal osteoporosis were randomized into three groups, 30 cases in each one. In the acupoint injection group, Shenshu (BL 23) and Zusanli (ST 36) were selected bilaterally. The injection 4 mL was prepared with salmon calcitonin 100 U (1 mL) and 0.9% sodium chloride injection. Each acupoint was stimulated with the injection, 1 mL. In the blank group, 0.9% sodium chloride injection was applied to bilateral Shenshu (BL 23) and Zusanli (ST 36), 1 mL at each acupoint. In the intramuscular injection group, salmon calcitonin 100 U was injected at gluteus maximus. The treatment was given once every two days in the patients of the three groups and lasted for 2 months. The levels of bone mineral density (BMD), bone alkaline phosphatase (NBAP), C-terminal telopeptides of typeIcollagen (CTX), urine calcium/creatinine (Ca/Cr) and the symptom score of osteoporosis were detected in the patients of the three groups before and after treatment. RESULTS: In the patients of the three groups, NBAP and BMD in lumbar vertebra after treatment were higher than those before treatment (all P<0.05); CTX, Ca/Cr and symptom score were lower than those before treatment (all P<0.05). After treatment, NBAP was (32.7+/-2.5) MUg/L in the acupoint injection group, higher than those in the blank group and the intramuscular injection group (both P<0.05). In the acupoint injection group, CTX was reduced to (239.7+/-63.6) MUmmol/L and Ca/Cr was reduced to 0.525+/-0.274, apparently lower than those in the blank group and intramuscular injection group (both P<0.05). After treatment, in the acupoint injection group, BMD of lumbar vertebra was (0.731+/-0.062) g/m2, higher than the level of the rest two groups (both P<0.05). After treatment, the symptom score was 5.2+/-0.6 in the acupoint injection group, lower than those in the blank group and intramuscular injection group (both P<0.05). CONCLUSIONS: Salmon calcitonin injec-tion at Zusanli (ST 36) and Shenshu (BL 23) achieves significant efficacy on postmenopausal osteoporosis, stimulating osteoblast activity and inhibiting bone absorption of osteoclast. PMID- 29231410 TI - [Analysis on factors for effects of motor function of cerebral palsy children assisted by acupuncture-Retrospective analysis with 520 cases attached]. AB - OBJECTIVE: To analyze the effects of motor function of cerebral palsy children by the adjuvant therapy of acupuncture and its factors retrospectively. METHODS: Five hundred and twenty cerebral palsy children in hospital (from January 2005 to December 2014) who meet the criteria were selected through Doctor Workstation of our hospital. The cases were divided into groups according to the type of cerebral palsy, gestational age, complication, treatment time and age. Based on the physical rehabilitation, all the patients were assisted by acupuncture. Scalp acupuncture was used at Zhiqizhen (seven-intelligent needles), motor area, foot motor-sensory area, etc. Body acupuncture were mainly at the governor vessel and yangming meridians of hand and foot. Treatment was given once every other day for eight months. Effects were evaluated by gross motor function classification system (GMFCS) and gross motor function measure (GMFM). RESULTS: 1 GMFCS:after eight-month treatment, the total effective rate of children with spastic cerebral palsy was superior to those of mixed type and involuntary movement type[77.9% (300/385) vs 60.3% (38/63), 56.9% (41/72), both P<0.01]. The total effective rates of the above three types with gestational age from 37 to 42 weeks were better than those of the corresponding types with gestational age (P<0.01, P<0.05). The efficacy of children with mental retardation and language disorderwas higher than that of epilepsy and hearing disorder (P<0.01, P<0.05). The total effective rates of patients in the three types with the age of 1-2 were better than those of the corresponding types with the age of 2-4 (all P<0.05). 2 GMFM:after three-month and eight-month treatment, the GMFM scores of the three types were increased in different degrees (all P<0.01), and after eight-month treatment, the score of the spastic type was increased more obviously than those of the other two types (both P<0.01). CONCLUSIONS: The motor function of cerebral palsy children can be improved assisted by acupuncture, and the effect may be related to treating time, cerebral palsy type, gestational age, complication and age. PMID- 29231411 TI - [Study of clinical application of manipulations of filiform needles to promote qi by data mining technique]. AB - OBJECTIVE: To analyze the diseases and effects of the manipulations to promote qi by filiform needles, with the help of data mining technique. METHODS: Literature about different manipulations to promote qi by filiform needles in recent 60 years was collected in China National Knowledge Infrastructure(CNKI). Then databases were established to mine the relativities among the diseases, subjects, acupoints selection law,routes and directions of meridian qi and effects. RESULTS: 1Total 489 articles were included. The basic manipulations with the frequency of 630 were on the top. The auxiliary and four methods of Feijingzouqi respectively appeared 70 times. The diseases in the internal medicine were treated with the basic and auxiliary methods of the higher frequencies, 311 and 44 times separately. While the four methods of Feijingzouqi were mostly used in the surgical area, 37 timestotally. 2The diseases treated from high to low by lifting, thrusting and twirling represented retention of urine, sequelae of stroke, pain in waist and lower limbs, of which the effect for retention of urine was better than those of the other two, and the lifting and thrusting method was superior to twirling. 3As for the auxiliary methods, 25 times were found about vibration needling; 18 times, twisting. The highest frequency of 6 times for the vibration needling was on the sequelae of stroke; while 4 times for the twisting, stranguria. 4As to the four methods of Feijingzouqi, Cangguitanxue was most frequently applied, and its highest frequency of 18 was on bi syndrome. CONCLUSIONS: Manipulations to promote qi by filiform needles are crucial to achieving the effects of acupuncture. The basic methods are widely used in clinic and have been seen good efficacy. While the auxiliary means assist to promote qi to stimulate the body,among which the four methods of Feijingzouqi are mainly to smooth the meridians and drive qi of patients with surgical diseases and take meridian blocking the priority. PMID- 29231412 TI - [Moxibustion for pediatric diseases in General Treatise on the Cause and Symptoms of Diseases]. AB - General Treatise on the Cause and Symptoms of Diseases was considered as the existing earliest monograph of TCM etiology and pathogenesis, and 6 volumes of total 50 volumes in this book involved pediatric diseases, which summarized the medical achievements of pediatrics before Sui Dynasty. Without detailed prescription, moxibustion was highly valued in this book and was applied for various types of pediatric emergency. With moxibustion for pediatric diseases in General Treatise on the Cause and Symptoms of Diseases as starting point, three aspects, including caution about moxibustion, moxibustion at back-shu and moxibustion for febrile convulsion were discussed in this article. PMID- 29231413 TI - [Effects of electroacupuncture on the activities of gliocytes of cervical spinal cord in rats with thyroid incisional pain]. AB - OBJECTIVE: To observe the impacts of electroacupuncture (EA) on microgliacytes and astrocytes of cervical spinal cord in rats with thyroid incisional pain and explore the mechanism of acupuncture anesthesia in thyroid surgery. METHODS: Sixty Wistar male rats were randomized into a normal group, a model group, a Futu (LI 18) group, a Hegu (LI 4)-Neiguan (PC 6) group and a Zusanli (ST 36) Yanglingquan (GB 34) group, 12 rats in each one. Except the normal group, a longitudinal incision, about 1.5 cm in length was done along the neck midline in the rats of the rest groups to prepare the model of thyroid incisional pain. In the Futu (LI 18) group, the Hegu (LI 4)-Neiguan (PC 6) group and the Zusanli (ST 36)-Yanglingquan (GB 34) group, after modeling for 4 h, 24 h and 48 h, EA was applied to bilateral "Futu" (LI 18), "Hegu" (LI 4) "Neiguan" (PC 6) and"Zusanli" (ST 36) "Yanglingquan" (GB 34) separately, once a day, continuously for 3 days. In the normal group and the model group, no any intervention was applied. The thermal radiant apparatus was used to detect the thermal pain threshold (PT). The fluorescence quantitative RT-PCR and the Western blotting (WB) were used to determine the expressions of protein and gene of microglia activation markers Iba1 and CD11b and the astrocyte specific protein marker, glial fibrillary acid protein (GFAP) in cervical spinal cord (C2 to C6) after intervention in the rats of each group. RESULTS: After intervention, as compared with the normal group, in the model group, the neck PT was reduced apparently (P<0.05), the expressions of Iba1 and CD11b and GFAP mRNA as well as the protein expressions in the spinal cord of C2 to C6 were up-regulated apparently (P<0.05, P<0.01). As compared with the model group, in the Futu (LI 18) and the Hegu (LI 4)-Neiguan (PC 6) group, PT was increased significantly (both P<0.05) and that did not change apparently in the Zusanli (ST 36)-Yanglingquan (GB 34) group (P>0.05). In the Futu (LI 18) group, the protein and gene expressions of Iba1, CD11b and GFAP were lower than those in the model group (all P<0.05). In the Hegu (LI 4)-Neiguan (PC 6) group, the expressions of Iba1 mRNA, CD11b protein, GFAP mRNA and protein were all lower apparently than those in the model group (all P<0.05). In the Zusanli (ST 36) Yanglingquan (GB 34) group, the expressions of Iba1, CD11b and GFAP proteins were not different significantly as compared with the model group (all P>0.05). In the Zusanli (ST 36)-Yanglingquan (GB 34) group, the expressions of Iba1 mRNA and CD11b mRNA and protein expressions in the spinal cord of C2 to C6 were higher apparently than those in the Futu (LI 18) group (P<0.01, P<0.05); the expressions of Iba1 mRNA and CD11b protein expressions were higher than those in the Hegu (LI 4)-Neiguan (PC 6) group (all P<0.05); GFAP mRNA and protein expressions were higher apparently than those in the Futu (LI 18) group and the Hegu (LI 4) Neiguan (PC 6) group (all P<0.05). CONCLUSIONS: EA at "Futu" (LI 18) or "Hegu" (LI 4), "Neiguan" (PC 6) relieves the acute neck incisional pain in the rats and its effect may be closely relevant with the down-regulation of the activities of microgliacytes and astrocytes in the spinal cords. PMID- 29231414 TI - [Effects of pretreatment of electroacupuncture on bupivacaine poisoning in rats]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) pretreatment at different times for heart arrest induced by bupivacaine poisoning in rats. METHODS: With a randomized, blind, control study, 24 SD rats were divided into a control group, a EA for 60 min (EA 60) group and a EA for 30 min (EA 30) group, 8 cases in each one. Rats in the EA 60 group and EA 30 groups were treated with EA at bilateral "Neiguan" (PC 6), "Zusanli" (ST 36) and "Fenglong" (ST 40) for 60 min and 30 min respectively. While no treatment was given in the control group. Then rats were monitored by leadIIelectrocardiograph; catheters were inserted into the femoral vein to open the vein access and into the carotis to monitor the arterial pressure. Three hours after EA, 10 mg/kg bupivacaine was injected through femoral vein. The mean arterial pressure (MAP) and heart rate (HR) were automatically recorded by PowerLab system. The time points when QRS widened by 20 percent and cardiac arrest and the survival rates were observed. RESULTS: After the injection of bupivacaine, five rats in the EA 60 group caught cardiac arrest,while all the rats in the other two groups caught it. The survival rates were not statistically significant among the three groups (P>0.05). The time of QRS widening by 20 percent in the EA 60 group was (87.4+/-14.8) s,which was longer than (63.6+/-14.2) s in the EA 30 group and (51.2+/-12.4) s in the control group (both P<0.05). From injection of bupivacaine to cardiac arrest, the time of (375.3+/-23.7) s in the EA 60 group and that of (328.3+/-47.7)s in the EA 30 group were more than (235.5+/-91.5) s in the control group (both P<0.05). After the injection, MAP and HR in the EA 60 group were higher than those in the EA 30 group and control group at most time points (all P<0.05). CONCLUSIONS: EA pretreatment apparently decreases the vulnerability of bupivacaine-induced heart arrest, with better protective effect of 60 min pretreatment than that of 30 min. PMID- 29231415 TI - [Professor WU Zhongchao's experience in the treatment of bi syndrome with fire needling therapy at lower he-sea points]. AB - Bi syndrome is classified into five categories. Based on the syndrome differentiation of meridians and collaterals and zangfu theories, Professor WU Zhongchao proposed the fire needling therapy at the lower he-sea points for five types of bi syndromes. Professor WU stresses on the flexible application of fire needling therapy for bi syndrome at the lower he-sea points and innovated the unique five techniques of fire needling therapy, named lifting and threating needle of small amplitude at the lower he-sea points, the stimulation along the relevant meri-dians before fire needling, detecting the sensitive sites by gentle pressing the relevant lower he-sea points, combining the movement of affected upper limb or joint during fire needling, or combining with contralateral needling technique, and controlling the depth of fire needling based on the duration of sickness and depth of affected site. He pointed out that Shangjuxu (ST 37) is for skin bi syndrome, Zusanli (ST 36) for muscle bi syndrome, Yanglingquan (GB 34) for tendon bi syndrome, Weizhong (BL 40) for bone bi syndrome and Xiajuxu (ST 39) for vessel bi syndrome. PMID- 29231416 TI - [Professor WANG Linpeng's experience of acupuncture for migraine based on different stages and types]. AB - By using the methods of experience summary and case report, professor WANG Linpeng's clinical experience of acupuncture for migraine was summarized.Professor WANG proposed the different acupuncture plans should be established according to the active stage and remission stage of migraine; in the active stage acupuncture should be applied at gallbladder meridian with penetration needling technique to reinforce the stimulation intensity; in the remission stage the aim was to regulate zang-fu and back-shu points should be emphasized.In addition, attention should be paid on acupuncture technique and preventive treatment.For menstruation-type and psychological disorder-type migraine, different acupuncture plans should be adopted and regulating meridian and spirit was essential in the treatment. PMID- 29231417 TI - [Exploration of application of clinical research coordinator in acupuncture and moxibustion study]. AB - To explore the application of clinical research coordinator(CRC) in acupuncture and moxibustion study. The present application of CRC in many countries, such as America and Japan, was analyzed, and the critical actions of CRC were summarized. CRCs are crucial party of the clinical research coordinators group (CRCG).It aims to help regulate works among patients, sponsors and researchers with altruism. Now there are problems in clinical acupuncture and moxibustion research management, and the experience of CRC can enhance the efficiency and research level. PMID- 29231418 TI - [Interpretation of Evidence-based Guidelines of Clinical Practice with Acupuncture and Moxibustion:Migraine of the version 2014]. AB - Evidence-based Guidelines of Clinical Practice with Acupuncture and Moxibustion:Migraine (Guideline) was updated in 2014 on the basis of the version 2011. In Guideline of the updated version, the evidence quality grade and GRADE were adopted for the evidence evaluation and recommendation grading in methodology, and the clinical feasibility was stressed. In text, the recognition of modern medicine was updated, the sta-ging treatment of acupuncture and moxibustion was emphasized, the inclusive articles were expanded and the important indexes of efficacy evaluation were increased and highlighted. The paper aims to provide the instruction for the application of Guideline of the version 2014. PMID- 29231419 TI - [Doubting the twirling angle of filiform needle in Science of Acupuncture and Moxibustion textbooks and National Standards]. AB - In National Standards (GB) as well as the textbooks used in TCM universities, the twirling angles of acupuncture manipulation vary a lot. By reviewing the previous editions of textbooks from 3 publication houses and comparing the relevant contents, the author calculated the arc lengths of various twirling angles based on the specification of filiform needle in National Standards (GB) and International Standards (ISO). The conclusion is that the twirling angles mentioned in National Standards (GB) and textbooks are too small and not in compliance with the clinical practice. Hence, it is not advisable to propose a rigid specific provision of twirling angle in acupuncture manipulation. PMID- 29231420 TI - [Objective reasons and the strategies on pain during the needle insertion and the key points in teaching program]. AB - Retrieving literature and summarizing the experience in lecturing acupuncture and clinical practice, the authors analyzed the objective reasons of pain during the needle insertion. Three factors are considered, including needles, skin tissue of inserting site and technique of insertion. The teaching program was discussed on how to alleviate or avoid pain during the concrete manipulation. It is viewed that no matter in teaching program of acupuncture or clinical operation, for alleviating pain during needle insertion, the key points must be on the rapid insertion through skin surface and the coordination of the puncture hand and pressing hand. PMID- 29231421 TI - [Understanding of needle-knife medicine on ashi point]. AB - The concept of ashi point and the understanding of modern acupoint research on ashi points were analyzed. According to the bowstring mechanics anatomy of needle knife medicine and mesh theory, it was believed ashi point was the warning of mechanical imbalance of bowstring mechanics anatomy. Ashi points were mainly distributed in the joint part of bowstring or stress concentration of string; the acupotomy could compensate for the subjectivity and arbitrariness of point selection of ashi, which also emphasized the importance of ashi point anatomy. PMID- 29231422 TI - [WANG Zhizhong and his Experience on Acupuncture and Moxibustion Therapy]. AB - WANG Zhizhong, born in the Southern Song Dynasty, was proficient in TCM theory and enjoyed summarizing proved prescriptions. During his spare time, he wrote Experience on Acupuncture and Moxibustion Therapy with scientific writing structure, wide quote of references and attached medical reports, which modified and enriched the content of acupoint therapy. This book played an important role as a link between past and future; it included a considerable number of moxibustion methods and was considered as the greatest medical achievement before Song Dynasty. In addition, this book contained the greatest number of proved prescriptions among the ancient acupuncture books, so its academic value was self evident. However, when examining and correcting the acupoints, WANG ignored the fact that acupuncture physicians had different clinical experience and their understanding on the body structure was discrepant, so the contradictions of location and indications of acupoints appeared in the book. PMID- 29231423 TI - [Evaluation of effect of acupuncture and moxibustion and level of intervention based on cumulative Meta-analysis and fuzzy comprehensive evaluation:sudden hearing loss]. AB - Clinical evidences of acupuncture and moxibustion for sudden hearing loss(SHL) were completely collected, and the quality of the evidences was evaluated by Jadad scale. Cumulative Meta-analysis and the time tendency test for the results were implemented by STATA 12.0. Descriptive and academic cross-sectional investigation was carried out among senior professional doctors with acupuncture and moxibustion background in 31 provin-ces of China, and the advices of specialists were analyzed by fussy comprehensive evaluation. Thirty-eight researches were included. Cumulative Meta-analysis indicated that acupuncture and moxibustion combined with medication achieved better cured and total effects compared with multiple medicines[RR=1.57, 95%CI(1.38,1.79); RR=1.34, 95%CI(1.28,1.81)], and the efficacy had no time variability. The cured and total effects of acupuncture and moxibustion were superior to those of multiple medicines, but the results needed to be further verified. Five hundred and sixty one questionnaires were put out in the 31 provinces, and 93.40% of ones were collected and eligible. Fuzzy comprehensive evaluation showed a tendency to overall improvement by acupuncture and moxibustion as the main intervention in the specialists' advice. Cumulative Meta-analysis and fussy comprehensive evaluation are applicable to estimate the effect and intervention level of acupuncture and moxibustion with low quality evidence. PMID- 29231424 TI - [Modern research progress of the safety effects of moxibustion smoke]. AB - According to the analysis regarding the basic researches and clinical literature of moxibustion smoke in recent ten years, it was found the low-concentration moxibustion smoke had unique application values for air disinfection, infectious diseases and skin diseases, etc. However, certain chemical components of long time high-concentration moxibustion smoke could cause toxic and adverse effects on respiratory system, immune system and circulation system. Therefore, the safety effects of moxibustion smoke were summarized, hoping to provide references for further clinical researches and evidence-based medicine. PMID- 29231425 TI - [From literature to academic history:the position and pathway of acupuncture theory research]. AB - There are two clues in academic inheritance of acupuncture, including theoretical inheritance and empirical inheritance. Up to now, the mainstream of acupuncture theory has not been in conformity with empirical clinic, and could not explain new clinical techniques. The existing acupuncture theories are in need of strict re-examination, and new academic achievements shall be carefully absorbed. The literature review, concepts research and academic history study are considered as key pathways of acupuncture theory research. PMID- 29231426 TI - [Row acupuncture at the gaps between phalanges for dorsal stretch of fingers after cerebral infarction]. AB - OBJECTIVE: To compare the effect differences between row acupuncture at the gaps between phalanges and physical therapy for the dorsal stretch of fingers after cerebral infarction. METHODS: Seven-one cases were randomized into a row acupuncture at the gaps between phalanges group (group A, 37 cases) and a physical therapy group (group B, 34 cases). Body acupuncture was applied in the two groups. Row acupuncture at the 1st, 2nd, and 3rd gaps between phalanges was used in the group A, with continuous wave of electroacupuncture. The two electrodes of nerve injury therapeutic apparatus were put in the muscle belly center of extensor digitorum of forearm in the group B. All the treatments were given for 30 min in the two groups, once a day and 10 times as one course. Three courses were required with 3 d at the interval. The dorsal stretch of metacarpophalangeal joints and the muscle force of common extensor of fingers were compared between the two groups before and after treatment. RESULTS: Compared with those before treatment, the dorsal stretch of metacarpophalangeal joints and the muscle force of common extensor of fingers were improved after treatment in the two groups (all P<0.05). There existed better effects in the group A on the dorsal stretch of the forefinger, middle finger and ring finger of metacarpophalangeal joints, as well as the muscle force of common extensor of fingers (all P<0.05). CONCLUSIONS: Row acupuncture at the gaps between phalanges achieves better effect than physical therapy for the dorsal stretch of fingers after cerebral infarction, based on body acupuncture. PMID- 29231427 TI - [The application of contralateral acupuncture for rehabilitation after acute closed achilles tendon rupture]. AB - OBJECTIVE: To observe the differences of affected-side ankle plantar flexors function and clinical efficacy between contralateral acupuncture combined with rehabilitation training and rehabilitation training alone for patients with acute closed achilles tendon rupture. METHODS: Seventy-four patients with acute closed achilles tendon rupture were randomly assigned to an observation group and a control group, 37 cases in each group. Patients in the both groups were treated with routine rehabilitation training after the operation for 12 weeks; besides, patients in the observation group were treated with contralateral acupuncture at Zusanli (ST 36), Yanglingquan (GB 34), Chengshan (BL 57), Taixi (KI 3) before rehabilitation training in the first 6 weeks. The treatment were given once a day, 5 times as 1 course with 2 d at the interval. The Biodex System 4 multi joint dynamometers system was applied to test and compare affected-side plantar flexion peak torque (PFPT), peak torque/body weight (PT/BW) and total work (TW) after 6 weeks, 8 weeks and 12 weeks. The efficacy evaluation was conducted after 6 weeks and 12 weeks, and the follow-up visit was conducted 12 weeks after end of treatment. RESULTS: The PFPT, PT/BW, TW in the observation group were significantly superior to those in the control group after 8 weeks and 12 weeks of treatment (all P<0.05); compared with those after 6 weeks, the PFPT, PT/BW, TW were significantly increased after 8 weeks of treatment (all P<0.05); compared with those after 6 weeks and 8 weeks, the PFPT, PT/BW, TW were significantly increased after 12 weeks of treatment (all P<0.05). After 12 weeks of treatment and at follow-up visit, the clinical excellent and effective rates in the observation group were higher than those in the control group[89.2% (33/37) vs 70.3% (26/37), 94.6% (35/37) vs 75.7% (28/37), both P<0.05]. CONCLUSIONS: During the postoperative rehabilitation of acute closed achilles tendon rupture, the contralateral acupuncture combined with rehabilitation training could improve ankle plantar flexors function and clinical efficacy better than rehabilitation training only. PMID- 29231428 TI - [Electroacupuncture combined with catgut implantation for postoperative pain of mixed hemorrhoids]. AB - OBJECTIVE: To compare the clinical effect differences among electroacupuncture (EA) combined with catgut implantation, simple EA and simple catgut implantation for postoperative pain of mixed hemorrhoids. METHODS: A total of 120 patients were randomly assigned into a combination group, an EA group, and a catgut implantation group, 40 cases in each one. All the interventions were applied for 30 min before the operation. The acupoints were Changqiang (GV 1) and Chengshan (BL 57). The pain scores were compared among the three groups 4 h, 12 h, 3 d, and 7 d after operation, as well as the score of maximum pain score within 24 h (24 h Max) after operation, the pain duration score within 24 h after operation, and the total dose of aulin to relieve pain within 7 d after the operation. RESULTS: The scores in the combination group were better than those in the other two groups, including the pain scores at all the time points after operation, the 24 h Max score and the pain duration score within 24 h after the operation, as well as the dose of aulin within 7 d after the operation (all P<0.05). The pain scores 4 h and 12 h after operation and the 24 h Max socre in the EA group were better than those in the catgut implantation group (all P<0.05). The pain scores 3 d and 7 d after operation in the catgut implantation group were superior to those in the EA group (both P<0.05). The pain duration score within 24 h after operation in the EA group was better than that in the catgut implantation group (P<0.05). As for the aulin dose within 7 d after operation, the dosage in the catgut implantation group was less than that in the EA group (P<0.05). CONCLUSIONS: EA combined with catgut implantation is more effective than simple EA and simple catgut implantation for postoperative pain of mixed hemorrhoid. The analgesic effect of EA is stronger and works faster, but the duration of analgesia of catgut implantation is longer. The combination of the two Methods can achieve better analgesia. PMID- 29231429 TI - [Comparison between manual acupuncture and electroacupuncture for hot flashes and sex hormone of perimenopausal syndrome]. AB - OBJECTIVE: To compare the effect and differences sex the influence of hormone levels of perimenopau-sal syndrome patients between manual acupuncture and electroacupuncture (EA). METHODS: A total of 50 cases with perimenopausal syndrome were randomly assigned into an manual acupuncture group (27 cases) and an EA group (23 cases), and 1 case dropped in the EA group. The acupoints in the two groups were Guanyuan (CV 4), Zigong (EX-CA 1), Tianshu (ST 25), and Sanyinjiao (SP 6). Acupuncture with 3-time small and even manipulation of lifting, thrusting and twirling was used in the acupuncture group, once 10 min. EA with sparse-dense wave and 10 Hz/50 Hz was applied in the EA group for 30 min. The treatments in the two groups were for continuous 8 weeks (24 times in total), once the other day, 3 times a week. The scores of 24-hour hot flashes even, menopausal rating scale (MRS) and menopause-specific quality of life questionnaire (MENQOL) were recorded before treatment and after 4-week and 8-week treatment, as well as 12 and 24 weeks after treatment. Serum sex hormone levels were tested before and after 8-week treatment as well as 12 weeks after treatment, including serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estracliol (E2). RESULTS: Compared with those before treatment, the 24-hour hot flashes even score, MRS and MENQOL scores were significantly lower after 4-week and 8-week treatments, 12 and 24 weeks after treatment (all P<0.05). All the above scores after 8-week treatment were lower than those after 4-week treatment (all P<0.05); and the scores 12 and 24 weeks after treatment were lower than those after 4-week and 8-week treatments (all P<0.05); all the scores after treatment were not significantly different at any time between the two groups (all P>0.05). Compared with those before treatment, serum FSH and E2 apparently improved in the two groups after 8-week treatment and 12 weeks after treatment (all P<0.05). LH levels did not significantly change in the two groups (all P>0.05). All the serum sex hormone levels showed no significant difference between the two groups (all P>0.05). CONCLUSIONS: Both acupuncture and EA can improve perimenopausal symptoms and serum sex hormone. The effects are similar. PMID- 29231430 TI - [Transcutaneous electrical acupoint stimulation for pregnancy of in vitro fertilization-embryo transfer]. AB - OBJECTIVE: To observe the impact of transcutaneous electrical acupoint stimulation (TEAS) before and after embryo transfer for the pregnancy of in vitro fertilization-embryo transfer (IVF-ET) patients. METHODS: A total of 1761 IVF-ET patients of natural cycle or hormone replacement cycle were randomly assigned into an observation group (735 cases) and a control group (1026 cases). IVF-ET was applied in the two groups. TEAS was used for 30 min separately in the observation group on 24 h before transfer and within 2 h after transfer. The acupoints were Zigong (EX-CA 1), Xuehai (SP 10) and Diji (SP 8); Zhongwan (CV 12), Guanyuan (CV 4), Zusanli (ST 36) and Taixi (KI 3). TEAS was not used in the control group. Biochemical pregnancy rate and clinical pregnancy rate were observed 14 d and 4-5 weeks after transfer in the two groups. RESULTS: The biochemical pregnancy rate in the observation group was 62.0% (456/735), which was better than 57.3% (588/1026) in the control group (P<0.05). The clinical pregnancy rate in the observation group was 51.2% (376/735), and it was better than 44.9% (461/1026) in the control group (P<0.05). CONCLUSIONS: TEAS could improve the pregnancy rate of IVF-ET patients, and it may be a safe and new assisted method for reproduction without pain. PMID- 29231431 TI - [Micro-invasive embedding combined with montelukast sodium for children cough variant asthma:a randomized controlled trial]. AB - OBJECTIVE: To observe the effects of micro-invasive embedding combined with montelukast sodium and simple montelukast sodium for children cough variant asthma (CVA). METHODS: A total of 240 patients were randomly assigned into an observation group and a control group, 120 cases in each one. Considering of cases dropping, 101 patients in the observation group and 105 cases in the control group were included. Montelukast sodium chewable tablets were applied before sleep for 3 months in the control group, 5 mg a time, once a day. Based on the treatment as the control group, micro-invasive embedding was used for 3 months in the observation group, twice in the first month and once in the other two months. The acupoints were Feishu (BL 13), Danzhong (CV 17), Dingchuan (EX-B 1), and Zusanli (ST 36). Follow-up was conducted 9 months after treatment in the two groups. The cough score, serum immunoglobulin (IgE, IgG, IgA), platelet activating factor (PAF) were observed before and after treatment. The indices were compared before and after treatment and at follow-up, including pulmonary function indices[peak expiratory flow rate (PEF), forced expiratory volume at the 1st second (FEV1)], and small airway function indices[forced expiratory flow rate with remaining 25% vital capacity (MEF25%), forced expiratory flow rate with remaining 50% vital capacity (MEF50%), forced expiratory flow rate with remaining 75% vital capacity (MEF75%) and mid expiratory flow rate (MEF25%-75%)]. Also, the total effects were evaluated. RESULTS: 1The total effective rate in the observation group was 93.1% (94/101), which was better than 87.6% (92/105) in the control group (P<0.05). The cough disappearance time of the cured children in the observation group was (10.38+/-2.64) d, and it was shorter than (10.72 +/-2.60) d of those in the control group (P<0.05). After treatment, the cough score apparently decreased compared with those before treatment in the two groups (both P<0.05), with better result in the observation group (P<0.05). At follow-up, the recurrence frequency of the observation group was (1.43+/-1.20), and it was less than (1.91+/-1.71) in the control group (P<0.05). 2The levels of serum IgA and IgG after treatment in the two groups increased, and those of serum IgE and PAF decreased, compared with those before treatment. There was statistically significance except IgG in the control group before and after treatment (all P<0.05), with better Results in the observation group after treatment (all P<0.05). 3 Compared with those before treatment, all the pulmonary function indices were improved obviously after treatment and at follow-up in the two groups (all P<0.05), without statistically significance between the two groups (both P>0.05). 4 There was no statistically significance before and after treatment on small airway function indices in the two groups (all P>0.05). The indices at follow-up increased compared with those before treatment in the two groups (all P<0.05), with better Results in the observation group (all P<0.05). CONCLUSIONS: Micro-invasive embedding combined with montelukast sodium achieved de-finite effect for children CVA, which can improve the body's immune and microcirculation. The effect is better than that of simple montelukast sodium on improving small airway function, etc. PMID- 29231432 TI - [Scalp acupuncture for epileptiform discharges of children with cerebral palsy]. AB - OBJECTIVE: To explore the effect of scalp acupuncture for children with cerebral palsy whose video-electroencephalogram(VEEG) showed epileptiform discharges. METHODS: A total of 184 children with cerebral palsy whose VEEG showed epileptiform discharges or those combined with epilepsy were randomly assigned into a combination group (99 cases) and a rehabilitation group (85 cases). All the cases were treated with the original antiepileptic drugs. The conventional physical training and massage were applied in the rehabilitation group for 3 courses with 20 d at the interval, once a day, 5 times a week and 15 times as one course. Based on the treatment as the rehabilitation group, scalp acupuncture was used in the combination group for 3 courses with 15 d at the interval, once the other day and 10 times as one course. Shenting (GV 24), Benshen (GB 13), Sishencong (EX-HN 1) were selected as the main acupoints, combined with motor zone, foot motor-sensory area, balance zone,and temple-three-needle etc. Clinical onset and VEEG results were observed before and after treatment. RESULTS: After treatment in the combination group, 27 cases improved; 47 cases had no effect; 25 cases aggravated. While in the rehabilitation group, 11 cases improved; 46 cases had no effect; 28 cases aggravated. There was no statistically significance between the two groups (P>0.05). As for the cases with epilepsy onset in the combination group, 8 cases improved; 4 cases had no effect; 4 cases aggravated. In the rehabilitation group, 4 cases had no effect; 7 cases aggravated. The result in the combination group was better than that in the rehabilitation group (P<0.05). As for the cases with epileptiform discharges in the combination group, 19 cases improved; 43 cases had no effect; 21 cases aggravated. In the rehabilitation group, 11 cases improved; 42 cases had no effect; 21 cases aggravated. There was no significance between the two groups (P>0.05). CONCLUSIONS: Scalp acupuncture therapy does not increase the risk of onset or epileptiform discharges in the children with cerebral palsy combined with epilepsy or epileptiform discharges. Scalp acupuncture combined with rehabilitation is better than simple rehabilitation for thosewith cerebral palsy and epilepsy onset. PMID- 29231433 TI - [Transcutaneous vagus nerve stimulation for primary insomnia and affective disorder:a report of 35 cases]. AB - OBJECTIVE: To observe and evaluate the clinical efficacy of transcutaneous vagus nerve stimulation (taVNS) at auricular concha for primary insomnia (PI) and affective disorder. METHODS: A total of 35 patients who met the diagnosis standard of PI in Diagnostic and statistical manual of mental disorders (5th edition) were included. The self-developed auricular vagus nerve stimulator (TENS 200A) was applied at auricular concha, 30 min per treatment, twice a day, 5 days a week for consecutive 4 weeks. The follow-up visit was conducted at the end of 6th week. The Pittsburg sleep quality index scale (PSQI), 17-items Hamilton depression scale (17HAMD) and Hamilton anxiety scale (HAMA) were applied for evaluation. The PSQI, HAMA and 17HAMD were observed before and after treatment; the safety was also observed. RESULTS: Compared before treatment, the PSQI was significantly decreased to (13.20+/-3.61) at the end of 2nd week (P<0.05); compared before treatment, the 17HAMD and HAMA were significantly decreased at the end of 4th week and 6th week (all P<0.05). No adverse reaction was observed. CONCLUSIONS: The taVNS could not only relieve PI symptoms, but also improve the depressive and anxiety symptoms, in addition, it may have positive long-term efficacy and safety. PMID- 29231434 TI - [Exploration on "three eye-needling" technique of acupuncture]. AB - The "three eye-needling" technique is one of the important component of Jin's three needling therapy, mainly used for the treatment of eye disorders such as optic atrophy, macular pigment degeneration, myopia, hyperopia, strabismus, amblyopia, diplopia, glaucoma, cataract, etc. In the paper, Jin's "three eye needling" technique is explored, including the keys of manipulation, operation procedure and basic skills. This technique is particularly for "mind regulation", focusing on tranquilizing, observing and concentrating the mind. The precise selection of point is the basic requirement, the technique for fixing, pressing and pricking are the most important link. The needle insertion with one hand is adopted with gentle rotation manipulation. Mind regulation, point selection and specific operation are coordinated with each other to bring the function of "three eye-needling" technique into play and achieve better therapeutic effects. PMID- 29231435 TI - [Acupuncture direction and analgesia]. AB - The acupuncture direction is closely related with the efficacy of acupuncture analgesia. In this article, the relationship between efficacy of acupuncture analgesia and factors, such as whether the needle towards disease location, whether the needle towards meridian direction, whether the needle following spinal cord direction and whether the needle following muscle direction, were analyzed. The previous clinical and literature research indicated that the needle towards disease location was superior to reverse direction, however, the efficacy of analgesia between needle following and reversing meridian, needle towards and at disease location, needles following and reversing spinal cord direction, needles following and reversing muscle direction was controversial. Therefore, the solutions to these problems will benefit the optimized acupuncture treatment plan for pain disorders. PMID- 29231436 TI - [Protective effect of acupuncture preconditioning on oxidative stress injury induced by myocardial ischemia-reperfusion injury in rats]. AB - OBJECTIVE: To observe the protective effect of acupuncture preconditioning at "Jiaji" (EX-B 2) on acute myocardial ischemia-reperfusion injury (MIRI) in the rats and explore the mechanism. METHODS: Fifty Wistar rats were randomly divided into a control group, a model group, a Jiaji group, a Neiguan group and a Quchi group, 10 rats in each one. In the Jiaji group, the Neiguan group and the Quchi group, electroacupuncture was given for preconditioning at "Jiaji" T4~T5 (EX-B 2), "Neiguan" (PC 6) and "Quchi" (LI 11) for 7 days before modeling. In the control group and the model group, the regular feeding was given, without any acupuncture. At the end of acupuncture, except the control group, ligating the left anterior descending coronary artery (LAD) was adopted to duplicate MIRI models in the rest groups. Electrocardio-gram (ECG) was monitored and ST-segment shift was analyzed. HE staining method was adopted to observe the morphology of cardiac tissue in the rats of the groups. The transmission electron microscope was used to observe myocardial cell ultrastructure. WST-1 method was used to determine the activity of serum superoxide dismutase (SOD), TBA method was used to determine the content of serum malondialehyde (MDA) and the real-time fluorescent quantitative PCR method to determine the expressions of Nrf 2 in ischemic myocardial tissue and downstream HO-1 gene. RESULTS: Compared with the control group, after LAD ligation, ST-segment was elevated and depressed in ECG apparently after reperfusion in the rest groups (all P<0.05). The ST-segment elevation in the Jiaji group and the Neiguan group was less than that in the model group (both P<0.05). Compared with the model group, SOD activity was increased apparently in the Jiaji group and the Neiguan group (both P<0.05), and MDA content was reduced apparently (both P<0.05). The effects in the Jiaji group were better than those in the Neiguan group (both P<0.05). Pathologically, "Jiajia" (EX-B 2) and "Neiguan" (PC 6) all improved the morphology of cardiac tissue and cell ultrastructure. The effects in the Jiaji group were much more significant and the improvements in the Quchi group were not apparent. Compared with the control group, the expressions of Nrf 2 and HO-1 gene in myocardial tissue were down-regulated in the model group (both P<0.05). Those were up regulated apparently in the Jiaji group and the Neiguan group as compared with the model group (P<0.05, P<0.01). The up-regulation times of the expressions of Nrf 2 and HO-1 gene in the Jiajia group were the highest in comparison. CONCLUSIONS: Acupuncture preconditioning at "Jiaji" (EX-B 2) has the protective effect on cardiac ischemia and reperfusion damage, which is probably relevant with the up-regulation of Nrf 2-ARE pathway expression, the activation of endogenous anti-oxidative pathway, the improvement of oxygen free radical scavenging capacity and the alleviation of lipid peroxide damage. PMID- 29231437 TI - [Effect and mechanism of electroacupuncture for postoperative ileus at perioperative stage]. AB - OBJECTIVE: To observe the intervention effect of electroacupuncture (EA) on small intestinal motility in the rats of postoperative ileus (POI) at perioperative stage and explore the mechanism on the regulation of interstitial cells of Cajal (ICC) in the treatment of POI. METHODS: Sixty heathy male SD rats were randomized into a sham-operation group, a model group, an EA group and a sham-EA group, 15 rats in each one. Except the sham-operation group, POI modeling was done in the rest groups. In the EA group, separately, 48 h, 24 h and 0.5 h before modeling, during modeling and 6 h, 12 h and 24 h after modeling, EA was given bilaterally to "Zusanli" (ST 36), 5 Hz, 1-2 mA, for 30 min. The sham-EA stimulation was given in the sham-EA group at the same time points. The same fixation was the only intervention in the model group. No intervention was applied in the sham operation group. Five rats were selected randomly from each group 6 h, 12 h and 24 h after modeling for the determination of small intestine motility and they were sacrificed. Afterwards, the small intestinal muscular layer was collected for the determination of c-kit and P2X7 mRNA. In 24 h of modeling, the immunofluorescence test was done for c-kit determination. RESULTS: In 6 h, 12 h and 24 h of modeling, in the model group, the EA groupand the sham-EA group, the small intestine motility was apparently lower than that in the sham-operation group at the same time points (all P<0.01). In 6 h and 12 h of modeling, the small intestine motility in the EA group was not different significantly as compared with that in the model group (both P>0.05). In 24 h of modeling, the small intestine motility in the EA group was better than that in the model group and the sham-EA group at the same time points (both P<0.05). The difference was not significant between the sham-EA group and the model group (P>0.05). In 6 h, 12 h and 24 h of modeling, c-kit mRNA expression of small intestine muscular layer was reduced apparently in the model group (all P<0.01) and P2X7 mRNA expression did not change apparently (all P>0.05). In 24 h of modeling, as compared with the model group and the sham-EA group, c-kit mRNA expression and positive cell area in the small intestine muscular layer were increased in the EA group (all P<0.01). CONCLUSIONS: EA effectively increases the small intestinal motility in POI rats, shortens the recovery time, which is probably closely relevant with the increase of ICC count in small intestinal muscular layer. PMID- 29231438 TI - [Infraoccipital needle-knife for cervical vertigo]. AB - OBJECTIVE: To observe the clinical effect differences between infraoccipital needle-knife and massage for cervical vertigo. METHODS: A total of 366 patients with cervical vertigo were randomly assigned into a needle-knife group (186 cases) and a massage group (180 cases). With cases dropping excluded, 183 cases in the needle-knife group and 176 cases in the massage group were included. Needle-knife was used at Fengchi (GB 20), infraoccipital ashi point, etc. in the needle-knife group. The treatment was given for one course, once three days, 5 times as one course. The traditional massage was applied in the massage group for one course, including systematic stroking, kneading, and the application of pressure and plucking, etc., once every two days and 7 times as one course. The dizziness handicap inventory (DHI) score was observed before and after treatment, as well as 3, 6, and 12 months after treatment. The effects were also evaluated. RESULTS: The total effective rate was 92.3% (169/183) in the needle-knife group, which was better than 85.2% (150/176) in the massage group (P<0.05). Compared with those before treatment, the DHI scores at all the observation time points after treatment were improved in the two groups (all P<0.05), with better improvements after treatment as well as 3 and 6 months after treatment in the needle-knife group (all P<0.05). There was no significant difference in the improvement of DHI scores between the two groups 12 months after treatment (P>0.05). The recurrence rate was 10.3% (12/117) in the needle-knife group, and it was 10.7% (11/103) in the massage group 12 months after treatment (P>0.05). CONCLUSIONS: Infraoccipital needle-knife achieves apparent effect for cervical vertigo, which is superior to massage in short period. PMID- 29231439 TI - [Professor LAI Xinsheng's clinical experience in the treatment of premature ovarian failure with tongyuan acupuncture technique and Chinese herbal medicine]. AB - In the treatment of premature ovarian failure (POF), professor LAI Xinsheng focuses on the determination of syndrome to seek for etiology, associating with the differentiation of meridian and collateral and that of zangfu organs. Professor LAI believes that POF is mainly manifested as amenorrhea and infertility, localized in the kidney, with the dysfunction of liver, spleen and heart. It is impacted by many pathological factors, such as cold blockage, qi stagnation, blood stagnation, blood deficiency, yin deficiency, etc., which leads to the damage of the thoroughfare vessel and the conception vessel and the blockage of menstrual flow. On the basis of four diagnostic Methods and syndrome differentiation, there are four common syndromes of POF, named qi and blood deficiency, qi and blood stagnation, liver and kidney deficiency and yang deficiency of spleen and kidney. Tongyuan acupuncture technique is summarized by Professor LAI Xinsheng on the basis of yinyang theory. It is an effective and scientific method for acupoint selection along the meridians. The acupoints on the back, communicating with the governor vessel and mind regulation, acting on the brain are selected to promote yang qi of the governor vessel. The back-shu points of five zang organs are selected to regulate the functions of internal organs. The acupoints on the abdomen and the conception vessel are selected to conduce qi to the primary so as to improve reproductive function. In the guidance of tongyuan acupuncture technique, the acupoint prescription is formed and the Chinese herbal medicines are selected in combination to improve ovarian function and regulate menstruation. Hence, the satisfactory therapeutic effects have been achieved. PMID- 29231440 TI - [Professor CHEN Xiuhua's experience in the treatment of atopic dermatitis]. AB - Professor CHEN Xiuhua's clinical experiences were introduced in the intervention on atopic dermatitis with external therapies of TCM acupuncture. On the basis of the theory as cultivating the earth and clearing the heart from professor CHEN Dacan and in terms of the disease stages and skin lesion characteristics, as well as in consideration of syndrome differen-tiation, the acupoints for strengthening the spleen and clearing heart fire are selected, such as Zhongwan (CV 12), Daheng (SP 15), Shuifen (CV 9), Tianshu (ST 25), Neiguan (PC 6) and Quchi (LI 11). For the repair of skin lesion, the integration of Chinese and western medicine is used, with the internal application and external use of Chinese herbal medicines involved. The topical ointments are selected rationally. The self-blood therapy is used with acupuncture, bleeding therapy and acupoint injection applied in combination on the basis of the theory of TCM zangfu organs and modern immunological mechanism, which stimulates the nonspecific immune response in the body and strengthens acupoint stimulus effects. Medical thread therapy of Guangxi Zhuang medicine is used in moxibustion for skin damage, which effectively stops itching and promotes wound healing and skin repair. PMID- 29231441 TI - [Current development of acupuncture-moxibustion in India:a case study of West Bengal]. AB - Acupuncture-moxibustion was introduced to India in mid-20th century and has been legislated in two provinces in India where the registration of acupuncture practitioners is implemented at present. In India, the central government recognizes that acupuncture-moxibustion is an approach of treatment and is permitted by the licensed doctor. Because of the weakness of the basic development of acupuncture-moxibustion in India, the go-vernment put great effort to support and protect their national traditional medicine. Acupuncture moxibustion development is mainly in the folk and in the progression for the provincial and governmental legislation. In the paper, by taking West Bengal as example, the legislation, clinical application, education and scientific research of acupuncture-moxibustion are analyzed so that an approach is explored for the further development of acupuncture-moxibustion in India. PMID- 29231442 TI - [Acupuncture with Point Location-a mandatory examination for American NCCAOM certification of acupuncture and oriental medicine]. AB - Acupuncture with Point Location is one of the mandatory examinations for the Diplomate of Oriental Medicine (Dipl.OM.) or Acupuncture (Dipl. Ac.) by American National Certification Commission for Acupuncture and Oriental Medicine (NCCAOM). In reference to NCCAOM Certification Handbook, Acupuncture with Point Location Expanded Content Outline, and Study Guide for Diplomates in Acupuncture Certification, the authors introduced the examination pattern and examination related contents including such aspects as safety and professional responsibilities, treatment plan, and point location and discussed additionally the enlightening effects on acupuncture practice and examination in universities and international associations of Chinese medicine in our country. PMID- 29231443 TI - [The placebo effects of acupuncture and moxibustion]. AB - The role of placebo effect in acupuncture and moxibustion efficacy was explored. Through the analysis of multiple factors including trust, expectation, understanding, doctor-patient relationship and social cultural environment, etc. in the literature at home and abroad, it was found the placebo effects, including patient's cognition, expectation, attention, preference and communication with doctor as well as doctor's suggestion, expectation and indirect regulation of diagnosis and treatment environment on patient's psychology, were essential factors for acupuncture efficacy. Therefore, it was concluded that the placebo effect was an inseparable part of acupuncture efficacy. PMID- 29231444 TI - [Analysis on property of meridian supramolecules by biological evolution path]. AB - With human placed in the whole nature, by following the biologic evolution path, the property of channel structure for "imprinting template" in meridian and zang fu was explored with supramolecular chemistry. In the history of biologic evolution, each molecule in "molecule society" gradually developed into various highly-ordered supramolecular bodies based on self-identification, self-assembly, self-organization, self-replicating of"imprinting template", and thereby the original biochemical system was established, and finally evolved into human. In the forming process of supramolecular bodies, the channel structure of"imprinting template" in guest supramolecular bodies would be kept by host supramolecular bodies, and communicate with the outside to exchange materials, energy, information, otherwise life phenomenon could not continue, for which it was the chemical nature of biolo-gical supramolecular bodies for body to develop meridian. Therefore, the human was a gigantic and complicated supramolecules body in biological nature, and possessed the supramolecules "imprinting template" at each stage of evolution, for which the meridians were formed. When meridians converged, acupoints appeared; when acupointsconverged, zang-fu appeared. With the promotion of the blood from heart, according to"imprinting template", the guest supramolecular bodies and host meridian produced qi-analysis, which was the qi-phenomenon of guest in meridian. It presented as zang-fu image of physiology and pathology as well as action regularities of medication and acupuncture tolerance, by which current various meridian viewpoints could be explained and propose the hypothesis of meridian supramolecular bodies. The meridian and its phenomenon was decide by its "imprinting template" of supramolecular bodies and self-reaction regularities, which abided through the living nature. This was the substance for meridian biology. PMID- 29231445 TI - [Development and inheritance of ZHENG's acupuncture school]. AB - ZHENG's acupuncture school in Gansu,represented by ZHENG Yulin and ZHENG Kuishan,is of great influence in China. ZHENG's acupuncture school originated from Huangdi Neijing(Inner Canon of Yellow Emperor) and Nanjing(Classic of Questioning),and shaped around Yuan Dynasty and Ming Dynasty. Professor ZHENG Kuishan has formed a unique "ZHENG's acupuncture" diagnosis and treatment system by inheritance and innovation. He clinically paid attention to basic training,obtaining qi and keeping spirit,as well as syndrome differentiation,reinforcing and reducing. Also,he took the priority the pressing hand with bilaterally needle manipulation. Besides,he thought important simplicity,innovation and acupoints selecting according to time. We inherited ZHENG's acupuncture from his family,teachers'techniques,international communication,college and university education and scientific research. In this article we prescribe the development,the inheritance and the protection measures of ZHENG's acupuncture school in terms of its origination,academic thought,and inheritance research,etc.,so as to provide references for further study and inheritance. PMID- 29231446 TI - [The indications of acupuncture-moxibustion in China state-compiled textbooks]. AB - The Acupuncture-moxibustion and Acupuncture-moxibustion therapy have been the state-compiled textbooks of acupuncture-moxibustion in colleges and universities of TCM for nearly more than half a century, which play a regulating and guiding role for acupuncture education and to a certain extent represent the development status of this discipline. The indications included in Acupuncture-moxibustion from 1th edition to 7th edition and Acupuncture-moxibustion therapy from 1th edition to 3rd edition were analyzed in this study, which was aimed to basically reflect the current situation of acupuncture indications. As a result, it was found the inheritance and innovation of indications were both reflected in each edition of textbooks, 1/3 of which occurred repeatedly in more than half of the textbooks, and 1/3 of which occurred only once. The indications were classified by internal medicine, surgery, gynecology, dermatology, orthopedics, etc., which were not consistent with system classification of modern medicine such as digestive system, respiratory system, etc. The indications were mainly named after TCM disease names, involving only several names of western medicine diseases, which were contradicted to the names adopted from journals and literature. This inconformity of classification method and naming method between TCM and western medicine was not only a difficulty for modern acupuncture and moxibustion, but also an essential factor to hinder the development of acupuncture, therefore comparative study was needed in the future. PMID- 29231447 TI - [Improving the researchers' compliance and the quality of clinical study on acupuncture and moxibustion:thoughts on the role conflict between doctors and researchers]. AB - The coordination and collaboration of many links are required to achieve the successful development of a high-quality clinical randomized controlled trial, in which, the compliance of the researchers affects the ultimate results and quality of the study since it is responsible for the safety and benefits of subjects in the trials and study quality. Focusing on the researchers' compliance, it is believed that the improvements in the researchers' compliance are very significant in the implementation of study scheme. At present, commonly, the researchers are of the low compliance, manifest as failure to obey the study scheme (such as inclusive criteria, enrollment sequence), failure to obey the rules of operation and data collection, failure to store the original documents but to modify the data, failure to report timely adverse events, etc. In view of clinical research monitors, the reasons on the low compliance are analyzed and the solutions are proposed. PMID- 29231448 TI - [Improvement of life quality of patients with allergic rhinitis treated with acupuncture on sphenopa-latine ganglion:a randomized controlled trial]. AB - OBJECTIVE: To compare the effects of acupuncture on sphenopalatine ganglion and acupuncture on the common acupoints for life quality of patients with allergic rhinitis(AR). METHODS: Eighty patients with AR,who were in accord with the inclusive criteria,were randomly divided into an observation group and a control group,40 cases in each one. Acupuncture on sphenopalatine ganglion was used in the observation group. The needle was inserted into the gap between zygoma and mandibular coronoid process about 55 mm. Acupuncture was adopted on the main acupoints,Yingxiang(LI 20),Yintang(GV 29) or Fengchi(GB 20) in the control group. The course was four weeks. Follow-up was applied one month after treatment. Rhinoconjunctivitis quality of life questionnaire (RQLQ),rhinitis symptoms scale and visual analogue scale(VAS) were evaluated at different time points before and after treatment,and follow-up was implemented to know the recurrence situation,satisfactory degree and adverse reaction. RESULTS: (1) RQLQ scores:along with treatment,the RQLQ scores were gradually apparently decreased in the two groups(P<0.01),and the reducing trend from the first week to the second week of the observation group was more obvious than that of the control group. The differences of the RQLQ scores at all timepoints after treatment between the two groups were not statistically significant(all P>0.05). The interaction of the time factor and the group factor had statistical significance(P<0.01). (2) Rhinitis symptoms scores:along with treatment,the scores presented decreasing trend in the two groups(P<0.01). The scores of the two groups after treatment and the interaction of the time factor and the group factor were not statistically different(both P>0.05). (3)VAS scores:the VAS scores after treatment were lower than those before treatment(both P<0.01). The differences before and after treatment were statistically significant(P<0.01),with more change in the observation group(P<0.05). (4)There was no statistical significance about the number of recurrence days between the two groups(P>0.05). (5) Above 80 percent patients were content with the therapeutic method in each group,with no statistical difference(P>0.05). (6)The method of the observation group spent less time. (7) Two patients with light adverse reaction came up in the observation group,but no special treatment was needed. CONCLUSIONS: Acupuncture on sphenopalatine ganglion acquires more obvious short-term effect than conventional acupuncture. It spends less time to relieve symptoms and improves life quality. PMID- 29231450 TI - [Effect of early rehabilitation combined with abdomen needle therapy for motor function and psychological obstacle of stroke]. AB - OBJECTIVE: To study the clinical effect of early rehabilitation combined with abdomen needle therapy for the motor function and psychological obstacle of stroke based on the western medical treatment. METHODS: Ninety patients with acute stroke were randomly divided into an observation group A,an observation group B and a control group, 30 cases in each group. Conventional western medical treatment and early rehabilitation for the affected limbs wete applied in the three groups for one month. Besides,abdomen needle therapy was used on Qihai(CV 6),Guanyuan(CV 4),Tianshu(ST 25),Daheng(SP 15),Huaroumen(ST 24),Wailing(ST 26),Shangfengshidian,Shangfengshiwaidian,Xiafengshidian and Xiafengshixiadian in the observation group A. The needles were retained for 20 min without activity of the affected limbs. Based on the treatment as the group A,early rehabilitation was adopted in the observation group B. All treatment was given once a day,and 10 times were taken as a course. Three courses were required with two days at the interval. Fugl-Meyer assessment(FMA),Hamilton anxiety scale(HAMA),Hamilton depression scale(HAMD) and China stroke scale(CSS) were used before and after treatment. RESULTS: Scores of FMA,HAMA,HAMD and CSS after treatment were improved than those before treatment in the three groups(all P<0.05). All the above scores of the two observation groups were better than those of the control group(all P<0.05). The scores of HAMA and HAMD of the observation group B were superior to those of the observation group A(both P<0.05). CONCLUSIONS: Conventional treatment combined with abdomen needle therapy can improve the motor function and the psychological obstacle of stroke,and the effect is better than that of the conventional treatment. Early rehabilitation based on the two therapeutic methods can help relieve psychological status. PMID- 29231449 TI - [Vascular cognitive impairment with no dementia treated with auricular acupuncture and acupuncture:a randomized controlled trial]. AB - OBJECTIVE: To compare the clinical efficacy on vascular cognitive impairment with no dementia (VCIND) between the combined therapy of auricular acupuncture and acupuncture and the simple acupuncture. METHODS: One hundred patients of VCIND were randomized into a combined therapy of auricular acupuncture and acupuncture group (a combined therapy group) and an acupuncture group, 50 cases in each one. The basic internal medicine treatment was applied in the two groups. Additionally, in the combined therapy group, auricular acupuncture and JIN's three needling therapy were used. pizhixia (AT4), xin (CO15), shen (CO10), gan (CO12), erzhong (HX1) were selected in auricular acupuncture, once every Monday, Wednesday and Friday; Niesanzhen, Zhisanzhen and Sishenzhen were selected in JIN's three needling therapy, once a day. In the acupuncture group, JIN's three needling therapy was just provided, once a day. The treatment was given for 4 weeks in the two groups. Montreal cognitive assessment (MoCA) and social function activities questionnaire (FAQ) were adopted for the evaluation comparison before treatment and in 2 weeks and 4 weeks after treatment in patients of the two groups. RESULTS: Compared with those before treatment, the total scores of MoCA were improved in 2 and 4 weeks after treatment in the two groups (all P<0.01). The score in the combined therapy group was improved more apparently as compared with that in the acupuncture group (P<0.01). FAQ score was reduced in the two groups (all P<0.05). The score in the combined therapy group was reduced more apparently as compared with that in the acupuncture group (P<0.05). As compared with the result in 2 weeks of treatment, MoCA score was improved in the two groups in 4 weeks of treatment (both P<0.01), the improvements in the combined therapygroup were more obvious than those in the acupuncture group (P<0.05) and FAQ score was reduced in the two groups (P<0.05), but the difference was not significant between the two groups (P>0.05). CONCLUSIONS: The combined therapy of auricular acupuncture and acupuncture effectively improve the cognitive function and social function, which are better than the effects of simple acupuncture in VCIND. The improvement of the combined therapy in social function is more advantageous in the treatment of the first two weeks. PMID- 29231451 TI - [Impacts of eye acupuncture on neurological deficit and Barthel index in patients of infarction hemiplegia]. AB - OBJECTIVE: To observe the impacts of eye acupuncture on neurological deficit and Barthel index in the patients of infarction hemiplegia and explore its function mechanism. METHODS: Ninety-six patients of infarction hemiplegia were randomized into an observation group and a control group, 48 cases in each one. In the control group, the routine western medicines such as thrombolysis and antiplatelet aggregation were used. In the observation group, on the basis of the treatment as the control group, eye acupuncture was added at Shangjiao and Xiajiao areas bilaterally, once a day, 5 times a week. Separately, before treatment and after 2 weeks' treatment the score changes of the modified Edinburgh Scandinavia stroke scale (MESSS) and the activity of daily life scale (ADL, Barthel index, BI) were observed and the efficacy was compared between the two groups. The plasma endothelin was determined and compared before and after treatment in the two groups. RESULTS: After treatment, the effective rate was 93.8% (45/48) in the observation group and was 79.2% (38/48) in the control group. The effective rate in the observation group was higher apparently than that in the control group (P<0.05). The scores of neurological deficit were (13.29+/-1.45) and (18.24+/-1.33) in the observation group and control group respectively after treatment, which all lower apparently than (28.44+/-1.45) and (28.14+/-1.89) before treatment (both P<0.05). Additionally, the difference was significant between the two groups after treatment (P<0.05). The scores of Barthel index were (82.33+/-1.56) and (63.34+/-2.14) in the observation group and control group respectively, which all higher apparently than (38.53+/-1.54) and (38.14+/-2.56) before treatment (both P<0.05), and the difference was significant between the two groups after treatment (P<0.05). The levels of plasma endothelin were (54.55+/-11.48)ng/L and (62.44+/-9.88)ng/L in the observation group and the control group after treatment respectively, which were all lower apparently than (78.24+/-9.25)ng/L and (78.14+/-10.78)ng/L before treatment (both P<0.05). Additionally, the difference was significant between the two groups after treatment (P<0.05). CONCLUSIONS: Eye acupuncture effectively improves the neurological deficit and Brathel index in the patients of infarction hemiplegia and comprehensively improves the efficacy. The effect mechanism is possibly relevant with reducing plasma endothelin. PMID- 29231452 TI - [Acupuncture and moxibustion based on meridian differentiation for cervical spondylosis radiculopathy:a randomized controlled trial]. AB - OBJECTIVE: To observe the difference of clinical effects of acupoints selected based on meridian differen-tiation and conventional method for cervical spondylosis radiculopathy(CSR) treated with acupuncture and moxibustion. METHODS: Sixty patients with CSR were randomly divided into an observation group and a control group,30 cases in each one. Ashi points of the injured meridians in the neck,namely six-he points,were selected in the observation group,matched with luo connecting points of the injured meridians on the same side and the interiorly exteriorly correlated meridians on the opposite side. Conventional acupuncture was used on Fengchi(GB 20),Jiaji(EX-B 2) of the neck,Tianzhu(BL 10),Jianjing(GB 21),Houxi(SI 3),Hegu(LI 4) and Waiguan(TE 5) on the affected side in the control group. Treatment was given once every other day,three times a week and total 12 times in the two groups. Twenty subscales for CSR and visual analogue scale(VAS) were observed before and after treatment,and total effects were evaluated after treatment. RESULTS: The effective rate of the observation group was 93.3%(28/30),which was better than 66.7%(20/30) of the control group(P<0.05). The scores of 20 subscales and VAS after treatment were all improved compared with those before treatment in the two groups(all P<0.01),with more apparent change in the observation group(both P<0.05). CONCLUSIONS: The effect of acupuncture and moxibustion based on meridian differentiation is obvious,and superior to that of conventional acupoints selection. PMID- 29231453 TI - [Impacts on physical and mental health of patients with polycystic ovary syndrome treated with electroacupuncture:a randomized controlled trial]. AB - OBJECTIVE: To explore the impacts on physical and mental health of the patients with polycystic ovary syndrome (PCOS) treated with electroacupuncture (EA) or Diane 35. METHODS: Seventy-two patients of PCOS were randomized into an acupuncture group and a western medication group, 36 cases in each group. In the acupuncture group, acupuncture was applied to relieving liver stagnation and regulating qi activity at Ganshu (BL 18), Danzhong (CV 17), Qimen (LR 14), Zhongwan (CV 4), Tianshu (ST 25), Guanyuan (CV 4), Zigong (EX-CA 1), Sanyinjiao (SP 6), Zusanli (ST 36) and Taichong (LR 3). After qi arrival, the electric stimulation was added for 30 min. Acupuncture treatment was given 3 times a week. In the western medication group, Diane 35 was taken since the 5th day of menstruation and lasted for 21 days. The cycle of treatment was 3 months in the two groups. Before treatment and at the end of treatment, the symptom scores were evaluated and the self-report symptom inventory, symptom checklist-90 (SCL-90) was used for the mental health evaluation and the comparison was made between the two groups. RESULTS: Compared with those before treatment in the same group, the symptom scores were reduced significantly after treatment in the two groups (both P<0.01). After treatment, the symptom scores in the acupuncture group were reduced significantly as compared with those in the western medicationgroup (P<0.01). After treatment, the scores of somatization, interpersonal sensitivity, depression, anxiety and hostility were reduced significantly as compared with those before treatment in the acupuncture group (all P<0.05). After treatment, the scores of somatization, interpersonal sensitivity, depression, anxiety, hostility and phobic factor were lower significantly than those in the western medication group (all P<0.05). CONCLUSIONS: EA with relieving liver stagnation and regulating qi activity reduces the symptom scores of PCOS and SCL-90 scores, acting on regulating both physical and mental conditions. The effects achieved with acupuncture are better than those with Diane 35. PMID- 29231454 TI - [Effect of governor moxibustion for restless legs syndrome of maintenance hemodialysis:a rando-mized controlled trial]. AB - OBJECTIVE: To observe the effect of governor moxibustion for restless legs syndrome(RLS) of maintenance hemodialysis. METHODS: Sixty-nine patients with RLS of maintenance hemodialysis were randomly divided into an observation group(34 cases) and a control group(35 cases). Conventional hemodialysis was applied in the two groups. Moxibustion was used at the governor vessel from Dazhui(GV 14) to Yaoshu(GV 2) separated by governor moxibustion powder and ginger mud in the observation group. Treatment was given once two weeks and continuous eight times were taken as a course. One course was adopted. Scores of international restless legs syndrome(IRLS) and Pittsburgh sleep quality index(PSQI) were observed before and after treatment and comprehensive effects were evaluated in the two groups. RESULTS: The total scores of IRLS and PSQI were decreased after treatment in the two groups(all P<0.01). And the above two scores after treatment of the observation group were apparently lower than those of the control group(both P<0.05). The cured and effective rate of the observation group was 58.8%(20/34),and that of the control group was 22.9%(8/35),with statistical difference(P<0.01). CONCLUSIONS: Governor moxibustion can effectively improve the symptoms and sleep quality of RLS of maintenance hemodialysis. PMID- 29231455 TI - [Clinical observation on anal pendant expansion after PPH of mixed hemorrhoid treated with acupuncture at Xialiao (BL 34) and Changqiang (GV 1)]. AB - OBJECTIVE: To compare the difference in the clinical efficacy on anal pendant expansion after PPH (procedure for prolapse and hemorrhoids) of mixed hemorrhoid between acupuncture at Xialiao (BL 34) and Chang-qiang (GV 1) and oral administration of diosmin. METHODS: Sixty cases of mixed hemorrhoids after PPH were randomized into an observation group and a control group, 30 cases in each one. In the observation group, since the 1st day, acupuncture had been applied to Xialiao (BL 34) and Changqiang (GV 1). The needles were retained for 30 min after qi arrival, and the treatment was given once a day, totally for 7 days. In the control group, diosmin tablets had been prescribed for oral administration since the 1st day, 0.9 g each time, twice a day, totally for 7 days. The degree, persistent time and the pain score of anal pendant expansion were compared on the 1st, 2nd, 3rd and 7th days after PPH between the two groups and the efficacy was evaluated. RESULTS: On the 1st day after PPH, the diffe-rences in the scores of the degree and persistent time of anal pendant expansion were not significant statistically between the two groups (all P>0.05), but the pain score in the observation group was lower than that in the control group (P<0.05) and lower than that before treatment (P<0.05). On the 2nd, 3rd and 7th days after PPH, the degree and persistent time of anal pendant expansion and pain score in the two groups were all lower than those before treatment (all P<0.05). The results in the observation group were better than those in the control group (all P<0.05). At the end of treatment (on the 7th day after PPH), the total effective rate in the observation group was higher than that in the control group[90.0% (27/30) vs 83.3% (25/30),P<0.05]. CONCLUSIONS: Acupuncture at Xialiao (BL 34) and Changqiang (GV 1) achieves the superior efficacy on anal pendant expansion after PPH of mixed hemorrhoids as compared with diosmin tablets. PMID- 29231456 TI - [Time-effect observation of stimulating effect on acupoints after micro-invasion embedding in healthy subjects]. AB - OBJECTIVE: To in vivo dynamically observe the time-effect characteristic of local stimulating effect on acupoints after micro-invasion embedding, which could provide references for the interval period of micro-invasion embedding. METHODS: With magnetic resonance imaging (MRI) technique, the local T2WI fat-suppression images and T2 Mapping 8-echo sequence images were collected at multiple time points from 8 healthy subjects who received embedding at left Sanyinjiao (SP 6).After the 8-echo sequence images were transformed into T2 Mapping images by using software FuncTool, the T2 average value of embedding area was measured, and the changes of local signal strength of T2WI fat-suppression images and T2 average value along with time after embedding at left Sanyinjiao (SP 6)were analyzed. RESULTS: Compared before embedding, the signal strength of local T2WI fat-suppression images and the T2 average value began to increase 8 h after being embedded(P<0.01); the signal strength of T2WI fat-suppression images and the T2 average value were significantly increased 3 d and 7 d after being embedded(all P<0.01);the signal strength of local T2WI fat-suppression images and the T2 average value 14 d after being embedded were lower than those at previous 2 time points, but higher than those before embedding(both P<0.01); 21 d, 28 d and 35 d after embedding, the signal strength of local T2WI fat-suppression images and the T2 average value were similar to those before treatment (all P>0.05). CONCLUSIONS: After micro-invasion embedding at Sanyinjiao (SP 6), the stimulation effect period on acupoint is approximately 21 days.When applying micro-invasion embedding under similar condition at acupoints which has similar structure as Sanyinjiao (SP 6), the interval period of embedding could consider 21 days as a reference. PMID- 29231457 TI - [Effect of electroacupuncture for immune function of patients treated with laparoscopic radical rectectomy for rectal cancer]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) combined with general anesthesia for the immune function of patients treated with laparoscopic radical rectectomy for rectal cancer. METHODS: Fifty patients who would receive selective laparoscopic radical rectectomy for rectal cancer with general anesthesia were randomly divided into an observation group and a control group,25 cases in each one. Fifteen minutes before anesthesia induction,patients in the observation group were treated with EA at Zusanli (ST 36) and Sanyinjiao (SP 6) until the end of operation. Sham acupuncture without piercing the skin was applied at the same acupoints in the control group, and electrodes were connected without stimulation. Interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-6 (IL-6) were quantitatively tested before anesthesia (T0), at the time of abdomen closing (T1) and one hour after anesthesia anabiosis (T2). And serum procalcitonin (PCT) level, leucocyte count and the number of cases with increasing leucocyte (the standard number>10*109/L) were measured on the first day after operation. RESULTS: The levels of IL-4 and IL-6 were increased apparently and the ratio of IFN-gamma/IL-4 was decreased at T2 compared with those before treatment in the control group (all P<0.05), but obvious change did not appear in the observation group (all P>0.05). The ratio of IFN-gamma/IL-4 was enhanced (P<0.05),and the levels of IL-4 and IL-6 were reduced (both P<0.05) at T2 in the observation group compared with those in the control group. The level of PCT of the observation group was markedly lower than that of the control group on the first day after operation (P<0.05). There was no statistical significance about leucocyte count and the number of cases with increasing leucocyte between the two groups (both P>0.05). CONCLUSIONS: EA at Zusanli (ST 36) and Sanyinjiao (SP 6) could alleviate the depressing immune function and inflammatory reaction of patients after laparoscopic radical rectectomy for rectal cancer. PMID- 29231458 TI - [Action mechanism of electroacupuncture at stomach meridian acupoints for oxidative damage in rats with gastric ulcer]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) at stomach meridian acupoints on expression of oxidation damage factors in serum and gastric mucosal cells in rats with gastric ulcer, and to explore the mechanism of EA at stomach meridian acupoints for oxidative damage in rats with gastric ulcer. METHODS: Forty clean-grade SD rats were randomly divided into a normal group, a model group, a stomach meridian group and a gallbladder meridian group, ten rats in each one. Except the normal group, rats in the remaining groups were applied the restraint-cold stress method to establish the model of gastric ulcer. Rats in the normal group and model group received no treatment; rats in the stomach meridian group were treated with EA at "Liangmen" (ST 21) and "Zusanli" (ST 36); rats in the gallbladder meridian group were treated with EA at "Riyue" (GB 24) and "Yanglingquan" (GB 34). The EA was given for 30 min, once a day for 7 days totally. The change of gastric mucosal morphology was observed by routine light microscope; enzyme linked immunosorbent assay was used to detect the expressions of malondialdehyde (MDA), glutathione peroxidase (GSH-px) and tumor necrosis factor-alpha (TNF-alpha), interleukin-2(IL-2), interleukin-6(IL-6) in serum and gastric mucosal cells of rats. RESULTS: After treatment, compared with the model group, the gastric mucosal damage index was decreased in the stomach meridian group and gallbladder meridian group (both P<0.05), the expressions of MDA, TNF alpha, IL-2 and IL-6 in serum and gastric mucosal cells were significantly decreased in the stomach meridian group (all P<0.01), but the contents of GSH-Px in serum and gastric mucosal cells were increased significantly (both P<0.01). Compared with the gallbladder meridian group, the gastric mucosal damage index as well as the expressions of MDA,TNF-alpha, IL-2 and IL-6 in serum and gastric mucosal cells were significantly decreased in the stomach meridian group rats (P<0.05, P<0.01), and the contents of GSH-px in serum and gastric mucosal cells were increased significantly (both P<0.01). CONCLUSIONS: EA at stomach meridian acupoints is likely to inhibit the expressions of oxidative damage factors to promote the repair of gastric mucosal injury, which indicates the correlation between meridians and zang-fu. PMID- 29231459 TI - [Effects of close-to-bone needling on expression of type-II collagen and markers in cartilage in rabbits with osteoarthritis of knee and imaging observation]. AB - OBJECTIVE: To observe the effects of close-to-bone needling (CBN) on the expressions of type-IIcollagen, pro-collagen type II C-terminal propeptide (PIICP) and C-telopeptide of type II collagen (CTX-II) in rabbits with knee osteoarthritis (KOA). METHODS: Among 40 New Zealand rabbits, 10 rabbits were selected into a normal group; the remaining 30 rabbits were made into KOA model, and X-ray was used to evaluate the results of model establishment. After the model was successfully made, the rabbits were randomly divided into a model group, a CBN group and a regular acupuncture group, ten rabbits in each one.Rabbits in the CBN group and the regular acupuncture group were treated at "Neixiyan" (EX-LE 4), "Dubi" (ST 35), "Yinlingquan" (SP 9), "Zusanli" (ST 36) and "Liangqiu" (ST 34). The CBN group applied CBN, and the depth of needling was appropriate with needles reaching bone; the regular acupuncture group applied regular acupuncture. The electroacupuncture(EA) device was used in the two groups, 20 min per treatment, once a day.Five days of treatment were taken as one course, and totally 4 courses were given with an interval of 2 days between courses. The normal group received identical fixation as model group. After treatment, magnetic resonance imaging (MRI) was used to perform imaging observation on knee; transmission electron microscopy (TEM) was used to observe the cell structure of knee joint cartilage;HE staining was used to observe the pathological change of knee; TUNEL was used to observe the apoptotic index; the expressions of type-II collagen proteins and mRNA were measured by Western-blot and reverse transcription-polymerase chain reaction (RT-PCR); the serum PIICP and CTX-II levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: After treatment, compared with the model group, in the CBN group and regular acupuncture group the articular cavity effusion was reduced without the subchondral bone edema; the cell structure of knee joint cartilage was regular with less apoptosis; the expressions of type-II collagen proteins and mRNA were significantly increased (all P<0.05), the PIICP levels were significantly increased (both P<0.05), but the CTX-II levels were significantly decreased (both P<0.05).The differences of the expressions of type-II collagen proteins and mRNA, the levels of PIICP and CTX-II between the CBN group and the regular acupuncture group were significant (all P<0.05); the differences between the CBN group and the normal group were non-significant (all P>0.05). CONCLUSIONS: CBN can significantly improve the pathological status of cartilage of KOA, reduce apoptosis, and is likely to regulate the expressions of PIICP and CTX-II to promote the type-II collagen, which is superior to regular acupuncture. PMID- 29231460 TI - [GAO Yuchun's experience in the treatment of insomnia]. AB - Professor GAO Yuchun's experience is introduced in insomnia treated with the acupuncture technique for regulating the governor vessel and calming down the mind. GAO's acupuncture technique is in one of the series of character techniques in the acupuncture academic school in the region of Hebei province. Professor GAO believes that insomnia resultes from the disharmony of the nutrient and the defensive and the dysfunction of spleen and stomach. The acupoints are selected on the basis of regulating the governor vessel, calming down the mind, nou rishing the water and the wood to harmonize the mind, strengthening the spleen and stomach to calm down the mind, in which the acupoints of the governor vessel and the yuan-primary points are used in combination. For regulating the governor vessel, Baihui (GV 20) and Shenting (GV 24) are used, combined with Zhongwan (CV 12) for regulating the nutrient and the defensive and calming down the mind. The yuan-primary points of the heart, liver and kidney meridians are selected to nourish water and wood and harmonize the mind. Tianshu (ST 25), Zhongwan (CV 12) and Yinlingquan (SP 9) are used to strengthen the spleen and stomach and for the treatment of the root cause of disease. Additionally, the sequence of needling, the needling techniques for reinforcing and reducing, as well as needle withdrawing are considered. The idea of regulating the governor vessel and calming down the mind as well as the needling techniques for insomnia are considerably introduced in the paper. PMID- 29231461 TI - [Experience of SONG Nanchang preventing bronchial asthma by blistering therapy of dog-day moxibustion]. AB - Professor SONG Nanchang owns unique experience of preventing bronchial asthma by the blistering therapy of dog-day moxibustion. He believes that the method has the action of festering moxibustion without its adverse reaction, the pathogenesis of asthma is the impairment of the dispersing and descending of the lung. When the lung,the spleen and the kidney are deficient,pathogenic factors,such as phlegm,damp and the cold,twist in the lung and the air passage is blocked, then asthma happens. Blistering therapy with little but fierce medicines acquires the features of specific but overall acupoints and more big blister. Meanwhile,with the emphasis on communication and nursing service,the therapy is apparently effective and worth widely using. PMID- 29231462 TI - [Safety test of air quality in simulated moxibustion clinic]. AB - The air quality of simulated moxibustion clinic was tested, which could provide references for the evaluation on air pollution in moxibustion clinic. After the clinical environment of moxibustion was established,the contents of CO,NO2, PM 10 and PM 2.5 in the air at 5 different time points (0.5 h, 1 h and 2 h after 10 moxa sticks were ignited as well as 5 min ventilation after 0.5 h moxibustion burning and 5 min ventilation after 1 h moxibustion burning) were measured by testing organizations.0.5 h, 1 h and 2 h after 10 moxa sticks were ignited, the content ranges of CO,NO2, PM 10 and PM 2.5 in the air were 15.9 to 37.0 mg/m3,0.012 6 to 0.022 4 mg/m3,0.22 to 1.28 mg/m3 and 0.13 to 0.53 mg/m3, respectively; the contents of CO, PM 10 and PM 2.5 were higher than national standard. With 5 min ventilation after 0.5 h moxibustion burning and 5 min ventilation after 1 h moxibustion burning, the content ranges of CO,NO2,PM 10 and PM 2.5 were 0.3 to 0.4 mg/m3,0.015 5 to 0.018 0 mg/m3,0.11 to 0.13 mg/m3 and 0.04 mg/m3, respectively; the contents of CO, PM 10 and PM 2.5 were lower than national standard. It is concluded that long-time moxibustion could cause relatively high concentration of moxa smoke, and the contents of CO, PM 10 and PM 2.5 in the air will exceed the national standard. However, by keeping good ventilation, the contents of CO,NO2,PM 10 and PM 2.5 in the air can be controlled within safe ranges. PMID- 29231463 TI - [Current status and clinical application prospect of Akabane's test]. AB - The Akabane's test is one of the meridian diagnostic methods. Compared with the current meridian diagnostic methods, it has the advantages of convenience and efficiency, but it also has several disadvantages such as the accuracy is difficult to control, the outcome interpretation is limited, etc. In this paper, the influence factors of Akabane's test were analyzed one by one, especially proposed personal opinion on outcome interpretation, which could ascertain the location and nature of disease, leading to disease syndrome. With accurate syndrome, the treatment plan could be established. The application prospect of Akabane's test was initially explored, and it was proposed that wearable automation equipment could be one of the development directions. PMID- 29231464 TI - [Feedback and evaluation on curriculum for major of acupuncture-moxibustion and tuina]. AB - In order to explore the existing problems of teaching, propose suggestions to optimize the teaching and improve the quality of acupuncture-moxibustion teaching, a questionnaire survey was performed to Grade 2008 undergraduates with the major of acupuncture-moxibustion and tuina in our university, and the teaching opinions feedback on main curriculums of acupuncture, including Meridians and Acupoints, Technique of Acupuncture and Moxibustion, Acupuncture Therapy, Selected Literature of Acupuncture and Experimental Acupuncture, were received. It was found out the ratio of curriculum to practice was in need of adjustment, and the link of student ability training was in need of improvement. It was proposed the teaching quality supervision system of acupuncture compulsory courses should be established; the student ability training should be improved; the unchanged pattern of final examination should be changed; the research group of teaching reform should be established. It was hoped this could provide reference for education and teaching reform of acupuncture-moxibustion and tuina in China. PMID- 29231465 TI - [Recognition and application of blood vessels in Zhu Bing Yuan Hou Lun]. AB - Through exploring the recognition and application of blood vessels in Zhu Bing Yuan Hou Lun (Treatise on the Causes and Manifestations of Diseases), it is found that the recognition and concrete application of blood vessels have been developed comprehensively as compared with those records in Nei Jing (Internal Classic). In general, the importance of blood vessels have been improved. For example, the close relationship between blood vessels and emotions and grouth have been emphasized, the body shape and mind been involved in the connotation of blood vessels, the blood vessels been of the top priority in the embryonic formation. In detail, the application of blood vessels has been more specific and flexible in tendency, in which, the vessels have been particularly mentioned in the tongue and eyes, as well as bleeding. All of those provide a certain reference to study the theoretic development of TCM, acupuncture and moxibustion in the periods of the Han and Tang Dynasties. PMID- 29231466 TI - [Discussion on Linggu,a DONG's extra point,and Hegu(LI 4)]. AB - Acupoints are the response points of diseases and the stimulated points by acupuncture and moxibustion. The authors take Linggu,a DONG's extra point,and Hegu(LI 4) as examples to explore the changing cha-racteristics of acupoints from the aspects of finding the response points based on groping acupoints,the features of diagnosis and treatment and action mechanism. It is believed that Hegu(LI 4) is located on the radialis side of the forefinger,and in the changeable status according to the function of the body. While Linggu,a radialis point of the second metacarpal,is related to Hegu(LI 4) which is moving in pathological situation. The conclusion is that other acupoints may be bound up with the body function and in changeable status. PMID- 29231467 TI - [On "the essence of acupuncture is treating spirit as priority"]. AB - From the content of spirit and treating spirit in traditional culture and Taoist culture, the implication of treating spirit in the Internal Classic is discussed, which is by long-time exercises, the body and mental status could achieve a high level of tranquility and calmness, not the mutual spirit focus of patients and physicians during acupuncture. It is emphasized that treating spirit is a long time basic training for acupuncturist before acupuncture. PMID- 29231468 TI - [Comparison and development of different scalp needling schools]. AB - The literature and relevant books on the scalp needling schools were retrieved to collect the main scalp needling schools and compare the point location principles and needling techniques so as to optimize the scalp needling scheme. Currently there are ten major schools of scalp acupuncture, representing for example by JIAO Shunfa, FANG Yunpeng and YU Zhishun, etc. The principles of stimulating localization are different among the schools, in which, YU Changde's skull line localization is mainly for the treatment of cerebrovascular diseases, ZHANG Mingjiu prefers the penetrating technique for the treatment of pain and mental disorders according to traditional meridian theory, and the other schools take the cortical functions into account for the stimulating localization. Regarding needling techniques, FANG Yunpeng stresses on the deep puncture to the periosteum, and the rest school masters puncture beneath the bonnet aponeurosis. The quick rotation of needle is required in JIAO Shunfa's scalp needling, YU Changde's skull needle, International Scalp Points Standardization and the needling technique for opening brain and promotion collateral. The long-term needle retaining is required in YU Zhishun's scalp needling and ZHU Mingqing's scalp needling. It is believed that the stimulating localization principles are not standardized, the theoretic evidences are not clear and the needling depth is different among the schools. There are no standard criteria on needling angle, depth, direction, rotating speed and needle retaining time. The evidence-based medicine is recommended. Through strict scientific design, based on the clinical and experimental evidences, it is required to determine the theoretic scientific evidence of scalp acupuncture, the specificity of stimulating areas, the effective stimulating areas and quantify the needling manipulations and clarify the optimal scheme of scalp needling. PMID- 29231469 TI - [Acupuncture for myocardial ischemia based on purinergic signaling:current status and perspectives]. AB - Coronary heart disease (CHD) is believed to be one of the major diseases with myocardial ischemia (MI) as basic pathological change. The clinical trials and experimental researches in the last 15 years were analyzed in this paper, and it was found that purinergic signaling could transduce the selective expression of molecular adenosine receptors A1, A2A, A2B, A3 in cardiovascular system, which had the potential to be a novel target for treating cardiovascular disease. Using purinergic receptors to explore the actions of acupuncture for myocardial ischemia provides new perspectives to elucidate the mechanism of acupuncture for MI. PMID- 29231471 TI - [Penetration acupuncture at Baxie(EX-UE 9) combined with rehabilitation for swelling hand of post-stroke shoulder-hand syndrome]. AB - OBJECTIVE: To compare the effects between penetration acupuncture at Baxie (EX-UE 9) combined with rehabilitation and simple rehabilitation for swelling hand in post-stroke shoulder-hand syndrome. METHODS: Sixty patients were randomly assigned into an observation group and a control group,30 cases in each one. Penetration acupuncture at Baxie (EX-UE 9) combined with rehabilitation were used in the observation group,and the acupoints were the affected Baxie (EX-UE 9) and Wailaogong (EX-UE 8). Simple rehabilitation was used in the control group. All the treatment was given for 3 weeks,5 days a week with 2 days at the interval,once a day. The swelling degree and motor function of the affected hand were assessed before and after treatment in the two groups. Also,the effects were compared. RESULTS: The swelling and motor function scores after treatment were improved compared with those before treatment in the two groups(all P<0.01),with better effects in the observation group(both P<0.01). The total effective rate was 93.3%(28/30) in the observation group,which was better than 73.3%(22/30) in the control group(P<0.01). CONCLUSIONS: Penetration acupuncture at Baxie (EX-UE 9) combined with rehabilitation can effectively and timely alleviate the swelling hand and motor function of post-stroke shoulder-hand syndrome,which are better than simple rehabilitation. PMID- 29231470 TI - [Impacts of mild moxibustion on immune indices and nailfold microcirculation in the subhealthy group]. AB - OBJECTIVE: To compare the difference in the clinical therapeutic effects of the regulation of subhealthy condition between the mild moxibustion on alternate days and Chinese herbal medicine. METHODS: Seventy-two participants of subhealthy condition were assigned into a mild moxibustion group (36 cases) and a medication group (36 cases) according to random number table. In the mild moxibustion group, the intervention of mild moxibustion with moxa stick was applied to Guanyuan (CV 4), Zusanli (ST 36) and Sanyinjiao (SP 6), once every other day. In the medication group, yupingfeng granules were prescribed for oral administration, three times a day. The treatment was continued for 2 months. Before and after treatment, the levels of IgA, IgM and IgG, SOD (superoxide dismutase), the total score of fatigue scale 14 (FS-14) and the score of nailfold microcirculation were observed separately. RESULTS: Compared with the results before treatment, the immune indices, the total score of FS-14 and the scores of nailfold microcirculation were all improved after treatment in the two groups, indicating the significant differences (P<0.05, P<0.01). In comparison between the two groups after treatment, the levels of immune globulin, e.g. IgM, IgG and SOD in the mild moxibustion group were higher in tendency than those in the medication group, but without significant differences (all P>0.05). The total score of FS-14 after treatment in the mild moxibustion group was lower than that in the medication group (P<0.05). After treatment, in the mild moxibustion group, for the nailfold microcirculation, the flow state score, the periloop score and the total score were all reduced more apparently as compared with those in the medication group (P<0.01, P<0.05). CONCLUSIONS: Mild moxibustion with moxa stick on alternate days apparently relieves fatigue state, immune dysfunction and microcirculatory impairment in the subhealthy group. The results are apparently superior to the treatment with yupingfeng granules. PMID- 29231472 TI - [Acupuncture with smoothing liver and regulating qi for post-stroke slow transit constipation and its gastrointestinal hormone level]. AB - OBJECTIVE: To compare the efficacy between acupuncture with smoothing liver and regulating qi and lactulose for post-stroke slow transit constipation(STC) and to explore the mechanism. METHODS: Sixty patients were randomized into an acupuncture group and a medication group,30 cases in each one. Based on the comprehensive stroke unit care,acupuncture with smoothing liver and regulating qi was used at Danzhong(CV 17),Qihai(CV 6),Tianshu(ST 25),Neiguan(PC 6),Gongsun(SP 4) and Taichong(LR 3) in the acupuncture group,once a day. Lactulose oral liquid was taken at a draught in the morning in the medication group,20 to 30 mL a time,once a day. The study period was 11 weeks,including 1-week baseline evaluation,6-week treatment and 4-week follow-up. We recorded the time of the first independent defecation,constipation symptom score,and gastrointestinal hormone level,including somatostatin(SS),motilin(MTL),P substance(SP) and vasoactive intestinal peptide(VIP). Also,the side effects were recorded at any time. RESULTS: The time of the first independent defecation was (30.18+/-16.14) h in the acupuncture group,which was significantly different from (43.22+/-28.42) h in the medication group(P<0.05). The constipation scores after 6-week treatment and at follow-up were lower than those before treatment in the two groups (all P<0.05),with better results in the acupuncture group(both P<0.05). MTL and SP increased,as well as SS and VIP decreased after treatment in the two groups(all P<0.05). The changes were better in the acupuncture group(all P<0.05). The side effect was not observed in the two groups. CONCLUSIONS: Acupuncture with smoothing liver and regulating qi achieves better effect than lactulose for post stroke STC in terms of efficacy onset,extent,and long term. The mechanism may relate to increasing excitatory regulatory peptide and reducing inhibitory regulatory peptide. PMID- 29231473 TI - [Clinical observation of slow transit constipation treated with acupuncture and modified weitong xiaopi formula]. AB - OBJECTIVE: To compare the difference in the clinical therapeutic effects on slow transit constipation (STC) among the combined therapy of acupuncture and herbal medicine, simple use of herbal medicine and simple use of western medication. METHODS: Ninety patients of STC were randomized into three groups, 30 cases in each one. In the combined therapy group, acupuncture was used in combination with the modified weitong xiaopi formula. In the Chinese herbal medicine group, the modified weitong xiaopi formula was adopted. In the western medication group, mosapride citrate capsules were used. The duration of the treatment was 28 days. Before and after treatment, the colonic transit test was applied, the self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were selected for assessment. The clinical therapeutic effects were compared among the three groups. RESULTS: The total effective rate was 96.7% (29/30) in the combined therapy group, better than 90.0% (27/30) in the Chinese herbal medicine group and 76.7% (23/30) in the western medication group (P<0.05). In each group, before and after treatment, the residual marker amount was reduced apparently in the colonic transit test (all P<0.01). After treatment, the residual marker amount in the combined therapy group was less than that in the Chinese herbal medicine group (P<0.05) and that in the western medication group (P<0.01). The residual marker amount in the Chinese herbal medicine group was less than that in the western medication group (P<0.01). Compared with those before treatment, the scores of SAS and SDS were decreased in the combined therapy group and Chinese herbal medicine group (both P<0.01). After treatment, the scores of SAS and SDS in the combined therapy group were lower obviously than those in the other two groups (both P<0.01). CONCLUSIONS: Under the guidance of xuanfu theory, the combination of acupuncture and Chinese herbal medicine improve appa-rently colonic function and relieve the conditions of anxiety and depression in STC patients. The therapeutic effects are better than those treated with simple use of Chinese herbal medicine and simple use of western medication. PMID- 29231474 TI - [Warm acupuncture for chronic atrophic gastritis with spleen-stomach deficiency cold]. AB - OBJECTIVE: To observe the clinical effect of warm acupuncture at Zhongwan(CV 12) for chronic atrophic gastritis(CAG) with spleen-stomach deficiency cold by the comparison with conventional acupuncture. METHODS: Sixty-two patients were randomly assigned into a warm acupuncture group and a conventional acupuncture group,31 cases in each one. The acupoints in the two groups were Zhongwan(CV 12),Zusanli(ST 36),Neiguan(PC 6),Gongsun(SP 4),Qihai(CV 6),Pishu(BL 20) and Weishu(BL 21). Warm acupuncture was intervened at Zhongwan(CV 12) in the warm acupuncture group. Twirling reinforcing was applied at Zhongwan(CV 12) in the conventional acupuncture group. All the treatment was given for 3 courses continuously,5 days as one course,once a day. TCM syndrome score and symptom rating scale were observed before and after treatment in the two groups,and the effects were compared. RESULTS: The total effective rate was 93.5%(29/31) in the warm acupuncture group,which was better than 87.0%(27/31) in the conventional acupuncture group(P<0.05). The TCM syndrome score and symptom rating score were improved in the two groups after treatment(P<0.01, P<0.05),with more apparent improvement in the warm acupuncture group(P<0.01,P<0.05). CONCLUSIONS: Warm acupuncture at Zhongwan(CV 12) can improve gastrointestinal discomfort,which is better than twirling reinforcing at Zhongwan(CV 12) for CAG with spleen-stomach deficiency cold. PMID- 29231475 TI - [Transcutaneous electrical nerve stimulation at Neiguan(PC 6) and Zusanli(ST 36) for clinical symptoms and life quality of gastroesophageal reflux patients]. AB - OBJECTIVE: To explore the effect of transcutaneous electrical nerve stimulation(TENS) for symptoms,life quality and sleep quality in patients with gastroesophageal reflux disease(GERD). METHODS: A total of 46 GERD patients were randomly assigned into an observation group and a control group,23 cases in each one. The conventional medication and nursing were applied in the two groups. TENS was used at Neiguan(PC 6) and Zusanli(ST 36) in the observation group for 4 weeks,20 min a time,twice a day. The indexes were compared between the two groups before and after treatment,including reflux disease questionnaire,the MOS 36-item short-form,Pittsburgh sleep quality index(PSQI). RESULTS: Except the factor score of gengral health in the control group, the symptoms,life quality and sleep quality were superior to those before treatment in the two group (all P<0.01). The symptom and PSQI scores in the observation group were lower than those in the control group(P<0.01,P<0.05). The scores of general health, life vitality and mental health in the observation group were more apparently improved than those in the control group (all P<0.05). CONCLUSIONS: TENS at Neiguan(PC 6) and Zusanli(ST 36) can improve the clinical symptoms,life quality and sleep quality of GERD based on the conventional treatment. PMID- 29231476 TI - [The heat-reinforcing needling for Kashin-Beck disease with cold-dampness blocking collaterals syndrome]. AB - OBJECTIVE: To compare the efficacy differences between heat-reinforcing needling and conventional treatment of western medicine on Kashin-Beck disease (KBD) with cold-dampness blocking collaterals syndrome. METHODS: Sixty KBD patients of cold dampness blocking collaterals syndrome were randomly assigned into a heat reinforcing needling group and a western medication group, 30 cases in each one. In the heat-reinforcing needling group, the heat-reinforcing needling was applied at local painful sites, combined with the acupoints based on the syndrome differentiation and the distal acupoints on the affected meridians. Acupuncture was given 30 min per time, once a day, the treatment of 5 days made 1 session; there was an interval of 2 days between two sessions. In the western medication group, sodium selenite tablets were prescribed for oral administration after meals, 2 tablets each time, once a day; ibuprofen sustained release capsules were prescribed for oral administration, 1 capsule each time, twice a day; vitamin C tablets were prescribed for oral administration, 2 tablets each time, three times a day. Four-week treatment was given in the two groups. The Western Ontaraio and Mcmaster Universities Osteoarthritis Index (WOMAC) was adopted to assess the involved joints; the safety was assessed in the process of treatment; the efficacy was analyzed, and the follow-up visit was conducted 3 months and 6 months after treatment, respectively. RESULTS: After 4-week treatment, the total effective rate was 96.7%(29/30) in the western medication group, which was superior to 90.0% (27/30) in the heat-reinforcing needling group (P<0.05). However, the safety in the heat-reinforcing needling group was superior to that in the western medication group (P<0.05). The improvements of joint function in 3 month and 6-month follow-up visits in heat-reinforcing needling group were superior to those in western medication group (both P<0.05). CONCLUSIONS: The heat-reinforcing needling for KBD is safe and effective with less adverse reactions. The short-term effect of heat-reinforcing needling isinferior to western medication, but the long-term efficacy is remarkably superior to western medication. PMID- 29231477 TI - [Analysis on the acupoint conception]. AB - To explore the original connotation of acupoint concept, investigating specifically Neijing (Internal Canon of Medicine) and the excavated medical literature as well as the relevant works, the study was conducted in terms of the three aspects, i.e. the early titling and basic meaning of acupoint, the initial analysis on "shu" and the connotation of acupoint concept. It is believed that the relationship of acupoint with meridian tropism and qi as well as the application and indication reflect the acupoint specialty rather than its substantive characteristics. The substantive characteristics of acupoint should reflect the experienced specific site on the body surface in treatment, which are the foundation of acupoint regularity. PMID- 29231478 TI - [Analogical acupoints:acupoints with similar functions in the body]. AB - Analogical acupoints refer to the acupoints with similar functions or effects for certain diseases. From ancient and modern literature, teaching material, modern experimental research and clinical research, the existence of analogical acupoints in the human body is confirmed from multiple levels and angles in this paper. Each acupoint could be considered as analogical acupoint for many diseases, and the analogical acupoints of each disease are overlapped. Therefore, analogical acupoints are not only the basis and premise of acupoint compatibility, but also the basic elements of compatibility. PMID- 29231479 TI - [Effects of electroacupuncture preconditioning on expression of aquaporin-1 and activity of protein kinase C in myocardium of rats with acute myocardial ischemia reperfusion injury]. AB - OBJECTIVE: To explore the partial action mechanism and the myocardial protective effect differences between electroacupuncture (EA) preconditioning at "Neiguan"(PC 6) and "Taiyuan"(LU 9) in rats with acute myocardial ischemia reperfusion injury. METHODS: Ninety-six Wistar rats were randomly assigned into a sham-operation group, a model group, a Neiguan group and a Taiyuan group, 24 rats in each one. The rats in the Neiguan group and Taiyuan group were treated with EA (2 Hz in frequency, 1 mA in intensity) at "Neiguan" (PC 6) and "Taiyuan" (LU 9) respectively, 20 min per treatment, once a day for consecutive 7 days. The rats in the sham-operation group and model group were treated with immobilization for the same time, and no EA was given. The model of myocardial ischemia-reperfusion injury was established in the model group, Neiguan group and Taiyuan group 24 h after the end of EA, while the rats in the sham-operation group were treated with sham operation (no ligation was made during surgery). The myocardial ischemic size, infarction size, activity of protein kinase C (PKC) and expression of aquaporin1 (AQP1) in each group were detected. RESULTS: Compared with sham operation group, the myocardial ischemic size, infarction size, AQP1 expression and PKC activity in the model group were significantly increased (all P<0.01); compared with the model group and Taiyuan group, the myocardial ischemic size, infarction size, PKC activity and AQP1 expression were significantly decreased in the Neiguan group (P<0.01, P<0.05). By Pearson correlation analysis, the changes of AQP1 expression were positively correlated with those of PKC activity after EA preconditioning. CONCLUSIONS: EA preconditioning at "Neiguan" (PC 6) could significantly decrease myocardial AQP1 expression and PKC activity in rats with acute myocardial ischemia-reperfusion injuing, but the effect of EA preconditioning at "Taiyuan"(LU 9) is not obvious; its protective effect is likely to be achieved by inhibiting PKC activity and AQP1 expression. PMID- 29231480 TI - [Effects of electroacupuncture on synaptic plasticity in hippocampal CA3 area of rats with chronic stress depression]. AB - OBJECTIVE: To explore the effects of electroacupuncture (EA) on behavioral function and synaptic plasticity in hippocampal CA3 area in rats with chronic stress depression. METHODS: According to the random number table method, 144 SD male rats were assigned into a blank group, a model group, an EA group and a fluoxetine group, then each group was divided into a 7 d subgroup, a 14 d subgroup and a 21 d subgroup, 12 rats in each subgroup. The chronic mild unpredictable stress stimulus combined with lonely breeding were applied to establish the depression model of rats, which was performed simultaneously with intervention treatment. The rats in the EA group were treated with EA (dilatational wave) at "Shenting" (GV 24) and "Baihui" (GV 20), while the rats in fluoxetine group were treated with intragastric administration of fluoxetine, once daily. With open-field test, sugar consumption experiment and transmission electron microscope, the changes of behavior and neuronal synapse inhippocampal CA3 area were observed. RESULTS: On 7 d, 14 d and 21 d, compared with the blank group, the open-field test score, sugar consumption and body mass were significantly lower in the model group (all P<0.01); compared with the model group, the open-field test score, sugar consumption and body mass were significantly higher in the EA group and the fluoxetine group on 14 d and 21 d (P<0.01, P<0.05). On 14 d and 21 d, compared with the blank group, the synapse in hippocampal CA3 area was significantly lower in the model group (both P<0.01); compared with the model group, the synapse in hippocampal CA3 area was significantly higher in the EA group and the fluoxetine group (P<0.01, P<0.05). The neurons cells in hippocampal CA3 area in the model group showed pyknosis and deformation from 7 d with fusion structure and unclear boundary of synapse, which were significantly improved on 21 d; the neurons cells in hippocampal CA3 area in the EA group and the fluoxetine group were significantly improved from 14 d and restored to normal level on 21 d, in addition, the structure of synapse restored to normal level. CONCLUSIONS: EA is involved in the regulation of synaptic plasticity in hippocampal CA3 area, and promotes the recovery of depression symptoms. PMID- 29231481 TI - [Effects of auricular point sticking on plasma motilin in patients after gynecological laparoscopic operation under general anesthesia]. AB - OBJECTIVE: To observe the clinical efficacy of auricular point sticking on prevention and treatment of gastrointestinal complications after gynecological laparoscopic operation of general anesthesia, and to explore whether it is achieved by regulating the secretion of plasma motilin (MTL). METHODS: Sixty patients who received selective gynecological laparoscopy under general anesthesia were randomly assigned into an observation group and a control group, 30 patients in each one. The patients in the observation group were treated with auricular point sticking at each morning and night, 30 min before anesthesia, revival after surgery and 24 h after surgery. The adhesive fabric with vaccaria seeds was pressed at shenmen (TF4), wei (CO4), benmen (CO3), jiaogan (AH6a) and pizhixia (AT4) for 3 to 5 min until the sensation of sourness, distension and numb appeared. The treatment was given for one week. The patients in the control group were treated only with similar adhesive fabric at auricular points at identical time points; each auricular point was pressed for 3 to 5 min. The anus exhaust time, defecating time and borborygmus were recorded; the level of plasma MTL was tested 30 min before anesthesia, 24 h after o-peration and 48 h after operation; the occurrence of nausea and vomiting from the end of operation to the end of treatment were also recorded. RESULTS: Compared with the control group, the occurrence of nausea after operation was reduced in the observation group (P<0.05), and the anus exhaust time and defecating time were shortened (both P<0.05), and the recovery of borborygmus was improved (P<0.05). The levels of MTL 24 h and 48 h after surgery were higher than those before operation in the two groups (all P<0.05); The levels of MTL 24 h and 48 h after surgery in the observation group were significantly lower than those in the control group (both P<0.05). CONCLUSIONS: The assist of auricular point sticking could reduce the occurrence of nausea-vomiting and accelerate the recovery of gastrointestinal function in gynecological laparoscopic operation under general anesthesia, which is likely to be related with the inhibition on excess secretion of MTL. PMID- 29231482 TI - [Optimal acupoint combination of transcutaneous electrical stimulation in artificial abortion operation]. AB - OBJECTIVE: To observe the clinical effects on analgesia, tranquilization and prevention of abortion syndrome of artificial abortion operation treated with transcutaneous electrical acupoint stimulation (TEAS) with different acupoint combination and explore the optimal acupoint combination of TEAS in artificial abortion operation. METHODS: Two hundred patients intended to artificial operation were randomized into No.1 group[Sanyinjiao (SP 6) + Zusanli (ST 36)], No.2 group[Sanyinjiao (SP 6) + Diji (SP 8)], No.3 group[Sanyinjiao (SP 6) + Taichong (LR 3)], No.4 group (cervical blockage anesthesia with lidocaine) and No.5 group (blank group, without any analgesia measure applied), 40 cases in each one. In the No.1, No.2 and No.3 groups, Sanyinjiao (SP 6) was the main acupoint, combined with Zusanli (ST 36), Dijin (SP 8) and Taichong (LR 3) respectively. TEAS was given 30 min before the operation till the end of operation. Mean arterial pressure, heart rate and oxygen saturation during operation, as well as bleeding amount were observed in the five groups. The visual analogue scale (VAS) score was observed during and 30 min after operation, and Ramsay score was observed during operation. Cervical relaxation degree and the incidence of artificial abortion syndrome were recorded. RESULTS: For VAS score during and 30 min after operation and Ramsay score during operation, the differences were significant statistically in the No. 1, No.2, No.3 and No.4 groups as compared with the No.5 group (P<0.01, P<0.05). The results in the No.2 group were better than those in the No.1, No.3 and No.4 groups (all P<0.05). For cervical relaxationdegree, the result in the No.2 group was better than that in each of the rest groups (P<0.01, P<0.05). For artificial abortion syndrome, the incidences in the No.2 and No.3 groups were lower than those in the No.4 and No.5 groups (all P<0.05). For bleeding amount and hemodynamic changes, the differences were not significant statistically among the five groups (all P>0.05). CONCLUSIONS: TEAS apparently reduces pain score during and 30 min after artificial abortion operation and achieves the satisfactory tranguilization effects. The combination of Sanyinjiao (SP 6) and Diji (SP 8) achieves the optimal effect of analgesia, tranquilization, dilating cervix and preventing from artificial abortion syndrome in the operation. PMID- 29231483 TI - [Efficacy on visual display terminal syndrome treated with jingjin therapy of Zhuang medicine]. AB - OBJECTIVE: To observe the efficacy and explore the effect mechanism on visual display terminal syndrome treated with jingjin therapy of Zhuang medicine. METHODS: Sixty-five patients of visual fatigue induced by the visual display terminal operation were treated with jingjin trigeminy therapy of Zhuang medicine, e.g. massage manipulation, acupuncture and cupping; acting on the specific stimulating areas in Zhuang medicine, relevant with orbit, temple, forehead, ear and Baihui (GV 20). Each treatment lasted 40 min, once every two or three days. Totally, 10 to 14 treatments were required. The scores of visual symptoms and the ocular hemodynamics before and after treatment were observed, and clinical effect were evaluated in the two groups. RESULTS: After treatment, the scores of visual symptoms were reduced apparently as compared with those before treatment (all P<0.05). The total effective rate was 84.6% (55/65). The peak systolic velocity (PSV), the end diastolic velocity (EDV) in anterior ciliary artery (ACA) and the central retinal artery (CRA) were improved obviously, indicating the significant differences before and after treatment (all P<0.05). CONCLUSIONS: The jingjin therapy of Zhuang medicine alleviates the visual symptoms in patients of visual fatigue and improves visual quality. The effects are related to the improvement of ocular microcirculation. PMID- 29231484 TI - [The ancient clinical application of umbilical therapy for retention of urine]. AB - By collecting relevant ancient literature, with retention of urine, umbilical therapy and Shenque (CV 8) as key words, various umbilical therapies for retention of urine from the Song dynasty to Qing dynasty were retrieved and summarized. The results indicated rich knowledge of umbilical therapy was recorded in ancient literature (the Song dynasty to the Qing dynasty), including 9 kinds of therapies e.g. sticking umbilical method, ironing umbilical method, pasting umbilical method, smearing umbilical method, filling umbilical method, sealing umbilical method, covering umbilical method, dripping umbilical method and bundling umbilical method. Moreover, the detailed methods were briefly explained. It is hoped to provide reference for modern application of umbilical therapy for retention of urine. PMID- 29231485 TI - [HE Xingwei's exploration and experience in the pathogenesis and treatment of motor impairment of the trunk after stroke]. AB - In the paper, it is introduced professor HE Xingwei's recognition on the pathogenesis and professor HE's experience in the treatment of the motor impairment of the trunk after stroke. Professor He believes that the motor impairment of the trunk after stroke is the essential factor affecting the rehabilitation in stroke. The motor impairment of the trunk after stroke results from brain marrow damage and spiritual impairment. Hence, regaining the consciousness and promoting the circulation of the governor vessel are the basic principles of the treatment, named regulating the mind and controlling qi, benefiting qi and warming yang, tonifying the kidney and filling up the essence, and promoting the circulation of the governor vessel. Those four therapeutic methods are equally important. Acupuncture, moxibusiton and herbal medicine are applied in combination in the treatment. Additionally, the psychotherapy and rehabilitation are the accessory therapies. PMID- 29231486 TI - [Professor GAO Yuchun's understandings of "treating spirit" and "acupuncture reinforcing and reducing" in Inner Canon of Yellow Emperor and clinical experience]. AB - To state professor GAO Yuchun's methods and understandings of "treating spirit" and "acupuncture reinforcing and reducing" by the systemic study of Inner Canon of Yellow Emperor and clinical experience. It is considered that "treating spirit" is the foundation of all kinds of acupuncture manipulations,and "acupuncture reinforcing and reducing" is an important means to treat disease by adjusting the deficiency and excess. We think that it is key to deeply understand various reinforcing and reducing manipulations and do zhiyihe, so as to achieve effects according to the two principles. PMID- 29231487 TI - [Discussion of acupuncture for diabetic peripheral neuropathy based on blood stasis theory]. AB - Based on the understanding of TCM and western medicine on diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN), the relationship between DPN pathogenesis and blood stasis of TCM is discussed from the perspective of modern medicine. It is indicated blood stasis is the key pathogenesis to DPN, and a two step acupuncture treatment of DPN from the theory of blood stasis is proposed. The first step is to analyze the pathogenesis of blood stasis, which could block the progress of the disease and diminish the symptoms. The second step is to apply acupuncture for pathological result of blood stasis by following the principle of eliminating exogenous pathogen, as a result, the purpose of treating both symptoms and root cause is achieved. PMID- 29231488 TI - [Clinical data analysis of 279 inpatients with acupuncture consultation in a comprehensive hospital]. AB - OBJECTIVE: To analyze the current status of acupuncture consultation in Peking Union Medical College Hospital, which could provide references and suggestions for the development of acupuncture at comprehensive hospitals and the treatment of diseases. METHODS: The source of departments, the number of patients, the number of consultation, treatment frequency, consultation reasons and western medicine diagnosis of 279 inpatients who received acupuncture consultation were analyzed. RESULTS: A total of 26 departments, including department of internal medicine, department of surgery, gynecology department, etc. and emergency department, requested for acupuncture consultation, in which the request from neurology department was the highest. The distribution of diseases was quite wide, mainly gastrointestinal dysfunction, cerebrovascular diseases, urinary retention, hiccup and pain-related symptoms. CONCLUSIONS: The indication of acupuncture is extensive, which could supplement the disadvantages of modern medicine and play a positive role in the adjuvant treatment of comprehensive hospital. It is suggested the communication and cooperation with other departments should be strengthened to promote development of acupuncture and improve the understanding and application of acupuncture for western medicine doctors. PMID- 29231489 TI - [Origin exploration of "the fifty-nine acupoints for febrile disease"]. AB - Fifty-nine acupoints for febrile disease is recorded in Huangdi Neijing (Huangdi's Internal Classics). By analyzing the combination of these acupoints, the writer discovered the acupoint composition and detected their origins from Huangdi's Internal Classics, in which the terms biaoben, qijie and beishu are involved in the theoretic evidence. The writer thought the "fifty-nine acupoints for febrile disease" implied the self-evolution of some acupuncture school in ancient time, which was formed by absorbing the theoretic experiences of the other schools. It is necessary to analyze and interpret the other literatures besides Huangdi's Internal Classics and probably obtain the further reorganization on it. PMID- 29231490 TI - [Discussing the relationship among the ashi point, tender point and myofascial trigger point]. AB - The conception and the history of ashi point, tender point and myofascial trigger point are described in the paper. All of three kinds of point are the reaction of musculoskeletal pain and visceral diseases. Theoretically, ashi point originates from the theory of muscle region of meridian, tender point from the theory of soft tissue and muscles and myofascial trigger point from the theory of muscular fasciae. Anatomically, ashi point is localized in the muscle region of meridian, on the boundary between muscles, tender point is on the muscular attachment to skeleton (the starting and ending points) and myofascial trigger point is on the motor point of neuromuscles. Pathologically, ashi point reflects the disorders of soft tissue and internal organ, tender point reflects the disorders of soft tissue and myofascial trigger point reflects the disorders of soft tissue and few disorders of internal organ. To identify the relationship among them is very significant in the target treatment with acupuncture. PMID- 29231491 TI - [Acupuncture expectation and its clinical evaluation]. AB - Acupuncture expectation refers to the subjective estimation for the effect of acupuncture to be applied. As sham acupuncture is usually used in acupuncture randomized clinical trials,there exists the effect of acupuncture expectation on subjects. It is necessary to evaluate and standardize it. The factors that influence the evaluation standard of acupuncture expectations are different acupuncture expectation value evaluations,evaluation criterions and time points. They will affect the evaluation of clinical efficacy. It is urgent to establish a unified evaluation standard to improve its reliability. PMID- 29231492 TI - [Literature study for acupoint selection rule of rheumatoid arthritis treated with acupuncture]. AB - To explore the clinical acupoint selection rule of rheumatoid arthritis(RA) treated with acupuncture by literature analysis. The related articles were retrieved in 6 Chinese and English databases,including CNKI,VIP,WANFANG,PubMed,Medline and Cochrane. We established a holistic acupoint database and a disease location acupoint database. The results show that there are 120 acupuncture prescriptions and 143 acupoints,with the highest frequency of Zusanli(ST 36). Local acupoints are mainly used for disease locations. The highest acupoin-tcombination frequency of 32 for mandibular joint shows Kunlun(BL 60) and Jiexi(ST 41);22 for finger joint,Baxie(EX-UE 9) and Zusanli(ST 36);28 for wrist joint,Yangxi(LI 5) and Yangchi(TE 4);24 for elbow joint,Quchi(LI 11) and Zusanli(ST 36);21 for shoulder joint,Jianyu(LI 15) and Zusanli(ST 36);13 for spine joint,Yaoyangguan(GV 3) and Shenzhu(GV 12);18 for hip joint,Zhibian(BL 54) and Huantiao(GB 30);20 for knee joint,Shenshu(BL 23) and Yanglingquan(GB 34);32 for ankle joint,Kunlun(BL 60) and Jiexi(ST 41);22 for toe joint,Baxie(EX-UE 9) and Zusanli(ST 36);25 for whole body joints,Yanglingquan(GB 34) and Zusanli(ST 36). Thirty new acupoint prescriptions are found by entropy clustering analysis for different disease regions induced by RA. There exists the acupoint selection rule for acupuncture treating RA and the new prescriptions need to be clinical verification. PMID- 29231493 TI - [A new textual criticism on block-printed edition of Zhenjiu Dacheng in the Ming dynasty]. AB - It has always been considered that Zhenjiu Dacheng (Compendium of Acupuncture and Moxibustion) printed by ZHAO Wenbing is the earliest version. In comparative study, it is found that there are two versions in the Ming dynasty, one is the original, stored in the Library of China Academy of Sciences and another one is the revision, stored in the Library of Tianjin University of TCM, Zhejiang Provincial Library and the Library of China Academy of Chinese Medical Sciences. The last item, Chengjiang (CV 24) in the Acupoint Indication of Conception Vessel in volume 7 is included in the revised edition, but not covered in the original one, which is the difference between the two versions. Both of the versions were in the Ming dynasty, rather than the block-printed one in the Qing dynasty. PMID- 29231494 TI - [Optimization of acupoint application scheme in the treatment of bronchial asthma based on the orthogonal design method]. AB - OBJECTIVE: To study the primary and secondary factors of the allergic history, the frequency of acupoint application and the time of acupoint application in the treatment of bronchial asthma and optimize its scheme. METHODS: Eighty patients of bronchial asthma were selected as the subjects in the orthogonal trial. The herbal medicines were the empirical formula of acupoint application (prepared at the ratio as 2:2:1:1:1:1:1:1:1 of semen brassicae, rhizome corydalis, unprocessed radix kansui, asarum sieboldii, ephedra, semen lepidii, syzygium aromaticum, cortex cinnamomi and fructus gleditsiae) and used on bilateral Feishu (BL 13), Xinshu (BL 15), Geshu (BL 17) and Shenshu (BL 23). Firstly, two groups were divided according to allergic history (40 cases with allergic history and 40 cases without allergic history), and then four subgroups were divided on the basis of the two main groups, 10 cases in each one. Through studying three factors and two levels, i.e. allergic history (Factor A:AI:with allergic history; AII:without allergic history), the frequency of acupoint application (Factor B:BI:4 times; BII:10 times, in which, in the group of 4-time applications, the application was given once every 10 days; in the group of 10-time applications, the application was given once every 4 days); and the time of application (Factor C:CI:4 h; CII:8 h), the optimal scheme was screened on the basis of the attack frequency before and after treatment and the score of the asthma quality life questionnaire (AQLQ) before treatment and 6 months after treatment in the patients of each group. RESULTS: 1 The orthogonal trial indicated that the best optimal scheme was AIBIICI, meaning the patients with allergic history were treated with acupoint application for 10 times, remained for 4 h. 2Factor B (frequency of acupoint application) and C (time of acpoint application) were the significant influential factors of AQLQ scores (both P<0.05). 3The comparison of the attack frequency and AQLQ score before and after treatment in all of the patients showed that the different combinations of factor levels induced the different impacts on the asthma attack frequency and AQLQ scores. Except in the group No.1 and the group No.5, the improvements were all significant in the rest groups, indicating the significant differences (P<0.05, P<0.01). CONCLUSIONS: Acupoint application reduces apparently the attack frequency of asthma in the patients and improves the living quality. The primary and secondary relationship among the allergic history, the frequency of acupoint application and the time of acupoint application for the impacts on the therapeutic effects are:the frequency of acupoint application > the time of acupoint application > the allergic history. The best optimal scheme is AIBIICI, meaning the patients with allergic history are treated with acupoint application for 10 times, remained for 4h. PMID- 29231495 TI - [Relapsing-remitting multiple sclerosis at remission stage treated with acupuncture:a randomized controlled trial]. AB - OBJECTIVE: To evaluate the differences in the therapeutic effects on relapsing remitting multiple sclerosis (RRMS) at remission stage between acupuncture at acupoints and shallow needling therapy at the nearby points. METHODS: Forty-two patients of RRMS were randomized into an observation group and a control group, 21 cases in each one. In the observation group, besides the basic treatment, acupuncture was applied according to WANG Leting's empirical prescriptions as "the empirical ten needles" "thirteen needles of the governor vessel" "twelve needles of hand and foot" as well as the symptomatic points. In the control group, the basic treatment was given. Additionally, the shallow needling therapy was given at the sites 0.2 to 0.3 cun lateral to the acupoints, and the arrival of qi was not required. In the two groups, acupuncture was given once a day for 5 days a week, continuously for 2 weeks. At the intervals of 2 weeks, totally the treatment of 3 months was required. The follow-up visit was conducted for 2 years. Separately, the scores of the expanded disability status scale (EDSS) before and in follow-up after treatment, the annual recurrent rate before and after treatment and recurrent interval after treatment were observed in the patients of the two groups. RESULTS: In the observation group, EDSS scores in 3 month and 6-month follow-up were reduced as compared with those before treatment (both P<0.05) and those in the 12-month and 24-month follow-up were increased (both P<0.05). In the control group, EDSS scores were increased in tendency continuously in 3-month, 6-month, 12-month and 24-month follow-up (all P<0.05). In each time point of follow-up, the different value of EDSS scores in the observation group was lower than that in the control group (P<0.05, P<0.01). The annual recurrent rates after treatment were reduced as compared with those before treatment in the two groups (both P<0.01) and the value in the observation group was lower than that in the control group (P<0.01). The recurrent interval in the observation group was longer than that in the control group[(441.56+/-65.37) d vs (382.78+/-59.33) d, P<0.01]. CONCLUSIONS: Acupuncture achieves the significant therapeutic effects on RRMS at the remission stage. This therapy relieves the symptoms of neural functional deficits, delays the time of occurrence and reduces the annual recurrent rate. PMID- 29231496 TI - [Acupuncture combined with auricular point sticking therapy for post stroke depression:a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical effects of acupuncture combined with auricular point sticking based on the western medication for post stroke depression (PSD). METHODS: Sixty patients with PSD were randomly assigned into an acupuncture plus auricular application group (a combination group) and a medication group, 30 cases in each one. 20 mg paroxetine hydrochloride was prescribed orally in the medication group, once a day for continuous 8 weeks. Based on the above treatment, 30-minute acupuncture was used in the combination group for 8 weeks at Baihui (GV 20), Sishencong (EX-HN 1), Shenting (GV 24), Yintang (GV 29), Shenmen (HT 7), Neiguan (PC 6), Taichong (LR 3), Hegu (LI 4), Zusanli (ST 36), Sanyinjiao (SP 6) and Fenglong (ST 40), once the other day and three times a week. Auricular point sticking therapy for 8 weeks was applied at shenmen (TF4), pizhixia (AT4), xin (CO15), and gan (CO12), with pressing 3 times a day and once 3-5 days. The total score and each factor scores of Hamilton's depression scale (HAMD) were observed in the two groups before and after treatment, and Asberg's antidepressant side-effect rating scale (SERS) and clinical effect were evaluated. RESULTS: After treatment, the total HAMD scores of the two groups decreased compared with those before treatment (both P<0.05), with better effect in the combination group (P<0.05). The scores of the combination group after treatment were lower than those in the medication group, including the anxiety/somatization factor, sleep disturbance factor, hopelessness factor (all P<0.05). The total effective rate of the combination group was 86.7% (26/30), which was better than 66.7% (20/30) of the medication group (P<0.05). The SERS score of the combination group was lower than that of the medication group (P<0.05). CONCLUSIONS: Acupuncture combined with auricular point sticking can improve the clinical symptoms and are effective and safe for PSD. PMID- 29231497 TI - [Effect and postoperative reactions of acupoint catgut embedding for prediabetes]. AB - OBJECTIVE: To observe the effect and safety of acupoint catgut embedding for prediabetes. METHODS: Eighty-six patients with prediabetes were randomly assigned into an observation group and a control group, 43 cases in each one. Diabetes health education was applied in the two groups. Catgut embedding was used at bilateral Pishu (BL 20), Weiwanxiashu (EX-B 3), Ganshu (BL 18), Shenshu (BL 23), and Zusanli (ST 36) in the observation group, once every 15 days for 6 times. The type and number of postoperative reactions of the last time had been recorded since the second embedding, and the situation of the last postoperative reactions was observed 15 days after treatment. Total cholesterol (TC), triglyceride (TG), fasting plasma glucose (FPG), 2 hours postprandial blood glucose (2hPG), glycosylated hemoglobin (HbA1c), empty stomach insulin (Ins) and TCM syndrome score were tested before and after treatment as well as 6 months after treatment. The clinical efficacy was evaluated. RESULTS: After treatment, the levels of TC, TG, FPG, 2hPG, HbA1c of the observation group were lower than those before treatment and those of the control group (all P<0.05). The Ins changed little after treatment and was not significantly different from that of the control group (both P>0.05). All the above indices had no significant difference at follow-up compared with those before treatment (all P>0.05). After treatment, the TCM syndrome score in the observation group was lower than that before treatment and that in the control group (both P<0.05). The TCM syndrome score at follow-up was better than that before treatment in the observation group (P<0.05). The total effective rate of the observation group was 76.7% (33/43) after treatment, which was superior to 30.2% (13/43) of the control group (P<0.05). The rates at follow-up was 37.2% (16/43) in the observation group and was 25.6% (11/43) in the control group (P>0.05). 18 postoperative reactions occurred 168 times totally after embedding, which could be divided into 5 categories, including 75 times (44.6%) of dietary inhibition, 41 times (24.4%) of abnormal feeling, 23 times (13.7%) of local discomfort, 21 times (12.5%) of general malaise, and 8 times (4.8%) of other symptoms. The postoperative peak responses were after the second and third operations. CONCLUSIONS: 3-month catgut embedding can improve some of the indices of prediabetes, but long-term healthy living habits need to be kept. There exist various postoperative reactions after embedding without blocking the treatment. PMID- 29231498 TI - [Impacts of abdominal acupuncture on lipid metabolism in olanzapine-induced obesity]. AB - OBJECTIVE: To discuss the impacts of abdominal acupuncture on serum leptin, adiponectin, total cholesterol and triglyceride in the patients of obesity induced by olanzapine. METHODS: Eighty-six obesity patients induced by olanzapine were randomized into an observation group (47 cases) and a control group (39 cases). The healthcare guide and the adjustment on diet and physical exercise were given in the two groups. Additionally, in the observation group, the abdominal acupuncture therapy was applied to Zhongwan (CV 12), Xiawan (CV 10), Qihai (CV 6), Guanyuan (CV 4), Tianshu (ST 25) and Shuidao (ST 28), once a day, 5 times a week. The treatment lasted for 3 months in the two groups. The body mass index (BMI), serum leptin, adiponectin, total cholesterol and triglyceride were compared before and after treatment in the patients of the two groups. RESULTS: After treatment, BMI, serum leptin, total cholesterol and triglyceride were all lower than those before treatment in the patients of the two groups (all P<0.05). Adiponectin was higher than that in the two groups before treatment (both P<0.05). After treatment, BMI, serum leptin, total cholesterol and triglyceride in the observation group were apparently lower than those in the control group (all P<0.05) and adiponectin was higher than that in the control group (P<0.05). CONCLUSIONS: Abdominal acupuncture regulates the transfer capacity of leptin signal and the secretion of adiponectin, promotes lipid metabolism and reduces the body mass in obesity patients induced by olanzapine. PMID- 29231499 TI - [Different acupuncture and moxibustion methods at Heding (EX-LE 2) for knee osteoarthritis with yang-deficiency and cold-stagnation syndrome]. AB - OBJECTIVE: To observe the differences for knee osteoarthritis (KOA) with yang deficiency and cold-stagnation syndrome among acupuncture plus ginger moxibustion at Heding (EX-LE 2) on the affected side, simple acupuncture and simple ginger moxibustion at the same acupoint. METHODS: Ninety patients were randomly assigned into an acupuncture group, a ginger moxibustion group and a combination group, 30 cases in each one. Acupuncture was used in the three groups at bilateral Liangqiu (ST 34), Xuehai (SP 10), and Dubi (ST 35), Neixiyan (EX-LE 4), Yanglingquan (GB 34), Zusanli (ST 36), Yinlingquan (SP 9), Sanyinjiao (SP 6), Xuanzhong (GB 39), Taichong (LR 3) on the affected side. Acupuncture at the affected Heding (EX-LE 2) was applied in the acupuncture group; ginger moxibustion at the affected Heding (EX-LE 2) in the ginger moxibustion group; ginger moxibustion after acupuncture at Heding (EX-LE 2) in the combination group. The treatment was given once a day, and 10 treatments made one session. There were 2 days at the interval between 2 sessions. Before and after (22/30), which was significantly higher than 46.7% (14/30) of the acupuncture group and 20.0% (6/30) of the ginger moxibustion group (both P<0.05), and the rate of the acupuncture group was higher than that of the ginger moxibustion group (P<0.05). Conclusion Based on acupuncture, ginger moxibustion at the affected Heding (EX-LE 2) after acupuncture at the same acupoint are more effective than simple acupuncture at the affected Heding (EX-LE 2) and simple ginger moxibustion at the acupoint for KOA with yang-deficiency and cold-stagnation syndrome. two-session treatment, knee function scores, visual analogue scale (VAS) score, and present pain intensity (PPI) score were compared in the three groups. The clinic effects were evaluated too. RESULTS: After treatment, the knee function scores of the three groups were all higher than those before treatment (all P<0.05), and the VAS score and PPI score were lower (all P<0.05). The differences before and after treatment for knee function, VAS and PPI score of the combination group were higher than those of the other two groups (all P<0.05), and the differences of the acupuncture group were higher than those of the ginger moxibustion group (all P<0.05). The cured and remarkable effective rate of the combination group was 73.3% (22/30), which was significantly higher than 46.7% (14/30) of the acupuncture group and 20.0% (6/30) of the ginger moxibustion group (both P<0.05), and the rate of the acupuncture group was higher than that of the ginger moxibustion group (P<0.05). CONCLUSIONS: Based on acupuncture, ginger moxibustion at the affected Heding (EX-LE 2) after acupuncture at the same acupoint are more effective than simple acupuncture at the affected Heding (EX-LE 2) and simple ginger moxibustion at the acupoint for KOA with yang-deficiency and cold-stagnation syndrome. PMID- 29231500 TI - [Impacts of electroacupuncture on benign prostatic hyperplasia and the levels of estrogen and androgen in patients]. AB - OBJECTIVE: To discuss the therapeutic effects of electroacupuncture on benign prostatic hyperplasia and the impacts on hormone levels in the patients. METHODS: Sixty patients were randomized into an electroacupuncture group and a medication group, 30 cases in each one. In the electroacupuncture group, electroacupuncture was applied to Zhongji (CV 3) and Qugu (CV 2), once a day, 5 times a week. In the medication group, tamsulosin hydrochloride sustained-release capsules were prescribed for oral administration, 0.2 mg, once a day. The duration of treatment was 6 weeks in both of the two groups. The changes in serum testosterone (T), estradiol (E2) and E2/T, the international prostate symptom score (IPSS) and its erectile function score (IIEF5) and serum prostate specific antigen (PSA) as well as the adverse reactions were observed before and after treatment in the two groups. The clinical therapeutic effects were compared between the two groups. RESULTS: Before and after treatment, the differences in serum T, E2 and E2/T were not significant in the electroacupuncture group (all P>0.05); the difference in E2/T was significant in the medication group (P<0.05). The differences in serum T, E2 and E2/T were not significant between the two groups (all P>0.05). IPSS was reduced as compared with that before treatment in the electroacupuncture group (P<0.05) and was not different significantly as compared with that before treatment in the medication group (P>0.05). The difference was significant in comparison of the two groups after treatment (P<0.05), and the electroacupuncture group was better. After treatment, the symptom severity was reduced apparently in the electroacupuncture group and the overall situation was better than that in the medication group (P<0.05). IIEF5 score and PSA were not different significantly before and after treatment in the two groups and between the two groups (all P>0.05). The total effective rate was 60.7% (17/28) in the electroacupuncture group, apparently better than 30.8% (8/26, P<0.05) in the the medication group. CONCLUSIONS: Electroacupucnture at Zhongji (CV 3) and Qugu (CV 2) apparently relieves the symptoms in the patients and the therapeutic effects are better than the oral administration of tamsulosin hydrochloride sustained release capsules, but electroacupuncture has not apparent impacts on serum T and E2 levels. PMID- 29231501 TI - [Herbal-partitioned moxibustion for moderate to severe persistent allergic rhinitis with spleen-qi deficiency syndrome]. AB - OBJECTIVE: To explore the clinical efficacy of herbal-partitioned moxibustion on moderate and severe persistent allergic rhinitis (AR) with spleen-qi deficiency syndrome. METHODS: With prospective case series study method, forty-seven patients of moderate and severe persistent AR with spleen-qi deficiency syndrome were treated with herbal-partitioned moxibustion at Yintang (GV 29), Shenque (CV 8), Hegu (LI 4) and Zusanli (ST 36), once every two days, three treatments a week, continuously for 8 weeks. The visual analogue scale (VAS), rhinoconjunctivitis quality of life questionnaire (RQLQ) and scores of spleen-qi deficiency syndrome were recorded before treatment, 2 weeks, 4 weeks and 8 weeks into treatment as well as 4 weeks after treatment; in addition, the improvement rate of each index was compared before and after treatment. RESULTS: Compared before treatment, the VAS, RQLQ and scores of spleen-qi deficiency syndrome were significantly reduced 2 weeks, 4 weeks and 8 weeks into treatment as well as 4 weeks after treatment (P<0.05, P<0.01). The efficacy was gradually increased 2 weeks, 4 weeks and 8 weeks into treatment (all P<0.01). On the 8 weeks into treatment, the improved and markedly effective rate was 59.6% (28/47) for VAS, 19.1% (9/47) for RQLQ and 14.9% (7/47) for scores of spleen-qi deficiency syndrome; the total effective rate was all 85.1% (40/47). Compared with 4 weeks after treatment, there was no significant difference (all P>0.05). CONCLUSIONS: The herbal-partitioned moxibustion has superior efficacy for moderate and severe persistent allergic rhinitis with spleen-qi deficiency syndrome. PMID- 29231502 TI - [Clinical observation of chronic perianal eczema treated with auricular point sticking therapy and western medication]. AB - OBJECTIVE: To observe the differences in the therapeutic effects on chronic perianal eczema between auricular point sticking therapy and auricular sticking pseudo-press therapy on the basis of the treatment with western medication. METHODS: Ninety patients were randomized into an auricular therapy group and an auricular pseudo-press therapy group (pseudo group), 45 cases in each one. The western medication was used in both of the groups. In the auricular therapy group, the auricular sticking method with semen vaccariae was added at Fengxi (SF1,zi), Shenshangxian (TG2p), Duipingjian (AT1,2,4i), Fei (CO14), Pi (CO13), Gangmen (HX5). The patients were advised to press each auricular point every day. In the pseudo group, the plaster was applied to the same auricular points without semen vaccariae used and pressing manipulation given. The auricular sticking therapy was used once every three days in the two groups. The treatment for 2 weeks was as one session and one or two sessions of treatment were given accordingly. The severity of perianal itching, the area of skin lesion, the form of skin lesion and the score of dermatology life quality index (DLQI) and the clinical therapeutic effects were compared before and after treatment in the two groups. The adverse reaction and recurrence rate in 1-year follow-up visit were observed during treatment. RESULTS: After treatment, the itching degree, the area of skin lesion, the form of skin lesion and DLQI score were all reduced apparently as compared with those before treatment in the patients of the two groups (all P<0.05). The results in the auricular sticking therapy group were better than those in the pseudo group (all P<0.05). The curative and markedly effective rate and the total effective rate in the auricular sticking therapy group were apparently better than those in the pseudo group[52.3% (23/44) vs 19.0% (8/42), 97.7% (43/44) vs 76.2% (32/42), both P<0.05]. The recurrence rate in the auricular sticking therapy group was lower apparently than that in the pseudo group[7.0% (3/43) vs 37.5% (12/32), P<0.05]. No severe adverse reactions were found during the treatment in the two groups. CONCLUSIONS: The auricular sticking therapy combined with western medication effectively release itching in chronic perianal eczema and local skin lesions, improve the living quality and reduce recurrence rate. PMID- 29231503 TI - [Clinical observation of infantile herpetic angina treated with acupuncture:a randomized controlled trial]. AB - OBJECTIVE: To observe the difference in the therapeutic effects on infantile herpetic angina among the treatments with western medication, acupuncture and the combined therapy of acupuncture and western medication. METHODS: One hundred and twenty children of herpetic angina were randomized into a western medication group, an acupuncture group and a combined therapy group, 40 cases in each one. Besides the basic treatment with symptomatic support, in the western medication group, ribavirin granules were prescribed for oral administration, 10 mg/kga day, three times a day, for 3 days. In the acupuncture group, acupuncture was applied at Fengchi (GB 20), Hegu (LI 4), Quchi (LI 11), Xiaguan (ST 7), Jiache (ST 6), Dicang (ST 4), Shaoshang (LU 11) and Shangyang (LI 1), once a day, for 3 days. In the combined therapy group, the treatments as the western medication group and the acupuncture group were used, in which, the oral administration with ribavirin granules and acupuncture were adopted for 3 days. The clinical therapeutic effects were compared after treatment and the follow-up visit was conducted since the 4th day at the end of treatment to compare the antifebrile time, herpes relieving time and the use frequency of ibuprofen oral liquid in the children among the three groups. RESULTS: After treatment, the total effective rate was 95.0% (39/40) in the combined therapy group, was 62.5% (25/40) in the western medication group and was 80.0% (32/40) in the acupuncture group. The result in the combined therapy group was better than those in the acupuncture group and the western medication group, indicating the significant differences (both P<0.05). The antifebrile time and the herpetic relief time in the combined therapy group were earlier than those in the acupuncture group and the western medication group, indicating the significant differences (both P<0.05). The use frequency of ibuprofen oral liquid in the combined therapy group was lower than those in the acupuncture group and the western medication group, indicating the significant difference (both P<0.05). CONCLUSIONS: The combined therapy with acupuncture and western medication relieve fever and herpes much more quickly and reduces the use frequency of ibuprofen oral liquid as compared with the simple use of acupuncture or western medication in the treatment of infantile herpetic angina, which achieve the much better therapeutic effects. PMID- 29231504 TI - [Explanation on acupoint intention]. AB - The spiritual qi "circulating" "exiting and entering", and "nothing relevant with skin, flesh, tendon and bone" are the clues to understand the original intention of acupoint recorded in Lingshu (Miraculous Pivota). In the paper, regarding the interpretation of these words and phrases in Shuowen Jiezi (Origin of Chinese Characters), in combination with TCM theory, the connotations of acupoint are summarized in 4 aspects, including the essential characteristics of the changes in the antipathogenic qi, functional property of pathway communication, the clinical features of diagnosis and treatment and the three-dimensional structural characteristics. It is enlightened that the antipathogenic qi and its changes are the most essential rather than the anatomic structure of acupoint. The application of acupuncture and moxibustion acts on qi activity of acupoint rather than flesh and joint. All of those mentioned above indicate the essential issues on the clinical therapeutic effects of acupuncture and moxibustion, which are significant and valuable nowadays in clinical practice. PMID- 29231505 TI - [Relationship between the distribution of spinal nerve posterior ramus and locations of acupoint in low back]. AB - OBJECTIVE: To explore the relationship between the distributions of posterior ramus of spinal nerve (PRSN) and locations of acupoint in low back through anatomical observation. METHODS: The regional anatomy was performed at five corpses to observe the distribution of erector spinae muscle and PRSN in areas of Jiaji points and back-shu points in low back. RESULTS: The T12, L1, L2, L3 and L4 PRSN distributed on both sides of the spine; the medial branches of PRSN travelled between spinalis thoracis muscle and longissimus thoracis muscle, while the lateral branches of PRSN travelled between longissimus thoracis muscle and iliocostalis lumborum muscle. CONCLUSIONS: Jiaji points and back-shu points in low back are closely associated with PRSN, particularly T12, L1, L2, L3 and L4. PMID- 29231506 TI - [Effects and mechanisms of different frequencies of electroacupuncture for learning and memory ability of Alzheimer's rats]. AB - OBJECTIVE: To observe the effects of different frequencies of electroacupuncture (EA) at "Baihui (GV 20)" and "Shenshu(BL 23)" for the learning and memory ability as well as glycogen synthase kinase-3beta (GSK-3beta) and growth associated protein-43 (GAP-43) in hippocampal tissue of rats with Alzheimer's disease(AD), so as to explore the mechanism of different frequencies of EA for the prevention and treatment of AD. METHODS: One hundred and twelve healthy Wistar male rats were divided into seven groups by random number table, namely a normal group, a sham operation group, a model group, an acupuncture group, a 2 Hz EA group, a 30 Hz EA group, and a 50 Hz EA group, 16 rats in each one. The rats in the normal group were conventionally raised in the laboratory without any treatment. 0.9% NaCl solution was injected into bilateral dentate convolution of hippocampus in rats of the sham operation group. AD model was established by beta-amyloid protein1-42 (Abeta1-42) injected into bilateral dentate convolution of hippocampus in the other groups. 15 days after establishment, no treatment was applied in the model and sham operation groups, and EA with corresponding frequencies at "Baihui (GV 20)" and "Shenshu (BL 23)" was used in the three EA groups for 2 sessions, once a day and 7 times as one session. There was 1 day between the two sessions. The same acupoints were adopted in the acupuncture group, without electrical connection. The escape latency, the first spanning platform time, and the number of crossing platform were tested in the Morris water maze immediately after treatment. The expressions of GSK-3beta and GAP-43 were examined by immunohistochemistry and Western blot. RESULTS: 1Morris water maze tests showed that the escape latency and the first spanning platform time significantly increased in the model group compared with those in the normal group (both P<0.01), and the number of crossing platform decreased (P<0.01). Compared with the model group, the escape latency and the first spanning platform times decreased in the acupuncture and three EA groups (all P<0.01), and the numbers of crossing platform increased (P<0.01). Compared with the acupuncture and 2 Hz, 30 Hz EA groups, the escape latency decreased in the 50 Hz EA group (P<0.01, P<0.05); the first spanning platform time reduced (all P<0.01); the number of crossing platform increased (P<0.01, P<0.05). 2The expressions of GSK 3beta and GAP-43 of the model group increased compared with those of the normal group(both P<0.01). The expressions of GSK-3beta in the acupuncture and three EA groups decreased compared with that in the model group (all P<0.01), and the expressions of GAP-43 increased (all P<0.01). The expressions of GSK-3beta decreased and GAP-43 increases in the 50 Hz EA group compared with those in the acupuncture group and 2 Hz, 30 Hz groups (all P<0.01). CONCLUSIONS: EA may promote synaptic damage rehabilitation by down regulating GSK-3beta and up regulating GAP-43 to improve learning and memory ability of AD rats. The effect of 50 Hz EA is better than those of 30 Hz and 2 Hz EA and acupuncture. PMID- 29231507 TI - [Effect of acupuncture treatment on gene expression of neurotransmitters of brain tissue in rats with post-stroke depression]. AB - OBJECTIVE: To observe the effects of acupuncture on mRNA of the neurotransmitter serotonin transporter (5-HTT), 5-HT1Areceptor (5-HT1AR), norepinephrinealpha2 receptor (NEalpha2R) in brain tissue in rats with post-stroke depression. METHODS: Forty male SD rats were randomly divided into a normal group, a model group, a medication group and an acupuncture group, 10 rats in each one. The model of post-stroke depression was established by occlusion of middle cerebral artery and chronic unpredictable mild stress method. After model was successfully established, the rats in the normal group and model group received no treatment; the rats in medication group were treated with intragastric administration of fluoxetine (2 mg/kg); the rats in acupuncture group were treated with acupuncture at "Baihui" (GV 20), "Fengfu" (GV 16), "Shenmen" (HT 7) and "Taichong" (LR 3) for 20 min, during which manual stimulation was given once, once a day, 7 days as one course, and totally 3 courses were given with an interval of one day between courses. The changes of rat behavior and 5-HT, NE were observed after intervention; the RT-PCR method was applied to observe the mRNA of 5-HTT, 5 HT1AR, NEalpha2R in hippocampus, raphe nucleus and locus coeruleus. RESULTS: After treatment, compared with the normal group, the Zea Longa score in the model group was increased, while sugar water consumption, the number of horizontal and vertical movement of open-field test was reduced (all P<0.01); compared with the model group, the Zea Longa score in the medication group and acupuncture group was reduced, while sugar water consumption, the number of horizontal and vertical movement of open-field test were increased (P<0.01, P<0.05); compared between the medication group and acupuncture group, the behavior changes were not significantly different (all P>0.05). After treatment, compared with the normal group, the content of 5-HT and NE in brain tissue and mRNA expression of 5-HTT, 5 HT1AR in hippocampus, raphe nucleus and locus coeruleus in the model group were reduced (all P<0.01), but the mRNA expression of NEalpha2R was increased (P<0.01);compared with the model group, the content of 5-HT and NE in brain tissue and mRNA expression of 5-HTT, 5-HT1AR in hippocampus, raphe nucleus and locus coeruleus in the medication group and acupuncture group were increased (P<0.01, P<0.05), while the mRNA expression of NEalpha2R was reduced (all P<0.01). The differences between medication group and acupuncture group were not significantly different (all P>0.05). CONCLUSIONS: Acupuncture could significantly improve behavioral change in rats with post-stroke depression, which may be related to the regulation of 5-HT, NE in cerebral cortex as well as mRNA expressions of 5-HTT, 5-HT1AR, NEalpha2R in hippocampus, raphe nucleus and locus coeruleus. PMID- 29231508 TI - [Effects of tooth extraction under acupuncture anesthesia]. AB - OBJECTIVE: To compare the effects for tooth extraction between acupuncture anesthesia and drug local block anesthesia. METHODS: Sixty patients were randomly assigned into an acupuncture group and a drug group, 30 cases in each one. Acupuncture was applied at Hegu (LI 4), Neiting (ST 44) and the affected side Xiaguan (ST 7), and Jiache (ST 6), etc. Arrachement was used after deqi and the needles were retained for 10 min after tooth extraction in the acupuncture group. Compound articaine hydrochloride injection was used to conventional local anesthesia, after which tooth extraction was implemented in the drug group. The effects of anesthesia and analgesia were compared between the two groups with pain rating index (PRI) and visual analogue scale (VAS). Besides, the bleeding amounts and adverse reaction rates during the operation and the blood pressure, pulse, and respiration before and after operation were observed. RESULTS: Tooth extraction was completed, and the excellent rates, PRI and VAS scores were not significantly different in the two groups (all P>0.05). The bleeding amounts and adverse reaction rates in the acupuncture group were lower than those in the drug group (P<0.01, P<0.05).The blood pressure, pulse and respiratory during surgery remained normal without significance between the two groups (all P>0.05). CONCLUSIONS: The effect of acupuncture anesthesia for tooth extraction is equal to that of drug anesthesia. Its analgesia is complete with stable vital signs and less adverse reactions. It is worthy of popularizing. PMID- 29231509 TI - [Summary of professor YANG Jun's experience for intractable facial paralysis]. AB - Professor YANG Jun's experience of diagnosis and treatment for intractable facial paralysis is introduced. Professor YANG focuses on the thinking model that combines TCM, western medicine and acupuncture, and adopts the differentiation system that combines disease differentiation, syndrome differentiation and meridian differentiation; he adopts the treatment integrates etiological treatment, overall regulation, symptomatic treatment as well as acupuncture, moxibustion, medication and flash cupping. The acupoints of yangming meridians are mostly selected, and acupoints of governor vessel such as Dazhui (GV 14) and Jinsuo (GV 8) are highly valued. The multiple-needles shallow-penetration insertion twirling lifting and thrusting technique are mostly adopted to achieve slow and mild acupuncture sensation; in addition, the facial muscles are pulled up with mechanics action. The intensive stimulation with electroacupuncture is recommended at Qianzheng (Extra), Yifeng (TE 17) and Yangbai (GB 14), which is given two or three treatments per week. PMID- 29231510 TI - [Study of the multidimensional perspectives on the theory of syndrome differentiation and treatment with acupuncture and moxibustion]. AB - Aiming at many questions nowadays in the study on the theory of syndrome differentiation and treatment with acupuncture and moxibustion, the relevant rules and important theoretic issues were discussed on the syndrome differentiation and treatment with acupuncture and moxibustion in the paper from the multidimensional perspectives, named the treatment in view of yinyang differentiation-pulse-based acupuncture, the treatment in view of meridian collateral (zangfu) differentiation, the treatment in view of body differentiation, the treatment in view of "four seas" differentiation, etc. It is proposed that the complicated multidimensional relationships of human body determine the multi-perspectives and multi-angles in the syndrome differentiation and treatment with acupuncture and moxibustion, in which, the theoretic principle of every approach to the syndrome differentiation and treatment has its relatively independent significance. Regarding the new study recognition, it is suggested that the pulse-based acupuncture of yinyang differentiation according to the comparison between the renying and the cunkuo pulse conditions works on the positive regulation of yinyang (qi) balance with acupuncture. Additionally, in the paper, the origins of five thoughts are put forward on the differentiation and treatment on the basis of meridians and collaterals, which enriches the connotation of this approach to the differentiation and treatment; the "five tissue" effects and "five-zang" effects are innovated and the theory is proposed originally on the "four seas" differentiation and treatment, etc. PMID- 29231511 TI - [Meridian differentiation of low back pain in Neijing (Inner Canon of Yellow Emperor)]. AB - There are various contents about diagnosis and treatment of low back pain in Neijing (Inner Canon of Yellow Emperor), which are closely related to meridians and collaterals, forming a complete theoretical system of meridian differentiation for low back pain. Its theory and application are interpreted in this paper from five main aspects, including 18 meridians and collaterals densely distributing in the tendons and bones of the waist, the pathogenesis of low back pain lying in the disorders of the meridian qi and blood, the nature of low back pain being reflected by the color and shape of meridians and collaterals, the disordered meridians of low back pain being first identified based on syndrome differentiation, the acupuncture prescription being selected according to meridian differentiation. The purpose of this paper is to guide clinical practice, explore the advantages and characteristics of meridian differentiation, and provide theoretical reference and evidence for promoting the standardization of TCM. PMID- 29231512 TI - [Discussion on "dry needling" being part of acupuncture]. AB - We think that all the methods of puncturing into the skin to prevent and treat diseases are belong to acupuncture science. In spite of its basic theory of meridian and acupoint, anatomy and physiology have been important parts of modern acupuncture science. "Dry needling", however, is limited to trigger point theory. As for the positions, acupuncture is applied mainly at acupoints, involving in skin, muscles, tendons, vessels and nerves; while "dry needling" is used mostly at muscles. The needles of acupuncture are in various lengths and diameters and its manipulations are abundant, including the traditional skills and the achievements of modern science and technology research, such as electroacupuncture. It is different from the "dry needling" with the single tool and manipulation. Thus, acupuncture is suitable for a large range of syndromes, but "dry needling" is mainly for fascia muscularis pain and other related disorders. The acupuncturists need to embrace Chinese and western medicine, which is more rigorous than the training for "dry needling" practitioners. Based on the above reasons, we consider "dry needling" as part of acupuncture science, and it is a method during the modern development of traditional acupuncture. PMID- 29231514 TI - [Development of non-traumatic-pain acupuncture-moxibustion apparatus and its industrialization]. AB - In order to alleviate the discomforts induced by the invasive manipulation of acupuncture, improve the acceptability of acupuncture-moxibustion therapy and promote the application of it in healthcare, the research team developed the non traumatic-pain acupuncture-moxibustion apparatus for disease treatment and prevention as well as healthcare, such as crude herbal moxibustion plus cupping device (cupping device), the healthcare cloth for warming the governor vessel (healthcare cloth) and the governor vessel intelligent diagnosis apparatus (diagnosis apparatus). Cupping device was developed through the integration of crude herb extract for moxibustion and silica gel, which is used specially on the governor vessel, Jiaji (EX-B2) and the bladder meridian of food-taiyang for chronic disorders and healthcare. The healthcare cloth was prepared with hi-tech thermal material and on the basis of yang nourishment of the governor vessel, acting on warming yang, benefiting qi and promoting qi circulation. It is applicable for the people of 7 body constitutions, such as neutral constitution, qi deficiency constitution and yang deficiency constitution to regulate the body constitution. The diagnosis apparatus integrates the functions of diagnosis and treatment as well as data analysis, implying the future of "internet+" medical development of TCM. The industrialization of non-traumatic-pain acupuncture moxibustion apparatus should be guided under the national policy and use fully the advantage of internet so as to maintain and promote the people's health through the industry-university-research cooperation. PMID- 29231513 TI - [Application of data mining on the relationship between deqi and effect]. AB - OBJECTIVE: To analyze the relationship between deqi and effect by data mining technique with retrieving clinical literature about acupuncture deqi since the founding of the country. METHODS: The modern computerization and data mining technologies were adopted to set up clinical literature about acupuncture deqi database. The relevant clinical literature was collected, screened, extracted, and statistical and correlation analyses were used so as to explore the relationship between deqi and effect. RESULTS: 82.1% (46/56) of the studies considered that deqi was related to the effect; 17.9% (10/56) of the studies considered that deqi was unrelated to the effect. The support of deqi related to the effect is 100% on dysmenorrhea and facial paralysis. 72% (18/25) of the the articles of pain syndrome considered that deqi was related to the effect; 28% (7/25)of the studies considered that deqi was unrelated to the effect. In the research of the relationship between the features of deqi and effect, 60.7% of the studies suggested that the sense of conduction was positively correlated with the effect. There were 21 studies on the relationship between the intensity of deqi and effect, involving a variety of diseases, which was related to the type of the disease. 58.3% (7/12) of the articles on dysmenorrhea and 63% (34/54) on pain syndrome supported conduction positively correlated to effect, showing the highest frequencies. 50% (3/6) of the papers on facial paralysis supported weak deqi sensation positively correlated to effect, which was the highest frequency. CONCLUSIONS: Most studies considered that deqi can improve clinical efficacy. The relationship between different features of deqi and effect is closely related to the disease. Further study may focus on high quality research on the relationship between deqi and the obvious effect achieved by acupuncture so as to summarize the law of deqi. PMID- 29231515 TI - [Reviews on acupuncture for cellular signal transduction in spinal cord injury]. AB - Investigating the influence of acupuncture on cellular signal transduction is an efficient pathway to reveal the action mechanism of acupuncture on spinal cord injury (SCI). In this study, the experiment research literature regarding acupuncture for SCI during past 10 years was reviewed and analyzed. As a result, it was found that acupuncture could regulate the expression of the first intercellular messenger as well as the second signal molecules including cyclic adenosine monophosphate, cyclic guanosine monophosphate, Ca2+, nitric oxide to intervene the apoptotic signaling pathway, Rho/Rock signaling pathway, Wnt signaling pathway, MAPK signaling pathway, Notch signaling pathway, etc., which could improve regeneration and repair of SCI. In conclusion, in future researches more attention should be paid to the cellular signal transduction networks and different effects among various acupoint combinations and acupuncture modalities on cellular signal transduction, which have an essential role for revelation of clinical application rules and optimization of clinical treatment protocol. PMID- 29231516 TI - [The principle of treating spirit in clinical acupuncture-moxibustion in terms of three-layer thought]. AB - Treating spirit,which relates to many philosophical theories and techniques,is key to the effect of acupuncture-moxibustion therapy. According to qi monism and the three-layer thought of nature-earth-human,it is believed that the spirit means the ability or possibility to communicate with the nature-earth-human,and response refers to the spirit-interlinking progress between persons and the nature-earth-human. While treating spirit is seen as keeping learning and practicing the progress. The author describes treating spirit by acupuncture moxibustion in terms of metaphysics and examples. It believes that treating spirit is inevitable as three-layer thought,which stems from traditional Chinese culture,is permeating into acupuncture-moxibustion theory. Treating spirit,a combination between medical ethics and techniques,indicates that doctors understand patients and diseases both generally and detailedly,with mental requirement for the two parts. PMID- 29231517 TI - [Efficacy on the range of motion of the lower limbs in patients of post-stroke spasmodic paralysis regulated with multi-directional stimulation technique]. AB - OBJECTIVE: To compare the efficacy between the multi-directional stimulation technique and routine needling technique in the range of motion (ROM) of the lower limbs in patients of post-stroke spasmodic paralysis. METHODS: Sixty patients were randomized into a multi-directional stimulation technique group and a routine needling technique group, 30 cases in each one. In the two groups, Biguan (ST 31), Fengshi (GB 31), Yang-lingquan (GB 34), Xiyangguan (GB 33), Zhongfeng (LR 4), Jiexi (ST 41), Qiuxu (GB 40), Kunlun (BL 60) and Xuanzhong (GB 39) on the affected side, scalp acupuncture sites and the acupoints on the upper limb of the affected side were selected. The even needling technique was used in the routine needling technique group and the multi-directional stimulation technique was used in the multi-directional stimulation technique group. The treatment was given once daily, 5 days a week, for 4 weeks totally. Before and after treatment, Fugl-Meyer function and Berg balance were scored. The three dimensional gait analysis was adopted to analyze ROM of hip, knee and ankle joints. RESULTS: Fugl-Meyer function score and Berg balance score were improved significantly after treatment as compared with those before treatment in the two groups (all P<0.01). The scores in the multi-directional stimulation technique group were all higher than those in the routine needling technique group (P<0.01, P<0.05). The abduction and adduction of hip joints and flexion-extension ROM were all improved after treatment as comparedwith those before treatment in the two groups (all P<0.05). The maximum flexibility and flexion extension ROM of knee joint were improved after treatment as compared with those before treatment in the two groups (all P<0.05), and the changes in extension of knee joint were not apparent (both P>0.05). After treatment, the maximal flexion and the flexion extension ROM of knee joint in the multi-directional stimulation technique group were improved significantly as compared with those in the routine needling technique group (both P<0.05). The maximal dorsal flexion of ankle joint in the multi-directional stimulation technique group after treatment was increased as compared with that before treatment (P<0.05), and the change was better than that in the routine needling technique group (P<0.05). CONCLUSIONS: Acupuncture effectively increases the maximal adduction angle and flexion-extension ROM of hip joint, and reduces abduction of hip joint. The multi-directional stimulation technique contributes to the flexion of knee joint and dorsal flexion of ankle joint and the maintenance of limb balance. The efficacy of it is better than that of routine acupuncture stimulation technique. PMID- 29231518 TI - [Clinical observation of dysphagia after cerebral infarction treated with awn like needle at Tiantu(CV 22)]. AB - OBJECTIVE: To observe the effect difference between awn-like needle at Tiantu(CV 22) and filiform needle for dysphagia after cerebral infarction. METHODS: One hundred patients were randomly assigned into an awn-like needle group and a filiform needle group,50 cases in each one. Based on the conventional western medicine for all the patients,awn-like needle was applied at Tiantu(CV 22) in the awn-like needle group;while acupuncture was used at Fengchi(GB 20),Shanglianquan(Extra),Shuigou(GV 26) and Tongli(HT 5) in the filiform needle group,combined with pricking at Jinjin(EX-HN 12), Yuye(EX-HN 13),posterior pharyngeal wall with three-edged needle method. All the treatment was given once a day for two weeks. Standard swallowing assessment scale(SSA) and modified Bathel index for daily life ability(MBI) were used and the efficacy was calculated after treatment. RESULTS: The scores of SSA and MBI were improved after treatment in the two groups(all P<0.01),and the results were better in the awn-like needle group than those in the filiform needle group(both P<0.05). The cured and effective rate of the awn-like needle group was 56.0%(28/50), which was obviously better than 30.0%(15/50) of the filiform needle group(P<0.05). CONCLUSIONS: Based on the conventional western treatment,awn-like needle and filiform needle can both improve dysphagia and daily life after cerebral infarction. But awn-like needle achieves better effect. PMID- 29231519 TI - [Clinical study for stroke treated with meridian-collateral diagnosis and therapy by WANG Juyi]. AB - OBJECTIVE: To compare the effect difference for stroke between meridian collateral diagnosis and therapy by WANG Juyiand conventional acupuncture with syndrome differentiation. METHODS: Totally 148 patients were assigned into an observation group(72 cases) and a control group(76 cases) by random number table,with 10 cases dropping out in the observation group. In the observation group,meridians were examined and differentiated and then the treating meridians and acupoints were defined. Corresponding acupuncture was used according to them. In the control group,acupuncture was applied at acupoints by internal differentiation and experience. Treatment was given once a day and five times a week,with total 20 times. The motion function of limbs and coloboma degree of nerve function were assessed by Fugl-Meyer score and National Institutes of Health Stroke Score(NIHSS) before and after treatment as well as at three-month follow-up. RESULTS: After treatment,the Fugl-Meyer scores increased and the NIHSS scores decreased in the two groups compared with those before treatment(all P<0.05). At follow-up three months after treatment,Fugl-Meyer score upgraded in the observation group (P<0.05) and NIHSS score declined in the two groups (both P<0.01) than those before treatment,and NIHSS scores were statistically different between the two groups(P<0.05). CONCLUSIONS: Meridian-collateral diagnosis and therapy by WANG Juyi has better long-term efficacy when it is compared with conventional acupuncture with syndrome differentiation for motion function of limbs and nerve function of stroke. PMID- 29231521 TI - [Acupotomy and acupuncture in the treatment of avascular necrosis of femoral head at the early and middle stages:a clinical randomized controlled trial]. AB - OBJECTIVE: To compare the efficacy difference between acupotomy and acupuncture in the treatment of avascular necrosis of femoral head at the early and middle stages. METHODS: The randomized controlled prospective study method was adopted. Sixty cases of avascular necrosis of femoral head at Ficat-ArletIto II stages were randomized into an acupotomy group (32 cases) and an acupuncture group (28 cases) by the third part. In the acupotomy group, the acupotomy was adopted for the loose solution at the treatment sites of hip joint, once every two weeks, totally for 3 times. In the acupuncture group, ashi points around the hip joint were selected and stimulated with warm acupuncture therapy, once every day, for 6 weeks. Harris hip score was observed before and after treatment. The efficacy was evaluated in the two groups. RESULTS: Harris hip score was improved significantly after treatment in the two groups (both P<0.05). The result in acupotomy group was better than that in the acupuncture group (P<0.05). The effective rate was 90.6% (29/32) in the acupotomy group, better than 75.0% (21/28) in the acupuncture group after treatment (P<0.05). CONCLUSIONS: Harris hip score and the effective rate in the acupotomy group are better than those in the treatment with routine acupuncture for avascular necrosis of femoral head at the early and middle stages. PMID- 29231520 TI - [Efficacy observation of post-stroke pseudo-bulbar palsy treated with quick needle insertion therapy at Aqiang point]. AB - OBJECTIVE: To explore the efficacy of local acupuncture therapy on post-stroke pseudo-bulbar palsy and the clinical advantageous protocol of local acupuncture therapy. METHODS: Eighty patients of post-stroke pseudo-bulbar palsy were randomized into a quick needle insertion group and a routine acupuncture group, 40 cases in each one. The western medicine, such as thrombolysis, lipid regulation, antiplatelet aggregation, antihypertension and hypoglycemic therapy method was all used in the two groups. On the basis of the treatment of western medicine, in the quick needle insertion group, the perpendicular needle insertion was used at Aqiang point, about 8 to 12 mm in depth. When the emptiness feeling presented under the needle, the needle went slowly for 2 mm more depth till cough occurred, and removed afterward. The treatment was given once every day, and totally 20 treatments were required. In the routine acupuncture group, Lianquan (CV 23) was stimulated. The needle was inserted toward the tongue root, about 40 mm in depth. The needle was rotated till the patient felt soreness and distention at the tongue root, and then retained for 30 min. The treatment was given once a day, and totally 20 treatments were required. The water swallow test score and clinical efficacy were evaluated before and after treatment. RESULTS: The curative rate was 80.0% (32/40) in the quick needle insertion group, better than 55.0% (22/40) in the routine acupuncture group (P<0.05). The total effective rate was 97.5% (39/40) in the quick needle insertion group and was 90.0% (36/40) in the routine acupuncture group, indicating no significant difference in comparison (P>0.05). The water swallow test scores decreased after treatment as compared with those before treatment in the two groups (both P<0.01), and the water swallow test scores after treatment of the two groups had no significant difference (P>0.05). CONCLUSIONS: Acupuncture at local point is effective for post-stroke pseudo-bulbar palsy.The curative rate of quick needle insertion at Aqiang point is better than routine acupuncture at Lianquan (CV 23). PMID- 29231522 TI - [Clinical observation of ankylosing spondylitis treated with moxibustion along the governor vessel and the conception vessel and salazosulfapyridine]. AB - OBJECTIVE: To observe the difference in the clinical efficacy on ankylosing spondylitis (AS) between the combined therapy of moxibustion along the governor vessel and the conception vessel and salazosulfapyridine (SASP) and the routine moxibustion. METHODS: Sixty-two patients of AS were randomized into two groups, 31 cases in each one with one case dnopping separately. In the two groups, SASP was prescribed for oral administration. In the observation group, the self prepared moxa powder, ginger granules and moxa wool were placed on the back, from Dazhui (GV 14) to Yaoshu (GV 2) and on the abdomen, from the inferior of the xiphoid process to the upper border of symphsis pubis, covering the running of the governor vessel and the conception vessel. In the control group, the routine moxibustion therapy was used, in which, the moxa box was placed on the back and abdomen alternatively. Each treatment lasted 2 h, once every 7 days, 3 treatments as one session. After 3 sessions of treatment, the symptom score, visual analogue scale (VAS) score, time of morning stiffness, Schober test, occiput-to-wall distance and thoracic mobility were observed before and after treatment. The clinical efficacy was evaluated in the two groups. RESULTS: The total effective rate was 86.7% (26/30) in the observation group, better than 73.3% (22/30) in the control group. The efficacy in the observation group was better than that in the control group (P<0.05). All of the observation indices after treatment were improved apparently as compared with those before treatment in the two groups (all P<0.01). After treatment, the improvements in the symptom score, VAS score, time of morning stiffness and Schober test in the observation group were better apparently than those in the control group (all P<0.01). CONCLUSIONS: On the basis of treatment with SASP, moxibustion along the governor vessel and the conception vessel achieves the definite efficacy on AS, better than the routine moxibustion therapy. PMID- 29231523 TI - [Clinical observation of gastrointestinal dysfunction after vascular surgery prevented by electroacupuncture]. AB - OBJECTIVE: To evaluate the preventative efficacy of preoperative electroacupuncture(EA) for gastrointestinal dysfunction after vascular surgery. METHODS: Sixty patients with the same general anesthesia before vascular surgery were randomly assigned to an observation group and a control group,30 cases in each one. In the observation group,acupuncture was used at bilateral Neiguan(PC 6),Zusanli(ST 36) and Shangjuxu(ST 37) in the forenoon and afternoon one day before surgery,with EA(continuous wave,15 Hz) at Zusanli(ST 36) and Shangjuxu(ST 37) for 20 min. The abdominal distension rate and degree as well as the length of stay in hospital after surgery were recorded. RESULTS: There was no statistic difference about the rate of abdominal distension between the two groups[16.7%(5/30) vs 36.7%(11/30),P>0.05)],but it was lighter in the observation group 72 hours after surgery(P<0.05). The length of stay in hospital in the observation group was shorter than that in the control group[(5.33+/-1.30) d vs (7.33+/-1.71) d,P<0.05]. CONCLUSIONS: Acupuncture at Neiguan(PC 6),Zusanli(ST 36) and Shangjuxu(ST 37) one day before surgery can improve gastrointestinal function after vascular surgery with general anesthesia,and it has some efficacy as to shorting the length of stay in hospital. PMID- 29231524 TI - [Clinical observation of superior gluteal nerve entrapment syndrome treated with needle-in-row combined with herb-partition moxibustion]. AB - OBJECTIVE: To compare the effects of need-in-row combined with herb-partition moxibustion,need-in-row and conventional acupuncture for superior gluteal nerve entrapment syndrome. METHODS: Totally 105 patients were randomly assigned into a combination group,a need-in-row group and an acupuncture group,35 cases in each one. In the combination group and needle-in-row group,needle-in-row therapy was used at the pain tendon region of the pathological waist-hip part,and TDP was combined. Also,herb-partition moxibustion was applied at the same part after needle-in-row in the combined group. In the acupuncture group,conventional acupuncture was implemented at Weizhong(BL 40),Yanglingquan(GB 34),Zhibian(BL 54),Huantiao(GB 30),Sanyinjiao(SP 6) and Jiaji of L1-L5(EX-B 2),and TDP was applied. All the treatment was given once a day for four weeks. The changes of pain scores were compared after treatment. RESULTS: The pain scores decreased obviously after treatment in all the groups(all P<0.05). The scores of the combination group and the needle-in-row group declined more apparently than that of the acupuncture group(both P<0.05). The score of the combination group reduced more obviously than that of the needle-in-low group(P<0.05). The markedly effective rates of the combination group and the needle-in-row group were 88.6%(31/35) and 68.6%(24/35),which were higher than 40.0%(14/35) of the acupuncture group(both P<0.05),and the markedly effective rate of the combination group was better than that of the needle-in-row group(P<0.05). CONCLUSIONS: Need in-row combined with herb-partition moxibustion show definite effect for superior gluteal nerve entrapment syndrome,and it is better than those of simple needle-in row therapy and conventional acupuncture. PMID- 29231525 TI - [Study on effect of voltage-gated calcium channel protein in meridian tissue cells exciting conduction]. AB - OBJECTIVE: To explore the material basis of conduction along meridian. METHODS: Sixty SD rats(30 males,30 females) were randomly assigned into a normal group,an acupuncture group,a verapamil blocking group and a 0.9%NaCl blocking group(control group),15 rats in each one. Fluo 3-AM(calcium fluorescence probe) was injected at the observation part in femoral stomach meridian of foot yangming(meridian part) and the approaching femoral meridian part(non-meridian part) in the normal group and the acupuncture group,and then incubation was applied. In the verapamil blocking group,verapamil was injected at local meridian part and non-meridian part,and in the control group 0.9%NaCl was injected. Then Fluo 3-AM was injected at the meridian part and non-meridian part in the two groups,and incubation was implemented. Ca2+ imaging changes in cells were recorded for more than 20 min after injection of every part in each group respectively. After the above operations in the last three groups,acupuncture was used at "Zusanli"(ST 36) immediately,with electroacupuncture for one min,then Ca2+ imaging changes in cells at the meridian and non-meridian parts were recorded for more than 20 min. RESULTS: In the normal group, Ca2+ fluorescence intensity at the meridian part was higher than that at the non-meridian part. In the acupuncture group,after acupuncture Ca2+ fluorescence intensity at the meridian part was obviously higher than before,but the change before and after acupuncture was not apparent at the non-meridian part. After verapamil blocking local calcium channel and acupuncture,the Ca2+ fluorescence of the meridian part did not strengthen,and the change of that before and after acupuncture at the non meridian part was not obvious. In the control group,after injecting 0.9%NaCl at local part,Ca2+ fluorescence intensities of the meridian and non-meridian parts showed no obvious change,so was that before and after acupuncture. CONCLUSIONS: The voltage-gated calcium channel at the meridian part is highly correlated with its tissue cells exciting conduction. PMID- 29231526 TI - [Correlation of propagated sensation along meridian and TCM constitution]. AB - OBJECTIVE: To explore the correlation between propagated sensation along meridian (PSM) and TCM constitution at different age stages. METHODS: According to age, 840 participants were divided into a youth group (326 cases), a middle aged group (243 cases) and an elderly group (271 cases). The TCM constitution of all the participants was evaluated, and the PSM test was performed. The distribution of TCM constitution, the occurring rate and transmission of PSM in each group were observed and compared; the correlation between PSM and the TCM constitution was preliminary investigated by Logistic regression analysis. RESULTS: The distribution of nine types of TCM constitution in three groups:the proportion of normal constitution and partial constitution were significantly different (all P<0.05); the occurring rate and transmission of PSM in three groups were not significantly different (all P>0.05); the proportion of occurring rate for nine types of TCM constitutions in the whole population, from high to low, presented special intrinsic quality, neutral quality, yin-deficiency quality, qi-deficiency quality, yang-deficiency quality, damp-heat quality, phlegm-dampness quality, qi stagnation quality and blood-stasis quality; besides, the proportion of occurring rate for different TCM constitutions in the youth group, middle aged group and elderly group was similar to that of whole population. The Logistic regression analysis results indicated the neutral quality (P=0.025) and special intrinsic quality (P=0.018) were positively while blood-stasis quality (P=0.043) was negatively related with PSM in all subjects; the qi-deficiency quality (P=0.025), phlegm-dampness quality (P=0.019), blood-stasis quality (P=0.012) and qi stagnation quality (P=0.035) were negatively related with PSM in youth group; the neutral quality (P=0.001) was positively related with PSM inthe middle aged group; the neutral quality (P=0.006) and yin deficiency quality (P=0.004) were positively related with PSM in the elderly group. CONCLUSIONS: The occurrence of PSM in different age stages is related with TCM constitution, which could be increased in clinical treatment to improve acupuncture efficacy. PMID- 29231527 TI - [SONG's theory on mast cells and meridian-acupoint and its research prospect]. AB - The historical origin of researches regarding acupuncture and mast cells (MCs) is reviewed, and the hypothesis that dermal MCs might be correlated with the acupuncture phenomena proposed by SONG Jimei in 1977 is introduced. This hypothesis, for the first time, suggests MCs could be the cellular basis of meridian sensation and arrival of qi (deqi) of acupoints. With independent tests of several research institutes, currently sufficient evidences prove the scientific values of SONG's theory as well as its potential values for the basic research and clinical practice of acupuncture. It is reported recently that MCs might receive signals from central nerve system and acupoint stimulation, showing cross-talk effects, therefore, MCs can be sensitized at acupoints. In this paper, with a review of 40-year research evidence, 15 biological characteristics regarding mast cells and acupuncture phenomena are identified, in the meanwhile, 10 key questions and research direction, including the distribution of MCs in skin and its general relationship with meridian-acupoint, etc. are proposed. PMID- 29231528 TI - [Comparison of electroacupuncture at lower he-sea points on HMGB 1 and nAchR alpha7 in rats with acute gastric mucosal lesion]. AB - OBJECTIVE: To observe the influence of electroacupuncture (EA) at lower he-sea points of stomach, large intestine, small intestine and gallbladder on interleukin-1beta (IL-1beta), high mobility group protein 1 (HMGB 1) and alpha 7 nicotinic acetylcholine receptor (nAchR alpha7) in rats with acute gastric mucosal lesion (AGML), so as to explore whether there is relative specificity in treating gastric viscera disease by stimulating Zusanli (ST 36). METHODS: Sixty healthy SD rats were randomly assigned into a blank group, a model group, a Zusanli group, a Shangjuxu group, a Xiajuxu group and a Yanglingquan group, ten rats in each one (half male and half female). The WRS method was applied to induce the AGML model except the rats in the blank group. The rats in the blank group were treated with routine diet; the rats in the model group were treated with immobilization at rat platform, 30 min per time; the rats in the Zusanli group, Shangjuxu group, Xiajuxu group and Yanglingquan group were treated with acupuncture and connected with EA device (dilatational wave 10 Hz/50 Hz, positive electrode on the left side and negative electrode on the right side, intensity was appropriate when rat hind leg slightly shook), 30 min per time. The treatment was given once a day. After consecutive 10-day treatment, the gastric tissue was collected and the damage of gastric mucosa was evaluated; ELISA method was applied to measure the content of serum IL-1beta and tissue HMGB 1; the Western blot method was applied to measure the expression of nAchR alpha7 receptor. RESULTS: (1) Compared with the model group, the ulcer index (UI) of gastric mucosa, serum IL-1beta and tissue HMGB 1 were lower, and the expression of nAchR alpha7 was increased in the remaining groups (P<0.05, P<0.01). (2) Compared with the Zusanli group, the UI of gastric tissue, serum IL-1beta and tissue HMGB 1 were higher in the Shangjuxu group, Xiajuxu group and Yanglingquan group (P<0.05, P<0.01), and the expression of nAchRalpha7 was reduced in the Yanglingquan group (P<0.01). CONCLUSIONS: (1) EA at digestive system-related lower he-sea points, through IL-1beta, HMGB 1 and nAchR alpha7, could regulate immune response, lighten inflammatory reaction and reduce mucosal injury, which could realize the intervention effect on AGML rats. (2) From the comparison, it is concluded the intervention effect of Zusanli group is superior to the other groups, partly indicating the relative specificity between Zusanli and stomach. PMID- 29231529 TI - [Effects of herb cake-separated moxibustion on spleen in immunosuppressive rabbits:a morphology study]. AB - OBJECTIVE: To observe the influence of different methods of moxibustion on spleen morphology in cyclophosphamide-induced immunosuppressive rabbits. METHODS: A total of 50 rabbits were randomly assigned into a blank group, a model group, a herbal cake-separated moxibustion group, a moxibustion group and a sham cake separated moxibustion group, 10 rabbits in each group. Except the blank group, the rabbits in each group were treated with intraperitoneal injection of cyclophosphamide (60 mg/kg), once a day, for 7 consecutive days to establish immunosuppressive model. After the model establishment, the rabbits in the herbal cake-separated moxibustion group were treated with herbal cake-separated moxibustion at "Shenque" (CV 8), "Guanyuan" (CV 4), "Zusanli" (ST 36), "Pishu" (BL 20) and "Shenshu" (BL 23); the moxa cone was placed on the herbal cake which was made of Liuwei Dihuang decoction, three cones for each acupoint. The rabbits in the moxibustion group were treated with moxa stick moxibustion which contained equal moxa of three moxa cones. The rabbits in the sham cake-separated moxibustion group were treated with cake which was made of flour. The acupoint selection in the above three groups was identical, and the intervention was given once every other day for totally 10 times. The rabbits in the blank group and model group were immobilized for identical time without any intervention. After treatment, the rabbits were sacrificed to collect the spleen. With routine HE staining, the morphology changes of spleen were observed under microscope. In addition, the white pulp, splenic corpuscle and the counts of lymphatic cells of lymphatic sheath around the arteries were observed. RESULTS: Compared with the blank group, the average size of white pulp and the radius of splenic corpuscle were reduced (both P<0.01), and the lymphatic cells of lymphatic sheath around the arteries were significantly decreased in the model group (P<0.01), but the counts of splenic nodule were increased without significant difference (P>0.05). Compared with the model group, the averagesize of white pulp and the radius of splenic corpuscle were significantly increased in the herbal cake-separated moxibustion group and moxibustion group (all P<0.01). The lymphatic cells of lymphatic sheath around the arteries were significantly increased in the herbal cake-separated moxibustion group and sham cake-separated moxibustion group (both P<0.01). Compared with the moxibustion group, the count of lymphatic cells of lymphatic sheath around the arteries was increased in the herbal cake-separated moxibustion (P<0.01). Compared with the sham cake-separated moxibustion group, the radius of splenic corpuscle was significant increased in the herbal cake separated moxibustion group (P<0.01). CONCLUSIONS: The improvement of herbal cake separated moxibustion on immunologic function is superior to moxibustion and sham cake-separated moxibustion in cyclophosphamide-induced rabbits. PMID- 29231530 TI - [Color spectrum of cupping mark detected by hyperspectral camera:a preliminary observation]. AB - OBJECTIVE: To perform quantitative observation on the color change of local skin after cupping, so as to explore objective and quantitative methods for skin response of cupping. METHODS: Seven health subjects were included. By quantitative meridian cupping instrument, cupping methods with four types of pressures were respectively performed on subjects for 5 min.The spectrum of cupping mark before and after the cupping was collected by hyperspectral camera, and the color change was recorded by digital camera. RESULTS: Before the cupping, the differences of back skin areas were not significant (P>0.05), and its average spectrum indicated two peaks at 540-550 nm and 580-590 nm. After cupping with different pressures, spectrum changes of skin were observed. For -0.02 MPa, the most significant reduction was observed at 550 nm (-12.1%, P<0.05); for -0.03 MPa, the most significant reduction was observed at 540 nm (-22.1%, P<0.05); for 0.04 MPa, the most significant reduction was observed at 610 nm (-26.7%, P<0.05); for -0.05 MPa, the most significant reduction was observed at several spectrums (all P<0.05). CONCLUSIONS: After cupping with different negative pressures, significant changes of spectrum are observed on skin; for different pressures, the spectrums of the most significant changes are different; the hyperspectral camera could be applied to perform quantitative observation on the color change of local skin. PMID- 29231531 TI - [Horn and cupping]. AB - Cupping, with an ancient name of horn method, possessed other different names and operational approaches through the history. There was wrong information about cupping which was passed on due to unawareness of predecessors. Through probing into the literature and history, this article summarizes and studies warming cupping, cupping over needles, water boiled cupping and fire cupping. PMID- 29231532 TI - [Present situation and development of acupuncture in the Netherlands]. AB - The development, present situation, educational institution and association, legislation and application of acupuncture therapy in the Netherlands are introduced. Acupuncture was introduced into the Netherlands about 400 years ago. At present, being one of the complementary and alternative medicine, acupuncture has not passed the national legislation yet. The nongovernmental source is given priority to the development of acupuncture and the educational institution is private. Even though acupuncture has not been listed in the basic medical insurance in the Netherlands, it becomes one of the additional items of the insurance company and its expenditure is reimbursed partially. The field of TCM in the Netherlands now is facing to the issues to be solved, including constructing the official medical institution, educating high-quality acupuncturists, promoting national legislation and adopting acupuncture into the basic medical insurance. PMID- 29231533 TI - [Discussion on several basic issues of acupuncture-moxibustion science]. AB - Nine basic issues on acupuncture-moxibustion science are discussed in this paper. The author believes those include the universal property of acupoints,the placebo effect of acupuncture and moxibustion,the continuous transmission of acupuncture information,the factors of the effects such as growth as well as acquired shape and properties,the classification evidence of acupoint function,the compatibility of acupoints,the change of functional state of acupoint and deqi. The universal property of acupoints means whether there is identical position of acupoint among different ethnic groups. The continuous transmission of acupuncture information is seen as whether the delivery which mainly shows as diffusion maintains active in special region and situation. The classification evidence of acupoint function refers to if there exists universal biological basis. PMID- 29231534 TI - [Discussion on some issues of medicated thread moxibustion of Zhuang ethnic group]. AB - The exploring,standardizing and summarizing of the medicated thread moxibustion of Zhuangethnic group are introduced. It is found that there are something deficiency needed to be improved about its system. Thus,we propose a few suggestions and supplements including the definition,the preparation and grasp of the threads,firing and moxibustion manipulation,its intensity of operation,the specification of the threads and moxibustion frequency. We hope that it will provide reference to the improvement of its system. PMID- 29231535 TI - [Exploration on professor WU Zhongchao's theory of occiput-nape function zone]. AB - Professor WU Zhongchao thinks that the occiput-nape region is the important pivot between the head and the trunk and is the extension of the function zone of the back-shu points. This zone is named as the occiput-nape function zone. The position includes the occipital area from Baihui (GV 20) to the margo inferior of occipital bone and the muchal region between the margo inferiors of the spinous process C1 to C7. In the paper, the occiput-nape function zone is verified in terms of the distribution characteristics of meridians and acupoints at the occiput-nape region, the anatomic feature, modern research and clinical application so that a new approach to clinical practice is provided. PMID- 29231536 TI - [Rules of acupoint selection for diabetic peripheral neuropathy based on data mining technology]. AB - The rules of acupoint selection for diabetic peripheral neuropathy (DPN) based on data mining technology are analyzed. Literature regarding acupuncture for DPN published in core journals from January of 2005 to December of 2014 was retrieved in CNKI database and Wanfang database to establish a database of acupuncture prescriptions, which were included into the TCM Inheritance Platform software (Version 2.0). The data mining methods, including rule analysis, revised mutual information, etc. were applied to analyze the acupuncture prescriptions and the frequency of each acupoint was calculated. The results indicated Zusanli (ST 36), Sanyinjiao (SP 6), Quchi (LI 11), Yanglingquan (GB 34), Hegu (LI 4), Shenshu (BL 23), etc. were mostly selected in acupuncture for DPN; in addition, 19 acupoint combinations were acquired. It is concluded that acupuncture for DPN applied reinforcing methods as main rules, accompanied with promoting blood and qi circulation; the acupoint selection focused on yangming meridians and back-shu points. PMID- 29231537 TI - [Research progress on mechanism of acupuncture for chronic atrophic gastritis]. AB - With the purpose of providing more references of acupuncture for chronic atrophic gastritis (CAG), the research achievements and action mechanism of acupuncture for CAG during past 20 years are summarized and analyzed. It is found that acupuncture could improve immune function, adjust central neural pathways, regulate gastroi-ntestinal hormone, increase stomach blood flow, regulate cytokines, increase gastric dynamics, control the gastric acid secretion, improve inflammatory response and regulate cell proliferation and apoptosis, which could strengthen gastric mucosa barrier. In addition, several problems and defects of related studies were pointed out, and reference and suggestion are provided for further clinical researches. PMID- 29231538 TI - [Establishing the acupuncture-moxibustion clinical trial registry and improving the transparence of clinical trials of acupuncture and moxibustion]. AB - As a kind of intervention measures of traditional Chinese medicine, acupuncture moxibustion is highly adopted on global clinical practice. Even though the global clinical trial registration system was established more than 10 years ago, the proportion of acupuncture-moxibustion clinical trial registration is still very low; and it is very problematic on the methodological quality and report quality in the published acupuncture-moxibustion clinical trials. In order to manage particularly the acupuncture-moxibustion clinical trials, China Academy of Chinese Medical Sciences, collaborated with China Association of Acupuncture and Moxibustion and World Federation of Acupuncture Societies, established the Acupuncture-Moxibustion Clinical Trail Registry (AMCTR). AMCTR is a secondary registry platform affiliated to the Chinese Clinical Trial Registry (ChiCTR) and WHO International Clinical Trials Registry Platform (ICTRP), specifically for the acceptance and management of clinical trials in the field of acupuncture and moxibustion. It is a nonprofit academic organization, located in China Academy of Chinese Medical Sciences. PMID- 29231539 TI - [Effects of GAO's neck acupuncture on swallowing function and quality of life in patients with post-stroke pseudobulbar palsy:a randomized controlled trial]. AB - OBJECTIVE: To observe the effects of GAO's neck acupuncture combined with swallowing rehabilitation on swallowing function and quality of life in patients with post-stroke pseudobulbar palsy. METHODS: One hundred patients were randomly assigned in to an observation group and a control group, 50 cases in each one. The patients in the control group were treated with basic pharmaceutical treatment, including neurotrophy medication and free radical scavenging medication as well as swallowing rehabilitation; the patients in the observation group, on the basis of those in the control group, were treated with GAO's neck acupuncture at Fengchi (GB 20), Yiming (EX-HN 14), Gongxue (Extra), Lianquan (CV 23), Wai Jinjin Yuye (Extra), Tunyan (Extra), Zhiqiang (Extra), Fayin (Extra), once a day, five times a week for continuous eight weeks. The Repetitive saliva swallowing test (RSST), standardized swallowing assessment (SSA) and swallow quality-of-life questionnaire (SWAL-QOL) before and after treatment in the two groups were observed; the relationship between disease location and frequency and efficacy of GAO's neck acupuncture was explored in the observation group. RESULTS: After treatment, the RSST, SSA and SWAL-QOL were superior to those before treatment (all P<0.01), with more significant results in the observation group (all P<0.01). The total effective rate was 91.7% (44/48) in the observation group, which was superior to 75.5% (37/49) in the control group (P<0.01). The frequency of disease onset was one in 11 patients and 2 and above in 37 patients in the observation group, and the efficacy of one onset of disease was 100.0% (11/11), which was superior to two and above of onset 89.2% (33/37, P<0.01). The number of patients with disease location at cortex and subcortex was 21, while that at capsula interna and basal ganglia was 27 in the observation group, the efficacy of two was similar (P>0.05). CONCLUSIONS: GAO's neck acupuncture combined with swallowing rehabilitation could effectively improve dysphagia and quality of life in patients with post-stroke pseudobulbar palsy. No correlation of lesion locations on acupuncture efficacy is observed, while onset frequency is inversely proportional to efficacy. PMID- 29231540 TI - [Acupuncture combined with rehabilitation training for the limb spasm after stroke]. AB - OBJECTIVE: To observe the different clinical effects on the limb spasm after stroke among acupuncture mainly at governor vessel (GV) and Jiaji (EX-B 2) combined with rehabilitation training, simple acupuncture and simple rehabilitation training. METHODS: Ninety patients according to admission sequence were randomized into a combination group, an acupuncture group and a rehabilitation group, 30 cases in each one. The comprehensive treatment was applied in the combination group. The same acupuncture was used in the acupuncture group; the same rehabilitation was used in the rehabilitation group. All the treatment was given for 4 courses with 1 d between the two courses, 10 times as one course, once a day. The modified Ashworth score (MAS), clinic spasticity index (CSI), Fugl-Meyer assessment (FMA), Barthel index (BI) were observed before and after treatment. The effects were compared among the three groups. RESULTS: After treatment, the MAS, CSI score of the three groups significantly decreased in comparison with those before treatment (all P<0.05), the FMA and BI score of the three groups increased in comparison with those before treatment (all P<0.05). The improvements for MAS, CSI, FMA and BI of the combination group were better than those of the acupuncture group and the rehabilitation group (all P<0.05). There were no statistical significance between the acupuncture group and the rehabilitation group (all P>0.05). The total effective rate of 90.0% (27/30) in the combination group was better than 76.7% (23/30) in the acupuncture group and 73.3% (22/30) in the rehabilitation group (both P<0.05). CONCLUSIONS: Acupuncture mainly at GV and Jiaji (EX-B 2) combined with rehabilitation training are superior to simple acupuncture and simple rehabilitation training on reducing muscle tonus for stroke patients with limb spasm, which can more effectively improve the ability of daily life and motor function. PMID- 29231541 TI - [Effects of transcutaneous electrical acupoint stimulation on treatment and prevention of postoperative sore throat after tracheal intubation under general anesthesia]. AB - OBJECTIVE: To observe the clinical efficacy of transcutaneous electrical acupoint stimulation (TEAS) at Hegu (LI 4) and Neiguan (PC 6) on treatment and prevention of postoperative sore throat (POST) after tracheal intubation under general anesthesia. METHODS: One hundred patients who received elective thyroid gland lobectomy with gradeIand II of American Society of Anesthesiologists criteria were randomly assigned into a TEAS group and an anesthesia group according to random number table method, 50 cases in each group. All the patients were treated with tracheal intubation under general anesthesia. Patients in the TEAS group were treated with TEAS (2 Hz/100 Hz, 8 to 12 mA) at Hegu (LI 4) and Neiguan (PC 6) from 30 min before anesthesia induction to the end of operation. Patients in the anesthesia group were treated with TEAS at the same acupoints but no electrical stimulation was given. The incidence rate, severity and visual analogue scale (VAS) of POST were recorded 1h, 6h, 12h and 24h after tracheal extubation, respectively. RESULTS: The incidence rate of POST was 12.0% (6/50), 22.0% (11/50) and 18.0% (9/50) 1h, 6h, 12h after tracheal extubation respectively in the TEAS group, which was significantly lower than 30.0% (15/50), 42.0% (21/50) and 36.0% (18/50) in the anesthesia group (all P<0.05). However, the incidence rate was not significantly different between the two groups 24h after extubation[14.0% (7/50) vs 28.0% (14/50), P>0.05]. Moreover, the VAS scores of the patients with POST in the TEAS group at each time point were lower than those in the anesthesia group (all P<0.05). CONCLUSIONS: TEAS at Hegu (LI 4) and Neiguan (PC 6) can effectively reduce the incidence rate and severity of POST induced by tracheal intubation under general anesthesia. PMID- 29231543 TI - [DONG's extraordinary acupoints for the ovarian function of polycystic ovary syndrome:a randomized controlled pilot trial]. AB - OBJECTIVE: To preliminary assess the efficacy of DONG's extraordinary acupoints for the ovarian function of polycystic ovary syndrome. METHODS: Fifty-six patients were randomized into an acupuncture group and a western medication group. In the acupuncture group, the acupoints were Fuke, Huanchao, Tianhuang (Yinlingquan, SP 9), Renhuang (Sanyinjiao, SP 6), Guanyuan (CV 4), Zigong (EX-CA 1). The treatment was used twice a week for continuous 12 weeks. In the western medication group, patients were given diane-35 for 3 menstrual cycles, once a day for 21 days with 7 days between the two sessions. The ratio of luteinizing hormone/flitropin (LH/FSH) was taken as the primary index, while the secondary indices were serum testosterone (T), FSH, LH, body mass index (BMI), the condition of ovary and menstruation. RESULTS: 1After treatment, the ratio of LH/FSH declined in both the two groups (P<0.05, P<0.01). The decreasing values of the two groups were not significantly different (P>0.05). 2T, LH and BMI dropped in the two groups (P<0.05, P<0.01). The decreasing values of the three indices between the two groups were not significantly different (all P>0.05). 3The size of ovary did not change significantly after treatment in the two groups (both P>0.05), but the reduction degree of ovary size of the acupuncture group was larger than that of the western medication group (P<0.05). The ovary number of more than 10 foliiculi in single ovary in the acupuncture group reduced compared with that before treatment (P<0.05). The reduction degree of ovary number with the above feature was not significantly different between the two groups (P>0.05). 4The times and days of menstruation within 3 months increased significantly in the two groups (all P<0.01), without significance of different valves between the two groups (both P>0.05). CONCLUSIONS: DONG's extraordinary acupoints could improve the ovarian function of polycystic ovary syndrome, whose effect is similar as diane-35. PMID- 29231542 TI - [Clinical research of electroacupuncture on the analgesic effect of thoracic perioperative stage]. AB - OBJECTIVE: To discuss the clinical therapeutic effects of electroacupuncture at Neimadian (Extra) and Neiguan (PC 6) on the analgesic effect of thoracic perioperative stage and its effect mechanism. METHODS: Sixty cases of esophageal cancer with elective radical resection under general anesthesia were divided into an observation group and a control group according to the operation sequence, 30 cases in each one. In the control group, the general anesthesia was simply applied and sufentanil was administered for patient controlled intravenous analgesia (PCIA) after operation. In the observation group, on the basis of the scheme as the control group, the electroacupuncture was used at Neimadian (Extra) and Neiguan (PC 6) 30 min before anesthesia induction and after operation, with continuous wave, tolerable intensity, lasting for 30 min. Separately, before acupuncture (T1) and 2h (T2), 12h (T3), 24h (T4) and 48h (T5) after operation, the plasma beta-endorphin (beta-EP), 5-hydroxytryptamine (5-HT) and prostaglandin E2 (PGE2) were determined. During operation, under the same state (from 50 to 60) of bispectrum of EEG (BIS), the intraoperative anesthetic dose was recorded. Using visual analogue scale (VAS), the pain degree was evaluated at T2, T3, T4 and T5 separately and the grade assessment of the therapeutic effects and safety were recorded at each time point. RESULTS: 1The total dosage of sufentanil in the observation group was less than that in the control group[(1.83+/-0.56) mg vs (2.54+/-0.62) mg, P<0.05]. 2VAS scores at T2, T3 and T4 in the patients of the observation group were all lower than those in the control group (all P<0.05). 3The levels of plasma beta-EP at T3, T4 and T5 in the observation group were increased significantly as compared with those in the control group (all P<0.05) and the levels of plasma 5-HT and PGE2 at T2, T3 and T4 were reduced significantly as compared with those in the control group (all P<0.05). 4 The excellent analgesia rates 2h,12h and 24h after operation in the observation group were better than those in the control group (all P<0.05). 5The rate of the A grade safety in the observation group was higher than that in the control group (P<0.05). CONCLUSIONS: Electroacupuncture at Neimadian (Extra) and Neiguan (PC 6) provides the safe and effective postoperative anesthesia of thoracic surgery and reduces the dosage of analgesics during the operation, which is possibly related to the increase of endogenous beta-EP and the inhibition on the release of 5-HT and PGE2. PMID- 29231544 TI - [Acupoint embedding for female functional constipation:a randomized controlled trial]. AB - OBJECTIVE: To compare the effects between acupoint embedding and oral medication for female functional constipation. METHODS: Fifty-six female patients were randomized into an embedding group and a medication group (1:1).There were 22 cases in the embedding group and 26 cases in the medication group with total 8 patients dropped out. The main embedding acupoints were Zhongwan (CV 12), bilateral Tianshu (ST 25) and Guanyuan (CV 4), combined with Xiawan (CV 10), Huaroumen (ST 24), Wailing (ST 26), Zhigou (TE 6) and Shangjuxu (ST 37). It was given once a week. Oral lactulose was applied in the medication group, 3 times a day. The treatment cycle was 8 weeks. The primary outcome was the percentage of patients whose weekly average number of complete spontaneous bowel movement (CSBM) was increased >= 2 compared with baseline during the last 6 weeks in the treatment period. The secondary efficacy indices were compared before and after treatment as well as at follow-up at the 12th week, including the weekly average number and increased number of CSBM, the quality of life of patients with constipation (PAC-QOL), the Bristol stool character score, and the assessment of difficulty in defecation. RESULTS: The percentage of patients whose weekly average number of CSBMs were increased >= 2 in the embedding group significantly increased compared with that in the medication group (P<0.05). The weekly average number of CSBM in the two groups increased after treatment compared with those before treatment (both P<0.01); the score of Bristol stool character improved (both P<0.01); the scores of PAC-QOL and difficulty in defecation decreased (all P<0.01). The increasing time of weekly average CSBM in the embedding group was higher than that in the medication group (P<0.01); the score of PAC-QOL in the embedding group after treatment was better than that in the medication group (P<0.01); the Bristol stool character and difficulty degree in the embedding group after treatment were superior to those in the medication group (both P<0.05). CONCLUSIONS: The acupoint embedding significantly improve the CSMB, Bristol stool character, the difficulty of defecation, and the quality of life for female patients with functional constipation. PMID- 29231545 TI - [Impacts of acupoint catgut embedding therapy on postpartum weight retention]. AB - OBJECTIVE: To observe the impacts of acupoint catgut embedding therapy on postpartum weight retention. METHODS: Seventy-one women of postpartum weight retention were divided into an observation group (35 cases) and a control group (36 cases) according to their own wishes when re-examination in 42 days after delivery. In the control group, the nutrition consultation was provided and the calories intake was controlled continuously for 20 weeks. In the observation group, on the basis of the treatment as the control group, the acupoint embedding therapy was applied to Zhongwan (CV 12), Zhongji (CV 3), Qihai (CV 6), Guanyuan (CV 4), Tianshu (ST 25), Guilai (ST 29), Shuifen (CV 9), Shousanli (LI 10), Zusanli (ST 36), Fenglong (ST 40) and Yinlingquan (SP 9). The sutures, No. 4-0 were cut as 2 to 4 mm in length and put into the embedding needle. After qi arrival, the sutures were pushed into the acupoints with the needle core and the needle was removed quickly. The treatment was given once every two weeks, continuously for 20 weeks. Totally, 10 times of acupoint catgut embedding therapy were required. Before and after treatment, the body mass, weight retention, body mass index (BMI), percentage of body fat (PBF), waist circumference (WC), waist hip ratio (WHR) and health promoting lifestyle profile (HPLP-II) were observed in the participants of the two groups. RESULTS: After treatment, body mass, weight retention, BMI, PBF, WC and WHR were all reduced as compared with those before treatment in the participants of the two groups, indicating the significant differences (all P<0.05). After treatment, the body mass, weight retention, BMI, PBF, WC and WHR in the participants of the observation group were lower than those in the control group, indicating the significant differences (all P<0.05). The score of every dimension of HPLP-II after treatment was higher than that before treatment in the participants of the observation group, indicating the significant differences (all P<0.05); and the scores of health responsibility, sports and spiritual growth in the observation group were higher than those in the control group, indicating the significant differences (all P<0.05). CONCLUSIONS: The acupoint catgut embedding therapy improves in the postpartum weight retention and achieves the satisfactory clinical therapeutic effects. PMID- 29231546 TI - [Therapeutic effects of the integrated acupuncture and Chinese herbal medicine on reflux esophagitis]. AB - OBJECTIVE: To compare the differences in the clinical therapeutic effects on reflux esophagitis among the combined therapy of huazhuo jiedu jiangni decoction (the decoction for resolving the turbid, detoxification and reducing the pathologic upward qi in short) and acupuncture, omeprazole and Chinese herbal medicine. METHODS: Ninety patients were randomized into 3 groups, 4 cases of them were dropped off. Finally, there were 29 cases in the combined therapy group with acupuncture and the decoction, 29 cases in the western medication group and 28 cases in the Chinese herbal medicine group in the statistical analysis. In the combined therapy group with acupuncture and the decoction, the decoction was prescribed recurrence rate. The therapeutic effects are better than the simple application of either Chinese herbal medicine or omeprazole. for oral administration. Additionally, acupuncture was applied to Neiguan (PC 6), Zusanli (ST 36), Zhongwan (CV 12), Ganshu (BL 18), Danshu (BL 19) and Taichong (LR 3). The decoction was applied one dose a day and acupuncture was once a day. In the western medication group, omeprazole capsules, 20 mg were prescribed for oral administration, twice a day. In the Chinese herbal medicine group, the decoction was simply applied. The treatment was 8 weeks in the 3 groups and the follow-up visit was 6 months. The score of reflux disorder questionnaire (RDQ) and the changes in esophageal mucosa under gastroscope were observed before and after treatment; the clinical therapeutic effects and recurrence rate were evaluated in the 3 groups. RESULTS: In 4 and 8 weeks of treatment, RDQ scores in the 3 groups were all reduced as compared with those before treatment (all P<0.05). In 4 weeks of treatment, RDQ score in the combined therapy group with acupuncture and Chinese herbal medicine was lower than that in the western medication group (P<0.05). In 8 weeks of treatment, RDQ score in the combined therapy group with acupuncture and Chinese herbal medicine was lower than those in the western medication group and the Chinese herbal medicine group (both P<0.05). In follow up visit for 6 months, the recurrence rate in the combined therapy group with acupuncture and the decoction was lower than those in the other two groups (both P<0.05). In 8 weeks of treatment, the total effective rate for clinical symptoms and that observed under gastroscope in the combined therapy group with acupuncture and the decoction were all better than those in the western medication group and the Chinese herbal medicine group (all P<0.05). CONCLUSIONS: The combined therapy of huazhuo jiedu jiangni decoction and acupuncture achieve the definite therapeutic effects on reflux esophagitis, relieve the symptoms, protect gastric mucosa and reduce the. PMID- 29231547 TI - [Effects of electroacupuncture at acupoints with different nerve segments on gastric emptying in OT gene knockout mice]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) at acupoints with different nerve segments on gastric emptying in oxytocin (OT) gene knockout mice, and to explore the role of paraventricular nucleus OT in EA regulating gastric function. METHODS: Twenty OT knockout mice and twenty wild-type mice (8-9 weeks old, male and female in half) were divided into a control group, a Zusanli (ST 36) group, a Neiguan (PC 6) group and a Weishu (BL 21) group randomly, 5 mice in each group. The mice in the control group received no acupuncture; the mice in the Zusanli (ST 36) group, Neiguan (PC 6) group and Weishu (BL 21) group were treated with EA at unilateral "Zusanli" (ST 36), "Neiguan" (PC 6) and "Weishu" (BL 21) for 15 min respectively. Subsequently, the mice were treated with intragastric administration with milk loaded with technetium-99m diethylene triamine pentaacetic acid (99mTc-DTPA), immediately followed by scanning of single photon emission computed tomography (SPECT) to test gastric emptying for 50 min; the original data was collected and analyzed to obtain the half gastric emptying time (GET 1/2), 50-min stomach residue rate and gastric emptying curve. RESULTS: The wild-type mice group:compare with the control group, after EA at "Zusanli" (ST 36) and "Neiguan" (PC 6), the GET 1/2 and 50-min stomach residue rate were significantly reduced, which could improve the gastric emptying of wild type mice (P<0.01, P<0.05); after EA at "Weishu" (BL 21), the GET 1/2 and 50-min stomach residue rate were significantly increased, which could inhibit the gastric emptying of wild-type mice (P<0.01, P<0.05). The OT gene knockout mice group:compared with the control group, EA at "Zusanli" (ST 36) and "Neiguan" (PC 6) had no significant effects on gastric emptying (both P>0.05); after EA at "Weishu" (BL 21), the GET 1/2 and 50-min stomach residue rate were significantly increased, which could inhibit the gastric emptying of OT gene knockout mice (both P<0.01). Gastric emptying curve:the gastric emptying of OT gene knockout mice was significantly faster than that of wild-type mice. CONCLUSIONS: The effects of EA at acupoints with different nerve segments on gastric emptying in mice are different, and the knockout of OT gene could accelerate the gastric emptying, and influence the acupuncture effect of several acupoints. It is suggested the paraventricular nucleus OT neurons, as the initiating device of autonomic nervous pathways, might participate in EA regulating the gastric function to inhibit the gastric emptying, with the form of neural and neuroendocrine. PMID- 29231548 TI - [Acupuncture for TGF-beta1 expression in lung tissues of asthma rats]. AB - OBJECTIVE: To explore the regulation of acupuncture for transforming growth factor beta1 (TGF-beta1) expression in the lung tissues of bronchial asthmatic rats. METHODS: Forty SPF male SD rats were randomly divided into a blank group, a model group, an acupuncture group and a shallow fast acupuncture group, 10 rats in each group. Asthma model was established in the model, acupuncture, and shallow fast acupuncture groups, and no intervention was applied in the blank and model groups. Before atomization excitation, 20 min acupuncture was applied at "Dazhui" (GV 14) "Feishu" (BL 13) "Fengmen" (BL 12) in the acupuncture group. Acupuncture only into skin without needle retained at the above acupoints was used in the shallow fast acupuncture group before atomization excitation from the day of model established. All the treatment was given 7 times, once the other day. The pathological lunge tissues of rats were observed by HE staining; the protein expression of TGF-beta1 in the lung tissues was examined by immunohistochemical staining and immunofluorescence staining. The TGF-beta1 expressions in bronchoalveolar lavage fluid (BALF) and serum were showed by ELISA. RESULTS: There were changes in the lung tissues in the model group, including mucus plug in the bronchial lumen, irregular bronchial epithelium, thick airway smooth muscle, local break, narrow lumen, a large number of inflammatory cell infiltration. The phenomena in the acupuncture group were improved and those in the shallow fast acupuncture group were not apparently changed compared with those in the model group. The IOD value of TGF-beta1 expression in the model group increased compared with that in the blank group (P<0.05); the positive expression in the acupuncture group was lower than those in the model and shallow fast acupuncture groups (both P<0.05). The contents of TGF-beta1 in BALF and serum of the acupuncture group were lower than those in the model and shallow fast acupuncture groups (all P<0.05). CONCLUSIONS: Acupuncture may improve airway inflammatory response and remolding of asthma by inhibiting TGF-beta1 expression. PMID- 29231549 TI - [Mechanism of acupoint transcutaneous electric stimulation on analgesic anesthesia in the patients undergoing general anesthesia anorectal operation]. AB - OBJECTIVE: To observe the regulatory effects of acupoint electric stimulation on the analgesic substances and the relevant indices of nerve-immunity-endocrine system in the patients undergoing general anesthesia anorectal operation. METHODS: One hundred and fifty-six patients undergoing hemorrhoids and anal fistula operation were randomized into three groups, 146 cases were included in the analysis. In the No.1 group (48 cases), the conventional intravenous general anesthesia was applied. In the No.2 group (50 cases), besides the conventional intravenous general anesthesia, the acupoint transcutaneous electric stimulation was combined at Neiguan (PC 6), Shenmen (HT 7), Shangliao (BL 31) and Ciliao (BL 32). operation in the No.2 and No.3 groups were lower apparently than that in the No.1 group (P<0.05, P<0.01). CONCLUSIONS: During the general anesthesia anorectal operation, the acupoint transcutaneous electric stimulation achieves analgesic anesthesia through effectively promoting the release of body analgesic substance and reducing the stress level in the operation. With the comprehensive acupoint selection as Neiguan (PC 6) and Shenmen (HT 7) and the local acupoints, the therapeutic effects are better in comparison with the simple selection of local acupoints. In the No.3 group (48 cases), besides the conventional intravenous general anesthesia, the acupoint transcutaneous electric stimulation was combined at Shangliao (BL 31) and Ciliao (BL 32). The electric stimulation was maintained till the end of operation. The patients' saliva was collected 0.5 h before operation and 1 h after operation separately. The indices that reflect the body pain regulation and nerve-immune-endocrine secretion were detected, such as opiophin protein (OPI), secretory immunoglobulin A (SIgA), saliva amylase (sAA), cortisol (Cor) and tumor necrosis factor alpha (TNF-alpha). The pain degree was observed 1 h after operation. RESULTS: In the No.2 group, OPI after operation was higher than that before operation (P<0.05). The difference value of OPI in the No.2 group was higher apparently than that in the No.1 group and the No.3 group (both P<0.05). SIgA after operation was higher than that before operation in the No.1 group (P<0.05). The difference values of SIgA, sAA, Cor in the No.2 group were lower apparently than those in the No.1 group (P<0.05, P<0.01). TNF alphabefore and after operation and its difference value among the groups were not significant statistically (all P>0.05). The pain degrees in 1 h after. PMID- 29231550 TI - [Protocol of Miao medical LIU's infant tuina genre "Tui Wu Jing" in western Hunan province for prevention of asthma recurrence]. AB - The Miao medical LIU's (LIU Kaiyun) infant tuina genre in western Hunan Province is one of the most famous infant tuina genres in China. Based on physiological and pathological characteristics of infants, generation-inhibition theory of five elements and Miao medical's promotion-inhibition theory of five-meridians, the tuina protocol of "Tui Wu Jing" was flexibly adjusted; according to different constitution types, including lung-deficiency type, spleen-deficiency type, kidney-deficiency type, qi-deficiency type, yin-deficiency type, yang-deficiency type, phlegm-wet type, phlegm-heat type, different protocols were adopted to prevent or reduce the asthma recurrence and reach the aim of regulating constitution and disease prevention. PMID- 29231551 TI - [The present situation and development of acupuncture and moxibustion in Taiwan]. AB - The development history, present situation, educational institution and association of acupuncture and moxibustion in Taiwan are reviewed. Acupuncture and moxibustion is considered as an invasive treatment in Taiwan, which has been introduced to Taiwan since the late Ming Dynasty and early Qing Dynasty, with a history of less than 400 years. At present, there are two acupuncture-related academic institutions and two educational institutions, which are all private. The acupuncture and moxibustion is applied for various diseases, and the cost is based on whether clinics and treatments are covered by medical insurance, so the differences are significant. PMID- 29231552 TI - [Analyzation of expressive elements for clinical RCT of acupuncture and moxibustion:taking peptic ulcer as an example]. AB - To explore the expressive elements for the clinical randomized controlled trials of acupuncture and moxibustion so as to provide reference for them, taking peptic ulcer as an example. Sixty-six papers from 1996 to 2015 were collected in domestic and overseas databases, including China National Knowledge Infrastructure (CNKI), WANFANG, VIP, China Biology Medicine (CBM), PubMed, Web of Science, Sciencedirect, Springer, Wiley. The expression qualities were evaluated according to the Consolidated Standards of Reporting Trials (CONSORT) and the Standards for Reporting Interventions in Clinical Trials of Acupuncture(STRICTA). We consider that the reports are not sound, especially their preface, trial design and intervention. PMID- 29231554 TI - [Teaching countermeasures on the student problems in the practice and training course of the science of acupuncture-moxibustion treatment]. AB - The student problems existing in the practice and training course of acupuncture moxibustion treatment include unsolid basic knowledge, inexperienced basic skills and poor comprehensive utilization ability. The writers proposed the effective countermeasures accordingly. Firstly, the students are required to go over the related knowledge in advance, targeting the weakness, and complement the basic knowledge. Secondly, the teachers provide the demonstration and guidance for the practice to improve the basic skills. Thirdly, the clinical simulation is adopted for the comprehensive training to enhance the comprehensive utilization ability. The countermeasures mentioned above improve effectively the basic skills and comprehensive ability in the students and lay the foundation for the future clinical work. PMID- 29231553 TI - [The method and application to construct experience recommendation platform of acupuncture ancient books based on data mining technology]. AB - OBJECTIVE: To construct a knowledge platform of acupuncture ancient books based on data mining technology, and to provide retrieval service for users. METHODS: The Oracle 10 g database was applied and JAVA was selected as development language; based on the standard library and ancient books database established by manual entry, a variety of data mining technologies, including word segmentation, speech tagging, dependency analysis, rule extraction, similarity calculation, ambiguity analysis, supervised classification technology were applied to achieve text automatic extraction of ancient books; in the last, through association mining and decision analysis, the comprehensive and intelligent analysis of disease and symptom, meridians, acupoints, rules of acupuncture and moxibustion in acupuncture ancient books were realized, and retrieval service was provided for users through structure of browser/server (B/S). RESULTS: The platform realized full-text retrieval, word frequency analysis and association analysis; when diseases or acupoints were searched, the frequencies of meridian, acupoints (diseases) and techniques were presented from high to low, meanwhile the support degree and confidence coefficient between disease and acupoints (special acupoint), acupoints and acupoints in prescription, disease or acupoints and technique were presented. CONCLUSIONS: The experience platform of acupuncture ancient books based on data mining technology could be used as a reference for selection of disease, meridian and acupoint in clinical treatment and education of acupuncture and moxibustion. PMID- 29231555 TI - [Brief discussion on "shidong" diseases and "suosheng" diseases in Miraculous Pivot and reference to differentiate them]. AB - According to Miraculous Pivot:meridian, the indications of twelve meridians were divided into two parts, the "shidong" diseases and "suosheng" diseases. Traditional Chinese medicine practitioners of later generation provided several assumptions to differentiate them, but a general conclusion was still not drawn. In this paper, the opinions of previous researches were summarized; based on this, the viewpoints of each opinion were reviewed, and the authors' opinion on method to differentiate "shidong" diseases and "suosheng" disease was proposed. It was concluded the differences of "shidong" diseases and "suosheng" disease in Miraculous Pivot was only based on style of the composing, not involving medical principles. The role of two parts on diagnosis and treatment was similar. PMID- 29231556 TI - [Characteristics and principles of acupoint selection in auricular plaster therapy for hypertension based on literature analysis]. AB - The characteristics and principles of acupoint selection in auricular plaster therapy for hypertension were explored. By searching CNKI (search time from 1950 to November of 2015), VIP database (search time from 1989 to November of 2015) and WanFang Database (search time from 1983 to November of 2015), the clinical research literature regarding auricular plaster therapy for hypertension was collected, and frequency statistics method was used for analysis. As a result, totally 117 articles were included. The auricular points with frequency from high to low were Jiangyagou, Shenmen (TF4), Gan (CO12), Xin (CO15), Shen (CO10), Jiaogan (AH6a), Pizhixia (AT4), Jiangyadian and Neifenmi. The TCM syndromes with frequency from high to low were excessive accumulation of phlegm-dampness syndrome, upper hyperactivity of liver yang syndrome, yin deficiency and yang hyperactivity syndrome and excessive liver-fire syndrome. In conclusion, based on cross-reference of TCM and modern medicine combination of zangfu and meridians differentiation and valuing the auricular points from clinical experience, the auricular plaster therapy for hypertension was characterized with "treating the principal and subordinate symptoms simultaneously and respectively" and "differentiation-based selection of auricular points to regulate zangfu", which could fully take the anti-hypertension advantages of non-pharmacotherapy. PMID- 29231557 TI - [Discussion on rules of acupoint selection for vascular dementia]. AB - OBJECTIVE: The clinical research literature regarding acupuncture treatment for vascular dementia was reviewed and analyzed to provide the references for clinical selection and compatibility of acupoints. METHODS: With computer and manual retrieval method, the clinical literature regarding acupuncture treatment for vascular dementia in recent 10 years was collected. The acupoint type, meridian and use frequency were analyzed. RESULTS: Totally 38 articles of acupuncture treatment for vascular dementia were screened; the most selected meridians were the governor vessel, gallbladder meridian, stomach meridian and spleen meridian; the main acupoints with frequency of more than 5 times were Baihui (GV 20), Sishencong (EX-HN 1), Shenting (GV 24), Fengchi (SP 40) and Shuigou (GV 26); the matching acupoints with frequency of more than 5 times were Fenglong (ST 40), Zusanli (ST 36), Taichong (LR 3), Taixi (KI 3), Sanyinjiao (SP 6), Xuehai (SP 10), Zhongwan (CV 12), Neiguan (PC 6), Fengchi (GB 20). CONCLUSIONS: The rules and characteristics of acupoint selection for vascular dementia were featured with taking the local acupoints at head as main points, combining disease differentiation and syndrome differentiation as clinical principle, valuing local acupoints and distal acupoints, applying various techniques of acupuncture and moxibustion and combing traditional acupuncture manipulation and modern electroacupuncture stimulation. PMID- 29231558 TI - [Impact of deqi on acupoint effects in patients with primary dysmenorrhea:a systematic review of randomized controlled trials]. AB - The effects of deqi (arrival of qi) on acupoint effects in patients with primary dysmenorrhea (PD) were evaluated.Ten literature databases,including China National Knowledge Infrastructure (CNKI),VIP Database,Wanfang Database,Chinese Biomedical Literature Database (CBM),Cochrane Library CENTRAL,MEDLINE,Embase,AMED, CINAHL Plus,PsycINFO were selected.In addition,5 registers of ongoing trials,the reference lists of included articles and grey literature website OpenGrey were added.The search time was from date of database establishment to August 2016;no restrictions were made on language or status of publication.All randomized controlled trials (RCTs) and quasi-randomized controlled trials (q-RCTs) which compared the effects of deqi and non-deqi on PD or compared the effects of different deqi elements on PD were included.The research quality was assessed according to Cochrane bias risk evaluation tool 5.1.0.The RevMan 5.3.5 was applied for quantitative analysis if insignificant clinical heterogenicity with I2 <= 75%,otherwise the results was summarized by qualitative analysis.As a result,6 RCTs involving 645 patients were included.Because of considerable clinical heterogeneity,only qualitative analysis was performed,which indicated 1 acupuncture could reduce pain and anxiety regardless of deqi,and the effects of deqi on pain relief were superior or equivalent to that of none-deqi,and the effects of deqi on anxiety relief were similar to that of none-deqi;2 the more intensity of deqi and higher number of acupoints selected,the better effects on pain alleviation,symptom relief and pain duration;3 the higher rate of deqi had a better acupoint effect on alleviating anxiety,but was not on pain relief;4 deqi appeared early and propagated to affected area could lead to faster onset on pain relief;5 the effects on relieving pain and symptoms was better when warm sensation in deqi or qi reaching affected area.Due to the few number,low quality and potential bias of included studies,it was not sufficient to draw clear conclusion regarding the effects of deqi on PD patients.This study protocol was registered in PROSPERO (CRD42016038518). PMID- 29231559 TI - [Discussion on inheritance,innovation and belongingness of acupuncture moxibustion research]. AB - Three points on the inheritance,innovation and belongingness of acupuncture moxibustion research are discussed in the paper,including the inheritance of acupuncture-moxibustion culture showing the soul of the development of acupuncture,the improvement of acupuncture-moxibustion presenting the close relationship with the innovation and its development belonging to the origin. It is considered that the inheritance of acupuncture-moxibustion culture takes the priority of its development. Innovation must be realized in order to exist better in the future medicine. The study of acupuncture-moxibustion can not be limited to the traditional acupuncture-moxibustion theory,but need to be in line with it. Explore actively the value of traditional acupuncture-moxibustion culture and its theory. The research and education of acupuncture-moxibustion must belong to TCM. With all the above condition,the innovation and development of acupuncture moxibustion could be better achieved. PMID- 29231560 TI - [Professor CHEN Rixin's views on moxibustion sensation]. AB - The sensation of heat-sensitive moxibustion (HSM) refers to the heat feeling at distal and deep part of the body when a patient is treated with moxibustion under unhealthy status, which may even transmits to the disease sites, instead of heat feeling at local and superficial part of the body. Professor CHEN Rixin has systema-tically studied the HSM sensation and its clinical laws through clinical practice; he points out different HSM sensations contain different physiological and pathological information of the human body, which could reflex the severity of diseases, so the collection of HSM information should be emphasized; the type and intensity of HSM sensation could guide the clinical acupoint selection and precise localization. The appearance and disappearance of HSM sensation could be applied to establish individual amount of moxibustion, and disappearance of HSM sensation is an appropriate signal for sufficient moxibustion time, which break through the concept of fixed time at each acupoint, and provide measurement standard to make full use of moxibustion. The criteria of indications for moxibustion is proposed, indicating the disease in which HSM sensations appear is the optimal indication. The deep and comprehensive understanding on the generation and change of HSM sensation could improve the standardization of HSM standard technique and its efficacy. PMID- 29231561 TI - [Effects of Tongdu Rezhen method for ankylosing spondylitis at early stage:a randomized controlled trial]. AB - OBJECTIVE: To compare the clinical efficacy differences between Tongdu Rezhen method and twirling-reinforcing needling method for ankylosing spondylitis (AS) at early stage. METHODS: Sixty-eight patients were randomly assigned to an observation group and a control group, 34 cases in each one. The acupoint selection in the two groups was identical, taking Dazhui (GV 14) and Mingmen (GV 4) as the main acupoints. Patients in the observation group were treated with Tongdu Rezhen method, while patients in the control group were treated with twirling-reinforcing needling method. The treatment was given once a day, and seven treatments were considered as one course of treatment. The TCM symptom grading quantitative standard score, Barthel ankylosing spondylitis disease activity index (BASDAI), Bath ankylosing spondylitis ankylosing spondylitis function index (BASFI) were compared in the two groups before and after 3 treatment courses; also the efficacy was evaluated. RESULTS: The total efficacy rate was 91.2% (31/34) in the observation group, which was superior to 79.4% (27/34) in the control group (P<0.05); after treatment, the TCM symptom grading quantitative standard score, BASDAI and BASFI were significantly improved in the two groups (all P<0.05), which were more significant in the observation group (all P<0.05). CONCLUSIONS: The Tongdu Rezhen method at Dazhui (GV 14) and Mingmen (GV 4) could effectively improve the symptoms of AS patients at early stage, which was superior to twirling-reinforcing needling method. PMID- 29231562 TI - [Needle-knife combined with pseudo-ginseng-cake moxibustion for primary knee osseous arthritis of blood stasis syndrome:a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy differences between needle-knife combined with pseudo-ginseng-cake moxibustion and oral administration of western medication for primary knee osseous arthritis (PKOA) of blood stasis syndrome. METHODS: Sixty cases of PKOA of blood stasis syndrome were randomly assigned to an observation group and a control group. Patients in the observation group (30 patients, 38 knees) were treated with needle-knife combined with pseudo-ginseng cake moxibustion, while patients in the control group (30 patients, 36 knees) were oral administration of western medication. The treatment was given three weeks continuously. The knee osteoarthritis outcome score (KOOS) was adopted to observe the knee pain, symptoms and stiffness, daily life, sport and entertainment function, daily life quality score and total score in the two groups before and after treatment. The follow-up visit was performed two months after the treatment to evaluate the long-term efficacy. RESULTS: The total effective rate was 97.4% (37/38) in the observation group, which was significantly superior to 77.8% (28/36) in the control group (P<0.05). Each item of KOOS was increased in the observation group after treatment and follow-up visit (P<0.05, P<0.01); the KOSS in the control group was also increased (all P<0.01) after treatment, and daily life and daily life quality score of knee in the follow-up visit were significantly increased (both P<0.01). The scores other than sport and entertainment function score in the observation were significantly higher than those in the control group (all P<0.01). CONCLUSIONS: The needle knife combined with pseudo-ginseng-cake moxibustion could significantly improve the symptoms of PKOA of blood stasis syndrome, which was superior to oral administration of western medication alone and had better long-term effects. PMID- 29231563 TI - [Acupuncture at Baihui(GV 20) and Shenting(GV 24) combined with basic treatment and regular rehabilitation for post-stroke cognitive impairment:a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical effect of acupuncture at Baihui(GV 20) and Shenting(GV 24) combined with rehabilitation for post-stroke cognitive impairment(PSCI). METHODS: Fifty patients with PSCI were randomly assigned to an observation group and a control group,25 cases in each one. In the control group,basic treatment and regular rehabilitation were applied. In the observation group,acupuncture at Baihui(GV 20) and Shenting(GV 24) and the same therapies as the control group were used for continuous four weeks,once a day and five times a week. Mini-mental state examination(MMSE) and Montreal cognitive assessment(MoCA) were observed before and after treatment in the two groups. RESULTS: After treatment,the scores of MMSE and MoCA were improved apparently(both P<0.05),with better results in the observation group(both P<0.05). CONCLUSIONS: Acupuncture at Baihui(GV 20) and Shenting(GV 24) combined with basic treatment and regular rehabilitation can obviously improve the cognitive function of PSCI,and the effect is superior to that of basic treatment and regular rehabilitation. PMID- 29231564 TI - [Effects of acupuncture on 1528 patients with obesity complicated with hyperlipidemia in different obesity levels]. AB - OBJECTIVE: To observe the clinical effect of acupuncture on obesity complicated with hyperlipidemia, and to explore the therapeutic differences among patients with different obesity levels. METHODS: A total of 1528 patients of obesity complicated with hyperlipidemia were enrolled into the study. According to the clinical symptoms and signs, they were treated with acupuncture according to the syndrome differentation. According to their obesity levels (A), body mass index (BMI) and body fat percentage (F%) before treatment, they were assigned into a mild obesity group, a moderate obesity group and a severe obesity group. The obesity index of body weight, A, BMI and F%, the blood lipid levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL-C) and high density lipoprotein (HDL-C) were observed before and after treatment. The total efficacy, weight loss effect and lipid-lowering effect were evaluated. RESULTS: 1 The constituent ratio of severe obesity in male patients overweighted that of female patients (P<0.01), and the obesity was positively correlated with age and disease duration (r=0.145 and 0.164, both P<0.01). 2 After treatment, the total effective rate was 98.9% (461/466), the weight loss rate was 99.4% (463/466) and lipid-lowering rate was 99.1% (462/466) in the mild obesity group, which were the all highest among three groups, indicating the lower obesity level achieved the better acupuncture efficacy. 3 Acupuncture can significantly regulate the obesity index and blood lipid levels (all P<0.01); the obesity was negatively correlated with BMI and HDL-C (all P<0.01), and positively correlated with F%, TC, TG and LDL-C (all P<0.01). CONCLUSIONS: Acupuncture has dual effects on obesity and hyperlipidemia, which is significantly effective for patients with different obesity levels; acupuncture has the optimal effect on mild obesity, and had the optimal regulation on F% and blood lipid levels on severe obesity; acupuncture has superior overall regulation effects on obesity complicated with hyperlipidemia. PMID- 29231565 TI - [Acupoint injection of human placenta tissue fluid combined with oral administration of metformin hydrochloride enteric-coated tablets treating type 2 diabetes:a randomized controlled trial]. AB - OBJECTIVE: To observe the difference for type 2 diabetes between acupoint injection of human placenta tissue fluid combined with oral administration of metformin and simple metformin. METHODS: Sixty patients with type 2 diabetes were randomly assigned into a medication group and an injection group,30 cases in each one. In the oral medication group,metformin hydrochloride enteric-coated tablets was applied orally for continuous eight weeks,0.25 g a time,twice a day. In the injection group,based on the same oral administration,human placenta tissue fluid was injected into Diji(SP 8) and Yishu(EX-B 5) for two courses(four weeks as one course),once every other day and three times a week. Fast blood glucose(FBG),postprandial blood glucose(PBG),glycosylated hemoglobin(HbAlc) and clinical effect were observed in the two groups before and after treatment. RESULTS: Compared with those before treatment,FBG,PBG and HbAlc were decreased in the two groups after treatment (all P<0.05),with more apparent change in the injection group(all P<0.05). The total effective rate of the injection group was 90.0%(27/30),which was obviously better than 63.3%(19/30) of the medication group (P<0.05). CONCLUSIONS: Acupoint injection of human placenta tissue fluid combined with metformin hydrochloride enteric-coated tablets for type 2 diabetes can better lower blood glucose than simple metformin hydrochloride enteric-coated tablets. PMID- 29231566 TI - [Effect of moxibustion combined with autohemotherapy of acupoint injection for life quality of allergic rhinitis with qi deficiency of lung and spleen:a randomized controlled trial]. AB - OBJECTIVE: To observe the effects of moxibustion combined with autohemotherapy of acupoint injection and simple moxibustion for allergic rhinitis(AR) with qi deficiency of lung and spleen and to explore its mechanism. METHODS: By random number table,75 patients who matched the criteria were assigned into a moxibustion combined with autohemotherapy of acupoint injection group(a combination group,37 cases) and a moxibustion group(38 cases). In the combination group,moxibustion was used at bilateral Yingxiang(LI 20) and injection bila-teral Feishu(BL 13),Pishu(BL 20) and Zusanli(ST 36). In the moxibustion group,moxibustion was applied bilaterally at all the above acupoints. Acupoint injection was given twice a week,and moxibustion once a day,seven days as a course. The patients were observed for four courses and followed up half a year after treatment. Rhinoconjunctivitis quality of life questionnaire(RQLQ) was compared before and after treatment and at follow-up. The short-term and long term effects as well as the changes of interferon-gamma(IFN-gamma),interleukin 4(IL-4) and immunoglobulin E(IgE) were observed in the two group. RESULTS: After treatment,the obviously effective rate of the combination group was 75.68%(28/37),which was higher than 52.63%(20/38) of the moxibustion group(P<0.05). But at follow-up, the obviously effective rate of the moxibustion group was 47.37%(18/38),which was better than 24.32%(9/37) of the combination group(P<0.05). Life quality of the two group in all aspects after treatment and at follow-up were apparently improved compared with the baseline(P<0.01,P<0.05). After treatment,the life quality,sleep condition,non nasal-eye symptoms,behavior issue of the combination group were superior to those of the moxibustion group(all P<0.05),and at follow-up,the above outcomes,the eye and nasal symptoms as well as emotional response of the mo-xibustion group were better(all P<0.05). There was statistical significance in the two group about serum IFN-gamma,IgE,IL 4 before and after treatment(P<0.01,P<0.05),and significance existed between the two groups(P<0.05). CONCLUSIONS: Moxibustion combined with autohemotherapy of acupoint injection can effectively improve the short-term quality of life of AR with qi deficiency of lung and spleen. The mechanism may be related to balancing the immune response of Th1 and Th2. PMID- 29231567 TI - [Scrapping therapy combined with Qingxin Zishen Decoction for perimenopausal syndrome with pattern of fire excess from yin deficiency]. AB - OBJECTIVE: To observe the efficacy difference between scrapping therapy combined with Qingxin Zishen Decoction and the single application of Qingxin Zishen Decoction for perimenopausal syndrome (PMS) with pattern of fire excess from yin deficiency. METHODS: Eighty patients were assinged into an observation group and a control group, 40 cases in each one. Patients in the control group were treated with oral administration of Qingxin Zishen Decoction to clear heart heat and nourish kidney. One dose of the decoction was taken by two times within one day. Based on the treatment of the control group, patients in the observation group were additionally treated with scrapping therapy along the urinary bladder meridian of foot-taiyang, heart meridian of hand-shaoyin and kidney meridian of foot-shaoyin; the scrapping therapy was performed at Back-shu points, Shenmen (HT 7), Yongquan (KI 1), Taixi (KI 3), Zhaohai (KI 6), Sanyinjiao (SP 6), Zusanli (ST 36), etc.; the treatment was given once every week. Four weeks of treatment were taken as one course in two groups, and totally 2 courses were given. The modified Kupperman score, menopausal quality of life (MENQOL), level of serum estrogen (E2), follicle stimulating hormone (FSH) and luteinizing hormone (LH) before and after treatment as well as the clinical efficacy were valuated between the two groups. RESULTS: After treatment, each item score and total score of modified Kupperman were reduced apparently in the two groups (P<0.01,P<0.05) except dyspareunia score in the control group. The score of hot flash and sweating, paresthesia, depression, fatigue, arthralgia, palpitation, formication, urinary symptoms and total score in the observation group were superior to those in the control group (P<0.01, P<0.05). After treatment, the total score and each dimension score of MENQOL were obviously decreased in the two groups (all P<0.01), and the scores of vasomotor symptoms, psychosocial condition and physical condition in the observation group were significantly lower than those in the control group (P<0.01, P<0.05). There were no significant differences of serum hormone levels before and after treatment between the two groups (all P>0.05), however, after treatment, the serum E2 level had the tendency to raise and serum LH, FSH levels had the tendency to decrease in the observation group. The total effective rate was 97.4% (37/38) in the observation group, which was higher apparently than 81.1% (30/37) in the control group (P<0.01). CONCLUSIONS: The scrapping therapy combined with Qingxin Zishen Decoction or the simple application of Qingxin Zishen Decoction can both improve PMS symptoms and the quality of life, delay the ovary recession; the combination of scrapping therapy and Qingxin Zishen Decoction achieve superior efficacy on PMS syndrome to the simple application of Qingxin Zishen Decoction. PMID- 29231569 TI - [Exploration of action and significance of yuan-source point for clinical diagnosis based on literature metrology]. AB - Modern literature on the physical property of the yuan-source point were collected from Chinese National Knowledge Infrastructure(CNKI) and China Biology Medicine(CBM) databases. The physical property,relevant diseases and yuan-source acupoints were analyzed through statistical analysis of literature metrology. It is considered that articles on the electrical resistance of acupoint account for the largest part,which are mainly related to hyperthyreosis and the change of menstrual cycle. The second part is radiation spectrum,which are mostly relevant to the coronary heart disease and then the physiological change of healthy people. As to the diseases,articles of cardiovascular diseases are taken the most proportion,which were treated with the 12 yuan-source points,Shenmen(HT 7) and Daling(PC 7). Also,the results present the physical property of yuan-source acupoints in the yin meridians is more sensitive to diseases and the physical property is specific to diseases. Besides,the yuan-source acupoint can show the pathological changes of its own meridian. PMID- 29231568 TI - [Effect of drug-spreading moxibustion for primary dysmenorrheal with cold-damp stagnation and its uterine artery blood flow]. AB - OBJECTIVE: To observe the effect difference between drug-spreading moxibustion and the oral administration of meloxicam for primary dysmenorrheal with cold stagnation and to explore its mechanism. METHODS: A total of 101 patients with primary dysmenorrheal were randomly assigned into a drug-moxibustion group(52 cases) and a western medication group(49 cases). Drug-spreading moxibustion was used on the lumbosacral acupoints area and then around lower abdominal five days before menstruation until the 3rd day of menstruation,once three days,while western medicine meloxicam was prescribed one day before menstruation,7.5 mg at a time,once a day and continuously for three days. The clinical effects after one course,namely three menstrual cycles,were compared between the two groups. Meanwhile,the resistance index(RI) and the pulsatility index (PI) of uterine artery and arcus arteriarum were examined through color Doppler ultrasound before and after treatment. RESULTS: After one-course treatment,the effective rate was 92.3%(48/52) in the drug-spreading moxibustion group,which was better than 67.3%(33/49) in the western medication group(P<0.05). Also,all the RI and PI in the drug-spreading moxibustion group were obviously decreased than those before treatment(all P<0.05),and the ones were superior to those of the western medication group(all P<0.05),which showed no apparent decrease after treatment(all P>0.05). CONCLUSIONS: Drug-spreading moxibustion can improve the symptoms of primary dysmenorrheal with cold-damp stagnation,and the effect is better than that of meloxicam. The mechanism may be related to improve the blood supply to the uterus. PMID- 29231570 TI - [Detection of pain thresholds of acupoints for irritable bowel syndrome]. AB - OBJECTIVE: To compare the pain thresholds of acupoints in the meridians related to irritable bowel syndrome(IBS) between IBS patients and healthy people. METHODS: Thirty-four healthy adults were collected into a normal group,and 60 patients with IBS were arranged into an IBS group. Pain thresholds were detected on the acupoints of large intestinal,small intestinal,stomach,spleen,gallbladder meridians and some commone use acupoints for IBS by pain measuring apparatus three times. Bilateral jing-well,xing-spring,shu-stream,jing-river,he-sea,front mu-alarm,lower he-sea,yuan-primary,luo-connecting and back shu-transport points of each meridian were selected as the main acupoints. And pain thresholds of acupoints common used in clinic were compared between the two groups. RESULTS: The thresholds of five shu-transport points and luo-connecting point of the large intestinal meridian in the IBS group were apparently lower than those in the normal group(all P<0.05),with Hegu(LI 4),Tianshu(ST 25),Shangjuxu(ST 37) and Dachangshu(BL 25) more decreasing(all P<0.01). The thresholds of five shu transport points,front mu-alarm point and yuan-primary point of the small intestinal meridian in the IBS group were obviously lower than those in the normal group(all P<0.05),with Zhizheng(SI 7),Xiajuxu(ST 39) and Xiaochangshu(BL 27) more decreasing(all P<0.01). The thresholds of Zusanli(ST 36),Weishu(BL 21),Yanglingquan(GB 34),Danshu(BL 19),Pishu(BL 20),Neiguan(PC 6),Taichong(LR 3),Taixi(KI 3),Sanyinjiao(SP 6) and Qihai(CV 6) in the IBS group were markedly lower than those in the normal group(all P<0.05). CONCLUSIONS: The pathological changes of IBS often appeared in the stomach,large intestinal,small intestinal,bladder meridians,and some acupoints in the liver,spleen and kidney meridians. When the functions of viscera are abnormal,the pain thresholds of related acupoints tend to decrease,and meridians and acupoints become sensitized from quiet state. PMID- 29231571 TI - [Discussion on specificity of acupoint effect based on "Sanli acupoint for du-fu diseases"]. AB - The specificity of acupoint effect is an important part of acupuncture theory. It has been one of the foci in acupuncture research domestically and abroad. This paper explores the specific relationship between Zusanli (ST 36) and stomach intestine function based on the ancient records on "Sanli acupoint for du-fu diseases" and the clinical and experimental researches on Zusanli(ST 36) treating digestive diseases. The physiological mechanism of the specificity is explained in terms of the spinal cord segment of Zusanli (ST 36) and gastrointestinal organs as well as the cerebral central effect of puncturing the acupoint. The aim of the paper is to provide more evidences for the specificity of acupoint effect indicated by "Sanli acupoint for du-fu diseases". PMID- 29231572 TI - [Anti-inflammatory and analgesia effects of electroacupuncture device of point injection on rats of inflammatory pain]. AB - OBJECTIVE: To explore the anti-inflammatory and analgesia mechanism of electroacupuncture (EA) device of point injection (PI) on rats of inflammatory pain. METHODS: 48 Sprague Dawley (SD) rats were randomly assigned into a control group, a model group, an EA+PI group, an EA device of PI (EAPI) group, an EA group and a PI group, eight rats in each one. The rats in the control group were subcutaneously injected with 50 MUL of liquid paraffin oil solvent into the dorsum of left hindpaw, while rats in the remaining groups were treated with 50 MUL of complete freund's adjuvant (CFA) at identical location to induce the model of inflammatory pain. After model establishment, the rats in the EA+PI group, EAPI group, EA group and PI group were treated with EA+PI,EA device of PI, EA and PI, respectively, once every other day (the 2nd day, 4th day and 6th day). Each treatment was given for 30 min. The mechanical withdrawal threshold, thermal withdrawal threshold and foot swelling before and 1 d to 6 d after model establishment were observed; the western blotting method was applied to measure IL-1beta expression in inflammatory tissue of skin. RESULTS: After model establishment, compared with the control group, the mechanical withdrawal threshold and thermal withdrawal threshold were reduced (all P<0.05) and the foot swelling was increased in the rest groups (all P<0.05). After treatment, the mechanical withdrawal threshold and thermal withdrawal threshold in the EAPI group were significantly increased compared with those in the EA+PI group, EA group and PI group (all P<0.05), but the foot swelling was reduced (all P<0.05). The IL-1beta expression in the model group was higher than that in the control group (P<0.05); after treatment, the IL-1beta expression in the EAPI group was lower than that in the model group, EA group and PI group (all P<0.05), but no significantly different from that in the EA+PI group (P>0.05). CONCLUSIONS: The efficacy of EA device of PI on inflammatory pain is superior to EA combined with PI, EA alone and PI alone, which is suitable for further popularization and application. PMID- 29231573 TI - [Effects of acupuncture at "Zusanli" (ST 36) on sensitive neurons of gastric distention in LHA-FN circuit in rats]. AB - OBJECTIVE: To observe the regulation effects of acupuncture at "Zusanli" (ST 36) on sensitive neurons of gastric distention (GD) in lateral hypothalamus area (LHA) and fastigial nuclear (FN) circuit, and to explore the central mechanism of acupuncture for gastric function. METHODS: A total of 101 rats were randomly assigned into a LHA group (50 rats) and a FN group (51 rats). Gastric distension surgery was performed in all the rats. According to the stereotaxic atlas of rat brain, the LHA and FN were located, followed by craniotomy. The endocranium was removed to exposure brain tissue, and warm paraffin oil was used to prevent desiccation. The electrical activities of neurons were probed by glass microelectrode to perform extracellular recording. The electrical activities of GD sensitive neurons in LHA were observed in LHA group, while those in FN were observed in FN group. One min after the electrical signal of neurons was recorded, acupuncture was given at left "Zusanli" (ST 36) with mild reinforcing and attenuating technique, 120~180 times/min for 1 min. The effects of acupuncture at "Zusanli" (ST 36) on spontaneous discharge of GD sensitive neurons in LHA and FN were observed. RESULTS: (1) Totally 54 LHA neurons of spontaneous discharge in LHA group and 85 FN neurons in FN group were recorded. GD-excitatory (GD-E) neurons were mainly in the LHA group (46.3%) and GD-non-response (GD-N) neurons were mainly in the FN group (54.12%). The average discharge frequency of GD-N neurons was (39.03+/-14.91) spikes/s, that of GD-E neurons was (19.67+/ 12.08) spikes/s, and that of GD-inhibitory (GD-I) neurons was (28.76+/-7.26) spikes/s, which were statistically different from those before GD (all P<0.01). (2) In LHA group, acupuncture excited the activity of GD-E neurons, and inhibited the activity of GD-I neurons (P<0.05); in FN group, acupuncture excited the activity of GD-I neurons, but showed no effect on GD-E neurons (P<0.01). CONCLUSIONS: The signal of GD and acupuncture could converge in LHA and FN; acupuncture presented different regulation effects on identical type of GD sensitive neurons in different nuclear groups; LHA-FN circuit might participate in central integration mechanism of acupuncture on gastric function. PMID- 29231574 TI - [Professor WU Zhongchao's experience of penetration needling]. AB - Professor WU Zhongchao has unique application of penetration needling in clinical treatment. Professor WU applies penetration needling along meridians, and the methods of penetration needling include self-meridian penetration, exterior interior meridian penetration, identical-name meridian penetration, different meridian penetration. The meridian differentiation is performed according to different TCM syndromes, locations and natures of diseases and acupoint nature, so as to make a comprehensive assessment. The qi movement during acupuncture is focused. In addition, attention is paid on anatomy and long-needle penetration; the sequence and direction of acupuncture is essential, and the reinforcing and reducing methods have great originality, presented with holding, waiting, pressing and vibrating. Based on classical acupoint, the acupoint of penetration needling is flexible, forming unique combination of acupoints. PMID- 29231575 TI - [WU Binghuang's academic thought and clinical experience of regulating immune function by acupuncture and moxibustion]. AB - WU Binghuang advocates painless acupuncture,qi arrival to strength the body and eliminate pathogenic factors,as well as enhancing the immune function. Also,he stresses the application of both the Chinese and western medicine theories. The academic thought and clinical experience of professor WU Binghuang regulating the immune function are explored through three aspects,namely the application of 12 yuan-source points and lower he acupoints,implementing moxibustion at health care points,the usage of acupoints related to immune organs. PMID- 29231576 TI - [Development of acupuncture in Israel]. AB - By collecting and analyzing information regarding the history development, current situation, legislation, health insurance, education and academic organizations of acupuncture in Israel, the development characteristics of acupuncture in Israel were summarized. The overall traditional medicine developed well in Israel, yet acupuncture have only appeared in Israel for 18 years. The proposal of Israeli Acupuncture Legislation Act improved the development of health insurance, education and public awareness of acupuncture in Israel. However, improvement in areas of education, legislation and health insurance are still in need. Suggestions are proposed to improve the education quality, acupuncture legislation, international cooperation, volunteer activities and cultural exchanges. In addition, the legislative process of acupuncture in the countries of "the Belt and Road", especially the Middle East countries, are promoted. PMID- 29231577 TI - [Investigation for use of The Name and Location of Acupoints(GB/T 12346-2006), national standard]. AB - To understand the use in recent 10 years of The Name and Location of Acupoints(GB/T 12346-2006),a standard of The People's Republic of China,so as to provide the evidence for its further establishment and revision,we investigated and analyzed the application of The Name and Location of Acupoints through relevant literature and the textbook. It is found that making use of the standard is being realized in various types of articles and it is described in almost all the textbooks. Implementing the standard intensively promotes the standardization of acupuncture-moxibustion education and clinical manipulation as well as the academic exchange domestically and overseas. In turn,its scientificalness and authority are further strengthened. PMID- 29231578 TI - [Learning method of self-evaluation and mutual-evaluation for practical teaching of Acupuncture and Moxibustion Technique curriculum:application and exploration]. AB - The application and significance of learning method of self-evaluation and mutual evaluation for practical teaching of Acupuncture and Moxibustion Technique curriculum were investigated. The practical teaching followed theory teaching in the curriculum plan, which applied grouping pattern to provide demonstration, practice and assessment. According to the technique points of practical teaching, the teachers established evaluation form and listed detailed points of self evaluation and mutual evaluation. The focus was student assessment, including individual self-evaluation, subject-evaluation intra-group evaluation, external group evaluation and teacher evaluation. 100 points were taken as maximum score, including 10 points in the self-evaluation from operator, 20 points in the evaluation from receiver, 20 points in the intra-group evaluation, 20 points in external-group evaluation and 30 points in teacher evaluation. Through practical application, it was found learning system of self-evaluation and mutual evaluation had important significance in promoting mutual learning among students, improving students' learning enthusiasm and initiative, and helping teachers understand and improve their roles. PMID- 29231579 TI - ["Flipped classroom" teaching model into the curriculum of Theories of Different Schools of Acupuncture and Moxibustion:exploration and practice]. AB - The "flipped classroom" teaching model practiced in the teaching of Theories of Different Schools of Acupuncture and Moxibustion curriculum was introduced. Firstly, the roles and responsibilities of teachers were clarified, indicating teachers provided examples and lectures, and a comprehensive assessment system was established. Secondly, the "flipped classroom" teaching model was split into online learning, classroom learning and offline learning. Online learning aimed at forming a study report by a wide search of relevant information, which was submitted to teachers for review and assessment. Classroom learning was designed to communicate study ideas among students and teachers. Offline learning was intended to revise and improve the study report and refined learning methods. Lastly, the teaching practice effects of "flip classroom" were evaluated by comprehensive rating and questionnaire assessment, which assessed the overall performance of students and overall levels of paper; the learning ability was enhanced, and the interest and motivation of learning were also improved. Therefore, "flipped classroom" teaching mode was suitable for the curriculum of Theories of Different Schools of Acupuncture and Moxibustion, and could be recommended into the teaching practice of related curriculum of acupuncture and tuina. PMID- 29231580 TI - [Theory and application regarding "stage by stage" acupuncture for diminished ovarian reserve]. AB - Based on a considerable number of ancient literature, clinical experience and modern scientific studies, a comprehensive study was performed on the TCM theory and treatment of diminished ovarian reserve. It was summarized that the two causes of diminished ovarian reserve were deficiency of the kidney essence and incoordination between Chong Vessel and Conception Vessel, so the treatment strategy of "stage by stage" acupuncture was proposed. It was pointed out acupoint selection should be in accordance with physiological basis of menstruation and waxing and waning of yin-yang. Therefore, acupuncture at different acupoints and meridians could regulate yin and yang and promote the normal yin-yang transformation, which could store and discharge the uterus. As a result, the function of ovary is recovered. This method has achieved significant clinical efficacy. PMID- 29231581 TI - [Clinical review of ankylosing spondylitis treated with acupuncture and medicine]. AB - Thirty-two articles from January 2000 to December 2014,with ankylosing spondylitis treated by acupuncture,moxibustion and medicines(Chinese medicine or western medicine) and statistically significant and effective results,were collected through Chinese National Knowledge Infrastructure(CNKI),WANFANG and VIP databases. It is concluded that there are various methods except medicines treating ankylosing spondylitis,including acupuncture,acupuncture combined with moxibustion,warm acupuncture,electroacupuncture,apitherapy,fire needle therapy,etc. Further studies are needed to be implemented so as to promote the combination therapy of acupuncture and medicine for ankylosing spondylitis,such as the standard cases of the combination therapy and mechanism. PMID- 29231582 TI - [Strategy programming for acupuncture development along One-Belt-One-Road countries]. AB - Acupuncture has been applied in 183 countries and regions and gradually become a name card as TCM spreads across the world. The international influence of which plays a significant role in enhancing TCM development. The laws and regulations of TCM acupuncture along One-Belt-One-Road countries were compared and analyzed in this article. With comprehensive research and analysis, the international development strategy of acupuncture was rationally proposed. Combined with the historical background of China's national initiative One-Belt-One-Road, the acupuncture was taken as a breakthrough to lead the global spreading of TCM culture and Chinese herbs, so as to enhance China's soft strength, which could further create a fine cultural environment for the economic prosperity of One Belt-One-Road countries. In addition, the strategy selection for China regarding TCM acupuncture development along One-Belt-One-Road countries was proposed, and the suggestive solution and implementation strategy for the essential missions and significant issues were provided. PMID- 29231583 TI - [Acupoint plaster therapy with midnight-noon ebb-flow hour-prescription method for senile osteoporosis:a randomized controlled trial]. AB - OBJECTIVE: To compare the clinical efficacy differences between acupoint plaster therapy with midnight-noon ebb-flow hour-prescription method and traditional acupoint plaster therapy for senile osteoporosis (SOP). METHODS: With randomized controlled blind design, 76 SOP patients with deficiency of liver and kidney syndrome were randomly divided into an observation group and a control group, 38 cases in each one. Based on oral administration of caltrate D, the patients in the observation group were treated with acupoint plaster therapy with midnight noon ebb-flow hour-prescription method at Yingu (KI 10), Taixi (KI 3), Dazhong (KI 4), Fuliu (KI 7) and Zhiyin (BL 67), while the patients in the control group were treated with traditional acupoint plaster therapy. Each plaster therapy lasted for 6 h, once a day; there was an interval of 2 d after consecutive 5-day treatment; 4 weeks were taken as one course, and totally 2 courses were given. Visual analogue scale (VAS) and Oswestry Disability Index (ODI) were used to evaluate the pain and dysfunction before intervention, after 4 weeks and 8 weeks intervention. Osteoporosis symptom rating sale and quality of life questionnaire of the European foundation for Osteoporosis (QUALEFFO-41) were adopted to evaluate the TCM syndrome and quality of life before and after 8-week intervention. RESULTS: All the outcomes were significantly improved after treatment in the two groups (P<0.01,P<0.05); after 4 weeks and 8 weeks of treatment, the VAS and ODI in the observation group were lower than those in the control group (all P<0.05). Repeated ANOVA indicated the VAS and ODI were significant in group effect, time effect and interaction effect (all P<0.01). Further comparison showed that VAS and ODI at later time points were lower than those in the early time points (all P<0.01). After the treatment, the scores of TCM syndrome and QUALEFFO-41 in the observation group were lower than those in the control group (all P<0.05). The effective rate was 85.7% (30/35) in the observation group, which was superior to the effective rate in the control group[74.3%(26/35), P<0.05]. CONCLUSIONS: The acupoint plaster therapy with midnight-noon ebb-flow hour-prescription method is superior to traditional acupoint plaster therapy in improving pain, dysfunction, TCM syndrome and quality of life in SOP patients; in addition, its clinical efficacy is significant. PMID- 29231584 TI - [Electrothermal acupuncture in the prevention and treatment of chemotherapy induced nausea and vomiting:a randomized controlled trial]. AB - OBJECTIVE: To observe the effectiveness and safety of electrothermal acupuncture in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV) in the cancerous patients of phlegm-stasis interaction in cisplatin containing chemotherapy. METHODS: Sixty cases of phlegm-stasis interaction in cisplatin-containing chemotherapy were randomized into a trial group and a control group, 30 cases in each one. In the control group, the intravenous drip of granisetron hydrochloride injection was adopted, 3 mg before and after cisplatin-containing chemotherapy 30 min, continuously for 3 days. 43 to 45C electrothermal acupuncture at zusanli(ST 36) for 30 min was used on the basis of the treatment as the control group in the trial group,once a day for 3 days. CINV, anti-nausea effects, Karnofsky score, the syndrome score of phlegm-stasis interaction, and relevant indices of safety were observed on the 1st and 7th days of cisplatin-containing chemotherapy separately. RESULTS: 1.Regarding CINV and anti-nausea effect, CINV did not occur before chemotherapy in the patients of the two groups. On the 1st and 7th days of chemotherapy, CINV in the trial group were milder than those in the control group (both P<0.05).The anti-nausea effects in the trail group were better than those of the control group.2.Regarding Karnofsky score and the syndrome score of phlegm-stasis interaction, the improvements on the 7th days of chemotherapy in the trial group were better than those in the control group, indicating the significant differences (both P<0.05). 3.Regarding the safety indies, there was no adverse reaction during the treatment in the two groups. CONCLUSIONS: The electrothermal acupuncture effectively relieves CINV, and improves self-care dbility and the symptoms of phlegm-stasis interaction. PMID- 29231585 TI - [Regulative effects of the acupuncture on glucose and lipid metabolism disorder in the patients of metabolic syndrome]. AB - OBJECTIVE: To observe the regulative effects of the acupuncture on glucose and lipid metabolism disorder in the patients of metabolic syndrome. METHODS: Seventy six patients of metabolic syndrome were rando-mized into an acupuncture plus western medicine group (37 cases) and a western medicine group (39 cases). In the western medicine group, the conventional western medication was used for 40 days. In the acupuncture plus western medicine group, the acupuncture was combined on the basis of the treatment as the western medicine group, the acupoints were Danzhong (CV 17), Zhongwan (CV 12), Tianshu (ST 25), etc. Ten treatments were as one session. There were 3 to 5 days of intervals between the sessions and totally 30 treatments were required. The body mass index (BMI), blood lipid, blood glucose, and comprehensive therapeutic effects were compared before and after treatment in the two groups. RESULTS: Before and after treatment, the differences were all significant in BMI, triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), plasma glucose of 2 hours post glucose-load (2 hPG), fasting insulin (FINS) and insulin resistance index (HOMA-IR) (all P<0.05) in the acupuncture plus western medicine group, and the results after treatment were superior to those before treatment; the difference was not significant in BMI (P>0.05) and those were all significant statistically in TG, TC, LDL-C, HDL-C, FBG, 2 hPG, FINS, HOMA-IR (all P<0.05) in the western medicine group, and the results after treatment were superior to those before treatment. After treatment, in comparison of the two groups, the results in the acupuncture plus western medicine group were better than those in the western medicine group. The differences were all signif-icant sta-tistically in BMI, TG, TC, LDL-C, HDL C, FBG, 2 hPG, FINS, HOMA-IR (all P<0.05). CONCLUSIONS: On the basis of the conventional western medicine, the acupuncture relieves apparently the clinical symptoms and rectifies glucose and lipid metabolism disorder in the patients of metabolic syndrome. PMID- 29231586 TI - [Effects of acupuncture on peripheral skeletal muscle exercise ability in patients with chronic obstructive pulmonary disease at stable phase]. AB - OBJECTIVE: To explore the effects of acupuncture on improving the peripheral skeletal muscle exercise ability in patients with chronic obstructive pulmonary disease (COPD) at stable phase. METHODS: Forty-four patients were randomly divided into an observation group (24 cases) and a control group (20 cases). Based on regular western medication treatment and aerobic training, acupuncture was used in the observation group and placebo acupuncture was used in the control group. The acupoints selected were Danzhong (CV 17), Rugen (ST 18), Guanyuan (CV 4), Zhongwan (CV 12), Tianshu (ST 25), etc., 2-3 times per week, and totally 14 treatments were given. The body mass index (BMI), average distance and average maximum heart rate recorded during bicycle exercise, six-min walking distance (6 MWD), maximum power (Wmax) and maximum heart rate (HRmax) recorded during exercise cardiopulmonary function test, and pulmonary function index including forced expiratory volume in one second/estimate value (FEV1%), forced vital capacity/estimate value (FVC%), FEV1/FVC and maximal voluntary ventilation (MVV) were observed in both groups before and after treatment. RESULTS: The BMI before and after treatment in the observation group was not significantly changed (P>0.05), while that in the control group was significantly reduced (P<0.05). Compared before treatment, the average distance of bicycle exercise, 6-MWD, Wmax, FEV1%, FVC% and MVV were significantly improved after treatment in the observation group (P<0.01, P<0.05), which were all superior to those in the control group (P<0.01, P<0.05). The treatment outcomes in the control group were not significantly changed after treatment (all P>0.05). CONCLUSIONS: Acupuncture combined with aerobic training of bicycle and conventional western medication could prevent the reducing of BMI in patients with COPD at stable phase, improve pulmonary ventilation function, and increase the function of peripheral skeletal muscle to improve its performance. PMID- 29231587 TI - [Clinical study of post-stroke upper limb spasmodic hemiplegia treated with jingou diaoyu needling technique and Bobath therapy]. AB - OBJECTIVE: To compare the difference in the clinical efficacy on post-stroke upper limb spasmodic hemiplegia between the combined therapy of jingou diaoyu needling technique and Bobath technology and simple Bobath technology. METHODS: Sixty patients were randomized into an observation group and a control group, 30 cases in each one. The usual medication of neurological internal medicine was used in the two groups. In the control group, Bobath facilitation technology was applied to the rehabilitation training. In the observation group, on the basis of the treatment as the control group, jingou diaoyu needling technique was used to stimulate Zhongfu (LU 1), Tianfu (LU 3), Chize (LU 5), Quchi (LI 11), Jianshi (PC 5) and Daling (PC 7). The treatment was given once a day; 5 treatments made one session and totally 4-week treatment was required in the two groups. The modified Ashworth scale, the modified Fugle-Meyer assessment (FMA) and the Barthel index (BI) were adopted to evaluate the muscular tension, the upper limb motor function and the activities of daily living (ADL) before and after treatment in the two groups. The clinical efficacy was compared between the two groups. RESULTS: Compared with those before treatment, the modified Ashworth scale, Fugl-Meyer score and BI score were all improved after treatment in the two groups (all P<0.01). The results in the observation group were better than those in the control group (all P<0.01). The total clinical effective rate was 93.3% (28/30) in the observation group and was 80.0% (24/30) in the control group. The efficacy in the observation group was better than that in the control group (P<0.05). CONCLUSIONS: The jingou diaoyu needling technique combined with Bobath therapy achieve the superior efficacy on post-stroke upper limb spasmodic hemiplegia as compared with the simple application Bobath therapy. This combined treatment effectively relieve spasmodic state and improve the upper limb motor function and the activities of daily living. PMID- 29231588 TI - [Acupoint catgut embedding therapy in treatment of anal fissure at I and II stages:a randomized controlled trial]. AB - OBJECTIVE: To evaluate the difference in the clinical therapeutic effects on anal fissure at I and II stages between the acupoint catgut embedding therapy and western medication. METHODS: Sixty patients of anal fissure at I and II stages were randomized into an embedding therapy group and a western medication group, 30 cases in each one. In the embedding therapy group, the acupoint catgut embedding therapy was applied at bilateral Tianshu (ST 25), Changqiang (GV 1), bilateral Chengshan (BL 57) and Tigangxue (Extra), once a week. In the western medication group, the external inunctum on the wound was given with 0.2% nitroglycerin ointment, once every morning and evening a day. The treatment lasted for 4 weeks continuously in the two groups. The follow-up visit was done for 3 months after treatment. The visual analogue scale (VAS) and anal pain duration were observed and recorded before treatment and on the 3rd day and the 7th day of treatment separately. The clinical therapeutic effects were compared between the two groups. RESULTS: After treatment, on the 3rd day and the 7th day of treatment, VAS score and anal pain duration were all reduced significantly as compared with those before treatment in the patients of the two groups (all P<0.01). The differences in the embedding therapy gruop were better than those in the western medication group before and after treatment (P<0.01,P<0.05). In the 2nd and 4th weeks after treatment, the clinical therapeutic effects in the embedding therapy group were better than those in the western medication group (both P<0.05). In 3-month follow-up, the recurrent case in the embedding therapy group was one, and the recurrent case in the western medication group was six. CONCLUSIONS: The acupoint catgut embedding therapy is safe and effective in the treatment of anal fissure at I and II stages and its recurrent case is lower as compared with the treatment of western medication. PMID- 29231589 TI - [Effects of moxibustion at Shenshu (BL 23) on level of sex hormones and AMH in sub-health peri-menopausal women]. AB - OBJECTIVE: To compare the effects between moxibustion at Shenshu (BL 23) and oral administration of Vitamin E on quality of life and mechanism in sub-health perimenopausal women, aiming to provide clinical evidence of moxibustion for health care of sub-health female. METHODS: Sixty participants were randomly divided into a moxibustion group and a medication group, 30 cases in each one. The volunteers in the moxibustion group were treated with mild moxibustion at bilateral Shenshu (BL 23) for 15 min, once a day; five treatments were considered as a course of treatment, and totally 4 courses were given with an interval of 2 days between courses. The volunteers in the medication group were treated with oral administration of soft capsule of Vitamin E, once a day, continuously for 28 days. The scores of quality of life and serum levels of sex hormones, anti Mullerian hormone (AMH) and inhibin B (INHB) were measured before and after treatment in the two groups. RESULTS: 1 Compared before treatment, the scores of quality of life in the two groups were both significantly increased after treatment (both P<0.01), which was more superior in the moxibustion group (P<0.05). 2 Compared before treatment, the serum levels of estradiol (E2) and progesterone in the moxibustion group were significantly increased after treatment, especially for premenopausal volunteers (both P<0.01). 3 After moxibustion, the serum level of AMH was significantly improved (P<0.01), however, the effect on INHB had no statistical difference (P>0.05). CONCLUSIONS: Moxibustion could effectively improve the quality of life in sub-health perimenopausal women, regulate the levels of sex hormones and AMH, improve ovarian reserve function, and delay ovarian aging. PMID- 29231590 TI - [Clinical therapeutic effect on bronchial asthma in children of different body constitutions treated with sanfu pingchuan plaster and sanjiu zhichuan plaster]. AB - OBJECTIVE: To observe the difference in the clinical therapeutic effects on bronchial asthma in children of different body constitutions treated with sanfu pingchuan plaster and sanjiu zhichuan plaster. METHODS: One hundred and twenty two children of bronchial asthma were divided into three groups according to TCM body constitutions, 42 cases in the qi deficiency constitution group, 40 cases in the yang deficiency constitution group and 40 cases in the phlegm damp constitution group. From 2011 to 2013, the acupoint plaster was applied to all of the children in the three groups during the dog days and the third nine-day period after the winter solstice each year. The average attack frequency and onset days of bronchial asthma and relevant immune function indicators were observed during treatment and 1 year after treatment in the children and the therapeutic effects were evaluated. RESULTS: 1In 2014, the acute attacks of bronchial asthma were (1.2+/-0.9) times and (1.4+/-0.4) times in the qi deficiency constitution group and the yang deficiency constitution group, all lower than (3.0+/-0.5) times in the phlegm damp constitution group (both P<0.05) separately. 2After treatment, in the qi deficiency constitution group and yang deficiency constitution group, the values of IgG, IgA and IgM were all increased as compared with those before treatment (all P<0.05). 3The total effective rate was over 95% in the children of the three groups. The clinical control rates in the qi deficiency constitution group and the yang deficiency constitution group were higher apparently than that in the phlegm damp constitution group, indicating the significant difference statistically (both P<0.05). CONCLUSIONS: The combined treatment of sanfu pingchuan plaster and sanjiu zhichuan plaster are effective on bronchial asthma in the children of different body constitutions. The therapeutic effects for the qi deficiency constitution and the yang deficiency constitution are more apparent than that for the phlegm damp constitution. PMID- 29231591 TI - [Exploration of acupoint combination and needling techniques in the reinforcing and reducing manipulation at different acupoints]. AB - The reinforcing and reducing manipulation at different acupoints is a kind of acupuncture manipulations and has satisfactory clinical therapeutic effects, combined with a proper needling techniques. The reinforcing needling method is used in the upper and the reducing one in the lower, the distal acupoints are combined with the nearby acupoints. The local acupoints or adjcant acupoints of the affected area are regarded as the nearby acupoints, e.g. the acupoints in the upper. The distant acupoints and the acupoints on the hand and foot are named as distal acupoints, e.g. the acupoint in the lower. In the reinforcing manipulation, the needle is inserted shallowly along the running direction of meridian. In the reducing manipulation, the needle is inserted deeply and against the running direction of meridian. The yin-yang couple needling technique is used with the combination of the front-mu and back-shu points. In the first option, the reinforcing and reducing needling method with rotating technique is predominated at the front-mu points, while that with lifting and thrusting technique is at the back-shu points. In the second option, when needling the back shu points, the needling sensation is transmitted along the transverse segment and far to the chest and abdomen. These two kinds of integration of acupoint combination and needling techniques display a certain clinical significance in improving the therapeutic effects of acupuncture. PMID- 29231592 TI - [Ultrasonic imaging research at Ashi points in neck-type cervical spondylosis]. AB - OBJECTIVE: To conduct the preliminary positioning and qualitative research of high-frequency ultrasonic imaging at Ashi points (including tender points and trigger points) in neck-type cervical spondylosis and explore the relevant law so as to provide the evidence for the selection of acupuncture scheme. METHODS: Thirty patients in compliance with the diagnostic criteria of neck-type cervical spondylosis were selected. The trigger points, tender points and placebo points were positioned on any of the three available oriented lines. The point-to-point high-frequency real-time dynamic ultrasonic imaging technology was used to scan and position each point and record the changes in ultrasound gradation anatomy and two-dimensional ultrasound in perimysium, two-dimensional and color Doppler ultrasonography and blood flow. The ultrasound characteristics were analyzed. RESULTS: 1Regarding the changes in ultrasound gradation anatomy and two dimensional ultrasound in perimysium, the anatomic gradation at trigger points and tender points was in the sequence as cutaneous layer, subcutaneous fat layer, shallow muscular tissue layer, deep muscular tissue layer and vertebrae. The linear high echo presented in cutaneous layer; the low echo in subcutaneous fat layer; the linear high echo in muscular fasciae; the low echo in muscular layer and the clear linear echo in its perimysium; the high echo and declined posterior echo in vertebrae. Compared with the placebo points, 93.3% of trigger points (28/30) presented enhanced or thickened perimysium echo (P<0.05), and 96.7% of tender points (29/30) presented enhanced or thickened perimysium echo (P<0.05). The differences were not significant between the trigger points and the tender points (P>0.05). 2In the two-dimensional ultrasonography, the clear linear echo presented in perimysium, the enhanced or thickened echo in perimysium of trigger points and tender points. In the color Doppler ultrasonography, the blinking unstable dotted blood flow signal or stable short rod-like blood flow signal presented in the trigger points and tender points. 3Regarding the condition of blood flow, 56.7% of trigger points (17/30) presented II degree of color blood flow signal and 83.3% of tender points (25/30) presented II degree of color blood flow signal; 0% of placebo points presented II degree of color blood flow signal. Compared with the placebo points, the differences in the rate of II degree of color blood flow signal were significant statistically at both the trigger points and the tender points (both P<0.05). The difference was not significant between the trigger points and tender points (P>0.05). CONCLUSIONS: In the high-frequency ultrasound imaging at trigger points and tender points in neck-type cervical spondylosis, the ultrasound imaging characteristics present, which are similar between the trigger points and the tender points. The high-frequency ultrasound imaging is valuable in positioning and quantitative research of Ashi points in cervical spondylosis and has a certain significance to guide treatment. PMID- 29231593 TI - [Impacts on urodynamic parameters and the protein expressions of M2 and M3 receptors of detrusor in the rats of detrusor hyperreflexia treated with ginger salt-isolated moxibustion at "Shenque" (CV 8)]. AB - OBJECTIVE: To discuss the effects on detrusor hyperreflexia treated with ginger salt-isolated moxibustion at "Shenque" (CV 8) and its mechanism. METHODS: Thirty female adult SD rats were selected. The model of detrusor hyperreflexia was prepared with complete spinal transection at T9, of which, 20 rats were randomized into a model group (10 rats) and a moxibustion group (10 rats). A sham operation group (10 rats) was set up for sham-spinal transection. In the moxibustion group, when urine incontinence occurred (about in 2 weeks of modeling), the ginger-salt-isolated moxibustion at "Shenque" (CV 8) was given, 3 moxa cones each time, once a day, continuously for 7 days. After treatment, in each group, the urodynamic parameters were determined, after which, the bladder detrusor was collected. Western blot was used to determine the protein expressions of M2 and M3 receptors. RESULTS: Compared with the sham-operation group, the micturition interval was shortened apparently (P<0.01); the maximal bladder pressure was increased apparently (P<0.01); the protein expression of M2 receptor in the detrusor was increased significantly (P<0.05) and that of M3 receptor had no apparent change (P>0.05) in the rats of the model group. Compared with the model group, the micturition interval was longer apparently (P<0.01), the maximal bladder pressure was reduced apparently (P<0.01), the protein expression of M2 receptor in the detrusor was reduced significantly (P<0.05) and that of M3 receptor had no apparent change (P>0.05) in the rats of the moxibustion group.Compared with the sham-operation group, the results of the above indicators were not different significantly in the moxibustion group (all P>0.05). CONCLUSIONS: The ginger-salt-isolated moxibustion at "Shenque" (CV 8) suppresses the overactive bladder in the rat with spinal transection and its effect mechanism is possibly relevant with reducing the protein expression of detrusor M2 and inhibiting the excessive contraction of the detrusor. PMID- 29231594 TI - [Regulation of acupuncture on expression of AKT protein in lung tissues of asthma rats]. AB - OBJECTIVE: To explore the effects of acupuncture on the expression of protein kinase B (PKB/AKT) in lung tissues of asthma rats. METHODS: Forty SPF male SD rats were randomly divided into a blank group, a model group, an acupuncture group and a blocker group, 10 rats in each one. The rat model of asthma was established by egg albumin stimulation in the model group, acupuncture group and blocker group. Since the establishment of rat model, the rats in the acupuncture group were treated with acupuncture at "Dazhui" (GV 14), "Feishu" (BL 13) and "Fengmen" (BL 12) before atomization; the rats in the blocker group were treated with intervention of blocker LY294002, once every two days, for 7 times. There was no treatment in the blank group and model group. HE staining was applied to observe the morphologic changes of lung tissues; the immunohistochemical method was applied to test the protein expression of AKT in lung tissue. RESULTS: HE staining indicated the infiltration and aggregation of a variety of inflammatory cells around airways, as well as bronchial smooth muscle spasm and confined lumen in the model group; in the acupuncture group and blocker group the inflammatory cells were less and confined lumen was relieved. Compared with the blank group, the protein expression of AKT was higher in the model group (P<0.05); compared with the model group, the protein expression of AKT in the acupuncture group and blocker group was reduced (both P<0.05); the differences between the acupuncture group and blank group, blocker group were not significant (both P>0.05). CONCLUSIONS: Acupuncture could reduce the protein expression of AKT in lung tissue in asthma rats, leading to relieved inflammation reaction and airway remodeling. PMID- 29231595 TI - [Effects of electroacupuncture on activation of microglia cells in spinal cord in rats with neuropathic pain]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) on the activation of microglia cells in the L4 to L6 spinal cord in rats with neuropathic pain, so as to investigate whether EA could inhibit the activation of spinal microglial cells and regulate the expression of brain-derived neurotrophic factor (BDNF) to achieve the analgesic effect. METHODS: Forty male Sprague Dawley rats were randomly divided into a normal group, a sham-model group, a model group and an EA group, 10 rats in each one. The rats in the normal group received no treatment; the rats in sham-model group were treated with operation to exposure sciatic nerve for 2 to 3 min (no knot); the rats in the remaining groups were treated with model establishment of chronic constrictive injury (CCI). 7 days after model establishment, the rats in the EA group were treated with EA at "Zusanli" (ST 36) and "Yanglingquan" (GB 34), 30 min per time, once a day for consecutive 7 days. Only immobilization was used in the remaining groups the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) of affected side feet were respectively measured before model establishment and 3 days, 5 days, 7 days, 10 days, 12 days and 14 days after model establishment; 14 days after model establishment, rats were sacrificed; the immunohistochemical method was used to measure the expression of Iba1 and BDNF in the sample of L4 to L6 spinal cord; real-time fluorescent quantitative PCR was used to measure the expression BDNF mRNA. RESULTS: Compared with the sham-model group, the pain threshold was decreased significantly in the model group (P<0.05), leading to hyperpathia. After EA treatment, compared with the model group, the pain threshold was increased significantly in the EA group (P<0.05). 14 days after operation, the microglia cells in the L4 to L6 spinal cord, expression of BDNF and level of mRNA in the model group were significantly higher than those in the normal group and sham-model group (all P<0.01); those in the EA group were significantly lower than those in the model group (all P<0.01). CONCLUSIONS: The analgesic effect on neuropathic pain is likely to be achieved by EA through inhibiting the activation of spinal microglia cells and down-regulating the expression of BDNF. PMID- 29231596 TI - [Current situation of acupuncture in New Zealand]. AB - The beginning of TCM acupuncture in New Zealand dates back to the middle of 19th century. After self-improvement for more than 100 years, TCM acupuncture has gained a considerable development. From the perspective of history and current situation, the development of acupuncture in New Zealand was elaborated in this article; in addition, the sustainable development of acupuncture was discussed from the perspective of education and training. In New Zealand, the TCM acupuncture and dry needling have played a dominant role in acupuncture treatments, which are practiced by TCM practitioners and physical therapists. The TCM acupuncture is widely applied in department of internal medicine, surgery, gynecology, and pediatrics, etc., while the dry needling is li-mited for traumatology and pain disorder. Therefore, including TCM acupuncture into the public medical and educational system in New Zealand should be an essential policy of Ministry of Health to provide welfare for the people. PMID- 29231597 TI - [Clinical experience of acupuncture and moxibustion in the diagnosis and treatment of persistent somatoform pain disorder]. AB - The clinical manifestation and clinical diagnosis and treatment of acupuncture for persistent somatoform pain disorder (PSPD) were observed to explore its etiology. It is found that the causative factor of PSPD is probably relevant with pain memory induced by the negative emotions during the first attack of pain, which is in the category of "depression" in TCM. In clinical diagnosis, the medical history should be explored to discover the potential etiology and determine the diagnosis. In treatment, the root cause should be considered, focusing on mind and qi regulation and associating with analgesia. It is different from the common treatment for analgesia in other pain disorders. For PSPD, the root cause is considerable, with "mind regulation" in priority. The acupoints relevant with mind on the head[such as Baihui (GV 20) and Sishencong (EX-HN1)], the acupoints for warming and tonifying the primary qi[such as Qihai (CV 6), Guanyuan (CV 4) and Zusanli (ST 36)] and the auricular points (such as xin (CO15), gan (CO12), shenmen (TF4), neifenmi (CO18)) are selected to regulate qi activity and calm down the mind. Additionally, the therapy for reliving pain specifically is applied with transcutaneous electric stimulation, 2 Hz/100 Hz, disperse-dense wave at bilateral Zusanli (ST 36) and Sanyinjiao (SP 6) to erase pain memory trace. Ultimately, the therapeutic effects are achieved for mind regulation and pain easing. PMID- 29231598 TI - [Analysis on the laws of acupoint selection and therapeutic operations with acupuncture based on the characteristics of postherpetic neuralgia]. AB - Postherpetic neuralgia is manifested as drastic lingering pain, which seriously impacts the survival quality of patient. In the paper, focusing on the time of postherpetic neuralgia and in association with the characteristics of symptoms such as the location and nature of pain and skin lesion, the etiology, location of sickness, nature of sickness and pathogenesis were differentiated, and the laws of acupoint selection and therapeutic operations were explored in the treatment with acupuncture. Regarding the apparent pain at night, especially during 23:00 to 3:00, Ashi points (Extra) and Jiaji (EX-B 2) were selected in terms of location differentiation. The acupoints on the liver and gallbladder meridians were specially selected and the supplementary acupoints were used according to general symptoms based on syndrome and symptom differentiation to improve the therapeutic effects. Regarding the therapeutic operation, the bloodletting puncture was used in terms of blood stagnation in collaterals. Additionally, the other operations were selected individually, such as filiform needle therapy, fire needling therapy, plum-blossom needle therapy and bleeding and cupping therapy. PMID- 29231599 TI - [Application of self-developed moxibustion thermometer in experiment teaching]. AB - In order to improve the teaching quality of moxibustion experiment, a moxibustion thermometer was self-developed to monitor the real-time and continuous data of moxibustion temperature at different time points during the experiment. After teacher's explanation and demonstration of experiment process, the students used the moxibustion thermometer to monitor the change of temperature data and extended the experiment design. In the process of experiment class, the students found the temperature of the object tested increased rapidly, arrived at the highest temperature and slowly reduced. In addition, with learned knowledge, the students were able to design the feasible experiment scheme. The self-developed moxibustion thermometer operates smoothly in actual teaching, with stable experiment data and less experiment error, which obtained satisfactory teaching effect. PMID- 29231600 TI - [Acupuncture schools in the Republic of China]. AB - The materials of 48 acupuncture schools in the Republic of China were collected. Their features were analyzed in terms of school running, students enrolling, curriculum setting and course contents, etc. The acupuncture schools at that time were established by private organizations, and opened up correspondence education. These schools mainly relied on advertisements to enroll students, and partially got government supports. The students were on different levels. They emphasized systematic acupuncture curriculum and clinical practice. Most schools absorbed western contents into courses, while few schools taught traditional acupuncture theories. The education model of acupuncture school during the Republic of China was continued after the foundation of the nation, especially laying the foundation for the establishment of department of acupuncture. PMID- 29231601 TI - [Exploration on two methods of waiting for qi in needle insertion and withdrawal of acupuncture reinforcing and reducing technique recorded in Neijing (The Yellow Emperor's Classic of Internal Medicine)]. AB - The reinforcing and reducing technique based on the speed of needle insertion and withdrawal is the important acupuncture technique recorded in Neijing (The Yellow Emperor's Classic of Internal Medicine). Regarding the speed of needle insertion and withdrawal, the timing of needle insertion and withdrawal is one of the key factors to judge the therapeutic effects. In the paper, the origin was studied on the two methods of waiting for qi recorded in Neijing (The Yellow Emperor's Classic of Internal Medicine), e.g. "waiting for respiratory qi" and "waiting for qi beneath needle"; and its application progression and clinical significance were explained. Of them, the "waiting for qi beneath needle" is mostly used to decide the timing of needle withdrawal and closely related to the therapeutic effects of reinforcing and reducing technique; and its application is fully developed in later generations. In Nanjing (Treaties on Difficult Questions), it stresses the needle insertion after waiting for qi with the assistant hand, lifting and thrusting manipulation is followed after arrival of qi beneath needle. This technique brings the impacts on the reinforcing and reducing technique of acupuncture in later generations. PMID- 29231602 TI - [Review on infrared temperature characteristics of acupoints in recent 10 years]. AB - In the paper, the study was reviewed on the infrared temperature characteristics of acupoints in recent 10 years. CNKI, WANFANG, VIP, SciVerse ScienceDirect and Springer databases were retrieved, with"infrared thermal imaging" and "acupoint" as the key words. The retrieving time was from January 1, 2006 to December 31, 2016. Totally, 468 relevant papers were searched and 169 papers of them were read carefully on acupoint infrared temperature. In terms of physiological condition, pathological condition and the stimulation methods such as acupuncture, moxibustion, tuina, embedding therapy and cupping therapy, the general situation was reviewed on the infrared temperature characteristics of acupoints separately. It was found that the study on infrared temperature characteristics of acupoints in physiological condition was limited and the characteristics discovered were not enough to systematically review the physiological and physical properties of acupoints. The study in terms of the pathological condition objectively reflected the effects and rules of diseases. It was showed in the study of acupoint infrared temperature characteristics after stimulation that the changes of infrared thermal imaging tempe-rature at some specific region induced by different therapies and parameters might be used to deduce the potential mechanism and optimal parameters or schemes of intervention method and contributed to the formation and deve-lopment of quantitative diagnosis and treatment. The authors believe that the study on infrared temperature characteristics of acupoint provides the active significance in the exploration on the physiological and physical characteristics of acupoint, the effects and rules of diseases as well as the quantitative diagnosis and treatment. PMID- 29231603 TI - [Warm-needling moxibustion for knee osteoarthritis:a randomized controlled trial]. AB - OBJECTIVE: To evaluate the clinical efficacy of warm-needling moxibustion for knee osteoarthritis (KOA), and to explore its effects on isokinetic strength of lower limb muscle. METHODS: Fifty cases of KOA were randomly divided into an observation group (25 cases) and a control group (21 cases), but 4 cases lost contact. The observation group was treated with warm-needling moxibustion at Dubi (ST 35), Neixiyan (EX-LE 4), Xuehai (SP 10), Liangqiu (ST 34), Yinlingquan (SP 9), Yanglingquan (GB 34), Weizhong (BL 40), Heyang (BL 55) and Fengshi (GB 31) for 40 min per treatment. The first 6 treatments were given once a day, and the last 6 treatments were given once every other day. 12 treatments were taken as one course, and totally 3-week treatment was given. No treatment was given in the control group for 3 weeks. The isokinetic strength of extensor muscle and flexor muscle, including the total work, absolute peak torque (aPT) and relative peak torque (rPT), and Western Ontario and McMaster Universities Arthritis Index (WOMAC), and comprehensive efficacy were observed and compared in the two groups. RESULTS: Compared before treatment, the total work, aPT and rPT of the extensor and flexor muscle increased significantly after treatment in the observation group (P<0.01, P<0.05), but the flextion/extention ratio was lowered (P<0.05). In the control group, aPT and rPT of flexor muscle were reduced after treatment (P<0.05, P<0.01). The total work, aPT and rPT of the extensor muscle in the observation group were higher than those in the control group after treatment (P<0.05, P<0.01), but the flextion/extention ratio was lowered (P<0.05). The item score and total score of WOMAC were reduced in the observation group after treatment (all P<0.01), but no significant change was observed in the control group (all P>0.05). The pain score, stiffness scores and total score of WOMAC in the observation group were lower than those in the control group (P<0.01, P<0.05); the score of daily function activities was declined in the observation group, but not significantly different from that in the control group (P>0.05). The total effective rate was 88.0% (22/25) in the observation group. CONCLUSIONS: Warm-needling moxibustion could relieve pain, improve function and muscle balance, strengthen extensor and flexor muscle power, especially extensor, which has superior clinical efficacy. PMID- 29231604 TI - [Clinical study of fire acupuncture with centro-square needles for knee osteoarthritis]. AB - OBJECTIVE: To compare the efficacy difference between fire acupuncture with centro-square needles (FACSN) and filiform needling (FN) for knee osteoarthritis (KOA). METHODS: Seventy-two patients were randomly assigned into an FACSN group and an FN group, 36 cases in each one. Ashi points, Xuehai (SP 10), Liangqiu (ST 34), Neixiyan (EX-LE 4), Dubi (ST 35), Zusanli (ST 36), Yanglingquan (GB 34) and Yinlingquan (SP 9) were selected in the two groups. The FACSN group was treated with FACSN, and three acupoints were selected for each treatment; the FN group was treated with FN, and all the acupoints were selected for each treatment. The cupping treatment was given after acupuncture in the two groups. The treatment was given once every other day, without treatment on Sundays. The treatment was given three times a week, 6 times as one course; totally 2 courses were provided. The visual analogue scale (VAS) and Western Ontario and McMaster Universities Arthritis Index (WOMAC) were observed in the two groups before treatment, two weeks, four weeks into treatment and at one-month follow-up visit. In addition, the comprehensive efficacy was compared between the two groups. RESULTS: Compared before treatment, the score of VAS and the total score of WOMAC were improved in the two groups at each time point after treatment (all P<0.01); the scores of VAS at each time point after treatment in FACSN group were lower than those in the FN group (all P<0.05); four weeks into treatment and at one-month follow-up visit, the total score of WOMAC in the FACSN group was lower than that in the FN group (both P<0.05). Two weeks into treatment, the total effective rate was 88.9% (32/36) in the FACSN group, which was higher than 61.1% (22/36) in the FN group (P<0.01); four weeks into treatment and at one-month follow-up visit, the cured and remarkable effective rates were 66.7% (24/36) and 83.3% (30/36) in the FACSN group, which were higher than 41.7% (15/36) and 44.4% (16/36) in the FN group (P<0.05, P<0.01), respectively. CONCLUSIONS: Fire acupuncture with centro-square needles has relatively high cured and remarkable effective rate for KOA, with rapid onset; as for pain relief, the efficacy is superior to filiform needling. PMID- 29231605 TI - [Clinical research of mild and moderate lumbar disc herniation of blood stagnation syndrome treated with qi-conducting needling technique at the governor vessel acupoints combined with electroacupuncture]. AB - OBJECTIVE: To compare the difference in the clinical therapeutic effects on mild and moderate lumbar disc herniation (LDH) of blood stagnation syndrome between qi conducting needling technique at the governor vessel acupoints combined with electroacupuncture (EA) and conventional EA. METHODS: Two hundred and one patients of LDH at the mild and moderate stage, differentiated as blood stagnation syndrome were randomized into an observation group (101 cases) and a control group (100 cases). In the observation group, the qi-conducting needling technique at the governor vessel acupoints and EA were used. The acupoints were Yaoyangguan (GV 3), Shiqizhui (EX-B 8), Huantiao (GB 30) and Yanglingquan (GB 34). After qi arrival, the qi-conducting needling technique was used at Yaoyangguan (GV 3) and Shiqizhui (EX-B 8); the EA was at Huantiao (GB 30) and Yanglingquan (GB 34). The treatment was given once every two days, 3 times a week. The treatment for 12 times was as one session. The observation lasted for 1 session. In the control group, the acupoints were the same as the observation group and stimulated with EA. The EA parameters, treatment frequency and duration were all the same as the observation group. The lumbar back pain score of Japanese Orthopedics Association (JOA) score before treatment, after treatment and in 3-month follow-up visit in the two groups, the infrared thermogram temperature in lumbar region and the relaxation area under curve (RAUC) before and after treatment as well as the short-term and the long-term therapeutic effects were compared between the two groups. RESULTS: The total short-term effective rate was 89.11% (90/101) and the total long-term effective rate was 91.11% (82/90) in the observation group, and those were 86.00% (86/100) and 89.53% (77/86) in the control group respectively, without significant differences between the groups (both P>0.05). The short-term clinical curative rate was 52.48% (53/101) and the long-term clinical curative rate was 55.56% (50/90) in the observation group, better than 36.00% (36/100) and 34.88% (30/86) in the control group (both P<0.05). Compared with those before treatment, JOA scores were all improved after treatment and in follow-up visit in the two groups (all P<0.01), without statistical significance at each time point between the two groups (all P>0.05). The infrared thermogram temperature was improved after treatment in the two groups (both P<0.01). The increasing amplitude in the observation group was higher than that in the control group (P<0.01). The lumbar RAUC after treatment was increased apparently as compared with that before treatment in the observation group (P<0.01) and larger than that in the control group (P<0.01). CONCLUSIONS: The qi-conducting needling technique at the governor vessel acupoints combined with EA achieve the better clinical therapeutic effects than regular EA in the treatment of mild and moderate LDH of blood stagnation sydrome. PMID- 29231606 TI - [Clinical study of medicinal-cake-separated moxibustion for senile osteoporosis]. AB - OBJECTIVE: To explore the clinical efficacy and partial mechanism of medicinal cake-separated moxibustion for senile osteoporosis. METHODS: Sixty cases of senile osteoporosis were randomly divided into an observation group and a control group according to the random digits table, 30 cases in each one. The two groups were both treated with basic treatment of western medicine. The acupoints included four groups:1 Dazhui (GV 14), Dazhu (BL 11) and Ganshu (BL 18); 2 Zhongwan (CV 12), Danzhong (CV 17) and Zusanli (ST 36); 3 Pishu (BL 20), Shenshu (BL 23) and Mingmen (GV 4); 4 Shenque (CV 8) and Guanyuan (CV 4). Each group of acupoints was selected for one treatment. The observation group was treated with medicinal-cake-separated moxibustion, and the medicinal cake was consisted of fructus psoraleae (30 g), prepared rehmannia root (30 g), atractylodes (30 g), codonopsis pilosula (30 g), epimedium herb (20 g), rhizoma curculiginis (20 g), syzygium aromaticum (5 g) and cinnamon (5 g). The control group was treated with wheat-flour-cake moxibustion. Each acupoint was treated with 5 moxa cones in the two groups. The treatment was given once every other day for six months. The symptom score, lumbar and hip bone mineral density (BMD), serum type I procollagen amino-terminal propeptide (PINP) and serum beta-type I collagen carboxy-terminal peptide (beta-CTX) were observed before and after treatment. RESULTS: After treatment, the symptom score and serum beta-CTX were significantly lowered (all P<0.05), while the lumbar and hip BMD and serum PINP were significantly increased (all P<0.05) of the two groups. After treatment, the symptom score and serum beta-CTX in the observation group were significantly lower than those in the control group (both P<0.05), while the lumbar and hip BMD and serum PINP in the observation group were significantly higher than those in the control group (all P<0.05). CONCLUSIONS: The medicinal-cake-separated moxibustion has significant efficacy for senile osteoporosis, which is superior to wheat-cake-se-parated moxibustion. PMID- 29231607 TI - [Clinical research on mild and moderate carpal tunnel syndrome treated with contralateral needling technique at distal acupoints and acupuncture at local acupoints]. AB - OBJECTIVE: To compare the differences in the clinical therapeutic effects on mild and moderate carpal tunnel syndrome between the combined therapy of regular acupuncture and contralateral needling technique at distal acupoints and the regular acupuncture. METHODS: Sixty patients of mild and moderate carpal tunnel syndrome were divided into an observation group and a control group according to random number table, 30 cases in each one. Laogong (PC 8), Daling (PC 7), Neiguan (PC 6), Yuji (LU 10) and Hegu (LI 4) were selected on the affected side in the two groups. In the observation group, the reducing needling technique with lifting and thrusting was applied at first to Taichong (LR 3) and Zhongfeng (LR 4) on the opposite side and afterwards those on the affected side were stimulated. In the control group, acupuncture was given at the acupoints on the affected side. The even-needling technique was used at the acupoints on the affected side in the patients of the two groups. Acupuncture was given once every day, 30 min each time. The treatment for 10 days was as one session. The therapeutic effects were evaluated after 3 sessions. The changes in median nerve electrophysiology, Levine's carpal tunnel syndrome questionnaire, the patient rated wrist evaluation (PRWE) and the evaluation of therapeutic effects were observed before and after treatment in the two groups. RESULTS: The total effective rate was 90.0% (27/30) in the observation group, better than 70.0% (21/30) in the control group (P<0.05). After treatment, the nerve sensory conduction velocity and the amplitude of median nerve were all increased in the two groups, indicating the significant differences (all P<0.05). The increase in the observation group was more apparent than that in the control group (all P<0.05). The symptom severity score (SSS) and function status score (FSS) were all reduced apparently after treatment in the two groups (both P<0.05). SSS and FSS in the observation group were lower apparently than those in the control group after treatment (both P<0.05). PRWE score after treatment was reducedapparently as compared with that before treatment in the two groups (both P<0.05). The result in the observation group was lower than that in the control group after treatment (P<0.05). CONCLUSIONS: The combined treatment of regular acupuncture technique and the contralateral needling technique at distal acupoints achieves the definite therapeutic effects on mild and moderate carpal tunnel syndrome, apparently superior to the regular needling technique. PMID- 29231608 TI - [Influence of electroacupuncture pretreatment on intestinal function in the patients of colorectal cancer surgery]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) pretreatment on the intestinal function, inflammatory reaction and blood lactic acid in the patients of colorectal cancer surgery. METHODS: Sixty patients of colorectal cancer laparotomy at selective period, aged from 18 to 59 years old were selected. According toI-III grade of American Society of Anesthesiologists (ASA), the patients were randomized into group A (total intravenous anesthesia), group B[total intravenous anesthesia combined with EA pretreatment at Zusanli (ST 36), Shangjuxu (ST 37) and Xiajuxu (ST 39) on the right side] and group C[total intravenous anesthesia combined with EA pretreatment at Zhongwan (CV 12), Tianshu (ST 25), Zusanli (ST 36), Shangjuxu (ST 37) and Xiajuxu (ST 39) on the right side], 20 cases in each one. The total intravenous anesthesia was applied to all of the three groups. EA pretreatment was used one day before surgery and 30 min before surgery at corresponding acupoints in the group B and group C separately, 30 min each time. After surgery, the recovery time of bowel sound, the recovery time of flatus, the recovery time of defecation, the duration of diet fasting, the time of peritoneal drainage tube withdrawal and the total peritoneal drainage volume were observed in the three groups. The venous blood was collected to determine white blood cell count (WBC) and neutrophil count (NEUT) before surgery (T0), 24 h after surgery (T1) and on the 5th day after surgery (T2) separately. The arterial blood was collected to determine the level of lactic acid before surgery (TI), after peritoneal douching (TII) and 24 h after surgery (TIII)separately. RESULTS: The recovery time of bowel sound, the recovery time of flatus, the duration of diet fasting and the time of peritoneal drainage tube withdrawal in the group C were apparently earlier than those in the group A (all P<0.05). WBC and NEUT at T1 in the group C were apparently less than those in the group A (both P<0.05). The differences in lactic acid at TI, TII and TIII were not significant statistically in comparison of the three groups (all P>0.05). CONCLUSIONS: The total intravenous anesthesia combined with EA pretreatment at Zusanli (ST 36), Shangjuxu (ST 37), Xiajuxu (ST 39), Tianshu (ST 25) and Zhongwan (CV 12) reduce the recovery time of bowel sound, the recovery time of flatus, the duration of diet fasting and the time of peritoneal drainage tube withdrawal so as to improve the recovery of intestinal function, reduce WBC in 24 h after surgery and alleviate inflammatory reaction. This therapy has no influence on blood lactic acid. PMID- 29231609 TI - [Manual acupuncture versus electroacupuncture for menopausal syndrome:a randomized controlled trial]. AB - OBJECTIVE: To compare the clinical therapeutic effects and safety on menopausal symptoms between manual acupuncture (MA) and electroacupuncture (EA). METHODS: Fifty patients were randomized into an MA group (25 cases) and an EA group (25 cases). In the MA group, the regular needling technique and pseudo-EA were used at Guanyuan (CV 4), Zigong (EX-CA 1), Tianshu (ST 25) and Sanyinjiao (SP 6). In the EA group, the acupoints were the same as the MA group and stimulated with EA and pseudo-MA (no manipulation applied in treatment), with disperse-dense wave, 10 Hz/50 Hz, 0.5 to 1.0 mA. In the two groups, the needles were retained for 30 min. The treatment was given once every two days, three times a week, totally for 8 consecutive weeks. The results of the menopause rating scale (MRS), the menopause-specific quality of life (MENQOL), the self-rating anxiety scale (SAS) and the self-rating depression scale (SDS), follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) as well as adverse reactions were evaluated before treatment, in 4 and 8 weeks of treatment separately. RESULTS: Compared with those before treatment, the scores of MRS, MENQOL, SAS and SDS were all reduced in the 4 and 8 weeks of treatment in the two groups (all P<0.05). The results in 8 weeks of treatment were lower than those in 4 weeks of treatment in the two groups (all P<0.05). The differen-ces were not significant statistically between the two groups (all P>0.05). Compared with those before treatment, the levels of FSH and LH reduced and E2 increased after treatment in the two groups, without significant differences (all P>0.05). The differences were not significant statistically between the two groups (all P>0.05). The severe adverse reactions were not found in the treatment of the two groups. CONCLUSIONS: Both manual acupuncture and electroacupuncture relieve the symptoms of depression and anxiety in menopausal syndrome,improve the living quality and do not induce apparent changes in serological sex hormones in the patients. PMID- 29231610 TI - [Application time-point and effect observation of fire needling therapy in IVF ET]. AB - OBJECTIVE: To observe the effects of the intervention with fire needling therapy on the uterine microenvironment at the specific time points of menstrual cycle and evaluate the effects on the assisted reproduction. METHODS: Sixty-eight patients of in vitro fertilization and embryo transplantation (IVF-ET) were randomized into an observation group (35 cases) and a control group (33 cases). The patients in the two groups all received post-IVF-ET corpus luteum support of the microstimulation scheme in the Clinical Reproduction Center of Jiangsu People's Hospital. In the control group, the regular sequential therapy of acupuncture was used. In the observation group, on the basis of the treatment as the control group, the intervention of fire needling therapy was applied after ovulation (the 1st time point, on the 1st day after ovulation) and at the end of premenstrual stage (the 2nd time point, 3 days before the menstruation). At the 1st time point, Shenshu (BL 23), Mingmen (GV 4) and Yaoyangguan (GV 3) were selected and at the 2nd time point, Shenshu (BL 23) and Ciliao (BL 32) were selected. The acupoints were stimulated from up to down and from the left to the right. The changes in TCM syndrome during the preparation, the endometrial thickness and types on the day of transplantation, the biochemical pregnant rate after transplantation and clinical pregnant rate were observed and compared in the patients of the two groups. RESULTS: After treatment, TCM syndrome scores were all reduced in the two groups (both P<0.05). In the observation group, the biochemical pregnant rate and clinical pregnant rate were slightly higher than those in the control group, without significant difference in comparison (both P>0.05). In the observation group, the endo-metrial thickness on the day of transplantation was higher than that in the control group (P<0.05). After treatment, the differences in TCM syndrome score and endometrial type were not significant statistically between the two groups (all P>0.05). CONCLUSIONS: The intervention of fire needling therapy at the specific time points of menstrual cycle relieves menstrual symptoms and increases endometrial thickness so as to assist embryo implantation in the patients of infertility. PMID- 29231611 TI - [Brief discussion on technique and application experience of penetrating moxibustion]. AB - The penetrating moxibustion technique is proposed based on experience of the ancients and clinical practice for many years. From the aspects of definition, action characteristics and technique at different parts, the advantage and application experience of penetrating moxibustion have been discussed. The adequate dose of moxibustion is necessary in penetrating moxibustion; in addition, moxibustion sensation should be penetrating; therefore, with a temperature of 43C for more than 20 min, sweating, flushing, speckle appearing after penetrating moxibustion. Due to individual differences of age, gender and constitution factors, the effects of penetrating moxibustion are different, in clinical practice the body reaction and patient's feelings should be deliberately focused on other than does or sore and blister of moxibustion. The technique is common used in the abdomen, waist and knee joint, etc. PMID- 29231612 TI - [Theoretical origin and clinical application of wrist-ankle acupuncture therapy]. AB - The theory of wrist-ankle acupuncture is consistent with traditional meridian collateral theory. For example, the body divisions of wrist-ankle acupuncture are corresponding to the distribution of 12 cutaneous regions of meridians, the needling sites of it are to the running courses of 12 meridians; the indications of it are to those of 12 meridians. The needling sites of wrist-ankle acupuncture are relevant with some special acupoints of acupuncture theory. For example, the 12-needling sites of wrist-ankle acupuncture are located similar to those of 12 meridian points and have very similar indications. The needling sites of it are located in the wrist and ankle regions, in which the five-shu points are located nearby, for meridian disorders. Most luo-connecting points are located near to the needling sites of wrist-ankle acupuncture or the needle tip points to. Additionally, the needling method of wrist-ankle acupuncture is consistent with some of the subcutaneous needling methods in traditional acupuncture therapy. On the basis of the aspects mentioned above, it is explained that wrist-ankle acupuncture is the development of traditional acupuncture and cannot be independent from the traditional theories of acupuncture and meridians. It is necessary to seek for the evidence from the traditional theories of TCM. The traditional theories of TCM are summarized from clinical practice, which can be newly verified from the practice of wrist-ankle acupuncture. PMID- 29231613 TI - [Effects of electroacupuncture on expression of MU-opioid receptor in nucleus ceruleus in rats with bone cancer pain-morphine tolerance]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) on pain behavior in rats with bone cancer pain and morphine tolerance, and to explore partial action mechanism. METHODS: Forty-two SD healthy female rats were randomly divided into a sham operation group (7 rats), a bone cancer pain group (8 rats), a morphine tolerance group (9 rats), an EA group (9 rats) and a sham EA group (9 rats). The rats in the sham operation group were treated with injection of phosphate buffer saline at medullary cavity of left-side tibia, and the rats in the remaining groups were injected with MRMT-1 breast cancer cells. After operation, no treatment was given to rats in the sham operation group and bone cancer pain group. 11 days after operation, rats in the morphine tole-rance group, EA group and sham EA group were treated with intraperitoneal injection of morphine hydrochloride, once every 12 hours, for 11 days to establish the model of bone cancer pain and morphine tolerance. One day after the establishment of this bone cancer pain model, the rats in the morphine tolerance group were injected with morphine, once every 12 hours (9:00 a.m. and 9:00 p.m.) for 7 days; the rats in the EA group and sham EA group were injected with morphine at 9:00 a.m., and treated with EA (2 Hz/100 Hz) and sham EA (only injected into the subcutaneous tissue) at bilateral "Zusanli" (ST 36) and "Kunlun" (BL 60), 30 min per treatment, once a day for 7 days. One day before cancer cell injection, 6 days, 8 days, 10 days after operation, after 30 min on 1 days, 5 days, 9 days, 11 days of morphine injection, and after 30 min on 1 days, 3 days, 5 days, 7 days of EA treatment, the paw withdrawal threshold (PWT) was measured in each group. On 11 day of morphine injection, HE staining was applied to observe the morphology and structure change of tibia in the sham operation group, bone cancer pain group and morphine tolerance group, random 2 rats in each group. On 7 days of EA treatment, fluorescent immunohistochemical method was applied to observe the expression of MU-opioid receptor positive cells in nucleus ceruleus in each group, random 4 rats in each one. RESULTS: After 10 days of the cancer cells injection, the PWT of 28 rats of bone cancer pain model (8 rats in the bone cancer pain group, 8 rats in the morphine tolerance group, 6 rats in the EA group and 6 rats in the sham EA group) was significantly lower than that of 7 rats in the sham operation group (P<0.01). After one day of morphine injection, the PWT of the morphine tolerance group, EA group and sham EA group was higher than that of the bone cancer pain group (all P<0.01); on 11 d of morphine injection, the PWT of the morphine tolerance group, EA group and sham EA group was not significantly different from that of the bone cancer pain group (all P>0.05). On 11 d of morphine injection, the tumor induced by cancer cells was observed in upper 1/3 tibia in the bone cancer pain group and morphine tolerance group, and the marrow cavity was filled with MRMT-1 cancer cells; no abnormal change was observed in the sham operation group. On 1 d, 3 d, 5 d and 7 d of EA treatment, the PWT of the cancer pain group, morphine tolerance group and sham EA group was lower than that of the EA group (all P<0.01). On 7 d of EA treatment, the positive expression of MOR in nucleus ceruleus in the cancer pain group, morphine tolerance group, EA group and sham EA group was lower than that in the sham operation group (P<0.01, P<0.05), and that in the cancer pain group, morphine tolerance group and sham EA group was lower than that in the EA group (all P<0.01). CONCLUSIONS: EA can improve mechanical pain threshold in rats with bone cancer pain-morphine tolerance, and improve the abnormal pain, which is likely to be involved with improvement of the MOR positive cells expression in nucleus ceruleus by EA. PMID- 29231614 TI - [Effects of preventative moxibustion on AMPK and mTOR in myocardial tissue in rats with exhaustive exercise]. AB - OBJECTIVE: To observe the effects of preventative moxibustion on adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in myocardial tissue in rats with exhaustive exercise, and to explore the action mechanism of preventative moxibustion for myocardial injury by exhaustive exercise. METHODS: Eighteen SD male rats were randomly divided into a blank group, an exhaustive exercise group and a moxibustion group, 6 rats in each one. Rats in the blank group were treated with immobilization for 5 min per day, without any intervention. Rats in the exhaustive exercise group were treated with no intervention in the first 10 days. Rats in the moxibustion group were treated with moxibustion at "Zusanli" (ST 36) and "Guanyuan" (CV 4), 5 cones for each acupoint, for 10 days.On 11th day, rats in the exhaustive exercise group and moxibustion group were sacrificed to collect sample after exhaustive swimming, and time of exhaustive exercise was recorded. HE staining was used to observe the inflammatory changes of myocardial tissue; colorimetric method was used to measure lactic dehydrogenase (LDH), activity of superoxide dismutase (SOD) and malonaldehyde (MDA); immune suppression method was used to measure the content of creatine kinase isoenzyme (CK-MB) in serum; Elisa method was used to measure the content of troponinT (cTnT) in serum; western blot method was applied to measure the content of AMPKalpha2 and mTOR in myocardial tissue. RESULTS: The time of exhaustive exercise was (4 831.17+/-689.88) s in the moxibustion group, which was longer than (3 509.50+/-1 232.49) s in the exhaustive exercise group (P<0.05); HE staining indicated structure of the myocardium was clear and inflammatory cell infiltration was reduced in the moxibustion group. Compared with the blank group, the contents of serum LDH, CK-MB, cTnT were increased in the exhaustive exercise group (all P<0.05); MDA content was increased and SOD activity was decreased (both P<0.05); the AMPK alpha2 content in myocardial tissue was increased and the mTOR content was decreased (both P<0.05). Compared with the exhaustive exercise group, the contents of serum LDH, CK-MB, cTnT were reduced in the moxibustion group (all P<0.05); MDA content was decreased and SOD activity was increased (both P<0.05); the AMPKalpha2 content in myocardial tissue was increased, and the mTOR content was decreased (both P<0.05); AMPKalpha2 and mTOR were negatively correlated (r=-0.764, P<0.05). CONCLUSIONS: Preventative moxibustion is likely to regulate the expression of AMPK and mTOR to induce signaling pathway to recover myocardial injury by exhaustive exercise. PMID- 29231615 TI - [Effects of different methods of acupuncture and moxibustion on functional constipation in rats:a comparative study]. AB - OBJECTIVE: To compare the effects of acupuncture, electroacupuncture (EA) and moxibustion on functional constipation in rats. METHODS: Sixty male Sprague Dawley rats were divided into a control group (n=8), a model group (n=11), a medication group (n=8), an acupuncture group (n=11), an EA group (n=11) and a moxibustion group (n=11) by random number table. The rats in the model group, medication group, acupuncture group, EA group and moxibustion group were treated with intragastric administration of loperamide hydrochloride for 6 days continuously to establish the functional constipation models, while equal volume of drinking water was administrated to rats in the control group at the same time. The rats in the acupuncture group, EA group and moxibustion group were respectively treated with acupuncture, EA and moxibustion at "Tianshu" (ST 25) and "Shangjuxu" (ST 37) one hour after intragastric administration; rats in the medication group were treated with intragastric administration of cisapride suspension. All the treatment was given once a day for 6 days. At the last day of intervention, the 24-hour food intake, stool quantity and its water content were measured in each group; the pushing rate of intestine was measured; the structure of colon tissue and acidic mucus in its mucous layer were observed by hematoxylin eosin dyeing and alcian blue dyeing; the expression of stem cell factor (SCF) and c-kit mRNA was detected by real-time PCR. RESULTS: Compared with the control group, the 24-hour food intake and stool quantity were reduced in the model group (both P<0.01), and the water content of stool and pushing rate of intestine were reduced (both P<0.01); compared with the model group, the stool quantity and its water content were increased in the medication group, acupuncture group, EA group (P<0.05, P<0.01), which were not significantly different from those in the moxibustion group (both P>0.05). The pushing rate of intestine in each intervention group was increased (all P<0.01). The 24-hour food intake and stool quantity in the medication group were not significantly different from those in the acupuncture group, EA group and moxibustion group (all P>0.05), and the water content of stool was only reduced in the moxibustion group (P<0.01). The pushing rate of intestine in the acupuncture group and moxibustion group was lower than that in the medication group (both P<0.01), while that in the EA group was not significantly different from that in the medication group (P>0.05). The water content of stool in the moxibustion group was lower than that in the acupuncture group and EA group (both P<0.01). The pushing rate of intestine in the acupuncture group and moxibustion group was lower than that in the EA group (both P<0.01). The HE staining result indicated the structure of colon tissue was normal, complete and similar in each group; the alcian blue staining indicated the acidic mucosubstance in the model group was lower than that in the control group; compared with the model group, the acidic mucosubstance in the medication group, acupuncture group, EA group and moxibustion group was all increased. Compared with the control group, the expression of SCF and c-kit mRNA was reduced in the model group (both P<0.05); compared with the model group, the expression of SCF and c-kit mRNA was increased in the medication group, acupuncture group, EA group and moxibustion group (all P<0.05); compared with the moxibustion group, the expression of c-kit mRNA was reduced in the acupuncture group and EA group (both P<0.05). CONCLUSIONS: Acupuncture, EA and moxibustion all can play a positive regulative role on functional constipation in rats, in which EA has the best efficacy, followed by acupuncture. PMID- 29231616 TI - [Recertification and continuing education of NCCAOM Diplomates of Acupuncture and Oriental Medicine]. AB - Diplomates certificated by National Certification Commission for Acupuncture and Oriental Medicine (NCCAOM) are needed to be recertified every four years. The certificate will be valid after 60 points of provided professional development activity (PDA). The different validity status of NCCAOM certificates, ways of participating continuing education and the requirements of PDA points including core competencies and professional enhancement (PE) are introduced in this paper. PMID- 29231617 TI - [Protocol optimization and quality control of large-scale acupuncture clinical trial for infertility]. AB - The design of research protocol and quality control are the key to ensure the quality of clinical trial. A randomized clinical trial regarding the effects of medication combined with acupuncture on live birth rate in polycystic ovary syndrome (PCOS), which was initially designed as a comparative effectiveness research, then added with an acupuncture control group and finally became a factorial analysis, is taken as an example to explain the protocol design and optimization process, demonstrating the high level of methodology design and international recognization. By a series of measurements, such as unified purchase of acupuncture equipment, multiple trainings and assessments for acupuncturists' knowledge and operation standardization, in-site supervision of local center experts, the standard operation of acupuncture could be ensured and the credibility and scientificity of research results could be improved. PMID- 29231619 TI - [The analysis on the funding of Natural Science Foundation of China for acupuncture projects from 2005 to 2015]. AB - The funding of Natural Science Foundation of China (NSFC) for acupuncture projects from 2005 to 2015 was summarized and analyzed. The results indicated during past 11 years, 711 projects regarding acupuncture were funded by NSFC, with a total of 281 million RMB, accounting for 12.39% in TCM projects. It was concluded the funding for acupuncture projects was increased year by year, but was still relatively weak; in addition, the funding was unbalanced in different areas and organizations, mainly in Beijing, Shanghai, Sichuan, Guangdong, Tianjin, and the continuity and variability both existed in research content and direction. PMID- 29231618 TI - [Visualization analysis of CiteSpace knowledge map for lumbar disc herniation treated with acupuncture and moxibustion]. AB - OBJECTIVE: To analyze the researches of acupuncture and moxibustion for lumbar disc herniation (LDH) in recent 15 years and summarize the research direction and collect the knowledge structure. METHODS: The relevant literature on acupuncture and moxibustion for the treatment of LDH was retrieved from CNKI. After Refworks format reversion, the CiteSpace software was used to create the reproductive map of the authors, research institutions and keywords in the literature on acupuncture and moxibustion for LDH. RESULTS: In the map, 701 authors were included and 11 authors of them had published >= 3 papers; 740 institutions were included and 20 institutions of them had published >= 3 papers; 149 keywords were included and 13 keywords of them had appeared >= 20 times. CONCLUSIONS: In a study of acupuncture and moxibustion for LDH, it is required to specify the nomenclature, strengthen the cooperation among institutions, promote the communication among authors and construct the treatment system, moreover, to deepen the study on the therapeutic methods, in which the researches have been conducted, and to explore a new therapeutic approach on the basis of the original therapeutic methods. PMID- 29231620 TI - [Briefs of Japanese acupuncture-moxibustion works of Chinese translation version in modern times]. AB - The authors collected 25 Japanese acupuncture-moxibustion works of Chinese translation version in modern times (1912-1960) and investigated them from 3 aspects, named the study on the mechanisms of acupuncture and moxibustion, the explanation of basic theory and clinical treatment with acupuncture and moxibustion. Generally speaking, Japanese acupuncture-moxibustion works of Chinese translation version explained the mechanisms of acupuncture and moxibustion in terms of the theory of western medicine rather than traditional one. It proposed the study on the phenomenon of meridian and collateral, which absorbed the anatomic knowledge of western medicine in the discussion on meridians, collaterals and acupoints; introduced diagnostic methods and techniques of acupuncture and moxibustion and adopted the classification of western medicine system and the diseases in western medicine to discuss the treatment with acupuncture and moxibustion. All of these reflect the academic characteristics of acupuncture and moxibustion in Japan at those times and the position of Chinese scholars, by which the Japanese medical works were introduced for the academic innovation. PMID- 29231621 TI - [Discussion on xuetou xingzou xuedao ge and meridian qi flowing cycle]. AB - The xuetou xingzou xuedao ge is the representative for traumatic injury treated with acupoints of shaolin traumatology. It is mentioned that blood circulates to different acupoints in the governor vessel and the conception vessel at different time divisions a day. In the paper, the relationship is discussed between the blood circulation and the qi flowing cycle in the governor vessel, the conception vessel and the 12 regular meridians. It is found that the time for blood passing by at acupoint is closely related to the time division in meridian qi flowing. The acupoints involved are related to the 12 regular meridians, the collaterals, the divergent regions of meridians and the muscle regions of meridians, and closely associated with zangfu functions. Additionally, the different views of scholars on the aucpoints to which blood flows were explained and the disputes on the location of qujing and liugong were analyzed. It needs clinical practice to give the rational judgment. Understanding and grasping this theory guides positively the proper treatment of traumatic injury at specific time a day and improves clinical therapeutic effects. PMID- 29231622 TI - [Development and application of new-type digital electric plum-blossom needle instrument]. AB - A new-type digital electric plum-blossom needle instrument of controllable and adjustable parameters was developed to achieve an automatic tapping instead of manual tapping technique and integrate the function of plum-blossom needle with that of micropulse electrical phase. The alternating current of periodic variation changes the direction of magnetic field around, induces the vibration of the cone head and tapping movement, outputs the micropulse current and acts on the affected area in treatment. The new-type digital electric plum-blossom needle instrument achieves the automatic tapping movement, precisely adjusts the stimulating strength and frequency according to diseases and integrates the tapping stimulation with pulse current to form circulation loop on the skin and intensify the therapeutic effects. This instrument is the big innovation of traditional plum-blossom needle. It is not only applicable for clinical treatment or family healthcare, but also for scientific research with the adoptable digital therapeutic parameters, which benefits the application and development of plum blossom needle therapy. PMID- 29231623 TI - Progressive multifocal leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy is a rare, opportunistic infection of the central nervous system caused by the John Cunningham virus (JCV). There is no effective antiviral treatment available, and restoring immunocompetence is essential for survival. If this occurs too quickly, however, the inflammatory response may prove fatal. This is an up-to-date review of the disorder, intended for clinicians responsible for immunomodulatory therapy. PMID- 29231624 TI - The resurrection of the body and the life everlasting. PMID- 29231625 TI - ? PMID- 29231627 TI - ? PMID- 29231626 TI - New pathogens, new challenges. PMID- 29231628 TI - The Norwegian System of Patient Injury Compensation is a successful scheme. PMID- 29231629 TI - Infections in the healthcare service - time for a smart approach. PMID- 29231631 TI - ? PMID- 29231630 TI - Tenuous link between chronic fatigue syndrome and pyruvate dehydrogenase deficiency. PMID- 29231632 TI - ? PMID- 29231633 TI - ? PMID- 29231634 TI - ? PMID- 29231635 TI - ? PMID- 29231637 TI - ? PMID- 29231636 TI - [Behavioural arrest]. PMID- 29231638 TI - ? PMID- 29231640 TI - ? PMID- 29231639 TI - Emergency medicine in the general practice internship in Finnmark county. AB - BACKGROUND: It is preferred that duty doctors in municipal health services participate in call-outs in emergency situations. The frequency of participation has previously been shown to vary. We wanted to examine the newly qualified doctors' expectations and experiences - both before and after the general practice internship - of emergency medicine and ambulance call-outs. MATERIAL AND METHOD: All 23 of the interns who were to undertake their general practice internship in Finnmark county in the period 2015-16 answered a questionnaire and participated in a focus group interview before the start of the internship. Twenty-one of the interns participated in the focus group interview after completing the internship. Each doctor took part in two interviews. We analysed the transcripts from the focus group interviews using the grounded theory method. RESULTS: The responses from the questionnaire before the general practice internship showed that the interns felt they needed more training in intravenous cannulation and in teamwork. Their expectations in connection with the challenges of call-outs are best characterised by the core category 'Can I do anything useful?' from the focus groups before the internship. After the internship, however, the core category 'It all went well in the end', was the best fit. Due to short transport times and their knowledge of certain patients, some of the doctors chose not to take part in call-outs. INTERPRETATION: During the general practice internship, the interns were initially anxious about whether they might be superfluous in call-outs, but eventually found their footing in the call-out role. The study shows that there is a need for more practice in certain practical procedures, and that doctors' non-technical skills need to be improved. This can be done through training in team leader roles before the general practice internship. PMID- 29231641 TI - [Medical history as joy and mountains]. PMID- 29231642 TI - [The care and nurses of Rikshospitalet's first 50 years]. PMID- 29231643 TI - ? PMID- 29231645 TI - [The military hospital which became a rikshospital]. PMID- 29231644 TI - [Eilert Sundt - our first epidemiologist]. PMID- 29231646 TI - [New epilepsy classification]. PMID- 29231647 TI - [Dichotomization of measurement variables - what is the price?]. PMID- 29231648 TI - ? PMID- 29231649 TI - An insightful pathography. PMID- 29231650 TI - ? PMID- 29231651 TI - ? PMID- 29231653 TI - ? PMID- 29231652 TI - ? PMID- 29231654 TI - ? PMID- 29231655 TI - ? PMID- 29231656 TI - [What should paramedics be called in Norwegian?]. PMID- 29231657 TI - [Urine has been used for so many things]. PMID- 29231658 TI - A man in his sixties from Southern Norway with intermittent fever. PMID- 29231659 TI - ? PMID- 29231660 TI - ? PMID- 29231661 TI - [A botanical anesthesia]. PMID- 29231662 TI - ? PMID- 29231663 TI - ? PMID- 29231664 TI - [Shame bone should be thrown out of the dictionaries]. PMID- 29231665 TI - ? PMID- 29231666 TI - Is the Norwegian System of Patient Injury Compensation in the best interests of patients? PMID- 29231668 TI - Ecclesiastical Endorsing Organizations. Final rule. AB - The Department of Veterans Affairs (VA) is amending its medical regulations by establishing in regulation the eligibility requirements that ecclesiastical endorsing organizations must meet in order to provide ecclesiastical endorsements of individuals seeking employment as VA chaplains, or of individuals who are seeking to be engaged by VA under contract or appointed as on-facility fee basis VA chaplains under the United States Code. VA considers veterans' spiritual care an integral part of their overall health care. As such, VA is committed to providing qualified VA chaplains to address the veterans' spiritual needs by engaging chaplains that are ecclesiastically endorsed. Ecclesiastical endorsement certifies that the individual is qualified to perform all the religious sacraments, rites, rituals, ceremonies and ordinances needed by members of a particular faith. PMID- 29231667 TI - [Stroke after discontinuation of new anticoagulants prior to surgery]. PMID- 29231669 TI - Single-Unit Cement-Retained Implant Restorations: Strategies, Protocols, and Techniques. PMID- 29231670 TI - Keep the Root and Rebuild the Tooth. PMID- 29231671 TI - The Aesthetic Zone Challenge. PMID- 29231672 TI - Medicare Program: Hospital Outpatient Prospective Payment and Ambulatory Surgical Center Payment Systems and Quality Reporting Programs. Final rule with comment period. AB - This final rule with comment period revises the Medicare hospital outpatient prospective payment system (OPPS) and the Medicare ambulatory surgical center (ASC) payment system for CY 2018 to implement changes arising from our continuing experience with these systems. In this final rule with comment period, we describe the changes to the amounts and factors usedto determine the payment rates for Medicare services paid under the OPPS and those paid under the ASC payment system. In addition, this final rule with comment period updates and refines the requirements for the Hospital Outpatient Quality Reporting (OQR) Program and the ASC Quality Reporting (ASCQR) Program. PMID- 29231673 TI - Practical Laser Applications in General Practice. PMID- 29231674 TI - Endodontic Disinfection: The Sonic Advantage. PMID- 29231675 TI - The post-operative cardiac surgery clinic: is objective utility at odds with patient satisfaction? PMID- 29231676 TI - Is CorMatrix really a recellularization scaffold as a pericardial substitute in cardiac surgery? PMID- 29231677 TI - Transfemoral aortic valve implantation after cardiac transplantation. PMID- 29231678 TI - Dental Implant Prosthetic Options. PMID- 29231679 TI - Aesthetics in Dentistry: It's More Than Beauty. PMID- 29231680 TI - Checklists Can Help Build Effective Teams. PMID- 29231681 TI - A Multidisciplinary Anterior Trauma Case: It Takes a Team! PMID- 29231682 TI - Creating a More Youthful Smile. PMID- 29231684 TI - Narrow-Body Dental Implants. PMID- 29231683 TI - Managing Endodontic Emergencies. PMID- 29231686 TI - A Challenging Mandibular Anterior Implant Case. PMID- 29231685 TI - A Mini Dental Implant Alternative to All-on-Four. PMID- 29231687 TI - Vital Handoffs: Do we give complete, high-quality reports when transferring care? PMID- 29231688 TI - Medical Devices; Immunology and Microbiology Devices; Classification of the Automated Indirect Immunofluorescence Microscope and Software-Assisted System. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the automated indirect immunofluorescence microscope and software-assisted system into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the automated indirect immunofluorescence microscope and software-assisted system's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 29231690 TI - Get in the Water. PMID- 29231689 TI - Minimally Invasive Bio-Rejuvenation Dentistry: A Conservative Approach to Full Mouth Rehabilitation. PMID- 29231691 TI - Medical Devices; Gastroenterology-Urology Devices; Classification of the Prostatic Artery Embolization Device. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the prostatic artery embolization device into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the prostatic artery embolization device's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 29231692 TI - Medicaid Mayhem or Masterpiece. PMID- 29231693 TI - Telephones and Cowbells. PMID- 29231694 TI - Cultivating a Relationship. PMID- 29231695 TI - Medicare Program; Revisions to Payment Policies Under the Physician Fee Schedule and Other Revisions to Part B for CY 2018; Medicare Shared Savings Program Requirements; and Medicare Diabetes Prevention Program. Final rule. AB - This major final rule addresses changes to the Medicare physician fee schedule (PFS) and other Medicare Part B payment policies such as changes to the Medicare Shared Savings Program, to ensure that our payment systems are updated to reflect changes in medical practice and the relative value of services, as well as changes in the statute. In addition, this final rule includes policies necessary to begin offering the expanded Medicare Diabetes Prevention Program model. PMID- 29231696 TI - Letters to the Editor: Really Mike? PMID- 29231697 TI - Health Education Assistance Loan (HEAL) Program. Final rule. AB - On July 1, 2014, the HEAL Program was transferred from the U.S. Department of Health and Human Services (HHS) to the U.S. Department of Education (the Department). To reflect this transfer and to facilitate the servicing of all HEAL loans that are currently held by the Department, the Secretary adds the HEAL Program regulations to the Department's chapter in the Code of Federal Regulations (CFR). PMID- 29231698 TI - An Improved Quadrant Class II Composite Technique. PMID- 29231699 TI - Reinforced Lithium Silicate Ceramic: A Case Report. PMID- 29231700 TI - Diabetes and the Dental Patient. PMID- 29231701 TI - Programmable and Shape-Memorizing Information Carriers. AB - Shape memory polymers (SMPs) are expected to play more and more important roles in space-deployable structures, smart actuators, and other high-tech areas. Nevertheless, because of the difficulties in fabrication and the programmability of temporary shape recovery, SMPs have not yet been widely applied in real fields. It is ideal to incorporate the different independent functional building blocks into a material. Herein, we designed a simple method to incorporate four functional building blocks: a neat epoxy-based shape memory (neat SMEP) resin, an SMEP composited with Fe3O4 (SMEP-Fe3O4), an SMEP composited with multiwalled carbon nanotubes, and an SMEP composited with p-aminodiphenylimide into a multicomposite, in which the four region surfaces could be programmed with different language code patterns according to a preset command by imprint lithography. Then, we aimed to reprogram the initially raised code patterns into temporary flat patterns using programming mold that, when triggered by a preset stimulus process such as an alternating magnetic field, radiofrequency field, 365 nm UV, and direct heating, could transform these language codes into the information passed by the customer. The concept introduced here will be applied to other available SMPs and provide a practical method to realize the information delivery. PMID- 29231702 TI - Stacked Injections of Biphasic Extractions for Improved Metabolomic Coverage and Sample Throughput. AB - Omics technologies attempt to provide comprehensive coverage of their target analytes. Comprehensive coverage of metabolites, the aim of nontargeted metabolomics applications, is hindered by the extreme diversity in physiochemical properties of the metabolome. One approach to deal with this challenge is the use of biphasic extractions. These methods generate two largely complementary extracts from a single sample, with an organic lipid-rich fraction and an aqueous fraction containing largely primary and secondary metabolites. To improve metabolite coverage, these two fractions are then independently analyzed resulting in a doubling of the experimental time. In this manuscript, we describe a novel injection approach, stacked injections of a biphasic extraction (SIBE), which enables simultaneous analysis of the two fractions. We demonstrate that SIBE offers nearly 3-fold more total peak area than a monophasic extract without dramatically increasing instrumentation time required for the analysis. The analytical variance is very slightly increased; however, significant improvements in retention time stability are obtained with SIBE vs monophasic injections. Collectively, these data indicate that SIBE is a viable injection approach whenever comprehensive metabolomic coverage is desired. PMID- 29231703 TI - Investigating the Effect of Column Geometry on Separation Efficiency using 3D Printed Liquid Chromatographic Columns Containing Polymer Monolithic Phases. AB - Effect of column geometry on the liquid chromatographic separations using 3D printed liquid chromatographic columns with in-column polymerized monoliths has been studied. Three different liquid chromatographic columns were designed and 3D printed in titanium as 2D serpentine, 3D spiral, and 3D serpentine columns, of equal length and i.d. Successful in-column thermal polymerization of mechanically stable poly(BuMA-co-EDMA) monoliths was achieved within each design without any significant structural differences between phases. Van Deemter plots indicated higher efficiencies for the 3D serpentine chromatographic columns with higher aspect ratio turns at higher linear velocities and smaller analysis times as compared to their counterpart columns with lower aspect ratio turns. Computational fluid dynamic simulations of a basic monolithic structure indicated 44%, 90%, 100%, and 118% higher flow through narrow channels in the curved monolithic configuration as compared to the straight monolithic configuration at linear velocities of 1, 2.5, 5, and 10 mm s-1, respectively. Isocratic RPLC separations with the 3D serpentine column resulted in an average 23% and 245% (8 solutes) increase in the number of theoretical plates as compared to the 3D spiral and 2D serpentine columns, respectively. Gradient RPLC separations with the 3D serpentine column resulted in an average 15% and 82% (8 solutes) increase in the peak capacity as compared to the 3D spiral and 2D serpentine columns, respectively. Use of the 3D serpentine column at a higher flow rate, as compared to the 3D spiral column, provided a 58% reduction in the analysis time and 74% increase in the peak capacity for the isocratic separations of the small molecules and the gradient separations of proteins, respectively. PMID- 29231704 TI - Site-Specific Glycan Heterogeneity Characterization by Hydrophilic Interaction Liquid Chromatography Solid-Phase Extraction, Reversed-Phase Liquid Chromatography Fractionation, and Capillary Zone Electrophoresis-Electrospray Ionization-Tandem Mass Spectrometry. AB - Reversed-phase chromatographic separation of glycopeptides tends to be dominated by the peptide composition. In contrast, capillary zone electrophoresis separation of glycopeptides is particularly sensitive to the sialic acid composition of the glycan. In this paper, we combine the two techniques to achieve superior N-glycopeptide analysis. Glycopeptides were first isolated from a tryptic digest using hydrophilic interaction liquid chromatography (HILIC) solid-phase extraction. The glycopeptides were separated using reversed-phase ultra high-performance liquid chromatography (UHPLC) to generate four fractions corresponding to different peptide backbones. Capillary zone electrophoresis electrospray ionization-tandem mass spectrometry (CZE-ESI-MS/MS) was used to analyze the fractions. We applied this method for the analysis of alpha-1-acid glycoprotein (AGP). A total of 268 site-specific N-glycopeptides were detected, representing eight different glycosylation sites from two isomers of AGP. Glycans included tetra-sialic acids with multi N-acetyllactosamine (LacNAc) repeats and unusual pentasialylated terminal sialic acids. Reversed-phase UHPLC coupled with CZE generated ~35% more N-glycopeptides than direct reversed-phase UHPLC-ESI MS/MS analysis and ~70% more N-glycopeptides than direct CZE-ESI-MS/MS analysis. This approach is a promising tool for global, site-specific glycosylation analysis of highly heterogeneous glycoproteins with mass-limited samples. PMID- 29231705 TI - A Simple and Convenient Aptasensor for Protein Using an Electronic Balance as a Readout. AB - The electronic balance, one of the most common pieces of equipment in the laboratory, is normally used to directly measure the weight of a target with high accuracy. However, little attention has been paid to the extension of its applications. In this study, an electronic balance was used as a readout to develop a novel aptasensor for protein quantification for the first time. Thrombin was selected as a model target, and its two aptamers recognizing different sites of the protein were used (one aptamer was immobilized on the surface of magnetic microparticles and the other aptamer was functionalized with platinum nanoparticles). The two aptamers were specifically bound with the thrombin to form a sandwich structure; thus, the platinum nanoparticles were linked to the magnetic microparticles, and they were separated by a magnet easily. The captured platinum nanoparticles effectively catalyzed the decomposition of H2O2, generating a large volume of O2 to discharge a certain amount of water in a drainage device, because the pressure in the vial is higher than that outside of the vial. The weight of water was accurately measured by an electronic balance. The weight of water increased with the increasing of the thrombin concentration in the range of 0 to 100 nM with a detection limit of 2.8 nM. This is the first time the use of an electronic balance as a signal readout for biomolecule quantitation in bioassay has been reported. PMID- 29231706 TI - Sodium-Rich Ferric Pyrophosphate Cathode for Stationary Room-Temperature Sodium Ion Batteries. AB - In this article, carbon-coated Na3.64Fe2.18(P2O7)2 nanoparticles (~10 nm) were successfully synthesized via a facile sol-gel method and employed as cathode materials for sodium-ion batteries. The results show that the carbon-coated Na3.64Fe2.18(P2O7)2 cathode delivers a high reversible capacity of 99 mAh g-1 at 0.2 C, outstanding cycling life retention of 96%, and high Coulomb efficiency of almost 100% even after 1000 cycles at 10 C. Furthermore, the electrochemical performances of full batteries consisting of carbon-coated Na3.64Fe2.18(P2O7)2 nanoparticles as the cathode and commercialized hard carbon as the anode are tested. The full batteries exhibit a reversible capacity of 86 mAh g-1 at 0.5 C and capacity retention of 80% after 100 cycles. Therefore, the above-mentioned cathode is a potential candidate for developing inexpensive sodium-ion batteries in large-scale energy storage with long life. PMID- 29231707 TI - Sulfonate Groups and Saccharides as Essential Structural Elements in Heparin Mimicking Polymers Used as Surface Modifiers: Optimization of Relative Contents for Antithrombogenic Properties. AB - Blood compatibility is a long sought-after goal in biomaterials research, but remains an elusive one, and in spite of extensive work in this area, there is still no definitive information on the relationship between material properties and blood responses such as coagulation and thrombus formation. Materials modified with heparin-mimicking polymers have shown promise and indeed may be seen as comparable to materials modified with heparin itself. In this work, heparin was conceptualized as consisting of two major structural elements: saccharide- and sulfonate-containing units, and polymers based on this concept were developed. Copolymers of 2-methacrylamido glucopyranose, containing saccharide groups, and sodium 4-vinylbenzenesulfonate, containing sulfonate groups, were graft-polymerized on vinyl-functionalized polyurethane (PU) surfaces by free radical polymerization. This graft polymerization method is simple, and the saccharide and sulfonate contents are tunable by regulating the feed ratio of the monomers. Homopolymer-grafted materials, containing only sulfonate or saccharide groups, showed different effects on cell-surface interactions including platelet adhesion, adhesion and proliferation of vascular endothelial cells, and adhesion and proliferation of smooth muscle cells. The copolymer grafted materials showed effects due to both sulfonate and saccharide elements with respect to blood responses, and the optimum composition was obtained at a 2:1 ratio of sulfonate to saccharide units (material designated as PU-PS1M1). In cell adhesion experiments, this material showed the lowest platelet and human umbilical vein smooth muscle cell density and the highest human umbilical vein endothelial cell density. Among the materials investigated, PU-PS1M1 also had the longest plasma clotting time. This material was thus shown to be multifunctional with a combination of properties, suggesting thromboresistant behavior in blood contact. PMID- 29231710 TI - Recent Advances in the Development of Chromophore-Based Chemosensors for Nerve Agents and Phosgene. AB - The extreme toxicity and ready accessibility of nerve agents and phosgene has caused an increase in the demand to develop effective systems for the detection of these substances. Among the traditional platforms utilized for this purpose, chemosensors including surface acoustic wave (SAW) sensors, enzymes, carbon nanotubes, nanoparticles, and chromophore based sensors have attracted increasing attention. In this review, we describe in a comprehensive manner recent progress that has been made on the development of chromophore-based chemosensors for detecting nerve agents (mimic) and phosgene. This review comprises two sections focusing on studies of the development of chemosensors for nerve agents (mimic) and phosgene. In each of the sections, the discussion follows a format which concentrates on different reaction sites/mechanisms involved in the sensing processes. Finally, chemosensors uncovered in these efforts are compared with those based on other sensing methods and challenges facing the design of more effective chemosensors for the detection of nerve agents (mimic) and phosgene are discussed. PMID- 29231711 TI - Embedding Capture-Magneto-Catalytic Activity into a Nanocatalyst for the Determination of Lipid Kinase. AB - The use of emerging nanocatalysts to investigate the activity of biocatalysts (protein enzymes, catalytic RNAs, etc.) is increasingly receiving attention from material, analytic, and biomedical scientists. Here, we have first fabricated a three-in-one nanocatalyst, the nitrilotriacetic acid (NTA)-modified magnetite nanoparticle (NTA-MNP), to develop an integrated magneto-colorimetric (MagColor) assay for lipid kinase activity so as to solve the inherent problems in a lipid kinase assay. On the basis of three integrated functions of the NTA-MNPs (capture, magnetic separation, and peroxidase activity), the catalytic activity of lipid kinase is directly converted to colorimetric signals. Therefore, the assay procedure is significantly simplified such that in one step the visual detection of lipid kinase activity is possible. Moreover, the whole system responds sensitively in the case that NTA-MNPs recognize a few numbers of the reaction sites, which efficiently initiates the chromogenic reaction of a large amount of chromogens; thus, the detection limit decreases to 6.5 +/- 5.8 fM, about three orders of magnitude lower as compared to that of enzyme-linked immune sorbent assay. So, by embedding desired functions into nanocatalysts, the assay for biocatalysts becomes easy, which may promisingly provide useful tools for biomedical and clinical research in the future. PMID- 29231708 TI - Atomically Precise Au25(SG)18 Nanoclusters: Rapid Single-Step Synthesis and Application in Photothermal Therapy. AB - Remarkable recent advances on Au25(SR)18 nanoclusters have led to significant applications in catalysis, sensing, and magnetism. However, the existing synthetic routes are complicated, particularly for the water-soluble Au25(SG)18 nanoclusters. Here, we report a single-step concentration and temperature controlled method for rapid synthesis of the Au25(SG)18 nanoclusters in as little as 2 h without the need for low-temperature reaction or even stirring. A systematic time-based investigation was carried out to study the effects of volume, concentration, and temperature on the synthesis of these nanoclusters. Further, we discovered for the first time that the Au25(SG)18 nanoclusters exhibit excellent photothermal activities in achieving 100% cell death for MDA-MB 231 breast cancer cells at a power of 10 W/cm2 using an 808 nm laser source, demonstrating applications toward photothermal therapy. PMID- 29231709 TI - Chemoselective Dual Labeling of Native and Recombinant Proteins. AB - The attachment of two different functionalities in a site-selective fashion represents a great challenge in protein chemistry. We report site specific dual functionalizations of peptides and proteins capitalizing on reactivity differences of cysteines in their free (thiol) and protected, oxidized (disulfide) forms. The dual functionalization of interleukin 2 and EYFP proceeded with no loss of bioactivity in a stepwise fashion applying maleimide and disulfide rebridging allyl-sulfone groups. In order to ensure broader applicability of the functionalization strategy, a novel, short peptide sequence that introduces a disulfide bridge was designed and site-selective dual labeling in the presence of biogenic groups was successfully demonstrated. PMID- 29231712 TI - Ion-Selective Optical Nanosensors Based on Solvatochromic Dyes of Different Lipophilicity: From Bulk Partitioning to Interfacial Accumulation. AB - The sensing mechanism of fluorescent ion-selective nanosensors incorporating solvatochromic dyes (SDs), with K+ as model ion, is shown to change as a function of dye lipophilicity. Water-soluble SDs obey bulk partitioning principles where the sensor response directly depends on the lipophilicity of the SD and exhibits an influence on the phase volume ratio of nanosensors to aqueous solution (dilution effect). A lipophilization of the SDs is shown to overcome these limitations. An interfacial accumulation mechanism is proposed and confirmed with Forster resonance energy transfer (FRET) with a ratiometric near-infrared fluorescence FRET pair. This work lays the foundation for operationally more robust ion-selective nanosensors incorporating SDs. PMID- 29231713 TI - Enzyme-Responsive Bioprobes Based on the Mechanism of Aggregation-Induced Emission. AB - Enzymes play an indispensable role in maintaining normal life activities. The abnormalities of content and activity in specific enzymes are usually associated with the occurrence and the development of major diseases. Correspondingly, fluorescent bioprobes with distinctive sensing mechanisms and different functionalities have attracted growing attention as convenient tools for optical probing and monitoring the activity of enzymes. Ideally and excitedly, the recently emerged luminogens with an aggregation-induced emission (AIE) feature could perfectly overcome the aggregation-caused quenching (ACQ) effect of conventional bioprobes. Based on the fantastic characteristics of AIE luminogens (AIEgens), specific enzyme bioprobes have been designed through integration with recognition units, demonstrating many advantages including low background interference, a high signal-to-noise ratio (SNR), and superior photostability. In this review, by presenting some typical examples, we summarize the working principle and structural design of specific AIEgen-based bioprobes that are triggered by enzymes and discuss their great potential in biomedical applications, with the aim to promote the future research of fluorescent bioprobes involving enzymes. PMID- 29231714 TI - Acid-Induced Multicolor Fluorescence of Pyridazine Derivative. AB - Smart luminescent materials that are responsive to external stimuli have received considerable attention. Here, we report a new D-A type 1,2-pyridiazine derivative (3,4,5,6-tetrakis(4-methoxyphenyl)pyridazine (TPP)) exhibiting turn-on fluorescence upon acid exposure both in solution and in the solid state. The protonation of the 1,2-pyridiazine ring caused a variation in the emission colors of the acidification species from blue (406 nm) to orange-red (630 nm) with a huge Deltalambdaem (224 nm). As a result, a synthetic rainbow of emission in solution could be achieved from one single molecule, and white photoluminescence was readily tuned by controlled protonation. A trifluoroacetic acid (TFA)-sensor film made from TPP was demonstrated as a TFA-sensitive surface with high sensitivity and reversibility. On the basis of these findings, we constructed a solid-state TPP film with a photoacid generator and demonstrated data encryption and decryption via a cascade protonation reaction that was well controlled by UV light. PMID- 29231715 TI - Nanoscale Structure-Property Relationships of Polyacrylonitrile/CNT Composites as a Function of Polymer Crystallinity and CNT Diameter. AB - Polyacrylonitrile (PAN)/carbon nanotube (CNT) composites are used as precursors for ultrastrong and lightweight carbon fibers. However, insights into the structure at the nanoscale and the relationships to mechanical and thermal properties have remained difficult to obtain. In this study, molecular dynamics simulation with accurate potentials and available experimental data were used to describe the influence of different degrees of PAN preorientation and CNT diameter on the atomic-scale structure and properties of the composites. The inclusion of CNTs in the polymer matrix is favored for an intermediate degree of PAN orientation and small CNT diameter whereas high PAN crystallinity and larger CNT diameter disfavor CNT inclusion. The glass transition at the CNT/PAN interface involves the release of rotational degrees of freedom of the polymer backbone and increased mobility of the protruding nitrile side groups in contact with the carbon nanotubes. The glass-transition temperature of the composite increases in correlation with the amount of CNT/polymer interfacial area per unit volume, i.e., in the presence of CNTs, for higher CNT volume fraction, and inversely with CNT diameter. The increase in glass-transition temperature upon CNT addition is larger for PAN of lower crystallinity than for PAN of higher crystallinity. Interfacial shear strengths of the composites are higher for CNTs of smaller diameter and for PAN with preorientation, in correlation with more favorable CNT inclusion energies. The lowest interfacial shear strength was observed in amorphous PAN for the same CNT diameter. PAN with ~75% crystallinity exhibited hexagonal patterns of nitrile groups near and far from the CNT interface which could influence carbonization into regular graphitic structures. The results illustrate the feasibility of near-quantitative insights into macroscale properties of polymer/CNT composites from simulations of nanometer scale composite domains. Guidance is most effective when key assumptions in experiment and simulation are closely aligned, such as exfoliation versus bundling of CNTs, size, type, potential defects of CNTs, and precise measures for polymer crystallinity. PMID- 29231716 TI - Response to Comment on "Molecular Mechanism of Dioxin Formation from Chlorophenol based on Electron Paramagnetic Resonance Spectroscopy". PMID- 29231717 TI - Dibenzopyrrolo[1,2-a][1,8]naphthyridines: Synthesis and Structural Modification of Fluorescent L-Shaped Heteroarenes. AB - The L-shaped, pi-extended pentacycle dibenzopyrrolo[1,2-a][1,8]naphthyridine and its derivatives were synthesized using two methods: fully intramolecular [2 + 2 + 2] cycloaddition and oxidative aromatization using substituted carbodiimide and modification of an electron-rich indole ring of an L-shaped skeleton via electrophilic reaction and cross-coupling. These L-shaped compounds emitted fluorescence in high quantum yield. The position of substituents affected the fluorescence color through two different mechanisms, pi-conjugation and skeletal distortion, which caused the substituted L-shaped compounds to emit fluorescence in a variety of colors and to exhibit solvato-fluorochromism. PMID- 29231718 TI - Virtual Water Scarcity Risk to the Global Trade System. AB - Local water scarcity risk (LWSR, meaning potential economic output losses in water-using sectors due to physical water scarcity) can be transmitted to downstream economies through the globalized supply chains. To understand the vulnerability of the global economy to water scarcity, we examine the impacts of local water scarcity risk on the global trade system from 1995 to 2009. We observe increasingly intensified geographical separation between physical water scarcity and production losses due to water scarcity. We identify top nation sectors in virtual water scarcity risk (VWSR) exports (indicating local water scarcity risk in each nation transmitted to foreign nations through its exports), including agriculture and utilities in major economies such as China, India, Spain, France, and Turkey. These nation-sectors are critical to the resilience of the global economy to water scarcity. We also identify top nation-sectors in virtual water scarcity risk imports (indicating each nation's vulnerability to foreign water scarcity risk through the global trade system), highlighting their vulnerability to distant water scarcity. Our findings reveal the need for nations to collaboratively manage and conserve water resources, and lay the foundation for firms in high VWSR-importing sectors to develop strategies to mitigate such risk. PMID- 29231719 TI - Quorum Sensing Disruption in Vibrio harveyi Bacteria by Clay Materials. AB - This work describes the use of clay minerals as catalysts for the degradation of quorum sensing molecule N-(3-oxooctanoyl)-dl-homoserine lactone. Certain clay minerals as a result of their surface properties and porosity can catalytically degrade the quorum sensing molecule into smaller fragments. The disruption of quorum sensing by clay in a growing Gram-negative Vibrio harveyi bacteria culture was also studied by monitoring luminescence and population density of the bacteria, wherein quenching of bacterial quorum sensing activity was observed by means of luminescence reduction. The results of this study show that food-grade clays can be used as biocatalysts in disrupting bacterial activity in various media. PMID- 29231720 TI - Phosphorylation of Isoflavones by Bacillus subtilis BCRC 80517 May Represent Xenobiotic Metabolism. AB - The soy isoflavones daidzein (DAI) and genistein (GEN) have beneficial effects on human health. However, their oral bioavailability is hampered by their low aqueous solubility. Our previous study revealed two water-soluble phosphorylated conjugates of isoflavones, daidzein 7-O-phosphate and genistein 7-O-phosphate, generated via biotransformation by Bacillus subtilis BCRC80517 cultivated with isoflavones. In this study, two novel derivatives of isoflavones, daidzein 4'-O phosphate and genistein 4'-O-phosphate, were identified by HPLC-ESI-MS/MS and 1H, 13C, and 31P NMR, and their biotransformation roadmaps were proposed. Primarily, isoflavone glucosides were deglycosylated and then phosphorylated predominantly into 7-O-phosphate conjugates with traces of 4'-O-phosphate conjugates. Inevitably, trace quantities of glucosides were converted into 6"-O-succinyl glucosides. GEN was more efficiently phosphorylated than DAI. Nevertheless, the presence of GEN prolonged the time until the exponential phase of cell growth, whereas the other isoflavones showed little effect on cell growth. Our findings provide new insights into the novel microbial phosphorylation of isoflavones involved in xenobiotic metabolism. PMID- 29231721 TI - Silylative Kinetic Resolution of Racemic 1-Indanol Derivatives Catalyzed by Chiral Guanidine. AB - Efficient kinetic resolution of racemic 1-indanol derivatives was achieved using triphenylchlorosilane by asymmetric silylation in the presence of chiral guanidine catalysts. The chiral guanidine catalyst (R,R)-N-(1-(beta naphthyl)ethyl)benzoguanidine was found to be highly efficient as only 0.5 mol % catalyst loading was sufficient to catalyze the reaction of various substrates with appropriate conversion and high s-values (up to 89). This catalyst system was successfully applied to the gram-scale silylative kinetic resolution of racemic 1-indanol with high selectivity. PMID- 29231722 TI - Selenium(IV) Sorption Onto gamma-Al2O3: A Consistent Description of the Surface Speciation by Spectroscopy and Thermodynamic Modeling. AB - The sorption processes of Se(IV) onto gamma-Al2O3 were studied by in situ Infrared spectroscopy, batch sorption studies, zeta potential measurements and surface complexation modeling (SCM) in the pH range from 5 to 10. In situ attenuated total reflection fourier-transform infrared (ATR FT-IR) spectroscopy revealed the predominant formation of a single inner-sphere surface species at the alumina surface, supporting previously reported EXAFS results, irrespective of the presence or absence of atmospherically derived carbonate. The adsorption of Se(IV) decreased with increasing pH, and no impact of the ionic strength was observed in the range from 0.01 to 0.1 mol L-1 NaCl. Inner-sphere surface complexation was also suggested from the shift of the isoelectric point of gamma Al2O3 observed during zeta potential measurements when Se(IV) concentration was 10-4 mol L-1. Based on these qualitative findings, the acid-base surface properties of gamma-Al2O3 and the Se(IV) adsorption edges were successfully described using a 1-pK CD-MUSIC model, considering one bidentate surface complex based on previous EXAFS results. The results of competitive sorption experiments suggested that the surface affinity of Se(IV) toward gamma-Al2O3 is higher than that of dissolved inorganic carbon (DIC). Nevertheless, from the in situ experiments, we suggest that the presence of DIC might transiently impact the migration of Se(IV) by reducing the number of available sorption sites on mineral surfaces. Consequently, this should be taken into account in predicting the environmental fate of Se(IV). PMID- 29231723 TI - Production of 3,4-cis- and 3,4-trans-Leucocyanidin and Their Distinct MS/MS Fragmentation Patterns. AB - (+)-2,3-trans-3,4-cis-Leucocyanidin was produced by acidic epimerization of (+) 2,3-trans-3,4-trans-leucocyanidin synthesized by reduction of (+) dihydroquercetin with NaBH4, and structures of the two stereoisomers purified by C18- and phenyl-reverse-phase high-performance liquid chromatography (HPLC) were confirmed by NMR spectroscopy. We confirm that only 3,4-cis-leucocyanidin is used by leucoanthocyanidin reductase as substrate. The two stereoisomers are quite stable in aqueous solution at -20 degrees C. Characterization of the two stereoisomers was also performed using electrospray ionization tandem mass spectrometry (ESI-MS/MS), and we discuss here for the first time the corresponding MS/MS fragmentation pathways, which are clearly distinct. The main difference is that of the mode of dehydration of the 3,4-diol in positive ionization mode, which involves a loss of hydroxyl group at either C3 or C4 for the 3,4-cis isomer but only at C3 for the 3,4-trans isomer. Tandem mass spectrometry therefore proves useful as a complementary methodology to NMR to identify each of the two stereoisomers. PMID- 29231724 TI - Tropylium-Promoted Oxidative Functionalization of Tetrahydroisoquinolines. AB - Structural modification of the tetrahydroisoquinoline (THIQ) framework is of significant interest to organic chemists due to its central role in heterocyclic and medicinal chemistry. Here we demonstrate an efficient metal-free method for the oxidative functionalization of THIQs at the C1 position, which is amenable to a diverse range of C-C coupling reactions. These reactions proceed through a hydride abstraction involving the tropylium ion followed by quenching the generated iminium intermediates with nucleophiles to afford THIQ derivatives with excellent efficiencies and interesting selectivities. PMID- 29231725 TI - Dibenzo[a,e]pentalenes with Low-Lying LUMO Energy Levels as Potential n-Type Materials. AB - Ambipolar organic semiconductors are of high interest for organic field-effect transistors. For n-type conduction, low LUMO energies are required. Dibenzo[a,e]pentalenes (DBPs) are promising compounds; however, few derivatives exist with energetically low-lying LUMO levels. Here, we present DBP derivatives with LUMO energies down to -3.73 eV and small bandgaps down to 1.63 eV determined through cyclic voltammetry, UV/vis absorption spectroscopy, and TDDFT calculations. Single-crystal X-ray diffraction analysis revealed a 1D pi-stacking mode. The addition of arylalkynyl substituents at the five-membered rings in a facile and versatile synthetic route allowed for tuning of the band gaps and LUMO energies. The synthetic route can easily be modified to access a variety of DBP derivatives. The LUMO energies of the DBP derivatives presented herein make them attractive for an application in n-type or ambipolar field-effect transistors. PMID- 29231726 TI - Activation of Small Molecules by the Metal-Amido Bond of Rhodium(III) and Iridium(III) (eta5-C5Me5)M-Aminopyridinate Complexes. AB - We report the synthesis and structural characterization of five-coordinate complexes of rhodium and iridium of the type [(eta5-C5Me5)M(N^N)]+ (3-M+), where N^N represents the aminopyridinate ligand derived from 2-NH(Ph)-6-(Xyl)C5H3N (Xyl = 2,6-Me2C6H3). The two complexes were isolated as salts of the BArF anion (BArF = B[3,5-(CF3)2C6H3]4). The M-Namido bond of complexes 3-M+ readily activated CO, C2H4, and H2. Thus, compounds 3-M+ reacted with CO under ambient conditions, but whereas for 3-Rh+, CO migratory insertion was fast, yielding a carbamoyl carbonyl species, 4-Rh+, the stronger Ir-Namido bond of complex 3-Ir+ caused the reaction to stop at the CO coordination stage. In contrast, 3-Ir+ reacted reversibly with C2H4, forming adduct 5-Ir+, which subsequently rearranged irreversibly to [Ir](H)(?C(Me)N(Ph)-) complex 6-Ir+, which contains an N-stabilized carbene ligand. Computational studies supported a migratory insertion mechanism, giving first a beta-stabilized linear alkyl unit, [Ir]CH2CH2N(Ph)-, followed by a multistep rearrangement that led to the final product 6-Ir+. Both beta- and alpha H eliminations, as well as their microscopic reverse migratory insertion reactions, were implicated in the alkyl-to-hydride-carbene reorganization. The analogous reaction of 3-Rh+ with C2H4 originated a complex mixture of products from which only a branched alkyl [Rh]C(H)(Me)N(Ph)- (5-Rh+) could be isolated, featuring a beta-agostic methyl interaction. Reactions of 3-M+ with H2 promoted a catalytic isomerization of the Ap ligand from classical kappa2-N,N' binding to kappa-N plus eta3-pseudoallyl coordination mode. PMID- 29231727 TI - An Anthracene-Incorporated [8]Cycloparaphenylene Derivative as an Emitter in Photon Upconversion. AB - The anthracene-incorporated [8]cycloparaphenylene 2 has been synthesized and its optoelectronic properties studied by UV-vis spectroscopy, cyclic voltammetry, and DFT calculations. NMR and computational studies indicate that the new cycloparaphenylene derivative possesses a Cs point group symmetry. The new CPP 2 exhibits peculiar optoelectronic properties: (i) fluorescence emission is blue shifted with respect to [8]cycloparaphenylene 1, and its quantum yield is higher; (ii) in the presence of an octaethylporphyrin Pd complex, as sensitizer, it undergoes a visible light upconversion. This is the first case in which a cycloparaphenylene derivative is involved as an emitter in low power light frequency conversion. PMID- 29231728 TI - Protective Effect of Mulberry (Morus alba L.) Extract against Benzo[a]pyrene Induced Skin Damage through Inhibition of Aryl Hydrocarbon Receptor Signaling. AB - Benzo[a]pyrene (B[a]P), a type of polycyclic aromatic hydrocarbon, is present in the atmosphere surrounding our environment. Although B[a]P is a procarcinogen, enzymatically metabolized benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) could intercalate into DNA to form bulky BPDE-DNA adducts as an ultimate carcinogenic product in human keratinocytes. The aim of this study was to evaluate the protective effect of mulberry extract, purified from the fruit of Morus Alba L., on B[a]P-induced cytotoxicity in human keratinocytes and its mechanisms of action. In this study, we confirmed that B[a]P induced nuclear translocation and the activation of aryl hydrocarbon receptor (AhR) were decreased by pretreatment of mulberry extract. Mulberry extract could decrease DNA damage through the suppression of B[a]P derived DNA adduct formation and restoration of cell cycle retardation at S phase in a dose-dependent manner. Additionally, cyanidin-3-glucoside (C3G), a major active compound of mulberry extract, showed biological activities to protect the cells from B[a]P exposure, similar to the effectivity of the mulberry extract. These results indicated that the inhibitory effect of C3G against B[a]P inducing skin cancer is attributable to repress the AhR signaling pathway. PMID- 29231729 TI - Simulation of Calcium Phosphate Species in Aqueous Solution: Force Field Derivation. AB - A new force field has been derived for the aqueous calcium phosphate system that aims to reproduce the key thermodynamic properties of the system, including free energies of hydration of the ions and the solubility of the solid mineral phases. Interactions of three phosphate anions (PO43-, HPO42-, and H2PO4-) with water were calibrated through comparison with the results obtained from ab initio molecular dynamics using both GGA and hybrid density functional theory with dispersion corrections. In the solid state, the force field has been evaluated by benchmarking against experiment and other existing models and is shown to reproduce the structural and mechanical properties well, despite the primary focus being on thermodynamics. To validate the force field, the thermodynamics of ion pairing for calcium phosphate species in water has been computed and shown to be in excellent agreement with experimental data. PMID- 29231730 TI - Selective Cation Exchange Enabled Growth of Lanthanide Core/Shell Nanoparticles with Dissimilar Structure. AB - Core/shell nanostructure is versatile for improving or integrating diverse functions, yet it is still limited to homeomorphism with isomorphic core and shell structure. Here, we delineate a selective cation exchange strategy to construct lanthanide core/shell nanoparticles with dissimilar structure. Hexagonal NaLnF4, a typical photon conversion material, was selected to grow cubic CaF2 shell to protect surface exposed Ln3+. Preferential cation exchange between Ca2+ and Na+ triggered the surface hexagonal-to-cubic structure evolution, which remediated the large barrier for heteroepitaxy of monocrystalline CaF2 shell. The heterostructured CaF2 shell leads to greatly enhanced upconversion emission with increased absolute quantum yield from 0.2% to 3.7%. Moreover, it is advantageous in suppressing the interfacial diffusion of Ln3+, as well as the leakage of Ln3+ from nanoparticle to aqueous system. These findings open up a new avenue for fabricating heterostructured core/shell nanoparticles, and are instructive for modulating various properties. PMID- 29231731 TI - Carbonylation Access to Phthalimides Using Self-Sufficient Directing Group and Nucleophile. AB - Herein we report a novel palladium-catalyzed oxidative carbonylation reaction for the synthesis of phthalimides with high atom- and step-economy. In our strategy, the imine and H2O, which are generated in situ from the condensation of aldehyde and amine, serve as self-sufficient directing group and nucleophile, respectively. This method provides rapid access to phthalimides starting from readily available materials in a one-pot manner. Various phthalimide derivatives are constructed efficiently, including medicinally and biologically active phthalimide-containing compounds. PMID- 29231732 TI - TEMPO-Mediated Synthesis of Tetrahydropyridinofullerenes: Reaction of [60]Fullerene with alpha-Methyl-Substituted Arylmethanamines and Aldehydes in the Presence of 4-Dimethylaminopyridine. AB - A series of scarce tetrahydropyridinofullerenes were synthesized by the metal free-mediated reaction of [60]fullerene with cheap and easily available alpha methyl-substituted arylmethanamines and aldehydes in the presence of 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO) and 4-dimethylaminopyridine (DMAP) in moderate to good yields comparable to the previously reported data for most monoadducts. The in situ generation of azadienes played a crucial role in the successful synthesis of tetrahydropyridinofullerenes. A plausible reaction mechanism was proposed to elucidate the reaction process. PMID- 29231733 TI - A Representative Synthetic Route for C5 Angucycline Glycosides: Studies Directed toward the Total Synthesis of Mayamycin. AB - This study discloses an efficient synthetic route for the regiospecific construction of a C5 glycoside angucycline representative of mayamycin. The key steps are intramolecular aldol condensation and Hauser annulation, and the key precursor for the aldol reaction is accessible through utilization of alpha lithiation of a vinyl ether. PMID- 29231734 TI - t-SNARE Transmembrane Domain Clustering Modulates Lipid Organization and Membrane Curvature. AB - The t-SNARE complex plays a central role in neuronal fusion. Its components, syntaxin-1 and SNAP25, are largely present in individual clusters and partially colocalize at the presumptive fusion site. How these protein clusters modify local lipid composition and membrane morphology is largely unknown. In this work, using coarse-grained molecular dynamics, the transmembrane domains (TMDs) of t SNARE complexes are shown to form aggregates leading to formation of lipid nanodomains, which are enriched in cholesterol, phosphatidylinositol 4,5 bisphosphate, and gangliosidic lipids. These nano-domains induce membrane curvature that would promote a closer contact between vesicle and plasma membrane. PMID- 29231735 TI - Novel Folate Binding Protein in Arabidopsis Expressed during Salicylic Acid Induced Folate Accumulation. AB - Increasing the quantity of natural folates in plant foods is recently gaining significant interest, owing to their acute deficiencies in various populations. This study observed that foliar salicylic acid treatment enhanced the accumulation of folates in Arabidopsis, which correlated with the increase in a folate binding protein (FBP) and the expression of mRNA of a putative folate binding protein At5G27830. A protein band corresponding to ~43 kDa was observed after resolving the affinity-purified protein on SDS-PAGE, and the partial amino acid sequence indicated that the protein is indeed At5G27830. Docking studies performed with At5G27830 confirmed specific binding of folic acid to predicted site. Heterologous expression of At5G27830 in the yeast resulted in significant uptake and accumulation of folic acid in cells. This novel study of a plant FBP will be useful for folate metabolic engineering of a wide range of crops. PMID- 29231736 TI - Preparation and Membrane Properties of Oxidized Ceramide Derivatives. AB - Ceramide is a bioactive lipid with important roles in several biological processes including cell proliferation and apoptosis. Although 3-ketoceramides that contain a keto group in place of the 3-OH group of ceramide occur naturally, ceramide derivatives oxidized at the primary 1-OH group have not been identified to date. To evaluate how the oxidative state of the 1-OH group affects the physical properties of membranes, we prepared novel ceramide derivatives in which the 1-OH group was oxidized to a carboxylic acid (PCerCOOH) or methylester (PCerCOOMe) and examined the rigidity of their monolayers and the formation of gel domains in palmitoyloleoylphosphatidylcholine (POPC) or sphingomyelin (SM) bilayers. As a result, PCerCOOH and PCerCOOMe exhibited membrane properties similar to those of native ceramide, although the deprotonated form of PCerCOOH, PCerCOO-, exhibited markedly lower rigidity and higher miscibility with POPC and SM. This was attributed to the electrostatic repulsion of the negative charge, which hampered the formation of the ceramide-enriched gel domain. The similarities in the properties of PCerCOOMe and ceramide revealed the potential to introduce various functional groups onto PCerCOOH via ester or amide linkages; therefore, these derivatives will also provide a new strategy for developing molecular probes, such as fluorescent ceramides, and inhibitors of ceramide related enzymes. PMID- 29231737 TI - Stability of Polyethylene Glycol and Zwitterionic Surface Modifications in PDMS Microfluidic Flow Chambers. AB - Blood-material interactions are crucial to the lifetime, safety, and overall success of blood contacting devices. Hydrophilic polymer coatings have been employed to improve device lifetime by shielding blood contacting materials from the natural foreign body response, primarily the intrinsic pathway of the coagulation cascade. These coatings have the ability to repel proteins, cells, bacteria, and other micro-organisms. Coatings are desired to have long-term stability, so that the nonthrombogenic and nonfouling effects gained are long lasting. Unfortunately, there exist limited studies which investigate their stability under dynamic flow conditions as encountered in a physiological setting. In addition, direct comparisons between multiple coatings are lacking in the literature. In this study, we investigate the stability of polyethylene glycol (PEG), zwitterionic sulfobetaine silane (SBSi), and zwitterionic polyethylene glycol sulfobetaine silane (PEG-SBSi) grafted by a room temperature, sequential flow chemistry process on polydimethylsiloxane (PDMS) over time under ambient, static fluid (no flow), and physiologically relevant flow conditions and compare the results to uncoated PDMS controls. PEG, SBSi, and PEG-SBSi coatings maintained contact angles below 20 degrees for up to 35 days under ambient conditions. SBSi and PEG-SBSi showed increased stability and hydrophilicity after 7 days under static conditions. They also retained contact angles <=40 degrees for all shear rates after 7 days under flow, demonstrating their potential for long-term stability. The effectiveness of the coatings to resist platelet adhesion was also studied under physiological flow conditions. PEG showed a 69% reduction in adhered platelets, PEG-SBSi a significant 80% reduction, and SBSi a significant 96% reduction compared to uncoated control samples, demonstrating their potential applicability for blood contacting applications. In addition, the presented coatings and their stability under shear may be of interest in other applications including marine coatings, lab on a chip devices, and contact lenses, where it is desirable to reduce surface fouling due to proteins, cells, and other organisms. PMID- 29231739 TI - Phospholipase A2-Induced Degradation and Release from Lipid-Containing Polymersomes. AB - Hybrid vesicles, comprising blends of amphiphilic block copolymers and phospholipids, have attracted significant attention recently because of their unique combination of chemical and physical properties. We report a method to make unilamellar hybrid vesicles with diameters of 100 nm by mixing polybutadiene block-poly(ethylene oxide) and phosphocholine lipids using a combination of solvent inversion and sonication. We show that homogeneous hybrid vesicles are formed when one component is a minor fraction. At compositions with balanced mass fractions, separate populations of similarly sized pure liposomes and hybrid vesicles are indicated. We investigate the release kinetics of calcein encapsulated in the lumen as hybrid large and giant unilamellar vesicles (LUVs and GUVs) of different compositions are exposed to phospholipase A2 (PLA2). PLA2 hydrolyzes lipids, which leads to dissolution of lipid domains and provides a trigger for the release of calcein as pores are formed. We demonstrate that depending on the polymer mole fraction, block copolymers can either protect or boost the rate of lipid degradation and thereby the release rate from nanoscale hybrid vesicles. Strong indications of lipid phase separation into nanoscale domains in LUVs are observed. Most importantly, hybrid GUV with lipids in the fluid phase release calcein slowly as lipids in the liquid-disordered phase do not phase-separate, but they show the fastest release of all blends as LUVs. This indicates phase separation on the nanoscale in contrast to on the microscale, but it also indicates retained high mobility of lipids between the nanoscale domains, which is absent for lipids in the gel phase. Our results demonstrate several ways in which nanoscale hybrid vesicles can and should be optimized for PLA2-triggered release of water-soluble compounds. PMID- 29231738 TI - Affinity Purification and Single-Molecule Analysis of Integral Membrane Proteins from Crude Cell-Membrane Preparations. AB - The function of integral membrane proteins is critically dependent on their naturally surrounding lipid membrane. Detergent-solubilized and purified membrane proteins are therefore often reconstituted into cell-membrane mimics and analyzed for their function with single-molecule microscopy. Expansion of this approach toward a broad range of pharmaceutically interesting drug targets and biomarkers however remains hampered by the fact that these proteins have low expression levels, and that detergent solubilization and reconstitution often cause protein conformational changes and loss of membrane-specific cofactors, which may impair protein function. To overcome this limitation, we here demonstrate how antibody modified nanoparticles can be used to achieve affinity purification and enrichment of selected integral membrane proteins directly from cell membrane preparations. Nanoparticles were first bound to the ectodomain of beta-secretase 1 (BACE1) contained in cell-derived membrane vesicles. In a subsequent step, these were merged into a continuous supported membrane in a microfluidic channel. Through the extended nanoparticle tag, a weak (~fN) hydrodynamic force could be applied, inducing directed in-membrane movement of targeted BACE1 exclusively. This enabled selective thousand-fold enrichment of the targeted membrane protein while preserving a natural lipid environment. In addition, nanoparticle-targeting also enabled simultaneous tracking analysis of each individual manipulated protein, revealing how their mobility changed when moved from one lipid environment to another. We therefore believe this approach will be particularly useful for separation in-line with single-molecule analysis, eventually opening up for membrane-protein sorting devices analogous to fluorescence-activated cell sorting. PMID- 29231740 TI - Conserved Activity of Reassociated Homotetrameric Protein Subunits Released from Mesoporous Silica Nanoparticles. AB - Mesoporous silica nanoparticles (MSN) with enlarged pores were prepared and characterized, and reversibly dissociated subunits of concanavalin A were entrapped in the mesopores, as shown by multiple biochemical and material characterizations. When loaded in the MSN, we demonstrated protein stability from proteases and, upon release, the subunits reassociated into active proteins shown through mannose binding and o-phthalaldehyde fluorescence. We have demonstrated a versatile and facile method to load homomeric proteins into MSN with potential applications in enhancing the delivery of large therapeutic proteins. PMID- 29231741 TI - Catalytic Enantioselective Tautomerization of Metastable Enamines. AB - The first example of catalytic enantioselective tautomerization of structurally labile but isolable enamines for accessing their chiral imine-tautomers is described. Kinetically stable enamine-based dibenzo[b,d]azepines were tautomerized by a simple chiral BINOL-phosphoric acid, providing a variety of seven-membered imine products bearing both central and axial stereogenic elements in good yields (up to 96%) with excellent enantio- and diastereoselectivities (up to 97% ee, >20:1 dr). PMID- 29231742 TI - Interactions and Supramolecular Organization of Sulfonated Indigo and Thioindigo Dyes in Layered Hydroxide Hosts. AB - Supramolecularly organized host-guest systems have been synthesized by intercalating water-soluble forms of indigo (indigo carmine, IC) and thioindigo (thioindigo-5,5'-disulfonate, TIS) in zinc-aluminum-layered double hydroxides (LDHs) and zinc-layered hydroxide salts (LHSs) by coprecipitation routes. The colors of the isolated powders were dark blue for hybrids containing only IC, purplish blue or dark lilac for cointercalated samples containing both dyes, and ruby/wine for hybrids containing only TIS. The as-synthesized and thermally treated materials were characterized by Fourier transform infrared, Fourier transform Raman, and nuclear magnetic resonance spectroscopies, powder X-ray diffraction, scanning electron microscopy, and elemental and thermogravimetric analyses. The basal spacings found for IC-LDH, TIS-LDH, IC-LHS, and TIS-LHS materials were 21.9, 21.05, 18.95, and 21.00 A, respectively, with intermediate spacings being observed for the cointercalated samples that either decreased (LDHs) or increased (LHSs) with increasing TIS content. UV-visible and fluorescence spectroscopies (steady-state and time-resolved) were used to probe the molecular distribution of the immobilized dyes. The presence of aggregates together with the monomer units is suggested for IC-LDH, whereas for TIS-LDH, IC LHS, and TIS-LHS, the dyes are closer to the isolated situation. Accordingly, while emission from the powder H2TIS is strongly quenched, an increment in the emission of about 1 order of magnitude was observed for the TIS-LDH/LHS hybrids. Double-exponential fluorescence decays were obtained and associated with two monomer species interacting differently with cointercalated water molecules. The incorporation of both TIS and IC in the LDH and LHS hosts leads to an almost complete quenching of the fluorescence, pointing to a very efficient energy transfer process from (fluorescent) TIS to (nonfluorescent) IC. PMID- 29231743 TI - Layered Halide Double Perovskites Cs3+nM(II)nSb2X9+3n (M = Sn, Ge) for Photovoltaic Applications. AB - Over the past few years, the development of lead-free and stable perovskite absorbers with excellent performance has attracted extensive attention. Much effort has been devoted to screening and synthesizing this type of solar cell absorbers. Here, we present a general design strategy for designing the layered halide double perovskites Cs3+nM(II)nSb2X9+3n (M = Sn, Ge) with desired photovoltaic-relevant properties by inserting [MX6] octahedral layers, based on the principles of increased electronic dimensionality. Compared to Cs3Sb2I9, more suitable band gaps, smaller carrier effective masses, larger dielectric constants, lower exciton binding energies, and higher optical absorption can be achieved by inserting variable [SnI6] or [GeI6] octahedral layers into the [Sb2I9] bilayers. Moreover, our results show that adjusting the thickness of inserted octahedral layers is an effective approach to tune the band gaps and carrier effective masses in a large range. Our work provides useful guidance for designing the promising layered antimony halide double perovskite absorbers for photovoltaic applications. PMID- 29231744 TI - Microfluidic Generation of Particle-Stabilized Water-in-Water Emulsions. AB - Herein, we present a microfluidic platform that generates particle-stabilized water-in-water emulsions. The water-in-water system that we use is based on an aqueous two-phase system of polyethylene glycol (PEG) and dextran (DEX). DEX droplets are formed passively, in the continuous phase of PEG and carboxylated particle suspension at a flow-focusing junction inside a microfluidic device. As DEX droplets travel downstream inside the microchannel, carboxylated particles that are in the continuous phase partition to the interface of the DEX droplets due to their affinity to the interface of PEG and DEX. As the DEX droplets become covered with carboxylated particles, they become stabilized against coalescence. We study the coverage and stability of the emulsions, while tuning the concentration and the size of the carboxylated particles, downstream inside the reservoir of the microfluidic device. These particle-stabilized water-in-water emulsions showcase good particle adsorption under shear, while being flowed through narrow microchannels. The intrinsic biocompatibility advantages of particle-stabilized water-in-water emulsions make them a good alternative to traditional particle-stabilized water-in-oil emulsions. To illustrate a biotechnological application of this platform, we show a proof-of-principle of cell encapsulation using this system, which with further development may be used for immunoisolation of cells for transplantation purposes. PMID- 29231745 TI - Persistence of social jetlag and sleep disruption in healthy young adults. AB - Sleep disruption has been associated with increased risks for several major chronic diseases that develop over decades. Differences in sleep/wake timing between work and free days can result in the development of social jetlag (SJL), a chronic misalignment between a person's preferred sleep/wake schedule and sleep/wake timing imposed by his/her work schedule. Only a few studies have examined the persistence of SJL or sleep disruption over time. This prospective investigation examined SJL and sleep characteristics over a 2-year period to evaluate whether SJL or poor sleep were chronic conditions during the study period. SJL and sleep measures (total sleep time [TST], sleep onset latency [SOL], wake after sleep onset [WASO]), and sleep efficiency [SE]), were derived from armband monitoring among 390 healthy men and women 21-35 years old. Participants wore the armband for periods of 4-10 days at 6-month intervals during the follow-up period (N = 1431 repeated observations). The consistency of SJL or sleep disruption over time was analyzed using generalized linear mixed models (GLMMs) for repeated measures. Repeated measures latent class analysis (RMLCA) was then used to identify subgroups among the study participants with different sleep trajectories over time. Individuals in each latent group were compared using GLMMs to identify personal characteristics that differed among the latent groups. Minor changes in mean SJL, chronotype, or TST were observed over time, whereas no statistically significant changes in SOL, WASO, or SE were observed during the study period. The RMLCA identified two groups of SJL that remained consistent throughout the study (low SJL, mean +/- SE: 0.4 +/- 0.04 h, 42% of the study population; and high SJL, 1.4 +/- 0.03 h, 58%). Those in the SJL group with higher values tended to be employed and have an evening chronotype. Similarly, two distinct subgroups were observed for SOL, WASO, and SE; one group with a pattern suggesting disrupted sleep over time, and another with a consistently normal sleep pattern. Analyses of TST identified three latent groups with relatively short (5.6 +/- 1.0 h, 21%), intermediate (6.5 +/- 1.0 h, 44%), and long (7.3 +/- 1.0 h, 36%) sleep durations, all with temporally stable, linear trajectories. The results from this study suggest that sleep disturbances among young adults can persist over a 2 year period. Latent groups with poor sleep tended to be male, African American, lower income, and have an evening chronotype relative to those with more normal sleep characteristics. Characterizing the persistence of sleep disruption over time and its contributing factors could be important for understanding the role of poor sleep as a chronic disease risk factor. PMID- 29231746 TI - Is there a role for charcoal in palliative diarrhea management? AB - OBJECTIVE: Symptomatic therapy is an intervention centered entirely on symptom management and pain relief. The utilization of charcoal in diarrhea management is a pertinent example of this type of medical care. Diarrhea is an ailment defined as an escalation in the frequency of bowel movements, unformed stool, abdominal discomfort, and pain. These symptoms can be extremely debilitating for patients, and effectuate frustration as well as severely dampening mood and overall well being. This narrative review aims to explore the use of charcoal in diarrhea management and its possible benefits in alleviating discomfort associated with these symptoms. METHODS: The authors used PubMed, MEDLINE, and Google Scholar searches on recent literature available on the role of activated charcoal in diarrhea management. RESULTS: It was found that the main precursors of diarrhea include drugs and bacterial infection. Activated charcoal has a firm history in its ability to attract and expel ingested toxins from the gastrointestinal tract. It acts to prevent system absorption of these adverse entities, adsorbing them on the surface of its particles, making it a suitable diarrheal treatment. CONCLUSIONS: Diarrhea can present itself alongside a multitude of treatments and conditions, such as chemotherapy, primary malignancy, intestinal, colorectal and pancreatic cancer, bacterial infection, and irritable bowel syndrome, making activated charcoal a potential therapy in these conditions. In comparison, with other common anti-diarrheal treatments, activated charcoal has exceptionally few side-effects. Overall, further research is necessary in order to wholly determine the effectiveness of charcoal in the management of diarrhea. PMID- 29231748 TI - Relationship between patient copayments in Medicare Part D and vaccination claim status for herpes zoster and tetanus-diphtheria-acellular pertussis. AB - OBJECTIVE: To assess the relationship between copay amount and vaccination claim submission status for tetanus-diphtheria-acellular pertussis (Tdap) and herpes zoster (GSK study identifier: HO-14-14319). METHODS: Retrospective analyses were performed using vaccination administrative claims data in patients aged >=65 years with >=1 claim for Tdap or zoster vaccines between 2012 and 2014. To avoid confounding by other financial responsibility, analyses were conducted among patients in the copayment phase of insurance. The impact of patient copay amount on vaccination claim status ("canceled" vs. "paid") was evaluated by logistic regression separately for Tdap and zoster, adjusting for patient and provider characteristics. RESULTS: A total of 81,027 (39.2% with canceled claims) and 346,417 patients (56.8% with canceled claims) were included in the Tdap and zoster analyses, respectively. Mean (standard deviation) copay for canceled vs. paid claims was $37.2 (18.4) vs. $31.1 (20.1) for Tdap and $64.9 (36.9) vs. $53.5 (38.8) for zoster. The adjusted odds ratios (ORs) for a canceled Tdap vaccine claim, compared with $0 copay, were 1.19 ($1-25 copay), 1.76 ($26-50 copay), 2.42 ($51-75 copay) and 2.40 ($76-100 copay), all p < .001. The adjusted ORs for a canceled zoster vaccine claim, compared with $0 copay, were 1.02 ($1-25), 1.39 ($26-50), 1.66 ($51-75), 2.07 ($76-100) and 2.71 (>$100), all p < .001 except for $1-25 (p = .172). CONCLUSIONS: High patient copay is a barrier to Tdap and zoster vaccinations in Medicare Part D patients. Providing vaccines at low or no copay may improve vaccination rates in these adults. GSK study identifier: HO-14-14319. PMID- 29231747 TI - Practice patterns to improve pre and post-transplant medication adherence in heart transplant centres: a secondary data analysis of the international BRIGHT study. AB - BACKGROUND: As medication non-adherence is a major risk factor for poor post transplant outcomes, we explored how adherence is assessed, enhanced and integrated across the transplant continuum. AIM: The aim of this study was to study practice patterns regarding pre- and post-transplant medication adherence assessment and interventions in international heart transplant centres. METHODS: We used data from the Building Research Initiative Group: chronic illness management and adherence in heart transplantation (BRIGHT) study, a cross sectional study conducted in 36 heart transplant centres in 11 countries. On a 27 item questionnaire, 100 clinicians (range one to five per centre) reported their practice patterns regarding adherence assessment and intervention strategies pre transplant, immediately post-transplant, less than one year, and one or more year post-transplant. Educational/cognitive, counselling/behavioural and psychosocial/affective strategies were assessed. Clinicians' responses (intervention present vs. absent; or incongruence in reporting intervention) were aggregated at the centre level. RESULTS: The adherence assessment method most commonly used along the transplant continuum was questioning patients (range 75 88.9%). Pre-transplant, all three categories of intervention strategy were applied. Providing reading materials (82.9%) or instructions (68.6%), involving family or support persons in education (91.4%), and establishing partnership (91.4%) were used most frequently. Post-transplant, strategies closely resembled those employed pre-transplant. Training patients (during recovery) and cueing were more often applied during hospitalisation (74.3%). After the first year post transplant, except for motivational interviewing (25.7-28.6%), the number of strategies decreased. CONCLUSIONS: Across the transplant continuum, diverse adherence interventions are implemented; however, post-transplant, the frequency of adherence interventions decreases. Therefore, increased investment is necessary in long-term adherence interventions. PMID- 29231749 TI - Individual differences in chronotypes associated with academic performance among Chilean University students. AB - A chronotype is an individual trait that determines circadian rhythm (dark/light cycle) characteristics, associated with bedtime, waking, and other daily activities. A chronotype is classified as morning, intermediate, and evening. The objective is to associate chronotypes with academic performance in university students. A cross-sectional study was performed to evaluate the chronotype of university students (n = 703) by Horne-Ostberg questionnaire and associated with academic performance. The group with higher GPAs had higher chronotype scores (p = 0.002). Morning and intermediate chronotypes exhibited better academic performance; however, more studies are necessary to determine the underlying causes, which could influence cognitive aspects. PMID- 29231750 TI - Concordance with prescribing information dosage recommendations for dipeptidyl peptidase-4 inhibitors among type 2 diabetes mellitus patients with moderate to severe chronic kidney disease. AB - OBJECTIVE: To estimate the proportion of patients with moderate to severe chronic kidney disease (CKD) whose initial dipeptidyl-peptidase-4 inhibitor (DPP4-i) dosage was concordant with prescribing information (label) recommendations in the United States. METHODS: Adult patients with type 2 diabetes mellitus (T2DM) who initiated a DPP4-i (linagliptin, sitagliptin, saxagliptin) between 1 January 2011 and 30 June 2014 were identified using electronic medical records and administrative claims, with index date being the date of first observed DPP4-i treatment. Patients were required to have chronic kidney disease (CKD) stage 3b, 4 or 5 (estimated Glomerular Filtration Rate [eGFR] value <45 ml/min/1.73 m2) during the 12 month pre-index period. Patients were classified as concordant or not concordant based on whether the first prescribed dose was consistent with label recommendations. Demographics, clinical characteristics, resource use and costs during pre-index were evaluated by DPP4-i concordance status. RESULTS: Of the 492 patients (323 sitagliptin, 57 saxagliptin, 112 linagliptin), 36.2% were prescribed doses that were not concordant with label recommendations (44.9% for sitagliptin, 57.9% for saxagliptin and 0% for linagliptin [which does not require dosage adjustment]). Concordant patients were slightly older (mean age 71 years vs. 68, p = .01) but had similar gender distribution (55% vs. 60% female, p = .31) compared to those who were not concordant. They had lower general health status (Charlson Comorbidity Score 2.6 vs. 2.2, p = .03), and had similar pre index all-cause total costs ($25,245 vs. $21,972, p = .68) and lower pre-index T2DM-related costs ($1618 vs. $1922, p = .05). CONCLUSIONS: More than a third of DPP4-i patients with CKD stage 3b or higher were prescribed doses not concordant with DPP4-i label dosage recommendations. PMID- 29231751 TI - Activation studies of the alpha- and beta-carbonic anhydrases from the pathogenic bacterium Vibrio cholerae with amines and amino acids. AB - The alpha- and beta-class carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic bacterium Vibrio cholerae, VchCAalpha, and VchCAbeta, were investigated for their activation with natural and non-natural amino acids and amines. The most effective VchCAalpha activators were L-tyrosine, histamine, serotonin, and 4-aminoethyl-morpholine, which had KAs in the range of 8.21-12.0 uM. The most effective VchCAbeta activators were D-tyrosine, dopamine, serotonin, 2-pyridyl-methylamine, 2-aminoethylpyridine, and 2-aminoethylpiperazine, which had KAs in the submicromolar - low micromolar range (0.18-1.37 uM). The two bacterial enzymes had very different activation profiles with these compounds, between each other, and in comparison to the human isoforms hCA I and II. Some amines were selective activators of VchCAbeta, including 2-pyridylmethylamine (KA of 180 nm for VchCAbeta, and more than 20 uM for VchCAalpha and hCA I/II). The activation of CAs from bacteria, such as VchCAalpha/beta has not been considered previously for possible biomedical applications. It would be of interest to study in more detail the extent that CA activators are implicated in the virulence and colonisation of the host by such pathogenic bacteria, which for Vibrio cholerae, is highly dependent on the bicarbonate concentration and pH in the surrounding tissue. PMID- 29231754 TI - Re: Editorial by Professors Brodbelt and Flint. PMID- 29231753 TI - Rates of insufficiency and deficiency of vitamin D levels in elite professional male and female skiers: A chronobiologic approach. AB - Vitamin D is essential for the maintenance and promotion of musculoskeletal health, for the functioning of the immune, cardiovascular and reproductive systems, and its main action is to keep calcium and phosphate plasmatic physiological concentrations at intestinal, renal and bony level. Vitamin D affects several parameters related to physical performance too and a particularly high percentage of vitamin D insufficiency and deficiency in professional athletes has been observed. Several variables are able to impair the synthesis of 25(OH)D in athletes, specifically both genetic and environmental factors, but the most probable explanation for the deficient/insufficient vitamin D levels is the insufficient ultraviolet B light (UVB) exposure during winter. To confirm this, the existence of a circannual rhythm of vitamin D in professional soccer players, highlighting a peak in summer and lowest values in winter regardless the period of the season, has been documented. Nonetheless, from what we are aware of, no other study adopted a chronobiologic approach to better understand and describe the circannual variations of serum 25(OH)D in other sport disciplines. Therefore, we studied serum vitamin D in a cohort of top-level professional skiers, during a period of three consecutive competitive seasons (2015, 2016 and 2017), in order to evaluate, with a rhythmometric approach, the vitamin D behavior along the year. The study population was composed by 152 professional Italian alpine skiers of FISI (Winter Sport Italian Federation), 63 females and 89 males (mean age: 24.1 +/- 3.2 years) and a total of 298 blood drawings were carried out to determine plasma 25(OH)D. Vitamin D data were compared between genders and then processed with the population mean cosinor tests to evaluate the presence of a circannual rhythm, both for female and male athletes. In total, 77 skiers (50.7%) showed, at least once during the three competitive seasons, an insufficient level of 25(OH)D and other 45 subjects (29.6%) showed a deficient status; no differences were observed between genders (mean for females: 26.9 +/- 8.1 ng/mL; mean for males: 27.4 +/- 7.6 ng/mL). In addition, the rhythmometric analysis highlighted the existence of a significant circannual rhythm for both female and male professional skiers; the acrophases (Phi) occurred in July and both MESOR (M) and amplitude (A) were comparable between the two groups. Our data indicate that, despite the physical effort spent, vitamin D follows a classical season associated rhythm with a peak in summer and a nadir in winter. Moreover, the percentage of insufficiency and deficiency is in line with that of the general population. In conclusion, our findings reinforce the hypothesis that there is no direct effect of physical activity on vitamin D metabolism and that the factors involved in the determination of vitamin D levels in the general population are valid also for athletes. PMID- 29231752 TI - Differences between Slovak and Dutch patients scheduled for coronary artery bypass graft surgery regarding clinical and psychosocial predictors of physical and mental health-related quality of life. AB - BACKGROUND: Differences in health-related quality of life in coronary artery disease patients and associated factors between patients of central and western European descent are rarely investigated. We aim to test differences between Dutch and Slovak health-related quality of life, whether nationality predicted health-related quality of life and if standardised beta weights of health-related quality of life determinants differ across countries. DESIGN: An observational multicentre study at university cardiac centres in the Netherlands and Slovakia. METHODS: In 226 coronary artery disease patients, health-related quality of life was measured by the Short Form Health Survey 36, anxiety and depression were measured using the Hospital Anxiety and Depression Scale, and type D personality was assessed with the 14-item Type D Scale. Multivariate analysis was used to explore the effect of patient characteristics on the physical and mental component summaries. Estimates of each predictor's beta value of the physical and mental component summaries in the Slovak and Dutch patient sample were separately calculated using the Cummings criterion for comparison of two independent betas. RESULTS: Stronger predictors of physical health-related quality of life in Slovak patients were educational level, current smoking, poor functional status, history of diabetes and amount of social support. In Dutch patients, only more symptoms of depression was a stronger predictor ( P<0.05). Regarding Slovak mental health related quality of life, stronger predictors were educational level, current smoking and amount of social support. Female gender, history of myocardial infarction and more symptoms of depression were stronger predictors in Dutch patients ( P<0.05). CONCLUSION: Descent and differences between both populations in determinants of health-related quality of life should be considered while planning care, follow-up, health education and rehabilitation. PMID- 29231755 TI - Pharmaceutical aspects of silver nanoparticles. AB - Silver nanoparticles are particles in the size ranging between 1 and 100 nm. The two major methods used for synthesis of silver nanoparticle are the physical and chemical methods with the disadvantage that they are expensive and can also have toxicity. Biological method is being used as an expedient alternative, as this approach is environment-friendly and less toxic and it includes plant extracts, microorganism, fungi, etc. The major applications of silver nanoparticles in the medical field include diagnostic applications and therapeutic applications, apart from its antimicrobial activity. Due to their nanotoxicity, AgNPs have a several drawbacks too. This review presents a complete view of the mechanism of action, synthesis, the pharmacokinetics of silver nanoparticles, different formulations of AgNPs used in biomedical applications, infertility management, antibacterial effects, skin damage, burns, cancer treatment, etc. and various applications of silver nanoparticles together with the possible toxicological challenge. PMID- 29231756 TI - Higher levels of circulating TIMP-4 in preeclampsia is strongly associated with clinical parameters and microRNA. AB - BACKGROUND: Preeclampsia results in maternal and fetal complications and some studies have reported the role of MMPs and TIMPs in its pathophysiology. Therefore, the aim of this study was to compare plasma TIMP-4 levels in preeclampsia and healthy pregnant; and to correlate these levels with clinical parameters and expression of Let7a-5p (3'UTR post-transcriptionally regulation) Methods: TIMP-4 was measured by ELISA and miR-Let7a-5p expression by qPCR. RESULTS: Elevated plasma TIMP-4 levels in preeclampsia compared to healthy pregnant was found 1450 +/- 411 vs. 775 +/- 210 pg/mL, respectively (p < 0.0001); these levels are correlated positively with serum liver enzymes (ALT, r = 0.84, p = 0.004; and AST, r = 0.51, p = 0.02); and negatively with newborn weight (r = 0.45, p = 0.04) in preeclampsia. Regarding Let7a-5p a negative but not significant correlation was found (r = -0.39, p = 0.06, including both healthy and preeclampsia). CONCLUSIONS: Preeclampsia present elevated levels of circulating TIMP-4 compared to healthy pregnant and these levels are correlated with clinical parameters of disease. PMID- 29231757 TI - Structured Protocol for Benign Biliary Anastomotic Strictures: Impact on Long Term Clinical Effectiveness. AB - OBJECTIVE: The purpose of this study is to compare long-term clinical effectiveness before and after implementation of a structured protocol for percutaneous drainage of benign anastomotic biliary strictures. MATERIALS AND METHODS: Three hundred five adult patients undergoing percutaneous biliary drainage for biliary anastomotic strictures between 1994 and 2015 were identified using Current Procedural Terminology billing codes, with 234 undergoing intervention before implementation of a structured protocol and 71 undergoing intervention after implementation of the protocol. The frequency of surgical anastomotic revision was compared between patients treated before and after the implementation of the structured protocol. Patient characteristics and treatment variables were also analyzed with respect to the frequency of surgical revision. A Kaplan-Meier analysis was performed to determine the long-term probabilities of avoiding surgical revision and patency rates. RESULTS: Overall, 72.8% of patients avoided surgical revision, with 71.1% before and 81.7% after the protocol was implemented (p = 0.1052). A larger maximum drain size was significantly associated with a lower frequency of surgical revision (p = 0.0006). The rates of surgical avoidance 5 years after treatment before and after protocol implementation were 69.1% and 80.8%, respectively. Patency rates 5 years after treatment before and after protocol implementation were 73.8% and 76.8%, respectively. CONCLUSION: Percutaneous drainage and management of benign biliary anastomotic strictures is an effective treatment regardless of the presence of a structured protocol. Although there was no significant benefit in terms of avoidance of surgical revision, the time until surgical revision and patency rates were increased with the protocol. In addition, a larger maximum drain size was associated with a better outcome. PMID- 29231758 TI - Dose Reduction With Dedicated CT Metal Artifact Reduction Algorithm: CT Phantom Study. AB - OBJECTIVE: The objective of this study was to compare reader accuracy detecting lesions near hardware in a CT phantom model at different radiation exposures using an advanced metal artifact reduction (MAR) algorithm and standard filtered back projection (FBP) techniques and to determine if radiation exposure could be decreased using MAR without compromising lesion detectability. MATERIALS AND METHODS: A CT phantom manufactured with spherical lesions of various sizes (10-20 mm) and attenuations (20-50 HU) embedded around cobalt-chromium spheres attached to titanium rods, simulating an arthroplasty, was scanned on a single CT scanner (FLASH, Siemens Healthcare) at 140 kVp and 0.6-mm collimation using clinical-dose (300 Quality Reference mAs [Siemens Healthcare]), low-dose (150 Quality Reference mAs), and high-dose (600 Quality Reference mAs) protocols. Images reconstructed with iterative MAR, advanced modeled iterative reconstruction (ADMIRE), and FBP with identical parameters were anonymized and independently reviewed by three radiologists. Accuracies for detecting lesions, measured as AUC, sensitivity, and specificity, were compared. RESULTS: Accuracy using MAR was significantly higher than that using FBP at all exposures (p values ranged from < 0.001 to 0.021). Sensitivity was also higher for MAR than for FBP at all exposures. Specificity was very high for both reconstruction techniques at all exposures with no significant differences. Accuracy of low-dose MAR was higher than and not inferior to standard-dose and high-dose FBP. MAR was significantly more sensitive than FBP in detecting smaller lesions (p = 0.021) and lesions near high streak artifact (p < 0.001). CONCLUSION: MAR improves reader accuracy to detect lesions near hardware and allows significant reductions in radiation exposure without compromising accuracy compared with FBP in a CT phantom model. PMID- 29231759 TI - Screening for Lung Cancer: Incidental Pulmonary Parenchymal Findings. AB - OBJECTIVE: Incidental pulmonary findings are commonly detected at lung cancer screening chest CT. Though most of these findings are clinically insignificant, it is difficult to prospectively determine which are potentially important to clinical care. The purpose of this review is to discuss the incidental pulmonary findings commonly detected at lung cancer screening chest CT. CONCLUSION: Incidental pulmonary findings most commonly fall into one of three categories: interstitial lung disease, emphysema, and airways disease (both small and large airways). PMID- 29231760 TI - The Impact of Dose Reduction in Quantitative Kinematic CT of Ankle Joints Using a Full Model-Based Iterative Reconstruction Algorithm: A Cadaveric Study. AB - OBJECTIVE: The objective of our study was to evaluate the quality and reproducibility of semiautomatic measurements of the ankle in low-dose kinematic CT studies using a full model-based iterative reconstruction (MBIR). MATERIALS AND METHODS: Kinematic CT was performed in five cadaveric ankles at three acquisition dose levels: standard dose (1020 mGy * cm), low dose (10% of the standard dose), and ultra-low-dose (1.5% of the standard dose). All images were reconstructed using a full MBIR algorithm. Two semiautomatic measurements (one distance and one angle) were performed by two readers. Registration error was evaluated. The bone aspect on CT and presence of metallic implants were considered in the analysis. The influence of dose on the measurements obtained, reproducibility, and image quality was assessed. RESULTS: With the standard- and low-dose protocols, registration quality was good (registration error, 0.65 4.72%), measurements were similar (p = 0.9), and reproducibility was excellent (intraclass correlation coefficient [ICC] = 0.881). With the ultra-low-dose protocol, the registration quality was poor, yielding measurements significantly different from the other protocols (p < 0.001) and poor reproducibility (ICC = 0.39). In a specimen with normal bone and no metal implant, the registration error was low (0.61-1.01%), measurements were similar (p > 0.5), and reproducibility was excellent (ICC, 0.885-0.996) for the three dose levels tested. CONCLUSION: Full MBIR allows reliable and reproducible measurements in ankle kinematic CT with a low-dose protocol, but an ultra-low-dose protocol may lead to unreliable results. PMID- 29231761 TI - A rapid method to identify Salmonella enterica serovar Gallinarum biovar Pullorum using a specific target gene ipaJ. AB - Salmonella enterica serovar Gallinarum biovar Pullorum (S. Pullorum) is the pathogen of pullorum disease, which leads to severe economic losses in many developing countries. Traditional methods to identify S. enterica have relied on biochemical reactions and serotyping, which are time-consuming with accurate identification if properly carried out. In this study, we developed a rapid polymerase chain reaction (PCR) method targeting the specific gene ipaJ to detect S. Pullorum. Among the 650 S. Pullorum strains isolated from 1962 to 2016 all over China, 644 strains were identified to harbour ipaJ gene in the plasmid pSPI12, accounting for a detection rate of 99.08%. Six strains were ipaJ negative because pSPI12 was not found in these strains according to whole genome sequencing results. There was no cross-reaction with other Salmonella serotypes, including Salmonella enterica serovar Gallinarum biovar Gallinarum (S. Gallinarum), which show a close genetic relationship with S. Pullorum. This shows that the PCR method could distinguish S. Gallinarum from S. Pullorum in one-step PCR without complicated biochemical identification. The limit of detection of this PCR method was as low as 90 fg/MUl or 102 CFU, which shows a high sensitivity. Moreover, this method was applied to identify Salmonella isolated from the chicken farm and the results were consistent with what we obtained from biochemical reactions and serotyping. Together, all the results demonstrated that this one-step PCR method is simple and feasible to efficiently identify S. Pullorum. PMID- 29231762 TI - Haemolytic anaemia and hepatocitolysis associated with hypermagnesaemia by repeated exposures to copper-calcium fungicides. AB - For the medical practice, our manuscript acts as a signal, despite only presenting three cases which feature the association between hepatocytolysis, haemolysis and hypermagnesaemia. This clinical-biologic triad was highlighted with the workers who through the nature of their profession were exposing themselves periodically to vapours which contained copper sulphate neutralised with calcium hydroxide, a fungicide used for fruit trees. We are exclusively assessing the haematological perturbation. In this aetiological context, the generating mechanism for haemolysis is very probable biochemical, where hypercupraemia interferes with cellular antioxidant defence mechanisms. Hypothetically, the role of the redox homeostasis disorder in the intravascular destruction of erythrocytes is sustained, and particularly the coexistence of cell cytolysis in the medullary erythroid compartment, which can be assimilated with a possible ineffective erythropoiesis. PMID- 29231764 TI - Relevance of chronotype for eating patterns in adolescents. AB - During adolescence, a shift from morningness to eveningness occurs, yet school continues to start early in the morning. Hence, adolescents are at risk for social jetlag, i.e. a discrepancy between biological and social timing. It remains to be determined whether chronotype associates with daily and daytime specific eating patterns during this potentially critical period. Therefore, the aim of the present study was to investigate whether chronotype is decisive for daily eating patterns [total energy intake (TEI, kcal), total macronutrient intake (% of TEI), eating occasion frequency (n/day), meal frequency (n/day), snack frequency (n/day), duration of nightly fasting], or daytime-specific eating patterns [morning (before 11 am) energy intake (% of TEI), morning macronutrient intake (% of morning energy intake), regular breakfast skipping (no morning energy intake at least on 2 of 3 days, yes/no), evening (after 6 pm) energy intake (% of TEI), evening macronutrient intake (% of evening energy intake), regular dinner skipping (no evening energy intake at least on 2 of 3 days, yes/no)] in German adolescents. Chronotype was assessed by use of the Munich Chronotype Questionnaire and is defined as the midpoint of sleep corrected for sleep-debt accumulated over the workweek (the later the midpoint of sleep, the later the chronotype). A total of 223 participants (10-18 years) provided 346 questionnaires and concurrent 3-day weighed dietary records. Associations between chronotype and eating patterns were analyzed cross-sectionally using multivariable linear and logistic mixed-effects regression models. Adolescents with earlier and later chronotypes did not differ in their daily eating patterns. With respect to daytime-specific eating patterns, 1 h delay in chronotype was associated with 4.0 (95% CI 2.5-6.6) greater odds of regular breakfast skipping (p < 0.0001). In addition, later chronotype was associated with higher evening energy intake (p = 0.0009). In conclusion, our data show that a later chronotype among adolescents is associated with a shift of food consumption toward later times of the day. Hence, adolescents' eating patterns appear to follow their internal clock rather than socially determined schedules. PMID- 29231763 TI - Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study. AB - Background Clinical observations and results from recent studies support the use of non-invasive vagus nerve stimulation (nVNS) for treating cluster headache (CH) attacks. This study compared nVNS with a sham device for acute treatment in patients with episodic or chronic CH (eCH, cCH). Methods After completing a 1 week run-in period, subjects were randomly assigned (1:1) to receive nVNS or sham therapy during a 2-week double-blind period. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 minutes after treatment initiation, without rescue treatment. Results The Full Analysis Set comprised 48 nVNS-treated (14 eCH, 34 cCH) and 44 sham-treated (13 eCH, 31 cCH) subjects. For the primary endpoint, nVNS (14%) and sham (12%) treatments were not significantly different for the total cohort. In the eCH subgroup, nVNS (48%) was superior to sham (6%; p < 0.01). No significant differences between nVNS (5%) and sham (13%) were seen in the cCH subgroup. Conclusions Combing both eCH and cCH patients, nVNS was no different to sham. For the treatment of CH attacks, nVNS was superior to sham therapy in eCH but not in cCH. These results confirm and extend previous findings regarding the efficacy, safety, and tolerability of nVNS for the acute treatment of eCH. PMID- 29231765 TI - Imaging corticotropin-releasing-factor and nociceptin in addiction and PTSD models. AB - Addiction is composed of three phases: intoxication, withdrawal, and craving. Negative reinforcement, strengthening a behaviour by removing an aversive stimulus, has been associated with the withdrawal phase. An imbalance of neurotransmitters within the brain's stress (nociceptin, neuropeptide Y) and anti stress (CRF, norepinephrine, etc.) system is attributed to negatively reinforced compulsive behaviours associated with relapse. Similarly, post-traumatic stress disorder is characterized by an overactive stress system. In a PTSD mouse model, rodents exhibited impaired cued-fear memory consolidation when nociceptin transmission was blocked. Furthermore, a single-nucleotide polymorphism has been identified between women diagnosed with PTSD and the severity of PTSD symptoms, suggesting a genetic basis. Therefore, it is critical to understand the functions and interactions between the brain's stress and anti-stress neurotransmitters, specifically nociceptin. This paper will examine the hypothalamic-pituitary adrenocortical axis, evaluate the functions of corticotropin-releasing-factor and nociceptin, discuss nociceptin's role as an anxiolytic or anxiogenic, and discuss PET-imaging studies-all of which targeted nociceptin receptors (NOP-R). Finally, the discussion of pharmacological interventions will be proposed as preventative or therapeutic treatments for those suffering from PTSD and substance-use disorders. PMID- 29231766 TI - Corrigendum. PMID- 29231767 TI - High-Altitude-Induced alterations in Gut-Immune Axis: A review. AB - High-altitude sojourn above 8000 ft is increasing day by day either for pilgrimage, mountaineering, holidaying or for strategic reasons. In India, soldiers are deployed to these high mountains for their duty or pilgrims visit to the holy places, which are located at very high altitude. A large population also resides permanently in high altitude regions. Every year thousands of pilgrims visit Holy cave of Shri Amarnath ji, which is above 15 000 ft. The poor acclimatization to high altitude may cause alteration in immunity. The low oxygen partial pressure may cause alterations in gut microbiota, which may cause changes in gut immunity. Effect of high altitude on gut-associated mucosal system is new area of research. Many studies have been carried out to understand the physiology and immunology behind the high-altitude-induced gut problems. Few interventions have also been discovered to circumvent the problems caused due to high-altitude conditions. In this review, we have discussed the effects of high-altitude induced changes in gut immunity particularly peyer's patches, NK cells and inflammatory cytokines, secretary immunoglobulins and gut microbiota. The published articles from PubMed and Google scholar from year 1975 to 2017 on high altitude hypoxia and gut immunity are cited in this review. PMID- 29231768 TI - Molecular imaging in neuropsychiatry. PMID- 29231769 TI - Liver transplantation beyond or downstaging within the Milan criteria for hepatocellular carcinoma. AB - INTRODUCTION: Unresectable hepatocellular carcinoma (HCC) is a common indication for liver transplantation (LT). The Milan criteria became standard criteria but expansion beyond the Milan criteria (tumor size and number) have resulted in similar post-transplant outcomes, thus suggesting LT is a viable treatment option for HCC presenting beyond the Milan criteria Areas covered: Expanded criteria and the use of downstaging therapies to meet Milan criteria are reviewed. Surrogates of tumor biology (including biomarkers and response to therapy) are described in detail. The controversy regarding treatment of HCV infection prior to transplant for HCC is addressed. Predictors of post-transplant recurrence and therapeutic options are explored. English-language manuscripts pertaining to LT criteria for HCC, downstaging, and tumor prognosis were reviewed. Effort was made to include manuscripts from throughout the world to ensure the reader a broad international perspective. Expert commentary: Patients can be successfully transplanted with HCC beyond Milan criteria, or patients beyond Milan criteria can be downstaged to within Milan criteria and achieve successful post-liver transplant outcomes. The current reliance on tumor burden (size and number) alone ignores the mounting data supporting the prognostic use of additional surrogates of tumor biology in identifying appropriate candidates. PMID- 29231770 TI - Pharmacological and non-pharmacological treatment of obstructive hypertrophic cardiomyopathy. AB - INTRODUCTION: Hypertrophic obstructive cardiomyopathy has been rising in prevalence, due to increased awareness and advanced imaging. For the symptomatic patient, pharmacological management remains an effective approach to the majority of patients with obstructive hypertrophic cardiomyopathy. However, a significant subset fails to improve sufficiently with medical therapy initially, or progressively becomes more symptomatic despite augmented medications over time. Most of the advances in the treatment of obstructive hypertrophic cardiomyopathy have therefore been made in the area of non-pharmacologic management, particularly septal reduction therapy. Both surgical myectomy and alcohol septal ablation have undergone iterative modifications that improve outcomes. Current guidelines support these therapies based on large observational studies, with choice of therapy based on a variety of factors but again based primarily on expert consensus opinion. Areas covered: This article reviews both pharmacological and non-pharmacological interventions to improve outflow tract obstruction and symptoms, and provides an algorithm for addressing the symptomatic obstructive patient. Expert commentary: Current options for hypertrophic cardiomyopathy allow the majority of patients to live their lives with no more than NYHA Class 2 heart failure symptoms. Treatment algorithms can add in identification of patients who may benefit from advanced therapies, and should be instituted routinely to improve care for the majority of patients with symptomatic hypertrophic cardiomyopathy. PMID- 29231771 TI - Spinal metastasis with neurologic deficits. AB - Background and purpose - A significant number of patients with spinal metastases are treated non-surgically, but may need surgical treatment at a later stage due to progression of symptoms. Therefore, we investigated the need for late surgical decompression in patients with spinal metastasis who were initially deemed as non surgical candidates, as well as the outcome of late surgery. Patients and methods - 116 patients who were referred to the orthopedic oncology department between 2002 and 2011 due to spinal metastasis with neurologic symptoms were deemed to be non-surgical candidates. The primary reason was minor neurologic deficits in 40 patients (M) and short survival (S) in 76 patients. Results - 8 patients underwent a late operation due to progression of the neurologic symptoms, all of them belonged to group M. M-patients with a modified Bauer score of less than 2 had both an inferior survival as well as a higher risk for late surgery. Postoperative improvement in neurologic function was noted in 5/8 operated patients, whilst 2 patients had stationary symptoms and 1 deteriorated. Interpretation - The need for late surgery arises in a minority of patients with spinal metastasis primarily treated non-surgically, and only in patients with minor neurologic compromise rather than poor general condition. An established prognostic score (modified Bauer) can be used to guide decision-making. Late surgical decompression is effective in restoring the neurologic status. PMID- 29231772 TI - Changes in the prevalence and severity of recurrent wheezing in infants: The results of two surveys administered 7 years apart. AB - OBJECTIVE: To identify changes in the prevalence and severity of recurrent wheezing (RW) in infants using data obtained from two surveys administered seven years apart. METHODS: A cross-sectional, international, population-based study in infants aged 12-15 months was conducted. Data were obtained from two surveys (S1 and S2, in 2005 and 2012, respectively) using the same methodology in three large Latin American cities: Curitiba (Brazil), Sao Paulo (Brazil), and Santiago (Chile). RESULTS: A decrease in the overall prevalence of RW was identified between S1 (23.3%) and S2 (20.4%), p = 0.004, but it was mainly driven by the reduction observed in Sao Paulo; in Curitiba and Santiago, this change was not significant. The mean prevalence of the following RW severity indicators remained high and stable: severe wheezing episodes (56.9% in S1 and 54.2% in S2, p = 0.32) and emergency department (ED) visits for wheezing (S1 = 68.1%, S2 70.9%, p = 0.21). A significant increase in admissions for wheezing (21.1% to 26.7%, p = 0.004) was observed. In Curitiba and Sao Paulo, there were significant increases in the prevalence of physician-diagnosed asthma and in the use of inhaled corticosteroids and oral antileukotrienes. CONCLUSIONS: The prevalence and severity of RW during the first year of life remained high over time, with remarkably high rates of ED visits, admissions for wheezing and use of asthma medications. This study suggests the need for considering early asthma diagnosis and to establish an appropriate treatment in infants with recurrent and severe asthma-like symptoms. PMID- 29231773 TI - Molecular imaging of autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a condition with onset in early childhood characterized by marked deficits in interpersonal interactions and communication and by a restricted and repetitive range of interests and activities. This review points out key recent findings utilizing molecular imaging including magnetic resonance spectroscopy (MRS) and nuclear neuroimaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). MRS indicates an excitatory/inhibitory imbalance in high-functioning autism. Dysfunction of neurotransmitter and glucose metabolism has been demonstrated by PET and SPECT. Levels of serotonin synthesis in typically developing children are approximately twice those of adults; after the age of 5 years, levels decrease to those of adults. In contrast, levels of serotonin synthesis of children with ASD increase between ages 2 and 15 to 1.5-times adult values. The dopamine transporter is increased in the orbitofrontal cortex of men with ASD. The serotonin transporter is reduced in the brains of children, adolescents, and adults with ASD. Reduced serotonin receptors in the thalamus of adults with ASD are associated with communication difficulties. Glucose metabolism is reduced in the brains of people with ASD. Molecular imaging will provide the preliminary data for promising therapeutic interventions. PMID- 29231774 TI - Modern management of diabetic foot osteomyelitis. The when, how and why of conservative approaches. AB - INTRODUCTION: Diabetic foot osteomyelitis (DFO) has long been considered a complex infection that is both difficult to diagnose and treat, and is associated with a high rate of relapse and limb loss. Areas covered: DFO can usually be diagnosed by a combination of clinical evaluation, serum inflammatory markers and plain X-ray. When the results of these procedures are negative or contradictory, advanced imaging tests or bone biopsy may be necessary. Staphylococcus aureus remains the most frequent microorganism isolated from bone specimens, but infection is often polymicrobial. Antibiotic therapy, preferably with oral agents guided by results of bone culture, for a duration of no more than six weeks, appears to be as safe and effective as surgery in cases of uncomplicated forefoot DFO. Surgery (which should be limb-sparing when possible) is always required for DFO accompanied by necrotizing fasciitis, deep abscess, gangrene or in cases not responding (either clinically or radiographically) to apparently appropriate antibiotic treatment. Expert commentary: Research in the past decade has improved diagnosis and treatment of DFO, and most cases can now be managed with a 'conservative' approach, defined as treatment either exclusively with antibiotics or with surgery removing as little bone and soft tissue as necessary. PMID- 29231775 TI - The airway hyperresponsiveness to methacholine may be predicted by impulse oscillometry and plethysmography in children with well-controlled asthma. AB - OBJECTIVE: Airway hyperresponsiveness (AHR) is a hallmark of asthma. Methacholine challenge test which is mostly used to confirm AHR is not routinely available. The aim of this study was to investigate the predictive values of fractional exhaled nitric oxide (FeNO), impulse oscillometry (IOS), and plethysmography for the assessment of AHR in children with well-controlled asthma. METHODS: 60 children with controlled allergic asthma aged 6-18 years participated in the study. FeNO measurement, spirometry, IOS, and plethysmography were performed. Methacholine challenge test was done to assess AHR. PC20 and dose response slope (DRS) of methacholine was calculated. RESULTS: Mild to severe AHR with PC20 < 4 mg/ml was confirmed in 31 (51.7%) patients. Baseline FeNO and total specific airway resistance (SRtot)%pred and residual volume (RV)%pred levels in plethysmography were significantly higher and FEV1%pred, FEV1/FVC%pred, MMEF%pred values were lower in the group with PC20 < 4 mg/ml. FeNO, SRtot%pred, and RV%pred levels were found to be positively correlated with DRS methacholine. The higher baseline FeNO, frequency dependence of resistance (R5-R20) in IOS and SRtot%pred in plethysmography were found to be significantly related to DRS methacholine in linear regression analysis (beta: 1.35, p = 0.046, beta: 4.58, p = 0.002, and beta: 0.78, p = 0.035, respectively). The cut-off points for FeNO and SRtot% for differentiating asthmatic children with PC20 < 4 mg/ml from those with PC20 >= 4 mg/ml were 28 ppb (sensitivity: 67.7%, specificity: 72.4%, p < 0.001) and 294.9% (sensitivity: 35.5%, specificity: 96.6%, p = 0.013), respectively. CONCLUSION: IOS and plethysmography may serve as reliable and practical tools for prediction of mild to severe methacholine induced AHR in otherwise "seemingly well controlled'' asthma. PMID- 29231777 TI - De Novo Transcriptome Study Identifies Candidate Genes Involved in Resistance to Austropuccinia psidii (Myrtle Rust) in Syzygium luehmannii (Riberry). AB - Austropuccinia psidii, causal agent of myrtle rust, was discovered in Australia in 2010 and has since become established on a wide range of species within the family Myrtaceae. Syzygium luehmannii, endemic to Australia, is an increasingly valuable berry crop. Plants were screened for responses to A. psidii inoculation, and specific resistance, in the form of localized necrosis, was determined in 29% of individuals. To understand the molecular basis underlying this response, mRNA was sequenced from leaf samples taken preinoculation, and at 24 and 48 h postinoculation, from four resistant and four susceptible plants. Analyses, based on de novo transcriptome assemblies for all plants, identified significant expression changes in resistant plants (438 transcripts) 48 h after pathogen exposure compared with susceptible plants (three transcripts). Most significantly up-regulated in resistant plants were gene homologs for transcription factors, receptor-like kinases, and enzymes involved in secondary metabolite pathways. A putative G-type lectin receptor-like kinase was exclusively expressed in resistant individuals and two transcripts incorporating toll/interleukin-1, nucleotide binding site, and leucine-rich repeat domains were up-regulated in resistant plants. The results of this study provide the first early gene expression profiles for a plant of the family Myrtaceae in response to the myrtle rust pathogen. PMID- 29231776 TI - Ilizarov technique combined with limited adjunctive surgical procedures for correction of relapsed talipes equinovarus in children. AB - Objective To evaluate the efficacy and safety of using the Ilizarov invasive distraction technique combined with limited surgical operations in the treatment of relapsed talipes equinovarus in children. Methods This retrospective study analysed the outcomes of paediatric patients with relapsed talipes equinovarus who were treated with the Ilizarov technique with moderate open limited soft tissue or bony operations. The International Clubfoot Study Group (ICFSG) classification system score was used to evaluate the deformities before and after surgery. Results The study evaluated 16 feet in 14 patients (nine boys). The correction time ranged from 6 to 12 weeks. The mean duration of frame application was 5.9 months. The gait was improved significantly in all patients. At final follow-up, the mean ankle dorsiflexion and plantarflexion ranges were 8.3 degrees and 34.6 degrees , respectively. The talocalcaneal angle improved from 10.0 degrees preoperatively to 28.3 degrees postoperatively in the anteroposterior plane; and from 4.1 degrees preoperatively to 42.1 degrees postoperatively in the lateral plane. The differences in the angle of plantarflexion, dorsiflexion, range of motion of the ankle joint and talocalcaneal angles pre- and postoperation were significant. Conclusions These current findings suggest that the Ilizarov technique combined with limited surgery effectively corrects relapsed talipes equinovarus in children. PMID- 29231778 TI - Case Study of an Epidemiological Approach Dissecting Historical Soybean Sclerotinia Stem Rot Observations and Identifying Environmental Predictors of Epidemics and Yield Loss. AB - Sclerotinia sclerotiorum is a significant threat to soybean production worldwide. In this study, an epidemiological approach was used to examine 11 years of historical data from a soybean management performance trial in order to advance our understanding of Sclerotinia stem rot (SSR) development and to identify environmental predictors of SSR epidemics and associated yield losses. Recursive partitioning analysis suggested that average air temperature and total precipitation in July were the most significant variables associated with disease severity. High levels of SSR disease severity index were observed when the average temperature in July was below 19.5 degrees C and total precipitation in July was moderate, between 20 and 108.5 mm. A biphasic sigmoidal curve accurately described the relationship between SSR disease severity index (DSI) and yield, with a DSI threshold of 22, below which minimal yield loss was observed. A 10% increase in the DSI, from 22.0 to 24.2, led to an 11% decrease in yield, from 3,308.14 to 2,951.29 kg/ha. Also, a yield threshold (3,353 kg/ha) that was higher than the annual U.S. average soybean yield (3,039.7 kg/ha) was suggested as an expected yield under low or no SSR pressure in the U.S. Midwest. These thresholds can allow soybean stakeholders to assess the value of disease control and establish an SSR baseline for cost-effective management to protect yields. Because S. sclerotiorum has more than 400 plant host species, and because having quantitative information concerning crop losses is crucial for decision making, this study shows the usefulness of historical data on SSR and, hence, can serve as a model in other SSR pathosystems (canola, dry bean, potato, pea, and so on). PMID- 29231779 TI - MAP kinases nomenclature: Time for curation. AB - The nomenclature of Mitogen Activated Protein Kinases (MAPKs) takes different formats composed of symbols, prefixes, suffixes, or descriptive acronyms of their functions that sometimes lead to confusion and make the indexed information redundant and inconsistent. To avoid such redundancy and reduce confusion, a curation of the terminology of MAP kinase families, and that of other protein families that present similar nomenclature issues, is required. Some arguable suggestions are presented here toward this goal. PMID- 29231780 TI - A priming dose protects against gold nanoparticles-induced proinflammatory cytokines mRNA expression in mice. AB - AIM: To study the effect of priming doses of gold nanoparticles (GNPs) on proinflammatory cytokines in different organs of mice. MATERIALS & METHODS: Mice were injected with a single or two doses (priming group) of GNPs (5, 20 and 50 nm) and sacrificed after 1 or 7 days. The mRNA expressions of IL-1beta, IL-6 and TNF-alpha were determined in liver, kidney and spleen. RESULTS: A single injection of 5 nm GNPs significantly increased the mRNA expressions of IL-1beta and IL-6 in liver, which were normalized on day 7. In spleen, the GNPs of all sizes significantly increased IL-1beta and IL-6 mRNA expressions on day 1 that persisted on day 7. The priming dose of GNPs protected the animals against the acute phase induction of IL-1beta and IL-6 expressions in liver and spleen. CONCLUSION: Primed animals showed protection against GNP-induced acute immune activation suggesting the importance of the priming dose in nanomedicine. PMID- 29231781 TI - Dynamic autoregulation of cerebral blood flow measured non-invasively with fast diffuse correlation spectroscopy. AB - Cerebral autoregulation (CA) maintains cerebral blood flow (CBF) in the presence of systemic blood pressure changes. Brain injury can cause loss of CA and resulting dysregulation of CBF, and the degree of CA impairment is a functional indicator of cerebral tissue health. Here, we demonstrate a new approach to noninvasively estimate cerebral autoregulation in healthy adult volunteers. The approach employs pulsatile CBF measurements obtained using high-speed diffuse correlation spectroscopy (DCS). Rapid thigh-cuff deflation initiates a chain of responses that permits estimation of rates of dynamic autoregulation in the cerebral microvasculature. The regulation rate estimated with DCS in the microvasculature (median: 0.26 s-1, inter quartile range: 0.19 s-1) agrees well (R = 0.81, slope = 0.9) with regulation rates measured by transcranial Doppler ultrasound (TCD) in the proximal vasculature (median: 0.28 s-1, inter quartile range: 0.10 s-1). We also obtained an index of systemic autoregulation in concurrently measured scalp microvasculature. Systemic autoregulation begins later than cerebral autoregulation and exhibited a different rate (0.55 s-1, inter quartile range: 0.72 s-1). Our work demonstrates the potential of diffuse correlation spectroscopy for bedside monitoring of cerebral autoregulation in the microvasculature of patients with brain injury. PMID- 29231782 TI - AKIN10 activity as a cellular link between metabolism and circadian-clock entrainment in Arabidopsis thaliana. AB - AKIN10, the catalytic subunit of the Snf1 (sucrose non-fermenting 1)-related kinase 1 (SnRK1) complex, acts as an energy sensor in plants. We showed that AKIN10-induced expression affects the pace of the circadian clock and particularly the phase of expression of GIGANTEA (GI). The AKIN10 effect on period length required TIME FOR COFFEE (TIC), a circadian-clock component with developmental and metabolic roles. Here we expand on the possible interactions between AKIN10, whose activity is involved in transcriptional reprogramming, and clock elements GI and TIC. We hypothesize how they could participate in clock entrainment through a metabolic signal derived from carbon pools and starch metabolism. Additionally, we consider further the role of cellular energy status to the clock through the formation of a hypothetical protein complex. We also demonstrate the role of AKIN10, but not its sequence-related kinase AKIN11, on clock periodicity. Altogether we present a model of action of these elements in metabolic-related clock entrainment. PMID- 29231783 TI - Dexamethasone exacerbates cytotoxic chemotherapy induced lethargy and weight loss in female tumor free mice. AB - Cytotoxic chemotherapy can induce a systemic inflammatory response which has been proposed to be an underlying mechanism of cancer treatment related fatigue. Dexamethasone, a synthetic glucocorticoid that has potent anti-inflammatory effects, is incorporated into chemotherapy regimens to prevent chemotherapy induced nausea and vomiting (CINV). The purpose of this study was to determine whether by suppressing cytotoxic chemotherapy-induced inflammation, dexamethasone could ameliorate chemotherapy induced fatigue/lethargy in tumor free mice. The effect of dexamethasone (DEX) on Cytoxan-Adriamycin (CA)-induced inflammation was assessed by measuring circulating levels of IL-1beta, TNF-alpha, IL-6, GCSF, KC, and MCP-1 twenty-four-hours post CA injection. Decline in voluntary wheel running activity (VWRA) from baseline (used as a proxy for fatigue/lethargy), body weight and composition, and food intake were monitored in mice administered four cycles of CA every two weeks with or without DEX. CA increased circulating levels of IL 6, GCSF, KC, and MCP-1 and caused a rapid decline in VWRA and body weight immediately following CA-injection. Although the acute CA-induced decline in VWRA and body weight was not evident in mice administered CA + DEX, DEX alone had a suppressive effect on VWRA, and body weight continued to decline in mice administered both CA and DEX while it returned to baseline in CA-treated mice. CA or DEX alone had no long term impact on VWRA but DEX exacerbated lethargy and weight loss in CA-treated mice. Despite dampening the systemic inflammatory response to chemotherapy, dexamethasone failed to ameliorate acute or long term chemotherapy related fatigue/lethargy. Our pre-clinical findings suggest that supportive therapies like dexamethasone used to acutely control nausea and vomiting in cancer patients may actually contribute to overall symptom burden in cancer patients. PMID- 29231784 TI - Feet kinematics upon slipping discriminate between recoveries and three types of slip-induced falls. AB - This study investigated the relationship between feet kinematics upon slipping while walking and the outcome of the slip. Seventy-one slips (induced by walking over an unexpectedly slippery surface) were analysed, which included 37 recoveries, 16 feet-split falls, 11 feet-forward falls and seven lateral falls. Feet kinematics differed between recoveries and three types of slip-induced falls, and a discriminant model including six measures of feet kinematics correctly predicted 87% of slip outcomes. Two potentially modifiable characteristics of the feet kinematics upon slipping that can improve the likelihood of successfully averting a fall were identified: (1) quickly arresting the motion of the slipping foot and (2) a recovery step that places the trailing toe approximately 0-10% body height anterior to the sacrum. These results may inform the development of task-specific balance training interventions that promote favourable recovery responses to slipping. Practitioner Summary: This study investigated the relationship between feet movements upon slipping and outcomes of the slip. Potentially modifiable characteristics that can reduce the likelihood of falling were: (1) quickly arresting slipping foot motion and (2) a recovery step that places the trailing toe approximately 0-10% body height anterior to the sacrum. PMID- 29231785 TI - The role of endomembrane-localized VHA-c in plant growth. AB - In plant cells, the vacuolar-type H+-ATPase (V-ATPase), a large multis'ubunit endomembrane proton pump, plays an important role in acidification of subcellular organelles, pH and ion homeostasis, and endocytic and secretory trafficking. V ATPase subunit c (VHA-c) is essential for V-ATPase assembly, and is directly responsible for binding and transmembrane transport of protons. In previous studies, we identified a PutVHA-c gene from Puccinellia tenuiflora, and investigated its function in plant growth. Subcellular localization revealed that PutVHA-c is mainly localized in endosomal compartments. Overexpression of PutVHA c enhanced V-ATPase activity and promoted plant growth in transgenic Arabidopsis. Furthermore, the activity of V-ATPase affected intracellular transport of the Golgi-derived endosomes. Our results showed that endomembrane localized-VHA-c contributes to plant growth by influencing V-ATPase-dependent endosomal trafficking. Here, we discuss these recent findings and speculate on the VHA-c mediated molecular mechanisms involved in plant growth, providing a better understanding of the functions of VHA-c and V-ATPase. PMID- 29231786 TI - Lack of Automatic Imitation in Newly Sighted Individuals. AB - Viewing a hand action performed by another person facilitates a response compatible action and slows a response-incompatible one, even when the viewed action is irrelevant to the task. This automatic imitation effect is taken as the clearest evidence for a direct mapping between action viewing and motor performance. But there is an ongoing debate whether this effect is innate or experience dependent. We tackled this issue by studying a unique group of newly sighted children who suffered from dense bilateral cataracts from early infancy and were surgically treated only years later. The newly sighted children were less affected by viewing task-irrelevant actions than were control children, even 2 years after the cataract-removal surgery. This strongly suggests that visually guided motor experience is necessary for the development of automatic imitation. At the very least, our results indicate that if imitation is based on innate mechanisms, these are clearly susceptible to long periods of visual deprivation. PMID- 29231787 TI - Using a quality improvement approach to improve maternal and neonatal care in North Kivu, Democratic Republic of Congo. AB - Providing quality health care services in humanitarian settings is challenging due to population displacement, lack of qualified staff and supervisory oversight, and disruption of supply chains. This study explored whether a participatory quality improvement (QI) intervention could be used in a protracted conflict setting to improve facility-based maternal and newborn care. A longitudinal quasi-experimental design was used to examine delivery of maternal and newborn care components at 12 health facilities in eastern Democratic Republic of Congo. Study facilities were split into two groups, with both groups receiving an initial "standard" intervention of clinical training. The "enhanced" intervention group then applied a QI methodology, which involved QI teams in each facility, supported by coaches, testing small changes to improve care. This paper presents findings on two of the study outcomes: delivery of active management of the third stage of labour (AMTSL) and essential newborn care (ENC). We measured AMTSL and ENC through exit interviews with post-partum women and matched partographs at baseline and endline over a 9-month period. Using generalised equation estimation models, the enhanced intervention group showed a greater rate of change than the control group for AMTSL (aOR 3.47, 95% CI: 1.17-10.23) and ENC (OR: 49.62, 95% CI: 2.79-888.28), and achieved 100% ENC completion at endline. This is one of the first studies where this QI methodology has been used in a protracted conflict setting. A method where health staff take ownership of improving care is of even greater value in a humanitarian context where external resources and support are scarce. PMID- 29231788 TI - The 2018 Inter-agency field manual on reproductive health in humanitarian settings: revising the global standards. AB - Since the 1990s, the Inter-agency field manual on reproductive health in humanitarian settings (IAFM) has provided authoritative guidance on reproductive health service provision during different phases of complex humanitarian emergencies. In 2018, the Inter-Agency Working Group on Reproductive Health in Crises will release a new edition of this global resource. In this article, we describe the collaborative and inter-sectoral revision process and highlight major changes in the 2018 IAFM. Key revisions to the manual include repositioning unintended pregnancy prevention within and explicitly incorporating safe abortion care into the Minimum Initial Service Package (MISP) chapter, which outlines a set of priority activities to be implemented at the outset of a humanitarian crisis; stronger guidance on the transition from the MISP to comprehensive sexual and reproductive health services; and the addition of a logistics chapter. In addition, the IAFM now places greater and more consistent emphasis on human rights principles and obligations, gender-based violence, and the linkages between maternal and newborn health, and incorporates a diverse range of field examples. We conclude this article with an outline of plans for releasing the 2018 IAFM and facilitating uptake by those working in refugee, crisis, conflict, and emergency settings. PMID- 29231789 TI - A Redescription of Serrasentis sagittifer (Rhadinorhynchidae: Serrasentinae) from Rachycentron canadum (Rachycentridae) with Comments on its Biology and its Relationship to Other Species of Serrasentis. AB - Adult and cystacanth forms of the acanthocephalan Serrasentis sagittifer from Australian coastal waters are redescribed and verified as the same species using both molecular and morphological data. This study provides the baseline 18S rDNA, 28S rDNA, and cox1 sequence data to serve as genetic barcode for S. sagittifer. The validity of the currently recognized species of Serrasentis is discussed. The most recently described species are junior synonyms of either Serrasentis nadakali or S. sagittifer, and a number of species are species inquirenda. When using morphological characters to distinguish the species of Serrasentis, consideration needs to be given to the maturity of the specimens, since the trunk elongates and the number and distribution of the ventral combs changes as worms mature, although the proboscis armature itself does not change. A simple key to assist in the identification of species of Serrasentis is provided. Adult S. sagittifer appear to be highly host specific to the cobia, Rachycentron canadum, in northern Australian waters, whereas cystacanths have been reported from a wide range of fish species. The relationship between host length and number of cystacanths shows that most paratenic infections are acquired as young fish, most likely via a crustacean intermediate host. PMID- 29231790 TI - Uptake of postabortion care services and acceptance of postabortion contraception in Puntland, Somalia. AB - Unsafe abortion is responsible for at least 9% of all maternal deaths worldwide; however, in humanitarian emergencies where health systems are weak and reproductive health services are often unavailable or disrupted, this figure is higher. In Puntland, Somalia, Save the Children International (SCI) implemented postabortion care (PAC) services to address the issue of high maternal morbidity and mortality due to unsafe abortion. Abortion is explicitly permitted by Somali law to save the life of a woman, but remains a sensitive topic due to religious and social conservatism that exists in the region. Using a multipronged approach focusing on capacity building, assurance of supplies and infrastructure, and community collaboration and mobilisation, the demand for PAC services increased as did the proportion of women who adopted a method of family planning post abortion. From January 2013 to December 2015, a total of 1111 clients received PAC services at the four SCI-supported health facilities. The number of PAC clients increased from a monthly average of 20 in 2013 to 38 in 2015. During the same period, 98% (1090) of PAC clients were counselled for postabortion contraception, of which 955 (88%) accepted a contraceptive method before leaving the facility, with 30% opting for long-acting reversible contraception. These results show that comprehensive PAC services can be implemented in politically unstable, culturally conservative settings where abortion and modern contraception are sensitive and stigmatised matters among communities, health workers, and policy makers. However, like all humanitarian settings, large unmet needs exist for PAC services in Somalia. PMID- 29231791 TI - Glucagon like peptide-2 and neoplasia; a systematic review. AB - INTRODUCTION: Glucagon like peptide-2 is synthesized from enteroendocrine L cells primarily located in the ileum and large intestine. GLP-2 stimulates crypt cell proliferation, increases intestinal blood flow, enhances gut barrier function, induces mucosal healing, and exerts an anti-apoptotic effect. Due to these effects GLP-2 is used in the treatment of short bowel syndrome (SBS). Areas covered: The aim of this systematic review was to provide information on the potential risk of intestinal neoplasia in patients receiving treatment with GLP 2. The literature search was performed independently by two authors in the following databases; Pubmed, Embase, Scopus, Web of Science and Cochrane. Expert commentary: This systematic review indicated that treatment with GLP-2(1-33) up to 30 months in humans without any known pre-existing cancer did not confer an increased risk of intestinal neoplasia in patients or animals. However, due to the small amount of patients studied it is premature to reach any final conclusions about GLP-2 - induced neoplasia. GLP-2(1-33) treatment in animals with a pre-induced cancer showed that GLP-2(1-33) may promote growth of existing neoplasia. PMID- 29231792 TI - Patient selection for mechanical thrombectomy in posterior circulation emergent large-vessel occlusion. AB - Triage of posterior circulation stroke from emergent large-vessel occlusion (pc ELVO) is challenging owing to the stuttering clinical course and potential for rapid decline. Growing clinical data support the use of mechanical thrombectomy in pc-ELVO, but there are limited data addressing the clinical and imaging criteria for patient selection. We present our triage algorithm used to select patients for endovascular therapy (EVT) in the setting of pc-ELVOS. We use a consecutive retrospective database from 2004 to 2016 to describe the practice patterns and prognostic factors for pc-ELVO patients treated using both medical and EVT. Patients with moderate to severe deficits (NIHSS > 10) did better when they received EVT ( p < 0.03), whereas patients with stable, mild deficits (NIHSS <= 10) did well (90% favorable outcome) regardless of treatment type. Roughly one third of patients presenting with mild deficits deteriorated to moderate to severe deficits (NIHSS > 10), most of whom subsequently received EVT (9 of 12), with 56% favorable outcomes. Cerebellar and brainstem infarct volumes were independent imaging predictors of outcome. These results can be used to define triage criteria for use of EVT in pc-ELVO in future practice and clinical trials. PMID- 29231793 TI - Acute rerupture after coil embolization of ruptured intracranial saccular aneurysms: A literature review. AB - Acute rerupture after coil embolization is defined as rerupture within three days after treatment; its prognosis is worse than that of rebleeding at other time periods. However, to date, little is known about complications during the acute phase. Therefore, we used the PubMed database to perform a review of acute rerupture after coil embolization of ruptured intracranial saccular aneurysms and increase our understanding. After reviewing the complications, we found that the cause of acute rerupture is unclear, but the following risk factors are involved: incomplete occlusion of the initial aneurysm, the presence of a hematoma adjacent to a ruptured aneurysm, an aneurysmal outpouching, poor Hunt-Hess grade at the time of treatment, and the location of the aneurysm in an anterior communicating artery. In addition, intraoperative rupture is a non-negligible cause. Acute rerupture after coil embolization mainly occurs within the first 24 hours after the procedure. Brain computed tomography is the gold standard for diagnosing acute rebleeding of a coiled aneurysm. For acute rerupture after coil embolization, prevention is critical, and complete occlusion of the aneurysm in the first session is the best protection against acute rebleeding. In addition, a restricted postembolization anticoagulation strategy is recommended for patients with high-risk aneurysms. For patients with an adjacent hematoma, surgical clipping is recommended. Most patients present no changes immediately after acute rebleeding because of their poor condition. However, surgical or endovascular treatments can be attempted if the patient is in an acceptable condition. Even so, the outcomes are typically unsatisfactory. PMID- 29231796 TI - Navigating 2018, a year in stroke! PMID- 29231795 TI - Quantification of parenchymal calcifications in chronic pancreatitis: relation to atrophy, ductal changes, fibrosis and clinical parameters. AB - OBJECTIVES: Parenchymal calcifications are considered a hallmark finding of chronic pancreatitis (CP), but little is known about its relation to the clinical presentation and other morphological features such as atrophy, fibrosis and ductal changes. The aim was to quantify the number and maximal size of parenchymal calcifications assessed on computed tomography (CT) and to explore the association with other CT and magnetic resonance imaging (MRI)-based pancreatic features and clinical parameters. METHODS: A well-characterised cohort of 54 CP patients was included. CT measurements included number and size of parenchymal calcifications, gland diameter and ductal diameter. MRI measurements included gland volume, ductal diameter, fibrosis (diffusion) and fatty infiltration (Dixon). Clinical parameters included body mass index (BMI), CP duration and aetiology, M-ANNHEIM clinical stage, tobacco use, alcohol consumption, the presence of diabetes, faecal elastase, clinical pain score and quality of life. RESULTS: There were no correlations between the number and size of parenchymal calcifications and any of the other morphological CT and MRI parameters (all p > .05), except for larger size of calcifications in patients with high number of calcifications (p < .001). The number of parenchymal calcifications was negatively correlated with BMI (r = -0.35, p = .0088). The number and size of parenchymal calcifications did not correlate with any of the other clinical parameters (all p > .2). CONCLUSION: Our findings could indicate the existence of parenchymal calcifications as an independent pathophysiological process involved in the development of CP. Translational impact: Quantifications of calcifications could, in combination with other imaging biomarkers, be a useful imaging marker relevant for characterising CP. PMID- 29231794 TI - Intracranial contrast transit times on digital subtraction angiography decrease more in patients with delayed intraparenchymal hemorrhage after Pipeline. AB - Background Pipeline embolization devices (PEDs) are used for endovascular treatment of cerebral aneurysms but can be associated with delayed ipsilateral intraparenchymal hemorrhage (DIPH). Changes in intracranial hemodynamics after PED are poorly understood. Objective Here, we assess hemodynamic changes after PED in patients and compare these changes in patients with and without DIPH (DIPH+ and DIPH-). Methods Records of patients with distal internal carotid artery (ICA) aneurysms treated with PED at our institution between 2012 and 2017 were retrospectively reviewed. Regions of interest were selected proximally to PED over the cavernous ICA and distally over the middle cerebral artery (MCA), and then transit times were determined using syngo iFlow software (Siemens). Ratio of MCA to ICA transit time was compared before, after treatment, and at follow-up. Ratios were also compared between DIPH+ and DIPH- subgroups. Correlations between aneurysm size, age, and ratios were investigated. Results Fifty-three patients were included. The ratio of MCA to ICA transit time decreased significantly after PED deployment (1.13 vs. 1.22, p < 0.01). The ratio in the DIPH + subgroup ( n = 4) was significantly lower (1.00 vs. 1.14, p = 0.01) and decreased significantly more (21% vs. 4.4%, p = 0.02) compared to the DIPH- subgroup ( n = 49). The ratio tended to be higher in larger aneurysms at baseline ( r = 0.25, p = 0.07) but not after PED treatment ( r = 0.11, p = 0.15). Age did not correlate with ratio. Conclusion The ratio of MCA to ICA transit time decreases following PED treatment and decreases more in patients with DIPH. These contrast transit time changes can be detected in real time immediately after PED deployment. PMID- 29231798 TI - N-cadherin knockdown leads to disruption of trophoblastic and endothelial cell interaction in a 3D cell culture model - New insights in trophoblast invasion failure. AB - INTRODUCTION: Trophoblast homing to maternal spiral arteries is mandatory for successful placentation. Cell-cell adhesion molecules regulate this process and adhesion molecule expression is altered in impaired placentation. We hypothesize that, similar to immune cell recruitment, trophoblast cell adherence and rolling are primarily mediated by adhesion molecules like, cadherins, immunoglobulins, selectins and their partnering ligands. Here, the interdependence of adhesion molecule expression in trophoblastic cell lines of diverse origin was investigated in relation to their interaction with endothelial cell networks on Matrigel(r) co-cultures and the effect of specific adhesion molecule knockdown analyzed. METHODS: Trophoblastic cells were labeled in red and co-cultured with green HUVEC networks on Matrigel(r). Association was quantified after collection of fluorescence microscopy pictures using Wimasis(r) internet platform and software. Expression of adhesion molecules was analyzed by PCR and Western blot, immuno-fluorescence and flow cytometry. The impact of adhesion molecules on trophoblast-endothelial-cell interaction was investigated using siRNA technique. RESULTS: N-cadherin and CD162 were specifically expressed in the trophoblast cell line HTR-8/SVneo, which closely adhere to and actively migrate toward HUVEC networks on Matrigel(r). Suppression of N-cadherin led to a significant alteration in trophoblast-endothelial cell interaction. Expression of VE-cadherin in closely interacting trophoblast cells was not confirmed in vitro. DISCUSSION: We identified N-cadherin to mediate specific interaction between HUVEC and the migrating trophoblast cells HTR-8/SVneo in a Matrigel(r) co-culture model. VE cadherin contribution could not be confirmed in vitro. Our results support the hypothesis that impaired N-cadherin but not VE-cadherin expression is involved in trophoblast recruitment to the maternal endothelium. PMID- 29231799 TI - The minimally invasive approach for distal radius fractures and malunions. AB - This article reviews the author's currently used minimal invasive approach for volar plating of distal radius fractures. A single longitudinal incision of 1.5 cm is drawn on the lateral aspect of the flexor carpi radialis tendon in order to insert a plate under the pronator quadratus. With the wrist flexed, the plate is applied on the anterior cortex of the radius to reduce the fracture. This approach offers the advantage of preserving ligamentotaxis, which facilitates the reduction, and the small scar improves the cosmetics. It is mainly indicated for extra-articular and simple intra-articular fractures of the distal radius. Relative contraindications are comminuted articular fractures in elderly osteoporotic patients. Functional and radiological results are comparable with those obtained with an extended flexor carpi radialis approach. My colleagues and I have used it for more than 2000 cases since 2012. This technique requires practise. Attempted conversion to a larger incision is possible in case of difficulty, but this is seldom necessary. PMID- 29231800 TI - Let's talk about sex work in humanitarian settings: piloting a rights-based approach to working with refugee women selling sex in Kampala. AB - Although it is well known that refugees engage in sex work as a form of livelihood, stigma and silence around this issue persist within humanitarian circles. As a result, these refugees' sexual and reproductive health and rights, and related vulnerabilities, remain overlooked. Their protection and health needs, which are significant, often go unmet at the field level. In 2016, the Women's Refugee Commission and Reproductive Health Uganda partnered to pilot a peer-education intervention tailored to meet the needs of refugee women engaged in sex work in Kampala. Findings from the pilot project suggest the feasibility of adapting existing rights-based and evidence-informed interventions with sex workers to humanitarian contexts. Findings further demonstrate how taking a community empowerment approach can facilitate these refugees' access to a range of critical information, services and support options - from information on how to use contraceptives, to referrals for friendly HIV testing and treatment, to peer counselling and protective peer networks. PMID- 29231801 TI - Correction: Journal of Aerosol Medicine and Pulmonary Drug Delivery 2017; 30/1:53 63 (DOI: 10.1089/jamp.2015.1282). PMID- 29231802 TI - Editorial: View of Cellular Biology through the Eye. PMID- 29231803 TI - Editorial: Recent Advances in the Field of Kinases and Kinase Inhibitors. PMID- 29231804 TI - Impact of point sources on antibiotic resistance genes in the natural environment: a systematic review of the evidence. AB - There is a growing concern about the role of the environment in the dissemination of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARG). In this systematic review, we summarize evidence for increases of ARG in the natural environment associated with potential sources of ARB and ARG such as agricultural facilities and wastewater treatment plants. A total of 5247 citations were identified, including studies that ascertained both ARG and ARB outcomes. All studies were screened for relevance to the question and methodology. This paper summarizes the evidence only for those studies with ARG outcomes (n = 24). Sixteen studies were at high (n = 3) or at unclear (n = 13) risk of bias in the estimation of source effects due to lack of information or failure to control for confounders. Statistical methods were used in nine studies; three studies assessed the effect of multiple sources using modeling approaches, and none reported effect measures. Most studies reported higher ARG concentration downstream/near the source, but heterogeneous findings hindered making any sound conclusions. To quantify increases of ARG in the environment due to specific point sources, there is a need for studies that emphasize analytic or design control of confounding, and that provide effect measure estimates. PMID- 29231805 TI - Understanding host-parasite relationship: the immune central nervous system microenvironment and its effect on brain infections. AB - The central nervous system (CNS) has been recognized as an immunologically specialized microenvironment, where immune surveillance takes a distinctive character, and where delicate neuronal networks are sustained by anti inflammatory factors that maintain local homeostasis. However, when a foreign agent such as a parasite establishes in the CNS, a set of immune defences is mounted and several immune molecules are released to promote an array of responses, which ultimately would control the infection and associated damage. Instead, a host-parasite relationship is established, in the context of which a close biochemical coevolution and communication at all organization levels between two complex organisms have developed. The ability of the parasite to establish in its host is associated with several evasion mechanisms to the immune response and its capacity for exploiting host-derived molecules. In this context, the CNS is deeply involved in modulating immune functions, either protective or pathogenic, and possibly in parasitic activity as well, via interactions with evolutionarily conserved molecules such as growth factors, neuropeptides and hormones. This review presents available evidence on some examples of CNS parasitic infections inducing different morbi-mortality grades in low- or middle income countries, to illustrate how the CNS microenvironment affect pathogen establishment, growth, survival and reproduction in immunocompetent hosts. A better understanding of the influence of the CNS microenvironment on neuroinfections may provide relevant insights into the mechanisms underlying these pathologies. PMID- 29231807 TI - How bacteria keep proteins moving. AB - Bacteria contain large numbers of negatively-charged proteins to avoid the electrostatic interactions with ribosomes that would dramatically reduce protein diffusion. PMID- 29231806 TI - A picorna-like virus suppresses the N-end rule pathway to inhibit apoptosis. AB - The N-end rule pathway is an evolutionarily conserved proteolytic system that degrades proteins containing N-terminal degradation signals called N-degrons, and has emerged as a key regulator of various processes. Viruses manipulate diverse host pathways to facilitate viral replication and evade antiviral defenses. However, it remains unclear if viral infection has any impact on the N-end rule pathway. Here, using a picorna-like virus as a model, we found that viral infection promoted the accumulation of caspase-cleaved Drosophila inhibitor of apoptosis 1 (DIAP1) by inducing the degradation of N-terminal amidohydrolase 1 (NTAN1), a key N-end rule component that identifies N-degron to initiate the process. The virus-induced NTAN1 degradation is independent of polyubiquitylation but dependent on proteasome. Furthermore, the virus-induced N-end rule pathway suppression inhibits apoptosis and benefits viral replication. Thus, our findings demonstrate that a virus can suppress the N-end rule pathway, and uncover a new mechanism for virus to evade apoptosis. PMID- 29231808 TI - Abelson tyrosine-protein kinase 2 regulates myoblast proliferation and controls muscle fiber length. AB - Muscle fiber length is nearly uniform within a muscle but widely different among different muscles. We show that Abelson tyrosine-protein kinase 2 (Abl2) has a key role in regulating myofiber length, as a loss of Abl2 leads to excessively long myofibers in the diaphragm, intercostal and levator auris muscles but not limb muscles. Increased myofiber length is caused by enhanced myoblast proliferation, expanding the pool of myoblasts and leading to increased myoblast fusion. Abl2 acts in myoblasts, but as a consequence of expansion of the diaphragm muscle, the diaphragm central tendon is reduced in size, likely contributing to reduced stamina of Abl2 mutant mice. Ectopic muscle islands, each composed of myofibers of uniform length and orientation, form within the central tendon of Abl2+/- mice. Specialized tendon cells, resembling tendon cells at myotendinous junctions, form at the ends of these muscle islands, suggesting that myofibers induce differentiation of tendon cells, which reciprocally regulate myofiber length and orientation. PMID- 29231809 TI - Structure-based membrane dome mechanism for Piezo mechanosensitivity. AB - Mechanosensitive ion channels convert external mechanical stimuli into electrochemical signals for critical processes including touch sensation, balance, and cardiovascular regulation. The best understood mechanosensitive channel, MscL, opens a wide pore, which accounts for mechanosensitive gating due to in-plane area expansion. Eukaryotic Piezo channels have a narrow pore and therefore must capture mechanical forces to control gating in another way. We present a cryo-EM structure of mouse Piezo1 in a closed conformation at 3.7A resolution. The channel is a triskelion with arms consisting of repeated arrays of 4-TM structural units surrounding a pore. Its shape deforms the membrane locally into a dome. We present a hypothesis in which the membrane deformation changes upon channel opening. Quantitatively, membrane tension will alter gating energetics in proportion to the change in projected area under the dome. This mechanism can account for highly sensitive mechanical gating in the setting of a narrow, cation-selective pore. PMID- 29231810 TI - Shigella entry unveils a calcium/calpain-dependent mechanism for inhibiting sumoylation. AB - Disruption of the sumoylation/desumoylation equilibrium is associated with several disease states such as cancer and infections, however the mechanisms regulating the global SUMO balance remain poorly defined. Here, we show that infection by Shigella flexneri, the causative agent of human bacillary dysentery, switches off host sumoylation during epithelial cell infection in vitro and in vivo and that this effect is mainly mediated by a calcium/calpain-induced cleavage of the SUMO E1 enzyme SAE2, thus leading to sumoylation inhibition. Furthermore, we describe a mechanism by which Shigella promotes its own invasion by altering the sumoylation state of RhoGDIalpha, a master negative regulator of RhoGTPase activity and actin polymerization. Together, our data suggest that SUMO modification is essential to restrain pathogenic bacterial entry by limiting cytoskeletal rearrangement induced by bacterial effectors. Moreover, these findings identify calcium-activated calpains as powerful modulators of cellular sumoylation levels with potentially broad implications in several physiological and pathological situations. PMID- 29231811 TI - Genome-wide mapping of sister chromatid exchange events in single yeast cells using Strand-seq. AB - Homologous recombination involving sister chromatids is the most accurate, and thus most frequently used, form of recombination-mediated DNA repair. Despite its importance, sister chromatid recombination is not easily studied because it does not result in a change in DNA sequence, making recombination between sister chromatids difficult to detect. We have previously developed a novel DNA template strand sequencing technique, called Strand-seq, that can be used to map sister chromatid exchange (SCE) events genome-wide in single cells. An increase in the rate of SCE is an indicator of elevated recombination activity and of genome instability, which is a hallmark of cancer. In this study, we have adapted Strand seq to detect SCE in the yeast Saccharomyces cerevisiae. We provide the first quantifiable evidence that most spontaneous SCE events in wild-type cells are not due to the repair of DNA double-strand breaks. PMID- 29231814 TI - A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency. AB - Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients' lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm-/- mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation. PMID- 29231812 TI - Oxytocin signaling in the medial amygdala is required for sex discrimination of social cues. AB - The neural control of social behaviors in rodents requires the encoding of pheromonal cues by the vomeronasal system. Here we show that the typical preference of male mice for females is eliminated in mutants lacking oxytocin, a neuropeptide modulating social behaviors in many species. Ablation of the oxytocin receptor in aromatase-expressing neurons of the medial amygdala (MeA) fully recapitulates the elimination of female preference in males. Further, single-unit recording in the MeA uncovered significant changes in the sensory representation of conspecific cues in the absence of oxytocin signaling. Finally, acute manipulation of oxytocin signaling in adults is sufficient to alter social interaction preferences in males as well as responses of MeA neurons to chemosensory cues. These results uncover the critical role of oxytocin signaling in a molecularly defined neuronal population in order to modulate the behavioral and physiological responses of male mice to females on a moment-to-moment basis. PMID- 29231813 TI - Evolutionary transitions between beneficial and phytopathogenic Rhodococcus challenge disease management. AB - Understanding how bacteria affect plant health is crucial for developing sustainable crop production systems. We coupled ecological sampling and genome sequencing to characterize the population genetic history of Rhodococcus and the distribution patterns of virulence plasmids in isolates from nurseries. Analysis of chromosome sequences shows that plants host multiple lineages of Rhodococcus, and suggested that these bacteria are transmitted due to independent introductions, reservoir populations, and point source outbreaks. We demonstrate that isolates lacking virulence genes promote beneficial plant growth, and that the acquisition of a virulence plasmid is sufficient to transition beneficial symbionts to phytopathogens. This evolutionary transition, along with the distribution patterns of plasmids, reveals the impact of horizontal gene transfer in rapidly generating new pathogenic lineages and provides an alternative explanation for pathogen transmission patterns. Results also uncovered a misdiagnosed epidemic that implicated beneficial Rhodococcus bacteria as pathogens of pistachio. The misdiagnosis perpetuated the unnecessary removal of trees and exacerbated economic losses. PMID- 29231815 TI - Endothelial cells express NKG2D ligands and desensitize antitumor NK responses. AB - Natural Killer (NK) cells confer protection from tumors and infections by releasing cytotoxic granules and pro-inflammatory cytokines upon recognition of diseased cells. The responsiveness of NK cells to acute stimulation is dynamically tuned by steady-state receptor-ligand interactions of an NK cell with its cellular environment. Here, we demonstrate that in healthy WT mice the NK activating receptor NKG2D is engaged in vivo by one of its ligands, RAE-1epsilon, which is expressed constitutively by lymph node endothelial cells and highly induced on tumor-associated endothelium. This interaction causes internalization of NKG2D from the NK cell surface and transmits an NK-intrinsic signal that desensitizes NK cell responses globally to acute stimulation, resulting in impaired NK antitumor responses in vivo. PMID- 29231817 TI - Plasmid-powered evolutionary transitions. AB - The acquisition of a virulence plasmid is sufficient to turn a beneficial strain of Rhodococcus bacteria into a pathogen. PMID- 29231816 TI - Cell lineage and cell cycling analyses of the 4d micromere using live imaging in the marine annelid Platynereis dumerilii. AB - Cell lineage, cell cycle, and cell fate are tightly associated in developmental processes, but in vivo studies at single-cell resolution showing the intricacies of these associations are rare due to technical limitations. In this study on the marine annelid Platynereis dumerilii, we investigated the lineage of the 4d micromere, using high-resolution long-term live imaging complemented with a live cell cycle reporter. 4d is the origin of mesodermal lineages and the germline in many spiralians. We traced lineages at single-cell resolution within 4d and demonstrate that embryonic segmental mesoderm forms via teloblastic divisions, as in clitellate annelids. We also identified the precise cellular origins of the larval mesodermal posterior growth zone. We found that differentially-fated progeny of 4d (germline, segmental mesoderm, growth zone) display significantly different cell cycling. This work has evolutionary implications, sets up the foundation for functional studies in annelid stem cells, and presents newly established techniques for live imaging marine embryos. PMID- 29231819 TI - Holding Area LINQ Trial (HALT). AB - BACKGROUND: Recent studies have shown that insertable cardiac monitors (ICMs) can be implanted out of the traditional hospital setting and efforts are being made to explore the feasibility of implanting these devices in a specific standardized location other than the operating room or a cardiac catherization/electrophysiology lab. METHODS: This was a prospective, non randomized, single center post-market clinical trial designed to occur in the holding area of a hospital operating room or cardiac catheterization/electrophysiology laboratory. The Medtronic Reveal LINQ ICM was implanted and patients were followed for 90 days post implant. This study was designed to observe any procedure related adverse events stemming from the holding area implantation. RESULTS: Twenty patients were implanted at our hospital in a holding room not traditionally associated with the electrophysiology/cardiac/operatory labs. One patient was lost to the 90-day follow up. In one case, ICM implantation led to diagnosis requiring removal of ICM before the 90 day follow up and insertion of a biventricular implantable cardioverter defibrillator (ICD). In the remaining 18 patients, there were no serious complications such as minor skin infections, systemic infections or procedure-related adverse events requiring device explant. CONCLUSION: When following a standardized protocol with attention to sterile technique, it is feasible to implant ICMs in a holding area with no procedure related adverse events (AE). PMID- 29231818 TI - Molecular basis of fatty acid taste in Drosophila. AB - Behavioral studies have established that Drosophila appetitive taste responses towards fatty acids are mediated by sweet sensing Gustatory Receptor Neurons (GRNs). Here we show that sweet GRN activation requires the function of the Ionotropic Receptor genes IR25a, IR76b and IR56d. The former two IR genes are expressed in several neurons per sensillum, while IR56d expression is restricted to sweet GRNs. Importantly, loss of appetitive behavioral responses to fatty acids in IR25a and IR76b mutant flies can be completely rescued by expression of respective transgenes in sweet GRNs. Interestingly, appetitive behavioral responses of wild type flies to hexanoic acid reach a plateau at ~1%, but decrease with higher concentration, a property mediated through IR25a/IR76b independent activation of bitter GRNs. With our previous report on sour taste, our studies suggest that IR-based receptors mediate different taste qualities through cell-type specific IR subunits. PMID- 29231821 TI - Familial atrioventricular nodal re-entrant tachycardia: A case seriers and a systematic review. AB - Multiple reports of familial clustering suggest that genetic factors may contribute in the pathogenesis of atrioventricular nodal re-entrant tachycardia (AVNRT). We report three cases of AVNRT in a father and his two sons along with a review of literature of other similar cases. Electrophysiological studies induced typical AVNRT, which was successfully eliminated by radiofrequency ablation in all of them. Of the 22 reported cases, 96% had typical (slow-fast) variant of AVNRT. The predominant pattern of inheritance appears to be autosomal dominant, though other patterns may exist. Further research is needed to understand the genetic influence of AVNRT and its pathophysiology. PMID- 29231820 TI - Higher defibrillation threshold in methamphetamine cardiomyopathy patients with implantable cardioverter-defibrillator. AB - INTRODUCTION: Identification of patients with an increased risk of high defibrillation thresholds (DFTs) is important in planning implantable cardioverter-defibrillator (ICD) procedures. Clinical observations have suggested that patients with methamphetamine cardiomyopathy (MACMP) have significantly elevated defibrillation thresholds. We hypothesized that MACMP patients would have higher DFT thresholds than controls and would require procedural changes during ICD implantation to accommodate higher thresholds. METHODS: We identified consecutive patients with MACMP undergoing ICD implantation at the academic center from 2003 to 2007. We then compared DFTs against age-and sex-matched controls. RESULTS: The MACMP (n = 10) group showed significantly increased DFT thresholds (23.7 +/- 6.7 J) compared with age and sex-matched controls (14.5 +/- 4.6 J, p < 0.005). Additionally, patients with MACMP had evidence of more severe congestive heart failure, with increased B-type natrieutic protein (BNP) levels (1173 +/- 784 vs 260 +/- 349, p = 0.02) and decreased left ventricular ejection fraction (LVEF) (17.8 +/- 9.4 vs 35.9 +/- 15.2, p = 0.02). MACMP patients required high output devices than controls (50% versus 0%, p = 0.03). Differences between groups remained significant despite adjusting for LVEF. CONCLUSIONS: Planning for ICD implantation should take into consideration a history of methamphetamine abuse, mandating DFT testing and empiric consideration of high output devices for such patients. PMID- 29231822 TI - Zero fluoroscopy radiofrequency ablation for Typical Atrioventricular Nodal Reentrant Tachycardia (AVNRT). PMID- 29231823 TI - A deadly mix - rheumatic mitral stenosis, preexcited atrial fibrillation, left atrial appendage thrombus and left atrial appendage accessory pathway. PMID- 29231824 TI - Family planning: accelerating the way ahead. PMID- 29231825 TI - When a hospital becomes a prison. PMID- 29231826 TI - Offline: The tasks facing Dr Tedros. PMID- 29231827 TI - Phage therapy: revival of the bygone antimicrobial. PMID- 29231828 TI - Qimin Zhan: driving medical research for better health in China. PMID- 29231829 TI - Political determinants of Sustainable Development Goals. PMID- 29231830 TI - Health-care delivery for long-term survivors of childhood cancer. PMID- 29231831 TI - Anonymity in HIV testing: implications for public health. PMID- 29231832 TI - Overestimation of cardiovascular outcome incidence. PMID- 29231833 TI - Antiplatelet cessation to manage bleeding events in elderly people. PMID- 29231835 TI - Department of Error. PMID- 29231834 TI - Overestimation of cardiovascular outcome incidence - Authors' reply. PMID- 29231836 TI - Antiplatelet cessation to manage bleeding events in elderly people - Authors' reply. PMID- 29231837 TI - The primary health-care system in China. AB - China has made remarkable progress in strengthening its primary health-care system. Nevertheless, the system still faces challenges in structural characteristics, incentives and policies, and quality of care, all of which diminish its preparedness to care for a fifth of the world's population, which is ageing and which has a growing prevalence of chronic non-communicable disease. These challenges include inadequate education and qualifications of its workforce, ageing and turnover of village doctors, fragmented health information technology systems, a paucity of digital data on everyday clinical practice, financial subsidies and incentives that do not encourage cost savings and good performance, insurance policies that hamper the efficiency of care delivery, an insufficient quality measurement and improvement system, and poor performance in the control of risk factors (such as hypertension and diabetes). As China deepens its health-care reform, it has the opportunity to build an integrated, cooperative primary health-care system, generating knowledge from practice that can support improvements, and bolstered by evidence-based performance indicators and incentives. PMID- 29231838 TI - China's Silk Road and global health. AB - In 2013, China proposed its Belt and Road Initiative to promote trade, infrastructure, and commercial associations with 65 countries in Asia, Africa, and Europe. This initiative contains important health components. Simultaneously, China launched an unprecedented overseas intervention against Ebola virus in west Africa, dispatching 1200 workers, including Chinese military personnel. The overseas development assistance provided by China has been increasing by 25% annually, reaching US$7 billion in 2013. Development assistance for health from China has particularly been used to develop infrastructure and provide medical supplies to Africa and Asia. China's contributions to multilateral organisations are increasing but are unlikely to bridge substantial gaps, if any, vacated by other donors; China is creating its own multilateral funds and banks and challenging the existing global architecture. These new investment vehicles are more aligned with the geography and type of support of the Belt and Road Initiative. Our analysis concludes that China's Belt and Road Initiative, Ebola response, development assistance for health, and new investment funds are complementary and reinforcing, with China shaping a unique global engagement impacting powerfully on the contours of global health. PMID- 29231839 TI - Millions in need of humanitarian assistance in Yemen. PMID- 29231840 TI - Autopsy learning module: a tool for assessing self-reflection and practice improvement competency. PMID- 29231841 TI - Thermoelectric properties of periodic quantum structures in the Wigner-Rode formalism. AB - Improving the thermoelectric Seebeck coefficient, while simultaneously reducing thermal conductivity, is required in order to boost thermoelectric (TE) figure of merit (ZT). A common approach to improve the Seebeck coefficient is electron filtering where 'cold' (low energy) electrons are restricted from participating in transport by an energy barrier (Kim and Lundstrom 2011 J. Appl. Phys. 110 034511, Zide et al 2010 J. Appl. Phys. 108 123702). However, the impact of electron tunneling through thin barriers and resonant states on TE properties has been given less attention, despite the widespread use of quantum wells and superlattices (SLs) in TE applications. In our work, we develop a comprehensive transport model using the Wigner-Rode formalism. We include the full electronic bandstructure and all the relevant scattering mechanisms, allowing us to simulate both energy relaxation and quantum effects from periodic potential barriers. We study the impact of barrier shape on TE performance and find that tall, sharp barriers with small period lengths lead to the largest increase in both Seebeck coefficient and conductivity, thus boosting power factor and TE efficiency. Our findings are robust against additional elastic scattering such as atomic-scale roughness at side-walls of SL nanowires. PMID- 29231842 TI - Smell of cells: Volatile profiling of stem- and non-stem cell proliferation. AB - Bacterial and cell cultures are known to emit a large number of volatile organic compounds (VOCs). Conventional biochemical methods are often destructive, time consuming and expensive. In contrast, VOC analysis of headspace over cultures may offer a non-destructive alternative for the monitoring of cell proliferation and metabolism. VOC profiles from cultures of murine pluripotent stem cells and fibroblasts were assessed every 24 h for 3 days. Pure cell media were measured as parallel controls. VOC analysis was highly standardized with respect to time of measurement and phases of cell growth. Cultures were grown in custom-made inert boxes. In order to determine the effects of fresh media supply on VOC emissions, both cell types were cultured with and without daily media exchange. VOCs from headspace were preconcentrated by means of needle trap micro-extraction and analysed by gas chromatography-mass spectrometry (GC-MS). Murine pluripotent stem cells emitted increasing concentrations of thiirane and methyl-methoxy-hydroxy methyl-amine (MMHA). Substance concentration correlated with cell numbers. Murine fibroblasts did not emit thiirane or MMHA. Concentrations of aldehydes, especially benzaldehyde, were lower in both cell cultures than in pure media samples. Daily media exchange resulted in higher cell numbers, but had no major effects on VOC concentrations emitted from the cells. Investigation and monitoring of volatile substances such as thiirane and MMHA may enhance the understanding of stem cell properties and lead to a destruction-free characterization of pluripotent stem cells. PMID- 29231843 TI - The Lipid Lowering and Cardioprotective Effects of Vernonia calvoana Ethanol Extract in Acetaminophen-Treated Rats. AB - Background: Paracetamol overdose/abuse as a result of self-medication is a common occurrence amongst people living in low/middle income countries. The present study was designed to investigate the hypolipidemic and cardioprotective potentials of Vernonia calvoana (VC) ethanol extract in acetaminophen (paracetamol)-treated rats. Methods: Thirty-five Wistar rats weighing 100-150 g were randomly assigned into five groups of seven rats each. Groups 2-5 received high doses of paracetamol to induce liver damage, while group 1 was used as normal control. Afterwards, they were allowed to receive varying doses of VC (group 3 and 4) or vitamin E (group 5), whilst groups 1 and 2 were left untreated. The treatment period lasted for twenty one days after which sera were harvested and assayed for serum lipid indices using standard methods. Results: Groups 3 to 5 treated animals indicated significant decrease (p < 0.001) in low density lipoprotein cholesterol (LDL-c), total cholesterol (TC) and triacylglycerol (TG) levels relative to the normal and acetaminophen-treated controls, the atherogenic index showed a significant decrease (p < 0.001) in all treated groups compared with normal and acetaminophen-treated controls. However, the VC- and vitamin E-treated groups showed significant (p < 0.001) increase in high density lipoprotein cholesterol (HDL-C) relative to the controls. Conclusions: Data from our study suggest that ethanol leaf extract of VC possesses probable hypolipidemic and cardioprotective effects. PMID- 29231844 TI - Collismycin C from the Micronesian Marine Bacterium Streptomyces sp. MC025 Inhibits Staphylococcus aureus Biofilm Formation. AB - Biofilm formation plays a critical role in antimicrobial resistance in Staphylococcus aureus. Here, we investigated the potential of crude extracts of 79 Micronesian marine microorganisms to inhibit S. aureus biofilm formation. An extract of Streptomyces sp. MC025 inhibited S. aureus biofilm formation. Bioactivity-guided isolation led to the isolation of a series of 2,2' bipyridines: collismycin B (1), collismycin C (2), SF2738 D (3), SF2738 F (4), pyrisulfoxin A (5), and pyrisulfoxin B (6). Among these bipyridines, collismycin C (2) was found to be the most effective inhibitor of biofilm formation by methicillin-sensitive S. aureus and methicillin-resistant S. aureus (MRSA), and this compound inhibited MRSA biofilm formation by more than 90% at a concentration of 50 MUg/mL. The antibiofilm activity of collismycin C was speculated to be related to iron acquisition and the presence and position of the hydroxyl group of 2,2'-bipyridines. PMID- 29231847 TI - Natural Knockouts: Natural Selection Knocked Out. AB - In functional genomics studies, research is dedicated to unveiling the function of genes using gene-knockouts, model organisms in which a gene is artificially inactivated. The idea is that, by knocking out the gene, the provoked phenotype would inform us about the function of the gene. Still, the function of many genes cannot be elucidated, because disruption of conserved sequences, including protein-coding genes, often does not directly affect the phenotype. Since the phenomenon was first observed in the early nineties of the last century, these so called 'no-phenotype knockouts' have met with great skepticism and resistance by died-in-the-wool selectionists. Still, functional genomics of the late 20th and early 21st centuries has taught us two important lessons. First, two or more unrelated genes can often substitute for each other; and second, some genes are only present in the genome in a silent state. In the laboratory, the disruption of such genes does not negatively influence reproductive success, and does not show measurable fitness effects of the species. The genes are redundant. Genetic redundancy, one of the big surprises of modern biology, can thus be defined as the condition in which the inactivation of a gene is selectively neutral. The no phenotype knockout is not just a freak of the laboratory. Genetic variants known as homozygous loss-of-function (HLOF) variants are of considerable scientific and clinical interest, as they represent experiments of nature qualifying as "natural knockouts". Such natural knockouts challenge the conventional NeoDarwinian appraisal that genetic information is the result of natural selection acting on random genetic variation. PMID- 29231846 TI - The Discrepant and Similar Responses of Genome-Wide Transcriptional Profiles between Drought and Cold Stresses in Cassava. AB - Background: Cassava, an important tropical crop, has remarkable drought tolerance, but is very sensitive to cold. The growth, development, and root productivity of cassava are all adversely affected under cold and drought. Methods: To profile the transcriptional response to cold and drought stresses, cassava seedlings were respectively subjected to 0, 6, 24, and 48 h of cold stress and 0, 4, 6, and 10 days of drought stress. Their folded leaves, fully extended leaves, and roots were respectively investigated using RNA-seq. Results: Many genes specifically and commonly responsive to cold and drought were revealed: genes related to basic cellular metabolism, tetrapyrrole synthesis, and brassinosteroid metabolism exclusively responded to cold; genes related to abiotic stress and ethylene metabolism exclusively responded to drought; and genes related to cell wall, photosynthesis, and carbohydrate metabolism, DNA synthesis/chromatic structure, abscisic acid and salicylic acid metabolism, and calcium signaling commonly responded to both cold and drought. Discussion: Combined with cold- and/or drought-responsive transcription factors, the regulatory networks responding to cold and drought in cassava were constructed. All these findings will improve our understanding of the specific and common responses to cold and drought in cassava, and shed light on genetic improvement of cold and drought tolerance in cassava. PMID- 29231848 TI - On-Line Corrosion Monitoring of Plate Structures Based on Guided Wave Tomography Using Piezoelectric Sensors. AB - Corrosion is a major safety and economic concern to various industries. In this paper, a novel ultrasonic guided wave tomography (GWT) system based on self designed piezoelectric sensors is presented for on-line corrosion monitoring of large plate-like structures. Accurate thickness reconstruction of corrosion damages is achieved by using the dispersive regimes of selected guided waves and a reconstruction algorithm based on full waveform inversion (FWI). The system makes use of an array of miniaturised piezoelectric transducers that are capable of exciting and receiving highly dispersive A0 Lamb wave mode at low frequencies. The scattering from transducer array has been found to have a small effect on the thickness reconstruction. The efficiency and the accuracy of the new system have been demonstrated through continuous forced corrosion experiments. The FWI reconstructed thicknesses show good agreement with analytical predictions obtained by Faraday's law and laser measurements, and more importantly, the thickness images closely resemble the actual corrosion sites. PMID- 29231849 TI - Evolution of Karyotypes in Chameleons. AB - The reconstruction of the evolutionary dynamics of karyotypes and sex determining systems in squamate reptiles is precluded by the lack of data in many groups including most chameleons (Squamata: Acrodonta: Chamaeleonidae). We performed cytogenetic analysis in 16 species of chameleons from 8 genera covering the phylogenetic diversity of the family and also phylogenetic reconstruction of karyotype evolution in this group. In comparison to other squamates, chameleons demonstrate rather variable karyotypes, differing in chromosome number, morphology and presence of interstitial telomeric signal (ITS). On the other hand, the location of rDNA is quite conserved among chameleon species. Phylogenetic analysis combining our new results and previously published data tentatively suggests that the ancestral chromosome number for chameleons is 2n = 36, which is the same as assumed for other lineages of the clade Iguania, i.e., agamids and iguanas. In general, we observed a tendency for the reduction of chromosome number during the evolution of chameleons, however, in Rieppeleon brevicaudatus, we uncovered a chromosome number of 2n = 62, very unusual among squamates, originating from a number of chromosome splits. Despite the presence of the highly differentiated ZZ/ZW sex chromosomes in the genus Furcifer, we did not detect any unequivocal sexual differences in the karyotypes of any other studied species of chameleons tested using differential staining and comparative genomic hybridization, suggesting that sex chromosomes in most chameleons are only poorly differentiated. PMID- 29231850 TI - Rational Design Approach for Enhancing Higher-Mode Response of a Microcantilever in Vibro-Impacting Mode. AB - This paper proposes an approach for designing an efficient vibration energy harvester based on a vibro-impacting piezoelectric microcantilever with a geometric shape that has been rationally modified in accordance with results of dynamic optimization. The design goal is to increase the amplitudes of higher order vibration modes induced during the vibro-impact response of the piezoelectric transducer, thereby providing a means to improve the energy conversion efficiency and power output. A rational configuration of the energy harvester is proposed and it is demonstrated that the new design retains essential modal characteristics of the optimal microcantilever structures, further providing the added benefit of less costly fabrication. The effects of structural dynamics associated with advantageous exploitation of higher vibration modes are analyzed experimentally by means of laser vibrometry as well as numerically via transient simulations of microcantilever response to random excitation. Electrical characterization results indicate that the proposed harvester outperforms its conventional counterpart (based on the microcantilever of the constant cross-section) in terms of generated electrical output. Reported results may serve for the development of impact-type micropower generators with harvesting performance that is enhanced by virtue of self-excitation of large intensity higher-order mode responses when the piezoelectric transducer is subjected to relatively low-frequency excitation with strongly variable vibration magnitudes. PMID- 29231845 TI - Maillard Proteomics: Opening New Pages. AB - Protein glycation is a ubiquitous non-enzymatic post-translational modification, formed by reaction of protein amino and guanidino groups with carbonyl compounds, presumably reducing sugars and alpha-dicarbonyls. Resulting advanced glycation end products (AGEs) represent a highly heterogeneous group of compounds, deleterious in mammals due to their pro-inflammatory effect, and impact in pathogenesis of diabetes mellitus, Alzheimer's disease and ageing. The body of information on the mechanisms and pathways of AGE formation, acquired during the last decades, clearly indicates a certain site-specificity of glycation. It makes characterization of individual glycation sites a critical pre-requisite for understanding in vivo mechanisms of AGE formation and developing adequate nutritional and therapeutic approaches to reduce it in humans. In this context, proteomics is the methodology of choice to address site-specific molecular changes related to protein glycation. Therefore, here we summarize the methods of Maillard proteomics, specifically focusing on the techniques providing comprehensive structural and quantitative characterization of glycated proteome. Further, we address the novel break-through areas, recently established in the field of Maillard research, i.e., in vitro models based on synthetic peptides, site-based diagnostics of metabolism-related diseases (e.g., diabetes mellitus), proteomics of anti-glycative defense, and dynamics of plant glycated proteome during ageing and response to environmental stress. PMID- 29231851 TI - Enhanced Methods to Estimate the Efficiency of Magnetic Nanoparticles in Imaging. AB - Magnetic resonance imaging (MRI) and magnetic particle imaging (MPI) are powerful methods in the early diagnosis of diseases. Both imaging techniques utilize magnetic nanoparticles that have high magnetic susceptibility, strong saturation magnetization, and no coercivity. FeraSpinTM R and its fractionated products have been studied for their imaging performances; however, a detailed magnetic characterization in their immobilized state is still lacking. This is particularly important for applications in MPI that require fixation of magnetic nanoparticles with the target cells or tissues. We examine the magnetic properties of immobilized FeraSpinTM R, its size fractions, and Resovist(r), and use the findings to demonstrate which magnetic properties best predict performance. All samples show some degree of oxidation to hematite, and magnetic interaction between the particles, which impact negatively on image performance of the materials. MRI and MPI performance show a linear dependency on the slope of the magnetization curve, i.e., initial susceptibility, and average blocking temperature. The best performance of particles in immobilized state for MPI is found for particle sizes close to the boundary between superparamagnetic (SP) and magnetically ordered, in which only Neel relaxation is important. Initial susceptibility and bifurcation temperature are the best indicators to predict MRI and MPI performance. PMID- 29231852 TI - Photorelaxation and Photorepair Processes in Nucleic and Amino Acid Derivatives. AB - Understanding the fundamental interaction between electromagnetic radiation and matter is essential for a large number of phenomena, with significance to civilization.[...]. PMID- 29231853 TI - Synthesis of Formate Esters and Formamides Using an Au/TiO2-Catalyzed Aerobic Oxidative Coupling of Paraformaldehyde. AB - A simple method for the synthesis of formate esters and formamides is presented based on the Au/TiO2-catalyzed aerobic oxidative coupling between alcohols or amines and formaldehyde. The suitable form of formaldehyde is paraformaldehyde, as cyclic trimeric 1,3,5-trioxane is inactive. The reaction proceeds via the formation of an intermediate hemiacetal or hemiaminal, respectively, followed by the Au nanoparticle-catalyzed aerobic oxidation of the intermediate. Typically, the oxidative coupling between formaldehyde (2 equiv) and amines occurs quantitatively at room temperature within 4 h, and there is no need to add a base as in analogous coupling reactions. The oxidative coupling between formaldehyde (typically 3 equiv) and alcohols is unprecedented and occurs more slowly, yet in good to excellent yields and selectivity. Minor side-products (2-12%) from the acetalization of formaldehyde by the alcohol are also formed. The catalyst is recyclable and can be reused after a simple filtration in five consecutive runs with a small loss of activity. PMID- 29231854 TI - Nisin in Combination with Cinnamaldehyde and EDTA to Control Growth of Escherichia coli Strains of Swine Origin. AB - Post-weaning diarrhoea (PWD) due to enterotoxigenic Escherichia coli (ETEC) is an economically important disease in pig production worldwide. Although antibiotics have contributed significantly to mitigate the economic losses caused by PWD, there is major concern over the increased incidence of antimicrobial resistance among bacteria isolated from pigs. Consequently, suitable alternatives that are safe and effective are urgently required. Many naturally occurring compounds, including the antimicrobial peptide nisin and a number of plant essential oils, have been widely studied and are reported to be effective as antimicrobial agents against pathogenic microorganisms. Here, we evaluate the potential of nisin in combination with the essential oil cinnamaldehyde and ethylenediaminetetraacetic acid (EDTA) to control the growth of E. coli strains of swine origin including two characterized as ETEC. The results reveal that the use of nisin (10 MUM) with low concentrations of trans-cinnamaldehyde (125 MUg/mL) and EDTA (0.25-2%) resulted in extended lag phases of growth compared to when either antimicrobial is used alone. Further analysis through kill curves revealed that an approximate 1-log reduction in E. coli cell counts was observed against the majority of targets tested following 3 h incubation. These results highlight the potential benefits of combining the natural antimicrobial nisin with trans-cinnamaldehyde and EDTA as a new approach for the inhibition of E. coli strains of swine origin. PMID- 29231855 TI - Differences of Rotavirus Vaccine Effectiveness by Country: Likely Causes and Contributing Factors. AB - Rotaviruses are a major cause of acute gastroenteritis in infants and young children worldwide and in many other mammalian and avian host species. Since 2006, two live-attenuated rotavirus vaccines, Rotarix(r) and RotaTeq(r), have been licensed in >100 countries and are applied as part of extended program of vaccination (EPI) schemes of childhood vaccinations. Whereas the vaccines have been highly effective in high-income countries, they were shown to be considerably less potent in low- and middle-income countries. Rotavirus associated disease was still the cause of death in >200,000 children of <5 years of age worldwide in 2013, and the mortality is concentrated in countries of sub Saharan Africa and S.E. Asia. Various factors that have been identified or suggested as being involved in the differences of rotavirus vaccine effectiveness are reviewed here. Recognition of these factors will help to achieve gradual worldwide improvement of rotavirus vaccine effectiveness. PMID- 29231856 TI - Involvement of UDP-Glucuronosyltransferases and Sulfotransferases in the Excretion and Tissue Distribution of Resveratrol in Mice. AB - Resveratrol is a naturally occurring polyphenolic compound with various pharmacological activities. It is unknown whether the expression of metabolizing enzymes correlates with resveratrol levels in organs and tissues. Therefore, we investigated the metabolism and tissue distribution of resveratrol in mice and assessed its association with the expression of UDP-glucuronosyltransferase (Ugt) and sulfotransferase (Sult) genes. Plasma, urine, feces, and various organs were analyzed using high-performance liquid chromatography at up to 8 h after intragastric resveratrol administration. The metabolism of resveratrol was pronounced, leading to the formation of resveratrol glucuronides and sulfates. Concentrations of resveratrol and its metabolites were high in the gastrointestinal organs, urine, and feces, but low in the liver and kidneys. In lung, heart, thymus, and brain tissues, parent resveratrol levels exceeded the sulfate and glucuronide concentrations. The formation of resveratrol conjugates correlated with the expression of certain Ugt and Sult genes. Reverse transcription quantitative PCR (RT-qPCR) analysis revealed high mRNA expression of Ugt1a1 and Ugt1a6a in the liver, duodenum, jejunum, ileum, and colon, leading to high concentrations of resveratrol-3-O-glucuronide in these organs. Strong correlations of resveratrol-3-O-sulfate and resveratrol-3-O-4'-O-disulfate formation with Sult1a1 mRNA expression were also observed, particularly in the liver and colon. In summary, our data revealed organ-specific expression of Sults and Ugts in mice that strongly affects resveratrol concentrations; this may also be predictive in humans following oral uptake of dietary resveratrol. PMID- 29231857 TI - Biodegradable Scaffolds for Bone Regeneration Combined with Drug-Delivery Systems in Osteomyelitis Therapy. AB - A great deal of research is ongoing in the area of tissue engineering (TE) for bone regeneration. A possible improvement in restoring damaged tissues involves the loading of drugs such as proteins, genes, growth factors, antibiotics, and anti-inflammatory drugs into scaffolds for tissue regeneration. This mini-review is focused on the combination of the local delivery of antibiotic agents with bone regenerative therapy for the treatment of a severe bone infection such as osteomyelitis. The review includes a brief explanation of scaffolds for bone regeneration including scaffolds characteristics and types, a focus on severe bone infections (especially osteomyelitis and its treatment), and a literature review of local antibiotic delivery by the combination of scaffolds and drug delivery systems. Some examples related to published studies on gentamicin sulfate-loaded drug-delivery systems combined with scaffolds are discussed, and future perspectives are highlighted. PMID- 29231858 TI - Anti-Allergic Activity of Monoacylated Ascorbic Acid 2-Glucosides. AB - 2-O-alpha-d-Glucopyranosyl-l-ascorbic acid (AA-2G) is one of the stable ascorbic acid (AA) derivatives known as provitamin C agents. We have previously synthesized two types of monoacylated derivatives of AA-2G, 6-O-acyl-2-O-alpha-d glucopyranosyl-l-ascorbic acids having a straight-acyl chain of varying length from C4 to C18 (6-sAcyl-AA-2G) and a branched-acyl chain of varying length from C6 to C16 (6-bAcyl-AA-2G) in order to improve the bioavailability of AA-2G. In this study, 6-sAcyl-AA-2G and 6-bAcyl-AA-2G per se showed the inhibitory effects on hyaluronidase activity and degranulation. 6-sAcyl-AA-2G exhibited strong inhibitory effects on hyaluronidase activity and degranulation in a concentration dependent manner, and the inhibitory effects tended to become stronger with increasing length of the acyl chain. 2-O-alpha-d-Glucopyranosyl-6-O-hexadecanoyl l-ascorbic acid (6-sPalm-AA-2G), which has a straight C16 acyl chain, was the most potent effective for inhibition of hyaluronidase activity and for inhibition of degranulation among the 6-sAcyl-AA-2G derivatives and the two isomers of 6 sPalm-AA-2G. Furthermore, percutaneous administration of 6-sPalm-AA-2G significantly inhibited IgE-mediated passive cutaneous anaphylaxis reaction in mice. These findings suggest that 6-sPalm-AA-2G will be useful for treatment of allergies. PMID- 29231859 TI - Rational Engineering of a Flavoprotein Oxidase for Improved Direct Oxidation of Alcohols to Carboxylic Acids. AB - The oxidation of alcohols to the corresponding carbonyl or carboxyl compounds represents a convenient strategy for the selective introduction of electrophilic carbon centres into carbohydrate-based starting materials. The O2-dependent oxidation of prim-alcohols by flavin-containing alcohol oxidases often yields mixtures of aldehyde and carboxylic acid, which is due to "over-oxidation" of the aldehyde hydrate intermediate. In order to directly convert alcohols into carboxylic acids, rational engineering of 5-(hydroxymethyl)furfural oxidase was performed. In an attempt to improve the binding of the aldehyde hydrate in the active site to boost aldehyde-oxidase activity, two active-site residues were exchanged for hydrogen-bond-donating and -accepting amino acids. Enhanced over oxidation was demonstrated and Michaelis-Menten kinetics were performed to corroborate these findings. PMID- 29231860 TI - Predicting the Functional Impact of CDH1 Missense Mutations in Hereditary Diffuse Gastric Cancer. AB - The role of E-cadherin in Hereditary Diffuse Gastric Cancer (HDGC) is unequivocal. Germline alterations in its encoding gene (CDH1) are causative of HDGC and occur in about 40% of patients. Importantly, while in most cases CDH1 alterations result in the complete loss of E-cadherin associated with a well established clinical impact, in about 20% of cases the mutations are of the missense type. The latter are of particular concern in terms of genetic counselling and clinical management, as the effect of the sequence variants in E cadherin function is not predictable. If a deleterious variant is identified, prophylactic surgery could be recommended. Therefore, over the last few years, intensive research has focused on evaluating the functional consequences of CDH1 missense variants and in assessing E-cadherin pathogenicity. In that context, our group has contributed to better characterize CDH1 germline missense variants and is now considered a worldwide reference centre. In this review, we highlight the state of the art methodologies to categorize CDH1 variants, as neutral or deleterious. This information is subsequently integrated with clinical data for genetic counseling and management of CDH1 variant carriers. PMID- 29231861 TI - Sulfonic Acid Functionalization of Different Zeolites and Their Use as Catalysts in the Microwave-Assisted Etherification of Glycerol with tert-Butyl Alcohol. AB - The etherification of glycerol with tert-butyl alcohol in the liquid phase, over different sulfonic acid functionalized zeolites, has been studied. The reaction was carried out using microwaves as a way of heating, measured at autogenous pressure and without any solvent. Dealuminated HY and HZSM-5 zeolites by acid treatment were functionalized with two different organosilica precursors: 3 mercaptopropyltrimethoxysilane (M), which incorporates thiol groups, and 2-(4 chlorosulfonylphenyl)ethyltrimethoxysilane (C), which incorporates the sulfonic acid groups directly. The thiol groups were oxidized into sulfonic groups employing hydrogen peroxide. The textural and structural properties of the solids were studied by XRD and N2 adsorption-desorption isotherms, whereas the incorporation of the organosilica in the zeolites was studied by TGA and XPS. The novelty functionalization of M gave rise to solids with the highest acidity, and exhibited the highest yields with more substituted ethers (Yh-GTBE = 13%), at 75 degrees C and 15 min of reaction time. In addition to the acidity, the textural properties of the zeolites played an important role in their activity; HY, with the largest size of the channels, were more active than the HZSM-5. PMID- 29231864 TI - Vibration Sensor Monitoring of Nickel-Titanium Alloy Turning for Machinability Evaluation. AB - Nickel-Titanium (Ni-Ti) alloys are very difficult-to-machine materials causing notable manufacturing problems due to their unique mechanical properties, including superelasticity, high ductility, and severe strain-hardening. In this framework, the aim of this paper is to assess the machinability of Ni-Ti alloys with reference to turning processes in order to realize a reliable and robust in process identification of machinability conditions. An on-line sensor monitoring procedure based on the acquisition of vibration signals was implemented during the experimental turning tests. The detected vibration sensorial data were processed through an advanced signal processing method in time-frequency domain based on wavelet packet transform (WPT). The extracted sensorial features were used to construct WPT pattern feature vectors to send as input to suitably configured neural networks (NNs) for cognitive pattern recognition in order to evaluate the correlation between input sensorial information and output machinability conditions. PMID- 29231863 TI - Silk Materials Functionalized via Genetic Engineering for Biomedical Applications. AB - The great mechanical properties, biocompatibility and biodegradability of silk based materials make them applicable to the biomedical field. Genetic engineering enables the construction of synthetic equivalents of natural silks. Knowledge about the relationship between the structure and function of silk proteins enables the design of bioengineered silks that can serve as the foundation of new biomaterials. Furthermore, in order to better address the needs of modern biomedicine, genetic engineering can be used to obtain silk-based materials with new functionalities. Sequences encoding new peptides or domains can be added to the sequences encoding the silk proteins. The expression of one cDNA fragment indicates that each silk molecule is related to a functional fragment. This review summarizes the proposed genetic functionalization of silk-based materials that can be potentially useful for biomedical applications. PMID- 29231865 TI - In Vivo Dual-Modality Fluorescence and Magnetic Resonance Imaging-Guided Lymph Node Mapping with Good Biocompatibility Manganese Oxide Nanoparticles. AB - Multifunctional manganese oxide nanoparticles (NPs) with impressive enhanced T1 contrast ability show great promise in biomedical diagnosis. Herein, we developed a dual-modality imaging agent system based on polyethylene glycol (PEG)-coated manganese oxide NPs conjugated with organic dye (Cy7.5), which functions as a fluorescence imaging (FI) agent as well as a magnetic resonance imaging (MRI) imaging agent. The formed Mn3O4@PEG-Cy7.5 NPs with the size of ~10 nm exhibit good colloidal stability in different physiological media. Serial FI and MRI studies that non-invasively assessed the bio-distribution pattern and the feasibility for in vivo dual-modality imaging-guided lymph node mapping have been investigated. In addition, histological and biochemical analyses exhibited low toxicity even at a dose of 20 mg/kg in vivo. Since Mn3O4@PEG-Cy7.5 NPs exhibited desirable properties as imaging agents and good biocompatibility, this work offers a robust, safe, and accurate diagnostic platform based on manganese oxide NPs for tumor metastasis diagnosis. PMID- 29231862 TI - Conserved Binding Regions Provide the Clue for Peptide-Based Vaccine Development: A Chemical Perspective. AB - Synthetic peptides have become invaluable biomedical research and medicinal chemistry tools for studying functional roles, i.e., binding or proteolytic activity, naturally-occurring regions' immunogenicity in proteins and developing therapeutic agents and vaccines. Synthetic peptides can mimic protein sites; their structure and function can be easily modulated by specific amino acid replacement. They have major advantages, i.e., they are cheap, easily-produced and chemically stable, lack infectious and secondary adverse reactions and can induce immune responses via T- and B-cell epitopes. Our group has previously shown that using synthetic peptides and adopting a functional approach has led to identifying Plasmodium falciparumconserved regions binding to host cells. Conserved high activity binding peptides' (cHABPs) physicochemical, structural and immunological characteristics have been taken into account for properly modifying and converting them into highly immunogenic, protection-inducing peptides (mHABPs) in the experimental Aotus monkey model. This article describes stereo-electron and topochemical characteristics regarding major histocompatibility complex (MHC)-mHABP-T-cell receptor (TCR) complex formation. Some mHABPs in this complex inducing long-lasting, protective immunity have been named immune protection-inducing protein structures (IMPIPS), forming the subunit components in chemically synthesized vaccines. This manuscript summarizes this particular field and adds our recent findings concerning intramolecular interactions (H-bonds or pi-interactions) enabling proper IMPIPS structure as well as the peripheral flanking residues (PFR) to stabilize the MHCII-IMPIPS-TCR interaction, aimed at inducing long-lasting, protective immunological memory. PMID- 29231867 TI - Bipolar Switching Properties of Neodymium Oxide RRAM Devices Using by a Low Temperature Improvement Method. AB - Bipolar resistive switching properties and endurance switching behavior of the neodymium oxide (Nd2O3) thin films resistive random access memory (RRAM) devices for a high resistive status/low resistive status (HRS/LRS) using a low temperature supercritical carbon dioxide fluid (SCF) improvement post-treatment process were investigated. Electrical and physical properties improvement of Nd2O3 thin films were measured by X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and current versus voltage (I-V) measurement. The metal-like behavior of ohmic conduction mechanism and metallic cluster reaction of hopping conduction mechanism in initial metallic filament path forming process of the SCF-treated thin films RRAM devices was assumed and discussed. Finally, the electrical conduction mechanism of the thin films RRAM derives for set/reset was also discussed and verified in filament path physical model. PMID- 29231868 TI - A Data-Driven Response Virtual Sensor Technique with Partial Vibration Measurements Using Convolutional Neural Network. AB - Measurement of dynamic responses plays an important role in structural health monitoring, damage detection and other fields of research. However, in aerospace engineering, the physical sensors are limited in the operational conditions of spacecraft, due to the severe environment in outer space. This paper proposes a virtual sensor model with partial vibration measurements using a convolutional neural network. The transmissibility function is employed as prior knowledge. A four-layer neural network with two convolutional layers, one fully connected layer, and an output layer is proposed as the predicting model. Numerical examples of two different structural dynamic systems demonstrate the performance of the proposed approach. The excellence of the novel technique is further indicated using a simply supported beam experiment comparing to a modal-model based virtual sensor, which uses modal parameters, such as mode shapes, for estimating the responses of the faulty sensors. The results show that the presented data-driven response virtual sensor technique can predict structural response with high accuracy. PMID- 29231866 TI - The Consequences of Being in an Infectious Biofilm: Microenvironmental Conditions Governing Antibiotic Tolerance. AB - The main driver behind biofilm research is the desire to understand the mechanisms governing the antibiotic tolerance of biofilm-growing bacteria found in chronic bacterial infections. Rather than genetic traits, several physical and chemical traits of the biofilm have been shown to be attributable to antibiotic tolerance. During infection, bacteria in biofilms exhibit slow growth and a low metabolic state due to O2 limitation imposed by intense O2 consumption of polymorphonuclear leukocytes or metabolically active bacteria in the biofilm periphery. Due to variable O2 availability throughout the infection, pathogen growth can involve aerobic, microaerobic and anaerobic metabolism. This has serious implications for the antibiotic treatment of infections (e.g., in chronic wounds or in the chronic lung infection of cystic fibrosis patients), as antibiotics are usually optimized for aerobic, fast-growing bacteria. This review summarizes knowledge about the links between the microenvironment of biofilms in chronic infections and their tolerance against antibiotics. PMID- 29231869 TI - Functional Characterization of the Versatile MYB Gene Family Uncovered Their Important Roles in Plant Development and Responses to Drought and Waterlogging in Sesame. AB - The MYB gene family constitutes one of the largest transcription factors (TFs) modulating various biological processes in plants. Although genome-wide analysis of this gene family has been carried out in some species, only three MYB members have been functionally characterized heretofore in sesame (Sesamum indicum L.). Here, we identified a relatively high number (287) of sesame MYB genes (SIMYBs) with an uncommon overrepresentation of the 1R-subfamily. A total of 95% of SIMYBs was mapped unevenly onto the 16 linkage groups of the sesame genome with 55 SIMYBs tandemly duplicated. In addition, molecular characterization, gene structure, and evolutionary relationships of SIMYBs were established. Based on the close relationship between sesame and Arabidopsis thaliana, we uncovered that the functions of SIMYBs are highly diverse. A total of 65% of SIMYBs were commonly detected in five tissues, suggesting that they represent key TFs modulating sesame growth and development. Moreover, we found that SIMYBs regulate sesame responses to drought and waterlogging, which highlights the potential of SIMYBs towards improving stress tolerance in sesame. This work presents a comprehensive picture of the MYB gene family in sesame and paves the way for further functional validation of the members of this versatile gene family. PMID- 29231870 TI - Improving the Care and Treatment of Monkeypox Patients in Low-Resource Settings: Applying Evidence from Contemporary Biomedical and Smallpox Biodefense Research. AB - Monkeypox is a smallpox-like illness that can be accompanied by a range of significant medical complications. To date there are no standard or optimized guidelines for the clinical management of monkeypox (MPX) patients, particularly in low-resource settings. Consequently, patients can experience protracted illness and poor outcomes. Improving care necessitates developing a better understanding of the range of clinical manifestations-including complications and sequelae-as well as of features of illness that may be predictive of illness severity and poor outcomes. Experimental and natural infection of non-human primates with monkeypox virus can inform the approach to improving patient care, and may suggest options for pharmaceutical intervention. These studies have traditionally been performed to address the threat of smallpox bioterrorism and were designed with the intent of using MPX as a disease surrogate for smallpox. In many cases this necessitated employing high-dose, inhalational or intravenous challenge to recapitulate the severe manifestations of illness seen with smallpox. Overall, these data-and data from biomedical research involving burns, superficial wounds, herpes, eczema vaccinatum, and so forth-suggest that MPX patients could benefit from clinical support to mitigate the consequences of compromised skin and mucosa. This should include prevention and treatment of secondary bacterial infections (and other complications), ensuring adequate hydration and nutrition, and protecting vulnerable anatomical locations such as the eyes and genitals. A standard of care that considers these factors should be developed and assessed in different settings, using clinical metrics specific for MPX alongside consideration of antiviral therapies. PMID- 29231871 TI - In Vivo Non-Destructive Monitoring of Capsicum Annuum Seed Growth with Diverse NaCl Concentrations Using Optical Detection Technique. AB - We demonstrate that optical coherence tomography (OCT) is a plausible optical tool for in vivo detection of plant seeds and its morphological changes during growth. To investigate the direct impact of salt stress on seed germination, the experiment was conducted using Capsicum annuum seeds that were treated with different molar concentrations of NaCl. To determine the optimal concentration for the seed growth, the seeds were monitored for nine consecutive days. In vivo two-dimensional OCT images of the treated seeds were obtained and compared with the images of seeds that were grown using sterile distilled water. The obtained results confirm the feasibility of using OCT for the proposed application. Normalized depth profile analysis was utilized to support the conclusions. PMID- 29231873 TI - Does Practicing CSR Makes Consumers Like Your Shop More? Consumer-Retailer Love Mediates CSR and Behavioral Intentions. AB - This research paper was designed to examine the influence of corporate social responsibility (CSR) associations and environmental concerns on consumer-retailer love and attitude toward the retailer, as well as the subsequent effects on consumer behavioral intentions regarding the retailer, such as repeat patronage intention and willingness to pay a premium price for products offered by the retailer. In this study, a questionnaire survey was conducted on consumers for the purpose of investigating five proposed hypotheses. This research applied partial least squares (PLS) to exam the hypotheses and analyze the data. The findings of this research indicated that CSR association and environmental concern both have positive effects on consumer-retailer love and attitude toward the retailer. Also, the results showed that consumer-retailer love has a significantly positive effect on consumer attitude towards the retailer. This paper establishes that consumer-retailer love and attitude toward a retailer are main mediators of the relationship between CSR associations, environmental concern, and consumer behavioral intentions. PMID- 29231872 TI - A Deeper Examination of Thorellius atrox Scorpion Venom Components with Omic Techonologies. AB - This communication reports a further examination of venom gland transcripts and venom composition of the Mexican scorpion Thorellius atrox using RNA-seq and tandem mass spectrometry. The RNA-seq, which was performed with the Illumina protocol, yielded more than 20,000 assembled transcripts. Following a database search and annotation strategy, 160 transcripts were identified, potentially coding for venom components. A novel sequence was identified that potentially codes for a peptide with similarity to spider omega-agatoxins, which act on voltage-gated calcium channels, not known before to exist in scorpion venoms. Analogous transcripts were found in other scorpion species. They could represent members of a new scorpion toxin family, here named omegascorpins. The mass fingerprint by LC-MS identified 135 individual venom components, five of which matched with the theoretical masses of putative peptides translated from the transcriptome. The LC-MS/MS de novo sequencing allowed to reconstruct and identify 42 proteins encoded by assembled transcripts, thus validating the transcriptome analysis. Earlier studies conducted with this scorpion venom permitted the identification of only twenty putative venom components. The present work performed with more powerful and modern omic technologies demonstrates the capacity of accomplishing a deeper characterization of scorpion venom components and the identification of novel molecules with potential applications in biomedicine and the study of ion channel physiology. PMID- 29231876 TI - Consistently Sampled Correlation Filters with Space Anisotropic Regularization for Visual Tracking. AB - Most existing correlation filter-based tracking algorithms, which use fixed patches and cyclic shifts as training and detection measures, assume that the training samples are reliable and ignore the inconsistencies between training samples and detection samples. We propose to construct and study a consistently sampled correlation filter with space anisotropic regularization (CSSAR) to solve these two problems simultaneously. Our approach constructs a spatiotemporally consistent sample strategy to alleviate the redundancies in training samples caused by the cyclical shifts, eliminate the inconsistencies between training samples and detection samples, and introduce space anisotropic regularization to constrain the correlation filter for alleviating drift caused by occlusion. Moreover, an optimization strategy based on the Gauss-Seidel method was developed for obtaining robust and efficient online learning. Both qualitative and quantitative evaluations demonstrate that our tracker outperforms state-of-the art trackers in object tracking benchmarks (OTBs). PMID- 29231875 TI - Live Faecalibacterium prausnitzii Does Not Enhance Epithelial Barrier Integrity in an Apical Anaerobic Co-Culture Model of the Large Intestine. AB - Appropriate intestinal barrier maturation during infancy largely depends on colonization with commensal bacteria. Faecalibacterium prausnitzii is an abundant obligate anaerobe that colonizes during weaning and is thought to maintain colonic health throughout life. We previously showed that F. prausnitzii induced Toll-like receptor 2 (TLR2) activation, which is linked to enhanced tight junction formation. Therefore, we hypothesized that F. prausnitzii enhances barrier integrity, an important factor in appropriate intestinal barrier maturation. In order to test metabolically active bacteria, we used a novel apical anaerobic co-culture system that allows the survival of both obligate anaerobic bacteria and oxygen-requiring intestinal epithelial cells (Caco-2). The first aim was to optimize the culture medium to enable growth and active metabolism of F. prausnitzii while maintaining the viability and barrier integrity, as measured by trans-epithelial electrical resistance (TEER), of the Caco-2 cells. This was achieved by supplementing the apical cell culture medium with bacterial culture medium. The second aim was to test the effect of F. prausnitzii on TEER across Caco-2 cell layers. Live F. prausnitzii did not improve TEER, which indicates that its benefits are not via altering tight junction integrity. The optimization of the novel dual-environment co-culturing system performed in this research will enable the investigation of new probiotics originating from indigenous beneficial bacteria. PMID- 29231874 TI - The Role of Aquaporins in Ocular Lens Homeostasis. AB - Abstract: Aquaporins (AQPs), by playing essential roles in the maintenance of ocular lens homeostasis, contribute to the establishment and maintenance of the overall optical properties of the lens over many decades of life. Three aquaporins, AQP0, AQP1 and AQP5, each with distinctly different functional properties, are abundantly and differentially expressed in the different regions of the ocular lens. Furthermore, the diversity of AQP functionality is increased in the absence of protein turnover by age-related modifications to lens AQPs that are proposed to alter AQP function in the different regions of the lens. These regional differences in AQP functionality are proposed to contribute to the generation and directionality of the lens internal microcirculation; a system of circulating ionic and fluid fluxes that delivers nutrients to and removes wastes from the lens faster than could be achieved by passive diffusion alone. In this review, we present how regional differences in lens AQP isoforms potentially contribute to this microcirculation system by highlighting current areas of investigation and emphasizing areas where future work is required. PMID- 29231877 TI - Effects of Resveratrol, Lovastatin and the mTOR-Inhibitor RAD-001 on Insulin Induced Genomic Damage In Vitro. AB - Diabetes mellitus (DM) is one of the major current health problems due to lifestyle changes. Before diagnosis and in the early years of disease, insulin blood levels are elevated. However, insulin generates low levels of reactive oxygen species (ROS) which are integral to the regulation of a variety of intracellular signaling pathways, but excess levels of insulin may also lead to DNA oxidation and DNA damage. Three pharmaceutical compounds, resveratrol, lovastatin and the mTOR-inhibitor RAD-001, were investigated due to their known beneficial effects. They showed protective properties against genotoxic damage and significantly reduced ROS after in vitro treatment of cultured cells with insulin. Therefore, the selected pharmaceuticals may be attractive candidates to be considered for support of DM therapy. PMID- 29231878 TI - Greek Medicine Practice at Ancient Rome: The Physician Molecularist Asclepiades. AB - Background: In the pre-Hellenistic period, the concept of medicine was not well defined. Usually, a disease was considered as a divine punishment and its treatment was devolved to the priests who asked for healing from the divinities. The only job that could be compared to medical practice was a kind of itinerant medicine, derived from the Egyptian therapeutic tradition based only on practical experience and performed by people that knew a number of remedies, mostly vegetable, but without any theoretical bases about the possible mechanisms of action. Opinions about the human nature (naturalistic thinking) and the origin of the illness and heal were the basis of Greek medicine practiced by ancient priests of Asclepius. However, with the evolution of the thought for the continuous research of "kappaomicronsigmaMUomicronsigma" (world) knowledge, philosophy woulld become an integral part of medicine and its evolution. This close relationship between philosophy and medicine is confirmed by the Greek physician Galen in the era of the Roman Empire. Methods: Philosophical thought looked for world knowledge starting from mathematics, physics, astronomy, chemistry, medicine, psychology, metaphysics, sociology, and ethics. We must keep in mind that, according to the ancient people, the physicians could not heal the patients without the aid of a "divine God" until medicine, thanks to the Hippocratic practice, became more independent from the supernatural, and contemporary, ethical, and professional. Many physicians were philosophers, as confirmed by their views of life, such as Hippocrates of Cos, Aristotle (hailed as the father of comparative anatomy and physiology), Pythagoras of Samos, Alcmaeon of Croton, Empedocles, Praxagoras, Erasistratus, Galen, and others, including Asclepiades of Bithynia (atomists affinity). Asclepiades, a Greek physician born in Prusa, studied in Athens and Alexandria. His thought was influenced by Democritus' theories, refusing extensively the Hippocratic ideas that diseases are a result of mood imbalance. Results: Differing from the current Hippocratic idea, only in extreme cases he prescribed medications and bloodletting, two of the most-used therapies of that time. He usually prescribed therapies based on the Epicurean thought, then consisting of walks and music, massages, and thermal baths. He anticipated the modern idea of the body consisting of atoms, and believed that between the atoms exist empty spaces called pores. As the founder of the so called Methodist School, he was the first to divide acute and chronic diseases, and thought that body weakness was dependent on the excessive width of the pores, while their excessive shrinkage determines fever. According to his student Caelius Aurelianus he was the first to adopt tracheotomy as an emergency therapy for diphtheria. Conclusions: Although it is very difficult to reconstruct the theories of Asclepiades of Bithynia because of the lack of original texts, this paper attempts to focus his role and his thought in affirming the Greek medical practice in ancient Rome and to highlight his modernity. PMID- 29231879 TI - Molybdenum Dichalcogenides for Environmental Chemical Sensing. AB - 2D transition metal dichalcogenides are attracting a strong interest following the popularity of graphene and other carbon-based materials. In the field of chemical sensors, they offer some interesting features that could potentially overcome the limitation of graphene and metal oxides, such as the possibility of operating at room temperature. Molybdenum-based dichalcogenides in particular are among the most studied materials, thanks to their facile preparation techniques and promising performances. The present review summarizes the advances in the exploitation of these MoX2 materials as chemical sensors for the detection of typical environmental pollutants, such as NO2, NH3, CO and volatile organic compounds. PMID- 29231880 TI - Facile Chemical Access to Biologically Active Norcantharidin Derivatives from Biomass. AB - Reductive amination of 2,5-diformylfuran (DFF) was used to implement the transition from bio-derived 5-hydroxymethylfurfural (HMF) to pharmaceuticals. The synthesized bis(aminomethyl)furans were utilized as building blocks for the construction of new derivatives with structural cores of naturally occurring biologically active compounds. Using the one-pot procedure, which included the Diels-Alder reaction followed by hydrogenation of the double bond, bio-derived analogues of the anticancer drug norcantharidin were obtained. The cyclization process was diastereoselective, and resulted in the formation of tricyclic products with the endo configuration. Analysis of cytotoxycity for the resulting tricyclic amine-containing compounds showed an increase of anticancer activity as compared with the unsubstituted norcantharimide. PMID- 29231882 TI - Performance Analysis of the IEEE 802.11p Multichannel MAC Protocol in Vehicular Ad Hoc Networks. AB - Vehicular Ad Hoc Networks (VANETs) employ multichannel to provide a variety of safety and non-safety applications, based on the IEEE 802.11p and IEEE 1609.4 protocols. The safety applications require timely and reliable transmissions, while the non-safety applications require efficient and high throughput. In the IEEE 1609.4 protocol, operating interval is divided into alternating Control Channel (CCH) interval and Service Channel (SCH) interval with an identical length. During the CCH interval, nodes transmit safety-related messages and control messages, and Enhanced Distributed Channel Access (EDCA) mechanism is employed to allow four Access Categories (ACs) within a station with different priorities according to their criticality for the vehicle's safety. During the SCH interval, the non-safety massages are transmitted. An analytical model is proposed in this paper to evaluate performance, reliability and efficiency of the IEEE 802.11p and IEEE 1609.4 protocols. The proposed model improves the existing work by taking serval aspects and the character of multichannel switching into design consideration. Extensive performance evaluations based on analysis and simulation help to validate the accuracy of the proposed model and analyze the capabilities and limitations of the IEEE 802.11p and IEEE 1609.4 protocols, and enhancement suggestions are given. PMID- 29231881 TI - The Effect of Different Coupling Agents on Nano-ZnO Materials Obtained via the Sol-Gel Process. AB - Hybrid nanomaterials based on zinc oxide were synthesized via the sol-gel method, using different silane coupling agents: (3-glycidyloxypropyl)trimethoxysilane (GPTMS), phenyltriethoxysilane (PhTES), octyltriethoxysilane (OTES), and octadecyltriethoxysilane (ODTES). Morphological properties and the silane precursor type effect on the particle size were investigated using dynamic light scattering (DLS), environmental scanning electron microscopy (ESEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and X-ray diffraction (XRD). The bonding characteristics of modified ZnO materials were investigated using Fourier transform infrared spectroscopy (FTIR). The final solutions were deposited on metallic substrate (aluminum) in order to realize coatings with various wettability and roughness. The morphological studies, obtained by ESEM and TEM analysis, showed that the sizes of the ZnO nanoparticles are changed as function of silane precursor used in synthesis. The thermal stability of modified ZnO materials showed that the degradation of the alkyl groups takes place in the 300-500 degrees C range. Water wettability study revealed a contact angle of 142 +/- 5 degrees for the surface covered with ZnO material modified with ODTES and showed that the water contact angle increases as the alkyl chain from the silica precursor increases. These modified ZnO materials, therefore, can be easily incorporated in coatings for various applications such as anti-corrosion and anti-icing. PMID- 29231883 TI - Silver Nanoparticles in the Lung: Toxic Effects and Focal Accumulation of Silver in Remote Organs. AB - The distribution of silver (Ag) into remote organs secondary to the application of Ag nanoparticles (Ag-NP) to the lung is still incompletely understood and was investigated in the rat with imaging methods. Dose-finding experiments were carried out with 50 nm- or 200 nm-sized polyvinyl pyrrolidine (PVP)-coated Ag-NP using alveolar macrophages in vitro and female rats, which received Ag-NP via intratracheal instillation. In the main study, we administered 37.5-300 ug per rat lung of the more toxic Ag50-PVP and assessed the broncho-alveolar lavage fluid (BALF) for inflammatory cells, total protein and fibronectin after three and 21 days. In parallel, lung tissue was analysed for DNA double-strand breaks and altered cell proliferation. While 75-150 ug Ag50-PVP per rat lung caused a reversible inflammation, 300 ug led to DNA damage, accelerated cell proliferation and progressively increasing numbers of neutrophilic granulocytes. Ag accumulation was significant in homogenates of liver and other peripheral organs upon lung dose of >=75 ug. Quantitative laser-ablation inductively-coupled plasma mass spectrometry (LA-ICP-MS) combined with enhanced dark field microscopy and autometallography revealed focal accumulations of Ag and/or Ag-NP in sections of peripheral organs: mediastinal lymph nodes contained Ag-NP especially in peripheral macrophages and Ag in argyrophilic fibres. In the kidney, Ag had accumulated within proximal tubuli, while renal filter structures contained no Ag. Discrete localizations were also observed in immune cells of liver and spleen. Overall, the study shows that concentrations of Ag-NP, which elicit a transient inflammation in the rat lung, lead to focal accumulations of Ag in peripheral organs, and this might pose a risk to particular cell populations in remote sites. PMID- 29231884 TI - Heavy Metal Contamination and Health Risk Assessment in the Vicinity of a Tailing Pond in Guangdong, China. AB - The purpose of this study was to assess heavy metal contamination and health risks for residents in the vicinity of a tailing pond in Guangdong, southern China. Water, soil, rice, and vegetable samples were collected from the area in the vicinity of the tailing pond. Results showed that surface water was just polluted by Ni and As, while groundwater was not contaminated by heavy metals. The concentrations of Pb, Zn, Cu, Cd, Ni, and As in the paddy soil exceeded the standard values but not those of Cr. In vegetable soils, the concentration of heavy metals was above the standard values except for Ni and As. Soil heavy metal concentrations generally decreased with increasing distance from the polluting source. Leafy vegetables were contaminated by Pb, Cr, Cd, and Ni, while the non leafy vegetables were contaminated only by Cr. There was a significant difference in heavy metal concentrations between leafy vegetables and non-leafy vegetables. Almost all the rice was polluted by heavy metals. Diet was the most significant contributor to non-carcinogenic risk, which was significantly higher than the safe level of 1. The total cancer risk was also beyond the safe range (10-6-10 4). Results revealed that there is a risk of potential health problems to residents in the vicinity of the tailing pond. PMID- 29231885 TI - Development of a Sequential Injection Analysis System for the Determination of Saccharin. AB - Saccharin is a powerfully sweet nonnutritive sweetener that has been approved for food-processing applications within the range of 100-1200 mg/kg. A simple, rapid, and cost-effective sequential injection analysis (SIA) technique was developed to determine the saccharin level. This method is based on the reaction of saccharin with p-chloranil in an ethanol medium with a hydrogen peroxide (H2O2) acceleration, and the resultant violet-red compound was detected using a UV-Vis spectrophotometer at lambdamax = 420 nm. To ascertain the optimal conditions for the SIA system, several parameters were investigated, including buffer flow rate and volume, p-chloranil concentration, and reactant volumes (saccharin, p chloranil, and H2O2). The optimum setup of the SIA system was achieved with a buffer flow rate, buffer volume, and draw-up time of 1.2 mL/min, 2900 uL, and ~145 s, respectively. The optimal p-chloranil concentration is 30 mM, and the best reactant volumes, presented in an ordered sequence, are as follows: 30 uL of H2O2, 450 uL of saccharin, and 150 uL of p-chloranil. The optimized SIA configuration produced a good linear calibration curve with a correlation coefficient (R2 = 0.9812) in the concentration range of 20-140 mg/L and with a detection limit of 19.69 mg/L. Analytical applications in different food categories also showed acceptable recovery values in the range of 93.1-111.5%. This simple and rapid SIA system offers great feasibility for the saccharin quality control in food-product processing. PMID- 29231886 TI - Feed Intake and Weight Changes in Bos indicus-Bos taurus Crossbred Steers Following Bovine Viral Diarrhea Virus Type 1b Challenge Under Production Conditions. AB - Bovine viral diarrhea virus (BVDV) has major impacts on beef cattle production worldwide, but the understanding of host animal genetic influence on illness is limited. This study evaluated rectal temperature, weight change and feed intake in Bos indicus crossbred steers (n = 366) that were challenged with BVDV Type 1b, and where family lines were stratified across three vaccine treatments of modified live (MLV), killed, (KV) or no vaccine (NON). Pyrexia classification based on 40.0 degrees C threshold following challenge and vaccine treatment were investigated for potential interactions with sire for weight change and feed intake following challenge. Pyrexia classification affected daily feed intake (ADFI, p = 0.05), and interacted with day (p < 0.001) for ADFI. Although low incidence of clinical signs was observed, there were marked reductions in average daily gain (ADG) and cumulative feed intake during the first 14 day post challenge; ADG (CV of 104%) and feed efficiency were highly variable in the 14 day period immediately post-challenge as compared to the subsequent 14-day periods. A sire * vaccine strategy interaction affected ADFI (p < 0.001), and a sire by time period interaction affected ADG (p = 0.03) and total feed intake (p = 0.03). This study demonstrates that different coping responses may exist across genetic lines to the same pathogen, and that subclinical BVDV infection has a measurable impact on cattle production measures. PMID- 29231887 TI - Real-Time Monitoring in Home-Based Cardiac Rehabilitation Using Wrist-Worn Heart Rate Devices. AB - Cardiac rehabilitation is a key program which significantly reduces the mortality in at-risk patients with ischemic heart disease; however, there is a lack of accessibility to these programs in health centers. To resolve this issue, home based programs for cardiac rehabilitation have arisen as a potential solution. In this work, we present an approach based on a new generation of wrist-worn devices which have improved the quality of heart rate sensors and applications. Real-time monitoring of rehabilitation sessions based on high-quality clinical guidelines is embedded in a wearable application. For this, a fuzzy temporal linguistic approach models the clinical protocol. An evaluation based on cases is developed by a cardiac rehabilitation team. PMID- 29231888 TI - Analysis and Prediction of Exon Skipping Events from RNA-Seq with Sequence Information Using Rotation Forest. AB - In bioinformatics, exon skipping (ES) event prediction is an essential part of alternative splicing (AS) event analysis. Although many methods have been developed to predict ES events, a solution has yet to be found. In this study, given the limitations of machine learning algorithms with RNA-Seq data or genome sequences, a new feature, called RS (RNA-seq and sequence) features, was constructed. These features include RNA-Seq features derived from the RNA-Seq data and sequence features derived from genome sequences. We propose a novel Rotation Forest classifier to predict ES events with the RS features (RotaF RSES). To validate the efficacy of RotaF-RSES, a dataset from two human tissues was used, and RotaF-RSES achieved an accuracy of 98.4%, a specificity of 99.2%, a sensitivity of 94.1%, and an area under the curve (AUC) of 98.6%. When compared to the other available methods, the results indicate that RotaF-RSES is efficient and can predict ES events with RS features. PMID- 29231889 TI - Exploring the Caste-Specific Multi-Layer Defense Mechanism of Formosan Subterranean Termites, Coptotermes formosanus Shiraki. AB - The survival and foraging of Coptotermesformosanus Shiraki in a microbe-rich environment reflect the adaptation of an extraordinary, sophisticated defense mechanism by the nest-mates. We aimed to explore the host pathogen interaction by studying caste-specific volatile chemistry and genes encoding the antioxidant defense of winged imagoes, nymphs, soldiers and workers of Formosan subterranean termites. Qualitative analyses of C.formosanus Shiraki performed by HS-SPME/GC-MS showed considerable variations in the chemical composition of volatile organic compounds (VOCs) and their proportions among all the castes. Winged imagoes produced the most important compounds such as naphthalene and n-hexanoic acid. The antifungal activity of these compounds along with nonanal, n-pentadecane, n tetradecane, n-heptadecane and methyl octanoate against the conidial suspensions of Metarhiziumanisopliae and Beauveriabassiana isolates enable us to suggest that the failure of natural fungal infection in the nest is due to the antiseptic environment of the nest, which is mainly controlled by the VOCs of nest-mates. In addition, conidial germination of M.anisopliae and B.bassiana isolates evaluated on the cuticle of each caste showed significant variations among isolates and different castes. Our results showed that the conidia of M.anisopliae 02049 exhibited the highest germination on the cuticle of all the inoculated castes. Moreover, we recorded the lowest germination of the conidia of B.bassiana 200436. Caste-specific germination variations enabled us to report for the first time that the cuticle of winged imagoes was found to be the most resistant cuticle. The analysis of the transcriptome of C.formosanus Shiraki revealed the identification of 17 genes directly involved in antioxidant defense. Expression patterns of the identified antioxidant genes by quantitative real-time PCR (qPCR) revealed the significantly highest upregulation of CAT, GST, PRXSL, Cu/Zn-SOD2, TXN1, TXN2, TXNL1, TXNL2, TXNL4A and TPx genes among winged imagoes upon infection with the most virulent isolate, M.anisopliae 02049. Furthermore, soldiers showed the least expression of genes encoding antioxidant defense. Our findings indicated that the volatile chemistry of nest-mates and genes encoding antioxidant defense greatly contribute to the survival and foraging of Formosan subterranean termites in a microbe-rich habitat. PMID- 29231890 TI - Development and Verification of a Novel Robot-Integrated Fringe Projection 3D Scanning System for Large-Scale Metrology. AB - Large-scale surfaces are prevalent in advanced manufacturing industries, and 3D profilometry of these surfaces plays a pivotal role for quality control. This paper proposes a novel and flexible large-scale 3D scanning system assembled by combining a robot, a binocular structured light scanner and a laser tracker. The measurement principle and system construction of the integrated system are introduced. A mathematical model is established for the global data fusion. Subsequently, a robust method is introduced for the establishment of the end coordinate system. As for hand-eye calibration, the calibration ball is observed by the scanner and the laser tracker simultaneously. With this data, the hand-eye relationship is solved, and then an algorithm is built to get the transformation matrix between the end coordinate system and the world coordinate system. A validation experiment is designed to verify the proposed algorithms. Firstly, a hand-eye calibration experiment is implemented and the computation of the transformation matrix is done. Then a car body rear is measured 22 times in order to verify the global data fusion algorithm. The 3D shape of the rear is reconstructed successfully. To evaluate the precision of the proposed method, a metric tool is built and the results are presented. PMID- 29231891 TI - Bioactive Compounds Produced by Hypoxylon fragiforme against Staphylococcus aureus Biofilms. AB - Treating infections organized in biofilms is a challenge due to the resistance of the pathogens against antibiotics and host immune cells. Many fungi grow in a wet environment, favorable for the growth of bacterial biofilms, and we speculated that fungi possess some strategies to control these bacterial biofilms. A fungus identified as Hypoxylon fragiforme, was collected in the Harz Mountains, Germany, and its mycelial culture was fermented in different culture media for 67 days to test its biological potential against bacterial biofilms. Sclerin, sclerin diacid and its 3-methyl monoester (methyl 1-(5-hydroxy-6-carboxylic-2,3,4 trimethylphenyl) propionate) are here described for the first time from this fungus. Sclerin and its diacid interfered with the biofilm formation of the pathogen Staphylococcus aureus, inhibiting 86% and 80% of the biofilm at 256 MUg mL-1, respectively, but not killing the bacterium. Interestingly, the monomethylester of sclerin diacid was inactive. Although these compounds did not possess any activity against a pre-formed biofilm, they prevented its formation at subtoxic concentrations. Furthermore, sclerin and its diacid displayed a high specificity against Staphylococcus aureus, indicating a good strategy against pathogenic biofilms when combined with antibiotics. PMID- 29231892 TI - Assessment of Plumage and Integument Condition in Dual-Purpose Breeds and Conventional Layers. AB - The assessment of plumage and integument condition in laying hens provides useful information about the occurrence of feather pecking and cannibalism. Although feather loss and skin injuries can result from mechanical abrasion or clinical diseases, they are valid animal-based indicators for behavioural disorders. This particularly applies to damage on the back and tail region of the hens. The aim was to evaluate the behaviour of dual-purpose breeds (Lohmann Dual, LD) and conventional layer hybrids (Lohmann Brown plus, LB+), and to compare a mere visual assessment (Visual Scoring, VSc), with a method involving the handling of individual animals (Hands-on Scoring, HSc). During weekly VSc, the hens' plumage and integument were scored on five body parts. HSc was carried out on seven study days applying the same scoring scale as for VSc. In LB+ hens, minor plumage damage started at 25 weeks and increased to the 71st week. With 99.5% of LB+ showing feather loss to a different extent, the back was the most severely affected body part. In contrast, only between 4.5% and 7% of LD showed minor feather loss at the end of the study. Integument damage reached a peak, with 6% affected LB+ in week 66. Injuries were found only sporadically in LD hens. Spearman's rho for the comparison of plumages scores given in VSc and HSc was >0.90 (p < 0.01) in both hybrids for most of the tested body regions and weeks, except for the breast/belly region. However, VSc and HSc were equally valid for detecting skin injuries of all of the body regions (rs > 0.86, p < 0.01). Damaging behaviour only occurred in the LB+ flocks, though both of the genetic strains were kept under the same conditions. The visual scoring method was suitable for detecting both plumage and integument damage. PMID- 29231894 TI - Incorporating Methyl and Phenyl Substituted Stannylene Units into Oligosilanes. The Influence on Optical Absorption Properties. AB - Molecules containing catenated heavy group 14 atoms are known to exhibit the interesting property of sigma-bond electron delocalization. While this is well studied for oligo- and polysilanes the current paper addresses the UV-absorption properties of small tin containing oligosilanes in order to evaluate the effects of Sn-Si and Sn-Sn bonds as well as the results of substituent exchange from methyl to phenyl groups. The new stannasilanes were compared to previously investigated oligosilanes of equal chain lengths and substituent pattern. Replacing the central SiMe2 group in a pentasilane by a SnMe2 unit caused a bathochromic shift of the low-energy band (lambdamax = 260 nm) of 14 nm in the UV spectrum. If, instead of a SnMe2, a SnPh2 unit is incorporated, the bathochromic shift of 33 nm is substantially larger. Keeping the SnMe2 unit and replacing the two central silicon with tin atoms causes shift of the respective band (lambda = 286 nm) some 26 nm to the red. A similar approach for hexasilanes where the model oligosilane [(Me3Si)3Si]2(SiMe2)2 (lambdamax = 253 nm) was modified in a way that the central tetramethyldisilanylene unit was exchanged for a tetraphenyldistannanylene caused a 50 nm bathochromic shift to a low-energy band with lambdamax = 303 nm. PMID- 29231895 TI - The Anomalous Influence of Spectral Resolution on Pulsed THz Time Domain Spectroscopy under Real Conditions. AB - We have studied the spectral resolution influence on the accuracy of the substance detection and identification at using a broadband THz pulse measured under real conditions (at a distance of more than 3 m from a THz emitter in ambient air with a relative humidity of about 50%). We show that increasing spectral resolution leads to manifestation of small-scale perturbations (random fluctuations) in the signal spectrum caused by the influence of the environment or the sample structure. Decreasing the spectral resolution allows us to exclude from consideration this small-scale modulation of the signal as well as to detect the water vapor absorption frequencies. This fact is important in practice because it allows us to increase the signal processing rate. In order to increase the detection reliability, it is advisable to decrease the spectral resolution up to values of not more than 40% of the corresponding spectral line bandwidth. The method of spectral dynamics analysis together with the integral correlation criteria is used for the substance detection and identification. Neutral substances such as chocolate and cookies are used as the samples in the physical experiment. PMID- 29231893 TI - Hypertrophic Cardiomyopathy-Past, Present and Future. AB - Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy with a prevalence of 1 in 500 in the general population. Since the first pathological case series at post mortem in 1957, we have come a long way in its understanding, diagnosis and management. Here, we will describe the history of our understanding of HCM including the initial disease findings, diagnostic methods and treatment options. We will review the current guidelines for the diagnosis and management of HCM, current gaps in the evidence base and discuss the new and promising developments in this field. PMID- 29231896 TI - Differential Expression of Serum MicroRNAs Supports CD4+ T Cell Differentiation into Th2/Th17 Cells in Severe Equine Asthma. AB - MicroRNAs (miRNAs) regulate post-transcriptional gene expression and may be exported from cells via exosomes or in partnership with RNA-binding proteins. MiRNAs in body fluids can act in a hormone-like manner and play important roles in disease initiation and progression. Hence, miRNAs are promising candidates as biomarkers. To identify serum miRNA biomarkers in the equine model of asthma we investigated small RNA derived from the serum of 34 control and 37 asthmatic horses. These samples were used for next generation sequencing, novel miRNA identification and differential miRNA expression analysis. We identified 11 significantly differentially expressed miRNAs between case and control horses: eca-miR-128, eca-miR-744, eca-miR-197, eca-miR-103, eca-miR-107a, eca-miR-30d, eca-miR-140-3p, eca-miR-7, eca-miR-361-3p, eca-miR-148b-3p and eca-miR-215. Pathway enrichment using experimentally validated target genes of the human homologous miRNAs showed a significant enrichment in the regulation of epithelial to-mesenchymal transition (key player in airway remodeling in asthma) and the phosphatidylinositol (3,4,5)-triphosphate (PIP3) signaling pathway (modulator of CD4+ T cell maturation and function). Downregulated miR-128 and miR-744 supports a Th2/Th17 type immune response in severe equine asthma. PMID- 29231897 TI - Assessment of a Salt Reduction Intervention on Adult Population Salt Intake in Fiji. AB - Reducing population salt intake is a global public health priority due to the potential to save lives and reduce the burden on the healthcare system through decreased blood pressure. This implementation science research project set out to measure salt consumption patterns and to assess the impact of a complex, multi faceted intervention to reduce population salt intake in Fiji between 2012 and 2016. The intervention combined initiatives to engage food businesses to reduce salt in foods and meals with targeted consumer behavior change programs. There were 169 participants at baseline (response rate 28.2%) and 272 at 20 months (response rate 22.4%). The mean salt intake from 24-h urine samples was estimated to be 11.7 grams per day (g/d) at baseline and 10.3 g/d after 20 months (difference: -1.4 g/day, 95% CI -3.1 to 0.3, p = 0.115). Sub-analysis showed a statistically significant reduction in female salt intake in the Central Division but no differential impact in relation to age or ethnicity. Whilst the low response rate means it is not possible to draw firm conclusions about these changes, the population salt intake in Fiji, at 10.3 g/day, is still twice the World Health Organization's (WHO) recommended maximum intake. This project also assessed iodine intake levels in women of child-bearing age and found that they were within recommended guidelines. Existing policies and programs to reduce salt intake and prevent iodine deficiency need to be maintained or strengthened. Monitoring to assess changes in salt intake and to ensure that iodine levels remain adequate should be built into future surveys. PMID- 29231898 TI - The Venom of the Spine-Bellied Sea Snake (Hydrophis curtus): Proteome, Toxin Diversity and Intraspecific Variation. AB - The spine-bellied sea snake (Hydrophis curtus) is known to cause human deaths, yet its venom composition has not yet been proteomically characterised. An indepth proteomic analysis was performed on H. curtus venom from two different seasons, January and June, corresponding to adults and subadults, respectively. Venoms from adult and subadult H. curtus individuals were compared using reversedphase high-performance liquid chromatography (RP-HPLC), matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) mass spectrometry and liquid chromatography electrospray ionisation mass spectrometry (LC-ESI-MS) to detect intraspecific variation, and the molecular weight data obtained with ESIMS were used to assess toxin diversity. RPHPLC and LCESIMS/MS were used to characterise the venom proteome and estimate the relative abundances of protein families present. The most abundant protein family in January and June venoms is phospholipase A2 (PLA2: January 66.7%; June 54.5%), followed by threefinger toxins (3FTx: January 30.4%; June 40.4%) and a minor component of cysteine-rich secretory proteins (CRISP: January 2.5%; June 5%). Trace amounts of snake venom metalloproteinases (SVMP), C-type lectins and housekeeping and regulatory proteins were also found. Although the complexity of the venom is low by number of families present, each family contained a more diverse set of isoforms than previously reported, a finding that may have implications for the development of next-generation sea snake antivenoms. Intraspecific variability was shown to be minor with one obvious exception of a 14,157-Da protein that was present in some January (adult) venoms, but not at all in June (subadult) venoms. There is also a greater abundance of short-chain neurotoxins in June (subadult) venom compared with January (adult) venom. These differences potentially indicate the presence of seasonal, ontogenetic or sexual variation in H. curtus venom. PMID- 29231899 TI - Do Individual and Neighborhood Characteristics Influence Perceived Air Quality? AB - Background: Despite improvements, air pollution still remains a major public health issue. Numerous epidemiological studies have demonstrated the adverse health effects of air pollution exposure based on modeled measures, but only a few have considered the health impact of perceived air quality. Improving our knowledge of individual perceptions is crucial to defining targeted actions and promoting appropriate intervention measures. Our objective is to investigate the relationship between subjective and objective measures of air pollution and to focus on how individual characteristics combined with the neighborhood socioeconomic deprivation index, measured at a fine spatial scale, may or may not alter this relationship. Materials and Methods: The subjective measures of air quality reported by a sample of Lyon residents were collected via an individual questionnaire. The objective measures of air pollution were modeled by the local air quality monitoring network of the Rhone-Alpes region at census block level. We used a socioeconomic deprivation index to capture the different socioeconomic dimensions at census block level. The statistical analysis was structured in two steps: (1) identification of individual determinants of the subjective measures of air quality using multiple correspondence analysis followed by hierarchical clustering; (2) identification of individual and contextual characteristics that may alter the relationship between the objective and subjective measures of air pollution. Results: Among the youngest and the middle aged population (ages 30 to 59), consistent results between level of satisfaction, perceived air quality and objective measures of air pollution were found whatever the individual characteristics of the population. It is less clear among the oldest population: globally no significant difference between the NO2 concentrations and the level of satisfaction was observed. Conclusions: We found a significant relationship between the subjective and objective measures of air pollution in many population sub-groups with different combinations of individual characteristics. The relationship is less clear among the oldest population, which confirms previous findings. Our finding highlights that age combined with low level of education and unemployment, or women or health problems as well as the neighborhood deprivation index influence the level of air quality satisfaction. PMID- 29231900 TI - Diffusion-Driven Charge Transport in Light Emitting Devices. AB - Almost all modern inorganic light-emitting diode (LED) designs are based on double heterojunctions (DHJs) whose structure and current injection principle have remained essentially unchanged for decades. Although highly efficient devices based on the DHJ design have been developed and commercialized for energy efficient general lighting, the conventional DHJ design requires burying the active region (AR) inside a pn-junction. This has hindered the development of emitters utilizing nanostructured ARs located close to device surfaces such as nanowires or surface quantum wells. Modern DHJ III-N LEDs also exhibit resistive losses that arise from the DHJ device geometry. The recently introduced diffusion driven charge transport (DDCT) emitter design offers a novel way to transport charge carriers to unconventionally placed ARs. In a DDCT device, the AR is located apart from the pn-junction and the charge carriers are injected into the AR by bipolar diffusion. This device design allows the integration of surface ARs to semiconductor LEDs and offers a promising method to reduce resistive losses in high power devices. In this work, we present a review of the recent progress in gallium nitride (GaN) based DDCT devices, and an outlook of potential DDCT has for opto- and microelectronics. PMID- 29231901 TI - LaAlO3:Mn4+ as Near-Infrared Emitting Persistent Luminescence Phosphor for Medical Imaging: A Charge Compensation Study. AB - Mn4+-activated phosphors are emerging as a novel class of deep red/near-infrared emitting persistent luminescence materials for medical imaging as a promising alternative to Cr3+-doped nanomaterials. Currently, it remains a challenge to improve the afterglow and photoluminescence properties of these phosphors through a traditional high-temperature solid-state reaction method in air. Herein we propose a charge compensation strategy for enhancing the photoluminescence and afterglow performance of Mn4+-activated LaAlO3 phosphors. LaAlO3:Mn4+ (LAO:Mn4+) was synthesized by high-temperature solid-state reaction in air. The charge compensation strategies for LaAlO3:Mn4+ phosphors were systematically discussed. Interestingly, Cl-/Na+/Ca2+/Sr2+/Ba2+/Ge4+ co-dopants were all found to be beneficial for enhancing LaAlO3:Mn4+ luminescence and afterglow intensity. This strategy shows great promise and opens up new avenues for the exploration of more promising near-infrared emitting long persistent phosphors for medical imaging. PMID- 29231902 TI - Mechanical, Thermodynamic and Electronic Properties of Wurtzite and Zinc-Blende GaN Crystals. AB - For the limitation of experimental methods in crystal characterization, in this study, the mechanical, thermodynamic and electronic properties of wurtzite and zinc-blende GaN crystals were investigated by first-principles calculations based on density functional theory. Firstly, bulk moduli, shear moduli, elastic moduli and Poisson's ratios of the two GaN polycrystals were calculated using Voigt and Hill approximations, and the results show wurtzite GaN has larger shear and elastic moduli and exhibits more obvious brittleness. Moreover, both wurtzite and zinc-blende GaN monocrystals present obvious mechanical anisotropic behavior. For wurtzite GaN monocrystal, the maximum and minimum elastic moduli are located at orientations [001] and <111>, respectively, while they are in the orientations <111> and <100> for zinc-blende GaN monocrystal, respectively. Compared to the elastic modulus, the shear moduli of the two GaN monocrystals have completely opposite direction dependences. However, different from elastic and shear moduli, the bulk moduli of the two monocrystals are nearly isotropic, especially for the zinc-blende GaN. Besides, in the wurtzite GaN, Poisson's ratios at the planes containing [001] axis are anisotropic, and the maximum value is 0.31 which is located at the directions vertical to [001] axis. For zinc-blende GaN, Poisson's ratios at planes (100) and (111) are isotropic, while the Poisson's ratio at plane (110) exhibits dramatically anisotropic phenomenon. Additionally, the calculated Debye temperatures of wurtzite and zinc-blende GaN are 641.8 and 620.2 K, respectively. At 300 K, the calculated heat capacities of wurtzite and zinc blende are 33.6 and 33.5 J mol-1 K-1, respectively. Finally, the band gap is located at the G point for the two crystals, and the band gaps of wurtzite and zinc-blende GaN are 3.62 eV and 3.06 eV, respectively. At the G point, the lowest energy of conduction band in the wurtzite GaN is larger, resulting in a wider band gap. Densities of states in the orbital hybridization between Ga and N atoms of wurtzite GaN are much higher, indicating more electrons participate in forming Ga-N ionic bonds in the wurtzite GaN. PMID- 29231903 TI - Darker Skin Tone Increases Perceived Discrimination among Male but Not Female Caribbean Black Youth. AB - BACKGROUND: Among most minority groups, males seem to report higher levels of exposure and vulnerability to racial discrimination. Although darker skin tone may increase exposure to racial discrimination, it is yet unknown whether skin tone similarly influences perceived discrimination among male and female Caribbean Black youth. OBJECTIVE: The current cross-sectional study tests the role of gender on the effects of skin tone on perceived discrimination among Caribbean Black youth. METHODS: Data came from the National Survey of American Life-Adolescent Supplement (NSAL-A), 2003-2004, which included 360 Caribbean Black youth (ages 13 to 17). Demographic factors (age and gender), socioeconomic status (SES; family income, income to needs ratio, and subjective SES), skin tone, and perceived everyday discrimination were measured. Linear regressions were used for data analysis. RESULTS: In the pooled sample, darker skin tone was associated with higher levels of perceived discrimination among Caribbean Black youth (b = 0.48; 95% Confidence Interval (CI) = 0.07-0.89). A significant interaction was found between gender and skin tone (b = 1.17; 95% CI = 0.49 1.86), suggesting a larger effect of skin tone on perceived discrimination for males than females. In stratified models, darker skin tone was associated with more perceived discrimination for males (b = 1.20; 95% CI = 0.69-0.72) but not females (b = 0.06; 95% CI = -0.42-0.55). CONCLUSION: Similar to the literature documenting male gender as a vulnerability factor to the effects of racial discrimination, we found that male but not female Caribbean Black youth with darker skin tones perceive more discrimination. PMID- 29231904 TI - Protective Effects of omega-3 PUFA in Anthracycline-Induced Cardiotoxicity: A Critical Review. AB - It has been demonstrated that omega-3 polyunsaturated fatty acids (omega-3 PUFA) may exert a beneficial role as adjuvants in the prevention and treatment of many disorders, including cardiovascular diseases and cancer. Particularly, several in vitro and in vivo preclinical studies have shown the antitumor activity of omega 3 PUFA in different kinds of cancers, and several human studies have shown that omega-3 PUFA are able to decrease the risk of a series of cardiovascular diseases. Several mechanisms have been proposed to explain their pleiotropic beneficial effects. omega-3 PUFA have also been shown to prevent harmful side effects (including cardiotoxicity and heart failure) induced by conventional and innovative anti-cancer drugs in both animals and patients. The available literature regarding the possible protective effects of omega-3 PUFA against anthracycline-induced cardiotoxicity, as well as the mechanisms involved, will be critically discussed herein. The study will analyze the critical role of different levels of omega-3 PUFA intake in determining the results of the combinatory studies with anthracyclines. Suggestions for future research will also be considered. PMID- 29231906 TI - Simulation of Cellular Energy Restriction in Quiescence (ERiQ)-A Theoretical Model for Aging. AB - Cellular responses to energy stress involve activation of pro-survival signaling nodes, compensation in regulatory pathways and adaptations in organelle function. Specifically, energy restriction in quiescent cells (ERiQ) through energetic perturbations causes adaptive changes in response to reduced ATP, NAD+ and NADP levels in a regulatory network spanned by AKT, NF-kappaB, p53 and mTOR. Based on the experimental ERiQ platform, we have constructed a minimalistic theoretical model consisting of feedback motifs that enable investigation of stress-signaling pathways. The computer simulations reveal responses to acute energetic perturbations, promoting cellular survival and recovery to homeostasis. We speculated that the very same stress mechanisms are activated during aging in post-mitotic cells. To test this hypothesis, we modified the model to be deficient in protein damage clearance and demonstrate the formation of energy stress. Contrasting the network's pro-survival role in acute energetic challenges, conflicting responses in aging disrupt mitochondrial maintenance and contribute to a lockstep progression of decline when chronically activated. The model was analyzed by a local sensitivity analysis with respect to lifespan and makes predictions consistent with inhibitory and gain-of-function experiments in aging. PMID- 29231905 TI - Short Chain Fatty Acids in the Colon and Peripheral Tissues: A Focus on Butyrate, Colon Cancer, Obesity and Insulin Resistance. AB - Increased dietary fiber consumption has been associated with many beneficial effects, including amelioration of obesity and insulin resistance. These effects may be due to the increased production of short chain fatty acids, including propionate, acetate and butyrate, during fermentation of the dietary fiber in the colon. Indeed, oral and dietary supplementation of butyrate alone has been shown to prevent high fat-diet induced obesity and insulin resistance. This review focuses on sources of short chain fatty acids, with emphasis on sources of butyrate, mechanisms of fiber and butyrate metabolism in the gut and its protective effects on colon cancer and the peripheral effects of butyrate supplementation in peripheral tissues in the prevention and reversal of obesity and insulin resistance. PMID- 29231909 TI - Ultrasound for the rheumatologist - focal myositis. PMID- 29231908 TI - Conjugated Polymer Nanoparticles for Bioimaging. AB - During the last decade, conjugated polymers have emerged as an interesting class of fluorescence imaging probes since they generally show high fluorescence brightness, high photostability, fast emission rates, non-blinking behavior and low cytotoxicity. The main concern related to most conjugated polymers is their lack of hydrophilicity and thereby poor bio-availability. This can, however, be overcome by the formulation of conjugated polymer nanoparticles in aqueous medium. This review provides an overview of the different techniques employed for the preparation of conjugated polymer nanoparticles, together with methods to improve their photoluminescence quantum yields. For selective targeting of specific cells, dedicated surface functionalization protocols have been developed, using different functional groups for ligand immobilization. Finally, conjugated polymer nanoparticles have recently also been employed for theranostic applications, wherein the particles are simultaneously used as fluorescent probes and carriers for anti-tumor drugs. PMID- 29231907 TI - Activated HGF-c-Met Axis in Head and Neck Cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent's pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal-epithelial transition factor (c-Met) and its ligand hepatocyte growth factor (HGF) are overexpressed in head and neck squamous cell carcinoma (HNSCC); and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act on several downstream effectors including phospholipase C gamma (PLCgamma), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K) alpha serine/threonine-protein kinase (Akt), mitogen activate protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes. PMID- 29231910 TI - [Clinical pictures of borreliosis]. AB - Lyme disease occurs in a variety of clinical manifestations, ranging from skin lesions, through musculoskeletal, neurological, and cardiac syndrome, to severe irreversible lesions. Borrelia burgdorferi's organotropy has an impact on the development of the disease. In initial management, it is important to implement effective treatment to prevent further progression of infection. Dominant skin lesions should be differentiated in detail. In the form of disseminated disease complex of clinical syndromes is observed but it requires of confirmation in immunoassays. A particular difficulty in the management of the posttreatment Lyme borreliosis syndrome is when a severe disease of the organ is present. Symptoms appear after months or years after antibiotic therapy in 10-20% of patients. In patients with a syndrome, a clinical picture may develop as an autoimmune response that has developed after active infection and effective treatment that could have eradicated the causative agent. It has also been shown that the presence of persistent inactive microorganisms after antibiotic treatment can trigger local symptoms. The complexity of the clinical picture of Lyme disease requires a reliable diagnosis and a wide variety of pathologies. PMID- 29231911 TI - [Difficulties in classifying body cavity fluids into transudate/ exudate depending on the various diagnostic criteria]. AB - : Disease processes may impair the production and reabsorption of fluid from in the body cavities, which results in its excessive accumulation. AIM: The aim of the study was the evaluation of difficulties regarding the classification of fluids from the body cavities into transudate/exudate observing the following: Light's criteria, total fluid protein concentration, and total protein ratio (TP ratio) and lactate dehydrogenase ratio (LDH ratio). MATERIALS AND METHODS: Retrospective analysis was conducted on pleural (N=314), peritoneal (N=114) and pericardial (N=10) fluids, which were tested for the total protein concentration and LDH activity both in fluid and serum and calculated on TP ratio and LDH ratio. RESULTS: Based on the total protein concentration, 278 fluids from pleural cavity were classified as an exudate; 36 as a transudate. Applying the Light's criteria 240 fluids were classified as an exudate; the remaining 74 fluids were classified as a transudate. Based on TP and LDH ratios, 229 fluids from pleural cavity were classified as an exudate; 85 as a transudate. Depending on the total protein concentration, 35 fluids from the peritoneal cavity were classified as an exudate; 79 as a transudate. Applying the Light's criteria 54 fluids were classified as an exudate; the remaining 60 fluids were classified as a transudate. Based on TP and LDH ratios, 22 fluids from peritoneal cavity were classified as an exudate; 92 as a transudate. Analysis of pericardial fluids, depending on the total protein concentration classified 9 of them as an exudate and 1 as a transudate. The same results were obtained by applying Light's criteria. Based on TP and LDH ratios, 7 fluids from pericardial cavity were classified as an exudate; 3 - as a transudate. CONCLUSIONS: Applying the Light's criteria or the total protein concentration in differential diagnostics of fluids from the body cavities resulted in qualification more of them as an exudates as compared to the analysis of the same fluids depending on the TP and LDH ratios. It can be assumed that some of the transudative/exudative fluids were incorrectly classified. Performed analysis suggest that more adequate criteria of the classification of fluids from the body cavities into transudate/exudate are of great importance. PMID- 29231912 TI - [Cerebroplacental ratio (CPR) and amniotic fluid index (AFI) as prognostic factors of terminating pregnancy with cesarean section after induction of labour]. AB - : AIM: The aim of the study was to estimate the value of the cerebroplacental ratio (CPR) and amniotic fluid index (AFI) in pregnancies after 41 week as prognostic factors of terminating pregnancy with cesarean section after induction of labour. MATERIALS AND METHODS: The study included 130 pregnant women, including 100 women, between 41 and 42 weeks of gestation, in whom induced labour resulted in a cesarean section due to three main indications: lack of progress of labour - group I - 44 pregnant women, signs of foetal distress - group II - 32 pregnant women and lack of response to induced labour - group III - 24 pregnant women. The control group (group IV) included 30 pregnant women between 41 and 42 completed weeks of gestation, in whom induction resulted in a physiological labour. CPR and AFI were analysed. The procedures were conducted with the use of Medison SA 9900 vaginal and abdominal probes. RESULTS: It was observed statistically significant difference beetween the studied and control groups with CPR (1.51+/-0.54 vs. 1.88+/-0.67 p<0,05). The lowest values of CPR were observed in Group II (1.18+/ -0.39). The AFI variable (5.93+/-3.19 p<0,05) was significantly lower in comparison to the other groups (I-10.27+/-4.3 p<0,05, III 9.24+/- 2.85 p<0,05, IV-9.43+/-3.46 p<0,05). There was a positive significant correlation between AFI and CPR (r=0.661; p=0.000 and r=0.610; p=0.000) in the group II. CONCLUSIONS: The values of CPR and AFI in pregnancies after 41 week could be prognostic factors of terminating pregnancy with cesarean section after induction of labour. An application of integrated model of evaluation of a foetus condition after 41 week of gestation (CPR, AFI and CTG) might allow to avoid making early decisions on performing labour induction, and thus, reduce the number of hastily conducted cesarean sections due to lack of response to oxytocin or due to lack of progress of labour. PMID- 29231913 TI - [Comparison of Cmac vs Vivasight devices in terms of time and effectiveness of intubation among medical students]. AB - : While analysing the use of the new videolaryngoscopes in the hands of the well experienced anaesthesiologists it is difficult to get answers to all intriguing questions and gain insights that might arise only from the untrained users. We can form a thesis that if a manikin, with the use of a particular device, is intubated quickly and effectively by the novices, it is probable that the more experienced operators will be even more satisfied with its use. AIM: The aim of our study was to evaluate the effectiveness of the use of these devices in the hands of the users untrained in intubation. We also wanted to find out what are the subjective perceptions of using the devices by unsuccessful users. We investigated intubation times, effectiveness as well as parameters such as tooth damage. The aim of the secondary and obvious benefit to students was familiarity Them with new advanced methods of clearing the upper respiratory tract with which they will probably meet in the future. MATERIALS AND METHODS: The study included 104 medical students. Every participant took three attempts to intubate the manikin using each device. The technical parameters of the devices have been studied by the experts from the Lodz University of Technology. RESULTS: The average time of intubation in the case of the Cmac was 28,3+/-10,1, while as regards the Vivasight the average time of intubation was 30,9+/-9,0. In order to check the statistical significance, the Mann - Whitney U test was used (p <0,005). A larger proportion of successful attempts that amounted to 60% were observed while using the CMAC. CONCLUSIONS: According to the subjective opinion of the students, the Cmac is easier to operate than the Vivasight. This study proved that videolaryngocopes can be a great tool for training new methods of intubation even during studies. PMID- 29231914 TI - Determinants of late-life depression in residents of long-term care facility. AB - : Mental disorders, such as dementia and depression, are beside chronic somatic diseases, the most common problem in residents of longterm care facilities (LTCF). Late-life depression refers to depressive symptoms that arise in adults older than 65 years. According to literature review, older people tend to differ from middle-aged adults in presentation of depression. AIM: Mental disorders, such as dementia and depression, are beside chronic somatic diseases, the most common problem in residents of longterm care facilities (LTCF). Late-life depression refers to depressive symptoms that arise in adults older than 65 years. According to literature review, older people tend to differ from middle aged adults in presentation of depression. MATERIALS AND METHODS: This cross sectional study was conducted over 290 residents in the LTCF in Cracow, using the interRAI-LTCF questionnaire for comprehensive geriatric assessment. The logistic regression was applied in analysis of data. RESULTS: Depression symptoms were observed in 33.8% of LTCF residents. In this population we found some independent of age variables significantly associated with depression, such as: daily pain, existence of psychiatric disorders other than depression, presence of behavioral and/or psychotic symptoms, sleep disturbances, dyspnea and feeling of loneliness. Interestingly, we noticed some differences in the manifestation of depression depending on age in older people. In "old-old" (aged 80 and older) LTCF residents, moderate dependency in activities of daily living (ADL), dyspnea and tendency to conflict with others, were significantly associated with higher prevalence of depression. In turn, "young-old" (younger than 80 years) residents presented more often symptoms of depression in response to stress experienced in last 90 days. CONCLUSIONS: In the light of our study results, depression in older people manifests with dominance of behavioral and/or psychotic symptoms what should be included in the diagnosis and differentiation with dementia and other psychiatric disorders. Moreover, findings from this study make a conclusion that late-life depression has more frequently organic background in very old residents and reactive nature in younger old residents. PMID- 29231915 TI - Lactobacillus gasseri endocarditis on the aortic valve bioprosthesis - a case report. AB - : Lactobacillus is a genus of Gram-positive, facultative anaerobic/ microaerophilic, rod-shaped bacteria. Lactobacilli constitute a significant component of the human microbiota in the oral cavity, gastrointestinal tract and female urogenital tract. They are also widely used as probiotics. Rarely, especially in patients with impaired immunity or with structural heart disease, do Lactobacilli become the pathogen responsible for serious infections, e.g. infective endocarditis (IE). CASE REPORT: The authors describe a case of an 80 year-old female with a past history of aortic valve replacement, mitral annuloplasty and pacemaker implantation admitted to hospital due to weakening, subfebrile state and chills. In transesophageal echocardiography vegetations on the aortic valve bioprosthesis were found, while pacemaker electrodes and mitral annulus were not involved in the endocarditis process. Bacteriological work-up revealed growth of L. gasseri. The patient was successfully treated with amoxicillin/clavulanate acid (six weeks) and with gentamycin (two weeks). No recurrence of the disease was observed during a six-month posthospital follow-up. Among different species of Lactobacillus, L. gasseri has not been reported as an IE pathogen so far. Lack of unequivocal data as to whether using probiotics may be responsible for infections, including IE, in patients with predisposing conditions. PMID- 29231916 TI - [The use of transdermal fentanyl in the treatment of patients suffering from chronic non-cancer pain - case reports]. AB - : The use of strong opioids for the treatment of chronic non-cancer pain (CNCP) has gained undisputed acceptance among specialists and should be considered when other pharmacological treatments are not effective or cause serious side effects. However, drugs from the third step of analgesic ladder still raise concerns among doctors and patients in the case of long-term therapy. A CASE REPORT: The authors present reports of three cases of patients with CNCP caused by musculoskeletal disorders and numerous comorbidities. In all cases, multidisciplinary treatment, that consisted of pharmacotherapy with strong opioids (72-hour transdermal fentanyl), physiotherapy, rehabilitation and psychotherapy, have been introduced. It allowed for good control of pain without significant side effects, symptoms of addiction nor tolerance. CONCLUSIONS: The presented cases illustrate the difficulties that occur during introducing opioid therapy in chronic non-cancer pain, particularly in the initial phase of treatment during setting of a transdermal opioid dose. They also confirm the safety and usefulness of opioid therapy in patients suffering from CNCP. PMID- 29231917 TI - Stable coronary artery disease - medical treatment. AB - The crucial issues in optimal medical therapy to improve prognosis and reduce angina symptoms are secondary prevention, effective control of concomitant diseases, risk factors and medical treatment. In spite of successful percutaneous coronary interventions (PCI) and medical treatment with beta-blockers, ACE inhibitors or angiotensin receptor blockers, statins and antiplatelet drugs, some patients are still symptomatic. In the era of PCI not sufficient attention is paid to other drugs reducing the incidence of angina episodes: calcium antagonists, long-acting nitrates, metabolic agents and novel antianginal drugs. Substantial part of secondary coronary interventions may be avoided if angina pectoris would be properly treated. In the light of the Courage and BARI trials' results, optimal medical therapy of angina pectoris remains important part of treatment. PMID- 29231918 TI - [Systemic treatment of early breast cancer - current state of knowledge after the conference St Gallen 2017]. AB - Breast cancer is the most commonly diagnosed malignancy in women around the globe. It is also the world's first cause of female deaths from cancer. With the introduction of screening programs in most developed countries, more and more cases of this cancer are diagnosed at local or localized stages, enabling radical treatment to be successful. At the same time, systemic treatment of early breast cancer is one of the most complex issues in clinical oncology. Because of the many prognostic factors that need to be taken into account when considering eligibility for treatment such as age, reproductive status (before or after menopause), type of cancer and severity of the disease, it is impossible to establish clear standards of conduct for many clinical situations. The international biennial St Gallen conference, the world's most prominent breast cancer specialists, who are struggling to address major clinical problems in the treatment of early breast cancer. St Gallen's recommendations address all issues related to the treatment of early breast cancer (in particular surgery, radiotherapy, and systemic treatment) and are set by a group of 52 experts by voting. This method allows us to establish consensus on issues that can not be clearly identified in the results of randomized clinical trials. In this way, more than 200 clinical issues were answered. The most important changes in day-to day practice are the duration of ajuvant hormone therapy (10 instead of 5 years), the possibility of using aromatase inhibitors (in combination with ovarian function suppresion) in premenopausal women with high risk of recurrence and the timing of sentinel node biopsy after neo-adjuvant chemotherapy. There are also recommendations, which patients should undergo genetic testing to assess the risk of recurrence of breast cancer. PMID- 29231919 TI - [Non-alcoholic liver disease - diagnosis and treatment]. AB - Non-alcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease in the developed world (15% to 40% of the adult population). Introduction of lifestyle changes including dietary intervention and increased physical activity is most often the first-line treatment and is intended to support not only the treatment of liver disease, but also for diseases associated with obesity, insulin resistance, diabetes and dyslipidemia. In addition to well known metformin, there are new classes of antidiabetic drugs, including GLP 1analog, SGLT-2 antagonist, pioglitazon. In addition, statins, vitamin E and pentoxyfiline are also recommended. In the absence of improvement of liver enzymes during the 6 months of treatment, liver biopsy should be considered. Simple hepatic steatosis (NAFL) is mild, but steatohepatitis (NASH) and fibrosis chance the prognosis and the risk of hepatocellular carcinoma (HCC) is higher. PMID- 29231920 TI - Two-colour serial femtosecond crystallography dataset from gadoteridol derivatized lysozyme for MAD phasing. AB - We provide a detailed description of a gadoteridol-derivatized lysozyme (gadolinium lysozyme) two-colour serial femtosecond crystallography (SFX) dataset for multiple wavelength anomalous dispersion (MAD) structure determination. The data was collected at the Spring-8 Angstrom Compact free-electron LAser (SACLA) facility using a two-colour double-pulse beam to record two diffraction patterns simultaneously in one diffraction image. Gadolinium lysozyme was chosen as a well established model system that has a very strong anomalous signal. Diffraction patterns from gadolinium lysozyme microcrystals were recorded to a resolution of 1.9 A in both colours. This dataset is publicly available through the Coherent X ray Imaging Data Bank (CXIDB) as a resource for algorithm development. PMID- 29231921 TI - An RNA-Seq atlas of gene expression in mouse and rat normal tissues. AB - Gene functionality is closely connected to its expression specificity across tissues and cell types. RNA-Seq is a powerful quantitative tool to explore genome wide expression. The aim of this study is to provide a comprehensive RNA-Seq dataset across the same 13 tissues for mouse and rat, two of the most relevant species for biomedical research. The dataset provides the transcriptome across tissues from three male C57BL6 mice and three male Han Wistar rats. We also describe our bioinformatics pipeline to process and technically validate the data. Principal component analysis shows that tissue samples from both species cluster similarly. We show by comparative genomics that many genes with high sequence identity with respect to their human orthologues also have a highly correlated tissue distribution profile and are in agreement with manually curated literature data for human. In summary, the present study provides a unique resource for comparative genomics and will facilitate the analysis of tissue specificity and cross-species conservation in higher organisms. PMID- 29231923 TI - Temporally inter-comparable maps of terrestrial wilderness and the Last of the Wild. AB - Wilderness areas, defined as areas free of industrial scale activities and other human pressures which result in significant biophysical disturbance, are important for biodiversity conservation and sustaining the key ecological processes underpinning planetary life-support systems. Despite their importance, wilderness areas are being rapidly eroded in extent and fragmented. Here we present the most up-to-date temporally inter-comparable maps of global terrestrial wilderness areas, which are essential for monitoring changes in their extent, and for proactively planning conservation interventions to ensure their preservation. Using maps of human pressure on the natural environment for 1993 and 2009, we identified wilderness as all 'pressure free' lands with a contiguous area >10,000 km2. These places are likely operating in a natural state and represent the most intact habitats globally. We then created a regionally representative map of wilderness following the well-established 'Last of the Wild' methodology; which identifies the 10% area with the lowest human pressure within each of Earth's 60 biogeographic realms, and identifies the ten largest contiguous areas, along with all contiguous areas >10,000 km2. PMID- 29231922 TI - Gene expression profiling in the intestinal mucosa of obese rats administered probiotic bacteria. AB - We investigated whether the administration of Lactobacillus paracasei CNCM I 4034, Bifidobacterium breve CNCM I-4035 and Lactobacillus rhamnosus CNCM I-4036 modulate the expression of genes in the intestinal mucosa of obese Zucker rats. Forty-eight Zucker-Leprfa/fa and 16 Zucker lean Lepr+/fa rats were used. Eight Zucker lean Lepr+/fa and 8 Zucker-Leprfa/fa rats were euthanized as a reference. The remaining 40 Zucker-Leprfa/fa rats were then assigned to receive 1010 colony forming units (CFU) of one of the three probiotic strains, a mixture of L. paracasei CNCM I-4034 and B. breve CNCM I-4035, or a placebo by oral administration for 30 days. An additional group of 8 Zucker lean Lepr+/fa rats received the placebo for 30 days. Over 27,000 rat genes were studied using a DNA array. Four animals per group were used. Total RNA was extracted from intestinal mucosa and cDNA was synthesized, fragmented and labeled. Labeled cDNA was hybridized using GeneChip kits, and the latter were scanned. Intensity values of each probe were processed and normalized to obtain an individual value for each set of probes. PMID- 29231924 TI - The mineralocorticoid receptor knockout in medaka is further validated by glucocorticoid receptor compensation. AB - To study the critical role of mineralocorticoid signalling, we generated a constitutive mineralocorticoid receptor (MR)-knockout (KO) medaka as the first adult-viable MR-KO animal. This KO medaka displayed abnormal behaviours affected by visual stimuli. In contrast, the loss of MR did not result in overt phenotypic changes in osmoregulation, despite the well-known osmoregulatory functions of MR in mammals. Since glucocorticoid receptor (GR) has been suggested to compensate for loss of MR, we examined expression of duplicated GRs with markedly different ligand sensitivities, in various tissues. qRT-PCR results revealed that the absence of MR induced GR1 in the brain and eyes, but not in osmoregulatory organs. This reinforces the important functions of glucocorticoid signalling, but the minor role of mineralocorticoid signalling, in fish osmoregulation. Because both 11-deoxycorticosterone (DOC) and cortisol are ligands for MR, whereas GRs are specific to cortisol, GR1 signalling may compensate for the absence of cortisol-MR, rather than that of DOC-MR. Thus, this GR expression suggests that our MR-KO model can be used specifically to characterize DOC-MR signalling. PMID- 29231925 TI - Expression profiling of the retina of pde6c, a zebrafish model of retinal degeneration. AB - Retinal degeneration often affects the whole retina even though the disease causing gene is specifically expressed in the light-sensitive photoreceptors. The molecular basis of the retinal defect can potentially be determined by gene expression profiling of the whole retina. In this study, we measured the gene expression profile of retinas microdissected from a zebrafish pde6cw59 (pde6c) mutant. This retinal-degeneration model not only displays cone degeneration caused by a cone-specific mutation, but also other secondary cellular changes starting from 4 days postfertilization (dpf). To capture the underlying molecular changes, we subjected pde6c and wild-type (WT) retinas at 5 dpf/ 120 h postfertilization (hpf) to RNA sequencing (RNA-Seq) on the Illumina HiSeq 2,000 platform. We also validated the RNA-Seq results by Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) of seven phototransduction genes. Our analyses indicate that the RNA-Seq dataset was of high quality, and effectively captured the molecular changes in the whole pde6c retina. This dataset will facilitate the characterization of the molecular defects in the pde6c retina at the initial stage of retinal degeneration. PMID- 29231926 TI - Predictors of Physical Fitness among Southwestern Native American Adolescents at Risk for Diabetes. AB - The prevalence of obesity is increasing among children nationally. Native American children from Zuni Pueblo appear to be at increased risk for obesity, which also increases the risk for the metabolic syndrome, diabetes, and cardiovascular disease. While exercise and physical fitness can prevent or forestall these developments, predictors of physical fitness in this population are unknown. Forty-seven Native American adolescents completed four aspects of the Presidential Fitness Challenge (push-ups, sit-ups, step-ups, and timed walking) during screening for another study, and fitness was empirically summarized with a Presidential Fitness Index. Correlative analyses were subsequently performed to elucidate predictors of fitness. Age was the only independent predictor of the Presidential Fitness Index. Other variables that were not found to be independent predictors included BMI percentile, waist circumference, fat free mass, total body fat, and HDL cholesterol. Among adolescent Southwest Native Americans, older children performed better on the Presidential Fitness Challenge. Additionally, BMI was not found to be an independent predictor of fitness. PMID- 29231927 TI - The SUMO guards for SNAIL. PMID- 29231928 TI - Erratum to "Automatic Segmentation of Ultrasound Tomography Image". AB - [This corrects the article DOI: 10.1155/2017/2059036.]. PMID- 29231929 TI - Modification of Ga2O3 by an Ag-Cr core-shell cocatalyst enhances photocatalytic CO evolution for the conversion of CO2 by H2O. AB - A core-shell structure of Ag-Cr dual cocatalyst loaded-Ga2O3 was found to significantly enhance the formation rate of CO and selectivity toward CO evolution for the photocatalytic conversion of CO2 where H2O is used as an electron donor. PMID- 29231930 TI - A self-assessed photosensitizer: inducing and dual-modal phosphorescence imaging of mitochondria oxidative stress. AB - Two novel Ir(iii)-nitroxide conjugates have been synthesized as mitochondria targeted multi-functional theranostic photosensitizers, capable of simultaneously inducing and dual-modal phosphorescence imaging of mitochondrial oxidative stress under two-photon excitation, thus realizing the photodynamic therapy of cancer and self-assessment of their PDT efficacies. PMID- 29231931 TI - Oxidative activation of leinamycin E1 triggers alkylation of guanine residues in double-stranded DNA. AB - It may be useful to develop prodrugs that are selectively activated by oxidative stress in cancer cells to release cell-killing reactive intermediates. However, relatively few chemical strategies exist for the activation of prodrugs under conditions of oxidative stress. Here we provide evidence for a novel process in which oxidation of a thiol residue in the natural product leinamycin E1 by H2O2 and other byproducts of cellular oxidative stress initiates generation of an episulfonium ion that selectively alkylates guanine residues in duplex DNA. PMID- 29231932 TI - Rhodium-mediated asymmetric transfer hydrogenation: a diastereo- and enantioselective synthesis of syn-alpha-amido beta-hydroxy esters. AB - The preparation of syn alpha-benzoylamido beta-hydroxy esters through asymmetric transfer hydrogenation (ATH) with a tethered Rh(iii)-DPEN complex via dynamic kinetic resolution (DKR) has been developed for the first time starting from alpha-benzoylamido beta-keto esters. A variety of alpha-benzoylamido beta-keto esters were converted under mild conditions into the corresponding syn alpha benzoylamino beta-hydroxy esters with high yields (up to 98%) and diastereomeric ratios (up to >99 : 1 dr) as well as excellent enantioselectivities (up to >99% ee). PMID- 29231933 TI - Perspectives of ruthenium(ii) polyazaaromatic photo-oxidizing complexes photoreactive towards tryptophan-containing peptides and derivatives. AB - RuII polyazaaromatic complexes have been studied with the aim of developing molecular tools for DNA and oligonucleotides. In this context, RuII-TAP (TAP = 1,4,5,8-tetraazaphenanthrene) complexes have been developed as specific photoreagents targeting the genetic material. The advantage of such compounds is due to the formation of photo-addition products between the Ru-TAP complex and the biomolecule, originating from a photo-induced electron transfer process that takes place between the excited Ru-TAP complex and guanine (G) bases of DNA. This photo-addition has been more recently extended to amino acids in view of applications involving peptides, such as inhibition or photocontrol of proteins. More particularly, tryptophan (Trp) and Trp-containing peptides are also able to be photo-oxidized by RuII-TAP complexes, leading to the formation of photo addition products. This mini review focuses on recent advances in the search for RuII polyazaaromatic photo-oxidizing complexes of interest as molecular tools and photoreagents for Trp-containing peptides and proteins. Different possible future directions in this field are also discussed. PMID- 29231934 TI - Multifunctional chiral phosphine-catalyzed [3+2] annulation of Morita-Baylis Hillman carbonates with cyclopentenones: asymmetric synthesis of 4-oxo hexahydropentalenes. AB - A multifunctional chiral phosphine-catalyzed enantioselective [3+2] annulation of Morita-Baylis-Hillman carbonates with cyclopentenones provides a direct approach to access functional 4-oxo-1,3a,4,5,6,6a-hexahydropentalene compounds. Moderate to good yields and excellent enantioselectivities (>90% ee) were obtained for a series of substrates under mild reaction conditions. PMID- 29231935 TI - Pure white light emission and charge transfer in organogels of symmetrical and unsymmetrical pi-chromophoric oligo-p-(phenyleneethynylene) bola-amphiphiles. AB - Two novel bola-amphiphilic oligo-p-(phenyleneethynylene) (OPE) dicarboxylates have been synthesized having non-polar and mixed-polar side chains. This led to gelation in both with vesicular morphology. Upon in situ loading of a suitable dye and redox-active molecule, pure white light emitting and charge transfer (CT) gels, respectively, were realized. PMID- 29231936 TI - Nitrogen-doped graphene quantum dots coupled with photosensitizers for one-/two photon activated photodynamic therapy based on a FRET mechanism. AB - A novel material with a large two-photon absorption cross-section was conjugated with a typical photosensitizer for inducing a FRET process. The photosensitizer can be excited by a one-/two-photon laser and then induced photo-toxicity in vitro and in vivo. The system presents great potential for improving treatment depth and the precision of traditional photodynamic therapy. PMID- 29231937 TI - Microfluidic formation of proteinosomes. AB - Herein we describe a novel microfluidic method for the generation of proteinosome micro-droplets, based on bovine serum albumin and glucose oxidase conjugated to PNIPAAm chains. The size of such water-in-oil droplets is regulated via control of the input reagent flow rate, with generated proteinosome populations exhibiting narrower size distributions than those observed when using standard bulk methodologies. Importantly, proteinosomes transferred from an oil to an aqueous-environment remain intact, become fully hydrated and exhibit an increase in average size. Moreover, functional proteinosomes prepared via microfluidics exhibit lower Km values and higher enzymatic activities than proteinosomes produced by bulk methodologies. PMID- 29231938 TI - Shear deformation-induced anisotropic thermal conductivity of graphene. AB - Graphene-based materials exhibit intriguing phononic and thermal properties. In this paper, we have investigated the heat conductance in graphene sheets under shear-strain-induced wrinkling deformation, using equilibrium molecular dynamics simulations. A significant orientation dependence of the thermal conductivity of graphene wrinkles (GWs) is observed. The directional dependence of the thermal conductivity of GWs stems from the anisotropy of phonon group velocities as revealed by the G-band broadening of the phonon density of states (DOS), the anisotropy of thermal resistance as evidenced by the G-band peak mismatch of the phonon DOS, and the anisotropy of phonon relaxation times as a direct result of the double-exponential-fitting of the heat current autocorrelation function. By analyzing the relative contributions of different lattice vibrations to the heat flux, we have shown that the contributions of different lattice vibrations to the heat flux of GWs are sensitive to the heat flux direction, which further indicates the orientation-dependent thermal conductivity of GWs. Moreover, we have found that, in the strain range of 0-0.1, the anisotropy ratio of GWs increases monotonously with increasing shear strain. This is induced by the change in the number of wrinkles, which is more influential in the direction perpendicular to the wrinkle texture. The findings elucidated here emphasize the utility of wrinkle engineering for manipulation of nanoscale heat transport, which offers opportunities for the development of thermal channeling devices. PMID- 29231939 TI - A first-principles study of the structural, mechanical and electronic properties of precipitates of Al2Cu in Al-Cu alloys. AB - The properties of precipitates are important in understanding the strengthening mechanism via precipitation during heat treatment and the aging process in Al-Cu based alloys, where the formation of precipitates is sensitive to temperature and pressure. Here we report a first-principles investigation of the effect of temperature and pressure on the structural stability, elastic constants and formation free energy for precipitates of Al2Cu, as well as their mechanical properties. Based on the formation enthalpy of Guinier-Preston (GP(I)) zones, the size of the GP(I) zone is predicted to be about 1.4 nm in diameter, which is in good agreement with experimental observations. The formation enthalpies of the precipitates are all negative, suggesting that they are all thermodynamically stable. The present calculations reveal that entropy plays an important role in stabilizing theta-Al2Cu compared with thetaC'-Al2Cu. The formation free energies of theta''-Al3Cu, thetaC'-Al2Cu, thetaD'-Al5Cu3 and thetat'-Al11Cu7 increase with temperature, while those of theta'-Al2Cu, thetaO'-Al2Cu and theta-Al2Cu decrease. The same trend is observed with the effect of pressure. The calculated elastic constants for the considered precipitation phases indicate that they are all mechanically stable and anisotropic, except thetaC'-Al2Cu. thetaD'-Al5Cu3 has the highest Vicker's hardness. The electronic structures are also calculated to gain insight into the bonding characteristics. The present results can help in understanding the formation of precipitates by different treatment processes. PMID- 29231940 TI - Femtosecond excited-state dynamics of fullerene-C60 nanoparticles in water. AB - Femtosecond excited-state dynamics of fullerene-C60 nanoparticles (nC60) having a mean size of 50 nm dispersed in pure water was studied by means of femtosecond transient absorption spectroscopy. The intermolecular charge-transfer (CT) excited state in solid C60 was directly and firstly observed by femtosecond 350 nm and 420 nm excitations, and its intrinsic lifetime of 0.35 ps was found. The CT excited state relaxed to the locally excited S1 state and excimers or directly to the ground state through geminate charge recombination. We also examined the laser fluence dependence of the CT excited-state dynamics. At a high laser fluence, the mutual interactions between neighboring CT excited states were observed immediately after the excitation. The interaction disappeared through the charge recombination in the geminate CT pair or between the neighboring CT excited states with a lifetime of 0.45 ps. After that, the locally excited S1 state decayed with a few ps lifetime independent of the fluence. In this paper, the mechanism and dynamics of the intermolecular CT excited state generated by UV light excitation is discussed in detail. PMID- 29231944 TI - Stability of plant virus-based nanocarriers in gastrointestinal fluids. AB - Cowpea mosaic virus (CPMV) is a plant virus which is being extensively investigated as a drug delivery and vaccine nanocarrier for parenteral administration. However, to date little is known about the suitability of plant based nanocarriers for oral delivery. In this study, the colloidal (i.e. aggregation), physical (i.e. denaturation) and chemical (i.e. digestion of the polypeptides) stability of CPMV and its empty virus-like particles (eVLPs) in conditions resembling the gastrointestinal fluids were evaluated. The nanoparticles were incubated in various simulated gastric and intestinal fluids and in pig gastric and intestinal fluids. CPMV and eVLPs had similar stabilities. In simulated gastric media, they were stable at pH >= 2.5. At lower pH destabilisation of the particle structure occurred, which, in turn, rendered the polypeptides extremely sensitive to pepsin digestion. However, both CPMV and eVLPs were stable in simulated intestinal fluids, in pig gastric fluids and in pig intestinal fluids. Thus CPMV, despite being a protein-based nanoparticle, was much more resistant to the harsh GI conditions than soluble proteins. Remarkably, both CPMV and eVLPs incubated in pig gastric and intestinal fluids were not subject to protein adsorption, with no formation of a detectable protein corona. The lack of a protein corona on CPMV and eVLP surfaces in GI fluids would imply that, if orally administered, these nanoparticles could maintain their native surface characteristics; thus, their biological interactions would remain predictable and unchanged. In summary, CPMV and eVLPs can be considered promising nanocarriers for applications requiring oral delivery, given their chemical, physical and colloidal stability and lack of protein adsorption from the environment in most of the tested conditions. PMID- 29231945 TI - Coordination-driven micellelization of block copolymers with gold(i) complexes induces remarkable phosphorescence enhancements with reversible mechanochromism. AB - The coordination-driven self-assembly of block copolymers with gold(i) complexes leads to the formation of spherical micelles with remarkable phosphorescence enhancements. The rising luminescence level increases unexpectedly with increasing the degree of polymerization of the noncoordinated block. Furthermore, one of the gold(i)-containing metallopolymers shows reversible mechanochromic luminescence. PMID- 29231946 TI - Full quantum dynamical investigation of the Eley-Rideal reaction forming H2 on a movable graphitic substrate at T = 0 K. AB - The dynamics of the Eley-Rideal abstraction reaction of hydrogen atoms on a movable graphitic surface is investigated for the first time in a numerically exact fully quantum setting. A system-bath strategy was applied where the two recombining H atoms and a substrate C atom form a relevant subsystem, while the rest of the lattice takes the form of an independent oscillator bath. High dimensional wavepacket simulations were performed in the collision energy range 0.2-1.0 eV with the help of the multi-layer multi-configuration time-dependent Hartree method, focusing on the collinear reaction on a zero-temperature surface. Results show that the dynamics is close to a sudden limit in which the reaction is much faster than the substrate motion. Unpuckering of the surface is fast (some tens of fs) but starts only after the formation of H2 is completed, thereby determining a considerable substrate heating (~0.8 eV per reactive event). Energy partitioning in the product molecule favors translational over vibrational energy, and H2 molecules are vibrationally hot (~1.5 eV) though to a lesser extent than previously predicted. PMID- 29231947 TI - Emulsion stabilisation by complexes of oppositely charged synthetic polyelectrolytes. AB - We investigate the possibility of stabilising oil-water emulsions from the polyelectrolyte complexes (PEC) obtained in mixtures of a strong cationic polyelectrolyte (poly(diallyldimethylammonium chloride), PDADMAC) and a weak anionic one (poly(acrylic acid)sodium salt, PAANa). Unlike other previous work however, both polyelectrolytes (PEL) are chosen as they are completely water soluble and possess no surface activity when present alone over nearly all the pH range. In water, the effects of PEL concentration, PEL mixing ratio and pH on the formation of PEC are studied in detail. At low pH where the anionic PEL is uncharged, complex coacervation occurs in which droplets rich in both polymers are dispersed in water. At intermediate pH, the PEC comprise a mixture of coacervate droplets and solid particles. At high pH where the anionic PEL is significantly charged, only complex coacervation is observed. On addition of dodecane followed by homogenisation, no stable emulsions arose from dispersions containing solid particle PEC due to either the large precursor particle aggregates or their inherent hydrophilicity. By contrast, oil-in-water emulsions stable to coalescence could be prepared from coacervate dispersions. We discuss the feasibility of the coacervate phase spreading at the oil-water interface in terms of the relevant spreading coefficients and compare the predictions with experiment for a range of oils. We encounter oils whose drops become engulfed by the coacervate phase as well as oils where no engulfing occurs. PMID- 29231948 TI - A tailored nanosheet decorated with a metallized dendrimer for angiography and magnetic resonance imaging-guided combined chemotherapy. AB - Considering the chemical exchange between gadolinium centers and water protons, nanosystems comprising gadolinium conjugated with high specific area nanocarriers might serve as more robust clinical tools for diagnosis and imaging-guided therapy. Herein, a pH-responsive nanosystem containing graphene oxide conjugated with a folic acid- and gadolinium-labeled dendrimer (FA-GCGLD) to boost its T1 contrast ability was developed, and doxorubicin (DOX) and colchicine (COLC) were efficiently loaded onto this nanosystem (FA-GCGLD-DOX/COLC). This nanosystem showed a prominent T1 contrast with an ultrahigh relaxivity of up to 11.6 mM-1 s 1 and pH-responsive drug release behavior. HepG2 cells treated with FA-GCGLD DOX/COLC were efficiently inhibited, and the cell contrast was enhanced. In vivo, the tumor accumulation of FA-GCGLD-DOX/COLC significantly increased, thereby facilitating the systemic delivery of particles and exerting tumor growth inhibition and an enhanced tumor contrast effect. Moreover, compared to free drugs, FA-GCGLD-DOX/COLC effectively decreased the drug resistance of the tumor, thereby improving the cancer chemotherapeutic efficacy. In addition, injecting rats with FA-GCGLD afforded excellent magnetic resonance angiography (MRA) images with high-resolution vascular structures because of the long blood circulation time of FA-GCGLD. Thus, this study provides a powerful tool for diverse applications in the biomedical field, including accurate diagnosis and chemotherapy of tumors and the detection of cardiovascular diseases. PMID- 29231951 TI - Phonomicrosurgery in Vocal Fold Nodules: Quantification of Outcomes in Professional and Non-Professional Voice Users. AB - : There are few data demonstrating the specific extent to which surgical intervention for vocal fold nodules (VFN) improves vocal function in professional (PVU) and non-professional voice users (NVU). The objective of this study was to compare and quantify results after phonomicrosurgery for VFN in these patient groups. METHODS: In a prospective clinical study, surgery was performed via microlaryngoscopy in 37 female patients with chronic VFN manifestations (38+/-12 yrs, mean+/-SD). Pre- and postoperative evaluations of treatment efficacy comprised videolaryngostroboscopy, auditory-perceptual voice assessment, voice range profile (VRP), acoustic-aerodynamic analysis, and voice handicap index (VHI 9i). The dysphonia severity index (DSI) was compared with the vocal extent measure (VEM). RESULTS: PVU (n=24) and NVU (n=13) showed comparable laryngeal findings and levels of suffering (VHI-9i 16+/-7 vs 17+/-8), but PVU had a better pretherapeutic vocal range (26.8+/-7.4 vs 17.7+/-5.1 semitones, p<0.001) and vocal capacity (VEM 106+/-18 vs 74+/-29, p<0.01). Three months postoperatively, all patients had straight vocal fold edges, complete glottal closure, and recovered mucosal wave propagation. The mean VHI-9i score decreased by 8+/-6 points. DSI increased from 4.0+/-2.4 to 5.5+/-2.4, and VEM from 95+/-27 to 108+/ 23 (p<0.001). Both parameters correlated significantly (rs=0.82). The average vocal range increased by 4.1+/-5.3 semitones, and the mean speaking pitch lowered by 0.5+/-1.4 semitones. CONCLUSIONS: These results confirm that phonomicrosurgery for VFN is a safe therapy for voice improvement in both PVU and NVU who do not respond to voice therapy alone. Top-level artistic capabilities in PVU were restored, but numeric changes of most vocal parameters were considerably larger in NVU. PMID- 29231952 TI - Musculoskeletal Symptoms Among Finnish Professional Orchestra Musicians. AB - BACKGROUND: The prevalence of musculoskeletal symptoms is high among professional musicians (73-88%). AIMS: We investigated the prevalence of musculoskeletal symptoms in Finnish symphony orchestra musicians. We compared individual instruments as well as the perceived demands of orchestral programs and difficulties in recovering after performances. METHODS: In this cross-sectional questionnaire 920 of 2,785 members of the Finnish Musicians' Union (33%) completed the questionnaire, including 361 full-time members of symphony orchestras. Questions about pain symptoms and frequency were based on the national survey done in 2011. RESULTS: Among the 361 full-time orchestra musicians, those playing all instruments experienced frequent pain, both in the last 30 days and exceeding 30 days in the last 12 months, in their neck or upper extremities. Female musicians experienced significantly more neck (69%), elbow (31%), and wrist (30%) pain than males (neck 52%, elbow 23%, wrist 19%). The profiles varied according to the different instruments and their playing positions. Musculoskeletal symptoms correlated with perceived demand of the orchestral program and difficulties in recovering after performances. Professional musicians experienced nearly twice as often neck pain in the last 30 days (female musicians 69%, male musicians 52%) than persons of the same age in the Finnish working population (female 41%, male 27%). CONCLUSION: Symphony orchestra musicians experience nearly twice as much musculoskeletal symptoms of the neck and upper extremities as others their age. To prevent musicians' playing related problems, special emphasis should be focused on recovery after concerts, including the special demands of different composers and the frequency of rehearsals and performances. PMID- 29231953 TI - Fundamental Tongue Motions for Trumpet Playing: A Study Using Cine Magnetic Resonance Imaging (Cine MRI). AB - OBJECTIVE: Though the motions of structures outside the mouth in trumpet performance have been reported, the dynamics of intraoral structures remain unelucidated. This study explored the tongue's movement in trumpet playing using cine magnetic resonance imaging (cine MRI) and demonstrated the effects of intraoral anatomical structures on changes in pitch and dynamics. METHODS: Cine MRI was applied to 18 trumpet players, who were divided into two groups (7 beginner, 11 advanced) based on their ability to play a certain high note. They were instructed to play a custom-made MRI-compatible simulated trumpet. Pitch change tasks and dynamics-change tasks were assigned. The positions of the anatomical points and intraoral areas were identified on outlined images, and the changes associated with each task were evaluated. RESULTS: A forward and upward projection of the tongue was observed in the production of higher pitches, and there were no significant differences in all areas. In louder dynamics, a backward and downward bending of the tongue occurred, the tongue area became smaller (p<0.001), and the oral cavity area became larger (p<0.001). No significant differences between beginner and advanced trumpet players were seen in the changes in pitch and dynamics. CONCLUSION: It was demonstrated using cine MRI that certain tongue movements were associated with each task. Tongue protrusion in the production of higher pitch and bending in louder dynamics can be rationalized using acoustics theory and the movements of anatomical structures. These findings seem to be consistent regardless of the player's proficiency. PMID- 29231954 TI - Movements of the Tongue during Lip Trills in Horn Players: Real-Time MRI Insights. AB - OBJECTIVE: Movements inside the oral cavity during lip trilling in horn-playing are poorly understood and controversial, particularly with respect to pedagogy. Developments in real-time magnetic resonance imaging (RT-MRI) allow representations of oral cavity movement during lip trill performance on a MRI compatible horn to be recorded and quantified. METHODS: We present RT-MRI data on 11 highly skilled horn players obtained from serial images acquired at acquisition times of 33.3, 18.2, and 10.0 ms (i.e., at 30, 55 and 100 frames/sec) as they performed sixteenth note, whole-step trills between Eb4 and F4 (concert pitch) at two tempos, ~60 bpm and as fast as possible. RESULTS: For fast trilling (mean speed 178.3+/-24.7 bpm), 7 of 11 subjects exclusively utilized a tongue movement strategy, 3 used both a tongue and jaw strategy, and 1 exclusively used a jaw strategy. For trilling at ~60 bpm, all 11 subjects used a tongue movement strategy. CONCLUSIONS: We suggest using these movement strategies in teaching whole-step trills. PMID- 29231955 TI - Musicians are High Consumers of Complementary and Alternative Healthcare Services: The Norwegian Musicians' Health Project. AB - OBJECTIVE: To estimate the use of analgesic medication and manual and alternative healthcare services among Norwegian musicians compared to the general workforce. METHODS: 1,607 musicians from the Norwegian Musicians' Union answered an online questionnaire about demographic characteristics, use of healthcare services, and use of medication. They were compared to a sample of the Norwegian workforce (n=2,610) from the Norwegian survey of level of living. Based on logistic regression analysis, adjusting for age, sex and education, we compared the self reported use of different forms of healthcare services and medication in musicians to the general workforce. RESULTS: Musicians reported a 2-fold increased use of manual (OR 1.87, CI 1.40-2.33) and complementary and alternative healthcare services (OR 2.58, CI 2.07-3.21) compared to the general workforce. Higher proportions of use of analgesic medication (OR 1.52, CI 1.21-1.89) were also evident in musicians. CONCLUSION: Musicians, as a whole, consistently reported higher use of manual and alternative healthcare services and use of analgesic medication than the general Norwegian workforce. PMID- 29231956 TI - Gender Diversity, Sexual Orientation, and Bone Health in the Maturing Dancer. AB - Gender identity forms an important aspect of still developing youths. Gender is traditionally classified into two distinct categories, female and male. Transgender is a general term that describes individuals who self-identity as male, female, both, or neither (i.e., gender fluid) and do not match the assigned at-birth gender. Adolescent transgender individuals are currently a marginal population. There are limited demographics on youths, but as of 2014 an estimate of 1.4 million adults in the USA identified as transgender. It does seem, however, as more adults embrace their gender diversity and come out as transgender, in some cases opting for surgical reassignment, more adolescents and families are accepting their diversity. A growing body of research highlights transgender adolescents and their specific medical and mental health needs. This review seeks to underscore physiological phenomena relevant to trans-individuals, particularly in adolescents maturing into young adults, and disseminate this knowledge to dance, health, and education professionals. PMID- 29231957 TI - Eating Disorders in Non-Dance Performing Artists: A Systematic Literature Review. AB - PURPOSE: Previous literature on dancers and athletes has shown a large impact of eating disorders (EDs) on these individuals, but there is limited research on EDs affecting non-dance performing artists (i.e., musicians, actors, etc.). This systematic review aimed to identify and evaluate the literature on EDs in non dance performing artists. METHODS: A systematic review of the literature was performed on 24 databases, using search terms related to EDs and non-dance performing artists. All results from the databases were systematically screened for inclusion and exclusion criteria. RESULTS: The initial search returned 86,383 total articles, which after screening and removal of duplicates and irrelevant papers yielded 129 results. After screening the 129 full-text results for eligibility, 10 studies met criteria for inclusion: 6 papers addressed EDs in musicians, and 4 papers addressed EDs in theatre performers. Most studies used questionnaires and body mass index (BMI) as diagnostic tools for EDs. Most were small-scale studies and participants were mostly students. Because of the studies' heterogeneity and varying quality, the results obtained were often contradictory and questionable. CONCLUSIONS: Although there has been a lot of literature in dancers, we found relatively few studies associating EDs with other performing artists, and most were inconsistent in their information. PMID- 29231958 TI - Medical Issues in Playing the Oboe: A Literature Review. AB - Playing a musical instrument can affect physical and mental health. A literature review was conducted to determine the prevalence of health problems among oboists, which medical conditions can be caused or exacerbated by playing, whether oboe playing can be a protective factor, and whether recommendations are possible as to who should or should not play the oboe. Searches in 7 databases (Medline, Embase, Cochrane Library, Web of Science, SocIndex, PsyIndex, Psychinfo) yielded a total of 950 studies; after exclusion of duplicates and those not meeting eligibility criteria, 37 articles were selected for final analysis. In addition, Google Scholar and a musicology library served as additional sources, revealing another 6 publications for inclusion. As a result, some evidence was found for musculoskeletal problems, focal dystonia, stress velopharyngeal incompetence, increased intraocular pressure and glaucoma, gastroesophageal reflux disease, lower pulmonary function, disease transmission via instruments, and hearing loss due to noise exposure. Playing the oboe may be protective against obstructive sleep apnea. However, due to small sample sizes, uncertain reproducibility of findings, and lack of accurate descriptions of problems reported by oboists, far more evidence would be necessary to answer the research questions conclusively. There was no evidence for causal relationships, and thus no recommendations can be made regarding who should (not) play the oboe. To improve the quality of medical care for these musicians and to implement prevention strategies, future investigations with more in-depth instrument specific analyses and higher numbers of participants are needed. PMID- 29231959 TI - Causal somatic mutations in urine DNA from persons with the CLOVES subgroup of the PIK3CA-related overgrowth spectrum. AB - Congenital lipomatous overgrowth with vascular, epidermal, and skeletal (CLOVES) anomalies and Klippel-Trenaunay (KTS) syndromes are caused by somatic gain-of function mutations in PIK3CA, encoding a catalytic subunit of phosphoinositide 3 kinase. Affected tissue is needed to find mutations, as mutant alleles are not detectable in blood. Because some patients with CLOVES develop Wilms tumor, we tested urine as a source of DNA for mutation detection. We extracted DNA from the urine of 17 and 24 individuals with CLOVES and KTS, respectively, and screened 5 common PIK3CA mutation hotspots using droplet digital polymerase chain reaction. Six of 17 CLOVES participants (35%) had mutant PIK3CA alleles in urine. Among 8 individuals in whom a mutation had been previously identified in affected tissue, 4 had the same mutant allele in the urine. One study participant with CLOVES had been treated for Wilms tumor. We detected the same PIK3CA mutation in her affected tissue, urine, and tumor, indicating Wilms tumors probably arise from PIK3CA mutant cells in patients with CLOVES. No urine sample from a participant with KTS had detectable PIK3CA mutations. We suggest that urine, which has the advantage of being collected non-invasively, is useful when searching for mutations in individuals with CLOVES syndrome. PMID- 29231960 TI - Prospective Validation of a Screening Tool to Identify Older Adults in Need of a Driving Evaluation. AB - OBJECTIVES: To prospectively validate and refine the 5-item "CRASH" screening tool for identifying older drivers needing a behind-the-wheel (BTW) test. DESIGN: Prospective observational study. SETTING: Geriatric and internal medicine primary care clinics affiliated with a tertiary care hospital and a local BTW program. PARTICIPANTS: Cognitively intact drivers aged 65 and older (N = 315). MEASUREMENTS: Participants completed baseline questionnaire (including CRASH tool) and assessments and BTW test (evaluator blinded to questionnaire results) and participated in 1-month telephone follow-up. Analysis included descriptive statistics and examination of predictive ability of the CRASH tool to discriminate normal (pass) from abnormal (conditional pass or fail) on the BTW test, with logistic regression and CART techniques for tool refinement. RESULTS: Two hundred sixty-six participants (84%) had a BTW test; of these, 17% had a normal rating and 83% an abnormal rating. Forty-five percent of those with an abnormal score were advised to limit driving under particular conditions. Neither the CRASH tool nor its individual component variables were significantly associated with the summary BTW score; in refined models with other variables, the best-performing tool had approximately 67% sensitivity and specificity for an abnormal BTW score. Most participants found the BTW test useful and were willing to pay a median of $50. At 1-month follow-up, no participants had stopped driving. CONCLUSION: The CRASH screening tool cannot be recommended for use in clinical practice. Findings on older adults' perceived utility of the BTW test and the stability of driving patterns at 1-month follow-up could be useful for future research studies and for design of older driver programs. PMID- 29231961 TI - A mechanism by which Astragalus polysaccharide protects against ROS toxicity through inhibiting the protein dephosphorylation of boar sperm preserved at 4 degrees C. AB - Numerous studies have shown that Astragalus polysaccharide (APS) has strong antioxidant effects and high practical value for preserving semen at low temperatures in vitro. However, to date, little attention has been paid to the precise mechanism of APS in sperm preservation at 4 degrees C. Thus, to gain further insight into the protective effects of APS, the present study was performed to assess the changes in sperm quality parameters, antioxidant capacity, ATP content, and protein phosphorylation levels. Here, we demonstrated that supplementation with APS could effectively preserve boar sperm quality parameters such as sperm motility, acrosome integrity, and mitochondrial membrane potential. Moreover, we found that the positive effects of APS on boar sperm quality were mainly due to the elimination of excessive mitochondrial ROS, the improvement of antioxidant capacities and the enhancement of ATP levels. Interestingly, by conducting a series of studies on protein phosphorylation, we also discovered that APS could protect boar sperm from oxidative stress and energy deficiency through inhibiting the protein dephosphorylation caused by ROS via the cAMP-PKA signaling pathway. To our knowledge, this is the first exploration of the molecular mechanism underlying the protective roles of APS toward ROS toxicity from the perspective of energy metabolism and protein modification. This study comprehensively provides novel insights into the action mechanism of the protective effects of antioxidants on sperm stored at 4 degrees C and reveals the practical feasibility of using APS as a boar semen extender supplement for assisted reproductive technology. PMID- 29231962 TI - Symptoms Reported by Frail Elderly Adults Independently Predict 30-Day Hospital Readmission or Emergency Department Care. AB - OBJECTIVES: To assess the degree to which self-reported symptoms predict unplanned readmission or emergency department (ED) care within 30 days of high risk, elderly adults enrolled in a posthospitalization care transition program (CTP). DESIGN: Retrospective cohort study. SETTING: Posthospitalization CTP at Mayo Clinic, Rochester, Minnesota, from January 1, 2013, through March 3, 2015. PARTICIPANTS: Frail, elderly adults (N = 230; mean age 83.5 +/- 8.3, 46.5% male). MEASUREMENTS: Charlson Comorbidity Index (CCI) and self-reported symptoms, measured using the Edmonton Symptom Assessment System (ESAS), were ascertained upon CTP enrollment. RESULTS: Mean CCI was 3.9 +/- 2.3. Of 51 participants returning to the hospital within 30 days of discharge, 13 had ED visits, and 38 were readmitted. Age, sex, and CCI were not significantly different between returning and nonreturning participants, but returning participants were significantly more likely to report shortness of breath (P = .004), anxiety (P = .02), depression (P = .02), and drowsiness (P = .01). Overall ESAS score was also a significant predictor of hospital return (P = .01). CONCLUSION: Four self reported symptoms and overall ESAS score, but not CCI, ascertained after hospital discharge were strong predictors of hospital return within 30 days. Including symptoms in risk stratification of high-risk elderly adults may help target interventions and reduce readmissions. PMID- 29231963 TI - Body composition in long-term survivors of acute lymphoblastic leukemia diagnosed in childhood and adolescence: A focus on sarcopenic obesity. AB - BACKGROUND: The late effects of treatment for acute lymphoblastic leukemia (ALL) include disordered body composition, especially obesity. Less attention has been focused on the loss of skeletal muscle mass (SMM) and the combined morbidity of sarcopenic obesity. METHODS: A cross-sectional study of body composition was undertaken via dual-energy x-ray absorptiometry in 75 long-term survivors of ALL (more than 10 years after the diagnosis). Measures were obtained of the fat mass (FM), fat-free mass (equivalent to the lean body mass [LBM]), and whole-body bone mineral content. Health-related quality of life (HRQL) was measured with the Health Utilities Index. RESULTS: The sum of the FM, LBM, and whole-body bone mineral content matched the total body weight measured directly (r = 0.998). The appendicular lean mass (ALM) was derived from the LBM in all 4 limbs and accounted for approximately 75% of the SMM. According to the fat mass index (FMI; ie, FM/height2 ), 12% of females and 18% of males were frankly obese by World Health Organization criteria. The median FMI z score was + 0.40, whereas the median z score for the appendicular lean mass index (ALMI; ie, ALM/height2 ) was 0.40. Sarcopenic obesity, defined as a positive FMI z score with a negative ALMI z score, was present in 32 subjects (43%). There were statistically significant and clinically important differences in overall HRQL between subjects with and without sarcopenic obesity. CONCLUSIONS: Sarcopenic obesity is prevalent in long term survivors of ALL, and this places them in double jeopardy from excess body fat and inadequate SMM (eg, a combination of metabolic and frailty syndromes). It is associated with an adverse impact on overall HRQL. Cancer 2018;124:1225-31. (c) 2017 American Cancer Society. PMID- 29231964 TI - Travel distance and stereotactic body radiotherapy for localized prostate cancer. AB - BACKGROUND: Definitive stereotactic body radiotherapy (SBRT) represents an emerging and debated treatment option for patients with prostate cancer, with potential economic savings and reports of short-term efficacy since 2006. The current study sought to define national trends in definitive prostate SBRT use and determine whether patterns vary by travel distance for treatment. METHODS: The National Cancer Data Base identified 181,544 men with localized prostate cancer who were treated with definitive external beam radiotherapy from 2004 through 2012. Joinpoint regression analyzed definitive prostate SBRT trends over time, whereas multivariable logistic regression defined the odds for its receipt by travel distance for treatment. RESULTS: Definitive prostate SBRT use increased from 1.8% in 2004 to 5.9% in 2012 (P for trend <.0001), with a joinpoint for increased use noted in 2006 (P<.0001). Higher SBRT use was found to be associated with longer travel distance for treatment, younger age, white race, more affluent zip code of residence, academic treatment center, favorable disease characteristics, and fewer comorbidities (all P<.0001). Compared with travel distances <25 miles for treatment, travel distances of 25 to 50 miles and >50 miles were associated with increasing adjusted odds of receipt of definitive prostate SBRT (1.63 [95% confidence interval, 1.51-1.76] and 2.35 [95% confidence interval, 2.14-2.57], respectively; both P < .0001). CONCLUSIONS: Definitive prostate SBRT use increased more than 3-fold since 2004, with a significant increase in use coinciding with early reports of short-term efficacy. Long distance travel for treatment was associated with greater than twice the odds of receipt of definitive prostate SBRT compared with short-distance travel, suggesting that treatment decisions with unknown long-term clinical implications may be strongly driven by sociodemographic factors. Cancer 2018;124:1141-9. (c) 2017 American Cancer Society. PMID- 29231965 TI - Mapping multi-scale vascular plant richness in a forest landscape with integrated LiDAR and hyperspectral remote-sensing. AB - The central role of floristic diversity in maintaining habitat integrity and ecosystem function has propelled efforts to map and monitor its distribution across forest landscapes. While biodiversity studies have traditionally relied largely on ground-based observations, the immensity of the task of generating accurate, repeatable, and spatially-continuous data on biodiversity patterns at large scales has stimulated the development of remote-sensing methods for scaling up from field plot measurements. One such approach is through integrated LiDAR and hyperspectral remote-sensing. However, despite their efficiencies in cost and effort, LiDAR-hyperspectral sensors are still highly constrained in structurally- and taxonomically-heterogeneous forests - especially when species' cover is smaller than the image resolution, intertwined with neighboring taxa, or otherwise obscured by overlapping canopy strata. In light of these challenges, this study goes beyond the remote characterization of upper canopy diversity to instead model total vascular plant species richness in a continuous-cover North Carolina Piedmont forest landscape. We focus on two related, but parallel, tasks. First, we demonstrate an application of predictive biodiversity mapping, using nonparametric models trained with spatially-nested field plots and aerial LiDAR hyperspectral data, to predict spatially-explicit landscape patterns in floristic diversity across seven spatial scales between 0.01-900 m2 . Second, we employ bivariate parametric models to test the significance of individual, remotely sensed predictors of plant richness to determine how parameter estimates vary with scale. Cross-validated results indicate that predictive models were able to account for 15-70% of variance in plant richness, with LiDAR-derived estimates of topography and forest structural complexity, as well as spectral variance in hyperspectral imagery explaining the largest portion of variance in diversity levels. Importantly, bivariate tests provide evidence of scale-dependence among predictors, such that remotely-sensed variables significantly predict plant richness only at spatial scales that sufficiently subsume geolocational imprecision between remotely-sensed and field data, and best align with stand components including plant size and density, as well as canopy gaps and understory growth patterns. Beyond their insights into the scale-dependent patterns and drivers of plant diversity in Piedmont forests, these results highlight the potential of remotely-sensible essential biodiversity variables for mapping and monitoring landscape floristic diversity from air- and space-borne platforms. PMID- 29231966 TI - The role of postmastectomy radiotherapy in patients with stage II breast cancer. PMID- 29231967 TI - Therapeutic potential of porcine bronchoalveolar fluid-derived mesenchymal stromal cells in a pig model of LPS-induced ALI. AB - In this study, we isolated mesenchymal stromal (stem) cells (MSCs) from broncho alveolar lavage fluid (BAL) of 2-6-week-old commercial pigs. BAL-MSCs displayed fibroblastic morphology and possessed self-renewal properties. Similar to bone marrow MSCs, BAL-MSCs expressed mesenchymal markers and both cell types lacked the expression of hematopoetic markers. BAL-MSCs, when cultured in differentiation induction media, differentiated into adipocytes, osteocytes, and chondrocytes. Next, we examined if BAL-MSCs have the ability to treat lipopolysaccharide (LPS)-induced acute lung injury (ALI) in a pig model. Five week-old commercial pigs were inoculated intra-tracheally with E. coli LPS (1 mg/kg body weight [b.wt.]). Twelve hours after the LPS inoculation, groups of pigs were inoculated intra-tracheally with BM-MSCs or BAL-MSCs (2 * 106 cells/kg b.wt.). Forty eight hours after the cells administration pigs were euthanized and neutrophils in BAL, lung lesions, and cytokines in lung lysates, and engraftment of MSCs in lungs were examined. Engraftment of BAL-MSCs in injured lungs was significantly higher than the BM-MSCs, however, both cell types were equally effective in attenuating LPS-induced ALI as evidenced by decreased inflammation, lung lesions, and proinflammatory cytokines in the lungs of pigs treated with BAL or BM-MSCs. These data in a preclinical large animal model suggest that BAL-MSCs may be used in clinical settings to treat ALI in humans. PMID- 29231968 TI - Value of magnetic resonance imaging for evaluating muscle inflammation: insights from a new mouse model of myositis. AB - Inflammatory myopathies or myositides represent a group of severe skeletal muscle diseases characterized by muscle weakness, elevation of serum creatine kinase levels and muscle inflammatory cell infiltrates. Despite the contribution of a growing number of myositis-specific autoantibodies and the existence of characteristic dermatological features in dermatomyositis, the definitive diagnosis of myositis requires pathological examination of a muscle biopsy [1, 2]. To limit false negatives, this biopsy should be performed in an area of active disease [2]. In this context, magnetic resonance imaging (MRI) has gained interest since T1-weighted images are able to determine muscle damage such as atrophy, fatty infiltration and their distribution [3, 4] while T2-weighted images help to detect edema and thus may inform on the activity of the disease, i.e. muscle inflammatory infiltrates. This article is protected by copyright. All rights reserved. PMID- 29231970 TI - Adaptation of the Utrecht-Management of Identity Commitments Scale (U-MICS) to the measurement of the parental identity domain. AB - The present studies examined the psychometric properties of the Utrecht Management of Identity Commitments Scale (U-MICS) adapted to the measurement of identity formation in the parental identity domain. As the parental identity domain has only been studied within the neo-Eriksonian approach to a very limited extent, the aim of these studies was to prepare a short, valid and reliable tool for the measurement of parental identity in order to fill this gap. The associations of commitment, in-depth exploration and reconsideration of commitment in the parental domain with well-being and with other identity constructs were analyzed. The results showed that parental identity formation is associated with mothers' satisfaction with life and trait anxiety and with identity formation in other areas as well. The initial results suggest that the adapted version of the U-MICS is a valid and reliable measure that can be used in future studies on parental identity formation. PMID- 29231971 TI - Enzooty of non-Hodgkin's malignant lymphoma of Papio hamadryas in Sukhumi monkey colony. Clinical and morphological signs of pre-lymphoma. AB - Inoculation of hamadryas baboons with blood of leukemia ill people-induced malignant non-Hodgkin's lymphoma in experimental animals for a very considerable latency period. At close contact of inoculated baboons with healthy non inoculated animals, the lymphoma spread between them. The epidemiological analysis, postmortem examination, histological analysis, tissue culturing, and PCR were used for the diagnostics of lymphoma and pre-lymphoma, purification, identification of STLV-1, and HVP viruses. Characteristic clinical and morphological signs designated by us as pre-lymphoma often precede the lymphoma development. In some cases, pre-lymphoma does not develop in lymphoma because animals die from various diseases and do not reach the point of the lymphoma development. The horizontal transmission of lymphoma arising with the participation of T-lymphotropic retrovirus STLV-1 is shown. PMID- 29231969 TI - Patient-reported outcomes enhance the survival prediction of traditional disease risk classifications: An international study in patients with myelodysplastic syndromes. AB - BACKGROUND: Current prognostic systems for myelodysplastic syndromes (MDS) are based on clinical, pathologic, and laboratory indicators. The objective of the current study was to develop a new patient-centered prognostic index for patients with advanced MDS by including self-reported fatigue severity into a well established clinical risk classification: the International Prognostic Scoring System (IPSS). METHODS: A total of 469 patients with advanced (ie, IPSS intermediate-2 or high-risk) MDS were analyzed. Untreated patients (280 patients) were recruited into an international prospective cohort observational study to create the index. The index then was applied to an independent cohort including pretreated patients with MDS from the Dana-Farber Cancer Institute in Boston, Massachusetts (189 patients). At baseline, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). RESULTS: A new prognostic index was developed: the FA IPSS(h), in which FA stands for fatigue and h for higher-risk. This new risk classification enabled the authors to distinguish 3 subgroups of patients with distinct survival outcomes (ie, risk-1, risk-2, and risk-3). Patients classified as FA-IPSS(h) risk-1 had a median overall survival (OS) of 23 months (95% confidence interval [95% CI], 19-29 months), whereas those with risk-2 had a median OS of 16 months (95% CI, 12-17 months) and those with risk-3 had a median OS of 10 months (95% CI, 4-13 months). The predictive accuracy of this new index was higher than that of the IPSS alone in both the development cohort as well as in the independent cohort including pretreated patients. CONCLUSIONS: The FA IPSS(h) is a novel patient-centered prognostic index that includes patients' self reported fatigue severity. The authors believe its use might enhance physicians' ability to predict survival more accurately in patients with advanced MDS. Cancer 2018;124:1251-9. (c) 2017 American Cancer Society. PMID- 29231972 TI - Prostate cancer screening with prostate-specific antigen: Where are we going? PMID- 29231973 TI - Comparative effectiveness of prostate cancer screening between the ages of 55 and 69 years followed by active surveillance. AB - BACKGROUND: Because of the recent grade C draft recommendation by the US Preventive Services Task Force (USPSTF) for prostate cancer screening between the ages of 55 and 69 years, there is a need to determine whether this could be cost effective in a US population setting. METHODS: This study used a microsimulation model of screening and active surveillance (AS), based on data from the European Randomized Study of Screening for Prostate Cancer and the Surveillance, Epidemiology, and End Results Program, for the natural history of prostate cancer and Johns Hopkins AS cohort data to inform the probabilities of referral to treatment during AS. A cohort of 10 million men, based on US life tables, was simulated. The lifetime costs and effects of screening between the ages of 55 and 69 years with different screening frequencies and AS protocols were projected, and their cost-effectiveness was determined. RESULTS: Quadrennial screening between the ages of 55 and 69 years (55, 59, 63, and 67 years) with AS for men with low-risk cancers (ie, those with a Gleason score of 6 or lower) and yearly biopsies or triennial biopsies resulted in an incremental cost per quality adjusted life-year (QALY) of $51,918 or $69,380, respectively. Most policies in which screening was followed by immediate treatment were dominated. In most sensitivity analyses, this study found a policy with which the cost per QALY remained below $100,000. CONCLUSIONS: Prostate-specific antigen-based prostate cancer screening in the United States between the ages of 55 and 69 years, as recommended by the USPSTF, may be cost-effective at a $100,000 threshold but only with a quadrennial screening frequency and with AS offered to all low-risk men. Cancer 2018;124:507-13. (c) 2017 American Cancer Society. PMID- 29231974 TI - Direct determination of amino acids in brewery worts produced by different processes by capillary zone electrophoresis. AB - The direct and simultaneous determination of cysteine, histidine, phenylalanine, lysine, tryptophan and arginine in brewery worts by capillary zone electrophoresis (CZE) was applied to evaluate the effects of temperature control and protease supplementation during mashing on the changes of these amino acids (AAs) wort composition. A cation exchange resin was used for AAs extraction from wort samples prior to CZE determination. The separation was achieved using a 50 mmol/L phosphate buffer at pH 12.5, containing 0.4 mmol/L cetyltrimethylammonium bromide (CTAB), as background electrolyte (BGE) solution; -20 kV; 20 degrees C and hydrodynamic injection time of 15 s, at 50 mbar. Recovery evaluation using worts led to values between 83.1 and 96.2%, demonstrating the method feasibility, which was successfully applied in the quantification of AAs in wort samples. This study showed that temperature control and addition of exogenous proteases in the mashing may increase the AAs concentration in wort, improving the final product quality (beer). The present method is a good alternative for monitoring specific AAs in worts and their determination can allow the brewing process optimization. PMID- 29231975 TI - The precise subcellular localization of Dlg in the Drosophila larva body wall using improved pre-embedding immuno-EM. AB - Discs-large (Dlg) plays important roles in nerve tissue and epithelial tissue in Drosophila. However, the precise positioning of Dlg in the neuromuscular junction remains to be confirmed using an optimized labeling method. In this study, we improved the method of pre-embedding immunogold electron microscopy without the osmic tetroxide procedure, and we found that Lowicryl K4 M resin and low temperature helped to preserve the authenticity of the labeling signal with relatively good contrast. Dlg was strongly expressed in the entire subsynaptic reticulum (SSR) membrane of type Ib boutons, expressed in parts of the SSR membrane of type Is boutons, weakly expressed in axon terminals and axons, and not expressed in pre- or postsynaptic membranes of type Is boutons. In muscle cells and stratum corneum cells, Dlg was expressed both in the cytoplasm and in organelles with biomembranes. The precise location of Dlg in SSR membranes, rather than in postsynaptic membranes, shows that Dlg, with its multiple domains, acts as a remote or indirect regulator in postsynaptic signal transduction. PMID- 29231976 TI - Reduced salivary flow rate and high levels of oxidative stress in whole saliva of children with Down syndrome. AB - AIM: To investigate salivary parameters between children with Down Syndrome (DS) and without DS. MATERIALS AND METHODS: Stimulated whole saliva was collected from 18 children with DS and 23 without DS. Salivary flow rate, pH, and salivary buffering capacity were determined. Cariogenic microorganisms were quantified by culture, and periodontopathogens by quantitative real-time polymerase chain reaction. The antioxidant profile was quantified spectrophotometrically, while malondialdehyde (MDA) was quantified by high-performance liquid chromatography. Data were analyzed by Mann-Whitney test and Spearman correlation (alpha = 0.05). RESULTS: Salivary flow rate was significantly lower in DS than in controls (p < 0.0001). Significant higher difference was observed for total protein dosage (p < 0.0001), superoxide dismutase activity (SOD) (p = 0.0002), and MDA (p < 0.001) in DS group. CONCLUSIONS: Reduced salivary flow rate might be an important factor in oral diseases development. High salivary levels of SOD and MDA show the significant influence of the oxidative stress and the early-onset periodontal disease in DS people. PMID- 29231977 TI - DIDS inhibits overexpression BAK1-induced mitochondrial apoptosis through GSK3beta/beta-catenin signaling pathway. AB - Bcl-2 homologous antagonist/killer (BAK1) is a critical regulator of mitochondrial apoptosis. Although upregulation of BAK1 induces apoptosis has been established, the underlying molecular mechanism is far from clear. 4,4' diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), an organic anion used as a blocker of anion exchangers and chloride channels, has been proved to rescue cell apoptosis both in vitro and in vivo. However, whether DIDS can inhibit BAK1 induced mitochondrial apoptosis remains undefined. Thus, this study aimed to explore whether DIDS could protect BAK1-induced apoptosis through GSK3beta/beta catenin signaling pathway. The results showed overexpression BAK1 in 293T cells induced mitochondrial apoptosis accompanied by increasing the expression levels of cleaved caspase-9, -3, poly (ADP-ribose) polymerase (PARP) and reducing the MMP. Furthermore, overexpression BAK1 decreased the expression levels of Ser9 GSK3beta and beta-catenin. In addition, lithium chloride (LiCl), an activator of Wnt/beta-catenin signaling pathway, markedly attenuated overexpression BAK1 induced mitochondrial apoptosis by restoring the expression levels of Ser9 GSK3beta and beta-catenin. Finally, DIDS absolutely abolished overexpression BAK1 mediated mitochondrial apoptosis through recovering the expression levels of Ser9 GSK3beta and beta-catenin. Taken together, our results reveal that DIDS blocks overexpression BAK1-induced mitochondrial apoptosis through GSK3beta/beta-catenin pathway. PMID- 29231978 TI - Impact of a shift in nuchal translucency measurements on the detection rate of first-trimester Down syndrome screening: A population-based study. AB - OBJECTIVE: To assess the distribution of nuchal translucency (NT) measurements following a national policy without credentialing and its impact on first trimester Down syndrome screening (DSS) detection rate. METHOD: All first trimester DSS data recorded in France (2010-2014) were collected by the laboratories in charge via an Internet database (https://www.bionuqual.org/echo.php). There was no minimal requirement for image quality to allow sonographers to enter the screening process. A subgroup of DSS with complete DS follow-up corresponded to 1614 sonographers. Based on the distribution of maternal age, DS detection rate was calculated and split as a function of the distribution of NT multiple of the median (MoM). RESULTS: Four thousand nine hundred forty-three sonographers performed 2,337,372 NT measurements. Median NT expressed in MoM was 0.83. Screenings with complete follow-up consisted of 197,417 screenings, in which DSS detection rates were respectively 70.4%, 70.9%, 79.4%, 87.7%, and 79.5% for the following median NT MoM ranges: <0.7, 0.70 to 0.79, 0.80 to 0.89, 0.90 to 0.99, and >0.99 (trend chi = 12.21; P = .0158). CONCLUSION: In France, following a policy of quality assessment without standardized credentialing, the distribution of NT measurements did not fit the expected distribution. Down syndrome detection rate was 10% lower in screenings by sonographers with a median NT < 0.80 MoM. PMID- 29231979 TI - Otitis media with effusion in the boxer: a report of seven cases. AB - The aim of this study was to describe otitis media with effusion in seven boxers. All dogs presented with a range of clinical signs, which included head shaking, neurological dysfunction, pain on opening of the mouth and reduction in hearing ability. Otitis media was confirmed under general anaesthesia in each case by video-otoscopic identification of a bulging pars tensa and subsequent myringotomy, which revealed a tenacious mucus plug within the middle ear. Brainstem auditory evoked response thresholds were elevated in all affected ears. In three cases, CT revealed soft tissue opacity in the affected bulla. All of the affected middle ears were flushed using warm sterile saline to remove the mucus. A combination of glucocorticoid and antibiotic in EDTA tris was instilled into the middle ears. After the initial middle ear flush under general anaesthesia, topical therapy was applied into the ear canals daily by the owners using the same combination of drugs. Dembrexine, a systemic mucolytic, was administered with food daily. Six out of seven dogs were also prescribed oral prednisolone. In each case, the middle ear effusion was sterile. All clinical signs resolved with treatment, with the exception of facial paralysis in two dogs. Otitis media with effusion should be considered a cause of otitis media in boxers. PMID- 29231980 TI - Reviewers 1988-1989. PMID- 29231982 TI - End of the beginning. PMID- 29231983 TI - Journal of Cutaneous Pathology. PMID- 29231985 TI - REPLY TO LETTER TO THE EDITOR. PMID- 29231984 TI - Evidence for increased chylomicron remnants in rheumatoid arthritis. AB - BACKGROUND: Levels of apolipoprotein (apo) B48 may be increased in conditions associated with systemic inflammation and increased cardiovascular disease (CVD) risk such as rheumatoid arthritis (RA). We aimed to evaluate apo B48 levels in patients with RA in relation to subclinical atherosclerosis. METHODS: Patients with RA (without CVD) and controls without RA but with high CVD risk (based on the presence of diabetes mellitus or a history of CVD) and healthy controls were included in this cross-sectional study. Carotid intima-media thickness (cIMT) was measured as a surrogate for vascular damage. RESULTS: In total, 312 patients with RA, 65 controls with high CVD risk and 36 healthy controls were included. Patients with RA had the highest mean apo B48 (10.00 +/- 6.65 mg/L) compared to controls with high CVD risk and healthy controls (8.37 +/- 5.16 and 5.22 +/- 2.46, P < .001). Triglycerides levels were comparable with controls. In RA, apo B48 correlated positively with triglycerides (r = .645; P < .001) but not with cIMT. However, in RA subjects not using lipid or blood pressure lowering medication, a weak correlation was found with cIMT (r = .157; P = .014). RA patients in the highest apo B48 tertile were more often rheumatoid factor positive and anti-CCP positive compared to the lowest tertile. CONCLUSION: Rheumatoid arthritis patients have higher levels of apo B48 compared to controls with high CVD risk and healthy controls, with normal levels of triglycerides. This accumulation of atherogenic chylomicron remnants may contribute to the elevated CVD risk in RA patients. PMID- 29231987 TI - LETTER TO THE EDITOR: Does cardiac output determine leg blood-flow? PMID- 29231988 TI - Methylation-based estimated biological age and cardiovascular disease. AB - BACKGROUND: DNA methylation changes over life at specific sites in the genome, which can be used to estimate "biological age." The aim of this population-based longitudinal cohort study was to investigate the association between estimated biological age and incident cardiovascular disease (CVD). MATERIALS AND METHODS: Based on formulas published by Hannum et al and Horvath et al, "biological age" was calculated using data from the Illumina 450k Bead Methylation chip in 832 participants free from cardiovascular disease in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study (50% women, all aged 70 years at the examination). The difference between estimated biological and chronological age was calculated (DiffAge). RESULTS: During 10 years of follow-up, 153 incident cases of cardiovascular disease occurred. In the sex-adjusted analyses, the Horvath estimation of DiffAge was significantly related to incident cardiovascular disease (HR 1.040, 95% CI 1.010-1.071, P = .0079). Thus, for each year of increased biological age, a 4% increased risk of future cardiovascular disease was observed. This relationship was still significant following adjustment for the traditional risk factors sex, BMI, diabetes, HDL and LDL cholesterol, systolic blood pressure and smoking (HR 1.033, 95% CI 1.004-1.063, P = .024). No such significant association was found using the Hannum formula. CONCLUSIONS: DNA methylation-based estimation of "biological age" per Horvath was associated with incident cardiovascular disease. PMID- 29231989 TI - Sexual imprinting and speciation between two Peromyscus species. AB - Sexual isolation, a reproductive barrier, can prevent interbreeding between diverging populations or species. Sexual isolation can have a clear genetic basis; however, it may also result from learned mate preferences that form via sexual imprinting. Here, we demonstrate that two sympatric species of mice-the white-footed mouse (Peromyscus leucopus) and its sister species, the cotton mouse (P. gossypinus)-hybridize only rarely in the wild despite co-occurrence in the same habitat and lack of any measurable intrinsic postzygotic barriers in laboratory crosses. We present evidence that strong conspecific mating preferences in each species result in significant sexual isolation. We find that these preferences are learned in at least one species: P. gossypinus sexually imprints on its parents, but in P. leucopus, additional factors influence mating preferences. Our study demonstrates that sexual imprinting contributes to reproductive isolation that reduces hybridization between otherwise interfertile species, supporting the role for learning in mammalian speciation. PMID- 29231990 TI - Tendon explant cultures to study the communication between adipose stem cells and native tendon niche. AB - Poor clinical outcomes of tendon repair, together with limited regenerative capacity of the tissue, have triggered the search for alternative regenerative medicine strategies. Human adipose-derived stem cells (hASCs) are being investigated as a promising cell source in contributing for tendon repopulation and reconstruction. However, the mechanisms involved in a potential beneficial effect in tendon regeneration are still to be uncovered. To gain further insights on the bi-directional crosstalk occurring between stem cells and the native tendon niche, it was used an indirect (trans-well) system for co-culturing human tendon explants and hASCs. The maintenance of tissue architecture was studied up to 14 days by histological techniques. The secretion of MMPs was evaluated at day 3. The behavior of hASCs was assessed regarding cell elongation and extracellular matrix (ECM) production. The paracrine communication enhanced collagenolytic activity of MMPs in co-cultures at day 3, in comparison to hASCs alone or tendon explants alone, suggesting that ECM remodeling is triggered early in culture. Moreover, hASCs were spontaneously more elongated in co-cultures and the deposition of collagen type III and tenascin-C by hASCs in co-culture was observed at a lower extent after 7 days, in comparison to hASCs alone, being lately recovered at day 14. Overall, explant co-cultures established herein may constitute a tool for replicating the first steps in tendon healing and help uncovering the bi-directional communication occurring between hASCs and the native tendon niche. PMID- 29231991 TI - Combination of TNM staging and pathway based risk score models in patients with gastric cancer. AB - Due to the complexity and heterogeneity of gastric cancer (GC) in individual patient, current staging system is inadequate for predicting outcome of GC. Comprehensive computational and bioinformatics approach may triumph for the prediction. In this study, GC patients were devided according to stage and treatment: curative surgery plus chemoradiotherapy in stage II, curative surgery plus chemoradiotherapy in stages III, and IV, unresectable metastatic gastric cancer. The training sets were downloaded from GEO datasets (GSE26253 and GSE14208). Gene set enrichment analysis (GSEA) was performed to explore enriched difference between recurrence and nonrecurrence. The core enrichment genes of enriched pathways significantly associated with recurrence or progression were identified using Cox proportional hazards analysis. Thereafter, the risk score models were externally validated in independent datasets-GSE15081 and The Cancer Genome Atlas (TCGA). We generated respective risk score models of patients in different stages and treatment. A five-gene signature comprising FARP1, SGCE, SGCA, LAMA4, and COL9A2 was strongly associated with recurrence of patients with curative surgery plus chemoradiotherapy in stage II. A six-gene signature consisting of SHH, NF1, AP4B1, COMP, MATN3, and CCL8 was correlated with recurrence of patients with curative surgery plus chemoradiotherapy in stages III and IV. And a four-gene signature composing of ABCC2, AHNAK2, RNF43, and GSPT2 was highly related to progression of patients with unresectable metastatic GC. Taking into consideration TNM stage and gene signature reflecting recurrence or progression, the risk score models significantly improved the accuracy in predicting outcome of GC. PMID- 29231992 TI - HCFU inhibits cervical cancer cells growth and metastasis by inactivating Wnt/beta-catenin pathway. AB - BACKGROUND: 1-hexylcarbamoyl-5-fluorouracil (HCFU), also known as carmofur, is an effective chemotherapeutic agent applied to several cancers. This study was aimed to explore the functional effects of HCFU on cervical cancer cells and tried to uncover its possible mechanism. METHODS: Two immortalized cervical cancer cell lines (HeLa and Caski) and primary cervical cancer cells prepared from two cervical cancer patients were used in this study. Cell viability, apoptosis, colony formation, migration, invasion, and the expressions of cell growth- and metastasis-associated factors were respectively assessed following 0-1 ug/mL of HCFU treatment for 0-48 h. Besides, the expressions of main factors in Wnt/beta catenin signaling pathway were detected following HCFU administration. RESULTS: As a result, HCFU significantly suppressed HeLa and Caski cells viability but promoted apoptosis, both in time- and dose-dependent manner (P < 0.05 or P < 0.01). Besides, HCFU reduced these two cell lines colony formation capacity, migration and invasion (P < 0.05, P < 0.01 or P < 0.001). In primary cervical cancer cells, cell viability was reduced (P < 0.05 or P < 0.01), the expressions of Cyclin D1, MMP2 and MMP9 were down-regulated, while the expression of E Cadherin was up-regulated after HCFU treatment. Further, HCFU down-regulated the expressions of intranuclear beta-catenin, c-Myc, and TCF-1, but has no impacts on intracytoplasmic beta-catenin expression in HeLa cells and primary cervical cancer cells. CONCLUSION: This study demonstrated an anti-growth and anti metastasis role of HCFU in cervical cancer cells. HCFU suppressed cervical cancer possibly via blocking Wnt/beta-catenin signaling pathway. This article is protected by copyright. All rights reserved. PMID- 29231993 TI - Etiology and long-term rebleeding of endoscopic ulcerative lesions in the small bowel in patients with obscure gastrointestinal bleeding: A multicenter cohort study. AB - BACKGROUND: Among patients with obscure gastrointestinal bleeding (OGIB), endoscopic ulcerative lesions in the small bowel have diverse etiologies and often cause rebleeding. Certain characteristics of patients or ulcerations may be reasonable indications for diagnostic balloon-assisted endoscopy (BAE) to assess etiology and may be risks of rebleeding; however, these characteristics are unclear. We aimed to elucidate appropriate indications for diagnostic BAE and predictors of long-term rebleeding in patients with small bowel ulcerative lesions. METHODS: We conducted a multicenter retrospective cohort study of 68 patients with OGIB, in whom small bowel ulcerative lesions were detected by capsule endoscopy (n = 60) and/or BAE (n = 43). Patients' characteristics, including medications and endoscopic findings, were evaluated. Predictors of the need for diagnostic BAE to determine ulceration etiology were identified by logistic regression analysis. Rebleeding risks were evaluated using Cox proportional hazards analysis. RESULTS: Single ulcerations were diagnosed in 26 patients, and multiple ulcerations were diagnosed in 42 patients. Among 43 patients who underwent BAE, ulceration etiology was identified in 12 (28%) patients. In the etiology identification, BAE was more useful for a single ulceration than for multiple ulcerations (P < 0.001). Among the 68 patients, rebleeding occurred in 14 (21%) patients during a mean follow-up period of 17 months. Aspirin use and multiple ulcerations were significant predictors of rebleeding (P < 0.05). CONCLUSIONS: When we manage small bowel ulcerative lesions in OGIB patients, a single ulceration is a reasonable indication for the diagnostic BAE. The rebleeding rate was lower for single ulcerations than for multiple ulcerations. PMID- 29231994 TI - NES1/KLK10 promotes trastuzumab resistance via activation of PI3K/AKT signaling pathway in gastric cancer. AB - Trastuzumab, a humanized antibody targeting human epidermal growth factor receptor 2 (HER2), exhibits remarkable therapeutic efficacy against HER2-positive gastric cancer. Acquired resistance to trastuzumab remains a barrier to patient survival and the mechanisms underlying this are still not well understood. The normal epithelial cell-specific-1 (NES1) gene, also named as KLK10, is recognized as a potential therapeutic target for reversing trastuzumab resistance. The aim of this study was to explore the potential role of KLK10 in trastuzumab resistance (TR) gastric cancer cells. We found that KLK10 was significantly upregulated in trastuzumab-resistant cell lines, SGC7901-TR and BGC-823-TR. In addition, down regulation of KLK10 reversed the resistance in trastuzumab resistant cells. Overexpression of KLK10 induced trastuzumab resistance, and activated the PI3K/AKT signaling pathway, while downregulation of KLK10 presented the opposite effects. Moreover, when the PI3K/AKT signaling pathway was inhibited, the effect of KLK10 on resistance was diminished. Furthermore, combination of trastuzumab and PI3K/AKT inhibitor XL147 effectively inhibited tumor growth in KLK10-overexpressing xenografts. Taken together, our findings show that KLK10 promotes trastuzumab resistance, at least in part, through the PI3K/AKT signaling pathway, suggesting that KLK10 is a potentially target to overcome trastuzumab resistance, and the combination might overcome trastuzumab resistance in KLK10-overexpressed gastric cancer patients. PMID- 29231995 TI - Identification of risk factors for neoplastic colonic polyps in young adults with bloody stool in comparison with those without symptom. AB - BACKGROUND AND AIMS: The incidence and disease burden of colorectal cancer (CRC) in young adults were increasing. However, there was a dearth of advice on how to identify young population at risk for neoplastic colonic polyps (NCPs) and CRC. We aimed to identify risk factors for NCPs and CRC in young adults presenting with bloody stool. METHODS: A total of 1496 subjects younger than 40 years old who underwent colonoscopy due to bloody stool from 2005 to 2014 were enrolled in this retrospective study as the study group, and 1481 age-matched and gender matched asymptomatic subjects who underwent colonoscopy for health checkup from 2011 to 2016 were enrolled as the control group at a tertiary center hospital. RESULTS: Multivariate analysis results showed that increasing age (odds ratio [OR] = 1.11, 95% confidence interval [CI]: 1.07-1.15, P < 0.001), higher body mass index (BMI) (OR = 1.07, 95%CI: 1.03-1.12, P = 0.001), diabetes mellitus (OR = 2.80, 95%CI: 1.06-7.42, P = 0.038), and positive family history of CRC (OR = 13.28, 95%CI: 5.70-30.97, P < 0.001) were identified as independent risk factors for NCPs in study group. The best cut-off values by receiver operating characteristic curve for age and BMI were 32 years old and 24.8 kg/m2 , respectively. More risk factors were associated with the higher risk for NCPs (OR = 2.17 every increasing one risk factor, P < 0.001). In the control group, no independent risk factors were identified. CONCLUSIONS: Adults aged <= 40 years with bloody stool who had increasing age (> 32 years old), higher BMI (> 24.8 kg/m2 ), diabetes mellitus, and positive family history of CRC had a higher detection rate of NCPs and CRC. PMID- 29231996 TI - Molecular mechanisms of tributyltin-induced alterations in cholesterol homeostasis and steroidogenesis in hamster testis: In vivo and in vitro studies. AB - Tributyltins (TBT) are ubiquitous and persistent environmental contaminants that disturb normal endocrine function including gonadal function in humans and marine organisms. TBT was administered through oral route to male Syrian hamsters at daily doses of 50, 100, and 150 ppm/kg for 65 days. Changes in testis morphology, immunohistochemistry of iNOS, 3beta-HSD, and 17beta-HSD, cholesterol transport receptor, nuclear receptors, and transcription factors were analyzed. TBT treatment affected each of these parameters to significant levels in a dose dependent manner compared to vehicle treated control. Real-time PCR and protein analyses revealed that expression levels of ApoE and LDL-R mRNA were up-regulated in the testis of TBT-treated animals while the expression levels of SR-B1, LXR, PPARs alpha, beta, and gamma, SCAP, SREBP 1 and 2, 3beta-HSD, 17beta-HSD, CYP17A1, and P450SCC were down-regulated. Leydig cells were isolated and separated adopting percoll gradient centrifugation under aseptic condition. The viability of Leydig cell was affected by TBT treatment in a dose- and time dependent manner. Further, the mechanism of action of TBT was ascertained by siRNA transfection of ApoE, which was upregulated, and SREBP, which was down regulated. These observations led us to infer that exposure to TBT hinders intracellular cholesterol transport resulting in abnormal sex steroid biosynthesis and alteration of steroidogenic enzyme activities. Finally, we could recognize ApoE and SREBP as the major factors regulating genes that control cholesterol biosynthesis and steroidogenesis that ultimately inhibit the synthesis of testosterone. Therefore, ApoE is one of the important molecular targets that can be intercepted in context of male infertility/male contraception. PMID- 29231997 TI - Immortalization of canine adipose-derived mesenchymal stem cells and their seminiferous tubule transplantation. AB - Adipose-derived mesenchymal stem cells (ADSCs) are proven to provide good effects in numerous tissue engineering application and other cell-based therapies. However, the difficulty in the proliferation of ADSCs, known as the "Hayflick limit" in vitro, limits their clinical application. Here, we immortalized canine ADSCs (cADSCs) with SV40 gene and transplanted them into busulfan-induced seminiferous tubules of infertile mice. The proliferation of these immortalized cells was improved significantly. Then, cellular differentiation assays showed that the immortalized cADSCs could differentiate into three-germ-layer cells, osteogenesis, chondrogenesis, adipogenesis phenotypes, and primordial germ cell like cells (PGCLCs). In addition, the immortalized cADSCs can proliferate in the busulfan-induced seminiferous tubules of infertile mice. These findings confirmed that the immortalized cADSCs maintain the criteria of cADSCs. PMID- 29231998 TI - Phosphorylated Tyr142 beta-catenin localizes to centrosomes and is regulated by Syk. AB - beta-catenin is a central component of adherent junctions and a key effector of canonical Wnt signaling, in which dephosphorylated Ser/Thr beta-catenin regulates gene transcription. beta-catenin phosphorylation at Tyr142 (PTyr142 beta catenin), which is induced by receptor and Src family Tyr kinases, represents a previously described beta-catenin switch from adhesive to migratory roles. In addition to classical beta-catenin roles, phosphorylated Ser/Thr beta-catenin and total beta-catenin were involved in centrosomal functions, including mitotic spindle formation and centrosome separation. Here we find that PTyr142 beta catenin is present in centrosomes in non-transformed and glioblastoma cells and that, in contrast to the Ser/Thr phosphorylated beta-catenin, PTyr142 beta catenin centrosomal levels drop in mitosis. Furthermore, we show that the inhibitor of Spleen Tyrosine Kinase (Syk) piceatannol decreases centrosomal PTyr142 beta-catenin levels, indicating that Syk regulates centrosome PTyr142 beta-catenin. Our findings suggest that PTyr142 beta-catenin and Syk may regulate centrosomal cohesion. This study highlights the contribution of different phosphorylated beta-catenin forms to the cell and centrosome cycles. PMID- 29231999 TI - GANT-61 and GDC-0449 induce apoptosis of prostate cancer stem cells through a GLI dependent mechanism. AB - Aberrant reactivation of the Sonic Hedgehog (SHH) signaling pathway promotes prostate cancer (PC) growth and progression by regulating cancer-related genes through its downstream effectors GLI1 and GLI2. Therefore, targeting the SHH-GLI pathway provides an alternative approach to avoid cancer progression. The aim of this study was to delineate the underlying molecular mechanisms by which GDC-0449 (a SMO receptor inhibitor) and GANT-61 (a GLI transcription factor inhibitor) regulate cellular proliferation and self-renewal in human PC stem cells (ProCSCs). Inhibition of the SHH signaling pathway by GANT-61 induced apoptosis with more efficacy than by GDC-0449 in ProCSCs and PC cell lines. GLI1 and GLI2 expression, promoter-binding activity and GLI-responsive luciferase reporter activity were all decreased with either GDC-0449 or GANT-61 treatment. Expression of Fas, DR4, DR5, and cleavage of caspase-3 and PARP were increased, whereas levels of PDGFR-alpha and Bcl-2 were reduced. Double knockout of GLI1 and GLI2 using shRNA abolished the effects observed with either GDC-0449 or GANT-61 treatment. Collectively, our results showed that GANT-61 and GDC-0449 induced ProCSC apoptosis by directly or indirectly inhibiting the activities of the GLI family transcription factors, may enhance the efficacy of PC treatment. PMID- 29232000 TI - Efficient resolution of venlafaxine and mechanism study via X-ray crystallography. AB - Numbers of resolving factors were investigated to improve resolution of venlafaxine 1. An effective resolving agent, O,O'-di-p-toluoyl-(R, R)-tartaric acid 2, was screened using similar method of 'Dutch resolution' from tartaric acid derivatives. The resolution efficiency was up to 88.4%, when the ratio of rac-1 and 2 was 1:0.8 in THF with little water (10:1 v/v). Enantiomerically pure venlafaxine was prepared with 99.1% ee in 82.2% yield. The chiral resolution mechanism was first explained through X-ray crystallographic study. One diastereomeric salt with well solubility forms a columnar supramolecular structure as the acidic salt (R)-1.2, while the other diastereomeric salt with less solubility forms a multilayered sandwich supramolecular structure by enantio differentiation self-assembly as the neutral salt 2(S)-1.2. The water molecules play a key role in the optical resolution, as indicated by the special structures of the diastereomeric salts. PMID- 29232001 TI - Novel sequence variants in the MKKS gene cause Bardet-Biedl syndrome with intra- and inter-familial variable phenotypes. PMID- 29232002 TI - Effects of microrna-93 on mouse cardiac microvascular endothelial cells injury and inflammatory response by mediating SPP1 through the NF-KappaB pathway. AB - BACKGROUND: This study aims to investigate the regulative role of microRNA-93 (miR-93) in mouse cardiac microvascular endothelial cells (CMECs) injury and inflammatory response by negatively targeting SPP1 gene via the NF-kappaB signaling pathway. METHODS: Healthy Balb/c mice were recruited to establish a mouse model with myocarditis using the CVB3 virus. Mice were grouped into normal, blank, negative control (NC), miR-93 inhibitor, miR-93 mimic, SPP1 short hairpin RNA (shRNA), and miR-93 mimic+SPP1 shRNA groups. Reverse transcription quantitative polymerase chain reaction and Western blot analysis were applied to determine the expressions of miR-93, SPP1, VEGFA, p50, p65, Bax, and Bcl-2. MTT assay was conducted to evaluate cell viability, annexin V-fluorescein isothiocyanate/propidium iodide double staining was conducted to examine cell apoptosis, enzyme-linked immunosorbent assay was conducted to measure secretion of inflammatory factors, and chemical colorimetry was conducted to determine NO secretion. RESULTS: SPP1 was a target gene of miR-93. Compared with the normal group, other six groups showed increased expressions of SPP1, p50, p65, VEGFA, and Bax, as well as cell apoptosis rate and secretion of cell inflammatory factors, and decreased expression of Bcl-2, cell viability, and NO secretion. Compared with the blank group, the miR-93 inhibitor group showed elevated expressions of SPP1, p50, p65, VEGFA, and Bax, as well as cell apoptosis rate and secretion of cell inflammatory factors, and reduced Bcl-2, cell viability, and NO secretion. While the miR-93 mimic and SPP1 shRNA groups displayed opposite results. CONCLUSION: Taking our results together, we conclude that upregulation of miR-93 reduces CMECs injury and inflammatory response by negatively targeting SPP1 via inactivating the NF-kappaB signaling pathway. PMID- 29232003 TI - Molecular dynamics insights into the structure, function, and substrate binding mechanism of mucin desulfating sulfatase of gut microbe Bacteroides fragilis. AB - The complex and dynamic consortia of microbiota that harbors the human gastrointestinal tract contributes ominously to the maintenance of health, the onset and progression of diverse spectrum of disorders. The capability of these enteric microbes to bloom within the gut mucosal milieu is often associated to the glycan metabolism of mucin-degrading bacteria. Accruing evidences suggests that the desulfation of mucin is a rate-limiting step in mucin degradation mechanism by colonic bacterial mucin-desulfating sulfatase enzymes (MDS) enzymes. Till date no experimental evidence is available on how conformational flexibility influences structure and substrate specificity by MDS of gut microbe Bacteroides fragilis. Henceforth, to gain deep insights into the missing but very imperative mechanism, we performed a comprehensive molecular dynamics study, principal component analysis and MM/PBSA binding free energies to gain insights into (i) the domain architecture and mode of substrate binding (ii) conformational dynamics and flexibility that influence the orientation of substrate, (iii) energetic contribution that plays very decisive role to the overall negative binding free energy and stabilities of the complexes (iv) critical residues of active site which influence binding and aid in substrate recognition. This is the first ever report, depicting the molecular basis of recognition of substrates and provides insights into the mode of catalysis by mucin desulfating sulfatase enzymes in gut microbiota. Overall, our study shed new insights into the unmapped molecular mechanisms underlying the recognition of various substrates by mucin desulfating sulfatase, which could be of great relevance in therapeutic implications in human gut microbiota associated disorders. PMID- 29232004 TI - Three types of preS1 start codon deletion variants in the natural course of chronic hepatitis B infection. AB - BACKGROUND AND AIM: Naturally occurring hepatitis B virus variants carrying a deletion in the preS1 start codon region may evolve during long-lasting virus host interactions in chronic hepatitis B (CHB). The aim of this study was to determine the immune phase-specific prevalent patterns of preS1 start codon deletion variants and related factors during the natural course of CHB. METHODS: A total of 399 CHB patients were enrolled. Genotypic analysis of three different preS1 start codon deletion variants (classified by deletion size: 15-base pair [bp], 18-bp, and 21-bp deletion variants) was performed. RESULTS: PreS1 start codon deletion variants were detected in 155 of 399 patients (38.8%). The predominant variant was a 15-bp deletion in the immune-tolerance phase (18/50, 36%) and an 18-bp deletion in the immune-clearance phase (69/183, 37.7%). A 21-bp deletion was the predominant variant in the low replicative phase (3/25, 12.0%) and reactivated hepatitis Be antigen (HBeAg)-negative phase (22/141, 15.6%). The 15-bp and 18-bp deletion variants were more frequently found in HBeAg-positive patients (P < 0.010 and P < 0.001, respectively), whereas the 21-bp deletion variant was more frequently found in HBeAg-negative patients (P < 0.001). On multiple logistic regression analyses, the 21-bp deletion variant was independently associated with liver cirrhosis (P = 0.006), and the 15-bp deletion variant was significantly related to an incomplete response to antiviral agents (P = 0.012). CONCLUSIONS: The predominant type of preS1 start codon deletion variants changes according to the immune phases of CHB infection, and each variant type is associated with different clinical parameters. PreS1 start codon deletion variants might interact with the host immune response differently according to their variant types. PMID- 29232005 TI - X-linked VACTERL-H caused by deletion of exon 3 in FANCB: A case report. PMID- 29232006 TI - Reconstruction of a large full-thickness abdominal wall defect with flow-through based alt flaps: A case report. AB - An extensive 35 * 20 cm sized full-thickness abdominal wall defect was created after resection of aggressive abdominal fibromatosis in a 19-year-old male patient. Immediate reconstruction was not possible due to prolonged operation time and resulting severe bowel edema. A silicone sheet with NPWT was applied over the exposed viscera. After 1 week, silicone sheet was substituted with a composite mesh. Then, abdominal wall reconstruction with bilateral free anterolateral thigh (ALT) flaps (30 * 12 cm and 25 * 12 cm sized) was performed. Since there was only a single reliable recipient vessel available, we linked 2 ALT free flaps sequentially in a flow-through fashion to the left inferior epigastric artery and vein. Two donor sites were closed primarily. The flap fully survived and the defect was covered successfully without any complication for 11 months of follow up. Multiple flaps may be needed for large full-thickness abdominal wall defect coverage. Linked fasciocutaneous free flaps could be a solution with a less donor site morbidity even in the case of limited available recipient vessels. The purpose of this study is to introduce our experience of extensive full-thickness abdominal wall reconstruction using only ipsilateral deep inferior epigastric vessels. PMID- 29232007 TI - Increased oxidative protection by high active vitamin E content and partial radiation crosslinking of UHMWPE. AB - Vitamin E stabilization successfully improved long-term oxidation resistance of wear-resistant ultra-high-molecular-weight polyethylene (UHMWPE) used for joint implants. Stabilization can be achieved by blending an antioxidant into the UHMWPE resin powder before consolidation and irradiation. Balancing the wear resistance and vitamin E content in the blend is the current challenge with this approach, because vitamin E hinders crosslinking of UHMWPE during irradiation, which decreases wear resistance. The vitamin E concentration in the blend is generally limited to less than 0.3 wt%. Wear- and oxidation-resistant UHMWPE has been obtained previously by consolidating blends of pre-irradiated UHMWPE powders (XPE) into an unmodified polyethylene matrix (PE), where the improvement in wear rate depended on the radiation dose and fraction of XPE. We hypothesized that increasing the vitamin E content in the unirradiated matrix would not compromise wear and would further improve the oxidative stability of XPE/PE blends. Pin-on disk wear testing showed that the XPE/PE blends containing 0.1-1.0 wt% vitamin E in the matrix had comparable wear rates. We used an aggressive accelerated aging test in the presence of the pro-oxidant squalene and oxidation induction time (OIT) test and found that higher amounts of vitamin E resulted in stronger oxidation resistance for XPE/PE blends. The mechanical strength and toughness of the blends were not affected by changing the vitamin E content in the matrix. Stabilizing UHMWPE with higher vitamin E content may extend the service life of UHMWPE implants. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1860-1867, 2018. PMID- 29232008 TI - International volunteer surgical project for cleft lip/cleft palate in Laos. PMID- 29232009 TI - Effect of the Wnt/beta-catenin signaling pathway on apoptosis, migration, and invasion of transplanted hepatocellular carcinoma cells after transcatheter arterial chemoembolization in rats. AB - This study aims to investigate the influence of the Wnt/beta-catenin signaling pathway on apoptosis, migration, and invasion of transplanted hepatocellular carcinoma (HCC) cells after transcatheter arterial chemoembolization (TACE) in rat models. A total of 80 rats were grouped into sham, TACE, Wnt-C59, and TACE + Wnt-C59 groups (n = 20). Ten days after model establishment, 10 rats in each group were executed to perform pathological examination and follow-up experiment, and the remaining 10 rats in each group were reared to observe the survival condition. RT-qPCR and Western blotting were applied to determine the expressions of Wnt1, beta-catenin, cyclin D1, c-met, vimentin, E-cadherin, and vascular endothelial growth factor (VEGF). ELISA was performed to measure the serum alpha fetoprotein (AFP) content of rats. Flow cytometry was used to evaluate cell apoptosis rate and transwell assay to examine cell migration and invasion. Compared with the TACE group, the Wnt-C59 and TACE + Wnt-C59 groups showed increased apoptosis and survival time (the TACE + Wnt-C59 group > the Wnt-C59 group). Compared with the sham group, the TACE + Wnt-C59 groups showed decreased cancer tissue weight and expressions of Wnt1, beta-catenin, cyclin D1, vimentin, c-met, and VEGF, but increased E-cadherin expression. Compared with the TACE group, the Wnt-C59 and TACE + Wnt-C59 groups showed decreased AFP level, migration, and invasion (the TACE + Wnt-C59 group < the Wnt-C59 group). These findings indicate inhibition of the Wnt/beta-catenin signaling pathway improves therapeutic effect on TACE via suppressing migration, invasion, and promoting apoptosis of transplanted HCC cells in rats. PMID- 29232010 TI - Protective effect of HSP27 in atherosclerosis and coronary heart disease by inhibiting reactive oxygen species. AB - OBJECTIVE: To clarify the mechanism of heat shock protein 27 (HSP27) as a diagnostic biomarker in coronary heart disease (CHD) and atherosclerosis (AS). METHOD: Expressions of HSP27 in patients with CHD and healthy controls were determined by enzyme-linked immunosorbent assay and the expressions of HSP27 in aortas of patients with CHD and healthy controls were measured by immunohistochemistry. Receiver operating characteristic curve was applied to assess the diagnostic performance of HSP27 in CHD. ApoE-/- mice were included and accordingly grouped. The expressions of HSP27 in AS plaque were measured by quantitative real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. AS plaque was observed using hematoxylin and eosin staining. DHE was used to detect reactive oxygen species (ROS) levels in aortas. The expressions of mitochondrial apoptosis-related proteins were measured by Western blot analysis. Cell apoptosis was determined by TUNEL staining. RESULTS: HSP27 was highly expressed in patients with CHD than in healthy controls ( P < 0.01). In comparison to the normal group, the model group had increased the relative positive area of HSP27 and higher expressions of HSP27, Bax, caspase-3, and apoptosis index (AI) but decreased Bcl-2 expression in AS plaque, as well as larger plaque areas and elevated ROS levels in the aorta (all P < 0.05). The HSP27-small interfering RNA group had increased expressions of Bax, caspase-3, and AI but decreased Bcl-2 and HSP27 expressions in AS plaque, as well as larger plaque areas, the relative positive area of HSP27 and higher ROS levels in aorta when compared with those in the model group (all P < 0.05). CONCLUSION: HSP27 exerts its protective role by suppressing ROS and AS progression by inhibiting mitochondria apoptosis pathway in CHD. PMID- 29232011 TI - Autograft immune effector cells and survival in autologous peripheral blood hematopoietic stem cell transplantation. AB - In addition to stem cells, T-cells, natural killer cells, dendritic cells, and monocytes are also collected and infused from the autograft in patients undergoing autologous peripheral blood hematopoietic stem cell transplantation. Recent reports have shown that these autograft immune effector cells can affect the clinical outcome postautologous peripheral blood hematopoietic stem cell transplantation. In this article, I will review the clinical impact on the survival of these autograft immune effector cells conferring the concept of autologous graft versus tumor effect. PMID- 29232012 TI - The genetics underlying natural variation of plant-plant interactions, a beloved but forgotten member of the family of biotic interactions. AB - Despite the importance of plant-plant interactions on crop yield and plant community dynamics, our understanding of the genetic and molecular bases underlying natural variation of plant-plant interactions is largely limited in comparison with other types of biotic interactions. By listing 63 quantitative trait loci (QTL) mapping and global gene expression studies based on plants directly challenged by other plants, we explored whether the genetic architecture and the function of the candidate genes underlying natural plant-plant interactions depend on the type of interactions between two plants (competition versus commensalism versus reciprocal helping versus asymmetry). The 16 transcriptomic studies are unevenly distributed between competitive interactions (n = 12) and asymmetric interactions (n = 4, all focusing on response to parasitic plants). By contrast, 17 and 30 QTL studies were identified for competitive interactions and asymmetric interactions (either weed suppressive ability or response to parasitic plants), respectively. Surprisingly, no studies have been carried out on the identification of genetic and molecular bases underlying natural variation in positive interactions. The candidate genes underlying natural plant-plant interactions can be classified into seven categories of plant function that have been identified in artificial environments simulating plant-plant interactions either frequently (photosynthesis, hormones), only recently (cell wall modification and degradation, defense pathways against pathogens) or rarely (ABC transporters, histone modification and meristem identity/life history traits). Finally, we introduce several avenues that need to be explored in the future to obtain a thorough understanding of the genetic and molecular bases underlying plant-plant interactions within the context of realistic community complexity. PMID- 29232013 TI - What are the medical indications for providing extremely premature infants with intensive care? PMID- 29232014 TI - Mutations of the glycine cleavage system genes possibly affect the negative symptoms of schizophrenia through metabolomic profile changes. AB - AIM: Hypofunction of N-methyl-D-aspartate receptors (NMDAR) may contribute to the pathophysiology of schizophrenia (SCZ). Recently, the glycine cleavage system (GCS) was shown to affect NMDAR function in the brain. GCS functional defects cause nonketotic hyperglycinemia, the atypical phenotype of which presents psychiatric symptoms similar to SCZ. Here, we examined the involvement of GCS in SCZ. METHODS: First, to identify the rare variants and the exonic deletions, we resequenced all the coding exons and the splice sites of four GCS genes (GLDC, AMT, GCSH, and DLD) in 474 patients with SCZ and 475 controls and performed multiplex ligation-dependent probe amplification analysis in SCZ. Next, we performed metabolome analysis using plasma of patients harboring GCS variants (n = 5) and controls (n = 5) by capillary electrophoresis time-of-flight mass spectrometry. The correlation between plasma metabolites and Positive and Negative Syndrome Scale score was further examined. RESULTS: Possibly damaging variants were observed in SCZ: A203V, S801N in GLDC, near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D in GLDC, a potential neural tube defect causative mutation; and R253X in AMT. Marked elevation of plasma 5-oxoproline (pyroglutamic acid), aspartate, and glutamate, which might affect NMDAR function, was observed in patients harboring GCS variants. The aspartate level inversely correlated with negative symptoms (r = -0.942, P = 0.0166). CONCLUSION: These results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate. PMID- 29232015 TI - Constant vigilance: plant functions guarded by resistance proteins. AB - Unlike animals, plants do not have an adaptive immune system and have instead evolved sophisticated and multi-layered innate immune mechanisms. To overcome plant immunity, pathogens secrete a diverse array of effectors into the apoplast and virtually all cellular compartments to dampen immune signaling and interfere with plant functions. Here we describe the scope of the arms race throughout the cell and summarize various strategies used by both plants and pathogens. Through studying the ongoing evolutionary battle between plants and key pathogens, we may yet uncover potential ways to achieve the ultimate goal of engineering broad spectrum resistant crops without affecting food quality or productivity. PMID- 29232016 TI - Characterization of H3.3 and HIRA expression and function in bovine early embryos. AB - Histone variant H3.3 is encoded by two distinct genes, H3F3A and H3F3B, that are closely associated with actively transcribed genes. H3.3 replacement is continuous and essential for maintaining correct chromatin structure during mouse oogenesis. Upon fertilization, H3.3 is incorporated to parental chromatin, and is required for blastocyst formation in mice. The H3.3 exchange process is facilitated by the chaperone HIRA, particularly during zygote development. We previously demonstrated that H3.3 is required for bovine early embryonic development; here, we explored the mechanisms of its functional requirement. H3F3A mRNA abundance is stable whereas H3F3B and HIRA mRNA are relatively dynamic during early embryonic development. H3F3B mRNA quantity is also considerably higher than H3F3A. Immunofluorescence analysis revealed an even distribution of H3.3 between paternal and maternal pronuclei in zygotes, and subsequent stage specific localization of H3.3 in early bovine embryos. Knockdown of H3.3 by targeting both H3F3A and H3F3B dramatically decreased the expression of NANOG (a pluripotency marker) and CTGF (Connective tissue growth factor; a trophectoderm marker) in bovine blastocysts. Additionally, we noted that Histone H3 lysine 36 dimethylation and linker Histone H1 abundance is reduced in H3.3-deficient embryos, which was similar to effects following knockdown of CHD1 (Chromodomain helicase DNA-binding protein 1). By contrast, no difference was observed in the abundance of Histone H3 lysine 4 trimethylation, Histone H3 lysine 9 dimethylation, or Splicing factor 3 B1. Collectively, these results established that H3.3 is required for correct epigenetic modifications and H1 deposition, dysregulation of which likely mediate the poor development in H3.3-deficient embryos. PMID- 29232018 TI - Controllable Syntheses of MOF-Derived Materials. AB - Metal-organic frameworks (MOFs), as an important kind of porous inorganic-organic hybrid materials with inherent outstanding physicochemistry characteristics, can be widely applied as versatile precursors for the facile preparation of functional MOF-derived materials. However, there are plenty of sophisticated factors during the synthetic process, which is far from reaching the goal of effectively controlling the nature of MOF-derived materials (such as the composition, morphology and surface area). Therefore, it is urgently necessary to develop regular protocols and concepts for controllable syntheses of MOF-derived materials. In this minireview, we mainly summarize and analyze complicated factors in the fabrication of MOF-derived materials according to recently reported literatures, and this provides a new insight into the rational design and syntheses of MOF-derived materials. PMID- 29232017 TI - Formation of pH-Resistant Monodispersed Polymer-Lipid Nanodiscs. AB - Polymer lipid nanodiscs are an invaluable system for structural and functional studies of membrane proteins in their near-native environment. Despite the recent advances in the development and usage of polymer lipid nanodisc systems, lack of control over size and poor tolerance to pH and divalent metal ions are major limitations for further applications. A facile modification of a low-molecular weight styrene maleic acid copolymer is demonstrated to form monodispersed lipid bilayer nanodiscs that show ultra-stability towards divalent metal ion concentration over a pH range of 2.5 to 10. The macro-nanodiscs (>20 nm diameter) show magnetic alignment properties that can be exploited for high-resolution structural studies of membrane proteins and amyloid proteins using solid-state NMR techniques. The new polymer, SMA-QA, nanodisc is a robust membrane mimetic tool that offers significant advantages over currently reported nanodisc systems. PMID- 29232019 TI - Thalamic Deep Brain Stimulation for Essential Tremor Also Reduces Voice Tremor. AB - OBJECTIVE: Voice tremor is a common feature of essential tremor (ET) that is difficult to treat medically and significantly affects quality of life. Deep brain stimulation (DBS) of the ventral intermediate nucleus (Vim) of the thalamus is effective in improving contralateral distal limb tremor and has been shown in limited studies to affect voice tremor. Our objective was to retrospectively evaluate whether Vim-DBS used to treat patients with essential motor tremor also effectively treated underlying concurrent voice tremor and assess whether particular lead locations were favorable for treating vocal tremor. MATERIALS AND METHODS: In this retrospective cohort study, patients had unilateral or bilateral lead placement and were monitored for up to 12 months. We used the Fahn-Tolosa Marin (FTM) subscore to assess vocal tremor. Changes in vocal tremor before and after stimulation and over several sessions were assessed. RESULTS: Of the 77 patients who met the inclusion criteria and were treated for essential tremor, 20 (26%) patients had vocal tremor prior to stimulation. Active Vim-DBS decreased the amplitude of voice tremor by 80% (p < 0.001). The mean FTM score as 1.24 pre operation, 1.08 post-implantation (consistent with a lesion effect), and 0.25 with stimulation. The effect magnitude was maintained at last follow-up with slight improvement over time (p < 0.05). Unilateral and bilateral stimulation resulted in similar degrees of tremor reduction. A model of the centroid of stimulation showed that Vim thalamic stimulation that is more anterior on average yielded better voice tremor control, significantly so on the left side (p < 0.05). Additionally, there was improvement in head, tongue, and face tremor scores (p < 0.05). CONCLUSIONS: Unilateral and bilateral Vim-DBS targeted to treat the motor component of essential tremor also dramatically decreased the amplitude of voice tremor in this group of patients, suggesting a potential benefit of this treatment for affected patients. PMID- 29232020 TI - Mechanochemical Preparation of Stable Sub-100 nm gamma Cyclodextrin:Buckminsterfullerene (C60) Nanoparticles by Electrostatic or Steric Stabilization. AB - Buckminster fullerene (C60 )'s main hurdle to enter the field of biomedicine is its low bioavailability, which results from its extremely low water solubility. A well-known approach to increase the water solubility of C60 is by complexation with gamma-cyclodextrins. However, the formed complexes are not stable in time as they rapidly aggregate and eventually precipitate due to attractive intermolecular forces, a common problem in inclusion complexes of cyclodextrins. In this study we attempt to overcome the attractive intermolecular forces between the complexes by designing custom gamma-cyclodextrin (gammaCD)-based supramolecular hosts for C60 that inhibit the aggregation found in native gammaCD C60 complexes. The approach entails the introduction of either repulsive electrostatic forces or increased steric hindrance to prevent aggregation, thus enhancing the biomedical application potential of C60 . These modifications have led to new sub-100 nm nanostructures that show long-term stability in solution. PMID- 29232021 TI - Investigation of diffusion kurtosis imaging for discriminating tumors from inflammatory lesions after treatment for bladder cancer. AB - BACKGROUND: The bladder wall may thicken resulting from chronic inflammation after initial treatment (transurethral resection [TUR] or neoadjuvant chemotherapy), which may mimic the feature of recurrent or residual bladder tumors (RBT). Therefore, it is critical to discriminate RBT from benign lesions after initial treatment. PURPOSE: To investigate whether diffusion kurtosis imaging (DKI) could discriminate RBT from post-therapy bladder inflammatory lesions. STUDY TYPE: Retrospective. SUBJECTS: Fifty patients diagnosed with bladder cancer underwent TUR or received neoadjuvant chemotherapy. FIELD STRENGTH/SEQUENCE: 3.0T MRI/conventional T1 -weighted imaging (T1 WI), T2 WI, and diffusion-weighted imaging (DWI) with nine b-values ranging from 0-2000 s/mm2 . ASSESSMENT: Mean diffusion coefficients (MDa , MDb , and MDc ) and mean kurtosis values (MKa , MKb , and MKc ) were obtained from three different measurement methods. The region of interest (ROI) was placed 1) to encompass the entire portion of the thickening bladder wall or to portions that were the most restricted, with a b-value of 2) 2000 s/mm2 or 3) 1000 s/mm2 . STATISTICAL TESTS: The independent-samples t-test was used to compare the differences between RBT and the inflammatory group. Differences in DKI parameters were analyzed by comparing the areas under the receiver-operator characteristic curves (AUCs). RESULTS: In patients with RBT, the MD (MDa , MDb , MDc ) values were significantly lower and the MK (MKa , MKb , MKc ) values were significantly higher than those in patients in the inflammatory lesions group (all P < 0.01). The AUC of MKb (0.934) was significantly larger than those of MDb , MKa , and MKc (0.793, P < 0.05; 0.694, P < 0.01; 0.719, P < 0.01, respectively). DATA CONCLUSION: MK obtained from DKI provided better performance than conventional DWI in distinguishing RBT from inflammatory lesions after bladder cancer treatment. MK calculated with high b-values setting provided better performance in differentiation. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage 3 J. Magn. Reson. Imaging 2017. PMID- 29232022 TI - The Catalytic Asymmetric Mukaiyama-Michael Reaction of Silyl Ketene Acetals with alpha,beta-Unsaturated Methyl Esters. AB - alpha,beta-Unsaturated esters are readily available but challenging substrates to activate in asymmetric catalysis. We now describe an efficient, general, and highly enantioselective Mukaiyama-Michael reaction of silyl ketene acetals with alpha,beta-unsaturated methyl esters that is catalyzed by a silylium imidodiphosphorimidate (IDPi) Lewis acid. PMID- 29232023 TI - The Chemical Record Lectureship: M. Gratzel / Baizer Award: F. Maran / Werner Prize and Hans G. A. Hellmann Prize: S. Luber / Max Bergmann Medal: J. Buchner. PMID- 29232025 TI - Hospital volume and outcomes of robot-assisted partial nephrectomy. AB - OBJECTIVE: To evaluate the impact of hospital volume on outcomes of robot assisted partial nephrectomy (RAPN). MATERIALS AND METHODS: Patients with renal cell carcinoma who underwent RAPN between 2010 and 2013 were identified in the National Cancer Database. Hospital yearly RAPN volume was categorized into groups by sorting patients as closely as possible into five groups of equal size (quintiles): very low; low; medium; high; and very high volume. Outcomes included 30-day mortality, 90-day mortality, open conversion, prolonged length of hospital stay (PLOS; defined as >3 days), 30-day readmission rate, and positive surgical margin (PSM) rate. Unadjusted analyses and multivariable logistic regressions were used to compare outcomes. Sensitivity analyses with hospital volume considered as a continuous variable were also performed. RESULTS: A total of 18 724 RAPN cases were included. Hospital volume quintiles were: very low volume, 1 7 cases (n = 3 693); low volume, 8-14 cases (n = 3 719); medium volume, 15-23 cases (n = 3 833); high volume, 24-43 cases (n = 3 649); and very high volume, >=44 cases (n = 3 830). There was no significant difference in 30-day or 90-day mortality among the five groups. Multivariable logistic regression analysis (reference: very low volume) showed that higher hospital volume was associated with lower odds of conversion (low [odds ratio {OR}: 0.88; P = 0.377]; medium [OR: 0.60; P = 0.001]; high [OR: 0.57; P < 0.001]; very high [OR: 0.47; P < 0.001]), lower odds of PLOS (low [OR: 0.93; P = 0.197], medium [OR: 0.75; P < 0.001]; high [OR: 0.62; P < 0.001]; very high [OR: 0.45; P < 0.001]), and lower odds of PSMs (low [OR: 0.76; P < 0.001]; medium [OR: 0.76, P < 0.001]; high [OR: 0.59; P < 0.001]; very high [OR: 0.34; P < 0.001]). Sensitivity analyses confirmed increasing hospital volume (per 1-case increase) was associated with lower odds of conversion (OR: 0.986; P < 0.001), PLOS (OR: 0.989; P < 0.001) and PSMs (OR: 0.984; P < 0.001). A difference in 30-day readmission rate was found in unadjusted analysis but not in adjusted analyses. CONCLUSION: Undergoing RAPN at higher-volume hospitals may have better peri-operative outcomes (conversion to open and LOS) and lower PSM rates. Future studies are needed to explore the detailed components that lead to the superior outcomes in higher-volume hospitals. PMID- 29232024 TI - Myocardial Perfusion Reserve Index in Children With Kawasaki Disease. AB - BACKGROUND: Coronary artery lesions in patients with Kawasaki disease (KD) can impair myocardial perfusion, yet evaluation of perfusion defects by cardiac magnetic resonance (MR) in children is often qualitative. PURPOSE: In this study we aimed to use a quantitative method of myocardial perfusion using stress cardiac MR-derived myocardial perfusion reserve index (MPRI) in children with KD and compare MPRI with ventricular mechanical performance evaluated by cardiac MR strain analysis. STUDY TYPE: This study was a retrospective review. SUBJECTS: Twenty-one children with a diagnosis of KD who underwent stress perfusion cardiac MR were compared with nine controls. FIELD STRENGTH/SEQUENCE: First-pass perfusion imaging using a T1 -weighted gradient echo sequence was performed at rest and stress after administration of adenosine with 1.5T or 3T magnets. ASSESSMENT: The MPRI was calculated as the ratio of maximum slope of myocardial enhancement during stress compared to rest and was evaluated with the American Heart Association 17 segment model. STATISTICAL TESTS: Demographic and clinical characteristics among KD patients and controls were compared using Student's t test for normally distributed continuous variables, Wilcoxon-rank sum test for nonnormally distributed variables, and chi2 for categorical variables. RESULTS: There was a significant decrease in MPRI in Segment 7 (1.53 vs. 2.23, P = 0.0058) in KD patients compared with controls. The reduction in MPRI in Segment 12 approached statistical significance (1.58 vs. 2.31, P = 0.0636). Three patients who underwent serial studies had decreased MPRI longitudinally. No differences were seen in circumferential or radial strain. DATA CONCLUSION: MPRI shows impaired myocardial perfusion in patients with KD. MPRI can change over time, suggestive of progressive coronary artery changes, which may precede fibrosis and mechanical decline. MPRI can assess segmental and global perfusion defects in patients with KD and should be a part of routine cardiac MR evaluation in KD. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage 3 J. Magn. Reson. Imaging 2017. PMID- 29232026 TI - Noncontrast-enhanced time-resolved 4D dynamic intracranial MR angiography at 7T: A feasibility study. AB - BACKGROUND: Arterial spin labeling (ASL) based-noncontrast-enhanced 4D MR angiography (NCE 4D MRA) shows potential in characterizing cerebrovascular hemodynamics in cerebrovascular disorders. Ultrahigh-field theoretically benefits ASL signal with increased inherent signal-to-noise ratio (SNR) and prolonged blood T1 , which may provide improved delineation of vasculature in 4D MRA. PURPOSE: To investigate the feasibility of NCE 4D MRA using 3D Cartesian trajectory and stack-of-stars (SOS) golden angle radial trajectory at 7T. STUDY TYPE: A prospective study. SUBJECTS: Six normal volunteers and eight patients with arteriovenous malformation (AVM). FIELD STRENGTH/SEQUENCE: NCE 4D MRA with Cartesian and radial trajectories were performed at 3T and 7T. ASSESSMENT: Subjective image quality of 4D MRA was evaluated using a 4-point scale by two experienced neuroradiologists. The characterization of AVM components with 4D MRA and DSA was also graded using the Spetzler-Martin grading scale. STATISTICAL TESTS: Cohen's kappa coefficient was calculated to evaluate the agreement between two readers within each 4D MRA technique (Cartesian and Radial). A Wilcoxon signed-rank test was performed to compare the subjective image quality scores of 4D MRA between Cartesian and radial trajectories, and between 7T and 3T, respectively. RESULTS: Good-to-excellent image quality was achieved in 4D MRA with both Cartesian (3.83 +/- 0.41) and radial (3.42 +/- 0.49) acquisitions in healthy volunteers at 7T. However, markedly reduced scan time was needed with radial acquisition. 4D MRA at 7T (3.31 +/- 0.59) shows better delineation of AVM lesion features, especially the vein drainage, compared with that of 3T (2.83 +/- 0.75), although no statistical significance was achieved (P = 0.180). DATA CONCLUSION: The feasibility of ASL based 4D MRA at 7T with Cartesian and SOS golden angle radial acquisition was demonstrated. The clinical evaluation of 4D MRA in AVMs between 3T and 7T suggested 7T 4D MRA images acquired with radial acquisition demonstrate excellent delineation of AVM features, especially the draining veins. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2017. PMID- 29232029 TI - The effects of subconjunctival bupivacaine, lidocaine, and mepivacaine on corneal sensitivity in healthy horses. AB - OBJECTIVE: To compare the efficacy and duration of effect of three local anesthetics on corneal sensitivity when administered subconjunctivally in horses. ANIMALS STUDIED: Eight healthy adult horses. PROCEDURE: A randomized, masked, crossover study design was used, with a two-week washout period between trials. The subconjunctival space of the randomly selected eye was injected with 0.2 mLs of bupivacaine (0.5%), lidocaine (2%), mepivacaine (2%), or saline. All horses received each medication once. The contralateral eye served as a control. The corneal touch threshold (CTT) was measured in both eyes with a Cochet-Bonnet esthesiometer prior to sedation with xylazine, after sedation, and at 10-min intervals after subconjunctival injection until corneal sensitivity returned to baseline. The total time of decreased CTT and the maximum decrease in CTT were compared for each medication using a general linear mixed model (P < 0.05). RESULTS: Total time of decreased CTT was 105.0 min for bupivacaine, 103.8 min for lidocaine, 138.8 min for mepivacaine, and 7.5 min for saline. All local anesthetics decreased CTT longer than saline (P < 0.001) and mepivacaine decreased CTT longer than lidocaine (P = 0.04). The mean minimum CTT was 1.67 cm for bupivacaine, 1.42 cm for lidocaine, and 0.73 cm for mepivacaine, which were all significantly less (P < 0.001) than saline (4.73 cm). No evidence of corneal toxicity was noted with any treatment. CONCLUSION: Subconjunctival injections of lidocaine, bupivacaine, and mepivacaine effectively and safely reduce corneal sensitivity in eyes of healthy horses for 1.5-2 h, and may be useful for providing perioperative analgesia for equine corneal procedures. PMID- 29232030 TI - Reproducibility of relaxometry of human lumbar vertebrae at 3 Tesla using 1 H MR spectroscopy. AB - BACKGROUND: MR spectroscopy is widely used for fat fraction quantification of human lumbar vertebrae. However, the measurements need to be corrected for relaxation effects. PURPOSE: The aim of this study was to determine the reproducibility of relaxometry in human lumbar vertebrae required for the correction of fat fraction measurements using magnetic resonance spectroscopy at 3 Tesla. Such information provides error estimates and guidance regarding reliability for future studies. STUDY TYPE: Prospective. SUBJECTS: Forty-six healthy volunteers (22 female [f], 24 male [m]) participated in this study. FIELD STRENGTH: All subjects underwent three consecutive multi-TE /multi-TR MR spectroscopy measurements at 3 Tesla. ASSESSMENT: A total of 2580 spectra of lumbar vertebrae L2 and L3 of 43 subjects (21f, 22m) were quantified using jMRUI software. Data were exported and mono-exponential fits were applied to the signals of water and fat compartments to derive relaxation times and calculate the fat fraction corrected for relaxation effects. Finally, relaxation times and fat fraction results of repeated measurements were analyzed for reproducibility. STATISTICAL TESTS: Reproducibility was evaluated by calculating the coefficient of variation (CV). Influences of volunteer age and sex were tested by analysis of covariance. RESULTS: The CV for all calculated parameters ranged between 1.22% (T2 of the fat compartment) and 3.02% (T1 of the fat compartment). Relaxation times and fat fraction were statistically different for female and male volunteers (P < 0.01) and relaxation times of the water compartment showed significant (P < 0.01) correlation with the fat fraction. DATA CONCLUSION: Based on repeated acquisitions using the measurement parameters applied in this study, magnetic resonance spectroscopy allowed a reproducible calculation of the fat fraction corrected for relaxation effects. T1 of the water compartment showed high reproducibility and correlation with the fat fraction. It, therefore, might be considered as a parameter linked to the composition of the water compartment and patient health. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage 1 J. Magn. Reson. Imaging 2017. PMID- 29232031 TI - Systematic review and meta-analysis of reported adverse events of long-term intranasal oxytocin treatment for autism spectrum disorder. AB - Recent studies have suggested oxytocin as a possible drug to treat social deficits caused by autism spectrum disorder (ASD), but the safety of intranasal oxytocin in autistic patients has not been established. The aim of this review was to characterize the side-effect profile of long-term intranasal oxytocin in treatment of ASD compared to placebo. All randomized controlled trials of intranasal oxytocin in the treatment of ASD published before 1 January 2017 that reported safety data were identified from databases, including PubMed, Embase, Cochrane Library, and International Pharmaceutical Abstract. Relevant data from the selected studies were then extracted for meta-analysis to estimate the pooled risk ratio for the most common adverse events. Descriptive analysis of severe adverse events was also conducted. Of the 223 participants in the five included studies, 123 were given oxytocin and 100 were given placebos. Nasal discomfort (14.3%), tiredness (7.2%), irritability (9.0%), diarrhea (4.5%), and skin irritation (4.5%) were the most common adverse events. None of these common adverse events was statistically associated with treatment allocation according to meta-analysis using pooled data (all P-values > 0.1). Five severe adverse events were reported, namely aggression (one in placebo, two in oxytocin) and seizures (one in placebo, one in oxytocin). Results from this systematic review support intranasal oxytocin as well tolerated and safe for use in the ASD population. Larger clinical trials should be conducted to establish the efficacy of intranasal oxytocin as a treatment of ASD. PMID- 29232032 TI - Erosive pustular dermatosis of the scalp: reappraisal of an underrecognized entity. AB - Erosive pustular dermatosis of the scalp (EPDS) is an inflammatory dermatosis of unknown etiology. Herein, we present a review of the disease and report our own clinical and histopathological experience in eleven patients. EPDS tends to spontaneously affect bald areas of the scalp in elderly individuals. A history of previous surgery at the same site - as observed in four of our patients - is common. Coronary artery disease, cerebrovascular insult, arterial hypertension, diabetes mellitus, and severe cases of cancer were frequent comorbidities. Most patients show an undulating clinical course despite topical anti-inflammatory treatment; in some individuals, the lesions heal with scarring. Histopathology reveals scaly crusts or erosions and granulation tissue-like changes in the dermis, evolving into a scar in more advanced stages. Apart from actinic/local damage, impaired immunity and microcirculation may be predisposing factors of the disease. Similar to pyoderma gangrenosum, EPDS must be considered in the context of nonhealing wounds in the elderly after the differential diagnoses mimicking EPDS have been ruled out. Given that previous or concomitant adjacent basal cell or squamous cell carcinoma is a common finding and that infiltrative variants extending beyond the clinically visible tumor may occur, histological mapping of the surrounding skin may be advisable in doubtful cases. PMID- 29232033 TI - Amyopathic dermatomyositis with anti-TIF1 gamma antibodies. PMID- 29232034 TI - Antibiotic Algae by Chemical Surface Engineering. AB - Chemical cell-surface engineering is a tool for modifying and altering cellular functions. Herein, we report the introduction of an antibiotic phenotype to the green alga Chlamydomonas reinhardtii by chemically modifying its cell surface. Flow cytometry and confocal microscopy studies demonstrated that a hybrid of the antibiotic vancomycin and a 4-hydroxyproline oligomer binds reversibly to the cell wall without affecting the viability or motility of the cells. The modified cells were used to inhibit bacterial growth of Gram-positive Bacillus subtilis cultures. Delivery of the antibiotic from the microalgae to the bacterial cells was verified by microscopy. Our studies provide compelling evidence that 1) chemical surface engineering constitutes a useful tool for the introduction of new, previously unknown functionality, and 2) living microalgae can serve as new platforms for drug delivery. PMID- 29232035 TI - Therapeutic effects of endoscopic ablation in patients with Hunner type interstitial cystitis. AB - OBJECTIVE: To investigate the efficacy of endoscopic ablation of Hunner lesions (HLs) in patients with interstitial cystitis (IC) and to find predictors of early recurrence of HLs. PATIENTS AND METHODS: A prospective study was performed of patients with Hunner type IC who underwent transurethral ablation. We repeated endoscopic ablation when symptoms and HLs recurred during the follow-up period. The primary endpoint was recurrence-free time. Secondary endpoints were a change in frequency, nocturia, and urgency episodes, and changes in visual analogue scale (VAS) pain scores and other symptom indices at follow-up visits. RESULTS: A total of 72 patients were analysed. The median (range) follow-up period was 29.5 (12.0-50.0) months. After primary ablation treatment, HLs recurred in 75.0% (54/72) of patients, and the median (sd) recurrence-free time was 12.0 (1.6) months. Amongst the 54 patients with recurrence, 50 underwent a second ablation treatment. HLs occurred in 44.0% (22/50) of individuals after the second operation, and the median (sd) recurrence-free time was 18.0 (5.1) months. Lower maximal cystometric capacity (odds ratio 1.01, 95% confidence interval 1.001 1.013) was the predictive factor for early recurrence. There were significant improvements in the VAS pain scores, O'Leary-Sant Interstitial Cystitis Symptom Index and Problem Index, Pelvic Pain and Urgency/Frequency Patient Symptom Scale after treatment (all, P < 0.05). CONCLUSIONS: Endoscopic ablation is an effective treatment option for HLs and significantly reduces pain and improves voiding symptoms. Repeat ablation upon recurrence could help symptom control and bladder preservation only if the bladder capacity is maintained. PMID- 29232036 TI - Diurnal variations in intraocular pressure and central corneal thickness and the correlation between these factors in dogs. AB - OBJECTIVE: To study the diurnal variation in intraocular pressure (IOP) and central corneal thickness (CCT) in healthy Beagles by rebound tonometry and ultrasonic pachymetry, respectively, in addition to determining whether a correlation exists between these two variables. ANIMALS STUDIED: Twenty eyes from 10 healthy Beagle dogs were included in the study. PROCEDURES: The IOP and CCT were measured by rebound tonometry and ultrasonic pachymetry, respectively, at 2 h intervals over an 8-hour period between 10:00 and 18:00. RESULTS: The mean values (+/- SD) of IOP obtained were 11.45 +/- 2.96 at 10:00, 10.00 +/- 1.89 at 12:00, 8.25 +/- 1.62 at 14:00, 7.05 +/- 1.05 at 16:00, and 6.55 +/- 1.36 at 18:00. The mean values (+/- SD) of CCT obtained were 554.95 +/- 72.41 at 10:00, 549.20 +/- 69.10 at 12:00, 566.15 +/- 80.56 at 14:00, 545.45 +/- 70.19 at 16:00, and 538.30 +/- 73.33 at 18:00. The IOP and CCT of dogs were found to decrease progressively from the first to the last measurement. There were statistically significant differences between the IOP (P = 0.000) and CCT values (P = 0.032) measured at different times of the day. There was no effect or interaction between gender and eye with the dependent variables. The IOP and CCT were found to be positively correlated (r = 0.213, P = 0.034). The regression equation demonstrated that for every 100 MUm increase in CCT, there was an elevation in IOP by 0.8 mmHg. CONCLUSIONS: The CCT and IOP values were lower in the afternoon/evening than in the morning, and these were positively correlated. Both findings are important for the diagnostic interpretation of IOP values in dogs. PMID- 29232037 TI - Combining Prostate Health Index density, magnetic resonance imaging and prior negative biopsy status to improve the detection of clinically significant prostate cancer. AB - OBJECTIVES: To determine the performance of Prostate Health Index (PHI) density (PHID) combined with MRI and prior negative biopsy (PNB) status for the diagnosis of clinically significant prostate cancer (PCa). PATIENTS AND METHODS: Patients without a prior diagnosis of PCa, with elevated prostate-specific antigen and a normal digital rectal examination who underwent PHI testing prospectively prior to prostate biopsy were included in this study. PHID was calculated retrospectively using prostate volume derived from transrectal ultrasonography at biopsy. Univariable and multivariable logistic regression modelling, along with receiver-operating characteristic (ROC) curve analysis, was used to determine the ability of serum biomarkers to predict clinically significant PCa (defined as either grade group [GG] >=2 disease or GG1 PCa detected in >2 cores or >50% of any one core) on biopsy. Age, PNB status and Prostate Imaging Reporting and Data System (PI-RADS) score were incorporated into the regression models. RESULTS: Of the 241 men who qualified for the study, 91 (37.8%) had clinically significant PCa on biopsy. The median (interquartile range) PHID was 0.74 (0.44-1.24); it was 1.18 (0.77-1.83) and 0.55 (0.38-0.89) in those with and without clinically significant PCa on biopsy, respectively (P < 0.001). On univariable logistic regression, age and PNB status were associated with clinically significant cancer. Of the tested biomarkers, PHID demonstrated the highest discriminative ability for clinically significant disease (area under the ROC curve [AUC] 0.78 for the univariable model). That continued to be the case in multivariable logistic regression models incorporating age and PNB status (AUC 0.82). At a threshold of 0.44, representing the 25th percentile of PHID in the cohort, PHID was 92.3% sensitive and 35.3% specific for clinically significant PCa; the sensitivity and specificity were 93.0% and 32.4% and 97.4% and 29.1% for GG >=2 and GG >=3 disease, respectively. In the 104 men who underwent MRI, PI-RADS score was complementary to PHID, with a PI-RADS score >=3 or, if PI-RADS score <=2, a PHID >=0.44, detecting 100% of clinically significant disease. For that subgroup, of the biomarkers tested, PHID (AUC 0.90) demonstrated the highest discriminative ability for clinically significant disease on multivariable logistic regression incorporating age, PNB status and PI-RADS score. CONCLUSIONS: In this contemporary cohort of men undergoing prostate biopsy for the diagnosis of PCa, PHID outperformed PHI and other PSA derivatives in the diagnosis of clinically significant cancer. Incorporating age, PNB status and PI-RADS score led to even further gains in the diagnostic performance of PHID. Furthermore, PI-RADS score was found to be complementary to PHID. Using 0.44 as a threshold for PHID, 35.3% of unnecessary biopsies could have been avoided at the cost of missing 7.7% of clinically significant cancers. Despite these encouraging results, prospective validation is needed. PMID- 29232038 TI - Novel techniques and preliminary results of ex vivo liver resection and autotransplantation for end-stage hepatic alveolar echinococcosis: A study of 31 cases. AB - Ex vivo liver resection combined with autotransplantation is a recently introduced approach to cure end-stage hepatic alveolar echinococcosis (HAE), which is considered unresectable by conventional radical resection due to echinococcal dissemination into the crucial intrahepatic conduits and adjacent structures. This article aims discuss the manipulation details and propose reasonable indications for this promising technique. All patients successfully underwent liver autotransplantation with no intraoperative mortality. The median weight of the autografts was 636 g (360-1300 g), the median operation time was 12.5 hours (9.4-19.5 hours), and the median anhepatic phase was 309 minutes (180- 460 minutes). Intraoperative blood loss averaged 1800 mL (1200-6000 mL). Postoperative complications occurred in 13 patients during hospitalization; 5 patients experienced postoperative complications classified as Clavien-Dindo grade III or higher, and 2 patients died of intraabdominal bleeding and acute cerebral hemorrhage, respectively. Twenty-nine patients were followed for a median of 14.0 months (3-42 months), and no HAE recurrence was detected. The technique requires neither an organ donor nor any postoperative immunosuppressant, and the success of the treatment relies on meticulous preoperative assessments and precise surgical manipulation. PMID- 29232039 TI - Hyperkeratosis lenticularis perstans in a patient with primary hyperaldosteronism. PMID- 29232041 TI - Lymphangioma circumscriptum of the vulva in a patient with Noonan syndrome. PMID- 29232040 TI - Geographic disparity in kidney transplantation under KAS. AB - The Kidney Allocation System fundamentally altered kidney allocation, causing a substantial increase in regional and national sharing that we hypothesized might impact geographic disparities. We measured geographic disparity in deceased donor kidney transplant (DDKT) rate under KAS (6/1/2015-12/1/2016), and compared that with pre-KAS (6/1/2013-12/3/2014). We modeled DSA-level DDKT rates with multilevel Poisson regression, adjusting for allocation factors under KAS. Using the model we calculated a novel, improved metric of geographic disparity: the median incidence rate ratio (MIRR) of transplant rate, a measure of DSA-level variation that accounts for patient casemix and is robust to outlier values. Under KAS, MIRR was 1.75 1.811.86 for adults, meaning that similar candidates across different DSAs have a median 1.81-fold difference in DDKT rate. The impact of geography was greater than the impact of factors emphasized by KAS: having an EPTS score <=20% was associated with a 1.40-fold increase (IRR = 1.35 1.401.45 , P < .01) and a three-year dialysis vintage was associated with a 1.57-fold increase (IRR = 1.56 1.571.59 , P < .001) in transplant rate. For pediatric candidates, MIRR was even more pronounced, at 1.66 1.922.27 . There was no change in geographic disparities with KAS (P = .3). Despite extensive changes to kidney allocation under KAS, geography remains a primary determinant of access to DDKT. PMID- 29232042 TI - Evaluation of visual motion perception ability in mice with knockout of the dyslexia candidate susceptibility gene Dcdc2. AB - Developmental dyslexia is a heritable disability characterized by difficulties in learning to read and write. The neurobiological and genetic mechanisms underlying dyslexia remain poorly understood; however, several dyslexia candidate risk genes have been identified. One of these candidate risk genes-doublecortin domain containing 2 (DCDC2)-has been shown to play a role in neuronal migration and cilia function. At a behavioral level, variants of DCDC2 have been associated with impairments in phonological processing, working memory and reading speed. Additionally, a specific mutation in DCDC2 has been strongly linked to deficits in motion perception-a skill subserving reading abilities. To further explore the relationship between DCDC2 and dyslexia, a genetic knockout (KO) of the rodent homolog of DCDC2 (Dcdc2) was created. Initial studies showed that Dcdc2 KOs display deficits in auditory processing and working memory. The current study was designed to evaluate the association between DCDC2 and motion perception, as these skills have not yet been assessed in the Dcdc2 KO mouse model. We developed a novel motion perception task, utilizing touchscreen technology and operant conditioning. Dcdc2 KOs displayed deficits on the Pairwise Discrimination task specifically as motion was added to visual stimuli. Following behavioral assessment, brains were histologically prepared for neuroanatomical analysis of the lateral geniculate nucleus (LGN). The cumulative distribution showed that Dcdc2 KOs exhibited more small neurons and fewer larger neurons in the LGN. Results compliment findings that DCDC2 genetic alteration results in anomalies in visual motion pathways in a subpopulation of dyslexic patients. PMID- 29232043 TI - An Erwinia amylovora yjeK mutant exhibits reduced virulence, increased chemical sensitivity and numerous environmentally dependent proteomic alterations. AB - The Gram-negative bacterium Erwinia amylovora causes fire blight, an economically important disease of apples and pears. Elongation factor P (EF-P) is a highly conserved protein that stimulates the formation of the first peptide bond of certain proteins and facilitates the translation of certain proteins, including those with polyproline motifs. YjeK and YjeA are two enzymes involved in the essential post-translational beta-lysylation of EF-P at a conserved lysine residue, K34. EF-P, YjeA and YjeK have been shown to be essential for the full virulence of Escherichia coli, Salmonella species and Agrobacterium tumefaciens, with efp, yjeA and yjeK mutants having highly similar phenotypes. Here, we identified an E. amylovora yjeK::Tn5 transposon mutant with decreased virulence in apple fruit and trees. The yjeK::Tn5 mutant also showed pleiotropic phenotypes, including reduced growth in rich medium, lower extracellular polysaccharide production, reduced swimming motility and increased chemical sensitivity compared with the wild-type, whilst maintaining wild-type level growth in minimal medium. All yjeK::Tn5 mutant phenotypes were complemented in trans with a plasmid bearing a wild-type copy of yjeK. Comprehensive, quantitative proteomics analyses revealed numerous, environmentally dependent changes in the prevalence of a wide range of proteins, in higher abundance and lower abundance, in yjeK::Tn5 compared with the wild-type, and many of these alterations could be linked to yjeK::Tn5 mutant phenotypes. The environmental dependence of the yjeK::Tn5 mutant proteomic alterations suggests that YjeK could be required for aspects of the environmentally dependent regulation of protein translation. YjeK activity may be critical to overcoming stress, including the challenging host environment faced by invading pathogenic bacteria. PMID- 29232044 TI - Potential medical liability risk as the result of a second opinion in dermatopathology. PMID- 29232045 TI - Occupational koebnerization of psoriasis caused by glyphosate. PMID- 29232046 TI - Male circumcision for the prevention of human immunodeficiency virus (HIV) acquisition: a meta-analysis. AB - We aimed to assess male circumcision for the prevention of human immunodeficiency virus (HIV) acquisition in heterosexual and homosexual men using all available data. A systematic literature review was conducted searching for studies that assessed male circumcision as a method to prevent HIV acquisition in homosexual and/or heterosexual men. PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov were searched in March 2017. A random effects model was used to calculate a pooled risk ratio (RR) and its associated 95% confidence interval (CI). In total, 49 studies were included in this meta analysis. The overall pooled RR for both homosexual and heterosexual men was 0.58 (95% CI 0.48-0.70), suggesting that circumcision was associated with a reduction in HIV risk. Circumcision was found to be protective for both homosexual and heterosexual men (RR: 0.80, 95% CI 0.69-0.92 and 0.28, 95% CI 0.14-0.59, respectively). Heterosexual men had a greater RR reduction (72% compared with 20% for homosexual men). There was significant heterogeneity among the studies (chi2 = 1378.34, df = 48; I2 = 97%). This meta-analysis shows that male circumcision was effective in reducing HIV risk for both heterosexual and homosexual men. PMID- 29232047 TI - Antibiotic prophylaxis in ureteroscopic lithotripsy: a systematic review and meta analysis of comparative studies. AB - OBJECTIVE: To explore the efficacy of antibiotic prophylaxis and the different strategies used to prevent infection in ureteroscopic lithotripsy (URL) by conducting a systematic review and meta-analysis. MATERIALS AND METHODS: A systematic literature search using Pubmed, Embase, Medline, the Cochrane Library, and the Chinese CBM, CNKI and VIP databases was performed to find comparative studies on the efficacy of different antibiotic prophylaxis strategies in URL for preventing postoperative infections. The last search was conducted on 25 June 2017. Summarized unadjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the efficacy of different antibiotic prophylaxis strategies. RESULTS: A total of 11 studies in 4 591 patients were included in this systematic review and meta-analysis. No significant difference was found in the risk of postoperative febrile urinary tract infections (fUTIs) between groups with and without antibiotic prophylaxis (OR: 0.82, 95% CI 0.40-1.67; P = 0.59). Patients receiving a single dose of preoperative antibiotics had a significantly lower risk of pyuria (OR: 0.42, 95% CI 0.25-0.69; P = 0.0007) and bacteriuria (OR: 0.25, 95% CI 0.11-0.58; P = 0.001) than those who did not. Intravenous antibiotic prophylaxis was not superior to single-dose oral antibiotic prophylaxis in reducing fUTI (OR: 1.00, 95% CI 0.26-3.88; P = 1.00). CONCLUSIONS: We concluded that preoperative antibiotic prophylaxis did not lower the risk of postoperative fUTI, but a single dose could reduce the incidence of pyuria or bacteriuria. A single oral dose of preventive antibiotics is preferred because of its cost-effectiveness. The efficacy of different types of antibiotics and other strategies could not be assessed in our meta-analysis. Randomized controlled trials with a larger sample size and more rigorous study design are needed to validate these conclusions. PMID- 29232048 TI - Chiral separation of helical chromenes with chloromethyl phenylcarbamate polysaccharide-based stationary phases. AB - Two chloromethyl phenylcarbamate-based chiral stationary phases, one containing an amylose-type chiral selector (Lux Amylose 2, from Phenomenex) and the other a cellulose-type one (Lux Cellulose-4, from Phenomenex), were successfully used for the chiral resolution of three helical chromenes featuring a helicene-like structure. The compound bearing a phenyl substituent on the helicene-like structure was enantioresolved at 25 degrees C with Lux Cellulose-4 and a n hexane/1-propanol 99:1 v/v eluent. With a n-hexane/2-propanol 99.8:0.2 v/v mobile phase, the same column (operated at 35 degrees C) provided the separation of the four isomers of the compound having a hexyl residue on the helicene-like motif and an additional asymmetric carbon. Lux Amylose-2 was necessary for the enantioseparation of the compound having the sole hexyl residue on the helical scaffold. For the last compound a n-hexane/2-propanol 99.8:0.2 v/v eluent was used, and the column temperature was fixed at 5 degrees C. The enantiomer elution order was appraised by using electronic circular dichroism and theoretical calculations. Notably, different thermodynamics of retention and enantioseparation were observed for molecules with pronounced structural similarity, that is, the enantiomer pairs of the compound containing the additional asymmetric carbon atom. Indeed, both entropically and enthalpically controlled adsorption and separation processes were observed. PMID- 29232049 TI - Shark island pedicle flap for reconstruction of the lateral nasal ala and perialar defects. PMID- 29232050 TI - Affinity extraction of emerging contaminants from water based on bovine serum albumin as a binding agent. AB - Affinity sorbents using bovine serum albumin as a binding agent were developed and tested for the extraction of environmental contaminants from water. Computer simulations based on a countercurrent distribution model were also used to study the behavior of these sorbents. Several model drugs, pesticides, and hormones of interest as emerging contaminants were considered in this work, with carbamazepine being used as a representative analyte when coupling the albumin column on-line with liquid chromatography and tandem mass spectrometry. The albumin column was found to be capable of extracting carbamazepine from aqueous solutions that contained trace levels of this analyte. Further studies of the bovine serum albumin sorbent indicated that it had higher retention under aqueous conditions than a traditional C18 support for most of the tested emerging contaminants. Potential advantages of using these protein-based sorbents included the low cost of bovine serum albumin and its ability to bind to a relatively wide range of drugs and related compounds. It was also shown how simulations could be used to describe the elution behavior of the model compounds on the bovine serum albumin sorbents as an aid in optimizing the retention and selectivity of these supports for use with liquid chromatography or methods such as liquid chromatography with tandem mass spectrometry. PMID- 29232051 TI - Case of myxedema coma induced by lithium carbonate in a patient with schizophrenia. PMID- 29232052 TI - The US Food and Drug Administration's tentative approval process and the global fight against HIV. AB - INTRODUCTION: In 2004, the US government began to utilize the Food and Drug Administration's (USFDA) tentative approval process (tFDA) as a basis to determine which HIV drugs are appropriate to be purchased and used in resource constrained settings. This process permits products that are not approved for marketing in the US, including medicines with active patents or marketing restrictions in the US, to be purchased and distributed in resource-constrained settings. Although the tFDA was originally intended to support the United States' President's Emergency Plan for AIDS Relief (PEPFAR), the USFDA list has become a cornerstone of international HIV programmes that support procurement of ARVs, such as the World Health Organization and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. Our objective in this article is to help the global HIV policy makers and implementers of HIV programmes better understand the benefits and limitations of the tFDA by providing an in-depth review of the relevant legal and regulatory processes. DISCUSSION: USFDA's dedicated tFDA process for ARVs used by the PEPFAR programme has a wide impact globally; however, the implementation and the regulatory processes governing the programme have not been thoroughly described in the medical literature. This paper seeks to help stakeholders better understand the legal and regulatory aspects associated with review of ARVs under the tFDA by describing the following: (1) the tFDA and its importance to global ARV procurement; (2) the regulatory pathways for applications under tFDA for the PEPFAR programme, including modifications to applications, review timelines and costs; (3) the role of US patents, US marketing exclusivity rights, and the Medicines Patents Pool in tFDA; and (4) an overview of how applications for PEPFAR programme are processed through the USFDA. We also provide a case study of a new ARV, tenofovir alafenamide fumarate (TAF), not yet reviewed by USFDA for PEPFAR use. CONCLUSIONS: In this paper, we describe the importance and implementation of USFDA's tentative approval process to review ARVs for resource-constrained settings. We also highlight the impact of patents and exclusivities on review of HIV drugs under tFDA and illustrate the concepts using a new HIV drug as an example. PMID- 29232053 TI - Differential diagnosis of otitis media with effusion using label-free Raman spectroscopy: A pilot study. AB - Otitis media with effusion (OME) is an important and common condition affecting hearing in pediatric patients characterized by the presence of fluid in the middle ear space. The fluid is normally described as serous or mucoid based on differences in the fluid viscosity. The differential diagnosis of two OMEs, namely serous and mucoid is of significant clinical value because while the former is self-limiting, surgical procedure is commonly required for the latter. However, accurate identification of fluid types remains a challenging target unattainable with current clinical modalities due to unavailability of nonperturbative molecular tools. Here, we report an emerging spectroscopy approach featuring Raman scattering and multivariate analysis of spectral patterns to discern serous and mucoid fluids, obtained from pediatric patients undergoing myringotomy and tube placement, by providing information of differentially expressed molecules with high specificity. We demonstrate the feasibility of Raman spectroscopy-based approach to categorize middle ear effusion based on the characteristic spectral markers, notably of mucin, with classification accuracy of 91% and 93% for serous and mucoid, respectively. Our findings pave the way for further development of such a tool for fully noninvasive application that will lead to objective and accurate diagnosis thereby reducing unnecessary visits and surgical procedures. PMID- 29232054 TI - High-speed microscopy for in vivo monitoring of lymph dynamics. AB - The lymphatic system contributes to body homeostasis by clearing fluid, lipids, plasma proteins and immune cells from the interstitial space. Many studies have been performed to understand lymphatic function under normal conditions and during disease. Nevertheless, a further improvement in quantification of lymphatic behavior is needed. Here, we present advanced bright-field microscopy for in vivo imaging of lymph vessels (LVs) and automated quantification of lymphatic function at a temporal resolution of 2 milliseconds. Full frame videos were compressed and recorded continuously at up to 540 frames per second. A new edge detection algorithm was used to monitor vessel diameter changes across multiple cross sections, while individual cells in the LVs were tracked to estimate flow velocity. The system performance initially was verified in vitro using 6- and 10-MUm microspheres as cell phantoms on slides and in 90-MUm diameter tubes at flow velocities up to 4 cm/second. Using an in vivo rat model, we explored the mechanisms of lymphedema after surgical lymphadenectomy of the mesentery. The system revealed reductions of mesenteric LV contraction and flow rate. Thus, the described imaging system may be applicable to the study of lymphatic behavior during therapeutic and surgical interventions, and potentially during lymphatic system diseases. PMID- 29232055 TI - Outcome of orthodontic palatal plate therapy for orofacial dysfunction in children with Down syndrome: A systematic review. AB - To evaluate the effects of orthodontic palatal plate therapy (OPPT) in the treatment of orofacial dysfunction in children with Down syndrome (DS). Indexed databases were searched. Clinical trials in DS allocated to test (treatment with palatal plates) versus control group (without palatal plates/special physiotherapy for orofacial stimulation) with follow-up of any time duration and assessing mouth closure, tongue position, active and inactive muscle function as outcomes. Study designs, subject demographics, frequency and duration of palatal plate therapy, method for assessment, follow-up period and outcomes were reported according to the PRISMA guidelines. Eight clinical studies were included. The risk of bias was considered high in three studies and moderate in 5 studies. The number of children with DS ranged between 9 and 42. The mean age of children with DS at the start of the study ranged between 2 months and 12 years. The duration of palatal plate therapy ranged between 4 months and 48 months. The follow-up period in all studies ranged from 12 to 58 months. All studies reported OPPT to be effective in improving orofacial disorders in children with DS. Most of the included studies suggest that palatal plate therapy in combination with physiotherapy/orofacial regulation therapy according to Castillo Morales/speech and language intervention seems to be effective in improving orofacial disorders in children with DS. However, the risk of bias of the included studies was high to moderate. Longitudinal trials with standardized evaluation methods, age of children at treatment initiation, treatment duration and standard orofacial outcomes are recommended. PMID- 29232056 TI - Associations between laterality of orofacial clefts and medical and academic outcomes. AB - Patients with oral clefts have an increased risk of other malformations, syndromes, and lower academic performance in school. Few studies have investigated if laterality of clefts is associated with medical and academic outcomes. Oral clefts have nonrandom laterality, with left-sided clefts occurring approximately twice as often as right-sided clefts. Using a retrospective study design, we examined potential associations of cleft attributes and outcomes in patients with cleft lip with or without cleft palate (CL/P) born in 2003-2010 who were treated at the Seattle Children's Craniofacial Center. The following variables were extracted from medical records: cleft type, medical history, maternal hyperglycemia, other malformations, and the need for academic support at school. We used logistic regression to examine risk of associations with outcomes of interest. Relative to patients with left-sided clefts, patients with bilateral CL/P were more likely to have a syndrome. Patients with nonsyndromic right-sided CL/P had a higher risk (OR and 95%CI: 3.5, 1.3-9.5, and 5.5, 1.9-16.0, respectively) of having other malformations and requiring academic support at school, when compared to patients with left-sided CL/P. Understanding the etiology of oral clefts is complicated, in part because both genetic and environmental factors contribute to the risk of developing a cleft. However, the different outcomes associated with cleft laterality suggest that right-sided clefts may have a distinct etiology. Using laterality to study cleft subgroups may advance our understanding of the etiology of this common birth defect. PMID- 29232062 TI - Testing scenario for intellectual disability, developmental delay, and autism challenged. PMID- 29232060 TI - Cover Image, Volume 176A, Number 1, January 2018. AB - The cover image, by Satoru Ikenoue et al., is based on the Clinical Report Discordant fetal phenotype of hypophosphatasia in two siblings, DOI: 10.1002/ajmg.a.38531. PMID- 29232064 TI - New Approaches to Fertility Awareness-Based Methods: Incorporating the Standard Days and TwoDay Methods into Practice. PMID- 29232063 TI - Exome sequencing helps diagnose infants in the ICU: Test results changed medical management for more than half of diagnosed babies. PMID- 29232065 TI - Mental Health: Illness and Wellness (2017/090). PMID- 29232067 TI - Clinical factors are associated with vitamin D levels in IBD patients: A retrospective analysis. AB - OBJECTIVE: There is growing evidence that vitamin D deficiency plays a role in the development and the course of inflammatory bowel disease (IBD). However, the correlation between vitamin D deficiency and clinical parameters in IBD is still not completely understood. METHODS: A retrospective study of IBD patients was performed. Vitamin D values were analyzed, regardless of vitamin D substitution administration, and correlated with clinical parameters such as medical therapy, anatomical situation, location of the disease and disease activity. Level of 25 hydroxyvitamin D [25(OH)D] <50 nmoL/L was regarded as vitamin D deficiency and <75 nmoL/L as insufficiency. RESULTS: In total, 208 IBD patients were analyzed, including 123 with Crohn's disease (CD) and 85 with ulcerative colitis (UC). Therapy with azathioprine did not affect the vitamin D values of either disease entity. But CD patients benefited from therapy with tumor necrosis factor-alpha inhibitor and exhibited significantly higher vitamin D levels than those without. Furthermore, significantly lower vitamin D levels were found if CD was located in the small bowel or if the small bowel had been resected. Moreover, significantly lower levels of vitamin D were detectable for high disease activity (reflected by high simple clinical colitis activity index values) in patients with UC. CONCLUSIONS: Vitamin D deficiency is common in patients with IBD. However, certain clinical situations lead to significantly lower vitamin D levels and may therefore require close monitoring for vitamin D deficiency. PMID- 29232069 TI - Medicare Program; CY 2018 Updates to the Quality Payment Program; and Quality Payment Program: Extreme and Uncontrollable Circumstance Policy for the Transition Year. Final rule with comment period and interim final rule with comment period. AB - The Medicare Access and CHIP Reauthorization Act of 2015 (MACRA) established the Quality Payment Program for eligible clinicians. Under the Quality Payment Program, eligible clinicians can participate via one of two tracks: Advanced Alternative Payment Models (APMs); or the Merit-based Incentive Payment System (MIPS). We began implementing the Quality Payment Program through rulemaking for calendar year (CY) 2017. This final rule with comment period provides updates for the second and future years of the Quality Payment Program. In addition, we also are issuing an interim final rule with comment period (IFC) that addresses extreme and uncontrollable circumstances MIPS eligible clinicians may face as a result of widespread catastrophic events affecting a region or locale in CY 2017, such as Hurricanes Irma, Harvey and Maria. PMID- 29232068 TI - Dynamic evaluation of a trilobal capillary-channeled polymer fiber shape for reversed phase protein separations and comparison to the eight-channeled form. AB - A new, trilobal-shaped capillary-channeled polymer fiber is under development to address the issues of poor A-term performance of the previous eight-channeled form. The trilobal geometry should provide better packing homogeneity due to the fewer potential orientations of the symmetric fiber geometry. Comparisons of separation efficiency and peak shape were made between the two fiber shapes through several dynamic parameters. Column hydrodynamics were investigated with two marker compounds, uracil and bovine serum albumin, with van Deemter plots of those two compounds revealing differences in the packing qualities between the different fiber shapes. Parametric fitting to the van Deemter, Knox, and Giddings equations provides insights into the column physical structures. Separation quality for both shapes was evaluated across differences in fiber packing density, gradient rate, and mobile phase linear velocity for the reversed phase separation of a four protein mixture, containing ribonuclease A, cytochrome c, lysozyme, and myoglobin. The results of this study lay the ground work for future efforts in the use of trilobal fibers for the separation of biomacromolecules. PMID- 29232070 TI - Schedules of Controlled Substances: Placement of FDA-Approved Products of Oral Solutions Containing Dronabinol [(-)-delta-9-trans-tetrahydrocannabinol (delta-9 THC)] in Schedule II. Final rule. AB - This final rule adopts without changes an interim final rule with request for comments published in the Federal Register on March 23, 2017. On July 1, 2016, the U.S. Food and Drug Administration (FDA) approved a new drug application for Syndros, a drug product consisting of dronabinol [(-)-delta-9-trans tetrahydrocannabinol (delta-9-THC)] oral solution. The Drug Enforcement Administration (DEA) maintains FDA-approved products of oral solutions containing dronabinol in schedule II of the Controlled Substances Act. PMID- 29232071 TI - Claims Procedure for Plans Providing Disability Benefits; 90-Day Delay of Applicability Date. Final rule; delay of applicabilitydate. AB - This document delays for ninety (90) days--through April 1, 2018--the applicability of a final rule amending the claims procedure requirements applicable to ERISA-covered employee benefit plans that provide disability benefits (Final Rule). The Final Rule was published in the Federal Register on December 19, 2016, became effective on January 18, 2017, and was scheduled to become applicable on January 1, 2018. The delay announced in this document is necessary to enable the Department of Labor to carefully consider comments and data as part of its effort, pursuant to Executive Order 13777, to examine regulatory alternatives that meet its objectives of ensuring the full and fair review of disability benefit claims while not imposing unnecessary costs and adverse consequences. PMID- 29232072 TI - Child Nutrition Programs: Flexibilities for Milk, Whole Grains, and Sodium Requirements. Interim final rule. AB - This interim final rule extends through school year 2018-2019 three menu planning flexibilities currently available to many Child Nutrition Program operators, giving them near-term certainty about Program requirements and more local control to serve nutritious and appealing meals to millions of children nationwide. These flexibilities include: Providing operators the option to offer flavored, low-fat (1 percent fat) milk in the Child Nutrition Programs; extending the State agencies' option to allow individual school food authorities to include grains that are not whole grain-rich in the weekly menu offered under the National School Lunch Program (NSLP) and School Breakfast Program (SBP); and retaining Sodium Target 1 in the NSLP and SBP. This interim final rule addresses significant challenges faced by local operators regarding milk, whole grains and sodium requirements and their impact on food development and reformulation, menu planning, and school food service procurement and contract decisions. The comments from the public on the long-term availability of these three flexibilities will help inform the development of a final rule, which is expected to be published in fall 2018 and implemented in school year 2019-2020. PMID- 29232073 TI - Medicare Program; Cancellation of Advancing Care Coordination Through Episode Payment and Cardiac Rehabilitation Incentive Payment Models; Changes to Comprehensive Care for Joint Replacement Payment Model: Extreme and Uncontrollable Circumstances Policy for the Comprehensive Care for Joint Replacement Payment Model. Final rule; interim final rule with comment period. AB - This final rule cancels the Episode Payment Models (EPMs) and Cardiac Rehabilitation (CR) Incentive Payment Model and rescinds the regulations governing these models. It also implements certain revisions to the Comprehensive Care for Joint Replacement (CJR) model, including: Giving certain hospitals selected for participation in the CJR model a one-time option to choose whether to continue their participation in the model; technical refinements and clarifications for certain payment, reconciliation and quality provisions; and a change to increase the pool of eligible clinicians that qualify as affiliated practitioners under the Advanced Alternative Payment Model (Advanced APM) track. An interim final rule with comment period is being issued in conjunction with this final rule in order to address the need for a policy to provide some flexibility in the determination of episode costs for providers located in areas impacted by extreme and uncontrollable circumstances. PMID- 29232074 TI - Focus On" Bioactive Dental Materials. PMID- 29232075 TI - Extra-Schedular Evaluations for Individual Disabilities. Final rule. AB - The Department of Veterans Affairs (VA) amends its adjudication regulation pertaining to extra-schedular consideration of a service-connected disability in exceptional compensation cases. This rule clarifies that an extra-schedular evaluation is to be applied to an individual service-connected disability when the disability is so exceptional or unusual that it makes application of the regular rating schedule impractical. An extra-schedular evaluation may not be based on the combined effect of more than one service-connected disability. For the reasons set forth in the proposed rule and in this final rule, VA is adopting the proposed rule as final, with two changes, as explained below. PMID- 29232076 TI - The Twenty-Fifth Amendment and the establishment of medical impairment panels: are the two safely compatible? PMID- 29232077 TI - Kudos for the Drinks Destroy Teeth App. PMID- 29232078 TI - Pediatric Dentistry Q and A. Same Answers/Different Perspectives. PMID- 29232079 TI - Behavioral Design Teams: The Next Frontier in Clinical Delivery Innovation? AB - Issue: A deep understanding of human behavior is critical to designing effective health care delivery models, tools, and processes. Currently, however, few mechanisms exist to systematically apply insights about human behavior to improve health outcomes. Behavioral design teams (BDTs) are a successful model for applying behavioral insights within an organization. Already operational within government, this model can be adapted to function in a health care setting. Goal: To explore how BDTs could be applied to clinical care delivery and review models for integrating these teams within health care organizations. Methods: Interviews with experts in clinical delivery innovation and applied behavioral science, as well as leaders of existing government BDTs. Findings and Conclusions: BDTs are most effective when they enjoy top-level executive support, are co-led by a domain expert and behavioral scientist, collaborate closely with key staff and departments, have access to data and IT support, and operate a portfolio of projects. BDTs could be embedded in health care organizations in multiple ways, including in or just below the CEO's office, within a quality improvement unit, or within an internal innovation center. When running a portfolio, BDTs achieve a greater number and diversity of insights at lower costs. They also become a platform for strategic learning and scaling. PMID- 29232080 TI - Radiation Safety and Protection in Pediatric Dentistry: Rectangular Collimation. PMID- 29232081 TI - How to Reach Millennials, Their Children and Others: Get an App! PMID- 29232082 TI - Overcoming "I'll Think About It." Handling Objections. PMID- 29232084 TI - Politics, Tectonic Plates and the Wall of Wine! PMID- 29232085 TI - Use of Paid and Unpaid Personal Help by Medicare Beneficiaries Needing Long-Term Services and Supports. AB - Issue: Older adults who reside in communities, as opposed to nursing homes or other residential institutions, are largely dependent on family and unpaid caregivers for assistance with daily activities, like preparing meals or laundry, and self-care tasks like bathing or dressing. For low-income older adults, assistance with such activities, also known as long-term services and supports (LTSS), can also come from Medicaid. These sources of support will be increasingly inadequate as the population ages. Goals: To examine the extent of paid and unpaid personal care assistance used by community-residing people who require LTSS; and to analyze how this differs by demographics and the economic status of Medicare beneficiaries. Methods: Descriptive analyses of the National Health and Aging Trends Study (NHATS), 2015. Findings and Conclusions: Medicare beneficiaries needing LTSS rely predominantly on unpaid care. Hours of unpaid care are not substantially lower when paid care is also received. Findings suggest that public financing of LTSS would not replace but rather supplement the contribution of family and unpaid caregivers to support individuals living independently in the community. PMID- 29232086 TI - Dentist is Best Job in U.S. PMID- 29232087 TI - Who Has Taught Them? PMID- 29232089 TI - Can We Ever Go Back? PMID- 29232090 TI - We Want You...To Join. PMID- 29232088 TI - Comparing the Affordable Care Act's Financial Impact on Safety-Net Hospitals in States That Expanded Medicaid and Those That Did Not. AB - Issue: Safety-net hospitals play a vital role in delivering health care to Medicaid enrollees, the uninsured, and other vulnerable patients. By reducing the number of uninsured Americans, the Affordable Care Act (ACA) was also expected to lower these hospitals' significant uncompensated care costs and shore up their financial stability. Goal: To examine how the ACA's Medicaid expansion affected the financial status of safety-net hospitals in states that expanded Medicaid and in states that did not. Methods: Using Medicare hospital cost reports for federal fiscal years 2012 and 2015, the authors compared changes in Medicaid inpatient days as a percentage of total inpatient days, Medicaid revenues as a percentage of total net patient revenues, uncompensated care costs as a percentage of total operating costs, and hospital operating margins. Findings and Conclusions: Medicaid expansion had a significant, favorable financial impact on safety-net hospitals. From 2012 to 2015, safety-net hospitals in expansion states, compared to those in nonexpansion states, experienced larger increases in Medicaid inpatient days and Medicaid revenues as well as reduced uncompensated care costs. These changes improved operating margins for safety-net hospitals in expansion states. Margins for safety-net hospitals in nonexpansion states, meanwhile, declined. PMID- 29232091 TI - The Risk of Living Too Long. PMID- 29232092 TI - Advice from a Citizen Legislator. PMID- 29232093 TI - Invasive Cervical Resorption: a look at four case studies. PMID- 29232094 TI - Advantages and Limitations of Cone Beam Computed Tomography. PMID- 29232095 TI - Address to IDA House of Delegates IDA President Dr. Jay Asdell May 21, 2016. PMID- 29232096 TI - Meet IDA's New Treasurer: Dr. Tom Blake. PMID- 29232097 TI - Correction to Competitive Inhibition Mechanism of Acetylcholinesterase without Catalytic Active Site Interaction: Study on Functionalized C60 Nanoparticles via in Vitro and in Silico Assays. PMID- 29232098 TI - Amyloid beta (1-40) Toxicity Depends on the Molecular Contact between Phenylalanine 19 and Leucine 34. AB - The formation of the hydrophobic contact between phenylalanine 19 (F19) and leucine 34 (L34) of amyloid beta (1-40) (Abeta(1-40)) is known to be an important step in the fibrillation of Abeta(1-40) peptides. Mutations of this putatively early molecular contact were shown to strongly influence the toxicity of Abeta(1 40) ( Das et al. ( 2015 ) ACS Chem. Neurosci. 6 , 1290 - 1295 ). Any mutation of residue F19 completely abolished the toxicity of Abeta(1-40), suggesting that a proper F19-L34 contact is crucial also for the formation of transient oligomers. In this work, we investigate a series of isomeric substitutions of L34, namely, d leucine, isoleucine, and valine, to study further details of this molecular contact. These replacements represent very minor alterations in the Abeta(1-40) structure posing the question how these alterations challenge the fibrillation kinetics, structure, dynamics, and toxicity of the Abeta(1-40) aggregates. Our work involves kinetic studies using thioflavin T, transmission electron microscopy, X-ray diffraction for the analysis of the fibril morphology, and nuclear magnetic resonance experiments for local structure and molecular dynamics investigations. Combined with cell toxicity assays of the mutated Abeta(1-40) peptides, the physicochemical and biological importance of the early folding contact between F19 and L34 in Abeta(1-40) is underlined. This implies that the F19-L34 contact influences a broad range of different processes including the initiation of fibrillation, oligomer stability, fibril elongation, local fibril structure, and dynamics and cellular toxicity. These processes do not only cover a broad range of diverse mechanisms, but also proved to be highly sensitive to minor modulations of this crucial contact. Furthermore, our work shows that the contact is not simply mediated by general hydrophobic interactions, but also depends on stereospecific mechanisms. PMID- 29232099 TI - Effect of Graphene-EC on Ag NW-Based Transparent Film Heaters: Optimizing the Stability and Heat Dispersion of Films. AB - To optimize the performance of silver nanowire (Ag NW) film heaters and explore the effect of graphene on a film, we introduced poly(3,4 ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) and graphene modified with ethyl cellulose (graphene-EC) into the film. The high-quality and well-dispersed graphene-EC was synthesized from graphene obtained by electrochemical exfoliation as a precursor. The transparent film heaters were fabricated via spin-coating. With the assistance of graphene-EC, the stability of film heaters was greatly improved, and the conductivity was optimized by adjusting the Ag NW concentration. The film heaters exhibited a fast and accurate response to voltage, accompanied by excellent environmental endurance, and there was no significant performance degradation after being operated for a long period of time. These results indicate that graphene-EC plays a crucial role in optimizing film stability and heat dispersion in the film. The Ag NW/PEDOT:PSS doped graphene-EC film heaters show a great potential in low-cost indium-tin oxide-free flexible transparent electrodes, heating systems, and transparent film heaters. PMID- 29232100 TI - Engineering Stability-Tunable DNA Micelles Using Photocontrollable Dissociation of an Intermolecular G-Quadruplex. AB - Because of their facile preparation, small size (<100 nm), programmable design, and biocompatibility, lipid-based DNA micelles show enormous potential as a tool to monitor biological events and treat human diseases. However, their structural stability in biological matrices suffers from spatiotemporal variability, thus limiting their in vivo use. Herein, we have engineered stability-tunable DNA micelle flares using photocontrollable dissociation of intermolecular G quadruplexes, which confers DNA micelle flares with robust structural stability against disruption by serum albumin. However, once exposed to light, the G quadruplex formation is blocked by strand hybridization, resulting in the loss of stability in the presence of serum albumin and subsequent cellular uptake. This programmable regulation to stabilize lipid-based micelles in the presence of fatty-acid-binding serum albumin should further the development of biocompatible DNA micelles for in vivo applications. PMID- 29232101 TI - A "Driver Switchover" Mechanism of Influenza Virus Transport from Microfilaments to Microtubules. AB - When infecting host cells, influenza virus must move on microfilaments (MFs) at the cell periphery and then move along microtubules (MTs) through the cytosol to reach the perinuclear region for genome release. But how viruses switch from the actin roadway to the microtubule highway remains obscure. To settle this issue, we systematically dissected the role of related motor proteins in the transport of influenza virus between cytoskeletal filaments in situ and in real-time using quantum dot (QD)-based single-virus tracking (SVT) and multicolor imaging. We found that the switch between MF- and MT-based retrograde motor proteins, myosin VI (myoVI) and dynein, was responsible for the seamless transport of viruses from MFs to MTs during their infection. After virus entry by endocytosis, both the two types of motor proteins are attached to virus-carrying vesicles. MyoVI drives the viruses on MFs with dynein on the virus-carrying vesicle hitchhiking. After role exchanges at actin-microtubule intersections, dynein drives the virus along MTs toward the perinuclear region with myoVI remaining on the vesicle moving together. Such a "driver switchover" mechanism has answered the long-pending question of how viruses switch from MFs to MTs for their infection. It will also facilitate in-depth understanding of endocytosis. PMID- 29232102 TI - Finding a Silver Bullet in a Stack of Proteins. PMID- 29232103 TI - Game Changers: New beta-Lactamase Inhibitor Combinations Targeting Antibiotic Resistance in Gram-Negative Bacteria. AB - Recent regulatory approvals for the beta-lactam inhibitor combinations of ceftazidime-avibactam and meropenem-vaborbactam have provided two novel therapeutic options for the treatment of multidrug-resistant infections caused by Gram-negative bacteria. Most importantly, these combination agents have satisfied an important medical need related to antibiotic-resistant Klebsiella pneumoniae that produce serine carbapenemases, especially the Klebsiella pneumoniae carbapenemase (KPC) enzymes. Both combinations contain non-beta-lactam beta lactamase inhibitors of novel chemical classes not previously developed as antibacterial agents, the diazabicyclooctanes and cyclic boronic acid derivatives. Their rapid development and approval programs have spurred a number of similar inhibitor combinations that will need to differentiate themselves for commercial success. Gaps still exist for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa, Acinetobacter spp., and metallo-beta lactamase-producing pathogens. Overall, the new beta-lactamase inhibitor combinations have infused new life into the search for new antibacterial agents to treat multidrug-resistant bacteria. PMID- 29232105 TI - Facile Supramolecular Approach to Nucleic-Acid-Driven Activatable Nanotheranostics That Overcome Drawbacks of Photodynamic Therapy. AB - Supramolecular chemistry provides a "bottom-up" method to fabricate nanostructures for biomedical applications. Herein, we report a facile strategy to directly assemble a phthalocyanine photosensitizer (PcS) with an anticancer drug mitoxantrone (MA) to form uniform nanostructures (PcS-MA), which not only display nanoscale optical properties but also have the capability of undergoing nucleic-acid-responsive disassembly. These supramolecular assemblies possess activatable fluorescence emission and singlet oxygen generation associated with the formation of free PcS, mild photothermal heating, and a concomitant chemotherapeutic effect associated with the formation of free MA. In vivo evaluations indicate that PcS-MA nanostructures have a high level of accumulation in tumor tissues, are capable of being used for cancer imaging, and have significantly improved anticancer effect compared to that of PcS. This study demonstrates an attractive strategy for overcoming the limitations of photodynamic cancer therapy. PMID- 29232104 TI - The Effects of Biological Fluids on Colloidal Stability and siRNA Delivery of a pH-Responsive Micellar Nanoparticle Delivery System. AB - Nanoparticles (NPs) interact with complex protein milieus in biological fluids, and these interactions have profound effects on NP physicochemical properties and function. Surprisingly, most studies neglect the impact of these interactions, especially with respect to NP-mediated siRNA delivery. Here, the effects of serum on colloidal stability and siRNA delivery of a pH-responsive micellar NP delivery system were characterized. Results show cationic NP-siRNA complexes aggregate in >=2% serum in buffer, but are stable in serum-free media. Furthermore, nonaggregated NP-siRNA delivered in serum-free media result in 4-fold greater siRNA uptake in vitro, compared to aggregated NP-siRNA. Interestingly, pH responsive membrane lysis behavior, which is required for endosomal escape, and NP-siRNA dissociation, necessary for gene knockdown, are significantly reduced in serum. Consistent with these data, nonaggregated NP-siRNA in serum-free conditions result in highly efficient gene silencing, even at doses as low as 5 nM siRNA. NP-siRNA diameter was measured at albumin and IgG levels mimicking biological fluids. Neither albumin nor IgG alone induces NP-siRNA aggregation, implicating other serum proteins in NP colloidal instability. Finally, as a proof of-principle that stability is maintained in established in vivo models, transmission electron microscopy reveals NP-siRNA are taken up by ductal epithelial cells in a nonaggregated state when injected retroductally into mouse salivary glands in vivo. Overall, this study shows serum-induced NP-siRNA aggregation significantly diminishes efficiency of siRNA delivery by reducing uptake, pH-responsive membrane lysis activity, and NP-siRNA dissociation. Moreover, these results highlight the importance of local NP-mediated drug delivery and are broadly applicable to other drug delivery systems. PMID- 29232106 TI - Ultrafast Sodiation of Single-Crystalline Sn Anodes. AB - Sodiation was performed on crystalline Sn cylinders using an in situ electron microscope to evaluate the rate performance of the Sn anode by directly measuring the sodiation rate. We observed that the sodiation rate of the Sn anode is more than 2 orders of magnitude higher than the lithiation rate of the Si anode under the same conditions. This unprecedented rate displayed by the Na-Sn system is attributed to the bond characteristics and crystalline-to-amorphous transformation of the Sn crystal at the thin interface of the Na-Sn diffusion couple. Here, using atomic simulations, we explain how and why the Sn anode exhibits this high rate performance by resolving the diffusion process of Na ions in the Na-Sn interfacial region and the electron structure of the crystalline Sn. This work provides a useful insight into the use of Sn as an attractive anode material for realizing ultrafast-charging batteries for electric vehicles and mobile devices. PMID- 29232107 TI - 2D Material-Based Nanofibrous Membrane for Photothermal Cancer Therapy. AB - One of the clinical challenges facing photothermal cancer therapy is health risks imposed by the photothermal nanoagents in vivo. Herein, a photothermal therapy (PTT) platform composed of a 2D material-based nanofibrous membrane as the agent to deliver thermal energy to tumors under near-infrared (NIR) light irradiation is described. The photothermal membrane, which is fabricated by an electrospinning poly(l-lactic acid) (PLLA) nanofibrous membrane loaded with bismuth selenide (Bi2Se3) nanoplates, exhibits very high photothermal conversion efficiency and long-term stability. Cell experiments and hematological analyses demonstrate that the Bi2Se3/PLLA membranes have excellent biocompatibility and low toxicity. PTT experiments performed in vivo with the Bi2Se3/PLLA membrane covering the tumor and NIR irradiation produce local hyperthermia to ablate the tumor with high efficiency. Different from the traditional systematical and local injection techniques, this membrane-based PTT platform is promising in photothermal cancer therapy, especially suitable for the treatment of multiple solid tumors or skin cancers, and long-term prevention of cancer recurrence after surgery or PTT, while eliminating the health hazards of nanoagents. PMID- 29232108 TI - Biocompatible Electroactive Tetra(aniline)-Conjugated Peptide Nanofibers for Neural Differentiation. AB - Peripheral nerve injuries cause devastating problems for the quality of patients' lives, and regeneration following damage to the peripheral nervous system is limited depending on the degree of the damage. Use of nanobiomaterials can provide therapeutic approaches for the treatment of peripheral nerve injuries. Electroactive biomaterials, in particular, can provide a promising cure for the regeneration of nerve defects. Here, a supramolecular electroactive nanosystem with tetra(aniline) (TA)-containing peptide nanofibers was developed and utilized for nerve regeneration. Self-assembled TA-conjugated peptide nanofibers demonstrated electroactive behavior. The electroactive self-assembled peptide nanofibers formed a well-defined three-dimensional nanofiber network mimicking the extracellular matrix of the neuronal cells. Neurite outgrowth was improved on the electroactive TA nanofiber gels. The neural differentiation of PC-12 cells was more advanced on electroactive peptide nanofiber gels, and these biomaterials are promising for further use in therapeutic neural regeneration applications. PMID- 29232109 TI - Impact of Chemical Cross-Linking on Protein Structure and Function. AB - Chemical cross-linking coupled with mass spectrometry is a popular technique for deriving structural information on proteins and protein complexes. Also, cross linking has become a powerful tool for stabilizing macromolecular complexes for single-particle cryo-electron microscopy. However, an effect of cross-linking on protein structure and function should not be forgotten, and surprisingly, it has not been investigated in detail so far. Here, we used kinetic studies, mass spectrometry, and NMR spectroscopy to systematically investigate an impact of cross-linking on structure and function of human carbonic anhydrase and alcohol dehydrogenase 1 from Saccharomyces cerevisiae. We found that cross-linking induces rather local structural disturbances and the overall fold is preserved even at a higher cross-linker concentration. The results establish general experimental conditions for chemical cross-linking with minimal effect on protein structure and function. PMID- 29232111 TI - A Hand-Held Optoelectronic Nose for the Identification of Liquors. AB - Successful discrimination of 14 representative liquors (including scotch, bourbon and rye whiskies, brandy, and vodka) was achieved using a 36-element colorimetric sensor array comprising multiple classes of cross-reactive, chemically responsive inks. In combination with a palm-sized image analyzer, the sensor array permits real-time identification of liquor products based on vapor analysis within 2 min. Changes in sensor spot colors before and after exposure to the vapors of the liquors that are partially oxidized as they are pumped over the sensor array provides a unique color difference pattern for each analyte. Facile identification of each liquor was demonstrated using several different multivariate analyses of the digital data library, including principal component, hierarchical cluster, and support vector machine analysis. The sensor array is also able to detect dilution (i.e., "watering") of liquors even down to 1% addition of water. This colorimetric sensor array is a promising portable adjunct to other available techniques for quality assurance of liquors and other alcoholic beverages. PMID- 29232110 TI - Kinetic Characterization of Prenyl-Flavin Synthase from Saccharomyces cerevisiae. AB - We have characterized the kinetics and substrate requirements of prenyl-flavin synthase from yeast. This enzyme catalyzes the addition of an isopentenyl unit to reduced flavin mononucleotide (FMN) to form an additional six-membered ring that bridges N5 and C6 of the flavin nucleus, thereby converting the flavin from a redox cofactor to one that supports the decarboxylation of aryl carboxylic acids. In contrast to bacterial enzymes, the yeast enzyme was found to use dimethylallyl pyrophosphate, rather than dimethylallyl phosphate, as the prenyl donor in the reaction. We developed a coupled assay for prenyl-flavin synthase activity in which turnover was linked to the activation of the prenyl-flavin-dependent enzyme, ferulic acid decarboxylase. The kinetics of the reaction are extremely slow: kcat = 12.2 +/- 0.2 h-1, and KM for dimethylallyl pyrophosphate = 9.8 +/- 0.7 MUM. The KM for reduced FMN was too low to be accurately measured. The kinetics of reduced FMN consumption were studied under pre-steady state conditions. The reaction of FMN was described well by first-order kinetics with a kapp of 17.4 +/- 1.1 h-1. These results indicate that a chemical step, most likely formation of the carbon-carbon bond between C6 of the flavin and the isopentenyl moiety, is substantially rate-determining in the reaction. PMID- 29232112 TI - Switchable Control of Antibiotic Activity: A Shape-Shifting "Tail" Strategy. AB - Bacterial resistance is emerging as a global threat, stemming partially from continuous exposure of pathogens to antibiotics of sublethal concentrations. Thus, novel molecular approaches capable of inactivating antibiotics, which prevent their final build-up in the environment, are highly desirable. Here, we report a proof-of-principle demonstration of a mechanically new strategy for switchable control of antibiotic activity, which regulates drug uptake across the outer membrane of Gram-negative bacteria by externally triggered shape shifting of a short, covalently attached "tail". The rationale behind this strategy is grounded in the size-selectivity of porin channels exploited by a large proportion of antibiotics for accessing intracellular targets, thus representing a general approach to control antibiotic availability in the environment which alleviates undue selection pressure for resistance. PMID- 29232113 TI - Hyperbranched Polyglycerol Loaded with (Zinc-)Porphyrins: Photosensitizer Release Under Reductive and Acidic Conditions for Improved Photodynamic Therapy. AB - An adaptable approach toward cleavable nanoparticle carrier systems for photodynamic therapy (PDT) is presented, comprising a biocompatible carrier loaded with multiple photosensitizer (PS) molecules related to the clinically employed PS Temoporfin, two linkers cleavable under different triggers and glyco targeting with mannose. A synthetic pathway to stimuli responsive hyperbranched polyglycerol (hPG) porphyrin conjugates via the copper(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC) or the strain-promoted alkyne-azide cycloaddition (SPAAC) has been developed. The PS 10,15,20-tris(3-hydroxyphenyl)-5-(2,3,4,5,6 pentafluorophenyl)porphyrin was functionalized with disulfide containing cystamine and acid-labile benzacetal linkers. Conjugates with reductively and pH labile linkers were thus obtained. Cleavage of the active PS agents from the polymer carrier is shown in several different release studies. The uptake of the conjugates into the cells is demonstrated via confocal laser scanning microscopy (CLSM) and flow cytometry. Finally, the antitumor and antibacterial phototoxicity of selected conjugates has been assessed in four different tumor cell lines and in cultures of the bacterium Staphylococcus aureus. The conjugates exhibited phototoxicity in several tumor cell lines in which conjugates with reductively cleavable linkers were more efficient compared to conjugates with acid-cleavable linkers. For S. aureus, strong phototoxicity was observed for a combination of the reductively cleavable and the pH labile linker and likewise for the cleavable conjugate with mannose targeting groups. The results thus suggest that the conjugates have potential for antitumor as well as antibacterial PDT. PMID- 29232114 TI - Anomalous Kinetics of Diffusion-Controlled Defect Annealing in Irradiated Ionic Solids. AB - The annealing kinetics of the primary electronic F-type color centers (oxygen vacancies with trapped one or two electrons) is analyzed for three ionic materials (Al2O3, MgO, and MgF2) exposed to intensive irradiation by electrons, neutrons, and heavy swift ions. Phenomenological theory of diffusion-controlled recombination of the F-type centers with much more mobile interstitial ions (complementary hole centers) allows us to extract from experimental data the migration energy of interstitials and pre-exponential factor of diffusion. The obtained migration energies are compared with available first-principles calculations. It is demonstrated that with the increase of radiation fluence both the migration energy and pre-exponent are decreasing in all three materials, irrespective of the type of irradiation. Their correlation satisfies the Meyer Neldel rule observed earlier in glasses, liquids, and disordered materials.The origin of this effect is discussed. This study demonstrates that in the quantitative analysis of the radiation damage of real materials the dependence of the defect migration parameters on the radiation fluence plays an important role and cannot be neglected. PMID- 29232115 TI - Arsenobetaine in Seawater: Depth Profiles from Selected Sites in the North Atlantic. AB - Arsenic occurs in marine waters, typically at concentrations of 1-2 MUg As kg-1, primarily as the inorganic species arsenate. Marine animals, however, contain extremely high levels of arsenic (typically 2000-20 000 MUg As kg-1 wet mass), most of which is present as arsenobetaine, an organic form of arsenic that has never been found in seawater. We report a method based on ion-exchange preconcentration and HPLC/mass spectrometry to measure arsenobetaine in seawater, and apply the method to samples of seawater collected at various depths from seven sites in the North Atlantic. Arsenobetaine was detected in most samples at levels ranging from 0.5 to 10 ng As kg-1, and was found at depths down to 4900 m. Furthermore, we report the presence of 15 additional organoarsenicals in seawater, 14 of which had never been detected in marine waters. The arsenobetaine depth profile was related, albeit weakly, to that of chlorophyll; this relationship probably reflects arsenobetaine's release to water from marine animals associated with the euphotic zone rather than its direct biosynthesis by primary producers. Future application of the new method for seawater analysis will shed new light on the biogeochemical cycle of marine arsenic. PMID- 29232117 TI - All-Fullerene-Based Cells for Nonaqueous Redox Flow Batteries. AB - Redox flow batteries have the potential to revolutionize our use of intermittent sustainable energy sources such as solar and wind power by storing the energy in liquid electrolytes. Our concept study utilizes a novel electrolyte system, exploiting derivatized fullerenes as both anolyte and catholyte species in a series of battery cells, including a symmetric, single species system which alleviates the common problem of membrane crossover. The prototype multielectron system, utilizing molecular based charge carriers, made from inexpensive, abundant, and sustainable materials, principally, C and Fe, demonstrates remarkable current and energy densities and promising long-term cycling stability. PMID- 29232116 TI - Two-Stage Enzymatic Preparation of Eicosapentaenoic Acid (EPA) And Docosahexaenoic Acid (DHA) Enriched Fish Oil Triacylglycerols. AB - Fish oil products in the form of triacylglycerols generally have relatively low contents of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and so it is of potential research and industrial interest to enrich the related contents in commercial products. Thereby an economical and efficient two-stage preparation of EPA and DHA enriched fish oil triacylglycerols is proposed in this study. The first stage was the partial hydrolysis of fish oil by only 0.2 wt.0/00 AY "Amano" 400SD which led to increases of EPA and DHA contents in acylglycerols from 19.30 and 13.09 wt % to 25.95 and 22.06 wt %, respectively. Subsequently, products of the first stage were subjected to transesterification with EPA and DHA enriched fatty acid ethyl esters (EDEE) as the second stage to afford EPA and DHA enriched fish oil triacylglycerols by using as low as 2 wt % Novozyme 435. EDEEs prepared from fish oil ethyl ester, and recycled DHA and EPA, respectively, were applied in this stage. Final products prepared with two different sources of EDEEs were composed of 97.62 and 95.92 wt % of triacylglycerols, respectively, with EPA and DHA contents of 28.20 and 21.41 wt % for the former and 25.61 and 17.40 wt % for the latter. Results not only demonstrate this two-stage process's capability and industrial value for enriching EPA and DHA in fish oil products, but also offer new opportunities for the development of fortified fish oil products. PMID- 29232118 TI - Heptanuclear Fe5Cu2-Phenylgermsesquioxane containing 2,2'-Bipyridine: Synthesis, Structure, and Catalytic Activity in Oxidation of C-H Compounds. AB - A new representative of an unusual family of metallagermaniumsesquioxanes, namely the heterometallic cagelike phenylgermsesquioxane (PhGeO2)12Cu2Fe5(O)OH(PhGe)2O5(bipy)2 (2), was synthesized and structurally characterized. Fe(III) ions of the complex are coordinated by oxa ligands: (i) cyclic (PhGeO2)12 and acyclic (Ph2Ge2O5) germoxanolates and (ii) O2- and (iii) HO moieties. In turn, Cu(II) ions are coordinated by both oxa (germoxanolates) and aza ligands (2,2'-bipyridines). This "hetero-type" of ligation gives in sum an attractive pagoda-like molecular architecture of the complex 2. Product 2 showed a high catalytic activity in the oxidation of alkanes to the corresponding alkyl hydroperoxides (in yields up to 30%) and alcohols (in yields up to 100%) and in the oxidative formation of benzamides from alcohols (catalyst loading down to 0.4 mol % in Cu/Fe). PMID- 29232119 TI - Catalytic Mechanism of Fungal Lytic Polysaccharide Monooxygenases Investigated by First-Principles Calculations. AB - Lytic polysaccharide monooxygenases (LPMOs) are Cu-containing enzymes that facilitate the degradation of recalcitrant polysaccharides by the oxidative cleavage of glycosidic bonds. They are gaining rapidly increasing attention as key players in biomass conversion, especially for the production of second generation biofuels. Elucidation of the detailed mechanism of the LPMO reaction is a major step toward the assessment and optimization of LPMO efficacy in industrial biotechnology, paving the way to utilization of sustainable fuel sources. Here, we used density functional theory calculations to study the reaction pathways suggested to date, exploiting a very large active-site model for a fungal AA9 LPMO and using a celloheptaose unit as a substrate mimic. We identify a copper oxyl intermediate as being responsible for H-atom abstraction from the substrate, followed by a rapid, water-assisted hydroxyl rebound, leading to substrate hydroxylation. PMID- 29232120 TI - Statistically Enhanced Model of In Situ Oil Sands Extraction Operations: An Evaluation of Variability in Greenhouse Gas Emissions. AB - Greenhouse gas (GHG) emissions associated with extraction of bitumen from oil sands can vary from project to project and over time. However, the nature and magnitude of this variability have yet to be incorporated into life cycle studies. We present a statistically enhanced life cycle based model (GHOST-SE) for assessing variability of GHG emissions associated with the extraction of bitumen using in situ techniques in Alberta, Canada. It employs publicly available, company-reported operating data, facilitating assessment of inter- and intraproject variability as well as the time evolution of GHG emissions from commercial in situ oil sands projects. We estimate the median GHG emissions associated with bitumen production via cyclic steam stimulation (CSS) to be 77 kg CO2eq/bbl bitumen (80% CI: 61-109 kg CO2eq/bbl), and via steam assisted gravity drainage (SAGD) to be 68 kg CO2eq/bbl bitumen (80% CI: 49-102 kg CO2eq/bbl). We also show that the median emissions intensity of Alberta's CSS and SAGD projects have been relatively stable from 2000 to 2013, despite greater than 6-fold growth in production. Variability between projects is the single largest source of variability (driven in part by reservoir characteristics) but intraproject variability (e.g., startups, interruptions), is also important and must be considered in order to inform research or policy priorities. PMID- 29232121 TI - Selectively Targeting the Kinome-Conserved Lysine of PI3Kdelta as a General Approach to Covalent Kinase Inhibition. AB - Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is limited to ~200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kdelta inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer a general strategy, as an alternative to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors. PMID- 29232122 TI - Negative Zero-Field-Cooled Magnetization in YMn0.5Cr0.5O3 due to Giant Coercivity and Trapped Field. AB - We report an intensive study on negative magnetization under zero-field-cooled (ZFC) mode in YMn0.5Cr0.5O3 polycrystalline samples. It has been found that the magnetization reversal in ZFC measurements is strongly related to a giant coercivity of the oxide. The giant coercivity may result from the cooperative effect of magnetocrystalline anisotropy and the Dzyaloshinsky-Moriya interaction, especially at temperatures below 10 K. By fitting the high-temperature paramagnetic data under nominal zero field, the value of the trapped field in a superconducting magnet has been derived to be around several Oe, which further demonstrates that the negative ZFC magnetization is an artifact caused by negative trapped field in combination with the giant coercivity. Consequently, we suggest that one has to be cautious of trapped field in superconducting magnets in understanding negative ZFC magnetization, especially in "hard" magnetic samples. PMID- 29232123 TI - Dendrite-Free Li-Metal Battery Enabled by a Thin Asymmetric Solid Electrolyte with Engineered Layers. AB - The key bottleneck troubling the application of solid electrolyte is the contradictory requirements from Li-metal and cathode, which need high modulus to block Li-dendrite penetration and flexibility to enable low interface resistance, respectively. This study describes a thin asymmetrical design of solid electrolyte to address these shortcomings. In this architecture, a rigid ceramic layer modified with an ultrathin polymer is toward Li-metal to accomplish dendrite-suppression of Li-anode, and a soft polymer-layer spreads over the exterior and interior of cathode to endow connected interface simultaneously. This ingenious arrangement endows solid Li-metal batteries with extremely high Coulombic efficiency and cyclability. This work will open up one avenue for realizing safe and long-life energy storage systems. PMID- 29232124 TI - Mechanistic Studies on Tryptophan Lyase (NosL): Identification of Cyanide as a Reaction Product. AB - Tryptophan lyase (NosL) catalyzes the formation of 3-methylindole-2-carboxylic acid and 3-methylindole from l-tryptophan. In this paper, we provide evidence supporting a formate radical intermediate and demonstrate that cyanide is a byproduct of the NosL-catalyzed reaction with l-tryptophan. These experiments require a major revision of the NosL mechanism and uncover an unanticipated connection between NosL and HydG, the radical SAM enzyme that forms cyanide and carbon monoxide from tyrosine during the biosynthesis of the metallo-cluster of the [Fe-Fe] hydrogenase. PMID- 29232125 TI - Structural and Computational Insight into the Catalytic Mechanism of Limonene Epoxide Hydrolase Mutants in Stereoselective Transformations. AB - Directed evolution of limonene epoxide hydrolase (LEH), which catalyzes the hydrolytic desymmetrization reactions of cyclopentene oxide and cyclohexene oxide, results in (R,R)- and (S,S)-selective mutants. Their crystal structures combined with extensive theoretical computations shed light on the mechanistic intricacies of this widely used enzyme. From the computed activation energies of various pathways, we discover the underlying stereochemistry for favorable reactions. Surprisingly, some of the most enantioselective mutants that rapidly convert cyclohexene oxide do not catalyze the analogous transformation of the structurally similar cyclopentene oxide, as shown by additional X-ray structures of the variants harboring this slightly smaller substrate. We explain this puzzling observation on the basis of computational calculations which reveal a disrupted alignment between nucleophilic water and cyclopentene oxide due to the pronounced flexibility of the binding pocket. In contrast, in the stereoselective reactions of cyclohexene oxide, reactive conformations are easily reached. The unique combination of structural and computational data allows insight into mechanistic details of this epoxide hydrolase and provides guidance for future protein engineering in reactions of structurally different substrates. PMID- 29232126 TI - Alkali and Alkaline Earth Metal Derivatives of Disila-Bridged Podands: Coordination Chemistry and Structural Diversity. AB - Within this study, the synthesis and coordination chemistry of open-chain ligands bearing disila-units is presented. Instead of basic 1:1 complexes, structural diversity was discovered in the variety of ligand and salt. Stable complexes of alkali and alkaline earth metal complexes were obtained by equimolar reactions of different salts with the disila-bridged podands 8,9-disila-EO5 (1) and 11,12 disila-EO7 (2) (EO5 = pentaethylene glycol; EO7 = heptaethylene glycol). The respective alkaline earth metal complexes of the type [Ca(8,9-disila-EO5)(OTf)2] (3), [Sr(8,9-disila-EO5)I2] (5), [Sr(11,12-disila-EO7)I]I (6), and [Ba(11,12 disila-EO7)OTf2] (7) (OTf = CF3SO3-) were characterized via single-crystal X-ray diffraction analyses. Within the reaction of the alkali metal salt NaPF6 with 1, the sodium ion acts as a template during the complexation process. Under elimination of one molecule of diethylene glycol, the dinuclear species [Na2(8,9,17,18-tetrasila-EO8)(PF6)2].EO2 (4) (EO8 = octaethylen glycol, EO2 = diethylene glycol) is obtained, in which the sodium cations are 7-fold coordinated within a disilane-bearing framework. The reaction of 2 with CsOTf failed, leading to recrystallization of anhydrous CsOTf. By means of DFT calculations it was shown that the disila-bearing ligands are burdened with negative hyperconjugation interactions between the silicon and the oxygen atoms, but the coordination by sufficiently hard cations can easily overcompensate the competing polarization. In contrast, soft Lewis acids barely share interactions with silicon-bonded oxygen atoms. All findings are consistent with observations made in solution according to 29Si NMR spectroscopical studies. PMID- 29232128 TI - Mechanisms Underlying the Formation of Complexes between Maize Starch and Lipids. AB - This study aimed to reveal the mechanism of formation of complexes between native maize starch (NMS) and different types of lipids, namely palmitic acid (PA), monopalmitate glycerol (MPG), dipalmitate glycerol (DPG), and tripalmitate glycerol (TPG). The complexing index followed the order of MPG (96.3%) > PA (41.8%) > TPG (8.3%) > DPG (1.1%), indicating that MPG formed more complexes with NMS than PA, and that few complexes were formed between NMS and DPG and TPG. The NMS-PA complex presented higher thermal transition temperatures and lower enthalpy change than the NMS-MPG complex, indicating that although MPG formed more starch complexes, they had less stable crystalline structures than the complex between NMS and PA. X-ray diffraction (XRD) and Raman spectroscopy showed that both MPG and PA formed V-type crystalline structures with NMS, and confirmed that no complexes were formed between NMS and DPG and TPG. We conclude that the monoglyceride formed more starch-lipid complex with maize starch than PA, but that the monoglyceride complex had a less stable structure than that formed with PA. The di- and triglycerides did not form complexes with maize starch. PMID- 29232127 TI - Measurement of Fructose-Asparagine Concentrations in Human and Animal Foods. AB - The food-borne bacterial pathogen, Salmonella enterica, can utilize fructose asparagine (F-Asn) as its sole carbon and nitrogen source. F-Asn is the product of an Amadori rearrangement following the nonenzymatic condensation of glucose and asparagine. Heating converts F-Asn via complex Maillard reactions to a variety of molecules that contribute to the color, taste, and aroma of heated foods. Among these end derivatives is acrylamide, which is present in some foods, especially in fried potatoes. The F-Asn utilization pathway in Salmonella, specifically FraB, is a potential drug target because inhibition of this enzyme would lead to intoxication of Salmonella in the presence of F-Asn. However, F-Asn would need to be packaged with the FraB inhibitor or available in human foods. To determine if there are foods that have sufficient F-Asn, we measured F-Asn concentrations in a variety of human and animal foods. The 400 pmol/mg F-Asn found in mouse chow is sufficient to intoxicate a Salmonella fraB mutant in mouse models of salmonellosis, and several human foods were found to have F-Asn at this level or higher (fresh apricots, lettuce, asparagus, and canned peaches). Much higher concentrations (11 000-35 000 pmol/mg dry weight) were found in heat-dried apricots, apples, and asparagus. This report reveals possible origins of F-Asn as a nutrient source for Salmonella and identifies foods that could be used together with a FraB inhibitor as a therapeutic agent for Salmonella. PMID- 29232129 TI - Effect of Structural Modifications to Glyoxal-bis(thiosemicarbazonato)copper(II) Complexes on Cellular Copper Uptake, Copper-Mediated ATP7A Trafficking, and P Glycoprotein Mediated Efflux. AB - Bis(thiosemicarbazonato)copper(II) complexes are of interest as potential therapeutics for cancer and neurodegenerative diseases as well as imaging agents for positron emission tomography (PET). The cellular uptake of six bis(thiosemcarbazonato)copper(II)complexes derived from glyoxal, with different functional groups Cu(gtsx) where x = different functional groups, was investigated in SKOV-3, HEK293, and HEK293 P-gp cell lines. Treatment of the cells with the copper complexes increased intracellular copper and increased levels of p-ERK due to activation of the Ras-Raf-MEK-ERK pathway. Treatment of SKOV-3 cells with low concentrations (MUM) of two of the copper complexes led to trafficking of the endogenous copper transporter ATP7A from the Golgi network to the cell membrane. Experiments in HEK293 and HEK293-P-gp cells suggest that Cu(gtsm) and Cu(gtse) are substrates for the P-gp efflux protein but the complex with a pyrrolidine functional group, Cu(gtspyr), is not. A PET experiment in mice showed that [64Cu]Cu(gtspyr) has reasonable brain uptake but high liver uptake. PMID- 29232130 TI - Atom Transfer Radical Polymerization of Multishelled Cationic Corona for the Systemic Delivery of siRNA. AB - We propose an effective siRNA delivery system by preparing poly(DAMA-HEMA) multilayered gold nanoparticles using multiple surface-initiated atom transfer radical polymerization processes. The polymeric multilayer structure is characterized by transmission electron microscopy, matrix-associated laser desorption/ionization time-of-flight mass spectrometry, UV-vis spectroscopy, Fourier transform infrared spectroscopy, dynamic light scattering, and zeta potential. The amount of siRNA electrostatically incorporated into the nanoparticle can be tuned by the number of polymeric shells, which in turn influences the cellular uptake and gene silencing effect. In a bioreductive environment, the interlayer disulfide bond breaks to release the siRNA from the degraded polymeric shells. Intravenously injected c-Myc siRNA-incorporated particles accumulate in the tumor site of a murine lung carcinoma model and significantly suppress the tumor growth. Therefore, the combination of a size tunable AuNP core and an ATRP-functionalized shell offers control and versatility in the effective delivery of siRNA. PMID- 29232132 TI - Cobalt and Vanadium Trimetaphosphate Polyanions: Synthesis, Characterization, and Electrochemical Evaluation for Non-aqueous Redox-Flow Battery Applications. AB - An electrochemical cell consisting of cobalt ([CoII/III(P3O9)2]4-/3-) and vanadium ([VIII/II(P3O9)2]3-/4-) bistrimetaphosphate complexes as catholyte and anolyte species, respectively, was constructed with a cell voltage of 2.4 V and Coulombic efficiencies >90% for up to 100 total cycles. The [Co(P3O9)2]4- (1) and [V(P3O9)2]3- (2) complexes have favorable properties for flow-battery applications, including reversible redox chemistry, high stability toward electrochemical cycling, and high solubility in MeCN (1.09 +/- 0.02 M, [PPN]4[1].2MeCN; 0.77 +/- 0.06 M, [PPN]3[2].DME). The [PPN]4[1].2MeCN and [PPN]3[2].DME salts were isolated as crystalline solids in 82 and 68% yields, respectively, and characterized by 31P NMR, UV/vis, ESI-MS(-), and IR spectroscopy. The [PPN]4[1].2MeCN salt was also structurally characterized, crystallizing in the monoclinic P21/c space group. Treatment of 1 with [(p BrC6H4)3N]+ allowed for isolation of the one-electron-oxidized spin-crossover (SCO) complex, [Co(P3O9)2]3- (3), which is the active catholyte species generated during cell charging. The success of the 1-2 cell provides a promising entry point to a potential future class of transition-metal metaphosphate-based all inorganic non-aqueous redox-flow battery electrolytes. PMID- 29232131 TI - Quantitative Assessment of the Energetics of Dopamine Translocation by Human Dopamine Transporter. AB - Computational evaluation of the energetics of substrate binding, transport, and release events of neurotransmitter transporters at the molecular level is a challenge, as the structural transitions of these membrane proteins involve coupled global and local changes that span time scales of several orders of magnitude, from nanoseconds to seconds. Here, we provide a quantitative assessment of the energetics of dopamine (DA) translocation through the human DA transporter (hDAT), using a combination of molecular modeling, simulation, and analysis tools. DA-binding and -unbinding events, which generally involve local configurational changes, are evaluated using free-energy perturbation or adaptive biasing force methods. The global transitions between the outward-facing state and the inward-facing state, on the other hand, require a dual-boost accelerated molecular dynamics simulation. We present results on DA-binding/unbinding energetics under different conditions, as well as the conformational energy landscape of hDAT in both DA-bound and -unbound states. The study provides a tractable method of approach for quantitative evaluation of substrate-binding energetics and efficient estimation of conformational energy landscape, in general. PMID- 29232133 TI - Alkali-Metal Trihalides: M+X3- Ion Pair or MX-X2 Complex? AB - The alkali-metal trihalides MX3 (M = Li, Na, K, Rb, and Cs; X = Cl, Br, and I) are systematically studied using coupled-cluster methods. Benchmarks using CCSD(T) against diatomic experimental results suggest satisfactory performance for the weighted core-valence basis sets (new basis sets for K, Rb, and Cs) selected for predicting reliable structures and harmonic vibrational frequencies. An isomer search using the B3LYP functional yields a planar, yet asymmetric T shaped C s structure as the global minimum for all MX3 species. Much higher level CCSD(T) computations show a moderate to strong distortion of the X3- anion by the M+ cation in the respective equilibrium geometries. Most obviously, for LiCl3, the two Cl-Cl distances are separated by 0.786 A. Even for CsI3, the structure least distorted from the M+X3- model, the two I-I distances differ by 0.243 A. It does not take much energy to distort the parent anions along an antisymmetric stretch, so this is no surprise. The normal modes of vibration of the MX3 molecules are in better agreement with matrix isolation experiments than previous calculations. And these normal modes reveal that, instead of the well-established antisymmetric and symmetric stretches of the "free" X3- anions, relatively localized and mutually perturbed X-X and M-X stretches are calculated. The suggestion emerges that the MX3 system may be alternatively described as an MX-X2 complex rather than the M+X3- ion pair. This perspective is supported by bonding analyses showing low electron densities at the bond critical points and natural bond orders between the MX and X2 moieties. The thermochemistry of fragmentations of MX3 to MX + X2 versus M+ + X3- also supports the alternative viewpoint of the bonding in this class of molecules. PMID- 29232134 TI - Localization of Cholesterol within Supported Lipid Bilayers Made of a Natural Extract of Tailor-Deuterated Phosphatidylcholine. AB - Cholesterol is an essential component of mammalian membranes and is known to induce a series of physicochemical changes in the lipid bilayer. Such changes include the formation of liquid-ordered phases with an increased thickness and a configurational order as compared to liquid-disordered phases. For saturated lipid membranes, cholesterol molecules localize close to the lipid head group tail interface. However, the presence of polyunsaturated lipids was recently shown to promote relocation of cholesterol toward the inner interface between the two bilayer leaflets. Here, neutron reflection is used to study the location of cholesterol (both non-deuterated and per-deuterated versions are used) within supported lipid bilayers composed of a natural mixture of phosphatidylcholine (PC). The lipids were produced in a genetically modified strain of Escherichia coli and grown under specific deuterated conditions to give an overall neutron scattering length density (which depends on the level of deuteration) of the lipids matching that of D2O. The combination of solvent contrast variation method with specific deuteration shows that cholesterol is located closer to the lipid head group-tail interface in this natural PC extract rather than in the center of the core of the bilayer as seen for very thin or polyunsaturated membranes. PMID- 29232135 TI - Equilibrium in Protic Ionic Liquids: The Degree of Proton Transfer and Thermodynamic Properties. AB - The degree of proton transfer and thermodynamic parameters of six acetate-based protic ionic liquids (PILs) were measured using nuclear magnetic resonance spectroscopy and calculated by van't Hoff analytical method, respectively. The degree of proton transfer of these PILs at 298 K spread over a large range, which is from 39.6% (1-methylpyrrolidinium acetate, [MpyrH][AcO]) to 94.4% (1 butylimidazolium acetate, [BuimH][AcO]). The calculated standard enthalpy change of the reaction (DeltarHmtheta) is from -23.30 to -7.80 kJ mol-1 and the standard entropy change of the reaction (DeltarSmtheta) is from -42.70 to -8.07 J mol-1 K 1. The correlation between the degree of proton transfer and aqueous DeltapKa or DeltarHmtheta was investigated as well. Furthermore, in some special cases, DeltarSmtheta, especially the entropy change of symmetry, also plays an important role in affecting the degree of proton transfer. PMID- 29232136 TI - Insights into Solid-Electrolyte Interphase Induced Li-Ion Degradation from in Situ Auger Electron Spectroscopy. AB - Surface reactions occurring on LiMn2O4, LiCoO2, LiNiO2, Li[Ni1/3Mn1/3Co1/3]O2, and LiFePO4 during charging and overcharging are studied by in situ and ex situ Auger electron spectroscopy. Carbon surface stability at the cathode solid electrolyte interphase (SEI), associated with carbonate formation, decomposition, and CO/CO2 evolution, on different electrodes during cycling correlates with their cycle life. To understand how associated CO and CO2 evolution affects cycle stability, LiMn2O4 is cycled in flowing gas. Flowing Ar enhances cycle life by a factor of 2, while flowing Ar with 1% CO2 reduces cycle life by a factor of 2. CO2 is proposed to degrade cycle life by trapping Li and metal ions as carbonate in the anode SEI. PMID- 29232137 TI - Inhibition of Human CYP3A4 by Rationally Designed Ritonavir-Like Compounds: Impact and Interplay of the Side Group Functionalities. AB - Structure-function relationships of nine rationally designed ritonavir-like compounds were investigated to better understand the ligand binding and inhibitory mechanism in human drug-metabolizing cytochrome P450 3A4 (CYP3A4). The analogs had a similar backbone and pyridine and tert-butyloxycarbonyl (Boc) as the heme-ligating and terminal groups, respectively. N-Isopropyl, N-cyclopentyl, or N-phenyl were the R1-side group substituents alone (compounds 5a-c) or in combination with phenyl or indole at the R2 position (8a-c and 8d-f subseries, respectively). Our experimental and structural data indicate that (i) for all analogs, a decrease in the dissociation constant (Ks) coincides with a decrease in IC50, but no relation with other derived parameters is observed; (ii) an increase in the R1 volume, hydrophobicity, and aromaticity markedly lowers Ks and IC50, whereas the addition of aromatic R2 has a more pronounced positive effect on the inhibitory potency than the binding strength; (iii) the ligands' association mode is strongly influenced by the mutually dependent R1-R2 interplay, but the R1-mediated interactions are dominant and define the overall conformation in the active site; (iv) formation of a strong H-bond with Ser119 is a prerequisite for potent CYP3A4 inhibition; and (v) the strongest inhibitor in the series, the R1-phenyl/R2-indole containing 8f (Ks and IC50 of 0.08 and 0.43 MUM, respectively), is still less potent than ritonavir, even under conditions that prevent the mechanism based inactivation of CYP3A4. Crystallographic data were essential for better understanding and interpretation of the experimental results, and suggested how the inhibitor design could be further optimized. PMID- 29232138 TI - Aufbau Rules for Solvated Electron Precursors: Be(NH3)40,+/- Complexes and Beyond. AB - Tetra-amino beryllium complexes and ions, Be(NH3)40,+/-, have a tetrahedral Be(NH3)42+ core with one, two, or three outer electrons orbiting its periphery. Our calculations reveal a new class of molecular entities, solvated electron precursors, with Aufbau rules (1s, 1p, 1d, 2s, 1f, 2p, 2d) that differ from their familiar hydrogenic counterparts and resemble those of jellium or nuclear-shell models. The core's radial electrostatic potential suffices to reproduce the chief features of the ab initio results. Wave function and electron-propagator methods combined with diffuse basis sets are employed to calculate accurate geometries, ionization energies, electron affinities, and excitation energies. PMID- 29232139 TI - Distinguishing Surface versus Bulk Hydroxyl Groups of Cellulose Nanocrystals Using Vibrational Sum Frequency Generation Spectroscopy. AB - In plant cell walls and cellulose-containing composites, nanocrystalline cellulose interacts with water molecules or matrix polymers through hydrogen bonding of the hydroxyl groups at the cellulose surface. These interactions play key roles in cellulose assembly in plant cell walls and mechanical properties of cellulose composites; however, they could not be studied properly due to the spectroscopic difficulty of selectively detecting the surface hydroxyl groups of nanocrystalline domains. This study employed the sum frequency scattering principle to distinguish the hydroxyl groups inside of the crystalline nanodomain of cellulose and those exposed at the surface of crystalline domains. The comparison of the spectra at various scattering angles revealed that the OH peak near ~3450 cm-1 comes from the weakly hydrogen-bonded OH groups at the surface of crystalline cellulose. Also, a time delay measurement found that the sharp vibrational features observed near 3700 cm-1 can be attributed to isolated OH groups not accessible by ambient water molecules. These findings allow the distinction of surface versus bulk OH groups in sum frequency generation vibrational spectroscopy. PMID- 29232140 TI - Structural Dependence of Salt-Responsive Polyzwitterionic Brushes with an Anti Polyelectrolyte Effect. AB - Some polyzwitterionic brushes exhibit a strong "anti-polyelectrolyte effect" and ionic specificity that make them versatile platforms to build smart surfaces for many applications. However, the structure-property relationship of zwitterionic polymer brushes still remains to be elucidated. Herein, we aim to study the structure-dependent relationship between different zwitterionic polymers and the anti-polyelectrolyte effect. To this end, a series of polyzwitterionic brushes with different cationic moieties (e.g., imidazolium, ammonium, and pyridinium) in their monomeric units and with different carbon spacer lengths (e.g., CSL = 1, 3, and 4) between the cation and anion were designed and synthesized to form polymer brushes via the surface-initiated atom transfer radical polymerization. All zwitterionic brushes were carefully characterized for their surface morphologies, compositions, wettability, and film thicknesses by atomic force microscopy, contact angle measurement, and ellipsometry, respectively. The salt responsiveness of all zwitterionic brushes to surface hydration and friction was further examined and compared both in water and in salt solutions with different salt concentrations and counterion types. The collective data showed that zwitterionic brushes with different cationic moieties and shorter CSLs in salt solution induced higher surface friction and lower surface hydration than those in water, exhibiting strong anti-polyelectrolyte effect salt-responsive behaviors. By tuning the CSLs, cationic moieties, and salt concentrations and types, the surface wettability can be changed from a highly hydrophobic surface (~60 degrees ) to a highly hydrophilic surface (~9 degrees ), while interfacial friction can be changed from ultrahigh friction (MU ~ 4.5) to superior lubrication (MU ~ 10-3). This work provides important structural insights into how subtle structural changes in zwitterionic polymers can yield great changes in the salt-responsive properties at the interface, which could be used for the development of smart surfaces for different applications. PMID- 29232141 TI - ZSM-5 Zeolite: Complete Al Bond Connectivity and Implications on Structure Formation from Solid-State NMR and Quantum Chemistry Calculations. AB - Al site distribution in the structurally complex and industrially important ZSM-5 zeolite is determined by studying the spectroscopic response of Al(OSi)4 units and using a self-consistent combination of up-to-date solid-state NMR correlations (29Si-27Al and 1H-27Al D-HMQC) and quantum chemistry methods (DFT D). To unravel the driving forces behind specific Al sitting positions, our approach focuses on ZSM-5 containing its more efficient OSDA, tetrapropylammonium. PMID- 29232143 TI - Heterogeneous Capillary Interactions of Interface-Trapped Ellipsoid Particles Using the Trap-Release Method. AB - Heterogeneous capillary interactions between ellipsoid particles at the oil-water interface were measured via optical laser tweezers. Two trapped particles were aligned in either tip-to-tip (tt) or side-to-side (ss) configurations via the double-trap method and were released from the optical traps, leading to particle particle attractions due to the capillary forces caused by quadrupolar interface deformation. On the basis of image analysis and calculations of the Stokes drag force, the capillary interactions between two ellipsoid particles with the same aspect ratio (E) were found to vary with the particle pairs that were measured, indicating that the interactions were nondeterministic or heterogeneous. Heterogeneous capillary interactions could be attributed to undulation of the interface meniscus due to chemical and/or geometric particle heterogeneity. The power law exponent for the capillary interaction Ucap ~ r-beta was found to be beta ~ 4 and was independent of the aspect ratio and particle configuration in long-range separations. Additionally, with regard to the tt configuration, the magnitude of the capillary force proportionally increased with the E value (E > 1) when two ellipsoid particles approached each other in the tt configuration. PMID- 29232144 TI - Interactions between Surface-Immobilized Antimicrobial Peptides and Model Bacterial Cell Membranes. AB - Sum frequency generation (SFG) vibrational spectroscopy was used to study surface immobilization effects on the interactions between antimicrobial peptide cecropin P1 (CP1) and model cell membranes. While free CP1 in solution interacted with a model cell membrane composed of a phosphatidylglycerol (PG) bilayer, electrostatic interaction led to the attachment of CP1 molecules onto the PG surface and the hydrophobic domain in the lipid bilayer enabled the peptides to insert into the bilayer and form alpha-helices from random coil structures. While CP1 molecules immobilized on a self-assembled monolayer interacted with PG lipid vesicles, the intensity of the SFG peak for the peptide alpha-helix decreased as the PG vesicle concentration increased. It was believed that when surface immobilized CP1 molecules interacted with lipid vesicles, they lay down on the surface or became random coils. When the immobilized CP1 interacted with a PG lipid monolayer on water, the strong interaction led to the lying-down orientation of all of the surface-immobilized peptides as well. Differently, no significant interactions between surface-immobilized CP1 with the mammalian cell membrane model 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer were observed. Our results suggest that, instead of membrane insertion, the electrostatic interactions between the surface cationic charges of CP1 and anionic bacterial membranes may play an important role in the antimicrobial activity of the surface-immobilized CP1 peptide. PMID- 29232142 TI - Janus Iron Oxides @ Semiconducting Polymer Nanoparticle Tracer for Cell Tracking by Magnetic Particle Imaging. AB - Iron oxides nanoparticles tailored for magnetic particle imaging (MPI) have been synthesized, and their MPI signal intensity is three-times that of commercial MPI contrast (Ferucarbotran, also called Vivotrax) and seven-times that of MRI contrast (Feraheme) at the same Fe concentration. MPI tailored iron oxide nanoparticles were encapsulated with semiconducting polymers to produce Janus nanoparticles that possessed optical and magnetic properties for MPI and fluorescence imaging. Janus particles were applied to cancer cell labeling and in vivo tracking, and as few as 250 cells were imaged by MPI after implantation, corresponding to an amount of 7.8 ng of Fe. Comparison with MRI and fluorescence imaging further demonstrated the advantages of our Janus particles for MPI-super sensitivity, unlimited tissue penetration, and linear quantitativity. PMID- 29232145 TI - Patterning Conjugated Polymers by Laser: Synergy of Nanostructure Formation in the All-Polymer Heterojunction P3HT/PCDTBT. AB - In this work we report a broad scenario for the patterning of semiconducting polymers by laser-induced periodic surface structures (LIPSS). Based on the LIPSS formation in the semicrystalline poly(3-hexylthiophene) (P3HT), we have extended the LIPSS fabrication to an essentially amorphous semiconducting polymer like poly[N-90-heptadecanyl-2,7-carbazole-alt-5,5-(40,70-di-2-thienyl-20,10,30 benzothiadiazole)] (PCDTBT). This polymer shows a good quality and well-ordered nanostructures not only at the 532 nm laser wavelength, as in the case of P3HT, but also at 266 nm providing gratings with smaller pitch. In addition, we have proven the feasibility of fabricating LIPSS in the P3HT/PCDTBT (1:1) blend, which can be considered as a model bulk-heterojunction for all-polymer solar cells. In spite of the heterogeneous roughness, due to phase separation in the blend, both P3HT and PCDTBT domains present well-defined LIPSS as well as a synergy for both components in the blend when irradiating at wavelengths of 532 and 266 nm. Both, P3HT and PCDTBT in the blend require lower fluence and less pulses in order to optimize LIPSS morphology than in the case of irradiating the homopolymers separately. Near edge X-ray absorption fine structure and Raman spectroscopy reveal a good chemical stability of both components in the blend thin films during LIPSS formation. In addition, scanning transmission X-ray spectro microscopy shows that the mechanisms of LIPSS formation do not induce a further phase segregation neither a mixture of the components. Conducting atomic force microscopy reveals a heterogeneous electrical conductivity for the irradiated homopolymer and for the blend thin films, showing higher electrical conduction in the trenches than in the ridge regions of the LIPSS. PMID- 29232146 TI - Switchable Photoacoustic Intensity of Methylene Blue via Sodium Dodecyl Sulfate Micellization. AB - The interaction between methylene blue (MB) and sodium dodecyl sulfate (SDS) has been widely studied spectroscopically, but details about their interactions remain unclear. Here, we combined photoacoustic (PA) imaging with nanoparticle tracking analysis (NTA) and spectroscopy to further elucidate this interaction. PA imaging of 0.05 mM MB showed a 492-fold increase in intensity upon the addition of 3.47 mM SDS. Higher concentrations above SDS's critical micelle concentration (CMC) at 8.67 mM decreased the PA intensity by 54 times. Relative quantum yield measurements indicated that PA intensity increased as a result of fluorescence quenching. Meanwhile, NTA indicated an increased number of nonmicellar MB/SDS clusters at SDS concentrations below the CMC varying in size from 80 to 400 nm as well as a decreased number above the CMC. This trend suggested that MB/SDS clusters are responsible for the PA intensity enhancement. Comparison of PA intensities and spectral shifts with MB/hexadecyltrimethylammonium bromide, MB/sodium octyl sulfate, and MB/sodium chloride demonstrated that MB was bound to the sulfate moiety of SDS before and after micellization. Our observations suggest that MB forms aggregates with SDS at premicellar concentrations, and the MB aggregates disassociate as monomers that are bound to the sulfate moiety of SDS at micellar concentrations. These findings further clarify the process by which MB and SDS interact and demonstrate the potential for developing MB-/SDS-based contrast agents. PMID- 29232147 TI - Incorporation of mRNA in Lamellar Lipid Matrices for Parenteral Administration. AB - Insertion of high molecular weight messenger RNA (mRNA) into lyotropic lipid phases as model systems for controlled release formulations for the mRNA was investigated. Low fractions of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) were used as an anchor to load the mRNA into a lamellar lipid matrix. Dispersions of zwitterionic lipid in the aqueous phase in the presence of increasing fractions of mRNA and cationic lipid were prepared, and the molecular organization was investigated as a function of mRNA and cationic lipid fraction. Insertion of both cationic lipid and mRNA was clearly proven from the physicochemical characteristics. The d-spacing of the lipid bilayers, as determined by small-angle X-ray scattering (SAXS) measurements, responded sensitively to the amount of inserted DOTAP and mRNA. A concise model of the insertion of the mRNA in the lipid matrices was derived, indicating that the mRNA was accommodated in the aqueous slab between lipid bilayers. Depending on the DOTAP and mRNA fraction, a different excess of water was present in this slab. Results from further physicochemical characterization, including determination of free and bound mRNA, zeta potential, and calorimetry data, were in line with this assumption. The structure of these concentrated lipid/mRNA preparations was maintained upon dilution. The functionality of the inserted mRNA was proven by cell culture experiments using C2C12 murine myoblast cells with the luciferase encoding mRNA. The described lipid phases as carriers for the mRNA may be applicable for different routes of local administration, where control of the release kinetics and the form of the released mRNA (bound or free) is required. PMID- 29232148 TI - Synthesis of the Tetracyclic Structure of Batrachotoxin Enabled by Bridgehead Radical Coupling and Pd/Ni-Promoted Ullmann Reaction. AB - The steroidal ABCD-ring system of the potent neurotoxin batrachotoxin was efficiently assembled in a convergent fashion. Bridgehead radical coupling between the simple AB-ring and D-ring fragments (3 and 4) formed the sterically congested linkage at the C9-oxygen-attached tetrasubstituted carbon. The C-ring was then cyclized by the Pd/Ni-promoted Ullmann reaction of the vinyl triflate and vinyl bromide of 19, giving rise to tetracyclic structure 1. PMID- 29232149 TI - Synthesis of Unsymmetrical Aza-Ullazines by Intramolecular Alkynyl-Carbonyl Metathesis. AB - A variety of aza-ullazines were synthesized in one step from readily accessible 3,5-dialkynyl-4-pyrrolopyridine via acylation followed by intramolecular alkynyl carbonyl metathesis. The reaction conditions were optimized, and the preparative scope was studied. The optoelectronic properties of selected aza-ullazines were studied by UV/vis and fluorescence spectroscopy. PMID- 29232150 TI - Unusual Ferroelectricity in Two-Dimensional Perovskite Oxide Thin Films. AB - Two-dimensional (2D) ferroelectricity have attracted much attention due to their applications in novel miniaturized devices such as nonvolatile memories, field effect transistors, and sensors. Since most of the commercial ferroelectric (FE) devices are based on ABO3 perovskite oxides, it is important to investigate the properties of 2D ferroelectricity in perovskite oxide thin films. Here, based on density functional theory (DFT) calculations, we find that there exist three kinds of in-plane FE states that originate from different microscopic mechanisms: (i) a proper FE state with the polarization along [110] due to the second-order Jahn-Teller effect related to the B ion with empty d-orbitals; (ii) a robust FE state with the polarization along [100] induced by the surface effect; (iii) a hybrid improper FE state with the polarization along [110] that is induced by the trilinear coupling between two rotational modes and the A-site displacement. Interestingly, the ferroelectricity in the latter two cases becomes stronger along with decreasing the thin film thickness, in contrast to the usual behavior. Moreover, the latter two FE states are compatible with magnetism since their stability does not depend on the occupation of the d-orbitals of the B-ion. These two novel 2D FE mechanisms provide new avenues to design 2D multiferroics, as we demonstrated in SrVO and CaFeO thin film cases. Our work not only reveals new physical mechanisms of 2D ferroelectricity in perovskite oxide thin films but also provides a new route to design the high-performance 2D FE and multiferroics. PMID- 29232152 TI - Flash Glucose Monitoring in Younger Individuals with Diabetes: Accuracy and Patient Experience in Real-World Settings. PMID- 29232154 TI - Translating Research into Health Policy: Stock Albuterol Legislation. PMID- 29232153 TI - Respiratory Responses to Ozone Exposure. MOSES (The Multicenter Ozone Study in Older Subjects). AB - RATIONALE: Acute respiratory effects of low-level ozone exposure are not well defined in older adults. OBJECTIVES: MOSES (The Multicenter Ozone Study in Older Subjects), although primarily focused on acute cardiovascular effects, provided an opportunity to assess respiratory responses to low concentrations of ozone in older healthy adults. METHODS: We performed a randomized crossover, controlled exposure study of 87 healthy adults (59.9 +/- 4.5 yr old; 60% female) to 0, 70, and 120 ppb ozone for 3 hours with intermittent exercise. Outcome measures included spirometry, sputum markers of airway inflammation, and plasma club cell protein-16 (CC16), a marker of airway epithelial injury. The effects of ozone exposure on these outcomes were evaluated with mixed-effect linear models. A P value less than 0.01 was chosen a priori to define statistical significance. MEASUREMENTS AND MAIN RESULTS: The mean (95% confidence interval) FEV1 and FVC increased from preexposure values by 2.7% (2.0-3.4) and 2.1% (1.3-2.9), respectively, 15 minutes after exposure to filtered air (0 ppb). Exposure to ozone reduced these increases in a concentration-dependent manner. After 120-ppb exposure, FEV1 and FVC decreased by 1.7% (1.1-2.3) and 0.8% (0.3-1.3), respectively. A similar concentration-dependent pattern was still discernible 22 hours after exposure. At 4 hours after exposure, plasma CC16 increased from preexposure levels in an ozone concentration-dependent manner. Sputum neutrophils obtained 22 hours after exposure showed a marginally significant increase in a concentration-dependent manner (P = 0.012), but proinflammatory cytokines (IL-6, IL-8, and tumor necrosis factor-alpha) were not significantly affected. CONCLUSIONS: Exposure to ozone at near ambient levels induced lung function effects, airway injury, and airway inflammation in older healthy adults. Clinical trial registered with www.clinicaltrials.gov (NCT01487005). PMID- 29232151 TI - Adjuvanted influenza vaccines. AB - In spite of current influenza vaccines being immunogenic, evolution of the influenza virus can reduce efficacy and so influenza remains a major threat to public health. One approach to improve influenza vaccines is to include adjuvants; substances that boost the immune response. Adjuvants are particularly beneficial for influenza vaccines administered during a pandemic when a rapid response is required or for use in patients with impaired immune responses, such as infants and the elderly. This review outlines the current use of adjuvants in human influenza vaccines, including what they are, why they are used and what is known of their mechanism of action. To date, six adjuvants have been used in licensed human vaccines: Alum, MF59, AS03, AF03, virosomes and heat labile enterotoxin (LT). In general these adjuvants are safe and well tolerated, but there have been some rare adverse events when adjuvanted vaccines are used at a population level that may discourage the inclusion of adjuvants in influenza vaccines, for example the association of LT with Bell's Palsy. Improved understanding about the mechanisms of the immune response to vaccination and infection has led to advances in adjuvant technology and we describe the experimental adjuvants that have been tested in clinical trials for influenza but have not yet progressed to licensure. Adjuvants alone are not sufficient to improve influenza vaccine efficacy because they do not address the underlying problem of mismatches between circulating virus and the vaccine. However, they may contribute to improved efficacy of next-generation influenza vaccines and will most likely play a role in the development of effective universal influenza vaccines, though what that role will be remains to be seen. PMID- 29232156 TI - Short-Term Effects of the Prone Positioning Maneuver on Lung and Chest Wall Mechanics in Patients with Acute Respiratory Distress Syndrome. PMID- 29232158 TI - Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update Summary. PMID- 29232159 TI - Zika-associated Shock and Multiorgan Dysfunction: A Comment. PMID- 29232157 TI - Bacterial Dissemination to the Brain in Sepsis. AB - RATIONALE: Sepsis causes brain dysfunction and neuroinflammation. It is unknown whether neuroinflammation in sepsis is initiated by dissemination of bacteria to the brain and sustained by persistent infection, or whether neuroinflammation is a sterile process resulting solely from circulating inflammatory mediators. OBJECTIVES: To determine if gut bacteria translocate to the brain during sepsis, and are associated with neuroinflammation. METHODS: Murine sepsis was induced using cecal ligation and puncture, and sepsis survivor mice were compared with sham and unoperated control animals. Brain tissue of patients who died of sepsis was compared with patients who died of noninfectious causes. Bacterial taxa were characterized by 16S ribosomal RNA gene sequencing in both murine and human brain specimens; compared among sepsis and nonsepsis groups; and correlated with levels of S100A8, a marker of neuroinflammation using permutational multivariate ANOVA. MEASUREMENTS AND MAIN RESULTS: Viable gut-associated bacteria were enriched in the brains of mice 5 days after surviving abdominal sepsis (P < 0.01), and undetectable by 14 days. The community structure of brain-associated bacteria correlated with severity of neuroinflammation (P < 0.001). Furthermore, bacterial taxa detected in brains of humans who die of sepsis were distinct from those who died of noninfectious causes (P < 0.001) and correlated with S100A8/A9 expression (P < 0.05). CONCLUSIONS: Although bacterial translocation is associated with acute neuroinflammation in murine sepsis, bacterial translocation did not result in chronic cerebral infection. Postmortem analysis of patients who die of sepsis suggests a role for bacteria in acute brain dysfunction in sepsis. Further work is needed to determine if modifying gut-associated bacterial communities modulates brain dysfunction after sepsis. PMID- 29232161 TI - Characterization of Novel Missense Variants of SERPINA1 Gene Causing Alpha-1 Antitrypsin Deficiency. AB - The SERPINA1 gene is highly polymorphic, with more than 100 variants described in databases. SERPINA1 encodes the alpha-1 antitrypsin (AAT) protein, and severe deficiency of AAT is a major contributor to pulmonary emphysema and liver diseases. In Spanish patients with AAT deficiency, we identified seven new variants of the SERPINA1 gene involving amino acid substitutions in different exons: PiSDonosti (S+Ser14Phe), PiTijarafe (Ile50Asn), PiSevilla (Ala58Asp), PiCadiz (Glu151Lys), PiTarragona (Phe227Cys), PiPuerto Real (Thr249Ala), and PiValencia (Lys328Glu). We examined the characteristics of these variants and the putative association with the disease. Mutant proteins were overexpressed in HEK293T cells, and AAT expression, polymerization, degradation, and secretion, as well as antielastase activity, were analyzed by periodic acid-Schiff staining, Western blotting, pulse-chase, and elastase inhibition assays. When overexpressed, S+S14F, I50N, A58D, F227C, and T249A variants formed intracellular polymers and did not secrete AAT protein. Both the E151K and K328E variants secreted AAT protein and did not form polymers, although K328E showed intracellular retention and reduced antielastase activity. We conclude that deficient variants may be more frequent than previously thought and that their discovery is possible only by the complete sequencing of the gene and subsequent functional characterization. Better knowledge of SERPINA1 variants would improve diagnosis and management of individuals with AAT deficiency. PMID- 29232160 TI - MicroRNA-145 Antagonism Reverses TGF-beta Inhibition of F508del CFTR Correction in Airway Epithelia. AB - RATIONALE: MicroRNAs (miRNAs) destabilize mRNA transcripts and inhibit protein translation. miR-145 is of particular interest in cystic fibrosis (CF) as it has a direct binding site in the 3'-untranslated region of CFTR (cystic fibrosis transmembrane conductance regulator) and is upregulated by the CF genetic modifier TGF (transforming growth factor)-beta. OBJECTIVES: To demonstrate that miR-145 mediates TGF-beta inhibition of CFTR synthesis and function in airway epithelia. METHODS: Primary human CF (F508del homozygous) and non-CF airway epithelial cells were grown to terminal differentiation at the air-liquid interface on permeable supports. TGF-beta (5 ng/ml), a miR-145 mimic (20 nM), and a miR-145 antagonist (20 nM) were used to manipulate CFTR function. In CF cells, lumacaftor (3 MUM) and ivacaftor (10 MUM) corrected mutant F508del CFTR. Quantification of CFTR mRNA, protein, and function was done by standard techniques. MEASUREMENTS AND MAIN RESULTS: miR-145 is increased fourfold in CF BAL fluid compared with non-CF (P < 0.01) and increased 10-fold in CF primary airway epithelial cells (P < 0.01). Exogenous TGF-beta doubles miR-145 expression (P < 0.05), halves wild-type CFTR mRNA and protein levels (P < 0.01), and nullifies lumacaftor/ivacaftor F508del CFTR correction. miR-145 overexpression similarly decreases wild-type CFTR protein synthesis (P < 0.01) and function (P < 0.05), and eliminates F508del corrector benefit. miR-145 antagonism blocks TGF beta suppression of CFTR and enhances lumacaftor correction of F508del CFTR. CONCLUSIONS: miR-145 mediates TGF-beta inhibition of CFTR synthesis and function in airway epithelia. Specific antagonists to miR-145 interrupt TGF-beta signaling to restore F508del CFTR modulation. miR-145 antagonism may offer a novel therapeutic opportunity to enhance therapeutic benefit of F508del CFTR correction in CF epithelia. PMID- 29232162 TI - Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also Using Insulin Glargine: SORELLA 2 Study. AB - BACKGROUND: SAR342434 (SAR-Lis) is a biosimilar (follow-on) of insulin lispro (U100; Humalog(r); Ly-Lis). This study aimed to show similar efficacy, safety, and immunogenicity of SAR-Lis versus Ly-Lis in adult patients with type 2 diabetes mellitus (T2DM) treated with multiple daily injections, while using insulin glargine (GLA-100; Lantus(r)) as basal insulin. METHODS: SORELLA 2 was a 6-month, randomized, open-label, Phase 3 study (NCT02294474). Insulin doses were adjusted to achieve fasting and 2-h postprandial glucose targets according to American Diabetes Association guidelines. Primary endpoint was the HbA1c change from baseline to week 26 (tested for noninferiority of SAR-Lis vs. Ly-Lis with a margin of 0.3%). Secondary endpoints included fasting plasma glucose (FPG), seven point self-monitored plasma glucose (SMPG) profiles, hypoglycemic events, treatment-emergent adverse events (TEAEs), and anti-insulin antibodies (AIA). RESULTS: A total of 505 patients were randomized (1:1) to multiple daily injections of SAR-Lis (n = 253) or Ly-Lis (n = 252) plus once-daily GLA-100. Least square (LS) mean (standard error) change in HbA1c from baseline to week 26 was similar in both treatment groups (SAR-Lis, -0.92% [0.051] and Ly-Lis, -0.85% [0.051]). Noninferiority at prespecified 0.3% noninferiority margin was demonstrated (LS mean difference of SAR-Lis vs. Ly-Lis: -0.07% [95% CI: -0.215 to 0.067]) as was inverse noninferiority. Similar changes in FPG, seven-point SMPG profiles, including postprandial glucose excursions and mean glucose over 24 h, and insulin dosages were observed in the two groups. Hypoglycemia, TEAEs, and AIA (incidence and prevalence) did not differ between groups. CONCLUSIONS: Results from this controlled study in patients with T2DM also using GLA-100 support similar efficacy and safety (including immunogenicity) of SAR-Lis and Ly-Lis. PMID- 29232163 TI - Application of mine water leaching protocol on coal fly ash to assess leaching characteristics for suitability as a mine backfill material. AB - Over the years, coal mining in the Mpumalanga Province of South Africa has negatively affected the environment by causing pollution of water resources, land subsidence and spontaneous coal combustion. Previous studies show that in-situ treatment of acid mine drainage (AMD) using coal fly ash (CFA) from local power stations was possible and sludge recovered out of such treatment can be used to backfill mines. In this article, the authors have attempted to understand the leaching characteristics of CFA when placed underground as a backfill material using the mine water leaching protocol (MWLP). The results show that the migration of contaminants between the coal fly ash and the AMD in the mine voids depends on the pH and quality of the mine water. While backfilling mine voids with CFA can neutralize and scavenge between 50% and 95% of certain environmentally sensitive elements from AMD such as Fe, Al, Zn, Cu, Ni, Co and Mn. At this moment, it is also important to point out that certain scavenged/removed contaminants from the AMD during initial phases of backfilling can be remobilized by the influx of acidic water into the mine voids. It has therefore been concluded that, while CFA can be used to backfill mine voids, the influx of fresh acidic mine water should be avoided to minimize the remobilization of trapped contaminants such as Fe, Al, Mn and As. However, the pozzolanic material resulting from the CFA-AMD interaction could prevent such influx. PMID- 29232164 TI - Effect of CT on Management Plan in Malleolar Ankle Fractures. AB - BACKGROUND: Conventionally ankle fractures have been classified using plain radiographs. Because of complex 3-dimensional anatomy and complexity of injuries, plain radiographs may not always be able to clearly depict the complete fracture pattern. There is a paucity of studies regarding the utility of computed tomography (CT) scanning in malleolar ankle fractures (MAFs). Hence, we conducted this study to further understand the role of the CT scan in MAFs. METHODS: A prospective study of 56 consecutive malleolar ankle fractures was conducted. In the first evaluation by a team of 3 observers, a management plan was made based on plain radiographs. All patients received a CT scan evaluation with a standard protocol. The second evaluation by the same team included formulating an operative plan based on the CT. RESULTS: In 13 (23.2%) cases, the management plan changed after CT evaluation. In most of the cases, the change in the management plan included an alteration in fixation of the posterior malleolus followed by lateral malleolus in 4 cases. Most of the changes took place in AO 44 type C followed by types B and A. Maximum change was noted in trimalleolar fractures followed by bimalleolar and unimalleolar. The most common morphological characteristic fracture identified on CT scan that was not evident on plain radiography was Chaput fracture in 17 cases. CONCLUSION: CT scan evaluation of MAFs changed the management plan in a significant number of cases, especially if the fractured fragment included a posterior malleolus, AO type C, and/or if 2 or more malleoli were fractured as noted on plain x rays. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29232165 TI - Reply: Zika-associated Shock and Multiorgan Dysfunction. PMID- 29232166 TI - Revisiting knowledge, attitudes and practice (KAP) on human papillomavirus (HPV) vaccination among female university students in Hong Kong. AB - Despite cervical cancer can be preventable by HPV vaccination, little is known on its associated factors among young females in Hong Kong. This study aimed to investigate the present situation regarding the self-reported knowledge, attitudes and practice (KAP) of Human Papillomavirus (HPV) vaccination and to examine their associated factors among female university students in Hong Kong. 195 respondents were recruited to complete a self-administered questionnaire from two local universities through convenience sampling. 8.2% respondents indicated that family doctors as sources of knowledge of HPV and HPV vaccination. 59.0% of the sample identified more than four knowledge items, 82.6% thought that HPV vaccines can effectively prevent cervical cancer and 47.2% received HPV vaccination. Regression analyses found those at older age, thought that they might be infected by HPV and received HPV would have a higher level of knowledge. Those who knew HPV is sexually transmitted, thought may be infected by HPV and received HPV vaccination would have positive attitude on HPV vaccination. Those at older ages, knew their university provided discounted vaccination for female students, and were not afraid of the side effects were associated with HPV vaccination. Family doctors should take a more prominent role in disseminating accurate and precise information. Advocacies should be emphasised on the risk of HPV as a sexually transmitted disease and the availability of discounted and safe HPV vaccines in tertiary educational institutions to increase the uptake rate of HPV vaccines for first-year and non-health major university students. PMID- 29232167 TI - Tigecycline Susceptibility of Klebsiella pneumoniae Complex and Escherichia coli Isolates from Companion Animals: The Prevalence of Tigecycline-Nonsusceptible K. pneumoniae Complex, Including Internationally Expanding Human Pathogenic Lineages. AB - Transmission of tigecycline-nonsusceptible pathogenic Enterobacteriaceae from companion animals to human should be a concern because tigecycline is a last-line drug for treating multidrug-resistant Enterobacteriaceae in human medicine. However, tigecycline susceptibility of Enterobacteriaceae isolated from companion animals has not been investigated. In this study, we investigated the tigecycline susceptibility of Klebsiella pneumoniae complex and Escherichia coli isolates from dogs and cats, and evaluated their human pathogenicity potential. Tigecycline susceptibility of K. pneumoniae, including Klebsiella quasipneumoniae (n = 86) and E. coli (n = 100) strains isolated from dogs and cats was investigated. The antimicrobial susceptibility, capsular serotype, multilocus sequence type, ompK36 group, presence of virulence genes, and serum resistance of tigecycline-nonsusceptible isolates were evaluated. All E. coli isolates were susceptible to tigecycline. Two K. pneumoniae (minimum inhibitory concentration [MIC], 4 mg/L) and one K. quasipneumoniae (MIC, 8 mg/L) isolates were tigecycline resistant. Sixteen K. pneumoniae and one K. quasipneumoniae isolates were tigecycline intermediate (2 mg/L). All tigecycline-nonsusceptible isolates (n = 20) were also ciprofloxacin nonsusceptible. These isolates harbored five to nine virulence genes; 16 isolates were resistant to the human serum. In addition, STs of 13 K. pneumoniae isolates were reported to be found in strains isolated from human; isolates considered high-risk clones in human (ST11, ST15, and ST147) were also identified. In conclusion, the isolation of tigecycline-nonsusceptible K. pneumoniae from companion animals is an impact from the viewpoint of One Health approach to antimicrobial resistance that companion animals are a reservoir of human pathogenic lineages. PMID- 29232168 TI - High-Throughput Screening Approach for Identifying Compounds That Inhibit Nonhomologous End Joining. AB - DNA double-strand breaks (DSBs) are repaired primarily by homologous recombination (HR) or nonhomologous end joining (NHEJ). Compounds that modulate HR have shown promise as cancer therapeutics. The V(D)J recombination reaction, which assembles antigen receptor genes in lymphocytes, is initiated by the introduction of DNA DSBs at two recombining gene segments by the RAG endonuclease, followed by the NHEJ-mediated repair of these DSBs. Here, using HyperCyt automated flow cytometry, we develop a robust high-throughput screening (HTS) assay for NHEJ that utilizes engineered pre-B-cell lines where the V(D)J recombination reaction can be induced and monitored at a single-cell level. This approach, novel in processing four 384-well plates at a time in parallel, was used to screen the National Cancer Institute NeXT library to identify compounds that inhibit V(D)J recombination and NHEJ. Assessment of cell light scattering characteristics at the primary HTS stage (83,536 compounds) enabled elimination of 60% of apparent hits as false positives. Although all the active compounds that we identified had an inhibitory effect on RAG cleavage, we have established this as an approach that could identify compounds that inhibit RAG cleavage or NHEJ using new chemical libraries. PMID- 29232169 TI - Dietary nonheme iron is equally bioavailable from ferritin or ferrous sulfate in thalassemia intermedia. AB - : Transfusion-independent patients with thalassemia intermedia (TI) develop fatal iron overload from excessive iron absorption triggered by ineffective erythropoiesis. More information about iron pharmacokinetics and nonheme, dietary iron absorption in such patients is needed to optimize management. To obtain more information, different forms of supplemental nonheme iron sources (ferritin and ferrous sulfate) were compared in 4 TI (hemoglobin <9 g/dL) and 6 control (hemoglobin 12-16 g/dL) patients. Serial serum iron concentrations were measured during the 24 hours following consumption of 1 mg/kg of elemental iron as ferritin or ferrous sulfate. Serum iron concentrations were also measured for one TI patient and one control patient 2 hours after the ingestion of 2 mg/kg of dietary iron in ferritin or ferrous sulfate. Maximum serum iron concentrations were observed 4 hours after the consumption of either dietary iron source. However, the serum iron values were unchanged for either dietary iron source, even at the higher doses of consumed iron. Thus, the bioavailability of dietary iron, either as ferritin or ferrous sulfate, was equivalent in both groups of patients. The pilot data support ferritin as an alternative dietary iron supplement to ferrous sulfate. ABBREVIATIONS: CRP C-reactive protein; Hb hemoglobin; IDA iron-deficient anemia; ICP inductively coupled plasma; IE ineffective erythropoiesis; SCD sickle cell disease; sTf transferrin saturation; TI thalassemia intermedia; TIBC total iron binding capacity; TM thalassemia major; Tf transferrin. PMID- 29232170 TI - Correlates of Never Testing for HIV Among Sexually Active Internet-Recruited Gay, Bisexual, and Other Men Who Have Sex with Men in the United States. AB - In the United States, gay, bisexual, and other men who have sex with men (GBMSM) are disproportionately affected by the HIV/AIDS epidemic. Despite great strides in HIV prevention, including biobehavioral HIV prevention strategies such as pre exposure prophylaxis and treatment as prevention, there has been relatively low uptake of these strategies. The success of biobehavioral prevention strategies requires HIV testing but a subset of GBMSM have never been tested. To optimize prevention efforts, we sought to understand the characteristics of GBMSM who report never testing for HIV. A sample of GBMSM was recruited online in 2012 to complete a cross-sectional survey of sexual behavior and sexual health. Bivariate and multivariable analyses were used to identify characteristics of "never testing for HIV." Of the 1170 participants, 151 (13%) reported never testing for HIV. In multivariable analyses, younger age, less education, endorsing a non-gay sexual identity, living in rural areas, not having a primary partner, living in unstable housing, and reporting regular condom use during anal sex were independently associated with never testing. We conclude that, despite a substantial focus on HIV testing among GBMSM in the United States, a proportion of sexually active, adult GBMSM report never having tested for HIV in their lifetimes. The current study illustrates the importance of addressing individual and structural factors that serve as barriers to HIV testing among GBMSM. Addressing these barriers will improve access to HIV testing and other biobehavioral HIV prevention strategies and, ultimately, alleviate disparities in HIV/AIDS in the United States. PMID- 29232171 TI - Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. AB - Purpose To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma. Methods An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma. Results Nine new observational studies, two systematic reviews, and an updated randomized controlled trial of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included. Recommendations Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (nonulcerated lesions < 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of > 1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher-risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors and details of the reference patient populations are included within the guideline. Additional information is available at www.asco.org/melanoma-guidelines and www.asco.org/guidelineswiki . PMID- 29232172 TI - HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. AB - Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining >= 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial. PMID- 29232173 TI - Tele-Pediatric Intensive Care for Critically Ill Children in Syria. AB - BACKGROUND: Armed conflicts can result in humanitarian crises and have major impacts on civilians, of whom children represent a significant proportion. Usual pediatric medical care is often disrupted and trauma resulting from war-related injuries is often devastating. High pediatric mortality rates are thus experienced in these ravaged medical environments. INTRODUCTION: Using simple communication technology to provide real-time management recommendations from highly trained pediatric personnel can provide substantive clinical support and have a significant impact on pediatric morbidity and mortality. MATERIALS AND METHODS: We implemented a "Tele-Pediatric Intensive Care" program (Tele-PICU) to provide real-time management consultation for critically ill and injured pediatric patients in Syria with intensive care needs. RESULTS: Over the course of 7 months, 19 cases were evaluated, ranging in age from 1 day to 11 years. Consultation questions addressed a wide range of critical care needs. Five patients are known to have survived, three were transferred, five died, and six outcomes were unknown. DISCUSSION: Based on this limited undertaking with its positive impact on survival, further development of Tele-PICU-based efforts with attention to implementation and barriers identified through this program is desirable. CONCLUSION: Even limited Tele-PICU can provide timely and potentially lifesaving assistance to pediatric care providers. Future efforts are encouraged. PMID- 29232174 TI - Analysis of Reported Balloon Malfunctions and Proposed Rescue Strategy for Malfunction during Airway Dilation. AB - Objective The rate of balloon dilator failure is unknown, and a rescue strategy for device malfunction has not been established. The purposes of this investigation were to determine the approximate number of balloon failures in the gastrointestinal tract and airway, evaluate the parameters required to rupture balloon dilators, and develop a rescue strategy to efficiently reestablish airway patency. Study Design Retrospective cohort and basic medical research. Setting Academic tertiary care medical center. Subjects and Methods The Manufacturer and User Facility Device Experience database was queried for adverse events associated with tracheal and esophageal dilators between January 1, 2014, and January 1, 2017. A bench-top model of airway stenosis was developed, and optimal conditions for the safe removal of a malfunctioning dilator were assessed (2, 4, 6 atm). Results There were 420 reported balloon malfunctions, including 104 cases with deflation/removal issues. The bench-top model determined that device rupture allowing for immediate removal occurs with needle puncture at balloon pressures >=8 atm. Balloons inflated to 6 atm required a median of 17.5 seconds (range, 0 55.3) for removal, in comparison with 30.2 seconds (range, 7.1-87.5) at 2 atm ( P > .05). Conclusion Balloon dilator malfunction is a significant problem that practitioners must be prepared for. Pressure >=8 atm (~33% overinflation) is required to consistently cause complete balloon dilator rupture via needle puncture. While counterintuitive, increasing the inflation pressure of a malfunctioning balloon (8-10 atm) may expedite rupture and safe removal. A rescue strategy for balloon malfunction is proposed. PMID- 29232175 TI - Developing a Newborn Resuscitation Telemedicine Program: A Comparison of Two Technologies. AB - BACKGROUND: Early work has demonstrated the feasibility and acceptance of newborn resuscitation telemedicine programs (NRTPs). The technology requirements for providing this type of emergency telemedicine service are unclear. INTRODUCTION: We hypothesized that during NRTP consults, a wired telemedicine cart would provide a more reliable and higher-quality user experience than a consumer-grade wireless tablet. MATERIALS AND METHODS: In this retrospective observational study, six spoke sites used consumer-grade wireless tablets during preintervention and wired coder/decoder (CODEC)-based telemedicine carts during postintervention. Both technologies used the same videoconferencing software. After the telemedicine consult, providers completed surveys assessing connection reliability, user satisfaction, and audio and video quality using a 1-5 Likert scale. RESULTS: Preintervention, users completed 99 consults and 95 surveys. Postintervention, users completed 73 consults and 192 surveys. Successful connection on first attempt was significantly improved with the wired cart compared with the wireless tablet (82.7% vs. 69.5%, p = 0.01), and the percentage of consults complicated by an unplanned disconnection was reduced (6.4% vs. 14.7%, p = 0.02). User satisfaction and video and audio quality ratings were significantly higher for the wired cart. DISCUSSION: The wired telemedicine cart increased connection reliability, which is important given the critical nature and long duration of NRTP consults. Audio-video quality was also improved, allowing for better visualization of the neonate and communication with the care team. CONCLUSIONS: Consumer-grade wireless tablets did not meet the program's technical requirements. Wired telemedicine carts improved reliability, user satisfaction, and audio-video quality. Wired carts may not fully meet NRTP requirements because of cart size and limited mobility. PMID- 29232176 TI - Molecular Characterization of Cronobacter sakazakii in Egypt, Survival and Thermoresistance at Different Temperatures: A Potential Public Health Risk. AB - Cronobacter sakazakii has been implicated in causing serious infections in neonates due to consumption of contaminated infant powdered milk. The zoonotic potential of the organism was not clear due to scarce evidence about the role of food animals in the transmission of infection. C. sakazakii was identified in infant powdered milk (n = 100), infant stool (n = 100), and dairy animal feces (n = 100) with the percentages of 1%, 2%, and 4%, respectively. The outer membrane protein A (ompA) gene was characterized in all isolates of different origin, while gene encoding for zinc-metaloprotease (zpx) was only identified in isolates from animal feces. Genotyping of C. sakazakii isolates using enterobacterial repetitive intergenic consensus polymerase chain reaction revealed heterogenicity. The survival and thermotolerance of one potentially virulent C. sakazakii isolate of animal origin were examined at different temperatures. The isolate could survive with a stationary number at refrigeration temperature and the number increased significantly at room temperature after 24 h. The isolate showed thermoresistance when subjected to temperature range from 54 degrees C to 64 degrees C with D values ranged from 13.79 and 4.64 min and z value of 14.42. To the best of our knowledge, this is the first report of C. sakazakii isolation from buffalo feces in Egypt. PMID- 29232177 TI - Metformin Effects on Metabolic Coupling and Tumor Growth in Oral Cavity Squamous Cell Carcinoma Coinjection Xenografts. AB - Objective Many aggressive head and neck cancers contain 2 metabolically coupled tumor compartments: a glycolytic stromal compartment with low caveolin-1 (CAV1) and high monocarboxylate transporter 4 (MCT4) expression and a highly proliferative carcinoma cell compartment with high MCT1. Metabolites are shuttled by MCTs from stroma to carcinoma to fuel tumor growth. We studied the effect of carcinoma-fibroblast coinjection and metformin administration on a mouse model of head and neck squamous cell carcinoma. Study Design Xenograft head and neck squamous cell carcinoma model. Setting Basic science laboratory. Subjects and Methods Oral cavity carcinoma cells were injected alone or as coinjection with human fibroblasts into nude mice to generate xenograft tumors. Tumors were excised and stained with immunohistochemistry for markers of metabolic coupling and apoptosis, including MCT1, MCT4, CAV1, and TUNEL assay (terminal deoxynucleotidyl transferase nick end labeling). Strength of staining was assessed by a pathologist or computer-assisted pathology software. Metformin was administered orally to mice to test effects on immunohistochemical markers in xenografts. Results Coinjection tumors were 2.8-fold larger ( P = .048) and had 1.4-fold stronger MCT1 staining ( P = .016) than tumors from homotypic carcinoma cell injection. Metformin decreased the size of coinjection xenograft tumors by 45% ( P = .025). Metformin reduced MCT1 staining by 28% ( P = .05) and increased carcinoma cell apoptosis 1.8-fold as marked by TUNEL assay ( P = .005). Metformin did not have a significant effect on tumor size when CAV1 knockdown fibroblasts were used in coinjection. Conclusion Coinjection with fibroblasts increases tumor growth and metabolic coupling in oral cavity cancer xenografts. Fibroblast CAV1 expression is required for metformin to disrupt metabolic coupling and decrease xenograft size. PMID- 29232178 TI - Rapid Decrease in KRT14 and TP53 mRNA Expression in the Buccal Mucosa of Patients Receiving Total-Body Irradiation for Allogeneic Stem Cell Transplantation. AB - The only curative treatment option for relapsed patients with acute myeloid leukemia (AML) is allogeneic stem cell transplantation. Depletion of hematopoietic stem cells and leukemic blast cells is achieved through the systemic administration of DNA damaging agents, including total-body irradiation (TBI) prior to transplantation. Since other tissues are radiosensitive, the identification of biomarkers could facilitate the management of additional toxicities. Buccal keratinocytes are readily accessible and could provide a source of cells for RNA analysis. In this study, we obtained miRNAs and mRNAs from daily buccal swabs collected from patients undergoing allogeneic stem cell transplantation. Unexpectedly, there was no prominent p53-induced mRNA or miRNA response in these samples, despite the fact that the p53 pathway is a well characterized radiation-inducible response. Instead, the expression of mRNAs encoding p53 and cytokeratin 14 (TP53 and KRT14, respectively) decreased precipitously within hours of the first radiation treatment. These patients went on to develop oral mucositis, however, it is unclear whether TP53 and/or KRT14 expression are predictive of this adverse event. Larger scale analysis of buccal epithelial samples from patients undergoing allogeneic stem cell transplantation appears to be warranted. PMID- 29232179 TI - Adenotonsillectomy for Obstructive Sleep Apnea in Children with Complex Chronic Conditions. AB - Objective To estimate the prevalence of persistent obstructive sleep apnea postadenotonsillectomy in children with complex chronic conditions. Study Design A retrospective cohort study. Setting The Hospital for Sick Children Sleep laboratory. Subjects Children <=18 years of age who had moderate to severe obstructive sleep apnea and had polysomnography pre- and postadenotonsillectomy. Methods Medical and polysomnographic data were reviewed. The prevalence of persistent obstructive sleep apnea postadenotonsillectomy was determined for the following groups: no complex chronic conditions, single-system complex chronic conditions, and multisystem complex chronic conditions. Results We reviewed data of 133 (84 male) children. Their mean (standard deviation) age was 5.5 (3.8) years. The persistent obstructive sleep apnea rate postadenotonsillectomy was highest in children with multisystem complex chronic conditions (57%), intermediate in children with single-system complex chronic conditions (29%), and lowest in children without complex chronic conditions (15%), P = .0004. The odds (confidence interval) of having persistent obstructive sleep apnea postadenotonsillectomy was 7.42 (2.16-25.51) times higher in children with multisystem complex chronic conditions vs no complex chronic conditions and 3.35 (1.16-9.64) times higher in children with multisystem complex chronic conditions vs single-system complex chronic conditions. Conclusions Although adenotonsillectomy is considered first-line therapy in healthy children older than 2 years for the treatment of obstructive sleep apnea, there is a significantly greater risk of persistent obstructive sleep apnea postadenotonsillectomy in children with complex chronic conditions. Therefore, other surgical procedures or nonsurgical management may need to be considered as first-line treatment for this cohort. PMID- 29232180 TI - A Randomized Study of a Mobile Behavioral Parent Training Application. AB - : Background/Introduction: Never before have parents had such immediate access to parenting support. The extension of the Internet to smartphones, offers the opportunity to provide families with the highest-quality information at the time and place that it can be the most useful. However, there remain considerable barriers to getting the right information to the right people at the right time. MATERIALS AND METHODS: This study includes the initial feasibility testing of a smartphone application "ParentNet" that attempts to deliver on the potential of empirically supported therapy by connecting family members with specific behavioral goals and outcomes in real time. Participation was solicited from community parenting support groups and through online social media. Data were collected from 73 parents and 88 children on child behavior (adult only) and satisfaction. RESULTS: Data analyses showed positive satisfaction and utilization results: (1) users rated the ParentNet app very positively (i.e., 85% of caregivers and 88% of youth would recommend the app to others), and (2) parenting behavior was improved with a small/moderate effect-size. DISCUSSION AND CONCLUSIONS: Findings from this initial testing are reviewed along with future development possibilities to be considered. Limitations of small pilot sample and brief administration period could have reduced effects. Further study would include a more robust sample. PMID- 29232181 TI - RESNA position on the application of power mobility devices for pediatric users. AB - This paper serves as an update to the previous RESNA Position on the Application of Power Wheelchairs for Pediatric Users with more current and additional scientific literature. This document contains typical clinical applications and best evidence from the literature supporting the application of power mobility (PM) for young children and to assist practitioners in decision-making and justification. It is RESNA' s position that age, limited vision or cognition, behavioral issues, and the ability to walk or propel a manual wheelchair short distances should not, in and of themselves, be used as discriminatory factors against providing PM for children. RESNA recommends early utilization of PM for children with mobility limitations as medically necessary, to promote integration and psycho-social development, reduce passive dependency, and to enhance participation, function, and independence. PMID- 29232182 TI - Design and Technical Validation of a Telemedicine Service for Rural Healthcare in Ecuador. AB - BACKGROUND: Telemedicine is becoming increasingly important in Ecuador, especially in areas such as rural primary healthcare and medical education. Rural telemedicine programs in the country need to be strengthened by means of a technological platform adapted to local surroundings and offering advantages such as access to specialized care, continuing education, and so on, combined with modest investment requirements. INTRODUCTION: This present article presents the design of a Telemedicine Platform (TMP) for rural healthcare services in Ecuador and a preliminary technical validation with medical students and teachers. MATERIALS AND METHODS: An initial field study was designed to capture the requirements of the TMP. In a second phase, the TMP was validated in an academic environment along three consecutive academic courses. Assessment was by means of user polls and analyzing user interactions as registered automatically by the platform. The TMP was developed using Web-based technology and open code software. RESULTS: One hundred twenty-four students and 6 specialized faculty members participated in the study, conducting a total of 262 teleconsultations of clinical cases and 226 responses, respectively. CONCLUSION: The validation results show that the TMP is a useful communication tool for the documentation and discussion of clinical cases. Moreover, its usage may be recommended as a teaching methodology, to strengthen the skills of medical undergraduates. The results indicate that implementing the system in rural healthcare services in Ecuador would be feasible. PMID- 29232183 TI - Loss of Substantia Nigra Hyperintensity at 3.0-T MR Imaging in Idiopathic REM Sleep Behavior Disorder: Comparison with 123I-FP-CIT SPECT. AB - Purpose To examine whether the loss of nigral hyperintensity (NH) on 3.0-T susceptibility-weighted (SW) magnetic resonance (MR) images can help identify high synucleinopathy risk in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Materials and Methods Between March 2014 and April 2015, 18 consecutively recruited patients with iRBD were evaluated with 3.0-T SW imaging and iodine 123-2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) single photon emission computed tomography and compared with 18 healthy subjects and 18 patients with Parkinson disease (PD). Two readers blinded to clinical diagnosis independently assessed the images. 123I-FP-CIT uptake ratios were compared by using the Kruskal-Wallis test, and intra- and interobserver agreements were assessed with the Cohen kappa. The synucleinopathy conversion according to NH status was evaluated in patients with iRBD after follow-up. Results NH was intact in seven patients with iRBD and lost in 11. The 123I-FP-CIT uptake ratios were comparable between those with intact NH (mean, 3.22 +/- 0.47) and healthy subjects (mean, 3.37 +/- 0.47) (P = .495). The 123I-FP CIT uptake ratios in the 11 patients with iRBD and NH loss (mean, 2.48 +/- 0.44) were significantly lower than those in healthy subjects (mean, 3.37 +/- 0.47; P < .001) but higher than those in patients with PD (mean, 1.80 +/- 0.33; P < .001). The intra- and interobserver agreements were excellent (kappa > 0.9). Five patients with iRBD and NH loss developed symptoms of parkinsonism or dementia 18 months after neuroimaging. Conclusion NH loss at 3.0-T SW imaging may be a promising marker for short-term synucleinopathy risk in iRBD. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29232184 TI - Feasibility and Safety of Intrathoracic Biopsy and Repeat Biopsy for Evaluation of Programmed Cell Death Ligand-1 Expression for Immunotherapy in Non-Small Cell Lung Cancer. AB - Purpose To determine feasibility and safety of biopsy and repeat biopsy for assessment of programmed cell death ligand-1 (PD-L1) status. Materials and Methods This retrospective analysis reviewed 101 patients who underwent transthoracic core needle biopsy for the KEYNOTE-001 (MK-3475) clinical trial of pembrolizumab, an antiprogrammed cell death-1 therapy for non-small cell lung cancer, from May 2012 to September 2014. Sixty-one male patients (mean age, 66.1 years; range 36-83 years) and 40 female patients (mean age, 66.8 years; age range, 36-90 years) were included. Data collected included population characteristics, treatment history, target location, size, and depth from pleura. Adequacy of the tissue sample for diagnostic testing and rates of biopsy-related complications were assessed. Statistical analysis was performed by using univariate and multivariate generalized linear models to determine significant risk factors for biopsy complications. Results A total of 110 intrathoracic biopsies were performed, and 101 (91.8%) were performed as repeat biopsies subsequent to a previous percutaneous or bronchoscopic biopsy or previous surgical biopsy or resection. More than 84.5% (93 of 110) of biopsies were performed in patients who had undergone previous local or systemic therapy. Specimens were adequate for evaluation of PD-L1 expression in 96.4% of biopsies. Procedure-related complications occurred in 28 biopsies (25.4%); pneumothorax was most common (22.7%). Overall mean number of core needle biopsy samples obtained was 7.9 samples. Conclusion Image-guided transthoracic core needle biopsy is an effective method for obtaining tissue for PD-L1 expression analysis. (c) RSNA, 2017. PMID- 29232186 TI - Cemented or cementless total knee arthroplasty? - Comparative results of 200 cases at a minimum follow-up of 11 years. AB - INTRODUCTION: Since 1996 we have been using cementless fixation with hydroxyapatite (HA) coating. The purpose of this paper is to compare survivorship of a series of 100 cemented Total Knee Arthroplasty (TKA) to a similar series of 100 cementless with a follow up of 11-16 years. Material methods: Both TKA are mobile bearing total knee postero-stabilized. They can be used with cement or without cement. Among 1030 New Wave TKATM implanted from 2002 to 2015 we have identified 100 cemented TKAs and 100 cementless TKAs. All these cases were primary replacement. Differences in survival probability were determined using log-rank test. RESULTS: Survival probabilities at 11 years of follow-up were: Cemented group: 90.2% CI95% [81.9-94.8]; Cementless group: 95.4% CI95% [88.1 98.2]. Comparison between both group showed significant difference, p = 0.32. DISCUSSION: The advantages of cementless TKA are bone stock preservation, cement debris protection and the potential to achieve biologic fixation. Cementless implants rely on a porous or roughened surface to facilitate bone formation. HA has been shown to accelerate bone integration and to decrease micro motion of the components and to increase fixation. With a survival probability of 90.2% (cemented version) and 95.4% (cementless version), this total knee prosthesis performs as intended in primary total knee arthroplasty. No statistical differences could be found between cemented and cementless implants. PMID- 29232185 TI - 18F-FDG PET Biomarkers Help Detect Early Metabolic Response to Irreversible Electroporation and Predict Therapeutic Outcomes in a Rat Liver Tumor Model. AB - Purpose To test the hypothesis that biomarkers of fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used for the early detection of therapeutic response to irreversible electroporation (IRE) of liver tumor in a rodent liver tumor model. Materials and Methods The institutional animal care and use committee approved this study. Rats were inoculated with McA-RH7777 liver tumor cells in the left median and left lateral lobes. Tumors were allowed to grow for 7 days to reach a size typically at least 5 mm in longest diameter, as verified with magnetic resonance (MR) imaging. IRE electrodes were inserted, and eight 100-MUsec, 2000-V pulses were applied to ablate the tumor tissue in the left median lobe. Tumor in the left lateral lobe served as a control in each animal. PET/computed tomography (CT) and MR imaging measurements were performed at baseline and 3 days after IRE for each animal. Additional MR imaging measurements were obtained 14 days after IRE. After 14-day follow-up MR imaging, rats were euthanized and tumors harvested for hematoxylin eosin, CD34, and caspase-3 staining. Change in the maximum standardized uptake value (DeltaSUVmax) was calculated 3 days after IRE. The maximum lesion diameter change (DeltaDmax) was measured 14 days after IRE by using axial T2-weighted imaging. DeltaSUVmax and DeltaDmax were compared. The apoptosis index was calculated by using caspase-3-stained slices of apoptotic tumor cells. Pearson correlation coefficients were calculated to assess the relationship between DeltaSUVmax at 3 days and DeltaDmax (or apoptosis index) at 14 days after IRE treatment. Results DeltaSUVmax, DeltaDmax, and apoptosis index significantly differed between treated and untreated tumors (P < .001 for all). In treated tumors, there was a strong correlation between DeltaSUVmax 3 days after IRE and DeltaDmax 14 days after IRE (R = 0.66, P = .01) and between DeltaSUVmax 3 days after IRE and apoptosis index 14 days after IRE (R = 0.57, P = .04). Conclusion 18F-FDG PET imaging biomarkers can be used for the early detection of therapeutic response to IRE treatment of liver tumors in a rodent model. (c) RSNA, 2017. PMID- 29232187 TI - Athletes beware before throwing towels to audiences. PMID- 29232188 TI - Cerebral germinoma revealed through a polydipsic polyuric syndrome in a 10-year old girl: case report. AB - Cerebral germinoma is rare. Although the imaging of the germinoma is very evocative, it's very polymorphic clinical expression is at the origin of misguided diagnosis, as illustrated in our case. We report the case of a 10-year old girl with diabetes insipidus evolving for 12 months associated with a decrease in visual acuity. Brain MRI (Magnetic Resonance Imaging) revealed a tumor process in the suprasellar region. The stereotaxic biopsy of the tumor confirmed the diagnosis of the hypothalamic germinoma, which allowed the patient to be treated by radiotherapy and chemotherapy. The incidence of cerebral germinoma, its clinical (principally diabetes insipidus) and radiological features as well as therapeutic strategies are discussed hereby. PMID- 29232189 TI - A rare cause of hypophysitis: tuberculosis. AB - OBJECTIVES: Hypophysitis is a heterogeneous inflammatory disease of pituitary gland. As it causes headache and visual defects, it mimics sellar tumors in clinical and radiological aspects. It may occur due to primary or secondary causes. Tuberculosis is one of the rare secondary causes of the hypophysitis. Subject and Results. A 30-year-old male patient presented with fatigue and headache. Panhypopituitarism was considered due to the results and the diagnostic magnetic resonance (MR) imaging revealed sagittal section diamater of pituitary gland higher than normal. Biopsy of the pituitary gland was concordant with the granulomatous hypophysitis. Other possible diagnosis was excluded. CONCLUSION: The tubercular hypophysitis, as a result of performed tests, is discussed hereby, in the case report. PMID- 29232190 TI - The effects of Curcuma longa and curcumin on reproductive systems. AB - OBJECTIVE: Curcuma longa (C. longa) was used in some countries such as China and India for various medicinal purposes. Curcumin, the active component of C. longa, is commonly used as a coloring agent in foods, drugs, and cosmetics. C. longa and curcumin have been known to act as antioxidant, anti-inflammatory, anti-mutagen, and anti-carcinogenic agents. Th e attempt of the present review was to give an effort on a detailed literature survey concentrated on the protective effects of C. longa and curcumin on the reproductive organs activity. METHODS: The databases such as, PubMed, Web of Science, Google Scholar, Scopus, and Iran- Medex, were considered. The search terms were "testis" or "ovary" and "Curcuma longa", "curcumin", "antioxidant effect", "anti-inflammatory effect" and "anti-cancer effect". RESULTS: C. longa and curcumin inhibited the production of the tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2) and increased the caspases (3, 8 and 9) activities in HL-60 prostate cancer. Furthermore, C. longa and curcumin suppressed the vascular endothelial growth factor (VEGF), phosphorylated signal transducers and activators of the transcription 3 (STAT) and matrix metalloproteinase-9 (MMP-9) in ovarian cancer cell line. CONCLUSION: C. longa and curcumin might decrease the risk of cancer and other malignant diseases in the reproductive system. C. longa and curcumin have a protective effect on the reproductive organs activity such as, anti-inflammatory, anti apoptotic, and antioxidant effects in normal cells but showed pro-apoptotic effects in the malignant cells. Therefore, different effects of C. longa and curcumin are dependent on the doses and the type of cells used in various models studied. PMID- 29232191 TI - Salivary adiponectin concentration in healthy adult males in relation to anthropometric measures and fat distribution. AB - OBJECTIVES: Body fat content, fat distribution, and adiponectin level are important variables in the development of obesity related complications. Anthropometric indices may provide an economic and faster method in measuring the risk for complications through their predictive effect of fat distribution and adiponectin concentration. We aimed to determine, which of the waist circumference (WC), waist-to-hip ratio (WHR), and body mass index (BMI) may be the best predictor for the total fat percentage (WF), visceral fat level (VF), and subcutaneous whole-body fat (SCWBF). We aimed also to investigate the potential use of the anthropometric measures and fat distribution as predictors for the salivary adiponectin level in the healthy adult males. SUBJECTS: A total of 88 adult males aged between 18-25 years with a wide range of BMI were studied. Anthropometric indices were measured using standardized methods and salivary adiponectin level was assessed using an enzyme-linked immunosorbent assay. RESULTS: In path analysis of the Structural Equation Model (SEM) using IBM@SPSS AMOS, version22, BMI and WC, but not WHR, were strong predictors for WF and SCWBF (p<0.05). BMI but not WC was a strong predictor for VF (p<0.001). WF was strong predictor for SCWBF (p<0.001), but not for VF. BMI, WC, WHR, WF, VF, and SCWBF were poor predictors of the salivary adiponectin level. CONCLUSION: BMI is the best predictor for the total body fat and fat distribution. However, WHR seems to be of a little value and the salivary adiponectin level independent of BMI and body fat in healthy adult Malay males. PMID- 29232192 TI - Vitamin E improved redox homeostasis in heart and aorta of hypothyroid rats. AB - OBJECTIVES: The objective of this study was to evaluate the effect of vitamin E on the oxidative stress parameters and antioxidant defense enzymes in the heart and aorta of 6-n-propylthiouracil (PTU)-induced hypothyroid rats. METHODS: The animals were divided into 4 experimental groups: Group 1 (Euthyroid) received tap water, Group 2 (Hypothyroid) received 0.05 % of PTU in dissolved in their drinking water, Group 3 (PTU+Vit E) hypothyroid rats treated with vitamin E, and Group 4 (Euthyroid+Vit E). Vitamin E was injected daily (20 mg/kg) to groups 3 and 4 via daily gavage for 6 weeks. Malondialdehyde (MDA) levels, total thiol levels, and the activities of Cu, Zn-superoxide dismutase (SOD) and catalase (CAT) were evaluated in the aortic and cardiac tissues. RESULTS: A significant decrease of thyroxine (T4) serum levels confirmed hypothyroidism in rats, which received PTU. The MDA level increased and total thiol level decreased in the hypothyroid group compared to control group (p<0.001). Th e activities of SOD and CAT significantly decreased in the hypothyroid rats in comparison to the control. Vitamin E treatment resulted in increased levels of total thiol, SOD, and CAT within aortic and cardiac tissues and decreased levels of MDA in comparison with the hypothyroid group (p<0.01-p<0.001). CONCLUSIONS: PTU-induced hypothyroidism resulted in oxidative stress. Chronic administration of vitamin E to hypothyroid rats decreased the oxidative stress markers in the aortic and cardiac tissues. PMID- 29232193 TI - Testosterone regulates granzyme K expression in rat testes. AB - OBJECTIVE: Testosterone depletion induces increased germ cell apoptosis in testes. However, limited studies exist on genes that regulate the germ cell apoptosis. Granzymes (GZM) are serine proteases that induce apoptosis in various tissues. Multiple granzymes, including GZMA, GZMB and GZMN, are present in testes. Th us, we investigated which granzyme may be testosterone responsive and possibly may have a role in germ cell apoptosis aft er testosterone depletion. METHODS: Ethylene dimethane sulfonate (EDS), a toxicant that selectively ablates the Leydig cells, was injected into rats to withdraw the testosterone. The testosterone depletion effects after 7 days post-EDS were verified by replacing the testosterone exogenously into EDS-treated rats. Serum or testicular testosterone was measured by radioimmunoassay. Using qPCR, mRNAs of granzyme variants in testes were quantified. The germ cell apoptosis was identified by TUNEL assay and the localization of GZMK was by immunohistochemistry. RESULTS: EDS treatment eliminated the Leydig cells and depleted serum and testicular testosterone. At 7 days post-EDS, testis weights were reduced 18% with increased germ cell apoptosis plus elevation GZMK expression. GZMK was not associated with TUNEL-positive cells, but was localized to stripped cytoplasm of spermatids. In addition, apoptotic round spermatids were observed in the caput epididymis. CONCLUSIONS: GZMK expression in testes is testosterone dependent. GZMK is located adjacent to germ cells in seminiferous tubules and the presence of apoptotic round spermatids in the epididymis suggest its role in the degradation of microtubules in ectoplasmic specializations. Thus, overexpression of GZMK may indirectly regulate germ cell apoptosis by premature release of round spermatids from seminiferous tubule lumen. PMID- 29232194 TI - Persistent ventricular bigeminy during anesthesia in pediatric patients: a case report of an 11-year-old child. AB - An 11-year-old male child with fractures in both bones in his left forearm presented for open reduction and internal fixation. The pre-anesthetic check-up and investigations did not reveal any pre-existing underlying cardio-respiratory disease. The patient had an uneventful peri-operative period during the operation and was comfortable without any anxiety or restlessness. After an uneventful induction and intubation as per routine protocol, the patient received 600 mg of amoxicillin+clavunate intravenously as an antibiotic. After 3 min, the patient developed persistent ventricular bigeminy with intermittent sinus rhythm, which returned to normal after 20 min. Open reduction and internal fixation of the fractures in both bones were done. Extubation and the post-op course were uneventful. To rule out the cause of arrhythmia, ECG, 2D-ECHO and serum electrolyte evaluation were done, however the results came back as normal. Many days later, the patient fell again on the same arm and revisited the ortho operation theatre for revision surgery. As the child was very cooperative and calm, he was given a supraclavicular block after proper counseling. Thirty minutes before tourniquet inflation as a routine method, 600 mg of amoxicillin+clavunate was administered. After 5 min, the patient developed persistent ventricular bigeminy. After 1 h, the child complained of chest pain and had redness of eyes and was restless. This was managed with 100% oxygen and an injection of 150 mg amiodarone intravenously. Surgery was postponed for further stabilization and optimization. Serum electrolytes were normal. The child was observed in the surgical intensive care unit with continuous ECG monitoring. Ventricular bigeminy with intermittent sinus rhythm persisted for 3 days. This was managed with metoprolol 12.5 mg BD and amiodarone 100 mg OD tablets. The opinion of a pediatric cardiologist was obtained and repeated 2D-ECHO results revealed no abnormality. After 5 days, the patient was discharged and surgery was rescheduled for 2 weeks later with continuation of metaprolol and amiodarone tablets. On the fourth occasion we avoided the injection of amoxicillin+clavunate and all anesthetic drugs, which might contribute to cardiac arrhythmia. The peri operative period was uneventful. An in-depth discussion of the case and ventricular dysrhythmias in the pediatric population is emphasized in this case report. PMID- 29232195 TI - Crossover design in transcranial direct current stimulation studies on motor learning: potential pitfalls and difficulties in interpretation of findings. AB - Crossover designs are used by a high proportion of studies investigating the effects of transcranial direct current stimulation (tDCS) on motor learning. These designs necessitate attention to aspects of data collection and analysis to take account of design-related confounds including order, carryover, and period effects. In this systematic review, we appraised the method sections of crossover designed tDCS studies of motor learning and discussed the strategies adopted to address these factors. A systematic search of 10 databases was performed and 19 research papers, including 21 experimental studies, were identified. Potential risks of bias were addressed in all of the studies, however, not in a rigorous and structured manner. In the data collection phase, unclear methods of randomization, various lengths of washout period, and inconsistency in the counteracting period effect can be observed. In the analytical procedures, the stratification by sequence group was often ignored, and data were treated as if it belongs to a simple repeated-measures design. An inappropriate use of crossover design can seriously affect the findings and therefore the conclusions drawn from tDCS studies on motor learning. The results indicate a pressing need for the development of detailed guidelines for this type of studies to benefit from the advantages of a crossover design. PMID- 29232196 TI - Mechanisms of action of intravenous immunoglobulin in septic encephalopathy. AB - Acute brain dysfunction associated with sepsis is a serious complication that results in morbidity and mortality. Intravenous immunoglobulin (IVIg) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Our results suggest that IVIgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might suppress classical complement pathway by reducing C5a activity and proapoptotic NF-kappaB and Bax expressions, thereby, inhibiting major inflammation and apoptosis cascades. Future animal model experiments performed with specific C5aR and NF-kappaB agonists/antagonists or C5aR-deficient mice might more robustly disclose the significance of these pathways. C5a, C5aR, and NF-kappaB, which were shown to be the key molecules in brain injury pathogenesis in sepsis, might also be utilized as potential targets for future treatment trials of septic encephalopathy. PMID- 29232197 TI - DNA-based construction at the nanoscale: emerging trends and applications. AB - The field of structural DNA nanotechnology has evolved remarkably-from the creation of artificial immobile junctions to the recent DNA-protein hybrid nanoscale shapes-in a span of about 35 years. It is now possible to create complex DNA-based nanoscale shapes and large hierarchical assemblies with greater stability and predictability, thanks to the development of computational tools and advances in experimental techniques. Although it started with the original goal of DNA-assisted structure determination of difficult-to-crystallize molecules, DNA nanotechnology has found its applications in a myriad of fields. In this review, we cover some of the basic and emerging assembly principles: hybridization, base stacking/shape complementarity, and protein-mediated formation of nanoscale structures. We also review various applications of DNA nanostructures, with special emphasis on some of the biophysical applications that have been reported in recent years. In the outlook, we discuss further improvements in the assembly of such structures, and explore possible future applications involving super-resolved fluorescence, single-particle cryo-electron (cryo-EM) and x-ray free electron laser (XFEL) nanoscopic imaging techniques, and in creating new synergistic designer materials. PMID- 29232198 TI - Beyond the Extraction Debate. PMID- 29232199 TI - 2017 JCO Orthodontic Practice Study. PMID- 29232200 TI - The shoulder spring for eruption of impacted canines. PMID- 29232201 TI - The future is now: How millennials, tech, and a chess-playing computer are changing orthodontics. PMID- 29232202 TI - Lower first-molar extractions and directional forces in high-angle class III treatment. PMID- 29232203 TI - Forsus reactivation with composite beads. PMID- 29232204 TI - The zygoma and the symphysis: new extra-alveolar sites for long mini-implants. PMID- 29232205 TI - Is the Lateral Transpsoas Approach to the Lumbar Spine Safe at L4-L5? PMID- 29232206 TI - Bupivacaine Indirectly Potentiates Glutamate-induced Intracellular Calcium Signaling in Rat Hippocampal Neurons by Impairing Mitochondrial Function in Cocultured Astrocytes. AB - BACKGROUND: Bupivacaine induces central neurotoxicity at lower blood concentrations than cardiovascular toxicity. However, central sensitivity to bupivacaine is poorly understood. The toxicity mechanism might be related to glutamate-induced excitotoxicity in hippocampal cells. METHODS: The intracellular free Ca concentration ([Ca]i), mitochondrial membrane potential, and reactive oxygen species generation were measured by fluorescence and two-photon laser scanning microscopy in fetal rat hippocampal neurons and astrocytes. RESULTS: In astrocyte/neuron cocultures, 300 MUM bupivacaine inhibited glutamate-induced increases in [Ca]i in astrocytes by 40% (P < 0.0001; n = 20) but significantly potentiated glutamate-induced increases in [Ca]i in neurons by 102% (P = 0.0007; n = 10). Ropivacaine produced concentration-dependent effects similar to bupivacaine (0.3 to 300 MUM). Tetrodotoxin did not mimic bupivacaine's effects. In pure cell cultures, bupivacaine did not affect glutamate-induced increases in [Ca]i in neurons but did inhibit increased [Ca]i in astrocytes. Moreover, bupivacaine produced a 61% decrease in the mitochondrial membrane potential (n = 20) and a 130% increase in reactive oxygen species generation (n = 15) in astrocytes. Cyclosporin A treatment suppressed bupivacaine's effects on [Ca]i, mitochondrial membrane potential, and reactive oxygen species generation. When astrocyte/neuron cocultures were incubated with 500 MUM dihydrokainic acid (a specific glutamate transporter-1 inhibitor), bupivacaine did not potentiate glutamate-induced increases in [Ca]i in neurons but still inhibited glutamate induced increases in [Ca]i in astrocytes. CONCLUSIONS: In primary rat hippocampal astrocyte and neuron cocultures, clinically relevant concentrations of bupivacaine selectively impair astrocytic mitochondrial function, thereby suppressing glutamate uptake, which indirectly potentiates glutamate-induced increases in [Ca]i in neurons. PMID- 29232207 TI - Mitigating Microvascular Leak during Fluid Resuscitation of Hemorrhagic Shock. PMID- 29232208 TI - Hospital Waiting Room. PMID- 29232210 TI - Response: "Percutaneous Vascular Interventions Versus Bypass Surgeries in Patients With Critical Limb Ischemia". PMID- 29232211 TI - Improving the Understanding of Perianal Crohn Fistula Through 3D Modeling. PMID- 29232209 TI - Recent progress in understanding HIV reservoirs. AB - PURPOSE OF REVIEW: Reservoirs of HIV-1-infected cells persist long-term despite highly effective antiretroviral suppression therapy and represent the main barrier against a cure for HIV-1. This review summarizes recent advances in understanding the complexity and diversity of viral reservoir cells. RECENT FINDINGS: Latently infected memory CD4 T cells are the predominant cell compartment responsible for viral persistence, but some studies suggest that myeloid cells, and possibly hematopoietic progenitors, can also serve as long term viral reservoirs. Specific phenotypic markers, including T-cell activation and exhaustion molecules, may denote CD4 T cells enriched for replication competent proviruses. Clonal proliferation of infected CD4 T cells in vivo represents an important mechanism responsible for the remarkable long-term stability of the viral reservoir. Multiple new assays, including near full-genome proviral sequencing and simplified versions of viral outgrowth assays, are being developed to analyze and quantify persisting reservoirs of HIV-1-infected cells. SUMMARY: Recent technological advances allow to profile the molecular structure and composition of viral reservoir cells in great detail. Continuous progress in understanding phenotypic and functional properties of viral reservoir cells provides clues for novel clinical interventions to destabilize viral persistence during antiretroviral therapy. PMID- 29232212 TI - Cost of Major Complications After Liver Resection in the United States: Are High volume Centers Cost-effective? AB - OBJECTIVE: The aim of the study was to estimate the cost of major complications after liver resection and determine whether high-volume (HV) centers are cost effective. METHODS: From 2002 to 2011, 96,107 cases of liver resection performed in the United States were identified using Nationwide Inpatient Sample. Hospitals were categorized as HV (150+ cases/yr), medium-volume (51-149 cases/yr), and low volume (LV) (1-50 cases/yr) centers. Multivariable regression analysis identified predictors of cost. Propensity score matching comparing cases with versus without complications and costs of specific complications were estimated. Cost effectiveness of HV centers was determined by calculating the incremental cost effectiveness ratio. RESULTS: After propensity score matching, the occurrence of a major complication added $33,855 extra cost, increased mean length of stay by 8.7 [95% confidence interval (CI), 8.4-9] days and increased risk of death by 9.3% (all P < 0.001). The cost of most common complications was wound infection (3.8%, $21,995), renal failure (2.8%, $19,201), respiratory failure (2.7%, $25,169), and hemorrhage (3.3%, $9,180), whereas sepsis (0.8%, $33,009), gastrointestinal bleeding (0.5%, $32,835), fistula (0.2%, $27,079), and foreign body removal (0.1%, $29,404) were most costly, but less frequent. Compared with LV centers, liver resection at HV centers was associated with $5109 (95% CI, 4409 5809, P < 0.001) more cost per case, yet on average 0.54 years (95% CI, 0.23 0.86) longer survival for an incremental cost-effectiveness ratio of $9392. CONCLUSIONS: HV centers were cost-effective at performing liver resection compared with LV centers. After liver resection, complications such as surgical site infection, respiratory failure, and renal failure contributed the most to annual cost burden. PMID- 29232213 TI - Postoperative Mortality After Nonelective Surgery for Inflammatory Bowel Disease Patients in the Era of Biologics. AB - OBJECTIVE: The aim of the study was to analyze recent trends in the rate of nonelective surgery and corresponding mortality for inflammatory bowel disease (IBD) patients since the rise of biologic use. BACKGROUND: Modern biologic therapy has improved outcomes for IBD, but little is known about the impact on mortality rates after nonelective surgery. METHODS: New York's Statewide Planning & Research Cooperative System was queried for hospital admissions for ulcerative colitis (UC) with concurrent colectomy and Crohn disease (CD) with concurrent small bowel resection or colectomy from 2000 to 2013. Mixed-effects analyses assessed patient, surgeon, and hospital-level factors and hospital-level variation associated with 30-day mortality after nonelective surgery. RESULTS: Between 2000 to 2006 and 2007 to 2013, the number of unscheduled IBD-related admissions increased by 50% for UC and 41% for CD, but no change in the proportion of nonelective surgery cases was observed (UC=38% vs 38%; CD=45% vs 42%) among 15,837 intestinal resections (UC=5,297; CD=10,540). Nonelective surgery mortality rates between 2000 to 2006 and 2007 to 2013 were high and increased for UC (10.2% vs 15%) but decreased for CD (3.3% vs 2.2%). Nonelective surgery in 2007 to 2013 was associated with an 82% increased risk of 30-day mortality in UC cases (odds ratio: 1.82; confidence interval: 1.19-2.62). After controlling for patient-level factors, large hospital-level variation was observed with 23-fold difference in mortality for both UC and CD. CONCLUSIONS: Although nonelective IBD surgery rates have remained stable, associated 30-day mortality for UC has doubled in recent years despite advances in medical management. Current clinical decision-making and care pathways must be further evaluated to improve outcomes in this high-risk population. PMID- 29232214 TI - Comparison Between Effectiveness of Ultrasound-Guided Corticosteroid Injection Above Versus Below the Median Nerve in Mild to Moderate Carpal Tunnel Syndrome: A Randomized Controlled Trial. AB - OBJECTIVE: In this study, the clinical effectiveness of ultrasound-guided corticosteroid injection "above" versus "below" the median nerve for treatment of patients with mild to moderate carpal tunnel syndrome was compared. DESIGN: This prospective randomized double-blind clinical trial included 44 patients with mild to moderate carpal tunnel syndrome. The subjects were randomly assigned to two groups to receive ultrasound-guided injection of 40 mg of triamcinolone either "above" or "below" the involved median nerve. Outcome measures were the Boston Carpal Tunnel Questionnaire, visual analog scale, electrophysiological tests, and ultrasonographic measurement of the median nerve cross-sectional area at baseline, 6, and 12 wks after the injection. RESULTS: All outcome measures improved significantly in both groups at 6 wks after intervention, and these improvements were persevered up to 12 wks of follow-up (all P values <0.05). However, there was no significant difference in measured outcomes between the two groups. No adverse effects were observed. CONCLUSIONS: Both above and under median nerve ultrasound-guided steroid injection techniques were effective in reducing the symptoms, improving the function, and improving electrodiagnostic and sonographic findings of carpal tunnel syndrome. However, the amount of improvement in the outcomes did not differ between groups, implying that none of technique has the superiority over another. PMID- 29232215 TI - Pulmonary Tumor Thrombotic Microangiopathy: Case Report and Review of Literature. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare rapidly progressive fatal disease that is difficult to diagnosis antemortem. Activation of the coagulation cascade and fibrocellular intimal thickening caused by embolism of tumor cells into pulmonary vasculature leads to extensive pulmonary hypertension and eventually death. We describe a case of PTTM with association of a presumed lung adenocarcinoma primary. Although rare in nature, PTTM should be a considered diagnosis with chronic dyspnea of unknown origin, severe pulmonary hypertension coupled with right-side heart failure, in the absence of pulmonary embolism. PMID- 29232227 TI - World Health Organization Responds to Concerns about Surgical Site Infection Prevention Recommendations. PMID- 29232228 TI - In Reply. PMID- 29232229 TI - Preoperative Prediction of Chronic Postsurgical Pain after Thoracotomy: Need for Adequately Sized Population-based Samples. PMID- 29232230 TI - In Reply. PMID- 29232231 TI - Keep American Society of Anesthesiologists Physical Status Classification System Simple, Stupid. PMID- 29232232 TI - In Reply. PMID- 29232233 TI - In Reply. PMID- 29232234 TI - Use of Vasopressin in Vasoplegic Syndrome with Reduced Ejection Fraction: Asking for Trouble. PMID- 29232235 TI - Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery: A Discussion of the Level of Evidence. PMID- 29232236 TI - Vasopressin versus Norepinephrine after Cardiopulmonary Bypass. PMID- 29232237 TI - In Reply. PMID- 29232238 TI - In Reply. PMID- 29232239 TI - Should the Dominant or Nondominant Hand Be Used for Applying Cricoid Pressure? PMID- 29232240 TI - Cricoid Pressure: Effective Measure or Ritual? PMID- 29232241 TI - In Reply. PMID- 29232242 TI - Prediction of Posthepatectomy Liver Failure Proposed by the International Study Group of Liver Surgery: Residual Liver Function Estimation With 99mTc-Galactosyl Human Serum Albumin Scintigraphy. AB - PURPOSE: The International Study Group of Liver Surgery (ISGLS) proposed a definition and grading system for posthepatectomy liver failure (PHLF). We evaluated the usefulness of residual liver function estimation using Tc galactosyl human serum albumin (Tc-GSA) for the prediction of PHLF. METHODS: Patients with liver tumors (n = 136) and scheduled for hepatectomy underwent Tc GSA scintigraphy. Based on their imaging data, the maximal GSA removal rate (GSA Rmax)was calculated using multicompartment analysis. We also calculated GSA-Rmax in the predicted residual liver (GSA-RL) whose volume was determined on computed tomography (CT) scans. We compared the age, sex, 15-minute indocyanine green retention rate; albumin, bilirubin, hyaluronic acid, and type 4 collagen levels; the Child-Pugh classification; residual liver volume; residual liver percentage; GSA-Rmax; and GSA-RL in patients with and without PHLF. Univariate and multivariate logistic analyses were used for statistical assessments. RESULTS: Of 136 patients, 17 (12.5%) met the ISGLS criteria for PHLF (ISGLS-PHLF). There was a statistically significant difference in the age, albumin level, Child-Pugh classification, residual liver volume, residual liver percentage, GSA-Rmax, and GSA-RL between patients with and without PHLF. Based on multivariate analysis, GSA-RL and the residual liver volume were significant independent predictors of ISGLS-PHLF (P = 0.004 and P = 0.038, respectively). The odds ratio was 149423 for GSA-RL and 1.003 for the residual liver volume. CONCLUSIONS: GSA-RL calculated using Tc-GSA scintigraphy was the most useful independent predictor for ISGLS PHLF. PMID- 29232243 TI - Artifactual Hepatic Metastasis on FDG PET/CT Secondary to Cryoablation for Adrenal Metastasis. AB - A 65-year-old woman with metastatic lung cancer was referred for CT-guided cryoablation of a right adrenal metastasis. For cryoablation, probes were placed into the adrenal region. FDG PET/CT 3 months later showed new activity in hepatic segment 6 initially suspected to be metastasis. Proximity of the hepatic lesion to the adrenal metastasis was a strange coincidence and prompted review of imaging from the cryoablation. CT showed the probe entered the liver, and postablation image demonstrated injury to the liver adjacent to the adrenal metastasis. Careful review of treatment history and imaging from ablation procedures are important to avoid this pitfall. PMID- 29232244 TI - "Occipital Tunnel" Sign on FDG PET for Differentiating Dementias. AB - PET using FDG is a critical tool for evaluation of dementias, with characteristic patterns of hypometabolism suggesting specific diagnoses. Hypometabolism in the occipital region is recognized as an important finding associated with dementia with Lewy bodies and posterior cortical atrophy. We describe here the novel "occipital tunnel" sign, which results from relative sparing of FDG uptake in the medial occipital (primary visual) cortex compared with more severe loss in the surrounding lateral occipital (visual association) cortex. This sign is useful for recognizing the occipital findings of dementia with Lewy bodies and posterior cortical atrophy, especially when viewing sagittal projections. PMID- 29232245 TI - Intense 68Ga-PSMA Uptake in Diverticulum of the Sigmoid Colon. AB - We present a case of a diverticulum of the sigmoid colon with intense prostate specific membrane antigen (PSMA) activity on Ga-PSMA PET/CT. CT scan and colonoscopy showed no signs of inflammation or malignancy. This case presents an addition to the collection of benign pitfalls when reporting PSMA PET/CT; however, a Ga-PSMA up-taking focus in the colon should always cause further examination, as malignant etiology must be ruled out. PMID- 29232246 TI - The Role of FDG PET in Diabetic Myonecrosis: A Rare and Underrecognized Complication of Diabetes. AB - A 66-year-old man with poorly controlled type 2 diabetes was admitted for acute bilateral calf pain in the context of coronary artery disease, chronic renal failure, and peripheral neuropathy. Lower-extremity Doppler ultrasound excluded deep vein thrombosis. FDG-PET was performed to exclude a suspected infection because of elevated white blood cells and inflammatory markers but normal creatinine kinase levels. PET scan demonstrated intense bilateral calf muscle and left thigh muscle uptake, which in combination with the patient's history was consistent with diabetic myonecrosis, a rare end-stage complication of diabetes. The patient was managed conservatively, and pain resolved following a typical self-limited course. PMID- 29232247 TI - Salivary Gland Activity Obscures Mandibular Metastasis of Prostate Carcinoma on 68Ga-Prostate-Specific Membrane Antigen PET. AB - We report a case of a 65-year-old man with prostate cancer; his treatment history included radical prostatectomy followed by radiation therapy and subsequent androgen deprivation therapy for more than 5 years. He currently presented with a history of rising prostate-specific antigen and complained of jaw aches. Ga prostate-specific membrane antigen PET/CT study performed for suspected biochemical recurrence demonstrated vertebral lesions and lesion in his jaw. Subsequent biopsy of jaw lesion demonstrated prostate cancer metastases. PMID- 29232249 TI - Clinical trials in valvular surgery: a 2018 update. AB - PURPOSE OF REVIEW: There is a growing emphasis on the conduct of large-scale, multicenter randomized controlled trials (RCTs) to guide decision-making in cardiac surgery. Here we review recent landmark RCTs in cardiac valvular surgery. RECENT FINDINGS: RCTs are the gold-standard level of data in medicine. However, there are unique challenges of conducting large-scale surgical trials including funding, blinding, generalizability, nonstandardization of the surgical technique, crossover, among others. Thus, the vast majority of clinical outcomes data in cardiac surgery are mainly from observational studies and most prospective data are small, single-center trials. The Cardiothoracic Surgery Network is the largest platform focused on the conduct of high-quality, multicenter cardiac surgical trials, which has already produced several seminal guideline-changing and practice-changing contributions to the surgical approach to functional mitral regurgitation, aortic stenosis, atrial fibrillation, and neuroprotective surgical adjuncts. SUMMARY: There continues to be great interest in the conduct of high-quality, RCTs to help guide surgical management of patients with valvular heart disease. PMID- 29232248 TI - Endocarditis in the setting of IDU: multidisciplinary management. AB - PURPOSE OF REVIEW: The purpose of this article is to provide a brief overview of the medical and surgical management of infective endocarditis secondary to IDU, with a focus on the underlying substance use disorder. RECENT FINDINGS: Patients with infective endocarditis secondary to IDU are often young with unique comorbidities including mental illness, chronic hepatitis C, HIV infection, which are often compounded by limited social and familial supports. The focus of management has been treatment of endocarditis using IV antibiotics alongside surgery. Surgical outcomes compare favorably with those of infective endocarditis in the general population but long-term outcomes of IDUs are significantly worse. This is primarily due to the high rate of recidivism of drug use and the risk of prosthetic valve infective endocarditis. Contemporary management of addiction utilizes an integrative approach, combining both pharmacologic and nonpharmacologic strategies while remaining patient-centered. Given the complexity of care required, we advocate for a multidisciplinary team-based approach including psychiatry, infectious disease, cardiology, cardiac surgery and social services. SUMMARY: Infective endocarditis secondary to IDU remains a medical and surgical challenge with dismal outcomes. Here we offer practical suggestions on the multidisciplinary management of this challenging and high-risk patient cohort. PMID- 29232250 TI - Results of a second examination of the right side of the colon in screening and surveillance colonoscopy: a systematic review and meta-analysis. AB - BACKGROUND: Screening colonoscopy is less effective in preventing proximal colon cancers than distal colon cancers. A repeat examination of the right side of the colon may increase the lesion detection. The study aimed to assess the results of a second examination of the right side of the colon with forward-view or retroflexion colonoscopy performed immediately after the initial examination. MATERIALS AND METHODS: We carried out a meta-analysis of all primary studies that performed a second examination of the right side of the colon with forward-view or retroflexion colonoscopy performed immediately after the initial examination. RESULTS: Six cohorts of five studies with 4155 participants were included in the final study. The adenoma detection rate (ADR) was 28.8% of the combined examinations compared with 24.1% of the single examination (P<0.001), for a pooled odds ratio of 1.34 [95% confidence interval (CI): 1.13-1.59]. For retroflexion assessment, ADR was achieved in 25.4% patients in the combined group, compared with 22.3% in the single examination group (P=0.002), for a pooled odds ratio of 1.19 (95% CI: 1.06-1.33). For forward-view assessment, ADR was achieved in 46.0% patients in the combined group, compared with 33.5% in the single examination group (P<0.001), for a pooled odds ratio of 1.76 (95% CI: 1.40 2.22). CONCLUSION: For ADR of the right side of the colon, a repeat examination could lead to a modest improvement in the detection of lesions in the proximal colon, irrespective of forward-view or retroflexion assessment. PMID- 29232251 TI - Are the brain's vascular and Alzheimer pathologies additive or interactive? AB - PURPOSE OF REVIEW: Alzheimer's disease and cerebrovascular disease (CVD) commonly co-occur. Whether CVD promotes the progression of Alzheimer's disease pathology remains a source of great interest. Recent technological developments have enabled us to examine their inter-relationship using quantifiable, biomarker based approaches. We provide an overview of advances in understanding the relationship between vascular and Alzheimer's disease pathologies, with particular emphasis on beta-amyloid and tau as measured by positron emission tomography and cerebrospinal fluid (CSF) concentration, and magnetic resonance imaging markers of small vessel disease (SVD). RECENT FINDINGS: The relationship between cerebral beta-amyloid and various markers of SVD has been widely studied, albeit with somewhat mixed results. Significant associations have been elucidated, particularly between beta-amyloid burden and white matter hyperintensities (WMH), as well as lobar cerebral microbleeds (CMB), with additive effects on cognition. There is preliminary evidence for an association between SVD and tau burden in vivo, although compared with beta-amyloid, fewer studies have examined this relationship. SUMMARY: The overlap between Alzheimer's disease and cerebrovascular pathologies is now being increasingly supported by imaging and CSF biomarkers, indicating a synergistic effect of these co pathologies on cognition. The association of WMH and CMB with Alzheimer's disease pathology does not establish direction of causality, for which long-term longitudinal studies are needed. PMID- 29232252 TI - Nicotinamide adenine dinucleotide and its related precursors for the treatment of Alzheimer's disease. AB - PURPOSE OF REVIEW: The current review discusses the biology and metabolism of the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+) in the central nervous system. We also review recent work suggesting important neuroprotective effects that may be associated with the promotion of NAD+ levels through NAD+ precursors against Alzheimer's disease. RECENT FINDINGS: Perturbations in the physiological homoeostatic state of the brain during the ageing process can lead to impaired cellular function, and ultimately leads to loss of brain integrity and accelerates cognitive and memory decline. Increased oxidative stress has been shown to impair normal cellular bioenergetics and enhance the depletion of the essential nucleotides NAD+ and ATP. NAD+ and its precursors have been shown to improve cellular homoeostasis based on association with dietary requirements, and treatment and management of several inflammatory and metabolic diseases in vivo. Cellular NAD+ pools have been shown to be reduced in the ageing brain, and treatment with NAD+ precursors has been hypothesized to restore these levels and attenuate disruption in cellular bioenergetics. SUMMARY: NAD+ and its precursors may represent an important therapeutic strategy to maintain optimal cellular homoeostatic functions in the brain. NAD+ precursors are available in a variety of foods and may be translated to the clinic in the form of supplements. PMID- 29232253 TI - Postoperative nausea and vomiting after unrestricted clear fluids before day surgery: A retrospective analysis. AB - BACKGROUND: Guidance on pre-operative fluids fasting policy continues to evolve. Current European guidelines encourage the intake of oral fluids up to 2 h before the induction of general anaesthesia. From October 2014, Torbay Hospital Day Surgery Unit commenced an unrestricted fluid policy, encouraging patients to drink clear fluids up until the time of transfer to theatre. OBJECTIVE: The aim of this study was to assess the incidence of postoperative nausea and vomiting before and after the change to the unrestricted pre-operative clear oral fluids. DESIGN: Retrospective, before and after study. SETTING: Single district general hospital between November 2013 and February 2016. PATIENTS: A total of 11 500 patients on the day case pathway who were receiving either sedation, general anaesthesia, regional anaesthesia or their combination. The data from these patients were collected routinely. This number of patients represents approximately 78% of all patients before the change in fluids policy and 74% after the change. Exclusions were patients undergoing a termination of pregnancy, or patients undergoing community dental procedures, from whom patient experience data are not collected. INTERVENTION: Introduction of a change to the day surgery pathway policy permitting unrestricted clear oral fluids preoperatively until transfer to theatre (from October 2014). MAIN OUTCOME MEASURES: Incidence of postoperative nausea and vomiting. RESULTS: The rates of nausea within 24 h postoperatively were 270/5192 (5.2%) when patients could not drink within 2 h of surgery, and 179/4724 (3.8%) when patients could drink up until surgery, a relative rate (95% confidence interval) of 0.73 (0.61 to 0.88), P = 0.00074. The corresponding rates of vomiting were 146/5186 (2.8%) and 104/4716 (2.2%), a relative rate (95% confidence interval) of 0.78 (0.61 to 1.00), P = 0.053. CONCLUSION: Our data suggest that the liberal consumption of clear fluids before the induction of scheduled day case anaesthesia reduced the rates of postoperative nausea and vomiting. PMID- 29232254 TI - Orthotropic live transplantation for cirrhosis from hepatitis C virus leads to correction of factor IX deficiency allowing for ankle arthroplasty without factor replacement in a patient with moderate haemophilia B. AB - : Liver transplantation is one of the treatments for haemophilic patients having severe liver cirrhosis who are infected with the hepatitis C virus. Patients with haemophilia can develop arthroplasty requiring surgical intervention, and the surgical outcomes of patients undergoing such procedures after liver transplant has not been reported. Treatment for arthropathy is important for improving the quality of life for patients who survive after liver transplantation. We report the first case of ankle arthroscopic arthrodesis in a patient with haemophilia B after undergoing living donor liver transplantation. We carefully monitored the patient's factor IX (FIX) plasma levels during his perioperative period, and we successfully performed his arthroscopic ankle arthrodesis without administration of any additional FIX concentrates. Our case has demonstrated the feasibility of joint surgery after liver transplantation without administration of additional clotting factors while monitoring FIX activity. PMID- 29232255 TI - Lack of grading agreement among international hemostasis external quality assessment programs. AB - : Laboratory quality programs rely on internal quality control and external quality assessment (EQA). EQA programs provide unknown specimens for the laboratory to test. The laboratory's result is compared with other (peer) laboratories performing the same test. EQA programs assign target values using a variety of methods statistical tools and performance assessment of 'pass' or 'fail' is made. EQA provider members of the international organization, external quality assurance in thrombosis and hemostasis, took part in a study to compare outcome of performance analysis using the same data set of laboratory results. Eleven EQA organizations using eight different analytical approaches participated. Data for a normal and prolonged activated partial thromboplastin time (aPTT) and a normal and reduced factor VIII (FVIII) from 218 laboratories were sent to the EQA providers who analyzed the data set using their method of evaluation for aPTT and FVIII, determining the performance for each laboratory record in the data set. Providers also summarized their statistical approach to assignment of target values and laboratory performance. Each laboratory record in the data set was graded pass/fail by all EQA providers for each of the four analytes. There was a lack of agreement of pass/fail grading among EQA programs. Discordance in the grading was 17.9 and 11% of normal and prolonged aPTT results, respectively, and 20.2 and 17.4% of normal and reduced FVIII results, respectively. All EQA programs in this study employed statistical methods compliant with the International Standardization Organization (ISO), ISO 13528, yet the evaluation of laboratory results for all four analytes showed remarkable grading discordance. PMID- 29232256 TI - Prognosis comparisons in acute ischemic stroke patients with thrombolysis and nonthrombolysis therapy: a retrospective study with larger sample size. AB - : We compared the short-term, middle-term and long-term primary outcomes between thrombolysis and nonthrombolysis therapy in acute ischemic stroke (AIS) patients. Medical records were collected from patients suffered from AIS between 2010 and 2013 and allocated into either the intravenous recombinant tissue plasminogen activator (as rt-PA group) treatment, or non-rt-PA treatment group (as control group). The primary outcomes included a proportion of patients with favorable outcome [as defined with a modified Rankin Scale (mRS) of 0-1], functional independence (mRS of 0-2) or with bad outcome (mRS of 5-6) at 3, 6 and 12 months and the overall mortality. The secondary outcome included the events of intracranial hemorrhage. A total of 357 patients from Xinhua Hospital were selected. At 3-month follow-up, 86 patients in rt-PA vs. 99 in control group had favorable outcome, 105 vs. 122 were independent and 23 vs. 27 had bad outcome. At 6-month follow-up, 101 patients in rt-PA vs. 104 in control group had favorable outcome, 114 vs. 124 were independent and 20 vs. 34 had bad outcome. At 12 months, 104 patients in rt-PA vs. 105 in control group had favorable outcome, 117 vs. 125 were independent and 12 vs. 32 had bad outcome. At the end of 12 months, more deaths occurred in control group (20) than in the rt-PA group (11), but it was not statistically significant. Alteplase treatment in AIS patients showed the superior primary outcomes compared with control group, especially during the middle/long follow-up. PMID- 29232257 TI - Economics of gynecologic morcellation. AB - PURPOSE OF REVIEW: As the Food and Drug Administration raised concern over the power morcellator in 2014, the field has seen significant change, with patients and physicians questioning which procedure is safest and most cost-effective. The economic impact of these decisions is poorly understood. RECENT FINDINGS: Multiple new technologies have been developed to allow surgeons to continue to afford patients the many benefits of minimally invasive surgery while minimizing the risks of power morcellation. At the same time, researchers have focused on the true benefits of the power morcellator from a safety and cost perspective, and consistently found that with careful patient selection, by preventing laparotomies, it can be a cost-effective tool. SUMMARY: Changes since 2014 have resulted in new techniques and technologies to allow these minimally invasive procedures to continue to be offered in a safe manner. With this rapid change, physicians are altering their practice and patients are attempting to educate themselves to decide what is best for them. This evolution has allowed us to refocus on the cost implications of new developments, allowing stakeholders the opportunity to maximize patient safety and surgical outcomes while minimizing cost. PMID- 29232258 TI - Development and history of morcellators. AB - PURPOSE OF REVIEW: Controversy exists surrounding extraction of tissue in gynecologic surgery using morcellators following cases of disseminated uterine cancers discovered after the use of electromechanical morcellators. This chapter traces the history of tissue extraction in gynecology and reviews the evolving scientific data and opinions regarding the future of morcellation. RECENT FINDINGS: Since the initial Food and Drug Administration warning about morcellation in 2014, subsequent studies do not support the Food and Drug Administration's high incidence of occult uterine cancer. Current research continues, focusing on methods of contained tissue morcellation, both laparoscopically and vaginally. SUMMARY: Minimally invasive surgical techniques have revolutionized gynecology, drastically reducing the need for open procedures. To maximize patient safety while preserving the rapid recovery and low morbidity of laparoscopic and vaginal approaches, optimal methods of tissue extraction need to be developed and promulgated. PMID- 29232259 TI - The experience of head and neck cancer survivorship (including laryngectomy): an integrated biopsychosocial model. AB - PURPOSE OF REVIEW: The head and neck cancer (HNC) survivorship experience is unique among cancer populations. This review seeks to explore the HNC survivor experience associated with altered upper aerodigestive tract (UADT) function using principles of survivorship. RECENT FINDINGS: HNC survivors experience complex physical, functional, and psychosocial challenges related to UADT dysfunction. Interventions need to address all of these dimensions being mindful of the survivor experience. Studies reveal related unmet needs of both HNC survivors and their family members. An expose of the HNC survivorship experience is timely since 2016/2017 contains the release of landmark position papers and guidelines in the field. These address the unique challenges faced by the HNC population, their management, and the triad psychosocial, functional, and physical survivor burden. Such developments will drive future care. SUMMARY: The head and neck survivorship experience is characterized by complex changes with broad impact when examined in an experiential framework. HNC survivor care demands clinical excellence from multiple disciplines that are positioned to enact recent HNC guidelines and adopt survivorship principles. Future research in this population that explores experiential aspects of altered UADT function would be valuable in informing clinical practice. A biopsychosocial framework is presented for conceptualizing the HNC survivorship experience. PMID- 29232260 TI - High-Alert Medication Stratification Tool-Revised: An Exploratory Study of an Objective, Standardized Medication Safety Tool. AB - OBJECTIVE: To develop an objective tool designed to standardize the identification of high-alert medications (HAMs) according to patient safety risk. METHODS: Medications were evaluated using the High-Alert Medication Stratification Tool (HAMST). Tool revision occurred through assessing medications on an organization-approved HAM list and comparing scores with control medications not included on the list. Because of variations in HAMST interpretation by end users in interdisciplinary committees, a revision of the scoring tool was completed to create the High-Alert Medication Stratification Tool-Revised (HAMST-R), and the assessment was repeated. Both tools range from 0 to 10, with 10 describing agents with highest risk. RESULTS: The median (interquartile range [IQR]) initial HAM (n = 44) score using HAMST was 6 (5-7). The median (IQR) control (n = 45) score was 1 (0-2). Using the modified tool, HAMST-R, the median (IQR) HAM score was 4 (4-6) versus 1 (0-1) for controls. Scores for HAMs were significantly higher than controls using both tools (P < 0.001). A HAMST-R score of 4 or higher defines medications as high alert, as this score includes 75% of HAMs and no controls. CONCLUSIONS: Through this exploratory study, clarification of the tool was required to increase its concurrent validity, interrater reliability, and implementation among other health systems. The revised tool, HAMST-R, is a newly developed, objective tool for standardized identification of HAMs. The tool may also be used for prospective identification of medications as high risk to patient safety during formulary review. PMID- 29232261 TI - Long-chain omega-3 fatty acids and cancer: any cause for concern? AB - PURPOSE OF REVIEW: Recently, concerns have been raised with regard to the recommended doses of marine long-chain omega-3 polyunsaturated fatty acids (LC omega-3 PUFAs) especially in relation to cancer risk and treatment. There is urgent need to clarify this point. This review considers the most recent evidence related to the potential risk of developing cancer with high LC-omega-3 PUFA intakes, and possible research strategies to better elucidate this matter. RECENT FINDINGS: The latest published recommendations have still highlighted the usefulness of an increased dietary intake of LC-omega-3 PUFAs for the prevention of some cardiovascular diseases. However, LC-omega-3 PUFAs have been related to the potential development and progression of cancer, and considerable debate exists on this issue. SUMMARY: The use of biomarkers reflecting the intake of LC omega-3 PUFAs as cancer risk markers is discussed, as well as the possibility that the reported beneficial/deleterious effects may be confined to specific subpopulations on the basis of genetic, metabolic, and nutritional characteristics. Recent advances on new strategies for a safer intake of LC-omega 3 PUFAs will be considered, as their dietary sources may be contaminated by toxic/carcinogenic compounds. Potentially future directions in this important research area are also discussed. PMID- 29232262 TI - Intermittent versus continuous feeding in critically ill adults. AB - PURPOSE OF REVIEW: Early enteral nutrition is recommended in critically ill adult patients. The optimal method of administering enteral nutrition remains unknown. Continuous enteral nutrition administration in critically ill patients remains the most common practice worldwide; however, its practice has recently been called into question in favor of intermittent enteral nutrition administration, where volume is infused multiple times per day. This review will outline the key differences between continuous and intermittent enteral nutrition, describe the metabolic responses to continuous and intermittent enteral nutrition administration and outline recent studies comparing continuous with intermittent enteral nutrition administration on outcomes in critically ill adults. RECENT FINDINGS: In separate studies, healthy humans and critically ill patients receiving intermittent nutrition (infused over 3 h) had improved whole body protein balance from negative to positive. These studies did not have an isonitrogenous control group. A randomized controlled trial of intermittent bolus versus continuous enteral nutrition in healthy humans found that intermittent bolus feeding increased mesenteric arterial blood flow, increased insulin and peptide YY and reduced blood glucose concentration. A randomized controlled trial comparing intermittent bolus to continuous enteral nutrition in critically ill patients did not demonstrate clinically relevant differences in glycemic variability, insulin use or tube feeding volume or caloric intake between the two groups. SUMMARY: Studies in healthy humans suggest that intermittent nutrient administration, as opposed to continuous, improves whole body protein synthesis. Unfortunately, similarly designed studies are lacking for critically ill patients. Future studies evaluating the impact of intermittent versus continuous nutrition administration on critical care outcomes should take into account factors such as protein quantity, protein quality and delivery route (enteral and/or parenteral). Until further studies are conducted in critically ill patients, a recommendation for or against intermittent nutrition delivery cannot be made. PMID- 29232263 TI - Can the critically ill patient generate sufficient energy to facilitate exercise in the ICU? AB - PURPOSE OF REVIEW: Trials of physical rehabilitation post critical illness have yet to deliver improved health-related quality of life in critical illness survivors. Muscle mass and strength are lost rapidly in critical illness and a proportion of patients continue to do so resulting in increased mortality and functional disability. Addressing this issue is therefore fundamental for recovery from critical illness. RECENT FINDINGS: Altered mitochondrial function occurs in the critically ill and is likely to result in decreased adenosine tri phosphate (ATP) production. Muscle contraction is a process that requires ATP. The metabolic demands of exercise are poorly understood in the ICU setting. Recent research has highlighted that there is significant heterogeneity in energy requirements between critically ill individuals undertaking the same functional activities, such as sit-to-stand. Nutrition in the critically ill is currently thought of in terms of carbohydrates, fat and protein. It may be that we need to consider nutrition in a more contextual manner such as energy generation or management of protein homeostasis. SUMMARY: Current nutritional support practices in critically ill patients do not lead to improvements in physical and functional outcomes, and it may be that alternative methods of delivery or substrates are needed. PMID- 29232264 TI - Fish oil-derived n-3 polyunsaturated fatty acids for the prevention and treatment of sarcopenia. AB - PURPOSE OF REVIEW: Muscle mass and function decline progressively starting in middle age, which can result in sarcopenia and affect people's mobility and independence later in life. Exercise training and increased protein intake are typically recommended to counteract the age-associated decline in muscle mass and function. However, few people comply with exercise recommendations and the effectiveness of high-protein intake to halt the decline in muscle mass and function has not been proven. This review aims to explore recent developments in the potential for fish-oil derived n-3 polyunsaturated fatty acids (n-3 PUFA) to improve muscle mass and function in older people. RECENT FINDINGS: The results from several recent studies demonstrate that dietary supplementation with fish oil-derived n-3 PUFA stimulates muscle protein synthesis and improves muscle mass and function in sedentary older adults and augments the resistance exercise training-induced increase in muscle strength in older adults. The exact mechanisms by which fish oil-derived n-3 PUFAs exert their beneficial effects on muscle mass and function remain to be elucidated. SUMMARY: Fish-oil supplementation has antisarcopenic effects and should be considered in the clinical care of older adults. PMID- 29232265 TI - The Value of Preoperative Exercise and Education for Patients Undergoing Total Hip and Knee Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Existing evidence regarding the value of preoperative education and/or exercise (prehabilitation) for patients undergoing total joint replacement is conflicting. The purpose of this study was to conduct an updated, comprehensive systematic review with meta-analyses to determine the longitudinal effects and efficacy of prehabilitation on postoperative outcomes in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA). METHODS: We searched 11 electronic databases (MEDLINE, AMED, CINAHL, Embase, Scopus, ProQuest, PEDro, SportDiscus, PsycINFO, and Cochrane) from their inception to May 2016 for randomized controlled trials that compared changes in pain, function, strength, anxiety, and hospital length of stay following THA or TKA. Two reviewers independently determined study eligibility, rated study quality, and extracted data. There were no restrictions on study dates, patient characteristics, or the follow-up time point at which postoperative outcomes were measured. We excluded trials comparing 2 interventions. Methodological quality assessments were performed using the Cochrane risk-of-bias tool. We calculated pooled estimates, with 95% confidence intervals (CIs), of standardized mean differences (SMDs). RESULTS: Thirty-five studies with 2,956 patients were included. After a preoperative program, patients undergoing THA, but not TKA, had significantly less postoperative pain than controls (SMD = 0.15, 95% CI = 0.03 to 0.27, p = 0.017). Postoperative function was also significantly improved compared with controls, with similar improvement after THA (SMD = 0.32, 95% CI = 0.15 to 0.50, p < 0.001) and TKA (SMD = 0.32, 95% CI = 0.06 to 0.57, p = 0.015). Significantly greater quadriceps strength was observed after TKA (SMD = 0.42, 95% CI = 0.16 to 0.68, p = 0.002). No significant differences in hamstring strength were observed between groups after TKA (p = 0.132). Small-to-moderate but nonsignificant improvements in anxiety (SMD = 0.17, 95% CI = -0.05 to 0.39; p = 0.128) were observed after THA, and length of stay was significantly shorter after TKA (SMD = 0.54, 95% CI = 0.24 to 0.84, p < 0.001) and THA (p = 0.027). CONCLUSIONS: Overall effect sizes for prehabilitation were small to moderate. In patients undergoing TKA, significant improvements were observed in function, quadriceps strength, and length of stay. In patients undergoing THA, significant improvements were observed in pain, function, and length of stay. Included studies were inconsistent with regard to the types of outcome measures reported, and the quality of the interventions varied. A more standardized approach to reporting of clinical trial interventions and patient compliance is needed to thoroughly evaluate the effects of prehabilitation on postoperative outcomes. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 29232266 TI - Controversies Surrounding the Management of the Isolated Type-II Radial-Head Fracture. PMID- 29232268 TI - Pelvic Organ Prolapse Repair Using the Uphold Vaginal Support System: 5-Year Follow-up. AB - OBJECTIVE: This study aimed to assess the long-term (5 years) outcomes of the Uphold Vaginal Support System for symptomatic vaginal apical prolapse with or without anterior colporraphy. METHODS: In total, 164 (81.2%) of 202 women operated on in 24 centers were reached for follow-up. Outcomes were assessed by using the Pelvic Organ Prolapse Quantification, the Pelvic Floor Distress Inventory 20, and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire questionnaires. Pain on pelvic area was evaluated using a visual analog scale. Adverse events and secondary procedures were recorded. RESULTS: An optimal outcome at the apical compartment (Pelvic Organ Prolapse Quantification stage <2) was achieved in 83.3% of patients (94% at 1 year). Quality of life improved in 78.8% of the women, with a significant decrease of bother in all domains (pelvic organ prolapse, rectoanal, urinary) compared with that preoperatively. Overall sexual satisfaction improved after 1 year, but the number of sexually active women was low. In total, 19.7% of patients had undergone repeat pelvic surgery during follow-up, most common of these were midurethral sling (38.4%), followed by prolapse-related operations. Mesh removal due to pain was performed in 3 women. Number of women with any pain decreased overall from 1 to 5 years, but 3 women had persistent severe pain despite treatment efforts (visual analog scale >=7). CONCLUSIONS: Apical objective and subjective outcomes were sustained after 5 years in women operated on for apical compartment prolapse by the Uphold Vaginal Support System. PMID- 29232267 TI - Concomitant Anterior Repair, Preoperative Prolapse Severity, and Anatomic Prolapse Outcomes After Vaginal Apical Procedures. AB - OBJECTIVE: The aim of the study was to compare anterior and overall prolapse prevalence at 1 year in surgical participants with or without concomitant anterior repair (AR) at the time of sacrospinous ligament fixation (SSLF) or uterosacral ligament suspension (ULS). METHODS: This is a secondary analysis of two surgical trials; concomitant AR was performed at surgeon's discretion. Anterior anatomic success was defined as pelvic organ prolapse quantification of prolapse point Ba <=0 and overall success was defined as pelvic organ prolapse quantification points Ba, Bp, and C <=0 at 12 months. RESULTS: Sixty-three percent (441/701) of the participants underwent concomitant AR and were older, more often postmenopausal, had previous hysterectomy, and had higher-stage anterior, but not apical prolapse. Anterior anatomic success was marginally but statistically better in the combined group (SSLF and ULS) with concomitant AR (82% vs 80%, P = 0.03). In subanalyses, the improvement in anatomic support with AR was observed only in the SSLF subgroup (81% vs 73%, P = 0.02) and mostly in the SSLF subgroup with higher preoperative stage (74% vs 57%, P = 0.02). Anterior repair did not improve success rates in participants with lower-stage prolapse or undergoing ULS. Overall success rates were similar to anterior anatomic success rates. Participants with higher-stage preoperative anterior prolapse had significantly lower success rates. CONCLUSIONS: In the absence of clinical trial data, this analysis suggests an AR should be considered for women with higher stage prolapse undergoing an SSLF. Preoperative prolapse severity is a strong predictor of poor anatomic outcomes with native tissue vaginal apical surgeries. PMID- 29232269 TI - MR-guided biopsy and focal therapy: new options for prostate cancer management. AB - PURPOSE OF REVIEW: Options for prostate cancer management are rapidly expanding. The recent advent of MRI technology has led to guided prostate biopsies by radiologists working in-bore or by urologists using MR/US fusion technology. The resulting tumor visualization now provides the option of focal therapy. Currently available are highly directed energies - focused ultrasound (HIFU), cryotherapy, and laser - all offering the hope of curing prostate cancer with few side effects. RECENT FINDINGS: MRI now enables visualization of many prostate cancers. MR/US fusion biopsy makes possible the targeted biopsy of suspicious lesions efficiently in the urology clinic. Several fusion devices are now commercially available. Focal therapy, a derivative of targeted biopsy, is reshaping the approach to treatment of some prostate cancers. Focal laser ablation, originally done in the MRI gantry (in-bore), promises to soon become feasible in a clinic setting (out-of-bore) under local anesthesia. Other focal therapy options, including HIFU and cryotherapy, are currently available. Herein are summarized outcomes data on focal therapy modalities. SUMMARY: MRI-guided biopsy is optimizing prostate cancer diagnosis. Focal therapy, an outgrowth of guided biopsy, promises to become a well tolerated and effective approach to treating many men with prostate cancer while minimizing the risks of incontinence and impotence from radical treatment. PMID- 29232270 TI - Novel focal therapy treatment options for prostate cancer. AB - PURPOSE OF REVIEW: Examine and discuss novel focal therapy treatment options for prostate cancer. RECENT FINDINGS: With the widespread adoption of mpMRI-guided biopsies for prostate cancer, use of image-guided treatment of prostate cancer has increased. Focal therapies leading to partial gland ablation such as partial prostatectomy, focal laser ablation, irreversible electroporation, vascular targeted photodynamic therapy, and focal radiofrequency ablation have emerged and begun to be properly evaluated. This review covers published phase 1 and 2 trials of each treatment and discusses potential limitations of each modality. SUMMARY: Focal therapy of prostate cancer is being actively investigated. On the basis of limited published data, the treatments appear to be well tolerated and have an acceptable side effect profile. Importantly, short-term oncologic control has been mixed and there are no long-term outcomes. The acquisition of more data is essential to evaluate these novel technology platforms. PMID- 29232271 TI - Robotic surgery in urology: facts and reality. What are the real advantages of robotic approaches for prostate cancer patients? AB - PURPOSE OF REVIEW: Despite the worldwile increasing use of robotic assistance for oncology surgery, no level 1 evidence-based benefit favoring robot-assisted radical prostatectomy (RARP) versus pure laparoscopic or open approaches has been demonstrated. We aimed to perform an update of the available evidence by evaluating most recent 2016-2017 data. RECENT FINDINGS: Population-based and prospective nonrandomized studies and one phase III randomised trial have been recently published. Early results from the phase III trial suggested that RARP led to similar early functional and oncologic outcomes compared with open radical prostatectomy. Shorter operative time, hospital stay, and lower complications rate and blood loss were reported in RARP group compared with open radical prostatectomy group. Population-based data did not demonstrate any benefit from one approach over another in terms of functional and oncologic outcomes. Robot assistance is predictive for improved potency recovery in organ-confined tumor in one large prospective trial. Main limitations, different among studies, were lack of randomization or single operator cohorts, short-term follow-up, and absence of confounding factors analysis. SUMMARY: Robotic assistance seems to confer better results than open radical prostatectomy procedures in terms of intra- and immediate postoperative parameters (operative time, blood loss and hospital stay). Clear advantages of one technique over another on robust functional or oncologic endpoints remain unproven. PMID- 29232272 TI - Relative Effects of Age, Race, and Stage on Mortality in Gestational Choriocarcinoma. AB - OBJECTIVE: Gestational choriocarcinoma is a malignant form of gestational trophoblastic disease that usually arises after a molar pregnancy, but may follow any antecedent pregnancy. Investigations in this rare cancer are limited. We evaluated the prognostic effects of age, race, and stage in choriocarcinomas diagnosed for 4 decades. METHODS: Patients diagnosed as having gestational choriocarcinoma between 1973 and 2014 from the Surveillance, Epidemiology, and End Results program were eligible. Relationships with overall survival and cancer specific survival were evaluated using log-rank testing and Cox modeling. Multivariate analyses included adjustments for age, race, and stage. RESULTS: There were 947 patients with choriocarcinoma including 403 non-Hispanic white (NHW) patients, 473 with distant stage, and 142 who died. Median age at diagnosis was 25 years for non-Hispanic black (NHB) patients and 35 years for Asian/Pacific Islanders (API) compared with 29 years for NHW patients (P = 0.0001). Five-year overall survival varied between 82% and 92% when diagnosed at the age of at least 40 years compared with less than 20 years (P < 0.0001), and from 85% to 95% in patients with distant vs local disease (P < 0.0001), respectively. Multivariate analysis demonstrated that age, race, and stage were independent predictors of mortality. Risk of death increased incrementally in patients diagnosed at 20 to 39 years of age (adjusted hazard ratio [aHR], 3.87; 95% confidence interval [CI], 1.69-8.86; P = 0.001) and at least 40 years of age (aHR, 7.18; 95% CI, 2.95 17.49; P < 0.0001) compared with 20 years or younger. Non-Hispanic black patients were the only racial group at higher risk of death compared with NHW patients (aHR, 1.86; 95% CI, 1.22-2.82; P < 0.004). Distant vs local disease added an additional risk of death (aHR, 2.43; 95% CI, 1.57-3.75; P < 0.0001) over that attributable to age at diagnosis and NHB race. Similar relationships to cancer specific survival were also observed (P < 0.05). CONCLUSIONS: Most patients with choriocarcinoma have excellent prognosis. However, NHB patients and patients who are diagnosed at the age of at least 20 years or have distant stage have significantly worse mortality. PMID- 29232273 TI - ACOG Practice Bulletin No. 191: Tubal Ectopic Pregnancy. AB - Ectopic pregnancy is defined as a pregnancy that occurs outside of the uterine cavity. The most common site of ectopic pregnancy is the fallopian tube. Most cases of tubal ectopic pregnancy that are detected early can be treated successfully either with minimally invasive surgery or with medical management using methotrexate. However, tubal ectopic pregnancy in an unstable patient is a medical emergency that requires prompt surgical intervention. The purpose of this document is to review information on the current understanding of tubal ectopic pregnancy and to provide guidelines for timely diagnosis and management that are consistent with the best available scientific evidence. PMID- 29232274 TI - The Diuretic Potential of Sacubitril/Valsartan: A Tale of 2 Patients. AB - BACKGROUND: Heart failure prevalence continues to rise in the United States causing significant morbidity and mortality and costing billions in healthcare expenditures. Consensus guidelines updated in 2016 recommend an angiotensin receptor-neprilysin inhibitor (ARNi) as a therapeutic option in lieu of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for the management of stage C heart failure with reduced ejection fraction (HFrEF). For chronic HFrEF patients with New York Heart Association class II or III symptoms tolerating an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, a change in therapy to an ARNi is recommended to further reduce morbidity and mortality. PURPOSE: We present a brief case series of 2 patients initiated on ARNi therapy for treatment of HFrEF and evaluate their fluid status and diuretic needs before and after ARNi dose optimization. CONCLUSIONS: After titration to target-dose ARNi therapy, both patients demonstrated improved fluid and electrolyte balance, as well as a reduction in diuretic therapy requirements, suggesting a mechanism of diuresis attributable to ARNi therapy. CLINICAL IMPLICATIONS: Angiotensin receptor-neprilysin inhibitor therapy seems to promote a clinically relevant diuresis in heart failure patients because of increased levels of functioning natriuretic peptides. Awareness of this diuretic potential may allow for optimization of heart failure regimens with pharmacologic agents demonstrated to improve morbidity and mortality, while preventing adverse effects that may occur with overdiuresis. PMID- 29232275 TI - Complex Decision-Making in Heart Failure: A Systematic Review and Thematic Analysis. AB - BACKGROUND: Heart failure follows a highly variable and difficult course. Patients face complex decisions, including treatment with implantable cardiac defibrillators, mechanical circulatory support, and heart transplantation. The course of decision-making across multiple treatments is unclear yet integral to providing informed and shared decision-making. Recognizing commonalities across treatment decisions could help nurses and physicians to identify opportunities to introduce discussions and support shared decision-making. OBJECTIVE: The specific aims of this review are to examine complex treatment decision-making, specifically implantable cardiac defibrillators, ventricular assist device, and cardiac transplantation, and to recognize commonalities and key points in the decisional process. METHODS: MEDLINE, CINAHL, PsycINFO, and Web of Science were searched for English-language studies that included qualitative findings reflecting the complexity of heart failure decision-making. Using a 3-step process, findings were synthesized into themes and subthemes. RESULTS: Twelve articles met criteria for inclusion. Participants included patients, caregivers, and clinicians and included decisions to undergo and decline treatment. Emergent themes were "processing the decision," "timing and prognostication," and "considering the future." Subthemes described how participants received and understood information about the therapy, making and changing a treatment decision, timing their decision and gauging health status outcomes in the context of their decision, the influence of a life or death decision, and the future as a factor in their decisional process. CONCLUSIONS: Commonalities were present across therapies, which involved the timing of discussions, the delivery of information, and considerations of the future. Exploring this further could help support patient-centered care and optimize shared decision-making interventions. PMID- 29232276 TI - Contemporary protease inhibitors and cardiovascular risk. AB - PURPOSE OF REVIEW: To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. RECENT FINDINGS: For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted with ritonavir (/r)], darunavir/r has been shown to be associated with increased CVD risk. The effect is cumulative with longer exposure increasing risk and an effect size comparable to what has been observed for previously developed protease inhibitors. Biological mechanisms may be overlapping and include perturbed lipid metabolism and accumulation of cholesterol derivatives within macrophages. Conversely, atazanavir/r has not been shown to be associated with CVD, possibly because of its ability to increase cardioprotective bilirubin levels. SUMMARY: Evidence linking protease inhibitors to CVD is based on observational studies only, whereas plausible biological explanations are well established and derived from randomized trials and controlled experiments. Given the possible association with clinical disease, a conservative approach to apply the data in daily practise is proposed which is focused on individualization of care based on underlying risk of CVD. PMID- 29232277 TI - Scaling up HIV self-testing in sub-Saharan Africa: a review of technology, policy and evidence. AB - PURPOSE OF REVIEW: HIV self-testing (HIVST) can provide complementary coverage to existing HIV testing services and improve knowledge of status among HIV-infected individuals. This review summarizes the current technology, policy and evidence landscape in sub-Saharan Africa and priorities within a rapidly evolving field. RECENT FINDINGS: HIVST is moving towards scaled implementation, with the release of WHO guidelines, WHO prequalification of the first HIVST product, price reductions of HIVST products and a growing product pipeline. Multicountry evidence from southern and eastern Africa confirms high feasibility, acceptability and accuracy across many delivery models and populations, with minimal harms. Evidence on the effectiveness of HIVST on increased testing coverage is strong, while evidence on demand generation for follow-on HIV prevention and treatment services and cost-effective delivery is emerging. Despite these developments, HIVST delivery remains limited outside of pilot implementation. SUMMARY: Important technology gaps include increasing availability of more sensitive HIVST products in low and middle-income countries. Regulatory and postmarket surveillance systems for HIVST also require further development. Randomized trials evaluating the effectiveness and cost effectiveness under multiple distribution models, including unrestricted delivery and with a focus on linkage to HIV prevention and treatment, remain priorities. Diversification of studies from west and central Africa and around blood-based products should be addressed. PMID- 29232278 TI - Low-dose oxygen therapy in COPD patients: are there any radiation-like risks? AB - PURPOSE OF REVIEW: Low-dose oxygen (LDO) supplementation is used by millions of COPD patients worldwide. The therapeutic benefits of LDO supplementation are well known. There are also several concerns regarding the potential for cellular harm from LDO in COPD patients. This review summarizes the current arguments and evidence pertaining to this important topic. RECENT FINDINGS: LDO therapy has been used in COPD patients for more than 50 years. Over the years, data from randomized controlled trials has confirmed that LDO provides survival benefit in COPD patients with severe hypoxemia. Recent data, however, show that LDO does not provide any morality benefit for patients with a less severe degree of hypoxemia. There are several theoretical concerns regarding use of LDO in COPD patients, including radiation-like cellular risks because of oxygen toxicity. However, none of these have been validated in human clinical trials and remain somewhat peripheral to the clinician deciding whether or not to initiate LDO in a hypoxemic COPD patient. SUMMARY: There is high-quality evidence that LDO is both well tolerated and highly efficacious for patients with COPD. There are several theoretical concerns regarding damage from oxygen free radicals from LDO in COPD patients. However, none of these have been validated or confirmed in human clinical trial data. Thus, the benefits of LDO clearly outweigh the risks from any theoretical concerns about oxygen toxicity. PMID- 29232279 TI - Association of chronic obstructive pulmonary disease with mild cognitive impairment and dementia. AB - PURPOSE OF REVIEW: As age expectancy increases, both dementia and chronic obstructive pulmonary disease (COPD) have become more prevalent. Dementia and COPD together, however, occur more commonly than would be predicted from the incidence of either alone, suggesting a link between these two common senescent diseases. The purpose of this article is to review the extant literature and report findings in a clinically meaningful manner. We will look at the level of evidence, the risk factors for co-occurrence of the two diseases and the differential effects upon cognitive domains in the population with dementia and COPD. RECENT FINDINGS: Cognitive impairment in patients with COPD may be 'dose dependent' with the duration of COPD. Patients with COPD appear to develop nonamnestic mild cognitive impairment (MCI) as opposed to amnestic MCI. Newer studies exploring the impact of oxygen therapy and pulmonary rehabilitation upon cognitive function have reported some positive findings. SUMMARY: Higher prevalence of MCI/dementia is seen in patients with COPD compared with age matched controls. Imaging findings and dementia/MCI biomarkers provide preliminary evidence for an indirect association of the two conditions. Although no causality can be drawn with the available data, there is some indication that the severity of hypoxemia correlates with the severity of cognitive dysfunction. PMID- 29232280 TI - Accuracy of self-reported hypertension: a systematic review and meta-analysis. AB - OBJECTIVE: To estimate the sensitivity and specificity of self-reported hypertension (HTN) as compared with the clinical diagnosis in epidemiological studies. METHODS: We searched MEDLINE, Embase, Scopus, Web of Science, LILACS, Google Scholar, and ProQuest Dissertations & Theses Global: Health & Medicine databases. In addition, we screened the references' lists of relevant reports to identify potentially eligible articles. There were no date or language restrictions. Studies were selected by two independent reviewers, who also extracted data and assessed methodological quality using the Quality Assessment of Diagnostic Accuracy Studies criteria. A meta-analysis was performed to summarize sensitivity and specificity across studies and estimate heterogeneity. RESULTS: Out of 2304 records, 22 were included, corresponding to a population of 112 517 adults (55% women). There was substantial variation in sensitivity and specificity across countries and age groups. Several different techniques, devices, and reference ranges were used to diagnose HTN, and self-reporting underestimated its prevalence in the majority of studies. The sensitivity was 42.1% (95% confidence interval 30.9-54.2) and the specificity was 89.5% (95% confidence interval 84.0-93.3), with high heterogeneity (I > 99%). CONCLUSION: Less than half of patients with HTN would not be identified by self-reporting in epidemiological studies. Self-reported HTN has important limitations and may represent an important source of bias in research depending on regional, socioeconomic, and cultural differences. PMID- 29232282 TI - Selected Food/Herb-Drug Interactions: Mechanisms and Clinical Relevance. AB - BACKGROUND: Food/Herb-drug interactions have become a major problem in health care. These interactions can lead to loss of therapeutic efficacy or toxic effects of drugs. AREAS OF UNCERTAINTY: To probe the clinical relevance of such interactions, the impact of food/herb intake on the clinical effects of drug administration has to be evaluated. Failure to identify and efficiently manage food-drug interactions can lead to serious consequences. A comprehensive knowledge of the mechanisms that underpin variability in disposition will help optimize therapy. DATA SOURCES: Electronic search of literatures from relevant databases were conducted. A total of 58 original scientific reports/review articles were obtained with the search strategy; of which 25 were found eligible to be included in the present review. Required data were extracted from these studies, and their methodologies were assessed. RESULTS AND CONCLUSIONS: This review updates our knowledge on clinical food-drug interactions with emphasis on mechanism and clinical implications. Results obtained from literature search identified interactions with selected foods/herbs generated from in vivo and in vitro studies. For example, interaction studies in humans revealed a reduction in the bioavailability of mercaptopurine when taken concurrently with substances containing xanthine oxidase (eg, cow milk); a reduction in the bioavailability of quinine with Garcinia kola; increased bioavailability/toxicity of felodipine, nifedipine, saquinavir, sildenafil with grape juice; increased bioavailability of felodipine, cisapride with red wine and diminished bioavailability of fexofenadine with apple. Pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. By evaluating the dietary patterns of patients and use of prescribed medications, health professionals will be well informed of potential interactions and associated adverse effects. PMID- 29232281 TI - Cross-sectional Areas of the Thoracic Aorta in Children and Adolescents With Repaired Tetralogy of Fallot Obtained by Cardiac Magnetic Resonance Angiography. AB - PURPOSE: Dilatation of the thoracic aorta is a well-known finding in corrected Tetralogy of Fallot. Complications are rare but can be life-threatening. Standard 1-dimensional (1D) measurements have several limitations. We sought to establish contrast-enhanced magnetic resonance angiography cross-sectional areas of the aorta that could serve as reference values and to identify parameters that are associated with aortic dilatation. MATERIALS AND METHODS: We enrolled 101 children and adolescents. The aortic areas were measured at the level of the aortic sinus (AS), the sinotubular junction (STJ), the ascending aorta (AA), the brachiocephalic trunk (TBC), and the descending aorta (DA). Sex-specific aortic dimensions were presented as percentile curves as well as regression equations. Furthermore volumetric and functional parameters as well as clinical data were analyzed to identify parameters that are associated with aortic dilatation. RESULTS: Aortic areas (mm) for female subjects were 139+366*body surface area (BSA) for the AS, 134+255*BSA for the STJ, 113+239*BSA for the AA, 88+185*BSA proximal to the TBC, and 2.9+88*BSA for the DA. Aortic areas (mm) for male subjects were 162+403*BSA for the AS, 171+258*BSA for the STJ, 151+233*BSA for the AA, 73+206*BSA proximal to the TBC, and 21+80*BSA for the DA. The postoperative interval and age at examination were parameters associated with aortic size. CONCLUSIONS: We provide aortic areas in children and adolescents after correction of Tetralogy of Fallot measured by contrast-enhanced magnetic resonance angiography. Our 2D data may better depict the geometry of enlarged aortae than standard 1D diameters and serve as reference values for evaluating aortic disease in these patients. PMID- 29232283 TI - Levocarnitine for the Treatment of Valproic Acid-Induced Hyperammonemic Encephalopathy in Children: The Experience of Large, Tertiary Care Pediatric Hospital and a Poison Center. AB - BACKGROUND: Although rare, symptomatic hyperammonemia is sometimes associated with valproic acid (VPA), especially in children. L-carnitine (levocarnitine), sometimes classified as an essential amino acid, is vital to mitochondrial utilization of fatty acids and can be helpful in treating this condition. The data supporting this, however, are limited. STUDY QUESTION: The aim of the study was to illustrate the role of L-carnitine in the treatment of patients with VPA induced hyperammonemic encephalopathy (VPE) at 2 different institutions. METHODS: Medical records of affected patients were reviewed; data collected included exposure history, clinical manifestations, physical examination, and laboratory values. RESULTS: There were 13 cases of VPE; 12 were associated with therapeutic dosing and 1 with an overdose. The maximum ammonia concentration was 557 MUmol/L, and blood concentrations of VPA ranged from 68 to 600 MUg/mL (therapeutic range 50-100 MUg/mL). In all cases, liver function tests were normal or only mildly increased. In this study, 12 patients received a daily dose of L-carnitine 100 mg/kg, and 1 received 200 mg/kg (intravenous infusion over 30 minutes) divided every 8 hours until clinical improvement. All patients made a full recovery. None developed adverse effects or reactions, and no cases of toxicity were reported. CONCLUSION: Our series suggests that intravenous L-carnitine, at a dose of 100 mg.kg.d in 3 divided doses each over 30 minutes until clinical improvement occurs, is a safe and effective treatment in the management of VPE in children. PMID- 29232284 TI - Thalidomide as a Cough Suppressant in Idiopathic Pulmonary Fibrosis. PMID- 29232285 TI - Cyclophosphamide-Induced Hearing Loss: Reversibility and Preventive Strategies. PMID- 29232286 TI - Poorly Differentiated Esophageal Neuroendocrine Carcinoma Treated With the CDK4/6 Inhibitor, Palbociclib: A Case Report and Literature Review. PMID- 29232287 TI - The Effects of Known Cardioprotective Drugs on Proinflammatory Cytokine Secretion From Human Coronary Artery Endothelial Cells. AB - BACKGROUND: Endothelial cell dysfunction in diabetes is involved in the pathogenesis and progression of premature atherosclerosis. High-dextrose has been shown to induce both oxidative stress and endoplasmic reticulum stress in cultured human coronary artery endothelial cells (HCAEC). STUDY QUESTION: To determine whether or not several classes of cardioprotective drugs inhibit proinflammatory cytokine expression by HCAEC. MEASURES AND OUTCOMES: To determine the effects of high dextrose on expression of proinflammatory cytokines by HCAEC, cells were treated with either 5.5 mM or 27.5 mM dextrose for 24 hours and interleukin-1beta (IL-1beta), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor alpha were measured by enzyme immunoassay in the presence or absence of known cardioprotective drugs, including select beta-blockers, statins, and renin-angiotensin system inhibitors. RESULTS: IL-1beta levels increased significantly in cells treated with high dextrose; however, IL-6 and IL-8 levels did not change. Treatment of cells with carvedilol, atenolol, and propranolol decreased levels of all 3 cytokines in cells exposed to either 5.5 or 27.5 mM dextrose. Similar effects on IL-1beta, IL-6, and IL-8 levels were observed when cells were treated with simvastatin, pravastatin, and the renin-angiotensin system inhibitors spironolactone, captopril, lisinopril, candesartan, and losartan. No Il-2 or tumor necrosis factor alpha expression was observed in any of the experiments indicating that HCAEC do not express these cytokines. CONCLUSIONS: We conclude that each of the classes of drugs tested possess pleiotropic anti-inflammatory activities and are effective in both low- and high-dextrose-treated cells. PMID- 29232288 TI - Low-Dose Rituximab for Hemolytic Anemia Retreatment in a Patient With Systemic Lupus Erythematosus. PMID- 29232289 TI - Phenytoin-Associated Hypocoagulability in a Septic Patient. PMID- 29232290 TI - Message From the President. PMID- 29232293 TI - Pressure and Flow Characteristics of a Novel Bidirectional Cannula for Cardiopulmonary Bypass. AB - OBJECTIVE: Femoral arterial cannulation is associated with a significant risk of lower limb ischemia. The aim of the study was to assess the pressure and flow in the femoral artery using a novel bidirectional femoral cannula in a sheep model of peripheral cardiopulmonary bypass. METHODS: Peripheral cardiopulmonary bypass was established using a multistage venous cannula inserted into the internal jugular vein and the bidirectional or a conventional arterial cannula into the femoral artery in seven adult ewes. Systemic and distal perfusion pressures and flow rates were measured during cardiopulmonary bypass with flow rates of 1, 2, 3, and 4 L/min. Lower limb venous oxygen saturation and lactate levels were also measured. RESULTS: A significantly higher blood flow in the lower limb using the bidirectional cannula was observed and compared with a conventional cannula at all flow rates (mean flow 115 mL/min vs 10 mL/min, P < 0.05). The mean distal perfusion pressure was also significantly higher in the bidirectional cannula group (86 mm Hg vs 45 mm Hg at 4 L/min of flow, P < 0.05). The bidirectional cannula was associated with higher venous oxygen saturations in the lower limb than in the conventional cannula group; however, lower limb lactate production was similar in the two groups. CONCLUSIONS: This in vivo data demonstrates superior distal flow and pressure characteristics of a novel bidirectional cannula compared with a conventional femoral cannula during peripheral cardiopulmonary bypass. PMID- 29232294 TI - The Need for Consistent Predictors of Success for Surgical Ablation of Atrial Fibrillation: A Call to Action. AB - OBJECTIVE: As with any medical therapy, identification of consistent and reliable outcome predictors is essential to understanding the efficacy of surgical ablation for atrial fibrillation. We originally intended to conduct a meta analysis on atrial fibrillation surgical ablation to identify clinical factors that are most often associated with success. However, these studies are greatly heterogeneous. We conducted a systematic review to identify trends in outcome predictors and to provide recommendations for more uniform data analysis and reporting. METHODS: Relevant studies published between January 2005 and September 2013 were identified. To minimize heterogeneity, data were extracted only from multivariate analyses of outcome predictors. The initial approach for meta analytic analyses was abandoned for a systematic review approach. RESULTS: From 604 initial citations, 19 studies with 5200 patients were included in the review. Systematic review of multivariable atrial fibrillation recurrence rates after surgical ablation revealed that studies were statistically heterogeneous, but atrial fibrillation recurrence after surgical ablation in mid-term follow-up was most often predicted by left atrium size, duration of atrial fibrillation, fine wave atrial fibrillation, age of patient, and atrial fibrillation type. CONCLUSIONS: The innate heterogeneity of published data precludes a meta-analysis for predictors of surgical ablation success. Of the few published studies that allow comparison, the most consistent predictors of failure were enlarged left atrium and long atrial fibrillation duration. These results underscore the need for consistent and reliable outcome predictors. We strongly recommend the development of a standardized system of measurement for consistent clinical parameters that can be used in outcome analyses for surgical ablation of atrial fibrillation. PMID- 29232295 TI - Pathways to Innovation in Cardiothoracic Surgery. PMID- 29232297 TI - Long-Term Success With Driveline Exit Site Relocation for Deep Driveline Infection in Left Ventricular Assist Device Patients. AB - OBJECTIVE: Driveline infection is a common complication of durable left ventricular assist device support. The majority involve the driveline exit site and can be treated with antibiotics and local wound care. Less frequently, these infections extend into deeper tissues and surgical debridement is necessary. Few studies have described the surgical strategy for treatment of deep driveline infection or have reported long-term outcomes. With a growing population of patients being implanted as destination therapy, there is an obvious need to evaluate and optimize treatment for complex driveline infections. METHODS: Outcomes of patients undergoing durable left ventricular assist device implantation at a single center between 2011 and 2017 were reviewed retrospectively. Data including occurrence of driveline infection, pathogen, time to driveline infection, and treatment strategy were abstracted from the electronic medical record. RESULTS: Driveline infection occurred in 10 (16.4%) of 61 patients at a median of 362 days (Q1 = 99, Q3 = 694) after primary left ventricular assist device implantation. Three (30.0%) of 10 driveline infections were categorized as deep and did not resolve with intravenous antibiotic therapy. In these cases, a multistage approach that included initial debridement and exteriorization of the infected driveline, followed by delayed surgical relocation of the driveline in a clean vascularized soft tissue bed, was used. Long-term device salvage was achieved in all cases. CONCLUSIONS: An aggressive surgical strategy, including debridement and formal relocation of the driveline exit site, can result in long-term device salvage after deep driveline infection. This approach is a less invasive alternative to device exchange for refractory driveline infections. PMID- 29232296 TI - Morbid Obesity Does not Increase Morbidity or Mortality in Robotic Cardiac Surgery. AB - OBJECTIVE: Morbid obesity (body mass index >= 35 kg/m) usually confers a higher perioperative risk in cardiac surgery. Robotic cardiac surgery may have many advantages for these high-risk patients. METHODS: We retrospectively reviewed patients undergoing robotic cardiac surgery from July 2013 to April 2017 at our institution. We compared the outcomes of morbidly obese patients versus nonobese patients. RESULTS: A total of 486 patients underwent robotic cardiac surgery (322 men, median age = 65 years). The robotic procedures were the following: totally endoscopic beating heart coronary artery bypass (n = 263), mitral valve surgery (n = 138), arrhythmia surgery (n = 33), adult congenital surgery (n = 16), pericardiectomy (n = 11), and others (n = 25). The cohorts were divided into the following: normal weight (body mass index < 25, n = 123), overweight (body mass index = 25 to < 30, n = 182), obesity (body mass index = 30 to < 35, n = 105), and morbid obesity (body mass index >= 35, n = 76). Morbidly obese patients had a higher rate of hypertension, dyslipidemia, and diabetes mellitus compared with normal or overweight patients. There were no significant differences in morbidity, mean length of intensive care unit stay (2.10 +/- 4.27 days), and hospital stay (4.48 +/- 5.61 days) among the groups. In-hospital mortality was 1.4% (7/486) with nonsignificant difference. CONCLUSIONS: Outcomes of robotic heart surgery in morbidly obese patients in our center were acceptable. Over a broad range of cardiac surgical procedures, morbid obesity was not associated with increased morbidity or mortality when these procedures were performed using a robotic approach. These findings can be beneficial in managing this challenging group of patients. PMID- 29232298 TI - Use of a New Expanded Polytetrafluoroethylene Multichordal Mitral Apparatus (MitraPatch) to Repair Complex Mitral Valve Lesions. AB - OBJECTIVE: We report a new expanded polytetrafluoroethylene multichordal mitral apparatus (MitraPatch) to simplify mitral repairs involving multiple cusps and sought to describe the surgical technique and demonstrate the efficacy of the device. METHODS: MitraPatch was laser cut from a single sheet of expanded polytetrafluoroethylene and mounted on a custom-designed handle. Surgical technique to deploy the apparatus on the native mitral valve was developed in ex vivo porcine hearts. Hemodynamic efficacy of repairing mitral prolapse and regurgitation was assessed in ex vivo hearts and in five 30-day chronic swine, with histopathology in an additional swine at 120 days after implantation. RESULTS: In ex vivo heart studies, leaflet coaptation was restored from 0 mm at the posterior prolapsing segment to 8.1 +/- 2.2 mm after repair with the MitraPatch (P < 0.05) and to 10.2 +/- 1.3 mm after the repair of the anterior leaflet (P < 0.05). In in vivo studies, valve function at 30 days was considered good, with none to trace regurgitation. Device was flexible, without tissue overgrowth or dehiscence. At 120 days, complete endothelialization was observed. CONCLUSIONS: The multichordal MitraPatch can potentially simplify complex mitral valve repairs involving multiple leaflet cusps, possibly enabling an optimal mitral repair even by surgeons without the focused high-volume experience. PMID- 29232299 TI - The Axillary Intra-Aortic Balloon Pump as a Bridge to Recovery Allows Early Ambulation in Long-Term Use: Case Series and Literature Review. AB - We evaluated the feasibility, tolerability, and efficacy of a strategy for transaxillary artery intra-aortic balloon pump placement for extended mechanical circulatory support of patients with postcardiotomy shock as a bridge to recovery. Patients requiring prolonged intra-aortic balloon pump support for postcardiotomy heart failure were identified. Intra-aortic balloon pump was tunneled through a 6-mm Dacron graft anastomosed to the right axillary artery. The intra-aortic balloon pump catheter is advanced under fluoroscopic guidance into the descending thoracic aorta. Three patients were transferred from outside facilities, requiring prolonged intra-aortic balloon pump support for postcardiotomy heart failure. Patients included a 54-year-old woman with occluded grafts and left ventricular thrombus after coronary artery bypass grafting, ejection fraction (EF) of 23.4% on dobutamine infusion, intra-aortic balloon pump support for 39 days, max daily ambulated distance of 1250 feet, and discharged home on day 51 on milrinone infusion; a 63-year-old man with kinked left internal mammary artery to left anterior descending artery graft (surgically repaired), multiple failed extubations requiring tracheostomy, EF of 15% on epinephrine and milrinone, intra-aortic balloon pump support for 43 days, max daily ambulated distance of 400 feet, and discharged home on day 54; and a 66-year-old man after redo coronary artery bypass grafting + carotid endarterectomy, with failure to wean off cardiopulmonary bypass requiring veno-arterial extracorporeal membrane oxygenator, EF of 20% on epinephrine and norepinephrine, intra-aortic balloon pump support for 41 days, max daily ambulated distance of 2800 feet, and discharged home on day 91. There were no infection, thromboembolic, cerebrovascular, bleeding, or intra-aortic balloon pump malpositioning/migration complications. We found that transaxillary artery intra-aortic balloon pump is well tolerated by patients and allows early ambulation and aggressive physical therapy in patients needing extended support. Duration of intra-aortic balloon pump support was up to 43 days with no complications. PMID- 29232300 TI - Three-Dimensional Printing of Life-Like Models for Simulation and Training of Minimally Invasive Cardiac Surgery. AB - OBJECTIVE: As the use of minimally invasive surgery in cardiothoracic surgery increases, so does the need for simulation and training. We developed a heart model for simulation and training of minimally invasive cardiac surgery, particularly minimally invasive mitral valve repair using our new three dimensional printing system. METHODS: Digital imaging and communication in medicine data from patient computed tomography, three-dimensional computer-aided design, and three-dimensional printing helped create replicas of the heart and thoracic cavity. A polyvinyl alcohol model material with a texture and physical properties similar to those of heart tissue was initially used in mitral valve replicas to simulate surgical procedures. To develop this material, we mechanically investigated the composition of each part of the porcine heart. RESULTS: We investigated the elastic modulus and breaking strength of the porcine heart. Based on investigation results, the cardiac model was set at rupture strength 20 MPa, elastic modulus 0.17 MPa, and moisture content 85%. This provided a biotexture and feeling exactly like a patient heart. Computed tomography scans confirmed that the model shape was nearly the same as that of a human heart. We simulated minimally invasive mitral valve repair, including ring annuloplasty, chordal reconstruction, resection and suture, and edge-to-edge repair. Full surgery simulations using this model used minimally invasive cardiac surgery tools including a robot. CONCLUSIONS: This life-like model can be used as a standard simulator to train younger, less experienced surgeons to practice minimally invasive cardiac surgery procedures and may help develop new operative tools. PMID- 29232301 TI - Robotic Mitral Valve Repair: The Learning Curve. AB - OBJECTIVE: Adoption of robotic mitral valve surgery has been slow, likely in part because of its perceived technical complexity and a poorly understood learning curve. We sought to correlate changes in technical performance and outcome with surgeon experience in the "learning curve" part of our series. METHODS: From 2006 to 2011, two surgeons undertook robotically assisted mitral valve repair in 458 patients (intent-to-treat); 404 procedures were completed entirely robotically (as-treated). Learning curves were constructed by modeling surgical sequence number semiparametrically with flexible penalized spline smoothing best-fit curves. RESULTS: Operative efficiency, reflecting technical performance, improved for (1) operating room time for case 1 to cases 200 (early experience) and 400 (later experience), from 414 to 364 to 321 minutes (12% and 22% decrease, respectively), (2) cardiopulmonary bypass time, from 148 to 102 to 91 minutes (31% and 39% decrease), and (3) myocardial ischemic time, from 119 to 75 to 68 minutes (37% and 43% decrease). Composite postoperative complications, reflecting safety, decreased from 17% to 6% to 2% (63% and 85% decrease). Intensive care unit stay decreased from 32 to 28 to 24 hours (13% and 25% decrease). Postoperative stay fell from 5.2 to 4.5 to 3.8 days (13% and 27% decrease). There were no in-hospital deaths. Predischarge mitral regurgitation of less than 2+, reflecting effectiveness, was achieved in 395 (97.8%), without correlation to experience; return-to-work times did not change substantially with experience. CONCLUSIONS: Technical efficiency of robotic mitral valve repair improves with experience and permits its safe and effective conduct. PMID- 29232302 TI - Minimally Invasive Septal Myectomy for Hypertrophic Obstructive Cardiomyopathy. AB - Surgical septal myectomy is the treatment of choice for patients with symptomatic hypertrophic obstructive cardiomyopathy refractory to medications. This report describes our minimally invasive approach for performing a septal myectomy via a ministernotomy that has been used at our institution for more than a decade. In particular, patient preparation, surgical technique, and clinical considerations are highlighted. Performed properly, this minimally invasive technique is a feasible and effective approach in our experience. PMID- 29232303 TI - Totally Endoscopic Cardiac Surgery for Atrial Septal Defect Repair on Beating Heart Without Robotic Assistance in 25 Patients. AB - OBJECTIVE: The aim of the study was to investigate the effectivity and safety of totally endoscopic cardiac surgery without robotic assistance for atrial septal defect (ASD) closure on beating hearts. METHODS: Twenty-five patients (adults/children: 15/10) underwent ASD closure using nonrobotically assisted totally endoscopic approach on beating heart. Three 5-mm trocars and one 12-mm trocar were used, only the superior vena cava is snared, filling the pleural and pericardial cavities with CO2, and the heart was beating during the surgery. Twenty-three patients had isolated secundum ASD (2 of which had severe tricuspid regurgitation) and two patients had ASD combined with partial anomalous pulmonary venous connection. All ASDs were closed using artificial patch, continuous suture; tricuspid regurgitations were repaired and the anomalous pulmonary veins were drained to the left atrium. RESULTS: No postoperative complications or deaths occurred. Mean +/- SD operation time and mean cardiopulmonary bypass time were 267.2 +/- 44.6 and 156.1 +/- 33.6 min, respectively. These patients were extubated within the first 5 hours, and the volume of blood drainage on the first day was less than 80 mL. Four days after surgery, patients did not need analgesics and were able to return to normal activities 1 week postoperatively. CONCLUSIONS: Totally endoscopic operation for ASD closure on beating heart is safe, with short recovery period, and surgical scars are of high cosmetic value, especially in a woman and girl. PMID- 29232304 TI - Rapid BRAF mutation tests in patients with advanced melanoma: comparison of immunohistochemistry, Droplet Digital PCR, and the Idylla Mutation Platform. AB - BRAF mutational testing has become a common practice in the diagnostic process of patients with advanced melanoma. Although time-consuming, DNA sequencing techniques are the current gold standard for mutational testing. However, in certain clinical situations, a rapid test result is required. In this study, the performance of three rapid BRAF mutation tests was compared. Thirty-nine formalin fixed paraffin-embedded melanoma tissue samples collected between 2007 and 2014 at a single center were included. These samples were analyzed by immunohistochemistry using the anti-BRAF-V600E (VE1) mouse monocolonal antibody (BRAF-VE1 IHC), a V600E-specific Droplet Digital PCR Test, and the Idylla BRAF- Mutation Test (Idylla). Results were compared with the results of conventional BRAF mutation testing, performed using high-resolution melting analysis followed by Sanger sequencing. Next-generation sequencing was performed on samples with discordant results. The Idylla test and Droplet Digital PCR Test correctly identified all mutated and wild-type samples. BRAF-VE1 IHC showed one discordant result. The Idylla test could identify BRAF-V600 mutations other than BRAF-V600E and was the fastest and least laborious test. The Idylla Mutation Test is the most suitable test for rapid BRAF testing in clinical situations on the basis of the broad coverage of treatment-responsive mutations and the fast procedure without the need to perform a DNA isolation step. PMID- 29232305 TI - BRAF-inhibitors can exert control of disease in BRAF T599I mutated melanoma: a case report. AB - BRAF signaling is involved in melanoma growth in more than half of metastatic patients. In the last few years, new drugs that block this pathway have significantly improved the outcomes of patients with metastatic melanoma. Ninety percent of BRAF mutations involve exon 15, and the most frequent, V600E, results from the amino acid change from valine (V) to glutamic acid (E). BRAF inhibitor treatments have shown a notable overall response rate and improvements in progression-free and overall survival. Rare BRAF mutations of codon 599 have been also described in a few patients with papillary thyroid cancer and melanoma. Nowadays, no evidence is available in the literature, describing the role of target therapies as treatment in patients with this specific codon mutation. We describe the case of a young woman with metastatic melanoma with a particular BRAF mutation, T599I, who has benefited from treatment with a BRAF inhibitor, vemurafenib. PMID- 29232306 TI - Differential effect of ABCB1 haplotypes on promoter activity. AB - OBJECTIVE: Promoter single-nucleotide polymorphisms (SNPs) of the ABCB1 gene, encoding the placental efflux transporter P-glycoprotein, can affect its expression and alter xenobiotic transfer from the maternal to the fetal circulation. Because SNPs are arranged in specific combinations as defined haplotypes, the aims of this study were to: (i) determine the placental haplotype structure of the ABCB1 promoter and (ii) determine the differential effect of these haplotypes on placental ABCB1 promoter activity. MATERIALS AND METHODS: DNA samples from 100 healthy placentas were PCR-amplified and sequenced to identify existing SNPs in the proximal ABCB1 promoter. The haplotype structure encompassing these SNPs was inferred by PHASE analysis. Luciferase reporter constructs representing these haplotypes were generated and transfected into human placental 3A cells and their effect on ABCB1 promoter activity was determined using a dual-luciferase assay. RESULTS: We identified 12 ABCB1 promoter SNPs. These SNPs were predicted by PHASE to segregate into 28 haplotypes with frequencies ranging between 0.019 and 0.88. We found 12 of these haplotypes in our population in addition to two haplotypes not predicted by PHASE. We also generated two haplotypes to determine individual SNP effects for a total of 16 studied. Compared with the ancestral haplotype, three haplotypes significantly up regulated (107-266% increase; P<0.05), one significantly down-regulated (95.4% decrease; P<0.01), and 12 had no statistically significant effect on ABCB1 promoter activity. DISCUSSION AND CONCLUSION: Our data show that the effect of SNPs on promoter activity depends on their presence in a specific haplotype. This indicates that haplotypes, rather than individual SNPs, could play a significant role in regulating placental P-glycoprotein expression and affect placental transfer and fetal exposure to xenobiotics. PMID- 29232307 TI - Outcome Measure Scores Predict Discharge Destination in Patients With Acute and Subacute Stroke: A Systematic Review and Series of Meta-analyses. AB - BACKGROUND AND PURPOSE: To identify the association between outcome measure score and discharge destination in adults following acute or subacute stroke in the United States. METHODS: A systematic literature search was performed in 3 databases using the PRISMA guidelines. Cohort studies were selected that included patients with acute or subacute stroke, which explored the relationship between scores on outcome measures and discharge destination. Four meta-analyses were performed. RESULTS: Nine articles met the inclusion criteria for systematic review and 5 for the series of meta-analyses. For every 1-point increase on the Functional Independence Measure (FIM), a patient is approximately 1.08 times more likely to be discharged home than to institutionalized care (odds ratio [OR] = 1.079; 95% confidence interval [CI], 1.056- 1.102). Patients with stroke who performed above-average (FIM >=80; NIH Stroke Scale [NIHSS] score <=5; etc) are 12 times (OR = 12.08; 95% CI, 3.550-41.07) more likely to discharge home. Patients who perform poorly (FIM <=39; NIHSS score >=14), experience discharge to institutionalized care 3.4 times (OR = 3.385; 95% CI, 2.591-4.422) more likely than home, with skilled nursing facility admission more likely than inpatient rehabilitation facility. Patients who perform average (FIM = 40-79; NIHSS score = 6-13) are 1.9 times (OR = 1.879; 95% CI, 1.227-2.877) more likely to be discharged to institutionalized care. DISCUSSION AND CONCLUSION: Outcome measure scores are strong predictors of discharge destination among patients with stroke and provide an objective means of early discharge planning. Discharge decisions should be made with consideration for patient-specific biopsychosocial factors that may supersede isolated results of the outcome measures, and further research needs to assess the success of the location that a patient is referred at discharge.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A194). PMID- 29232308 TI - A Backward Walking Training Program to Improve Balance and Mobility in Acute Stroke: A Pilot Randomized Controlled Trial. AB - BACKGROUND AND PURPOSE: Strategies to address gait and balance deficits early poststroke are minimal. The postural and motor control requirements of Backward Walking Training (BWT) may provide benefits to improve balance and walking speed in this population. This pilot study (1) determined the feasibility of administering BWT during inpatient rehabilitation and (2) compared the effectiveness of BWT to Standing Balance Training (SBT) on walking speed, balance, and balance-related efficacy in acute stroke. METHODS: Eighteen individuals 1-week poststroke were randomized to eight, 30-minute sessions of BWT or SBT in addition to scheduled therapy. Five-Meter Walk Test, 3-Meter Backward Walk Test, Activities-Specific Balance Confidence Scale, Berg Balance Scale, Sensory Organization Test, and Function Independence Measure-Mobility were assessed pre- and postintervention and at 3 months poststroke. RESULTS: Forward gait speed change (BWT: 0.75 m/s; SBT: 0.41 m/s), assessed by the 5-Meter Walk Test, and backward gait speed change (BWT: 0.53 m/s; SBT: 0.23 m/s), assessed by the 3-Meter Backward Walk Test, preintervention to 1-month retention were greater for BWT than for SBT (P < 0.05). Group difference effect size from preintervention to 1-month retention was large for Activities-Specific Balance Confidence Scale, moderate for Berg Balance Scale and Function Independence Measure-Mobility, and small for Sensory Organization Test. DISCUSSION AND CONCLUSIONS: Individuals 1-week poststroke tolerated 30 min/d of additional therapy. At 1-month postintervention, BWT resulted in greater improvements in both forward and backward walking speed than SBT. Backward walking training is a feasible important addition to acute stroke rehabilitation. Future areas of inquiry should examine BWT as a preventative modality for future fall incidence.Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A193). PMID- 29232309 TI - A Bispecific Antibody Based on Pertuzumab Fab Has Potent Antitumor Activity. AB - Human epidermal growth factor receptor 2 (HER2) is frequently overexpressed and activated in metastatic breast cancers. Monoclonal antibodies targeting Her2, such as trastuzumab and pertuzumab, have become important targeted therapies for patients with HER2-positive breast cancer. Both trastuzumab and pertuzumab can reduce Her2 positive tumor burden by inhibiting Her2 signaling and inducing ADCC activities (antibody dependent cell-mediated cytotoxicity). In this study, we have generated a bispecific antibody, Her2(Per)-S-Fab, by linking the pertuzumab Fab to an anti-CD16 single domain antibody. The Her2(Per)-S-Fab can be expressed and purified efficiently from Escherichia coli. In vitro and in vivo experiments showed Her2(Per)-S-Fab had potent cytotoxicity against Her2-positive tumor cells. Thus, Her2(Per)-S-Fab may provide an alternative to treat Her2-positive cancer patients. PMID- 29232310 TI - Comparison of Paliperidone Palmitate and Risperidone Long-Acting Injection in Schizophrenic Patients: Results From a Multicenter Retrospective Cohort Study in France. AB - PURPOSE/BACKGROUND: The study objective was to compare the impact of being treated by paliperidone palmitate (PP) or risperidone long-acting injection (RLAI) on the length of stay on initial hospitalization, rehospitalization risk, and treatment duration in schizophrenic patients. METHODS: We conducted an observational retrospective cohort study in 43 centers in France, including schizophrenic patients who initiated a treatment by PP or RLAI during initial hospitalization. The follow-up periods started in September 2012 for the RLAI group (median follow-up duration, 233 days) and in June 2013 for the PP group (259 days). Statistical analyses were based on Cox regression models, with propensity score weighting to account for differences in patients' characteristics. FINDINGS/RESULTS: The analysis included 347 patients: 197 in the PP treatment group and 150 in the RLAI group. Compared with patients on RLAI, patients on PP were significantly more likely to have nonpsychiatric comorbidities, to have been on previous antipsychotic therapy, or to have been hospitalized for psychiatric care in the previous year. With regard to length of stay on initial hospitalization, there was no statistically significant difference between both groups (hazard ratio, 1.13 [0.97; 1.31]). Being on PP was associated with similar times to first rehospitalization compared with RLAI (hazard ratio, 0.92 [0.65; 1.30]). IMPLICATIONS/CONCLUSIONS: We observed nonsignificant differences in initial hospitalization duration and time to rehospitalization between PP and RLAI, potentially due to lack of statistical power. A trend was observed in favor of PP with regard to time to treatment discontinuation, although this result was compromised by patients who switched between RLAI and PP. PMID- 29232311 TI - Lithium + Colchicine: A Potential Strategy to Reduce Pro-inflammatory Effects of Lithium Treatment. AB - PURPOSE: Rosenblat and McIntyre (Acta Psychiatr Scand. 2015;132: 180-191) propose that immune disorders are important mediators between bipolar disorders and medical comorbidities. Rosenblat et al (Bipolar Disord. 2016;18:89-101) present a meta-analysis showing that adjunctive anti-inflammatory agents could evoke moderate antidepressant responses in bipolar disorders. We propose using the anti inflammatory drug colchicine to improve the long-term safety and efficacy of lithium treatment for bipolar disorders. METHODS: This report is based on searches of the PubMed and Web of Science databases. RESULTS: Bipolar disorders are associated with significant medical comorbidities such as hypertension, overweight/obesity, diabetes mellitus, metabolic syndrome, and arteriosclerosis, accompanied by enhanced release of pro-inflammatory markers during changes in mood state. During lithium therapy, granulocyte-colony stimulating factor, CD34+ hematopoietic stem/progenitor cells, and neutrophil elastase enter the circulation with activated neutrophils to promote the extravascular migration of activated neutrophils and enhance tissue inflammation. Concurrent treatment with lithium and low-dose colchicine could facilitate the responsiveness of bipolar patients to lithium by reducing leukocyte tissue emigration, the release of neutrophil elastase, and the release of leukocyte pro-inflammatory cytokines such as IL-1beta that are regulated by the NLRP3 inflammasome assembly complex. CONCLUSIONS: Concurrent therapy with lithium and low-dose colchicine could reduce complications involving leukocyte-mediated inflammatory states in bipolar patients and promote patient acceptance and responsiveness to lithium therapy. PMID- 29232312 TI - Improvement of Smoking Abstinence Rates With Increased Varenicline Dosage: A Propensity Score-Matched Analysis. AB - PURPOSE/BACKGROUND: It is unclear whether increasing the dose of varenicline beyond the standard dose of 2 mg/d would improve smoking abstinence. METHODS: We examined the effect of 3 mg/d of varenicline on smoking abstinence among smokers who had reduced their smoking by 50% or more in response to 2 mg/d for at least 6 weeks but had not quit smoking. Of 2833 patients treated with varenicline, dosage of a subset of 73 smokers was increased to 3 mg/d after 6 weeks. We used a propensity score analysis involving multiple baseline covariates to create a comparative sample of 356 smokers who remained on 2 mg/d. All smokers received concurrent and similar smoking-cessation counseling. RESULTS: At 3 months, we found higher 7-day point prevalence smoking-abstinence rate in the 3-mg group (26%) than in the 2-mg group (11.5%, chi = 10.60, P < 0.001; risk ratio [RR], 2.3; 95% confidence interval [CI], 1.4-3.6). The difference in abstinence rates remained significant at the 6-month (P < 0.001; RR, 2.6; 95% CI, 1.6-3.9) and 9 month follow-up (P < 0.001; RR, 2.2; 95% CI, 1.4-3.3). CONCLUSIONS: A relatively small increase in the daily dose of varenicline seems to offer a benefit for those who are not able to achieve total abstinence after approximately 6 weeks of 2 mg/d. PMID- 29232314 TI - Postexercise Fructose-Maltodextrin Ingestion Enhances Subsequent Endurance Capacity. AB - PURPOSE: Restoring skeletal muscle and hepatic glycogen content during short-term (<6 h) recovery from prolonged exercise is pertinent for athletes seeking to maximize performance in repeated exercise bouts. Previous research suggests that coingestion of fructose-glucose carbohydrate sources augments hepatic and has equivalent effects on skeletal muscle glycogen storage during short-term recovery from prolonged exercise compared with isocaloric glucose ingestion. The aim of the present investigation was to determine whether this has a discernible effect on subsequent exercise capacity. METHODS: Eight trained endurance runners and triathletes performed two experimental trials in a single-blind, randomized, and counterbalanced crossover design. Trials involved treadmill running to exhaustion at 70% VO2max, a 4-h recovery with 90 g.h of glucose-maltodextrin (GLU + MAL) or fructose-maltodextrin (FRU + MAL) ingestion (1:1.5 ratio), and a second bout of treadmill running to exhaustion at 70% VO2max. RESULTS: Exercise capacity in bout 2 was significantly greater with FRU + MAL (81.4 +/- 22.3 vs 61.4 +/- 9.6 min, P = 0.02), a large magnitude effect (effect size = 1.84 +/- 1.12, 32.4% +/- 19.9%). Total carbohydrate oxidation rates were not significantly different during bout 1 or 2 between trials, although total carbohydrate oxidized in bout 2 was significantly greater with FRU + MAL (223 +/- 66 vs 157 +/- 26 g, P = 0.02). Ingested carbohydrate oxidation rates were greater during bout 2 with FRU + MAL (P = 0.001). Plasma glucose and nonesterified fatty acid concentrations were not significantly different between trials. Plasma lactate concentrations were significantly greater during recovery before bout 2 with FRU + MAL (P = 0.001). Self-reported nausea and stomach fullness during bout 2 were marginally in favor of FRU + MAL. CONCLUSION: Short-term recovery of endurance capacity was significantly enhanced with FRU + MAL versus GLU + MAL ingestion during recovery. PMID- 29232315 TI - Beneficial Effects of Exercise Pretreatment in a Sporadic Alzheimer's Rat Model. AB - PURPOSE: This study aimed to examine the effects of swimming exercise pretreatment on a streptozotocin (STZ)-induced sporadic Alzheimer's disease (AD) rat model and provide an initial understanding of related molecular mechanisms. METHODS: Male 2.5-month-old Sprague-Dawley rats were divided into the following four groups: (a) control, (b) swim + vehicle, (c) STZ without swim, and (d) swim + STZ. The Barnes maze task and novel object recognition test were used to measure hippocampus-dependent spatial learning and working memory, respectively. Immunofluorescence staining, Western blot analysis, enzyme-linked immunosorbent assay (ELISA) analysis, and related assay kits were used to assess synaptic proteins, inflammatory cytokines, total antioxidant capacity, antioxidant enzymes, amyloid-beta production, and tau hyperphosphorylation. RESULTS: Behavioral tests revealed that exercise pretreatment could significantly inhibit STZ-induced cognitive dysfunction (P < 0.05). STZ animals displayed significant loss of presynaptic/postsynaptic markers in the hippocampal CA1 that was reversed by exercise pretreatment (P < 0.05). STZ rats also displayed increased reactive gliosis, release of proinflammatory cytokines, and oxidative damage, effects attenuated by preexercise (P < 0.05, between-treatment changes). Likewise, preexercise significantly induced protein expression (P < 0.001) and DNA-binding activity (P = 0.015) of Nrf2 and downstream antioxidant gene expression in the hippocampal CA1 region (P < 0.05). STZ rats had increased levels of amyloid-beta (1-42) and tau hyperphosphorylation that were significantly ameliorated by exercise (P < 0.05). Histological studies showed that exercise imparted substantial neuroprotection (P < 0.001), suppressing neuronal apoptosis-like cell death in the hippocampal CA1 compared with the STZ control group (P < 0.001). CONCLUSIONS: Exercise pretraining exerts multifactorial benefits on AD that support its use as a promising new therapeutic option for prevention of neurodegeneration in the elderly and/or AD population. PMID- 29232316 TI - PRIME: A Novel Low-Mass, High-Repetition Approach to Improve Function in Older Adults. AB - INTRODUCTION: The ability to maintain functional independence in a rapidly aging population results in an increased life expectancy without corresponding increases in health care costs. The accelerated decline in VO2peak after the age of 65 yr is primarily due to peripheral tissue changes rather than centrally mediated factors. The purpose of this study was to determine whether the Peripheral Remodeling through Intermittent Muscular Exercise (PRIME) approach, consisting of a low-mass, high-repetition/duration skeletal muscle focused training regimen would provide superior functional benefits in participants older than 70 yr old and at risk for losing functional independence. METHODS: In this clinical trial, 107 participants were randomized to 4 wk of either standard aerobic training (AT) or PRIME (phase 1). This was followed by 8 wk of a progressive whole-body aerobic and resistance training (AT + RT) for all participants (phase 2). The major outcome measures were cardiorespiratory fitness (peak oxygen consumption [VO2peak]), muscular fitness (1 repetition maximal strength [1RM]), and physical function (Senior Fitness Test [SFT] scores). Results were analyzed under a per-protocol criterion. RESULTS: Thirty-eight PRIME and 38 AT participants completed the 3-month protocols. VO2peak, 1RM, and SFT scores all increased significantly after 12 wk for both treatment groups (P < 0.05). However, relative to AT, participants randomized to PRIME demonstrated a greater increase in VO2peak (2.37 + 1.83 vs 1.50 + 1.82 mL.kg.min, P < 0.05), 1RM (48.52 + 27.03 vs 28.01 + 26.15 kg, P < 0.01) and SFT (22.50 + 9.98 vs 18.66 + 9.60 percentile, P < 0.05). CONCLUSIONS: Participants experienced greater increases in cardiorespiratory and muscular fitness and physical function when PRIME training was initiated before a combined AT + RT program. This novel exercise approach may be advantageous to individuals with other chronic disease conditions characterized by low functional capacity. PMID- 29232317 TI - Attitude of Nursing Students Toward Scientific Research: A Cross-Sectional Study in Turkey. AB - BACKGROUND: Nursing, a social applied science, is a dynamic profession. Professional nurses must be curious, investigative, and open to learning as well as practice critical and analytic thinking to sustain their professionalism. PURPOSE: The aim of this study was to determine the attitudes of nursing students toward scientific research. METHODS: A descriptive and cross-sectional study design was used. This study was conducted at a nursing department of a university in Turkey. A sample of 375 nursing students participated. Data were collected using the "Personal Information Form" and "Attitude Scale towards Scientific Studies." Standard descriptive statistical methods, correlation, Mann-Whitney U, Kruskal-Wallis, and post hoc Bonferroni were used in data analysis. RESULTS: Nearly all (90.1%) of the participants were female, and 33.9% were sophomore (second-year) students. Junior (third-year) students held the most positive attitudes toward research, as compared with the participants in other academic years. Participants who had participated in scientific activities held more positive attitudes toward research than those who had not. Participants who had prior experience doing scientific research showed more positive attitudes toward research and researchers than those without this experience. Being older, having scientific research experience, following the continuous broadcasts related to nursing, and participating in scientific activities all significantly influenced attitude toward research (p < .05). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Although nursing students who participated in this study exhibited generally positive attitudes toward scientific research, they had relatively little experience participating in scientific activities. Therefore, to foster a positive scientific research culture among undergraduate students, grants should be provided that encourage wider participation in scientific activities and offer opportunities for undergraduate students to do scientific research. PMID- 29232318 TI - Significant Effect of Acupressure in Elevating Blood Stem Cell Factor During Chemotherapy in Patients With Gynecologic Cancer. AB - BACKGROUND: Chemotherapy is used mainly to treat and control the progression of gynecological cancer. Bone marrow suppression, one of the adverse side effects of chemotherapy, may decrease immune function, increasing the risk of serious, fatal infections. PURPOSE: The aims of this study were to evaluate the effectiveness of noninvasive acupressure in preventing and diminishing chemotherapy-induced myelosuppression in patients with gynecologic cancer and to determine whether this effect is associated with the regulation of the expressions of granulocyte macrophage colony-stimulating factor and stem cell factor (SCF). METHODS: In total, 28 women with gynecological cancer were randomly assigned either to the experimental group (n = 10) or to the control group (n = 18). The experimental group received acupressure of 5-minute duration to the Hegu (LI4), Quchi (LI11), Xuehai (SP10), Sanyinjiao (SP6), Taixi (K3), Zusanli (ST36), Taichong (LR3), and Baihui (GV20) points, respectively, three times per day for 6 weeks. The control group did not receive the acupressure intervention. The blood count, including white blood cells, platelets, and hemoglobin, and serum levels for SCF and granulocyte-macrophage colony-stimulating factor were assessed before (pretest) and 6 weeks after (posttest) the participants' first course of chemotherapy. RESULTS: At posttest, blood hemoglobin had significantly decreased from (mean +/- SD) 11.6 +/- 2.2 to 10.8 +/-1.6 mg/dl (p = .03) in the control group. However, no significant pretest-posttest difference in hemoglobin concentration (11.4 +/- 1.0 vs. 10.9 +/- 1.1 mg/dl) was detected in the experimental group. Levels of SCF increased significantly between pretest and posttest in both the control group (from 1196.10 +/- 293.17 to 1325.05 +/- 253.77 ng/ml; p = .01) and the acupressure group (from 1046.78 +/- 469.52 to 1387.06 +/- 310.00 ng/ml; p = .007). In addition, a borderline difference (p = .05) in mean pretest-posttest SCF increase was found between the acupressure group (340.28 +/- 255.46 ng/ml) and the control group (128.94 +/- 250.64 ng/ml). Finally, a significant time dependent interactive effect was found between acupressure and the increased blood level of SCF at posttest (beta = 211.34, p = .02). CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings support that acupressure on specific acupoints increases blood SCF levels significantly, which may help protect chemotherapy patients from experiencing reduced hemoglobin levels and may relieve chemotherapy induced myelosuppression in patients with gynecologic cancer. This noninvasive approach is suggested for practical implementation in patients undergoing a course of chemotherapy. PMID- 29232319 TI - Knowledge of the Warning Signs of Foot Ulcer Deterioration Among Patients With Diabetes. AB - BACKGROUND: Seeking treatment in a timely manner may prevent lower limb amputation subsequent to diabetic foot ulcers. Knowledge regarding the warning signs is one important factor that is related to the timely treatment seeking of patients with diabetic foot ulcers. However, there is no previous research on which aspects of such knowledge that patients with diabetes are lacking. PURPOSE: The aims of this study were to test the psychometric properties of a questionnaire that was designed to assess the knowledge of the warning signs of diabetic foot ulcer deterioration and to determine the knowledge of these warning signs among patients with a history of diabetic foot ulcers. METHODS: A cross sectional study design was used. Patients with a history of diabetic foot ulcers were recruited using convenience sampling (N = 385). Data were analyzed using Spearman's rank correlation and the Mann-Whitney U test. RESULTS: The questionnaire showed good known-group validity, satisfied internal consistency (Kuder-Richardson Formula 20 = .82), and exhibited acceptable 2-week test-retest reliability (Spearman's rho coefficient = .75). More than 30% of the participants were unaware of the warning signs of peripheral vascular insufficiency and severe infection. Of the participants, 75.8% felt that the time to seek medical treatment of diabetic foot ulcers was when they experienced wound deterioration. Those who held this opinion had significantly less knowledge regarding the warning signs of diabetic foot ulcer deterioration than did those who had not. Other factors that were significantly associated with less knowledge included being older, having less education, not having an existing foot ulcer, having no foot ulcer treatment history, and never having received education regarding foot ulcers. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The questionnaire showed adequate validity and reliability and thus may be used by healthcare practitioners and researchers to assess the knowledge of at-risk patients regarding the warning signs of diabetic foot ulcer deterioration. Patient education regarding the importance of timely treatment seeking and warning signs should be promoted. PMID- 29232320 TI - The Impact of Osteoarthritis on the Functioning and Health Status of a Low-Income Population: An Example of a Disability Paradox. AB - OBJECTIVE: The aim of this study was to measure the impact of osteoarthritis on the functioning and health status of individuals living in a low-income urban community in Mexico. METHODS: We conducted a cross-sectional, community-based study from December 2014 to November 2015, using the Community Oriented Program for Control of Rheumatic Diseases methodology to identify cases of musculoskeletal disease in a sample of adults older than 18 years in Pueblo Nuevo, Apodaca, Mexico. Two rheumatologists confirmed all cases of osteoarthritis (OA) using predefined criteria. Functioning was evaluated through (a) self-report of difficulty doing personal care, work, and leisure activities; (b) the modified Stanford Health Assessment Questionnaire-Disability Index; and (c) the Timed Up and Go test. Health status was evaluated using the EuroQoL 5 Dimensions. Statistical analyses were performed using chi tests and logistic regression models. RESULTS: Four hundred thirty-nine individuals with a mean age of 45.2 years were included, and 83 cases of OA were confirmed. The presence of OA was not significantly associated with having difficulties to do personal care, work, or leisure activities, but it was significantly associated with a higher Health Assessment Questionnaire-Disability Index score, longer time to complete the Timed Up and Go, and lower health status. CONCLUSIONS: Osteoarthritis is associated with having higher disability and worse health status in the community studied. A disability paradox was detected as some individuals perceived disability for doing standard activities but did not present disability performing their real-life activities. This underlies the importance of addressing the mental dimension during the management of this population. PMID- 29232321 TI - Elevated Interleukin 1beta and Interleukin 6 Levels in the Serum of Children With Hyperuricemia. AB - PURPOSES: The aim of this study was to investigate the serum levels and clinical significance of interleukin 1beta (IL-1beta) and IL-6 in children with hyperuricemia (HUA). METHODS: We included 71 children with HUA and 71 children with no HUA as control subjects. Children with HUA were divided into groups I and II according to whether they had a history of acute gout-like attacks (including sudden monoarthritis of rapid onset with intense pain and swelling). Group I was examined twice (A, in the acute phase; B, in the remission phase). Serum IL-1beta and IL-6 levels were measured by enzyme-linked immunosorbent assay. RESULTS: Serum IL-1beta and IL-6 levels were increased in children with HUA and were overall statistically different from the control group (P < 0.05, respectively). Serum IL-1beta and IL-6 were significantly higher in group IA in comparison with group IB, group II, and control subjects (P < 0.05, respectively), as well as in groups IB and II compared with control subjects (P < 0.05, respectively). In group IB, the serum IL-1beta and IL-6 concentrations were higher than those in group II, but there were no statistical differences (P > 0.05). In addition, in children with HUA, serum IL-1beta and IL-6 levels were positively associated with white blood cell count, neutrophil count, monocyte count, uric acid levels, erythrocyte sedimentation rate, C-reactive protein, blood urea nitrogen, and serum creatinine levels (all P < 0.05), but were not associated with triglycerides, total cholesterol, low-density lipoprotein cholesterol, or high density lipoprotein cholesterol levels (all P > 0.05). CONCLUSION: IL-1beta and IL-6 levels are increased in children with hyperuricemia, even if they have not had acute gout. Further studies are necessary to fully characterize the significance of IL-1beta and IL-6 found in HUA children, and whether they could be correlated with long-term prognosis. PMID- 29232322 TI - Incidence of Antidrug Antibodies in Rheumatoid Arthritis Patients From Argentina Treated With Adalimumab, Etanercept, or Infliximab in a Real-World Setting. AB - BACKGROUND: Biologic agents may induce immune responses that could impact drug action. OBJECTIVES: The aims of this study were to assess antidrug antibodies (ADAs) in patients with rheumatoid arthritis (RA) from Argentina treated with etanercept, adalimumab, or infliximab at a single visit and correlate it with efficacy outcomes. METHODS: In this subset analysis of a noninterventional, multinational, cross-sectional study (NCT01981473), adult patients with RA treated continuously for 6 to 24 months with etanercept, adalimumab, or infliximab were evaluated for ADAs and trough drug concentrations of 2 days or less prior to the next scheduled dose. Efficacy measurements included Disease Activity Score based on a 28-joint count-erythrocyte sedimentation rate, low disease activity, and Health Assessment Questionnaire-Disability Index. Targeted medical history of injection site/infusion reactions, serum sickness, and thromboembolic events were reported. RESULTS: Baseline demographics, disease characteristics, and duration of treatment of the 119 patients (etanercept: n = 54, adalimumab: n = 52, infliximab: n = 13) were similar across all groups. No etanercept-treated patient tested positive for ADAs compared with 19 (36.5%) of 52 patients and 4 (30.8%) of 13 patients treated with adalimumab and infliximab, respectively. In adalimumab- and infliximab-treated patients, ADA presence correlated negatively with trough drug levels. A greater proportion of ADA negative patients achieved Health Assessment Questionnaire-Disability Index of 0.5 or less and had better composite efficacy measures compared with ADA-positive patients. The rate of targeted medical events reported was low. CONCLUSIONS: In this subset analysis, RA patients from Argentina treated with adalimumab or infliximab, but not etanercept, tested positive for ADAs. Antidrug antibody negative patients showed a tendency toward better clinical outcomes compared with ADA-positive patients. PMID- 29232323 TI - Racial Variation in Total Knee Replacement in a Diverse Nationwide Clinical Trial. AB - OBJECTIVE: Racial variation in total knee replacement (TKR) utilization in the United States has been reported in administrative database studies. We investigated racial variation in TKR procedures in a diverse cohort with severe knee pain followed in an ongoing clinical trial. METHODS: VITAL (VITamin D and OmegA-3 TriaL) is a nationwide, randomized controlled trial of 25,874 adults, 20% of whom are black. We identified a subgroup highly likely to have knee osteoarthritis based on severity of knee pain, physician-diagnosed knee osteoarthritis, and inability to walk 2 to 3 blocks without pain. Participants completed a modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at baseline and self-reported incident TKR annually in follow-up. Using Cox regression, we analyzed the association of black versus white race with TKR, adjusting for demographic and socioeconomic characteristics, comorbidities, and WOMAC pain and function. RESULTS: Among 1070 participants who met the inclusion criteria, black participants reported worse baseline WOMAC pain (45 vs. 32, P < 0.001) and worse function (45 vs. 32, P < 0.001). During a median of 3.6 years (interquartile range, 3.2, 3.8 years) of follow-up, TKRs were reported by 180 participants. Black participants were less likely to undergo TKR (11% vs. 19%). After adjustment, the hazard ratio for TKR for black versus white participants was 0.51 (95% confidence interval, 0.32-0.81). Lower use of TKR among black participants was observed across all levels of income and education. CONCLUSIONS: Despite worse baseline knee pain and function, black participants had much lower adjusted risk of having TKR than white participants, demonstrating persistent racial disparity in TKR utilization. PMID- 29232324 TI - Vaccination Recommendations for Adults With Autoimmune Inflammatory Rheumatic Diseases in Latin America. AB - BACKGROUND/OBJECTIVE: Patients with autoimmune inflammatory rheumatic diseases (AIRDs) are at increased risk of contracting severe infections and suffering complications, particularly when they are receiving immunomodulating therapy. Vaccination is an important means to prevent many potential infections and thereby reduce the morbidity and mortality associated with AIRD. The purpose of this consensus document is to provide health care professionals with recommendations for the vaccination of AIRD patients who reside in Latin America. The recommendations were developed by an expert committee from the region based on a review of the literature and their clinical experience. METHODS: The Americas Health Foundation (AHF) used PubMed and EMBASE to identify clinicians and scientists with an academic or hospital affiliation and who had published in the field of adult vaccination and rheumatic diseases since 2010. As a result of this effort, AHF convened an 8-member panel of clinical and scientific experts from Latin America. Both the AHF and panel members conducted a careful literature review to identify relevant publications in the areas of adult vaccination and rheumatology, and the sum of the articles identified was provided to the entire panel. Prior to the conference, panelists were each asked to prepare a written response to a salient issue on the subject, identified by AHF. RESULTS AND CONCLUSIONS: During the conference, each response was edited by the entire group, through numerous drafts and rounds of discussion until a complete consensus on vaccination recommendations for adult patients with AIRDs was obtained, including 7 key recommendations. PMID- 29232325 TI - Utility of Electronic Medical Records in Community Rheumatology Practice for Assessing Quality of Care Indicators for Gout: A Feasibility Study. AB - OBJECTIVES: With comprehensive capture of information on patient encounters, electronic medical records (EMRs) may have utility for assessing adherence to quality indicators (QIs) in gout. Our objectives were to translate 10 previously established gout QIs into relevant EMR data and evaluate and describe the feasibility of using EMRs to assess gout QIs. METHODS: Using EMRs from 3 community rheumatology practices in Vancouver, British Columbia, Canada, we identified gout patients seen between January 1, 2012, and December 31, 2013. We translated each gout QI into potential EMR variables that would allow identification of patients the QI pertains to and whether the QI could be assessed. We extracted deidentified EMR data on gout diagnosis, medications, laboratory tests, radiological tests, and clinical notes and calculated the percent availability of data for each QI. RESULTS: We included 125 patients with gout, with mean age of 64 +/- 17 years and with males comprising 78%. Overall, there were sufficient EMR data to allow translation of 7 QIs and assessment of 6 QIs including therapy-related gout QIs (69%-83% data availability) and one counseling-related QI (8% data availability). The highest percent data availability was observed in the single QI translated into EMR data and assessed based on diagnostic codes and prescription medications and not laboratory tests. CONCLUSIONS: Electronic medical records are promising tools for assessing QIs for gout. It was feasible to translate seven gout QIs into relevant EMR variables and there was sufficient EMR data to feasibly assess six of these QIs -Our findings lend evidence to support the utility of EMRs for ut QI assessment, with implications for helping improve management of this disease. PMID- 29232326 TI - Certolizumab Pegol-Induced Heart Failure. PMID- 29232327 TI - An Interview of Robert J. Kurman, MD: Learning, Teaching, Passing the Torch. PMID- 29232329 TI - Cortisol and Subjective Stress Responses to Acute Psychosocial Stress in Fibromyalgia Patients and Control Participants. AB - OBJECTIVE: Hypothalamic-pituitary-adrenal axis dysfunction may play a role in fibromyalgia (FM) pathogenesis but it remains understudied in this disorder. Furthermore, early childhood adversities (ECA) are common in FM, but whether they moderate stress reactivity is unknown. Hence, we investigated cortisol and subjective responses to acute psychosocial stress in FM and controls, while adjusting for ECA. METHODS: Twenty-seven female FM patients and 24 age-matched female controls were recruited in a tertiary care center and through advertisements, respectively. The Childhood Trauma Questionnaire was used to measure ECA history. Salivary cortisol levels and subjective stress ratings were measured at multiple time points before and after the Trier Social Stress Test (TSST) was administered. RESULTS: Significant main effects of group [F(1,43) = 7.04, p = .011, lower in FM] and ECA [F(1,43) = 5.18, p = .028, higher in participants with ECA] were found for cortisol responses. When excluding controls with ECA (n = 5), a significant group-by-time interaction was found [F(6,39) = 2.60, p = .032], driven by a blunted response to the stressor in FM compared with controls (p = .037). For subjective stress responses, a significant main effect of group [F(1,45) = 10.69, p = .002, higher in FM] and a trend toward a group-by time interaction effect [F(6,45) = 2.05, p = .078, higher in FM 30 minutes before and 30 and 75 minutes after the TSST, and impaired recovery (difference immediately after - 30 minutes after the TSST) in FM] were found. CONCLUSIONS: Blunted cortisol responsivity to the TSST was observed in FM patients compared with controls without ECA. FM patients had higher subjective stress levels compared with controls, particularly at baseline and during recovery from the TSST. In FM patients, ECA history was not associated with cortisol or subjective stress levels or with responsivity to the TSST. Future research should investigate the mechanisms underlying hypothalamic-pituitary-adrenal axis dysregulation in FM. PMID- 29232328 TI - Novel CYP2A6 diplotypes identified through next-generation sequencing are associated with in-vitro and in-vivo nicotine metabolism. AB - OBJECTIVES: Smoking patterns and cessation rates vary widely across smokers and can be influenced by variation in rates of nicotine metabolism [i.e. cytochrome P450 2A6 (CYP2A6), enzyme activity]. There is high heritability of CYP2A6 mediated nicotine metabolism (60-80%) owing to known and unidentified genetic variation in the CYP2A6 gene. We aimed to identify and characterize additional genetic variants at the CYP2A6 gene locus. METHODS: A new CYP2A6-specific sequencing method was used to investigate genetic variation in CYP2A6. Novel variants were characterized in a White human liver bank that has been extensively phenotyped for CYP2A6. Linkage and haplotype structure for the novel single nucleotide polymorphisms (SNPs) were assessed. The association between novel five SNP diplotypes and nicotine metabolism rate was investigated. RESULTS: Seven high frequency (minor allele frequencies >=6%) noncoding SNPs were identified as important contributors to CYP2A6 phenotypes in a White human liver bank (rs57837628, rs7260629, rs7259706, rs150298687 (also denoted rs4803381), rs56113850, rs28399453, and rs8192733), accounting for two times more variation in in-vitro CYP2A6 activity relative to the four established functional CYP2A6 variants that are frequently tested in Whites (CYP2A6*2, *4, *9, and *12). Two pairs of novel SNPs were in high linkage disequilibrium, allowing us to establish five-SNP diplotypes that were associated with CYP2A6 enzyme activity (rate of nicotine metabolism) in-vitro in the liver bank and in-vivo among smokers. CONCLUSION: The novel five-SNP diplotype may be useful to incorporate into CYP2A6 genotype models for personalized prediction of nicotine metabolism rate, cessation success, and response to pharmacotherapies. PMID- 29232330 TI - FOVEAL AVASCULAR ZONE AREA ANALYSIS USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY BEFORE AND AFTER IDIOPATHIC EPIRETINAL MEMBRANE SURGERY. AB - PURPOSE: To determine the size of the foveal avascular zone (FAZ) by optical coherence tomography angiography before and after idiopathic epiretinal membrane surgery. METHODS: Thirteen consecutive patients (13 eyes) with unilateral epiretinal membrane were studied retrospectively. Optical coherence tomography angiography was used to measure the FAZ area within 3 mm * 3 mm scans of the superficial (superficial FAZ) and deep plexus layers (deep FAZ) before and 6 months after vitrectomy. The unaffected fellow eyes were used as controls. RESULTS: The mean superficial and deep FAZ areas at 6 months after vitrectomy (0.080 +/- 0.038 and 0.113 +/- 0.045 mm, respectively) were significantly (P < 0.0001, P = 0.0035) larger than the corresponding mean preoperative FAZ areas (0.056 +/- 0.030 and 0.082 +/- 0.035 mm). However, the areas of FAZ expansion were small (0.024 +/- 0.013 and 0.031 +/- 0.031 mm). The mean postoperative superficial and deep FAZ areas were significantly (P < 0.0001, P < 0.0001) smaller than those of fellow eyes (0.295 +/- 0.108 and 0.410 +/- 0.142 mm). Multiple regression analysis showed that preoperative FAZ area had the highest correlation with postoperative FAZ area (P < 0.05). CONCLUSION: This study showed horizontal contraction of the FAZ area in eyes with epiretinal membrane. Because preoperative FAZ area correlates with postoperative FAZ area, FAZ area may be a useful parameter for determining timing of surgery for epiretinal membrane. PMID- 29232331 TI - THEORETICAL GAS CONCENTRATIONS ACHIEVING 100% FILL OF THE VITREOUS CAVITY IN THE POSTOPERATIVE PERIOD: A Gas Eye Model Study. AB - PURPOSE: To determine the concentrations of different gas tamponades in air to achieve 100% fill of the vitreous cavity postoperatively and to examine the influence of eye volume on these concentrations. METHODS: A mathematical model of the mass transfer dynamics of tamponade and blood gases (O2, N2, and CO2) when injected into the eye was used. Mass transfer surface areas were calculated from published anatomical data. The model has been calibrated from published volumetric decay and composition results for three gases sulphahexafluoride (SF6), hexafluoroethane (C2F6), or perfluoropropane (C3F8). The concentrations of these gases (in air) required to achieve 100% fill of the vitreous cavity postoperatively without an intraocular pressure rise were determined. The concentrations were calculated for three volumes of the vitreous cavity to test whether ocular size influenced the results. RESULTS: A table of gas concentrations was produced. In a simulation of pars plana vitrectomy operations in which an 80% to 85% fill of the vitreous cavity with gas was achieved at surgery, the concentrations of the 3 gases in air to achieve 100% fill postoperatively were 10% to 13% for C3F8, 12% to 15% for C2F6, and 19% to 25% for SF6. These were similar to the so-called "nonexpansive" concentrations used in the clinical setting. The calculations were repeated for three different sizes of eye. Aiming for an 80% fill at surgery and 100% postoperatively, an eye with a 4 mL vitreous cavity required 24% SF6, 15% C2F6, or 13% C3F8; 7.2 mL required 25% SF6, 15% C2F6, or 13% C3F8; and 10 mL required 25% SF6, 16% C2F6, or 13% C3F8. When using 100% gas (e.g., used in pneumatic retinopexy), to achieve 100% fill postoperatively, the minimum vitreous cavity fill at surgery was 43% for SF6, 29% for C2F6, and 25% for C3F8 and was only minimally changed by variation in the size of the eye. CONCLUSION: A table has been produced, which could be used for surgical innovation in gas usage in the vitreous cavity. It provides concentrations for different percentage fills, which will achieve a moment postoperatively with a full fill of the cavity without a pressure rise. Variation in axial length and size of the eye does not seem to alter the values in the table significantly. Those using pneumatic retinopexy need to increase the volume of gas injected with increased size of the eye to match the percentage fill of the vitreous cavity recommended for a given tamponade agent. PMID- 29232332 TI - OUTCOMES OF REPEAT PARS PLANA VITRECTOMY AFTER FAILED SURGERY FOR PROLIFERATIVE VITREORETINOPATHY. AB - PURPOSE: To evaluate outcomes of repeat pars plana vitrectomy for proliferative vitreoretinopathy after previous failed pars plana vitrectomy. METHODS: This is a retrospective case series including 51 eyes of 50 patients who underwent repeat surgery after failed previous pars plana vitrectomy for proliferative vitreoretinopathy from 2000 to 2015 at the Kresge Eye Institute, Detroit, MI. Patients were classified into successful and unsuccessful groups. Success was defined as retinal reattachment, silicone oil removed, and best-corrected visual acuity (BCVA) >=5/200 at the final follow-up visit. RESULTS: Forty-three eyes (84.3%) were successfully reattached at the last follow-up. Seventeen (33.3%) eyes were deemed successful and 34 (66.7%) eyes unsuccessful according to our criteria. Compared with the successful group, eyes in the unsuccessful group had more eyes with preoperative BCVA <5/200 (P < 0.001), preoperative BCVA of hand motion or worse (P = 0.002), preoperative flare >=Grade 2+ (P = 0.03), preoperative posterior breaks (P = 0.02), previous retinectomy (P = 0.04), and final postoperative hypotony (intraocular pressure <= 5 mmHg) (P = 0.005). Eyes with silicone oil removed were more likely to have BCVA >=5/200 (P < 0.001) at the final follow-up visit. Location of patients >100 miles (P = 0.04) from Detroit and preoperative BCVA of hand motion or worse (P = 0.01) were significantly associated with failure in the logistic regression analysis. CONCLUSION: Success after repeat surgery for proliferative vitreoretinopathy should include ambulatory vision, retinal reattachment, and silicone oil removal. We identified several preoperative and perioperative factors that were associated with success in the bivariate and logistic analyses. The decision to perform surgical reoperation in these patients should be based on multiple factors, most importantly preoperative BCVA. PMID- 29232334 TI - INTRAVITREAL ZIV-AFLIBERCEPT FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: 52 Week Results. AB - PURPOSE: To evaluate the 52-week safety and efficacy of intravitreal ziv aflibercept in patients with neovascular age-related macular degeneration. METHODS: All patients received three monthly intravitreal injections of 0.05 mL of ziv-aflibercept (1.25 mg) followed by a pro re nata regimen. The best corrected visual acuity and spectral domain optical coherence tomography were obtained at baseline and monthly. Full-field and multifocal electroretinograms were obtained at baseline and 4, 13, 26, and 52 weeks. For some full-field electroretinography parameters, we calculated the differences between baseline and 52 weeks and then compared those differences between treated and untreated fellow eyes. RESULTS: Fifteen patients were included and 14 completed the 52-week follow-up. The mean best-corrected visual acuity improved from 0.95 +/- 0.41 (20/200) at baseline to 0.75 +/- 0.51 (20/125) logarithm of the minimum angle of resolution at 52 weeks (P = 0.0066). The baseline central retinal thickness decreased from 478.21 +/- 153.48 MUm to 304.43 +/- 98.59 MUm (P = 0.0004) at 52 weeks. Full-field electroretinography parameters used to assess retinal toxicity after intravitreal injections (rod response and oscillatory potentials) remained unchanged during follow-up. The average multifocal electroretinography macular response in 5 degrees showed increased N1-P1 amplitude and decreased P1 implicit time (P < 0.05). One patient presented with intraocular inflammation after the seventh intravitreal procedure. CONCLUSION: The results suggested that intravitreal ziv-aflibercept might be safe and effective for treating neovascular age-related macular degeneration. More patients and a longer follow-up are needed to confirm the long-term outcomes of intravitreal ziv-aflibercept. PMID- 29232333 TI - STRUCTURAL ANALYSIS AND COMPREHENSIVE SURGICAL OUTCOMES OF THE SUTURELESS INTRASCLERAL FIXATION OF SECONDARY INTRAOCULAR LENSES IN HUMAN EYES. AB - PURPOSE: To describe surgical outcomes and structural characteristics of intraocular lenses (IOLs) implanted with transconjunctival sutureless intrascleral (SIS) fixation in human eyes. DESIGN: Retrospective interventional surgical case series involving live and cadaveric human eyes. METHODS: In this study, we investigated the surgical outcomes and structural anatomy of secondary IOLs implanted with the SIS technique in human eyes. All cases involving SIS IOL fixation performed at a single academic center from January 1, 2012, through July 30, 2016, were reviewed to describe the surgical technique, common indications, clinical outcomes, and the rate of common operative complications. To investigate the structure of SIS-fixated IOLs in vivo, slit-lamp biomicroscopy, ultrasound biomicroscopy, and intraoperative endoscopy were analyzed to describe anatomical outcomes. The primary anatomical outcomes were the optic pupillary centration and location of haptic externalization. Results were correlated with cadaveric human eyes that underwent the SIS-IOL technique. Cadaveric eyes were imaged and analyzed using high-resolution photography for centration, stress measurements at the haptic-optic junction, and qualitative descriptors of IOL optic and haptic position. RESULTS: A total of 122 consecutive patients who underwent IOL placement using SIS technique were included in the study with mean follow-up of 1.52 years (range, 0.4-4.5 years). The majority (75%) of patients received a new 3-piece IOL for primary aphakia or after IOL exchange. The other patients (25%) had a dislocated 3-piece IOL that was rescued using the SIS technique. Preoperative mean Snellen visual acuity was 20/633 (logarithm of the minimum angle of resolution = 1.501). At the final visit, the mean best-corrected visual acuity was 20/83 (logarithm of the minimum angle of resolution = 0.6243) and final mean spherical equivalent was -0.57 diopters. The most common complications were vitreous hemorrhage (22% of eyes), which resolved spontaneously in most cases, and cystoid macular edema. The rates of IOL dislocation, IOL decentration, haptic erosion, IOL tilting, iris capture, and endophthalmitis were low. Intraoperative endoscopy and ultrasound biomicroscopy demonstrated a securely fixated IOL and well-centered optic without iris or ciliary body touch. Structural study of cadaveric eyes confirmed IOL optic and haptic anatomy observed during live human surgery. The ab interno haptic insertion was the anterior pars plana, away from the iris, ciliary processes and ora serrata. The degree of haptic externalization was correlated with the degree of strain on the haptic-optic junction. The angle of the haptic-optic junction in SIS-fixated IOLs (33.97 degrees ) was not significantly different compared with overlaid native nonfixated IOL (32.93 degrees ) but increased slightly with degree of haptic tip externalization (36.26 and 39.16 for 2 and 3 mm haptic externalizations, respectively). CONCLUSION: In this comprehensive study, we demonstrate the surgical outcomes achieved with SIS fixation of IOLs. Surgical and postoperative complications do occur, albeit at a low rate, and can effectively be managed with excellent anatomical and visual outcomes. The structural and anatomical data in this study may help guide SIS placement and optimize long-term surgical results. PMID- 29232335 TI - ENDOGENOUS KLEBSIELLA PNEUMONIAE ENDOPHTHALMITIS IN NORTHERN CALIFORNIA. AB - PURPOSE: To report the clinical features, treatment modalities, and visual outcomes in 12 eyes with endogenous Klebsiella pneumoniae endophthalmitis (EKPE). METHODS: The medical records of all patients diagnosed with EKPE at Stanford Hospital (Palo Alto, CA) and Santa Clara Valley County Hospital (Santa Clara, CA) from January 2000 to March 2017 were retrospectively reviewed. RESULTS: A total of 10 patients (12 eyes) were diagnosed with EKPE. The median age at presentation was 56, 80% were male, and 30% were non-Asian. Presenting visual acuities ranged from 20/20 to no light perception. Of the 12 eyes 10 received a tap and injection (range, 1-33 injections per eye), 2 eyes underwent primary enucleation or evisceration, and 1 patient underwent pars plana vitrectomy after tap and injection. Final visual acuities ranged from no light perception (six eyes) to 20/300 or better (five eyes). Five patients eventually underwent evisceration or enucleation. All cases were associated with positive blood and/or vitreous cultures and had concurrent systemic infection. CONCLUSION: Endogenous Klebsiella pneumoniae endophthalmitis is a rare, but devastating, ocular infection. Most cases in this series resulted in light perception vision or worse, and almost half required enucleation or evisceration. In light of the virulence of EKPE, early diagnosis and treatment should be initiated in all suspected cases. PMID- 29232336 TI - COMPARISON AMONG DIFFERENT DIAGNOSTIC METHODS IN THE STUDY OF TYPE AND ACTIVITY OF CHOROIDAL NEOVASCULAR MEMBRANES IN AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To determine interobserver and intraobserver agreement in classifying the subtypes of choroidal neovascularization (CNV) and the decision of retreatment in patients affected by exudative age-related macular degeneration. Different imaging techniques were evaluated individually and compared with multiimaging. METHODS: Fifty-two patients with naive CNV in age-related macular degeneration were evaluated after 3 monthly intravitreal injections of ranibizumab. Choroidal neovascularization subtype and activity were evaluated using spectral domain optical coherence tomography, infrared light, fundus autofluorescence, fluorescein angiography (FA), and indocyanine green angiography (ICGA). The evaluation was performed independently by 10 different retina specialists, 2 for each test. Other two operators analyzed all the information available together. RESULTS: The interobserver k regarding the types of CNV was 0.69 for multiimaging, 0.63 for spectral domain optical coherence tomography, 0.43 for FA, and 0.46 for ICGA. The k values for interobserver for retreatment decision were 0.77 for multiimaging, 0.88 for spectral domain optical coherence tomography, 0.61 for infrared, 0.37 for fundus autofluorescence, 0.25 for FA, and 0.23 for ICGA. Fluorescein angiography, spectral domain optical coherence tomography, ICGA, and infrared showed good association with multiimaging on defining CNV activity (P = 0.0003, P < 0.0001, P = 0.01, and P = 0.05, respectively). CONCLUSION: Optical coherence tomography and infrared evaluations of CNV activity were reproducible and strongly associated with multiimaging, whereas FA and ICGA evaluations showed poor reproducibility. PMID- 29232337 TI - RETINAL TELANGIECTASIA IN PATIENTS WITH PATHOLOGIC MYOPIA: A CASE SERIES. AB - PURPOSE: To describe the characteristics of retinal telangiectasia in eyes with pathologic myopia. METHODS: The study included 10 patients (18 eyes) who were diagnosed with pathologic myopia combined with retinal telangiectasia. The patients visited our retinal clinic every 3 months. Nine eyes underwent vitrectomy for vision-threatening complications after diagnosis. All eyes underwent comprehensive ophthalmologic examinations including multimodal retinal imaging at presentation and at each follow-up. RESULTS: Retinal telangiectasia in pathologic myopia was characterized by saccular aneurysmal dilatation of the capillary bed without hard exudates in color fundus photographs and hyporeflective saccular structure in infrared reflectance fundus photographs, and it was filled in the early retinal arteriovenous phase with minimal dye leakage in the late phase of fundus fluorescein angiography. Spectral domain optical coherence tomography and optical coherence tomographic angiography showed that retinal telangiectasia was primarily located in the superficial retina, together with myopic traction maculopathy. In the 9 eyes that underwent vitrectomy, the retinal telangiectasia regressed within 3 months of surgery. Retinal telangiectasia remained stable in the other nine eyes, but these eyes were at risk of spontaneous bleeding. CONCLUSION: Retinal telangiectasia is a relatively quiescent and uncommon disorder in patients with pathologic myopia that might be closely related to myopic traction maculopathy. PMID- 29232338 TI - INTERNAL LIMITING MEMBRANE PEELING VERSUS INVERTED FLAP TECHNIQUE FOR TREATMENT OF FULL-THICKNESS MACULAR HOLES: A COMPARATIVE STUDY IN A LARGE SERIES OF PATIENTS. AB - BACKGROUND: The inverted flap (IF) technique has recently been introduced in macular hole (MH) surgery. The IF technique has shown an increase of the success rate in the case of large MHs and in MHs associated with high myopia. This study reports the anatomical and functional results in a large series of patients affected by MH treated using pars plana vitrectomy and gas tamponade combined with internal limiting membrane (ILM) peeling or IF. METHODS: This is a retrospective, consecutive, nonrandomized comparative study of patients affected by idiopathic or myopic MH treated using small-gauge pars plana vitrectomy (25- or 23-gauge) between January 2011 and May 2016. The patients were divided into two groups according to the ILM removal technique (complete removal vs. IF). A subgroup analysis was performed according to the MH diameter (MH < 400 um and MH >= 400 um), axial length (AL < 26 mm and AL >= 26 mm), and the presence of chorioretinal atrophy in the macular area (present or absent). RESULTS: We included 620 eyes of 570 patients affected by an MH, 300 patients underwent pars plana vitrectomy and ILM peeling and 320 patients underwent pars plana vitrectomy and IF. Overall, 84.94% of the patients had complete anatomical success characterized by MH closure after the operation. In particular, among the patients who underwent only ILM peeling the closure rate was 78.75%; among the patients who underwent the IF technique, it was 91.93% (P = 0.001); and among the patients affected by full-thickness MH >=400 um, success was achieved in 95.6% of the cases in the IF group and in 78.6% in the ILM peeling group (P = 0.001); among the patients with an axial length >=26 mm, success was achieved in 88.4% of the cases in the IF group and in 38.9% in the ILM peeling group (P = 0.001). Average preoperative best-corrected visual acuity was 0.77 (SD = 0.32) logarithm of the minimum angle of resolution (20/118 Snellen) in the peeling group and 0.74 (SD = 0.33) logarithm of the minimum angle of resolution (20/110 Snellen) in the IF group (P = 0.31). Mean postoperative best-corrected visual acuity was 0.52 (SD = 0.42) logarithm of the minimum angle of resolution (20/66 Snellen) in the peeling group and 0.43 (SD = 0.31) logarithm of the minimum angle of resolution (20/53 Snellen) in the IF group (P = 0.003). CONCLUSION: Vitrectomy associated with the inverted ILM flap technique seems to be effective surgery for idiopathic and myopic large MHs, improving both functional and anatomical outcomes. PMID- 29232339 TI - The Role of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography in Well-Differentiated Neuroendocrine Tumors: A Case-Based Approach Illustrates Potential Benefits and Challenges. PMID- 29232340 TI - Ablative Therapies for Locally Advanced Pancreatic Cancer. AB - The vast majority of patients who present with pancreatic adenocarcinoma have locally advanced or metastatic disease at the time of presentation without possibility of cure. Although in recent years there have been some new promising chemotherapy regimens that improve overall survival by a few months, the prognosis remains dismal. There is, however, a subset of patients who experience durable stable disease or partial responses after initial courses of chemotherapy with locally advanced disease. In these select patients, there remains interest in local ablative therapy with or without resection as a means for local control, palliation of symptoms, and possible improved survival. This review describes the techniques, complications, and expected benefits of several ablative techniques as a treatment modality for locally advanced pancreatic cancer. PMID- 29232341 TI - Evidence-Based Management of Drains Following Pancreatic Resection: A Systematic Review. AB - Many pancreatic surgeons continue to use intraperitoneal drains, but others have limited or avoided their use, believing this improves outcomes. We conducted a systematic review and meta-analysis of the literature assessing outcomes in pancreatectomy without drains, selective drainage, and early drain removal. We searched PubMed, Embase, and the Cochrane Library databases and conducted a systematic review of randomized and nonrandomized studies comparing routine intra abdominal drainage versus no drainage, selective drain use, and early versus late drain removal after pancreatectomy, with major complications as the primary outcome. A meta-analysis of the literature assessing routine use of drains was conducted using the random-effects model. A total of 461 articles met search criteria from PubMed (168 articles), Embase (263 articles), and the Cochrane Library (30 articles). After case reports and articles without primary data on complications were excluded, 14 studies were identified for systematic review. Definitive evidence-based recommendations cannot be made regarding the management of drains following pancreatectomy because of limitations in the available literature. Based on available evidence, the most conservative approach, pending further data, is routine placement of a drain and early removal unless the patient's clinical course or drain fluid amylase concentration suggests a developing fistula. PMID- 29232342 TI - Intraoperative Near-Infrared Fluorescence Imaging of Multiple Pancreatic Neuroendocrine Tumors: A Case Report. AB - Multiple endocrine neoplasia type 1 syndrome can feature pancreatic neuroendocrine lesions that have the potential to degenerate into malignancies (pancreatic neuroendocrine tumors [PNETs]). Resection is required in selected cases and aims to cure patients and to prevent metastasis. Preoperative imaging is important to assess the number, size, and location of PNETs. However, sensitivity of preoperative imaging modalities to detect small lesions can be rather disappointing. This makes intraoperative reassessment of the pancreas crucial. Methylene blue (MB) accumulates in neuroendocrine lesions after intravenous administration. Methylene blue emits fluorescence of approximately 700 nm and can be visualized using a dedicated near-infrared (NIR) fluorescence imaging system. We present a 58-year-old male patient with multiple endocrine neoplasia type 1 syndrome and 2 lesions suspected as PNETs identified during regular follow-up. Intraoperative administration of MB allowed successful NIR fluorescence imaging of multiple lesions missed by preoperative imaging. After confirmation by intraoperative ultrasound, this new finding led to a major change in treatment: from enucleations to total pancreatectomy. Histopathologic examination confirmed that the fluorescent lesions were indeed neuroendocrine lesions ranging from microadenomas to PNETs. This case demonstrates that intraoperative assessment of neuroendocrine lesions can be improved by intraoperative NIR fluorescence imaging using MB, a safe and relatively easy technique. PMID- 29232343 TI - Simultaneous Glucagon and Vasoactive Intestinal Peptide Producing Pancreatic Neuroendocrine Tumors in a Patient With Multiple Endocrine Neoplasia Type 1: A Case Report and Literature Review. PMID- 29232344 TI - Telotristat Ethyl for Patients With Carcinoid Syndrome Associated With Chest Pain and Hypertension. PMID- 29232345 TI - Factors Associated With Lack of Vision Improvement in Children With Cortical Visual Impairment. AB - BACKGROUND: Improvement in vision has been noted in children with cortical visual impairment (CVI), resulting from disparate types of brain injury. The purpose of our study was to determine the risk factors associated with poor recovery of vision in this group of patients. METHODS: Case records of children who were born before 2010 with at least 4 follow-up visits for CVI were reviewed for underlying etiologies of CVI, visual acuity (VA), and associated neurological and ophthalmological disorders. VA was assessed in 6 qualitative grades. Changes in VA were recorded as the difference between the grades of VA at presentation and the last follow-up visit. The outcome was calculated as a ratio of actual improvement to potential improvement in grades of qualitative VA. Multiple linear regression determined factors associated with lack of vision improvement in all children and based on etiology. RESULTS: Fifty-three children with CVI were identified. The median age at presentation was 13.6 months (range: 2.9-76.4 months) and the median follow-up was 5.8 years (1.1-16.3 years). CVI resulted from central nervous system (CNS) malformation (9.4%), hypoxic/inflammatory injury (15.1%), seizures (24.5%), and combined causes (51.0%). Vision improvement was noted in 83% of children. Lack of VA improvement was associated with older age at presentation in all children with CVI and within each etiological group except CNS malformation. None of the other investigated variables were associated with poor recovery of VA. CONCLUSIONS: Most of the children with CVI showed improvement in vision. Older age at presentation, but not etiology of CVI, was associated with poor improvement in VA. PMID- 29232346 TI - Editorial. PMID- 29232347 TI - Gaming in Nursing Education: A Literature Review. AB - AIM: The aim of this research was to investigate videogame-based learning in nursing education and establish how videogames are currently employed and how they link to the development of decision-making, motivation, and other benefits. BACKGROUND: Although digital game-based learning potentially offers a safe and convenient environment that can support nursing students developing essential skills, nurse educators are typically slow to adopt such resources. METHOD: A comprehensive search of electronic databases was conducted, followed by a thematic analysis of the literature. RESULTS: Evaluations of identified games found generally positive results regarding usability and effectiveness of videogames in nursing education. Analysis of advantages of videogames in nursing education identified potential benefits for decision-making, motivation, repeated exposure, logistical, and financial value. CONCLUSION: Despite the paucity of games available and the methodological limitations identified, findings provide evidence to support the potential effectiveness of videogames as a learning resource in nursing education. PMID- 29232349 TI - Management of Intussusception in the Pediatric Emergency Department: Risk Factors for Recurrence. AB - BACKGROUND: The standard treatment for intussusception is air reduction enema (ARE) with inpatient observation for 24 to 48 hours to monitor for recurrence. More recent but limited observations suggest that patients who have undergone successful ARE can safely be discharged after 4 to 6 hours of observation. Our primary objective was to identify risk factors associated with early recurrence. Our secondary objectives included validating risk criteria from prior studies and identifying risk factors for ARE failures. DESIGN/METHODS: A retrospective cohort study of children discharged from a large urban quaternary hospital with a final diagnosis of intussusception (International Classification of Diseases, Ninth Revision, code 560.0) or who underwent ARE from 2005 to 2015 was identified. Demographic data, radiology images, and clinical course were recorded. Repeat visits, cases with incomplete medical records, and those with incorrect diagnoses were excluded. RESULTS: A total of 250 cases were identified. Two hundred cases were included for analysis. Fifty were excluded. Of the 163 who had successful reduction with ARE, 22 patients (13.5%) recurred, and 12 (7.3%) recurred within 48 hours. Fever (odds ratio, 4.25; P = 0.04; 95% confidence interval, 1.04-17.3) and female sex (odds ratio, 7.94; P = 0.01; 95% confidence interval, 1.82-34.6) were independently associated with early recurrence. No radiologic features were associated with early recurrence. CONCLUSIONS: Early recurrence after successful ARE was low, although more frequent in girls and in those with fever over 100.4 degrees F. We therefore advocate for prospective studies to validate these risk criteria to identify patients who are at low risk for early recurrence and may qualify for early discharge from the emergency department. PMID- 29232350 TI - A Mild Laryngeal Cleft Causes Severe Symptoms. AB - Diagnosis and treatment of laryngeal clefts (LCs) particularly type I pose a challenge. Although rare, type I LCs are becoming increasingly identified in recent years, and this is perhaps due to both an increased awareness and better diagnostic modalities. We report a young infant presenting with feeding difficulty and respiratory distress related to LC. The pertinent literature is also reviewed. PMID- 29232351 TI - Randomized Clinical Trial of Lidocaine Analgesia for Transurethral Bladder Catheterization Delivered via Blunt Tipped Applicator in Young Children. AB - OBJECTIVE: Transurethral bladder catheterization (TUBC) is a painful, frequently performed procedure for collecting sterile urine. We sought to determine if administration of intraurethral lidocaine before TUBC using a blunt tipped syringe decreases procedural pain in young children in the pediatric emergency department. METHODS: Randomized clinical trial of children 0 to 36 months old requiring TUBC for collection of urine in a pediatric emergency department was performed. Patients received intraurethral 2% lidocaine jelly or usual care (no analgesia). Randomization was stratified by sex. Intraurethral lidocaine jelly was administered via Uro-Jet, 5 minutes before TUBC. Baseline child state, lidocaine application, TUBC, and child state 1 minute post-TUBC were videotaped. Neither providers nor parents were blinded to study arm. Videos were scored by a trained, independent, blinded reviewer using the Faces, Legs, Arms, Cry, and Consolability (FLACC) and Modified Behavioral Pain Score scales. Pain scores were compared using the Wilcoxon rank sum test. Our primary outcome was difference in FLACC scores between groups. RESULTS: Eighty children were enrolled in the study, and 73 had analyzable data. No differences were detected in pain by mean FLACC score between intervention (8; 95% confidence interval, 7-9) and control (9; 95% confidence interval, 8-10) groups. There were no differences between groups in mean FLACC score when stratified by age or sex or in mean Modified Behavioral Pain Score. CONCLUSIONS: Intraurethral lidocaine for TUBC for urine collection using a blunt tipped applicator did not improve procedural pain scores. Pain scores were high across groups. Further study should be performed to improve analgesia for this highly painful procedure. PMID- 29232352 TI - Case Report of a 5-Year-Old With Epiglottitis: An Atypical Presentation of an Uncommon Disease. AB - Epiglottitis is a rarely encountered infection in pediatrics since the advent of the conjugate Haemophilus influenzae type b vaccine first introduced in the United States in 1985. However, the disease remains a much feared infection in pediatrics. The literature reiterates the importance of early recognition, avoidance of agitating the patient, and the need for securing the airway in the operating room as key and essential features to a good outcome. However, with only 1 case per 200,000 children reported in the United States in 2006, most practitioners have never encountered this infection. The following is a case of a previously healthy and immunized child who presented to our emergency department and whose condition was ultimately diagnosed as epiglottitis. PMID- 29232353 TI - Improving Pediatric Preparedness in Critical Access Hospital Emergency Departments: Impact of a Longitudinal In Situ Simulation Program. AB - OBJECTIVES: Critical access hospitals (CAH) see few pediatric patients. Many of these hospitals do not have access to physicians with pediatric training. We sought to evaluate the impact of an in situ pediatric simulation program in the CAH emergency department setting on care team performance during resuscitation scenarios. METHODS: Five CAHs conducted 6 high-fidelity pediatric simulations over a 12-month period. Team performance was evaluated using a validated 35-item checklist representing commonly expected resuscitation team interventions. Checklists were scored by assigning zero point for "yes" and 1 point for "no". A lower final score meant more items on the list had been completed. The Kruskal Wallis rank test was used to assess for differences in average scores among institutions. A linear mixed effects model with a random institution intercept was used to examine trends in average scores over time. P < 0.05 was considered significant. RESULTS: The Kruskal-Wallis rank test showed no difference in average scores among institutions. (P = 0.90). Checklist scores showed a significant downward trend over time, with a scenario-to-scenario decrease of 0.022 (P < 0.01). One hundred percent of providers surveyed in the last month stated they would benefit from ongoing scenarios. CONCLUSIONS: Regularly scheduled pediatric simulations in the CAH emergency department setting improved team performance over time on expected resuscitation tasks. The program was accepted by providers. Implementation of simulation-based training programs can help address concerns regarding pediatric preparedness in the CAH setting. A future project will look at the impact of the program on patient care and safety. PMID- 29232355 TI - Proximal Junctional Kyphosis: Inter- and Intraobserver Reliability of Radiographic Measurements in Adult Spinal Deformity. AB - STUDY DESIGN: Reliability study of radiographic measures of proximal junctional kyphosis (PJK) in patients with adult spinal deformity (ASD). OBJECTIVE: To assess impacts of level of proximal endpoint and vertebral fracture on reliability of measurement of junctional kyphosis. SUMMARY OF BACKGROUND DATA: Radiographic assessment is important in determining management of patients with PJK or proximal junctional failure (PJF). No study to date has evaluated the reliability of radiographic measurement of the junctional kyphotic angle after surgery for ASD. METHODS: Postoperative radiographs from 52 patients with ASD were divided into four categories based on the level of the upper instrumented vertebra (UIV) and the presence or absence of PJF: upper thoracic without failure (UT), thoracolumbar without failure (TL), upper thoracic with PJF (UTF), and thoracolumbar with PJF (TLF). Nine surgeon reviewers performed radiographic measurements of kyphosis between UIV+2 and UIV twice at least 4 weeks apart. Intraclass correlation coefficients (ICC) were calculated to determine inter- and intraobserver reliability. RESULTS: Interobserver reliability for measurements of UT, TL, UTF, and TLF were all "almost perfect" with ICC scores of 0.917, 0.965, 0.956, and 0.882, and 0.932, 0.975, 0958, and 0.989, for sessions 1 and 2, respectively. Similarly, ICCs for kyphosis measurements for the TL and TLF group had "almost perfect" agreement with means of 0.898 (range: 0.817-0.969) and 0.976 (range: 0.931-0.995), respectively. ICCs for measurements for the UT and UTF groups all had "substantial" or "almost perfect" agreement with means of 0.801 (range: 0.662-0.942) and 0.879 (range: 0.760-0.988), respectively. CONCLUSION: The present study demonstrates high inter- and intraobserver reliability of PJK measurement following instrumented fusion for ASD, independent of the presence or absence of PJF. Although slightly lower for upper thoracic than for thoracolumbar proximal endpoints, all ICCs consistently reached at least "substantial agreement" and "near perfect agreement" for most. LEVEL OF EVIDENCE: 4. PMID- 29232356 TI - Drugs for postmenopausal osteoporosis. PMID- 29232357 TI - Comparison table: Drugs for postmenopausal osteoporosis. PMID- 29232358 TI - Genetic Polymorphisms of Insulin-Like Growth Factor 1 Are Associated with Osteosarcoma Risk and Prognosis. AB - BACKGROUND Insulin-like growth factor 1 (IGF-1) gene plays an important role in bone and soft tumors. IGF-1 gene polymorphisms have been revealed to be correlated with the carcinogenesis and progression of solid malignancies. We therefore hypothesized that IGF-1 genetic polymorphisms might be associated with the risks and outcomes of osteosarcomas in Chinese individuals. MATERIAL AND METHODS This study included 173 conventional osteosarcoma individuals and 175 tumor-free controls. Five single nucleotide polymorphisms (SNPs) of IGF-1 (rs6214, rs6218, rs35767, rs5742612, and rs5742714) were genotyped. DNA was extracted from peripheral blood and analyzed for SNP genotyping using PCR. RESULTS We found that rs6218 had a predictive role for the susceptibility and progression of osteosarcoma. The presence of TC and CC genotypes of rs6218 indicated higher risk of osteosarcoma. In addition, rs6218 TC and CC genotypes were discovered to be associated with later stage and elevated risk of osteosarcoma metastasis. CONCLUSIONS IGF-1 polymorphisms are potential prognostic predictors of osteosarcoma susceptibility and outcomes. PMID- 29232359 TI - Microbiology: Trapping Rac1. PMID- 29232360 TI - Neurobiology: Defining your territory. PMID- 29232361 TI - Resistance mechanisms: Watering down a warhead. PMID- 29232362 TI - RNA modifications: Ribosomes get decorated. PMID- 29232363 TI - Notch signaling: A sweet strategy. PMID- 29232364 TI - Protein engineering: Finding the best ligase. PMID- 29232365 TI - Monitoring compliance with standards of care for chronic diseases using healthcare administrative databases in Italy: Strengths and limitations. AB - BACKGROUND: A recent comprehensive report on healthcare quality in Italy published by the Organization of Economic Co-operation and Development (OECD) recommended that regular monitoring of quality of primary care by means of compliance with standards of care for chronic diseases is performed. A previous ecological study demonstrated that compliance with standards of care could be reliably estimated on regional level using administrative databases. This study compares estimates based on administrative data with estimates based on GP records for the same persons, to understand whether ecological fallacy played a role in the results of the previous study. METHODS: We compared estimates of compliance with diagnostic and therapeutic standards of care for type 2 diabetes (T2DM), hypertension and ischaemic heart disease (IHD) from administrative data (IAD) with estimates from medical records (MR) for the same persons registered with 24 GP's in 2012. Data were linked at an individual level. RESULTS: 32,688 persons entered the study, 12,673 having at least one of the three diseases according to at least one data source. Patients not detected by IAD were many, for all three conditions: adding MR increased the number of cases of T2DM, hypertension, and IHD by +40%, +42%, and +104%, respectively. IAD had imperfect sensitivity in detecting population compliance with therapies (adding MR increased the estimate, from +11.5% for statins to +14.7% for antithrombotics), and, more substantially, with diagnostic recommendations (adding MR increased the estimate, from +23.7% in glycated hemoglobin tests, to +50.5% in electrocardiogram). Patients not detected by IAD were less compliant with respect to those that IAD correctly identified (from -4.8 percentage points in proportion of IHD patients compliant with a yearly glycated hemoglobin test, to -40.1 points in the proportion of T2DM patients compliant with the same recommendation). IAD overestimated indicators of compliance with therapeutic standards (significant differences ranged from 3.3. to 3.6 percentage points) and underestimated indicators of compliance with diagnostic standards (significant differences ranged from -2.3 to -14.1 percentage points). CONCLUSION: IAD overestimated the percentage of patients compliant with therapeutic standards by less than 6 percentage points, and underestimated the percentage of patients compliant with diagnostic standards by a maximum of 14 percentage points. Therefore, both discussions at local level between GP's and local health unit managers and discussions at central level between national and regional policy makers can be informed by indicators of compliance estimated by IAD, which, based on those results, have the ability of signalling critical or excellent clusters. However, this study found that estimates are partly flawed, because a high number of patients with chronic diseases are not detected by IAD, patients detected are not representative of the whole population of patients, and some categories of diagnostic tests are markedly underrecorded in IAD (up to 50% in the case of electrocardiograms). Those results call to caution when interpreting IAD estimates. Audits based on medical records, on the local level, and an interpretation taking into account information external to IAD, on the central level, are needed to assess a more comprehensive compliance with standards. PMID- 29232367 TI - Correction: Identifying influential neighbors in animal flocking. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1005822.]. PMID- 29232366 TI - Estimating the impact of antiretroviral treatment on adult mortality trends in South Africa: A mathematical modelling study. AB - BACKGROUND: Substantial reductions in adult mortality have been observed in South Africa since the mid-2000s, but there has been no formal evaluation of how much of this decline is attributable to the scale-up of antiretroviral treatment (ART), as previous models have not been calibrated to vital registration data. We developed a deterministic mathematical model to simulate the mortality trends that would have been expected in the absence of ART, and with earlier introduction of ART. METHODS AND FINDINGS: Model estimates of mortality rates in ART patients were obtained from the International Epidemiology Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaboration. The model was calibrated to HIV prevalence data (1997-2013) and mortality data from the South African vital registration system (1997-2014), using a Bayesian approach. In the 1985 2014 period, 2.70 million adult HIV-related deaths occurred in South Africa. Adult HIV deaths peaked at 231,000 per annum in 2006 and declined to 95,000 in 2014, a reduction of 74.7% (95% CI: 73.3%-76.1%) compared to the scenario without ART. However, HIV mortality in 2014 was estimated to be 69% (95% CI: 46%-97%) higher in 2014 (161,000) if the model was calibrated only to HIV prevalence data. In the 2000-2014 period, the South African ART programme is estimated to have reduced the cumulative number of HIV deaths in adults by 1.72 million (95% CI: 1.58 million-1.84 million) and to have saved 6.15 million life years in adults (95% CI: 5.52 million-6.69 million). This compares with a potential saving of 8.80 million (95% CI: 7.90 million-9.59 million) life years that might have been achieved if South Africa had moved swiftly to implement WHO guidelines (2004 2013) and had achieved high levels of ART uptake in HIV-diagnosed individuals from 2004 onwards. The model is limited by its reliance on all-cause mortality data, given the lack of reliable cause-of-death reporting, and also does not allow for changes over time in tuberculosis control programmes and ART effectiveness. CONCLUSIONS: ART has had a dramatic impact on adult mortality in South Africa, but delays in the rollout of ART, especially in the early stages of the ART programme, have contributed to substantial loss of life. This is the first study to our knowledge to calibrate a model of ART impact to population level recorded death data in Africa; models that are not calibrated to population level death data may overestimate HIV-related mortality. PMID- 29232368 TI - Ascorbic acid promotes cardiomyogenesis through SMAD1 signaling in differentiating mouse embryonic stem cells. AB - Numerous groups have documented that Ascorbic Acid (AA) promotes cardiomyocyte differentiation from both mouse and human ESCs and iPSCs. AA is now considered indispensable for the routine production of hPSC-cardiomyocytes (CMs) using defined media; however, the mechanisms involved with the inductive process are poorly understood. Using a genetically modified mouse embryonic stem cell (mESC) line containing a dsRED transgene driven by the cardiac-restricted portion of the ncx1 promoter, we show that AA promoted differentiation of mESCs to CMs in a dose and time-dependent manner. Treatment of mPSCs with AA did not modulate total SMAD content; however, the phosphorylated/active forms of SMAD2 and SMAD1/5/8 were significantly elevated. Co-administration of the SMAD2/3 activator Activin A with AA had no significant effect, but the addition of the nodal co-receptor TDGF1 (Cripto) antagonized AA's cardiomyogenic-promoting ability. AA could also reverse some of the inhibitory effects on cardiomyogenesis of ALK/SMAD2 inhibition by SB431542, a TGFbeta pathway inhibitor. Treatment with BMP2 and AA strongly amplified the positive cardiomyogenic effects of SMAD1/5/8 in a dose dependent manner. AA could not, however, rescue dorsomorphin-mediated inhibition of ALK/SMAD1 activity. Using an inducible model system, we found that SMAD1, but not SMAD2, was essential for AA to promote the formation of TNNT2+-CMs. These data firmly demonstrate that BMP receptor-activated SMADs, preferential to TGFbeta receptor-activated SMADs, are necessary to promote AA stimulated cardiomyogenesis. AA-enhanced cardiomyogenesis thus relies on the ability of AA to modulate the ratio of SMAD signaling among the TGFbeta-superfamily receptor signaling pathways. PMID- 29232369 TI - Accelerated decline in cardiac stem cell efficiency in Spontaneously hypertensive rat compared to normotensive Wistar rat. AB - Cardiac hypertrophy is recognized as an independent risk factor for cardiac failure. Efficient management of hypertensive heart disease requires identification of factors that can possibly mediate the transition from hypertrophy to failure. Resident cardiac stem cells have a prominent role in the maintenance of cardiac tissue homeostasis. Decline in the proportion of healthy cardiac stem cells (CSCs) can affect tissue regeneration. In pathological conditions, apart from natural aging, an adverse microenvironment can lead to decrease in efficiency of CSCs. A systematic analysis of cardiac stem cell characteristics in pathological conditions has not been reported so far. Therefore, this study was designed with the objective of examining the age associated variation in stem cell attributes of Spontaneously hypertensive rat (SHR) in comparison with normotensive Wistar rat. Spontaneously hypertensive rat was used as the experimental model since the cardiac remodeling resembles the clinical course of hypertensive heart disease. CSCs were isolated from atrial explants. Stem cell attributes were assessed in 1-week, 6, 12 and 18-month-old male SHR, in comparison with age matched Wistar rats. In 1-week-old pups, stem cell attributes of SHR and Wistar were comparable. Migration potential, proliferative capacity, TERT expression, telomerase activity and the proportion of c-kit+ cells decreased with age, both in SHR and Wistar. DNA damage and the proportion of senescent CSCs increased with age both in SHR and Wistar rats. Age associated increase was observed in the oxidative stress of stem cells, possibly mediated by the enhanced oxidative stress in the microenvironment. The changes were more pronounced in SHR, and as early as six months of age, there was significant decrease in efficiency of CSCs of SHR compared to Wistar. The density of healthy CSCs determined as a fraction of the differentiated cells was remarkably low in 18-month-old SHR. Age associated decrease in functionally efficient CSCs was therefore accelerated in SHR. Considering the vital role of CSCs in the maintenance of a healthy myocardium, decrease in functionally efficient CSCs can be a precipitating factor in pathological cardiac remodeling. Elevated ROS levels in CSCs of SHR lends scope for speculation that decrease in efficiency of CSCs is mediated by oxidative stress; and that modulation of the microenvironment by therapeutic interventions can restore a healthy stem cell population and facilitate maintenance of cardiac homeostasis and prevent cardiac decompensation. PMID- 29232370 TI - Spatio-temporal variations of conservation hotspots based on ecosystem services in Xishuangbanna, Southwest China. AB - Integrating biodiversity and ecosystem services (BES) has been viewed as an appropriate approach to identifying conservation priorities. Taking Xishuangbanna tropical region in Southwest China, different BESs (habitat quality [used as a proxy for biodiversity], carbon storage, and water yield) were quantified using the InVEST model and conservation hotspots from 1976, 1990, and 2010 were identified by overlapping and ranking the service layers. Results showed that BESs areas were unevenly distributed. High habitat quality and carbon storage areas located in the eastern part of the region were mainly occupied by broad leaved forest, while high water yield areas were covered by grassland and tropical forests. Recognized hotspots were primarily composed of the broad-leaved forest and shrub grassland. However, these habitat types declined by nearly 50% from 1.25*105 ha to 0.63*105 ha and became more fragmented during the study period. We also found that the sub-watersheds which decreased in BES had fewer hotspots distributed and suffered greater landscape fragmentation. Our study further explored the impacts of land-use conversion on BES, and illustrated the necessity and feasibility of BESs in identifying potential conservation areas. PMID- 29232371 TI - Treatment effect of mTOR-inhibition on tissue composition of renal angiomyolipomas in tuberous sclerosis complex (TSC). AB - PURPOSE: Tuberous sclerosis complex (TSC)-associated renal angiomyolipoma (AML) have a high lifetime risk of acute bleeding. MTOR-inhibitors are a promising novel treatment for TSC-AML, however adequate response to therapy can be difficult to assess. Early changes in MRI signal may serve as a novel early indicator for a satisfactory response to mTOR-inhibitor therapy of AML. MATERIALS AND METHODS: Thirty-eight patients with the definite diagnosis of tuberous sclerosis receiving everolimus therapy and n = 19 patients without specific therapy were included. 1.5 Tesla MRI was performed including sequences with a selective fat suppression. Patients were investigated prior to the initiation of therapy (baseline) and after <3 months (n = 21 patients), 3 to 6 months (n = 32) and 18 to 24 months (n = 28). Signal and size changes of renal AMLs were assessed at all different timepoints. Signal-to-noise-ratio (SNR), contrast-to-noise-ratio (CNR) and size of angiomyolipomas were evaluated. RESULTS: Signal changes in 273 AMLs were evaluated. A significant and strong decrease of the CNR of AMLs following the initiation of therapy was measured in the fat-suppressed MR sequence at all time points, compared to the baseline: From 7.41+/-6.98 to 3.84+/ 6.25 (p <= 0.05p = 0.002), 3.36+/-6.93 (p<0.0001), and 2.50+/-6.68 (p<0.0001) after less than 3 months, 3-6 months or 18-24 months of everolimus treatment, respectively. Also, a significant, however less pronounced, reduction of angiomyolipoma size in the different groups was measured (from baseline 2022.2+/ 2657.7 mm2 to 1854.4+/-1670.9 mm2 (p = 0.009), 1875.5+/-3190.1 mm2 (p<0.001), and 1365.8 +/- 1628.8 mm2 (p<0.0001) after less than 3 months, 3-6 months or 18-24 months of everolimus treatment, respectively). No significant changes in CNR (p>0.05) and size (p>0.05) were measured in the control group. CONCLUSION: mTOR inhibitor therapy in TSC patients results in an early and pronounced fatty transformation of AMLs on MRI. Fatty transformation could represent a novel early indicator of response to therapy in this patient collective. PMID- 29232372 TI - Attenuated expression of MTR in both prenatally androgenized mice and women with the hyperandrogenic phenotype of PCOS. AB - Polycystic ovary syndrome (PCOS) is a common endocrine, metabolic and heterogeneous disorder in women of reproductive age, the exact etiology of which remains unknown. To unravel the molecular mechanisms underlying the hyperandrogenic phenotype of PCOS, prenatally androgenized (PNA) mice were used to mimic this phenotype in women with PCOS. Using microarray analysis, 1188 differentially expressed genes, including 671 upregulated and 517 downregulated genes, were identified in ovaries from PNA mice. Five differentially expressed genes (Aldh1a7, Bhmt, Mtr, Nrcam, Ptprg) were validated, and decreased MTR expression was shown in ovaries of PNA mice. In addition, results from qRT-PCR showed decreased MTR expression in granulosa cells (GCs) from women with the hyperandrogenic phenotype of PCOS. Serum levels of S-adenosyl methionine (SAM), the downstream product of MTR, were also decreased in PNA mice and women with the hyperandrogenic phenotype of PCOS. Our study provides evidence that the hyperandrogenic phenotype of PCOS is linked to abnormal folate one-carbon metabolism. PMID- 29232374 TI - Antiretroviral therapy and population mortality: Leveraging routine national data to advance policy. AB - In a Perspective, Amitabh Suthar and Till Barnighausen discuss progress made so far in reducing HIV-related mortality in South Africa and keys towards further population mortality reductions going forward. PMID- 29232373 TI - Disentangling metabolic functions of bacteria in the honey bee gut. AB - It is presently unclear how much individual community members contribute to the overall metabolic output of a gut microbiota. To address this question, we used the honey bee, which harbors a relatively simple and remarkably conserved gut microbiota with striking parallels to the mammalian system and importance for bee health. Using untargeted metabolomics, we profiled metabolic changes in gnotobiotic bees that were colonized with the complete microbiota reconstituted from cultured strains. We then determined the contribution of individual community members in mono-colonized bees and recapitulated our findings using in vitro cultures. Our results show that the honey bee gut microbiota utilizes a wide range of pollen-derived substrates, including flavonoids and outer pollen wall components, suggesting a key role for degradation of recalcitrant secondary plant metabolites and pollen digestion. In turn, multiple species were responsible for the accumulation of organic acids and aromatic compound degradation intermediates. Moreover, a specific gut symbiont, Bifidobacterium asteroides, stimulated the production of host hormones known to impact bee development. While we found evidence for cross-feeding interactions, approximately 80% of the identified metabolic changes were also observed in mono colonized bees, with Lactobacilli being responsible for the largest share of the metabolic output. These results show that, despite prolonged evolutionary associations, honey bee gut bacteria can independently establish and metabolize a wide range of compounds in the gut. Our study reveals diverse bacterial functions that are likely to contribute to bee health and provide fundamental insights into how metabolic activities are partitioned within gut communities. PMID- 29232375 TI - A persistent lack of international representation on editorial boards in environmental biology. AB - The scholars comprising journal editorial boards play a critical role in defining the trajectory of knowledge in their field. Nevertheless, studies of editorial board composition remain rare, especially those focusing on journals publishing research in the increasingly globalized fields of science, technology, engineering, and math (STEM). Using metrics for quantifying the diversity of ecological communities, we quantified international representation on the 1985 2014 editorial boards of 24 environmental biology journals. Over the course of 3 decades, there were 3,827 unique scientists based in 70 countries who served as editors. The size of the editorial community increased over time-the number of editors serving in 2014 was 4-fold greater than in 1985-as did the number of countries in which editors were based. Nevertheless, editors based outside the "Global North" (the group of economically developed countries with high per capita gross domestic product [GDP] that collectively concentrate most global wealth) were extremely rare. Furthermore, 67.18% of all editors were based in either the United States or the United Kingdom. Consequently, geographic diversity-already low in 1985-remained unchanged through 2014. We argue that this limited geographic diversity can detrimentally affect the creativity of scholarship published in journals, the progress and direction of research, the composition of the STEM workforce, and the development of science in Latin America, Africa, the Middle East, and much of Asia (i.e., the "Global South"). PMID- 29232376 TI - Che1/AATF interacts with subunits of the histone acetyltransferase core module of SAGA complexes. AB - General Control Non-derepressible 5 (GCN5) and Alteration/Deficiency in Activation 2 and 3 proteins (ADA2 and ADA3, respectively) are subunits of the Histone AcetylTransferase (HAT) module of SAGA- and ATAC-type co-activators. We previously reported four new interacting partners of human ADA3 identified by screening a human fetal brain cDNA library using yeast two hybrid technology. One of these partners was Apoptosis-Antagonizing Transcription Factor (AATF), also known as Che-1, an RNA polymerase II-binding protein with a number of roles in different cellular processes including regulation of transcription, cell proliferation, cell cycle control, DNA damage responses and apoptosis. Che-1/AATF is a potential therapeutic target for cancer treatments. In this study, we aimed to identify whether besides ADA3, other components of the HAT modules of SAGA and ATAC complexes, human ADA2 and GCN5 also interact with Che-1/AATF. Co immunoprecipitation and co-localization experiments were used to demonstrate association of AATF both with two ADA2 isoforms, ADA2A and ADA2B and with GCN5 proteins in human cells and yeast two-hybrid assays to delineate domains in the ADA2 and GCN5 proteins required for these interactions. These findings provide new insights into the pathways regulated by ADA-containing protein complexes. PMID- 29232377 TI - Association between infrastructure and observed quality of care in 4 healthcare services: A cross-sectional study of 4,300 facilities in 8 countries. AB - BACKGROUND: It is increasingly apparent that access to healthcare without adequate quality of care is insufficient to improve population health outcomes. We assess whether the most commonly measured attribute of health facilities in low- and middle-income countries (LMICs)-the structural inputs to care-predicts the clinical quality of care provided to patients. METHODS AND FINDINGS: Service Provision Assessments are nationally representative health facility surveys conducted by the Demographic and Health Survey Program with support from the US Agency for International Development. These surveys assess health system capacity in LMICs. We drew data from assessments conducted in 8 countries between 2007 and 2015: Haiti, Kenya, Malawi, Namibia, Rwanda, Senegal, Tanzania, and Uganda. The surveys included an audit of facility infrastructure and direct observation of family planning, antenatal care (ANC), sick-child care, and (in 2 countries) labor and delivery. To measure structural inputs, we constructed indices that measured World Health Organization-recommended amenities, equipment, and medications in each service. For clinical quality, we used data from direct observations of care to calculate providers' adherence to evidence-based care guidelines. We assessed the correlation between these metrics and used spline models to test for the presence of a minimum input threshold associated with good clinical quality. Inclusion criteria were met by 32,531 observations of care in 4,354 facilities. Facilities demonstrated moderate levels of infrastructure, ranging from 0.63 of 1 in sick-child care to 0.75 of 1 for family planning on average. Adherence to evidence-based guidelines was low, with an average of 37% adherence in sick-child care, 46% in family planning, 60% in labor and delivery, and 61% in ANC. Correlation between infrastructure and evidence-based care was low (median 0.20, range from -0.03 for family planning in Senegal to 0.40 for ANC in Tanzania). Facilities with similar infrastructure scores delivered care of widely varying quality in each service. We did not detect a minimum level of infrastructure that was reliably associated with higher quality of care delivered in any service. These findings rely on cross-sectional data, preventing assessment of relationships between structural inputs and clinical quality over time; measurement error may attenuate the estimated associations. CONCLUSION: Inputs to care are poorly correlated with provision of evidence-based care in these 4 clinical services. Healthcare workers in well-equipped facilities often provided poor care and vice versa. While it is important to have strong infrastructure, it should not be used as a measure of quality. Insight into health system quality requires measurement of processes and outcomes of care. PMID- 29232378 TI - Genetic variations at 8q24 and gastric cancer susceptibility: A meta-analysis study. AB - BACKGROUND: Published data on the association between genetic variants on the 8q24 chromosome and gastric cancer (GC) susceptibility are inconclusive. Here we present a meta-analysis designed to evaluate the relationship between 8q24 variants (single nucleotide polymorphisms (SNPs) labeled rs6983267 and rs1447295) and risk of developing GC. METHODS: A literature search was performed using studies published on PubMed, Science Direct, OVID and Web of Science databases up to December 2016. Studies were selected based on our enrollment criteria, relevant data was extracted from each study and the odds ratios (OR), and 95% confidence intervals (CI) were calculated and used to assess the strength of associations found between 8q24 polymorphisms and GC risk. Conclusions about acceptable strong associations were made after taking into account sample heterogeneity and sensitivity analyses. RESULTS: A total of seven studies containing ten case-control studies were selected. Among these studies were six studies of 1,421 GC patients and 3,393 controls examining the role of the rs6983267 SNP and four studies including 779 cases and 1,266 controls examining rs1447295 SNP. The pooled results of these studies indicated that there was no significant association between both genetic variants and GC susceptibility using an allele, dominant, recessive and homozygote genetic models. When using a heterozygote genetic model, a significant increase was found in the association of GC risk for rs6983267 SNP (OR = 1.07, 95% CI = 1.01-1.12, P = 0.015), whereas for rs1447295 SNP a significant decreased risk was detected (OR = 0.82, 95% CI = 0.69-0.98, P = 0.030). In subgroup analyses based on ethnicity and genotyping methods, similar non-significant results were observed for the rs1447295 variant using the four genetic models (allele, dominant, recessive or homozygote models) and for the rs6983267 variant using only the allele, recessive and homozygote models. However, after a multiple testing correction to our calculations, these associations remained non-significant. CONCLUSION: Meta-analysis of gastrointestinal cancer genetic analysis studies did not confirm an association between 8q24 chromosome polymorphisms (specifically rs6983267 and rs1447295) and susceptibility to GC in the general populations. PMID- 29232379 TI - Comparison of nalbuphine and sufentanil for colonoscopy: A randomized controlled trial. AB - OBJECTIVES: Nalbuphine is as effective as morphine as a perioperative analgesic but has not been compared directly with sufentanil in clinical trials. The aims of this study were to compare the efficacy and safety of nalbuphine with that of sufentanil in patients undergoing colonoscopy and to determine the optimal doses of nalbuphine in this indication. METHODS: Two hundred and forty consecutive eligible patients aged 18-65 years with an American Society of Anesthesiologists classification of I-II and scheduled for colonoscopy were randomly allocated to receive sufentanil 0.1 MUg/kg (group S), nalbuphine 0.1 mg/kg (group N1), nalbuphine 0.15 mg/kg (group N2), or nalbuphine 0.2 mg/kg (group N3). Baseline vital signs were recorded before the procedure. The four groups were monitored for propofol sedation using the bispectral index, and pain relief was assessed using the Visual Analog Scale and the modified Behavioral Pain Scale for non intubated patients. The incidences of respiratory depression during endoscopy, nausea, vomiting, drowsiness, and abdominal distention were recorded in the post anesthesia care unit and in the first and second 24-hour periods after colonoscopy. RESULTS: There was no significant difference in analgesia between the sufentanil group and the nalbuphine groups (p>0.05). Respiratory depression was significantly more common in group S than in groups N1 and N2 (p<0.05). The incidence of nausea was significantly higher in the nalbuphine groups than in the sufentanil group in the first 24 hours after colonoscopy (p<0.05). CONCLUSIONS: Nalbuphine can be considered as a reasonable alternative to sufentanil in patients undergoing colonoscopy. Doses in the range of 0.1-0.2 mg/kg are recommended. The decreased risks of respiratory depression and apnea make nalbuphine suitable for patients with respiratory problems. PMID- 29232380 TI - Inhibition of GRP78 abrogates radioresistance in oropharyngeal carcinoma cells after EGFR inhibition by cetuximab. AB - The EGFR-specific mAb cetuximab is one of the most effective treatments for oropharyngeal carcinoma, while patient responses to EGFR inhibitors given alone are modest. Combination treatment with radiation can improve the efficacy of treatment through increasing radiosensitivity, while resistance to radiation after administration of cetuximab limits its efficiency. Radiation and drugs can damage the endoplasmic reticulum (ER) homeostatic state and result in ER stress (ERS), subsequently causing resistance to radiation and drugs. Whether the ERS pathway is involved in radioresistance after administration of cetuximab has not been reported. Herein, we show that cetuximab could increase the radiosensitivity of FaDu cells but not Detroit562 cells. In addition, cetuximab inhibited the radiation-induced activation of the ERS signalling pathway IRE1alpha/ATF6-GRP78 in FaDu cells, while this effect was absent in Detroit562 cells. Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB) repair and autophagy. More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells. Immunohistochemistry showed that overexpression of both GRP78 and EGFR was associated with a poor prognosis in oropharyngeal carcinoma patients (P<0.05). Overall, the results of this study show that radioresistance after EGFR inhibition by cetuximab is mediated by the ERS signalling pathway IRE1alpha/ATF6-GRP78. This suppression was consequently unable to inhibit radiation-induced DSB repair and autophagy in oropharyngeal carcinoma cells, which conferred resistance to radiotherapy and cetuximab. These results suggest that the cooperative effects of radiotherapy and cetuximab could be further improved by inhibiting GRP78 in non-responsive oropharyngeal carcinoma patients. PMID- 29232381 TI - Effects of experimental nitrogen fertilization on planktonic metabolism and CO2 flux in a hypereutrophic hardwater lake. AB - Hardwater lakes are common in human-dominated regions of the world and often experience pollution due to agricultural and urban effluent inputs of inorganic and organic nitrogen (N). Although these lakes are landscape hotspots for CO2 exchange and food web carbon (C) cycling, the effect of N enrichment on hardwater lake food web functioning and C cycling patterns remains unclear. Specifically, it is unknown if different eutrophication scenarios (e.g., modest non point vs. extreme point sources) yield consistent effects on auto- and heterotrophic C cycling, or how biotic responses interact with the inorganic C system to shape responses of air-water CO2 exchange. To address this uncertainty, we induced large metabolic gradients in the plankton community of a hypereutrophic hardwater Canadian prairie lake by adding N as urea (the most widely applied agricultural fertilizer) at loading rates of 0, 1, 3, 8 or 18 mg N L-1 week-1 to 3240-L, in situ mesocosms. Over three separate 21-day experiments, all treatments of N dramatically increased phytoplankton biomass and gross primary production (GPP) two- to six-fold, but the effects of N on autotrophs plateaued at ~3 mg N L-1. Conversely, heterotrophic metabolism increased linearly with N fertilization over the full treatment range. In nearly all cases, N enhanced net planktonic uptake of dissolved inorganic carbon (DIC), and increased the rate of CO2 influx, while planktonic heterotrophy and CO2 production only occurred in the highest N treatments late in each experiment, and even in these cases, enclosures continued to in-gas CO2. Chemical effects on CO2 through calcite precipitation were also observed, but similarly did not change the direction of net CO2 flux. Taken together, these results demonstrate that atmospheric exchange of CO2 in eutrophic hardwater lakes remains sensitive to increasing N loading and eutrophication, and that even modest levels of N pollution are capable of enhancing autotrophy and CO2 in-gassing in P-rich lake ecosystems. PMID- 29232382 TI - Charting the transcriptional landscape of cells of renin lineage following podocyte depletion. AB - Renin producing cells of the juxtaglomerulus, herein called cells of renin lineage (CoRL), have garnered recent interest for their propensity to act as a progenitor source for various kidney cell types including podocytes. Despite recent advances, the process of transdifferentiation of CoRL to podocytes is poorly understood. In this study, we employed a transgenic reporter mouse line which permanently labels CoRL with ZsGreen fluorescent protein, allowing for isolation by fluorescence-activated cell sorting. At 5 days following induction of abrupt podocyte ablation via anti-podocyte sheep IgG, mice were sacrificed and CoRL were isolated by FACS. RNA was subsequently analyzed by microarray. Gene set enrichment analysis (GSEA) was performed and revealed that CoRL display a distinct phenotype following podocyte ablation, primarily consisting of downregulation of metabolic processes and upregulation of immuno-modulatory processes. Additionally, RNA-biology and cell cycle-related processes were also upregulated. Changes in gene expression or activity of a core set of transcription factors including HNF1 and E2F were identified through changes in enrichment of their respective target genes. However, integration of results from transcription factor and canonical pathway analysis indicated that ERR1 and PU box family members may be the major contributors to the post-podocyte ablation phenotype of CoRL. Finally, top ranking genes were selected from the microarray based analysis and confirmed by qPCR. Collectively, our results provide valuable insights into the transcriptional regulation of CoRL following abrupt podocyte ablation. PMID- 29232383 TI - Low doses of oxygen ion irradiation cause long-term damage to bone marrow hematopoietic progenitor and stem cells in mice. AB - During deep space missions, astronauts will be exposed to low doses of charged particle irradiation. The long-term health effects of these exposures are largely unknown. We previously showed that low doses of oxygen ion (16O) irradiation induced acute damage to the hematopoietic system, including hematopoietic progenitor and stem cells in a mouse model. However, the chronic effects of low dose 16O irradiation remain undefined. In the current study, we investigated the long-term effects of low dose 16O irradiation on the mouse hematopoietic system. Male C57BL/6J mice were exposed to 0.05 Gy, 0.1 Gy, 0.25 Gy and 1.0 Gy whole body 16O (600 MeV/n) irradiation. The effects of 16O irradiation on bone marrow (BM) hematopoietic progenitor cells (HPCs) and hematopoietic stem cells (HSCs) were examined three months after the exposure. The results showed that the frequencies and numbers of BM HPCs and HSCs were significantly reduced in 0.1 Gy, 0.25 Gy and 1.0 Gy irradiated mice compared to 0.05 Gy irradiated and non-irradiated mice. Exposure of mice to low dose 16O irradiation also significantly reduced the clongenic function of BM HPCs determined by the colony-forming unit assay. The functional defect of irradiated HSCs was detected by cobblestone area-forming cell assay after exposure of mice to 0.1 Gy, 0.25 Gy and 1.0 Gy of 16O irradiation, while it was not seen at three months after 0.5 Gy and 1.0 Gy of gamma-ray irradiation. These adverse effects of 16O irradiation on HSCs coincided with an increased intracellular production of reactive oxygen species (ROS). However, there were comparable levels of cellular apoptosis and DNA damage between irradiated and non-irradiated HPCs and HSCs. These data suggest that exposure to low doses of 16O irradiation induces long-term hematopoietic injury, primarily via increased ROS production in HSCs. PMID- 29232384 TI - First evidence of bighead carp wild recruitment in Western Europe, and its relation to hydrology and temperature. AB - Bighead carp (Hypophthalmichthys nobilis) have been introduced throughout Europe, mostly unintentionally, and little attention has been given to their potential for natural reproduction. We investigated the presence of young-of-the-year bighead carp in an irrigation canal network of Northern Italy and the environmental conditions associated with spawning in 2011-2015. The adult bighead carp population of the canal network was composed by large, likely mature, individuals with an average density of 45.2 kg/ha (over 10 fold more than in the main river). The 29 juvenile bighead carp found were 7.4-13.1 cm long (TL) and weighed 9.5-12.7 g. Using otolith-derived spawning dates we estimated that these juveniles were 94-100 days old, placing their fertilization and hatch dates in mid-to-end-June. Using this information in combination with thermal and hydraulic data, we examined the validity of existing models predicting the onset of spawning conditions and the viability of egg pathways to elucidate spawning location of the species. While evidence of reproduction was not found every year, we determined that potentially viable spawning conditions (annual degree-days and temperature thresholds) and pathways of egg drift suitable for hatching are present in short, slow-flowing canals. PMID- 29232385 TI - Sustaining visceral leishmaniasis elimination in Bangladesh - Could a policy brief help? AB - Bangladesh has made significant progress towards elimination of visceral leishmaniasis, and is on track to achieve its target of less than one case per 10,000 inhabitants in each subdistrict in 2017. As the incidence of disease falls, it is likely that the political capital and financial resources dedicated towards the elimination of visceral leishmaniasis may decrease, raising the prospect of disease resurgence. Policy memos may play a crucial role during the transition of the elimination plan from the 'attack' to the 'consolidation' and 'maintenance' phases, highlighting key stakeholders and areas where ongoing investment is crucial. An example of a policy brief is outlined in this paper. The background to the current elimination efforts is highlighted, with emphasis on remaining uncertainties including the impact of disease reservoirs and sustainable surveillance strategies. A stakeholder map is provided outlining the current and projected future activities of key bodies. Identification of key stakeholders subsequently frames the discussion of three key policy recommendations in the Bangladeshi context for the transition to the consolidation and maintenance phases of the elimination program. Recommendations include determining optimal vector control and surveillance strategies, shifting the emphasis towards horizontal integration of disease programs, and prioritising remaining research questions with a focus on operational and technical capacity. Achieving elimination is as much a political as a scientific question. Integrating the discussion of key stakeholders with policy priorities and the research agenda provides a novel insight into potential pathways forwards in the elimination of visceral leishmaniasis in Bangladesh and in the rest of the Indian subcontinent. PMID- 29232386 TI - On the calculation of betweenness centrality in marine connectivity studies using transfer probabilities. AB - Betweenness has been used in a number of marine studies to identify portions of sea that sustain the connectivity of whole marine networks. Herein we highlight the need of methodological exactness in the calculation of betweenness when graph theory is applied to marine connectivity studies based on transfer probabilities. We show the inconsistency in calculating betweeness directly from transfer probabilities and propose a new metric for the node-to-node distance that solves it. Our argumentation is illustrated by both simple theoretical examples and the analysis of a literature data set. PMID- 29232387 TI - Improved sample treatment protocol for accurate detection of live Salmonella spp. in food samples by viability PCR. AB - Culture-based detection is still considered as the standard way for detection of Salmonella in foods, although molecular methods, such as viability PCR (vPCR), have been introduced to overcome some disadvantages of traditional culture methods. Despite the success of the vPCR methodology, the problem of false positive results is a major drawback, especially when applied to environmental samples, hindering the interpretation of the results. To improve the efficiency of vPCR, many approaches have been introduced by several authors during the last years. In the present work, the combination of PEMAX dye, double tube change, and double photo-activation step was established as a strategy to improve vPCR protocol. By combining these approaches, we developed an improved sample treatment protocol able to neutralize DNA signals of up to 5.0*107 dead cells/sample from both pure culture and artificially contaminated food samples. Our results indicate that vPCR can work reliable and has a potential for high throughput detection of live Salmonella cells in food samples, minimizing false positive signals. PMID- 29232388 TI - More than the eyes can see: The worrying scenario of canine leishmaniasis in the Brazilian side of the triple border. AB - A cross-sectional epidemiological study in the extreme-west of the state of Parana was carried out to access the prevalence, distribution, and risk variables of canine Visceral Leishmaniases (cVL). This study was conducted in three areas, two cities of far west of Parana state: Foz do Iguacu (FI) and Santa Terezinha de Itaipu (STI), and along two transects between these two municipalities. To sample the entire urban area, the cities (FI and STI) were divided into a grid of squares of 400 m2 (patch). Among the 526 patches, 123 in FI, 40 in the transects and 33 in STI were selected according to the 'worst scenario' criterion. In the transect areas, in each 0.86 km five dogs from houses were surveyed to leishmaniasis. In each patch, blood of five dogs from houses (and from neighborhood when necessary) in the areas that seemed to be the most appropriate for the proliferation of vector were surveyed. The infection of the dogs by cVL were assessed using two serological tests were used (cELISA and TR-DPP(r)), and, for those seropositive for both methods, the PCR method were used. Moreover, dogs presenting clinical signs or cutaneous lesions were sampled to PCR. The identification of Leishmania species was confirmed using PCR-RFLP followed by DNA sequencing. Micro, meso and macro scale environmental variables were also surveyed and statistically analyzed. The prevalence rate Leishmania infantum was 23.8% in FI, 4.7% in STI and 9.1% in the transects areas. Among the extrinsic variables analysed, the number of vectors and the presence of infected dogs in neighbouring were positively correlated with the occurrence of infected dogs. Dog size was positively correlated with cVL infection, while the quality of the dog's nutrition affected cVL negatively. As for cutaneous leishmaniasis (CL), the first registry of dogs infected with L. braziliensis in the region shows that there is potential for transmission in peri-urban areas, since environmental conditions allow the proliferation of vectors capable of transmitting this species of parasite. cVL is widely spread in FI, with high prevalence. This supports the hypothesis that the parasite has been present in the region for longer than previously believed, despite the fact that the presence of leishmaniais in the region has only been recognized recently. It is important to control the population of dogs infected with L. infantum (parasite and non-antibodies) to prevent the spread of the disease to other dogs and also to people in the region. PMID- 29232389 TI - Bridging the quality chasm in maternal, newborn, and child healthcare in low- and middle-income countries. AB - In a Perspective, Lars Ake Persson discusses the need to focus on quality of care to improve maternal, newborn, and child healthcare. PMID- 29232390 TI - Clinicopathological hallmarks and biomarkers of colorectal neuroendocrine neoplasms. AB - Chromogranin A (CgA) is a well-established marker for diagnosis and follow up of patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). Recently, it has been shown that plasma levels of CgA correlate with tumor load and predict survival of patients with NEN of the small bowel. It is assumed that this is as well valid for NEN of the colon and rectum, however, this is not supported by data. To evaluate this assumption, we analyzed 62 patients with NEN of the colon and rectum listed in the Marburg GEP-NEN registry for clinicopathological characteristics, expression and plasma levels of CgA. The present study demonstrates that immunohistochemical CgA and synaptophysin are good markers for histological diagnosis in patients with NEN of the colon and rectum. However, plasma CgA is a poor marker to follow-up these patients because only a minority exhibited increased levels which did not increase significantly during tumor progression. In contrast to NEN of the small bowel, there is no correlation of CgA plasma levels with tumor burden or survival. Patients with NEN of the colon and rectum displayed a relatively good prognosis resulting in a median survival of 8.5 years. However, a subset of patients affected by G3 neoplasms, exhibited a poorer prognosis with a median survival of 2.5 years. Taken together, CgA is a valuable marker for immunohistochemical diagnosis, but CgA plasma concentration is not suitable to mirror tumor burden or prognosis in patients with NEN of the colon and rectum. PMID- 29232392 TI - Experimental and numerical study of the failure process and energy mechanisms of rock-like materials containing cross un-persistent joints under uniaxial compression. AB - Joints and fissures in natural rocks have a significant influence on the stability of the rock mass, and it is often necessary to evaluate strength failure and crack evolution behavior. In this paper, based on experimental tests and numerical simulation (PFC2D), the macro-mechanical behavior and energy mechanism of jointed rock-like specimens with cross non-persistent joints under uniaxial loading were investigated. The focus was to study the effect of joint dip angle alpha and intersection angle gamma on the characteristic stress, the coalescence modes and the energy release of jointed rock-like specimens. For specimens with gamma = 30 degrees and 45 degrees , the UCS (uniaxial compression strength), CIS (crack initiation stress) and CDiS (critical dilatancy stress) increase as alpha increases from 0 degrees to 75 degrees . When gamma = 60 degrees and 75 degrees , the UCS, CIS and CDiS increase as alpha increases from 0 degrees to 60 degrees and decrease when alpha is over 60 degrees . Both the inclination angle alpha and intersection angle gamma have great influence on the failure pattern of pre-cracked specimens. With different alpha and gamma, specimens exhibit 4 kinds of failure patterns. Both the experimental and numerical results show that the energy of a specimen has similar trends with characteristic stress as alpha increases. PMID- 29232391 TI - Studies of the structure-antioxidant activity relationships and antioxidant activity mechanism of iridoid valepotriates and their degradation products. AB - Oxidative stress has been associated with diverse diseases, including obesity, cancer and neurodegeneration. In fact, Valeriana jatamansi Jones (valerian) and its extracts possess strong antioxidant activities that extend their application in clinical practice to the treatment of these illnesses, even though the underlying mechanisms are not well understood. Iridoid valepotriate, a characteristic iridoid ester in valerian with poor chemical stability, possesses considerable antioxidant components. The original compounds and their degradation products have been found to exhibit strong antioxidant activities. However, the relationship between their structure and antioxidant effects and the mechanism underlying their oxidation resistance remain unclear. A forced degradation study using three iridoid valepotriates (valtrate, acevaltrate and 1-beta acevaltrate) was performed in this work, and the structures of their degradation products were estimated by TLC-MS and LC-MS. Comparison of the antioxidant activities of the iridoid valepotriates before and after forced degradation revealed that degradation reduced the activities of the iridoid valepotriates in free radical scavenging and cytotoxic and cell apoptosis tests. The results suggested that the oxirane nucleus is important for defining the antioxidant profile of iridoid valepotriate. We uncovered possible mechanisms that could explain the antioxidant activities, including the generation of two hydroxyl groups through intramolecular transfer of an H* from an oxirane ring and a reduction in ROS levels through interactions with GABAergic signalling pathways. PMID- 29232393 TI - Lack of association between serum syndecan-4, myocardial fibrosis and ventricular dysfunction in subjects with chronic Chagas disease. AB - BACKGROUND: Syndecan-4 is a transmembrane glycoprotein associated with inflammation and fibrosis. Increased syndecan-4 levels were previously detected after acute myocardial infarction and in subjects with heart failure. However, the levels of syndecan-4 in subjects with Chagas disease have not so far been investigated. The aim of this study was to investigate the potential role of serum sydencan-4 as a novel biomarker for myocardial fibrosis and cardiac dysfunction in subjects with Chagas disease. METHODS: This study comprised subjects with Chagas disease (n = 56), being 14 (25%) with the indeterminate form, 16 (29%) with the cardiac form without ventricular dysfunction, and 26 (46%) with the cardiac form with ventricular dysfunction. RESULTS: Syndecan-4 serum concentrations did not correlate with presence or absence of myocardial fibrosis (P = 0.386) nor disease severity in subjects with Chagas disease (P = 0.918). Additionally, no correlation was found either between the degree of myocardial fibrosis and serum syndecan-4 [r = 0.08; P = 0.567] or between left ventricular ejection fraction and syndecan-4 [r = 0.02; P = 0.864]. In contrast, NT-proBNP levels correlated with ejection fraction and myocardial fibrosis. CONCLUSIONS: Our results demonstrate the lack of correlations between serum syndecan-4, myocardial fibrosis and cardiac dysfunction in subjects with Chagas disease. Further studies are required to show if syndecan-4 concentrations can be marker for prognosis assessment or disease progression. PMID- 29232394 TI - External auditory exostoses in the Xuchang and Xujiayao human remains: Patterns and implications among eastern Eurasian Middle and Late Pleistocene crania. AB - In the context of Middle and Late Pleistocene eastern Eurasian human crania, the external auditory exostoses (EAE) of the late archaic Xuchang 1 and 2 and the Xujiayao 15 early Late Pleistocene human temporal bones are described. Xujiayao 15 has small EAE (Grade 1), Xuchang 1 presents bilateral medium EAE (Grade 2), and Xuchang 2 exhibits bilaterally large EAE (Grade 3), especially on the right side. These cranial remains join the other eastern Eurasian later Pleistocene humans in providing frequencies of 61% (N = 18) and 58% (N = 12) respectively for archaic and early modern human samples. These values are near the upper limits of recent human frequencies, and they imply frequent aquatic exposure among these Pleistocene humans. In addition, the medial extents of the Xuchang 1 and 2 EAE would have impinged on their tympanic membranes, and the large EAE of Xuchang 2 would have resulted in cerumen impaction. Both effects would have produced conductive hearing loss, a serious impairment in a Pleistocene foraging context. PMID- 29232395 TI - Testing the event witnessing status of micro-bloggers from evidence in their micro-blogs. AB - This paper demonstrates a framework of processes for identifying potential witnesses of events from evidence they post to social media. The research defines original evidence models for micro-blog content sources, the relative uncertainty of different evidence types, and models for testing evidence by combination. Methods to filter and extract evidence using automated and semi-automated means are demonstrated using a Twitter case study event. Further, an implementation to test extracted evidence using Dempster Shafer Theory of Evidence are presented. The results indicate that the inclusion of evidence from micro-blog text and linked image content can increase the number of micro-bloggers identified at events, in comparison to the number of micro-bloggers identified from geotags alone. Additionally, the number of micro-bloggers that can be tested for evidence corroboration or conflict, is increased by incorporating evidence identified in their posting history. PMID- 29232396 TI - Fatty acids rather than hormones restore in vitro angiogenesis in human male and female endothelial cells cultured in charcoal-stripped serum. AB - Charcoal-stripped serum (CSS) is a well-accepted method to model effects of sex hormones in cell cultures. We have recently shown that human endothelial cells (ECs) fail to growth and to undergo in vitro angiogenesis when cultured in CSS. However, the mechanism(s) underlying the CSS-induced impairment of in vitro EC properties are still unknown. In addition, whether there is any sexual dimorphism in the CSS-induced EC phenotype remains to be determined. Here, by independently studying human male and female ECs, we found that CSS inhibited both male and female EC growth and in vitro angiogenesis, with a more pronounced effect on male EC sprouting. Reconstitution of CSS with 17-beta estradiol, dihydrotestosterone, or the lipophilic thyroid hormone did not restore EC functions in both sexes. On the contrary, supplementation with palmitic acid or the acetyl-CoA precursor acetate significantly rescued the CSS-induced inhibition of growth and sprouting in both male and female ECs. We can conclude that the loss of metabolic precursors (e.g., fatty acids) rather than of hormones is involved in the impairment of in vitro proliferative and angiogenic properties of male and female ECs cultured with CSS. PMID- 29232397 TI - Distribution and prevalence of vector-borne diseases in California chipmunks (Tamias spp.). AB - California, with 13 chipmunk (Tamias) species, has more than any other state or country, occupying habitats ranging from chaparral to the high peaks of the Sierra Nevada. Chipmunks host zoonotic pathogens including Yersinia pestis, Anaplasma phagocytophilum, relapsing fever (RF) Borrelia spp., Borrelia burgdorferi, and spotted fever group (SFG) Rickettsia species. Chipmunk species are often not differentiated by public health workers, yet different species utilize different ecological niches and may have intrinsically different capacities for maintaining vector-borne pathogens and infecting vectors. We surveyed over 700 individuals from nine species of chipmunks throughout California for exposure to and infection by Y. pestis, A. phagocytophilum, RF Borrelia spp., Borrelia burgdorferi, and SFG Rickettsia species. DNA of all five pathogens was found and all chipmunks except Merriam's chipmunk (T. merriami) were PCR-positive for at least one of the pathogens. Anaplasma phagocytophilum was most common (40.0%, 2/5) in Sonoma chipmunks (T. sonomae) from Marin county and B. burgdorferi most common (37.5%, 27/72) in redwood chipmunks (T. ochrogenys) from Mendocino county. RF Borrelia spp. was detected in 2% (6/297) of redwood chipmunks in Mendocino county and 10% (1/10) of both least (T. minimus) and lodgepole (T. speciosus) chipmunks in the western Sierra. Exposure to SFG Rickettsia spp. was found in the Northern Coastal region (Del Norte, Humboldt and Mendocino counties) and in the northern and western Sierra in several species of chipmunks. Y. pestis infection was found only in the western Sierra-in a yellow pine (T. amoenus) and a long-eared (T. quadrimaculatus) chipmunk. Though more data are needed to thoroughly understand the roles that different chipmunk species play in disease transmission, our findings suggest that some chipmunk species may be more important to the maintenance of vector-borne diseases than others within each geographic area. PMID- 29232398 TI - Remote ischemic preconditioning attenuates cardiopulmonary bypass-induced lung injury. AB - The use of cardiopulmonary bypass (CPB) in cardiac surgeries is known to induce pathological changes in vital organs such as lungs. Remote ischemic preconditioning (RIPC) is a protective strategy that has shown to be able to reduce tissue damage related to ischemia-reperfusion injury (IRI). The current study seeks to evaluate the beneficial effects of limb RIPC on lung tissues and function in a rat CPB model. RIPC, which consisted of three cycles of 5-min ischemia and subsequently 5-min reperfusion, was induced in the hind limbs of the animals via a tourniquet. Bronchoalveolar lavage (BAL) fluid analysis and hematoxylin and eosin staining revealed that limb RIPC could significantly attenuate CPB-induced pulmonary injury, as evidenced by a combination of lower total BAL protein content, less severe alveolar wall thickening and reduced intra alveolar neutrophil infiltration. Consistently, RIPC was also found to improve the proliferation capacity of the bronchioalveolar stem cells isolated from the lung tissues in rats subjected to surgical procedure with CPB. These beneficial effects translated into significantly improved lung function. Further investigation suggested that RIPC could up-regulate the serum levels of several anti-inflammatory cytokines such as interleukin (IL)-4 and 10, which might play a role in its pulmonoprotective effects. Taken together, the current study provided convincing evidence that limb RIPC could be a useful strategy for minimizing CPB induced organ injuries in patients undergoing CPB surgery. PMID- 29232399 TI - Maternal white blood cell count cannot identify the presence of microbial invasion of the amniotic cavity or intra-amniotic inflammation in women with preterm prelabor rupture of membranes. AB - OBJECTIVE: The main aim of this study was to determine the relationship between the maternal white blood cell (WBC) count at the time of hospital admission in pregnancies complicated by preterm prelabor rupture of membranes (PPROM) and the presence of microbial invasion of the amniotic cavity (MIAC) and/or intra amniotic inflammation (IAI). The second aim was to test WBC diagnostic indices with respect to the presence of MIAC and/or IAI. METHODS: Four hundred and seventy-nine women with singleton pregnancies complicated by PPROM, between February 2012 and June 2017, were included in this study. Maternal blood and amniotic fluid samples were collected at the time of admission. Maternal WBC count was assessed. Amniotic fluid interleukin-6 (IL-6) concentration was measured using a point-of-care test, and IAI was characterized by an IL-6 concentration of >= 745 pg/mL. MIAC was diagnosed based on a positive polymerase chain reaction result for the Ureaplasma species, Mycoplasma hominis, and/or Chlamydia trachomatis and/or for the 16S rRNA gene. RESULTS: Women with MIAC or IAI had higher WBC counts than those without (with MIAC: median, 12.8 * 109/L vs. without MIAC: median, 11.9 * 109/L; p = 0.0006; with IAI: median, 13.7 * 109/L vs. without IAI: median, 11.9 * 109/L; p < 0.0001). When the women were divided into four subgroups based on the presence of MIAC and/or IAI, the women with both MIAC and IAI had a higher WBC count than those with either IAI or MIAC alone, and those without MIAC and IAI [both MIAC and IAI: median, 14.0 * 109/L; IAI alone: 12.1 * 109/L (p = 0.03); MIAC alone: 12.1 * 109/L (p = 0.0001); and without MIAC and IAI: median, 11.8 * 109/L (p < 0.0001)]. No differences in the WBC counts were found among the women with IAI alone, MIAC alone, and without MIAC and IAI. CONCLUSION: The women with both MIAC and IAI had a higher maternal WBC count at the time of hospital admission than the remaining women with PPROM. The maternal WBC count at the time of admission showed poor diagnostic indices for the identification of the presence of both MIAC and IAI. Maternal WBC count at the time of admission cannot serve as a non-invasive screening tool for identifying these complications in women with PPROM. PMID- 29232400 TI - Biological characterization of a novel in vitro cell irradiator. AB - To evaluate the overall robustness of a novel cellular irradiator we performed a series of well-characterized, dose-responsive assays to assess the consequences of DNA damage. We used a previously described novel irradiation system and a traditional 137Cs source to irradiate a cell line. The generation of reactive oxygen species was assessed using chloromethyl-H2DCFDA dye, the induction of DNA DSBs was observed using the comet assay, and the initiation of DNA break repair was assessed through gammaH2AX image cytometry. A high correlation between physical absorbed dose and biologic dose was seen for the production of intracellular reactive oxygen species, physical DNA double strand breaks, and modulation of the cellular double stand break pathway. The results compared favorably to irradiation with a traditional 137Cs source. The rapid, straightforward tests described form a reasonable approach for biologic characterization of novel irradiators. These additional testing metrics go beyond standard physics testing such as Monte Carlo simulation and thermo-luminescent dosimeter evaluation to confirm that a novel irradiator can produce the desired dose effects in vitro. Further, assessment of these biological metrics confirms that the physical handling of the cells during the irradiation process results in biologic effects that scale appropriately with dose. PMID- 29232401 TI - Dynamic MRI to quantify musculoskeletal motion: A systematic review of concurrent validity and reliability, and perspectives for evaluation of musculoskeletal disorders. AB - PURPOSE: To report evidence for the concurrent validity and reliability of dynamic MRI techniques to evaluate in vivo joint and muscle mechanics, and to propose recommendations for their use in the assessment of normal and impaired musculoskeletal function. MATERIALS AND METHODS: The search was conducted on articles published in Web of science, PubMed, Scopus, Academic search Premier, and Cochrane Library between 1990 and August 2017. Studies that reported the concurrent validity and/or reliability of dynamic MRI techniques for in vivo evaluation of joint or muscle mechanics were included after assessment by two independent reviewers. Selected articles were assessed using an adapted quality assessment tool and a data extraction process. Results for concurrent validity and reliability were categorized as poor, moderate, or excellent. RESULTS: Twenty articles fulfilled the inclusion criteria with a mean quality assessment score of 66% (+/-10.4%). Concurrent validity and/or reliability of eight dynamic MRI techniques were reported, with the knee being the most evaluated joint (seven studies). Moderate to excellent concurrent validity and reliability were reported for seven out of eight dynamic MRI techniques. Cine phase contrast and real-time MRI appeared to be the most valid and reliable techniques to evaluate joint motion, and spin tag for muscle motion. CONCLUSION: Dynamic MRI techniques are promising for the in vivo evaluation of musculoskeletal mechanics; however results should be evaluated with caution since validity and reliability have not been determined for all joints and muscles, nor for many pathological conditions. PMID- 29232402 TI - Chagas disease vector blood meal sources identified by protein mass spectrometry. AB - Chagas disease is a complex vector borne parasitic disease involving blood feeding Triatominae (Hemiptera: Reduviidae) insects, also known as kissing bugs, and the vertebrates they feed on. This disease has tremendous impacts on millions of people and is a global health problem. The etiological agent of Chagas disease, Trypanosoma cruzi (Kinetoplastea: Trypanosomatida: Trypanosomatidae), is deposited on the mammalian host in the insect's feces during a blood meal, and enters the host's blood stream through mucous membranes or a break in the skin. Identifying the blood meal sources of triatomine vectors is critical in understanding Chagas disease transmission dynamics, can lead to identification of other vertebrates important in the transmission cycle, and aids management decisions. The latter is particularly important as there is little in the way of effective therapeutics for Chagas disease. Several techniques, mostly DNA-based, are available for blood meal identification. However, further methods are needed, particularly when sample conditions lead to low-quality DNA or to assess the risk of human cross-contamination. We demonstrate a proteomics-based approach, using liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify host specific hemoglobin peptides for blood meal identification in mouse blood control samples and apply LC-MS/MS for the first time to Triatoma dimidiata insect vectors, tracing blood sources to species. In contrast to most proteins, hemoglobin, stabilized by iron, is incredibly stable even being preserved through geologic time. We compared blood stored with and without an anticoagulant and examined field-collected insect specimens stored in suboptimal conditions such as at room temperature for long periods of time. To our knowledge, this is the first study using LC-MS/MS on field-collected arthropod disease vectors to identify blood meal composition, and where blood meal identification was confirmed with more traditional DNA-based methods. We also demonstrate the potential of synthetic peptide standards to estimate relative amounts of hemoglobin acquired when insects feed on multiple blood sources. These LC-MS/MS methods can contribute to developing Ecohealth control strategies for Chagas disease transmission and can be applied to other arthropod disease vectors. PMID- 29232403 TI - Genomics clarifies taxonomic boundaries in a difficult species complex. AB - Efforts to taxonomically delineate species are often confounded with conflicting information and subjective interpretation. Advances in genomic methods have resulted in a new approach to taxonomic identification that stands to greatly reduce much of this conflict. This approach is ideal for species complexes, where divergence times are recent (evolutionarily) and lineages less well defined. The California Roach/Hitch fish species complex is an excellent example, experiencing a convoluted geologic history, diverse habitats, conflicting species designations and potential admixture between species. Here we use this fish complex to illustrate how genomics can be used to better clarify and assign taxonomic categories. We performed restriction-site associated DNA (RAD) sequencing on 255 Roach and Hitch samples collected throughout California to discover and genotype thousands of single nucleotide polymorphism (SNPs). Data were then used in hierarchical principal component, admixture, and FST analyses to provide results that consistently resolved a number of ambiguities and provided novel insights across a range of taxonomic levels. At the highest level, our results show that the CA Roach/Hitch complex should be considered five species split into two genera (4 + 1) as opposed to two species from distinct genera (1 +1). Subsequent levels revealed multiple subspecies and distinct population segments within identified species. At the lowest level, our results indicate Roach from a large coastal river are not native but instead introduced from a nearby river. Overall, this study provides a clear demonstration of the power of genomic methods for informing taxonomy and serves as a model for future studies wishing to decipher difficult species questions. By allowing for systematic identification across multiple scales, taxonomic structure can then be tied to historical and contemporary ecological, geographic or anthropogenic factors. PMID- 29232404 TI - Antioxidant, antiapoptotic and amino acid balance regulating activities of 1,7 dihydroxy-3,4,8-trimethoxyxanthone against dimethylnitrosamine-induced liver fibrosis. AB - Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injury which could be caused by viral, autoimmune, drugs, and so on. Unfortunately, there was no effective therapy available for liver fibrosis in clinic. In this study, we identified the anti-fibrotic effects of 1,7-dihydroxy 3,4,8-trimethoxyxanthone (ZYC-1) on the dimethylnitrosamine (DMN)-induced rat model. ZYC-1 was isolated from Swertia punicea Hemsl and was administrated to DMN induced rat model. ZYC decreased the hyaluronic acid (HA), type IV collagen (CIV) and hydroxyproline (Hyp) levels and inhibited the expression of alpha smooth muscle actin (alpha-SMA) and transforming growth factor beta 1 (TGF-1beta). The anti-fibrotic effect of ZYC-1 was also confirmed by Sirius Red staining. Finally, we identified 42 differentially expressed proteins by using proteomics analysis after ZYC-1 treatment, of which 17 were up-regulated and 25 were down-regulated. These Most of the 42 proteins are involved in the oxidative stress pathway, the mitochondrial-mediated apoptotic pathway and the amino acid metabolism pathway. Our study presented the first elucidated mechanisms of xanthone on liver fibrosis in vivo. This study pointed out that ZYC-1 may be used as a lead compound for hepatofibrosis treatment. PMID- 29232405 TI - Monitoring butterflies using counts of puddling males: A case study of the Rajah Brooke's Birdwing (Trogonoptera brookiana albescens). AB - The Rajah Brooke's Birdwing, Trogonoptera brookiana, is a large, iconic butterfly that is facing heavy commercial exploitation and habitat loss. Males of some subspecies exhibit puddling behavior. A method of conservation monitoring was developed for subspecies albescens in Ulu Geroh, Peninsular Malaysia, where the males consistently puddle in single-species aggregations at stable geothermal springs, reaching well over 300 individuals when the population is at its highest. Digital photography was used to conduct counts of numbers of males puddling. The numbers of birdwings puddling were significantly correlated with counts of birdwings in flight, but were much higher. The numbers puddling during the peak hour were correlated with numbers puddling throughout the day and could be predicted using the numbers puddling at an alternative hour, enabling flexibility in the time of counts. Average counts for three images taken at each puddle at three peak hours between 1400-1600 hours over 2-3 days were used as a monthly population index. The numbers puddling were positively associated with higher relative humidity and brightness during monitoring hours. Monthly counts of birdwings from monitoring of puddles over a period of two years are presented. The minimum effort required for a monitoring program using counts of puddling males is discussed, as well as the potential of using the method to monitor other species of puddling butterflies. PMID- 29232406 TI - Compatible topologies and parameters for NMR structure determination of carbohydrates by simulated annealing. AB - The use of NMR methods to determine the three-dimensional structures of carbohydrates and glycoproteins is still challenging, in part because of the lack of standard protocols. In order to increase the convenience of structure determination, the topology and parameter files for carbohydrates in the program Crystallography & NMR System (CNS) were investigated and new files were developed to be compatible with the standard simulated annealing protocols for proteins and nucleic acids. Recalculating the published structures of protein-carbohydrate complexes and glycosylated proteins demonstrates that the results are comparable to the published structures which employed more complex procedures for structure calculation. Integrating the new carbohydrate parameters into the standard structure calculation protocol will facilitate three-dimensional structural study of carbohydrates and glycosylated proteins by NMR spectroscopy. PMID- 29232407 TI - Temporal changes in cardiac oxidative stress, inflammation and remodeling induced by exercise in hypertension: Role for local angiotensin II reduction. AB - Exercise training reduces renin-angiotensin system (RAS) activation, decreases plasma and tissue oxidative stress and inflammation in hypertension. However, the temporal nature of these phenomena in response to exercise is unknown. We sought to determine in spontaneously hypertensive rats (SHR) and age-matched WKY controls the weekly effects of training on blood pressure (BP), plasma and left ventricle (LV) Ang II and Ang-(1-7) content (HPLC), LV oxidative stress (DHE staining), gene and protein expression (qPCR and WB) of pro-inflammatory cytokines, antioxidant enzymes and their consequence on hypertension-induced cardiac remodeling. SHR and WKY were submitted to aerobic training (T) or maintained sedentary (S) for 8 weeks; measurements were made at weeks 0, 1, 2, 4 and 8. Hypertension-induced cardiac hypertrophy was accompanied by acute plasma Ang II increase with amplified responses during the late phase of LV hypertrophy. Similar pattern was observed for oxidative stress markers, TNF alpha and interleukin-1beta, associated with cardiomyocytes' diameter enlargement and collagen deposition. SHR-T exhibited prompt and marked decrease in LV Ang II content (T1 vs T4 in WKY-T), normalized oxidative stress (T2), augmented antioxidant defense (T4) and reduced both collagen deposition and inflammatory profile (T8), without changing cardiomyocytes' diameter and LV hypertrophy. These changes were accompanied by decreased plasma Ang II content (T2-T4) and reduced BP (T8). SHR-T and WKY-T showed parallel increases in LV and plasma Ang-(1-7) content. Our data indicate that early training-induced downregulation of LV ACE AngII-AT1 receptor axis is a crucial mechanism to reduce oxidative/pro inflammatory profile and improve antioxidant defense in SHR-T, showing in addition this effect precedes plasma RAS deactivation. PMID- 29232408 TI - Immunodominant cytomegalovirus-specific CD8+ T-cell responses in sub-Saharan African populations. AB - More than 90% of children in Africa are infected with cytomegalovirus (CMV) by the age of 12 months. However, the high-frequency, immunodominant CD8+ T-cell responses that control CMV infection have not been well studied in African populations. We therefore sought to define the immunodominant CMV-specific CD8+ T cell responses within sub-Saharan African study subjects. Among 257 subjects, we determined the CD8+ T-cell responses to overlapping peptides spanning three of the most immunogenic CMV proteins, pp65, IE-1 and IE-2, using IFN-gamma ELISpot assays. A bioinformatics tool was used to predict optimal epitopes within overlapping peptides whose recognition was statistically associated with expression of particular HLA class I molecules. Using this approach, we identified 16 predicted novel CMV-specific epitopes within CMV-pp65, IE-1 and IE 2. The immunodominant pp65-specific, IE-1, IE-2 responses were all either previously well characterised or were confirmed using peptide-MHC tetramers. The novel epitopes identified included an IE-2-specific epitope restricted by HLA*B*44:03 that induced high-frequency CD8+ T-cell responses (mean 3.4% of CD8+ T-cells) in 95% of HLA-B*44:03-positive subjects tested, in one individual accounting for 18.8% of all CD8+ T-cells. These predicted novel CMV-specific CD8+ T-cell epitopes identified in an African cohort will facilitate future analyses of immune responses in African populations where CMV infection is almost universal during infancy. PMID- 29232409 TI - Lupeol and stigmasterol suppress tumor angiogenesis and inhibit cholangiocarcinoma growth in mice via downregulation of tumor necrosis factor alpha. AB - Lupeol and stigmasterol, major phytosterols in various herbal plants, possess anti-inflammatory activities and have been proposed as candidates for anti-cancer agents, but their molecular mechanisms are still unclear. Here, we investigated the effects of lupeol and stigmasterol on tumor and endothelial cells in vitro and their anti-cancer activities in vivo. Our results demonstrated that lupeol and stigmasterol suppressed cell viability, migration, and morphogenesis of human umbilical vein endothelial cells (HUVECs) but not cholangiocarcinoma (CCA) cells. Expression analyses showed that the treatment of both compounds significantly reduced the transcript level of tumor necrosis factor-alpha (TNF-alpha), and Western blot analyses further revealed a decrease in downstream effector levels of VEGFR-2 signaling, including phosphorylated forms of Src, Akt, PCL, and FAK, which were rescued by TNF-alpha treatment. In vivo, lupeol and stigmasterol disrupted tumor angiogenesis and reduced the growth of CCA tumor xenografts. Immunohistochemical analyses confirmed a decrease in CD31-positive vessel content and macrophage recruitment upon treatment. These findings indicate that lupeol and stigmasterol effectively target tumor endothelial cells and suppress CCA tumor growth by their anti-inflammatory activities and are attractive candidates for anti-cancer treatment of CCA tumors. PMID- 29232410 TI - Early variations of laboratory parameters predicting shunt-dependent hydrocephalus after subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Hydrocephalus is a frequent complication following subarachnoid hemorrhage. Few studies investigated the association between laboratory parameters and shunt-dependent hydrocephalus. This study aimed to investigate the variations of laboratory parameters after subarachnoid hemorrhage. We also attempted to identify predictive laboratory parameters for shunt-dependent hydrocephalus. METHODS: Multiple imputation was performed to fill the missing laboratory data using Bayesian methods in SPSS. We used univariate and multivariate Cox regression analyses to calculate hazard ratios for shunt dependent hydrocephalus based on clinical and laboratory factors. The area under the receiver operating characteristic curve was used to determine the laboratory risk values predicting shunt-dependent hydrocephalus. RESULTS: We included 181 participants with a mean age of 54.4 years. Higher sodium (hazard ratio, 1.53; 95% confidence interval, 1.13-2.07; p = 0.005), lower potassium, and higher glucose levels were associated with higher shunt-dependent hydrocephalus. The receiver operating characteristic curve analysis showed that the areas under the curve of sodium, potassium, and glucose were 0.649 (cutoff value, 142.75 mEq/L), 0.609 (cutoff value, 3.04 mmol/L), and 0.664 (cutoff value, 140.51 mg/dL), respectively. CONCLUSIONS: Despite the exploratory nature of this study, we found that higher sodium, lower potassium, and higher glucose levels were predictive values for shunt-dependent hydrocephalus from postoperative day (POD) 1 to POD 12 16 after subarachnoid hemorrhage. Strict correction of electrolyte imbalance seems necessary to reduce shunt-dependent hydrocephalus. Further large studies are warranted to confirm our findings. PMID- 29232411 TI - Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism. AB - Rev-erb alpha, known as nuclear receptor 1D1 (NR1D1), regulates circadian rhythm, modulates glucose and lipid metabolism, and inflammatory response. However, little is known about the effect of Rev-erb agonist on the progression of myocardial infarction (MI) and heart failure. To investigate it, wild-type male mice underwent sham-operation or permanent ligation of the left anterior descending coronary artery to create MI model. Rev-erb agonist SR9009 (100 mg/kg/day) or vehicle was intraperitoneally administered. Echocardiography was performed to evaluate cardiac function 1 week after surgery. The gene and protein expression levels in the left ventricles (LVs) were determined with real-time PCR, western blotting, and immunofluorescence. Moreover, immune cell infiltration into the LVs was analyzed by flow cytometry. Survival rate and reduced LV function were significantly improved by the treatment with SR9009 after MI. The expression level and plasma concentration of brain natriuretic peptide were significantly lower in MI mice treated with SR9009 (MI+SR) than in MI mice treated with vehicle (MI+V). Moreover, the mRNA expression levels of inflammatory related molecules such as Il6, Mcp1, Ly6g, Cd11b, matrix metallopeptidase (Mmp)9, and the protein expression levels of phosphorylated NF-kappaB p65, phosphorylated ERK, and phosphorylated p38 were also significantly lower in MI+SR than in MI+V. Immunofluorescence intensity for MMP-9 was enhanced in the LVs, but was less so in MI+SR than in MI+V. Furthermore, infiltrations of neutrophils and proinflammatory macrophages in the LVs were dramatically increased in MI+V and were significantly suppressed in MI+SR. Rev-erb agonist SR9009 treatment inhibited post-MI mortality and improved cardiac function through modulating inflammation and remodeling process. PMID- 29232413 TI - Determinants of dietary diversity and the potential role of men in improving household nutrition in Tanzania. AB - Good nutrition is a prerequisite for a healthy and active life, especially for agriculture-dependent households. However, diets in most households in Tanzania lack diversity because the intake of meat, poultry, fish, and vegetables and fruits is low. This study estimates factors influencing dietary diversity of the household, children under five years, and women using primary survey data. It qualitatively assesses male dietary patterns and men's potential role in improving the nutritional status of the entire household. The findings show that the most consumed foods within the household are cereals, vegetables, oils and fats, spices, condiments and beverages. Children (d = 0.4; p<0.05) and women (d = 0.5; p<0.01) in female-headed households have low dietary diversity compared to those in male-headed households. Women and children access less diverse diets since 46% and 26%, achieved minimum dietary diversity respectively. Production of vegetables (coef. 0.34; p<0.05) play an important role in improving the dietary diversity of women. Gender (coef. 0.05; p<0.10) and education of the household head (coef. 0.02; p<0.01), food preparation and nutrition training (coef. 0.10; p<0.05) are important factors influencing dietary diversity of the members of a household. Results suggest that there is a need to support community-based programs to provide information on food and the importance of vegetables, their preparation, consumption and utilization to address food and nutrition challenges. Men can contribute towards improving household nutrition security by reducing consumption of food away from the home, especially during periods of food shortages. We recommend the use of complementary quantitative research to determine the patterns and dynamics of men's dietary diversity and compare it with that of other household members. PMID- 29232412 TI - The opposite effects of nandrolone decanoate and exercise on anxiety levels in rats may involve alterations in hippocampal parvalbumin-positive interneurons. AB - The aim of this study was to evaluate the behavioral effects of chronic (six weeks) nandrolone decanoate (ND, 20 mg/kg, s.c., weekly in single dose) administration (in order to mimic heavy human abuse), and exercise (swimming protocol of 60 minutes a day, five days in a row/two days break), applied alone and simultaneously with ND, in male rats (n = 40). Also, we evaluated the effects of those protocols on hippocampal parvalbumin (PV) content and the possible connection between the alterations in certain parts of hippocampal GABAergic system and behavioral patterns. Both ND and exercise protocols induced increase in testosterone, dihydrotestosterone and estradiol blood levels. Our results confirmed anxiogenic effects of ND observed in open field (OF) test (decrease in the locomotor activity, as well as in frequency and cumulative duration in the centre zone) and in elevated plus maze (EPM) test (decrease in frequency and cumulative duration in open arms, and total exploratory activity), that were accompanied with a mild decrease in the number of PV interneurons in hippocampus. Chronic exercise protocol induced significant increase in hippocampal PV neurons (dentate gyrus and CA1 region), followed by anxiolytic-like behavioral changes, observed in both OF and EPM (increase in all estimated parameters), and in evoked beam-walking test (increase in time to cross the beam), compared to ND treated animals. The applied dose of ND was sufficient to attenuate beneficial effects of exercise in rats by means of decreased exercise-induced anxiolytic effect, as well as to reverse exercise-induced augmentation in number of PV immunoreactive neurons in hippocampus. Our results implicate the possibility that alterations in hippocampal PV interneurons (i.e. GABAergic system) may be involved in modulation of anxiety level induced by ND abuse and/or extended exercise protocols. PMID- 29232414 TI - Influence of Trp flipping on carbohydrate binding in lectins. An example on Aleuria aurantia lectin AAL. AB - Protein-carbohydrate interactions are very often mediated by the stacking CH-pi interactions involving the side chains of aromatic amino acids such as tryptophan (Trp), tyrosine (Tyr) or phenylalanine (Phe). Especially suitable for stacking is the Trp residue. Analysis of the PDB database shows Trp stacking for 265 carbohydrate or carbohydrate like ligands in 5 208 Trp containing motives. An appropriate model system to study such an interaction is the AAL lectin family where the stacking interactions play a crucial role and are thought to be a driving force for carbohydrate binding. In this study we present data showing a novel finding in the stacking interaction of the AAL Trp side chain with the carbohydrate. High resolution X-ray structure of the AAL lectin from Aleuria aurantia with alpha-methyl-l-fucoside ligand shows two possible Trp side chain conformations with the same occupation in electron density. The in silico data shows that the conformation of the Trp side chain does not influence the interaction energy despite the fact that each conformation creates interactions with different carbohydrate CH groups. Moreover, the PDB data search shows that the conformations are almost equally distributed across all Trp-carbohydrate complexes, which would suggest no substantial preference for one conformation over another. PMID- 29232416 TI - Berberine from Argemone mexicana L exhibits a broadspectrum antibacterial activity. AB - The Argemone mexicana L, commonly found on desolate land in the Marathwada region of Maharashtra state, India, has been used for treating oral cavity infections. We sought to investigate the antimicrobial potential of A. mexicana L. In this study, cold aqueous and methanolic extracts were prepared from the A. mexicana L leaves. These extracts were tested for their antibacterial activities against selected bacterial isolates. The antibacterial activity and MICs were tested using the agar well diffusion method and broth dilution method, respectively. The cold aqueous and methanolic extracts of A. mexicana L leaves inhibited growth of clinical isolates of Staphylococcus aureus, Bacillus cereus, Escherichia coli and Pseudomonas aeruginosa.The antibacterial potentiality of A. mexicana L extracts was compared with Streptomycin - the reference antibiotic used in this study. The active ingredient of antibacterial potentiality within the A. mexicana L extract was purified and characterized by TLC, HPLC and NMR analysis. Structural elucidation of Berberine and its bioactivity both, from the A. mexicana L and commercial preparation, is investigated. PMID- 29232415 TI - Serological detection of Tick-Borne Relapsing Fever in Texan domestic dogs. AB - Tick-Borne Relapsing Fever (TBRF) is caused by spirochetes in the genus Borrelia. Very limited information exists on the incidence of this disease in humans and domestic dogs in the United States. The main objective of this study is to evaluate exposure of dogs to Borrelia turicatae, a causative agent of TBRF, in Texas. To this end, 878 canine serum samples were submitted to Texas A&M Veterinary Medical Diagnostic Laboratory from October 2011 to September 2012 for suspected tick-borne illnesses. The recombinant Borrelial antigen glycerophosphodiester phosphodiesterase (GlpQ) was expressed, purified, and used as a diagnostic antigen in both ELISA assays and Immunoblot analysis. Unfortunately, due to significant background reaction, the use of GlpQ as a diagnostic marker in the ELISA assay was not effective in discriminating dogs exposed to B. turicatae. Nevertheless, immunoblot assays showed that 17 out of 853 samples tested were considered to be seropositive, which constitutes 1.99% of all Texas samples tested in this study. The majority of positive samples were from central and southern Texas. Exposure to TBRF spirochetes may be seasonal, with 70.59% (12 out of 17) of the cases detected between June and December. In addition, 2 out of the 17 sero-reactive cases (11.76%) showed reactivity to both B. burgdorferi (causative agent of Lyme disease) and B. turicatae (a causative agent of TBRF). This is the first report of TBRF sero-prevalence in companion animals in an endemic area. Our findings further indicate that B. turicatae is maintained in domestic canids in Texas in regions where human disease also occurs, suggesting that domestic dogs could serve as sentinels for this disease. PMID- 29232417 TI - Evaluation of the suitability of mitochondrial DNA for species identification of microtraces and forensic traces. AB - The objective of the study was to demonstrate how mitochondrial DNA (mtDNA) can be used to determine the species origin of animal microtraces. The study included pieces of cat and dog hair without the root, a fragment of cooked chicken bone (0.1g), three goose down samples (0.028 g), a pork swab, a pork scratching (5*5*5 mm), and pork lard (0.22 g). DNA was isolated from all of these samples using the method appropriate for the particular source material. The extracts had DNA concentration exceeding 5.4 ng/ul with A260/280 purity range of 1.14-1.88. Next, the samples were subjected to PCR and real-time PCR with species-specific primers and primers complementary to mitochondrial DNA (mtDNA). Control reactions based on the amplification of eukaryotic-specific fragment (18S rRNA) were additionally performed. PCR and real-time PCR products for detection of species-specific mtDNA were obtained for all templates, whereas during the detection of eukaryote DNA no product was obtained for dog and cat hair only. The poor quality of the obtained DNA did not prevent the analysis. The results showed that mitochondrial DNA is suitable for identification of small or highly processed samples, in which genomic DNA often cannot be analyzed. PMID- 29232418 TI - Nano-emulsions as vehicles for topical delivery of forskolin. AB - Two O/W forskolin-loaded nano-emulsions (0.075% wt.) based on medium chain triglycerides (MCT) and stabilized by a nonionic surfactant (Polysorbate 80 or Polysorbate 40) were studied as forskolin delivery systems. The nano-emulsions were prepared by the PIC method. The mean droplet size of the nano-emulsions with Polysorbate 80 and Polysorbate 40 with oil/surfactant (O/S) ratios of 20/80 and 80% water concentration, measured by Dynamic Light Scattering (DLS), was of 118 nm and 111 nm, respectively. Stability of the formulations, as assessed by light backscattering for 24 h, showed that both nano-emulsions were stable at 25 degrees C. Studies of forskolin in vitro skin permeation from the nano-emulsions and from a triglyceride solution were carried out at 32 degrees C, using Franz type diffusion cells. A mixture of PBS/ethanol (60/40 v/v) was used as a receptor solution. The highest flux and permeability coefficient was obtained for the system stabilized with Polysorbate 80 (6.91+/-0.75 ug . cm-2.h-1 and 9.21 . 10 3+/-1.00 . 10-3 cm . h-1, respectively) but no significant differences were observed with the flux and permeability coefficient value of forskolin dissolved in oil. The obtained results showed that the nano-emulsions developed in this study could be used as effective carriers for topical administration of forskolin. PMID- 29232419 TI - Mycobacterium marinum remains an unrecognized cause of indolent skin infections. AB - We identified 5 patients who had cutaneous lesions with cultures that yielded Mycobacterium marinum. It was discovered that all 5 patients had a home aquarium, and infection was preceded by trauma to the hand. However, the association between the development of the infection and exposure of the trauma site to the aquarium was not initially established until repeated questioning was performed. Skin biopsies or incision and drainage were performed for all patients, and the diagnosis was established by culture of the specimens. The mean time from initial presentation to diagnosis and initiation of appropriate treatment was 91 days (range, 21-245 days). Prolonged therapy for 2 to 6 months was necessary for resolution of the infection. PMID- 29232420 TI - Atypical herpes zoster presentation in a healthy vaccinated pediatric patient. AB - We report the case of a 6-year-old girl with no notable medical history who presented to the dermatology clinic for evaluation of left leg pain with an overlying erythematous rash of 4 days' duration. Clinical examination revealed pink patches and plaques in a unilateral L5 distribution with an isolated pinpoint vesicle. Direct fluorescent antibody testing confirmed varicella-zoster virus (VZV) infection, establishing a diagnosis of herpes zoster (HZ). The patient previously had received the VZV vaccine in the left leg and arm and had no history of primary VZV infection. We summarize this case and discuss the epidemiology and clinical characteristics of HZ in vaccinated children. PMID- 29232421 TI - Ulcerative sarcoidosis: a prototypical presentation and review. AB - Although rare, ulcerative sarcoidosis is an acknowledged morphologic variant of cutaneous sarcoidosis encountered in both the United States and worldwide, particularly in patients with skin of color. Herein, we present a patient with prototypical ulcerative sarcoidosis to highlight this unusual presentation of a relatively rare cutaneous condition. We also review 34 additional cases drawn from the English-language literature to define historical presentation, associated findings, treatments, and outcomes. PMID- 29232422 TI - Atypical disseminated herpes zoster: management guidelines in immunocompromised patients. AB - Reactivation of the varicella-zoster virus (VZV) causes dermatomal herpes zoster (HZ) and more rarely severe disseminated HZ including diffuse rash, encephalitis, hepatitis, and pneumonitis. An atypical form of VZV infection, disseminated HZ has been described primarily in immunocompromised hosts. We report 2 cases of atypical disseminated HZ in immunocompromised patients presenting with diffuse, nondermatomal, vesicular eruptions. We also provide a review of the literature and summarize the current guidelines for the treatment and prophylaxis of HZ in patients with human immunodeficiency virus (HIV) infection, solid organ transplantation (SOT), and hematopoietic stem cell transplantation (HSCT). Given the atypical presentation of VZV infection among some immunocompromised patients, this case series emphasizes the need for clinical suspicion for disseminated HZ to facilitate timely diagnosis and initiation of antiviral therapy. Clinician awareness of methods for prevention and treatment of VZV infection in immunocompromised individuals also is critical to minimize the risk for disease and associated morbidity in these patients. PMID- 29232423 TI - A case of leprosy in central Florida. AB - Hansen disease, also known as leprosy, is a chronic granulomatous infectious disease that is caused by Mycobacterium leprae. We report an unusual case of a 65 year-old man who presented with multiple anesthetic, annular, erythematous, scaly plaques with a raised border without any known exposures to leprosy. Histologic examination revealed a perineural lymphohistiocytic infiltrate and rare bacilli demonstrated on Fite staining. After confirmation with polymerase chain reaction (PCR) and consultation with the National Hansen's Disease Program (Baton Rouge, Louisiana), the patient was placed on a regimen of rifampicin 600 mg once monthly and dapsone 100 mg once daily for 6 months, which showed considerable improvement. This case demonstrates the identification of leprosy in central Florida, a region that is not known to be endemic to the disease. Leprosy, however rare, must be part of a practitioner's differential diagnosis even without history of traditional exposures. PMID- 29232424 TI - Syphilis and the dermatologist. PMID- 29232425 TI - Black eschars on the face and body. PMID- 29232426 TI - Solitary tender nodule on the back. PMID- 29232427 TI - What's eating you? scabies in the developing world. AB - Scabies infestation is a major cause of impetigo and subsequent renal failure in the developing world, and efforts to eradicate widespread infestation are underway. Ivermectin, topical sulfur, and topical benzyl benzoate often are used to treat widespread outbreaks. PMID- 29232428 TI - Clinical pearl: a simple and effective technique for improving surgical closures for the early-learning resident. PMID- 29232429 TI - Red scaly rash following tattoo application. PMID- 29232430 TI - Asymptomatic pink plaque on the scapula. PMID- 29232431 TI - Primary mucinous carcinoma of the eyelid treated with Mohs micrographic surgery. PMID- 29232432 TI - Acrodermatitis enteropathica in a patient with short bowel syndrome. PMID- 29232433 TI - Over-the-counter topical musculoskeletal pain relievers used with a heat source: a dangerous combination. PMID- 29232434 TI - Linear porokeratosis associated with multiple squamous cell carcinomas. AB - Linear porokeratosis is a rare subtype of porokeratosis with a higher rate of malignant transformation than other subtypes of porokeratosis. Identification of cornoid lamellae on histology allows for definitive diagnosis, which makes high clinical suspicion and appropriate biopsy essential in establishing the correct diagnosis and developing an effective management plan. We present a case report of linear porokeratosis and discuss aspects of etiology, diagnosis, and management. PMID- 29232435 TI - An atypical syphilis presentation. AB - We present a case of lichenoid secondary syphilis in the genital area in the absence of other cutaneous or systemic manifestations. The patient did not experience an eruption on the palmar or plantar surfaces, which is rare. This case also is unique because of the intense pruritus associated with the genital lesions, a remarkable dissimilarity from typical secondary syphilitic eruptions that tend to be asymptomatic. PMID- 29232437 TI - New ways to maintain or disrupt metabolic homeostasis. PMID- 29232436 TI - Cellular versus acellular grafts for diabetic foot ulcers: altering the protocol to improve recruitment to a comparative efficacy trial. AB - Diabetic foot ulcers (DFUs) have a substantial impact on public health. The standard of care (SOC) for DFUs consists of a multidisciplinary approach involving glycemic control, wound care with debridement of necrotic tissue, application of a moist dressing, infection control, use of off-loading devices, and patient education. New therapeutic devices aim to target the extracellular matrix (ECM) that is impaired in DFU; however, there is insufficient data on the effectiveness of such therapies along with lack of evidence on their long-term effectiveness. We hypothesized that there is no difference in healing between the cellular matrix and an acellular matrix relative to SOC. To test this hypothesis, we conducted a randomized, single-blind clinical trial in patients with nonhealing DFUs that included 3 treatment arms: (1) SOC, (2) SOC plus a bioengineered ECM with living fibroblasts, and (3) SOC plus a bioengineered ECM devoid of cells. Our trial currently is closed for enrollment, as we have reached our target population size. Amendments to the protocol were made to help reach this threshold. PMID- 29232438 TI - Refractory or relapsed aggressive B-cell lymphoma failing (R)-CHOP: an analysis of patients treated on the RICOVER-60 trial. AB - Background: The prognosis of elderly patients with aggressive B-non-Hodgkin's lymphoma after first lymphoma-related treatment failure (TF-L) is not well described. Methods: We analysed patient characteristics including the presence of MYC rearrangements and MYC-expression immunohistochemistry (IHC) at diagnosis and modalities of salvage therapy and their impact on the prognosis of patients between 61 and 80 years who had been treated on the RICOVER-60 trial. Results: TF L occurred in 301 of the 1222 (24.6%) patients; 297 patients could be analysed. Prognosis was extremely poor in patients with primary progressive disease or early relapse (<=12 months) with median survivals of 3.3 and 6.4 months. Survival after TF-L was significantly lower in patients pretreated with R-CHOP compared with CHOP (23.0% versus 36.4% at 2 years, P = 0.016). In patients with MYC translocation at diagnosis Rituximab reduced the risk of TF-L from 58.8% to 26.3%. Survival after TF-L was significant longer for patients after CHOP without MYC translocations (31.8% versus 0% at 2 years, P < 0.001) or negative MYC-IHC (41.0% versus 16.8% at 2 years, P = 0.017) but not after R-CHOP. 224 patients (75.4%) received salvage therapy. Rituximab was part of salvage therapy in 57.4% and improved 2-year survival rate from 20.7% to 46.8% (P < 0.001). The benefit of R was significant after first-line CHOP [2-year overall survival (OS) 49.6% versus 19.1%, P < 0.001] as well as after R-CHOP (2-year OS 33.1% and 22.5%, P = 0.034). For patients pretreated with R-CHOP long-term survival was below 15% regardless of the treatment chosen. Conclusion: MYC rearrangement and IHC are adverse prognostic factors after TF-L for CHOP treated patients, rituximab as part of first-line therapy reduced the effects of MYC-break. Rituximab improves results of any type of salvage therapy; however, survival after progression/relapse of aggressive B-cell lymphoma in elderly patients pretreated with (R)-CHOP is poor regardless of treatment chosen. PMID- 29232441 TI - JJCO Paper of the Year and Highly Commended Paper. PMID- 29232440 TI - Farewell message from the Editor-in-Chief. PMID- 29232442 TI - The estimates of five-year liver cancer prevalence in adult population in 2012. PMID- 29232444 TI - Chris Barnard 50th Heart Transplant Anniversary. PMID- 29232443 TI - Thanking All Peer Reviewers. PMID- 29232445 TI - Christiaan Barnard's defining moment: The epic first human heart transplant performed 50 years ago by Chris Barnard is discussed by David Cooper MD who was with Barnard at Groote Schuur Hospital in Cape Town. PMID- 29232446 TI - 50th Anniversary of the first Human Heart Transplant-How is it seen today? PMID- 29232447 TI - Fifty years of heart transplantation: A journey of courage, innovation and persistence, celebrated in Cape Town. PMID- 29232448 TI - Vladimir Petrovich Demikhov (1916-1998): A pioneer of transplantation ahead of his time, who lived out the end of his life as an unknown and in poor circumstances. PMID- 29232449 TI - Heart Transplantation in Bad Oeynhausen, Germany: The Heart Transplant program at the Heart and Diabetes Center Bad Oeynhausen, University Hospital, Ruhr - University Bochum University, Germany. PMID- 29232450 TI - Heart Transplantation in Spain: A review of the heart transplant programme in Spain from its beginning in 1984 by Marisa Crespo-Leiro MD. PMID- 29232439 TI - Body mass index and breast cancer survival: a Mendelian randomization analysis. AB - Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. Methods: We used individual-level data from six large breast cancer case cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta analysis. Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95). Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases. PMID- 29232451 TI - Commemorative Mural in Cape Town: A new mural of African themes was inaugurated at the Faculty of Health Sciences Art Exhibition in Cape Town to celebrate Chris Barnard's epic first human heart transplant 50 years ago. PMID- 29232452 TI - Heart Transplants, Reflections, & Expectations: Sir Magdi Yacoub reviews the history of heart transplantation and discusses expectations. PMID- 29232454 TI - Empiric treatment for persistent abdominal symptoms after travel: a practical option for a protracted problem? PMID- 29232453 TI - Detection of Zika virus in Aedes mosquitoes from Mexico. AB - Background: We report on the results of an entomovirological surveillance system of Aedes populations performed by the Ministry of Health of the central state of San Luis Potosi, Mexico. Methods: Indoor adult Aedes aegypti and Aedes albopictus pools collected at San Martin, Tamazunchale, Ciudad Valles, Metlapa, Ebano, Tamuin and Axtla during the dry season of 2016 were examined for the presence of dengue (DENV), chikungunya (CHIKV) and Zika (ZIKV) viruses using real-time PCR. Results: Both Ae. aegypti and Ae. albopictus were found to be infected with ZIKV in the absence of confirmed symptomatic human cases. Conclusions: The entomovirological surveillance system analysed here identified both Ae. aegypti and Ae. albopictus infected with ZIKV which triggered an immediate aggressive vector control campaign. PMID- 29232455 TI - Nocturnal decrease of arterial oxygen content-hidden stimulus for erythropoietin secretion at altitude. PMID- 29232456 TI - Susceptibility to measles in migrant population: implication for policy makers. AB - Background: Despite a large measles outbreak is taking place in WHO European region, currently no data are available on measles immunization coverage in the asylum seeker and migrants hosted in this area. Methods: Two hundred and fifty six migrants upon their arrival in Italy on March, April and May 2016 were screened for measles virus IgG antibodies by chemiluminescence immunoassay (Liaison XL analyzer, Diasorin, Italy). The virus susceptibility in this cohort, the differences between the official country reported and the observed measles immunization coverage and the impact of current measles outbreak on the asylum seekers hosted in the largest Asylum Seeker centres of Italy, were evaluated. Results: The prevalence of subjects with positive result for measles IgG antibodies ranged between 79.9% and 100%. In Senegal, Mali, Nigeria, Pakistan and Bangladesh, the measles IgG seroprevalence observed was greater than the vaccinal coverage reported by WHO after I dose of vaccine. Based on data regarding the II dose coverage, the ASs population presented a seroprevalence greater to that expected. Conclusion: On the basis of the results obtained, extraordinary screening and vaccination campaigns in the migrant population, especially in the course of large outbreaks, could represent a resource to reach an adequate measles immunization coverage and to control this infectious disease. PMID- 29232457 TI - Imported malaria in northern Italy: epidemiology and clinical features observed over 18 years in the Teaching Hospital of Brescia. AB - Background: Even though malaria incidence is decreasing worldwide, travel-related cases reported in Europe have remained stable in recent years. In Italy, incidence had increased in the 1990s, reaching a peak in 1999; a slow decline was then reported over the subsequent decade. To our knowledge, few published data are available on imported malaria in Italy since 2010. In this article we aimed to analyse trends in imported malaria in the teaching hospital of Brescia, northern Italy, over the last 18 years. Methods: All malaria cases diagnosed from 1999 to 2016 in Spedali Civili Hospital, Brescia, were retrospectively identified. Demographic, clinical and travel-related data were described. Results: A total of 1200 cases of imported malaria were diagnosed in Brescia during the study period. Among them, 225 were children. A trend of increasing paediatric cases was identified over the study period, while cases in adults were stable. Most cases were diagnosed between August and October. Patients were most likely exposed in sub-Saharan Africa (87.2%). The main reported travel reason was travelling to visit friends and relatives (66.0%). A significantly higher risk of severe malaria was observed in non-immune patients and children visiting friend and relatives (P < 0.001 and P = 0.006, respectively). Conclusions: Our study reveals a relatively stable incidence in imported malaria cases with a peak during the summertime. A large and increasing paediatric burden of disease was identified. Imported malaria requires attention since in Italy a potential reappearance of autochthonous Plasmodium vivax malaria transmission cannot be excluded. Preventive action and physician awareness should be especially directed to children visiting friends and relatives in endemic countries and to non-immune patients since they both represent high-risk groups for severe malaria. PMID- 29232458 TI - The effectiveness of empirical anti-parasitic treatment in returning travellers with persistent abdominal symptoms. AB - Background: Persistent abdominal symptoms (PAS) are common among returning travellers. In the absence of sensitive tests to identify intestinal parasites, gastrointestinal (GI) symptoms often remain a diagnostic challenge. In this study we examined the effectiveness of empirical anti-parasitic treatment in returning travellers with PAS despite no positive stool-test. Methods: A retrospective study among returning travellers who approached the clinic between the years 2014 and 2016 with GI complaints without a positive stool-test. The empirical treatment included broad-spectrum anti-parasitic agents-oral Tinidazole and Albendazole. A follow-up questionnaire was performed at least 6 months post treatment. Results: A total of 102 patients responded the questionnaire-50% women; average age 31.14 (+/-12.20) years. The average duration of complaints before treatment was 16.52 (+/-30.06) months. Common GI symptoms included abdominal pain (83.3%) and diarrhoea (78.4%); 67.6% of the patients complained of extreme fatigue. Overall, 69% of the patients reported an improvement in GI symptoms, 37% of them reported full recovery within a few weeks post-treatment. Furthermore, there was an improvement in the energy level and general well-being in 68% and 70% of the patients, respectively. Only 33% of the patients reported minor side effects related to the treatment. Conclusions: The improvement in GI symptoms, energy level and general well-being shortly after anti-parasitic treatment justifies this empirical approach in returning-travellers with PAS despite negative stool-tests. The association between fatigue and PAS post-travel and the improvement in both as a response to treatment defines fatigue as part of a new syndrome-'Post-travel fatigue and abdominal symptoms'. PMID- 29232459 TI - Definitive diagnosis in suspected Middle East Respiratory Syndrome Coronavirus cases. AB - We evaluated the microbiological diagnosis in 14 patients with epidemiological and clinical suspicion of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) attended in a non-endemic area between June 2015 and January 2017. While no MERS CoV was detected, other respiratory viruses were identified in 12 cases and Mycoplasma pneumoniae in 1 case. PMID- 29232460 TI - Travel with CPAP machines: how frequent and what are the problems? AB - Background: Obstructive sleep apnoea syndrome is a common condition for which continuous positive airways pressure (CPAP) is the standard treatment. The condition affects a population of which a substantial proportion will be travelling. Methods: We use a questionnaire survey of CPAP users to gain understanding regarding the behaviours, attitudes and problems surrounding travel with CPAP machines during travel and while abroad. All CPAP patients on our database at a UK district general hospital reviewed over a period of 4 years were sent a postal questionnaire. Results: A response rate of 53% was achieved giving data on 588 trips. In the last 2 years, 63.7% of respondents had travelled; reasons for not travelling were CPAP related in only five cases. Travellers took their CPAP machines on 81% of trips. A similar proportion of patients took their CPAP machines regardless of the mode of travel, destination or length of holiday. Problems with checking in the CPAP machine were encountered in 4% of trips, all as part of air travel. Just over a third of patients faced problems either with the power cord, adapter or transport of the CPAP machine. Of those taking overnight flights, half did not sleep and none used their CPAP machines in flight. CPAP usage while away did not differ to usage at home. Conclusions: This is the first report to describe in some detail CPAP machine use and associated problems in travel and while away. The data may aid the targeting of brief interventions in CPAP clinics as well as helping to standardize the process of check-in in order to help travellers with CPAP machines. PMID- 29232461 TI - Tabanus bovinus in Bolivia? PMID- 29232462 TI - Incidence and spectrum of health problems among travellers to Myanmar. AB - Background: The number of international travellers visiting Myanmar increases each year. However, information about pre-travel preparation and incidence of health problems among these travellers is limited. Methods: This cross-sectional study was conducted at three international airports in Thailand. Travellers returning from Myanmar completed questionnaires querying demographic profile, pre travel health preparations and health problems during their stay in Myanmar. Results: From March 2015 to May 2017, we collected and analysed questionnaires completed by 397 Thai and 467 non-Thai travellers (total: 50.1% men, median age 37 years). Non-Thai travellers were from Europe (59%), Northern America (21.4%), Asia (16.5%) and Australia or New Zealand (3.0%). Approximately 74% of non-Thais sought pre-travel health information; only 36% of Thais did so. Tourism was the main purpose for travel among both Thais (58.4%) and non-Thais (85.2%). Non-Thais were more likely than Thais to travel as backpackers and perform outdoor activities such as trekking, cycling or swimming. The average length of stay in Myanmar among non-Thais was significantly longer than that of Thais (26.58 days vs 7.08 days, P < 0.001). Health problems were reported by 22.9% of non-Thais; the most common was diarrhoea (21.0%) followed by upper respiratory tract symptoms (9.2%), fever (3.4%) and skin problems (3.0%). Only 12.6% of Thais reported health problems, the most common being upper respiratory tract symptoms (7.6%), followed by diarrhoea (3.1%), fever (2.8%) and skin problems (2.0%). Most health problems were mild and self-limited in both groups. Only one Thai and eight non-Thai travellers required a doctor's visit during their trip to Myanmar, and two non-Thais required hospitalization. Conclusions: Health problems are not very common among travellers to Myanmar. Overall, health problems were reported among 18.2% of travellers in our study. Most problems were mild, with spontaneous recovery. Only two foreign travellers required hospitalization. PMID- 29232463 TI - Ultrasonography: current status, challenges, and future directions. PMID- 29232464 TI - Treatment of recurrent ovarian cancer. AB - Despite optimal surgery and appropriate first-line chemotherapy, ~70%-80% of patients with epithelial ovarian cancer will develop disease relapse. The same modalities as used primarily are available for treatment of recurrent ovarian cancer (ROC). The rationale for repetitive surgery in ROC was based on a stable body of retrospective data; however, prospective data were missing. Now, preliminary data from the prospective AGO-DESKTOP III give evidence that surgery for ROC seems to be of benefit for selected patients with platinum-sensitive relapse undergoing complete resection. With respect to systemic therapy, tumor histology, BRCA status, the platinum-free interval (PFI) and previous treatment with bevacizumab (anti-VEGF monoclonal antibody) are considered the most important features that influence treatment choice in ROC. In patients with resistant or refractory relapse (PFI < 6 months), monotherapy with a non-platinum drug or participation in clinical trials is indicated. The association of non platinum monotherapy with bevacizumab, followed by maintenance has been approved in this setting in some European countries due to PFS benefit. In patients with partially sensitive relapse (PFI between 6 and 12 months), two options are available: platinum doublets or non-platinum therapy (single agent or combination). The pegylated liposomal doxorubicin/trabectedin combination represents a viable alternative in patients that cannot receive platinum. In platinum-sensitive patients, treatment with platinum-based combinations is associated with PFS advantage compared with single agents or non-platinum combinations. The presence of germline or somatic BRCA mutations allows platinum responsive patients to optimize chemotherapy efficacy and prolonging PFS by the use of olaparib (PARP inhibitor) given as maintenance therapy until progression. In patients not pretreated with bevacizumab in first line, the carboplatin/gemcitabine/bevacizumab combination, followed by maintenance is a viable alternative in platinum-sensitive patients (PFI> 6 months). The integration of surgery, with a 'personalized' approach by the use of antiangiogenic agent and of PARP inhibitors is affecting survival of patients with recurrent disease and will help epithelial ovarian cancer to become a chronic disease. PMID- 29232465 TI - New treatments in ovarian cancer. AB - In targeting DNA repair pathways of the most genomic instable cancer, poly (adenosine diphosphate [ADP])-ribose polymerase inhibitors (PARPi) have been demonstrated as the most effective drug since platinum in high grade serous or endometrioid ovarian cancer. Immunotherapy is strongly pushing the door of ovarian cancer and has the ambition to change the fate of this deadly disease when combined with chemotherapy, vascular endothelial growth factor inhibitor or PARPi. The activity of PARPi could also be improved by modulators of the cell cycle, which are required to give time enough for DNA repair. Even more ambitious are drug targeting the driver p53 mutation or the pathway which inhibit tumor cell apoptosis. Some original approaches still give life to new chemotherapy compounds such as the marine derivative lurbinectedin or the immunoconjugate mirvetuximab soravtansine including a monoclonal antibody targeting the folate receptor. PMID- 29232466 TI - Real-world evidence in the treatment of ovarian cancer. AB - Introduction: 'Real-world evidence (RWE)' refers to information on the utilization and outcome of new therapies and technologies in clinical practice. RWE may include single institution cohort studies, population-based health services studies, or (inter)national data on survival and mortality. This paper reviews RWE on the impact of treatment in ovarian cancer. Materials and methods: A literature review of publications addressing population level survival outcomes of new surgical and systemic treatment interventions in ovarian cancer was undertaken. In addition, literature and international cancer registry trends in ovarian cancer survival, mortality and incidence rates were compiled. These latter were utilized to make inferences on the relative impact of new treatments as well as changing incidence rates on observed mortality trends. Results: The last four decades have seen new systemic and surgical treatments introduced into practice for ovarian cancer based on randomized trial evidence. However, there has been little published on population level uptake and survival outcomes of those interventions. Exceptions were population studies on intraperitoneal chemotherapy and neoadjuvant chemotherapy. One paper demonstrated modest uptake of intraperitoneal chemotherapy and evidence of improved survival. Cancer registry statistics revealed falling incidence rates (~1%-2% per year) for ovarian cancer across Europe, North America and elsewhere over the last three to four decades. Mortality rates also declined by ~1%-2% per year over this period. Population 5-year relative survival estimates also improved over this period [from 33.7% in 1975 to 46.2% in 2008 (SEER data)]. Conclusions: There are few RWE studies of specific treatments in ovarian cancer. Trends in relative survival and population mortality have shown improvements. Mortality changes can be explained in part by reductions in ovarian cancer incidence rates (speculated to be due to use of oral contraceptives and reduction in postmenopausal hormone use). However, it is plausible that at least some of the mortality reduction is related to improved survival of patients with the introduction of effective new treatments. PMID- 29232467 TI - Immunotherapy in ovarian cancer. AB - Immunological destruction of tumors is a multistep, coordinated process that can be modulated or targeted at several critical points to elicit tumor rejection. These steps in the cancer immunity cycle include: (i) generation of sufficient numbers of effector T cells with high avidity recognition of tumor antigens in vivo; (ii) trafficking and infiltration into the tumor; (iii) overcoming inhibitory networks in the tumor microenvironment; (iv) direct recognition of tumor antigens and generation of an effector anti-tumor response; and (v) persistence of the anti-tumor T cells. In an effort to understand whether the immune system plays a role in controlling ovarian cancer, our group and others demonstrated that the presence of tumor infiltrating lymphocytes (TILs) is associated with improved clinical outcome in ovarian cancer patients. Recently, we hypothesized that the quality of infiltrating T cells could also be a critical determinant of outcome in ovarian cancer patients. In the past decade, several immune-based interventions have gained regulatory approval in many solid tumors and hematologic malignancies. These interventions include immune checkpoint blockade, cancer vaccines, and adoptive cell therapy. There are currently no approved immune therapies for ovarian cancer. Immunotherapy in ovarian cancer will have to consider the immune suppressive networks within the ovarian tumor microenvironment; therefore, a major direction is to develop biomarkers that would predict responsiveness to different types of immunotherapies, and allow for treatment selection based on the results. Moreover, such biomarkers would allow rational combination of immunotherapies, while minimizing toxicities. In this review, the current understanding of the host immune response in ovarian cancer patients will be briefly reviewed, progress in immune therapies, and future directions for exploiting immune based strategies for long lasting durable cure. PMID- 29232468 TI - The new classifications of ovarian, fallopian tube, and primary peritoneal cancer and their clinical implications. AB - The roles of histologic characterization and staging are to provide reproducible metrics for cancer classification with which to direct the most appropriate clinical care and to yield the most stable reliable system to allow both prospective and retrospective data analysis. Both the histologic and staging classifications of malignant ovarian/tubal/peritoneal cancers have recently changed. The World Health Organization sponsored a review and reclassification of the pathology of cancers of the ovaries, fallopian tubes, and peritoneum, and published these updates in 2014. In so doing, they codified the two-tiered grading system that has been in use in serous ovarian cancers for nearly a decade. In parallel, FIGO reviewed and updated the surgical staging system, applied to all histotypes of ovarian, tubal, and peritoneal cancers, also published in 2014. In both cases, the changes made are meant to encompass a better understanding of disease, but both have important merits and drawbacks. Changes in staging complicate analysis of retrospective data against current data. Though in some aspects controversial, the changes overall are meant to represent a better biologic understanding of disease that we hope will lead to an improvement in patient care and directed therapy. PMID- 29232469 TI - Acquired chemotherapy resistance in ovarian cancer. AB - Most women diagnosed with high-grade serous ovarian cancer (HGSC) develop recurrent disease and chemotherapy resistance, despite initially responding to treatment. The genomic characteristics of HGSC samples collected at initial surgery have been extensively studied. However, due to challenges of sample collection following treatment, much less is known about the molecular features of recurrent disease. Our recent studies have identified mechanisms of acquired resistance and biomarkers in recurrent HGSCs that could lead to improved treatment approaches. PMID- 29232470 TI - How can molecular abnormalities influence our clinical approach. AB - Background: Despite improvements in diagnostics and treatment, the clinical outcome of epithelial ovarian cancer remains poor over the last three decades. Recent high-throughput genomic studies have demonstrated ovarian cancer as a highly heterogeneous entity with distinctive molecular signatures among different or even within the same histotype. In this article, we review the molecular genetics of epithelial ovarian cancer and how they have been translated into modern clinical trials, as well as their implications in patient stratification for more targeted and personalized approaches. Patients and methods: Multiple genomic studies were collected to summarize the major advances in understanding ovarian cancer-associated molecular abnormalities with emphasis on their potential clinical applicability to rationalize the design of recent clinical trials. Results: The clinical management of ovarian cancer can significantly benefit from comprehensive molecular profiling studies, which have uncovered the distinctiveness of ovarian cancer subsets bearing characteristic genomic aberrance and consequentially dysregulated genes and pathways underlying the tumor progression and chemoresistance. Genomics studies have demonstrated a powerful tool to delineate the molecular basis responsible for diverse clinical behaviors associated with tumor histology and grade. In addition, molecular signatures obtained by integrated 'omics' analyses have promised opportunities for novel therapeutic or stratification biomarkers to tailor current clinical management as well as novel predictive tools of clinical end points including patient prognosis and therapeutic efficacy. Conclusions: Recent progress in understanding the molecular landscape of ovarian cancer has profoundly shifted the design of clinical trials from empirical, unitary paradigms to more rationalized and personalized regimes. Correspondingly, a promising prospective has emerged for ovarian cancer patients to have considerably improved outcome upon careful alignment of patient characteristics, therapeutic biomarkers and targeting approaches. Nevertheless, extensive validation and inference of potential biomarkers are pressing demands on both bioinformatic and biological levels to warrant sufficient clinical relevance for potential translation, so that the performance of related clinical trial can be well predicted and achieved. PMID- 29232471 TI - Cytoreductive surgery for ovarian cancer: quality assessment. AB - Surgery is the cornerstone of treatment of ovarian cancer. Given the importance of achieving no or minimal macroscopic residual disease at primary surgery, performing an assessment of the quality of ovarian cancer surgery is crucial. Assessing the quality of care and surgical outcome allows us to establish baseline information, set standards of care and clear priorities, enable benchmarking against peers, and sustain quality improvement. We know that suboptimal care exists and variation in outcomes results. One way to monitor variation in outcomes is through a clinical quality registry (CQR). A CQR collects a defined minimum dataset to measure performance of an individual or center against a range of clinical quality indicators and provides risk-adjusted, benchmarked data to participating institutions. CQR's are an excellent quality assurance measure as they capture all cases (an opt out system). They permit detection and analysis of unwarranted variations in care. This can provide indications of a systems or process problem, thereby motivating health care providers to improve services and care. Several groups have either developed quality indicators for advanced ovarian cancer surgery (The Scottish Cancer Taskforce and the European Society of Gynecological Oncology) or are in the process of doing so (Australian Society of Gynaecological Oncologists). Indicators should be evidence-based and determined by extensive discussion with experts and stakeholders to ensure appropriateness and buy-in. The Scottish Cancer Taskforce and European Society of Gynecological Oncology have set targets for their quality performance measures, which should provide a quantitative framework for improving care in the surgical management of ovarian cancer. PMID- 29232472 TI - Harmonising clinical trials within the Gynecologic Cancer InterGroup: consensus and unmet needs from the Fifth Ovarian Cancer Consensus Conference. AB - The Gynecologic Cancer InterGroup (GCIG) Fifth Ovarian Cancer Consensus Conference (OCCC) was held in Tokyo, Japan from 7 to 9 November 2015. It provided international consensus on 15 important questions in 4 topic areas, which were generated in accordance with the mission statement to establish 'International Consensus for Designing Better Clinical Trials'. The methodology for obtaining consensus was previously established and followed during the Fifth OCCC. All 29 clinical trial groups of GCIG participated in program development and deliberations. Draft consensus statements were discussed in topic groups as well as in a plenary forum. The final statements were then presented to all 29 member groups for voting and documentation of the level of consensus. Full consensus was obtained for 11 of the 15 statements with 28/29 groups agreeing to 3 statements, and 27/29 groups agreeing to 1 statement. The high acceptance rate of the statements among trial groups reflects the fact that we share common questions, and recognise important unmet needs that will guide future research in ovarian cancer. PMID- 29232473 TI - Front-line therapy of advanced epithelial ovarian cancer: standard treatment. AB - Paclitaxel and carboplatin combination chemotherapy has remained the standard of care in the front-line therapy of advanced epithelial ovarian cancer during the last decade. Maintenance chemotherapy has not been proven to impact on overall survival. Acceptable alternatives include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal chemotherapy. In particular, anti-angiogenic therapy has been identified as the most promising targeted therapy, and the addition of bevacizumab to first-line chemotherapy followed by a maintenance period of bevacizumab in monotherapy has shown to prolong progression-free survival. This was considered the proof of concept of the value of anti-angiogenic therapy in the front-line of ovarian cancer, and the results of two additional clinical trials with anti-angiogenic tyrosine kinase inhibitors have shown results in the same direction. PMID- 29232474 TI - Is intraperitoneal chemotherapy still an acceptable option in primary adjuvant chemotherapy for advanced ovarian cancer? AB - : The role of intraperitoneal (i.p.) chemotherapy in treating newly diagnosed advanced epithelial ovarian cancer (EOC) has been the subject of controversy for almost three decades. Three large intergroup phase III trials (GOG 104, 114, 172) have demonstrated a survival benefit associated with i.p. over intravenous (i.v.) therapy in advanced, low-volume EOC. Despite the positive clinical trial results and a subsequent National Cancer Institute alert in 2006, i.p. treatment has not been widely accepted as the standard of care in the United States and is infrequently used in Europe. The hesitancy of clinicians to use i.p. therapy is likely attributed to higher toxicity, inconvenience, catheter complications, and clinical trial design issues. On the other hand, In a long-term follow-up report from these trials, we showed that the effect of i.p. chemotherapy extends beyond 10 years and that the more cycles of i.p. therapy portends for improved survival over similar cycles of i.v. therapy with younger patients having a higher likelihood of completing 6 cycles of i.p. TREATMENT: More recently, a fourth randomized phase III trial, GOG 252, failed to show a survival advantage associated with i.p. cisplatin and i.p. carboplatin over dose-dense i.v. paclitaxel and carboplatin. Since the use of bevacizumab was incorporated in all arms of the study, this anti-vascular agent may have equalized or negated the clinical advantage of i.p. chemotherapy and dose-dense weekly as suggested in GOG 262. We are awaiting the results of the Asian iPocc trial comparing dose-dense paclitaxel to i.p. chemotherapy without bevacizumab, though the differences in the tumor histology and pharmacokinetics in Asian versus non-Asian patients may influence the interpretation of the results worldwide. In this review, we review the polarizing opinions on the relevance of i.p. therapy in today's clinical armamentarium. Never before, have oncologists examined the same datasets with divergent conclusions. This topic is confusing to patients and clinicians alike and has led to inconsistent guidelines and reimbursement. However, it might be time to move on. Now more than ever, we have novel combinations to personalize upfront treatments for advanced ovarian cancer. In addition to i.p. therapy we also need to focus on targeted therapy, biomarkers, survivorship, and the sequencing of therapy. PMID- 29232476 TI - Comment on Haakvort et al. 2017, Hepatology 65:281-293. PMID- 29232475 TI - Front-line therapy of advanced ovarian cancer: new approaches. AB - Background: The 5-year survival of ovarian cancer has slowly increased but to date much of this has been due to the use of more lines of treatment rather than better first-line therapy. In this setting, there has been little improvement over the past 15 years. The introduction of new treatments to extend time to first progression and overall survival remains a key objective of clinical research. Design: The focus of research in the previous decade has been on the incorporation of anti-angiogenic therapy or dose-dense scheduling of paclitaxel (Taxol) to improve outcome. The new trials being conducted build on the knowledge gained and are focussing on two new areas of research, the use of PARP (poly-ADP ribose polymerase) inhibitors and immunotherapy. Results: Ongoing randomised trials using PARP inhibitors or immune checkpoint inhibits are reviewed and the potential benefits and challenges of using these agents are discussed. Conclusions: Improvements in outcome from some of the many open trials may present challenges; interpretation of the outcome data needs to be taken in the context of clinical benefit and a health-economic assessment. The latter is becoming ever-more important as the cost of trials with combinations of targeted therapy is very great. PMID- 29232477 TI - Behavior-driven arc expression is reduced in all ventral hippocampal subfields compared to CA1, CA3, and dentate gyrus in rat dorsal hippocampus. AB - Anatomical connectivity and lesion studies reveal distinct functional heterogeneity along the dorsal-ventral axis of the hippocampus. The immediate early gene Arc is known to be involved in neural plasticity and memory and can be used as a marker for cell activity that occurs, for example, when hippocampal place cells fire. We report here, that Arc is expressed in a greater proportion of cells in dorsal CA1, CA3, and dentate gyrus (DG), following spatial behavioral experiences compared to ventral hippocampal subregions (dorsal CA1 = 33%; ventral CA1 = 13%; dorsal CA3 = 23%; ventral CA3 = 8%; and dorsal DG = 2.5%; ventral DG = 1.2%). The technique used here to obtain estimates of numbers of behavior-driven cells across the dorsal-ventral axis, however, corresponds quite well with samples from available single unit recording studies. Several explanations for the two- to-threefold reduction in spatial behavior-driven cell activity in the ventral hippocampus can be offered. These include anatomical connectivity differences, differential gain of the self-motion signals that appear to alter the scale of place fields and the proportion of active cells, and possibly variations in the neuronal responses to non-spatial information within the hippocampus along its dorso-ventral axis. PMID- 29232478 TI - Customizing Photoredox Properties of PXX-based Dyes through Energy Level Rigid Shifts of Frontier Molecular Orbitals. AB - Here we describe the synthesis of electron-rich PXX derivatives in which the energy levels of the excited states have been rigidly shifted through the insertion of imide groups. This has allowed the development of a new series of oxygen-doped photoredox-active chromophores with improved oxidizing and reducing properties. Capitalizing on the dehalogenation of organic halides as a model reaction, we could investigate the photooxidative and photoreductive potential of these molecules in model chemical transformations. Depending on the substrate, solvent and dye the reaction mechanism can follow different paths. This prompted us to consider the first chemoselective transformation protocol, in which two different C-Br bonds could be chemoselectively reacted through the sequential photoactivation of two different colorants. PMID- 29232480 TI - Reply (to LTE HEP-17-2075). PMID- 29232481 TI - Tracking of Areal Bone Mineral Density From Age Eight to Young Adulthood and Factors Associated With Deviation From Tracking: A 17-Year Prospective Cohort Study. AB - We have previously shown that bone mineral density (BMD) tracks strongly from age 8 to 16 years. This study aimed to describe whether this strong tracking continued to age 25 years and describe factors associated with deviation from tracking. Ninety-nine participants were followed from age 8 to 25 years and 197 participants from age 16 to 25 years. Outcomes measured were BMD at the spine, hip, and total body (by dual-energy X-ray absorptiometry [DXA]). Other factors measured were anthropometrics, inhaled corticosteroids (ICS) use, history of being breastfed, sports participation, fitness (by physical work capacity [PWC170 ]), lean mass (LM), and fat mass (FM) (by DXA). There was moderate to strong tracking of BMD from age 8 to 25 years (correlation coefficients: males, 0.59 to 0.65; females, 0.70 to 0.82) and strong tracking from age 16 to 25 years (males, 0.81 to 0.83; females, 0.84 to 0.88) after adjustment for change in body size. From age 8 to 25 years, 54% to 56% of participants kept their BMD tertile position. PWC170 at age 8 years, relative and absolute change in LM, and sports participation at age 25 years predicted males would improve their tertile position or remain in the highest tertile of spine or hip BMD. However, relative and absolute change in FM had the opposite association in males while absolute change in FM predicted positive deviation in females. From age 16 to 25 years, LM, PWC170 , sports participation at age 16 years, and change in LM, PWC170 , and sports participation at age 25 years predicted positive deviation in males. LM at age 16 years was positively associated and PWC170 negatively associated with positive deviation in females. BMD tracks from childhood to early adulthood in both males and females. There appears to be greater capacity to alter tracking before age 16 years. Increasing LM in both sexes and improving fitness and sports participation in males during growth might be effective strategies to improve BMD in early adulthood. (c) 2017 American Society for Bone and Mineral Research. PMID- 29232479 TI - Metabolomic Pathways to Osteoporosis in Middle-Aged Women: A Genome-Metabolome Wide Mendelian Randomization Study. AB - The metabolic state of the body can be a major determinant of bone health. We used a Mendelian randomization approach to identify metabolites causally associated with bone mass to better understand the biological mechanisms of osteoporosis. We tested bone phenotypes (femoral neck, total hip, and lumbar spine bone mineral density [BMD]) for association with 280 fasting blood metabolites in 6055 women from TwinsUK cohort with genomewide genotyping scans. Causal associations between metabolites and bone phenotypes were further assessed in a bidirectional Mendelian randomization study using genetic markers/scores as instrumental variables. Significant associations were replicated in 624 participants from the Hong Kong Osteoporosis Study (HKOS). Fifteen metabolites showed direct associations with bone phenotypes after adjusting for covariates and multiple testing. Using genetic instruments, four of these metabolites were found to be causally associated with hip or spine BMD. These included androsterone sulfate, epiandrosterone sulfate, 5alpha-androstan-3beta17beta-diol disulfate (encoded by CYP3A5), and 4-androsten-3beta17beta-diol disulfate (encoded by SULT2A1). In the HKOS population, all four metabolites showed significant associations with hip and spine BMD in the expected directions. No causal reverse association between BMD and any of the metabolites were found. In the first metabolome-genomewide Mendelian randomization study of human bone mineral density, we identified four novel biomarkers causally associated with BMD. Our findings reveal novel biological pathways involved in the pathogenesis of osteoporosis. (c) 2017 American Society for Bone and Mineral Research. PMID- 29232482 TI - Validation of a contextualized assessment of smoking behaviour in students. AB - AIMS: The aim of this study was to validate an audio simulation of culture specific social contexts associated with smoking to provide a medium for researchers to investigate social-contextual influences on tobacco use in the laboratory. METHODS: Eighty-one students (34.6% men; n = 28) listened to five audio simulations of peer social contexts where offers to smoke tobacco were made [Smoking Simulated Intoxication Digital Elicitation (S-SIDE)]. For each social scenario, participants answered questions about their willingness to accept the offer to smoke and completed measures of smoking cognitions and tobacco use. Thirty days later, participants completed online assessments of smoking behaviour. RESULTS: Willingness to accept smoking offers in the S-SIDE procedure was related to smoking at both time-points (T1: r(81) = 0.37, P < 0.001;T2: r(81) = 0.36, P = 0.001). Performance on the simulation improved prediction of smoking at 1 month follow-up over and above smoking expectancies, F(2,74) = 4.27, P = 0.02; R2 = 0.21; DeltaR2 = 0.09, as well as other indices of smoking willingness, F(2,75) = 4.22, P = 0.02; R2 = 0.22: DeltaR2 = 0.09, while neither expectancies nor willingness was related to smoking above and beyond the simulation. CONCLUSIONS: Social context plays an important role in smoking related decision-making and simulated social contexts have potential for the study of context-related decision-making in addiction. PMID- 29232483 TI - Epitope-Resolved Detection of Peanut-Specific IgE Antibodies by Surface Plasmon Resonance Imaging. AB - Peanut allergy can be life-threatening and is mediated by allergen-specific immunoglobulin E (IgE) antibodies. Investigation of IgE antibody binding to allergenic epitopes can identify specific interactions underlying the allergic response. Here, we report a surface plasmon resonance imaging (SPRi) immunoassay for differentiating IgE antibodies by epitope-resolved detection. IgE antibodies were first captured by magnetic beads bearing IgE epsilon-chain-specific antibodies and then introduced into an SPRi array immobilized with epitopes from the major peanut allergen glycoprotein Arachis hypogaea h2 (Ara h2). Differential epitope responses were achieved by establishing a binding environment that minimized cross-reactivity while maximizing analytical sensitivity. IgE antibody binding to each Ara h2 epitope was distinguished and quantified from patient serum samples (10 MUL each) in a 45 min assay. Excellent correlation of Ara h2 specific IgE values was found between ImmunoCAP assays and the new SPRi method. PMID- 29232484 TI - Juvenile social experience and differential age-related changes in the dendritic morphologies of subareas of the prefrontal cortex in rats. AB - Juvenile social interactions have been shown to influence the dendritic complexity of neurons in the prefrontal cortex (PFC). In particular, social play induces pruning of the cells in the medial prefrontal cortex (mPFC), whereas interacting with multiple partners, whether those interactions involve play or not, increases the complexity of cells in the orbital frontal cortex (OFC). Previous studies suggest that these changes differ in their stability during adulthood. In the present study, rats were reared in groups of either four (quads) or two (pairs) and the brains of the rats from each rearing condition were then harvested at 60 days (i.e., shortly after sexual maturity) and 100 days (i.e., fully adult). The rats housed with multiple partners had more complex neurons of the OFC at 60 days and this complexity declined to a comparable level to that of pair housed rats by 100 days. In contrast, the play-induced changes of the mPFC remained similar at both ages. These findings suggest that the changes in the PFC induced by different social experiences in the juvenile period differ in how long they are maintained in adulthood. Differences in the functions regulated by the OFC and the mPFC are considered with regard to these differences in the stability of juvenile-induced neural changes. PMID- 29232485 TI - Retraction: 'Imaging characteristics of liver Langerhans cell histiocytosis in children' by Hui Liu, Xueying Long, Xiaoyi Wang, Wenzheng Li and Yigang Pei. AB - : The above article from Pediatrics International, published as an Accepted Article online on April 28, 2017 in Wiley Online Library (http://wileyonlinelibrary.com) has been withdrawn by agreement between the authors, the Journal Editor-in-Chief, Atsushi Manabe, and John Wiley & Sons Australia, Ltd, on behalf of the Japan Pediatric Society. The withdrawal has been agreed at the request of the authors who have identified some serious problems that need to be addressed and who have found that some important information is missing. REFERENCE: 1 Liu, H., Long, X., Wang, X., Li W. and Pei, Y. (2017), Imaging characteristics of liver Langerhans cell histiocytosis in children. Pediatrics International. Doi 10.1111/ped.13313. PMID- 29232486 TI - An Essential Warning. PMID- 29232487 TI - Relation of social constraints on disclosure to adjustment among Chinese American cancer survivors: A multiprocesses approach. AB - PURPOSE: The present study examines the association between social constraints and depressive symptoms among Chinese American breast cancer survivors, and the mechanism underling this association. A multiprocesses model is tested to examine the mediating roles of ambivalence over emotional expression (AEE), avoidance, intrusive thoughts, and social support in the association between social constraints and depressive symptoms among Chinese American breast cancer survivors. METHODS: Ninety-six Chinese American breast cancer survivors were recruited from Chinese community organizations. They were asked to complete a questionnaire package that assessed social constraints, AEE, avoidance, intrusive thoughts, social support, depressive symptoms, and demographic information. Path analysis was conducted to test the hypothesized model. RESULTS: The overall and specific indirect effects of social constraints on depressive symptoms through AEE, avoidance, intrusive thoughts, and social support are significant. When the mediators are controlled for, the direct effect of social constraints on depressive symptoms is no longer significant. CONCLUSIONS: A multiprocesses model of social constraints and depressive symptoms is tested in a sample of Chinese American breast cancer survivors. The findings suggest that the existence of multiple pathways through which social constraints may associate with depressive symptoms among Chinese American breast cancer survivors. PMID- 29232488 TI - Catalytic Asymmetric Synthesis of Trifluoromethylated gamma-Amino Acids through the Umpolung Addition of Trifluoromethyl Imines to Carboxylic Acid Derivatives. AB - Novel cinchona alkaloid derived chiral phase-transfer catalysts enabled the highly chemo-, regio-, diastereo-, and enantioselective umpolung addition of trifluoromethyl imines to alpha,beta-unsaturated N-acyl pyrroles. With a catalyst loading ranging from 0.2 to 5.0 mol %, this new catalytic asymmetric transformation provides facile and high-yielding access to highly enantiomerically enriched chiral trifluoromethylated gamma-amino acids and gamma lactams. PMID- 29232489 TI - Achieving Biocompatible SABRE: An in vitro Cytotoxicity Study. AB - Production of a biocompatible hyperpolarized bolus for signal amplification by reversible exchange (SABRE) could open the door to simple clinical diagnosis via magnetic resonance imaging. Essential to successful progression to preclinical/clinical applications is the determination of the toxicology profile of the SABRE reaction mixture. Herein, we exemplify the cytotoxicity of the SABRE approach using in vitro cell assays. We conclude that the main cause of the observed toxicity is due to the SABRE catalyst. We therefore illustrate two catalyst removal methods: one involving deactivation and ion-exchange chromatography, and the second using biphasic catalysis. These routes produce a bolus suitable for future in vivo study. PMID- 29232490 TI - CO2 to Terpenes: Autotrophic and Electroautotrophic alpha-Humulene Production with Cupriavidus necator. AB - We show that CO2 can be converted by an engineered "Knallgas" bacterium (Cupriavidus necator) into the terpene alpha-humulene. Heterologous expression of the mevalonate pathway and alpha-humulene synthase resulted in the production of approximately 10 mg alpha-humulene per gram cell dry mass (CDW) under heterotrophic conditions. This first example of chemolithoautotrophic production of a terpene from carbon dioxide, hydrogen, and oxygen is a promising starting point for the production of different high-value terpene compounds from abundant and simple raw materials. Furthermore, the production system was used to produce 17 mg alpha-humulene per gram CDW from CO2 and electrical energy in microbial electrosynthesis (MES) mode. Given that the system can convert CO2 by using electrical energy from solar energy, it opens a new route to artificial photosynthetic systems. PMID- 29232491 TI - Anhedonia is associated with suicidal ideation independently of depression: A meta-analysis. AB - BACKGROUND: Anhedonia is considered a suicide risk factor in patients with major affective disorders. Here, we wanted to quantify the association between anhedonia and current suicidal ideation according to the absence/presence of between-group differences for depressive scores and psychiatric disorders. METHODS: We performed a meta-analysis of data on studies retrieved from Medline, Web of Science, and PsycINFO from 1965 to 2016 using, among others, the terms (suicid* or depression) and anhedonia. RESULTS: We identified 15 observational case-control studies that investigated the anhedonia differences in individuals with and without current (i.e., within the past week, independently of the lifetime suicidality status) suicidal ideation (defined as thoughts of killing oneself). Overall, 657 subjects with and 6,690 subjects without current suicidal ideation could be compared. Anhedonia level was higher in the group with current suicidal ideation than in the group without, with a medium effect size (standardized mean difference = 0.57, z = 5.43, P < 0.001, 95% confidence interval, CI = 0.37-0.79). The association between anhedonia and current suicidal ideation remained significant when controlling for depression and psychiatric disorders. The anhedonia scales used in the selected studies did not allow investigating consummatory and motivational anhedonia separately. CONCLUSION: Our major finding is the robust association between anhedonia and current suicidal ideation, independently of depression. This is highly relevant for the clinicians' daily practice and might help improving suicidal risk detection and the development of new therapeutic strategies for suicide prevention. PMID- 29232492 TI - Use of split-free nano-liquid chromatography-mass spectrometry/high resolution mass spectrometry interface to improve the detection of alpha-cobratoxin in equine plasma for doping control. AB - Cobra (Naja naja kaouthia) venom contains a toxin called alpha-cobratoxin (alpha Cbtx) containing 71 amino acids (MW 7821 Da) with a reported analgesic power greater than morphine. In 2013, the first analytical method for the detection of alpha-Cbtx in equine plasma was developed by Bailly-Chouriberry et al, allowing the confirmation of the presence of alpha-Cbtx at low concentrations (1-5 ng/mL or 130-640 fmol/mL) in plasma samples. To increase the method sensitivity and therefore to improve the detection of alpha-Cbtx in post-administration plasma samples, a nano-liquid chromatography-mass spectrometry/high resolution mass spectrometry (nLC-MS/HRMS) method was developed. This new method allowed us to confirm the presence of alpha-Cbtx in plasma samples spiked at 100 pg/mL (12.8 fmol/mL) and the detection of alpha-Cbtx was obtained in plasma samples collected 72 hours post-administration (50 pg/mL or 6.4 fmol/mL) which was defined as the limit of detection (LOD). The presented method is 20-fold more sensitive compared to the method previously described. PMID- 29232493 TI - [Carboxyl-11 C]Labelling of Four High-Affinity cPLA2alpha Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography. AB - Cytosolic phospholipase A2alpha (cPLA2alpha) may play a critical role in neuropsychiatric and neurodegenerative disorders associated with oxidative stress and neuroinflammation. An effective PET radioligand for imaging cPLA2alpha in living brain might prove useful for biomedical research, especially on neuroinflammation. We selected four high-affinity (IC50 2.1-12 nm) indole-5 carboxylic acid-based inhibitors of cPLA2alpha, namely 3-isobutyryl-1-(2-oxo-3-(4 phenoxyphenoxy)propyl)-1H-indole-5-carboxylic acid (1); 3-acetyl-1-(2-oxo-3-(4-(4 (trifluoromethyl)phenoxy)phenoxy)propyl)-1H-indole-5-carboxylic acid (2); 3-(3 methyl-1,2,4-oxadiazol-5-yl)-1-(2-oxo-3-(4-phenoxyphenoxy)propyl)-1H-indole-5 carboxylic acid (3); and 3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(3-(4-octylphenoxy) 2-oxopropyl)-1H-indole-5-carboxylic acid (4), for labelling in carboxyl position with carbon-11 (t1/2 =20.4 min) to provide candidate PET radioligands for imaging brain cPLA2alpha. Compounds [11 C]1-4 were obtained for intravenous injection in adequate overall yields (1.1-5.5 %) from cyclotron-produced [11 C]carbon dioxide and with moderate molar activities (70-141 GBq MUmol-1 ) through the use of Pd0 mediated [11 C]carbon monoxide insertion on iodo precursors. Measured logD7.4 values were within a narrow moderate range (1.9-2.4). After intravenous injection of [11 C]1-4 in mice, radioactivity uptakes in brain peaked at low values (<=0.8 SUV) and decreased by about 90 % over 15 min. Pretreatments of the mice with high doses of the corresponding non-radioactive ligands did not alter brain time activity curves. Brain uptakes of radioactivity after administration of [11 C]1 to wild-type and P-gp/BCRP dual knock-out mice were similar (peak 0.4 vs. 0.5 SUV), indicating that [11 C]1 and others in this structural class, are not substrates for efflux transporters. PMID- 29232494 TI - Reconstructing relational information. AB - Hippocampal involvement in learning and remembering relational information has an extensive history, often focusing specifically on spatial information. In humans, spatial reconstruction (SR) paradigms are a powerful tool for evaluating an individuals' spatial-relational memory. In SR tasks, participants study locations of items in space and subsequently reconstruct the studied display after a short delay. Previous work has revealed that patients with hippocampal damage are impaired both in overall placement accuracy as well as on a specific measure of relational memory efficacy, "swaps" (i.e., when the relative location of two items is reversed). However, the necessity of the hippocampus for other types of spatial-relational information involved in reconstruction behaviors (e.g., where in the environment and relative to which other items an item was located) have not yet been investigated systematically. In this work, three patients with hippocampal damage and nine healthy matched comparison participants performed an SR task. An analysis framework was developed to independently assess three first order types of relations: (1) memory for the binding of specific item identities to locations, (2) memory for arrangement of items in relation to each other or the environment bounds, regardless of memory for the item identity, and (3) higher-order, compound relational errors (i.e., errors involving multiple pieces of relational information). Reconstruction errors were evaluated to determine the degree to which patients and comparisons differed (or not) on each type of spatial-relational information. Data revealed that the primary group difference in performance was for identity-location information. However, when the locations of items were evaluated without regarding the identities, no group difference was found in the number of item placements to studied locations. The present work provides a principled approach to analysis of SR data and clarifies our understanding of the types of spatial relations impaired in hippocampal damaged. PMID- 29232495 TI - Encapsulation of Homogeneous Catalysts in Mesoporous Materials Using Diffusion Limited Atomic Layer Deposition. AB - The heterogenization of homogeneous metal complex catalysts has attracted great attention. The encapsulation of metal complexes into nanochannels of mesoporous materials is achieved by coating metal oxides at/near the pore entrance by diffusion-limited atomic layer deposition (ALD) to produce a hollow plug. The pore size of the hollow plug is precisely controlled on the sub-nanometer scale by the number of ALD cycles to fit various metal complexes with different molecular sizes. Typically, Co or Ti complexes are successfully encapsulated into the nanochannels of SBA-15, SBA-16, and MCM-41. The encapsulated Co and Ti catalysts show excellent catalytic activity and reusability in the hydrolytic kinetic resolution of epoxides and asymmetric cyanosilylation of carbonyl compounds, respectively. This ALD-assisted encapsulation method can be extended to the encapsulation of other homogeneous catalysts into different mesoporous materials for various heterogeneous reactions. PMID- 29232496 TI - Force-Induced Catastrophes on Energy Landscapes: Mechanochemical Manipulation of Downhill and Uphill Bifurcations Explains the Ring-Opening Selectivity of Cyclopropanes. AB - The mechanochemistry of ring-opening reactions of cyclopropane derivatives turns out to be unexpectedly rich and puzzling. After showing that a rare so-called uphill bifurcation in the case of trans-gem-difluorocyclopropane turns into a downhill bifurcation upon substitution of fluorine by chlorine, bromine, and iodine in the thermal activation limit, the dichloro derivative is studied systematically in the realm of mechanochemical activation. Detailed exploration of the force-transformed potential energy surface of trans-gem dichlorocyclopropane in terms of Dijkstra path analysis unveils a hitherto unknown topological catastrophe where the global shape of the energy landscape is fundamentally changed. From thermal activation up to moderately large forces, it is an uphill bifurcation that decides about dis- versus conrotatory ring-opening followed by separate transition states along both pathways. Above a critical force, the two distinct transition states merge to yield a single transition state such that the decision about the dis- versus conrotatory ring-opening process is taken at a newly established downhill bifurcation. The discovery of a force-induced qualitative change of the topology of a reaction network vastly transcends the previous understanding of the ring-opening reaction of this species. It would be astonishing to not discover a wealth of such catastrophes for mechanochemically activated reactions, which will greatly extend the known opportunities to manipulate chemical reaction networks. PMID- 29232497 TI - Evaluation of olfaction and taste function in type 2 diabetic patients with and without peripheral neuropathy. AB - AIMS: Olfaction and gustation in patients with diabetes mellitus have great significance on quality of life, and their impairment may result in possible hazards. A limited number of studies have been performed to determine the alteration of both gustatory and olfactory function in type 2 diabetic patients with diabetic peripheral neuropathy (DPN). The aim of this study was to determine whether type 2 diabetic patients, with and without DPN, exhibit major olfactory and gustatory dysfunction using validated and dependable techniques. METHODS: An observational-analytical case-control study was conducted. Sixty patients with type 2 diabetes mellitus (T2DM) and 30 healthy control subjects with a mean age of 57.1 +/- 8.4 were included in the study. Patients with T2DM were recruited from the endocrinology outpatient clinic. After clinical evaluation and electromyography examination, patients with T2DM were divided into the 2 groups, with and without DPN. After a 10-hour fasting period, blood samples were taken for the measurement of serum creatinine, lipids, and HbA1c. For the quantitative assessment of olfactory function, all participants underwent butanol threshold test and odour identification test. Gustatory function was tested administering a whole-mouth above-threshold test using sucrose solutions. RESULTS: The control subjects showed significantly higher Sniffin' sticks and butanol threshold scores than the diabetic patients without DPN (P = .001 and P = .009). No significant difference was found in the gustatory function test between these 2 groups (P = .116). Diabetic patients with DPN had lower Sniffin' sticks scores, butanol threshold scores, and higher sucrose thresholds compared to the controls (P < .001, P < .001, and P = .002). There were no significant differences between diabetic patients with or without DPN regarding Sniffin' sticks scores, butanol threshold, and sucrose thresholds (P = .302, P = .181, and P = .118). CONCLUSION: In conclusion, this study demonstrates that T2DM is associated with olfactory and gustatory dysfunction. The fact that there was no difference between the diabetic patients with and without DPN elicits the idea of central neuropathy. This novel finding might facilitate the addition of olfactory and gustatory tests to the methodological spectrum of afferent pathway investigations. PMID- 29232498 TI - Actinide-Pnictide (An-Pn) Bonds Spanning Non-Metal, Metalloid, and Metal Combinations (An=U, Th; Pn=P, As, Sb, Bi). AB - The synthesis and characterisation is presented of the compounds [An(TrenDMBS ){Pn(SiMe3 )2 }] and [An(TrenTIPS ){Pn(SiMe3 )2 }] [TrenDMBS =N(CH2 CH2 NSiMe2 But )3 , An=U, Pn=P, As, Sb, Bi; An=Th, Pn=P, As; TrenTIPS =N(CH2 CH2 NSiPri3 )3 , An=U, Pn=P, As, Sb; An=Th, Pn=P, As, Sb]. The U-Sb and Th-Sb moieties are unprecedented examples of any kind of An-Sb molecular bond, and the U-Bi bond is the first two-centre-two-electron (2c-2e) one. The Th-Bi combination was too unstable to isolate, underscoring the fragility of these linkages. However, the U Bi complex is the heaviest 2c-2e pairing of two elements involving an actinide on a macroscopic scale under ambient conditions, and this is exceeded only by An-An pairings prepared under cryogenic matrix isolation conditions. Thermolysis and photolysis experiments suggest that the U-Pn bonds degrade by homolytic bond cleavage, whereas the more redox-robust thorium compounds engage in an acid base/dehydrocoupling route. PMID- 29232499 TI - Magnetic Field-Enhanced 4-Electron Pathway for Well-Aligned Co3 O4 /Electrospun Carbon Nanofibers in the Oxygen Reduction Reaction. AB - The sluggish reaction kinetics of the oxygen reduction reaction (ORR) has been the limiting factor for fuel energy utilization, hence it is desirable to develop high-performance electrocatalysts for a 4-electron pathway ORR. A constant low current (50 MUA) electrodeposition technique is used to realize the formation of a uniform Co3 O4 film on well-aligned electrospun carbon nanofibers (ECNFs) with a time-dependent growth mechanism. This material also exhibits a new finding of mT magnetic field-induced enhancement of the electron exchange number of the ORR at a glassy carbon electrode modified with the Co3 O4 /ECNFs catalyst. The magnetic susceptibility of the unpaired electrons in Co3 O4 improves the kinetics and efficiency of electron transfer reactions in the ORR, which shows a 3.92 electron pathway in the presence of a 1.32 mT magnetic field. This research presents a potential revolution of traditional electrocatalysis by simply applying an external magnetic field on metal oxides as a replacement for noble metals to reduce the risk of fuel-cell degradation and maximize the energy output. PMID- 29232500 TI - Developmental Osteology of the Parafrontal Bones of the Sphaerodactylidae. AB - Well-resolved phylogenetic hypotheses and ontogenetic data are often necessary for investigating the evolution of structural novelty. The Sphaerodactylidae comprises 12 genera of predominantly miniaturized geckos. The genera Aristelliger and Teratoscincus are exceptions, with taxa reaching snout-to-vent lengths far exceeding those of other sphaerodactylids. These two genera possess enigmatic, supraorbital ossifications-parafrontal bones-which are encountered nowhere else among squamates. At the time of their discovery, these structures were believed to be the result of evolutionary convergence. Although relationships between other sphaerodactylids remain unresolved, recent molecular and morphological data have supported a close relationship between Aristelliger and Teratoscincus. We investigated the ontogeny of parafrontal bones to better understand relationships between sphaerodactylid body size and the presence of parafrontals, and to evaluate whether ontogenetic data support the homology of parafrontals between Aristelliger and Teratoscincus. We hypothesize that the parafrontals of Aristelliger and Teratoscincus are homologous and that there is a threshold body size in sphaerodactylids below which parafrontals do not develop, thus explaining their absence from the miniaturized taxa. The presence of parafrontals was investigated in all sphaerodactylid genera using cleared-and-stained, radiographed, and skeletonized specimens. Total surface area of parafrontals was measured for seven species of Aristelliger and six species of Teratoscincus throughout their ontogeny. Histology was used to investigate the cellular composition of the parafrontals throughout their ontogeny. Our data suggest that parafrontals have evolved in parallel from a homologous, parafrontal precursor and that the onset of parafrontal development is not strictly dependent on a threshold body size. Anat Rec, 301:581-606, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29232501 TI - A Kinetic Dearomatization Strategy for an Expedient Biomimetic Route to the Bielschowskysin Skeleton. AB - Bielschowskysin (1), the flagship of the furanocembranoid diterpene family, has attracted attention from chemists owing to its intriguing and daunting polycyclic architecture and medicinal potential against lung cancer. The high level of functionalization of 1 poses a considerable challenge to synthesis. Herein, a stereoselective furan dearomatization strategy of furanocembranoids was achieved via the intermediacy of chlorohydrins. The stereochemical course of the kinetic dearomatization was established, and the C3 configuration of the resulting exo enol ether intermediates proved to be essential to complete the late-stage transannular [2+2] photocycloaddition. Overall, this biomimetic strategy starting from the natural product acerosolide (9) featured an unprecedented regio- and highly stereoselective furan dearomatization, which provided rapid access to the pivotal exo-enol ethers en route to the intricate bielschowskyane skeleton. PMID- 29232502 TI - Do treatment patterns alter beliefs cancer patients hold regarding oral oncolytic agents? AB - OBJECTIVE: Cancer patients, particularly those prescribed with oral oncolytic medications, face treatment side effects and temporary and permanent stoppages of treatment. This research examines how events during treatment affect patients' beliefs regarding oral oncolytic medications. METHODS: A total of 272 cancer patients initiating 1 of 28 oral oncolytic agents were followed for 12 weeks. Assessments of Beliefs About Medications Questionnaire, symptoms, physical function, and depression measures were performed during telephone interviews at intake (medication start) and 4, 8, and 12 weeks. Electronic medical record audits identified dates of temporary and permanent medication stoppages. Linear mixed-effects models were used for longitudinal analyses of the Beliefs About Medications Questionnaire scores in relation to patient characteristics, symptom severity, and medication stoppages. RESULTS: Over the initial 12 weeks, beliefs about the necessity of oral medications have increased, concerns have decreased, and interference of medications with daily lives has increased. Permanent stoppage of a medication predicted significant declines in beliefs about its necessity over time. Male patients, those less educated, those reporting higher symptom severity, and those experiencing temporary stoppages had greater concerns. Interference of medications with daily life was higher for males, increased with higher symptom severity, and differed by drug category. CONCLUSIONS: Patients' beliefs in the necessity of their oral medication were affected only by a permanent drug stoppage. Symptom severity, education, and patient sex affected patients' beliefs about their concerns with their medications and the interference medications posed for their daily lives. Interventions may need to target the distinct dimensions of beliefs during treatment with oral oncolytic agents. PMID- 29232503 TI - Calculation of Magnetic Shielding Constants with meta-GGA Functionals Employing the Multipole-Accelerated Resolution of the Identity: Implementation and Assessment of Accuracy and Efficiency. AB - We present a highly efficient implementation for density functional calculations of chemical shielding constants. It employs the multipole-accelerated resolution of the identity for the calculation of the Coulomb part, which complements the usage of low order scaling routines for the evaluation of the exchange correlation part and the Hartree-Fock exchange part. Introduced errors for shifts of chemical shielding constants of H, C, F, and P are evaluated for respective test sets of molecules and are related to the accuracy of shifts obtained with hybrid and nonhybrid functionals of the generalized gradient approximation type as well as for meta-GGA functionals themselves. Efficiency is demonstrated for alpha-d-glucose chains with more than 2500 atoms on a single CPU as well as with an OpenMP parallelized version. PMID- 29232504 TI - A Genetic Toolbox for Modulating the Expression of Heterologous Genes in the Cyanobacterium Synechocystis sp. PCC 6803. AB - Cyanobacteria, genetic models for photosynthesis research for decades, have recently become attractive hosts for producing renewable fuels and chemicals, owing to their genetic tractability, relatively fast growth, and their ability to utilize sunlight, fix carbon dioxide, and in some cases, fix nitrogen. Despite significant advances, there is still an urgent demand for synthetic biology tools in order to effectively manipulate genetic circuits in cyanobacteria. In this study, we have compared a total of 17 natural and chimeric promoters, focusing on expression of the ethylene-forming enzyme (EFE) in the cyanobacterium Synechocystis sp. PCC 6803. We report the finding that the E. coli sigma70 promoter Ptrc is superior compared to the previously reported strong promoters, such as PcpcB and PpsbA, for the expression of EFE. In addition, we found that the EFE expression level was very sensitive to the 5'-untranslated region upstream of the open reading frame. A library of ribosome binding sites (RBSs) was rationally designed and was built and systematically characterized. We demonstrate a strategy complementary to the RBS prediction software to facilitate the rational design of an RBS library to optimize the gene expression in cyanobacteria. Our results show that the EFE expression level is dramatically enhanced through these synthetic biology tools and is no longer the rate-limiting step for cyanobacterial ethylene production. These systematically characterized promoters and the RBS design strategy can serve as useful tools to tune gene expression levels and to identify and mitigate metabolic bottlenecks in cyanobacteria. PMID- 29232505 TI - Installing Guest Molecules at Specific Sites within Scaffold Protein Crystals. AB - Protein crystals are porous self-assembling materials that can be rapidly evolved by mutagenesis. We aimed to develop scaffold assisted crystallography techniques in an engineered protein crystal with large pores (>13 nm). Guest molecules were installed via a single covalent bond to attempt to reduce the conformational freedom and achieve high-occupancy structures. We used four different conjugation strategies to attach guest molecules to three different cysteine sites within pre existing protein crystals. In all but one case, the presence of the adduct was obvious in the electron density. Structure determination of larger guest molecules may be feasible due to the large pores of the engineered scaffold crystals. PMID- 29232506 TI - Thiolactone Chemistry-Based Combinatorial Methodology to Construct Multifunctional Polymers for Efficacious Gene Delivery. AB - Hydrophobic segments and amino moieties in polymeric nonviral gene vectors play important roles in overcoming a cascade of barriers for efficient gene delivery. However, it remains a great challenge to facilely construct well-defined multifunctional polymers through optimization of the amino and hydrophobic groups. Herein, we choose thiolactone chemistry to perform the ring opening reaction of varying hydrophobic groups-modified thiolactones by various amines to generate mercapto groups for further Michael addition reaction with poly[2 (acryloyloxy)ethyl methacrylate] (PAOEMA). Based on the combinatorial methodology, a series of multifunctional polymers were prepared and screened. The polymer (P3D) from tetraethylenepentamine and heptafluorobutyric acid functionalized thiolactone is the most efficacious one with significantly higher gene transfection efficiency and lower cytotoxicity compared with polyethylenimine (PEI) (branched average Mw ~ 25 000 Da) and Lipofectamine 2000. Cellular uptake and intracellular distribution studies indicate that P3D complexes show high-efficiency endocytosis and excellent endosomal escape. Accordingly, thiolactone chemistry-based combinatorial methodology allows for facile integration of multifunctional groups to prepare simultaneous efficacious and low-cytotoxic gene delivery vectors. PMID- 29232507 TI - Interfacial Deposition of Ru(II) Bipyridine-Dicarboxylate Complexes by Ligand Substitution for Applications in Water Oxidation Catalysis. AB - Water oxidation is a critical step in artificial photosynthesis and provides the protons and electrons used in reduction reactions to make solar fuels. Significant advances have been made in the area of molecular water oxidation catalysts with a notable breakthrough in the development of Ru(II) complexes that use a planar "bda" ligand (bda is 2,2'-bipyridine-6,6'-dicarboxylate). These Ru(II)(bda) complexes show lower overpotentials for driving water oxidation making them ideal for light-driven applications with a suitable chromophore. Nevertheless, synthesis of heterogeneous Ru(II)(bda) complexes remains challenging. We discuss here a new "bottom-up" synthetic method for immobilizing these catalysts at the surface of a photoanode for use in a dye-sensitized photoelectrosynthesis cell (DSPEC). The procedure provides a basis for rapidly screening the role of ligand variations at the catalyst in order to understand the impact on device performance. The best results of a water-oxidation DSPEC photoanode based on this procedure reached 1.4 mA/cm2 at pH 7 in 0.1 M [PO4H2] /[PO4H]2-solution with minimal loss in catalytic behavior over 30 min, and produced an incident photon to current efficiency (IPCE) of 24.8% at 440 nm. PMID- 29232508 TI - Programmable Payload Release from Transient Polymer Microcapsules Triggered by a Specific Ion Coactivation Effect. AB - Stimuli-responsive materials activated by a pair of molecular or ionic species are of interest in the design of chemical logic gates and signal amplification schemes. There are relatively few materials whose coactivated response has been well-characterized. Here, we demonstrate a specific ion coactivation (SICA) effect at the interfaces of transient polymer solids and liquid solutions. We found that depolymerization of the transient polymer, cyclic poly(phthalaldehyde) (cPPA), exhibited a SICA effect when the cPPA core-shell microcapsules were suspended in ion-containing acidic methanol solutions. Significant acceleration in cPPA depolymerization rate is triggered by the combination of acid and ion coactivators. Intriguingly, the SICA effect is related to the Hofmeister behavior. The SICA effect is primarily determined by anions, and cations exhibit a secondary effect that modulates the coactivation strength. Based on these observations, we developed cPPA programmable microcapsules whose payload release rates depend on the composition and concentration of the salt/acidic-methanol solutions. PMID- 29232509 TI - Evidence for Nonstomatal Uptake of Hg by Aspen and Translocation of Hg from Foliage to Tree Rings in Austrian Pine. AB - To determine whether trees are reliable biomonitors of air mercury (Hg) pollution concentrations were measured in bark, foliage, and tree rings. Data were developed using 4-year old Pinus and Populus trees grown from common genetic stock in Oregon and subsequently transferred to four air treatments differing in gaseous oxidized mercury (GOM) chemistry and total gaseous Hg (TGM) concentrations. Soil of a subset of trees was spiked with HgBr2 in solution to test for root uptake. Results indicate no significant effect of the soil spike or GOM compounds on tree tissue Hg concentrations. TGM treatment had a significant effect on Pinus and Populus foliage, and Pinus year 5 growth ring concentrations. Populus foliar Hg concentrations were highest in the exposure where 24 h TGM concentrations were highest, indicating the importance of the nonstomatal pathway for uptake. Pinus tree ring concentrations were correlated to day time TGM concentrations suggesting Hg accumulation into tree rings is by way of the stomata and subsequent translocation by way of phloem. Populus leaves and Pinus rings can be used as biomonitors for TGM concentrations over space. However, the use of trees as temporal proxies requires further investigation due to radial translocation observed in active sapwood tree rings. PMID- 29232510 TI - Synthesis and Thermoelectric Properties of Charge-Compensated SyPdxCo4-xSb12 Skutterudites. AB - Recently, the electronegative elements (e.g., S, Se, Cl, and Br) filled skutterudites have attracted great attention in thermoelectric community. Via doping of some electron donors at the Sb sites, these electronegative elements can be filled into the voids of CoSb3 forming thermodynamically stable compounds, which greatly extends the scope of filled skutterudites. In this study, we show that doping appropriate elements at the Co sites can also stabilize the electronegative elements in the voids of CoSb3. A series of SyPdxCo4-xSb12 compounds were successfully fabricated by a traditional solid state reaction method combined with a spark plasma sintering technique. The phase composition and electrical and thermal transport properties were systematically characterized, and the related mechanisms were deeply discussed. It is found that the charge compensation between Pd doping and S filling is the main reason for the formation of thermodynamically stable SyPdxCo4-xSb12 compounds. Filling S element in the voids of CoSb3 provides additional holes to reduce the carrier concentration while scarcely affecting the carrier mobility. However, doping Pd at the Co sites not only changes the carrier scattering mechanism but also deteriorates the carrier mobility. Low lattice thermal conductivities are observed in these SyPdxCo4-xSb12 compounds, which are attributed to the low resonant frequency of the S element. Finally, a maximal figure of merit of 0.85 is obtained for S0.05Pd0.25Co3.75Sb12 at 700 K. PMID- 29232511 TI - Quadratic Response Properties from TDDFT: Trials and Tribulations. AB - We report on the efficient turbomole implementation of quadratic response properties within the time-dependent density functional theory (TDDFT) context that includes the static and dynamic dipole hyperpolarizability, ground-to excited-state two-photon absorption amplitudes (through a single residue) and state-to-state one-photon absorption amplitudes (through a double residue). Our implementation makes full use of arbitrary (including non-Abelian) point-group symmetry as well as permutational symmetry and enables the calculation of nonlinear properties with hybrid density functionals for molecules with hundreds of atoms and thousands of basis functions at a cost that is a fixed multiple of the cost of the corresponding linear properties. Using the PBE0 hybrid density functional, we show that excited-state absorption spectra computed within the pseudowavefunction approach contain the qualitative features of transient absorption spectra tracking excimer formation in perylene diimide dimers, two photon absorption cross sections for a series of highly twisted fused porphyrin chains are semiquantitatively reproduced, and the computed dynamic hyperpolarizability of several calix[4]arene stereoisomers yield simulated hyper Raleigh scattering signals consistent with experiment. In addition, we show that the incorrect pole structure of adiabatic TDDFT properties can cause incorrect excited-state absorption spectra and overly resonant hyperpolarizabilities, and discuss possible remedies. PMID- 29232512 TI - Direct Anionic Effect on Water Structure and Indirect Anionic Effect on Peptide Backbone Hydration State Revealed by Thin-Layer Infrared Spectroscopy. AB - In this work, the anionic effect on water structure and on the peptide backbone and water interaction was investigated directly in aqueous solution using thin layer transmission infrared spectroscopy. The chaotropic anions were found to weaken the water hydrogen-bonding strength and red shift the HOH bending frequency, while the kosmotropic anions were found to strengthen the water hydrogen-bonding network and blue shift the HOH bending frequency. The kosmotropes, especially F-, blue shift the vibrational frequencies of both amide II and amide III bands of N-methylacetamide (NMA), indicating NMA is in the "salting-in" state; while the chaotropes (Cl-, NO3-, Br-, I-, and SCN-) red shift the frequencies of the two normal modes, indicating NMA is in the "salting-out" state. Furthermore, the changes of the vibrational frequencies of the HOH bending, amide II and III bands were found to generally follow the Hofmeister anionic series. Our results suggest that hydrated anion influences the peptide backbone mainly through the N-H group, but a weak and indirect effect through the amide C?O group also contributes. Thus, these amide modes can be used as vibrational measures of anionic influences on peptide backbone's hydration state. Our work also suggests that deuteration of the amide unit decreases the sensitivity of the amide II and III vibrational modes in this regard. PMID- 29232513 TI - Zeolite Adsorption Free Energies from ab Initio Potentials of Mean Force. AB - The ability of metal-exchanged zeolites to chemisorb small gas molecules is key to their performance as heterogeneous catalysts and gas-separating agents. Here, we propose and evaluate an ab initio potential of mean force (PMF) method for computing adsorption free energies of representative small molecules to Cu exchanged sites in SSZ-13 zeolite. We show that Cu ions are mobilized by adsorbates and, as a result, computed free energies are significantly more negative than those obtained from a conventional harmonic oscillator model. PMF derived free energies are consistent with available experiment and, in many cases, with a dynamics-based quasi-harmonic analysis (QHA). The PMF approach avoids the artificial partitioning of degrees of freedom intrinsic to the QHA. On the basis of the PMF results, we propose a simple correlation to estimate free energies from computed adsorption energies and gas-phase entropies. PMID- 29232514 TI - Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1 Inhibitors. AB - We initiated our structure-activity relationship (SAR) studies for selective ACC1 inhibitors from 1a as a lead compound. SAR studies of bicyclic scaffolds revealed many potent and selective ACC1 inhibitors represented by 1f; however most of them had physicochemical issues, particularly low aqueous solubility and potent CYP inhibition. To address these two issues and improve the druglikeness of this chemical series, we converted the bicyclic scaffold into a monocyclic framework. Ultimately, this lead us to discover a novel monocyclic derivative 1q as a selective ACC1 inhibitor, which showed highly potent and selective ACC1 inhibition as well as acceptable solubility and CYP inhibition profiles. Since compound 1q displayed favorable bioavailability in mouse cassette dosing testing, we conducted in vivo PD studies of this compound. Oral administration of 1q significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of more than 30 mg/kg. Accordingly, our novel series of selective ACC1 inhibitors represents a set of useful orally available research tools, as well as potential therapeutic agents for cancer and fatty acid related diseases. PMID- 29232515 TI - Parametrization and Benchmark of Long-Range Corrected DFTB2 for Organic Molecules. AB - We present the parametrization and benchmark of long-range corrected second-order density functional tight binding (DFTB), LC-DFTB2, for organic and biological molecules. The LC-DFTB2 model not only improves fundamental orbital energy gaps but also ameliorates the DFT self-interaction error and overpolarization problem, and further improves charge-transfer excited states significantly. Electronic parameters for the construction of the DFTB2 Hamiltonian as well as repulsive potentials were optimized for molecules containing C, H, N, and O chemical elements. We use a semiautomatic parametrization scheme based on a genetic algorithm. With the new parameters, LC-DFTB2 describes geometries and vibrational frequencies of organic molecules similarly well as third-order DFTB3/3OB, the de facto standard parametrization based on a GGA functional. LC-DFTB2 performs well also for atomization and reaction energies, however, slightly less satisfactorily than DFTB3/3OB. PMID- 29232516 TI - Highly Enantioselective Synthesis of Propargyl Amides through Rh-Catalyzed Asymmetric Hydroalkynylation of Enamides: Scope, Mechanism, and Origin of Selectivity. AB - Chiral propargyl amides are particularly useful structural units in organic synthesis. The enantioselective synthesis of propargyl amide is highly desirable. Conventional approach involves the use of a stoichiometric amount of metal reagent or chiral auxiliary. In comparison, direct alkynylation with terminal alkyne is attractive because it avoids the use of stoichiometric organometallic reagent. The asymmetric coupling of aldehyde, amine, and alkyne (A3-coupling) provides an efficient method for the synthesis of N-alkyl and N-aryl-substituted propargyl amines, but this strategy is not amenable for the direct enantioselective synthesis of propargyl amide. We have developed a new strategy and report here a Rh-catalyzed asymmetric hydroalkynylation of enamides. Alkynylations occur regioselectively at the alpha position of an enamide to produce chiral propargyl amides. High yield and enantioselectivity were observed. Previous alkynylation methods to prepare chiral propargyl amine involve the nucleophilic addition to an electron-deficient imine. In contrast, our current approach proceeds through regioselective hydroalkynylation of an electron-rich alkene. Kinetic studies indicated that migratory insertion of the enamide to the rhodium hydride is turnover limiting. Computational studies revealed the origin of regio- and enantioselectivities. This novel strategy provides an efficient method to access chiral propargyl amides directly from terminal alkynes. PMID- 29232517 TI - Formation of C9H2 and C10H2 from Reactions C3H + C6H2 and C4H + C6H2. AB - The reactions of C3H and C4H radicals with C6H2 were investigated for the first time. Reactants C3H, C4H, and C6H2 were synthesized in two beams of C2H2 diluted with helium by pulsed high-voltage discharge. We measured translational-energy distributions, angular distributions, and photoionization-efficiency spectra of C9H2 and C10H2 produced from the title reactions in a crossed molecular-beam apparatus using synchrotron vacuum-ultraviolet photoionization. The C3H (C4H) + C6H2 reaction releases 42% (33%) of available energy into the translational degrees of freedom of product C9H2 (C10H2) + H and scatters products into a nearly isotropic angular distribution. The photoionization-efficiency spectrum of C9H2 (C10H2) is in good agreement with that of C9H2 (C10H2) produced from the C7H (C8H) + C2H2 reaction. The ionization threshold, after deconvolution, was determined as 8.0 +/- 0.1 eV for C9H2 and 8.8 +/- 0.1 eV for C10H2. The combination of measurements of product translational-energy release and photoionization-efficiency spectra indicates productions of 3HC9H/c-1HC3(C)C5H/c 1HC7(C)CH + H and 1HC10H + H in the two title reactions, which are supported also by quantum-chemical calculations. Ratios branching to the three isomers of C9H2 remain unknown. This work demonstrates that long carbon-chain molecules (e.g., C9H2 and C10H2) can be synthesized from reactions of CmH (e.g., m = 3 and 4) radicals with polyynes (e.g., HC6H) and gives some valuable implications to planetary, interstellar, and combustion chemistry. PMID- 29232518 TI - Theoretical Study on the Photoinduced Electron Transfer Mechanisms of Different Peroxynitrite Probes. AB - The development of probes for rapid and selective detection of peroxynitrite in vivo is of great importance in biological science. We investigate different photoinduced electron transfer (PIET) processes of two generations of peroxynitrite probes. Each has fluorescein and phenol moieties; one is conjugated by an ether linkage while the other is conjugated via an amine linkage. Using theoretical calculations, we demonstrated that the PIET in the probe with an ether linkage occurs from the benzoic acid to the xanthene moiety. In contrast, the PIET in the probe with an amine linkage occurs from the phenol moiety to the fluorescein. This suggests that better sensitivity can be accomplished in probes with an amine linkage than with an ether linkage. Following this model, we designed two novel peroxynitrite probes and simulated their detection capabilities in the near-infrared region. PMID- 29232519 TI - Using Density Based Indexes and Wave Function Methods for the Description of Excited States: Excited State Proton Transfer Reactions as a Test Case. AB - To provide tools to interpret photochemical reactions, in this paper we demonstrate how a recently developed density-based index (DCT), up to now used in conjunction with time dependent density functional theory methods, can be extended to multiconfigurational methods. This index can guide chemists in the interpretation of photochemical reactions providing a measure of the spatial extent of a photoinduced charge transfer and, more generally, of charge transfer phenomena. This qualitative and quantitative description can be particularly relevant in the case of multiconfigurational calculations providing a simple tool for the interpretation of their complex outputs. To prove the potentiality of this approach we have considered a simple intramolecular excited state proton transfer reaction as study case and applied both wave function (CASSCF-CASPT2) and density-based methods in conjunction with a DCT analysis. Our results confirm that, also in the case of multiconfigurational methods, the DCT provides very useful information about the structural reorganization of a molecule at the excited state. PMID- 29232520 TI - Controlling the Dynamic Instability of Capped Metal Nanoparticles on Metallic Surfaces. AB - Small metal nanoparticles (NPs) with core-sizes ranging from 1 to 3 nm constitute a bridge between molecules and colloids with unique electronic, catalytic, and other properties. Many applications entail immobilization onto solid supports, but while NP behavior in solution is well studied, the effect of the interaction between NPs and the substrate surface is understood less. Here, we follow the structural evolution of thiolated monolayer-protected AuNPs on Au(111) substrates at the single-particle level in real-time using high-resolution in situ scanning tunneling microscopy. We show how the reactivity of the substrate affects the stability of the immobilized NPs and how their structural identity can be preserved. Entropically driven redistribution of the NP's protective capping layer is an important element in the disintegration process and at the same time rather generic. Our findings may thus have wider implications on the design and optimization of functional surfaces involving NPs, made of materials other than Au. PMID- 29232521 TI - Immunoglobulin Fc-Fused Peptide without C-Terminal Arg or Lys Residue Augments Neuropilin-1-Dependent Tumor Vascular Permeability. AB - Neuropilin-1 (NRP1), which functions as a coreceptor for vascular endothelial growth factor (VEGF) and is implicated in vascular permeability and tumorigenesis, has been targeted by peptides that specifically bind to the VEGF binding region on NRP1. Like natural VEGF ligands, all known peptides with NRP1 binding activity bind only through a carboxy (C)-terminal R/K-x-x-R/K sequence motif (x stands for any amino acids); this strict requirement is called the C-end rule (CendR). Here, we report immunoglobulin Fc-fused NRP1-specific peptides deviating from CendR. We screened a yeast surface-displayed Fc-fused non-CendR peptide library against NRP1 and isolated Fc-V12, wherein V12 peptide comprising 12 amino acids has a PPRV sequence at its C-terminal end. Although Fc-V12 lacked the CendR motif, it showed selective binding to the VEGF-binding region of NRP1 and triggered cellular internalization of NRP1, which resulted in enhanced extravasation into tumor tissues and tumor tissue penetration of the Fc-fused peptide along with the coinjected chemical drug in tumor-bearing mice. Through a saturation mutagenesis study, we identified that the Val residue at the C terminus of Fc-V12 is crucial for NRP1 binding. We further improved NRP1 affinity of Fc-V12 (KD = ~761 nM) through directed evolution of the upstream sequence of PPRV to obtain Fc-V12-33 (KD = ~17.4 nM), which exhibited enhanced NRP1-mediated vascular permeability as compared with Fc-V12. Our results provide functional Fc fused non-CendR peptides, which bind to the VEGF-binding region of NRP1 and enhance vascular permeability, expanding the sequence space of NRP1-targeting peptides. PMID- 29232522 TI - Molecular analysis of anthocyanin-related genes in ornamental cabbage. AB - Ornamental cabbage (Brassica oleracea var. acephala) is a winter-grown and important decorative plant of the family Brassicaceae, which displays an exceptional coloration in the central leaves of the rosette. Anthocyanins are the key determinant of the red, purple, and blue colors of vegetative and reproductive parts of many plant species including ornamental cabbage. Total anthocyanin content was measured spectrophotometrically, and the highest anthocyanin content was detected in the red followed by light-red and white ornamental cabbage lines. Anthocyanin biosynthesis is controlled by members of three different transcription factor (TF) families, such as MYB, basic helix-loop helix (bHLH), and WD40 repeats (WDR), which function as a MBW complex. We identified three MYB, six bHLH, and one WDR TFs that regulate anthocyanin biosynthesis in ornamental cabbage. The expression of the regulatory and biosynthetic genes for anthocyanin synthesis was determined by qPCR. The tested structural genes of the anthocyanin pathway were shown to be up-regulated in the red followed by light-red ornamental cabbage lines; however, the expression levels of the late biosynthetic genes were barely detected in the white ornamental cabbage lines. Among the regulatory genes, BoPAP2 (MYB), BoTT8, BoEGL3.1, and BoMYC1.2 (bHLH), and BoTTG1 (WDR) were identified as candidates for the regulation of anthocyanin biosynthesis. This work could be useful for the breeding of novel colorful ornamental cabbage cultivars. PMID- 29232523 TI - Exercise training differentially alters axial and appendicular marrow cellularity in old mice. AB - Aging gradually renders bone marrow hematopoietically inactive. Endurance exercise reverses this phenotype in young mice. Here, we determine the effects in aged mice. Twenty-two month old mice (n = 6) underwent a progressive exercise training protocol. In appendicular bones, marrow cellularity increased by 51% (p < 0.05) and marrow CFU, CFU-GM, and CAFC increased by 12%, 71%, and 86%, respectively (p < 0.05). Vertebral cellularity remained unchanged. The mechanical forces associated with treadmill exercise training may be responsible for these observations. PMID- 29232524 TI - Growing the IBCLC Workforce: A Florida Needs Assessment. AB - BACKGROUND: Florida has fewer International Board Certified Lactation Consultants (IBCLCs) per 1,000 live births than the national average. An important strategy to support breastfeeding entails creating opportunities to prepare and train IBCLCs from underrepresented groups. However, it can be difficult for individuals to access lactation education and gain clinical experience necessary to become an IBCLC. Research aim: The Building a Better Breastfeeding Network project was a needs assessment designed to assess the interest in an IBCLC training program in Florida and perceived barriers and facilitators to completing such a program. METHODS: An online survey was distributed via email to non-IBCLC students and maternal and child healthcare workers in Florida. Microsoft Excel was used to complete descriptive analyses. RESULTS: Surveys were initiated by 1,939 eligible individuals from diverse racial and ethnic backgrounds across the state, 86% of whom responded that they would be possibly to very interested in an IBCLC training program. For those interested, cost was perceived as a potential barrier to enrolling in a program, but flexible course schedules and scholarship or financial aid availability would further attract participants. More than half were interested in working with underserved populations or in low-resource settings, but Black and Hispanic participants were significantly more likely to express interest in working in those settings. CONCLUSION: Due to the high level of interest in an IBCLC training program in Florida, a formal lactation training program may be successful in attracting diverse students, particularly if funding and program flexibility needs are met. PMID- 29232525 TI - A Modified Ficoll-Paque Gradient Method for Isolating Mononuclear Cells from the Peripheral and Umbilical Cord Blood of Humans for Biobanks and Clinical Laboratories. AB - Although the Ficoll-Paque method is classically used to isolate peripheral blood mononuclear cells (PBMCs), modifications in this method are required for a more rapid and economic output for biobanks and clinical laboratories, particularly in developing countries. In this study, we addressed this issue by modifying the Ficoll-Paque method for the isolation of PBMCs or mononuclear cells from the peripheral and the umbilical cord blood of healthy and diseased (infected, anemic, and chronic obstructive pulmonary disease) adult individuals. In the modified method, we initiated the cell isolation process from the buffy coat layer, which appears in the interface between the plasma and sediments after centrifugation, instead of using the whole blood as described in the classic method. Although the PBMC yield by the modified method was about 12% less than in the classic method, the number of PBMCs isolated by the modified method was more than one million, which is enough for different research/diagnostic purposes, such as multi-omics detection. Assessment of cell viability and purity by hematology analyzer and trypan blue showed no significant difference between the viability and purity of the PBMCs isolated by these two methods in almost all groups, except samples from the infected and cord blood groups, where lower PBMC purity with higher granulocyte contamination were observed. In addition, at delayed processing time points, all parameters for the two methods were decreased in a time-dependent manner, especially at 8, 12, or 24 hours after the sample collection. In summary, the performance of PBMC isolation by the classic and modified methods mainly relies on the PBMC ratio in original samples. The modified method could be preferred for PBMC isolation because of its time and cost savings, especially for the biobanks and clinical laboratories in developing countries. PMID- 29232526 TI - Prevention of Childhood Obesity in Child Health Services: Follow-Up of the PRIMROSE Trial. AB - BACKGROUND: Childhood obesity is an urgent public health concern, and there's a need for long-term, high-quality, primary prevention trials targeting parents of young children. The aim of the current study was to evaluate the long-term effect of a parental support program based on motivational interviewing (MI). METHODS: A cluster randomized controlled trial was carried out in eight Swedish counties. Participating families (N = 1355) were enrolled when the child was 9 months old, and participated in nine sessions during ~39 months. The aim was to pomote healthy food and physical activity (PA) habits using MI and principles from cognitive behavioral therapy. Nurses in Swedish child health services delivered the intervention, and the control group received usual healthcare. The current study was a 1-year follow-up of effects on children's weight-related measures. Regression analyses were conducted using generalized estimating equations, including analyses to investigate potential parental moderators of the effect. RESULTS: There were no statistically significant intervention effects at follow up [BMI difference = -0.13, p = 0.29, overweight relative risk (RR) = 0.96, p = 0.78, obesity RR = 0.57, p = 0.20]. Maternal waist circumference and unhealthy eating and paternal PA moderated the effect, but effects were small and failed to reach statistical significance after correction for multiple comparisons. CONCLUSIONS: A parent-focused primary prevention intervention based on MI delivered within child health services did not result in effects at 1-year follow up. The results were in line with those obtained at post-assessment and indicated no late onset of effect. Further studies exploring individual and contextual factors influencing the outcome are called for. PMID- 29232527 TI - Seroprevalence of Francisella tularensis in Austrian Hunting Dogs. AB - Based on initial reports of infection with Francisella tularensis in dogs in northern Europe, a serological study in hunting dogs was conducted in Austria. Five (6.25%) tested positive. The results highlight the potential for disease transmission to dogs and raise the question of whether dogs could be a source of infection for humans. PMID- 29232528 TI - UPMC's Population Health Management Strategy: A Road Map to High-Value Health Care. PMID- 29232529 TI - Arantius Ligament Suspension: A Novel Technique for Retraction of the Left Lateral Lobe Liver During Laparoscopic Isolated Caudate Lobectomy. AB - BACKGROUND: Laparoscopic isolated caudate lobectomy remains a challenging procedure because of its deep location and proximity to the important vessels. We present a novel technique, Arantius ligament suspension, which could improve operative field exposure in laparoscopic isolated caudate lobectomy through retraction of the left lateral lobe liver. MATERIALS AND METHODS: The Arantius ligament suspension technique was performed in 6 selected patients during laparoscopic isolated caudate lobectomy in our center: 2 with symptomatic hepatic cavernous hemangioma and 4 with hepatocellular carcinoma (HCC). The Arantius ligament suspension technique was performed using a 2-0 polypropylene suture (Prolen2-0(r); Ethicon, Somerville, NJ), which was secured to the Arantius ligament with surgical clips at its halfway point and the left lateral lobe of liver would be retracted toward the abdominal wall when the suture was tightened. Perioperative data of these patients and follow-up data of HCC patients were retrospectively reviewed. RESULTS: All 6 procedures were completed without conversion to open surgery or requiring additional ports. The mean tumor size was 5.4 cm (2.2-7.8 cm), the mean blood loss was 260 mL (50-440 mL), and no patients required blood transfusion during the operation. The mean time required for this technique was 2 minutes 5 seconds (1 minutes 36 seconds-2 minutes 44 seconds) and the mean duration of entire surgery was 249 minutes (173-300 minutes). The mean postoperative hospital stay was 7 days (5-9 days) and no postoperative complication related to the suspension procedure occurred. CONCLUSIONS: Our outcomes demonstrated the Arantius ligament suspension technique is a feasible and ideal method during laparoscopic isolated caudate lobectomy for providing a rapid and safe left lateral lobe retraction. PMID- 29232530 TI - Pediatric Endoscopic Pilonidal Sinus Treatment, a Revolutionary Technique to Adopt in Children with Pilonidal Sinus Fistulas: Our Preliminary Experience. AB - AIM: This study aimed to report our preliminary experience with pediatric endoscopic pilonidal sinus treatment (PEPSiT). PATIENTS AND METHODS: We retrospectively reviewed the reports of 15 patients, 6 girls and 9 boys, with an average age of 16 years (range 13-18) with noninfected pilonidal sinus disease who underwent PEPSiT in our institution over an 18-month period. Four cases were redo-procedures, for recurrence of disease after open excision repair. Surgical outcomes of sinus healing, recurrence of disease, postoperative pain, hospital stay, analgesic requirements, and patient satisfaction levels were evaluated and a comparison analysis with classic open repair was performed. RESULTS: All procedures were performed under subarachnoid spinal anesthesia. We always adopted a fistuloscope, an endoscopic forceps, and a monopolar electrode to remove the hairs and to heal the fistula. The average length of surgery was 28.5 minutes (range 26-41). No intraoperative or postoperative complications were reported. The average pain score evaluated using Visual Analogue Scale (VAS) pain scale during the first 48 postoperative hours was 3.2 (range 2-5). The average analgesic requirement was 22 hours (range 16-28). The average hospital stay length was 28 hours (range 22-48). They changed dressing daily, by applying a topical solution of eosin 2% and a silver sulfadiazine spray. At 1 month postoperatively, the external openings were closed in all patients and no recurrence was recorded at a mean follow-up of 6 month. PEPSiT was associated with a significantly shorter, painless, and better outcome compared to open technique. CONCLUSION: On the basis of our preliminary experience, we believe that PEPSiT is a promising technique for surgical treatment of pilonidal sinus in children. It is technically easy and quick to perform, with a short and painless hospital stay, without recurrences in our series. It allows operated patients an early return to full daily activities without restrictions that happen for the classic treatment. PMID- 29232531 TI - Key Elements of a Population-Based Approach to Improving Birth Outcomes. PMID- 29232532 TI - Reconsideration of Laparoscopic Kasai Operation for Biliary Atresia. AB - INTRODUCTION: Minimal invasive surgery for all kinds of surgical diseases had been practiced for years. The laparoscopic Kasai operation is one of the most challenging procedures and remains controversial for treating biliary atresia (BA). PURPOSE: This work presented the initial experience of our Institute and compared the outcomes of open and laparoscopic Kasai operations for BA. MATERIALS AND METHODS: Patients 18 years old and younger, and were operated in our Institute for BA from January 2011 to August 2017, were included in this study. General and operative data and outcomes from open and laparoscopic groups were retrospectively collected and analyzed. RESULTS: A total of 23 patients (13 for conventional open operation and 10 for the laparoscopic procedure) received Kasai portoenterostomy. The mean operative age and body weight in the open versus laparoscopic groups were 57.15 +/- 20.14 days old and 4.03 +/- 0.69 kg versus 57.70 +/- 43.06 days old and 4.49 +/- 1.48 kg, respectively, and no statistical difference was observed. The mean operative times were 209.62 +/- 60.40 and 293.50 +/- 39.09 minutes in the open and laparoscopic groups, respectively. The mean follow-up durations were 54.62 +/- 22.00 and 23.30 +/- 11.87 months for the open and laparoscopic patients, correspondingly. No statistically significant differences were observed for hospital stay and outcomes (including early jaundice clearance rate, episodes of cholangitis, and 2-year native liver survival rate) between the open and the laparoscopic Kasai operations. CONCLUSION: Experienced pediatric laparoscopic surgeons may reconsider the laparoscopic Kasai operation for application to BA treatment. PMID- 29232533 TI - Laparoscopic Abdominal Transanal Proctocolectomy with Coloanal Anastomosis Is a Good Surgical Option in Selective Patients with Low-Lying Rectal Cancer: A Retrospective Analysis Based on a Single Surgeon's Experience. AB - PURPOSE: We intended to identify the oncological outcome for rectal cancer over the past 20 years and whether or not sphincter-preserving surgery is an appropriate approach for low-lying rectal cancer. MATERIALS AND METHODS: The oncological outcomes from a total of 418 patients who electively underwent rectal cancer surgery for a lesion located within 8 cm of the anal verge by a single colorectal surgeon were reviewed retrospectively. RESULTS: Of 418 patients, 175 patients underwent low anterior resection (LAR), 172 laparoscopic abdominal transanal proctocolectomy with coloanal anastomosis (LATA), and 71 abdominoperineal resection (APR). The factors related to the disease-free survival (DFS) were neoadjuvant chemoradiation (P = .016), pathologic stage (P < .001), circumferential margin involvement (P < .001), and initial (P = .016) and postoperative serum carcinoembryonic antigen level (P < .001). The factors related to the overall survival (OS) were similar with those related to DFS. Compared with DFS, OS, and local recurrence among three surgical techniques, APR was significantly poorer in DFS (P < .001), OS (P < .001), and local recurrence (P = .001), than was LAR or LATA. DISCUSSION: The LATA procedure is a technically feasible and oncologically safe surgical option for low-lying rectal cancer. We suggest that LATA may be a good surgical option in selective low-lying rectal cancer patients. PMID- 29232534 TI - Detection of Dengue Virus in Bat Flies (Diptera: Streblidae) of Common Vampire Bats, Desmodus rotundus, in Progreso, Hidalgo, Mexico. AB - Blood-feeding arthropods play a major role in the transmission of several flaviviruses, which represent an important problem for human health. Currently, dengue is one of the most important arboviral emerging diseases worldwide. Furthermore, some previous studies have reported the presence of viral nucleic acids and antibodies against dengue virus (DENV) in wild animals. Our knowledge of the role played by wildlife reservoirs in the sylvatic transmission and maintenance of DENV remains limited. Our objective was to screen blood-feeding ectoparasites (bat flies) and their common vampire bat (Desmodus rotundus) hosts, for flaviviruses in Hidalgo, Mexico. We detected Flavivirus sequences in 38 pools of ectoparasites (Diptera: Streblidae, Strebla wiedemanni and Trichobius parasiticus) and 8 tissue samples of D. rotundus by RT-PCR and semi-nested PCR using FlaviPF1S, FlaviPR2bis, and FlaviPF3S primers specific for NS5, a gene highly conserved among flaviviruses. Phylogenetic inference analysis performed using the maximum likelihood algorithm implemented in PhyML showed that six sequences clustered with DENV (bootstrap value = 53.5%). Although this study supports other reports of DENV detection in bats and arthropods other than Aedes mosquitoes, the role of these ectoparasitic flies and of hematophagous bats in the epidemiology of DENV still warrants further investigation. PMID- 29232536 TI - Enhancing the Effectiveness of Work Groups and Teams: A Reflection. AB - Teamwork has been at the core of human accomplishment across the millennia, and it was a focus of social psychological inquiry on small group behavior for nearly half a century. However, as organizations world-wide reorganized work around teams over the past two decades, the nature of teamwork and factors influencing it became a central focus of research in organizational psychology and management. In this article, I reflect on the impetus, strategy, key features, and scientific contribution of "Enhancing the Effectiveness of Work Groups and Teams," by Kozlowski and Ilgen, a review monograph published in Psychological Science in the Public Interest in 2006. PMID- 29232537 TI - Laparoscopic Versus Conventional Open Surgery in Intersphincteric Resection for Low Rectal Cancer: A Systematic Review and Meta-Analysis. AB - AIM: This meta-analysis aims at comparing laparoscopic intersphincteric resection (LISR) with conventional open ISR (OISR) for low rectal cancer (LRC) in terms of intraoperative, postoperative, pathological, and survival outcomes. MATERIALS AND METHODS: A systematic literature search with no limits was performed in PubMed and Ovid. The last search was performed on May 27, 2017. The outcomes of interests included intraoperative outcomes: operative time and blood loss; postoperative outcomes: hospital day, postoperative hospital day, time to first flatus, time to normal diet, ileus, intra-abdominal abscess, anastomotic leakage, anastomotic stricture, wound infection, pneumonia, urinary complication, morbidity, and mortality; pathological outcomes: lymph node harvested, R0 resection rate, distance of proximal resection margin, distal resection margin and circumferential resection margin (CRM), and positive CRM; survival outcomes: 3-year overall survival (OS), 3-year disease-free survival (DFS), 5-year OS, and 5-year DFS. RESULTS: Six articles and two abstracts published between 2010 and 2016 were included in our meta-analysis. When compared with OISR, LISR was associated with comparable operative time, less blood loss, shorter length of postoperative hospital day, quick time to first flatus, less incidence of morbidity, and pneumonia. Besides, the two groups were comparable in pathological and survival outcomes. CONCLUSIONS: Our results demonstrated that LISR had comparable operative time, less blood loss and postoperative morbidity, and comparable pathological and survival outcomes when compared with OISR. So LISR was safe and feasible in LRC surgery. Besides, more randomized clinical trials are needed to investigate the deeper effect of LISR in the future. PMID- 29232538 TI - When to Choose Transplant in Follicular Lymphoma: Navigating a Complex Landscape. PMID- 29232535 TI - Why Interventions to Influence Adolescent Behavior Often Fail but Could Succeed. AB - We provide a developmental perspective on two related issues: (a) why traditional preventative school-based interventions work reasonably well for children but less so for middle adolescents and (b) why some alternative approaches to interventions show promise for middle adolescents. We propose the hypothesis that traditional interventions fail when they do not align with adolescents' enhanced desire to feel respected and be accorded status; however, interventions that do align with this desire can motivate internalized, positive behavior change. We review examples of promising interventions that (a) directly harness the desire for status and respect, (b) provide adolescents with more respectful treatment from adults, or (c) lessen the negative influence of threats to status and respect. These examples are in the domains of unhealthy snacking, middle school discipline, and high school aggression. Discussion centers on implications for basic developmental science and for improvements to youth policy and practice. PMID- 29232539 TI - How to Identify and Manage Cognitive Dysfunction After Breast Cancer Treatment. AB - Attention and memory dysfunction is a common complaint among patients with breast cancer that can be reported during and up to several years after treatment. It can negatively affect patients' quality of life and their ability to work. This phenomenon has mainly been studied in patients with breast cancer who are treated with adjuvant chemotherapy. Women describe concentration problems and difficulties with word finding, multitasking, or remembering new information, as well as more effort and time needed to accomplish these tasks. Such cognitive dysfunction is subtle or moderate and occurs in 15% to 25% of patients. Older patients seem more likely to experience cognitive decline with chemotherapy than do young women with breast cancer. Patients who report that cognitive dysfunction has affected their daily lives for 6 to 12 months after the end of chemotherapy or during hormone therapy may need referral to a neuropsychologist. During the cognitive assessment, the etiology of their cognitive complaints is sought and neuropsychological tests are administered to assess objective cognitive functioning. Psychological factors-fatigue and pain-should be assessed systematically with cognitive complaints to identify precisely the cause of the problems. A nonpharmacologic approach-mainly cognitive rehabilitation-seems to be the most promising for the management of these difficulties, but these preliminary results require confirmation. In the future, early detection of cognitive impairment and cognitive rehabilitation should be included in the portfolio of oncology supportive care to facilitate the return to work of young women and to avoid potential repercussions on adherence to oral treatments and on autonomy in older patients. PMID- 29232540 TI - Early Relapse in Follicular Lymphoma: High Risks and High Stakes. PMID- 29232541 TI - Chemobrain: An Opportunity in Cancer Survivorship to Enhance Patient Wellness. PMID- 29232543 TI - Survivors of Cancer Need Support Managing Cancer-Related Cognitive Impairment. PMID- 29232542 TI - Allogeneic Transplantation for Follicular Lymphoma: Does One Size Fit All? AB - Follicular lymphoma (FL) exhibits striking biologic and clinical heterogeneity. Patients with newly diagnosed asymptomatic or low-bulk disease may be observed or managed with immunotherapies alone. Chemoimmunotherapy is considered a standard treatment for patients with advanced, symptomatic disease. In patients with FL who achieve at least a partial remission after first-line chemoimmunotherapy, autologous (auto-) hematopoietic cell transplantation (HCT) consolidation is not recommended; however, most patients with FL experience disease relapse after frontline therapies, with the experience of therapy failure within 2 years of first-line treatments predicting poor survival. Despite remarkable efficacy, even in patients who experience failure with other therapies, auto-HCT and allogeneic (allo-) HCT remain underutilized in relapsed/refractory FL, even among healthy and younger patients. Early use of auto-HCT consolidation should be considered a standard therapy option for high-risk patients who experience early failure of chemoimmunotherapy (< 2 years). For patients with FL who experience failure of frontline therapies late (> 2 years), deferring auto-HCT until later in the disease course is reasonable. Allo-HCT is best reserved for medically fit individuals with heavily pretreated disease, persistent marrow involvement, refractory, but low-bulk, disease, and in those who experience a failure to mobilize stem cells for auto-HCT. Allo-HCT is also a reasonable option for patients with FL who experience failure with a prior autograft; lower-intensity conditioning regimens and HLA-matched related donors are preferred in that setting. Future research should focus on the eradication of minimal residual disease before HCT and the prevention of disease relapse after HCT by integrating novel targeted agents into pre-HCT and post-HCT regimens. PMID- 29232545 TI - Influence of the social determinants of health on access to healthcare services among refugees in Australia. AB - Refugees in Australia are not fully utilising the healthcare system for several reasons and this may be affecting their overall health outcomes. This qualitative systematic review examined the influence of the social determinants of health on refugees' access to healthcare services in Australia. Electronic databases were searched using terms relating to refugees, social determinants, healthcare services, barriers, enablers and Australia. Only peer-reviewed studies published in English since 2006, which focused on refugees and specifically discussed social determinants influencing refugees' access to healthcare services in Australia, were included. The studies were critically analysed using standard Critical Appraisal Skills Programme Tools. Eight studies were included in the review. Findings reveal multiple factors influence refugees' access to healthcare in Australia, and these can be conceptualised within a social-ecological model of health; that is, they operate across individual, interpersonal, environmental, organisational and policy levels. The novel finding of this review was the re occurrence of similar influences across multiple healthcare service settings in Australia. The prevalence and re-occurring nature of the social determinants of health suggests that refugees are experiencing multilayered barriers to accessing Australian healthcare. All levels of a social-ecological model must be addressed in any attempt to break down these barriers. PMID- 29232546 TI - Breaking Down Barriers to Chemoresistance: Role of Chemotherapy-Induced Osteoblastic Jagged1. AB - Bone metastases are incurable. The bone microenvironment has always been a suspect for this clinical enigma, but the exact mechanisms have been unclear. In this issue of Cancer Cell, Zheng and colleagues provide evidence that chemotherapy itself induces chemoresistance of bone metastases, mediated by osteoblast Jagged1-induced tumor Notch signaling. PMID- 29232547 TI - AML Therapy: Wake Up the Guardian and Cut Loose the Executioners. AB - In this issue of Cancer Cell, Pan et al. show that a combination therapy designed to reactivate the p53 tumor suppressor while antagonizing the anti-apoptotic function of Bcl-2 is highly active in preclinical models of refractory acute myeloid leukemia (AML). The results may move the needle in this hard-to-treat malignancy. PMID- 29232548 TI - Genomic Biomarkers Predicting Response to Selective CDK4/6 Inhibition: Progress in an Elusive Search. AB - In this issue of Cancer Cell, Gong et al. have analyzed the sensitivity of 560 cell lines to the selective CDK4/6 inhibitor abemaciclib and have defined cancers with specific genomic "D-cyclin activating features (DCAF)" as particularly vulnerable. These findings will facilitate patient selection as development of this drug class continues. PMID- 29232549 TI - Stressing Out PanIN: NRF2 Pushes over the Edge. AB - The mechanisms by which chronic stress promote the development of pancreatic ductal adenocarcinoma (PDAC) are poorly defined. In this issue of Cancer Cell, Todoric et al. discover a role for impaired autophagy in the development of PDAC through p62-mediated activation of NRF2. PMID- 29232550 TI - Glut3 Addiction: A Druggable Vulnerability in Glioblastoma. AB - The link between GBM molecular subtype and response to treatment remains undefined. In this issue of Cancer Cell, Cosset and colleagues define a subpopulation of patients within the proneural/classical subtype sensitive to integrin blockade because of a Glut3 addiction. These findings reveal context dependent druggable vulnerability in a subpopulation of GBM. PMID- 29232551 TI - Inflammation, ROS, and Mutagenesis. AB - It has long been hypothesized that reactive oxygen species (ROS) are responsible for the association between chronic inflammatory diseases and increased tumor incidence. In this issue of Cancer Cell, Canli et al. now demonstrate that amplified ROS production specifically by myeloid cells is sufficient to promote intestinal mutagenesis. PMID- 29232552 TI - Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy. AB - Bone metastasis is a major health threat to breast cancer patients. Tumor-derived Jagged1 represents a central node in mediating tumor-stromal interactions that promote osteolytic bone metastasis. Here, we report the development of a highly effective fully human monoclonal antibody against Jagged1 (clone 15D11). In addition to its inhibitory effect on bone metastasis of Jagged1-expressing tumor cells, 15D11 dramatically sensitizes bone metastasis to chemotherapy, which induces Jagged1 expression in osteoblasts to provide a survival niche for cancer cells. We further confirm the bone metastasis-promoting function of osteoblast derived Jagged1 using osteoblast-specific Jagged1 transgenic mouse model. These findings establish 15D11 as a potential therapeutic agent for the prevention or treatment of bone metastasis. PMID- 29232553 TI - Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy. AB - Evasion of apoptosis is a hallmark of cancer. Bcl-2 and p53 represent two important nodes in apoptosis signaling pathways. We find that concomitant p53 activation and Bcl-2 inhibition overcome apoptosis resistance and markedly prolong survival in three mouse models of resistant acute myeloid leukemia (AML). Mechanistically, p53 activation negatively regulates the Ras/Raf/MEK/ERK pathway and activates GSK3 to modulate Mcl-1 phosphorylation and promote its degradation, thus overcoming AML resistance to Bcl-2 inhibition. Moreover, Bcl-2 inhibition reciprocally overcomes apoptosis resistance to p53 activation by switching cellular response from G1 arrest to apoptosis. The efficacy, together with the mechanistic findings, reveals the potential of simultaneously targeting these two apoptosis regulators and provides a rational basis for clinical testing of this therapeutic approach. PMID- 29232554 TI - Genomic Aberrations that Activate D-type Cyclins Are Associated with Enhanced Sensitivity to the CDK4 and CDK6 Inhibitor Abemaciclib. AB - Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer. The results suggest multiple additional classes of cancer that may benefit from CDK4/6-inhibiting drugs such as abemaciclib. PMID- 29232555 TI - mTORC2 Promotes Tumorigenesis via Lipid Synthesis. AB - Dysregulated mammalian target of rapamycin (mTOR) promotes cancer, but underlying mechanisms are poorly understood. We describe an mTOR-driven mouse model that displays hepatosteatosis progressing to hepatocellular carcinoma (HCC). Longitudinal proteomic, lipidomics, and metabolomic analyses revealed that hepatic mTORC2 promotes de novo fatty acid and lipid synthesis, leading to steatosis and tumor development. In particular, mTORC2 stimulated sphingolipid (glucosylceramide) and glycerophospholipid (cardiolipin) synthesis. Inhibition of fatty acid or sphingolipid synthesis prevented tumor development, indicating a causal effect in tumorigenesis. Increased levels of cardiolipin were associated with tubular mitochondria and enhanced oxidative phosphorylation. Furthermore, increased lipogenesis correlated with elevated mTORC2 activity and HCC in human patients. Thus, mTORC2 promotes cancer via formation of lipids essential for growth and energy production. PMID- 29232557 TI - Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis. AB - Increased oxidative stress has been suggested to initiate and promote tumorigenesis by inducing DNA damage and to suppress tumor development by triggering apoptosis and senescence. The contribution of individual cell types in the tumor microenvironment to these contrasting effects remains poorly understood. We provide evidence that during intestinal tumorigenesis, myeloid cell-derived H2O2 triggers genome-wide DNA mutations in intestinal epithelial cells to stimulate invasive growth. Moreover, increased reactive oxygen species (ROS) production in myeloid cells initiates tumor growth in various organs also in the absence of a carcinogen challenge in a paracrine manner. Our data identify an intricate crosstalk between myeloid cell-derived ROS molecules, oxidative DNA damage, and tumor necrosis factor alpha-mediated signaling to orchestrate a tumor promoting microenvironment causing invasive cancer. PMID- 29232558 TI - High-throughput Phenotyping of Lung Cancer Somatic Mutations. PMID- 29232556 TI - MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma. AB - ATG4B stimulates autophagy by promoting autophagosome formation through reversible modification of ATG8. We identify ATG4B as a substrate of mammalian sterile20-like kinase (STK) 26/MST4. MST4 phosphorylates ATG4B at serine residue 383, which stimulates ATG4B activity and increases autophagic flux. Inhibition of MST4 or ATG4B activities using genetic approaches or an inhibitor of ATG4B suppresses autophagy and the tumorigenicity of glioblastoma (GBM) cells. Furthermore, radiation induces MST4 expression, ATG4B phosphorylation, and autophagy. Inhibiting ATG4B in combination with radiotherapy in treating mice with intracranial GBM xenograft markedly slows tumor growth and provides a significant survival benefit. Our work describes an MST4-ATG4B signaling axis that influences GBM autophagy and malignancy, and whose therapeutic targeting enhances the anti-tumor effects of radiotherapy. PMID- 29232559 TI - Cilostazol, a phosphodiesterase 3 inhibitor, activates proteasome-mediated proteolysis and attenuates tauopathy and cognitive decline. AB - Alzheimer's disease and several variants of frontotemporal degeneration including progressive supranuclear palsy and corticobasal degeneration are characterized by the accumulation of abnormal tau protein into aggregates. Most proteins, including tau, are degraded via the ubiquitin proteasome system, but when abnormal tau accumulates, the function of 26S proteasomes is downregulated. The negative effect of tau aggregates on the function of the proteasome can have deleterious consequences on protein homeostasis and disease progression. Developing therapies aimed at clearing abnormal tau are thus of considerable interest. In the present study, we investigated the effect of cilostazol, an FDA approved selective phosphodiesterase 3 inhibitor, on a mouse model of tauopathy (line rTg4510). Administration of cilostazol for 30 days enhanced proteasome function via the cyclic adenosine 3',5'-monophosphate/protein kinase A pathway and attenuated tauopathy and cognitive decline in rTg4510 mice. These results suggest that cilostazol, or other FDA-approved drugs acting via the same pathway, has the potential to be repurposed for the treatment of patients with early-stage tauopathy. PMID- 29232560 TI - The Effect of Tranexamic Acid and Gender on Intraoperative Bleeding in Orthognathic Surgery-A Randomized Controlled Trial. AB - PURPOSE: The purpose of this randomized trial was to measure the effect of intravenously administered tranexamic acid (TXA) on intraoperative blood loss (IOB) in patients undergoing bimaxillary orthognathic surgery (OS). MATERIALS AND METHODS: The authors designed and implemented a double-blinded placebo-controlled trial composed of patients eligible for OS at the Hospital of South West Denmark (Esbjerg, Denmark) from August 2014 through September 2016. The primary predictor variable was a single intravenous dose of TXA 1 g administered preoperatively or an equivalent saline placebo. The primary outcome was IOB determined by milliliters of blood in the suction canister and gauzes deducted from the volume of saline used intraoperatively. RESULTS: The study population consisted of 96 patients. The TXA group (n = 51) and the placebo group (n = 45) showed a median IOB of 275 and 403 mL (P = .005), respectively. A significant effect of TXA was detected in women (median IOB, 153 mL [96 to 233 mL] in TXA group vs 329 mL [185 to 582 mL] in placebo group; P < .001), whereas no significant effect of TXA on IOB was detected in men (median IOB, 367 mL [275 to 472 mL] in TXA group vs 429 mL [275 to 655 mL] in placebo group; P = .23). No correlations were found between IOB and procedure length, procedure type, or hematologic markers (platelets, hemoglobin, and hematocrit). CONCLUSION: In contrast to other studies, this double-blinded randomized controlled trial found a hemostatic effect of TXA in women and none in men who underwent bimaxillary OS. To focus on the specific effect of TXA in men, future studies should include larger male samples. PMID- 29232561 TI - Development of artificial intelligence approach to forecasting oyster norovirus outbreaks along Gulf of Mexico coast. AB - This paper presents an artificial intelligence-based model, called ANN-2Day model, for forecasting, managing and ultimately eliminating the growing risk of oyster norovirus outbreaks. The ANN-2Day model was developed using Artificial Neural Network (ANN) Toolbox in MATLAB Program and 15-years of epidemiological and environmental data for six independent environmental predictors including water temperature, solar radiation, gage height, salinity, wind, and rainfall. It was found that oyster norovirus outbreaks can be forecasted with two-day lead time using the ANN-2Day model and daily data of the six environmental predictors. Forecasting results of the ANN-2Day model indicated that the model was capable of reproducing 19years of historical oyster norovirus outbreaks along the Northern Gulf of Mexico coast with the positive predictive value of 76.82%, the negative predictive value of 100.00%, the sensitivity of 100.00%, the specificity of 99.84%, and the overall accuracy of 99.83%, respectively, demonstrating the efficacy of the ANN-2Day model in predicting the risk of norovirus outbreaks to human health. The 2-day lead time enables public health agencies and oyster harvesters to plan for management interventions and thus makes it possible to achieve a paradigm shift of their daily management and operation from primarily reacting to epidemic incidents of norovirus infection after they have occurred to eliminating (or at least reducing) the risk of costly incidents. PMID- 29232562 TI - TM6SF2: A novel target for plasma lipid regulation. AB - Transmembrane 6 superfamily 2 (TM6SF2), a gene identified at the locus 19p12, has been recognized to regulate plasma lipids. Here, we provide an overview of the roles of TM6SF2 as a novel target for plasma lipid regulation. We first review the association of TM6SF2 variant with plasma lipid traits, cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). Then, we present an overview about the in vivo validation of TM6SF2 as a regulator of plasma lipid levels using mice, with overexpression or knockdown/knockout of TM6SF2. Thereafter, we discuss the mechanisms underlying TM6SF2 regulation of lipid metabolism involving intestinal cholesterol absorption and hepatic cholesterol biosynthesis and transport. In conclusion, increasing evidence suggests that TM6SF2 may be a major regulator of plasma lipid levels and become a therapeutic target in cardiovascular disease. PMID- 29232563 TI - Immunologic burden links periodontitis to acute coronary syndrome. AB - BACKGROUND AND AIMS: Periodontitis, a common polymicrobial inflammatory disease in the tooth supporting tissues, is a risk factor for coronary artery disease. One of the proposed underlying mechanisms is the systemic immune response to periodontal infection. We studied how serum antibodies against seven periodontal pathogens and their subgingival levels associate with each other, periodontitis, and coronary artery disease. METHODS: The Parogene cohort included 505 Finnish patients (mean age 63 y) who underwent coronary angiography, and clinical and radiographic oral examinations. Coronary diagnosis was defined as no significant coronary artery disease (<50% stenosis, n = 152), stable coronary artery disease (>=50% stenosis, n = 184) and acute coronary syndrome (n = 169). Levels of subgingival Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Porphyromonas endodontalis, Prevotella intermedia, Tannerella forsythia, Campylobacter rectus, and Fusobacterium nucleatum were determined by checkerboard DNA-DNA hybridization. Serum antibody (IgA/IgG) levels were analyzed with enzyme linked immunosorbent assay (ELISA). Aggregate IgA/IgG burdens were calculated by summing and standardizing the serum antibody levels. RESULTS: Patients with active periodontitis were characterized by higher levels of subgingival bacteria and corresponding IgA/IgG response. Quartiles 2-4 of serum IgA/IgG burden indicated higher risk for acute coronary syndrome (OR 1.84, 95%CI 1.01-3.35 for IgA; OR 1.87, 95%CI 1.01-3.46 for IgG) independently of established cardiovascular risk factors, body mass index, number of teeth, subgingival bacterial levels and periodontal diagnosis. CONCLUSIONS: Our findings support the hypothesis that the association between periodontitis and cardiovascular diseases is partly mediated by the immunologic response for periodontal pathogens. PMID- 29232564 TI - Neonatal mortality and morbidity in the post-implementation period of a neonatal teaching program in provincial hospitals in Laos. AB - OBJECTIVES: Aim of this study was to analyze neonatal mortality and morbidity in the post-implementation period of a neonatal teaching program to examine a possible impact on neonatal outcomes. STUDY DESIGN: This study is a retrospective data analysis of all neonatal patients treated in five provincial hospitals in Laos after implementation of a neonatal teaching program. METHODS: A simulation based teaching program aims to have positive impact on the theoretical and practical skill of hospital staff in the field of newborn care. A comparison between pre-implementation and post-implementation data of newborns admitted to provincial hospitals in Laos was used to quantify the effect of repetitive teaching on neonatal outcomes. RESULTS: Neonatal mortality and morbidity as well as case fatality rates of infections and asphyxia decreased in the post implementation period. In contrast, neonatal mortality rate as well as case fatality rate of prematurity increased. The total neonatal mortality rate increased in the post-implementation period. CONCLUSIONS: The pre-implementation and post-implementation data enable longitudinal comparisons between hospitals and highlight the differences between hospitals concerning neonatal mortality and morbidity in provincial hospitals in Laos. These data can serve as a basis for an individual adaption of the teaching program to the unique requirements of each single hospital. PMID- 29232565 TI - Parental bonding and adolescents' depressive and anxious symptoms in Pakistan. AB - INTRODUCTION: A quantitative cross sectional study was carried out to investigate the role of parental bonding in relation to depressive and anxious symptoms among secondary school adolescents in Pakistan. The study also aimed to investigate the construct validity of the parental bonding inventory in the cultural context of Pakistan. METHODS: The sample consisted of 1124 adolescents recruited from eight secondary schools in Rawalpindi, Pakistan. Urdu translated versions of Parental Bonding Instrument (Qadir et al., 2005) and Hospital Anxiety and Depression Scales (Mumford et al., 1991) were administered in classroom settings. Confirmatory factor analysis (CFA) and Structural Equation Modeling (SEM) were used to analyze the data. RESULTS: Results from the CFA of the Urdu version of the Parental Bonding Instrument supported a modified version of the three factor model proposed by Kendler (1996) consisting of warmth, protectiveness and authoritarianism. Based on SEM, we found a significant relationship between low parental warmth and depression symptoms among adolescents, whereas maternal protectiveness was a significant predictor for anxiety. Parental authoritarianism was not a significant predictor for depression or anxiety. DISCUSSION: Findings of this study indicate that parental bonding is a central construct within a developmental framework in the cultural context of Pakistan, and is important when considering long-term psychosocial functioning of individuals. It should be explored further in clinical populations of Pakistani adolescents to ascertain significance of these constructs for interventions. PMID- 29232566 TI - Association of total zinc, iron, copper and selenium intakes with depression in the US adults. AB - BACKGROUND: The aim of present study was to examine the associations of total zinc, iron, copper and selenium intakes from diet and supplements with depression. METHODS: Cross-sectional study used data from the National Health and Nutrition Examination Survey (NHANES) 2009-2014 in the present study. Logistic regression models and restricted cubic spline models were applied to examine the associations of total zinc, iron, copper and selenium intakes with depression. RESULTS: A total of 14834 adults aged 18 years or older (7399 men and 7435 women) were included in the present study. Total zinc, iron, copper and selenium intakes were inversely associated with depression in unadjusted model and age- and gender adjusted model. The multivariate adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of depression were 0.68 (0.49-0.94) and 0.46 (0.32-0.67) for the highest versus lowest quartile of copper and selenium intakes, respectively. The inverse associations of depression were statistically significant for the quartile 3 versus lowest quartile of total zinc (OR: 0.70; 95% CI: 0.49-0.99) and iron intake (OR: 0.66 95% CI: 0.50-0.87). Compared to those below the RDA (Recommended Dietary Allowance), participants who met the RDA for zinc (OR: 0.74; 95% CI: 0.56-0.99), copper (OR: 0.68; 95% CI: 0.56-0.82) and selenium (OR: 0.52; 95% CI: 0.39, 0.71) had significantly lower odds of depression. LIMITATIONS: This was a cross-sectional study, limiting causal inferences. Assessment of depression was based on a self- report scale. CONCLUSION: Total zinc, iron, copper and selenium intakes may be inversely associated with depression. PMID- 29232567 TI - Mapping network connectivity among symptoms of social anxiety and comorbid depression in people with social anxiety disorder. AB - BACKGROUND: Social anxiety disorder (SAD) and depressive symptoms often covary. Yet, uncertainty still abounds vis-a-vis the individual symptom-to-symptom associations between these two disorders. Inspired by the network approach to psychopathology that conceptualizes comorbidity as a natural consequence arising from bridge symptoms that can transmit activation from one disorder to the other, we applied network analytic methods to characterize the associations among core symptoms of SAD-i.e. fear and avoidance of social situations-and comorbid depressive symptoms among 174 individuals with DSM-IV-TR criteria for SAD. METHODS: We first explored the general structure of these symptoms by estimating a regularized partial correlation network using the graphical LASSO algorithm. Then, we specifically focused on the symptoms' importance and influence. Of critical interest was the estimation of the unique influence of each symptom from one disorder to all symptoms of the other disorder using a new metric called bridge expected influence. RESULTS: The graphical LASSO revealed several cross associations between SAD and comorbid depression. For each disorder, symptoms exhibiting the strongest cross-association with the other disorder were identified. LIMITATIONS: Given our cross-sectional data, our findings can only suggest hypotheses about cause-effect relationships. CONCLUSIONS: This study adds to a small but growing empirical literature revealing that the co-occurrence between two disorders is best portrayed as sets of symptom-to-symptom connections. As some individual symptoms show differential association in the co occurrence between SAD and depression, those symptoms may be valuable targets for future research and treatment. PMID- 29232569 TI - Source analysis of epileptiform discharges in absence epilepsy using Magnetoencephalography (MEG). AB - PURPOSE: Magnetoencephalography (MEG) was used to record and localize the sources of the epileptiform discharges, in absence epilepsy, at three different time intervals to infer the sources of involvement during generation and propagation. METHODS: Twenty patients with absence epilepsy (M:F=1:1; age: 10.2+/-3.4years), which included 12 patients with childhood absence epilepsy (CAE) and 8 patients with juvenile absence epilepsy (JAE), were recruited in this prospective MEG based study. MEG epileptiform discharges were divided into three sub-groups based on the duration viz., 1s (very short),>1-9.9s (short) and >=10s (long) and the discharges of each group were averaged independently in each patient. MEG source analysis was performed on these averaged discharges, of each of the subgroups, at the onset, during middle and offset. RESULTS: The source locations obtained, in lobar and gyri levels, were compared across these three groups of varying duration of discharges and in the CAE and JAE subjects. It was observed that the most frequent location of sources from the sublobar, limbic and frontal lobes in all the discharge groups at different time intervals. Also, it was noted that there were only subtle and variable degree of the differences of source localization of epileptic discharges among CAE and JAE subgroups. CONCLUSION: The study provided novel findings regarding origin and propagation of sources of epileptiform discharges in patients with childhood and juvenile absence epilepsies. Such analysis further improves the understanding of network involvement of subcortical and cortical regions in these patients. PMID- 29232568 TI - Prior systemic treatment increased the incidence of somatic mutations in metastatic breast cancer. AB - BACKGROUND: Understanding the biology of breast cancer is important for guiding treatment strategies and revealing resistance mechanisms. Our objectives were to investigate the relationship between previous systemic therapy exposure and mutational spectrum in metastatic breast cancer and to identify clinicopathological factors associated with identified frequent somatic mutations. METHODS: Archival tissues of patients with metastatic breast cancer were subjected to hotspot molecular testing by next-generation sequencing. The variables that significantly differed (P < 0.05) in univariate analysis were selected to fit multivariate models. Logistic models were fit to estimate the association between mutation status and clinical variables of interest. Five-fold cross-validation was performed to estimate the prediction error of each model. RESULTS: A total of 922 patients were included in the analysis. In multivariate analysis, previous systemic treatment before molecular testing (N = 186) was associated with a significantly higher rate of TP53 and PIK3CA mutations compared with the lack of systemic treatment (P < 0.001 for both). CONCLUSION: Systemic treatment exposure is an independent risk factor for high rates of TP53 and PIK3CA mutation, which suggests the importance of testing samples after systemic therapy to accurately assess mutations. It is worth testing the gene profile when tumours become resistant to systemic treatments. PMID- 29232570 TI - Development of an orthosis for simultaneous three-dimensional correction of clubfoot deformity. AB - BACKGROUND: Clubfoot is a three-dimensional deformity of the foot in which the foot is twisted in three mutually perpendicular planes from the normal shape of the foot. Of the various treatment methods that are available to manage clubfoot, non-operative approaches are preferred. The conventional non-operative method of treatment is to apply a series of casts to the infant's clubfoot to gradually manipulate its position. However, prolonged use of casts can result in skin rash, skin dehydration and ulcers on the soft skin of an infant. Treatment using orthosis represents an alternative non-operative and convenient technique because an orthosis can be put on and taken off at any time. METHODS: In the present study, an orthosis was developed according to the rotation of three mutually perpendicular planes and was subsequently tested on five patients over the duration of one week. FINDINGS: In all five cases, the desired incremental correction to the clubfoot was achieved through the one week intervention with the orthosis. No form of rash, dehydration, ulcers, and so on were observed on the skin of any baby involved in the study during or following application of the orthosis. INTERPRETATION: By using the developed orthosis, partial correction of the clubfoot deformity was achieved over a short period of time. However the widespread use of this device for extended durations and with a larger number of patients will generate further evidence of the extent to which this orthosis can reliably treat clubfoot. PMID- 29232571 TI - Investigating the excited state optical properties and origin of large stokes shift in Benz[c,d]indole N-Heteroarene BF2 dyes with ab initio tools. AB - Density Functional Theory and Time Dependent Density Functional Theory computations reveal experimental trends accurately and provide an insight into the origin of red shifted optical spectra, large Stokes shift, nonlinear optical responses and quantitative description of the singlet-triplet energy gap of recently synthesized highly fluorescent membrane permeable benz[c,d]indole N heteroarene BF2 rigidified BBN and BBC dyes. Our results benchmark the importance of the DFT functionals and polarization functions using the accurate basis set for the calculations of excitation energies, band gaps, dipole moment, non-linear optical properties and geometrical parameters. The anomalous increase in dipole moment in the excited state and pronounced geometric distortion are found to be responsible for the increased Stokes shift in BBN dyes. The resultant decrease in the HOMO-LUMO energy gap was found to be responsible for the red shift in BBC dyes. Enhanced nonlinear optical properties and inverse relationship between the Stokes shift and static hyperpolarizability were found in these dyes. Their possible potential therapeutic use as a photosensitizer in photodynamic therapy is proposed on the basis of vertical triplet energies resulting in the range of 0.78 to 0.88eV. The singlet-triplet energetic gaps suggest that the simple variation of the N-heteroarenes or their post functionalization can lead to the efficient generation of singlet oxygen. Further, we compared these new class of dyes with conventional aza-BODIPY and BODIPY dyes, thereby confirming their use as alternative promising candidates for nonlinear optics, triplet sensitizers, and imaging. PMID- 29232572 TI - Facile biological synthetic strategy to morphologically aligned CeO2/ZrO2 core nanoparticles using Justicia adhatoda extract and ionic liquid: Enhancement of its bio-medical properties. AB - In this study, a typical green synthesis route has approached for CeO2/ZrO2 core metal oxide nanoparticles using ionic liquid mediated Justicia adhatoda extract. This synthesis method is carried out at simple room temperature condition to obtain the core metal oxide nanoparticles. XRD, SEM and TEM studies employed to study the crystalline and surface morphological properties under nucleation, growth, and aggregation processes. CeO2/ZrO2 core metal oxides display agglomerated nano stick-like structure with 20-45nm size. GC-MS spectroscopy confirms the presence of vasicinone and N,N-Dimethylglycine present in the plant extract, which are capable of converting the corresponding metal ion precursor to CeO2/ZrO2 core metal oxide nanoparticles. In FTIR, the corresponding stretching for Ce-O and Zr-O bands indicated at 498 and 416cm-1 and Raman spectroscopy also supports typical stretching frequencies at 463 and 160cm-1. Band gap energy of the CeO2/ZrO2 core metal oxide is 3.37eV calculated from UV- DRS spectroscopy. The anti-bacterial studies performed against a set of bacterial strains the result showed that core metal oxide nanoparticles more susceptible to gram positive (G+) bacteria than gram-negative (G-) bacteria. A unique feature of the antioxidant behaviors core metal oxides reduces the concentration of DPPH radical up to 89%. The CeO2/ZrO2 core metal oxide nanoparticles control the S. marcescent bio-film formation and restrict the quorum sensing. The toxicology behavior of CeO2/ZrO2 core metal oxide NPs is found due to the high oxygen site vacancies, ROS formation, smallest particle size and higher surface area. This type of green synthesis route may efficient and the core metal oxide nanoparticles will possess a good bio-medical agent in future. PMID- 29232573 TI - Radioprotective effects of Silymarin on the sperm parameters of NMRI mice irradiated with gamma-rays. AB - Free radicals and reactive oxygen species (ROS) are generated using various endogenous systems or from external sources such as exposure to different physiochemicals. Ionizing radiation damage to the cell can be caused by the direct or indirect effects of radiotherapy processes. Silymarin (SM), a flavanolignan compound, has been identified as a natural potent antioxidant with cytoprotection activities due to scavenging free radicals. The aim of the present study was to evaluate the radioprotective effect of SM on sperm parameters of mice induced by gamma-rays. A total number of 40 adult, male NMRI mice were randomly divided into four equal groups. The control group was neither treated with SM nor irradiated by gamma-rays. The second group was only irradiated with 2Gy of gamma-rays. The third group was firstly treated with 50mg/kg of SM for 7 consecutive days, and one day later, last injections were irradiated by 2Gy of gamma-rays. The fourth groups received only 50mg/kg of SM for 7 consecutive days. All the animals were treated intraperitoneally. Histopathological and morphometrical examinations were performed. The data were analyzed using ANOVA and Tukey post hoc test. A value of p<0.05 was considered significant. The results showed that in the radiation-only group when compared with those treated with SM and irradiated, a significant different was observed in testicular parameters and DNA damage (p<0.05). In conclusion, SM can be considered as a promising herbal radioprotective agent in complementary medicine which may play an important role to protect normal spermatocytes against possible effects of gamma-radiation-induced cellular damage. PMID- 29232574 TI - Imaging analysis of superficial soft tissue lymphomas. AB - PURPOSE: To describe imaging findings in superficial soft tissue lymphomas, especially those located in the skin and subcutaneous layer. MATERIALS AND METHODS: This study included 44 pathologically confirmed superficial lymphoma lesions. Imaging analysis included the size, margin, location, morphology, homogeneity and multiplicity. RESULTS: A nodular form was the most common (21/44, 47.7%) morphology, and of them, 18 demonstrated a streaky appearance. Most of the lesions demonstrated ill-defined margins (26/44, 59.1%) and homogeneous patterns (35/44, 79.5%). CONCLUSIONS: The imaging findings of superficial soft tissue lymphomas were non-specific. However, if images show multiple nodular lesions with ill-defined margins, we should consider this diagnosis. PMID- 29232575 TI - Dual factor model of mental health: Co-occurrence of positive mental health and suicide ideation in inpatients and outpatients. AB - Positive and negative mental health are independent but correlated concepts. Yet, it is unknown whether positive mental health does co-occur with suicide ideation. The present study aimed to determine the proportion of patients who have positive mental health as well as suicide ideation. Inpatients (N=100) and outpatients (N=182) completed self-report measures of positive mental health, suicide ideation and lifetime suicide attempts. Eleven outpatients (6%) and ten inpatients (10%) with suicide ideation reported moderate to high levels of positive mental health. Lifetime suicide attempts were less likely in inpatients who suffered from suicide ideation in the presence of positive mental health. Positive mental health does co-occur with suicide ideation and should be considered as a protective factor in suicide risk assessments. PMID- 29232577 TI - Attachment and motivational systems: Relevance of sensitivity to punishment for eating disorder psychopathology. AB - An altered balance of reward and inhibition systems may explain Eating Disorder (ED) behaviors and could be related to difficulties in socio-emotional processing. According to attachment theory, early interaction with caregivers affects the ability to regulate emotion in adult interpersonal situation. The aim of our study was to investigate if insecure attachment may be related to ED symptomatology through changes in reward and inhibition systems. Seventy-eight people affected by EDs and 45 healthy controls (HC) filled in the Attachment Style Questionnaire (ASQ), the Behavioral Inhibition System-Behavioral Activation System Scale (BIS-BAS) and the Eating Disorders Inventory-2 (EDI-2) questionnaire. ED people reported significantly higher scores than HC in EDI-2 scores, all dimensions of insecure attachment style and sensitivity to punishment (BIS score). In ED patients, ASQ anxiety scores correlated with almost all EDI-2 subscores and sensitivity to punishment. The association between anxious attachment style and ED symptomatology (drive to thinness and body dissatisfaction) was totally mediated by an indirect effect of sensitivity to punishment. These findings suggest, for the first time, increased sensitivity to punishment as a pathway that may explain the relationship between anxious attachment and ED symptomatology highlighting the relevance to target social experiences as an important psychotherapeutic focus. PMID- 29232576 TI - Effects of oxytocin on cortisol reactivity and conflict resolution behaviors among couples with substance misuse. AB - Social stress, particularly in the form of dyadic conflict, is a well-established correlate of substance use disorders (SUD). The neuropeptide oxytocin can enhance prosocial behavior and mitigate addictive behaviors. These effects may be, in part, a result of oxytocin's ability to attenuate hypothalamic-pituitary-adrenal (HPA) axis dysregulation. However, only one study to date has examined the effects of oxytocin on neuroendocrine reactivity or conflict resolution behavior among couples. Participants (N = 33 couples or 66 total participants) were heterosexual couples in which one or both partners endorsed substance misuse. Using a double-blind, placebo-controlled, repeated-measures design and an evidence-based behavioral coding system, we compared the impact of oxytocin (40 IU) vs. placebo on cortisol reactivity and conflict resolution behaviors. Among women, oxytocin attenuated cortisol response following the task. Oxytocin was also associated with increased Distress Maintaining Attributions and decreased Relationship Enhancing Attributions. Among men, oxytocin was associated with decreased Distress Maintaining Attributions, and both oxytocin and placebo yielded declines in Relationship Enhancing Attributions. The findings support emerging hypotheses that oxytocin may have differential effects in men and women, and indicate the need for future efforts to translate oxytocin's positive neurobiological effects into therapeutic behavioral changes. PMID- 29232579 TI - Structure-based identification of a NEDD8-activating enzyme inhibitor via drug repurposing. AB - NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degradation. Meanwhile, drug repurposing is a cost efficient strategy to identify new therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compound 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compound 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degradation of the neddylation substrate p53. PMID- 29232578 TI - Hetero-Diels-Alder reactions of novel 3-triazolyl-nitrosoalkenes as an approach to functionalized 1,2,3-triazoles with antibacterial profile. AB - The generation and reactivity of 3-triazolyl-nitrosoalkenes are reported for the first time. The study showed that hetero-Diels-Alder reaction of these heterodienes is an interesting synthetic strategy to functionalized 1,2,3 triazoles, including 1,2,3-triazolyl-pyrroles, 1,2,3-triazolyl-dipyrromethanes and 1,2,3-triazolyl-indoles. The evaluation of the antibacterial profile against Gram-positive and Gram-negative strains revealed the new 5,5' diethyldipyrromethane bearing a side chain incorporating a triazole and oxime moieties. The antibacterial profile detected was within the Clinical and Laboratory Standard Institute (CLSI) range and against important Staphylococcus species including Methicillin-resistant strain (S. aureus ATCC 25923, S. epidermidis ATCC 12228 and S. simulans ATCC 27851 and MRSA). Interestingly, this new 1,2,3-triazole presented hemocompatibility and low in silico toxicity profile similar to antibiotics current in use. It also has an usual antibiofilm activity against MRSA, which reinforced its potential as a new antibacterial prototype. PMID- 29232580 TI - Design and synthesis of novel quinacrine-[1,3]-thiazinan-4-one hybrids for their anti-breast cancer activity. AB - In an attempt to develop effective and safe anticancer agents, we designed, synthesized and examined 23 novel quinacrine (QC) derivatives by combining the 9 aminoacridine scaffold and the [1,3]thiazinan-4-ones group. Most of these hybrids showed strong anticancer activities, among which 3-(3-(6-chloro-2-methoxyacridin 9-ylamino)propyl)-2-(thiophen-2-yl)-1,3-thiazinan-4-one (25; VR151) effectively killed many different cancer cell types, including eight breast cancer cell lines with different genetic background, two prostate cancer and two lung cancer cell lines. In contrast, compound 25 is less effective against non-cancer cells, suggesting it may be less toxic to humans. Our data showed that cancer cells are arrested in S phase for a prolonged period due to the down-regulation of DNA replication, leading to eventual cell death. We have also shown that the S phase arrest may be resulted by the down-regulation of cyclin A coupled with the continued up-regulation of cyclin E, which coincide with the down-regulation of mTor-S6K and mTor-4EBP1 pathways. PMID- 29232581 TI - Homo- and heteroleptic Pt(II) complexes of ONN donor hydrazone and 4-picoline: A synthetic, structural and detailed mechanistic anticancer investigation. AB - Two series of homoleptic Pt(II)(hydrazone)Cl (C1a-C5a) and heteroleptic Pt(II)(hydrazone)(4-picoline). BF4 (C1b-C5b) complexes were prepared and characterized by 1H, 13C, 19F NMR and HR ESI-MS. Structure of C2b was confirmed by single crystal X-ray analysis. These complexes were studied for their in vitro anticancer activities in human multiple cancer cells including breast (MCF-7), liver (HepG2), lung (H460), colon (HCT116) and cervical (Hela) cancers. C1a-C5a and C1b-C5b showed considerable anticancer effect. The overall anticancer effect of all these complexes was higher in liver (HepG2) and lung (H460) cancer cell lines and the effect of C2b and C3b was observed to be the highest among these 10 complexes. Therefore, we selected C2b and C3b to study their in vitro anticancer mechanism in HepG2 and H460 cancer cells. C2b and C3b changed cancer cell morphology and inhibited cell migration. The anticancer mechanistic studies demonstrated that C2b and C3b induced cell apoptosis, as evidenced by DAPI and AO/EB staining and flow cytometry analyses. Moreover, qRT-PCR and western blotting analysis showed that H460 and HepG2 cells treated with C2b and C3b significantly increased the expression of p53, p63, p21, p15, Bax and decreased Bcl-2 and c-Myc levels. The DNA binding property of these complexes was investigated by gel electrophoresis using pBR322 plasmid DNA. Taken together, the results obtained from the present study demonstrated the potentials of this new class of Pt(II) complexes in reduction of cell viability, suppression of cell migration and acceleration of apoptosis in different cancer cells. PMID- 29232582 TI - Discovery and evolution of aloperine derivatives as a new family of HCV inhibitors with novel mechanism. AB - Aloperine (1), a Chinese natural product with a unique endocyclic scaffold, was first identified to be a potent hepatitis C virus (HCV) inhibitor in our laboratory. Thirty-four new aloperine derivatives were designed, synthesized and evaluated for their anti-HCV activities taking 1 as the lead. Among them, compound 7f exhibited the potential potency with EC50 values in a micromolar range against both wild-type and direct-acting antiviral agents (DAAs)-resistant variants, and synergistically inhibited HCV replication with approved DAAs. Furthermore, it also owned a good oral pharmacokinetic and safety profile, suggesting a highly druglike nature. The primary mechanism showed that 7f might target host components, distinctly different from the DAAs currently used in clinic. Therefore, we consider aloperine derivatives to be a novel class of anti HCV agents, and compound 7f has been selected as a promising antiviral candidate for further investigation. PMID- 29232583 TI - Development of novel bis-pyrazole derivatives as antitumor agents with potent apoptosis induction effects and DNA damage. AB - A series of bis-pyrazole derivatives were designed and synthesized, and their antitumor effects in vitro and in vivo were investigated. Several compounds displayed good antiproliferative activity with IC50 values in low-micromolar range against three human cancer cell lines in vitro, superior to 5-FU. The most potent compound 10M selectively inhibited human hepatocellular carcinoma cells but not non-tumor liver cell proliferation in vitro, and significantly triggered SMMC-7721 cell apoptosis by cleavage of both PARP and caspase-3 in a concentration-dependent manner. Further study revealed that the potent activity in the cell growth inhibition and apoptosis induction effects of 10M were related to DNA damage and activation of the p53 signaling pathway. Moreover, 10M showed low acute toxicity to mice and significant growth inhibition of the hepatoma tumor in vivo. PMID- 29232584 TI - Natural product inspired library synthesis - Identification of 2,3 diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis. AB - A natural product inspired library was synthesized based on 2,3-diarylbenzofuran and 2,3-diaryl-2,3-dihydrobenzofuran scaffolds. The library of forty-eight compounds was prepared by utilizing Pd-catalyzed one-pot multicomponent reactions and ruthenium-catalyzed intramolecular carbenoid C-H insertions. The compounds were evaluated for antibacterial activity in a panel of test systems including phenotypic, biochemical and image-based screening assays. We identified several potent inhibitors that block intracellular replication of pathogenic Chlamydia trachomatis with IC50 <= 3 MUM. These new C. trachomatis inhibitors can serve as starting points for the development of specific treatments that reduces the global burden of C. trachomatis infections. PMID- 29232585 TI - Synthesis of new triterpenic monomers and dimers as potential antiproliferative agents and their molecular docking studies. AB - In the current investigation, new monomers of myrrhanone B and lupeolic acid were prepared via reaction of triterpenic acids with linkers in the presence of K2CO3. In addition, new bis-myrrhanone B homodimers, myrrhanone B-myrrhanol B heterodimers, and bis-myrrhanone beta-boswellic acids heterodimer were prepared. Evaluation of these compounds on the proliferation of four different human cancer cell lines, viz., FaDu (pharynx carcinoma), A2780 (ovarian carcinoma), HT29 (colon adenocarcinoma) and A375 (malignant melanoma) has been performed. It is worth mentioning that compounds 4, 7, 8, 10, and 11 possess potent antiproliferative effect towards HT29 cancer cells with IC50 values of 8.1 MUM, 5.4 MUM, 8.8 MUM, 6.8 MUM, and 8.2 MUM, respectively. In addition, these compounds display good to moderate antiproliferative activities towards A2780 and A375 with IC50 values ranging from 10.4 to 24.2 MUM. Moreover, the molecular docking studies of most active compounds (4, 7, 8, 10 and 11) with six anti cancer drug targets DHFR, VEGFR2, HER-2/neu, CDK6, hCA-IX and LOX also carried, in order to know the mode of binding interaction and energy of this class of compounds. PMID- 29232586 TI - Synthesis and biological evaluation of coumarin derivatives containing imidazole skeleton as potential antibacterial agents. AB - Emergence of multidrug-resistant bacteria causes an urgent need for new generation of antibiotics, which may have a different mechanism of inhibition or killing action from the existing. Here, we report on the design, synthesis, and biological evaluation of thirty-nine coumarin derivatives in order to solve the antibacterial resistance by targeting at the inhibition of biosynthesis pathway of fatty acids. Their antibacterial activities against Escherichia coli, Staphylococcus aureus, Streptococcus agalactiae, and Flavobacterium cloumnare are tested and action mechanism against the key enzyme in bacterial fatty acid synthesis pathway are studied. The results show that compounds 13 and 18 have potent and broad spectrum antimicrobial activity. In addition, 9, 14 and 19 show eminent antimicrobial efficacy toward S. aureus, S. agalactiae, and F. cloumnare. Mechanistically, coumarin derivatives display the antibacterial activity via the control of FabI and FabK function. The structure-activity relationship analysis indicate that the length of linker and imidazole substitute group could significantly influence the antimicrobial activity, as well as the inhibitory activity against FabI and FabK. The structural optimization analysis of coumarin suggest that derivatives 9, 13, 14, 18 and 19 could be a viable way of preventing and controlling bacteria and considered as promising lead compounds for the development of commercial drugs. PMID- 29232587 TI - Discovery of naphtho[1,2-d]oxazole derivatives as potential anti-HCV agents through inducing heme oxygenase-1 expression. AB - A number of naphtho[1,2-d]oxazole derivatives were synthesized and evaluated for their anti-HCV virus activity. Among them, compound 18 was the most active, exhibited approximately 21-folds more active anti-HCV activity (IC50 of 0.63 MUM) than that of ribavirin (IC50 = 13.16 MUM). Compound 18 was less cytotoxic than ribavirin, and the selective index (SI) of 18 is approximately 28-folds higher than that of ribavirin (229.10 v.s. 8.08). By using heme oxygenase-1 (HO-1) promoter-based assay and western blotting, compound 18 could induce HO-1 promoter activity, and protein expression. The antiviral effect of compound 18 was attenuated by HO-1 specific inhibitor SnPP treatment, which indicated that compound 18 suppressed HCV replication through inducing HO-1 expression. We further found that compound 18 reduced bach1 expression resulting in increasing the activity of Nrf-2 binding element. Moreover, the induction of HO-1 by compound 18 reduced HCV NS3/4A protease activity and induced the antiviral interferon responses. Therefore, compound 18 can be considered as a supplemental antiviral agent or a lead compound for further developing more effective agents against HCV replication. PMID- 29232588 TI - Bioactive products from singlet oxygen photooxygenation of cannabinoids. AB - Photooxygenation of Delta8 tetrahydrocannabinol (Delta8-THC), Delta9 tetrahydrocannabinol (Delta9-THC), Delta9 tetrahydrocannabinolic acid (Delta9 THCA) and some derivatives (acetate, tosylate and methyl ether) yielded 24 oxygenated derivatives, 18 of which were new and 6 were previously reported, including allyl alcohols, ethers, quinones, hydroperoxides, and epoxides. Testing these compounds for their modulatory effect on cannabinoid receptors CB1 and CB2 led to the identification of 7 and 21 as CB1 partial agonists with Ki values of 0.043 MUM and 0.048 MUM, respectively and 23 as a cannabinoid with high binding affinity for CB2 with Ki value of 0.0095 MUM, but much less affinity towards CB1 (Ki 0.467 MUM). The synthesized compounds showed cytotoxic activity against cancer cell lines (SK-MEL, KB, BT-549, and SK-OV-3) with IC50 values ranging from 4.2 to 8.5 MUg/mL. Several of those compounds showed antimicrobial, antimalarial and antileishmanial activities, with compound 14 being the most potent against various pathogens. PMID- 29232589 TI - Peptides having antimicrobial activity and their complexes with transition metal ions. AB - Peptide antibiotics are produced by bacterial, mammalian, insect or plant organisms in defense against invasive microbial pathogens. Therefore, they are gaining importance as anti-infective agents. There are a number of antibiotics that require metal ions to function properly. Metal ions play a key role in their action and are involved in specific interactions with proteins, nucleic acids and other biomolecules. On the other hand, it is well known that some antimicrobial agents possess functional groups that enable them interacting with metal ions present in physiological fluids. Some findings support a hypothesis that they may alter the serum metal ions concentration in humans. Complexes usually have a higher positive charge than uncomplexed compounds. This means that they might interact more tightly with polyanionic DNA and RNA molecules. It has been shown that several metal ion complexes with antibiotics promote degradation of DNA. Some of them, such as bleomycin, form stable complexes with redox metal ions and split the nucleic acids chain via the free radicals mechanism. However, this is not a rule. For example blasticidin does not cause DNA damage. This indicates that some peptide antibiotics can be considered as ligands that effectively lower the oxidative activity of transition metal ions. PMID- 29232590 TI - Mode repulsion of ultrasonic guided waves in rails. AB - Accurate computation of dispersion characteristics of guided waves in rails is important during the development of inspection and monitoring systems. Wavenumber versus frequency curves computed by the semi-analytical finite element method exhibit mode repulsion and mode crossing which can be difficult to distinguish. Eigenvalue derivatives, with respect to the wavenumber, are used to investigate these regions. A term causing repulsion between two modes is identified and a condition for two modes to cross is established. In symmetric rail profiles the mode shapes are either symmetric or antisymmetric. Symmetric and antisymmetric modes can cross each other while the modes within the symmetric and antisymmetric families do not appear to cross. The modes can therefore be numbered in the same way that Lamb waves in plates are numbered, making it easier to communicate results. The derivative of the eigenvectors with respect to wavenumber contains the same repulsion term and shows how the mode shapes swop during a repulsion. The introduction of even a small asymmetry appears to lead to repulsion forces that prevent any mode crossings. Measurements on a continuously welded rail track were performed to illustrate a mode repulsion. PMID- 29232591 TI - Impact of time on ultrasonic cavitation peening via detection of surface plastic deformation. AB - During ultrasonic cavitation peening, bubbles repeatedly form and collapse, which leads to high impact loads on the treated surface. At the initial stage of ultrasonic cavitation peening, the most obvious change is plastic deformation instead of mass loss on the treated specimen surface. Meanwhile the plastic deformation is beneficial for mechanical surface properties. As the cavitation exposure time increases, erosion and damage are inflicted on the metal surface due to the increase in the number of collapse events. In this respect, the treatment time is a key parameter to improve the specimen surface properties during this manufacturing process. However, the influence of treatment time on the surface properties has not yet been thoroughly investigated. In this paper, it is the first time to utilize the plastic deformation to evaluate the optimal treatment time at different input power. The plastic deformation can be deduced by the mass loss and the volume change on the treated specimen surface. Using plastic deformation, the modification of surface hardness and roughness are investigated at different cavitation exposure intervals and vibration amplitudes. It is found that significant improvement of the microhardness on the treated surface occurs at the end of incubation period. Higher vibration amplitudes of the horn tip lead to shorter incubation period and higher microhardness. PMID- 29232592 TI - The impact of oral arsenic and all-trans-retinoic acid on coagulopathy in acute promyelocytic leukemia. AB - The aim of our study was to evaluate the impact of oral arsenic (the realgar indigo naturalis formula, RIF) and all-trans retinoic acid (ATRA) on coagulopathy in acute promyelocytic leukemia (APL) compared with intravenous arsenic trioxide (ATO) and ATRA during induction. Mitoxantrone was added to all the patients at a dose of 1.4mg/m2 per day for 5-7 days. D-dimer levels, prothrombin time (PT), fibrinogen (Fbg) levels and the platelet count were comparably analyzed among 83 newly diagnosed APL patients treated with RIF (n=45) or with ATO (n=38). Since induction therapy with RIF and ATRA, the median levels of Fbg, PT and platelets were recovered to the normal range within 4days, 10days and 28days, respectively. The last day of platelet and plasma transfusion was day 12 (range: 0-24 days) and day 3 (range: 0-27 days), respectively. Among the 42 patients with a disseminated intravascular coagulation (DIC) score=4, the consumption of transfused platelets was less in the RIF group than that in the ATO group (P=0.037). In the 17 patients with a DIC score <4, prompt recovery of Fbg levels (P=0.028) was observed in the RIF group compared with that in the ATO group (P=0.401). RIF and ATO showed similar effects on the recovery of coagulopathy in APL patients. RIF had a potential beneficial effect in accelerating the recovery of thrombocytopenia and hypofibrinogenemia for subclinical DIC patients. PMID- 29232593 TI - Improvement of the association between self-reported pill count and varenicline levels following exclusion of participants with misreported pill count: A commentary on Peng et al. (2017). AB - INTRODUCTION: We previously reported poor associations between salivary varenicline and pill counts, and a substantial overestimation of adherence by pill counts in "Measures and predictors of varenicline adherence in the treatment of nicotine dependence" (Peng et al., 2017). We have since conducted supplementary analyses characterizing, and then excluding, individuals with established inaccurate pill count recall. METHODS: Based on published varenicline pharmacokinetics (including drug levels, and the long half-life) and our detection limits, conservatively we should be able to detect varenicline in anyone who took at least one pill during the 48h prior to saliva collection; thus, those reporting 1 or more pills in this time frame but who had undetectable salivary varenicline were deemed to have inaccurate pill count recall. Correlations between pill counts and salivary varenicline, and Receiver Operating Characteristics curve analyses were conducted following exclusion of participants with inaccurate pill count recall. RESULTS: Nearly 20% of our participants (N=67/376) had inaccurate self-reported pill counts. These participants were younger, non-white, lower income, and unmarried (evaluated using chi-square or Mann-Whitney U test). Following exclusion of these individuals, the correlations between salivary varenicline and pill count improved and the area under the curve (AUC) of pill counts for discriminating adherence improved modestly. CONCLUSION: When the 20% of individuals with inaccurate pill count recall were excluded, an improved association between self-reported pill count and salivary varenicline was observed, albeit still weak. A substantial overestimation of adherence by pill counts relative to salivary varenicline is still observed even after exclusion of almost 20% of the group having established inaccurate reporting suggesting that these individuals, with identifiable inaccuracies, were only part of the overestimation of adherence. PMID- 29232594 TI - Understanding face familiarity. AB - It has been known for many years that identifying familiar faces is much easier than identifying unfamiliar faces, and that this familiar face advantage persists across a range of tasks. However, attempts to understand face familiarity have mostly used a binary contrast between 'familiar' and 'unfamiliar' faces, with no attempt to incorporate the vast range of familiarity we all experience. From family members to casual acquaintances and from personal to media exposure, familiarity is a more complex categorisation than is usually acknowledged. Here we model levels of familiarity using a generic statistical analysis (PCA combined with LDA) computed over some four thousand naturally occurring images that include a large variation in the numbers of images for each known person. Using a strong test of performance with entirely novel, untrained everyday images, we show that such a model can simulate widely documented effects of familiarity in face recognition and face matching, and offers a natural account of the internal feature advantage for familiar faces. Furthermore, as with human viewers, the benefits of familiarity seem to accrue from being able to extract consistent information across different photos of the same face. We argue that face familiarity is best understood as reflecting increasingly robust statistical descriptions of idiosyncratic within-person variability. Understanding how faces become familiar appears to rely on both bottom-up statistical image descriptions (modelled here with PCA), and top-down processes that cohere superficially different images of the same person (modelled here with LDA). PMID- 29232595 TI - A unified computational account of cumulative semantic, semantic blocking, and semantic distractor effects in picture naming. AB - Computational models of lexical selection in spoken word production have been applied to semantic interference effects in picture naming response times obtained with continuous naming, blocked-cyclic naming, and picture-word interference paradigms. However, a unified computational account of the effects in the three paradigms is lacking. Here, I show that the inclusion of conceptual bias in the WEAVER++model (Levelt, Roelofs, & Meyer, 1999) explains cumulative semantic and semantic blocking effects while preserving the model's account of semantic distractor effects. The key assumptions of the account are (1) lexical selection by competition, and (2) a conceptual origin and lexical locus of the semantic effects. I provide a proof of concept of the account by reporting computer simulation results, addressing behavioral and neuroimaging evidence. The assumptions are sufficient for a unified account of semantic effects in the three paradigms, contrary to pessimistic views of this area. PMID- 29232596 TI - Distinguishing languages from dialects: A litmus test using the picture-word interference task. AB - Linguists have been working to develop objective criteria for distinguishing languages from dialects for well over half a century. The prevailing view amongst sociolinguists is that no objective criteria can be formulated. The aim of this study is to examine whether language processing can provide insights into this problem by comparing bidialectal behavioural effects to bilingual effects reported in the literature. Previous research has demonstrated that when bilinguals name an object in Lx while simultaneously processing a translation equivalent distractor word in Ly, naming times are sped up relative to an unrelated condition (Costa, Miozzo, & Caramazza, 1999). Using the same methodology, we evaluated whether a comparable facilitation effect arises when the distractor word is a dialectal or register variant of the picture name. Across 5 experiments we found no trace of translation equivalent facilitation. Instead, we repeatedly observed between-dialect and between-register interference, in contrast to the between-language facilitation effect. This behavioural divergence between bilingual vs. bidialectal processing suggests that this paradigm could provide an objective litmus tests for identifying the boundary between dialects and languages. PMID- 29232597 TI - Evaporation effect on two-dimensional wicking in porous media. AB - We analyze the effect of evaporation on expanding capillary flow for losses normal to the plane of a two-dimensional porous medium using the potential flow theory formulation of the Lucas-Washburn method. Evaporation induces a finite steady state liquid flux on capillary flows into fan-shaped domains which is significantly greater than the flux into media of constant cross section. We introduce the evaporation-capillary number, a new dimensionless quantity, which governs the frontal motion when multiplied by the scaled time. This governing product divides the wicking behavior into simple regimes of capillary dominated flow and evaporative steady state, as well as the intermediate regime of evaporation influenced capillary driven motion. We also show flow dimensionality and evaporation reduce the propagation rate of the wet front relative to the Lucas-Washburn law. PMID- 29232598 TI - High-performance bimetallic alloy catalyst using Ni and N co-doped composite carbon for the oxygen electro-reduction. AB - In this study, a novel synthesis method for the bimetallic alloy catalyst is reported, which is subsequently used as an oxygen reduction catalyst in polymer electrolyte membrane fuel cells (PEMFCs). The support prepared from the Ni chelate complex shows a mesoporous structure with a specific surface area of ca. 400 m2 g-1 indicating the suitable support for PEMFC applications. Ethylenediamine is converted to the nitrogen and carbon layers to protect the Ni particles which will diffuse into the Pt lattice at 800 degrees C. The PtNi/NCC catalyst with PtNi cores and Pt-rich shells is successfully formed when acid treated as evidenced by line scan profiles. The catalyst particles thus synthesized are well-dispersed on the N-doped carbon support, while the average particle size is ca. 3 nm. In the PEMFC test, the maximum power density of the PtNi/NCC catalyst shows approximately 25% higher than that of the commercial Pt/C catalyst. The mass activity of the PtNi/NCC catalyst showed approximately 3-fold higher than that of the commercial Pt/C catalyst. The mass activity strongly depends on the ratio of Pt to Ni since the strain effect can be strong for catalysts due to the mismatch of lattice parameters of the Ni and Pt. PMID- 29232599 TI - Bioinspired self-standing macroporous Au/ZnO sponges for enhanced photocatalysis. AB - A self-standing macroporous noble metal-zinc oxide (ZnO) sponge of robust 3D network has been fabricated through in-situ growth method. The key to the construction of the bioinspired sponge lies in the choice of commercial polyurethane sponge (CPS) with interconnected and junction-free macroporous structure as the skeleton to support Au/ZnO nanorods (Au/ZnONRs). The resultant Au/ZnO/CPS not only exhibits hierarchical structures representing physical features of CPS, but also demonstrates durable superior photocatalytic activity and hydrogen generation capability. In addition, we have adopted various irradiations to investigate the effect of UV light and visible light on the photocatalytic performance of Au/ZnO/CPS individually. In detail, the photocatalytic properties of Au/ZnO/CPS and ZnO/CPS have been monitored and compared under irradiations of different wavelengths (200-1100, 350-780, 200-420 and 420-780 nm) for 90 min to reveal the effect of irradiation wavelength on the activity of photocatalysts. A possible mechanism between irradiation wavelength and photocatalytic degradation efficiency is proposed. The facile in-situ growth approach presented herein can be easily scaled up, affording a convenient method for the preparation of self-standing 3D macroporous materials, which holds great potential for the application in both environmental purification and solar-to hydrogen energy conversion. PMID- 29232600 TI - A retrospective review of phyllodes tumours of the breast: A single institution experience. AB - BACKGROUND: Phyllodes tumours are rare and histologically diverse, posing challenges in prognosis and treatment. Due to their rarity, they have seldom been studied. PURPOSE: The purpose was to investigate clinical practices in the management of phyllodes tumours, as well as patient outcomes to contribute to the limited body of knowledge surrounding these tumours. METHODS: A retrospective review was conducted on all patients with phyllodes tumours at a single institution. Descriptive analyses were conducted on demographic, disease and treatment (breast-conserving surgery, mastectomy, surgical re-excision, adjuvant/palliative radiation, palliative chemotherapy) information. Overall and disease-free survivals were analyzed, and the cumulative incidence of recurrence and metastases was compared. RESULTS: 79 patients with phyllodes tumours of the breast were included in the study. Tumours were classified as malignant, borderline, or benign in 67.1%, 21.5%, and 11.4% of patients, respectively. There were no statistically significant differences in overall or disease-free survival between patients with benign, borderline or malignant disease. Only patients with malignant disease developed recurrence or metastases. Those with malignant disease who received mastectomies had a lower 10-year cumulative incidence of recurrence; however this was not statistically significant (p = 0.69). All patients had negative surgical margins due to a re-excision or mastectomy following margin-positive breast conserving surgery. Of all risk factors assessed, necrosis was significantly associated with increased incidence of recurrence (local or distant) in patients with malignant disease (p = 0.03). CONCLUSION: The presence of tumour necrosis is a significant negative prognostic factor. Breast-conserving surgery may be adequate in providing local control, given negative surgical margins. PMID- 29232601 TI - Marine microalgae for production of biofuels and chemicals. AB - Marine microalgae are recognized as promising feedstocks for biofuels and chemicals owing to their higher growth rates than those of terrestrial crop plants. We aimed to summarize the production of biofuels and chemicals by marine microalgae and to discuss their advantages and potential from the aspect of bioprocess. The present circumstances of the microalgae industry were briefly described and large-scale industrial plants for microalgae production, where some marine microalgae are cultivated, were introduced. The advantages of marine microalgae in terms of water and land usage were also discussed. Finally, novel genome editing tools that could further exploit the potential of marine microalgae were reviewed. The present study provided comprehensive information regarding current biotechnology using marine microalgae. PMID- 29232602 TI - Cooperative protein unfolding. A statistical-mechanical model for the action of denaturants. AB - Knowledge of protein stability is of utmost importance in various fields of biotechnology. Protein stability can be assessed in solution by increasing the concentration of denaturant and recording the structural changes with spectroscopic or thermodynamic methods. The standard interpretation of the experimental data is to assume a 2-state equilibrium between completely folded and completely unfolded protein molecules. Here we propose a cooperative model based on the statistical-mechanical Zimm-Bragg theory. In this model protein unfolding is driven by the weak binding of a rather small number of denaturant molecules, inducing the cooperative unfolding with multiple dynamic intermediates. The modified Zimm-Bragg theory is applied to published thermodynamic and spectroscopic data leading to the following conclusions. (i) The binding constant KD is correlated with the midpoint concentration, c0, of the unfolding reaction according to c0?1/KD. The better the binding of denaturant the lower is the concentration to achieve unfolding. (ii) The binding constant KD agrees with direct thermodynamic measurements. A rather small number of bound denaturants suffices to induce the cooperative unfolding of the whole protein. (iii) Chemical unfolding occurs in the concentration range DeltacD=cend-cini. The theory predicts the unfolding energy per amino acid residue as gnu=RTKD(cend cini). The Gibbs free energy of an osmotic gradient of the same size is DeltaGDiff=-RTln(cend/cini). In all examples investigated DeltaGDiff exactly balances the unfolding energy gnu. The total unfolding energy is thus close to zero. (iv) Protein cooperativity in chemical unfolding is rather low with cooperativity parameters sigma>=3x10-3. As a consequence, the theory predicts a dynamic mixture of conformations during the unfolding reaction. The probabilities of individual conformations are easily accessible via the partition function Z(cD,sigma). PMID- 29232604 TI - Identifying gaps in the implementation of naloxone programs for laypersons in the United States. PMID- 29232603 TI - A highly regular fucan sulfate from the sea cucumber Stichopus horrens. AB - A highly regular fucan sulfate SHFS was isolated from the sea cucumber Stichopus horrens by extraction of the body walls in the presence of papain followed by ion exchange and gel permeation chromatography. SHFS had MW of about 140 kDa and contained fucose and sulfate in the molar ratio of about 1:1. Chemical and NMR spectroscopic methods were applied for the structural characterization of the polysaccharide. SHFS was shown to have linear molecules built up of 3-linked alpha-l-fucopyranose 2-sulfate residues. Anticoagulant properties of SHFS were assessed in vitro in comparison with the LMW heparin (enoxaparin) and totally sulfated 3-linked alpha-l-fucan. SHFS was found to have the lowest activity, and hence, both sulfate groups at O-2 and O-4 of fucosyl units seem to be important for anticoagulant effect of sulfated homo-(1 -> 3)-alpha-l-fucans. PMID- 29232605 TI - Correlating charge heterogeneity data generated by agarose gel isoelectric focusing and ion exchange chromatography methods. AB - An isoelectric focusing method (IEF) has been used to assess the charge heterogeneity profile of a monoclonal antibody during the early stages of product development. A more precise and sensitive ion exchange chromatography (IEC/CEX) method was developed and implemented as development progressed and was used concurrently with IEF for lot release and to monitor charge heterogeneity. Charge variants resolved by both methods (IEC and IEF) were purified and characterized. Tryptic peptide mapping and N- linked oligosaccharide profile analyses of the IEC and IEF fractions indicated a structural correlation between the charge variants separated by these two methods. The major sources of molecular heterogeneity were due to the variation in the sialyated carbohydrate structure and heavy chain C terminal lysine truncation. By monitoring the rates of change in the charge heterogeneity profiles of the monoclonal antibody stored at elevated temperatures by the IEC and IEF methods, a positive correlation between the two methods was established. This approach enabled replacement of the IEF method with the more precise IEC method. PMID- 29232606 TI - Microwave assisted synthesis for A2E and development of LC-ESI-MS method for quantification of ocular bisretinoids in human retina. AB - PURPOSE: To develop a microwave assisted method for the rapid synthesis of A2E and also to develop a method to quantify N-retinylidene-N retinylethanolamine(A2E), all-trans retinal dimer (ATRD), A2-glycerophospho ethanolamine (A2GPE), dihydropyridine phosphatidyl ethanolamine (A2DHPE) and monofuran A2E (MFA2E) in age matched retina. METHODS: The development of microwave assisted synthesis of A2E, its purification and characterization for its utility in quantification in human retina. The semi-quantitative method development using LC-ESI-MS, LC-ESI-MS/MS and LC-APCI-MS/MS from pooled macula and peripheral retina for the bisretinoid analysis has been done. RESULTS: Maximum A2E conversion using microwave assisted process took place at 80 degrees C for 45min with a yield of 55.01%. Highly sensitive and specific mass spectrometric method was developed using reverse phase C-18 separation with positive electrospray ionization and positive atmospheric phase chemical ionization of tandom mass spectrometry. A gradient mobile phase separation was achieved using water and methanol with 0.1% TFA. Multiple reaction monitoring acquisition for ESI and APCI was performed at ATRD m/z 551.2/522.2, A2GPE m/z 746.4/729.5, A2DHPEm/z 594.4/576.5, MFA2E m/z 608.2/591.2, A2E m/z 592.4/418.2. Method was validated using LC-ESI-SIM mode to determine selectivity, linearity, sensitivity, precision and accuracy. CONCLUSION: An attempt towards optimization of the synthetic procedure of A2E was made so as to reduce the lengthy reaction time without compromising the yield. Developed method was capable enough for the detection of low level of bisretinids in retina. PMID- 29232607 TI - Simultaneous UPLC-MS/MS analysis of two stable isotope labeled versions of sucrose in mouse plasma and brain samples as markers of blood-brain barrier permeability and brain vascular space. AB - Blood Brain Barrier (BBB) permeability is frequently compromised in the course of diseases affecting the central nervous system (CNS). Sucrose is a low molecular weight, hydrophilic marker with slow permeability at the naive BBB and therefore one of the widely used indicators of barrier integrity. Our laboratory recently developed a highly sensitive UPLC-MS/MS method for stable isotope labeled [13C12]sucrose in biological matrices. Correction of total brain concentration for contribution of intravascular space is required in such experiments in order to accurately measure BBB permeability, and it is often accomplished by vascular perfusion with buffer solutions prior to brain sampling. The purpose of the present study was to develop a UPLC-MS/MS method, which allows simultaneous analysis of two different stable isotope labeled sucrose variants, one of which can be utilized as a vascular marker. The first analyte, [13C12]sucrose, serves to quantify brain uptake clearance as a measure of BBB permeability, while the second analyte, [13C6]sucrose, is administered just before termination of the animal experiment and is considered as the vascular marker. [2H2]sucrose is used as the internal standard for both 13C labeled compounds. Because the majority of recent studies on CNS diseases employ mice, another objective was to validate the new technique in this species. The UPLC-MS/MS method was linear (r2 >= 0.99) in the tested concentration ranges, from 10 to 1000 ng/mL for both analytes in plasma, from 2 to 400 ng/g [13C12]sucrose in brain and from 10 to 400 ng/g [13C6]sucrose in brain. It was also validated in terms of acceptable intra and inter run accuracy and precision values (n = 5). The dual analyte technique was applied in a study in mice. One group received intravenous bolus injections of 10 mg/kg [13C12]sucrose at time 0, and 10 mg/kg [13C6]sucrose at 14.5 min, and subsequent terminal blood and brain sampling was performed at 15 min. For comparison, another group received an intravenous bolus dose of 10 mg/kg [13C12]sucrose and was submitted to transcardiac perfusion with buffer after 15 min. We demonstrate that the two alternative techniques to correct for intravascular content deliver equivalent values for brain concentration and brain uptake clearance. PMID- 29232608 TI - Rapid preparative separation of monoclonal antibody charge variants using laterally-fed membrane chromatography. AB - Monoclonal antibodies undergo various forms of chemical transformation which have been shown to cause loss in efficacy and alteration in pharmacokinetic properties of these molecules. Such modified antibody molecules are known as variants. They also display physical properties such as charge that are different from intact antibody molecules. However, the difference in charge is very subtle and separation based on it is quite challenging. Charge variants are usually separated using ion-exchange column chromatography or isoelectric focusing. In this paper, we report a rapid and scalable method for fractionating monoclonal antibody charge variants, based on the use of cation exchange laterally-fed membrane chromatography (LFMC). Starting with a sample of monoclonal antibody hIgG1-CD4, three well-resolved fractions were obtained using either pH or salt gradient. These fractions were identified as acidic, neutral and basic variants. Each of these fractions contained intact heavy and light chains and so antibody fragmentation had no role in variant generation. The separation was comparable to that using column chromatography but was an order of magnitude faster. PMID- 29232609 TI - Influence of direct and sequential extraction methodology on metabolic profiling. AB - A systematic comparison was made of the detected metabolite profiles for two plant materials (black beans and soybeans) and a dietary supplement (black cohosh) extracted using sequential (hexane, ethyl acetate, and 50% aqueous methanol) and direct extraction with three solvent systems (80% aqueous methanol, methanol/chloroform/water (2.5:1:1, v/v/v) and water). Extracts were analyzed by LC-MS (without derivatization) and GC-FID (with BSTFA/TMCS derivatizations). For sequential extraction, HPLC-UV and BSTFA/TMCS-derivatized GC-FID detection were more responsive to the polar molecules with a rough distribution of 10%, 10%, and 80% of the total signals in hexane, ethyl acetate, and 50% aqueous methanol, respectively. With HPLC-MS detection, the distribution of signals was more balanced, roughly 40%, 30%, and 30% for the same extracts (hexane, ethyl acetate, and 50% aqueous methanol). For direct extraction, HPLC-UV and BSTFA/TMCS derivatized 4GC-FID provided signals between 60% and 150% of the total sequential extracted signals. The overlap of signals for the 3 sequential extracts ranged from 1% to 3%. The overlap of the signals for direct extraction with the total for sequential extraction ranged from 15% to 98%. With HPLC-MS detection, signals varied from 30% to 40% of the total signals for sequential extraction. Multivariate analysis showed that the components for the sequential and direct extracts were statistically different. However, each extract, sequential or direct, allowed discrimination between the 3 plant materials. PMID- 29232610 TI - Electrospun polydimethylsiloxane/polyacrylonitrile/titanium dioxide nanofibers as a new coating for determination of alpha-linolenic acid in milk by direct immersion-solid phase nanoextraction. AB - In this study, polydimethylsiloxane/polyacrylonitrile/titanium dioxide (PDMS/PAN/TiO2) nanofibers were synthesized via electrospinning method to extract and quantify alpha-linolenic acid (ALA, C18:3), as a model analyte, in milk by direct immersion-solid phase nanoextraction (DI-SPNE) with gas chromatography flame ionization detector (GC-FID). The affecting factors on the electrospinning process such as, PDMS concentration, amount of TiO2 nanoparticles (NPs), voltage, and electrospinning distance were optimized using Taguchi's orthogonal design. The SPNE experimental conditions such as, extraction time, agitation rate, pH and salt concentration, were also optimized using response surface methodology (RSM) based on a central composite design (CCD). Under optimized conditions, the resulting calibration curve was linear in the range of 1-4000ngmL-1 with R2=0.998. The intraday, interday, and fiber-to-fiber repeatability were calculated and the corresponding relative standard deviation was less than 9% in all the cases. The limit of detection and limit of quantification were found to be 0.2 and 0.6ngmL-1, respectively. Omega-3 enriched milk was used as a real sample and the value of relative recoveries were measured to be in the range of 92-106%. PMID- 29232611 TI - Ocean acidification increases the toxic effects of TiO2 nanoparticles on the marine microalga Chlorella vulgaris. AB - Concerns about the environmental effects of engineered nanoparticles (NPs) on marine ecosystems are increasing. Meanwhile, ocean acidification (OA) has become a global environmental problem. However, the combined effects of NPs and OA on marine organisms are still not well understood. In this study, we investigated the effects of OA (pH values of 7.77 and 7.47) on the bioavailability and toxicity of TiO2 NPs to the marine microalga Chlorella vulgaris. The results showed that OA enhanced the growth inhibition of algal cells caused by TiO2 NPs. We observed synergistic interactive effects of pH and TiO2 NPs on oxidative stress, indicating that OA significantly increased the oxidative damage of TiO2 NPs on the algal cells. Importantly, the elevated toxicity of TiO2 NPs associated with OA could be explained by the enhanced internalization of NPs in algal cells, which was attributed to the slighter aggregation and more suspended particles in acidified seawater. Overall, these findings provide useful information on marine environmental risk assessments of NPs under near future OA conditions. PMID- 29232612 TI - Aliphatic hydrocarbons recovered in vegetables from soils based on their in-situ distribution in various soil humus fractions using a successive extraction method. AB - Aliphatic hydrocarbons (AHs) are major petroleum contaminants in the environment. In this study, the AHs bound to various soil endogenetic humus fractions were separated through successive extraction. Most of the AHs (46.1%) in soils were adsorbed onto/into humic acids (HA) and a small quantity of AHs (9.6%) were organic solvent extractable. AHs in B. chinensis were also analyzed since their potential risks to the residents through ingestion. AHs from C21 to C34, so called high molecular weight AHs (HMWAHs), were dominant AHs in B. chinensis (85.5%) and soils (70.4%), followed by AHs from C16 to C21, whose mobility can be enhanced via binding to fulvic acids and then can be taken up by plant root lipids (soil-plant pathway). HMWAHs were mainly HA-bound and then were detained in the top soil layers. HMWAHs associated with fine topsoil particles could be transported to B. chinensis via the soil-air-plant pathway, including resuspension and aboveground plant cuticle capture. Results from Principal Component Analysis combined with Regression Analysis supported this assumption due to the positive correlations between HMWAHs concentration in B. chinensis and fine particle contents in soils. This work presents the distributions of petroleum contaminants that result from previously described behavior mechanisms. PMID- 29232613 TI - Fire hazard of titanium powder layers mixed with inert nano TiO2 powder. AB - Metallic dust layers are highly sensitive to ignition from common ignition sources, even when mixed with high percentages of inert solids. In turn, dust layer fires are a potential ignition source for dust explosions or other damaging fires. Flame spread velocity (FSV), as a potential parameter for evaluating fire hazard, was investigated for titanium powder layers mixed with inert nano TiO2 powder in both natural convection and in forced airflow conditions. Increased mass percentage of nano TiO2 powder decreased FSV of Ti powder mixtures as expected. The mixing ratio of nano TiO2 to fully suppress layer fires was 80% and 90% for micro and nano Ti powder, respectively. Mechanisms governing flame spread across a layer of nano Ti powder differed from those of a layer of micro Ti powder. FSV in no airflow conditions was higher than in aided airflow for micro Ti powder because conduction was the dominant heat transfer mechanism. However, FSV in no airflow was lower than in opposed airflow for nano Ti powder because convection/radiation was the dominant heat transfer mechanism. A fly fire phenomenon contributed to greater FSVs and higher fire hazard with nano Ti powder mixtures under aided airflow conditions. PMID- 29232614 TI - Evaluation of carbon nanotube based copper nanoparticle composite for the efficient detection of agroviruses. AB - We report a biosensor that combines the construction of a three-dimensional nanocomposite with electrochemical methods for the detection of viruses in plants. This is the first report, where carbon nanotubes are used as a conductive frame to anchor highly electrolytic agglomerates of copper nanoparticles to detect agroviruses. Morphological analysis of nanocomposite revealed the presence of carbon nanotubes having a diameter of 50-100nm with copper nanoparticles of 20 100nm, attached in the form of bunches. This material was applied to assess the infection caused by geminiviruses which are a major threat to the cotton plants in Asian and African countries. The hybridization events were studied by monitoring differential pulse voltammetry signals using methylene blue as a redox indicator. In the presence of target DNA, sensor signals decreased from 7*10-4 to 1*10-4Ampere. The probe exhibited 97.14% selectivity and the detection limit was found to be 0.01ngMUL-1. The developed biosensor is stable for at least four weeks, losing only 4.3% of the initial signal value. This sensor was able to detect the presence of viruses in sap extracted from cotton leaves, thus providing a promising platform to detect a range of other crops-infecting viruses. PMID- 29232615 TI - A wind tunnel study on the effect of trees on PM2.5 distribution around buildings. AB - Vegetation, especially trees, is effective in reducing the concentration of particulate matter. Trees can efficiently capture particles, improve urban air quality, and may further decrease the introduction of outdoor particles to indoor air. The objective of this study is to investigate the effects of trees on particle distribution and removal around buildings using wind tunnel experiments. The wind tunnel is 18m long, 12m wide, and 3.5m high. Trees were modeled using real cypress branches to mimic trees planted around buildings. At the inlet of the wind tunnel, a "line source" of particles was released, simulating air laden with particulate matter. Experiments with the cypress tree and tree-free models were conducted to compare particle concentrations around the buildings. The results indicate that cypress trees clearly reduce PM2.5 concentrations compared with the tree-free model. The cypress trees enhanced the PM2.5 removal rate by about 20%. The effects of trees on PM2.5 removal and distribution vary at different heights. At the base of the trees, their effect on reducing PM2.5 concentrations is the most significant. At a great height above the treetops, the effect is almost negligible. PMID- 29232616 TI - Towards understanding sparse filtering: A theoretical perspective. AB - In this paper we present a theoretical analysis to understand sparse filtering, a recent and effective algorithm for unsupervised learning. The aim of this research is not to show whether or how well sparse filtering works, but to understand why and when sparse filtering does work. We provide a thorough theoretical analysis of sparse filtering and its properties, and further offer an experimental validation of the main outcomes of our theoretical analysis. We show that sparse filtering works by explicitly maximizing the entropy of the learned representations through the maximization of the proxy of sparsity, and by implicitly preserving mutual information between original and learned representations through the constraint of preserving a structure of the data. Specifically, we show that the sparse filtering algorithm implemented using an absolute-value non-linearity determines the preservation of a data structure defined by relations of neighborhoodness under the cosine distance. Furthermore, we empirically validate our theoretical results with artificial and real data sets, and we apply our theoretical understanding to explain the success of sparse filtering on real-world problems. Our work provides a strong theoretical basis for understanding sparse filtering: it highlights assumptions and conditions for success behind this feature distribution learning algorithm, and provides insights for developing new feature distribution learning algorithms. PMID- 29232617 TI - Shared reality in interpersonal relationships. AB - Close relationships afford us opportunities to create and maintain meaning systems as shared perceptions of ourselves and the world. Establishing a sense of mutual understanding allows for creating and maintaining lasting social bonds, and as such, is important in human relations. In a related vein, it has long been known that knowledge of significant others in one's life is stored in memory and evoked with new persons-in the social-cognitive process of 'transference'-imbuing new encounters with significance and leading to predictable cognitive, evaluative, motivational, and behavioral consequences, as well as shifts in the self and self-regulation, depending on the particular significant other evoked. In these pages, we briefly review the literature on meaning as interpersonally defined and then selectively review research on transference in interpersonal perception. Based on this, we then highlight a recent series of studies focused on shared meaning systems in transference. The highlighted studies show that values and beliefs that develop in close relationships (as shared reality) are linked in memory to significant-other knowledge, and thus, are indirectly activated (made accessible) when cues in a new person implicitly activate that significant-other knowledge (in transference), with these shared beliefs then actively pursued with the new person and even protected against threat. This also confers a sense of mutual understanding, and all told, serves both relational and epistemic functions. In concluding, we consider as well the relevance of co construction of shared reality n such processes. PMID- 29232618 TI - Pediatric medicolegal autopsy in France: A forensic histopathological approach. AB - The aim of postmortem medicolegal examination in pediatric death is primarily to establish the circumstances and causes of death and to exclude child abuse. In France, pediatric death is systematically documented by medicolegal or medical autopsy. In case of medicolegal autopsy, the complementary examinations, requested and financed by justice, are rarely limited to a histopathological examination. However in medical autopsies other tools are available to the pathologist as toxicology, biochemistry and molecular biology. The purpose of this article is to evaluate the efficacy of forensic histopathology in pediatric forensic autopsies. We analyze the main causes of pediatric death in a forensic context. Between 2004 and 2015, 157 infant deaths were identified in Marseille university hospital. The forensic histopathology and autopsy reports of all 157 cases were available for systematic review. Medical or surgical causes represented 41,3% of deaths in our center, accidental causes 8.1% and child abuse 28,8%. The definitive diagnosis was made at autopsy in 30% of cases and at histopathological examination in 70% highlighting that forensic histopathology is an indispensable tool in pediatric medicolegal autopsies. Significant histological abnormalities may be detected in selected organs such as the brain, lungs, heart, liver, adrenal glands and kidneys in spite of macroscopically normal appearances. This justifies systematic sampling of all organs. Despite the implementation of the French sudden infant death protocol which recommends medical autopsies, too many pediatric autopsies are carried out in a medicolegal context. 30% of the cases remain without diagnosis at the end of the autopsy and histological examination. This number could be reduced by the contribution of others laboratory investigation. PMID- 29232619 TI - Engineering of protein nanopores for sequencing, chemical or protein sensing and disease diagnosis. AB - Biological systems contain highly-ordered structures performing diverse functions. The elegant structures of biomachines have inspired the development of nanopores as single molecule sensors. Over the years, the utility of nanopores for detecting a wide variety of analytes have rapidly emerged for sensing, sequencing and diagnostic applications. Several protein channels with diverse shapes and sizes, such as motor channels from bacteriophage Phi29, SPP1, T3, and T4, as well as alpha-hemolysin, MspA, aerolysin, FluA, OmpF/G, CsgG, ClyA, have been continually investigated and developed as nanopores. Herein, we focus on advances in biological nanopores for single molecule sensing and DNA sequencing from a protein engineering standpoint for changing pore sizes, altering charge distributions, enhancing sensitivity, improving stability, and imparting new detection capabilities. PMID- 29232620 TI - High social trust associated with increased depressive symptoms in a longitudinal South African sample. AB - Several studies have documented a protective association between social trust and mental and physical health, but gaps in knowledge remain. Debates regarding the contextual versus individual nature of social trust are ongoing; research from low- and middle-income countries is lacking, and study designs have been limited for causal inference. To address these gaps, we examined the association between social trust and depressive symptoms using three waves of the National Income Dynamics Study, a longitudinal South African survey. We used individual fixed effects models to assess the association between changes in scores on the Center for Epidemiological Studies Depression Scale Short Form (CES-D-10) and in individual-level and district-level personalized and generalized trust among 15,670 individuals completing at least two waves of the NIDS adult questionnaire. High individual-level generalized trust was unexpectedly associated with increased depressive symptoms scores while district generalized trust did not show an association. We also found a cross-level interaction between individual and district-level personalized trust. High individual trust was associated with increased depressive symptoms scores when district trust was low; however, as district-level trust increased, higher individual trust was associated with reduced depressive symptoms. Our unexpected results suggest that trust may not always be beneficial for depressive symptoms, but rather, that its effects may depend on context. In the South African setting where social trust is low, being very likely to trust may be associated with worse depressive symptoms in some circumstances. PMID- 29232622 TI - Cognitive mechanisms underlying third graders' arithmetic skills: Expanding the pathways to mathematics model. AB - A modified pathways to mathematics model was used to examine the cognitive mechanisms underlying arithmetic skills in third graders. A total of 269 children were assessed on tasks tapping the four pathways and arithmetic skills. A path analysis showed that symbolic number processing was directly supported by the linguistic and approximate quantitative pathways. The direct contribution from the four pathways to arithmetic proficiency varied; the linguistic pathway supported single-digit arithmetic and word problem solving, whereas the approximate quantitative pathway supported only multi-digit calculation. The spatial processing and verbal working memory pathways supported only arithmetic word problem solving. The notion of hierarchical levels of arithmetic was supported by the results, and the different levels were supported by different constellations of pathways. However, the strongest support to the hierarchical levels of arithmetic were provided by the proximal arithmetic skills. PMID- 29232621 TI - Timing of poverty in childhood and adolescent health: Evidence from the US and UK. AB - Childhood poverty is associated with poorer adolescent health and health behaviours, but the importance of the timing of poverty remains unclear. There may be critical or sensitive periods in early life or early adolescence, or poverty may have cumulative effects throughout childhood. Understanding when poverty is most important can support efficient timing of interventions to raise family income or buffer against the effects of low income, but answers may vary across social contexts. The US and the UK are a useful comparison with similar liberal approaches to cash transfers, but very different approaches to healthcare provision. Utilising data from large population studies in the US (n = 9408; born 1979-1996) and UK (n = 1204; born 1991-1997), this study employs a structured life course approach to compare competing hypotheses about the importance of the timing or pattern of childhood exposure to poverty in predicting adolescent health limitations, symptoms of psychiatric distress, and smoking at age 16 (age 15/16 in US). Household income histories identified experience of poverty (measured as <60% of the national median equivalised income for a given year) in early life (ages 0-5), mid-childhood (ages 6-10) and early adolescence (ages 11 15). The Bayesian Information Criterion (BIC) compared fit across models with variables representing different life course patterns of exposure to poverty. Adolescent distress was not associated with poverty in either country. In both countries, however, variables representing cumulative or persistent experiences of poverty exhibited optimal fit of all poverty exposure variables in predicting adolescent smoking and health limitations. There was also evidence of an early life sensitive period for smoking in the US. Poverty was more persistent in the US, but associations between poverty and outcomes were consistent across countries. Although poverty can have cumulative effects on health and behaviour, early interventions may offer the best long-term protection. PMID- 29232623 TI - Determinants of child maltreatment in Nepal: Results from the 2014 Nepal multiple indicator cluster survey (the 2014 NMICS). AB - We examined the prevalence of child maltreatment as measured by the level of physical (moderate to severe) and emotional abuse and child labor, and the associated household level determinants of child maltreatment in Nepal. We used a nationally representative data set from the fifth round of the Nepal Multiple Indicator Cluster Survey (the 2014 NMICS). The main independent variables were household level characteristics. Dependent variables included child experience of moderate to severe physical abuse, emotional abuse, and child labor (domestic work and economic activities). Bivariate analyses and logistic regressions were used to examine the associations between independent and dependent variables. The results showed that nearly half of the children (49.8%) had experienced moderate physical abuse, 21.5% experienced severe physical abuse, and 77.3% experienced emotional abuse. About 27% of the children had engaged in domestic work and 46.7% in various economic activities. At bivariate level, educational level of household's head and household wealth status had shown significant statistical association with child maltreatment (p<0.001). Results from multivariate logistic regressions showed that higher education levels and higher household wealth status protected children from moderate to severe physical abuse, emotional abuse and child labor. In general, child maltreatment is a neglected social issue in Nepal and the high rates of child maltreatment calls for mass awareness programs focusing on parents, and involving all stakeholders including governments, local, and international organizations. PMID- 29232624 TI - Genomic form of rhodopsin DNA nanoparticles rescued autosomal dominant Retinitis pigmentosa in the P23H knock-in mouse model. AB - Retinitis pigmentosa (RP) is a group of inherited retinal degenerative conditions and a leading cause of irreversible blindness. 25%-30% of RP cases are caused by inherited autosomal dominant (ad) mutations in the rhodopsin (Rho) protein of the retina, which impose a barrier for developing therapeutic treatments for this genetically heterogeneous disorder, as simple gene replacement is not sufficient to overcome dominant disease alleles. Previously, we have explored using the genomic short-form of Rho (sgRho) for gene augmentation therapy of RP in a Rho knockout mouse model. We have shown improved gene expression and fewer epigenetic modifications compared with the use of a Rho cDNA expression construct. In the current study, we altered our strategy by delivering a codon-optimized genomic form of Rho (co-sgRho) (for gene replacement) in combination with an RNAi-based inactivation of endogenous Rho alleles (gene suppression of both mutant Rho alleles, but mismatched with the co-sgRho) into a homozygous RhoP23H/P23H knock in (KI) RP mouse model, which has a severe phenotype of adRP. In addition, we have conjugated a cell penetrating TAT peptide sequence to our previously established CK30PEG10 diblock co-polymer. The DNAs were compacted with CK30PEG10 TAT diblock co-polymer to form DNA nanoparticles (NPs). These NPs were injected into the sub-retinal space of the KI mouse eyes. As a proof of concept, we demonstrated the efficiency of this strategy in the partial improvement of visual function in the RhoP23H/P23H KI mouse model. PMID- 29232625 TI - Prenatal detection of trisomy 8 mosaicism: Pregnancy outcome and follow up of a series of 17 consecutive cases. AB - OBJECTIVE: To study the outcome of a series of individuals with prenatal detection of trisomy 8 mosaicism by chorionic villus sampling (CVS) and/or amniocentesis. STUDY DESIGN: The databases of two Italian genetics units were reviewed to identify all consultations requested during pregnancy because of trisomy 8 mosaicism. To evaluate the pregnancy outcome, the regional registry of congenital malformations (including terminations of pregnancies) was consulted; additional follow-up data were collected by a telephone interview. The following outcomes were analysed: delivery, pre- and post-natal growth, psychomotor development, major malformations, other diseases/complications. RESULTS: A total of 17 consecutive cases of trisomy 8 mosaicism were identified. Fourteen cases were first detected among women undergoing prenatal diagnosis by CVS; the remaining ones were identified among women who underwent amniocentesis. In most cases diagnosed by CVS, the chromosomal anomaly was only detected in long-term cell cultures (10/14) and was not confirmed by amniocentesis (11/13). There were two terminations of pregnancy and 15 live births; no major birth defects were observed among live born infants and only a case with prenatal and postnatal growth retardation was observed (mean age at follow-up interview was 5.9 years). CONCLUSION: Our data showed an overall positive prognosis for cases with an apparent confined placental mosaicism and those with low-level mosaicism in amniotic fluid if no congenital anomalies were detected by foetal ultrasound examinations. However, larger studies are warranted to better define the associated risk of neurodevelopmental anomalies. PMID- 29232626 TI - Targeted isolation and identification of bioactive compounds lowering cholesterol in the crude extracts of crabapples using UPLC-DAD-MS-SPE/NMR based on pharmacology-guided PLS-DA. AB - The anti-hyperlipidemic effects of crude crabapple extracts derived from Malus 'Red jade', Malus hupehensis (Pamp.) Rehd. and Malus prunifolia (Willd.) Borkh. were evaluated on high-fat diet induced obese (HF DIO) mice. The results revealed that some of these extracts could lower serum cholesterol levels in HF DIO mice. The same extracts were also parallelly analyzed by LC-MS in both positive and negative ionization modes. Based on the pharmacological results, 22 LC-MS variables were identified to be correlated with the anti-hyperlipidemic effects using partial least square discriminant analysis (PLS-DA) and independent samples t-test. Further, under the guidance of the bioactivity-correlated LC-MS signals, 10 compounds were targetedly isolated and enriched using UPLC-DAD-MS-SPE and identified/elucidated by NMR together with MS/MS as citric acid(1), p-coumaric acid(2), hyperoside(3), myricetin(4), naringenin(5), quercetin(6), kaempferol(7), gentiopicroside(8), ursolic acid(9) and 8-epiloganic acid(10). Among these 10 compounds, 6 compounds, hyperoside(3), myricetin(4), naringenin(5), quercetin(6), kaempferol(7) and ursolic acid(9), were individually studied and reported to indeed have effects on lowering the serum lipid levels. These results demonstrated the efficiency of this strategy for drug discovery. In contrast to traditional routes to discover bioactive compounds in the plant extracts, targeted isolation and identification of bioactive compounds in the crude plant extracts using UPLC-DAD-MS-SPE/NMR based on pharmacology-guided PLS-DA of LC-MS data brings forward a new efficient dereplicated approach to natural products research for drug discovery. PMID- 29232627 TI - The phenomenology of cell size control. AB - Cells control their size through an intricate balance of cell growth, cell division, and cell death. Extensive work on unicellular model organisms revealed that cell-size-dependent cell cycle progression accounts for major aspects of cell size regulation and provided insights into the underlying molecular mechanisms. Nevertheless, elaborate live-cell imaging approaches still reveal new phenomenological observations that challenge our simplified models of size regulation and raise the question of what determines optimal cell size. Here, I aim to give a conceptual overview of the many processes contributing to cell size regulation and summarize recent developments in the field. PMID- 29232628 TI - Epithelial plasticity in the mammary gland. AB - Many epithelial tissues rely on multipotent stem cells for the proper development and maintenance of their diverse cell lineages. Nevertheless, the identification of multipotent stem cell populations within the mammary gland has been a point of contention over the past decade. In this review, we provide a critical overview of the various lineage-tracing studies performed to address this issue and conclude that although multipotent stem cells exist in the embryonic mammary placode, the postnatal mammary gland instead contains distinct unipotent progenitor populations that contribute to stage-specific development and homeostasis. This begs the question of why differentiated mammary epithelial cells can exhibit stem cell behavior in culture. We speculate that such reprogramming potential is repressed in situ under normal conditions but revealed in vitro and might drive breast cancer development. PMID- 29232629 TI - On lithium doping in two stable nano-flakes of the B24: The double-ring versus the quasiplanar configuration. AB - The stable local minima due to the addition of the Li atom to the double-ring and the quasiplanar configurations of the B24 molecule have been searched on the doublet potential energy surface to reveal the structural and electronic features of the Li@B24 system. We report two and seven stable local minima without imaginary vibrational frequency for the Li@B24(double-ring) and the Li@B24(quasiplanar) systems, respectively. The criteria of the adsorption energy, the vertical ionization (VI) energy, the deformation energy, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energy gap, the atomic charges, the spin density distribution, the electron transfer (ET), atoms in molecules (AIM) analysis and the nonlinear optical (NLO) properties have been investigated for all the reported molecules of the Li@B24 system in the present paper. Our results present that both thermodynamic and chemical stability of the Li atom doping to the quasiplanar configuration of the B24 molecule are more than those of the double-ring configuration. Additionally, both the double-ring and the quasiplanar configurations can produce the Li@B24 system with values of high first hyperpolarizability (betatotal) due to the Li atom doping. In all the reported molecules of the Li@B24 system, electron density of the Li atom decreases due to the existence of the double-ring and the quasiplanar configurations confirming the role of the electron donor for the Li atom. In contrast, both decreasing and increasing electron density have been observed in the B atoms of the Li@B24 system. However, the role of electron acceptor (increasing electron density) for the B atoms is more dominant than the role of electron donor (decreasing electron density). This result highlights chemical flexibility of the B atoms. PMID- 29232630 TI - Opioid drugs and stercoral perforation of the colon: Case report and review of literature. AB - INTRODUCTION: Stercoral perforation of the colon is a rare pathology, which is believed to be caused by an increased intraluminal pressure created by a fecaloma. Opioid induced constipation is a rare and often unsuspected cause of colonic perforation. PRESENTATION OF CASE: We report the case of a 58-year-old woman, who presented to the emergency department (ED) with severe hypotension, abdominal pain and gastrointestinal bleeding. She was found to have a diffusely tender and distended abdomen. Her history was positive for long-term suboxone use and chronic constipation. Abdominopelvic computed tomography (CT) scan revealed a bowel perforation, ascites and fecal impaction. Emergency laparotomy revealed extensive stool in the peritoneal cavity as well as hemoperitoneum. There was a fecal bolus with perforation located in the sigmoid colon. On postoperative day (POD) six, a second abdominopelvic CT scan was performed and results revealed the necessity of a second exploratory laparotomy. She had multiple loculated abscesses within the small bowel and other areas, which were opened and washed out. DISCUSSION: Due to the inflating use of drugs in the opioid class, the recognition of this pathology has become increasingly important. The action of the drug on the mu-opioid receptors, any patients taking opioid medications are at risk for constipation progressing to stercoral perforation and should be monitored closely. CONCLUSION: Patients presenting with chronic constipation, fecal impaction on imaging and clinical signs of peritonitis or sepsis, should consider stercoral perforation in their differential diagnosis since early detection is key to reduce mortality rates in these cases. PMID- 29232631 TI - Ambiguous genitalia-A social dilemma in Bangladesh: A case report. AB - INTRODUCTION: Ambiguous Genitalia is a form of birth defect in which sex of the newborn cannot be readily distinguishable because of atypical appearance of the external genitalia. CASE REPORT-CLINICAL FINDINGS: The patient, an 8 months old baby, was identified as a female baby since birth; but, some senior members of their neighborhood raised confusion regarding sex differentiation of the child. On examination, there was enlarged clitoris or micropenis, bifid scrotum or labioscrotal fold, and separate presence of urethral and vaginal orifices. Right testis was found in the middle of right inguinal canal and left testis was found near the deep inguinal ring. CASE REPORT-DIAGNOSIS, THERAPEUTIC INTERVENTION AND OUTCOME: The ultrasonogram showed a rudimentary uterus measuring 26.7*7.27mm with no ovary and the right testis was found in the mid inguinal canal while the left testis was in the deep inguinal ring. Diagnostic endoscopic procedure showed normal appearing testes in deep inguinal ring, about 2cm vaginal remnant with normal urethra and bladder. Hormonal study revealed low serum testosterone with normal DHT and high oestradiol while the karyotyping revealed 46XY. After 3 months of hormonal treatment, multiple surgical interventions were taken to correctly determine the sex of the child. Later on the patient was discharged with follow up advices. CONCLUSION: 'Ambiguous genitalia' is considered as a taboo in Bangladesh; hence, the social awareness regarding this curable disorder is a timely need in Bangladesh. PMID- 29232632 TI - Inactivation of Escherichia coli O157:H7 and Salmonella deposited on gloves in a liquid state and subjected to drying conditions. AB - Gloves are worn by workers harvesting ready-to-eat produce as a deterrent for contaminating the produce with enteric pathogens that may reside on their hands. As fields are not sterile environments, the probability for gloves to become contaminated still exists and therefore it is critical to understand the conditions that affect the survival of pathogens on gloves. Both Escherichia coli O157:H7 and Salmonella deposited on glove surfaces in a liquid state survived longer when the pathogen had been suspended in lettuce sap than when suspended in water. Despite this protection, pathogens deposited on clean single-use gloves were more likely to survive during drying than pathogens deposited on dirty gloves (a film of lettuce sap had been applied to the surface prior to pathogen application and soil had been ground into the gloves). Survival of both E. coli O157:H7 and Salmonella was biphasic with the greatest losses occurring during the first hour of drying followed by much slower losses in the ensuing hours. Pathogens grown in rich media (tryptic soy broth) versus minimal media (M9) as well as those cultured on solid agar versus liquid broth were also more likely to be resistant to desiccation when deposited onto gloves. Although survival of E. coli O157:H7 on nitrile gloves was in general greater than it was on latex gloves, the relative survival of Salmonella on the two glove types was inconsistent. Due to these inconsistencies, no one glove type is considered better than another in reducing the risk for contamination with enteric pathogens. In addition, the extended survival of what are generally referred to as stress-resistant pathogens suggests that gloves either be changed frequently during the day or washed in a disinfectant to reduce the risk of glove contamination that could otherwise contaminate product handled with the contaminated gloves. PMID- 29232633 TI - Carbazole alkaloids from Clausena hainanensis with their potential antiproliferative activities. AB - Five new carbazole alkaloids, clausehainanines A-E (1-5), together with seven known analogues (6-12) were isolated from the stems and leaves of C. hainanensis. Their structures were elucidated by extensive spectroscopic methods. Among them, compounds 1-5 were an unusual type of carbazole alkaloids, possessing diverse isopentenyl derivatives as substituents at C-2. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Alkaloids 1-12 showed significant antiproliferative effects against various human cancer cell lines with IC50 values ranging from 0.12 to 15.56 MUM. These findings suggest that the discoveries of these carbazole alkaloids with significant cytotoxic activities isolated from C. hainanensis could be of great importance to the development of new anticancer agents. PMID- 29232634 TI - Biological evaluation of new imidazole derivatives tethered with indole moiety as potent alpha-glucosidase inhibitors. AB - A series of triarylimidazoles substituted with 2-arylindoles (4a-4j) were prepared and evaluated for their in vitro alpha-Glucosidase inhibition. alpha Glucosidase inhibition assay displayed a new class of highly potent agents The new compounds showed significant alpha-glucosidase inhibitory activity as compared to the standard inhibitor acrabose. Structures of synthesized compounds were determined by using Mass spectrometry FT-IR, 1H NMR and 13C NMR. PMID- 29232635 TI - Symptom recovery and relationship to structure of corpus callosum in individuals with an 'at risk mental state'. AB - Previous studies have revealed that changes in sub-threshold psychotic symptoms observed in individuals with an 'at risk mental state' (ARMS) are associated with biological changes in the corpus callosum (CC). To elucidate the biological background for resilience against transition to psychosis, we investigated the relationship between CC structural changes and recovery of sub-threshold psychotic symptom in subjects with ARMS who did not develop psychosis (ARMS-N). Sixteen healthy controls and 42 ARMS (37 ARMS-N) subjects participated this study. The volumes of five sub-regions of the CC were analyzed using MRI. The sub threshold psychotic symptoms of the ARMS were measured using the Scale of Prodromal Symptoms (SOPS). Imaging and symptoms were re-administered in the ARMS group 52 weeks later. Significant baseline volume differences in the mid posterior CC, central CC and mid-anterior CC were found between the controls and the ARMS-N subjects. These findings suggest that biological abnormalities are present in a so-called "false-positive" group of individuals. For the ARMS-N subjects, improvement in negative symptoms significantly correlated with an increase in the volume of the central CC at follow-up. This finding may suggest that a neurobiological 'resilience' is associated with symptom recovery. PMID- 29232636 TI - Magnetite/Lanthanum hydroxide for phosphate sequestration and recovery from lake and the attenuation effects of sediment particles. AB - An effective approach for eutrophication control and phosphate recovery remains a longstanding challenge. Herein, we present a new technique for phosphate sequestration in lake and phosphate recovery using novel magnetically recoverable magnetite/lanthanum hydroxide [M-La(OH)3] hybrids that can be prepared using a simple one-pot synthesis method. Batch studies show that M-La(OH)3 exhibits a strong sorption towards phosphate with sorption capacities of up to 52.7 mg-P/g at pH 7.0 in water. A simple model indicates that the efficiency of M-La(OH)3 for phosphate sequestration in lake is significantly attenuated by 34-45% compared to that in water, due to interference from sediment particles. However, our results demonstrate that sediments suspensions mixed with a M-La(OH)3 content of 1-3% exhibit a capability of up to 1.2 mg-P/g for sequestering external phosphate compared with that of 0.2 mg-P/g for pristine sediment at pH 7.3. M-La(OH)3-mixed sediment suspensions appear to effectively sequester phosphate over an environmentally relevant pH range from 4 to 8.5. Phosphorus (P) fractionation experiments indicate that the enhanced phosphate sorption by M-La(OH)3-mixed sediment suspensions is mainly due to the increased fractions of NaOH-P and inorganic P. This work indicates that the M-La(OH)3 has the potential for phosphate sequestration and recovery from lake. PMID- 29232637 TI - Copper(II) complexes based on tripodal pyrazolyl amines: Synthesis, structure, magnetic properties and anticancer activity. AB - The Cu(II) complexes [Cu(bpdmpz)Cl]ClO4 (1), [Cu(bdmpzp)Cl]ClO4 (2-ClO4), [Cu(bdmpzp)Cl]PF6 (2-PF6) and [Cu(tdmpza)Cl]ClO4 (3), bpdmpzp=[bis[((2 pyridylmethyl)-di(3,5-dimethyl-1H-pyrazolyl)methyl)]amine, bdmpzp=[bis((di(3,5 dimethyl-1H-pyrazolyl)methyl)-(2-pyridylmethyl)]amine and tdmpza=tris[di(3,5 dimethyl-1H-pyrazolyl)-methyl)]amine were synthesized and characterized by elemental analysis, magnetic and conductivity measurements, electrospray ionization mass spectrometry, infrared and electronic spectroscopy, and X-ray crystallography. The magnetic properties of the complexes, measured at variable temperature, revealed weak antiferromagnetic intermolecular interactions. The cytotoxicity of the complexes 1, 2-ClO4, 3, and 4 ([Cu(bedmpzp)Cl]PF6, where bedmpzp=[bis(3,5-dimethyl-1H-pyrazol-1-yl-1-ethyl)-(2-pyridylmethyl)]amine), was investigated against four human cancer cell lines: A2780 (ovarian), A2780R (cisplatin-resistant variant), HOS (aggressive bone tumors), CaCo2 (epithelial colorectal adenocarcinoma) and on healthy human hepatocytes. The complex 4 was the most cytotoxic one, with IC50=1.4MUM (A2780), 8.3MUM (A2780R), 4.7MUM (HOS) and 10.8MUM (CaCo2). The mass spectrometry-based interaction studies, involving selected sulfur-containing biomolecules and small model proteins, revealed pro oxidant effects of complexes 1 and 4 and differences in stability of both complexes in the mixtures containing the model protein cytochrome c after 24h incubation, complex 1 formed 1:1 adduct, the formation of which was accompanied by the loss of one dimethylpyrazole pendant arm from the bpdmpz ligand, while the complex 4 composition remained intact and the complex formed both 1:1 and 1:2 adducts (cytochrome c vs. Cu(II)-complex). PMID- 29232639 TI - Tracking variations of fluorescent dissolved organic matter during wastewater treatment by accumulative fluorescence emission spectroscopy combined with principal component, second derivative and canonical correlation analyses. AB - Accumulative fluorescence emission (AFE) spectroscopy combined with principal component analysis (PCA), second derivative and canonical correlation analysis (CCA) was firstly developed into an available tool to track variations in dissolved organic matter (DOM) fractions and contents during wastewater treatment. Samples were collected from a wastewater treatment plant with a traditional anaerobic/anoxic/oxic (A2O) process. The AFE spectroscopy deduced from the sum of intensities along the excitation wavelengths of fluorescence excitation emission matrix (EEM), could distinctly track tyrosine-like, tryptophan-like, fulvic-like substances. The AFE spectroscopy with the PCA not only disaggregated DOM fractions into the tyrosine-like, tryptophan-like, microbial humic-like, fulvic-like and humic-like substances, but discriminated DOM fractions from the physical sedimentation, anaerobic/anoxic and oxic processes. Absolute areas of fluorescence components obtained by the second derivative AFF spectra had positive liner correlations with Fmax of the relevant components modeling from EEM-PARAFAC, especially the tryptophan-like (R2 = 0.95, p < 0.01) and tyrosine-like (R2 = 0.83, p < 0.01) substances. The CCA of the sites presented that the potential factors contained the tryptophan-like and tyrosine-like substances. This indirectly proved that the tryptophan-like and tyrosine-like substances were the dominant components of fluorescent DOM, which were further removed in A2O than the other fluorescent components. The CCA of the fluorescent components exhibited that the potential factors included the sites #1 to #6, which were located in the original wastewater, sand setting, primary sedimentation, anaerobic, anoxic, facultative units. This elaborated that the fluorescent components were mainly degraded in the physical sedimentation, anaerobic and anoxic processes. PMID- 29232638 TI - Engineering a self-sufficient Mycobacterium tuberculosis CYP130 by gene fusion with the reductase-domain of CYP102A1 from Bacillus megaterium. AB - CYP130 belongs to the subset of cytochrome P450s from Mycobacterium tuberculosis (Mtb) that have been structurally characterized. Despite several efforts for its functional characterization, CYP130 is still considered an orphan enzyme for which no endogenous or exogenous substrate has been identified. In addition, functional redox-partners for CYP130 have not been clearly established yet, hampering the elucidation of its physiological role. In the present study, a catalytically active fusion protein involving CYP130 and the NADPH reductase domain of CYP102A1 from Bacillus megaterium was created. By screening a panel of known substrates of human P450s, dextromethorphan N-demethylation was identified as a reaction catalyzed by CYP130. The fusion enzyme showed higher catalytic activity, when compared to CYP130 reconstituted with a selection of non-native redox-partners. Molecular dynamics simulation studies based on the crystal structure of CYP130 revealed two primary docking poses of dextromethorphan within the active site consistent with the experimentally observed N-demethylation reaction during the entire molecular dynamics simulation. The dextromethorphan N demethylation reaction was strongly inhibited by azole-drugs and maybe applied to identify mechanism-based inhibitors of CYP130. Furthermore, the present active CYP130-fusion protein may facilitate the identification of endogenous substrates from Mtb. PMID- 29232640 TI - Decomposition of ibuprofen in water via an electrochemical process with nano sized carbon black-coated carbon cloth as oxygen-permeable cathode integrated with ultrasound. AB - The main aim of the present investigation was the treatment of ibuprofen (IBP) polluted aquatic phase using a novel oxygen-permeable cathode (OPC)-equipped electrochemical process (ECP) integrated with ultrasound (US). According to kinetic modeling, the decomposition rate of IBP by the integrated process was 3.2 * 10-2 min-1 which was significant in comparison with the OPC-equipped ECP (1.4 * 10-2 min-1) and US alone (2.4 * 10-3 min-1). Increasing the current resulted in the enhanced generation of H2O2 and consequently, improved the degradation of IBP in the solution. Excessive concentrations of Na2SO4 as supporting electrolyte led to no significant enhancement in the reactor efficiency. At initial IBP concentration of 1 mg L-1, complete removal of IBP with reaction rate of 1.7 * 10 1 min-1 was happened within a short reaction time of 30 min. The pulse mode of US led to more than 10% increase in the removal efficiency compared with the normal mode. The presence of scavenging compound of methanol caused the highest drop in the efficiency of the integrated treatment process, indicating the substantial role of free hydroxyl radicals in the degradation of IBP. Intermediate byproducts generated in the solution during the decomposition were also identified and interpreted. PMID- 29232641 TI - Effect of thiacloprid on early life stages of common carp (Cyprinus carpio). AB - Toxicity of the neonicotinoid pesticide thiacloprid to embryos and larvae of common carp Cyprinus carpio was assessed under laboratory conditions. Carp embryos and larvae were exposed to thiacloprid at four concentrations: 4.5 (environmental concentration), 45, 225, and 450 MUg/L for 35 days and compared to a non-treated control group. The effects on lipid peroxidation, antioxidant enzyme levels (superoxide dismutase, glutathione reductase, catalase, glutathione S-transferase, and reduced glutathione), mortality, growth, development, and histopathogenesis were assessed. Thiacloprid at tested concentrations were not associated with negative effects on hatching, behaviour, embryo viability, or Fulton's condition factor. Carp exposed to 45 MUg/L thiacloprid showed lower weight and length compared to controls. Thiacloprid at 225 and 450 MUg/L delayed development and led to lower weight and length of carp. Significantly lower superoxide dismutase and glutathione reductase activity was observed at all tested concentrations of thiacloprid compared with the control group. Chronic thiacloprid exposure of early-life stages of carp affected ontogeny and growth rate, and inhibited antioxidant capacity. PMID- 29232642 TI - Feasibility of the UV/AA process as a pretreatment approach for bioremediation of dye-laden wastewater. AB - Biodegradability and toxicity are two important indexes in considering the feasibility of a chemical process for environmental remediation. The acetylacetone (AA) mediated photochemical process has been proven as an efficient approach for dye decolorization. Both AA and its photochemical degradation products had a high bioavailability. However, the biocompatibility and ecotoxicology of the UV/AA treated solutions are unclear yet. In the present work, we evaluated the biocompatibility and toxicity of the UV/AA treated solutions at both biochemical and organismal levels. The biodegradability of the treated solution was evaluated with the ratio of 5-d biological oxygen demand (BOD5) to chemical oxygen demand (COD) and a 28-d activated sludge assay (Zahn Wellens tests). The UV/AA process significantly improved the biodegradability of the tested dye solutions. Toxicity was assessed with responses of microorganisms (microbes in activated sludge and Daphnia magna) and plants (bok choy, rice seed, and Arabidopsis thaliana) to the treated solutions, which showed that the toxicity of the UV/AA treated solutions was lower or comparable to that of the UV/H2O2 counterparts. The results are helpful for us to determine whether the UV/AA process is applicable to certain wastewaters and how the UV/AA process could be effectively combined into a sequential chemical-biological water treatment. PMID- 29232643 TI - Mechanical, corrosion and biocompatibility behaviour of Mg-3Zn-HA biodegradable composites for orthopaedic fixture accessories. AB - Development of biodegradable implants has grown into one of the important areas in medical science. Degradability becomes more important for orthopaedic accessories used to support fractured and damaged bones, in order to avoid second surgery for their removal after healing. Clinically available biodegradable orthopaedic materials are mainly made of polymers or ceramics. These orthopaedic accessories have an unsatisfactory mechanical strength, when used in load-bearing parts. Magnesium and its alloys can be suitable candidate for this purpose, due to their outstanding strength to weight ratio, biodegradability, non-toxicity and mechanical properties, similar to natural bone. The major drawback of magnesium is its low corrosion resistance, which also influences its mechanical and physical characteristics in service condition. An effort has been taken in this research to improve the corrosion resistance, bioactivity and mechanical strength of biodegradable magnesium alloys by synthesizing Mg-3wt% Zn matrix composite, reinforced with thermally treated hydroxyapatite(HA) [Ca10(PO4)6(OH)2], a bioactive and osteogenic ceramic. Addition of 5wt% HA is found effective in reducing the corrosion rate by 42% and improvement in the compressive yield strength of biodegradable magnesium alloy by 23%. In-vitro evaluation, up to 56 days, reveal improved resistance to degradation with HA reinforcement to Mg. Osteoblast cells show better growth and proliferation on HA reinforced surfaces of the composite. Mg-HA composite structure shows impressive potential to be used in orthopaedic fracture fixing accessories. PMID- 29232645 TI - Pre-optimization of spinal surgery patients: Development of a neurosurgical enhanced recovery after surgery (ERAS) protocol. AB - OBJECTIVE: Despite surgical, technological, medical, and anesthetic improvements, patient outcomes following elective neurosurgical procedures can be associated with high morbidity. Enhanced recovery after surgery (ERAS) protocols are multimodal care pathways designed to optimize patient outcomes by addressing pre , peri-, and post-operative factors. Despite significant data suggesting improved patient outcomes with the adoption of these pathways, development and implementation has been limited in the neurosurgical population. METHODS/RESULTS: This study protocol was designed to establish the feasibility of a randomized controlled trial to assess the efficacy of implementation of an ERAS protocol on the improvement of clinical and patient reported outcomes and patient satisfaction scores in an elective inpatient spine surgery population. Neurosurgical patients undergoing spinal surgery will be recruited and randomly allocated to one of two treatment arms: ERAS protocol (experimental group) or hospital standard (control group). The experimental group will undergo interventions at the pre-, peri-, and post-operative time points, which are exclusive to this group as compared to the hospital standard group. CONCLUSIONS: The present proposal aims to provide supporting data for the application of these specific ERAS components in the spine surgery population and provide rationale/justification of this type of care pathway. This study will help inform the design of a future multi-institutional, randomized controlled trial. RESULTS: of this study will guide further efforts to limit post-operative morbidity in patients undergoing elective spinal surgery and to highlight the impact of ERAS care pathways in improving patient reported outcomes and satisfaction. PMID- 29232644 TI - Past 15-year trends in lifetime cocaine use among US high school students. AB - BACKGROUND: Most recent research on adolescent drug use has focused on alcohol, tobacco, and marijuana. Less is known about the recent epidemiology of adolescent cocaine use, which has serious health consequences. PURPOSE: To describe recent trends in cocaine use by U.S. high school students, and identify differences in lifetime and repeated use across sex and racial/ethnic groups. METHODS: We used data from the national Youth Risk Behavior Surveys (YRBS) from 1999 to 2015. We estimated the prevalence of lifetime cocaine use (LCU) and repeated lifetime cocaine use (RLCU) across years by race/ethnicity and sex and tested for linear and quadratic trends. RESULTS: The prevalence of LCU decreased from 1999 to 2015 (9.54%-5.19%). RLCU also decreased (5.13%-2.84%). Despite the overall decline, LCU and RLCU both rose between 2009-2015 (LCU:2.78%-5.19%, RLCU:1.58%-2.84%). Boys had higher rates of LCU and RLCU than girls (LCU:6.42% vs 4.65%; RLCU:3.69% vs 2.18%). American Indian/Alaskan Native, Native Hawaiian/Pacific Islander, and Hispanic adolescents had the highest overall prevalence of LCU. Black adolescents' LCU patterns differed from other racial/ethnic groups. The prevalence of LCU among Black boys increased over time, while the prevalence for Black girls remained consistently low. CONCLUSIONS: Adolescent cocaine use is less common today than in the 1990s. However, rates of adolescent cocaine use have risen across all racial/ethnic groups in the past few years. Public health efforts should address at risk groups with particularly high or rising rates of cocaine use. PMID- 29232646 TI - Determination of UV filters in human breast milk using turbulent flow chromatography and babies' daily intake estimation. AB - UV filters (UV-Fs) are a group of hormonally active chemical compounds used to protect against the deleterious effects of UVA and UVB solar radiation, which are currently present in most consumer goods (personal care products, plastics, fabrics, paints, etc). Last years the concern about these emerging contaminants has been on the rise, and increasing efforts are being taken in order to properly asses the hazard that the exposure to these compounds in the early stages of life may pose. In this study, a new method for the analysis of 11 UV-Fs residues in human breast milk samples has been developed. The method is based on turbulent flow chromatography coupled to liquid chromatography-tandem mass spectrometry (TFC-HPLC-MS/MS). The validated method was successfully applied to 79 human breast milk samples from mothers in Barcelona (Spain). Twenty-four per cent of the samples contained UV-Fs, with major contributors being oxybenzone (benzophenone 3, BP3), its metabolite 4,4'-dihydroxybenzophenone (4DHB), and UV320 showing maximum concentrations of 779.9, 73.3, and 523.6ngg-1 milk, respectively. Additionally, the plastic containers of the milks were also analysed, revealing high concentrations of BP3 and 4DHB, up to 10.6ugg-1 plastic. The calculated mean SigmaUV-Fs were useful to estimate the daily intake (EDI) by babies, which were 69.1ug d-1kg-1 body weight. PMID- 29232647 TI - Changes in the physicochemical structure and pyrolysis characteristics of wheat straw after rod-milling pretreatment. AB - Pyrolysis is increasingly used for raw biomass conversion. In this study, the effects of rod-milling pretreatment (RMP) on the physicochemical properties and pyrolysis characteristics of wheat straw (WS) was found. The mechanism behind these changes was further analyzed. RMP appreciably reduced the particle size and cellulose crystallinity, and increased the specific surface area and pore volume of WS. Under RMP, with an increasing conversion rate alpha, the activation energy E was expressed as a para-curve, whereas it was expressed as a tangent curve for samples that underwent hammer-milling pretreatment (HMP). At the same alpha, the thermal degradation temperature for RMP was lower than that for HMP. The E value clearly decreased with RMP, and increased following a wave-like pattern with increased rod-milling strength (RMS). The lowest E value (118.69 or 108.97 kJ/mol) was obtained with a milling time of 60 min. Hence, RMP is an environmental-friendly and effective method for improving the efficiency of pyrolysis. PMID- 29232648 TI - Template-directed fabrication of MIL-101(Cr)/mesoporous silica composite: Layer packed structure and enhanced performance for CO2 capture. AB - A novel hybrid material constituted of MIL-101(Cr) and mesoporous silica was successfully assembled through an in-situ hydrothermal method. The MCM-41 with well-ordered mesopores acted as the structure-directing agent, which regulated the growth of MIL-101(Cr) crystals along a certain direction and restricted the expansion of framework. Meanwhile, the hydroxyl groups existed in MCM-41 preferentially coordinated with the Cr3+ centers in MOF, followed by the layer packed arrangement of MIL-101(Cr) nanocrystals on the surface of matrix. The structural characterizations further revealed that the introduction of MCM-41 could increase the micropore volume and specific surface area. The MIL 101(Cr)@MCM-41 exhibited higher CO2 uptake capacity and adsorption rate compared with the original MIL-101(Cr) at 298 K and 1 bar. Via ideal adsorbed solution theory (IAST), it could be further predicted that the composite was more inclined to adsorb CO2 than N2. The calculated isosteric heats of CO2 adsorption and desorption activation energy demonstrated that the interaction between CO2 molecules and the composite was also enhanced. The as-prepared MIL-101(Cr)@MCM-41 showed good reusability and could be easily regenerated without any reduction in its CO2 adsorption capacity. Hence, this study opened up a new pathway for designing hierarchical porous structured MOF-based materials with advanced gas separation performance. PMID- 29232649 TI - Multi-hypothesis tracking of the tongue surface in ultrasound video recordings of normal and impaired speech. AB - Characterizing tongue shape and motion, as they appear in real-time ultrasound (US) images, is of interest to the study of healthy and impaired speech production. Quantitative anlaysis of tongue shape and motion requires that the tongue surface be extracted in each frame of US speech recordings. While the literature proposes several automated methods for this purpose, these either require large or very well matched training sets, or lack robustness in the presence of rapid tongue motion. This paper presents a new robust method for tongue tracking in US images that combines simple tongue shape and motion models derived from a small training data set with a highly flexible active contour (snake) representation and maintains multiple possible hypotheses as to the correct tongue contour via a particle filtering algorithm. The method was tested on a database of large free speech recordings from healthy and impaired speakers and its accuracy was measured against the manual segmentations obtained for every image in the database. The proposed method achieved mean sum of distances errors of 1.69 +/- 1.10 mm, and its accuracy was not highly sensitive to training set composition. Furthermore, the proposed method showed improved accuracy, both in terms of mean sum of distances error and in terms of linguistically meaningful shape indices, compared to the three publicly available tongue tracking software packages Edgetrak, TongueTrack and Autotrace. PMID- 29232650 TI - Internal validation of two new retrotransposons-based kits (InnoQuant(r) HY and InnoTyper(r) 21) at a forensic lab. AB - Obtaining a genetic profile from pieces of evidence collected at a crime scene is the primary objective of forensic laboratories. New procedures, methods, kits, software or equipment must be carefully evaluated and validated before its implementation. The constant development of new methodologies for DNA testing leads to a steady process of validation, which consists of demonstrating that the technology is robust, reproducible, and reliable throughout a defined range of conditions. The present work aims to internally validate two new retrotransposon based kits (InnoQuant(r) HY and InnoTyper(r) 21), under the working conditions of the Laboratorio de Policia Cientifica da Policia Judiciaria (LPC-PJ). For the internal validation of InnoQuant(r) HY and InnoTyper(r) 21 sensitivity, repeatability, reproducibility, and mixture tests and a concordance study between these new kits and those currently in use at LPC-PJ (Quantifiler(r) Duo and GlobalFilerTM) were performed. The results obtained for sensitivity, repeatability, and reproducibility tests demonstrated that both InnoQuant(r) HY and InnoTyper(r) 21 are robust, reproducible, and reliable. The results of the concordance studies demonstrate that InnoQuant(r) HY produced quantification results in nearly 29% more than Quantifiler(r) Duo (indicating that this new kit is more effective in challenging samples), while the differences observed between InnoTyper(r) 21 and GlobalFilerTM are not significant. Therefore, the utility of InnoTyper(r) 21 has been proven, especially by the successful amplification of a greater number of complete genetic profiles (27 vs. 21). The results herein presented allowed the internal validation of both InnoQuant(r) HY and InnoTyper(r) 21, and their implementation in the LPC-PJ laboratory routine for the treatment of challenging samples. PMID- 29232651 TI - Body packing and intra-vaginal body pushing of cocaine: A case report. AB - Drug trafficking is an international problem. The prevalence of drug trafficking and newer concealing methods has been ever increasing. Body packing is described as using the abdominal or pelvic cavity for concealing illegal drugs. Body pushers smuggle illicit drugs by inserting them into rectum or vagina. These cases are either presented to the emergency departments as Body Packer Syndrome or as asymptomatic cases for observation, detained for alleged possession of contraband substances. We report a unique case of an asymptomatic white female who was detained at Mumbai International Airport under suspicion and brought to hospital for observation. X ray and CT scan examination revealed 7 wrapped packets in gastrointestinal track and 1 large packet in vagina. A case of female body packer using multiple modalities of concealment especially in vagina is rare in India so it is becomes imperative to present this case in the light of body packing and body pushing of contraband substances. PMID- 29232652 TI - Effect of ornithine decarboxylase and norspermidine in modulating cell division in the green alga Chlamydomonas reinhardtii. AB - The extensive genetic resources of Chlamydomonas has led to its widespread use as a model system for understanding fundamental processes in plant cells, including rates of cell division potentially modulated through polyamines. Putrescine was the major polyamine in both free (88%) and membrane-bound fractions (93%) while norspermidine was the next most abundant in these fractions accounting for 11% and 6%, respectively. Low levels of diaminopropane, spermidine and spermine were also observed although no cadaverine or norspermine were detected. Ornithine decarboxylase (ODC, EC 4.1.1.17) activity was almost five times higher than arginine decarboxylase (ADC, EC 4.1.1.19) and is the major route of putrescine synthesis. The fluoride analogue of ornithine (alpha-DFMO) inhibited membrane associated ODC activity whilst simultaneously stimulating cell division in a dose dependent manner. Following exposure to alpha-DFMO the putrescine content in the cells declined while the norspermidine content increased over two fold. Addition of norspermidine to cultures stimulated cell division mimicking the effects observed using DFMO and also reversed the inhibitory effects of cyclohexylamine on growth. The results reveal that ODC is the major route to polyamine formation in the Chlamydomonas CC-406 cell-wall mutant, in contrast to the preferential ADC route reported for Chlorella vulgaris, suggesting that significant species differences exist in biosynthetic pathways which modulate endogenous polyamine levels in green algae. PMID- 29232654 TI - CXCL12-CXCR4 axis in feline mammary carcinoma. PMID- 29232653 TI - Salicylic acid and broad spectrum of NBS-LRR family genes are involved in SMV soybean interactions. AB - Soybean mosaic virus (SMV) is a severe pathogen reducing crop yield and seed quality of soybean. Although several resistance gene loci including Rsv1, Rsv3 and Rsv4 are identified in some soybean varieties, most of the soybean genes related to SMV infection are still not characterized. In order to reveal genome wide gene expression profiles in response to SMV infection, we used transcriptome analysis to determine SMV-responsive genes in susceptible variety Hefeng25. Time course RNA-seq analysis at 1, 5 and 10 dpi identified many deregulated pathways and gene families. "Plant-pathogen interaction" pathway with KEGG No. of KO04626 was highly enriched and dozens of NBS-LRR family genes were significantly down regulated at 5 dpi. qRT-PCR analyses were performed to verify expression patterns of these genes and most were in accordance with the RNA-seq data. As NBS-LRR family proteins are broadly involved in plant immunity responses, our results indicated the importance of this time point (5 dpi) for SMV-soybean interaction. Consistent with it, SMV titer was increased from 1 dpi to 10 dpi and peaked at 5 dpi. Expression of SA (salicylic acid) marker gene PR-1 was induced by SMV infection. Application of exogenous MeSA, an active form of SA, primed the plant resistant to virus infection and reduced SMV accumulation in soybean. Interestingly, MeSA treatment also significantly upregulated expressions of SMV responsive NBS-LRR genes. Compared with susceptible line Hefeng25, endogenous SA level was higher and was consistently induced by SMV infection in resistant variety RV8143. Moreover, expressions of NBS-LRR family genes were up-regulated by SMV infection in RV8143, while they were down-regulated by SMV infection in Hefeng25. Our results implied that SA and NBS-LRR family genes were involved in SMV-soybean interaction. SMV could compromise soybean defense responses by repression of NBS-LRR family genes in Hefeng25, and SA was implicated in this interaction process. PMID- 29232655 TI - Towards specific inhibition of mTORC2. PMID- 29232656 TI - Targeting oral cancer epigenome via LSD1. PMID- 29232657 TI - TC-PTP nuclear trafficking in keratinocytes. PMID- 29232658 TI - A Meta-Analysis of Randomized Controlled Trials on the Use of Suction Drains Following Rectal Surgery. AB - BACKGROUND: Anastomotic leakage is one of the most feared complications of rectal resections. The role of drains in limiting this occurrence or facilitating its early recognition is still poorly defined. We aimed to study whether the presence of prophylactic pelvic drains affects the surgical outcomes of patients undergoing rectal surgery with extraperitoneal anastomosis. METHODS: PubMed, EMBASE, and the Cochrane Library were systematically searched for randomized controlled trials comparing drained with undrained anastomoses following rectal surgery. We evaluated possible differences on the relative incidences of anastomotic leakage, pelvic collection or sepsis, bowel obstruction, reoperation rate, and overall mortality. A meta-analysis of relevant studies was performed with RevMan 5.3. RESULTS: A total of 760 patients from 4 randomized controlled studies were considered eligible for data extraction. The use of drains did not show any advantage in terms of anastomotic leak (OR 0.99), pelvic complications (OR 0.87), reintervention (OR 0.84) and mortality. Contrariwise, the incidence of postoperative bowel obstruction was significantly higher in the drained group (OR 1.61). CONCLUSIONS: The routine utilization of pelvic drains does not confer any significant advantage in the prevention of postoperative complications after rectal surgery with extraperitoneal anastomosis. Moreover, a higher risk of postoperative bowel obstruction can be of concern. PMID- 29232659 TI - Phytosphingosine Prevents the Formation of Young Salivary Biofilms in vitro. AB - Dental biofilms are formed in a multistep process that is initiated by the adhesion of oral bacteria to the dental hard surface. As dental biofilms are associated with oral diseases their control is necessary in order to maintain oral health. Recently, it was revealed that phytosphingosine (PHS)-treated hydroxyapatite discs showed anti-adhesive activity in a static in vitro biofilm model against Streptococcus mutans. The goal of the present study was to further unravel the anti-adhesive and anti-biofilm properties of PHS in both static and dynamic in vitro biofilm models against a full salivary inoculum. After 3 h under static conditions, bacterial adherence on PHS-treated cover glass slides was reduced by 60% compared to the untreated surface. After 6 and 24 h under static conditions, no significant differences in bacterial adherence were observed between PHS-treated and untreated cover glass slides. However, under dynamic conditions, i.e., the presence of shear forces, virtually no bacterial adherence was observed for up to 16 h on PHS-coated surfaces. Besides, PHS showed a strong bactericidal activity on salivary biofilms. Treatment of a 3- and 6-h statically grown biofilm resulted in a 99 and 94% reduction of viable cells, respectively, which was effectuated within minutes. In principle, these anti-adherence and anti biofilm properties make PHS a promising candidate ingredient for use in oral care products aimed at oral microbial control. PMID- 29232660 TI - Vanishing Pancreatic Cysts during Follow-Up: Another Step Towards De-Emphasizing Cyst Size as a Major Clinical Predictor of Malignancy. AB - INTRODUCTION: In the management of pancreatic cystic neoplasms (PCN), size plays a crucial role as the expression of disease progression. While many evidences regarding the natural history of growing pancreatic cysts exist, almost no data are available regarding cysts with a reduction in size. METHODS: Radiological and clinical data from patients of the dedicated pancreatic cysts outpatient clinic of the Department of General and Pancreatic Surgery, University of Verona Hospital were retrospectively reviewed. Patients diagnosed with PCNs reducing in size during follow-up were reviewed. RESULTS: From a total of 3,146 patients, we identified 12 (0.38%) vanishing/reducing cysts without a history of pancreatitis. Most of them were presumed IPMN (66.6%). The median follow-up was 69 months and the median cyst's size 30 mm (range 10-49). Most of the patients (75%) experienced a reduction in cyst size (median reduction of 8 mm, range 6-22) after a median time of 12 months (range 6-63), 3 patients experienced a complete disappearance of the cyst. CONCLUSION: Cyst size reduction during follow-up is a rare phenomenon of unknown explanation. It adds to the debate regarding the role of size as a clinical predictor whenever a definite diagnosis of a PCN cannot be reached. PMID- 29232661 TI - Downregulation of Long Noncoding RNA Gas5 Affects Cell Cycle and Insulin Secretion in Mouse Pancreatic beta Cells. AB - BACKGROUND: Evidence shows that long non-coding RNAs (lncRNAs) are involved in individual development, cell differentiation, cell cycle processes and other important life processes and are closely related to major human diseases, including diabetes. Recent studies have reported that lncRNAs are involved in beta cell functions and that lncRNA Gas5 levels decreased in T2DM patients' serum. The purpose of this study was to clarify the role of lncRNA Gas5 in mouse beta cell functions in vitro and in vivo. METHODS: lncRNA Gas5 expression in T2DM and normal mouse tissues was analyzed using qRT-PCR. RNAi, qRT-PCR, Annexin V FITC assays, western blot, GSIS and RIA were performed to detect the effects of lncRNA Gas5 on insulin synthesis and secretion in vitro and in vivo. RESULTS: The lncRNA Gas5 level was significantly decreased in db/db mice. However, lncRNA Gas5 expression was relatively high in the pancreas of normal mice. Knockdown of lncRNA Gas5 expression led to cell cycle G1 arrest and impaired insulin synthesis and secretion in Min6 cells. Further, knockdown of lncRNA Gas5 expression in primary isolated islets resulted in decreased expression of insulin gene and transcription factors, Pdx1 and MafA. These results indicate that lncRNA Gas5 might perform as a new regulator, maintaining beta cell identity and function by affecting insulin synthesis and secretion. PMID- 29232662 TI - A Multicenter Clinical Evaluation of Data Logging in Cochlear Implant Recipients Using Automated Scene Classification Technologies. AB - Currently, there are no studies assessing everyday use of cochlear implant (CI) processors by recipients by means of objective tools. The Nucleus 6 sound processor features a data logging system capable of real-time recording of CI use in different acoustic environments and under various categories of loudness levels. In this study, we report data logged for the different scenes and different loudness levels of 1,366 CI patients, as recorded by SCAN. Monitoring device use in cochlear implant recipients of all ages provides important information about the listening conditions encountered in recipients' daily lives that may support counseling and assist in the further management of their device settings. The findings for this large cohort of active CI users confirm differences between age groups concerning device use and exposure to various noise environments, especially between the youngest and oldest age groups, while similar levels of loudness were observed. PMID- 29232663 TI - Serum Leptin, Resistin, and Adiponectin Concentrations in Psoriasis: A Meta Analysis of Observational Studies. AB - BACKGROUND: Psoriasis is an immune-mediated, inflammatory disease. Adipokines contribute to the regulation of immune-mediated processes and inflammation. OBJECTIVE: The aim of our study was to systematically review the literature for studies that have evaluated the circulating concentrations of adipokines in patients with psoriasis and controls and to meta-analyze the best evidence available. METHODS: Eligible were studies that have assessed leptin, resistin, or adiponectin concentrations in psoriatic patients and a reference group. The study was conducted in adherence with the PRISMA standards. RESULTS: Psoriatic patients had higher leptin concentrations compared to controls (random effects model, mean difference, MD = 5.64 ng/mL, 95% CI: 3.00-8.29, p < 0.0001). Heterogeneity among studies was high (I2 = 95.9%). Psoriatic patients had higher resistin concentrations compared to controls (MD = 4.66 ng/mL, 95% CI: 2.62-6.69, p < 0.0001). Heterogeneity was high (I2 = 99.2%). Finally, psoriatic patients had lower adiponectin concentrations compared to controls (MD = -1.87 MUg/mL, 95% CI: -2.76 to -0.98, p < 0.0001). Heterogeneity was high (I2 = 95.9%). CONCLUSION: The study supported the hypothesis that leptin and resistin concentrations are higher and adiponectin concentrations are lower in patients with psoriasis compared to controls. Hereby, the suggested pathogenic link between psoriasis and metabolic syndrome/obesity is reinforced and the role of comorbidities in psoriasis is highlighted. PMID- 29232664 TI - Vaccination Practices in Pediatric Dialysis Patients Across Europe. A European Pediatric Dialysis Working Group and European Society for Pediatric Nephrology Dialysis Working Group Study. AB - BACKGROUND: Data on the immunization practices in pediatric chronic kidney disease (CKD) patients are scarce. The purpose of this study was to evaluate current vaccination practices for children on dialysis across European pediatric nephrology centers. METHODS: A total of 18 tertiary pediatric nephrology centers from 12 European countries were included in the study. The data on universal national immunization programs and immunization practices for children with chronic disease or risk were recorded from European Center for Disease Prevention and Control and the World Health Organization. The immunization practices and center protocols for monitoring antibody titers after vaccination in dialysis patients were obtained through a questionnaire. RESULTS: All centers included in the study recommended immunization against hepatitis B virus (HBV), diphtheria, tetanus, pertussis, Hemophilus influenzae type b (Hib), poliomyelitis, measles, mumps, rubella (MMR), and streptococcus pneumonia in dialysis patients. In 16 centers, dialysis patients were vaccinated against influenza virus annually. HBV protective antibody titers were measured in 17 centers (during dialysis period in 14 centers, during pre-renal transplantation preparations in 14 centers or in both times in 11 centers). Hepatitis A virus (HAV) was reported to be followed in 13 centers, in 8 centers during dialysis period, and in 11 centers during pre-RTx preparations. MMR and varicella-zoster virus (VZV) protective antibody titers were measured during the dialysis period or before renal transplantation (RTx) in 12 and 15 centers, respectively, and in 6 centers both titers were checked both times. CONCLUSION: There are variations in vaccination practice across Europe. Children with CKD, those undergoing dialysis, and transplant candidates should receive age-appropriate vaccinations before RTx as well as before the transition to adult nephrology clinics and antibody levels should be monitored to evaluate the immunization status before and after RTx. PMID- 29232665 TI - The Laryngeal Mask Airway and Its Use in Neonatal Resuscitation: A Critical Review of Where We Are in 2017/2018. AB - Studies using videotape recordings and respiratory function monitoring have shown that both face mask (FM) application and endotracheal tube (ETT) placement represent a challenge for resuscitators. Hence, there is a strong need for devices that can largely be used independently of individual operator training levels, in order to ensure more reliable support in time-critical situations, such as neonatal resuscitation. The laryngeal mask airway device (LMA) has evolved as a potentially very valuable tool. We conducted a systematic review of studies evaluating the use of the LMA in neonatal resuscitation. An electronic literature search of large medical databases was performed to identify relevant publications on the use of an LMA during neonatal delivery room (DR) resuscitation. Following a rigorous systematic review, we identified a total of 7 randomized controlled trials with results indicating that initial respiratory management of newborn infants with an LMA is feasible for a defined subgroup of infants, but the evidence is still insufficient to recommend the LMA instead of FM ventilation in the DR. There is, in particular, a dearth of evidence of the use of LMA in neonates born before 34 weeks' gestational age or weighing <1,500 g at birth. There were no reports on significant complications following the use of LMA; however, evidence is still limited regarding short- and long-term outcomes. We conclude that the limited currently available evidence suggests that the use of the LMA is a feasible and safe alternative to mask ventilation of late preterm and term infants in the DR. The potential use of LMA resuscitation, in particular for low-gestation and low-birth-weight infants, needs further study. PMID- 29232666 TI - Validation of the Hebrew Version of the Eating Assessment Tool-10 (H-EAT-10). AB - BACKGROUND AND OBJECTIVES: Dysphagia is a common disability with different etiologies. In order to measure dysphagia symptom severity and effects on quality of life, the Eating Assessment Tool (EAT-10) was developed and validated in the English language. We aimed to develop a Hebrew version of the EAT-10 and to evaluate its internal consistency, test-retest reliability, and validity in Hebrew-speaking adults with dysphagia. SUBJECTS AND METHODS: The Hebrew EAT-10 (H EAT-10) questionnaire was completed by 132 patients: 56 patients with dysphagia and 76 controls. Internal consistency analysis was calculated using Cronbach alpha, and test-retest reliability was calculated using intraclass correlation coefficient in order to assess clinical validity. RESULTS: Internal consistency and test-retest reliability were found to be high in the H-EAT-10 (Cronbach alpha = 0.955 and intraclass correla tion = 0.98). In addition, H-EAT-10 scores in the dysphagia group were found to be significantly higher than those in the control group (p < 0.001). CONCLUSION: This study demonstrated that H-EAT-10 is a reliable and valid tool that may be implemented for clinical practice and research on dysphagia in a Hebrew-speaking population. PMID- 29232667 TI - Correlation between Subpubic Arch Angle and Mode of Delivery in Large-for Gestational-Age Fetuses. AB - OBJECTIVES: A narrow subpubic arch angle (SPA) has been associated with a higher risk of operative delivery and prolonged labor. The aim of this study was to evaluate the correlation between SPA and labor outcome in a cohort of women delivering a large-for-gestational-age (LGA) fetus. METHODS: An observational study involving two Italian tertiary centers (Parma and Rome) was carried out. Nulliparous women referred to the antepartum clinic between 35 and 39 weeks due to an increased risk of having an LGA fetus at birth were prospectively selected for the study purpose. Within the study cohort, SPA measurements were obtained by means of transperineal 3D ultrasound. Elective caesarean section and birth weight below 3,750 g represented exclusion criteria. In the final study group, SPA values were compared between the patients who underwent spontaneous vaginal delivery (SVD) and those who were submitted to unplanned obstetric intervention (UOI) due to prolonged or arrested labor (vacuum delivery or caesarean section). RESULTS: Overall, 129 women were included, and the mean birthweight of the neonates was 4,066 +/- 263.03 g. SVD occurred in 63 patients (48.8%), whereas UOI due to prolonged or arrested labor was performed in 66 (51.2%), including 21 cases of vacuum delivery and 45 caesarean sections. The SPA was significantly smaller among women who underwent UOI than in those who achieved SVD (107.9 +/- 13.4 vs. 120.7 +/- 9.4 degrees , p < 0.001). Furthermore, SPA width was inversely correlated with labor length (p < 0.001). Multivariable logistic regression analysis showed that a smaller SPA (OR 1.091, 95% CI 1.051-1.134, p < 0.001) and an increased birthweight (OR 1.002, 95% CI 1.000-1.004, p = 0.037) were independent risk factors for operative delivery. CONCLUSION: SPA measurement before labor is helpful in predicting the risk of operative delivery due to prolonged or arrested labor among nulliparous women delivering LGA fetuses. PMID- 29232668 TI - Revised Reference Values for the Intake of Sodium and Chloride. AB - BACKGROUND: In January 2017, the nutrition societies of -Germany, Austria and Switzerland revised the reference values for sodium and chloride intake. METHODS: For adults, the estimated value for sodium intake was derived on the basis of a balance study. The estimated values for children and adolescents were extrapolated from this estimated value considering differences in body mass. For infants aged 0 to under 4 months, an estimated value was set based on the sodium intake via breast milk. From this value the estimated value for infants aged 4 to under 12 months was also derived by extrapolation. The estimated value for lactating women takes into account the fact that the sodium loss via breast milk is compensated through homoeostatic mechanisms. Except for infants, the reference values for chloride intake were derived based on the estimated values for sodium intake. RESULTS: For adults, pregnant and lactating women, the estimated values for sodium and chloride intake are set at 1,500 and 2,300 mg/day. DISCUSSION AND CONCLUSION: Reference values for sodium and chloride can be derived in terms of estimated values. Considering dietary recommendations for sodium and chloride, it must be taken into account that high intake of sodium chloride (salt) is associated with adverse health effects, for example, hypertension and cardiovascular diseases. Therefore, it is necessary to lower salt intake in the general population. PMID- 29232669 TI - Implication of Haemodiafiltration Flow Rate on Amikacin Pharmacokinetic Parameters in Critically Ill Patients. AB - BACKGROUND: To analyse the effect of haemodiafiltration (CVVHDF) flow rate on amikacin pharmacokinetics and blood concentrations. METHODS: Prospective observational study. Patients receiving CVVHDF and amikacin treatment were included. Pharmacokinetic parameters were calculated using Bayesian analysis. Spearman correlation test was used in order to assess the influence of CVVHDF flux on amikacin minimum concentration (Cmin) and plasma clearance. RESULTS: Thirty patients undergoing CVVHDF procedures were included. The treatment with amikacin started at an initial mean dose of 12.4 (4.1) mg/kg/day. An association between the flow rate and Cmin value (r = 0.261; p = 0.161) and plasma clearance was found (r = 0.268; p = 0.152). Four patients (13.3%) were not able to achieve peak concentration over MIC value higher than 8. In 4 patients, amikacin had to be discontinued due to a high Cmin value. CONCLUSIONS: Amikacin clearance in patients with CVVHDF is affected by the flow rate used. Therefore, CVVHDF dose should be taken into account when dosing amikacin. PMID- 29232670 TI - Some Galeomorph Sharks Express a Mammalian Microglia-Specific Protein in Radial Ependymoglia of the Telencephalon. AB - Ionized calcium-binding adapter molecule 1 (Iba1), also known as allograft inflammatory factor 1 (AIF-1), is a highly conserved cytoplasmic scaffold protein. Studies strongly suggest that Iba1 is associated with immune-like reactions in all Metazoa. In the mammalian brain, it is abundantly expressed in microglial cells and is used as a reliable marker for this cell type. The present study used multiple-label microscopy and Western blotting to examine Iba1 expression in the telencephalon of 2 galeomorph shark species, the swellshark (Cephaloscyllium ventriosum) and the horn shark (Heterodontus francisci), a member of an ancient extant order. In the swellshark, high Iba1 expression was found in radial ependymoglial cells, many of which also expressed glial fibrillary acidic protein. Iba1 expression was absent from most cells in the horn shark (with the possible exception of perivascular cells). The difference in Iba1 expression between the species was supported by protein analysis. These results suggest that radial ependymoglia of the elasmobranchs may be functionally related to mammalian microglia and that Iba1 expression has undergone evolutionary changes in this cartilaginous group. PMID- 29232672 TI - Use of a Novel Device to Assess Intraoral and Intrapharyngeal Baropressure during Sound Production. AB - OBJECTIVE: We developed a novel device that simultaneously measures oral and intrapharyngeal baropressure. The transducer has the advantage that it can be placed in any region. We determined the effect of different speech samples on baropressure in these regions. PATIENTS AND METHODS: Seven healthy individuals produced speech samples comprising vowels and consonants (e.g., /aka/, /apa/, and /ash/). Two transducers were installed into the experimental plate at the incisive papillae and center of the Ah-line; a third transducer was placed in the mid-pharyngeal cavity. During each task, 3 parameters were analyzed: peak pressure, mean pressure, and the temporal relationship between sound signals and pressure changes. RESULTS: The mean pressure did not change during the production of a single vowel; however, the pressure transiently increased during the production of the speech samples, depending on the place of articulation. Moreover, the place of articulation affected the onset and peak timing of pressure changes. CONCLUSIONS: These findings indicate that pressure changes during the production of speech samples reflect the functional aspects of speech production. In particular, simultaneous pressure recordings at multiple locations would provide precise information about speech production, compared to pressure studies that used a single pressure transducer. PMID- 29232671 TI - Predicting Trajectories of Functional Decline in 60- to 70-Year-Old People. AB - BACKGROUND: Early identification of people at risk of functional decline is essential for delivering targeted preventive interventions. OBJECTIVE: The aim of this study is to identify and predict trajectories of functional decline over 9 years in males and females aged 60-70 years. METHODS: We included 403 community dwelling participants from the InCHIANTI study and 395 from the LASA study aged 60-70 years at baseline, of whom the majority reported no functional decline at baseline (median 0, interquartile range 0-1). Participants were included if they reported data on >=2 measurements of functional ability during a 9-year follow up. Functional ability was scored with 6 self-reported items on activities of daily living. We performed latent class growth analysis to identify trajectories of functional decline and applied multinomial regression models to develop prediction models of identified trajectories. Analyses were stratified for sex. RESULTS: Three distinct trajectories were identified: no/little decline (219 males, 241 females), intermediate decline (114 males, 158 females), and severe decline (36 males, 30 females). Higher gait speed showed decreased risk of functional limitations in males (intermediate limitations, odds ratio [OR] 0.74, 95% CI 0.57-0.97; severe limitations, OR 0.42, 95% CI 0.26-0.66). The final model in males further included the predictors fear of falling and alcohol intake (no/little decline, area under the receiver operating curve [AUC] 0.68, 95% CI 0.62-0.73; intermediate decline, AUC 0.63, 95% CI 0.56-0.69; severe decline, AUC 0.79, 95% CI 0.71-0.87). In females, higher gait speed showed a decreased risk of intermediate limitations (OR 0.51, 95% CI 0.38-0.68) and severe limitations (OR 0.18, 95% CI 0.07-0.44). Other predictors in females were age, living alone, economic satisfaction, balance, physical activity, BMI, and cardiovascular disease (no/little decline, AUC 0.80, 95% CI 0.75-0.85; intermediate decline, AUC 0.74, 95% CI 0.69-0.79; severe decline, AUC 0.95, 95% CI 0.91-0.99). CONCLUSION: Already in people aged 60-70 years, 3 distinct trajectories of functional decline were identified in these cohorts over a 9-year follow-up. Predictors of trajectories differed between males and females, except for gait speed. Identification of people at risk is the basis for targeting interventions. PMID- 29232673 TI - Association Between Urinary Alpha1-Microglobulin Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study. AB - BACKGROUND: We aimed to explore the association between urinary alpha1 microglobulin (A1M) levels and nonalcoholic fatty liver disease (NAFLD) in a Chinese population. STUDY: We performed a cross-sectional study among 2,215 Chinese who attended their annual health examination at First Affiliated Hospital, College of Medicine, Zhejiang University. Urinary A1M-creatinine ratio and other clinical and laboratory parameters were measured. RESULTS: A total of 20.9% of subjects fulfilled the diagnostic criteria of NAFLD. NAFLD subjects had significantly higher urinary A1M-creatinine ratios. These levels were positively associated with NAFLD prevalence. The association between A1M-creatinine ratio and NAFLD was independent of hyperglycemia status. Stepwise regression showed that urinary A1M-creatinine ratio was significantly associated with the risk for NAFLD. Urinary A1M-creatinine ratio was an independent factor predicting advanced fibrosis (FIB-4 >=1.3) in NAFLD patients. CONCLUSIONS: Our results showed a significant association between urinary A1M-creatinine ratio and NAFLD. PMID- 29232674 TI - Speech and Language Pathologists' Voice Use in Working Environments: A Field Study Using Ambulatory Phonation Monitoring. AB - OBJECTIVE: The aim of this study was to evaluate the speech and language pathologists' (SLPs) voice production during a typical working day. PATIENTS AND METHODS: A total of 28 SLPs, all females, were enrolled. According to the type of treated disease, the cohort of SLPs was divided into 4 groups (7 SLPs focused on the rehabilitation of dysphagic adult clients; 7 SLPs focused on the rehabilitation of deaf children; 7 SLPs focused on the rehabilitation of dysphonic adult clients; and 7 SLPs focused on the rehabilitation of aphasic adult clients). The voice production evaluation was performed using ambulatory phonation monitoring (APM). RESULTS: Significant differences in the APM results were found between the 4 groups of SLPs. In particular, SLPs focusing on the treatment of dysphonic and deaf clients experienced a higher vocal load than SLPs focusing on the treatment of aphasic and dysphagic clients. CONCLUSION: SLPs may experience heavy vocal loads during working hours. In addition, it seems that some rehabilitation settings could be more vocally demanding than others. PMID- 29232675 TI - Evaluation of Novel Anticaries Adhesive in a Secondary Caries Animal Model. AB - We investigated the anticaries properties of an adhesive containing dimethylaminododecyl methacrylate (DMADDM) in vivo via a secondary caries animal model. Cavities were prepared in the maxillary first molars of Wistar rats. DMADDM-containing adhesives were applied on one side and commercial adhesives on the opposite side as a control. After a 3-week feeding period to induce secondary caries, the molars were harvested for the evaluation of the secondary caries. Lesion depth (LD) and mineral loss (ML) were measured via a micro-CT method, and a modified Keyes scoring method yielded scores for the caries lesions. Statistical analysis was divided into 2 parts: a correlation analysis between 2 evaluations with one-way ANOVA and a least-significant differences (LSD) test, and an evaluation of anticaries adhesives with a paired samples t test. The results showed that: (1) secondary caries was successfully produced in rats; (2) there was a correlation between the modified Keyes scoring method and micro-CT in the evaluation of the secondary caries; (3) the adhesive containing DMADDM significantly reduced both LD and ML (according to micro-CT), and also lowered the scores (based on the modified Keyes scoring method). This suggests that the novel DMADDM adhesive could perform an anticaries function in vivo via the secondary caries animal model which was also developed and testified in research. Secondary caries is one of the major reasons leading to the failure of caries restoration treatment. As a solution, anticaries adhesives perform well in biofilm inhibition in vitro. However, the lack of secondary caries animal models limits the evaluation of anticaries adhesives in vivo. PMID- 29232676 TI - Progressive Development of Aberrant Smooth Muscle Cell Phenotype in Abdominal Aortic Aneurysm Disease. AB - Abdominal aortic aneurysm (AAA) is a silent, progressive disease with a high mortality and an increasing prevalence with aging. Smooth muscle cell (SMC) dysfunction contributes to gradual dilatation and eventual rupture of the aorta. Here we studied phenotypic characteristics in SMC cultured from end-stage human AAA (>=5 cm) and cells cultured from a porcine carotid artery (PCA) model of early and end-stage aneurysm. Human AAA-SMC presented a secretory phenotype and expressed elevated levels of the differentiation marker miR-145 (2.2-fold, p < 0.001) and the senescence marker SIRT-1 (1.3-fold, p < 0.05), features not recapitulated in aneurysmal PCA-SMC. Human and end-stage porcine aneurysmal cells were frequently multi-nucleated (3.9-fold, p < 0.001, and 1.8-fold, p < 0.01, respectively, vs. control cells) and displayed an aberrant nuclear morphology. Human AAA-SMC exhibited higher levels of the DNA damage marker gammaH2AX (3.9 fold, p < 0.01, vs. control SMC). These features did not correlate with patients' chronological age and are therefore potential markers for pathological premature vascular aging. Early-stage PCA-SMC (control and aneurysmal) were indistinguishable from one another across all parameters. The principal limitation of human studies is tissue availability only at the end stage of the disease. Refinement of a porcine bioreactor model would facilitate the study of temporal modulation of SMC behaviour during aneurysm development and potentially identify therapeutic targets to limit AAA progression. PMID- 29232678 TI - Effects of Guanidinoacetic Acid Loading on Biomarkers of Cardiometabolic Risk and Inflammation. PMID- 29232677 TI - Presence of Initial Caries Lesions as a Risk Factor for Caries in Preschool Children: A Cohort Study. AB - The aim of this study was to evaluate the influence of initial noncavitated caries lesions on cavitated caries increment in preschool children. A 2-year cohort study was designed to include the participants of a survey on dental caries performed in 2010. Preschool children (12-59 months old) were examined for dental caries and classified as children with no caries lesions, with only initial lesions, with at least 1 moderate caries lesion, and with extensive lesions. Socioeconomic data were also collected. After 2 years, 466 children were re-examined (follow-up rate of 72.9%) only for cavitated lesions. Association between caries incidence at 2 levels of severity and caries experience and other variables was evaluated using hierarchical Poisson regression analysis. The children with moderate and extensive caries lesions at baseline presented a higher risk of presenting both outcomes than the children with no caries lesions. Nevertheless, the children with only initial lesions had a higher risk of developing at least 1 new cavitated carious lesion, but not for a more severe increment in caries. Subgroup analysis stratified by the children's age showed that the influence of the presence of initial caries lesions on cavitated caries increment was only observed in children aged 12-35 months. In conclusion, although the presence of moderate and extensive lesions at baseline is a significant predictor for cavitated caries increment after 2 years in preschool children at all ages, the presence of only initial caries lesions is also associated, but with less severe caries incidence. PMID- 29232679 TI - Clinicopathological and Prognostic Features of Surgical Management in Duodenal Gastrointestinal Stromal Tumors. AB - BACKGROUND AND OBJECTIVES: The rarity of duodenal gastrointestinal stromal tumors (DGIST) led to only limited data being available on their management and prognosis. We retrospectively analyzed the clinicopathological features, surgical treatments, adjuvant therapy, and prognosis of DGIST. METHODS: Sixty-one patients were identified at diagnosis of primary DGIST from February 2005 to December 2015. One hundred twenty six patients with small intestinal gastrointestinal stromal tutors (GIST) were selected as control groups. Survival analyses were calculated using the Kaplan-Meier method. RESULTS: Three- and five-year recurrence/metastasis-free survival rates of patients with DGIST were similar to those of patients with small intestinal GIST (p > 0.05 for all). Out of 61 cases with DGIST, 45 patients were treated with Limited Resection (LR). Sixteen patients were treated with Pancreaticoduodenectomy (PD). The 3- and 5-year recurrence/metastasis-free survival rates of the PD group and LR group were of no significant difference (p > 0.05 for all). Univariate analysis indicated that factors including surgical approaches, mitotic count, size, and risk grades were significantly associated with recurrence/metastasis-free survival (log-rank test, p < 0.05). Multivariate analysis demonstrated that the mitotic count was independently correlated with a worse recurrence/metastasis-free survival. CONCLUSIONS: Patients with radical resected DGIST had a favourable prognosis, which is similar to that of small intestinal GIST. Both LR and PD were optimal choices for treating DGIST. PMID- 29232680 TI - Is Outpatient Control of Long-Term Non-Invasive Ventilation Feasible in Chronic Obstructive Pulmonary Disease Patients? AB - BACKGROUND: Long-term non-invasive ventilation (NIV) is an established and increasingly used treatment option for patients with chronic hypercapnic chronic obstructive pulmonary disease (COPD). Following inpatient NIV establishment, inpatient control visits regularly occur thereafter. However, it remains unclear whether such control visits can also be performed in an outpatient setting, which, in turn, would reduce costs, patient burden and the complications related to hospitalization. OBJECTIVES: To investigate an outpatient setting with predefined criteria for hospitalization for patients with chronic hypercapnic COPD. METHODS: An outpatient clinic located within the hospital in the vicinity of the respiratory care unit provided predefined criteria for hospitalization of COPD patients receiving long-term NIV therapy. The results of this setting were retrospectively analysed. RESULTS: A total of 130 outpatient visits (80 patients) were analysed. In 93 cases (71.5%), hospital admission was not necessary, while hospitalization was performed in 37 cases (28.5%). Out of these, 7 cases with acute conditions required prompt hospitalization. Patients without hospitalization had better PaCO2 values (45.40 +/- 5.27 vs. 50.05 +/- 8.04, p = 0.002) and Severe Respiratory Insufficiency Questionnaire Summary scores (55.54 +/- 19.74 vs. 41.82 +/- 19.59, p = 0.012). CONCLUSION: Outpatient control of long term NIV in a hospital setting is feasible and has the capacity to identify stable COPD patients in whom NIV therapy is sufficient according to predefined criteria. These patients may not require hospitalization and may account for more than two thirds of cases. PMID- 29232684 TI - Beyond Autism: Introducing the Dialectical Misattunement Hypothesis and a Bayesian Account of Intersubjectivity. AB - Drawing on sociocultural theories and Bayesian accounts of brain function, in this article we construe psychiatric conditions as disorders of social interaction to fully account for their complexity and dynamicity across levels of description and temporal scales. After an introduction of the theoretical underpinnings of our integrative approach, we take autism spectrum conditions (ASC) as a paradigm example and discuss how neurocognitive hypotheses can be translated into a Bayesian formulation, i.e., in terms of predictive processing and active inference. We then argue that consideration of individuals (even within a Bayesian framework) will not be enough for a comprehensive understanding of psychiatric conditions and consequently put forward the dialectical misattunement hypothesis, which views psychopathology not merely as disordered function within single brains but also as a dynamic interpersonal mismatch that encompasses various levels of description. Moving from a mere comparison of groups, i.e., "healthy" persons versus "patients," to a fine-grained analysis of social interactions within dyads and groups of individuals will open new avenues and may allow to avoid an overly neurocentric scope in psychiatric research as well as help to reduce social exclusion. PMID- 29232685 TI - Surgical Management of Deep Brain Stimulator Scalp Erosion without Hardware Removal. AB - BACKGROUND: Scalp erosion in patients with deep brain stimulation (DBS) hardware is an uncommon complication that lacks a clearly defined management strategy. Previous studies have described various therapies including conservative treatment with antibiotics and surgical debridement with or without hardware removal. OBJECTIVES: The aim of this study was to review the efficacy of a hardware-sparing management strategy for the treatment of scalp erosion. METHODS: Five patients with previous DBS implantation presented with scalp erosion and visible hardware exposure at the calvarial burr hole site, and underwent tension free, vascularized, rotational scalp flap, with preservation of the leads under the pericranium. Two of the procedures were performed after an unsuccessful attempt at primary closure and 3 as a primary procedure. Each patient was followed clinically for at least 14 months postoperatively to evaluate for wound healing and adverse effects. RESULTS: The median duration from initial DBS hardware implantation to erosion and revision surgery was 12 months (range 1.5-62 months). Three patients were documented to have positive intraoperative cultures in spite of the absence of purulence. At the last follow-up, all patients were noted to have complete wound-healing and no evidence of infection or erosion. CONCLUSIONS: DBS scalp erosion can be managed by rotational scalp flap without hardware removal, even in cases where infection is identified. PMID- 29232686 TI - The Effect of Classroom Capacity on Vocal Fatigue as Quantified by the Vocal Fatigue Index. AB - OBJECTIVE: Previous research has concluded that teachers are at a higher-than normal risk for voice issues that can cause occupational limitations. While some risk factors have been identified, there are still many unknowns. PATIENTS AND METHODS: A survey was distributed electronically with 506 female teacher respondents. The survey included questions to quantify three aspects of vocal fatigue as captured by the Vocal Fatigue Index (VFI): (1) general tiredness of voice (performance), (2) physical discomfort associated with voicing (pain), and (3) improvement of symptoms with rest (recovery). The effect of classroom capacity on US teachers' self-reported experience of vocal fatigue was analyzed. RESULTS: The results indicated that a classroom's capacity significantly affected teachers' reported amounts of vocal fatigue, while a teacher's age also appeared to significantly affect the reported amount of vocal fatigue. A quadratic rather than linear effect was seen, with the largest age effect occurring at around 40 45 years in all three factors of the VFI. CONCLUSION: Further factors which may affect vocal fatigue must be explored in future research. By understanding what increases the risk for vocal fatigue, educators and school administrators can take precautions to mitigate the occupational risk of short- and long-term vocal health issues in school teachers. PMID- 29232687 TI - Photochemotherapy and Graft-versus-Leukemia Reaction in Acute Leukemia: Tumor Immunity and Survival Are Dependent on Timing of Photochemotherapy of the Skin. AB - BACKGROUND: Cure of acute leukemia after transplantation is mediated by the grafted cells. We investigated the graft-versus-leukemia effect (GVL) in patients with cutaneous acute graft-versus-host disease (GVHD) treated with photochemotherapy (psoralen and ultraviolet light type A). METHOD: Forty-seven patients with acute leukemia were followed 5,000 days after transplantation to assess survival and GVL by multivariate analysis. The primary predictor was time to treatment of cutaneous acute GVHD by photochemotherapy separated into treatment start during the first week of acute GVHD versus after the first week of acute GVHD. RESULTS: Photochemotherapy started after the first week of acute GVHD predicted GVL with a hazard ratio (HR) of 3.94 (95% confidence interval, CI, 1.67-9.33, p = 0.0018) and survival with preserved GVL with an HR of 2.63 (95% CI 1.30-5.32, p = 0.007). The effects on GVL and survival with preserved GVL were present regardless of whether the patients were transplanted in remission or relapse (p < 0.05). Chronic GVHD came earlier in the group that started photochemotherapy after 1 week of acute GHVD, but chronic GVHD did not increase the GVL. CONCLUSION: The timing of photochemotherapy after cutaneous acute GVHD may direct the GVL and predict long-term leukemia-free survival. PMID- 29232688 TI - Genotype- and Cell-Specific Dynamics of Tandem Repeat Patterns in Aegilops speltoides Tausch (Poaceae, Triticeae). AB - In wild plant populations, chromosome rearrangements lead to the wide intraspecific polymorphisms in the abundance and patterns of highly repetitive DNA. However, despite the large amount of accumulated data, the impact of the complex repetitive DNA fraction on genome reorganization and functioning and the mechanisms balancing and maintaining the structural integrity of the genome are not fully understood. Homologous recombination is thought to play a key role in both genome reshuffling and stabilization, while the contribution of nonhomologous recombination seems to be undervalued. Here, tandem repeat patterns and dynamics during pollen mother cell development were addressed, with a focus on the meiotic recombination that determines chromosome/genome repatterning and stabilization under cross-pollination and artificial hybridization in wild goatgrass, Aegilops speltoides. Native plants from contrasting allopatric populations and artificially created intraspecific hybrids were investigated using a FISH approach. Cytogenetic analysis uncovered a wide spectrum of genotype and cell-specific chromosomal rearrangements, suggesting intensive repatterning of both parental and hybrid genomes. The data obtained provide evidence that repetitive elements serve as overabundant and ubiquitous resources for maintaining chromosome architecture/genome integrity through homologous and nonhomologous recombination at the intraorganismal level, and genotype-specific repatterning underlies intrapopulation polymorphisms and intraspecific diversification in the wild. PMID- 29232689 TI - A computational model for regulation of nanoscale glucan exposure in Candida albicans. AB - Candida albicans is a virulent human opportunistic pathogen. It evades innate immune surveillance by masking an immunogenic cell wall polysaccharide, beta glucan, from recognition by the immunoreceptor Dectin-1. Glucan unmasking by the antifungal drug caspofungin leads to changes in the nanostructure of glucan exposure accessible to Dectin-1. The physical mechanism that regulates glucan exposure is poorly understood, but it controls the nanobiology of fungal pathogen recognition. We created computational models to simulate hypothetical physical processes of unmasking glucan in a biologically realistic distribution of cell wall glucan fibrils. We tested the predicted glucan exposure nanostructural features arising from these models against experimentally measured values. A completely spatially random unmasking process, reflective of random environmental damage to the cell wall, cannot account for experimental observations of glucan unmasking. However, the introduction of partially edge biased unmasking processes, consistent with an unmasking contribution from active, local remodeling at glucan exposure sites, produces markedly more accurate predictions of experimentally observed glucan nanoexposures in untreated and caspofungin treated yeast. These findings suggest a model of glucan unmasking wherein cell wall remodeling processes in the local nanoscale neighborhood of glucan exposure sites are an important contributor to the physical process of drug-induced glucan unmasking in C. albicans. PMID- 29232691 TI - Effect of food simulating liquids on the flexural strength of a methacrylate and silorane-based composite. AB - OBJECTIVE: The purpose of this study was to assess the effect of food-simulating liquids on the flexural strength of a methacrylate-based and a silorane-based resin composite. MATERIALS AND METHODS: In this in vitro study, sixty specimens of Filtek P90 and Filtek Z350 composite were prepared in a customized mold (2 * 2 * 25 mm). The specimens of each composite were divided into five subgroups as follows: one as a control group and the other four groups included distilled water, heptane, 2% citric acid, and 50% aqueous ethanol. The specimens were stored in the solutions for one week at 37 degrees C, and the control group was stored at room temperature for the same period of time. Then, flexural strength values were measured. The statistical analysis was performed by One-Way ANOVA, Paired T test and post hoc LSD at a significance level of 0.05. RESULTS: In the control group, the mean flexural strength of Filtek P90 and Filtek Z350 were 155.1 MPa and 147.3 MPa, respectively, and there was no significant difference (P value>0.05). The mean flexural strength of Filtek P90 and Filtek Z350 significantly decreased in ethanol (P-value <0.05). Immersion in 0.02 N citric acid and heptane had no significant effect on the flexural strength of Filtek P90 and Filtek Z350. The maximum flexural strength of Filtek P90 was in the heptane group (192.6 MPa) and minimum flexural strength was in ethanol group (92.7 MPa) the maximum flexural strength of Filtek Z350 was in the heptane group (163.2 MPa) and minimum flexural strength was in the ethanol group (104.7 MPa). CONCLUSION: The flexural strength of tested resin composites significantly affected by ethanol solution. The flexural strength of resin composites was not affected by other food simulating liquids. PMID- 29232690 TI - RNA interference in Fasciola gigantica: Establishing and optimization of experimental RNAi in the newly excysted juveniles of the fluke. AB - Fasciolosis caused by Fasciola gigantica is a neglected tropical disease but a constraint on the growth and productivity of cattle, buffaloes and sheep in the tropical countries of Asia and Africa. Resistance to commonly used anthelmintics in Fasciola has increased the need to search for alternative therapeutic targets. RNA interference is the current tool of choice in the search for such targets in Fasciola. The susceptibility of juvenile Fasciola hepatica to double stranded (ds) RNA induced RNAi has been established but in F. gigantica a single preliminary report on RNAi induced mRNA transcript knockdown is available. Here we optimized conditions for RNAi in the liver fluke F.gigantica targeting six genes including superoxide dismutase (SOD), sigma class of glutathione-s transferase (GST), cathepsin (Cat) L1-D, Cat B1, Cat B2 and Cat B3 that showed robust transcriptional silencing of the targets following exposure of the newly excysted juveniles (NEJs) to long (170-223 nt) dsRNA. Knockdown was shown to be concentration dependent with significant mRNA transcript suppression occurring at 5 ng / MUl that showed further suppression with the increase in the dsRNA concentration. The dsRNA induced persistent silencing of the mRNA transcript of SOD and sigmaGST up to 15 days of observation. Delivery of the long dsRNA and siRNA to the newly excysted juveniles by soaking method was found to be efficient by tracking the uptake and diffusion of Cy3 labelled siRNA and long dsRNA in the flukes. Off-target effects of dsRNA trigger on some of the non-target genes were detected in the present investigation on RNAi in F. gigantica. The dsRNA induced superoxide dismutase protein suppression while impact of RNAi on other target proteins was not studied. There is no in vitro culture system for prolonged survival of the F. gigantica and in the present study in vitro maintenance of the NEJs is reported for a period of 3 weeks. The present study is the first attempt on optimization of RNAi protocols in F. gigantica where long dsRNA allowed for an efficient and persistent gene silencing, opening prospects for functional validation of putative vaccine and therapeutic targets in this neglected parasite. PMID- 29232692 TI - Trachomatous scarring among children in a formerly hyper-endemic district of Tanzania. AB - BACKGROUND: Associations between repeated ocular infections with Chlamydia trachomatis in childhood and conjunctival scarring in adulthood are well established. Trachomatous scarring (TS) in children has also been observed in hyper-endemic areas, but data are scant regarding childhood scarring in areas where trachoma has been reduced to hypo-endemic levels. METHODS/PRINCIPLE FINDINGS: In this cross-sectional study, a random sample of children, ages 1-9 years, were selected from 38 communities in the formerly hyper-endemic district of Kongwa, Tanzania. Each participant received an ocular examination and eye-swab test for C. trachomatis infection. Conjunctival photographs were taken and analyzed at 5x magnification to determine scarring presence and severity. Community-level case clustering was assessed using intra-class correlation coefficients, and associations between TS presence and demographic/clinical factors were assessed using contingency table analyses. 1,496 children (78% of eligible) participated in this study. The mean age was 5.5 years and 51% were female. Scarring prevalence was 2.1% (95% CI: 1.5%- 3.0%). The prevalence of follicular trachoma and ocular C. trachomatis infection were 3.2% and 6.5%, respectively. Most TS cases (68.7%) fell into the mildest category, grade S1. 18.7% were grade S2; 12.6% were grade S3. No significant associations were seen between TS presence and age, sex, follicular trachoma, or active ocular C. trachomatis infection (p-values: 0.14, 0.48, 0.27, 0.15, respectively). Thirty communities (78.9%) had 0-1 TS cases, and the most seen in any single community was four cases. Three years ago, follicular trachoma prevalence averaged 4.9% in communities with 0-1 TS cases, but 7.6% in communities with 2-4 TS cases (p value: 0.08). CONCLUSIONS: In this formerly hyper-endemic district of Tanzania, TS was rare in 1-9 year-olds and usually mild when present. Communities with higher rates of follicular trachoma in the past were more likely to have >=2 cases of scarring, but the association was not statistically significant. PMID- 29232694 TI - Hyperbranched poly(epsilon-lysine) substrate presenting the laminin sequence YIGSR induces the formation of spheroids in adult bone marrow stem cells. AB - Unlike the fibroblast-like cells formed upon monolayer culture of human mesenchymal stem cells, the natural stem cell niche of the bone marrow and other types of tissues favours the formation of 3-dimensional (3D) cell clusters. The structuring and biological activity of these clusters are regulated by the contacts established by cells with both the basement membrane and neighbour cells and results in their asymmetric division and the consequent maintenance of both a stem population and a committed progeny. The present work demonstrates the potential of a synthetic substrate to mimic the stem cell niche in vitro. The side amino groups of a linear Poly-L-lysine were modified with hyperbranched poly (epsilon-lysine) peptides, named as dendrons, tethered with the laminin-mimicking sequence, YIGSR. These dendrons presented the YIGSR sequence at the uppermost molecular branching ensuring a controlled spacing of the bioligand. When used to coat the surface of tissue culture plates in a serum-free in vitro cell culture system, the substrate was able to mimic the most relevant features of the basement membrane of the stem cell niche, i.e. the mesh structure of Collagen Type IV and the availability of laminin bioligands relevant to integrin biorecognition. The substrate biomimetic properties were tested for their ability to support the formation of human bone marrow mesenchymal stem cells (hMSCs) 3D spheroids similar to those observed in the natural stem cell niches and their ability to maintain stem cell pluripotency markers. These features were related to the substrate-specific expression and localisation of (i) cell adhesion receptors (i.e. beta-integrin and N-cadherin), (ii) transcription factors of pluripotency markers and cytoskeleton protein and (iii) regulators of cell migration throughout cell culture passages 2 to 4. The results clearly demonstrate the formation of 3D spheroids starting from the asymmetric division of substrate-adhering spread cells, the clustering of relevant integrins and the expression of specific intracellular pathways controlling cytoskeleton formation suggesting their potential use as a substrate for the handling of stem cells prior to transplantation procedures. PMID- 29232695 TI - Integrative assessment of climate change for fast-growing urban areas: Measurement and recommendations for future research. AB - Over the 20th century, urbanization has substantially shaped the surface of Earth. With population rapidly shifting from rural locations towards the cities, urban areas have dramatically expanded on a global scale and represent crystallization points of social, cultural and economic assets and activities. This trend is estimated to persist for the next decades, and particularly the developing countries are expected to face rapid urban growth. The management of this growth will require good governance strategies and planning. By threatening the livelihoods, assets and health as foundations of human activities, another major global change contributor, climate change, became an equally important concern of stakeholders. Based on the climate trends observed over the 20th century, and a spatially explicit model of urbanization, this paper investigates the impacts of climate change in relation to different stages of development of urban areas, thus evolving a more integrated perspective on both processes. As a result, an integrative measure of climate change trends and impacts is proposed and estimated for urban areas worldwide. We show that those areas facing major urban growth are to a large extent also hotspots of climate change. Since most of these hotspots are located in the Global South, we emphasize the need for stakeholders to co-manage both drivers of global change. The presented integrative perspective is seen as a starting point to foster such co-management, and furthermore as a means to facilitate communication and knowledge exchange on climate change impacts. PMID- 29232693 TI - Host factors that promote retrotransposon integration are similar in distantly related eukaryotes. AB - Retroviruses and Long Terminal Repeat (LTR)-retrotransposons have distinct patterns of integration sites. The oncogenic potential of retrovirus-based vectors used in gene therapy is dependent on the selection of integration sites associated with promoters. The LTR-retrotransposon Tf1 of Schizosaccharomyces pombe is studied as a model for oncogenic retroviruses because it integrates into the promoters of stress response genes. Although integrases (INs) encoded by retroviruses and LTR-retrotransposons are responsible for catalyzing the insertion of cDNA into the host genome, it is thought that distinct host factors are required for the efficiency and specificity of integration. We tested this hypothesis with a genome-wide screen of host factors that promote Tf1 integration. By combining an assay for transposition with a genetic assay that measures cDNA recombination we could identify factors that contribute differentially to integration. We utilized this assay to test a collection of 3,004 S. pombe strains with single gene deletions. Using these screens and immunoblot measures of Tf1 proteins, we identified a total of 61 genes that promote integration. The candidate integration factors participate in a range of processes including nuclear transport, transcription, mRNA processing, vesicle transport, chromatin structure and DNA repair. Two candidates, Rhp18 and the NineTeen complex were tested in two-hybrid assays and were found to interact with Tf1 IN. Surprisingly, a number of pathways we identified were found previously to promote integration of the LTR-retrotransposons Ty1 and Ty3 in Saccharomyces cerevisiae, indicating the contribution of host factors to integration are common in distantly related organisms. The DNA repair factors are of particular interest because they may identify the pathways that repair the single stranded gaps flanking the sites of strand transfer following integration of LTR retroelements. PMID- 29232696 TI - Effect of temperature on fatty acid metabolism in skeletal muscle mitochondria of untrained and endurance-trained rats. AB - We studied the effects of various assay temperatures, representing hypothermia (25 degrees C), normothermia (35 degrees C), and hyperthermia (42 degrees C), on the oxidation of lipid-derived fuels in rat skeletal muscle mitochondria of untrained and endurance-trained rats. Adult 4-month-old male Wistar rats were assigned to a training group (rats trained on a treadmill for 8 weeks) or a sedentary control group. In skeletal muscle mitochondria of both control and trained rats, an increase in the assay temperature from 25 degrees C to 42 degrees C was accompanied by a consistent increase in the oxidation of palmitoylcarnitine and glycerol-3-phosphate. Moreover, endurance training increased mitochondrial capacity to oxidize the lipid-derived fuels at all studied temperatures. The endurance training-induced increase in mitochondrial capacity to oxidize fatty acids was accompanied by an enhancement of mitochondrial biogenesis, as shown by the elevated expression levels of Nrf2, PGC1alpha, and mitochondrial marker and by the elevated expression levels of mitochondrial proteins involved in fatty acid metabolism, such as fatty acid transporter CD36, carnitine palmitoyltransferase 1A (CPT1A), and acyl-CoA dehydrogenase (ACADS). We conclude that hyperthermia enhances but hypothermia attenuates the rate of the oxidation of fatty acids and glycerol-3-phosphate in rat skeletal muscle mitochondria isolated from both untrained and trained rats. Moreover, our results indicate that endurance training up-regulates mitochondrial biogenesis markers, lipid-sustained oxidative capacity, and CD36 and CPT1A proteins involved in fatty acid transport, possibly via PGC1alpha and Nrf2 signaling pathways. PMID- 29232697 TI - Self-management of type 2 diabetes in gulf cooperation council countries: A systematic review. AB - AIMS: This study aimed to systematically review intervention studies on self management of type 2 diabetes in Gulf Cooperation Council (GCC) countries to determine the most effective self-management strategies for individuals with type 2 diabetes in this region. METHODS: A search strategy was developed using multiple databases: Medline and Embase (via Ovid), CINAHL (via EBSCO), and PubMed. Study and intervention characteristics, intervention structure, content, cultural adaptation, and outcomes were extracted from the included studies. To be included in the review the studies should have met the following criteria: have examined the effectiveness of at least one intervention involving a type 2 DSME programme, have involved participants over 18 years old diagnosed with type 2 diabetes, have taken place to in a GCC country, have a study design that was observational, quasi-experimental or controlled, have reported at least one individual and have a quantitative outcome. A narrative data synthesis was used to describe the studies and comment on their methodological quality. RESULTS: Of the 737 retrieved papers, only eight met the inclusion criteria. Only one study was a randomised controlled trial. A statistically significant improvement in HbA1c was reported in five of the eight studies. There was a significant improvement in physical activity levels as reported in four of the eight studies. Only three studies referred to aspects of cultural design or adaptation of the intervention implemented. CONCLUSIONS: Self-management interventions may have a positive impact on HbA1 levels in patients with type 2 diabetes in the GCC area. A greater emphasis placed on culturally appropriate self-management programmes may improve the effectiveness of self-management interventions for adults with type 2 diabetes in the GCC. PMID- 29232698 TI - Low-energy extracorporeal shockwave therapy (ESWT) improves metaphyseal fracture healing in an osteoporotic rat model. AB - PURPOSE: As result of the current demographic changes, osteoporosis and osteoporotic fractures are becoming an increasing social and economic burden. In this experimental study, extracorporeal shock wave therapy (ESWT), was evaluated as a treatment option for the improvement of osteoporotic fracture healing. METHODS: A well-established fracture model in the metaphyseal tibia in the osteoporotic rat was used. 132 animals were divided into 11 groups, with 12 animals each, consisting of one sham-operated group and 10 ovariectomized (osteoporotic) groups, of which 9 received ESWT treatment. Different energy flux intensities (0.15 mJ/mm2, 0.35 mJ/mm2, or 0.55 mJ/mm2) as well as different numbers of ESWT applications (once, three times, or five times throughout the 35 day healing period) were applied to the osteoporotic fractures. Fracture healing was investigated quantitatively and qualitatively using micro-CT imaging, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, histomorphometric analysis and biomechanical analysis. RESULTS: The results of this study show a qualitative and quantitative improvement in the osteoporotic fracture healing under low-energy (energy flux intensity: 0,15 mJ/mm2) ESWT and with fewer treatment applications per healing period. CONCLUSION: In conclusion, low-energy ESWT seems to exhibit a beneficial effect on the healing of osteoporotic fractures, leading to improved biomechanical properties, enhanced callus-quantity and -quality, and an increase in the expression of bone specific transcription factors. The results suggest that low-energy ESWT, as main treatment or as adjunctive treatment in addition to a surgical intervention, may prove to be an effective, simple to use, and cost-efficient option for the qualitative and quantitative improvement of osteoporotic fracture healing. PMID- 29232699 TI - CXCR4 blockade decreases CD4+ T cell exhaustion and improves survival in a murine model of polymicrobial sepsis. AB - Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis. Results indicate that CXCR4 is selectively upregulated on naive CD4+ and CD8+ T cells and CD4+ central memory T cells following the induction of sepsis, and that CXCR4 antagonism resulted in a significant decrease in sepsis-induced mortality. We probed the mechanistic basis for these findings and found that CXCR4 antagonism significantly increased the number of peripheral CD4+ and CD8+ T cells following sepsis. Moreover, mice treated with the CXCR4 antagonist contained fewer PD-1+ LAG-3+ 2B4+ cells, suggesting that blockade of CXCR4 mitigates CD4+ T cell exhaustion during sepsis. Taken together, these results characterize CXCR4 as an important pathway that modulates immune dysfunction and mortality following sepsis, which may hold promise as a target for future therapeutic intervention in septic patients. PMID- 29232701 TI - Differential impact of white matter hyperintensities on long-term outcomes in ischemic stroke patients with large artery atherosclerosis. AB - BACKGROUND: The presence of white matter hyperintensity (WMH) is related to poor long-term outcomes in stroke patients. However, the long-term outcome is unknown in patients with both large artery atherosclerosis (LAA) and WMH. METHODS: We investigated the impact of WMH on long-term outcome in patients with LAA. Consecutive patients in a prospective stroke registry were included. Patients were followed for a median of 7.7 years (interquartile range, 5.6-9.7). The degree of WMH was assessed by Fazekas grade on fluid-attenuated inversion recovery images. Total WMH burden was calculated by summation of Fazekas scores in periventricular and deep white matter. Severe WMH was defined as total burden score >= 3. RESULTS: Among 2529 patients, 639 patients (25.3%) were classified with the LAA subtype. After applying exclusion criteria, the data from 538 patients were analyzed. The mean patient age was 65.7 +/- 10.3 years. Severe WMHs were found in 243 patients (45.2%). During follow-up, 200 patients (37.2%) died. Cox regression analysis showed that LAA patients with severe WMH had a 1.50-fold (95% CI, 1.12-2.00, p = 0.007) higher death rate compared to those without. In the older age group (>=65 years), Cox regression revealed that patients with severe WMH had a 1.75-fold (95% CI, 1.15-2.65, p = 0.008) higher 5-year death rate, whereas the younger age group did not have this association. CONCLUSION: The degree of WMH might be a surrogate marker for long-term outcome in patients with LAA. Atherosclerotic burdens in both small and large arteries might impact long-term prognosis in ischemic stroke patients. PMID- 29232700 TI - SYGL-1 and LST-1 link niche signaling to PUF RNA repression for stem cell maintenance in Caenorhabditis elegans. AB - Central questions in regenerative biology include how stem cells are maintained and how they transition from self-renewal to differentiation. Germline stem cells (GSCs) in Caeno-rhabditis elegans provide a tractable in vivo model to address these questions. In this system, Notch signaling and PUF RNA binding proteins, FBF-1 and FBF-2 (collectively FBF), maintain a pool of GSCs in a naive state. An open question has been how Notch signaling modulates FBF activity to promote stem cell self-renewal. Here we report that two Notch targets, SYGL-1 and LST-1, link niche signaling to FBF. We find that SYGL-1 and LST-1 proteins are cytoplasmic and normally restricted to the GSC pool region. Increasing the distribution of SYGL-1 expands the pool correspondingly, and vast overexpression of either SYGL-1 or LST-1 generates a germline tumor. Thus, SYGL-1 and LST-1 are each sufficient to drive "stemness" and their spatial restriction prevents tumor formation. Importantly, SYGL-1 and LST-1 can only drive tumor formation when FBF is present. Moreover, both proteins interact physically with FBF, and both are required to repress a signature FBF mRNA target. Together, our results support a model in which SYGL-1 and LST-1 form a repressive complex with FBF that is crucial for stem cell maintenance. We further propose that progression from a naive stem cell state to a state primed for differentiation relies on loss of SYGL-1 and LST-1, which in turn relieves FBF target RNAs from repression. Broadly, our results provide new insights into the link between niche signaling and a downstream RNA regulatory network and how this circuitry governs the balance between self renewal and differentiation. PMID- 29232702 TI - Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice. AB - Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency. PMID- 29232703 TI - Knowledge and awareness of and perception towards cardiovascular disease risk in sub-Saharan Africa: A systematic review. AB - INTRODUCTION: Cardiovascular diseases (CVDs) are the most common cause of non communicable disease mortality in sub-Saharan African (SSA) countries. Gaps in knowledge of CVD conditions and their risk factors are important barriers in effective prevention and treatment. Yet, evidence on the awareness and knowledge level of CVD and associated risk factors among populations of SSA is scarce. This review aimed to synthesize available evidence of the level of knowledge of and perceptions towards CVDs and risk factors in the SSA region. METHODS: Five databases were searched for publications up to December 2016. Narrative synthesis was conducted for knowledge level of CVDs, knowledge of risk factors and clinical signs, factors influencing knowledge of CVDs and source of health information on CVDs. The review was registered with Prospero (CRD42016049165). RESULTS: Of 2212 titles and abstracts screened, 45 full-text papers were retrieved and reviewed and 20 were included: eighteen quantitative and two qualitative studies. Levels of knowledge and awareness for CVD and risk factors were generally low, coupled with poor perception. Most studies reported less than half of their study participants having good knowledge of CVDs and/or risk factors. Proportion of participants who were unable to identify a single risk factor and clinical symptom for CVDs ranged from 1.8% in a study among hospital staff in Nigeria to a high of 73% in a population-based survey in Uganda and 7% among University staff in Nigeria to 75.1% in a general population in Uganda respectively. High educational attainment and place of residence had a significant influence on the levels of knowledge for CVDs among SSA populations. CONCLUSION: Low knowledge of CVDs, risk factors and clinical symptoms is strongly associated with the low levels of educational attainment and rural residency in the region. These findings provide useful information for implementers of interventions targeted at the prevention and control of CVDs, and encourages them to incorporate health promotion and awareness campaigns in order to enhance knowledge and awareness of CVDs in the region. PMID- 29232704 TI - Do early neural correlates of visual consciousness show the oblique effect? A binocular rivalry and event-related potential study. AB - When dissimilar images are presented one to each eye, we do not see both images; rather, we see one at a time, alternating unpredictably. This is called binocular rivalry, and it has recently been used to study brain processes that correlate with visual consciousness, because perception changes without any change in the sensory input. Such studies have used various types of images, but the most popular have been gratings: sets of bright and dark lines of orthogonal orientations presented one to each eye. We studied whether using cardinal rival gratings (vertical, 0 degrees , and horizontal, 90 degrees ) versus oblique rival gratings (left-oblique, -45 degrees , and right-oblique, 45 degrees ) influences early neural correlates of visual consciousness, because of the oblique effect: the tendency for visual performance to be greater for cardinal gratings than for oblique gratings. Participants viewed rival gratings and pressed keys indicating which of the two gratings they perceived, was dominant. Next, we changed one of the gratings to match the grating shown to the other eye, yielding binocular fusion. Participants perceived the rivalry-to-fusion change to the dominant grating and not to the other, suppressed grating. Using event-related potentials (ERPs), we found neural correlates of visual consciousness at the P1 for both sets of gratings, as well as at the P1-N1 for oblique gratings, and we found a neural correlate of the oblique effect at the N1, but only for perceived changes. These results show that the P1 is the earliest neural activity associated with visual consciousness and that visual consciousness might be necessary to elicit the oblique effect. PMID- 29232705 TI - Etv2-miR-130a-Jarid2 cascade regulates vascular patterning during embryogenesis. AB - Remodeling of the primitive vasculature is necessary for the formation of a complex branched vascular architecture. However, the factors that modulate these processes are incompletely defined. Previously, we defined the role of microRNAs (miRNAs) in endothelial specification. In the present study, we further examined the Etv2-Cre mediated ablation of DicerL/L and characterized the perturbed vascular patterning in the embryo proper and yolk-sac. We mechanistically defined an important role for miR-130a, an Etv2 downstream target, in the mediation of vascular patterning and angiogenesis in vitro and in vivo. Inducible overexpression of miR-130a resulted in robust induction of vascular sprouts and angiogenesis with increased uptake of acetylated-LDL. Mechanistically, miR-130a directly regulated Jarid2 expression by binding to its 3'-UTR region. Over expression of Jarid2 in HUVEC cells led to defective tube formation indicating its inhibitory role in angiogenesis. The knockout of miR-130a showed increased levels of Jarid2 in the ES/EB system. In addition, the levels of Jarid2 transcripts were increased in the Etv2-null embryos at E8.5. In the in vivo settings, injection of miR-130a specific morpholinos in zebrafish embryos resulted in perturbed vascular patterning with reduced levels of endothelial transcripts in the miR-130a morphants. Further, co-injection of miR-130a mimics in the miR-130a morphants rescued the vascular defects during embryogenesis. qPCR and in situ hybridization techniques demonstrated increased expression of jarid2a in the miR-130a morphants in vivo. These findings demonstrate a critical role for Etv2-miR-130a-Jarid2 in vascular patterning both in vitro and in vivo. PMID- 29232706 TI - Biventricular differences in beta-adrenergic receptor signaling following burn injury. AB - Burn injury detrimentally affects the myocardium, primarily due to over activation of beta-adrenergic receptors (beta-AR). Autopsy reports from our institution reveal that patients often suffer from right ventricle (RV) failure. Since burn injury affects beta-AR signaling in the left ventricle (LV), we proposed that beta-AR signaling may also be altered in the RV. A rodent model with a scald burn of 60% of the total body surface area was used to test this hypothesis. Ventricles were isolated 7 days post-burn. We examined the expression of beta-ARs via Western blotting and the mRNA expression of downstream signaling proteins via qRT-PCR. Cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activity were measured in membrane and cytosolic fractions, respectively, using enzyme immunoassay kits. beta1-AR protein expression was significantly increased in the RV following burn injury compared to non-burned RV but not in the LV (p = 0.0022). In contrast, beta2-AR expression was unaltered among the groups while Galphai expression was significantly higher in the LV post-burn (p = 0.023). B-arrestin-1 and G-protein coupled receptor kinase-2 mRNA expression were significantly increased in the left ventricle post burn (p = 0.001, p<0.0001, respectively). cAMP production and PKA activity were significantly lower in the LV post-burn (p = 0.0063, 0.0042, respectively). These data indicate that burn injury affects the beta-AR signaling pathway in the RV independently of the LV. Additionally, non-canonical beta-AR signaling may be activated in the RV as cAMP production and PKA activity were unchanged despite changes in beta1-AR protein expression. PMID- 29232707 TI - Genetic mapping of QTL for maize leaf width combining RIL and IF2 populations. AB - Leaf width is an important component of plant architecture that affects light capture during photosynthesis and wind circulation under dense planting conditions. To improve understanding of the genetic mechanisms involved in leaf width at different positions, a comprehensive evaluation using the RIL (Recombinant Inbred Line) and IF2 (Immortalized F2) populations and a subsequent meta-analysis were performed. Forty-seven QTL associated with leaf width at different positions below the tassel were detected. The individual effects of QTL explained 3.5% to 17.0% of the observed phenotypic variation, and ten QTL explained over 10%. The initial QTL were integrated into eight mQTL (meta-QTL) through a meta-analysis. Our results suggested that leaf widths at different positions may be affected by several of the same mQTL and may also be regulated by many different mQTL. These results provide useful information for breeding high density tolerant inbred lines and hybrid cultivars, as well as for using marker-assisted selection for important mQTL. PMID- 29232709 TI - Local setting influences the quantity of household food waste in mid-sized South African towns. AB - The world faces a food security challenge with approximately 868 million people undernourished and about two billion people suffering from the negative health consequences of micronutrient deficiencies. Yet, it is believed that at least 33% of food produced for human consumption is lost or wasted along the food chain. As food waste has a negative effect on food security, the present study sought to quantify household food waste along the rural-urban continuum in three South African mid-sized towns situated along an agro-ecological gradient. We quantified the types of foods and drinks that households threw away in the previous 48 hours and identified the causes of household food waste in the three sites. More households wasted prepared food (27%) than unprepared food (15%) and drinks (8%). However, households threw away greater quantities of unprepared food in the 48 hour recall period (268.6+/-610.1 g, 90% confidence interval: 175.5 to 361.7 g) compared to prepared food (121.0+/-132.4 g, 90% confidence interval: 100.8 to 141.3 g) and drinks (77.0+/-192.5 ml, 90% confidence interval: 47.7 to 106.4 ml). The estimated per capita food waste (5-10 kg of unprepared food waste, 3-4 kg of prepared food waste and 1-3 litres of drinks waste per person per year) overlaps with that estimated for other developing countries, but lower than most developed countries. However, the estimated average amount of food waste per person per year for this study (12.35 kg) was higher relative to that estimated for developing countries (8.5 kg per person per year). Household food waste was mainly a result of consumer behavior concerning food preparation and storage. Integrated approaches are required to address this developmental issue affecting South African societies, which include promoting sound food management to decrease household food waste. Also, increased awareness and educational campaigns for household food waste reduction interventions are discussed. PMID- 29232708 TI - Elimination of trachoma as a public health problem in Ghana: Providing evidence through a pre-validation survey. AB - BACKGROUND: In order to achieve elimination of trachoma, a country needs to demonstrate that the elimination prevalence thresholds have been achieved and then sustained for at least a two-year period. Ghana achieved the thresholds in 2008, and since 2011 has been implementing its trachoma surveillance strategy, which includes community and school screening for signs of follicular trachoma and trichiasis, in trachoma-endemic districts. In 2015-2016, the country conducted a district level population-based survey to validate elimination of trachoma as a public health problem. METHODS: As per WHO recommendations, a cross sectional survey, employing a two-stage cluster random sampling methodology, was used across 18 previously trachoma endemic districts (evaluation units (EUs) in the Upper West and Northern Regions of Ghana. In each EU 24 villages were selected based on probability proportional to estimated size. A minimum of 40 households were targeted per village and all eligible residents were examined for clinical signs of trachoma, using the WHO simplified grading system. The number of trichiasis cases unknown to the health system was determined. Household environmental risk factors for trachoma were also assessed. RESULTS: Data from 45,660 individuals were examined from 11,099 households across 18 EUs, with 27,398 (60.0%) children aged 1-9 years and 16,610 (36.4%) individuals 15 years and above All EUs had shown to have maintained the WHO elimination threshold for Trachomatous inflammation-Follicular (TF) (<5.0% prevalence) in children aged 1-9 years old. The EU TF prevalence in children aged 1-9 years old ranged from between 0.09% to 1.20%. Only one EU (Yendi 0.36%; 95% CI: 0.0-1.01) failed to meet the WHO TT elimination threshold (< 0.2% prevalence in adults aged 15 and above). The EU prevalence of trichiasis (TT) unknown to the health system in adults aged >=15 years, ranged from 0.00% to 0.36%. In this EU, the estimated TT backlog is 417 All TT patients identified in the study, as well as through on going surveillance efforts will require further management. A total of 75.9% (95% CI 72.1-79.3, EU range 29.1-92.6) of households defecated in the open but many households had access to an improved water source 75.9% (95%CI: 71.5-79.8, EU range 47.4-90.1%), with 45.5% (95% CI 41.5-49.7%, EU range 28.4-61.8%) making a round trip of water collection < 30 minutes. CONCLUSION: The findings from this survey indicate elimination thresholds have been maintained in Ghana in 17 of the 18 surveyed EUs. Only one EU, Yendi, did not achieve the TT elimination threshold. A scheduled house-by-house TT case search in this EU coupled with surgery to clear the backlog of cases is necessary in order for Ghana to request validation of elimination of trachoma as a public health problem. PMID- 29232710 TI - Stabilizing patterns in time: Neural network approach. AB - Recurrent and feedback networks are capable of holding dynamic memories. Nonetheless, training a network for that task is challenging. In order to do so, one should face non-linear propagation of errors in the system. Small deviations from the desired dynamics due to error or inherent noise might have a dramatic effect in the future. A method to cope with these difficulties is thus needed. In this work we focus on recurrent networks with linear activation functions and binary output unit. We characterize its ability to reproduce a temporal sequence of actions over its output unit. We suggest casting the temporal learning problem to a perceptron problem. In the discrete case a finite margin appears, providing the network, to some extent, robustness to noise, for which it performs perfectly (i.e. producing a desired sequence for an arbitrary number of cycles flawlessly). In the continuous case the margin approaches zero when the output unit changes its state, hence the network is only able to reproduce the sequence with slight jitters. Numerical simulation suggest that in the discrete time case, the longest sequence that can be learned scales, at best, as square root of the network size. A dramatic effect occurs when learning several short sequences in parallel, that is, their total length substantially exceeds the length of the longest single sequence the network can learn. This model easily generalizes to an arbitrary number of output units, which boost its performance. This effect is demonstrated by considering two practical examples for sequence learning. This work suggests a way to overcome stability problems for training recurrent networks and further quantifies the performance of a network under the specific learning scheme. PMID- 29232711 TI - Dependence of prevalence of contiguous pathways in proteins on structural complexity. AB - Allostery is a regulatory mechanism in proteins where an effector molecule binds distal from an active site to modulate its activity. Allosteric signaling may occur via a continuous path of residues linking the active and allosteric sites, which has been suggested by large conformational changes evident in crystal structures. An alternate possibility is that the signal occurs in the realm of ensemble dynamics via an energy landscape change. While the latter was first proposed on theoretical grounds, increasing evidence suggests that such a control mechanism is plausible. A major difficulty for testing the two methods is the ability to definitively determine that a residue is directly involved in allosteric signal transduction. Statistical Coupling Analysis (SCA) is a method that has been successful at predicting pathways, and experimental tests involving mutagenesis or domain substitution provide the best available evidence of signaling pathways. However, ascertaining energetic pathways which need not be contiguous is far more difficult. To date, simple estimates of the statistical significance of a pathway in a protein remain to be established. The focus of this work is to estimate such benchmarks for the statistical significance of contiguous pathways for the null model of selecting residues at random. We found that when 20% of residues in proteins are randomly selected, contiguous pathways at the 6 A cutoff level were found with success rates of 51% in PDZ, 30% in p53, and 3% in MutS. The results suggest that the significance of pathways may have system specific factors involved. Furthermore, the possible existence of false positives for contiguous pathways implies that signaling could be occurring via alternate routes including those consistent with the energetic landscape model. PMID- 29232712 TI - Bioinformatic analysis reveals new determinants of antigenic 14-3-3 proteins and a novel antifungal strategy. AB - The ubiquitously expressed 14-3-3 family of proteins is evolutionarily conserved from yeast to mammals. Their involvement in humoral and cellular immune responses is emerging through studies in drosophila and humans. In humans, a select group of 14-3-3 isoforms are antigenic; however the determinants of their antigenicity are not known. Here, we show that although mammalian 14-3-3 proteins are mostly conserved, subtle differences between their isoforms may give rise to their antigenicity. We observed syntenic relations among all the isoforms of 14-3-3 for mammals, but not with that of birds or amphibians. However, the parasitic 14-3-3 isoforms, which have known antigenic properties, show unique sequence, structure and evolution compared to the human 14-3-3. Moreover we report, for the first time the existence of a bacterial 14-3-3 protein. Contrary to the parasitic isoforms, both bacterial and yeast 14-3-3 exhibited significant homology with mammalian 14-3-3 in protein sequence as well as structure. Furthermore, a human 14-3-3 inhibitor caused significant killing of Candida albicans, which could be due to the inhibition of the structurally similar yeast homologue of 14-3-3, BMH, which is essential for its life cycle. Overall, our bioinformatic analysis combined with the demonstration of a novel antifungal role of a peptide inhibitor of human 14-3-3 indicates that the sequences and structural similarities between the mammalian, bacterial and fungal proteins are likely determinants of the antigenic nature of these proteins. Further, we propose that molecular mimicry triggered by microbial infections with either yeast or bacteria may contribute to the antigenic role of human 14-3-3. PMID- 29232713 TI - Long disordered regions of the C-terminal domain of Abelson tyrosine kinase have specific and additive functions in regulation and axon localization. AB - Abelson tyrosine kinase (Abl) is a key regulator of actin-related morphogenetic processes including axon guidance, where it functions downstream of several guidance receptors. While the long C-terminal domain (CTD) of Abl is required for function, its role is poorly understood. Here, a battery of mutants of Drosophila Abl was created that systematically deleted large segments of the CTD from Abl or added them back to the N-terminus alone. The functionality of these Abl transgenes was assessed through rescue of axon guidance defects and adult lethality in Abl loss-of-function, as well as through gain-of-function effects in sensitized slit or frazzled backgrounds that perturb midline guidance in the Drosophila embryonic nerve cord. Two regions of the CTD play important and distinct roles, but additive effects for other regions were also detected. The first quarter of the CTD, including a conserved PxxP motif and its surrounding sequence, regulates Abl function while the third quarter localizes Abl to axons. These regions feature long stretches of intrinsically disordered sequence typically found in hub proteins and are associated with diverse protein-protein interactions. Thus, the CTD of Abl appears to use these disordered regions to establish a variety of different signaling complexes required during formation of axon tracts. PMID- 29232714 TI - Cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in seropositive kidney transplant recipients. AB - Although cytomegalovirus (CMV) specific cell-mediated immunity (CMI) has been suggested as a predictive marker for CMV infection, proper CMI monitoring strategy in CMV-seropositive recipients and optimal method are not defined. The aim of this study was to evaluate two interferon gamma release assays during early post-transplant period as a predictor of the development of CMV infection in CMV-seropositive patients. A total of 124 CMV-seropositive recipients who received kidney transplantation from CMV-seropositive donor were prospectively examined. At pre-transplant and post-transplant 1 and 3 months, CMV-CMIs were tested using QuantiFERON-CMV assay (QF-CMV) and CMV specific T cell ELISPOT against CMV pp65 and IE-1 antigens (pp65-ELISPOT, IE-1-ELISPOT). CMV DNAemia occurred in 16 (12.9%) patients within 3 months after transplant. Post-transplant pp65 or IE-1 ELISPOT response, but not QF-CMV, was significantly associated with CMV DNAemia. The pp65 ELISPOT (cut-off; 30 spots/200,000 cells) and IE-1 ELISPOT (10 spots/200,000 cells) at post-transplant 1 month predicted the risk of post transplant CMV DNAemia (P = 0.019). Negative predictive values (NPV) for protection from CMV DNAemia in case of positive ELISPOT results were 94.5% (95% CI: 86.9-97.8%) and 97.6% (95% CI: 86.3-99.6%) in pp65-ELISPOT and IE-1-ELISPOT assays, respectively. These results suggest that the variability may exist between CMV ELISPOT assays and QF-CMV, and CMV ELISPOT at post-transplant 1 month can identify the risk of CMV DNAemia in seropositive kidney transplant recipients. PMID- 29232715 TI - Profound loss of neprilysin accompanied by decreased levels of neuropeptides and increased CRP in ulcerative colitis. AB - Neprilysin (NEP, CD10) acts to limit excessive inflammation partly by hydrolyzing neuropeptides. Although deletion of NEP exacerbates intestinal inflammation in animal models, its role in ulcerative colitis (UC) is not well explored. Herein, we aimed to demonstrate changes in NEP and associated neuropeptides at the same time in colonic tissue. 72 patients with UC and 27 control patients were included. Patients' demographic data and laboratory findings, five biopsy samples from active colitis sites and five samples from uninvolved mucosa were collected. Substance P (SP), calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) were extracted from freshly frozen tissues and measured using ELISA. Levels of NEP expression were determined using immunohistochemistry and immunoreactivity scores were calculated. GEBOES grading system was also used. We demonstrated a profound loss (69.4%) of NEP expression in UC, whereas all healthy controls had NEP expression. Patients with UC had lower neuronal SP; however non-neuronal SP remained similar. UC patients had also lower neuronal and non-neuronal VIP levels. CGRP were low in general and no significant changes were observed. Additionally, CRP positive patients with UC had higher rates of NEP loss (80% vs 51.9%) and lower SP levels when compared with CRP negative patients with UC. Concurrent decreases in SP and VIP with profound loss of NEP expression observed in UC is likely to be one of the factors in pathogenesis. Further studies are required to define the role of neuropeptides and NEP in UC. PMID- 29232716 TI - Comparative transcriptome analysis unveils the tolerance mechanisms of Citrus hystrix in response to 'Candidatus Liberibacter asiaticus' infection. AB - Citrus Huanglongbing (HLB), a highly devastating citrus disease, is associated with 'Candidatus Liberibacter asiacitus' (CLas), a member of phloem-inhabiting alpha-proteobacteria. HLB can affect all cultivated citrus and no cure is currently available. Previous studies showed that Kaffir lime (Citrus hystrix), primarily grown in South Asia and Southeast Asia, was tolerant to HLB but the molecular mechanism remains unknown. In this study, gene expression profiling experiments were performed on HLB-tolerant C. hystrix and HLB-susceptible C. sinensis three months after inoculation with CLas using RNA-seq data. Differentially expressed genes (DEGs) in the two citrus cultivars were mainly involved in diverse cellular functions including carbohydrate metabolism, photosynthesis, cell wall metabolism, secondary metabolism, hormone metabolism and oxidation/reduction processes. Notably, starch synthesis and photosynthesis process were not disturbed in CLas-infected C. hystrix. Most of the DEGs involved in cell wall metabolism and secondary metabolism were up-regulated in C. hystrix. In addition, the activation of peroxidases, Cu/Zn-SOD and POD4, may also enhance the tolerance of C. hystrix to CLas. This study provides an insight into the host response of HLB-tolerant citrus cultivar to CLas. C. hystrix is potentially useful for HLB-tolerant/resistant citrus breeding in the future. PMID- 29232717 TI - The relationship of depression in asthma-chronic obstructive pulmonary disease overlap syndrome. AB - PURPOSE: To clarify the relationship between asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) and depression. METHODS: We identified 10,911 patients who received an ACOS diagnosis and concurrent treatment between January 2000 and December 2009. Subjects without ACOS were included in the non-ACOS cohort (n = 10,911). Cox proportional hazard regression analysis was performed to compare the risk of depression between the ACOS and non-ACOS cohorts. RESULTS: The risk of depression was higher in the ACOS cohort than in the non-ACOS cohort (adjusted hazard ratios (aHRs) = 1.67, 95% confidence interval [CI] = 1.48-1.88). In the ACOS cohort, the aHRs for depression were [2.44 (95% CI = 1.45-4.11); 2.36 (95% CI = 1.58-3.52)] in patients [aged 20-39 years; without comorbidity]. In the ACOS cohort, the aHRs for depression were 1.70 (95% CI = 1.51-1.93) and 1.84 (95% CI = 1.55-2.19) in patients without inhaled corticosteroids (ICSs) and oral steroids (OSs) use, respectively. Moreover, the aHRs for the risk of depression were 1.16 (95% CI = 0.95-1.41) and 1.12 (95% CI = 0.96-1.29) in patients with ICSs and OSs use, respectively. CONCLUSION: The risk of depression is higher in ACOS patients, even in those without comorbidities or in young adults. The events of the depression were not significant difference in patients receiving the ICSs/OSs between the ACOS and the non-ACOS cohorts. PMID- 29232719 TI - QTL mapping of antixenosis resistance to common cutworm (Spodoptera litura Fabricius) in wild soybean (Glycine soja). AB - The common cutworm (CCW; Spodoptera litura Fabricius) is a serious herbivorous insect pest of soybean (Glycine max) in Asia and Oceania. Previously, we identified quantitative trait loci (QTLs) for CCW-antibiosis-resistance, CCW-1 and CCW-2, and antixenosis-resistance, qRslx1 and qRslx2, in the cultivar 'Himeshirazu'. The effects of these QTLs are useful in the breeding of CCW resistant cultivars. In this study, we conducted an antixenosis bioassay on CCW using recombinant inbred lines derived from a cross between a wild soybean (Glycine soja) and the leading cultivar 'Fukuyutaka' to identify CCW-resistance genes in G. soja. The QTL analysis revealed six and four novel antixenosis resistance QTLs in 2012 and 2013, respectively. Among them, the QTLs on chromosomes 2 and 7, designated qRslx4 and qRslx3, respectively, were stably detected in both years. qRslx3 exhibited the largest effect in both years, suggesting that qRslx3 can be exploited in the breeding of CCW-resistant soybean. Furthermore, qRslx3 and qRslx4 can be used, along with previously reported QTLs from 'Himeshirazu', to enhance the CCW-resistance of soybean cultivars because their chromosomal positions are unique. These new CCW-resistance QTLs from G. soja should play important roles in the breeding of CCW-resistant soybean cultivars. PMID- 29232720 TI - Inhibitors in Hemophilia: Treatment Challenges and Novel Options. AB - Hemophilia A (HA) and hemophilia B (HB) are rare congenital severe bleeding disorders, that may be controlled by proper administration of adequate prophylaxis with factor VIII (FVIII), and factor IX (FIX) concentrates, respectively, to prevent joint damage due to recurrent bleeding. However, approximately 30% of patients develop inhibitory antibodies that render factor replacement therapy ineffective. Due to the high variability of patients' bleeding tendency, there is a need to "individually tailor treatment" for this unique group of patients. While replacement therapy with FVIII or FIX can be used for treating HA or HB patients with low responding inhibitors, hemophilia patients with high-responding inhibitors are treated with bypassing agents. Unfortunately, the Bethesda assay applied for inhibitor measurement in most laboratories does not fully predict either bleeding tendency or therapy response. Immune tolerance induction (ITI) may eradicate most inhibitors, yet treatment is challenging during bleeding episodes. The role of bypassing agents and their various treatment strategies still deserves attention. Recently, new nonreplacement therapies have emerged for patients with hemophilia including patients with inhibitors. Adequate monitoring of bypassing therapy and of the new nonreplacement therapies in inhibitor patients is extremely challenging, thus global hemostatic assays are increasingly used to assess clot formation. This review aims to summarize the current treatment and monitoring challenges for inhibitor patients; in this perspective, we will discuss our institutional approach for optimal decision-making and individual therapy tailoring. PMID- 29232718 TI - An Arabidopsis Nucleoporin NUP85 modulates plant responses to ABA and salt stress. AB - Several nucleoporins in the nuclear pore complex (NPC) have been reported to be involved in abiotic stress responses in plants. However, the molecular mechanism of how NPC regulates abiotic stress responses, especially the expression of stress responsive genes remains poorly understood. From a forward genetics screen using an abiotic stress-responsive luciferase reporter (RD29A-LUC) in the sickle 1 (sic-1) mutant background, we identified a suppressor caused by a mutation in NUCLEOPORIN 85 (NUP85), which exhibited reduced expression of RD29A-LUC in response to ABA and salt stress. Consistently, the ABA and salinity induced expression of several stress responsive genes such as RD29A, COR15A and COR47 was significantly compromised in nup85 mutants and other nucleoporin mutants such as nup160 and hos1. Subsequently, Immunoprecipitation and mass spectrometry analysis revealed that NUP85 is potentially associated with HOS1 and other nucleoporins within the nup107-160 complex, along with several mediator subunits. We further showed that there is a direct physical interaction between MED18 and NUP85. Similar to NUP85 mutations, MED18 mutation was also found to attenuate expression of stress responsive genes. Taken together, we not only revealed the involvement of NUP85 and other nucleoporins in regulating ABA and salt stress responses, but also uncovered a potential relation between NPC and mediator complex in modulating the gene expression in plants. PMID- 29232722 TI - Primary or Redo Posterior Sagittal Anorectoplasty without a Stoma: To Feed or Not to Feed? PMID- 29232721 TI - The Immunoregulatory Activities of Activated Protein C in Inflammatory Disease. AB - Tissue injury prompts the initiation of host defense responses to limit blood loss, restrict pathogen entry, and promote repair. Biochemical and cellular pathways that lead to blood coagulation serve a fundamental role in generating a physical barrier at the wound site, but have also evolved to promote immune response to injury. Similarly, anticoagulant pathways that attenuate clot formation also regulate innate and adaptive immune responses. Of particular importance is activated protein C (APC) which serves as a principal regulator of thrombin generation, shapes the innate immune response to infection, and has been shown to contribute to the adaptive immune response in several preclinical models of autoimmune disease. APC controls blood coagulation by proteolytic degradation of procoagulant activated cofactors essential for fibrin clot development, but also cleaves multiple additional substrates and interacts with cell surface receptors to exert additional physiologically important roles. In this review, we focus on the molecular mechanisms utilized by APC to limit inflammation and, in particular, current understanding of the basis for APC anticoagulant and signaling activities. In particular, we provide an overview of established and emerging signaling pathways initiated by APC on endothelial cells, monocytes, neutrophils, dendritic cells, and T cells to control and regulate immune cell physiology. Finally, we consider the impact of APC activity in the context of both acute and chronic inflammatory disease, and the continuing efforts to harness the immunoregulatory properties of recombinant APC for therapeutic use. PMID- 29232724 TI - Inter-Rater Reliability of Air/Saline HyCoSy, HyFoSy and HyFoSy Combined With Power Doppler for Screening Tubal Patency. AB - Purpose To estimate the inter-observer reliability and agreement of offline analyses of three different ultrasound techniques for assessing tubal patency. Methods 100 tubes (n = 100) in 50 women were evaluated for tubal patency between November 2013 and July 2015 using ultrasound as index tests and laparoscopy as the reference standard. Three different ultrasound techniques were applied: two dimensional grayscale ultrasound using air + saline as the contrast media (2D HyCoSy); two- and three-dimensional grayscale ultrasound using foam as the contrast media (2 D/3D-HyFoSy); and the same technique but adding bi-directional power Doppler (2 D/3D-Doppler-HyFoSy). The videos containing full standardized exams using these three techniques were split into three parts, anonymized, encoded, randomized and reassessed in Nov. 2015 by two observers who assessed tubal patency using standardized criteria. These observers were blinded to any clinical information and each other's results. Proportions of observed agreement (po) and Cohen's Kappa (kappa) including the 95 % confidence intervals (CI) were calculated. Results The inter-observer reliability/agreement in 2 D/3D-Doppler HyFoSy (po = 0.99, kappa = 0.95, 95 % CI: 0.93 - 0.97) was higher compared to 2D air/saline-HyCoSy (po = 0.83, kappa = 0.55, 95 % CI: 0.40 - 0.68) and 2 D/3D HyFoSy (po = 0.92, kappa = 0.67, 95 % CI: 0.54 - 0.76). Conclusion The inter observer reliability and agreement of the diagnosis of tubal patency evaluating stored videos are improved when foam and power Doppler are used during acquisition. Therefore, this technique may be preferred to minimize misclassification and misdiagnosis. PMID- 29232723 TI - Biopsy of Liver Target Lesions under Contrast-Enhanced Ultrasound Guidance - A Multi-Center Study. AB - PURPOSE: To retrospectively characterize the prevalence and impact of contrast enhanced ultrasound (CEUS) as a guidance technique for the biopsy of liver target lesions (LTLs) at six interventional ultrasound centers. MATERIALS AND METHODS: The six participating centers retrospectively selected all patients in whom biopsy needles were positioned in LTLs during CEUS. The prevalence of CEUS-guided biopsies at each center between 2005 and 2016, contrast agent consumption, procedure indications, diagnostic yield and complications were assessed. Informed consent was obtained for all patients. RESULTS: CEUS-guided biopsy of LTLs was carried out in 103 patients (68 M/35 F, median age: 69 yrs) with 103 liver target lesions (median size: 20 mm) using cutting needles (18 - 20 g) in 94 cases (91.2 %). CEUS-guided biopsy represented 2.6 % (range: 0.8 - 7.7 %) of 3818 biopsies on LTLs carried out at the participating centers. Indications to CEUS-guided biopsy were: a target lesion not visible on non-enhanced US (27.2 %), improvement of conspicuity of the target (33 %), choice of non-necrotic area inside the target (39.8 %). 26 patients (25.2 %) had a previously non-diagnostic cyto-histological exam. The diagnostic accuracy of the technique was 99 %. No major complications followed infusion of contrast agent or biopsy performance. CONCLUSION: The indications for CEUS-guided biopsy for LTLs are limited, but CEUS can be useful in challenging clinical scenarios, e. g. poorly visualized or invisible lesions or sampling of non-necrotic areas in the target lesions. There is also a potential advantage in using CEUS to guide repeat biopsies after unsuccessful sampling performed using the standard ultrasound technique. PMID- 29232725 TI - Value of Contrast-Enhanced Ultrasound Quantification Criteria for Identifying Patients not Responding to Bevacizumab-Based Therapy for Colorectal Liver Metastases. AB - PURPOSE: To evaluate changes in tumor vascularization parameters based on contrast-enhanced ultrasound (CEUS) quantification criteria of at least one visible liver metastasis as an early predictor of non-response to chemotherapy, including bevacizumab for colorectal cancer (CRC) liver metastases. MATERIALS AND METHODS: This multicenter prospective study included patients who received first line bevacizumab-based chemotherapy. Tumor enhancement measured using CEUS within one liver metastasis and in relation to the surrounding healthy liver was quantified within 8 days before the first infusion of bevacizumab (E0), 24 hours after the end of the first infusion of bevacizumab (E1), in the 24 hours before the 2nd and 3 rd infusion of bevacizumab on day 15 (E2) and day 30 (E3), respectively, and after 2 months of treatment (E4). Endpoints were tumor response using RECIST criteria at 2 months, progression-free survival (PFS) and overall survival (OS). RESULTS: Among the 137 patients included in this study, 109 were analyzed. Only CEUS parameters calculated in relation to healthy liver were significant. High wash-in and wash-out rates at baseline were significantly associated with a better tumor response. Increases over time E2-E0 and E3-E0 for peak enhancement were significantly associated with shorter progression-free survival. Increases over time E2-E0 and E3-E0 for peak enhancement and wash-in area under the curve were significantly associated with a shorter overall survival. CONCLUSION: This large study demonstrated that early dynamic changes in the vascularity of liver metastases evaluated by quantified CEUS are associated with outcome in patients receiving first-line bevacizumab-based treatment for metastatic CRC. PMID- 29232726 TI - [Subtalare Screw Arthroereisis for the Treatment of Symptomatic, Flexible Pes Planovalgus]. AB - BACKGROUND: The purpose of this study was to determine the functional outcomes and radiographic results of the talus-stop screw method as minimally invasive subtalar arthroereisis in pediatric and juvenile flexible flatfoot. MATERIAL AND METHODS: We retrospectively evaluated 73 feet from 41 children using the talus stop-screw method, for the period between 2002 and 2011. The age at time of surgery ranged between nine and 14 years. The radiological assessment included measuring the calcaneal pitch, talar declination, talo-first metatarsal angle (Meary) and calcaneal-first metatarsal angle (Costa-Bartani) in the lateral view. To evaluate talo-navicular alignment in the anteroposterior view, the talo-first metatarsalbase angles were measured. To describe the amount of planovalgus deformity in lateral and anteroposterior view, we determined a tarsometatarsal index by adding the talo-first metatarsal and talo-first metatarsal base angles. RESULTS: 95% of patients were satisfied or very satisfied with postoperative results for morphology, pain and activity level. 95% of patients exhibited no limitations in daily life or sports activity due to foot pain, fatigue or repetitive distorsion. 96% of patients would undergo the surgery again, if necessary. Full weight bearing could be achieved after a mean time of 8.1 (range, 2 - 21) days. All measured postoperative angles improved significantly, except talar inclination. CONCLUSIONS: The talus-stop screw method as a minimally invasive subtalar arthroereisis is a safe and effective treatment for the flexible pes planovalgus deformity in children and adolescents. It preserves canalis tarsi and its proprioceptive structures. The major complication rate is low and, with a vertically inserted cancellous screw, this is an economic procedure. The TMT-index incorporating both planes in pes planovalgus feet appears to be a more precise method to determine this multiplanar deformity and to evaluate treatment options and results. PMID- 29232727 TI - [Radial Head Fracture - Management Recommendations]. AB - The radial head is pivotal in the functional anatomy of the elbow and forearm. It is an important stabiliser, together with the collateral ligaments and the processus coronoideus. Due to the pivotal importance, optimal therapies are essential for the function of elbow and forearm, independently of trauma severity. The present article presents current diagnostic testing, classifications and treatment options for radial head fractures. PMID- 29232728 TI - [Conjunction of Orthopaedic and Trauma Surgery - the Leipzig Model - Three Years Experiences of O & U + P at the University Hospital Leipzig]. AB - The establishment and implementation of the combined specialisation of orthopaedic and trauma surgery in daily routine was and still is a huge challenge for all stakeholders. In recent years, major efforts have been made by the professional associations, the specialty societies and all parties involved in the implementation of this project. Basically, there is no general recipe for the implementation of such a concept. For each centre or clinic, the local structural, professional and historical circumstances must be meticulously taken into account when considering implementation of this concept. Therefore, the authors would like to report on the strategy of Leipzig University Hospital in combining to the clinics for orthopaedics, traumatology and plastic surgery into a single and interdisciplinary department and the first three years of experience and further development since its implementation. PMID- 29232730 TI - Response to Letter to the Editor. PMID- 29232729 TI - [Influence of Synovial Fluid on Lubrication of Articular Cartilage in Vitro - A Review]. AB - Articular cartilage possesses unique tribological properties that are essential to reduce friction and wear. Especially under boundary lubrication conditions, synovial fluid as a whole, and its components ("biolubricants"), are important in assuring near frictionless/contactless lubrication of the joint surfaces. Therefore, several in vitro tribological models have been developed in recent years to investigate possible interdependencies. The aim of this article is to give a cursory overview of the influence of synovial fluid and its components on boundary lubrication of articular cartilage surfaces in vitro. PMID- 29232731 TI - Risk Factors for Postoperative Venous Thromboembolic Complications after Microsurgical Breast Reconstruction. AB - BACKGROUND: Venous thromboembolism (VTE) is a significant cause of postoperative morbidity and a focus of patient safety initiatives. Despite giving appropriate prophylaxis in accordance with the Caprini risk assessment model, we observed a high incidence of VTE in patients undergoing microsurgical breast reconstruction at our institution. To explore factors contributing to these events, we compared patients undergoing microsurgical breast reconstruction who sustained postoperative VTEs to those who did not. METHODS: A retrospective review of all patients who underwent microsurgical free flap breast reconstruction at Montefiore Medical Center from January 2009 to January 2016 was conducted. Patients were divided into two cohorts; those sustaining postoperative VTE and those who did not. Patients were compared based on demographics, comorbidities, operative time, estimated intraoperative blood loss, need for transfusion, volume of transfusion, and discharge on postoperative aspirin. RESULTS: A total of 133 patients underwent microsurgical breast reconstruction during the study period. Nine patients (6.8%) had postoperative VTE and there was one (0.8%) death. Patients having VTE were more likely to be Hispanic (33.3%, n = 3) in the VTE group versus 8.1% (n = 6) in the control group (p = 0.011), more likely to have an increased mean transfusion volume (455.5 +/- 367.8 vs. 139.51 +/- 221.7 mL, p = 0.03), and were more likely to be discharged without aspirin (77.8%, n = 7 and 58.1%, n = 72; p = 0.003). CONCLUSION: Patients sustaining postoperative VTE after microsurgical breast reconstruction are more likely to have an increased volume of blood transfusions and lack of discharge on postoperative aspirin. PMID- 29232732 TI - High Salt Intake Promotes Different Responses to Urodilatin and Uroguanylin in the Isolated Rat Kidney. AB - Urodilatin (UD) and uroguanylin (UGN) have been implicated in the regulation of salt and water homeostasis, particularly in the balance handling of salt intake. In this sense, the aim of the present work was to study the main effects of these peptides in kidneys from animals subjected to high NaCl (2%) intake, during 10 days in metabolic cages. The control group received only normal water, whereas the treated group drank 2% solution of NaCl (NaCl 2%). In addition, we studied effect of subthreshold UD (0.14 nM) and UGN (0.06 MUM) doses in NaCl 2% after a 30-min control period. Kidney perfusion was performed with Krebs-Henseleit containing 6 g% bovine albumin previously dialyzed. The effects of UD (0.14 nM) promoted reduction of PP, RVR, and UF in the NaCl 2% group. We also observed an increase in %TNa+ and %TCl-. The main effects of UGN in NaCl 2% were increase in PP, UF, and GFR, followed by a reduction in %TNa+ and %TCl-. After an increased intake of salt, physiological pathways are activated and regulated in order to eliminate excess sodium. In this study, we observed that in a subthreshold dose, UD does not promotes natriuresis and diuresis, suggesting that UGN is an important hormone in inducing salt excretion in a chronic salt overload. Therefore, the effects herein described may play a contributory role in the regulation of kidney function after ingestion of salty meals. PMID- 29232733 TI - Extracorporeal Membrane Oxygenation in Postcardiotomy Pediatric Patients-15 Years of Experience Outside Europe and North America. PMID- 29232734 TI - Impact of Surgery on Growth, Pulmonary Functions, and Acute Pulmonary Exacerbations in Children with Non-Cystic Fibrosis Bronchiectasis. PMID- 29232735 TI - Clinical Outcome of Urgent Thoracotomy in Patients with Penetrating and Blunt Chest Trauma: A Retrospective Survey. PMID- 29232737 TI - ? PMID- 29232736 TI - [Left Ventricular Assist Device Therapy - Ways to Improve the Ambulatory Care]. AB - The use of left-ventricular assist device therapy (LVAD) in terminal heart failure patients is increasing. Many patients are receiving LVAD-therapy as final solution (destination therapy). After discharge from the implanting heart center patient-centered care has to be implemented on an outpatient basis. A responsible ambulatory treatment of this severe heart failure population requires knowledge about LVAD specific problems (general medical care, long term complications, device management). The referring cardiologist as well as the private practitioner should be more involved in the care of patients with LVAD. By this means patients safety would increase and the overall costs decline not at least due to fewer hospital readmissions. PMID- 29232738 TI - ? PMID- 29232740 TI - ? PMID- 29232739 TI - ? PMID- 29232741 TI - ? PMID- 29232742 TI - ? PMID- 29232743 TI - ? PMID- 29232744 TI - ? PMID- 29232745 TI - ? PMID- 29232746 TI - ? PMID- 29232747 TI - ? PMID- 29232748 TI - [Combined Posteromedial and Anterolateral Approach in the "floating position" - Two Column Fracture of the Tibia Head]. AB - Background The posterior tibial plateau is often affected in intra-articular tibial fractures. Moreover, treating these posterior fractures is recognised as an important prognostic factor. Open reduction and internal fixation of lateral and posterior two column tibial plateau fractures can be achieved via a combined reversed L-shape approach and an anterolateral approach in the floating position without intraoperative repositioning of the patient. Material and Methods The operative procedure starts in the posterior position with visualisation of the posterior column after lateral retraction of the medial head of the M. gastrocnemius. The posterior fragment is then reduced and fixated. This is followed by reversed patient tilt, and slight flexion and varus stress on the knee. An anterolateral approach is performed with visualisation of the lateral column, direct reduction and internal fixation of the lateral tibia plateau. Results Since June 2014, 14 two column tibial plateau fracture patients with posterior and lateral column involvement have been treated according to this technique. The median follow-up was 306 days (IQR 194 - 438); 1 patient was lost to follow-up. During the last outpatient visit, 7 patients reported pain to some extent. At a median of 110 days (IQR 96 - 181), 10 patients showed a full range of motion. One deep infection was noted postoperatively. At the 3 to 4 month postoperative CT control, 10 of 14 patients showed successful reduction with restored alignment, whereas in 8 of 14 patients there was a congruent articular surface without significant articular steps (< 2 mm). Conclusion We have demonstrated that the surgical treatment of two column fractures of posterior and lateral tibial plateau fractures is technically possible via a combined posterior reversed L-shaped and anterolateral approach in a floating position without the necessity of intraoperatively repositioning of the patient. Although the number of patients was limited, the clinical and radiographic outcome was rather good. PMID- 29232749 TI - ? PMID- 29232750 TI - [A Novel Technique for the Preparation of a 3- or 5-Stranded Hamstring Graft for Individualised Single-Bundle ACL or PCL Reconstruction]. AB - Objective Development of a preparation technique for hamstring tendons to ensure a maximum of intraoperative flexibility during individualised cruciate ligament surgery. Indications Primary ACL- and PCL-reconstruction as well as cases of later revision. Method Three- or five-stranded grafts can be obtained with the use of semitendinosus and gracilis tendons with fiber tape enforcement and use of a conventional femoral cortical suspensory fixation device. Fibre tape and knotting style ensure free motion of the continous loop. Through its simplicity, the technique offers the highest grade of intraoperative scalability. PMID- 29232751 TI - [Prosthetics and Orthotics: Prosthetic Fitting in Lower Extremity in Transfemoral Amputation]. AB - Modern prosthetic equipment often enables reintegration of patients with the amputation of a lower limb into their private life, their professional and social environment to a large extent. Provisioning of the lower extremity with artificial limbs aims at a life as normal as possible for the involved individual. The modules are selected in an interdisciplinary team. An optimal fitting of the socket, the correct static set-up, the appropriate fitting as well as cosmetic aspects are the essential basis for a sufficient provisioning. Knee and foot components should be chosen according to the individual patient's situation including their prognostic mobility classification. PMID- 29232752 TI - Simultaneous Determination of Rosuvastatin, Rosuvastatin-5 S-lactone, and N desmethyl Rosuvastatin in Human Plasma by UPLC-MS/MS and Its Application to Clinical Study. AB - OBJECTIVE: A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay was developed and validated for the simultaneous quantification of rosuvastatin (RST), rosuvastatin-5 S-lactone (RSTL), and N-desmethyl rosuvastatin (DM-RST) in human plasma. METHODS: Sample was prepared by liquid-liquid extraction with ethyl acetate from 100 MUL acidulated buffered plasma. Then analytes were chromatographically separated using an Acquity UPLC HSS T3 column (3.0 mm*100 mm, 1.8 um) by 0.1% formic acid and gradient acetonitrile at a flow rate of 0.30 mL/min. Three analytes and internal standards (carbamazepine) were eluted in 3.5 min. Mass spectrometry detection was performed through positive ion electrospray ionization (ESI). RESULTS: The calibration curves for three analytes were linear (R>=0.9987, n=3) within the concentration range of 0.1-50 ng/mL for RST and RSTL, and 0.2-100 ng/mL for DM-RST. Mean extraction recoveries were enhanced by means of acidulated plasma using ammonium acetate of pH 4.0, which ranged within 75.3-98.8% for three analytes. Intra- and inter precision and accuracy were 88.2-96.4%. CONCLUSIONS: This present method was lower LLOQ, less time consuming (3.5 min), less plasma consuming (100 uL) and simpler sample preparation. And it was successfully applied to determine steady state concentrations of RST, RSTL and DM-RST in a clinical study of RST for patients with coronary artery disease (CAD). PMID- 29232753 TI - Solvent Extraction and GC-MS Analysis of Sesame Seeds for Determination of Bioactive Antioxidant Fatty Acid/Fatty Oil Components. AB - The seed kernels of Sesamum indicum L. (family: Pedaliaceae) were extracted with ethanol and yield of components determined by Gas Chromatography/Mass Spectrometry (GC/MS). The free radical scavenging activities of ethanolic extract against1, 1-Diphenyl-2-picrylhydrazyl (DPPH) were determined by UV spectrophotometer at 517 nm. Phytochemical screening revealed the presence of numerous bioactive compounds including steroids, phenolic, terpenoids, fatty acids and different types of ester compounds. The ethanolic extract was purified and analyzed by GC MS.The prevailing compounds found in ethanolic extract were Carvacrol (0.04%),Sesamol (0.11%), 4-Allyl-2-methoxy-phenol(0.04%),Palmitic acid (1.08%), cis-9-Hexadecenal (85.40%), Lineoleoyl chloride (0.52%), Palmitic acid beta-monoglyceride (0.40%), Dihydro-aplotaxene (0.61%), Oleoyl chloride (1.11%), (+)-Sesamin (4.73%), 1,3-Benzodioxole, 5-[4-(1,3-benzodioxol-5-yloxy)tetrahydro-1 H,3 H-furo [3,4-c]furan-1-yl], [1 S-(1,3,4,6alpha.), (2.01%)], 6-Nitrocholest-5 en-3-yl acetate (0.22%), Ergost-5-en-3beta-ol (2.35%) and 24 Propylidenecholesterol (0.16%). The presence ofsaturated and unsaturated fatty acids in ethanolicextract justifies the use of this plant to treat many ailments in folk and traditional medicine. Ethanolic extract have shown significant antioxidant activity(IC50120.38+/-2.8 ug/ml). The presence of phenolic (Sesamol), lignin (Sesamin) compounds and unsaturated fatty acids are reported as possible contributor for antioxidantactivity of seed extract. PMID- 29232754 TI - [Measurement of the Strength of Human Musculus Orbicularis Oculi Using Video Analysis]. AB - Introduction Current methods to measure the of strength of the musculus orbicularis oculi are limited by high proneness to examiner error or by their complex and impracticable set-ups. Our aim was to develop a simple and practicable method to measure eye lid power via video analysis. Methods 50 healthy subjects were included. A deformable single use lid speculum was used. Forced maximum lid closure was recorded via a video slit lamp. Analysis of the video data was performed with open source tracking software. The maximum and minimum distances of the inserted lid speculum were detected. The rigidity and mechanical characteristics of the lid speculum were tested separately. In this way, lid power could be determined by analysis of the maximum compression of the lid speculum. To explore the impact of age and sex on eye lid power, Pearson's correlation coefficient was evaluated. ICC (intra class correlation) was analysed as a measure of reliability. Results In three repeated measurements in 9 subjects, an ICC of alpha = 0.91 was detected. With 50 healthy subjects, the range of lid power was 0.62 - 4.72 N. No correlation was found between the age of the subjects and eyelid power (Pearson's correlation coefficient = 0.054). A weak correlation was found between the sex of the subjects and eyelid power. For female subjects, the mean power was 1.82 N and for male subjects 2.58 N (Pearson's correlation coefficient = 0.428). Discussion A test series of 50 healthy subjects exhibited a wide range of lid power. The wide range makes it difficult to distinguish between pathological and normal eyelid power. The major application field of the method may therefore be in inner-individual measurements of known eyelid pathologies, such as paresis of the facial nerve or ocular myasthenia. PMID- 29232756 TI - [The Conundrum of Relationships in the Multivariate Dataset of nvAMD Treatment]. AB - Background The evaluation of relationships in clinical case series is complicated by statistical pitfalls, one of which is spurious correlation. In this case, one or more potential factors are actually not related to a target measure, yet it may be wrongly inferred that they are. This may be due to either coincidence or the presence of a one or more confounding unregarded factors. In randomised clinical trials, it is attempted to eliminate such confounding factors or to control them by randomisation. However, this approach is not applicable in retrospective case series, and other statistical methods must be applied, such as multivariate analyses, taking into account all known variables. Patients/Material and Methods Statistical evaluation of the impact of different variables on the change in visual acuity after year 2 in a cohort of 1300 cases of nvAMD. The investigated variables are: visual acuity (VA) at baseline, central retinal thickness at baseline, age at baseline, mean interval between visits, number of injections, initial gain in VA after upload, and a change of the anti-VEGF compound. The target outcome measure was the change in VA as letter score at the end of year 2. Results All investigated variables have a marked impact on VA outcome when only single regression analysis is performed. Initial analysis of a switch in therapy gives a seemingly large effect on VA. However, multivariate analysis to avoid spurious correlations shows that only the following variables influence VA outcome with statistical significance: VA at baseline, initial gain in VA after upload, number of injections, mean interval between visits, and central retinal thickness at baseline. A switch in therapy had no statistically significant effect on VA outcome. Conclusion A switch in anti-VEGF therapy is not causally related to better VA outcome. In the statistical evaluation of non randomised, retrospective case series, special attention must be given to potential confounding variables. When subgroups under investigation are not well balanced for confounding factors, misleading spurious correlations can result, leading to incorrect inferences. PMID- 29232755 TI - [Effect of the Age-Related Corneal Elasticity on Applanation Tonometry]. AB - Elevated intraocular pressure (IOP) is accepted to be one important criterion for glaucoma and is usually measured by applanation or rebound tonometry. The individual uncertainty due to central cornea thickness (CCT) is thereby corrected, while the error induced by age-related elastic modulus (EM) change of the cornea is ignored. To investigate its influence on IOP measurement, we derive a model including also the elastic modulus. Our approach is based on known equations from experimental physics and several assumptions being justified in this paper. Our correction values are in good agreement with the Dresden correction table for low CCT values up to 650 um using a mean EM of 0.29 MPa. An EM variation from 0.2 to 0.5 MPa, which relates to ages from infancy to 90 years, results in an IOP error of up to 10 mmHg. A variation of the cornea curvature from 7.4 mm to 8.0 mm results in a total IOP change of about 3 mmHg, which is usually neglected. The derived model shows that established correction formulas can be insufficient for a reliable IOP determination. In many cases, the conventionally measured IOP may be precise enough, but the uncertainty in IOP determination due to CCT and EM influence are almost in the same range. Measuring the IOP using applanation methods with established correction formulas should not be overestimated without to respect the EM of the cornea. PMID- 29232757 TI - [Real-life Data on the Treatment of Diabetic Macular Oedema in Germany]. AB - Background Controlled prospective clinical trials on the treatment of diabetic macular oedema (DME) using anti-VEGF compounds show very good results in visual acuity gain over several years. To date, only limited data are available from comparable studies under real-life settings in clinical routine. However, real life data from other indications for anti-VEGF treatment suggest that, in clinical routine, gain in visual acuity is less pronounced and cannot be maintained over a longer period of time, which is related to the significantly lower number of injections administered in clinical routine. Here we report a case series from our clinical routine of patients treated with ranibizumab for visual significant DME. Patients/Material and Methods Retrospective case series of 335 cases with follow-up of up to 3 years. All cases in our clinic treated for visual significant DME with at least one injection of ranibizumab were evaluated for the course of visual acuity gain and number of injections received. Results A mean gain in visual acuity (VA) of + 5.6 and + 3.7 letters was found in years one and two, respectively, with a median VA of logMAR 0.52 (decimal 0.3) at baseline. The steepest increase in VA is found during the first 4 months, with a less pronounced increase up to month 16. The mean number of injections was 5.7, 3.2 and 1.1 for years one, two, and three, respectively. Conclusions Results of real life treatment in clinical routine are found to fall behind controlled, prospective trials, as found to the findings in other anti-VEGF indications: mean gain in VA is lower than in prospective trials, and the initial gain cannot be fully maintained over a prolonged time period. Similarly, the number of injections received is markedly lower than in controlled trials. This can partially be explained by differences in study populations and a negative selection bias in longer term results. However, additional barriers that hamper timely treatment tailored to disease activity requirements must be identified and circumvented where possible. PMID- 29232758 TI - [Time Course of Changes in Visual Acuity After a Single Injection of Aflibercept or Ranibizumab in Neovascular Age-related Macular Degeneration - Analysis of Aggregated Real Life Data]. AB - Background Treatment of neovascular age-related macular degeneration (nvAMD) under real life conditions may differ from controlled prospective trials with respect to the number of injections and long term preservation of visual acuity. In many instances, intervals for controls and re-injection cannot be maintained as frequently as required. This case series examines actual intervals for control and re-injection visits, in order to estimate how prolonged intervals have an impact on momentary visual acuity and how long term visual outcome is affected. Patients/Material and Methods Retrospective case series of 1,324 eyes with nvAMD, treated with a total of 8,150 ranibizumab injections (according to the PRN regimen) or 1,725 aflibercept injections (according to a fixed regimen), during the observation period of up to 3 years. The evaluation covered the time interval between visits, impact of this on the course of visual acuity, as well as the number of injections throughout treatment. Results Planned intervals of 4 or 8 weeks between visits were more often exceeded in the PRN regimen than with the fixed regimen. Visual acuity does not peak after 4 weeks, but only between 6 and 8 weeks. No statistically significant difference between aflibercept and ranibizumab was found. If the mean interval for re-injection was maintained at 4 6 weeks, this gave the greatest gains in visual acuity at end of years 1 and 2, respectively. Any prolongation of these intervals was accompanied by worse long term visual acuity. The fixed regimen is associated with consistently briefer re treatment intervals during years 2 and 3, than with the PRN regimen. Conclusion Our data point to the importance of frequent controls accompanied by timely retreatment, as these have a major impact on visual outcome. It therefore appears to be more important to choose a treatment plan that facilitates frequent re injections than to select either of the two compounds. PMID- 29232759 TI - Involvement of CYP1B1 in interferon gamma-induced alterations of epithelial barrier integrity. AB - BACKGROUND AND PURPOSE: CYP1B1 and CYP1A1 are important extra-hepatic cytochromes, expressed in the colon and involved in the metabolism of dietary constituents and exogenous compounds. CYP1B1 expression is increased by pro inflammatory cytokines, and it has been recently implicated in regulation of blood brain barrier function. We investigated its involvement in the increased permeability of the intestinal epithelial barrier observed in inflammatory conditions. EXPERIMENTAL APPROACH: Epithelial monolayers formed by human T84 colon carcinoma cells cultured on transwells, were disrupted by incubation with IFNgamma (10 ng.mL-1 ). Monolayer integrity was measured using transepithelial electrical resistance. CYP1A1 and CYP1B1 inhibitors or inducers were applied apically. Potential mechanisms of action were investigated using RT-qPCR. KEY RESULTS: IFNgamma disrupts the barrier integrity of the T84 monolayers and increases CYP1B1 and HIF1alpha mRNA expression. CYP1B1 induction is inhibited by the NF-kappaB inhibitor ammonium pyrrolidinedithiocarbamate (100 MUM) but not by the HIF1alpha inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (50 MUM). Inhibition of CYP1B1 with the selective inhibitor 2,4,3',5'-tetramethoxystilbene (100 nM) partly reverses the effects of IFNgamma on epithelial permeability. CONCLUSIONS AND IMPLICATIONS: These data suggest that increased expression of CYP1B1 is involved in the effects of IFNgamma on epithelial permeability. Inhibition of CYP1B1 counteracts the alterations of epithelial barrier integrity induced by IFNgamma and could thus have a therapeutic potential in disorders of intestinal permeability associated with inflammation. PMID- 29232760 TI - The association of keratoconus with blepharitis. AB - BACKGROUND: Identifying potentially treatable risk factors for the progression of keratoconus is of great importance. The purpose of this study was to determine the association between blepharitis and keratoconus. METHODS: In this prospective, comparative, observational study, 50 keratoconus participants from the central district of the Clalit Health Services Health Maintenance Organization in Israel underwent comprehensive eye examination. Seventy-two healthy medical personnel of similar ages were randomly chosen as a control group. The signs and symptoms of blepharitis in each participant were assessed. A thorough survey of the eyelids (scales and foam on the eyelashes, missing eyelashes and expression of meibomian gland contents) was performed. All participants were required to complete two questionnaires: the Ocular Surface Disease Index questionnaire and a questionnaire regarding symptoms, signs and risk factors for blepharitis. RESULTS: Blepharitis was more common in keratoconus participants than in the control group (24 per cent versus 2.8 per cent, p < 0.001). A higher proportion of keratoconus participants reported rubbing their eyes more than once a day (36 per cent versus 11.1 per cent, p = 0.002) as well as red and tired eyes (12 per cent versus zero per cent, p = 0.009). On external eye examination, signs of blepharitis and meibomian gland dysfunction were found more frequently in the keratoconus group (p < 0.05). CONCLUSIONS: Signs and symptoms of blepharitis occur more often in keratoconus participants than in healthy individuals. Blepharitis-related inflammation and associated eye rubbing may contribute to disease progression. PMID- 29232761 TI - Profile of ethnicity, living arrangements and loneliness amongst older adults in Aotearoa New Zealand: A national cross-sectional study. AB - OBJECTIVE: To explore the patterns of living arrangements, ethnicity and loneliness amongst older adults (aged 65+ years) living at home. METHODS: National interRAI-HC (International Residential Assessment Instrument-Home Care) assessments conducted between 1 September 2012 and 31 January 2016 were analysed. Analysis focused on the associations between loneliness and both ethnic groups and living arrangements. RESULTS: There were 71 859 eligible participants, with average age 82.7 years, comprising Maori (5%), Pasifika (3%), Asian (2%) and European/Other (89%) ethnic identification. Most stated that they were not lonely (79%), but those living alone were more likely to be lonely (29%) than those living with others (14%) (P < 0.05). Amongst those living alone, significant differences in the likelihood of being lonely emerged between ethnic groups (P < 0.05). CONCLUSIONS: Ethnic identification and living arrangements were significantly associated with the likelihood of loneliness for those having an interRAI-HC assessment. Efforts to reduce the negative impacts of loneliness need a nuanced approach. PMID- 29232762 TI - Review article: Best practice management of low back pain in the emergency department (part 1 of the musculoskeletal injuries rapid review series). AB - Low back pain (LBP) is a common presentation to the ED, and a frequent cause of disability globally. The ED management is often associated with high rates of imaging, misuse and overuse of pharmacology and subsequent financial implications. Given this, improved quality of care for patients with LBP in ED is essential. This rapid review investigated best practice for the assessment and management of LBP in the ED. PubMed, CINAHL, EMBASE, TRIP and the grey literature, including relevant organisational websites, were searched in 2015. Primary studies, systematic reviews and guidelines were considered for inclusion. English-language articles published in the past 10 years that addressed acute LBP assessment, management or prognosis in the ED or acute setting were included. Data extraction of included articles was conducted, followed by quality appraisal to rate the level of evidence where possible. The search revealed 1538 articles, of which 38 were included in the review (n = 8 primary articles, n = 13 systematic reviews and n = 17 guidelines). This rapid review provides clinicians managing LBP in the ED a summary of the best available evidence to risk stratify and enhance the quality of care, optimising patient outcomes. Consistent evidence was found to support the use of 'red flags' to screen for serious pathologies, diagnostic tests being reserved for use only in the presence of red flags, the judicious prescribing of opioids, identification of psychosocial risk factors as predictors of poorer outcome and promotion of early return to work and function. PMID- 29232763 TI - Lymphangiectasia. PMID- 29232764 TI - Brain biopsy performed with the RONNA G3 system: a case study on using a novel robotic navigation device for stereotactic neurosurgery. AB - BACKGROUND: Robotic neuronavigation is becoming an important tool for neurosurgeons. We present a case study of a frameless stereotactic biopsy guided by the RONNA G3 robotic neuronavigation system. METHODS: A 45 year-old patient with a history of vertigo, nausea and vomiting was diagnosed with multiple periventricular lesions. Neurological status was unremarkable. A frameless robotic biopsy of a brain lesion was performed. RESULTS: Three tissue samples were obtained. There were no intraoperative or postoperative complications. Histological analysis showed a B-cell lymphoma. After merging the preoperative CT scan with the postoperative MRI and CT scans, the measured error between the planned and the postoperatively measured entry point was 2.24 mm and the measured error between the planned and postoperatively measured target point was 2.33 mm. CONCLUSIONS: The RONNA G3 robotic system was used to navigate a Sedan brain biopsy needle to take tissue samples and could be a safe and precise tool for brain biopsy. PMID- 29232765 TI - Influence of mouth and jaw movements on dynamics of spontaneous eye blink activity assessed during slitlamp biomicroscopy. AB - BACKGROUND: To evaluate oculo-mandibular interactions during evaluation of spontaneous eye blink rate (SEBR) of normal young adult human subjects while seated at a slitlamp. METHODS: Repeat video recordings of five minutes duration were made on 76 young adult emmetropic subjects aged 18-25 years. The subjects were instructed to direct their gaze horizontally toward a distant target with the entire cornea of the left eye illuminated with a broad beam cobalt blue light. Repeat recordings were made: (a) on the following day in silence in group one; (b) immediately in silence for group two; and (c) immediately either while holding their mouth open slightly or while responding to casual conversation for groups three and four. RESULTS: For group one the averaged SEBR values for the first and second recordings were 13.5 and 14.6 blinks/minute, and similar results were obtained for group two if the subjects were relaxed (for example 13.9 and 12.0 blinks/minute). A slight, but statistically significant, time-related decline in SEBR was usually noted. For non-relaxed (restless) subjects exhibiting spontaneous mouth and jaw movements while being videographed, the averaged SEBR values were around 27 blinks/minute. For groups three and four, analyses of those individuals who managed to maintain a mouth open posture for the video recordings, the averaged SEBR was 7.2 blinks/minute, while those engaged in casual conversation had an averaged SEBR of 20.3 blinks/minute. CONCLUSIONS: Mouth and jaw movements and a non-relaxed state can substantially affect spontaneous eye blinking. PMID- 29232766 TI - Combined Erlotinib and PF-03084014 treatment contributes to synthetic lethality in head and neck squamous cell carcinoma. AB - OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is characterized by high mortality and low survival rates. As an epidermal growth factor receptor (EGFR) inhibitor, Erlotinib has been approved for treatment of various tumours. PF-03084014 is a selective inhibitor of Notch1 signalling. This study aimed to explore new approaches for simultaneously targeting EGFR and Notch1 signalling to attenuate tumour growth and improve survival. MATERIALS AND METHODS: Cell proliferation was determined by CCK-8 assay and Flow cytometry. Cell invasive ability was determined by Transwell assay. Western blot was used to test the expression of Notch1 and EGFR pathway. Cleaved Caspase-3 staining and TUNEL assay were used to verify the apoptosis through combined treatment. RESULTS: We first confirmed proliferative inhibition and cell death in HNSCC with combined Erlotinib and PF-03084014 treatment. Moreover, we found PF-03084014 reversed the increased invasion induced by Erlotinib. In a preclinical therapeutic drug trial in vivo, combined treatment effectively abrogated tumour growth. Most importantly, one mechanism was found that PF-03084014 alone could activate the PI3K/AKT signalling, the downstream of EGFR signalling, and Erlotinib alone could activate the intracellular domain of Notch1 (NICD), while combined treatment of PF-03084014 and Erlotinib suppressed the HNSCC growth. CONCLUSIONS: These results suggested that concomitant inhibition of the Notch1 and EGFR pathways represented a rational strategy for promoting apoptosis in HNSCC and overcoming treatment resistance. PMID- 29232767 TI - A Comparative Immunohistochemical Study of Anal Canal Epithelium in Humans and Swine, Focusing on the Anal Transitional Zone Epithelium and the Anal Glands. AB - To better understand the cellular origins and differentiation of anal canal epithelial neoplasms, the immunohistochemical profiles of the anal canal epithelium in humans and swine were evaluated. Formalin-fixed tissue sections were immunostained for mucin (MUC: MUC2, MUC5AC, MUC5B), desmoglein 3 (DGS3), p63, CDX2, SOX2, and alpha-smooth muscle actin (alpha-SMA). The anal transitional zone (ATZ) epithelium covered the anal sinus and consisted of a stratified epithelium with mucous cells interspersed within the surface lining. Anal glands opened into the anal sinus. Ducts and acini of intraepithelial or periepithelial mucous type were the main structures of human anal glands, whereas those of swine were compound tubuloacinar mixed glands. Distal to the ATZ epithelium, non keratinized stratified squamous epithelium merged with the keratinized stratified squamous epithelium of the perianal skin. MUC5AC expression predominated over MUC5B expression in the ATZ epithelium, while MUC5B expression was higher in the anal glands. SOX2 was positive in the ATZ epithelium, anal glands, and squamous epithelium except in the perianal skin. In humans, DGS3 was expressed in the ATZ epithelium, anal gland ducts, and squamous epithelium. p63 was detected in the ATZ epithelium, anal glands, and squamous epithelium. Myoepithelial cells positive for alpha-SMA and p63 were present in the anal glands of swine. Colorectal columnar cells were MUC5B+ /MUC2+ /CDX2+ /MUC5AC- /SOX2- . The ATZ epithelium seems to be a distinctive epithelium, with morphological and functional features allowing smooth defecation. The MUC5AC+ /SOX2+ /MUC2- /CDX2- profile of the ATZ epithelium and anal glands is a useful feature for diagnosing adenocarcinoma arising from these regions. Anat Rec, 301:796-805, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29232768 TI - Modification of the Thrombolysis in Myocardial Infarction risk score for patients presenting with chest pain to the emergency department. AB - OBJECTIVE: To develop a modified Thrombolysis in Myocardial Infarction (TIMI) score to effectively risk stratify patients presenting to the ED with chest pain. METHODS: A prospective observational study was conducted at two metropolitan EDs. Data were obtained during patient interview. The primary outcome was major adverse cardiovascular events (MACE) within 30 days of presentation. Two separate modifications of the TIMI score were developed. These scores were compared to the original TIMI in terms of the area under the receiver operating characteristic curve and diagnostic accuracy statistics (sensitivity, specificity, positive and negative predictive values). RESULTS: Of 1760 patients, 364 (20.7%) experienced 30 day MACE. The first modified TIMI score was a simplified TIMI (s-TIMI) including four variables: age >=65 years, three or more risk factors, high sensitivity troponin (hs-cTnI) and electrocardiogram changes. The second score included the same four variables plus two Global Registry of Acute Coronary Events (GRACE) variables (systolic blood pressure and estimated glomerular filtration rate). This score was termed the GRACE TIMI (g-TIMI). s-TIMI had a lower sensitivity compared to the original TIMI score (93.41 and 96.98%), but higher specificity (45.49 and 24.50%). The g-TIMI had a sensitivity of 98.90% and specificity of 14.90%. CONCLUSIONS: Attempts to modify the TIMI score yielded two scores with added predictive utility in comparison to the original TIMI model. The addition of GRACE variables (g-TIMI) increased sensitivity for MACE, but decreased the specificity of the model. The s-TIMI score yielded good specificity but had sensitivity that would not be acceptable by emergency physicians. The s TIMI may be useful as part of an accelerated chest pain protocol. PMID- 29232769 TI - Anti-Parkinsonian and anti-dyskinetic profiles of two novel potent and selective nociceptin/orphanin FQ receptor agonists. AB - BACKGROUND AND PURPOSE: We previously showed that nociceptin/orphanin FQ opioid peptide (NOP) receptor agonists attenuate the expression of levodopa-induced dyskinesia in animal models of Parkinson's disease. We now investigate the efficacy of two novel, potent and chemically distinct NOP receptor agonists, AT 390 and AT-403, to improve Parkinsonian disabilities and attenuate dyskinesia development and expression. EXPERIMENTAL APPROACH: Binding affinity and functional efficacy of AT-390 and AT-403 at the opioid receptors were determined in radioligand displacement assays and in GTPgammaS binding assays respectively, conducted in CHO cells. Their anti-Parkinsonian activity was evaluated in 6 hydroxydopamine hemi-lesioned rats whereas the anti-dyskinetic properties were assessed in 6-hydroxydopamine hemi-lesioned rats chronically treated with levodopa. The ability of AT-403 to inhibit the D1 receptor-induced phosphorylation of striatal ERK was investigated. KEY RESULTS: AT-390 and AT-403 selectively improved akinesia at low doses and disrupted global motor activity at higher doses. AT-403 palliated dyskinesia expression without causing sedation in a narrow therapeutic window, whereas AT-390 delayed the appearance of abnormal involuntary movements and increased their duration at doses causing sedation. AT 403 did not prevent the priming to levodopa, although it significantly inhibited dyskinesia on the first day of administration. AT-403 reduced the ERK phosphorylation induced by SKF38393 in vitro and by levodopa in vivo. CONCLUSIONS AND IMPLICATIONS: NOP receptor stimulation can provide significant albeit mild anti-dyskinetic effect at doses not causing sedation. The therapeutic window, however, varies across compounds. AT-403 could be a potent and selective tool to investigate the role of NOP receptors in vivo. PMID- 29232770 TI - Review article: NEXUS criteria to rule out cervical spine injury among older patients: A systematic review. AB - The National Emergency X-Radiography Utilization Study (NEXUS) criteria were derived from a heterogeneous group of adult blunt trauma patients, with the outcome measure assessed most commonly using plain X-ray radiographs. Recent observations have suggested inadequacy of these criteria for excluding injury in population subgroups such as the elderly. The aim of this systematic review was to determine the sensitivity of the NEXUS criteria in excluding cervical spine injury among older patients aged >=65 years. A systematic review of the literature published prior to 1 January 2017 that reported on the performance of the NEXUS criteria among older patients was conducted. The databases OVID Embase and OVID Medline were searched. The sensitivity of the NEXUS criteria was recalculated for each study among older patients. There were seven studies included in this review. All studies were considered to be at risk of bias and rated down for quality of evidence. Emergency physicians were assessors in all included studies. Sensitivity of the NEXUS criteria among older patients ranged from 66% to 100%. Variable sensitivity was demonstrated when the NEXUS criteria were applied to older blunt trauma patients. This questions the applicability of the NEXUS criteria in this subgroup. PMID- 29232771 TI - Laparoscopic distal pancreatectomy for intrapancreatic accessory spleen: a case report. PMID- 29232773 TI - [Clinical application of percutaneous vertebral augmentation in treating osteoporotic compression fracture of vertebral body]. PMID- 29232772 TI - S-Nitrosohemoglobin Levels and Patient Outcome After Transfusion During Pediatric Bypass Surgery. AB - Banked blood exhibits impairments in nitric oxide (NO)-based oxygen delivery capability, reflected in rapid depletion of S-nitrosohemoglobin (SNO-Hb). We hypothesized that transfusion of even freshly-stored blood used in pediatric heart surgery would reduce SNO-Hb levels and worsen outcome. In a retrospective review (n = 29), the percent of estimated blood volume (% eBV) replaced by transfusion directly correlated with ventilator time and inversely correlated with kidney function; similar results were obtained in a prospective arm (n = 20). In addition, an inverse association was identified between SNO-Hb and postoperative increase in Hb (?Hb), reflecting the amount of blood retained by the patient. Both SNO-Hb and ?Hb correlated with the probability of kidney dysfunction and oxygenation-related complications. Further, regression analysis identified SNO-Hb as an inverse predictor of outcome. The findings suggest that SNO-Hb and ?Hb are prognostic biomarkers following pediatric cardiopulmonary bypass, and that maintenance of red blood cell-derived NO bioactivity might confer therapeutic benefit. PMID- 29232774 TI - [Percutaneous short segment pedicle screw fixation with vertebral augmentation for the treatment of single level thoracolumbar osteoporosis fracture]. AB - OBJECTIVE: To explore clinical outcomes of percutaneous short segment pedical screw fixation with bone cement augmentation in treating single level thoracolumbar osteoporotic fracture. METHODS: From January 2009 to January 2013, 48 single level thoracolumbar osteoporotic fracture patients without neurological symptoms were treated with percutaneous short segment pedicle screw fixation with bone cement augmentation. Among them, including 22 males and 26 females aged from 55 to 72 years old with an average of 62.2 years old. The time from injury to operation varied from 8 h to 9 d(mean 4.5 d). According to Denis fracture classification, 35 cases were compression fractures and 13 cases were burst fractures. Nine vertebrae located on T11, 15 vertebrae on T12, 14 vertebrae on L1, 7 vertebrae on L2, and 3 vertebrae on L3. Anterior vertebral body height, sagittal Cobb angle, sagittal index(SI), failure of internal fixation and recurrence of kyphosis were observed before and after operation. RESULTS: All patients were followed up from 24 to 48 months with an average of 32.5 months. Operative time ranged from 60 to 140 min with an average of 85 min;blood loss ranged from 50 to 100 ml with an average of 75 ml. Before operation, at 3 d and 1 year after operation, anterior vertebral body height respectively was (56.4+/ 2.6)%, (91.2+/-1.6)% and (86.9+/-3.2)%; sagittal Cobb angle respectively was(26.6+/-3.2) degrees , (6.2+/-1.0) degrees and (6.8+/-1.5) degrees ; SI respectively was(51.6+/-4.2)%, (90.2+/-5.9)% and (88.7+/-4.2)%; VAS respectively was(7.6+/-1.2), (2.8+/-1.9), (1.1+/-0.4) points. There were significant differences above items between before operation and at 3 d after operation, while no significance between 1 year and 3 d after operation. No neurologic damage, internal fixation failure and recurrence of kyphosis occurred. CONCLUSIONS: Percutaneous short segment pedicle screw fixation with bone cement augmentation in treating single level thoracolumbar osteoporotic fracture has advantages of less trauma, and could effectively restore normal physiological load transmission of spinal, avoid failure of internal fixation and recurrence of kyphosis. PMID- 29232775 TI - [Percutaneous short segment pedicle screw fixation with vertebral augmentation for the treatment of single level thoracolumbar osteoporosis fracture]. AB - OBJECTIVE: To explore the safety and clinical effects of percutaneous vertebroplasty and pedicle screw fixation in treating osteoporotic thoracolumbar burst fracture. METHODS: From April 2011 to April 2014, 32 patients with osteoporotic thoracolumbar burst fracture were treated with percutaneous vertebroplasty and pedicle screw fixation. There were 13 males and 19 females, aged in ranging from 60 to 73 years old(averaged 65.6 years). All fractures were single thoracolumbar fracture and 4 cases located on T11, 9 on T12, 16 on L3; and 3 on L2. Cobb angle, vertebral anterior compression rate, vertebral posterior compression rate, spinal canal occupying ratio were compared, visual analogue scale (VAS) and Oswestry Disability Index(ODI) were analyzed before and after operation. RESULTS: The mean operation time was 65.7 min(ranged, 60 to 120 min) and blood loss was 25.2 ml (ranged, 20 to 50 ml). The operative incisions obtained primary healing. All patients were followed up from 12 to 48 months with an average of 20.6 months. Vertebral anterior compression rate and vertebral posterior compression rate were respectively corrected from preoperative (49.70+/ 5.89)%, (17.36+/-4.11)% to (6.00+/-2.10)%, (5.48+/-1.65)% at 2 d after operation, and (6.06+/-1.57)%, (5.68+/-1.82)% at last follow up. Cobb angle and spinal canal occupying ratio were respectively corrected from preoperative (13.34+/-3.56) degrees , (22.77+/-5.83)% to(2.86+/-0.95) degrees , (5.02+/-1.93)% at 2 d after operation, and (3.04+/-0.94) degrees , (5.15+/-1.93)% at last follow up. VAS and ODI were respectively decreased from preoperative (6.84+/-0.88)points, (77.50+/ 5.10)% to(1.94+/-0.72) points, (17.94+/-4.82)% at 2 d after operation, and (1.63+/-0.83) points, (15.63+/-5.19)% at last follow up. Cement leakage occurred in 3 cases. No internal fixation failure and intractable lower back pain were found. CONCLUSIONS: Percutaneous vertebroplasty and pedicle screw fixation could restore vertebral body height, improve spinal canal occupying, correct kyphosis, relieve pain, improve life quality, and it is a safe and effective method in treating osteoporotic thoracolumbar burst fracture. PMID- 29232776 TI - [Efficacy evaluation of unilateral lamina osteotomy replantation versus fenestration in nucleus pulposus resection of lumbar disc herniation]. AB - OBJECTIVE: To evaluate the clinical effects of unilateral lamina osteotomy replantation versus fenestration in the treatment of unilateral lumbar disc herniation. METHODS: The clinical date of 119 patients with unilateral lumbar disc herniation underwent surgical treatment from May 2012 to August 2014 were retrospective analyzed. There were 64 males and 54 females, aged from 40 to 59 years old with an average of 49.6 years. Among them, 58 patients were treated with lamina fenestration and decompression and nucleus pulposus resection(fenestration group);61 patients were treated with unilateral lamina osteotomy and replantation after nucleus pulposus resection (replantation group). The incidence rate of nerve and dural injury during operation, lamina healing rate, the recurrent rates of postoperative low back and leg pain were observed. According to the standard of JOA score, the clinical effects was compared between two groups. RESULTS: A hundred and seventeen patients were followed up more than 1 year, each group 1 case was lost to follow up. The injury rate of nerve and dural was 3.33%, 5.00% respectively in replantation group, while 7.02%, 8.77% respectively in fenestration group, there was no significant differences between two groups(P>0.05). One year after operation, there was significant difference in the recurrent rate of low back pain and JOA, VAS scores between two groups, replantation group was better than that of fenestration group(P<0.05). CT showed the osteotomy of 2 cases had not obtained bone healing in replantation group with lamina healing rate of 96.7%, no loosening or breakage of titanium plates and screws were found. CONCLUSIONS: The design of unilateral lamina osteotomy replantation is more reasonable. Widen surgical vision not only guarantee the spinal stability, but also prevent epidural adhesion, which reduce the lower back and leg pain recurrence. It is a safe and effective new approach to treat lumbar disc herniation. PMID- 29232777 TI - [Surgical options for delayed osteoporotic vertebral collapse]. AB - OBJECTIVE: To investigate the surgical options and clinical effects of delayed osteoporotic vertebral collapse. METHODS: From May 2010 to October 2014, 19 patients (20 vertebrae) with delayed osteoporotic vertebral collapse(Kummell's disease) were enrolled in this study. There were 7 males and 12 females, aged from 65 to 87 years old with a mean of (73.5+/-5.62) years. According to Li staging system of Kummell's disease, 3 cases were stage II, 13 cases (14 vertebrae) were stage III without spinal cord injury, 3 cases were stage III with spinal cord injury. Patients were respectively treated with percutaneous vertebroplasty(PVP) or percutaneous kyphoplasty(PKP) on the basis of the degree of postural reduction during operation. Injected cement volume, cement leakage, vertebral height restoration and local kyphotic reduction were observed. Visual analogue scale (VAS) and Oswestry Disability Index(ODI) were respectively used to assess the pain and function before and after operation. Frankel grade were used to evaluate neurological status. RESULTS: Seven vertebrae with satisfactory postural reduction were treated with PVP, 13 vertebrae with unsatisfactory postural reduction were treated with PKP, 3 patients with spinal cord injury were treated with decompression and posterior short segment fixation at the same time. All patients were followed up from 10 to 48 months with an average of 21.2 months. Cement leakage occurred in 4 cases with no symptom, 1 cases in PVP group and 3 cases in PKP group, there was no significant difference between two groups(P=0.561). The priming volume of cement was (6.40+/-0.94) ml in PVP group and (5.46+/-1.09) ml in PKP group (P>0.05). Three days after operation vs preoperation, the vertebral height restoration and kyphotic improvement was(31.71+/-11.35)%, (9.79+/-4.64) degrees in PVP group and (24.77+/-8.51)%, (8.15+/-2.97) degrees in PKP. There was no significant difference between two groups(P>0.05). Three days after operation, VAS of low back pain and ODI in all patients were improved than preoperative data(P<0.05), but there was no significant difference between two groups or between postoperative at 3 d and final follow up(P>0.05). Nerve function of 3 patients underwent decompression and fixation from Frankel D to E. CONCLUSIONS: According to Li staging system and the degree of introperative postural reduction, individualized surgical treatment for Kummell's disease can obtain good clinical results. Bad postural reduction during operation maybe a risk factor of cement leakage. PMID- 29232778 TI - [The cost effectiveness analysis of minimally invasive surgery and conservative treatment in elderly osteoporotic spinal fracture]. AB - OBJECTIVE: To evaluate the cost effectiveness of conservative treatment, percutaneous vertebroplasty(PVP)and percutaneous kyphoplasty(PKP)for elderly osteoporotic vertebral compression fracture(OVCF). METHODS: The clinical data of 152 patients with osteoporotic vertebral compression fractures, collected in the orthopedic department of 309th Hospital of PLA from October 2013 to July 2014, was retrospectively analyzed. According to the therapeutic methods, the patients who met the inclusion criteria were divided into conservative treatment group (51 cases), percutaneous vertebroplasty group (50 cases) and percutaneous kyphoplasty group(51 cases). The average medical cost (C) in hospital period and 1 year after discharging, and the treatment effect (E) according to standard of "cure" (VAS score less than or equal to 2) or "improvement" (VAS score was 3 to 8) was recorded. Then the C/E value indicated the cost effectiveness in different standards. RESULTS: The average hospitalization days of the PVP and PKP group was 3 to 5 days with an average of(3.4+/-0.6) days. The conservative group was 12 to 15 days with an average of (14.0+/-0.6) days. During the hospitalization period, the cost effectiveness of the conservative group, PVP group and PKP group were RMB 1 253.88, 935.75, 983.99 yuan, respectively, according to the standard of "cure". The PVP group was superior to the PKP group and the latter was superior to the conservative group. If "improvement" was used as the standard of evaluation, the results were RMB 97.80, 449.16, 501.84 yuan, respectively, suggesting that the conservative group was better than the PVP group and the latter was better than the PKP group. After hospital discharge, the cost effectiveness of the conservative group, PVP group and PKP group were RMB 3 834.05, 1 878.41 and 1 916.11 yuan, respectively, according to the standard of "cure". The PVP group was superior to the PKP group and the latter exceeded the conservative group. CONCLUSIONS: The study showed that the PVP was the best choice at the evaluation criterion of "cure", while taking "improvement" as the evaluation criterion, the conservative treatment was the best one. Either way, the PVP was the best choice after hospital discharge. PMID- 29232779 TI - [Analysis of clinical effects of three operative methods for osteoporotic vertebral compression fracture]. AB - OBJECTIVE: To explore the clinical outcomes of percutaneous vertebroplasty(PVP), percutaneous kyphoplasty(PKP) and percutaneous hollow pedicle screw with lateral holes implanted bone cement reinforcement in treating osteoporotic vertebral compression fracture(OVCF). METHODS: From May 2012 to November 2013, the clinical data of 90 patients with osteoporotic vertebral compression fracture were retrospectively analyzed. According to the different methods of operation, the patients were divided into three groups, including the percutaneous hollow pedicle screw with lateral holes implanted bone cement reinforcement group (group A), percutaneous vertebroplasty group (group B), percutaneous kyphoplasty group (group C), each group had 30 patients. Pre operative, postoperative at 1 day, 3 months, 1 year, the back pain was assessed by visual analogue scale(VAS), and vertebral height compression ratio, Cobb angle were measured by X-rays. RESULTS: All operations were successful and no complications such as postoperative infections and deep vein thrombosis were found. At the final follow up, there were 2 patients with mild postoperative back pain in group A;7 patients with moderate postoperative back pain, 4 patients with severe postoperative back pain, 2 patients with postoperative vertebral refracture in group B; 5 patients with moderate postoperative back pain, 3 patients with severe postoperative back pain, 4 patients with postoperative vertebral refracture in group C. Postoperative VAS, vertebral height compression ratio, Cobb angle of all patients have obviously improved than preoperative(P<0.05). On 1 day, 3 months, 1 year after operation, there was significant difference between group A and group B, C(P<0.05), there was no significant difference between group B and group C(P>0.05). There was no significant difference in group A above items and different times(P>0.05), and there was significant difference in group B, C above items and different times(P<0.05). CONCLUSIONS: The effect of PVP and PKP on the immediately postoperative pain relief was more than percutaneous hollow pedicle screw with lateral holes implanted bone cement reinforcement in treating osteoporotic vertebral compression fracture, but, residual back pain can happen in different extent in the patients underwent PVP and PKP. Percutaneous hollow pedicle screw with lateral holes implanted bone cement reinforcement technique has obvious advantage in recovery of the vertebral height, correction of vertebral deformity, reduction of postoperative back pain. PMID- 29232780 TI - [Risk factors for the collapse of cemented vertebral bodies after the minimally invasive vertebral augmentation procedures]. AB - OBJECTIVE: To evaluate the incidence rate, the independent factors, and the prevention measures of the collapse of cemented vertebral bodies after minimally invasive vertebral augmentation procedures including percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty(PKP). METHODS: From January 2012 to June 2013, 154 patients with single segmental osteoporotic vertebral compression fractures(OVCF)were treated with PVP or PKP. There were 65 males and 89 females, ranging in age from 57 to 90 years old, with a mean of (76.20+/-9.35) years old. All the patients were followed up, and the duration ranged from 6 to 30 months, with a mean of (15.43+/-6.81) months. All the patients were arranged to perform X ray examination, and some of the patients were arranged to do MRI examination during the follow up period. Possible risk factors were studied including gender, age, surgical approach(PVP or PKP), lumbar spine bone mineral density, treated vertebral level, the presence of osteonecrosis in the vertebral body, filling pattern of the cement, and the restoration of anterior vertebral height. The Chi square test and the multivariate Logistic regression model were used to analyze the risk factors. RESULTS: The collapse of cemented vertebral bodies were found in 29 patients, and the total incidence rate of following time was 18.83%. A Multivariable Logistic Regression analysis revealed that the independent risk factors affecting the incidence rate of the collapse included surgical approach (OR=0.171, P=0.010), lumbar spine bone mineral density(OR=0.242, P=0.024), the presence of osteonecrosis in the vertebral body(OR=12.225, P=0.003), filling pattern of the cement(OR=10.461, P=0.000), and anterior vertebral height restoration(OR=0.316, P=0.019). CONCLUSIONS: The incidence rate of the collapse was high and was associated with many risk factors. Surgical approach, lumbar spine bone mineral density, the presence of osteonecrosis in the vertebral body, filling pattern of the cement, and anterior vertebral height restoration were the independent risk factors affecting the incidence rate of the collapse. Careful selection of patients before operation, symmetric cement distribution and fluid aspiration during operation, positive treatment of osteoporosis after operation would be the potential ways to avoid collapse of cemented vertebral bodies. PMID- 29232781 TI - [Effect evaluation of over 5 year follow up of unilateral pedicle screw fixation with transforaminal lumbar interbody fusion for lumbar degenerative diseases]. AB - OBJECTIVE: To evaluate the clinical effects of over 5 year follow up of unilateral pedicle screw fixation with transforaminal lumbar interbody fusion(TLIF) in treating lumbar degenerative diseases. METHODS: The clinical data of 24 patients with lumbar degenerative disease underwent unilateral pedicle screw fixation with transforaminal lumbar interbody fusion from March 2007 to October 2009, were retrospectively analyzed. There were 13 males and 11 females, aged from 34 to 68 years old with an average of 52 years. Postoperative pain and functional results were analyzed by the visual analogue scale(VAS) and Oswestry Disability Index(ODI). Radiological examination was obtained for each patient to assess the height of intervertebral space, postoperative intervertebral fusion conditions and general complications. RESULTS: All patients were followed up from 5 to 8 years with an average of 6.7 years. VAS scores of low back pain and leg pain decreased from preoperative 7.82+/-0.71, 8.42+/-1.24 to postoperative 1.87+/ 0.81, 2.23+/-1.62, respectively(P<0.05). ODI decreased from preoperative(53.42+/ 8.26)% to postoperative(12.45+/-7.67)%(P<0.05). Postoperative intervertebral space height in different segments were improved than preoperative(P<0.05), but in final follow up it was decreased than 3 months after operation(P<0.05). There was no significant difference in the postoperative intervertebral space height between the operated side and non operated side. But at final follow up, the intervertebral space height of non operated side was obviously loss. At final follow up, the fusion rate was 95.8%. The incidence of adjacent segment degeneration was 45.8%. The paraspinal muscle fibrosis incidence was 8.3%. No complications such as secondary scoliosis, intervertebral height loss, cage slippage, screw loosening and internal fixation breakage were found. CONCLUSIONS: Unilateral pedicle screw fixation with TLIF is a satisfactory method and can obtain good effects in treating lumbar degenerative diseases according to over 5 year follow up, however, its indications should be well considered. But the problems such as intervertebral space height of operated side loss and adjacent segment degeneration after unilateral pedicle screw fixation need further clinical study. PMID- 29232782 TI - [The causes and prevention of C5 nerve root palsy after anterior cervical decompression and fusion]. AB - OBJECTIVE: To analyze the causes of muscular paralysis due to C5 nerve root injury after anterior cervical decompression and fusion (ACDF) and explore its prevention way. METHODS: From January 2005 to December 2015, 310 patients underwent ACDF in our hospital. Of them, 9 cases occurred muscular paralysis due to C5 nerve root injury after operation. The clinical data of 9 patients were retrospectively analyzed. There were 8 males and 1 female, aged from 51 to 84 years with an average of 64 years. Two cases underwent internal fixation and intervertebral fusion with one segment, 6 cases with two segments, 1 case with three segments. Simple deltoid muscle weakness, pain, numbness happened in 7 cases, simultaneously biceps brachii muscle weakness, pain, numbness in 2 cases. Muscle strength was 0 grade in 1 case, 1 grade in 3 cases, 2 grades in 4 cases, 3 grades in 1 case. RESULTS: The follow up time of 9 patients was more than 12 months and the longest was 24 months with an average of 14 months. Muscle strength of 7 patients recovered to 4-5 grades. Recovering time after operation was directly proportional to the degree of injury, those patients with muscle strength level more than 2, usually could have significant improvement within 3 weeks. The JOA score improved from 10.89+/-1.89 preoperatively to 8.92+/-1.91 postoperative C5 nerve root palsy to 14.48+/-2.10 at final follow up, with significant difference(P<0.05). CONCLUSIONS: More complicated factors result in C5 nerve root injury after ACDF. Except those suffered severe grinding contusion and amputation, most of the patients can get satisfactory prognosis. Strict control of the operation indication, selection of the right surgical segment with accurate manipulation, control of the distraction of intervertebral space and the width of the multilevel anterior cervical corpectomy, are main methods to prevent the complication. PMID- 29232783 TI - [Anatomical characteristics and surgical selections of upper lumbar disc herniation]. AB - OBJECTIVE: To explore the anatomical characteristics and surgical selections of upper lumbar disc herniation, and evaluate its clinical effects. METHODS: From January 2009 to January 2013, 26 patients with upper lumbar disc herniation were treated in our department. There were 16 males and 10 females, aged from 28 to 51 years old with an average of 45.7 years, 4 cases were in L1,2, 9 cases in L2,3, and 13 cases in L3,4. The data was collected including distance between outer edge of lower facet and the spinous process, the outer edge of the isthmus and spinous process, the lower edge of lamina and the upper edge of the intervertebral space, nerve root arising points and lower edge of the corresponding pedicle. Transforaminal discectomy and interbody fusion combined with pedicle screw fixation was performed in patients with L1,2, L2,3 herniated disk and 5 patients with L3,4 herniated disk complicated with lumbar instability. However another 8 patients with L3,4 herniated disk were treated with posterior fenestration decompression. Clinical effects were evaluated by Japanese Orthopaedic Association(JOA). The relative height rate(R) of the intervertebral space was measured preoperatively and 1 year postoperatively. The fusion of the bone graft was also observed. RESULTS: Intraoperative anatomical measurement was taken in all patients. All patients were followed up for more than 1 year with an average of 16 months, and all incisions got healing, JOA was improved from preoperative(10.13+/-1.49) points to last follow up (25.21+/-2.13) points with the improvement rate of 79.9%. Among the patients underwent fusion operation, 17 cases obtained bone fusion and 1 case maybe non fusion and no internal fixation failure was found;the R value was (0.231+/-0.056) mm preoperatively, however (0.345+/-0.076) mm at 1 year after operation with statistical difference(P<0.05). In the patient underwent posterior fenestration decompression, the R value was(0.243+/-0.036) mm preoperatively, and (0.212+/-0.046) mm at 1 year after operation without statistical difference (P>0.05). No spinal instability and lumbar disc herniation recurrence were found in these patients. CONCLUSIONS: According to the anatomical characteristics of L1,2 and L3,4 herniated disk, these patients could be treated with transforaminal discectomy and interbody fusion. The anatomical characteristics and clinical manifestations of L3,4 herniated disk is similar with the lower lumbar disc herniation, for the patients, an appropriate surgical method should be chosen according to the lumbar stability. PMID- 29232784 TI - [Treatment of displaced femoral neck fracture in young adults with close reduction and femoral neck locking plate fixation]. AB - OBJECTIVE: To investigate the clinical effects of close reduction and proximal femoral locking plate fixation for the treatment of femoral neck fractures in young adults. METHODS: From August 2010 to 2014 August, 54 patients with displaced femoral neck fracture were treated with closed reduction and proximal cannulated screw locking plate fixation. There were 34 males and 20 females, aged from 18 to 55 years with an average of 39.8 years. The informations of fracture healing and complications were recorded after operation. According to Harris criteria, the function of hip joint was evaluated. RESULTS: All patients were followed up from 4 to 24 months with an average of 11.3 months. Three cases occurred fracture nonunion, fracture union rate was 94.4%(51/54), union time was from 3 to 6 months with an average of 4.1 months. Among the healed 51 cases, the median of femoral neck shorten was 0.8 mm with the mean of (0.48+/-0.46) mm. No complications such as infection, internal fixation displacement were found during follow up. According to Harris criteria, 40 cases obtained excellent results, 9 good, 2 fair, 3 poor. CONCLUSIONS: Close reduction and proximal femoral locking plate fixation is an effective method in treating femoral neck fracture in young adults, it has advantages of avoiding the femoral neck crispation, reliable fixation, high rate of fracture union and good functional recovery. PMID- 29232785 TI - [Treatment of trigger finger with located needle knife]. AB - OBJECTIVE: To investigate the clinical effects of located needle knife in the treatment of trigger finger. METHODS: The clinical data of 133 patients(145 fingers) with trigger finger underwent treatment with located needle knife from September 2010 to March 2014 were retrospectively analyzed. There were 37 males(40 fingers) and 96 females (105 fingers), aged from 18 to 71 years old with a mean of 51.8 years. Course of disease was from 1 to 19 months with an average of 8.2 months. Affected fingers included 82 thumbs, 12 index fingers, 11 middle fingers, 36 ring fingers, and 4 little fingers. According to the standard of Quinnell grade, 42 fingers were grade III, 92 fingers were grade IV, and 11 fingers were grade V. Firstly the double pipe gab was put into the distal edge of hypertrophic tendon sheath, then small knife needle was used to release the sheath proximally along the tendon line direction. The informations of wound healing and nerve injury, postoperative finger function, finger pain at 6 months were observed. RESULTS: The operation time was from 8 to 25 min with an average of 9.8 min. All the patients were followed up from 6 to 26 months with an average of 12.5 months. No complications such as the wound inflammation and seepage, vascular or nerve injuries were found. According to the standard of Quinnell grade, 123 fingers got excellent results, 15 good, 7 poor. CONCLUSIONS: It's a good choice to treat trigger finger with located needle knife in advantage of minimal invasion, simple safe operation, and it should be promoted in clinic. PMID- 29232786 TI - [Treatment of the postoperative infection of limbs fracture after internal fixation with vacuum sealing drainage (VSD) combined with continual irrigation]. AB - OBJECTIVE: To explore the clinical effects of VSD combined with continual irrigation in treating the infection of limbs fracture after internal fixation. METHODS: From March 2010 to June 2015, 10 patients with infection of limbs fracture after internal fixation were treated with VSD combined with continual irrigation. There were 7 males and 3 females, aged from 11 to 58 years with an average of 34.4 years. Course of disease was from 1 to 8 months with an average of 4.8 months. Postoperative infection occurred in fractures of ulna and radius of 4 cases, tibiofibular fractures of 3 cases, calcaneal fractures of 2 cases, femoral fractures of 1 case. Eight infections were open fracture and 2 infections were close fracture. In additon to above treatment, antibiotics, dressing changing or skingrafting were used in the patients. Informations of wound surface healing, change dressings, original infection focus were observed. RESULTS: All infections got control, the wound healing after change dressings or skingrafting, and no complications such as osteomyelitis were found. The mean treatment time was 38.4 days(ranged, 29 to 45 days) and replacement times was 2.2 times(ranged, 1 to 4 times). All patients were followed up, no recurrent infections were found at 1 year after fracture healing. CONCLUSIONS: VSD combined with continual irrigation can effectively decrease the incidence of complications and promote the wound growth, healing and considerably shorten the healing time. It is an effective method for the treatment of infection of limbs fracture after internal fixation. PMID- 29232787 TI - [Surgical treatment for huge tophi of: a case report]. PMID- 29232788 TI - [Triple no loop Endobutton plate combined with Orthcord line for the treatment of acromioclavicular dislocation of Tossy type III]. AB - OBJECTIVE: To explore the clinical effects of the triple no loop Endobutton plate combined with Orthcord line in treating acromioclavicular dislocation of Tossy type III. METHODS: Between February 2011 and September 2013, 36 patients with acromioclavicular dislocation of Tossy type III were treated with triple no loop Endobutton plate and Orthcord line. There were 21 males and 15 females, aged from 9 to 48 years old with an average of (26.41+/-14.05) years. Couse of disease was from 2 to 7 days in the patients. The patients had the clinical manifestations such as shoulder pain, extension limited, acromioclavicular tenderness, positive organ point sign. Clinical effects were assessed by acromioclavicular scoring system. RESULTS: Thirty six patients were followed up from 8 to 15 months with an average of (12.2+/-4.3) months. All incisions got primary healing. At the final follow up, all shoulder pain vanished, acromioclavicular joints without tenderness, negative organ point sign. No redislocation and steel plate loosening were found. According to the acromioclavicular scoring system, 31 cases obtained excellent results, 5 good. CONCLUSIONS: The method of triple no loop Endobutton plate combined with Orthcord line for acromioclavicular dislocation of Tossy type III has advantage of less risk and complication, good functional rehabilitation and is an ideal method. PMID- 29232790 TI - [Diagnosis and treatment for thoracic spinal stenosis caused by tophaceous gout: a case report]. PMID- 29232789 TI - [Surgical treatment for terrible triad of the elbow through medial and lateral approach]. AB - OBJECTIVE: To investigate the clinical effects of medial and lateral approach in treating terrible triad of the elbow. METHODS: From May 2010 from May 2014, 11 patients with terrible triad of the elbow were treated through medial and lateral approach. There were 6 males and 5 females, aged from 25 to 56 years with an average of 35.2 years old. The time from injury to operation was from 1 to 13 days with an average of 5.9 days. Fracture of radial head according to Mason typing, 2 cases were type I, 7 cases were type II, 2 cases were type III. Ulnar coronoid fracture according to Regan-Morrey typing, 3 cases were type I, 7 cases were type II, 1 case was type III. Postoperative complications were observed and Mayo elbow performance score(MEPS) was used to assess the elbow joint function. RESULTS: All patients were followed up from 6 to 24 months with an average of 15.5 months. All fractures obtained healing with an average time of 14 weeks (ranged from 10 to 18 weeks). According to Mayo to assess the results, total score was 78.2+/-11.7, 2 cases got excellent results, 7 good, 1 fair, 1 poor. At final follow up, the mean range of motion was (108+/-21) degrees in flexion, (12+/-8) degrees in extension, (66+/-13) degrees in pronation, (28+/-18) degrees in supination. The varus angle of the elbow ranged from 5 degrees to 8 degrees in 3 cases and the valgus angle was 8 degrees in 1 case. CONCLUSIONS: Treatment of the terrible triad of the elbow through medial and lateral approach can obtain satisfactory clinical effects, restore the elbow stability, allow early motion postoperatively, and promote the joint functional rehabilitation. PMID- 29232791 TI - [Application of mechanical measurement in assessment of neck pain and manual therapy]. AB - Manual therapy is one of the effective methods in treating neck pain. It has certain advantages in the short term to ease the symptoms of neck pain. In recent years, using different mechanical sensors and imaging equipment with computer software, the researchers found the difference of cervical activity between health adult and patients with neck pain. They also analyzed the kinematics, magnitude of force, stress and strain of the related structure and other mechanical parameters during cervical manipulation. These biomechanical researches revealed the functional anomaly caused by neck pain, reflect the safety of cervical manipulation, explain the abnormal stress of neck pain and the adjusting role of manipulation. Relatively speaking, these studies are too basic, and their analysis also are limited for the stress and strain about internal tissue. Study to aim directly at above problems will have important significance in understanding neck pain and standardizing manipulation therapy. PMID- 29232792 TI - [Role of Toll like receptors and inflammasome in aseptic loosening]. AB - Aseptic loosening, ascribes to particle induced osteolysis, is the most common reason for total joint arthroplasty failure. Wear particles, liberated from the surface of prostheses, mediate the expression of inflammatory cytokines in macrophages and increase the osteoclastogenesis. However, it remains unclear how macrophages can recognize wear particles and be induced by wear particles. Recently, a number of studies have demonstrated that Toll like receptors and inflammasome may play a critical role in osteolysis. However, the mechanism of activation of Toll like receptors and the relationship between TLR pathway and downstream signaling pathways still remain unclear. It will be beneficial to understand the pathogenesis of aseptic loosening by exploring these mechanisms. This article highlights the role of Toll like receptors and inflammasome in aseptic loosening, which is helpful to the development of therapies that prevent wear particle induced aseptic loosening. PMID- 29232793 TI - [Progress on diagnosis and treatment of the terrible triad of elbow joint]. AB - The terrible triad of elbow is a kind of complex elbow fracture dislocation, after reduction, it should get a concentric circles joint reduction and elbow stability, if radial and coronoid process fractures is less piece, the conservative treatment can be performed, but regularly follow up is mandatory. If surgical treatment was chosen, radial head fractures and the lateral collateral ligament complex must be repaired. Single lateral approach can be used and also can be combined with anteromedial approach in surgery. Some problems are still controversial in the treatment of coronoid process fracture with Morry type I and type II, such as fixation or not, whether additional external fixation and repair of the medial collateral ligament injury at the same time. PMID- 29232794 TI - [Clinical Evaluation of Diagnostic and Treatment Protocol of Idiopathic Retroperitoneal Fibrosis Incorporating Consideration of Possible IgG4-Related Disease]. AB - About half of idiopathic retroperitoneal fibrosis might be classified as a IgG4 related disease, a newly characterized disease that is especially known to be sensitive to steroid therapy. We developed a new protocol for diagnosis and treatment of retroperitoneal fibrosis, which included aggressive diagnosis of IgG4- related disease. We retrospectively reviewed 22 cases with idiopathic retroperitoneal fibrosis that were diagnosed and treated according to our protocol. Of them, 10 patients (45.5%) had no evidence of IgG4- related disease (non-IgG4RD group), whereas 12 patients (54.5%) were diagnosed with IgG4-related disease (IgG4RD group). All patients received steroid therapy, and 13 patients (59.1%) underwent ureteral stenting or received prednisolone (PNS). There was no severe adverse event and planned steroid therapy was completed in all patients. In principle, maintenance steroid therapy was continued after induction therapy in the IgG4RD group, whereas steroid therapy was discontinued in the non-IgG4RD group. Regression of retroperitoneal plaque was achieved in all 22 patients. Four (57.1%) out of 7 patients and 3 (50.0%) out of 6 patients achieved freedom from ureteral stent or PNS in the non-IgG4RD group and IgG4RD group, respectively. All 3 patients with PNS became catheter-free after treatment, whereas only 4 (40.0%) of the 10 patients withureteral stent could become stent-free. Steroid therapy could be discontinued in 7 patients (70.0%) in the non-IgG4RD group. The results of this study suggest that similar efficacy of steroid therapy can be expected in the non-IgG4RD group and IgG4RD group. PMID- 29232795 TI - [Clinical Study of Testicular Fasciotomy for Testicular Torsion]. AB - Between November 2011 and November 2014, we performed a tunica albuginea incision with tunica vaginalis flap coverage (TAI+TVFC) on 5 out of 15 patients who underwent surgery for testicular torsion. Of those 15 patients, 7 underwent orchidopexy alone (Group A), 5 underwent TAI+TVFC (Group B), and 3 underwent an orchidectomy procedure (Group C). All were followed for 1 year and preservation of testicular volume >50% on the contralateral side in ultrasound measurements was considered as salvaged. During the follow-up examinations, no testicular atrophy was noted in Group A. In Group B, tension and testis color were immediately improved in all 5 patients after TAI+TVFC, while blood perfusion was also improved after the operation. Also 3 patients in Group B were considered to be salvaged, while testicular atrophy occurred in 2 after 8 or more hours from onset until surgery. Our results indicated that TAI+ TVFC is useful for restoring blood flow after surgery for testicular torsion, although the so-called'Golden time'for torsion surgery has a significant impact in such cases. PMID- 29232796 TI - [Four Cases of Bacteremia Caused by Helicobacter cinaedi in the Urological Ward at About the Same Time]. AB - Here we report the outbreak of bacteremia caused by Helicobacter cinaedi (H. cinaedi) in the urology ward. Case 1 was a man in his seventies with prostate cancer. Bacteremia caused by H. cinaedi developed 6 days after robot-assisted radical prostatectomy. Case 2 was a man in his sixties with small cell carcinoma of the prostate. Bacteremia developed at 5 days of docetaxel therapy. Case 3 was a man in his fifties with left renal pelvis carcinoma. Bacteremia developed 3 days after laparoscopic left nephroureterectomy. Case 4 was a man in his seventies with right renal pelvic carcinoma and bladder cancer. Bacteremia developed 22 days after laparoscopic right nephroureterectomy and laparoscopic radical cystectomy. Each bacteremia occurred almost simultaneously. Fortunately, all 4 cases were treated by antibiotics successfully and there were no cases of recurrence. Whole environmental inspection of the ward did not reveal H. cinaedi. However, multilocus sequence typing proved the strains in cases 3 and 4 to be the same. Therefore, cross-infection was suspected. H. cinaedi can develop to a pathogen of immunocompromised infection. This report clarified that this pathogen can cause bacteremia in the urology ward. PMID- 29232797 TI - [A Case of Adrenal Leiomyosarcoma]. AB - A 61-year-oldman presentedwith a chief complaint of abdominal pain. Enhancedcomputed tomography andmagnetic resonance imaging showeda left adrenal mass with a diameter of 7 cm with heterogeneous enchancement. He was referredto our hospital for further treatment. No endocrinological abnormality was detected. The tumor showed abnormal uptake on fludeoxyglucose positron emission tomography scan. Preoperative diagnosis was left adrenocortical carcinoma (cT2N0M0). Tumor excision was performedandpathological findings on the resectedspecimen revealedleiomyosarcoma of the left adrenal grand. The patient has been followed up for 16 months with no additional treatment. No evidence of local recurrence or metastasis was seen. PMID- 29232798 TI - [Solitary Fibrous Tumor of the Kidney]. AB - A 59-year-old woman was referred to our hospital with the finding of an incidentaloma in her right kidney. Computed tomographyand magnetic resonance imaging showed a solid tumor, approximately8 cm in diameter, at the lower pole of the right kidney. Partial nephrectomy was performed without a renal vessel clamp. Histopathologically, fibroblast-like spindle cells were proliferating with rich collagenous fibers, and tumor cells were infiltrated into the renal parenchyma. The tumor cells were stained positive with CD34, CD99, and bcl-2. The tumor was diagnosed as solitaryfibrous tumor originating from the kidney based on these histopathological findings. The patient was followed 3 years after surgery with neither recurrence nor metastasis. PMID- 29232799 TI - [A Case of Adult Mature Teratoma Located in Retroperitoneum]. AB - A 35-year-old man wasreferred to our hospital for treatment of a right adrenal tumor detected by ultrasonography during a physical check-up. Contrast-enhanced abdominal computed tomography revealed a poorly enhanced 74 mm tumor situated adjacent to the upper pole of the right kidney. The tumor consisted of fat with peripheral calcification. Magnetic resonance imaging also revealed a right retroperitoneal tumor with fatty contents and well-circumscribed capsule. The endocrine examination revealed the tumor as non-functioning. These findings were suggestive of a right adrenal myelolipoma. We performed laparoscopic right adrenalectomy because of its large size and malignant potency. The pathological examination revealed the retroperitoneal tumor asa mature teratoma existing apart from the adrenal gland. Primary retroperitoneal teratomasare relatively rare. Herein, we report thiscas e of adult mature teratoma occurring in the retroperitoneum. PMID- 29232800 TI - [A Case of Fulminant Hepatitis after Administration of Abiraterone Acetate]. AB - A 77-year-old man with castration-resistant prostate cancer (CRPC) received abiraterone acetate in October 2014. He visited our outpatient clinic because of general malaise and anorexia 27 days after starting abiraterone acetate. The lab test showed hepatic dysfunction (aspartate transaminase, AST 440 U/l, alanine transaminase, ALT 420 U/l) and the elevation of liver enzymes continued on the next day even after stopping abiraterone acetate. Three days later, he was hospitalized due to severe elevation of liver enzymes (AST 1,171 U/l, ALT 1,487 U/l) , and the decreased prothrombin activity (60.5%). The result of the lab test were negative for viral and autoimmune hepatitis. Three days after admission, he entered hepatic coma (grade III) and prothrombin activity decreased (23.2%) , compatible with fulminant hepatitis. Plasma exchange and steroid pulse therapy were started the next day, but he died 39 days after starting abiraterone acetate. In addition, the result of drug-induced lymphocyte stimulation test performed 3 days before his death was possibly positive. PMID- 29232801 TI - [Early Diagnosis of Squamous Cell Carcinoma of the Urinary Bladder Reached by Routine Abdominal Ultrasonography in a Patient on Self-Catheterization : A Case Report]. AB - A 69-year-old woman was referred to our department for refractory cystitis. Incomplete emptying of the bladder was observed, and symptoms did not improve after medication. Clean intermittent catheterization was initiated. Two years after introduction of catheterization, a mass in the bladder dome was detected by routine abdominal ultrasonography. She was diagnosed with malignant tumor of the bladder diverticulum based on cystoscopy, computed tomography, and magnetic resonance imaging. Partial cystectomy and lymph node dissection was performed following transurethral resection of the bladder tumor. Histopathology revealed squamous cell carcinoma and no signs of lymph node metastasis. She is alive and recurrence-free 28 months after surgery. PMID- 29232802 TI - [Sarcomatoid Urothelial Carcinoma of the Bladder Including an Osteosarcoma Element]. AB - A 68-year-old Japanese man was referred to Tsukuba University Hospital for bladder cancer treatment. He had undergone a transurethral resection of a bladder tumor (TURBT) at a local hospital, but the pathological specimen did not contain muscle layer. Abdominal computed tomography (CT) and magnetic resonance imaging revealed a 3 cm non-papillary bladder tumor with muscle invasion, but there was no apparent calcification. The patient underwent re-TURBT at our hospital for diagnosis and staging. A non-papillary pedunculated tumor was identified in the bladder dome, and it contained a small papillary part. The non-papillary part was stony hard and difficult to cut with electrocautery, whereas the small papillary part was easily cut. Histologically, the non-papillary part was composed of sarcomatous elements including osteosarcoma, chondrosarcoma, and spindle cell sarcoma. The papillary part was composed of high-grade urothelial carcinoma and spindle cell sarcoma. Muscularis propria was not present in the specimen. Since the staging study with CT was negative for metastases, we performed a total cystectomy with an ileal conduit under the clinical diagnosis of muscle-invasive sarcomatoid urothelial carcinoma. The pathological findings were identical to those of the re-TURBT specimens, and our diagnosis was pTxN0 sarcomatoid urothelial carcinoma. The patient received adjuvant chemotherapy with two courses of gemcitabine and cisplatin. There was neither recurrence nor metastases during the 20-month follow-up. Reports of sarcomatoid urothelial carcinoma of the bladder with an osteosarcoma element are rare, and only eight other cases hane been reported in the Japanese literature. PMID- 29232803 TI - [Successful Embolization for Recurrent Varicocele of Testis after Microsurgical Subinguinal Varicocelectomy]. AB - Microscopic subinguinal varicocelectomy has a recurrence of less than 1%, and varicocele recurrence is supposed to be an uncommon post-surgery adverse event. At present, no guidelines exist for the management of recurrent varicoceles after surgery. In this report, we present two cases of post-surgery recurrent varicocele of the testis. Case_1 : A 23-year-old male patient who had undergone microscopic subinguinal varicocelectomy for a grade 3 varicocele was referred to our hospital because of recurrent varicocele. Retrograde venography revealed the persistence of dilated spermatic veins. The former surgeon preserved the dilated vas deferens vein, and this was considered a possible cause of persistence of dilated spermatic veins. The vein considered as vas deferens vein was actually an internal spermatic vein. Case_2 : A 28-year-old male patient complained of recurrence of varicocele two months after the original operation for a grade 3 varicocele. Internal spermatic vessels were slightly visualized on retrograde venography. The possible cause of persistence in this case was insufficient ligation of the internal spermatic vessels. We performed embolization in both cases of recurrent varicocele. Both cases were successfully treated, and there has been no recurrence. Our findings suggest that percutaneous transcatheter embolization of the testicular vein may be effective in the management of postsurgical recurrent varicocele of the testis. PMID- 29232804 TI - Lymphovascular invasion as a negative prognostic factor for triple-negative breast cancer after surgery. AB - PURPOSE: This study aimed to evaluate the prognostic effects of lymphovascular invasion (LVI) in triple-negative breast cancer (TNBC) patients who underwent surgical resection. MATERIALS AND METHODS: A total of 63 non-metastatic TNBC patients who underwent surgical resection were retrospectively investigated from 2007 to 2016 in Inje University Busan Paik Hospital. Pathological tests revealed that 12 patients (19.0%) had LVI. Approximately 61.9% (n = 39) of the patients' samples stained positive for p53. Additional chemotherapy and radiotherapy (RT) were performed in 53 (84.1%) and 47 (74.6%) patients, respectively. RESULTS: The median follow-up period was 39.5 months (range, 5.9 to 123.0 months). The pathological T stage (p = 0.008), N stage (p = 0.014), and p53 positivity (p = 0.044) were associated with LVI. Overall, the 3-year disease-free survival (DFS) rate and overall survival (OS) rate were 85.4% and 90.2%, respectively. Ten patients (15.9%) experienced relapse. LVI (n = 12) was associated with relapses (p = 0.016). p53 positivity was correlated with poor DFS (p = 0.048). Furthermore, LVI was related to poor DFS (p = 0.011) and OS (p = 0.001) and considered as an independent prognostic factor for DFS (p = 0.039). The 3-year DFS of patients with LVI (n = 12) was only 58.3%. Adjuvant RT minimized the negative prognostic effect of LVI on DFS (p = 0.068 [with RT] vs. p = 0.011 [without RT]). CONCLUSION: LVI was related to the detrimental effects of disease progression and survival of TNBC patients. Thus, a more effective treatment strategy is needed for TNBC patients with LVI. PMID- 29232805 TI - Value of imaging study in predicting pelvic lymph node metastases of uterine cervical cancer. AB - PURPOSE: To evaluate the diagnostic accuracy of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/computed tomography (PET/CT) in predicting pelvic lymph node (LN) metastases in patients with cervical cancer. MATERIALS AND METHODS: From January 2009 to March 2015, 114 patients with FIGO stage IA1-IIB uterine cervical cancer who underwent hysterectomy with pelvic lymphadenectomy and took CT, MRI, and PET/CT before surgery were enrolled in this study. The criteria for LN metastases were a LN diameter >=1.0 cm and/or the presence of central necrosis on CT, a LN diameter >=1.0 cm on MRI, and a focally increased FDG uptake on PET/CT. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for pelvic LN metastases were estimated. RESULTS: The sensitivity, specificity, PPV, NPV, and accuracy for detection of pelvic LN metastases were 51.4%, 85.9%, 41.3%, 90.1%, and 80.3% for CT; 24.3%, 96.3%, 56.3%, 86.8%, and 84.6% for MRI; and 48.6%, 89.5%, 47.4%, 90.0%, and 82.9% for PET/CT, respectively. The sensitivity of PET/CT and CT was higher than that of MRI (p=0.004 and p= 0.013, respectively). The specificity of MRI was higher than those of PET/CT and CT (p=0.002 and p=0.001, respectively). The difference of specificity between PET/CT and CT was not statistically significant (p=0.167). CONCLUSION: These results indicate that preoperative CT, MRI, and PET/CT showed low to moderate sensitivity and PPV, and moderate to high specificity, NPV, and accuracy. More efforts are necessary to improve sensitivity of imaging modalities in order to predict pelvic LN metastases. PMID- 29232806 TI - Multifaceted Adjunct for Prevention of Cerebrospinal Fluid Leak Following External Ventricular Drain Placement To Minimize Incidence of Infection. PMID- 29232807 TI - Retrospective Analysis and Comment on the Time Interval Between Surgery and Onset of Guillain-Barre Syndrome. PMID- 29232808 TI - Letter to the Editor Regarding "Risk Factors to Predict Neurologic Complications After Endovascular Treatment of Unruptured Paraclinoid Aneurysms". PMID- 29232809 TI - Letter to the Editor Regarding "Endoscopic Endonasal Surgery for Pituitary Apoplexy: Evidence On a 75 Case-Series From a Tertiary Care Center". PMID- 29232810 TI - In Reply to the Letter to the Editor Regarding "Endoscopic Endonasal Surgery for Pituitary Apoplexy: Evidence On a 75 Case-Series From a Tertiary Care Center". PMID- 29232811 TI - Letter to the Editor Regarding "Neurologic Outcome After Decompressive Craniectomy: Predictors of Outcome in Different Pathologic Conditions". PMID- 29232812 TI - In Reply to the Letter to the Editor Regarding "Neurologic Outcome After Decompressive Craniectomy: Predictors of Outcome in Different Pathologic Conditions". PMID- 29232813 TI - Letter to the Editor Regarding "Anatomic Dissection of Arachnoid Membranes Encircling the Pituitary Stalk on Fresh Non-Formalin-Fixed Specimens: Anatomoradiologic Correlations and Clinical Applications in Craniopharyngioma Surgery". PMID- 29232814 TI - In Reply to the Letter to the Editor Regarding "Anatomic Dissection of Arachnoid Membranes Encircling the Pituitary Stalk on Fresh Non-Formalin-Fixed Specimens: Anatomoradiologic Correlations and Clinical Applications in Craniopharyngioma Surgery". PMID- 29232815 TI - Body Mass Index >35 as Independent Predictor of Mortality in Severe Traumatic Brain Injury: Statistical and Methodologic Issues. PMID- 29232816 TI - In Reply to the Letter to the Editor "Body Mass Index >35 as Independent Predictor of Mortality in Severe Traumatic Brain Injury: Statistical and Methodologic Issues". PMID- 29232817 TI - Validation of Predictive Scoring System for Ventriculoperitoneal Shunt Insertion After Aneurysmal Subarachnoid Hemorrhage: Statistical and Methodologic Issues. PMID- 29232818 TI - In Reply to the Letter to the Editor "Validation of Predictive Scoring System for Ventriculoperitoneal Shunt Insertion After Aneurysmal Subarachnoid Hemorrhage: Statistical and Methodologic Issues". PMID- 29232819 TI - Letter to the Editor Regarding "The Prognostic Impact of Ventricular Opening in Glioblastoma Surgery: A Retrospective Single Center Analysis". PMID- 29232820 TI - In Reply to the Letter to the Editor Regarding "The Prognostic Impact of Ventricular Opening in Glioblastoma Surgery: A Retrospective Single Center Analysis". PMID- 29232822 TI - Microglia M2A Polarization as Potential Link between Food Allergy and Autism Spectrum Disorders. AB - Atopic diseases are frequently co-morbid with autism spectrum disorders (ASD). Allergic responses are associated with an activation of mast cells, innate lymphoid cells, and Th2 cells. These cells produce type-2 cytokines (IL4 and IL13), which stimulate microglia and macrophages to adopt a phenotype referred to as 'alternative activation' or 'M2A'. M2A-polarized macrophages and microglia play a physiological role in tissue repair by secreting growth factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1. In ASD there is evidence for increased type-2 cytokines, microglia activation, M2A polarization, and increased levels of growth factors. In neurons, these growth factors drive a signal transduction pathway that leads to activation of the enzyme mammalian Target of Rapamycin (mTOR), and thereby to the inhibition of autophagy. Activation of mTOR is an effect that is also common to several of the genetic forms of autism. In the central nervous system, redundant synapses are removed via an autophagic process. Activation of mTOR would diminish the pruning of redundant synapses, which in the context of ASD is likely to be undesired. Based on this line of reasoning, atopic diseases like food allergy, eczema or asthma would represent risk factors for autism spectrum disorders. PMID- 29232824 TI - Development of Gentle Slope Light Guide Structure in a 3.4 MUm Pixel Pitch Global Shutter CMOS Image Sensor with Multiple Accumulation Shutter Technology. AB - CMOS image sensors (CISs) with global shutter (GS) function are strongly required in order to avoid image degradation. However, CISs with GS function have generally been inferior to the rolling shutter (RS) CIS in performance, because they have more components. This problem is remarkable in small pixel pitch. The newly developed 3.4 um pitch GS CIS solves this problem by using multiple accumulation shutter technology and the gentle slope light guide structure. As a result, the developed GS pixel achieves 1.8 e- temporal noise and 16,200 e- full well capacity with charge domain memory in 120 fps operation. The sensitivity and parasitic light sensitivity are 28,000 e-/lx.s and -89 dB, respectively. Moreover, the incident light angle dependence of sensitivity and parasitic light sensitivity are improved by the gentle slope light guide structure. PMID- 29232826 TI - Iterative Refinement of Transmission Map for Stereo Image Defogging Using a Dual Camera Sensor. AB - Recently, the stereo imaging-based image enhancement approach has attracted increasing attention in the field of video analysis. This paper presents a dual camera-based stereo image defogging algorithm. Optical flow is first estimated from the stereo foggy image pair, and the initial disparity map is generated from the estimated optical flow. Next, an initial transmission map is generated using the initial disparity map. Atmospheric light is then estimated using the color line theory. The defogged result is finally reconstructed using the estimated transmission map and atmospheric light. The proposed method can refine the transmission map iteratively. Experimental results show that the proposed method can successfully remove fog without color distortion. The proposed method can be used as a pre-processing step for an outdoor video analysis system and a high-end smartphone with a dual camera system. PMID- 29232823 TI - Improving Cerebral Blood Flow after Arterial Recanalization: A Novel Therapeutic Strategy in Stroke. AB - Ischemic stroke is caused by a disruption in blood supply to a region of the brain. It induces dysfunction of brain cells and networks, resulting in sudden neurological deficits. The cause of stroke is vascular, but the consequences are neurological. Decades of research have focused on finding new strategies to reduce the neural damage after cerebral ischemia. However, despite the incredibly huge investment, all strategies targeting neuroprotection have failed to demonstrate clinical efficacy. Today, treatment for stroke consists of dealing with the cause, attempting to remove the occluding blood clot and recanalize the vessel. However, clinical evidence suggests that the beneficial effect of post stroke recanalization may be hampered by the occurrence of microvascular reperfusion failure. In short: recanalization is not synonymous with reperfusion. Today, clinicians are confronted with several challenges in acute stroke therapy, even after successful recanalization: (1) induce reperfusion, (2) avoid hemorrhagic transformation (HT), and (3) avoid early or late vascular reocclusion. All these parameters impact the restoration of cerebral blood flow after stroke. Recent advances in understanding the molecular consequences of recanalization and reperfusion may lead to innovative therapeutic strategies for improving reperfusion after stroke. In this review, we will highlight the importance of restoring normal cerebral blood flow after stroke and outline molecular mechanisms involved in blood flow regulation. PMID- 29232825 TI - Galectin-1 Inhibitor OTX008 Induces Tumor Vessel Normalization and Tumor Growth Inhibition in Human Head and Neck Squamous Cell Carcinoma Models. AB - Galectin-1 is a hypoxia-regulated protein and a prognostic marker in head and neck squamous cell carcinomas (HNSCC). Here we assessed the ability of non peptidic galectin-1 inhibitor OTX008 to improve tumor oxygenation levels via tumor vessel normalization as well as tumor growth inhibition in two human HNSCC tumor models, the human laryngeal squamous carcinoma SQ20B and the human epithelial type 2 HEp-2. Tumor-bearing mice were treated with OTX008, Anginex, or Avastin and oxygen levels were determined by fiber-optics and molecular marker pimonidazole binding. Immuno-fluorescence was used to determine vessel normalization status. Continued OTX008 treatment caused a transient reoxygenation in SQ20B tumors peaking on day 14, while a steady increase in tumor oxygenation was observed over 21 days in the HEp-2 model. A >50% decrease in immunohistochemical staining for tumor hypoxia verified the oxygenation data measured using a partial pressure of oxygen (pO2) probe. Additionally, OTX008 induced tumor vessel normalization as tumor pericyte coverage increased by approximately 40% without inducing any toxicity. Moreover, OTX008 inhibited tumor growth as effectively as Anginex and Avastin, except in the HEp-2 model where Avastin was found to suspend tumor growth. Galectin-1 inhibitor OTX008 transiently increased overall tumor oxygenation via vessel normalization to various degrees in both HNSCC models. These findings suggest that targeting galectin-1-e.g., by OTX008-may be an effective approach to treat cancer patients as stand-alone therapy or in combination with other standards of care. PMID- 29232827 TI - Setting Housing Standards to Improve Global Health. AB - Developing World Health Organization international guidelines is a highly formal process. Yet the resulting guidelines, which Member States are encouraged, but not required to adopt, are a powerful way of developing rigorous policy and fostering implementation. Using the example of the housing and health guidelines, which are currently being finalised, this paper outlines the process for developing WHO guidelines. This includes: forming a Guidelines Review Group that represents all regions of the world, and ensures gender balance and technical expertise; identifying key health outcomes of interest; commissioning systematic reviews of the evidence; assessing the evidence; and formulating recommendations. The strength of each recommendation is assessed based on the quality of the evidence, along with consideration of issues such as equity, acceptability, and feasibility of the implementation of the recommendation. The proposed housing guidelines will address: cold and hot indoor temperatures, home injuries, household crowding, accessibility and access to active travel infrastructure. PMID- 29232828 TI - 1T1R Nonvolatile Memory with Al/TiO2/Au and Sol-Gel-Processed Insulator for Barium Zirconate Nickelate Gate in Pentacene Thin Film Transistor. AB - A one-transistor and one-resistor (1T1R) architecture with a resistive random access memory (RRAM) cell connected to an organic thin-film transistor (OTFT) device is successfully demonstrated to avoid the cross-talk issues of only one RRAM cell. The OTFT device, which uses barium zirconate nickelate (BZN) as a dielectric layer, exhibits favorable electrical properties, such as a high field effect mobility of 5 cm2/Vs, low threshold voltage of -1.1 V, and low leakage current of 10-12 A, for a driver in the 1T1R operation scheme. The 1T1R architecture with a TiO2-based RRAM cell connected with a BZN OTFT device indicates a low operation current (10 MUA) and reliable data retention (over ten years). This favorable performance of the 1T1R device can be attributed to the additional barrier heights introduced by using Ni (II) acetylacetone as a substitute for acetylacetone, and the relatively low leakage current of a BZN dielectric layer. The proposed 1T1R device with low leakage current OTFT and excellent uniform resistance distribution of RRAM exhibits a good potential for use in practical low-power electronic applications. PMID- 29232829 TI - Of Energy and Entropy: The Ineluctable Impact of Aging in Old Age Dementia. AB - Alzheimer's disease (AD) represents the most common form of dementia among older age subjects, and despite decades of studies, the underlying mechanisms remain unresolved. The definition of AD has changed over the past 100 years, and while early-onset AD is commonly related to genetic mutations, late-onset AD is more likely due to a gradual accumulation of age-related modifications. "Normal brain aging" and AD may represent different pathways of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age related changes (ARCs) affecting the brain may be considered as biologic manifestations of increasing entropy, a measure of disorder. Late-onset AD may be regarded as the final effect of a reduced energy production, due to exhausted mitochondria, and an increased entropy in the brain. This unique trajectory enables a bioenergetics-centered strategy targeting disease-stage specific profile of brain metabolism for disease prevention and treatment. PMID- 29232830 TI - Evidence of Altered Glycosylation of Serum Proteins Prior to Pancreatic Cancer Diagnosis. AB - Biomarkers for the early detection of pancreatic cancer are urgently needed. The aim of this pilot study was to evaluate changes in serum N-glycoproteins and their glycosylation status prior to clinical presentation of pancreatic cancer that may be potential biomarkers. Prediagnosis serum samples pooled according to five time-to-diagnosis groups and a non-cancer control pool were digested with trypsin, labelled with mass tags, and subjected to titanium dioxide capture, deglycosylation, and 2D-LC-MS/MS profiling. Unbound peptides were profiled in parallel. Across the sample groups, 703 proteins were quantified and 426 putative sites of N-glycosylation were identified with evidence of several novel sites. Altered proteins with biomarker potential were predominantly abundant inflammatory response, coagulation, and immune-related proteins. Whilst glycopeptide profiles largely paralleled those of their parent proteins, there was evidence of altered N-glycosylation site occupancy or sialic acid content prior to diagnosis for some proteins, most notably of immunoglobulin gamma chains. alpha-1-Antitrypsin was tested as a biomarker, but found not to complement carbohydrate antigen 19-9 (CA19-9) in early detection of cancer. In conclusion, we provide preliminary evidence of altered glycosylation of several serum proteins prior to pancreatic cancer diagnosis, warranting further investigation of these proteins as early biomarkers. These changes may be largely driven by inflammatory processes that occur in response to tumour formation and progression. PMID- 29232832 TI - Hybrid Orientation Based Human Limbs Motion Tracking Method. AB - One of the key technologies that lays behind the human-machine interaction and human motion diagnosis is the limbs motion tracking. To make the limbs tracking efficient, it must be able to estimate a precise and unambiguous position of each tracked human joint and resulting body part pose. In recent years, body pose estimation became very popular and broadly available for home users because of easy access to cheap tracking devices. Their robustness can be improved by different tracking modes data fusion. The paper defines the novel approach orientation based data fusion-instead of dominating in literature position based approach, for two classes of tracking devices: depth sensors (i.e., Microsoft Kinect) and inertial measurement units (IMU). The detailed analysis of their working characteristics allowed to elaborate a new method that let fuse more precisely limbs orientation data from both devices and compensates their imprecisions. The paper presents the series of performed experiments that verified the method's accuracy. This novel approach allowed to outperform the precision of position-based joints tracking, the methods dominating in the literature, of up to 18%. PMID- 29232833 TI - Formation of Surface and Quantum-Well States in Ultra Thin Pt Films on the Au(111) Surface. AB - The electronic structure of the Pt/Au(111) heterostructures with a number of Pt monolayers n ranging from one to three is studied in the density-functional theory framework. The calculations demonstrate that the deposition of the Pt atomic thin films on gold substrate results in strong modifications of the electronic structure at the surface. In particular, the Au(111) s-p-type Shockley surface state becomes completely unoccupied at deposition of any number of Pt monolayers. The Pt adlayer generates numerous quantum-well states in various energy gaps of Au(111) with strong spatial confinement at the surface. As a result, strong enhancement in the local density of state at the surface Pt atomic layer in comparison with clean Pt surface is obtained. The excess in the density of states has maximal magnitude in the case of one monolayer Pt adlayer and gradually reduces with increasing number of Pt atomic layers. The spin-orbit coupling produces strong modification of the energy dispersion of the electronic states generated by the Pt adlayer and gives rise to certain quantum states with a characteristic Dirac-cone shape. PMID- 29232831 TI - Analgesic-Like Activity of Essential Oil Constituents: An Update. AB - The constituents of essential oils are widely found in foods and aromatic plants giving characteristic odor and flavor. However, pharmacological studies evidence its therapeutic potential for the treatment of several diseases and promising use as compounds with analgesic-like action. Considering that pain affects a significant part of the world population and the need for the development of new analgesics, this review reports on the current studies of essential oils' chemical constituents with analgesic-like activity, including a description of their mechanisms of action and chemical aspects. PMID- 29232834 TI - Individual Data Linkage of Survey Data with Claims Data in Germany-An Overview Based on a Cohort Study. AB - Research based on health insurance data has a long tradition in Germany. By contrast, data linkage of survey data with such claims data is a relatively new field of research with high potential. Data linkage opens up new opportunities for analyses in the field of health services research and public health. Germany has comprehensive rules and regulations of data protection that have to be followed. Therefore, a written informed consent is needed for individual data linkage. Additionally, the health system is characterized by heterogeneity of health insurance. The lidA-living at work-study is a cohort study on work, age and health, which linked survey data with claims data of a large number of statutory health insurance data. All health insurance funds were contacted, of whom a written consent was given. This paper will give an overview of individual data linkage of survey data with German claims data on the example of the lidA study results. The challenges and limitations of data linkage will be presented. Despite heterogeneity, such kind of studies is possible with a negligibly small influence of bias. The experience we gain in lidA will be shown and provide important insights for other studies focusing on data linkage. PMID- 29232835 TI - Expression Profile of Genes Regulating Steroid Biosynthesis and Metabolism in Human Ovarian Granulosa Cells-A Primary Culture Approach. AB - Because of the deep involvement of granulosa cells in the processes surrounding the cycles of menstruation and reproduction, there is a great need for a deeper understanding of the ways in which they function during the various stages of those cycles. One of the main ways in which the granulosa cells influence the numerous sex associated processes is hormonal interaction. Expression of steroid sex hormones influences a range of both primary and secondary sexual characteristics, as well as regulate the processes of oogenesis, folliculogenesis, ovulation, and pregnancy. Understanding of the exact molecular mechanisms underlying those processes could not only provide us with deep insight into the regulation of the reproductive cycle, but also create new clinical advantages in detection and treatment of various diseases associated with sex hormone abnormalities. We have used the microarray approach validated by RT-qPCR, to analyze the patterns of gene expression in primary cultures of human granulosa cells at days 1, 7, 15, and 30 of said cultures. We have especially focused on genes belonging to ontology groups associated with steroid biosynthesis and metabolism, namely "Regulation of steroid biosynthesis process" and "Regulation of steroid metabolic process". Eleven genes have been chosen, as they exhibited major change under a culture condition. Out of those, ten genes, namely STAR, SCAP, POR, SREBF1, GFI1, SEC14L2, STARD4, INSIG1, DHCR7, and IL1B, belong to both groups. Patterns of expression of those genes were analyzed, along with brief description of their functions. That analysis helped us achieve a better understanding of the exact molecular processes underlying steroid biosynthesis and metabolism in human granulosa cells. PMID- 29232836 TI - Spasticity Management in Disorders of Consciousness. AB - Background: Spasticity is a motor disorder frequently encountered after a lesion involving the central nervous system. It is hypothesized to arise from an anarchic reorganization of the pyramidal and parapyramidal fibers and leads to hypertonia and hyperreflexia of the affected muscular groups. While this symptom and its management is well-known in patients suffering from stroke, multiple sclerosis or spinal cord lesion, little is known regarding its appropriate management in patients presenting disorders of consciousness after brain damage. Objectives: Our aim was to review the occurrence of spasticity in patients with disorders of consciousness and the therapeutic interventions used to treat it. Methods: We conducted a systematic review using the PubMed online database. It returned 157 articles. After applying our inclusion criteria (i.e., studies about patients in coma, unresponsive wakefulness syndrome or minimally conscious state, with spasticity objectively reported as a primary or secondary outcome), 18 studies were fully reviewed. Results: The prevalence of spasticity in patients with disorders of consciousness ranged from 59% to 89%. Current treatment options include intrathecal baclofen and soft splints. Several treatment options still need further investigation; including acupuncture, botulin toxin or cortical activation by thalamic stimulation. Conclusion: The small number of articles available in the current literature highlights that spasticity is poorly studied in patients with disorders of consciousness although it is one of the most common motor disorders. While treatments such as intrathecal baclofen and soft splints seem effective, large randomized controlled trials have to be done and new therapeutic options should be explored. PMID- 29232837 TI - A Burkholderia pseudomallei Outer Membrane Vesicle Vaccine Provides Cross Protection against Inhalational Glanders in Mice and Non-Human Primates. AB - Burkholderia mallei is a Gram-negative, non-motile, facultative intracellular bacillus and the causative agent of glanders, a highly contagious zoonotic disease. B. mallei is naturally resistant to multiple antibiotics and there is concern for its potential use as a bioweapon, making the development of a vaccine against B. mallei of critical importance. We have previously demonstrated that immunization with multivalent outer membrane vesicles (OMV) derived from B. pseudomallei provide significant protection against pneumonic melioidosis. Given that many virulence determinants are highly conserved between the two species, we sought to determine if the B. pseudomallei OMV vaccine could cross-protect against B. mallei. We immunized C57Bl/6 mice and rhesus macaques with B. pseudomallei OMVs and subsequently challenged animals with aerosolized B. mallei. Immunization with B. pseudomallei OMVs significantly protected mice against B. mallei and the protection observed was comparable to that achieved with a live attenuated vaccine. OMV immunization induced the production of B.mallei-specific serum IgG and a mixed Th1/Th17 CD4 and CD8 T cell response in mice. Additionally, immunization of rhesus macaques with B. pseudomallei OMVs provided protection against glanders and induced B.mallei-specific serum IgG in non-human primates. These results demonstrate the ability of the multivalent OMV vaccine platform to elicit cross-protection against closely-related intracellular pathogens and to induce robust humoral and cellular immune responses against shared protective antigens. PMID- 29232838 TI - Design and Synthesis of New Benzothiazole Compounds as Selective hMAO-B Inhibitors. AB - In the current work a new class of novel benzothiazole-hydrazone derivatives was designed and synthesized as hMAO-B inhibitors. Structures of the obtained compounds (3a-3j) were characterized by IR, 1H-NMR, 13C-NMR, and HRMS spectroscopic methods. The inhibitory activity of compounds (3a-3j) against hMAO A and hMAO-B enzymes was evaluated by using an in vitro fluorometric method. According to activity results, some of the synthesized compounds displayed selective and significant hMAO-B enzyme inhibitor activity. Compound 3e was the most active derivative in the series with an IC50 value of 0.060 uM. Furthermore, cytotoxicity of compound 3e was investigated and found to be non-cytotoxic. Absorption, distribution, metabolism, and excretion (ADME) and blood-brain barrier (BBB) permeability predictions were performed for all compounds. It was determined that these compounds may have a good pharmacokinetic profiles. Binding modes between the most active compound 3e and the hMAO-B enzyme were analyzed by docking studies. It was observed that there is a strong interaction between compound 3e and enzyme active site. PMID- 29232840 TI - One-Pot Lipase-Catalyzed Enantioselective Synthesis of (R)-(-)-N-Benzyl-3 (benzylamino)butanamide: The Effect of Solvent Polarity on Enantioselectivity. AB - The use of the solvent engineering has been applied for controlling the resolution of lipase-catalyzed synthesis of beta-aminoacids via Michael addition reactions. The strategy consisted of the thermodynamic control of products at equilibrium using the lipase CalB as a catalyst. The enzymatic chemo- and enantioselective synthesis of (R)-(-)-N-benzyl-3-(benzylamino)butanamide is reported, showing the influence of the solvent on the chemoselectivity of the aza Michael addition and the subsequent kinetic resolution of the Michael adduct; both processes are catalyzed by CalB and both are influenced by the nature of the solvent medium. This approach allowed us to propose a novel one-pot strategy for the enzymatic synthesis of enantiomerically enriched beta-aminoesters and beta aminoacids. PMID- 29232841 TI - Two-Channel SPR Sensor Combined Application of Polymer- and Vitreous-Clad Optic Fibers. AB - By combining a polymer-clad optic fiber and a vitreous-clad optic fiber, we proposed and fabricated a novel optic fiber surface plasmon resonance (SPR) sensor to conduct two-channel sensing at the same detection area. The traditional optic fiber SPR sensor has many disadvantages; for example, removing the cladding requires corrosion, operating it is dangerous, adjusting the dynamic response range is hard, and producing different resonance wavelengths in the sensing area to realize a multi-channel measurement is difficult. Therefore, in this paper, we skillfully used bare fiber grinding technology and reverse symmetry welding technology to remove the cladding in a multi-mode fiber and expose the evanescent field. On the basis of investigating the effect of the grinding angle on the dynamic range change of the SPR resonance valley wavelength and sensitivity, we combined polymer-clad fiber and vitreous-clad fiber by a smart design structure to realize at a single point a two-channel measurement fiber SPR sensor. In this paper, we obtained a beautiful spectral curve from a multi-mode fiber two-channel SPR sensor. In the detection range of the refractive rate between 1.333 RIU and 1.385 RIU, the resonance valley wavelength of channel I shifted from 622 nm to 724 nm with a mean average sensitivity of 1961 nm/RIU and the resonance valley wavelength of channel II shifted from 741 nm to 976 nm with a mean average sensitivity of 4519 nm/RIU. PMID- 29232839 TI - Agarwood Essential Oil Displays Sedative-Hypnotic Effects through the GABAergic System. AB - Although agarwood has been used as a tranquilizer in Asian countries for hundreds of years, the underlying pharmacological basis is still unclear. This study investigated the sedative-hypnotic effect of agarwood essential oil (AEO) using locomotor activity and pentobarbital-induced sleeping assays in mice. Single (1 day) and multiple (7- and 14-days) administrations of 60 mg/kg AEO generated significant sedative effect on inhibiting locomotor activity and hypnotic effect on pentobarbital-induced sleeping in mice. Interestingly, prolonged AEO treatment did not result in obvious desensitization. Concoitant measurement of the levels of brain neurotransmitters using ultrafast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) indicated that AEO had no significant effect on the levels of glutamic acid (Glu) and gamma-aminobutyric acid (GABA) in the brain. However, the sedative-hypnotic effects were blocked by the type A GABA (GABAA) receptor antagonists bicuculline and flumazenil. In addition, AEO significantly elevated the expression of GABAA receptor subunits and subtypes in the cerebral cortex. Furthermore, AEO increased chlorine ion (Cl-) influx through GABAA receptors in human neuroblastoma cells. These results together demonstrate that AEO exerts its sedative-hypnotic effects through regulating gene expression of GABAA receptors and potentiating GABAA receptor function. PMID- 29232842 TI - A New Laccase Based Biosensor for Tartrazine. AB - Laccase enzyme, a commonly used enzyme for the construction of biosensors for phenolic compounds was used for the first time to develop a new biosensor for the determination of the azo-dye tartrazine. The electrochemical biosensor was based on the immobilization of laccase on functionalized methacrylate-acrylate microspheres. The biosensor membrane is a composite of the laccase conjugated microspheres and gold nanoparticles (AuNPs) coated on a carbon-paste screen printed electrode. The reaction involving tartrazine can be catalyzed by laccase enzyme, where the current change was measured by differential pulse voltammetry (DPV) at 1.1 V. The anodic peak current was linear within the tartrazine concentration range of 0.2 to 14 MUM (R2 = 0.979) and the detection limit was 0.04 MUM. Common food ingredients or additives such as glucose, sucrose, ascorbic acid, phenol and sunset yellow did not interfere with the biosensor response. Furthermore, the biosensor response was stable up to 30 days of storage period at 4 degrees C. Foods and beverage were used as real samples for the biosensor validation. The biosensor response to tartrazine showed no significant difference with a standard HPLC method for tartrazine analysis. PMID- 29232843 TI - Recent Development of Non-Peptide GnRH Antagonists. AB - The decapeptide gonadotropin-releasing hormone, also referred to as luteinizing hormone-releasing hormone with the sequence (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro Gly-NH2) plays an important role in regulating the reproductive system. It stimulates differential release of the gonadotropins FSH and LH from pituitary tissue. To date, treatment of hormone-dependent diseases targeting the GnRH receptor, including peptide GnRH agonist and antagonists are now available on the market. The inherited issues associate with peptide agonists and antagonists have however, led to significant interest in developing orally active, small molecule, non-peptide antagonists. In this review, we will summarize all developed small molecule GnRH antagonists along with the most recent clinical data and therapeutic applications. PMID- 29232845 TI - Hybrid Signal Processing Technique to Improve the Defect Estimation in Ultrasonic Non-Destructive Testing of Composite Structures. AB - This work proposes a novel hybrid signal processing technique to extract information on disbond-type defects from a single B-scan in the process of non destructive testing (NDT) of glass fiber reinforced plastic (GFRP) material using ultrasonic guided waves (GW). The selected GFRP sample has been a segment of wind turbine blade, which possessed an aerodynamic shape. Two disbond type defects having diameters of 15 mm and 25 mm were artificially constructed on its trailing edge. The experiment has been performed using the low-frequency ultrasonic system developed at the Ultrasound Institute of Kaunas University of Technology and only one side of the sample was accessed. A special configuration of the transmitting and receiving transducers fixed on a movable panel with a separation distance of 50 mm was proposed for recording the ultrasonic guided wave signals at each one millimeter step along the scanning distance up to 500 mm. Finally, the hybrid signal processing technique comprising the valuable features of the three most promising signal processing techniques: cross-correlation, wavelet transform, and Hilbert-Huang transform has been applied to the received signals for the extraction of defects information from a single B-scan image. The wavelet transform and cross-correlation techniques have been combined in order to extract the approximated size and location of the defects and measurements of time delays. Thereafter, Hilbert-Huang transform has been applied to the wavelet transformed signal to compare the variation of instantaneous frequencies and instantaneous amplitudes of the defect-free and defective signals. PMID- 29232844 TI - Protection of Mice from Lethal Vaccinia Virus Infection by Vaccinia Virus Protein Subunits with a CpG Adjuvant. AB - Smallpox vaccination carries a high risk of adverse events in recipients with a variety of contra-indications for live vaccines. Although alternative non replicating vaccines have been described in the form of replication-deficient vaccine viruses, DNA vaccines, and subunit vaccines, these are less efficacious than replicating vaccines in animal models. DNA and subunit vaccines in particular have not been shown to give equivalent protection to the traditional replicating smallpox vaccine. We show here that combinations of the orthopoxvirus A27, A33, B5 and L1 proteins give differing levels of protection when administered in different combinations with different adjuvants. In particular, the combination of B5 and A27 proteins adjuvanted with CpG oligodeoxynucleotides (ODN) gives a level of protection in mice that is equivalent to the Lister traditional vaccine in a lethal vaccinia virus challenge model. PMID- 29232846 TI - Home Camera-Based Fall Detection System for the Elderly. AB - Falls are the leading cause of injury and death in elderly individuals. Unfortunately, fall detectors are typically based on wearable devices, and the elderly often forget to wear them. In addition, fall detectors based on artificial vision are not yet available on the market. In this paper, we present a new low-cost fall detector for smart homes based on artificial vision algorithms. Our detector combines several algorithms (background subtraction, Kalman filtering and optical flow) as input to a machine learning algorithm with high detection accuracy. Tests conducted on over 50 different fall videos have shown a detection ratio of greater than 96%. PMID- 29232847 TI - Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators. AB - It has been proven that specific isoforms of human carbonic anhydrase (hCA) are able to fine-tune physiological pathways connected to signal processing, and that decreased CAs expression negatively influences cognition, leading to mental retardation, Alzheimer's disease, and aging-related cognitive dysfunctions. For this reason, a small library of natural and synthetic nitrogen containing cyclic derivatives was assayed as activators of four human isoforms of carbonic anhydrase (hCA I, II, IV and VII). Most of the compounds activated hCA I, IV and VII in the micromolar range, with KAs ranging between 3.46 and 80.5 MUM, whereas they were not active towards hCA II (KAs > 100 MUM). Two natural compounds, namely l-(+)-ergothioneine (1) and melatonin (2), displayed KAs towards hCA VII in the nanomolar range after evaluation by a CO2 hydration method in vitro, showing a rather efficient and selective activation profile with respect to histamine, used as a reference compound. Corroborated with the above in vitro findings, a molecular modelling in silico approach has been performed to correlate these biological data, and to elucidate the binding interaction of these activators within the enzyme active site. PMID- 29232848 TI - A Metagenomic and in Silico Functional Prediction of Gut Microbiota Profiles May Concur in Discovering New Cystic Fibrosis Patient-Targeted Probiotics. AB - Cystic fibrosis (CF) is a life-limiting hereditary disorder that results in aberrant mucosa in the lungs and digestive tract, chronic respiratory infections, chronic inflammation, and the need for repeated antibiotic treatments. Probiotics have been demonstrated to improve the quality of life of CF patients. We investigated the distribution of gut microbiota (GM) bacteria to identify new potential probiotics for CF patients on the basis of GM patterns. Fecal samples of 28 CF patients and 31 healthy controls (HC) were collected and analyzed by 16S rRNA-based pyrosequencing analysis of GM, to produce CF-HC paired maps of the distribution of operational taxonomic units (OTUs), and by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) for Kyoto Encyclopedia of Genes and Genomes (KEGG) biomarker prediction. The maps were scanned to highlight the distribution of bacteria commonly claimed as probiotics, such as bifidobacteria and lactobacilli, and of butyrate-producing colon bacteria, such as Eubacterium spp. and Faecalibacterium prausnitzii. The analyses highlighted 24 OTUs eligible as putative probiotics. Eleven and nine species were prevalently associated with the GM of CF and HC subjects, respectively. Their KEGG prediction provided differential CF and HC pathways, indeed associated with health-promoting biochemical activities in the latter case. GM profiling and KEGG biomarkers concurred in the evaluation of nine bacterial species as novel putative probiotics that could be investigated for the nutritional management of CF patients. PMID- 29232849 TI - In Vitro Investigation of Wear of CAD/CAM Polymeric Materials Against Primary Teeth. AB - The aim of the study was to evaluate the effects of polymeric computer-aided design/computer-aided manufacturing CAD/CAM materials on antagonistic primary tooth wear. Five CAD/CAM polymeric materials were examined: Vipi Block Monocolor (VBM), Yamahachi polymethylmethacrylate (PMMA) (YAP), Mazic Duro (MZD), Vita Enamic (ENA), and Pekkton (PEK). All of the specimens were tested in a thermomechanical loading machine with the primary canine as the antagonist (50 N, 1.2 * 105 cycles, 1.7 Hz, 5/55 degrees C). The wear losses of the antagonist tooth and the restorative materials were calculated using reverse modelling software and an electronic scale. VBM and ENA showed significantly higher antagonist tooth wear than PEK (p < 0.05), but there was no significant difference observed among VBM, YAP, MZD, and ENA (p > 0.05). PEK showed the largest value in both material volumetric and weight losses. In terms of material volumetric losses, there was no significant difference between all of the groups (p > 0.05). In terms of material weight losses, PEK was significantly larger than ENA (p < 0.05), but there was no significant difference between VBM, YAP, MZD, and ENA (p > 0.05). Volumetric and weight losses of materials showed similar wear behaviour. However, the wear patterns of antagonists and materials were different, especially in PEK. PMID- 29232850 TI - An AST-ELM Method for Eliminating the Influence of Charging Phenomenon on ECT. AB - Electrical capacitance tomography (ECT) is a promising imaging technology of permittivity distributions in multiphase flow. To reduce the effect of charging phenomenon on ECT measurement, an improved extreme learning machine method combined with adaptive soft-thresholding (AST-ELM) is presented and studied for image reconstruction. This method can provide a nonlinear mapping model between the capacitance values and medium distributions by using machine learning but not an electromagnetic-sensitive mechanism. Both simulation and experimental tests are carried out to validate the performance of the presented method, and reconstructed images are evaluated by relative error and correlation coefficient. The results have illustrated that the image reconstruction accuracy by the proposed AST-ELM method has greatly improved than that by the conventional methods under the condition with charging object. PMID- 29232851 TI - A Novel Prebiotic Blend Product Prevents Irritable Bowel Syndrome in Mice by Improving Gut Microbiota and Modulating Immune Response. AB - Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder yet it still lacks effective prevention therapies. The aim of this study is to determine whether a novel prebiotic blend (PB) composed of fructo oligosaccharide (FOS), galactooligosaccharide (GOS), inulin and anthocyanins could be effective in preventing the development of IBS. We explored the possible mechanisms both in animal and in cells. Post-infectious IBS models in C57BL/6 mice were established and were pretreated with the PB, PB and probiotic strains 8 weeks in advance of infection. Eight weeks after infection, intestinal tissues were collected for assessing histomorphology, visceral sensitivity, barrier function, pro-inflammatory cytokines expression and proteomics analysis. Fecal samples were also collected for microbiota analysis. The pro-inflammatory cytokines expression in Caco-2 cells were evaluated after co-incubation with PB and Salmonella typhimurium 14028. The results showed that PB significantly decreased the pro-inflammatory cytokines both in infected Caco-2 cells and PI-IBS models. The loss of body weight, decreased expression of tight junction protein Occludin (OCLN), and changes of the microbiota composition induced by infections could be greatly improved by PB intervention (p < 0.05). The proteomics analysis revealed that this function was associated with Peroxisome proliferator-activated receptor (PPAR)gamma pathway. PMID- 29232853 TI - An Exploration of Intent to Use Telehealth at Home for Patients with Chronic Diseases. AB - Telecare is defined as care practiced at a distance. It is an effective strategy for improving the self-health care management of home-patients with chronic diseases. The purpose of this study was to explore the intent to use of telehealth patients. The correlation between the self-care behaviors, the intent to use of telehealth, and the effects on physiological indicators of patients with chronic disease at home were studied. A cross-sectional study design employing purposive sampling was selected. The structured questionnaire 'Telecare Usage Intention Scale and Self-Care Behavior Scale' were used, 'HbA1c, glucose levels and monthly blood pressure measurements' were analyzed in this thirteen month study. The self-care behaviors of the participants were positively correlated with their intent to use telehealth (p < 0.01). The results also indicated that HbA1c, glucose levels and frequency BP measurement of the participants improved significantly after using telecare (p < 0.005). The results indicated a strong intent to use telehealth and positive perception of telecare services by in-home patients with a chronic disease. Telehealth improves the self care behavior of in-home chronic disease patients and enhances medical professionals' ability to deliver quality and effective healthcare. PMID- 29232852 TI - Hippeastrum reticulatum (Amaryllidaceae): Alkaloid Profiling, Biological Activities and Molecular Docking. AB - The Amaryllidaceae family has proven to be a rich source of active compounds, which are characterized by unique skeleton arrangements and a broad spectrum of biological activities. The aim of this work was to perform the first detailed study of the alkaloid constituents of Hippeastrum reticulatum (Amaryllidaceae) and to determine the anti-parasitological and cholinesterase (AChE and BuChE) inhibitory activities of the epimers (6alpha-hydroxymaritidine and 6beta hydroxymaritidine). Twelve alkaloids were identified in H. reticulatum: eight known alkaloids by GC-MS and four unknown (6alpha-hydroxymaritidine, 6beta hydroxymaritidine, reticulinine and isoreticulinine) by NMR. The epimer mixture (6alpha-hydroxymaritidine and 6beta-hydroxymaritidine) showed low activity against all protozoan parasites tested and weak AChE-inhibitory activity. Finally, a molecular docking analysis of AChE and BuChE proteins showed that isoreticulinine may be classified as a potential inhibitory molecule since it can be stabilized in the active site through hydrogen bonds, pi-pi stacking and hydrophobic interactions. PMID- 29232854 TI - Editorial for Special Issue: The Insecticidal Bacterial Toxins in Modern Agriculture. PMID- 29232855 TI - Magnetic Marking and Intraoperative Detection of Primary Draining Lymph Nodes in High-Risk Prostate Cancer Using Superparamagnetic Iron Oxide Nanoparticles: Additional Diagnostic Value. AB - Sentinel lymph node dissection (sLND) using a magnetometer and superparamagnetic iron oxide nanoparticles (SPIONs) as a tracer was successfully applied in prostate cancer (PCa). Radioisotope-guided sLND combined with extended pelvic LND (ePLND) achieved better node removal, increasing the number of affected nodes or the detection of sentinel lymph nodes outside the established ePLND template. We determined the diagnostic value of additional magnetometer-guided sLND after intraprostatic SPION-injection in high-risk PCa. This retrospective study included 104 high-risk PCa patients (PSA >20 ng/mL and/or Gleason score >= 8 and/or cT2c) from a prospective cohort who underwent radical prostatectomy with magnetometer-guided sLND and ePLND. The diagnostic accuracy of sLND was assessed using ePLND as a reference standard. Lymph node metastases were found in 61 of 104 patients (58.7%). sLND had a 100% diagnostic rate, 96.6% sensitivity, 95.6% specificity, 96.6% positive predictive value, 95.6% negative predictive value, 3.4% false negative rate, and 4.4% false positive rate (detecting lymph node metastases outside the ePLND template). These findings demonstrate the high sensitivity and additional diagnostic value of magnetometer-guided sLND, exceeding that of ePLND through the individualized extension of PLND or the detection of sentinel lymph nodes/lymph node metastases outside the established node template in high-risk PCa. PMID- 29232856 TI - Resveratrol-Loaded Lipid Nanocarriers: Correlation between In Vitro Occlusion Factor and In Vivo Skin Hydrating Effect. AB - Lipid nanocarriers show occlusive properties that may be related to their ability to improve skin hydration. The aim of this work was to evaluate the relationship between in vitro occlusion factor and in vivo skin hydration for three types of lipid nanocarriers: nanoemulsions (NEs), solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). These lipid nanocarriers were loaded with trans-resveratrol (RSV) and incorporated in gel vehicles. In vitro occlusion factor was in the order SLNs > NLCs > NEs. Gels containing unloaded or RSV loaded lipid nanocarriers were applied on the back of a hand of 12 healthy volunteers twice a day for one week, recording skin hydration changes using the instrument Soft Plus. An increase of skin hydration was observed for all lipid nanocarriers (SLNs > NLCs > NEs). RSV loading into these nanocarriers did not affect in vitro and in vivo lipid nanocarriers effects. A linear relationship (r2 = 0.969) was observed between occlusion factor and in vivo increase of skin hydration. Therefore, the results of this study showed the feasibility of using the occlusion factor to predict in vivo skin hydration resulting from topical application of different lipid nanocarriers loading an active ingredient with no inherent hydrating activity. PMID- 29232857 TI - miR-34a Regulates Sperm Motility in Zebrafish. AB - Increasing attention has been focused on the role of microRNAs in post transcription regulation during spermatogenesis. Recently, the miR-34 family has been shown to be involved in the spermatogenesis, but the clear function of the miR-34 family in spermatogenesis is still obscure. Here we analyzed the function of miR-34a, a member of the miR-34 family, during spermatogenesis using miR-34a knockout zebrafish generated by the clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9) system. miR-34a knockout zebrafish showed no obvious defects on testis morphology and sperm quantity. However, we found a significant increase in progressive sperm motility that is one of the pivotal factors influencing in vitro fertilization rates, in the knockout zebrafish. Moreover, breeding experiments showed that, when miR-34a knockout male zebrafish mated with the wide-type females, they had a higher fertilization rate than did the wide-type males. Glycogen synthase kinase-3a (gsk3a), a potential sperm motility regulatory gene was predicted to be targeted by miR-34a, which was further supported by luciferase reporter assays, since a significant decrease of luciferase activity was detected upon ectopic overexpression of miR-34a. Our findings suggest that miR-34a downregulates gsk3a by targeting its 3' untranslated region, and miR-34a/gsk3a interaction modulates sperm motility in zebrafish. This study will help in understanding in the role of the miR-34 family during spermatogenesis and will set paths for further studies. PMID- 29232858 TI - Novel Effective Small-Molecule Antibacterials against Enterococcus Strains. AB - Enterococcus species cause increasing numbers of infections in hospitals. They contribute to the increasing mortality rates, mostly in patients with comorbidities, who suffer from severe diseases. Enterococcus resistances against most antibiotics have been described, including novel antibiotics. Therefore, there is an ongoing demand for novel types of antibiotics that may overcome bacterial resistances. We discovered a novel class of antibiotics resulting from a simple one-pot reaction of indole and o-phthaldialdehyde. Differently substituted indolyl benzocarbazoles were yielded. Both the indole substitution and the positioning at the molecular scaffold influence the antibacterial activity towards the various strains of Enterococcus species with the highest relevance to nosocomial infections. Structure-activity relationships are discussed, and the first lead compounds were identified as also being effective in the case of a vancomycin resistance. PMID- 29232859 TI - Competitive Promoter-Associated Matrix Attachment Region Binding of the Arid3a and Cux1 Transcription Factors. AB - Arid3a/Bright/Dril1 is a B cell-specific transactivator that regulates immunoglobulin heavy chain (IgH) gene transcription by binding promoter and enhancer-associated matrix attachment regions (MARs) within the IgH gene locus. Promoter MAR-mediated Arid3a transactivation is antagonized by direct competition of MAR binding by Cux1/CDP-a ubiquitously expressed repressor originally termed NF-MUNR. We report that the NF-MUNR complex includes Arid3a in B cells but not in non-B cells through mobility shift assays. The binding activity of NF-MUNR and Arid3a in B cells is reciprocally altered during the cell division cycle and by the B cell mitogen lipopolysaccharide LPS. LPS treatment had no effect on Arid3a localization but increased its total abundance within the nucleus and cytoplasm. We show that this increased level of Arid3a is capable of displacing Cux from the MARs to facilitate IgH gene transcription. Finally, we showed that the MARs (termed Bf150 and Tx125) associated with the VH1 rearranged variable region expressed in the S107 murine plasmacytoma, can repress reporter gene transcription in non-B cells and that they can relieve the repression mediated by EMU enhancer in B cells. These results have significant implications for early human development and demonstrate that MARs in IgH locus, NF-uNR and Arid3a regulate IgH gene expression in a concerted fashion. This paves the way for future studies examining the misregulation of this pathway in pediatric disease. PMID- 29232861 TI - Detection of Network Motif Based on a Novel Graph Canonization Algorithm from Transcriptional Regulation Networks. AB - Network motifs are patterns of complex networks occurring significantly more frequently than those in random networks. They have been considered as fundamental building blocks of complex networks. Therefore, the detection of network motifs in transcriptional regulation networks is a crucial step in understanding the mechanism of transcriptional regulation and network evolution. The search for network motifs is similar to solving subgraph searching problems, which has proven to be NP-complete. To quickly and effectively count subgraphs of a large biological network, we propose a novel graph canonization algorithm based on resolving sets. This method has been implemented in a command line interface (CLI) program sgip using the SeqAn library. Comparing to Babai's algorithm, this approach has a tighter complexity bound, o ( exp ( n log 2 n + 4 log n ) ) , on strongly regular graphs. Results on several simulated datasets and transcriptional regulation networks indicate that sgip outperforms nauty on many graph cases. The source code of sgip is freely accessible in https://github.com/seqan/seqan/tree/master/apps/sgip and the binary code in http://packages.seqan.de/sgip/. PMID- 29232862 TI - Effect of Oxylipins, Terpenoid Precursors and Wounding on Soft Corals' Secondary Metabolism as Analyzed via UPLC/MS and Chemometrics. AB - The effect of three oxylipin analogues, a terpenoid intermediate and wounding on the secondary metabolism of the soft corals Sarcophyton glaucum and Lobophyton pauciflorum was assessed. Examined oxylipins included prostaglandin (PG-E1), methyl jasmonate (MeJA), and arachidonic acid (AA) in addition to the diterpene precursor geranylgeranylpyrophosphate (GGP). Post-elicitation, metabolites were extracted from coral heads and analyzed via UPLC-MS followed by multivariate data analyses. Both supervised and unsupervised data analyses were used for sample classification. Multivariate data analysis revealed clear segregation of PG-E1 and MeJA elicited S. glaucum at 24 and 48 h post elicitation from other elicitor samples and unelicited control group. PG-E1 was found more effective in upregulating S. glaucum terpene/sterol levels compared to MeJA. Metabolites showing upregulation in S. glaucum include campestene-triol and a cembranoid, detected at ca. 30- and 2-fold higher levels compared to unelicited corals. Such an elicitation effect was less notable in the other coral species L. pauciflorum, suggesting a differential oxylipin response in soft corals. Compared to MeJA and PG, no elicitation effect was observed for GGP, AA or wounding on the metabolism of either coral species. PMID- 29232860 TI - Innate Lymphoid Cells (ILCs) as Mediators of Inflammation, Release of Cytokines and Lytic Molecules. AB - Innate lymphoid cells (ILCs) are an emerging group of immune cells that provide the first line of defense against various pathogens as well as contributing to tissue repair and inflammation. ILCs have been classically divided into three subgroups based on their cytokine secretion and transcription factor profiles. ILC nomenclature is analogous to that of T helper cells. Group 1 ILCs composed of natural killer (NK) cells as well as IFN-gamma secreting ILC1s. ILC2s have the capability to produce TH2 cytokines while ILC3s and lymphoid tissue inducer (LTis) are subsets of cells that are able to secrete IL-17 and/or IL-22. A recent subset of ILC known as ILC4 was discovered, and the cells of this subset were designated as NK17/NK1 due to their release of IL-17 and IFN-gamma. In this review, we sought to explain the subclasses of ILCs and their roles as mediators of lytic enzymes and inflammation. PMID- 29232863 TI - A Two-Dimensional Human Minilung System (Model) for Respiratory Syncytial Virus Infections. AB - Human respiratory syncytial virus (HRSV) is a major cause of serious pediatric respiratory diseases that lacks effective vaccine or specific therapeutics. Although our understanding about HRSV biology has dramatically increased during the last decades, the need for adequate models of HRSV infection is compelling. We have generated a two-dimensional minilung from human embryonic stem cells (hESCs). The differentiation protocol yielded at least six types of lung and airway cells, although it is biased toward the generation of distal cells. We show evidence of HRSV replication in lung cells, and the induction of innate and proinflammatory responses, thus supporting its use as a model for the study of HRSV-host interactions. PMID- 29232864 TI - Differences in Spontaneous Intracerebral Hemorrhage Cases between Urban and Rural Regions of Taiwan: Big Data Analytics of Government Open Data. AB - This study evaluated the differences in spontaneous intracerebral hemorrhage (sICH) between rural and urban areas of Taiwan with big data analysis. We used big data analytics and visualization tools to examine government open data, which included the residents' health medical administrative data, economic status, educational status, and relevant information. The study subjects included sICH patients of Taipei region (29,741 cases) and Eastern Taiwan (4565 cases). The incidence of sICH per 100,000 population per year in Eastern Taiwan (71.3 cases) was significantly higher than that of the Taipei region (42.3 cases). The mean coverage area per hospital in Eastern Taiwan (452.4 km2) was significantly larger than the Taipei region (24 km2). The residents educational level in the Taipei region was significantly higher than that in Eastern Taiwan. The mean hospital length of stay in the Taipei region (17.9 days) was significantly greater than that in Eastern Taiwan (16.3 days) (p < 0.001). There were no significant differences in other medical profiles between two areas. Distance and educational barriers were two possible reasons for the higher incidence of sICH in the rural area of Eastern Taiwan. Further studies are necessary in order to understand these phenomena in greater depth. PMID- 29232865 TI - Does the Short-Term Effect of Air Pollution Influence the Incidence of Spontaneous Intracerebral Hemorrhage in Different Patient Groups? Big Data Analysis in Taiwan. AB - Spontaneous intracerebral hemorrhage (sICH) has a high mortality rate. Research has demonstrated that the occurrence of sICH is related to air pollution. This study used big data analysis to explore the impact of air pollution on the risk of sICH in patients of differing age and geographic location. 39,053 cases were included in this study; 14,041 in the Taipei region (Taipei City and New Taipei City), 5537 in Taoyuan City, 7654 in Taichung City, 4739 in Tainan City, and 7082 in Kaohsiung City. The results of correlation analysis indicated that there were two pollutants groups, the CO and NO2 group and the PM2.5 and PM10 group. Furthermore, variations in the correlations of sICH with air pollutants were identified in different age groups. The co-factors of the influence of air pollutants in the different age groups were explored using regression analysis. This study integrated Taiwan National Health Insurance data and air pollution data to explore the risk factors of sICH using big data analytics. We found that PM2.5 and PM10 are very important risk factors for sICH, and age is an important modulating factor that allows air pollutants to influence the incidence of sICH. PMID- 29232866 TI - Urinary Concentrations of Triclosan, Benzophenone-3, and Bisphenol A in Taiwanese Children and Adolescents. AB - The purpose of this study was to determine the levels of urinary triclosan (TCS), benzophenone-3 (BP-3), and bisphenol A (BPA) in 52 children and 71 adolescents. The effects of age and sex on the levels of urinary TCS, BP-3, and BPA were explored, respectively. Results demonstrated the overall detection rates of urinary TCS, BP-3, and BPA were 18.7%, 8.1%, and 49.6%, respectively. The females had higher TCS concentrations than males (p = 0.051). The detection rate of urinary BP-3 in females (12.3%) was higher than that in males (0%) (p = 0.015). Moreover, the detection rate of urinary BP-3 in adolescents (14.1%) was higher than that in children (0%) (p = 0.005). For children, no urinary BP-3 was found. There were no differences in detection rates and concentrations of urinary TCS, BP-3, and BPA between males and females, respectively. For adolescents, urinary BP-3 was only found in the females. Urinary TCS levels in females were higher than those in males (p = 0.047). The present study showed that urinary TCS concentrations in females were significantly higher than those in males, respectively. In addition, BP-3 was only detected in urine samples of female adolescents. Sex and age were the important factors influencing urinary TCS and BP-3 concentrations. PMID- 29232867 TI - Race, Ethnicity, Income Concentration and 10-Year Change in Urban Greenness in the United States. AB - Background: Cross-sectional studies suggest urban greenness is unequally distributed by neighborhood demographics. However, the extent to which inequalities in greenness have changed over time remains unknown. Methods: We estimated 2001 and 2011 greenness using Moderate-resolution Imaging Spectroradiometer (MODIS) satellite-derived normalized difference vegetative index (NDVI) in 59,483 urban census tracts in the contiguous U.S. We fit spatial error models to estimate the association between baseline census tract demographic composition in 2000 and (1) 2001 greenness and (2) change in greenness between 2001 and 2011. Results: In models adjusted for population density, climatic factors, housing tenure, and Index of Concentration at the Extremes for income (ICE), an SD increase in percent White residents (a 30% increase) in 2000 was associated with 0.021 (95% CI: 0.018, 0.023) higher 2001 NDVI. We observed a stepwise reduction in 2001 NDVI with increased concentration of poverty. Tracts with a higher proportion of Hispanic residents in 2000 lost a small, statistically significant amount of greenness between 2001 and 2011 while tracts with higher proportions of Whites experienced a small, statistically significant increase in greenness over the same period. Conclusions: Census tracts with a higher proportion of racial/ethnic minorities, compared to a higher proportion of White residents, had less greenness in 2001 and lost more greenness between 2001 and 2011. Policies are needed to increase greenness, a health promoting neighborhood asset, in disadvantaged communities. PMID- 29232868 TI - Signal Subspace Smoothing Technique for Time Delay Estimation Using MUSIC Algorithm. AB - In civil engineering, Time Delay Estimation (TDE) is one of the most important tasks for the media structure and quality evaluation. In this paper, the MUSIC algorithm is applied to estimate the time delay. In practice, the backscattered echoes are highly correlated (even coherent). In order to apply the MUSIC algorithm, an adaptation of signal subspace smoothing is proposed to decorrelate the correlation between echoes. Unlike the conventional sub-band averaging techniques, we propose to directly use the signal subspace, which can take full advantage of the signal subspace and reduce the influence of noise. Moreover, the proposed method is adapted to deal with any radar pulse shape. The proposed method is tested on both numerical and experimental data. Both results show the effectiveness of the proposed method. PMID- 29232869 TI - Position Tracking During Human Walking Using an Integrated Wearable Sensing System. AB - Progress has been made enabling expensive, high-end inertial measurement units (IMUs) to be used as tracking sensors. However, the cost of these IMUs is prohibitive to their widespread use, and hence the potential of low-cost IMUs is investigated in this study. A wearable low-cost sensing system consisting of IMUs and ultrasound sensors was developed. Core to this system is an extended Kalman filter (EKF), which provides both zero-velocity updates (ZUPTs) and Heuristic Drift Reduction (HDR). The IMU data was combined with ultrasound range measurements to improve accuracy. When a map of the environment was available, a particle filter was used to impose constraints on the possible user motions. The system was therefore composed of three subsystems: IMUs, ultrasound sensors, and a particle filter. A Vicon motion capture system was used to provide ground truth information, enabling validation of the sensing system. Using only the IMU, the system showed loop misclosure errors of 1% with a maximum error of 4-5% during walking. The addition of the ultrasound sensors resulted in a 15% reduction in the total accumulated error. Lastly, the particle filter was capable of providing noticeable corrections, which could keep the tracking error below 2% after the first few steps. PMID- 29232871 TI - Thin-Film Quantum Dot Photodiode for Monolithic Infrared Image Sensors. AB - Imaging in the infrared wavelength range has been fundamental in scientific, military and surveillance applications. Currently, it is a crucial enabler of new industries such as autonomous mobility (for obstacle detection), augmented reality (for eye tracking) and biometrics. Ubiquitous deployment of infrared cameras (on a scale similar to visible cameras) is however prevented by high manufacturing cost and low resolution related to the need of using image sensors based on flip-chip hybridization. One way to enable monolithic integration is by replacing expensive, small-scale III-V-based detector chips with narrow bandgap thin-films compatible with 8- and 12-inch full-wafer processing. This work describes a CMOS-compatible pixel stack based on lead sulfide quantum dots (PbS QD) with tunable absorption peak. Photodiode with a 150-nm thick absorber in an inverted architecture shows dark current of 10-6 A/cm2 at -2 V reverse bias and EQE above 20% at 1440 nm wavelength. Optical modeling for top illumination architecture can improve the contact transparency to 70%. Additional cooling (193 K) can improve the sensitivity to 60 dB. This stack can be integrated on a CMOS ROIC, enabling order-of-magnitude cost reduction for infrared sensors. PMID- 29232872 TI - Markov Chain Realization of Joint Integrated Probabilistic Data Association. AB - A practical probabilistic data association filter is proposed for tracking multiple targets in clutter. The number of joint data association events increases combinatorially with the number of measurements and the number of targets, which may become computationally impractical for even small numbers of closely located targets in real target-tracking applications in heavily cluttered environments. In this paper, a Markov chain model is proposed to generate a set of feasible joint events (FJEs) for multiple target tracking that is used to approximate the multi-target data association probabilities and the probabilities of target existence of joint integrated probabilistic data association (JIPDA). A Markov chain with the transition probabilities obtained from the integrated probabilistic data association (IPDA) for single-target tracking is designed to generate a random sequence composed of the predetermined number of FJEs without incurring additional computational cost. The FJEs generated are adjusted for the multi-target tracking environment. A computationally tractable set of these random sequences is utilized to evaluate the track-to-measurement association probabilities such that the computational burden is substantially reduced compared to the JIPDA algorithm. By a series of simulations, the track confirmation rates and target retention statistics of the proposed algorithm are compared with the other existing algorithms including JIPDA to show the effectiveness of the proposed algorithm. PMID- 29232870 TI - Synthesis and Characterization of Nanofunctionalized Gelatin Methacrylate Hydrogels. AB - Given the importance of the extracellular medium during tissue formation, it was wise to develop an artificial structure that mimics the extracellular matrix while having improved physico-chemical properties. That is why the choice was focused on gelatin methacryloyl (GelMA), an inexpensive biocompatible hydrogel. Physicochemical and mechanical properties were improved by the incorporation of nanoparticles developed from two innovative fabrication processes: High shear fluid and low frequencies/high frequencies ultrasounds. Both rapeseed nanoliposomes and nanodroplets were successfully incorporated in the GelMA networks during the photo polymerization process. The impact on polymer microstructure was investigated by Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and enzymatic degradation investigations. Mechanical stability and viscoelastic tests were conducted to demonstrate the beneficial effect of the functionalization on GelMA hydrogels. Adding nanoparticles to GelMA improved the surface properties (porosity), tuned swelling, and degradability properties. In addition, we observed that nanoemulsion didn't change significantly the mechanical properties to shear and compression solicitations, whereas nanoliposome addition decreased Young's modulus under compression solicitations. Thus, these ways of functionalization allow controlling the design of the material by choosing the type of nanoparticle (nanoliposome or nanoemulsion) in function of the application. PMID- 29232873 TI - Continuous-Flow Production of Injectable Liposomes via a Microfluidic Approach. AB - Injectable liposomes are characterized by a suitable size and unique lipid mixtures, which require time-consuming and nonstraightforward production processes. The complexity of the manufacturing methods may affect liposome solubility, the phase transition temperatures of the membranes, the average particle size, and the associated particle size distribution, with a possible impact on the drug encapsulation and release. By leveraging the precise steady state control over the mixing of miscible liquids and a highly efficient heat transfer, microfluidic technology has proved to be an effective and direct methodology to produce liposomes. This approach results particularly efficient in reducing the number of the sizing steps, when compared to standard industrial methods. Here, Microfluidic Hydrodynamic Focusing chips were produced and used to form liposomes upon tuning experimental parameters such as lipids concentration and Flow-Rate-Ratios (FRRs). Although modelling evidenced the dependence of the laminar flow on the geometric constraints and the FRR conditions, for the specific formulation investigated in this study, the lipids concentration was identified as the primary factor influencing the size of the liposomes and their polydispersity index. This was attributed to a predominance of the bending elasticity modulus over the vesiculation index in the lipid mixture used. Eventually, liposomes of injectable size were produced using microfluidic one-pot synthesis in continuous flow. PMID- 29232874 TI - Alkaline Material Effects on Roots of Teeth. AB - The aim of this review was to identify and analyse all studies related to the effects of alkaline materials used in dentistry on roots of teeth. The first part of the review focused on mechanical property alterations of root dentine due to sodium hypochlorite (SH) used as an irrigant solution based on MeSH (Medical Subject Heading) terms from a previous study by Pascon et al in 2009. The second part reviewed literature on calcium hydroxide (CH), mineral trioxide aggregate (MTA) and other alkaline materials used as root canal dressings or filling materials. Additional MeSH terms used included "compressive strength", "elastic modulus" "flexural strength", "fracture strength" and "fracture resistance". The language filter was English. Of the initial 205 articles identified, 49 were included in this review, of which 29 were on SH, 21 on CH/MTA, and 1 relating to both. Many in vitro studies indicated a strong link between reduced mechanical properties of roots of teeth or radicular dentine treated with SH, and when sealers or root fillings with CH- or MTA-based materials were placed in contact with roots or radicular dentine. Recent literature indicates that the association between reduced mechanical properties and alkaline sealers and/or root-filling materials is not as straightforward as previously assumed, and requires further investigation using more valid experimental models. PMID- 29232875 TI - Optimization of Ultrasound-Assisted Extraction, HPLC and UHPLC-ESI-Q-TOF-MS/MS Analysis of Main Macamides and Macaenes from Maca (Cultivars of Lepidium meyenii Walp). AB - Ultrasound-assisted extraction (UAE), using petroleum ether as the solvent, was systematically applied to extract main macamides and macaenes from Maca hypocotyls. Extraction yield was related with four variables, including ratio of solution to solid, extraction temperature, extraction time, and extraction power. On the basis of response surface methodology (RSM), the optimal conditions were determined to be the ratio of solution to solid as 10:1 (mL/g), the extraction temperature of 40 degrees C, the extraction time of 30 min, and the extraction power of 200 W. Based on the optimal extraction method of UAE, the total contents of ten main macamides and two main macaenes of Maca cultivated in twenty different areas of Tibet were analyzed by HPLC and UHPLC-ESI-Q-TOF-MS/MS. This study indicated that UAE was able to effectively extract macamides alkaloids from Maca hypocotyls. Quantitative analysis showed that geographical origins, not ecotypes, played a more important role on the accumulation of active macamides in Maca. PMID- 29232876 TI - Evaluation of Fibrin-Based Interpenetrating Polymer Networks as Potential Biomaterials for Tissue Engineering. AB - Interpenetrating polymer networks (IPNs) have gained great attention for a number of biomedical applications due to their improved properties compared to individual components alone. In this study, we investigated the capacity of newly developed naturally-derived IPNs as potential biomaterials for tissue engineering. These IPNs combine the biologic properties of a fibrous fibrin network polymerized at the nanoscale and the mechanical stability of polyethylene oxide (PEO). First, we assessed their cytotoxicity in vitro on L929 fibroblasts. We further evaluated their biocompatibility ex vivo with a chick embryo organotypic culture model. Subcutaneous implantations of the matrices were subsequently conducted on nude mice to investigate their biocompatibility in vivo. Our preliminary data highlighted that our biomaterials were non-cytotoxic (viability above 90%). The organotypic culture showed that the IPN matrices induced higher cell adhesion (across all the explanted organ tissues) and migration (skin, intestine) than the control groups, suggesting the advantages of using a biomimetic, yet mechanically-reinforced IPN-based matrix. We observed no major inflammatory response up to 12 weeks post implantation. All together, these data suggest that these fibrin-based IPNs are promising biomaterials for tissue engineering. PMID- 29232877 TI - Effective Partnership in Community-Based Health Promotion: Lessons from the Health Literacy Partnership. AB - This paper aims to explore key elements needed to successfully develop healthy partnerships and collaborative working in community-based health promotion. It draws upon the lessons learned from a case study with the Health Literacy Partnership in Stoke-on-Trent, UK in developing the health literacy strategy in the area. The process was underpinned by respect for diverse yet complementary perspectives and skills from the grassroots up. This involved engagement with key stakeholders, development and support for community projects, and sharing of good practice with other national and local organizations. Stakeholders involved in developing the strategy also had a keen interest in health literacy and a strong commitment to promoting health and well-being in the area. Through patience, perseverance, and continuous open communication and learning, the health literacy strategy in Stoke-on-Trent, UK is beginning to have a ripple effect into local practice, and will potentially influence policy in the future. PMID- 29232878 TI - Determinants of Hospital Pharmacists' Job Satisfaction in Romanian Hospitals. AB - Aim: The purpose of this study is to identify the level of job satisfaction among hospital pharmacists in Romania in relation to environmental, socio-demographic, and individual factors. Material and Methods: Seventy-eight hospital pharmacists were included in the research. The Job Satisfaction Scale was used to measure the level of satisfaction with their current jobs, and the TAS-20 was used to evaluate emotional experience and awareness. Additionally, 12 items were formulated in order to identify the reasons for dissatisfaction with jobs, such as budget, number of working hours, legislation, relationships with colleagues, hospital departments, or stakeholders. Data were analyzed using IBM SPSS Statistics version 23. Results: The analyses of the data revealed a low level of satisfaction regarding the pay-promotion subscale, a high level of satisfaction with the management-interpersonal relationship dimension, and a high level of satisfaction regarding the organization-communication subscale. Seventy-four percent of subjects are dissatisfied about the annual budget, and 86.3% are not at all satisfied with present legislation. Conclusions: These results are important for hospital pharmacists and hospital management in order to focus on health policies, management, and environmental issues, with the purpose of increasing the level of satisfaction among hospital pharmacists. PMID- 29232879 TI - The Alteration of Nasopharyngeal and Oropharyngeal Microbiota in Children with MPP and Non-MPP. AB - Background: In recent years, the morbidity of Mycoplasma pneumoniae pneumonia (MPP) has increased significantly in China. A growing number of studies indicate that imbalanced respiratory microbiota is associated with various respiratory diseases. Methods: We enrolled 119 children, including 60 pneumonia patients and 59 healthy children. Nasopharyngeal (NP) and oropharyngeal (OP) sampling was performed for 16S ribosomal RNA (16S rRNA) gene analysis of all children. Sputum and OP swabs were obtained from patients for pathogen detection. Results: Both the NP and OP microbiota of patients differ significantly from that of healthy children. Diseased children harbor lower microbial diversity and a simpler co occurrence network in NP and OP. In pneumonia patients, NP and OP microbiota showed greater similarities between each other, suggesting transmission of NP microbiota to the OP. Aside from clinically detected pathogens, NP and OP microbiota analysis has also identified possible pathogens in seven cases with unknown infections. Conclusion: NP and OP microbiota in MPP and non-MPP are definitely similar. Respiratory infection generates imbalanced NP microbiota, which has the potential to transmit to OP. Microbiota analysis also promises to compliment the present means of detecting respiratory pathogens. PMID- 29232880 TI - The Genome of the Northern Sea Otter (Enhydra lutris kenyoni). AB - The northern sea otter inhabits coastal waters of the northern Pacific Ocean and is the largest member of the Mustelidae family. DNA sequencing methods that utilize microfluidic partitioned and non-partitioned library construction were used to establish the sea otter genome. The final assembly provided 2.426 Gbp of highly contiguous assembled genomic sequences with a scaffold N50 length of over 38 Mbp. We generated transcriptome data derived from a lymphoma to aid in the determination of functional elements. The assembled genome sequence and underlying sequence data are available at the National Center for Biotechnology Information (NCBI) under the BioProject accession number PRJNA388419. PMID- 29232881 TI - The Genome of the Beluga Whale (Delphinapterus leucas). AB - The beluga whale is a cetacean that inhabits arctic and subarctic regions, and is the only living member of the genus Delphinapterus. The genome of the beluga whale was determined using DNA sequencing approaches that employed both microfluidic partitioning library and non-partitioned library construction. The former allowed for the construction of a highly contiguous assembly with a scaffold N50 length of over 19 Mbp and total reconstruction of 2.32 Gbp. To aid our understanding of the functional elements, transcriptome data was also derived from brain, duodenum, heart, lung, spleen, and liver tissue. Assembled sequence and all of the underlying sequence data are available at the National Center for Biotechnology Information (NCBI) under the Bioproject accession number PRJNA360851A. PMID- 29232883 TI - Same Abbreviated Injury Scale Values May Be Associated with Different Risks to Mortality in Trauma Patients: A Cross-Sectional Retrospective Study Based on the Trauma Registry System in a Level I Trauma Center. AB - The Abbreviated Injury Scale (AIS) measures injury severity of a trauma patient with a numeric method for ranking anatomy-based specific injuries. The summation of the squares of the three most severe injuries in the AIS of six predefined body regions comprises the Injury Severity Score (ISS). It assumes that the mortality of a given AIS value is similar across all body regions. However, such an assumption is less explored in the literature. In this study, we aimed to compare the mortality rates of the patients with the same AIS value in different injured body regions in a level I trauma center. Hospitalized adult trauma patients with isolated serious to critical injury (AIS of 3 to 5) between 1 January 2009, and 31 December 2016, from the Trauma Registry System in a level I trauma center were grouped according to the injured body regions (including, the head/neck, thorax, abdomen, or extremities) and were exclusively compared according to their AIS stratum. Categorical data were compared using the two sided Fisher exact or Pearson chi-square tests. ANOVA with Games-Howell post hoc test was performed to assess the differences in continuous data of the patients with injury in different body regions. The primary outcome of the study was in hospital mortality. The adjusted odds ratios (AORs) were estimated using a stepwise selection of a multivariable regression model adjusted by controlling the confounding variables such as sex, age, comorbidities, and ISS. Survival curves were estimated with the Kaplan-Meier approach with a corresponding log rank test. The patients with AIS of 5 for abdomen injury and those with AIS of 3 for extremity injury had a significantly lower odds of adjusted mortality (adjusted odds ratio (AOR) 0.1, 95% confidence interval (CI) 0.01-0.39, p = 0.004 and AOR 0.3, 95% CI 0.15-0.51, p < 0.001, respectively) than that of the patients with head/neck injury. However, the patients with AIS of 4 for extremity injury demonstrated significantly higher odds of adjusted mortality (AOR 8.4, 95% CI 2.84-25.07, p < 0.001) than the patients with head/neck injury. This study found that the risks to mortality in the patients with a given AIS value of serious to critical injury in different injured body regions were not the same, even after controlling for confounding variables such as sex, age, comorbidities, and ISS. PMID- 29232882 TI - Seasonal Influenza Vaccine Acceptance among Pregnant Women in Zhejiang Province, China: Evidence Based on Health Belief Model. AB - Background: Reasons for acceptance of seasonal influenza vaccine (SIV) vaccination among pregnant women in China are poorly understood. We assessed the intention to accept SIV among pregnant women in Zhejiang province, by using a self-administrated structured questionnaire developed on the basis of health belief model (HBM). Methods: From 1 January to 31 March 2014, pregnant women with >=12 gestational weeks who attended antenatal clinics (ANCs) at public hospitals in 6 out of 90 districts were surveyed using a self-administered questionnaire that covered knowledge, attitudes, and beliefs related to SIV vaccination and influenza infection. We examined the associations between the acceptance of SIV vaccination and the demographic factors and HBM constructs using the logistic regression model, calculating the adjusted odds ratio (AOR). Results: Of the 1252 participants, 76.28% were willing to receive the SIV vaccination during their current pregnancy. High levels of perceived susceptibility of influenza (AOR = 1.75 (95%CI: 1.36-2.08)), high levels of perceived severity of influenza (AOR = 1.62 (95%CI: 1.25-1.95)), high level of perceived benefits of vaccination (AOR = 1.97 (95%CI: 1.76-2.21)), and high levels of cues to action were positively associated with the acceptance of SIV vaccination among pregnant women (AOR = 2.03 (95%CI: 1.70-2.69)), while high level of perceived barriers of vaccination was a negative determinant (AOR = 0.76 (95%CI: 0.62-0.94)). Conclusions: Poor knowledge and negative attitude towards SIV were associated with the poor acceptance of SIV. Health providers' recommendations were important to pregnant women's acceptance of SIV. Health education and direct communication strategies on SIV vaccination and influenza infection are necessary to improve the acceptance of SIV vaccination among pregnant women. PMID- 29232884 TI - Practicing Dentists' Self-Efficacy and Associated Factors in Managing the Treatment of Adults with Mental and Physical Disabilities: An Exploratory Cross Sectional Study in Riyadh, Saudi Arabia. AB - Background: Provision of oral healthcare to adults with mental and physical disabilities (AMPD) remains a challenging area across various healthcare systems. The present study aimed to assess self-reported efficacy and investigate factors associated with self-efficacy in the management of AMPD among practicing dentists in Saudi Arabia. Methods: A pilot-tested, self-administered questionnaire was distributed to a convenience sample of 1000 dentists. Descriptive and inferential analyses were performed on the collected responses. Results: Among the respondents (54%), 43% were males. Only 14% described their self-efficacy in managing AMPD as "High". Multivariable regression analyses revealed significant associations between "High" self-efficacy and male gender (Odd ratio (OR) = 2.39, 95% CI = 1.16-4.89), experience practicing dentistry for 11 years or more (OR = 2.19, 95% CI = 1.04-4.47), specialization in pediatric dentistry (OR = 3.98, 95% CI = 1.31-12.07), previous experience in managing AMPD (OR = 4.23, 95% CI = 1.59 11.22), and awareness of regulations for managing AMPD (OR = 2.62, 95% CI = 1.42 4.38). The interaction of gender x age was significantly associated (p = 0.028) with "High" self-efficacy. Gender-stratified analyses revealed a significant association between age and "High" self-efficacy among male dentists only. Conclusions: The findings of the present study highlight that a large percentage of dentists reported "Low/Moderate" self-efficacy in managing AMPD, particularly among female dentists. However, further studies are required to verify the factors associated with self-efficacy in the present study, and to identify other factors that may influence self-efficacy in managing AMPD. PMID- 29232885 TI - Design, Synthesis, and Fungicidal Activity of Novel Thiosemicarbazide Derivatives Containing Piperidine Fragments. AB - In order to discover novel eco-friendly lead compounds for plant pathogenic fungi control, a series of benzaldehyde thiosemicarbazide derivatives with a piperidine moiety have been designed and synthesized. Fungicidal activities of all the synthesized compounds were evaluated in vitro. The results indicated that all the title compounds exhibited moderate to good fungicidal activities. Compound 3b displayed excellent activities against Pythium aphanidermatum, Rhizoctonia solani, Valsa mali, and Gaeu-mannomyces graminsis, with EC50 values lower than 10 MUg/mL. Especially, in the case of Pythium aphanidermatum, its activity (EC50 = 1.6 MUg/mL) is superior to the commercial azoxystrobin (EC50 = 16.9 MUg/mL) and close to fluopicolide (EC50 = 1.0 MUg/mL). Initial structure-activity relationship (SAR) analysis showed that the heterocyclic piperidine group can influence the biological activities of the title compounds significantly. The fungicidal activity of compounds with piperidine is better than that of compounds without piperidine. The highly-active compound 3b, with its simple structure and easy synthetic route, is worthy to be further studied as a new lead fungicide. PMID- 29232887 TI - Should the Contribution of One Additional Lame Cow Depend on How Many Other Cows on the Farm Are Lame? AB - Welfare Quality(r) proposes a system for aggregation according to which the total welfare score for a group of animals is a non-linear effect of the prevalence of welfare scores across the individuals within the group. Three assumptions serve to justify this: (1) experts do not follow a linear reasoning when they assess a welfare problem; (2) it serves to prevent compensation (severe welfare problems hidden by scoring well on other aspects of welfare); (3) experts agree on the weight of different welfare measures. We use two sources of data to examine these assumptions: animal welfare data from 44 Danish dairy farms with Danish Holstein Friesian cows, and data from a questionnaire study with a convenience sample of 307 experts in animal welfare, of which we received responses from over 50%. Our main results were: (1) the total group-level welfare score as assigned by experts is a non-linear function of the individual animal welfare states within the group; (2) the WQ system does not prevent what experts perceive as unacceptable compensation; (3) the level of agreement among experts appears to vary across measures. Our findings give rise to concerns about the proposed aggregation system offered by WQ. PMID- 29232886 TI - The Diverse Range of Possible Cell Membrane Interactions with Substrates: Drug Delivery, Interfaces and Mobility. AB - The cell membrane has gained significant attention as a platform for the development of bio-inspired nanodevices due to its immune-evasive functionalities and copious bio-analogs. This review will examine several uses of cell membranes such as (i) therapeutic delivery carriers with or without substrates (i.e., nanoparticles and artificial polymers) that have enhanced efficiency regarding copious cargo loading and controlled release, (ii) exploiting nano-bio interfaces in membrane-coated particles from the macro- to the nanoscales, which would help resolve the biomedical issues involved in biological interfacing in the body, and (iii) its effects on the mobility of bio-moieties such as lipids and/or proteins in cell membranes, as discussed from a biophysical perspective. We anticipate that this review will influence both the development of novel anti-phagocytic delivery cargo and address biophysical problems in soft and complex cell membrane. PMID- 29232888 TI - A Comparison of the Social-Adaptive Perspective and Functionalist Perspective on Guilt and Shame. AB - Within the field of guilt and shame two competing perspectives have been advanced. The first, the social-adaptive perspective, proposes that guilt is an inherently adaptive emotion and shame is an inherently maladaptive emotion. Thus, those interested in moral character development and psychopathology should work to increase an individual's guilt-proneness and decrease an individual's shame proneness. The functionalist perspective, in contrast, argues that both guilt and shame can serve a person adaptively or maladaptively-depending on the situational appropriateness, duration, intensity, and so forth. This paper reviews the research conducted supporting both positions; critiques some issues with the most widely used guilt- and shame-proneness measure in the social-adaptive research (the TOSCA) and discusses the differences in results found when assessing guilt and shame at the state versus trait level. The conclusion drawn is that although there is broad support for the functionalist perspective across a wide variety of state and trait guilt/shame studies, the functionalist perspective does not yet have the wealth of data supporting it that has been generated by the social adaptive perspective using the TOSCA. Thus, before a dominant perspective can be identified, researchers need to (1) do more research assessing how the social adaptive perspective compares to the functionalist perspective at the state level and (2) do more trait research within the functionalist perspective to compare functionalist guilt- and shame-proneness measures with the TOSCA. PMID- 29232889 TI - Preparation, Characterization, and Biological Activities of Topical Anti-Aging Ingredients in a Citrus junos Callus Extract. AB - In this study, we prepared and characterized a callus extract from Citrus junos and assessed its utility as a source of topical anti-aging ingredients. Callus extract was produced by aqueous extraction from Citrus junos grown on Murashige and Skoog medium with picloram as a growth regulator. After measuring the total phenolic and flavonoid contents, the major phenolic compound in calli was identified as p-hydroxycinnamoylmalic acid (1) by spectroscopic analysis. The total phenol content in the extract was determined to be 24.50 +/- 0.43 mg/g of gallic acid equivalents; however, the total flavonoid content of the extract was not determined. The biological activities of the callus extract, in terms of skin anti-aging, were assessed by measuring the anti-tyrosinase activity in, and melanogenesis by, melanoma cells; and proliferation of, and procollagen synthesis by, human fibroblasts. The callus extract was incorporated into nanoliposomes (NLs) to improve its percutaneous absorption. Addition of the callus extract resulted in a 1.85-fold decrease in the melanin content of melanocytes compared with that with arbutin. The extract (500 MUg/mL) significantly promoted the proliferation of, and procollagen synthesis by, fibroblasts (by 154% and 176%, respectively). In addition, the flux through the human epidermis of Citrus junos callus extract incorporated into NLs was 17.67-fold higher than that of the callus extract alone. These findings suggest that Citrus junos callus extract loaded NLs have promise as an anti-aging cosmetic, as well as having a skin lightening effect. PMID- 29232890 TI - Active Wireless System for Structural Health Monitoring Applications. AB - The use of wireless sensors in Structural Health Monitoring (SHM) has increased significantly in the last years. Piezoelectric-based lead zirconium titanate (PZT) sensors have been on the rise in SHM due to their superior sensing abilities. They are applicable in different technologies such as electromechanical impedance (EMI)-based SHM. This work develops a flexible wireless smart sensor (WSS) framework based on the EMI method using active sensors for full-scale and autonomous SHM. In contrast to passive sensors, the self-sensing properties of the PZTs allow interrogating with or exciting a structure when desired. The system integrates the necessary software and hardware within a service-oriented architecture approach able to provide in a modular way the services suitable to satisfy the key requirements of a WSS. The framework developed in this work has been validated on different experimental applications. Initially, the reliability of the EMI method when carried out with the proposed wireless sensor system is evaluated by comparison with the wireless counterpart. Afterwards, the performance of the system is evaluated in terms of software stability and reliability of functioning. PMID- 29232892 TI - New Three-Dimensional Porous Electrode Concept: Vertically-Aligned Carbon Nanotubes Directly Grown on Embroidered Copper Structures. AB - New three-dimensional (3D) porous electrode concepts are required to overcome limitations in Li-ion batteries in terms of morphology (e.g., shapes, dimensions), mechanical stability (e.g., flexibility, high electroactive mass loadings), and electrochemical performance (e.g., low volumetric energy densities and rate capabilities). Here a new electrode concept is introduced based on the direct growth of vertically-aligned carbon nanotubes (VA-CNTs) on embroidered Cu current collectors. The direct growth of VA-CNTs was achieved by plasma-enhanced chemical vapor deposition (PECVD), and there was no application of any post treatment or cleaning procedure. The electrochemical behavior of the as-grown VA CNTs was analyzed by charge/discharge cycles at different specific currents and with electrochemical impedance spectroscopy (EIS) measurements. The results were compared with values found in the literature. The as-grown VA-CNTs exhibit higher specific capacities than graphite and pristine VA-CNTs found in the literature. This together with the possibilities that the Cu embroidered structures offer in terms of specific surface area, total surface area, and designs provide a breakthrough in new 3D electrode concepts. PMID- 29232891 TI - The Effect of Polyphenol-Rich Interventions on Cardiovascular Risk Factors in Haemodialysis: A Systematic Review and Meta-Analysis. AB - End-stage kidney disease is a strong risk factor for cardiovascular-specific mortality. Polyphenol-rich interventions may attenuate cardiovascular disease risk factors; however, this has not been systematically evaluated in the hemodialysis population. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, the following databases were searched: Cochrane Library (http://www.cochranelibrary.com/), MEDLINE (https://health.ebsco.com/products/medline-with-full-text), Embase (https://www.elsevier.com/solutions/embase-biomedical-research), and CINAHL (https://www.ebscohost.com/nursing/products/cinahl-databases/cinahl-complete). Meta-analyses were conducted for measures of lipid profile, inflammation, oxidative stress, and blood pressure. Risk of bias was assessed using the Cochrane Collaboration Risk of Bias tool and quality of the body of evidence was assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Twelve studies were included for review. Polyphenol-rich interventions included soy, cocoa, pomegranate, grape, and turmeric. Polyphenol-rich interventions significantly improved diastolic blood pressure (Mean Difference (MD) -5.62 mmHg (95% Confidence Interval (CI) -8.47, 2.78); I2 = 2%; p = 0.0001), triglyceride levels (MD -26.52 mg/dL (95% CI -47.22, -5.83); I2 = 57%; p = 0.01), and myeloperoxidase (MD -90.10 (95% CI -135.84, 44.36); I2 = 0%; p = 0.0001). Included studies generally had low or unclear risks of bias. The results of this review provide preliminary support for the use of polyphenol-rich interventions for improving cardiovascular risk markers in haemodialysis patients. Due to the limited number of studies for individual polyphenol interventions, further studies are required to provide recommendations regarding individual polyphenol intervention and dose. PMID- 29232893 TI - Pharmacy Students' Knowledge and Attitude toward Registration Trials and Clinical Research: A Survey in a Japanese University Hospital. AB - Clinical research plays a fundamental role in establishing new treatments. Clinical research coordinators are considered essential in clinical research, and medical professionals such as pharmacists often take on this role. Pharmacy students can be considered future candidates for this task. We used questionnaires to survey the knowledge of and attitudes toward registration trials and clinical research of pharmacy students at Tokushima University Hospital. All pharmacy students (103) to whom questionnaires were sent responded. Almost all respondents were aware of registration trials and clinical research. More than 90% were aware of the existence of clinical research coordinators, and about half (48.6%) understood their role. In clinical research terminology, most respondents were aware of informed consent and related issues, but fewer than 20% were aware of more practical things. In total, 29.1% and 40.8% of the respondents were willing to carry out and coordinate research. These findings suggest that pharmacy students have basic knowledge of clinical research and that many students are willing to carry out and coordinate clinical research. More practical exposure to clinical research may help to strengthen their future contribution. Further studies may help to determine how to provide education on registration trials and clinical research to pharmacy students. PMID- 29232895 TI - Effects of Weight Loss on Advanced Glycation End Products in Subjects with and without Diabetes: A Preliminary Report. AB - Advanced glycation end-products (AGEs) are formed endogenously as a normal ageing process and during food processing. High levels of AGEs have been implicated in the development of both macrovascular disease and microvascular disease. The purpose of this secondary analysis was to determine whether a major AGE species, Nepsilon-carboxymethyllysine (CML), was reduced after weight loss. CML values decreased by 17% after weight loss. Participants with diabetes and pre-diabetes had a lower CML values at baseline and a smaller change in CML than overweight participants without diabetes. We conclude that, in addition to the known health benefits, weight loss may reduce AGEs. Randomized studies of the effect of weight loss on AGE in people with and without type 2 diabetes are needed to confirm these results. PMID- 29232894 TI - Significant Down-Regulation of "Biological Adhesion" Genes in Porcine Oocytes after IVM. AB - Proper maturation of the mammalian oocyte is a compound processes determining successful monospermic fertilization, however the number of fully mature porcine oocytes is still unsatisfactory. Since oocytes' maturation and fertilization involve cellular adhesion and membranous contact, the aim was to investigate cell adhesion ontology group in porcine oocytes. The oocytes were collected from ovaries of 45 pubertal crossbred Landrace gilts and subjected to two BCB tests. After the first test, only granulosa cell-free BCB+ oocytes were directly exposed to microarray assays and RT-qPCR ("before IVM" group), or first in vitro matured and then if classified as BCB+ passed to molecular analyses ("after IVM" group). As a result, we have discovered substantial down-regulation of genes involved in adhesion processes, such as: organization of actin cytoskeleton, migration, proliferation, differentiation, apoptosis, survival or angiogenesis in porcine oocytes after IVM, compared to oocytes analyzed before IVM. In conclusion, we found that biological adhesion may be recognized as the process involved in porcine oocytes' successful IVM. Down-regulation of genes included in this ontology group in immature oocytes after IVM points to their unique function in oocyte's achievement of fully mature stages. Thus, results indicated new molecular markers involved in porcine oocyte IVM, displaying essential roles in biological adhesion processes. PMID- 29232896 TI - Dietary Animal Plasma Proteins Improve the Intestinal Immune Response in Senescent Mice. AB - Increased life expectancy has promoted research on healthy aging. Aging is accompanied by increased non-specific immune activation (inflammaging) which favors the appearance of several disorders. Here, we study whether dietary supplementation with spray-dried animal plasma (SDP), which has been shown to reduce the activation of gut-associated lymphoid tissue (GALT) in rodents challenged by S. aureus enterotoxin B (SEB), and can also prevent the effects of aging on immune system homeostasis. We first characterized GALT in a mouse model of accelerated senescence (SAMP8) at different ages (compared to mice resistant to accelerated senescence; SAMR1). Second, we analyzed the SDP effects on GALT response to an SEB challenge in SAMP8 mice. In GALT characterization, aging increased the cell number and the percentage of activated Th lymphocytes in mesenteric lymph nodes and Peyer's patches (all, p < 0.05), as well as the expression of IL-6 and TNF-alpha in intestinal mucosa (both, p < 0.05). With respect to GALT response to the SEB challenge, young mice showed increased expression of intestinal IL-6 and TNF-alpha, as well as lymphocyte recruitment and activation (all, p < 0.05). However, the immune response of senescent mice to the SEB challenge was weak, since SEB did not change cell recruitment or the percentage of activated Th lymphocytes. Mice supplemented with SDP showed improved capacity to respond to the SEB challenge, similar to the response of the young mice. These results indicate that senescent mice have an impaired mucosal immune response characterized by unspecific GALT activation and a weak specific immune response. SDP supplementation reduces non-specific basal immune activation, allowing for the generation of specific responses. PMID- 29232898 TI - UV-Induced Photocatalytic Cashmere Fibers. AB - Cashmere with UV-induced photocatalytic properties is developed for the first time by applying nanocrystalline anatase TiO2 colloid that is free of inorganic acids and organic solvents via a facile low-temperature one-step sol-gel process. The coated cashmere exhibits remarkable UV-induced photodegradation of methyl orange. Furthermore, the photocatalytic nano-coating on cashmere exhibits significant stability after repetitive washing cycles without the need for chemical or physical pretreatment, where the photocatalytic activities remain almost unchanged after three washing cycles while maintaining a water contact angle above 150 degrees . The one-step functionalization process also minimizes the impact on the peculiar intrinsic properties of cashmere. These findings indicate that cashmere combining reproducible UV-induced photocatalytic activity with stable superhydrophobicity has potential in practical applications. PMID- 29232899 TI - A Dual-Butterfly Structure Gyroscope. AB - This paper reports a dual-butterfly structure gyroscope based on the traditional butterfly structure. This novel structure is composed of two butterfly structures, each of which contains a main vibrational beam, four proof masses, and a coupling mechanism. The coupling mechanism in this proposed structure couples the two single butterfly structures and keeps the driving mode phases of the two single butterfly gyroscopes exactly opposite, increasing the double difference of traditional butterfly gyroscopes to a quad difference, which has the potential advantage of improving bias instability and g-sensitivity. The gyroscope was fabricated using a standard microfabrication method and tested in laboratory conditions. The experimental results show a Q-factor of 10,967 in driving mode and there were two peaks in the frequency responses curve of sensing direction due to unavoidable fabrication errors. Scale factor and bias instability were also measured, reaching a scale factor of 10.9 mV/ degrees /s and a bias instability of 10.7 degrees /h, according to the Allan Variance curve. PMID- 29232897 TI - Biomimetic Sensors for the Senses: Towards Better Understanding of Taste and Odor Sensation. AB - Taste and smell are very important chemical senses that provide indispensable information on food quality, potential mates and potential danger. In recent decades, much progress has been achieved regarding the underlying molecular and cellular mechanisms of taste and odor senses. Recently, biosensors have been developed for detecting odorants and tastants as well as for studying ligand receptor interactions. This review summarizes the currently available biosensing approaches, which can be classified into two main categories: in vitro and in vivo approaches. The former is based on utilizing biological components such as taste and olfactory tissues, cells and receptors, as sensitive elements. The latter is dependent on signals recorded from animals' signaling pathways using implanted microelectrodes into living animals. Advantages and disadvantages of these two approaches, as well as differences in terms of sensing principles and applications are highlighted. The main current challenges, future trends and prospects of research in biomimetic taste and odor sensors are discussed. PMID- 29232900 TI - A Practical, Robust and Fast Method for Location Localization in Range-Based Systems. AB - Location localization technology is used in a number of industrial and civil applications. Real time location localization accuracy is highly dependent on the quality of the distance measurements and efficiency of solving the localization equations. In this paper, we provide a novel approach to solve the nonlinear localization equations efficiently and simultaneously eliminate the bad measurement data in range-based systems. A geometric intersection model was developed to narrow the target search area, where Newton's Method and the Direct Search Method are used to search for the unknown position. Not only does the geometric intersection model offer a small bounded search domain for Newton's Method and the Direct Search Method, but also it can self-correct bad measurement data. The Direct Search Method is useful for the coarse localization or small target search domain, while the Newton's Method can be used for accurate localization. For accurate localization, by utilizing the proposed Modified Newton's Method (MNM), challenges of avoiding the local extrema, singularities, and initial value choice are addressed. The applicability and robustness of the developed method has been demonstrated by experiments with an indoor system. PMID- 29232901 TI - A Novel Passive Wireless Sensing Method for Concrete Chloride Ion Concentration Monitoring. AB - In this paper, a novel approach for concrete chloride ion concentration measuring based on passive and wireless sensor tag is proposed. The chloride ion sensor based on RFID communication protocol is consisting of an energy harvesting and management circuit, a low dropout voltage regulator, a MCU, a RFID tag chip and a pair of electrodes. The proposed sensor harvests energy radiated by the RFID reader to power its circuitry. To improve the stability of power supply, a three stage boost rectifier is customized to rectify the harvested power into dc power and step-up the voltage. Since the measured data is wirelessly transmitted, it contains miscellaneous noises which would decrease the accuracy of measuring. Thus, in this paper, the wavelet denoising method is adopted to denoise the raw data. Besides, a monitoring software is developed to display the measurement results in real-time. The measurement results indicate that the proposed passive sensor tag can achieve a reliable communication distance of 16.3 m and can reliably measure the chloride ion concentration in concrete. PMID- 29232902 TI - Rapid Assessment of Stakeholder Concerns about Public Health. An Introduction to a Fast and Inexpensive Approach Applied on Health Concerns about Intensive Animal Production Systems. AB - To effectively manage environmental health risks, stakeholders often need to act collectively. Stakeholders vary in their desire to act due to many factors, such as knowledge, risk perception, interests, and worldviews. Understanding their perceptions of the issues at stake is crucial to support the risk governance process. Even though concern assessment is a pivotal element of risk governance, few tools for rapid assessment are reported in the literature. We tested a rapid and relatively cheap approach, taking the Dutch debate on Intensive Animal Production Systems (IAPS) and health as an example. Dutch policy-oriented publications on IAPS and health and ten semi-structured in-depth interviews with a variety of stakeholders were analyzed to identify stakeholders and concerns involved in the Dutch debate about IAPS and health. Concerns were mapped and a stakeholder network was derived. Three classes of concerns were recognized in the discussions about IAPS and health: concerns related to health risks, concerns regarding the activity causing the risks (IAPS), and concerns about the process to control the risks. The notions of 'trust' and 'scientific uncertainty' appeared as important themes in the discussions. Argumentation based on concerns directly related to health risks, the activity causing the risk (IAPS), and its risk management can easily become muddled up in a societal debate, limiting the development of effective action perspectives. Acknowledging these multiple stakeholder concerns can clarify the positions taken by stakeholders and allow for more and other action perspectives to develop. PMID- 29232903 TI - Pediatric Thermal Burns and Treatment: A Review of Progress and Future Prospects. AB - Burn injuries are a devastating critical care problem. In children, burns continue to be a major epidemiologic problem around the globe resulting in significant morbidity and death. Apparently, treating these burn injuries in children and adults remains similar, but there are significant physiological and psychological differences. The dermal layer of the skin is generally thinner in neonates, infants, and children than in adults. Enhanced evaporative loss and need for isotonic fluids increases the risk of hypothermia in the pediatric population. The pain management of the children with major burns challenges the skills of the personnel of every unit. Managing these wounds requires intensive therapeutic treatment for multi-organ dysfunction, and surgical treatment to prevent sepsis and other complications that further delay wound closure. Alternatives to the practice of donor site harvest and autografting for the treatment of severe burns and other complex skin defects are urgently needed for both adult and pediatric populations. This review article focuses on thermal burn pathophysiology and pain management and provides an overview of currently approved products used for the treatment of pediatric burn wounds. A new promising approach has been presented as a first-line therapy in the treatment of burns to reduce surgical autografting in pediatric patients. PMID- 29232904 TI - An Expanded Multi-Organ Disease Phenotype Associated with Mutations in YARS. AB - Whole exome sequence analysis was performed in a Swedish mother-father-affected proband trio with a phenotype characterized by progressive retinal degeneration with congenital nystagmus, profound congenital hearing impairment, primary amenorrhea, agenesis of the corpus callosum, and liver disease. A homozygous variant c.806T > C, p.(F269S) in the tyrosyl-tRNA synthetase gene (YARS) was the only identified candidate variant consistent with autosomal recessive inheritance. Mutations in YARS have previously been associated with both autosomal dominant Charcot-Marie-Tooth syndrome and a recently reported autosomal recessive multiorgan disease. Herein, we propose that mutations in YARS underlie another clinical phenotype adding a second variant of the disease, including retinitis pigmentosa and deafness, to the spectrum of YARS-associated disorders. PMID- 29232905 TI - Evaluation of Propagation Characteristics Using the Human Body as an Antenna. AB - In this paper, an inhomogeneous human body model was presented to investigate the propagation characteristics when the human body was used as an antenna to achieve signal transmission. Specifically, the channel gain of four scenarios, namely, (1) both TX electrode and RX electrode were placed in the air, (2) TX electrode was attached on the human body, and RX electrode was placed in the air, (3) TX electrode was placed in the air, and RX electrode was attached on the human body, (4) both the TX electrode and RX electrode were attached on the human body, were studied through numerical simulation in the frequency range 1 MHz to 90 MHz. Furthermore, the comparisons of input efficiency, accepted efficiency, total efficiency, absorption power of human body, and electric field distribution of different distances of four aforementioned scenarios were explored when the frequency was at 44 MHz. In addition, the influences of different human tissues, electrode position, and the distance between electrode and human body on the propagation characteristics were investigated respectively at 44 MHz. The results showed that the channel gain of Scenario 4 was the maximum when the frequency was from 1 MHz to 90 MHz. The propagation characteristics were almost independent of electrode position when the human body was using as an antenna. However, as the distance between TX electrode and human body increased, the channel gain decreased rapidly. The simulations were verified by experimental measurements. The results showed that the simulations were in agreement with the measurements. PMID- 29232907 TI - A Game-Theory Based Incentive Framework for an Intelligent Traffic System as Part of a Smart City Initiative. AB - Intelligent Transportation Systems (ITSs) can be applied to inform and incentivize travellers to help them make cognizant choices concerning their trip routes and transport modality use for their daily travel whilst achieving more sustainable societal and transport authority goals. However, in practice, it is challenging for an ITS to enable incentive generation that is context-driven and personalized, whilst supporting multi-dimensional travel goals. This is because an ITS has to address the situation where different travellers have different travel preferences and constraints for route and modality, in the face of dynamically-varying traffic conditions. Furthermore, personalized incentive generation also needs to dynamically achieve different travel goals from multiple travellers, in the face of their conducts being a mix of both competitive and cooperative behaviours. To address this challenge, a Rule-based Incentive Framework (RIF) is proposed in this paper that utilizes both decision tree and evolutionary game theory to process travel information and intelligently generate personalized incentives for travellers. The travel information processed includes travellers' mobile patterns, travellers' modality preferences and route traffic volume information. A series of MATLAB simulations of RIF was undertaken to validate RIF to show that it is potentially an effective way to incentivize travellers to change travel routes and modalities as an essential smart city service. PMID- 29232908 TI - A Hybrid Feature Model and Deep-Learning-Based Bearing Fault Diagnosis. AB - Bearing fault diagnosis is imperative for the maintenance, reliability, and durability of rotary machines. It can reduce economical losses by eliminating unexpected downtime in industry due to failure of rotary machines. Though widely investigated in the past couple of decades, continued advancement is still desirable to improve upon existing fault diagnosis techniques. Vibration acceleration signals collected from machine bearings exhibit nonstationary behavior due to variable working conditions and multiple fault severities. In the current work, a two-layered bearing fault diagnosis scheme is proposed for the identification of fault pattern and crack size for a given fault type. A hybrid feature pool is used in combination with sparse stacked autoencoder (SAE)-based deep neural networks (DNNs) to perform effective diagnosis of bearing faults of multiple severities. The hybrid feature pool can extract more discriminating information from the raw vibration signals, to overcome the nonstationary behavior of the signals caused by multiple crack sizes. More discriminating information helps the subsequent classifier to effectively classify data into the respective classes. The results indicate that the proposed scheme provides satisfactory performance in diagnosing bearing defects of multiple severities. Moreover, the results also demonstrate that the proposed model outperforms other state-of-the-art algorithms, i.e., support vector machines (SVMs) and backpropagation neural networks (BPNNs). PMID- 29232906 TI - Histology of the Ovary of the Laying Hen (Gallus domesticus). AB - The laying hen (Gallus domesticus) is a robust animal model for epithelial ovarian cancer. The use of animal models is critical in identifying early disease markers and developing and testing chemotherapies. We describe the microscopic characteristics of the normally functioning laying hen ovary and proximal oviduct to establish baselines from which lesions associated with ovarian cancer can be more readily identified. Ovaries and oviducts were collected from 18-month-old laying hens (n = 18) and fixed in 10% neutral buffered formalin. Hematoxylin- and eosin-stained sections were examined by light microscopy. Both post-ovulatory follicular regression and atresia of small follicles produce remnant clusters of vacuolated cells with no histological evidence that scar tissue persists. Infiltrates of heterophils are associated with atresia of small follicles, a relationship not previously documented in laying hen ovaries. Because these tissues can be mistaken for cancerous lesions, we present a detailed histological description of remnant Wolffian tissues in the laying hen ovary. Immunohistochemical staining for pancytokeratin produced a positive response in ovarian surface epithelium and staining for vimentin produced a positive response in granulosa cells of follicles. Epithelial cells lining glands of the remnant epoophoron had a positive response to both pancytokeratin and vimentin, a result also observed in women. PMID- 29232910 TI - Exploratory Temporal and Spatial Analysis of Myocardial Infarction Hospitalizations in Calgary, Canada. AB - Spatial and temporal analyses are critical to understand the pattern of myocardial infarction (MI) hospitalizations over space and time, and to identify their underlying determinants. In this paper, we analyze MI hospitalizations in Calgary from 2004 to 2013, stratified by age and gender. First, a seasonal trend decomposition analyzes the seasonality; then a linear regression models the trend component. Moran's I and hot spot analyses explore the spatial pattern. Though exploratory, results show that most age and gender groups feature a statistically significant decline over the 10 years, consistent with previous studies in Canada. Decline rates vary across ages and genders, with the slowest decline observed for younger males. Each gender exhibits a seasonal pattern with peaks in both winter and summer. Spatially, MI hot spots are identified in older communities, and in socioeconomically and environmentally disadvantaged communities. In the older communities, higher MI rates appear to be more highly associated with demographics. Conversely, worse air quality appears to be locally associated with higher MI incidence in younger age groups. The study helps identify areas of concern, where MI hot spots are identified for younger age groups, suggesting the need for localized public health policies to target local risk factors. PMID- 29232909 TI - Synergistic Effects of Bacillus amyloliquefaciens (GB03) and Water Retaining Agent on Drought Tolerance of Perennial Ryegrass. AB - Water retaining agent (WRA) is widely used for soil erosion control and agricultural water saving. Here, we evaluated the effects of the combination of beneficial soil bacterium Bacillus amyloliquefaciens strain GB03 and WRA (the compound is super absorbent hydrogels) on drought tolerance of perennial ryegrass (Lolium perenne L.). Seedlings were subjected to natural drought for maximum 20 days by stopping watering and then rewatered for seven days. Plant survival rate, biomass, photosynthesis, water status and leaf cell membrane integrity were measured. The results showed that under severe drought stress (20-day natural drought), compared to control, GB03, WRA and GB03+WRA all significantly improved shoot fresh weight, dry weight, relative water content (RWC) and chlorophyll content and decreased leaf relative electric conductivity (REC) and leaf malondialdehyde (MDA) content; GB03+WRA significantly enhanced chlorophyll content compared to control and other two treatments. Seven days after rewatering, GB03, WRA and GB03+WRA all significantly enhanced plant survival rate, biomass, RWC and maintained chlorophyll content compared to control; GB03+WRA significantly enhanced plant survival rate, biomass and chlorophyll content compared to control and other two treatments. The results established that GB03 together with water retaining agent promotes ryegrass growth under drought conditions by improving survival rate and maintaining chlorophyll content. PMID- 29232911 TI - Spontaneous Charge Generation in Flowing Albumin Solutions at 35 degrees C and 38 degrees C. AB - The time dependence of a charge accumulation in a 10-15 M albumin solution, flowing through a measuring cell of an analytical flow system injector, had a nonlinear character under certain conditions, within a human physiological temperature range. Sharp charge increases depended on albumin concentration. This effect must be taken into consideration when generating models that describe electrokinetic phenomena in flowing protein solutions and when developing analytical flow systems for the registration of biomolecules in low concentration ranges. PMID- 29232912 TI - Investigating Lushan Earthquake Victims' Individual Behavior Response and Rescue Organization. AB - Research concerning the impact of earthquake victims' individual behavior and its association with earthquake-related injuries is lacking. This study examined this relationship along with effectiveness of earthquake rescue measures. The six most severely destroyed townships during the Lushan earthquake were examined; 28 villages and three earthquake victims' settlement camp areas were selected as research areas. Inclusion criteria comprised living in Lushan county for a longtime, living in Lushan county during the 2013 Lushan earthquake, and having one's home destroyed. Earthquake victims with an intellectual disability or communication problems were excluded. The earthquake victims (N (number) = 5165, male = 2396) completed a questionnaire (response rate: 94.7%). Among them, 209 were injured (5.61%). Teachers (p < 0.0001, OR (odds ratios) = 3.33) and medical staff (p = 0.001, OR = 4.35) were more vulnerable to the earthquake than were farmers. Individual behavior was directly related to injuries, such as the first reaction after earthquake and fear. There is an obvious connection between earthquake-related injury and individual behavior characteristics. It is strongly suggested that victims receive mental health support from medical practitioners and the government to minimize negative effects. The initial reaction after an earthquake also played a vital role in victims' trauma; therefore, earthquake related experience and education may prevent injuries. Self-aid and mutual help played key roles in emergency, medical rescue efforts. PMID- 29232913 TI - Pharmacoeconomic Analysis of Drugs Used in the Treatment of Pneumonia in Paediatric Population in a Tertiary Care Hospital in India-A Cost-of-Illness Study. AB - AIMS AND OBJECTIVES: The cost of antibiotic therapy for the treatment of pneumonia in the inpatient paediatric population can have a major impact on the healthcare expenditure. We planned to assess the direct and indirect costs of diagnosis and medical treatment of paediatric patients with community acquired pneumonia who are hospitalized in a tertiary care hospital in India. METHODS: 125 children with a diagnosis of pneumonia who were admitted to the inpatient department of a paediatric hospital receiving antibiotic treatment were observed. Data on clinical presentation and resources consumed were collected and the costs of pneumonia treatment were calculated. Descriptive statistics (mean +/- standard deviation (SD)) were used to evaluate data regarding demographics, drugs prescribed and cost (direct and indirect cost). Multivariate regression analysis was used to find out predictors of direct and indirect cost. RESULTS: Among all pneumonia admissions, mild-to-moderate pneumonia constitutes 76.8%, and 23.2% children were admitted with severe pneumonia; 105 children out of 125 (84%) were suffering from associated disorders along with pneumonia. The majority of antibiotics prescribed belonged to beta lactams (52%) followed by aminoglycosides (19%), macrolides (13%) and peptides (11%). Parenteral routes of administration were used in a majority of patients as compared to oral. The average cost per patient in management of pneumonia was 12245 +/- 593 INR ($187.34 +/- 9.07). PMID- 29232914 TI - Characterization and Bone Response of Carbonate-Containing Apatite-Coated Titanium Implants Using an Aqueous Spray Coating. AB - We performed thin carbonate-containing apatite (CA) coating on titanium (Ti) by an aqueous spray coating (ASC) method that consisted of a Ca-CO3-PO4 complex. Two different CA coatings were produced by two different spray amounts and were heat treated after spraying. We evaluated three-dimensional structures, adhesiveness to Ti, and durability of the CA film. In addition, we performed immersion experiments in simulated body fluid (SBF), and bone responses were evaluated after implantation into a femoral bone defect in rats. The bonding ability of ASC coated implant into the bone was examined by push-in tests. Unique network structures with small particles were identified on CA coatings. Although heat treatment produced no significant difference in surface morphology, scratch tests revealed that heat treatment improved the adhesion of CA coatings to Ti. Crystal formation progressed on CA-coated specimens, and the sample placement direction influenced crystal formation and growth in SBF immersion. Animal implantation experiments revealed significantly greater bone-to-implant contact ratio and bone mass in both cortical and bone marrow, respectively, four weeks after implantation. Push-in tests suggested that the bonding of the CA coating to Ti is clinically acceptable. Therefore, we conclude that CA coating to Ti by the ASC method would be possible for clinical applications, including dentistry. PMID- 29232916 TI - Stereotactically Standard Areas: Applied Mathematics in the Service of Brain Targeting in Deep Brain Stimulation. AB - The concept of stereotactically standard areas (SSAs) within human brain nuclei belongs to the knowledge of the modern field of stereotactic brain microanatomy. These are areas resisting the individual variability of the nuclear location in stereotactic space. This paper summarizes the current knowledge regarding SSAs. A mathematical formula of SSAs was recently invented, allowing for their robust, reproducible, and accurate application to laboratory studies and clinical practice. Thus, SSAs open new doors for the application of stereotactic microanatomy to highly accurate brain targeting, which is mainly useful for minimally invasive neurosurgical procedures, such as deep brain stimulation. PMID- 29232915 TI - Histologic Grade Is Predictive of Incidence of Epidermal Growth Factor Receptor Mutations in Metastatic Lung Adenocarcinoma. AB - Activating epidermal growth factor receptor (EGFR) mutations in metastatic non small cell lung cancer (NSCLC) are associated with a high response rate to EGFR tyrosine kinase inhibitor (TKI). The current guidelines recommend routine EGFR mutational analysis prior to initiating first line systemic therapy. The clinical characteristics including smoking status, histologic type, sex and ethnicity are known to be associated with the incidence of EGFR mutations. We retrospectively analyzed 277 patients with metastatic NSCLC within Kaiser Permanente Northern California (KPNC); among these patients, 83 were positive for EGFR mutations. We performed both univariate and multivariable logistic regressions to identify predictors of EGFR mutations. We found that histologic grade was significantly associated with the incidence of EGFR mutation, regardless of ethnicity, sex and smoking status. In grade I (well differentiated) and II (moderately differentiated), histology was associated with significantly higher incidence of EGFR mutations compared to grade II-III (moderate-to-poorly differentiated) and III (poorly differentiated). Ever-smokers with grade III lung adenocarcinoma had 1.8% incidence of EGFR mutations. This study indicates that histologic grade is a predictive factor for the incidence of EGFR mutations and suggests that for patients with grade II-III or III lung adenocarcinoma, prompt initiation of first line chemotherapy or immunotherapy is appropriate while awaiting results of EGFR mutational analysis, particularly for patients with history of smoking. PMID- 29232917 TI - Lactobacillus plantarum with Broad Antifungal Activity as a Protective Starter Culture for Bread Production. AB - Bread is a staple food consumed worldwide on a daily basis. Fungal contamination of bread is a critical concern for producers since it is related to important economic losses and safety hazards due to the negative impact of sensorial quality and to the potential occurrence of mycotoxins. In this work, Lactobacillus plantarum UFG 121, a strain with characterized broad antifungal activity, was analyzed as a potential protective culture for bread production. Six different molds belonging to Aspergillus spp., Penicillium spp., and Fusarium culmorum were used to artificially contaminate bread produced with two experimental modes: (i) inoculation of the dough with a commercial Saccharomyces cerevisiae strain (control) and (ii) co-inoculation of the dough with the commercial S. cerevisiae strain and with L. plantarum UFG 121. L. plantarum strain completely inhibited the growth of F. culmorum after one week of storage. The lactic acid bacterium modulated the mold growth in samples contaminated with Aspergillus flavus, Penicillium chrysogenum, and Penicillium expansum, while no antagonistic effect was found against Aspergillus niger and Penicillium roqueforti. These results indicate the potential of L. plantarum UFG 121 as a biocontrol agent in bread production and suggest a species- or strain-depending sensitivity of the molds to the same microbial-based control strategy. PMID- 29232918 TI - Population-Specific Associations of Deleterious Rare Variants in Coding Region of P2RY1-P2RY12 Purinergic Receptor Genes in Large-Vessel Ischemic Stroke Patients. AB - The contribution of low-frequency and damaging genetic variants associated with platelet function to ischemic stroke (IS) susceptibility remains unknown. We employed a deep re-sequencing approach in Polish patients in order to investigate the contribution of rare variants (minor allele frequency, MAF < 1%) to the IS genetic susceptibility in this population. The genes selected for re-sequencing consisted of 26 genes coding for proteins associated with the surface membrane of platelets. Targeted pooled re-sequencing (Illumina HiSeq 2500) was performed on genomic DNA of 500 cases (patients with history of clinically proven diagnosis of large-vessel IS) and 500 controls. After quality control and prioritization based on allele frequency and damaging probability, follow-up individual genotyping of deleterious rare variants was performed in patients from the original cohort. Gene-based analyses identified an association between IS and 6 rare functional and damaging variants in the purinergic genes (P2RY1 and P2RY12 locus). The predicted properties of the most damaging rare variants in P2RY1 and P2RY12 were confirmed by using mouse fibroblast cell cultures transfected with plasmid constructs containing cDNA of mutated variants (FLIPR on FlexStation3). This study identified a putative role for rare variants in P2RY1 and P2RY12 genes involved in platelet reactivity on large-vessel IS susceptibility in a Polish population. PMID- 29232919 TI - The Food Contaminants Nivalenol and Deoxynivalenol Induce Inflammation in Intestinal Epithelial Cells by Regulating Reactive Oxygen Species Release. AB - Fusarium mycotoxins are fungal metabolites whose ability to affect cereal grains as multi-contaminants is progressively increasing. The trichothecene mycotoxins nivalenol (NIV) and deoxynivalenol (DON) are often found in almost all agricultural commodities worldwide. They are able to affect animal and human health, including at the intestinal level. In this study, NIV, both alone and in combination with DON, induced inflammation and increased the inflammatory response induced by lipopolysaccharide (LPS) plus Interferon-gamma (IFN) in the non-tumorigenic intestinal epithelial cell line (IEC-6). The inflammatory response induced by NIV and DON involves tumor necrosis factor-alpha (TNF-alpha) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, nitrotyrosine formation, reactive oxygen species (ROS) release, Nuclear Factor-kappaB (NF-kappaB), Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inflammasome activation. The pro-inflammatory effect was strongly induced by NIV and by the mycotoxin mixture, when compared to DON alone. Mechanistic studies indicate a pivotal role for ROS in the observed pro inflammatory effects induced by mycotoxins. In this study, the interactions between NIV and DON point out the importance of their food co-contamination, further highlighting the risk assessment process that is of growing concern. PMID- 29232920 TI - Genetic Dissection of Leaf Senescence in Rice. AB - Leaf senescence, the final stage of leaf development, is a complex and highly regulated process that involves a series of coordinated actions at the cellular, tissue, organ, and organism levels under the control of a highly regulated genetic program. In the last decade, the use of mutants with different levels of leaf senescence phenotypes has led to the cloning and functional characterizations of a few genes, which has greatly improved the understanding of genetic mechanisms underlying leaf senescence. In this review, we summarize the recent achievements in the genetic mechanisms in rice leaf senescence. PMID- 29232921 TI - The Importance of the Circadian Clock in Regulating Plant Metabolism. AB - Carbohydrates are the primary energy source for plant development. Plants synthesize sucrose in source organs and transport them to sink organs during plant growth. This metabolism is sensitive to environmental changes in light quantity, quality, and photoperiod. In the daytime, the synthesis of sucrose and starch accumulates, and starch is degraded at nighttime. The circadian clock genes provide plants with information on the daily environmental changes and directly control many developmental processes, which are related to the path of primary metabolites throughout the life cycle. The circadian clock mechanism and processes of metabolism controlled by the circadian rhythm were studied in the model plant Arabidopsis and in the crops potato and rice. However, the translation of molecular mechanisms obtained from studies of model plants to crop plants is still difficult. Crop plants have specific organs such as edible seed and tuber that increase the size or accumulate valuable metabolites by harvestable metabolic components. Human consumers are interested in the regulation and promotion of these agriculturally significant crops. Circadian clock manipulation may suggest various strategies for the increased productivity of food crops through using environmental signal or overcoming environmental stress. PMID- 29232922 TI - Study on the Correlation between Gene Expression and Enzyme Activity of Seven Key Enzymes and Ginsenoside Content in Ginseng in Over Time in Ji'an, China. AB - Panax ginseng is a traditional medicine. Fresh ginseng is one of the most important industries related to ginseng development, and fresh ginseng of varying ages has different medicinal properties. Previous research has not systematically reported the correlation between changes in key enzyme activity with changes in ginsenoside content in fresh ginseng over time. In this study, for the first time, we use ginseng samples of varying ages in Ji'an and systematically reported the changes in the activity of seven key enzymes (HMGR, FPS, SS, SE, DS, CYP450, and GT). We investigated the content of ginsenoside and gene expression of these key enzymes. Ginsenoside content was measured using HPLC. HPLC, GC-MS, and LC-MS were combined to measure the enzyme activity of the key enzymes. Quantitative PCR was used in the investigation of gene expression. By analyzing the correlation between the enzyme activity and the transcription level of the key enzymes with ginsenoside content, we found that DS and GT enzyme activities are significantly correlated with the ginsenoside content in different ages of ginseng. Our findings might provide a new strategy to discriminate between ginseng of different years. Meanwhile, this research provides important information for the in-depth study of ginsenoside biosynthesis. PMID- 29232924 TI - Ferrocene and Transition Metal Bis(Dicarbollides) as Platform for Design of Rotatory Molecular Switches. AB - Design of rotatory molecular switches based on extremely stable sandwich organometallic complexes ferrocene and bis(dicarbollide) complexes of transition metals is reviewed. The "on"-"off" switching in these systems can be controlled by various external stimuli such as change of the solution pH, interactions with coordinating species or redox reactions involving the central atom or substituents in the ligands. PMID- 29232923 TI - An Oldie but Goodie: Lithium in the Treatment of Bipolar Disorder through Neuroprotective and Neurotrophic Mechanisms. AB - Lithium has been used for the treatment of bipolar disorder (BD) for the last sixty or more years, and recent studies with more reliable designs and updated guidelines have recommended lithium to be the treatment of choice for acute manic, mixed and depressive episodes of BD, along with long-term prophylaxis. Lithium's specific mechanism of action in mood regulation is progressively being clarified, such as the direct inhibition on glycogen synthase kinase 3beta, and its various effects on neurotrophic factors, neurotransmitters, oxidative metabolism, apoptosis, second messenger systems, and biological systems are also being revealed. Furthermore, lithium has been proposed to exert its treatment effects through mechanisms associated with neuronal plasticity. In this review, we have overviewed the clinical aspects of lithium use for BD, and have focused on the neuroprotective and neurotrophic effects of lithium. PMID- 29232925 TI - Deep Sea Water Improves Abnormalities in Lipid Metabolism through Lipolysis and Fatty Acid Oxidation in High-Fat Diet-Induced Obese Rats. AB - Deep sea water (DSW) is a natural marine resource that has been utilized for food, agriculture, cosmetics, and medicine. The aim of this study was to investigate whether DSW has beneficial lipid metabolic effects in an animal model. Our previous in vitro study indicated that DSW significantly decreased the intracellular triglyceride and glycerol-3-phosphate dehydrogenase activity in 3T3 L1 adipocytes. DSW also inhibited the gene levels of adipocyte differentiation, lipogenesis, and adipocytokines, and up-regulated gene levels of lipolysis and fatty acid oxidation. In the present study, the results showed that body weight, liver, adipose tissue, hepatic triglycerides and cholesterol, and serum parameters in the high-fat diet (HFD) + DSW groups were significantly lower compared to the HFD group. Moreover, the fecal output of total lipids, triglycerides, and cholesterol in the HFD + DSW groups was significantly higher than that of the HFD group. Regarding gene expression, DSW significantly increased the gene levels of lipolysis and fatty acid oxidation, and decreased the gene levels of adipocytokine in the adipose tissue of rats with HFD-induced obesity. These results indicate a potential molecular mechanism by which DSW can suppress obesity in rats with HFD-induced obesity through lipolysis and fatty acid oxidation. PMID- 29232927 TI - Lutein Esterification in Wheat Flour Increases the Carotenoid Retention and Is Induced by Storage Temperatures. AB - The present study aimed to evaluate the effects of long-term storage on the carotenoid pigments present in whole-grain flours prepared from durum wheat and tritordeum. As expected, higher storage temperatures showed a catabolic effect, which was very marked for free carotenoid pigments. Surprisingly, for both cereal genotypes, the thermal conditions favoured the synthesis of lutein esters, leading to an enhanced stability, slower degradation, and, subsequently, a greater carotenoid retention. The putative involvement of lipase enzymes in lutein esterification in flours is discussed, particularly regarding the preferential esterification of the hydroxyl group with linoleic acid at the 3' in the epsilon-ring of the lutein molecule. The negative effects of processing on carotenoid retention were less pronounced in durum wheat flours, which could be due to an increased esterifying activity (the de novo formation of diesterified xanthophylls was observed). Moreover, clear differences were observed for tritordeum depending on whether the lutein was in a free or esterified state. For instance, lutein-3'-O-monolinoleate showed a three-fold lower degradation rate than free lutein at 37 degrees C. In view of our results, we advise that the biofortification research aimed at increasing the carotenoid contents in cereals should be based on the selection of varieties with an enhanced content of esterified xanthophylls. PMID- 29232926 TI - Differential Effects of sEH Inhibitors on the Proliferation and Migration of Vascular Smooth Muscle Cells. AB - Epoxyeicosatrienoic acid (EET) is a cardioprotective metabolite of arachidonic acid. It is known that soluble epoxide hydrolase (sEH) is involved in the metabolic degradation of EET. The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in the pathogenesis of atherosclerosis and restenosis. Thus, the present study investigated the effects of the sEH inhibitor 12-(((tricyclo(3.3.1.13,7)dec-1-ylamino)carbonyl)amino) dodecanoic acid (AUDA) on platelet-derived growth factor (PDGF)-induced proliferation and migration in rat VSMCs. AUDA significantly inhibited PDGF induced rat VSMC proliferation, which coincided with Pin1 suppression and heme oxygenase-1 (HO-1) upregulation. However, exogenous 8,9-EET, 11,12-EET, and 14,15 EET treatments did not alter Pin1 or HO-1 levels and had little effect on the proliferation of rat VSMCs. On the other hand, AUDA enhanced the PDGF-stimulated cell migration of rat VSMCs. Furthermore, AUDA-induced activation of cyclooxygenase-2 (COX-2) and subsequent thromboxane A2 (TXA2) production were required for the enhanced migration. Additionally, EETs increased COX-2 expression but inhibited the migration of rat VSMCs. In conclusion, the present study showed that AUDA exerted differential effects on the proliferation and migration of PDGF-stimulated rat VSMCs and that these results may not depend on EET stabilization. PMID- 29232928 TI - Beverage Consumption Patterns among Overweight and Obese African American Women. AB - The goal of this research was to assess patterns of beverage consumption and the contribution of total beverages and classes of beverages to overall energy intake and weight status. We conducted an analysis in a community-based study of 280 low income overweight and obese African American women residing in the rural South. Participants provided baseline data including demographic characteristics, weight and two 24-h food and beverage dietary recalls. Mean energy intake from beverages was approximately 273 +/- 192 kcal/day or 18.3% of total energy intake. The most commonly reported beverage was plain water, consumed by 88.2% of participants, followed closely by sweetened beverages (soft drinks, fruit drinks, sweetened teas, sweetened coffees and sweetened/flavored waters) consumed by 78.9% of participants. In multiple regression analyses total energy and percent energy from beverages and specific categories of beverages were not significantly associated with current body mass index (BMI). It is widely accepted that negative energy balance may lead to future weight loss. Thus, reducing consumption of beverages that contribute energy but not important nutrients (e.g., sugar sweetened beverages) could be an effective strategy for promoting future weight loss in this population. PMID- 29232929 TI - Refractive Index Sensor Based on a Metal-Insulator-Metal Waveguide Coupled with a Symmetric Structure. AB - In this study, a new refractive index sensor based on a metal-insulator-metal waveguide coupled with a notched ring resonator and stub is designed. The finite element method is used to study the propagation characteristics of the sensor. According to the calculation results, the transmission spectrum exhibits a typical Fano resonance shape. The phenomenon of Fano resonance is caused by the coupling between the broadband spectrum and narrowband spectrum. In the design, the broadband spectrum signal is generated by the stub, while the narrowband spectrum signal is generated by the notched ring resonator. In addition, the structural parameters of the resonators and the structure filled with media of different refractive indices are varied to study the sensing properties. The maximum achieved sensitivity of the sensor reached 1071.4 nm/RIU. The results reveal potential applications of the coupled system in the field of sensors. PMID- 29232930 TI - Effects of Bacterial Fermentation on the Biochemical Constituents and Antioxidant Potential of Fermented and Unfermented Soybeans Using Probiotic Bacillus subtilis (KCTC 13241). AB - Fermented soybeans, cheonggukjang (CKJ), are considered to be more wholesome than soybeans in Korea. To select the best soybean cultivar for making functional CKJ, a comparison was made between the biological activities of four soybean cultivars in their unfermented soybean (UFS) and CKJ states. Changes in 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical-scavenging activity, 2,2'-azino-bis (3 ethylbenzothiazoline-6-sulphonic acid) (ABTS) assays, superoxide dismutase (SOD) like activity, total phenolic compounds, total amino acids, and isoflavones were investigated. The levels of DPPH, ABTS, SOD-like activity, and total phenolic compounds increased in CKJ among all cultivars. The isoflavone aglycone and total amino acids showed the highest amount in CKJ prepared from soybean cultivar Aga 3. These results suggest that the improved antioxidant activity of CKJ in all cultivars might occur because of the higher levels of aglycones and total phenolic compounds achieved during fermentation. Moreover, CKJ prepared from soybean cultivar Aga 3 showed higher antioxidant activity than the other cultivars and so can be considered for the commercial production of functional foods in the future. PMID- 29232932 TI - Adjuvant Probiotics and the Intestinal Microbiome: Enhancing Vaccines and Immunotherapy Outcomes. AB - Immune defence against pathogenic agents comprises the basic premise for the administration of vaccines. Vaccinations have hence prevented millions of infectious illnesses, hospitalizations and mortality. Acquired immunity comprises antibody and cell mediated responses and is characterized by its specificity and memory. Along a similar congruent yet diverse mode of disease prevention, the human host has negotiated from in utero and at birth with the intestinal commensal bacterial cohort to maintain local homeostasis in order to achieve immunological tolerance in the new born. The advent of the Human Microbiome Project has redefined an appreciation of the interactions between the host and bacteria in the intestines from one of a collection of toxic waste to one of a symbiotic existence. Probiotics comprise bacterial genera thought to provide a health benefit to the host. The intestinal microbiota has profound effects on local and extra-intestinal end organ physiology. As such, we further posit that the adjuvant administration of dedicated probiotic formulations can encourage the intestinal commensal cohort to beneficially participate in the intestinal microbiome-intestinal epithelia-innate-cell mediated immunity axes and cell mediated cellular immunity with vaccines aimed at preventing infectious diseases whilst conserving immunological tolerance. The strength of evidence for the positive effect of probiotic administration on acquired immune responses has come from various studies with viral and bacterial vaccines. We posit that the introduction early of probiotics may provide significant beneficial immune outcomes in neonates prior to commencing a vaccination schedule or in elderly adults prior to the administration of vaccinations against influenza viruses. PMID- 29232934 TI - Two B-C-O Compounds: Structural, Mechanical Anisotropy and Electronic Properties under Pressure. AB - The structural, stability, mechanical, elastic anisotropy and electronic properties of two ternary light element compounds, B2CO2 and B6C2O5, are systematically investigated. The elastic constants and phonon calculations reveal that B2CO2 and B6C2O5 are both mechanically and dynamically stable at ambient pressure, and they can stably exist to a pressure of 20 GPa. Additionally, it is found that B2CO2 and B6C2O5 are wide-gap semiconductor materials with indirect energy gaps of 5.66 and 5.24 eV, respectively. The hardness calculations using the Lyakhov-Oganov model show that B2CO2 is a potential superhard material. Furthermore, the hardness of B6C2O5 is 29.6 GPa, which is relatively softer and more easily machinable compared to the B2CO2 (41.7 GPa). The elastic anisotropy results show that B6C2O5 exhibits a greater anisotropy in the shear modulus, while B2CO2 exhibits a greater anisotropy in Young's modulus at ambient pressure. PMID- 29232931 TI - Molecular Mechanisms and Management of a Cutaneous Inflammatory Disorder: Psoriasis. AB - Psoriasis is a complex chronic inflammatory cutaneous disorder. To date, robust molecular mechanisms of psoriasis have been reported. Among diverse aberrant immunopathogenetic mechanisms, the current model emphasizes the role of Th1 and the IL-23/Th17 axis, skin-resident immune cells and major signal transduction pathways involved in psoriasis. The multiple genetic risk loci for psoriasis have been rapidly revealed with the advent of a novel technology. Moreover, identifying epigenetic modifications could bridge the gap between genetic and environmental risk factors in psoriasis. This review will provide a better understanding of the pathogenesis of psoriasis by unraveling the complicated interplay among immunological abnormalities, genetic risk foci, epigenetic modification and environmental factors of psoriasis. With advances in molecular biology, diverse new targets are under investigation to manage psoriasis. The recent advances in treatment modalities for psoriasis based on targeted molecules are also discussed. PMID- 29232933 TI - A Split-Luciferase Reporter Recognizing GFP and mCherry Tags to Facilitate Studies of Protein-Protein Interactions. AB - The use of fluorescently-tagged proteins in microscopy has become routine, and anti-GFP (Green fluorescent protein) affinity matrices are increasingly used in proteomics protocols. However, some protein-protein interactions assays, such as protein complementation assays (PCA), require recloning of each protein as a fusion with the different parts of the complementation system. Here we describe a generic system where the complementation is separated from the proteins and can be directly used with fluorescently-tagged proteins. By using nanobodies and performing tests in cell-free expression systems, we accelerated the development of multiple reporters, detecting heterodimers and homodimers or oligomers tagged with GFP or mCherry. We demonstrate that the system can detect interactions at a broad range of concentrations, from low nanomolar up to micromolar. PMID- 29232935 TI - Extraction Optimization of Flavonoids from Hypericum formosanum and Matrix Metalloproteinase-1 Inhibitory Activity. AB - Hypericum formosanum is a valuable herb in Taiwan. In this study, response surface methodology was employed to optimize the ultrasound-assisted extraction of flavonoids from Hypericum formosanum. A central composite design with three variables (ethanol concentration, extraction time, and extraction temperature) was applied. Experimental results were fitted to the second order polynomial model and one-way analysis of variance was used to determine the goodness of fit of the model and the optimal conditions for responses. The optimal conditions for the maximum extraction yield of total flavonoid content (101.1 mg/g) using ultrasound-assisted extraction were ethanol concentration, 73.5%; extraction time, 38.3 min; and extraction temperature, 62.5 degrees C. The predicted result was consistent with the experimental result obtained under optimal extraction conditions. Hyperoside, astilbin, quercitrin, and quercetin from Hypericum formosanum extract (HFE) were identified by Ultra performance liquid chromatography-diode array detector-mass (UPLC-DAD-MS). HFE significantly reduced matrix metalloproteinase-1 protein expression in human skin keratinocyte cells, induced by advanced glycation end products. PMID- 29232936 TI - Food (In)Security in Rapidly Urbanising, Low-Income Contexts. AB - Urbanisation in low and middle-income nations presents both opportunities and immense challenges. As urban centres grow rapidly, inadequate housing and the lack of basic infrastructure and services affect a large and growing proportion of their population. There is also a growing body of evidence on urban poverty and its links with environmental hazards. There is, however, limited knowledge of how these challenges affect the ways in which poor urban residents gain access to food and secure healthy and nutritious diets. With some important exceptions, current discussions on food security continue to focus on production, with limited attention to consumption. Moreover, urban consumers are typically treated as a homogenous group and access to food markets is assumed to be sufficient. This paper describes how, for the urban poor in low and middle-income countries, food affordability and utilisation are shaped by the income and non-income dimensions of poverty that include the urban space. PMID- 29232937 TI - Modular Bayesian Networks with Low-Power Wearable Sensors for Recognizing Eating Activities. AB - Recently, recognizing a user's daily activity using a smartphone and wearable sensors has become a popular issue. However, in contrast with the ideal definition of an experiment, there could be numerous complex activities in real life with respect to its various background and contexts: time, space, age, culture, and so on. Recognizing these complex activities with limited low-power sensors, considering the power and memory constraints of the wearable environment and the user's obtrusiveness at once is not an easy problem, although it is very crucial for the activity recognizer to be practically useful. In this paper, we recognize activity of eating, which is one of the most typical examples of a complex activity, using only daily low-power mobile and wearable sensors. To organize the related contexts systemically, we have constructed the context model based on activity theory and the "Five W's", and propose a Bayesian network with 88 nodes to predict uncertain contexts probabilistically. The structure of the proposed Bayesian network is designed by a modular and tree-structured approach to reduce the time complexity and increase the scalability. To evaluate the proposed method, we collected the data with 10 different activities from 25 volunteers of various ages, occupations, and jobs, and have obtained 79.71% accuracy, which outperforms other conventional classifiers by 7.54-14.4%. Analyses of the results showed that our probabilistic approach could also give approximate results even when one of contexts or sensor values has a very heterogeneous pattern or is missing. PMID- 29232938 TI - Factors associated with time to diagnosis from symptom onset in patients with early rheumatoid arthritis. AB - Background/Aims: To identify the factors associated with time to diagnosis after symptom onset in patients with early rheumatoid arthritis (RA). Methods: Early RA patients with <= 1 year of disease duration in the KORean Observational study Network for Arthritis (KORONA) database were included in this analysis. Patients were further divided into two groups according to the time to diagnosis from symptom onset: the early diagnosis group (time to diagnosis <= 1 year) and the late diagnosis group (time to diagnosis > 1 year). Using the multivariable regression model, we identified factors associated with early diagnosis. Results: Among 714 early RA patients, 401 patients (56.2%) and 313 patients (43.8%) were included in the early diagnosis and late diagnosis groups, respectively. The mean disease duration was 0.47 years in the early diagnosis group and 0.45 years in the late diagnosis group. In multivariable model analysis, greater age at onset (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.02 to 1.05), high school education or higher (OR, 1.68; 95% CI, 1.14 to 2.47), higher income (OR, 1.48; 95% CI, 1.05 to 2.08), and initial small joint involvement (OR, 1.42; 95% CI, 1.02 to 1.98) were factors associated with early diagnosis. At diagnosis, disease activity scores using 28 joints on diagnosis (3.81 +/- 1.44 vs. 3.82 +/- 1.42, p = 0.92) and functional disability (0.65 +/- 0.61 vs. 0.57 +/- 0.62, p = 0.07) did not different between the two groups. However, hand joint erosion on X-ray (37.8% vs. 25.6%, p < 0.01) was more common in the late diagnosis group than the early diagnosis group. Conclusions: Older onset age, higher educational level and income, and initial small joint involvement were positive factors for early diagnosis of RA. PMID- 29232939 TI - Clinical and economic analysis of the 2009 H1N1 influenza pandemic among pregnant Korean women. AB - Background/Aims: Unlike Western countries, the 2009 pandemic influenza infection among pregnant women was reported as mild in a previous interim study in South Korea. However, several mortalities were reported thereafter, suggesting that nationwide data were lacking. Methods: This case-control study covers the entire 2009 pandemic inf luenza period, from May 2009 to February 2010. The clinical and economic data of pregnant (case) and age-matched non-pregnant (control) women with influenza A (H1N1) pdm09 virus (H1N1pdm09) infection were retrospectively collected from nine hospitals in South Korea. Results: A total of 130 pregnant women with H1N1pdm09 infection were identified. The mean age of the pregnant women was 31.1 years (range, 19 to 41) and mean gestational age was 18.4 weeks (range, 3 to 40). Both case and control groups were similar in terms of age (p = 0.43) and comorbidities (p = 0.18). The overall rate of complications was comparable between the two groups (p = 0.648). However, mortality was reported only among the cases, so mean economic per capita burden is estimated to be higher for pregnant women compared to the control (4,821,992 Korean won [KRW] vs. 351,233 KRW, p = 0.31). Obstetric complications were observed in 12 cases, including preterm labor (n = 7), low birth-weight (n = 3), miscarriage (n = 1), stillbirth (n = 1), and cleft lip (n = 1). Conclusions: Although statistically insignificant, the detrimental impact of influenza A H1N1pdm09 on pregnancy can be serious in some complicated cases in South Korea. Thus, the strong recommendation of influenza vaccination should be maintained for pregnant women as a high priority. PMID- 29232941 TI - Korean rheumatology workforce from 1992 to 2015: current status and future demand. AB - Background/Aims: Rheumatology in Korea has rapidly advanced in the 24 years since the subspecialty board certification program was established in 1992. The objective of this investigation was to analyze the distribution of rheumatology practices in Korea in order to better understand the rheumatology workforce. Methods: Using a membership list from the Korean College of Rheumatology (KCR), we obtained information on practicing rheumatologists. We mapped the ratio of rheumatologists to the general population and to patients with rheumatologic disease using data from Statistics Korea and the 2015 Health Insurance Review & Assessment Service (HIRA). Results: In the 16 administrative districts of Korea in 2015, there were 311 practicing rheumatologists on the list of KCR members. There were 218 members practicing in metropolitan areas and 93 members in the provinces. The mean number of rheumatologists per 100,000 people was 0.60, with 0.33/100,000 in the provinces, but 0.92/100,000 in metropolitan areas, a 2.7-fold difference. The number of rheumatologists per 100,000 patients with chronic rheumatic disease was 17.21 in metropolitan areas but 6.57 in the provinces, according to 2015 HIRA data. This geographic maldistribution emerged as a problem; indeed, the regional disparity in the distribution of Korean rheumatologists was striking when compared to the published medical professional distribution in 2014. Conclusions: Because of the uneven distribution of rheumatologists, it is likely that some patients with chronic rheumatic conditions have limited access to rheumatology care. Thus, a policy-based approach is needed to alleviate this disparity. PMID- 29232940 TI - No benefit of hypomethylating agents compared to supportive care for higher risk myelodysplastic syndrome. AB - BACKGROUND/AIMS: This study evaluated the role of hypomethylating agents (HMA) compared to best supportive care (BSC) for patients with high or very-high (H/VH) risk myelodysplastic syndrome (MDS) according to the Revised International Prognostic Scoring System. METHODS: A total of 279 H/VH risk MDS patients registered in the Korean MDS Working Party database were retrospectively analyzed. RESULTS: HMA therapy was administered to 205 patients (73.5%), including 31 patients (11.1%) who then received allogeneic hematopoietic cell transplantation (allo-HCT), while 74 patients (26.5%) received BSC or allo-HCT without HMA. The 3-year overall survival (OS) rates were 53.1% +/- 10.7% for allo HCT with HMA, 75% +/- 21.7% for allo-HCT without HMA, 17.3% +/- 3.6% for HMA, and 20.8% +/- 6.9% for BSC groups (p < 0.001). In the multivariate analysis, only allo-HCT was related with favorable OS (hazard ratio [HR], 0.356; p = 0.002), while very poor cytogenetic risk (HR, 5.696; p = 0.042), age >= 65 years (HR, 1.578; p = 0.022), Eastern Cooperative Oncology Group performance status (ECOG PS) 2 to 4 (HR, 2.837; p < 0.001), and transformation to acute myeloid leukemia (AML) (HR, 1.901; p = 0.001) all had an adverse effect on OS. CONCLUSION: For the H/VH risk group, very poor cytogenetic risk, age >= 65 years, ECOG PS 2 to 4, and AML transformation were poor prognostic factors. HMA showed no benefit in terms of OS when compared to BSC. Allo-HCT was the only factor predicting a favorable long-term outcome. The use of HMA therapy did not seem to have an adverse effect on the transplantation outcomes. However, the conclusion of this study should be carefully interpreted and proven by large scale research in the future. PMID- 29232942 TI - Predictors for the need for endoscopic therapy in patients with presumed acute upper gastrointestinal bleeding. AB - Background/Aims: Selecting patients with an urgent need for endoscopic hemostasis is difficult based only on simple parameters of presumed acute upper gastrointestinal bleeding. This study assessed easily applicable factors to predict cases in need of urgent endoscopic hemostasis due to acute upper gastrointestinal bleeding. Methods: The consecutively included patients were divided into the endoscopic hemostasis and nonendoscopic hemostasis groups. We reviewed the enrolled patients' medical records and analyzed various variables and parameters for acute upper gastrointestinal bleeding outcomes such as demographic factors, comorbidities, symptoms, signs, laboratory findings, rebleeding rate, and mortality to evaluate simple predictive factors for endoscopic treatment. Results: A total of 613 patients were analyzed, including 329 patients in the endoscopic hemostasis and 284 patients in the non-endoscopic hemostasis groups. In the multivariate analysis, a bloody nasogastric lavage (adjusted odds ratio [AOR], 6.786; 95% confidence interval [CI], 3.990 to 11.543; p < 0.0001) and a hemoglobin level less than 8.6 g/dL (AOR, 1.768; 95% CI, 1.028 to 3.039; p = 0.039) were independent predictors for endoscopic hemostasis. Significant differences in the morbidity rates of endoscopic hemostasis were detected between the group with no predictive factors and the group with one or more predictive factors (OR, 2.677; 95% CI, 1.920 to 3.733; p < 0.0001). Conclusions: A bloody nasogastric lavage and hemoglobin < 8.6 g/dL were independent predictors of endoscopic hemostasis in patients with acute upper gastrointestinal bleeding. PMID- 29232944 TI - Band Structure Engineering of Cs2AgBiBr6 Perovskite through Order-Disordered Transition: A First-Principle Study. AB - Cs2AgBiBr6 was proposed as one of the inorganic, stable, and nontoxic replacements of the methylammonium lead halides (CH3NH3PbI3, which is currently considered as one of the most promising light-harvesting material for solar cells). However, the wide indirect band gap of Cs2AgBiBr6 suggests that its application in photovoltaics is limited. Using the first-principle calculation, we show that by controlling the ordering parameter at the mixed sublattice, the band gap of Cs2AgBiBr6 can vary continuously from a wide indirect band gap of 1.93 eV for the fully ordered double-perovskite structure to a small pseudodirect band gap of 0.44 eV for the fully random alloy. Therefore, one can achieve better light absorption simply by controlling the growth temperature and thus the ordering parameters and band gaps. We also show that controlled doping in Cs2AgBiBr6 can change the energy difference between ordered and disordered Cs2AgBiBr6, thus providing further control of the ordering parameters and the band gaps. Our study, therefore, provides a novel approach to carry out band structure engineering in the mixed perovskites for optoelectronic applications. PMID- 29232943 TI - Effect of Helicobacter pylori eradication on the regression of gastric polyps in National Cancer Screening Program. AB - BACKGROUND/AIMS: Western guidelines recommend Helicobacter pylori eradication in H. pylori-associated gastric polyps; however, there is no standard guideline in Korea. The aim of this study is to assess the effect of H. pylori eradication on the regression of gastric hyperplastic polyps in National Cancer Screening Cohort, representative of general population. METHODS: Among participants in National Cancer Screening Program, subjects who had H. pylori positive gastric hyperplastic polyps less than 10 mm and underwent follow-up endoscopy and H. pylori testing were enrolled. The effect of H. pylori eradication on hyperplastic gastric polyps was estimated using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 183 H. pylori infected subjects with hyperplastic polyp at baseline underwent follow-up endoscopy and H. pylori test after mean of 2.2 years. Successful H. pylori eradication markedly induced the disappearance of hyperplastic polyps comparing to non-eradication group (83.7% vs. 34.1%, p = 0.001). Successful eradication increased the possibility of disappearance of hyperplastic polyps (adjusted OR, 5.56; 95% CI, 2.63 to 11.11). Polyp size was inversely related with the disappearance of hyperplastic polyps (adjusted OR, 59; 95% CI, 0.48 to 0.71). CONCLUSIONS: Eradication of H. pylori infection may induce disappearance of gastric hyperplastic polyps in National Cancer Screening Cohort. PMID- 29232945 TI - Ultraviolet-Ray-Induced Sea Cucumber (Stichopus japonicus) Melting Is Mediated by the Caspase-Dependent Mitochondrial Apoptotic Pathway. AB - Sea cucumber body-wall melting occurs under certain circumstances. We have shown that apoptosis but not autolysis plays a critical role in the initial stage. However, it is still unclear how apoptosis is triggered in this process. In this study, we examined the levels of reactive oxygen species (ROS), the levels of B cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax) proteins, the depolarization of mitochondrial transmembrane potentials, and cytochrome c (Cyt c) release during sea cucumber melting induced by ultraviolet (UV) exposure. We also investigated the contribution of caspase in this process by injecting a pan caspase inhibitor. Our data showed that UV exposure stimulates ROS production, dysfunction of mitochondria, and the release of Cyt c in sea cucumber coelomic fluid cells and body walls. We found a decrease of Bcl-2 and increase of Bax in the mitochondria after UV exposure. We also demonstrated that these changes are associated with elevated caspase-9 and -3 activity. Finally, our data showed that the inhibition of caspases-9 and -3 using an inhibitor suppresses UV-induced sea cucumber melting. These results suggest that apoptosis during sea cucumber melting is mediated by mitochondrial dysfunction and follows the activation of the caspase-signaling pathway. This study presents a novel insight into the mechanism of sea cucumber melting. PMID- 29232946 TI - Huntingtin Polyglutamine-Dependent Protein Aggregation in Reconstituted Cells. AB - One of the aims of synthetic biology is bottom-up construction of reconstituted human cells for medical uses. To that end, we generated giant unilamellar vesicles (GUVs) that contained a HeLa cell extract, which comprises a cell-free protein synthesis (CFPS) system. Then we expressed Huntingtin protein fragments that contained polyglutamine (polyQ) sequences (Htt-polyQ), a hallmark of Huntington's disease. That system produced polyQ-dependent protein aggregates, as previously demonstrated in living cells. We next simplified the system by generating GUVs that contained purified human factors, which reconstituted a CFPS system. Htt-polyQ fragments expressed in these GUVs also formed protein aggregates. Moreover, an N-terminal deletion mutant, which had failed to form protein aggregates in living cells, also failed to form protein aggregates in the reconstituted GUVs. Thus, the GUV systems that encapsulated a human CFPS system could serve as reconstituted cells for studying neurological diseases. PMID- 29232947 TI - Spin Control Induced by Molecular Charging in a Transport Junction. AB - The ability of molecules to maintain magnetic multistability in nanoscale junctions will determine their role in downsizing spintronic devices. While spin injection from ferromagnetic leads gives rise to magnetoresistance in metallic nanocontacts, nonmagnetic leads probing the magnetic states of the junction itself have been considered as an alternative. Extending this experimental approach to molecular junctions, which are sensitive to chemical parameters, we demonstrate that the electron affinity of a molecule decisively influences its spin transport. We use a scanning tunneling microscope to trap a meso-substituted iron porphyrin, putting the iron center in an environment that provides control of its charge and spin states. A large electron affinity of peripheral ligands is shown to enable switching of the molecular S = 1 ground state found at low electron density to S = 1/2 at high density, while lower affinity keeps the molecule inactive to spin-state transition. These results pave the way for spin control using chemical design and electrical means. PMID- 29232948 TI - Realizing Large-Area Arrays of Semiconducting Fullerene Nanostructures with Direct Laser Interference Patterning. AB - We present a laser interference patterning method for the facile fabrication of large-area and high-contrast arrays of semiconducting fullerene nanostructures, which does not rely on a tedious application of sacrificial photoresists or photomasks. A solution-deposited phenyl-C61-butyric acid methyl ester (PCBM) fullerene thin film is exposed to a spatially modulated illumination intensity, as realized by a two-beam laser interference. The PCBM molecules exposed to strong intensity are photochemically transformed into a low-solubility dimeric state, so that the nontransformed PCBM molecules can be selectively removed in a subsequent solution-based development step. Following brief exposure to green laser light (lambda = 532 nm, t = 5 s, p = 0.17 W cm-2) in the designed two-beam interference setup, and a 1 min development in a tuned acetone-chloroform solution, we realize well-defined and ordered PCBM nanostripe patterns with a fwhm line width of ~200 nm and a repetition rate of ~2.900 lines mm-1 over a large area of 1 cm2. We demonstrate that a desired high contrast is effectuated because the initial PCBM-dimer transformation rate is dependent on the square of the illumination intensity. The semiconducting functionality of the patterned fullerene is verified in a field-effect transistor experiment, where a typical PCBM nanostripe featured an electron mobility of 5.3 * 10-3 cm2 V-1 s-1 and an on/off ratio of 3 * 103. PMID- 29232949 TI - Antioxidative Flavan-3-ol Dimers from the Leaves of Camellia fangchengensis. AB - Camellia fangchengensis Liang et Zhong, belonging to the genus Camellia sect. Thea (Theaceae), is an endemic tea species to the south and southwest areas of Guangxi province, People's Republic of China. Known as a wild tea plant, the leaves have been used for producing green tea or black tea by the local people of its growing area. HPLC and LC-MS analysis showed the leaves contain oligomeric catechins as major phenolic components. Further detailed phytochemical study led to the identification of five flavan-3-ol dimers (1-5) including two new ones, fangchengbisflavans A (1) and B (2) from the leaves of C. fangchengensis, together with six known monomers (6-11) and one glucoside (12), in addition to gallic acid (13). Their structures were determined by extensive spectroscopic analysis. Most of the isolates displayed significant antioxidant activities in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis(3-ethylbenzothiazoline-6 sulfonic acid) (ABTS+) radical scavenging assays. The results suggested that the leaves of C. fangchengensis, rich in flavan-3-ol oligomers and monomers as potent antioxidants, could be a valuable plant resource for the production of tea and natural beverages. PMID- 29232950 TI - Highly Fluorescent Metal-Organic-Framework Nanocomposites for Photonic Applications. AB - Metal-organic frameworks (MOFs) are porous hybrid materials built up from organic ligands coordinated to metal ions or clusters by means of self-assembly strategies. The peculiarity of these materials is the possibility, according to specific synthetic routes, to manipulate both the composition and ligands arrangement in order to control their optical and energy-transport properties. Therefore, optimized MOFs nanocrystals (nano-MOFs) can potentially represent the next generation of luminescent materials with features similar to those of their inorganic predecessors, that is, the colloidal semiconductor quantum dots. The luminescence of fluorescent nano-MOFs is generated through the radiative recombination of ligand molecular excitons. The uniqueness of these nanocrystals is the possibility to pack the ligand chromophores close enough to allow a fast exciton diffusion but sufficiently far from each other preventing the aggregation induced effects of the organic crystals. In particular, the formation of strongly coupled dimers or excimers is avoided, thus preserving the optical features of the isolated molecule. However, nano-MOFs have a very small fluorescence quantum yield (QY). In order to overcome this limitation and achieve highly emitting systems, we analyzed the fluorescence process in blue emitting nano-MOFs and modeled the diffusion and quenching mechanism of photogenerated singlet excitons. Our results demonstrate that the excitons quenching in nano-MOFs is mainly due to the presence of surface-located, nonradiative recombination centers. In analogy with their inorganic counterparts, we found that the passivation of the nano-MOF surfaces is a straightforward method to enhance the emission efficiency. By embedding the nanocrystals in an inert polymeric host, we observed a +200% increment of the fluorescence QY, thus recovering the emission properties of the isolated ligand in solution. PMID- 29232951 TI - On-Surface Route for Producing Planar Nanographenes with Azulene Moieties. AB - Large aromatic carbon nanostructures are cornerstone materials due to their increasingly active role in functional devices, but their synthesis in solution encounters size and shape limitations. New on-surface strategies facilitate the synthesis of large and insoluble planar systems with atomic-scale precision. While dehydrogenation is usually the chemical zipping reaction building up large aromatic carbon structures, mostly benzenoid structures are being produced. Here, we report on a new cyclodehydrogenation reaction transforming a sterically stressed precursor with conjoined cove regions into a planar carbon platform by incorporating azulene moieties in their interior. Submolecular resolution STM is used to characterize this exotic large polycyclic aromatic compound on Au(111) yielding unprecedented insight into a dehydrogenative intramolecular aryl-aryl coupling reaction. The resulting polycyclic aromatic carbon structure shows a [18]annulene core hosting peculiar pore states confined at the carbon cavity. PMID- 29232952 TI - Ethyl Carbamate Formation Regulated by Lactic Acid Bacteria and Nonconventional Yeasts in Solid-State Fermentation of Chinese Moutai-Flavor Liquor. AB - This study aimed to identify specific microorganisms related to the formation of precursors of EC (ethyl carbamate) in the solid-state fermentation of Chinese Moutai-flavor liquor. The EC content was significantly correlated with the urea content during the fermentation process (R2 = 0.772, P < 0.01). Differences in urea production and degradation were found at both species and functional gene levels by metatranscriptomic sequencing and culture-dependent analysis. Lactobacillus spp. could competitively degrade arginine through the arginine deiminase pathway with yeasts, and most Lactobacillus species were capable of degrading urea. Some dominant nonconventional yeasts, such as Pichia, Schizosaccharomyces, and Zygosaccharomyces species, were shown to produce low amounts of urea relative to Saccharomyces cerevisiae. Moreover, unusual urea degradation pathways (urea carboxylase, allophanate hydrolase, and ATP independent urease) were identified. Our results indicate that EC precursor levels in the solid-state fermentation can be controlled using lactic acid bacteria and nonconventional yeasts. PMID- 29232953 TI - Mitochondrial Signs and Subcellular Imaging Provide Insight into the Antifungal Mechanism of Carabrone against Gaeumannomyces graminis var. tritici. AB - Carabrone, a botanical bicyclic sesquiterpenic lactone, has broad-spectrum antifungal activity and is particularly efficient against the devastating phytopathogen Gaeumannomyces graminis var. tritici (Ggt). The antifungal mechanism of carabrone against Ggt, however, remains unclear. The main objective of this study was to investigate the subcellular localization of carabrone in Ggt to gain a better understanding of its mechanism of action. When Ggt was exposed to carabrone (EC50 value of 28.45 MUg/mL) for 7 days, a decline in mitochondrial concentration together with some obvious alternations in mitochondrial structure, including hazy outlines, medullary transitions, excess accumulation of unclear settlings, and vacuolar degeneration, were observed, indicating that carbrone may act on the mitochondria directly. A fluorescent conjugate (TTY) was thus designed and synthesized as a surrogate of carabrone that possessed comparable antifungal activity against Ggt (EC50 of 33.68 MUg/mL). Additionally, a polyclonal antibody specific to carabrone and with a high titer (256 000) was also prepared by immunizing mice. Subsequently, two imaging techniques, the use of the fluorescent conjugate (FC) and immunofluorescence (IF), were applied to determine the subcellular localization of carabrone. Both FC and IF fluorescent signals demonstrated its mitochondrial localization with a Pearson's coefficient of 0.83 for FC and 0.86 for IF. These results imply that carabrone exerts its antifungal activity against Ggt by interfering with mitochondrial function. PMID- 29232954 TI - Efficacy and Safety Profiles of Oral Atorvastatin-Loaded Nanoparticles: Effect of Size Modulation on Biodistribution. AB - Atorvastatin calcium (AC)-loaded nanoparticles (NPs) of mean particle diameter <100 nm and narrow distribution were prepared and characterized. Their in vivo PK as well as PD measures following oral administration in different dosage regimens in hyperlipidemic rats were evaluated. The results revealed that the oral bioavailability of two selected AC-NPs formulations was 235% and 169% relative to Lipitor. However, the treatment regimens were not superior in reducing serum total cholesterol (TC), low-density lipoproteins (LDL), and triglycerides (TG) levels compared to Lipitor. Moreover, the AC-NPs treatments were associated with significant adverse effects observed biochemically and histologically. These results were contradictory with those obtained from a previous study in which similarly formulated AC-NPs of mean particle diameter >200 nm were found to be more safe and effective in reducing TC, LDL, and TG levels when administered to hyperlipiemic rats at reduced dosing frequency compared to daily dose of Lipitor despite their lower oral bioavailability. The discrepant correlation between pharmacokinetics (PK) and pharmacodynamics (PD) results was suggested to pertain to the different biodistribution profiles of AC-NPs depending on their sizes. Hereby, we provide a simple approach of particle size modulation to enhance the efficacy and safety of atorvastatin. PMID- 29232955 TI - DNA-Decorated Two-Dimensional Crystalline Nanosheets. AB - Design and synthesis of high aspect ratio 2D nanosheets with surface having ultradense array of information-rich molecule such as DNA is extremely challenging. Herein, we report a universal strategy based on amphiphilicity driven self-assembly for the crafting of high aspect ratio, 2D sheets that are densely surface-decorated with DNA. Microscopy and X-ray analyses have shown that the sheets are crystalline. The most unique feature of the sheets is DNA-directed surface addressability, which is demonstrated through the decoration of either faces of the sheet with gold nanoparticles through sequence-specific DNA hybridization. Our results suggest that this design strategy can be applied as a general approach for the synthesis of DNA decorated high aspect ratio sheets, which may find potential applications in materials science, drug delivery, and nanoelectronics. PMID- 29232957 TI - Quartz crystal microbalance with dissipation as a biosensing platform to evaluate cell-surface interactions of osteoblast cells. AB - Quartz crystal microbalance with dissipation (QCM-D) is one of the powerful techniques, which allow real time, quantitative and noninvasive analysis of the interaction of different cell types with various modified surfaces. In this study, the dynamic adhesion behavior of human fetal osteoblastic bone (hfOB) cell lines was first monitored on untreated and hydrophilically treated gold sensor surfaces as reference substrates. Adhesion was also observed under light microscopy to facilitate the evaluation. Cells increased their surface contact area and spread more on hydrophilic surfaces, and showed distinct profile with an increased rigidity at the interfacial layer, which is assigned to extracellular matrix remodeling. Further, the adhesion strength and kinetics were characterized on cell adhesive (poly-l-lysine and fibronectin) and repellent (bovine serum albumin) surfaces. The overall results indicated that protein-mediated specific interactions contributed mostly to the dissipation changes (DeltaD) or acoustic ratio (DeltaD/Deltaf). Finally, the potential of QCM-D to distinguish healthy and cancerous cells were evaluated by comparing the results of hfOB cells with that of SaOS-2 (osteosarcoma) cancerous cells. Cancerous cells interacted more strongly and showed more viscoelastic characteristic than the healthy cells. PMID- 29232958 TI - ARCHITECT HIV Combo Ag/Ab and RealTime HIV-1 Assays Detect Diverse HIV Strains in Clinical Specimens. AB - Periodic evaluation of the impact of viral diversity on diagnostic tests is critical to ensure current technologies are keeping pace with viral evolution. To determine whether HIV diversity impacts the ARCHITECT HIV Combo Ag/Ab (HIV Combo) or RealTime HIV-1 (RT) assays, a set of N = 199 HIV clinical specimens from Cameroon, Senegal, Saudi Arabia, and Thailand were sequenced and tested in both assays. The panel included historical groups N and P specimens and a newly identified group N specimen. These and specimens classified as H, U (unclassified)/URF (unique recombinant form), CRF (circulating recombinant form) 01, 02, 06, 09, 11, 13, 18, 22, 37, and 43 were detected by both the RT assay (1.75-6.84 log copies/ml) and the HIV Combo assay (3.26-1121.96 sample to cutoff ratios). Sequence alignment identified 3 or fewer mismatches to the RT assay oligos in 82.4% of samples. Altogether, these data demonstrate the HIV Combo and RT assays detect diverse strains of HIV in clinical specimens. PMID- 29232959 TI - Escherichia coli biofilm formation and dispersion under hydrodynamic conditions on metal surfaces. AB - The aim of this study was to analyze the impact of hydrodynamic forces on the multiplication of E. coli, and biofilm formation and dispersion. The experiments were provided in a flow chamber simulating a cleaning-in-place system. Biofilm biomass was measured using a crystal violet dye method. The results show that hydrodynamic forces affect not only biofilm formation and dispersion but the multiplication of E. coli in the first place. We found more biofilm biomass on the rough surface than on the smooth one. The results of the biofilm formation test show that laminar flow promotes the biofilm growth over 72 h, meanwhile turbulent flow after 48 h causes decrease in biomass. The results of the biofilm dispersion test, in contrast, show that laminar flow removed less biofilm from both materials that turbulent flow did. Therefore, taking into account these findings in cleaning-in-place technology can substantially reduce E. coli multiplication and biofilm formation. PMID- 29232960 TI - Ocrelizumab: A New B-cell Therapy for Relapsing Remitting and Primary Progressive Multiple Sclerosis. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of ocrelizumab, a new B-cell-targeted therapy for multiple sclerosis (MS). DATA SOURCES: A comprehensive search of PubMed and OVID/MEDLINE was conducted using search terms ocrelizumab and multiple sclerosis using the date range of 1946 through October 2017. STUDY SELECTION AND DATA EXTRACTION: All English-language, human-subject articles related to ocrelizumab and MS were evaluated. DATA SYNTHESIS: Ocrelizumab was approved in March 2017 for the treatment of relapsing or primary progressive MS (PPMS). A phase II trial established 600 mg intravenously every 6 months as the preferred dosing schedule. Two phase III trials evaluated the efficacy of ocrelizumab in patients with relapsing remitting MS, and individual and pooled analysis demonstrated a significant reduction in annualized relapse rate ( P < 0.001 pooled), disability progression at 12 weeks ( P < 0.001 pooled), and gadolinium-enhancing lesions on magnetic resonance imaging (MRI; P < 0.001). Patients with PPMS were evaluated in a third phase III trial, which showed a significant decrease in disease progression at 12 weeks ( P = 0.03) and volume of T2-weighted lesions on MRI ( P < 0.001). As with other monoclonal antibodies, adverse effects seen with ocrelizumab were primarily infusion-related reactions and infection. CONCLUSIONS: Ocrelizumab demonstrated efficacy in the treatment of relapsing and PPMS and is the first therapy approved for patients with PPMS. PMID- 29232961 TI - Friendships and social participation as markers of quality of life of adolescents and adults with fragile X syndrome and autism. AB - Friendships and social participation are key domains of quality of life for individuals with intellectual disabilities. This study examined the friendships, social and recreational activities, and family social networks of individuals with intellectual disabilities from two distinct diagnostic groups: individuals diagnosed with fragile X syndrome (n = 81) compared with those diagnosed with autistic disorder (n = 226). Within each diagnostic group, individuals in two developmental stages were compared: adolescence and adulthood. Quality of life in friendships and social participation domains was notably low for individuals with fragile X and those with autism. Individuals with fragile X had more friendships and a less negative social impact on the family than individuals with autism. Across both groups, adolescents spent less time with friends and neighbors, and more time in exercising, than did adults. PMID- 29232962 TI - Meaning in hoarding: perspectives of people who hoard on clutter, culture and agency. AB - Hoarding has become increasingly prominent in clinical practice and popular culture in recent years, giving rise to extensive research and commentary. Critical responses in the social sciences have criticised the cultural assumptions built in to the construct of 'hoarding disorder' and expressed fears that it may generate stigma outweighing its benefits; however, few of these studies have engaged directly with 'hoarders' themselves. This paper reports on in-depth, semi-structured interviews with 10 individuals living in England, who received assessment and intervention for hoarding from Social Services. Their narratives drew on the cultural repertoire of values and discourses around waste and worth, the mediation of sociality and relationships through material objects, physical constraints on keeping order and the role played by mental health. Analysing these perspectives anthropologically shows how dominant models of hoarding, such as the DSM-5 paradigm, potentially lend themselves to reductionist understandings that efface the meaning 'hoarding' may have and thereby deny agency to the person labelled as 'hoarder'. More culturally informed analysis, by contrast, affords insights into the complex landscape of value, waste, social critique, emotion, interpersonal relationships and practical difficulties that may underlie hoarding cases, and points the way to more person-centred practice and analysis. PMID- 29232963 TI - Integrative study of cell damage and cancer risk in gas station attendants. AB - Gas station attendants are potentially exposed to carcinogenic substances. This study aimed to evaluate chronic occupational exposed gas station attendant's according to genetic parameters and its relationship with cancer predisposition. Forty gas station attendants were recruited and paired with 40 control subjects. Thousand cells from each subject were analyzed counting the number of pyknotic (PYC), karyolitic (KYL), karyorrhetic (KHC), condensed chromatin (CC), binucleated (BN), basal cells (BC), Nuclear buds (Nbud), and differentiated cells (DIFF). More 2.000 differentiated cells were analyzed counting micronucleated (MNi) and nuclear buds (NBud). We observed a statistical increase in BC and decrease in DIFF (p < 0.05). PYC, CC, KYL, MN, NBud were statistically increased (p < 0.05). All in all, our data showed elevated DNA damage, chromosomal instability, and cell cycle disturbing in our group of gas station attendants. It is a clear risk for their health in future and could be classified as a cancer predisposition. PMID- 29232964 TI - A Randomized Controlled Trial of Family Finding: A Relative Search and Engagement Intervention for Youth Lingering in Foster Care. AB - BACKGROUND: Youth who have experienced foster care are at risk of negative outcomes in adulthood. The family finding model aims to promote more positive outcomes by finding and engaging relatives of children in foster care in order to provide options for legal and emotional permanency. OBJECTIVES: The present study tested whether family finding, as implemented in North Carolina from 2008 through 2011, improved child welfare outcomes for youth at risk of emancipating foster care without permanency. RESEARCH DESIGN: A randomized controlled trial evaluation was carried out in nine counties in North Carolina. All children eligible for intervention services between 2008 and 2011 underwent random assignment. Effects were tested with an intent-to-treat design. Outcome data were obtained for all subjects from child welfare administrative data. Additional outcome data for a subset of older youth came from in-person interviews. SUBJECTS: Subjects included 568 children who were in foster care, were 10-17 years old (at time of referral), had no identified permanent placement resource, and had no plan for reunification. MEASURES: The confirmatory outcome was moves to more family-like placements, whether through a step-down in foster care placement or discharge from foster care to legal permanency. RESULTS: No impact on the confirmatory outcome was observed. Findings regarding exploratory impacts are also described; these must be interpreted with caution, given the large number of outcomes compared. CONCLUSIONS: The evaluation failed to find evidence that family finding improves the outcomes of older youth at risk of emancipation from foster care. PMID- 29232965 TI - Structural and functional changes in the somatosensory cortex in euthymic females with bipolar disorder. AB - OBJECTIVE:: Current evidence from neuroimaging data suggests possible dysfunction of the fronto-striatal-limbic circuits in individuals with bipolar disorder. Somatosensory cortical function has been implicated in emotional recognition, risk-taking and affective responses through sensory modalities. This study investigates anatomy and function of the somatosensory cortex in euthymic bipolar women. METHODS:: In total, 68 right-handed euthymic women (bipolar disorder = 32 and healthy controls = 36) between 16 and 45 years of age underwent high resolution anatomical and functional magnetic resonance imaging during the mid follicular menstrual phase. The somatosensory cortex was used as a seed region for resting-state functional connectivity analysis. Voxel-based morphometry was used to evaluate somatosensory cortical gray matter volume between groups. RESULTS:: We found increased resting-state functional connectivity between the somatosensory cortex and insular cortex, inferior prefrontal gyrus and frontal orbital cortex in euthymic bipolar disorder subjects compared to healthy controls. Voxel-based morphometry analysis showed decreased gray matter in the left somatosensory cortex in the bipolar disorder group. Whole-brain voxel-based morphometry analysis controlled by age did not reveal any additional significant difference between groups. CONCLUSION:: This study is the first to date to evaluate anatomy and function of the somatosensory cortex in a well-characterized sample of euthymic bipolar disorder females. Anatomical and functional changes in the somatosensory cortex in this population might contribute to the pathophysiology of bipolar disorder. PMID- 29232966 TI - Sex differences in the relationship between prolactin levels and impaired processing speed in early psychosis. AB - INTRODUCTION: Hyperprolactinaemia is commonly observed in people with psychotic disorders due to D2 receptor blockade by antipsychotic drugs, although it may also exist in drug-naive patients with first-episode psychosis. Recent studies suggest that hyperprolactinaemia may have a negative impact on cognitive function in people with early psychosis. We aimed to explore whether there are sex differences in the association between prolactin levels and cognitive performance in early psychosis patients. METHODS: We studied 60 young patients with early psychosis (aged 18-35 years, 35% females) and a sex- and age-matched control group of 50 healthy subjects. Cognitive assessment was performed with the MATRICS Consensus Cognitive Battery. Prolactin, total cortisol, follicular-stimulating hormone, luteal hormone and sex steroids (testosterone in men, oestradiol and progesterone in women) were measured in plasma. Salivary cortisol was measured at different sampling times (awakening response, 10:00 and 23:00). Psychopathological status was assessed, and antipsychotic treatment was registered. Multiple linear regression analyses were used to explore the relationship between prolactin and cognitive tasks while adjusting for covariates. RESULTS: Prolactin levels were associated with impaired processing speed in men, and this association was independent of cortisol and testosterone. In women, prolactin levels were not associated with processing speed tasks, although we observed a negative effect of prolactin on verbal learning and spatial working memory in female healthy subjects. The male-dependent effect maintained its significance after adjusting for education status, antipsychotic treatment and negative symptoms. CONCLUSION: Our study demonstrates that the previously reported association between high prolactin levels and impaired cognitive processes in early psychosis is restricted to men. PMID- 29232967 TI - A latent class analysis of psychotic symptoms in the general population. AB - OBJECTIVE: Individuals with psychotic symptoms may actually correspond to various subgroups, characterized by different patterns of psychotic symptoms as well as specific sociodemographic and clinical correlates. We aimed to identify groups of individuals from the general population with specific patterns of psychotic symptoms. METHODS: In a 38,694-subject survey, a latent class analysis was performed to identify subgroups based on the distribution of seven psychotic symptoms taken from the Mini International Neuropsychiatric Interview. The different classes were subsequently compared according to sociodemographic and clinical correlates. RESULTS: The best fit was obtained with a four-class solution, including the following: (1) a class with a low prevalence of all psychotic symptoms ('LOW', 85.9%); (2) a class with a high prevalence of all psychotic symptoms ('HAL + DEL', 1.7%); and classes with a high prevalence of (3) hallucinations ('HAL', 4.5%) or (4) delusions ('DEL', 7.9%). The HAL + DEL class displayed higher rates of history of trauma, social deprivation and migrant status, while the HAL and DEL classes displayed intermediate rates between HAL + DEL and LOW. HAL + DEL displayed the highest rates of psychotic and non-psychotic disorders and the use of mental health treatment, while HAL and DEL displayed intermediate rates of these disorders between HAL + DEL and LOW. In comparison to the HAL class, psychotic and substance use disorders were more frequent in the DEL class, while anxiety and mood disorders were less frequent. CONCLUSION: These findings support the hypothesis of a continuum model relating the level of psychotic symptoms to the level of global psychopathology. PMID- 29232968 TI - Altered cerebellar functional connectivity in remitted bipolar disorder: A resting-state functional magnetic resonance imaging study. AB - OBJECTIVES: Several recent studies have reported a strong association between the cerebellar structural and functional abnormalities and psychiatric disorders. However, there are no studies to investigate possible changes in cerebellar functional connectivity in bipolar disorder. This study aimed to examine the whole-brain functional connectivity pattern of patients with remitted bipolar disorder II, in particular in the cerebellum. METHODS: A total of 25 patients with remitted bipolar disorder II and 25 controls underwent resting-state functional magnetic resonance imaging and neuropsychological tests. Voxel-wise whole-brain connectivity was analyzed using a graph theory approach: functional connectivity strength. A seed-based resting-state functional connectivity analysis was further performed to investigate abnormal functional connectivity pattern of those regions with changed functional connectivity strength. RESULTS: Remitted bipolar disorder II patients had significantly decreased functional connectivity strength in the bilateral posterior lobes of cerebellum (mainly lobules VIIb/VIIIa). The seed-based functional connectivity analyses revealed decreased functional connectivity between the right posterior cerebellum and the default mode network (i.e. right posterior cingulate cortex/precuneus and right superior temporal gyrus), bilateral hippocampus, right putamen, left paracentral lobule and bilateral posterior cerebellum and decreased functional connectivity between the left posterior cerebellum and the right inferior parietal lobule and bilateral posterior cerebellum in patients with remitted bipolar disorder II. CONCLUSION: Our results suggest that cerebellar dysconnectivity, in particular distributed cerebellar-cerebral functional connectivity, might be associated with the pathogenesis of bipolar disorder. PMID- 29232970 TI - Primary Coronary Intervention in Octogenarians and Nonagenarians With ST-Segment Elevation Myocardial Infarction: A Canadian Single-Center Perspective. AB - The proportion of individuals >80 years of age constitute an increasing proportion of patients who present with ST-segment elevation myocardial infarction (STEMI). The objective of this study is to evaluate in-hospital outcomes and 1-year survival of very elderly patients who present with an STEMI and undergo primary percutaneous coronary intervention (pPCI). Between 2009 and 2015, individuals >80 years of age (very elderly patients) with an STEMI presenting at a single tertiary Canadian care center were included in the study. A random sample of 100 individuals aged 65 to 69 years over the same time period were selected as a control group. A total of 284 patients were included in the study population including 100 controls, 164 octogenarians, and 20 nonagenarians. Of total, 1661 pPCIs occurred during this study period with the very elderly population (>80 years) comprising 11.1% of the total pPCIs. Compared with controls, individuals aged >80 are more likely to have a delay in treatment with increased rates of bleeding, acute kidney injury, rehospitalization, and a trend toward longer hospital stays following pPCI for STEMI. Although in-hospital and 1 year mortality were similar between both cohorts >80 years of age with STEMI, their overall survival was reduced compared with controls. PMID- 29232969 TI - PTSD Symptoms Mediate the Relationship Between Sexual Abuse and Substance Use Risk in Juvenile Justice-Involved Youth. AB - Juvenile justice-involved youth face disproportionate rates of sexual abuse, which increases the risk of post-traumatic stress disorder (PTSD) and substance use disorders (SUDs), both of which are associated with poor long-term outcomes. The present study tested two mediation and moderation models, controlling for age, race, and history of physical abuse, with gender as a moderator, to determine whether PTSD symptoms serve as a risk factor and/or mechanism in the relationship between sexual abuse and substance use. Data were examined for 197 juvenile justice-involved youth (mean age = 15.45, 68.9% non-White, 78.4% male) that completed court-ordered psychological assessments. Results indicated that PTSD symptoms significantly mediated the relationship between sexual abuse and drug (beta = 3.44, confidence interval [CI] [0.26, 7.41]; test for indirect effect z = 2.41, p = .02) and alcohol use (beta = 1.42, CI [0.20, 3.46]; test for indirect effect z = 2.23, p = .03). PTSD symptoms and gender were not significant moderators. Overall, PTSD symptoms mediate the relationship between sexual abuse and SUDs in juvenile justice-involved youth, which suggests viability of targeting PTSD symptoms as a modifiable risk factor to reduce the effects of sexual abuse on substance use in this high-risk population. PMID- 29232971 TI - Heart Rate and Blood Pressure: "Connecting the Dots" in Epidemiology and Pathophysiology. AB - There is robust evidence from epidemiological and clinical studies showing that elevated heart rate (HR) constitutes a powerful predictor of morbidity and mortality in patients with hypertension, underlining the significance of HR measurement in them. Autonomous nervous system dysfunction and atherosclerosis are important features in the pathogenesis of the untoward events. However, the relationship between HR and blood pressure (BP) is complex and differs depending on the type of BP measurement which is considered. This differentiation implicates complex physiological mechanisms and is of clinical importance regarding the divergent effect of the different types of antihypertensive agents on these parameters. The aim of this review is to summarize the current evidence on the relationship between HR and BP based on epidemiological, clinical, and experimental studies. PMID- 29232972 TI - Association of Resting Heart Rate With Arterial Stiffness and Low-Grade Inflammation in Women With Systemic Lupus Erythematosus. AB - Resting heart rate (RHR) is associated with arterial stiffness, inflammation, and cardiovascular (CV) and all-cause mortality in the general population and in patients at high CV risk. We assessed the association of RHR with arterial stiffness and low-grade inflammation (LGI) in a cross-sectional study that included 101 women with systemic lupus erythematosus (SLE) without a history of CV disease or arrhythmia or who were under treatment that may cause bradycardia. Pulse wave velocity (PWV; a measure of arterial stiffness), RHR, and markers of LGI (ie, C-reactive protein, fibrinogen, erythrocyte sedimentation rate, insulin, and homeostatic model assessment index) were measured. The patients with the highest RHR (quartile 4; mean RHR = 87.2 bpm) had a PWV 0.61 m/s (95% confidence interval [CI]: 0.08-1.14; P = .024) greater than patients with the lowest RHR (quartile 1; RHR = 63.0 bpm), independent of age, systolic blood pressure, disease activity, smoking, and being physically inactive. Similarly, patients with the highest RHR (quartile 4) showed a significantly less favorable clustered LGI index than patients in quartile 1 ( b = .58; 95% CI: 0.212-0.948; P = .002). Higher RHR is associated with greater arterial stiffness and LGI in women with SLE. Further research to determine the prognostic value of RHR in this population is warranted. PMID- 29232973 TI - Chemical constituents from the fruiting bodies of Phellinus igniarius. AB - A new tirucallane-type triterpenoid igniarine (1), and four known compounds meshimakobnol A (2), meshimakobnol B (3), ergosterol (4) and ergosterol peroxide (5), were purified from the methanol extracts of the fruiting bodies of Phellinus igniarius (DC. ex Fr.) Quel. The structure of 1 was elucidated using a combination of 1D and 2D NMR techniques and HR-ESI-MS analyses. In addition, the isolated compounds were examined for their cytotoxicity against several tumour cell lines and part of the tested compounds demonstrated weak cytotoxicity. PMID- 29232974 TI - Evaluation Influence: The Evaluation Event and Capital Flow in International Development. AB - BACKGROUND: Assessing program effectiveness in human development is central to informing foreign aid policy-making and organizational learning. Foreign aid effectiveness discussions have increasingly given attention to the devaluing effects of aid flow volatility. This study reveals that the external evaluation event influences actor behavior, serving as a volatility-constraining tool. METHOD: A case study of a multidonor aid development mechanism served examining the influence of an evaluation event when considering anticipatory effects. The qualitative component used text and focus group data combined with individual interview data (organizations n = 10, including 26 individuals). Quantitative data included financial information on all 75 capital investments. The integrated theory of influence and model of alternative mechanisms used these components to identify the linkage between the evaluation event and capital flow volatility. RESULTS: Aid approved in the year of the midterm evaluation was disbursed by the mechanism with low capital volatility. Anticipating the evaluation event influenced behavior resulting in an empirical record that program outcomes were enhanced and the mechanism was an improved organization. IMPLICATIONS: Formative evaluations in a development program can trigger activity as an interim process. That activity provides for a more robust assessment of ultimate consequence of interest. Anticipating an evaluation can stimulate donor reality testing. The findings inform and strengthen future research on the influence of anticipating an evaluation. Closely examining activities before, during, and shortly after the evaluation event can aid development of other systematic methods to improve understanding this phenomenon, as well as improve donor effectiveness strategies. PMID- 29232975 TI - Mass spectrometric studies on selective androgen receptor modulators (SARMs) using electron ionization and electrospray ionization/collision-induced dissociation. AB - Selective androgen receptor modulators (SARMs) have been identified as a promising class of drug candidates potentially applicable to diverse pathological conditions commonly associated with significantly reduced muscle mass. Due to a suspected and meanwhile repeatedly proven misuse of SARMs in elite and amateur sport, sustaining constantly updated doping control analytical methods is critical for sports drug testing laboratories. These test methods predominantly utilize mass spectrometry-based instrumentations and, consequently, studies on the mass spectrometric behavior of new compounds and, where available, their metabolic products are vital for comprehensive doping controls. In this communication, the dissociation patterns of three new SARM drug candidates referred to as GSK2881078, PF-06260414, and TFM-4 AS-1 as observed under electron ionization as well as electrospray ionization/collision-induced dissociation are discussed. By means of high resolution/high accuracy tandem mass spectrometry employing quadrupole-orbitrap mass analyzers, information on precursor-product ion relationships and elemental compositions was obtained and subsequently utilized to suggest dissociation routes of the target compounds. This information can contribute to future studies concerning structure assignments of metabolites and accelerate the identification of related substances if distributed and/or illicitly used in the world of sport. PMID- 29232976 TI - Application of MALDI-TOF/TOF-MS for relative quantitation of alpha- and beta-Asp7 isoforms of amyloid-beta peptide. AB - It is known that aspartic acid isomerization process plays a role in aging processes and may be used as a marker for aging of natural materials. As for Alzheimer's disease, the most abundant modification in the peptide profile is the aspartate isomerization of amyloid-beta. Liquid chromatography-electrospray ionization-mass spectrometry/mass spectrometry-based approaches with Collision Induced Dissociation (CID) or Electron Capture Dissociation (ECD) fragmentation provide a good and precise method for the relative quantitation of iso- to normal amyloid-beta peptides but require additional time consuming steps. In this study, MALDI-TOF/TOF-matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MS) method was developed as a high-throughput approach for the relative quantitation of the isomerized form of the amyloid-beta peptide. PMID- 29232977 TI - Two competing ionization processes in ESI-MS analysis of N-(1,3 diphenylallyl)benzenamines: formation of the unusual [M-H]+ ion versus the regular [M+H]+ ion. AB - A series of N-(1,3-diphenylallyl)benzenamine derivatives (M) were investigated by electrospray ionization mass spectrometry in the positive-ion mode. Both the anomalous [M-H]+ and the regular [M+H]+ were observed in the ESI mass spectra. The occurrence of [M-H]+ has been supported by accurate mass spectrometry, liquid chromatography mass spectrometry, and tandem mass spectrometry analysis. Calculation results indicated that formation of [M-H]+ is attributed to the ion molecule reaction of M with the protonated ESI solvent molecule (e.g. CH3OH2+) via hydride abstraction from a tertiary Csp3-H. The competing ionization processes leading to [M-H]+ or [M+H]+ were significantly affected by the concentration of formic acid in the electrospray ionization solvent and the proton affinity of the N atom. PMID- 29232978 TI - Primary health care reform, dilemmatic space and risk of burnout among health workers. AB - Health system changes may increase primary health care workers' dilemmatic space, created when reforms contravene professional values. Dilemmatic space may be a risk factor for burnout. This study partnered with six Australian primary health care services (in South Australia: four state government-managed services including one Aboriginal health team and one non-government organisation and in Northern Territory: one Aboriginal community-controlled service) during a period of change and examined workers' dilemmatic space and incidence of burnout. Dilemmatic space and burnout were assessed in a survey of 130 staff across the six services (58% response rate). Additionally, 63 interviews were conducted with practitioners, managers, regional executives and health department staff. Dilemmatic space occurred across all services and was associated with higher rates of self-reported burnout. Three conditions associated with dilemmatic space were (1) conditions inherent in comprehensive primary health care, (2) stemming from service provision for Aboriginal and Torres Strait Islander peoples and (3) changes wrought by reorientation to selective primary health care in South Australia. Responses to dilemmatic space included ignoring directives or doing work 'under the radar', undertaking alternative work congruent with primary health care values outside of hours, or leaving the organisation. The findings show that comprehensive primary health care was contested and political. Future health reform processes would benefit from considering alignment of changes with staff values to reduce negative effects of the reform and safeguard worker wellbeing. PMID- 29232979 TI - Gendered accounts of managing diabetes in same-sex relationships: A discursive analysis of partner support. AB - The gendered dimensions of partner support in relationships where one partner has a chronic condition has been a recurring focus within the literature on gender and health. Such literature however typically focuses exclusively on heterosexual couples while same-sex relationships are rendered invisible, leading to the discourse around partner support being heteronormative. This article examines gendered dimensions within accounts of lesbian, gay and bisexual people with diabetes using a discursive psychological approach. The analysis identifies how participants drew upon a range of interpretative repertoires, including: (1) notions that women are more caring than men; (2) that men can take control in an emergency; (3) that gay men are caring; (4) that grown men can take care of themselves; and (5) that gay men are more independent than heterosexual men. It is argued that rather than simply dismissing heteronormative repertoires of gender and health, non-heterosexuals draw upon them in ways that display ideological tensions. PMID- 29232980 TI - Effectiveness of aquatic versus land physiotherapy in the treatment of peripheral neuropathies: a randomized controlled trial. AB - OBJECTIVE: To compare the effects on gait and balance of aquatic physiotherapy versus on-land training, in the context of an inpatient rehabilitation treatment tailored for peripheral neuropathies. DESIGN: Parallel-group, single-center, single-blind randomized controlled trial. SUBJECTS AND SETTING: Consecutive patients affected by peripheral neuropathy admitted in our Neuro-Rehabilitation Unit. INTERVENTIONS: Patients received a four-week rehabilitation program composed by daily sessions of conventional physiotherapy and three sessions/week of specific treatment (aquatic vs. on-land). MAIN MEASURES: Primary outcome measures were Berg Balance Scale and Dynamic Gait Index. Secondary outcome measures were Neuropathic Pain Scale, Overall Neuropathy Limitations Scale, Functional Independence Measure, Functional Ambulation Classification, Conley Scale and Medical Research Council Scale score for the strength of hip and ankle flexor and extensor muscles. For each scale, we calculated the difference between the scores at discharge and admission and compared it between the two groups. RESULTS: Forty patients were enrolled: 21 in the water-based rehabilitation group and 19 in the land-based one. Patients were similar between groups. When comparing the groups, we found that "in-water" patients had a significant better improvement in the Dynamic Gait Index score (6.00 (4.00, 7.25) vs. 4.00 (1.25, 6.00), P = 0.0433). On the opposite, the "on-land" group showed a better improvement of the Functional Ambulation Classification score (1.0 (0.75, 1.0) vs. 1.0 (1.0, 2.0), P = 0.0386). CONCLUSION: Aquatic physiotherapy showed an effect comparable to the land-based rehabilitation on gait and balance dysfunctions of neuropathic patients. PMID- 29232981 TI - Transcutaneous electrical nerve stimulation improves walking capacity and reduces spasticity in stroke survivors: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate (1) the effectiveness of transcutaneous electrical nerve stimulation (TENS) at improving lower extremity motor recovery in stroke survivors and (2) the optimal stimulation parameters for TENS. REVIEW METHODS: A systematic search was conducted for studies published up to October 2017 using eight electronic databases (CINAHL, ClinicalTrials.gov, the Cochrane Central Register of Controlled Trials, EMBASE, MEDLINE, PEDro, PubMed and Web of Science). Randomized controlled trials that evaluated the effectiveness of the application of TENS at improving lower extremity motor recovery in stroke survivors were assessed for inclusion. Outcomes of interest included plantar flexor spasticity, muscle strength, walking capacity and balance. RESULTS: In all, 11 studies met the inclusion criteria which involved 439 stroke survivors. The meta-analysis showed that TENS improved walking capacity, as measured by either gait speed or the Timed Up and Go Test (Hedges' g = 0.392; 95% confidence interval (CI) = 0.178 to 0.606) compared to the placebo or no-treatment control groups. TENS also reduced paretic plantar flexor spasticity, as measured using the Modified Ashworth Scale and Composite Spasticity Scale (Hedges' g = -0.884; 95% CI = -1.140 to -0.625). The effect of TENS on walking capacity in studies involving 60 minutes per sessions was significant (Hedges' g = 0.468; 95% CI = 0.201-0.734) but not in study with shorter sessions (20 or 30 minutes) (Hedges' g = 0.254; 95% CI = -0.106-0.614). CONCLUSION: The results support the use of repeated applications of TENS as an adjunct therapy for improving walking capacity and reducing spasticity in stroke survivors. PMID- 29232982 TI - Antioxidant and antimicrobial properties of Casteanea sativa Miller chestnut honey produced on Mount Etna (Sicily). AB - The aim of this study was the evaluation of antibacterial and antioxidant properties of Monofloral Etna Castanea sativa Miller honeys. Escherichia coli ATCC 25,922, Pseudomonas aeruginosa ATCC 27,853, Enterococcus faecalis ATCC 29,211 and Staphylococcus aureus ATCC 29,213 were investigated for their susceptibilities to two different honeys. Antioxidant activity was evaluated by ORAC, NO scavenger assays, FRAP and DPPH. Antioxidant activity and antibacterial properties were compared with chestnut honeys from different geographical areas and with Manuka honey. UPLC-MS/MS was used for major components characterisation. PMID- 29232983 TI - Simulation of the influence of constant uniform magnetic field on a miniature LIT mass spectrometer. AB - In this paper, the effects of constant uniform magnetic fields on a miniature linear ion trap mass spectrometer with hyperbolic electrodes are simulated using SIMION 8.0 3D software. Magnetic fields in different directions have different effects on the trajectories of the trapped ions and the shape of the ion cloud. When the magnetic field is applied in the z-direction, namely the ion injection direction, the magnetic field will cause the ions focusing to the z-axis, and exert a compression effect on the ion cloud. When the magnetic field is applied in the x-y plane, the original ion cloud will be expanded due to the action of the applied magnetic field, and the ion cloud plane after expansion is always perpendicular to the direction of the magnetic field. The discovery of influence field of magnetic will bring some useful inspiration for the improvement of ion trapping efficiency, mass resolution, sensitivity and trapping capacity, which is conductive to the performance enhancement utilization of magnetic field, even in the industrial application development and other aspects. PMID- 29232985 TI - Outcome of Robotic Radical Prostatectomy in Men Over 74. AB - INTRODUCTION: We set out to evaluate outcomes in patients over 74 after robotic radical prostatectomy. MATERIALS AND METHODS: Six hundred forty-seven patients over 74 (>=75) were analyzed for preoperative factors (body mass index [BMI], American Society of Anestesiologists classification [ASA], prostate-specific antigen [PSA], International prostate symptome score [IPSS], International index of erectile function [IIEF]), operative and perioperative characteristics (technique, erythrocyte conc., complications), and histopathological results. After 12 months, following items were assessed: PSA, frequency of urine loss, number of pads used (including safety), incontinence at night, and potency as quantified by IIEF-5. RESULTS: Mean age in the group <75 was 64.8 years (range 46 74 years) and in the group >=75 76.9 years (75-88). No statistically significant differences could be detected in terms of BMI, ASA score, or preoperative PSA, respectively. IPSS and IIEF were significantly worse in the group >=75. Major complications (>Clavien-Dindo III) were found in 1.6% vs. 1.3% (>=75) of cases. Minor complications were encountered in 22.8% vs. 26.3% (>=75). There was a remarkably high percentage of locally advanced disease (73.3% vs. 71.0%) in both groups. Patients >=75 showed a tendency toward more aggressive cancer and more frequent nodal involvement; we found a higher percentage of R1-resections (19.5% vs. 30.4%, p < 0.05) and PSA relapse after 1 year (12.3% vs. 22.8%, p < 0.05). Twelve months pad-free continence rate (69.9% vs. 63.2%) showed no statistically significant difference between both groups as did the preservation rate of erectile function. CONCLUSION: We could show that robotic prostatectomy can be carried out safely with good functional and histopathological results in patients >=75. It is therefore questionable if elderly patients can be precluded from curative radical treatment solely because of their age. PMID- 29232986 TI - Simultaneous inter-arm and inter-leg systolic blood pressure differences to diagnose peripheral artery disease: a diagnostic accuracy study. PMID- 29232987 TI - Radium-223 international early access program: results from the Spanish subset. AB - AIM: To report results from the Spanish subset included in the radium-223 international early access program (iEAP). PATIENTS & METHODS: Ninety patients with castration-resistant prostate cancer and bone metastases received radium-223 55 kBq/kg every 4 weeks for six cycles. RESULTS: The median time to disease progression was 8 months and to prostate-specific antigen progression was 4 months. The percentage of patients with >=50% confirmed declines in prostate specific antigen was 9%. The median overall survival was 14 months. Grade 3 or 4 treatment emergent adverse events (TEAEs) occurred in 34% of patients (serious TEAEs 28%, TEAEs leading to discontinuation 27%). CONCLUSION: Outcomes of the Spanish subset are consistent with the iEAP. Radium-223 was generally well tolerated with no safety concerns. PMID- 29232988 TI - Does antibiotic treatment duration affect the outcomes of exacerbations of asthma and COPD? A systematic review. AB - Asthma and chronic obstructive pulmonary disease (COPD) cause significant morbidity and mortality worldwide, primarily through exacerbations. Exacerbations are often treated with antibiotics but their optimal course duration is uncertain. Reducing antibiotic duration may influence antimicrobial resistance but risks treatment failure. The objective of this article is to review published literature to investigate whether shorter antibiotic therapy duration affects clinical outcomes in the treatment of asthma and COPD exacerbations. We systematically searched electronic databases (MEDLINE, EMBASE, CINAHL, World Health Organisation International Clinical Trial Registry Platform, the Cochrane library, and ISRCTN) with no language, location, or time restrictions. We retrieved observational and controlled trials comparing different durations of the same oral antibiotic therapy in the treatment of acute exacerbations of asthma or COPD in adults. We found no applicable studies for asthma exacerbations. We included 10 randomized, placebo-controlled trials for COPD patients, all from high-income countries. The commonest studied antibiotic class was fluoroquinolones. Antibiotic courses shorter than 6 days were associated with significantly fewer overall adverse events (risk ratio (RR): 0.84, 95% confidence interval (CI): 0.75-0.93, p = 0.001) when compared with those of 7 or more days. There was no statistically significant difference for clinical success or bacteriological eradication in sputum (RR: 1.00, 95% CI: 0.88-1.13 and RR: 1.06, 95% CI: 0.79-1.44, respectively). Shorter durations of antibiotics for COPD exacerbations do not seem to confer a higher risk of treatment failure but are associated with fewer adverse events. This is in keeping with previous studies in community acquired pneumonia, but studies were heterogeneous and differed from usual clinical practice. Further observational and prospective work is needed to explore the significance of antibiotic duration in the treatment of asthma and COPD exacerbations. PMID- 29232990 TI - Positive and negative ion mode comparison for the determination of DNA/peptide noncovalent binding sites through the formation of "three-body" noncovalent fragment ions. AB - Gas-phase fragmentation of single strand DNA-peptide noncovalent complexes is investigated in positive and negative electrospray ionization modes.Collision induced dissociation experiments, performed on the positively charged noncovalent complex precursor ions, have confirmed the trend previously observed in negative ion mode, i.e. a high stability of noncovalent complexes containing very basic peptidic residues (i.e. R > K) and acidic nucleotide units (i.e. Thy units), certainly incoming from the existence of salt bridge interactions. Independent of the ion polarity, stable noncovalent complex precursor ions were found to dissociate preferentially through covalent bond cleavages of the partners without disrupting noncovalent interactions. The resulting DNA fragment ions were found to be still noncovalently linked to the peptides. Additionally, the losses of an internal nucleic fragment producing "three-body" noncovalent fragment ions were also observed in both ion polarities, demonstrating the spectacular salt bridge interaction stability. The identical fragmentation patterns (regardless of the relative fragment ion abundances) observed in both polarities have shown a common location of salt bridge interaction certainly preserved from solution. Nonetheless, most abundant noncovalent fragment ions (and particularly three-body ones) are observed from positively charged noncovalent complexes. Therefore, we assume that, independent of the preexisting salt bridge interaction and zwitterion structures, multiple covalent bond cleavages from single-stranded DNA/peptide complexes rely on an excess of positive charges in both electrospray ionization ion polarities. PMID- 29232989 TI - Impact of cataract on health-related quality of life in a longitudinal Japanese chronic obstructive pulmonary cohort. AB - Cigarette smoking increases the risk of developing both cataract and chronic obstructive pulmonary disease (COPD). The prevalence of cataract and the clinical characteristics of COPD patients with cataract were retrospectively investigated in a 2-year observational COPD cohort. We analyzed 395 patients with complete data on ophthalmologic evaluation (319 subjects with COPD and 76 subjects at risk of COPD). There was no difference in the prevalence of cataract between COPD patients and those at risk (47.0% vs. 42.1%, p = 0.44). Age >= 75 years, low body mass index, and hypertension were independently associated with cataract as a comorbidity in COPD. The incidence of exacerbation within 2 years was significantly higher in COPD patients with cataract than those without cataract (36.6% vs. 18.3%, p = 0.0019). COPD patients with cataract exhibited significantly higher COPD assessment test score compared to those without cataract (13.7 +/- 8.9 vs. 11.5 +/- 7.2, p = 0.0240). Overall St George's Respiratory Questionnaire score and each component were significantly worse in COPD patients with cataract compared to those without cataract. COPD patients with cataract exhibited poor health-related quality of life and frequent exacerbations. The association between cataract and exacerbations of COPD deserves further attention. PMID- 29232991 TI - Mass spectrometry imaging of illicit drugs in latent fingerprints by matrix-free and matrix-assisted desorption/ionization techniques. AB - Compared with classical matrix-assisted laser-desorption ionization mass spectrometry (MALDI), the matrix free-based strategies generate a cleaner background, without significant noise or interference coming from an applied matrix, which is beneficial for the analysis of small molecules, such as drugs of abuse. In this work, we probed the detection efficiency of methamphetamine, heroin and cocaine in nanostructure-assisted laser desorption-ionization (NALDI) and desorption electrospray ionization and compared the sensitivity of these two matrix-free tools with a standard MALDI mass spectrometry experiment. In a typical mass spectrometry imaging (MSI) setup, papillary line latent fingerprints were recorded as a mixture a common skin fatty acid or interfering cosmetics with a drug. In a separate experiment, all drugs (1 uL of 1 MUM standard solution) were detected by all three ionization techniques on a target. In the case of cocaine and heroin, NALDI mass spectrometry was the most sensitive and revealed signals even from 0.1 MUM solution. The drug/drug contaminant (fatty acid or cosmetics) MSI approach could be used by law enforcement personnel to confirm drug abusers of having come into contact with the suspected drug by use of fingerprint scans at time of apprehension which can aid in reducing the work of lab officials. PMID- 29232992 TI - Cleft lip and palate in context: Learning from, and adding to, the sociological literature on long-term conditions. AB - Cleft lip and palate is a common congenital anomaly affecting males and females. While there is psychological research on cleft lip and palate, there is relatively little research exploring the social context of cleft lip and palate and the experiences of living with the condition on a daily basis. Drawing on common themes emerging from sociological work which have explored the experiences of people living with long-term conditions (uncertainty, social relations, self esteem and self-image and biomedical concerns), we argue that these themes can be used to help elucidate the experiences of people living with cleft lip and palate. Within this framework, the findings of a qualitative study exploring the experiences of people living with cleft lip and palate are presented. The results suggest that all four themes can be found within the accounts of people living with cleft lip and palate, and there are many commonalities between the experiences of these people and those living with other long-term conditions. Conversely there are interesting areas of divergence. Unlike most long-term conditions, cleft lip and palate is not degenerative and treatment means symptoms will reduce over time. This is reflected in narratives around 'normality' as the endpoint of the care pathway. In addition, prenatal diagnosis means that the vast majority of participants within this study were born into, and grew up within, the care pathway. This has implications for the way in which cleft lip and palate is understood and the provision of information, relationships with members of the care team over time and the temporal and contextualised impact of cleft lip and palate on social relations and the self. PMID- 29232993 TI - Evaluation of Metatarsal Head Resurfacing Hemiarthroplasty in the Surgical Treatment of Hallux Rigidus: A Retrospective Study and Mid- to Long-Term Follow up. AB - BACKGROUND: The aim of this study was to evaluate the mid- to long-term outcomes of metatarsal head resurfacing hemiarthroplasty in the surgical treatment of advanced-stage hallux rigidus. METHODS: We performed a retrospective review of 57 consecutive patients (25 [43.9%] males, 32 [56.1%] females; mean age, 61.0 +/- 6.4 years) who underwent first metatarsal head resurfacing hemiarthroplasty (HemiCAP) for hallux rigidus between August 2007 and September 2010. Sixty-five implantations were performed in 57 patients; 8 patients underwent bilateral procedures. All patients were clinically rated prior to surgery and at the final follow-up visit using the American Orthopaedic Foot and Ankle Society (AOFAS) hallux metatarsophalangeal-interphalangeal scale and first metatarsophalangeal joint range of motion (MTPJ ROM). RESULTS: The median follow-up duration was 81 (range = 8-98) months. The median preoperative AOFAS score was 34 (range = 22-59) points, which had increased to 83 (range = 26-97) points at the final follow-up visit (P < .001). The median preoperative first MTPJ ROM was 25 degrees (range = 15 degrees to 40 degrees ), which had increased to 75 degrees (range = 30 degrees to 85 degrees ) at the final follow-up visit (P < .001). CONCLUSIONS: First MTPJ hemiarthroplasty is an effective treatment method that recovers toe function and first MTPJ ROM, and provides good mid- to long-term functional outcomes. LEVELS OF EVIDENCE: Level IV: Retrospective case series. PMID- 29232994 TI - Tautomerism of uracil and related compounds: A mass spectrometry study. AB - It has been demonstrated that uracil has a preponderant tautomeric form, but it is also known that different tautomers co-exist in this equilibrium. In this work, mass spectrometry is used as a helpful tool to analyse the equilibria, using derivative compounds to forbid the presence of some tautomers and ion trap mass spectrometry to follow relevant fragmentation pathways. Theoretical calculations were performed to confirm tautomers abundance by energy minimization in gas phase. Analysis of mass spectra of uracil, three methyl-substituted uracils, 2-thiouracil and three benzouracils suggest that uracil exists mainly as three tautomers in gas phase: one major structure that corresponds to the classical structure of uracil (pyrimidine-2,4(1H,3H)-dione) bearing two carbonyls and two NH moieties, and two minor enolic forms (4-hydroxypyrimidin-2(1H)-one and 2-hydroxypyrimidin-4(1H)-one). Such tautomeric distribution is supported by theoretical calculations, which show that they are the three most stable tautomers. PMID- 29232995 TI - Tissue imaging with in situ solid-phase extraction micro-funnel based spray ionization mass spectrometry. AB - Current imaging mass spectrometry techniques are faced with a major challenge related to ion suppression effect. Data regarding low-abundance components or low polarity compounds cannot be normally obtained presumably because of the discrimination effect of easily ionized chemical components on desorption/ionization process. In this study, a new method was proposed to obtain images of chemical components in biological tissues or sections through in situ solid-phase extraction in sorbent mounted micro-funnel based spray ionization mass spectrometry. An imprint of a strawberry section was formed by gently pressing against a 2D array of micro-funnels. The sorbent mounted micro-funnels were then subjected to in situ single-pixel solid-phase extraction to alleviate the matrix-related ion suppression effect. The achievable spatial resolution is approximately 250 um. The imaging of the spatial distribution of low-abundance or low-polarity chemicals in the strawberry imprint could be obtained by using a gradient elution strategy. Results demonstrated that the "not observed" remark does not necessarily indicate that a specific compound is non-existent when traditional imaging mass spectrometry techniques are used. The proposed method can be applied to conduct low-abundance chemical imaging through in situ single pixel sample pretreatment. PMID- 29232997 TI - Stereospecificity of the Hofmann elimination in the gas phase. AB - The Hofmann elimination of ammonium ions having a single positive charge is demonstrated to exhibit stereospecificity with regard to expulsion of neutral alkene. For the 3-hexyl series of threo and erythro 4-monodeuterated ions (3 hexylammonium ion; N,N,N-trimethyl- d3-3-hexylammonium ion; N-ethyl-3 hexylammonium ion; N-methyl, N-ethyl-3-hexylammonium ion; N,N-dimethyl, N-ethyl-3 hexylammonium ion), the upper limit of the E:Z ratio of the expelled alkene (r) approaches 2 (the stereospecificity) with a deuterium isotope effect close to 2.0, although the effects of isotopic substitution diminish the E:Z ratio somewhat. Two fragmentations compete with that reaction: hydride shift (which gives the same products but with hydrogen scrambling) and loss of a neutral amine to give an alkyl cation. These competing reactions render our calculation approximate, but the results suggest a value not too far from the upper limit. PMID- 29232996 TI - Structural elucidation of fucosylated chondroitin sulfates from sea cucumber using FTICR-MS/MS. AB - Fucosylated chondroitin sulfates are complex polysaccharides extracted from sea cucumber. They have been extensively studied for their anticoagulant properties and have been implicated in other biological activities. While nuclear magnetic resonance spectroscopy has been used to extensively characterize fucosylated chondroitin sulfate oligomers, we herein report the first detailed mass characterization of fucosylated chondroitin sulfate using high-resolution Fourier transform ion cyclotron resonance mass spectrometry. The two species of fucosylated chondroitin sulfates considered for this work include Pearsonothuria graeffei (FCS-Pg) and Isostichopus badionotus (FCS-Ib). Fucosylated chondroitin sulfate oligosaccharides were prepared by N-deacetylation-deaminative cleavage of the two fucosylated chondroitin sulfates and purified by repeated gel filtration. Accurate mass measurements obtained from electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry measurements confirmed the oligomeric nature of these two fucosylated chondroitin sulfate oligosaccharides with each trisaccharide repeating unit averaging four sulfates per trisaccharide. Collision-induced dissociation of efficiently deprotonated molecular ions through Na/H+ exchange proved useful in providing structurally relevant glycosidic and cross-ring product ions, capable of assigning the sulfate modifications on the fucosylated chondroitin sulfate oligomers. Careful examination of the tandem mass spectrometry of both species deferring in the positions of sulfate groups on the fucose residue (FCS-Pg-3,4- OS) and (FCS-Ib-2,4- OS) revealed cross-ring products 0,2Aalphaf and 2,4X2alphaf which were diagnostic for (FCS-Pg-3,4- OS) and 0,2X2alphaf diagnostic for (FCS-Ib-2,4- OS). Mass spectrometry and tandem mass spectrometry data acquired for both species varying in oligomer length (dp3-dp15) are presented. PMID- 29232998 TI - Regio-isomeric effects in tandem mass spectra of sulfonium cations generated from thiacyclane based sulfonium salts under soft ionization conditions. AB - The influence of regio-isomerism of even-electron sulfonium ions on tandem electrospray and matrix-assisted laser desorption/ionization mass spectra recorded by using collision-induced dissociation was investigated. The initial organic sulfides belonged to isomeric thiabicyclane series (substituted 7- and 8 thiabicyclo[4.3.0]nonanes, 2- and 3-thiabicyclo[4.4.0]decanes) and phenylthiolanes. To investigate by the abovementioned mass spectrometry methods, the sulfides were preliminary S-alkylated by methyl, ethyl iodides, their deuterated analogs and trialkoxonium tetrafluoroborates to form corresponding sulfonium salts. The latter salts readily gave off corresponding sulfonium cations under abovementioned desorption/ionization conditions and these cations were precursor ions in collision-induced dissociation experiments. The main quantitative and frequently qualitative differences between collision-induced dissociation spectra of isomers were manifested in mass numbers and relative intensities of the ions Alk-S+ = CHR (formal structure) that originated from the destruction of sulfur-containing ring. Corresponding peaks are particularly abundant for cations Alk-S+ = CH2 and their intensities are usually greater than for other C-substituted homologues. Qualitative difference between fragmentation features of 2- and 3-phenylthiolanium cations is that only the latter can eliminate neutral C2H4S molecule. PMID- 29232999 TI - Using Synthetic Controls to Evaluate the Effect of Unique Interventions: The Case of Say Yes to Education. AB - BACKGROUND: "Place-based" scholarships seek to improve student outcomes in urban school districts and promote urban revitalization in economically challenged cities. Say Yes to Education is a unique district-wide school reform effort adopted in Syracuse, NY, in 2008. It includes full-tuition scholarships for public and private universities, coupled with extensive wraparound support services in schools. OBJECTIVES: This study uses synthetic control methods to evaluate the effect of Say Yes on district enrollment and graduation rates. It also introduces the synthetic control method and provides guidance for its use in evaluating single-site interventions. METHOD: Combining school district-level data from the National Center for Education Statistics' Common Core of Data and New York State School Report Cards, this article uses synthetic control methods to construct a synthetic comparison district to estimate counterfactual enrollment and graduation trends for Syracuse. RESULTS: We find that Say Yes to Education was associated with enrollment increases in the Syracuse City School District, a district that had previously experienced decades of sustained enrollment declines. We do not find consistent evidence of changes in graduation rates following adoption of the program. CONCLUSIONS: Graduation rate analyses demonstrate that estimates of treatment effects can be sensitive to choices that the researcher has to make in applying synthetic control methods, particularly when pretreatment outcome measures appear to have considerable amounts of noise. PMID- 29233000 TI - Analysis of air-, moisture- and solvent-sensitive chemical compounds by mass spectrometry using an inert atmospheric pressure solids analysis probe. AB - A novel method has been developed that enables chemical compounds to be transferred from an inert atmosphere glove box and into the atmospheric pressure ion source of a mass spectrometer whilst retaining a controlled chemical environment. This innovative method is simple and cheap to implement on some commercially available mass spectrometers. We have termed this approach inert atmospheric pressure solids analysis probe ( iASAP) and demonstrate the benefit of this methodology for two air-/moisture-sensitive chemical compounds whose characterisation by mass spectrometry is now possible and easily achieved. The simplicity of the design means that moving between iASAP and standard ASAP is straightforward and quick, providing a highly flexible platform with rapid sample turnaround. PMID- 29233001 TI - Arachidonic acid attenuates brain damage in a rat model of ischemia/reperfusion by inhibiting inflammatory response and oxidative stress. AB - The aim of the present study was to study the effects of arachidonic acid (ARA) in a rat brain ischemia/reperfusion model induced by middle cerebral artery occlusion (MCAO). A total of 50 rats were randomly divided into five groups: control group, MCAO group, MCAO + ARA 0.3 g/kg group, MCAO + ARA 1 g/kg group, and MCAO + ARA 3 g/kg group. The MCAO + ARA groups received ARA by intraperitoneal injection daily for 14 consecutive days, while the rats in the control and MCAO groups were given equivalent volume of saline. We detected the Morris water maze test and pathological changes to investigate the ischemia/reperfusion injury. The protein levels of tumor necrosis factor-alpha and interleukin-6 in the hippocampus were detected by enzyme-linked immunosorbent assay kits. In addition, the activities of superoxide dismutase, glutathione peroxidase, and malondialdehyde were assayed in hippocampus homogenates to evaluate the oxidative stress after ischemia/reperfusion. The results indicated that ARA administration decreased biochemical parameters of inflammation and oxidative stress. Morris water maze test and histopathological examination further verified the protective effects of ARA on ischemia/reperfusion injury rats. These findings demonstrated that ARA could protect MCAO-induced brain injury rats by inhibition of inflammation and oxidative stress, suggesting that it may have potential as a therapy for cerebral ischemia/reperfusion injury. PMID- 29233002 TI - Social participation following a stroke: an assessment in accordance with the international classification of functioning, disability and health. AB - OBJECTIVE: Evaluate, code and qualify the participation of Brazilian stroke survivors based on the international classification of functioning, disability and health (ICF) and identify predictors of post-stroke participation. METHODS: An exploratory, observational, cross-sectional study was conducted involving 78 individuals with hemiparesis stemming from a stroke. The stroke specific quality of life (SS-QOL) was used to evaluate the participation component of the ICF. The geriatric depression scale was used to screen depressive symptoms; the functional independence measure (FIM) was used to measure the degree of dependence; grip strength was determined using a dynamometer; and cognitive status was evaluated using the mini mental state examination. The one-way analysis of variance followed by the Bonferroni test was used for the comparison the participation scores of different groups (age and marital status). The independent t-test was used for the comparisons of the other groups (sex, time since the occurrence of stroke (<12 months or >12 months) and degree of functional independence). Multiple linear regression was employed to identify measures capable of predicting participation. RESULTS: Based on the classification and qualifiers of the ICF, the individuals analyzed exhibited a moderate level of participation. Participation was significantly associated with time since the occurrence of stroke (F = 2.46; 95% confidence interval (CI) = -23.67-0.34; p = 0.05), degree of functional independence (F = 2.40; 95% CI = -33.0 to -18.93; p < 0.001) and marital status (married or widowed) (F = 2.6; p = 0.05). No statistically significant associations were found with regard to age, sex or affected side of the body. Functional independence was the main predictor of participation (F = 99.2; r2 = 0.57; p <0.001) and the occurrence of depressive symptoms was a moderate predictor (F =12.78; r2 = 0.40; p = 0.001). CONCLUSIONS: Twenty-four ICF categories were coded and qualified with the use of the SS-QOL, enabling the participation component of the ICF biopsychosocial model to be easily evaluated in clinical practice. Overall, the sample in the present study demonstrated a moderate decline in participation following a stroke and only the "social roles" domain was severely affected. The FIM was the main predictor of participation and the depression was a moderate predictor. Therefore, health professionals involved in the rehabilitation of these patients should focus on the promotion of functional independence and improvements in emotional health to optimize social participation following a stroke. Implications for Rehabilitation The Brazilian stroke individuals analyzed exhibited a moderate level of participation. Functional independence was the main predictor of participation and the occurrence of depressive symptoms was a moderate predictor. Age, sex and affected side of the body were not predictors of participation. Our findings support that twenty-four International classification of functioning, disability and health categories were coded and qualified with the use of the stroke specific quality of life. Rehabilitation of social functioning post stroke patients should be focused on the promotion of functional independence and improvement in emotional health. This study offers a participation assessment model that can facilitate the incorporation of the ICF in the clinical practice. PMID- 29233003 TI - C-F bond activation of trifluoroethanol and trifluoroacetic acid catalysed by the dimolybdate anion, [Mo2O6(F)]- ?. AB - Two gas-phase catalytic cycles involving C-F bond activation of trifluoroethanol and trifluoroacetic acid were detected by multistage mass spectrometry experiments. A binuclear dimolybdate centre [Mo2O6(F)]- acts as the catalyst in each cycle. The first cycle, entered via the reaction of [Mo2O6(OH)]- with trifluoroethanol and elimination of water to form [Mo2O6(OCH2CF3)]-, proceeds via four steps: (1) oxidation of the alkoxo ligand and its elimination as aldehyde; (2) reaction of [Mo2O5(OH)]- with trifluoroethanol and elimination of water to form [Mo2O5(OCH2CF3)]; (3) decomposition of the alkoxo ligand via loss of 1,1 difluoroethene; and (4) reaction of [Mo2O6(F)]- with a second equivalent of trifluoroethanol to regenerate Mo2O6(OCH2CF3)]-. Steps (2) and (3) do not occur at room temperature and require collisional activation to proceed. The second cycle is entered via the reaction of [Mo2O6(OH)]- with trifluoroacetic acid and elimination of water to form [Mo2O6(O2CCF3)]- and involves two steps only: (1) fluoride transfer to a molybdenum centre to form [Mo2O6(F)]-; (2) reaction of [Mo2O6(F)]- with trifluoroacetic acid and loss of water to regenerate [Mo2O6(O2CCF3)]-. Comparisons are made with the chemistry of [Mo2O6(OH)]- reacting with acetic acid. PMID- 29233004 TI - Matched Comparison Group Design Standards in Systematic Reviews of Early Childhood Interventions. AB - BACKGROUND: Systematic reviews assess the quality of research on program effectiveness to help decision makers faced with many intervention options. Study quality standards specify criteria that studies must meet, including accounting for baseline differences between intervention and comparison groups. We explore two issues related to systematic review standards: covariate choice and choice of estimation method. OBJECTIVE: To help systematic reviews develop/refine quality standards and support researchers in using nonexperimental designs to estimate program effects, we address two questions: (1) How well do variables that systematic reviews typically require studies to account for explain variation in key child and family outcomes? (2) What methods should studies use to account for preexisting differences between intervention and comparison groups? METHODS: We examined correlations between baseline characteristics and key outcomes using Early Childhood Longitudinal Study-Birth Cohort data to address Question 1. For Question 2, we used simulations to compare two methods-matching and regression adjustment-to account for preexisting differences between intervention and comparison groups. RESULTS: A broad range of potential baseline variables explained relatively little of the variation in child and family outcomes. This suggests the potential for bias even after accounting for these variables, highlighting the need for systematic reviews to provide appropriate cautions about interpreting the results of moderately rated, nonexperimental studies. Our simulations showed that regression adjustment can yield unbiased estimates if all relevant covariates are used, even when the model is misspecified, and preexisting differences between the intervention and the comparison groups exist. PMID- 29233005 TI - Unimolecular dissociation of anions derived from succinic acid (H2Su) in the gas phase: HSu- and ClMgSu-. Relationship to CO2 fixation. AB - Electrospray ionization of mixtures of succinic acid (here denoted H2Su) and magnesium chloride in water/methanol give rise to ions of the type ESu- (E = H or ClMg). The unimolecular dissociation of these ions was studied by collisionally induced dissociation mass spectrometry and interpreted by quantum chemical calculations (density functional theory and the composite Gaussian-4 method) of relevant parts of the potential energy surfaces. The major dissociation pathways from HSu- were seen to be dehydration and decarboxylation, while ClMgSu- mainly undergoes decarboxylation. The latter reaction proceeds without barrier for the reverse reaction; addition of CO2 to a Grignard type structure ClMg(CH2CH2CO2)-. In contrast, addition of CO2 to the analogous H(CH2CH2CO2)- ion has a substantial barrier. Dehydration of HSu- gives rise to deprotonated succinic anhydride via a transition state for the key intramolecular proton transfer having an entropically favorable seven-member ring structure. The succinate systems studied here are compared to the previously reported analogous maleate systems, providing further insight to the structure-reactivity relationship. PMID- 29233006 TI - Occupational exposure to photocopiers and their toners cause genotoxicity. AB - Photocopier machines are inevitable office equipment, but they are also sources of air pollution. Millions of people across the world are involved in the operation and maintenance of photocopiers. We aimed to evaluate the potential genotoxic effects of exposure to photocopiers in photocopier operators and maintenance personnel by Comet assay. This study involved 50 photocopier operators, 61 maintenance personnel and 52 controls. Both the photocopier exposed groups exhibited significantly increased DNA damage when compared to controls. Cumulative exposure to photocopiers was the most significant contributor for genotoxicity ( p < 0.001). Genotoxicity among photocopier maintenance personnel may be due to the presence of carbon black, iron, silicon, magnetite and the high levels of other elements in the photocopier toners. Genotoxicity among photocopier operators might be due to exposure to high levels of particulate matter and volatile organic compounds emitted by photocopiers during operation. Research is essential to improve toner manufacturing processes and chemical composition of toners to reduce genotoxicity. Clean technologies are the need of the day to cut down on particulate matter and volatile organic compound emissions from photocopiers. PMID- 29233007 TI - Investigation of hypersensitivity potential of diacetyl by determining cytokine profiles. AB - Exposure to chemicals in workplace settings leads to significant occupational diseases related to hypersensitivity reactions. In recent years, diacetyl which is used as a food additive is thought to be as an important hazard due to its sensitization potency for worker's health. Therefore, in this study, we aimed to investigate the sensitization potency of diacetyl for the purpose of its hazard evaluation. Nonradioactive ex vivo local lymph node assay: BrdU-enzyme-linked immunosorbent assay (ELISA) method with short-term and long-term exposure protocols were conducted based on animal welfare principles. As end points, lymphocyte proliferation, cytokine releases, and total serum IgE levels were measured by ELISA method. After short-term dermal exposure to diacetyl, primary Th1 cytokine interleukin-2 (IL-2) and Th2 cytokines IL-4 and IL-13 levels were significantly increased relatively to vehicle control, whereas such significant increases were not observed in long-term exposure. According to our measurements of IgE levels after long-term dermal exposures to chemicals, diacetyl led to significant increase. In conclusion, the findings that showed significant increases in IL-13 and total serum IgE levels induced with diacetyl can be relevant to respiratory sensitizing hazard of this chemical. PMID- 29233009 TI - Microbial consortia: a critical look at microalgae co-cultures for enhanced biomanufacturing. AB - Monocultures have been the preferred production route in the bio-industry, where contamination has been a major bottleneck. In nature, microorganisms usually exist as part of organized communities and consortia, gaining benefits from co habitation, keeping invaders at bay. There is increasing interest in the use of co-cultures to tackle contamination issues, and simultaneously increase productivity and product diversity. The feasibility of extending the natural phenomenon of co-habitation to the biomanufacturing industry in the form of co cultures requires careful and systematic consideration of several aspects. This article will critically examine and review current work on microbial co-cultures, with the intent of examining the concept and proposing a design pipeline that can be developed in a biomanufacturing context. PMID- 29233010 TI - Introduction to Special Issue: External Validity and Policy. PMID- 29233008 TI - Non-polar compounds of Persian Gulf sea cucumber Holothuria parva selectively induce toxicity on skin mitochondria isolated from animal model of melanoma. AB - PURPOSE: Melanoma is a highly aggressive and deadly cancer with a poor prognosis given its drug resistance. A defect in apoptosis is one of the key mechanisms that contribute to drug resistance in Melanoma. An important sea marine animal is the Holothuria parva, also known as the sea cucumber, which has various pharmacological activities. Compounds obtained from sea cucumbers have shown to have anticancer activity through induction of apoptosis singling. MATERIALS AND METHODS: In the present study, selective toxicity and apoptotic effect of three extracts of H. parva were assessed on skin mitochondria isolated from mouse animal models of melanoma. The mitochondria was isolated from melanoma cells via differential centrifuges and treated with various concentrations (250, 500 and 1000 ug/ml) of metanolic, diethyl ether and n-hexane extracts of H. parva. RESULTS: All the applied concentrations (250, 500 and 1000 ug/ml) of three extracts of H. parva increased the reactive oxygen species (ROS) generation only in the skin mitochondria isolated from melanoma cells group (in comparison to the control group). Additionally, all three extracts (250, 500 and 1000 ug/ml) induced swelling within the mitochondria, the collapse of the mitochondrial membrane potential (MMP) and the release of cytochrome c from the mitochondria. Flow-cytometry analysis demonstrated that n-hexane and diethyl ether extracts of H. parva selectively and progressively induced apoptosis only on melanoma but not healthy control skin cells group. CONCLUSIONS: Given these results, the potentially bioactive compounds found in H. parva render it a strong candidate for further research in molecular identification and confirmatory in vivo studies. Clinical trials are also warranted in the general process of novel drug discovery for the treatment of melanoma cancer. PMID- 29233011 TI - Immobilized inulinase: a new horizon of paramount importance driving the production of sweetener and prebiotics. AB - In recent times, inulinase has emerged as one the most prominent and industrially upcoming enzymes applied to meet the ever increasing demand of d-fructose and fructooligosaccharides (FOS) as sweetener and prebiotics in the food and pharmaceutical industry, respectively. This review deals with types of inulinase and the attempts made to modify it for better thermal stability and shelf life. The ease of immobilization of inulinase has led us to the path of experimenting with different methods of enzyme immobilization since 1979. Several modes of immobilization ranging from simple cross-linking of enzymes onto a polymer support to nanoparticles have been applied over the years. The approach and concept of this review provide a yet unexplored focus on pioneering advances for the development of white biotechnology, for instance production of immobilized inulinase-based reusable biocatalysts and bioreactors designed for their use and for the continuous production of fructose and FOS. PMID- 29233012 TI - Living Independently: Exploring the Experiences of Visually Impaired People Living in Age-Related and Lifetime Housing Through Qualitative Synthesis. AB - OBJECTIVES: The aim of this study is to gain a deeper understanding of the experiences of visually impaired older people living independently at home. BACKGROUND: As populations are aging globally, there is now an increase in the prevalence of visual impairment. That means for ongoing and future aging-in-place strategies that seek to enable older people to remain independent for longer, more attention needs to be given to the needs of those with visual impairment. As people develop visual impairment, they use adaptive strategies including modifying long-term homes or relocating to more suitable accommodation. In the United Kingdom, aging-in-place strategies include employing statutory lifetime home standards (LTHS) in the home or relocating to sheltered housing to live independently with support available if required. METHODS: To get a better understanding of the needs of the visually impaired in the home, 12 interviews with six visually impaired occupants of LTHS homes and six from sheltered accommodation were analyzed separately using interpretative phenomenological analysis. Secondly, qualitative synthesis was used to further analyze themes generated from both samples before interview results were conceptualized in two superordinate concepts, namely, "negotiating priorities" and "understanding visual impairment." RESULTS: Participants from both groups had similar needs and were willing to compromise by living with some negative features. Those who coped well with moving utilized various resources. CONCLUSIONS: These findings will shed more understanding on providing good quality housing for those with visual impairment wanting to live either independently or within healthcare home environments. PMID- 29233013 TI - Biotechnological potential for degradation of isoprene: a review. AB - Isoprene, the ubiquitous, highly emitted non-methane volatile hydrocarbon, affects atmospheric chemistry and human health, and this makes its removal from the contaminated environment imperative. Physicochemical degradation of isoprene is inefficient and generates secondary pollutants. Therefore, biodegradation can be considered as the safer approach for its efficient abatement. This review summarizes efforts in this regard that led to tracking the diverse groups of isoprene degrading bacteria such as Methanotrophs, Xanthobacter, Nocardia, Alcaligenes, Rhodococcus, Actinobacteria, Alphaproteobacteria, Bacteriodetes, Pseudomonas, and Alcanivorax. Biodegradation of isoprene by such bacteria in batch and continuous modes has been elaborated. The products, pathways and the key enzymes associated with isoprene biodegradation have also been presented. PMID- 29233014 TI - Family Perceptions of Family Nursing in a Magnet Institution During Acute Hospitalizations of Older Adult Patients. AB - Family involvement during hospitalizations of older adults with chronic illnesses may benefit both patients and family. However, there is a limited amount of research focused on families of older adults managing chronic illness. This study describes family member perceptions of the relationship between family and nurses when an older adult with diabetes is hospitalized in a Magnet institution. The Calgary Family Intervention Model guided the study. A family member of 60 older adult patients completed the Family Function, Family Health, and Social Support Instrument. The results revealed positive perceptions from family members regarding their perceptions of family nursing practice. Family health, however, was found to decrease slightly as loved ones are hospitalized more frequently, and is an area where nurses may provide improved social support. Future research might target the implementation of a targeted family-level intervention designed to improve family outcomes as well as family nursing practice. PMID- 29233015 TI - The benefits of folic acid-modified gold nanoparticles in CT-based molecular imaging: radiation dose reduction and image contrast enhancement. AB - X-ray computed tomography (CT) requires an optimal compromise between image quality and patient dose. While high image quality is an important requirement in CT, the radiation dose must be kept minimal to protect the patients from ionizing radiation-associated risks. The use of probes based on gold nanoparticles (AuNPs) along with active targeting ligands for specific recognition of cancer cells may be one of the balanced solutions. Herein, we report the effect of folic acid (FA) modified AuNP as a targeted nanoprobe on the contrast enhancement of CT images as well as its potential for patient dose reduction. For this purpose, nasopharyngeal KB cancer cells overexpressing FA receptors were incubated with AuNPs with and without FA modification and imaged in a CT scanner with the following X-ray tube parameters: peak tube voltage of 130 KVp, and tube current time products of 60, 90, 120, 160 and 250 mAs. Moreover, in order to estimate the radiation dose to which the patient was exposed during a head CT protocol, the CT dose index (CTDI) value was measured by an X-ray electrometer by changing the tube current-time product. Raising the tube current-time product from 60 to 250 mAs significantly increased the absorbed dose from 18 mGy to 75 mGy. This increase was not associated with a significant enhancement of the image quality of the KB cells. However, an obvious increase in image brightness and CT signal intensity (quantified by Hounsfield units [HU]) were observed in cells exposed to nanoparticles without any increase in the mAs product or radiation dose. Under the same Au concentration, KB cells exposed to FA-modified AuNPs had significantly higher HU and brighter CT images than those of the cells exposed to AuNPs without FA modification. In conclusion, FA-modified AuNP can be considered as a targeted CT nanoprobe with the potential for dose reduction by keeping the required mAs product as low as possible while enhancing image contrast. PMID- 29233016 TI - The association between the metabolic syndrome and metabolic syndrome score and pulmonary function in non-smoking adults. AB - OBJECTIVE: This study assessed the association of metabolic syndrome and metabolic syndrome score with the predicted forced vital capacity and predicted forced expiratory volume in 1 s (predicted forced expiratory volume in 1 s) values in Korean non-smoking adults. METHODS: We analysed data obtained from 6684 adults during the 2013-2015 Korean National Health and Nutrition Examination Survey. RESULTS: After adjustment for related variables, metabolic syndrome ( p < 0.001) and metabolic syndrome score ( p < 0.001) were found to be inversely associated with the predicted forced vital capacity and forced expiratory volume in 1 s values. The odds ratios of restrictive pulmonary disease (the predicted forced vital capacity < 80.0% with forced expiratory volume in 1 s/FVC ? 70.0%) by metabolic syndrome score with metabolic syndrome score 0 as a reference group showed no significance for metabolic syndrome score 1 [1.061 (95% confidence interval, 0.755-1.490)] and metabolic syndrome score 2 [1.247 (95% confidence interval, 0.890-1.747)], but showed significant for metabolic syndrome score 3 [1.433 (95% confidence interval, 1.010-2.033)] and metabolic syndrome score ? 4 [1.760 (95% confidence interval, 1.216-2.550)]. In addition, the odds ratio of restrictive pulmonary disease of the metabolic syndrome [1.360 (95% confidence interval, 1.118-1.655)] was significantly higher than those of non-metabolic syndrome. CONCLUSION: Metabolic syndrome and metabolic syndrome score were inversely associated with the predicted forced vital capacity and forced expiratory volume in 1 s values in Korean non-smoking adults. In addition, metabolic syndrome and metabolic syndrome score were positively associated with the restrictive pulmonary disease. PMID- 29233017 TI - SOS1 gene polymorphisms are associated with gestational diabetes mellitus in a Chinese population: Results from a nested case-control study in Taiyuan, China. AB - Gestational diabetes mellitus is a growing public health concern due to its large disease burden; however, the underlying pathophysiology remains unclear. Therefore, we examined the relationship between 107 single-nucleotide polymorphisms in insulin signalling pathway genes and gestational diabetes mellitus risk using a nested case-control study. The SOS1 rs7598922 GA and AA genotype were statistically significantly associated with reduced gestational diabetes mellitus risk ( ptrend = 0.0006) compared with GG genotype. At the gene level, SOS1 was statistically significantly associated with gestational diabetes mellitus risk after adjusting for multiple comparisons. Moreover, AGGA and GGGG haplotypes in SOS1 gene were associated with reduced risk of gestational diabetes mellitus. Our study provides evidence for an association between the SOS1 gene and risk of gestational diabetes mellitus; however, its role in the pathogenesis of gestational diabetes mellitus will need to be verified by further studies. PMID- 29233019 TI - 'The expertness of his healer': Diagnosis, disclosure and the power of a profession. AB - Diagnosis is one of medicine's most important tools. It structures the relationship between patient and diagnostician, organises illness and provides access to resources. In this article, I reveal how the manner in which a serious diagnosis is revealed creates a kind of 'epistemic posture' reinforcing the power of medical knowledge, and contributing to medical authority. To achieve this, I explore historical material written by and for doctors about the disclosure of difficult diagnoses. Using historical data for sociological purposes follows Zerubavel, who asserts that phenomena should be studied across eras, media and cultures. I have chosen to focus on how diagnostic disclosure, as described by mid-19th to mid-20th century doctors, serves to promote the profession of medicine. The means of revealing a diagnosis served as a demonstration of, and a means for deflecting threats to, medicine's esoteric nature. The historical data provide a novel approach for understanding how diagnosis operates, even today, to confirm the professional status of the doctor. PMID- 29233018 TI - Type 1 diabetic patients have better endothelial function after simultaneous pancreas-kidney transplantation than after kidney transplantation with continued insulin therapy. AB - The purpose of this study was to analyse the influence of simultaneous pancreas kidney or kidney transplantation on endothelial function and systemic inflammation in type 1 diabetic patients with end-stage renal disease. In 39 simultaneous pancreas-kidney, 39 type 1 diabetic kidney and 52 non-diabetic kidney recipients, flow-mediated dilatation was measured. Additionally, blood glycated haemoglobin, serum creatinine and lipids, plasma nitrites [Formula: see text] and nitrates, asymmetric dimethylarginine, soluble vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin, high-sensitivity C reactive protein, tumour necrosis factor-alpha, interleukin 1beta and interleukin 6 concentrations were assessed. During 58 +/- 31 months follow-up period, flow mediated dilatation and [Formula: see text] were greater in simultaneous pancreas kidney than in type 1 diabetic kidney recipients [10.4% +/- 4.7% vs 7.7% +/- 4.2%, p < 0.05 and 0.94 (0.74-1.34) vs 0.24 (0.20-0.43) MUmol/L, p < 0.01, respectively]. In type 1 diabetic patients after simultaneous pancreas-kidney or kidney transplantation, [Formula: see text] correlated with flow-mediated dilatation (r = 0.306, p < 0.05) and with blood glycated haemoglobin (r = -0.570, p < 0.001). The difference in [Formula: see text] was linked to blood glycated haemoglobin and estimated glomerular filtration rate, whereas the difference in flow-mediated dilatation was linked to [Formula: see text]. The levels of inflammatory markers (except soluble vascular cell adhesion molecule-1) were similar in simultaneous pancreas-kidney and type 1 diabetic kidney recipients. Improved endothelial function in type 1 diabetic patients with end-stage renal disease after simultaneous pancreas-kidney compared to kidney transplantation is associated with normalisation of glucose metabolism but not with improvement in plasma pro-inflammatory cytokines. PMID- 29233020 TI - Development of a data-processing method based on Bayesian k-means clustering to discriminate aneugens and clastogens in a high-content micronucleus assay. AB - Genotoxicants can be identified as aneugens and clastogens through a micronucleus (MN) assay. The current high-content screening-based MN assays usually discriminate an aneugen from a clastogen based on only one parameter, such as the MN size, intensity, or morphology, which yields low accuracies (70-84%) because each of these parameters may contribute to the results. Therefore, the development of an algorithm that can synthesize high-dimensionality data to attain comparative results is important. To improve the automation and accuracy of detection using the current parameter-based mode of action (MoA), the MN MoA signatures of 20 chemicals were systematically recruited in this study to develop an algorithm. The results of the algorithm showed very good agreement (93.58%) between the prediction and reality, indicating that the proposed algorithm is a validated analytical platform for the rapid and objective acquisition of genotoxic MoA messages. PMID- 29233021 TI - Amitriptyline modulated Ca2+ signaling and induced Ca2+-independent cell viability in human osteosarcoma cells. AB - Amitriptyline is a widely used tricyclic antidepressant, which acts primarily as a serotonin-norepinephrine reuptake inhibitor. This study examined the effect of amitriptyline on Ca2+ homeostasis and its related mechanism in MG63 human osteosarcoma cells. Amitriptyline evoked cytosolic-free Ca2+ concentrations ([Ca2+]i) rises concentration dependently. Amitriptyline-evoked Ca2+ entry was confirmed by Mn2+-induced quench of fura-2 fluorescence. This entry was inhibited by Ca2+ entry modulators nifedipine, econazole, SKF96365, the protein kinase C (PKC) activator phorbol 12-myristate 13 acetate but was not affected by the PKC inhibitor GF109203X. In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin (TG) inhibited amitriptyline-evoked [Ca2+]i rises by 95%. Conversely, treatment with amitriptyline abolished TG evoked [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 inhibited amitriptyline-evoked [Ca2+]i rises by 70%. Amitriptyline killed cells at 200-500 MUM in a concentration-dependent fashion. Chelating cytosolic Ca2+ with 1,2-bis(2 aminophenoxy)ethane- N, N, N', N'-tetraacetic acid/AM did not reverse amitriptyline-induced cytotoxicity. Collectively, our data suggest that in MG63 cells, amitriptyline induced [Ca2+]i rises by evoking PLC-dependent Ca2+ release from the endoplasmic reticulum and Ca2+ entry via PKC-regulated store-operated Ca2+ entry. Amitriptyline also induced Ca2+-disassociated cell death. PMID- 29233022 TI - Reduced inflammatory response by transcatheter, as compared to surgical aortic valve replacement. AB - OBJECTIVES: The inflammatory response to on-pump cardiac surgery is well known. Systemic inflammatory response syndrome after transcatheter valve implantation (TAVI) has been reported. The objective of this study was to study the inflammatory response during TAVI, and compare with the response during surgical aortic valve replacement. METHODS: Eighteen patients undergoing transcatheter implantation, either by a transfemoral (n = 9) or transaortal (n = 9) approach were compared with eighteen patients admitted for surgical replacement. Blood samples per- and postoperatively were analysed for C3bc, terminal complement complex, myeloperoxidase, macrophage inflammatory protein-1beta, monocyte chemo attractant peptide-1, eotaxin, IL-6 and troponin-T. All markers were measured at defined time points and the areas under the curve were compared. RESULTS: Activation of complement, granulocytes, monocytes and eosinophils were significantly lower in the transcatheter group as compared to the surgical group (<0.01). There was no difference in generation of troponin T and IL-6. A small difference in complement activation was observed between the transfemoral and transaortal placement of TAVI. There was no significant difference in clinical outcomes between the TAVI and surgical groups. DISCUSSION: Activation and release of inflammatory markers was significantly less during with TAVI as compared to SAVR, particularly for markers associated with extracorporeal circulation. TAVI and SAVR generated the same degree of IL-6 and troponin T, indicating that the burden on the myocardial tissue was the same. Clinical Trials: Gov ID: NCT03074838 Unique protocol ID: 2012/7919. PMID- 29233023 TI - Improving the efficacy-safety balance of polypharmacology in multi-target drug discovery. AB - INTRODUCTION: Polypharmacology has emerged as an essential paradigm for modern drug discovery process. Multiple lines of evidence suggest that agents capable of modulating multiple targets in a selective manner may offer also improved balance between therapeutic efficacy and safety compared to single-targeted agents. Areas covered: Herein, the authors review the recent progress made in experimental and computational strategies for addressing the critical challenges with rational discovery of selective multi-targeted agents within the context of polypharmacological modelling. Specific focus is placed on multi-targeted mono therapies, although examples of combinatorial polytherapies are also covered as an important part of the polypharmacology paradigm. The authors focus mainly on anti-cancer treatment applications, where polypharmacology is playing a key role in determining the efficacy-toxicity trade-off of multi-targeting strategies. Expert opinion: Even though it is widely appreciated that complex polypharmacological interactions can contribute both to therapeutic and adverse side-effects, systematic approaches for improving this balance by means of integrated experimental-computational strategies are still lacking. Future developments will be needed for comprehensive collection and harmonization of systems-wide target selectivity data, enabling better utilization and control for multi-targeted activities in the drug development process. Additional areas of future developments include model-based strategies for drug combination screening and improved pre-clinical validation options with animal models. PMID- 29233025 TI - Ralstonia eutropha H16 in progress: Applications beside PHAs and establishment as production platform by advanced genetic tools. AB - Ralstonia eutropha strain H16 is a Gram-negative non-pathogenic betaproteobacterium ubiquitously found in soils and has been the subject of intensive research for more than 50 years. Due to its remarkable metabolically versatility, it utilizes a broad range of renewable heterotrophic resources. The substrate utilization range can be further extended by metabolic engineering as genetic tools are available. It has become the best studied "Knallgas" bacterium capable of chemolithoautotrophic growth with hydrogen as the electron donor and carbon dioxide as the carbon source. It also serves as a model organism to study the metabolism of poly(beta-hydroxybutyrate), a polyester which is accumulated within the cells for storage of both carbon and energy. Thermoplastic and biodegradable properties of this polyhydroxyalkanoate (PHA) have attracted much biotechnical interest as a replacement for fossil resource-based plastics. The first applications of R. eutropha aimed at chemolithoautotrophic production of single cell protein (SCP) for food and feed and the synthesis of various PHAs. The complete annotated genome is available allowing systematic biology approaches together with data provided by available omics studies. Besides PHAs, novel biopolymers of 2-hydroxyalkanoates and polythioesters or cyanophycin as well as chemicals such as alcohols, alkanes, alkenes, and further interesting value added chemicals significantly recently extended the range of products synthesized by R. eutropha. High cell density cultivations can be performed without too much effort and the available repertoire of genetic tools is rapidly growing. Altogether, this qualifies R. eutropha strain H16 to become a production platform strain for a large spectrum of products. PMID- 29233026 TI - Evaluation of 4-methyl-2-[(2-methylbenzyl) amino]-1,3-thiazole-5-carboxylic acid against hyperglycemia, insulin sensitivity, and oxidative stress-induced inflammatory responses and beta-cell damage in the pancreas of streptozotocin induced diabetic rats. AB - 4-Methyl-2-[(2-methylbenzyl) amino]-1,3-thiazole-5-carboxylic acid (bioactive compound (BAC)), a novel thiazole derivative, is a xanthine oxidase inhibitor and free radical scavenging agent. Effects of BAC on hyperglycemia, insulin sensitivity, oxidative stress, and inflammatory mediators were evaluated in streptozotocin (STZ)-induced neonatal models of non-insulin-dependent diabetes mellitus (NIDDM) rats where NIDDM was induced in neonatal pups with single intraperitoneal injection of STZ (100 mg/kg). The effect of BAC (10 and 20 mg/kg, p.o.) for 3 weeks was evaluated by the determination of blood glucose, oral glucose tolerance test (OGTT), HbA1c level, insulin level, insulin sensitivity, and insulin resistance (IR). Furthermore, inflammatory mediators (tumor necrosis factor-alpha and interleukin-6) and oxidative stress were estimated in serum and pancreatic tissue, respectively. Significant alteration in the level of blood glucose, OGTT, HbA1c, insulin level, insulin sensitivity, in addition variation in the antioxidant status and inflammatory mediators, and alteration in histoarchitecture of pancreatic tissue confirmed the potential of BAC in STZ induced neonatal models of NIDDM rats. Pretreatment with BAC restored the level of glucose by decreasing the IR and increasing the insulin sensitivity. Furthermore, BAC balanced the antioxidant status and preserved the inflammatory mediators. Histological studies of pancreatic tissues showed normal architecture after BAC administration to diabetic rats. Altogether, our results suggest that BAC successfully reduces the blood glucose level and possesses antioxidant as well as anti-inflammatory activities. This leads to decreased histological damage in diabetic pancreatic tissues, suggesting the possibility of future diabetes treatments. PMID- 29233027 TI - Effects of phosphodiestrase type 5 inhibitors in epinephrine-induced arrhythmia in rats: Involvement of lactate dehydrogenase and creatine kinase downregulation and adiponectin expression. AB - Cardiac arrhythmia is a common cause of mortality, and its progression may be due to abnormal sympathetic nerve activity and catecholamine release. Besides, lactate dehydrogenase (LDH) and creatine kinase (CK) downregulation and adiponectin expression play important roles in promoting coronary artery disease. The study aimed to examine the possible cardioprotective effect of members of phosphodiesterase type 5 (PDE-5) inhibitors in epinephrine-induced arrhythmia in rats. Arrhythmia was induced by cumulative boluses of epinephrine (4, 8, 16, 32, 64, and 128 mg/kg) given at 10-min intervals. Rats were randomly allocated into five groups. Group I: Normal control group received only saline. Group II: Rats injected with epinephrine and served as arrhythmia group. Groups III, IV, and V: Rats received daily oral sildenafil (0.5 mg/kg), vardenafil (3 mg/kg), and tadalafil (10 mg/kg), respectively, for 30 days prior to epinephrine injections. Injection of epinephrine to rats decreased heart rate and QTc interval but increased RR interval and duration of arrhythmia. Epinephrine group had lower serum reduced glutathione (GSH) and adiponectin levels and higher serum malondialdehyde (MDA), nitric oxide (NO), heart LDH, and CK contents. Histopathological investigations of epinephrine group provoked necrotic changes with strong positive immunoreactivity for caspases-3. While pretreatment of rats with PDE-5 inhibitors improved GSH and adiponectin contents, ameliorated serum MDA and NO levels and heart LDH and CK contents and corrected epinephrine-induced histopathological changes. PDE-5 inhibitors may delay epinephrine-induced arrhythmia through expression of adiponectin and downregulation of heart LDH and CK. PMID- 29233029 TI - Molecular hepatoprotective effects of lipoic acid against carbon tetrachloride induced liver fibrosis in rats: Hepatoprotection at molecular level. AB - BACKGROUND: Liver fibrosis is a noteworthy well-being issue that can prompt the progression of liver cirrhosis and hepatocellular carcinoma. Prominently, many antioxidants have been shown to have defensive impacts against liver fibrosis. AIM: Subsequently, in the present study, the viability of alpha-lipoic acid (alpha-LA) in ensuring against carbon tetrachloride (CCl4)-actuated liver fibrosis and the mechanism(s) involved in this defensive impact were considered in rats. RESULTS: The present results uncovered that in the CCl4-treated group, the expression of antioxidant enzymes and matrix metalloproteinase-13 (MMP-13) messenger RNA (mRNA) was downregulated ( p < 0.05), and the levels of lipid peroxide and nitric oxide were increased ( p < 0.05) in the treated rat livers along with increased collagen deposition compared to that of the control group. Also, the gene expression levels of the proinflammatory factors interleukin-6 and tumor necrosis factor-alpha, nuclear factor-kappa B (NF-kappaB) p65, transforming growth factor-alpha, and inducible nitric oxide synthase (iNOS) were upregulated significantly ( p < 0.05) in the CCl4 group. These negative impacts were all restrained by alpha-LA. CONCLUSIONS: These outcomes show that alpha-LA might be compelling at forestalling collagen deposition and hepatic oxidative stress as well as downregulating the expression of hepatic proinflammatory cytokines, iNOS, and NF-kappaB and upregulating MMP-13 expression. PMID- 29233030 TI - Hydrodynamic cavitation as a strategy to enhance the efficiency of lignocellulosic biomass pretreatment. AB - Hydrodynamic cavitation (HC) is a process technology with potential for application in different areas including environmental, food processing, and biofuels production. Although HC is an undesirable phenomenon for hydraulic equipment, the net energy released during this process is enough to accelerate certain chemical reactions. The application of cavitation energy to enhance the efficiency of lignocellulosic biomass pretreatment is an interesting strategy proposed for integration in biorefineries for the production of bio-based products. Moreover, the use of an HC-assisted process was demonstrated as an attractive alternative when compared to other conventional pretreatment technologies. This is not only due to high pretreatment efficiency resulting in high enzymatic digestibility of carbohydrate fraction, but also, by its high energy efficiency, simple configuration, and construction of systems, besides the possibility of using on the large scale. This paper gives an overview regarding HC technology and its potential for application on the pretreatment of lignocellulosic biomass. The parameters affecting this process and the perspectives for future developments in this area are also presented and discussed. PMID- 29233028 TI - Therapeutic effects of oral liothyronine on aluminum phosphide poisoning as an adjuvant therapy: A clinical trial. AB - BACKGROUND: In aluminum phosphide (AlP) poisoning, death is mainly due to cardiovascular failure and refractory acute heart failure. There is a lot of evidence showing thyroid hormones have cardioprotective effects. OBJECTIVE: The purpose of this study was to evaluate the effect of oral liothyronine in the treatment of AlP poisoning. METHODS: Twenty-four patients from intensive care unit of Baharloo Hospital, Tehran, Iran, were included based on the inclusion and exclusion criteria. They were randomly divided into two parallel groups of 12 cases and 12 controls. Intervention in the case group was administration of 50 ug liothyronine via nasogastric tube after gastric lavage, in the first 6 h of poisoning. In both groups, the routine treatment of AlP poisoning was performed. Blood samples were prepared at the beginning of the study and after 12 h. Patients were followed up till discharge from the hospital or death. RESULTS: The findings demonstrated that oral liothyronine was able to significantly improve systolic blood pressure, arterial blood pH, and total thiol molecules and also could decrease lipid peroxidation, increase catalase activity, and prevent further decline in total antioxidant capacity. CONCLUSION: Liothyronine administration is effective in controlling AlP poisoning and can improve patients' outcome. PMID- 29233031 TI - The endoscopic surveillance of the transplanted small intestine: a single center experience and a proposal for a grading score. AB - OBJECTIVE: Microscopic examination of endoscopic biopsies forms the basis of acute cellular rejection (ACR) monitoring after intestinal transplantation (ITx). The endoscopy findings during acute rejection (AR) are known but a grading system for its severity is lacking. We designed and implemented a five-stage grading score based on acknowledged endoscopic features of AR, to allow a faster preliminary diagnosis of AR and intra- and interpatient comparisons. METHODS: Two investigators reviewed and graded the endoscopy reports after 28 ITx using a novel score and correlated the results with pathology findings. RESULTS: We reviewed 512 ileoscopies: 370 examinations (74%) were normal (G0), 59 had mild alterations (erythema, edematous villi-G1) and 36 showed moderate changes (erosions, blunted villi-G2); 17 ileoscopies revealed advanced changes (ulcerations, villus loss-G3). In 18 endoscopies the changes were severe (mucosal loss-G4). Inter-reviewer agreement was very good (kappa = 0.81). Biopsies from 86 endoscopy sessions (17%) indicated ACR with 63 cases having moderate or severe ACR. For mild ACR the sensitivity of the score was 29% and the specificity was 86% whereas the positive (PPV) and negative predictive values (NPVs) were 14% and 93% respectively. During advanced ACR the sensitivity and specificity were 92% and 86%, respectively whereas the PPV and NPV were 49% and 98% respectively. CONCLUSIONS: Endoscopy alone has a limited ability to reliably diagnose intestinal ACR. We suggest a novel grading score summarizing ACR findings and allowing comparisons between intestinal graft endoscopies. PMID- 29233032 TI - The impact of laboratory chow for rats in the experiments: Chemical and biological evaluation of nine grain-based diet options. AB - Cereal-based diets formulated as semi-purified diets can provide flexibility for researchers, enabling open controlled formulas, besides being cheaper than purified diets. Seeking to widen the researchers' options in their experimental design developments, we aimed at assaying the chemical score, growth performance and protein utilization of nine semi-purified experimental chows. These diets were formulated at 17.8%, 12% and 8% protein contents, using three variations of ingredients for each one, as follows: casein (C), casein+soybean meal (C+S, 1:1 w/w protein) and casein+soybean meal+corn gluten meal (C+S+G, 1:1:1 w/w protein), without cysteine supplementation and setting casein 17.8% (AIN-93G) as reference diet. The diets C and C+S (17.8%) had the Cys as the limiting amino acid once the addition of gluten turns the Lys as second limiting. All diets had the potential for promoting growth with body mass gain, feed conversion ratio (FCR; chow consumed per body weight gain, average 3.12) and feed efficiency ratio (FER; body weight gain per chow consumed, average 0.3), except for C+S+G 8% (FCR = 6 g; FER = 0.13). These variations were mainly due to the protein amounts independently from the protein ingredient used and could characterize the C+S+G 8% as unable to support growth. For the other parameters (digestibility, net protein ratio, net protein utilization and protein efficiency ratio), there were no relevant differences between the diets. We can conclude that 17.8%, 12% and 8% chows (C and C+S) allowed a proper combination of ingredients from the point of view of palatability, nutrient availability/utilization, metabolic processes, growth performance and feed utilization parameters. PMID- 29233033 TI - Influence of age on arsenic-induced behavioral and cholinergic perturbations: Amelioration with zinc and alpha-tocopherol. AB - This study was planned to determine arsenic (As) (10 mg/kg body weight given through oral gavage) induced behavioral and cholinergic perturbations in three different age groups of rats; young (postnatal day 21), adult (3 months), and aged (18 months) at 7 days post-acute exposure ( n = 6 for each of the four groups of all three age points). Further, we also evaluated the ameliorative effect of essential metal zinc (Zn; 0.02% through drinking water) and an antioxidant, alpha-tocopherol (vitamin E; 125 mg/kg body weight through oral gavage) against As-induced neurotoxicity. As exposure showed significant alterations in behavioral functions (open-field behavior, total locomotor activity, grip strength, exploratory behavior, and water maze learning). Cholinergic studies in three brain regions (cerebral cortex, cerebellum, and hippocampus) of different age groups also showed significant increase in acetylcholine levels and a decrease in acetylcholinesterase activity. These effects were more pronounced in hippocampus followed by cerebral cortex and cerebellum. Among the three different age points, aged animals were found to be more vulnerable to the As-induced toxicity as compared to young and adult animals suggesting that As neurotoxicity is age dependent. These As-induced alterations were significantly reversed following supplementation with Zn or vitamin E. However, vitamin E was found to elicit greater protection as compared to Zn in restoring the altered behavioral and cholinergic perturbations, providing evidence for As-induced oxidative damage. PMID- 29233034 TI - Base deficit is a predictor of mortality in organophosphate insecticide poisoning. AB - OBJECTIVE: Organophosphate insecticide (OPI) self-poisoning is a major medical problem in many countries. Several studies have demonstrated that the base deficit (BD) is a prognostic tool that is correlated with the severity of injury and predicted mortality, particularly in trauma patients. Here, we aimed to investigate the prognostic significance of BD in OPI poisoning. METHODS: This retrospective observational study was conducted between January 1, 2006, and January 31, 2015, at a single emergency department (ED). The BD values were divided into quartiles according to the number of patients: 3 mEq/L or less, 3 5.9 mEq/L, 6-9.9 mEq/L, and 10 mEq/L or greater. Survival at 30 days from ED admission was estimated using the Kaplan-Meier survival analysis. RESULTS: Among 154 patients, 31 died, yielding a mortality of 20.1%. The highest BD quartile (>= 10 mEq/L) and the 6-9.9 mEq/L group were associated with an increased risk of 30 day mortality. Patients with a BD of 10 mEq/L or greater had a 5.85-fold higher risk of 30-day mortality and patients with a BD of 6-9.9 mEq/L had a 5.40-fold higher risk of 30-day mortality compared to patients with a BD of 3 mEq/L or less. The area under the curves of the BD and the Acute Physiology and Chronic Health Evaluation II score for mortality were 0.748 (95% confidence interval (CI), 0.660-0.835) and 0.852 (95% CI, 0.789-0.915), respectively. CONCLUSIONS: This study showed that the BD is a predictor of 30-day mortality in patients with OPI poisoning. PMID- 29233036 TI - Increased levels of the novel hepatokine fetuin B in patients with intrahepatic cholestasis of pregnancy. AB - OBJECTIVES: To investigate liver-derived plasma protein fetuin B levels in healthy pregnant women and pregnant women with intrahepatic cholestasis of pregnancy (ICP). MATERIALS AND METHODS: Forty women with ICP and 40 healthy pregnant women were included in this cross-sectional study. The serum fetuin B levels of these patients were analyzed. The patients were followed up to delivery. RESULTS: Maternal age, gravida, parity, BMI at assessment, and gestational age at blood sampling were similar between the ICP and control groups (p > .05). However, the gestational age at delivery and the birth weight were significantly lower in the ICP group (p < .05). Total bile acid (TBA) levels and liver function tests were significantly higher in the ICP group than in the control group (p < .0001 and < .0001, respectively). In addition, serum fetuin B concentrations were significantly higher in the ICP group than in the control group (p < .0001). The best cutoff for fetuin B serum concentration was 5540.2 pg/mL. Serum values greater than this threshold had 80% sensitivity and 65% specificity for the diagnosis of ICP. CONCLUSIONS: Serum fetuin B was higher in patients with ICP compared to healthy pregnant women and might be a new biomarker. PMID- 29233035 TI - From the wound to the bench: exoproteome interplay between wound-colonizing Staphylococcus aureus strains and co-existing bacteria. AB - Wound-colonizing microorganisms can form complex and dynamic polymicrobial communities where pathogens and commensals may co-exist, cooperate or compete with each other. The present study was aimed at identifying possible interactions between different bacteria isolated from the same chronic wound of a patient with the genetic blistering disease epidermolysis bullosa (EB). Specifically, this involved two different isolates of the human pathogen Staphylococcus aureus, and isolates of Bacillus thuringiensis and Klebsiella oxytoca. Particular focus was attributed to interactions of S. aureus with the two other species, because of the high staphylococcal prevalence among chronic wounds. Intriguingly, upon co cultivation, none of the wound isolates inhibited each other's growth. Since the extracellular proteome of bacterial pathogens is a reservoir of virulence factors, the exoproteomes of the staphylococcal isolates in monoculture and co culture with B. thuringiensis and K. oxytoca were characterized by Mass Spectrometry to explore the inherent relationships between these co-exisiting bacteria. This revealed a massive reduction in the number of staphylococcal exoproteins upon co-culturing with K. oxytoca or B. thuringiensis. Interestingly, this decrease was particularly evident for extracellular proteins with a predicted cytoplasmic localization, which were recently implicated in staphylococcal virulence and epidemiology. Furthermore, our exoproteome analysis uncovered potential cooperativity between the two different S. aureus isolates. Altogether, the observed exoproteome variations upon co-culturing are indicative of unprecedented adaptive mechanisms that set limits to the production of secreted staphylococcal virulence factors. PMID- 29233037 TI - Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein can reflect systemic lupus erythematosus activity. AB - Serum Mac-2-binding protein (M2BP) is elevated in various chronic inflammatory diseases, and evidence suggests that glycosylation of M2BP induces discrete biological effects. However, the role of serum M2BP in systemic lupus erythematosus (SLE) is still unclear. Recently, a Wisteria floribunda agglutinin positive-M2BP (WFA+-M2BP) immunoassay has shown promise in detecting highly glycosylated M2BP. In this study, by using WFA+-M2BP immunoassay, we measured serum M2BP in 203 SLE patients and evaluated its clinical significance. Eighty patients were classified as having active SLE and 123 patients as having inactive SLE. The median serum M2BP was higher in patients with active SLE than in those with inactive SLE (2.1 vs. 0.9, p < 0.001). In multivariate linear regression analysis, serum M2BP, anti-dsDNA, C3 and erythrocyte sedimentation rate (ESR) were associated with SLEDAI-2K. Serum M2BP also strongly correlated with laboratory variables related to SLEDAI-2K, ESR and C-reactive protein. Furthermore, multivariate logistic regression analysis demonstrated that serum M2BP was useful in predicting active SLE. Finally, following immunosuppressive treatment, elevated serum M2BP significantly decreased along with improvement in disease activity. These findings suggest that serum M2BP might contribute to the inflammatory process in SLE, and measuring serum M2BP might be a useful marker to assess SLE disease activity. PMID- 29233038 TI - Juvenile systemic lupus erythematosus in Turkey: demographic, clinical and laboratory features with disease activity and outcome. AB - Objectives This paper aims to assess in a retrospective fashion the clinical and laboratory features, severity and outcome of juvenile systemic lupus erythematosus (jSLE) from a referral center in Turkey. Methods We have included all jSLE patients ( n = 92) diagnosed according to the revised American College of Rheumatology 1997 criteria between January 2004 and January 2017. Results The most prevalent clinical feature in our cohort was mucocutaneous manifestations (97.8%), followed by constitutional (81.5%), hematological (59.8%) and musculoskeletal manifestations (56.5%). Renal involvement was observed in 38% ( n = 35) of the patients, whereas biopsy-proven lupus nephritis was detected in 29.3% ( n = 27) of the cohort. Neurologic involvement was seen in 15 (16.3%) individuals. Among the patients positive for anticardiolipin IgM and/or IgG ( n = 11, 12%), only three developed antiphospholipid antibody syndrome. The mean SLEDAI-2K scores at disease onset (10.5 +/- 4.8) showed a substantial decrease at last visit (4.3 +/- 4.6). One-quarter of the patients (26.1%, n = 24) had damage according to the PedSDI criteria with a mean score of 0.45 +/- 1.0 (range 0-7). When the PedSDI damage items were evaluated individually, growth failure was the most frequent damage criterion ( n = 6), followed by seizure ( n = 5). Two patients died during the designated study period of end-stage renal disease. The five-year and 10-year survival rate of our cohort was 100% and 94.4%, respectively. Conclusions Given the lower frequency of nephritis and central nervous system disease and lower basal disease activity and damage scores, we could conclude that children with jSLE in Turkey have a more favorable course compared to Asian and African American children, as expected from Caucasian ethnicity. PMID- 29233039 TI - Characterization, antibacterial, total antioxidant, scavenging, reducing power and ion chelating activities of green synthesized silver, copper and titanium dioxide nanoparticles using Artemisia haussknechtii leaf extract. AB - Recently, major problem related to pathogenic bacteria is augmentation of antibiotic resistance which has been changed treatment and recovery of millions of infectious patients. The present study reports an eco-friendly, rapid and easy method for synthesis of silver (Ag), copper (Cu) and titanium dioxide (TiO2) nanoparticles (NPs) using Artemisia haussknechtii leaf aqueous extract with antibacterial activities against multi-drug resistance (MDR) bacteria species. Three different concentrations (0.001, 0.01 and 0.1 M) of AgNO3, CuSO4 and TiO (OH)2 were investigated for obtaining optimum NPs green synthesis. Total phenolic content, total flavonoid content of leaf extract and total antioxidant activity (DPPH) assay were determined as radical scavenging methods. UV-Visible spectroscopy, Fourier transform infrared spectroscopy analysis, X-ray diffraction, energy dispersive X-ray spectroscopy, field emission scanning electron microscope and atomic force microscopy (AFM) were used due to NPs characterization. The size average of the Ag, Cu and TiO2 NPs obtained were respectively 10.69 +/- 5.55, 35.36 +/- 44.4 and 92.58 +/- 56.98 nm. In the case of antibacterial assay, disc diffusion assay, minimum inhibitory concentration, minimum bactericidal concentration, bacterial growth and morphology of four MDR species Staphylococcus aureus ATCC 43300, Staphylococcus epidermidis ATCC 12258, Serratia marcescens ATTC13880 and Escherichia coli ATCC 25922 were evaluated. Results of this study demonstrated that A. haussknechtii leaf extract with various groups of phytochemicals such as phenols and flavonoids had suitable ability in green synthesis of Ag, Cu and TiO2 NPs. Also, Ag and Cu NPs had more antibacterial activities compared to TiO2 NPs. PMID- 29233040 TI - Integrin-beta4 is a novel transcriptional target of TAp73. AB - As a member of p53 family, p73 has attracted intense investigations due to its structural and functional similarities to p53. Among more than ten p73 variants, the transactivation (TA) domain-containing isoform TAp73 is the one that imitates the p53's behavior most. TAp73 induces apoptosis and cell cycle arrest, which endows it the capacity of tumour suppression. Also, it can exert diverse biological influences on cells through activating a complex and context dependent transcriptional programme. The transcriptional activities further broaden its roles in more intricate biological processes. In this article, we report that p73 is a positive regulator of a cell adhesion related gene named integrin beta4 (ITGB4). This finding may have implications for the dissection of the biological mechanisms underlining p73 functions. PMID- 29233041 TI - Cardiotoxicity evaluation of nine alkaloids from Rhizoma Coptis. AB - PURPOSE: Alkaloids derived from Rhizoma Coptis (RC) has been widely applied to clinical treatments in China. However, the toxicity of RC and the alkaloids from RC remained controversial. The research is designed to clarify the cardiotoxic compounds found in RC. METHODS: In this study, the real-time cellular analysis cardio system and the high-content analysis were applied to monitor the function of cardiomyocytes (CMs) in the treatment of nine alkaloids in RC. Luciferase coupled adenosine triphosphate (ATP) assay was used to detect cell viability. RESULTS: The results showed that berberine, palmatine, berbamine, and oxyberberine were cardiotoxic, which resulted in arrhythmia and cardiac arrest on CMs in a time- and dose-dependent manner. Meanwhile, berbamine and oxyberberine caused shrinkage and detachment on CMs at 10 MUM. Cytotoxicity was induced by these two compounds with decline in cell index and ATP depletion. Cardiotoxicity or cytotoxicity was not observed in the other five alkaloids within 10 MUM. CONCLUSION: For the first time, the cardiotoxicity of the nine alkaloids was evaluated to clarify the cardiotoxic components in RC. Furthermore, the experimental evidences were provided to support the safety of drug application. PMID- 29233042 TI - Healthcare Utilization Characteristics for Intranasal Midazolam Versus Rectal Diazepam. AB - To investigate connections between patient demographics, health care utilization, prescription use, and refills for patients using intranasal midazolam, per rectum diazepam, or both. A retrospective cohort contained patients with epilepsy prescribed intranasal midazolam, per rectum diazepam, or both. We analyzed number of emergency department visits, ambulance services, urgent care visits, and unplanned hospitalizations. A total of 5458 patients were identified. Patients on intranasal midazolam had on average 1.53 fewer emergency department visits (95% confidence interval 1.16-1.89, P < .0001), 0.29 fewer uses of ambulance services (95% confidence interval 0.17-0.41, P < .0001), and 0.60 fewer urgent care visits (95% confidence interval 0.36-0.83, P < .0001) compared to patients in the per rectum diazepam group. Patients with commercial insurance were more likely to have intranasal midazolam prescription (odds ratio = 1.73, 95% confidence interval 1.42-2.11, P < .0001). The results substantiate the cost-effective benefits of prescribing intranasal midazolam compared to per rectum diazepam because several aspects of health care utilization were decreased in those using intranasal midazolam. PMID- 29233043 TI - Topical dimethyl sulfoxide inhibits corneal neovascularization and stimulates corneal repair in rabbits following acid burn. AB - Neovascularization of the cornea is characterized by the growth of blood vessels caused by imbalances between angiogenic and anti-angiogenic factors. We investigated whether the expression of Vascular endothelial growth factor (VEGF), Vascular endothelial growth factor receptor (VEGF), Vascular endothelial growth inhibitor (VEGI) receptors, as well as topical drug treatments, participate in regulating corneal neovascularization after corneal damage and remodeling. We used 72 mature male New Zealand rabbits. Corneal burns were induced by hydrofluoric acid under general anesthesia. The rabbits then were treated with indomethacin or dimethyl sulfoxide (DMSO). The animals were euthanized on days 2, 7 and 14 after injury. Each cornea was fixed with 10% neutral formalin. On days 2, 7 and 14, VEGF, flk1/KDR and flt1/fms were strongly expressed in the epithelial, stromal and inflammatory cells, but not in the corneal endothelial cells. On day 7, newly formed blood vessels were observed growing toward the center of the cornea. In the control, indomethacin treated, DMSO-treated, and indomethacin + DMSO-treated animals, VEGI, VEGF, and the receptors, flk1/KDR, flt1/fms and flt4, were expressed at different densities in the neovascular regions. This was particularly evident in the indomethacin- and indomethacin + DMSO-treated groups on days 7 and 14, compared to day 2. Treatment with VEGF and DMSO stimulated repair of corneal damage. We suggest that VEGI in the endothelial cells of neovascularized cornea may act as a signaling protein that promotes balance between cell proliferation and apoptosis. Topical administration of DMSO inhibited corneal neovascularization more effectively than indomethacin. PMID- 29233044 TI - Haplotype-based association of renin gene polymorphisms with essential hypertension in Han population of northern china. AB - INTRODUCTION: The renin gene has been suggested as a good candidate in the study of genetic mechanism of essential hypertension. However, studies on the contribution of renin gene polymorphisms to essential hypertension, have not had consistent outcomes. The purpose of the present study is to explore the association of renin gene polymorphisms with essential hypertension in the Han population of northern China. METHODS: A case-control study was conducted among 3090 Han farmers (1533 essential hypertension patients and 1557 normotensives). Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and polymerase chain reaction-sequencing. RESULTS: The genotypic and allelic distributions of rs2368564 in essential hypertension and control was significant statistically ( p<0.001). The allelic distribution of rs10900557 showed marginal statistical significance ( p=0.048). There were no significant differences in other genotypic and allelic distributions ( p>0.05). In the haplotypes comprised by the six single-nucleotide polymorphisms, there were differences in the distribution of haplotypes A-T-C-G-C-A, A-T-C-G-C-G, G-C-T-G-T A and G-C-T-G-T-G in both groups, and their differences reached to significant levels, respectively. After having corrected for false discovery rate, this association still remained significant. CONCLUSIONS: The current study provides evidence for a possible association of renin gene polymorphisms with essential hypertension in a Han population of northern China. PMID- 29233046 TI - How is a new category "born"? On mechanisms of formation, cycles of recognition, and the looping effect of "national trauma". AB - This article explores the mechanisms underlying the formation of a new category in the Israeli therapeutic field-"national trauma." By comparing the two different paths of emergence of this category, the research reexamines the meaning of Hacking's concept "looping effect" and, in particular, the issue of awareness of the categorized individuals and the categorizing knowledge-producers to the effects of a categorization. This study demonstrates that the formation of "national trauma" is both an intentional product of the efforts and ideology of practitioners and an unintentional outcome of their scientific and interventional activities. The comparative analysis allows us to elaborate the distinctions between the different social circles of recognition of new professional categories and different forms of affinity between the new category and an established social group. Understanding these distinctions is particularly valuable in relation to those problematic cases in which the new professional category is a highly contested object. PMID- 29233045 TI - The alpha-amylase and alpha-glucosidase inhibitory activities of the dichloromethane extracts and constituents of Ferulago bracteata roots. AB - CONTEXT: Ferulago (Apiaceae) species have been used since ancient times for the treatment of intestinal worms, hemorrhoids, and as a tonic, digestive, aphrodisiac, or sedative, as well as in salads or as a spice due to their special odors. OBJECTIVES: This study reports the alpha-amylase and alpha-glucosidase inhibitory activities of dichloromethane extract and bioactive compounds isolated from Ferulago bracteata Boiss. & Hausskn. roots. MATERIALS AND METHODS: The isolated compounds obtained from dichloromethane extract of Ferulago bracteata roots through bioassay-guided fractionation and isolation process were evaluated for their in vitro alpha-amylase and alpha-glucosidase inhibitory activities at 5000-400 ug/mL concentrations. Compound structures were elucidated by detailed analyses (NMR and MS). RESULTS: A new coumarin, peucedanol-2'-benzoate (1), along with nine known ones, osthole (2), imperatorin (3), bergapten (4), prantschimgin (5), grandivitinol (6), suberosin (7), xanthotoxin (8), felamidin (9), umbelliferone (10), and a sterol mixture consisted of stigmasterol (11), beta sitosterol (12) was isolated from the roots of F. bracteata. Felamidin and suberosin showed significant alpha-glucosidase inhibitory activity (IC50 0.42 and 0.89 mg/mL, respectively) when compared to the reference standard acarbose (IC50 4.95 mg/mL). However, none of the tested extracts were found to be active on alpha-amylase inhibition. DISCUSSION AND CONCLUSIONS: The present study demonstrated that among the compounds isolated from CH2Cl2 fraction of F. bracteata roots, coumarins were determined as the main chemical constituents of this fraction. This is the first report on isolation and characterization of the bioactive compounds from root extracts of F. bracteata and on their alpha-amylase and alpha-glucosidase inhibitory activities. PMID- 29233047 TI - RNAi of Grp78 may disturb the fusion of ICR mouse palate cultured in vitro. AB - RNA interference (RNAi) is a powerful tool to silence or minimize gene expression, and palate culture in vitro is an important technique for study of the palate development. Our previous study demonstrated that the gene expression of glucose-regulated protein-78 (Grp78) was downregulation in the all-trans retinoic acid-induced mouse models of cleft palate (CP) during embryogenesis. To find the role of Grp78, the small interfering RNA (siRNA) of this gene carried by fluorescent vector was injected with a microinjector, through which about 30 pmol siRNA was injected into the Institute of Cancer Research (ICR) mouse palate explants. After 6, 12, 24, 48, and 72 h, these palate explants were removed from culture to observe their fluorescent and Alcian blue-staining phenotypes, and the expression of the unfolded protein response (UPR) key members (Grp78, Inositol responsive enzyme 1, protein kinase RNA-like endoplasmic reticulum kinase, activating transcription factor-6 and X-box binding protein-1) was measured. After cultured for 72 h, the partially or completely fused bilateral palates were observed in the control siRNA group, while CPs were found in the Grp78 siRNA group. In the Grp78 siRNA group, the relatively mRNA abundance of the key genes belonged to UPR at each time point was lower than that of the control siRNA group, and their protein expression also displayed the same change. By the system of RNAi strategies with mouse palate culture, we found the siRNA of Grp78 disturbed the fusion of mouse palate cultured in vitro. PMID- 29233048 TI - Benzimidazole derivatives endowed with potent antileishmanial activity. AB - Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC50 values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5 trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles. PMID- 29233049 TI - Which Language R You Speaking? /r/ as a Language Marker in Tyrolean and Italian Bilinguals. AB - Across languages of the world the /r/ sound is known for its variability. This variability has been investigated using articulatory models as well as in sociolinguistic studies. The current study investigates to what extent /r/ is a marker of a bilingual's dominant language. To this end, a reading task was carried out by bilingual speakers from South Tyrol, who produce /r/ differently according to whether they dominantly speak Tyrolean or Italian. The recorded reading data were subsequently used in a perception experiment to investigate whether South Tyrolean bilingual listeners are able to identify the dominant language of the speaker. Results indicate that listeners use /r/ as a cue to determine the dominant language of the speaker whilst relying on articulatory distinctions between the variants. It is furthermore shown that /r/ correlates with three interdependent variables: the sociolinguistic background of the speakers, their speech production, and how their speech is perceived. PMID- 29233050 TI - Polo is not solo in meiosis. PMID- 29233051 TI - Analyses of Complaints, Investigations of Allegations, and Deficiency Citations in United States Nursing Homes. AB - Quality of care in nursing homes has been evaluated from varying perspectives, but few studies analyze complaints made to surveyors. This study analyzed complaints, investigations, and citations for nursing homes nationwide. Using the complaint and survey data sets, analyses match nursing home complaints with findings of investigations conducted. Results showed the average complaint rate was 13.3 complaints per 100 residents and that 43.2% of complaint allegations were substantiated, with complaints about care and services provided being the most prevalent. Variability was noted among the Centers for Medicare and Medicaid Services regions and, on average, 47.5% of facilities had five or more complaints in a given year. While additional research could evaluate the effect of complaint investigations on nursing home quality, results indicated that complaints and subsequent investigations provide further information regarding quality for residents. Results also suggest improvements in the training for surveyors and more consistency across Centers for Medicare and Medicaid Services survey regions. PMID- 29233052 TI - Nebulized Heparin With N-Acetylcysteine and Albuterol Reduces Duration of Mechanical Ventilation in Patients With Inhalation Injury. AB - OBJECTIVE: Nebulized heparin has been proposed to improve pulmonary function in patients with inhalation injuries. The purpose of this study was to evaluate the impact of nebulized heparin with N-acetylcysteine (NAC) and albuterol on the duration of mechanical ventilation in burn patients. METHODS: This is a retrospective study evaluating mechanically ventilated adult patients admitted to a regional burn center with inhalation injury. Outcomes were compared between patients who were prescribed a combination of nebulized heparin with NAC and albuterol versus similar patients who did not. RESULTS: A total of 48 patients met inclusion criteria (heparin n = 22; nonheparin n = 26). Patients in the nonheparin group had higher percentage of total body surface area (TBSA) burned (29.00 [5.75-51.88] vs 5.25 [0.50-13.25] %TBSA; P = .009), longer duration of mechanical ventilation (6.50 [2.75-17.00] vs 3.00 [1.00-8.25] days; P = .022), and longer intensive care unit length of stay (LOS) (3.00 [3.00-28.75] vs 5.50 days [2.00-11.25]; P = .033). Upon regression, use of heparin was the only variable associated with reducing the duration of mechanical ventilation ( P = .039). CONCLUSION: Nebulized heparin in combination with NAC and albuterol was associated with a significant reduction in the duration of mechanical ventilation. PMID- 29233053 TI - Evaluation of a Pharmacist-Driven Aldosterone Antagonist Stewardship Program in Patients With Heart Failure. AB - OBJECTIVE: To evaluate the impact of a pharmacist-driven initiative to optimize aldosterone antagonist use in patients with heart failure with reduced ejection fraction (HFrEF) at a large community hospital. METHODS: This single-center, retrospective cohort study compared patients with heart failure before and after the implementation of the initiative. Data for pre- and postinitiative patients were retrospectively collected to assess patient characteristics and aldosterone antagonist use. The primary outcome was a composite of eligible patients with heart failure discharged on aldosterone antagonist therapy or with a documented reason for ineligibility before and after commencement of pharmacist-driven aldosterone antagonist initiative. RESULTS: The preinitiative cohort included 96 patients and the postinitiative cohort contained 92 patients. When the 3 month pre- and postinitiative groups were assessed, the primary outcome was noted in 60 (63%) of 96 patients in the preinitiative group and 87 (95%) of 92 patients in the postinitiative group ( P < .0001). CONCLUSION: In patients with HFrEF, a pharmacist-driven aldosterone antagonist optimization initiative significantly increased appropriate prescribing and documentation for aldosterone antagonist therapy. PMID- 29233054 TI - Pretreatment serum lactate dehydrogenase as a prognostic indicator for oral cavity squamous cell carcinoma. AB - OBJECTIVES: To examine whether lactate dehydrogenase (LDH) can predict the prognosis of oral cavity squamous cell carcinoma (OSCC) and to determine the optimal cut-off values for LDH. METHODS: This retrospective study included 184 patients with OSCC, treated with surgery between 2006 and 2014. The association between LDH and T, N classification was investigated using the Mann-Whitney test. Cut-off values for LDH were determined with a recursive partitioning analysis (RPA). Survival rates were estimated using the Kaplan-Meier method. A Cox hazard model was used to assess the prognostic capability of LDH. RESULTS: There was no association between LDH and T or N classification (p = .657, .619, respectively). RPA determined the cut-off values for LDH as 160 and 220 IU/L. The five year survival for low-, moderate-, and high-LDH groups were 87.7, 73.7, and 50.9%, respectively (p < .001). The hazard ratios (HRs) for death in moderate- and high LDH groups were 2.92 (95%CI =1.02-12.30, p = .001) and 7.36 (95%CI =2.54-31.20, p < .001), respectively. The model including LDH-based stratification (Akaike's information criterion (AIC) = 516) was better than the model including clinical stage (AIC =528). CONCLUSION: Pretreatment serum LDH is an independent prognostic factor for overall survival in patients with OSCC. PMID- 29233055 TI - Universal Screening Program in Pregnant Women and Newborns at-Risk for Sickle Cell Disease: First Report from Northern Italy. AB - The implementation of screening programs for early detection of patients with sickle cell disease has become necessary in Italy as a result of the high rate of migration from areas with a high prevalence of the disease (Sub-Saharan Africa, Middle East and the Balkans). Following a pilot study performed in the province of Modena, Italy in 2011-2013, an official screening program was established on May 31 2014 for all pregnant women, free-of-charge for the family according to the National Guidelines for Physiological Pregnancy. Hemoglobin (Hb) profiles of pregnant women within 10 weeks of pregnancy, of new mothers at delivery and of the newborns of mothers with variant Hb profiles (newborns at-risk), were evaluated by high performance liquid chromatography (HPLC). Samples from 17,077 new mothers were analyzed and 993 showed alteration of Hb patterns (5.8%) (1.0% Hb AS carriers); of the 1011 at-risk newborns, four (0.4%) carried sickle cell disease and 90 (8.9%) were Hb AS carriers. These data show that early diagnosis of sickle cell disease or carrier status can be obtained in high-risk newborns, providing valuable information on the frequency of these conditions in geographic areas in which the disease is historically rare. PMID- 29233056 TI - Looking at the past through a telescope: adults postdated their earliest childhood memories. AB - Our previous studies have consistently shown a telescoping error in children's dating of earliest childhood memories. Preschool children through adolescents systematically date their earliest memories at older ages, in comparison with the age estimates provided by their parents or by themselves previously. In the current study, we examined the dating of earliest childhood memories in two samples of college adults and collected independent age estimates from their parents. Consistent with our findings with children, adults significantly postdated their earlier memories by approximately 12 months (Study 1) and 6 months (Study 2). The actual age of earliest memories was 2.5 years after adjusted for telescoping errors, 1 year earlier than what is commonly believed at 3.5 years. These findings challenge commonly held theoretical assumptions about childhood amnesia and highlight critical methodological issues in the study of childhood memory. PMID- 29233058 TI - Correction to: An et al., Diagnostic role of cone beam computed tomography for the position of straight array. PMID- 29233057 TI - From Servicescape to Loyalty in the Medical Tourism Industry: A Medical Clinic's Service Perspective. AB - Medical tourism organizations have increasingly recognized that loyalty makes a medical clinic a marketing success. To increase understanding of the importance of medical clinics, this study examined the roles of servicescapes, emotions, and satisfaction in the development of customer loyalty toward medical clinics and destination. Data were collected among international medical tourists visiting Korea. Results identified that dimensions of medical clinics' servicescape (ie, medical clinic environment, medical treatment, staff, and doctor) influenced emotions and satisfaction among international medical tourists. Also, positive emotions and the 2 dimensions of satisfaction with a medical clinic and doctor mediate the influence of medical clinics' servicescapes on 2 types of loyalty (the medical clinic and Korea for medical care). Overall, these findings indicate that the interrelationship of servicescapes, positive emotion, and satisfaction is essential in influencing international medical tourists' loyalty to a medical clinic. PMID- 29233059 TI - A new manometry device for evaluating the sphincter of Oddi using a fiber-optic pressure sensor. AB - INTRODUCTION: Although measuring the pressure of the sphincter of Oddi and the bile duct is considered to be an important examination, called Sphincter of Oddi manometry (SOM), some complications related to the SOM device remain unsolved. MATERIAL AND METHODS: To decrease adverse complications, we developed a 0.46 mm manometry and we performed some in vitro studies. RESULTS: We successfully developed a 0.46 mm SOM. The diameter is the thinnest size used in endoscopic examinations. The results of in vitro studies show the suitability as SOM. CONCLUSION: This device will decrease the risks related to SOM examination. To confirm the safety and feasibility, further studies including in vivo studies will be needed. PMID- 29233060 TI - Ignoring theory and misinterpreting evidence: the false belief in fear appeals. AB - Use of fear appeals assumes that when people are emotionally confronted with the negative effects of their behaviour they will change that behaviour. That reasoning is simple and intuitive, but only true under specific, rare circumstances. Risk perception theories predict that if people will experience a threat, they want to counter that threat. However, how they do so is determined by their coping efficacy level: if efficacy is high, they may change their behaviour in the suggested direction; if efficacy is low, they react defensively. Research on fear appeals should be methodologically sound, comparing a threatening to a non-threatening intervention under high and low efficacy levels, random assignment and measuring behaviour as outcome. We critically review extant empirical evidence and conclude that it does not support positive effects of fear appeals. Nonetheless, their use persists and is even promoted by health psychology researchers, causing scientific insights to be ignored or misinterpreted. PMID- 29233061 TI - Inter- and intra-tester reliability of sensibility testing in healthy individuals. AB - Static two-point discrimination (S2PD) and Semmes-Weinstein monofilament (SWM) tests are the most widely used tests for evaluation of sensory deterioration. It is a necessity to know the inter- and intra-tester reliability of these tests to determine the suitability of method. Another important point in evaluation of sensory deterioration is whether or not there is a reference point which can be compared with the test results. So, it is important to know the reliability of sensory evaluation tests on the healthy extremities. The aim of this study was to evaluate the inter- and intra-tester reliability of the S2PD and SWM tests applied to the fingers of healthy individuals. One hundred and sixty three healthy fingers from 83 individuals were included into the study. An experienced orthopaedic surgeon and a physiotherapist examined all the individuals separately. The reliability of the S2PD test was found to be little and low. The reliability of the SWM test was determined as low and moderate. The reproducibility scores of both tests were at a poor level. Therefore, in the evaluation of states with sensory deterioration, the use of the healthy contralateral extremities as a standard reference point could be considered unreliable. Prognosis, grading or follow-up of treatment should not be made according to the results of the S2PD and SWM tests only. It would be more correct to use these tests as a diagnostic tool rather than quantitative follow-up for neurological function in pathological conditions. PMID- 29233062 TI - Possible Age-Related Progression of Attentional Impairment in ADHD and Its Attenuation by Past Diagnosis and Treatment. AB - OBJECTIVE: The aim of the study is to evaluate attentional impairment in different age groups with ADHD. METHOD: In all, 58 children, 73 adolescents, and 104 adults with ADHD were evaluated using the Test of Variables of Attention (TOVA). Subjects with comorbidities or psychotropic treatment were not included. RESULTS: Considering Response Time Variability (RTV), adults were 10.6 and 4.0 times more likely to be severely impaired (standard score < 40) than children and adolescents, respectively. Adults were twice as likely as adolescents to be very impaired (standard score< 70) in Omissions. Considering d' (decrement of attentional performance over time), all severely impaired participants were adults. Age predicted impairment in Attention Performance Index (API), RTV, and d', but not Omissions or Commissions. Past treatment with stimulants predicted less impairment in d', past diagnosis predicted less impairment in RTV, and each predicted less impairment in Omissions and API. CONCLUSION: Adults had more attentional impairment than children and adolescents. Past diagnosis and treatment were associated with less ADHD-related attentional impairment. PMID- 29233063 TI - Can Neoliberal Capitalism Affect Human Evolution? AB - The connection between genes and health outcomes is significantly moderated by social factors. Health inequalities result from the differential accumulation of exposures and resource access rooted in class-based circumstances. In the neoliberal era in the United States, changed physical and socioeconomic conditions facing the poorer members of society have been characterized as traumatogenic (capable of producing a wound or injury). This paper will argue that research that points to the transgenerational influence of environmental impacts on health suggests 2 important reconsiderations of the link between the economy and health. First, an understanding of the health of any society requires an understanding not only of current but also past environmental conditions and the economy that produces those conditions. Second, it suggests that the way in which economic policy is analyzed needs to be reconsidered to incorporate the transgenerational impacts of environmental conditions produced by those policies. PMID- 29233064 TI - Legal strategies to protect sexual and reproductive health and rights in the context of the refugee crisis in Europe: a complaint before the European Ombudsperson. AB - In the context of the refugee crisis in Europe, the measures taken by the institutions and bodies of the European Union as they relate to respecting, protecting, and ensuring human rights have proven to be woefully inadequate. The development of a restrictive, defensive, security-based immigration policy has led to failure by European countries and the European Union to fulfil their human rights obligations. Specifically, the Agreement struck between the European Union and Turkey on 18 March 2016, in addition to externalising borders, placed economic and political considerations centre stage, leading to serious violations of the human rights of refugees and migrants, including their sexual and reproductive rights. In an effort to identify the failures and the institutions responsible for promoting the necessary measures to mitigate the negative impacts these policies have had, the international human rights organisation Women's Link Worldwide lodged a complaint with the European Ombudsperson. In its complaint, Women's Link alleges maladministration by the European Commission for its failure to carry out a human rights impact assessment of the 18 March 2016 EU-Turkey Agreement and the reports on its implementation. Such an assessment should include a gender perspective and a children's rights approach, and its omission is not only a failure to comply with international human rights standards, but also directly and negatively affects women's and children's rights. PMID- 29233065 TI - Understanding the role of glycogen synthase kinase-3 in L-DOPA-induced dyskinesia in Parkinson's disease. AB - INTRODUCTION: Levodopa (L-DOPA) is the most commonly used drug for Parkinson's disease (PD), but its long-term use is associated with various complications, including L-DOPA-induced dyskinesia (LID). Many studies have suggested that L DOPA neurotoxicity and LID are associated with glycogen synthase kinase-3 (GSK-3) activation. Areas covered: LID is caused by striatal dopamine (DA) denervation in PD and pulsatile L-DOPA treatment. These factors lead to dysregulated DA transmission, abnormal intracellular signaling and transcription factors in striatal neurons, and altered gene expression and plasticity at corticostriatal synapses. The mechanisms of L-DOPA toxicity involve oxidative stress, L-DOPA oxidation to quinone, mitochondrial dysfunction, and alpha-synuclein. GSK-3 has been suggested to play key roles in all the mechanisms associated of L-DOPA toxicity and LID in PD. Expert opinion: GSK-3 plays critical roles in L-DOPA induced neurotoxicity, and the development of specific methods to inhibit GSK-3 function may help prevent L-DOPA neurotoxicity and LID in PD. However, balanced GSK-3 inhibition and less beta-catenin degradation is essential for preventing LID, because too much GSK-3 inhibition increases beta-catenin levels, which is related to cancers. PMID- 29233066 TI - Response to Jenny et al. (DOI: 10.1089/neu.2016.4687): Biomechanical Response of the Infant Head to Shaking: An Experimental Investigation. PMID- 29233067 TI - Normobaric hyperoxia after stroke: a word of caution. PMID- 29233068 TI - Altered Functional Expression of beta-Adrenergic Receptors in Rhesus Monkey Embryonic Stem Cell-Derived Cardiomyocytes. AB - Pluripotent stem cells have demonstrated the potential to generate large numbers of functional cardiomyocytes (CMs) from different cell sources. Besides Wnt signaling, additional pathways are involved in early cardiac development and function. To date however, no study exists showing the effects of perturbing the canonical Wnt pathway using nonhuman primate embryonic stem (ES) cells. In this study, we investigated the effect of canonical Wnt inhibition during differentiation of nonhuman primate ES cell-derived CMs under defined, growth factor conditions. Rhesus monkey ES (rES) cells were differentiated into spontaneously beating CMs in the absence (control) or presence (treated) of Wnt inhibitor Dickkopf1 (DKK1), vascular endothelial growth factor, and basic fibroblast growth factor combined or added in a sequential manner during differentiation. Quantification and functional characterization of CMs were assessed by molecular and electrophysiological techniques. Analysis revealed no difference in average ratio of spontaneously beating clusters in both control and treated groups. However, the percentage of CMs was significantly reduced and the expressions of specific cardiac markers tested were also decreased in the treated group. Interestingly, we found that in CMs obtained from treated group, beta adrenergic receptors (beta-ARs) were less expressed, their function was altered and electrophysiological studies revealed differences in action potential responsiveness to beta-AR stimulation. We demonstrated that the Wnt/beta-catenin pathway inhibitor, DKK1 associated with other growth factors repressed functional expression of beta-ARs in rES cell-derived CMs. Thus, control of this pathway in each cell line and source is important for proper basic research and further cell therapy applications. PMID- 29233070 TI - Editorial. PMID- 29233069 TI - Where Next for Opioids and the Law? Despair, Harm Reduction, Lawsuits, and Regulatory Reform. PMID- 29233071 TI - Biomarkers of Stroke Recovery: Consensus-Based Core Recommendations from the Stroke Recovery and Rehabilitation Roundtable. AB - The most difficult clinical questions in stroke rehabilitation are "What is this patient's potential for recovery?" and "What is the best rehabilitation strategy for this person, given her/his clinical profile?" Without answers to these questions, clinicians struggle to make decisions regarding the content and focus of therapy, and researchers design studies that inadvertently mix participants who have a high likelihood of responding with those who do not. Developing and implementing biomarkers that distinguish patient subgroups will help address these issues and unravel the factors important to the recovery process. The goal of the present paper is to provide a consensus statement regarding the current state of the evidence for stroke recovery biomarkers. Biomarkers of motor, somatosensory, cognitive and language domains across the recovery timeline post stroke are considered; with focus on brain structure and function, and exclusion of blood markers and genetics. We provide evidence for biomarkers that are considered ready to be included in clinical trials, as well as others that are promising but not ready and so represent a developmental priority. We conclude with an example that illustrates the utility of biomarkers in recovery and rehabilitation research, demonstrating how the inclusion of a biomarker may enhance future clinical trials. In this way, we propose a way forward for when and where we can include biomarkers to advance the efficacy of the practice of, and research into, rehabilitation and recovery after stroke. PMID- 29233072 TI - Improving the Development, Monitoring and Reporting of Stroke Rehabilitation Research: Consensus-Based Core Recommendations from the Stroke Recovery and Rehabilitation Roundtable. AB - Recent reviews have demonstrated that the quality of stroke rehabilitation research has continued to improve over the last four decades but despite this progress, there are still many barriers in moving the field forward. Rigorous development, monitoring and complete reporting of interventions in stroke trials are essential in providing rehabilitation evidence that is robust, meaningful and implementable. An international partnership of stroke rehabilitation experts committed to develop consensus-based core recommendations with a remit of addressing the issues identified as limiting stroke rehabilitation research in the areas of developing, monitoring and reporting stroke rehabilitation interventions. Work exploring each of the three areas took place via multiple teleconferences and a two-day meeting in Philadelphia in May 2016. A total of 15 recommendations were made. To validate the need for the recommendations, the group reviewed all stroke rehabilitation trials published in 2015 (n=182 papers). Our review highlighted that the majority of publications did not clearly describe how interventions were developed or monitored during the trial. In particular, under-reporting of the theoretical rationale for the intervention and the components of the intervention call into question many interventions that have been evaluated for efficacy. More trials were found to have addressed the reporting of interventions recommendations than those related to development or monitoring. Nonetheless, the majority of reporting recommendations were still not adequately described. To progress the field of stroke rehabilitation research and to ensure stroke patients receive optimal evidence-based clinical care, we urge the research community to endorse and adopt our recommendations. PMID- 29233073 TI - Determining the likely place of HIV acquisition for migrants in Europe combining subject-specific information and biomarkers data. AB - In most HIV-positive individuals, infection time is only known to lie between the time an individual started being at risk for HIV and diagnosis time. However, a more accurate estimate of infection time is very important in certain cases. For example, one of the objectives of the Advancing Migrant Access to Health Services in Europe (aMASE) study was to determine if HIV-positive migrants, diagnosed in Europe, were infected pre- or post-migration. We propose a method to derive subject-specific estimates of unknown infection times using information from HIV biomarkers' measurements, demographic, clinical, and behavioral data. We assume that CD4 cell count (CD4) and HIV-RNA viral load trends after HIV infection follow a bivariate linear mixed model. Using post-diagnosis CD4 and viral load measurements and applying the Bayes' rule, we derived the posterior distribution of the HIV infection time, whereas the prior distribution was informed by AIDS status at diagnosis and behavioral data. Parameters of the CD4-viral load and time-to-AIDS models were estimated using data from a large study of individuals with known HIV infection times (CASCADE). Simulations showed substantial predictive ability (e.g. 84% of the infections were correctly classified as pre- or post-migration). Application to the aMASE study ( n = 2009) showed that 47% of African migrants and 67% to 72% of migrants from other regions were most likely infected post-migration. Applying a Bayesian method based on bivariate modeling of CD4 and viral load, and subject-specific information, we found that the majority of HIV-positive migrants in aMASE were most likely infected after their migration to Europe. PMID- 29233074 TI - "You have to take action": changing knowledge and attitudes towards newborn care practices during crisis in South Sudan. AB - Highest rates of neonatal mortality occur in countries that have recently experienced conflict. International Medical Corps implemented a package of newborn interventions in June 2016, based on the Newborn health in humanitarian settings: field guide, targeting community- and facility-based health workers in displaced person camps in South Sudan. We describe health workers' knowledge and attitudes toward newborn health interventions, before and after receiving clinical training and supplies, and recommend dissemination strategies for improved uptake of newborn guidelines during crises. A mixed methods approach was utilised, including pre-post knowledge tests and in-depth interviews. Study participants were community- and facility-based health workers in two internally displaced person camps located in Juba and Malakal and two refugee camps in Maban from March to October 2016. Mean knowledge scores for newborn care practices and danger signs increased among 72 community health workers (pre-training: 5.8 [SD: 2.3] vs. post-training: 9.6 [SD: 2.1]) and 25 facility-based health workers (pre training: 14.2 [SD: 2.7] vs. post-training: 17.4 [SD: 2.8]). Knowledge and attitudes toward key essential practices, such as the use of partograph to assess labour progress, early initiation of breastfeeding, skin-to-skin care and weighing the baby, improved among skilled birth attendants. Despite challenges in conflict-affected settings, conducting training has the potential to increase health workers' knowledge on neonatal health post-training. The humanitarian community should reinforce this knowledge with key actions to shift cultural norms that expand the care provided to women and their newborns in these contexts. PMID- 29233075 TI - Confidence intervals for differences between volumes under receiver operating characteristic surfaces (VUS) and generalized Youden indices (GYIs). AB - This article explores both existing and new methods for the construction of confidence intervals for differences of indices of diagnostic accuracy of competing pairs of biomarkers in three-class classification problems and fills the methodological gaps for both parametric and non-parametric approaches in the receiver operating characteristic surface framework. The most widely used such indices are the volume under the receiver operating characteristic surface and the generalized Youden index. We describe implementation of all methods and offer insight regarding the appropriateness of their use through a large simulation study with different distributional and sample size scenarios. Methods are illustrated using data from the Alzheimer's Disease Neuroimaging Initiative study, where assessment of cognitive function naturally results in a three-class classification setting. PMID- 29233076 TI - Sea-change in reproductive health in emergencies: how systemic improvements to address the MISP were achieved. AB - The Minimum Initial Services Package (MISP) for reproductive health has been the minimum standard for reproductive health service provision in humanitarian emergencies since 1995. Assessments of acute humanitarian settings in 2004 and 2005 revealed few MISP services in place and low knowledge of the MISP among humanitarian responders. Just 10 years later, assessments of humanitarian settings in 2013 and 2015 found largely consistent availability of MISP services and high awareness of the MISP as a standard among responders. We describe the multi-pronged strategy undertaken by the Women's Refugee Commission and other Inter-agency Working Group on Reproductive Health in Crises (IAWG) member agencies to effect systemic improvements in the availability of the MISP at the onset of humanitarian responses. We find that investments in fact-finding missions, awareness-raising, capacity development, policy harmonisation, targeted funding, emergency risk management, and community resilience-building have been critical to facilitating a sea-change in reproductive health responses in acute, large-scale emergencies. Efforts were underpinned by collaborative, inter-agency partnerships in which organisations were committed to working together to achieve shared goals. The strategies, activities, and achievements contain valuable lessons for the health sector, including reproductive health, and other sectors seeking to better integrate emerging or marginalised issues into humanitarian action. PMID- 29233077 TI - New Technologies: Real-time Telepathology Systems-Novel Cost-effective Tools for Real-time Consultation and Data Sharing. AB - Real-time telepathology for use in investigative and regulated preclinical toxicology studies is now feasible. Newly developed microscope-integrated telepathology systems enable geographically remote stakeholders to view the live histopathology slide as seen by the study pathologist within the microscope. Simultaneous online viewing and dialog between study pathologist and remote colleagues is an efficient and cost-effective means for consultation, pathology working groups, and peer review, facilitating good science and economic benefits by enabling more timely and informed clinical decisions. PMID- 29233079 TI - A Diagnostic Approach for Rodent Progressive Cardiomyopathy and Like Lesions in Toxicology Studies up to 28 Days in the Sprague Dawley Rat (Part 2 of 2). AB - To test the diagnostic approach described in part 1 of this article, 2 exercises were completed by pathologists from multiple companies/agencies. Pathologist's examination of whole slide image (WSI) heart sections from rats using personal diagnostic approaches (exercise #1) corroborated conclusions from study #1. Using the diagnostic approach described in part 1, these pathologists examined the same WSI heart sections (exercise #2) to determine whether that approach increased consistency of diagnosis of rodent progressive cardiomyopathy (PCM) lesions. In exercise #2, there was improved consistency of categorization of small borderline morphologies and mild lesions, but a decrement in consistency of categorizing minimal lesions. Exercises 1 and 2 suggest the described diagnostic approach is representative of that in use by the majority of toxicologic pathologists across companies/agencies and that application by all may improve diagnostic consistency of PCM/like lesions. Additionally, a criterion of approximately 5% heart section involvement is suggested for separating mild from moderate or greater severity. While evidence is not absolute, until further investigation shows otherwise, microscopic changes resembling PCM, but located in the epicardial and subepicardial region of the right ventricle, may be considered as part of the spectrum of PCM. PMID- 29233082 TI - Test procedure and sample size determination for a proportion study using a double-sampling scheme with two fallible classifiers. AB - Double sampling is usually applied to collect necessary information for situations in which an infallible classifier is available for validating a subset of the sample that has already been classified by a fallible classifier. Inference procedures have previously been developed based on the partially validated data obtained by the double-sampling process. However, it could happen in practice that such infallible classifier or gold standard does not exist. In this article, we consider the case in which both classifiers are fallible and propose asymptotic and approximate unconditional test procedures based on six test statistics for a population proportion and five approximate sample size formulas based on the recommended test procedures under two models. Our results suggest that both asymptotic and approximate unconditional procedures based on the score statistic perform satisfactorily for small to large sample sizes and are highly recommended. When sample size is moderate or large, asymptotic procedures based on the Wald statistic with the variance being estimated under the null hypothesis, likelihood rate statistic, log- and logit-transformation statistics based on both models generally perform well and are hence recommended. The approximate unconditional procedures based on the log-transformation statistic under Model I, Wald statistic with the variance being estimated under the null hypothesis, log- and logit-transformation statistics under Model II are recommended when sample size is small. In general, sample size formulae based on the Wald statistic with the variance being estimated under the null hypothesis, likelihood rate statistic and score statistic are recommended in practical applications. The applicability of the proposed methods is illustrated by a real data example. PMID- 29233080 TI - Mathematics ability and related skills in preschoolers born very preterm. AB - Children born very preterm (VPT) are at risk for academic, behavioral, and/or emotional problems. Mathematics is a particular weakness and better understanding of the relationship between preterm birth and early mathematics ability is needed, particularly as early as possible to aid in early intervention. Preschoolers born VPT (n = 58) and those born full term (FT; n = 29) were administered a large battery of measures within 6 months of beginning kindergarten. A multiple-mediation model was utilized to characterize the difference in skills underlying mathematics ability between groups. Children born VPT performed significantly worse than FT-born children on a measure of mathematics ability as well as full-scale IQ, verbal skills, visual-motor integration, phonological awareness, phonological working memory, motor skills, and executive functioning. Mathematics was significantly correlated with verbal skills, visual-motor integration, phonological processing, and motor skills across both groups. When entered into the mediation model, verbal skills, visual motor integration, and phonological awareness were significant mediators of the group differences. This analysis provides insights into the pre-academic skills that are weak in preschoolers born VPT and their relationship to mathematics. It is important to identify children who will have difficulties as early as possible, particularly for VPT children who are at higher risk for academic difficulties. Therefore, this model may be used in evaluating VPT children for emerging difficulties as well as an indicator that if other weaknesses are found, an assessment of mathematics should be conducted. PMID- 29233083 TI - Bootstrap-based procedures for inference in nonparametric receiver-operating characteristic curve regression analysis. AB - Prior to using a diagnostic test in a routine clinical setting, the rigorous evaluation of its diagnostic accuracy is essential. The receiver-operating characteristic curve is the measure of accuracy most widely used for continuous diagnostic tests. However, the possible impact of extra information about the patient (or even the environment) on diagnostic accuracy also needs to be assessed. In this paper, we focus on an estimator for the covariate-specific receiver-operating characteristic curve based on direct regression modelling and nonparametric smoothing techniques. This approach defines the class of generalised additive models for the receiver-operating characteristic curve. The main aim of the paper is to offer new inferential procedures for testing the effect of covariates on the conditional receiver-operating characteristic curve within the above-mentioned class. Specifically, two different bootstrap-based tests are suggested to check (a) the possible effect of continuous covariates on the receiver-operating characteristic curve and (b) the presence of factor-by curve interaction terms. The validity of the proposed bootstrap-based procedures is supported by simulations. To facilitate the application of these new procedures in practice, an R-package, known as npROCRegression, is provided and briefly described. Finally, data derived from a computer-aided diagnostic system for the automatic detection of tumour masses in breast cancer is analysed. PMID- 29233084 TI - A model for meta-analysis of correlated binary outcomes: The case of split-body interventions. AB - In several areas of clinical research, it is common for trials to assign different sites of the participants' bodies to different interventions. For example, a randomized controlled trial comparing surgical techniques for correcting myopia may randomize each eye of a participant to a different operation. Under such bilateral ('split-body') interventions, the observations from each participant are correlated. It is challenging to account for these correlations at the meta-analysis level, especially when the outcome is rare. Here, we present a meta-analysis model based on the bivariate binomial distribution. Our model can synthesize studies on patients who received one intervention at one body site, patients who received two interventions at different sites or a mixture of these two groups. The model can analyse studies with zero events in one or both treatment arms and can handle the case of incomplete data reporting. We use simulations to assess the performance of our model and to compare it with the bivariate beta-binomial model. In the case of bilateral interventions, our model performed well and outperformed the bivariate beta-binomial model in all scenarios explored. We illustrate our methods using two previously published meta-analyses from the fields of orthopaedics and ophthalmology. We conclude that our model constitutes a useful new tool for the meta-analysis of binary outcomes in the presence of split-body interventions. PMID- 29233085 TI - An oncology clinical trial design with randomization adaptive to both short- and long-term responses. AB - In oncology clinical trials, both short-term response and long-term survival are important. We propose an urn-based adaptive randomization design to incorporate both of these two outcomes. While short-term response can update the randomization probability quickly to benefit the trial participants, long-term survival outcome can also change the randomization to favor the treatment arm with definitive therapeutic benefit. Using generalized Friedman's urn, we derive an explicit formula for the limiting distribution of the number of subjects assigned to each arm. With prior or hypothetical knowledge on treatment effects, this formula can be used to guide the selection of parameters for the proposed design to achieve desirable patient number ratios between different treatment arms, and thus optimize the operating characteristics of the trial design. Simulation studies show that the proposed design successfully assign more patients to the treatment arms with either better short-term tumor response or long-term survival outcome or both. PMID- 29233086 TI - Functional polymorphisms in asporin and CILP together with joint loading predispose to hand osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is the most common degenerative joint disease afflicting people in the Western world and has a strong genetic influence. The aim of this study was to examine the association of two known functional polymorphisms in the TGF-beta inhibiting genes, asporin (ASPN) and cartilage intermediate layer protein (CILP), with hand OA and potential gene-occupational hand loading interaction. RESULTS: Statistically significant interaction of the CILP rs2073711 T and ASPN D15 alleles with hand OA was observed (OR = 2.48, 95% CI 1.27-4.85, p = 0.008) in a Finnish hand OA cohort of 543 women (aged 45-63). When stratified by variation in working tasks, low variation of working tasks increased the risk further (OR = 3.00, 95% CI 1.35-6.66, p = 0.007). Based on the analysis of ASPN and CILP protein-coding regions, functional studies were performed with one observed variant, rs41278695 in the ASPN gene. Analyses showed that bone morphogenetic protein 2 (BMP2) mediated expression of aggrecan (Agc1) and type II collagen (Col2a1) was significantly suppressed (p = 0.011 and p = 0.023, respectively) in a murine chondrocytic cell line (ATDC5) with cells stably expressing ASPN rs41278695. CONCLUSIONS: The carriage of either ASPN D15 or CILP rs2073711 TT is associated with increased risk of symmetrical hand OA, particularly in individuals with low variation in work tasks. ASPN rs41278695 SNP had an effect on Agc1 and Col2a1 gene expression when induced with BMP-2 suggesting an effect on the cartilage extracellular matrix composition. PMID- 29233087 TI - Stroke Prevention Rehabilitation Intervention Trial of Exercise (SPRITE) - a randomised feasibility study. AB - BACKGROUND: The value of cardiac rehabilitation (CR) after a transient ischaemic attack (TIA) or minor stroke is untested despite these conditions sharing similar pathology and risk factors to coronary heart disease. We aimed to evaluate the feasibility of conducting a trial of an adapted home-based CR programme, 'The Healthy Brain Rehabilitation Manual', for patients following a TIA/minor stroke, participants' views on the intervention and, to identify the behaviour change techniques (BCTs) used. METHODS: Clinicians were asked to identify patients attending the Ulster Hospital, Belfast within 4 weeks of a first TIA or minor stroke. Those who agreed to participate underwent assessments of physical fitness, cardiovascular risk, quality of life and mental health, before random allocation to: Group (1) standard/usual care; (2) rehabilitation manual or (3) manual plus pedometer. All participants received telephone support at 1 and 4 weeks, reassessment at 6 weeks and an invitation to a focus group exploring views regarding the study. Two trained review authors independently assessed the manual to identify the BCTs used. RESULTS: Twenty-eight patients were invited to participate, with 15 (10 men, 5 women; 9 TIA, 6 minor stroke; mean age 69 years) consenting and completing the study. Mean time to enrolment from the TIA/stroke was 20.5 days. Participants completed all assessment measures except VO2max testing, which all declined. The manual and telephone contact were viewed positively, as credible sources of advice. Pedometers were valued highly, particularly for goal-setting. Overall, 36 individual BCTs were used, the commonest being centred around setting goals and planning as well as social support. CONCLUSION: Recruitment and retention rates suggest that a trial to evaluate the effectiveness of a novel home-based CR programme, implemented within 4 weeks of a first TIA/minor stroke is feasible. The commonest BCTs used within the manual revolve around goals, planning and social support, in keeping with UK national guidelines. The findings from this feasibility work have been used to further refine the next stage of the intervention's development, a pilot study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02712385 . This study was registered prospectively on 18/03/2016. PMID- 29233088 TI - Left atrial enlargement and clinical considerations in patients with or without a residual interatrial shunt after closure of the left atrial appendage with the WATCHMANTM-device. AB - BACKGROUND: Interventional closure of the left atrial appendage (LAA) in patients with non-valvular atrial fibrillation, high thromboembolic and bleeding risk or bleeding history is an alternative therapeutic strategy to oral anticoagulation. It is not known if the exclusion of the LAA from the blood circulation affects the left atrial volume (LAV) and consequently its prognostic value or the circulatory performance of the heart in humans. METHODS: We aimed to prospectively assess potential changes in baseline LAV, left ventricular ejection fraction (LVEF), NT-proBNP-level and the covered distance in the 6-min walk-test 6 weeks and 6 months after LAA closure with the WATCHMANTM device. We used serial 3-dimensional transthoracic and transesophageal echocardiography to assess LAV, residual interatrial shunt and device performance in 58 consecutive patients with successful LAA closure. RESULTS: Accurate 3D-echocardiographic data for LAV measurements were evaluable for 51 (91%) patients. Maximum LAV (LAVmax) at baseline was 102.8 +/- 30.8 ml and increased significantly to 107.7 +/- 32.8 ml after 6 weeks (p < 0.01) and 113.5 +/- 34.2 ml after 6 months (p < 0.01). Minimal LAV (LAVmin) increased from 76.9 +/- 29.5 ml at baseline to 81.8 +/- 30.2 ml after 45 days (p < 0.01) and 82.1 +/- 33.3 ml after 6 months (p < 0.01). Similarly, their indexes to BSA (LAVImax and LAVImin) increased significantly, as well. Patients without a residual left-to-right interatrial shunt showed a significantly higher increase in LAVmax or LAVmin. Baseline LVEF, NT-proBNP-level or the distance covered at the 6-min walk test did not significantly change 6 weeks or 6 months after LAA closure. CONCLUSIONS: LAVmax and LAVmin increase significantly after interventional LAA closure. LA enlargement does not correlate with clinical progression of heart failure. Persistent left-to-right interatrial shunt counteracts the LA enlargement. A reduced LA compliance after exclusion of the LAA from the blood circulation with consecutive increase in LA pressure may be a potential cause of LA enlargement and warrants further investigation. TRIAL REGISTRATION: German Clinical Trials Register ID: DRKS00010768 ; Registration Date 07.07.2016. PMID- 29233089 TI - De novo transcriptome assembly from flower buds of dioecious, gynomonoecious and chemically masculinized female Coccinia grandis reveals genes associated with sex expression and modification. AB - BACKGROUND: Coccinia grandis (ivy gourd), is a dioecious member of Cucurbitaceae having heteromorphic sex chromosomes. Chromosome constitution of male and female plants of C. grandis is 22A + XY and 22A + XX respectively. Earlier we showed that a unique gynomonoecious form of C. grandis (22A + XX) also exists in nature bearing morphologically hermaphrodite flowers (GyM-H). Additionally, application of silver nitrate (AgNO3) on female plants induces stamen development leading to the formation of morphologically hermaphrodite flowers (Ag-H) despite the absence of Y-chromosome. Due to the unavailability of genome sequence and the slow pace at which sex-linked genes are identified, sex expression and modification in C. grandis are not well understood. RESULTS: We have carried out a comprehensive RNA Seq study from early-staged male, female, GyM-H, and Ag-H as well as middle staged male and GyM-H flower buds. A de novo transcriptome was assembled using Trinity and annotated by BLAST2GO and Trinotate pipelines. The assembled transcriptome consisted of 467,233 'Trinity Transcripts' clustering into 378,860 'Trinity Genes'. Female_Early_vs_Male_Early, Ag_Early_vs_Female_Early, and GyM H_Middle_vs_Male_Middle comparisons exhibited 35,694, 3574, and 14,954 differentially expressed transcripts respectively. Further, qRT-PCR analysis of selected candidate genes validated digital gene expression profiling results. Interestingly, ethylene response-related genes were found to be upregulated in female buds compared to male buds. Also, we observed that AgNO3 treatment suppressed ethylene responses in Ag-H flowers by downregulation of ethylene responsive transcription factors leading to stamen development. Further, GO terms related to stamen development were enriched in early-staged male, GyM-H, and Ag-H buds compared to female buds supporting the fact that stamen growth gets arrested in female flowers. CONCLUSIONS: Suppression of ethylene responses in both male and Ag-H compared to female buds suggests a probable role of ethylene in stamen suppression similar to monoecious cucurbits such as melon and cucumber. Also, pollen fertility associated GO terms were depleted in middle-staged GyM-H buds compared to male buds indicating the necessity of Y-chromosome for pollen fertility. Overall, this study would enable identification of new sex-biased genes for further investigation of stamen arrest, pollen fertility, and AgNO3 mediated sex modification. PMID- 29233090 TI - DNA methylation regulates discrimination of enhancers from promoters through a H3K4me1-H3K4me3 seesaw mechanism. AB - BACKGROUND: DNA methylation at promoters is largely correlated with inhibition of gene expression. However, the role of DNA methylation at enhancers is not fully understood, although a crosstalk with chromatin marks is expected. Actually, there exist contradictory reports about positive and negative correlations between DNA methylation and H3K4me1, a chromatin hallmark of enhancers. RESULTS: We investigated the relationship between DNA methylation and active chromatin marks through genome-wide correlations, and found anti-correlation between H3K4me1 and H3K4me3 enrichment at low and intermediate DNA methylation loci. We hypothesized "seesaw" dynamics between H3K4me1 and H3K4me3 in the low and intermediate DNA methylation range, in which DNA methylation discriminates between enhancers and promoters, marked by H3K4me1 and H3K4me3, respectively. Low methylated regions are H3K4me3 enriched, while those with intermediate DNA methylation levels are progressively H3K4me1 enriched. Additionally, the enrichment of H3K27ac, distinguishing active from primed enhancers, follows a plateau in the lower range of the intermediate DNA methylation level, corresponding to active enhancers, and decreases linearly in the higher range of the intermediate DNA methylation. Thus, the decrease of the DNA methylation switches smoothly the state of the enhancers from a primed to an active state. We summarize these observations into a rule of thumb of one-out-of-three methylation marks: "In each genomic region only one out of these three methylation marks {DNA methylation, H3K4me1, H3K4me3} is high. If it is the DNA methylation, the region is inactive. If it is H3K4me1, the region is an enhancer, and if it is H3K4me3, the region is a promoter". To test our model, we used available genome-wide datasets of H3K4 methyltransferases knockouts. Our analysis suggests that CXXC proteins, as readers of non-methylated CpGs would regulate the "seesaw" mechanism that focuses H3K4me3 to unmethylated sites, while being repulsed from H3K4me1 decorated enhancers and CpG island shores. CONCLUSIONS: Our results show that DNA methylation discriminates promoters from enhancers through H3K4me1-H3K4me3 seesaw mechanism, and suggest its possible function in the inheritance of chromatin marks after cell division. Our analyses suggest aberrant formation of promoter like regions and ectopic transcription of hypomethylated regions of DNA. Such mechanism process can have important implications in biological process in where it has been reported abnormal DNA methylation status such as cancer and aging. PMID- 29233091 TI - A gradient of frequency-dependent synaptic properties along the longitudinal hippocampal axis. AB - BACKGROUND: The hippocampus is a functionally heterogeneous brain structure and specializations of the intrinsic neuronal network may crucially support the functional segregation along the longitudinal axis of the hippocampus. Short-term synaptic plasticity plays fundamental roles in information processing and may be importantly involved in diversifying the properties of local neuronal network along the hippocampus long axis. Therefore, we aimed to examine the properties of the cornu ammonis 1 (CA1) synapses along the entire dorsoventral axis of the rat hippocampus using field excitatory postsynaptic potentials from transverse rat hippocampal slices and a frequency stimulation paradigm. RESULTS: Applying a ten pulse stimulus train at frequencies from 0.1 to 100 Hz to the Schaffer collaterals we found a gradually diversified pattern of frequency-dependent synaptic effects along the dorsoventral hippocampus axis. The first conditioned response was facilitated along the whole hippocampus for stimulus frequencies 10 40 Hz. However, steady-state responses or averaged responses generally ranged from maximum synaptic facilitation in the most dorsal segment of the hippocampus to maximum synaptic depression in the most ventral segment of the hippocampus. In particular, dorsal synapses facilitated for stimulus frequency up to 50 Hz while they depressed at higher frequencies (75-100 Hz). Facilitation at dorsal synapses was maximal at stimulus frequency of 20 Hz. On the contrary, the most ventral synapses showed depression regardless of the stimulus frequency, only displaying a transient facilitation at the beginning of 10-50 Hz stimulation. Importantly, the synapses in the medial hippocampus displayed a transitory behavior. Finally, as a whole the hippocampal synapses maximally facilitated at 20 Hz and increasingly depressed at 50-100 Hz. CONCLUSION: The short-term synaptic dynamics change gradually along the hippocampal long axis in a frequency-dependent fashion conveying distinct properties of information processing to successive segments of the structure, thereby crucially supporting functional segregation along the dorsoventral axis of the hippocampus. PMID- 29233092 TI - Heart rate variability after radiofrequency ablation of epicardial ganglionated plexuses on the ovine left atrium. AB - BACKGROUND: Ganglionated plexuses (GP) are terminal parts of cardiac autonomous nervous system (ANS). Radiofrequency ablation (RFA) for atrial fibrillation (AF) possibly affects GP. Changes in heart rate variability (HRV) after RFA can reflect ANS modulation. METHODS: Epicardial RFA of GP on the left atrium (LA) was performed under the general anesthesia in 15 mature Romanov sheep. HRV was used to assess the alterations in autonomic regulation of the heart. A 24 - hour ECG monitoring was performed before the ablation, 2 days after it and at each of the 12 following months. Ablation sites were evaluated histologically. RESULTS: There was an instant change in HRV parameters after the ablation. A standard deviation of all intervals between normal QRS (SDNN), a square root of the mean of the squared differences between successive normal QRS intervals (RMSSD) along with HRV triangular index (TI), low frequency (LF) power and high frequency (HF) power decreased, while LF/HF ratio increased. Both the SDNN, LF power and the HF power changes persisted throughout the 12 - month follow - up. Significant decrease in RMSSD persisted only for 3 months, HRV TI for 6 months and increase in LF/HF ratio for 7 months of the follow - up. Afterwards these three parameters were not different from the preprocedural values. CONCLUSIONS: Epicardial RFA of GP's on the ovine left atrium has lasting effect on the main HRV parameters (SDNN, HF power and LF power). The normalization of RMSSD, HRV TI and LF/HF suggests that HRV after epicardial RFA of GPs on the left atrium might restore over time. PMID- 29233093 TI - Physiological and transcriptomic responses in the seed coat of field-grown soybean (Glycine max L. Merr.) to abiotic stress. AB - BACKGROUND: Understanding how intensification of abiotic stress due to global climate change affects crop yields is important for continued agricultural productivity. Coupling genomic technologies with physiological crop responses in a dynamic field environment is an effective approach to dissect the mechanisms underpinning crop responses to abiotic stress. Soybean (Glycine max L. Merr. cv. Pioneer 93B15) was grown in natural production environments with projected changes to environmental conditions predicted for the end of the century, including decreased precipitation, increased tropospheric ozone concentrations ([O3]), or increased temperature. RESULTS: All three environmental stresses significantly decreased leaf-level photosynthesis and stomatal conductance, leading to significant losses in seed yield. This was driven by a significant decrease in the number of pods per node for all abiotic stress treatments. To understand the underlying transcriptomic response involved in the yield response to environmental stress, RNA-Sequencing analysis was performed on the soybean seed coat, a tissue that plays an essential role in regulating carbon and nitrogen transport to developing seeds. Gene expression analysis revealed 49, 148 and 1,576 differentially expressed genes in the soybean seed coat in response to drought, elevated [O3] and elevated temperature, respectively. CONCLUSIONS: Elevated [O3] and drought did not elicit substantive transcriptional changes in the soybean seed coat. However, this may be due to the timing of sampling and does not preclude impacts of those stresses on different tissues or different stages in seed coat development. Expression of genes involved in DNA replication and metabolic processes were enriched in the seed coat under high temperate stress, suggesting that the timing of events that are important for cell division and proper seed development were altered in a stressful growth environment. PMID- 29233094 TI - Short- and long-term outcomes in infective endocarditis patients: a systematic review and meta-analysis. AB - BACKGROUND: Despite advances in medical knowledge, technology and antimicrobial therapy, infective endocarditis (IE) is still associated with devastating outcomes. No reviews have yet assessed the outcomes of IE patients undergoing short- and long-term outcome evaluation, such as all-cause mortality and IE related complications. We conducted a systematic review and meta-analysis to examine the short- and long-term mortality, as well as IE-related complications in patients with definite IE. METHODS: A computerized systematic literature search was carried out in PubMed, Scopus and Google Scholar from 2000 to August, 2016. Included studies were published studies in English that assessed short-and long-term mortality for adult IE patients. Pooled estimations with 95% confidence interval (CI) were calculated with DerSimonian-Laird (DL) random-effects model. Sensitivity and subgroup analyses were also performed. Publication bias was evaluated using inspection of funnel plots and statistical tests. RESULTS: Twenty five observational studies (retrospective, 14; prospective, 11) including 22,382 patients were identified. The overall pooled mortality estimates for IE patients who underwent short- and long-term follow-up were 20% (95% CI: 18.0-23.0, P < 0.01) and 37% (95% CI: 27.0-48.0, P < 0.01), respectively. The pooled prevalence of cardiac complications in patients with IE was found to be 39% (95%CI: 32.0 46.0) while septic embolism and renal complications accounted for 25% (95% CI: 20.0-31) and 19% (95% CI: 14.0-25.0) (all P < 0.01), respectively. CONCLUSION: Irrespective of the follow-up period, a significantly higher mortality rate was reported in IE patients, and the burden of IE-related complications were immense. Further research is needed to assess the determinants of overall mortality in IE patients, as well as well-designed observational studies to conform our results. PMID- 29233095 TI - The distinctive cell division interactome of Neisseria gonorrhoeae. AB - BACKGROUND: Bacterial cell division is an essential process driven by the formation of a Z-ring structure, as a cytoskeletal scaffold at the mid-cell, followed by the recruitment of various proteins which form the divisome. The cell division interactome reflects the complement of different interactions between all divisome proteins. To date, only two cell division interactomes have been characterized, in Escherichia coli and in Streptococcus pneumoniae. The cell divison proteins encoded by Neisseria gonorrhoeae include FtsZ, FtsA, ZipA, FtsK, FtsQ, FtsI, FtsW, and FtsN. The purpose of the present study was to characterize the cell division interactome of N. gonorrhoeae using several different methods to identify protein-protein interactions. We also characterized the specific subdomains of FtsA implicated in interactions with FtsZ, FtsQ, FtsN and FtsW. RESULTS: Using a combination of bacterial two-hybrid (B2H), glutathione S transferase (GST) pull-down assays, and surface plasmon resonance (SPR), nine interactions were observed among the eight gonococcal cell division proteins tested. ZipA did not interact with any other cell division proteins. Comparisons of the N. gonorrhoeae cell division interactome with the published interactomes from E. coli and S. pneumoniae indicated that FtsA-FtsZ and FtsZ-FtsK interactions were common to all three species. FtsA-FtsW and FtsK-FtsN interactions were only present in N. gonorrhoeae. The 2A and 2B subdomains of FtsANg were involved in interactions with FtsQ, FtsZ, and FtsN, and the 2A subdomain was involved in interaction with FtsW. CONCLUSIONS: Results from this research indicate that N. gonorrhoeae has a distinctive cell division interactome as compared with other microorganisms. PMID- 29233096 TI - Evaluation of scoring systems without endoscopic findings for predicting outcomes in patients with upper gastrointestinal bleeding. AB - BACKGROUND: Risk scoring systems are used to evaluate patients with upper gastrointestinal bleeding (UGIB). We compared Glasgow-Blatchford score (GBS), modified GBS (mGBS), and Pre-endoscopy Rockall score (Pre-E RS) for immediate application without endoscopic findings in predicting the need of interventions and the 30-day mortality in patients with UGIB. METHODS: Patients who visited the emergency room with UGIB from January 2007 to June 2016 were included. GBS, mGBS, and Pre-E RS were obtained for all patients. The area under the receiver operating characteristic curves (AUC) was used to assess the accuracy of the scoring systems to determine the need for interventions and 30-day mortality. Also, we investigated the potential cutoff scores for predicting 30-day mortality and the need for interventions. RESULTS: In predicting the need for interventions, GBS (AUC = 0.727) and mGBS (AUC = 0.733) outperformed Pre-E RS (AUC = 0.564, P < 0.0001). In predicting 30-day mortality, Pre-E RS (AUC = 0.929) outperformed GBS (AUC = 0.664, P < 0.0001) and mGBS (AUC = 0.652, P < 0.0001). Based on AUC analyses of sensitivities and specificities, the optimal cutoff mGBS and GBS for the need for interventions was 9 (70.71% sensitivity, 89.35% specificity) and 9 (73.57% sensitivity, 82.90% specificity) respectively, and optimal cutoff Pre-E RS for 30-day mortality was 4 (88.0% sensitivity, 97.52% specificity). CONCLUSIONS: GBS and mGBS are considered to be moderately accurate in making an early decision about the need of interventions in patients with UGIB. Pre-E RS is considered to be highly accurate in early detection of patients at high risk for 30-day mortality without endoscopic findings. In addition, we suggested potential cutoff scores to predict the need of interventions for GBS and mGBS, and 30-day mortality for Pre-E RS. Further studies are needed to confirm the clinical applicability of results. PMID- 29233097 TI - Individualized support for informal caregivers of people with dementia - effectiveness of the German adaptation of REACH II. AB - BACKGROUND: Individualized, outreach and structured multicomponent interventions are a promising intervention approach to relieve the burden of informal caregivers of people with dementia. In this study, we adapted and evaluated a multicomponent intervention (Resources for Enhancing Alzheimer's Caregiver Health II, REACH II), which was developed in the USA, to the German health-care system. Therefore the project is called the German adaptation of REACH II (in German: Deutsche Adaptation der REACH II, DE-REACH). METHODS: The effectiveness of DE REACH was examined in a randomized, controlled trial on 92 informal caregivers of people with dementia. The intervention comprised 12 individual two-weekly sessions (9 at home with the informal caregiver and 3 via telephone) and combined five modules. The reduction of the burden of the informal caregivers was chosen as the primary outcome. RESULTS: The results showed a great stabilizing effect of the intervention on caregiver burden (effect size d = 0.91), that is, comparing pre- and post-measurements the burden decreased very slightly in the intervention group whereas it increased very strongly in the control group. After a three month follow-up period this effect decreased from a great to a moderate effect. There were also improvements as a result of the intervention in somatization, health-related psychological quality of life and the reaction of the informal caregivers in response to challenging behaviors of the relative with dementia. Moreover, the frequency of challenging behaviors of the affected person itself was reduced in favor of the intervention. CONCLUSION: The findings of this study provide further evidence for the impact of multicomponent support interventions for informal caregivers of people with dementia. CLINICAL TRIAL REGISTRATION: NCT01690117 . Registered September 17, 2012. PMID- 29233098 TI - Intractable ascites associated with mycophenolate in a simultaneous kidney pancreas transplant patient: a case report. AB - BACKGROUND: Mycophenolic acid (MPA), either given as an ester pro-drug or as an enteric-coated sodium salt, is the most commonly prescribed anti-proliferative immunosuppressive agent used following organ transplantation and widely applied in immune-mediated diseases. Clinicians are well aware of common adverse reactions related to MPA treatment, in particular diarrhea, leukopenia and infections. Here we report a case of severe, persistent ascites associated with MPA treatment. The otherwise unexplained and intractable ascites, requiring repeated paracenteses for more than 8 months, rapidly ceased with stopping the MPA treatment. To our knowledge this is the first case of severe ascites associated with MPA treatment reported in the scientific literature. CASE PRESENTATION: A 45-year old female with type 1 diabetes mellitus received a simultaneous kidney-pancreas transplant. The surgery was uneventful. However, post-operatively she developed severe transudative ascites requiring in total more than 40 paracenteses treatments draining in the average 2.8 l of ascites fluid. The ascites formation persisted despite exclusion of a surgical complication, fully functioning kidney and pancreas allografts, lack of any significant proteinuria, normalization of circulating albumin levels, intensive use of diuretics and deliberate attempts to increase the intervals between the paracentesis treatments. Various differential diagnoses, including infectious, hepatic, vascular and cardiac causes were ruled out. Nine months after surgery enteric-coated mycophenolate sodium was switched to azathioprine after which ascites completely resolved. When mycophenolate was recommenced abdominal fullness and weight gain reoccurred. The patient had to be switched to long-term azathioprine treatment. More than 1 year post-conversion the patient remains free of ascites. CONCLUSION: MPA is the most widely used antimetabolite immunosuppressive agent. We suggest to consider MPA treatment in the differential diagnosis of severe and unexplained ascites in transplant and non-transplant patients. PMID- 29233100 TI - High blood glucose levels are associated with higher risk of colon cancer in men: a cohort study. AB - BACKGROUND: High levels of blood glucose are thought to be associated with colorectal cancer (CRC) and hyperinsulinemia, an interstage in the development of CRC. The purpose of this study was to examine associations between incident CRC and blood glucose; plasma insulin; and the homeostasis model assessment for insulin resistance (HOMA2-IR), respectively, and to determine whether these associations were dependent on sex and cancer site. METHODS: The Malmo Diet and Cancer cardiovascular cohort comprises 6103 individuals. During 81,781 person years of follow-up, 145 cases of CRC were identified. The hazard ratio of measured blood glucose and plasma insulin and calculated HOMA2-IR were estimated with Cox proportional hazard regression. RESULTS: An association was found between high levels of blood glucose and risk of CRC (HR: 1.72 for the highest compared with the lowest quartile; 95% CI: 1.05, 2.84; ptrend = 0.044), and colon cancer (HR: 1.70 for the highest compared with the lowest quartile; 95% CI: 0.87, 3.33; ptrend = 0.032). In men, an association was found between blood glucose and CRC (HR: 2.80 for the highest compared with the lowest quartile; 95% CI: 1.37, 5.70; ptrend = 0.001), and colon cancer (HR: 4.48 for the highest compared with the lowest quartile; 95% CI: 1.27, 15.84; ptrend = 0.007), but this was not found in women. No associations between plasma insulin, or HOMA2-IR, and CRC, were found. CONCLUSION: High levels of blood glucose in men are associated with risk of colon cancer. The findings contribute to facilitating to identify those most in need of prevention and screening. PMID- 29233099 TI - Pronounced strain-specific chemosensory receptor gene expression in the mouse vomeronasal organ. AB - BACKGROUND: The chemosensory system plays an important role in orchestrating sexual behaviors in mammals. Pheromones trigger sexually dimorphic behaviors and different mouse strains exhibit differential responses to pheromone stimuli. It has been speculated that differential gene expression in the sensory organs that detect pheromones may underlie sexually-dimorphic and strain-specific responses to pheromone cues. RESULTS: We have performed transcriptome analyses of the mouse vomeronasal organ, a sensory organ recognizing pheromones and interspecies cues. We find little evidence of sexual dimorphism in gene expression except for Xist, an essential gene for X-linked gene inactivation. Variations in gene expression are found mainly among strains, with genes from immune response and chemosensory receptor classes dominating the list. Differentially expressed genes are concentrated in genomic hotspots enriched in these families of genes. Some chemosensory receptors show exclusive patterns of expression in different strains. We find high levels of single nucleotide polymorphism in chemosensory receptor pseudogenes, some of which lead to functionalized receptors. Moreover, we identify a number of differentially expressed long noncoding RNA species showing strong correlation or anti-correlation with chemoreceptor genes. CONCLUSIONS: Our analyses provide little evidence supporting sexually dimorphic gene expression in the vomeronasal organ that may underlie dimorphic pheromone responses. In contrast, we find pronounced variations in the expression of immune response related genes, vomeronasal and G-protein coupled receptor genes among different mouse strains. These findings raised the possibility that diverse strains of mouse perceive pheromone cues differently and behavioral difference among strains in response to pheromone may first arise from differential detection of pheromones. On the other hand, sexually dimorphic responses to pheromones more likely originate from dimorphic neural circuits in the brain than from differential detection. Moreover, noncoding RNA may offer a potential regulatory mechanism controlling the differential expression patterns. PMID- 29233101 TI - Learning from older peoples' reasons for participating in demanding, intensive epidemiological studies: a qualitative study. AB - BACKGROUND: Recruitment rates of older people in epidemiological studies, although relatively higher than in clinical trials, have declined in recent years. This study aimed to explore motivating factors and concerns among older participants in an intensive epidemiological study (Hertfordshire Sarcopenia Study - HSS) and identify those that could aid future recruitment to epidemiological studies and clinical trials. METHODS: Participants of the HSS fasted overnight and travelled several hours each way to the research facility at an English hospital for extensive diet/lifestyle questionnaires and investigations to assess muscle including blood tests and a muscle biopsy. We conducted semi-structured interviews with 13 participants (ten women) at the research facility in May-October 2015. The interviews were audio-taped, transcribed verbatim, coded and analysed thematically by three researchers. RESULTS: We identified personal motives for participation (potential health benefit for self and family; curiosity; comparing own fitness to others; socialising). Altruistic motives (benefit for other people; belief in importance of research) were also important. Participants voiced a number of external motives related to the study uniqueness, organisation and safety record; family support; and just 'being asked'. Anxiety about the biopsy and travel distance were the only concerns and were alleviated by smooth and efficient running of the study. CONCLUSIONS: Personal and altruistic reasons were important motivators for these older people to participate in demanding, intensive research. They valued belonging to a birth cohort with previous research experience, but personal contact with the research team before and after consent provided reassurance, aided recruitment to HSS and could be readily replicated by other researchers. Any fears or concerns related to certain aspects of a demanding, intensive study should ideally be explored at an early visit to establish a good relationship with the research team. PMID- 29233102 TI - The gene-treatment interaction of paraoxonase-1 gene polymorphism and statin therapy on insulin secretion in Japanese patients with type 2 diabetes: Fukuoka diabetes registry. AB - BACKGROUND: Although statins deteriorate glucose metabolism, their glucose lowering effects have emerged in some situations. Here, we assessed whether these effects are a consequence of statins' interaction with paraoxonase (PON)1 enzyme polymorphism. METHODS: Adult Japanese type 2 diabetes patients (n = 3798) were enrolled in a cross-sectional study. We used Q192R polymorphism of the PON1 gene as a representative single-nucleotide polymorphism and focused on the effects of the wild-type Q allele, in an additive manner. For patients with and without statin therapy, the associations of this allele with fasting plasma glucose (FPG), HbA1c, C-peptide, HOMA2-%beta, and HOMA2-IR were investigated separately using a linear regression model, and were compared between groups by testing interactions. Sensitivity analyses were performed using propensity score to further control the imbalance of characteristics between groups. RESULTS: Among patients with statin therapy, there were linear associations of the number of Q alleles with decreased FPG and HbA1c, and with increased serum C peptide and HOMA2-%beta (all P < 0.01 for trends), while such associations were not observed among those without statin therapy. These differences were statistically significant only for serum C peptide and HOMA2-%beta (P < 0.01 for interactions). These associations remained significant after multiple explanatory variable adjustment. Sensitivity analyses using propensity score showed broad consistency of these associations. CONCLUSIONS: Patients with the Q allele of the PON1 Q192R polymorphism who were treated with statins exhibited improvement in glucose metabolism, especially in insulin secretion, suggesting the importance of genotyping PON1 Q192R to identify those who could benefit from statin therapy. PMID- 29233103 TI - Anxiety and depression among patients with chronic obstructive pulmonary disease and general population in rural Nepal. AB - BACKGROUND: Anxiety and depression are usually under diagnosed among the patients with Chronic Obstructive Pulmonary Disease (COPD), which has a negative impact on patient quality of life through restriction of activities, loss of independence, and decreased social functioning. The purpose of this study was to describe the levels and characteristics of anxiety and depression in patients with COPD in Nepal as compared to the general population. METHODS: A hospital-based observational comparative analytical study was conducted in the United Mission Hospital, Tansen and the Okhaldhunga Community Hospital, Okhaldhunga, Nepal from June 1st 2015 to April 15th 2016. A convenience sample of two groups of participants were recruited: patients with COPD (study group) and visitors to the facility (comparison group). Anxiety and depression were measured with the Beck Anxiety and Depression Inventory Scale. RESULTS: A total of 198 individuals participated in the study; 93 with COPD and 105 from the general population. The mean age of the respondents was 58.24 +/- 12.04 (40-82) years. The mean scores for anxiety and depression in COPD group were 23.76+/- 9.51 and 27.72+/- 9.37 respectively, while in comparison group, the mean score for anxiety was 8.01+/- 6.83 and depression was 11.60 +/- 8.42. Both anxiety and depression scores were statistically significant between the groups with p value <0.001. CONCLUSIONS: Anxiety and depression were almost three times more common in COPD patients compared to the participants from the general population. Early assessment and multi-model treatment of anxiety and depression should be part of management in COPD. PMID- 29233104 TI - TLR4-NOX2 axis regulates the phagocytosis and killing of Mycobacterium tuberculosis by macrophages. AB - BACKGROUND: Macrophages stand at the forefront of both innate and adapted immunity through their capacities to recognize, engulf, and eliminate foreign particles, and to stimulate adapted immune cells. They are also involved in controlling pro- and anti-inflammatory pathways. Macrophage activity against Mycobacterium tuberculosis (M. tuberculosis) has been shown to involve Toll-like receptor (TLR) activation and ROS production. Previous studies have shown that lipopolysaccharide (LPS), through TLR4, could activate macrophages, improve their bactericidal ROS production, and facilitate anti-infective immune responses. We sought to better understand the role of the TLR4-NOX2 axis in macrophage activation during M. tuberculosis infection. METHODS: THP-1 macrophages and PMA primed THP-1 macrophages [THP-1(A)] were treated with LPS and infected by M. tuberculosis. Cells were analyzed by flow cytometry for TLR4 expression, ROS production, phagocytosis, and killing of M. tuberculosis. Western blotting was used to analyze NOX2 expression. Inhibitors of the TLR4-NOX2 pathway were used to assess this pathway's role in these processes, and their role in LPS activation of macrophages. RESULTS: We found that THP1-derived macrophages or PMA primed THP 1 macrophages exhibit higher surface TLR4 levels and increased NOX2 expression levels following LPS treatment. M. tuberculosis infection reduced these levels, but LPS was able to limit the negative effects of M.tb. Additionally, LPS increases THP-1(A) cells' bactericidal activities including phagocytosis, ROS production, and destruction of M. tuberculosis. Significantly, all of these activities are impaired when TLR4 or NOX2 are inhibited. CONCLUSION: These studies demonstrate the importance of the TLR4-NOX2 axis in M. tuberculosis elimination by macrophages and may lead to novel therapies for tuberculosis and other bacterial infections. PMID- 29233105 TI - Salidroside attenuates hypoxia-induced pulmonary arterial smooth muscle cell proliferation and apoptosis resistance by upregulating autophagy through the AMPK mTOR-ULK1 pathway. AB - BACKGROUND: Recent studies have shown that both adenosine monophosphate activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) are energy sensors and are related to autophagy. Our recent reports have shown that salidroside can exert protective effects against hypoxia-induced pulmonary arterial smooth muscle cell (PASMC) proliferation and apoptosis resistance through the AMPK pathway. This study aims to explore the relationship among AMPK, mTOR and ULK1 in PASMCs under hypoxic conditions and to investigate whether the protective effects of salidroside are related to the autophagic cell death pathway. METHODS: Rat PASMCs were cultured and divided into five groups: the normoxia, hypoxia, hypoxia + MHY1485 (mTOR agonist), hypoxia + rapamycin (mTOR inhibitor) and hypoxia + salidroside groups. Hypoxic cells were treated as indicated for 24 h. Cell viability was evaluated by the CCK-8 assay. Cell apoptosis was measured by the TUNEL assay. The autophagy flux of PASMCs was evaluated with tandem mRFP-GFP fluorescence microscopy. Autophagosomes were detected by electron microscopy. Protein expression of LC3, p62, AMPK, P-AMPK (Thr 172), P-ULK1 (Ser 555 and Ser 317), mTOR, P-mTOR (Ser 2448), ULK1 and P-ULK1 (Ser 757) was detected by western blot assay. RESULTS: PASMC proliferation and apoptosis resistance were observed under hypoxic conditions. Autophagy flux, the number of autophagosomes and the LC3II/LC3I ratio were increased in the hypoxia group compared with the normoxia group, whereas p62 expression was decreased. Treatment with rapamycin or salidroside reversed hypoxia-induced PASMC proliferation and apoptosis resistance and further increased autophagy flux, autophagosome levels and the LC3II/LC3I ratio but decreased p62 expression. Treatment with MHY1485 reversed hypoxia-induced PASMC apoptosis resistance and decreased autophagy flux as well as increased autophagosome levels, the LC3II/LC3I ratio and p62 expression. P-AMPK (Thr 172) and P-ULK1 (Ser 555) of the AMPK-ULK1 pathway were increased in the hypoxia group and were further increased in the salidroside group. Rapamycin and MHY1485 had no effect on either P-AMPK (Thr 172) or P-ULK1 (Ser 555). Phosphorylation of ULK1 at serine 317 did not significantly affect the five groups. Furthermore, P-mTOR (Ser 2448) and P-ULK1 (Ser 757) of the AMPK-mTOR-ULK1 pathway were decreased in the hypoxia group and were further decreased in the salidroside group. MHY1485 increased the expression of both P-mTOR(Ser 2448) and P-ULK1(Ser 757), whereas rapamycin had the opposite effect. CONCLUSIONS: Salidroside might inhibit hypoxia-induced PASMC proliferation and reverse apoptosis resistance via the upregulation of autophagy through both the AMPKalpha1-ULK1 and AMPKalpha1-mTOR-ULK1 pathways. PMID- 29233106 TI - Genetic diversity and distribution of Mycobacterium tuberculosis genotypes in Limpopo, South Africa. AB - BACKGROUND: Tuberculosis remains a major health problem and knowledge of the diversity of Mycobacterium tuberculosis strains in specific geographical regions can contribute to the control of the disease. This study describes the genetic profile of M. tuberculosis in five districts of Limpopo Province. METHODS: A total 487 isolates were collected from the National Health Laboratory Services from all regions/districts of Limpopo Province. Only 215 isolates were confirmed to be M. tuberculosis by Bactec Mycobacterium Growth Indicator Tube 960(r) and Rhodamine-Auramine staining. Isolates were subcultured on Lowenstein-Jensen medium agar slants to validate purity. They were spoligotyped and data analysed using the international spoligotyping database 4 (SpolDB4). RESULTS: Of the 215 isolates, 134 (62.3%) were genotyped into 21 genotype families while 81 (37.7%) were orphans. The 81 orphans were further subjected to resolution employing SpolDB3/RIM. Overall, the study revealed a high diversity of strains of 32 predominantly the non-Beijing lineages: the LAM- LAM3 (9.8%), LAM9 (4.7%) and LAM11- ZWE (3.3%), the T-T1(15.0%), T2 (0.9%), T2-T3 (1.4%), the CAS-CAS1-Delhi 5 (1.9%) and CAS1-KILI (1.4%) the MANU2 (1.4%), U (0.5%), X-X1(1.4%), X3 (1.9%), S (9.8%), CAS (1.4%), LAM7(0.9%), T3(0.5%), LAM8(4.7%), T4(1.4%), X2(0.4%), AI5(1.9%), LAM1(0.5%), FAMILY33 (1.9%), EAI4(1.4%), M. microti (1.9%). The Beijing and Beijing-like families were (14.9%) and (0.9%), respectively. A total of 28(13%) clusters and 77(36%) unique cases were identified. Beijing strain (SIT 1) formed the biggest cluster constituting 14%, followed by LAM3 (SIT 33), T1 (SIT 53) and LAM4 (SIT 811) with 7%, 5.1% and 2.8%, respectively. The Beijing family was the only genotype found in all the five districts and was predominant in Mopani (18.8%), Sekhukhune (23.7%) and Vhembe (23.3%). Dominant genotypes in Capricorn and Waterberg were LAM3 (11.9%) and T1 (13.3%), respectively. CONCLUSION: A wide diversity of lineages was demonstrated at district level. A high number of clusters per district provided evidence of on-going transmission in this Province. PMID- 29233107 TI - Correlation of occupational stress with depression, anxiety, and sleep in Korean dentists: cross-sectional study. AB - BACKGROUND: This study aimed to investigate the degree of occupational stress and the clinical mental state of dentists. In addition, we investigated the correlation of occupational stress with depression, anxiety, and sleep among dentists in Korea. METHODS: A cross-sectional survey on 231 dentists was conducted using the Doctor Job Stress Scale, Center for Epidemiologic Studies Depression Scale (CES-D), State-Trait Anxiety Index (STAI), and Pittsburgh Sleep Quality Index (PSQI). Correlation of occupational stress with mental health was investigated by adjusted multiple regression analysis. RESULTS: The scores of CES D, STAI, and PSQI revealed a significant correlation with the Doctor Job Stress Scale (t = 3.93, P < 0.0001; t = 4.05, P < 0.0001; t = 4.18, P < 0.0001, respectively). In particular, patient factors and clinical responsibility/judgment factors were significantly associated with depression (t = 2.80, P = 0.0056; t = 4.93, P < 0.0001, respectively), anxiety (t = 2.35, P = 0.0195; t = 5.11, P < 0.0001, respectively), and sleep (t = 3.78, P = 0.0002; t = 4.30, P < 0.0001, respectively), whereas work factors were not associated with any mental health state. CONCLUSIONS: This study confirms that dentists as professions experience more severe mental states. For successful mental health care among dentists, stress management focusing on interpersonal relationship with patients and responsibility as an expert rather than the intensity of work should be considered. PMID- 29233108 TI - Association between risk of asthma and gene polymorphisms in CHI3L1 and CHIA: a systematic meta-analysis. AB - BACKGROUND: Previous studies have indicated that chitinase 3-like 1 (CHI3L1) gene rs4950928 polymorphism and acidic mammalian chitinase (AMCase or CHIA) gene rs10494132 polymorphism are associated with the risk of asthma. However, the results are inconsistent because of small sample size and varied ethnicity and age in studies. Therefore, a systematic meta-analysis was important to clarify the effect of CHI3L1 rs4950928 polymorphism and CHIA rs10494132 variant on asthma risk. METHODS: An electronic literature search was conducted to identify all the eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and sensitivity analysis as well as publication bias were assessed to investigate the associations. All statistical analyses were performed using STATA 12.0. RESULTS: Eight published articles with 10 case-control studies were included, 5 studies were of CHI3L1 rs4950928 polymorphism and another 5 studies involved CHIA rs10494132 polymorphism. Overall, no significant association was found between CHI3L1 polymorphism and asthma susceptibility. After stratified according to ethnicity, CHI3L1 rs4950928 variant was associated with decreased asthma risk in Caucasians (GG + GC vs. CC: OR = 0.621, 95% CI = 0.484-0.797, P = 0.000; GC vs. CC: OR = 0.612, 95% CI = 0.470-0.796, P = 0.000; G vs. C: OR = 0.696, 95% CI = 0.567-0.856, P = 0.001). When stratified population by age, there was no association in children under all genetic models. As for CHIA rs10494132 polymorphism, no evidence of association between CHIA rs10494132 polymorphism and asthma risk was identified. Furthermore, subgroup analysis by ethnicity revealed a positive correlation between CHIA rs10494132 polymorphism and asthma risk among Asians (TT vs. TC + CC: OR = 1.476, 95% CI = 1.071-2.032, P = 0.017; T vs. C: OR = 1.326, 95% CI = 1.024-1.717, P = 0.032). Additionally, in the subgroup analysis conducted according to age, CHIA rs10494132 variant was also found to be associated with the increased risk of asthma in children (TT vs. TC + CC: OR = 1.472, 95% CI = 1.067-2.030, P = 0.019; T vs. C: OR = 1.320, 95% CI = 1.016 1.713, P = 0.037). CONCLUSIONS: The G allele of CHI3L1 rs4950928 might be a protective factor against the development of asthma. However, the rs10494132 polymorphism of CHIA might be a risk factor for asthma. PMID- 29233109 TI - Prevalence and correlates of substance use among health care students in Nepal: a cross sectional study. AB - BACKGROUND: Substance use among health care students threatens professional standards and the delivery of quality services, potentially placing the public at risk. Therefore, our study aims to determine the prevalence and correlates associated with substance use among Nepalese health care students. METHOD: A cross-sectional survey using a self-administered health professional questionnaire was conducted among pharmacy, nursing, and public health students at three universities in Nepal in 2010. RESULTS: We analyzed data from 407 respondents (response rate, 82%) with a mean age of 22 years (standard deviation = 3.71). The overall lifetime prevalence of substance use (i. e., illegal use of prescription drugs and illegal drug use) was 42.8%. Marijuana was the most commonly used illegal drug (8.8%) and minor opiates (e.g., codeine cough syrups) were the most widely used illegal prescription drugs (32.4%). Substance use was directly associated with cigarette smoking, peer influence, and heavy drinking. In addition, respondents reported some major and minor dysfunctions because of their substance use. CONCLUSION: The prevalence of substance use among health care students at the three universities in Nepal was high. Peer influence, cigarette smoking, and heavy drinking were significant predictors of substance use. PMID- 29233110 TI - Accounting for misclassification bias of binary outcomes due to underscreening: a sensitivity analysis. AB - BACKGROUND: Diagnostic tests are performed in a subset of the population who are at higher risk, resulting in undiagnosed cases among those who do not receive the test. This poses a challenge for estimating the prevalence of the disease in the study population, and also for studying the risk factors for the disease. METHODS: We formulate this problem as a missing data problem because the disease status is unknown for those who do not receive the test. We propose a Bayesian selection model which models the joint distribution of the disease outcome and whether testing was received. The sensitivity analysis allows us to assess how the association of the risk factors with the disease outcome as well as the disease prevalence change with the sensitivity parameter. RESULTS: We illustrated our model using a retrospective cohort study of children with asthma exacerbation that were evaluated for pneumonia in the emergency department. Our model found that female gender, having fever during ED or at triage, and having severe hypoxia are significantly associated with having radiographic pneumonia. In addition, simulation studies demonstrate that the Bayesian selection model works well even under circumstances when both the disease prevalence and the screening proportion is low. CONCLUSION: The Bayesian selection model is a viable tool to consider for estimating the disease prevalence and in studying risk factors of the disease, when only a subset of the target population receive the test. PMID- 29233111 TI - Effectiveness of two community-based strategies on disease knowledge and health behaviour regarding malaria, diarrhoea and pneumonia in Ghana. AB - BACKGROUND: Ghana has developed two community-based strategies that aim to increase access to quality treatment for malaria, diarrhoea and suspected pneumonia, and to improve household and family practices: integrated Community Case Management (iCCM) and Community-based Health Planning and Services (CHPS). The objective of the study was to assess the effectiveness of iCCM and CHPS on disease knowledge and health behaviour regarding malaria, diarrhoea and pneumonia. METHODS: A household survey was conducted two and eight years after implementation of iCCM in the Volta and Northern Regions of Ghana respectively, and more than ten years of CHPS implementation in both regions. The study population included 1356 carers of children under- five years of age who had fever, diarrhoea and/or cough in the two weeks prior to the interview. Disease knowledge was assessed based on the knowledge of causes and identification of signs of severe disease and its association with the sources of health education messages received. Health behaviour was assessed based on reported prompt care seeking behaviour, adherence to treatment regime, utilization of mosquito nets and having improved sanitation facilities, and its association with the sources of health education messages received. RESULTS: Health education messages from community-based agents (CBAs) in the Northern Region were associated with the identification of at least two signs of severe malaria (adjusted Odds Ratio (OR) 1.8, 95%CI 1.0, 3.3, p = 0.04), two practices that can cause diarrhoea (adjusted OR 4.7, 95%CI 1.4, 15.5, p = 0.02) 0and two signs of severe pneumonia (adjusted OR 7.7, 95%CI2.2, 26.5, p = 0.01)-the later also associated with prompt care seeking behaviour (p = 0.04). In the Volta Region, receiving messages on diarrhoea from CHPS was associated with the identification of at least two signs of severe diarrhoea (adjusted OR 3.6, 95%CI 1.4, 9.0), p = 0.02). iCCM was associated with prompt care seeking behaviour in the Volta Region and CHPS with prompt care seeking behaviour in the Northern Region (p < 0.5). CONCLUSIONS: Both iCCM and CHPS were associated with disease knowledge and health behaviour, but this was more pronounced for iCCM and in the Northern Region. HBC should continue to be considered as the strategy through which community-IMCI is implemented. PMID- 29233112 TI - Napsin A levels in epithelial lining fluid as a diagnostic biomarker of primary lung adenocarcinoma. AB - BACKGROUND: It is crucial to develop novel diagnostic approaches for determining if peripheral lung nodules are malignant, as such nodules are frequently detected due to the increased use of chest computed tomography scans. To this end, we evaluated levels of napsin A in epithelial lining fluid (ELF), since napsin A has been reported to be an immunohistochemical biomarker for histological diagnosis of primary lung adenocarcinoma. METHODS: In consecutive patients with indeterminate peripheral lung nodules, ELF samples were obtained using a bronchoscopic microsampling (BMS) technique. The levels of napsin A and carcinoembryonic antigen (CEA) in ELF at the nodule site were compared with those at the contralateral site. A final diagnosis of primary lung adenocarcinoma was established by surgical resection. RESULTS: We performed BMS in 43 consecutive patients. Among patients with primary lung adenocarcinoma, the napsin A levels in ELF at the nodule site were markedly higher than those at the contralateral site, while there were no significant differences in CEA levels. Furthermore, in 18 patients who were undiagnosed by bronchoscopy and finally diagnosed by surgery, the napsin A levels in ELF at the nodule site were identically significantly higher than those at the contralateral site. In patients with non-adenocarcinoma, there were no differences in napsin A levels in ELF. The area under the receiver operator characteristic curve for identifying primary lung adenocarcinoma was 0.840 for napsin A and 0.542 for CEA. CONCLUSION: Evaluation of napsin A levels in ELF may be useful for distinguishing primary lung adenocarcinoma. PMID- 29233113 TI - Clinicopathologic and endoscopic features of early-stage colorectal serrated adenocarcinoma. AB - BACKGROUND: Serrated adenocarcinoma (SAC) is a distinct colorectal carcinoma variant that accounts for approximately 7.5% of all advanced colorectal carcinomas. While its prognosis is worse than conventional carcinoma, its early stage clinicopathologic features are unclear. We therefore aimed to clarify the clinicopathologic and endoscopic characteristics of early-stage SACs. METHODS: Forty consecutive early-stage SAC patients at Hiroshima University Hospital were enrolled; SACs were classified into epithelial serration (Group A, n = 17) and non-epithelial serration (Group B, n = 23) groups. Additionally, we classified serrated adenoma into 4 types: sessile serrated adenoma (SSA), traditional serrated adenoma (TSA), unclassified, and non-serrated adenoma type. RESULTS: There were significant differences between Groups A and B in terms of tumor size (27.6 vs. 43.1 mm), incidences of T1 carcinoma (71% vs. 13%), and having the same color as normal mucosa (47% vs. 17%), respectively (p <0.01). In SACs >20 mm, the incidence of T1 carcinoma in Group A (70%) was significantly greater than that in Group B (13%) (p <0.05). There were significant differences in 'Japan NBI Expert Team' type 3 and type V pit pattern classifications between the 2 groups. The average TSA-type tumor size (42.6 mm) was significantly larger than that of the SSA (17.2 mm) and non-serrated component types (18.3 mm). The incidences of submucosal invasion in SSA- (80%), unclassified- (100%), and non-serrated-type (100%) tumors were significantly higher than that in the TSA type (11%). CONCLUSIONS: Epithelial serration in the cancerous area and a non-TSA background indicated aggressive behavior in early-stage SACs. PMID- 29233114 TI - Exploring knowledge and attitudes toward non-communicable diseases among village health teams in Eastern Uganda: a cross-sectional study. AB - BACKGROUND: Community health workers are essential personnel in resource-limited settings. In Uganda, they are organized into Village Health Teams (VHTs) and are focused on infectious diseases and maternal-child health; however, their skills could potentially be utilized in national efforts to reduce the growing burden of non-communicable diseases (NCDs). We sought to assess the knowledge of, and attitudes toward NCDs and NCD care among VHTs in Uganda as a step toward identifying their potential role in community NCD prevention and management. METHODS: We administered a knowledge, attitudes and practices questionnaire to 68 VHT members from Iganga and Mayuge districts in Eastern Uganda. In addition, we conducted four focus group discussions with 33 VHT members. Discussions focused on NCD knowledge and facilitators of and barriers to incorporating NCD prevention and care into their role. A thematic qualitative analysis was conducted to identify salient themes in the data. RESULTS: VHT members possessed some knowledge and awareness of NCDs but identified a lack of knowledge about NCDs in the communities they served. They were enthusiastic about incorporating NCD care into their role and thought that they could serve as effective conduits of knowledge about NCDs to their communities if empowered through NCD education, the availability of proper reporting and referral tools, and visible collaborations with medical personnel. The lack of financial remuneration for their role did not emerge as a major barrier to providing NCD services. CONCLUSIONS: Ugandan VHTs saw themselves as having the potential to play an important role in improving community awareness of NCDs as well as monitoring and referral of community members for NCD-related health issues. In order to accomplish this, they anticipated requiring context-specific and culturally adapted training as well as strong partnerships with facility-based medical personnel. A lack of financial incentivization was not identified to be a major barrier to such role expansion. Developing a role for VHTs in NCD prevention and management should be a key consideration as local and national NCD initiatives are developed. PMID- 29233115 TI - Development and validation of college students' tuberculosis knowledge, attitudes and practices questionnaire (CS-TBKAPQ). AB - BACKGROUND: China faces many challenges in controlling tuberculosis (TB). One significant challenge is the control of college students' TB. In particular, cross-sectional studies of college students' knowledge, attitudes and practices (KAP) in regard to TB have attracted substantial attention. However, few measurement tools have been developed to aid processes related to expert consultation, pre-testing, reliability and validity testing. Our study developed the College Students' TB Knowledge Attitudes and Practices Questionnaire (CS TBKAPQ) following the scale development steps. METHODS: The construction of the CS-TBKAPQ was based on the Theory of Knowledge, Attitude, Belief, and Practice (KABP or KAP). The item pool was compiled from literature reviews and individual interviews. The reliability validation was assessed by calculating Cronbach's alpha coefficient, the split-half reliability coefficient, and the test-retest reliability coefficient. Construct validity was assessed using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). The diagnostic accuracy was evaluated using the World Health Organization Advocacy, Communication and Social Mobilization KAP Survey Questionnaire (WHO-TBKAPQ) as the reference standard. RESULTS: A total of 31 questionnaire items were proposed. Cronbach's alpha coefficient, the split-half reliability coefficient and the test-retest reliability coefficient were 0.86, 0.78 and 0.91. Four factors that explained 62.52% of the total variance were also identified in EFA and confirmed in CFA. The CFA model fit indices were x 2 /df = 1.82 (p < 0.001), GFI = 0.925, AGFI = 0.900, RMR = 0.068, and RMSEA = 0.049. The CS-TBKAPQ was significantly correlated with the WHO-TBKAPQ and the Chinese Public TB KAP Questionnaire (CDC-TBKAPQ) developed by the Chinese Center for Disease Control and Prevention (r = 0.59, 0.60, p < 0.001). The receiver operating characteristics curve (ROC) analysis suggested a cut-off point of 47.5, with which the CS-TBKAPQ showed a sensitivity of 73.63% and a specificity of 80.51% in identifying students with low-level KAP. The positive and negative predictive values were 83.23% and 69.91%. CONCLUSIONS: The findings of this study demonstrate that the CS-TBKAPQ is a reliable and valid tool for measuring the KAP towards TB in college students. PMID- 29233116 TI - Reference ranges for foetal nasal bone length, prenasal thickness, and interocular distance at 18 to 24 weeks' gestation in low-risk pregnancies. AB - BACKGROUND: The aim of the present study was to establish the normal ranges for foetal nasal bone length (NBL), prenasal skin thickness (PNT), interocular distance (IOD), and ratio of prenasal thickness to- nasal bone length (PNT/ NBL) at 18-24 weeks using two-dimensional (2D) ultrasound. METHODS: This study was a retrospective study of prenatal ultrasonographic records from 407 foetuses between 18 and 24 weeks gestational age (GA). The NBL, PNT, IOD, PNT/ NBL ratio, biparietal diameter (BPD), and femur length (FL) were investigated. The relationships among NBL, PNT, IOD, PNT/ NBL, and GA were evaluated. Additionally, descriptive statistics for NBL, PNT, and IOD values for each gestational week were obtained. RESULTS: There was a significant association between GA and NBL, PNT, and IOD between 18 and 24 weeks. NBL increased from a mean of 5.5 mm to 8.3 mm, PNT increased from a mean of 3.5 mm to 5.1 mm, and IOD increased from a mean of 11.1 mm to 14.5 mm. PNT/NBL ratio did not change with gestational age. CONCLUSIONS: This study showed normal ranges for NBL, PNT, IOD, and PNT/ NBL ratios for foetuses between 18 and 24 weeks in low-risk pregnancies. There was a positive linear relationship between GA and NBL, PNT, and IOD. The PNT/NBL ratio might be a more useful measurement than NBL or PNT alone. PMID- 29233117 TI - Elizabethkingia miricola as an opportunistic oral pathogen associated with superinfectious complications in humoral immunodeficiency: a case report. AB - BACKGROUND: Elizabethkingia miricola is a rare Gram-negative bacterium found in water and clinical specimens. Typical culturing methods often misidentify Elizabethkingia spp. as Flavobacterium or Chryseobacterium. Although diagnosis is based on culturing samples taken from sterile sites, such as blood, a proper identification of this bacterium requires an expertise that goes beyond the capabilities of a typical clinical laboratory. CASE PRESENTATION: A 35-year-old woman diagnosed with common variable immunodeficiency was admitted to our center. Previous treatment with antibiotics (amoxicillin plus clavulanate, first and third generation of cephalosporins, macrolides) and systemic corticosteroids (up to 120 mg/day of prednisolone) failed to arrest the spread of inflammation. Gingival recession was observed in her oral cavity, resulting in an apparent lengthening of her teeth. In addition to typical commensal bacteria, including streptococci and neisseriae, strains of Rothia mucilaginosa and Elizabethkingia miricola were identified upon a detailed microbiological examination using a MALDI-TOF MS Biotyper system. The presence of the latter strain correlated with severe periodontitis, lack of IgA in her saliva and serum, a very low IgG concentration (< 50 mg/dl), IgM-paraproteinemia, decreases in C3a and C5a and microvascular abnormality. High-dose immunoglobulin (to maintain IgG > 500 mg/dl) and targeted levofloxacin treatment resulted in immune system reconstitution, oral healing, and eradication of the Elizabethkingia infection. CONCLUSIONS: E. miricola rarely causes disease in healthy individuals. However, the overgrowth of commensal bacteria, lack of IgG/IgA, microvasculopathy and complement cascade activation in patients with humoral immunodeficiency may facilitate Elizabethkingia invasion. Overuse of antibiotics, particularly beta-lactams, may cause mucosal colonization by E. miricola, followed by its multiplication combined with periodontitis that prompts bacterial translocation. MALDI-TOF Biotyper analysis may become a method of choice for identification of Elizabethkingia infections. PMID- 29233118 TI - Risks and complications of transurethral resection of bladder tumors in patients receiving antiplatelet and/or anticoagulant therapy: a retrospective cohort study. AB - BACKGROUND: Information on the safety of transurethral resection of bladder tumors (TURBT) in patients receiving anti-thromboembolic drugs is currently lacking. This study aimed to evaluate the clinical safety of TURBT in patients receiving anti-thromboembolic agents compared with patients not taking these agents and patients who interrupted their use perioperatively. METHODS: We retrospectively analyzed data for patients who underwent TURBT at Jichi Medical University Saitama Medical Center from September 2013 to August 2016.Patients who underwent surgery while receiving antiplatelet and/or anticoagulant drugs were allocated to the continuation group, those who interrupted these drugs comprised the interruption group, and those who did not use these agents were designated as the control group. We compared the patient characteristics, hemoglobin levels, and complications among the three groups. RESULTS: A total of 174 patients were analyzed including 19, 18, and 137 in the continuation, interruption, and control groups, respectively. There were no significant differences in patient and tumor characteristics, apart from age, among the three groups. Decreases in hemoglobin levels were similar in the continuation, interruption, and control groups (-0.50 g/dl, -0.40 g/dl, and -0.50 g/dl, respectively).Significantly more patients in the continuation group experienced clot retention compared with the control group (21% vs 5%, p = 0.03). Large tumor size tended to be a risk factor for clot retention in the continuation group (p = 0.07). No patient in the continuation or interruption group required blood transfusion, compared with two patients (1%) in the control group. No patients in any of the groups experienced cardiovascular events during their hospital stay or required rehospitalization for hematuria after discharge. CONCLUSIONS: TURBT can be performed safely in patients who continue to take antiplatelet and/or anticoagulant agents, without increasing the risks of severe hemorrhage and blood transfusion. However, the risk of postoperative clot retention may be increased in these patients. PMID- 29233119 TI - Psychological wellbeing and physical activity in children and adolescents with inflammatory bowel disease compared to healthy controls. AB - BACKGROUND: Children and adolescents with inflammatory bowel disease (IBD) report impairments in daily activities, social interactions and coping. Findings regarding psychological functioning are inconsistent, while limited information is available on objectively assessed physical activity (PA). The aims of the present study were therefore to compare anthropometric dimensions, blood values, psychological functioning and PA of children and adolescents with IBD with healthy controls. METHODS: Forty-seven children and adolescents took part in the study. Of these, 23 were diagnosed with IBD (mean age: 13.88 years, 44% females). The IBD group was divided into a medically well adjusted "remission-group" (n = 14; IBD-RE) and a group with an "active state" of disease (n = 8; IBD-AD). Healthy controls (n = 24; HC) were age- and gender-matched. Participants' anthropometric data, blood values and objective PA were assessed. Further, participants completed questionnaires covering socio-demographic data and psychological functioning. RESULTS: Participants with IBD-AD showed higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) values, haemoglobin, and leukocyte values. IBD-AD had poorer psychological functioning and lower PA (average steps per day) compared to IBD-RE and HC. No mean differences were found between IBD-RE and HC. CONCLUSIONS: The pattern of results suggests that effective medical treatment of IBD in children and adolescents is associated with favorable physiological parameters, psychological dimensions and PA. Psychological counselling of children and adolescents in an active state of IBD seem to be advised in addition to standard treatment schedules. TRIAL REGISTRATION: NCT NCT02264275 ; Registered 8 October 2014. PMID- 29233120 TI - Prediction of 5-year overall survival in cervical cancer patients treated with radical hysterectomy using computational intelligence methods. AB - BACKGROUND: Computational intelligence methods, including non-linear classification algorithms, can be used in medical research and practice as a decision making tool. This study aimed to evaluate the usefulness of artificial intelligence models for 5-year overall survival prediction in patients with cervical cancer treated by radical hysterectomy. METHODS: The data set was collected from 102 patients with cervical cancer FIGO stage IA2-IIB, that underwent primary surgical treatment. Twenty-three demographic, tumor-related parameters and selected perioperative data of each patient were collected. The simulations involved six computational intelligence methods: the probabilistic neural network (PNN), multilayer perceptron network, gene expression programming classifier, support vector machines algorithm, radial basis function neural network and k-Means algorithm. The prediction ability of the models was determined based on the accuracy, sensitivity, specificity, as well as the area under the receiver operating characteristic curve. The results of the computational intelligence methods were compared with the results of linear regression analysis as a reference model. RESULTS: The best results were obtained by the PNN model. This neural network provided very high prediction ability with an accuracy of 0.892 and sensitivity of 0.975. The area under the receiver operating characteristics curve of PNN was also high, 0.818. The outcomes obtained by other classifiers were markedly worse. CONCLUSIONS: The PNN model is an effective tool for predicting 5-year overall survival in cervical cancer patients treated with radical hysterectomy. PMID- 29233121 TI - Do retreatment tuberculosis patients need special treatment response follow-up beyond the standard regimen? Finding of five-year retrospective study in pastoralist setting. AB - BACKGROUND: Treatment outcomes serve as proxy measures of the quality of tuberculosis treatment provided by the health care system, and it is essential to evaluate the effectiveness of Directly Observed Therapy-Short course program in controlling the disease, and reducing treatment failure, default and death. Hence, we evaluated tuberculosis treatment success rate, its trends and predictors of unsuccessful treatment outcome in Ethiopian Somali region where 85% of its population is pastoralist. METHODS: A retrospective review of 5 years data (September 2009 to August 2014) was conducted to evaluate the treatment outcome of 1378 randomly selected tuberculosis patients treated in Kharamara, Dege-habour and Gode hospitals. We extracted data on socio-demographics, HIV Sero-status, tuberculosis type, treatment outcome and year using clinical chart abstraction sheet. Tuberculosis treatment outcomes were categorized into successful (cured and/or completed) and unsuccessful (died/failed/default) according to the national tuberculosis guideline. Data was entered using EpiData 3.1 and analyzed using SPSS 20. Chi-square (chi2) test and logistic regression model were used to reveal the predictors of unsuccessful treatment outcome at P <= 0.05 significance level. RESULT: The majority of participants was male (59.1%), pulmonary smear negative (49.2%) and new cases (90.6%). The median age was 26 years [IQR: 18-40] and HIV co-infection rate was 4.6%. The overall treatment success rate was 86.8% [95%CI: 84.9% - 88.5%]; however, 4.8%, 7.6% and 0.7% of patients died, defaulted and failed to cure respectively. It fluctuated across the years and ranged from 76.9% to 94% [p < 0.001]. The odds of death/failure [AOR = 2.4; 95%CI = 1.4-3.9] and pulmonary smear positivity [AOR = 2.3; 95%CI = 1.6-3.5] were considerably higher among retreatment patients compared to new counterparts. Unsuccessful treatment outcome was significantly higher in less urbanized hospitals [p < 0.001]. Treatment success rate had insignificant difference between age groups, genders, tuberculosis types and HIV status (P > 0.05). CONCLUSION: This study revealed that the overall tuberculosis treatment success rate has realized the global target for 2011-2015. However, it does not guarantee its continuity as adverse treatment outcomes might unpredictably occur anytime and anywhere. Therefore, continual effort to effectively execute DOTS should be strengthened and special follow-up mechanism should be in place to monitor treatment response of retreatment cases. PMID- 29233122 TI - Composite hemangioendothelioma of the forehead and right eye; a case report. AB - BACKGROUND: Hemangioendothelioma includes several types of vascular neoplasms , as well as both benign and malignant growth. CASE PRESENTATION: This study evaluated a case of a 78-year-old female diagnosed with composite hemangioendothelioma (CHE). This patient had an 18-month history of painless inflammatory lesions and erythema on the left forehead and right upper eyelid. The clinical and pathologic characteristics of the CHE were evaluated in the present study. CONCLUSION: The evidence of the coexistence of variable components of the CHE in our study emphasized the importance of distinctive morphology and biology, and should be considered in the differential diagnosis of other vascular lesions. PMID- 29233123 TI - Impact of place of residence on place of death in Wales: an observational study. AB - BACKGROUND: Previous research in England showed that deprivation level of a person's place of residence affects the place of death and quality of care received at the end of life. People dying in their preferred place of death has also been shown to act as an indication for high quality of end of life care services and social equality. This study expands on current research to explore the effects of deprivation and place of residence on health related choices and place of death in Wales. METHODS: We used ten years combined mortality statistics from 2005 to 2014 and Welsh Index of Multiple Deprivation rankings for each lower super output area. After accounting for the population's age, the number of deaths in Hospital, Hospice, Home, Care Home, Psychiatric Units, and Elsewhere were compared across deprivation quintiles. RESULTS: Distribution of place of death was found to be concentrated in three places - hospital (60%), home (21%) and care home (13%). Results from this study shows a high number of hospital deaths, especially for more deprived areas, despite being the least preferred place of death. CONCLUSION: This is the first Welsh study investigating place of death in relation to deprivation, which could be of major importance to academics, end of life care providers and policy makers interested in to reduce health care inequality in Wales. PMID- 29233124 TI - Increase in esodeviation under cycloplegia with 0.5% tropicamide and 0.5% phenylephrine mixed eye drops in patients with hyperopia and esotropia. AB - BACKGROUD: To evaluate the manifestations of increased esodeviation under cycloplegia with 0.5% tropicamide and 0.5% phenylephrine in children with hyperopia and esotropia. METHODS: We reviewed the medical record of 34 children with hyperopia and esotropia who underwent a prism alternate cover test before and after instillation of mixed eye drops containing 0.5% tropicamide and 0.5% phenylephrine between November 2014 and October 2015. Increased angle of deviation was defined as 10 prism diopters (PD) or greater deviation after cycloplegia. The factors related to increased angle of deviation were evaluated using univariable and multivariable logistic regression analysis. RESULTS: The median age was 5.0 years (interquartile range, 3.75 to 5.0) and 12 patients (35.3%) were male. The median manifested refractive (MR) was +2.13 diopters (D) (+0.92 to +4.47) and cycloplegic refractive (CR) was +3.50 D (+1.72 to +5.66). The median difference between MR and CR was +0.88 D (+0.50 to +1.28). Thirteen patients (38.2%) showed increased esodeviation under cycloplegia and all had accommodative esotropia. A larger difference between MR and CR was the only significant factor affecting increased esodeviation in both univariable (OR = 4.72, P = 0.029) and multivariable (OR = 5.22, P = 0.047) analyses. CONCLUSION: Children with hyperopia and esotropia often showed an increased angle of deviation after instillation of 0.5% tropicamide and 0.5% phenylephrine. This phenomenon reminded the clinicians that cycloplegics can have a different effect on esodeviation and suggested that increased angle of esodeviation may help to reveal the latent deviation in some patients with hyperopia and esotropia. PMID- 29233125 TI - Low prevalence of lipid metabolism abnormalities in APOE epsilon2-genotype and male patients 60 years or older with schizophrenia. AB - BACKGROUND: Schizophrenia is a serious mental disorder largely manageable with atypical antipsychotics; however, these drugs have been associated with glucose/lipid metabolism issues such as diabetes and hyperlipidaemia. Apolipoprotein E (APOE) is the most abundant apolipoprotein, and APOE genotypes have been correlated with lipid metabolism phenotypes in an age-dependent manner. Studies examining the relationship between the APOE genotype and lipid abnormalities in patients with schizophrenia have been inconclusive, but primarily focused on adult patient populations. Therefore, we explored the correlations between the APOE genotype and glucose/lipid metabolism indicators and abnormalities in hospitalized patients 60 years or older with schizophrenia with a history of long-term antipsychotics use. METHODS: We assessed APOE genotype, age, weight, height, blood glucose, triglycerides, cholesterol, high density lipoprotein, and low-density lipoprotein in a total of 294 patients. APOE genotypes were divided into three groups: APOE epsilon2 (epsilon2/epsilon2 and epsilon2/epsilon3), APOE epsilon3 (epsilon3/epsilon3), and APOE epsilon4 (epsilon3/epsilon4 and epsilon4/epsilon4), and comparisons were conducted among these groups or according to epsilon2 carrier status. RESULTS: APOE epsilon3/epsilon3 was the most common genotype (68.3%) and at least one epsilon3 allele was present in 81.8% ofpatients. There were no differences in antipsychotics type or dose according to the APOE genotype, but serum cholesterol values varied near significantly (P = 0.052) and low-density lipoprotein values varied significantly according to genotype (P < 0.05, lowest in the APOE epsilon2 genotype). Men had lower cholesterol and low-density lipoprotein levels (P < 0.05) than women. Compared to patients administered typical antipsychotics, those administered atypical antipsychotics had higher triglyceride, cholesterol, and low-density lipoprotein levels (P < 0.05). Stepwise linear regressions showed that cholesterol and low-density lipoprotein levels were influenced by sex, the APOE epsilon2 genotype, and atypical antipsychotics use. CONCLUSIONS: In the context of atypical antipsychotics use, carriers of the APOE epsilon2-genotype and male patients with schizophrenia 60 years or older may be less likely to develop a lipid metabolism abnormality. PMID- 29233126 TI - Positive prognostic value of HER2-HER3 co-expression and p-mTOR in gastric cancer patients. AB - BACKGROUND: The HER2-HER3 heterodimer significantly decreases survival in breast cancer patients. However, the prognostic value of HER2-HER3 overexpression remains unknown in gastric cancer (GC). METHODS: The expression levels of HER2, HER3, Akt, p-Akt, mTOR and p-mTOR were examined in specimens from 120 GC patients by immunohistochemistry and quantitative reverse transcription-PCR. The associations of HER proteins, PI3K/Akt/mTOR pathway-related proteins, clinicopathological features of GC, and overall survival (OS) were assessed. To comprehensively evaluate the prognostic values of pathway-related proteins, meta analyses were conducted with STATA 11.0. RESULTS: HER2 overexpression was significantly associated with HER3 levels (P = 0.02). HER3 was highly expressed in gastric cancer tissues. High HER2 and HER3 levels were associated with elevated p-Akt and p-mTOR amounts (P < 0.05). Furthermore, HER2-HER3 co expression was associated with high p-Akt and p-mTOR (P < 0.05) levels. Meanwhile, p-mTOR overexpression was tightly associated with differentiation, depth of invasion, lymph node metastasis, TNM stage and OS (P < 0.05). By meta analyses, Akt, p-Akt, and mTOR levels were unrelated to clinicopathological characters. HER3 overexpression was associated with depth of invasion (OR = 2.39, 95%CI 1.62-3.54, P < 0.001) and lymph node metastasis (OR = 2.35, 95%CI 1.34 4.11, P = 0.003). Further, p-mTOR overexpression was associated with patient age, tumor location, depth of invasion (OR = 1.63, 95%CI 1.08-2.45, P = 0.02) and TNM stage (OR = 1.73, 95%CI 1.29-2.32, P < 0.001). In addition, HER2-HER3 overexpression corresponded to gradually shortened 5-year OS (P < 0.05), and significant relationships were shown among HER3, p-mTOR overexpression, and 1-, 3 , 5-year OS (P < 0.05). CONCLUSIONS: HER2-HER3 co-expression may potentially enhance mTOR phosphorylation. HER2-HER3 co-expression and p-mTOR are both related to the prognosis of GC patients. PMID- 29233127 TI - Lesion based diagnostic performance of dual phase 99mTc-MIBI SPECT/CT imaging and ultrasonography in patients with secondary hyperparathyroidism. AB - BACKGROUND: We aimed to evaluate the diagnostic performance of 99mTc-MIBI SPECT/CT and ultrasonography in patients with secondary hyperparathyroidism (SHPT), and explored the factors that affect the diagnostic performance. METHODS: 99mTc-MIBI SPECT/CT and ultrasonography were performed in 50 patients with SHPT within 1 month before they underwent surgery. Imaging results were confirmed by the pathology. Pearson correlation analysis was used to determine the correlation of PTH level with clinical data. The optimal cutoff value for predicting positive 99mTc-MIBI results was evaluated by ROC analysis in lesions diameter. RESULTS: Forty-nine patients had a positive 99mTc-MIBI imaging results and 39 patients had positive ultrasonography results. The sensitivities of 99mTc-MIBI and ultrasonography were 98.00% and 78.00%, respectively. A total of 199 lesions were resected in 50 patients. Among them, 183 lesions were proved to be parathyroid hyperplasia. On per-lesion basis analysis, the sensitivity and specificity of 99mTc-MIBI and ultrasonography were 59.34% and 75.00% vs 46.24% and 80.00%, respectively. The Pearson correlation analysis showed that the serum AKP and PTH level had a significant linear association (r = 0.699, P < 0.001). The lesion diameter was a statistically significant predictive factor in predicting positive 99mTc-MIBI SPECT/CT. The optimal cutoff value for predicting positive 99mTc-MIBI results evaluated by ROC analysis in lesions diameter was 8.05 mm. CONCLUSION: Dual phase 99mTc-MIBI SPECT/CT imaging had a higher sensitivity in patients with SHPT than ultrasonography. Therefore, using 99mTc-MIBI positioning the lesion could be an effective method pre-surgical in patients with SHPT. PMID- 29233128 TI - Double Up Food Bucks program effects on SNAP recipients' fruit and vegetable purchases. AB - BACKGROUND: To encourage the consumption of more fresh fruits and vegetables, the 2014 United Sates Farm Bill allocated funds to the Double Up Food Bucks Program. This program provided Supplemental Nutrition Assistance Program beneficiaries who spent $10 on fresh fruits and vegetables, in one transaction, with a $10 gift card exclusively for Michigan grown fresh fruits and vegetables. This study analyzes how fruit and vegetable expenditures, expenditure shares, variety and purchase decisions were affected by the initiation and conclusion, as well as any persistent effects of the program. METHODS: Changes in fruit and vegetable purchase behaviors due to Double Up Food Bucks in a supermarket serving a low income, predominantly Hispanic community in Detroit, Michigan were evaluated using a difference in difference fixed effects estimation strategy. RESULTS: We find that the Double Up Food Bucks program increased vegetable expenditures, fruit and vegetable expenditure shares, and variety of fruits and vegetables purchased but the effects were modest and not sustainable without the financial incentive. Fruit expenditures and the fruit and vegetable purchase decision were unaffected by the program. CONCLUSIONS: This study provides valuable insight on how a nutrition program influences a low-income, urban, Hispanic community's fruit and vegetable purchase behavior. Policy recommendations include either removing or lowering the purchase hurdle for incentive eligibility and dropping the Michigan grown requirement to better align with the customers' preferences for fresh fruits and vegetables. PMID- 29233129 TI - Basal wall hypercontraction of Takotsubo cardiomyopathy in a patient who had been diagnosed with dilated cardiomyopathy: a case report. AB - BACKGROUND: Takotsubo cardiomyopathy is characterized by the basal hypercontractility and apical ballooning of the left ventriculum and T-wave inversion in the electrocardiogram. It has been suggested that Takotsubo cardiomyopathy might underlie the pathogenesis of persistent cardiac dysfunction; however, few reports are present demonstrating the advent of Takotsubo cardiomyopathy in patients with idiopathic cardiomyopathy. CASE PRESENTATION: A 64-year-old women was admitted due to dyspnea on effort and lower extremity edema. She had been diagnosed with idiopathic dilated cardiomyopathy 2.5 years before owing to the reduced left ventricular ejection fraction (24%), normal coronary artery, and interstitial fibrosis of the myocardial samples. On admission, her electrocardiogram showed giant negative T wave in II, III, aVF, and precordial leads. Echocardiography showed dyskinesis of the left ventricular apex and hypercontraction of the basal wall, which had not been observed in the previous examinations. Coronary angiography showed normal coronary arteries, and apical ballooning and basal hypercontractility was confirmed by left ventriculography. On day 15 of admission, contraction of apical wall was recovered, and basal hypercontraction was disappeared. CONCLUSION: The present case is the first report demonstrating appearance the transient basal wall hypercontraction along with the advent of Takotsubo cardiomyopathy in a patient diagnosed with dilated cardiomyopathy. Whether such findings are indicative of fair prognosis and have the utility of understanding the pathogenesis of dilated cardiomyopathy needs further investigation. PMID- 29233130 TI - Antibiotics for treatment of acute exacerbation of chronic obstructive pulmonary disease: a network meta-analysis. AB - BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is the most common reason for the hospitalization and death of pulmonary patients. The use of antibiotics as adjuvant therapy for AECOPD, however, is still a matter of debate. METHODS: In this study, we searched the PubMed, EmBase, and Cochrane databases for randomized controlled trials published until September 2016 that evaluated the use of antibiotics for AECOPD treatment. The major outcome variables were clinical cure rate and adverse effects. The microbiological response rate, relapse of exacerbation, and mortality were also analysed. A random-effect network was used to assess the effectiveness and tolerance of each antibiotic used for AECOPD treatment. RESULTS: In this meta analysis, we included 19 articles that assessed 17 types of antibiotics used in 5906 AECOPD patients. The cluster ranking showed that dirithromycin had a high clinical cure rate with a low rate of adverse effects. Ofloxacin, ciprofloxacin, and trimethoprim-sulfamethoxazole had high clinical cure rates with median rates of adverse effects. In terms of the microbiological response rate, only doxycycline was significantly better than placebo (odds ratio (OR), 3.84; 95% confidence interval (CI), 1.96-7.54; p < 0.001). There were no other significant results with respect to the frequency of recurrence or mortality. CONCLUSIONS: Our study indicated that dirithromycin is adequate for improving the clinical cure rate of patients with AECOPD with few adverse effects. Ofloxacin, ciprofloxacin, and trimethoprim-sulfamethoxazole are also recommended for disease treatment. However, caution should still be exercised when using antibiotics to treat AECOPD. Trial Registration Not applicable. PMID- 29233131 TI - Individual class evaluation and effective teaching characteristics in integrated curricula. AB - BACKGROUND: In an integrated curriculum, multiple instructors take part in a course in the form of team teaching. Accordingly, medical schools strive to manage each course run by numerous instructors. As part of the curriculum management, course evaluation is conducted, but a single, retrospective course evaluation does not comprehensively capture student perception of classes by different instructors. This study aimed to demonstrate the need for individual class evaluation, and further to identify teaching characteristics that instructors need to keep in mind when preparing classes. METHODS: From 2014 to 2015, students at one medical school left comments on evaluation forms after each class. Courses were also assessed after each course. Their comments were categorized by connotation (positive or negative) and by subject. Within each subject category, test scores were compared between positively and negatively mentioned classes. The Mann-Whitney U test was performed to test group differences in scores. The same method was applied to the course evaluation data. RESULTS: Test results for course evaluation showed group difference only in the practice/participation category. However, test results for individual class evaluation showed group differences in six categories: difficulty, main points, attitude, media/contents, interest, and materials. That is, the test scores of classes positively mentioned in six domains were significantly higher than those of negatively mentioned classes. CONCLUSIONS: It was proved that individual class evaluation is needed to manage multi-instructor courses in integrated curricula of medical schools. Based on the students' extensive feedback, we identified teaching characteristics statistically related to academic achievement. School authorities can utilize these findings to encourage instructors to develop effective teaching characteristics in class preparation. PMID- 29233133 TI - User testing of an adaptation of fishbone diagrams to depict results of systematic reviews. AB - BACKGROUND: Summary of findings tables in systematic reviews are highly informative but require epidemiological training to be interpreted correctly. The usage of fishbone diagrams as graphical displays could offer researchers an effective approach to simplify content for readers with limited epidemiological training. In this paper we demonstrate how fishbone diagrams can be applied to systematic reviews and present the results of an initial user testing. METHODS: Findings from two systematic reviews were graphically depicted in the form of the fishbone diagram. To test the utility of fishbone diagrams compared with summary of findings tables, we developed and pilot-tested an online survey using Qualtrics. Respondents were randomized to the fishbone diagram or a summary of findings table presenting the same body of evidence. They answered questions in both open-ended and closed-answer formats; all responses were anonymous. Measures of interest focused on first and second impressions, the ability to find and interpret critical information, as well as user experience with both displays. We asked respondents about the perceived utility of fishbone diagrams compared to summary of findings tables. We analyzed quantitative data by conducting t-tests and comparing descriptive statistics. RESULTS: Based on real world systematic reviews, we provide two different fishbone diagrams to show how they might be used to display complex information in a clear and succinct manner. User testing on 77 students with basic epidemiological training revealed that participants preferred summary of findings tables over fishbone diagrams. Significantly more participants liked the summary of findings table than the fishbone diagram (71.8% vs. 44.8%; p < .01); significantly more participants found the fishbone diagram confusing (63.2% vs. 35.9%, p < .05) or indicated that it was difficult to find information (65.8% vs. 45%; p < .01). However, more than half of the participants in both groups were unable to find critical information and answer three respective questions correctly (52.6% in the fishbone group; 51.3% in the summary of findings group). CONCLUSIONS: Fishbone diagrams are compact visualizations that, theoretically, may prove useful for summarizing the findings of systematic reviews. Initial user testing, however, did not support the utility of such graphical displays. PMID- 29233134 TI - Predictors of need for help with weight loss among overweight and obese men and women in the Netherlands: a cross-sectional study. AB - BACKGROUND: Need for help is perceived as an important first step towards weight related health-care use among overweight and obese individuals and several studies have reported gender as an important predisposing characteristic of need for help. Therefore, the goal of the current study is to gain insight into factors that might determine need for help for weight loss in men and women. METHODS: In the current study, data from the Dutch cross-sectional survey Health Monitor 2012 was used. Overweight and obese men (N = 2218) and women (N = 2002) aged 19-64 years were selected for the current study. Potential predictors of need for help were age, ethnicity, marital status, educational level, perceived health, weight status, comorbidities, physical activity level, and income. Multiple logistic regression analyses were conducted separately among men and women to establish prediction models of need for help for weight loss. RESULTS: The mean age of the adult women in this study population was 47.7 years and 68% was medium educated, whereas the mean age of men was 49.0 years and 63.0% was medium educated. Of the respondents, 24.9% indicated they either felt a need for help for weight loss, 6.4% already received help and 68.7% felt no need for help. Women were more likely to indicate a need for help than men (OR = 2.17). Among both genders, need for help was significantly predicted by obesity (ORmen = 3.80, ORwomen = 2.20) and "poor" perceived health (ORmen = 2.14, ORwomen = 1.94). Besides, "unmarried" (ORmen = 1.57) and suffering from comorbidities (ORmen = 1.26) predicted need for help among men. Whereas among women, need for help was predicted by younger age (i.e. 19-34 years (ORwomen = 2.07) and 35-49 years (ORwomen = 1.35)). CONCLUSION: The current study revealed specific predictors of need for help for weight loss for men and women. Among men, the strongest predictors were obesity and poor perceived health, whereas among women need for help was most strongly predicted by obesity and young age. Insight into these specific predictors enables health professionals to reach overweight individuals with a need for help for weight loss by connecting their need to available support. PMID- 29233132 TI - Intraoral scanners in dentistry: a review of the current literature. AB - BACKGROUND: Intraoral scanners (IOS) are devices for capturing direct optical impressions in dentistry. The purpose of this narrative review on the use of IOS was to: (1) identify the advantages/disadvantages of using optical impressions compared to conventional impressions; (2) investigate if optical impressions are as accurate as conventional impressions; (3) evaluate the differences between the IOS currently available commercially; (4) determine the current clinical applications/limitations in the use of IOS. METHODS: Electronic database searches were performed using specific keywords and MeSH terms. The searches were confined to full-text articles written in English and published in peer-reviewed journals between January 2007 and June 2017. RESULTS: One hundred thirty-two studies were included in the present review; among them, 20 were previous literature reviews, 78 were in vivo clinical studies (6 randomized controlled/crossover trials, 31 controlled/comparative studies; 24 cohort studies/case series; 17 case reports) and 34 were in vitro comparative studies. CONCLUSIONS: Optical impressions reduce patient discomfort; IOS are time-efficient and simplify clinical procedures for the dentist, eliminating plaster models and allowing better communication with the dental technician and with patients; however, with IOS, it can be difficult to detect deep margin lines in prepared teeth and/or in case of bleeding, there is a learning curve, and there are purchasing and managing costs. The current IOS are sufficiently accurate for capturing impressions for fabricating a whole series of prosthetic restorations (inlays/onlays, copings and frameworks, single crowns and fixed partial dentures) on both natural teeth and implants; in addition, they can be used for smile design, and to fabricate posts and cores, removable partial prostheses and obturators. The literature to date does not support the use of IOS in long-span restorations with natural teeth or implants. Finally, IOS can be integrated in implant dentistry for guided surgery and in orthodontics for fabricating aligners and custom-made devices. PMID- 29233135 TI - Biotic and abiotic drivers of intraspecific trait variation within plant populations of three herbaceous plant species along a latitudinal gradient. AB - BACKGROUND: The importance of intraspecific trait variation (ITV) is increasingly acknowledged among plant ecologists. However, our understanding of what drives ITV between individual plants (ITVBI) at the population level is still limited. Contrasting theoretical hypotheses state that ITVBI can be either suppressed (stress-reduced plasticity hypothesis) or enhanced (stress-induced variability hypothesis) under high abiotic stress. Similarly, other hypotheses predict either suppressed (niche packing hypothesis) or enhanced ITVBI (individual variation hypothesis) under high niche packing in species rich communities. In this study we assess the relative effects of both abiotic and biotic niche effects on ITVBI of four functional traits (leaf area, specific leaf area, plant height and seed mass), for three herbaceous plant species across a 2300 km long gradient in Europe. The study species were the slow colonizing Anemone nemorosa, a species with intermediate colonization rates, Milium effusum, and the fast colonizing, non-native Impatiens glandulifera. RESULTS: Climatic stress consistently increased ITVBI across species and traits. Soil nutrient stress, on the other hand, reduced ITVBI for A. nemorosa and I. glandulifera, but had a reversed effect for M. effusum. We furthermore observed a reversed effect of high niche packing on ITVBI for the fast colonizing non-native I. glandulifera (increased ITVBI), as compared to the slow colonizing native A. nemorosa and M. effusum (reduced ITVBI). Additionally, ITVBI in the fast colonizing species tended to be highest for the vegetative traits plant height and leaf area, but lowest for the measured generative trait seed mass. CONCLUSIONS: This study shows that stress can both reduce and increase ITVBI, seemingly supporting both the stress-reduced plasticity and stress-induced variability hypotheses. Similarly, niche packing effects on ITVBI supported both the niche packing hypothesis and the individual variation hypothesis. These results clearly illustrates the importance of simultaneously evaluating both abiotic and biotic factors on ITVBI. This study adds to the growing realization that within-population trait variation should not be ignored and can provide valuable ecological insights. PMID- 29233136 TI - Socioeconomic inequality in abdominal obesity among older people in Purworejo District, Central Java, Indonesia - a decomposition analysis approach. AB - BACKGROUND: Obesity has become a global health challenge as its prevalence has increased globally in recent decades. Studies in high-income countries have shown that obesity is more prevalent among the poor. In contrast, obesity is more prevalent among the rich in low- and middle-income countries, hence requiring different focal points to design public health policies in the latter contexts. We examined socioeconomic inequalities in abdominal obesity in Purworejo District, Central Java, Indonesia and identified factors contributing to the inequalities. METHODS: We utilised data from the WHO-INDEPTH Study on global AGEing and adult health (WHO-INDEPTH SAGE) conducted in the Purworejo Health and Demographic Surveillance System (HDSS) in Purworejo District, Indonesia in 2010. The study included 14,235 individuals aged 50 years and older. Inequalities in abdominal obesity across wealth groups were assessed separately for men and women using concentration indexes. Decomposition analysis was conducted to assess the determinants of socioeconomic inequalities in abdominal obesity. RESULTS: Abdominal obesity was five-fold more prevalent among women than in men (30% vs. 6.1%; p < 0.001). The concentration index (CI) analysis showed that socioeconomic inequalities in abdominal obesity were less prominent among women (CI = 0.26, SE = 0.02, p < 0.001) compared to men (CI = 0.49, SE = 0.04, p < 0.001). Decomposition analysis showed that physical labour was the major determinant of socioeconomic inequalities in abdominal obesity among men, explaining 47% of the inequalities, followed by poor socioeconomic status (31%), <= 6 years of education (15%) and current smoking (11%). The three major determinants of socioeconomic inequalities in abdominal obesity among women were poor socio economic status (48%), physical labour (17%) and no formal education (16%). CONCLUSION: Abdominal obesity was more prevalent among older women in a rural Indonesian setting. Socioeconomic inequality in abdominal obesity exists and concentrates more among the rich population in both sexes. The inequality gap is less prominent among women, indicating a trend towards obesity being more common in poor women. Policies to address social determinants of health need to be developed to address the socioeconomic inequality gaps in obesity, with particular focus on addressing the existing burden of obesity among the better off population group, while preventing the imminent burden of obesity among the worst-off group, particularly among women. PMID- 29233137 TI - Rational modification of substrate binding site by structure-based engineering of a cellobiose 2-epimerase in Caldicellulosiruptor saccharolyticus. AB - BACKGROUND: Lactulose, a synthetic disaccharide, has received increasing interest due to its role as a prebiotic, specifically proliferating Bifidobacilli and Lactobacilli and enhancing absorption of calcium and magnesium. The use of cellobiose 2-epimerase (CE) is considered an interesting alternative for industrial production of lactulose. CE reversibly converts D-glucose residues into D-mannose residues at the reducing end of unmodified beta-1,4-linked oligosaccharides, including beta-1,4-mannobiose, cellobiose, and lactose. Recently, a few CE 3D structure were reported, revealing mechanistic details. Using this information, we redesigned the substrate binding site of CE to extend its activity from epimerization to isomerization. RESULTS: Using superimposition with 3 known CE structure models, we identified 2 residues (Tyr114, Asn184) that appeared to play an important role in binding epilactose. We modified these residues, which interact with C2 of the mannose moiety, to prevent epimerization to epilactose. We found a Y114E mutation led to increased release of a by product, lactulose, at 65 degrees C, while its activity was low at 37 degrees C. Notably, this phenomenon was observed only at high temperature and more reliably when the substrate was increased. Using Y114E, isomerization of lactose to lactulose was investigated under optimized conditions, resulting in 86.9 g/l of lactulose and 4.6 g/l of epilactose for 2 h when 200 g/l of lactose was used. CONCLUSION: These results showed that the Y114E mutation increased isomerization of lactose, while decreasing the epimerization of lactose. Thus, a subtle modification of the active site pocket could extend its native activity from epimerization to isomerization without significantly impairing substrate binding. While additional studies are required to scale this to an industrial process, we demonstrated the potential of engineering this enzyme based on structural analysis. PMID- 29233138 TI - Correction to: Characteristics of therapeutic alliance in musculoskeletal physiotherapy and occupational therapy practice: a scoping review of the literature. AB - CORRECTION: Following publication of the original article [1], an erratum was initiated in order to include supplementary material that was not updated and not included during the online submission of the authors' corrections. The additional corrections, included below, are to Appendix II. The original article has been corrected. PMID- 29233139 TI - Demand-related factors influencing caregivers' awareness of malaria tests and health workers' testing practices, in Makarfi, Nigeria. AB - BACKGROUND: Despite the World Health Organization's recommendation of malaria test-treat strategy, which is the treatment of parasitological confirmed malaria cases with anti-malarials, presumptive diagnosis of malaria remains fairly common in Nigeria. The reasons for this have not been established in Makarfi, Nigeria, despite the high burden of malaria in the area. A study was conducted among caregivers of febrile children less than 5 years presenting for treatment to understand their awareness of malaria diagnostic testing and being offered testing by clinicians, the determinants of these outcomes, and caregivers' perspectives of health workers' testing practices. METHODS: Using mixed-methods, data was combined from sub-analysis of cross-sectional survey data (n = 295) and focus group discussions (n = 4) with caregivers conducted in Makarfi General Hospital (Kaduna State, Nigeria) and surrounding communities in 2011. Bivariate and multivariate analysis of the quantitative survey data was conducted to examine associations of caregivers' sociodemographic characteristics with testing awareness and having ever been offered testing. Transcripts from focus group discussions (FGD) were analysed for emerging themes related to caregivers' perspectives on malaria testing. RESULTS: Among surveyed caregivers who were predominantly female (81.7%), not formally educated (72.5%), and were housewives (68.8%); only 5.3% were aware of any diagnostic testing for malaria, and only 4.3% had ever been offered a malaria test by a health worker. Having at least a primary level education (adjusted odds ratio [aOR] 20.3, 95% CI 4.5-92.1) and living within 5 km of the hospital (aOR 4.3, 95% CI 1.5-12.5) were determinants of awareness of malaria testing. Also, these were determinants of previously having been offered a test (aOR 9.9, 95% CI 2.1-48.7; and aOR 4.0, 95% CI 1.1 14.7). FGD showed many caregivers believed that malaria testing was for severe illness only, and that proximity to a health facility and cost of treatment influenced the seeking and receiving of care. CONCLUSIONS: Uptake of malaria testing prior to treatment can be improved by increasing its awareness and addressing misunderstandings among caregivers, promoting testing practices among health workers, and availing caregivers living farther from health centres alternative opportunities for community case management of febrile illnesses. PMID- 29233140 TI - Selection, characterization, and thermal stabilization of llama single domain antibodies towards Ebola virus glycoprotein. AB - BACKGROUND: A key advantage of recombinant antibody technology is the ability to optimize and tailor reagents. Single domain antibodies (sdAbs), the recombinantly produced variable domains derived from camelid and shark heavy chain antibodies, provide advantages of stability and solubility and can be further engineered to enhance their properties. In this study, we generated sdAbs specific for Ebola virus envelope glycoprotein (GP) and increased their stability to expand their utility for use in austere locals. Ebola virus is extremely virulent and causes fatal hemorrhagic fever in ~ 50 percent of the cases. The viral GP binds to host cell receptors to facilitate viral entry and thus plays a critical role in pathogenicity. RESULTS: An immune phage display library containing more than 107 unique clones was developed from a llama immunized with a combination of killed Ebola virus and recombinantly produced GP. We panned the library to obtain GP binding sdAbs and isolated sdAbs from 5 distinct sequence families. Three GP binders with dissociation constants ranging from ~ 2 to 20 nM, and melting temperatures from ~ 57 to 72 degrees C were selected for protein engineering in order to increase their stability through a combination of consensus sequence mutagenesis and the addition of a non-canonical disulfide bond. These changes served to increase the melting temperatures of the sdAbs by 15-17 degrees C. In addition, fusion of a short positively charged tail to the C-terminus which provided ideal sites for the chemical modification of these sdAbs resulted in improved limits of detection of GP and Ebola virus like particles while serving as tracer antibodies. CONCLUSIONS: SdAbs specific for Ebola GP were selected and their stability and functionality were improved utilizing protein engineering. Thermal stability of antibody reagents may be of particular importance when operating in austere locations that lack reliable refrigeration. Future efforts can evaluate the potential of these isolated sdAbs as candidates for diagnostic or therapeutic applications for Ebola. PMID- 29233141 TI - Neck-specific exercises with internet-based support compared to neck-specific exercises at a physiotherapy clinic for chronic whiplash-associated disorders: study protocol of a randomized controlled multicentre trial. AB - BACKGROUND: Globally, neck pain is the fourth most common condition associated with longer periods of living with disability. Annually, approximately 0.3% of the population of Western countries undergo whiplash trauma, and half of those individuals will develop chronic problems with high costs for the individual and society. Evidence for chronic whiplash-associated disorders (WAD) treatment is scarce, though neck-specific training at a physiotherapy clinic twice a week for 12 weeks has demonstrated good results. More efficient, flexible rehabilitation with reduced waiting times and lower costs is needed, ideally replacing lengthy on-site treatment series by healthcare providers. Internet-based care has been shown to be a viable alternative for a variety of diseases and interventions, but studies are lacking on Internet-based interventions for individuals with chronic neck problems. The aim of the trial described here is to compare the effects of an Internet-based neck-specific exercise programme to the same exercises performed at a physiotherapy clinic in regards to self-reported and clinical measures, as well as cost-effectiveness. METHODS: This prospective, randomized controlled trial will involve 140 participants. Measurements will be made at baseline, 3 months (end of treatment), and 15 months (12 months after end of intervention) and will include ratings of pain, disability, satisfaction with care, work ability, quality of life, and cost-effectiveness. DISCUSSION: The study results may contribute to the development of a more effective rehabilitation, flexible and equal care, shorter waiting times, increased availability, and lower costs for healthcare and society. TRIAL REGISTRATION: ClinicalTrials.gov Protocol ID: NCT03022812 , initial release 12/20/2016. PMID- 29233142 TI - Role of disturbed fatty acids metabolism in the pathophysiology of diabetic erectile dysfunction. AB - BACKGROUND: Vasculogenic erectile dysfunction (VED) is considered as a common complication among people with type 2 diabetes (T2D). We tested whether changes in fatty acid (FAs) classes measured in erythrocytes are associated with increased risk of diabetic VED along with related risk factors. METHODS: We assessed erythrocyte FAs composition, lipid peroxidation parameters and inflammatory cytokines among 72 T2D men with VED, 78 T2D men without VED and 88 healthy volunteers with similar age. Biochemical, hepatic, lipid and hormonal profiles were measured. RESULTS: T2D people with VED had significant decrease in the indexes of Delta6-desaturase and elongase activities compared to the other studied groups. The same group of participants displayed lower erythrocytes levels of dihomo-gamma-linolenic acid (C20:3n-6) (P < .001), precursor of the messenger molecule PGE1 mainly involved in promoting erection. Moreover, absolute SFAs concentration and HOMA IR levels were higher in T2D people with VED when compared to controls and associated with impaired NO concentration (1.43 vs 3.30 ng/L, P < .001). Our results showed that IL-6 and TNF-alpha were significantly increased and positively correlated with MDA levels only in T2D people with VED (r = 0.884, P = .016 and r = 0.753, P = .035; respectively) suggesting a decrease in the relative availability of vasodilator mediators and an activation of vasoconstrictors release. CONCLUSION: Our findings show that the deranged FAs metabolism represents a potential marker of VED in progress, or at least an indicator of increased risk within men with T2D. PMID- 29233144 TI - Evaluation of serum prolidase activity and oxidative stress markers in men with BPH and prostate cancer. AB - BACKGROUND: Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are diseases of elderly men and are related to increased oxidative stress (OS). Although prolidase has a role in collagen metabolism, it is also used to evaluate OS in many diseases. However, there is a lack of data about serum prolidase activity (SPA) in prostate cancer. The aim of this study was to evaluate and compare SPA levels in males with BPH and PCa. METHODS: Evaluation was made of a total of 81 men who underwent transrectal ultrasound guided prostate biopsy for a definitive diagnosis due to high PSA levels. Patients were separated into 2 groups as BPH and PCa patients. Pre-biopsy malondialdehyde (MDA), superoxide dismutase (SOD), PSA levels and serum prolidase activities (SPA) were compared between the groups and the correlations of SPA with the other parameters were also investigated in both groups. RESULTS: BPH was diagnosed in 51 patients and PCa in 30. The mean age of patients was similar in both groups as 63.25 +/- 5.81 years in the BPH group 65.30 +/- 7.35 years in the PCa group(p:0.081). The median MDA and SOD levels were insignificantly increased in the PCa patients. SPA values were similar in BPH and PCa patients. SPA did not correlate with age, PSA, MDA or SOD levels in either group. CONCLUSIONS: Our study results revealed that serum prolidase activity is similar in BPH and PCa cases and is not correlated with MDA, SOD or PSA levels. PMID- 29233143 TI - Relative hyperglycemia is associated with complications following an acute myocardial infarction: a post-hoc analysis of HI-5 data. AB - BACKGROUND: Hyperglycemia is associated with increased morbidity and mortality in patients with an acute myocardial infarction (AMI). We evaluated whether complications after AMI are associated with absolute or relative glycemia. METHODS: A total of 192 patients with AMI were randomized to intensive or conventional insulin therapy. Absolute glycemia was defined as mean blood glucose level (BGL) during the first 24 h following randomization. Relative glycemia was defined by the stress hyperglycaemia ratio (SHR), calculated as mean BGL divided by average glucose concentration over the prior 3 months estimated from glycosylated haemoglobin. The primary endpoint was a "complicated AMI", defined as an AMI complicated by death, congestive cardiac failure, arrhythmia, cardiac arrest, reinfarction, cardiogenic shock, inotrope use or emergency revascularization. RESULTS: There was not a significant association between mean BGL and complicated AMI (odds ratio (OR) 1.05 per mmol/L glucose increment, 95% confidence intervals (CI) 0.93-1.19). In contrast, SHR was positively associated with a complicated myocardial infarction (OR 1.22 per 0.1 SHR increment, 95% CI 1.06-1.42), and individual complications of death (OR 1.55, 95% CI 1.14-2.11), congestive cardiac failure (OR 1.27, 95% CI 1.05-1.54), arrhythmia (OR 1.31, 95% CI 1.12-1.54) and cardiogenic shock (OR 1.42, 95% CI 1.03-1.97). The relationship between SHR and a complicated AMI was independent of diabetic status, intensive insulin therapy, sex and hypoglycemia. CONCLUSIONS: Relative, but not absolute, glycemia during insulin treatment is independently associated with complications after an AMI. Future studies should investigate whether basing therapeutic glycaemic targets on relative glycemia improves patient outcomes. PMID- 29233145 TI - Suppression of interleukin-6 increases enterovirus A71 lethality in mice. AB - BACKGROUND: Enterovirus A71 (EV-A71) infection can induce fatal encephalitis in young children. Clinical reports show that interleukin-6 (IL-6) levels in the serum and cerebrospinal fluid of infected patients with brainstem encephalitis are significantly elevated. We used a murine model to address the significance of endogenous IL-6 in EV-A71 infection. RESULTS: EV-A71 infection transiently increased serum and brain IL-6 protein levels in mice. Most importantly, absence of IL-6 due to gene knockout or depletion of IL-6 using neutralizing monoclonal antibody enhanced the mortality and tissue viral load of infected mice. Absence of IL-6 increased the damage in the central nervous system and decreased the lymphocyte and virus-specific antibody responses of infected mice. CONCLUSIONS: Endogenous IL-6 functions to clear virus and protect the host from EV-A71 infection. Our study raises caution over the use of anti-IL-6 antibody or pentoxifylline to reduce IL-6 for patient treatment. PMID- 29233146 TI - Apical periodontitis in southern Estonian population: prevalence and associations with quality of root canal fillings and coronal restorations. AB - BACKGROUND: Apical periodontitis (AP) is an inflammatory disease around the apex of a tooth root. Reported prevalence of AP ranges from 27% to 83% while the data about most post-Soviet countries are still missing. Knowing the prevalence of AP within a certain population helps to plan the treatment need and evaluate the success of endodontic interventions. We aimed to collect data about prevalence and determining factors of AP for the first time in Estonia. METHODS: The cross sectional study included 6552 patients (age 35.5+/-19.2 years). Radiographic examination was applied to investigate the prevalence of AP and quality of endodontic treatment. RESULTS: AP was diagnosed in 54.7% of subjects. Endodontically treated teeth were present in 58.2% of subjects. Periapical finding was present in 44.6% of endodontically treated and in 30.8% of untreated teeth. Out of 181,495 teeth, 52.7% were intact. AP was diagnosed in 6.3% of teeth, 6.9% of teeth were endodontically treated. Risk factors for AP included caries (OR = 2.30), male gender (OR = 1.44), too short (OR = 1.76) or too long root canal filling (OR = 2.51), root canal filling of low density (OR = 1.61) while not orthodontic appliance. Lower AP risk was associated with restoration of the tooth - filling (OR = 0.45), crown (OR = 0.34) and bridge (OR = 0.33). CONCLUSIONS: AP is highly prevalent in Southern Estonian population. Most cases are associated with root canal-treated teeth. The overall quality of root canal fillings tends to be low, consistent with the mediocre outcome of treatment. Considerable efforts are required to improve the standards of endodontic treatment. PMID- 29233147 TI - Neutrophil extracellular traps are downregulated by glucocorticosteroids in lungs in an equine model of asthma. AB - BACKGROUND: Severe neutrophilic asthma is poorly responsive to glucocorticosteroids (GC). Neutrophil extracellular traps (NETs) within the lungs have been associated with the severity of airway obstruction and inflammation in asthma, and were found to be unaffected by GC in vitro. As IL-17 is overexpressed in neutrophilic asthma and contributes to steroid insensitivity in different cell types, we hypothesized that NETs formation in asthmatic airways would be resistant to GC through an IL-17 mediated pathway. METHODS: Six neutrophilic severe asthmatic horses and six healthy controls were studied while being treated with dexamethasone. Lung function, bronchoalveolar lavage fluid (BALF) cytology and NETs formation, as well as the expression of CD11b and CD13 by blood and airway neutrophils were evaluated. The expression of IL-17 and its role in NETs formation were also studied. RESULTS: Airway neutrophils from asthmatic horses, as opposed to blood neutrophils, enhanced NETs formation, which was then decreased by GC. GC also tended to decrease the expression of CD11b in blood neutrophils, but not in airway neutrophils. IL-17 mRNA was increased in BALF cells of asthmatic horses and was unaffected by GC. However, both GC and IL-17 inhibited NETs formation in vitro. CONCLUSION: GC decreased NETs formation in vitro and also in vivo in the lungs of asthmatic horses. However, airway neutrophil activation during asthmatic inflammation was otherwise relatively insensitive to GC. The contribution of IL-17 to these responses requires further study. PMID- 29233148 TI - DNA repair protein APE1 is involved in host response during pneumococcal meningitis and its expression can be modulated by vitamin B6. AB - BACKGROUND: The production of reactive oxygen species (ROS) during pneumococcal meningitis (PM) leads to severe DNA damage in the neurons and is the major cause of cell death during infection. Hence, the use of antioxidants as adjuvant therapy has been investigated. Previous studies have demonstrated the possible participation of apurinic/apyrimidinic endonuclease (APE1) during PM. The aims of this study were to investigate the APE1 expression in the cortical and hippocampal tissues of infant Wistar rats infected with Streptococcus pneumoniae and its association with cell death and understand the role of vitamin B6 (vitB6) as a protective factor against cell death. METHODS: APE1 expression and oxidative stress markers were analyzed at two-time points, 20 and 24 h post infection (p.i.), in the cortex (CX) and hippocampus (HC) of rats supplemented with vitB6. Statistical analyses were performed by the nonparametric Kruskal-Wallis test using Dunn's post test. RESULTS: Our results showed high protein levels of APE1 in CX and HC of infected rats. In the CX, at 20 h p.i., vitB6 supplementation led to the reduction of expression of APE1 and apoptosis-inducing factor, while no significant changes in the transcript levels of caspase-3 were observed. Furthermore, levels of carbonyl content and glutamate in the CX were reduced by vitB6 supplementation at the same time point of 20 h p.i.. Since our data showed a significant effect of vitB6 on the CX at 20 h p.i. rather than that at 24 h p.i., we evaluated the effect of administering a second dose of vitB6 at 18 h p.i. and sacrifice at 24 h p.i.. Reduction in the oxidative stress and APE1 levels were observed, although the latter was not significant. Although the levels of APE1 was not significantly changed in the HC with vitB6 adjuvant therapy, vitB6 supplementation prevented the formation of the truncated form of APE1 (34 kDa) that is associated with apoptosis. CONCLUSIONS: Our data suggest that PM affects APE1 expression, which can be modulated by vitB6. Additionally, vitB6 contributes to the reduction of glutamate and ROS levels. Besides the potential to reduce cell death and oxidative stress during neuroinflammation, vitB6 showed enhanced effect on the CX than on the HC during PM. PMID- 29233149 TI - Advances in clinical pharmacy education in Germany: a quasi-experimental single blinded study to evaluate a patient-centred clinical pharmacy course in psychiatry. AB - BACKGROUND: The pharmacy profession has shifted towards patient-centred care. To meet the new challenges it is necessary to provide students with clinical competencies. A quasi-experimental single-blinded teaching and learning study was carried out using a parallel-group design to evaluate systematically the benefits of clinical teaching in pharmacy education in Germany. METHODS: A clinical pharmacy course on a psychiatric ward was developed and implemented for small student groups. The learning aims included: the improvement of patient and interdisciplinary communication skills and the identification and management of pharmaceutical care issues. The control group participated only in the preparation lecture, while the intervention group took part in the complete course. The effects were assessed by an objective structured clinical examination (OSCE) and a student satisfaction survey. RESULTS: The intervention group achieved significantly better overall results on the OSCE assessment (46.20 +/- 10.01 vs. 26.58 +/- 12.91 of a maximum of 90 points; p < 0.0001).The practical tasks had the greatest effect, as reflected in the outcomes of tasks 1-5 (34.94 +/- 9.60 vs. 18.63 +/- 10.24 of a maximum of 60 points; p < 0.0001). Students' performance on the theoretical tasks (tasks 6-10) was improved but unsatisfying in both groups considering the maximum score (11.50 +/- 4.75 vs. 7.50 +/- 4.00 of a maximum of 30 points; p < 0.0001). Of the students, 93% rated the course as practice-orientated, and 90% felt better prepared for patient contact. Many students suggested a permanent implementation and an extension of the course. CONCLUSIONS: The results suggest that the developed ward-based course provided learning benefits for clinical skills. Students' perception of the course was positive. Implementation into the regular clinical pharmacy curriculum is therefore advisable. PMID- 29233150 TI - A prospective study of magnetic resonance imaging and ultrasonography (MRI/US) fusion targeted biopsy and concurrent systematic transperineal biopsy with the average of 18-cores to detect clinically significant prostate cancer. AB - BACKGROUND: This study compared the detection rates for clinically significant prostate cancer (CSPC) between magnetic resonance imaging and ultrasonography (MRI/US)-fusion-targeted biopsy (TB), systematic biopsy (SB) and combination of TB and SB. METHODS: This prospective study evaluated simultaneous TB and SB for consecutive patients with suspicious lesions that were detected using pre-biopsy multiparametric MRI. A commercially available real-time virtual sonography system was used to perform the MRI/US-fusion TB with the transperineal technique. The prostate imaging reporting and data system version 2 (PI-RADS v2) was assigned to categorize the suspicious lesions. RESULTS: A total of 177 patients were included in this study. The detection rate for CSPC was higher using SB, compared to TB (57.1% vs 48.0%, p = 0.0886). The detection rate for CSPC was higher using the combination of TB and SB, compared to only SB (63.3% vs 57.1%, p = 0.2324). Multivariate analysis revealed that PIRADS v2 category 4 and an age of <65 years were independent predictors for TB upgrading (vs. the SB result). CONCLUSIONS: PI RADS v2 category 4 and an age of <65 years were predictive factors of upgrading the Gleason score by MRI/US-fusion TB. Thus, MRI/US-fusion TB may be appropriate for patients with those characteristics. TRIAL REGISTRATION: This study was retrospectively registered at the University Hospital Medical Information Network ( UMINID000025911 ) in Jan 30, 2017. PMID- 29233151 TI - Suppression of PTPN6 exacerbates aluminum oxide nanoparticle-induced COPD-like lesions in mice through activation of STAT pathway. AB - BACKGROUND: Inhaled nanoparticles can deposit in the deep lung where they interact with pulmonary cells. Despite numerous studies on pulmonary nanotoxicity, detailed molecular mechanisms of specific nanomaterial-induced lung injury have yet to be identified. RESULTS: Using whole-body dynamic inhalation model, we studied the interactions between aluminum oxide nanoparticles (Al2O3 NPs) and the pulmonary system in vivo. We found that seven-day-exposure to Al2O3 NPs resulted in emphysema and small airway remodeling in murine lungs, accompanied by enhanced inflammation and apoptosis. Al2O3 NPs exposure led to suppression of PTPN6 and phosphorylation of STAT3, culminating in increased expression of the apoptotic marker PDCD4. Rescue of PTPN6 expression or application of a STAT3 inhibitor, effectively protected murine lungs from inflammation and apoptosis, as well as, in part, from the induction of chronic obstructive pulmonary disease (COPD)-like effects. CONCLUSION: In summary, our studies show that inhibition of PTPN6 plays a critical role in Al2O3 NPs-induced COPD-like lesions. PMID- 29233152 TI - Hyperuricemia and metabolic syndrome in type 2 diabetes mellitus patients at Hawassa university comprehensive specialized hospital, South West Ethiopia. AB - BACKGROUND: Metabolic syndrome is a cluster of the most dangerous heart attack risk factors such as diabetes and prediabetes, abdominal obesity, high cholesterol and high blood pressure. Hyperuricemia is a condition in which the serum uric acid concentration is greater than 5.5 mg per deciliter for child and greater than 7.2 and 6.0 mg per deciliters for male and female adults respectively. METHODS: A cross-sectional study was conducted to determine the magnitude of hyperuricemia and associated factors among type 2 diabetes mellitus patients at Hawassa Comprehensive Specialized Hospital (HCSH) from February 28 to May 30 /2017. A random sampling technique was used to include 319 study subjects and a signed consent had been provided by each study subject before running any data collection. An interviewer administered structured questionnaire was used to collect socio-demographic and some clinically useful data. In addition to this, we reviewed the records of the study subjects to obtain other useful clinical data. Five milliliter blood specimen was collected from each study subjects after overnight fasting. A25TM Bio-System Random Access chemistry analyzer was used for blood sample analysis. All data were checked visually, coded and entered into epi data version 3.4 and statistical analysis was performed using SPSS version 20.0 software. Bi-variate and multivariate logistic regressions were used to determine the association between explanatory and the outcome variables. RESULTS: The prevalence of hyperuricemia and metabolic syndrome among type 2 diabetic patients in the study area were 33.8%(n = 106) and 70.1% (n = 220) respectively. Having age greater or equal to 45 years (AOR: 1.9, CI: 1.-3.2, P value =0.015) and having metabolic syndrome (AOR: 2.6, CI: 1.5-4.7, P value = 0.001) were the determinant variables for hyperuricemia among type 2 diabetic patients. CONCLUSION: There was high prevalence of hyperuricemia among type 2 diabetic patients with high prevalence of metabolic syndrome. Therefore, regular health information about life style modification, early diagnosis and treatment for hyperuricemia and metabolic syndrome are essential to reduce hyperuricemia and metabolic syndrome in type 2 diabetic patients. PMID- 29233153 TI - Application of different patella height indices in patients undergoing total knee arthroplasty. AB - BACKGROUND: One complication of total knee arthroplasty (TKA) is patella baja (PB). Patellar tendon shortening and joint line elevation are two main causes of PB. The purpose of this study was to determine the incidence of PB before and after TKA by measuring the patellar height and provide evidence for choosing a suitable index. METHODS: In total, 256 consecutive patients who underwent primary TKA were included in this study. Radiographic measurements were performed; the Insall-Salvati (IS) index, modified IS (MIS) index, Blackburne-Peel (BP) index, and Caton-Deschamps (CD) index were computed; and the incidence of PB was calculated before and after the operation. The consistency between the IS and MIS indices and between the BP and CD indices was analyzed. RESULTS: The preoperative incidence of true PB (TPB) and pseudo-PB (PPB) was 9.4 and 0.8%, respectively. The postoperative incidence of TPB and PPB was 10.2 and 9.0%, respectively. The consistency between the IS and MIS indices was moderate preoperatively (pre-kappa = 0.602) and postoperatively (post-kappa = 0.742). The consistency between the BP and CD indices was moderate preoperatively (pre-kappa = 0.742) and good postoperatively (post-kappa = 0.797). CONCLUSION: The incidence of PB, especially PPB, increased after TKA. The CD and BP indices are of greater importance for the diagnosis of PB after TKA. The MIS index is a better choice than the IS index to measure the length of the patellar tendon. To measure the height of the joint line, the BP index is better postoperatively and the CD index is better preoperatively. PMID- 29233154 TI - Assessing physical therapist students' self-efficacy: measurement properties of the Physiotherapist Self-Efficacy (PSE) questionnaire. AB - BACKGROUND: Apart from skills, and knowledge, self-efficacy is an important factor in the students' preparation for clinical work. The Physiotherapist Self Efficacy (PSE) questionnaire was developed to measure physical therapy (TP) students' self-efficacy in the cardiorespiratory, musculoskeletal, and neurological clinical areas. The aim of this study was to establish the measurement properties of the Dutch PSE questionnaire, and to explore whether self-efficacy beliefs in students are clinical area specific. METHODS: Methodological quality of the PSE was studied using COSMIN guidelines. Item analysis, structural validity, and internal consistency of the PSE were determined in 207 students. Test-retest reliability was established in another sample of 60 students completing the PSE twice. Responsiveness of the scales was determined in 80 students completing the PSE at the start and the end of the second year. Hypothesis testing was used to determine construct validity of the PSE. RESULTS: Exploratory factor analysis resulted in three meaningful components explaining similar proportions of variance (25%, 21%, and 20%), reflecting the three clinical areas. Internal consistency of each of the three subscales was excellent (Cronbach's alpha > .90). Intra Class Correlation Coefficient was good (.80). Hypothesis testing confirmed construct validity of the PSE. CONCLUSION: The PSE shows excellent measurement properties. The component structure of the PSE suggests that self-efficacy about physiotherapy in PT students is not generic, but specific for a clinical area. As self-efficacy is considered a predictor of performance in clinical settings, enhancing self-efficacy is an explicit goal of educational interventions. Further research is needed to determine if the scale is specific enough to assess the effect of educational interventions on student self-efficacy. PMID- 29233155 TI - A meta-model for computer executable dynamic clinical safety checklists. AB - BACKGROUND: Safety checklist is a type of cognitive tool enforcing short term memory of medical workers with the purpose of reducing medical errors caused by overlook and ignorance. To facilitate the daily use of safety checklists, computerized systems embedded in the clinical workflow and adapted to patient context are increasingly developed. However, the current hard-coded approach of implementing checklists in these systems increase the cognitive efforts of clinical experts and coding efforts for informaticists. This is due to the lack of a formal representation format that is both understandable by clinical experts and executable by computer programs. METHODS: We developed a dynamic checklist meta-model with a three-step approach. Dynamic checklist modeling requirements were extracted by performing a domain analysis. Then, existing modeling approaches and tools were investigated with the purpose of reusing these languages. Finally, the meta-model was developed by eliciting domain concepts and their hierarchies. The feasibility of using the meta-model was validated by two case studies. The meta-model was mapped to specific modeling languages according to the requirements of hospitals. RESULTS: Using the proposed meta-model, a comprehensive coronary artery bypass graft peri-operative checklist set and a percutaneous coronary intervention peri-operative checklist set have been developed in a Dutch hospital and a Chinese hospital, respectively. The result shows that it is feasible to use the meta-model to facilitate the modeling and execution of dynamic checklists. CONCLUSIONS: We proposed a novel meta-model for the dynamic checklist with the purpose of facilitating creating dynamic checklists. The meta-model is a framework of reusing existing modeling languages and tools to model dynamic checklists. The feasibility of using the meta-model is validated by implementing a use case in the system. PMID- 29233156 TI - Prevalence of Epstein-Barr virus DNA and Porphyromonas gingivalis in Japanese peri-implantitis patients. AB - BACKGROUND: Peri-implantitis (PI) is an inflammatory reaction associated with functional deterioration of supporting bones around the dental implant. Recent studies suggested Epstein-Barr virus (EBV) is involved in the pathogenesis of periodontitis. We investigated the association between EBV and Porphyromonas gingivalis in Japanese PI patients. METHODS: Fifteen periodontally healthy individuals, 15 healthy implant patients and 15 PI patients were recruited. Forty five subgingival plaque samples were collected from the deepest probing pocket depth (PPD) site from each patient. Real-time PCR was used to detect EBV DNA and P. gingivalis. RESULTS: EBV and P. gingivalis were detected in 7 and 3 PPD sites of the healthy controls, in 9 and 4 PPD sites of the healthy implants, and in 13 and 14 PPD sites of the PI patients. P. gingivalis and coexistence of EBV and P. gingivalis were detected significantly higher in the PI patients than healthy controls and healthy implant patients. EBV was detected significantly higher in the PI patients than healthy controls. CONCLUSIONS: Higher levels of EBV and P. gingivalis were detected in PPD sites of PI patients. These results suggest that coexistence of EBV and P. gingivalis may serve pathogenic factors cause for PI in Japanese dental patients. PMID- 29233158 TI - Etiology of isolated pontine infarctions: a study based on high-resolution MRI and brain small vessel disease scores. AB - BACKGROUND: In this retrospective study, we investigated the main pathogenesis of the two types of isolated pontine infarction: paramedian pontine infarcts (PPIs) and small deep pontine infarcts (SDPIs). METHODS: Acute ischemic stroke patients, comprising 117 PPI patients and 40 SDPI patients, were enrolled. High-resolution magnetic resonance imaging (HR-MRI) and routine MRI sequences were performed for each patient, and clinical data were collected. The following brain small vessel disease (SVD) features of the MRI scans were each rated (0 or 1) separately: asymptomatic lacunar infarcts, white matter lesions (WMLs), deep and infratentorial cerebral microbleeds (CMBs), and enlarged perivascular spaces in the basal ganglia. The ratings were also summed in an ordinal "SVD score" (range: 0-4). The difference in the SVD score between the PPI and SDPI groups was determined. The presence and location of basilar artery (BA) atherosclerotic plaques (based on HR-MRI) in the two groups was evaluated. RESULTS: There was a significant difference in the total SVD score and three of the four independent SVD features (asymptomatic lacunar infarcts, WMLs, and deep and infratentorial CMBs) between the two groups. The prevalence of BA plaques relevant to the infarcts in the PPI group was significantly higher than that in the SDPI group, whereas the prevalence of plaques irrelevant to the infarcts was similar between the two groups. The degree of BA stenosis was slightly higher in the PPI group than in the SDPI group. Diabetes mellitus was much more prevalent in the PPI group. The National Institute of Health Stroke Scale score was higher in the PPI group, which is in accordance with the larger infarct size in the PPI group. CONCLUSION: BA atherosclerosis may be the major cause of PPI, while SVD may be the main mechanism underlying SDPI. HR-MRI combined with the total SVD score should be helpful to explore the pathogenesis underlying isolated pontine infarctions, especially in cases involving low-grade BA stenosis. PMID- 29233157 TI - Medical student INtervention to promote effective nicotine dependence and tobacco HEalthcare (MIND-THE-GAP): single-centre feasibility randomised trial results. AB - BACKGROUND: Although brief cessation advice from healthcare professionals increases quit rates, smokers typically do not get this advice during hospitalisation, possibly due to resource issues, lack of training and professionals' own attitudes to providing such counselling. Medical students are a potentially untapped resource who could deliver cessation counselling, while upskilling themselves and changing their own attitudes to delivering such advice in the future; however, no studies have investigated this. We aimed to determine if brief student-led counselling could enhance motivation to quit and smoking cessation behaviours among hospitalised patients. METHODS: A mixed-methods, 2-arm pilot feasibility randomised controlled trial with qualitative process evaluation enrolled 67 hospitalised adult smokers, who were recruited and randomized to receive a brief medical student-delivered cessation intervention (n = 33) or usual care (n = 34); 61 medical students received standardised cessation training and 33 were randomly assigned to provide a brief in-hospital consultation and follow-up support by phone or in-person one week post-discharge. Telephone follow up at 3- and 6-months assessed scores on the Motivation to Stop Smoking Scale (MTSS; primary outcome) and several other outcomes, including 7-day point prevalent abstinence, quit attempts, use of cessation medication, and ratings of student's knowledge and efficacy. Data were analysed as intention to treat (ITT) using penalised imputation, per protocol, and random effects repeated measures. Focus group interviews were conducted with students post-intervention to elicit their views on the training and intervention process. RESULTS: Analyses for primary and most secondary outcomes favoured the intervention group, although results were not statistically significant. Point prevalence abstinence rates were significantly higher for the intervention group during follow-up for all analyses except 6-month ITT analysis. Fidelity was variable. Patients rated students as being "very" knowledgeable about quitting and "somewhat" helpful. Qualitative results showed students were glad to deliver the intervention; were critical of current cessation care; felt constrained by their inability to prescribe cessation medications and wanted to include cessation and other behavioural counselling in their normal history taking. CONCLUSIONS: It appears feasible for medical students to be smoking cessation interventionists during their training, although their fidelity to the intervention requires further investigation. A definitive trial is needed to determine if medical students are effective cessation counsellors and if student-led intervention could be tailored for other health behaviours. TRIAL REGISTRATION: NCT02601599 (retrospectively registered 1 day after first participant recruited on November 3rd 2015). PMID- 29233160 TI - Comparison of mortality prediction models in acute respiratory distress syndrome undergoing extracorporeal membrane oxygenation and development of a novel prediction score: the PREdiction of Survival on ECMO Therapy-Score (PRESET Score). AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy in acute respiratory distress syndrome (ARDS) patients but is associated with complications and costs. Here, we validate various scores supposed to predict mortality and develop an optimized categorical model. METHODS: In a derivation cohort, 108 ARDS patients (2010-2015) on veno-venous ECMO were retrospectively analysed to assess four established risk scores (ECMOnet-Score, RESP-Score, PRESERVE-Score, Roch-Score) for mortality prediction (receiver operating characteristic analysis) and to identify by multivariable logistic regression analysis independent variables for mortality to yield the new PRESET-Score (PREdiction of Survival on ECMO Therapy-Score). This new score was then validated both in independent internal (n = 82) and external (n = 59) cohorts. RESULTS: The median (25%; 75% quartile) Sequential Organ Failure Assessment score was 14 (12; 16), Simplified Acute Physiology Score II was 62.5 (57; 72.8), median intensive care unit stay was 17 days (range 1-124), and mortality was 62%. Only the ECMOnet Score (area under curve (AUC) 0.69) and the RESP-Score (AUC 0.64) discriminated survivors and non-survivors. Admission pHa, mean arterial pressure, lactate, platelet concentrations, and pre-ECMO hospital stay were independent predictors of death and were used to build the PRESET-Score. The score's internal (AUC 0.845; 95% CI 0.76-0.93; p < 0.001) and external (AUC 0.70; 95% CI 0.56-0.84; p = 0.008) validation revealed excellent discrimination. CONCLUSIONS: While our data confirm that both the ECMOnet-Score and the RESP-Score predict mortality in ECMO treated ARDS patients, we propose a novel model also incorporating extrapulmonary variables, the PRESET-Score. This score predicts mortality much better than previous scores and therefore is a more precise choice for decision support in ARDS patients to be placed on ECMO. PMID- 29233159 TI - Determinants of excessive daytime sleepiness in two First Nation communities. AB - BACKGROUND: Excessive daytime sleepiness may be determined by a number of factors including personal characteristics, co-morbidities and socio-economic conditions. In this study we identified factors associated with excessive daytime sleepiness in 2 First Nation communities in rural Saskatchewan. METHODS: Data for this study were from a 2012-13 baseline assessment of the First Nations Lung Health Project, in collaboration between two Cree First Nation reserve communities in Saskatchewan and researchers at the University of Saskatchewan. Community research assistants conducted the assessments in two stages. In the first stage, brochures describing the purpose and nature of the project were distributed on a house by house basis. In the second stage, all individuals age 17 years and older not attending school in the participating communities were invited to the local health care center to participate in interviewer-administered questionnaires and clinical assessments. Excessive daytime sleepiness was defined as Epworth Sleepiness Scale score > 10. RESULTS: Of 874 persons studied, 829 had valid Epworth Sleepiness Scale scores. Of these, 91(11.0%) had excessive daytime sleepiness; 12.4% in women and 9.6% in men. Multivariate logistic regression analysis indicated that respiratory comorbidities, environmental exposures and loud snoring were significantly associated with excessive daytime sleepiness. CONCLUSIONS: Excessive daytime sleepiness in First Nations peoples living on reserves in rural Saskatchewan is associated with factors related to respiratory co-morbidities, conditions of poverty, and loud snoring. PMID- 29233161 TI - Id-1 promotes migration and invasion of non-small cell lung cancer cells through activating NF-kappaB signaling pathway. AB - BACKGROUND: Numerous studies have shown that Id-1 (Inhibitor of differentiation 1) is upregulated in several cancers and associated with tumor malignant characters. However, the clinical significance and biological role of Id-1 in non small cell lung cancer (NSCLC) remains unclear. METHODS: We used RT-PCR, Western blot and Immunohistochemistry to measure Id-1 expression in NSCLC tissues and matched adjacent noncancerous tissues. The expression pattern of Id-1 in NSCLC tissues was determined by scoring system of immunohistochemical analysis. The Kaplan-Meier method was used to calculate the survival curve, and log-rank test to determine statistical significance. The Id-1 gene was overexpressed or downreuglated with Lentiviral vectors in NSCLC cells. And, the migration ability of NSCLC cells was tested in a Transwell Boyden Chamber. RESULTS: We found that Id-1 is generally expressed higher in NSCLC tissues compared with matched adjacent noncancerous tissues. We also found that high Id-1 expression in tumor tissues is significantly correlated with tumor progression and poor survival in NSCLC patients. Furthermore, our experimental data revealed that knockdown of Id 1 significantly suppressed the proliferation, migration and invasion of NSCLC cells, whereas ectopic expression of Id-1 promoted the malignant phenotype of NSCLC cells. Mechanistic study showed that NF-kappaB signaling pathway contributed to the effects of Id-1 in NSCLC cells. Moreover, blocking the NF kappaB pathway significantly inhibited the tumor-promoting actions of Id-1 in NSCLC cells. CONCLUSIONS: We identified a tumorigenic role of Id-1 in NSCLC and provided a novel therapeutic target for NSCLC patients. PMID- 29233162 TI - Sarcomatoid hepatocellular carcinoma (SHC): a case report. AB - BACKGROUND: Sarcomatoid hepatocellular carcinoma (SHC) is a rare malignant hepatic tumor. Recurrent interventional therapies such as transcatheter arterial chemo-embolization (TACE), radiofrequency ablation (RFA), and percutaneous ethanol injection have been reported previously utilized in a majority of SHC cases. To date, the exact pathogenic mechanisms underlying sarcomatoid transformation of hepatocellular carcinoma (HCC) remain unknown. CASE PRESENTATION: In this study, we report a 68-year-old female SHC patient admitted to our hospital due to discrete abdominal distention for more than 20 days. Abdominal computed tomography (CT) with tri-phase enhancement revealed portal vein tumor thrombi (PVTT) and a left hepatic lobe lesion measuring 110.0 mm * 160.0 mm. The patient subsequently underwent liver resection, after which pathological examination revealed proliferation of spindle-shaped SHC cells. A sarcomatoid, T4 stage carcinoma was eventually diagnosed. Forty-seven days after the operation, tri-phase enhanced CT detected extensive lesions in the liver, spleen, peritoneum, omentum majus, and mesentery, indicating SHC recurrence and metastases. Combination chemotherapy with pirarubicin and cisplatin was initiated for 1 cycle, but terminated due to resultant severe myelosuppression and medication intolerance. The patient was lost to therapy after 3 months of follow up. CONCLUSIONS: This case is unique because of hepatitis C virus infection. We should consider the possibility of this disease in patients with atypical clinical presentation. PMID- 29233163 TI - Intra-articular injection of expanded autologous bone marrow mesenchymal cells in moderate and severe knee osteoarthritis is safe: a phase I/II study. AB - BACKGROUND: Knee osteoarthritis (KOA) is a major health problem especially in the aging population. There is a need for safe treatment that restores the cartilage and reduces the symptoms. The use of stem cells is emerging as a possible option for the moderate and severe cases. This study aimed at testing the safety of autologous bone marrow mesenchymal stem cells (BM-MSCs) expanded in vitro when given intra-articularly to patients with stage II and III KOA. As a secondary end point, the study tested the ability of these cells to relieve symptoms and restore the knee cartilage in these patients as judged by normalized knee injury and Osteoarthritis Outcome Score (KOOS) and by magnetic resonance imaging (MRI). METHODS: Thirteen patients with a mean age of 50 years suffering from KOA stages II and III were given two doses of BM-MSCs 1 month apart totaling 61 * 106 +/- 0.6 * 106 by intra-articular injection in a phase I prospective clinical trial. Each patient was followed for a minimum of 24 months for any adverse events and for clinical outcome using normalized KOOS. Cartilage thickness was assessed by quantitative MRI T2 at 12 months of follow-up. RESULTS: No severe adverse events were reported up to 24 months follow-up. Normalized KOOS improved significantly. Mean knee cartilage thickness measured by MRI improved significantly. CONCLUSION: BM-MSCs given intra-articularly are safe in knee osteoarthrosis. Despite the limited number of patients in this study, the procedure described significantly improved the KOOS and knee cartilage thickness, indicating that they may enhance the functional outcome as well as the structural component. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02118519. PMID- 29233165 TI - The Global Fund's paradigm of oversight, monitoring, and results in Mozambique. AB - BACKGROUND: The Global Fund is one of the largest actors in global health. In 2015 the Global Fund was credited with disbursing close to 10 % of all development assistance for health. In 2011 it began a reform process in response to internal reviews following allegations of recipients' misuse of funds. Reforms have focused on grant application processes thus far while the core structures and paradigm have remained intact. We report results of discussions with key stakeholders on the Global Fund, its paradigm of oversight, monitoring, and results in Mozambique. METHODS: We conducted 38 semi-structured in-depth interviews in Maputo, Mozambique and members of the Global Fund Board and Secretariat in Switzerland. In-country stakeholders were representatives from Global Fund country structures (eg. Principle Recipient), the Ministry of Health, health or development attaches bilateral and multilateral agencies, consultants, and the NGO coordinating body. Thematic coding revealed concerns about the combination of weak country oversight with stringent and cumbersome requirements for monitoring and evaluation linked to performance-based financing. RESULTS: Analysis revealed that despite the changes associated with the New Funding Model, respondents in both Maputo and Geneva firmly believe challenges remain in Global Fund's structure and paradigm. The lack of a country office has many negative downstream effects including reliance on in-country partners and ineffective coordination. Due to weak managerial and absorptive capacity, more oversight is required than is afforded by country team visits. In-country partners provide much needed support for Global Fund recipients, but roles, responsibilities, and accountability must be clearly defined for a successful long-term partnership. Furthermore, decision-makers in Geneva recognize in-country coordination as vital to successful implementation, and partners welcome increased Global Fund engagement. CONCLUSIONS: To date, there are no institutional requirements for formalized coordination, and the Global Fund has no consistent representation in Mozambique's in-country coordination groups. The Global Fund should adapt grant implementation and monitoring procedures to the specific local realities that would be illuminated by more formalized coordination. PMID- 29233164 TI - Upper thoracic spine mobilization and mobility exercise versus upper cervical spine mobilization and stabilization exercise in individuals with forward head posture: a randomized clinical trial. AB - BACKGROUND: Although upper cervical and upper thoracic spine mobilization plus therapeutic exercises are common interventions for the management of forward head posture (FHP), no study has directly compared the effectiveness of cervical spine mobilization and stabilization exercise with that of thoracic spine mobilization and mobility exercise in individuals with FHP. METHODS: Thirty-two participants with FHP were randomized into the cervical group or the thoracic group. The treatment period was 4 weeks, with follow-up assessment at 4 and 6 weeks after the initial examination. Outcome measures including the craniovertebral angle (CVA), cervical range of motion, numeric pain rating scale (NPRS), pressure pain threshold, neck disability index (NDI), and global rating of change (GRC) were collected. Data were examined with a two-way repeated-measures analysis of variance (group * time). RESULTS: Participants in the thoracic group demonstrated significant improvements (p < .05) in CVA, cervical extension, NPRS, and NDI at the 6-week follow-up compared with those in the cervical group. In addition, 11 of 15 (68.8%) participants in the thoracic group compared with 8 of 16 participants (50%) in the cervical group showed a GRC score of +4 or higher at the 4-week follow-up. CONCLUSIONS: The combination of upper thoracic spine mobilization and mobility exercise demonstrated better overall short-term outcomes in CVA (standing position), cervical extension, NPRS, NDI, and GRC compared with upper cervical spine mobilization and stabilization exercise in individuals with FHP. TRIAL REGISTRATION: KCT0002307 , April 11, 2017 (retrospectively registered). PMID- 29233166 TI - Balancing selection and trans-specific polymorphisms. AB - Balancing selection maintains variation for evolution. A recent study investigated the extent of balancing selection in two Brassicaceae species and highlighted its importance for adaptation. PMID- 29233167 TI - Interventions for domestic violence among pregnant women in low- and middle income countries: a systematic review protocol. AB - BACKGROUND: Violence during pregnancy is a global problem, associated with serious health risks for both the mother and baby. Evaluation of interventions targeted for reducing or controlling domestic violence (DV) is still in its infancy, and the majority of findings are primarily from high-income countries (HICs). Therefore, there is an urgent need for generating evidence of DV interventions among pregnant women in low- and middle-income countries (LMICs). METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines will be employed to structure the review. A comprehensive search will be carried out via electronic databases including MEDLINE, CINAHL, Scopus, Embase, Web of Science, PsycINFO, and The Cochrane library. Gray literature will also be scrutinized for potential articles. An optimal search strategy has been developed following consultations with subject-matter experts and librarians. This search strategy will be adapted to the different databases. Experimental studies evaluating DV interventions among pregnant women from LMICs will be included in the review. The review will only include literature written in English. Two reviewers will independently screen and assess studies for inclusion in the review. A third author will resolve any discrepancies between the reviewers. Risk of bias will be assessed based on the Cochrane risk of bias assessment tool, and overall quality of the evidence will be judged using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. Findings will be presented with the narrative synthesis, and if applicable, they will be further quantified using random-effects meta-analysis. Effect size, risk ratio for dichotomous variables, and standardized mean differences for continuous variables will be calculated for each outcome using Review Manager 5.3. DISCUSSION: Systematic reviews to evaluate the efficacy of interventions to address DV within the perinatal context have been limited. Hence, no one intervention has emerged as substantially effective towards addressing perinatal DV and associated health consequences. The evidence generated from this systematic review will inform researchers and policy makers about the effectiveness of existing DV interventions among pregnant women in LMICs and provide recommendations for future research in this area. This in turn will contribute towards violence prevention in LMICs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017073938. PMID- 29233168 TI - A protocol for a systematic review of economic evaluation studies conducted on neonatal systemic infections in South Asia. AB - BACKGROUND: Neonatal systemic infections and their consequent impairments give rise to long-lasting health, economic and social effects on the neonate, the family and the nation. Considering the dearth of consolidated economic evidence in this important area, this systematic review aims to critically appraise and consolidate the evidence on economic evaluations of management of neonatal systemic infections in South Asia. METHODS: Full and partial economic evaluations, published in English, associated with the management of neonatal systemic infections in South Asia will be included. Any intervention related to management of neonatal systemic infections will be eligible for inclusion. Comparison can include a placebo or alternative standard of care. Interventions without any comparators will also be eligible for inclusion. Outcomes of this review will include measures related to resource use, costs and cost effectiveness. Electronic searches will be conducted on PubMed, CINAHL, MEDLINE (Ovid), EMBASE, Web of Science, EconLit, the Centre for Reviews and Dissemination Library (CRD) Database, Popline, IndMed, MedKnow, IMSEAR, the Cost Effectiveness Analysis (CEA) Registry and Pediatric Economic Database Evaluation (PEDE). Conference proceedings and grey literature will be searched in addition to performing back referencing of bibliographies of included studies. Two authors will independently screen studies (in title, abstract and full-text stages), extract data and assess risk of bias. A narrative summary and tables will be used to summarize the characteristics and results of included studies. DISCUSSION: Neonatal systemic infections can have significant economic repercussions on the families, health care providers and, cumulatively, the nation. Pediatric economic evaluations have focused on the under-five age group, and published consolidated economic evidence for neonates is missing in the developing world context. To the best of our knowledge, this is the first review of economic evidence on neonatal systemic infections in the South Asian context. Further, this protocol provides an underst anding of the methods used to design and evaluate economic evidence for methodological quality, transparency and focus on health equity. This review will also highlight existing gaps in research and identify scope for further research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017047275. PMID- 29233170 TI - Acceptance of a systematic review as a thesis: survey of biomedical doctoral programs in Europe. AB - BACKGROUND: Systematic reviews (SRs) have been proposed as a type of research methodology that should be acceptable for a graduate research thesis. The aim of this study was to analyse whether PhD theses in European biomedical graduate programs can be partly or entirely based on SRs. METHODS: In 2016, we surveyed individuals in charge of European PhD programs from 105 institutions. The survey asked about acceptance of SRs as the partial or entire basis for a PhD thesis, their attitude towards such a model for PhD theses, and their knowledge about SR methodology. RESULTS: We received responses from 86 individuals running PhD programs in 68 institutions (institutional response rate of 65%). In 47% of the programs, SRs were an acceptable study design for a PhD thesis. However, only 20% of participants expressed a personal opinion that SRs meet the criteria for a PhD thesis. The most common reasons for not accepting SRs as the basis for PhD theses were that SRs are 'not a result of a PhD candidate's independent work, but more of a team effort' and that SRs 'do not produce enough new knowledge for a dissertation'. The majority of participants were not familiar with basic concepts related to SRs; questions about meta-analyses and the type of plots frequently used in SRs were correctly answered by only one third of the participants. CONCLUSIONS: Raising awareness about the importance of SRs and their methodology could contribute to higher acceptance of SRs as a type of research that forms the basis of a PhD thesis. PMID- 29233169 TI - An evidence-based gamified mHealth intervention for overweight young adults with maladaptive eating habits: study protocol for a randomized controlled trial. AB - BACKGROUND: Cognitive behavior therapy (CBT) is the first-line of treatment for overweight and obesity patients whose problems originate in maladaptive eating habits (e.g., emotional eating). However, in-person CBT is currently difficult to access by large segments of the population. The proposed SIGMA intervention (i.e., the Self-help, Integrated, and Gamified Mobile-phone Application) is a mHealth intervention based on CBT principles. It specifically targets overweight young adults with underlying maladaptive behaviors and cognitions regarding food. The SIGMA app was designed as a serious game and intended to work as a standalone app for weight maintenance or alongside a calorie-restrictive diet for weight loss. It uses a complex and novel scoring system that allows points earned within the game to be supplemented by points earned during outdoor activities with the help of an embedded pedometer. METHODS/DESIGN: The efficacy of the SIGMA mHealth intervention will be investigated within a randomized, placebo-controlled trial. The intervention will be set to last 2 months with a 3-month follow-up. Selected participants will be young overweight adults with non-clinical maladaptive eating habits embodied by food cravings, binge eating, and emotional eating. The primary outcomes will be represented by changes in (1) self-reported maladaptive thoughts related to eating and body weight, (2) self-reported maladaptive eating behaviors in the range of urgent food cravings, emotional eating or binge eating, (3) as well as biased attentional processing of food items as indexed by reaction times. Secondary outcomes will be represented by changes in weight, Body Mass Index, general mood, and physical activity as indexed by the number of steps per day. DISCUSSION: Through an evidence-based cognitive behavioral approach and a user friendly game interface, the SIGMA intervention offers a significant contribution to the development of a cost-effective and preventive self-help tool for young overweight adults with maladaptive eating habits. TRIAL REGISTRATION: ISRCTN, ID: 70907354 . Registered on 6 February 2017. The ISRCTN registration is in line with the World Health Organization Trial Registration Data Set. The present paper represents the original version of the protocol. Any changes to the protocol will be communicated to ISRCTN. PMID- 29233171 TI - Deep infiltrating ureteral endometriosis with catamenial hydroureteronephrosis: a case report. AB - BACKGROUND: This aim of this case report is to raise awareness of ureteral endometriosis in women of reproductive age with hydronephrosis in the absence of urolithiasis to enable early diagnosis and prevent loss of renal function. CASE PRESENTATION: A 44-year-old Asian woman presented with a 4-year history of cyclic right flank pain and right hydronephrosis during menstruation. Despite several evaluations by physicians, including gynecologists, the cause of her symptoms was not diagnosed. On transvaginal ultrasonography, the uterus was observed deviated to the right, with a nodular lesion at the right uterosacral ligament, and the right ovary was attached to the uterus with no apparent cystic lesion. Magnetic resonance imaging showed a mass in the right uterine wall and mild wall thickening with delayed enhancement of the right distal ureter. Right ureteral endometriosis was suspected. Diagnostic laparoscopy revealed narrowing of the distal right ureter between the right uterosacral ligament and the right ovary with adhesions caused by deep infiltrating endometriosis. The adhesion bands and infiltrating endometriosis around the right ureter were dissected. CONCLUSIONS: The nonspecific symptoms of ureteral endometriosis can result in incorrect diagnosis, with renal damage as a result of prolonged hydronephrosis. A high index of suspicion and use of imaging modalities enable earlier diagnosis and preservation of renal function. PMID- 29233172 TI - The effects of austerity measures on quality of healthcare services: a national survey of physicians in the public and private sectors in Portugal. AB - BACKGROUND: The European Union member countries reacted differently to the 2008 economic and financial crisis. However, few countries have monitored the outcomes of their policy responses, and there is therefore little evidence as to whether or not savings undermined the performance of health systems. We discuss the situation in Portugal, where a financial adjustment program was implemented between 2011 and 2014, and explore the views of health workers on the effects of austerity measures on quality of care delivery. METHODS: A nationwide survey of physicians' experiences was conducted in 2013-2014 (n = 3442). We used a two-step model to compare public and private services and look at the possible moderating effects of the physicians' specialty and years of practice. Our data analysis included descriptive statistics, the independent t test, analysis of variance (ANOVA), multivariate logistic regression, General Linear Model Univariate Analysis, non-parametric methods (bootstrap), and post hoc probing. RESULTS: Mainly in the public sector, the policy goal of maintaining quality of care was undermined by a lack of resources, the deterioration in medical residency conditions, and to a lesser extent, greater administrative interference in clinical decision-making. Differences in public and private services showed that the effects of the austerity measures were not the same throughout the health system. Our results also showed that physicians with similar years of practice and in the same medical specialty did not necessarily experience the same pressures. CONCLUSIONS: The debate on the effects of austerity measures should focus more closely on health workers' concrete experiences, as they demonstrate the non-linearity between policy setting and expected outcomes. We also suggest that it is necessary to explore the interplay between lower quality and the undermining of trust relationships in health. PMID- 29233173 TI - The importance of health behaviours in childhood for the development of internalizing disorders during adolescence. AB - BACKGROUND: Poor mental health constitutes a considerable global public health burden with approximately half of all cases of poor mental health having their onset before the age of 14 years. The identification of modifiable risk factors early in life is therefore essential to prevention, however, there are presently very few longitudinal studies on health behaviours for mental health to inform public health decision makers and to justify preventive action. We examined the importance of diet quality, physical activity (PA) and sedentary behaviours in childhood for internalizing disorder throughout adolescence. METHODS: We linked data from a population-based lifestyle survey among 10 and 11 year old grade five students in the Canadian province of Nova Scotia with physician diagnoses of internalizing disorders from administrative health records. We applied negative binomial regressions to examine the associations of health behaviours with the number of health care provider contacts with a diagnosis of internalizing disorder. RESULTS: Of the 4875 students, 23.9% had one or more diagnoses for internalizing disorder between the age of 10 or 11 years and 18 years. The number of health care provider contacts with a diagnosis of internalizing disorder was statistically significant higher among students with less variety in their diets, and among students who reported less PA and more time using computers and video games. The number of health care provider contacts was also higher for girls, and for students with low self-esteem and from low-income households. CONCLUSIONS: These findings suggest that diets and active lifestyles in childhood affect mental health during adolescence, and imply that succxessful health promotion programs targeting children's diets and activity will contribute to the prevention of mental health disorders in addition to the prevention of chronic diseases later in life. PMID- 29233174 TI - Sprifermin (rhFGF18) modulates extracellular matrix turnover in cartilage explants ex vivo. AB - BACKGROUND: Sprifermin (recombinant human fibroblast growth factor 18) is in clinical development as a potential disease-modifying osteoarthritis drug (DMOAD). In vitro studies have shown that cartilage regenerative properties of sprifermin involve chondrocyte proliferation and extracellular matrix (ECM) production. To gain further insight into the process of sprifermin in the cartilage tissue, this study aimed at investigating the ECM turnover of articular cartilage explants in a longitudinal manner. METHODS: Bovine full-depth articular cartilage explants were stimulated with sprifermin or placebo at weekly intervals, similar to the dosing regimen used in clinical trials. Pre-culturing with oncostatin M and tumour necrosis factor-alpha, was also used to induce an inflammatory state before treatment. Metabolic activity was measured using AlamarBlue, and chondrocyte proliferation was visualized by immuno-histochemical detection of proliferating cell nuclear antigen. ECM turnover was quantified by biomarker ELISAs; ProC2 reflecting type II collagen formation, CS846 reflecting aggrecan formation, active MMP9, C2M and AGNx2 reflecting matrix metalloproteinase activity, and AGNx1 reflecting aggrecanase activity. RESULTS: Sprifermin was able to reach the chondrocytes through the extracellular matrix, as it increased cell proliferation and metabolic activity of explants. ProC2 and CS846 was dose-dependently increased (P < 0.05) by sprifermin compared to placebo, while C2M and AGNx2 were unaffected, active MMP9 was slightly decreased, and AGNx1 was slightly increased. Over the course of treatment, the temporal order of ECM turnover responses was AGNx1, then ProC2, followed by CS846 and MMP9. Pro-inflammatory activation of the explants diminished the ECM turnover responses otherwise observed under non-inflammatory conditions. CONCLUSIONS: The data suggest that sprifermin has chondrogenic effects on articular cartilage ex vivo, exerted through a sequential process of ECM turnover; aggrecan degradation seems to occur first, while type II collagen and aggrecan production increased at a later time point. In addition, it was observed that these chondrogenic effects are dependent on the inflammatory status of the cartilage prior to treatment. PMID- 29233175 TI - Exome sequencing of multiple-sclerosis patients and their unaffected first-degree relatives. AB - OBJECTIVES: The understanding of complex multifactorial diseases requires the availability of a variety of data for a large-number of affected individuals. In this data note here we provide whole exome sequencing data from a set of non familiar multiple-sclerosis (MS) patients as well as their unaffected first degree relatives. This data might help the identification of genomic alterations, including single nucleotide polymorphisms, de novo variations and structural genomic variations, such as copy-number alterations that may impact this disease. DATA DESCRIPTION: This dataset comprises the full exome of 28 Brazilian subjects grouped in eight distinct families, consisting of four complete trios (mother patient-father) plus another four complete trios with one added unaffected sibling. In total, we present the full exome data of eight patients diagnosed with recurrent remittent multiple sclerosis. Diagnoses were made by experienced neurologists and all enrolled patients had at least 5 years of follow up and specific MS treatment. Exomes were sequenced from leukocyte-derived DNA, after the capture of exons using biotinylated probes, in the Ion Proton platform. For each exome we generated an average of 66.1 million good quality mapped reads with an average length of ~ 160nt. On average, for 90% of the exome a vertical coverage above 20* was reached. PMID- 29233176 TI - Uncoordinated expression of DNA methylation-related enzymes in human cancer. AB - BACKGROUND: In addition to the important roles played by 5-methylcytosine (5mC), emerging evidence suggests that 5mC derivatives, such as 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), also exhibit regulatory functions in physiological and pathological processes. Four cytosine modifications (5mC, 5hmC, 5fC and 5caC) are produced and erased by a cyclic enzymatic cascade mediated by DNA methyltransferases (DNMTs), ten-eleven translocation (TET) family enzymes and thymine DNA glycosylase (TDG). Stable maintenance of the DNA methylation profile is important for normal cell homeostasis, but its underlying mechanisms are largely unknown. METHODS: The expression levels of 7 DNA methylation-related enzymes from normal mouse tissues were assessed using quantitative real-time RT-PCR (qRT-PCR). The gene expression data and related information of human normal tissues and tumor tissues were obtained from the Genotype-Tissue Expression (GTEx) and the Cancer Genome Atlas (TCGA), respectively. RESULTS: We observed significant positive correlations among the expression levels of DNA methylation-related enzymes in various mice and human normal tissues. By contrast, we found significantly decreased correlations in various tumor tissues compared with their corresponding normal tissues. Furthermore, we also found that alterations in these correlations are associated with several clinicopathological characteristics of cancer patients. CONCLUSIONS: These observations suggest that uncoordinated expression of DNA methylation-related enzymes is another epigenetic hallmark of cancer. Our work provides important insights into an additional regulatory layer of the DNA methylation maintenance machinery. PMID- 29233177 TI - Influences of perfectionism and motivational climate on attitudes towards doping among Korean national athletes: a cross sectional study. AB - BACKGROUND: The motives for elite athletes to dope are related primarily to maintaining and improving their physical performance. Especially, elite athletes training to compete in the Olympics may feel unique situational pressure, which may in turn induce powerful motivation for doping and predict doping behavior. This study aimed to investigate possible factors associated with attitudes towards doping in Korean national athletes who competed in the Rio 2016 Olympic Games. METHODS: A total of 198 athletes (95 female, 103 male) completed the questionnaire, which covered demographic information, doping-related experiences, Performance Enhancement Attitude Scale (PEAS), Perfectionism in Sports Scale (PSS; coach's criticism, concern over mistakes, and personal standards), and Perceived Motivational Climate in Sport Questionnaire-2 (PMCSQ-2; ego-involving and task-involving climates). Pearson's correlation coefficients were used to identify correlations among PEAS, PSS, and PMCSQ-2 scores, and stepwise multiple linear regression was performed to investigate possible factors significantly associated with attitudes towards doping. RESULTS: The coach's criticism of PSS was slightly or weakly related to the concern over mistakes of PSS and the ego involving climate of PMCSQ-2, respectively. And the concern over mistakes sub scale of perfectionism was related to attitudes towards doping, but weakly. CONCLUSIONS: Effective anti-doping policy should meet athletes' perfectionism, and more studies that identify other factors that influence athletes' doping attitudes are needed. PMID- 29233178 TI - Draft genome sequence of Paenibacillus sp. EZ-K15 isolated from wastewater systems. AB - OBJECTIVES: Paenibacillus species, belonging to the family Paenibacillaceae, are able to survive for long periods under adverse environmental conditions. Several Paenibacillus species produce antimicrobial compounds and are capable of biodegradation of various contaminants; therefore, more investigations at the genomic level are necessary to improve our understanding of their ecology, genetics, as well as potential biotechnological applications. DATA DESCRIPTION: In the present study, we describe the draft genome sequence of Paenibacillus sp. EZ-K15 that was isolated from nitrocellulose-contaminated wastewater samples. The genome comprises 7,258,662 bp, with a G+C content of 48.6%. This whole genome shotgun project has been deposited at DDBJ/ENA/GenBank under the accession PDHM00000000. Data demonstrated here can be used by other researchers working or studying in the field of whole genome analysis and application of Paenibacillus species in biotechnological processes. PMID- 29233179 TI - Immature morphological properties in subcellular-scale structures in the dentate gyrus of Schnurri-2 knockout mice: a model for schizophrenia and intellectual disability. AB - Accumulating evidence suggests that subcellular-scale structures such as dendritic spine and mitochondria may be involved in the pathogenesis/pathophysiology of schizophrenia and intellectual disability. Previously, we proposed mice lacking Schnurri-2 (Shn2; also called major histocompatibility complex [MHC]-binding protein 2 [MBP-2], or human immunodeficiency virus type I enhancer binding protein 2 [HIVEP2]) as a schizophrenia and intellectual disability model with mild chronic inflammation. In the mutants' brains, there are increases in C4b and C1q genes, which are considered to mediate synapse elimination during postnatal development. However, morphological properties of subcellular-scale structures such as dendritic spine in Shn2 knockout (KO) mice remain unknown. In this study, we conducted three dimensional morphological analyses in subcellular-scale structures in dentate gyrus granule cells of Shn2 KO mice by serial block-face scanning electron microscopy. Shn2 KO mice showed immature dendritic spine morphology characterized by increases in spine length and decreases in spine diameter. There was a non significant tendency toward decrease in spine density of Shn2 KO mice over wild type mice, and spine volume was indistinguishable between genotypes. Shn2 KO mice exhibited a significant reduction in GluR1 expression and a nominally significant decrease in SV2 expression, while PSD95 expression had a non-significant tendency to decrease in Shn2 KO mice. There were significant decreases in dendrite diameter, nuclear volume, and the number of constricted mitochondria in the mutants. Additionally, neuronal density was elevated in Shn2 KO mice. These results suggest that Shn2 KO mice serve as a unique tool for investigating morphological abnormalities of subcellular-scale structures in schizophrenia, intellectual disability, and its related disorders. PMID- 29233181 TI - Why they eat, what they eat: patterns of wild edible plants consumption in a tribal area of Western Himalaya. AB - BACKGROUND: From time immemorial, wild plants have been used for edible purposes. They still continue to be a major source of nutrition for tribal people. However, unfortunately, their use is now declining. This has implications in food security, narrowing genetic base, and future leads. The present study was, therefore, carried out in Chhota Bhangal region of Western Himalaya to analyze uses of wild edible plants (WEP) and the motivations behind their use or abandonment. METHODS: Field surveys were conducted to the study area from January 2016 to March 2017. Household surveys, group discussions, free listing, and structured questionnaires were used to elicit information on WEP. WEP use was categorized into six categories (vegetables, fruits, chutney, flavoring food, raw food, and local brew). Trends of use (continuing, decreasing, increasing, and not used) and motivations (environmental, economic, sociocultural, agriculture and land use practices, and human-wildlife conflict) behind their use were analyzed. RESULTS: Fifty plant species were used by the local people for edible purposes under six WEP categories. Mean and median of WEP used per respondent was 22.3 and 21, respectively. Highest number of these were used as vegetable (mean 8.9) while lowest were used as brew (mean 0.4). Out of the 50 WEP used, 20 were prioritized for motivation analyses. Though plant use is still maintained in the area, changes are evident. Almost 50% of the respondents revealed that they still continue the use of WEP while 36% reported trends of declining use as compared to 5-10 years back. Close to 10% respondents have stopped consuming WEP now and ~ 3% reported an increase in the use of WEP. Among the WEP categories, use of chutney showed an increasing trend. Sociocultural motivations were found to play a prime role, both, in limiting and promoting WEP use. Taste and aroma were the major sociocultural reasons behind using WEP while modernization and changing lifestyle were the main reasons behind declining use of WEP. CONCLUSIONS: The study concludes that though use of WEP is still maintained in the area, changes in consumption trends are evident. Sociocultural motivations guided use of WEP in the area. PMID- 29233180 TI - Distinct cytokine patterns may regulate the severity of neonatal asphyxia-an observational study. AB - BACKGROUND: Neuroinflammation and a systemic inflammatory reaction are important features of perinatal asphyxia. Neuroinflammation may have dual aspects being a hindrance, but also a significant help in the recovery of the CNS. We aimed to assess intracellular cytokine levels of T-lymphocytes and plasma cytokine levels in moderate and severe asphyxia in order to identify players of the inflammatory response that may influence patient outcome. METHODS: We analyzed the data of 28 term neonates requiring moderate systemic hypothermia in a single-center observational study. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Neonates were divided into a moderate (n = 17) and a severe (n = 11) group based on neuroradiological and amplitude integrated EEG characteristics. Peripheral blood mononuclear cells were assessed with flow cytometry. Cytokine plasma levels were measured using Bioplex immunoassays. Components of the kynurenine pathway were assessed by high performance liquid chromatography. RESULTS: The prevalence and extravasation of IL-1b + CD4 cells were higher in severe than in moderate asphyxia at 6 h. Based on Receiver operator curve analysis, the assessment of the prevalence of CD4+ IL 1beta+ and CD4+ IL-1beta+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia. Intracellular levels of TNF alpha in CD4 cells were increased at all time points compared to 6 h in both groups. At 1 month, intracellular levels of TNF-alpha were higher in the severe group. Plasma IL-6 levels were higher at 1 week in the severe group and decreased by 1 month in the moderate group. Intracellular levels of IL-6 peaked at 24 h in both groups. Intracellular TGF-beta levels were increased from 24 h onwards in the moderate group. CONCLUSIONS: IL-1beta and IL-6 appear to play a key role in the early events of the inflammatory response, while TNF-alpha seems to be responsible for prolonged neuroinflammation, potentially contributing to a worse outcome. The assessment of the prevalence of CD4+ IL-1beta+ and CD4+ IL-1beta+ CD49d+ cells at 6 h appears to be able to predict the severity of the insult at an early stage in asphyxia. PMID- 29233183 TI - Restoring synaptic plasticity and memory in mouse models of Alzheimer's disease by PKR inhibition. AB - Alzheimer's disease (AD) is a neurodegenerative disorder associated with deficits in cognition and synaptic plasticity. While accumulation of amyloid beta (Abeta) and hyper-phosphorylation of tau are parts of the etiology, AD can be caused by a large number of different genetic mutations and other unknown factors. Considering such a heterogeneous nature of AD, it would be desirable to develop treatment strategies that can improve memory irrespective of the individual causes. Reducing the phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) was shown to enhance long-term memory and synaptic plasticity in naive mice. Moreover, hyper-phosphorylation of eIF2alpha is observed in the brains of postmortem AD patients. Therefore, regulating eIF2alpha phosphorylation can be a plausible candidate for restoring memory in AD by targeting memory enhancing mechanism. In this study, we examined whether PKR inhibition can rescue synaptic and learning deficits in two different AD mouse models; 5XFAD transgenic and Abeta1-42-injected mice. We found that the acute treatment of PKR inhibitor (PKRi) can restore the deficits in long-term memory and long-term potentiation (LTP) in both mouse models without affecting the Abeta load in the hippocampus. Our results prove the principle that targeting memory enhancing mechanisms can be a valid candidate for developing AD treatment. PMID- 29233182 TI - Apparent Life-Threatening Events (ALTE): Italian guidelines. AB - Five years after the first edition, we have revised and updated the guidelines, re-examining the queries and relative recommendations, expanding the issues addressed with the introduction of a new entity, recently proposed by the American Academy of Pediatrics: BRUE, an acronym for Brief Resolved Unexplained Events. In this manuscript we will use the term BRUE only to refer to mild, idiopathic cases rather than simply replace the acronym ALTE per se.In our guidelines the acronym ALTE is used for severe cases that are unexplainable after the first and second level examinations.Although the term ALTE can be used to describe the common symptoms at the onset, whenever the aetiology is ascertained, the final diagnosis may be better specified as seizures, gastroesophageal reflux, infection, arrhythmia, etc. Lastly, we have addressed the emerging problem of the so-called Sudden Unexpected Postnatal Collapse (SUPC), that might be considered as a severe ALTE occurring in the first week of life. PMID- 29233184 TI - Effects of Angelicae Pubescentis and Loranthi Decotion on repairing knee joint cartilages in rats. AB - BACKGROUND: Knee osteoarthritis (KOA) is a common orthopedics disease and its pathological changes at early stage are the damage and loss of articular cartilage. Traditional Chinese medicine (TCM) prescription contains multiple components and has the unique advantages of the diversity of targets.We compared the traditional Chinese medical formulae (Angelicae Pubescentis and Loranthi decotion, APLD, or Duhuo Jisheng) with a western medicine (glucosamine sulfate, GS) to treat the rat arthritis models, and tracked the outcomes. METHODS: Thirty two Wistar rats (weight 180 +/- 10 g, 6-week-old) were randomly divided into four groups (eight for each): group A as normal control group (no surgery and no drug treatment), group B as SIA (surgery-induced arthritis) model control without drug treatment, group C as SIA model + APLD, and group D as SIA model + GS. Anterior cruciate ligament in the knee joint of both hind legs from each rat in groups B, C, and D was shown and cut off to establish the SIA model. After 6 weeks of the surgery, rats in group C or D were treated with APLD or GS, respectively, for 8 weeks. Bone X-ray examination, histological images, and determination of genes of collagen II and aggrecan were performed. At week 14, both knee joint gap and bone structure disappeared in rats of group B, but they were visible in rats of groups A, C, and D. RESULTS: Histological images revealed that the structure and composition of the knee joint cartilage were significantly degenerated in group B and improved in group C. Genes of collagen II and aggrecan were significantly increased in both group C and D. CONCLUSION: APLD or GS gavage treatment for knee osteoarthritis (KOA) rat models was effective on the proliferation of cartilage chondrocytes and the damaged knee joint tissue repairing, and the APLD showed slightly superior in general. PMID- 29233185 TI - Phosphoproteomics reveals network rewiring to a pro-adhesion state in annexin-1 deficient mammary epithelial cells. AB - BACKGROUND: Annexin-1 (ANXA1) plays pivotal roles in regulating various physiological processes including inflammation, proliferation and apoptosis, and deregulation of ANXA1 functions has been associated with tumorigenesis and metastasis events in several types of cancer. Though ANXA1 levels correlate with breast cancer disease status and outcome, its distinct functional involvement in breast cancer initiation and progression remains unclear. We hypothesized that ANXA1-responsive kinase signaling alteration and associated phosphorylation signaling underlie early events in breast cancer initiation events and hence profiled ANXA1-dependent phosphorylation changes in mammary gland epithelial cells. METHODS: Quantitative phosphoproteomics analysis of mammary gland epithelial cells derived from ANXA1-heterozygous and ANXA1-deficient mice was carried out using stable isotope labeling with amino acids in cell culture (SILAC)-based mass spectrometry. Kinase and signaling changes underlying ANXA1 perturbations were derived by upstream kinase prediction and integrated network analysis of altered proteins and phosphoproteins. RESULTS: We identified a total of 8110 unique phosphorylation sites, of which 582 phosphorylation sites on 372 proteins had ANXA1-responsive changes. A majority of these phosphorylation changes occurred on proteins associated with cytoskeletal reorganization spanning the focal adhesion, stress fibers, and also the microtubule network proposing new roles for ANXA1 in regulating microtubule dynamics. Comparative analysis of regulated global proteome and phosphoproteome highlighted key differences in translational and post-translational effects of ANXA1, and suggested closely coordinated rewiring of the cell adhesion network. Kinase prediction analysis suggested activity modulation of calmodulin-dependent protein kinase II (CAMK2), P21-activated kinase (PAK), extracellular signal-regulated kinase (ERK), and IkappaB kinase (IKK) upon loss of ANXA1. Integrative analysis revealed regulation of the WNT and Hippo signaling pathways in ANXA1-deficient mammary epithelial cells, wherein there is downregulation of transcriptional effects of TEA domain family (TEAD) suggestive of ANXA1-responsive transcriptional rewiring. CONCLUSIONS: The phosphoproteome landscape uncovered several novel perspectives for ANXA1 in mammary gland biology and highlighted its involvement in key signaling pathways modulating cell adhesion and migration that could contribute to breast cancer initiation. PMID- 29233186 TI - Prevalence and associations for use of a traditional medicine provider in the SAMINOR 1 Survey: a population-based study on Health and Living Conditions in Regions with Sami and Norwegian Populations. AB - BACKGROUND: In Northern Norway, traditional medicine (TM) is shaped by both Christianity and traditional Sami nature worship. The healing rituals may include prayer and the use of tools such as moss, water, stones, wool and soil. Examples of TM modalities offered is cupping, blood-stemming, laying on of hands, healing prayers, and rituals. The purpose of this study was to investigate the prevalence of the use of TM in areas with predominantly Sami and Norwegian populations, and the influence of ethnicity, geography, gender, age, education, household income, religiosity and self-reported health on such use. METHODS: The study is based on data collected in the first SAMINOR Survey (SAMINOR 1) conducted in 2003/2004, including three self-administered questionnaires, clinical measures, and blood analyses. Data was collected in 24 municipalities in Norway known to have a substantial population of Sami. All residents aged 30 and 36-78/79 years in the predefined regions were invited regardless of ethnic background (N = 27,987). Of these, 16,865 (60.3%) accepted to participate and gave their consent to medical research. RESULTS: Of the 16,544 people responding to the question about TM use, 2276 (13.8%) reported to have used TM once or more during their lifetime. The most outstanding characteristic of the TM users was the affiliation to the Laestadian church, where 34.3% (n = 273) reported such use, followed by an inner Finnmark residence (31.1%, n = 481) and a Sami ethnicity (25.7%, n = 1014). Women were slightly more likely to use TM compared to men (15.9% and 11.5% accordingly, p < 0.001), and the TM users were slightly younger than the non-TM users (mean age 52.3 versus 54.3 years, p < 0.001). The TM users also had lower income (p < 0.001) than the non-TM users. We found no significant differences between the TM users and the non-TM users concerning years of education, and whether the participants were living with a spouse/partner or not. CONCLUSION: Further studies are necessary to examine the development of TM use in Norway over time, and use in areas with mainly Norwegian inhabitants. There is also a lack of studies quantifying TM use among Sami people in Sweden, Finland and Russia. PMID- 29233187 TI - Graphene-based dental adhesive with anti-biofilm activity. AB - BACKGROUND: Secondary caries are considered the main cause of dental restoration failure. In this context, anti-biofilm and bactericidal properties are desired in dental materials against pathogens such as Streptococcus mutans. To this purpose, graphene based materials can be used as fillers of polymer dental adhesives. In this work, we investigated the possibility to use as filler of dental adhesives, graphene nanoplatelets (GNP), a non toxic hydrophobic nanomaterial with antimicrobial and anti-biofilm properties. RESULTS: Graphene nanoplatelets have been produced starting from graphite intercalated compounds through a process consisting of thermal expansion and liquid exfoliation. Then, a dental adhesive filled with GNPs at different volume fractions has been produced through a solvent evaporation method. The rheological properties of the new experimental adhesives have been assessed experimentally. The adhesive properties have been tested using microtensile bond strength measurements (u-TBS). Biocidal activity has been studied using the colony forming units count (CFU) method. The anti biofilm properties have been demonstrated through FE-SEM imaging of the biofilm development after 3 and 24 h of growth. CONCLUSIONS: A significantly lower vitality of S. mutans cells has been demonstrated when in contact with the GNP filled dental adhesives. Biofilm growth on adhesive-covered dentine tissues demonstrated anti-adhesion properties of the produced materials. u-TBS results demonstrated no significant difference in u-TBS between the experimental and the control adhesive. The rheology tests highlighted the necessity to avoid low shear rate regimes during adhesive processing and application in clinical protocol, and confirmed that the adhesive containing the 0.2%wt of GNPs possess mechanical properties comparable with the ones of the control adhesive. PMID- 29233189 TI - Head to head comparison of Prasugrel versus Ticagrelor in patients with acute coronary syndrome: a systematic review and meta-analysis of randomized trials. AB - BACKGROUND: Prasugrel and Ticagrelor are emerging antiplatelet drugs that might have the potential to replace currently used antiplatelet agents. Previous analyses comparing prasugrel with ticagrelor mainly focused on an indirect comparison whereas direct comparison was reported only in a few recently published trials. We aimed to systematically carry out a head to head comparison of the adverse clinical outcomes which were associated with prasugrel versus ticagrelor in patients with acute coronary syndrome (ACS). METHODS: Studies comparing prasugrel with ticagrelor (head to head comparison) were searched from online databases. Adverse cardiovascular outcomes were considered as the primary endpoints whereas bleeding outcomes were considered as the secondary endpoints in this analysis. The latest version of the RevMan software was used to carry out subgroup analyses whereby odds ratios (OR) with 95% confidence intervals (CI) and the calculated probability (P) were generated. RESULTS: Four studies with a total number of 563 patients (2012 - 2016) were included (282 patients were treated with prasugrel and 281 patients were treated with ticagrelor). Results of this analysis did not show any significant difference in mortality between prasugrel and ticagrelor with OR: 1.52, 95% CI: 0.42 - 5.45; P = 0.52. In addition, myocardial infarction, major adverse cardiac events, stroke and stent thrombosis were also not significantly different with OR: 0.59, 95% CI: 0.08 - 4.58; P = 0.62, OR: 0.91, 95% CI: 0.37 - 2.21; P = 0.83, OR: 0.60, 95% CI: 0.08 - 4.58; P = 0.62 and OR: 0.59, 95% CI: 0.08 - 4.58; P = 0.62 respectively. Thrombolysis in myocardial infarction (TIMI) defined minor bleeding, and minimal bleeding were also not significantly different between these two newer antiplatelet agents with OR: 3.11, 95% CI: 0.48 - 19.94; P = 0.23, and OR: 2.39, 95% CI: 0.35 - 16.42; P = 0.38 respectively. Moreover, bleeding defined by the academic research consortium was also similarly manifested with OR: 0.92, 95% CI: 0.39 - 2.13; P = 0.84. CONCLUSION: In patients with ACS, both prasugrel and ticagrelor showed similar adverse cardiovascular outcomes and bleeding events. No significant difference was observed between these two newer antiplatelet agents during this head to head comparison. However, upcoming trials with long term follow up periods might be expected to completely solve this important clinical issue. PMID- 29233188 TI - The RIO protein kinase-encoding gene Sj-riok-2 is involved in key reproductive processes in Schistosoma japonicum. AB - BACKGROUND: Schistosomiasis is one of the most prevalent parasitic diseases worldwide and is caused by parasitic trematodes of the genus Schistosoma. The pathogenesis of schistosomiasis is caused by eggs whose production is the consequence of the pairing of schistosomes and the subsequent sexual maturation of the female. Previous studies have demonstrated that protein kinases are involved in processes leading to the male-induced differentiation of the female gonads, ovary and vitellarium. Right open reading frame protein kinase 2 (RIOK-2) is a member of the atypical kinase family and shown in other organisms to be responsible for ribosomal RNA biogenesis and cell-cycle progression, as well as involves in nematode development. However, nothing is known about its functions in any trematode including schistosome. METHODS: We isolated and characterized the riok-2 gene from S. japonicum, and detected the transcriptional profiles of Sj-riok-2 by using real-time PCR and in situ hybridization. RNAi-mediated knockdown of Sj-riok-2 was performed, mitotic activities were detected by EdU incorporation assay and morphological changes on organs were observed by confocal laser scanning microscope (CLSM). RESULTS: In silico analyses of the amino acid sequence of Sj-RIOK-2 revealed typical features of this class of kinases including a winged helix (wHTH) domain and a RIO kinase domain. Sj-riok-2 is transcribed in different developmental stages of S. japonicum, with a higher abundance in adult females and eggs. Localization studies showed that Sj-riok-2 was mainly transcribed in female reproductive organs. Experiments with adult schistosomes in vitro demonstrated that the transcriptional level of Sj-riok-2 was affected by pairing. Knocking down Sj-riok-2 by RNAi reduced cell proliferation in the vitellarium and caused the increased amount of mature oocytes in ovary and an accumulation of eggs within the uterus. CONCLUSIONS: Sj riok-2 is involved in the reproductive development and maturation of female S. japonicum. Our findings provide first evidence for a pairing-dependent role of Sj riok-2 in the reproductive development and maturation of female S. japonicum. Thus this study contributes to the understanding of molecular processes controlling reproduction in schistosomes. PMID- 29233190 TI - Microvascular effects of intravenous esmolol in patients with normal cardiac function undergoing postoperative atrial fibrillation: a prospective pilot study in cardiothoracic surgery. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is commonplace after cardiothoracic surgery. A rate control strategy using short-acting beta blockers is recommended as a first-line therapy in patients without hemodynamic instability. Microcirculatory effects of POAF and esmolol have not yet been investigated. We hypothesized that POAF without hemodynamic instability would induce microvascular dysfunction which could be reversed by intravenous esmolol. METHODS: Twenty-five cardiothoracic surgical patients with POAF were included in the study. Microcirculation was assessed by peripheral near-infrared spectroscopy (NIRS) in association with a vascular occlusion test (VOT) before esmolol infusion, during incremental doses of esmolol (25, 50, 100, and 200 MUg/kg/min), and after a return to sinus rhythm. Esmolol was given to control heart rate to between 60 and 90 beats/min. Regional tissue oxygen saturation variables (StO2, StO2 min, StO2 max, and ?StO2) and desaturation/resaturation speeds during VOT were recorded to evaluate the microcirculation. RESULTS: StO2 and resaturation speed were significantly improved when POAF returned to sinus rhythm (StO2 64% +/ 6 versus 67% +/- 6, P < 0.01; resaturation speed 0.53%/s (0.42-0.97) versus 0.66%/s (0.51-1.04), P = 0.020). ?StO2 was significantly decreased after a return to sinus rhythm (7.9% +/- 4.8 versus 6.1% +/- 4.7, P = 0.026). During esmolol infusion, we found a significant decrease in both heart rate (P < 0.001) and blood pressure (P < 0.001), and a non-significant dose-dependent increase in StO2 (P = 0.081) and resaturation speed (P = 0.087). CONCLUSION: POAF without hemodynamic instability is associated with significant impairment in the microcirculation which could be partially reversed by intravenous esmolol. PMID- 29233192 TI - Methanolic extract of Euchelus asper exhibits in-ovo anti-angiogenic and in vitro anti-proliferative activities. AB - BACKGROUND: The marine environment is a rich source of bioactive natural products. Many of the marine bioactive compounds have been derived successfully from molluscs. Euchelus asper is a marine mollusc which is commonly found in the intertidal rocky regions of the Mumbai coast. The present study was focused on evaluating the anti-angiogenic and anti- proliferative activities of methanolic extract of Euchelus asper (EAME). METHODS: The anti-angiogenic activity of EAME (50-800 MUg/mL) was assessed by chick chorio-allantoic membrane (CAM) model wherein multiple parameters in the CAM blood vessels were analysed through morphometric and histological investigations. In vitro testing of EAME (5-20 MUg/mL) included its cytotoxicity against three different cancer cell lines, its effect on cell proliferation by wound healing assay as well as their relevant molecular mechanisms. Statistical analysis was carried out by two-tailed student's t test for two unpaired groups. RESULTS: Analysis of CAM revealed that the extract is effective in reducing the branching points of the 1st order blood vessels or capillaries of CAM. Histological analysis of CAM showed significant decrease in capillary plexus and compartmentalization along with increase in mesodermal blood vessels, thus establishing its anti-angiogenicity. Further, EAME exhibited moderate but significant cytotoxicity against A549 non-small cell lung carcinoma cell line. We also demonstrated that the cytotoxicity of EAME in A549 was associated with its apoptotic activity by subG1 phase arrest. Lastly, EAME significantly reduced A549 proliferation by reducing the expression of Matrix metalloproteinase-2 (MMP-2) and Matrix metalloproteinase-9 (MMP-9). CONCLUSION: Overall, our study suggested that EAME has potential to inhibit tumour angiogenic and proliferative activity and may be a potential source for development of new anti-cancer pharmaceuticals. PMID- 29233193 TI - Bovine leptospirosis in urban and peri-urban dairy farming in low-income countries: a "One Health" issue? AB - Global trends in urbanization are increasing the spread of neglected zoonotic infections such as leptospirosis, and reducing the number of human cases of leptospirosis is best accomplished by controlling the infection in the animal reservoir. The aim of this study was to determine the seroprevalence of Leptospira borgpetersenii serovar Hardjo and L. interrogans serovar Hardjo (L. Hardjo) exposure and to assess the associated risk factors for infection in small scale dairy farming in the urban and peri-urban area of Dushanbe, Tajikistan. The true individual seroprevalence among the dairy cows was 13%, and the level of seroprevalence was positively associated with older cows and with communal grazing practices. The study shows that dairy cows are commonly exposed to L. Hardjo in the study region, and this constitutes a public health risk and demonstrates the importance of including urban and peri-urban areas, where large numbers of humans and animals coexist, when investigating zoonotic infections and when planning and implementing control measures for cattle-associated leptospirosis. PMID- 29233191 TI - MKRMDA: multiple kernel learning-based Kronecker regularized least squares for MiRNA-disease association prediction. AB - BACKGROUND: Recently, as the research of microRNA (miRNA) continues, there are plenty of experimental evidences indicating that miRNA could be associated with various human complex diseases development and progression. Hence, it is necessary and urgent to pay more attentions to the relevant study of predicting diseases associated miRNAs, which may be helpful for effective prevention, diagnosis and treatment of human diseases. Especially, constructing computational methods to predict potential miRNA-disease associations is worthy of more studies because of the feasibility and effectivity. METHODS: In this work, we developed a novel computational model of multiple kernels learning-based Kronecker regularized least squares for MiRNA-disease association prediction (MKRMDA), which could reveal potential miRNA-disease associations by automatically optimizing the combination of multiple kernels for disease and miRNA. RESULTS: MKRMDA obtained AUCs of 0.9040 and 0.8446 in global and local leave-one-out cross validation, respectively. Meanwhile, MKRMDA achieved average AUCs of 0.8894 +/- 0.0015 in fivefold cross validation. Furthermore, we conducted three different kinds of case studies on some important human cancers for further performance evaluation. In the case studies of colonic cancer, esophageal cancer and lymphoma based on known miRNA-disease associations in HMDDv2.0 database, 76, 94 and 88% of the corresponding top 50 predicted miRNAs were confirmed by experimental reports, respectively. In another two kinds of case studies for new diseases without any known associated miRNAs and diseases only with known associations in HMDDv1.0 database, the verified ratios of two different cancers were 88 and 94%, respectively. CONCLUSIONS: All the results mentioned above adequately showed the reliable prediction ability of MKRMDA. We anticipated that MKRMDA could serve to facilitate further developments in the field and the follow-up investigations by biomedical researchers. PMID- 29233194 TI - Ibuprofen plasma concentration profile in deliberate ibuprofen overdose with circulatory depression treated with therapeutic plasma exchange: a case report. AB - BACKGROUND: Inquiries relating to ibuprofen overdose have more than tripled in the last ten years in our poison control center. Although the vast majority of cases have a benign clinical course, there are few severe or even fatal cases present with refractory circulatory failure. CASE PRESENTATION: We describe a case of a 48 year-old male with suicidal mono-ingestion of approximately 72 g ibuprofen. Despite an initial rapid spontaneous drop in the total ibuprofen plasma concentration (IPC) from 550 to 275 mcg/mL within the first 5 h after admission, the patient developed a circulatory failure, refractory to aggressive fluid resuscitation and high doses of vasopressors. Due to ibuprofen's favorable pharmacokinetics (>95% bound to albumin, low volume of distribution) and in the absence of specific therapeutic alternatives thereby avoiding escalating vasopressor doses, therapeutic plasma exchange (TPE) for extracorporeal elimination of ibuprofen was considered as a therapeutic rescue option. An improvement of hemodynamics with a significant reduction of vasopressors was observed with TPE-initiation. However, neither the observed IPC-profile nor a pharmacokinetic (PK) simulation provided evidence for a quantitative effective elimination of ibuprofen by TPE. Based on PK-modeling we calculated an overall ibuprofen half-life of 17.2 h for the entire observation period over 5 days. CONCLUSIONS: To our knowledge this is the first report of a severe ibuprofen-mono intoxication treated with TPE and providing serial IPCs over a period of five days, indicating an estimated fivefold overall-elimination half-life of 17.2 h. Despite TPE clinically improved persistent hemodynamic instability, this procedure was neither consistent with the observed IPC-profile nor correlated with a meaningful quantitative elimination of ibuprofen. PMID- 29233195 TI - Intact striatal dopaminergic modulation of reward learning and daily-life reward oriented behavior in first-degree relatives of individuals with psychotic disorder. AB - BACKGROUND: Abnormalities in reward learning in psychotic disorders have been proposed to be linked to dysregulated subcortical dopaminergic (DA) neurotransmission, which in turn is a suspected mechanism for predisposition to psychosis. We therefore explored the striatal dopaminergic modulation of reward processing and its behavioral correlates in individuals at familial risk for psychosis. METHODS: We performed a DA D2/3 receptor [18F]fallypride positron emission tomography scan during a probabilistic reinforcement learning task in 16 healthy first-degree relatives of patients with psychosis and 16 healthy volunteers, followed by a 6-day ecological momentary assessment study capturing reward-oriented behavior in the everyday life. RESULTS: We detected significant reward-induced DA release in bilateral caudate, putamen and ventral striatum of both groups, with no group differences in its magnitude nor spatial extent. In both groups alike, greater extent of reward-induced DA release in all regions of interest was associated with better performance in the task, as well as in greater tendency to be engaged in reward-oriented behavior in the daily life. CONCLUSIONS: These findings suggest intact striatal dopaminergic modulation of reinforcement learning and reward-oriented behavior in individuals with familial predisposition to psychosis. Furthermore, this study points towards a key link between striatal reward-related DA release and pursuit of ecologically relevant rewards. PMID- 29233196 TI - Online prevention of disordered eating in at-risk young-adult women: a two country pragmatic randomized controlled trial. AB - BACKGROUND: Disordered eating (DE) is a widespread, serious problem. Efficacious prevention programs that can be delivered at-scale are needed. METHODS: A pragmatic randomized controlled trial of two online programs was conducted. Participants were young-adult women from Australia and New Zealand seeking to improve their body image. Media Smart-Targeted (MS-T) and Student Bodies (SB) were both 9-module interventions released weekly, whilst control participants received positive body image information. Primary [Eating Disorder Examination Questionnaire (EDE-Q) Global], secondary (DE risk factors) and tertiary (DE) outcome measures were completed at baseline, post-program, 6- and 12-month follow up. RESULTS: Baseline was completed by 608 women (M age = 20.71 years); 33 were excluded leaving 575 randomized to: MS-T (N = 191); SB (N = 190) or control (N = 194). Only 66% of those randomized to MS-T or SB accessed the intervention and were included in analyses with controls; 78% of this sample completed measures subsequent to baseline. Primary intent-to-treat (ITT) analyses revealed no differences between groups, while measure completer analyses found MS-T had significantly lower EDE-Q Global than controls at 12-month follow-up. Secondary ITT analyses found MS-T participants reported significantly higher quality of life-mental relative to both SB and controls (6-month follow-up), while MS-T and controls had lower clinical impairment relative to SB (post-program). Amongst measure completers, MS-T scored significantly lower than controls and SB on 5 variables. Of those with baseline DE, MS-T participants were significantly less likely than controls to have DE at 12-month follow-up. CONCLUSIONS: Given both programs were not therapist-moderated, MS-T has potential to achieve reductions in DE risk at low implementation costs. PMID- 29233197 TI - Takayasu arteritis in paediatrics. AB - Takayasu arteritis is an idiopathic chronic granulomatous panarteritis predominantly affecting the aorta and its main branches. Although idiopathic, genetic contribution to disease susceptibility is being increasingly recognised. Rare in children, Takayasu arteritis is a worldwide disease with significant morbidity and mortality. Its diagnosis is a challenge and requires awareness of the condition as clinical features at presentation are non-specific and assessing disease activity is difficult. In the inflammatory stage, treatment is essential to prevent the insidious course and vascular damage: stenotic, occlusive lesions, aneurysms, and aortic regurgitation. New imaging modalities, such as CT scan, MRI, and 18F-fluorodeoxyglucose positron emission tomography, have expanded the possibilities for non-invasive diagnosis and monitoring; however, digital subtraction arteriography remains the gold standard for the diagnosis of Takayasu arteritis. Steroids are the first-line medical treatment. The combined use of methotrexate, cyclophosphamide, azathioprine, mycophenolate mofetil, and biological agents is common. Revascularisation therapy should be considered in uncontrolled hypertension secondary to renal artery stenosis, symptomatic coronary ischaemia, cerebrovascular disease, severe aortic regurgitation, limb ischaemia, and aneurysms at risk of rupture, using surgical or endovascular procedures and taking into consideration that complications, especially restenosis, are frequent. Disease activity increases the likelihood of complications after revascularisation. Surgical intervention has shown better long-term outcomes, although the endovascular approach is evolving. The aim of this review was to describe key points of the diagnosis, treatment, and follow-up of Takayasu arteritis in childhood. PMID- 29233198 TI - Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension. AB - BACKGROUND: Macitentan is an orally active, potent, dual endothelin receptor antagonist and is the only registered treatment for pulmonary arterial hypertension that significantly reduced morbidity and mortality in a long-term event-driven study. Aim Few studies compared the clinical efficacy and safety of switch from bosentan to macitentan only in adult patients with pulmonary arterial hypertension. We aimed to evaluate the clinical efficacy and safety of switch from bosentan to macitentan in children and young adults. METHODS: This is a single-institution, 24-week prospective study. Patients ?12 years of age with idiopathic/heritable pulmonary arterial hypertension or related to CHD or residual pulmonary arterial hypertension due to repaired congenital systemic-to pulmonary shunts and on bosentan therapy were included. Concomitant treatment with oral phosphodiesterase type 5 inhibitors and inhaled prostanoids was allowed. Outcome measures included change from baseline to week 24, in the 6 minute walk distance, functional class, oxygen saturation at rest/after 6-minute walk distance test, systolic pulmonary artery pressure estimated by echocardiography, and brain natriuretic peptide levels. Safety end points included adverse events laboratory abnormalities. RESULTS: A total of 13 patients - 5 male and 8 female - completed the study. The mean age was 20.3+/-6.5 years (12-35) and weight was 54.0+/-14.5 kg (27-75). Five patients were ?18 years of age. Macitentan improved 6-minute walk distance from baseline (mean: 466+/-35 m (300-590)), at 12 weeks (mean: 494+/-78 m (325-590), +28 m) (p0.05). None of the patients had anaemia, hepatotoxicity, and peripheral oedema. CONCLUSIONS: Our study is the first study that showed that switch from bosentan to macitentan significantly improved exercise capacity in children and young adults with pulmonary arterial hypertension and is well tolerated without any adverse events. PMID- 29233199 TI - Hypoplastic left heart in Turner's syndrome: a primary indication for transplant? AB - Survival for hypoplastic left heart syndrome patients following the Norwood procedure is 71-90%. Mortality in patients with Turner's syndrome and hypoplastic left heart syndrome after conventional palliation (Norwood operation) has been reported as high as 80%. This questions the approach of traditional staged palliation. Here, we report a patient with hypoplastic left heart syndrome and Turner's syndrome bridged to orthotopic heart transplantation following a hybrid procedure. PMID- 29233201 TI - Intergenerational transmission of violence: The mediating role of adolescent psychopathology symptoms. AB - Evidence on the intergenerational continuity of intimate partner violence (IPV) suggests small to moderate associations between childhood exposure and young adult IPV involvement, suggesting an indirect effects model. Yet, few prospective studies have formally tested meditational mechanisms. The current study tested a prospective (over 9 years) moderated-mediational model in which adolescent psychopathology symptoms (i.e., internalizing, externalizing, and combined) mediated the association between exposure to IPV in middle childhood and young adult IPV perpetration. In a more novel contribution, we controlled for proximal young adult partner and relationship characteristics. The sample consisted of n = 205 participants, who were, on average, assessed for exposure to parent IPV at age 12.30 years, adolescent psychopathology symptoms at age 15.77 years, and young adult IPV at 21.30 years of age. Data suggest a small, significant direct path from IPV exposure to young adult perpetration, mediated only through adolescent externalizing. Gender moderation analyses reveal differences in sensitivity to exposure across developmental periods; for males, effects of exposure were intensified during the transition to adolescence, whereas for females, effects were amplified during the transition to adulthood. In both cases, the mediational role of psychopathology symptoms was no longer significant once partner antisocial behavior was modeled. Findings have important implications for both theory and timing of risk conveyance. PMID- 29233200 TI - First Rescue Under the Rubble: The Medical Aid in the First Hours After the Earthquake in Amatrice (Italy) on August 24, 2016. AB - : Specific Event Identifiers a. Event Type: Earthquake measuring 6.2 (SD=0.016) on the moment magnitude; b. Event Onset: August 24, 2016 - 03:36:32 CEST (01:36 UTC); c. Location of Event: Central Italy, in the town of Amatrice; d. Geographic Coordinates: latitude (DMS): 42 degrees 37'45.77"N; longitude (DMS): 13 degrees 17'18.14"E; elevation: 955 meters above sea-level; e. Dates: August 24, 2016 at 4:48 AM; f. Response Type: Medical Relief. ABSTRACT: On August 24, 2016, an earthquake hit the town of Amatrice (Italy). This study aims to document the first medical aid provided to earthquake victims in Amatrice immediately following the earthquake. Patient data were collected and recorded during the first clinical evaluation and before definitive hospitalization. Blood gas tests were performed on survivors extricated from the rubble using the iSTAT (Abbott Point of Care Inc.; Princeton, New Jersey USA) handheld blood analyzer. Performing "victim-side" blood gas tests could provide concrete information to facilitate clinical evaluation and decision making when treating buried victims. After a natural disaster, it is essential to provide effective analgo-sedation to victims. Blasetti AG , Petrucci E , Cofini V , Pizzi B , Scimia P , Pozone T , Necozione S , Fusco P , Marinangeli F . First rescue under the rubble: the medical aid in the first hours after the earthquake in Amatrice (Italy) on August 24, 2016. Prehosp Disaster Med. 2018;33(1):109-113. PMID- 29233202 TI - Thinness in young schoolchildren in Serbia: another case of the double burden of malnutrition? AB - OBJECTIVE: Thinness is rarely highlighted or regularly monitored among children in developed countries although it may be rather frequent and pose a significant risk to children's health. We aimed to describe the prevalence of mild, moderate and severe thinness among young Serbian schoolchildren. DESIGN: Cross-sectional study of schoolchildren aged 6-9 years. Children were assessed for weight, height and BMI as part of the WHO European Childhood Obesity Surveillance Initiative in Serbia. Thinness grades were defined as gender- and age-specific cut-offs for BMI according to the International Obesity Task Force criteria. SETTING: Serbia, September to November 2015. SUBJECTS: Students (n 4861) in grades 2 and 3 (6-9 years, 2397 girls). RESULTS: Overall prevalence of thinness in Serbian schoolchildren was 9.6 %. Mild thinness was clearly the largest category with a prevalence of 7.6 %, moderate thinness was present in 1.7 % of children and severe thinness was found in 0.3 % of children. OR indicated a significant risk of being thin for girls (1.44 times higher compared with boys) and children attending schools with no health-focused educational programme (1.57 times more likely to be thin than peers enrolled in schools with such programmes). In addition, OR for thinness tended to be 1.23 times higher in children living in an economically disadvantaged region of Serbia (P=0.06). CONCLUSIONS: A rather high prevalence of thinness highlights this malnutrition disorder as an emerging health issue that should trigger public health policies to tackle thinness, especially in girls of young age and children living in economically disadvantaged areas. PMID- 29233203 TI - Social exclusion of people with severe mental illness in Switzerland: results from the Swiss Health Survey. AB - AIMS: People with severe mental illness (SMI) have a high risk of living socially excluded from the mainstream society. Policy initiatives and health systems aim to improve the social situation of people who suffer from mental health disabilities. The aim of this study was to explore the extent of social exclusion (employment and income, social network and social activities, health problems) of people with SMI in Switzerland. METHODS: Data from the Swiss Health Survey 2012 were used to compare the social exclusion magnitude of people with SMI with those suffering from severe physical illness, common mental illness and the general population. RESULTS: With the exception of Instrumental Activities of Daily Living, we found a gradient of social exclusion that showed people with SMI to be more excluded than the comparison groups. Loneliness and poverty were widespread among people with SMI. Logistic regression analyses on each individual exclusion indicator revealed that people with SMI and people with severe physical illness were similarly excluded on many indicators, whereas people with common mental illness and the general population were much more socially included. CONCLUSIONS: In contrast to political and health system goals, many people with SMI suffer from social exclusion. Social policy and clinical support should increase the efforts to counter exclusionary trends, especially in terms of loneliness and poverty. PMID- 29233204 TI - Is there a role for vitamin D in supporting cognitive function as we age? AB - Globally, an estimated 46 million people are currently living with dementia and this figure is projected to increase 3-fold by 2050, highlighting this major public health concern and its substantial associated healthcare costs. With pharmacological treatment yet to reach fruition, the emphasis on evidence-based preventative lifestyle strategies is becoming increasingly important and several modifiable lifestyle factors have been identified that may preserve cognitive health. These include good cardiovascular health, physical activity, low alcohol intake, smoking and a healthy diet, with growing interest in vitamin D. The aim of the present paper is to review the evidence supporting the potential roles of vitamin D in ageing and cognitive health in community-dwelling older adults. Furthermore, to describe the utility and challenges of cognitive assessments and outcomes when investigating vitamin D in this context. Evidence indicates that serum 25-hydroxyvitamin D (25(OH)D) may impact brain health. There is a biological plausibility from animal models that vitamin D may influence neurodegenerative disorders, through several mechanisms. Epidemiological evidence supports associations between low serum 25(OH)D concentrations and poorer cognitive performance in community-dwelling older populations, although an optimal 25(OH)D level for cognitive health could not be determined. The effect of raising 25(OH)D concentrations on cognitive function remains unclear, as there is a paucity of interventional evidence. At a minimum, it seems prudent to aim to prevent vitamin D deficiency in older adults, with other known common protective lifestyle factors, as a viable component of brain health strategies. PMID- 29233205 TI - Effect of dietary habits on the risk of metabolic syndrome: Yazd Healthy Heart Project. AB - OBJECTIVE: Metabolic syndrome (MetS) refers to a group of risk factors that increase the risk of cardiovascular mortality and morbidity. Dietary habits are among the most important risk factors for MetS. The current study aimed at assessing the effect of dietary habits on the risk of MetS in a 10-year follow-up study in central Iran. DESIGN: Cohort study. SETTING: Yazd, Iran. SUBJECTS: Participants aged 20-74 years without any history of MetS, who were originally recruited for Yazd Healthy Heart Project (YHHP) during 2005-2006, were revisited during 2015-2016. At phase I of YHHP, demographic data, anthropometric measurements, five components of MetS, biochemical tests and dietary habits were evaluated; and the same data were collected in phase II. RESULTS: A total of 1092 participants were eligible to be included in the present study. After follow-up, the 10-year cumulative incidence of MetS was 56.1 %. After adjustment for potential confounders, increased risk of MetS (hazard ratio; 95 % CI) was found in those who did not try to control their body weight (1.57; 1.06, 2.35), did not usually eat salad (1.91; 1.22, 3.00) and added salt to their food (1.57, 1.06, 2.33). These associations were stronger in men than in the total population after subgroup analysis, but were not present in women. CONCLUSIONS: Dietary habits affect the risk of MetS in the Iranian population. Lifestyle interventions are needed to improve dietary habits to reduce the risk of MetS. Future studies are highly recommended to confirm our results in other populations. PMID- 29233206 TI - Parental work characteristics and diet quality among pre-school children in dual parent households: results from a population-based cohort in Taiwan. AB - OBJECTIVE: To examine the relationship between parental work characteristics and diet quality among pre-school children in dual-parent households. DESIGN: Cross sectional study. Parental work characteristics were measured by the types of combined parental work schedules and work hours. The main outcome variables included meal eating habits as well as 'health-conscious food' and 'unhealthy non core food' dietary patterns derived by using principal component analysis. Sociodemographic covariates were considered to reduce confounding and selection biases. SETTING: The Taiwan Birth Cohort Study, Taiwan. SUBJECTS: A population based sample of 18 046 children. RESULTS: Multiple regression analyses indicated that compared with having both parents working standard schedules, having at least one parent who worked non-standard schedules was significantly associated with a lower likelihood of a child eating breakfast every day and a higher consumption of unhealthy non-core foods. If only one parent was employed and worked standard schedules, the children demonstrated greater odds of having home prepared dinner most of the time. The mother's working long hours was associated with lower odds of eating breakfast every day, more frequent consumption of unhealthy non-core foods and a lower frequency of healthy food consumption. CONCLUSIONS: The findings raise concern that parents' non-standard work schedules and mother's long working hours have negative effects on diet quality of pre school children. Policy implications include the need for a multifaceted approach to supporting working parents so as to create healthier food environments. PMID- 29233207 TI - The dynamic pattern of PLIN3 in pig oocytes and cumulus cells during in vitro maturation. AB - Lipid droplets (LDs) are the main energy resource for porcine preimplantation embryonic development. PLIN3 has been implicated in LD formation and regulation. Therefore, this study aimed to detect the dynamic pattern of PLIN3 in pig oocytes and cumulus cells (CC) during in vitro maturation (IVM), and to determine the relationship between PLIN3 and LD content. IVM with cumulus-enclosed oocytes (CEO), cumulus-denuded oocytes (DO) and the CCs denuded from the corresponding oocytes (DCC) was performed in porcine follicular fluid (PFF) or PFF-free optimized medium. DO and the DCC were cultured together under the same conditions as described above, while the DO was named DTO and the DCC was named DTCC in this group. Firstly, our results revealed LDs distributed widely in oocytes and CC, while the PLIN3 protein coated these LDs and spread out ubiquitously in the cytoplasm. Secondly, not only the mRNA level but also at protein level of PLIN3 in immature naked oocytes (IO) was higher than that in matured CEO, DO and DTO. Although PLIN3 was expressed at lower levels in CC from immature oocytes (ICC), the protein level of PLIN3 was comparably higher in the ECC and DCC groups. The triglyceride (TG) content in CEO and DO was significantly less abundant compared with that in IO. Therefore, our results indicated that co-culturing of oocytes and CC might affect PLIN3 expression levels in CC but not in oocytes. Lipid accumulation in pig oocytes during maturation might be affected by PLIN3 cross talk between oocytes and CC. PMID- 29233208 TI - Training early childcare providers in evidence-based nutrition strategies can help improve nutrition policies and practices of early childcare centres serving racially and ethnically diverse children from low-income families. AB - OBJECTIVE: We evaluated the extent to which providing training and technical assistance to early childcare centre (ECC) directors, faculty and staff in the implementation of evidence-based nutrition strategies improved the nutrition contexts, policies and practices of ECC serving racially and ethnically diverse, low-income children in Broward County, Florida, USA. The nutrition strategies targeted snack and beverage policies and practices, consistent with Caring for Our Children National Standards. DESIGN: We used the nutrition observation and document review portions of the Environment and Policy Assessment and Observation (EPAO) instrument to observe ECC as part of a one-group pre-test/post-test evaluation design. SETTING: ECC located within areas of high rates of poverty, diabetes, minority representation and unhealthy food index in Broward County, Florida, USA. SUBJECTS: Eighteen ECC enrolled, mean 112.9 (sd 53.4) children aged 2-5 years; 12.3 (sd 7.2) staff members; and 10.2 (sd 4.6) children per staff member at each centre. RESULTS: We found significant improvements in centres' overall nutrition contexts, as measured by total EPAO nutrition scores (P=0.01). ECC made specific significant gains within written nutrition policies (P=0.03) and nutrition training and education (P=0.01). CONCLUSIONS: Our findings support training ECC directors, faculty and staff in evidence-based nutrition strategies to improve the nutrition policies and practices of ECC serving racially and ethnically diverse children from low-income families. The intervention resulted in improvements in some nutrition policies and practices, but not others. There remains a need to further develop the evaluation base involving the effectiveness of policy and practice interventions within ECC serving children in high-need areas. PMID- 29233209 TI - Rapid regression of large cardiac rhabdomyomas in neonates after sirolimus therapy. AB - Cardiac rhabdomyomas are the most common tumours in children and are typically seen in association with the tuberous sclerosis complex. Although benign and often associated with spontaneous regression, in rare circumstances surgical resection is indicated to relieve obstruction or other mass-related effects. Recent clinical trials have demonstrated the benefits of mammalian target of rapamycin inhibitors for the treatment of other tumour sub-types associated with tuberous sclerosis. Here we report rapid regression of several massive cardiac rhadomyomas in two neonates with the use of the mammalian target of rapamycin inhibitor sirolimus. PMID- 29233210 TI - Optical coherence tomography indices of structural retinal pathology in schizophrenia. AB - BACKGROUND: Prior optical coherence tomography (OCT) studies of schizophrenia have identified thinning of retinal layers. However, findings have varied across reports, and most studies have had serious methodological limitations. To address unresolved issues, we determined whether: (1) retinal thinning in schizophrenia occurs independently of comorbid medical conditions that affect the retina; (2) thinning is independent of antipsychotic medication dose; (3) optic nerve parameters are abnormal in schizophrenia; and (4) OCT indices are related to visual and cognitive impairments common in schizophrenia. METHODS: A total of 32 people with schizophrenia and 32 matched controls participated. Spectral domain OCT generated data on retinal nerve fiber layer (RNFL), macula, and ganglion cell inner plexiform layer (GCL-IPL) thickness, in addition to cup volume and the cup to-disc ratio at the optic nerve head. Subjects with schizophrenia also completed measures of symptoms, visual processing, and IQ. RESULTS: The groups did not differ on RNFL, macula, or GCL-IPL thickness. However, thinning of these layers was related to the presence of diabetes or hypertension across the sample as a whole. The schizophrenia group demonstrated enlarged cup volume and an enlarged cup-to-disc ratio in both eyes, which were unrelated to medical comorbidity, but were related to increased cognitive symptoms. CONCLUSIONS: Past reports of retinal thinning may be artifacts of medical comorbidity that is over-represented in schizophrenia, or other confounds. However, optic nerve head abnormalities may hold promise as biomarkers of central nervous system abnormality, including cognitive decline, in schizophrenia. PMID- 29233211 TI - Toxicity of marine pollutants on the ascidian oocyte physiology: an electrophysiological approach. AB - In marine animals with external fertilization, gametes are released into seawater where fertilization and embryo development occur. Consequently, pollutants introduced into the marine environment by human activities may affect gametes and embryos. These xenobiotics can alter cell physiology with consequent reduction of fertilization success. Here the adverse effects on the reproductive processes of the marine invertebrate Ciona intestinalis (ascidian) of different xenobiotics: lead, zinc, an organic tin compound and a phenylurea herbicide were evaluated. By using the electrophysiological technique of whole-cell voltage clamping, the effects of these compounds on the mature oocyte plasma membrane electrical properties and the electrical events of fertilization were tested by calculating the concentration that induced 50% normal larval formation (EC50). The results demonstrated that sodium currents in mature oocytes were reduced in a concentration-dependent manner by all tested xenobiotics, with the lowest EC50 value for lead. In contrast, fertilization current frequencies were differently affected by zinc and organic tin compound. Toxicity tests on gametes demonstrated that sperm fertilizing capability and fertilization oocyte competence were not altered by xenobiotics, whereas fertilization was inhibited in zinc solution and underwent a reduction in organic tin compound solution (EC50 value of 1.7 uM). Furthermore, fertilized oocytes resulted in a low percentage of normal larvae with an EC50 value of 0.90 uM. This study shows that reproductive processes of ascidians are highly sensitive to xenobiotics suggesting that they may be considered a reliable biomarker and that ascidians are suitable model organisms to assess marine environmental quality. PMID- 29233212 TI - Percutaneous closure of a large patent ductus arteriosus in a preterm newborn weighing 1400 g without using arterial sheath: an innovative technique. AB - Percutaneous closure of patent ductus arteriosus is well established in infants weighing >5 kg, but data regarding outcome of preterm especially very low birth weight infants is minimal. Although surgical ligation of patent ductus arteriosus is the preferred and well-accepted modality of treatment after failure of drug therapy in preterm infants, it has also got its own demerits in such a small and fragile subset. Device closure in infants weighing <1.5 kg is rarely attempted because of high chances of complications, especially acute arterial injury due to the arterial sheath. We received a 1.4-kg ventilator-dependent infant for closure of large patent ductus arteriosus. Percutaneous closure of patent ductus arteriosus was done successfully and the infant was discharged on room air with a weight of 1.8 kg. We present here an innovative technique in which successful patent ductus arteriosus device closure was done in a 1.4-kg infant without using arterial sheath. PMID- 29233213 TI - Transcatheter closure of congenital perimembranous ventricular septal defect using the Amplatzer duct occluder 2. AB - OBJECTIVE: The objective of this study was to explore the clinical effect of the transcatheter closure of congenital perimembranous ventricular septal defect using the Amplatzer duct occluder 2. METHODS: Between February 2012 and December 2016, 51 patients were subjected to Amplatzer duct occluder 2 for transcatheter closure of perimembranous ventricular septal defect. A total of 51 patients with perimembranous ventricular septal defect who underwent transcatheter closure by the conventional membranous ventricular septal occluder comprised the control group. The success rate and complications were compared, and indications of Amplatzer duct occluder 2 for perimembranous ventricular septal defect were explored. RESULTS: The success rate of the interventional procedure was 98.0% (50/51) in the group of Amplatzer duct occluder 2 versus 100% in the group of conventional membranous ventricular septal occluder. The mean age of the patients of Amplatzer duct occluder group was 5.0+/-3.7 years (range: 1.5-25.0), and the mean weight was 19.3+/-8.1 kg (range: 11.0-52.0). The mean outlet diameter of the defects was 2.8+/-0.6 mm (range: 1.8-5.1) as measured by transthoracic echocardiography. The device was implanted by a retrograde approach in 40 patients and antegrade approach in 10 patients. No statistical significance was observed in the incidence of complication and hospitalisation duration between the two groups; however, the Amplatzer duct occluder 2 group was cost-effective (p<0.05) and required less fluoroscopy time (p<0.05). Neither deaths nor new onset of aortic and tricuspid insufficiency occurred during the median 26.2 months (range: 3-65) of follow-up. CONCLUSIONS: Amplatzer duct occluder 2 has advantages of simple manipulation and less medical costs compared with conventional device in transcatheter closure of small type perimembranous ventricular septal defect. PMID- 29233214 TI - Microdroplet fusion mass spectrometry: accelerated kinetics of acid-induced chlorophyll demetallation. AB - Kinetics of acid-induced chlorophyll demetallation was recorded in microdroplets by fusing a stream of microdroplets containing 40 uM chlorophyll a or b dissolved in methanol with a stream of aqueous microdroplets containing 35 mM hydrochloric acid (pH = 1.46). The kinetics of the demetallation of chlorophyll in the fused microdroplets (14 +/- 6 um diameter; 84 +/- 18 m s-1 velocity) was recorded by controlling the traveling distance of the fused microdroplets between the fusion region and the inlet of a mass spectrometer. The rate of acid-induced chlorophyll demetallation was about 960 +/- 120 times faster in the charged microdroplets compared with that reported in bulk solution. If no voltage was applied to the sprayed microdroplets, then the acceleration factor was about 580 +/- 90, suggesting that the applied voltage is not a major factor determining the acceleration. Chlorophyll a was more rapidly demetallated than chlorophyll b by a factor of ~26 in bulk solution and ~5 in charged microdroplets. The demetallation kinetics was second order in the H+ concentration, but the acceleration factor of microdroplets compared with bulk solution appeared to be unchanged in going from pH = 1.3 to 7.0. The water:methanol ratio of the fused microdroplets was varied from 7:3 to 3:7 causing an increase in the reaction rate of chlorophyll a demetallation by 20%. This observation demonstrates that the solvent composition, which has different evaporation rates, does not significantly affect the acceleration. We believe that a major portion of the acceleration can be attributed to confinement effects involving surface reactions rather than either to evaporation of solvents or to the introduction of charges to the microdroplets. PMID- 29233215 TI - Unraveling amyloid formation paths of Parkinson's disease protein alpha-synuclein triggered by anionic vesicles. AB - Amyloid formation of the synaptic brain protein alpha-synuclein (alphaS) is related to degeneration of dopaminergic neurons in Parkinson's disease patients. alphaS is thought to function in vesicle transport and fusion and it binds strongly to negatively charged vesicles in vitro. Here we combined circular dichroism, fluorescence and imaging methods in vitro to characterize the interaction of alphaS with negatively charged vesicles of DOPS (1,2-dioleoyl-sn glycero-3-phospho-L-serine, sodium salt) and DOPG (1,2-dioleoyl-sn-glycero-3 phospho-(1'-rac-glycerol), sodium salt) and the consequences of such interactions on alphaS amyloid formation. We found that lipid head-group chemistry modulates alphaS interactions and also affects amyloid fiber formation. During the course of the experiments, we made the unexpected discovery that pre-formed alphaS oligomers, typically present in a small amount in the alphaS starting material, acted as templates for linear growth of anomalous amyloid fibers in the presence of vesicles. At the same time, the remaining alphaS monomers were restricted from vesicle-mediated nucleation of amyloid fibers. Although not a dominant process in bulk experiments, this hidden alphaS aggregation pathway may be of importance in vivo. PMID- 29233216 TI - Nucleic acids: function and potential for abiogenesis. AB - The emergence of functional cooperation between the three main classes of biomolecules - nucleic acids, peptides and lipids - defines life at the molecular level. However, how such mutually interdependent molecular systems emerged from prebiotic chemistry remains a mystery. A key hypothesis, formulated by Crick, Orgel and Woese over 40 year ago, posits that early life must have been simpler. Specifically, it proposed that an early primordial biology lacked proteins and DNA but instead relied on RNA as the key biopolymer responsible not just for genetic information storage and propagation, but also for catalysis, i.e. metabolism. Indeed, there is compelling evidence for such an 'RNA world', notably in the structure of the ribosome as a likely molecular fossil from that time. Nevertheless, one might justifiably ask whether RNA alone would be up to the task. From a purely chemical perspective, RNA is a molecule of rather uniform composition with all four bases comprising organic heterocycles of similar size and comparable polarity and pK a values. Thus, RNA molecules cover a much narrower range of steric, electronic and physicochemical properties than, e.g. the 20 amino acid side-chains of proteins. Herein we will examine the functional potential of RNA (and other nucleic acids) with respect to self-replication, catalysis and assembly into simple protocellular entities. PMID- 29233217 TI - Chromatin-remodeling for transcription. AB - The nucleosome serves as a general gene repressor, preventing all initiation of transcription except that which is brought about by specific positive regulatory mechanisms. The positive mechanisms begin with chromatin-remodeling by complexes that slide, disrupt, or otherwise alter the structure and organization of nucleosomes. RSC in yeast and its counterpart PBAF in human cells are the major remodeling complexes for transcription. RSC creates a nucleosome-free region in front of a gene, flanked by strongly positioned +1 and -1 nucleosomes, with the transcription start site typically 10-15 bp inside the border of the +1 nucleosome. RSC also binds stably to nucleosomes harboring regulatory elements and to +1 nucleosomes, perturbing their structures in a manner that partially exposes their DNA sequences. The cryo-electron microscope structure of a RSC nucleosome complex reveals such a structural perturbation, with the DNA largely unwrapped from the nucleosome and likely interacting with a positively charged surface of RSC. Such unwrapping both exposes the DNA and enables its translocation across the histone octamer of the nucleosome by an ATP-dependent activity of RSC. Genetic studies have revealed additional roles of RSC in DNA repair, chromosome segregation, and other chromosomal DNA transactions. These functions of RSC likely involve the same fundamental activities, DNA unwrapping and DNA translocation. PMID- 29233218 TI - Secondary nucleation of monomers on fibril surface dominates alpha-synuclein aggregation and provides autocatalytic amyloid amplification. AB - Parkinson's disease (PD) is characterized by proteinaceous aggregates named Lewy Bodies and Lewy Neurites containing alpha-synuclein fibrils. The underlying aggregation mechanism of this protein is dominated by a secondary process at mildly acidic pH, as in endosomes and other organelles. This effect manifests as a strong acceleration of the aggregation in the presence of seeds and a weak dependence of the aggregation rate on monomer concentration. The molecular mechanism underlying this process could be nucleation of monomers on fibril surfaces or fibril fragmentation. Here, we aim to distinguish between these mechanisms. The nature of the secondary processes was investigated using differential sedimentation analysis, trap and seed experiments, quartz crystal microbalance experiments and super-resolution microscopy. The results identify secondary nucleation of monomers on the fibril surface as the dominant secondary process leading to rapid generation of new aggregates, while no significant contribution from fragmentation was found. The newly generated oligomeric species quickly elongate to further serve as templates for secondary nucleation and this may have important implications in the spreading of PD. PMID- 29233220 TI - A new paradigm for atomically detailed simulations of kinetics in biophysical systems. AB - The kinetics of biochemical and biophysical events determined the course of life processes and attracted considerable interest and research. For example, modeling of biological networks and cellular responses relies on the availability of information on rate coefficients. Atomically detailed simulations hold the promise of supplementing experimental data to obtain a more complete kinetic picture. However, simulations at biological time scales are challenging. Typical computer resources are insufficient to provide the ensemble of trajectories at the correct length that is required for straightforward calculations of time scales. In the last years, new technologies emerged that make atomically detailed simulations of rate coefficients possible. Instead of computing complete trajectories from reactants to products, these approaches launch a large number of short trajectories at different positions. Since the trajectories are short, they are computed trivially in parallel on modern computer architecture. The starting and termination positions of the short trajectories are chosen, following statistical mechanics theory, to enhance efficiency. These trajectories are analyzed. The analysis produces accurate estimates of time scales as long as hours. The theory of Milestoning that exploits the use of short trajectories is discussed, and several applications are described. PMID- 29233221 TI - Lysozyme's lectin-like characteristics facilitates its immune defense function. AB - Interactions between human lysozyme (HL) and the lipopolysaccharide (LPS) of Klebsiella pneumoniae O1, a causative agent of lung infection, were identified by surface plasmon resonance. To characterize the molecular mechanism of this interaction, HL binding to synthetic disaccharides and tetrasaccharides representing one and two repeating units, respectively, of the O-chain of this LPS were studied. pH-dependent structural rearrangements of HL after interaction with the disaccharide were observed through nuclear magnetic resonance. The crystal structure of the HL-tetrasaccharide complex revealed carbohydrate chain packing into the A, B, C, and D binding sites of HL, which primarily occurred through residue-specific, direct or water-mediated hydrogen bonds and hydrophobic contacts. Overall, these results support a crucial role of the Glu35/Asp53/Trp63/Asp102 residues in HL binding to the tetrasaccharide. These observations suggest an unknown glycan-guided mechanism that underlies recognition of the bacterial cell wall by lysozyme and may complement the HL immune defense function. PMID- 29233222 TI - Understanding membrane-active antimicrobial peptides. AB - Bacterial membranes represent an attractive target for the design of new antibiotics to combat widespread bacterial resistance to traditional inhibitor based antibiotics. Understanding how antimicrobial peptides (AMPs) and other membrane-active agents attack membranes could facilitate the design of new, effective antimicrobials. AMPs, which are small, gene-encoded host defense proteins, offer a promising basis for the study of membrane-active antimicrobial agents. These peptides are cationic and amphipathic, spontaneously binding to bacterial membranes and inducing transmembrane permeability to small molecules. Yet there are often confusions surrounding the details of the molecular mechanisms of AMPs. Following the doctrine of structure-function relationship, AMPs are often viewed as the molecular scaffolding of pores in membranes. Instead we believe that the full mechanism of AMPs is understandable if we consider the interactions of AMPs with the whole membrane domain, where interactions induce structural transformations of the entire membrane, rather than forming localized molecular structures. We believe that it is necessary to consider the entire soft matter peptide-membrane system as it evolves through several distinct states. Accordingly, we have developed experimental techniques to investigate the state and structure of the membrane as a function of the bound peptide to lipid ratio, exactly as AMPs in solution progressively bind to the membrane and induce structural changes to the entire system. The results from these studies suggest that global interactions of AMPs with the membrane domain are of fundamental importance to understanding the antimicrobial mechanisms of AMPs. PMID- 29233223 TI - A stretched conformation of DNA with a biological role? AB - We have discovered a well-defined extended conformation of double-stranded DNA, which we call Sigma-DNA, using laser-tweezers force-spectroscopy experiments. At a transition force corresponding to free energy change DeltaG = 1.57 +/- 0.12 kcal (mol base pair)-1 60 or 122 base-pair long synthetic GC-rich sequences, when pulled by the 3'-3' strands, undergo a sharp transition to the 1.52 +/- 0.04 times longer Sigma-DNA. Intriguingly, the same degree of extension is also found in DNA complexes with recombinase proteins, such as bacterial RecA and eukaryotic Rad51. Despite vital importance to all biological organisms for survival, genome maintenance and evolution, the recombination reaction is not yet understood at atomic level. We here propose that the structural distortion represented by Sigma DNA, which is thus physically inherent to the nucleic acid, is related to how recombination proteins mediate recognition of sequence homology and execute strand exchange. Our hypothesis is that a homogeneously stretched DNA undergoes a 'disproportionation' into an inhomogeneous Sigma-form consisting of triplets of locally B-like perpendicularly stacked bases. This structure may ensure improved fidelity of base-pair recognition and promote rejection in case of mismatch during homologous recombination reaction. Because a triplet is the length of a gene codon, we speculate that the structural physics of nucleic acids may have biased the evolution of recombinase proteins to exploit triplet base stacks and also the genetic code. PMID- 29233224 TI - Ribosome structural dynamics in translocation: yet another functional role for ribosomal RNA. AB - Ribosomes are remarkable ribonucleoprotein complexes that are responsible for protein synthesis in all forms of life. They polymerize polypeptide chains programmed by nucleotide sequences in messenger RNA in a mechanism mediated by transfer RNA. One of the most challenging problems in the ribosome field is to understand the mechanism of coupled translocation of mRNA and tRNA during the elongation phase of protein synthesis. In recent years, the results of structural, biophysical and biochemical studies have provided extensive evidence that translocation is based on the structural dynamics of the ribosome itself. Detailed structural analysis has shown that ribosome dynamics, like aminoacyl tRNA selection and catalysis of peptide bond formation, is made possible by the properties of ribosomal RNA. PMID- 29233225 TI - Photosynthetic water splitting by the Mn4Ca2+OX catalyst of photosystem II: its structure, robustness and mechanism. AB - The biological energy cycle of our planet is driven by photosynthesis whereby sunlight is absorbed by chlorophyll and other accessory pigments. The excitation energy is then efficiently transferred to a reaction centre where charge separation occurs in a few picoseconds. In the case of photosystem II (PSII), the energy of the charge transfer state is used to split water into oxygen and reducing equivalents. This is accomplished by the relatively low energy content of four photons of visible light. PSII is a large multi-subunit membrane protein complex embedded in the lipid environment of the thylakoid membranes of plants, algae and cyanobacteria. Four high energy electrons, together with four protons (4H+), are used to reduce plastoquinone (PQ), the terminal electron acceptor of PSII, to plastoquinol (PQH2). PQH2 passes its reducing equivalents to an electron transfer chain which feeds into photosystem I (PSI) where they gain additional reducing potential from a second light reaction which is necessary to drive CO2 reduction. The catalytic centre of PSII consists of a cluster of four Mn ions and a Ca2+ linked by oxo bonds. In addition, there are seven amino acid ligands. In this Article, I discuss the structure of this metal cluster, its stability and the probability that an acid-base (nucleophilic-electrophilic) mechanism catalyses the water splitting reaction on the surface of the metal-cluster. Evidence for this mechanism is presented from studies on water splitting catalysts consisting of organo-complexes of ruthenium and manganese and also by comparison with the enzymology of carbon monoxide dehydrogenase (CODH). Finally the relevance of our understanding of PSII is discussed in terms of artificial photosynthesis with emphasis on inorganic water splitting catalysts as oxygen generating photoelectrodes. PMID- 29233226 TI - What can be learned about the enzyme ATPase from single-molecule studies of its subunit F1? AB - We summarize the different types of single molecule experiments on the F1 component of FOF1-ATP Synthase and what has been learned from them. We also describe results from our recent studies on interpreting the experiments using a chemical-mechanical theory for these biological motors. PMID- 29233227 TI - DNA partitions into triplets under tension in the presence of organic cations, with sequence evolutionary age predicting the stability of the triplet phase. AB - Using atomistic simulations, we show the formation of stable triplet structure when particular GC-rich DNA duplexes are extended in solution over a timescale of hundreds of nanoseconds, in the presence of organic salt. We present planar stacked triplet disproportionated DNA (Sigma DNA) as a possible solution phase of the double helix under tension, subject to sequence and the presence of stabilising co-factors. Considering the partitioning of the duplexes into triplets of base pairs as the first step of operation of recombinase enzymes like RecA, we emphasise the structure-function relationship in Sigma DNA. We supplement atomistic calculations with thermodynamic arguments to show that codons for 'phase 1' amino acids (those appearing early in evolution) are more likely than a lower entropy GC-rich sequence to form triplets under tension. We further observe that the four amino acids supposed (in the 'GADV world' hypothesis) to constitute the minimal set to produce functional globular proteins have the strongest triplet-forming propensity within the phase 1 set, showing a series of decreasing triplet propensity with evolutionary newness. The weak form of our observation provides a physical mechanism to minimise read frame and recombination alignment errors in the early evolution of the genetic code. PMID- 29233219 TI - A molecular engineering toolbox for the structural biologist. AB - Exciting new technological developments have pushed the boundaries of structural biology, and have enabled studies of biological macromolecules and assemblies that would have been unthinkable not long ago. Yet, the enhanced capabilities of structural biologists to pry into the complex molecular world have also placed new demands on the abilities of protein engineers to reproduce this complexity into the test tube. With this challenge in mind, we review the contents of the modern molecular engineering toolbox that allow the manipulation of proteins in a site-specific and chemically well-defined fashion. Thus, we cover concepts related to the modification of cysteines and other natural amino acids, native chemical ligation, intein and sortase-based approaches, amber suppression, as well as chemical and enzymatic bio-conjugation strategies. We also describe how these tools can be used to aid methodology development in X-ray crystallography, nuclear magnetic resonance, cryo-electron microscopy and in the studies of dynamic interactions. It is our hope that this monograph will inspire structural biologists and protein engineers alike to apply these tools to novel systems, and to enhance and broaden their scope to meet the outstanding challenges in understanding the molecular basis of cellular processes and disease. PMID- 29233228 TI - Disease and Non-Battle Traumatic Injuries Evaluated by Emergency Physicians in a US Tertiary Combat Hospital. AB - : Introduction Analysis of injuries during military operations has focused on those related to combat. Non-combat complaints have received less attention, despite the need for many troops to be evacuated for non-battle illnesses in Iraq. This study aims to further characterize the disease and non-battle injuries (DNBIs) seen at a tertiary combat hospital and to describe the types of procedures and medications used in the management of these cases. METHODS: In this observational study, patients were enrolled from a convenience sample with non-combat-related diseases and injuries who were evaluated in the emergency department (ED) of a US military tertiary hospital in Iraq from 2007-2008. The treating emergency physician (EP) used a data collection form to enroll patients that arrived to the ED whose injury or illness was unrelated to combat. RESULTS: Data were gathered on 1,745 patients with a median age of 30 years; 84% of patients were male and 85% were US military personnel. The most common diagnoses evaluated in the ED were abdominal disorders, orthopedic injuries, and headache. Many cases involved intravenous access, laboratory testing, and radiographic testing. Procedures performed included electrocardiogram, lumbar puncture, and intubation. CONCLUSION: Disease and non-battle traumatic injuries are common in a tertiary combat hospital. Emergency providers working in austere settings should have the diagnostic and procedural skills to evaluate and treat DNBIs. Bebarta VS , Mora AG , Ng PC , Mason PE , Muck A , Maddry JK . Disease and non-battle traumatic injuries evaluated by emergency physicians in a US tertiary combat hospital. Prehosp Disaster Med. 2018;33(1):53-57. PMID- 29233229 TI - Effects of PI3K and FSH on steroidogenesis, viability and embryo development of the cumulus-oocyte complex after in vitro culture. AB - The purpose of this study was to evaluate the effects of FSH and PI3K on the nuclear maturation, viability, steroidogenesis and embryo development of bovine cumulus-oocyte complexes (COCs). Oocyte maturation was achieved with MIV B, MIV B+100 uM LY294002, MIV B+10 ng/mL follicle stimulating hormone (FSH), or MIV B+10 ng/mL FSH+100 uM LY294002 treatments for 22-24 h. After the cultured COCs were denuded, oocytes were separated into those that extruded polar bodies (mature) and those that did not, and real-time polymerase chain reaction (PCR) for BAX, BCL2, LHR, FSHR, CYP11A1, CYP19A1 and HSD17B1 genes was performed. The culture medium was collected to determine the levels of 17beta-estradiol (E2) and progesterone (P4). The trypan blue test was used to study COC viability, and embryo development was evaluated. FSH increased nuclear maturation and PI3K blocked the maturation but did not influence oocyte viability. BAX and BCL2 expression levels in the cumulus cells were only affected by FSH, and the BAX levels decreased after treatment with LY294002. FSH increased the levels of E2 and P4, however inhibition of PI3K decreased E2 levels. MIV B enhanced levels of LHR, FSHR, CYP11A1, CYP19A1 and HSD17B1, whereas LY294002 inhibited the expression levels of all genes. MIV B+FSH decreased the expression levels of all genes except CYP11A1. LY294002 did not demonstrate any effects in the presence of FSH. Embryo development was significantly decreased when the MIV B+FSH medium was used. In conclusion, FSH controls the steroidogenesis, viability and gene expression in COCs. PI3K plays essential roles in nuclear maturation, steroidogenesis and embryo development. PMID- 29233230 TI - Priority actions for addressing the obesity epidemic in England. AB - OBJECTIVE: To prioritise policy actions for government to improve the food environment and contribute to reduced obesity and related diseases. DESIGN: Cross sectional study applying the Food Environment Policy Index (Food EPI) in two stages. First, the evidence on all relevant policies was compiled, through an Internet search of government documents, and reviewed for accuracy and completeness by government officials. Second, independent experts were brought together to identify critical gaps and prioritise actions to fill those gaps, through a two-stage rating process. SETTING: England. SUBJECTS: A total of seventy-three independent experts from forty-one organisations were involved in the exercise. RESULTS: The top priority policy actions for government identified were: (i) control the advertising of unhealthy foods to children; (ii) implement the levy on sugary drinks; (iii) reduce the sugar, fat and salt content in processed foods (leading to an energy reduction); (iv) monitor school and nursery food standards; (v) prioritise health and the environment in the 25-year Food and Farming Plan; (vi) adopt a national food action plan; (vii) monitor the food environment; (viii) apply buying standards to all public institutions; (ix) strengthen planning laws to discourage less healthy food offers; and (x) evaluate food-related programmes and policies. CONCLUSIONS: Applying the Food EPI resulted in agreement on the ten priority actions required to improve the food environment. The Food EPI has proved to be a useful tool in developing consensus for action to address the obesity epidemic among a broad group of experts in a complex legislative environment. PMID- 29233231 TI - Coronary sinus ostial atresia with persistent left superior caval vein in a patient with congenitally corrected transposition of the great arteries. AB - We present a case of a 57-year-old man with congenitally corrected transposition of great vessels who was found to have coronary ostial atresia with cranial flow through left superior vena cava on CT with contrast injection in coronary tributaries. As such, he was ineligible for cardiac resynchronization therapy. PMID- 29233232 TI - Phyllis M. Tookey Kerridge and the science of audiometric standardization in Britain. AB - The provision of standardized hearing aids is now considered to be a crucial part of the UK National Health Service. Yet this is only explicable through reference to the career of a woman who has, until now, been entirely forgotten. Dr Phyllis Margaret Tookey Kerridge (1901-1940) was an authoritative figure in a variety of fields: medicine, physiology, otology and the construction of scientific apparatus. The astounding breadth of her professional qualifications allowed her to combine features of these fields and, later in her career, to position herself as a specialist to shape the discipline of audiometry. Rather than framing Kerridge in the classic 'heroic-woman' narrative, in this article we draw out the complexities of her career by focusing on her pursuit of standardization of hearing tests. Collaboration afforded her the necessary networks to explore the intricacies of accuracy in the measurement of hearing acuity, but her influence was enhanced by her ownership of Britain's first Western Electric (pure-tone) audiometer, which she placed in a specially designed and unique 'silence room'. The room became the centre of Kerridge's hearing aid clinic that, for the first time, allowed people to access free and impartial advice on hearing aid prescription. In becoming the guardian expert and advocate of the audiometer, Kerridge achieved an objectively quantified approach to hearing loss that eventually made the latter an object of technocratic intervention. PMID- 29233233 TI - Chromosome 22q11 deletion in a patient with pulmonary atresia, intact ventricular septum, and confluent branch pulmonary arteries. AB - In this study, we report a patient with pulmonary atresia with intact ventricular septum (PA/IVS), confluent pulmonary arteries supplied by an arterial duct, and chromosome 22q11.2 microdeletion. The 22q11.2 deletion syndrome has been associated with anomalies of the outflow tracts, such as tetralogy of Fallot with either pulmonary stenosis or atresia, but we are aware of a solitary case described with pulmonary atresia when the ventricular septum is intact. The presence of genetic malformations can have long-term co-morbidities. By describing our patient, we aim to create awareness of this rare association. PMID- 29233235 TI - The Year in Review. PMID- 29233236 TI - Looking Forward in the New Year. PMID- 29233237 TI - Medical Implications of Space Radiation Exposure Due to Low-Altitude Polar Orbits. AB - INTRODUCTION: Space radiation research has progressed rapidly in recent years, but there remain large uncertainties in predicting and extrapolating biological responses to humans. Exposure to cosmic radiation and solar particle events (SPEs) may pose a critical health risk to future spaceflight crews and can have a serious impact on all biomedical aspects of space exploration. The relatively minimal shielding of the cancelled 1960s Manned Orbiting Laboratory (MOL) program's space vehicle and the high inclination polar orbits would have left the crew susceptible to high exposures of cosmic radiation and high dose-rate SPEs that are mostly unpredictable in frequency and intensity. METHODS: In this study, we have modeled the nominal and off-nominal radiation environment that a MOL-like spacecraft vehicle would be exposed to during a 30-d mission using high performance, multicore computers. RESULTS: Projected doses from a historically large SPE (e.g., the August 1972 solar event) have been analyzed in the context of the MOL orbit profile, providing an opportunity to study its impact to crew health and subsequent contingencies. DISCUSSION: It is reasonable to presume that future commercial, government, and military spaceflight missions in low-Earth orbit (LEO) will have vehicles with similar shielding and orbital profiles. Studying the impact of cosmic radiation to the mission's operational integrity and the health of MOL crewmembers provides an excellent surrogate and case-study for future commercial and military spaceflight missions.Chancellor JC, Aunon Chancellor SM, Charles J. Medical implications of space radiation exposure due to low-altitude polar orbits. Aerosp Med Hum Perform. 2018; 89(1):3-8. PMID- 29233238 TI - Neck Kinematics and Electromyography While Wearing Head Supported Mass During Running. AB - BACKGROUND: Advanced combat helmets (ACH) coupled with night-vision goggles (NVG) are required for tactical athletes during training and service. Head and neck injuries due to head supported mass (HSM) are a common occurrence in military personnel. The current study aimed to investigate the effects of HSM on neck muscle fatigue that may lead to chronic stress and injury of the head and neck. METHODS: Subjects wore an ACH and were affixed with electromagnetic sensors to obtain kinematic data, as well as EMG electrodes to obtain muscle activations of bilateral sternocleidomastoid, upper trapezius, and paraspinal muscles while running on a treadmill. Subjects performed a 2-min warmup at a walking pace, a 5 min warmup jog, running at a pace equal to 90% maximum heart rate until absolute fatigue, and lastly a 2-min cooldown at a walking pace. Kinematic and EMG data were collected over each 2-min interval. Days later, the same subjects wore the same ACH in addition to the NVG and performed the same protocol as the first session. RESULTS: This study showed significant differences in muscle activation of the right upper trapezius [F(1,31) = 10.100] and both sternocleidomastoid [F(1,31) = 12.280] muscles from pre-fatigue to absolute fatigue. There were no significant differences noted in the kinematic variables. DISCUSSION: This study suggests that HSM can fatigue bilateral neck flexors and rotators, as well as fatigue the neck extensors and rotators on the contralateral side of the mounted NVG.Hanks MM, Sefton JM, Oliver GD. Neck kinematics and electromyography while wearing head supported mass during running. Aerosp Med Hum Perform. 2018; 89(1):9 13. PMID- 29233239 TI - Perfluorocarbon in Delayed Recompression with a Mixed Gender Swine Model of Decompression Sickness. AB - INTRODUCTION: Perfluorocarbons (PFC) are fluorinated hydrocarbons that dissolve gases to a much greater degree than plasma and hold promise in treating decompression sickness (DCS). The efficacy of PFC in a mixed gender model of DCS and safety in recompression therapy has not been previously explored. METHODS: Swine (25 kg; N = 104; 51 male and 53 female) were randomized into normal saline solution (NSS) or PFC emulsion treatment groups and subjected to compression on air in a hyperbaric chamber at 200 fsw for 31 min. Then the animals were decompressed and observed for signs of DCS. Afterwards, they were treated with oxygen and either PFC (4 cc . kg-1) or NSS (4 cc . kg-1). Surviving animals were observed for 4 h, at which time they underwent recompression therapy using a standard Navy Treatment Table 6. After 24 h the animals were assessed and then euthanized. RESULTS: Survival rates were not significantly different between NSS (74.04%) and PFC (66.67%) treatment groups. All swine that received recompression treatment survived to the end of the study and no seizures were observed in either PFC or NSS animals. Within the saline treated swine group there were no significant differences in DCS survival between male (75.00%, N = 24) and female (73.08%, N = 26) swine. Within the PFC treated swine, survival of females (51.85%, N = 27) was significantly lower than males (81.48%, N = 27). DISCUSSION: In this large animal mixed gender efficacy study in DCS, PFC did not improve mortality or spinal cord injury, but appears safe during recompressive therapy. Gender differences in DCS treatment with PFC will need further study.Cronin WA, Hall AA, Auker CR, Mahon RT. Perfluorocarbon in delayed recompression with a mixed gender swine model of decompression sickness. Aerosp Med Hum Perform. 2018; 89(1):14-18. PMID- 29233240 TI - Sleep on Long Haul Layovers and Pilot Fatigue at the Start of the Next Duty Period. AB - INTRODUCTION: Layovers are critical for pilot recovery between flights and minimum layover durations are required by regulation. However, research on the factors affecting layover sleep and safety performance indicators (SPIs) before subsequent flights is relatively sparse. The present project combined data from 6 studies, including 8 long-range and 5 ultra-long range out-and-back trips across a range of different layover destinations (299 pilots in 4-person crews, 410 layovers, 1-3 d layover duration). METHODS: Sleep was monitored via actigraphy from 3 d pre-trip to at least 3 d post-trip. Pilots rated their sleepiness (Karolinska Sleepiness Scale, KSS) and fatigue (Samn-Perelli scale, SP) at duty start for the inbound flight. Mixed model ANOVAs identified independent associations between fatigue and sleepiness SPIs and operational factors (domicile time of duty start for the inbound flight in six 4-h bins, layover duration, and total sleep time (TST) in the 24 h prior to inbound duty start). RESULTS: TST was greatest on layovers ending between 1200-1559 domicile time (time in the city from which the outbound flight departed) and TST was a significant predictor of both KSS and SP ratings at duty start for the inbound flight. DISCUSSION: TST in the 24 h prior to the inbound flight was greatest when duty start time allowed for the inclusion of a full domicile night time period. In this dataset, circadian end-time of layovers is a key determinant of pilot fatigue status at the beginning of the inbound duty period.Cosgrove J, Wu LJ, van den Berg M, Signal TL, Gander PH. Sleep on long haul layovers and pilot fatigue at the start of the next duty period. Aerosp Med Hum Perform. 2018; 89(1):19-25. PMID- 29233241 TI - Protective Knee Braces and the Biomechanics of the Half-Squat Parachute Landing. AB - INTRODUCTION: Knee injuries are common among paratroopers and skydivers during landing maneuvers. The aim of this study was to investigate the effects of dropping height and the use of protective knee braces on parachute landing biomechanics. METHODS: The study cohort consisted of 30 male elite paratroopers with formal parachute landing training and more than 2 yr of parachute jumping experience. Each participant was instructed to jump off a platform at two different heights (40 and 80 cm, respectively) and land on force plates in a half squat posture. All participants tested three different knee brace conditions (no brace, elastic brace, and semi-rigid brace) at each height. RESULTS: With an increase in dropping height, peak vertical ground reaction forces (GRF), peak flexion angle, peak flexion angular displacement, peak abduction angle, peak abduction angular displacement, peak extorsion angle, and peak extorsion angular displacement of the knee joint all increased. As compared without the use of a brace, use of an elastic or semi-rigid knee brace significantly reduced peak flexion angle, peak flexion angular displacement, peak abduction angular displacement, and peak extorsion angle, while there were no significant differences in peak vertical GRF or peak extorsion angular displacement. The semi rigid brace provided the greatest restriction against peak abduction angle (3-6 degrees ). DISCUSSION: The elastic and semi-rigid knee braces both effectively restricted motion stability of the knee joint in the sagittal and coronal planes. The semi-rigid brace had a more marked effect, although the comfort of this device should be improved.Wu D, Zheng C, Wu J, Wang L, Wei X, Wang L. Protective knee braces and the biomechanics of the half-squat parachute landing. Aerosp Med Hum Perform. 2018; 89(1):26-31. PMID- 29233242 TI - Preflight, In-Flight, and Postflight Imaging of the Cervical and Lumbar Spine in Astronauts. AB - BACKGROUND: Back pain is a common complaint during spaceflight that is commonly attributed to intervertebral disc swelling in microgravity. Ultrasound (US) represents the only imaging modality on the International Space Station (ISS) to assess its etiology. The present study investigated: 1) The agreement and correlation of spinal US assessments as compared to results of pre- and postflight MRI studies; and 2) the trend in intervertebral disc characteristics over the course of spaceflight to ISS. METHODS: Seven ISS astronauts underwent pre- and postflight US examinations that included anterior disc height and anterior intervertebral angles with comparison to pre- and postflight MRI results. In-flight US images were analyzed for changes in disc height and angle. Statistical analysis included repeated measures ANOVA with Bonferroni post hoc analysis, Bland-Altman plots, and Pearson correlation. RESULTS: Bland-Altman plots revealed significant disagreement between disc heights and angles for MRI and US measurements while significant Pearson correlations were found in MRI and US measurements for lumbar disc height (r2 = 0.83) and angle (r2 = 0.89), but not for cervical disc height (r2 = 0.26) or angle (r2 = 0.02). Changes in anterior intervertebral disc angle-initially increases followed by decreases-were observed in the lumbar and cervical spine over the course of the long-duration mission. The cervical spine demonstrated a loss of total disc height during in-flight assessments (~0.5 cm). DISCUSSION: Significant disagreement but significant correlation was noted between US and MRI measurements of disc height and angle. Consistency in imaging modality is important for trending measurements and more research related to US technique is required.Harrison MF, Garcia KM, Sargsyan AE, Ebert D, Riascos-Castaneda RF, Dulchavsky SA. Preflight, in-flight, and postflight imaging of the cervical and lumbar spine in astronauts. Aerosp Med Hum Perform. 2018; 89(1):32-40. PMID- 29233243 TI - Pilot Mental Health, Negative Life Events, and Improving Safety with Peer Support and a Just Culture. AB - BACKGROUND: In the last 35 yr, 17 commercial aviation accidents and incidents, with 576 fatalities, could likely have been attributed to mental disease of a pilot. Screening tools for mental health risks in airline pilots are needed. There is growing interest in pilot peer-support programs and how to incorporate them in a just culture, meaning that pilots can report mental health complaints without a risk of job or income loss. We combined findings from aviation accidents and incidents with a search of scientific literature to provide data based recommendations for screening, peer-support, and a just culture approach to mental health problems. METHODS: Commercial aviation accidents and incidents in which a mental disorder of a pilot was thought to play a role were reviewed. Subsequently, PubMed and PsychInfo literature searches were performed on peer support programs, just culture human resource management, and the risk of negative life events on developing suicidal ideation and behavior in comparable professional groups. RESULTS: Lethal accidents were mostly related to impaired coping with negative life events. Negative life events are clearly related to suicidal thoughts, attempts, and completed suicide. A protective effect of peer support programs on mental health problems has not been established, although peer-support programs are generally appreciated by those involved. We did not find relevant literature on just culture. DISCUSSION: Negative life events are likely a useful screening tool for mental health risks. There is still a lack of evidence on how peer-support groups should be designed and how management of mental health risks can be implemented in a just culture.Mulder S, de Rooy D. Pilot mental health, negative life events, and improving safety with peer support and a just culture. Aerosp Med Hum Perform. 2018; 89(1):41-51. PMID- 29233244 TI - Modeling Predictors of Duties Not Including Flying Status. AB - INTRODUCTION: The purpose of this study was to reuse available datasets to conduct an analysis of potential predictors of U.S. Air Force aircrew nonavailability in terms of being in "duties not to include flying" (DNIF) status. METHODS: This study was a retrospective cohort analysis of U.S. Air Force aircrew on active duty during the period from 2003-2012. Predictor variables included age, Air Force Specialty Code (AFSC), clinic location, diagnosis, gender, pay grade, and service component. The response variable was DNIF duration. Nonparametric methods were used for the exploratory analysis and parametric methods were used for model building and statistical inference. RESULTS: Out of a set of 783 potential predictor variables, 339 variables were identified from the nonparametric exploratory analysis for inclusion in the parametric analysis. Of these, 54 variables had significant associations with DNIF duration in the final model fitted to the validation data set. The predicted results of this model for DNIF duration had a correlation of 0.45 with the actual number of DNIF days. Predictor variables included age, 6 AFSCs, 7 clinic locations, and 40 primary diagnosis categories. DISCUSSION: Specific demographic (i.e., age), occupational (i.e., AFSC), and health (i.e., clinic location and primary diagnosis category) DNIF drivers were identified. Subsequent research should focus on the application of primary, secondary, and tertiary prevention measures to ameliorate the potential impact of these DNIF drivers where possible.Tvaryanas AP, Griffith C Jr. Modeling predictors of duties not including flying status. Aerosp Med Hum Perform. 2018; 89(1):52-57. PMID- 29233245 TI - Occupational-Specific Strength Predicts Astronaut-Related Task Performance in a Weighted Suit. AB - BACKGROUND: Future space missions beyond low Earth orbit will require deconditioned astronauts to perform occupationally relevant tasks within a planetary spacesuit. The prediction of time-to-completion (TTC) of astronaut tasks will be critical for crew safety, autonomous operations, and mission success. This exploratory study determined if the addition of task-specific strength testing to current standard lower body testing would enhance the prediction of TTC in a 1-G test battery. METHODS: Eight healthy participants completed NASA lower body strength tests, occupationally specific strength tests, and performed six task simulations (hand drilling, construction wrenching, incline walking, collecting weighted samples, and dragging an unresponsive crewmember to safety) in a 48-kg weighted suit. The TTC for each task was recorded and summed to obtain a total TTC for the test battery. Linear regression was used to predict total TTC with two models: 1) NASA lower body strength tests; and 2) NASA lower body strength tests + occupationally specific strength tests. RESULTS: Total TTC of the test battery ranged from 20.2-44.5 min. The lower body strength test alone accounted for 61% of the variability in total TTC. The addition of hand drilling and wrenching strength tests accounted for 99% of the variability in total TTC. DISCUSSION: Adding occupationally specific strength tests (hand drilling and wrenching) to standard lower body strength tests successfully predicted total TTC in a performance test battery within a weighted suit. Future research should couple these strength tests with higher fidelity task simulations to determine the utility and efficacy of task performance prediction.Taylor A, Kotarsky CJ, Bond CW, Hackney KJ. Occupational-specific strength predicts astronaut-related task performance in a weighted suit. Aerosp Med Hum Perform. 2018; 89(1):58-62. PMID- 29233246 TI - Intraocular Lens Use in an Astronaut During Long Duration Spaceflight. AB - BACKGROUND: The purpose of this paper is to report the first use of an intraocular lens (IOL) in an astronaut during long duration spaceflight (LDSF). An astronaut developed a unilateral cataract and underwent phacoemulsification with insertion of an acrylic IOL. Approximately 15 mo later he flew on a Soyuz spacecraft to the International Space Station (ISS), where he successfully completed a 6-mo mission. CASE REPORT: Ocular examination, including ultrasound (US), was performed before, during, and after his mission and he was questioned regarding visual changes during each portion of his flight. DISCUSSION: We documented no change in IOL position during his space mission. This astronaut reported excellent and stable vision during liftoff, entry into microgravity (MG), 6 mo on the ISS, descent, and landing. Our results suggest that modern IOLs are stable, effective, and well tolerated during LDSF.Mader TH, Gibson CR, Schmid JF, Lipsky W, Sargsyan AE, Garcia K, Williams JN. Intraocular lens use in an astronaut during long duration spaceflight. Aerosp Med Hum Perform. 2018; 89(1):63-65. PMID- 29233247 TI - Pelvic Organ Prolapse in a Fighter Pilot with Alpha-1 Antitrypsin Deficiency. AB - BACKGROUND: Few researchers have studied symptomatic younger to middle-aged women with pelvic organ prolapse. The association between highly strenuous activity and prolapse symptoms is largely theoretical. It is also known that a genetic component likely contributes to early-onset pelvic organ prolapse, but prevention and treatment with respect to this has not been explored. Service restrictions differ for active duty women who are diagnosed with symptomatic pelvic organ prolapse. CASE REPORT: We present a case of a 33-yr-old Gravida 1 Para 1 fighter pilot who developed symptomatic pelvic organ prolapse after a vaginal delivery. Her prolapse symptoms initially prevented her from flying due to exacerbation of pain and pressure. Her exam demonstrated Stage III pelvic organ prolapse. She was treated with a course of physical therapy and ring with support pessary which allowed the patient to return to flight status after 5 mo. After completing the course of physical therapy, her physical exam improved to Stage II pelvic organ prolapse. A few months later, the patient reported that distracting vaginal pain recurred with the highest G forces. Coincidently, the patient was also diagnosed with pulmonary sequela of alpha-1 antitrypsin deficiency and disqualified from flight status. DISCUSSION: This case illustrates the capability of decreasing pelvic organ prolapse with conservative measures, even in extreme environments, but it also identifies a possible association between an elastase activity defect and susceptibility to pelvic organ prolapse.Buckley K, Gann J, Barbier H, Greer J. Pelvic organ prolapse in a fighter pilot with alpha-1 antitrypsin deficiency. Aerosp Med Hum Perform. 2018; 89(1):66-69. PMID- 29233248 TI - Results of AMHP Journal Survey on Open Access. AB - Day PC. Results of AMHP journal survey on Open Access. Aerospace Med Hum Perform. 2018; 89(1):70-71. PMID- 29233249 TI - You're the Flight Surgeon. AB - Kitz R. You're the flight surgeon: blepharitis. Aerosp Med Hum Perform. 2018; 89(1):72-74. PMID- 29233250 TI - You're the Flight Surgeon. AB - Mahakian CG. You're the flight surgeon: hypersensitivity pneumonitis. Aerosp Med Hum Perform. 2018; 89(1):74-77. PMID- 29233251 TI - This Month in Aerospace Medicine History. PMID- 29233252 TI - Improvement of Versatility and Analytical Range of AOAC Official Method 2015.06 for Selenium. AB - AOAC Official Method 2015.06 is not applicable for infant formula without selenium addition because of lack of sensitivity. In addition, Method 2015.06 specifies hydrogen gas as the cell gas of inductively coupled plasma (ICP)-MS instruments. There are only a few manufacturers who have formally adopted hydrogen gas. To expand the applicability of Method 2015.06 for infant formulas with lower selenium content and for ICP-MS instruments that do not use hydrogen gas as the cell gas, we modified the conditions of Method 2015.06. The results exhibited a good linearity (coefficient of determination >0.999) when the range of standard concentration was set from 0.4 to 16.0 MUg/L and the cell gas was replaced with helium gas. The measurement precision was improved to an intermediate precision RSD value of 3.49%, and the recovery factor was 103.1%. This study demonstrates that helium gas can be used as the cell gas (easing restrictions in selecting an ICP-MS instrument) and expands the applicability of this method to infant formula samples with lower selenium content by modifying the sample preparation method. PMID- 29233253 TI - Assessment of HIV molecular surveillance capacity in the European Union, 2016. AB - IntroductionExpanding access to HIV antiretroviral treatment is expected to decrease HIV incidence and acquired immunodeficiency syndrome (AIDS) mortality. However, this may also result in increased HIV drug resistance (DR). Better monitoring and surveillance of HIV DR is required to inform treatment regimens and maintain the long term effectiveness of antiretroviral drugs. As there is currently no formal European Union (EU)-wide collection of HIV DR data, this study aimed to assess the current HIV molecular surveillance capacity in EU/European Economic Area (EEA) countries in order to inform the planning of HIV DR monitoring at EU level. Methods: Thirty EU/EEA countries were invited to participate in a survey on HIV molecular surveillance capacity, which also included laboratory aspects. Results: Among 21 responding countries, 13 reported using HIV sequence data (subtype and/or DR) for surveillance purposes at national level. Of those, nine stated that clinical, epidemiological and sequence data were routinely linked for analysis. Discussion/conclusion: We identified similarities between existing HIV molecular surveillance systems, but also found important challenges including human resources, data ownership and legal issues that would need to be addressed.Information on capacities should allow better planning of the phased introduction of HIV DR surveillance at EU/EEA level. PMID- 29233254 TI - Factors associated with four atypical cases of congenital syphilis in England, 2016 to 2017: an ecological analysis. AB - Four isolated cases of congenital syphilis born to mothers who screened syphilis negative in the first trimester were identified between March 2016 and January 2017 compared with three cases between 2010 and 2015. The mothers were United Kingdom-born and had no syphilis risk factors. Cases occurred in areas with recent increases in sexually-transmitted syphilis among women and men who have sex with men, some behaviourally bisexual, which may have facilitated bridging between sexual networks. PMID- 29233255 TI - Burkholderia stabilis outbreak associated with contaminated commercially available washing gloves, Switzerland, May 2015 to August 2016. AB - We describe an outbreak of Burkholderia stabilis associated with contaminated washing gloves, a commercially available Class I medical device. Triggered by an increase in Burkholderia cepacia complex (BCC) bacteremias and the detection of BCC in unopened packages of washing gloves, an ad hoc national outbreak committee comprising representatives of a public health organisation, a regulatory agency, and an expert association convened and commissioned an outbreak investigation. The investigation included retrospective case finding across Switzerland and whole genome sequencing (WGS) of isolates from cases and gloves. The investigation revealed that BCC were detected in clinical samples of 46 cases aged 17 to 91 years (33% females) from nine institutions between May 2015 and August 2016. Twenty-two isolates from case patients and 16 from washing gloves underwent WGS. All available outbreak isolates clustered within a span of < 19 differing alleles, while 13 unrelated clinical isolates differed by > 1,500 alleles. This BCC outbreak was rapidly identified, communicated, investigated and halted by an ad hoc collaboration of multiple stakeholders. WGS served as useful tool for confirming the source of the outbreak. This outbreak also highlights current regulatory limitations regarding Class I medical devices and the usefulness of a nationally coordinated outbreak response. PMID- 29233256 TI - Analysis of OXA-204 carbapenemase-producing Enterobacteriaceae reveals possible endoscopy-associated transmission, France, 2012 to 2014. AB - OXA-48-like beta-lactamase producing bacteria are now endemic in several European and Mediterranean countries. Among this carbapenemase family, the OXA-48 and OXA 181 variants predominate, whereas other variants such as OXA-204 are rarely reported. Here, we report the molecular epidemiology of a collection of OXA-204 positive enterobacterial isolates (n = 29) recovered in France between October 2012 and May 2014. This study describes the first outbreak of OXA-204-producing Enterobacteriaceae in Europe, involving 12 isolates of an ST90 Escherichia coli clone and nine isolates of an ST147 Klebsiella pneumoniae clone. All isolates co produced the cephalosporinase CMY-4, and 60% of them co-produced the extended spectrum beta-lactamase CTX-M-15. The blaOXA-204 gene was located on a 150-kb IncA/C plasmid, isolated from various enterobacterial species in the same patient, indicating a high conjugative ability of this genetic vehicle. PMID- 29233257 TI - Investigation using whole genome sequencing of a prolonged restaurant outbreak of Salmonella Typhimurium linked to the building drainage system, England, February 2015 to March 2016. AB - Following notification of a Salmonella enterica serovar Typhimurium gastroenteritis outbreak, we identified 82 cases linked to a restaurant with symptom onset from 12 February 2015 to 8 March 2016. Seventy-two cases had an isolate matching the nationally unique whole genome sequencing profile (single nucleotide polymorphism (SNP) address: 1.1.1.124.395.395). Interviews established exposure to the restaurant and subsequent case-control analysis identified an association with eating carvery buffet food (adjusted odds ratios (AOR): 20.9; 95% confidence interval (CI): 2.2 - infinity). Environmental inspections, food/water testing, and a food trace-back investigation were inconclusive. Repeated cycles of cleaning were undertaken, including hydrogen peroxide fogging, however, transmission continued. After 7 months of investigation, environmental swabbing identified 106 isolates from kitchen surfaces and restaurant drains matching the outbreak profile. We found structural faults with the drainage system and hypothesised that a reservoir of bacteria in drain biofilm and underfloor flooded areas may have sustained this outbreak. Ineffective drain water-traps (U-bends) may have also contributed by allowing transmission of contaminated aerosols into the kitchen environment. These findings suggest that routine swabbing of sink drain points and inspection of drainage systems should be considered in future outbreak scenarios. PMID- 29233258 TI - Investigation of the perceptual thresholds of tooth whiteness. AB - OBJECTIVE: To investigate the tooth whiteness perceptibility thresholds of the average observer to changes in the CIELAB values and an optimised whiteness Index for dentistry (WIO) based on psychophysical studies. METHODS: A psychophysical experiment based on visual assessments of digital images of teeth on a calibrated display with a group of observers (n=32) has been conducted to determine the perceptual thresholds in tooth whiteness. Digital simulations of a tooth that is identical in shape to the left incisor in the image of teeth were superimposed on to images. The colour of the simulated tooth was varied and observers were asked to respond whether there was a difference in whiteness between the left incisor and the simulated tooth. Thresholds for detection of differences in whiteness were independently determined in four conditions: DeltaL*, Deltaa*, Deltab* and a blue optical whitening direction. Raw data were fitted using a non-parametric approach and thresholds of CIELAB and WIO for each conditions were calculated. RESULTS: Estimates of the threshold of the four conditions of DeltaL*, Deltaa*, Deltab* and a blue covarine optical tooth whitening direction were 1.14, 3.24, 1.11 and 1.51 respectively, with the corresponding WIO thresholds of 2.77, 6.52, 3.09 and 1.99 respectively. CONCLUSIONS: The thresholds for tooth whiteness perception in CIELAB space and WIO space were determined. The findings demonstrate that for a whitening treatment with a blue covarine optical technology, a colour change of about 2 WIO units would be noticeable. CLINICAL SIGNIFICANCE: This study gives a better understanding of the tooth whiteness perception threshold, and will help clinicians identify perceivable differences in tooth colour during matching and whitening procedures. PMID- 29233259 TI - The in vitro and in vivo reproducibility of a video-based digital imaging system for tooth colour measurement. AB - OBJECTIVES: To assess the robustness of a new custom built video-based digital imaging system (VDIS) for measuring tooth colour and whiteness under in vitro and in vivo conditions. METHODS: The VDIS imaging system was developed for tooth colour measurement and evaluated in vitro and in vivo. The in vitro validation used extracted human teeth (HT, n=14) stored in water and VITA Classical shade guide tabs (SG, n=16). These were measured by the VDIS at baseline, 5min, 2h, 1 week and 2 weeks to evaluate the system repeatability. For in vivo validation, adult volunteers (male/female, n=34) with two natural, unrestored central incisors had their teeth imaged using the VDIS at baseline, 5min and 2h (3 images each) by two different operators to evaluate time and operator effects. Between taking individual images, subjects moved from the imaging-frame to assess the effect of re-positioning on reproducibility. From the in vitro and in vivo images, the average tooth RGB values were obtained, and the CIELAB values and a tooth whiteness index WIO value were calculated. Repeatability and reproducibility of VDIS imaging system was assessed using appropriate repeated measurement analysis techniques and ANOVA. RESULTS: The measurement variations in vitro were between 1 and 2 units of DeltaWIO and the average colour differences were less than 1 DeltaE*ab unit. For the in vivo study, analysis of the CIELAB parameters and WIO showed that subject variability accounted for between 82 and 99% of the observed variability in the measurement process. The operator variability was less than 0.5% and the overall measurement error was found to be only 0.3% for WIO. Across assessment times the variability was less than 0.5%. CONCLUSIONS: The dental imaging system V-DIS was shown to be a highly reproducible means for tooth colour and whiteness measurement. CLINICAL SIGNIFICANCE: Digital imaging based techniques gives a highly reproducible approach to measuring tooth colour. PMID- 29233260 TI - Tooth whitening evaluation of blue covarine containing toothpastes. AB - OBJECTIVES: To measure the tooth whitening effects delivered immediately after brushing with silica-based toothpastes containing blue covarine in vitro and in vivo. METHODS: Salivary pellicle coated human extracted teeth were brushed with either a slurry of a toothpaste containing blue covarine (BC), a formulation containing an increased level of blue covarine (BC+) or a negative control toothpaste containing no blue covarine. The colour of the specimens were measured in vitro using either a Minolta chromameter or a VITA Easyshade spectrophotometer, before and after brushing and changes in CIELAB values and tooth Whiteness Index (WIO) values calculated. In a double-blind cross-over clinical study, subjects brushed with either BC or BC+ toothpaste and tooth colour changes were measured with a digital image analysis system. RESULTS: The in vitro studies demonstrated that toothpastes containing blue covarine gave a significantly (p<0.05) greater change in b* and WIO values than the negative control toothpaste; the BC+ toothpaste gave a significantly greater increase in b* and WIO values than the BC toothpaste, and BC+ gave a significant increase in shade change versus the negative control. Clinical results showed that BC and BC+ gave a significant reduction in b* (p<0.0001) and increase in WIO (p<0.0001) from baseline indicating significant tooth whitening had occurred. The parameter changes were significantly greater when brushing with the BC+ toothpaste than with the BC toothpaste (WIO p=0.006; b* p=0.013). CONCLUSIONS: Toothpastes containing blue covarine gave a statistically significant reduction in tooth yellowness and improvement in tooth whiteness immediately after brushing in both in vitro and clinical studies. In addition, the higher concentration blue covarine toothpaste gave statistically significant greater tooth whitening benefits than the lower concentration blue covarine toothpaste. CLINICAL SIGNIFICANCE: The silica-based toothpastes containing blue covarine evaluated in the current study gave tooth whitening benefits immediately after one brush. PMID- 29233261 TI - In vivo molecular imaging tools facilitate drug discovery. PMID- 29233262 TI - Medicinal Chemistry strategies for PET tracer discovery. AB - The detection of gamma rays, resulting from decay of positron emitting isotopes, allows exquisitely sensitive detection of probes radiolabeled with such isotopes. These probes can be designed for high affinity binding to specific molecular targets and be used as tools in the early development of drugs, particularly for neuropsychiatric disorders. Availability of novel tracers requires dedicated resources and selection assays. Many of the selection assays are similar to those used for discovery of clinical compounds, although the distribution and clearance of target specific radioligands requires different in vitro and in vivo methods and new derivatives. PMID- 29233263 TI - Discovery of PET radiopharmaceuticals at the academia-industry interface. AB - Project-specific collaborations between academia and pharmaceutical partners are a growing phenomenon within molecular imaging and in particular in the positron emission tomography (PET) radiopharmaceutical community. This cultural shift can be attributed in part to decreased public funding in academia in conjunction with the increased reliance on outsourcing of chemistry, radiochemistry, pharmacology and molecular imaging studies by the pharmaceutical industry. This account highlights some of our personal experiences working with industrial partners to develop new PET radiochemistry methodologies for drug discovery and neuro-PET research studies. These symbiotic academic-industrial partnerships have not only led to novel radiotracers for new targets but also to the application of new carbon-11 and fluorine-18 labeling methodologies and technologies to label previously unprecedented compounds for in vivo evaluations. PMID- 29233264 TI - Imaging the glutamate receptor subtypes-Much achieved, and still much to do. AB - Functional imaging of glutamate receptors using PET imaging modality can be used to study numerous CNS disorders and also to select appropriate doses of clinically relevant glutamate-receptor-targeting candidate drugs. Great strides have been made in developing PET imaging probes for the non-invasive detection of glutamate receptors in the brain. This review highlights recent progress made towards the development of glutamatergic PET imaging agents. Focus is placed on PET imaging probes that have been labelled with either carbon-11 or fluorine-18. PMID- 29233265 TI - Use of carbon-11 labelled tool compounds in support of drug development. AB - The pharmaceutical industry is facing key challenges to improve return on R&D investment. Positron emission tomography (PET), by itself or in combination with complementary technologies such as magnetic resonance imaging (MRI), provides a unique opportunity to confirm a candidate's ability to meet the so-called 'three pillars' of drug development. Positive confirmation provides confidence for go/no go decision making at an early stage of the development process and enables informed clinical progression. Whereas fluorine-18 has probably gained wider use in the community, there are benefits to using carbon-11 given the greater flexibility the use of this isotope permits in adaptive clinical study design. This review explores the scope of available carbon-11 chemistries and provides clinical examples to highlight its value in PET studies in support of drug development. PMID- 29233266 TI - Inflammation and DNA damage: Probing pathways to cancer and neurodegeneration. AB - Cancer and neurodegeneration represent two opposite ends of the biological spectrum but contain many common biological mechanisms. Two such mechanisms include the elevated levels of oxidative stress and DNA damage. In this brief review, we describe current approaches for imaging these biological pathways with the molecular imaging technique, Positron Emission Tomography (PET), and the potential of PET imaging studies to measure the efficacy of anticancer drugs and strategies for delaying the progression of neurodegenerative disorders. PMID- 29233267 TI - Discovery and development of SV2A PET tracers: Potential for imaging synaptic density and clinical applications. AB - Imaging synaptic density in vivo has promise for numerous research and clinical applications in the diagnosis and treatment monitoring of neurodegenerative and psychiatric diseases. Recent developments in the field of PET, such as SV2A human imaging with the novel tracers UCB-A, UCB-H and UCB-J, may help in realizing this potential and bring significant benefit for the patients suffering from these diseases. This review provides an overview of the most recent progress in the field of SV2A PET imaging, its potential for use as a biomarker of synaptic density and the future development areas. PMID- 29233268 TI - School is a game: Faculty set the rules. AB - Some students often exhibit less-than-ideal learning behaviors such as cramming for exams, focusing on memorization versus comprehension, multi-tasking during class, etc. One approach to understanding and addressing these issues is through a "school as game" mental model. Success in the "game of school", especially in rigorous professional and graduate programs, requires not only knowledge and skill, but also strategy. Because of time demands, students must often make strategic decisions regarding class attendance, attention, study time, and study methods. This commentary describes a mental model in which faculty can examine student learning behaviors within the context of their teaching and assessment criteria. Instructors should consider how both the written and unwritten rules of their courses may actually incentivize undesirable student learning behaviors. PMID- 29233269 TI - Transitioning from pharmacy practice into administration. AB - Transitioning from a pharmacy practice faculty member into an administrator will offer new challenges you have never faced in your career. Whether you are currently considering a transition in your career or have recently made such a transition, many questions will come up along the way. Through this commentary, I offer some advice from my own personal trials and errors as I continue on my administrative journey, and I hope this will help you in yours. PMID- 29233270 TI - On being a successful clinician educator: Lessons learned to share with new practitioners. AB - This article discusses lessons learned by a pharmacy clinician-educator during the early stage of her career in academia. In particular, the importance of establishing good mentoring relationships is highlighted as is the need for flexibility, board certification, publications, and loyalty to one's institution. The purpose of this article is to provide new clinician-educators with specific action steps - i.e. principles for success, to combine with self-motivation in order to promote longevity in academia and a sense of personal fulfillment and accomplishment. PMID- 29233271 TI - Know your medicine: A novel student-led community service learning program. AB - INTRODUCTION: The objective of this article is to describe the efforts of the student pharmacist organization called Know Your Medicine (KYM) as they conduct medication therapy management (MTM) for older adults and underserved communities. METHODS: Patients brought medications, immunization records, and health concerns to KYM events during academic years 2012-2013 and 2013-2014. Student pharmacists performed health screenings, created personalized medication records (PMR), made recommendations, created personal action plans (PAP), and conducted follow-up phone calls. RESULTS: Student pharmacists provided MTM services for a total of 107 patients. The mean duration of a KYM appointment was 62+/-21min, and student pharmacists provided a mean of 3.5+/-2.1 recommendations per patient. Patients had a mean age of 78+/-11 years, 4.5+/-3.2 disease states, 6.9+/-4.6 prescriptions, 1.9+/-1.9 OTC medications, and 2.8+/-2.6 vitamins or herbals. At the time of the follow-up phone call, a mean of 2.6+/-1.9 recommendations per patient had been followed. DISCUSSION AND CONCLUSIONS: Student pharmacists successfully implemented a new MTM program for older adults and underserved communities. This program can serve as an example of how other pharmacy colleges and schools might implement MTM training and real-world MTM experience for their student pharmacists. PMID- 29233272 TI - Stakeholders' perceptions on competency and assessment program of entry-level pharmacists in developing countries. AB - OBJECTIVES: To assess the stakeholders' perceptions on the competency of entry level pharmacists and the use of written licensure examination as the primary assessment for licensure decisions on entry-level pharmacists who have completed the Pharmacy Internship Program1 (PIP) in developing countries. METHOD: A cross sectional survey was conducted among stakeholders in which they completed a web based 21-item pre-tested questionnaire to determine their views regarding the competency outcomes and assessment program for entry-level pharmacist. RESULTS: The stakeholders rated the entry-level pharmacists to possess all competencies except research skills. Stakeholders suggested improvement of the program by defining the competency framework and training preceptors. However, stakeholders disagree on using written examination as the primary assessment for licensure decision and suggested the incorporation of other performance-based assessments like preceptor's assessment reports. CONCLUSION: Stakeholders are uncertain on entry-level pharmacists in developing countries possessing adequate research competencies and think their assessment program for licensure need more than written examination to assess all required competencies. PMID- 29233273 TI - A qualitative analysis of student-written law and ethics cases: A snapshot of PY2 student experience. AB - INTRODUCTION: This study was designed to better understand pharmacy students' experiences and recognition of legal and ethical tensions existing in pharmacy practice as demonstrated in student-written law and ethics cases. METHODS: A qualitative analysis of 132 student-written cases representing the team efforts of 1053 students over a 12-year time period was conducted. Student-written cases were coded and analyzed thematically. RESULTS: Our results demonstrate the types of ethical and legal issues our students have experienced in pharmacy practice during the first five quarters of their professional education. Our data highlight three themes: 1) ethical dilemmas presented when the law is misapplied; 2) ethical dilemmas presented when an institutional policy or law was viewed as insufficient; and 3) ethical dilemmas presented as provider distress. The third theme was further subdivided into five subthemes. CONCLUSION: The themes that emerged from this study represent some of the ethical dilemmas that second professional year students have encountered and how these dilemmas may intersect with legal boundaries. Educators can use cases demonstrating these themes to reinforce law and ethics education in the curriculum, thus helping prepare students for pharmacy practice. This article recommends how and when to use case examples. PMID- 29233274 TI - Students' perceptions of and amount of diabetes education in Canadian schools of pharmacy. AB - OBJECTIVE: To determine the amount of diabetes content taught at Canadian schools of pharmacy, and students' perceptions of diabetes education. METHODS: Between September 23 and October 23, 2015, faculty members at each pharmacy school were asked to provide the amount of didactic, interactive, and elective hours devoted to diabetes education. These faculty members subsequently emailed an electronic web-survey to all fourth year pharmacy students to ascertain their perceptions of the amount of diabetes-related material they received and comfort level pertaining to diabetes education. RESULTS: Representatives from each pharmacy school (10/10; 100%) reported the amount of diabetes education provided at their schools (range of 18-43.5hours; mean 25.3hours). Student responses were obtained from 90% (9/10) of pharmacy schools; a total of 313/1216 (25.7%) students completed the questionnaire. The majority of pharmacy students (53.2%; 166/313) reported feeling the overall amount of diabetes content in their curriculum was just right while 46.2% (144/313) felt there was too little. 95.6% (299/313) disagreed diabetes received too much attention in the curriculum. A post-hoc analysis revealed that students who attended schools with more contact hours or a diabetes-specific elective felt more comfortable with dealing with certain diabetes patients and situations. CONCLUSIONS: Pharmacy schools vary in the amount of diabetes content taught in their curriculum. Students were split between feeling they received enough diabetes education or too little; students who received more content reported greater comfort in dealing with most diabetes patients and situations. This information is useful for pharmacy schools looking to evaluate their curricular diabetes content. PMID- 29233275 TI - Change in self-assessed comfort level of first-year pharmacy students as an alternative approach to measure teaching effectiveness and learning outcomes. AB - INTRODUCTION: Objective measures for assessing teaching effectiveness and learning outcomes in the pharmacy curriculum are needed for improving quality of instruction and faculty development. The purpose of this article is to introduce a new teaching assessment method that focuses on self-assessed change in student comfort with the topics taught rather than evaluation of the instructor and to evaluate its performance in comparison to conventional student evaluations of teaching (SET). METHODS: Six successive cohorts of first-year pharmacy students were surveyed regarding their comfort level at the beginning and end of a 10-week pharmacology course. The change in self-assessed comfort level (DeltaSACL) was interpreted as the amount of learning that occurred. This indicator was compared to ratings of a statement from SET designed to obtain the same information. RESULTS: An increasing DeltaSACL suggests an increase in learning over time. Differences were observed between DeltaSACL and corresponding results from SET, suggesting that there could be extrinsic factors influencing the results. DISCUSSION AND CONCLUSIONS: The use of DeltaSACL could provide an alternative or complementary approach to assess teaching effectiveness that focuses less on the instructor and more on the actual student learning outcomes. PMID- 29233276 TI - Comparison of long-term knowledge retention in lecture-based versus flipped team based learning course delivery. AB - OBJECTIVES: To determine whether team based learning (TBL) is superior to traditional lecture -based learning in confidence and knowledge retention one year later. DESIGN: A survey was administered 17 months after a completion of a required over-the-counter /self-care (OTC) course to two different cohorts of students. The survey assessed confidence and knowledge related to OTC topics. The lecture group had a traditional lecture based classroom experience; the intervention group experienced a TBL format throughout the entire course. ASSESSMENT: One hundred forty-seven students of 283 enrolled (51.9%) in the lecture group and 222 of 305 (72.8%) students in the TBL group participated in the knowledge assessment and survey. Demographic data including student grade point averages (GPA) and confidence were similar in both groups. Mean assessment scores (+/-SD) on OTC knowledge was significantly higher in the traditional lecture based group versus the TBL group; 62.9+/-19.3 vs. 54.9+/-15.7 (p=0.001). CONCLUSION: Although TBL is thought to improve student engagement and mastery of material, after an initial implementation of TBL, knowledge retention in the long term appears to be lower than lecture based learning. PMID- 29233277 TI - Overview of a co-curricular professional development program in a college of pharmacy. AB - The goal of a professional program at a school or college of pharmacy is to produce competent and professional pharmacy practitioners. In 2009, The American College of Clinical Pharmacy published a white paper to assist in the teaching of professionalism in schools/colleges of pharmacy to include traits such as responsibility, commitment to excellence, respect for others, honesty and integrity, and care with compassion. In February 2015, the Accreditation Council for Pharmacy Education released their updated accreditation standards (Standards 2016) which introduced the concept of co-curricular activities (Standard 12.3): experiences that complement, augment, and/or advance what is learned in the formal didactic and experiential curriculum. This article details the Professional Development Curriculum at Western University of Health Sciences (WesternU) College of Pharmacy as a potential educational model that promotes professionalism through mandating co-curricular activities for student pharmacists. PMID- 29233278 TI - Drugs of Abuse and Addiction: An integrated approach to teaching. AB - BACKGROUND AND PURPOSE: To describe the design, implementation, and student perceptions of a Drugs of Abuse and Addiction elective course utilizing an integrated teaching model. EDUCATIONAL ACTIVITY AND SETTING: Third-year pharmacy students enrolled in the two credit hour elective. Teaching methodology included didactic lecture, journal club, simulated addiction assignment with reflection, debates, external speakers, site visit to a residential drug court program and research paper with presentation. FINDINGS: A course objective survey was administered upon course completion. All students strongly agreed that having science- and clinical-based faculty members develop and deliver course content was beneficial. Additionally, all students agree to strongly agree that their research project helped them integrate and comprehend the science and practice surrounding drugs of abuse and addiction. DISCUSSION AND SUMMARY: Students enjoyed an integrated teaching approach and multiple teaching methodologies leading to increased engagement and enhancement of student learning. Course enrollment was beneficial for personalized learning, but limited student perspective. PMID- 29233279 TI - Pharmacy student engagement in the evaluation of medication documentation within an ambulatory care electronic medical record. AB - BACKGROUND AND PURPOSE: An abundance of literature supports the benefits of electronic medical records (EMR) for improving overall healthcare quality. Identifying preventative care opportunities, reducing medical and medication related errors and incorporating clinical practice guidelines are just a few attributes of EMR implementation. The goals of this study were to engage experiential pharmacy students in the assessment of medication related documentation discrepancies in a newly implemented EMR system and to provide exposure to various aspects of conducting research. EDUCATIONAL ACTIVITY AND SETTING: Pharmacy students screened patient charts over a three-month period to identify documentation discrepancies, including omissions of medications and medical problems and duplication of medications. Students conducted medication reconciliation for a total of one-hundred thirty-four patients. FINDINGS: Medication omissions were identified for 46% of patients, medical problem omissions were identified for 38% of patients, and thirty-two duplicate medications were identified. SUMMARY: Engaging pharmacy students in the quality improvement project afforded an interactive learning experience, highlighting firsthand the challenges associated with electronic documentation and the associated potential negative implications to patient care. Additionally, students gained exposure to various components of research including data collection, assessment, entry, analysis and future implications. PMID- 29233280 TI - Implementation of a longitudinal early immersion student pharmacist health system internship program. AB - PURPOSE: The initiation, implementation, and benefits of a longitudinal early immersion student pharmacist health system internship are described. EDUCATIONAL ACTIVITY: A two-year longitudinal internship experience was implemented to provide exposure into distributional operations, direct patient care activities, and health-system pharmacy administration. The intent of the program was to create an opportunity for student pharmacists to enhance the quality of their education with practical experience by immersing them early in their careers within the healthcare system. Early in their academic training the student interns were exposed to a broad range of services and programs while contributing longitudinally to the service line through quality improvement projects and distributional operations. The first year primarily focuses on distributional operations with direct patient care shadowing, while the second year targets intern involvement in hematology/oncology direct patient care activities. In this role, they are able to serve as pharmacist extenders. SUMMARY: Our comprehensive, longitudinal two-year health-system pharmacy internship program offers student pharmacists a unique early immersion experience that builds upon itself throughout their didactic training but is outside of the academic requirements. Students are exposed to distributional operations, direct patient care activities, and health system pharmacy administration prior to APPE rotations. PMID- 29233281 TI - Debate as an alternative method for medical literature evaluation. AB - BACKGROUND AND PURPOSE: To determine the student impression of utilizing a debate style journal club as an alternative approach for preceptors to teach medical literature evaluation skills to pharmacy students undergoing Advance Pharmacy Practice Experiences (APPE) in both acute care and ambulatory care. EDUCATIONAL ACTIVITY AND SETTING: Students were asked to debate on a controversial topic or two drugs with similar indications. Each side had to research supporting evidence based medicine and use literature appraisal skills to incorporate the information logically into an oral debate style format. Approximately fifteen minutes were allotted for each debate, allowing five minutes for each opening argument, three minutes for each rebuttal, and two minutes for each closing argument. Students were then asked to complete a post-debate survey using a Likert Scale to evaluate their perception of the debate style journal club. FINDINGS: Following implementation of the debate style journal club, students reported being more confident with their ability to find, compare, and retain information from primary literature with a mean of 4.1, 4.2, and 4.4 respectively on a Likert Scale. Students also reported overall enjoyment and satisfaction with a mean of 4.0. SUMMARY: Debate style journal clubs have the capability to teach pharmacy students vital literature appraisal skills, and are a well-liked alternative to the traditional style journal club. Incorporating this method improved student interest as well as increased their ability to find, compare, and retain the information gathered from primary literature. PMID- 29233282 TI - The use of debates as an active learning tool in a college of pharmacy healthcare delivery course. AB - BACKGROUND AND PURPOSE: To describe the use of debates, and to evaluate student performance and perceptions, when student debates are incorporated as an active learning tool in a required pharmacy healthcare delivery course. EDUCATIONAL ACTIVITY AND SETTING: Student live debates replaced 15% of a traditional lecture based course. Twelve healthcare controversies were debated by student teams each year. Student perception of debate utility and opinion on topics, pre- and post debate, were measured via a voluntary survey. Both peer and instructor's assessments of team performances, as well as individual student performance on the debate-based questions on course exams, contributed to course grade. FINDINGS: The average survey response rates were 76% (2014) and 86% (2015). Fifteen-54% of student respondents changed their opinion on individual debate topics due to the debates. Although exam performance on debate-based questions was no better than on lecture-based questions, respondents who found the debates useful or very useful in mastering course material increased by 19% post versus pre-debate surveys. SUMMARY: Debates are an effective active learning tool for engaging students in controversial subjects. Assessment of student performance should include student and instructor evaluations, and can be incorporated into the course grade. PMID- 29233283 TI - Criteria for evaluating global health partnerships in colleges of pharmacy and health sciences. AB - BACKGROUND AND PURPOSE: The demand for international experiences as part of education and training for healthcare providers continues to increase. As schools/colleges of pharmacy increase training opportunities in global health, there is a demand for a strategic way to evaluate opportunities. Evaluation tools can be utilized to facilitate this type of assessment. EDUCATIONAL ACTIVITY AND SETTING: The purpose of this article is to highlight two different international experiential education site evaluation tools, discuss lessons learned when applying these tools in the field, and outline steps for a college of pharmacy to create their own tool to meet institution specific needs. FINDINGS: The involvement of key stakeholders is important to developing an evaluation tool. Identification and prioritization of key criteria for assessing partnerships is essential. There are many criteria and each institution may consider a unique set of criteria, the most appropriate way to evaluate these, and who should be completing this evaluation. DISCUSSION AND SUMMARY: An evaluation tool may serve as a framework of discussion for new and existing international partnerships. The use of a global partnership evaluation tool allows for a more consistent discussion when deciding if the partnership is appropriate for both parties, helps the involved faculty know what criteria are required to be evaluated and outlines what resources should be considered. PMID- 29233284 TI - Development and evaluation of an overseas clinical rotation program for undergraduate pharmacy students in Japan. AB - BACKGROUND AND PURPOSE: Internationalization of pharmacists, as well as pharmacy students, in terms of both the knowledge to care for international patients and to have medical information literacy, is a current concern in Japan. EDUCATIONAL ACTIVITY AND SETTING: Keio University Faculty of Pharmacy has developed an elective course for pharmacy students, based on written agreements with the United States and Thailand that establish a student clinical rotation exchange program. The exchange program lasts for four to six weeks and involves clinical rotations in hospitals abroad during the students' sixth year. Rotations follow a four-week didactic preparatory course. The course objectives are to acquire the knowledge, skills, and attitude needed to function as leading pharmacists with an international perspective. METHODS: We asked students to complete a feedback survey inquiring about the usefulness of preparatory courses, self-evaluation pre and post-rotation satisfaction with the program, and overall self-assessment. FINDINGS: Twenty-four out of 41, i.e., 58.5% of the students replied with feedback. All respondents replied that the preparatory course was useful. They also replied that, based on their self-evaluation, they were satisfied with their level of English language skill improvement after the rotation. Pharmaceutical knowledge satisfaction, however, was slightly decreased. All respondents replied that this program was of a satisfactory nature, with 71%, 63%, and 92% of the respondents replying that they could acquire the knowledge, skills, and attitude program objectives respectively. SUMMARY: It is possible to successfully develop an overseas clinical rotation program. Students were quite satisfied upon completion and achieved the expected objectives. PMID- 29233285 TI - Assessment of clinical and educational interventions that Advanced Pharmacy Practice Experience (APPE) students contributed to a family medicine residency program. AB - BACKGROUND AND PURPOSE: The literature firmly establishes that clinical interventions made by pharmacy students on Advanced Pharmacy Practice Experience (APPE) rotations contribute significantly to cost-savings realized by the hosting practice sites. The Accreditation Council for Pharmacy Education (ACPE) specifies the experiential curricula include opportunities for students to learn about, from, and with other members of the healthcare team through interprofessional education activities. EDUCATIONAL ACTIVITY: This study assesses clinical and educational interventions contributed by APPE students at a family medicine residency program to determine the extent students were engaged in the interprofessional team and physicians' receptiveness to the recommendations. FINDINGS: Student interventions made from January 2009 to September 2012 were recorded in a Microsoft Excel Spreadsheet. Data was evaluated to determine 1) the most common types of clinical and educational interventions, 2) potential associated cost-savings/avoidance, and 3) provider receptiveness to recommendations based upon acceptance rates. A standardized scheme was utilized to assign a cost savings value according to Midwest America Division of Hospital Corporation of America (HCA) clinical savings standards. Pharmacy students contributed 2868 interventions in 3.5 years. A total of 59.2% of interventions were clinical and accounted for an estimated cost savings of $55,892. The remaining 40.8% of interventions were pharmacy care activities, none were associated with a cost savings and three-fourths were considered educational. Intervention acceptance rate was over 80%, showing providers were very receptive to pharmacy students. SUMMARY: This study lends support that APPE students provide substantial clinical and educational contributions to healthcare providers and patients affiliated with family medicine residency programs. Additionally, healthcare providers and patients are very receptive to pharmacy students as members of the interprofessional team. PMID- 29233286 TI - Student pharmacists' preparedness to evaluate primary literature pre- and post Advanced Pharmacy Practice Experiences. AB - BACKGROUND AND PURPOSE: The primary objective of this study was to assess the effect of formal primary literature evaluation (PLE) during advanced pharmacy practice experiences (APPEs) on student pharmacists' preparedness and knowledge related to literature evaluation. EDUCATIONAL ACTIVITY AND SETTING: A perception of preparedness survey and knowledge assessment was given to student pharmacists pre- and post-APPEs. Student pharmacists were also asked to characterize their opportunities for formal PLE during APPEs. Literature evaluation experiences, knowledge base and preparedness data were compared between student pharmacists who completed two or more PLE on APPE and those who did not. FINDINGS: A total of 211 student pharmacists completed 529 formal PLE during their APPE experiences. Quiz grades and average perception of preparedness increased significantly from pre- to post-APPE regardless of whether student pharmacists had the opportunity for formal PLE on APPE. Student pharmacists who completed two or more PLE on APPE stated they felt more confident in evaluating primary literature after APPE, had greater post-APPE preparedness scores and a trend towards higher post-APPE quiz scores. DISCUSSION AND CONCLUSION: APPEs provide an important opportunity for student pharmacists to improve their PLE knowledge. PMID- 29233287 TI - A community-based partnership collaborative practice agreement project to teach innovation in care delivery. AB - BACKGROUND AND PURPOSE: To explore students' perceptions (self-assessment) of their preparedness to develop collaborative practice agreements (CPAs) before and after delivery of one CPA-focused classroom lectures and 2) a CPA development student project in partnership with a local community-based pharmacy. EDUCATIONAL ACTIVITY AND SETTING: A CPA-focused didactic lecture and subsequent project were given to second-year (P2) pharmacy students enrolled in a community pharmacy elective course at the University of Tennessee College of Pharmacy. Pre- and post surveys were administered using an online survey platform to assess student perceptions. Responses for each survey question were summarized using frequencies, and chi-square analysis was conducted to assess the association between pre- and post-scores on each question. FINDINGS: Students were significantly more likely to rate themselves as prepared or completely prepared to develop a CPA in a community pharmacy setting (chi2=61.21, p<0.01) after the course and project. Students also noted that they felt they were prepared or very prepared to work within a team to develop and implement a CPA in a community pharmacy setting (chi2=37.60, p<0.01). SUMMARY: This study demonstrated that a didactic classroom lecture series followed by a student project partnered with a local community pharmacy improved perceived knowledge, preparedness, and ability to implement CPAs in a community pharmacy. Through intentional exposure of students to scope-of-practice expanding opportunities like CPAs, pharmacy educators can potentially accelerate the evolution of community pharmacy practice. PMID- 29233288 TI - Student pharmacists' perceptions of immunizations. AB - PURPOSE: The primary aim of this study was to explore changes in knowledge level, perceived importance and apprehension of immunizations by first year pharmacy students pre- vs. post-immunization education and training. EDUCATIONAL ACTIVITY: First year pharmacy students at the University of California San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences (UC San Diego SSPPS) completed a pre- and post-immunization training course questionnaire. Knowledge base and perceived importance level of immunizations including hepatitis B, influenza, measles, mumps, rubella (MMR), varicella, tetanus, diphtheria, pertussis (Tdap), meningococcal and human papilloma virus (HPV) were assessed. In addition, apprehension of needle administration and fears regarding safety and efficacy were evaluated. FINDINGS: Of 120 students, 85 (71%) completed pre- and post course questionnaires for this study. Mean knowledge test scores increased from 56% pre-course to 83% post-course. Pre-course, 73% of participants considered immunizations as very important in preventing future disease outbreaks. Post course, this percentage climbed to 94%. Prior to taking the course, 52% of students were apprehensive about administering injections; however, after completing the course this percentage declined to 33%. The majority of students who had been fearful prior to the course retained their fears of receiving needle injections. The proportion of students believing immunizations should be a personal choice, not mandatory, did not significantly change from pre-course (49%) to post-course (44%). SUMMARY: The UC San Diego SSPPS immunization course increased student knowledge of immunization facts and the perceived importance of immunizations. However, a substantial portion of students retained apprehension about administering and receiving needle injections and the proportion believing immunizations should be a personal choice, almost half, did not change appreciably. PMID- 29233289 TI - The impact of participation in a Research/Writing Group on scholarly pursuits by non-tenure track clinical faculty. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the success of a faculty Research/Writing Group (RWG) by quantifying the amount of scholarly productivity from participants in the group compared with that of a matched cohort. EDUCATIONAL ACTIVITY AND SETTING: The RWG meets monthly to discuss current projects, providing an assessment of their scholarly activity. Participants offer ideas on improvement, resources and possible platforms for presentations and/or publications. FINDINGS: To evaluate the success of this model, scholarly production from the participants in the RWG was compared to a matched group of clinical non-tenure track faculty not participating in the group over a three year period. Faculty perception of RWG participation was evaluated by data collected through a survey using Qualtrics. SUMMARY: Participation in the RWG provided these junior faculty the support system to feel confident in their pursuit of scholarly activities; and therefore, they outpaced their counterparts in dissemination of their research. PMID- 29233290 TI - An evaluation of the opportunities for collaborative practice occurring in and the impact of interprofessional education on advanced pharmacy practice experiences. AB - BACKGROUND: To evaluate the impact of interprofessional (IP) education (IPE) programs during the first three years of a four-year doctor of pharmacy program on student preparedness and ability to function as a collaborative team member and to garner student feedback on collaboration experienced during the Advanced Pharmacy Practice Experiences (APPEs). INTERPROFESSIONAL EDUCATION ACTIVITY: Likert scale based statements and open-ended questions were added to the student course evaluations for the APPEs for two graduating classes of students. Quantitative data were analyzed using SPSS (repeated measures ANOVA and MANOVA). Thematic analysis by three reviewers reaching consensus was used to evaluate the qualitative data. Students reported being well prepared for IP collaboration (average ratings ranged from a mean of 3.37-3.46 on a scale of 1-4; 1=not at all prepared and 4=very well prepared). On average, students spent 26-50% of their time working with colleagues from other healthcare professions. In describing their preparedness for IP collaboration, the IP core competency of teams/teamwork was addressed in 50% of the submitted responses. The competencies of values/ethics, roles/responsibilities and IP communication were addressed by 2%, 20% and 28% of the written responses, respectively. DISCUSSION: Required longitudinal IP programs in the first three years of the pharmacy curriculum contribute to the students' perceived preparedness for collaborative practice during their APPEs. Developing practice sites to increase the opportunities for students to practice collaboratively is key. Further education of and emphasis by preceptors relative to the IPE competencies is desired. PMID- 29233291 TI - Impact of a fictional reading intervention on empathy development in student pharmacists. AB - OBJECTIVE: Determine the impact of a short longitudinal literary fiction intervention on empathy development in student pharmacists as measured by the Jefferson Scale of Empathy - Health Profession Students (JSE-HPS) version. METHODS: Twenty-one student pharmacists were randomized to an intervention consisting of reading short excerpts of literary fiction over eight weeks (n=11) or a control group not participating in the intervention (n=10). Both groups completed the JSE-HPS at baseline and completion of the literary intervention. Categorical data were compared using a chi-square or Fisher's exact test, and continuous data were compared using paired or independent t-tests for within and across group comparisons respectively. RESULTS: JSE-HPS scores increased in the intervention group (112.1+/-10.7 to 116.1+/-7.4; p=0.201) while they decreased in the control group (118.7+/-12.6 to 113.0+/-15.9; p=0.188). Changes across groups were not statistically significant (p=0.061). CONCLUSIONS: Students randomized to an eight-week literature intervention demonstrated a non-statistically significant increase in empathy as measured by the JSE-HPS questionnaire. Similar increases were not observed in students randomized to a control group. As a result, this intervention may represent a novel way to foster empathy in student pharmacists using an intervention requiring few resources. Further research is needed with larger sample sizes, ideally across multiple institutions, in order to validate the effectiveness of this intervention. PMID- 29233292 TI - Geriatric care curriculum in US PharmD programs: What's happening? AB - OBJECTIVES: Current Accreditation Council for Pharmacy Education (ACPE) Standards are not explicit regarding geriatrics content. The objective of this review is to describe published examples of how care for older adults is integrated into Doctor of Pharmacy (PharmD) curricula at accredited schools/colleges of pharmacy across the United States. METHODS: PubMed and Embase databases were searched. Manuscripts addressing care for older adults in pharmacy curriculum in the United States were included in the review. RESULTS: Thirteen PharmD programs have thirteen published examples of how geriatric care was integrated into their curriculum. The most common way geriatric care is integrated into PharmD programs is through Introductory Pharmacy Practice Experiences (IPPE) followed by existing course content and elective course content. CONCLUSION: There is a wide variety of curriculum strategies currently being utilized to incorporate geriatric education into PharmD programs in the United States. However, this may not be sufficient to support the care of the growing older adult population. PMID- 29233293 TI - Protein-Protein Interactions. PMID- 29233294 TI - The Keap1-Nrf2 protein-protein interaction: A suitable target for small molecules. AB - The transcription factor Nrf2 controls pathways involved in oxidative-stress defense and is a potential pharmacological target for the treatment of chronic diseases. Activators of Nrf2 that have undergone clinical development are reactive molecules that are either associated with safety issues or for which it is unclear if their pharmacological efficacy depends on the activation of Nrf2. Therefore, the clinical validity of Nrf2 activation is not yet proven. The activity of Nrf2 is inhibited by Keap1 via a protein-protein interaction. Its structural characteristics allowed the identification of reversible small molecule inhibitors of the Keap1-Nrf2 interaction that can hopefully elucidate the therapeutic potential of Nrf2 activation. PMID- 29233295 TI - Novel approaches to targeting BRD4. AB - Inhibition of bromo and extra-terminal (BET) bromodomains, including BRD4, has emerged as a new exciting epigenetic target for oncology, in particular. Recently, novel alternatives to the traditional use of reversible small molecules have emerged, including proteolytic targeting BET agents and irreversible binding inhibitors. These alternatives to reversible inhibitors may offer some advantage and can be used as tools to further decipher the underlying biology. Supportive pre-clinical data have these novel approaches bound for clinical development in the near future. PMID- 29233296 TI - Protein-protein and protein-chromatin interactions of LEDGF/p75 as novel drug targets. AB - Lens epithelium-derived growth factor p75 (LEDGF/p75), a transcriptional co activator, plays an important role in tethering protein complexes to the chromatin. Through this tethering function LEDGF/p75 is implicated in a diverse set of human diseases including HIV infection and mixed lineage leukemia, an aggressive form of cancer with poor prognosis. Here we provide an overview of recent progress in resolving protein-protein and protein-chromatin interaction mechanisms of LEDGF/p75. This review will focus on two well-characterized domains, the PWWP domain and the integrase binding domain (IBD). The PWWP domain interacts with methylated lysine 36 in histone H3, a marker of actively transcribed genes. The IBD interacts with the IBD binding motif, available in cellular binding partners of LEDGF/p75. Each domain forms an interesting new target for drug discovery. PMID- 29233297 TI - PPI inhibitor and stabilizer development in human diseases. AB - All processes in living organisms are regulated by, or at least influenced by, protein-protein interactions (PPI). Membrane proteins play a fundamental part in this class of interactions: by providing inter-cellular communication and sensing capabilities to the cell, they lead to downstream regulation signaling events. It is therefore not surprising that PPI modulators are of keen interest when developing drug-like molecules for a range of diseases and medical conditions. However, techniques for exploiting PPIs in meaningful ways have only recently become readily available. This review is meant to provide a brief overview of applied techniques for PPI elucidation, and present various case studies of PPI exploitation ranging from early discovery efforts to now-approved market drugs. PMID- 29233298 TI - Feeding the flame for careers in academia. PMID- 29233299 TI - How a more detailed understanding of culture is needed before successful educational change can be made. AB - INTRODUCTION: The profession of pharmacy is being afforded many important opportunities, and continues to face many challenges. To successfully address these issues schools and colleges of pharmacy must have a complete understanding of their current context, which includes culture. However, little of the work on culture in pharmacy education specifically defines what these cultures are, and equally importantly how this understanding of culture can be used to make changes, improve student learning, and ultimately develop pharmacists better prepared to improve patient outcomes. PERSPECTIVE: Organizational culture has been defined in a multitude of ways in the literature. Martin's three perspectives approach, which combines integrated, differentiated, and fragmented understandings, offers one way to approach defining culture and leveraging that definition of change. Furthermore, the organizational culture profile (OCP), is one tool that can be used to identify and differentiate between Martin's three perspectives. IMPLICATIONS: Culture plays an important role in academic pharmacy, but before it can reach its highest potential in improving student outcomes, and faculty experience, it must be completely understood. Martin's approach and the OCP offer one way to achieve this objective. PMID- 29233300 TI - Pharmacy informatics: A call to action for educators, administrators, and residency directors. AB - Pharmacy informatics involves the customization and application of information technology to improve medication-related processes. It is a critical function given the recent expansion of technology and prevalence of medication use throughout healthcare. Despite the necessity for pharmacy involvement, many pharmacists and student pharmacists are unaware of how to get started in informatics. Ideally, training should start early with student pharmacists being enrolled in introductory courses taught by leaders in the field. Students especially interested in informatics can build upon their classroom experience with postgraduate year two (PGY2) residencies in several informatics-related areas. Additionally, current pharmacists can gather information from national pharmacy organizations and local information technology pharmacists to prepare for projects in the field. These approaches provide opportunities for all pharmacists to expand their knowledge and establish the basis for highly motivated pharmacists to become experts in informatics. PMID- 29233301 TI - Toolkit for US colleges/schools of pharmacy to prepare learners for careers in academia. AB - INTRODUCTION: The objective of this article is to provide an academic toolkit for use by colleges/schools of pharmacy to prepare student pharmacists/residents for academic careers. METHODS: Through the American Association of Colleges of Pharmac (AACP) Section of Pharmacy Practice, the Student Resident Engagement Task Force (SRETF) collated teaching materials used by colleges/schools of pharmacy from a previously reported national survey. The SRETF developed a toolkit for student pharmacists/residents interested in academic pharmacy. RESULTS: Eighteen institutions provided materials; five provided materials describing didactic coursework; over fifteen provided materials for an academia-focused Advanced Pharmacy Practice Experiences (APPE), while one provided materials for an APPE teaching-research elective. SRETF members created a syllabus template and sample lesson plan by integrating submitted resources. Submissions still needed to complete the toolkit include examples of curricular tracks and certificate programs. DISCUSSION AND CONCLUSIONS: Pharmacy faculty vacancies still exist in pharmacy education. Engaging student pharmacists/residents about academia pillars of teaching, scholarship and service is critical for the future success of the academy. PMID- 29233302 TI - Validation of a motivation survey tool for pharmacy students: Exploring a link to professional identity development. AB - INTRODUCTION: Self-determination theory (SDT), which describes a continuum of motivation regulators, is proposed as an appropriate framework to study pharmacy student motivation. The aim was to develop a Pharmacy Motivation Scale (Pharm-S) to determine motivation regulators in undergraduate students and explore a possible link to professional identity development. METHODS: The Pharm-S was adapted from the SDT-based, Sports Motivation Scale (SMS-II), and administered to undergraduate students in an Australian pharmacy course. Convergent validity was assessed by conducting a correlation analysis between the Pharm-S and MacLeod Clark Professional Identity Scale (MCPIS-9). RESULTS: Face, content and construct validity were established for the Pharm-S through the analysis of 327 survey responses. Factor analysis extracted four of the six theoretical subscales as proposed by SDT (variance explained: 65.7%). Support for the SDT structure was confirmed by high factor loadings in each of the subscales and acceptable reliability coefficients. Subscale correlations revealed a simplex pattern, supporting the presence of a motivation continuum, as described by SDT. A moderate positive correlation (0.64) between Pharm-S responses and the validated professional identity instrument, MCPIS-9, indicated a possible link between levels of motivation and professional identity. DISCUSSION: and conclusions: Content and structural validity and internal consistency of the Pharm-S confirmed the reliability of the Pharm-S as a valid tool to assess motivational regulators. Pharm-S and the MCPIS-9 were positively correlated, lending support to a link between motivation and professional identity. This suggests a potential role for the Pharm-S as a valid tool to measure pharmacy student professional identity development. PMID- 29233303 TI - Student perceptions of the impact and value of incorporation of reflective writing across a pharmacy curriculum. AB - INTRODUCTION: To assess student perceptions regarding the impact and value of incorporating written reflection across a pharmacy curriculum. METHODS: Throughout the first three years of the pharmacy curriculum, students use the "What, So What, Now What" format to write 18 reflections within five didactic and six experiential courses. For the 93 students in the class of 2015, individual course evaluation questions measuring perceptions of the impact of reflective writing on their achievement of curricular outcomes were analyzed. Student perceptions of reflective writing's value and impact on their professional development were obtained via a survey administered to the class of 2015 after their third professional year. RESULTS: Students identified reflection (100%) and written reflection (98%) as having some degree of importance to their professional development. However, only 42% of students felt that reflective writing had an appreciable or significant impact on their professional development. Most students indicated that reflective writing had a positive impact on their sensitivity to specific patient populations, ethical behavior, interpersonal skills, and ability to provide patient-centered, interprofessional care. CONCLUSION: This study found that most students found some value in reflective writing, felt that reflective writing positively impacted their self awareness and professional behaviors, and were able to identify benefits of the reflective writing program. PMID- 29233304 TI - Perspective of Saudi undergraduate pharmacy students on pharmacovigilance and adverse drug reaction reporting: A National Survey. AB - INTRODUCTION: The purpose of this study was to evaluate Saudi undergraduate pharmacy students' knowledge, attitude, and readiness towards pharmacovigilance and reporting of adverse drug reactions (ADRs). METHODS: A cross-sectional survey was conducted between January 15, 2016 and February 18, 2016 using a structured, validated and pilot-tested questionnaire among senior (year 4, 5, and 6) undergraduate pharmacy students enrolled at a governmental or private university/college. Students completed an online 27-item questionnaire developed using Google FormsTM. The questionnaire consisted of four sections: demographics; knowledge about pharmacovigilance and ADR reporting; attitudes towards ADR reporting; and pharmacy students' readiness towards ADR reporting. RESULTS: Two hundred and fifty-nine students completed the questionnaire. Most of the participants were females (n=174; 67.2%) and were year 4 (n=128; 49.4%) students. Out of a total possible score of seven, the mean knowledge score (SD) was 4.15 (1.1). Multiple linear regression showed that after adjusting for gender and program of study (BPharm/PharmD), year of the study was found to be an independent predictor (p=0.03) of the total knowledge score. More than half of the respondents (n=166; 64.1%) acknowledged that they do not know how to report ADRs to the relevant authorities in Saudi Arabia. The majority (n=213; 82.2%) of respondents believed that information on how to report ADRs should be taught to senior pharmacy students. PMID- 29233305 TI - Motivational interviewing education: Creation and assessment of a learning module implemented among advanced pharmacy practice students. AB - BACKGROUND AND PURPOSE: The purpose of this prospective nonrandomized study (quasi-experimental), pre-/post-intervention design was to implement and assess a formal orientation training program for Advanced Pharmacy Practice Experience (APPE) students focusing on skills related to motivational interviewing (MI). EDUCATIONAL ACTIVITY AND SETTING: Students were assessed on their knowledge, perceived ability, and perceived need to incorporate MI in practice using a pre /posttest. Ability was assessed via student-conducted patient interviews, and performance was compared to published standards. Satisfaction with the training program was reviewed using a Likert scale questionnaire. Fourteen APPE students from three colleges of pharmacy were enrolled based on pre-assigned community experience placement. Students participated in a didactic training phase consisting of on-line knowledge acquisition and assessments. A modeling phase was implemented with role-play experiences and simulated video assessments. A shadowing phase was incorporated consisting of students observing a preceptor prior to independently conducting patient interviews. Interactions were audio recorded and reviewed by a preceptor with verbal and written feedback provided twice monthly using a standardized rubric. FINDINGS: Data revealed statistically significant improvements in all categories of the pre-/posttest. MI ability results showed statistically significant improvements as well. Performance scores were higher than goal values in video simulated assessments. Overall student satisfaction with the training program was 4.3 out of 5. DISCUSSION AND CONCLUSIONS: Data suggests the training program increased students understanding and ability to perform MI in patient interviews. High quality of student performance is also suggested due to trained students' post scores being higher than goal values published by scoring manual. PMID- 29233306 TI - Integration and assessment of the situation-background-assessment-recommendation framework into a pharmacotherapy skills laboratory for interprofessional communication and documentation. AB - BACKGROUND AND PURPOSE: The situation-background-assessment-recommendation (SBAR) framework is a commonly used method to structure verbal communication in the nursing and medicine disciplines and increases the effectiveness of interprofessional communication. The purpose of this manuscript is to describe how the SBAR framework is integrated into a pharmacotherapy skills laboratory for interprofessional communication and to report on student agreement of perceived realism, preparedness, and fairness of assessment relating to simulated SBAR activities. EDUCATIONAL ACTIVITY AND SETTING: Simulated, authentic interactions with healthcare providers were incorporated into a pharmacotherapy skills laboratory using the SBAR framework. Activities culminated with a performance based assessment (PBA) exam which included verbal and written SBAR stations. Students completed a PBA exit survey reporting level of agreement with perceived realism, preparedness, and fairness of assessment related to the exam and answered open-ended questions reporting what they most and least liked. FINDINGS: After completion of the PBA exam, students reported they agreed or strongly agreed (78%) the PBA was realistic to practice. Students reported increased agreement they were prepared to verbally communicate recommendations compared to document recommendations in the written SBAR framework (64% and 52% agreed or strongly agreed, respectively). Thematic content analysis revealed students preferred to document in the SBAR format and felt it was more realistic than the subjective-objective-assessment-plan (SOAP) note format. DISCUSSION AND SUMMARY: The SBAR framework is relevant for pharmacist verbal communication and written documentation. Incorporation of the SBAR framework into a skills laboratory appears to prepare students for a PBA that was perceived as both realistic and fair. PMID- 29233307 TI - Understanding the early effects of team-based learning on student accountability and engagement using a three session TBL pilot. AB - BACKGROUND AND PURPOSE: This study examined the early effects of a team based learning (TBL) pilot, including differences in student engagement with TBL compared to lectures, and student accountability, preferences, and satisfaction with TBL. EDUCATIONAL ACTIVITY AND SETTING: Three TBL sessions were delivered in the nephrology section of pharmacotherapy and then students completed the team based learning student assessment instrument (TBL-SAI), which assesses TBL relative to lecture on three subscales (i.e., student accountability, preferences, and satisfaction). Students also completed a modified engagement instrument for a lecture and again for a TBL session. FINDINGS: All students (160) participated in the survey (100% response rate). When comparing TBL and lecture engagement, five of eight statements were statistically significantly different. In TBL, students reported the strongest agreement with statements related to contributions (i.e., contributing fair share [mean 3.97], contributing meaningfully [mean 3.96]). Using the TBL-SAI, the mean score for accountability (30.64) was higher than neutral (24) indicating a higher level of accountability with TBL. Student satisfaction with TBL was neutral (mean 26.62, neutral = 27). DISCUSSION AND CONCLUSIONS: In a three-session pilot, TBL had positive effects on engagement and accountability. Early positive effects could aid programs in building and maintaining momentum with the TBL approach while working towards outcomes that may take longer to achieve, such as changes in professionalism or teamwork. Duration of exposure and perseverance through the transition to TBL may be important in developing preferences and satisfaction. This study provides insights to programs and instructors about student perceptions and attitudes as TBL is introduced. PMID- 29233308 TI - Evaluation of students' perceptions of the Socrative application versus a traditional student response system and its impact on classroom engagement. AB - BACKGROUND AND PURPOSE: Student response systems (SRSs) or "clickers" are common tools that lecturers can implement into didactic lectures. Socrative is a convenient and free SRS application that can be downloaded on personal handheld devices and used by faculty and students. It is unknown if students prefer using this application and what advantages or disadvantages can be seen with Socrative's use. PURPOSE: To measure student preference of standard SRS methods compared to Socrative as well as the impact of Socrative use on student engagement during delivery of clinical pharmacy instruction EDUCATIONAL ACTIVITY AND SETTING: Standard SRS and Socrative incorporated lectures were presented to students during an infectious disease module. Students were given a survey at the end of the semester to determine the primary endpoint of preference for each application. The survey used a Likert scale of 1-5, with 1 = strongly disagree and 5= strongly agree. Secondary endpoints included assessing the number of questions asked, participation, and classroom time utilized. FINDINGS: A total of 114 surveys were completed and six were excluded due to discrepancies or reporting bias. A higher mean scoring for classroom facilitation of active learning (4.48 vs. 3.99, p < 0.0001) and student-reported active participation in class (4.45 vs. 3.60, p < 0.0001) was found for Socrative compared to SRSs, respectively. SUMMARY: In comparison with traditional SRS methods, students felt Socrative helped them to more actively participate in class and facilitated a better environment for asking and receiving answers to classroom questions. PMID- 29233309 TI - Incorporating the American Pharmacists Association's Delivering Medication Therapy Management services certificate program into an accelerated pharmacy curriculum. AB - BACKGROUND AND PURPOSE: To describe the incorporation of the American Pharmacists Association (APhA) Delivering Medication Therapy Management (MTM) Services program into a PharmD curriculum and to describe student perceptions of the program. EDUCATIONAL ACTIVITY AND SETTING: The program was delivered over 12 months to students on two campuses via two didactic courses in the second professional year and during the first two advanced pharmacy practice experiences in the third professional year of an accelerated school of pharmacy program. FINDINGS: Student perceptions were assessed by review of responses to the APhA MTM program evaluation survey. DISCUSSION AND SUMMARY: Incorporation of the APhA MTM program into an accelerated PharmD program required careful planning and coordination amongst faculty and course coordinators. Students perceived that the program was valuable, met their educational needs, and incorporated effective learning experiences and cases. These perceptions were reinforced by the high percentage of students who completed the program. PMID- 29233310 TI - Incorporating age-related special populations into a pharmacy skills laboratory course sequence. AB - BACKGROUND AND PURPOSE: The purpose was this study was to evaluate the incorporation of geriatric and pediatric therapeutic concepts into a pharmacy skills laboratory (PSL) course sequence. Secondary outcomes were to describe the incorporation and evaluate the assessment effectiveness of these topics. Educational activity and setting Teaching materials and assessment data from the PSL course were evaluated for inclusion of content regarding age-related special populations. FINDINGS: Materials reviewed from 205 PSL sessions held over four years demonstrated 89 (41.5%) sessions incorporated age-related topics using a variety of methods. Quiz and exam item performance was acceptable with an average difficulty index of 77.2% +/- 21.3 and 85.8% +/- 12.8, respectively. The average objective structured clinical exam (OSCE) score was also satisfactory at 83.2% +/ 3. DISCUSSION AND CONCLUSIONS: Age-related topics were included in several PSL sessions. These incorporation strategies were deemed to be effective as students performed well on written assessments and OSCEs. Additional PSL sessions were identified as potential targets for incorporating age-related special populations into future PSL offerings. PMID- 29233311 TI - Development, implementation, and evaluation of a service-learning series for pharmacy students using a public health tool. AB - BACKGROUND AND PURPOSE: The purpose of this article is to describe the utility of the Assessment, Development, Assurance: Pharmacist's Tool (ADAPT) during the design, delivery, and assessment of service-learning events by pharmacy students. EDUCATIONAL ACTIVITY AND SETTING: The ADAPT instrument was used to develop a series of five service-learning events that featured a health promotion program delivered by 19 pharmacy students and attended by over 200 senior citizens at local senior centers. Student competence was assessed prior to participating in the service-learning activities and each student completed a reflection following the event. Senior center directors evaluated both the quality of the health promotion program as well as the interaction with the sponsoring college of pharmacy. FINDINGS: Pharmacy students reported achievement of health promotion learning objectives based on self-evaluations. Responses to reflections also indicate that students gained insight to and appreciation for several of the public health essential services, which are the basis of the ADAPT instrument. Feedback from the senior center directors was consistently positive. DISCUSSION AND SUMMARY: Use of the ADAPT instrument helped to facilitate the delivery of a high-quality, comprehensive service-learning series at local senior centers that had a solid public health foundation. Colleges and schools of pharmacy should strongly consider consulting the tool prior to planning any future health promotion activities for students. PMID- 29233312 TI - Implementation of an online ethics course into a pharmacy curriculum. AB - BACKGROUND AND PURPOSE: To evaluate students' ethical reasoning skills after implementation of a series of online modules containing ethical content. EDUCATIONAL ACTIVITY AND SETTING: A four-module online ethics series was created and embedded in the learning management system of a second-year pharmacy skills lab course. The Defining Issues Test Version 2 (DIT-2) was administered before and after completion of the ethics module series. Results of the DIT-2 were used to evaluate the impact of the modules on students' ethical thinking ability. An optional written survey utilizing Likert-scale questions was administered at the end of the study to assess students' perceptions of the course. FINDINGS: A total of 134 students were enrolled in this study. After removal of voluntary exclusions and unreliable data, 107 DIT-2 tests were evaluated. The study failed to demonstrate a statistically significant increase in pre- and posttest DIT-2 scores. Student scores were higher than other pharmacy students' scores that were previously reported in the literature. Thirty-four (26.1%) students participated in the optional survey. The results demonstrated perceived value of the online ethics series, with students indicating improved understanding, confidence, and ability to consider other perspectives when dealing with medical ethical dilemmas. SUMMARY: Implementing an online ethics series into a pharmacy curriculum failed to produce statistically significant increases in ethical thinking ability as measured by the DIT-2. However, students indicated a benefit from participating in the course as evidenced by responses to a post-course survey. PMID- 29233313 TI - Pharmacy student involvement in a transition of care program. AB - BACKGROUND AND PURPOSE: Cape Fear Valley Medical Center (CFVMC) implemented a Community Paramedic Program (CPP) to improve the transition of hospitalized patients to the home setting. In this program, paramedics conduct home visits for 30 days after qualifying patients are discharged. This article describes pharmacy services provided to CPP patients by fourth-year pharmacy students on Advanced Pharmacy Practice Experiences (APPE) that assisted with home visits. EDUCATIONAL ACTIVITY AND SETTING: Students were oriented to the CPP and patient interview technique was assessed through a role-play scenario. A standardized form was created to record drug-related problems (DRP) identified and patient education provided to patients. The primary outcome describes types of DRP identified and education provided. Secondary outcomes compare the types and average number of DRP per patient identified by students as compared to the standard of care (pharmacist review of medications electronically) and trends in patients readmitted within 30 days following discharge. FINDINGS: Eleven students visited 124 patients and recorded 145 DRP. Extra/continuation of medications stopped at discharge and issues related to medication safety were the most common DRP. The most frequent type of education provided was medication use related. On average, students provided one counseling session per patient. DISCUSSION AND SUMMARY: Student involvement is an added benefit to the CPP by providing face to face education and re-assessment of medications at follow-up visits. This article summarizes a unique teaching platform utilizing students to extend care. Real world experiences in programs like the CPP provide students the opportunity to sharpen critical thinking and problem-solving skills necessary for maturing professionally. PMID- 29233314 TI - A structured mentoring program to develop junior faculty into successful co coordinators of a large multi-instructor pathophysiology course. AB - BACKGROUND AND PURPOSE: To develop and implement a system for junior clinical faculty to become successful course coordinators with the use of a mentoring program and ensure that student performance and satisfaction are maintained at a high level. EDUCATIONAL ACTIVITY AND SETTING: For five years, first-time faculty discussion group leaders in a required large (>225 students) multi-instructor pathophysiology course opted into a structured mentoring program for course coordination in the subsequent year. Program categories included course material development, exam and quiz management, discussion group management, and communication among students, faculty, and staff. FINDINGS: Mentors' previous coordination experience ranged from a few years to over a decade. Faculty participants included three second-year faculty. Each participant successfully undertook a full co-coordinator role the following year. Subsequently, each then became a lead mentor the following year for new participants. Exam quality/reliability statistics were sustained at a high level, course evaluations and student performance improved throughout the program, and all mentor/mentee reflections demonstrated a positive and impactful experience. DISCUSSION AND SUMMARY: Course coordination can be a small percentage of clinical faculty workload, yet is a significant time commitment. Pharmacy resident certificate or new faculty academy programs often do not include course coordination, which is a vital, higher level function/role. Structured mentoring early in professional career of junior faculty aids in the assumption of pedagogical leadership roles, while also developing mentoring skills of mid-level faculty. PMID- 29233315 TI - Student pharmacist experiences as inpatient psychiatry medication education group leaders during an early immersion program. AB - BACKGROUND AND PURPOSE: While research suggests that pharmacists generally hold positive attitudes toward consumers of psychiatric medications, they often feel less comfortable talking about these medications and providing services for patients with mental illness. The purpose of this program was to train second and third year student pharmacists as psychiatry medication education groups leaders and to examine resulting student self-efficacy and mental health stigma. EDUCATIONAL ACTIVITY AND SETTING: In partnership with the University of North Carolina (UNC) Eshelman School of Pharmacy, the inpatient psychiatry service at UNC Medical Center expanded weekly medication education groups with the help of trained student pharmacists. All second- and third-year student pharmacists were invited to participate. Pre/post surveys and reflection statements were collected from 13 students that received training, provided informed consent, and participated in one or more medication education groups. Data were analyzed with a mixed methods approach. FINDINGS: Student responses revealed an increase in student self-efficacy (p < 0.05), improved understanding of mental illness, and new strategies for engaging in direct patient care. DISCUSSION AND SUMMARY: Results from this study suggest that students gained an appreciation for pharmacists and the workplace while developing self-efficacy and strategies for engaging with patients with mental illness as a part of medication education groups. PMID- 29233316 TI - Pharmacy residents as primary educators within a professional pharmacy elective. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the impact of a course change from a faculty-led professional pharmacy elective to a primarily pharmacy resident-led course on student satisfaction and learning. EDUCATIONAL ACTIVITY AND SETTING: In 2014, pharmacy residents were transitioned into primary teaching roles in a drug-induced diseases elective to increase student exposure to residents and different teaching styles. Student learning roles did not change. Course evaluations and grades were compared between the resident-led year and prior year. FINDINGS: There was no significant difference between overall course grades during the resident-led year (94.2 +/- 36.6 in 2014 vs. 94.1 +/- 2.7 in 2013; p=0.975). Course evaluations were similar to the previous year and students provided favorable feedback. DISCUSSION AND SUMMARY: This pharmacy resident-led elective allowed for resident integration in to an interactive professional elective. Student satisfaction with the course remained similar to the previous year and overall course grades did not differ. PMID- 29233317 TI - Student pharmacists provide tobacco use prevention education to elementary school children: A pilot experience. AB - BACKGROUND AND PURPOSE: The purpose of this article is to describe a service learning experience involving tobacco prevention education and to measure the education's effect on the learners' knowledge of tobacco products. EDUCATIONAL ACTIVITY AND SETTING: Student pharmacists planned and presented a 40-min tobacco prevention education program using the Tar Wars curriculum to fourth and fifth grade students at three suburban elementary schools in Western Massachusetts. Mean scores on a five-question assessment given to school age children before and after the presentation were compared. A total of 206 elementary school students in ten classrooms participated. FINDINGS: The average survey score increased from 1.87 on the pre-survey to 3.72 out of a maximum of five on the post-survey (P<0.01). DISCUSSION AND SUMMARY: Student pharmacists provided tobacco prevention education to three suburban elementary schools. The children demonstrated an increase in short-term knowledge regarding tobacco use. Tobacco prevention is a unique co-curricular opportunity for student pharmacists to get involved in their community. PMID- 29233318 TI - A course for developing interprofessional skills in pre-professional honor students using humanities and media. AB - BACKGROUND AND PURPOSE: To design and implement an undergraduate honors course for pre-health professional students that develops interpersonal skills through use of a variety of humanities. EDUCATIONAL ACTIVITY AND SETTING: A three credit hour course in an honors seminar sequence was developed by pharmacy practice faculty and with input from faculty in mass communications, philosophy, applied communication studies and history. The course utilized a variety of media such as literature, film, and podcasts to foster student discussion about a variety of health-related topics. Topics included public health, stigmatization, portrayals of health care providers, patient experiences, health care ethics, aging, and death and dying. Students were assessed using pre-class assignments and reflective writings as well as a formal written and oral presentation on a selected health-related book. A quasi-experimental design was used to assess the impact of the course on desired course outcomes. FINDINGS: The first course offering was to 22 undergraduate pre-health professional honors students. Pre- and post-course surveys on students' perceptions and students' reflective writings revealed achievement of desired course outcomes. Post-course evaluations also revealed positive perceptions about the course. DISCUSSION: The design of this course provided an outlet for students to read and enjoy various forms of media, while also meeting its goal of exposing students to a variety of humanities. The course allowed students to think critically about various health care issues, and to begin to develop interpersonal skills. SUMMARY: The course could be adapted for pharmacy by developing affective domains of the Accreditation Council for Pharmacy Education (ACPE) Standards. PMID- 29233319 TI - Student perceptions of digital badges in a drug information and literature evaluation course. AB - BACKGROUND AND PURPOSE: The purpose of this article is to describe student perceptions of implementation of digital badges in a drug information and literature evaluation course. EDUCATIONAL ACTIVITY AND SETTING: Two digital badges were developed as voluntary learning opportunities. Student perceptions were obtained through pre- and post-survey instruments consisting of selected questions from the Motivated Strategies for Learning Questionnaire. FINDINGS: The response rate was 69% (106/153). At baseline, 53% of respondents agreed that digital badges could help them better understand course material. More students agreed they would share earned digital badges on LinkedIn (68%) than Facebook (19%). Most students who earned digital badges agreed that badges helped increase their confidence in course material (73%), focus on specific learning objectives (55%), look deeper into course competencies (64%), and were a useful adjunct to the traditional teaching method (82%). DISCUSSION AND SUMMARY: Digital badges were perceived by students as a positive adjunct to learning and may provide a novel mechanism for development of an electronic skills-based portfolio. PMID- 29233320 TI - The description and evaluation of virtual worlds in clinical pharmacy education in Northern Sweden. AB - BACKGROUND AND PURPOSE: The purpose of this article is to describe and evaluate the use of a three-dimensional virtual world (3DVW) in a clinical pharmacy course. EDUCATIONAL ACTIVITY AND SETTING: Students are provided with training opportunities in simulated ward rounds and patient meetings in a 3DVW. The 3DVW enables students to practice communication with patients and colleagues in a professional manner. To evaluate the course and use of the 3DVW, an online course evaluation was completed by students after they had finished the clinical pharmacy course. FINDINGS: Forty-two students completed the online course evaluation (62%). Most students (83%) reported that they could adopt the role of a clinical pharmacist in the 3DVW. Sixty percent reported that the environment felt authentic, although some noted that "it can never be quite the same as sitting next to a real person to talk". More than half of the students (66%) described the use of the 3DVW as a worthwhile exercise. The majority (93%) rated the overall quality of the course as good or very good, with 76% reporting that the pedagogical design of the course helped them with their studies. DISCUSSION AND SUMMARY: Students at Umea University valued the use of 3DVWs in clinical pharmacy teaching. However, there is a need to make the virtual environment more realistic and easier to use. The invaluable feedback gathered from students will help to improve the future use of virtual worlds in pharmacy education. PMID- 29233321 TI - Utilization of a virtual patient for advanced assessment of student performance in pain management. AB - BACKGROUND AND PURPOSE: To assess student performance and achievement of course objectives following the integration of a virtual patient case designed to promote active, patient-centered learning in a required pharmacy course. EDUCATIONAL ACTIVITY AND SETTING: DecisionSimTM (Kynectiv, Inc., Chadsford, PA), a dynamic virtual patient platform, was used to implement an interactive patient case to augment pain management material presented during a didactic session in a pharmacotherapy course. Simulation performance data were collected and analyzed. Student exam performance on pain management questions was compared to student exam performance on nearly identical questions from a prior year when a paper based case was used instead of virtual patient technology. FINDINGS: Students who performed well on the virtual patient case performed better on exam questions related to patient assessment (p = 0.0244), primary pharmacological therapy (p = 0.0001), and additional pharmacological therapy (p = 0.0001). Overall exam performance did not differ between the two groups. However, students with exposure to the virtual patient case demonstrated significantly better performance on higher level Bloom's Taxonomy questions that required them to create pharmacotherapy regimens (p=0.0005). Students in the previous year (exposed only to a paper patient case) performed better in calculating conversions of opioids for patients (p = 0.0001). SUMMARY: Virtual patient technology may enhance student performance on high-level Bloom's Taxonomy examination questions. This study adds to the current literature demonstrating the value of virtual patient technology as an active-learning strategy. PMID- 29233322 TI - Using simplistic simulations to enhance learning in a nephrology pharmacotherapeutics module. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the effect of a simplistic simulation exercise in a nephrology module on pharmacy students' learning in a three-year concentrated curriculum. EDUCATIONAL ACTIVITY AND SETTING: Second year pharmacy students participated in a two-part simulation on electrolyte imbalances and dialysis in a nephrology pharmacotherapeutics module. Students completed a seven-item anonymous survey at the end of the simulation on a five-point Likert scale to examine the effect of the simulation and their attitudes to the exercise. Additionally, exam scores were assessed at the end of the module to measure learning. FINDINGS: A total of 65 students completed the activity. Seventy-eight percent of students agreed that the simulation was a valuable learning experience and 76.9% reported that the simulations gave them real-world knowledge. Exam scores in the group who performed the simulations were higher on the assessment compared to those without the experience (p < 0.01) DISCUSSION AND SUMMARY: Participation in the simulation had positive effects on students' attitudes, learning, and exam scores. This experience was a successful active-learning method for enhancing learning in pharmacy education. PMID- 29233323 TI - Evaluation of two different poverty simulations with professional phase pharmacy students. AB - BACKGROUND AND PURPOSE: Pharmacy students will interact with patients who struggle to receive the health care they need. Since attitudes can influence behavior, exposure to these struggles may positively improve patient care. This study evaluates a group of student responses to two different interventions approximately 9 months apart. The primary objectives of this study were to: (1) identify if SPENT, an online game, could alone improve students' attitudes towards those living in poverty, (2) determine if changes imparted by SPENT were retained for nine months, and (3) identify if CAPS, a live simulation, has an additional benefit. EDUCATIONAL ACTIVITY AND SETTING: Student participants completed both the SPENT online game and the CAPS simulation. Students were asked to complete the Undergraduate Perceptions of Poverty Tracking Survey (UPPTS) before and after each simulation FINDINGS: Ninety-nine first year and second year professional phase pharmacy students completed both interventions and all surveys. The average pre-survey and post survey "scores" for the SPENT game were 133.52 and 135.54, a statistically significant improvement (p=0.046). When comparing the SPENT post "score" and the pre-survey score of CAPS (136.45) there was no significant difference (p=0.423). The average pre-survey and post survey "scores" for CAPS were 136.45 and 139.18, a statistically significant improvement (p=0.001). An analysis of the overall change showed a statistically significant improvement of 5.6667 (p<0.001). DISCUSSION: Both the online SPENT game and CAPS live simulation interventions had positive effects on the students' empathy towards people living in poverty. PMID- 29233324 TI - Development and evaluation of a continuing pharmacy education (CPE) program in thrombosis management. AB - BACKGROUND AND PURPOSE: A continuing education (CE) course in thrombosis management for pharmacists was developed through the Office of Continuing Professional Development (CPD) at the University of Toronto to address pharmacists' needs for the knowledge and skills to provide care to patients receiving anticoagulants. This article describes the development of the course as well as the evaluation designed to assess its impact on pharmacists' knowledge, attitudes, and changes in practice. EDUCATIONAL ACTIVITY AND SETTING: A three-day course was developed. Outcomes were evaluated using a feedback questionnaire, pre and post-session quizzes and semi-structured interviews conducted six months after course completion. Participant satisfaction, knowledge acquisition and perceived change in knowledge, skills and practice were evaluated. FINDINGS: Thirty-seven pharmacists enrolled in the program, 21 of whom participated in a semi-structured interview. More than 90% reported that the program exceeded their expectations. Pharmacists' knowledge in thrombosis care improved significantly after each day of the course. Participants felt the greatest benefits of the program were increases in knowledge and confidence and the opportunity to network. The case-based discussions and practical tips gained from experts and peers were highly ranked. Participants strongly agreed that they were applying what they learned in the course to clinical practice, and they provided numerous examples of how their practice changed because of the program. DISCUSSION AND SUMMARY: The development of this CE course demonstrates application of best practices in continuing education. The evaluation of the program suggests that a CE course in thrombosis improves pharmacist knowledge, confidence and ability to incorporate what was learned into practice. This course design and evaluation can serve as a model for other CE courses for pharmacists as this field continues to grow and encourages thoughtful use of theoretical principles and well-designed evaluation for continual improvement of CE. PMID- 29233325 TI - Malaysian pharmacy students' intention to provide smoking cessation counseling. AB - BACKGROUND AND PURPOSE: Malaysian National Quit Smoking Program had proposed to integrate smoking cessation counseling skills into all relevant healthcare curricula as one of its strategies to increase the number of Malaysians giving up smoking. More effective implementation of the curricula can be facilitated by further understanding the factors influencing students' intention in terms of providing smoking cessation counseling. This study, guided by Integrated Behavior Model (IBM), aimed to explore the factors which influenced pharmacy undergraduates in providing smoking cessation counseling. EDUCATIONAL ACTIVITY AND SETTING: Following the elicitation study, the IBM-guided questionnaire was developed and distributed to students from two pharmacy schools which agreed to participate, each representing public and private institutions. FINDINGS: A total of 387 pharmacy students participated yielding a 83% response rate. Multiple regression analysis revealed that all three, namely, attitude (23%), perceived norm (16%), and personal agency (16%) were significant predictors of students' intention. Further analysis revealed 'experiential attitude', a component of attitude as the strongest predictor. In other words, students who felt more comfortable had higher intention to provide smoking cessation counseling. SUMMARY: An implication of this study is that tobacco-related curricula with an emphasis to enhance students' comfort level in providing counseling would be of value for these future pharmacists in terms of their intention as well as actual provision of smoking cessation counseling through the mediation of "experiential attitude" and personal agency. PMID- 29233326 TI - Validation of learning assessments: A primer. AB - The Accreditation Council for Pharmacy Education's Standards 2016 has placed greater emphasis on validating educational assessments. In this paper, we describe validity, reliability, and validation principles, drawing attention to the conceptual change that highlights one validity with multiple evidence sources; to this end, we recommend abandoning historical (confusing) terminology associated with the term validity. Further, we describe and apply Kane's framework (scoring, generalization, extrapolation, and implications) for the process of validation, with its inferences and conclusions from varied uses of assessment instruments by different colleges and schools of pharmacy. We then offer five practical recommendations that can improve reporting of validation evidence in pharmacy education literature. We describe application of these recommendations, including examples of validation evidence in the context of pharmacy education. After reading this article, the reader should be able to understand the current concept of validation, and use a framework as they validate and communicate their own institution's learning assessments. PMID- 29233328 TI - Pharmacoeconomics education in Yemen. PMID- 29233327 TI - Appraising the role of the virtual patient for therapeutics health education. AB - BACKGROUND: Face-to-face instruction, paper-based case-studies and clinical placements remain the most commonly used teaching methods for therapeutics curricula. Presenting clinical content in a didactic manner presents challenges in engaging learners and developing their clinical reasoning skills which may be overcome by inclusion of the virtual patient (VP). Currently there is limited literature examining the use of the VP in therapeutics teaching and learning. This review aimed to determine the role of VPs in therapeutics education, specifically the impact on student experiences, performance, and clinical skills. METHODS: A search of primary literature was conducted with search terms including virtual patient, education, health, AND learning. Boolean operators were applied to include studies from health relevant fields with article titles and abstracts vetted. RESULTS: Nine of the 21 included studies were control-matched, and all but one compared VPs to traditional teaching. VPs enhanced the learning experience in all 17 studies that measured this outcome. Fourteen studies measured performance and clinical skills and 12 found VPs were beneficial, while two did not. The VP was not superior to traditional teaching in all studies, but the VP appeared beneficial to the student learning experience. Discrepancy was found between the impact of VPs on short- and long-term knowledge. IMPLICATIONS: The VP appears to enhance the student learning experience and has a role in therapeutics education, however a blended-learning (BL) approach may be required to account for individual learning styles. Additional investigation is required to clarify the efficacy of the VP, particularly as a component of BL, on longer term knowledge retention. PMID- 29233329 TI - Bedside-to-Bench and Back Again: Surgeon-Initiated Translational Research. PMID- 29233330 TI - Surgical Removal and Replacement of Chronically Implanted Transcatheter Aortic Prostheses: How I Teach It. PMID- 29233331 TI - The Society of Thoracic Surgeons Adult Cardiac Surgery Database: 2018 Update on Outcomes and Quality. AB - Through nearly 3 decades of iterative refinement, The Society of Thoracic Surgeons Adult Cardiac Surgery Database has evolved into one of the most comprehensive and respected clinical data registries in health care. It is a widely acknowledged exemplar for accurately benchmarking risk-adjusted outcomes in cardiac surgery and underpins all quality measurement and improvement activities of The Society of Thoracic Surgeons. This is the latest in a series of annual reports that outlines current national aggregate outcomes and volume trends in cardiac surgery and summarizes database-related work in quality measurement and performance improvement during the past year. PMID- 29233332 TI - Invited Commentary. PMID- 29233333 TI - Invited Commentary. PMID- 29233334 TI - Reply. PMID- 29233335 TI - Antiinflammatory Effect of Antiplatelet Therapy. PMID- 29233336 TI - Reply. PMID- 29233337 TI - Deairing in Aortic Valve Surgery. PMID- 29233338 TI - Do the EXCEL and NOBLE Trial Results Change Meta-Analysis Findings? PMID- 29233339 TI - Reply. PMID- 29233340 TI - Reply. PMID- 29233341 TI - Importance of Awareness of Type II Error. PMID- 29233342 TI - PAS-Port in Coronary Artery Bypass Grafting. PMID- 29233343 TI - Reply. PMID- 29233344 TI - Vancomycin Paste and Sternal Wound Infections. PMID- 29233345 TI - Reply. PMID- 29233346 TI - Reply. PMID- 29233347 TI - Finding Value in the National Cancer Database: The Robotic Experience. PMID- 29233348 TI - Unplanned Readmission After Lung Resection: Some Observations. PMID- 29233349 TI - Hassan Najafi, May 22, 1930-May 20, 2017. AB - Dr Hassan Najafi, an immigrant from Iran who became the 18th president of The Society of Thoracic Surgeons, died on May 20, 2017. He had also served as chair of the American Board of Thoracic Surgery and the Residency Review Committee for Thoracic Surgery, and was a founding member and first president of the Thoracic Surgery Directors Association. A superb technical surgeon, educator, and investigator, Dr Najafi led the Department of Cardiovascular and Thoracic Surgery at Rush University Medical Center for 25 years. Refined and charismatic, he was wholly devoted to his patients, family, trainees, colleagues, and our profession. PMID- 29233350 TI - Invited Commentary. PMID- 29233351 TI - Invited Commentary. PMID- 29233352 TI - Progressive Stenosis of Both Main Bronchi Associated With Recurrent Infections of a Carinal Pouch. AB - A 55-year-old woman was referred to our department with a bilateral stenosis of both main bronchi starting at the level of the carina and a blind-ended pouch originating from the carina. Differential diagnosis of diffuse narrowing of the intrathoracic central airways was excluded during the diagnostic workup. Recurrent infection of the blind-ended pouch remained a possible explanation of this unusual type of stenosis. Carinal resection and reconstruction by end-to-end anastomosis of the trachea to the right main bronchus and reimplantation of the left main bronchus to the intermediate bronchus with intraoperative extracorporeal membrane oxygen support resulted in an excellent long-term outcome. PMID- 29233353 TI - Modified Cabrol Shunt for Atrioventricular Groove Rupture After Mitral Valve Replacement. AB - Rupture of the atrioventricular (AV) groove is the Achilles' heel of mitral valve replacement, and it has been associated with high rates of mortality. Here, we report successful management of a type 1 AV groove disruption using a modified Cabrol shunt to the right atrium in a patient with a severely calcified mitral annulus. PMID- 29233354 TI - Cardiac Computed Tomography as an Imaging Modality in Coronary Anomalies. AB - Coronary artery fistulae and coronary aneurysms are rare anomalies. When they become symptomatic, they require precise anatomic information to allow for planning of the therapeutic procedure. We report a case in which both fistulae and aneurysm were present. The required information could only be obtained by electrocardiogram-gated computed tomography with reformation. This imaging modality should be considered in every case of fistula or coronary aneurysm. PMID- 29233355 TI - Thoracic Pseudoaneurysm Caused By Malignant Lymphoma. AB - We describe the case of a 69-year-old man with a thoracic pseudoaneurysm caused by a diffuse large B-cell lymphoma. He had a large mass inside the aortic arch. Five weeks later, an asymptomatic aneurysm protruding from the minor curvature of the distal aortic arch was observed. We suspected a mycotic pseudoaneurysm and performed total arch replacement with an omental pedicle flap graft. Intraoperative tissue cultures and histopathologic tests identified no bacteria, however. Eventually, a pathologic examination revealed that the structure initially suspected to be an intramural thrombus was a diffuse large B-cell lymphoma. PMID- 29233356 TI - Transcatheter Valve-in-Valve Replacement Through Apicoaortic Conduit for Aortic Bypass Valve Failure. AB - We report a case of a 69-year-old woman who required an apicoaortic bypass conduit after stenosis of a biological aortic prosthesis valve previously implanted 4 years earlier. The patient was admitted to the emergency department 8 years later with a diagnosis of congestive heart failure. Echocardiography and nuclear magnetic resonance revealed severe regurgitation of the conduit valve. Because the patient had a very high Society of Thoracic Surgeons risk score associated to an acute angle between the aorta artery and the apicoaortic conduit, we decided to perform an antegrade and direct transcatheter valve-in valve implantation on the apicoaortic valve, with a good result. PMID- 29233357 TI - Venous Cannulation for Cardiopulmonary Bypass in the Case of Anomaly of the Inferior Vena Cava. AB - Congenital anomalies of the inferior vena cava and its tributaries are quite uncommon; however, since the development of cross-sectional imaging, they have been described more frequently. Most of them are usually asymptomatic, although they can have clinical implications. We report a case of a rare anomaly of the inferior vena cava in a 54-year-old man admitted to our hospital for complicated native aortic valve endocarditis, requiring urgent surgery, and making necessary an alternative venous cannulation for establishing cardiopulmonary bypass circulation. PMID- 29233358 TI - Prosthetic Valve-on-Valve Mitral Valve Re-Replacement: A Novel Approach. AB - Repeat mitral valve replacement in patients who underwent mechanical replacement during infancy may be technically very difficult due to the small-sized annulus accommodating the prosthesis. That can lead to dense fibrosis of the small annulus onto the sewing cuff. An attempt at explanting the prosthesis carries high risk of circumflex coronary artery injury or atrioventricular junction disruption. We present a novel approach to prevent a disaster in such a difficult scenario-implanting the new prosthesis above the previous prosthetic housing after removing the prosthetic leaflets. PMID- 29233359 TI - Supra-Annular Mitral Valve Replacement in an Infant With Infective Endocarditis. AB - We report the case of a female neonate born at 40 weeks' gestation with no known risk factors. On postnatal day 27, she was transferred to the pediatric intensive care unit and intubated for cardiorespiratory failure; she was diagnosed with group B streptococcus infective endocarditis. Mitral valve vegetations did not improve with antibiotic therapy. Mitral valve surgery was performed on postnatal day 36. A mechanical mitral valve with short-segment polytetrafluoroethylene skirt was inserted into the supra-annular position; gentian violet was applied to the sewing ring and skirt. She was discharged from the hospital after 6 weeks with good cardiac function and normal sinus rhythm. PMID- 29233360 TI - Single-Ventricle Palliation in a 4-Year-Old With Ehlers-Danlos Syndrome. AB - We report the case of a 4-year-old boy with Ehlers-Danlos syndrome undergoing single-ventricle palliation for an unbalanced atrioventricular canal defect. No reports of single-ventricle palliation in the setting of connective tissue disorders exist in the current literature. Unique findings on the patient's preoperative imaging included a disproportionately large neoaortic root and a regurgitant atrioventricular valve, which may foretell the need for future intervention. PMID- 29233361 TI - Bronchial Involvement in Rosai Dorfman Disease. PMID- 29233362 TI - Huge Calcified Aneurysm of the Left Ventricle. PMID- 29233363 TI - Anticoagulant-Free Off-Pump Left Ventricular Assist Device Implant. AB - Implantable left ventricular assist device (LVAD) therapy is an established treatment for advanced heart failure. LVADs are usually implanted using intra operative anticoagulation with or without cardiopulmonary bypass. We describe an anticoagulant-free off-pump LVAD implant technique to circumvent potential complications associated with conventional approaches. This technique is safe and is probably the least invasive surgical approach for LVAD implantation. PMID- 29233364 TI - Epicardial 15-MHz Echocardiography for Effective Repair of Coronary Arteriovenous Fistula. AB - In the era of catheter intervention, the surgical repair of coronary arteriovenous fistula needs to be free from residual shunt. Intraoperative epicardial 15-MHz echocardiography helps to find the residual shunt after ligation or obliteration of anomalous vessels. Here we report our method of the echo-assisted surgical repair of coronary arteriovenous fistula in 7 adult patients. The method made the operation for coronary arteriovenous fistula free from residual shunt, but care should be taken to the development of new vessels after the operation. PMID- 29233365 TI - Acute Trans-Diaphragmatic Herniation of the Caudate Lobe of the Liver. AB - Diaphragmatic liver herniation is often associated with thoracoabdominal trauma. Spontaneous diaphragmatic rupture is a thoracoabdominal emergency and requires a high index of suspicion combined with high-resolution imaging studies for establishing an accurate and timely diagnosis. We present a case report of a patient who was admitted to the emergency department with severe substernal chest pain and shortness of breath who was diagnosed with spontaneous diaphragmatic rupture and caudate liver herniation. The caudate lobe was incarcerated, contributing to the patient's symptoms. A celiotomy was performed and the defect was repaired primarily. PMID- 29233366 TI - Lung Cancer Surgery in Partial Anomalous Pulmonary Venous Connection Patients. AB - We report pulmonary resections for lung cancers in 2 patients with partial anomalous pulmonary venous connection (PAPVC) identified preoperatively. In case 1, right upper lobectomy was performed as the definitive operation for both lung cancer and PAPVC in the same lobe. In case 2, because lung cancer and PAPVC existed in different lobes, cardiac catheterization was performed to evaluate the need for correction of the PAPVC. Then, left lower lobectomy was safely performed without correcting the PAPVC located in the left upper lobe. The treatment plan for patients with PAPVC who require pulmonary resection should be carefully considered. PMID- 29233367 TI - Electronic cigarette use, knowledge, and perceptions among health professional students. AB - INTRODUCTION: Our study evaluated the electronic cigarette (e-cigarette) use, knowledge, and perceptions of health professional students enrolled in one of five colleges at a single academic health center. METHODS: A 56-item survey was conducted to examine the use, knowledge, and perceptions of e-cigarettes among health professional students. An e-cigarette knowledge score was calculated according to correct responses to eight true-false survey items, with possible scores ranging from zero to eight points. Regressions were used to determine associations between students' enrolled college/discipline and e-cigarette knowledge scores and to identify associations between three perception domains (smoking cessation, harm reduction, and enhanced regulation) and e-cigarette use. RESULTS: Of the 853 students responding, 24.2% reported e-cigarette ever-use. Of e-cigarette ever users, 85.5% had used within the past year, and 23.1% used e cigarettes for smoking cessation. Participants from the colleges of public health, pharmacy, and nursing had significantly higher knowledge scores, compared to those in allied health. Knowledge scores from college of medicine participants did not differ significantly compared to scores from allied health. Perceptions of using e-cigarettes for smoking cessation, reduced harm compared to tobacco, and reduced e-cigarette regulation were significantly associated with using e cigarettes. DISCUSSION AND CONCLUSIONS: Self-reported ever-use of e-cigarettes among health professional students in this sample was 3.5-6 times higher than previously reported among medical and nursing students. Substantial gaps in e cigarette knowledge exist. Enhancing health professionals' preparedness to effectively advise patients about the benefits and harms of e-cigarettes is crucial. PMID- 29233368 TI - Faculty perception of team-based learning over multiple semesters. AB - INTRODUCTION: Perspectives from faculty regarding team-based learning (TBL) are not well understood. Previous studies describe faculty preference for TBL due to increased student interaction despite requiring increased time for design. The perception of changes in faculty workload over multiple semesters has not been measured. This research evaluates faculty workload and perceived student engagement after implementing TBL in a required non-prescription medication course over multiple semesters. METHODS: TBL was implemented in the non prescription medication course and continued for three consecutive semesters. Faculty members' perception of TBL was captured using an anonymous survey. The survey was an 11 item questionnaire with five Likert-type response options to identify changes in workload, training, and student interaction using TBL. RESULTS: Twenty-eight total responses were collected from 10 faculty members who taught in at least one of the four semesters. Results were aggregated based on the number of semesters faculty continually taught in the course. More respondents agreed than disagreed that participation from and interactions with students increased with the TBL course compared to traditional lectures. However, more respondents believed the TBL course approach was more difficult and reported increased workload in the initial semester taught. Enjoyment of teaching increased for a majority of respondents. DISCUSSION AND CONCLUSIONS: This is the first study to explore the impact of TBL implementation over multiple semesters. These data can be used to help implement TBL in pharmacy school curricula. PMID- 29233369 TI - Do fourth year pharmacy students use Facebook to form workplace-based learning peer groups during rotations? AB - INTRODUCTION: The objective of this study was to gain an understanding of whether pharmacy students are using Facebook(r) to create formal or informal workplace based peer groups to learn from each other and share information while completing their advanced pharmacy practice experiences (APPEs). METHODS: Fourth-year pharmacy students from two colleges of pharmacy in the same geographical area were recruited by email to participate. Inclusion criteria were: completion of two or more APPEs, current assignment to an APPE rotation in the local area, and a Facebook(r) profile. Two focus groups, of eight students each were conducted on each of the two colleges' campuses. An incentive to participate was provided. Thematic analysis was used to analyze responses. RESULTS: Students reported using Facebook(r) to learn about rotation expectations, roles/responsibilities, and preceptors. However, frequency and depth of interactions varied among the participants. Most participants noted that they prefer more private methods of communication to learn about APPE experiences. Students found Facebook(r) to be a good source of motivation and support during experiential learning. DISCUSSION: The use of social media sites like Facebook(r) may help students form "virtual" workplace-based peer groups during APPEs. CONCLUSION: Pharmacy schools interested in providing support for formal workplace-based learning groups should consider using social media sites as one component of this program. PMID- 29233370 TI - Female pharmacists' career perceptions in Saudi Arabia: A survey at an academic center in Jeddah. AB - OBJECTIVES: This study aimed to describe existing patterns of female pharmacy students' perceptions and their expectations regarding employment, job sectors, salaries, difficulties, and burdens, and to understand students' long-term prospects for employment in the pharmaceutical sector. The second objective was to assess students' perceptions of their careers in the short- and long-term. METHODS: This prospective survey was conducted on female pharmacy students at King Abdulaziz University, Jeddah from January 12, 2013 through January 21, 2013. The survey instrument was distributed online using Survey Monkey and was designed to assess students' opinions regarding employment in pharmacy. RESULTS: A total of 108 students responded to the surveyed. Approximately half reported that they would prefer to work in the government sector (50.9%), followed by the academic field (19.4%). Community pharmacies were underrepresented in the responses. Students' working durations, their preferred working shifts, and their 10-year prospects differed significantly from what was expected (p < 0.001). Similarly, students' preferences to work specific shifts (p < 0.001) and their long-term prospects (p < 0.001) were significantly different from what was expected. Participants perceived community and private pharmacies as the least rewarding in terms of remuneration. Approximately 61.1% of the participants perceived salaries at private hospitals to range between $1865 and $2397/month (p < 0.001). CONCLUSION: Female graduates anticipate challenges in the pharmacy workforce, especially in the pharmaceutical sector. Lack of training, job stability, as well as religious and cultural constraints appeared to influence female graduate's decision to join a particular sector in the pharmacy field. PMID- 29233371 TI - Experience with the script concordance test to develop clinical reasoning skills in pharmacy students. AB - BACKGROUND: The script concordance test (SCT) is used to assess clinical reasoning and was originally developed for medical learners. The Accreditation Council for Pharmacy Education (ACPE) endorses the need for pharmacy students to develop clinical reasoning skills, but there is little documentation of use of the SCT for pharmacy learners. EDUCATIONAL ACTIVITY: A script concordance test activity was designed for a diabetes and metabolic syndrome pharmacotherapy course. Twenty-five cases were created and evaluated by an expert panel of 20 practicing pharmacists. Ten cases were presented as a formative activity in class. The students, design team, teaching team, and expert panel evaluated the activity. CRITICAL ANALYSIS OF THE EDUCATIONAL ACTIVITY: The SCT was received positively from the students, design team, teaching team, and expert panel. The design team noted that case writing was different for this approach and that the inclusion of various perspectives from panelists was beneficial. Although the activity was formative in nature, the teaching team scored the students and this provided insight into areas where the students may struggle. SUMMARY: This report provides information on the formative use of the SCT in the classroom, as well as categories of items suitable for pharmacy. The SCT provides an approach to illustrate clinical reasoning and clinical decision making among content experts and can be used to stimulate clinical discussions among student learners and content experts. The SCT could help incorporate clinical reasoning skills in a pharmacy curriculum to meet ACPE standards. PMID- 29233372 TI - A novel use of photovoice methodology in a leadership APPE and pharmacy leadership elective. AB - BACKGROUND AND PURPOSE: The purpose of this article is to describe and assess the effectiveness of an innovative teaching approach in an advanced pharmacy practice experience (APPE) and leadership elective. EDUCATIONAL ACTIVITY AND SETTING: Three cohorts of students [(2014: n = 14), (2015: n = 17), (2016: n = 19)] were introduced to the photovoice (PV) method in their leadership APPE. PV required students to take, present, and discuss photographs within their cohorts. PV was used as a teaching method with the intention that the process would compel students to be involved in leadership development throughout experiential rotations, participate in discussions related to leadership development, and engage in creative activity. Group discussions from the class of 2014 were recorded and transcribed. Students from all cohorts were asked to participate in an electronic survey containing items based on PV learning objectives. All students were asked to participate in semi-structured interviews about PV. FINDINGS AND DISCUSSION: The inductive coding method was used to identify themes from discussion transcripts. Analysis of themes revealed 51.5% of the PV photographs related to emotional intelligence. Development of others and strong teams were themes represented in 44.3% of photographs. Survey data indicated all respondents agreed PV was a valuable method to describe learning in leadership. Interview coding revealed themes related to emotional intelligence and development of teams. SUMMARY: The PV method was an effective teaching tool in a leadership APPE and elective course. PV is a teaching method to be utilized in a variety of experiential learning environments to better enhance the professional development of pharmacy students. PMID- 29233373 TI - Interprofessional education in pharmacology using high-fidelity simulation. AB - BACKGROUND: This study examined the feasibility of an interprofessional high fidelity pharmacology simulation and its impact on pharmacy and nursing students' perceptions of interprofessionalism and pharmacology knowledge. INTERPROFESSIONAL EDUCATION ACTIVITY: Pharmacy and nursing students participated in a pharmacology simulation using a high-fidelity patient simulator. Faculty-facilitated debriefing included discussion of the case and collaboration. To determine the impact of the activity on students' perceptions of interprofessionalism and their ability to apply pharmacology knowledge, surveys were administered to students before and after the simulation. Attitudes Toward Health Care Teams scale (ATHCT) scores improved from 4.55 to 4.72 on a scale of 1-6 (p = 0.005). Almost all (over 90%) of the students stated their pharmacology knowledge and their ability to apply that knowledge improved following the simulation. DISCUSSION: A simulation in pharmacology is feasible and favorably affected students' interprofessionalism and pharmacology knowledge perceptions. IMPLICATIONS: Pharmacology is a core science course required by multiple health professions in early program curricula, making it favorable for incorporation of interprofessional learning experiences. However, reports of high-fidelity interprofessional simulation in pharmacology courses are limited. This manuscript contributes to the literature in the field of interprofessional education by demonstrating that an interprofessional simulation in pharmacology is feasible and can favorably affect students' perceptions of interprofessionalism. This manuscript provides an example of a pharmacology interprofessional simulation that faculty in other programs can use to build similar educational activities. PMID- 29233374 TI - Curriculum renewal: Alignment of introductory pharmacy practice experiences with didactic course content. AB - BACKGROUND AND PURPOSE: The University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences (SSPPS) used the opportunity of curriculum renewal to integrate knowledge and skills learned from didactic courses into the introductory pharmacy practice experiences (IPPEs) occurring simultaneously. This paper describes and evaluates the meaningful application of course content into IPPEs, and evaluates the success using qualitative feedback. EDUCATIONAL ACTIVITY AND SETTING: Students entering the renewed curriculum starting in fall 2012 were provided a list of pharmacy skills and activities from didactic course directors that reinforced course content for that semester. The skills and activities were to be completed during the students' IPPE visits in the community or health systems settings, depending on the program year and semester. FINDINGS: Students successfully completed course assignments during their IPPE course program. Not all activities could be completed as designed, and many required modification, including simulated experiences. Feedback from faculty and preceptor members of the school's experiential education committee demonstrated that these activities were valuable and improved learning of course material, but were challenging to implement. DISCUSSION AND SUMMARY: A renewed curriculum that mapped course assignments for completion in experiential settings was successfully established, after some modifications. The program was modified at regular intervals to improve the ability of preceptors to complete these activities in their individual practice environment. A balance between the school providing guidance on what activities students should perform and allowing unstructured independent learning with the preceptor is needed for an optimal experience. PMID- 29233375 TI - Pharmacy student perspectives regarding curricular renewal with experiential alignment. AB - BACKGROUND AND PURPOSE: To evaluate pharmacy students' ability to perform and perspectives regarding a purposeful mapping of curricular content into experiential settings for application. EDUCATIONAL ACTIVITY AND SETTING: Students were given a list of activities developed by their curricular course directors that were to be completed during their introductory pharmacy practice experiences (IPPEs). Students were tasked with completing each assignment at their community or health system pharmacy site, and verify completion with their preceptor. Students were surveyed regarding their completion of these activities, who the tasks were performed on, and the value students perceived from the exercises. FINDINGS: Students ranked that the curricular mapping to experiential courses were successful. Average student responses reflected that the activities had value and positively impacted their learning. Many students struggled to find specific patient examples to complete the activities the way the course designed them. Changes to the structure of these activities was necessary for student success. DISCUSSION AND SUMMARY: Students felt that the curricular mapping of assignments into IPPEs was meaningful and improved their learning. Not all students were able to complete assignments as described. PMID- 29233376 TI - A pharmacy student's role as a teaching assistant in an undergraduate medicinal chemistry course - Implementation, evaluation, and unexpected opportunities for educational outreach. AB - BACKGROUND AND PURPOSE: To describe 1) a pharmacy student's teaching assistant (TA) role in an undergraduate medicinal chemistry course, 2) an active learning module co-developed by the TA and instructor, and 3) the unexpected opportunities for pharmacy educational outreach that resulted from this collaboration. EDUCATIONAL ACTIVITY AND SETTING: Medicinal Chemistry (CHM3413) is an undergraduate course offered each fall at Palm Beach Atlantic University (PBA). As a TA for CHM3413, a pharmacy student from the Gregory School of Pharmacy (GSOP) at PBA co-developed and implemented an active learning module emphasizing foundational medicinal chemistry concepts as they pertain to performance enhancing drugs (PEDs). Surveys assessed undergraduate students' perceived knowledge of medicinal chemistry concepts, PEDs, and TA involvement. FINDINGS: Students' (total n = 60, three fall semesters) perceived confidence in knowledge of medicinal chemistry concepts and PEDs increased significantly (p < 0.001) after the TA's module. Nearly 93% of students acknowledged this was their first interaction with a TA at PBA, ~ 82% "agreed/strongly agreed" that the TA provided effective instruction, and ~ 62% "agreed/strongly agreed" that TA availability raised overall confidence in CHM3413. Unexpected "side-effects" of this collaboration included opportunities for the TA and instructor to discuss health risks associated with PED usage with student-athletes and coaches at PBA. DISCUSSION: This collaboration developed the pharmacy student's teaching skills and reinforced knowledge of foundational pharmaceutical science concepts for both the TA and undergraduate students. Unexpected "side-effects" that resulted from this collaboration included opportunities for the TA and instructor to discuss health risks associated with PED usage with student-athletes in PBA's athletic department. SUMMARY: Educational/interprofessional outreach opportunities resulted from a pharmacy student TA's involvement in an undergraduate medicinal chemistry course. An advanced pharmacy practice experience elective in sports pharmacy (based on Ambrose's model) begins Fall 2017. PMID- 29233377 TI - Application of a systematic approach to evaluating psychometric properties of a cumulative exit-from-degree objective structured clinical examination (OSCE). AB - BACKGROUND AND PURPOSE: Objective structured clinical examinations (OSCEs) are considered gold standard performance-based assessments yet comprehensive evaluation data is currently lacking. The objective of this study was to critically evaluate the psychometric properties of a cumulative OSCE for graduating pharmacy students in Qatar for which policies and procedures were adapted from a Canadian context. EDUCATIONAL ACTIVITY AND SETTING: A 10-station OSCE was conducted for graduating students in Qatar. Evaluation included assessment of pass rates, predictive validity, concurrent validity, internal validity, content validity, interrater reliability, and internal consistency. FINDINGS: Twenty-six students completed the OSCE. Three stations achieved pass rates < 80%. Scores from professional skills and case-based learning courses, formative OSCEs, and cumulative grade point averages correlated with OSCE scores (p < 0.05). Average correlation between assessors' analytical and global scoring was moderate (r = 0.52). Average interrater reliability was excellent for analytical scoring (ICC = 0.88) and moderate for global scoring (ICC = 0.61). Excellent internal consistency was demonstrated for overall performance (alpha = 0.927). Students generally agreed stations represented real practice scenarios (range per station, 30-100%). DISCUSSION AND SUMMARY: The evaluation model identified strengths and weaknesses in assessment and curricular considerations. The OSCE demonstrated acceptable validity and reliability as an adapted assessment. PMID- 29233378 TI - A team-based interprofessional education course for first-year health professions students. AB - BACKGROUND AND PURPOSE: Interprofessional education (IPE) is required within pharmacy education, and should include classroom-based education along with experiential interprofessional collaboration. For classroom-based education, small-group learning environments may create a better platform for engaging students in the essential domain of interprofessional collaboration towards meaningful learning within IPE sub-domains (interprofessional communication, teams and teamwork, roles and responsibilities, and values and ethics). Faculty envisioned creating a small-group learning environment that was inviting, interactive, and flexible using situated learning theory. This report describes an introductory, team-based, IPE course for first-year health-professions students; it used small-group methods for health-professions students' learning of interprofessional collaboration. EDUCATIONAL ACTIVITY AND SETTING: The University of Toledo implemented a 14-week required course involving 554 first year health-sciences students from eight professions. The course focused on the Interprofessional Education Collaborative's (IPEC) Core Competencies for Interprofessional Collaboration. Students were placed within interprofessional teams of 11-12 students each and engaged in simulations, standardized-patient interviews, case-based communications exercises, vital signs training, and patient safety rotations. Outcomes measured were students' self-ratings of attaining learning objectives, perceptions of other professions (from word cloud), and satisfaction through end-of-course evaluations. FINDINGS: This introductory, team-based IPE course with 554 students improved students' self assessed competency in learning objectives (p < 0.01, Cohen's d = 0.9), changed students' perceptions of other professions (via word clouds), and met students' satisfaction through course evaluations. DISCUSSION AND SUMMARY: Through triangulation of our various assessment methods, we considered this course offering a success. This interprofessional, team-based, small-group strategy to teaching and learning IPE appeared helpful within this interactive, classroom based course. PMID- 29233379 TI - Implementation of a skills practical to first-year pharmacy students. AB - BACKGROUND AND PURPOSE: Objective structured clinical examinations (OSCEs) are being implemented in pharmacy schools across the country. As part of a new curriculum, a practical with an OSCE component was implemented for the first time at the West Virginia University School of Pharmacy. EDUCATIONAL ACTIVITY AND SETTING: A practical with an OSCE component was developed for first-year professional pharmacy students in a foundational pharmacy skills course. The OSCE component assessed insulin and inhaler counseling and blood pressure skills. A written exam covered material from throughout the semester. FINDINGS: A total of 76 students completed the practical. The average grade was a 27.8 out of 30 points. A total of 62 faculty hours were needed for the implementation of this OSCE. DISCUSSION AND SUMMARY: An OSCE that assessed a variety of foundational pharmacy skills was designed and implemented to first year pharmacy students using limited faculty time and resources. PMID- 29233380 TI - Comparison of electronic versus paper rubrics to assess patient counseling experiences in a skills-based lab course. AB - BACKGROUND AND PURPOSE: To evaluate an electronic counseling rubric to facilitate timely student feedback and explore differences in student performance, student anxiety, and self-perceived preparedness in a high stakes practical exam when using a paper rubric versus an electronic rubric. EDUCATIONAL ACTIVITY AND SETTING: Two cohorts of students in the third professional year were evaluated using the same rubric criteria: cohort 1 (n = 97) used traditional paper rubrics and cohort 2 (n = 104) used electronic rubrics. Cohorts were surveyed to measure anxiety and perceived preparedness in patient counseling skills one week prior to a practical exam, and cohort responses were compared. Student practical exam performance was also compared between the two cohorts. FINDINGS: Results showed no significant relationship between electronic rubric use and student anxiety (p = 0.07) or student exam performance [average score 53.42 points (SD 3.65) and 53.93 points (SD 3.78) in Cohort 1 and Cohort 2, respectively]. Perceived exam preparedness was higher among students using electronic rubrics, with timing of feedback being the mediating process in increasing preparedness (p < 0.01). DISCUSSION AND SUMMARY: Electronic rubrics resulted in more timely feedback on patient counseling skills, and students felt more prepared for their practical exam. This did not result in a significant difference in practical exam performance between the two cohorts. Additional methods to incorporate electronic rubrics into the course will be explored. PMID- 29233381 TI - Pharmacy resident-led student mentoring program: A focus on developing mentoring skills. AB - BACKGROUND AND PURPOSE: Formalized mentoring programs are often credited for influencing professional development of mentees. Unfortunately, little information exists regarding advancement of mentoring skills. We report the development and evaluation of a program to cultivate mentoring skills in pharmacy residents. EDUCATIONAL ACTIVITY AND SETTING: Advanced pharmacy practice experience students and pharmacy residents were contacted for program participation. Resident mentors were paired with a student mentee for the program. Mentors were provided resources and support throughout the program. Sessions were held to facilitate mentoring relationships and to discuss professional development topics. Pre- and post-perception surveys were administered to mentors to measure changes in mentoring comfort and ability. Only matched pre- and post-surveys were included for analysis. The program was held and evaluated over two separate academic years FINDINGS: Fifty-three residents mentored 54 students over two cycles of the program. Mentors' matched perception surveys (n = 26) reported increased comfort in mentoring (p < 0.001), increased confidence in delivery of subjective content (p < 0.001), increased comfort in providing written and oral feedback (p = 0.013), and increased effectiveness in provision of written and oral feedback (p = 0.004 and p = 0.013 respectively). Mentors also reported heightened belief that serving as a student mentor will be beneficial to their long-term career goals (p = 0.034). DISCUSSION AND SUMMARY: Overall, this formal resident-led student mentoring program improved resident comfort serving in a mentoring role. PMID- 29233382 TI - "It's like rotations, but in the classroom": Creation of an innovative course to prepare students for advanced pharmacy practice experiences. AB - BACKGROUND AND PURPOSE: The purpose of this article is to discuss the course development and results of a survey assessing students' perceived confidence in performing various skills after completion of this course. EDUCATIONAL ACTIVITY AND SETTING: The course was taught using a model in which all activities performed by students took place in a fictitious health system. The course was created to give students the opportunity to learn in an environment that closely mimicked advanced pharmacy practice experiences (APPEs) while in the didactic setting. Higher order active learning activities and case-based exams were utilized in the course. Students' perceived level of confidence in performing skills practiced in the course was assessed via survey after completion of each semester of the course and after the first introductory pharmacy practice experience (IPPE). Course coordinators hypothesized that this course design would improve students' perceived level of confidence in performing skills utilized in the clinical practice setting. FINDINGS: Survey data from two class cohorts were analyzed. Students' perceived level of confidence in performing skills necessary in clinical practice increased as a result of the course. DISCUSSION: This course provided students an opportunity to experience an APPE environment while still in the didactic setting. The course design meets the Center for the Advancement of Pharmacy Education (CAPE) outcomes and aids in making students "APPE-ready" prior to the start of the P4 year. SUMMARY: This unique and innovative course format allowed students to integrate knowledge learned in previous courses and apply it in a manner like what is expected in the clinical setting. PMID- 29233383 TI - Implementation of a pharmacy research committee to enhance the pharmacy resident research experience. AB - BACKGROUND AND PURPOSE: Most postgraduate year 1 (PGY1) pharmacy residents complete at least one research project as part of their graduation requirements. The research skills learned prepare residents to address research questions and generate evidence-based recommendations for patient care. However, there are multiple steps involved in a research project, and streamlining this process can be difficult. EDUCATIONAL ACTIVITY AND SETTING: Northwestern Memorial Hospital (NMH), a large academic center located in Chicago, IL, developed a research committee (RC) to facilitate research within the department of pharmacy for residents and to maintain residency research support materials. These materials included a charter to help guide the organizational structure and operations of the RC, research timelines, and a seminar series. FINDINGS: The RC works to ensure that the residents overcome any challenges that they may incur during their research projects by setting clear expectations and milestones. Feedback is provided by the residents and incorporated into the research process and support materials. DISCUSSION: The RC allows for individualized attention and personalization of the research experience for each resident. The program endeavors each year to provide the message that publication should be the final goal of a research project and not presentation at a conference. SUMMARY: Pharmacy residents receive support from the RC from throughout the year, not only when issues surround their project arise. Institutions may implement or modify existing programs based upon the resources provided. PMID- 29233384 TI - Community education by advanced pharmacy practice experience students: Increasing electronic cigarette awareness amongst teens. AB - BACKGROUND AND PURPOSE: An electronic cigarette (e-cigarette) is a device used to mimic the experience of smoking tobacco cigarettes. Considering their growing popularity amongst adolescents, it is imperative that education surrounding e cigarettes be provided. The purpose of this project is to describe the development and delivery of a pilot interactive presentation and survey tool by doctor of pharmacy (PharmD) candidates to gauge the use and understanding of e cigarettes amongst teens. EDUCATIONAL ACTIVITY AND SETTING: An interactive presentation providing information on e-cigarettes was created by a PharmD candidate, and presented to 357 high school students in Massachusetts and New Hampshire. An anonymous survey tool was administered after the presentation to evaluate students' perception, use, and knowledge of e-cigarettes. FINDINGS: When asked which is safer, an e-cigarette or a tobacco cigarette, most students (84%) responded "neither," and most stated that they learned something new from the presentation. Of the 96% of students that indicated they had heard of e cigarettes, 27% of them had tried one. PharmD candidates reported increased confidence in public speaking and preparation of patient-suitable material. DISCUSSION: This pilot project provided both education to adolescents and insight into their experience and understanding of the potential harms of e-cigarettes. Having a PharmD candidate deliver the presentation may have increased the students' level of comfort. SUMMARY: An interactive, PharmD candidate-delivered presentation about e-cigarettes is an innovative method to both provide education about e-cigarettes, and ascertain information about knowledge and use in adolescents. Facilitating presentations like this could be successful in other settings or topics. PMID- 29233385 TI - Traditional lecture versus jigsaw learning method for teaching Medication Therapy Management (MTM) core elements. AB - BACKGROUND AND PURPOSE: To determine if traditional didactic lecture or the jigsaw learning method is more effective to teach the medication therapy management (MTM) core elements in a first year pharmacy course. EDUCATIONAL ACTIVITY AND SETTING: Traditional didactic lecture and a pre-class reading assignment were used in the fall semester cohort, and the jigsaw method was used in the spring semester cohort. Jigsaw is a cooperative learning strategy requiring students to assume responsibility for learning, and subsequently teaching peers. The students were responsible for reading specific sections of the pre-class reading, and then teaching other students in small groups about their specific reading assignments. To assess potential differences, identical pre- and post-tests were administered before and after the MTM section. Additionally, grade performance on an in-class project and final exam questions were compared, and students were surveyed on perceptions of teaching method used. FINDINGS: A total of 45 and 43 students completed both the pre- and post-test in the fall and spring (96% and 93% response rate), respectively. Improvement in post-test scores favored the traditional method (p = 0.001). No statistical differences were noted between groups with grade performance on the in-class project and final exam questions. However, students favored the jigsaw method over traditional lecture and perceived improvements in problem solving skills, listening/communication skills and encouragement of cooperative learning (p = 0.018, 0.025 and 0.031). SUMMARY: Although students favored the jigsaw learning method, traditional didactic lecture was more effective for the pre- and post knowledge test performance. This may indicate that traditional didactic lecture is more effective for more foundational content. PMID- 29233386 TI - A national survey on the current status of informatics residency education in pharmacy. AB - BACKGROUND AND PURPOSE: Upon completion of their post-graduate training, pharmacy informatics residents need to be prepared to interact with clinical and technology experts in the new healthcare environment. This study describes pharmacy informatics residency programs within the United States. EDUCATIONAL ACTIVITY AND SETTING: Preliminary information for all pharmacy informatics residency programs was accessed from program webpages. An email was sent out to programs asking them to respond to a six-item questionnaire. This questionnaire was designed to elicit information on attributes of the program, behaviors of the preceptors and residents, and attitudes of the residency directors. FINDINGS: Of 22 pharmacy informatics residencies identified, nineteen (86%) participated. Twenty (91%) were second post-graduate year (PGY2) residencies. Ten (45%) were accredited by the American Society of Health-System Pharmacists (ASHP), while eight (36%) were candidates for accreditation. Hospital (17/22, 77%) and administrative offices (3/22, 14%) were the predominant training sites for pharmacy informatics residents. Large institutions were the predominant training environment for the pharmacy informatics resident, with 19 of 22 (86%) institutions reporting a licensed bed count of 500 or more. The median (range) number of informatics preceptors at a site was six to eight. Regarding barriers to pharmacy informatics residency education, residency directors reported that residents did not feel prepared based on the limited availability of curricular offerings. DISCUSSION AND SUMMARY: In the United States, relatively few residencies are explicitly focused on pharmacy informatics. Most of these are accredited and hospital affiliated, especially with large institutions (>500 beds). PMID- 29233387 TI - Combining rhetoric and role-play to introduce and develop patient presentation skills in third year pharmacy students. AB - BACKGROUND AND PURPOSE: To implement a mock rounds activity designed to introduce and develop patient presentation skills in pharmacy students. EDUCATIONAL ACTIVITY AND SETTING: The sample population included third-year pharmacy students enrolled at the University of New Mexico (UNM) and Virginia Commonwealth University (VCU) during Fall 2011, 2012, and 2013. A mock rounds activity was developed and implemented in the Pharmaceutical Care Lab setting. Students were assigned an infectious disease case and asked to create an assessment and plan to present orally to an acting preceptor in a small group laboratory setting. Summative assessment of student performance was evaluated using a standardized rubric. FINDINGS: A total of 621 students (VCU: 371; UNM: 250) from both universities participated in the mock rounds activity. Data was collected using the rubric. Students scored highest in the areas of respectfulness (94.8% exceeds expectations) and completion time (86.9% exceeds expectations). The lowest ratings were in the areas of logical flow and organization (73.7% exceeds expectations) and ability to answer preceptors' questions (73.3% exceeds expectations). DISCUSSION AND SUMMARY: A simulated mock rounds activity enabled students to practice patient case presentation skills and receive summative feedback prior to Advanced Pharmacy Practice Experiences. PMID- 29233388 TI - Peer teaching as an educational tool in Pharmacy schools; fruitful or futile. AB - BACKGROUND: In the past decade, various health care programs have implemented diverse types of peer-assisted learning (PAL) programs, in particularly peer teaching (PT), due to their reported benefits for students (both those undertaking teaching and those being taught), teachers, and educational institutes. Unfortunately, peer teaching is still under-recognized in pharmacy programs worldwide when compared to other health care programs. The aim of this review is to provide an overview of the published literature centered on formal PT programs that are implemented in pharmacy schools. In addition, this review focuses on the methodologies adopted for peer teacher recruitment and training as well as the benefits gained by students (both those undertaking teaching and those being taught). The rationales behind PT implementation are recapitulated as well. Finally, a simple scheme for successful implementation of PT activity is provided to serve as a groundwork for educators. METHODS: Pre-defined key terms were used to search for experimental peer teaching activities in pharmacy schools between January 2000 and June 2016. Titles were selected based on pre-set eligibility criteria. Only complete research articles with clear design and evaluation sections were included in this review. Studies about inter professional peer teaching activities between pharmacy students and other healthcare professions were also included. RESULTS: Six relevant educational research articles containing peer teaching activities were included. A lot of variety exists between different pharmacy courses implementing PT, the format/setting of PT, how peer teachers are selected, and how training and evaluation are implemented. The studies reviewed confirmed that PT was well received by most of the students and had a positive impact on their learning outcome. These findings cannot be generalized due to the insufficient number of studies published beside their methodological limitations and inadequate descriptions of the PT format. IMPLICATIONS: Though PT may be regarded as a feasible teaching strategy, care must be taken during implementation to ensure the fulfillment of the educational objectives. Proper validation of any PT initiative is required before incorporation into the pharmacy curriculum. More research using proper design and suitable sample sizes are recommended to determine the effect of PT activity on students' learning, skills development and confidence. PMID- 29233389 TI - 2017 in review: Spotlight on trainee research. PMID- 29233390 TI - Transgender students in pharmacy school, part 1: What academic administrators need to know. AB - While gender transition is a very exciting time for most students embarking upon this personal journey, it is not without its stressors as well. For students choosing to further their education and become pharmacists, the complexity and demands of pharmacy education during the transition period can be one such additive stressor. As pharmacy educators and administrators, we have the ability to help shape this professional journey and alleviate stress by maintaining our obligation to provide a safe and non-discriminatory learning environment for all students. Therefore, this two-part commentary will serve as a means to provide information and insights to administrators and faculty advisors in order to ensure transgender students, including those actively undergoing gender transition, achieve both a successful transition and pharmacy school career. PMID- 29233391 TI - Transgender students in pharmacy school part 2: How faculty advisors can support their advisees. AB - Faculty advisors serve a critical role in the success of pharmacy students during their academic careers, frequently serving as a problem-solver or sounding board during times of both triumph and struggle. Additionally, faculty advisors help students overcome barriers along their journey to ensure a successful progression through pharmacy school. This role is particularly important to transgender students, given the additional barriers they may face, which were highlighted in Part One of the commentary on transgender students in pharmacy school. To help faculty serve as a successful mentor to transgender advisees, Part Two of the commentary provides resources and insights into advising transgender students, including those actively undergoing gender transition. PMID- 29233392 TI - Supporting quality in experiential education through enhanced faculty engagement. AB - INTRODUCTION: There are ongoing assessment and improvement activities related to strategies to improve the quality of education in the complex and resource intensive area of experiential education (EE). One undescribed approach for design and delivery of EE programs for schools and colleges, with reliance on volunteer preceptors, is to utilize clinical practice faculty in formal partnerships with EE leadership to enhance curriculum and assessment. COMMENTARY AND IMPLICATIONS: Clinical practice faculty, who possess practice setting expertise, can serve as course directors for advanced pharmacy practice experience (APPE) rotations. In this role, they can collaborate with EE faculty and staff to create more course-specific expectations, learning objectives, and criteria for APPE rotation experiences. This model could increase consistency for students and preceptors, using an approach that is analogous to content experts serving as course directors in didactic curriculum. This commentary explores the potential of this strategy to increase quality and consistency in EE. PMID- 29233393 TI - Assessing self-assessment practices: A survey of U.S. colleges and schools of pharmacy. AB - OBJECTIVE: This study quantifies and describes student self-assessment approaches in colleges of pharmacy across the United States. METHODS: Faculty members identified as assessment directors from college websites at U.S. colleges of pharmacy were electronically surveyed. Prior to distribution, feedback and question validation was sought from select assessment directors. Surveys were distributed and recorded, via Qualtrics(r) survey software and analyzed in Microsoft Excel(r). RESULTS: Responses were received from 49 colleges of pharmacy (n = 49/134, 37% response rate). The most commonly used strategies were reflective essays (n = 44/49, 90%), portfolios (n = 40/49, 82%), student self evaluations (n = 35/49, 71%) and questionnaires/surveys/checklists (n = 29/49, 59%). Out of 49 submitted surveys, 35 programs noted students received feedback on self-assessment. Feedback came most commonly from faculty (n = 31/35, 88%). Thirty-four programs responded regarding self-assessment integration including fifteen colleges (n = 15/34, 44%) that integrated self-assessment both into the curriculum and co-curricular activities, while 14 (n = 14/34, 41%) integrated self-assessment exclusively into the curriculum, and five (n = 5/34, 15%) used self-assessment exclusively in co-curricular activities. DISCUSSION AND CONCLUSIONS: Student self-assessment is a critical first step of the Continuing Professional Development (CPD) process. Colleges and schools of pharmacy use a wide variety of methods to develop this skill in preparing future practitioners. PMID- 29233394 TI - Validity and reliability of an application review process using dedicated reviewers in one stage of a multi-stage admissions model. AB - INTRODUCTION: With increased emphasis placed on non-academic skills in the workplace, a need exists to identify an admissions process that evaluates these skills. This study assessed the validity and reliability of an application review process involving three dedicated application reviewers in a multi-stage admissions model. METHODS: A multi-stage admissions model was utilized during the 2014-2015 admissions cycle. After advancing through the academic review, each application was independently reviewed by two dedicated application reviewers utilizing a six-construct rubric (written communication, extracurricular and community service activities, leadership experience, pharmacy career appreciation, research experience, and resiliency). Rubric scores were extrapolated to a three-tier ranking to select candidates for on-site interviews. Kappa statistics were used to assess interrater reliability. A three-facet Many Facet Rasch Model (MFRM) determined reviewer severity, candidate suitability, and rubric construct difficulty. RESULTS: The kappa statistic for candidates' tier rank score (n = 388 candidates) was 0.692 with a perfect agreement frequency of 84.3%. There was substantial interrater reliability between reviewers for the tier ranking (kappa: 0.654-0.710). Highest construct agreement occurred in written communication (kappa: 0.924-0.984). A three-facet MFRM analysis explained 36.9% of variance in the ratings, with 0.06% reflecting application reviewer scoring patterns (i.e., severity or leniency), 22.8% reflecting candidate suitability, and 14.1% reflecting construct difficulty. DISCUSSION AND CONCLUSIONS: Utilization of dedicated application reviewers and a defined tiered rubric provided a valid and reliable method to effectively evaluate candidates during the application review process. These analyses provide insight into opportunities for improving the application review process among schools and colleges of pharmacy. PMID- 29233395 TI - Knowledge, attitudes and beliefs regarding human immunodeficiency virus and in home testing among a regional sample of student pharmacists. AB - INTRODUCTION: Pharmacists identify the importance of education on human immunodeficiency virus (HIV); however, research suggests deficits in knowledge regarding recommendations and testing devices. With proper training, student pharmacists can play an important role in counseling patients on the importance of HIV testing and providing instruction on in-home testing. The objective of the study was to assess student pharmacists' knowledge, attitudes and beliefs of HIV and the use of an in-home, over-the-counter HIV testing device. METHODS: A cross sectional electronic survey was conducted among an estimated sample of 2077 students from six regional schools of pharmacy. The questionnaire consisted of 40 closed-ended, fixed-choice items delivered using school/organizational listservs. Surveys were e-mailed during March and April 2016 with a reminder e-mail sent two weeks later. Key outcomes included real and perceived knowledge, attitudes and beliefs of HIV in general and of the OraQuick(r) In-Home HIV test. RESULTS: A total of 387 student pharmacists participated (response rate of 18.6%). Respondents expressed positive perception of knowledge regarding HIV in general (67.6% highly agree/agree to five-item scale) but considerably lower attitude/beliefs for the in-home HIV test (16.7% highly agree/agree overall to five-item scale). Perceptions of general HIV knowledge were higher for students in later professional years (p < 0.001), post-completion of infectious disease curriculum with inclusion of the in-home HIV test (p < 0.001), and if the respondent had personally received an HIV test (p < 0.01). CONCLUSIONS: Opportunities exist to improve knowledge of HIV and the use of the OraQuick(r) In Home HIV test among student pharmacists. PMID- 29233396 TI - Inter-rater reliability of a reflective rubric to assess pharmacy students' reflective thinking. AB - INTRODUCTION: Many health education programs aspire to foster reflective practices to enhance the reflective thinking of students during their study years and throughout their professional careers. Given the increasing attention paid to incorporating reflective practice activities into health education and evidence attributed to rater variability, it is important for educators to carefully consider the assessment criteria and reliability of assessment tools. A reflective rubric was developed to assess pharmacy students' levels of reflection from a reflective writing task. This study investigates the inter-rater reliability (IRR) of a rubric as a tool to assess the levels of reflective thinking apparent in students' written statements. METHODS: The research involved four raters from different disciplines utilizing a rubric to assess a random sample of the same forty-three reflective statements from a cohort of two hundred and sixty-four students. The IRR was measured using the intra-class correlation coefficient (ICC), using a two-way random effects model (ANOVA) with absolute agreement, to determine reliability of the assessment tool among the raters. RESULTS: Results showed measures between the raters for (i) overall reflective statement scores, and (ii) average scores for stages of reflection with an "almost perfect" agreement, ICC = 0.81 (95% CI 0.61-0.90), (F(42, 126) = 7.83, p < 0.01); and ICC = 0.89 (95% CI 0.83-0.93), (F(42, 840) = 12.49, p < 0.01) respectively. DISCUSSION AND CONCLUSIONS: The proposed rubric utilized by four raters showed high agreement with each other's scores, and is a tool for academic assessment of pharmacy students' reflective thinking processes. PMID- 29233397 TI - Assessment of student pharmacists' ethical decision-making. AB - INTRODUCTION: In previous research, investigators have expressed concern about the ethical ambivalence of pharmacists in decision-making. The objectives of this study were to examine student pharmacists': 1) attitudes and responses regarding specific common ethical situations and 2) perceived level of difficulty in making ethical decisions. METHODS: A self-administered 38-item survey was given to second and third year student pharmacists at Purdue University. The survey comprised five sections, including: 1) attitudes towards common ethical situations, 2) responses to specific ethical scenarios, 3) emergency lending, 4) perceived level of difficulty in resolving ethical dilemmas, and 5) demographics. RESULTS: Over 90% of students agreed or strongly agreed that pharmacists have the right to refuse to dispense a medication for clinical reasons, while 45.3% agreed or strongly agreed that pharmacists had the right to refuse to dispense for moral or religious reasons. Greater than 20% of students were undecided about dispensing syringes without a prescription, pseudoephedrine tablets to a frequent purchaser, and lethal doses of narcotics. In eight out of nine cases involving ethical decision-making, over 70% of students perceived the decision to be somewhat problematic. DISCUSSION AND CONCLUSIONS: Exploration of student pharmacists' perceptions of specific ethical situations assists in identifying areas of uncertainty in decision-making and informing educational interventions that may foster ethical development of future pharmacy professionals. PMID- 29233398 TI - An evidence-based analysis of learning practices: the need for pharmacy students to employ more effective study strategies. AB - INTRODUCTION: Learning is a process of constructing neural connections between what is being learned and what has already been learned. Superficial thought processes associated with memorization produce shallow, short-term learning. Higher-order thought processing (critical thinking) produces deep, long-term learning. Pharmacy students should study in ways that enable them to retain and apply what they learn. PREDOMINANT LEARNING PRACTICES: Investigators who surveyed the learning practices of pharmacy students have reported that most students resort to cramming in preparation for an upcoming exam. The practice of routinely keeping up with course material through regular study is much less common. Most students highlight or re-read material when studying rather than quizzing themselves, and many multitask or study with distractions such as texting, checking e-mails or using social media. EVIDENCE-BASED LEARNING PRACTICES: Studies in cognitive psychology and education provide evidence to confirm the efficacy of the following learning practices: plan and manage study time, space out and repeat study, interleave (mix up) topics or methods, incorporate retrieval practice (self-quizzing, deliberative reading, or written paraphrasing), minimize distractions, leverage mistakes, and sleep at least seven hours a night. CONCLUSION: Pharmacy students need to become proficient, lifelong learners. A superficial, memorization-oriented approach to learning is detrimental to professional growth. Faculty members should guide students to employ more effective evidence-based study strategies, while also exploring how curricular design, course content, academic policy or pedagogy might be predisposing students to pursue suboptimal learning practices. The issue calls for the academy to focus greater attention on how students learn. PMID- 29233399 TI - Management education within pharmacy curricula: A need for innovation. AB - OBJECTIVE: To encourage the academy to pursue innovative management education strategies within pharmacy curricula and highlight these experiences in a scholarly dialogue. SUMMARY: Management has often been a dreaded, dry, and often neglected aspect of pharmacy curricula. With the release of Center for Advancement of Pharmacy Education (CAPE) Educational Outcomes 2013 as well as Entry-Level Competencies Needed for Community Pharmacy Practice by National Association of Chain Drug Stores (NACDS) Foundation, National Community Pharmacists Association (NCPA), and Accreditation Council for Pharmacy Education (ACPE) in 2012, managerial skills have seen a new emphasis in pharmacy education. Further, management has greater emphasis within ACPE "Standards 2016" through adoption of CAPE Educational Outcomes 2013 into the standards. Previous literature has shown success of innovative learning strategies in management education such as active learning, use of popular television shows, and emotional intelligence. The academy must build a more extensive scholarly body of work highlighting successful educational strategies to engage pharmacy students in an often-dreaded subject through applying the Scholarship of Teaching and Learning. PMID- 29233400 TI - Teachable Moments Matter for: An analysis of the use of Pharmacy Curriculum Outcomes Assessment (PCOA) scores within one professional program. AB - Editors Note: The Teachable Moments Matter category of articles is designed to offer readers insight into a methodological issue identified within a companion article. Written in collaboration with one of these authors, these articles provide an opportunity to focus on a challenge experienced by the authors and, in the process, provide one or more perspectives as to how to successfully navigate this issue. Notably, this "issue" is not necessarily a problem (as this first paper in this series demonstrates). The Journal hopes this case-based approach will help highlight an issue nuance in context, something that might get "lost" in the entirety of a full-length article. This article discusses the importance of communicating a conceptual framework (i.e., theory) as a basis for scholarly articles. A specific example in the companion article is use of validity theory. In our community of researchers, we need to better communicate a conceptual framework as a basis to allow others to build on and grow our knowledge in pharmacy education. PMID- 29233401 TI - An analysis of the use of Pharmacy Curriculum Outcomes Assessment (PCOA) scores within one professional program. AB - OBJECTIVE: The Pharmacy Curriculum Outcomes Assessment (PCOA) is a recent assessment requirement for US pharmacy professional programs. This study analyses PCOA scores for uses described in the 2016 Standards with data from one professional program. METHODS: PCOA data were analyzed for two consecutive classes (n=215) of pharmacy students at the end of their didactic curriculum to explore relationships among PCOA scores, grade point average (GPA), and North American Pharmacist Licensure Examination (NAPLEX) scores utilizing regression analyses. RESULTS: Decisions about student learning based on PCOA scores and GPA indicated remediation would have been prescribed for approximately 7% of students. In comparison, NAPLEX scores revealed a 1% failure rate among the study sample. Relationships between PCOA scores and GPA (r=0.47) and NAPLEX (r=0.51) were moderate to large, respectively. GPA explained a larger portion of unique variance (14%) than PCOA (8%) in NAPLEX scores. CONCLUSIONS: In this sample of students, academic decisions would have varied depending upon the learning assessment, which is consistent with a moderate correlation between GPA and PCOA scores. Although PCOA scores correlate with GPA and NAPLEX, PCOA scores explained a smaller portion of unique variance in NAPLEX scores than GPA. The ongoing establishment of validity evidence of PCOA scores is important for meaningful interpretation of scores for the intended uses. PMID- 29233402 TI - The use of Twitter to facilitate engagement and reflection in a constructionist learning environment. AB - OBJECTIVES: Determine students' self-reported use of Twitter in a health systems course and gauge their perceptions of its value and utility for self-guided supplementation of course material, and evaluate the quality of students' reflections from information they found on Twitter. METHODS: Students in a health systems course create a Twitter account to remain abreast of current developments in pharmacy and health systems. They were afforded the autonomy to follow organizations/individuals they chose and write reflective mini-papers on selected tweets from their Twitter feed prior to each course session. A self-administered survey solicited students' favor toward various aspects of the Twitter reflection assignment. An examination of students' reflections as the course progressed was also undertaken. RESULTS: Approximately 2/3 of the students enrolled in the course responded to the survey. Student perceptions of the Twitter assignment were quite favorable, with highest favor related to facets regarding the construction of their own learning and continuation of engagement throughout the course. Responses to open-ended questions corroborated students' perceptions of their own learning, as did the content and quality of their reflections during progression of the course. CONCLUSIONS: The course design reinforced previous claims outside of pharmacy that Twitter can be a useful tool to reinforce or create new learning paradigms, but especially under the auspices of established theory, such as a constructivist environment employing constructionism pedagogy. A course like health systems in programs of academic pharmacy might especially benefit from use of Twitter and such course design. PMID- 29233403 TI - Perceptions of pharmacists' role in the health care team through student pharmacist led point-of-care screenings and its future application in health care. AB - INTRODUCTION: The public is largely unaware of changing pharmacy roles and continues to underutilize pharmacists as mainly a dispensing service, often overlooking direct patient care components. This paper evaluates the public perceptions of pharmacists' through student led point-of-care screenings and comprehensive medication reviews. METHODS: An IRB approved longitudinal retrospective study design was used to survey participants who attended College of Pharmacy sponsored health fairs in 2013. The survey contained questions related to patient understanding of the current pharmacy scope of practice, patient's reported level of comfort with the expanding roles of pharmacy, insurance coverage, demographics, income and whom the patients report that they seek first for medical related advice. RESULTS: One hundred participants were surveyed. By a large majority, the health care practitioner that patients reported that they currently sought out for general health information was a physician. All of the participants reported that they considered pharmacists as reliable sources of general health information. Of the 96 participants that completed the survey question regarding their willingness to seek out a pharmacist in the future to have their blood pressure, blood sugar, cholesterol, and/or bone density checked, 89 (92.7%) surveyed answered yes. Only 50 patients (50%) reported being aware that pharmacists have the capability to perform these point-of-care screenings. Participants responded that they felt "comfortable" (78 patients, 83.4%) followed by "trusting" (36 patients, 38.7%). DISCUSSION: The patients surveyed recognized pharmacists as the medication experts; however, many did not understand the capacity to which pharmacists' scope of practice allows them to deliver care to patients. In this study, almost all of the patients stated that they would consider seeking out a pharmacist to receive point-of-care screenings, but only half were aware that a pharmacist is capable of conducting these screenings. All felt that pharmacists are a reliable source of general health information and medication related needs, regardless of the patients' education level or household income. CONCLUSION: With the shortage of primary care providers, expansion of the scope of pharmaceutical practice is necessary. Although the public may not fully understand pharmacists' scope of practice, they are comfortable with pharmacists' knowledge related to general health needs outside of medications. The reported public comfort and trust of pharmacist knowledge and skills justify expanding the scope of pharmaceutical practice. PMID- 29233404 TI - Student performance on a knowledge-based exam may predict student ability to communicate effectively with a standardized patient during an objective structured clinical examination. AB - BACKGROUND: The purpose of this article is to describe the extent that student performance on in-class exams in a drug information course is associated with student performance on medication counseling in a high-stakes assessment using standardized patients (SP). METHODS: Students completed two traditional knowledge based exams during a drug information and communication course. The objective structured clinical examination (OSCE) was the final exam for the course. The OSCE consisted of the student counseling an SP on the use of a medication. A counseling rubric was developed for use in a second-year (P2) OSCE based on the Indian Health Services counseling model and social cognitive theory. Multiple linear regression was used to examine if traditional exams and student admission characteristics were associated with student performance on the OSCE. RESULTS: A total of 78 P2 students took the in-class exams and the OSCE. Students with higher scores on the second in-class traditional, knowledge-based exam had significantly higher scores on the OSCE. CONCLUSION: A traditional knowledge based exam on pharmacist-patient communication was associated with students' actual counseling performance on an OSCE. Faculty may be able to use exam scores to target students at high risk of doing poorly on a medication counseling OSCE. PMID- 29233405 TI - Tone and style in pharmacy course syllabi. AB - OBJECTIVE: Syllabi are a part of the teaching and learning experience in pharmacy curricula. Yet, little has been done to understand the effects of these documents. Studies in Psychology and Social Work report important effects of style and tone of syllabi on student perceptions and performance. We sought to describe a cross-sectional pattern in the tone and style of pharmacy course syllabi. METHODS: We retrieved syllabi via US pharmacy institutions and association website searches. The tone was characterized as "warm" or "cold" based on the publications in Psychology and Social Work higher education. QSR NVivo(r) software was used to code syllabi. Subsequently, categories of style and tone were quantified in a descriptive manner. RESULTS: We retrieved 416 pharmacy course syllabi from 30 public universities (69.8%) and 13 private universities (30.2%) across curricular disciplines. After observing saturation where no new patterns arose, 141 syllabi were analyzed. CONCLUSIONS: Pharmacy course syllabi were rarely warm in tone and did not fully employ the components of the syllabus as a potential learning tool. This may have important implications on student teacher interactions, professional development, and student perceptions and academic performance. More work should be done to determine whether and in what manner style and tone may affect pharmacy student learning and engagement. PMID- 29233406 TI - Common teaching activities and self-perceived teaching proficiency in PGY2 residencies. AB - OBJECTIVE: To describe common teaching activities included in post-graduate residencies, identify residents' self-perceived ability to perform the activities, and report characteristics of residents who did not feel post graduate residency training prepared them for an academic career. METHODS: Residency Directors of PGY-2 ASHP-accredited U.S. residency programs in the July 2013-June 2014 cycle were asked to forward a 16-item online survey to PGY-2 residents. The survey was designed to determine teaching activities from a list of 21 common activities and measure self-perception of skill development. Residents who felt unprepared for academia were analyzed. RESULTS: There were 446 residents in PGY-2 residencies in the 2013/2014 residency cycle and 237 (53%) completed the survey. Common teaching activities included delivering lectures and developing handouts, motivating students and providing feedback on rotation, and delivering continuing education programs. Comparisons between the activity occurrence and incidence of self-perceived proficiency were similar for all 21 activities. Forty residents originally intended to pursue academia but only 19 entered academia. Twenty-six residents reported not feeling adequately prepared as an influencing factor, significantly less exposure to several common teaching activities, and less self-perceived ability to perform the activities in 15 out of 21 common teaching activities. CONCLUSION: PGY2 residents reported self efficacy for all teaching activities experienced during residency training. Residents who felt unprepared to enter academia were exposed to significantly less teaching activities and reported less self-efficacy to perform the skills. Closer attention to the types of teaching activities included in residency programs is warranted. PMID- 29233407 TI - The importance of clinical research skills according to PharmD students, first year residents, and residency directors. AB - PURPOSE: Research has a prominent role within the field of pharmacy practice. However, no studies have assessed the importance of research methods in pharmacy education from the perspective of students, residents, or residency directors. METHODS: Questionnaires were administered online in spring 2014 to four respondent groups: University of Colorado fourth year PharmD (P4) students, post graduate year 1 (PGY1) residents, and PGY1 and post-graduate year 2 (PGY2) residency directors. Descriptive statistics were used to characterize respondents; t-tests and chi-square tests were used to compare groups of respondents. RESULTS: Respondents included 255 PGY1 residency directors, 155 PGY2 residency directors, 35 PGY1 residents, and 87 P4 students. Response rates ranged from 26% (residency directors) to nearly 60% (P4 students and PGY1 residents). PGY1 residents and PGY1/PGY2 residency directors ranked research experience lowest among ten characteristics with respect to their importance when competing for a residency or being a successful resident. Among six specific clinical research skills, PGY1 residents and PGY1/PGY2 residency directors ranked "identifying and writing a research question" as the most important for successfully completing a residency research project or when selecting a PGY1/PGY2 resident. CONCLUSIONS: Perceived importance of clinical research skills by P4 students, current residents, and residency program directors is low. This is in opposition to opinions from several national organizations that proclaim the importance of clinical research skills in doctor of pharmacy curricula. Pharmacy programs must continue to further develop clinical research skills and abilities of future graduates while being cognizant of these perception barriers when developing strategies to enhance research experiences within their curricular programs. PMID- 29233408 TI - Structured academic discussions through an online education-specific platform to improve Pharm.D. students learning outcomes. AB - OBJECTIVE: To facilitate active academic discussions using an online, education centered platform and reinforce concepts, in order to improve overall course outcomes. MATERIALS AND METHODS: A third year integrated pharmacotherapy course was enrolled on an online searchable platform, Piazza(r), to facilitate academic discussions. Students could ask, answer, and explore content, and build on submitted answers in wiki style in collaboration. Instructor posted learning objectives, endorsed student responses with correct answers and led follow-up discussions. Review sessions were conducted on this platform before all major exams. A student t-test was used to compare class performance with those of previous years. RESULTS: In a post-activity qualitative survey, most students appreciated the less stressful, online interaction with peers and faculty. For 15 medicinal chemistry course hours, there were 83 posts on Piazza(r) with 303 total contributions, 107 student responses, and 546min of group discussion time. 94% of questions received student responses and 89% of those were endorsed by the instructor. Students enjoyed pre-exam discussions, organization of the page, and reinforcing material on complex learning objectives. This discussion forum fostered personal exploration of content by the students, which led to better performance on examinations. CONCLUSIONS: Involving the use of an online, education-centered platform for student discussions was an effective means of increasing class engagement with the course material. Student performance on exams was significantly improved in both cohorts that utilized active learning compared to the cohort without active learning (p=0.001 and p= 0.002 respectively). Piazza(r) can be utilized for any course and across disciplines. PMID- 29233409 TI - Five years of lesson modification to implement non-traditional learning sessions in a traditional-delivery curriculum: A retrospective assessment using applied implementation variables. AB - : Non-traditional learning (NTL), including aspects of self-directed learning (SDL), may address self-awareness development needs. Many factors can impact successful implementation of NTL. OBJECTIVES: To share our multi-year experience with modifications that aim to improve NTL sessions in a traditional curriculum. To improve understanding of applied implementation variables (some of which were based on successful SDL implementation components) that impact NTL. METHODS: We delivered a single lesson in a traditional-delivery curriculum once annually for five years, varying delivery annually in response to student learning and reaction-to-learning results. At year 5, we compared student learning and reaction-to-learning to applied implementation factors using logistic regression. RESULTS: Higher instructor involvement and overall NTL levels predicted correct exam responses (p=0.0007 and p<0.0001, respectively). Exam responses were statistically equivalent between the most traditional and highest overall NTL deliveries. Students rated instructor presentation skills and teaching methods higher when greater instructor involvement (p<0.0001, both) and lower overall NTL levels (P<0.0001, both) were used. Students perceived that teaching methods were most effective when lower student involvement and higher technology levels (p<0.0001, both) were used. CONCLUSION: When implementing NTL sessions as a single lesson in a traditional-delivery curriculum, instructor involvement appears essential, while the impact of student involvement and educational technology levels varies. PMID- 29233410 TI - Teaching students to become effective educators through an academic elective course. AB - INTRODUCTION: 2013 CAPE outcomes and 2016 ACPE accreditation standards state student graduates should be "able to educate all audiences by determining the most effective and enduring ways to impart information and assess learning". RATIONALE AND OBJECTIVE: The purpose of this article is to describe the implementation of a professional elective that achieves this outcome and improves students' abilities to teach, communicate, and conduct peer and self-assessment. The Learn to Teach course is a 2-credit hour elective offered to second professional year pharmacy students over an 11-week quarter. METHODS: Quantitative and qualitative data was collected from 2010 to 2015 and included students' overall course grades, grades on the formal presentation, and student course evaluations. Peer and self-assessment scores were compared to faculty scores to see if there was any correlation. RESULTS: 116 students have participated in the elective course from 2010 to 2015, 64% of which completed a course evaluation. The mean grade achieved in the course was 93.5%. The mean faculty formal presentation grade for the course was 90.9% and the mean peer assessment grade was 96.2%. The peer and faculty presentation grades showed a 23.8% correlation. Overall, students strongly agreed/agreed that the course objectives were clear (average score of 3.79/4) and course assessments correlated with the course objectives (average score of 3.81/4). CONCLUSION: The academic elective has been well received and successfully completed by professional students over the last several years. The skills taught in this academic elective course are applicable to a variety of future pharmacy careers. PMID- 29233411 TI - Utilization of external reviews by colleges of pharmacy during the promotion and tenure process for pharmacy practice faculty. AB - OBJECTIVE: To evaluate the use of external reviews by colleges of pharmacy (COP) during the promotion and tenure process for pharmacy practice faculty. METHODS: A 25-item web-based survey was sent to 112 Pharmacy Practice Department Chairs. Results were analyzed via descriptive statistics. RESULTS: Fifty-four of 112 colleges (48%) responded to the survey, although respondents had the option to skip questions. Of those who responded, 82% utilize external review in their Promotion and Tenure evaluation. At the majority of colleges that responded, reviewers are selected from a combination of sources including the candidates' personal list and in most circumstances someone other than the candidate contacts the reviewer to determine interest and availability. At almost all responding colleges, the reviewer receives the candidate's curriculum vitae and specific guidelines for completing the review. Based upon 40 respondents, colleges request the reviewer(s) to evaluate the candidate's research (100%), teaching (80%), clinical practice (73%) and external service (73%). CONCLUSION: The goal of this project was to examine the current use of external review during the Promotion and Tenure process for pharmacy practice faculty. This data is a sample of what is being done at the schools that responded. The majority of responding COP utilize external reviews, however methods and requirements vary considerably. PMID- 29233412 TI - Forecasting academic success through implementation of an online prerequisite review tutorials program for first year pharmacy students. AB - OBJECTIVE: Online prerequisite review (OPR) tutorials were designed and implemented to reinforce foundational scientific material in order to protect in class time, foster self-directed learning, and ensure all students have similar baseline knowledge. METHODS: Twenty-one tutorials covering undergraduate prerequisite material were developed by faculty and organized into six core modules, comprising basic biology, chemistry, and physiology topics. A quiz on this material was given on the first day of each course. This score was correlated with the final exam score at course completion. Additional student and faculty feedback was collected through surveys. RESULTS: 2372 quiz-exam pairings were collected over three consecutive fall semesters. A one point increase in the quiz score was associated with a 3.6 point (95% confidence interval 3.1-4.0) higher exam score, as well as a greater probability of passing the exam (P<0.0001). Furthermore, simple linear regression revealed a positive correlation between quiz and exam scores (P<0.0001). Three full years of student survey data revealed an overwhelmingly positive perception of the OPR tutorials, and surveyed faculty reported better use of class time and improved student competency and participation. CONCLUSIONS: Implementation of OPR tutorials may give faculty more efficient use of class time, and their associated quizzes serve as an early indicator for students at-risk of not passing who are candidates for early interventions. Furthermore, the OPR tutorial design gives it great transferability to biomedical post-graduate programs. PMID- 29233413 TI - Assessing student knowledge, confidence, accuracy, and proficiency in providing Medicare Part D assistance. AB - PURPOSE: To assess the impact of coordinated didactic, simulation-based, and experiential learning on pharmacy students' knowledge and confidence with Medicare Part D and their accuracy and proficiency with the Medicare Plan Finder Tool. EDUCATIONAL ACTIVITY: Forty-two pharmacy students participated in a two semester Medicare Part D elective course in which didactic, simulation-based and experiential learning methods were employed. Students' knowledge, confidence, accuracy, and proficiency were assessed at three course time points: first day of class, last day of in-class education, and after completion of outreach. FINDINGS: Student confidence with Part D and efficiency using the Plan Finder Tool significantly improved at each successive time point (p<0.01). Student knowledge was significantly improved both on the last day of class and after outreach completion as compared to the first day of class (p<0.01). SUMMARY: Basic Part D knowledge improved with the didactic and simulation-based portion of the course. The experiential component improved student confidence and efficiency in helping Medicare beneficiaries. PMID- 29233415 TI - Development and evaluation of an intermediate-level elective course on medical Spanish for pharmacy students. AB - BACKGROUND AND PURPOSE: The Spanish-speaking population in the United States is increasing rapidly, and there is a need for additional educational efforts, beyond teaching basic medical Spanish terminology, to increase the number of Spanish-speaking pharmacists able to provide culturally appropriate care to this patient population. This article describes the development and evaluation of an intermediate-level elective course where students integrated pharmacy practice skills with Spanish-language skills and cultural competency. Educational Activity and Setting: Medical Spanish for Pharmacists was developed as a two-credit elective course for pharmacy students in their third-professional-year who possessed a certain level of Spanish language competence. The course was designed so that students would combine patient care skills such as obtaining a medication list and providing patient education, and pharmacotherapy knowledge previously learned in the curriculum, along with Spanish-language skills, and apply them to simulated Spanish-speaking patients. Elements to promote cultural competency were integrated throughout the course through a variety of methods, including a service learning activity. FINDINGS: Successful attainment of course goals and objectives were demonstrated through quizzes, assignments, examinations, and an objective structured clinical examination (OSCE). Based on these course assessments, students performed well during both offerings of the course. DISCUSSION: While the class cohort size was small in the two offerings of the course, the Medical Spanish for Pharmacists elective may still serve as an example for other pharmacy programs as an innovative approach in combining Spanish language, specific pharmacy skills, cultural competency, and service learning. PMID- 29233414 TI - Teaching drug utilization review skills via a simulated clinical decision making exercise. AB - BACKGROUND: Drug utilization review (DUR) is a central role of the pharmacist, especially within the community pharmacy setting. Previous literature has shown risk of "alert fatigue", supporting the necessity of pharmacists to utilize a step-wise approach in evaluation of drug therapy during the verification process. Many students are intimidated by this process, and may lack verification practice or experience until their first day as a licensed pharmacist. EDUCATIONAL ACTIVITY AND SETTING: An innovative skills-based laboratory exercise was developed for third-year pharmacy students to develop DUR skills. Through simulation of patient prescriptions, profiles, and drug information resources, students were tasked with completing a DUR for each patient case. Students were expected evaluate the clinical significance of various drug-related problems, determine if they would or would not dispense the prescription, and were required to provide rationale for their decision. FINDINGS: This learning activity was well-received by the student population; however, students struggled with the volume of cases along with identifying a solution to the clinical scenario. On average, students required nine minutes per case, which is likely longer than community pharmacists can devote to a single DUR in practice. DISCUSSION: In response, to student challenges with the activity, the number of cases was condensed to highlight key concepts and cases that facilitated strong discussion. To improve students' approach to the DUR process, faculty developed a vodcast to watch prior to the activity explaining a systematic approach to the DUR process as well as considerations a pharmacist should have. SUMMARY: Development and integration of an active-learning, simulated dispensing activity allowed students to gain valuable experience completing the DUR process, a foundational community pharmacy practice skill; however, repeated experience should be provided to ensure competency. PMID- 29233416 TI - Implementing and sustaining a mentorship program at a college of pharmacy: The Keys to Successful Mentorship. AB - OBJECTIVE: To evaluate mentor and mentee opinions of The Keys to Successful Mentorship, a longitudinal student-led mentorship program established at a college of pharmacy. EDUCATIONAL ACTIVITY AND SETTING: In 2008, a mentorship program was created whereby first year pharmacy students (mentees) were paired with third year pharmacy students (mentors). An anonymous survey was administered to second (P2) and fourth (P4) year pharmacy students identifying strengths and weaknesses of the program. FINDINGS: Results of the survey administered to the P2 and P4 pharmacy students revealed that there was a strong desire to take part in the mentorship program. Of the respondents, 77% of P2 and 70% of P4 students stated the mentorship program aided in their professional growth. Mentors disagreed significantly more than mentees that participation in the program should be optional. Qualitative findings suggested that the program assisted students in building professional relationships and networks, better prepared them for experiential training, and helped with post-graduate decisions. CONCLUSION: The implementation of a longitudinal student-led mentorship program was supported by student pharmacists and may aid in their professional development. PMID- 29233417 TI - Comparison of student confidence and perceptions of biochemistry concepts using a team-based learning versus traditional lecture-based format. AB - PURPOSE: To evaluate differences in student confidence and perceptions of biochemistry concepts using a team-based learning (TBL) format versus a traditional lecture-based format at two universities. EDUCATIONAL ACTIVITY: Two pedagogies (TBL vs lecture-based) were utilized to deliver biochemistry concepts at two universities in a first-professional year, semester-long biochemistry course. A 21-item instrument was created and administered pre-post semester to assess changes in confidence in learning biochemistry concepts using Bandura's Social Cognitive Theory (eight items, 5-point, Likert-type) and changes in student perceptions of biochemistry utilizing the theory of planned behavior (TPB) domains (13 items, 7- point, Likert-type). Wilcoxon signed-rank tests were used to evaluate pre-post changes, and Mann Whitney U tests for differences between universities. FINDINGS: All students (N=111) had more confidence in biochemistry concepts post-semester, but TBL students (N=53) were significantly more confident. TBL students also had greater agreement that they are expected to actively engage in science courses post-semester, according to the perceptions of biochemistry subscale. No other differences between lecture and TBL were observed post-semester. SUMMARY: Students in a TBL course had greater gains in confidence. Since students often engage in tasks where they feel confident, TBL can be a useful pedagogy to promote student learning. PMID- 29233418 TI - Integrating parts of the APhA Career Pathway Evaluation Program for pharmacy professionals into a career development lab. AB - BACKGROUND AND PURPOSE: To use parts of the APhA Career Pathway Evaluation Program for Pharmacy Professionals in a career development laboratory designed to provide students with relevant information that will help them prepare for successful careers across the profession of pharmacy. EDUCATIONAL ACTIVITY AND SETTING: Students enrolled in the second professional year of pharmacy school participated in an interactive three-hour career development laboratory. Students completed the APhA Career Pathway Evaluation Program for Pharmacy Professionals Online Assessment Tool prior to the laboratory. In class, the students were randomized into eight groups. Two career profiles were assigned to each group for discussion during a thirty-minute brainstorming session. The groups reported their knowledge for each career profile to the entire class, and the instructors supplemented the discussion with details and more specific information about each profile. FINDINGS: Two years of data were collected (n=300 students). One hundred and twenty four (41.3%) students responded to the voluntary post-laboratory survey questions. Overall, students rated the career pathway activities favorably with an average score of 8.13 out of 10. After participation in the discussion, 74 (59.7%) respondents indicated their career interests had been impacted. SUMMARY: This career development laboratory is one example of how the APhA Career Pathway Evaluation Program for Pharmacy Professionals can be effectively incorporated into the PharmD curriculum in order to help students explore the various career options they might not have otherwise discovered on their own. PMID- 29233419 TI - Implementation and impact of a chronic kidney disease elective for second-year pharmacy students. AB - BACKGROUND AND PURPOSE: Pharmacists can make a great impact on the management of chronic kidney disease (CKD), which is a highly prevalent and costly disorder. This article describes the implementation and impact of a CKD elective course for second-year pharmacy students, which aimed to expose students to CKD and enhance their ability to care for these patients. EDUCATIONAL ACTIVITY AND SETTING: Topics associated with CKD were covered in a fifteen-week, three credit hour course. Various active-learning techniques were utilized, including student presentations of pharmacotherapy and primary literature, team-based learning though patient case discussions, and interactions with standardized and actual patients. Surveys designed to assess students' career goals and level of confidence with assessing primary literature, delivering presentations to peers, working as members of a team, and communicating with patients were administered at the beginning and end of the course. FINDINGS: Twenty-three students (100%) participated in the initial survey, and nineteen (86.4%) participated in the final survey. Students gave more positive responses on the final survey that they were considering a career in ambulatory care (P=0.03), planning to pursue a career in ambulatory care (P=0.02), considering a career in kidney disease management (P=0.02), and planning to pursue a career in kidney disease management (P=0.0498). Students also felt more confident in their ability to assess primary literature (P=0.005) and deliver presentations to their peers (P=0.02). SUMMARY: Courses such as this can expose students to new and unique career paths and help them develop key skills to promote a successful and fulfilling pharmacy career. PMID- 29233421 TI - Motivations, career aspiration, and learning experience of students in the pharmacy program at Kuwait University: A tool to guide curriculum development. AB - PURPOSE: To determine students' motivating factors in the choice of pharmacy, career aspirations, and perceptions about learning experiences in the current pharmacy curriculum. ACTIVITY: A descriptive cross-sectional survey of pharmacy students was performed at Kuwait University FINDINGS: The most common reason to pursue pharmacy was that they were not admitted to medicine or dentistry (40.5%). About half of students were seeing themselves employed in hospital pharmacies immediately after graduation. Over two-thirds of respondents 'agreed' or 'strongly agreed' that the pharmacy program developed their problem-solving skills (78.5%) and improved their communication skills (66.4%). Students also admitted that the teaching staff seemed more interested in testing memorization (72.5%), that feedback on student work was usually provided in the form of grades (66.4%), and that the workload is putting a lot of pressure on them (88%). SUMMARY: The survey identifies key elements that needs to be improved in the next iteration of the program (entry-level PharmD). PMID- 29233420 TI - Student pharmacist perceived benefit of a sequential training model for health testing. AB - PURPOSE: This article describes the health testing training process used at Presbyterian College School of Pharmacy and evaluates perceptions of the sequential training model among students in their first, second, and third professional years. EDUCATIONAL ACTIVITY AND SETTING: After observing student deficiencies in the knowledge and skills necessary for performing health tests, despite receiving didactic training within the core curriculum, faculty members searched for supplemental training programs used by other schools of pharmacy. No literature regarding structured programs was found. Consequently, faculty developed test-specific training modules for a variety of health screenings. Students who participated in the sequential self-learning followed by a live skills assessment were surveyed to determine their perceptions of the training. FINDINGS: During the 2014-2015 academic year, 78 students successfully completed health testing training modules. Of these students, 56 (72%) completed an attitudinal survey designed to assess their perceptions. Nearly 93% of respondents perceived improved confidence after completing the training. Regardless of the year in pharmacy school, 88% of respondents believe they would not have been adequately prepared to conduct the health test(s) without this training. SUMMARY: Student perception and acceptance of health testing training were positive. Using sequential training modules to teach and reinforce the skills necessary for performing health tests can improve student ability and confidence. Consequently, students have the opportunity to impact the health of the community while becoming practice ready in the area of health testing. PMID- 29233422 TI - Implementation of a virtual dispensing simulator to support US pharmacy education. AB - INTRODUCTION: A key element for pharmacy practice defined by the Accreditation Council for Pharmacy Education (ACPE) is medication use systems management. A web based community pharmacy simulation originally created for Australian pharmacy students was adapted for pharmacy students in the United States (US). The objective of this study was to collaboratively adapt an existing international simulation program for utility in the US and measure student perceptions of a web based community pharmacy simulation program in three US schools of pharmacy. METHODS: An Australian development team in collaboration with US pharmacy school faculty modified the existing MyDispense software to create a virtual environment that accurately represented US community pharmacy practice. Students at three US schools of pharmacy used the newly adapted version of MyDispense and were surveyed on their prior experience in community pharmacy and their perceptions of MyDispense as a learning tool. RESULTS: Overall 241 (44%) students completed the satisfaction survey. Approximately 40% of these students worked in a community pharmacy before starting pharmacy school. Most students agreed or strongly agreed that MyDispense was straightforward to learn (76%), was more realistic than addressing similar paper cases (73%), and offered a learning opportunity to safely make errors (84%). Qualitative thematic analysis revealed that MyDispense allowed students to practice how to gather patient information and ask appropriate questions, counsel patients, and practice the dispensing process. DISCUSSION AND CONCLUSIONS: Response to the US version of My Dispense is positive and proves to be a viable option for introducing and reinforcing community pharmacy practice skills to students during in their pharmacy education. PMID- 29233423 TI - Complementary and alternative medicine education in U.S. schools and colleges of pharmacy. AB - INTRODUCTION: The objective of this survey is to provide an update on the state of complementary and alternative medicine (CAM) education and describe instructional and assessment methods across schools and colleges of pharmacy. METHODS: One hundred thirty-five schools of pharmacy were contacted to participate in a survey describing the incorporation of CAM education into their respective curricula. The survey also inquired about perceived barriers and future plans for CAM-related courses. RESULTS: Ninety-six schools responded to the survey (71.1%), with all schools reporting that CAM is incorporated into the curriculum. Topics covered, teaching strategies, and assessment methods varied among the 74 elective and 116 required courses described. Respondents listed lack of evidence to support CAM use as the most common barrier to CAM education, and 50% of respondents reported plans for expansion of CAM education at their schools. CONCLUSIONS: CAM education in pharmacy curricula has grown over the last decade, but remains varied in topics taught and teaching methods. PMID- 29233424 TI - Design, implementation, and evaluation of an online elective course on current topics in pharmacy. AB - INTRODUCTION: To describe the design and implementation of the Current Topics in Professional Pharmacy online elective course and evaluate the degree to which the course improved student pharmacists' awareness of and interest in current topics affecting the profession of pharmacy. METHODS: A one-credit hour online summer elective included weekly modules of current topics affecting the profession of pharmacy, along with a longitudinal final project in which students created their own current topic module. Each module consisted of assigned reference materials and online discussion forum posts to answer discussion questions and share professional opinions. Student achievement of curricular outcomes and course specific objectives was measured utilizing pre- and post-course surveys, assessment of weekly module forum posts, and a final course knowledge and comprehension quiz. RESULTS: Student self-rated awareness and desire to stay updated on current topics in pharmacy increased significantly from pre-survey to post-survey (39.7% to 98.3% agree or strongly agree, p<0.001; 25.9-87.9%, p<0.001, respectively). Student confidence in their ability to formulate and effectively express their professional opinion also significantly improved (67.2% to 93.1%, p<0.001). Seven of the 12 course competencies assessed by the survey significantly improved from pre- to post-course. The majority of students agreed or strongly agreed that the course adequately addressed all 12 pre-selected Accreditation Council for Pharmacy Education (ACPE) Appendix B content areas. CONCLUSIONS: Performance assessment and survey results demonstrated achievement of curricular outcomes and course objectives. Students completing the course showed an increased interest and awareness related to current topics affecting the profession of pharmacy. PMID- 29233425 TI - Examining differences between P1 versus P2 students as teaching assistants in a P1 skills-based course. AB - INTRODUCTION: The purpose of this study was to assess differences between the use of first-year (P1; "peer") versus second-year (P2; "near-peer") students as teaching assistants (TA) in a first-year, skills-based course. METHODS: The practicum course assesses competence in the provision of screening services and patient counseling. TAs review weekly material followed by a one-on-one assessment of each student using a grading rubric. Both qualitative and quantitative data were analyzed to determine if there was a difference in performance between the peer and near-peer teaching assistants. RESULTS: Sixteen peer and 33 near-peer TAs were evaluated by 210 students for six different skill assessments in practicum. There was no significant difference between peer and near-peer TAs in both student perception of TA performance and in TA grading of student performance. CONCLUSIONS: There is no difference in the use of peer versus near-peer TAs in evaluating first-year pharmacy students in the skills based course. Using peer TAs over near-peer TAs can be useful when faced with scheduling and other resource conflicts. PMID- 29233426 TI - Analysis of pharmacy student motivators and deterrents for professional organization involvement. AB - INTRODUCTION: The purpose of this study was to determine motivators and deterrents impacting a student pharmacist's decision to join professional organizations. The goal was to create a list of meaningful factors that organizations can use for membership recruitment. METHODS: This descriptive study utilized a blinded electronic survey sent to eight accredited pharmacy schools in Ohio, Michigan, Wisconsin, Indiana, Illinois, and Kentucky. The survey assessed motivating and hindering factors, as well as demographic data. RESULTS: Eight hundred fifty-six students completed the survey, a 15.05% participation rate. Professional development and networking were the top two endorsed motivational factors, selected as significant by 88.0% and 87.5% respectively. Upon chi-square analysis, networking (p<0.001), involvement opportunities (p=0.01), and scholarships (p=0.02) were motivating factors with which membership was found to be significantly influenced. Networking and involvement opportunities were more significant for members while scholarships were a greater motivator among nonmembers. Time required for involvement and cost were the most commonly selected hindrances with 78% and 76% respectively identifying these as significant barriers. The hindering factor found to be significantly different between active members and nonmembers was bylaws/rules of the organization (p=0.032), with non-members rating this as a greater consideration than current members. DISCUSSION AND CONCLUSIONS: Multiple factors contribute to a student's decision to join a professional organization. Those active members find greater significance in networking involvement opportunities. Non-member students found scholarships more motivating and recognize bylaws as a consideration for membership more than current members. These results emphasize the multifactorial nature of membership and may direct future membership initiatives. PMID- 29233427 TI - Master of Pharmacy students' knowledge and awareness of antibiotic use, resistance and stewardship. AB - INTRODUCTION: Antibiotic resistance has become a global public health concern. In this study, we investigated the knowledge and awareness of antibiotic use, resistance and stewardship, held by the pharmacy students currently studying at the University of Brighton. METHODS: This was a cross-sectional, online survey, and email invitations to participate were sent to all students attending our Master of Pharmacy (MPharm) course (n=583). Students' knowledge was assessed with 29 items; responses for these were totaled before comparison among students. Comparison of scores between groups of students was performed using the Kruskal Wallis or the Mann-Whitney U test, as appropriate. RESULTS: The response rate was 32%. The overall median knowledge score was 7.9. There was a statistically significant difference in knowledge scores between years of study (p=0.02), particularly between year of study 1 (7.6) and 4 (8.3). A statistically significant difference was found between the knowledge scores of male (8.4) and female (7.9) students (p=0.03). Most students believed a strong knowledge of antibiotics, and microbiology and infection control is important for their pharmacy careers and more than 90% agreed that antibiotic resistance will be a greater clinical problem in the future. DISCUSSION AND CONCLUSIONS: Although the MPharm students studied achieved good overall knowledge scores, a significant proportion showed a lack of understanding with regards to some important aspects of antibiotic resistance mechanisms, factors promoting the emergence and spread of antibiotic resistance, and antibiotic stewardship policies. PMID- 29233428 TI - Training student pharmacists to administer emergency pediatric influenza vaccine: A comparison of traditional vs. just-in-time training. AB - INTRODUCTION: This study compared traditional training (TT) and just-in-time training (JITT) of P3 student pharmacists regarding interest, confidence, and comfort pre- and post-training (primary objective); and assessment and administration competency (secondary objective) during a simulated influenza vaccination clinic. METHODS: Student pharmacists were randomized 1:1 to receive either TT or JITT, completed pre- and post-training surveys assessing interest, confidence and comfort; and evaluated on performance during a simulated emergency infant vaccination. An infant manikin simulated a child <1 year of age, and an actor role-played the mother. All students received a briefing about the simulated mass vaccination prior to their performance assessment. Survey differences between groups were analyzed by ANOVA. The competency assessment was analyzed by a Chi-square or Fisher's exact test for individual steps and Student t-test for mean scores. RESULTS: Pre-training interest was high and maintained post-training. Pre-training confidence and comfort levels were low and improved in both groups. Mean competency scores were comparable between the TT and JITT groups. Comparing groups, TT students more commonly missed proper injection site selection and care; while JITT missed distracting the infant and administration documentation. DISCUSSION AND CONCLUSIONS: JITT for student pharmacists to learn skills required to immunize infants elicits similar outcomes (interest, confidence, comfort, and administration competency) as TT for emergency pediatric influenza vaccination. PMID- 29233429 TI - Pharmacy students' perceptions of the usefulness of motivational interviewing and the use of mobile health applications on patient counseling in the future. AB - INTRODUCTION: To explore student pharmacists' perceptions of 1) future patient counseling, 2) use of mobile health applications (mHealth apps), and 3) usefulness of motivational interviewing (MI) in patient encounters and potential app messaging. METHODS: A cross-sectional design with first and second year pharmacy students (n=315) at a multi-campus university after exposure to mHealth app and MI curricular content. A questionnaire assessed perceptions of 1) future patient counseling, 2) using apps for personal use and professional encounters, and 3) potential practicality and usefulness of MI principles/skills in apps messaging. RESULTS: Over 70% of students perceived they will be counseling future patients for medication therapy/comprehensive disease management; 91% believed it is an important role as a future pharmacist. A majority own a smartphone (98%), have used an mHealth app to monitor/change a health behavior (73%), and are likely to recommend an mHealth app in future patient encounters (90%). Perceptions of counseling importance and likelihood to recommend an mHealth app varied by gender (women higher than men, p<0.01, p<0.01) and previous mHealth app use (yes higher than no, p<0.05, p<0.001). Most students reported a high likelihood of incorporating MI into current (88%) and future (91%) patient encounters and particularly noted 'supporting self-efficacy' as a useful MI principle to incorporate into mHealth app messaging. DISCUSSION AND CONCLUSIONS: Those using apps for personal health behavior change(s) perceived future patient counseling as important and were more likely to recommend mHealth apps during those future encounters. Results may inform curricular development to prepare future pharmacists for the high-tech, patient-centered practice that is inevitable. PMID- 29233430 TI - Assessment of SOAP note evaluation tools in colleges and schools of pharmacy. AB - INTRODUCTION: To describe current methods used to assess SOAP notes in colleges and schools of pharmacy. METHODS: Members of the American Association of Colleges of Pharmacy Laboratory Instructors Special Interest Group were invited to share assessment tools for SOAP notes. Content of submissions was evaluated to characterize overall qualities and how the tools assessed subjective, objective, assessment, and plan information. RESULTS: Thirty-nine assessment tools from 25 schools were evaluated. Twenty-nine (74%) of the tools were rubrics and ten (26%) were checklists. All rubrics included analytic scoring elements, while two (7%) were mixed with holistic and analytic scoring elements. A majority of the rubrics (35%) used a four-item rating scale. Substantial variability existed in how tools evaluated subjective and objective sections. All tools included problem identification in the assessment section. Other assessment items included goals (82%) and rationale (69%). Seventy-seven percent assessed drug therapy; however, only 33% assessed non-drug therapy. Other plan items included education (59%) and follow-up (90%). DISCUSSION AND CONCLUSIONS: There is a great deal of variation in the specific elements used to evaluate SOAP notes in colleges and schools of pharmacy. Improved consistency in assessment methods to evaluate SOAP notes may better prepare students to produce standardized documentation when entering practice. PMID- 29233431 TI - Development and delivery of an interdisciplinary course in mobile health (mHealth). AB - BACKGROUND: Interdisciplinary practice is a primary focus within the United States health care system. Despite the existence of interdisciplinary educational efforts in pharmacy for many years, the practice only recently entered mainstream health care education. Informatics offers interdisciplinary educational opportunities. Mobile health (mHealth), an informatics sub-discipline, is the use of mobile devices for health and wellness activities. We used the mHealth domain as the context for an interdisciplinary learning experience for pharmacy and computer science and software engineering (CSSE) students. EDUCATIONAL ACTIVITY: Educational activities focused on creating an mHealth course sequence and an mHealth application (app). Students worked in teams to complete various assignments, including developing and presenting a course proposal, building a purchase plan for mHealth equipment, developing an mHealth app prototype, delivering a disease state presentation (pharmacy students only), developing use case scenarios (CSSE students only), and completing peer evaluations. CRITICAL ANALYSIS OF THE EDUCATIONAL ACTIVITY: Course evaluations were only available from pharmacy students. They indicated an overall favorable rating (mean 3.27-3.55; 4=strongly agree). Survey data collected after students entered the workforce indicated that students felt better prepared than their colleagues to work with individuals from other disciplines (mean 4.82; 5=strongly agree). Students also indicated using the knowledge from course proposal development in their careers (mean 4.27; 5=strongly agree). Through team interactions, students learned from each other while overcoming challenges related to terminology and content areas. Skills learned through team interactions reflect real-world processes and are expected to support students' future professional responsibilities. PMID- 29233432 TI - Design and activity evaluation of an Advanced-Introductory Pharmacy Practice Experience (aIPPE) course for assessment of student APPE-readiness. AB - BACKGROUND AND PURPOSE: The newly implemented Advanced-Introductory Pharmacy Practice Experience (aIPPE) course at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences was designed to assess student readiness for Advanced Pharmacy Practice Experience (APPE) and provide formative feedback regarding skills and abilities needed to be successful during subsequent coursework and practice experiences. EDUCATIONAL ACTIVITY AND SETTING: The aIPPE is a full-time, six week (240hours) direct patient care rotation occurring in the spring semester of the third-professional year following a longitudinal integrated IPPE program. Required aIPPE course elements mimic the activities and expectations students should anticipate encountering during APPE training. FINDINGS: All students participating in the initial aIPPE course offering were described as APPE-Ready. Students and preceptors described the aIPPE course as successful in achieving the primary outcome of preparing students for improved downstream performance. SUMMARY: The aIPPE provided students opportunities to demonstrate readiness to enter advanced pharmacy practice experience. PMID- 29233433 TI - Interprofessional objective structured teaching exercise (iOSTE) to train preceptors. AB - BACKGROUND AND PURPOSE: Interprofessional education (IPE) is important in the education of all health care students, yet limited IPE training has been provided to preceptors who train these students in the clinical setting. Simulation using the standardized student model has been used to train health care preceptors in medicine. To our knowledge, there are no reports utilizing interprofessional objective structured teaching exercises (iOSTE) to train pharmacy preceptors. The primary objectives of this pilot study were to evaluate the effects of iOSTE on the pharmacy preceptors' perceived importance of the Interprofessional Education Collaborative (IPEC) core competencies and confidence in precepting interprofessional students. Additionally, data were collected regarding pharmacy preceptors' prior experiences in simulation and debriefing. EDUCATIONAL ACTIVITY AND SETTING: Preceptors (n=23) participated in an iOSTE and debriefed with trained standardized nursing and pharmacy students caring for a trained standardized asthma patient. FINDINGS: Pre- versus post-iOSTE survey data showed statistically significant improvements in all self-confidence related items, including the following abilities: precept students from different disciplines (p=0.004), facilitate a simulation activity (p=0.001), conduct the debriefing process (p<0.001), and discuss with students the IPE core competencies (p=0.001). Additionally, responses to post-iOSTE survey questions assessing the learning activity showed high ratings (median=5, interquartile range=4 to 5). Pharmacy preceptors increased their teaching ability and confidence level in communicating with students from other health care professions. SUMMARY: These findings indicate that iOSTE is a useful and well-received method for preceptor development. PMID- 29233434 TI - Assessing students' knowledge regarding the roles and responsibilities of a pharmacist with focus on care transitions through simulation. AB - BACKGROUND AND PURPOSE: To evaluate the impact of a pharmacist-focused transitions of care (TOC) simulation on students' perceptions and knowledge of pharmacist roles in the healthcare continuum. Educational Activity and Setting: Two simulations, highlighting pharmacist roles in various practice settings, were conducted within the Pharmaceutical Skills courses in the third-year doctor of pharmacy curriculum. Patient cases were built utilizing electronic medical records (EMR). Students' knowledge was assessed before and after the simulations regarding pharmacist involvement in medication reconciliation, reduction in patient readmissions, reduction of inappropriate medication use, roles and communication on an interprofessional team, and involvement with health information technology (HIT) during care transitions. FINDINGS: Fifty-one third year pharmacy students were anonymously evaluated prior to and following the simulation to assess changes in knowledge and perceptions during the fall semester. Thirty-two (62.7%) students completed the pre-simulation and 21 (41.2%) students completed the post-simulation assessments, respectively. In the spring semester, 40 (80%) students completed the pre-simulation and 23 (46%) students finished the post-simulation assessments. Students predominately had community pharmacy work experience (n=28, 55%). Overall, students enjoyed the variety of pharmacist-led encounters throughout the simulation and assessments demonstrated an increase in knowledge after the simulations. SUMMARY: TOC simulations enhance students' understanding of the significant impact that pharmacists have in ensuring continuity of care as members of an interdisciplinary team. PMID- 29233435 TI - Creation of an active learning healthcare communications course using simulations relevant to pharmacy practice. AB - BACKGROUND AND PURPOSE: The purpose of this project was to design and develop a health care communications course built around practice-like simulations and active learning in the first year of a professional pharmacy program. EDUCATIONAL ACTIVITY AND SETTING: A three-credit health care communications course was divided into one didactic (two hours per week) and three simulation components (one hour per week). The simulation components consisted of one written patient education pamphlet, three group presentations, and three one-on-one patient counseling sessions. This was accomplished by breaking the class of approximately 75 students into eight separate sections, each consisting of 8-10 students and one instructor. Each week four sections were devoted to counseling role-plays: half in the role of pharmacists and half as patients. The other four sections were devoted to hour-long professional group presentations-half in the presenting group and half as audience. The students' performance in the simulated counseling sessions and group presentations has been tracked and analyzed to determine if the simulated exercises had a positive impact on the students' active communications skills. FINDINGS: Consistently, over the first four years of the implementation of the course, students' communications skills, as measured by faculty assessments, in both professional group presentations and one-on-one counseling sessions significantly improved. DISCUSSION AND SUMMARY: Incorporation of active-learning simulation exercises into a healthcare communications course has a positive impact on the development of students' communications skills. This creates a foundation upon which students can build over the remainder of the professional program and into their future careers. PMID- 29233436 TI - Efficacy of formative evaluation using a focus group for a large classroom setting in an accelerated pharmacy program. AB - BACKGROUND AND PURPOSE: Formative evaluation is a process utilized to improve communication between students and faculty. This evaluation method allows the ability to address pertinent issues in a timely manner; however, implementation of formative evaluation can be a challenge, especially in a large classroom setting. Using mediated formative evaluation, the purpose of this study is to determine if a student based focus group is a viable option to improve efficacy of communication between an instructor and students as well as time management in a large classroom setting. EDUCATIONAL ACTIVITY AND SETTING: Out of 140 total students, six students were selected to form a focus group - one from each of six total sections of the classroom. Each focus group representative was responsible for collecting all the questions from students of their corresponding sections and submitting them to the instructor two to three times a day. Responses from the instructor were either passed back to pertinent students by the focus group representatives or addressed directly with students by the instructor. This study was conducted using a fifteen-question survey after the focus group model was utilized for one month. A printed copy of the survey was distributed in the class by student investigators. Questions were of varying types, including Likert scale, yes/no, and open-ended response. FINDINGS: One hundred forty surveys were administered, and 90 complete responses were collected. Surveys showed that 93.3% of students found that use of the focus group made them more likely to ask questions for understanding. The surveys also showed 95.5% of students found utilizing the focus group for questions allowed for better understanding of difficult concepts. General open-ended answer portions of the survey showed that most students found the focus group allowed them to ask questions more easily since they did not feel intimidated by asking in front of the whole class. No correlation was found between demographic characteristics and survey responses. This may demonstrate that students in similar large classroom settings may respond in a similar fashion. DISCUSSION AND SUMMARY: An overwhelmingly positive result suggests focus groups may be a valuable addition to communication routes currently employed in classrooms. The focus group offers an alternate pathway to improve student understanding in larger lecture classroom environments and may encourage more students to seek answers to questions in a timely manner without breaking classroom flow. PMID- 29233437 TI - 'The bus analogy': A new analogy to help pharmacy students conceptualize the well stirred model. AB - BACKGROUND AND PURPOSE: To determine whether an analogy relating a city bus to the well-stirred model for high extraction drugs administered intravenously improves pharmacy students' self-perceived and objectively-assessed understanding. EDUCATIONAL ACTIVITY AND SETTING: Fifty-two entry-to-practice pharmacy students enrolled in an elective clinical pharmacokinetics course completed a questionnaire and quiz before and after the bus analogy presentation. Pre- and post test questionnaires consisted of five items measuring (on five point unipolar scale) students' self-perceived understanding of the model. Pre- and posttest quizzes contained one case-based question requiring mathematical, graphical, and intuitive understanding. Student's paired t-test with unequal variances was used to compare pre- and posttest results. FINDINGS: The bus analogy significantly improved students' self-perceived understanding of the model for all questionnaire items (p<0.01 each) and students' pre- and posttest mean quiz results (p<0.0001). SUMMARY: The bus analogy significantly improved pharmacy students' understanding of the well-stirred model both subjectively and objectively, and should be an adjunct to pharmacokinetics curricula. PMID- 29233438 TI - Student-led co-curricular medical Spanish training in a pharmacy professional program. AB - BACKGROUND AND PURPOSE: This paper describes a student-led co-curricular training program to increase pharmacy student proficiency with medical Spanish terminology. Western University of Health Sciences (WesternU) pharmacy students frequently can interact with Spanish-speaking patients in experiential rotations. Moreover, the clear majority of program graduates remain in California, a state with a high Spanish-speaking population. Developing foundational knowledge of medical Spanish terminology can enhance communication with Spanish-speaking patients, who may have limited English proficiency and experience a lack of language concordance when interacting with the healthcare system. Providing training in medical terminology in another language is important because communication barriers have been associated with adverse medical outcomes, such as poor medication adherence. EDUCATIONAL ACTIVITY AND SETTING: The development of the training logistics and materials are described for replication of the process, whether with medical Spanish or other languages. Students in the pharmacy program developed the medical Spanish training that is now a robust co curricular activity with over 100 students participating in the training each semester. An important aspect of the WesternU co-curricular activity is that students develop materials, create learning activities, and facilitate training. PMID- 29233439 TI - An investigation of final year pharmacy students' moral reasoning ability, and their views on professionalism and fitness to practice panel determinations: A questionnaire study. AB - BACKGROUND AND PURPOSE: The aim was to establish pharmacy students' moral reasoning ability and obtain their views on professionalism and fitness to practice (FtP) determinations involving pharmacists. EDUCATIONAL ACTIVITY AND SETTING: Following ethical approval and piloting, final year pharmacy students at Queen's University Belfast (QUB) (n=119) were invited to participate in a questionnaire study. Section A was a validated moral reasoning assessment tool [Defining Issues Test (DIT2); five moral dilemmas], Section B was FtP cases and professionalism. Distribution occurred at a compulsory class. DIT2 data were scored by the University of Alabama. Descriptive statistics and non-parametric tests were used with significance level set at 0.05 a priori. FINDINGS: The response rate was 94.1% (112/119) and the 'DIT2 P score mean' (postconventional schema) was 25.21+/-14.10. Almost all [(98.2% (110/112)] fully understood the term "professionalism" and 83.9% (94/112) considered it reasonable for a professional code to apply always (within university and out socializing). Differences in opinions existed depending on what the FtP case related to. Students were significantly more likely to consider a 12-month suspension 'very lenient' or 'lenient' for a pharmacist's personal use of illicit drugs compared with theft of money/cosmetics (42.0% versus 64.3%; p=0.031). There were no significant differences between male and female responses/scores and no strong correlations between DIT2 scores and FtP/professionalism responses. DISCUSSION AND SUMMARY: Pharmacy students appeared to understand professionalism and accepted being bound by a code. A level of discrimination between the FtP cases was evident. Moral reasoning ability was lower than expected for future healthcare professionals (see manuscript) requiring attention. PMID- 29233440 TI - Incorporation of practice testing to improve knowledge acquisition in a pharmacotherapy course. AB - BACKGROUND AND PURPOSE: To incorporate and assess the impact of a coordinated practice testing activity on pharmacy student knowledge acquisition, retention, and perception as an effective study technique in a pharmacotherapy course. EDUCATIONAL ACTIVITY AND SETTING: Students were instructed to individually create, exchange, complete, and discuss solutions to weekly, cumulative practice tests of targeted material during the first unit of the course. Students completed surveys on their perceptions of practice testing. Unit and final examination scores were compared to the previous year. FINDINGS: Comparison of average unit examinations scores showed only minimal improvement in knowledge acquisition, and no impact was detected in knowledge retention. Most students in the course did not perceive practice testing to be beneficial in learning or retaining unit material. DISCUSSION AND SUMMARY: Incorporating a coordinated practice testing activity may have minimally improved knowledge acquisition in our pharmacotherapy course. However, limitations exist which make it difficult to attribute improvement solely to our learning activity. PMID- 29233441 TI - Professional and pre-professional pharmacy students' perceptions of team based learning (TBL) at a private research-intensive university. AB - BACKGROUND AND PURPOSE: Pharmacy students need to develop critical thinking and problem-solving skills as well as be a valuable team member. The use of team based learning (TBL) fosters effective team collaboration, enables continuous active and self-directed learning, and requires both individual and team accountability. The purpose was to evaluate pharmacy students' perceptions and experiences related to TBL in different years of the pharmacy curriculum. EDUCATIONAL ACTIVITY AND SETTING: Two classes, Introduction to the Profession of Pharmacy (intro), a required course, and Self-Care/Non-Prescription Medications (self-care), an elective course, utilize the TBL approach. Students enrolled in both courses were recruited to complete a validated questionnaire during the last class. FINDINGS: There was 100% participation; the majority of students, regardless of course, expressed positive attitudes towards TBL. Variations, relevance of TBL activities and the use of TBL as a learning strategy, between the required intro class and the elective self-care class were observed using a Mann-Whitney U test (p<0.05). DISCUSSION: Both cohorts of pharmacy students positively rated the TBL sessions in terms of learning effectiveness. It's important to consider the differences in professional development in these students and how this may impact their perceptions of TBL. TBL imparts more responsibility and accountability on the individual student allowing for the development of self-directed learners. SUMMARY: Students, regardless of their year, found TBL to be an effective learning strategy. Third professional year (P3) pharmacy students further along in the curriculum are more accepting of TBL and are better able to appreciate the benefits of active and self-directed learning as well as working within a team. PMID- 29233442 TI - Preparing students for residency interviews through a residency interview boot camp. AB - BACKGROUND AND PURPOSE: To describe the offering of the residency boot camp activity at one college of pharmacy for students in their fourth professional year. EDUCATIONAL ACTIVITY AND SETTING: Student pharmacists in their final professional year of pharmacy school were invited to participate in a voluntary residency boot camp activity. Originally, the activity consisted of four parts: (1) guidance on preparing for residency interviews; (2) a 1:1 mock interview with a resident, faculty member, residency preceptor or area program director; (3) a review of the student's curriculum vitae (CV) and letter of intent; and (4) a review of the application timeline and process. Based on the feedback, the activity was changed to include five parts: (1) orientation/welcome session, (2) mock interview, (3) case presentation, (4) podium presentation, and (5) a debriefing session on the day's activities and to answer any remaining student questions about the residency application process. In the second offering of the residency boot camp, students were invited to complete a voluntary pre- and post assessment of their perceived readiness for residency interviews. The activity has evolved based on student feedback to focus predominately on the group and 1:1 interviews. FINDINGS: Since starting the activity in 2013, 14 of the 21 students (67%) from the class of 2014, 16 of the 25 students (64%) from the class of 2015 and 24 of the 26 students (92%) from the class of 2016 that applied for residency training participated in the residency boot camp activity. For the Fall 2014 offering where a survey was conducted, the pre- and post-survey instrument used a Likert Scale, ranging from "strongly disagree" (score of 1) to "strongly agree" (score of "5"). DISCUSSION: and conclusions: Simulated exercises such as a residency boot camp can expose student pharmacists to important interview readiness skills. Student pharmacists involved in this activity demonstrated a perceived positive effect of such activities. PMID- 29233443 TI - Educating medical residents through podcasts developed by PharmD students. AB - BACKGROUND AND PURPOSE: Podcasts are increasingly popular in education due to their accessibility, portability, and scheduling flexibility. Pharmacy students often interact with resident physicians during advanced pharmacy practice experiences, but few studies have evaluated their ability to teach medical residents about pharmacotherapy concepts or how these interactions might impact their own development. We sought to evaluate the efficacy of pharmacy student created podcasts in two areas: the ability to increase medical resident understanding of selected medical topics and the effect on the pharmacy student's confidence in teaching. EDUCATIONAL ACTIVITY AND SETTING: Eight fourth-year pharmacy students created enhanced podcasts and assessment questions on a medical topic. The assessment questions were split randomly into pre- and post-podcast assessments to be given to residents. The assessment quizzes and podcast comprised content modules that were delivered to consenting medical residents at two week intervals. Pharmacy student confidence was evaluated with pre- and post experience surveys, which were administered before they created the podcast and after they viewed the aggregate results of resident assessments of their podcast. FINDINGS: Overall, 79.3% (23/29) of residents participated with an average of 44% participation on each module. Resident knowledge increased as evidenced by the overall aggregate score, significantly improving from 36% prior to podcasts to 76% following podcasts (p=0.001). When rated on a 1-10 scale, average pharmacy student confidence in teaching their topic also significantly increased from 5.63 to 8.00 (p=0.041). SUMMARY: Podcasts are an effective method for medical residents to learn from pharmacy students and may also improve pharmacy students' confidence in their abilities. PMID- 29233444 TI - Assessing a traditional case-based application exercise and a student question creation exercise on student performance and perceptions. AB - BACKGROUND AND PURPOSE: To compare the impact of a traditional case-based application exercise with a student question creation exercise on a) student exam performance, b) student perceptions of enjoyment, competence, understanding, effort, interest in continuing participation, and interest in the subject. EDUCATIONAL ACTIVITY AND SETTING: Subjects were 84 second-year pharmacy students in a pharmacotherapy course. The research focus was active learning involving the topic of chronic kidney disease-mineral bone disorder. Student teams were randomly assigned to either case-based or student question creation exercises using PeerWise. Student performance was assessed by a pre- and posttest and on block and final exams. After completion, an online survey assessed student perceptions of both exercises. FINDINGS: Statistically significant differences were revealed in favor of the student question creation group on enjoyment and interest in the subject matter. No statistically differences were found between the traditional case-based group and the student question creation group on gain score from pre-test to posttest. The student question creation group performed slightly better than the case-based application group on two of the five questions on the block exam but none of these differences reached statistical significance. DISCUSSION AND CONCLUSIONS: Students randomly assigned to groups that created and reviewed questions exhibited slightly improved summative exam performance and reported significantly more positive perceptions than students engaging in a more traditional case-based learning activity. Student question creation has demonstrated potential as a useful learning activity. Despite inherent difficulties in designing studies involving educational research in a controlled environment, students who have submitted, created, rated, and answered peers' questions have overall performed well. PMID- 29233445 TI - Entrepreneurship skills development through project-based activity in Bachelor of Pharmacy program. AB - BACKGROUND AND PURPOSE: To provide pharmacy students with an opportunity to develop entrepreneurial thinking and skills. EDUCATIONAL ACTIVITY: A business proposal building project-based activity was integrated into a two-credit hour pharmacy management course during the eighth semester of the bachelor of pharmacy degree program. The student groups submitted their proposals, mimicking the process of submitting business proposals and obtaining approval in the real world. Essential management tasks including operation procedures, location and layout design, inventory management, personnel management, marketing management, and finance management were taught step-by-step so that students could work on a similar scenario with their proposal building. Students' career preferences were also measured at the beginning and end of the course. Course was assessed by written exffigam and rubric based project evaluation. Student feedbacks of the project were collected using a five-point Likert scale. FINDINGS: The project based activity was well integrated in the course. The project helped the students (n=72) to understand management concepts more clearly, which was reflected by their significantly higher (p<0.01) grades compared to previous year. Students' feedback was overwhelmingly positive (mean score of 4.53 on the scale of 5). Students developed both interest and confidence to start a pharmacy as a result of this activity. SUMMARY: The project was successfully designed and executed in a pharmacy management course within a bachelor of pharmacy curriculum. Based on the response received in this project, efforts will be made to provide guidance and support to the students by calling field experts such as pharmacy owners and financiers. PMID- 29233446 TI - Overview of a pharmacist anticoagulation certificate program. AB - BACKGROUND AND PURPOSE: To describe the design of an ongoing anticoagulation certificate program and annual renewal update for pharmacists. EDUCATIONAL ACTIVITY AND SETTING: Components of the anticoagulation certificate program include home study, pre- and posttest, live sessions, case discussions with evaluation and presentation, an implementation plan, and survey information (program evaluation and use in practice). Clinical reasoning skills were assessed through case work-up and evaluation prior to live presentation. An annual renewal program requires pharmacists to complete home study and case evaluations. FINDINGS: A total of 361 pharmacists completed the anticoagulation certificate program between 2002 and 2015. Most (62%) practiced in ambulatory care and 38% in inpatient care settings (8% in both). In the past four years, 71% were working in or starting anticoagulation clinics in ambulatory and inpatient settings. In their evaluations of the program, an average of 90% of participants agreed or strongly agreed the lecture material was relevant and objectives were met. SUMMARY: Pharmacists are able to apply knowledge and skills in management of anticoagulation. This structured practice-based continuing education program was intended to enhance pharmacy practice and has achieved that goal. The certificate program in anticoagulation was relevant to pharmacists who attended the program. PMID- 29233447 TI - Reflections on a year-long student and pharmacist paired mentorship program. AB - BACKGROUND AND PURPOSE: Mentorship programs can play a significant role in the professional development of a variety of individuals, including student pharmacists and practitioners. Many mentorship programs have been described in the literature, but the literature pertaining to mentorship programs for student pharmacists specifically is varied. EDUCATIONAL ACTIVITY AND SETTING: A leadership society at one school of pharmacy established a formal mentorship program to aid the professional development of student pharmacists. This year long program matched third-year student pharmacists with practicing pharmacists. This paper describes the development of the program, along with perceived benefits and challenges associated with implementation. FINDINGS: The mentor (n=8) and mentee (n=17) respondents provided positive feedback (100% and 94%, respectively) regarding the mentorship program. Most mentors and mentees noted they enjoyed having the opportunity to network and gained different perspectives on issues related to pharmacy. The challenges most noted by both the mentors and mentees were time limitations and scheduling conflicts. More consistent communication between mentors and mentees was noted as an area of improvement for future programs. DISCUSSION: The described program may create avenues to achieve professional development elements of the 2016 Accreditation Council for Pharmacy Education (ACPE) Standards and 2013 Center for Advancement of Pharmacy Education (CAPE) Outcomes. Continued, regular evaluation is important to help with process improvement, address challenges, and ensure the program is meeting desired objectives. Adjustments may be needed based on participant feedback, available resources, and student interest. SUMMARY: Overall, the program was successful, helping participants grow personally and professionally. With modifications, other institutions may utilize this data to develop similar programs. PMID- 29233448 TI - Introducing problem-based learning into a Canadian-accredited Middle Eastern educational setting. AB - BACKGROUND AND PURPOSE: Adaption of active learning strategies into new cultures and contexts requires careful consideration to maximize effectiveness and meet intended objectives. The aim of this paper was to describe the adaption and implementation of problem-based learning (PBL) within a pharmacy curriculum in a Middle Eastern context. EDUCATIONAL ACTIVITY AND SETTING: PBL was implemented into the curriculum at Qatar University in 2014 and expanded in subsequent years to include differing courses and contexts. The process was blueprinted to align with international accreditation standards. A SWOC (Strengths, Weaknesses, Opportunities, Challenges) analysis was completed to identify cultural and contextual facilitators and barriers regarding implementation and achievement of target outcomes. FINDINGS: Strengths included novelty, enhancement of learning, engagement, and accreditation alignment. Weaknesses included student preparation and buy in, facilitation inconsistency, and logistical support. Opportunities included expansion, departmental support, timing, and congruency with practice skills. Challenges included student resistance, departmental engagement, assessment, expansion, and cultural norms in teaching and learning. DISCUSSION AND SUMMARY: PBL provided benefit but also presented many cultural and contextual challenges of adaption from Western settings. Future work should focus addressing these cultural factors, to promote effectiveness of PBL as an active learning strategy. PMID- 29233449 TI - A pilot study assessing the value of 3D printed molecular modelling tools for pharmacy student education. AB - BACKGROUND AND PURPOSE: Medicinal chemistry and pharmacology are difficult topics to both teach and learn given the complex nature of drug mechanisms and drug receptor interactions. This highlights the need for innovative teaching methods to deliver this information to students. One such method is through three dimensional (3D) printing of enzymes and ligands in the teaching of molecular modelling concepts relating to drug-receptor and enzyme interactions be ligands. This type of printing has been shown to be beneficial in several educational settings; however, to our knowledge, its effectiveness in pharmacy, medicinal chemistry and pharmacology learning and teaching is largely unknown. Therefore, the aim of this study was to evaluate pharmacy student perceptions and the educational benefits of 3D printed molecules in molecular modelling with regards to engagement and learning outcomes when used in a drug-target interaction topic. EDUCATIONAL ACTIVITY AND SETTING: This aim was achieved through administering students a short questionnaire designed to evaluate their engagement and learning outcomes with students also free to provide comments. FINDINGS: This study found that nearly all (>90%) students found the activity was useful in improving both student engagement and learning outcomes. DISCUSSION AND SUMMARY: In conclusion, 3D printing may provide an alternative learning activity to help pharmacy students understand the drug-target interaction. PMID- 29233450 TI - Interprofessional education and distance education: A review and appraisal of the current literature. AB - BACKGROUND: Interprofessional education (IPE) is becoming essential for students and healthcare professionals. An evolving approach to implement it is via distance education. Distance education can provide a viable solution to deliver IPE in a variety of settings. METHODS: A literature search on PubMed and Academic Search Complete databases was conducted, revealing 478 articles ranging from the years of 1971-2015. The articles were screened for relevance using the following inclusion criteria: 1) Is this study implementing IPE? 2) Is this study utilizing the instructional delivery method of distance education? 3) Does this study contain students from two or more healthcare professions? RESULTS: Fifteen studies met the inclusion criteria and were systematically analyzed to identify data relevant for this review. Findings from this review provide a description of the teaching methods involved in distance education in promoting IPE and an assessment of the continuing use of distance education to foster IPE. Success varied depending upon on the distance-based instructional model utilized to facilitate IPE. IMPLICATIONS: Incorporating distance education to implement IPE can be an opportunity to develop team collaboration and communication skills among students. Teaching models presented in this review have the potential to be adapted to methods that leverage the power of evolving technology. Further research is needed to understand which distance education instructional delivery models best maximize the IPE experience. PMID- 29233451 TI - Hyperglycaemic hyperosmolar syndrome in a 5-year-old girl with newly diagnosed type 2 diabetes mellitus. PMID- 29233452 TI - Downregulation of Caspase 8 in a group of Iranian breast cancer patients - A pilot study. AB - PURPOSE: It is now well known that evading apoptosis, as a cancer hallmark, can lead to tumour initiation, progression and metastasis. As a result of genome wide association studies, an initiator protease in this pathway, caspase 8 (CASP8), has been found to be an important gene regarding breast cancer susceptibility. The alterations of the expression of this gene have been reported in breast cancer cell lines. Given that in previous studies expression analysis of this gene had only been done in breast cancer cell lines, in this study we aimed to evaluate the expression of this gene in breast cancer tissues versus adjacent normal tissues, using real-time quantitative method. METHODS: Caspase 8 mRNA expression was quantified using comparative RT-qPCR in 27 fresh frozen breast tumours and 27 adjacent normal tissues. Moreover, relationship between the expression changes of CASP8 in tumour tissue and various clinical and pathological features were evaluated in an Iranian population. RESULTS: The present study showed that expression of CASP8 was significantly reduced in tumour tissues compared to neighbouring normal tissues (p = .004). CASP8 expression was significantly correlated with the status of hormone receptors (ER and PR). CONCLUSION: To the best of our knowledge, this study is the first report on reduced expression of CASP8 in breast cancer versus adjacent normal tissues. Our data support previous results obtained from cell lines and therefore highlights the seminal role of the induction of CASP8 expression, as a novel therapeutic approach, in order to sensitize tumour cells to apoptotic stimuli. PMID- 29233453 TI - Cytological diagnosis of a rare case of cutaneous metastasis from transitional cell carcinoma, renal pelvis. AB - Transitional cell carcinoma (TCC) arising from renal pelvis rarely gives rise to cutaneous metastasis. Due to the insufficient literature, the exact incidence is not known till date. Moreover, the diagnosis is confirmed on histopathological examination with the aid of immunohistochemistry wherever needed. We are presenting a case of a 70-year-old female with metastatic TCC from the renal pelvis to the abdominal skin, which was diagnosed on cytology alone along with the cell block preparation. We also highlight the important cytomorphological and immunohistochemical features noted, which need to be known to avoid any diagnostic delay. PMID- 29233454 TI - Does radiotherapy prior to surgery improve long term prognosis in pediatric colorectal cancer in lower- and upper-middle income countries with limited resources? Our experience and literature review. AB - Colorectal carcinoma in children and adolescents is extremely rare, with an annual incidence <0.3 cases per million, most frequently reported in the second decade of life. It accounts for severe morbidity and poor prognosis owing to the low index of suspicion, delayed diagnosis, advanced stage at presentation and the aggressive tumor nature. Patients present with abdominal pain, vomiting, constipation, abdominal distension, rectal tenesmus, iron-deficiency anemia, change in bowel habit and weight loss. Rectal bleeding is an uncommon presentation in children. Bowel obstruction presents frequently in children compared to adults. In 90% of pediatric cases, colorectal carcinoma occurs sporadically. In 10%, predisposing conditions and syndromes are identified. We present a case study of a 12-year-old female with advanced colorectal cancer without a predisposing disease or syndrome, who received radio-chemotherapy ten weeks prior to radical abdominopelvic surgery, followed by radio-chemotherapy postoperatively, with a positive outcome. PMID- 29233456 TI - Corneal, Conjunctival effects and blood flow changes related to silicone hydrogel lens wear and their correlations with end of day comfort. AB - PURPOSE: First, to examine how wearing high and low modulus lenses with two different base curves affected lens fit, and the corneal tissue and bulbar conjunctival vascular tissue (bulbar redness and blood velocity). Secondly, to quantify the associations between these baseline and outcome variables and the third purpose was to correlate these variables with end of day comfort. METHODS: Thirty participants wore higher (PureVision (PV) 8.3, 8.6) and lower (Acuvue Advance (AA) 8.3, 8.7) modulus silicone hydrogel lenses for two weeks on a daily wear basis. Lens fitting characteristics were examined. Corneal epithelial thickness was measured and the cornea and conjunctiva were assessed. RBC velocity was estimated from high magnification bulbar conjunctival images. Subjective comfort/dryness was reported by participants using visual analogue scales. RESULTS: AA lenses were rated the most comfortable (ANOVA, p=0.041). The least movement was while using the AA 8.3 base curve lens (Tukey p=0.028). Steep AA and PV lenses showed significantly higher conjunctival staining at the 2 week visit (ANOVA, p=0.029). There was a significant decrease in RBC velocity with both steeper AA lenses vs PV lenses (Tukey, p=0.001). Comparing baseline and 2 week visits, there was a significant negative correlation for the PV 8.3 between comfort and superior bulbar staining (r=-0.53). For both the PV 8.3 and AA 8.3 reduced RBC velocity was correlated with dryness (r=0.61 and r=0.91, respectively). CONCLUSIONS: Physical differences in contact lenses affect structural and vascular functional aspects of the ocular surface and these may be associated with symptoms of dryness. PMID- 29233455 TI - Genetic variation of cytochrome P450 in Uyghur Chinese population. AB - Interindividual and interethnic variability of drug responses could be attributed to the differences of genetic polymorphisms in the drug metabolizing enzymes and transporters genes among the populations. Here we reviewed the studies of genetic variations in Uyghur Chinese of fifteen CYP450 genes including CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP2W1, CYP3A4, CYP3A5, CYP4A11, and CYP17A1, which totally covered 277 variants. We also collected the data of 277 variants covered in our study in two extensive population sequencing projects, the International HapMap Project (Hap-Map) and the 1000 Genomes Project and compared them with the data of Uyghur Chinese. The results suggested that remarkable differences of variants allele frequencies of CYP450 genes were existed among Uyghur Chinese and other world populations and drug doses should be adjusted clinically in Uyghur in contrast to Han Chinese and Caucasians. PMID- 29233457 TI - Antimicrobial efficacy of a novel povidone iodine contact lens disinfection system. AB - PURPOSE: Contact lens (CL) wear is a risk factor for the acquisition of microbial keratitis. Accordingly, compliance to manufacturers' recommended hygiene and disinfection procedures are vital to safe (CL) use. In this study we evaluated a novel povidone-iodine (PI) (CL) disinfection system (cleadew, Ophtecs Corporation, Japan) against a range of bacterial, fungal and Acanthamoeba. METHODS: Antimicrobial assays were conducted according to ISO 14729 using the recommended strains of bacteria and fungi, with and without the presence of organic soil. Regrowth of bacteria and fungi in the disinfection system was also examined. The activity on biofilms formed from Stenotrophomonas maltophilia and Achromobacter sp. was evaluated. Efficacy against A. castellanii trophozoites and cysts was also investigated. RESULTS: The PI system gave >4 log10 kill of all bacteria and fungi following the manufacturer's recommended disinfection and cleaning time of 4h, with or without the presence of organic soil. No regrowth of organisms was found after 14days in the neutralized solution. In the biofilm studies the system resulted in at least a 7 log10 reduction in viability of bacteria. For Acanthamoeba, >3 log10 kill of trophozoites and 1.1-2.8 log10 kill for the cyst stage was obtained. CONCLUSIONS: The PI system effective against a variety of pathogenic microorganisms under a range of test conditions. Strict compliance to recommended CL hygiene procedures is essential for safe CL wear. The use of care systems such as PI, with broad spectrum antimicrobial activity, may aid in the prevention of potentially sight threatening microbial keratitis. PMID- 29233458 TI - Development of hyper osmotic resistant CHO host cells for enhanced antibody production. AB - Cell culture platform processes are generally employed to shorten the duration of new product development. A fed-batch process with continuous feeding is a conventional platform process for monoclonal antibody production using Chinese hamster ovary (CHO) cells. To establish a simplified platform process, the feeding method can be changed from continuous feed to bolus feed. However, this change induces a rapid increase of osmolality by the bolus addition of nutrients. The increased osmolality suppresses cell culture growth, and the final product concentration is decreased. In this study, osmotic resistant CHO host cells were developed to attain a high product concentration. To establish hyper osmotic resistant CHO host cells, CHO-S host cells were passaged long-term in a hyper osmotic basal medium. There were marked differences in cell growth of the original and established host cells under iso- (328 mOsm/kg) or hyper-osmolality (over 450 mOsm/kg) conditions. Cell growth of the original CHO host cells was markedly decreased by the induction of osmotic stress, whereas cell growth of the hyper osmotic resistant CHO host cells was not affected. The maximum viable cell concentration of hyper osmotic resistant CHO host cells was 132% of CHO-S host cells after the induction of osmotic stress. Moreover, the hyper osmotic resistant characteristic of established CHO host cells was maintained even after seven passages in iso-osmolality basal medium. The use of hyper osmotic resistance CHO host cells to create a monoclonal antibody production cell line might be a new approach to increase final antibody concentrations with a fed batch process. PMID- 29233459 TI - Invasive meningococcal disease due to ciprofloxacin-resistant Neisseria meningitidis sequence type 4821: The first case in Japan. AB - We present a 4-year-old girl who developed invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup C sequence type (ST)-4821. She was hospitalized due to fever, vomiting, rash and altered consciousness. Serogroup C N. meningitidis was isolated from blood culture taken on admission and was confirmed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, a biochemical test, and molecular microbiological analysis. The patient was successfully treated with 50 mg/kg ceftriaxone every 12 hours for 7 days without any complications. The isolate was susceptible to a wide variety of beta-lactams and rifampin but was resistant to ciprofloxacin. The isolate harbored gyrA T91I and parC S87I mutations at the quinolone-resistance determining regions. Multi-locus sequence typing revealed the isolates as ST 4821, which was identical to an endemic clone frequently detected in China. However, neither the patient nor her family members had traveled abroad. To our knowledge, this report is the first to describe an IMD patient caused by ciprofloxacin-resistant N. meningitidis ST-4821 in Japan, and is the first community-acquired IMD case due to this strain outside of China. The high proportion of ciprofloxacin resistance and hypervirulent features of this ST-4821 strain raise special public health concerns. We still consider ciprofloxacin is still appropriate drug for post-exposure chemoprophylaxis in Japan. However, nationwide surveillance for susceptibility of IMD isolates is necessary to establish the regional antibiogram, and thereby to avoid chemoprophylaxis failure. PMID- 29233460 TI - Molecular typing of methicillin-resistant Staphylococcus aureus: Comparison of PCR-based open reading frame typing, multilocus sequence typing, and Staphylococcus protein A gene typing. AB - The recently developed PCR-based open reading frame typing (POT) method is a useful molecular typing tool. Here, we evaluated the performance of POT for molecular typing of methicillin-resistant Staphylococcus aureus (MRSA) isolates and compared its performance to those of multilocus sequence typing (MLST) and Staphylococcus protein A gene typing (spa typing). Thirty-seven MRSA isolates were collected between July 2012 and May 2015. MLST, spa typing, and POT were performed, and their discriminatory powers were evaluated using Simpson's index analysis. The MRSA isolates were classified into 11, 18, and 33 types by MLST, spa typing, and POT, respectively. The predominant strains identified by MLST, spa typing, and POT were ST8 and ST764, t002, and 93-191-127, respectively. The discriminatory power of MLST, spa typing, and POT was 0.853, 0.875, and 0.992, respectively, indicating that POT had the highest discriminatory power. Moreover, the results of MLST and spa were available after 2 days, whereas that of POT was available in 5 h. Furthermore, POT is rapid and easy to perform and interpret. Therefore, POT is a superior molecular typing tool for monitoring nosocomial transmission of MRSA. PMID- 29233461 TI - Long-term safety of subcutaneous immunotherapy with TO-204 in Japanese patients with house dust mite-induced allergic rhinitis and allergic bronchial asthma: Multicenter, open label clinical trial. AB - BACKGROUND: To evaluate the long-term safety of subcutaneous immunotherapy with TO-204, a standardized house dust mite (HDM) allergen extracts, we conducted a multicenter, open label clinical trial. METHODS: Japanese patients aged 5-65 years were eligible for the study, if they had HDM-induced allergic rhinitis (AR), allergic bronchial asthma (BA), or both. TO-204 was administered in a dose titration scheme, and the maintenance dose was determined according to the predefined criteria. The treatment period was 52 weeks, and patients who were willing to continue the treatment received TO-204 beyond 52 weeks. This clinical trial is registered at the Japan Pharmaceutical Information Center (Japic CTI 121900). RESULTS: Between July 2012 and May 2015, 44 patients (28 with AR and 16 with allergic BA) were enrolled into the study. All patients were included in the analysis. The duration of treatment ranged from 23 to 142 weeks and the median maintenance dose was 200 Japanese allergy units (JAU). Adverse events occurred in 22 patients (50%). The most common adverse event was local reactions related to the injection sites. Four patients experienced anaphylactic reactions when they were treated with the dose of 500 JAU. Two patients experienced anaphylactic shock with the doses of 1000 JAU at onset. These 6 patients could continue the study with dose reduction. CONCLUSIONS: Safety profile of TO-204 was acceptable in Japanese patients with HDM-induced AR or allergic BA. Higher doses should be administered carefully, because the risk of anaphylaxis increased at doses of 500 or 1000 JAU. PMID- 29233462 TI - Recent advancement to prevent the development of allergy and allergic diseases and therapeutic strategy in the perspective of barrier dysfunction. AB - Therapeutic strategy in late 20th century to prevent allergic diseases was derived from a conceptual framework of allergens elimination which was as same as that of coping with them after their onset. Manifold trials were implemented; however, most of them failed to verify the effectiveness of their preventive measures. Recent advancement of epidemiological studies and cutaneous biology revealed epidermal barrier dysfunction plays a major role of allergen sensitization and development of atopic dermatitis which ignites the inception of allergy march. For this decade, therapeutic strategy to prevent the development of food allergy has been confronted with a paradigm shift from avoidance and delayed introduction of allergenic foods based on the theoretical concept to early introduction of them based on the clinical and epidemiological evidences. Especially, prevention of peanut allergy and egg allergy has been established with the highest evidence verified by randomized controlled trials, although application in clinical practice should be done with attention. This paradigm shift concerning food allergy was also due to the discovery of cutaneous sensitization risk of food allergens for an infant with eczema revealed by prospective studies. Here we have recognized the increased importance of prevention of eczema/atopic dermatitis in infancy. Two randomized controlled trials using emollients showed successful results in prevention of atopic dermatitis in infancy; however, longer term safety and prognosis including allergy march should be pursued. To establish more fundamental strategy for prevention of the development of allergy, further studies clarifying the mechanisms of interaction between barrier dysfunction and microbial milieu are needed with macroscope to understand the relationship between allergic diseases and a diversity of environmental influences. PMID- 29233463 TI - Climate Change, Well-being, and Carbon. PMID- 29233464 TI - Making Choices to Fit in While Changing the Culture. PMID- 29233465 TI - Physical demands and technical performance in Australian Football League Women's (AFLW) competition match-play. AB - OBJECTIVES: To compare positional differences in the physical and technical demands of Australian Football League Women's (AFLW) match-play. A secondary aim was to examine the time course changes in activity profiles during AFLW match play. DESIGN: Longitudinal observational study. METHODS: Global positioning system data were collected from 26 players (6 positional groups) from the same club during seven AFLW matches. Absolute and relative physical performance data were categorised into total distance, high-speed running (>14.4kmh-1, HSR), very high-speed running (>18.0kmh-1, VHSR), and sprinting distance (>20.0kmh-1, Sprint). Technical performance data was obtained from a commercial statistics provider. A mixed model analysis was used to examine differences between positional groups and playing quarters. RESULTS: Absolute measures of running performance did not differ between position groups. Relative total distance was moderately greater (ES=~0.80, p<0.05) for midfielders, small backs and small forwards (125-128mmin-1) than tall backs and tall forwards (102-107mmin-1). Relative HSR distance was greater (ES=~0.73) for midfielders and small backs (~28mmin-1) than tall backs (17mmin-1). Analysis of technical performance indicators showed: midfielders and small forwards had the most inside 50s; tall backs had the highest number of rebound 50s; tall forwards scored more goals; while midfielders made more tackles (p<0.05). All relative running performance measures were reduced in the fourth quarter when compared to the first and second quarters (ES=0.32-0.77). CONCLUSIONS: These data can be used as benchmarks for temporal analysis of AFLW match demands and assist in developing specific training strategies. PMID- 29233466 TI - Physiotherapists use a small number of behaviour change techniques when promoting physical activity: A systematic review comparing experimental and observational studies. AB - OBJECTIVES: Physiotherapists promote physical activity as part of their practice. This study reviewed the behaviour change techniques physiotherapists use when promoting physical activity in experimental and observational studies. DESIGN: Systematic review of experimental and observational studies. METHODS: Twelve databases were searched using terms related to physiotherapy and physical activity. We included experimental studies evaluating the efficacy of physiotherapist-led physical activity interventions delivered to adults in clinic based private practice and outpatient settings to individuals with, or at risk of, non-communicable diseases. Observational studies reporting the techniques physiotherapists use when promoting physical activity were also included. The behaviour change techniques used in all studies were identified using the Behaviour Change Technique Taxonomy. The behaviour change techniques appearing in efficacious and inefficacious experimental interventions were compared using a narrative approach. RESULTS: Twelve studies (nine experimental and three observational) were retained from the initial search yield of 4141. Risk of bias ranged from low to high. Physiotherapists used seven behaviour change techniques in the observational studies, compared to 30 behaviour change techniques in the experimental studies. Social support (unspecified) was the most frequently identified behaviour change technique across both settings. Efficacious experimental interventions used more behaviour change techniques (n=29) and functioned in more ways (n=6) than did inefficacious experimental interventions (behaviour change techniques=10 and functions=1). CONCLUSIONS: Physiotherapists use a small number of behaviour change techniques. Less behaviour change techniques were identified in observational studies compared to experimental studies, suggesting physiotherapists use less BCTs clinically than experimentally. PMID- 29233467 TI - Aspergillus fumigatus-sensitive IgE is associated with bronchial hypersensitivity in a murine model of neutrophilic airway inflammation. AB - Neutrophils are the predominant inflammatory cells that infiltrate airways during acute exacerbation of asthma. The importance of A. fumigatus sensitization, and IgE response in the airways in patients with acute asthma is unclear. Rockefeller (RK) mice were sensitized with A. fumigatus extract protein. The animals were subsequently challenged with different degrees of A. fumigatus contamination in the cage bedding. All groups of mice were euthanized to obtain bronchoalveolar lavage fluid (BALF) for cytological and Elisa assays, and lung tissue for histological analysis. Moreover, several bioassays were conducted to determine whether BALF IgE antibodies can activate mast cells. In this study, we demonstrated that exposure of sensitized mice to a known concentration of A. fumigatus conidia produces bronchial hyperreactivity with marked neutrophilic bronchial infiltration and increased BALF IgE, capable of triggering mast cell degranulation. This study suggests that IgE may play a role in bronchial hyperreactivity associated to A. fumigatus exposure in mice. Mice sensitized and challenged with this fungus showed characteristics of severe asthma, with an increase of BALF neutrophils, histological changes consistent with severe asthma and an increase of IgE capable of triggering type I hypersensitivity. PMID- 29233468 TI - Butyrate suppresses motility of colorectal cancer cells via deactivating Akt/ERK signaling in histone deacetylase dependent manner. AB - Butyrate is a typical short chain fatty acid produced by gut microbiota of which the dysmetabolism has been consistently associated with colorectal diseases. However, whether butyrate affects metastatic colorectal cancer is not clear. In this study we investigated in vitro the effect of butyrate on motility, a significant metastatic factor of colorectal cancer cells and explored the potential mechanism. By using wound healing and transwell-based invasion models, we demonstrated that pretreatment of butyrate significantly inhibited motility of HCT116, HT29, LOVO and HCT8 cells, this activity was further attributed to deactivation of Akt1 and ERK1/2. Suberanilohydroxamic acid (SAHA), another HDAC inhibitor, mimicked the inhibitory effect of butyrate on cell motility and deactivation of Akt/ERK. Furthermore, by silencing of HDAC3 with siRNA, we confirmed dependence of butyrate's effect on HDAC3, the similar reduced cell motility observed under HDAC3 silencing also indicates the significance of HDAC itself in cell motility. In conclusion, we confirmed the HDAC3-relied activity of butyrate on inhibiting motility of colorectal cancer cells via deactivating Akt/ERK signaling. Our data indicate that modulating butyrate metabolism is an effective therapeutic strategy of metastatic colorectal cancer; and HDAC3 might be a novel target for management of colorectal cancer metastasis. PMID- 29233469 TI - Olfactory dysfunctions in drug-naive Parkinson's disease with mild cognitive impairment. AB - BACKGROUND: Evaluation of olfactory function is valuable for the detection of pre motor state of Parkinson's disease (PD). PD patients have an increased risk of associated dementia and one-third of PD patients have mild cognitive impairment (MCI) at the time of diagnosis. However, the characteristics of olfactory dysfunction in PD-MCI patients are unclear. This study examined the relationship between olfactory dysfunction and cognitive function in drug-naive PD at the time of diagnosis with the patterns of olfactory function in PD-MCI patients using the Korean version of the Sniffin' stick test II (KVSS II). METHODS: A total of 66 drug-naive PD patients were enrolled. A neuropsychiatric assessment battery and KVSS II were performed. For the statistical analyses, univariate, multivariable linear regression and Student's t-test were used to determine the relationship between the variables and olfactory function. RESULTS: Olfactory dysfunction was more prevalent in the PD-MCI group than in the PD-normal cognition (PD-CN) group. Each domains of odor threshold, discrimination, identification and total olfactory score were more impaired in the PD-MCI group than the PD-CN group. Whether cognitive impairment was single or multiple domain was not affected. CONCLUSION: PD-MCI is more likely to be associated with severe olfactory impairment than PD-CN. There may be more extensive neurodegenerative processes affecting olfaction in PD-MCI patients. With further investigation and validation using neuropathological data, an objective olfactory function test could be used as a tool to evaluate disease progression. Further studies with prospective design investigating the prognostic value of olfactory dysfunction in PD-MCI patients are essential. PMID- 29233470 TI - Isolated Contralateral Axillary Lymph Node Involvement in Breast Cancer Represents a Locally Advanced Disease Not Distant Metastases. AB - BACKGROUND: Breast cancer metastases to an ipsilateral supraclavicular lymph node is assigned a N3 status in the TNM system and thus classified as stage III disease in the American Joint Commission on Cancer staging manual. Breast cancer metastatic to contralateral axillary lymph node (CAM) without metastases to any other distant organ is currently assigned M1 status (stage IV) instead of N3 (stage III). PATIENTS AND METHODS: We retrospectively reviewed the medical records of breast cancer patients diagnosed with CAM for their clinical presentation, pathologic diagnoses, treatment, and follow-up data. Patients who had distant metastases at the time of CAM diagnosis were excluded from the study. RESULTS: We report 12 breast cancer patients who developed CAM but no evidence of metastases in any other distant organ documented with extensive imaging workup. Imaging studies and thorough pathologic evaluation of the prophylactic total mastectomy specimen did not reveal a primary in the breast to account for the metastases in the axillary node. CONCLUSION: Findings of our study as well as previous studies support that lymph node metastases in the contralateral axilla represents a locoregional spread of the tumor from the index breast via lymphatics rather than hematogenous spread. Therefore, isolated CAM in breast cancer patients should not be classified as stage IV disease. PMID- 29233471 TI - Resolvin D1 regulates epithelial ion transport and inflammation in cystic fibrosis airways. AB - BACKGROUND: Cystic Fibrosis (CF) lung disease is characterised by dysregulated ion transport that promotes chronic bacterial infection and inflammation. The impact of the specialised pro-resolution mediator resolvin D1 (RvD1) on airway surface liquid (ASL) dynamics and innate defence had not yet been investigated in CF airways. METHODS: Ex vivo studies were performed on primary cultures of alveolar macrophages and bronchial epithelial cells from children with CF and in human bronchial epithelial cell lines; in vivo studies were performed in homozygous F508del-CFTR mice treated with vehicle control or RvD1 (1-100nM). RESULTS: RvD1 increased the CF ASL height in human bronchial epithelium and restored the nasal trans-epithelial potential difference in CF mice by decreasing the amiloride-sensitive Na+ absorption and stimulating CFTR-independent Cl- secretion. RvD1 decreased TNFalpha induced IL-8 secretion and enhanced the phagocytic and bacterial killing capacity of human CF alveolar macrophages. CONCLUSION: RvD1 resolves CF airway pathogenesis and has therapeutic potential in CF lung disease. PMID- 29233472 TI - Drugs during pregnancy and breast feeding in women diagnosed with Cystic Fibrosis - An update. PMID- 29233473 TI - Changes in the electrocorticogram after implantation of intracranial electrodes in humans: The implant effect. AB - OBJECTIVE: Subacute and long-term electrocorticographic (ECoG) changes in ambulatory patients with depth and cortical strip electrodes were evaluated in order to determine the length of the implant effect. METHODS: ECoG records were assessed in patients with medically intractable epilepsy who had depth and/or strip leads implanted in order to be treated with brain-responsive stimulation. Changes in total spectral power, band-limited spectral power, and spike rate were assessed. RESULTS: 121 patients participating in trials of the RNS(r) System had a total of 93994 ECoG records analyzed. Significant changes in total spectral power occurred from the first to second months after implantation, involving 55% of all ECoG channels (68% of strip and 47% of depth lead channels). Significant, but less pronounced, changes continued over the 2nd to 5th post-implant months, after which total power became more stable. Similar patterns of changes were observed within frequency bands and spike rate. CONCLUSIONS: ECoG spectral power and spike rates are not stable in the first 5 months after implantation, presumably due to neurophysiological and electrode-tissue interface changes. SIGNIFICANCE: ECoG data collected in the first 5 months after implantation of intracranial electrodes may not be fully representative of chronic cortical electrophysiology. PMID- 29233474 TI - Prevention of skin injuries associated with non-invasive mechanical ventilation. PMID- 29233475 TI - In response to the question "who has the most impressive laboratory?". PMID- 29233478 TI - Consciousness, Representation, Action: The Importance of Being Goal-Directed. AB - Recent years have witnessed fierce debates on the dependence of consciousness on interactions between a subject and the environment. Reviewing neuroscientific, computational, and clinical evidence, I will address three questions. First, does conscious experience necessarily depend on acute interactions between a subject and the environment? Second, does it depend on specific perception-action loops in the longer run? Third, which types of action does consciousness cohere with, if not with all of them? I argue that conscious contents do not necessarily depend on acute or long-term brain-environment interactions. Instead, consciousness is proposed to be specifically associated with, and subserve, deliberate, goal-directed behavior (GDB). Brain systems implied in conscious representation are highly connected to, but distinct from, neural substrates mediating GDB and declarative memory. PMID- 29233476 TI - E2F/DP Prevents Cell-Cycle Progression in Endocycling Fat Body Cells by Suppressing dATM Expression. AB - To understand the consequences of the complete elimination of E2F regulation, we profiled the proteome of Drosophila dDP mutants that lack functional E2F/DP complexes. The results uncovered changes in the larval fat body, a differentiated tissue that grows via endocycles. We report an unexpected mechanism of E2F/DP action that promotes quiescence in this tissue. In the fat body, dE2F/dDP limits cell-cycle progression by suppressing DNA damage responses. Loss of dDP upregulates dATM, allowing cells to sense and repair DNA damage and increasing replication of loci that are normally under-replicated in wild-type tissues. Genetic experiments show that ectopic dATM is sufficient to promote DNA synthesis in wild-type fat body cells. Strikingly, reducing dATM levels in dDP-deficient fat bodies restores cell-cycle control, improves tissue morphology, and extends animal development. These results show that, in some cellular contexts, dE2F/dDP dependent suppression of DNA damage signaling is key for cell-cycle control and needed for normal development. PMID- 29233477 TI - Molecular Anatomy of the Developing Human Retina. AB - Clinical and genetic heterogeneity associated with retinal diseases makes stem cell-based therapies an attractive strategy for personalized medicine. However, we have limited understanding of the timing of key events in the developing human retina, and in particular the factors critical for generating the unique architecture of the fovea and surrounding macula. Here we define three key epochs in the transcriptome dynamics of human retina from fetal day (D) 52 to 136. Coincident histological analyses confirmed the cellular basis of transcriptional changes and highlighted the dramatic acceleration of development in the fovea compared with peripheral retina. Human and mouse retinal transcriptomes show remarkable similarity in developmental stages, although morphogenesis was greatly expanded in humans. Integration of DNA accessibility data allowed us to reconstruct transcriptional networks controlling photoreceptor differentiation. Our studies provide insights into human retinal development and serve as a resource for molecular staging of human stem-cell-derived retinal organoids. PMID- 29233480 TI - Forecasting the prevalence of preclinical and clinical Alzheimer's disease in the United States. AB - INTRODUCTION: We forecast the prevalence of preclinical and clinical Alzheimer's disease (AD) and evaluated potential impacts of primary and secondary preventions in the United States. METHODS: We used a multistate model incorporating biomarkers for preclinical AD with US population projections. RESULTS: Approximately 6.08 million Americans had either clinical AD or mild cognitive impairment due to AD in 2017 and that will grow to 15.0 million by 2060. In 2017, 46.7 million Americans had preclinical AD (amyloidosis, neurodegeneration, or both), although many may not progress to clinical disease during their lifetimes. Primary and secondary preventions have differential impact on future disease burden. DISCUSSION: Because large numbers of persons are living with preclinical AD, our results underscore the need for secondary preventions for persons with existing AD brain pathology who are likely to develop clinical disease during their lifetimes as well as primary preventions for persons without preclinical disease. PMID- 29233479 TI - Monitoring Neurodegeneration in Glaucoma: Therapeutic Implications. AB - Glaucoma is one of the leading causes of blindness globally, and is characterized by loss of retinal ganglion cells (RGCs). Because vision loss in glaucoma is not reversible, therapeutic interventions early in disease are highly desirable. However, owing to the current limitations in evaluating glaucomatous neurodegeneration, it is challenging to monitor the disease severity and progression objectively, and to design rational therapeutic strategies accordingly. Therefore, there is a clear need to identify quantifiable molecular biomarkers of glaucomatous neurodegeneration. As such, in our opinion, molecular biomarker(s) that specifically reflect stress or death of RGCs, and which correlate with disease severity, progression, and response to therapy, are highly desirable. PMID- 29233481 TI - Road traffic noise and determinants of saliva cortisol levels among adolescents. AB - OBJECTIVES: The understanding of determinants for saliva cortisol levels in adolescents is limited. This study investigated the role of road traffic noise exposure, noise annoyance and various other factors for saliva cortisol levels. METHODS: We collected morning and evening saliva samples from 1751 adolescents from the BAMSE birth cohort based in Stockholm County. Facade noise levels from road traffic were estimated at the residences of the study subjects and repeated questionnaires and medical examinations provided extensive information on various exposures and conditions, including annoyance to noise from different sources. Cortisol was measured using radioimmunoassay. Associations between determinants and saliva cortisol levels were analysed using linear regression. RESULTS: Morning saliva cortisol levels were significantly higher in females than in males (geometric mean 42.4 and 35.0 nmol/l, respectively) as well as in subjects with allergy related diseases. Height and age were related to saliva cortisol levels as well as sampling season. Road traffic noise exposure was not associated with saliva cortisol, however, annoyance to noise tended to increase the levels. Saliva cortisol levels appeared particularly high among those who were highly annoyed and exposed to road traffic noise levels >= 55 dB Lden (50.5 nmol/l, p = 0.02). CONCLUSION: Our findings suggest that individual perception of noise may be of importance for saliva cortisol levels. The results also point to the complexity of using saliva cortisol as a marker of noise exposure in adolescents. PMID- 29233482 TI - Comparison of single-port and three-port laparoscopic salpingectomy in the management for tubal pregnancy. AB - BACKGROUND: To compare the short-term outcome of patients undergoing single-port laparoscopic salpingectomy (SP-LS) and conventional three-port laparoscopic salpingectomy (C-LS). METHODS: A retrospective evaluation of 112 patients with tubal pregnancies treated by one surgeon at a single teaching hospital. Among these, 47 patients were treated with SP-LS and the remaining 65 were treated with C-LS. RESULTS: The characteristics of patients were similar in both groups. There were no statistically significant differences in operative time, estimated blood loss, intraoperative and immediate postoperative complications, and length of hospital stay between both groups. Time to bowel recanalization (6.2 +/- 1.0 vs. 7.2 +/- 1.4 h, p < 0.05) and postoperative visual analog scale for pain scores (3.0 +/- 0.5 vs. 3.6 +/- 0.6, p < 0.005) were significantly lower in the SP-LS group compared with those in the C-LS group. CONCLUSION: Our study demonstrated the feasibility to use the single-port laparoscopic salpingectomy in the management of women with tubal pregnancy, which showed the similar or better outcome compared with the use of conventional three-port laparoscopic salpingectomy. PMID- 29233484 TI - Increasing incidence of All-Terrain Vehicle trauma admissions in the pediatric and adult populations: An evaluation of injury types and severity. AB - OBJECTIVES: All Terrain Vehicles (ATVs) are increasing in popularity and becoming larger and faster at a production level. As a Level I Trauma Center, we perceived a disproportionately high volume of ATV-related admissions. Our goal was to study injury patterns and severity in adult and pediatric populations. METHODS: All ATV related trauma admissions at a single Level I trauma center were retrospectively analyzed over a seven-year period. RESULTS: On-road incidents were more likely to result in a higher average Injury Severity Score (ISS) (p < 0.05). Higher ISS also occurred in children, un-helmeted, and impaired rider groups (p < 0.05). The pediatric population was more likely to have a major head injury (62.5% of children versus 31.8% of adults, p < 0.05) while thoracic injury was more common in adults (43.4% of adults versus 16.7% of children, p < 0.05). Death rates were similar in both adult and pediatric populations. CONCLUSION: ATV-related injuries vary depending on incident characteristics and patient populations. On-road use incurs a significant increase in injury severity. The pediatric population is significantly more likely to incur a severe injury and the presenting injury pattern differs from the adult population. Knowledge of population and presentation trends can help direct trauma care providers in the care and management of injured ATV riders. PMID- 29233483 TI - Development and validation of a modified TaqMan based real-time PCR assay targeting the lipl32 gene for detection of pathogenic Leptospira in canine urine samples. AB - A modified TaqMan real-time polymerase chain reaction targeting a 138bp fragment within the lipl32 gene was developed to identify exclusively pathogenic Leptospira spp. in dog urine samples. Thirty-five samples from dogs with suspected clinical leptospirosis and 116 samples from apparently healthy dogs were tested for presence of leptospiral DNA using the TaqMan-based assay. The results were compared with those from a well-established conventional PCR targeting the 16S RNA encoding gene associated with nucleotide sequencing analysis. The overall agreement between the assays was 94.8% (confidence interval [CI] 95% 88-100%). The newly developed assay presented 91.6% (CI 95% 71.5-98.5%) relative sensitivity (22[+] lipl32 PCR/24[+] 16S RNA and sequencing), 100% (CI 95% 96.3-100%) relative specificity and 98.7% accuracy (CI 95% 94.8-100%). The lipl32 assay was able to detect and quantify at least 10 genome equivalents/reaction. DNA extracted from 17 pathogenic Leptospira spp., 8 intermediate/saprophytic strains and 21 different pathogenic microorganisms were also tested using the lipl32 assay, resulting in amplification exclusively for pathogenic leptospiral strains. The results also demonstrated high intra and inter-assay reproducibility (coefficient of variation 1.50 and 1.12, respectively), thereby qualifying the newly developed assay as a highly sensitive, specific and reliable diagnostic tool for leptospiral infection in dogs using urine specimens. PMID- 29233485 TI - Body fat affects mouse reproduction, ovarian hormone release, and response to follicular stimulating hormone. AB - We investigated the effects of body fat content on mouse fecundity, ovarian hormone release, and their response to follicle stimulation hormone (FSH). 4 types of females were produced: lean (group 1), normal (group 2), slightly fat (group 3), and significantly fat (group 4). The body weights, fat content, fertility rate, embryo number produced, retarded and degenerated embryo percentage, the release of progesterone (P4), testosterone (T), and insulin-like growth factor I (IGF-I) by isolated ovaries cultured with and without FSH (1.0IU/mL medium) were evaluated. A gradual increase in body weight and fat contents from groups 1 to 4 was observed. Group 2 had higher fertility rate than those from the other groups. Groups 2 and 3 had fewer retarded and degenerated embryos that those from groups 1 and 4. Embryo production rate was not different among the groups. P4 and T secretion was higher from group 4 than in those from groups 1-3; secretion of IGF-I of group 3 was less than that of groups 1, 2, and 4. FSH promoted ovarian T output in all groups and stimulated ovarian P4 release in groups 1, 3, and 4, but not in group 2. FSH did not affect IGF-I release in any group. Therefore, both malnutrition and overfeeding can affect body weight and fat content in female mice, reducing embryo quality or developmental capacity, but not fertility and embryo production. Excess weight or fat can have stimulatory effects on ovarian P4 and T, but inhibitory effects on ovarian IGF-I release. Both leanness and excess weight or fat can induce the stimulatory action of FSH on ovarian P4. PMID- 29233486 TI - Cetuximab Combined With Induction Oxaliplatin and Capecitabine, Followed by Neoadjuvant Chemoradiation for Locally Advanced Rectal Cancer: SWOG 0713. AB - BACKGROUND: Neoadjuvant chemoradiation (NCRT) is standard treatment for locally advanced rectal cancer. Pathologic complete response (pCR) has associated with improved survival. In modern phase III trials of NCRT, pCR ranges from 10% to 20%. Cetuximab improves response in KRAS (KRAS proto-oncogene) wild type (wt) metastatic colorectal cancer. S0713 was designed to assess improvement in pCR with additional use of cetuximab with induction chemotherapy and NCRT for locally advanced, KRAS-wt rectal cancer. PATIENTS AND METHODS: Patient eligibility: stage II to III biopsy-proven, KRAS-wt rectal adenocarcinoma; no bowel obstruction; adequate hematologic, hepatic and renal function; performance status of 0 to 2. Target enrollment: 80 patients. TREATMENT: induction chemotherapy with wCAPOX (weekly capecitabine and oxaliplatin) and cetuximab followed by the same regimen concurrent with radiation (omitting day 15 oxaliplatin). If fewer than 7 pCRs were observed at planned interim analysis after 40 patients received all therapy, the study would close. Eighty eligible patients would provide 90% power given a true pCR rate > 35% at a significance of 0.04. The regimen would lack future interest if pCR probability was <= 20%. RESULTS: Between February 2009 and April 2013, 83 patients registered. Four were ineligible and 4 not treated, leaving 75 evaluable for clinical outcomes and toxicity, of whom 65 had surgery. Of 75 patients, 20 had pCR (27%; 95% confidence interval [CI], 17%-38%); 19 (25%) had microscopic cancer; 36 (48%) had minor/no response (including 10 without surgery). Three-year disease-free survival was 73% (95% CI, 63%-83%). CONCLUSION: Our trial did not meet the pCR target of 35%. Toxicity was generally acceptable. This regimen cannot be recommended outside the clinical trial setting. PMID- 29233487 TI - Genetic counselling, patient education, and informed decision-making in the genomic era. AB - Genomic technologies are now being applied to reproductive genetic screening. Circulating cell-free DNA testing in pregnancy for fetal chromosomal abnormalities is becoming more widely used as a screening test, and expanded carrier screening for autosomal and X-linked recessive conditions for more than a hundred conditions is available to couples for testing before and during pregnancy. These are most typically available as a commercial test. The purpose of reproductive genetic screening is to facilitate autonomous reproductive choices. Previous studies would suggest that many women do not make informed decisions about prenatal genetic screening, and the introduction of genomic technologies has generally added to the ethical debate. Appropriate pre-test genetic counselling is recommended, and healthcare providers should include information that is balanced, accurate and up-to-date, comprising written and/or e-learning tools, as well as providing psychosocial support so that couples consider the pros and cons of being tested and can make informed decisions. PMID- 29233488 TI - Obstructive Sleep Apnea and Cardiovascular Risk: From Evidence to Experience in Cardiology. PMID- 29233489 TI - "Everything Should be Made as Simple as Possible but Not Simpler". PMID- 29233490 TI - Pulse Wave Velocity and Central Blood Pressure: Normal and Reference Values in Older People in Spain. PMID- 29233491 TI - Utility of myeloperoxidase in the differential diagnosis of acute coronary syndrome. AB - OBJECTIVES: To determine the usefulness of myeloperoxidase in discriminating between patients with acute coronary syndrome and patients with chest pain by other causes. METHODS: The study included all patients over 18 years of age who come consecutively to the emergency department from September 2015 to December 2015 with chest pain of non-traumatic origin. The initial patient evaluation was performed according to the study protocol for patients with suspected acute coronary syndrome (ACS) in our Emergency Department. This included the serial measurement of troponin, and in this case myeloperoxidase, with serialization on admission and at 6h. For the determination of myeloperoxidase (MPO), a single step sandwich enzyme immunoassay by Siemens, automated on a Dimension analyser, was used. RESULTS: Statistically significant differences were observed in the concentration of myeloperoxidase at time 0 among patients diagnosed with ACS: 505 (413)pmol/L, and non-ACS patients: 388 (195)pmol/L (p<.001), as well as at 6h (p<.001). An area under the curve ROC of 0.824 was obtained at 6h for ACS patients, with a confidence interval of 95% from 0.715 to 0.933 and a level of significance of p<.001. Statistically significant differences were also found in the concentration of myeloperoxidase at time 0 and at 6h among patients with ACS and patients with heart disease other than coronary artery disease. CONCLUSIONS: The concentration of MPO helps to differentiate between ACS and non-ACS patients, as well as between ACS patients and patients with heart diseases other than coronary artery disease. PMID- 29233492 TI - [Haemophagocytic syndrome secondary to endocarditis due to Bartonella henselae]. PMID- 29233493 TI - [A first step to teaching basic life support in schools: Training the teachers]. AB - INTRODUCTION: Teachers may have an essential role in basic life support (BLS) training in schoolchildren. However, few data are available about their BLS learning abilities. AIM: To quantitatively assess the quality of BLS when performed by school teachers after a brief and simple training program. MATERIALS AND METHODS: A quasi-experimental study with no control group, and involving primary and secondary education teachers from four privately managed and public funded schools was conducted in 3 stages: 1st. A knowledge test, 2nd: BLS training, and 3rd: Performance test. Training included a 40minutes lecture and 80minutes hands-on session with the help feedback on the quality of the chest compressions. RESULTS: A total of 81 teachers were included, of which 60.5% were women. After training, the percentage of subjects able to perform the BLS sequence rose from 1.2% to 46% (P<.001). Chest compression quality also improved significantly in terms of: correct hands position (97.6 vs. 72.3%; P<.001), mean depth (48.1 vs. 38.8mm; P<.001), percentage that reached recommended depth (46.5 vs. 21.5%; P<.001), percentage of adequate decompression (78.7 vs. 61.2%; P<.05), and percentage of compressions delivered at recommended rate (64.2 vs. 26.9%; P<.001). CONCLUSIONS: After and brief and simple training program, teachers of privately managed public funded schools were able to perform the BLS sequence and to produce chest compressions with a quality similar to that obtained by staff with a duty to assist cardiac arrest victims. The ability of schoolteachers to deliver good-quality BLS is a pre-requisite to be engaged in BLS training for schoolchildren. PMID- 29233494 TI - [Kawasaki giant coronary aneurysms in infants with Kawasaki disease]. PMID- 29233495 TI - Antibacterial resistance patterns of extended spectrum beta-lactamase -producing enteropathogenic Escherichia coli strains isolated from children. AB - BACKGROUND AND STUDY AIM: This study aimed to determine the antibacterial resistance patterns of extended spectrum beta-lactamase (ESBL)-producing enteropathogenic Escherichia coli (EPEC) isolated from Iranian children and to investigate its genetic patterns. PATIENTS AND METHODS: 192 non-repeats EPEC isolates were collected from stool samples of the children with and without diarrhoea. The EPEC strains were isolated from 1355 stool specimens obtained from 247 children with diarrhoea (0-10 years old; mean age, 5.5 years) and 1108 children without any gastrointestinal symptoms (0-10 years old; mean age, 6.8 years) during the summer months in three Iranian provinces, Tehran, Ilam and Mazandaran. Strains biochemically identified as E. coli were selected and were identified by the presence of eaeA and bfpA as EPEC virulence genes. Antimicrobial susceptibilities were determined by disc diffusion method. The isolates were confirmed to be ESBL producers by the double disk synergy test (DDST). The beta-lactamase genes (blaTEM, blaSHV, blaCTX-M, blaOXA) and insertion sequence ISEcp1 were detected by PCR method. RESULTS: The highest antibiotic susceptibility was detected to imipenem (100%), followed by gentamicin (82.3%) and ciprofloxacin (79.2%). The highest resistance was detected to cefpodoxime (97.9%), trimethoprim (60.7%), and tetracycline (58.4%), respectively. Totally, 153 EPEC strains (79.7%) were ESBL-producing by DDST test. The PCR showed that 84 (43.8%) EPEC isolates were positive for ESBLs encoding genes. Among 153 ESBLs producing EPEC, TEM was present in 9.2% of isolates. Also, CTX-M and SHV genes were detected in 7.2% and 7.8%, respectively. The SHV positive strains were associated with the highest resistance rate to tetracycline (56.5%), although the TEM and OXA were associated with the highest resistance rate to gentamicin (23.1%) and ciprofloxacin (21.4%). CONCLUSIONS: The study revealed that 79.7% of EPEC isolates from Iranian children were ESBL-producing and were comparable with the non ESBL-producing isolates regarding susceptibility to the antibiotics. PMID- 29233496 TI - Identifying Warfarin Control With Stroke and Bleed Risk Scores. AB - Warfarin decreases stroke risk in atrial fibrillation patients, with efficacy and safety impacted by the quality of warfarin control, as measured by time in therapeutic range (TTR). Stroke and bleed risk scores are calculated prior to commencing warfarin, so it would be beneficial if these scores also identified likely warfarin control. Some studies have investigated CHADS2, CHA2DS2VASc, and HASBLED individually for this purpose, but application of all scores to diverse ethnic populations and at sites with differing overall control has not been investigated. The aim of this study was to determine if these commonly used risk scores could identify poor warfarin control. Retrospective data was collected for non-valvular AF patients receiving warfarin between January and June 2014 in Australia and Singapore. Patient data was used to calculate TTR and risk scores. Mean TTR was used for analysis and comparison to categorised scores. There were 3199 patients in Australia and 1171 in Singapore. At both sites, mean TTR decreased according to HASBLED category, and there was a statistically higher percentage of patients achieving a TTR>65% in the low HASBLED category. The association between HASBLED scores and TTR was independent of lower dosing in higher risk patients, particularly in Australia. No significant differences were found in mean TTR according to CHADS2 at either site. Time in therapeutic range significantly decreased according to high CHA2DS2VASc category in Singapore, but no differences were found in Australia. Of the bleed and stroke risk models, HASBLED is most suitable to identify a patient's potential TTR and ability to achieve TTR>65%. A high HASBLED score may assist prescribers in determining potential suitability to warfarin, and assist prescribers in deciding on the most suitable anticoagulant for patients. PMID- 29233497 TI - Early and Late Survival of On-Pump Cardiac Surgery Patients Formerly Affected by Lymphoma. AB - BACKGROUND: Survival after cardiac surgery of patients formerly affected by lymphoma has not been well defined. METHODS: Forty-five consecutive patients having prior Hodgkin's (HL patients, n=26) or non-Hodgkin's lymphoma (non-HL patients, n=19) underwent on-pump cardiac surgery at the authors' institution (2001-2016). Ischaemic, valvular, and ischaemic plus valvular heart disease were present in 14, 13, and 18 patients, respectively. Concomitant aortic disease was treated in three cases. The expected operative risk was calculated by the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II. The 10-year survival was estimated by the Kaplan-Meier method and the Charlson Comorbidity Index (CCI). The Cox proportional-hazards regression was used to evaluate the effect of some risk factors on survival. RESULTS: With respect to non-HL patients, HL patients were younger (mean age, 52.5 vs. 64.7 years, p=0.0017) and underwent cardiac surgery later after lymphoma occurrence (median gap, 21.5 vs. 9.6 years, p=0.0079). No other intergroup differences as baseline characteristics, risk profiles (median EuroSCORE II, 2.3% vs. 3%, p=0.78), and in hospital mortality (7.7% vs. 10.5%, p=0.99) were found. Older age, severe left ventricular dysfunction, and HL history were predictors of cardiac or cerebrovascular death (p<0.1). The 10-year, crude (40.4%) and adjusted (39.1%) nonparametric estimates of survival were lower than the expected survival by CCI (77.5%, p<0.0001). The 10-year nonparametric estimate of freedom from malignancy was 66.3%. CONCLUSIONS: Immediate and long-term survival after on-pump cardiac surgery of patients formerly affected by lymphoma were worse than expected, according to universally used predictive scoring systems. There was an increased risk of malignant tumour. PMID- 29233498 TI - Proton Pump Inhibitors and Cardiovascular Events: A Systematic Review. AB - BACKGROUND: Proton pump inhibitors (PPIs) are a commonly prescribed medication that recent data has linked to an increased risk of cardiovascular morbidity and all cause morbidity. The current study sought to perform a systematic review to investigate the link between PPIs and morbidity and mortality METHODS: A systematic review was carried out as per the PRISMA guidelines, with information databases including Pubmed, Medline, and the Cochrane Review Database. English language studies of all types published from January 1990 to October 2016 were considered. Dichotomous analysis generating odds ratios was performed using RevMan Version 5.3. RESULTS: Thirty-seven studies were considered, of which five directly compared the effect of PPI use on mortality and/or cardiovascular morbidity (including 22,427 patients in mortality datasets, and 354,446 patients in morbidity datasets). For patients taking PPIs, all cause mortality (OR 1.68 [95% CI 1.53-1.84], p<0.001) and rate of major cardiovascular events (OR 1.54 [95% CI 1.11-2.13], p=0.01) were significantly higher. CONCLUSIONS: The current systematic review demonstrates that, in patients using PPIs, there was a significant increase in morbidity due to cardiovascular disease. Careful consideration should be given to the prescription of PPIs while clinical equipoise remains. Further research in the area is required. PMID- 29233499 TI - The role of the carboxyl ester lipase (CEL) gene in pancreatic disease. AB - The enzyme carboxyl ester lipase (CEL), also known as bile salt-dependent or stimulated lipase (BSDL, BSSL), hydrolyzes dietary fat, cholesteryl esters and fat-soluble vitamins in the duodenum. CEL is mainly expressed in pancreatic acinar cells and lactating mammary glands. The human CEL gene resides on chromosome 9q34.3 and contains a variable number of tandem repeats (VNTR) region that encodes a mucin-like protein tail. Although the number of normal repeats does not appear to significantly influence the risk for pancreatic disease, single-base pair deletions in the first VNTR repeat cause a syndrome of endocrine and exocrine dysfunction denoted MODY8. Hallmarks are low fecal elastase levels and pancreatic lipomatosis manifesting before the age of twenty, followed by development of diabetes and pancreatic cysts later in life. The mutant protein forms intracellular and extracellular aggregates, suggesting that MODY8 is a protein misfolding disease. Recently, a recombined allele between CEL and its pseudogene CELP was discovered. This allele (CEL-HYB) encodes a chimeric protein with impaired secretion increasing five-fold the risk for chronic pancreatitis. The CEL gene has proven to be exceptionally polymorphic due to copy number variants of the CEL-CELP locus and alterations involving the VNTR. Genome-wide association studies or deep sequencing cannot easily pick up this wealth of genetic variation. CEL is therefore an attractive candidate gene for further exploration of links to pancreatic disease. PMID- 29233500 TI - Tumor budding is a prognostic factor linked to epithelial mesenchymal transition in pancreatic ductal adenocarcinoma. Study report and literature review. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a devastatingly poor prognosis. Surgical resection is undertaken in only 20% of patients. Most of well known prognostic factors reflect tumor stage more than its biology. So it is important to identify new biological indicators related to survival in order to develop new therapies. OBJECTIVE: To determine the relation between tumor budding and Epithelial Mesenchymal Transition (EMT) and to evaluate their impact on survival for patients after resection of PDAC. METHODS: We herein report a retrospective study of 50 patients with resected PDAC. Tumor budding, immunohistochemical expression of vimentin and other standard factors were correlated with survival using the Kaplan-Meier method and Cox multivariable survival analysis. For tumor budding assessment, an inter-observer variability study was performed using 100 images of tumor slides stained with Hematoxylin & Eosin and Pan-Cytokeratin. RESULTS: Tumor budding was present in all tumors. A substantial agreement between six pathologists was established in distinguishing high-grade from low-grade budding (kappa = 0.6 and 0.73 for H&E and PCK images respectively). High-grade budding was identified in 56% of tumors (28/50). It was an adverse prognostic factor independent of tumor size, resection margins status, nodal status and vascular invasion (p = 0.008). Tumor budding was significantly associated with vimentin expression (p = 0.002). CONCLUSIONS: The association of tumor budding with vimentin expression supported the idea that EMT is a key process in PDAC responsible for progression and drug resistance. Consequently, the elucidation of EMT molecular biology and development of new targeted therapy may improve disease outcome. PMID- 29233501 TI - Does ovarian stimulation regimen affect IVF outcome? a two-centre, real-world retrospective study using predominantly cleavage-stage, single embryo transfer. AB - In this study, ovarian stimulation using highly purified human menopausal gonadotrophin (HP-HMG) and recombinant FSH (rFSH) for IVF were compared in two large assisted reproduction technique centres in Sweden. A total of 5902 women underwent 9631 oocyte retrievals leading to 8818 embryo transfers (7720 on day 2): single embryo transfers (74.2%); birth rate per embryo transfer (27.7%); multiple birth rate (5.0%); incidence of severe ovarian hyperstimulation syndrome (0.71%). Compared with ovarian stimulation with rFSH, women who received HP-HMG were older, had higher dosages of gonadotrophins administered, fewer oocytes retrieved and more embryos transferred. After multivariate analysis controlling for age and generalized estimating equation model, no differences were found in delivery outcomes per embryo transfers between HP-HMG and rFSH, independent of gonadotrophin releasing hormone analogue (GnRH) used. Logit curves for live birth rate suggested differences for various subgroups, most prominently for women with high oocyte yield or when high total doses were used. Differences were not significant, perhaps owing to skewed distributions of the FSH compounds versus age and other covariates. These 'real-life patients' had no differences in live birth rate between HP-HMG and rFSH overall or in subgroups of age, embryo score, ovarian sensitivity or use of GnRH analogue regimen. PMID- 29233502 TI - Is there an association between artificial sweetener consumption and assisted reproduction outcomes? AB - Previous studies have suggested an association between high intake of sweetened beverages and a number of adverse health outcomes. In this cross-sectional study, we investigated the association between daily consumption of sweetened soft drinks or coffee and the outcome of intracytoplasmic sperm injection (ICSI) treatment. Patients (n = 524) were interviewed by a nutritionist before ICSI treatment, using a food frequency questionnaire. Regression analysis showed that consumption of >=3 servings of regular soft drinks or any amount of diet soft drinks was associated with oocyte dysmorphism, diminished embryo quality on days 2 and 3 of culture, and a mild effect on blastocyst formation, implantation and pregnancy rate. Consumption of artificially sweetened coffee was negatively associated with embryo quality on days 2 and 3. However, consumption of coffee or soft drinks was not associated with the odds of live birth. Even so, patients should be advised about the potential negative effects of sugar and artificial sweeteners before attempting infertility treatment. This study is limited by the use of a non-validated food frequency questionnaire, lack of information on quantity of sweeteners consumed, and lack of data on glucose levels in blood serum or follicular fluid. Further investigation is warranted. PMID- 29233503 TI - Decreased expression of FOXA2 promotes eutopic endometrial cell proliferation and migration in patients with endometriosis. AB - Endometriosis is characterized by eutopic endometrial cell 'metastasis' to ectopic foci. FOXA2 is a member of the forkhead transcription factor family, which may participate in transcriptional regulation in endometrial cells and contribute to the aetiology of endometriosis. This study investigated the roles played by FOXA2 in eutopic endometrium using endometriosis samples. Western blotting showed that the relative expression of FOXA2 was significantly reduced in eutopic endometrium from patients with endometriosis (n = 14) compared with endometriosis-free controls (n = 16) (0.69 +/- 0.07 versus 1.24 +/- 0.06, P < 0.05). To mimic eutopic endometrium of endometriosis, primary eutopic endometrial stromal cells (ESC) of controls were harvested and transfected with FOXA2 siRNA. MTT assay showed that cell viability of ESC with transfected FOXA2 siRNA increased significantly, whereas the apoptosis rate decreased as indicated by flow cytometry experiments (both P < 0.05). Wound healing assays revealed that transfection of FOXA2 siRNA promoted ESC migration. Moreover, real-time PCR analysis showed progesterone-induced FOXA2 expression in ESC under physiological conditions. In conclusion, these findings indicate that FOXA2 might be a progesterone-induced gene, which may participate in the 'metastatic' process of eutopic endometrium to ectopic loci in patients with endometriosis. PMID- 29233504 TI - The utility of anti-Mullerian hormone in women with chronic kidney disease, on haemodialysis and after kidney transplantation. AB - Women with renal disease have menstrual and gonadal dysfunction manifesting as hormonal imbalance. Anti-Mullerian hormone (AMH) is a potential measure of ovarian reserve. We examined circulating AMH concentrations in young women with renal failure, determined associations with clinical characteristics, and compared AMH with age-matched healthy individuals. AMH was measured in 77 women: 26 had chronic kidney disease (CKD), 26 were on haemodialysis (HD), and 25 had a kidney transplant. Random AMH levels were highest in women on HD [HD 2.9 (1.1 5.2), CKD 1.6 (0.7-2.2), transplant 1.5 (1.0-4.2) ng/ml]. On multiple linear regression, AMH was 53% higher [95% CI 0.20-0.98, P = 0.002] in women on HD and decreased by 20% per 5-year increase in age (P < 0.001). AMH was 43% lower in women with renal failure compared with 600 age-matched controls [1.7 (0.9-3.8) versus 3.0 (1.9-5.0) ng/ml, P < 0.001]; however, we found no difference in AMH between those on HD and healthy individuals [2.9 (1.1-5.2) versus 3.0 (1.9-5.0) ng/ml]. AMH may be a useful biomarker in female renal patients with non-dialysis dependent renal disease pursuing pregnancy. In contrast, AMH levels are higher in HD but unlikely to reflect ovarian reserve. PMID- 29233505 TI - Outcome measurement in plastic surgery. AB - Outcome measurement in plastic surgery is often surgeon-centred, and clinician derived. Greater emphasis is being placed on patient-reported outcomes (PROs), in which the patients' perspective is measured directly from them. Numerous patient reported outcome measures (PROMs) have been developed in a range of fields, with a number of good quality PROMs in plastic surgery. They can be deployed to support diagnosis, disease severity determination, referral pathways, treatment decision-making, post-operative care and in determining cost-effectiveness. In order to understand the impact of disease and health interventions, appropriate PROMs are a logical choice in plastic surgery, where many conditions involve detriment of function or cosmesis. PROMS can be classified as disease-specific, domain-specific, dimension-specific, population-specific and generic. Choosing the correct outcome and measure can be nebulous. The two most important considerations are: is it suitable for the intended purpose? And how valid is it? Measurement that combines being patient-centred and aligning with clinicians' understanding is achievable, and can be studied scientifically. Rational design of new PROMs and considered choice of measures is critical in clinical practice and research. There are a number of tools that can be employed to assess the quality of PROMs that are outlined in this overview. Clinicians should consider the quality of measures both in their own practice and when critically appraising evidence. This overview of outcome measurement in plastic surgery provides a tool set enabling plastic surgeons to understand, implement and analyse outcome measures across clinical and academic practice. PMID- 29233506 TI - Option grids in melanoma: An underused tool. PMID- 29233507 TI - Bleeding on the cutting edge: A systematic review of anticoagulant and antiplatelet continuation in minor cutaneous surgery. AB - BACKGROUND: Anticoagulant and antiplatelet (AC/AP) use is common and practice surrounding AC/AP continuation or cessation peri-operatively for minor cutaneous surgery lacks evidence-based consensus. OBJECTIVE: To determine the risks of haemorrhagic and thromboembolic complications associated with the continuation or cessation of AC/AP therapy in minor cutaneous surgery. METHODS: A systematic literature search was conducted using PubMed, MEDLINE, Embase and CENTRAL, to identify all articles involving the use of AC/AP in patients undergoing minor cutaneous surgery, including skin grafts and local flaps. Eligible studies were randomised control trials, prospective studies and retrospective studies in the English language. Studies investigating free-flap repairs, oculoplastic surgery and hand surgery were excluded. RESULTS: 30 studies included data from over 14,000 patients, of which more than 5000 took regular AC/AP therapy. Thromboembolic events were rare but carry high morbidity and even mortality, and in these studies three events were associated with cessation of AC/AP. There was no increase in haemorrhagic complications in patients taking aspirin monotherapy, but evidence is conflicting regarding warfarin and clopidogrel monotherapy, which shows a small increase in rate of bleeding complications. However, no increase in wound dehiscence, graft failure, wound infection or cosmetic outcome was seen. Too few studies investigated DOAC use to draw reliable conclusions. Data are sparse in comparing multiple versus single AC/AP regimens. Use of skin grafts or local flaps may have a greater complication rate than direct closure in patients on one or more AC/AP, but evidence is limited. CONCLUSION: A case-by-case risk assessment is warranted in all patients but where possible, clinicians should prioritise meticulous haemostasis over cessation of agents. PMID- 29233509 TI - Temporal muscle atrophy: Not only the approach but the way you get it. PMID- 29233508 TI - Updated anatomy of the buccal space and its implications for plastic, reconstructive and aesthetic procedures. AB - BACKGROUND: The buccal space is an integral deep facial space which is involved in a variety of intra- and extra-oral pathologies and provides a good location for the harvest of the facial artery. The age-related anatomy of this space was investigated and compared to previous reports. METHODS: We conducted anatomic dissections in 102 fresh frozen human cephalic specimens (45 males, 57 females; age range 50-100 years) and performed additional computed tomographic, magnetic resonance and 3-D surface volumetric imaging studies to visualize the boundaries and the contents of the buccal space after injection of contrast enhancing material. RESULTS: The mean vertical extent of contrast agent injected into the buccal space was 25.2 +/- 4.3 mm and did not significantly differ between individuals of different age (p = 0.77) or gender (p = 0.13). The maximal injected volume was 10.02 cc [range: 3.09-10.02] without significant influence of age (p = 0.13) or gender (p = 0.81). The change in surface volume was 3.64 +/- 1.04 cc resulting in a mean surface-volume-coefficient of 0.87 +/- 0.12 without being statistically significant influenced by age (p = 0.53) or gender (p = 0.78). CONCLUSIONS: The facial artery was constantly identified within the buccal space whereas the facial vein was found to course within its posterior boundary. The buccal space did not undergo age-related changes in volume or size which highlights this space is a reliable and predictable landmark for various plastic, reconstructive and aesthetic procedures. PMID- 29233510 TI - Patient-specific puzzle implant preformed with 3D-printed rapid prototype model for combined orbital floor and medial wall fracture. AB - BACKGROUND: The management of combined orbital floor and medial wall fractures involving the inferomedial strut is challenging due to absence of stable cornerstone. In this article, we proposed surgical strategies using customized 3D puzzle implant preformed with Rapid Prototype (RP) skull model. METHODS: Retrospective review was done in 28 patients diagnosed with combined orbital floor and medial wall fracture. Using preoperative CT scans, original and mirror imaged RP skull models for each patient were prepared and sterilized. In all patients, porous polyethylene-coated titanium mesh was premolded onto RP skull model in two ways; Customized 3D jigsaw puzzle technique was used in 15 patients with comminuted inferomedial strut, whereas individual 3D implant technique was used in each fracture for 13 patients with intact inferomedial strut. Outcomes including enophthalmos, visual acuity, and presence of diplopia were assessed and orbital volume was measured using OsiriX software preoperatively and postoperatively. RESULTS: Satisfactory results were achieved in both groups in terms of clinical improvements. Of 10 patients with preoperative diplopia, 9 improved in 6 months, except one with persistent symptom who underwent extraocular muscle rupture. 18 patients who had moderate to severe enophthalmos preoperatively improved, and one remained with mild degree. Orbital volume ratio, defined as volumetric ratio between affected and control orbit, decreased from 127.6% to 99.79% (p < 0.05) in comminuted group, and that in intact group decreased from 117.03% to 101.3% (p < 0.05). CONCLUSION: Our surgical strategies using the jigsaw puzzle and individual reconstruction technique provide accurate restoration of combined orbital floor and medial wall fractures. PMID- 29233511 TI - Robotic nipple-sparing mastectomy with immediate reconstruction by robotically harvested latissimus dorsi muscle in a single position: Cadaveric study. PMID- 29233512 TI - Response to oral sucrosomial iron supplementation in patients undergoing bariatric surgery. The BARI-FER study. AB - BACKGROUND: Chronic intravenous iron administration is often required after bariatric surgery. Oral sucrosomial iron has a particular form of absorption and may represent an alternative treatment. OBJECTIVE: To assess the effect of switching to oral sucrosomial iron in patients receiving intravenous iron supplementation after bariatric surgery. PATIENTS AND METHODS: A case-control study was conducted on 40 women of childbearing age, of whom 20 were switched to oral sucrosomial iron, while 20 patients continued on intravenous iron sucrose every three months. RESULTS: No significant differences were seen in Hb, ferritin, and TSI levels before and after three months of treatment with sucrosomial iron. CONCLUSION: Oral sucrosomial iron could be an alternative in patients who require parenteral treatment with iron after bariatric surgery. PMID- 29233513 TI - The effect of marital status on social and gender inequalities in diabetes mortality in Andalusia. AB - OBJECTIVE: To assess the modifying effect of marital status on social and gender inequalities in mortality from diabetes mellitus (DM) in Andalusia. MATERIAL AND METHODS: A cross-sectional study was conducted using the Andalusian Longitudinal Population Database. DM deaths between 2002 and 2013 were analyzed by educational level and marital status. Age-adjusted rates (AARs) and mortality rate ratios (MRRs) were calculated using Poisson regression models, controlling for several social and demographic variables. The modifying effect of marital status on the association between educational level and DM mortality was evaluated by introducing an interaction term into the models. All analyses were performed separately for men and women. RESULTS: There were 18,158 DM deaths (10,635 women and 7,523 men) among the 4,229,791 people included in the study. The risk of death increased as the educational level decreased. Marital status modified social inequality in DM mortality in a different way in each sex. Widowed and separated/divorced women with the lowest educational level had the highest MRRs, 5,1 (95%CI: 3,6-7,3) and 5,6 (95% CI:3,6-8,5) respectively, while single men had the highest MRR, 3,1 (95%CI: 2,7-3,6). CONCLUSIONS: Educational level is a key determinant of DM mortality in both sexes, and is more relevant in women, while marital status also plays an outstanding role in men. Our results suggest that in order to address inequalities in DM mortality, the current focus on individual factors and self-care should be extended to interventions on the family, the community, and the social contexts closest to patients. PMID- 29233514 TI - Terms, concepts and definitions in clinical artificial nutrition. The ConT-SEEN Project. AB - BACKGROUND: Imprecision in terms used in the field of clinical nutrition may lead to misinterpretations among professionals. OBJECTIVE: For this reason, the Spanish Society of Endocrinology and Nutrition (SEEN) promoted this document on the terms and definitions used in clinical artificial nutrition (enteral and parenteral), establishing an agreement between Spanish experts of this specialty. METHODS: Forty-seven specialists in endocrinology and nutrition, members of the Nutrition Area of the SEEN, participated between April and September 2016. After a systematic literature review, 52 concepts were proposed. The coordinators included two additional concepts, and 57were finally selected by the working group: 13 of a general nature, 30 referring to enteral nutrition and 14 to parenteral nutrition. The degree of agreement was subsequently determined using a two-round Delphi process. It was finally ratified by consistency and concordance analysis. RESULTS: Fifty-four of the 57 terms had a very consistent agreement and were concordant. Only three showed no concordance, of whom two were very consistent and one inconsistent. In conclusion, there was consensus in the definition of 54 basic terms in the practice of clinical nutrition. PMID- 29233515 TI - Clinical characteristics, complications and management of patients with type 2 diabetes with and without diabetic kidney disease (DKD): A comparison of data from a clinical database. AB - BACKGROUND AND OBJECTIVES: The main objective of this study was to assess the percentage of co-morbid nephropathy in type 2 diabetes patients using the CKD-EPI equation and to compare the clinical characteristics and treatments of patients with type 2 diabetes with nephropathy with those of patients without nephropathy PATIENTS AND METHODS: This was a cross-sectional analysis of the demographic and clinical data registered in the IDIBAPS Biobank database. Patients were considered to have nephropathy if the diagnosis was reported in their clinical history, albuminuria (>30 mg/g) was indicated as present in the last urine test available, or an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2 was calculated using the CKD-EPI equation. RESULTS: Clinical data were obtained from 1,397 patients with a diagnosis of type 2 diabetes. The percentage of patients with nephropathy was 29.3% (N= 369) (95% confidence interval, 26.8% to 31.9%); however, only 109 (7.8%) patients had a nephropathy diagnosis reported in their clinical history. Compared with patients without nephropathy, patients with nephropathy have a higher mean age, higher frequency of diabetes complications and received insulin more frequently. CONCLUSION: Our results show that the percentage of type 2 diabetes patients with nephropathy was high and that this comorbidity was associated with a significantly higher frequency of diabetes macro- and microvascular complications (compared to diabetes patients without DKD). PMID- 29233516 TI - Editorial overview: Aggression and violence. PMID- 29233517 TI - Pediatric Weight Management Evidence-Based Practice Guidelines: Components and Contexts of Interventions. PMID- 29233518 TI - Nasal patency and otorhinolaryngologic-orofacial features in children. AB - INTRODUCTION: Nasal obstruction is a common symptom in childhood, related to rhinitis and pharyngeal tonsil hypertrophy. In the presence of nasal obstruction, nasal patency may be reduced, and nasal breathing is replaced by mouth breathing. Orofacial and otorhinolaryngologic changes are related to this breathing mode. Objective evaluation of upper airways may be obtained through nasal patency measurement. OBJECTIVE: To compare nasal patency and otorhinolaryngologic orofacial features in children. METHODS: One hundred and twenty three children, 6 12 year-old, and of both sexes underwent speech therapy evaluation, according to Orofacial Myofunctional Evaluation protocol, clinical and endoscopic otorhinolaryngologic examination and nasal patency measurement, using the absolute and predicted (%) peak nasal inspiratory flow values. RESULTS: Lower values of absolute and estimated peak nasal inspiratory flow values were found in children with restless sleep (p=0.006 and p=0.002), nasal obstruction report (p=0.027 and p=0.023), runny nose (p=0.004 and p=0.012), unsystematic lip closure during mastication (p=0.040 and p=0.026), masticatory speed reduced (p=0.006 and p=0.008) and altered solid food swallowing (p=0.006 and p=0.001). Absolute peak nasal inspiratory flow was lower in children with pale inferior turbinate (p=0.040), reduced hard palate width (p=0.037) and altered speech (p=0.004). Higher absolute values were found in children with increased tongue width (p=0.027) and, higher absolute and predicted (%) in children with mild everted lip (p=0.008 and p=0.000). CONCLUSIONS: Nasal patency was lower in children with restless sleep, rhinitis signs and symptoms, hard palate width reduced and with changes in mastication, deglutition and speech functions. It is also emphasized that most of the children presented signs and symptom of allergic rhinitis. PMID- 29233519 TI - Inhibition of central de novo ceramide synthesis restores insulin signaling in hypothalamus and enhances beta-cell function of obese Zucker rats. AB - OBJECTIVES: Hypothalamic lipotoxicity has been shown to induce central insulin resistance and dysregulation of glucose homeostasis; nevertheless, elucidation of the regulatory mechanisms remains incomplete. Here, we aimed to determine the role of de novo ceramide synthesis in hypothalamus on the onset of central insulin resistance and the dysregulation of glucose homeostasis induced by obesity. METHODS: Hypothalamic GT1-7 neuronal cells were treated with palmitate. De novo ceramide synthesis was inhibited either by pharmacological (myriocin) or molecular (si-Serine Palmitoyl Transferase 2, siSPT2) approaches. Obese Zucker rats (OZR) were intracerebroventricularly infused with myriocin to inhibit de novo ceramide synthesis. Insulin resistance was determined by quantification of Akt phosphorylation. Ceramide levels were quantified either by a radioactive kinase assay or by mass spectrometry analysis. Glucose homeostasis were evaluated in myriocin-treated OZR. Basal and glucose-stimulated parasympathetic tonus was recorded in OZR. Insulin secretion from islets and beta-cell mass was also determined. RESULTS: We show that palmitate impaired insulin signaling and increased ceramide levels in hypothalamic neuronal GT1-7 cells. In addition, the use of deuterated palmitic acid demonstrated that palmitate activated several enzymes of the de novo ceramide synthesis pathway in hypothalamic cells. Importantly, myriocin and siSPT2 treatment restored insulin signaling in palmitate-treated GT1-7 cells. Protein kinase C (PKC) inhibitor or a dominant negative PKCzeta also counteracted palmitate-induced insulin resistance. Interestingly, attenuating the increase in levels of hypothalamic ceramides with intracerebroventricular infusion of myriocin in OZR improved their hypothalamic insulin-sensitivity. Importantly, central myriocin treatment partially restored glucose tolerance in OZR. This latter effect is related to the restoration of glucose-stimulated insulin secretion and an increase in beta-cell mass of OZR. Electrophysiological recordings also showed an improvement of glucose-stimulated parasympathetic nerve activity in OZR centrally treated with myriocin. CONCLUSION: Our results highlight a key role of hypothalamic de novo ceramide synthesis in central insulin resistance installation and glucose homeostasis dysregulation associated with obesity. PMID- 29233521 TI - The Elements of Translational Chemical Biology. AB - A causal relationship between target activity modulation by small molecules and phenotypic consequence is the cornerstone of chemical biology and drug discovery. Here we articulate elements of translational chemical biology, as guideposts to ensure the appropriate use of chemical probes and the conclusions drawn from cellular studies with these molecules. PMID- 29233520 TI - 5-FU or mitomycin C hepatic arterial infusion after failure of arterial oxaliplatin in patients with colorectal cancer unresectable liver metastases. AB - INTRODUCTION: Hepatic arterial infusion (HAI) chemotherapy with oxaliplatin is an accepted option in the management of colorectal cancer (CRC) with dominant liver metastases (LM). However, despite prolonged control, some patients experience disease progression. On the other hand, oxaliplatin leads to dose-limiting toxicity. In these cases, the use of a second-line HAI with an alternative drug has never been reported to date. We evaluated treatment outcomes in patients receiving second-line HAI with 5-FU or mitomycin C, after first-line HAI of oxaliplatin in heavily pretreated patients. MATERIAL AND METHODS: Between March 2010 and June 2016, this observational study included 24 patients with unresectable CRC LM and treated with HAI of 5-FU (17 patients) or mitomycin C (7 patients), after HAI of oxaliplatin. RESULTS: Mean age was 61.7 years. Forty-two percent of patients (10/24) had extra-hepatic metastases and 75% (18/24) at least 8 liver metastases. Including HAI of oxaliplatin, all patients had previously received at least 2 lines of chemotherapy+/-targeted agents (100%) and 96% (23/24) received concomitant systemic therapies together with HAI of 5-FU or mitomycin C. The overall objective response rate and disease control rate were, respectively, 42% (10/24) and 71% (17/24). Median progression-free survival and overall survival (OS) were, respectively, 5.6 and 25.8 months; hepatic progression-free survival was 8.5months. Thirteen percent (3/24) of the patients received further curative intent treatment after HAI 5-FU and mitomycin C. No toxic death occurred and the toxicity profile was acceptable. CONCLUSIONS: HAI of 5-FU or mitomycin C is an alternative option in patients with predominant CRC LM, when they experience disease progression or do not tolerate HAI of oxaliplatin. PMID- 29233522 TI - Subcutaneous implant-based breast reconstruction, a modern challenge in postmastectomy radiation planning. AB - PURPOSE: A growing trend in breast reconstruction has been placement of tissue expanders in the pre pectoral space. This is a change from the practice of placement under the pectoralis major with or without an acellular dermal matrix (ADM) sling. The move toward pre pectoral placement with an ADM wrap has the intent of decreasing post-operative pain and decreasing animation deformities. The cosmesis of pre pectoral reconstructions in the setting of post mastectomy radiation has also appeared improved in our early experience, when compared to submuscular reconstructions. We sought to review the risks and benefits of this technique in the setting of post mastectomy radiation. METHODS AND MATERIALS: Cases of ADM wrapped prepectoral tissue expander breast reconstructions in patients needing postmastectomy radiation therapy were reviewed in a single institution. RESULTS: Thirty patients were treated with ADM wrapped prepectoral tissue expanders. On review of radiation plans, there were patients with anatomical variations, for whom standard dosimetric criteria were not met with partially wide tangent fields. Use of a medial electron field matched to steep photon tangents was not advised due to undercoverage of the tumor bed related to implant placement. Boost treatment was also omitted as a result of concerns regarding the implant location. CONCLUSIONS: While new advances in plastic surgery may improve on cosmetic outcomes for breast cancer patients, increased discussion with radiation oncologists is needed to appropriately select candidates for these procedures. Prospective trials are necessary to ensure that these new techniques do not compromise oncologic outcomes. PMID- 29233523 TI - Stereotactic body radiation therapy for stage I non-small cell lung cancer: The importance of treatment planning algorithm and evaluation of a tumor control probability model. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) is increasingly used to treat early-stage non-small cell lung cancer (NSCLC). A previous report introduced the term size-adjusted biologically effective dose (sBED), which accounts for tumor diameter and biologically effective dose (BED) and may be used to predict the likelihood of local control following SBRT. Here we seek to replicate those findings using a separate dataset. METHODS AND MATERIALS: We queried the RSSearch Patient Registry for patients treated with SBRT for stage I NSCLC. Kaplan-Meier survival curves, log-rank testing, and Cox proportional hazards modeling were used to evaluate tumor diameter, BED, and treatment planning algorithm as predictors of local control. sBED was defined as BED minus 10 times the tumor diameter (in centimeters). Tumor control probability (TCP) modeling was performed to characterize the relationship between sBED and the likelihood of local control 2 years after SBRT. RESULTS: A total of 928 patients met inclusion criteria. Median BED was 115.5 Gy, and 59% of patients had T1 tumors. Local control rates following treatments planned using a pencil beam algorithm were inferior to those observed following treatments planned using a Monte Carlo algorithm (89% vs 96% at 2 years, log-rank P = .022). In a multivariable Cox model adjusted for tumor diameter and BED, the use of a pencil beam planning algorithm was associated with increased risk of local failure (hazard ratio, 2.39; 95% confidence interval, 1.08-5.29; P = .032). TCP modeling, restricted to patients treated using a Monte Carlo algorithm, demonstrated that sBED values of 60, 80, and 100 Gy yield predicted TCP rates of 91%, 95%, and 97%, respectively. CONCLUSIONS: Using a large, multi-institutional database, we found a strong association between treatment planning algorithm and local control rates following SBRT for early-stage NSCLC. sBED is a useful tool for predicting the likelihood of local control following SBRT in this setting. PMID- 29233525 TI - Relationships between temporomandibular joint disk displacements and condylar volume. AB - OBJECTIVES: The aim of this study was to assess the relationship between mandibular condylar volume and disk displacement status in adult males and females. STUDY DESIGN: We evaluated 122 temporomandibular joints in 61 patients using magnetic resonance imaging (MRI) and computed tomography (CT). MRI data were used to assign disk status as normal disk position (NR), disk displacement with reduction (DDR), or disk displacement without reduction (DDNR). CT data were used to calculate total condylar volume and its components, cortical volume, and trabecular volume. The relationships among condylar volume, disk status, and gender were tested with 2-way analysis of variance. RESULTS: Condylar volumes significantly correlated with disk displacement, tending to decrease as displacement increased. There were significant differences in both total condylar volume and trabecular volume among the DD status (NR > DDR > DDNR), whereas cortical volume was significantly different only between NR/DDR and DDNR (NR/DDR > DDNR). The volume decreases associated with temporomandibular joint DD were found in both males and females, with greater decreases in men than in women as DD progressed. CONCLUSIONS: Condylar volumes are significantly associated with disk displacement status. Joints with nonreducing disks showed the smallest condylar volumes in both males and females. PMID- 29233527 TI - Cutaneous Leiomyosarcoma: On the Importance of Histologic Location. PMID- 29233524 TI - The real deal: Willingness-to-pay and satiety expectations are greater for real foods versus their images. AB - Laboratory studies of human dietary choice have relied on computerized two dimensional (2D) images as stimuli, whereas in everyday life, consumers make decisions in the context of real foods that have actual caloric content and afford grasping and consumption. Surprisingly, few studies have compared whether real foods are valued more than 2D images of foods, and in the studies that have, differences in the stimuli and testing conditions could have resulted in inflated bids for the real foods. Moreover, although the caloric content of food images has been shown to influence valuation, no studies to date have investigated whether 'real food exposure effects' on valuation reflect greater sensitivity to the caloric content of real foods versus images. Here, we compared willingness-to pay (WTP) for, and expectations about satiety after consuming, everyday snack foods that were displayed as real foods versus 2D images. Critically, our 2D images were matched closely to the real foods for size, background, illumination, and apparent distance, and trial presentation and stimulus timing were identical across conditions. We used linear mixed effects modeling to determine whether effects of display format were modulated by food preference and the caloric content of the foods. Compared to food images, observers were willing to pay 6.62% more for (Experiment 1) and believed that they would feel more satiated after consuming (Experiment 2), foods displayed as real objects. Moreover, these effects appeared to be consistent across food preference, caloric content, as well as observers' estimates of the caloric content of the foods. Together, our results confirm that consumers' perception and valuation of everyday foods is influenced by the format in which they are displayed. Our findings raise important new insights into the factors that shape dietary choice in real-world contexts and highlight potential avenues for improving public health approaches to diet and obesity. PMID- 29233526 TI - No increased risk of carcinogenesis with mesh-based hernia repairs. AB - BACKGROUND: The use of synthetic mesh has been placed under considerable scrutiny. We sought to evaluate whether there is a link between placement of synthetic polypropylene mesh for hernia repair and a subsequent cancer diagnosis. METHODS: Adult men undergoing mesh-based hernia repair from January 2008-December 2009 in New York State were identified and followed through December 2014. Control cohorts of men undergoing cholecystectomy and total knee replacement were control cohorts. RESULTS: 1894 patients undergoing hernia repair, 912 patients in the cholecystectomy control cohort, and 1099 in the TKA control cohort with a cancer diagnosis. In the matched analyses of mesh-based hernia repair and cholecystectomy patients 6.5% vs. 7.1% developed cancer. In the matched analysis of hernia patients and TKA patients, 9.3% vs. 9.1% developed cancer. No association between mesh-based hernia surgery and increased risk of cancer was found. CONCLUSIONS: Mesh-based hernia repair was not associated with an increased risk of subsequent development of cancer in men. PMID- 29233528 TI - [Overview of feelings and practices of gynecologists and obstetricians for the noninvasive prenatal testing in France]. AB - OBJECTIVES: To evaluate the feelings and practices of French obstetrician gynecologists in prescribing the noninvasive prenatal testing (NIPT) before the release of the French High Authority of Health recommendations. METHODS: Descriptive, declarative and transversal study, analyzing the feelings and practices of obstetrician-gynecologists, members of the French College of Gynecologists and Obstetricians (CNGOF) between February and May 2017 using an online questionnaire. Practitioners' feedback was self-assessed for several clinical situations using a numerical scale ranging from 1 to 10. This experience was rated as "good" (grades 6 to 10) or "bad" (grades 1-5). RESULTS: Overall, 529 practitioners (29.2%) of 1812 CNGOF members, answered the online questionnaire. A "good" feeling was found for more than 65% of the practitioners audited. Feelings were significantly better for obstetricians, sonographers (P<0.05) and CPDPN members (P=0.003) compared to other practitioners. Situations where the DPNI was proposed "systematically" were risks greater than 1/250 (70.9%), between 1/250 and 1/500 (59.4%), greater than 1/250 associated with history of spontaneous miscarriages and/or fetal death in utero (66%), greater than 1/250 associated with pregnancy resulting from PMA (68.3%), history of fetal aneuploidy (54%) and a parent carrying a Robertsonian translocation (51.6%). CONCLUSION: This study highlights a good overall feeling of the practitioners with the NIPT. PMID- 29233530 TI - Corrigendum to Intestinal Preconditioning Ameliorates Ischemia-Reperfusion Induced Acute Lung Injury in Rats: An Experimental Study [Journal of Surgical Research 160(2) (2010) 294-301]. PMID- 29233529 TI - Innovating patient care delivery: DSRIP's interrupted time series analysis paradigm. AB - INTRODUCTION: Adoption of Medicaid Section 1115 waiver is one of the many ways of innovating healthcare delivery system. The Delivery System Reform Incentive Payment (DSRIP) pool, one of the two funding pools of the waiver has four categories viz. infrastructure development, program innovation and redesign, quality improvement reporting and lastly, bringing about population health improvement. BACKGROUND: A metric of the fourth category, preventable hospitalization (PH) rate was analyzed in the context of eight conditions for two time periods, pre-reporting years (2010-2012) and post-reporting years (2013 2015) for two hospital cohorts, DSRIP participating and non-participating hospitals. The study explains how DSRIP impacted Preventable Hospitalization (PH) rates of eight conditions for both hospital cohorts within two time periods. METHODS: Eight PH rates were regressed as the dependent variable with time, intervention and post-DSRIP Intervention as independent variables. PH rates of eight conditions were then consolidated into one rate for regressing with the above independent variables to evaluate overall impact of DSRIP. An interrupted time series regression was performed after accounting for auto-correlation, stationarity and seasonality in the dataset. RESULTS: In the individual regression model, PH rates showed statistically significant coefficients for seven out of eight conditions in DSRIP participating hospitals. In the combined regression model, the coefficient of the PH rate showed a statistically significant decrease with negative p-values for regression coefficients in DSRIP participating hospitals compared to positive/increased p-values for regression coefficients in DSRIP non-participating hospitals. CONCLUSION AND IMPLICATIONS: Several macro- and micro-level factors may have likely contributed DSRIP hospitals outperforming DSRIP non-participating hospitals. Healthcare organization/provider collaboration, support from healthcare professionals, DSRIP's design, state reimbursement and coordination in care delivery methods may have led to likely success of DSRIP. LEVEL OF EVIDENCE: IV, a retrospective cohort study based on longitudinal data. PMID- 29233531 TI - Genomic landscape of ovarian clear cell carcinoma via whole exome sequencing. AB - OBJECTIVE: To analyze whole exome sequencing (WES) data on ovarian clear cell carcinoma (OCCC) in Korean patients via the technique of next generation sequencing (NGS). Genomic profiles were compared between endometriosis-associated OCCC (EMS-OCCC) and Non-EMS-OCCC. METHODS: We used serum samples and cancer tissues, stored at the Seoul National University Hospital Human Biobank, that were initially collected from women diagnosed with OCCC between 2012 and 2016. In total, 15 patients were enrolled: 5 with pathologically confirmed EMS-OCCC and 10 with Non-EMS-OCCC. We performed NGS WES on 15 fresh frozen OCCC tissues and matched serum samples, enabling comprehensive genomic characterization of OCCC. RESULTS: OCCC was characterized by complex genomic alterations, with a median of 178 exonic mutations (range, 111-25,798) and a median of 343 somatic copy number variations (range, 43-1,820) per tumor sample. In all, 54 somatic mutations were discovered across 14 genes, including PIK3CA (40%), ARID1A (40%), and KRAS (20%) in the 15 Korean OCCCs. Copy number gains in NTRK1 (33%), MYC (40%), and GNAS (47%) and copy number losses in TET2 (73%), TSC1 (67%), BRCA2 (60%), and SMAD4 (47%) were frequent. The significantly altered pathways were associated with proliferation and survival (including the PI3K/AKT, TP53, and ERBB2 pathways) in 87% of OCCCs and with chromatin remodeling in 47% of OCCCs. No significant differences in frequencies of genetic alterations were detected between EMS-OCCC and Non-EMS-OCCC groups. CONCLUSION: We successfully characterized the genomic landscape of 15 Korean patients with OCCC. We identified potential therapeutic targets for the treatment of this malignancy. PMID- 29233533 TI - Disorganization of the Retinal Inner Layers as a Predictor of Visual Acuity in Eyes With Macular Edema Secondary to Vein Occlusion. PMID- 29233532 TI - Clinical characteristics and outcomes of patients with BRCA1 or RAD51C methylated versus mutated ovarian carcinoma. AB - OBJECTIVE: In ovarian carcinoma, mutations in homologous recombination DNA repair (HRR) genes, including BRCA1 and RAD51C, are associated with increased survival and specific clinical features. Promoter hypermethylation is another mechanism of reducing gene expression. We assessed whether BRCA1 and RAD51C promoter hypermethylation is associated with similar survival and clinical characteristics. METHODS: Promoter methylation of BRCA1 and RAD51C was evaluated using methylation-sensitive PCR in 332 primary ovarian carcinomas. Damaging germline and somatic mutations in 16 HRR genes were identified using BROCA sequencing. RESULTS: BRCA1 methylation was detected in 22 carcinomas (6.6%) and RAD51C methylation in 9 carcinomas (2.7%). These small numbers limited the power to detect differences in survival and platinum sensitivity. Mutations in one or more HRR genes were found in 95 carcinomas (29%). Methylation of BRCA1 or RAD51C was mutually exclusive with mutations in these genes (P=0.001). Patients whose carcinomas had BRCA1 methylation (57.7years+/-2.5) or BRCA1 mutations (54.1years+/-1.4) were younger than those without (63.3years+/-0.8; P=0.029, P<0.0001). BRCA1 methylation and germline BRCA1 mutation were associated with high grade serous (HGS) histology (P=0.045, P=0.001). BRCA1 mutations were associated with increased sensitivity to platinum chemotherapy while BRCA1 methylation was not (P=0.034, P=0.803). Unlike HRR mutations, methylation was not associated with improved overall survival compared to cases without methylation or mutation. CONCLUSIONS: Patients with BRCA1-methylated carcinomas share clinical characteristics with patients with BRCA1-mutated carcinomas including younger age and predominantly HGS histology. However, unlike mutation, RAD51C and BRCA1 methylation were not associated with improved survival or greater sensitivity to platinum chemotherapy. PMID- 29233534 TI - Reply. PMID- 29233535 TI - History of the American Journal of Ophthalmology: A 100th Anniversary Update. PMID- 29233537 TI - Life-threatening parkinsonism-hyperpyrexia syndrome following bilateral deep brain stimulation of the subthalamic nucleus. AB - Parkinsonism-hyperpyrexia syndrome (PHS), or neuroleptic malignant syndrome (NMS), is a neurophysiologic reaction to the acute withdrawal/decrease of central dopamine levels. It is a severe complication characterized by rigidity, change in consciousness level, fever, hypertension, and autonomic instability, that can be fatal. To the best of our knowledge, PHS following deep brain stimulation (DBS) of subthalamic nucleus (STN) surgery due to anti-Parkinson drug discontinuation has been previously reported only six times. Half of these cases resulted in fatalities. Herein, we report on an early diagnosed case of PHS following bilateral STN-DBS which was successfully treated with the administration of dopamine agonists, fluid replacement, and activation of DBS. PMID- 29233536 TI - LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor. AB - Ghrelin, an appetite-stimulatory hormone secreted by the stomach, was discovered as a ligand for the growth hormone secretagogue receptor (GHSR). Through GHSR, ghrelin stimulates growth hormone (GH) secretion, a function that evolved to protect against starvation-induced hypoglycemia. Though the biology mediated by ghrelin has been described in great detail, regulation of ghrelin action is poorly understood. Here, we report the discovery of liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous antagonist of GHSR. LEAP2 is produced in the liver and small intestine, and its secretion is suppressed by fasting. LEAP2 fully inhibits GHSR activation by ghrelin and blocks the major effects of ghrelin in vivo, including food intake, GH release, and maintenance of viable glucose levels during chronic caloric restriction. In contrast, neutralizing antibodies that block endogenous LEAP2 function enhance ghrelin action in vivo. Our findings reveal a mechanism for fine-tuning ghrelin action in response to changing environmental conditions. PMID- 29233538 TI - Borrelia burgdorferi serology and diagnosis of Lyme disease in the healthcare area of Santiago de Compostela (Galicia, Spain): 2006-2016. PMID- 29233539 TI - Effect of tetracalcium phosphate/monetite toothpaste on dentin remineralization and tubule occlusion in vitro. AB - OBJECTIVES: To investigate the tubule occlusion and remineralization potential of a novel toothpaste with active tetracalcium phosphate/monetite mixtures under de/remineralization cycling. METHODS: Dentin de/remineralization cycling protocol consisted of demineralization in 1% citric acid at pH 4.6 with following remineralization with toothpastes and soaking in artificial saliva. Effectiveness of toothpastes to promote remineralization was evaluated by measurement of microhardness recovery, analysis of surface roughness, thickness of coating and scanning electron microscopy. RESULTS: The novel tetracalcium phosphate/monetite dentifrice had comparable remineralization potential as commercial calcium silicate/phosphate (SENSODYNE(r)) and magnesium aluminum silicate (Colgate(r)) toothpastes and significantly higher than control saliva (p<0.02). Surface roughness was significantly lower after treatment with prepared and SENSODYNE(r) dentifirice (p<0.05). The coatings on dentin surfaces was significantly thicker after applying toothpastes as compared to negative control (p<0.001). CONCLUSIONS: The new fluoride toothpaste formulation with bioactive tetracalcium phosphate/monetite calcium phosphate mixture effectively occluded dentin tubules and showed good dentin remineralization potential under de/remineralization cycling. It could replace professional powder preparation based on this mixture. It was demonstrated that prepared dentifrice had comparable properties with commercial fluoride calcium silicate/phosphate or magnesium aluminum silicate dentifrices. PMID- 29233540 TI - Smear layer-deproteinizing improves bonding of one-step self-etch adhesives to dentin. AB - OBJECTIVES: Smear layer deproteinizing was proved to reduce the organic phase of smear layer covered on dentin surface. It was shown to eliminate hybridized smear layer and nanoleakage expression in resin-dentin bonding interface of two-step self-etch adhesive. This study aimed to investigate those effects on various one step self-etch adhesives. METHODS: Four different one-step self-etch adhesives were used in this study; SE One (SE), ScotchbondTM Universal (SU), BeautiBond Multi (BB), and Bond Force (BF). Flat human dentin surfaces with standardized smear layer were prepared. Smear layer deproteinizing was carried out by the application of 50ppm hypochlorous acid (HOCl) on dentin surface for 15s followed by Accel(r) (p-toluenesulfinic acid salt) for 5s prior to adhesive application. No surface pretreatment was used as control. Microtensile bond strength (MUTBS) and nanoleakage under TEM observation were investigated. The data were analyzed by two-way ANOVA and Tukey's post-hoc test and t-test at the significant level of 0.05. RESULTS: Smear layer deproteinizing significantly improved MUTBS of SE, SU, and BB (p<0.001). Hybridized smear layer observed in control groups of SE, BB, and BF, and reticular nanoleakage presented throughout the hybridized complex in control groups of BB and BF were eliminated upon the smear layer deproteinizing. SIGNIFICANCE: Smear layer deproteinizing by HOCl and Accel(r) application could enhance the quality of dentin for bonding to one-step self-etch adhesives, resulting in the improving MUTBS, eliminating hybridized smear layer and preventing reticular nanoleakage formation in resin-dentin bonding interface. PMID- 29233542 TI - Natural killer cells and anti-tumor immunity. AB - Immune checkpoint inhibitors harness the power of the immune system to fight cancer. The clinical success achieved with antibodies against the inhibitory T cell receptors PD-1 and CTLA4 has focused attention on the possibility of manipulating other immune cells, in particular those involved in innate immunity. Here we review the role of innate lymphoid cells (ILCs) and their contribution to tumor immunity. As the prototypical ILC, the natural killer (NK) cell has an intrinsic ability to detect and kill cancer cells. NK cells are dependent on the cytokine interleukin (IL)-15 for their development and effector activity. We discuss the role of the Suppressor of cytokine (SOCS) proteins in negatively regulating IL-15 and NK cell responses and the potential for targeting these small intracellular regulators as new immune checkpoints. PMID- 29233543 TI - Learning of supermicrosurgical vascular anastomosis: MicroChirSim(r) procedural simulator versus Anastomosis Training Kit(r) procedural simulator. AB - Many biological and non-biological simulators have been developed to reduce the length of the learning curve for supermicrosurgery. All of them have disadvantages. The goal of this study was to evaluate the feasibility of the new MicrochirSim(r) (0.5mm) non-biological procedural simulator by comparing it to the Anastomosis Training Kit(r) (2mm). After viewing a video of end-to-end anastomosis of a rat-tail artery, 10 residents in surgery reproduced the same technique on a procedural simulator: 5 on the MicroChirSim(r) (group 1) and 5 on the Anastomosis Training Kit(r) (group 2). The 10 residents then each performed five end-to-end anastomoses of the rat-tail artery on which they were evaluated. The average length of the procedure was 33minutes in group 1 and 45minutes in group 2. The average number of suture points was 3.7 in group 1 and 5.4 in group 2, which suggests training with a 0.5mm simulator improves suturing. The anastomosis was patent in 25 cases in group 1 and in 22 cases in group 2. The anastomosis was free of leaks in 25 cases in group 1 and in 19 cases in group 2. In conclusion, the MicroChirSim(r) procedural simulator accelerates the learning curve for vascular supermicrosurgery. PMID- 29233544 TI - Changes in the pressure distribution by wrist angle and hand position in a wrist splint. AB - The study was conducted to provide basic data to develop a system that distributes pressure over a broader area by measuring and analyzing pressures in various wrist angles and hand positions while wearing a wrist splint. With 0, 15, 30, and 45 degrees of wrist extension, full-finger extension and finger flexion, pressure distribution changes were measured three times. Average peak pressure was analyzed and mean value picture (MVP) in zones 3-5 was calculated. A one-way Anova was conducted to identify changes in pressure distribution by wrist angle and hand position. Mean peak pressure values (kPa) in zones 3-5 changed depending on the wrist angle. Peak pressures (kPa) changed significantly in 15, 30, and 45 degrees wrist extension, depending on the hand position. Since pressure distributions differ depending the wrist angle and hand position (finger flexion), it is necessary to consider how pressure varies in each wrist position and to provide information on postures that should be avoided during tasks and occupational activities based on various wrist angles or hand positions. PMID- 29233545 TI - Epiploic appendagitis at term pregnancy. The importance of expert imaging: A case report. PMID- 29233541 TI - Combination Therapies Targeting HDAC and IKK in Solid Tumors. AB - The rationale for developing histone deacetylase (HDAC) inhibitors (HDACi) as anticancer agents was based on their ability to induce apoptosis and cell cycle arrest in cancer cells. However, while HDACi have been remarkably effective in the treatment of hematological malignancies, clinical studies with HDACi as single agents in solid cancers have been disappointing. Recent studies have shown that, in addition to inducing apoptosis in cancer cells, class I HDACi induce IkappaB kinase (IKK)-dependent expression of proinflammatory chemokines, such as interleukin-8 (IL8; CXCL8), resulting in the increased proliferation of tumor cells, and limiting the effectiveness of HDACi in solid tumors. Here, we discuss the mechanisms responsible for HDACi-induced CXCL8 expression, and opportunities for combination therapies targeting HDACs and IKK in solid tumors. PMID- 29233546 TI - Quantitative risk assessment of salmon louse-induced mortality of seaward migrating post-smolt Atlantic salmon. AB - The Norwegian government recently implemented a new management system to regulate salmon farming in Norway, aiming to promote environmentally sustainable growth in the aquaculture industry. The Norwegian coast has been divided into 13 production zones and the volume of salmonid production in the zones will be regulated based on salmon lice effects on wild salmonids. Here we present a model for assessing salmon louse-induced mortality of seaward-migrating post-smolts of Atlantic salmon. The model quantifies expected salmon lice infestations and louse-induced mortality of migrating post-smolt salmon from 401 salmon rivers draining into Norwegian coastal waters. It is assumed that migrating post-smolts follow the shortest path from river outlets to the high seas, at constant progression rates. During this migration, fish are infested by salmon lice of farm origin according to an empirical infestation model. Furthermore, louse-induced mortality is estimated from the estimated louse infestations. Rivers draining into production zones on the West Coast of Norway were at the highest risk of adverse lice effects. In comparison, rivers draining into northerly production zones, along with the southernmost production zone, were at lower risk. After adjusting for standing stock biomass, estimates of louse-egg output varied by factors of up to 8 between production zones. Correlation between biomass adjusted output of louse infestation and densities of farmed salmon in the production zones suggests that a large-scale density-dependent host-parasite effect is a major driver of louse infestation rates and parasite-induced mortality. The estimates are sensitive to many of the processes in the chain of events in the model. Nevertheless, we argue that the model is suited to assess spatial and temporal risks associated with farm-origin salmon lice. PMID- 29233547 TI - The developing spectrum of gastric-type cervical glandular lesions. AB - Adenocarcinoma of the cervix is less common than squamous cell carcinoma, although its relative prevalence is increasing. Oncogenic (high-risk) human papillomavirus (HPV) infection is implicated in the development of approximately 90% of all cervical adenocarcinomas. Of the remaining non-HPV associated tumours, the most frequent is gastric-type adenocarcinoma (GAS), which is recognised by the World Health Organization as a form of mucinous adenocarcinoma of the cervix. Minimal deviation adenocarcinoma (MDA) of mucinous type (adenoma malignum) is considered an extremely well differentiated variant of GAS and is encompassed within the category of GAS. The concept of gastric-type cervical glandular lesions has emerged over recent decades and our understanding of the full spectrum of benign, premalignant and malignant lesions is still evolving. Established benign lesions, which are rare, include simple gastric metaplasia and lobular endocervical glandular hyperplasia (LEGH) (complex gastric metaplasia). Postulated premalignant lesions comprise atypical LEGH and gastric-type adenocarcinoma in situ (gAIS); these are probably related lesions for which the umbrella term 'gAIS' has been proposed. The term 'gastric-type' derives from the morphological resemblance of the glandular epithelium to that seen in the stomach and pancreaticobiliary tree; intestinal metaplasia with goblet cells and neuroendocrine cells are present in some cases. A gastric immunophenotype has been demonstrated using markers of pyloric gland mucin, MUC6 and HIK1083. Uncommonly, gastric-type cervical glandular lesions involve multiple sites in the female genital tract and it may be problematic to discern whether these represent independent synchronous or metastatic lesions. There is also an association between gastric-type cervical lesions and Peutz-Jeghers syndrome. Awareness of the spectrum of gastric-type lesions is important, as the diagnostic features of both gAIS and GAS, particularly well differentiated examples, may be subtle, and p16 immunohistochemistry is usually negative. GAS has a much poorer prognosis than HPV-associated cervical adenocarcinoma, with propensity for presentation at advanced stage and wide dissemination to unusual sites such as the ovary, omentum and peritoneum. Although uncommon, GAS is likely to increase in relative prevalence with the introduction of HPV vaccination and precursor lesions will not be detected by primary HPV-based screening programs. PMID- 29233549 TI - Trimodality therapy for older patients with bladder cancer: Overtreatment or benefit? PMID- 29233550 TI - Risk of fetal death in growth-restricted fetuses with umbilical and/or ductus venosus absent or reversed end-diastolic velocities before 34 weeks of gestation: a systematic review and meta-analysis. AB - OBJECTIVE: The objective of the study was to establish the risk of fetal death in early-onset growth-restricted fetuses with absent or reversed end-diastolic velocities in the umbilical artery or ductus venosus. DATA SOURCES: A systematic search was performed to identify relevant studies published in English, Spanish, French, Italian, or German using the databases PubMed, ISI Web of Science, and SCOPUS, without publication time restrictions. STUDY ELIGIBILITY CRITERIA: The study criteria included observational cohort studies and randomized controlled trials of early-onset growth-restricted fetuses (diagnosed before 34 weeks of gestation), with information on the rate of fetal death occurring before 34 weeks of gestation and absent or reversed end-diastolic velocities in the umbilical artery and/or ductus venosus. STUDY APPRAISAL AND SYNTHESIS METHODS: For quality assessment, 2 reviewers independently assessed the risk of bias using the Newcastle-Ottawa Scale for observational studies and the Cochrane Collaboration's tool for randomized trials. For the meta-analysis, odds ratio for both fixed and random-effects models (weighting by inverse of variance) were used. Heterogeneity between studies was assessed using tau2, chi2 (Cochrane Q), and I2 statistics. Publication bias was assessed by a funnel plot for meta-analyses and quantified by the Egger method. RESULTS: A total of 31 studies were included in this meta analysis. The odds ratios for fetal death (random-effects models) were 3.59 (95% confidence interval, 2.3-5.6), 7.27 (95% confidence interval, 4.6-11.4), and 11.6 (95% confidence interval, 6.3-19.7) for growth-restricted fetuses with umbilical artery absent end-diastolic velocities, umbilical artery reversed end-diastolic velocities, and ductus venosus absent or reversed end-diastolic velocities, respectively. There was no substantial heterogeneity among studies for any of the analyses. CONCLUSION: Early-onset growth-restricted fetuses with either umbilical artery or ductus venosus absent or reserved end-diastolic velocities are at a substantially increased risk for fetal death. PMID- 29233548 TI - The impact of actual body weight-based chemotherapy dosing and body size on adverse events and outcome in older patients with breast cancer: Results from Cancer and Leukemia Group B (CALGB) trial 49907 (Alliance A151436). AB - OBJECTIVE: Actual weight-based (AWB) chemotherapy dosing is recommended for obese patients in the 2012 ASCO Clinical Practice Guideline. CALGB 49907, which utilized ABW-based adjuvant chemotherapy dosing, was a phase 3 trial in women age>=65years with early stage breast cancer, providing the opportunity to examine impact of such dosing on toxicities and outcome in older patients with breast cancer. MATERIALS AND METHODS: Adverse event data were available for 615 of 633 enrolled patients. Objectives were to assess grade>=3 hematologic/non-hematologic toxicities by treatment arm, age, study entry BSA/BMI, and relapse-free (RFS) and overall survival (OS) by BSA/BMI. RESULTS: The 615 patients were sub-grouped by BSA (quartiles) and standard BMI categories, with BMI underweight/normal weight categories combined. Overall, grade>=3 non-hematologic and hematologic toxicities occurred in 39.8% and 28.3% of patients, respectively. There were no significant differences in grade>=3 toxicities among BSA quartiles. However, more grade>=3 hematologic toxicities occurred in the underweight/normal weight BMI subgroup compared to overweight/obese subgroups (p=0.048). Type of chemotherapy and age had no impact on toxicity occurrence by BSA/BMI categories. RFS was superior in the 25th-50th BSA percentile patients in univariate analysis (p=0.042), as was OS in both univariate and multivariate analyses (p=0.007, p=0.009, respectively). No differences in RFS or OS were found by BMI categories. CONCLUSION: Obesity was not correlated with adverse relapse or survival outcome, and grade>=3 toxicities were not greater with ABW-based dosing. This supports safety and efficacy of ABW based dosing as per the 2012 ASCO clinical practice guideline. ClinicalTrials.gov Identifier: NCT00024102 (49907). PMID- 29233551 TI - Generation of Adrenal Chromaffin-like Cells from Human Pluripotent Stem Cells. AB - Adrenomedullary chromaffin cells are catecholamine (CA)-producing cells originating from trunk neural crest (NC) via sympathoadrenal progenitors (SAPs). We generated NC and SAPs from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) in vitro via BMP2/FGF2 exposure, ascertained by qPCR and immunoexpression of SOX10, ASCL1, TFAP2alpha, and PHOX2B, and by fluorescence-activated cell sorting selection for p75NTR and GD2, and confirmed their trunk-like HOX gene expression. We showed that continuing BMP4 and curtailing FGF2 in vitro, augmented with corticosteroid mimetic, induced these cells to upregulate the chromaffin cell-specific marker PNMT and other CA synthesis and storage markers, and we demonstrated noradrenaline and adrenaline by Faglu and high-performance liquid chromatography. We showed these human cells' SAP-like property of migration and differentiation into cells expressing chromaffin cell markers by implanting them into avian embryos in vivo and in chorio-allantoic membrane grafts. These cells have the potential for investigating differentiation of human chromaffin cells and for modeling diseases involving this cell type. PMID- 29233552 TI - A Refined Culture System for Human Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Organoids. AB - Gut epithelial organoids are routinely used to investigate intestinal biology; however, current culture methods are not amenable to genetic manipulation, and it is difficult to generate sufficient numbers for high-throughput studies. Here, we present an improved culture system of human induced pluripotent stem cell (iPSC) derived intestinal organoids involving four methodological advances. (1) We adopted a lentiviral vector to readily establish and optimize conditioned medium for human intestinal organoid culture. (2) We obtained intestinal organoids from human iPSCs more efficiently by supplementing WNT3A and fibroblast growth factor 2 to induce differentiation into definitive endoderm. (3) Using 2D culture, followed by re-establishment of organoids, we achieved an efficient transduction of exogenous genes in organoids. (4) We investigated suspension organoid culture without scaffolds for easier harvesting and assays. These techniques enable us to develop, maintain, and expand intestinal organoids readily and quickly at low cost, facilitating high-throughput screening of pathogenic factors and candidate treatments for gastrointestinal diseases. PMID- 29233553 TI - Breast Cancers Activate Stromal Fibroblast-Induced Suppression of Progenitors in Adjacent Normal Tissue. AB - Human breast cancer cells are known to activate adjacent "normal-like" cells to enhance their own growth, but the cellular and molecular mechanisms involved are poorly understood. We now show by both phenotypic and functional measurements that normal human mammary progenitor cells are significantly under-represented in the mammary epithelium of patients' tumor-adjacent tissue (TAT). Interestingly, fibroblasts isolated from TAT samples showed a reduced ability to support normal EGF-stimulated mammary progenitor cell proliferation in vitro via their increased secretion of transforming growth factor beta. In contrast, TAT fibroblasts promoted the proliferation of human breast cancer cells when these were co transplanted in immunodeficient mice. The discovery of a common stromal cell mediated mechanism that has opposing growth-suppressive and promoting effects on normal and malignant human breast cells and also extends well beyond currently examined surgical margins has important implications for disease recurrence and its prevention. PMID- 29233554 TI - Accelerated and Improved Differentiation of Retinal Organoids from Pluripotent Stem Cells in Rotating-Wall Vessel Bioreactors. AB - Pluripotent stem cells can be differentiated into 3D retinal organoids, with major cell types self-patterning into a polarized, laminated architecture. In static cultures, organoid development may be hindered by limitations in diffusion of oxygen and nutrients. Herein, we report a bioprocess using rotating-wall vessel (RWV) bioreactors to culture retinal organoids derived from mouse pluripotent stem cells. Organoids in RWV demonstrate enhanced proliferation, with well-defined morphology and improved differentiation of neurons including ganglion cells and S-cone photoreceptors. Furthermore, RWV organoids at day 25 (D25) reveal similar maturation and transcriptome profile as those at D32 in static culture, closely recapitulating spatiotemporal development of postnatal day 6 mouse retina in vivo. Interestingly, however, retinal organoids do not differentiate further under any in vitro condition tested here, suggesting additional requirements for functional maturation. Our studies demonstrate that bioreactors can accelerate and improve organoid growth and differentiation for modeling retinal disease and evaluation of therapies. PMID- 29233555 TI - Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice. AB - Huntington's disease (HD) is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP)-grade human embryonic stem cell-derived neural stem cell (hNSC) line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain derived neurotrophic factor (BDNF) in both models. These findings hold promise for future development of stem cell-based therapies. PMID- 29233556 TI - Contribution of ATOH1+ Cells to the Homeostasis, Repair, and Tumorigenesis of the Colonic Epithelium. AB - ATOH1 is a master transcription factor for the secretory lineage differentiation of intestinal epithelial cells (IECs). However, the comprehensive contribution of ATOH1+ secretory lineage IECs to the homeostasis, repair, and tumorigenesis of the intestinal epithelium remains uncertain. Through our ATOH1+ cell-lineage tracing, we show here that a definite number of ATOH1+ IECs retain stem cell properties and can form ATOH1+IEC-derived clonal ribbons (ATOH1+ICRs) under completely homeostatic conditions. Interestingly, colonic ATOH1+ IECs appeared to exhibit their stem cell function more frequently compared with those of the small intestine. Consistently, the formation of ATOH1+ICRs was significantly enhanced upon dextran sodium sulfate colitis-induced mucosal damage. In addition, colonic ATOH1+ IECs acquired tumor stem cell-like properties in the azoxymethane-DSS tumor model. Our results reveal an unexpected contribution of colonic ATOH1+ IECs to maintaining the stem cell population under both homeostatic and pathologic conditions and further illustrate the high plasticity of the crypt-intrinsic stem cell hierarchy. PMID- 29233557 TI - BGJ398 for FGFR-altered advanced cholangiocarcinoma. PMID- 29233558 TI - Combined androgen blockade for salivary gland carcinoma. PMID- 29233560 TI - Tumour infiltrating lymphocytes in breast cancer: increasing clinical relevance. PMID- 29233561 TI - Real and spurious hypoxemia in a patient with extreme hyperleukocytosis. PMID- 29233559 TI - Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. AB - BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2 positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2 positive breast cancer, and luminal-HER2-negative breast cancer. METHODS: Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0 10% immune cells in stromal tissue within the tumour), intermediate (11-59%), and high TILs (>=60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. FINDINGS: In the luminal-HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0.0001 for each subtype, chi2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0.93 [95% CI 0.87-0.98], p=0.011) and HER2-positive breast cancer (0.94 [0.89-0.99], p=0.017), but not in luminal-HER2-negative tumours (1.02 [0.96-1.09], p=0.46). The increase in TILs was also associated with longer overall survival in TNBC (0.92 [0.86-0.99], p=0.032), but had no association in HER2-positive breast cancer (0.94 [0.86 1.02], p=0.11), and was associated with shorter overall survival in luminal-HER2 negative tumours (1.10 [1.02-1.19], p=0.011). INTERPRETATION: Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2 positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal-HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. FUNDING: Deutsche Krebshilfe and European Commission. PMID- 29233562 TI - Comparison of radiation therapy modalities for hepatocellular carcinoma with portal vein thrombosis: A meta-analysis and systematic review. AB - PURPOSE: We performed a meta-analysis and systematic review to compare the radiotherapy (RT) modalities for hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT). MATERIALS AND METHODS: We searched the PubMed, EMBASE, Medline, and Cochrane library databases. The primary endpoint was the 1-year overall survival (OS), and response rate (RR), local control (LC), 2-year OS, and grade >=3 toxicity incidence were evaluated as secondary endpoints. RESULTS: Thirty seven studies comprising 2513 patients were included. The pooled 1-year OS rates for the 3-dimensional conformal RT (3DCRT), selective internal RT (SIRT), and stereotactic body RT (SBRT) groups were 43.8% [95% confidence interval (CI): 37.6 50.2], 46.5% (95% CI: 37.7-55.6), and 48.5% (95% CI: 39.4-57.8). These inter group differences were not statistically significant (p = 0.635). The pooled response rates were 51.3% (95% CI: 45.7-57.0), 33.3% (95% CI: 18.0-53.2), and 70.7 (95% CI: 63.7-76.8) for 3DCRT, SIRT, and SBRT groups, respectively; p = 0.001 and 0.031 for 3DCRT vs. SBRT and SIRT, respectively. The most common grade >= 3 complications were lymphocytopenia and bilirubin abnormalities in the 3DCRT and SIRT groups, respectively. Grade >= 3 complication was rare in SBRT group. CONCLUSIONS: OS did not differ among the modalities, although the response rates vary among modalities. PMID- 29233563 TI - Polysomnography results versus clinical factors to predict post-operative respiratory complications following pediatric adenotonsillectomy. PMID- 29233565 TI - Lower Esophageal Disorders in Childhood Evaluated by Transabdominal Ultrasound and Fluoroscopy: A Pictorial Essay. PMID- 29233567 TI - Obtaining continuous BrAC/BAC estimates in the field: A hybrid system integrating transdermal alcohol biosensor, Intellidrink smartphone app, and BrAC Estimator software tools. AB - Biosensors have been developed to measure transdermal alcohol concentration (TAC), but converting TAC into interpretable indices of blood/breath alcohol concentration (BAC/BrAC) is difficult because of variations that occur in TAC across individuals, drinking episodes, and devices. We have developed mathematical models and the BrAC Estimator software for calibrating and inverting TAC into quantifiable BrAC estimates (eBrAC). The calibration protocol to determine the individualized parameters for a specific individual wearing a specific device requires a drinking session in which BrAC and TAC measurements are obtained simultaneously. This calibration protocol was originally conducted in the laboratory with breath analyzers used to produce the BrAC data. Here we develop and test an alternative calibration protocol using drinking diary data collected in the field with the smartphone app Intellidrink to produce the BrAC calibration data. We compared BrAC Estimator software results for 11 drinking episodes collected by an expert user when using Intellidrink versus breath analyzer measurements as BrAC calibration data. Inversion phase results indicated the Intellidrink calibration protocol produced similar eBrAC curves and captured peak eBrAC to within 0.0003%, time of peak eBrAC to within 18min, and area under the eBrAC curve to within 0.025% alcohol-hours as the breath analyzer calibration protocol. This study provides evidence that drinking diary data can be used in place of breath analyzer data in the BrAC Estimator software calibration procedure, which can reduce participant and researcher burden and expand the potential software user pool beyond researchers studying participants who can drink in the laboratory. PMID- 29233568 TI - The Impact of Spino-Pelvic Alignment on Total Hip Arthroplasty Outcomes: A Critical Analysis of Current Evidence. AB - BACKGROUND: In this review, we (1) evaluated the effect of adult spine deformity (ASD) and its surgical correction on patients who had a total hip arthroplasty (THA); (2) evaluated the outcomes of THA in patients who have had previous spinal fusion; and (3) we presented an algorithm on how to surgically address patients who simultaneously require THA and ASD correction. METHODS: A comprehensive literature search was conducted. Our final analysis included 14 studies. Overall, there were 3 studies that reported on the impact of ASD on THA outcomes, 6 studies reported on the effect of ASD correction on THA outcomes, and 5 studies reported on the effect of spinal fusion on THA outcomes. RESULTS: Patients with concurrent ASD and THA are at increased risk of THA dislocations and revisions with studies reporting a compiled 2.9% dislocation rate in 1167 patients. Patients who underwent ASD correction demonstrated a post-operative reduction of acetabular anteversion (mean reduction range 4.96 degrees -11.2 degrees , P < .001) and tilt (mean -7 degrees +/- 10 degrees , P < .001). In THA patients with concurrent lumbosacral fusion, dislocation rates ranged between 3% at 1 year and 7.5% at 2 years compared to 0.4%-2.1% dislocation rates in matching cohorts (P < .001). CONCLUSION: Spine balance can alter THA outcomes, but the exact mechanism is yet to be elucidated. We aimed at bridging the gap between hip and spine surgeons with an up-to-date analysis of the best available evidence and presented an algorithm for approaching patients who may simultaneously need ASD correction and THA. PMID- 29233566 TI - Activation of thyroid antigen-reactive B cells in recent onset autoimmune thyroid disease patients. AB - Autoimmune thyroid disease (AITD), including Hashimoto's thyroiditis (HT) and Graves' disease (GD), is the most common autoimmune disorder in the United States, affecting over 20 million people. At the time of diagnosis, both HD and GD are characterized by the accumulation of B and T lymphocytes in the thyroid gland and production of autoantibodies targeting the thyroid, indicating that a breach in tolerance of autoreactive lymphocytes has occurred. However, few studies have sought to understand the underlying pathogenesis of AITD that ultimately leads to production of autoantibodies and loss of thyroid function. In this study, we analyzed the phenotype of thyroid antigen-reactive B cells in the peripheral blood of recent onset and long standing AITD patients. We found that in recent onset patients thyroid antigen-reactive B cells in blood no longer appear anergic, rather they express CD86, a marker of activation. This likely reflects activation of these cells leading to their production of autoantibodies. Hence, this study reports the early loss of anergy in thyroid antigen-reactive B cells, an event that contributes to development of AITD. PMID- 29233569 TI - Continuous Adductor Canal Blocks Provide Superior Ambulation and Pain Control Compared to Epidural Analgesia for Primary Knee Arthroplasty: A Randomized, Controlled Trial. AB - BACKGROUND: Adductor canal blocks (ACBs) are an alternative to femoral nerve blocks that minimize lower extremity weakness. However, it is unclear whether this block will provide analgesia that is equivalent to techniques, such as epidural analgesia. The purpose of this randomized controlled trial was to compare continuous ACBs with epidural analgesia for primary total knee arthroplasty. METHODS: Following institutional review board approval, 145 patients were randomized to 1 of 3 groups: combined spinal-epidural (CSE), spinal + continuous ACB (CACB), or general + CACB. Epidural analgesia was used postoperatively in the CSE group, and an adductor canal catheter was used in the CACB groups. Power analysis determined that 84 patients per group were needed to demonstrate a 35% increase in ambulation with an alpha of 0.05 at a power of 90%. RESULTS: At interim analysis, 13 patients were removed for protocol deviations, leaving 45 in CSE, 41 in spinal + CACB and 46 in general + CACB groups. Patient demographics were similar in all comparisons suggesting appropriate randomization. Patients in the CACB groups walked further on postoperative day 1, 2, and 3 (P = .02). Mean daily pain scores were lower in the CACB groups (4.1 CSE, 3.0 spinal + CACB, 3.4 general + CACB, P = .009). There was no significant difference in total opioid consumption between groups (158 morphine equivalents CSE, 149 spinal + CACB, and 172 general + CACB). More patients reported being "very satisfied" in CACB groups (68% general + CACB, 63% spinal + CACB, and 36% CSE; P = .001). CONCLUSION: Continuous adductor analgesia provides superior ambulation, lower pain scores, faster discharge, and greater patient satisfaction when compared to epidural analgesia for primary total knee arthroplasty. PMID- 29233570 TI - Letter to the Editor on "Arthrofibrosis Associated With Total Knee Arthroplasty". PMID- 29233571 TI - Chloride validity in Emergency Department settings. PMID- 29233573 TI - Re-irradiation in Gynaecological Malignancies: A Review. AB - Re-irradiation in gynaecological malignancies has become an increasingly frequent consideration. This can be delivered in multiple settings, with the most common being a patient with a history of cervical cancer developing a new vaginal cancer or endometrial cancer with local recurrence after hysterectomy and adjuvant pelvic radiation. A systematic review of the literature has unearthed a handful of reports, most delivering brachytherapy, with a small number on both external beam radiotherapy and stereotactic ablative radiotherapy. A detailed review of these papers suggests that it is not possible to draw any firm conclusions or put forward guidelines for this challenging area of gynaecological oncology. Here the author has provided a brief account of each paper, followed by a discussion of the literature, aiming to outline some very broad principles for management. It is recommended that such patients be referred to centres that treat high volumes of gynaecological malignancies, as the experience of the treating oncologist may be the most important factor in the management of these patients. PMID- 29233574 TI - The Principles and Practice of Re-irradiation in Clinical Oncology: An Overview. AB - Long-term cancer survivors are at risk of the development of recurrence or a new primary cancer that requires a second (or third) radio-oncological treatment. Publications on re-irradiation have been followed and are summarised in this overview. Information from clinical and experimental animal studies suggests that specific normal tissues can tolerate a considerable retreatment radiation dose. However, the risk of normal tissue damage and the impact on the quality of life must be considered. If a second course of radiotherapy needs to be administered, this should be done with maximum care and accuracy. Optimum conformation of the dose to the planning target volume is required. For radiobiological reasons - in order to reduce the risk of late effects - hyperfractionation protocols should be applied for curative treatments. Alternatively, small volume exposure may be considered in a highly conformal, image-guided stereotactic approach. PMID- 29233572 TI - Hospitalization of HIV positive patients: Significant demand affecting all hospital sectors. AB - BACKGROUND: In a context of the evolution of severe morbidities in patients living with HIV (PLWH), the aim of this study was to describe reasons for hospitalization and the mode of care for the patients requiring hospitalization. METHODS: All admissions (>=24h) of PLWH to 10 hospitals in the south of Paris (COREVIH Ile-de-France Sud) between 1/1/2011 and 12/31/2011 were identified. The hospital database and the file of patients followed in the HIV referral department of each hospital were matched. Detailed clinical and biological data were collected, by returning to the individual medical records, for a random sample (65% of hospitalized patients). RESULTS: A total of 3013 hospitalizations (1489 patients) were recorded in 2011. The estimated rate of hospitalized patients was about 8% among the 10105 PLWH routinely managed in COREVIH Ile-de France Sud in 2011. The majority (58.5%) of these hospitalizations occurred in a unit other than the HIV referral unit. Non-AIDS-defining infections were the main reason for admission (16.4%), followed by HIV-related diseases (15.6%), hepatic/gastrointestinal diseases (12.0%), and cardiovascular diseases (10.3%). The median length of stay was 5 days overall (IQR: 2-11), it was longer among patients admitted to a referral HIV care unit than to another ward. HIV infection had been diagnosed >10 years previously in 61.4% of these hospitalized patients. They often had associated comorbidities (coinfection HCV/HVB 40.5%, smoking 45.8%; hypertension 33.4%, dyslipidemia 28.8%, diabetes 14.8%). Subjects over 60 years old accounted for 15% of hospitalized patients, most of them were virologically controlled under HIV treatment, and cardiovascular diseases were their leading reason for admission. CONCLUSION: Needs for hospitalization among PLWH remain important, with a wide variety in causes of admission, involving all hospital departments. It is essential to prevent comorbidities to reduce these hospitalizations, and to maintain a link between the management of PLWH, that becomes rightly, increasing ambulatory, and recourse to specialized inpatient services. PMID- 29233576 TI - Changing Epidemiology of Haemophilus influenzae in Children. AB - Haemophilus influenzae remains a common cause of illness in children throughout the world. Before the introduction of vaccination, H influenzae type b (Hib) disease was the leading cause of bacterial meningitis in young children and a frequent cause of pneumonia, epiglottitis, and septic arthritis. Clinicians should remain diligent in counseling parents on the dangers of Hib and provide vaccination starting at 2 months of age. The epidemiology of invasive H influenzae disease is shifting. It is imperative that clinicians recognize the changing epidemiology and antibiotic resistance patterns for H influenzae to optimize care in hospital and ambulatory settings. PMID- 29233577 TI - Infections in Children on Biologics. AB - Biologics target various pathways to modify immunologic activity. Biologic use to treat pediatric patients continues to expand; but limited data exist regarding infectious complications of these agents, especially for newer agents. Infectious events reported in the literature for pediatric patients indicate that a variety of bacterial, mycobacterial, viral, and fungal infections can occur. Further pediatric-specific reports are needed to fill knowledge gaps in the complications related to these agents. PMID- 29233578 TI - Morgagni Hernia as a Reversible Cause of Hypercapnic Respiratory Failure. PMID- 29233575 TI - Midkine Controls Arteriogenesis by Regulating the Bioavailability of Vascular Endothelial Growth Factor A and the Expression of Nitric Oxide Synthase 1 and 3. AB - Midkine is a pleiotropic factor, which is involved in angiogenesis. However, its mode of action in this process is still ill defined. The function of midkine in arteriogenesis, the growth of natural bypasses from pre-existing collateral arteries, compensating for the loss of an occluded artery has never been investigated. Arteriogenesis is an inflammatory process, which relies on the proliferation of endothelial cells and smooth muscle cells. We show that midkine deficiency strikingly interferes with the proliferation of endothelial cells in arteriogenesis, thereby interfering with the process of collateral artery growth. We identified midkine to be responsible for increased plasma levels of vascular endothelial growth factor A (VEGFA), necessary and sufficient to promote endothelial cell proliferation in growing collaterals. Mechanistically, we demonstrate that leukocyte domiciled midkine mediates increased plasma levels of VEGFA relevant for upregulation of endothelial nitric oxide synthase 1 and 3, necessary for proper endothelial cell proliferation, and that non-leukocyte domiciled midkine additionally improves vasodilation. The data provided on the role of midkine in endothelial proliferation are likely to be relevant for both, the process of arteriogenesis and angiogenesis. Moreover, our data might help to estimate the therapeutic effect of clinically applied VEGFA in patients with vascular occlusive diseases. PMID- 29233579 TI - Why do certain primary health care teams respond better to intimate partner violence than others? A multiple case study. AB - OBJECTIVE: To analyse how team level conditions influenced health care professionals' responses to intimate partner violence. METHODS: We used a multiple embedded case study. The cases were four primary health care teams located in a southern region of Spain; two of them considered "good" and two s "average". The two teams considered good had scored highest in practice issues for intimate partner violence, measured via a questionnaire (PREMIS - Physicians Readiness to Respond to Intimate Partner Violence Survey) applied to professionals working in the four primary health care teams. In each case quantitative and qualitative data were collected using a social network questionnaire, interviews and observations. RESULTS: The two "good" cases showed dynamics and structures that promoted team working and team learning on intimate partner violence, had committed social workers and an enabling environment for their work, and had put into practice explicit strategies to implement a women centred approach. CONCLUSIONS: Better individual responses to intimate partner violence were implemented in the teams which: 1) had social workers who were knowledgeable and motivated to engage with others; 2) sustained a structure of regular meetings during which issues of violence were discussed; 3) encouraged a friendly team climate; and 4) implemented concrete actions towards women-centred care. PMID- 29233580 TI - Colorectal carcinoma in the frail surgical patient. Implementation of a Work Area focused on the Complex Surgical Patient improves postoperative outcome. AB - INTRODUCTION: Advanced age and comorbidity impact on post-operative morbi mortality in the frail surgical patient. The aim of this study is to assess the impact of a comprehensive, multidisciplinary and individualized care delivered to the frail patient by implementation of a Work Area focused on the Complex Surgical Patient (CSPA). METHODS: Retrospective study with prospective data collection. Ninety one consecutive patients, classified as frail (ASAIII or IV, Barthel<80 and/or Pfeiffer>3) underwent curative radical surgery for colorectal carcinoma between 2013 and 2015. GroupI: 35 patients optimized by the CSPA during 2015. GroupII: 56 No-CSPA patients, treated prior to CSPA implementation, during 2014-2015. Group homogeneity, complication rate, length of stay, reoperations, readmissions, costs and overall mortality were analyzed and adjusted by Diagnosis Related Group (DRG). RESULTS: There were no statistically significant differences in term of age, gender, ASA classification, body mass index, tumor staging and type of surgical intervention between the two groups. Major complications (Clavien-DindoIII-IV) (12.5% vs. 28.5%, P=.04), hospital stay (12.6+/-6days vs. 15.2+/-6days, P=0.041), readmissions (12.5% vs. 28.3%, P<0.041), and patient episode cost weighted according to DRG (3.29+/-1 vs. 4.3+/-1, P=0.008) were statistically inferior in Group CSPA. There were no differrences in reoperations (6.2% vs. 5.3%) or mortality (6.2% vs. 7.1%). 96.9% of patients of GroupI manifested having received a satisfactory attention and quality of life. CONCLUSIONS: Implementation of a CSPA, delivering surgical care to frail colorectal cancer patients, involves a reduction of complications, length of stay and readmissions, and is a cost-effective arrangement. PMID- 29233581 TI - Giant Esophageal Liposarcoma in Asymptomatic Young Patient. PMID- 29233582 TI - Influence of involuntary cigarette smoke inhalation on osseointegration: a systematic review and meta-analysis of preclinical studies. AB - There are no studies that have systematically reviewed the influence of involuntary cigarette smoke inhalation (ICSI) on the stability of implants. The aim of the present study was to perform a systematic review and meta-analysis of preclinical studies that assessed the influence of involuntary cigarette smoke inhalation ICSI on osseointegration. Indexed databases (PubMed, Google-Scholar, Scopus, EMBASE, and Web of Knowledge) were searched till September 2017. Titles and abstracts of studies identified using the above-described protocol were independently screened by 2 authors. Full-texts of studies judged by title and abstract to be relevant were independently evaluated for the stated eligibility criteria. Nine studies were included. Six studies showed that ICSI compromised bone area contact around implants. In 4 studies, peri-implant bone mineral density was significantly higher in the control group than among subjects exposed to ICSI. For the effects of ICSI on the osseointegration of dental implants, significant differences could be observed for bone-to-implant contact for test subjects in cancellous (Z=-4.08, p<0.001) and cortical bone (Z=-4.31, p<0.001) respectively. ICSI may negatively influence osseointegration of dental implants. It is imperative to educate patients about the negative effects of passive smoking on dental and systemic health. PMID- 29233584 TI - Sono- and photoelectrocatalytic processes for the removal of ionic liquids based on the 1-butyl-3-methylimidazolium cation. AB - In this work, sono- and photoelectrolysis of synthetic wastewaters polluted with the ionic liquids 1-Butyl-3-methylimidazolium acetate (BmimAc) and chloride (BmimCl) were investigated with diamond anodes. The results were compared to those attained by enhancing bare electrolysis with irradiation by UV light or with the application of high-frequency ultrasound (US). Despite its complex heterocyclic structure, the Bmim+ cation was successfully depleted with the three technologies that were tested and was mainly transformed into four different organic intermediates, an inorganic nitrogen species and carbon dioxide. Regardless of the technology that was evaluated, removal of the heterocyclic ring is much less efficient (and much slower) than oxidation of the counter ion. In turn, the counter ion influences the rate of removal of the ionic liquid cation. Thus, the electrolysis and photoelectrolysis of BmimAc are much less efficient than sonoelectrolysis, but their differences become much less important in the case of BmimCl. In this later case, the most efficient technology is photoelectrolysis. This result is directly related to the generation of free radicals in the solution by irradiation of the electrochemical system with UV light, which contributes significantly to the removal of Bmim+. PMID- 29233583 TI - Diagnostic Approach to the Acute Abdomen. AB - The acute abdomen is a term used to characterize an animal presented as an emergency, in a more or less severe critical state, and for which medical and possibly surgical treatment will be necessary. To succeed, the clinician should use a systematic approach, have an excellent knowledge of the bovine abdominal anatomy, and have a good understanding of the pathophysiology of abdominal pain. Good clinical judgment, critical analysis, and good client communication skills are also essential. This article presents and discusses those necessary skills in the context of field practice. PMID- 29233585 TI - Tim-4 expression increases in ischemic stroke patients and is associated with poor outcome. AB - T cell immunoglobin and mucin domain (Tim)-4 on monocytes is involved in immune regulation. Here, we investigated Tim-4 expression on circulating monocytes and in plasma of ischemic stroke. Tim-4 expression was significantly increased on day 2 and day 5 after stroke. Furthermore, stroke severity was positively correlated with Tim-4 expression on monocytes or in plasma. Increased Tim-4 expression was related to stroke associated with infection (SAI) on day 2. Up-regulated Tim-4 expression on monocytes or in plasma on day 2 was a risk predictor of outcome. Our findings suggest that Tim-4 can act as a prognostic biomarker of ischemic stroke. PMID- 29233588 TI - Changes in circulating miRNAs in healthy overweight and obese subjects: Effect of diet composition and weight loss. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA molecules that can play an important role in several chronic metabolic conditions, including obesity. However, to date little is known about how they are regulated. Weight loss induced by surgical procedures has been effective at modulating specific circulating miRNAs, but the effect of energy-restricted diets with different macronutrient compositions on circulating miRNAs is not well understood. The objective of the present analysis was to explore the effect of three energy restricted diets of different macronutrient composition and carbohydrate quality on plasma miRNA levels. METHODS: The GLYNDIET study is a 6-month, parallel, randomized clinical trial conducted on overweight and obese subjects who were randomized to one of three different dietary intervention groups: i) a moderate carbohydrate and low glycemic index diet (LGI), ii) a moderate-carbohydrate and high glycemic index diet (HGI), and iii) a low-fat and high glycemic index diet (LF). We assessed the genome-wide circulating miRNA profile in a subsample of eight randomly selected participants. A total of 8 miRNAs (miR-411, miR-432, miR 99b, miR-340, miR-423, miR-361, let-7c) were differently quantified according to diet intervention, and were therefore longitudinally validated in 103 participants before and after the energy-restricted diets. RESULTS: Circulating miR-361 levels were lower in the LGI group than in the HGI group, even after adjusting for differences in weight loss. The intra-group analyses demonstrated a significant down-regulation of all miRNAs screened in our study subjects after the LGI intervention. Similarly, miR-139 and miR-340 were down-regulated after the HGI intervention, while miR-139, miR-432 and miR-423 were down-regulated after the low-fat diet. Changes in circulating miR-139 and let-7c were significantly associated with changes in lipid profile and insulin resistance. CONCLUSION: An energy-restricted low-glycemic index diet down-regulates circulating miRNA-361 more than an energy-restricted high-glycemic index, regardless of the magnitude of the weight loss. PMID- 29233586 TI - Does patients' experience of general practice affect the use of emergency departments? Evidence from Australia. AB - AS Emergency Department (ED) attendances have been growing rapidly, various strategies have been employed in Australia to improve access to General Practitioner (GP) care, particularly after normal working hours, in order to reduce the demand for ED. However, there has been little attention paid to the quality of GP care and whether that influences ED attendances. This paper investigates whether ED use is affected by patients' experience of GP care, using the logit model to analyse data from a survey of Australian consumers (1758 individuals). Not surprisingly, we find that people with poor health status and a greater number of chronic conditions are more likely to visit the ED. We also find that, after correcting for health status and sociodemographic factors, patients with a better GP experience are less likely to visit the ED. This suggests that policies aimed at improving the quality of primary care are also important in reducing unplanned hospital use. PMID- 29233587 TI - Combined capillary-venous-lymphatic malformations without overgrowth in patients with Klippel-Trenaunay syndrome. AB - OBJECTIVE: Klippel-Trenaunay syndrome (KTS) is described in the literature as a complex syndrome characterized by various combinations of capillary, venous, and lymphatic malformations associated with limb overgrowth. In the first description by Maurice Klippel and Paul Trenaunay, tridimensional bone hypertrophy was believed to be the cause of limb enlargement. The purpose of this study was primarily to assess the presence of real bone hypertrophy as a cause of enlargement of the limb and to underline the rare presence of undergrowth of the affected limb in patients with KTS. METHODS: A two-center retrospective review including 17 KTS patients with various combinations of capillary, venous, and lymphatic malformation affecting the lower limb was performed. Differences in limb dimension were evaluated clinically. Width and length discrepancy of the affected limb was measured with radiologic imaging. RESULTS: We found an increase of length in the affected limb in 80% of the patients. The leg length discrepancy varied from 0.2 to 2.6 cm. The median leg length discrepancy was found to be 1.4 cm. Three patients had a reduced length of the affected limb. Girth enlargement of the affected extremity was noticed in 60% of the patients, and 2 of 17 patients had hypotrophy of the involved limb. Hypertrophy (an increase in both length and width) of the bone was found in none of our cases, and the circumferential enlargement of the affected extremity was related only to soft tissue enlargement. CONCLUSIONS: In the literature, KTS is considered the prototype of overgrowth syndromes associated with complex vascular malformations. The majority of our patients showed limb length increase associated with soft tissue enlargement without an increase of bone width; there were also two patients with limb undergrowth. A real bone overgrowth (an increase in both length and width) was not present in our patients. Therefore, we could consider the absence of real bone hypertrophy as probably a new aspect of such confusing and controversial definitions of KTS. In addition, it would be more accurate to classify KTS patients on the basis of their phenotypic features (type of vascular malformation, types of overgrown tissue) rather than by use of an outdated eponym. PMID- 29233589 TI - Factors contributing to the selection of dietary protein food sources. AB - Protein is the only dietary macronutrient required for life. As such, it is reasonable to consider dietary protein as the centerpiece of a healthy eating pattern. To do so requires consideration of what type of protein should be eaten. Account should be taken of the quality of the protein, the density of the protein in the protein food source, and the non-protein components of protein food source. The quality of protein can be quantified based on the amount and profile of essential amino acids (EAAs), as well as the true ileal digestibility of the EAAs in the protein. The density of protein in a food source can be quantified on the basis of the amount of total calories ingested to achieve intake of the daily requirement of all EAAs. Non-protein components of protein food sources can be considered in terms of the amount and nature of fat, carbohydrate and fiber, as well as the content of micronutrients. Potential beneficial effects of high quality protein food sources should be balanced against any possible adverse effects. When all of these factors are considered we conclude that animal-based protein foods (e.g., eggs, dairy, meat, fish, poultry) occupy an important place in a healthy eating pattern. PMID- 29233591 TI - Cardiac surgery blues: The midterm impact of postoperative delirium and the association with mood disorders. PMID- 29233590 TI - Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation. AB - Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B5), a precursor of the fundamental enzyme cofactor coenzyme A. CJ-15,801, an enamide analogue of pantothenate isolated from the fungus Seimatosporium sp. CL28611, was previously shown to inhibit P. falciparum proliferation in vitro by targeting pantothenate utilization. To inform the design of next generation analogues, we set out to synthesize and test a series of synthetic enamide-bearing pantothenate analogues. We demonstrate that conservation of the R-pantoyl moiety and the trans-substituted double bond of CJ 15,801 is important for the selective, on-target antiplasmodial effect, while replacement of the carboxyl group is permitted, and, in one case, favored. Additionally, we show that the antiplasmodial potency of CJ-15,801 analogues that retain the R-pantoyl and trans-substituted enamide moieties correlates with inhibition of P. falciparum pantothenate kinase (PfPanK)-catalyzed pantothenate phosphorylation, implicating the interaction with PfPanK as a key determinant of antiplasmodial activity. PMID- 29233592 TI - A bridge too many? PMID- 29233593 TI - Anterior mediastinal tissue volume is correlated with antiacetylcholine receptor antibody level in myasthenia gravis. AB - OBJECTIVES: Extended thymectomy is a treatment option for myasthenia gravis (MG), but the surgical indications are controversial. Pathologic features of the thymus can be used to predict surgical outcomes, but there is no reliable method for evaluating these characteristics preoperatively. The purpose of this study was to determine whether anterior mediastinal tissue volume, as measured via 3 dimensional computed tomography (3DCT) volumetry, correlates with serum anti acetylcholine receptor antibody (AChRAb) levels in patients undergoing thymectomy for myasthenia gravis. Therefore, we investigated the relationships among anterior mediastinal tissue volume determined by 3DCT volumetry and AChRAb levels. METHODS: The subjects were 28 patients who underwent extended thymectomy and were enrolled retrospectively. We measured volume of the anterior mediastinum and calculated the volumes of more than -30 Hounsfield units (V-30) by using 3DCT volumetry and compared them with perioperative AChRAb levels. The significance of their volumes in MG was examined by comparison with 53 patients without MG. RESULTS: V-30 values were related to age and were significantly greater in patients with MG than in patients without MG (P < .001). V-30 values were correlated positively with preoperative AChRAb levels (rho = 0.505, P = .006) and inversely with the post/preoperative AChRAb ratio (rho = -0.453, P = .018). The histologic nonadipose tissue ratio was correlated with the V-30/volume of the anterior mediastinum (rho = 0.700, P < .001). CONCLUSIONS: This method for evaluation of the anterior mediastinal tissue volume and AChRAb production may be helpful in establishing a treatment plan for MG. PMID- 29233594 TI - Wise surgeons learn from others' experiences. PMID- 29233595 TI - Doodling in the margins. PMID- 29233596 TI - A prediction model for lymph node metastasis in T1 esophageal squamous cell carcinoma. AB - BACKGROUND: Endoscopic resection is widely used for the treatment of T1 esophageal cancer, but it cannot be used to treat lymph node metastasis (LNM). This study aimed to develop a prediction model for LNM in patients with T1 esophageal squamous cell carcinoma. METHODS: A prospectively maintained database of all patients who underwent surgery for esophageal cancer between January 2002 and June 2010 was retrospectively reviewed, and patients with T1 squamous cell carcinoma were included in this study. Correlations between LNM and clinicopathological variables were evaluated using univariable and multivariable logistic regression analyses. The penalized maximum likelihood method was used to estimate regression coefficients. A prediction model was developed and internally validated using a bootstrap resampling method. Model performance was evaluated in terms of calibration, discrimination, and clinical usefulness. RESULTS: A total of 240 patients (197 male, 43 female) with a mean age of 57.9 years (standard deviation +/- 8.3 years) were included in the analysis. The incidence of LNM was 16.3%. The prediction model consisted of four variables: grade, T1 stage, tumor location and tumor length. The model showed good calibration and good discrimination with a C-index of 0.787 (95% confidence interval [CI], 0.711 0.863). After internal validation, the optimism-corrected C-index was 0.762 (95% CI, 0.686-0.838). Decision curve analysis demonstrated that the prediction model was clinically useful. CONCLUSIONS: Our prediction model can facilitate individualized prediction of LNM in patients with T1 esophageal squamous cell carcinoma. This model can aid surgical decision making in patients who have undergone endoscopic resection. PMID- 29233597 TI - Predicting postoperative pulmonary complications: The answer may be right in front of our noses! PMID- 29233598 TI - Predictors of early operative mortality and long-term survival in octogenarians undergoing open and endovascular repair of abdominal aortic aneurysm. AB - BACKGROUND: The study aims to report outcomes of open repair (OR) and endovascular aneurysm repair (EVAR) in octogenarians. METHODS: Consecutive patients aged between 80 and 89 who underwent OR or EVAR were identified from a prospectively collected departmental database. Short-term outcomes included 30 days mortalities and perioperative complications; long-term outcomes included overall survival and re-intervention using the Kaplan-Meier method. Logistic regression was used to identify predictors for operative mortality and Cox regression analysis was used to identify predictors for long-term survival. RESULTS: From January 1999 to December 2013, 53 underwent open repairs (23 emergency and 30 elective) and 115 underwent endovascular repairs (11 emergency and 104 elective). For elective procedures, 30 days operative mortalities were 6.7% and 0% in OR and EVAR respectively (Chi square test, p = 0.049). For emergency procedures, 30 days mortalities were 39.1% and 27.2% respectively (Chi square test, p = 0.705). Overall 5 years survival rates were 40.4% and 36.7% after OR and EVAR respectively. Rupture of aneurysm (Odd ratio 18.8, 95% CI 3.4 104.5, p = 0.001) was the only predictor for 30 days mortality. Rupture of aneurysm (Hazard ratio 2.0, 95% CI 1.3-3.3, p = 0.003), history of lung disease (Hazard ratio 1.7, 95% CI 1.0-2.9, p = 0.039) and history of renal disease (Hazard ratio 2.1, 95% CI 1.4-3.1, p < 0.001) were independent predictors for long-term overall survival. CONCLUSION: Decision of AAA repair in octogenarians should not be based on age alone. Both elective OR and EVAR had acceptable perioperative risk, but emergency repair, lung disease and renal impairment predicted poor long-term survival. PMID- 29233599 TI - Corrigendum to "Multidisciplinary approach to optimize management of patients with chronic hepatitis C and alcoholic liver disease" [J Formos Med Assoc (2016) 1097-1098]. PMID- 29233600 TI - Noise reduction in FLAIR2 images using Total Generalized Variation, Gaussian and Wiener filtering. AB - PURPOSE: Multiplication of FLAIR and T2-weighted MRI scans results in images (called FLAIR2) with an improved contrast-to-noise ratio (CNR) for multiple sclerosis (MS) lesions but with a reduced signal-to-noise ratio (SNR). Denoising of these images may therefore further improve FLAIR2 image quality. The purpose of this work is to present a systematic investigation of FLAIR2 image denoising methods using Gaussian, Wiener and Total Generalized Variation (TGV) filtering approaches. MATERIALS AND METHODS: T2-weighted and FLAIR data of four MS patients were used. For CNR and SNR measurements, each scan was performed up to three times. TGV, Gaussian and Wiener filtering was applied to T2, FLAIR and the FLAIR2 data. FLAIR2 images were afterwards additionally created using all combinations of input data (native, filtered T2 and filtered FLAIR). SNR and CNR measurements were performed using the subtraction method for all FLAIR2 approaches (native and filtered input data) and for twenty MS lesions. Additionally, quantitative analysis of filtering based image blurring was performed on all data sets. RESULTS: FLAIR2 images denoised with TGV showed the highest SNR and CNR, while SNR values were similar for Gaussian and Wiener filtered images. The average CNR over 20 MS lesions within the native FLAIR2 (32.99) achieved an improvement to 91.17, 82.33 and 56.07 corresponding to TGV, Wiener and Gaussian filtering. FLAIR multiplied with T2.denoised showed no improvement, while FLAIR.denoised multiplied with T2 showed an increase by a factor of two to the native, not filtered FLAIR2. Blurring was most pronounced in Gaussian filtered images and similar in TGV and Wiener filtered images. CONCLUSION: FLAIR images filtered with Wiener or TGV multiplied with the unfiltered T2 results in FLAIR2 images with increased SNR and CNR and with minimal edge blurring. PMID- 29233601 TI - Coping with 'Dark Sides of the Sun' through Photoreceptor Signaling. AB - Plants grow in constantly changing environments, including highly variable light intensities. Sunlight provides the energy that drives photosynthesis and is thus of the utmost importance for plant growth and the generation of oxygen, which the majority of life on Earth depends on. However, exposure to either insufficient or excess levels of light can have detrimental effects and cause light stress. Whereas exposure to insufficient light limits photosynthetic activity, resulting in 'energy starvation', exposure to excess light can damage the photosynthetic apparatus. Furthermore, strong sunlight is associated with high levels of potentially damaging UV-B radiation. Different classes of photoreceptors play important roles in coping with the negative aspects of sunlight, for which specific mechanisms are emerging that are reviewed here. PMID- 29233602 TI - Interactive effects of temperature and food availability on the growth of Arctica islandica (Bivalvia) juveniles. AB - The interest in Arctica islandica growth biology has recently increased due to the widespread use of its shell as a bioarchive. Although temperature and food availability are considered key factors in its growth, their combined influence has not been studied so far under laboratory conditions. We tested the interactive effect of temperature and food availability on the shell and tissue growth of A. islandica juveniles (9-15 mm in height) in a multi-factorial experiment with four food levels (no food, low, medium, and high) and three different temperatures (3, 8, 13 degrees C). Shell and tissue growth were observed in all treatments, with significant differences occurring only among food levels (2-way ANOVA; P-value < 0.05). Siphon activity (% open siphons), however, was affected by temperature, food, and the interaction between them (2 way ANOVA; P-value < 0.05). Siphon observations, as indication of feeding activities, played a key role to better understand the growth variation between individuals. PMID- 29233603 TI - Individual Susceptibility Analysis Using Patient-derived Slice Cultures of Colorectal Carcinoma. AB - BACKGROUND: Nonresponse to chemotherapy in colorectal carcinoma (CRC) is still a clinical problem. For most established treatment regimens, no predictive biomarkers are available. Patient-derived tumor slice culture may be a promising ex vivo technology to assess the drug susceptibility in individual tumors. METHODS: Patient-derived slice cultures of CRC specimens were prepared according to a standardized protocol and treated with different concentrations of 5 fluorouracil (5-FU) and an adapted FOLFOX regimen (5-FU and oxaliplatin) to investigate histologic response. Additionally, a semi-automatized readout using fluorescent stain-specific segmentation algorithms for Image J was established to quantify changes in tumor proliferation. Nonresponse to chemotherapy was defined as persisting tumor cell proliferation. RESULTS: Slices treated with 5-FU showed lower tumor cell fractions and dose-dependent alterations of proliferating tumor cells compared with controls (1 MUM, Delta +3%; 10 MUM, Delta -9%; 100 MUM, Delta -15%). Individual tumor samples were examined and differences in chemotherapy susceptibility could be observed. Untreated slice cultures contained an average tumor cell fraction of 31% +/- 7%. For all samples, the histopathologic characteristics exhibited some degree of intratumoral heterogeneity with regard to tumor cell morphology and distribution. The original tumor matched the features found in slices at baseline and after 3 days of cultivation. CONCLUSIONS: Patient-derived slice cultures may help to predict response to clinical treatment in individual patients with CRC. Future studies need to address the problem of tumor heterogeneity and evolution. Prospective correlation of ex vivo results with the clinical course of treated patients is warranted. PMID- 29233604 TI - Axonal excitability changes and acute symptoms of oxaliplatin treatment: In vivo evidence for slowed sodium channel inactivation. AB - OBJECTIVE: Neurotoxicity is the most frequent dose-limiting side effect of the anti-cancer agent oxaliplatin, but the mechanisms are not well understood. This study used nerve excitability testing to investigate the pathophysiology of the acute neurotoxicity. METHODS: Questionnaires, quantitative sensory tests, nerve conduction studies and nerve excitability testing were undertaken in 12 patients with high-risk colorectal cancer treated with adjuvant oxaliplatin and in 16 sex- and age-matched healthy controls. Examinations were performed twice for patients: once within 3 days after oxaliplatin treatment (post-infusion examination) and once shortly before the following treatment (recovery examination). RESULTS: The most frequent post-infusion symptoms were tingling paresthesias and cold allodynia. The most prominent nerve excitability change was decreased superexcitability of motor axons which correlated with the average intensity of abnormal sensations (Spearman Rho = 0.80, p < .01). The motor nerve excitability changes were well modeled by a slowing of sodium channel inactivation, and were proportional to dose/m2 with a half-life of about 10d. CONCLUSIONS: Oxaliplatin induces reversible slowing of sodium channel inactivation in motor axons, and these changes are closely related to the reversible cold allodynia. However, further studies are required due to small sample size in this study. SIGNIFICANCE: Nerve excitability data provide an index of sodium channel dysfunction: an objective biomarker of acute oxaliplatin neurotoxicity. PMID- 29233605 TI - Measuring vaccine acceptance among Canadian parents: A survey of the Canadian Immunization Research Network. AB - Parental decision making about childhood vaccinations is complex and multidimensional. There is a perception that the number of parents having concerns regarding childhood vaccinations has been increasing in Canada. The aim of this study was to explore vaccine hesitancy among Canadian parents and to examine factors associated with a parent's intention to vaccinate his/her child. Informed by the Theory of Planned Behaviour (TPB) this study assesses potential associations between parents' knowledge, attitudes and beliefs toward vaccination and their intention to vaccinate their child in the future. A national sample of Canadian parents of children aged 24-59 months (N = 2013) was surveyed using an online survey methodology. Half of the surveyed parents strongly intended to have their child vaccinated in the future. Parents' information needs and searches as well as parents' trust in different institutions were associated with intention to vaccinate. Parents who reported having frequently looked for vaccine information, who considered that it was their role as parents to question vaccines, or who had previously experienced difficulty accessing vaccination services were less likely to strongly intend to vaccinate their child in the future. Parents who had a high level of trust in doctors and public health were most likely to strongly intend to vaccinate their child. Results of the multivariate analysis showed that positive attitudes (aOR = 8.0; 95% CI: 6.0, 10.4), higher perceived social support (aOR = 3.0; 95% CI: 2.3, 3.93), and higher perceived behavioural control (aOR = 1.8; 95% CI: 1.4, 2.43) were associated with parents' intention to vaccinate their child. Findings of this study suggest that trust-building interventions that promote pro-vaccine social norms and that address negative attitudes toward vaccination could enhance vaccine acceptance among Canadian parents. PMID- 29233606 TI - Staphylococcus aureus and Atopic Dermatitis: A Complex and Evolving Relationship. AB - Staphylococcus aureus is frequently isolated from the skin of atopic dermatitis (AD) patients during flares. The normal microbiota is disrupted and the diversity of the microorganisms on the skin is reduced. Many species that produce inhibitors of S. aureus growth decline. Strains from S. aureus clonal complex 1 are enriched among AD sufferers whereas the CC30 strains most frequently isolated from nasal carriers in the normal population are much rarer in AD. S. aureus expresses several molecules that contribute to the intensity of symptoms, including delta-toxin which stimulates mast cells, alpha-toxin which damages keratinocytes, phenol-soluble modulins which stimulate cytokine release by keratinocytes, protein A which triggers inflammatory responses from keratinocytes, superantigens which trigger B cell expansion and cytokine release, and proinflammatory lipoproteins. Proteases contribute to disruption of the epidermal barrier. S. aureus isolated from AD patients adheres to the deformed corneocytes from AD patients in a clumping factor B-dependent fashion. Novel targeted therapies for AD have recently been introduced to clinical practice with many more in development, including monoclonal antibodies that specifically target cytokines and their receptors, and a bacteriophage lysin that eliminates S. aureus from AD skin. PMID- 29233607 TI - The concept of frailty in intensive care. AB - Our population is ageing and this is also reflected in the ageing of the hospital and intensive care population. Along with ageing, there is also an increase in age-related chronic health conditions or co-morbidities, which in turn affects the patient's functional state. There is an increasing need to describe a patient's clinical condition in terms of their functional capacity, such as frailty. Frailty is an age-related syndrome which reduces physiological and cognitive reserves. As a result, frailty increases people's vulnerability to insults such as infection and trauma. The concept of frailty also indicates prognosis and levels of health from a patient's perspective rather than simply from the acute reason for admission to the intensive care. Understanding the concept of frailty may facilitate our awareness of long-term outcomes after intensive care as well as being a trigger for considering its prognostic implications and the need to honestly and empathetically begin discussions with patients and their carers and how the patient's own goals of care could be established around this information. PMID- 29233608 TI - Reverters from PD-MCI to cognitively intact are at risk for future cognitive impairment: Analysis of the PPMI cohort. AB - INTRODUCTION: Past studies have shown that a large portion of individuals with Parkinson's disease (PD) and mild cognitive impairment (MCI) will revert to a cognitively intact (CI) status in the future. Aging studies have shown that individuals who revert from MCI to CI are at increased risk for reconverting to MCI or dementia in the future. The current study examined if individuals who revert from PD-mild cognitive impairment (PD-MCI) to CI will be at increased risk for future PD-MCI and Parkinson's disease dementia (PDD). METHOD: The study utilized data from the Parkinson's Progression Markers Initiative (PPMI). The sample included 364 newly diagnosed PD participants who were followed annually for up to 4 years. Based on the first and second assessments, we identified individuals who were CI at each assessment (CI-Stable) and individuals who were PD-MCI at baseline but then reverted to CI (Reversion). Analyses examined if participants in the Reversion group were at greater risk, relative to the CI Stable group, for cognitive impairment at future assessments. RESULTS: Participants in the Reversion group were at greater risk for future cognitive impairment (PD-MCI or PDD) at the 2nd, 3rd and 4th annual follow-up, relative to the CI-Stable group. The Reversion group continued to be at increased risk for future cognitive impairment when adjusting for age, gender, education, depressive symptoms, and motor severity. CONCLUSION: A large proportion of individuals with PD-MCI will not show evidence of cognitive impairment within a year. However, these "reverters" continue to be at risk for future development of cognitive impairment. PMID- 29233609 TI - Development of a template to facilitate reflection among student pharmacists. AB - BACKGROUND: Reflective practice activities utilizing appropriate tools enhance learning during and after experiential placements. Reflective tools described in the literature, used to support students on traditional placements of a duration of at least two weeks, sit at the unstructured end of a continuum (completely unstructured to just minimal structure). Additionally, non-traditional settings in role-emerging placements are of value as an alternative for experiential education. There were no reflective tools in the literature to provide a means of supporting pharmacy students as novice reflectors in non-traditional settings. OBJECTIVES: To develop one fit-for-purpose tool that students could utilize across their experiences, regardless of type or duration of experiential placement. METHODS: A multi-phased approach was adopted, including a mix of methodologies: interviews, focus groups, informal feedback from stakeholders, and grading reflective accounts utilizing Mezirow's categories of reflection. A range of stakeholders were involved at each stage to ensure the reflective tool was fit for-purpose. These included students, placement preceptors, and academic staff acting as graders of student reflective accounts. RESULTS: A total of 24 students participated in focus groups, 13 supervisors/preceptors engaged in interviews and informal feedback, and 853 student reflective accounts were graded, over 3 years. The final tool that has been developed and evaluated in this research supported students to develop to critical reflectors (6% - Phase 2 increased to 62.9% - Phase 3). CONCLUSIONS: This novel and innovative approach supports novice reflectors, encourages reflection on action and enhances professional development. It is a structured yet flexible tool, for which there was a gap in the published literature. It can be utilized in varied placements in pharmacy curricula internationally. PMID- 29233610 TI - A dosimetrist's sarcoma journey. PMID- 29233611 TI - Analysis of Factors Associated With In-hospital Mortality in Lung Cancer Chemotherapy Patients With Neutropenia. AB - Lung cancer, compared with other solid tumors, is associated with high mortality rates from febrile neutropenia. The risk factors associated with in-hospital mortality were identified and compared for patients with lung cancer and patients with other solid tumors. Hospitalization data from the University Health Consortium database inclusive of 2004 to 2012 were analyzed. The study population included all adult patients with solid tumors who developed neutropenia. Cancer type, the presence of neutropenia, and further subgroups were determined using International Classification of Diseases, 9th revision, Clinical Modification codes. The primary study outcome was in-hospital mortality in lung cancer patients versus those with other solid tumors. Further analysis concentrated on comparisons of the 2 groups. The analysis included data from 11,111 lung cancer patients and 49,975 patients with other solid tumors. Overall, 4290 patients (7.0%) died. Lung cancer was associated with highest mortality (11.2% compared with other solid tumors, 6.1%; P < .0001). The lung cancer patients were older and more likely to have multiple comorbidities, and the risk of mortality was directly related to the number of comorbidities. Four additional risk factors for mortality were identified: pneumonia, sepsis, any infection, and intensive care unit stay. Pneumonia occurred more commonly in the lung cancer patients (26.4% vs. 10.3%) and was associated with comorbid pulmonary disease, which also occurred more often in the lung cancer patients (52.1% vs. 24.0%). We found that lung cancer patients presenting with febrile neutropenia were older, had more comorbidities, had a greater incidence of comorbid pulmonary disease, and were more likely to have pneumonia. Awareness of these risk factors for mortality should guide clinicians for more personalized approaches to chemotherapy, supportive care decisions, pneumonia and comorbidities. PMID- 29233612 TI - Association between long sleep duration and increased risk of obesity and type 2 diabetes: A review of possible mechanisms. AB - For the last two decades research has revealed an alarming association between short sleep duration and metabolic disorders. In tandem, the hormonal, behavioral, and genetic mechanisms underlying this relationship have been extensively investigated and reviewed. However, emerging evidence is revealing that excessive sleep duration has remarkably similar deleterious effects. Unfortunately, to date there has been little attention to what drives this connection. This narrative review therefore aims to summarize existing epidemiological findings, experimental work, and most importantly putative molecular and behavioral mechanisms connecting excessive sleep duration with both obesity and type 2 diabetes mellitus. It will also address recent findings suggesting a worrisome bidirectional effect such that metabolic disorders create a positive feedback loop which further perpetuates excessive sleep. PMID- 29233613 TI - Complete response of a metastatic porocarcinoma treated with paclitaxel, cetuximab and radiotherapy. PMID- 29233614 TI - Monoterpene indole alkaloid azine derivatives as MDR reversal agents. AB - Aiming at generating a library of bioactive indole alkaloid derivatives as multidrug resistance (MDR) reversers, two epimeric indole alkaloids (1 and 2) were submitted to chemical transformations, giving rise to twenty-four derivatives (5-28), bearing new aromatic or aliphatic azine moieties. The structure of the compounds was established by 1D and 2D NMR (COSY, HMBC, HMQC and NOESY) experiments. Two different strategies were employed for assessing their anti-MDR potential, namely through the evaluation of their activity as inhibitors of typical MDR ABC transporters overexpressed by cell transfection, such as ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP), or by evaluating their ability as collateral sensitivity (CS) agents in cells overexpressing MRP1. A considerable MDR reversing activity was observed for compounds bearing the aromatic azine moiety. The strongest and most selective P-gp inhibition was found for the epimeric azines 5 and 6, bearing a para-methylbenzylidene moiety. Instead, compounds 17 and 18 that possess a di-substituted benzylidene portion with methoxy and hydroxyl groups, selectively inhibited MRP1 drug-efflux. None of these compounds inhibited BCRP. Compounds 5, 6 and 18 were further investigated in drug combination experiments, which corroborated their anti-MDR potential. Moreover, it was observed that compound 12, with an aromatic azine moiety, and compounds 23-26, sharing a new aliphatic substituent, displayed a CS activity, selectively killing MRP1-overexpressing cells. Among these last compounds, it could be established that addition of 19, 23 and 25 to MRP1-overexpressing cells led to glutathione depletion triggering cell death through apoptosis. PMID- 29233615 TI - Diet Quality, Inflammation, and Quality of Life in Breast Cancer Survivors: A Cross-Sectional Analysis of Pilot Study Data. AB - BACKGROUND: Modifiable lifestyle factors, such as diet quality, could reduce inflammation and improve quality of life (QOL) in breast cancer survivors, but data are inconclusive. OBJECTIVE: To determine whether diet quality, as measured by Healthy Eating Index-2010 (HEI-2010) score, is associated with inflammation, health status, or functional outcomes affecting QOL in survivors of early-stage breast cancer. DESIGN: This is a cross-sectional, secondary analysis of baseline data collected from breast cancer survivors after completion of primary therapy and before random assignment to a pilot nutritional intervention aimed at reducing side effects of aromatase inhibitor treatment. PARTICIPANTS/SETTING: Participants were 44 postmenopausal women with stage I to III endocrine receptor positive breast cancer receiving outpatient care at a midwestern cancer center between November 2011 and October 2013. MAIN OUTCOME MEASURES: Primary outcomes were serum proinflammatory cytokines (interleukin-6 [IL-6], IL-17, and tumor necrosis factor-alpha receptor 2 [TNFR-2]). Secondary outcomes included QOL measured by the Stanford Health and Disability Questionnaire and the Functional Assessment of Cancer Therapy-Breast with Endocrine Subscale. STATISTICAL ANALYSES PERFORMED: Pearson correlation coefficients (r) and linear regression models were used to evaluate the relationship of dietary variables with inflammatory cytokines and QOL measures. RESULTS: A higher overall HEI-2010 score (healthier diet) was associated with lower IL-6 (r=-0.46; P=0.002) and TNFR-2 (r=-0.41; P=0.006); however, associations were attenuated by body mass index (BMI) (IL=6 [r=-0.26; P=0.10]; TNFR-2 [r=-0.30; P=0.06]). In women with prior chemotherapy, a higher HEI-2010 score was strongly associated with lower IL-6 (r=-0.67; P=0.009) and TNFR-2 (r=-0.59; P=0.03) after BMI adjustment. There were no significant correlations between HEI-2010 score and QOL measures after adjustment for BMI. CONCLUSIONS: These data suggest the need for more rigorous investigation into the relationship of diet quality, BMI, and inflammation in breast cancer survivors. PMID- 29233616 TI - N-term 2017: Proteostasis via the N-terminus. AB - N-term 2017 was the first international meeting to bring together researchers from diverse disciplines with a shared interest in protein N-terminal modifications and the N-end rule pathway of ubiquitin-mediated proteolysis, providing a platform for interdisciplinary cross-kingdom discussions and collaborations, as well as strengthening the visibility of this growing scientific community. PMID- 29233617 TI - Efficient low-power TOBSY sequences for fast MAS. AB - Through-bond J-coupling based experiments in solid-state NMR spectroscopy are challenging because the J couplings are typically much smaller than the dipolar couplings. This often leads to a lower transfer efficiency compared to dipolar coupling based sequences. One of the reasons for the low transfer efficiency are the second-order cross terms involving the strong heteronuclear dipolar couplings leading to fast magnetization decay. Here, we show that by employing a symmetry based C9 sequence, which was carefully selected to suppress second-order terms, efficient polarization transfers of up to 80% can be achieved without decoupling on fully protonated two-spin model systems at a MAS frequency of 55.5 kHz with rf field amplitudes of about 25 kHz. In addition, we analyse the effects of rf inhomogeneity and crystallites selection due to the polarization preparation method on the TOBSY transfer efficiency. We demonstrate on small model substances as well as on deuterated and 100% back-exchanged ubiquitin that C9391 and C9481 are efficient and practical TOBSY sequences at experimental conditions ranging from proton Larmor frequencies of 400-850 MHz, and MAS frequencies ranging from 55.5 to 111.1 kHz. PMID- 29233618 TI - Nutritional impact on gene expression and competence of oocytes used to support embryo development and livebirth by cloning procedures in goats. AB - Changes in the nutritional plan have been shown to affect oocyte quality, crucial to oocyte donors animals used in cloning. This study aimed to evaluate the impact of diets with increasing nutritional levels (maintenance diet=M; 1.3M; 1.6M; 1.9M) fed to goats for four weeks on follicular fluid composition, gene expression and oocyte competence used to cloning in goats. Donor females were superovulated for the retrieval of matured oocytes and physical measurements reported. After four weeks, groups receiving diets above maintenance increased thickness of subcutaneous adipose tissue and body weight, with higher values in 1.9M Group (P<0.05). Treatments did not affect follicular density, number of aspirated follicles, retrieved and matured oocytes. Animals from 1.3M group had lower (P<0.05) maturation rate (44.0%) and number of viable oocytes (65.3%) than M (68.8%) and 1.9M (76.0%). Follicular fluid glucose concentrations increased with nutritional levels (P=0.010), with a difference (P<0.05) between groups 1.9M (11.4+/-2.6mg/dL) and M (2.6+/-0.5mg/dL). The diet did not affect the expression of GDF9, BMP15, and BAX genes in oocytes, but BCL2 and apoptotic index were significantly higher (P<0.05) in the 1.3M and 1.6M groups than the other groups. Following the transfer of cloned embryos, one fetus was born live of a twin pregnancy in the 1.9M Group. The association between energy intake and oocyte quality suggests better nutritional use by oocytes when the maximum flow was used (1.9M), but the optimal feeding level in cloning still needs refinement. PMID- 29233619 TI - FTO affects food cravings and interacts with age to influence age-related decline in food cravings. AB - The fat mass and obesity associated gene (FTO) was the first gene identified by genome-wide association studies to correlate with higher body mass index (BMI) and increased odds of obesity. FTO remains the locus with the largest and most replicated effect on body weight, but the mechanism whereby FTO affects body weight and the development of obesity is not fully understood. Here we tested whether FTO is associated with differences in food cravings and a key aspect of dopamine function that has been hypothesized to influence food reward mechanisms. Moreover, as food cravings and dopamine function are known to decline with age, we explored effects of age on relations between FTO and food cravings and dopamine function. Seven-eight healthy subjects between 22 and 83years old completed the Food Cravings Questionnaire and underwent genotyping for FTO rs9939609, the first FTO single nucleotide polymorphism associated with obesity. Compared to TT homozygotes, individuals carrying the obesity-susceptible A allele had higher total food cravings, which correlated with higher BMI. Additionally, food cravings declined with age, but this age effect differed across variants of FTO rs9939609: while TT homozygotes showed the typical age-related decline in food cravings, there was no such decline among A carriers. All subjects were scanned with [18F]fallypride PET to assess a recent proposal that at the neurochemical level FTO alters dopamine D2-like receptor (DRD2) function to influence food reward related mechanisms. However, we observed no evidence of FTO effects on DRD2 availability. PMID- 29233620 TI - Regulation of extracellular matrix vesicles via rapid responses to steroid hormones during endochondral bone formation. AB - Endochondral bone formation is a precise and highly ordered process whose exact regulatory framework is still being elucidated. Multiple regulatory pathways are known to be involved. In some cases, regulation impacts gene expression, resulting in changes in chondrocyte phenotypic expression and extracellular matrix synthesis. Rapid regulatory mechanisms are also involved, resulting in release of enzymes, factors and micro RNAs stored in extracellular matrisomes called matrix vesicles. Vitamin D metabolites modulate endochondral development via both genomic and rapid membrane-associated signaling pathways. 1alpha,25 dihydroxyvitamin D3 [1alpha,25(OH)2D3] acts through the vitamin D receptor (VDR) and a membrane associated receptor, protein disulfide isomerase A3 (PDIA3). 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] affects primarily chondrocytes in the resting zone (RC) of the growth plate, whereas 1alpha,25(OH)2D3 affects cells in the prehypertrophic and upper hypertrophic cell zones (GC). This includes genomically directing the cells to produce matrix vesicles with zone specific characteristics. In addition, vitamin D metabolites produced by the cells interact directly with the matrix vesicle membrane via rapid signal transduction pathways, modulating their activity in the matrix. The matrix vesicle payload is able to rapidly impact the extracellular matrix via matrix processing enzymes as well as providing a feedback mechanism to the cells themselves via the contained micro RNAs. PMID- 29233621 TI - Corrigendum to "EEG signatures accompanying auditory figure-ground segregation" [NeuroImage (2017) volume 141, pp. 108-119]. PMID- 29233622 TI - Underrepresentation of adolescents with respiratory, mental health, and developmental disabilities using American Community Survey (ACS) questions. AB - BACKGROUND: Disability prevalence estimates are used to identify populations, establish priorities and allocate funding for a broad range of federal, state, and local initiatives. Increasingly, these estimates are based on a set of six questions developed and tested for use in the American Community Survey (ACS). A key assumption about the ACS disability screeners is that they sufficiently capture the entire population of people with disabilities, but some studies indicate that certain disability groups are underrepresented. OBJECTIVES: The objective of this study is to explore potential underrepresentation of certain disability groups identified by the ACS disability questions. METHODS: We compared disability prevalence rates from two data sources for adolescents with disabilities, aged 14 to 16, who receive Supplemental Security Income (SSI, n = 2051). The Social Security Administration (SSA) provided disability determination data for each adolescent, and adolescents (or proxy-rater) provided baseline self report data about functional limitation based on the six ACS disability questions. RESULTS: Approximately 17% of the sample did not endorse any ACS questions. Excluding SSA categories with cell counts less than 10, the top five conditions not captured by ACS questions included respiratory conditions (38%), mood disorders (28%), other mental disorders (27%), schizophrenic and other psychotic disorders (27%) and developmental disorders (20%). CONCLUSIONS: Our findings suggest that people with mental health and developmental disabilities and those with respiratory conditions are among those groups under-represented by the ACS disability questions. Changes or additions to ACS questions should be considered to ensure that all disability groups are addressed in public health planning. PMID- 29233624 TI - First and second trimester screening for fetal structural anomalies. AB - Fetal structural anomalies are found in up to 3% of all pregnancies and ultrasound-based screening has been an integral part of routine prenatal care for decades. The prenatal detection of fetal anomalies allows for optimal perinatal management, providing expectant parents with opportunities for additional imaging, genetic testing, and the provision of information regarding prognosis and management options. Approximately one-half of all major structural anomalies can now be detected in the first trimester, including acrania/anencephaly, abdominal wall defects, holoprosencephaly and cystic hygromata. Due to the ongoing development of some organ systems however, some anomalies will not be evident until later in the pregnancy. To this extent, the second trimester anatomy is recommended by professional societies as the standard investigation for the detection of fetal structural anomalies. The reported detection rates of structural anomalies vary according to the organ system being examined, and are also dependent upon factors such as the equipment settings and sonographer experience. Technological advances over the past two decades continue to support the role of ultrasound as the primary imaging modality in pregnancy, and the safety of ultrasound for the developing fetus is well established. With increasing capabilities and experience, detailed examination of the central nervous system and cardiovascular system is possible, with dedicated examinations such as the fetal neurosonogram and the fetal echocardiogram now widely performed in tertiary centers. Magnetic resonance imaging (MRI) is well recognized for its role in the assessment of fetal brain anomalies; other potential indications for fetal MRI include lung volume measurement (in cases of congenital diaphragmatic hernia), and pre-surgical planning prior to fetal spina bifida repair. When a major structural abnormality is detected prenatally, genetic testing with chromosomal microarray is recommended over routine karyotype due to its higher genomic resolution. PMID- 29233623 TI - A timeless biology. AB - Contrary to claims that physics is timeless while biology is time-dependent, we take the opposite standpoint: physical systems' dynamics are constrained by the arrow of time, while living assemblies are time-independent. Indeed, the concepts of "constraints" and "displacements" shed new light on the role of continuous time flow in life evolution, allowing us to sketch a physical gauge theory for biological systems in long timescales. In the very short timescales of biological systems' individual lives, time looks like "frozen" and "fixed", so that the second law of thermodynamics is momentarily wrecked. The global symmetries (standing for biological constrained trajectories, i.e. the energetic gradient flows dictated by the second law of thermodynamics in long timescales) are broken by local "displacements" where time is held constant, i.e., modifications occurring in living systems. Such displacements stand for brief local forces, able to temporarily "break" the cosmic increase in entropy. The force able to restore the symmetries (called "gauge field") stands for the very long timescales of biological evolution. Therefore, at the very low speeds of life evolution, time is no longer one of the four phase space coordinates of a spacetime Universe: it becomes just a gauge field superimposed to three-dimensional biological systems. We discuss the implications in biology: when assessing living beings, the underrated role of isolated "spatial" modifications needs to be emphasized, living apart the evolutionary role of time. PMID- 29233625 TI - Clinical Use of Neuromuscular Electrical Stimulation for Neuromuscular Rehabilitation: What Are We Overlooking? AB - The clinical success of neuromuscular electrical stimulation (NMES) for neuromuscular rehabilitation is greatly compromised by the poor consideration of different physiological and methodological issues that are not always obvious to the clinicians. Therefore, the aim of this narrative review is to reexamine some of these fundamental aspects of NMES using a tripartite model perspective. First, we contend that NMES does not actually bypass the central nervous system but results in a multitude of neurally mediated responses that contribute substantially to force generation and may engender neural adaptations. Second, we argue that too much emphasis is generally placed on externally controllable stimulation parameters while the major determinant of NMES effectiveness is the intrinsically determined muscle tension generated by the current (ie, evoked force). Third, we believe that a more systematic approach to NMES therapy is required in the clinic and this implies a better identification of the patient specific impairment and of the potential "responders" to NMES therapy. On the basis of these considerations, we suggest that the crucial steps to ensure the clinical effectiveness of NMES treatment should consist of (1) identifying the neuromuscular impairment with clinical assessment and (2) implementing algorithm based NMES therapy while (3) properly dosing the treatment with tension controlled NMES and eventually amplifying its neural effects. PMID- 29233627 TI - Sentinel node biopsy in desmoplastic thin melanoma: Histogenetic recommendations. PMID- 29233626 TI - ICP-MS measurement of toxic and essential elements in human breast milk. A comparison of alkali dilution and acid digestion sample preparation methods. PMID- 29233628 TI - Xanthogranulomatous pyelonephritis in a paediatric cohort (1963-2016): Outcomes from a large single-center series. AB - BACKGROUND: Xanthogranulomatous pyelonephritis (XGP) is an uncommon chronic destructive granulomatous inflammation of the kidney. It was first described in 1916, and is thought to affect 6/1000 cases of pyelonephritis. Its manifestations are varied, and with a limited number of cases in the literature, the optimal diagnosis and management of XGP in the paediatric cohort is still unknown. MATERIAL AND METHODS: The medical records of children who were diagnosed and treated for XGP at the current unit during the period 1963-2016, inclusive, were retrospectively reviewed. Information pertaining to each patient was recorded, including: demographic data, past medical history, clinical and biochemical characteristics, diagnostic procedures, treatment methods, histopathologic diagnosis of the removed specimen, and outcome. RESULTS: A total of 66 children with a median age of 4.84 years (range 1.1-14.81), with an M:F ratio 1.35:1 underwent nephrectomy for XGP and had a median follow-up of 7.19 years (range 0.11-17.45). The most common presentations were systemic illness (62.1%), pain (60.6%), urinary tract infections (54.5%) and an abdominal mass (39.4%); pyrexia was present in 53%. Biochemical abnormalities included anaemia (86.3%), thrombocytosis (80.3%) and hypomagnesemia (65.1%). There was an 83.3% concordance between intraoperative cultures and positive mid-stream urines. Index kidneys were significantly larger than the contralateral side (mean 1.32 cm; P = 0.002). Staging of XGP demonstrated extension beyond the kidney in 79% of kidneys. Computed tomography (CT) was performed in 11 cases (Summary figure). Dimercaptosuccinic acid (DMSA) scan showed 0-10% function in 90.47% of cases. Surgical procedures included nephrectomy (n = 63) and partial nephrectomy (n = 3). Perioperative complications included colonic resections (n = 5) and abscess formation in 18%. CONCLUSIONS: This is the largest series to date of XGP in a paediatric cohort. XGP should be included in the differential diagnosis of all children presenting with perirenal or psoas abscesses, renal masses and/or non functioning kidneys with/or without associated urolithiasis. Clinical awareness and a high index of suspicion is required to achieve the correct pre-operative diagnosis and appropriate management. PMID- 29233629 TI - Achieving hepatitis C elimination in Europe - To treatment scale-up and beyond. PMID- 29233630 TI - Higher risk of renal disease in chronic hepatitis C patients: Antiviral therapy survival benefit in patients on hemodialysis. AB - BACKGROUND & AIMS: Several studies have shown that chronic hepatitis C (CHC) infection has a negative impact on kidney function, as well as survival, in patients with chronic kidney disease (CKD) or on hemodialysis. The aim of this nationwide registry study was to describe renal disease in Swedish patients with CHC. METHODS: In the present study, patients were identified for CHC (B18.2) and CKD (N18) according to the International Classification of Diseases (ICD)-10 in the nationwide Swedish inpatient care day surgery (1997-2013) and non-primary outpatient care (2001-2013) patient registries. Hemodialysis was defined using the procedure code in the non-primary outpatient care. For each patient, up to five non-CHC diagnosed age/sex/place of residency-matched comparators were drawn from the general population at the time of diagnosis. Follow-up started at the date of CHC diagnosis and patients accrued person-time until, whichever came first, death, emigration or December 31st, 2013. RESULTS: Between 2001 and 2013, 42,522 patients received a CHC diagnosis. Of these patients, 2.5% (1,077/45,222) were diagnosed with CKD during 280,123 person-years, compared with 0.7% (1,454/202,694) in the matched general population comparators (1,504,765 person years), resulting in a standardized incidence ratio (SIR) of 4.0. There was a 3.3 7.0-fold risk of patients with CHC requiring hemodialysis. Overall, 17% of patients with CHC receiving hemodialysis were treated for CHC; 24% in the treated cohort died compared with 56% of the untreated cohort (p <0.0001), with antiviral treatment improving survival with an odds ratio of 3.901 (p = 0.001). CONCLUSIONS: The results from this nationwide registry study showed that patients with CHC are at a higher risk of developing CKD. Furthermore, hepatitis C treatment seemed to improve survival for patients with CHC on hemodialysis compared with untreated patients. LAY SUMMARY: Hepatitis C is an infectious disease that mainly infects the liver, but has also been shown to have negative effects on other organs. This nationwide study demonstrates an increased risk of hepatitis C patients developing reduced kidney function and the need for dialysis. The study also showed improved survival in dialysis patients who received antiviral treatment. PMID- 29233631 TI - A rare case of portosystemic shunt: Variation of Abernethy malformation. PMID- 29233632 TI - Rationale and design of the worldwide prospective multicenter registry on radiation dose estimates of cardiac CT angiography in daily practice in 2017 (PROTECTION VI). AB - BACKGROUND: Cardiac computed tomography angiography (cardiac CTA) is an increasingly used versatile imaging method to evaluate coronary and cardiac morphology. Owing to improvements in technology, image quality has continuously improved over the last 10-20 years. At the same time, numerous non-randomized and randomized studies have been performed to reduce the associated radiation exposure. Currently, it is unclear if the advances in technology and knowledge about radiation reduction translated into reduced levels of cardiac CTA radiation dose in daily clinical practice as well as a wide utilization of dose-saving strategies. METHODS: The PROTECTION VI study is a multicenter, prospective, worldwide registry designed to evaluate radiation dose exposure, utilization of dose-saving strategies and diagnostic image quality during cardiac CTA in current daily practice. Assessment of image quality will be addressed by the evaluation of diagnostic image quality at the local study site and the calculation of quantitative image quality parameters in an imaging core laboratory. Above 4000 patients will be enrolled from approximately 70 sites in Europe, North America, South America, Asia and Australia. The study will analyze median radiation dose levels, image quality, frequency of use and efficacy of algorithms for dose reduction, and patient and study-related predictors associated with radiation dose. CONCLUSIONS: The PROTECTION VI study is designed to provide a reliable estimate of current radiation dose for cardiac CTA and to assess the potential for additional dose reductions. PMID- 29233633 TI - Dynamic CT angiography for the diagnosis of patients with thoracic outlet syndrome: Correlation with patient symptoms. AB - INTRODUCTION: Vasculo-nervous structures serving the upper limbs may be compressed as they pass through three areas: the inter-scalene triangle (IST), the costo-clavicular space (CCS) and the retropectoralis minor space (RMS). The diagnosis of thoracic outlet syndrome (TOS) is essentially clinical, but requires imaging to specify the site of compression, its grade and the existence of predisposing anatomical factors, in order to guide the treatment and eliminate the main differential diagnoses. MATERIAL AND METHODS: Images from 141 patients who underwent dynamic CT angiography of the thoracic outlets from June 2008 to January 2015 were analyzed retrospectively. Patients had unilateral or bilateral vascular, neurological, mixed or atypical symptoms. We studied the degree of stenosis of the subclavian artery with the following grading system: 1 (0-<25%), 2 (25-<50%), 3 (50-<75%), 4 (75-100%). The site of stenosis and the presence of underlying anatomical predisposing factors were also taken in account. RESULTS: A total of 221 thoracic outlets were analyzed. Symptoms were neurological, mixed, vascular and atypical in 30%, 28%, 13% and 12%, respectively. Among patients with bilateral acquisitions, 38 outlets were asymptomatic; 40% of symptomatic outlets and only 5% of asymptomatic ones had grade 3 or 4 stenosis. 63% of the stenosis were in the CCS and 37% in the IST; 21% had a predisposing anatomical factor most often a costo-clavicular anomaly, associated with significant stenosis in 50% of cases. CONCLUSION: Vascular stenosis of more than 50% on dynamic CT angiography is strongly associated with TOS. Predisposing factors were present in 21% of cases, causing significant vascular stenosis in half, underscoring the need for functional evaluation. PMID- 29233635 TI - Therapeutic benefit of environmental enrichment on optic neuritis. AB - Optic neuritis (ON) is an inflammatory, demyelinating, neurodegenerative, and presently untreatable condition of the optic nerve which might induce blindness. We analyzed the effect of environmental enrichment (EE) on visual pathway damage provoked by experimental ON induced by a microinjection of bacterial lipopolysaccharide (LPS) into the optic nerve. For this purpose, LPS was microinjected into the optic nerve from male Wistar rats. After injection, one group of animals was submitted to EE, and another group remained in standard environment (SE) for 21 days. EE prevented the decrease in pupil light reflex (PLR), visual evoked potentials, retinal anterograde transport, phosphorylated neurofilament immunoreactivity, myelination (luxol fast blue staining), and axon (toluidine blue staining) and retinal ganglion cell (Brn3a-immunoreactivity) number. EE also prevented microglial/macrophage reactivity (Iba-1- and ED1 immunoreactivity), and astrocytosis (glial fibrillary acidic protein immunostaining) induced by experimental ON. LPS-injected optic nerves displayed oxidative damage and increased inducible nitric oxide synthase, cyclooxygenase-2, and interleukin-1beta and TNFalpha mRNA levels which were prevented by EE. EE increased optic nerve brain-derived neurotrophic factor levels. When EE started at 4 (but not 7) days post-injection of LPS, a preservation of the PLR was observed at 21 days post-LPS, which was blocked by the daily administration of ANA-12 from day 4 to day 7 post-LPS. Moreover, EE from day 4 to day 7 post-LPS significantly preserved the PLR at 21 days post-injection. Taken together, our data suggest that EE preserved visual functions and reduced neuroinflammation of the optic nerve. PMID- 29233637 TI - Compound heterozygous familial hypercholesterolemia in a Chinese boy with a de novo and transmitted low-density lipoprotein receptor mutation. AB - BACKGROUND: Homozygous familial hypercholesterolemia is characterized by extremely elevated serum low-density lipoprotein cholesterol (LDL-C) levels and increased risk of cardiovascular complications due to biallelic mutations in LDL receptor (LDLR). OBJECTIVE: We present a 10-year-old Chinese homozygous familial hypercholesterolemia boy with biallelic LDLR mutations including an extremely rare de novo mutation. METHODS: Detailed family history and clinical and biochemical data were gathered from the pedigree. Genomic DNA was isolated and the reported LDL-related genes (LDLR, APOB, PCSK9, ABCG5, ABCG8, ANGPTL3, APOC3, and LDLRAP1) were sequenced. RESULTS: The proband displayed extensive cutaneous and tendon xanthomas together with elevated serum LDL-C level of 14.87 mmol/L (575 mg/dL). A combination of simvastatin 40 mg daily and ezetimibe 10 mg daily resulted in 57% lowering of LDL-C. The proband had compound heterozygous LDLR disease-causing mutations, including p.(His583Tyr) variant transmitted from the mother and a de novo p.(Gln242*) variant on the paternal allele. CONCLUSIONS: Our report supports the role of genetic testing in the proband and the parents for accurate genetic counseling. Our patient had marked lowering of LDL-C with a combination of statin and ezetimibe but may require additional therapy. PMID- 29233634 TI - Epicardial adipose tissue density and volume are related to subclinical atherosclerosis, inflammation and major adverse cardiac events in asymptomatic subjects. AB - BACKGROUND: We investigated whether epicardial adipose tissue (EAT) volume and density are related to early atherosclerosis, plaque inflammation and major adverse cardiac events (MACE, cardiac death and myocardial infarction) in asymptomatic subjects. METHODS: EAT volume and density were quantified from non contrast cardiac CT in 456 asymptomatic individuals (age 60.3 +/- 8.3; 68% with CCS>0) from the prospective EISNER trial. EAT volume and density were examined in relation to coronary calcium score (CCS), inflammatory biomarkers and MACE. RESULTS: EAT volume was higher and EAT density lower in subjects with coronary calcium compared to subjects without [89 vs 74 cm3, p < 0.001] [-76.9 vs -75.7 HU,p = 0.024]. EAT volume was lowest in individuals with no coronary calcium and was significant higher in subjects with early atherosclerosis (CCS 1-99) [74 vs 87 cm3,p = 0.016] and in subjects with more advanced atherosclerosis (CCS>=100) [89 cm3,p = 0.002]). EAT volume was independently related to serum levels of PAI 1, and MCP-1 and inversely related to adiponectin and HDL-cholesterol (p < 0.05). EAT density was inversely related to PAI-1 and LDL-cholesterol and positively associated to adiponectin, sICAM-1 and HDL-cholesterol (p < 0.05). EAT density was more significantly associated with MACE [(HR 0.8, 95%CI:0.7-0.98), p = 0.029] than EAT volume or CCS. CONCLUSION: EAT volume was higher and density lower in subjects with coronary calcium compared to subjects with CCS = 0, with similar EAT volume in CCS<100 and CCS>=100. Lower EAT density and increased EAT volume were associated with coronary calcification, serum levels of plaque inflammatory markers and MACE, suggesting that dysfunctional EAT may be linked to early plaque formation and inflammation. PMID- 29233638 TI - Gene editing & stem cells. PMID- 29233636 TI - Amylin in Alzheimer's disease: Pathological peptide or potential treatment? AB - Alzheimer's disease (AD) is a neurodegenerative disease for which we currently lack effective treatments or a cure. The pancreatic peptide hormone amylin has recently garnered interest as a potential pharmacological target for the treatment of AD. A number of studies have demonstrated that amylin and amylin analogs like the FDA-approved diabetes drug pramlintide can reduce amyloid burden in the brain and improve cognitive symptoms of AD. However, other data suggest that amylin may have pathological effects in AD due to its propensity to misfold and aggregate under certain conditions. Here, the literature supporting a beneficial versus harmful role of amylin in AD is reviewed. Additionally, several critical gaps in the literature are discussed, such as our limited understanding of the amylin system during aging and in disease states, as well as complexities of amylin receptor signaling and of changing pathophysiology during AD progression that might underlie the seemingly conflicting or contradictory results in the amylin/AD literature. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 29233639 TI - Role of the Functional Polymorphism of Survivin Gene (-31G/C) and Risk of Breast Cancer in a North Indian Population. AB - INTRODUCTION: Survivin is an apoptosis inhibitor and plays a primary role in cancer development and progression. One of the most common polymorphism of the survivin promoter -31G/C (rs9904341) influences its expression and is associated with the risk of cancer development. This study was conducted to explore survivin promoter gene -31G/C (rs9904341) polymorphism and the risk of breast cancer. PATIENTS AND METHODS: The study group included 190 pathologically confirmed breast cancer patients, in addition to 200 distinct cancer-free controls from Jammu and Kashmir region of India, where breast cancer is the most common cancer in women. Single nucleotide polymorphism genotyping for -31G/C polymorphism in the survivin promoter region was done using a polymerase chain reaction restriction fragment length polymorphism method. RESULTS: The variant genotype/allele was found in 54.1% of the cases compared with 46.5% of controls. The combined prevalence of genotype GC+CC was significantly higher in patients compared with the control group (P = .02). Analyses of odds ratios (ORs) in the patient and control groups indicated that the presence of homozygous CC genotype was associated with increased risk for development of breast cancer (OR, 2.04; 95% confidence interval [CI], 1.07-2.98). The gene frequencies for G and C alleles were statistically different between patient and control groups (OR, 1.37; 95% CI, 1.03-1.84). CONCLUSION: The results suggest the association of 31G/C survivin polymorphism at a genotypic and allelic level in breast cancer. PMID- 29233640 TI - Rapid Response to Larotrectinib (LOXO-101) in an Adult Chemotherapy-Naive Patients With Advanced Triple-Negative Secretory Breast Cancer Expressing ETV6 NTRK3 Fusion. PMID- 29233641 TI - Biphasic hierarchical extracellular matrix scaffold for osteochondral defect regeneration. AB - OBJECTIVE: To investigate the effect of decellularized osteochondral extracellular matrix (ECM) scaffold for osteochondral defect regeneration. DESIGN: We compared the histological features and microstructure of degenerated cartilage to normal articular cartilage. We also generated and evaluated osteochondral ECM scaffolds through decellularization technology. Then scaffolds were implanted to osteochondral defect in rabbit model. After 12 weeks surgery, regeneration tissues were analyzed by histology, immunohistochemistry evaluation. And possible mechanisms of angiogenesis and cell migration were explored. RESULTS: We demonstrated decreased cell numbers, formation of fibrous cartilage, lost microstructure and worse permeability in degenerated cartilage compared to normal cartilage. We also generated an osteochondral ECM scaffold with a hierarchical structure that exhibited low immunogenicity, high bioactivity, and well biocompatibility. We found that the ECM scaffold promoted tissue regeneration in osteochondral defects, which was dependent on the scaffold constituents and stratified three-dimensional microstructure as well as on its ability to inhibit angiogenesis and stimulate cell migration. CONCLUSIONS: Our findings demonstrated that the biphasic hierarchical ECM scaffold represents a novel and effective biomaterial that can be used in the treatment of osteochondral defect. PMID- 29233642 TI - Acute inescapable stress alleviates fear extinction recall deficits caused by serotonin transporter abolishment. AB - Life stress increases risk for developing post-traumatic stress disorder (PTSD), and more prominently so in short-allele carriers of the serotonin transporter linked polymorphic region (5-HTTLPR). Serotonin transporter knockout (5-HTT-/-) rats show compromised extinction (recall) of conditioned fear, which might mediate the increased risk for PTSD and reduce the therapeutic efficacy of exposure therapy. Here, we assessed whether acute inescapable stress (IS) differentially affects fear extinction and extinction recall in 5-HTT-/- rats and wildtype controls. Surprisingly, IS experience improved fear extinction recall in 5-HTT-/- rats to the level of wildtype animals, while wildtypes were unaffected by this IS. Thus, whereas 5-HTT-/- rats evidently were more responsive to the stressor, the behavioral consequences presented themselves as adaptive. PMID- 29233644 TI - Looking at late repolarization to see early disease. PMID- 29233645 TI - Response to cardiac resynchronization therapy: Dichotomous or continuous variable? PMID- 29233643 TI - Trichostatin A inhibits deacetylation of histone H3 and p53 by SIRT6. AB - SIRT6 is an epigenetic modification enzyme that regulates gene transcription through its deacetylase activity. In addition to histone protein, SIRT6 also modify other proteins and enzymes, some of which are central players in metabolic reprogramming and aging process. Therefore, SIRT6 has emerged as a therapeutic target for the treatment of metabolic disorder and age-related diseases. Here, we report that SIRT6 deacetylates lysine 382 of p53 in short synthetic peptide sequence and in full length p53. Further studies showed that the deacetylation of H3K9Ac and p53K382Ac are insensitive to nicotinamide inhibition, but are sensitive to trichostatin A (TSA) inhibition. Detailed kinetic analysis revealed that TSA competes with the peptide substrate for inhibition, and this inhibition is unique to SIRT6 in the sirtuin family. Taken together, this study not only suggests potential roles of SIRT6 in regulating apoptosis and stress resistance via direct deacetylation of p53, but also provides lead compound for the development of potent and selective SIRT6 inhibitors. PMID- 29233646 TI - Induced Brugada syndrome: Possible sources of arrhythmogenesis. AB - Brugada syndrome is an inherited cardiac condition with the potential for development of life-threatening arrhythmias in relatively young individuals without significant structural cardiac abnormalities. The condition is characterized by a distinct coved-type ST segment elevation in the right precordial leads (V1-V3). This hallmark pattern (type 1) is often dynamic and sometimes concealed, and may be unmasked in certain conditions or under the effect of certain agents, which include variation of sympathovagal balance, hormones, metabolic factors and drugs. These factors may not only modulate electrocardiographic morphology and induce the characteristic type 1 pattern, but also predispose to ventricular arrhythmias. The risk of malignant arrhythmias in acute events with induced type 1 pattern may be imminent, particularly if the patient in fact has Brugada syndrome. The physician should be aware of the modulating factors that may underlie a Brugada pattern, and be able to recognize, identify and promptly correct them. The mechanisms responsible for the type 1 pattern and possible associated ventricular arrhythmias induced by these modulating factors have attracted growing attention and interest. Furthermore, not all induced Brugada ECG patterns are observed in patients with Brugada syndrome, existing the possibility for acquired Brugada patterns/syndrome and Brugada phenocopies. This paper reviews the modulating factors associated with induced type 1 pattern as possible causes of arrhythmogenesis, particularly in Brugada syndrome patients, describes some of the probable underlying mechanisms, and discusses the concepts of acquired Brugada syndrome and Brugada phenocopies. PMID- 29233647 TI - Right atrial function with speckle tracking echocardiography: Do we really need it? PMID- 29233648 TI - Left atrial dysfunction in light-chain cardiac amyloidosis and hypertrophic cardiomyopathy - A comparative three-dimensional speckle-tracking echocardiographic analysis from the MAGYAR-Path Study. AB - INTRODUCTION: While cardiac amyloidosis (CA) is a rare systemic disease characterized by extracellular deposition of protein-derived fibrils, hypertrophic cardiomyopathy (HCM) is histopathologically characterized by myocyte hypertrophy and disarray, interstitial fibrosis, and small intramural coronary arteriole dysplasia. The aim of the present study was to compare left atrial (LA) volumetric and functional characteristics between light-chain (AL) CA and HCM by three-dimensional (3D) speckle-tracking echocardiography (STE). METHODS: The AL CA group initially consisted of 17 patients with AL-CA, but one patient was excluded due to inadequate image quality, and so the study population consisted of 16 patients (mean age: 64.0+/-9.6 years, five men). Their results were compared with data on 20 age-matched HCM patients (mean age: 59.8+/-5.2 years, 10 men) and on 16 age-matched healthy controls (mean age: 58.2+/-7.2 years, six men). Complete two-dimensional Doppler echocardiography and 3D-STE were performed in all cases. RESULTS: Significantly increased LA volumes were observed in both AL-CA and HCM compared with the control group. Only active atrial emptying fraction was found to be significantly reduced in AL-CA patients compared to controls. Peak global and mean segmental circumferential, longitudinal and area strains showed significant reductions in AL-CA patients compared with controls, but only peak mean segmental longitudinal strain differed significantly between HCM patients and controls. While no differences were demonstrated in global and mean segmental strain at atrial contraction between HCM patients and controls, AL CA patients showed reductions in certain strain parameters compared to controls and HCM patients. CONCLUSIONS: Different patterns of LA functional characteristics were demonstrated in AL-CA and HCM patients by 3D-STE. PMID- 29233650 TI - Impact of erdosteine on chronic bronchitis and COPD: A meta-analysis. AB - A previous meta-analysis suggested that the treatment with erdosteine was associated with significant amelioration of the cumulative global efficacy index and symptoms in comparison to placebo or other mucolytics. However, this conclusion was criticized because the meta-analysis, as it had been done, made it impossible to preclude the potential operation of selection biases within and across trials, and identify any realised benefits of an individual patient data approach. Taking into consideration these criticisms and also the publication of two further recent articles focused on the prevention of chronic obstructive pulmonary disease (COPD) exacerbations with erdosteine, we have carried out a quantitative synthesis via meta-analysis of the currently available data on the use of this drug. Our findings included data from ten studies involving 1278 patients and show that erdosteine is able to improve the clinical score of patients with chronic bronchitis and COPD, and also reduces the overall risk of chronic bronchitis/COPD exacerbations, and reduces the risk of experiencing at least one exacerbation. Furthermore, our data suggest that erdosteine can lengthen the time to the first COPD exacerbation, reduce the duration of a COPD exacerbation and the risk of hospitalization from COPD. The documented effect of erdosteine in reducing the occurence and/or influencing COPD exacerbations is important because it indicates that erdosteine can be added to the list of drugs that can be recommended for treating COPD. PMID- 29233649 TI - Immune protection efficacy of FAdV-4 surface proteins fiber-1, fiber-2, hexon and penton base. AB - The spread of hydropericardium syndrome has recently become serious in China since 2015. There is, therefore, an urgent need for new, safe and effective vaccines that prevent the disease. Here, the immune protection induced by Escherichia coli-expressed capsid proteins of fowl adenovirus serotype 4, including fiber-1, fiber-2, penton base and hexon (loop-1 region) were compared in chickens at different inoculation amounts. According to challenge mortalities and tissue gross/micro lesion results, fiber-2 induced the best protection, followed by fiber-1 and hexon. Fiber-1 and fiber-2 provided complete protection against 105.5 TCID50 viral load challenge with 100 or 50MUg doses per chicken, respectively. Penton could induce effective protection only at the high dosage of 200MUg per chicken. The immunoprotective characteristics of these FAdV-4 capsid proteins may prove useful for developing subunit vaccines to control hydropericardium syndrome. PMID- 29233651 TI - Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (RORgamma/RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity. AB - We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORgammat inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor alpha (LXRalpha). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRalpha activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies. PMID- 29233652 TI - Synthesis and evaluation of a class of 1,4,7-triazacyclononane derivatives as iron depletion antitumor agents. AB - Iron depletion has been confirmed as an efficient strategy for cancer treatment. In the current study, a series of 1,4,7-triazacyclononane derivatives HE-NO2A, HP NO2A and NE2P2A, as well as the bifunctional chelators p-NO2-PhPr-NE3TA and p-NH2 PhPr-NE3TA were synthesized and evaluated as iron-depleting agents for the potential anti-cancer therapy against human hepatocellular carcinoma. The cytotoxicity of these chelators was measured using hepatocellular cancer cells and compared with the clinically available iron depletion agent DFO and the universal metal chelator DTPA. All these 1,4,7-triazacyclononane-based chelators exhibited much stronger antiproliferative activity than DFO and DTPA. Among them, chelators with phenylpropyl side chains, represented by p-NO2-PhPr-NE3TA and p NH2-PhPr-NE3TA, displayed the highest antiproliferative activity against HepG2 cells. Hence, these compounds are attractive candidates for the advanced study as iron depletion agents for the potential anti-cancer therapy, and could be further in conjugation with a targeting moiety for the future development in targeted iron depletion therapy. PMID- 29233654 TI - Trophic modulation of gamma oscillations: The key role of processing protease for Neuregulin-1 and BDNF precursors. AB - Gamma oscillations within the cerebral cortex and hippocampus are associated with cognitive processes, including attention, sensory perception, and memory formation; a deficit in gamma regulation is a common symptom of neurologic and psychiatric disorders. Accumulating evidence has suggested that gamma oscillations result from the synchronized activity of cell assemblies coordinated mainly by parvalbumin-positive inhibitory interneurons. The modulator molecules for parvalbumin-positive interneurons are major research targets and have the potential to control the specific oscillatory rhythm and behavior originating from neural coordination. Neuregulin-1 and brain-derived neurotrophic factor have been focused on as synaptic trophic factors that are associated with gamma oscillations. Synaptic activity converts precursor trophic factors into their biologically active forms by proteolytic cleavage, which could, in turn, modulate cell excitability and synaptic plasticity through each receptor's signaling. From these findings, the processing of trophic factors by proteases in a synaptic microenvironment might involve gamma oscillations during cognition. Here, we review the trophic modulation of gamma oscillations through extracellular proteolysis and its implications in neuronal diseases. PMID- 29233653 TI - Design, synthesis and structure-activity relationship evaluation of novel LpxC inhibitors as Gram-negative antibacterial agents. AB - LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To develop novel LpxC inhibitors with good antibacterial activities and biological metabolism, we summarized the basic skeleton of reported LpxC inhibitors, designed and synthesized several series of compounds and tested their antibacterial activities against Escherichial coli and Pseudomonas aeruginosa in vitro. Structure-activity relationships have been discussed in this article. The metabolism stability of YDL-2, YDL-5, YDL-8, YDL-14, YDL-20-YDL-23 have been evaluated in liver microsomes, which indicated that the 2-amino isopropyl group may be a preferred structure than the 2-hydroxy ethyl group in the design of LpxC inhibitors. PMID- 29233655 TI - Recombinant human erythropoietin protects against brain injury through blunting the mTORC1 pathway in the developing brains of rats with seizures. AB - AIMS: Recurrent seizures can result in neuronal death, cognitive deficits and intellectual disability, which causes devastating damage in children. Recombinant human erythropoietin (rhEPO) is considered a neuroprotective factor in many nervous system diseases. However, the precise mechanisms through which rhEPO exerts its neuroprotective effects on epilepsy remain unknown. Thus, in this study, we determined whether rhEPO protects against brain injury by inducing cortical neuronal autophagy through blunting the mammalian target of rapamycin complex 1 (mTORC1) pathway in the developing brains of rats with seizures. MAIN METHODS: We used kainic acid to induce recurrent seizures in rats. Nissl staining and TUNEL analysis were used to evaluate the neuronal damage and apoptotic cells. Western blot analysis was employed to evaluate the phospho-mammalian target of rapamycin (p-mTOR)/mTOR protein ratio, the phospho-ribosomal protein S6 (S6)/S6 protein ratio, the microtubule-associated protein light chain 3 (LC3) II/I protein ratio and sequestosome 1 (P62/SQSTM1) protein expression levels. KEY FINDINGS: rhEPO reversed the decrease in the number of Nissl-positive neurons and the increase in the number of apoptotic cells in the kainic acid group. Notably, rhEPO induced autophagy and inhibited the mTORC1 pathway to protect against brain injury in rats with seizures. Treating rats with rapamycin blocked the mTORC1 pathway and masked the abovementioned effects of rhEPO. SIGNIFICANCE: Based on these results, rhEPO protects against brain injury by activating autophagy through blunting the mTORC1 pathway in developing rats with seizures. PMID- 29233656 TI - The atypical protein kinase RIOK3 contributes to glioma cell proliferation/survival, migration/invasion and the AKT/mTOR signaling pathway. AB - The RIO (right open reading frame) protein kinases include RIOK1, RIOK2 and RIOK3. Emerging evidence has suggested an important role of RIO kinases in cancer cell proliferation, apoptosis, migration and invasion. However, the expression profile and specific roles of RIOK3 are largely unknown during glioma progression. In the current study, quantitative real-time PCR, Western blot, and immunohistochemical analysis showed that RIOK3 was upregulated in glioma tissues. Available database analysis revealed that higher levels of RIOK3 were associated with poorer survival outcome in glioma patients. Flow cytometry, CCK8 and EdU assays showed that downregulation of RIOK3 arrested cell cycle progression and inhibited glioma cell proliferation. Wound healing, transwell and gelatin zymography assays revealed that silencing RIOK3 decreased glioma cell migration and invasion. Furthermore, the downregulation of RIOK3 significantly decreased the activity of AKT/mTOR signaling and induced apoptosis in glioma cells. Overexpression of RIOK3 showed the opposite effects on glioma cell proliferation, migration, invasion and the AKT/mTOR pathway. These results indicate that high RIOK3 levels in gliomas appear to contribute to the growth and expansion of this cancer, and may thus serve as a novel therapeutic target. PMID- 29233658 TI - Between and within laboratory reliability of mouse behaviour recorded in home cage and open-field. AB - BACKGROUND: Reproducibility of behavioural findings between laboratories is difficult due to behaviour being sensitive to environmental factors and interactions with genetics. The objective of this study was to investigate reproducibility of behavioural data between laboratories using the PhenoTyper home cage observation system and within laboratory reproducibility using different lighting regimes. NEW METHOD: The ambulatory activity of C57BL/6 and DBA/2 mice was tested in PhenoTypers in two laboratories under near identical housing and testing conditions (Exp. 1). Additionally activity and anxiety were also assessed in the open-field test. Furthermore, testing in either a normal or inverted light/dark cycle was used to determine effects of lighting regime in a within-laboratory comparison in Aberdeen (Exp. 2). RESULTS: Using the PhenoTyper similar circadian rhythms were observed across laboratories. Higher levels of baseline and novelty-induced activity were evident in Aberdeen compared to Utrecht although strain differences were consistent between laboratories. Open field activity was also similar across laboratories whereas strain differences in anxiety were different. Within laboratory analysis of different lighting regimes revealed that behaviour of the mice was sensitive to changes in lighting. COMPARISON WITH EXISTING METHODS: Utilisation of a home cage observation system facilitates the reproducibility of activity but not anxiety-related behaviours across laboratories by eliminating environmental factors known to influence reproducibility in standard behavioural tests. CONCLUSIONS: Standardisation of housing/test conditions resulted in reproducibility of home cage and open field activity but not anxiety-related phenotypes across laboratories with some behaviours more sensitive to environmental factors. Environmental factors include lighting and time of day. PMID- 29233657 TI - PCB95 and PCB153 change dopamine levels and turn-over in PC12 cells. AB - Polychlorinated biphenyls (PCB) exposure at low chronic levels is a significant public health concern. Animal and epidemiological studies indicate that low PCB body burden may cause neurotoxicity and be a risk factor for neurodegenerative diseases. In the current study, we measured the ability of two non-dioxin like PCBs, 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153) and 2,2'3,5',6 pentachlorobiphenyl (PCB95), to alter dopamine (DA) levels and metabolism using the dopaminergic PC12 cell line. Our hypothesis is that treatment of PC12 cells with non-toxic concentrations of PCB153 or PCB95 for 12 and 24 h will have different effects due to different congener structures. Levels of DA and of 3,4 dihydroxyphenylacetaldehyde (DOPAL), 3, 4-dihyroxylphenylethanol (DOPET), and 3,4 dihyroxylphenylacetic acid (DOPAC) metabolite, gene expression of the dopamine synthesis enzyme tyrosine hydroxylase (TH) and the vesicular monoamine transporter (VMAT2), and gene expression of the anti-oxidant enzymes Cu/Zn and Mn superoxide oxidase (Cu/ZnSOD, MnSOD), glutathione peroxidase (GPx) and catalase were determined. PCB153 decreased intracellular and extracellular levels of DA after 12 h exposure and this was consistent with an increase in DA metabolites. After 24 h, the level of DA in medium increased compared to the control. In contrast, PCB95 exposure increased the intracellular DA level and decreased DA in medium consistent with a down-regulation of VMAT2 expression at 12 h. After 24 h exposure, PCB95 increased DA levels in media. Expression of TH mRNA increased slightly following 12 h but not at 24 h exposure. MnSOD mRNA increased up to 6-7 fold and Cu/ZnSOD increased less than two-fold after treatment with both congeners. Catalase expression was up-regulated following 24 h exposure to PCB153 and PCB95, but GPx expression was down-regulated after 12 h exposure to PCB95 only. These results suggest that PCB153 and PCB95 are neurotoxic and affect DA turnover with structure-dependent differences between these two congeners. PMID- 29233659 TI - Klotho upregulation contributes to the neuroprotection of ligustilide against cerebral ischemic injury in mice. AB - Klotho, an aging-suppressor gene, encodes a protein that potentially acts as a neuroprotective factor. Our previous studies showed that ligustilide minimizes the cognitive dysfunction and brain damage induced by cerebral ischemia; however, the underlying mechanisms remain unclear. This study aims to investigate whether klotho is involved in the protective effects of ligustilide against cerebral ischemic injury in mice. Cerebral ischemia was induced by bilateral common carotid arterial occlusion. Neurobehavioral tests as well as Nissl and Fluoro Jade B staining were used to evaluate the protective effects of ligustilide in cerebral ischemia, and Western blotting and ELISA approaches were used to investigate the underlying mechanisms. Administration of ligustilide prevented the development of neurological deficits and reduced neuronal loss in the hippocampal CA1 region and the caudate putamen after cerebral ischemia. The protective effects were associated with inhibition of the RIG-I/NF-kappaB p65 and Akt/FoxO1 pathways and with prevention of inflammation and oxidative stress in the brain. Further, downregulation of klotho could attenuate the neuroprotection of ligustilide against cerebral ischemic injury. Ligustilide exerted neuroprotective effects in mice after cerebral ischemia by regulating anti inflammatory and anti-oxidant signaling pathways. Furthermore, klotho upregulation contributes to the neuroprotection of LIG against cerebral ischemic injury. These results indicated that ligustilide may be a promising therapeutic agent for the treatment of cerebral ischemia. PMID- 29233660 TI - Negative inotropic effects of diadenosine tetraphosphate are mediated by protein kinase C and phosphodiesterases stimulation in the rat heart. AB - Extracellular diadenosine polyphosphates (ApnA) are recently considered as an endogenous signaling compounds with transmitter-like activity which present in numerous tissues, including heart. It has been demonstrated previously that extracellular ApnA cause alteration of the heart functioning via purine receptors in different mammalian species. Nevertheless, principal intracellular pathways which underlie ApnA action in the heart remain unknown. In the present study the role of the P2Y-associated intracellular regulatory pathway in the mediation of diadenosine tetraphosphate (Ap4A) effects in the rat heart has been investigated for the first time. Extracellular Ap4A caused significant decreasing of the ventricular inotropy. Ap4A evoked reduction of the left ventricle contractility in the isolated Langendorff-perfused rat hearts, decreasing of the Ca2+ transients in the enzymatically isolated ventricular cardiomyocytes and induced shortening of action potentials in the ventricle multicellular preparations. The inhibitory effects of Ap4A in the rat heart were significantly attenuated by protein kinase C (PKC) inhibitor chelerythrine but these effects were not affected by NO-synthase inhibitor L-NAME and guanylyl cyclase (sGC) inhibitor ODQ. In addition, substantial attenuation of Ap4A-caused negative inotropy in the left ventricle was produced by nonselective phsophodiesterase (PDE) inhibitor IBMX, while PDE type 2 inhibitor EHNA was ineffective. In conclusion, our results allow suggesting that Ap4A-induced inhibitory effects in the rat heart are mediated by PKC, but not by NO/sGC/PKG-related signaling pathway. In addition, PDE stimulation may contribute to Ap4A-caused inhibition of the rat heart contractility. PMID- 29233662 TI - Reply to Jae Hung Jung, Julia L. Han, and Philipp Dahm's Letter to the Editor re: Vasileios I. Sakalis, Markos Karavitakis, Dina Bedretdinova, et al. Medical Treatment of Nocturia in Men with Lower Urinary Tract Symptoms: Systematic Review by the European Association of Urology Guidelines Panel for Male Lower Urinary Tract Symptoms. Eur Urol 2017;72:757-69. PMID- 29233661 TI - Hypoglycemic mechanism of a novel proteoglycan, extracted from Ganoderma lucidum, in hepatocytes. AB - Protein tyrosine phosphatase 1 B (PTP1B) is one of main causes involved in type 2 diabetes, it dephosphorylates insulin receptor substrate (IRS) and dysregulates insulin signaling pathway, thus inducing insulin resistance. Our previous work first reported that FYGL, a neutral hyperbranched proteoglycan ingredient extracted from Ganoderma lucidum, has hypoglycemic activity in vivo and inhibitory potency on PTP1B in vitro, but the underlying mechanism was still unclear. In this study, we sought to investigate effects of FYGL on insulin signaling pathway involved with PTP1B as the targeting point in hepatocytes. We found that FYGL inhibited overexpression of PTP1B in liver tissues of ob/ob mice and HepG2 cells, significantly improved the phosphorylation of IRS1 on tyrosine residues, activated phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) cascades and increased phosphorylation of glycogen synthesis kinase-3beta (GSK3beta), finally enhanced insulin-stimulated glycogen synthesis in HepG2 cells and decreased blood glucose in insulin resistance model mice. Our study clearly illustrated the hypoglycemic mechanism of a novel proteoglycan possibly used in type 2 diabetes management in vivo. PMID- 29233663 TI - Re: Christopher J.D. Wallis, Zachary Klaassen, Bimal Bhindi, et al. Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naive Prostate Cancer: A Systematic Review and Network Meta-analysis. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2017.10.002. PMID- 29233664 TI - Performance of a Prostate Cancer Genomic Classifier in Predicting Metastasis in Men with Prostate-specific Antigen Persistence Postprostatectomy. AB - BACKGROUND: Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. OBJECTIVE: To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n=150) or undetectable (n=327) based on post-RP PSA nadir >=0.1 ng/ml. OUTCOME MEASUREMENTS AND STATISITICAL ANALYSIS: Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. RESULTS AND LIMITATIONS: The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02-19.41, p=0.001), detectable PSA (HR: 4.26, 95% CI: 1.16-21.8, p=0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46-70.7, p=0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p<0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48-22.7, p=0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. CONCLUSIONS: Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. PATIENT SUMMARY: Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy. PMID- 29233665 TI - Eccentric hamstring strength deficit and poor hamstring-to-quadriceps ratio are risk factors for hamstring strain injury in football: A prospective study of 146 professional players. AB - OBJECTIVES: The purpose of this study was to investigate whether preseason isokinetic strength measures were predictive of future HSI among professional football players. DESIGN: Prospective cohort study, Level of evidence 2. METHODS: A total of 169 professional players participated in a preseason isokinetic strength screening, followed by a 10-month competitive season. Testing protocol included the concentric performance of both knee flexion and extension at 60degs 1 and 240degs-1 and the eccentric performance of the knee flexor at 30degs-1. Strength deficits, bilateral differences, and hamstring to quadriceps strength ratios were computed. Univariate and multivariate logistic regressions were used to identify potential risk factors of HSI. Receiver operating characteristic (ROC) curves were used to investigate the sensitivity and specificity of the strength measures. RESULTS: Forty-one acute HSIs were sustained, and 12% (n=5) reoccurred within the study period. In the multivariate analysis, we have shown an association between the injury risk and eccentric hamstring peak torque below 2.4Nmkg-1 (OR=5.59; 95% CI, 2.20-12.92); concentric H/Q ratio below 50.5% (OR=3.14; 95% CI, 1.37-2.22); players with previous injury of HSI (OR=3.57; 95% CI, 3.13-8.62). ROC analysis displayed an area under curve (AUC) of 0.77, indicating fair combined sensitivity and specificity of the overall predicting model. CONCLUSIONS: Professional football players with significant lower isokinetic hamstring strength, lower hamstring-to-quadriceps strength ratio, and a previous injury of HSI were linked to an increased risk of acute HSI. PMID- 29233666 TI - EMG amplitude, fatigue threshold, and time to task failure: A meta-analysis. AB - OBJECTIVES: Electromyographic (EMG) fatigue threshold (EMGFT) is utilised as a correlate of critical power, torque, and force thresholds that establishes a theoretical exercise intensity-the power, torque, or force at which the rate of change of EMG amplitude (DeltaEM-G) is zero-below which neuromuscular fatigue is negligible and unpredictable. Recent studies demonstrating neuromuscular fatigue below critical thresholds raise questions about the construct validity of EMGFT. The purpose of this analysis is to evaluate the construct validity of EMGFT by aggregating DeltaEM-G and time to task failure (Tlim) data. DESIGN: Meta analysis. METHODS: Database search of MEDLINE, SPORTDiscus, Web of Science, and Cochrane (inception - September 2016) conducted using terms relevant to EMG and muscle fatigue. Inclusion criteria were studies reporting agonist muscle EMG amplitude data during constant force voluntary isometric contractions taken to task failure. Linear and nonlinear regression models were used to relate DeltaEM G and Tlim data extracted from included studies. RESULTS: Regression analyses included data from 837 healthy adults from 43 studies. Relationships between DeltaEM-G and Tlim were strong in both nonlinear (R2=0.65) and linear (R2=0.82) models. DeltaEM-G at EMGFT was significantly nonzero overall and in 3 of 5 cohorts in the nonlinear model (p<0.01) and in 2 of 5 cohorts in the linear model. CONCLUSIONS: EMGFT lacks face validity as currently calculated; models for more precise EMGFT calculation are proposed. A new framework for prediction of task failure using EMG amplitude data alone is presented. The DeltaEM-G vs. Tlim relationship remains consistent across sexes and force vs. position tasks. PMID- 29233667 TI - Knee confidence in youth and young adults at risk of post-traumatic osteoarthritis 3-10 years following intra-articular knee injury. AB - OBJECTIVES: To examine differences in knee confidence between individuals with a history of youth sport-related knee injury and uninjured controls. DESIGN: Historical cohort study. METHODS: Participants include 100 individuals who sustained a youth sport-related intra-articular knee injury 3-10 years previously and 100 age-, sex- and sport-matched uninjured controls. Outcomes included: Knee confidence (Knee Osteoarthritis and Outcome Score); fat mass index (FMI; dual energy X-ray absorptiometry); and weekly physical activity (modified Godin Shephard Leisure Time Questionnaire). Mean within-pair differences (95% CI) were calculated for all outcomes. Unadjusted and adjusted (FMI and physical activity) conditional (matched-design) logistic regression (OR 95% CI) examined the association between injury history and knee confidence. RESULTS: Median age of participants was 22 years (range 15-26) and median age at injury was 16 years (range 9-18). Forty-nine percent (95% CI; 39.0, 59.0) of previously injured participants were bothered by knee confidence, compared to 12% (5.5, 18.5) of uninjured participants. Although there was no between group difference in physical activity, injured participants had higher FMI compared to controls (within-pair difference; (95% CI): 1.05kg/m2; (0.53, 1.57)). Logistic regression revealed that injured participants had 5.0 (unadjusted OR; 95% CI; 2.4, 10.2) and 7.5 times (adjusted OR; 95% CI: 2.7, 21.1) greater odds of being bothered by knee confidence than controls. CONCLUSIONS: Knee confidence differs between individuals with a previous youth sport-related knee injury and healthy controls. Knee confidence may be an important consideration for evaluating osteoarthritis risk after knee injury and developing secondary prevention strategies. PMID- 29233668 TI - Expression of HMGB1 in maternal exposure to fine particulate air pollution induces lung injury in rat offspring assessed with micro-CT. AB - OBJECTIVES: Maternal particulate matter with less than 2.5 MUm in diameter (PM2.5) is associated with an increased risk for acute lower respiratory infections and allergic airway inflammation; however, its effect on the developing lung remains unclear. The aim of this study is to determine the effect of maternal PM2.5 during pregnancy on lung development in offspring. METHODS: Timed pregnant Sprague-Dawley rats were treated with PM2.5 (0.1, 0.5, 2.5, or 7.5 mg/kg) once every 3 days from day 0-18 of pregnancy and delivered at term. Lungs were obtained on postnatal day 0, the structure of the lung was analyzed by quantitative micro-computed tomography (CT) and the levels of proinflammatory cytokines were analyzed using enzyme-linked immunosorbent assay (ELISA). The expression of high mobility group box-1 (HMGB1) was also detected by immunohistochemistry, Western blotting, and quantitative RT-PCR. RESULTS: Ground glass opacity and high-density volumes in CT slice images of maternal PM2.5 exposure rats were observed. The concentrations of IL-1, IL-6 and TNF-alpha were significantly increased by 2.36-, 3.91- and 4.36-fold, respectively, in the rats of the PM-7.5 group compared with the rats in the control group. The PM2.5 treated rats showed a significant upregulated expression of HMGB1 in lungs. CONCLUSIONS: PM2.5 exposure during pregnancy results in lung inflammation in offspring mediated by increased HMGB1 expression, followed by upregulated IL-1, IL-6 and TNF-alpha secretions, which may contribute to the development of inflammatory lung diseases in later life. PMID- 29233669 TI - Using voice to create hospital progress notes: Description of a mobile application and supporting system integrated with a commercial electronic health record. AB - We describe the development and design of a smartphone app-based system to create inpatient progress notes using voice, commercial automatic speech recognition software, with text processing to recognize spoken voice commands and format the note, and integration with a commercial EHR. This new system fits hospital rounding workflow and was used to support a randomized clinical trial testing whether use of voice to create notes improves timeliness of note availability, note quality, and physician satisfaction with the note creation process. The system was used to create 709 notes which were placed in the corresponding patient's EHR record. The median time from pressing the Send button to appearance of the formatted note in the Inbox was 8.8 min. It was generally very reliable, accepted by physician users, and secure. This approach provides an alternative to use of keyboard and templates to create progress notes and may appeal to physicians who prefer voice to typing. PMID- 29233670 TI - Safety and efficacy of lumen-apposing metal stents with and without simultaneous double-pigtail plastic stents for draining pancreatic pseudocyst. AB - BACKGROUND AND AIMS: Lumen-apposing metal stents (LAMSs) are used to perform necrosectomy in walled-off necrosis (WON). Although necrosectomy is not required for pancreatic pseudocyst (PP), an increasing number of PPs are also being drained with LAMSs in view of their ease of deployment. The aim of the present study was to evaluate the safety and efficacy of using LAMSs to drain PPs. METHODS: At 1 tertiary center from January 2014 to May 2016, all consecutive patients with PPs were drained by LAMSs, and the data were retrospectively reviewed. After observing cyst-cavity infection in patients enrolled initially (group I), 10F double-pigtail stents (DPSs) were placed across LAMSs in the subsequent patients (group II). Data on technical success, PP resolution, adverse events, and reintervention rates were collected. RESULTS: Forty-seven patients with PPs (mean size, 9.5 +/- 4.0 cm) were enrolled (group I, 24; group II, 23). There was 1 perforation at deployment (technical success, 98%). In the remaining 46 patients, resolution of the PP was observed in 44 patients (96%). Four patients (17%) in group I presented with PP infection requiring reinterventions. Food material was observed in the cyst cavity. None of the patients in group II had PP infection (relative risk, .84; 95% confidence interval, .71-1.0; P = .054). CONCLUSIONS: Similar to WON, LAMSs are also effective in endoscopic drainage of PPs. However, there was a trend toward higher PP infection with LAMSs, and placing a DPS across the LAMS minimized this risk. PMID- 29233671 TI - Endoscopic detection rate of sessile serrated lesions in Lynch syndrome patients is comparable with an age- and gender-matched control population: case-control study with expert pathology review. AB - BACKGROUND AND AIMS: Carcinogenesis in Lynch syndrome involves fast progression of adenomas to colorectal cancer (CRC) because of microsatellite instability. The role of sessile serrated lesions (SSLs) and the serrated neoplasia pathway in these patients is unknown. The aim of this matched case-control study was to compare endoscopic detection rates and distribution of SSLs in Lynch syndrome patients with a matched control population. METHODS: We collected data of Lynch syndrome patients with a proven germline mutation who underwent colonoscopy between January 2011 and April 2016 in 2 tertiary referral hospitals. Control subjects undergoing elective colonoscopy from 2011 and onward for symptoms or surveillance were selected from a prospectively collected database. Patients were matched 1:1 for age, gender, and index versus surveillance colonoscopy. An expert pathology review of serrated polyps was performed. The primary outcomes included the detection rates and distribution of SSLs. RESULTS: We identified 321 patients with Lynch syndrome who underwent at least 1 colonoscopy. Of these, 223 Lynch syndrome patients (mean age, 49.3; 59% women; index colonoscopy, 56%) were matched to 223 control subjects. SSLs were detected in 7.6% (95% confidence interval, 4.8-11.9) of colonoscopies performed in Lynch syndrome patients and in 6.7% (95% confidence interval, 4.1-10.8) of control subjects (P = .86). None of the detected SSLs in Lynch syndrome patients contained dysplasia. CONCLUSIONS: The detection rate of SSLs in Lynch syndrome patients undergoing colonoscopy is comparable with a matched population. These findings suggest that the role of the serrated neoplasia pathway in CRC development in Lynch syndrome seems to be comparable with that in the general population. PMID- 29233672 TI - Time latencies of Helicobacter pylori eradication after peptic ulcer and risk of recurrent ulcer, ulcer adverse events, and gastric cancer: a population-based cohort study. AB - BACKGROUND AND AIMS: Helicobacter pylori is associated with peptic ulcer disease and gastric cancer. Therefore we wanted to test how various lengths of delays in H pylori eradication therapy influence the risk of recurrent peptic ulcer, ulcer adverse events, and gastric cancer. METHODS: This population-based nationwide Swedish cohort study included 29,032 patients receiving H pylori eradication therapy after peptic ulcer disease in 2005 to 2013. Predefined time intervals between date of peptic ulcer diagnosis and date of eradication therapy were analyzed in relation to study outcomes. Cox regression provided hazard ratios (HRs) and 95% confidence intervals (95% CIs), adjusted for age, sex, comorbidity, history of ulcer disease, use of ulcerogenic drugs, and use of proton pump inhibitors (PPIs). RESULTS: Compared with eradication therapy within 7 days of peptic ulcer diagnosis, eradication therapy within 8 to 30, 31 to 60, 61 to 365, and >365 days corresponded with HRs of recurrent ulcer of 1.17 (95% CI, 1.08 1.25), 2.37 (95% CI, 2.16-2.59), 2.96 (95% CI, 2.76-3.16), and 3.55 (95% CI, 3.33 3.79), respectively. The corresponding HRs for complicated ulcer were 1.55 (95% CI, 1.35-1.78), 3.19 (95% CI, 2.69-3.78), 4.00 (95% CI, 3.51-4.55), and 6.14, (95% CI, 5.47-6.89), respectively. For gastric cancer the corresponding HRs were .85 (95% CI, .32-2.23), 1.31 (95% CI, .31-5.54), 3.64 (95% CI, 1.55-8.56), and 4.71 (95% CI, 2.36-9.38), respectively. CONCLUSIONS: Delays in H pylori eradication therapy after peptic ulcer diagnosis time-dependently increase the risk of recurrent ulcer, even more so for complicated ulcer, starting from delays of 8 to 30 days. PMID- 29233674 TI - Exploring the relationship between frontal asymmetry and emotional dampening. AB - Cardiovascular emotional dampening is the term used to describe the inverse relationship between resting blood pressure and emotional responsivity which extends from normotensive to hypertensive ranges. Little is known about its underlying physiological mechanisms, but it is thought to involve some disruption in emotion processing. One area that has yet to be explored in the literature is the relationship between emotional dampening and frontal asymmetry, a psychophysiological indicator for motivational direction and emotional valence bias. The present study explored that relationship using data from a sample of 48 healthy college students. Measures of baseline resting blood pressure and frontal cortical activity were recorded, after which participants completed a series of emotion-related tasks. Results revealed a significant relationship between resting systolic blood pressure and left frontal activity. Likewise, left frontal activity was associated with neutral appraisal of emotionally valenced stimuli within the tasks. The findings from the present study yield support for a link between emotional dampening and left frontal activity. Implications are discussed. PMID- 29233675 TI - Mutation in populations governed by a Galton-Watson branching process. AB - A population genetics model based on a multitype branching process, or equivalently a Galton-Watson branching process for multiple alleles, is presented. The diffusion limit forward Kolmogorov equation is derived for the case of neutral mutations. The asymptotic stationary solution is obtained and has the property that the extant population partitions into subpopulations whose relative sizes are determined by mutation rates. An approximate time-dependent solution is obtained in the limit of low mutation rates. This solution has the property that the system undergoes a rapid transition from a drift-dominated phase to a mutation-dominated phase in which the distribution collapses onto the asymptotic stationary distribution. The changeover point of the transition is determined by the per-generation growth factor and mutation rate. The approximate solution is confirmed using numerical simulations. PMID- 29233673 TI - Conventional versus traction-assisted endoscopic submucosal dissection for gastric neoplasms: a multicenter, randomized controlled trial (with video). AB - BACKGROUND AND AIMS: The aim of this study was to clarify whether dental floss clip (DFC) traction improves the technical outcomes of endoscopic submucosal dissection (ESD). METHODS: A superiority, randomized control trial was conducted at 14 institutions across Japan. Patients with single gastric neoplasm meeting the indications of the Japanese guidelines for gastric treatment were enrolled and assigned to receive conventional ESD or DFC traction-assisted ESD (DFC-ESD). Randomization was performed according to a computer-generated random sequence with stratification by institution, tumor location, tumor size, and operator experience. The primary endpoint was ESD procedure time, defined as the time from the start of the submucosal injection to the end of the tumor removal procedure. RESULTS: Between July 2015 and September 2016, 640 patients underwent randomization. Of these, 316 patients who underwent conventional ESD and 319 patients who underwent DFC-ESD were included in our analysis. The mean ESD procedure time was 60.7 and 58.1 minutes for conventional ESD and DFC-ESD, respectively (P = .45). Perforation was less frequent in the DFC-ESD group (2.2% vs .3%, P = .04). For lesions located in the greater curvature of the upper or middle stomach, the mean procedure time was significantly shorter in the DFC-ESD group (104.1 vs 57.2 minutes, P = .01). CONCLUSIONS: Our findings suggest that DFC-ESD does not result in shorter procedure time in the overall patient population, but it can reduce the risk of perforation. When selectively applied to lesions located in the greater curvature of the upper or middle stomach, DFC ESD provides a remarkable reduction in procedure time. PMID- 29233676 TI - Targeting epigenome with dietary nutrients in cancer: Current advances and future challenges. AB - Tumorigenesis and epigenetic are closely linked with each other. Epigenetic changes are potential regulators of gene expression without involving any change in the DNA itself. More interestingly, epigenetic changes are reversible heritable changes which pass through generations. Many dietary bioactive ingredients regulate epigenetic control of cells and influence biochemical processes. Correlation between epigenetic regulation and cancer onset has been well established. Recent studies provide important information on the role of bioactive dietary components in cancer prevention and therapy. Several bioactive components are responsible for modification of the epigenome by affecting DNA methylation, histone modification, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs). This review summarizes recent advancements in this field and describes the role of many bioactive components in regulating human epigenome and how these modifications can be exploited for prevention and treatment of cancer. PMID- 29233678 TI - Detection of simultaneous multi-mutations using base-quenched probe. AB - The base-quenched probe method for detecting single nucleotide polymorphisms (SNPs) relies on real-time PCR and melting-curve approaches. Here, we applied the most common commercial fluorophores including FAM, HEX, CY5, CY3, TET, JOE, Texas Red and ROX for labeling probes to detect multi-mutations simultaneously according to the different fluorescence channels. Accuracy of the method was confirmed by direct sequencing. The results demonstrated that all above dyes could be influenced by bases and could be applied to detect SNPs. Furthermore, this method was applied to detect APOM rs707921, APOM rs707922 and MCP-1 rs1024611 simultaneously, which was demonstrated successfully. PMID- 29233677 TI - Alzheimer's disease and gut microbiota modifications: The long way between preclinical studies and clinical evidence. AB - Recent studies have suggested the role of an infectious component in the pathogenesis of Alzheimer's disease (AD). In light of this, research has focused on some bacteria constituting the intestinal microbial flora which can produce amyloid. Once generated, the latter hypothetically triggers a systemic inflammatory response which compromises complex brain functions, such as learning and memory. Clinical studies have shown that, in cognitively impaired elderly patients with brain amyloidosis, there is lower abundance in the gut of E. rectale and B. fragilis, two bacterial species which have an anti-inflammatory activity, versus a greater amount of pro-inflammatory genera such as Escherichia/Shigella. According to these findings, some clinical studies have demonstrated that supplementation with Lactobacilli- and Bifidobacteria- based probiotics has improved cognitive, sensory and emotional functions in subjects with AD. Moreover, certain herbal products, in particular dietetic polyphenols, have proved capable of restoring dysbiosis and, therefore, their prebiotic role could be effective in counteracting the onset of AD regardless of their activity of free radical scavenging or enhancement of the cell stress response. One of the recent greatest novelties in the field of neurodegenerative diseases is the chance to prevent or slow down AD progression with agents, such as probiotics and prebiotics, acting outside the central nervous system. PMID- 29233679 TI - Graphene paper supported MoS2 nanocrystals monolayer with Cu submicron-buds: High performance flexible platform for sensing in sweat. AB - Flexible sweat biosensors are of considerable current interest for the development of wearable smart miniature devices. In this work, we report a novel type of flexible and electrochemical sweat platform fabricated by depositing Cu submicron buds on freestanding graphene paper (GP) carrying MoS2 nanocrystals monolayer for bio-functional detection of glucose and lactate. Quantitative analysis of glucose and lactate was carried out by using amperometric i-t method. Linear ranges were obtained between 5 and 1775 MUM for glucose and 0.01-18.4 mM for lactate, and their corresponding limits of detection were 500 nM and 0.1 MUM, respectively. The platform demonstrates fast response, good selectivity, superb reproducibility and outstanding flexibility, which enable its use for monitoring glucose and lactate in human perspiration. The strategy of structurally integrating 3D transition metal, 0D transition metal sulfide and 2D graphene will provide new insight into the design of flexible electrodes for sweat glucose and lactate monitoring and a wider range of applications in biosensing, bioelectronics, and lab-on-a-chip devices. PMID- 29233680 TI - New Fpg probe chemistry for direct detection of recombinase polymerase amplification on lateral flow strips. AB - Rapid, cost-effective and sensitive detection of nucleic acids has the ability to improve upon current practices employed for pathogen detection in diagnosis of infectious disease and food testing. Furthermore, if assay complexity can be reduced, nucleic acid amplification tests could be deployed in resource-limited and home use scenarios. In this study, we developed a novel Fpg (Formamidopyrimidine DNA glycosylase) probe chemistry, which allows lateral flow detection of amplification in undiluted recombinase polymerase amplification (RPA) reactions. The prototype nucleic acid lateral flow chemistry was applied to a human genomic target (rs1207445), Campylobacter jejuni 16S rDNA and two genetic markers of the important food pathogen E. coli O157:H7. All four assays have an analytical sensitivity between 10 and 100 copies DNA per amplification. Furthermore, the assay is performed with fewer hands-on steps than using the current RPA Nfo lateral flow method as dilution of amplicon is not required for lateral flow analysis. Due to the simplicity of the workflow, we believe that the lateral flow chemistry for direct detection could be readily adapted to a cost effective single-use consumable, ideal for use in non-laboratory settings. PMID- 29233681 TI - Studies on the development of antibodies for the highly hydrophobic plasticizers DINCH and DEHT. AB - Diisononylcyclohexane-1,2-dicarboxylate (DINCH) and di-2-ethylhexyl terephthalate (DEHT), two of the most important substitutes for phthalate plasticizers, are used for a wide range of applications. Consequently, an increasing occurrence in urine and environmental samples is reported. Reliable and fast analytical methods for the quantification of these plasticizers are needed. So far, mainly GC-MS or LC-MS methods are used. We aimed to develop the first antibodies and immunoassays allowing for high-throughput analysis of samples. We designed two DINCH hapten structures and one DEHT hapten structure and employed hapten-protein conjugates for the immunization of rabbits. Sensitive competitive enzyme-linked immunosorbent assays (ELISAs) against each hapten using the produced polyclonal antibodies were established. Yet, binding of DINCH to the respective antibodies was not observed in neither direct nor indirect assay formats, even when using protein conjugates with the heterologous haptens and different carrier proteins in the indirect format. The use of surfactants and solvents in the sample buffer did not result in recognition of the plasticizers. Also, no binding of DEHT in ELISA employing the respective antibodies was detected. We speculate that the production of antibodies against these highly hydrophobic molecules is not possible via our route, however a different hapten design could overcome this obstacle. PMID- 29233683 TI - Caspase-mediated cleavage of X-ray repair cross-complementing group 4 promotes apoptosis by enhancing nuclear translocation of caspase-activated DNase. AB - X-ray repair cross-complementing group 4 (XRCC4), a repair protein for DNA double strand breaks, is cleaved by caspases during apoptosis. In this study, we examined the role of XRCC4 in apoptosis. Cell lines, derived from XRCC4-deficient M10 mouse lymphoma cells and stably expressing wild-type XRCC4 or caspase resistant XRCC4, were established and treated with staurosporine (STS) to induce apoptosis. In STS-induced apoptosis, expression of wild-type, but not caspase resistant, XRCC4 in XRCC4-deficient cells enhanced oligonucleosomal DNA fragmentation and the appearance of TUNEL-positive cells by promoting nuclear translocation of caspase-activated DNase (CAD), a major nuclease for oligonucleosomal DNA fragmentation. CAD activity is reportedly regulated by the ratio of two inhibitor of CAD (ICAD) splice variants, ICAD-L and ICAD-S mRNA, which, respectively, produce proteins with and without the ability to transport CAD into the nucleus. The XRCC4-dependent promotion of nuclear import of CAD in STS-treated cells was associated with reduction of ICAD-S mRNA and protein, and enhancement of phosphorylation and nuclear import of serine/arginine-rich splicing factor (SRSF) 1. These XRCC4-dependent, apoptosis-enhancing effects were canceled by depletion of SRSF1 or SR protein kinase (SRPK) 1. In addition, overexpression of SRSF1 in XRCC4-deficient cells restored the normal level of apoptosis, suggesting that SRSF1 functions downstream of XRCC4 in activating CAD. This XRCC4-dependent, SRPK1/SRSF1-mediated regulatory mechanism was conserved in apoptosis in Jurkat human leukemia cells triggered by STS, and by two widely used anti-cancer agents, Paclitaxel and Vincristine. These data imply that the level of XRCC4 expression could be used to predict the effects of apoptosis-inducing drugs in cancer treatment. PMID- 29233682 TI - Potential role of MG53 in the regulation of transforming-growth-factor-beta1 induced atrial fibrosis and vulnerability to atrial fibrillation. AB - Atrial fibrosis plays a critical role in atrial fibrillation (AF) by the transforming growth factor (TGF)-beta1/Smad pathway. The disordered differentiation, proliferation, migration and collagen deposition of atrial fibroblasts play significant roles in atrial fibrosis. Mitsugumin (MG)53 is predominantly expressed in myocardium of rodents and has multiple biological functions. However, the role of MG53 in cardiac fibrosis remains unclear. This study provided clinical and experimental evidence for the involvement of MG53 in atrial fibrosis in humans and atrial fibrosis phenotype in cultured rat atrial fibroblasts. In atrial tissue from patients we demonstrated that MG53 was expressed in human atrium. Expression of MG53 increased with the extent of atrial fibrosis, which could induce AF. In cultured atrial fibroblasts, depletion of MG53 by siRNA caused down-regulation of the TGF-beta1/Smad pathway, while overexpression of MG53 by adenovirus up-regulated the pathway. MG53 regulated the proliferation and migration of atrial fibroblasts. Besides, exogenous TGF-beta1 suppressed expression of MG53. In conclusion, we demonstrated that MG53 was expressed in human atrium, and may be a potential upstream of the TGF-beta1/Smad pathway in human atrium and rat atrial fibroblasts. This suggests that MG53 is a potential regulator of atrial fibrosis induced by the TGF-beta1/Smad pathway in patients with AF. PMID- 29233684 TI - mmu-miR-1963 negatively regulates the ameloblast differentiation of LS8 cell line by directly targeting Smoc2 3'UTR. AB - RUNX2 is a key regulator of osteogenic differentiation and odontoblastic differentiation. RUNX2 mutations could cause Cleidocranial dysplasia (CCD; OMIM119600), which is featured by abnormal development of bone and teeth. By using microRNA array, we identified a large number of microRNAs that showed different expression between wild-type Runx2 group and mutant groups. The aim of this study is to find out the effect of mmu-miR-1963, which was downregulated in all mutant Runx2 groups, on the ameloblast differentiation of LS8 cells. qPCR and Western Blot results showed the suppressive effect of mmu-miR-1963 on ameloblast differentiation of LS8 cell line. We further confirmed Smoc2 as one direct target of mmu-miR-1963. For the first time, we showed that mmu-miR-1963 could regulate the ameloblast differentiation of LS8 by targeting Smoc2. This study suggests the suppressive role of mmu-miR-1963 on ameloblast differentiation of LS8 via directly targeting the 3'UTR of Smoc2. We also demonstrated that Smoc2 itself could promote the ameloblast differentiation of LS8 for the first time. Our results indicate a novel explanation to the enamel hypoplasia phenotype in part of CCD patients. PMID- 29233685 TI - Contrast enhanced ultrasound in mixed hepatocellular cholangiocarcinoma: Case series and review of the literature. AB - BACKGROUND: Mixed hepatocellular cholangiocarcinoma is a rare form of primary liver cancer. AIMS: The aim of this study is to report the results of the use of contrast enhanced ultrasound in a series of patients with confirmed mixed hepatocellular cholangiocarcinoma and to provide an updated literature review. METHODS: Between January 2012 and October 2016, 25 Asian patients with confirmed mixed hepatocellular cholangiocarcinoma were included in this bicentric retrospective analysis. Clinical data as well recorded images of a standardized conventional B-mode ultrasound and contrast-enhanced ultrasound examination were interpreted by two blinded, independent, experienced radiologists in consensus. RESULTS: All mixed hepatocellular cholangiocarcinoma lesions were heteroechoic on B-mode ultrasound, with ill-defined margins and irregular shapes. Arterial phase hyperenhancement was present in all 25 patients. Late-phase washout and hypoenhancement was present in 24/25 (96%) patients. However, rim-enhancement and early wash-out (which are common in cholangiocellular carcinoma) were found in over 60% of the cases. CONCLUSION: Contrast-enhanced ultrasound demonstrated findings not typical for HCC in a large proportion of patients with confirmed mixed hepatocellular cholangiocarcinoma. Therefore, histological confirmation is crucial, especially in lesions with atypical findings. PMID- 29233686 TI - Exercise has the guts: How physical activity may positively modulate gut microbiota in chronic and immune-based diseases. AB - Limited animal and human research findings suggests that exercise might have a beneficial role for health gut. Cardiorespiratory fitness correlates with health associated gut parameters such as taxonomic diversity and richness. Physical exercise may augment intestinal microbial diversity through several mechanisms including promotion of an anti-inflammatory state. Disease-associated microbial functions were linked to distinct taxa in previous studies of familial type 1 diabetes mellitus (T1D). An integrated multi-approach in the study of T1D, including physical exercise, is advocated. The present review explores how exercise might modulate gut microbiota and microbiome characteristics in chronic and immune-based diseases, given the demonstrated relationship between gut function and human health. PMID- 29233687 TI - Interferon-free direct-acting antiviral therapy for acute hepatitis C virus infection in HIV-infected individuals: A literature review. AB - Dramatic rises in hepatitis C virus (HCV) coinfection rates in human immunodeficiency virus (HIV)-infected individuals have been observed recently, largely attributable to increasing recreational drug use combined with increased testing for HCV. In the era of direct-acting antiviral (DAA) therapy, treatment of acute HCV infection in HIV-infected individuals with short durations of these drugs may potentially reduce the disease and economic burden associated with HCV infection as well as reducing the likelihood of onward HCV transmission. We performed an extensive literature search of PubMed, Embase and Google Scholar up to 05 September 2017 for clinical trials of acute HCV infection in HIV-infected individuals. In the studies identified, rates of sustained virologic response at 12 weeks post-treatment (SVR12) ranged from 21% with 6 weeks of therapy up to 92% with 12 weeks of therapy with sofosbuvir and ribavirin. Ledipasvir/sofosbuvir for 6 weeks achieved an SVR of 77%. No HIV-related events occurred regardless of whether patients were receiving antiretroviral therapy (ART) and DAAs were well tolerated. Data is currently limited with regards to optimal regimens and durations of therapy, which need to be tailored based on potential interactions with concurrent ART and consideration for the fact that patients with higher baseline HCV RNA levels may require an extended duration of treatment. PMID- 29233688 TI - A preliminary investigation of the toxic effects of Benzylpenicilloic acid. AB - Benzylpenicilloic acid (BPNLA) is a major cleavage product of benzylpenicillin G (BP) generated after heating treatment. It is found in animal derived products from the unstable residual penicillin. Previous studies have only reported the allergic reaction caused by BPNLA, but not described its toxicity. In this study, the toxicity of BPNLA was evaluated to report the potential public health risk posed by animal derived products using in vivo and in vitro models, including the acute toxicity assays, cytotoxicity assays, apoptosis assays and cell cycle progression assay. The LD50 value for BPNLA was 8.48 g/kg [bw] intraperitoneally. BPNLA showed cytotoxicity and inhibition of cell proliferation on SK-N-SH cells, MRC-5 cells and GC-1 cells. Further, Annexin-v/PI staining and Hoechst 33342 staining showed increased cell apoptosis and nucleus morphological changes with toxic levels of BPNLA. BPNLA arrested cells in G1 phase and reduced cells population in S phase in a dose-dependent manner. This work suggests that BPNLA might be a potential toxic agent and might have public health significance. However, the toxic concentrations of BPNLA are relatively high compared to levels that would result from the degradation of antibiotics residues in meat from animals that have received a therapeutic dose of benzylpenicillin. PMID- 29233690 TI - A case of multiple myeloma presenting with diffuse osteosclerosis and multiple bone infarcts. PMID- 29233689 TI - In vitro toxicity evaluation of estragole-containing preparations derived from Foeniculum vulgare Mill. (fennel) on HepG2 cells. AB - Estragole, a common component of herbs and spices, is a wellknown genotoxic hepatocarcinogen in rodents, whereas its potential toxic effect in humans is still debated. In the European contest, one of the major sources of human exposure to this phytochemical is Foeniculum vulgare Mill. (fennel). Therefore, the aim of this study was to evaluate the in vitro toxicity of estragole in the context of two complex phytochemical mixtures derived from fennel: fennel seed powder (FSPw) and fennel seed essential oil (FSEO). The estragole-containing preparations were analysed for their ability to cause cytotoxicity, genotoxicity, apoptosis and cell cycle perturbation in the human hepatoma (HepG2) cell line. None of the tested concentrations of FSPw induced DNA damage, nor apoptosis or cell cycle perturbation. Although FSEO did not induce any genetic damage as well, it exerted marked dose-dependent apoptotic effects on HepG2 cells with a concurrent cell cycle arrest in G2/M at the highest tested dose. Although prospective analyses are required to clarify the observed toxic effects of FSEO, our results support the hypothesis that the genotoxicity of estragole may be significantly reduced or null in the context of botanical mixtures. PMID- 29233691 TI - Enthesopathy in rheumatoid arthritis and spondyloarthritis: An ultrasound study. AB - OBJECTIVE: We aimed to compare the prevalence of enthesopathy seen on ultrasonography (US) in spondyloarthritis (SpA) and rheumatoid arthritis (RA) and compared it to healthy controls. METHODS: All included patients with RA (2010 ACR/EULAR criteria) and SpA (ASAS criteria) and healthy controls underwent clinical and US evaluation of enthesis at seven sites (quadriceps, proximal and distal patellar, Achilles and triceps tendons, plantar aponeurosis and lateral epicondyle enthesis). The Glasgow Ultrasound Enthesitis Scoring System (GUESS) and the Madrid Sonographic Enthesitis Index (MASEI) scores were determined by two sonographers blinded to clinical data. RESULTS: We included 30 patients with RA (mean age: 55.7+/-14.8 years, mean disease duration 10.5+/-7.9years); 41 with SpA (mean age: 45.3+/-15.4 years, mean disease duration 9.2+/-8.7years) and 26 healthy controls (HC) (mean age: 50.4+/-17.3years). Patients with SpA and RA had similar prevalence of painful enthesis of examined sites (17% vs. 14%, non significant [ns]), but more than among in healthy controls (3%, P<0.05 for RA and SpA comparison). Comparison between SpA and RA patients revealed that at least one US enthesis abnormality was found with similar frequency (46% and 48% sites [ns]) but both rheumatic diseases had higher frequency of US enthesis abnormality than HC (31%, P<0.05 for RA and SpA comparison). The mean MASEI score was 8.5+/ 7.3 for RA patients, 7.8+/-6.5 for SpA patients (ns) and 3.4+/-2.8 for healthy controls (P<0.05 for RA and SpA comparison). Overall, 6 RA (20%) and 4 SpA (10%) patients had a MASEI score>=18 (ns). None of the healthy controls had a MASEI score>=18 (P<0.05 for RA and SpA comparison). The mean GUESS score was 5.8+/-3.1 and 6.3+/-3.9 for RA and SpA patients (ns), and 4.0+/-3.1 for healthy controls (P<0.01 vs. SpA and <0.05 vs. RA). CONCLUSIONS: RA and SpA patients did not differ in entheseal abnormalities seen on US. Such US features may have low specificity in inflammatory conditions affecting joints and enthesis such as SpA and RA. PMID- 29233692 TI - Epigenetic regulation of hibernation-associated HP-20 and HP-27 gene transcription in chipmunk liver. AB - The chipmunk hibernation-related proteins (HPs) HP-20 and HP-27 are components of a 140-kDa complex that dramatically decreases in the blood during hibernation. The HP-20 and HP-27 genes are expressed specifically in the liver and are downregulated in hibernating chipmunks. Hibernation-associated physiological changes are assumed to be under genetic control. Therefore, to elucidate the molecular mechanisms of hibernation, here we examined the mechanisms behind the altered HP-20 and HP-27 gene expression in nonhibernating versus hibernating chipmunks. Chromatin immunoprecipitation (ChIP) analyses revealed that histone H3 on the HP-20 and HP-27 gene promoters was highly acetylated at lysine (K) 9 and K14 and highly trimethylated at K4 in the liver of nonhibernating chipmunks, while these active histone modifications were nearly absent in hibernating chipmunks. Furthermore, histone acetyltransferases and a histone methyltransferase were associated with the HP-20 and HP-27 gene promoters primarily in nonhibernating chipmunks. Consistent with a previous finding that HNF-1 and USF can activate HP-20 and HP-27 gene transcription by binding to the proximal promoter region, ChIP-quantitative PCR (qPCR) analyses revealed that significantly less HNF-1 and USF were bound to these gene promoters in hibernating than in nonhibernating chipmunks. These findings collectively indicated that the hibernation-associated HP-20 and HP-27 gene expression is epigenetically regulated at the transcriptional level by the binding of HNF-1 and USF to their proximal promoters, and that histone modification has a key role in hibernation-associated transcriptional regulation. PMID- 29233693 TI - Thermostable DNA helicase improves the sensitivity of digital PCR. AB - DNA/RNA helicases, which catalyze the unwinding of duplex nucleic acids using the energy of ATP hydrolysis, contribute to various biological functions involving DNA or RNA. Euryarchaeota-specific helicase Tk-EshA (superfamily 2) from the hyperthermophilic archaeon Thermococcus kodakarensis has been used to decrease generation of mis-amplified products (noise DNAs) during PCR. In this study, we focused on another type (superfamily 1B) of helicase, Tk-Upf1 (TK0178) from T. kodakarensis, and compared its effectiveness in PCR and digital PCR with that of Tk-EshA. For this purpose, we obtained Tk-Upf1 as a recombinant protein and assessed its enzymatic characteristics. Among various double-stranded DNA (dsDNA) substrates (forked, 5' overhung, 3' overhung, and blunt-ended duplex), Tk-Upf1 had the highest unwinding activity toward 5' overhung DNAs. Noise DNAs were also eliminated in the presence of Tk-Upf1 at concentrations 10-fold lower than those required to yield a comparable reduction with Tk-EshA. When a 5' or 3' overhung mis-annealed primer was included as a competitive primer along with specific primers, noise DNAs derived from the mis-annealed primer were eliminated in the presence of Tk-Upf1. In digital PCR, addition of Tk-EshA or Tk-Upf1 increased fluorescent intensities and improved separation between common and risk allele clusters, indicating that both helicases functioned as signal enhancers. In comparison with Tk-EshA, a smaller amount of Tk-Upf1 was required to improve the performance of digital PCR. PMID- 29233694 TI - Insight of nitric oxide signaling: A potential biomarker with multifaceted complex mechanism in colorectal carcinogenesis. AB - Colorectal carcinogenesis (CRC) is the most important health concerns throughout the World as the tumour cells rapidly spread and abruptly grow in colon and rectum to further organs. Several etiological factors are associated with colorectal carcinogenesis. During invasion and proliferation of tumour cells, various mechanistic molecular pathways are involved in the cells. Nitric Oxide pathway (NO) is one of the important cellular mechanisms associated with tumour cells initiation, invasion and progression. Epidemiological evidences suggest that NO has potential role in development of cancer. The multidisciplinary action of NO on the initiation of cancer depends on several factors including cell type, metastasis stage, and organs involved. This review emphasizes the biological significance of NO in each step of cancer metastasis, its controversial effects for carcinogenesis including initiation, invasion and progression. PMID- 29233695 TI - Structural basis for substrate specificity of meso-diaminopimelic acid decarboxylase from Corynebacterium glutamicum. AB - l-lysine is an essential amino acid that is widely used as a food supplement for humans and animals. meso-Diaminopimelic acid decarboxylase (DAPDC) catalyzes the final step in the de novol-lysine biosynthetic pathway by converting meso diaminopimelic acid (meso-DAP) into l-lysine by decarboxylation reaction. To elucidate its molecular mechanisms, we determined the crystal structure of DAPDC from Corynebacterium glutamicum (CgDAPDC). The PLP cofactor is bound at the center of the barrel domain and forms a Schiff base with the catalytic Lys75 residue. We also determined the CgDAPDC structure in complex with both pyridoxal 5'-phosphate (PLP) and the l-lysine product and revealed that the protein has an optimal substrate binding pocket to accommodate meso-DAP as a substrate. Structural comparison of CgDAPDC with other amino acid decarboxylases with different substrate specificities revealed that the position of the alpha15 helix in CgDAPDC and the residues located on the helix are crucial for determining the substrate specificities of the amino acid decarboxylases. PMID- 29233696 TI - Molecular cloning and characterization of the glutathione reductase gene from Stipa purpurea. AB - Reactive oxygen species (ROS) are a key factor in abiotic stresses; excess ROS is harmful to plants. Glutathione reductase (GR) plays an important role in scavenging ROS in plants. Here, a GR gene, named SpGR, was cloned from Stipa purpurea and characterized. The full-length open reading frame was 1497 bp, encoding 498 amino acids. Subcellular localization analysis indicated that SpGR was localized to both the plasma membrane and nucleus. The expression of SpGR was induced by cold, salt, and drought stresses. Functional analysis indicated that ectopic expression of SpGR in Arabidopsis thaliana resulted in greater tolerance to salt stress than that of wild-type plants, but no difference under cold or drought treatments. The results of GR activity and GSSG and GSH content analyses suggested that, under salt stress, transgenic plants produced more GR to reduce GSSG to GSH for scavenging ROS than wild-type plants. Therefore, SpGR may be a candidate gene for plants to resist abiotic stress. PMID- 29233697 TI - Retrospective analysis of 471 surgically treated zygomaticomaxillary complex fractures. AB - PURPOSE: Zygomaticomaxillary complex (ZMC) fractures are frequent in facial trauma; only fractures of the mandible are more common. Although the frequency of these fractures is geographically consistent, the aetiology differs widely among countries and even regions. Differences in socio-economic status and the ageing population seem to be two causes. This retrospective epidemiological study evaluates patients who were surgically treated for ZMC fractures at a Swiss university clinic. MATERIALS AND METHODS: This study included 471 patients who were surgically treated for ZMC fractures in an oral and maxillofacial surgery clinic at a Swiss university hospital between January 2004 and December 2012. Complicated fractures such as LeFort II/III and bilateral ZMC fractures were excluded. Data on gender, age, and type of trauma were recorded. Fractures were classified by aetiology: motorised road traffic (car or motorcycle), bicycle, interpersonal violence, sports, falls (both less than and greater than 3 m in height) and other causes. RESULTS: A total of 350 patients were male (74%), and 121 were female (26%). The ZMC fractures were most likely to occur in the third decade (117 cases, 25%). A predominance of male patients was found in the young age groups, but an equal ratio was found in the elderly groups. Etiologically, falls of less than 3 m were the most common cause of ZMC fractures (125 cases, 27%). Interpersonal violence was second (88 patients, 19%); male patients dominated this group, which had a male-to-female ratio of 21:1. A predominance of male patients was found in every subdivision when analysing by aetiology and gender. The lowest proportion of males (57%) was found for falls of less than 3 m. CONCLUSION: In our study, interpersonal violence and falls outnumbered road traffic accidents among causes of maxillofacial fractures. This is probably a consequence of strict road and work laws. Additionally, the older and more active populations accounted for the highest proportion of falls, and young male patients were the predominant victims of ZMC fractures. PMID- 29233698 TI - Ex corpore linguae: A cohort analysis after a unique surgical technique in oral cancer resection. AB - OBJECTIVE: Resection of posteriorly located oral squamous cell carcinomas (OSCCs) remains challenging for head and neck surgeons. However, several surgical techniques, such as lip and mandibular splitting, as well as submental "visor drop-down" of intraoral soft tissues, have been proposed for this purpose. Merrick et al. suggested that a pedicled genial drop-down surgical approach should be used to resect dorsally located OSCCs. Our study investigated patient outcomes following this surgical procedure, as no previous study has analyzed long-term follow-up data. MATERIAL AND METHODS: All patients who underwent surgery using the pedicled genial "visor drop-down" approach at the Maxillofacial Department of the University Hospital Giessen in Germany between 1995 and 2010 were included in this study. In addition, our study required that patients diagnosed with OSCC had no history of other intraoral malignancy or any other form of malignancy. A preliminary questionnaire was completed for each patient based on retrospective analysis of available data from medical reports. RESULTS: A total of 51 patients fulfilled all inclusion and exclusion criteria and were evaluated retrospectively. In total, 32 patients were excluded from the study due to OSCC recurrence or acquisition of a different type of malignancy. The male to female distribution of patients in our study was 30 to 21 (58.8%-41.2%), and the mean ages of female and male patients were 57.7 (SD 14.3) and 55.7 (SD 14.4) years, respectively. Approximately 76.5% of tumors were located along the dorsal aspect of the tongue, 17.6% were along the floor of the mouth, 3.9% were in the dorsal mandibular region, and 1.9% were in the dorsal palatal region. The mean overall operation time was 6.25 h, and 28 patients received microvascular flaps for reconstruction. Results of final histopathological examination suggested primary in-sano resection of the tumor in 84.3% of patients. Overall, the 5-year postoperative survival rate was 52.9%; 31.3% of the patient cohort was not followed up for the full 5-year period. In addition, 15.7% of the patients included in our study died during the study period. Unimpaired functional outcomes in terms of swallowing and speech were observed in 86.3% of patients. CONCLUSION: The pedicled genial "visor drop-down" approach, also known as the ex corpore linguae, is a suitable method for the radical resection of dorsally located OSCCs, with a promising 5-year survival rate and satisfactory postoperative oral function. PMID- 29233699 TI - Comparative finite element analysis of skull mechanical properties following parietal bone graft harvesting in adults. AB - INTRODUCTION: Parietal bone grafts are commonly used in cranio-maxillo-facial surgery. Both the outer and the internal layer of the calvarium can be harvested. The bone defect created by this harvesting may induce significant weakening of the skull that has not been extensively evaluated. Our aim was to evaluate the consequences of parietal bone graft harvesting on mechanical properties of the skull using a finite element analysis. METHODS: Finite elements models of the skull of 3 adult patients were created from CT scans. Parietal external and internal layer harvest models were created. Frontal, lateral, and parietal loading were modeled and von Mises stress distributions were compared. RESULTS: The maximal von Mises stress was higher for models of bone harvesting, both on the whole skull and at the harvested site. Maximal von Mises stress was even higher for models with internal layer defect. CONCLUSIONS: Harvesting parietal bone modifies the skull's mechanical strength and can increase the risk of skull fracture, mainly on the harvested site. Outer layer parietal graft harvesting is indicated. Graft harvesting located in the upper part of the parietal bone, close to the sagittal suture and with smooth internal edges and corners should limit the risk of fracture. PMID- 29233700 TI - Volumetric analysis of keratocystic odontogenic tumors and non-neoplastic jaw cysts - Comparison and its clinical relevance. AB - The keratocystic odontogenic tumor (KCOT) is capable of causing vast osseous destruction. Histopathological examination is pivotal for diagnosis. The diagnostic process can sometimes be hindered by tissue inflammation of KCOTs with loss of defining criteria, resulting in misdiagnosis as an odontogenic jaw cyst. We discuss the possible merits of volumetric analysis when facing this particular diagnostic dilemma and for pathophysiological characterization of KCOTs. We included 114 patients, of whom 27 were histopathologically diagnosed with a KCOT and 87 with dentigerous (n = 41) and periapical cyst (n = 46). Semiautomatic segmentation and radiological analysis of preoperative cone beam computed tomography (CBCT) image data was carried out using ITK-SNAP. The mean volumetric extent of KCOTs is significantly higher compared to non-neoplastic odontogenic jaw cysts (p = 0.001). The mean volume and standard deviation for KCOTs and non neoplastic odontogenic jaw cysts was 10381 mm3 +/- 6410 and 5813 mm3 +/- 4425, respectively. Volumetric analysis reveals that KCOTs significantly exceed the mean size of non-neoplastic odontogenic jaw cysts, adding an argument in favor of the neoplastic nature of KCOTs. In the case of difficult histopathological examination, lesions with a size exceeding a value of about 3000 mm3 could be considered for close clinico-radiologic follow-up. PMID- 29233701 TI - In vivo effects of geranylgeraniol on the development of bisphosphonate-related osteonecrosis of the jaws. AB - BACKGROUND: Bisphosphonate-related osteonecrosis of the jaws (BRONJ) is a complication of the bisphosphonate (BP) treatment and its pathopysiology is still not fully understood. The existing preventive and treatment options require updates and more attention. Geranylgeraniol (GGOH) so far demonstrated an increased activity and viability of the cells previously treated with zoledronic acid (ZA). The aim of this study was to evaluate the in vivo effects of GGOH on the development of BRONJ. MATERIALS AND METHODS: A total of 30 male Wistar rats were included in the study, divided into three groups: two experimental groups (EG1 and EG2) and a control group (CG). Rats from EG1 and EG2 were treated with 0,06 mg/kg ZA ip weekly in a duration of five weeks, while CG received saline ip. On the third week all animals underwent extraction of the lower right first molars. The rats from EG2 received a local solution of GGOH in concentration of 5 mM in the socket every day after the tooth extraction. The analyses included clinical evaluation on the wound healing and pathohistological evaluation for presence and level of osteonecrosis. RESULTS: EG2 showed significantly improved wound healing and tissue proliferation, when compared to EG1. EG2 significantly differed from EG1 and CG (p<0,05) for the presence of microscopical osteonecrosis (80% vs 22,2% vs 0%). Regarding to the number of empty lacunes without osteocytes and the level of necrosis, all groups demonstrated significant differences. CONCLUSION: Geranylgeraniol in a form of local solution may be a promising option for prevention and treatment of BRONJ. PMID- 29233702 TI - Endoscopic endonasal repair with polyethylene implants in medial orbital wall fractures: A prospective study on 25 cases. AB - The aim of the study was to assess the mid-term effectiveness and safety of an original technique consisting of reconstructing fractures of the medial wall of the orbit with porous polyethylene implants with an exclusive transnasal approach. Twenty-five patients were treated. Each patient underwent a pre operative ophthalmologic evaluation and a CT scan. The surgery started with an anteroposterior ethmoidectomy of the fractured side; all the fractured bone fragments were removed and all usual landmarks of healthy bony margins were identified. A Medpor sheet was placed endoscopically to reconstruct the fractured wall. Each patient received an immediate postoperative CT scan, and was evaluated at day 1, 7, 30 and 6 months after surgery clinically and with an endoscopic examination. In all patients, preoperative enophthalmos and/or diplopia were corrected. The CT scans showed excellent reconstruction of the fractured bony walls. The immediate postoperative period was characterized by a very high degree of subjective comfort. No perioperative complications were detected. At the 6 months follow up, all meshes appeared covered by epithelialized mucosa at the endoscopic inspection, and clinical results were stable. Scars or lid complications are always prevented. The technique described has become the standard to treat medial wall fractures in our department. PMID- 29233703 TI - The risk of osteonecrosis on alveolar healing after tooth extraction and systemic administration of antiresorptive drugs in rodents: a systematic review. AB - PURPOSE: There is much concern about the increasing number of patients with medication-related osteonecrosis of the jaw (MRONJ), and many studies have been published in an attempt to understand the pathophysiology of this condition. This study aimed to systematically review the literature on MRONJ arising in rodents under antiresorptive drug therapy after tooth extraction. METHODS: A search of electronic databases, including LILACS, PROQUEST, PubMed, SCOPUS, and the Web of Science. RESULTS: The search resulted in 2319 titles after removing the duplicates, and one paper was identified using the reference list. Ninety-eight full-text papers were then screened for eligibility, resulting in 20 for inclusion in the final qualitative synthesis. The quality of the articles was assessed using the 'ARRIVE' tool. CONCLUSION: Despite the wide heterogeneity of the methodologies used by the authors, the current available evidence suggests that the combination of bisphosphonate and/or denosumab therapy and tooth extraction is associated with osteonecrosis of the jaw in rodents. PMID- 29233704 TI - Risk factors for post-operative complications after procedures for autologous bone augmentation from different donor sites. AB - AIM: The aim of this study has been to identify risk factors for post-operative complications after grafting bone from different donor sites prior to implant placement. MATERIAL AND METHODS: The study encompassed 279 patients who underwent autologous bone augmentations in a 2-stage procedure, harvested from three intraoral and one extraoral donor sites, as well as sinus floor elevations prior to implant placement. The following complications were recorded: soft tissue dehiscence; wound infection; bone graft exposure; sensory disturbance; sinusitis symptoms; haemorrhage; graft failure; implant failure. Complications were correlated with: patient age; smoking status; history of gingivitis/periodontitis; cause of tooth loss; jaw area; dental situation; sinus membrane perforation; surgeons' experience. RESULTS: 279 patients underwent 456 augmentation procedures, involving 546 sites. 436 grafts were successful. 525 implants were inserted into 436 augmented sites in 273 patients. 20 grafts were lost due to complications. 2 implants were removed before prosthetic restoration. 2 implants were lost within 2 years after placement. Age (p = 0.0009, Odds Ratio = 2.44), smoking (p < 0.0001, Odds Ratio = 2.47), Approximal Plaque Index (p < 0.0001, Odds Ratio = 6.64), Sulcus Bleeding Index (p < 0.0001, Odds Ratio = 39.06) and dental situation (p < 0.0001) were significantly correlated with higher post-operative morbidity. Cause of tooth loss (p = 0.7399), jaw area (p = 0.6725), sinus membrane perforation (p = 0.0762) and surgeons' experience (p = 0.0939) did not influence complication rates. CONCLUSIONS: Patients over 40 years old, smokers, a history of periodontitis, and augmentation in tooth gaps involving more than one tooth represent a significantly increased risk of there being post-operative complications compared with patients younger than 40 years old, non-smokers, no history of periodontitis, only a single-tooth gap, or free end arch situations. PMID- 29233705 TI - Systematics and phylogeography of the widely distributed African skink Trachylepis varia species complex. AB - A systematic study of the Trachylepis varia complex was conducted using mitochondrial and nuclear DNA markers for individuals sampled across the species range. The taxonomic history of T. varia has been complicated and its broad geographic distribution and considerable phenotypic variation has made taxonomic revision difficult, leading earlier taxonomists to suggest that T. varia is a species complex. We used maximum likelihood and Bayesian inference to estimate gene trees and a multilocus time-tree, respectively, and we used these trees to identify the major clades (putative species) within T. varia. Additionally, we used morphological and color pattern data to distinguish and revise the taxonomy of the southern African clades. The major clades recovered in the multilocus time tree were recovered in each of gene trees, although the relationships among these major clades differed across gene trees. Genetic data support the existence of at least eight species within the T.varia complex, each of which originated during the mid to late Miocene or early Pliocene. We focus our systematic discussion on the southern African members of the T. varia complex, revive Trachylepis damarana (Peters, 1870) and T. laevigata (Peters, 1869), and designate lectotypes for T.damarana and T. varia. PMID- 29233706 TI - Molecular systematics and biogeography of lowland antpittas (Aves, Grallariidae): The role of vicariance and dispersal in the diversification of a widespread Neotropical lineage. AB - We infer phylogenetic relationships, divergence times, and the diversification history of the avian Neotropical antpitta genera Hylopezus and Myrmothera (Grallariidae), based on sequence data (3,139 base pairs) from two mitochondrial (ND2 and ND3) and three nuclear nuclear introns (TGFB2, MUSK and FGB-I5) from 142 individuals of the 12 currently recognized species in Hylopezus and Myrmothera and 5 outgroup species. Phylogenetic analyses recovered 19 lineages clustered into two major clades, both distributed in Central and South America. Hylopezus nattereri, previously considered a subspecies of H. ochroleucus, was consistently recovered as the most divergent lineage within the Grallaricula/Hylopezus/Myrmothera clade. Ancestral range estimation suggested that modern lowland antpittas probably originated in the Amazonian Sedimentary basin during the middle Miocene, and that most lineages within the Hylopezus/Myrmothera clade appeared in the Plio-Pleistocene. However, the rate of diversification in the Hylopezus/Myrmothera clade appeared to have remained constant through time, with no major shifts over the 20 million years. Although the timing when most modern lineages of the Hylopezus/Myrmothera clade coincides with a period of intense landscape changes in the Neotropics (Plio-Pleistocene), the absence of any significant shifts in diversification rates over the last 20 million years challenges the view that there is a strict causal relationship between intensification of landscape changes and cladogenesis. The relative old age of the Hylopezus/Myrmothera clade coupled with an important role ascribed to dispersal for its diversification, favor an alternative scenario whereby long term persistence and dispersal across an ever-changing landscape might explain constant rates of cladogenesis through time. PMID- 29233707 TI - Phylogenetic characterization of transporter proteins in the cnidarian dinoflagellate symbiosis. AB - Metabolic exchange between cnidarians and their symbiotic dinoflagellates is central to maintaining their mutualistic relationship. Sugars are translocated to the host, while ammonium and nitrate are utilized by the dinoflagellates (Symbiodinium spp.). We investigated membrane protein sequences of each partner to identify potential transporter proteins that move sugars into cnidarian cells and nitrogen products into Symbiodinium cells. We examined the facilitated glucose transporters (GLUT), sodium/glucose cotransporters (SGLT), and aquaporin (AQP) channels in the cnidarian host as mechanisms for sugar uptake, and the ammonium and high-affinity nitrate transporters (AMT and NRT2, respectively) in the algal symbiont as mechanisms for nitrogen uptake. Homologous protein sequences were used for phylogenetic analysis and tertiary structure deductions. In cnidarians, we identified putative glucose transporters of the GLUT family and glycerol transporting AQP proteins, as well as sodium monocarboxylate transporters and sodium myo-inositol cotransporters homologous to SGLT proteins. We hypothesize that cnidarians use GLUT proteins as the primary mechanism for glucose uptake, while glycerol moves into cells by passive diffusion. We also identified putative AMT proteins in several Symbiodinium clades and putative NRT2 proteins only in a single clade. We further observed an upregulation of expressed putative AMT proteins in Symbiodinium, which may have emerged as an adaptation to conditions experienced inside the host cell. This study is the first to identify transporter sequences from a diversity of cnidarian species and Symbiodinium clades, which will be useful for future experimental analyses of the host symbiont proteome and the nutritional exchange of Symbiodinium cells in hospite. PMID- 29233708 TI - Extraction and physicochemical properties of polysaccharides from Ziziphus Jujuba cv. Muzao by ultrasound-assisted aqueous two-phase extraction. AB - In this paper, ultrasound-assisted aqueous two-phase extraction (UAATPE) performed via a one-step procedure was applied to extract polysaccharides from Ziziphus Jujuba cv. Muzao. Using an ethanol/ammonium sulfate system as a multiphase solvent, effects of UAATPE on extraction of ZMP, such as solvent-to material ratio, composition of aqueous two-phase system, and extraction time and temperature, were investigated using response surface methodology on basis of results of single-factor experiment. The final optimal conditions were ATPS composition: 29% ethanol and 15% (NH4)2SO4, extraction time: 38min, extraction temperature: 48 degrees C, solvent-to-material ratio: 30, and microwave power: 70W. Under these conditions, the experimental extraction yield was 8.18%. Chemical analysis revealed that ZMP were composed of rhamnose, arabinose, xylose, mannose, glucose, galactose, and galacturonic acid, at a ratio of 1.46:2.47:2.27:1.12:1.00:1.57:5.40, respectively. The structures were also characterized with UV, FTIR, and SEM. The DPPH and ABTS radical scavenging activities showed ZMP had moderately antioxidant activity. PMID- 29233709 TI - Metabolomics analysis of alloxan-induced diabetes in mice using UPLC-Q-TOF-MS after Crassostrea gigas polysaccharide treatment. AB - Diabetes has become a global and serious health issues which causes a variety of complications. This study aims to explore the hypoglycemic effect of Crassostrea gigas polysaccharide (CGPS) and the dynamic changes in the endogenous small molecule metabolites of urine from normal group, model group and CGPS high dose group by metabolomic approach (UPLC-Q-TOF-MS). In our study, the CGPS treatment could reduce the fasting blood glucose levels and recover the triglycerides (TG), total cholesterol (TC) and glycosylated serum protein (GSP) levels in serum of diabetic mice. Urine samples in normal group, model group and CGPS high dose group were dispersed in the PLS-DA score plots. Nineteen metabolites in urine such as l-carnitine, hippuric acid, pantothenate and ornithine were selected as potential therapeutic biomarkers and related metabolic pathways of CGPS for treating diabetes. They were mainly involved in amino acid metabolism, carbohydrate metabolism and purine metabolism. These data suggested that CGPS has antidiabetic activity and urine metabolites provided new understanding of CGPS for treating diabetes and its complications. PMID- 29233710 TI - Magnetic field-driven drug release from modified iron oxide-integrated polysaccharide hydrogel. AB - Salecan is a novel water-soluble extracellular beta-glucan and suitable for the hydrogel preparation due to its excellent physicochemical and biological properties. The present article describes the fabrication and characterization of a pH/magnetic field-driven hydrogel based on salecan-g-poly(vinylacetic acid-co-2 hydroxyethyl acrylate) [poly(VA-co-HEA)] copolymer and Fe3O4@Agarose nanoparticles for drug release testing. Vibrating sample magnetometer characterization verified that integration of Fe3O4@Agarose nanoparticles in the copolymer provided the sensitivity to magnetic fields. The doxorubicin hydrochloride (DOX) release test showed a pH/magnetic field-triggered and sustained release property, and the release could be accelerated under mildly acidic conditions or the presence of an external magnetic field. Meanwhile, the increase in salecan content could also enhance the release rate. Cytotoxicity assays revealed that the released DOX maintained relatively high killing efficacy of A549 cells. In sum, these salecan-g-poly(VA-co-HEA)/Fe3O4@Agarose hydrogels were well-suited for magnetically targeted drug delivery systems. PMID- 29233711 TI - Antitumor effect and molecular mechanism of antioxidant polysaccharides from Salvia miltiorrhiza Bunge in human colorectal carcinoma LoVo cells. AB - Salvia miltiorrhiza Bunge polysaccharides (SMP) was comprehensively investigated in this study. The polysaccharides were extracted by the method of water boiling and ethanol precipitation with high purity. The monosaccharide composition of SMP was characterized using the established HPLC-UV protocol with PMP precolumn derivatization, and the results indicate that the polysaccharides are mainly composed of d-galactose (Gal), d-glucose (Glc) and d-galacturonic acid (GalUA), and their mole percentages are 64.5%, 31.1% and 4.4%, respectively. In addition, the antioxidant potential of SMP was evaluated in terms of reducing power, scavenging ability against DPPH, superoxide and hydroxyl free radicals. The results indicate that polysaccharides from S. miltiorrhiza Bunge possess versatile antioxidant activities in a dose-dependent manner. Furthermore, SMP is observed with high inhibition ratio against LoVo cells (typical tumor cells) in both dose- and time-dependent manners. FCM analysis demonstrates that SMP is able to induce apoptosis of LoVo cells, arrest the cell cycle at S phase, as well as elevate the intracellular reactive oxygen pressure. These findings for the first time reveal the potential anti-tumor mechanism of SMP, suggesting that SMP may serve a natural anticancer agent with lower cost and cytotoxicity, as well as a bioactive factor for functional food development. PMID- 29233712 TI - Removal of lead (II) from aqeouos waste using (CD-PCL-TiO2) bio-nanocomposites. AB - Lead (Pb) pollution is our water system is a major concern, as this metal is toxic even at low concentration. This study aim to fabricate a bio-nanocomposite (cyclodextrin-polycaprolactone titanium dioxide) that will be used as an adsorbent for the removal of lead in aqueous waste. In this study, titanium dioxide was synthesized via sol-gel technique then incorporated in a polymer blend (CD-PCL) via solution blending method. The resulting bio-nanocomposites were characterized using Scanning Electron Microscopy (SEM), transmission electron microscope (TEM) and Brunauer Emmett and Teller (BET). The effect of how factors such as pH, concentration and adsorbent dose affect the removal efficiency of the bio-nanocomposites were studies. Maximum adsorption of lead obtained was 98% at pH 9.7, 10 ppm with 0.005 g dosage. Kinetic studies and adsorption isotherms were also investigated. The adsorption data fit Langmuir isotherm. Pb (II) obeyed pseudo-second order kinetics. PMID- 29233713 TI - Purification and biochemical characterization of a thermostable and acid-stable alpha-amylase from Bacillus licheniformis B4-423. AB - Novel thermostable amylase need to be continuously explored with the improvement of industrial requirements. A new acidophilic and thermostable amylase producing bacterium isolated from spring was identified as Bacillus strain on the basis of 16S rDNA. The amylase was purified by ammonium sulphate precipitation, gel chromatography and anion exchange chromatography. SDS-PAGE revealed that the enzyme was monomeric with a molecular weight of 58 kDa. The amylase exhibited optimal activity at pH 5.0 and temperature 100 degrees C. Then the enzyme showed high stability in pH ranges 4.0-10.0 and more than 90% of maximal activity was found from 20 degrees C to 80 degrees C. Apart from good stability toward SDS and non-ionic detergent, the purified enzyme exhibited high compatibility with some inhibitors such as urea and EDTA. The results demonstrated the stability of the enzyme in different organic solvents. Moreover, we determined the amylase gene, compared the structure with alpha-amylase BAA and BLA and found some thermostability determinants in our enzyme. Overall, presenting various properties were including high thermostability, Ca2+-independency, broad temperature and pH profiles, organic-solvent tolerance as well as excellent stability with detergents. Such characteristics have not been reported for this type of enzyme, and the alpha-amylase will be a suitable candidate in industrial fields. PMID- 29233714 TI - Bi-layered nanocomposite bandages for controlling microbial infections and overproduction of matrix metalloproteinase activity. AB - Chronic diabetic wounds is characterised by increased microbial contamination and overproduction of matrix metalloproteases that would degrade the extracellular matrix. A bi-layer bandage was developed, that promotes the inhibition of microbial infections and matrix metalloprotease (MMPs) activity. Bi-layer bandage containing benzalkonium chloride loaded gelatin nanoparticles (BZK GNPs) in chitosan-Hyaluronic acid (HA) as a bottom layer and sodium alendronate containing chitosan as top layer was developed. We hypothesized that the chitosan-gelatin top layer with sodium alendronate could inhibit the MMPs activity, whereas the chitosan-HA bottom layer with BZK GNPs (240+/-66nm) would enable the elimination of microbes. The porosity, swelling and degradation nature of the prepared Bi layered bandage was studied. The bottom layer could degrade within 4days whereas the top layer remained upto 7days. The antimicrobial activity of the BZK NPs loaded bandage was determined using normal and clinical strains. Gelatin zymography shows that the proteolytic activity of MMP was inhibited by the bandage. PMID- 29233715 TI - Catalytic activation of Bacillus laccase after temperature treatment: Structural & biochemical characterization. AB - Laccases belong to a family of multicopper oxidases that have strong oxidation ability towards phenolic compounds. Here, more detailed investigations were carried out on a Bacillus laccase with remarkable behavior of activation after thermal treatment. The kcat of the enzyme was increased 2.5 fold after 50 min incubation at 70 degrees C. Copper content determination revealed a molar copper to protein ratio of 3.2 in the both sample. The present paper concerns the differences which are induced in enzyme structure after thermal treatment using common biochemical methods Intrinsic fluorescence of the enzyme was increased after incubation at 70 degrees C indicating higher compactness of the structure in comparison to untreated molecules. Quenching analysis did not show any significant changes in flexibility of the enzyme structure. The local changes in secondary structures were also obvious by far-UV circular dichroism when non incubated and incubated laccase were compared. Oligomerization studies of the enzyme using gas-phase electrophoretic mobility macromolecule analysis (GEMMA) did not prove any oligomerization. PMID- 29233716 TI - Zika and travel: Public health implications and communications for blood donors, sperm donors and pregnant women. PMID- 29233717 TI - The influence of visual and phonological features on the hemispheric processing of hierarchical Navon letters. AB - The possibility of allocating attentional resources to the "global" shape or to the "local" details of pictorial stimuli helps visual processing. Investigations with hierarchical Navon letters, that are large "global" letters made up of small "local" ones, consistently demonstrate a right hemisphere advantage for global processing and a left hemisphere advantage for local processing. Here we investigated how the visual and phonological features of the global and local components of Navon letters influence these hemispheric advantages. In a first study in healthy participants, we contrasted the hemispheric processing of hierarchical letters with global and local items competing for response selection, to the processing of hierarchical letters in which a letter, a false letter conveying no phonological information or a geometrical shape presented at the unattended level did not compete for response selection. In a second study, we investigated the hemispheric processing of hierarchical stimuli in which global and local letters were both visually and phonologically congruent (e.g. large uppercase G made of smaller uppercase G), visually incongruent and phonologically congruent (e.g. large uppercase G made of small lowercase g) or visually incongruent and phonologically incongruent (e.g. large uppercase G made of small lowercase or uppercase M). In a third study, we administered the same tasks to a right brain damaged patient with a lesion involving pre-striate areas engaged by global processing. The results of the first two experiments showed that the global abilities of the left hemisphere are limited because of its strong susceptibility to interference from local letters even when these are irrelevant to the task. Phonological features played a crucial role in this interference because the interference was entirely maintained also when letters at the global and local level were presented in different uppercase vs. lowercase formats. In contrast, when local features conveyed no phonological information, the left hemisphere showed preserved global processing abilities. These findings were supported by the study of the right brain damaged patient. These results offer a new look at the hemispheric dominance in the attentional processing of the global and local levels of hierarchical stimuli. PMID- 29233718 TI - Right anterior cerebellum BOLD responses reflect age related changes in Simon task sequential effects. AB - Participants are slower to report a feature, such as color, when the target appears on the side opposite the instructed response, than when the target appears on the same side. This finding suggests that target location, even when task-irrelevant, interferes with response selection. This effect is magnified in older adults. Lengthening the inter-trial interval, however, suffices to normalize the congruency effect in older adults, by re-establishing young-like sequential effects (Aisenberg et al., 2014). We examined the neurological correlates of age related changes by comparing BOLD signals in young and old participants performing a visual version of the Simon task. Participants reported the color of a peripheral target, by a left or right-hand keypress. Generally, BOLD responses were greater following incongruent than congruent targets. Also, they were delayed and of smaller amplitude in old than young participants. BOLD responses in visual and motor regions were also affected by the congruency of the previous target, suggesting that sequential effects may reflect remapping of stimulus location onto the hand used to make a response. Crucially, young participants showed larger BOLD responses in right anterior cerebellum to incongruent targets, when the previous target was congruent, but smaller BOLD responses to incongruent targets when the previous target was incongruent. Old participants, however, showed larger BOLD responses to congruent than incongruent targets, irrespective of the previous target congruency. We conclude that aging may interfere with the trial by trial updating of the mapping between the task irrelevant target location and response, which takes place during the inter-trial interval in the cerebellum and underlays sequential effects in a Simon task. PMID- 29233720 TI - A pragmatic randomized comparative effectiveness trial of transitional care for a socioeconomically diverse population: Design, rationale and baseline characteristics. AB - Transitional care programs have been widely used to reduce readmissions and improve the quality and safety of the handoff process between hospital and outpatient providers. Very little is known about effective transitional care interventions among patients who are uninsured or with Medicaid. This paper describes the design and baseline characteristics of a pragmatic randomized comparative effectiveness trial of transitional care. Northwestern Medical Group- Transitional Care (NMG-TC) care model was developed to address the needs of patients with multiple medical problems that required lifestyle changes and were amenable to office-based management. We present the design, evaluation methods and baseline characteristics of NMG-TC trial patients. Baseline demographic characteristics indicate that our patient population is predominantly male, Medicaid insured and non-white. This study will evaluate two methods for implementing an effective transitional care model in a medically complex and socioeconomically diverse population. PMID- 29233719 TI - A randomized study of dietary composition during weight-loss maintenance: Rationale, study design, intervention, and assessment. AB - BACKGROUND: While many people with overweight or obesity can lose weight temporarily, most have difficulty maintaining weight loss over the long term. Studies of dietary composition typically focus on weight loss, rather than weight loss maintenance, and rely on nutrition education and dietary counseling, rather than controlled feeding protocols. Variation in initial weight loss and insufficient differentiation among treatments confound interpretation of results and compromise conclusions regarding the weight-independent effects of dietary composition. The aim of the present study was to evaluate three test diets differing in carbohydrate-to-fat ratio during weight-loss maintenance. DESIGN AND DIETARY INTERVENTIONS: Following weight loss corresponding to 12+/-2% of baseline body weight on a standard run-in diet, 164 participants aged 18 to 65years were randomly assigned to one of three test diets for weight-loss maintenance through 20weeks (test phase). We fed them high-carbohydrate (60% of energy from carbohydrate, 20% fat), moderate-carbohydrate (40% carbohydrate, 40% fat), and low-carbohydrate (20% carbohydrate, 60% fat) diets, controlled for protein content (20% of energy). During a 2-week ad libitum feeding phase following the test phase, we assessed the effect of the test diets on body weight. OUTCOMES: The primary outcome was total energy expenditure, assessed by doubly-labeled water methodology. Secondary outcomes included resting energy expenditure and physical activity, chronic disease risk factors, and variables to inform an understanding of physiological mechanisms by which dietary carbohydrate-to-fat ratio might influence metabolism. Weight change during the ad libitum feeding phase was conceptualized as a proxy measure of hunger. PMID- 29233721 TI - Antitumor miR-150-5p and miR-150-3p inhibit cancer cell aggressiveness by targeting SPOCK1 in head and neck squamous cell carcinoma. AB - OBJECTIVE: Our recent studies have revealed that both strands of pre-miRNAs, the guide strand and the passenger strand, are involved in cancer pathogenesis. Analyses of miRNA expression signatures by RNA sequencing in head and neck squamous cell carcinoma (HNSCC) showed that both of the strands of pre-miR-150 (miR-150-5p and miR-150-3p) were significantly downregulated, and that these miRNAs acted as antitumor miRNAs in HNSCC cells. The aim of this study was to identify oncogenic genes in HNSCC cells that were regulated by miR-150-5p and miR 150-3p. METHODS: Genome-wide gene expression studies, in silico analyses and dual luciferase reporter assays were carried out to predict miR-150-5p and miR-150-3p regulation in HNSCC cells. Knockdown assay was applied to investigate the functional significance of the target gene. Overall patient survival as a function of target gene expression was estimated by The Cancer Genome Atlas (TCGA) database. RESULTS: A total of 19 genes were putative targets of both miR 150-5p and miR-150-3p regulation. Among them, SPOCK1 (SPARC/osteonectin, cwcv and kazal-like domains proteoglycan 1) was directly regulated by both miRNAs in HNSCC cells. Knockdown studies using si-SPOCK1 showed that expression of SPOCK1 enhanced HNSCC cell aggressiveness. Overexpression of SPOCK1/SPOCK1 was confirmed in HNSCC clinical specimens. Interestingly, analysis of a large number of patients in the TCGA database (n=248) demonstrated that patients with high SPOCK1 expression had significantly shorter survival than did those with low SPOCK1 expression (P=0.0003). Moreover, 15 pathways were identified as SPOCK1-mediated downstream pathways. CONCLUSION: Downregulation of both strands of pre-miR-150 (miR-150-5p and miR-150-3p) and overexpression of SPOCK1 contribute to the aggressive nature of HNSCC. The involvement of passenger strand miRNA in the regulation of HNSCC pathogenesis is a novel concept in RNA research. PMID- 29233723 TI - The different faces of the p. A53T alpha-synuclein mutation: A screening of Greek patients with parkinsonism and/or dementia. AB - BACKGROUND: The p. A53T mutation in the alpha-synuclein (SNCA) gene is a rare cause of autosomal dominant Parkinson's disease (PD). Although generally rare, it is particularly common in the Greek population due to a founder effect. A53T positive PD patients often develop dementia during disease course and may very rarely present with dementia. METHODS: We screened for the p. A53T SNCA mutation a total of 347 cases of Greek origin with parkinsonism and/or dementia, collected over 15 years at the Neurogenetics Unit, Eginition Hospital, University of Athens. Cases were classified into: "pure parkinsonism", "pure dementia" and "parkinsonism plus dementia". RESULTS: In total, 4 p. A53T SNCA mutation carriers were identified. All had autosomal dominant family history and early onset. Screening of the "pure parkinsonism" category revealed 2 cases with typical PD. The other two mutation carriers were identified in the "parkinsonism plus dementia" category. One had a diagnosis of PD dementia and the other of behavioral variant frontotemporal dementia. Screening of patients with "pure dementia" failed to identify any further A53T-positive cases. CONCLUSIONS: Our results confirm that the p. A53T SNCA mutation is relatively common in Greek patients with PD or PD plus dementia, particularly in cases with early onset and/or autosomal dominant family history. PMID- 29233722 TI - County-level contextual factors associated with diabetes incidence in the United States. AB - PURPOSE: Health and administrative systems are facing spatial clustering in chronic diseases such as diabetes. This study explores how geographic distribution of diabetes in the United States is associated with socioeconomic and built environment characteristics and health-relevant policies. METHODS: We compiled nationally representative county-level data from multiple data sources. We standardized characteristics to a mean = 0 and a SD = 1 and modeled county level age-adjusted diagnosed diabetes incidence in 2013 using 2-level hierarchical linear regression. RESULTS: Incidence of age-standardized diagnosed diabetes in 2013 varied across U.S. counties (n = 3109), ranging from 310 to 2190 new cases/100,000, with an average of 856.4/100,000. Socioeconomic and health related characteristics explained ~42% of the variation in diabetes incidence across counties. After accounting for other characteristics, counties with higher unemployment, higher poverty, and longer commutes had higher incidence rates than counties with lower levels. Counties with more exercise opportunities, access to healthy food, and primary care physicians had fewer diabetes cases. CONCLUSIONS: Features of the socioeconomic and built environment were associated with diabetes incidence; identifying the salient modifiable features of counties can inform targeted policies to reduce diabetes incidence. PMID- 29233724 TI - Caprine neonatal spinal ultrasonography. AB - Spinal ultrasonography is a safe, rapid, and non-invasive diagnostic tool that allows visualization of the spinal cord and its surrounding meninges. The non ossified spinous processes were used as an acoustic window for imaging the spinal cord in human and canine neonates. No available literatures have been published describing the ultrasonographic appearance of caprine neonatal spinal cord. The present study was performed on 20 one day-old goat kids. Sagittal and transverse ultrasound scans were obtained using 8MHz linear transducer. The spinal cord appeared as a tubular anechoic to hypoechoic structure within the spinal canal. The cord was surrounded by hyperechoic dura and pia matter as well as the anechoic subarachnoid space in-between. The mean sagittal diameter of the cord at the cervical region was (4.6+/-0.3mm), the thoracic region (3.9+/-0.2mm), and the lumbar region (4.3+/-1.1mm). The sagittal diameter of the cord at the cervical and lumbar regions was significantly wider than the diameter at the thoracic region. Identification of the normal ultrasonographic appearance of caprine neonatal spinal cord may represent the basis for diagnosing congenital spinal cord lesions. PMID- 29233725 TI - AMD3100 treatment attenuates pulmonary angiogenesis by reducing the c-kit (+) cells and its pro-angiogenic activity in CBDL rat lungs. AB - Recent studies have shown that pulmonary angiogenesis is an important pathological process in the development of hepatopulmonary syndrome (HPS), and growing evidence has indicated that Stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) axis is involved in pulmonary vascular disease by mediating the accumulation of c-kit+ cells. This study aimed to test the effect of AMD3100, an antagonist of CXCR4, in HPS pulmonary angiogenesis. Common bile duct ligation (CBDL) rats were used as experimental HPS model and were treated with AMD3100 (1.25mg/kg/day, i.p.) or 0.9% saline for 3weeks. The sham rats underwent common bile duct exposure without ligation. The c-kit+ cells accounts and its angiogenic-related functions, prosurvival signals, pulmonary angiogenesis and arterial oxygenation were analysed in these groups. Our results showed that pulmonary SDF-1/CXCR4, Akt, Erk and VEGF/VEGFR2 were significantly activated in CBDL rats, and the numbers of circulating and pulmonary c-kit+ cells were increased in CBDL rats compared with control rats. Additionally, the angiogenic related functions of c-kit+ cells and pulmonary microvessel counts were also elevated in CBDL rats. CXCR4 inhibition reduced pulmonary c-kit+ cells and microvessel counts and improved arterial oxygenation within 3weeks in CBDL rats. The pulmonary prosurvival signals and pro-angiogenic activity of c-kit+ cells were also down-regulated in AMD3100-treated rats. In conclusion, AMD3100 treatment attenuated pulmonary angiogenesis in CBDL rats and prevented the development of HPS via reductions in pulmonary c-kit+ cells and inhibition of the prosurvival signals. Our study provides new insights in HPS treatment. PMID- 29233726 TI - Understanding the Factors That Control the Quality of Mini-Tablet Compression: Flow, Particle Size, and Tooling Dimension. AB - Despite the increasing importance of mini-tablet for its advantages as pediatric formulations and in modified-release applications, its popularity is limited due to the lack of formulation and processing knowledge in developing such dosage forms. In this study, common grades of microcrystalline cellulose and roller compacted granules with a range of powder properties were used to evaluate the critical material properties required for the successful manufacturing of 1.7-mm mini-tablets. It was found that blends with small particle size had poor flow properties that did not support consistent die filling and also tended to cause tooling jam and damage. While the granulation process was effective in improving blend flow properties by increasing particle size, it is imperative to avoid very large particles that could also cause inadequate flow by blocking the space within the die. Successful mini-tablet compression could be achieved by removing particles larger than roughly 1/3 of the die diameter or milling the granules using a screen less than 1/3 of the die diameter. PMID- 29233727 TI - A Mathematical Model and Experimental Verification of Optimal Nozzle Diameter in Needle-Free Injection. AB - Needle-free injection (NFI), as an alternative drug delivery strategy, owns great potential. It is able to reduce complaints about needle phobia and avoid the occurring of accidental needle stick injuries. The nozzle diameter is inherently important in determining the injection dose, injection depth, and pain associated with NFIs. In this work, needle-free injectors with nozzle diameters of 0.17, 0.20, 0.30, 0.40, and 0.50 mm were studied in the simulation and experiment. This article optimizes the mathematical model for spring-powered NFI by considering the hydraulic loss due to the abrupt change in the nozzle exit area and the friction force between the piston and ampoule. We explore the dispersion pattern in gels with different nozzle diameters. Mice insulin injection was conducted to investigate the pharmacological effect of different injection methods. The experimental results show that there is the best dispersion effect and available injection depth while the nozzle diameter is 0.30 mm, which is in agreement with the result predicted by the mathematical model. Also, there is a satisfactory pharmacological effect on the mice insulin injection under the same injection condition. Undoubtedly, the mathematical model is capable of predicting the suitable nozzle diameter under the given conditions. PMID- 29233729 TI - Prediction of replication sites in Saccharomyces cerevisiae genome using DNA segment properties: Multi-view ensemble learning (MEL) approach. AB - Autonomous replication sequences (ARS) are essential for the replication of Saccharomyces cerevisiae genome. The content and context of ARS sites are distinct from other segments of the genome and these factors influence the conformation and thermodynamic profile of DNA that favor binding of the origin recognition complex proteins. Identification of ARS sites in the genome is a challenging task because of their organizational complexity and degeneracy present across the intergenic regions. We considered a few properties of DNA segments and divided them into multiple subsets (views) for computational prediction of ARS sequences. Our approach utilized these views for learning classification models in an ensemble manner and accordingly predictions were made. This approach maximized the prediction accuracy over the traditional way where all features are selected at once. Our study also revealed that major groove width and major groove depth are the most prominent properties that distinguished ARS from other segments of the genome. Our investigation also provides clue about the most suitable classifier for a given feature set, and this strategy may be useful for finding ARS in other closely related species. PMID- 29233728 TI - Characterization of the Hydrodynamics in a Miniaturized Dissolution Apparatus. AB - The hydrodynamics of a miniaturized dissolution apparatus was characterized using computational fluid dynamics simulations and analyzed in relation to the biorelevance and robustness of measurements of drug dissolution and precipitation kinetics from supersaturated drug solutions. The effect of using 3 different agitator geometries operated at 50, 100, 150, and 200 rpm as well as different positioning of an UV probe in the vessel was systematically evaluated. The computational fluid dynamics simulations were validated using a particle streak velocimetry experiment. The results show that the choice of agitator geometry influences the hydrodynamics of the system and indicates that an off-center probe position may result in more robust measurements. Furthermore, the study shows that the agitator geometry has a significant effect on supersaturation studies due to differences in the hydrodynamic shear produced by the agitator. PMID- 29233730 TI - Cyclic Concatenated Genetic Encoder: A mathematical proposal for biological inferences. AB - The organization of the genetic information and its ability to be conserved and translated to proteins with low error rates have been the subject of study by scientists from different disciplines. Recently, it has been proposed that living organisms display an intra-cellular transmission system of genetic information, similar to a model of digital communication system, in which there is the ability to detect and correct errors. In this work, the concept of Concatenated Genetic Encoder is introduced and applied to the analysis of protein sequences as a tool for exploring evolutionary relationships. For such purposes Error Correcting Codes (ECCs) are used to represent proteins. A methodology for representing or identifying proteins by use of BCH codes over Z20 and F4*Z5 is proposed and cytochrome b6-f complex subunit 6-OS sequences, corresponding to different plants species, are analyzed according to the proposed methodology and results are contrasted to phylogenetic and taxonomic analyses. Through the analyses, it was observed that using BCH codes only some sequences are identified, all of which differ in one amino acid from the original sequence. In addition, mathematical relationships among identified sequences are established by considering minimal polynomials, where such sequences showed a close relationship as revealed in the phylogenetic reconstruction. Results, here shown, point out that communication theory may provide biology of interesting and useful tools to identify biological relationships among proteins, however the proposed methodology needs to be improved and rigorously tested in order to become into an applicable tool for biological analysis. PMID- 29233731 TI - Do Different Diagnostic Criteria Impact Polycystic Ovary Syndrome Diagnosis for Adolescents? AB - STUDY OBJECTIVE: Although early diagnosis of polycystic ovary syndrome (PCOS) in adolescents might allow for earlier treatment and prevention of chronic disorders, incorrect or premature diagnosis carries risks of unnecessary treatment and psychological distress. There is no consensus concerning which diagnostic criteria to use for adolescents and current criteria vary. The objective of this study was to determine whether using different diagnostic criteria will affect PCOS diagnosis in adolescents. DESIGN, SETTING, AND PARTICIPANTS: Fifty-two patients aged 13-18 years with at least 2 of the following criteria were included in the study: (1) oligomenorrhea or amenorrhea; (2) Clinical or biochemical hyperandrogenism; and (3) polycystic ovaries on ultrasonography. Patients were then categorized according to the 6 different criteria for PCOS. National Institutes of Health, Rotterdam criteria, Androgen Excess Society, Amsterdam criteria, Endocrine Society criteria, and the Pediatric Endocrine Society criteria. The characteristics of adolescents who were diagnosed with PCOS were also evaluated. INTERVENTIONS AND MAIN OUTCOME MEASURES: Forty-one patients out of 52 (78.8%) received diagnosis with National Institutes of Health and Endocrine Society criteria, all with Rotterdam criteria, 45/52 (86.5%) with Androgen Excess Society criteria, 36/52 (69.2%) with Amsterdam criteria and 34/52 (65.4%) with the Pediatric Endocrine Society criteria. RESULTS AND CONCLUSION: This study shows that the choice of guideline used does have a great effect on whether an adolescent received the PCOS diagnosis or not. For physicians using the broader criteria, care should be taken to ensure the patient does not receive diagnosis because of the physiological changes seen during puberty, which might mimic PCOS. For those using stricter criteria, close monitoring of patients who do not receive diagnosis is necessary to prevent chronic complications. PMID- 29233732 TI - Foley Catheter as a Vaginal Stent in a Toddler with Vaginal Rhabdomyosarcoma. AB - BACKGROUND: Sarcoma botryoides is a variant of embryonal rhabdomyosarcoma with cure rates exceeding 90%. Vaginal presentation is rare and treatment includes chemotherapy and local radiation. Sequelae of vaginal radiation in this age group have not been well defined. However, vaginal stenosis is a known result of pelvic radiation in adult women with vaginal dilation as the primary method of prevention and treatment. CASE: An 18-month-old child was diagnosed with vaginal rhabdomyosarcoma and underwent chemotherapy and vaginal brachytherapy radiation treatment. Six weeks after completion of radiation, vaginoscopy was performed with placement of a nonlatex Foley catheter to prevent vaginal stricture. When removed, vaginal patency was normal with no vaginal erosion. SUMMARY AND CONCLUSION: Use of a soft, flexible, nonlatex catheter might prevent vaginal stricture in a young child. PMID- 29233733 TI - Effect and mechanism of dioscin from Dioscorea spongiosa on uric acid excretion in animal model of hyperuricemia. AB - ETHNOPHARMACOLOGY RELEVANCE: Dioscin, a spirostane glycoside, the rhizoma of Dioscorea septemloba (Diocoreacea) is used for diuresis, rheumatism, and joints pain. Given the poor solubility and stability of Dioscin, we proposed a hypothesis that Dioscin's metabolite(s) are the active substance(s) in vivo to contribute to the reducing effects on serum uric acid levels. AIM OF THE STUDY: The aim of this study is to identify the active metabolite(s) of Dioscin in vivo and to explore the mechanism of its antihyperuricemic activity. MATERIALS AND METHODS: After oral administration of Dioscin in potassium oxonate (PO) induced hyperuricemia rats and adenine-PO induced hyperuricemia mice models, serum uric acid and creatinine levels, clearance of uric acid and creatinine, fractional excretion of uric acid, and renal pathological lesions were determined were used to evaluate the antihyperuricemic effects. Renal glucose transporter-9 (GLUT-9) and organic anion transporter-1 (OAT-1) expressions were analyzed by western blotting method. Renal uric acid excretion was evaluated using stably urate transporter-1 (URAT-1) transfected human epithelial kidney cell line. Intestinal uric acid excretion was evaluated by measuring the transcellular transport of uric acid in HCT116 cells. RESULTS: In hyperuricemia rats, both 25 and 50mg/kg of oral Dioscin decreased serum uric acid levels over 4h. In the hyperuricemia mice, two weeks treatment of Dioscin significantly decreased serum uric acid and creatinine levels, increased clearance of uric acid and creatinine, increased fractional excretion of uric acid, and reduced renal pathological lesions caused by hyperuricemia. In addition, renal GLUT -9 was significantly down-regulated and OAT-1 was up-regulated in Dioscin treated hyperuricemia mice. Dioscin's metabolite Tigogenin significantly inhibited uric acid re-absorption via URAT1 from 10 to 100MUM. Diosgenin and Tigogenin increased uric acid excretion via ATP binding cassette subfamily G member 2 (ABCG2). CONCLUSION: Decreasing effect of Dioscin on serum uric acid level and enhancing effect on urate excretion were confirmed in hyperuricemia animal models. Tigogenin, a metabolite of Dioscin, was identified as an active substance with antihyperuricemic activity in vivo, through inhibition of URAT1 and promotion of ABCG2. PMID- 29233735 TI - N-terminal acetylation modulates Bax targeting to mitochondria. AB - The pro-apoptotic Bax protein is the main effector of mitochondrial permeabilization during apoptosis. Bax is controlled at several levels, including post-translational modifications such as phosphorylation and S-palmitoylation. However, little is known about the contribution of other protein modifications to Bax activity. Here, we used heterologous expression of human Bax in yeast to study the involvement of N-terminal acetylation by yNaa20p (yNatB) on Bax function. We found that human Bax is N-terminal (Nt-)acetylated by yNaa20p and that Nt-acetylation of Bax is essential to maintain Bax in an inactive conformation in the cytosol of yeast and Mouse Embryonic Fibroblast (MEF) cells. Bax accumulates in the mitochondria of yeast naa20Delta and Naa25-/- MEF cells, but does not promote cytochrome c release, suggesting that an additional step is required for full activation of Bax. Altogether, our results show that Bax N terminal acetylation by NatB is involved in its mitochondrial targeting. PMID- 29233736 TI - Fumonisin B1 induces oxidative stress in oesophageal (SNO) cancer cells. AB - Fumonisin B1 (FB1) is a ubiquitous contaminant of maize that is epidemiologically linked to oesophageal cancer (OC) in South Africa. FB1-induced oxidative stress mediates toxicity in animals and human cell lines, but the effects relating to OC are limited. Given the species-specific effects of FB1, this study investigated FB1-mediated toxicity and oxidative stress in spindle-shaped N-cadherin (+) CD45 (-) osteoblastic (SNO) cells. Following exposure to FB1 (0-20 MUM) for 48 h, mitochondrial membrane potential and intracellular reactive oxygen species (iROS) were measured (flow cytometry). Malondialdehyde concentration (lipid peroxidation) was determined spectrophotometrically. ATP and reduced glutathione (GSH) concentrations were quantified using luminometry, gene expression of SOD2 by qPCR and protein expression of SOD2, GPx1, Nrf2 and HSP70 by western blotting. Mitochondrial depolarization increased at 10 MUM and 20 MUM FB1, with a concomitant reduction in ATP, iROS and GSH at both concentrations. Lipid peroxidation increased at 10 MUM FB1 exposure. While transcript levels of SOD2 were significantly increased, protein levels decreased. Protein expression of GPx1, Nrf2 and HSP70 increased. In contrast to the 10 MUM and 20 MUM FB1 treatment, mitochondrial depolarization decreased at 1.25 MUM FB1. Intracellular ROS and ATP were decreased and lipid peroxidation increased. Decreased GSH was accompanied by a decrease in GPx1 protein levels, and increased HSP70 and Nrf2. SOD2 expression and protein levels were significantly increased. Overall these results indicate that FB1 caused increased ROS that were counteracted by engaging the antioxidant defense. Furthermore, the peculiar response at 1.25 MUM FB1 is noteworthy, as compared to the other two concentrations tested. PMID- 29233737 TI - Exercise and cardiovascular events: Is there any J curve relation? PMID- 29233738 TI - Prevalence of transforming growth factor beta-induced gene corneal dystrophies in Chinese refractive surgery candidates. AB - PURPOSE: To determine the prevalence of the transforming growth factor (TGF) beta induced gene corneal dystrophies in refractive surgery candidates in China. SETTING: Five hospitals in China. DESIGN: Prospective case series. METHOD: Refractive surgical candidates from 5 preselected eye hospitals/centers in China were recruited after providing informed consent. All patients had slitlamp biomicroscopy and collection of a buccal swab as a source of DNA for screening of the TGF beta-induced gene for the 5 most common mutations associated with Reis Buckler corneal dystrophy, Thiel-Behnke corneal dystrophy, granular corneal dystrophy type 1, granular corneal dystrophy type 2, and lattice corneal dystrophy type 1. RESULTS: Of the 2068 refractive surgery candidates analyzed, 4 had corneal opacities in both eyes on slitlamp examination. Screening for the TGF beta-induced gene found the heterozygous p.R124H mutation associated with granular corneal dystrophy type 2 in each of the 4 individuals with corneal opacities as well as in a fifth individual who did not have any corneal opacities, for a prevalence of 0.24%. Exacerbation of dystrophic corneal deposition developed after laser refractive surgery in 2 individuals who did not have preoperative TGF beta-induced gene screening. CONCLUSIONS: The prevalence of the TGF beta-induced gene corneal dystrophies in Chinese refractive surgery candidates was estimated to be approximately 0.24%. Genetic testing is recommended to identify and exclude from candidacy all individuals with a TGF beta-induced gene dystrophy before elective keratorefractive surgery to avoid causing accelerated postoperative dystrophic deposition. PMID- 29233739 TI - Early-onset childhood atopic dermatitis is related to NLRP2 repression. PMID- 29233740 TI - European Resuscitation Council Guidelines for Resuscitation: 2017 update. PMID- 29233742 TI - How to Approach a Hodgkin Lymphoma Patient With Relapse After Autologous SCT: Allogeneic SCT. AB - Hodgkin lymphoma (HL) is a highly curable B-cell lymphoma, and ~90% of patients who present with early-stage (stage I-II) disease and 70% of patients who present with late-stage disease will be cured with standard frontline treatment. For patients with relapsed or refractory (r/r) disease after initial therapy, the standard of care is salvage chemotherapy, followed by autologous transplantation (autoSCT). Although this approach will cure a significant proportion of patients, upto 50% of patients will experience disease progression after autoSCT, and this population has historically had a very poor prognosis. In the past, further salvage chemotherapy, followed by allogeneic transplantation (alloSCT), has been the only option associated with a significant probability of long-term survival, owing to a graft-versus-lymphoma effect. However, this approach has been complicated by high rates of treatment-related morbidity and mortality and a high risk of disease relapse. Furthermore, many patients have been unable to proceed to alloSCT because of disease refractoriness, poor performance status, or the lack of a donor. However, significant therapeutic advances in recent years have greatly expanded the options for patients with post-autoSCT r/r HL. These include the anti-CD30 antibody-drug conjugate brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab, as well as increasing experience with alternative donor alloSCT, especially from haploidentical donors. In the present review, we discuss the current role of alloSCT in the treatment of HL after autoSCT relapse. PMID- 29233741 TI - Cyclooxygenase enzyme activity does not impair respiratory motor plasticity after one night of intermittent hypoxia. AB - Although inflammation is prevalent in many clinical disorders challenging breathing, we are only beginning to understand the impact of inflammation on neural mechanisms of respiratory control. We recently demonstrated one form of respiratory motor plasticity is extremely sensitive to even mild inflammation induced by a single night (8 h) of intermittent hypoxia (IH-1), mimicking aspects of obstructive sleep apnea. Specifically, phrenic long-term facilitation (pLTF) following moderate acute intermittent hypoxia (AIH) is abolished by IH-1, but restored by high doses of the non-steroidal anti-inflammatory drug, ketoprofen. Since a major target of ketoprofen is cyclooxygenase (COX) enzymes, we tested the involvement of COX in IH-1 suppression of pLTF using the selective COX inhibitor NS-398. Systemic COX inhibition (3 mg/kg, i.p., 3 h before AIH) had no effect on pLTF in normoxia treated rats (76 +/- 40% change from baseline, n = 6), and did not restore pLTF in IH-1 treated rats (-9 +/- 7% baseline, n = 6). Similarly, spinal COX inhibition (27 mM, 12 MUl, i.t.) had no effect on pLTF in normoxic rats (76 +/- 34% baseline, n = 7), and did not significantly restore pLTF after IH-1 (37 +/- 18% baseline, n = 7). COX-2 protein is expressed in identified phrenic motor neurons of both normoxia and IH-1 exposed rats, but immunolabeling was minimal in surrounding microglia; IH-1 had no discernable effect on COX-2 immunoreactivity. We conclude that the inflammatory impairment of pLTF by IH-1 is independent of COX enzyme activity or upregulated COX-2 expression. PMID- 29233743 TI - A Phase II Trial of Rituximab Combined With Pegfilgrastim in Patients With Indolent B-cell Non-Hodgkin Lymphoma. AB - BACKGROUND: To explore the role of augmenting neutrophil function in B-cell lymphoma, we conducted a phase II study evaluating the safety and clinical efficacy of pegfilgrastim and rituximab in low-grade CD20+ B-cell non-Hodgkin lymphoma (B-NHL). PATIENTS AND METHODS: Twenty patients with indolent B-NHL were treated with rituximab (375 mg/m2) every other week for 4 doses, followed by every 2 months for 4 additional doses. Pegfilgrastim was administered subcutaneously 3 days before each dose of rituximab. Clinical activity and tolerability were assessed using standard criteria. Biologic monitoring included phenotype characteristics of the host neutrophils, changes in oxidative burst, and functional assays. RESULTS: The patient demographics included median age of 64 years, 70% were male, 70% had follicular lymphoma, and 90% had stage III-IV disease. The median number of previous therapies was 2 (range, 0-5); 90% had received previous anti-CD20 monoclonal antibody therapy. The addition of pegfilgrastim to rituximab did not increase rituximab-related toxicities. The overall response rate was 60% (12 of 20), with a complete response (CR) rate of 35% (7 of 20). The median progression-free survival (PFS) duration was 17.9 months (95% confidence interval, 9.9-27.6 months); the median overall survival was not reached. A shorter time-to-peak oxidative burst after the first dose of pegfilgrastim was associated with greater CR rates (P = .04) and longer PFS (P = .03). CONCLUSION: The pegfilgrastim-rituximab combination was well tolerated, with favorable outcomes compared with historical controls. A shorter time-to-peak oxidative burst was associated with higher CR rates and longer PFS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B-NHL. PMID- 29233744 TI - A flavonoid compound library screen revealed potent antiviral activity of plant derived flavonoids on human enterovirus A71 replication. AB - Hand Foot Mouth Disease (HFMD), resulting from human enterovirus A71 (HEVA71) infection can cause severe neurological complications leading to fatality in young children. Currently, there is no approved antiviral for therapeutic treatment against HEVA71 infection. In this study, a 500-compound flavonoid library was screened to identify potential inhibitors of HEVA71 using high throughput immunofluorescence-based phenotypic screening method. Two lead flavonoid compounds, ST077124 and ST024734 at the non-cytotoxic concentration of 50 MUM were found to be effective antivirals that inhibited replication of HEVA71, reducing infectious viral titers by 3.5 log10 PFU/ml and 2.5 log10 PFU/ml respectively. Our study revealed that ST077124 is a specific antiviral compound that inhibits human enteroviruses while ST024734 exhibited antiviral activity against human enteroviruses as well as dengue virus type-2. We also identified that both compounds affected the viral RNA transcription and translation machinery of HEVA71 but did not interfere with the viral internal ribosomal entry site (IRES) activity. Hence, our findings strongly suggest that ST077124 and ST024734 are effective antiviral compounds of minimal cytotoxicity and could serve as promising therapeutic agents against HEVA71 infection. PMID- 29233745 TI - RetroPath2.0: A retrosynthesis workflow for metabolic engineers. AB - Synthetic biology applied to industrial biotechnology is transforming the way we produce chemicals. However, despite advances in the scale and scope of metabolic engineering, the research and development process still remains costly. In order to expand the chemical repertoire for the production of next generation compounds, a major engineering biology effort is required in the development of novel design tools that target chemical diversity through rapid and predictable protocols. Addressing that goal involves retrosynthesis approaches that explore the chemical biosynthetic space. However, the complexity associated with the large combinatorial retrosynthesis design space has often been recognized as the main challenge hindering the approach. Here, we provide RetroPath2.0, an automated open source workflow for retrosynthesis based on generalized reaction rules that perform the retrosynthesis search from chassis to target through an efficient and well-controlled protocol. Its easiness of use and the versatility of its applications make this tool a valuable addition to the biological engineer bench desk. We show through several examples the application of the workflow to biotechnological relevant problems, including the identification of alternative biosynthetic routes through enzyme promiscuity or the development of biosensors. We demonstrate in that way the ability of the workflow to streamline retrosynthesis pathway design and its major role in reshaping the design, build, test and learn pipeline by driving the process toward the objective of optimizing bioproduction. The RetroPath2.0 workflow is built using tools developed by the bioinformatics and cheminformatics community, because it is open source we anticipate community contributions will likely expand further the features of the workflow. PMID- 29233746 TI - Amino Acid Variants of HLA-DRB1 Confer Susceptibility to Dapsone Hypersensitivity Syndrome in Addition to HLA-B*13:01. AB - Dapsone hypersensitivity syndrome is a rare yet severe adverse drug reaction caused by dapsone, a principal drug in multidrug therapy for leprosy. HLA-B*13:01 has been identified as a strong risk factor of dapsone hypersensitivity syndrome; however, its low positive predictive value indicated that additional genetic variants may be involved in the disease development. To discover contributing genetic variants within HLA loci in addition to HLA-B*13:01, we performed a high coverage next-generation sequencing (NGS)-based HLA typing analysis in 103 dapsone-hypersensitive and 857 dapsone-tolerant HLA-B*13:01-positive leprosy patients in a Chinese population. Five amino acid variants in high linkage disequilibrium of HLA-DRB1 were significantly associated with dapsone hypersensitivity syndrome (positions 133, 142, -17, 11, and 13). DRB1*16:02 and DRB1*15:01 tagged by these risk-conferring amino acid residues were associated at a nominal significance level. This study identifies five amino acid variants within HLA-DRB1 that are in high linkage disequilibrium and significantly associated with dapsone hypersensitivity syndrome in a Chinese population. PMID- 29233747 TI - Structural changes of homodimers in the PDB. AB - Protein complexes are involved in various biological phenomena. These complexes are intrinsically flexible, and structural changes are essential to their functions. To perform a large-scale automated analysis of the structural changes of complexes, we combined two original methods. An application, SCPC, compares two structures of protein complexes and decides the match of binding mode. Another application, Motion Tree, identifies rigid-body motions in various sizes and magnitude from the two structural complexes with the same binding mode. This approach was applied to all available homodimers in the Protein Data Bank (PDB). We defined two complex-specific motions: interface motion and subunit-spanning motion. In the former, each subunit of a complex constitutes a rigid body, and the relative movement between subunits occurs at the interface. In the latter, structural parts from distinct subunits constitute a rigid body, providing the relative movement spanning subunits. All structural changes were classified and examined. It was revealed that the complex-specific motions were common in the homodimers, detected in around 40% of families. The dimeric interfaces were likely to be small and flat for interface motion, while large and rugged for subunit-spanning motion. Interface motion was accompanied by a drastic change in contacts at the interface, while the change in the subunit-spanning motion was moderate. These results indicate that the interface properties of homodimers correlated with the type of complex-specific motion. The study demonstrates that the pipeline of SCPC and Motion Tree is useful for the massive analysis of structural change of protein complexes. PMID- 29233748 TI - Rationale Behind the Use of Double-Layer Polypropylene Patch (G-patch) Dural Substitute During Decompressive Craniectomy as an Adhesion Preventive Material for Subsequent Cranioplasty with Special Reference to Flap Elevation Time. AB - OBJECTIVE: Dural substitutes are used in decompressive craniectomy (DC) to prevent adhesions during subsequent cranioplasty. Current literature attributes them to reduced blood loss and reduction in operative time of cranioplasty. The use of double-layer substitute has rarely been documented. We studied the use of double-layer G-patch as a dural substitute in DC and evaluated its outcome during subsequent cranioplasty with special focus on flap elevation time and blood loss during cranioplasty. METHODS: We performed emergency frontotemporoparietal decompressive craniectomy using a double layer of G-patch as dural substitute. Subsequent cranioplasty was done in these 35 patients. The development of adhesion formation between the tissue layers, amount of blood loss, and flap elevation time were recorded. RESULTS: During the cranioplasty, a clear and smooth plane of dissection was found between the 2 layers of G-patch in all cases. Average flap elevation time was 21.8 minutes, and average time taken for cranioplasty was 124.12 minutes. Average blood loss was 83 mL. None of the patients required re-exploration for infection of bone flap or postoperative bleed. CONCLUSIONS: While evaluating the use of dural substitute during DC as an adhesion preventive material for subsequent cranioplasty, flap elevation time and blood loss should be taken into account rather than operative time. Double-layer G-patch during DC facilitates subsequent cranioplasty by preventing adhesions between the layers, resulting in easier dissection and reduced blood loss. PMID- 29233749 TI - An Amendment to the Neidre and MacNab Classification System for Lumbosacral Nerve Root Anomaly and Its Implication in Percutaneous Endoscopic Lumbar Discectomy. AB - BACKGROUND: Lumbar disc herniation complicated with nerve root anomaly presents great challenges to diagnosis and treatment. Improper selection of surgical procedures may cause inferior outcomes and neurologic injury. CASE DESCRIPTION: A 66-year old man presented with low back pain and radicular symptoms involving bilateral L5 and S1 nerve roots. Instead of percutaneous endoscopic lumbar discectomy, aggressive decompression was carried out because of a deviation between the examination and imaging findings. Surgical detection disclosed a confluent nerve root comprising 2 adjacent contributions that arose from the thecal sac exiting from the left L5/S1 foramen, in the absence of the root otherwise exiting through the caudal foramen. We found that the overwhelming left radicular symptoms were attributable to compression on this swelling anomalous root by a narrowed L5/S1 root cannula. Aggressive decompression and distraction of the intervertebral space successfully released the nerve root. Twenty months postoperatively, the patient experienced evident relief of the radicular symptoms and improvement of muscle strength with no complication. CONCLUSIONS: Lumbosacral nerve root anomaly should be remembered and ruled out before selecting surgical methods. Inappropriate procedures can not alleviate the symptoms associated with the anomalous roots and may expose such patients to the risk of neural injury. In clinical practice, surgeons should select percutaneous endoscopic lumbar discectomy with caution, and stop the procedure instantly when unexplainable radicular irritation is evoked. PMID- 29233750 TI - Fibrin hydrogels as a xenofree and rapidly degradable support for transplantation of retinal pigment epithelium monolayers. AB - : Recent phase 1 trials of embryonic stem cell and induced pluripotent stem cell (iPSCs) derived RPE transplants for the treatment of macular degeneration have demonstrated the relative safety of this process. However, there is concern over clumping, thickening, folding, and wrinkling of the transplanted RPE. To deliver a flat RPE monolayer, current phase 1 trials are testing synthetic substrates for RPE transplantation. These substrates, however, cause localized inflammation and fibrosis in animal models due to long degradation times. Here we describe the use of thin fibrin hydrogels as a support material for the transplantation of RPE. Fibrin was formed into a mechanically rigid support that allow for easy manipulation with standard surgical instruments. Using fibrinolytic enzymes, fibrin hydrogels were degraded on the scale of hours. The rate of degradation could be controlled by varying the fibrinolytic enzyme concentration used. RPE cells degraded fibrin spontaneously. To preserve the fibrin support during differentiation of iPSCs to RPE, media was supplemented with the protease inhibitor aprotinin. iPSC-RPE on fibrin gels remained viable, generated monolayers with characteristic cobblestone appearance and dark pigmentation, and expressed mRNA and protein markers characteristic of RPE in the eye. Following differentiation of the cells, addition of fibrinolytic enzymes fully and rapidly degraded the fibrin support leaving behind an intact, viable iPSC-RPE monolayer. In conclusion, human fibrin hydrogels provide a xeno-free support on which iPSCs can be differentiated to RPE cells for transplant which can be rapidly degraded under controlled conditions using fibrinolytic enzymes without adverse effects to the cells. STATEMENT OF SIGNIFICANCE: Stem cell-derived retinal pigment epithelial (RPE) cell transplantation is currently in phase 1 clinical trials for macular degeneration (MD). A major obstacle in these studies is delivering the RPE as a living, flat sheets without leaving behind foreign materials in the retina. Here we investigate the suitability of using hydrogels made from human blood-derived proteins for RPE transplant. Our data shows that these fibrin hydrogels are rigid enough for use in surgery, support growth of stem cell derived RPE, and are easily degraded within hours without damage to the RPE sheet. These fibrin hydrogels offer a promising solution to transplant RPE for patients with MD. PMID- 29233752 TI - Mammalian zygotic genome activation. AB - Zygotic genome activation (ZGA) denotes the initiation of gene expression after fertilization. It is part of the complex oocyte-to-embryo transition (OET) in which a highly specialized cell - the oocyte - is fertilized and transformed into a zygote that gives rise to an embryo that will develop into a newborn. From the perspective of gene expression, the OET reflects reprogramming of germ cell gene expression into the new developmental program of the zygote. This reprogramming occurs at transcriptional and post-transcriptional levels. This review will discuss selected aspects of mammalian ZGA, highlighting shared features and evolved differences observed in commonly investigated mammals and non-mammalian model animals. PMID- 29233751 TI - Differential binding of antibodies in PANDAS patients to cholinergic interneurons in the striatum. AB - Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus, or PANDAS, is a syndrome of acute childhood onset of obsessive-compulsive disorder and other neuropsychiatric symptoms in the aftermath of an infection with Group A beta-hemolytic Streptococcus (GABHS). Its pathophysiology remains unclear. PANDAS has been proposed to result from cross-reactivity of antibodies raised against GABHS with brain antigens, but the targets of these antibodies are unclear and may be heterogeneous. We developed an in vivo assay in mice to characterize the cellular targets of antibodies in serum from individuals with PANDAS. We focus on striatal interneurons, which have been implicated in the pathogenesis of tic disorders. Sera from children with well-characterized PANDAS (n = 5) from a previously described clinical trial (NCT01281969), and matched controls, were infused into the striatum of mice; antibody binding to interneurons was characterized using immunofluorescence and confocal microscopy. Antibodies from children with PANDAS bound to ~80% of cholinergic interneurons, significantly higher than the <50% binding seen with matched healthy controls. There was no elevated binding to two different populations of GABAergic interneurons (PV and nNOS-positive), confirming the specificity of this phenomenon. Elevated binding to cholinergic interneurons resolved in parallel with symptom improvement after treatment with intravenous immunoglobulin. Antibody-mediated dysregulation of striatal cholinergic interneurons may be a locus of pathology in PANDAS. Future clarification of the functional consequences of this specific binding may identify new opportunities for intervention in children with this condition. PMID- 29233754 TI - Molecular characterization, tissue distribution and differential nutritional regulation of putative Elovl5 elongase in silver barb (Puntius gonionotus). AB - Fatty acid desaturase (Fads) and elongase (Elovl) are two important enzymes involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) in fishes. Silver barb (Puntius gonionotus) is considered a promising medium carp species for freshwater aquaculture in Asia. Earlier, Delta6 fads cDNA was characterized to understand the molecular mechanism of LC-PUFA biosynthesis in this species. In the present study elovl5-like elongase full-length cDNA was cloned and characterized by RACE (rapid amplification of cDNA ends), and analyzed its basal expression in various organs/tissues by quantitative real time PCR (qRT PCR) assay. Differential expression of elovl5 cDNA in various tissues following replacement of fish oil (FO) with linseed oil (LO) in the diet also studied. The full length cDNA sequence of silver barb elovl5-like elongase consisted of 1853bp, including an open reading frame (ORF) of 876bp encoding a precursor protein of 291 amino acids possessing the entire characteristic features of Elovl protein. The elovl5 transcript was constitutively expressed in all the tissues examined: muscle, liver, brain, kidney, skin, intestine, gill and eye. The expression of elovl5 gene was upregulated, whereas the serum biochemical constituents were either remain unchanged or lowered following replacement of FO with LO in the diets. We report for the first time, an in silico 3D structure model of elongase protein from silver barb. All these findings may contribute to a better understanding the potential regulatory mechanisms involved and may be useful for enhancing endogenous LC-PUFA production in silver barb. PMID- 29233755 TI - Postoperative fasting after general anaesthesia: A survey of French anaesthesiology practices. AB - BACKGROUND: Preoperative fasting is well codified worldwide. In contrast, the literature on the postoperative fasting (POF) is scarce, leading to potentially wide discrepancies among anaesthesiology practices. This survey assessed French POF practices. METHODS: From March 2013 to January 2014, a survey was conducted among anaesthesiologists, members of the French Society of Anaesthesiology and Intensive Care Medicine (SFAR). The POF durations of either fluid or solid food intake was assessed according to airway management procedures (endotracheal intubation [EI] or laryngeal mask [LMA]) and age of the patients (adult or paediatric). RESULTS: Seven hundred and fifty-four surveys were returned (67% from public hospital practitioners and 33% from private hospital and clinic practitioners). The majority of anaesthesiologists allowed fluid intake 2h after EI and immediately after discharge from PACU following LMA. For solid food resumption, it was 2h for children and 4h for adults after EI and 2h for both children and adults after LMA. Regardless of the airway management procedures, fasting was permitted immediately after PACU discharge more frequently in public than in private hospitals (36% vs. 33%, P<0.05). Four hours after the end of surgery, the rate was significantly higher in private than in public hospitals (93% vs. 89 %, P<0.001). CONCLUSIONS: All in all, POF lasted less than 4hours after surgery regardless of airway management. They were shorter with regard to fluid intake, paediatric patients and LMA in comparison with solid food, adult patients and EI respectively. PMID- 29233753 TI - Targeting the 26S Proteasome To Protect Against Proteotoxic Diseases. AB - Aggregates of misfolded proteins can compromise the function of the 26S proteasome complex, leaving neurons susceptible to accelerated and impaired protein homeostasis, thereby contributing to the pathogenesis of neurodegeneration. Strategies aimed at enhancing the function of the 26S proteasome via phosphorylation of key subunit epitopes have been effective in reducing protein aggregates in mouse models of disease. We discuss how phosphodiesterase (PDE) inhibitors and G protein-coupled receptor (GPCR)-targeted drugs might be considered as candidate therapeutics, acting on second messenger signal transduction. The range of candidates might address the need for region-, cell-, or even cellular compartment-specific modulation. Given the array of clinical and experimental drugs targeting cAMP/cGMP signaling, we propose that proteasome activators targeting secondary messengers might be exploited as novel agents for the treatment or prevention of some neurodegenerative diseases. PMID- 29233756 TI - Paediatric minimally invasive abdominal and urological surgeries: Current trends and perioperative management. AB - Minimally invasive surgery during abdominal, thoracic and urological procedures has become the standard management of many surgical interventions in adults. Recent development of smaller devices has allowed the management of many paediatric surgeries using these minimally invasive techniques. However, the lack of knowledge of (a) adequate management of haemodynamic and respiratory alterations occurring during those procedures and (b) postoperative advantages of these techniques over open surgeries, still impairs their development. The current review aimed to clarify mechanisms of those haemodynamic and respiratory alterations, propose easy rules in order to overcome them and shed the light on potential postoperative advantages of minimally invasive surgery in paediatrics. PMID- 29233757 TI - The in vitro effect of Antimicrobial Photodynamic Therapy on dental microcosm biofilms from partially erupted permanent molars: A pilot study. AB - BACKGROUND: Antimicrobial Photodynamic Therapy (aPDT) could enhance the prevention of dental caries lesions in pits and fissures of partially erupted molars, by killing microorganisms from complex dental biofilms. This pilot study aimed to evaluate the effect of Antimicrobial Photodynamic Therapy (aPDT) on the viability of specific microorganism groups of dental microcosm biofilms from occlusal surfaces of first permanent molars in eruption. METHODS: Dental microcosm biofilms grown on bovine enamel blocks, from dental plaque collected on occlusal surfaces of a partially erupted lower right first permanent molar, with McBain medium plus 1% sucrose in anaerobic condition at 37 degrees C for 72 h. The experiments were performed in eight groups: L-P- = no treatment (control), L18.75P- = 18.75 J/cm2 LED, L37.5P- = 37.5 J/cm2 LED, L75P- = 75 J/cm2 LED, L-P+ = 200 mM TBO, L18.75P+ = 200 mM TBO + 18.75 J/cm2 LED, L37.5P+ = 200 mM TBO + 37.5 J/cm2 LED, and L75P+ = 200 mM TBO + 75 J/cm2 LED. The counts of total microorganisms, total streptococci and mutans streptococci were determined on selective media agar plates by colony-forming units per mL. The log-transformed counts were analyzed by Kruskal-Wallis and post-hoc Dunn's test (P < 0.05). RESULTS: The counts of all microorganisms treated in the group L75P+ were statistically lower than those treated in L-P-. The aPDT promoted a significant reduction of microorganisms, with a trend of dose-dependent effect. CONCLUSION: TBO-mediated aPDT was effective in reducing the viability of specific microbial groups in dental microcosm biofilms originated from occlusal of permanent molars in eruption. PMID- 29233758 TI - L. donovani XPRT: Molecular characterization and evaluation of inhibitors. AB - Among all PRT enzymes of purine salvage pathway in Leishmania, XPRT (Xanthine phosphoribosyl transferase) is unique in its substrate specificity and their non existence in human. It is an interesting protein not only for drug designing but also to understand the molecular determinants of its substrate specificity. Analysis of the 3D model of L. donovani XPRT (Ld-XPRT) revealed that Ile 209, Glu 215 and Tyr 208 may be responsible for the altered substrate specificity of Ld XPRT. Comparisons with it's nearest homologue in humans, revealed significant differences between the two. A 28 residue long unique motif was identified in Ld XPRT, which showed highest fluctuation upon substrate binding during MD simulations. In kinetic analysis, Ld-XPRT could phosphoribosylate xanthine, hypoxanthine and guanine with Km values of 7.27, 8.13, 8.48MUM and kcat values of 2.24, 1.82, 1.19min-1 respectively. Out of 159 compounds from docking studies, six compounds were characterized further by fluorescence spectroscopy, CD spectroscopy and enzyme inhibition studies. Fluorescence quenching experiment was performed to study the binding of inhibitors with Ld-XPRT and dissociation constants were calculated. Four compounds are bi-substrate analogues and show competitive inhibition with both the substrates (Xanthine and PRPP) of Ld-XPRT. The CD spectral analysis revealed that the binding of inhibitors to Ld-XPRT induce change in its tertiary structure, where as its secondary structure pattern remains unchanged. Two Ld-XPRT inhibitors (dGDP and cGMP), which also have ability to inhibit Leishmanial HGPRT, are predicted as potential drug candidates as it can inhibit both the important enzymes of the purine salvage pathway. PMID- 29233759 TI - Active-site mutations improved the transglycosylation activity of Stenotrophomonas maltophilia chitinase A. AB - Transglycosylation (TG) by family 18 chitinases is of special interest due to the many biological applications of long-chain chitooligosaccharides (CHOS). In the current study, the TG activity of chitinase A from Stenotrophomonas maltophilia (StmChiA) was improved through structure-guided mutations within and around the active site. Three independent mutants were created, targeting Trp residues from the -3 and -1 subsites and the central catalytic Asp from the DxDxE motif of StmChiA. The former was replaced with Ala and the latter with Asn. Changes in the hydrolytic and TG activities of the enzymes were assessed by monitoring the product profile of each mutant by high-performance liquid chromatography. All three mutants showed increased TG activity. Increased in the higher TG activity of mutant W306A was accompanied by increased hydrolysis. However, this mutant also accumulated substantial amounts of TG products during the first 15-30min of the reaction. In contrast, mutants D464N and W679A showed reduced hydrolysis, which was accompanied by the gradual accumulation of TG products up to 12h. Molecular docking studies with chitohexaose showed that the side chains of Trp residues mediate stacking interactions with sugar residues from the -3 and -1 subsites, indicating the importance of these residues in the enzymatic activity of StmChiA. Overall, mutants of the glycon-binding site (W306A and W679A) appear to produce long-chain CHOS more efficiently than the catalytic mutant D464N. PMID- 29233760 TI - Recovery after shoulder arthroscopy: Inpatient versus outpatient management. AB - INTRODUCTION: Shoulder arthroscopy is particularly suited to outpatient surgery, thanks to advances in anesthetic and analgesic techniques. The main goal of this study was to compare postoperative recovery after shoulder arthroscopy between outpatient and inpatient management. HYPOTHESIS: There is no difference in functional recovery between inpatient and outpatient management. MATERIALS AND METHOD: A single-center, single-operator prospective study was conducted. Both groups received patient-controlled analgesia via an interscalene catheter. The inclusion criterion was shoulder arthroscopy for rotator cuff tendinopathy. The choice between inpatient and outpatient management was left to the patient. The study endpoint was postoperative recovery assessed on QOR-15 at days 1, 2, 3, 4 and 7 and on Quick-DASH at 6 weeks. RESULTS: Forty-nine patients were included, divided into 2 groups. The outpatient (OP) and inpatient (IP) groups were comparable. Reconstructive surgery accounted for 54% of cases in OP versus 62% in IP. There was no significant difference in recovery in the first postoperative days (QOR-15) or at 6 weeks (Quick-DASH) (p>0.05). Pain on visual analog scale (VAS) was significantly greater in OP after discharge home. DISCUSSION: No significant difference in postoperative recovery was observed between groups. Nevertheless, pain management and patient information for outpatients need improving. LEVEL OF EVIDENCE: II, comparative study. PMID- 29233762 TI - Arthroscopically assisted reduction of acute acromioclavicular joint dislocation using a single double-button device: Medium-term clinical and radiological outcomes. AB - INTRODUCTION: Double-button devices for endoscopic management of acute acromioclavicular joint dislocation (ACJD) provide satisfactory short-term functional and radiological results. However, little exists in the literature regarding the long- and medium-term results of these implants, especially regarding the evolution of the acromioclavicular joint (ACJ). HYPOTHESIS: Satisfactory and steady long- and medium-term outcomes can be achieved in patients with acute ACJD undergoing endoscopically assisted ACJ repair using a single double-button device. MATERIAL AND METHOD: A retrospective single-center study was conducted in patients with acute Rockwood III and IV ACJD treated endoscopically with a single double-button device from October 2008 to October 2010, allowing a minimum 5-year follow-up. Functional evaluation used Constant and Quick-DASH scores. Clinical evidence of dislocation recurrence was combined with bilateral Zanca views to assess coracoclavicular distance. Acromioclavicular osteoarthritis was evaluated on the Paxinos test and Zanca views. RESULTS: Nineteen of the 25 operated patients were seen at a mean 76.9+/-8.5 months' follow-up. Mean age was 34.4+/-8.3 years. Mean Constant and Quick-DASH scores were 96.2+/-5.1 and 0.9+/-1.6 points, respectively. Four patients had a recurrence of their initial dislocation, 3 of whom had positive Paxinos test, whereas the 15 patients without recurrence had a negative test (p=0.004). Five patients had radiological evidence of ACJ osteoarthritis: all 4 patients with recurrence and 1 without (p=0.001). CONCLUSION: Long- and medium-term radioclinical outcome of endoscopically assisted management of acute ACJD using a single double-button device seems to be satisfactory and steady over time. Recurrence of the initial dislocation appears to be related to onset of degenerative ACJ arthropathy. LEVEL OF EVIDENCE: Therapeutic type IV Retrospective case series. PMID- 29233761 TI - The new digit tourniquet ForgetMeNot(r). AB - BACKGROUND: Digit tourniquets are widely used in the operating room and even more often in the emergency department to allow the exploration of injuries. A rolled surgical glove finger or silicone catheter placed at the base of the digit is a common method. However, rolled glove tourniquets are easily forgotten under the dressing and may then cause ischemia, which may require amputation. Silicone catheters are expensive single-use devices that may fail to provide effective exsanguination and must be removed by cutting, which may result in skin lesions. The ForgetMeNot(r) digit tourniquet (Arex, Palaiseau, France) was designed to overcome these drawbacks. The objective of this study was to assess the use of ForgetMeNot(r) in our clinical practice. HYPOTHESIS: The ForgetMeNot(r) digit tourniquet is easy to position and remove, effective, and difficult to accidentally leave in place. MATERIAL AND METHODS: ForgetMeNot(r) is composed of two solid cylindrical silicone strands emerging from a central crosspiece bearing two holes through which the ends of the strands can be threaded until stopped by beads on each strand. The device can be sterilised and re-used. It is easy to put in place and to remove. Threading the ends through the holes in the crosspiece forms two loops, which are passed around the tip of the finger. The device is then rolled down to the base of the digit, wrapping around itself and thus tightening gradually. At the end of the surgical procedure, pulling on the flat central crosspiece releases the device. ForgetMeNot(r) was tested by junior and senior surgeons in 86 patients. The following were assessed: pain, tourniquet time, effectiveness of exsanguination, complications, and the learning curve. RESULTS: Positioning the device caused no pain. No patient reported paraesthesia. Remembering to remove the device was made easy by its bright blue or yellow colour. The pressure applied ensured effective exsanguination of the digit. In no case was cutting the device required for removal. Each device was sterilised and re-used several times. DISCUSSION: The new digit tourniquet ForgetMeNot(r) is unlikely to be forgotten, effective, easy to use, re-usable, and associated with a low risk of skin lesions upon removal. LEVEL OF EVIDENCE: III, retrospective uncontrolled study. PMID- 29233763 TI - Application of 3D cultured multicellular spheroid tumor models in tumor-targeted drug delivery system research. AB - Tumor-targeted drug delivery systems are promising for their advantages in enhanced tumor accumulation and reduced toxicity towards normal organs. However, few nanomedicines have been successfully translated into clinical application. One reason is the gap between current pre-clinical and clinical studies. The prevalent in vitro models utilized in pre-clinical phase are mainly based on the two-dimensional (2D) cell culture and are limited by the difficulty of simulating three-dimensional physiological conditions in human body, such as three dimensional (3D) architecture, cell heterogeneity, nutrient gradients and the interaction between cells and the extracellular matrix (ECM). In addition, traditional animal models have drawbacks such as high-cost, long periods and physiological differences between animal and human. On the other hand, the employment of 3D tumor cell culture models, especially multicellular tumor spheroids (MCTS), has increased significantly in recent decades. These models have been shown to simulate 3D structures of tumors in vitro with relatively low cost and simple protocols. Currently, MCTS have also been widely exploited in drug delivery system research for comprehensive study of drug efficacy, drug penetration, receptor targeting, and cell recruitment abilities. This review summarizes the delivery barriers for nano-carriers presented in tumor microenvironment, the characteristics and formation methods for applicable multicellular tumor spheroid culture models and recent studies related to their applications in tumor-targeted drug delivery system research. PMID- 29233764 TI - Annulus-Sparing Tetralogy of Fallot Repair: Low Risk and Benefits to Right Ventricular Geometry. AB - BACKGROUND: Annulus-sparing repair of tetralogy of Fallot (TOF) carries a potential increased risk of reoperation for restenosis and unproven benefits on right ventricular (RV) geometry. METHODS: Primary TOF repairs (n = 434) between 2000 and 2012 were studied using risk-adjusted parametric techniques. Progression of cardiac dimensions was analyzed using repeated measures regression using reports of all 2,103 echocardiograms undertaken throughout the study period, to a maximum follow-up of 13.7 years. RESULTS: Repair was at a mean age of 180 days: AS approach in 296 (68%) patients; and transannular patch in 138 (32%). Intraoperative revisions (for residual stenosis) were required in 135 patients (29%). There have been 4 deaths (survival 99%). Surgical reoperation for recurrent right ventricular outflow tract stenosis was occasionally required in both groups at comparable rates (transannular patch, 5 of 136 [4%]; annulus sparing repair, 14 of 296 [5%]; p = 0.83). Larger increases in RV end-diastolic dimensions were evident in transannular patch patients versus annulus-sparing repair patients (p < 0.0001). Other risks for RV dilation included worse grade of postoperative pulmonary regurgitation, larger right ventricular end-diastolic dimension at the time of diagnosis, and higher operative weight (all p < 0.0001). Factors associated with successful annulus-sparing repair included (1) pulmonary annulus greater than 7 mm, right ventricular end-diastolic dimension greater than 1.2 cm, and tricuspid annulus greater than 1.4 cm (all preoperatively); and (2) right ventricular outflow tract diameter greater than 10 mm and right ventricular systolic pressure less than 50 mm Hg (both intraoperatively after repair). CONCLUSIONS: Pursuit of annulus-sparing repair strategies can lower the use of transannular patch to approximately 30% with low risk of reoperation for the patient. Annulus-sparing repair is associated with significantly reduced long term RV dilation. Pulmonary valve enlargement to approximately 10 mm and right ventricular systolic pressure less than 50 mm Hg during annulus-sparing repair are associated with low risk of recurrent stenosis. PMID- 29233765 TI - Invited Commentary. PMID- 29233766 TI - Use of the Perceval Sutureless Valve in Active Prosthetic Aortic Valve Endocarditis. AB - BACKGROUND: Surgical treatment of active prosthetic aortic valve endocarditis presents a challenge for cardiac surgeons because of tissue friability and destruction caused by infection. Sutureless prostheses, such as the Perceval S (LivaNova, Saluggia, Italy), have emerged as an option among the different surgical approaches for these complicated cases. METHODS: This study presents data from 9 patients who underwent aortic valve re-replacement with the Perceval S because of active prosthetic aortic valve endocarditis between January 2014 and August 2016. Hemodynamic performance (mean transprosthetic gradient and type of aortic regurgitation) was assessed intraoperatively after weaning from cardiopulmonary bypass, at discharge, and to 6 months postoperatively. RESULTS: After weaning from cardiopulmonary bypass, cases 1 and 3 through 6 had no or trivial aortic regurgitation, cases 7 and 8 presented with trivial to mild regurgitation, case 9 showed mild intraprosthetic regurgitation, and case 2 had mild periprosthetic regurgitation. Cases 4 and 7 died of septic shock and multiorgan failure in the perioperative period. In the remaining patients, severity of aortic regurgitation maintained practically invariable at discharge compared with intraoperative results. These 7 patients did well at 6-month follow up, with good clinical and hemodynamic performance of the Perceval S prosthesis. The median of mean transprosthetic gradient was 11 mm Hg (interquartile range: 10 to 12 mm Hg). Only patient 2 showed mild periprosthetic regurgitation; patient 9 showed mild intraprosthetic insufficiency, and the remaining patients had no or trivial regurgitation. CONCLUSIONS: The sutureless Perceval S valve is a reasonable alternative for surgical treatment of prosthetic aortic valve endocarditis. PMID- 29233767 TI - Patch Repair of Anomalous Origin of Left Anterior Descending Artery From the Right Coronary Artery. AB - Coronary artery anomalies occur in an estimated 1.3% of the population. We present the case of a 52-year-old man who had a less common anomaly of a left anterior descending artery arising from the right coronary ostium, causing ischemia and chest pain, demonstrated by perfusion scan. The usual options for management of coronary anomalies were not suitable for this anatomy, and therefore we present a case of patch augmentation of the arteries. PMID- 29233768 TI - Vaccine development targeting lipopolysaccharide structure modification. AB - Vaccines are one of the most important methods for preventing infectious disease. Structural modification of lipopolysaccharide (LPS) provides a strategy for the development of live attenuated vaccines, either by altering the immunogenicity or by attenuating virulence of the bacteria. This review summarizes various approaches that utilize LPS mutants as whole-cell vaccines. PMID- 29233769 TI - Historical evolution of regulatory standards for occupational and consumer exposures to industrial talc. AB - Talc has been used historically in a wide range of industrial applications and consumer products. The composition and purity of talc used for industrial purposes can vary greatly depending on the source and may contain asbestos minerals. The developing science associated with the health risks of asbestos had an effect on the talc industry throughout the 20th century. This review presents a detailed analysis of the evolution of regulatory standards impacting the use of industrial talc in the U.S. from the early 20th century through the 1990s. While it was recognized by the 1930s that airborne exposures to talc dust at high concentrations could cause lung disease, it was not until later that concerns were raised about the health risks associated with potential occupational exposures to asbestos from industrial talc. Regulatory agencies adopted occupational standards for industrial talc in the early 1970s, but the terminology used to define and characterize talc and other associated minerals varied between agencies. In addition, the complex and varying mineralogy of industrial talc led to inconsistent and imprecise interpretation of studies concerning health risk and occupational health standards among individual agencies. PMID- 29233770 TI - Dissipation kinetics, pre-harvest residue limits, and dietary risk assessment of the systemic fungicide metalaxyl in Swiss chard grown under greenhouse conditions. AB - The residual behavior of the systemic fungicide, metalaxyl, in Swiss chard cultivated at two different locations under greenhouse conditions was investigated using high-performance liquid chromatography coupled with an ultraviolet detector (HPLC-UVD). Samples were randomly collected over 14 days and extracted using acetonitrile, partitioned using solid sodium chloride, and a solid-phase extraction (SPE) NH2 cartridge was used for cleanup. The linearity over a concentration range 0.05-50 mg/L was excellent with a coefficient of determination (R2) of 0.9997. The recovery rate ranged from 77.05 to 88.92% with relative standard deviations (RSDs) <= 10.74, and the limits of detection (LOD) and quantification (LOQ) were 0.0033 and 0.01 mg/kg, respectively. The initial (2 h after application) deposits were 4.69 and 5.90 mg/kg for sites 1 and 2, respectively, which increased to 4.95 and 6.57 mg/kg, respectively, one day post application, owing to the systemic properties of the fungicide. The dissipation half-life was 5.3 and 6.0 days for sites 1 and 2, respectively. The pre-harvest residue limit (PHRL) suggested that if 55.38 and 47.23 mg/kg was applied 10 days before harvest or 33.28 and 30.73 mg/kg was applied 5 days before harvest (for sites 1 and 2, respectively) then the concentration will fall below the maximum residue limit (MRL = 20.0 mg/kg) at the time of harvest. The dietary risk assessment, estimated as hazard quotient (RQ%), indicate that metalaxyl can be safely used in/on Swiss chard, with no hazardous effects expected for consumers. PMID- 29233771 TI - Toxicological evaluation of beta-Galactosidase enzyme produced by Papiliotrema terrestris. AB - beta-Galactosidase (EC 3.2.1.23) is a glycoside hydrolase that catalyzes the release of sugar monomers from beta-galactoside oligosaccharides via hydrolysis of glycosidic bonds, and has potential uses in the food industry. The safety of this enzyme and its production organism, Papiliotrema terrestris (P. terrestris), are described herein. P. terrestris was non-pathogenic upon intravenous (IV) administration of 2.4 * 108 cfu and oral administration of 1.3 * 109 cfu. Genotoxic results for the enzyme concentrate were negative in a bacterial reverse mutation test (Ames test) and chromosome aberration test in cultured Chinese hamster lung fibroblast (CHL/IU) cells. In a 13-week oral gavage study in Sprague Dawley rats, no adverse effects were observed in any of the tested group and a No Observed Adverse Effects Level (NOAEL) of 2000 mg/kg bw/day [total organic solids (TOS) 1800 mg/kg bw/day)] was established, which was the highest dosage tested. Allergenicity sequence analysis revealed no evidence suggesting that beta galactosidase is an allergen. The data presented in this study support the conclusion that beta-galactosidase produced from P. terrestris is safe for use in food production. PMID- 29233772 TI - Genetic toxicological assessment and anti-arthritic effects of an ethanolic extract obtained from Salvia lachnostachys Benth leaves in mice. AB - In the present study, mice were subjected to prolonged treatment with ethanolic extract of Salvia lachnostachys Benth leaves (SLEE), and the inflammatory and arthritic parameters were evaluated using the Complete Freund's Adjuvant (CFA) model. The genotoxicity of SLEE were also assayed using genetic toxicological tests. For the CFA model, 28 male C57BL/6 mice were distributed randomly into four groups (control, 50 mg/kg of SLEE, 100 mg/kg of SLEE and dexamethasone) for the evaluation of hyperalgesia and paw edema for 21 days after injection of CFA into the paw. To conduct the toxicogenetic assessments (comet assay and micronuclei assay), apoptosis and splenic phagocytosis were evaluated in male Swiss mice after the administration of saline (control group), cyclophosphamide (positive control group) and SLEE (10, 100 and 1000 mg/kg). SLEE significantly reduced the mechanical hyperalgesia and edema caused by CFA injection. The results of the toxicogenetic assessment revealed no toxicogenetic potential in the mice, and the evaluation of apoptosis showed an increase in apoptotic cells in the spleen after 72 h of treatment with SLEE (1000 mg/kg). SLEE exhibited anti arthritic activity with no toxicogenetic damage. These toxicogenic results support the safety of SLEE. PMID- 29233773 TI - Repeated oral dose toxicity study on hydrolysable tannin rich fraction isolated from fruit pericarps of Terminalia chebula Retz in Wistar albino rats. AB - Terminalia chebula fruits are one of the richest sources of hydrolysable tannins and it is well known medicinal agent in traditional systems of medicine for treatment of various chronic ailments. In the present study, hydrolysable tannin rich fraction (HTF) was isolated from 80% hydroalcoholic extract of Terminalia chebula fruit pericarps and it was studied for acute and repeated dose oral toxicity in Wistar albino rats. HTF did not show any toxic symptoms or mortality at single dose administration of 5000 mg/kg/p.o followed by observation for 14 days. On repeated dose 28 days oral toxicity study, administration of HTF at 1000 mg/kg showed marked reduction in body weight, food intake and water intake when compared with vehicle control. It was also observed that HTF could increase serum urea, glucose and AST level significantly when compared with vehicle control indicating mild disturbances in liver and kidney functions. On histopathological screening, HTF treatment showed a mild granulomatous inflammation in the liver and all other organs remained normal. It was concluded that following 28 days repeated dose oral administration, HTF caused mild disturbances in liver and kidney function which was indicated by reduced body weight, food and water intake, serum parameters and histological observations. PMID- 29233774 TI - Spurious intraoperative PTH results observed with 2nd, but not with 3rd generation PTH assays. AB - We report here an interference that has been observed with 2nd generation PTH assays (PTH2), but not with 3rd generation PTH ones (PTH3), during PTH monitoring occurring in a surgical intervention for the resection of a parathyroid adenoma. The patient was cured and calcium levels returned to normal the next day, but PTH did not decrease with PTH2 whereas it decreased by 50% with PTH3 assays during the intervention. The reason is probably a PTH fragment released by the parathyroid gland during surgery. This fragment possesses the C-terminal part of the peptide but lacks the first amino-acids and may thus be considered as a member of the non-(1-84) PTH fragments family. It has also a longer half-life than 1-84 PTH. To avoid reporting spurious results to the surgeons, we thus recommend using PTH3 assays for monitoring of intra-operative PTH. PMID- 29233775 TI - An exploration of the role of asymptomatic infections in the epidemiology of dengue viruses through susceptible, asymptomatic, infected and recovered (SAIR) models. AB - It is estimated that 20-97% of all dengue infections could be asymptomatic. I used SIR models to investigate the epidemiological role of such infections, by adding an asymptomatic class (SAIR models). Upon infection in one of the models, a human becomes either symptomatic or asymptomatic. In the other, a human becomes asymptomatic and may progress to being symptomatic. The robustness of results from these models is examined by incorporating the mosquito-vector into one of the models, followed by simulating epidemic dynamics stochastically. Results from the first two models were very similar, with epidemics typically lasting less than one year. When mosquitoes were explicitly modelled in a high-transmission setting, if the level or duration of infectivity from asymptomatic infections was high relative to symptomatic infections, dengue would become endemic. Under stochastic simulation this effect of asymptomatic infections leading to dengue persisting was no longer guaranteed. Longer durations in asymptomatic infections had a higher chance of causing dengue's persistence in stochastic simulation, indicating that this may be more of a key determinant for dengue's persistence to 10 years than the infectivity of such infections. Otherwise, the level and duration of infectivity from asymptomatic infections had similar effects on R0 and other epidemiological measures. With all models, outbreaks often led to a larger proportion of the population being immune than suggested by monitoring symptomatic dengue infections. This population would be at risk of developing severe dengue in a subsequent outbreak with a different dengue serotype, and would have to be determined via expansion factors. PMID- 29233776 TI - Bovine mastitis: An appraisal of its alternative herbal cure. AB - Bovine mastitis is globally recognized as the most common and costly disease affecting dairy herds. The disease causes huge financial losses to dairy industries by reduced yield and milk quality, deaths and culling of affected cows and also by associated treatment costs. The disease occurs due to invasion of the mammary glands by pathogenic bacteria followed by their multiplication in the milk producing tissues. The most common treatment method available against bovine mastitis is the intra-mammary infusion of antibiotics. However, their use is associated with the problem of antimicrobial resistance. This scenario has made search for alternative treatment approaches necessary. Medicinal plants with their well-established history are an excellent natural product resource used as an alternative therapy. Antibacterial agents from plants can act as important sources of novel antibiotics, efflux pump inhibitors, compounds that target bacterial virulence or can be used in combination with existing drugs. The plants form an essential component of ethno-veterinary medicine used in the treatment of different diseases like bovine mastitis. This review article attempts to provide an overview of the different medicinal plants used in the treatment of bovine mastitis. Antimicrobial studies of these plant species and some of their isolated constituents have been reviewed in detail. It highlights the logic and precedence behind mining this important natural product resource. Our own research findings in this direction and future scope of research are also discussed briefly. PMID- 29233777 TI - Characterization and pathogenicity of Fusarium species associated with leaf spot of mango (Mangifera indica L.). AB - Leaf spot diseases are mainly caused by fungi including Fusarium. In the present study several species of Fusarium were isolated from the leaf spot lesion of mango (Mangifera indica L.) Based on morphological characteristics, TEF-1alpha sequences and phylogenetic analysis, five species were identified as F. proliferatum, F. semitectum, F. mangiferae, F. solani and F. chlamydosporum. Pathogenicity test indicated that representative isolates of F. proliferatum, F. semitectum and F. chlamydosporum were pathogenic on mango leaves causing leaf spot with low to moderate virulence. Nevertheless, abundance of spots on the leaf can disrupt photosynthesis which in turn reduced growth, and lead to susceptibility to infection by opportunistic pathogens due to weakening of the plant. Fusarium solani and F. mangiferae were non-pathogenic and it is possible that both species are saprophyte which associated with nutrient availability on the surface of the leaf through decaying leave tissues. The occurrence of Fusarium spp. on the leaf spot lesion and the effect from the disease needs to be considered when developing disease management method of mango cultivation as numerous spot on the leaves could effect the photosynthesis process and finally giving low yield and less quality of mango. PMID- 29233778 TI - Phenotypic indications of FtsZ inhibition in hok/sok-induced bacterial growth changes and stress response. AB - The hok/sok locus has been shown to enhance the growth of bacteria in adverse growth conditions such as high temperature, low starting-culture densities and antibiotic treatment. This is in addition to their well-established plasmid stabilization effect via post-segregational killing of plasmid-free daughter cells. It delays the onset of growth by prolonging the lag phase of bacterial culture, and increases the rate of exponential growth when growth eventually begins. This enables the cells adapt to the prevailing growth conditions and enhance their survival in stressful conditions. These effects functionally complement defective SOS response mechanism, and appear analogous to the growth effects of FtsZ in the SOS pathway. In this study, the role of FtsZ in the hok/sok-induced changes in bacterial growth and cell division was investigated. Morphologic studies of early growth-phase cultures and cells growing under temperature stress showed elongated cells typical of FtsZ inhibition/deficiency. Both ftsZ silencing and over-expression produced comparable growth effects in control cells, and altered the growth changes observed otherwise in the hok/sok+ cells. These changes were diminished in SOS-deficient strain containing mutant FtsZ. The involvement of FtsZ in the hok/sok-induced growth changes may be exploited as drug target in host bacteria, which often propagate antibiotic resistance elements. PMID- 29233779 TI - Molecular cloning and characterization of a novel vip3-type gene from Bacillus thuringiensis and evaluation of its toxicity against Helicoverpa armigera. AB - Vegetative insecticidal proteins (Vips) represent the second generation of insecticidal trans-genes that will complement the Bacillus thuringiensis delta endotoxins in future. A new vip3A gene was cloned from the promising native isolate, B. thuringiensis JK37 obtained from the soils of maize field. The entire coding sequence of the gene (2370 bp) was amplified and cloned into pET28a(+) expression vector. The deduced amino acid sequence of the vip3A gene revealed variation of several amino acid residues with that of the known vip3A genes and this gene was designated as vip3Aa61 by the B. thuringiensis nomenclature committee. The recombinant pET28a(+)-vip3Aa61 was transformed and expressed in Escherichia coli strain BL21 (DE3) under the control of T7 promoter. SDS-PAGE and Western blot analysis confirmed the expression of an 89 kDa protein. Insect bioassays with 2nd instar larvae of Helicoverpa armigera, one of the most notorious pest affecting various crops including cotton and chick pea displayed toxicity. The toxicity of Vip3Aa61 was expressed as mean lethal concentration (LC50), which was 169.63 ng cm-2. The novel vip3Aa gene may be used for the construction of transgenic plants expressing insecticidal protein for the control of lepidopteran insect pests. PMID- 29233780 TI - A novel series of N-acyl substituted indole-linked benzimidazoles and naphthoimidazoles as potential anti inflammatory, anti biofilm and anti microbial agents. AB - A novel N-acyl substituted indole-linked benzimidazoles and naphthoimidazoles were synthesized. Their chemical structures were confirmed using spectroscopic tools including 1H NMR, 13C NMR and CHN-elemental analyses. Anti inflammatory activity for all target compounds was evaluated in-vitro. The synthesized compounds hinder the biofilm formation and control the growth of the pathogen, Staphylococcus epidermis. Anti microbial activity of the compounds was evaluated against both Gram negative and Gram positive bacteria such as Staphylococcus aureus (MTCC 2940), Pseudomonas aeruginosa (MTCC424), Escherchia coli (MTCC 443) and Enterococcus fecalis. PMID- 29233781 TI - Synthesis and in vitro evaluation of 2-(((2-ether)amino)methylene)-dimedone derivatives as potential antimicrobial agents. AB - The study was designed with an aim to synthesize a series of 2-(((2 ether)amino)methylene)-dimedone derivatives and evaluate the synthesized compounds for antimicrobial activity. Compound library was synthesized by reaction with alkyl, alkenyl, alkynyl and alicyclic bromo-compounds. Characterization of the synthesized compounds was performed by 1H NMR, 13C NMR and mass spectral techniques. The compounds were evaluated for their antibacterial activity against Gram-positive (Staphylococcus aureus, Bacillus subtilis, Clostridium sporogenes) and Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli). The activity of these compounds was also evaluated against fungi (Aspergillus fumigatus, Penicillium chrysogenum, Fusarium oxysporum, Candida albicans) and molds (A. niger and A. oryzae). Broth microdilution method and CLSI guidelines with minor modification were used for the determination of anti-bacterial and antifungal activity, respectively. Although four compounds (4i, 4j, 4k and 4l) showed good antibacterial activity but compound 4k was found to be most active chemotype in the series. Compound 4k was found to be active against S. aureus, B. cereus and B. subtilis bacterial strains at one dilution lower compared to the control ciprofloxacin. Antibacterial activity of compound 4k was comparable to ciprofloxacin against S. pyogenes and M. luteus. The compound 4d, 4e and 4s showed good antifungal and antimold activity compared to other chemotypes. However, in comparison to fluconazole both the compounds showed lower activity. The results merit the antimicrobial promise of the 2-(((2-ether)amino)methylene)-dimedone analogs. PMID- 29233783 TI - Transcranial direct current stimulation of 20- and 30-minutes combined with sertraline for the treatment of depression. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) can be an effective treatment for depression, however, the duration of the stimulation session, among other parameters, needs to be optimized. METHODS: 69 mild to moderately depressed patients (age 37.6+/-10.5years, 19 men) were randomized into three groups - 30-, 20-minute or sham tDCS. 10 daily sessions of anodal/sham tDCS of the left DLPFC (0.5mA; electrode 3,5*7cm) combined with 50mg/day of sertraline were performed. Mood, cognition and BDNF level were assessed before and after the treatment. RESULTS: A significant difference between groups was observed in the percent change of the Hamilton Depression Rating Scale (F(2, 66)=10.1; p<0.001). Sham group (43.4%+/-18.1) had a smaller improvement compared to the 30-minute (63.8%+/ 13.4; 95% CI: 11.23-29.44; p=0.00003) and 20-minute group (53.2%+/-15.3; 95% CI: 0.21-19.26; p=0.045). 30-minute group had significantly greater percent improvement than 20-minute group (95% CI: 1.74-19.46; p=0.02). Responders constituted 89%, 68%, and 50% and remitters - 70%, 27%, and 35% in the 30-, 20 minute and sham groups, respectively. A significant difference in the number of responders was observed between 30-minute vs. sham group (odds ratio=8; 95% CI, 2.59-24.69; p=0.001), in remission rate - between 30-minute vs. sham (odds ratio=4.40; 95% CI, 2.02-9.57; p=0.02) and vs. 20-minute (odds ratio=6.33; 95% CI, 2.85-14.10; p=0.003) groups. Two hypomania cases and one case of blood pressure elevation were detected in the 20-minute group. Among neuropsychological tests, only the change in Digit Span Backwards test showed a significant interaction between groups (TIME*GROUP; F(2, 65)=6,6, p=0.002); a greater improvement was observed in both active groups compared to sham (p<0.05). The change in BDNF level after the treatment did not show the significant difference between groups. CONCLUSIONS: tDCS of 20- or 30-minutes combined with sertraline are efficient for the treatment of mild and moderate depression; the effect of 30min stimulation exceeds the one obtained from 20min. PMID- 29233782 TI - Expression of superantigens and the agr system in Staphylococcus epidermidis. AB - Infections with coagulase-negative staphylococci (CoNS) can involve the production of toxins such as superantigens, which contribute to tissue degradation and inflammatory immune responses. The accessory gene regulator (agr) quorum sensing system coordinates the expression of most S. aureus virulence factors. Therefore, the aim of this study was to investigate the expression of these superantigens and the presence of the agr locus in CoNS strains isolated from blood cultures. PCR was used to detect enterotoxin and agr genes and expression was analyzed by RT-PCR. Expression of the sea gene was observed in one S. epidermidis isolate andof sec-1 in two, seg and sei were expressed concomitantly in one isolate, and sei was expressed in another isolate. The agr group I was detected in S. epidermidis expressing the sea, seg and sei genes, whereas agr group II was detected in isolates expressing thesec-1 gene. The agr groups were only expressed in strains expressing thesec-1 gene. The results show that enterotoxin genes are highly frequent in CoNS isolated from clinical specimens and confirm the toxin-producing ability of these strains. The agr group II may be associated with enterotoxin C production by S. epidermidis, increasing the virulence of strains isolated from blood cultures and consequently the severity of sepsis caused by these organisms. PMID- 29233784 TI - Altered natural killer cell cytokine profile in type 2 autoimmune hepatitis. AB - Type 2 autoimmune hepatitis (AIH-2) is a rare disease presenting in early childhood. The immunopathogenetic mechanisms are poorly characterized, although a defect of regulatory T cells (Treg) has been shown. There is virtually no information on innate immune responses and natural killer (NK) cells in particular. We have performed an extended immunophenotypic and functional analysis of NK cells in children with AIH-2. We show that NK cell frequency is reduced in this setting and that the balance between NK activating and inhibitory receptors is skewed toward activation. More importantly, NK cells display an altered cytokine pattern characterized by increased IFNgamma and reduced IL2 production which could contribute to impaired Treg function. Exposure of mononuclear cells to IL2 resulted in normalization of NK IFNgamma production. Thus, our findings support treatment of AIH-2 with low-dose IL2, which would result in normalization of NK cell function and expansion of the Treg cell subset. PMID- 29233785 TI - Angiotensin II receptor blocker valsartan ameliorates cardiac fibrosis partly by inhibiting miR-21 expression in diabetic nephropathy mice. AB - Cardiac fibrosis with diabetic nephropathy (DN) is one of major diabetic complications. miR-21 and MMP-9 were closely associated with fibrosis diseases. Angiotensin II receptor blockers (ARB) have cardioprotective effects. However, it remains unclear whether miR-21 was involved in the mechanism of cardiac fibrosis with DN by target MMP-9 and ARB ameliorates cardiac fibrosis partly by inhibiting miR-21 expression. In this study, In Situ Hybridization(ISH), RT-PCR, cell transfection, western blotting and laser confocal telescope were used, respectively. ISH showed that miR-21, concentrated in cytoplasmic foci in the proximity of the nucleus, was mainly localized in cardiac fibroblasts and at relatively low levels in cardiomyocytes within cardiac tissue with DN. RT-PCR showed that miR-21 expression was significantly enhanced in cardiac tissue with DN, accompanied by the increase of col-IV, FN, CVF, PVCA, LVMI, HWI and NT-pro BNP (p < 0.05). Bioinformatics analysis and Luciferase reporter gene assays showed that MMP-9 was a validated target of miR-21. Furthermore, cell transfection experiments showed that miR-21 overexpression directly decreased MMP 9 expression. Interestingly, miR-21 levels in cardiac tissue was positively correlated with ACR (r = -0.870, P = 0.003), whereas, uncorrelated with SBP, HbA1C and T-Cho (p > 0.05). More importantly, ARB can significantly decrease miR 21 expression in cardiac tissue, cardiac fibroblasts and serum. Overall, our results suggested that miR-21 may contribute to the pathogenesis of cardiac fibrosis with DN by target MMP-9, and that miR-21 may be a new possible therapeutic target for ARB in cardiac fibrosis with DN. PMID- 29233786 TI - Insulin-like Growth Factor 1 (IGF-1) as a marker of cognitive decline in normal ageing: A review. AB - Insulin-like Growth Factor 1 (IGF-1) and its signaling pathway play a primary role in normal growth and ageing, however serum IGF-1 is known to reduce with advancing age. Recent findings suggest IGF-1 is essential for neurogenesis in the adult brain, and this reduction of IGF-1 with ageing may contribute to age related cognitive decline. Experimental studies have shown manipulation of the GH/GF-1 axis can slow rates of cognitive decline in animals, making IGF-1 a potential biomarker of cognition, and/or its signaling pathway a possible therapeutic target to prevent or slow age-related cognitive decline. A systematic literature review and qualitative narrative summary of current evidence for IGF-1 as a biomarker of cognitive decline in the ageing brain was undertaken. Results indicate IGF-1 concentrations do not confer additional diagnostic information for those with cognitive decline, and routine clinical measurement of IGF-1 is not currently justified. In cases of established cognitive impairment, it remains unclear whether increasing circulating or brain IGF-1 may reverse or slow down the rate of further decline. Advances in neuroimaging, genetics, neuroscience and the availability of large well characterized biobanks will facilitate research exploring the role of IGF-1 in both normal ageing and age-related cognitive decline. PMID- 29233787 TI - Anal advancement flap versus lateral internal sphincterotomy for chronic anal fissure- a systematic review and meta-analysis. AB - BACKGROUND: Chronic anal fissures (CAF) are common and associated with reduced quality of life. Lateral internal sphincterotomy (LIS) is frequently carried out but carries a significant risk of anal incontinence. Anal advancement flap (AAF) has been advocated as an alternative, 'sphincter-preserving' procedure. We aimed to perform a systematic review and meta-analysis to compare the efficacy of both techniques in the treatment of CAF. METHODS: The online databases of PubMed/Medline, CINAHL, EMBASE and Cochrane Central Register of Controlled Trials were searched from inception to January 2017. All studies that investigated and reported outcomes of LIS and AAF for treatment of CAF were included. The primary outcome measure was anal incontinence while secondary outcomes included unhealed fissure and wound complication rates. Random effects models were used to calculate pooled effect size estimates. RESULTS: Four studies (2 randomized controlled trials and 2 retrospective studies) describing 300 patients (150 LIS, 150 AAF) fulfilled our inclusion criteria. There was significant clinical heterogeneity among the trials. On random effects analysis, AAF was associated with a significantly lower rate of anal incontinence compared to LIS (OR = 0.06, 95% CI = 0.01 to 0.36, p = .002). However, there were no statistically significant differences in unhealed fissure (OR = 2.21, 95% CI = 0.25 to 19.33, p = .47) or wound complication rates (OR = 1.41, 95% CI = 0.50 to 4.99 p = .51) between AAF and LIS. CONCLUSIONS: AAF is associated with less incontinence, but similar wound complications as well as a similar rate of unhealed fissures compared to LIS. However, further well-executed, multi-centre randomized trials are required to provide stronger evidence. PMID- 29233788 TI - Day case laparoscopic cholecystectomy: Safety and feasibility in obese patients. AB - INTRODUCTION: Day-case laparoscopic cholecystectomy (DCLC) is not universally adopted and its use is limited to patients selected by non-standardized criteria. Since laparoscopic cholecystectomy is considered technically more difficult in obese patients, a high body mass index (BMI) is often considered an exclusion criterion for DCLC. The aim of this research is to define the feasibility and safety of day case laparoscopic cholecystectomy in obese patients. PRESENTATION OF CASE: Data from 730 consecutive patients preoperatively considered suitable for DCLC were analysed. BMI was not considered as parameter of selection and patients were divided in two groups (Obese, 294; Non-obese, 436) according to a BMI >= 30 or < 30 kg/m2, respectively. Outcomes measured were morbidity, open conversion rates, hospitalization rates, length of hospital stay and readmission. Overall morbidity and open conversion rates were similar in both groups. No significant differences were observed among the two groups in terms of hospitalization rates (p 0.0533), early complications (p 0.2536), length of hospital stay (p 0.3780) and readmission rates (p 0.4286). DISCUSSION: Day case laparoscopic cholecystectomy is a widely used surgical technique despite not routinely used in every health system. However, many factors related to the patient and procedure, as well as the expertise of surgical-anesthesiologist team, can influence the feasibility of DCLC. Moreover a well-organized health community system is necessary to protect and follow the patients up. Our readmission and complication rates showed how a day case laparoscopic cholecystectomy, if performed in the right setting, is a safe procedure also for patient with a raised BMI. We enrolled a large population of patients and the statistical analysis demonstrated no significant differences among the obese and non-obese patient regarding the primary and secondary endpoints. CONCLUSIONS: DCLC is a safe and effective procedure in obese patients with morbidity, hospital admission and readmission rates similar to those observed in non-obese patients. PMID- 29233789 TI - Predictive Performance of Four Programmed Cell Death Ligand 1 Assay Systems on Nivolumab Response in Previously Treated Patients with Non-Small Cell Lung Cancer. AB - INTRODUCTION: Nivolumab has demonstrated efficacy against metastatic NSCLC. Four programmed cell death ligand 1 (PD-L1) immunohistochemistry (IHC) assay systems are available for identification of responders among patients with NSCLC, and these assays show some differing characteristics. Accordingly, in this study, we evaluated the ability of these assays to identify responders to nivolumab therapy. METHODS: We retrospectively analyzed patients with previously treated advanced NSCLC, who received nivolumab between January 2016 and September 2016. Specimens were stained using four PD-L1 IHC assays (28-8, 22C3, SP142, and SP263). We classified patients as having test results that were strongly positive (tumor proportion score [TPS] >=50%), weakly positive (TPS 1%-49%), or negative (TPS <1%). RESULTS: A total of 40 patients with NSCLC and their specimens were analyzed. Analytical comparisons demonstrated good concordance of PD-L1-stained tumor cells among the 28-8, 22C3, and SP263 assays (weighted kappa coefficient 0.64-0.71), whereas the SP142 assay showed lower concordance with other assays (weighted kappa coefficient 0.39-0.55). Progression-free survival in patients showing strongly positive PD-L1 staining classified by 28-8, 22C3, and SP263 assays was significantly longer than that in patients with a negative result for PD-L1 staining. Predictive performance of response to nivolumab, as assessed by receiver operating characteristic analysis, was also equivalent among the 28-8, 22C3, and SP263 assays (area under the curve 0.75-0.82), whereas the SP142 assay exhibited lower predictive performance (area under the curve 0.68). CONCLUSIONS: The 28-8, 22C3, and SP263 PD-L1 IHC assays showed equivalent predictive performance, whereas the SP142 assay showed lower predictive performance. PMID- 29233791 TI - Incidental Anterior Mediastinal Nodular Lesions on Chest CT in Asymptomatic Subjects. AB - OBJECTIVE: The aim of this study was to investigate the prevalence and characteristics of nodular lesions in the anterior mediastinum that had been found incidentally on screening chest computed tomography (CT) in asymptomatic subjects. METHODS: We included 56,358 consecutive participants (mean age 52.4 +/- 10.5 years; male-female ratio 35,306:21,052) who underwent a baseline low-dose chest CT scan as part of a health checkup from 2006 through 2013. After the presence of anterior mediastinal nodular lesion had been confirmed, their CT findings, confirmatory diagnosis, and interval CT scan were reviewed. The standardized prevalence ratio for thymic epithelial tumor was calculated on the basis of the Republic of Korea cancer statistics for 2014. RESULTS: Of the 56,358 participants, 413 (0.73%) had lesions (95% confidence interval: 0.66-0.80%); the prevalence increased with age (p <0.001) and a history of malignancy (p = 0.005). Of the lesions, 85.2% were smaller than 2 cm, 61.3% were round, and 80.2% had CT attenuation higher than 20 Hounsfield units. Among 51 proven cases, 39 lesions (76.9%) were benign and 12 (23.1%) were malignant. The standardized prevalence ratio for thymic epithelial tumor was 2.04 (95% confidence interval: 1.01-3.42). Of 11 resected thymic epithelial tumors, five were carcinomas, 10 were stage I or II, and all were completely resected without recurrence. Of the 237 unconfirmed cases with a follow-up CT scan, 82.2% were stable, 8.9% had increased, and the other 8.9% had decreased. CONCLUSIONS: The prevalence of incidental nodular lesion was 0.73%. Most lesions had CT features that were indistinguishable from thymic epithelial tumors, but a considerable portion of the lesions were suspected to be benign. Incidental thymic epithelial tumors were more prevalent than clinically detected tumors, were early-stage cancer, and showed favorable outcomes. PMID- 29233790 TI - Preclinical Evidence for Combined Use of Aromatase Inhibitors and NSAIDs as Preventive Agents of Tobacco-Induced Lung Cancer. AB - INTRODUCTION: A hormonal role in NSCLC development is well documented. We previously showed that the aromatase inhibitor (AI) anastrozole decreased development of tobacco carcinogen-induced lung tumors in a murine lung cancer prevention model and that aromatase and estrogen receptor were expressed in pulmonary inflammatory cells. METHODS: We utilized a tobacco carcinogen-induced lung tumor mouse model by treatment with 4-(methylnitrosoamino)-1-(3-pyridyl)-1 butanone (NNK), to determine whether an AI combined with nonsteroidal anti inflammatory drugs results in greater lung tumor prevention effects compared to single-agent treatment. RESULTS: Combination of anastrozole (0.1 mg/kg/d) with aspirin (25 mg/kg/d) after NNK exposure resulted in significantly fewer and smaller lung tumors than did single-agent treatments and was accompanied by maximum decreases in circulating beta-estradiol (E2) and interleukin-6, tumor infiltrating macrophages, and tumoral Ki67, phospho-mitogen-activated protein kinase, phospho-signal transducer and activator of transcription 3, and interleukin-17A expression. Preneoplasia arising after combination treatment showed the lowest Sox-2 expression, suggesting an inhibitory effect on proliferative capacity in the airways by blocking both E2 and inflammation. Anastrozole combined with ibuprofen instead of aspirin also showed enhanced antitumor effects. Moreover, male mice treated with NNK that received E2 in their drinking water showed greater levels of pulmonary macrophages and inflammatory markers than did the control, confirming an E2 effect on inflammation in the microenvironment. CONCLUSIONS: Our results suggest a benefit to joint targeting of the estrogen and inflammatory pathways for NSCLC prevention. Combining AIs with nonsteroidal anti-inflammatory drugs reduces circulating E2, proinflammatory cytokines, and macrophage recruitment in the lung microenvironment after tobacco exposure. This strategy could be particularly effective in women who have underlying pulmonary inflammatory diseases. PMID- 29233792 TI - N-acetylcysteine supplementation increases exercise performance and reduces oxidative stress only in individuals with low levels of glutathione. AB - Most of the evidence indicates that chronic antioxidant supplementation induces negative effects in healthy individuals. However, it is currently unknown whether specific redox deficiencies exist and whether targeted antioxidant interventions in deficient individuals can induce positive effects. We hypothesized that the effectiveness of antioxidant supplements to decrease oxidative stress and promote exercise performance depends on the redox status of the individuals that receive the antioxidant treatment. To this aim, we investigated whether N-acetylcysteine (NAC) supplementation would enhance exercise performance by increasing glutathione concentration and by reducing oxidative stress only in individuals with low resting levels of glutathione. We screened 100 individuals for glutathione levels and formed three groups with low, moderate and high levels (N = 36, 12 per group). After by-passing the regression to the mean artifact, by performing a second glutathione measurement, the individuals were supplemented with NAC (2 * 600mg, twice daily, for 30 days) or placebo using a double-blind cross-over design. We performed three whole-body performance tests (VO2max, time trial and Wingate), measured two systemic oxidative stress biomarkers (F2 isoprostanes and protein carbonyls) and assessed glutathione-dependent redox metabolism in erythrocytes (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase and NADPH). The low glutathione group improved after NAC supplementation in VO2max, time trial and Wingate by 13.6%, 15.4% and 11.4%, respectively. Thirty days of NAC supplementation were sufficient to restore baseline glutathione concentration, reduce systemic oxidative stress and improve erythrocyte glutathione metabolism in the low glutathione group. On the contrary, the 30-day supplementation period did not affect performance and redox state of the moderate and high glutathione groups, although few both beneficial and detrimental effects in performance were observed. In conclusion, individuals with low glutathione levels were linked with decreased physical performance, increased oxidative stress and impaired redox metabolism of erythrocytes. NAC supplementation restored both performance and redox homeostasis. PMID- 29233793 TI - Licochalcone A activates Keap1-Nrf2 signaling to suppress arthritis via phosphorylation of p62 at serine 349. AB - Licochalcone A (LCA) is derived from glycyrrhizae radix with antimicrobial, antitumor and anti-inflammatory activities. However, the anti-arthritic function of LCA and underlying mechanism has not been yet explored. The current study investigated the anti-arthritic effect of LCA and elucidated the underlying mechanism. The results showed that LCA significantly suppressed arthritis via the activation of SQSTM1 (p62)/nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling in the collagen-induced arthritis (CIA) model of DBA mice. In coincided with the results, this anti-arthritic effect of LCA was remarkably diminished in the collagen antibody-induced arthritis (CAIA) model of Nrf2-/- mice. These findings indicate that p62/Nrf2 signaling is a crucial pathway for the induction and treatment of arthritis. To further validate the effect of LCA on the arthritis, rheumatoid arthritis synovial fibroblasts (RASFs) isolated from the synovium of RA patients were employed in the study. In coincided with in vivo results, LCA inhibited the cell proliferation and arrested the cell cycle, induced apoptosis, suppressed pro-inflammatory cytokine secretion and increased expression of antioxidant enzymes via the activation of Keap1-Nrf2 signaling by enhancing p62 phosphorylation and expression, Nrf2 accumulation and Nrf2 nucleus translocation. Findings in the current study provide evidence that p62-Keap1-Nrf2 axis is a pivotal signaling pathway in development of arthritis and therapeutic efficacy of drugs, and LCA activates of Keap1-Nrf2 signaling to suppress arthritis by phosphorylation of p62 at Ser349. Collectively, LCA is valuable to be further investigated as a lead compound for application in anti-arthritis, and interference with the interaction between Nrf2 and Keap1 by phosphorylation of p62 may be a promising strategy for the discovery of anti-arthritic agents. PMID- 29233794 TI - Relevance of 4-F4t-neuroprostane and 10-F4t-neuroprostane to neurological diseases. AB - F4-neuroprostanes (F4-NeuroPs) are non-enzymatic oxidized products derived from docosahexaenoic acid (DHA) and are suggested to be oxidative damage biomarkers of neurological diseases. However, 128 isomers can be formed from DHA oxidation and among them, 4(RS)-4-F4t-NeuroP (4-F4t-NeuroP) and 10(RS)-10-F4t-NeuroP (10-F4t NeuroP) are the most studied. Here, we report the identification and the clinical relevance of 4-F4t-NeuroP and 10-F4t-NeuroP in plasma of four different neurological diseases, including multiple sclerosis (MS), autism spectrum disorders (ASD), Rett syndrome (RTT), and Down syndrome (DS). The identification and the optimization of the method were carried out by gas chromatography/negative-ion chemical ionization tandem mass spectrometry (GC/NICI MS/MS) using chemically synthesized 4-F4t-NeuroP and 10-F4t-NeuroP standards and in oxidized DHA liposome. Both 4-F4t-NeuroP and 10-F4t-NeuroP were detectable in all plasma samples from MS (n = 16), DS (n = 16), ASD (n = 9) and RTT (n = 20) patients. While plasma 10-F4t-NeuroP content was significantly higher in patients of all diseases as compared to age and gender matched healthy control subjects (n = 61), 4-F4t-NeuroP levels were significantly higher in MS and RTT as compared to healthy controls. Significant positive relationships were observed between relative disease severity and 4-F4t-NeuroP levels (r = 0.469, P <0.0001), and 10 F4t-NeuroP levels (r = 0.757, P < 0.0001). The study showed that the plasma amount ratio of 10-F4t-NeuroP to 4-F4t-NeuroP and the plasma amount as individual isomer can be used to discriminate between different brain diseases. Overall, by comparing the different types of disease, our plasma data indicates that 4-F4t NeuroP and 10-F4t -NeuroP: i) are biologically synthesized in vivo and circulated, ii) are related to clinical severity of neurological diseases, iii) are useful to identify shared pathogenetic pathways in distinct brain diseases, and iv) appears to be distinctive for different neurological conditions, thus representing potentially new biological disease markers. Our data strongly suggest that in vivo DHA oxidation follows preferential chemical rearrangements according to different brain diseases. PMID- 29233795 TI - Using Microsimulation to Estimate the Future Health and Economic Costs of Salmonellosis under Climate Change in Central Queensland, Australia. AB - BACKGROUND: The incidence of salmonellosis, a costly foodborne disease, is rising in Australia. Salmonellosis increases during high temperatures and rainfall, and future incidence is likely to rise under climate change. Allocating funding to preventative strategies would be best informed by accurate estimates of salmonellosis costs under climate change and by knowing which population subgroups will be most affected. OBJECTIVE: We used microsimulation models to estimate the health and economic costs of salmonellosis in Central Queensland under climate change between 2016 and 2036 to inform preventative strategies. METHODS: We projected the entire population of Central Queensland to 2036 by simulating births, deaths, and migration, and salmonellosis and two resultant conditions, reactive arthritis and postinfectious irritable bowel syndrome. We estimated salmonellosis risks and costs under baseline conditions and under projected climate conditions for Queensland under the A1FI emissions scenario using composite projections from 6 global climate models (warm with reduced rainfall). We estimated the resulting costs based on direct medical expenditures combined with the value of lost quality-adjusted life years (QALYs) based on willingness-to-pay. RESULTS: Estimated costs of salmonellosis between 2016 and 2036 increased from 456.0 QALYs (95% CI: 440.3, 473.1) and AUD29,900,000 million (95% CI: AUD28,900,000, AUD31,600,000), assuming no climate change, to 485.9 QALYs (95% CI: 469.6, 503.5) and AUD31,900,000 (95% CI: AUD30,800,000, AUD33,000,000) under the climate change scenario. CONCLUSION: We applied a microsimulation approach to estimate the costs of salmonellosis and its sequelae in Queensland during 2016-2036 under baseline conditions and according to climate change projections. This novel application of microsimulation models demonstrates the models' potential utility to researchers for examining complex interactions between weather and disease to estimate future costs. https://doi.org/10.1289/EHP1370. PMID- 29233796 TI - Tracking Trachoma: How The Gambia Is Eliminating an Ancient Disease. PMID- 29233797 TI - Manure Irrigation: Environmental Benefits, Potential Human Health Risks. PMID- 29233798 TI - Reading Caplan in Karachi. AB - Bioethics education and discussions about ethical dilemmas are being increasingly reduced to teaching students how to balance the four, easily memorised philosophical principles popularised by influential American philosophers Tom Beauchamp and Jim Childress. The reality is that human beings approach and comprehend moral issues in diverse ways shaped by shared histories, cultural norms and values, kinship systems, lived experiences and existing socio-political realities. Therefore, ethical discourse limited to a culturally myopic Principlism that disregards the indigenous landscape can be an abstract and meaningless venture. The different moral lenses through which people can view the same issue is highlighted in this essay. It compares the analyses offered by American bioethicist Arthur Caplan of the blocking of polio vaccination by militants in northern Pakistan and of issues related to posthumous insemination, with the more nuanced, contextualised discussions about both topics offered by Pakistani students of bioethics in our Center. For this discipline to resonate with and make an impact on those we teach, an inclusive, more reflective and socially relevant approach is required. In my opinion, bioethics is a contact sport that should not be transformed into merely an academic exercise. PMID- 29233799 TI - A Survey of Medical Oncology Training in Australian Medical Schools: Pilot Study. AB - BACKGROUND: Oncology is a rapidly evolving field with continuous advancements in the diagnosis and treatment of cancer. Therefore, it is important that medical students are provided with the knowledge and experience required to care for oncology patients and enable them to diagnose and manage toxicities of novel therapeutic agents. OBJECTIVE: This study was performed to understand the medical students' perspective of the oncology education provided in universities across Australia and identify areas of education that could potentially be modified or improved to ultimately attract more students to a career in oncology. METHODS: This pilot cross-sectional study consisted of an 18-question survey that was submitted online to medical students in their final year and interns rotating to the Tamworth Hospital. RESULTS: The survey was completed by 94 fifth-year medical students and interns. Oncology was taught both theoretically and clinically for 68% (63/93) of participants, and 48% (44/92) had an exclusive oncology rotation. Both theoretical and clinical oncology assessments were conducted for only 21% (19/92) of participants. Overall, 42% (38/91) of participants were satisfied with their oncology education, and 78% (40/51) were dissatisfied with the number of oncology teaching hours. The importance of a career in oncology was rated as low by 46% (41/90) of participants. CONCLUSIONS: This pilot study indicates that there are potential areas to improve oncology teaching in Australian universities. The majority of surveyed students were dissatisfied with the number of teaching hours they receive in oncology. More global assessment of students and/or interns from other Australian institutes may yield further useful information. PMID- 29233800 TI - Participant-Centric Initiatives and Medical Research: Scoping Review Protocol. AB - BACKGROUND: Significant advances in digital technologies have meant that health care data can be collected, stored, transferred, and analyzed for research purposes more easily than ever before. Participant-centric initiatives (PCI) are defined as "tools, programs, and projects that empower participants to engage in the research process" using digital technologies and have the potential to provide a number of benefits to both participants and researchers, including the promotion of public trust in medical research, improved quality of research, increased recruitment and retention, and improved health care delivery. OBJECTIVE: The main objective of this scoping review is to describe the extent and range of PCIs across the United Kingdom, United States, and Japan that are designed to facilitate medical research. METHODS: The methodological framework described by Levac et al will be applied to this scoping review. We will search electronic databases (MEDLINE, EMBASE, PsychINFO, Cumulative Index to Nursing, and Allied Health Literature and CiNii), grey literature sources, Internet search engines (Google and Bing), and hand search key journals and reference lists of relevant articles. All digital tools and programs will be eligible for inclusion if there is a description of key features and functions that fall within the parameters of a PCI. Only those that play a role in medical research will be included. RESULTS: Preliminary searches conducted in MEDLINE and EMBASE retrieved 1820 and 2322 results, respectively. The scoping review will be completed by January 2018. CONCLUSIONS: The scoping review will be the first to map the extent and range of PCIs currently available across the United Kingdom, United States, and Japan, and will be the first review to contribute to a better understanding of what PCIs patients may benefit from. Researchers and practitioners will be able to use information in this review as a guide for patients and also as a guide for the development of future tools and programs. The results will be disseminated through a peer-reviewed publication and conference presentations. PMID- 29233801 TI - Getting to the Root of Fine Motor Skill Performance in Dentistry: Brain Activity During Dental Tasks in a Virtual Reality Haptic Simulation. AB - BACKGROUND: There is little evidence considering the relationship between movement-specific reinvestment (a dimension of personality which refers to the propensity for individuals to consciously monitor and control their movements) and working memory during motor skill performance. Functional near-infrared spectroscopy (fNIRS) measuring oxyhemoglobin demands in the frontal cortex during performance of virtual reality (VR) psychomotor tasks can be used to examine this research gap. OBJECTIVE: The aim of this study was to determine the potential relationship between the propensity to reinvest and blood flow to the dorsolateral prefrontal cortices of the brain. A secondary aim was to determine the propensity to reinvest and performance during 2 dental tasks carried out using haptic VR simulators. METHODS: We used fNIRS to assess oxygen demands in 24 undergraduate dental students during 2 dental tasks (clinical, nonclinical) on a VR haptic simulator. We used the Movement-Specific Reinvestment Scale questionnaire to assess the students' propensity to reinvest. RESULTS: Students with a high propensity for movement-specific reinvestment displayed significantly greater oxyhemoglobin demands in an area associated with working memory during the nonclinical task (Spearman correlation, rs=.49, P=.03). CONCLUSIONS: This small-scale study suggests that neurophysiological differences are evident between high and low reinvesters during a dental VR task in terms of oxyhemoglobin demands in an area associated with working memory. PMID- 29233802 TI - How, When and Why People Seek Health Information Online: Qualitative Study in Hong Kong. AB - BACKGROUND: The Internet has become an established source for health information. The number of individuals using the Internet to search for health information, ranging from healthy lifestyle advice to treatment and diseases, continues to grow. Scholars have emphasized the need to give greater voice and influence to health consumers. Hong Kong, being one of the most technologically advanced and connected cities in the world, has one of the highest Internet penetration rates in the world. Given the dearth of research in an Asian context, Hong Kong is an excellent platform to study individuals' perceptions (eg, benefits and limitations on seeking health information online and how the information is used) on health information seeking. OBJECTIVE: The aim of this paper was to study individuals' perceptions on health information seeking and to document their Internet information-seeking behaviors. METHODS: Five focus groups (n=49) were conducted from November 2015 to January 2016 with individuals across different age groups (18 years or above). Focus group contents were audiotaped, transcribed, and analyzed using thematic analysis techniques. RESULTS: Older (55+ years) and less educated respondents were less likely to use the Internet to search for health information. Among individuals who obtained health information via the Internet, regardless of the severity of the health issue, the Internet was always the first source for information. Limited doctor consultation time and barriers to accessing professional health services were the main reasons for using the Internet. Convenience and coverage were regarded as the main advantages, whereas credibility and trustworthiness of health information were noted as limitations. The use of Web-based health information varied among individuals; hence, the implications on the doctor-patient relationship were mixed. CONCLUSIONS: The prevalent and increasing use of the Internet for health information seeking suggests the need for health care professionals to understand how it can be optimally utilized to improve health outcomes. Strategies for communicating and disseminating credible health information in a form that users can understand and use are essential. Due to the rapid technological and related behavioral changes, online health information seeking and its effects need to be closely monitored. PMID- 29233803 TI - A Smartphone App to Reduce Sugar-Sweetened Beverage Consumption Among Young Adults in Australian Remote Indigenous Communities: Design, Formative Evaluation and User-Testing. AB - BACKGROUND: The disproportionate burden of noncommunicable disease among Indigenous Australians living in remote Indigenous communities (RICs) is a complex and persistent problem. Smartphones are increasingly being used by young Indigenous adults and therefore represent a promising method to engage them in programs seeking to improve nutritional intake. OBJECTIVE: This study aimed to consult RIC members to inform the content of a smartphone app that can be used to monitor and reduce sugar-sweetened beverage intake in RICs. METHODS: The study was conducted in two phases. The formative phase involved a simulated grocery selection activity with think aloud ("think aloud shop"), a semistructured interview, a questionnaire outlining current smartphone and app use, and a paper prototyping activity. A preliminary end-user testing phase involved a think aloud prototype test and a semistructured interview regarding user satisfaction. Convenience sampling was used to recruit 20 18- to 35-year-old smartphone users for each phase from two RICs in the Northern Territory, Australia. Thematic analysis of transcribed audio recordings was used to identify determinants of food choice from the think aloud shop; themes related to the Theory of Planned Behavior (TPB) from the eating behaviors interview; and usability, comprehension, and satisfaction with the app from the preliminary end-user testing. RESULTS: Smartphone use in RICs is currently different to that found in urban environments; in particular, extremely low use of Facebook, restricted variety of phone types, and limited Internet access. Findings regarding promoting app engagement indicate that utilizing an opt-in approach to social features such as leader boards and team challenges is essential. The inclusion of games was also shown to be important for satisfaction, as were the use of audio features, contextually embedded dissemination, and streamlined app design for comprehension in this target group. CONCLUSIONS: This research provides critical insights and concrete recommendations for the development of lifestyle improvement apps targeted toward disadvantaged young adults in nonurban settings, specifically RICs. It serves as a framework for future app development projects using a consultative user-centered design approach, supporting calls for the increased use of this strategy in app development. PMID- 29233805 TI - Designing Microblog Direct Messages to Engage Social Media Users With Suicide Ideation: Interview and Survey Study on Weibo. AB - BACKGROUND: While Web-based interventions can be efficacious, engaging a target population's attention remains challenging. We argue that strategies to draw such a population's attention should be tailored to meet its needs. Increasing user engagement in online suicide intervention development requires feedback from this group to prevent people who have suicide ideation from seeking treatment. OBJECTIVE: The goal of this study was to solicit feedback on the acceptability of the content of messaging from social media users with suicide ideation. To overcome the common concern of lack of engagement in online interventions and to ensure effective learning from the message, this research employs a customized design of both content and length of the message. METHODS: In study 1, 17 participants suffering from suicide ideation were recruited. The first (n=8) group conversed with a professional suicide intervention doctor about its attitudes and suggestions for a direct message intervention. To ensure the reliability and consistency of the result, an identical interview was conducted for the second group (n=9). Based on the collected data, questionnaires about this intervention were formed. Study 2 recruited 4222 microblog users with suicide ideation via the Internet. RESULTS: The results of the group interviews in study 1 yielded little difference regarding the interview results; this difference may relate to the 2 groups' varied perceptions of direct message design. However, most participants reported that they would be most drawn to an intervention where they knew that the account was reliable. Out of 4222 microblog users, we received responses from 725 with completed questionnaires; 78.62% (570/725) participants were not opposed to online suicide intervention and they valued the link for extra suicide intervention information as long as the account appeared to be trustworthy. Their attitudes toward the intervention and the account were similar to those from study 1, and 3 important elements were found pertaining to the direct message: reliability of account name, brevity of the message, and details of the phone numbers of psychological intervention centers and psychological assessment. CONCLUSIONS: This paper proposed strategies for engaging target populations in online suicide interventions. PMID- 29233804 TI - End User and Implementer Experiences of mHealth Technologies for Noncommunicable Chronic Disease Management in Young Adults: Systematic Review. AB - BACKGROUND: Chronic noncommunicable diseases (NCDs) such as asthma, diabetes, cancer, and persistent musculoskeletal pain impose an escalating and unsustainable burden on young people, their families, and society. Exploring how mobile health (mHealth) technologies can support management for young people with NCDs is imperative. OBJECTIVE: The aim of this study was to identify, appraise, and synthesize available qualitative evidence on users' experiences of mHealth technologies for NCD management in young people. We explored the perspectives of both end users (young people) and implementers (health policy makers, clinicians, and researchers). METHODS: A systematic review and meta-synthesis of qualitative studies. Eligibility criteria included full reports published in peer-reviewed journals from January 2007 to December 2016, searched across databases including EMBASE, MEDLINE (PubMed), Scopus, and PsycINFO. All qualitative studies that evaluated the use of mHealth technologies to support young people (in the age range of 15-24 years) in managing their chronic NCDs were considered. Two independent reviewers identified eligible reports and conducted critical appraisal (based on the Joanna Briggs Institute Qualitative Assessment and Review Instrument: JBI-QARI). Three reviewers independently, then collaboratively, synthesized and interpreted data through an inductive and iterative process to derive emergent themes across the included data. External validity checking was undertaken by an expert clinical researcher and for relevant content, a health policy expert. Themes were subsequently subjected to a meta-synthesis, with findings compared and contrasted between user groups and policy and practice recommendations derived. RESULTS: Twelve studies met our inclusion criteria. Among studies of end users (N=7), mHealth technologies supported the management of young people with diabetes, cancer, and asthma. Implementer studies (N=5) covered the management of cognitive and communicative disabilities, asthma, chronic self-harm, and attention deficit hyperactivity disorder. Quality ratings were higher for implementer compared with end user studies. Both complementary and unique user themes emerged. Themes derived for end users of mHealth included (1) Experiences of functionality that supported self-management, (2) Acceptance (technical usability and feasibility), (3) Importance of codesign, and (4) Perceptions of benefit (self-efficacy and empowerment). For implementers, derived themes included (1) Characteristics that supported self-management (functional, technical, and behavior change); (2) Implementation challenges (systems level, service delivery level, and clinical level); (3) Adoption considerations for specific populations (training end users; specific design requirements); and (4) Codesign and tailoring to facilitate uptake and person-centered care. CONCLUSIONS: Synthesizing available data revealed both complementary and unique user perspectives on enablers and barriers to designing, developing, and implementing mHealth technologies to support young people's management of their chronic NCDs. TRIAL REGISTRATION: PROSPERO CRD42017056317; http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD 42017056317 (Archived by WebCite at http://www.webcitation.org/6vZ5UkKLp). PMID- 29233807 TI - GMC says that it should regulate physician associates. PMID- 29233809 TI - London hospital boss resigns over financial pressure as trust is placed in special measures. PMID- 29233806 TI - Mobile Health Technology (mDiab) for the Prevention of Type 2 Diabetes: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: The prevalence of type 2 diabetes is increasing in epidemic proportions in low- and middle-income countries. There is an urgent need for novel methods to tackle the increasing incidence of diabetes. The ubiquity of mobile phone use and access to Internet makes mobile health (mHealth) technology a viable tool to prevent and manage diabetes. OBJECTIVE: The objective of this randomized controlled trial is to implement and evaluate the feasibility, cost effectiveness, and sustainability of a reality television-based lifestyle intervention program. This intervention program is delivered via a mobile phone app (mDiab) to approximately 1500 Android smartphone users who are adults at a high risk for type 2 diabetes from three cities in India, namely, Chennai, Bengaluru, and New Delhi. METHODS: The mDiab intervention would be delivered via a mobile phone app along with weekly coach calls for 12 weeks. Each participant will go through a maintenance phase of 6 to 8 months post intervention. Overall, there would be 3 testing time points in the study: baseline, post intervention, and the end of follow-up. The app will enable individuals to track their weight, physical activity, and diet alongside weekly video lessons on type 2 diabetes prevention. RESULTS: The study outcomes are weight loss (primary measure of effectiveness); improvement in cardiometabolic risk factors (ie, waist circumference, blood pressure, glucose, insulin, and lipids); and improvement in physical activity, quality of life, and dietary habits. Sustainability will be assessed through focus group discussions. CONCLUSIONS: If successful, mDiab can be used as a model for translational and implementation research in the use of mHealth technology for diabetes prevention and may be further expanded for the prevention of other noncommunicable diseases such as hypertension and cardiovascular diseases. TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2015/07/006011 http://ctri.nic.in/Clinicaltrials/pdf_generate.php? trialid=11841 (Archived by WebCite at http://www.webcitation.org/6urCS5kMB). PMID- 29233810 TI - The BMJ charity appeal Christmas 2017: help MSF bring essential healthcare to millions of people in war torn Yemen. PMID- 29233812 TI - Proposals for opt-out organ donation launched for England. PMID- 29233813 TI - A case of isolated bicuspid pulmonary valve. AB - We present a 73 years old woman who presented with pelvic cancer, ongoing sepsis and presumably a new diastolic murmur. Her transthoracic echocardiogram, as part of a sepsis screen, showed an abnormal pulmonary valve with moderate regurgitation. Trans-oesophageal echocardiography using 3D imaging showed a bicuspid pulmonary valve as the cause for the moderate regurgitation, but with no clear source of infection. Bicuspid pulmonary valve as an isolated clinical entity is a rare finding in clinical practice. Bicuspid pulmonary valves tend to be more commonly associated with other congenital cardiac anomalies. Whereas, the incidence of bicuspid aortic valve is estimated to be about 1-2%, the incidence of bicuspid pulmonary valve is thought to be much lower at around 0.1%. This could be an underestimate due to difficulty in visualising the pulmonary valve en face on standard two-dimensional echocardiography. The true prevalence of the condition may be uncovered by the routine use of 3D echocardiography. PMID- 29233811 TI - Dissecting the Roles of the Calcineurin Pathway in Unisexual Reproduction, Stress Responses, and Virulence in Cryptococcus deneoformans. AB - The Ca2+/calmodulin-dependent protein phosphatase calcineurin orchestrates sexual reproduction, stress responses, and virulence via branched downstream pathways in the opportunistic human fungal pathogen Cryptococcus neoformans The calcineurin binding protein Cbp1, the calcineurin temperature suppressor Cts1, the calcineurin-responsive zinc finger transcription factor Crz1, and the calcineurin targets Pbp1, Tif3, and Puf4, all function downstream of calcineurin to orchestrate distinct cellular processes. To elucidate how the calcineurin pathway regulatory network governs unisexual reproduction, stress responses, and virulence, we have analyzed the self-filamentous C. deneoformans strain, XL280alpha, and generated double mutants of these calcineurin downstream genes. We demonstrated that calcineurin governs unisexual reproduction at different sexual developmental stages, in which the initiation of the yeast-hyphal morphological transition is independent of Crz1, whereas the sporulation process is dependent on Crz1. Calcineurin-dependent unisexual reproduction is independent of the pheromone response pathway. Crz1 synergistically interacts with different calcineurin downstream targets in responding to ER, high-calcium, and cell wall stresses. We observed a widespread synergy suggesting that these proteins function in complex branched pathways downstream of calcineurin with some functional redundancy, which may allow efficient signaling network rewiring within the pathway for prompt adaptation to changing environments. Finally, we showed that deletion of PBP1 or TIF3 in the cna1? mutant background conferred a modest level of growth tolerance at 37 degrees , but that the cna1? pbp1? and cna1? tif3? double mutants were both avirulent, suggesting that calcineurin may control virulence via mechanisms beyond thermotolerance. PMID- 29233814 TI - Philippines halts dengue immunisation campaign owing to safety risk. PMID- 29233815 TI - Dual-release hydrocortisone treatment: glycometabolic profile and health-related quality of life. AB - OBJECTIVE: Adrenal insufficiency (AI) is a chronic condition associated with increased mortality and morbidity. The treatment of AI in the last years has been object of important changes due to the development of a dual-release preparation of hydrocortisone. It differs from previous therapeutic strategy as it contemplates a once-daily tablet that allows more closely mimicking the physiological circadian cortisol rhythm. The aim of the study was to evaluate the effects of dual-release hydrocortisone treatment on the glycometabolic profile and health-related quality of life of patients with AI. DESIGN AND METHODS: In this clinical open trial, we enrolled ten patients with primary AI (41 +/- 2.67 years) and nine patients with AI secondary to hypopituitarism (53.2 +/- 17.7 years). We evaluated the glycometabolic profile before and 3, 6, 9 and 12 months after dual-release hydrocortisone administration. We also evaluated health related quality of life, estimated by the AddiQol questionnaire. The mean dose administered of dual-release hydrocortisone was 28.33 +/- 6.68 mg/day. RESULTS: One female hypopituitary patient dropped out from the study. After 12 months of treatment, the mean dosage administered of dual-release hydrocortisone was significantly lower (P < 0.05) and all patients reported improved quality of life and well-being. The glycometabolic profile improved and the glycosylated hemoglobin decreased significantly in patients with primary AI (6.25 +/- 0.2 vs 5.35 +/- 0.17, P < 0.05). In contrast, hypopituitary patients had worse glycometabolic profile and a trend toward hypertriglyceridemia. CONCLUSIONS: Dual release hydrocortisone treatment improved the quality of life of patients with AI, and it allowed a decrease of cortisol dosage administered in the absence of side effects. The glycometabolic profile worsened in hypopituitary patients. PMID- 29233816 TI - Testosterone level and risk of type 2 diabetes in men: a systematic review and meta-analysis. AB - BACKGROUND: Type 2 diabetes is a risk factor for testosterone deficiency and impaired sex steroid status. Some studies also investigated the association of testosterone level with diabetes risk in men, but reported controversial findings. To clarify this issue, we conducted a systematic review and meta analysis. METHODS: PubMed, EMBASE and Web of Science were searched for eligible cohort or nested case-control studies published up to August 15, 2017. Meta analysis was used to calculate the pooled relative risk (RR) of type 2 diabetes associated with higher testosterone level. RESULTS: Thirteen cohort or nested case-control studies with 16,709 participants were included. Meta-analysis showed that higher total testosterone level could significantly decrease the risk of type 2 diabetes in men (RR = 0.65; 95% CI 0.50-0.84; P = 0.001), and higher free testosterone level could also decrease the risk of type 2 diabetes in men (RR = 0.94; 95% CI 0.90-0.99; P = 0.014). After excluding two studies that did not calculate RRs by quartiles of testosterone levels, both higher total testosterone and free testosterone levels could decrease the risk of type 2 diabetes in men, and the pooled RRs were 0.62 (95% CI 0.51-0.76; P < 0.001) and 0.77 (95% CI 0.61 0.98; P = 0.03), respectively. CONCLUSION: This meta-analysis suggests that higher testosterone level can significantly decrease the risk of type 2 diabetes in men. Therefore, combined with previous researches, the findings above suggest a reverse-causality scenario in the relation between testosterone deficiency and risk of type 2 diabetes in men. PMID- 29233818 TI - Importance of the Unstirred Water Layer and Hepatocyte Membrane Integrity In Vitro for Quantification of Intrinsic Metabolic Clearance. AB - Prediction of clearance-a vital component of drug discovery-remains in need of improvement and, in particular, requires more incisive assessment of mechanistic methodology in vitro, according to a number of recent reports. Although isolated hepatocytes have become an irreplaceable standard system for the measurement of intrinsic hepatic clearance mediated by active uptake transport and metabolism, the lack of prediction reliability appears to reflect a lack of methodological validation, especially for highly cleared drugs, as we have previously shown. Here, novel approaches were employed to explore fundamental experimental processes and associated potential limitations of in vitro predictions of clearance. Rat hepatocytes deemed nonviable by trypan blue staining showed undiminished metabolic activity for probe cytochrome P450 (P450) substrates midazolam and propranolol; supplementation with NADPH enhanced these activities. Extensive permeabilization of the plasma membrane using saponin showed either full or minimal P450 activity, depending on the presence or absence of 1 mM NADPH, respectively. The shaking of incubations facilitated P450 metabolic rates up to 5-fold greater than static incubation, depending on intrinsic clearance, indicating the critical influence of the unstirred water layer (UWL). Permeabilization allowed static incubation metabolic rates to approach those of shaking for intact cells, indicating an artificially induced breakdown of the UWL. Permeabilization combined with shaking allowed an increased metabolic rate for saquinavir, resolving the membrane permeability limitation for this drug. These findings advance the interpretation of the rate-limiting processes involved in intrinsic clearance measurements and could be critical for successful in vitro prediction. PMID- 29233817 TI - Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients. AB - Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs). IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS). The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS. PMID- 29233820 TI - Adaptive reprogramming of NK cells in X-linked lymphoproliferative syndrome. PMID- 29233819 TI - Characterization of Interactions Among CYP1A2, CYP2B4, and NADPH-cytochrome P450 Reductase: Identification of Specific Protein Complexes. AB - Cytochromes P450s (P450s) catalyze oxygenation reactions via interactions with their redox partners. However, other proteins, particularly other P450s, also have been shown to form complexes that modulate P450 function. Previous studies showed that CYP1A2 and CYP2B4 form a complex when reconstituted into phospholipid vesicles; however, details of the interactions among the P450s and NADPH cytochrome P450 reductase (POR) have not been fully characterized. The goal of this study was to examine P450 complex formation in living cells, using bioluminescence resonance energy transfer (BRET). Various pairs of P450 and POR constructs were tagged with either green fluorescent protein or Renilla luciferase, and transfected into human embryonic kidney 293T cells. Complexes were demonstrated by measuring energy transfer between the tags, and disruption of the complex was verified by cotransfection with unlabeled P450-system proteins. CYP1A2 and CYP2B4 formed a stable complex that could not be disrupted by cotransfection of untagged POR. Interactions of both P450s with POR were detected, with untagged CYP1A2 disrupting the POR-CYP2B4 interaction. In contrast, untagged CYP2B4 did not affect the POR-CYP1A2 interaction. These data are consistent with POR preferentially binding to the CYP1A2 moiety of CYP1A2 CYP2B4. BRET-detectable homomeric CYP1A2-CYP1A2 also was detected, and was disrupted by cotransfection of either POR or CYP2B4. Both CYP1A2 and CYP2B4 activities were affected by their coexpression in a manner consistent with formation of the high-affinity POR-CYP1A2-CYP2B4 complex. These findings demonstrate that CYP1A2 and CYP2B4 form a heteromeric POR-CYP1A2-CYP2B4 complex in living cells that has altered catalytic activities relative to the homomeric enzymes. PMID- 29233822 TI - Hematopoietic stem cell gene therapy for IFNgammaR1 deficiency protects mice from mycobacterial infections. AB - Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by severe infections caused by weakly virulent mycobacteria. Biallelic null mutations in genes encoding interferon gamma receptor 1 or 2 (IFNGR1 or IFNGR2) result in a life-threatening disease phenotype in early childhood. Recombinant interferon gamma (IFN-gamma) therapy is inefficient, and hematopoietic stem cell transplantation has a poor prognosis. Thus, we developed a hematopoietic stem cell (HSC) gene therapy approach using lentiviral vectors that express Ifngammar1 either constitutively or myeloid specifically. Transduction of mouse Ifngammar1-/- HSCs led to stable IFNgammaR1 expression on macrophages, which rescued their cellular responses to IFN-gamma. As a consequence, genetically corrected HSC-derived macrophages were able to suppress T-cell activation and showed restored antimycobacterial activity against Mycobacterium avium and Mycobacterium bovis Bacille Calmette-Guerin (BCG) in vitro. Transplantation of genetically corrected HSCs into Ifngammar1-/- mice before BCG infection prevented manifestations of severe BCG disease and maintained lung and spleen organ integrity, which was accompanied by a reduced mycobacterial burden in lung and spleen and a prolonged overall survival in animals that received a transplant. In summary, we demonstrate an HSC-based gene therapy approach for IFNgammaR1 deficiency, which protects mice from severe mycobacterial infections, thereby laying the foundation for a new therapeutic intervention in corresponding human patients. PMID- 29233824 TI - Role for Immune Therapy in Advanced Breast Cancer. AB - In a phase Ib/II trial, adding the PD-1 inhibitor pembrolizumab to trastuzumab showed clinical benefit in patients with advanced HER2-positive breast cancer who had developed resistance to trastuzumab. The study also identified tumor infiltrating lymphocyte levels as a potential biomarker of response to treatment. PMID- 29233821 TI - Activity of the PI3K-delta,gamma inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. AB - Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 3-kinase (PI3K) delta/gamma isoforms currently in clinical development. PI3K-delta/gamma inhibition may directly inhibit malignant T-cell growth, making duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a phase 1, open-label study of duvelisib in patients with relapsed or refractory PTCL (n = 16) and CTCL (n = 19), along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed grade 3 and 4 adverse events were transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), maculopapular rash (17%), and neutropenia (17%). Responders and nonresponders had markedly different changes in serum cytokine profiles induced by duvelisib. In vitro, duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) vs 0 of 7 lines lacking pAKT (P = .024) and exceeded cell killing by the PI3K-delta-specific inhibitor idelalisib. Administration of duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell-autonomous and immune-mediated effects. This trial was registered at www.clinicaltrials.gov as #NCT01476657. PMID- 29233823 TI - Large Cardiac Muscle Patches Engineered From Human Induced-Pluripotent Stem Cell Derived Cardiac Cells Improve Recovery From Myocardial Infarction in Swine. AB - BACKGROUND: Here, we generated human cardiac muscle patches (hCMPs) of clinically relevant dimensions (4 cm * 2 cm * 1.25 mm) by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human induced-pluripotent stem cells in a fibrin scaffold and then culturing the construct on a dynamic (rocking) platform. METHODS: In vitro assessments of hCMPs suggest maturation in response to dynamic culture stimulation. In vivo assessments were conducted in a porcine model of myocardial infarction (MI). Animal groups included: MI hearts treated with 2 hCMPs (MI+hCMP, n=13), MI hearts treated with 2 cell-free open fibrin patches (n=14), or MI hearts with neither experimental patch (n=15); a fourth group of animals underwent sham surgery (Sham, n=8). Cardiac function and infarct size were evaluated by MRI, arrhythmia incidence by implanted loop recorders, and the engraftment rate by calculation of quantitative polymerase chain reaction measurements of expression of the human Y chromosome. Additional studies examined the myocardial protein expression profile changes and potential mechanisms of action that related to exosomes from the cell patch. RESULTS: The hCMPs began to beat synchronously within 1 day of fabrication, and after 7 days of dynamic culture stimulation, in vitro assessments indicated the mechanisms related to the improvements in electronic mechanical coupling, calcium-handling, and force generation, suggesting a maturation process during the dynamic culture. The engraftment rate was 10.9+/ 1.8% at 4 weeks after the transplantation. The hCMP transplantation was associated with significant improvements in left ventricular function, infarct size, myocardial wall stress, myocardial hypertrophy, and reduced apoptosis in the periscar boarder zone myocardium. hCMP transplantation also reversed some MI associated changes in sarcomeric regulatory protein phosphorylation. The exosomes released from the hCMP appeared to have cytoprotective properties that improved cardiomyocyte survival. CONCLUSIONS: We have fabricated a clinically relevant size of hCMP with trilineage cardiac cells derived from human induced-pluripotent stem cells. The hCMP matures in vitro during 7 days of dynamic culture. Transplantation of this type of hCMP results in significantly reduced infarct size and improvements in cardiac function that are associated with reduction in left ventricular wall stress. The hCMP treatment is not associated with significant changes in arrhythmogenicity. PMID- 29233825 TI - Rapid Responses to Avapritinib (BLU-285) in Mastocytosis. AB - In a phase I trial of avapritinib (formerly BLU-285), which targets D816V mutant KIT, for the treatment of advanced systemic mastocytosis, patients experienced rapid and durable disease control. The overall response rate was 72%, and 56% of patients experienced a complete or partial response. No patients discontinued treatment due to adverse events, most of which were mild to moderate in nature. PMID- 29233826 TI - Association of Atrial Fibrillation and Oral Anticoagulant Use With Perioperative Outcomes After Major Noncardiac Surgery. AB - BACKGROUND: We examined the association of atrial fibrillation (AF) and oral anticoagulant use with perioperative death and bleeding among patients undergoing major noncardiac surgery. METHODS AND RESULTS: A population-based study of patients aged 66 years and older who underwent elective (n=87 257) or urgent (n=35 930) noncardiac surgery in Ontario, Canada (April 2012 to March 2015) was performed. Outcomes were compared between AF groups using inverse probability of treatment weighting using the propensity score. Of 4612 urgent surgical patients with AF, treatments before surgery included warfarin (n=1619), a direct oral anticoagulant (DOAC) (n=729), and no anticoagulation (n=2264). After urgent surgery, the death rate within 30 days was significantly higher in patients with AF compared with patients with no AF (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.12-1.45). In contrast, among 4769 elective surgical patients with AF treated with warfarin (n=1453), a DOAC (n=1165), or no anticoagulation (n=2151), prior AF was not associated with higher mortality. Comparing patients with AF who were or were not anticoagulated, there was no difference in 30-day mortality after urgent (HR, 0.95; 95% CI, 0.79-1.14) or elective (HR, 0.65; 95% CI, 0.38-1.09) surgery. There was no difference in 30-day mortality between patients with AF treated with a DOAC or warfarin after urgent (HR, 0.91; 95% CI, 0.70-1.18) or elective (HR, 1.64; 95% CI, 0.77-3.53) surgery. Bleeding and thromboembolic rates did not differ significantly among patients with AF prescribed a DOAC or warfarin. CONCLUSIONS: Prior AF was associated with 30-day mortality among patients undergoing urgent surgery. In patients with AF, neither the preoperative use of oral anticoagulants, nor the type of agent (either a DOAC or warfarin) were associated with the rate of 30-day mortality. PMID- 29233827 TI - Stress Echocardiography Positivity Predicts Cancer Death. AB - BACKGROUND: Stress echocardiography (SE) predicts cardiac death, but an increasing share of cardiac patients eventually die of cancer. The aim of the study was to assess whether SE positivity predicts cancer death. METHODS AND RESULTS: In a retrospective analysis of prospectively acquired single-center, observational data, we evaluated 4673 consecutive patients who underwent SE from 1983 to 2009. All patients were cancer-free at index SE and were followed up for a median of 131 months (interquartile range 134). We separately analyzed predetermined end points: cardiovascular, cancer, and noncardiovascular, noncancer death, with and without competing risk. SE was positive in 1757 and negative in 2916 patients; 869 cardiovascular, 418 cancer, and 625 noncardiovascular, noncancer deaths were registered. The 25-year mortality was higher in SE-positive than in SE-negative patients, considering cardiovascular (40% versus 31%; P<0.001) and cancer mortality (26% versus 17%; P<0.01). SE positivity was a strong predictor of cancer (cause-specific hazard ratio 1.19; 95% confidence interval, 1.16-1.73; P=0.05) and cardiovascular mortality (1.18; 95% confidence interval, 1.03-1.35; P=0.02). Fine-Gray analysis to account for competing risk gave similar results. Cancer risk diverged after 15 years, whereas differences were already significant at 5 years for cardiovascular risk. CONCLUSIONS: SE results predict cardiovascular and cancer mortality. SE may act as a proxy of the shared risk factor milieu for cancer or cardiovascular death. PMID- 29233828 TI - E2F1 interacts with BCL-xL and regulates its subcellular localization dynamics to trigger cell death. AB - E2F1 is the main pro-apoptotic effector of the pRB-regulated tumor suppressor pathway by promoting the transcription of various pro-apoptotic proteins. We report here that E2F1 partly localizes to mitochondria, where it favors mitochondrial outer membrane permeabilization. E2F1 interacts with BCL-xL independently from its BH3 binding interface and induces a stabilization of BCL xL at mitochondrial membranes. This prevents efficient control of BCL-xL over its binding partners, in particular over BAK resulting in the induction of cell death. We thus identify a new, non-BH3-binding regulator of BCL-xL localization dynamics that influences its anti-apoptotic activity. PMID- 29233830 TI - Placental abruption leading to hysterectomy. AB - A 32-year-old multigravid patient at 21 weeks gestation presents with major concealed placental abruption and subsequent fetal demise. During an eventually failed misoprostol regime aiming for vaginal delivery she develops severe disseminated intravascular coagulopathy. Subsequent hysterotomy reveals Couvelaire uterus with major haemorrhage and requires subtotal hysterectomy for haemostasis. This case highlights the severity of the systemic response to abruption and fetal demise in utero and the multifactorial nature of its management. PMID- 29233829 TI - Smad3-mediated recruitment of the methyltransferase SETDB1/ESET controls Snail1 expression and epithelial-mesenchymal transition. AB - During epithelial-mesenchymal transition (EMT), reprogramming of gene expression is accompanied by histone modifications. Whether EMT-promoting signaling directs functional changes in histone methylation has not been established. We show here that the histone lysine methyltransferase SETDB1 represses EMT and that, during TGF-beta-induced EMT, cells attenuate SETDB1 expression to relieve this inhibition. SETDB1 also controls stem cell generation, cancer cell motility, invasion, metastatic dissemination, as well as sensitivity to certain cancer drugs. These functions may explain the correlation of breast cancer patient survival with SETDB1 expression. At the molecular level, TGF-beta induces SETDB1 recruitment by Smad3, to repress Smad3/4-activated transcription of SNAI1, encoding the EMT "master" transcription factor SNAIL1. Suppression of SNAIL1 mediated gene reprogramming by SETDB1 occurs through H3K9 methylation at the SNAI1 gene that represses its H3K9 acetylation imposed by activated Smad3/4 complexes. SETDB1 therefore defines a TGF-beta-regulated balance between histone methylation and acetylation that controls EMT. PMID- 29233831 TI - The Efficacy of the proprioceptive neuromuscular facilitation (PNF) approach in stroke rehabilitation to improve basic activities of daily living and quality of life: a systematic review and meta-analysis protocol. AB - INTRODUCTION: Proprioceptive neuromuscular facilitation (PNF) is a widely used rehabilitation concept, although its efficacy has not yet been demonstrated in stroke survivors. The aim of this systematic review is to identify, assess and synthesise the potential benefits of using PNF to improve the activities of daily living (ADL) and quality of life (QoL) of individuals with stroke. METHODS AND ANALYSIS: A systematic electronic search will be conducted in MEDLINE, Embase, CENTRAL and PEDro. We will include randomised or quasi-randomised controlled trials of PNF interventions conducted in stroke survivors up to April 2017. Two review authors will independently select relevant studies and will extract data using the Cochrane handbook for systematic reviews of interventions approach and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The methodological quality will be assessed by using the PEDro scale. Finally, with the permitted numeric data, we will carry out a meta-analysis. ETHICS AND DISSEMINATION: Ethical considerations will not be required. Results will be disseminated in a peer-review journal. This systematic review aims to examine the effects of PNF (neurophysiological approach) in order to clarify its efficacy in improving ADL and QoL in the rehabilitation process of stroke survivors. PROSPERO REGISTRATION NUMBER: CRD42016039135. PMID- 29233833 TI - Scoring hypoechogenic areas in one parotid and one submandibular gland increases feasibility of ultrasound in primary Sjogren's syndrome. AB - OBJECTIVE: To assess whether ultrasonographic scoring of (i) both parotid and submandibular salivary glands and (ii) all individual components of the Hocevar scoring system, is needed for classifying patients as primary Sjogren's syndrome (pSS). METHODS: Ultrasound examination of the major salivary glands (sUS) was performed in 204 consecutive patients clinically suspected (n=171) or diagnosed (n=33) with pSS.Parenchymal echogenicity, homogeneity, hypoechogenic areas, hyperechogenic reflections and salivary gland posterior border were scored in left and right parotid and submandibular glands. Logistic regression analyses were performed to assess which glands and sUS components contributed significantly to classification as pSS or non-pSS according to the 2016 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) criteria. RESULTS: 116 (57%) patients were classified as pSS, the remaining as non-pSS. Instead of scoring both sides (area under the curve; AUC=0.856, Nagelkerke R2=0.526), multivariate analysis showed that sUS scoring of only right (AUC=0.850; R2=0.518) or left (AUC=0.852; R2=0.511) parotid and submandibular glands is sufficient to predict ACR-EULAR classification. Moreover, all individual components of the Hocevar scoring system significantly predicted classification. Multivariate analysis showed that parenchymal echogenicity and hypoechogenic areas contributed independently to ACR-EULAR classification (AUC=0.857; R2=0.539). Scoring these components in one parotid and one submandibular gland highly predicted ACR-EULAR classification (AUC=0.855; R2=0.539). Scoring only hypoechogenic areas on one side showed almost similar results (AUC=0.846; R2=0.498). CONCLUSION: sUS examination of parotid and submandibular glands on one side is sufficient to predict classification of patients according to the ACR-EULAR criteria. To further increase feasibility of sUS in outpatient clinics worldwide, only hypoechogenic areas can be scored. PMID- 29233832 TI - Exome-wide association study identifies four novel loci for systemic lupus erythematosus in Han Chinese population. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE. However, the majority of them reside in non-coding sequences. The contributions of coding variants have not yet been systematically evaluated. METHODS: We performed a large-scale exome-wide study in 5004 SLE cases and 8179 healthy controls in a Han Chinese population using a custom exome array, and then genotyped 32 variants with suggestive evidence in an independent cohort of 13 246 samples. We further explored the regulatory effect of one novel non-coding single nucleotide polymorphism (SNP) in ex vivo experiments. RESULTS: We discovered four novel SLE gene regions (LCT, TPCN2, AHNAK2 and TNFRSF13B) encompassing three novel missense variants (XP_016859577.1:p.Asn1639Ser, XP_016859577.1:p.Val219Phe and XP_005267356.1:p.Thr4664Ala) and two non-coding variants (rs10750836 and rs4792801) with genome-wide significance (pmeta <5.00*10-8). These variants are enriched in several chromatin states of primary B cells. The novel intergenic variant rs10750836 exhibited an expression quantitative trait locus effect on the TPCN2 gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for TPCN2 (P=1.38*10-3) whose expression level was reduced significantly in patients with SLE (P<2.53*10-2) and was suggested to be further modulated by rs10750836 in CD19+ B cells (P=7.57*10-5) in ex vivo experiments. CONCLUSIONS: This study identified three novel coding variants and four new susceptibility gene regions for SLE. The results provide insights into the biological mechanism of SLE. PMID- 29233835 TI - Right Atrial Deformation in Predicting Outcomes in Pediatric Pulmonary Hypertension. AB - BACKGROUND: Elevated right atrial (RA) pressure is a risk factor for mortality, and RA size is prognostic of adverse outcomes in pulmonary hypertension (PH). There is limited data on phasic RA function (reservoir, conduit, and pump) in pediatric PH. We sought to evaluate (1) the RA function in pediatric PH patients compared with controls, (2) compare the RA deformation indices with Doppler indices of diastolic dysfunction, functional capacity, biomarkers, invasive hemodynamics, and right ventricular functional indices, and (3) evaluate the potential of RA deformation indices to predict clinical outcomes. METHODS AND RESULTS: Sixty-six PH patients (mean age 7.9+/-4.7 years) were compared with 36 controls (7.7+/-4.4 years). RA and right ventricular deformation indices were obtained using 2-dimensional speckle tracking (2DCPA; TomTec, Germany). RA strain, strain rates, emptying fraction, and right ventricular longitudinal strain were measured. RA function was impaired in PH patients versus controls (P<0.001). There were significant associations between RA function with invasive hemodynamics (P<0.01). RA reservoir, pump function, the rate of RA filling, and atrial minimum volume predicted adverse clinical outcomes (hazard ratio [HR], 0.15; confidence interval [CI], 0.03-0.73; P<0.01; HR, 0.05; CI, 0.003-0.43; P<0.004; HR, 0.04; CI, 0.006-0.56; P<0.01; and HR, 8.6; CI, 1.6-37.2; P<0.01, respectively). CONCLUSIONS: RA deformation properties are significantly altered in pediatric PH patients. Progressive worsening of RA reservoir and conduit functions is related to changes in right ventricular diastolic dysfunction. RA reservoir function, pump function, the rate of atrial filling, and atrial minimum volume emerged as outcome predictors in pediatric PH. PMID- 29233837 TI - Radiomics to Identify High-Risk Atherosclerotic Plaque From Computed Tomography: The Power of Quantification. PMID- 29233834 TI - The Arabidopsis ALF4 protein is a regulator of SCF E3 ligases. AB - The cullin-RING E3 ligases (CRLs) regulate diverse cellular processes in all eukaryotes. CRL activity is controlled by several proteins or protein complexes, including NEDD8, CAND1, and the CSN Recently, a mammalian protein called Glomulin (GLMN) was shown to inhibit CRLs by binding to the RING BOX (RBX1) subunit and preventing binding to the ubiquitin-conjugating enzyme. Here, we show that Arabidopsis ABERRANT LATERAL ROOT FORMATION4 (ALF4) is an ortholog of GLMN The alf4 mutant exhibits a phenotype that suggests defects in plant hormone response. We show that ALF4 binds to RBX1 and inhibits the activity of SCFTIR1, an E3 ligase responsible for degradation of the Aux/IAA transcriptional repressors. In vivo, the alf4 mutation destabilizes the CUL1 subunit of the SCF Reduced CUL1 levels are associated with increased levels of the Aux/IAA proteins as well as the DELLA repressors, substrate of SCFSLY1 We propose that the alf4 phenotype is partly due to increased levels of the Aux/IAA and DELLA proteins. PMID- 29233836 TI - Radiomic Features Are Superior to Conventional Quantitative Computed Tomographic Metrics to Identify Coronary Plaques With Napkin-Ring Sign. AB - BACKGROUND: Napkin-ring sign (NRS) is an independent prognostic imaging marker of major adverse cardiac events. However, identification of NRS is challenging because of its qualitative nature. Radiomics is the process of extracting thousands of quantitative parameters from medical images to create big-data data sets that can identify distinct patterns in radiological images. Therefore, we sought to determine whether radiomic analysis improves the identification of NRS plaques. METHODS AND RESULTS: From 2674 patients referred to coronary computed tomographic angiography caused by stable chest pain, expert readers identified 30 patients with NRS plaques and matched these with 30 non-NRS plaques with similar degree of calcification, luminal obstruction, localization, and imaging parameters. All plaques were segmented manually, and image data information was analyzed using Radiomics Image Analysis package for the presence of 8 conventional and 4440 radiomic parameters. We used the permutation test of symmetry to assess differences between NRS and non-NRS plaques, whereas we calculated receiver-operating characteristics' area under the curve values to evaluate diagnostic accuracy. Bonferroni-corrected P<0.0012 was considered significant. None of the conventional quantitative parameters but 20.6% (916/4440) of radiomic features were significantly different between NRS and non NRS plaques. Almost half of these (418/916) reached an area under the curve value >0.80. Short- and long-run low gray-level emphasis and surface ratio of high attenuation voxels to total surface had the highest area under the curve values (0.918; 0.894 and 0.890, respectively). CONCLUSIONS: A large number of radiomic features are different between NRS and non-NRS plaques and exhibit excellent discriminatory value. PMID- 29233838 TI - Right Atrial Contractile Function in Pediatric Pulmonary Hypertension: A Novel Marker for Disease Severity? PMID- 29233839 TI - Genetics of tumors of the adrenal cortex. AB - This review describes the molecular alterations observed in the various types of tumors of the adrenal cortex, excluding Conn adenomas, especially the alterations identified by genomic approaches these last five years. Two main forms of bilateral adrenocortical tumors can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenal disease (PPNAD), which can be sporadic or part of Carney complex and primary bilateral macro nodular adrenal hyperplasia (PBMAH). The bilateral nature of the tumors suggests the existence of an underlying genetic predisposition. PPNAD and Carney complex are mainly due to germline-inactivating mutations of PRKAR1A, coding for a regulatory subunit of PKA, whereas PBMAH genetic seems more complex. However, genome-wide approaches allowed the identification of a new tumor suppressor gene, ARMC5, whose germline alteration could be responsible for at least 25% of PBMAH cases. Unilateral adrenocortical tumors are more frequent, mostly adenomas. The Wnt/beta-catenin pathway can be activated in both benign and malignant tumors by CTNNB1 mutations and by ZNRF3 inactivation in adrenal cancer (ACC). Some other signaling pathways are more specific of the tumor dignity. Thus, somatic mutations of cAMP/PKA pathway genes, mainly PRKACA, coding for the catalytic alpha-subunit of PKA, are found in cortisol-secreting adenomas, whereas IGF-II overexpression and alterations of p53 signaling pathway are observed in ACC. Genome-wide approaches including transcriptome, SNP, methylome and miRome analysis have identified new genetic and epigenetic alterations and the further clustering of ACC in subgroups associated with different prognosis, allowing the development of new prognosis markers. PMID- 29233841 TI - Small intestinal neuroendocrine tumours and fibrosis: an entangled conundrum. AB - Small intestinal neuroendocrine tumours (SI-NETs) are neoplasms characterized by their ability to secrete biogenic amines and peptides. These cause distinct clinical pathology including carcinoid syndrome, marked by diarrhoea and flushing, as well as fibrosis, notably mesenteric fibrosis. Mesenteric fibrosis often results in significant morbidity by causing intestinal obstruction, oedema and ischaemia. Although advancements have been made to alleviate symptoms of carcinoid syndrome and prolong the survival of patients with SI-NETs, therapeutic options for patients with mesenteric fibrosis are still limited. As improved insight in the complex pathogenesis of mesenteric fibrosis is key to the development of new therapies, we evaluated the literature for known and putative mediators of fibrosis in SI-NETs. In this review, we discuss the tumour microenvironment, growth factors and signalling pathways involved in the complex process of fibrosis development and tumour progression in SI-NETs, in order to elucidate potential new avenues for scientific research and therapies to improve the management of patients suffering from the complications of mesenteric fibrosis. PMID- 29233842 TI - Doctor fails: early warning signs of physician fatigue? PMID- 29233840 TI - The microbiome in PTEN hamartoma tumor syndrome. AB - Germline PTEN mutations defining PTEN hamartoma tumor syndrome (PHTS) confer heritable predisposition to breast, endometrial, thyroid and other cancers with known age-related risks, but it remains impossible to predict if any individual will develop cancer. In the general population, gut microbial dysbiosis has been linked to cancer, yet is unclear whether these are associated in PHTS patients. In this pilot study, we aimed to characterize microbial composition of stool, urine, and oral wash from 32 PTEN mutation-positive individuals using 16S rRNA gene sequencing. PCoA revealed clustering of the fecal microbiome by cancer history (P = 0.03, R2 = 0.04). Fecal samples from PHTS cancer patients had relatively more abundant operational taxonomic units (OTUs) from family Rikenellaceae and unclassified members of Clostridia compared to those from non cancer patients, whereas families Peptostreptococcaceae, Enterobacteriaceae, and Bifidobacteriaceae represented relatively more abundant OTUs among fecal samples from PHTS non-cancer patients. Functional metagenomic prediction revealed enrichment of the folate biosynthesis, genetic information processing and cell growth and death pathways among fecal samples from PHTS cancer patients compared to non-cancer patients. We found no major shifts in overall diversity and no clustering by cancer history among oral wash or urine samples. Our observations suggest the utility of an expanded study to interrogate gut dysbiosis as a potential cancer risk modifier in PHTS patients. PMID- 29233843 TI - Cesarean delivery rates among family physicians versus obstetricians: a population-based cohort study using instrumental variable methods. AB - BACKGROUND: Previous research suggests that family physicians have rates of cesarean delivery that are lower than or equivalent to those for obstetricians, but adjustments for risk differences in these analyses may have been inadequate. We used an econometric method to adjust for observed and unobserved factors affecting the risk of cesarean delivery among women attended by family physicians versus obstetricians. METHODS: This retrospective population-based cohort study included all Canadian (except Quebec) hospital deliveries by family physicians and obstetricians between Apr. 1, 2006, and Mar. 31, 2009. We excluded women with multiple gestations, and newborns with a birth weight less than 500 g or gestational age less than 20 weeks. We estimated the relative risk of cesarean delivery using instrumental-variable-adjusted and logistic regression. RESULTS: The final cohort included 776 299 women who gave birth in 390 hospitals. The risk of cesarean delivery was 27.3%, and the mean proportion of deliveries by family physicians was 26.9% (standard deviation 23.8%). The relative risk of cesarean delivery for family physicians versus obstetricians was 0.48 (95% confidence interval [CI] 0.41-0.56) with logistic regression and 1.27 (95% CI 1.02-1.57) with instrumental-variable-adjusted regression. INTERPRETATION: Our conventional analyses suggest that family physicians have a lower rate of cesarean delivery than obstetricians, but instrumental variable analyses suggest the opposite. Because instrumental variable methods adjust for unmeasured factors and traditional methods do not, the large discrepancy between these estimates of risk suggests that clinical and/or sociocultural factors affecting the decision to perform cesarean delivery may not be accounted for in our database. PMID- 29233845 TI - Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand. AB - RATIONALE: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis. OBJECTIVE: The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise. METHODS AND RESULTS: We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by beta1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity. CONCLUSIONS: These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease. PMID- 29233846 TI - VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression. AB - RATIONALE: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. OBJECTIVE: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. METHODS AND RESULTS: We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and beta-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/beta-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. CONCLUSIONS: These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system. PMID- 29233848 TI - G Protein-Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus. AB - G protein-coupled receptors (GPCRs) continue to be important discovery targets for the treatment of type 2 diabetes mellitus (T2DM). Many GPCRs are directly involved in the development of insulin resistance and beta-cell dysfunction, and in the etiology of inflammation that can lead to obesity-induced T2DM. This review summarizes the current literature describing a number of well-validated GPCR targets, but also outlines several new and promising targets for drug discovery. We highlight the importance of understanding the role of these receptors in the disease pathology, and their basic pharmacology, which will pave the way to the development of novel pharmacological probes that will enable these targets to fulfill their promise for the treatment of these metabolic disorders. PMID- 29233847 TI - Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors. AB - Allosteric modulators of G protein-coupled receptors, including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS 986122 is a positive allosteric modulator (PAM) of the MU-opioid receptor (u-OR). BMS-986187 is a structurally distinct PAM for the delta-opioid receptor (delta OR) that has been reported to exhibit 100-fold selectivity in promoting delta-OR over MU-OR agonism. We used ligand binding and second-messenger assays to show that BMS-986187 is an effective PAM at the MU-OR and at the kappa-opioid receptor (kappa-OR), but it is ineffective at the nociceptin receptor. The affinity of BMS 986187 for delta-ORs and kappa-ORs is approximately 20- to 30-fold higher than for MU-ORs, determined using an allosteric ternary complex model. Moreover, we provide evidence, using a silent allosteric modulator as an allosteric antagonist, that BMS-986187 and BMS-986122 bind to a similar region on all three traditional opioid receptor types (u-OR, delta-OR, and kappa-OR). In contrast to the dogma surrounding allosteric modulators, the results indicate a possible conserved allosteric binding site across the opioid receptor family that can accommodate structurally diverse molecules. These findings have implications for the development of selective allosteric modulators. PMID- 29233849 TI - Evidence That Isoprene Emission Is Not Limited by Cytosolic Metabolites. Exogenous Malate Does Not Invert the Reverse Sensitivity of Isoprene Emission to High [CO2]. AB - Isoprene is synthesized via the chloroplastic 2-C-methyl-d-erythritol 4 phosphate/1-deoxy-d-xylulose 5-phosphate pathway (MEP/DOXP), and its synthesis is directly related to photosynthesis, except under high CO2 concentration, when the rate of photosynthesis increases but isoprene emission decreases. Suppression of MEP/DOXP pathway activity by high CO2 has been explained either by limited supply of the cytosolic substrate precursor, phosphoenolpyruvate (PEP), into chloroplast as the result of enhanced activity of cytosolic PEP carboxylase or by limited supply of energetic and reductive equivalents. We tested the PEP-limitation hypotheses by feeding leaves with the PEP carboxylase competitive inhibitors malate and diethyl oxalacetate (DOA) in the strong isoprene emitter hybrid aspen (Populus tremula * Populus tremuloides). Malate feeding resulted in the inhibition of net assimilation, photosynthetic electron transport, and isoprene emission rates, but DOA feeding did not affect any of these processes except at very high application concentrations. Both malate and DOA did not alter the sensitivity of isoprene emission to high CO2 concentration. Malate inhibition of isoprene emission was associated with enhanced chloroplastic reductive status that suppressed light reactions of photosynthesis, ultimately leading to reduced isoprene substrate dimethylallyl diphosphate pool size. Additional experiments with altered oxygen concentrations in conditions of feedback-limited and non feedback-limited photosynthesis further indicated that changes in isoprene emission rate in control and malate-inhibited leaves were associated with changes in the share of ATP and reductive equivalent supply for isoprene synthesis. The results of this study collectively indicate that malate importantly controls the chloroplast reductive status and, thereby, affects isoprene emission, but they do not support the hypothesis that cytosolic metabolite availability alters the response of isoprene emission to changes in atmospheric composition. PMID- 29233850 TI - LTR_retriever: A Highly Accurate and Sensitive Program for Identification of Long Terminal Repeat Retrotransposons. AB - Long terminal repeat retrotransposons (LTR-RTs) are prevalent in plant genomes. The identification of LTR-RTs is critical for achieving high-quality gene annotation. Based on the well-conserved structure, multiple programs were developed for the de novo identification of LTR-RTs; however, these programs are associated with low specificity and high false discovery rates. Here, we report LTR_retriever, a multithreading-empowered Perl program that identifies LTR-RTs and generates high-quality LTR libraries from genomic sequences. LTR_retriever demonstrated significant improvements by achieving high levels of sensitivity (91%), specificity (97%), accuracy (96%), and precision (90%) in rice (Oryza sativa). LTR_retriever is also compatible with long sequencing reads. With 40k self-corrected PacBio reads equivalent to 4.5* genome coverage in Arabidopsis (Arabidopsis thaliana), the constructed LTR library showed excellent sensitivity and specificity. In addition to canonical LTR-RTs with 5'-TG...CA-3' termini, LTR_retriever also identifies noncanonical LTR-RTs (non-TGCA), which have been largely ignored in genome-wide studies. We identified seven types of noncanonical LTRs from 42 out of 50 plant genomes. The majority of noncanonical LTRs are Copia elements, with which the LTR is four times shorter than that of other Copia elements, which may be a result of their target specificity. Strikingly, non-TGCA Copia elements are often located in genic regions and preferentially insert nearby or within genes, indicating their impact on the evolution of genes and their potential as mutagenesis tools. PMID- 29233851 TI - Incremental Shuttle Walk Test to Assess and Prescribe Exercise for Subjects With Bronchiectasis: Hallway Versus Treadmill. AB - INTRODUCTION: The incremental shuttle walk test was initially developed to be carried out in a hallway (ISWT-H) but has been modified to be performed on a treadmill (ISWT-T). However, it is still unknown whether performance on ISWT-H and ISWT-T are similar in patients with bronchiectasis. In this study, we compared the performance, physiological responses, and perception of effort between the ISWT-T with a handrail and ISWT-H for subjects with bronchiectasis. We also sought to estimate and compare the prescription for training intensity with both tests. METHODS: This was a cross-sectional study in which 24 subjects with bronchiectasis were evaluated on 2 different days (24 h apart). Distance walked (m) was compared between the ISWT-H and ISWT-T. A training session was held on a treadmill at 75% of the speed obtained from both tests. The walking distance, oxygen uptake (VO2 ), carbon dioxide production (VCO2 ), heart rate, and ventilation (VE) were measured. RESULTS: There was a difference in the walking distance between the ISWT-T and ISWT-H, but physiological responses for VO2 , VCO2 , heart rate, and VE were similar. However, the speed estimated for training was different, as were the VO2 , VCO2 , and heart rate. CONCLUSIONS: The ISWT-T with handrail and the ISWT-H are not interchangeable in subjects with bronchiectasis. A slower speed of training intensity may occur when the test is performed in a hallway, as originally described, and this may underestimate responses to aerobic training. PMID- 29233852 TI - Inhalation Sedation in Subjects With ARDS Undergoing Continuous Lateral Rotational Therapy. AB - INTRODUCTION: Isoflurane has shown better sedation control and potential benefits in patients with ARDS compared to propofol or midazolam, but the practical use during continuous lateral rotational therapy remains unknown. We therefore compared isoflurane with propofol and midazolam regarding sedation depth (per the Richmond Agitation-Sedation Scale), opioid consumption, lung function, and hemodynamics in patients treated with continuous lateral rotational therapy. METHODS: 38 consecutive critically ill surgical subjects were retrospectively studied using a hospital database. All subjects suffered from ARDS and were treated with continuous lateral rotational therapy between May 2010 and September 2013. Nineteen subjects were sedated with propofol or midazolam and compared with 19 subjects sedated with isoflurane using the AnaConDa-system. RESULTS: Isoflurane sedation resulted in significantly lower Richmond Agitation-Sedation Scale scores compared with propofol or midazolam. Despite deep isoflurane sedation, opioid consumption could be significantly reduced. Spontaneous breathing was possible in 90% of the subjects on isoflurane sedation compared with 16% of the subjects sedated with propofol or midazolam. The difference between peak inspiratory pressure and PEEP was significantly decreased after 24 h of isoflurane sedation. Oxygenation (PaO2 /FIO2 ) improved in both groups. Hemodynamics and need for vasopressor therapy were comparable between groups. CONCLUSIONS: This study supports the feasibility of isoflurane sedation using continuous lateral rotational therapy. PMID- 29233853 TI - Variation in Pediatric Procedural Sedations Across Children's Hospital Emergency Departments. AB - OBJECTIVES: Describe the trends in pediatric sedation use over time and determine variation in use of procedural sedation across children's hospital emergency departments (EDs). METHODS: We analyzed ED data from 35 hospitals within the Pediatric Health Information System for patients <19 years old who received sedation medications and were discharged from 2009 to 2014. Patients with chronic comorbidities or undergoing intubation were excluded. We determined frequency and trends in use of sedation and compared these between EDs. Descriptive statistics with appropriate weighting were used. RESULTS: Of the 1 448 011 patients potentially requiring sedation who presented to the ED, 99 951 (7.9%) underwent procedural sedation. Medication usage in 2014 included ketamine (73.7%), fentanyl and midazolam (15.9%), ketofol (7.3%), and propofol (2.7%). Use of fentanyl and midazolam increased, whereas use of ketamine, pentobarbital, etomidate, chloral hydrate, and methohexital decreased over time. Significant variation exists in the use of sedation across hospitals; in 2014, the sedation rate ranged 0.2% to 32.0%, with a median of 8.0%. The diagnosis with the largest variation in procedural sedation use was dislocation, with sedation rates ranging from 2% to 35%. CONCLUSIONS: There is significant variability across pediatric EDs in the use of procedural sedation, suggesting sedations may be performed too often or too little in some hospitals. PMID- 29233854 TI - Efficacy of educational video game versus traditional educational apps at improving physician decision making in trauma triage: randomized controlled trial. AB - OBJECTIVE: To determine whether a behavioral intervention delivered through a video game can improve the appropriateness of trauma triage decisions in the emergency department of non-trauma centers. DESIGN: Randomized clinical trial. SETTING: Online intervention in national sample of emergency medicine physicians who make triage decisions at US hospitals. PARTICIPANTS: 368 emergency medicine physicians primarily working at non-trauma centers. A random sample (n=200) of those with primary outcome data was reassessed at six months. INTERVENTIONS: Physicians were randomized in a 1:1 ratio to one hour of exposure to an adventure video game (Night Shift) or apps based on traditional didactic education (myATLS and Trauma Life Support MCQ Review), both on iPads. Night Shift was developed to recalibrate the process of using pattern recognition to recognize moderate-severe injuries (representativeness heuristics) through the use of stories to promote behavior change (narrative engagement). Physicians were randomized with a 2*2 factorial design to intervention (game v traditional education apps) and then to the experimental condition under which they completed the outcome assessment tool (low v high cognitive load). Blinding could not be maintained after allocation but group assignment was masked during the analysis phase. MAIN OUTCOME MEASURES: Outcomes of a virtual simulation that included 10 cases; in four of these the patients had severe injuries. Participants completed the simulation within four weeks of their intervention. Decisions to admit, discharge, or transfer were measured. The proportion of patients under-triaged (patients with severe injuries not transferred to a trauma center) was calculated then (primary outcome) and again six months later, with a different set of cases (primary outcome of follow up study). The secondary outcome was effect of cognitive load on under-triage. RESULTS: 149 (81%) physicians in the game arm and 148 (80%) in the traditional education arm completed the trial. Of these, 64/100 (64%) and 58/100 (58%), respectively, completed reassessment at six months. The mean age was 40 (SD 8.9), 283 (96%) were trained in emergency medicine, and 207 (70%) were ATLS (advanced trauma life support) certified. Physicians exposed to the game under-triaged fewer severely injured patients than those exposed to didactic education (316/596 (0.53) v 377/592 (0.64), estimated difference 0.11, 95% confidence interval 0.05 to 0.16; P<0.001). Cognitive load did not influence under-triage (161/308 (0.53) v 155/288 (0.54) in the game arm; 197/300 (0.66) v 180/292 (0.62) in the traditional educational apps arm; P=0.66). At six months, physicians exposed to the game remained less likely to under-triage patients (146/256 (0.57) v 172/232 (0.74), estimated difference 0.17, 0.09 to 0.25; P<0.001). No physician reported side effects. The sample might not reflect all emergency medicine physicians, and a small set of cases was used to assess performance. CONCLUSIONS: Compared with apps based on traditional didactic education, exposure of physicians to a theoretically grounded video game improved triage decision making in a validated virtual simulation. Though the observed effect was large, the wide confidence intervals include the possibility of a small benefit, and the real world efficacy of this intervention remains uncertain. TRIAL REGISTRATION: clinicaltrials.gov; NCT02857348 (initial study)/NCT03138304 (follow-up). PMID- 29233855 TI - The Plastid Lipocalin LCNP Is Required for Sustained Photoprotective Energy Dissipation in Arabidopsis. AB - Light utilization is finely tuned in photosynthetic organisms to prevent cellular damage. The dissipation of excess absorbed light energy, a process termed nonphotochemical quenching (NPQ), plays an important role in photoprotection. Little is known about the sustained or slowly reversible form(s) of NPQ and whether they are photoprotective, in part due to the lack of mutants. The Arabidopsis thaliana suppressor of quenching1 (soq1) mutant exhibits enhanced sustained NPQ, which we term qH. To identify molecular players involved in qH, we screened for suppressors of soq1 and isolated mutants affecting either chlorophyllide a oxygenase or the chloroplastic lipocalin, now renamed plastid lipocalin (LCNP). Analysis of the mutants confirmed that qH is localized to the peripheral antenna (LHCII) of photosystem II and demonstrated that LCNP is required for qH, either directly (by forming NPQ sites) or indirectly (by modifying the LHCII membrane environment). qH operates under stress conditions such as cold and high light and is photoprotective, as it reduces lipid peroxidation levels. We propose that, under stress conditions, LCNP protects the thylakoid membrane by enabling sustained NPQ in LHCII, thereby preventing singlet oxygen stress. PMID- 29233858 TI - Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury. AB - Cellular bioenergetic failure caused by mitochondrial dysfunction is a key process of alveolar epithelial injury during acute respiratory distress syndrome (ARDS). Prolyl hydroxylases (PHDs) act as cellular oxygen sensors, and their inhibition activates hypoxia-inducible factor (HIF), resulting in enhanced cellular glycolytic activity, which could compensate for impaired mitochondrial function and protect alveolar epithelial cells from ARDS. Here, we evaluated the effects of pharmacological PHD inhibition with dimethyloxalylglycine (DMOG) on alveolar epithelial cell injury using in vitro and in vivo ARDS models. We established an in vitro model of alveolar epithelial injury mimicking ARDS by adding isolated neutrophils and LPS to cultured MLE12 alveolar epithelial cells. DMOG treatment protected MLE12 cells from neutrophil-LPS-induced ATP decline and cell death. Knockdown of HIF-1alpha or inhibition of glycolysis abolished the protective effect of DMOG, suggesting that it was exerted by HIF-1-dependent enhancement of glycolysis. Additionally, intratracheal DMOG administration to mice protected the alveolar epithelial barrier and improved arterial oxygenation, preventing ATP decline during LPS-induced lung injury. In summary, enhancement of glycolysis by PHD inhibition is a potential therapeutic approach for ARDS, protecting alveolar epithelial cells from bioenergetic failure and cell death. Tojo, K., Tamada, N., Nagamine, Y., Yazawa, T., Ota, S., Goto, T. Enhancement of glycolysis by inhibition of oxygen-sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury. PMID- 29233856 TI - Structure of the Arabidopsis JMJ14-H3K4me3 Complex Provides Insight into the Substrate Specificity of KDM5 Subfamily Histone Demethylases. AB - In chromatin, histone methylation affects the epigenetic regulation of multiple processes in animals and plants and is modulated by the activities of histone methyltransferases and histone demethylases. The jumonji domain-containing histone demethylases have diverse functions and can be classified into several subfamilies. In humans, the jumonji domain-containing Lysine (K)-Specific Demethylase 5/Jumonji and ARID Domain Protein (KDM5/JARID) subfamily demethylases are specific for histone 3 lysine 4 trimethylation (H3K4me3) and are important drug targets for cancer treatment. In Arabidopsis thaliana, the KDM5/JARID subfamily H3K4me3 demethylase JUMONJI14 (JMJ14) plays important roles in flowering, gene silencing, and DNA methylation. Here, we report the crystal structures of the JMJ14 catalytic domain in both substrate-free and bound forms. The structures reveal that the jumonji and C5HC2 domains contribute to the specific recognition of the H3R2 and H3Q5 to facilitate H3K4me3 substrate specificity. The critical acidic residues are conserved in plants and animals with the corresponding mutations impairing the enzyme activity of both JMJ14 and human KDM5B, indicating a common substrate recognition mechanism for KDM5 subfamily demethylases shared by plants and animals and further informing efforts to design targeted inhibitors of human KDM5. PMID- 29233857 TI - Timing of food intake impacts daily rhythms of human salivary microbiota: a randomized, crossover study. AB - The composition of the diet (what we eat) has been widely related to the microbiota profile. However, whether the timing of food consumption (when we eat) influences microbiota in humans is unknown. A randomized, crossover study was performed in 10 healthy normal-weight young women to test the effect of the timing of food intake on the human microbiota in the saliva and fecal samples. More specifically, to determine whether eating late alters daily rhythms of human salivary microbiota, we interrogated salivary microbiota in samples obtained at 4 specific time points over 24 h, to achieve a better understanding of the relationship between food timing and metabolic alterations in humans. Results revealed significant diurnal rhythms in salivary diversity and bacterial relative abundance ( i.e., TM7 and Fusobacteria) across both early and late eating conditions. More importantly, meal timing affected diurnal rhythms in diversity of salivary microbiota toward an inverted rhythm between the eating conditions, and eating late increased the number of putative proinflammatory taxa, showing a diurnal rhythm in the saliva. In a randomized, crossover study, we showed for the first time the impact of the timing of food intake on human salivary microbiota. Eating the main meal late inverts the daily rhythm of salivary microbiota diversity which may have a deleterious effect on the metabolism of the host. Collado, M. C., Engen, P. A., Bandin, C., Cabrera-Rubio, R., Voigt, R. M., Green, S. J., Naqib, A., Keshavarzian, A., Scheer, F. A. J. L., Garaulet, M. Timing of food intake impacts daily rhythms of human salivary microbiota: a randomized, crossover study. PMID- 29233859 TI - Intraring allostery controls the function and assembly of a hetero-oligomeric class II chaperonin. AB - Class II chaperonins are essential multisubunit complexes that aid the folding of nonnative proteins in the cytosol of archaea and eukarya. They use energy derived from ATP to drive a series of structural rearrangements that enable polypeptides to fold within their central cavity. These events are regulated by an elaborate allosteric mechanism in need of elucidation. We employed mutagenesis and experimental analysis in concert with in silico molecular dynamics simulations and interface-binding energy calculations to investigate the class II chaperonin from Thermoplasma acidophilum. Here we describe the effects on the asymmetric allosteric mechanism and on hetero-oligomeric complex formation in a panel of mutants in the ATP-binding pocket of the alpha and beta subunits. Our observations reveal a potential model for a nonconcerted folding mechanism optimized for protecting and refolding a range of nonnative substrates under different environmental conditions, starting to unravel the role of subunit heterogeneity in this folding machine and establishing important links with the behavior of the most complex eukaryotic chaperonins.-Shoemark, D. K., Sessions, R. B., Brancaccio, A., Bigotti, M. G. Intraring allostery controls the function and assembly of a hetero-oligomeric class II chaperonin. PMID- 29233860 TI - Pathway analysis of transcriptomic data shows immunometabolic effects of vitamin D. AB - Unbiased genomic screening analyses have highlighted novel immunomodulatory properties of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). However, clearer interpretation of the resulting gene expression data is limited by cell model specificity. The aim of the current study was to provide a broader perspective on common gene regulatory pathways associated with innate immune responses to 1,25(OH)2D, through systematic re-interrogation of existing gene expression databases from multiple related monocyte models (the THP-1 monocytic cell line (THP-1), monocyte-derived dendritic cells (DCs) and monocytes). Vitamin D receptor (VDR) expression is common to multiple immune cell types, and thus, pathway analysis of gene expression using data from multiple related models provides an inclusive perspective on the immunomodulatory impact of vitamin D. A bioinformatic workflow incorporating pathway analysis using PathVisio and WikiPathways was utilized to compare each set of gene expression data based on pathway-level context. Using this strategy, pathways related to the TCA cycle, oxidative phosphorylation and ATP synthesis and metabolism were shown to be significantly regulated by 1,25(OH)2D in each of the repository models (Z-scores 3.52-8.22). Common regulation by 1,25(OH)2D was also observed for pathways associated with apoptosis and the regulation of apoptosis (Z-scores 2.49-3.81). In contrast to the primary culture DC and monocyte models, the THP-1 myelomonocytic cell line showed strong regulation of pathways associated with cell proliferation and DNA replication (Z-scores 6.1-12.6). In short, data presented here support a fundamental role for active 1,25(OH)2D as a pivotal regulator of immunometabolism. PMID- 29233861 TI - Restoration of metabolic inflammation-related ghrelin resistance by weight loss. AB - High-fat diet (HFD)-induced metabolic inflammation in the central and peripheral organs contributes to the pathogenesis of obesity. Long-term HFD blunts signaling by ghrelin, a gastric-derived orexigenic peptide, in the vagal afferent nerve via a mechanism involving in situ activation of inflammation. This study was undertaken to investigate whether ghrelin resistance is associated with progressive development of metabolic inflammation. In mice, ghrelin's orexigenic activity was abolished 2-4 weeks after the commencement of HFD (60% of energy from fat), consistent with the timing of accumulation and activation of macrophages and microglia in the nodose ganglion and hypothalamus. Calorie restricted weight loss after 12-week HFD feeding restored ghrelin responsiveness and alleviated the upregulation of macrophage/microglia activation markers and inflammatory cytokines. HSP72, a chaperone protein, was upregulated in the hypothalamus of HFD-fed mice, potentially contributing to prevention of irreversible neuron damage. These results demonstrate that ghrelin resistance is reversible following reversal of the HFD-induced inflammation and obesity phenotypes. PMID- 29233862 TI - Prolactin-releasing peptide improved leptin hypothalamic signaling in obese mice. AB - The situation following anti-obesity drug termination is rarely investigated, eventhough a decrease in body weight needs to be sustained. Therefore, this study examined the impact of twice-daily peripheral administration of 5 mg/kg [N-palm gammaGlu-Lys11] prolactin-releasing peptide 31 (palm11-PrRP31) in mice with diet induced obesity (DIO from consuming a high-fat diet) after 28 days of treatment (palm11-PrRP31 group) and after 14 days of peptide treatment followed by 14 days of discontinuation (palm11-PrRP31 + saline group). At the end of the treatment, cumulative food intake, body weight and subcutaneous fat weight/body weight ratio and leptin plasma level were reduced significantly in both the palm11-PrRP31 group and the palm11-PrRP31 + saline group compared to the saline control group. This reduction correlated with significantly increased FOSB, a marker of long term neuronal potentiation, in the nucleus arcuatus and nucleus tractus solitarii, areas known to be affected by the anorexigenic effect of palm11 PrRP31. Moreover, activation of leptin-related hypothalamic signaling was registered through an increase in phosphoinositide-3-kinase, increased phosphorylation of protein kinase B (PKB, AKT) and enhanced extracellular signal regulated kinase 1/2 phosphorylation. Besides, lowered apoptotic markers c-JUN N terminal kinase and c-JUN phosphorylation were registered in the hypothalami of both palm11-PrRP31-treated groups. This study demonstrates that palm11-PrRP31 positively affects feeding and leptin-related hypothalamic signaling, not only after 28 days of treatment but even 14 days after the termination of a 14-day long treatment without the yo-yo effect. PMID- 29233864 TI - DepHining membrane identity. AB - How do organelles coordinate their unique molecular identities between their cytosolic-facing surface membranes and their interior? In this issue, Naufer et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201702179) discover an intriguing link between phagosome acidification and lipid signposts on their outer membrane. PMID- 29233863 TI - Cobl-like promotes actin filament formation and dendritic branching using only a single WH2 domain. AB - Local actin filament formation powers the development of the signal-receiving arbor of neurons that underlies neuronal network formation. Yet, little is known about the molecules that drive these processes and may functionally connect them to the transient calcium pulses observed in restricted areas in the forming dendritic arbor. Here we demonstrate that Cordon-Bleu (Cobl)-like, an uncharacterized protein suggested to represent a very distantly related, evolutionary ancestor of the actin nucleator Cobl, despite having only a single G actin-binding Wiskott-Aldrich syndrome protein Homology 2 (WH2) domain, massively promoted the formation of F-actin-rich membrane ruffles of COS-7 cells and of dendritic branches of neurons. Cobl-like hereby integrates WH2 domain functions with those of the F-actin-binding protein Abp1. Cobl-like-mediated dendritic branching is dependent on Abp1 as well as on Ca2+/calmodulin (CaM) signaling and CaM association. Calcium signaling leads to a promotion of complex formation with Cobl-like's cofactor Abp1. Thus, Ca2+/CaM control of actin dynamics seems to be a much more broadly used principle in cell biology than previously thought. PMID- 29233865 TI - DICER- and MMSET-catalyzed H4K20me2 recruits the nucleotide excision repair factor XPA to DNA damage sites. AB - Ultraviolet (UV) irradiation triggers the recruitment of DNA repair factors to the lesion sites and the deposition of histone marks as part of the DNA damage response. The major DNA repair pathway removing DNA lesions caused by exposure to UV light is nucleotide excision repair (NER). We have previously demonstrated that the endoribonuclease DICER facilitates chromatin decondensation during lesion recognition in the global-genomic branch of NER. Here, we report that DICER mediates the recruitment of the methyltransferase MMSET to the DNA damage site. We show that MMSET is required for efficient NER and that it catalyzes the dimethylation of histone H4 at lysine 20 (H4K20me2). H4K20me2 at DNA damage sites facilitates the recruitment of the NER factor XPA. Our work thus provides evidence for an H4K20me2-dependent mechanism of XPA recruitment during lesion recognition in the global-genomic branch of NER. PMID- 29233868 TI - Signalling mechanisms in autophagy: an introduction to the issue. AB - Essays in Biochemistry volume 61 (issue 6), entitled Signalling Mechanisms in Autophagy, covers a range of topics in autophagy signalling, touching on emerging new details on the mechanisms of autophagy regulation, novel aspects of selective autophagy and how autophagy functions in organelle homeostasis. It also looks at how autophagy research is leading to better understanding of human disease and plant biology that can be exploited for the benefit of society. PMID- 29233866 TI - Rho GTPase signaling complexes in cell migration and invasion. AB - Cell migration is dependent on the dynamic formation and disassembly of actin filament-based structures, including lamellipodia, filopodia, invadopodia, and membrane blebs, as well as on cell-cell and cell-extracellular matrix adhesions. These processes all involve Rho family small guanosine triphosphatases (GTPases), which are regulated by the opposing actions of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPase activity needs to be precisely tuned at distinct cellular locations to enable cells to move in response to different environments and stimuli. In this review, we focus on the ability of RhoGEFs and RhoGAPs to form complexes with diverse binding partners, and describe how this influences their ability to control localized GTPase activity in the context of migration and invasion. PMID- 29233872 TI - Regulation of selective autophagy: the p62/SQSTM1 paradigm. AB - In selective autophagy, cytoplasmic components are selected and tagged before being sequestered into an autophagosome by means of selective autophagy receptors such as p62/SQSTM1. In this review, we discuss how selective autophagy is regulated. An important level of regulation is the selection of proteins or organelles for degradation. Components selected for degradation are tagged, often with ubiquitin, to facilitate recognition by autophagy receptors. Another level of regulation is represented by the autophagy receptors themselves. For p62, its ability to co-aggregate with ubiquitinated substrates is strongly induced by post translational modifications (PTMs). The transcription of p62 is also markedly increased during conditions in which selective autophagy substrates accumulate. For other autophagy receptors, the LC3-interacting region (LIR) motif is regulated by PTMs, inhibiting or stimulating the interaction with ATG8 family proteins. ATG8 proteins are also regulated by PTMs. Regulation of the capacity of the core autophagy machinery also affects selective autophagy. Importantly, autophagy receptors can induce local recruitment and activation of ULK1/2 and PI3KC3 complexes at the site of cargo sequestration. PMID- 29233871 TI - Interplay of autophagy, receptor tyrosine kinase signalling and endocytic trafficking. AB - Vesicular trafficking events play key roles in the compartmentalization and proper sorting of cellular components. These events have crucial roles in sensing external signals, regulating protein activities and stimulating cell growth or death decisions. Although mutations in vesicle trafficking players are not direct drivers of cellular transformation, their activities are important in facilitating oncogenic pathways. One such pathway is the sensing of external stimuli and signalling through receptor tyrosine kinases (RTKs). The regulation of RTK activity by the endocytic pathway has been extensively studied. Compelling recent studies have begun to highlight the association between autophagy and RTK signalling. The influence of this interplay on cellular status and its relevance in disease settings will be discussed here. PMID- 29233870 TI - The mammalian ULK1 complex and autophagy initiation. AB - Autophagy is a vital lysosomal degradation pathway that serves as a quality control mechanism. It rids the cell of damaged, toxic or excess cellular components, which if left to persist could be detrimental to the cell. It also serves as a recycling pathway to maintain protein synthesis under starvation conditions. A key initial event in autophagy is formation of the autophagosome, a unique double-membrane organelle that engulfs the cytosolic cargo destined for degradation. This step is mediated by the serine/threonine protein kinase ULK1 (unc-51-like kinase 1), which functions in a complex with at least three protein partners: FIP200 (focal adhesion kinase family interacting protein of 200 kDa), ATG (autophagy-related protein) 13 (ATG13), and ATG101. In this artcile, we focus on the regulation of the ULK1 complex during autophagy initiation. The complex pattern of upstream pathways that converge on ULK1 suggests that this complex acts as a node, converting multiple signals into autophagosome formation. Here, we review our current understanding of this regulation and in turn discuss what happens downstream, once the ULK1 complex becomes activated. PMID- 29233869 TI - mTORC1 as the main gateway to autophagy. AB - Cells and organisms must coordinate their metabolic activity with changes in their environment to ensure their growth only when conditions are favourable. In order to maintain cellular homoeostasis, a tight regulation between the synthesis and degradation of cellular components is essential. At the epicentre of the cellular nutrient sensing is the mechanistic target of rapamycin complex 1 (mTORC1) which connects environmental cues, including nutrient and growth factor availability as well as stress, to metabolic processes in order to preserve cellular homoeostasis. Under nutrient-rich conditions mTORC1 promotes cell growth by stimulating biosynthetic pathways, including synthesis of proteins, lipids and nucleotides, and by inhibiting cellular catabolism through repression of the autophagic pathway. Its close signalling interplay with the energy sensor AMP activated protein kinase (AMPK) dictates whether the cell actively favours anabolic or catabolic processes. Underlining the role of mTORC1 in the coordination of cellular metabolism, its deregulation is linked to numerous human diseases ranging from metabolic disorders to many cancers. Although mTORC1 can be modulated by a number of different inputs, amino acids represent primordial cues that cannot be compensated for by any other stimuli. The understanding of how amino acids signal to mTORC1 has increased considerably in the last years; however this area of research remains a hot topic in biomedical sciences. The current ideas and models proposed to explain the interrelationship between amino acid sensing, mTORC1 signalling and autophagy is the subject of the present review. PMID- 29233874 TI - Autophagy's secret life: secretion instead of degradation. AB - Autophagy is conventionally described as a degradative, catabolic pathway and a tributary to the lysosomal system where the cytoplasmic material sequestered by autophagosomes gets degraded. However, autophagosomes or autophagosome-related organelles do not always follow this route. It has recently come to light that autophagy can terminate in cytosolic protein secretion or release of sequestered material from the cells, rather than in their degradation. In this review, we address this relatively new but growing aspect of autophagy as a complex pathway, which is far more versatile than originally anticipated. PMID- 29233873 TI - ER homeostasis and autophagy. AB - The endoplasmic reticulum (ER) is a key site for lipid biosynthesis and folding of nascent transmembrane and secretory proteins. These processes are maintained by careful homeostatic control of the environment within the ER lumen. Signalling sensors within the ER detect perturbations within the lumen (ER stress) and employ downstream signalling cascades that engage effector mechanisms to restore homeostasis. The most studied signalling mechanism that the ER employs is the unfolded protein response (UPR), which is known to increase a number of effector mechanisms, including autophagy. In this chapter, we will discuss the emerging role of autophagy as a UPR effector pathway. We will focus on the recently discovered selective autophagy pathway for ER, ER-phagy, with particular emphasis on the structure and function of known mammalian ER-phagy receptors, namely FAM134B, SEC62, RTN3 and CCPG1. Finally, we conclude with our view of where the future of this field can lead our understanding of the involvement of ER-phagy in ER homeostasis. PMID- 29233875 TI - To be or not to be cell autonomous? Autophagy says both. AB - Although cells are a part of the whole organism, classical dogma emphasizes that individual cells function autonomously. Many physiological and pathological conditions, including cancer, and metabolic and neurodegenerative diseases, have been considered mechanistically as cell-autonomous pathologies, meaning those that damage or defect within a selective population of affected cells suffice to produce disease. It is becoming clear, however, that cells and cellular processes cannot be considered in isolation. Best known for shuttling cytoplasmic content to the lysosome for degradation and repurposing of recycled building blocks such as amino acids, nucleotides, and fatty acids, autophagy serves a housekeeping function in every cell and plays key roles in cell development, immunity, tissue remodeling, and homeostasis with the surrounding environment and the distant organs. In this review, we underscore the importance of taking interactions with the microenvironment into consideration while addressing the cell autonomous and non-autonomous functions of autophagy between cells of the same and different types and in physiological and pathophysiological situations. PMID- 29233876 TI - Molecular control of chaperone-mediated autophagy. AB - Chaperone-mediated autophagy (CMA) is a selective form of autophagy in which cytosolic proteins bearing a pentapeptide motif biochemically related to the KFERQ sequence, are recognized by the heat shock protein family A member 8 (HSPA8) chaperone, delivered to the lysomal membrane, and directly translocated across the lysosomal membrane by a protein complex containing lysosomal associated membrane protein 2a (Lamp2a). Since its discovery over two decades ago, the importance of this pathway in cell proteostasis has been made increasingly apparent. Deregulation of this pathway has been implicated in a variety of diseases and conditions, including lysosomal storage diseases, cancer, neurodegeneration and even aging. Here, we describe the main molecular features of the pathway, its regulation, cross-talk with other degradation pathways and importance in disease. PMID- 29233877 TI - Understanding and exploiting autophagy signaling in plants. AB - Autophagy is an essential catabolic pathway and is activated by various endogenous and exogenous stimuli. In particular, autophagy is required to allow sessile organisms such as plants to cope with biotic or abiotic stress conditions. It is thought that these various environmental signaling pathways are somehow integrated with autophagy signaling. However, the molecular mechanisms of plant autophagy signaling are not well understood, leaving a big gap of knowledge as a barrier to being able to manipulate this important pathway to improve plant growth and development. In this review, we discuss possible regulatory mechanisms at the core of plant autophagy signaling. PMID- 29233879 TI - Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance. AB - Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) at lysosomes plays a pivotal role in cell growth control where an array of large multiprotein complexes relay nutrient, energy, and growth signal inputs through mTORC1. In cancer cells, such regulation often becomes disconnected, leading to uncontrolled cell growth and an elevation in cellular stress. Consequently, cancer cells often lose homeostatic balance as they grow in unfavorable conditions, i.e. when nutrients and energy are limited yet mTORC1 is still aberrantly activated. Cancer cells lose signaling flexibility because of hyperactive mTORC1 that leads to heightened cellular stress and loss of nutrient and energy homeostasis, all of which are potential avenues for cancer therapy. Cancer cells often enhance mTORC1 to drive cell growth and proliferation, while also maintaining their survival. Autophagy regulation by mTORC1 is critically involved in nutrient and energy homeostasis, cell growth control, and survival. Studying mTORC1 and autophagy as a potential therapeutic target for cancer treatment has been the focus of a wide range of research over the past few decades. This review will explore the signaling pathways central to mTORC1 and autophagy regulation, and cancer vulnerabilities while considering anticancer therapies. PMID- 29233878 TI - Host-pathogen interactions and subversion of autophagy. AB - Macroautophagy ('autophagy'), is the process by which cells can form a double membraned vesicle that encapsulates material to be degraded by the lysosome. This can include complex structures such as damaged mitochondria, peroxisomes, protein aggregates and large swathes of cytoplasm that can not be processed efficiently by other means of degradation. Recycling of amino acids and lipids through autophagy allows the cell to form intracellular pools that aid survival during periods of stress, including growth factor deprivation, amino acid starvation or a depleted oxygen supply. One of the major functions of autophagy that has emerged over the last decade is its importance as a safeguard against infection. The ability of autophagy to selectively target intracellular pathogens for destruction is now regarded as a key aspect of the innate immune response. However, pathogens have evolved mechanisms to either evade or reconfigure the autophagy pathway for their own survival. Understanding how pathogens interact with and manipulate the host autophagy pathway will hopefully provide a basis for combating infection and increase our understanding of the role and regulation of autophagy. Herein, we will discuss how the host cell can identify and target invading pathogens and how pathogens have adapted in order to evade destruction by the host cell. In particular, we will focus on interactions between the mammalian autophagy gene 8 (ATG8) proteins and the host and pathogen effector proteins. PMID- 29233880 TI - Autophagy impairment in Parkinson's disease. AB - Parkinson's disease (PD) is a debilitating movement disorder typically associated with the accumulation of intracytoplasmic aggregate prone protein deposits. Over recent years, increasing evidence has led to the suggestion that the mutations underlying certain forms of PD impair autophagy. Autophagy is a degradative pathway that delivers cytoplasmic content to lysosomes for degradation and represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Autophagy up-regulation is a promising therapeutic strategy that is being explored for its potential to protect cells against the toxicity of aggregate-prone proteins in neurodegenerative diseases. Here, we describe how the mutations in different subtypes of PD can affect different stages of autophagy. PMID- 29233881 TI - Autophagy in health and disease: focus on the cardiovascular system. AB - Autophagy is a highly conserved mechanism of lysosome-mediated protein and organelle degradation that plays a crucial role in maintaining cellular homeostasis. In the last few years, specific functions for autophagy have been identified in many tissues and organs. In the cardiovascular system, autophagy appears to be essential to heart and vessel homeostasis and function; however defective or excessive autophagy activity seems to contribute to major cardiovascular disorders including heart failure (HF) or atherosclerosis. Here, we review the current knowledge on the role of cardiovascular autophagy in physiological and pathophysiological conditions. PMID- 29233883 TI - Uncorking AMPA receptors. AB - New JGP study explains how auxiliary proteins relieve polyamine block of AMPARs. PMID- 29233882 TI - Dysregulation of autophagy as a common mechanism in lysosomal storage diseases. AB - The lysosome plays a pivotal role between catabolic and anabolic processes as the nexus for signalling pathways responsive to a variety of factors, such as growth, nutrient availability, energetic status and cellular stressors. Lysosomes are also the terminal degradative organelles for autophagy through which macromolecules and damaged cellular components and organelles are degraded. Autophagy acts as a cellular homeostatic pathway that is essential for organismal physiology. Decline in autophagy during ageing or in many diseases, including late-onset forms of neurodegeneration is considered a major contributing factor to the pathology. Multiple lines of evidence indicate that impairment in autophagy is also a central mechanism underlying several lysosomal storage disorders (LSDs). LSDs are a class of rare, inherited disorders whose histopathological hallmark is the accumulation of undegraded materials in the lysosomes due to abnormal lysosomal function. Inefficient degradative capability of the lysosomes has negative impact on the flux through the autophagic pathway, and therefore dysregulated autophagy in LSDs is emerging as a relevant disease mechanism. Pathology in the LSDs is generally early-onset, severe and life limiting but current therapies are limited or absent; recognizing common autophagy defects in the LSDs raises new possibilities for therapy. In this review, we describe the mechanisms by which LSDs occur, focusing on perturbations in the autophagy pathway and present the latest data supporting the development of novel therapeutic approaches related to the modulation of autophagy. PMID- 29233884 TI - Revisiting multimodal activation and channel properties of Pannexin 1. AB - Pannexin 1 (Panx1) forms plasma membrane ion channels that are widely expressed throughout the body. Panx1 activation results in the release of nucleotides such as adenosine triphosphate and uridine triphosphate. Thus, these channels have been implicated in diverse physiological and pathological functions associated with purinergic signaling, such as apoptotic cell clearance, blood pressure regulation, neuropathic pain, and excitotoxicity. In light of this, substantial attention has been directed to understanding the mechanisms that regulate Panx1 channel expression and activation. Here we review accumulated evidence for the various activation mechanisms described for Panx1 channels and, where possible, the unitary channel properties associated with those forms of activation. We also emphasize current limitations in studying Panx1 channel function and propose potential directions to clarify the exciting and expanding roles of Panx1 channels. PMID- 29233885 TI - A perspective on Na and K channel inactivation. AB - We are wired with conducting cables called axons that rapidly transmit electrical signals (e.g., "Ouch!") from, for example, the toe to the spinal cord. Because of the high internal resistance of axons (salt water rather than copper), a signal must be reinforced after traveling a short distance. Reinforcement is accomplished by ion channels, Na channels for detecting the signal and reinforcing it by driving it further positive (to near 50 mV) and K channels for then restoring it to the resting level (near -70 mV). The signal is called an action potential and has a duration of roughly a millisecond. The return of membrane voltage (Vm) to the resting level after an action potential is facilitated by "inactivation" of the Na channels: i.e., an internal particle diffuses into the mouth of any open Na channel and temporarily blocks it. Some types of K channels also show inactivation after being open for a time. N-type inactivation of K channels has a relatively fast time course and involves diffusion of the N-terminal of one of the channel's four identical subunits into the channel's inner mouth, if it is open. This mechanism is similar to Na channel inactivation. Both Na and K channels also display slower inactivation processes. C inactivation in K channels involves changes in the channel's outer mouth, the "selectivity filter," whose normal function is to prevent Na+ ions from entering the K channel. C inactivation deforms the filter so that neither K+ nor Na+ can pass. PMID- 29233888 TI - Mitochondrial energy generation disorders: genes, mechanisms and clues to pathology. AB - Inherited disorders of oxidative phosphorylation cause the clinically and genetically heterogeneous diseases known as mitochondrial energy generation disorders, or mitochondrial diseases. Over the last three decades, mutations causing these disorders have been identified in almost 290 genes, but many patients still remain without a molecular diagnosis. Moreover, while knowledge of the genetic causes is continually expanding, understanding into how these defects lead to cellular dysfunction and organ pathology is still incomplete. Here, we review recent developments in disease gene discovery, functional characterization, and shared pathogenic parameters influencing disease pathology that offer promising avenues towards development of effective therapies. PMID- 29233887 TI - ST6Gal-I sialyltransferase promotes tumor necrosis factor (TNF)-mediated cancer cell survival via sialylation of the TNF receptor 1 (TNFR1) death receptor. AB - Activation of the tumor necrosis factor receptor 1 (TNFR1) death receptor by TNF induces either cell survival or cell death. However, the mechanisms mediating these distinct outcomes remain poorly understood. In this study, we report that the ST6Gal-I sialyltransferase, an enzyme up-regulated in numerous cancers, sialylates TNFR1 and thereby protects tumor cells from TNF-induced apoptosis. Using pancreatic and ovarian cancer cells with ST6Gal-I knockdown or overexpression, we determined that alpha2-6 sialylation of TNFR1 had no effect on early TNF-induced signaling events, including the rapid activation of NF-kappaB, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and Akt (occurring within 15 min). However, upon extended TNF treatment (6-24 h), cells with high ST6Gal-I levels exhibited resistance to TNF-induced apoptosis, as indicated by morphological evidence of cell death and decreased activation of caspases 8 and 3. Correspondingly, at these later time points, high ST6Gal-I expressers displayed sustained activation of the survival molecules Akt and NF kappaB. Additionally, extended TNF treatment resulted in the selective enrichment of clonal variants with high ST6Gal-I expression, further substantiating a role for ST6Gal-I in cell survival. Given that TNFR1 internalization is known to be essential for apoptosis induction, whereas survival signaling is initiated by TNFR1 at the plasma membrane, we examined TNFR1 localization. The alpha2-6 sialylation of TNFR1 was found to inhibit TNF-induced TNFR1 internalization. Thus, by restraining TNFR1 at the cell surface via sialylation, ST6Gal-I acts as a functional switch to divert signaling toward survival. These collective findings point to a novel glycosylation-dependent mechanism that regulates the cellular response to TNF and may promote cancer cell survival within TNF-rich tumor microenvironments. PMID- 29233886 TI - Structural insights into the mechanisms of CNBD channel function. AB - Cyclic nucleotide-binding domain (CNBD) channels are a family of ion channels in the voltage-gated K+ channel superfamily that play crucial roles in many physiological processes. CNBD channels are structurally similar but functionally very diverse. This family includes three subfamilies: (1) the cyclic nucleotide gated (CNG) channels, which are cation-nonselective, voltage-independent, and cyclic nucleotide-gated; (2) the hyperpolarization-activated cyclic nucleotide gated (HCN) channels, which are weakly K+ selective, hyperpolarization-activated, and cyclic nucleotide-gated; and (3) the ether-a-go-go-type (KCNH) channels, which are strongly K+ selective, depolarization-activated, and cyclic nucleotide independent. Recently, several high-resolution structures have been reported for intact CNBD channels, providing a structural framework to better understand their diverse function. In this review, we compare and contrast the recent structures and discuss how they inform our understanding of ion selectivity, voltage dependent gating, and cyclic nucleotide-dependent gating within this channel family. PMID- 29233889 TI - Transcriptionally inducible Pleckstrin homology-like domain, family A, member 1, attenuates ErbB receptor activity by inhibiting receptor oligomerization. AB - Feedback control is a key mechanism in signal transduction, intimately involved in regulating the outcome of the cellular response. Here, we report a novel mechanism by which PHLDA1, Pleckstrin homology-like domain, family A, member 1, negatively regulates ErbB receptor signaling by inhibition of receptor oligomerization. We have found that the ErbB3 ligand, heregulin, induces PHILDA1 expression in MCF-7 cells. Transcriptionally-induced PHLDA1 protein directly binds to ErbB3, whereas knockdown of PHLDA1 increases complex formation between ErbB3 and ErbB2. To provide insight into the mechanism for our time-course and single-cell experimental observations, we performed a systematic computational search of network topologies of the mathematical models based on receptor dimer tetramer formation in the ErbB activation processes. Our results indicate that only a model in which PHLDA1 inhibits formation of both dimers and tetramer can explain the experimental data. Predictions made from this model were further validated by single-molecule imaging experiments. Our studies suggest a unique regulatory feature of PHLDA1 to inhibit the ErbB receptor oligomerization process and thereby control the activity of receptor signaling network. PMID- 29233890 TI - Phosphate (Pi)-regulated heterodimerization of the high-affinity sodium-dependent Pi transporters PiT1/Slc20a1 and PiT2/Slc20a2 underlies extracellular Pi sensing independently of Pi uptake. AB - Extracellular phosphate (Pi) can act as a signaling molecule that directly alters gene expression and cellular physiology. The ability of cells or organisms to detect changes in extracellular Pi levels implies the existence of a Pi-sensing mechanism that signals to the body or individual cell. However, unlike in prokaryotes, yeasts, and plants, the molecular players involved in Pi sensing in mammals remain unknown. In this study, we investigated the involvement of the high-affinity, sodium-dependent Pi transporters PiT1 and PiT2 in mediating Pi signaling in skeletal cells. We found that deletion of PiT1 or PiT2 blunted the Pi-dependent ERK1/2-mediated phosphorylation and subsequent gene up-regulation of the mineralization inhibitors matrix Gla protein and osteopontin. This result suggested that both PiTs are necessary for Pi signaling. Moreover, the ERK1/2 phosphorylation could be rescued by overexpressing Pi transport-deficient PiT mutants. Using cross-linking and bioluminescence resonance energy transfer approaches, we found that PiT1 and PiT2 form high-abundance homodimers and Pi regulated low-abundance heterodimers. Interestingly, in the absence of sodium dependent Pi transport activity, the PiT1-PiT2 heterodimerization was still regulated by extracellular Pi levels. Of note, when two putative Pi-binding residues, Ser-128 (in PiT1) and Ser-113 (in PiT2), were substituted with alanine, the PiT1-PiT2 heterodimerization was no longer regulated by extracellular Pi These observations suggested that Pi binding rather than Pi uptake may be the key factor in mediating Pi signaling through the PiT proteins. Taken together, these results demonstrate that Pi-regulated PiT1-PiT2 heterodimerization mediates Pi sensing independently of Pi uptake. PMID- 29233892 TI - Stable Signal Peptides and the Response to Secretion Stress in Staphylococcus aureus. AB - Protein secretion is essential, but how it is managed is poorly understood. In bacteria, most secreted proteins require release from the outer surface of the cytoplasmic membrane by type I signal peptidase (SPase), which cleaves the mature protein from its membrane-bound N-terminal signal peptide. As the first step that occurs outside the protected cytoplasmic environment and because insufficient activity can rapidly result in the toxic accumulation of preproteins, the activity of SPase is expected to be closely monitored and perhaps supplemented when insufficient. Indeed, we previously demonstrated that inhibition of SPase in Staphylococcus aureus results in derepression of the ayrRABC operon, which encodes an alternate mechanism to release proteins. However, in this case, the proteins are released with partially intact signal peptides, with the exception of IsaA, which is released with a virtually intact signal peptide. Here we show that mutation of AyrA [ayrA(R233K)] results in constitutive derepression of ayrRABC and that mutation of IsaA's signal peptide [isaA(K2Q)] results in hyperderepression upon SPase inhibition, which also requires AyrA. Further studies demonstrate that the inducing signal for ayrRABC derepression is accumulation of a subset of preproteins with signal peptides that are stable toward further processing and that the signal is critically amplified by the K2Q mutation and relayed to AyrR by AyrA. These results elucidate the mechanism by which S. aureus monitors and responds to secretion stress. The presence of ayrRA in other bacteria suggests that it may represent a general strategy linking membrane stress to appropriate transcriptional responses.IMPORTANCE Bacteria interact with their environment by secreting proteins that perform a myriad of functions, and the final step is the release of the mature protein from the cell surface via the activity of type I signal peptidase (SPase). While the bacterial response to many stresses is understood in some detail, almost nothing is known about how cells respond to secretion stress, such as insufficient SPase activity, which would eventually result in cell death. We previously demonstrated that the inhibition of SPase in Staphylococcus aureus results in the derepression of the ayrRABC operon, which can functionally replace SPase, but which is normally repressed by AyrR. We now demonstrate that the inducing signal for derepression is accumulation of a subset of preproteins with signal peptides that are stable to further processing and that the signal is relayed to AyrR via AyrA. PMID- 29233891 TI - The FtsLB subcomplex of the bacterial divisome is a tetramer with an uninterrupted FtsL helix linking the transmembrane and periplasmic regions. AB - In Escherichia coli, FtsLB plays a central role in the initiation of cell division, possibly transducing a signal that will eventually lead to the activation of peptidoglycan remodeling at the forming septum. The molecular mechanisms by which FtsLB operates in the divisome, however, are not understood. Here, we present a structural analysis of the FtsLB complex, performed with biophysical, computational, and in vivo methods, that establishes the organization of the transmembrane region and proximal coiled coil of the complex. FRET analysis in vitro is consistent with formation of a tetramer composed of two FtsL and two FtsB subunits. We predicted subunit contacts through co-evolutionary analysis and used them to compute a structural model of the complex. The transmembrane region of FtsLB is stabilized by hydrophobic packing and by a complex network of hydrogen bonds. The coiled coil domain probably terminates near the critical constriction control domain, which might correspond to a structural transition. The presence of strongly polar amino acids within the core of the tetrameric coiled coil suggests that the coil may split into two independent FtsQ-binding domains. The helix of FtsB is interrupted between the transmembrane and coiled coil regions by a flexible Gly-rich linker. Conversely, the data suggest that FtsL forms an uninterrupted helix across the two regions and that the integrity of this helix is indispensable for the function of the complex. The FtsL helix is thus a candidate for acting as a potential mechanical connection to communicate conformational changes between periplasmic, membrane, and cytoplasmic regions. PMID- 29233894 TI - Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait. AB - Extreme antibiotic resistance in bacteria is associated with the expression of powerful inactivating enzymes and other functions encoded in accessory genomic elements. The contribution of core genome processes to high-level resistance in such bacteria has been unclear. In the work reported here, we evaluated the relative importance of core and accessory functions for high-level resistance to the aminoglycoside tobramycin in the nosocomial pathogen Acinetobacter baumannii Three lines of evidence establish the primacy of core functions in this resistance. First, in a genome scale mutant analysis using transposon sequencing and validation with 594 individual mutants, nearly all mutations reducing tobramycin resistance inactivated core genes, some with stronger phenotypes than those caused by the elimination of aminoglycoside-inactivating enzymes. Second, the core functions mediating resistance were nearly identical in the wild type and a deletion mutant lacking a genome resistance island that encodes the inactivating enzymes. Thus, most or all of the core resistance determinants important in the absence of the enzymes are also important in their presence. Third, reductions in tobramycin resistance caused by different core mutations were additive, and highly sensitive double and triple mutants (with 250-fold reductions in the MIC) that retained accessory resistance genes could be constructed. Core processes that contribute most strongly to intrinsic tobramycin resistance include phospholipid biosynthesis, phosphate regulation, and envelope homeostasis.IMPORTANCE The inexorable increase in bacterial antibiotic resistance threatens to undermine many of the procedures that transformed medicine in the last century. One strategy to meet the challenge antibiotic resistance poses is the development of drugs that undermine resistance. To identify potential targets for such adjuvants, we identified the functions underlying resistance to an important class of antibiotics for one of the most highly resistant pathogens known. PMID- 29233893 TI - Diversification of Type VI Secretion System Toxins Reveals Ancient Antagonism among Bee Gut Microbes. AB - Microbial communities are shaped by interactions among their constituent members. Some Gram-negative bacteria employ type VI secretion systems (T6SSs) to inject protein toxins into neighboring cells. These interactions have been theorized to affect the composition of host-associated microbiomes, but the role of T6SSs in the evolution of gut communities is not well understood. We report the discovery of two T6SSs and numerous T6SS-associated Rhs toxins within the gut bacteria of honey bees and bumble bees. We sequenced the genomes of 28 strains of Snodgrassella alvi, a characteristic bee gut microbe, and found tremendous variability in their Rhs toxin complements: altogether, these strains appear to encode hundreds of unique toxins. Some toxins are shared with Gilliamella apicola, a coresident gut symbiont, implicating horizontal gene transfer as a source of toxin diversity in the bee gut. We use data from a transposon mutagenesis screen to identify toxins with antibacterial function in the bee gut and validate the function and specificity of a subset of these toxin and immunity genes in Escherichia coli Using transcriptome sequencing, we demonstrate that S. alvi T6SSs and associated toxins are upregulated in the gut environment. We find that S. alvi Rhs loci have a conserved architecture, consistent with the C terminal displacement model of toxin diversification, with Rhs toxins, toxin fragments, and cognate immunity genes that are expressed and confer strong fitness effects in vivo Our findings of T6SS activity and Rhs toxin diversity suggest that T6SS-mediated competition may be an important driver of coevolution within the bee gut microbiota.IMPORTANCE The structure and composition of host associated bacterial communities are of broad interest, because these communities affect host health. Bees have a simple, conserved gut microbiota, which provides an opportunity to explore interactions between species that have coevolved within their host over millions of years. This study examined the role of type VI secretion systems (T6SSs)-protein complexes used to deliver toxic proteins into bacterial competitors-within the bee gut microbiota. We identified two T6SSs and diverse T6SS-associated toxins in bacterial strains from bees. Expression of these genes is increased in bacteria in the bee gut, and toxin and immunity genes demonstrate antibacterial and protective functions, respectively, when expressed in Escherichia coli Our results suggest that coevolution among bacterial species in the bee gut has favored toxin diversification and maintenance of T6SS machinery, and demonstrate the importance of antagonistic interactions within host-associated microbial communities. PMID- 29233895 TI - Disabling a Type I-E CRISPR-Cas Nuclease with a Bacteriophage-Encoded Anti-CRISPR Protein. AB - CRISPR (clustered regularly interspaced short palindromic repeat)-Cas adaptive immune systems are prevalent defense mechanisms in bacteria and archaea. They provide sequence-specific detection and neutralization of foreign nucleic acids such as bacteriophages and plasmids. One mechanism by which phages and other mobile genetic elements are able to overcome the CRISPR-Cas system is through the expression of anti-CRISPR proteins. Over 20 different families of anti-CRISPR proteins have been described, each of which inhibits a particular type of CRISPR Cas system. In this work, we determined the structure of type I-E anti-CRISPR protein AcrE1 by X-ray crystallography. We show that AcrE1 binds to the CRISPR associated helicase/nuclease Cas3 and that the C-terminal region of the anti CRISPR protein is important for its inhibitory activity. We further show that AcrE1 can convert the endogenous type I-E CRISPR system into a programmable transcriptional repressor.IMPORTANCE The CRISPR-Cas immune system provides bacteria with resistance to invasion by potentially harmful viruses, plasmids, and other foreign mobile genetic elements. This study presents the first structural and mechanistic insight into a phage-encoded protein that inactivates the type I-E CRISPR-Cas system in Pseudomonas aeruginosa The interaction of this anti-CRISPR protein with the CRISPR-associated helicase/nuclease proteins Cas3 shuts down the CRISPR-Cas system and protects phages carrying this gene from destruction. This interaction also allows the repurposing of the endogenous type I-E CRISPR system into a programmable transcriptional repressor, providing a new biotechnological tool for genetic studies of bacteria encoding this type I-E CRISPR-Cas system. PMID- 29233896 TI - Retargeting Lentiviruses via SpyCatcher-SpyTag Chemistry for Gene Delivery into Specific Cell Types. AB - We report a simple strategy for the creation of lentiviral vectors specific to any desired target cells. SpyTag is inserted into an engineered Sindbis virus envelope protein and displayed on the lentivirus surface to create Sindbis virus SpyTag pseudoparticles (Sind-SpyTag-pp). The SpyTag serves as the covalent anchoring site for a target-cell-specific cell-binding protein (CBP) that is fused to a truncated SpyCatcher (SpyCatcherDelta). Target-cell-specific lentiviruses are created by mixing the Sind-SpyTag-pp and CBP-SpyCatcherDelta in vitro We first used a HER2-binding designed ankyrin repeat protein (DARPin.9.26) as the model CBP. The DARPin-conjugated lentivirus transduced HER2+ SKOV3 cells with an infectious titer of 5.2 * 106 IU/ml, >500-fold higher than the unfunctionalized "naked" virions (<104 IU/ml). The ability of the DARPin conjugated lentivirus to transduce HER2+ cells correlated with the surface expression level of HER2. Furthermore, these lentiviruses preferentially transduced HER2+ cells in cocultures containing HER2+ and HER2- cells. To enable the use of commercially available monoclonal antibodies (MAbs) as the CBP, we developed a convenient click chemistry-based approach to conjugate MAb-derived Fab fragments to a variant SpyCatcherDelta protein containing a nonnatural amino acid, 4-azido-l-phenylalanine (AzF). Using the HER2-binding trastuzumab as a model cell-specific MAb, we created Fab-conjugated lentiviral vectors that transduced HER2+ SKOV3 cells with an infectious titer of 2.8 * 106 IU/ml, on par with the result achieved using the DARPin-SpyCatcherDelta fusion protein. The ability to create cell-specific lentiviral vectors through chemical conjugation of a CBP should make this approach generalizable to any antibody, giving it broad utility for a wide range of research and clinical applications.IMPORTANCE Lentiviral vectors hold great potential in gene therapy. However, it remains a major hurdle to robustly engineer cell-specific lentiviral vectors. This article reports a simple and effective strategy to functionalize lentiviral vectors with cell-binding proteins, thus retargeting these viruses to cells expressing the binding partner of the CBP. The CBP is genetically or chemically linked to the SpyCatcher. The SpyTag is displayed on the virion surface as a fusion to an engineered Sindbis virus envelope protein and is used as the anchorage site for SpyCatcher-linked CBP. Using this strategy, we created lentiviral vectors highly infectious toward HER2+ cancer cells. The ability to rapidly create cell-specific lentiviral vectors targeting a wide range of cell types should accelerate the development of custom lentiviral vectors for many research and clinical applications. PMID- 29233897 TI - Phylogenetics of a Fungal Invasion: Origins and Widespread Dispersal of White Nose Syndrome. AB - Globalization has facilitated the worldwide movement and introduction of pathogens, but epizoological reconstructions of these invasions are often hindered by limited sampling and insufficient genetic resolution among isolates. Pseudogymnoascus destructans, a fungal pathogen causing the epizootic of white nose syndrome in North American bats, has exhibited few genetic polymorphisms in previous studies, presenting challenges for both epizoological tracking of the spread of this fungus and for determining its evolutionary history. We used single nucleotide polymorphisms (SNPs) from whole-genome sequencing and microsatellites to construct high-resolution phylogenies of P. destructans Shallow genetic diversity and the lack of geographic structuring among North American isolates support a recent introduction followed by expansion via clonal reproduction across the epizootic zone. Moreover, the genetic relationships of isolates within North America suggest widespread mixing and long-distance movement of the fungus. Genetic diversity among isolates of P. destructans from Europe was substantially higher than in those from North America. However, genetic distance between the North American isolates and any given European isolate was similar to the distance between the individual European isolates. In contrast, the isolates we examined from Asia were highly divergent from both European and North American isolates. Although the definitive source for introduction of the North American population has not been conclusively identified, our data support the origin of the North American invasion by P. destructans from Europe rather than Asia.IMPORTANCE This phylogenetic study of the bat white-nose syndrome agent, P. destructans, uses genomics to elucidate evolutionary relationships among populations of the fungal pathogen to understand the epizoology of this biological invasion. We analyze hypervariable and abundant genetic characters (microsatellites and genomic SNPs, respectively) to reveal previously uncharacterized diversity among populations of the pathogen from North America and Eurasia. We present new evidence supporting recent introduction of the fungus to North America from a diverse Eurasian population, with limited increase in genetic variation in North America since that introduction. PMID- 29233898 TI - Prophages and Growth Dynamics Confound Experimental Results with Antibiotic Tolerant Persister Cells. AB - Bacterial persisters are phenotypic variants that survive antibiotic treatment in a dormant state and can be formed by multiple pathways. We recently proposed that the second messenger (p)ppGpp drives Escherichia coli persister formation through protease Lon and activation of toxin-antitoxin (TA) modules. This model found considerable support among researchers studying persisters but also generated controversy as part of recent debates in the field. In this study, we therefore used our previous work as a model to critically examine common experimental procedures to understand and overcome the inconsistencies often observed between results of different laboratories. Our results show that seemingly simple antibiotic killing assays are very sensitive to variations in culture conditions and bacterial growth phase. Additionally, we found that some assay conditions cause the killing of antibiotic-tolerant persisters via induction of cryptic prophages. Similarly, the inadvertent infection of mutant strains with bacteriophage phi80, a notorious laboratory contaminant, apparently caused several of the phenotypes that we reported in our previous studies. We therefore reconstructed all infected mutants and probed the validity of our model of persister formation in a refined assay setup that uses robust culture conditions and unravels the dynamics of persister cells through all bacterial growth stages. Our results confirm the importance of (p)ppGpp and Lon but no longer support a role of TA modules in E. coli persister formation under unstressed conditions. We anticipate that the results and approaches reported in our study will lay the ground for future work in the field.IMPORTANCE The recalcitrance of antibiotic tolerant persister cells is thought to cause relapsing infections and antibiotic treatment failure in various clinical setups. Previous studies identified multiple genetic pathways involved in persister formation but also revealed reproducibility problems that sparked controversies about adequate tools to study persister cells. In this study, we unraveled how typical antibiotic killing assays often fail to capture the biology of persisters and instead give widely differing results based on poorly controlled experimental parameters and artifacts caused by cryptic as well as contaminant prophages. We therefore established a new, robust assay that enabled us to follow the dynamics of persister cells through all growth stages of bacterial cultures without distortions by bacteriophages. This system also favored adequate comparisons of mutant strains with aberrant growth phenotypes. We anticipate that our results will contribute to a robust, common basis for future studies on the formation and eradication of antibiotic-tolerant persisters. PMID- 29233899 TI - Detection of Cytosolic Shigella flexneri via a C-Terminal Triple-Arginine Motif of GBP1 Inhibits Actin-Based Motility. AB - Dynamin-like guanylate binding proteins (GBPs) are gamma interferon (IFN-gamma) inducible host defense proteins that can associate with cytosol-invading bacterial pathogens. Mouse GBPs promote the lytic destruction of targeted bacteria in the host cell cytosol, but the antimicrobial function of human GBPs and the mechanism by which these proteins associate with cytosolic bacteria are poorly understood. Here, we demonstrate that human GBP1 is unique among the seven human GBP paralogs in its ability to associate with at least two cytosolic Gram negative bacteria, Burkholderia thailandensis and Shigella flexneri Rough lipopolysaccharide (LPS) mutants of S. flexneri colocalize with GBP1 less frequently than wild-type S. flexneri does, suggesting that host recognition of O antigen promotes GBP1 targeting to Gram-negative bacteria. The targeting of GBP1 to cytosolic bacteria, via a unique triple-arginine motif present in its C terminus, promotes the corecruitment of four additional GBP paralogs (GBP2, GBP3, GBP4, and GBP6). GBP1-decorated Shigella organisms replicate but fail to form actin tails, leading to their intracellular aggregation. Consequentially, the wild type but not the triple-arginine GBP1 mutant restricts S. flexneri cell-to cell spread. Furthermore, human-adapted S. flexneri, through the action of one its secreted effectors, IpaH9.8, is more resistant to GBP1 targeting than the non human-adapted bacillus B. thailandensis These studies reveal that human GBP1 uniquely functions as an intracellular "glue trap," inhibiting the cytosolic movement of normally actin-propelled Gram-negative bacteria. In response to this powerful human defense program, S. flexneri has evolved an effective counterdefense to restrict GBP1 recruitment.IMPORTANCE Several pathogenic bacterial species evolved to invade, reside in, and replicate inside the cytosol of their host cells. One adaptation common to most cytosolic bacterial pathogens is the ability to coopt the host's actin polymerization machinery in order to generate force for intracellular movement. This actin-based motility enables Gram negative bacteria, such as Shigella species, to propel themselves into neighboring cells, thereby spreading from host cell to host cell without exiting the intracellular environment. Here, we show that the human protein GBP1 acts as a cytosolic "glue trap," capturing cytosolic Gram-negative bacteria through a unique protein motif and preventing disseminated infections in cell culture models. To escape from this GBP1-mediated host defense, Shigella employs a virulence factor that prevents or dislodges the association of GBP1 with cytosolic bacteria. Thus, therapeutic strategies to restore GBP1 binding to Shigella may lead to novel treatment options for shigellosis in the future. PMID- 29233901 TI - Immune-Mediated Damage Completes the Parabola: Cryptococcus neoformans Pathogenesis Can Reflect the Outcome of a Weak or Strong Immune Response. AB - Cryptococcosis occurs most frequently in immunocompromised individuals. This has led to the prevailing view that this disease is the result of weak immune responses that cannot control the fungus. However, increasingly, clinical and experimental studies have revealed that the host immune response can contribute to cryptococcal pathogenesis, including the recent study of L. M. Neal et al. (mBio 8:e01415-17, 2017, https://doi.org/10.1128/mBio.01415-17) that reports that CD4+ T cells mediate tissue damage in experimental murine cryptococcosis. This finding has fundamental implications for our understanding of the pathogenesis of cryptococcal disease; it helps explain why immunotherapy has been largely unsuccessful in treatment and provides insight into the paradoxical observation that HIV-associated cryptococcosis may have a better prognosis than cryptococcosis in those with no known immune impairment. The demonstration that host-mediated damage can drive cryptococcal disease provides proof of concept that the parabola put forth in the damage-response framework has the flexibility to depict complex and changing outcomes of host-microbe interaction. PMID- 29233900 TI - Systematic CRISPR-Cas9-Mediated Modifications of Plasmodium yoelii ApiAP2 Genes Reveal Functional Insights into Parasite Development. AB - Malaria parasites have a complex life cycle with multiple developmental stages in mosquito and vertebrate hosts, and different developmental stages express unique sets of genes. Unexpectedly, many transcription factors (TFs) commonly found in eukaryotic organisms are absent in malaria parasites; instead, a family of genes encoding proteins similar to the plant Apetala2 (ApiAP2) transcription factors is expanded in the parasites. Several malaria ApiAP2 genes have been shown to play a critical role in parasite development; however, the functions of the majority of the ApiAP2 genes remain to be elucidated. In particular, no study on the Plasmodium yoelii ApiAP2 (PyApiAP2) gene family has been reported so far. This study systematically investigated the functional roles of PyApiAP2 genes in parasite development. Twenty-four of the 26 PyApiAP2 genes were selected for disruption, and 12 were successfully knocked out using the clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9 (CRISPR-Cas9) method. The effects of gene knockout (KO) on parasite development in mouse and mosquito stages were evaluated. Ten of 12 successfully disrupted genes, including two genes that have not been functionally characterized in any Plasmodium species previously, were shown to be critical for P. yoelii development of sexual and mosquito stages. Additionally, seven of the genes were labeled for protein expression analysis, revealing important information supporting their functions. This study represents the first systematic functional characterization of the P. yoelii ApiAP2 gene family and discovers important insights on the roles of the ApiAP2 genes in parasite development.IMPORTANCE Malaria is a parasitic disease that infects hundreds of millions of people, leading to an estimated 0.35 million deaths in 2015. A better understanding of the mechanism of gene expression regulation during parasite development may provide important clues for disease control and prevention. In this study, systematic gene disruption experiments were performed to study the functional roles of members of the Plasmodium yoelii ApiAP2 (PyApiAP2) gene family in parasite development. Genes that are critical for the development of male and female gametocytes, oocysts, and sporozoites were characterized. The protein expression profiles for seven of the PyApiAP2 gene products were also analyzed, revealing important information on their functions. This study provides expression and functional information for many PyApiAP2 genes, which can be explored for disease management. PMID- 29233902 TI - T Cell Production of GM-CSF Protects the Host during Experimental Tuberculosis. AB - Although classically associated with myelopoiesis, granulocyte-macrophage colony stimulating factor (GM-CSF) is increasingly recognized as being important for tuberculosis (TB) resistance. GM-CSF is expressed by nonhematopoietic and hematopoietic lineages following infection with Mycobacterium tuberculosis and is necessary to restrict M. tuberculosis growth in experimental models. Until the recent study by Rothchild et al. (mBio 8:e01514-17, 2017, https://doi.org/10.1128/mBio.01514-17), it was unknown whether GM-CSF-producing T cells contribute to TB resistance. Rothchild et al. identify which conventional and nonconventional T cell subsets produce GM-CSF during experimental TB, establish their protective nature using a variety of approaches, and provide a mechanistic basis for their ability to restrict M. tuberculosis growth. This commentary discusses the significance of these findings to basic and applied TB research. As translated to human disease, these findings suggest vaccine-mediated expansion of GM-CSF-producing T cells could be an effective prophylactic or therapeutic TB strategy. PMID- 29233903 TI - Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients. AB - : Purpose: The microenvironment of head and neck squamous cell carcinomas (HNSCC) is highly immunosuppressive. HNSCCs expressing elevated levels of PD-L1 have especially poor outcome. Exosomes that carry PD-L1 and suppress T-cell functions have been isolated from plasma of patients with HNSCC. The potential contributions of PD-L1+ exosomes to immune suppression and disease activity are evaluated.Experimental Design: Exosomes isolated from plasma of 40 HNSCC patients by size exclusion chromatography were captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. The percentages and mean fluorescence intensities (MFI) of PD-L1+ and PD-1+ exosome/bead complexes were correlated with the patients' clinicopathologic data. PD-L1high or PD-L1low exosomes were incubated with activated CD69+ human CD8+ T cells +/- PD-1 inhibitor. Changes in CD69 expression levels on T cells were measured. Patients' plasma was tested for soluble PD-L1 (sPD-L1) by ELISA.Results: Levels of PD-L1 carried by exosomes correlated with patients' disease activity, the UICC stage and the lymph node status (P = 0.0008-0.013). In contrast, plasma levels of sPD L1 or exosome PD-1 levels did not correlate with any clinicopathologic parameters. CD69 expression levels were inhibited (P < 0.03) by coincubation with PD-L1high but not by PD-L1low exosomes. Blocking of PD-L1+ exosome signaling to PD-1+ T cells attenuated immune suppression.Conclusions: PD-L1 levels on exosomes, but not levels of sPD-L1, associated with disease progression in HNSCC patients. Circulating PD-L1+ exosomes emerge as useful metrics of disease and immune activity in HNSCC patients. SIGNIFICANCE: Circulating PD-L1high exosomes in HNC patients' plasma but not soluble PD-L1 levels associate with disease progression. Clin Cancer Res; 24(4); 896-905. (c)2017 AACR. PMID- 29233904 TI - Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human. AB - Purpose: Mesothelioma has been regarded as a nonimmunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis. Previously, we demonstrated that autologous tumor lysate-pulsed dendritic cell (DC) immunotherapy increased T-cell response toward malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source. The purpose of this study was to investigate whether allogeneic lysate-pulsed DC immunotherapy is effective in mice and safe in humans.Experimental Design: First, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate or injected with PBS (negative control). Survival and tumor-directed T cell responses of these mice were monitored. Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25, or 50 million DCs per vaccination. DC vaccination consisted of autologous monocyte derived DCs pulsed with tumor lysate from five mesothelioma cell lines.Results: In mice, allogeneic lysate-pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose-limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months [95% confidence interval (CI), 4.1-20.3] and median OS not reached (median follow-up = 22.8 months).Conclusions: DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. Clin Cancer Res; 24(4); 766-76. (c)2017 AACR. PMID- 29233905 TI - Neddylation Blockade Diminishes Hepatic Metastasis by Dampening Cancer Stem-Like Cells and Angiogenesis in Uveal Melanoma. AB - Purpose: Liver metastasis is the major and direct cause of death in patients with uveal melanoma (UM). There is no effective therapy for patients with metastatic UM. Improved treatments of hepatic metastatic patients with UM were urgently needed. Inspired by readily detectable key components in the neddylation pathway in UM cells, we aimed at exploring whether neddylation pathway was a therapeutic target for liver metastatic UM.Experimental Design: Expression of key proteins in the neddylation pathway in UM was detected by Western blotting, real-time quantitative RT-PCR (qRT-PCR), and immunohistochemical staining. Cellular proliferation, apoptosis, cell cycle, migration, and cancer stem-like cells (CSCs) properties were examined upon treatment with MLN4924, a potent and selective NAE inhibitor. Antitumor activity and frequency of CSCs were determined by using a NOD-SCID mouse xenograft model. Liver metastasis was evaluated by use of a NOD-scid-IL2Rg-/- mouse model.Results: NAE1 expression was readily detectable in UM. Inhibition of the neddylation pathway by MLN4924 repressed the CSCs properties in UM (capacities of tumorsphere formation and serially replating, aldehyde dehydrogenase-positive cells, and frequency of CSC) through Slug protein degradation. MLN4924 treatment disturbed the paracrine secretion of NF-kappaB-mediated VEGF-C and its dependent angiogenesis. The inhibitory effect of neddylation blockade on proliferation, which was confirmed by xenografted UM tumor in NOD-SCID mice, was involved in activation of ATM-Chk1-Cdc25C DNA damage response, and G2-M phase arrest. Neddylation inhibition profoundly inhibited hepatic metastasis in UM.Conclusions: Our studies validate the neddylation pathway as a promising therapeutic target for the treatment of patients with hepatic metastasis of UM. Clin Cancer Res; 24(15); 3741-54. (c)2017 AACRSee related commentary by Yang et al., p. 3477. PMID- 29233906 TI - Skeletal muscle insulin signaling and whole-body glucose metabolism following acute sleep restriction in healthy males. AB - Sleep restriction is associated with impaired glucose metabolism and insulin resistance, however, the underlying mechanisms leading to this impairment are unknown. This study aimed to assess whether the decrease in insulin sensitivity observed after sleep restriction is accompanied by changes in skeletal muscle PKB activity. Ten healthy young males participated in this randomized crossover study which included two conditions separated by a 3-week washout period. Participants underwent two nights of habitual sleep (CON) and two nights of sleep which was restricted to 50% of habitual sleep duration (SR) in the home environment. Whole body glucose tolerance and insulin sensitivity were assessed by an oral glucose tolerance test after the second night of each condition. Skeletal muscle tissue samples were obtained from the vastus lateralis to determine PKB activity. Findings displayed no effect of trial on plasma glucose concentrations (P = 0.222). Plasma insulin area under the curve was higher after sleep restriction compared to the control (P = 0.013). Matsuda index was 18.6% lower in the sleep restriction (P = 0.010). Fold change in PKB activity from baseline tended to be lower in the sleep restriction condition at 30 min (P = 0.098) and 120 min (P = 0.087). In conclusion, we demonstrated decreased whole-body insulin sensitivity in healthy young males following two nights of sleep restriction. Skeletal muscle insulin signaling findings are inconclusive and require further study to examine any potential changes. PMID- 29233907 TI - Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors. AB - Glucagon-like peptide-1 (GLP-1) is an incretin hormone increasing postprandial insulin release. GLP-1 also induces diuresis and natriuresis in humans and rodents. The GLP-1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP-1 treatment leads to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP-1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP-1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect of acute intrarenal infusion of GLP-1. We hypothesized that GLP-1 would increase diuresis and natriuresis and reduce MAP in SHR. Immunohistochemical staining and in situ hybridization for the GLP-1 receptor were used to localize GLP-1 receptors in the kidney. Sevoflurane anesthetized normotensive Sprague-Dawley rats and SHR received a 20 min intrarenal infusion of GLP-1 and changes in MAP, RBF, heart rate, dieresis, and natriuresis were measured. The vasodilatory effect of GLP-1 was assessed in isolated interlobar arteries from normo- and hypertensive rats. We found no expression of GLP-1 receptors in the kidney from SHR. However, acute intrarenal infusion of GLP-1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP-1 in SHR are caused either by extrarenal GLP-1 receptors activating other mechanisms (e.g., insulin) to induce the renal changes observed or possibly by an alternative renal GLP-1 receptor. PMID- 29233908 TI - Regulation of PPARGC1A gene expression in trained and untrained human skeletal muscle. AB - Promoter-specific expression of the PPARGC1A gene in untrained and trained human skeletal muscle was investigated. Ten untrained males performed a one-legged knee extension exercise (for 60 min) with the same relative intensity both before and after 8 weeks of cycling training. Samples from the m. vastus lateralis of each leg were taken before and after exercise. Postexercise PPARGC1A gene expression via the canonical promoter increased by ~100% (P < 0.05) in exercised and nonexercised untrained muscles, but did not change in either leg after training program. In untrained and trained exercised muscle, PPARGC1A gene expression via the alternative promoter increased by two orders of magnitude (P < 0.01). We found increases in postexercise content of dephosphorylated (activated) CRTC2, a coactivator of CREB1, in untrained exercised muscle and in expression of CREB1 related genes in untrained and trained exercised muscle (P < 0.01-0.05); this may partially explain the increased expression of PPARGC1A via the alternative promoter. In addition, comparison of the regulatory regions of both promoters revealed unique conserved motifs in the alternative promoter that were associated with transcriptional repressors SNAI1 and HIC1. In conclusion, in untrained muscle, exercise-induced expression of the PPARGC1A gene via the canonical promoter may be regulated by systemic factors, while in trained muscle the canonical promoter shows constitutive expression at rest and after exercise. Exercise-induced expression of PPARGC1A via the alternative promoter relates to intramuscular factors and associates with activation of CRTC2-CREB1. Apparently, expression via the alternative promoter is regulated by other transcription factors, particularly repressors. PMID- 29233909 TI - Oral Contraceptives and Renal Water Handling: A diurnal study in young women. AB - To test the hypothesis that use of oral contraceptives (OC) changes diurnal variation in fluid balance mechanisms including blood pressure, secretion of vasopressin and oxytocin, and renal water and electrolyte excretion. Fifteen naturally cycling (NC) women in mid-follicular phase and 11 long-term OC users were included in a 24-h standardized inpatient study for measurements of vasopressin, oxytocin, sodium, and osmolality in plasma as well as urinary excretion of electrolytes, aquaporin-2, and prostaglandin E2. Blood pressure and heart rate were monitored noninvasively. Plasma vasopressin showed circadian rhythm (P = 0.02) and were similar in both groups (P = 0.18) including nighttime increases (P < 0.001). There was no circadian rhythm in plasma oxytocin within (P = 0.84) or between groups (P = 0.22). OC users had significantly lower plasma osmolality (Deltaosm: 3.05 +/- 0.29 mosm/kg, P = 0.04) and lower plasma sodium (DeltaNa+: 0.91 +/- 0.09 mmol/l, P = 0.05). The two groups showed similar nighttime decreases in diuresis (1.08 +/- 0.04 mL/(kg.h), P < 0.001) and increases in urine osmolality (109 +/- 9 mosm/kg, P = 0.02), but similar rates of excretion of Aquaporin-2, prostaglandin E2 and sodium. Nighttime decreases in mean arterial pressure of approximately 13% were significant in both groups (P < 0.001), but 24-h average mean arterial pressure was significantly higher in OC users than in controls (+4.7 +/- 0.4 mmHg, P = 0.02). Packed cell volumes were similar between groups (P = 0.54). OC does not change the diurnal patterns of renal fluid excretion, but resets the osmoreceptors for vasopressin release and leads to a significant increase in arterial blood pressure. PMID- 29233910 TI - Targeting CDK1 and MEK/ERK Overcomes Apoptotic Resistance in BRAF-Mutant Human Colorectal Cancer. AB - The BRAFV600E mutation occurs in approximately 8% of human colorectal cancers and is associated with therapeutic resistance that is due, in part, to reactivation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin dependent kinase 1 (CDK1) upregulation in a subset of human BRAFV600E colorectal cancers. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAFV600E colorectal cancer cells. BRAFV600E colorectal cancer cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1, 2, 5, 9 inhibitors). Combination of RO-3306 or dinaciclib with cobimetinib (MEK inhibitor) cooperatively enhanced apoptosis and reduced clonogenic survival versus monotherapy. Cells isogenic or ectopic for BRAFV600E displayed resistance to CDK1 inhibitors, as did cells with ectopic expression of constitutively active MEK CDK1 inhibitors induced a CASP8-dependent apoptosis shown by caspase-8 restoration in deficient NB7 cells that enhanced dinaciclib induced CASP3 cleavage. CDK inhibitors suppressed pro-CASP8 phosphorylation at S387, as shown by drug withdrawal, which restored p-S387 and increased mitosis. In a colorectal cancer xenograft model, dinaciclib plus cobimetinib produced significantly greater tumor growth inhibition in association with a caspase dependent apoptosis versus either drug alone. The Cancer Genome Atlas (TCGA) transcriptomic dataset revealed overexpression of CDK1 in human colorectal cancers versus normal colon. Together, these data establish CDK1 as a novel mediator of apoptosis resistance in BRAFV600E colorectal cancers whose combined targeting with a MEK/ERK inhibitor represents an effective therapeutic strategy.Implications: CDK1 is a novel mediator of apoptosis resistance in BRAFV600E colorectal cancers whose dual targeting with a MEK inhibitor may be therapeutically effective. Mol Cancer Res; 16(3); 378-89. (c)2017 AACR. PMID- 29233911 TI - N- and O-glycosylation Analysis of Human C1-inhibitor Reveals Extensive Mucin type O-Glycosylation. AB - Human C1-inhibitor (C1-Inh) is a serine protease inhibitor and the major regulator of the contact activation pathway as well as the classical and lectin complement pathways. It is known to be a highly glycosylated plasma glycoprotein. However, both the structural features and biological role of C1-Inh glycosylation are largely unknown. Here, we performed for the first time an in-depth site specific N- and O-glycosylation analysis of C1-Inh combining various mass spectrometric approaches, including C18-porous graphitized carbon (PGC)-LC-ESI QTOF-MS/MS applying stepping-energy collision-induced dissociation (CID) and electron-transfer dissociation (ETD). Various proteases were applied, partly in combination with PNGase F and exoglycosidase treatment, in order to analyze the (glyco)peptides. The analysis revealed an extensively O-glycosylated N-terminal region. Five novel and five known O-glycosylation sites were identified, carrying mainly core1-type O-glycans. In addition, we detected a heavily O-glycosylated portion spanning from Thr82-Ser121 with up to 16 O-glycans attached. Likewise, all known six N-glycosylation sites were covered and confirmed by this site specific glycosylation analysis. The glycoforms were in accordance with results on released N-glycans by MALDI-TOF/TOF-MS/MS. The comprehensive characterization of C1-Inh glycosylation described in this study will form the basis for further functional studies on the role of these glycan modifications. PMID- 29233912 TI - Dynamic secretome of Trichomonas vaginalis: Case study of beta-amylases. AB - The secretion of virulence factors by parasitic protists into the host environment plays a fundamental role in multifactorial host-parasite interactions. Several effector proteins are known to be secreted by Trichomonas vaginalis, a human parasite of the urogenital tract. However, a comprehensive profiling of the T. vaginalis secretome remains elusive, as do the mechanisms of protein secretion. In this study, we used high-resolution label-free quantitative MS to analyze the T. vaginalis secretome, considering that secretion is a time- and temperature-dependent process, to define the cutoff for secreted proteins. In total, we identified 2 072 extracellular proteins, 89 of which displayed significant quantitative increases over time at 37 degrees C. These 89 bona fide secreted proteins were sorted into 13 functional categories. Approximately half of the secreted proteins were predicted to possess transmembrane helixes. These proteins mainly include putative adhesins and leishmaniolysin-like metallopeptidases. The other half of the soluble proteins include several novel potential virulence factors, such as DNaseII, pore-forming proteins, and beta amylases. Interestingly, current bioinformatic tools predicted the secretory signal in only 18% of the identified T. vaginalis-secreted proteins. Therefore, we used beta-amylases as a model to investigate the T. vaginalis secretory pathway. We demonstrated that two beta-amylases (BA1 and BA2) are transported via the classical endoplasmic reticulum-to-Golgi pathways, and in the case of BA1, we showed that the protein is glycosylated with multiple N-linked glycans of Hex5HexNAc2 structure. The secretion was inhibited by brefeldin A but not by FLI 06. Another two beta-amylases (BA3 and BA4), which are encoded in the T. vaginalis genome but absent from the secretome, were targeted to the lysosomal compartment. Collectively, under defined in vitro conditions, our analysis provides a comprehensive set of constitutively secreted proteins that can serve as a reference for future comparative studies, and it provides the first information about the classical secretory pathway in this parasite. PMID- 29233913 TI - Reference Quality Genome Assemblies of Three Parastagonospora nodorum Isolates Differing in Virulence on Wheat. AB - Parastagonospora nodorum, the causal agent of Septoria nodorum blotch in wheat, has emerged as a model necrotrophic fungal organism for the study of host-microbe interactions. To date, three necrotrophic effectors have been identified and characterized from this pathogen, including SnToxA, SnTox1, and SnTox3. Necrotrophic effector identification was greatly aided by the development of a draft genome of Australian isolate SN15 via Sanger sequencing, yet it remained largely fragmented. This research presents the development of nearly finished genomes of P. nodorum isolates Sn4, Sn2000, and Sn79-1087 using long-read sequencing technology. RNAseq analysis of isolate Sn4, consisting of eight time points covering various developmental and infection stages, mediated the annotation of 13,379 genes. Analysis of these genomes revealed large-scale polymorphism between the three isolates, including the complete absence of contig 23 from isolate Sn79-1087, and a region of genome expansion on contig 10 in isolates Sn4 and Sn2000. Additionally, these genomes exhibit the hallmark characteristics of a "two-speed" genome, being partitioned into two distinct GC equilibrated and AT-rich compartments. Interestingly, isolate Sn79-1087 contains a lower proportion of AT-rich segments, indicating a potential lack of evolutionary hotspots. These newly sequenced genomes, consisting of telomere-to telomere assemblies of nearly all 23 P. nodorum chromosomes, provide a robust foundation for the further examination of effector biology and genome evolution. PMID- 29233914 TI - Had1 Is Required for Cell Wall Integrity and Fungal Virulence in Cryptococcus neoformans. AB - Calcineurin modulates environmental stress survival and virulence of the human fungal pathogen Cryptococcus neoformans Previously, we identified 44 putative calcineurin substrates, and proposed that the calcineurin pathway is branched to regulate targets including Crz1, Pbp1, and Puf4 in C. neoformans In this study, we characterized Had1, which is one of the putative calcineurin substrates belonging to the ubiquitously conserved haloacid dehalogenase beta phosphoglucomutase protein superfamily. Growth of the had1? mutant was found to be compromised at 38 degrees or higher. In addition, the had1? mutant exhibited increased sensitivity to cell wall perturbing agents, including Congo Red and Calcofluor White, and to an endoplasmic reticulum stress inducer dithiothreitol. Virulence studies revealed that the had1 mutation results in attenuated virulence compared to the wild-type strain in a murine inhalation infection model. Genetic epistasis analysis revealed that Had1 and the zinc finger transcription factor Crz1 play roles in parallel pathways that orchestrate stress survival and fungal virulence. Overall, our results demonstrate that Had1 is a key regulator of thermotolerance, cell wall integrity, and virulence of C. neoformans. PMID- 29233916 TI - Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes. AB - Adults older than 65 account for most of the deaths caused by respiratory influenza A virus (IAV) infections, but the underlying mechanisms for this susceptibility are poorly understood. IAV RNA is detected by the cytosolic sensor retinoic acid-inducible gene I (RIG-I), which induces the production of type I interferons (IFNs) that curtail the spread of the virus and promote the elimination of infected cells. We have previously identified a marked defect in the IAV-inducible secretion of type I IFNs, but not proinflammatory cytokines, in monocytes from older (>65 years) healthy human donors. We found that monocytes from older adults exhibited decreased abundance of the adaptor protein TRAF3 (tumor necrosis factor receptor-associated factor 3) because of its increased proteasomal degradation with age, thereby impairing the primary RIG-I signaling pathway for the induction of type I IFNs. We determined that monocytes from older adults also failed to effectively stimulate the production of the IFN regulatory transcription factor IRF8, which compromised IFN induction through secondary RIG I signaling. IRF8 played a central role in IFN induction in monocytes, because knocking down IRF8 in monocytes from younger adults was sufficient to replicate the IFN defects observed in monocytes from older adults, whereas restoring IRF8 expression in older adult monocytes was sufficient to restore RIG-I-induced IFN responses. Aging thus compromises both the primary and secondary RIG-I signaling pathways that govern expression of type I IFN genes, thereby impairing antiviral resistance to IAV. PMID- 29233915 TI - Highly Efficient Site-Specific Mutagenesis in Malaria Mosquitoes Using CRISPR. AB - Anopheles mosquitoes transmit at least 200 million annual malaria infections worldwide. Despite considerable genomic resources, mechanistic understanding of biological processes in Anopheles has been hampered by a lack of tools for reverse genetics. Here, we report successful application of the CRISPR/Cas9 system for highly efficient, site-specific mutagenesis in the diverse malaria vectors Anopheles albimanus, A. coluzzii, and A. funestus When guide RNAs (gRNAs) and Cas9 protein are injected at high concentration, germline mutations are common and usually biallelic, allowing for the rapid creation of stable mutant lines for reverse genetic analysis. Our protocol should enable researchers to dissect the molecular and cellular basis of anopheline traits critical to successful disease transmission, potentially exposing new targets for malaria control. PMID- 29233918 TI - RhoB controls the Rab11-mediated recycling and surface reappearance of LFA-1 in migrating T lymphocytes. AB - The regulation of cell adhesion and motility is complex and requires the intracellular trafficking of integrins to and from sites of cell adhesion, especially in fast-moving cells such as leukocytes. The Rab family of guanosine triphosphatases (GTPases) is essential for vesicle transport, and vesicles mediate intracellular integrin trafficking. We showed that RhoB regulates the vesicular transport of the integrin LFA-1 along the microtubule network in migrating T lymphocytes. Impairment in RhoB function resulted in the accumulation of both LFA-1 and the recycling endosomal marker Rab11 at the rear of migrating T lymphocytes and decreased the association between these molecules. T lymphocytes lacking functional RhoB exhibited impaired recycling and subsequently decreased surface amounts of LFA-1, leading to reduced T cell adhesion and migration mediated by the cell adhesion molecule ICAM-1 (intercellular adhesion molecule 1). We propose that vesicle-associated RhoB is a regulator of the Rab11-mediated recycling of LFA-1 to the cell surface, an event that is necessary for T lymphocyte motility. PMID- 29233917 TI - C-reactive protein promotes bone destruction in human myeloma through the CD32 p38 MAPK-Twist axis. AB - Bone destruction is a hallmark of myeloma and affects 80% of patients. Myeloma cells promote bone destruction by activating osteoclasts. In investigating the underlying mechanism, we found that C-reactive protein (CRP), a protein secreted in increased amounts by hepatocytes in response to myeloma-derived cytokines, activated myeloma cells to promote osteoclastogenesis and bone destruction in vivo. In mice bearing human bone grafts and injected with multiple myeloma cells, CRP bound to surface CD32 (also known as FcgammaRII) on myeloma cells, which activated a pathway mediated by the kinase p38 MAPK and the transcription factor Twist that enhanced the cells' secretion of osteolytic cytokines. Furthermore, analysis of clinical samples from newly diagnosed myeloma patients revealed a positive correlation between the amount of serum CRP and the number of osteolytic bone lesions. These findings establish a mechanism by which myeloma cells are activated to promote bone destruction and suggest that CRP may be targeted to prevent or treat myeloma-associated bone disease in patients. PMID- 29233919 TI - Diacylglycerol kinase alpha deficiency alters inflammation markers in adipose tissue in response to a high-fat diet. AB - Conversion of diacylglycerol to phosphatidic acid is mediated by diacylglycerol kinases (DGKs), with DGKalpha specifically linked to adaptive immune responses. We determined the role of DGKalpha in obesity and inflammatory responses to a high-fat diet (HFD). DGKalpha KO and WT littermates were either a) chow-fed, b) HFD-fed for 12 weeks (Long-Term HFD), or c) HFD-fed for 3 days (Acute HFD). Body weight/composition, oxygen consumption, food intake, and glucose tolerance was unaltered between chow-fed DGKalpha KO and WT mice. Insulin concentration during the intraperitoneal glucose tolerance (IPGT) test was elevated in chow-fed DGKalpha KO mice, suggesting mild insulin resistance. Insulin concentration during the IPGT test was reduced in Long-Term HFD-fed DGKalpha KO mice, suggesting a mild enhancement in insulin sensitivity. Acute HFD increased hormone sensitive lipase protein abundance and altered expression of interleukin 1beta mRNA, an inflammatory marker in perigonadal adipose tissue of DGKalpha KO mice. In conclusion, DGKalpha ablation is associated with mild alterations in insulin sensitivity. However, DGKalpha is dispensable for whole body insulin-mediated glucose uptake, hepatic glucose production, and energy homeostasis. Our results suggest DGKalpha aids in modulating the early immune response of adipose tissue following an acute exposure to HFD, possibly through modulation of acute T-cell action. PMID- 29233920 TI - Global sale of tobacco products and electronic nicotine delivery systems in community pharmacies. AB - OBJECTIVE: To estimate the proportion of countries/territories that allow sales of tobacco products and electronic nicotine delivery systems (ENDS) in community pharmacies. METHODS: International Pharmaceutical Federation (FIP) member organisations were contacted by email and asked to respond to a two-item survey assessing whether their country/territory allowed sales of (a) tobacco products and (b) ENDS in community pharmacies. RESULTS: Of 95 countries/territories contacted, responses were received from 60 (63.2%). Seven countries (11.7%) reported that tobacco products were sold in community pharmacies, and 11 countries (18.3%) reported that ENDS were sold in community pharmacies. CONCLUSIONS: Among the FIP member organisations, there are few countries that allow the sale of tobacco products and ENDS in community pharmacies, with ENDS being more likely than tobacco products to be sold. PMID- 29233921 TI - Integrated analysis of motif activity and gene expression changes of transcription factors. AB - The ability to predict transcription factors based on sequence information in regulatory elements is a key step in systems-level investigation of transcriptional regulation. Here, we have developed a novel tool, IMAGE, for precise prediction of causal transcription factors based on transcriptome profiling and genome-wide maps of enhancer activity. High precision is obtained by combining a near-complete database of position weight matrices (PWMs), generated by compiling public databases and systematic prediction of PWMs for uncharacterized transcription factors, with a state-of-the-art method for PWM scoring and a novel machine learning strategy, based on both enhancers and promoters, to predict the contribution of motifs to transcriptional activity. We applied IMAGE to published data obtained during 3T3-L1 adipocyte differentiation and showed that IMAGE predicts causal transcriptional regulators of this process with higher confidence than existing methods. Furthermore, we generated genome wide maps of enhancer activity and transcripts during human mesenchymal stem cell commitment and adipocyte differentiation and used IMAGE to identify positive and negative transcriptional regulators of this process. Collectively, our results demonstrate that IMAGE is a powerful and precise method for prediction of regulators of gene expression. PMID- 29233922 TI - Deep experimental profiling of microRNA diversity, deployment, and evolution across the Drosophila genus. AB - To assess miRNA evolution across the Drosophila genus, we analyzed several billion small RNA reads across 12 fruit fly species. These data permit comprehensive curation of species- and clade-specific variation in miRNA identity, abundance, and processing. Among well-conserved miRNAs, we observed unexpected cases of clade-specific variation in 5' end precision, occasional antisense loci, and putatively noncanonical loci. We also used strict criteria to identify a large set (649) of novel, evolutionarily restricted miRNAs. Within the bulk collection of species-restricted miRNAs, two notable subpopulations are splicing-derived mirtrons and testes-restricted, recently evolved, clustered (TRC) canonical miRNAs. We quantified miRNA birth and death using our annotation and a phylogenetic model for estimating rates of miRNA turnover. We observed striking differences in birth and death rates across miRNA classes defined by biogenesis pathway, genomic clustering, and tissue restriction, and even identified flux heterogeneity among Drosophila clades. In particular, distinct molecular rationales underlie the distinct evolutionary behavior of different miRNA classes. Mirtrons are associated with high rates of 3' untemplated addition, a mechanism that impedes their biogenesis, whereas TRC miRNAs appear to evolve under positive selection. Altogether, these data reveal miRNA diversity among Drosophila species and principles underlying their emergence and evolution. PMID- 29233923 TI - The landscape of miRNA editing in animals and its impact on miRNA biogenesis and targeting. AB - Adenosine-to-inosine (A-to-I) RNA editing regulates miRNA biogenesis and function. To date, fewer than 160 miRNA editing sites have been identified. Here, we present a quantitative atlas of miRNA A-to-I editing through the profiling of 201 pri-miRNA samples and 4694 mature miRNA samples in human, mouse, and Drosophila. We identified 4162 sites present in ~80% of the pri-miRNAs and 574 sites in mature miRNAs. miRNA editing is prevalent in many tissue types in human. However, high-level editing is mostly found in neuronal tissues in mouse and Drosophila Interestingly, the edited miRNAs in neuronal and non-neuronal tissues in human gain two distinct sets of new targets, which are significantly associated with cognitive and organ developmental functions, respectively. Furthermore, we reveal that miRNA editing profoundly affects asymmetric strand selection. Altogether, these data provide insight into the impact of RNA editing on miRNA biology and suggest that miRNA editing has recently gained non-neuronal functions in human. PMID- 29233924 TI - DNA mismatch repair preferentially protects genes from mutation. AB - Mutation is the source of genetic variation and fuels biological evolution. Many mutations first arise as DNA replication errors. These errors subsequently evade correction by cellular DNA repair, for example, by the well-known DNA mismatch repair (MMR) mechanism. Here, we determine the genome-wide effects of MMR on mutation. We first identify almost 9000 mutations accumulated over five generations in eight MMR-deficient mutation accumulation (MA) lines of the model plant species, Arabidopsis thaliana We then show that MMR deficiency greatly increases the frequency of both smaller-scale insertions and deletions (indels) and of single-nucleotide variant (SNV) mutations. Most indels involve A or T nucleotides and occur preferentially in homopolymeric (poly A or poly T) genomic stretches. In addition, we find that the likelihood of occurrence of indels in homopolymeric stretches is strongly related to stretch length, and that this relationship causes ultrahigh localized mutation rates in specific homopolymeric stretch regions. For SNVs, we show that MMR deficiency both increases their frequency and changes their molecular mutational spectrum, causing further enhancement of the GC to AT bias characteristic of organisms with normal MMR function. Our final genome-wide analyses show that MMR deficiency disproportionately increases the numbers of SNVs in genes, rather than in nongenic regions of the genome. This latter observation indicates that MMR preferentially protects genes from mutation and has important consequences for understanding the evolution of genomes during both natural selection and human tumor growth. PMID- 29233925 TI - A20/TNFAIP3 Regulates the DNA Damage Response and Mediates Tumor Cell Resistance to DNA-Damaging Therapy. AB - A competent DNA damage response (DDR) helps prevent cancer, but once cancer has arisen, DDR can blunt the efficacy of chemotherapy and radiotherapy that cause lethal DNA breakage in cancer cells. Thus, blocking DDR may improve the efficacy of these modalities. Here, we report a new DDR mechanism that interfaces with inflammatory signaling and might be blocked to improve anticancer outcomes. Specifically, we report that the ubiquitin-editing enzyme A20/TNFAIP3 binds and inhibits the E3 ubiquitin ligase RNF168, which is responsible for regulating histone H2A turnover critical for proper DNA repair. A20 induced after DNA damage disrupted RNF168-H2A interaction in a manner independent of its enzymatic activity. Furthermore, it inhibited accumulation of RNF168 and downstream repair protein 53BP1 during DNA repair. A20 was also required for disassembly of RNF168 and 53BP1 from damage sites after repair. Conversely, A20 deletion increased the efficiency of error-prone nonhomologous DNA end-joining and decreased error-free DNA homologous recombination, destablizing the genome and increasing sensitivity to DNA damage. In clinical specimens of invasive breast carcinoma, A20 was widely overexpressed, consistent with its candidacy as a therapeutic target. Taken together, our findings suggest that A20 is critical for proper functioning of the DDR in cancer cells and it establishes a new link between this NFkappaB-regulated ubiquitin-editing enzyme and the DDR pathway.Significance: This study identifies the ubiquitin-editing enzyme A20 as a key factor in mediating cancer cell resistance to DNA-damaging therapy, with implications for blocking its function to leverage the efficacy of chemotherapy and radiotherapy. Cancer Res; 78(4); 1069-82. (c)2017 AACR. PMID- 29233926 TI - Targeting CDK6 and BCL2 Exploits the "MYB Addiction" of Ph+ Acute Lymphoblastic Leukemia. AB - Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is currently treated with BCR-ABL1 tyrosine kinase inhibitors (TKI) in combination with chemotherapy. However, most patients develop resistance to TKI through BCR ABL1-dependent and -independent mechanisms. Newly developed TKI can target Ph+ ALL cells with BCR-ABL1-dependent resistance; however, overcoming BCR-ABL1 independent mechanisms of resistance remains challenging because transcription factors, which are difficult to inhibit, are often involved. We show here that (i) the growth of Ph+ ALL cell lines and primary cells is highly dependent on MYB mediated transcriptional upregulation of CDK6, cyclin D3, and BCL2, and (ii) restoring their expression in MYB-silenced Ph+ ALL cells rescues their impaired proliferation and survival. Levels of MYB and CDK6 were highly correlated in adult Ph+ ALL (P = 0.00008). Moreover, Ph+ ALL cells exhibited a specific requirement for CDK6 but not CDK4 expression, most likely because, in these cells, CDK6 was predominantly localized in the nucleus, whereas CDK4 was almost exclusively cytoplasmic. Consistent with their essential role in Ph+ ALL, pharmacologic inhibition of CDK6 and BCL2 markedly suppressed proliferation, colony formation, and survival of Ph+ ALL cells ex vivo and in mice. In summary, these findings provide a proof-of-principle, rational strategy to target the MYB "addiction" of Ph+ ALL.Significance: MYB blockade can suppress Philadelphia chromosome-positive leukemia in mice, suggesting that this therapeutic strategy may be useful in patients who develop resistance to imatinib and other TKIs used to treat this disease. Cancer Res; 78(4); 1097-109. (c)2017 AACR. PMID- 29233928 TI - Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma. AB - Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment.Significance: Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. Cancer Res; 78(4); 865-76. (c)2017 AACR. PMID- 29233927 TI - Comprehensive Mutation and Copy Number Profiling in Archived Circulating Breast Cancer Tumor Cells Documents Heterogeneous Resistance Mechanisms. AB - Addressing drug resistance is a core challenge in cancer research, but the degree of heterogeneity in resistance mechanisms in cancer is unclear. In this study, we conducted next-generation sequencing (NGS) of circulating tumor cells (CTC) from patients with advanced cancer to assess mechanisms of resistance to targeted therapy and reveal opportunities for precision medicine. Comparison of the genomic landscapes of CTCs and tissue metastases is complicated by challenges in comprehensive CTC genomic profiling and paired tissue acquisition, particularly in patients who progress after targeted therapy. Thus, we assessed by NGS somatic mutations and copy number alterations (CNA) in archived CTCs isolated from patients with metastatic breast cancer who were enrolled in concurrent clinical trials that collected and analyzed CTCs and metastatic tissues. In 76 individual and pooled informative CTCs from 12 patients, we observed 85% concordance in at least one or more prioritized somatic mutations and CNA between paired CTCs and tissue metastases. Potentially actionable genomic alterations were identified in tissue but not CTCs, and vice versa. CTC profiling identified diverse intra- and interpatient molecular mechanisms of endocrine therapy resistance, including loss of heterozygosity in individual CTCs. For example, in one patient, we observed CTCs that were either wild type for ESR1 (n = 5/32), harbored the known activating ESR1 p.Y537S mutation (n = 26/32), or harbored a novel ESR1 p.A569S (n = 1/32). ESR1 p.A569S was modestly activating in vitro, consistent with its presence as a minority circulating subclone. Our results demonstrate the feasibility and potential clinical utility of comprehensive profiling of archived fixed CTCs. Tissue and CTC genomic assessment are complementary, and precise combination therapies will likely be required for effective targeting in advanced breast cancer patients.Significance: These findings demonstrate the complementary nature of genomic profiling from paired tissue metastasis and circulating tumor cells from patients with metastatic breast cancer. Cancer Res; 78(4); 1110-22. (c)2017 AACR. PMID- 29233929 TI - Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle-Related Transcription and Attenuated Androgen Response. AB - Increasing evidence suggests the presence of minor cell subpopulations in prostate cancer that are androgen independent and poised for selection as dominant clones after androgen deprivation therapy. In this study, we investigated this phenomenon by stratifying cell subpopulations based on transcriptome profiling of 144 single LNCaP prostate cancer cells treated or untreated with androgen after cell-cycle synchronization. Model-based clustering of 397 differentially expressed genes identified eight potential subpopulations of LNCaP cells, revealing a previously unappreciable level of cellular heterogeneity to androgen stimulation. One subpopulation displayed stem-like features with a slower cell doubling rate, increased sphere formation capability, and resistance to G2-M arrest induced by a mitosis inhibitor. Advanced growth of this subpopulation was associated with enhanced expression of 10 cell-cycle related genes (CCNB2, DLGAP5, CENPF, CENPE, MKI67, PTTG1, CDC20, PLK1, HMMR, and CCNB1) and decreased dependence upon androgen receptor signaling. In silico analysis of RNA-seq data from The Cancer Genome Atlas further demonstrated that concordant upregulation of these genes was linked to recurrent prostate cancers. Analysis of receiver operating characteristic curves implicates aberrant expression of these genes and could be useful for early identification of tumors that subsequently develop biochemical recurrence. Moreover, this single-cell approach provides a better understanding of how prostate cancer cells respond heterogeneously to androgen deprivation therapies and reveals characteristics of subpopulations resistant to this treatment.Significance: Illustrating the challenge in treating cancers with targeted drugs, which by selecting for drug resistance can drive metastatic progression, this study characterized the plasticity and heterogeneity of prostate cancer cells with regard to androgen dependence, defining the character or minor subpopulations of androgen independent cells that are poised for clonal selection after androgen-deprivation therapy. Cancer Res; 78(4); 853-64. (c)2017 AACR. PMID- 29233931 TI - Inner Workings: Spacecraft dare to fly close to the sun. PMID- 29233932 TI - Core Concept: Cryopreservation aims to engineer novel ways to freeze, store, and thaw organs. PMID- 29233934 TI - Chronic infusion of taurolithocholate into the brain increases fat oxidation in mice. AB - Bile acids can function in the postprandial state as circulating signaling molecules in the regulation of glucose and lipid metabolism via the transmembrane receptor TGR5 and nuclear receptor FXR. Both receptors are present in the central nervous system, but their function in the brain is unclear. Therefore, we investigated the effects of intracerebroventricular (i.c.v.) administration of taurolithocholate (tLCA), a strong TGR5 agonist, and GW4064, a synthetic FXR agonist, on energy metabolism. We determined the effects of chronic i.c.v. infusion of tLCA, GW4064, or vehicle on energy expenditure, body weight and composition as well as tissue specific fatty acid uptake in mice equipped with osmotic minipumps. We found that i.c.v. administration of tLCA (final concentration in cerebrospinal fluid: 1 MUM) increased fat oxidation (tLCA group: 0.083 +/- 0.006 vs control group: 0.036 +/- 0.023 kcal/h, F = 5.46, P = 0.04) and decreased fat mass (after 9 days of tLCA infusion: 1.35 +/- 0.13 vs controls: 1.96 +/- 0.23 g, P = 0.03). These changes were associated with enhanced uptake of triglyceride-derived fatty acids by brown adipose tissue and with browning of subcutaneous white adipose tissue. I.c.v. administration of GW4064 (final concentration in cerebrospinal fluid: 10 MUM) did not affect energy metabolism, body composition nor bile acid levels, negating a role of FXR in the central nervous system in metabolic control. In conclusion, bile acids such as tLCA may exert metabolic effects on fat metabolism via the brain. PMID- 29233936 TI - Heat-not-Burn Tobacco Products: Tobacco Industry Claims No Substitute for Science. PMID- 29233935 TI - Ligand-Dependent Interaction of PPARdelta With T-Cell Protein Tyrosine Phosphatase 45 Enhances Insulin Signaling. AB - Peroxisome proliferator-activated receptor (PPAR) delta plays a pivotal role in metabolic homeostasis through its effect on insulin signaling. Although diverse genomic actions of PPARdelta are postulated, the specific molecular mechanisms whereby PPARdelta controls insulin signaling have not been fully elucidated. We demonstrate here that short-term activation of PPARdelta results in the formation of a stable complex with nuclear T-cell protein tyrosine phosphatase 45 (TCPTP45) isoform. This interaction of PPARdelta with TCPTP45 blocked translocation of TCPTP45 into the cytoplasm, thereby preventing its interaction with the insulin receptor, which inhibits insulin signaling. Interaction of PPARdelta with TCPTP45 blunted interleukin 6-induced insulin resistance, leading to retention of TCPTP45 in the nucleus, thereby facilitating deactivation of the signal transducer and activator of transcription 3 (STAT3)-suppressor of cytokine signaling 3 (SOCS3) signal. Finally, GW501516-activated PPARdelta improved insulin signaling and glucose intolerance in mice fed a high-fat diet through its interaction with TCPTP45. This novel interaction of PPARdelta constitutes the most upstream component identified of the mechanism downregulating insulin signaling. PMID- 29233937 TI - Provider Perspectives on Use of Medical Marijuana in Children With Cancer. AB - BACKGROUND: Although medical marijuana (MM) may have utility in the supportive care of children with serious illness, it remains controversial. We investigated interdisciplinary provider perspectives on legal MM use in children with cancer. METHODS: We sent a 32-item, cross-sectional survey to 654 pediatric oncology providers in Illinois, Massachusetts, and Washington characterizing MM practices, knowledge, attitudes, and barriers. Forty-eight percent responded; 44% (n = 288) were included in analyses. Providers were stratified by status as legally eligible to certify (ETC) for MM. We used Fisher's exact and Wilcoxon rank tests and univariate and multivariate logistic regression models for group comparisons. RESULTS: The provider median age was 35 years (range 22-70 years); 33% were ETC (83 physicians; 13 Washington state advance practice providers). Thirty percent of providers received >=1 request for MM in the previous month. Notably, only 5% of all providers knew state-specific regulations. ETC providers were more likely to know that MM is against federal laws (P < .0001). Whereas most providers (92%) reported willingness to help children with cancer access MM, in adjusted models, ETC providers were less likely to indicate approval of patient MM use by smoking, oral formulations, as cancer-directed therapy, or to manage symptoms (P < .005 for all). Forty-six percent of all providers cited the absence of standards around formulations, potency, or dosing to be the greatest barrier to recommending MM. CONCLUSIONS: Most pediatric oncology providers are willing to consider MM use in children with cancer and receive frequent inquiries. However, ETC providers endorse less favorable attitudes overall. The absence of standards is an important barrier to recommending MM. PMID- 29233930 TI - Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer. AB - OBJECTIVE: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes. DESIGN: RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants. RESULTS: Fifteen critical RGs are summarised below: RG1: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3: Pressing need for prevention trials; RG4: Lack of integration of different prevention approaches; RG5: Lack of optimal strategies for CRC screening; RG6: Lack of effective triage systems for invasive investigations; RG7: Imprecise pathological assessment of CRC; RG8: Lack of qualified personnel in genomics, data sciences and digital pathology; RG9: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10: Need for novel technologies/interventions to improve curative outcomes; RG11: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12: Lack of reliable biomarkers to guide stage IV treatment; RG13: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14: Lack of coordination of CRC research/funding; RG15: Lack of effective communication between relevant stakeholders. CONCLUSION: Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years. PMID- 29233939 TI - No reason to reconsider HIF-2 as an oncogene in neuroblastoma and other cancer forms. PMID- 29233938 TI - Regulation of Hormonal Control, Cell Reprogramming, and Patterning during De Novo Root Organogenesis. AB - Body regeneration through formation of new organs is a major question in developmental biology. We investigated de novo root formation using whole leaves of Arabidopsis (Arabidopsis thaliana). Our results show that local cytokinin biosynthesis and auxin biosynthesis in the leaf blade followed by auxin long distance transport to the petiole leads to proliferation of J0121-marked xylem associated tissues and others through signaling of INDOLE-3-ACETIC ACID INDUCIBLE28 (IAA28), CRANE (IAA18), WOODEN LEG, and ARABIDOPSIS RESPONSE REGULATORS1 (ARR1), ARR10, and ARR12. Vasculature proliferation also involves the cell cycle regulator KIP-RELATED PROTEIN2 and ABERRANT LATERAL ROOT FORMATION4, resulting in a mass of cells with rooting competence that resembles callus formation. Endogenous callus formation precedes specification of postembryonic root founder cells, from which roots are initiated through the activity of SHORT ROOT, PLETHORA1 (PLT1), and PLT2. Primordia initiation is blocked in shr plt1 plt2 mutant. Stem cell regulators SCHIZORIZA, JACKDAW, BLUEJAY, and SCARECROW also participate in root initiation and are required to pattern the new organ, as mutants show disorganized and reduced number of layers and tissue initials resulting in reduced rooting. Our work provides an organ regeneration model through de novo root formation, stating key stages and the primary pathways involved. PMID- 29233940 TI - Reply to Liu: Inflammation before implantation both in evolution and development. PMID- 29233941 TI - Implantation in eutherians: Which came first, the inflammatory reaction or attachment? PMID- 29233942 TI - Making two-photon processes dominate one-photon processes using mid-IR phonon polaritons. AB - Phonon polaritons are guided hybrid modes of photons and optical phonons that can propagate on the surface of a polar dielectric. In this work, we show that the precise combination of confinement and bandwidth offered by phonon polaritons allows for the ability to create highly efficient sources of polariton pairs in the mid-IR/terahertz frequency ranges. Specifically, these polar dielectrics can cause emitters to preferentially decay by the emission of pairs of phonon polaritons, instead of the previously dominant single-photon emission. We show that such two-photon emission processes can occur on nanosecond time scales and can be nearly 2 orders of magnitude faster than competing single-photon transitions, as opposed to being as much as 8-10 orders of magnitude slower in free space. These results are robust to the choice of polar dielectric, allowing potentially versatile implementation in a host of materials such as hexagonal boron nitride, silicon carbide, and others. Our results suggest a design strategy for quantum light sources in the mid-IR/terahertz: ones that prefer to emit a relatively broad spectrum of photon pairs, potentially allowing for new sources of both single and multiple photons. PMID- 29233943 TI - ATG-dependent phagocytosis in dendritic cells drives myelin-specific CD4+ T cell pathogenicity during CNS inflammation. AB - Although reactivation and accumulation of autoreactive CD4+ T cells within the CNS are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), the mechanisms of how these cells recognize their target organ and induce sustained inflammation are incompletely understood. Here, we report that mice with conditional deletion of the essential autophagy protein ATG5 in classical dendritic cells (DCs), which are present at low frequencies in the nondiseased CNS, are completely resistant to EAE development following adoptive transfer of myelin-specific T cells and show substantially reduced in situ CD4+ T cell accumulation during the effector phase of the disease. Endogenous myelin peptide presentation to CD4+ T cells following phagocytosis of injured, phosphatidylserine-exposing oligodendroglial cells is abrogated in the absence of ATG5. Pharmacological inhibition of ATG-dependent phagocytosis by the cardiac glycoside neriifolin, an inhibitor of the Na+, K+-ATPase, delays the onset and reduces the clinical severity of EAE induced by myelin-specific CD4+ T cells. These findings link phagocytosis of injured oligodendrocytes, a pathological hallmark of MS lesions and during EAE, with myelin antigen processing and T cell pathogenicity, and identify ATG-dependent phagocytosis in DCs as a key regulator in driving autoimmune CD4+ T cell-mediated CNS damage. PMID- 29233944 TI - Ethylene promotes root hair growth through coordinated EIN3/EIL1 and RHD6/RSL1 activity in Arabidopsis. AB - Root hairs are an extensive structure of root epidermal cells and are critical for nutrient acquisition, soil anchorage, and environmental interactions in sessile plants. The phytohormone ethylene (ET) promotes root hair growth and also mediates the effects of different signals that stimulate hair cell development. However, the molecular basis of ET-induced root hair growth remains poorly understood. Here, we show that ET-activated transcription factor ETHYLENE INSENSITIVE 3 (EIN3) physically interacts with ROOT HAIR DEFECTIVE 6 (RHD6), a well-documented positive regulator of hair cells, and that the two factors directly coactivate the hair length-determining gene RHD6-LIKE 4 (RSL4) to promote root hair elongation. Transcriptome analysis further revealed the parallel roles of the regulator pairs EIN3/EIL1 (EIN3-LIKE 1) and RHD6/RSL1 (RHD6 LIKE 1). EIN3/EIL1 and RHD6/RSL1 coordinately enhance root hair initiation by selectively regulating a subset of core root hair genes. Thus, our work reveals a key transcriptional complex consisting of EIN3/EIL1 and RHD6/RSL1 in the control of root hair initiation and elongation, and provides a molecular framework for the integration of environmental signals and intrinsic regulators in modulating plant organ development. PMID- 29233945 TI - Resource limitation prevents the emergence of drug resistance by intensifying within-host competition. AB - Slowing the evolution of antimicrobial resistance is essential if we are to continue to successfully treat infectious diseases. Whether a drug-resistant mutant grows to high densities, and so sickens the patient and spreads to new hosts, is determined by the competitive interactions it has with drug-susceptible pathogens within the host. Competitive interactions thus represent a good target for resistance management strategies. Using an in vivo model of malaria infection, we show that limiting a resource that is disproportionately required by resistant parasites retards the evolution of drug resistance by intensifying competitive interactions between susceptible and resistant parasites. Resource limitation prevented resistance emergence regardless of whether resistant mutants arose de novo or were experimentally added before drug treatment. Our work provides proof of principle that chemotherapy paired with an "ecological" intervention can slow the evolution of resistance to antimicrobial drugs, even when resistant pathogens are present at high frequencies. It also suggests that a broad range of previously untapped compounds could be used for treating infectious diseases. PMID- 29233946 TI - Dopamine prediction error responses update demand. PMID- 29233947 TI - Reply to Mohlin et al.: High levels of EPAS1 are closely associated with key features of low-risk neuroblastoma. PMID- 29233948 TI - Intercellular competition and levels of development: The plasticity of inevitability. PMID- 29233949 TI - Association between SULT1A1 Arg213His (rs9282861) Polymorphism and Risk of Breast Cancer: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The Arg213His (rs9282861) polymorphism of Sulfotransferase Family 1A Member 1 (SULT1A1) gene has been associated with risk of breast cancer in some epidemiological studies. Therefore, this systematic review and meta-analysis was conducted to evaluate the association of SULT1A1 Arg213His (rs9282861) polymorphism with susceptibility to breast cancer. STUDY DESIGN: A systematic review and meta-analysis. METHODS: A comprehensive literature search for eligible studies was conducted in PubMed, Elsevier, Science Direct, Scopus and Google Scholar databases up to Oct 5, 2017. Pooled odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) were used to evaluate the strength of the association using fixed effects models and random effects models. RESULTS: Twenty relevant case-control studies involving 11077 cases and 14798 controls were included in this meta-analysis. Overall, there was a significant association between the SULT1A1 Arg213His (rs9282861) polymorphism and risk of breast cancer in the allele mode (A vs. G: OR=1.117, 95% CI: 1.011, 1.233, P=0.029) and the homozygote model (AA vs. GG: OR=1.288, 95% CI: 1.036, 1.601, P=0.022). Subgroup analysis based on ethnicity suggested SULT1A1 Arg213His (rs9282861) polymorphism had a subtly increased breast cancer risk among Asian population, but not Caucasians. Further, subgroup analyses, significant associations were observed in hospital-based group, RFLP-PCR group, and high quality studies subgroups. CONCLUSIONS: SULT1A1 Arg213His (rs9282861) polymorphism might be associated with breast cancer risk, especially among Asian population. Moreover, the SULT1A1 Arg213His polymorphism is of high clinical relevance by ethnicity and would be a useful marker to identify patients who are at higher risk for breast cancer. PMID- 29233950 TI - Should Lifestyles Be a Criterion for Healthcare Rationing? Evidence from a Portuguese Survey. AB - BACKGROUND: We evaluated whether different personal responsibilities should influence the allocation healthcare resources and whether attitudes toward the penalization of risk behaviours vary among individual's sociodemographic characteristics and health related habits. STUDY DESIGN: A cross-sectional study. METHODS: We developed an online survey and made it available on various social networks for six months, during 2015. The sample covered the population aged 18 yr and older living in Portugal and we got 296 valid answers. Respondents faced four lifestyle choices: smoking, consumption of alcoholic beverages, unhealthy diet and illegal drug use, and should decide whether each one is relevant when establishing healthcare priorities. Logistic regressions were used to explore the relation of respondents' sociodemographic characteristics and health related behaviours in the likelihood of agreeing with the patients engaged in risky behaviour deserve a lower priority. RESULTS: Using illegal drugs was the behaviour most penalized (65.5%) followed by heavy drinkers (61.5%) and smoking (51.0%). The slight penalization was the unhealthy dieting (29.7%). The sociodemographic characteristics had different impact in penalization of the risks' behaviours. Moreover, the respondents who support the idea that unhealthy lifestyles should have a lower priority, all strongly agreed that the smoking habit (OR=36.05; 95% CI: 8.72, 149.12), the unhealthy diets (OR=12.87; 95% CI: 3.21, 51.53), drink alcohol in excess (OR=20.51; 95% CI: 12.09, 85.46) and illegal drug use (OR=73.21; 95% CI: 9.78, 97.83) must have a lower priority in the access to healthcare. CONCLUSIONS: The respondents accept the notion of rationing healthcare based on lifestyles. PMID- 29233951 TI - Exposure Assessment, Biological Monitoring, and Liver Function Tests of Operating Room Personnel Exposed to Halothane in Hamedan Hospitals, West of Iran. AB - BACKGROUND: Occupational exposure to halogenated hydrocarbons has been associated with halothane hepatitis, an increase of liver enzymes, and congenital malformations. The objectives of this study were to investigate whether bromide, a urinary metabolite of halothane, could be used as a biological marker of exposure to this anesthetic gas and assessment of associated exposure to halothane with any significant changes in conventional parameters of liver function (serum aminotransferase activities). STUDY DESIGN: A cross-sectional study. METHODS: Seventy-five anesthesiologists, anesthesia nurses, operating room nurses, and surgeons (exposed group) and 75 matched unexposed individuals (reference group) were selected randomly from two public hospitals in Hamadan City, western Iran. Atmospheric concentrations of halothane in the breathing zone of the exposed subjects and urinary bromide levels were measured by headspace gas chromatography. Similarly, serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by the enzymatic method using an automatic Prestige instrument. RESULTS: Mean atmospheric concentrations of halothane and urinary bromide levels for exposed subjects were 1.49 +/-1.36 ppm and 0.83 +/-0.29 mM, respectively. A relatively good correlation was found between exposure to halothane and urinary bromide levels (r=0.38). The chi-squared test results showed that the proportions of the subjects with abnormal ALT and AST among the women exposed were significantly higher than those of reference individuals (P<0.05). CONCLUSIONS: Urinary bromide can be used as a potential biomarker of exposure to halothane, although additional studies are necessary to further validate these initial findings. PMID- 29233952 TI - Epidemiological Study of Mortality Rate from Alcohol and Illicit Drug Abuse in Iran. AB - BACKGROUND: The estimate of mortality associated with illicit opiate use provides useful information to those directing and monitoring local, national and international policies and programs. This study investigated the epidemiology of mortality due to the illegal consumption of narcotics and psychotropic substances in the Iran to provide evidence-based public health data for useful programs and actions aimed at preventing drug-related mortality. STUDY DESIGN: A cross sectional study. METHODS: The information regarding all cases of psychotropic positive was collected from Legal Medicine Organization, occurred on Mar 2015 to Feb 2016. Demographic and epidemiological data were extracted from recorded documents. Data were then analyzed in Stata software. RESULTS: Overall, 2306 died cases from opioid or psychotropic abuse were evaluated. The mean age of the subjects was 36.07+/-12.61 yr, they were mostly single male, and 88.64% of them had Iranian nationality. The mortality rate from opiate and psychotropic abuse in the whole country was 38.22 per 1000000 population. The most common location of death was at home or in another private residence. History of overdose, suicide, hospitalization in psychiatric hospital, staying in prison and substance abuse in the family observed in some people who died from drug abuse. CONCLUSIONS: Mortality rate from substance abuse is more among unmarried young men aged 30-39 yr with low education level also in self-employed. We suggest policies to prevent this person accessing and using drug. PMID- 29233953 TI - Clustering and Combining Pattern of High-Risk Behaviors among Iranian University Students: A Latent Class Analysis. AB - BACKGROUND: High-risk behaviors are increasing among young adults worldwide. We aimed to identify university students' subgroups on the basis of high-risk behaviors and to assess the role of age, living alone, religious beliefs, and parental support in the membership of specific subgroups. STUDY DESIGN: A cross sectional study METHODS: The study was conducted in Bushehr (south of Iran) from November to December 2016. The sample included 977 university students selected through random sampling. The data were collected using a self-administered questionnaire. Then, latent class analysis was used to classify the students. RESULTS: Totally, five latent classes were identified as follows: low risk, high risk, somewhat low risk, hookah user, and very high risk. Notably, 7.7% and 2.5% of the students belonged to high risk and very high risk classes, respectively. The results suggested the protective effect of familial support and religiosity on high-risk behaviors. CONCLUSIONS: This study indicated the co-occurrence of high-risk behaviors. The findings can be used to plan and evaluate interventions by considering risk factors and protective factors in universities. PMID- 29233954 TI - The Effect of a Theory of Planned Behavior-based Educational Intervention on Sexual and Reproductive Health in Iranian Adolescent Girls: A Randomized Controlled Trial. AB - BACKGROUND: We aimed to assess the effect of a theory of planned behavior (TPB) based educational intervention on attitude, norms, parental control, behavioral control, and intention in high school girls in Tehran, Iran. STUDY DESIGN: Randomized controlled trial. METHODS: This study was conducted among 578 high school girls, 12 to 16 yr, in Tehran, Iran in 2016. The subjects were randomly assigned to the experimental (n=289) and control (n=289) groups using multistage random cluster sampling. TPB is the basis for both education and evaluation; therefore, the TPB-based questionnaire was used before and after the intervention. The intervention included three months education and six months follow up. The obtained data were analyzed using SPSS version 16 through statistical tests and analysis of covariance. RESULTS: Significant improvement in attitude (difference=16.8; 95% CI: 15.3, 18.3), subjective norms (16.4; 95% CI=14.83 to 18.11), perceived behavioral control (18.0; 95% CI: 16.6, 19.4), perceived parental control (17%; 95% CI: 15.1, 18.9), behavioral intention (18.4%; 95 CI: 14.8, 18.3), and behavior (18.5; 95% CI:16.8, 20.2) was observed in experimental group compared to control group (P<0.001). CONCLUSIONS: Theory based educational intervention in sexual and reproductive health can effectively reduce the high-risk behaviors related to sexual and reproductive health in adolescent girls. Health and education policy-makers are advised to review the current education programs and replace them with new influential education programs related to sexual and reproductive health in the school system. PMID- 29233955 TI - The Effect of Various Stabilizers on Preserving Immunogenicity of Lyophilized Mumps Vaccines. AB - BACKGROUND: Chemical stabilizers are added to live attenuated vaccines for enhancing the virus stability. The aim of this study was to evaluate the effect of various stabilizers on preserving immunogenicity of lyophilized mumps vaccines. STUDY DESIGN: An experimental study. METHODS: Three mumps vaccines with different formulations were inoculated to three groups of Guinea pigs. Sterile water was injected to eight Guinea pigs as a control group. Blood samples were collected before inoculation and on 14, 28 and 42 d after vaccine injection. Mumps antibodies in the sera were measured using hemagglutination inhibition assay (HAI). RESULTS: All three formulated mumps vaccines induced antibody in Guinea pigs after two weeks. Formulation 1 containing trehalose dihydrate and formulation 2 comprised human serum albumin stimulated antibodies in the higher level than Razi routine formulation. CONCLUSIONS: Various stabilizers have different preservation potencies that differently affect immune response against virus. More stable and more immunogenic vaccines can be produced using stabilizers containing trehalose dihydrate. PMID- 29233956 TI - Cesarean Section and Socioeconomic Status in Tehran, Iran. AB - BACKGROUND: Socioeconomic status (SES) is linked to a wide range of maternity services including Cesarean section (CS). The objective of this study was to determine the rate of CS and to examine the effect of SES on CS rate. STUDY DESIGN: Cross-sectional study. METHODS: This study included 4308 pregnant women who gave singleton birth in Tehran, Iran in July 2015. To evaluate the effect of SES on CS, logistic regression model was used after adjusting for others variables. RESULTS: The CS rate was 72.0% and its rate in private hospitals was significantly higher than in public hospitals (91.7 vs 62.6%, P<0.001). After adjusting for demographic characteristics of mothers, obstetrical data and newborn's information, economic status (ES) was associated with an increased rate of CS (OR= 1.22; 95% CI=1.16-1.28). CONCLUSIONS: Independently of biological or clinical factors, ES is associated with an increased rate of CS in Tehran, Iran. PMID- 29233957 TI - Dynamic Monitoring of Erythrocyte Distribution Width (RDW) and Platelet Distribution Width (PDW) in Treatment of Acute Myocardial Infarction. AB - BACKGROUND This study investigated the role of erythrocyte distribution width (RDW) and platelet distribution width (PDW) in evaluating the treatment efficacy for acute myocardial infarction (AMI). MATERIAL AND METHODS A total of 120 AMI patients receiving conventional myocardial infarction treatment were included. The patients were divided into an effective group and an ineffective group based on treatment efficacy. The RDW and PDW were measured before and after treatment. We used the independent samples t test, chi-square test, logistic regression, and ROC curves for analysis. RESULTS The change and change rate of RDW and PDW were significantly improved (p<0.01) and the positive change rate of RDW, PDW, and RDW + PDW were significantly lower in the effective group compared with those in the ineffective group (p<0.01). The change and change rate of RDW and PDW are independent factors for treatment efficacy evaluation (p<0.05). ROC curve analysis showed that the changes and change rate of RDW and PDW were all significant in evaluating treatment efficacy (p<0.05). CONCLUSIONS The change and change rate of RDW and PDW or their combination can be used to evaluate treatment efficacy; however, the absolute value of RDW and PDW are not as significant. PMID- 29233959 TI - Highly enantioselective catalytic synthesis of chiral pyridines. AB - General methods to prepare chiral pyridine derivatives are greatly sought after due to their significance in medicinal chemistry. Here, we report highly enantioselective catalytic transformations of poorly reactive beta-substituted alkenyl pyridines to access a wide range of alkylated chiral pyridines. The simple methodology involves reactivity enhancement via Lewis acid (LA) activation, the use of readily available and highly reactive Grignard reagents, and a copper-chiral diphosphine ligand catalyst. Apart from allowing the introduction of different linear, branched, cyclic, and functionalised alkyl chains at the beta-position of alkenyl pyridines, the catalytic system also shows high functional group tolerance. PMID- 29233958 TI - Complement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking. AB - Regeneration of skeletal muscle following injury is accompanied by transient inflammation. Here we show that complement is activated in skeletal muscle injury and plays a key role during regeneration. Genetic ablation of complement C3 or its inactivation with Cobra Venom Factor (CVF) result in impaired muscle regeneration following cardiotoxin-induced injury in mice. The effect of complement in muscle regeneration is mediated by the alternative pathway and C3a receptor (C3aR) signaling, as deletion of Cfb, a key alternative pathway component, or C3aR leads to impaired regeneration and reduced monocyte/macrophage infiltration. Monocytes from C3aR-deficient mice express a reduced level of adhesion molecules, cytokines and genes associated with antigen processing and presentation. Exogenous administration of recombinant CCL5 to C3aR-deficient mice rescues the defects in inflammatory cell recruitment and regeneration. These findings reveal an important role of complement C3a in skeletal muscle regeneration, and suggest that manipulating complement system may produce therapeutic benefit in muscle injury and regeneration. PMID- 29233961 TI - Publisher Correction: Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus. AB - In the original PDF version of this Article, which was published on 16 October 2017, the publication date was incorrectly given as 10 October 2017. This has now been corrected in the PDF; the HTML version of the paper was correct from the time of publication. PMID- 29233960 TI - Multiplexed in vivo homology-directed repair and tumor barcoding enables parallel quantification of Kras variant oncogenicity. AB - Large-scale genomic analyses of human cancers have cataloged somatic point mutations thought to initiate tumor development and sustain cancer growth. However, determining the functional significance of specific alterations remains a major bottleneck in our understanding of the genetic determinants of cancer. Here, we present a platform that integrates multiplexed AAV/Cas9-mediated homology-directed repair (HDR) with DNA barcoding and high-throughput sequencing to simultaneously investigate multiple genomic alterations in de novo cancers in mice. Using this approach, we introduce a barcoded library of non-synonymous mutations into hotspot codons 12 and 13 of Kras in adult somatic cells to initiate tumors in the lung, pancreas, and muscle. High-throughput sequencing of barcoded Kras HDR alleles from bulk lung and pancreas reveals surprising diversity in Kras variant oncogenicity. Rapid, cost-effective, and quantitative approaches to simultaneously investigate the function of precise genomic alterations in vivo will help uncover novel biological and clinically actionable insights into carcinogenesis. PMID- 29233962 TI - Lipoteichoic acid deficiency permits normal growth but impairs virulence of Streptococcus pneumoniae. AB - Teichoic acid (TA), a crucial cell wall constituent of the pathobiont Streptococcus pneumoniae, is bound to peptidoglycan (wall teichoic acid, WTA) or to membrane glycolipids (lipoteichoic acid, LTA). Both TA polymers share a common precursor synthesis pathway, but differ in the final transfer of the TA chain to either peptidoglycan or a glycolipid. Here, we show that LTA exhibits a different linkage conformation compared to WTA, and identify TacL (previously known as RafX) as a putative lipoteichoic acid ligase required for LTA assembly. Pneumococcal mutants deficient in TacL lack LTA and show attenuated virulence in mouse models of acute pneumonia and systemic infections, although they grow normally in culture. Hence, LTA is important for S. pneumoniae to establish systemic infections, and TacL represents a potential target for antimicrobial drug development. PMID- 29233963 TI - A Paleocene penguin from New Zealand substantiates multiple origins of gigantism in fossil Sphenisciformes. AB - One of the notable features of penguin evolution is the occurrence of very large species in the early Cenozoic, whose body size greatly exceeded that of the largest extant penguins. Here we describe a new giant species from the late Paleocene of New Zealand that documents the very early evolution of large body size in penguins. Kumimanu biceae, n. gen. et sp. is larger than all other fossil penguins that have substantial skeletal portions preserved. Several plesiomorphic features place the new species outside a clade including all post-Paleocene giant penguins. It is phylogenetically separated from giant Eocene and Oligocene penguin species by various smaller taxa, which indicates multiple origins of giant size in penguin evolution. That a penguin rivaling the largest previously known species existed in the Paleocene suggests that gigantism in penguins arose shortly after these birds became flightless divers. Our study therefore strengthens previous suggestions that the absence of very large penguins today is likely due to the Oligo-Miocene radiation of marine mammals. PMID- 29233964 TI - Molecular predictors of post-transplant survival in acute myeloid leukemia. PMID- 29233966 TI - From ATP synthase dimers to C-ring conformational changes: unified model of the mitochondrial permeability transition pore. PMID- 29233965 TI - Coupling between oxygen redox and cation migration explains unusual electrochemistry in lithium-rich layered oxides. AB - Lithium-rich layered transition metal oxide positive electrodes offer access to anion redox at high potentials, thereby promising high energy densities for lithium-ion batteries. However, anion redox is also associated with several unfavorable electrochemical properties, such as open-circuit voltage hysteresis. Here we reveal that in Li1.17-x Ni0.21Co0.08Mn0.54O2, these properties arise from a strong coupling between anion redox and cation migration. We combine various X ray spectroscopic, microscopic, and structural probes to show that partially reversible transition metal migration decreases the potential of the bulk oxygen redox couple by > 1 V, leading to a reordering in the anionic and cationic redox potentials during cycling. First principles calculations show that this is due to the drastic change in the local oxygen coordination environments associated with the transition metal migration. We propose that this mechanism is involved in stabilizing the oxygen redox couple, which we observe spectroscopically to persist for 500 charge/discharge cycles. PMID- 29233967 TI - Whole-genome sequencing for an enhanced understanding of genetic variation among South Africans. AB - The Southern African Human Genome Programme is a national initiative that aspires to unlock the unique genetic character of southern African populations for a better understanding of human genetic diversity. In this pilot study the Southern African Human Genome Programme characterizes the genomes of 24 individuals (8 Coloured and 16 black southeastern Bantu-speakers) using deep whole-genome sequencing. A total of ~16 million unique variants are identified. Despite the shallow time depth since divergence between the two main southeastern Bantu speaking groups (Nguni and Sotho-Tswana), principal component analysis and structure analysis reveal significant (p < 10-6) differentiation, and FST analysis identifies regions with high divergence. The Coloured individuals show evidence of varying proportions of admixture with Khoesan, Bantu-speakers, Europeans, and populations from the Indian sub-continent. Whole-genome sequencing data reveal extensive genomic diversity, increasing our understanding of the complex and region-specific history of African populations and highlighting its potential impact on biomedical research and genetic susceptibility to disease. PMID- 29233968 TI - HRD1 prevents apoptosis in renal tubular epithelial cells by mediating eIF2alpha ubiquitylation and degradation. AB - Apoptosis of renal tubular epithelial cells is a key feature of the pathogenicity associated with tubulointerstitial fibrosis and other kidney diseases. One factor that regulates important cellular processes like apoptosis and cell proliferation is HRD1, an E3 ubiquitin ligase that acts by promoting ubiquitylation and degradation of its target protein. However, the detailed mechanisms by which HRD1 acts as a regulator of apoptosis in renal tubular epithelial cells have not been established. In our previous liquid chromatography-tandem mass spectrometry (LC MS/MS) study (Mol Endocrinol. 2016;30:600-613), we demonstrated that one substrate of HRD1 was eIF2alpha, a critical protein in the PERK-eIF2alpha-ATF4 CHOP signaling pathway of endoplasmic reticulum (ER) stress. Here, we show that eIF2alpha expression was increased and HRD1 expression decreased when apoptosis was induced in HKC-8 cells by palmitic acid (PA) or high glucose (HG). HRD1 expression was also lower in kidney tissues from mice with diabetic nephropathy (DN) than in control mice. Forced expression of HRD1 also inhibited apoptosis in HKC-8 cells, while HRD1 overexpression decreased the expression of phosphorylated eIF2alpha and eIF2alpha. Further analysis indicated that HRD1 interacted with eIF2alpha and promoted its ubiquitylation and degradation by the proteasome. Moreover, the HRD1 protection of PA-treated HKC-8 cells was blunted by transfection with Myc-eIF2alpha. Thus, eIF2alpha ubiquitylation by HRD1 protects tubular epithelial cells from apoptosis caused by HG and PA, indicating a novel upstream target for therapeutic prevention of renal tubulointerstitial injury. PMID- 29233969 TI - Receptor-interacting protein 140 as a co-repressor of Heat Shock Factor 1 regulates neuronal stress response. AB - Heat shock response (HSR) is a highly conserved transcriptional program that protects organisms against various stressful conditions. However, the molecular mechanisms modulating HSR, especially the suppression of HSR, is poorly understood. Here, we found that RIP140, a wide-spectrum cofactor of nuclear hormone receptors, acts as a co-repressor of heat shock factor 1 (HSF1) to suppress HSR in healthy neurons. When neurons are stressed such as by heat shock or sodium arsenite (As), cells engage specific proteosome-mediated degradation to reduce RIP140 level, thereby relieving the suppression and activating HSR. RIP140 degradation requires specific Tyr-phosphorylation by Syk that is activated in stressful conditions. Lowering RIP140 level protects hippocampal neurons from As stress, significantly it increases neuron survival and improves spine density. Reducing hippocampal RIP140 in the mouse rescues chronic As-induced spatial learning deficits. This is the first study elucidating RIP140-mediated suppression of HSF1-activated HSR in neurons and brain. Importantly, degradation of RIP140 in stressed neurons relieves this suppression, allowing neurons to efficiently and timely engage HSR programs and recover. Therefore, stimulating RIP140 degradation to activate anti-stress program provides a potential preventive or therapeutic strategy for neurodegeneration diseases. PMID- 29233970 TI - Dynamical trade-offs arise from antagonistic coevolution and decrease intraspecific diversity. AB - Trade-offs play an important role in evolution. Without trade-offs, evolution would maximize fitness of all traits leading to a "master of all traits". The shape of trade-offs has been shown to determine evolutionary trajectories and is often assumed to be static and independent of the actual evolutionary process. Here we propose that coevolution leads to a dynamical trade-off. We test this hypothesis in a microbial predator-prey system and show that the bacterial growth defense trade-off changes from concave to convex, i.e., defense is effective and cheap initially, but gets costly when predators coevolve. We further explore the impact of such dynamical trade-offs by a novel mathematical model incorporating de novo mutations for both species. Predator and prey populations diversify rapidly leading to higher prey diversity when the trade-off is concave (cheap). Coevolution results in more convex (costly) trade-offs and lower prey diversity compared to the scenario where only the prey evolves. PMID- 29233971 TI - Implication of 4E-BP1 protein dephosphorylation and accumulation in pancreatic cancer cell death induced by combined gemcitabine and TRAIL. AB - Pancreatic cancer cells show varying sensitivity to the anticancer effects of gemcitabine. However, as a chemotherapeutic agent, gemcitabine can cause intolerably high levels of toxicity and patients often develop resistance to the beneficial effects of this drug. Combination studies show that use of gemcitabine with the pro-apoptotic cytokine TRAIL can enhance the inhibition of survival and induction of apoptosis of pancreatic cancer cells. Additionally, following combination treatment there is a dramatic increase in the level of the hypophosphorylated form of the tumour suppressor protein 4E-BP1. This is associated with inhibition of mTOR activity, resulting from caspase-mediated cleavage of the Raptor and Rictor components of mTOR. Use of the pan-caspase inhibitor Z-VAD-FMK indicates that the increase in level of 4E-BP1 is also caspase-mediated. ShRNA-silencing of 4E-BP1 expression renders cells more resistant to cell death induced by the combination treatment. Since the levels of 4E-BP1 are relatively low in untreated pancreatic cancer cells these results suggest that combined therapy with gemcitabine and TRAIL could improve the responsiveness of tumours to treatment by elevating the expression of 4E-BP1. PMID- 29233972 TI - IRF8-dependent molecular complexes control the Th9 transcriptional program. AB - Interferon regulatory factors (IRF) have critical functions in lymphoid development and in immune response regulation. Although many studies have described the function of IRF4 in CD4+ T cells, few have focused on the IRF4 homologue, IRF8. Here, we show that IRF8 is required for Th9 differentiation in vitro and in vivo. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boosts Il9 transcription. By contrast, IRF8 deficiency promotes the expression of other genes such as Il4, as IRF8 dimerises with the transcriptional repressor ETV6 and inhibits Il4 expression. In vivo, IRF8 is essential for the anti-tumour effects of Th9 cells in mouse melanoma models. Our results show that IRF8 complexes boost the Th9 program and repress Il4 expression to modulate Th9 cell differentiation, thereby implicating IRF8 as a potential therapeutic target to affect Th9 responses in cancer therapy. PMID- 29233973 TI - parasitised feathered dinosaurs as revealed by Cretaceous amber assemblages. AB - Ticks are currently among the most prevalent blood-feeding ectoparasites, but their feeding habits and hosts in deep time have long remained speculative. Here, we report direct and indirect evidence in 99 million-year-old Cretaceous amber showing that hard ticks and ticks of the extinct new family Deinocrotonidae fed on blood from feathered dinosaurs, non-avialan or avialan excluding crown-group birds. A ?Cornupalpatum burmanicum hard tick is entangled in a pennaceous feather. Two deinocrotonids described as ?Deinocroton draculi gen. et sp. nov. have specialised setae from dermestid beetle larvae (hastisetae) attached to their bodies, likely indicating cohabitation in a feathered dinosaur nest. A third conspecific specimen is blood-engorged, its anatomical features suggesting that deinocrotonids fed rapidly to engorgement and had multiple gonotrophic cycles. These findings provide insight into early tick evolution and ecology, and shed light on poorly known arthropod-vertebrate interactions and potential disease transmission during the Mesozoic. PMID- 29233974 TI - Author Correction: Nanoscale control of competing interactions and geometrical frustration in a dipolar trident lattice. AB - The original version of this article contained an error in the legend to Figure 4. The yellow scale bar should have been defined as '~600 nm', not '~600 um'. This has now been corrected in both the PDF and HTML versions of the article. PMID- 29233975 TI - Essential thrombocythemia vs. pre-fibrotic/early primary myelofibrosis: discrimination by laboratory and clinical data. PMID- 29233976 TI - Uncovering active precursors in colloidal quantum dot synthesis. AB - Studies of the fundamental physics and chemistry of colloidal semiconductor nanocrystal quantum dots (QDs) have been central to the field for over 30 years. Although the photophysics of QDs has been intensely studied, much less is understood about the underlying chemical reaction mechanism leading to monomer formation and subsequent QD growth. Here we investigate the reaction mechanism behind CdSe QD synthesis, the most widely studied QD system. Remarkably, we find that it is not necessary for chemical precursors used in the most common synthetic methods to directly react to form QD monomers, but rather they can generate in situ the same highly reactive Cd and Se precursors that were used in some of the original II-VI QD syntheses decades ago, i.e., hydrogen chalcogenide gas and alkyl cadmium. Appreciating this surprising finding may allow for directed manipulation of these reactive intermediates, leading to more controlled syntheses with improved reproducibility. PMID- 29233977 TI - The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury. AB - Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood. Therefore, we lack efficient therapeutic strategies to treat this pathology. Here we show that APAP interferes with the formation of mitochondrial respiratory supercomplexes via the mitochondrial negative regulator MCJ, and leads to decreased production of ATP and increased generation of ROS. In vivo treatment with an inhibitor of MCJ expression protects liver from acetaminophen-induced liver injury at a time when N-acetylcysteine, the standard therapy, has no efficacy. We also show elevated levels of MCJ in the liver of patients with acetaminophen overdose. We suggest that MCJ may represent a therapeutic target to prevent and rescue liver injury caused by acetaminophen. PMID- 29233978 TI - An oomycete plant pathogen reprograms host pre-mRNA splicing to subvert immunity. AB - The process of RNA splicing influences many physiological processes, including plant immunity. However, how plant parasites manipulate host RNA splicing process remains unknown. Here we demonstrate that PsAvr3c, an avirulence effector from oomycete plant pathogen Phytophthora sojae, physically binds to and stabilizes soybean serine/lysine/arginine-rich proteins GmSKRPs. The SKRPs are novel proteins that associate with a complex that contains plant spliceosome components, and are negative regulators of plant immunity. Analysis by RNA-seq data indicates that alternative splicing of pre-mRNAs from 401 soybean genes, including defense-related genes, is altered in GmSKRP1 and PsAvr3c overexpressing lines compared to control plants. Representative splicing events mediated by GmSKRP1 and PsAvr3c are tested by infection assays or by transient expression in soybean plants. Our results show that plant pathogen effectors can reprogram host pre-mRNA splicing to promote disease, and we propose that pathogens evolved such strategies to defeat host immune systems. PMID- 29233980 TI - Author Correction: Improved genome recovery and integrated cell-size analyses of individual uncultured microbial cells and viral particles. AB - The original version of this Article contained errors in the units of concentration of three reagents listed in the Methods. These errors have all been corrected in both the PDF and HTML versions of the Article. PMID- 29233979 TI - Extracellular vesicles from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) protect against renal ischemia/reperfusion injury via delivering specificity protein (SP1) and transcriptional activating of sphingosine kinase 1 and inhibiting necroptosis. AB - Renal ischemia-reperfusion is a main cause of acute kidney injury (AKI), which is associated with high mortality. Here we show that extracellular vesicles (EVs) secreted from hiPSC-MSCs play a critical role in protection against renal I/R injury. hiPSC-MSCs-EVs can fuse with renal cells and deliver SP1 into target cells, subsequently active SK1 expression and increase S1P formation. Chromatin immunoprecipitation (ChIP) analyses and luciferase assay were used to confirm SP1 binds directly to the SK1 promoter region and promote promoter activity. Moreover, SP1 inhibition (MIT) or SK1 inhibition (SKI-II) completely abolished the renal protective effect of hiPSC-MSCs-EVs in rat I/R injury mode. However, pre-treatment of necroptosis inhibitor Nec-1 showed no difference with the administration of hiPSC-MSCs-EVs only. We then generated an SP1 knockout hiPSC MSC cell line by CRISPR/Cas9 system and found that SP1 knockout failed to show the protective effect of hiPSC-MSCs-EVs unless restoring the level of SP1 by Ad SP1 in vitro and in vivo. In conclusion, this study describes an anti-necroptosis effect of hiPSC-MSCs-EVs against renal I/R injury via delivering SP1 into target renal cells and intracellular activating the expression of SK1 and the generation of S1P. These findings suggest a novel mechanism for renal protection against I/R injury, and indicate a potential therapeutic approach for a variety of renal diseases and renal transplantation. PMID- 29233981 TI - A miR-327-FGF10-FGFR2-mediated autocrine signaling mechanism controls white fat browning. AB - Understanding the molecular mechanisms regulating beige adipocyte formation may lead to the development of new therapies to combat obesity. Here, we report a miRNA-based autocrine regulatory pathway that controls differentiation of preadipocytes into beige adipocytes. We identify miR-327 as one of the most downregulated miRNAs targeting growth factors in the stromal-vascular fraction (SVF) under conditions that promote white adipose tissue (WAT) browning in mice. Gain- and loss-of-function experiments reveal that miR-327 targets FGF10 to prevent beige adipocyte differentiation. Pharmacological and physiological beta adrenergic stimulation upregulates FGF10 levels and promotes preadipocyte differentiation into beige adipocytes. In vivo local delivery of miR-327 to WATs significantly compromises the beige phenotype and thermogenesis. Contrarily, systemic inhibition of miR-327 in mice induces browning and increases whole-body metabolic rate under thermoneutral conditions. Our data provide mechanistic insight into an autocrine regulatory signaling loop that regulates beige adipocyte formation and suggests that the miR-327-FGF10-FGFR2 signaling axis may be a therapeutic targets for treatment of obesity and metabolic diseases. PMID- 29233982 TI - CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARgamma and inhibit adipogenesis. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is the master regulator of adipocyte differentiation and is closely linked to the development of obesity. Despite great progress in elucidating the transcriptional network of PPARgamma, epigenetic regulation of this pathway by histone modification remains elusive. Here, we found that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, directly bound to PPARgamma through the co repressor nuclear receptor (CoRNR) box 2 and repressed the transcriptional activity and adipogenic potential of PPARgamma. Upon CACUL1 depletion, less SIRT1 and more LSD1 were recruited to the PPARgamma-responsive gene promoter, leading to increased histone H3K9 acetylation, decreased H3K9 methylation, and PPARgamma activation during adipogenesis in 3T3-L1 cells. These findings were reversed upon fasting or resveratrol treatment. Further, gene expression profiling using RNA sequencing supported the repressive role of CACUL1 in PPARgamma activation and fat accumulation. Finally, we confirmed CACUL1 function in human adipose-derived stem cells. Overall, our data suggest that CACUL1 tightly regulates PPARgamma signaling through the mutual opposition between SIRT1 and LSD1, providing insight into its potential use for anti-obesity treatment. PMID- 29233984 TI - Prodigious submarine landslides during the inception and early growth of volcanic islands. AB - Volcanic island inception applies large stresses as the ocean crust domes in response to magma ascension and is loaded by eruption of lavas. There is currently limited information on when volcanic islands are initiated on the seafloor, and no information regarding the seafloor instabilities island inception may cause. The deep sea Madeira Abyssal Plain contains a 43 million year history of turbidites among which many originate from mass movements in the Canary Islands. Here, we investigate the composition and timing of a distinctive group of turbidites that we suggest represent a new unique record of large-volume submarine landslides triggered during the inception, submarine shield growth, and final subaerial emergence of the Canary Islands. These slides are predominantly multi-stage and yet represent among the largest mass movements on the Earth's surface up to three or more-times larger than subaerial Canary Islands flank collapses. Thus whilst these deposits provide invaluable information on ocean island geodynamics they also represent a significant, and as yet unaccounted, marine geohazard. PMID- 29233983 TI - Endocytosis regulates TDP-43 toxicity and turnover. AB - Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease. ALS-affected motor neurons exhibit aberrant localization of a nuclear RNA binding protein, TDP-43, into cytoplasmic aggregates, which contributes to pathology via unclear mechanisms. Here, we demonstrate that TDP-43 turnover and toxicity depend in part upon the endocytosis pathway. TDP-43 inhibits endocytosis, and co localizes strongly with endocytic proteins, including in ALS patient tissue. Impairing endocytosis increases TDP-43 toxicity, aggregation, and protein levels, whereas enhancing endocytosis reverses these phenotypes. Locomotor dysfunction in a TDP-43 ALS fly model is also exacerbated and suppressed by impairment and enhancement of endocytic function, respectively. Thus, endocytosis dysfunction may be an underlying cause of ALS pathology. PMID- 29233985 TI - Mating system manipulation and the evolution of sex-biased gene expression in Drosophila. AB - Sex differences in dioecious animals are pervasive and result from gene expression differences. Elevated sexual selection has been predicted to increase the number and expression of male-biased genes, and experimentally imposing monogamy on Drosophila melanogaster has led to a relative feminisation of the transcriptome. Here, we test this hypothesis further by subjecting another polyandrous species, D. pseudoobscura, to 150 generations of experimental monogamy or elevated polyandry. We find that sex-biased genes do change in expression but, contrary to predictions, there is usually masculinisation of the transcriptome under monogamy, although this depends on tissue and sex. We also identify and describe gene expression changes following courtship experience. Courtship often influences gene expression, including patterns in sex-biased gene expression. Our results confirm that mating system manipulation disproportionately influences sex-biased gene expression but show that the direction of change is dynamic and unpredictable. PMID- 29233986 TI - Reproducible flaws unveil electrostatic aspects of semiconductor electrochemistry. AB - Predicting or manipulating charge-transfer at semiconductor interfaces, from molecular electronics to energy conversion, relies on knowledge generated from a kinetic analysis of the electrode process, as provided by cyclic voltammetry. Scientists and engineers encountering non-ideal shapes and positions in voltammograms are inclined to reject these as flaws. Here we show that non idealities of redox probes confined at silicon electrodes, namely full width at half maximum <90.6 mV and anti-thermodynamic inverted peak positions, can be reproduced and are not flawed data. These are the manifestation of electrostatic interactions between dynamic molecular charges and the semiconductor's space charge barrier. We highlight the interplay between dynamic charges and semiconductor by developing a model to decouple effects on barrier from changes to activities of surface-bound molecules. These findings have immediate general implications for a correct kinetic analysis of charge-transfer at semiconductors as well as aiding the study of electrostatics on chemical reactivity. PMID- 29233987 TI - Controlling supercurrents and their spatial distribution in ferromagnets. AB - Spin-triplet Cooper pairs induced in ferromagnets form the centrepiece of the emerging field of superconducting spintronics. Usually the focus is on the spin polarization of the triplets, potentially enabling low-dissipation magnetization switching. However, the magnetic texture which provides the fundamental mechanism for generating triplets also permits control over the spatial distribution of supercurrent. Here we demonstrate the tailoring of distinct supercurrent pathways in the ferromagnetic barrier of a Josephson junction. We combine micromagnetic simulations with three-dimensional supercurrent calculations to design a disk shaped structure with a ferromagnetic vortex which induces two transport channels across the junction. By using superconducting quantum interferometry, we show the existence of two channels. Moreover, we show how the supercurrent can be controlled by moving the vortex with a magnetic field. This approach paves the way for supercurrent paths to be dynamically reconfigured in order to switch between different functionalities in the same device. PMID- 29233988 TI - Comprehensive phase diagram of two-dimensional space charge doped Bi2Sr2CaCu2O8+x. AB - The phase diagram of hole-doped high critical temperature superconductors as a function of doping and temperature has been intensively studied with chemical variation of doping. Chemical doping can provoke structural changes and disorder, masking intrinsic effects. Alternatively, a field-effect transistor geometry with an electrostatically doped, ultra-thin sample can be used. However, to probe the phase diagram, carrier density modulation beyond 1014 cm-2 and transport measurements performed over a large temperature range are needed. Here we use the space charge doping method to measure transport characteristics from 330 K to low temperature. We extract parameters and characteristic temperatures over a large doping range and establish a comprehensive phase diagram for one-unit-cell-thick BSCCO-2212 as a function of doping, temperature and disorder. PMID- 29233989 TI - Round complexity in the local transformations of quantum and classical states. AB - In distributed quantum and classical information processing, spatially separated parties operate locally on their respective subsystems, but coordinate their actions through multiple exchanges of public communication. With interaction, the parties can perform more tasks. But how the exact number and order of exchanges enhances their operational capabilities is not well understood. Here we consider the minimum number of communication rounds needed to perform the locality constrained tasks of entanglement transformation and its classical analog of secrecy manipulation. We provide an explicit construction of both quantum and classical state transformations which, for any given r, can be achieved using r rounds of classical communication exchanges, but no fewer. To show this, we build on the common structure underlying both resource theories of quantum entanglement and classical secret key. Our results reveal that highly complex communication protocols are indeed necessary to fully harness the information-theoretic resources contained in general quantum and classical states. PMID- 29233990 TI - Balancing mcr-1 expression and bacterial survival is a delicate equilibrium between essential cellular defence mechanisms. AB - MCR-1 is a lipid A modifying enzyme that confers resistance to the antibiotic colistin. Here, we analyse the impact of MCR-1 expression on E. coli morphology, fitness, competitiveness, immune stimulation and virulence. Increased expression of mcr-1 results in decreased growth rate, cell viability, competitive ability and significant degradation in cell membrane and cytoplasmic structures, compared to expression of catalytically inactive MCR-1 (E246A) or MCR-1 soluble component. Lipopolysaccharide (LPS) extracted from mcr-1 strains induces lower production of IL-6 and TNF, when compared to control LPS. Compared to their parent strains, high-level colistin resistance mutants (HLCRMs) show reduced fitness (relative fitness is 0.41-0.78) and highly attenuated virulence in a Galleria mellonella infection model. Furthermore, HLCRMs are more susceptible to most antibiotics than their respective parent strains. Our results show that the bacterium is challenged to find a delicate equilibrium between expression of MCR-1-mediated colistin resistance and minimalizing toxicity and thus ensuring cell survival. PMID- 29233991 TI - Structure of outer membrane protein G in lipid bilayers. AB - beta-barrel proteins mediate nutrient uptake in bacteria and serve vital functions in cell signaling and adhesion. For the 14-strand outer membrane protein G of Escherichia coli, opening and closing is pH-dependent. Different roles of the extracellular loops in this process were proposed, and X-ray and solution NMR studies were divergent. Here, we report the structure of outer membrane protein G investigated in bilayers of E. coli lipid extracts by magic angle-spinning NMR. In total, 1847 inter-residue 1H-1H and 13C-13C distance restraints, 256 torsion angles, but no hydrogen bond restraints are used to calculate the structure. The length of beta-strands is found to vary beyond the membrane boundary, with strands 6-8 being the longest and the extracellular loops 3 and 4 well ordered. The site of barrel closure at strands 1 and 14 is more disordered than most remaining strands, with the flexibility decreasing toward loops 3 and 4. Loop 4 presents a well-defined helix. PMID- 29233993 TI - Publisher Correction: Enhanced generation and anisotropic Coulomb scattering of hot electrons in an ultra-broadband plasmonic nanopatch metasurface. AB - The originally published version of this Article contained an error in Equation 1. The two h terms were missing from this equation. This has now been corrected in the PDF and HTML versions of the Article. PMID- 29233992 TI - Global unleashing of transcription elongation waves in response to genotoxic stress restricts somatic mutation rate. AB - Complex molecular responses preserve gene expression accuracy and genome integrity in the face of environmental perturbations. Here we report that, in response to UV irradiation, RNA polymerase II (RNAPII) molecules are dynamically and synchronously released from promoter-proximal regions into elongation to promote uniform and accelerated surveillance of the whole transcribed genome. The maximised influx of de novo released RNAPII correlates with increased damage sensing, as confirmed by RNAPII progressive accumulation at dipyrimidine sites and by the average slow-down of elongation rates in gene bodies. In turn, this transcription elongation 'safe' mode guarantees efficient DNA repair regardless of damage location, gene size and transcription level. Accordingly, we detect low and homogenous rates of mutational signatures associated with UV exposure or cigarette smoke across all active genes. Our study reveals a novel advantage for transcription regulation at the promoter-proximal level and provides unanticipated insights into how active transcription shapes the mutagenic landscape of cancer genomes. PMID- 29233994 TI - Voltage-gated sodium channels assemble and gate as dimers. AB - Fast opening and closing of voltage-gated sodium channels are crucial for proper propagation of the action potential through excitable tissues. Unlike potassium channels, sodium channel alpha-subunits are believed to form functional monomers. Yet, an increasing body of literature shows inconsistency with the traditional idea of a single alpha-subunit functioning as a monomer. Here we demonstrate that sodium channel alpha-subunits not only physically interact with each other but they actually assemble, function and gate as a dimer. We identify the region involved in the dimerization and demonstrate that 14-3-3 protein mediates the coupled gating. Importantly we show conservation of this mechanism among mammalian sodium channels. Our study not only shifts conventional paradigms in regard to sodium channel assembly, structure, and function but importantly this discovery of the mechanism involved in channel dimerization and biophysical coupling could open the door to new approaches and targets to treat and/or prevent sodium channelopathies. PMID- 29233995 TI - Adeno-associated virus serotype rh10 is a useful gene transfer vector for sensory nerves that innervate bone in immunodeficient mice. AB - Adeno-associated virus (AAV) is frequently used to manipulate gene expression in the sensory nervous system for the study of pain mechanisms. Although some serotypes of AAV are known to have nerve tropism, whether AAV can distribute to sensory nerves that innervate the bone or skeletal tissue has not been shown. This information is crucial, since bone pain, including cancer-induced bone pain, is an area of high importance in pain biology. In this study, we found that AAVrh10 transduces neurons in the spinal cord and dorsal root ganglia of immunodeficient mice with higher efficacy than AAV2, 5, 6, 8, and 9 when injected intrathecally. Additionally, AAVrh10 has tropism towards sensory neurons in skeletal tissue, such as bone marrow and periosteum, while it occasionally reaches the sensory nerve fibers in the mouse footpad. Moreover, AAVrh10 has higher tropic affinity to large myelinated and small peptidergic sensory neurons that innervate bone, compared to small non-peptidergic sensory neurons that rarely innervate bone. Taken together, these results suggest that AAVrh10 is a useful gene delivery vector to target the sensory nerves innervating bone. This finding may lead to a greater understanding of the molecular mechanisms of chronic bone pain and cancer-induced bone pain. PMID- 29233996 TI - PEPD is a pivotal regulator of p53 tumor suppressor. AB - p53 tumor suppressor responds to various cellular stresses and regulates cell fate. Here, we show that peptidase D (PEPD) binds and suppresses over half of nuclear and cytoplasmic p53 under normal conditions, independent of its enzymatic activity. Eliminating PEPD causes cell death and tumor regression due to p53 activation. PEPD binds to the proline-rich domain in p53, which inhibits phosphorylation of nuclear p53 and MDM2-mediated mitochondrial translocation of nuclear and cytoplasmic p53. However, the PEPD-p53 complex is critical for p53 response to stress, as stress signals doxorubicin and H2O2 each must free p53 from PEPD in order to achieve robust p53 activation, which is mediated by reactive oxygen species. Thus, PEPD stores p53 for the stress response, but this also renders cells dependent on PEPD for survival, as it suppresses p53. This finding provides further understanding of p53 regulation and may have significant implications for the treatment of cancer and other diseases. PMID- 29233997 TI - Polymorphic design of DNA origami structures through mechanical control of modular components. AB - Scaffolded DNA origami enables the bottom-up fabrication of diverse DNA nanostructures by designing hundreds of staple strands, comprised of complementary sequences to the specific binding locations of a scaffold strand. Despite its exceptionally high design flexibility, poor reusability of staples has been one of the major hurdles to fabricate assorted DNA constructs in an effective way. Here we provide a rational module-based design approach to create distinct bent shapes with controllable geometries and flexibilities from a single, reference set of staples. By revising the staple connectivity within the desired module, we can control the location, stiffness, and included angle of hinges precisely, enabling the construction of dozens of single- or multiple hinge structures with the replacement of staple strands up to 12.8% only. Our design approach, combined with computational shape prediction and analysis, can provide a versatile and cost-effective procedure in the design of DNA origami shapes with stiffness-tunable units. PMID- 29233998 TI - Pulsed electroconversion for highly selective enantiomer synthesis. AB - Asymmetric synthesis of molecules is of crucial importance to obtain pure chiral compounds, which are of primary interest in many areas including medicine, biotechnology, and chemistry. Various methods have been used very successfully to increase the enantiomeric yield of reaction pathways, but there is still room for the development of alternative highly enantioselective reaction concepts, either as a scientific challenge of tremendous fundamental significance, or owing to the increasing demand for enantiopure products, e.g., in the pharmaceutical industry. In this context, we report here a strategy for the synthesis of chiral compounds, based on pulsed electrochemical conversion. We illustrate the approach with the stereospecific electroreduction of a prochiral model molecule at chiral mesoporous metal structures, resulting in an enantiomeric excess of over 90%. This change of paradigm opens up promising reaction schemes for the straightforward synthesis of high-added-value molecules. PMID- 29233999 TI - Multiplexed 3D super-resolution imaging of whole cells using spinning disk confocal microscopy and DNA-PAINT. AB - Single-molecule localization microscopy (SMLM) can visualize biological targets on the nanoscale, but complex hardware is required to perform SMLM in thick samples. Here, we combine 3D DNA points accumulation for imaging in nanoscale topography (DNA-PAINT) with spinning disk confocal (SDC) hardware to overcome this limitation. We assay our achievable resolution with two- and three dimensional DNA origami structures and demonstrate the general applicability by imaging a large variety of cellular targets including proteins, DNA and RNA deep in cells. We achieve multiplexed 3D super-resolution imaging at sample depths up to ~10 um with up to 20 nm planar and 80 nm axial resolution, now enabling DNA based super-resolution microscopy in whole cells using standard instrumentation. PMID- 29234001 TI - Revisiting unexploited antibiotics in search of new antibacterial drug candidates: the case of gamma-actinorhodin. AB - Of the thousands of natural product antibiotics discovered to date, only a handful have been developed for the treatment of bacterial infection. The clinically unexploited majority likely include compounds with untapped potential as antibacterial drugs, and in view of the ever-growing unmet medical need for such agents, warrant systematic re-evaluation. Here we revisit the actinorhodins, a class that was first reported 70 years ago, but which remains poorly characterized. We show that gamma-actinorhodin possesses many of the requisite properties of an antibacterial drug, displaying potent and selective bactericidal activity against key Gram-positive pathogens (including Staphylococcus aureus and enterococci), a mode of action distinct from that of other agents in clinical use, an extremely low potential for the development of resistance, and a degree of in vivo efficacy in an invertebrate model of infection. Our findings underscore the utility of revisiting unexploited antibiotics as a source of novel antibacterial drug candidates. PMID- 29234000 TI - Peritoneal tissue-resident macrophages are metabolically poised to engage microbes using tissue-niche fuels. AB - The importance of metabolism in macrophage function has been reported, but the in vivo relevance of the in vitro observations is still unclear. Here we show that macrophage metabolites are defined in a specific tissue context, and these metabolites are crucially linked to tissue-resident macrophage functions. We find the peritoneum to be rich in glutamate, a glutaminolysis-fuel that is exploited by peritoneal-resident macrophages to maintain respiratory burst during phagocytosis via enhancing mitochondrial complex-II metabolism. This niche supported, inducible mitochondrial function is dependent on protein kinase C activity, and is required to fine-tune the cytokine responses that control inflammation. In addition, we find that peritoneal-resident macrophage mitochondria are recruited to phagosomes and produce mitochondrially derived reactive oxygen species, which are necessary for microbial killing. We propose that tissue-resident macrophages are metabolically poised in situ to protect and exploit their tissue-niche by utilising locally available fuels to implement specific metabolic programmes upon microbial sensing. PMID- 29234002 TI - Dual-energy micro-CT for quantifying the time-course and staining characteristics of ex-vivo animal organs treated with iodine- and gadolinium-based contrast agents. AB - Chemical staining of soft-tissues can be used as a strategy to increase their low inherent contrast in X-ray absorption micro-computed tomography (micro-CT), allowing to obtain fast three-dimensional structural information of animal organs. Though some staining agents are commonly used in this context, little is known about the staining agents' ability to stain specific types of tissues; the times necessary to provide a sufficient contrast; and the effect of staining solution in distorting the tissue. Here we contribute to studies of animal organs (mouse heart and lungs) using staining combined with dual-energy micro-CT (DECT). DECT was used in order to obtain an additional quantitative measure for the amount of staining agents within the sample in 3D maps. Our results show that the two staining solutions used in this work diffuse differently in the tissues studied, the staining times of some tens of minutes already produce high-quality micro-CT images and, at the concentrations applied in this work, the staining solutions tested do not cause relevant tissue distortions. While one staining solution provides images of the general morphology of the organs, the other reveals organs' features in the order of a hundred micrometers. PMID- 29234003 TI - Systolic dysfunction associated with carfilzomib use in patients with multiple myeloma. PMID- 29234004 TI - Harmonic phase in polar liquids and spin ice. AB - Many liquid or liquid-like states remain stable down to temperatures well below the interaction energy scale, where mean-field theory predicts an ordering transition. In magnetism, correlated states such as spin ice and the spin liquid have been described as Coulomb phases, governed by an emergent gauge principle. In the physical chemistry of polar liquids, systems that evade mean field order have, in contrast, been described by Onsager's theory of the reaction field. Here we observe that in the low-temperature limit, Onsager's theory may be cast as a prototypical theory of the Coulomb phase. However at finite temperature, it describes a distinct geometrical state, characterised by harmonic functions. This state, labelled here the 'harmonic phase', is shown to occur experimentally in spin ice, a dipolar lattice system. It is suggested to be relevant to more general dipolar liquids. PMID- 29234006 TI - Enhancing size based size separation through vertical focus microfluidics using secondary flow in a ridged microchannel. AB - High throughput size based separation and sorting of bioparticles and cells is critical to a variety of biomedical processing steps for medical diagnostics and pharmaceutical purification. Improving microfluidic size-based particle/cell sorting is a challenge to better address the need for generating more homogeneous subpopulations for study and use. We propose a novel advance to microfluidic sorting devices that uses three-dimensional focusing of the sample to optimally position particles to amplify the size-dependent differences in trajectories caused by differential secondary flows. The result is an increase in the purity of small particles by 35- fold and large particles by 8-fold in comparison to unfocused flow. Our simulated and experimental data reveal for the first time that positioning particles in three-dimensional space can be used to better leverage the differential lateral movement of particles with different sizes as they flow in microchannel with transverse secondary flows. The focusing approach may also be useful to improve positioning of particles with inertial channels with multiple equilibrium positions. This technique performs continuous-flow, high throughput size based sorting of millions of particles and cells in a minute without any pre and post-processing. We have also demonstrated improved enrichment and recovery of white blood cells from human blood. PMID- 29234005 TI - Proteomic analyses identify ARH3 as a serine mono-ADP-ribosylhydrolase. AB - ADP-ribosylation is a posttranslational modification that exists in monomeric and polymeric forms. Whereas the writers (e.g. ARTD1/PARP1) and erasers (e.g. PARG, ARH3) of poly-ADP-ribosylation (PARylation) are relatively well described, the enzymes involved in mono-ADP-ribosylation (MARylation) have been less well investigated. While erasers for the MARylation of glutamate/aspartate and arginine have been identified, the respective enzymes with specificity for serine were missing. Here we report that, in vitro, ARH3 specifically binds and demodifies proteins and peptides that are MARylated. Molecular modeling and site directed mutagenesis of ARH3 revealed that numerous residues are critical for both the mono- and the poly-ADP-ribosylhydrolase activity of ARH3. Notably, a mass spectrometric approach showed that ARH3-deficient mouse embryonic fibroblasts are characterized by a specific increase in serine-ADP-ribosylation in vivo under untreated conditions as well as following hydrogen peroxide stress. Together, our results establish ARH3 as a serine mono-ADP-ribosylhydrolase and as an important regulator of the basal and stress-induced ADP-ribosylome. PMID- 29234007 TI - Insights into the structure and assembly of a bacterial cellulose secretion system. AB - Secreted exopolysaccharides present important determinants for bacterial biofilm formation, survival, and virulence. Cellulose secretion typically requires the concerted action of a c-di-GMP-responsive inner membrane synthase (BcsA), an accessory membrane-anchored protein (BcsB), and several additional Bcs components. Although the BcsAB catalytic duo has been studied in great detail, its interplay with co-expressed subunits remains enigmatic. Here we show that E. coli Bcs proteins partake in a complex protein interaction network. Electron microscopy reveals a stable, megadalton-sized macromolecular assembly, which encompasses most of the inner membrane and cytosolic Bcs components and features a previously unobserved asymmetric architecture. Heterologous reconstitution and mutational analyses point toward a structure-function model, where accessory proteins regulate secretion by affecting both the assembly and stability of the system. Altogether, these results lay the foundation for more comprehensive models of synthase-dependent exopolysaccharide secretion in biofilms and add a sophisticated secretory nanomachine to the diverse bacterial arsenal for virulence and adaptation. PMID- 29234008 TI - A modular synthesis of tetracyclic meroterpenoid antibiotics. AB - Stachyflin, aureol, smenoqualone, strongylin A, and cyclosmenospongine belong to a family of tetracyclic meroterpenoids, which, by nature of their unique molecular structures and various biological properties, have attracted synthetic and medicinal chemists alike. Despite their obvious biosynthetic relationship, only scattered reports on the synthesis and biological investigation of individual meroterpenoids have appeared so far. Herein, we report a highly modular synthetic strategy that enabled the synthesis of each of these natural products and 15 non-natural derivatives. The route employs an auxiliary controlled Diels-Alder reaction to enable the enantioselective construction of the decalin subunit, which is connected to variously substituted arenes by either carbonyl addition chemistry or sterically demanding sp2-sp3 cross-coupling reactions. The selective installation of either the cis- or trans-decalin stereochemistry is accomplished by an acid-mediated cyclization/isomerization reaction. Biological profiling reveals that strongylin A and a simplified derivative thereof have potent antibiotic activity against methicillin-resistant Staphylococcus aureus. PMID- 29234009 TI - Childhood behaviour problems show the greatest gap between DNA-based and twin heritability. AB - For most complex traits, DNA-based heritability ('SNP heritability') is roughly half that of twin-based heritability. A previous report from the Twins Early Development Study suggested that this heritability gap is much greater for childhood behaviour problems than for other domains. If true, this finding is important because SNP heritability, not twin heritability, is the ceiling for genome-wide association studies. With twice the sample size as the previous report, we estimated SNP heritabilities (N up to 4653 unrelated individuals) and compared them with twin heritabilities from the same sample (N up to 4724 twin pairs) for diverse domains of childhood behaviour problems as rated by parents, teachers, and children themselves at ages 12 and 16. For 37 behaviour problem measures, the average twin heritability was 0.52, whereas the average SNP heritability was just 0.06. In contrast, results for cognitive and anthropometric traits were more typical (average twin and SNP heritabilities were 0.58 and 0.28, respectively). Future research should continue to investigate the reasons why SNP heritabilities for childhood behaviour problems are so low compared with twin estimates, and find ways to maximise SNP heritability for genome-wide association studies. PMID- 29234010 TI - Loss of the molecular clock in myeloid cells exacerbates T cell-mediated CNS autoimmune disease. AB - The transcription factor BMAL1 is a core component of the molecular clock, regulating biological pathways that drive 24 h (circadian) rhythms in behaviour and physiology. The molecular clock has a profound influence on innate immune function, and circadian disruption is linked with increased incidence of multiple sclerosis (MS). However, the mechanisms underlying this association are unknown. Here we show that BMAL1 and time-of-day regulate the accumulation and activation of various immune cells in a CNS autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). In myeloid cells, BMAL1 maintains anti inflammatory responses and reduces T cell polarization. Loss of myeloid BMAL1 or midday immunizations to induce EAE create an inflammatory environment in the CNS through expansion and infiltration of IL-1beta-secreting CD11b+Ly6Chi monocytes, resulting in increased pathogenic IL-17+/IFN-gamma+ T cells. These findings demonstrate the importance of the molecular clock in modulating innate and adaptive immune crosstalk under autoimmune conditions. PMID- 29234011 TI - Multinational patterns of seasonal asymmetry in human movement influence infectious disease dynamics. AB - Seasonal variation in human mobility is globally ubiquitous and affects the spatial spread of infectious diseases, but the ability to measure seasonality in human movement has been limited by data availability. Here, we use mobile phone data to quantify seasonal travel and directional asymmetries in Kenya, Namibia, and Pakistan, across a spectrum from rural nomadic populations to highly urbanized communities. We then model how the geographic spread of several acute pathogens with varying life histories could depend on country-wide connectivity fluctuations through the year. In all three countries, major national holidays are associated with shifts in the scope of travel. Within this broader pattern, the relative importance of particular routes also fluctuates over the course of the year, with increased travel from rural to urban communities after national holidays, for example. These changes in travel impact how fast communities are likely to be reached by an introduced pathogen. PMID- 29234014 TI - Estimation of the molecular vibration of gases using electron microscopy. AB - Reactions in gaseous phases and at gas/solid interfaces are widely used in industry. Understanding of the reaction mechanism, namely where, when, and how these gaseous reactions proceed, is crucial for the development of further efficient reaction systems. To achieve such an understanding, it is indispensable to grasp the dynamic behavior of the gaseous molecules at the active site of the chemical reaction. However, estimation of the dynamic behavior of gaseous molecules in specific nanometer-scale regions is always accompanied by great difficulties. Here, we propose a method for the identification of the dynamic behavior of gaseous molecules using an electron spectroscopy observed with a transmission electron microscope in combination with theoretical calculations. We found that our method can successfully identify the dynamic behavior of some gaseous molecules, such as O2 and CH4, and the sensitivity of the method is affected by the rigidity of the molecule. The method has potential to measure the local temperature of gaseous molecules as well. The knowledge obtained from this technique is fundamental for further high resolution studies of gaseous reactions using electron microscopy. PMID- 29234013 TI - The Differentiation Stage of Transplanted Stem Cells Modulates Nerve Regeneration. AB - In regenerative medicine applications, the differentiation stage of implanted stem cells must be optimized to control cell fate and enhance therapeutic efficacy. We investigated the therapeutic potential of human induced pluripotent stem cell (iPSC)-derived cells at two differentiation stages on peripheral nerve regeneration. Neural crest stem cells (NCSCs) and Schwann cells (NCSC-SCs) derived from iPSCs were used to construct a tissue-engineered nerve conduit that was applied to bridge injured nerves in a rat sciatic nerve transection model. Upon nerve conduit implantation, the NCSC group showed significantly higher electrophysiological recovery at 1 month as well as better gastrocnemius muscle recovery at 5 months than the acellular group, but the NCSC-SC group didn't. Both transplanted NCSCs and NCSC-SCs interacted with newly-growing host axons, while NCSCs showed better survival rate and distribution. The transplanted NCSCs mainly differentiated into Schwann cells with no teratoma formation, and they secreted higher concentrations of brain-derived neurotrophic factor and nerve growth factor than NCSC-SCs. In conclusion, transplantation of iPSC-NCSCs accelerated functional nerve recovery with the involvement of stem cell differentiation and paracrine signaling. This study unravels the in vivo performance of stem cells during tissue regeneration, and provides a rationale of using appropriate stem cells for regenerative medicine. PMID- 29234012 TI - Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors. AB - Smad transcription factors activated by TGF-beta or by BMP receptors form trimeric complexes with Smad4 to target specific genes for cell fate regulation. The CAGAC motif has been considered as the main binding element for Smad2/3/4, whereas Smad1/5/8 have been thought to preferentially bind GC-rich elements. However, chromatin immunoprecipitation analysis in embryonic stem cells showed extensive binding of Smad2/3/4 to GC-rich cis-regulatory elements. Here, we present the structural basis for specific binding of Smad3 and Smad4 to GC-rich motifs in the goosecoid promoter, a nodal-regulated differentiation gene. The structures revealed a 5-bp consensus sequence GGC(GC)|(CG) as the binding site for both TGF-beta and BMP-activated Smads and for Smad4. These 5GC motifs are highly represented as clusters in Smad-bound regions genome-wide. Our results provide a basis for understanding the functional adaptability of Smads in different cellular contexts, and their dependence on lineage-determining transcription factors to target specific genes in TGF-beta and BMP pathways. PMID- 29234015 TI - High-Resolution Single Particle Zeta Potential Characterisation of Biological Nanoparticles using Tunable Resistive Pulse Sensing. AB - Physicochemical properties of nanoparticles, such as size, shape, surface charge, density, and porosity play a central role in biological interactions and hence accurate determination of these characteristics is of utmost importance. Here we propose tunable resistive pulse sensing for simultaneous size and surface charge measurements on a particle-by-particle basis, enabling the analysis of a wide spectrum of nanoparticles and their mixtures. Existing methodologies for measuring zeta potential of nanoparticles using resistive pulse sensing are significantly improved by including convection into the theoretical model. The efficacy of this methodology is demonstrated for a range of biological case studies, including measurements of mixed anionic, cationic liposomes, extracellular vesicles in plasma, and in situ time study of DNA immobilisation on the surface of magnetic nanoparticles. The high-resolution single particle size and zeta potential characterisation will provide a better understanding of nano bio interactions, positively impacting nanomedicine development and their regulatory approval. PMID- 29234016 TI - Activity-Dependent Regulation of Alternative Cleavage and Polyadenylation During Hippocampal Long-Term Potentiation. AB - Long-lasting forms of synaptic plasticity that underlie learning and memory require new transcription and translation for their persistence. The remarkable polarity and compartmentalization of neurons raises questions about the spatial and temporal regulation of gene expression within neurons. Alternative cleavage and polyadenylation (APA) generates mRNA isoforms with different 3' untranslated regions (3'UTRs) and/or coding sequences. Changes in the 3'UTR composition of mRNAs can alter gene expression by regulating transcript localization, stability and/or translation, while changes in the coding sequences lead to mRNAs encoding distinct proteins. Using specialized 3' end deep sequencing methods, we undertook a comprehensive analysis of APA following induction of long-term potentiation (LTP) of mouse hippocampal CA3-CA1 synapses. We identified extensive LTP-induced APA changes, including a general trend of 3'UTR shortening and activation of intronic APA isoforms. Comparison with transcriptome profiling indicated that most APA regulatory events were uncoupled from changes in transcript abundance. We further show that specific APA regulatory events can impact expression of two molecules with known functions during LTP, including 3'UTR APA of Notch1 and intronic APA of Creb1. Together, our results reveal that activity-dependent APA provides an important layer of gene regulation during learning and memory. PMID- 29234017 TI - Protein quantitative trait locus study in obesity during weight-loss identifies a leptin regulator. AB - Thousands of genetic variants have been associated with complex traits through genome-wide association studies. However, the functional variants or mechanistic consequences remain elusive. Intermediate traits such as gene expression or protein levels are good proxies of the metabolic state of an organism. Proteome analysis especially can provide new insights into the molecular mechanisms of complex traits like obesity. The role of genetic variation in determining protein level variation has not been assessed in obesity. To address this, we design a large-scale protein quantitative trait locus (pQTL) analysis based on a set of 1129 proteins from 494 obese subjects before and after a weight loss intervention. This reveals 55 BMI-associated cis-pQTLs and trans-pQTLs at baseline and 3 trans-pQTLs after the intervention. We provide evidence for distinct genetic mechanisms regulating BMI-associated proteins before and after weight loss. Finally, by functional analysis, we identify and validate FAM46A as a trans regulator for leptin. PMID- 29234018 TI - Dynamics of RIF1 SUMOylation is regulated by PIAS4 in the maintenance of Genomic Stability. AB - RIF1 plays a key role in inhibiting DNA end resection and promoting NHEJ mediated DNA double stand break repair in G1. However, whether SUMOlyation may regulate RIF1 functions is still largely unknown. Here, we report that RIF1 is SUMOlyated in response to DNA damage. We identified PIAS4 as the primary SUMO E3 ligase required for the SUMOylation of RIF1 protein. Mammalian cells compromised of PIAS4 expression, show impaired RIF1 SUMOylation and defective for the disassembly of DNA damage responsive RIF1 foci. Mechanistically, we show that PIAS4 knockdown abrogates UHRF1-dependent ubiquitination of RIF1, compromising RIF1 protein turnover. We detected intense RPA foci that colocalize with RIF1 foci in PIAS4 knockdown cells. These data highlight an important role of PIAS4 dependent regulation of RIF1, likely mediated by SUMOylation, in the disassembly of RIF1 DNA damage response (DDR) foci. We propose that unresolved RIF1 protein at sites of DNA damage in PIAS4-depleted cells largely accumulates in S phase, and subsequently leads to DNA double strand breaks. Therefore, PIAS4 promotes genomic stability by regulating the timely removal of RIF1 from sites of DNA damage. PMID- 29234019 TI - Analysis of the cervical microbiome and potential biomarkers from postpartum HIV positive women displaying cervical intraepithelial lesions. AB - The cervical microbiota composition and diversity of HIV-positive women in the postpartum period is unknown. Using a high-throughput bacterial 16S rRNA gene sequencing, we identified four community state types (CSTs). CST III (Lactobacillusdominant) and CST IV (IV-A, IV-B.1, IV-B.2; high-diversity) were found in 41% and 59% of samples, respectively. We did not find association of any CST to postpartum period (six or twelve months), HPV infection or cytology (normal or lesion). However, five bacterial genera were associated with cervical lesions (Gardnerella, Aerococcus, Schlegelella, Moryella and Bifidobacterium), with significant odds ratio (OR) of 40 (2.28-706) for the presence of Moryella and 3.5 (1.36-8.9) for Schlegelella. Longitudinal analysis of samples at postpartum that regressed (lesion to normal), progressed (normal to lesion) and maintained the cytology (lesion or normal) evidenced Gardnerella with a significantly higher abundance in regressing lesions. In the current study, we report the first data on the cervical microbiota of HIV-positive women in the postpartum period. Consistent with previous studies of HIV-negative cohorts, HIV positive women present a stable cervical microbiota of high-diversity in the postpartum period. Our results highlight that specific microbiota species may serve as sensors for changes in the cervical microenvironment associated with cervical lesions. PMID- 29234020 TI - From Discovery to Translation: Characterization of C-Mannosyltryptophan and Pseudouridine as Markers of Kidney Function. AB - Using a non-targeted metabolomics platform, we recently identified C mannosyltryptophan and pseudouridine as non-traditional kidney function markers. The aims of this study were to obtain absolute concentrations of both metabolites in blood and urine from individuals with and without CKD to provide reference ranges and to assess their fractional excretions (FE), and to assess the agreement with their non-targeted counterparts. In individuals without/with CKD, mean plasma and urine concentrations for C-mannosyltryptophan were 0.26/0.72 umol/L and 3.39/4.30 umol/mmol creatinine, respectively. The respective concentrations for pseudouridine were 2.89/5.67 umol/L and 39.7/33.9 umol/mmol creatinine. Median (25th, 75th percentiles) FEs were 70.8% (65.6%, 77.8%) for C mannosyltryptophan and 76.0% (68.6%, 82.4%) for pseudouridine, indicating partial net reabsorption. Association analyses validated reported associations between single metabolites and eGFR. Targeted measurements of both metabolites agreed well with the non-targeted measurements, especially in urine. Agreement for composite nephrological measures FE and urinary metabolite-to-creatinine ratio was lower, but could be improved by replacing non-targeted creatinine measurements with a standard clinical creatinine test. In summary, targeted quantification and additional characterization in relevant populations are necessary steps in the translation of non-traditional biomarkers in nephrology from non-targeted discovery to clinical application. PMID- 29234022 TI - Ringing phenomenon based measurement of weak mode-coupling strength in an optical microresonator. AB - There is always a coupling between the degenerate clockwise (CW) and counter clockwise (CCW) modes in a whisperinggallery- mode (WGM) optical microresonator, since the surface of the microresonator can not be perfectly smooth. It is important to measure this coupling strength in many applications. When the coupling strength is strong, the conventional method by observing mode splitting in the stationary spectrum can be used to measure its value. However, when the coupling strength is weak, the conventional method will not work. We experimentally demonstrate that the ringing phenomenon can be used to measure weak coupling strength between the CW and CCW modes in a WGM optical microresonator. PMID- 29234021 TI - Workflow assessing the effect of gait alterations on stresses in the medial tibial cartilage - combined musculoskeletal modelling and finite element analysis. AB - Knee osteoarthritis (KOA) is most common in the medial tibial compartment. We present a novel method to study the effect of gait modifications and lateral wedge insoles (LWIs) on the stresses in the medial tibial cartilage by combining musculoskeletal (MS) modelling with finite element (FE) analysis. Subject's gait was recorded in a gait laboratory, walking normally, with 5 degrees and 10 degrees LWIs, toes inward ('Toe in'), and toes outward ('Toe out wide'). A full lower extremity MRI and a detailed knee MRI were taken. Bones and most soft tissues were segmented from images, and the generic bone architecture of the MS model was morphed into the segmented bones. The output forces from the MS model were then used as an input in the FE model of the subject's knee. During stance, LWIs failed to reduce medial peak pressures apart from Insole 10 degrees during the second peak. Toe in reduced peak pressures by -11% during the first peak but increased them by 12% during the second. Toe out wide reduced peak pressures by 15% during the first and increased them by 7% during the second. The results show that the work flow can assess the effect of interventions on an individual level. In the future, this method can be applied to patients with KOA. PMID- 29234023 TI - Discriminating single-bacterial shape using low-aspect-ratio pores. AB - Conventional concepts of resistive pulse analysis is to discriminate particles in liquid by the difference in their size through comparing the amount of ionic current blockage. In sharp contrast, we herein report a proof-of-concept demonstration of the shape sensing capability of solid-state pore sensors by leveraging the synergy between nanopore technology and machine learning. We found ionic current spikes of similar patterns for two bacteria reflecting the closely resembled morphology and size in an ultra-low thickness-to-diameter aspect-ratio pore. We examined the feasibility of a machine learning strategy to pattern analyse the sub-nanoampere corrugations in each ionic current waveform and identify characteristic electrical signatures signifying nanoscopic differences in the microbial shape, thereby demonstrating discrimination of single-bacterial cells with accuracy up to 90%. This data-analytics-driven microporescopy capability opens new applications of resistive pulse analyses for screening viruses and bacteria by their unique morphologies at a single-particle level. PMID- 29234024 TI - Patterns of biophonic periodicity on coral reefs in the Great Barrier Reef. AB - The coral reefs surrounding Lizard Island in the Great Barrier Reef have a diverse soundscape that contains an array of bioacoustic phenomena, notably choruses produced by fishes. Six fish choruses identified around Lizard Island exhibited distinctive spatial and temporal patterns from 2014 to 2016. Several choruses displayed site fidelity, indicating that particular sites may represent important habitat for fish species, such as fish spawning aggregations sites. The choruses displayed a broad range of periodicities, from diel to annual, which provides new insights into the ecology of vocalising reef fish species and the surrounding ecosystem. All choruses were affected by one or more environmental variables including temperature and moonlight, the latter of which had a significant influence on the timing and received sound levels. These findings highlight the utility of passive acoustic tools for long-term monitoring and management of coral reefs, which is highly relevant in light of recent global disturbance events, particularly coral bleaching. PMID- 29234025 TI - H3K14ac is linked to methylation of H3K9 by the triple Tudor domain of SETDB1. AB - SETDB1 is an essential H3K9 methyltransferase involved in silencing of retroviruses and gene regulation. We show here that its triple Tudor domain (3TD) specifically binds to doubly modified histone H3 containing K14 acetylation and K9 methylation. Crystal structures of 3TD in complex with H3K14ac/K9me peptides reveal that peptide binding and K14ac recognition occurs at the interface between Tudor domains (TD) TD2 and TD3. Structural and biochemical data demonstrate a pocket switch mechanism in histone code reading, because K9me1 or K9me2 is preferentially recognized by the aromatic cage of TD3, while K9me3 selectively binds to TD2. Mutations in the K14ac/K9me binding sites change the sub-nuclear localization of 3TD. ChIP-seq analyses show that SETDB1 is enriched at H3K9me3 regions and K9me3/K14ac is enriched at SETDB1 binding sites overlapping with LINE elements, suggesting that recruitment of the SETDB1 complex to K14ac/K9me regions has a role in silencing of active genomic regions. PMID- 29234026 TI - Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state. AB - Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimer's disease the amyloid-beta peptide (Abeta) misfolds into neurotoxic oligomers and assembles into amyloid fibrils. The Bri2 protein associated with Familial British and Danish dementias contains a BRICHOS domain, which reduces Abeta fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible non-fibrillar aggregation. How these different activities are mediated is not known. Here we show that Bri2 BRICHOS monomers potently prevent neuronal network toxicity of Abeta, while dimers strongly suppress Abeta fibril formation. The dimers assemble into high-molecular-weight oligomers with an apparent two-fold symmetry, which are efficient inhibitors of non-fibrillar protein aggregation. These results indicate that Bri2 BRICHOS affects qualitatively different aspects of protein misfolding and toxicity via different quaternary structures, suggesting a means to generate molecular chaperone diversity. PMID- 29234027 TI - High efficiency and long-term intracellular activity of an enzymatic nanofactory based on metal-organic frameworks. AB - Enhancing or restoring enzymatic function in cells is highly desirable in applications ranging from ex vivo cellular manipulations to enzyme replacement therapies in humans. However, because enzymes degrade in biological milieus, achieving long-term enzymatic activities can be challenging. Herein we report on the in cellulo properties of nanofactories that consist of antioxidative enzymes encapsulated in metal-organic frameworks (MOFs). We demonstrate that, while free enzymes display weak activities for only a short duration, these efficient nanofactories protect human cells from toxic reactive oxygen species for up to a week. Remarkably, these results are obtained in spite of the nanofactories being localized in lysosomes, acidic organelles that contain a variety of proteases. The long-term persistence of the nanofactories is attributed to the chemical stability of MOF in low pH environment and to the protease resistance provided by the protective cage formed by the MOF around the encapsulated enzymes. PMID- 29234029 TI - Electron nematic effect induced by magnetic field in antiferroquadrupole phase of CeB 6. AB - Spatial anisotropy generated spontaneously in the translationally invariant metallic phase, i.e. electron nematic effect, addresses a great challenge for both experimentalists and theoreticians. An interesting option for the realization of the electron nematic phase is provided by the system with orbital ordering, as long as both orbitally ordered states and electron nematic phases possess broken spatial symmetry. Here we report the detailed study of the angular dependences of the magnetoresistance in the orbitally ordered antiferroquadrupole (AFQ) phase of CeB6. Our data allowed revealing the electron nematic effect, which develops when magnetic field exceeds a critical value of 0.3-0.5T. As a result, new transition inside the AFQ phase corresponding to the change of the symmetry of magnetic scattering on spin fluctuations in CeB6 is discovered. PMID- 29234028 TI - The representation of colored objects in macaque color patches. AB - An important question about color vision is how does the brain represent the color of an object? The recent discovery of "color patches" in macaque inferotemporal (IT) cortex, the part of the brain responsible for object recognition, makes this problem experimentally tractable. Here we recorded neurons in three color patches, middle color patch CLC (central lateral color patch), and two anterior color patches ALC (anterior lateral color patch) and AMC (anterior medial color patch), while presenting images of objects systematically varied in hue. We found that all three patches contain high concentrations of hue selective cells, and that the three patches use distinct computational strategies to represent colored objects: while all three patches multiplex hue and shape information, shape-invariant hue information is much stronger in anterior color patches ALC/AMC than CLC. Furthermore, hue and object shape specifically for primate faces/bodies are over-represented in AMC, but not in the other two patches. PMID- 29234030 TI - Escherichia coli outer membrane vesicles can contribute to sepsis induced cardiac dysfunction. AB - Sepsis induced cardiac dysfunction (SIC) is a severe complication to sepsis which significantly worsens patient outcomes. It is known that bacteria have the capacity to release outer membrane vesicles (OMVs), which are nano-sized bilayered vesicles composed of lipids and proteins, that can induce a fatal inflammatory response. The aim of this study was to determine whether OMVs from a uropathogenic Escherichia coli strain can induce cardiac dysfunction, and to elucidate any mechanisms involved. OMVs induced irregular Ca2+ oscillations with a decreased frequency in cardiomyocytes through recordings of intracellular Ca2+ dynamics. Mice were intraperitoneally injected with bacteria-free OMVs, which resulted in increased concentration of pro-inflammatory cytokine levels in blood. Cytokines were increased in heart lysates, and OMVs could be detected in the heart after OMVs injection. Troponin T was significantly increased in blood, and echocardiography showed increased heart wall thickness as well as increased heart rate. This study shows that E. coli OMVs induce cardiac injury in vitro and in vivo, in the absence of bacteria, and may be a causative microbial signal in SIC. The role of OMVs in clinical disease warrant further studies, as bacterial OMVs in addition to live bacteria may be good therapeutic targets to control sepsis. PMID- 29234031 TI - Modelling of the impact of universal added sugar reduction through food reformulation. AB - Food reformulation has been suggested to be one of the strategies to reduce population added sugar (AS) intake. This study aims to investigate the untested assumption that a reduction in AS through reformulation will result in a reduction in population intakes of AS and energy. Plausible dietary data from 4,140 respondents of an Australian national nutrition survey were used. Dietary modelling was performed at AS reductions of 10%, 15%, and 25% using four strategies: simple removal of AS or replacement with non-nutritive sweeteners (NNS), and replacement of AS with NNS and either: polyols, 50% fibres or 50% maltodextrin. Paired t-tests were conducted to compare the intake of energy, fat, and AS pre- and post-reformulation. The chosen reformulation strategies resulted in a projected reduction in AS and energy, with the greatest reduction found in 25% reformulation which was the highest level modelled. The overall projected mean (SD) reduction in energy and AS after 25% reformulation was 114 (92) kJ/day and 11.73 (7.52) g/day, p < 0.001. To conclude, product reformulation may be a potentially useful strategy for reducing AS intake. Although the magnitude of projected reduction was small at the individual level, the impact may be meaningful at a population level. PMID- 29234032 TI - Heat Failure Phenotypes Induced by Knockdown of DAPIT in Zebrafish: A New Insight into Mechanism of Dilated Cardiomyopathy. AB - The pathogenesis of heart failure associated with dilated cardiomyopathy (DCM) may result in part from adenosine triphosphate (ATP) dysregulation in the myocardium. Under these conditions, diabetes-associated protein in insulin sensitive tissue (DAPIT), which is encoded by the upregulated during skeletal muscle growth 5 (USMG5) gene, plays a crucial role in energy production by mitochondrial ATP synthase. To determine whether USMG5 is related to the development of heart failure, we performed clinical and experimental studies. Microarray analysis showed that the expression levels of USMG5 were positively correlated with those of natriuretic peptide precursor A in the human failed myocardium. When endogenous z-usmg5 in zebrafish was disrupted using morpholino (MO) oligonucleotides, the pericardial sac and atrial areas were larger and ventricular fractional shortening was reduced compared to in the control MO group. The expression levels of natriuretic peptides were upregulated in the z usmg5 MO group compared to in controls. Further, microarray analysis revealed that genes in the calcium signalling pathway were downregulated in the z-usmg5 MO group. These results demonstrate that DAPIT plays a crucial role in the development of heart failure associated with DCM and thus may be a therapeutic target for heart failure. PMID- 29234033 TI - lncTCF7 is a negative prognostic factor, and knockdown of lncTCF7 inhibits migration, proliferation and tumorigenicity in glioma. AB - Long noncoding RNAs (lncRNAs) have been shown to play critical roles in cancer. lncTCF7 (gene symbol: WSPAR) has been reported to maintain stemness in hepatocellular carcinoma (HCC) stem cells. However, little is known about the role of lncTCF7 in glioma. The aim of this study was to identify the role of lncTCF7 in the pathogenesis of glioma. We analysed the relationship of lncTCF7 expression with clinicopathological characteristics in glioma patients. Our results showed that lncTCF7 expression was increased in glioma tissues compared with that in normal brain tissues (P < 0.001). Moreover, lncTCF7 was significantly associated with WHO grade (I-II vs. III-IV; P = 0.006) and tumour size (<3 cm vs. T >= 3 cm; P = 0.025). Meanwhile, patients with high lncTCF7 expression levels exhibited markedly worse overall survival prognoses (P < 0.01). Loss of function assays revealed that knockdown of lncTCF7 significantly inhibited glioma cell migration, proliferation and tumorigenicity in vitro and in vivo. Furthermore, we found that hypoxia induced lncTCF7 expression in an autocrine manner through IL-6 in glioma. In conclusion, lncTCF7 may play a vital role in glioma progression and serves as a potential prognostic biomarker in glioma patients, providing new targets for glioma therapy. PMID- 29234034 TI - Electrochemical Production of Glycolic Acid from Oxalic Acid Using a Polymer Electrolyte Alcohol Electrosynthesis Cell Containing a Porous TiO2 Catalyst. AB - A liquid flow-type electrolyser that continuously produces an alcohol from a carboxylic acid was constructed by employing a polymer electrolyte, named a polymer electrolyte alcohol electrosynthesis cell (PEAEC). Glycolic acid (GC, an alcoholic compound) is generated on anatase TiO2 catalysts via four-electron reduction of oxalic acid (OX, a divalent carboxylic acid), accompanied with water oxidation, which achieves continuous electric power storage in easily stored GC. Porous anatase TiO2 directly grown on Ti mesh (TiO2/Ti-M) or Ti felt (TiO2/Ti-F) was newly fabricated as a cathode having favourable substrate diffusivity. A membrane-electrode assembly composed of the TiO2/Ti-M, Nafion 117, and an IrO2 supported on a gas-diffusion carbon electrode (IrO2/C) was applied to the PEAEC. We achieved a maximum energy conversion efficiency of 49.6% and a continuous 99.8% conversion of 1 M OX, which is an almost saturated aqueous solution at room temperature. PMID- 29234035 TI - Publisher Correction: Precision cosmology from future lensed gravitational wave and electromagnetic signals. AB - The original PDF version of this Article inadvertently highlighted the author surnames and omitted the publication date. These have now been corrected in the PDF version of the Article. The HTML version was correct from the time of publication. PMID- 29234036 TI - Laboratory layered latte. AB - Inducing thermal gradients in fluid systems with initial, well-defined density gradients results in the formation of distinct layered patterns, such as those observed in the ocean due to double-diffusive convection. In contrast, layered composite fluids are sometimes observed in confined systems of rather chaotic initial states, for example, lattes formed by pouring espresso into a glass of warm milk. Here, we report controlled experiments injecting a fluid into a miscible phase and show that, above a critical injection velocity, layering emerges over a time scale of minutes. We identify critical conditions to produce the layering, and relate the results quantitatively to double-diffusive convection. Based on this understanding, we show how to employ this single-step process to produce layered structures in soft materials, where the local elastic properties vary step-wise along the length of the material. PMID- 29234037 TI - Dynamic regulation of TREK1 gating by Polycystin 2 via a Filamin A-mediated cytoskeletal Mechanism. AB - Mechanosensing is essential for several physiological functions including touch and pain sensations, osmoregulation, and controlling the myogenic tone of resistance arteries. Understanding how mechanosensitive ion channels (MSCs) are gated can provide important information regarding these processes. We have previously demonstrated that during pathological conditions such as polycystic kidney disease, polycystin 2 (TRPP2) inhibits the activity of potassium-selective MSCs through a filamin A-mediated cytoskeletal effect, and renders tubular epithelial cells susceptible to apoptosis. However, the nature of this cytoskeletal inhibition remains poorly understood. In this study we use a combination of electrophysiology, structured illumination microscopy, and fluorescence recovery after photobleaching (FRAP) to examine the dynamic nature of the TRPP2-mediated cytoskeletal inhibition of the potassium-selective MSC TREK1. Our data indicate that this inhibition of MSC activity occurs through an accelerated cytoskeletal inhibition, and ultimately decreases the open probability of the TREK1 channel. These results shed light on a novel mode of regulation of MSCs gating, which may be at play in several physiological functions. PMID- 29234038 TI - Sodium tanshinone IIA sulfate adjunct therapy reduces high-sensitivity C-reactive protein level in coronary artery disease patients: a randomized controlled trial. AB - High-sensitivity C-reactive protein (hs-CRP) is independently associated with cardiovascular events in coronary artery disease (CAD) patients and reducing the hs-CRP level may further benefit this population. We conduct this parallel design, randomized-controlled trial to assess the effectiveness of adjunct sodium tanshinone IIA sulfate (STS) therapy on circulating inflammation markers in CAD patients. Unstable angina or non-ST-elevation myocardial infarction patients with increased hs-CRP level were randomly assigned to atorvastatin-based standard medical therapy or standard therapy plus STS injection (80 mg, once daily for 14 consecutive days). The primary outcome was hs-CRP level. After the 14-day treatment, the experimental group (n = 35) exhibited significantly lower levels of hs-CRP than the control group (n = 35) (1.72 vs 3.20 mg/L, p = 0.0191). Lower levels of interleukin-6, monocyte chemotactic protein-1 (MCP-1), and soluble CD40 ligand were also observed in the experimental group. Angina symptoms were also better controlled in the experimental group. At 30 days after treatment completion, MCP-1 levels remained lower in the experimental group than in the control group (313.88 vs 337.91 pg/mL, p = 0.0078). No serious adverse events occurred. Our study demonstrates that on the basis of standard medical therapy, STS further reduce elevated hs-CRP and other circulating inflammation markers in CAD patients. (Chictr.org number: ChiCTR-TRC-12002361). PMID- 29234039 TI - Forming quasicrystals by monodisperse soft core particles. AB - In traditional approaches to form quasicrystals, multiple competing length scales involved in particle size, shape, or interaction potential are believed to be necessary. It is unexpected that quasicrystals can be formed by monodisperse, isotropic particles interacting via a simple potential that does not contain explicit multiple length scales to stabilize quasicrystals. Here, we report the surprising finding of the formation of such quasicrystals in high-density systems of soft-core particles. Although there are length scales naturally introduced in our model systems, they do not establish the quasicrystalline order. In two dimensions, we find not only dodecagonal but also octagonal quasicrystals, which have not been found yet in soft quasicrystals. In such unexpected quasicrystals, particles tend to form pentagons, which are essential elements to develop the quasicrystalline order. Our findings thus pave an unexpected and simple way to form quasicrystals and pose a challenge for theoretical understanding of quasicrystals. PMID- 29234040 TI - Efficacy and safety of stereotactic radiosurgery for pulmonary metastases from osteosarcoma: Experience in 73 patients. AB - Osteosarcoma pulmonary metastases are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic radiosurgery (SRS) can be an alternative to surgery that can achieve high rates of local control with limited toxicity. From January 2005 to December 2013, 73 patients who developed pulmonary metastasis during period of adjuvant chemotherapy or follow-up were analyzed. 33 patients were treated by stereotactic radiosurgery using the body gamma-knife system. A total dose of 50 Gy was delivered at 5 Gy/fraction to the 50% isodose line covering the planning target volume, whereas a total dose of 70 Gy was delivered at 7 Gy/fraction to the gross target volume. The other 40 patients were treated by surgical resection. Four-year progression-free survival rate, four year survival rate, median time of PRPFS (post-relapse progress-free survival) and PROS (post-relapse overall survival) in SRS group were parallel to that in surgical group. Patients tolerated gamma knife radiosurgery well. Our study demonstrates that SRS is well-tolerated with excellent local control and less complications. SRS should be considered as a potential option in patients with pulmonary metastases from osteosarcoma, especially in those who are medically inoperable, refuse surgery. PMID- 29234041 TI - Evolution of a flipped pathway creates metabolic innovation in tomato trichomes through BAHD enzyme promiscuity. AB - Plants produce hundreds of thousands of structurally diverse specialized metabolites via multistep biosynthetic networks, including compounds of ecological and therapeutic importance. These pathways are restricted to specific plant groups, and are excellent systems for understanding metabolic evolution. Tomato and other plants in the nightshade family synthesize protective acylated sugars in the tip cells of glandular trichomes on stems and leaves. We describe a metabolic innovation in wild tomato species that contributes to acylsucrose structural diversity. A small number of amino acid changes in two acylsucrose acyltransferases alter their acyl acceptor preferences, resulting in reversal of their order of reaction and increased product diversity. This study demonstrates how small numbers of amino acid changes in multiple pathway enzymes can lead to diversification of specialized metabolites in plants. It also highlights the power of a combined genetic, genomic and in vitro biochemical approach to identify the evolutionary mechanisms leading to metabolic novelty. PMID- 29234042 TI - cfDNA correlates with endothelial damage after cardiac surgery with prolonged cardiopulmonary bypass and amplifies NETosis in an intracellular TLR9-independent manner. AB - Cardiopulmonary bypass (CPB) provokes inflammation culminating in organ dysfunction and increased mortality. Recently, neutrophil extracellular traps (NETs) have been found to be involved in a variety of cardiovascular diseases promoting tissue and organ injury. Here, we aimed to elaborate the proinflammatory potential of circulating cell-free (cf)DNA in patients undergoing cardiac surgery with CPB. Plasma was collected pre- and postoperatively as well as at d1, d3, d5 and d8 after surgery. At d1, we found circulating cfDNA levels to be significantly increased in patients with prolonged CPB duration (>100 min) when compared to those with shorter CPB times (CPB < 100 min). Increased CPB duration yielded in higher levels of circulating mitochondrial (mt)DNA, soluble thrombomodulin (sCD141) and ICAM-1, reflecting endothelial damage. Positive correlation between cfDNA and sCD141 was demonstrated at all time points. Plasma and cfDNA from patients with CPB > 100 min induced NETs release by neutrophils from healthy donors which was not suppressed by inhibitors of intracellular toll like receptor (TLR)9. DNA binding to neutrophils' surface (s)TLR9 has been evidenced. Altogether, we demonstrate that elevated plasma cfDNA might be useful to assess CPB-mediated detrimental effects, including endothelial damage, in cardiac surgical patients with prolonged CPB duration. cfDNA-triggered NETosis is independent of classical TLR9 signaling. PMID- 29234044 TI - A reduced cell-based phase model for tissue polarity alignment through global anisotropic cues. AB - Ordered polarity alignment of cell populations plays vital roles in biology, such as in hair follicle alignment and asymmetric cell division. Although cell polarity is uniformly oriented along a tissue axis in many tissues, its mechanism is not well understood. In this paper, we propose a theoretical framework to understand the generic dynamical properties of polarity alignment in interacting cellular units, where each cell is described by a reaction-diffusion system, and the cells further interact with one another through the contacting surfaces between them. Using a perturbation method under the assumption of weak coupling between cells, we derive a reduced model in which polarity of each cell is described by only one variable. Essential dynamical properties including the effects of cell shape, coupling heterogeneity, external signal and noise can be clarified analytically. In particular, we show that the anisotropicity of the system, such as oriented cell elongation and axial asymmetry in the coupling strength, can serve as a global cue that drives the uniform orientation of cell polarity along a certain axis. Our study bridges the gap between detailed and phenomenological models, and it is expected to facilitate the study of polarity dynamics in various nonequilibrium systems. PMID- 29234043 TI - Multipulse sodium magnetic resonance imaging for multicompartment quantification: Proof-of-concept. AB - We present a feasibility study of sodium quantification in a multicompartment model of the brain using sodium (23Na) magnetic resonance imaging. The proposed method is based on a multipulse sequence acquisition and simulation at 7 T, which allows to differentiate the 23Na signals emanating from three compartments in human brain in vivo: intracellular (compartment 1), extracellular (compartment 2), and cerebrospinal fluid (compartment 3). The intracellular sodium concentration C 1 and the volume fractions alpha 1, alpha 2, and alpha 3 of all respective three brain compartments can be estimated. Simulations of the sodium spin 3/2 dynamics during a 15-pulse sequence were used to optimize the acquisition sequence by minimizing the correlation between the signal evolutions from the three compartments. The method was first tested on a three-compartment phantom as proof-of-concept. Average values of the 23Na quantifications in four healthy volunteer brains were alpha 1 = 0.54 +/- 0.01, alpha 2 = 0.23 +/- 0.01, alpha 3 = 1.03 +/- 0.01, and C 1 = 23 +/- 3 mM, which are comparable to the expected physiological values [Formula: see text] ~ 0.6, [Formula: see text] ~ 0.2, [Formula: see text] ~ 1, and [Formula: see text] ~ 10-30 mM. The proposed method may allow a quantitative assessment of the metabolic role of sodium ions in cellular processes and their malfunctions in brain in vivo. PMID- 29234045 TI - Soil biota in vineyards are more influenced by plants and soil quality than by tillage intensity or the surrounding landscape. AB - Tillage is known for its adverse effects on soil biota, at least in arable agroecosystems. However, in vineyards effects might differ as tillage is often performed during dry periods or only in every other inter-row allowing species to re-colonise disturbed areas. We examined the response of earthworms (lumbricids), springtails (collembola) and litter decomposition to periodically mechanically disturbed (PMD) and permanently green covered (PGC) vineyard inter-rows and assessed whether site effects are altered by the surrounding landscape. In commercial vineyards in Austria we sampled earthworms by handsorting, springtails by soil coring and pitfall trapping and installed litter decomposition bags. Earthworm species diversity increased with plant biomass under PMD but not under PGC; earthworm density was unaffected by tillage but increased with plant biomass mainly at high soil quality (soil fertility index). Springtail species diversity was unaffected by tillage; springtail densities (mainly larger species) were reduced under PGC. Litter decomposition was little affected by investigated parameters. Landscape heterogeneity affected the functional diversity of surface springtails, but did not influence soil-dwelling springtails, earthworms or litter decomposition. We conclude that effects on soil biota of periodical tillage in vineyards need not necessarily be detrimental and will be modified by plant biomass and soil quality. PMID- 29234046 TI - Broadband light trapping strategies for quantum-dot photovoltaic cells (>10%) and their issues with the measurement of photovoltaic characteristics. AB - Bandgap tunability and broadband absorption make quantum-dot (QD) photovoltaic cells (PVs) a promising candidate for future solar energy conversion systems. Approaches to improving the electrical properties of the active layer increase efficiency in part. The present study focuses on optical room for enhancement in QD PVs over wide spectrum in the near-infrared (NIR) region. We find that ray optical light trapping schemes rather than the nanophotonics approach may be the best solution for enhancing broadband QD PVs by suppressing the escape probability of internal photons without spectral dependency. Based on the theoretical study of diverse schemes for various bandgaps, we apply a V-groove structure and a V-groove textured compound parabolic trapper (VCPT) to PbS-based QD PVs along with the measurement issues for PVs with a light scattering layer. The efficiency of the best device is improved from 10.3% to 11.0% (certified to 10.8%) by a V-groove structure despite the possibility of underestimation caused by light scattering in small-area devices (aperture area: 0.0625 cm2). By minimizing such underestimation, even greater enhancements of 13.6% and 15.6% in short circuit current are demonstrated for finger-type devices (0.167 cm2 without aperture) and large-area devices (2.10 cm2 with an aperture of 0.350 cm2), respectively, using VCPT. PMID- 29234047 TI - Inhibition of NHEJ repair by type II-A CRISPR-Cas systems in bacteria. AB - Type II CRISPR-Cas systems introduce double-strand breaks into DNA of invading genetic material and use DNA fragments to acquire novel spacers during adaptation. These breaks can be the substrate of several DNA repair pathways, paving the way for interactions. We report that non-homologous end-joining (NHEJ) and type II-A CRISPR-Cas systems only co-occur once among 5563 fully sequenced prokaryotic genomes. We investigated experimentally the possible molecular interactions using the NHEJ pathway from Bacillus subtilis and the type II-A CRISPR-Cas systems from Streptococcus thermophilus and Streptococcus pyogenes. Our results suggest that the NHEJ system has no effect on CRISPR immunity. On the other hand, we provide evidence for the inhibition of NHEJ repair by the Csn2 protein. Our findings give insights on the complex interactions between CRISPR Cas systems and repair mechanisms in bacteria, contributing to explain the scattered distribution of CRISPR-Cas systems in bacterial genome. PMID- 29234048 TI - Gene length as a regulator for ribosome recruitment and protein synthesis: theoretical insights. AB - Protein synthesis rates are determined, at the translational level, by properties of the transcript's sequence. The efficiency of an mRNA can be tuned by varying the ribosome binding sites controlling the recruitment of the ribosomes, or the codon usage establishing the speed of protein elongation. In this work we propose transcript length as a further key determinant of translation efficiency. Based on a physical model that considers the kinetics of ribosomes advancing on the mRNA and diffusing in its surrounding, as well as mRNA circularisation and ribosome drop-off, we explain how the transcript length may play a central role in establishing ribosome recruitment and the overall translation rate of an mRNA. According to our results, the proximity of the 3' end to the ribosomal recruitment site of the mRNA could induce a feedback in the translation process that would favour the recycling of ribosomes. We also demonstrate how this process may be involved in shaping the experimental ribosome density-gene length dependence. Finally, we argue that cells could exploit this mechanism to adjust and balance the usage of its ribosomal resources. PMID- 29234049 TI - A Novel Classification Indicator of Type 1 and Type 2 Diabetes in China. AB - Because of the differences of treatment, it is extremely important to classify the types of diabetes, especially for the diagnosis made by clinician. In this study, we proposed a novel scheme calculating an indicator of classifying diabetes, which contains two stages: the first is a model of feature extraction, 17 features are automatically extracted from the curve of glucose concentration acquired by continuous glucose monitoring system (CGM); the second is a model of diabetes parameter regression based on an ensemble learning algorithm named double-Class AdaBoost. 1050 curves of glucose concentration of type 1 and type 2 diabetics were acquired at the Department of Endocrinology in People's Hospital of Zhengzhou University China, and an upper threshold MU was set to 7 mmol/L, 8 mmol/L, 9 mmol/L, 10 mmo/L, and 11 mmol/L respectively according to the guideline of WHO. The experiments show that the coincidence rate of our scheme and clinical diagnosis is 90.3%. The novel indicator extends the criteria in diagnosing types of diabetes and provides doctors with a scalar to classify diabetes of type 1 and type 2. PMID- 29234050 TI - A different vision of dyslexia: Local precedence on global perception. AB - Individuals perceive the wor(l)d hierarchically. Firsty, the global visual scene is processed by the right hemisphere, and later, the local features are perceived by the left hemisphere. Based on this hierarchical analysis, humans evolved unique communication ability: reading. However, for about 10% of people reading acquisition is extremely difficult, they are affected by a heritable neurodevelopmental disorder called dyslexia. Differences in perceiving the wor(l)d might be one of the causes of reading disabilities. Here we show multiple causal links between the global before local perception and learning to read. Five behavioral experiments in 353 children reveal that: (i) a local before global perception characterizes three independent groups of unselected children with dyslexia; (ii) two global before local perception trainings improve reading skills in children with dyslexia; and stringently (iii) pre-reading local before global perception longitudinally predicts future poor readers. Challenging the uni-causal and left-lateralized phonological explanation of dyslexia, our results demonstrate that learning to read depends also on an efficient right neural network for the global analysis of the visual scene. These results provide new insights in learning strategies and pave the way for early identification and possible prevention programs. PMID- 29234051 TI - Lagrangian Statistics and Intermittency in Gulf of Mexico. AB - Due to the nonlinear interaction between different flow patterns, for instance, ocean current, meso-scale eddies, waves, etc, the movement of ocean is extremely complex, where a multiscale statistics is then relevant. In this work, a high time-resolution velocity with a time step 15 minutes obtained by the Lagrangian drifter deployed in the Gulf of Mexico (GoM) from July 2012 to October 2012 is considered. The measured Lagrangian velocity correlation function shows a strong daily cycle due to the diurnal tidal cycle. The estimated Fourier power spectrum E(f) implies a dual-power-law behavior which is separated by the daily cycle. The corresponding scaling exponents are close to -1.75 and -2.75 respectively for the time scale larger (resp. 0.1 <= f <= 0.4 day-1) and smaller (resp. 2 <= f <= 8 day-1) than 1 day. A Hilbert-based approach is then applied to this data set to identify the possible multifractal property of the cascade process. The results show an intermittent dynamics for the time scale larger than 1 day, while a less intermittent dynamics for the time scale smaller than 1 day. It is speculated that the energy is partially injected via the diurnal tidal movement and then transferred to larger and small scales through a complex cascade process, which needs more studies in the near future. PMID- 29234052 TI - Direct evidence of an efficient energy transfer pathway from jellyfish carcasses to a commercially important deep-water species. AB - Here we provide empirical evidence of the presence of an energetic pathway between jellyfish and a commercially important invertebrate species. Evidence of scavenging on jellyfish carcasses by the Norway lobster (Nephrops norvegicus) was captured during two deployments of an underwater camera system to 250-287 m depth in Sognefjorden, western Norway. The camera system was baited with two Periphylla periphylla (Scyphozoa) carcasses to simulate the transport of jellyfish detritus to the seafloor, hereby known as jelly-falls. N. norveigus rapidly located and consumed a large proportion (>50%) of the bait. We estimate that the energy input from jelly-falls may represent a significant contribution to N. norvegicus energy demand (0.21 to 10.7 times the energy required for the population of N. norvegicus in Sognefjorden). This potentially high energetic contribution from jelly-falls highlights a possible role of gelatinous material in the support of commercial fisheries. Such an energetic pathway between jelly-falls and N. norvegicus could become more important with increases in jellyfish blooms in some regions. PMID- 29234053 TI - Liquid-Crystal-Based Electrically Tuned Electromagnetically Induced Transparency Metasurface Switch. AB - In this study, a structure to realize a switchover between two different responses of electromagnetically induced transparency (EIT) was designed and implemented by simulation. Taking advantage of the anisotropy in the structure and the coupling between the radiative and dark elements, a metasurface switch with modulation depth of over 85% between orthogonal polarization incident light illuminations was demonstrated. The key mode switchover between the "on" and "off" states was achieved by electrically changing the dressing light polarization with a liquid crystals layer pre-aligned with a mature technology, without changing the incident light and an expected and reversible transition from an EIT-like spectrum to a strong spectral dip was observed. The modulation in the EIT switch fabricated with the proposed straightforward approach is a promising tool to control the groping velocity delay. PMID- 29234054 TI - Antagonistic effect of dopamine structural analogues on human GABArho1 receptor. AB - GABAergic and dopaminergic pathways are co-localized in several areas of the central nervous system and recently several reports have shown co-release of both neurotransmitters. The GABA-A receptor (beta and rho1 subunits) is modulated by dopamine (DA) and, interestingly, GABArho1 can be modulated by several biogenic amines. Here we explored the effects of the metabolites of the dopaminergic pathway and other structural analogues of DA on GABArho1 and the DA gated ion channel (LGC-53) from Caenorhabditis elegans expressed in Xenopus laevis oocytes. Our findings show an antagonistic effect of the metabolite 3-Methoxytyramine (3 MT, IC50 = 285 +/- 30 uM) with similar potency compared to DA on induced GABA currents; however, it was inactive on LGC-53. The structural DA analogues and metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 2 phenylethylamine (beta-PEA) and 4-amino-1-butanol (4-AM-1-OH), antagonized GABArho1 currents, whereas beta-PEA acted as partial agonists on LGC-53, indicating that the putative binding sites of both receptors may share structural characteristics. These results suggest that the DA metabolites 3-MT, DOPAC and HVA modulate GABArho1 and possibly affect the activity of the receptors that include this subunit in vivo. PMID- 29234055 TI - Oral immunotherapy combined with omalizumab for high-risk cow's milk allergy: a randomized controlled trial. AB - We evaluated the efficacy and safety of oral immunotherapy (OIT) combined with 24 weeks of omalizumab (OMB) at inducing desensitization in children with cow's milk allergy (CM) compared with an untreated group. The present study was a prospective randomized controlled trial. Sixteen patients (age, 6-14 years) with high IgE levels to CM were enrolled in the present study. Patients were randomized 1:1 to receive OMB-OIT group or untreated group. The primary outcome was the induction of desensitization at 8 weeks after OMB was discontinued in OMB OIT treated group and at 32 weeks after study entry. None of the 6 children in the untreated group developed desensitization to CM while all of the 10 children in the OIT-OMB treated group achieved desensitization (P < 0.001). A significantly decreased wheal diameter in response to a skin prick test using CM was found in the OMB-OIT treated group (P < 0.05). These data suggest that OIT combined with OMB using microwave heated CM may help to induce desensitization for children with high-risk CM allergy. This prospective randomized controlled trial was intended for 50 participants but was prematurely discontinued due to overwhelming superiority of OMB combined with microwave heated OIT over CM avoidance. PMID- 29234058 TI - Relation of Ultrasound Findings and Abdominal Symptoms obtained with the CFAbd Score in Cystic Fibrosis Patients. AB - Abdominal symptoms are a hallmark of Cystic fibrosis (CF). Yet, their association with morphological abnormalities of different abdominal organs is still poorly understood. Aim was therefore to relate these symptoms, assessed with a questionnaire, to findings in abdominal ultrasound (US). In 114 CF patients of all ages, findings in US considering seventeen specific parameters were related to abdominal symptoms compiled with our novel CF-specific 26-modal symptom score (CFAbd-Score). US abnormalities were detected in 95% of the patients. Most frequent findings were pancreatic lipomatosis (88%), liver steatosis (37%), hepatomegaly (31%), and thickened bowel walls (23%). Highest burden of GI symptoms was clearly associated with pancreatic lipomatosis (p = 0.036). In detail, patients revealing this pathology reported higher rates of abdominal pain (p = 0.018), flatulence (p = 0.006), heartburn (p = 0.04), and reflux of stomach content (p = 0.006). Patients with pancreatic sufficiency had less US-findings (p = 0.033), which in turn was associated with lower rates of abdominal symptoms. The majority of them were carriers of class IV-VI or G551D mutations. Our approach gives new insights regarding the underestimated multi-organ abdominal involvement in CF. The new score can be of high interest e.g. as a complementary tool to assess the gastrointestinal effects of promising novel CF therapeutics. PMID- 29234057 TI - Effect of carnosine supplementation on the plasma lipidome in overweight and obese adults: a pilot randomised controlled trial. AB - Carnosine has been shown to reduce oxidation and glycation of low density lipoprotein hence improving dyslipidaemia in rodents. The effect of carnosine on human plasma lipidome has thus far not been investigated. We aimed to determine whether carnosine supplementation improves the plasma lipidome in overweight and obese individuals. Lipid analysis was performed by liquid chromatography mass spectrometry in 24 overweight and obese adults: 13 were randomly assigned to 2 g carnosine daily and 11 to placebo, and treated for 12 weeks. Carnosine supplementation maintained trihexosylceramide (0.01 +/- 0.19 vs -0.28 +/- 0.34 nmol/ml, p = 0.04), phosphatidylcholine (77 +/- 167 vs -81 +/- 196 nmol/ml, p = 0.01) and free cholesterol (20 +/- 80 vs -69 +/- 80 nmol/ml, p = 0.006) levels compared to placebo. Trihexosylceramide was inversely related with fasting insulin (r = -0.6, p = 0.002), insulin resistance (r = -0.6, p = 0.003), insulin secretion (r = -0.4, p = 0.05) and serum carnosinase 1 activity (r = -0.3, p = 0.05). Both phosphatidylcholine and free cholesterol did not correlate with any cardiometabolic parameters. Our data suggest that carnosine may have beneficial effects on the plasma lipidome. Future larger clinical trials are needed to confirm this. PMID- 29234056 TI - Identification and characterization of two functional variants in the human longevity gene FOXO3. AB - FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays, the longevity alleles of both variants show considerable enhancer activities that are reversed by IGF-1 treatment. An eQTL database search reveals that the alleles are also associated with higher FOXO3 mRNA expression in various human tissues, which is in line with observations in long-lived model organisms. In summary, we present experimental evidence for a functional link between common intronic variants in FOXO3 and human longevity. PMID- 29234059 TI - p16Ink4a and p21Cip1/Waf1 promote tumour growth by enhancing myeloid-derived suppressor cells chemotaxis. AB - p16Ink4a and p21Cip1/Waf1 act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16Ink4 and p21Cip1/Waf1, namely, tumour promotion through chemotaxis. In monocytic myeloid derived suppressor cells (Mo-MDSCs), p16Ink4 and p21Cip1/Waf1 are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK mediated phosphorylation and inactivation of SMAD3. Thus, deletion of p16 Ink4 and p21 Cip1/Waf1 reduces CX3CR1 expression, thereby inhibiting Mo-MDSC accumulation in tumours expressing CX3CL1 and suppressing the tumour progression in mice. Notably, blockade of the CX3CL1/CX3CR1 axis suppresses tumour growth, whereas inactivation of CDKs elicits the opposite effect. These findings reveal an unexpected function of p16 Ink4a and p21 Waf1/Cip1 and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development. PMID- 29234060 TI - Heat-killed Lactobacillus casei confers broad protection against influenza A virus primary infection and develops heterosubtypic immunity against future secondary infection. AB - Lactic acid bacteria (LAB) are the common probiotics. Here, we investigated the antiviral protective effects of heat-killed LAB strain Lactobacillus casei DK128 (DK128) on influenza viruses. Intranasal treatment of mice with DK128 conferred protection against different subtypes of influenza viruses by lessening weight loss and lowering viral loads. Protection via heat-killed DK128 was correlated with an increase in alveolar macrophage cells in the lungs and airways, early induction of virus specific antibodies, reduced levels of pro-inflammatory cytokines and innate immune cells. Importantly, the mice that were protected against primary viral infection as a result of heat-killed DK128 pretreatment developed subsequent heterosubtypic immunity against secondary virus infection. For protection against influenza virus via heat-killed DK128 pretreatment, B cells and partially CD4 T cells but not CD8 T cells were required as inferred from studies using knockout mouse models. Our study provides insight into how hosts can be equipped with innate and adaptive immunity via heat-killed DK128 treatment to protect against influenza virus, supporting that heat-killed LAB may be developed as anti-virus probiotics. PMID- 29234061 TI - Evaluation of promoting effect of a novel Cu-bearing metal stent on endothelialization process from in vitro and in vivo studies. AB - Drug eluting stents (DES) have been extensively applied nowadays and reduce the incidence of in-stent restenosis (ISR) greatly as compared with bare metal stents (BMS). However, the development of DES is hindered by the risk of late stent thrombosis (LST) due to delayed re-endothelialization, while endothelialization is an important process related to ISR and LST after implantation. 316L is a traditional stent material without bioactivity and have a high risk of ISR. Cu is recognized for angiogenesis stimulation in these years. Hence a copper bearing 316L stainless steel (316L-Cu) was prepared and evaluated about its effect on endothelialization in this paper. Compared with traditional 316L, it was proved that 316L-Cu increased the proliferation of co-cultured human umbilical vein endothelial cells (HUVECs) at first day. Moreover, HUVECs stretched better on the surface of 316L-Cu. It also improved the expression of angiogenesis related genes and tube formation ability in vitro. 316L-Cu-BMS, DES and 316L-BMS were implanted in swine to evaluate the re-endothelialization ability in vivo. And 316L-Cu-BMS showed the best effect on endothelialization with good biosafety. Consequently, 316L-Cu is a kind of promising BMS material for coronary field. PMID- 29234062 TI - Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells. AB - Inhibition of protein-protein interactions by small molecules offers tremendous opportunities for basic research and drug development. One of the fundamental challenges of this research field is the broad lack of available lead structures from nature. Here, we demonstrate that modifications of a chromone-based inhibitor of the Src homology 2 (SH2) domain of the transcription factor STAT5 confer inhibitory activity against STAT3. The binding mode of the most potent STAT3 inhibitor Erasin was analyzed by the investigation of structure-activity relationships, which was facilitated by chemical synthesis and biochemical activity analysis, in combination with molecular docking studies. Erasin inhibits tyrosine phosphorylation of STAT3 with selectivity over STAT5 and STAT1 in cell based assays, and increases the apoptotic rate of cultured NSCLC cells in a STAT3 dependent manner. This ability of Erasin also extends to HCC-827 cells with acquired resistance against Erlotinib, a clinically used inhibitor of the EGF receptor. Our work validates chromone-based acylhydrazones as privileged structures for antagonizing STAT SH2 domains, and demonstrates that apoptosis can be induced in NSCLC cells with acquired Erlotinib resistance by direct inhibition of STAT3. PMID- 29234063 TI - The Sam-Sam interaction between Ship2 and the EphA2 receptor: design and analysis of peptide inhibitors. AB - The lipid phosphatase Ship2 represents a drug discovery target for the treatment of different diseases, including cancer. Its C-terminal sterile alpha motif domain (Ship2-Sam) associates with the Sam domain from the EphA2 receptor (EphA2 Sam). This interaction is expected to mainly induce pro-oncogenic effects in cells therefore, inhibition of the Ship2-Sam/EphA2-Sam complex may represent an innovative route to discover anti-cancer therapeutics. In the present work, we designed and analyzed several peptide sequences encompassing the interaction interface of EphA2-Sam for Ship2-Sam. Peptide conformational analyses and interaction assays with Ship2-Sam conducted through diverse techniques (CD, NMR, SPR and MST), identified a positively charged penta-amino acid native motif in EphA2-Sam, that once repeated three times in tandem, binds Ship2-Sam. NMR experiments show that the peptide targets the negatively charged binding site of Ship2-Sam for EphA2-Sam. Preliminary in vitro cell-based assays indicate that -at 50 uM concentration- it induces necrosis of PC-3 prostate cancer cells with more cytotoxic effect on cancer cells than on normal dermal fibroblasts. This work represents a pioneering study that opens further opportunities for the development of inhibitors of the Ship2-Sam/EphA2-Sam complex for therapeutic applications. PMID- 29234064 TI - Homeostatic plasticity and synaptic scaling in the adult mouse auditory cortex. AB - It has been demonstrated that sensory deprivation results in homeostatic adjustments recovering neuronal activity of the deprived cortex. For example, deprived vision multiplicatively scales up mEPSC amplitudes in the primary visual cortex, commonly referred to as synaptic scaling. However, whether synaptic scaling also occurs in auditory cortex after auditory deprivation remains elusive. Using periodic intrinsic optical imaging in adult mice, we show that conductive hearing loss (CHL), initially led to a reduction of primary auditory cortex (A1) responsiveness to sounds. However, this was followed by a complete recovery of A1 activity evoked sounds above the threshold for bone conduction, 3 days after CHL. Over the same time course patch-clamp experiments in slices revealed that mEPSC amplitudes in A1 layers 2/3 pyramids scaled up multiplicatively in CHL mice. No recovery of sensory evoked A1 activation was evident in TNFalpha KO animals, which lack synaptic scaling. Additionally, we could show that the suppressive effect of sounds on visually evoked visual cortex activity completely recovered along with TNFalpha dependent A1 homeostasis in WT animals. This is the first demonstration of homeostatic multiplicative synaptic scaling in the adult A1. These findings suggest that mild hearing loss massively affects auditory processing in adult A1. PMID- 29234065 TI - Volatile and bioactive compounds in opercula from Muricidae molluscs supports their use in ceremonial incense and traditional medicines. AB - Muricidae molluscs are the source of a valuable purple dye that was traded as a luxury item in the Mediterranean region and by the late Byzantine was reserved for royalty and priests. Less well known is the use of muricid opercula in sacred incense and traditional medicines, although they are still used as rare ingredients today. This study provides the first chemical assessment of opercula from Muricidae, based on several traditional preparation procedures. Chemical analysis of opercula smoke revealed aromatic phenols, which act as fragrance stabilisers and produce a "medicinal" odour. Analysis of lipid extracts revealed pharmaceutically active compounds, including brominated indoles, choline esters and adenosine, consistent with their traditional medical applications. Depending on the preparation procedures, toxic pyridine was also detected. ICP-MS analysis of muricid opercula shows the presence of essential macro and microelements, as well as metals, some of which exceed the recommended safe levels for human use. Nevertheless, these findings support the Muricidae as an historically important marine resource, providing Biblical dyes, medicines and perfume. The opercula contains biologically active compounds and produces smoke containing volatile scent compounds, consistent with their identification as the most likely source of onycha, a controversial ingredient in sacred incense. PMID- 29234066 TI - Programing stimuli-responsiveness of gelatin with electron beams: basic effects and development of a hydration-controlled biocompatible demonstrator. AB - Biomimetic materials with programmable stimuli responsiveness constitute a highly attractive material class for building bioactuators, sensors and active control elements in future biomedical applications. With this background, we demonstrate how energetic electron beams can be utilized to construct tailored stimuli responsive actuators for biomedical applications. Composed of collagen-derived gelatin, they reveal a mechanical response to hydration and changes in pH-value and ion concentration, while maintaining their excellent biocompatibility and biodegradability. While this is explicitly demonstrated by systematic characterizing an electron-beam synthesized gelatin-based actuator of cantilever geometry, the underlying materials processes are also discussed, based on the fundamental physical and chemical principles. When applied within classical electron beam lithography systems, these findings pave the way for a novel class of highly versatile integrated bioactuators from micro- to macroscales. PMID- 29234067 TI - The Human Blood-Nerve Barrier Transcriptome. AB - The blood-nerve barrier (BNB), formed by tight junction-forming microvessels within peripheral nerve endoneurium, exists to regulate its internal microenvironment essential for effective axonal signal transduction. Relatively little is known about the unique human BNB molecular composition. Such knowledge is crucial to comprehend the relationships between the systemic circulation and peripheral nerves in health, adaptations to intrinsic or extrinsic perturbations and alterations that may result in disease. We performed RNA-sequencing on cultured early- and late-passage adult primary human endoneurial endothelial cells and laser-capture microdissected endoneurial microvessels from four cryopreserved normal adult human sural nerves referenced to the Genome Reference Consortium Human Reference 37 genome browser, using predefined criteria guided by known transcript or protein expression in vitro and in situ. We identified 12881 common transcripts associated by 125 independent biological networks, defined as the normal adult BNB transcriptome, including a comprehensive array of transporters and specialized intercellular junctional complex components. These identified transcripts and their interacting networks provide insights into peripheral nerve microvascular morphogenesis, restrictive barrier formation, influx and efflux transporters with relevance to understanding peripheral nerve homeostasis and pharmacology, including targeted drug delivery and the mediators of leukocyte trafficking in peripheral nerves during normal immunosurveillance. PMID- 29234068 TI - Fluctuations in instantaneous frequency predict alpha amplitude during visual perception. AB - Rhythmic neural activity in the alpha band (8-13 Hz) is thought to have an important role in the selective processing of visual information. Typically, modulations in alpha amplitude and instantaneous frequency are thought to reflect independent mechanisms impacting dissociable aspects of visual information processing. However, in complex systems with interacting oscillators such as the brain, amplitude and frequency are mathematically dependent. Here, we record electroencephalography in human subjects and show that both alpha amplitude and instantaneous frequency predict behavioral performance in the same visual discrimination task. Consistent with a model of coupled oscillators, we show that fluctuations in instantaneous frequency predict alpha amplitude on a single trial basis, empirically demonstrating that these metrics are not independent. This interdependence suggests that changes in amplitude and instantaneous frequency reflect a common change in the excitatory and inhibitory neural activity that regulates alpha oscillations and visual information processing. PMID- 29234070 TI - Dielectric Barrier Discharge based Mercury-free plasma UV-lamp for efficient water disinfection. AB - A structurally simple dielectric barrier discharge based mercury-free plasma UV light source has been developed for efficient water disinfection. The source comprises of a dielectric barrier discharge arrangement between two co-axial quartz tubes with an optimized gas gap. The outer electrode is an aluminium baked foil tape arranged in a helical form with optimized pitch, while the inner electrode is a hollow aluminium metallic rod, hermetically sealed. Strong bands peaking at wavelengths 172 nm and 253 nm, along with a weak band peaking at wavelength 265 nm have been simultaneously observed due to plasma radiation from the admixture of xenon and iodine gases. The developed UV source has been used for bacterial deactivation studies using an experimental setup that is an equivalent of the conventional house-hold water purifier system. Deactivation studies for five types of bacteria, i.e., E. coli, Shigella boydii, Vibrio, Coliforms and Fecal coliform have been demonstrated with 4 log reductions in less than ten seconds. PMID- 29234069 TI - The Human DNA glycosylases NEIL1 and NEIL3 Excise Psoralen-Induced DNA-DNA Cross Links in a Four-Stranded DNA Structure. AB - Interstrand cross-links (ICLs) are highly cytotoxic DNA lesions that block DNA replication and transcription by preventing strand separation. Previously, we demonstrated that the bacterial and human DNA glycosylases Nei and NEIL1 excise unhooked psoralen-derived ICLs in three-stranded DNA via hydrolysis of the glycosidic bond between the crosslinked base and deoxyribose sugar. Furthermore, NEIL3 from Xenopus laevis has been shown to cleave psoralen- and abasic site induced ICLs in Xenopus egg extracts. Here we report that human NEIL3 cleaves psoralen-induced DNA-DNA cross-links in three-stranded and four-stranded DNA substrates to generate unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct. Furthermore, while Nei and NEIL1 also cleave a psoralen-induced four-stranded DNA substrate to generate two unhooked DNA duplexes with a nick, NEIL3 targets both DNA strands in the ICL without generating single-strand breaks. The DNA substrate specificities of these Nei like enzymes imply the occurrence of long uninterrupted three- and four-stranded crosslinked DNA-DNA structures that may originate in vivo from DNA replication fork bypass of an ICL. In conclusion, the Nei-like DNA glycosylases unhook psoralen-derived ICLs in various DNA structures via a genuine repair mechanism in which complex DNA lesions can be removed without generation of highly toxic double-strand breaks. PMID- 29234071 TI - Identification and validation of FaP1D7, a putative marker associated with the biosynthesis of methyl butanoate in cultivated strawberry (Fragaria x ananassa). AB - Breeding strawberry (Fragaria x ananassa) with enhanced fruit flavour is one of the top breeding goals of many strawberry-producing countries. Although several genes involved in the biosynthetic pathways of key aroma compounds have been identified, the development and application of molecular markers associated with fruit flavour remain limited. This study aims to identify molecular markers closely linked to genes controlling strawberry aroma. A purpose-built Subtracted Diversity Array (SDA) known as Fragaria Discovery Panel (FDP) was used for marker screening. Polymorphic sequences associated with key aroma compounds were identified from two DNA bulks with extreme phenotypes, established using 50 F1 progeny plants derived from Juliette X 07-102-41 cross, two strawberry genotypes differing in aroma profile. A total of 49 polymorphic markers for eight key aroma compounds were detected using genotypic data of the extreme DNA bulks and phenotypic data obtained from gas chromatography-mass spectrometry (GC-MS). A similarity search against the physical maps of Fragaria vesca revealed that FaP1D7 is linked to genes potentially involved in the synthesis of methyl butanoate. A C/T SNP was detected within the feature, which could possibly be converted to a molecular tool for rapid screening of the strawberry accessions for their methyl butanoate production capacity. PMID- 29234072 TI - Biochemical and transcriptomic analyses of drought stress responses of LY1306 tobacco strain. AB - This study aimed to investigate drought resistance of the LY1306 tobacco strain. Seedlings of tobacco strains LY1306, ZhongYan 100 (ZY100) and Hong Hua Da Jin Yuan (HHDJY) were treated with polyethylene glycol (PEG)-6000 to induce osmotic stress. As validation, water-deficit-induced drought treatments, including mild drought (MD; watering 1.5 L/week) and severe drought (SD, without watering) were carried out. Changes in cell morphology, leaf water potential, antioxidant enzyme activity, as well as contents of malondialdehyde (MDA) and proline were determined for each treatment. Transcriptome sequencing was performed for the seedlings treated with 15% PEG-6000. No obvious changes were observed in morphology of LY1306 and ZY100 under osmotic or drought stress; whereas, visible wilting was observed in HHDJY. Superoxide dismutase and peroxidase activities of LY1036 and ZY100 under osmotic stress were significantly higher than those of HHDJY. Under SD, the MDA content of LY1306 was significantly lower and the proline content of LY1306 was significantly higher than that of HHDJY. Differential genes between LY1306, ZY100 and HHDJY were enriched in functions about alpha-linolenic acid, and arginine and proline metabolisms. LY1306 could increase its antioxidant enzyme activities and proline accumulation in response to drought stress, probably by regulating drought resistance-related pathways and genes. PMID- 29234073 TI - Identification of two novel genes SLC15A2 and SLCO1B3 associated with maintenance dose variability of warfarin in a Chinese population. AB - Warfarin is a commonly prescribed and effective oral anticoagulant. Genetic polymorphisms associated with warfarin metabolism and sensitivity have been implicated in the wide inter-individual dose variation that is observed. Several algorithms integrating patients' clinical characteristics and genetic polymorphism information have been explored to predict warfarin dose. However, most of these algorithms could explain only over half of the variation in a warfarin maintenance dose, suggesting that additional genetic factors may exist and need to be identified. Here, a drug absorption, distribution, metabolism and excretion (ADME) Core Panel Kit-based pharmacogenetic study was performed to screen for warfarin dose-associated SNP sites in Han-Chinese population patients taking warfarin therapy, and the screen was followed by pyrosequencing-based validation. Finally, we confirmed that the common variant rs9923231 in VKORC1 and two novel genes, SLC15A2 (rs1143671 and rs1143672) and SLCO1B3 (rs4149117 and rs7311358), are associated with the warfarin maintenance dose. As has been shown for those carriers with the variant rs9923231 in VKORC1, it was suggested that those subjects with homozygous minor alleles in those four SNPs should take a lower warfarin dose than those carrying the wild type alleles. Together with the established predictor rs9923231 in VKORC1, those four novel variants on SLC15A2 and SLCO1B3 should be considered as useful biomarkers for warfarin dose adjustment in clinical practice in Han-Chinese populations. PMID- 29234074 TI - Motion guided Spatiotemporal Sparsity for high quality 4D-CBCT reconstruction. AB - Conventional cone-beam computed tomography is often deteriorated by respiratory motion blur, which negatively affects target delineation. On the other side, the four dimensional cone-beam computed tomography (4D-CBCT) can be considered to describe tumor and organ motion. But for current on-board CBCT imaging system, the slow rotation speed limits the projection number at each phase, and the associated reconstructions are contaminated by noise and streak artifacts using the conventional algorithm. To address the problem, we propose a novel framework to reconstruct 4D-CBCT from the under-sampled measurements-Motion guided Spatiotemporal Sparsity (MgSS). In this algorithm, we try to divide the CBCT images at each phase into cubes (3D blocks) and track the cubes with estimated motion field vectors through phase, then apply regional spatiotemporal sparsity on the tracked cubes. Specifically, we recast the tracked cubes into four dimensional matrix, and use the higher order singular value decomposition (HOSVD) technique to analyze the regional spatiotemporal sparsity. Subsequently, the blocky spatiotemporal sparsity is incorporated into a cost function for the image reconstruction. The phantom simulation and real patient data are used to evaluate this algorithm. Results show that the MgSS algorithm achieved improved 4D-CBCT image quality with less noise and artifacts compared to the conventional algorithms. PMID- 29234075 TI - Replay of large-scale spatio-temporal patterns from waking during subsequent NREM sleep in human cortex. AB - Animal studies support the hypothesis that in slow-wave sleep, replay of waking neocortical activity under hippocampal guidance leads to memory consolidation. However, no intracranial electrophysiological evidence for replay exists in humans. We identified consistent sequences of population firing peaks across widespread cortical regions during complete waking periods. The occurrence of these "Motifs" were compared between sleeps preceding the waking period ("Sleep Pre") when the Motifs were identified, and those following ("Sleep-Post"). In all subjects, the majority of waking Motifs (most of which were novel) had more matches in Sleep-Post than in Sleep-Pre. In rodents, hippocampal replay occurs during local sharp-wave ripples, and the associated neocortical replay tends to occur during local sleep spindles and down-to-up transitions. These waves may facilitate consolidation by sequencing cell-firing and encouraging plasticity. Similarly, we found that Motifs were coupled to neocortical spindles, down-to-up transitions, theta bursts, and hippocampal sharp-wave ripples. While Motifs occurring during cognitive task performance were more likely to have more matches in subsequent sleep, our studies provide no direct demonstration that the replay of Motifs contributes to consolidation. Nonetheless, these results confirm a core prediction of the dominant neurobiological theory of human memory consolidation. PMID- 29234076 TI - Molecular mechanism of K65 acetylation-induced attenuation of Ubc9 and the NDSM interaction. AB - The negatively charged amino acid-dependent sumoylation motif (NDSM) carries an additional stretch of acidic residues downstream of the consensus Psi-K-x-E/D sumoylation motif. We have previously shown that acetylation of the SUMO E2 conjugase enzyme, Ubc9, at K65 downregulates its binding to the NDSM and renders a selective decrease in sumoylation of substrates with the NDSM motif. Here, we provide detailed structural, thermodynamic, and kinetics results of the interactions between Ubc9 and its K65 acetylated variant (Ac-Ubc9K65) with three NDSMs derived from Elk1, CBP, and Calpain2 to rationalize the mechanism beneath this reduced binding. Our nuclear magnetic resonance (NMR) data rule out a direct interaction between the NDSM and the K65 residue of Ubc9. Similarly, we found that NDSM binding was entropy-driven and unlikely to be affected by the negative charge by K65 acetylation. Moreover our NMR, mutagenesis and molecular dynamics simulation studies defined the sequence of the NDSM as Psi-K-x-E/D-x1-x2-(x3/E/D) (x4/E/D)-xn and determined that K74 and K76 were critical Ubc9 residues interacting with the negatively charged residues of the NDSM. PMID- 29234077 TI - High-Capacity Free-Space Optical Communications Between a Ground Transmitter and a Ground Receiver via a UAV Using Multiplexing of Multiple Orbital-Angular Momentum Beams. AB - We explore the use of orbital-angular-momentum (OAM)-multiplexing to increase the capacity of free-space data transmission to moving platforms, with an added potential benefit of decreasing the probability of data intercept. Specifically, we experimentally demonstrate and characterize the performance of an OAM multiplexed, free-space optical (FSO) communications link between a ground transmitter and a ground receiver via a moving unmanned-aerial-vehicle (UAV). We achieve a total capacity of 80 Gbit/s up to 100-m-roundtrip link by multiplexing 2 OAM beams, each carrying a 40-Gbit/s quadrature-phase-shift-keying (QPSK) signal. Moreover, we investigate for static, hovering, and moving conditions the effects of channel impairments, including: misalignments, propeller-induced airflows, power loss, intermodal crosstalk, and system bit error rate (BER). We find the following: (a) when the UAV hovers in the air, the power on the desired mode fluctuates by 2.1 dB, while the crosstalk to the other mode is -19 dB below the power on the desired mode; and (b) when the UAV moves in the air, the power fluctuation on the desired mode increases to 4.3 dB and the crosstalk to the other mode increases to -10 dB. Furthermore, the channel crosstalk decreases with an increase in OAM mode spacing. PMID- 29234078 TI - Wettability alteration of calcite oil wells: Influence of smart water ions. AB - Further enhancement of crude oil recovery in the enhanced recovery stage from calcite oil wells is a major global challenge for oil industry. Experimental results suggest that ions present in sea water, also called smart water, have a significant influence on the wettability alteration (less oil wet) of calcite surface. In this paper, by utilizing Density Functional Theory (DFT) and Quantum Molecular Dynamics (QMD) simulations, we investigate the effect of additive ions of sea water in oil recovery by using acetic acid as a model compound of crude oil molecules. We find that Na+ ions precipitate to the calcite surface and form Na acetate. The binding energy of Na acetate is larger than original oil molecule (acetic acid), which reduces oil recovery. On the other hand, Mg2+ and [Formula: see text] ions can also reach to the calcite surface in proximity and modify the calcite surface. The binding energy of oil molecule on modified calcite surface is smaller than on pure calcite surface, which enhances oil recovery. Our results might help in understanding interaction among oil, water and additives ions of smart water for further experimental investigations. PMID- 29234079 TI - A genetic screen to discover SUMOylated proteins in living mammalian cells. AB - Post-translational modification by the Small Ubiquitin-related Modifier (SUMO) is indispensable for diverse biological mechanisms. Although various attempts have been made to discover novel SUMO substrate proteins to unveil the roles of SUMOylation, the reversibility of SUMOylation, and the differences in the SUMOylation level still makes it difficult to explore infrequently-SUMOylated proteins in mammalian cells. Here, we developed a method to screen for mammalian SUMOylated proteins using the reconstitution of split fluorescent protein fragments in living mammalian cells. Briefly, the cells harboring cDNAs of SUMOylated proteins were identified by the reconstituted fluorescence emission and separated by cell sorting. The method successfully identified 36 unreported SUMO2-substrate candidates with distinct intracellular localizations and functions. Of the candidates, we found Atac2, a histone acetyltransferase, was SUMOylated at a lysine 408, and further modified by multiple SUMOs without isoform specificity. Because the present method is applicable to other SUMO isoforms and mammalian cell-types, it could contribute to a deeper understanding of the role of SUMOylation in various biological contexts. PMID- 29234080 TI - Genomic diversity and macroecology of the crop wild relatives of domesticated pea. AB - There is growing interest in the conservation and utilization of crop wild relatives (CWR) in international food security policy and research. Legumes play an important role in human health, sustainable food production, global food security, and the resilience of current agricultural systems. Pea belongs to the ancient set of cultivated plants of the Near East domestication center and remains an important crop today. Based on genome-wide analysis, P. fulvum was identified as a well-supported species, while the diversity of wild P. sativum subsp. elatius was structured into 5 partly geographically positioned clusters. We explored the spatial and environmental patterns of two progenitor species of domesticated pea in the Mediterranean Basin and in the Fertile Crescent in relation to the past and current climate. This study revealed that isolation by distance does not explain the genetic structure of P. sativum subsp. elatius in its westward expansion from its center of origin. The genetic diversity of wild pea may be driven by Miocene-Pliocene events, while the phylogenetic diversity centers may reflect Pleisto-Holocene climatic changes. These findings help set research and discussion priorities and provide geographical and ecological information for germplasm-collecting missions, as well as for the preservation of extant diversity in ex-situ collections. PMID- 29234081 TI - High flux water purification using aluminium hydroxide hydrate gels. AB - Filtration of aqueous liquids has wide implications, for example for provision of clean drinking water. Nevertheless, many people still lack access to safe water and suffer from preventable water-borne microbial diseases. This study reports a new ultrafiltration-range separation technology using a gelatinous layer of aluminium hydroxide polyhydrate as a secondary membrane on a retaining fabric that enables simple and cost-effective production of filtered water. Properties include at least 4-fold higher flux rates than currently available membranes, pressure-resistance, impenetrability to filtered particles, easy cleaning by backwashing and simple, cost-effective replacement by gel injection. Depending on the substrate, filtration is achieved through a packed bed of 1-2 nm hydrate gel globules, partly by mechanical straining with a size exclusion of approx. 10 nm and partly by physical adsorption. As a result, filtration of water (e.g. turbid river water) contaminated with colloids and microorganisms, including viruses, yields clear water that is free of measurable particles or detectable microorganisms. However, small water-soluble molecules (salts, sugars, proteins) remain in the filtrate. The findings demonstrate the potential for wide applicability of hydrate gels in high-flux and low-cost water purification devices. PMID- 29234082 TI - Rebound of Cotton leaf curl Multan virus and its exclusive detection in cotton leaf curl disease outbreak, Punjab (India), 2015. AB - Cotton leaf curl disease (CLCuD) outbreaks caused by CLCuD associated begomoviruses (CABs) significantly constrain cotton production in India and Pakistan. In comparison to the CABs circulating in Pakistan, molecular epidemiology, evolution and recombination patterns of CABs circulating in India are less studied. In this work, we characterized CAB complex sequences obtained from the most recent outbreak (Punjab, India, 2015), and rigorously analyzed them with reference to GenBank sequences, submitted from India, Pakistan and other neighbouring countries, using contemporary bioinformatics approaches. In this manuscript, we illustrate the detection of a recombinant, phylogenetically distinct clade of Cotton leaf curl Multan virus (CLCuMuV), suggesting rebound of CLCuMuV in this region. Interestingly, we could not detect Cotton leaf curl Kokhran virus-Burewala strain (CLCuKoV-Bu), which was prevalent in this region, until now. Our study thus indicates substitution of the 'virulent resistance breaking' CLCuKoV-Bu by the re-emerging CLCuMuV recombinants. Our findings corroborate with that of a very recent study from Pakistan and we here discuss epidemiological links between the CAB complexes reported in these two studies. Taken together, these observations signify a shifting epidemiology of CABs, and seem to correlate with the recent prediction of the 'third epidemic' of CLCuD in the Indian subcontinent. PMID- 29234083 TI - Nod2 is required for the early innate immune clearance of Acinetobacter baumannii from the lungs. AB - Acinetobacter baumannii (A. baumannii) is a significant cause of severe nosocomial pneumonia in immunocompromised individuals world-wide. With limited treatment options available, a better understanding of host immnity to A. baumannii infection is critical to devise alternative control strategies. Our previous study has identified that intracellular Nod1/Nod2 signaling pathway is required for the immune control of A. baumannii in airway epithelial cells in vitro. In the current study, using Nod2-/- mice and an in vivo sublethal model of pulmonary infection, we show that Nod2 contributes to the early lung defense against A. baumannii infection through reactive oxygen species (ROS)/reactive nitrogen species (RNS) production as Nod2-/- mice showed significantly reduced production of ROS/RNS in the lungs following A. baumannii infection. Consistent with the higher bacterial load, A. baumannii-induced neutrophil recruitment, cytokine/chemokine response and lung pathology was also exacerbated in Nod2-/- mice at early time points post-infection. Finally, we show that administration of Nod2 ligand muramyl dipeptide (MDP) prior to infection protected the wild- type mice from A. baumannii pulmonary challenge. Collectively, Nod2 is an important player in the early lung immunity against A. baumannii and modulating Nod2 pathway could be considered as a viable therapeutic strategy to control A. baumannii pulmonary infection. PMID- 29234084 TI - Nonvolatile Bio-Memristor Based on Silkworm Hemolymph Proteins. AB - This paper reports the first successful fabrication of an ITO/silkworm hemolymph/Al bio-memristor using silkworm hemolymph as the active layer. Experiments demonstrate that the silkworm hemolymph bio-memristor is a nonvolatile rewritable bipolar memory device with a current switching ratio exceeding 103. The state of the bio-memristor can be retained for more than 104 seconds and remains stable for at least 500 cycles. Tests of 1/f noise have shown that the resistance switching characteristics of the silkworm hemolymph bio memristor are related to the formation and breaking of conductive filaments, which result from the migration of oxygen ions and the oxidation and reduction of metal cations in the silkworm hemolymph film. The naturally non-toxic silkworm hemolymph offers advantages for human health, environmental protection, and biocompatibility. The proposed nonvolatile rewritable bio-memristor based on silkworm hemolymph possesses great application potential. PMID- 29234085 TI - Repeatability of corneal elevation maps in keratoconus patients using the tomography matching method. AB - To assess repeatability of corneal tomography in successive measurements by Pentacam in keratoconus (KC) and normal eyes based on the Iterative Closest Point (ICP) algorithm. The study involved 143 keratoconic and 143 matched normal eyes. ICP algorithm was used to estimate six single and combined misalignment (CM) parameters, the root mean square (RMS) of the difference in elevation data pre (PreICP-RMS) and post (PosICP-RMS) tomography matching. Corneal keratometry, expressed in the form of M, J0 and J45 (power vector analysis parameters), was used to evaluate the effect of misalignment on corneal curvature measurements. The PreICP-RMS and PosICP-RMS were statistically higher (P < 0.01) in KC than normal eyes. CM increased significantly (p = 0.00), more in KC (16.76 +/- 20.88 MUm) than in normal eyes (5.43 +/- 4.08 MUm). PreICP-RMS, PosICP-RMS and CM were correlated with keratoconus grade (p < 0.05). Corneal astigmatism J0 was different (p = 0.01) for the second tomography measurements with misalignment consideration (-1.11 +/- 2.35 D) or not (-1.18 +/- 2.35 D), while M and J45 kept similar. KC corneas consistently show higher misalignments between successive tomography measurements and lower repeatability compared with healthy eyes. The influence of misalignment is evidently clearer in the estimation of astigmatism than spherical curvature. These higher errors appear correlated with KC progression. PMID- 29234086 TI - N-acetylcysteine-functionalized coating avoids bacterial adhesion and biofilm formation. AB - N-acetyl cysteine (NAC) is an FDA-approved drug clinically applied on a broad range of pathologies. Further research has been conducted with this drug to benefit from its antimicrobial activity potential. However, NAC has a very short half-life and therefore strategies that accomplish high local concentrations would be beneficial. In this study, covalent immobilization of NAC was performed, in order to obtain long-lasting high local concentration of the drug onto a chitosan(Ch)-derived implant-related coating. For the development of NAC functionalized Ch films, water-based carbodiimide chemistry was applied to avoid the use of toxic organic solvents. Here we report the optimization steps performed to immobilize NAC onto the surface of pre-prepared Ch coatings, to ensure full exposure of NAC. Surface characterization using ellipsometry, water contact angle measurements and X-ray photoelectron spectroscopy (XPS), demonstrated the success of NAC immobilization at 4 mg/mL. Quartz crystal microbalance with dissipation (QCM-D) demonstrated that surface immobilized NAC decreases protein adsorption to Ch coatings. Biological studies confirmed that immobilized NAC4 avoids methicillin-resistant Staphylococcus aureus adhesion to Ch coating, impairing biofilm formation, without inducing cytotoxic effects. This is particularly interesting towards further developments as a prevention coating. PMID- 29234087 TI - Conformational Switch Regulates the DNA Cytosine Deaminase Activity of Human APOBEC3B. AB - The APOBEC3B (A3B) single-stranded DNA (ssDNA) cytosine deaminase has important roles in innate immunity but is also a major endogenous source of mutations in cancer. Previous structural studies showed that the C-terminal catalytic domain of human A3B has a tightly closed active site, and rearrangement of the surrounding loops is required for binding to substrate ssDNA. Here we report structures of the A3B catalytic domain in a new crystal form that show alternative, yet still closed, conformations of active site loops. All-atom molecular dynamics simulations support the dynamic behavior of active site loops and recapitulate the distinct modes of interactions that maintain a closed active site. Replacing segments of A3B loop 1 to mimic the more potent cytoplasmic deaminase APOBEC3A leads to elevated ssDNA deaminase activity, likely by facilitating opening of the active site. These data collectively suggest that conformational equilibrium of the A3B active site loops, skewed toward being closed, controls enzymatic activity by regulating binding to ssDNA substrates. PMID- 29234088 TI - Tear proteome analysis in ocular surface diseases using label-free LC-MS/MS and multiplexed-microarray biomarker validation. AB - We analyzed the tear film proteome of patients with dry eye (DE), meibomian gland dysfunction (MGD), and normal volunteers (CT). Tear samples were collected from 70 individuals. Of these, 37 samples were analyzed using spectral-counting-based LC-MS/MS label-free quantitation, and 33 samples were evaluated in the validation of candidate biomarkers employing customized antibody microarray assays. Comparative analysis of tear protein profiles revealed differences in the expression levels of 26 proteins, including protein S100A6, annexin A1, cystatin S, thioredoxin, phospholipase A2, antileukoproteinase, and lactoperoxidase. Antibody microarray validation of CST4, S100A6, and MMP9 confirmed the accuracy of previously reported ELISA assays, with an area under ROC curve (AUC) of 87.5%. Clinical endpoint analysis showed a good correlation between biomarker concentrations and clinical parameters. In conclusion, different sets of proteins differentiate between the groups. Apolipoprotein D, S100A6, S100A8, and ceruloplasmin discriminate best between the DE and CT groups. The differences between antileukoproteinase, phospholipase A2, and lactoperoxidase levels allow the distinction between MGD and DE, and the changes in the levels of annexin A1, clusterin, and alpha-1-acid glycoprotein 1, between MGD and CT groups. The functional network analysis revealed the main biological processes that should be examined to identify new candidate biomarkers and therapeutic targets. PMID- 29234090 TI - Modeling and optimization of thermal conductivity and viscosity of MnFe2O4 nanofluid under magnetic field using an ANN. AB - This research investigates the applicability of an ANN and genetic algorithms for modeling and multiobjective optimization of the thermal conductivity and viscosity of water-based spinel-type MnFe2O4 nanofluid. Levenberg-Marquardt, quasi-Newton, and resilient backpropagation methods are employed to train the ANN. The support vector machine (SVM) method is also presented for comparative purposes. Experimental results demonstrate the efficacy of the developed ANN with the LM-BR training algorithm and the 3-10-10-2 structure for the prediction of the thermophysical properties of nanofluids in terms of the significantly superior accuracy compared to developing the correlation and employing SVM regression. Moreover, the genetic algorithm is implemented to determine the optimal conditions, i.e., maximum thermal conductivity and minimum nanofluid viscosity, based on the developed ANN. PMID- 29234089 TI - Impact of treatment on resting cerebral blood flow and metabolism in obsessive compulsive disorder: a meta-analysis. AB - Neurobiological models of obsessive-compulsive disorder (OCD) posit that its clinical symptoms such as repetitive thoughts and behaviors are related to hyperactivity in the cortico-striato-thalamo-cortical (CSTC) circuit. Small scale neuroimaging studies have shown that treatment of OCD is associated with reduced activity across different brain structures within this circuitry. We performed the first meta-analysis of positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies that investigated cerebral blood flow or glucose metabolism in patients with OCD before and after pharmacological or psychological treatment. We calculated standardized mean differences for the regions-of-interest most often reported. The meta-analysis revealed small reductions in activity in the caudate nucleus and orbitofrontal cortex after treatment with a serotonin reuptake inhibitor or cognitive behavioral therapy. Small reductions were also observed in the thalamus when one SPECT study with a large opposite effect was excluded from the analysis. Meta-regression analyses for the caudate nucleus showed no significant effect of the type of treatment, decrease in symptom severity, mean duration until the follow-up scan, or year of publication. These results show that pharmacological and psychological treatments reduce resting CSTC circuit activity, and provide further support for the CSTC circuit model in OCD. PMID- 29234092 TI - Advantage of early orchiopexy for undescended testis: Analysis of testicular growth percentage ratio in patients with unilateral undescended testicle. AB - This study reports the experience of our tertiary referral center and proposes a new indicator, the growth percentage ratio (GPR), for determining the optimal timing of surgical intervention. A retrospective review of boys who underwent orchiopexy for undescended testis from 2001 to 2013 was conducted. We analyzed testicular volumes in different age groups using the UDT to normally descended testis ratio and testicular GPR. A total of 134 boys with unilateral undescended testicle underwent regular ultrasonography follow-up examinations for more than a mean of 3.9 years. Forty-five (33.4%) of them underwent orchiopexy before the age of one year. Orchiopexy at this age resulted in a GPR (2.02 +/- 0.40) that was significantly higher than the GPRs in the second (1 < age <= 2 years, 1.25 +/- 0.13, p = 0.004) and third (age > 2 years, 1.24 +/- 0.14 p = 0.008) age groups. The undescended testicle grew faster when orchiopexy was performed before one year of age. Orchiopexy performed within one year from birth significantly accelerates the growth of the UDT, as determined using the GPR, compared to other age groups. The present clinical evidence indicates that orchiopexy should be performed before one year of age. PMID- 29234091 TI - Structural reorganization of the early visual cortex following Braille training in sighted adults. AB - Training can induce cross-modal plasticity in the human cortex. A well-known example of this phenomenon is the recruitment of visual areas for tactile and auditory processing. It remains unclear to what extent such plasticity is associated with changes in anatomy. Here we enrolled 29 sighted adults into a nine-month tactile Braille-reading training, and used voxel-based morphometry and diffusion tensor imaging to describe the resulting anatomical changes. In addition, we collected resting-state fMRI data to relate these changes to functional connectivity between visual and somatosensory-motor cortices. Following Braille-training, we observed substantial grey and white matter reorganization in the anterior part of early visual cortex (peripheral visual field). Moreover, relative to its posterior, foveal part, the peripheral representation of early visual cortex had stronger functional connections to somatosensory and motor cortices even before the onset of training. Previous studies show that the early visual cortex can be functionally recruited for tactile discrimination, including recognition of Braille characters. Our results demonstrate that reorganization in this region induced by tactile training can also be anatomical. This change most likely reflects a strengthening of existing connectivity between the peripheral visual cortex and somatosensory cortices, which suggests a putative mechanism for cross-modal recruitment of visual areas. PMID- 29234094 TI - Facile Fabrication of Porous Conductive Thermoplastic Polyurethane Nanocomposite Films via Solution Casting. AB - Porous conductive polymers are one of important materials, featuring lightweight, large specific surface area and high porosity. Non-solvent induced phase separation is widely employed to prepare porous polymer sheet materials. Through utilizing water vapor in ambient environment as the non-solvent, a facile approach was developed to produce porous conductive polymer nanocomposites using the conventional solution-casting method. Without using any non-solvent liquids, porous carbon nanofiber/thermoplastic polyurethane (CNF/TPU) nanocomposites were prepared directly by solution casting of their dimethylformamide (DMF) solutions under ambient conditions. The strength of the CNF framework played a key role in preventing the collapse of pores during DMF evaporation. The dependence of porous structures on CNF loading was studied by scanning electron microscopy and porosity measurement. The influence of CNF loading on the mechanical properties, electrical conductivity and piezoresistive behavior was explored. PMID- 29234093 TI - CRISPR/Cas9 microinjection in oocytes disables pancreas development in sheep. AB - One of the ultimate goals of regenerative medicine is the generation of patient specific organs from pluripotent stem cells (PSCs). Sheep are potential hosts for growing human organs through the technique of blastocyst complementation. We report here the creation of pancreatogenesis-disabled sheep by oocyte microinjection of CRISPR/Cas9 targeting PDX1, a critical gene for pancreas development. We compared the efficiency of target mutations after microinjecting the CRISPR/Cas9 system in metaphase II (MII) oocytes and zygote stage embryos. MII oocyte microinjection reduced lysis, improved blastocyst rate, increased the number of targeted bi-allelic mutations, and resulted in similar degree of mosaicism when compared to zygote microinjection. While the use of a single sgRNA was efficient at inducing mutated fetuses, the lack of complete gene inactivation resulted in animals with an intact pancreas. When using a dual sgRNA system, we achieved complete PDX1 disruption. This PDX1-/- fetus lacked a pancreas and provides the basis for the production of gene-edited sheep as a host for interspecies organ generation. In the future, combining gene editing with CRISPR/Cas9 and PSCs complementation could result in a powerful approach for human organ generation. PMID- 29234095 TI - Enclaves of genetic diversity resisted Inca impacts on population history. AB - The Inca Empire is claimed to have driven massive population movements in western South America, and to have spread Quechua, the most widely-spoken language family of the indigenous Americas. A test-case is the Chachapoyas region of northern Peru, reported as a focal point of Inca population displacements. Chachapoyas also spans the environmental, cultural and demographic divides between Amazonia and the Andes, and stands along the lowest-altitude corridor from the rainforest to the Pacific coast. Following a sampling strategy informed by linguistic data, we collected 119 samples, analysed for full mtDNA genomes and Y-chromosome STRs. We report a high indigenous component, which stands apart from the network of intense genetic exchange in the core central zone of Andean civilization, and is also distinct from neighbouring populations. This unique genetic profile challenges the routine assumption of large-scale population relocations by the Incas. Furthermore, speakers of Chachapoyas Quechua are found to share no particular genetic similarity or gene-flow with Quechua speakers elsewhere, suggesting that here the language spread primarily by cultural diffusion, not migration. Our results demonstrate how population genetics, when fully guided by the archaeological, historical and linguistic records, can inform multiple disciplines within anthropology. PMID- 29234097 TI - Observation of deformation twinning and martensitic transformation during nanoindentation of a transformation-induced plasticity steel. AB - For the first time, deformation twinning and martensitic transformation were observed in retained austenite in a low-alloyed transformation-induced plasticity steel using nanoindentation in conjunction with electron backscattering diffraction and transmission electron microscopy. Dislocation glide, martensite formation and deformation twinning were correlated to pop-ins and deviation from linearity in the load-displacement curve. Deformation twinning was found to enhance the stability of retained austenite. This observation furthers our understanding of RA stability during straining of low-alloyed multiphase TRIP steel. PMID- 29234096 TI - Transit and integration of extracellular mitochondria in human heart cells. AB - Tissue ischemia adversely affects the function of mitochondria, which results in impairment of oxidative phosphorylation and compromised recovery of the affected organ. The impact of ischemia on mitochondrial function has been extensively studied in the heart because of the morbidity and mortality associated with injury to this organ. As conventional methods to preserve cardiac cell viability and contractile function following ischemia are limited in their efficacy, we developed a unique approach to protect the heart by transplanting respiration competent mitochondria to the injured region. Our previous animal experiments showed that transplantation of isolated mitochondria to ischemic heart tissue leads to decreases in cell death, increases in energy production, and improvements in contractile function. We also discovered that exogenously-derived mitochondria injected or perfused into ischemic hearts were rapidly internalised by cardiac cells. Here, we used three-dimensional super-resolution microscopy and transmission electron microscopy to determine the intracellular fate of endocytosed exogenous mitochondria in human iPS-derived cardiomyocytes and primary cardiac fibroblasts. We found isolated mitochondria are incorporated into cardiac cells within minutes and then transported to endosomes and lysosomes. The majority of exogenous mitochondria escape from these compartments and fuse with the endogenous mitochondrial network, while some of these organelles are degraded through hydrolysis. PMID- 29234098 TI - A Wide Dynamic Range Polarization Sensing Long Wave Infrared Detector. AB - We present the design, fabrication, and characterization of an infrared (IR) polarization sensing detector with a wide dynamic range and sub-wavelength dimensions. The detector consists of two orthogonal slot antennas, each loaded with two microbolometers at its edges. The polarization of the incoming IR radiation is detected by comparing the received power levels in the bolometer pairs corresponding to each slot antenna. The IR radiation is sensed by applying a dc bias voltage to each antenna and measuring the changes in the dc current caused by the change of the bolometer resistance as they absorb the incoming IR radiation. In this design, the ratio of the absorbed power in the bolometers is a one to one function of the polarization of the incident wave. A prototype of this detector, designed to have maximum sensitivity at lambda = 10.6 MUm, was designed, fabricated, and characterized. The fabricated detector has an area of 0.7lambda * 0.7lambda, where lambda is the free-space wavelength. The polarization sensing response is characterized under different angles of incidence. The measurement results show that the device has a dynamic range of 24 dB between two orthogonal orientations of EM wave polarization for incidence angles in the range of +/-20 degrees from boresight. PMID- 29234099 TI - Characterization of ozone in the lower troposphere during the 2016 G20 conference in Hangzhou. AB - Recently, atmospheric ozone pollution has demonstrated an aggravating tendency in China. To date, most research about atmospheric ozone has been confined near the surface, and an understanding of the vertical ozone structure is limited. During the 2016 G20 conference, strict emission control measures were implemented in Hangzhou, a megacity in the Yangtze River Delta, and its surrounding regions. Here, we monitored the vertical profiles of ozone concentration and aerosol extinction coefficients in the lower troposphere using an ozone lidar, in addition to the vertical column densities (VCDs) of ozone and its precursors in the troposphere through satellite-based remote sensing. The ozone concentrations reached a peak near the top of the boundary layer. During the control period, the aerosol extinction coefficients in the lower lidar layer decreased significantly; however, the ozone concentration fluctuated frequently with two pollution episodes and one clean episode. The sensitivity of ozone production was mostly within VOC-limited or transition regimes, but entered a NOx-limited regime due to a substantial decline of NOx during the clean episode. Temporary measures took no immediate effect on ozone pollution in the boundary layer; instead, meteorological conditions like air mass sources and solar radiation intensities dominated the variations in the ozone concentration. PMID- 29234100 TI - A Bi-fluorescence complementation system to detect associations between the Endoplasmic reticulum and mitochondria. AB - Close contacts between the endoplasmic reticulum membrane and the mitochondrial outer membrane facilitate efficient transfer of lipids between the organelles and coordinate Ca2+ signalling and stress responses. Changes to this coupling is associated with a number of metabolic disorders and neurodegenerative diseases including Alzheimer's, Parkinson's and motor neuron disease. The distance between the two membranes at regions of close apposition is below the resolution of conventional light microscopy, which makes analysis of these interactions challenging. Here we describe a new bifluorescence complementation (BiFC) method that labels a subset of ER-mitochondrial associations in fixed and living cells. The total number of ER-mitochondria associations detected by this approach increases in response to tunicamycin-induced ER stress, serum deprivation or reduced levels of mitofusin 2 (MFN2). This method will facilitate the analysis of dynamic interactions between the ER and mitochondrial membranes. PMID- 29234101 TI - Spatial-Temporal Variation of Drought in China from 1982 to 2010 Based on a modified Temperature Vegetation Drought Index (mTVDI). AB - Droughts cause huge losses of society and environment, therefore it is important to study the spatial-temporal pattern of drought. The traditional remote sensing drought indices (AVI, VCI and TCI) only consider the single factor representing the soil moisture (surface temperature or NDVI). The comprehensive remote sensing drought indices (VSWI and TVDI) can estimate the soil moisture more accurately, but they are not suitable for large scale region especially with great elevation variation. In this study, a modified Temperature Vegetation Drought Index (mTVDI) was constructed based on the correction of elevation and dry edge. Compared with the traditional drought indices, mTVDI had a better relationship with soil moisture in all selected months (R = -0.376, -0.406, -0.459, and -0.265, p < 0.05). mTVDI was used to analyze the spatial-temporal patterns of drought in China from 1982 to 2010. The results showed that droughts appeared more frequently in Northwest China and the southwest of Tibet while drought centers of North and Southwest China appeared in Huanghuaihai Plain and Yunnan-Guizhou Plateau respectively. The frequency of drought was increasing as a whole while the frequency of severe drought increased significantly by 4.86% and slight drought increased slowly during 1982 to 2010. The results are useful for the understanding of drought and policy making of climate change. PMID- 29234102 TI - Endometrial apoptosis and neutrophil infiltration during menstruation exhibits spatial and temporal dynamics that are recapitulated in a mouse model. AB - Menstruation is characterised by synchronous shedding and restoration of tissue integrity. An in vivo model of menstruation is required to investigate mechanisms responsible for regulation of menstrual physiology and to investigate common pathologies such as heavy menstrual bleeding (HMB). We hypothesised that our mouse model of simulated menstruation would recapitulate the spatial and temporal changes in the inflammatory microenvironment of human menses. Three regulatory events were investigated: cell death (apoptosis), neutrophil influx and cytokine/chemokine expression. Well-characterised endometrial tissues from women were compared with uteri from a mouse model (tissue recovered 0, 4, 8, 24 and 48 h after removal of a progesterone-secreting pellet). Immunohistochemistry for cleaved caspase-3 (CC3) revealed significantly increased staining in human endometrium from late secretory and menstrual phases. In mice, CC3 was significantly increased at 8 and 24 h post-progesterone-withdrawal. Elastase+ human neutrophils were maximal during menstruation; Ly6G+ mouse neutrophils were maximal at 24 h. Human endometrial and mouse uterine cytokine/chemokine mRNA concentrations were significantly increased during menstrual phase and 24 h post progesterone-withdrawal respectively. Data from dated human samples revealed time dependent changes in endometrial apoptosis preceding neutrophil influx and cytokine/chemokine induction during active menstruation. These dynamic changes were recapitulated in the mouse model of menstruation, validating its use in menstrual research. PMID- 29234103 TI - An Exhaustive Search Algorithm to Aid NMR-Based Structure Determination of Rotationally Symmetric Transmembrane Oligomers. AB - Nuclear magnetic resonance (NMR) has been an important source of structural restraints for solving structures of oligomeric transmembrane domains (TMDs) of cell surface receptors and viral membrane proteins. In NMR studies, oligomers are assembled using inter-protomer distance restraints. But, for oligomers that are higher than dimer, these distance restraints all have two-fold directional ambiguity, and resolving such ambiguity often requires time-consuming trial-and error calculations using restrained molecular dynamics (MD) with simulated annealing (SA). We report an Exhaustive Search algorithm for Symmetric Oligomer (ExSSO), which can perform near-complete search of the symmetric conformational space in a very short time. In this approach, the predetermined protomer model is subject to full angular and spatial search within the symmetry space. This approach, which can be applied to any rotationally symmetric oligomers, was validated using the structures of the Fas death receptor, the HIV-1 gp41 fusion protein, the influenza proton channel, and the MCU pore. The algorithm is able to generate approximate oligomer solutions quickly as initial inputs for further refinement using the MD/SA method. PMID- 29234104 TI - Conjunction of potential G-quadruplex and adjacent cis-elements in the 5' UTR of hepatocyte nuclear factor 4-alpha strongly inhibit protein expression. AB - Hepatocyte nuclear factor 4-alpha (HNF4alpha) is a well established master regulator of liver development and function. We identified the in vitro presence of a stable secondary structure, G-quadruplex (G4) in the 5' UTR of P1-HNF4A, the predominant HNF4alpha isoform(s) in adult liver. Our data suggest that the cooperation of G4 and the adjacent putative protein-binding sites within the 5' UTR was necessary and sufficient to mediate a strong translational repression. This was supported by analysis of deleted/mutated 5'UTRs and two native regulatory single-nucleotide polymorphisms in the 5'UTR. Additional results indicated that G4 motifs in the 5' UTRs of other liver-enriched transcription factors also inhibited protein expression. Moreover, pyridostatin, a G4 ligand, specifically potentiated the translational suppressing effect of P1-HNF4A-5' UTR. In summary, the present study provides the first evidence of the presence of G4 in human P1-HNF4A-5' UTR in vitro, and establishes a novel working model of strong inhibition of protein translation via interactions of G4 with potential RNA-binding proteins (RBPs). The protein expression of the tumor suppressor HNF4alpha may be inhibited by interactions of RBPs with the G4 motif in the 5' UTR to promote cell proliferation during liver development and carcinogenesis. PMID- 29234105 TI - All-nanotube stretchable supercapacitor with low equivalent series resistance. AB - We report high-performance, stable, low equivalent series resistance all-nanotube stretchable supercapacitor based on single-walled carbon nanotube film electrodes and a boron nitride nanotube separator. A layer of boron nitride nanotubes, fabricated by airbrushing from isopropanol dispersion, allows avoiding problem of high internal resistance and short-circuiting of supercapacitors. The device, fabricated in a two-electrode test cell configuration, demonstrates electrochemical double layer capacitance mechanism and retains 96% of its initial capacitance after 20 000 electrochemical charging/discharging cycles with the specific capacitance value of 82 F g-1 and low equivalent series resistance of 4.6 Omega. The stretchable supercapacitor prototype withstands at least 1000 cycles of 50% strain with a slight increase in the volumetric capacitance from 0.4 to 0.5 mF cm-3 and volumetric power density from 32 mW cm-3 to 40 mW cm-3 after stretching, which is higher than reported before. Moreover, a low resistance of 250 Omega for the as-fabricated stretchable prototype was obtained, which slightly decreased with the strain applied up to 200 Omega. Simple fabrication process of such devices can be easily extended making the all nanotube stretchable supercapacitors, presented here, promising elements in future wearable devices. PMID- 29234106 TI - First demonstration of coherent Cherenkov radiation matched to circular plane wave. AB - We observed coherent Cherenkov radiation matched to a circular plane wave (CCR MCP) for the first time using a hollow conical dielectric made of a high-density polyethylene. The refractive index and the absorption coefficient of the dielectric were evaluated to be 1.537 +/- 0.004 and 0.006 +/- 0.028 by measuring the pulse formed by the interference between the CCR-MCP and the coherent diffraction radiation. These values were consistent with the values shown in a reference for the high-density polyethylene. In accordance with the theory of the Cherenkov radiation, the spectrum of the CCR-MCP shifted towards higher wavenumbers compared to that of the coherent diffraction radiation. The intensity of the CCR-MCP beam was proportional to the height of the hollow conical dielectric and was 3 times the intensity of the coherent diffraction radiation. The CCR-MCP technique can produce broadband terahertz-wave sources with unprecedented power at compact accelerator facilities. PMID- 29234107 TI - Bulky Lesion Bypass Requires Dpo4 Binding in Distinct Conformations. AB - Translesion DNA synthesis is an essential process that helps resume DNA replication at forks stalled near bulky adducts on the DNA. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon (PAH) that can be metabolically activated to benzo[a]pyrene diol epoxide (BPDE), which then can react with DNA to form carcinogenic DNA adducts. Here, we have used single-molecule florescence resonance energy transfer (smFRET) experiments, classical molecular dynamics simulations, and nucleotide incorporation assays to investigate the mechanism by which the model Y-family polymerase, Dpo4, bypasses a (+)-cis-B[a]P-N 2-dG adduct in DNA. Our data show that when (+)-cis-B[a]P-N 2-dG is the templating base, the B[a]P moiety is in a non-solvent exposed conformation stacked within the DNA helix, where it effectively blocks nucleotide incorporation across the adduct by Dpo4. However, when the media contains a small amount of dimethyl sulfoxide (DMSO), the adduct is able to move to a solvent-exposed conformation, which enables error-prone DNA replication past the adduct. When the primer terminates across from the adduct position, the addition of DMSO leads to the formation of an insertion complex capable of accurate nucleotide incorporation. PMID- 29234108 TI - Mother-to-newborn transmission of mycobacterial L-forms and Vdelta2 T-cell response in placentobiome of BCG-vaccinated pregnant women. AB - The ability of bacteria to exist as a population of self-replicating forms with defective or entirely missing cell wall (L-forms) is an adaptive mechanism for their survival and reproduction under unfavorable conditions. Bacterial mother-to fetus transfer is a universal phenomenon in the animal kingdom. However, data about vertical transfer of L bacterial forms are extremely scarce. Bacille Calmette-Guerin is an attenuated strain of M. bovis and the only licensed vaccine used for tuberculosis prevention. We already have shown that filterable L-forms of BCG exist freely in the vaccine and are able to reproduce and to form colonies. The present study was focused on the placental microbiome in the context of mother's BCG vaccination. Here we report an isolation of filterable mycobacterial L-form cultures from gestational tissues and blood of healthy newborns delivered by healthy BCG-vaccinated mothers after normal pregnancy. Of note, vertically transmitted mycobacterial L-forms as a part of placentobiome of the pregnant women didn't influence the number of resident pathogen-reactive Vdelta2 cells. Placenta colonization with mycobacterial L-forms occurs by maternal blood-to-decidua transfer very early in gestation. Together, these data showed that BCG L-forms have the capacity to pass trans-placental barrier and that maternal BCG vaccination affects the placentobiome. PMID- 29234109 TI - The AP-1 transcription factor JunB is required for Th17 cell differentiation. AB - Interleukin (IL)-17-producing T helper (Th17) cells are crucial for host defense against extracellular microbes and pathogenesis of autoimmune diseases. Here we show that the AP-1 transcription factor JunB is required for Th17 cell development. Junb-deficient CD4+ T cells are able to develop in vitro into various helper T subsets except Th17. The RNA-seq transcriptome analysis reveals that JunB is crucial for the Th17-specific gene expression program. Junb deficient mice are completely resistant to experimental autoimmune encephalomyelitis, a Th17-mediated inflammatory disease, and naive T helper cells from such mice fail to differentiate into Th17 cells. JunB appears to activate Th17 signature genes by forming a heterodimer with BATF, another AP-1 factor essential for Th17 differentiation. The mechanism whereby JunB controls Th17 cell development likely involves activation of the genes for the Th17 lineage specifying orphan receptors RORgammat and RORalpha and reduced expression of Foxp3, a transcription factor known to antagonize RORgammat function. PMID- 29234110 TI - Macroscopic phase separation of superconductivity and ferromagnetism in Sr0.5Ce0.5FBiS2-x Se x revealed by MUSR. AB - The compound Sr0.5Ce0.5FBiS2 belongs to the intensively studied family of layered BiS2 superconductors. It attracts special attention because superconductivity at T sc = 2.8 K was found to coexist with local-moment ferromagnetic order with a Curie temperature T C = 7.5 K. Recently it was reported that upon replacing S by Se T C drops and ferromagnetism becomes of an itinerant nature. At the same time T sc increases and it was argued superconductivity coexists with itinerant ferromagnetism. Here we report a muon spin rotation and relaxation study (MUSR) conducted to investigate the coexistence of superconductivity and ferromagnetic order in Sr0.5Ce0.5FBiS2-x Se x with x = 0.5 and 1.0. By inspecting the muon asymmetry function we find that both phases do not coexist on the microscopic scale, but occupy different sample volumes. For x = 0.5 and x = 1.0 we find a ferromagnetic volume fraction of ~8 % and ~30 % at T = 0.25 K, well below T C = 3.4 K and T C = 3.3 K, respectively. For x = 1.0 (T sc = 2.9 K) the superconducting phase occupies most (~64 %) of the remaining sample volume, as shown by transverse field experiments that probe the Gaussian damping due to the vortex lattice. We conclude ferromagnetism and superconductivity are macroscopically phase separated. PMID- 29234111 TI - Generation and Analysis of High-Gain Orbital Angular Momentum Vortex Wave Using Circular Array and Parasitic EBG with oblique incidence. AB - This paper presents an effective method for high-gain orbital angular momentum (OAM) vortex wave generation based on the integration of a circular antenna array (CAA) with a parasitic electromagnetic band gap (EBG) structure, which is referred to as the EP-CAA. The resonant height of the EBG structure at different oblique incidences is analyzed parametrically based on the defect mode transmission mechanism to achieve reasonable predictions of a consistent 3-dB gain bandwidth with optimal gain enhancement for different OAM modes. The effective radiation aperture of the EP-CAA at oblique incidence is proposed for analytical calculation of the aperture efficiency of the OAM beams (OAM-AE). A Wilkinson power divider (W-PD) is designed to extend the operating bandwidth of the EP-CAA, and the proposed W-PD arrangement is applicable for feasible OAM modes. Fabricated prototypes of the EP-CAA carrying four OAM modes operating at 10 GHz are measured to verify the effectiveness of the theoretical analysis, the maximum realized gain for different OAM modes are confirmed to be enhanced by at least 6 dB in 5% 3-dB gain bandwidth. The divergence angles of different OAM modes can be effectively concentrated using the proposed EP-CAA. PMID- 29234112 TI - A switch in nucleotide affinity governs activation of the Src and Tec family kinases. AB - The Tec kinases, closely related to Src family kinases, are essential for lymphocyte function in the adaptive immune system. Whilst the Src and Abl kinases are regulated by tail phosphorylation and N-terminal myristoylation respectively, the Tec kinases are notable for the absence of either regulatory element. We have found that the inactive conformations of the Tec kinase Itk and Src preferentially bind ADP over ATP, stabilising both proteins. We demonstrate that Itk adopts the same conformation as Src and that the autoinhibited conformation of Src is independent of its C-terminal tail. Allosteric activation of both Itk and Src depends critically on the disruption of a conserved hydrophobic stack that accompanies regulatory domain displacement. We show that a conformational switch permits the exchange of ADP for ATP, leading to efficient autophosphorylation and full activation. In summary, we propose a universal mechanism for the activation and autoinhibition of the Src and Tec kinases. PMID- 29234113 TI - Principles of Economic Rationality in Mice. AB - Humans and non-human animals frequently violate principles of economic rationality, such as transitivity, independence of irrelevant alternatives, and regularity. The conditions that lead to these violations are not completely understood. Here we report a study on mice tested in automated home-cage setups using rewards of drinking water. Rewards differed in one of two dimensions, volume or probability. Our results suggest that mouse choice conforms to the principles of economic rationality for options that differ along a single reward dimension. A psychometric analysis of mouse choices further revealed that mice responded more strongly to differences in probability than to differences in volume, despite equivalence in return rates. This study also demonstrates the synergistic effect between the principles of economic rationality and psychophysics in making quantitative predictions about choices of healthy laboratory mice. This opens up new possibilities for the analyses of multi dimensional choice and the use of mice with cognitive impairments that may violate economic rationality. PMID- 29234116 TI - The response of an arboreal mammal to livestock grazing is habitat dependant. AB - Inappropriate livestock grazing is implicated in the decline of vertebrate fauna species globally. Faunal responses to grazing can interact with the vegetation community in which they occur. We measured the response of an arboreal marsupial, the common brushtail possum (Trichosurus vulpecula vulpecula) to different cattle grazing strategies and vegetation types, and examined whether micro-habitat selection is driving this response. We hypothesised that where arboreal habitat is intact, brushtail possums would be resistant to the impacts of heavy grazing. We conducted a mark-recapture survey among four grazing treatments and in two vegetation types (Box and Ironbark), at a 20-year grazing trial in northern Australia. We found that brushtail possums were resistant to the impact of heavy grazing in both vegetation types, but preferred the heavy grazing treatment in the Box vegetation type. Complex arboreal habitat and low ground cover was preferred, and high grass cover and low tree species richness avoided. Most individuals exclusively used one vegetation type, with few using both, suggesting a 'matrix' vegetation between the Box and Ironbark may be creating a movement barrier. Vegetation type should provide a context for determining the benefits to arboreal wildlife of adopting a particular grazing management strategy. PMID- 29234114 TI - Probing the requirement for CD38 in retinoic acid-induced HL-60 cell differentiation with a small molecule dimerizer and genetic knockout. AB - CD38 is an ectoenzyme and receptor with key physiological roles. It metabolizes NAD+ to adenosine diphosphate ribose (ADPR) and cyclic ADPR, regulating several processes including calcium signalling. CD38 is both a positive and negative prognostic indicator in leukaemia. In all-trans retinoic acid (RA)-induced differentiation of acute promyelocytic leukaemia and HL-60 cells, CD38 is one of the earliest and most prominently upregulated proteins known. CD38 overexpression enhances differentiation, while morpholino- and siRNA-induced knockdown diminishes it. CD38, via Src family kinases and adapters, interacts with a MAPK signalling axis that propels differentiation. Motivated by evidence suggesting the importance of CD38, we sought to determine whether it functions via dimerization. We created a linker based on the suicide substrate arabinosyl-2' fluoro-2'-deoxy NAD+ (F-araNAD+), dimeric F-araNAD+, to induce homodimerization. CD38 homodimerization did not affect RA-induced differentiation. Probing the importance of CD38 further, we created HL-60 cell lines with CRISPR/Cas9-mediated CD38 truncations. Deletion of its enzymatic domain did not affect differentiation. Apart from increased RA-induced CD11b expression, ablation of all but the first six amino acids of CD38 affected neither RA-induced differentiation nor associated signalling. Although we cannot discount the importance of this peptide, our study indicates that CD38 is not necessary for RA induced differentiation. PMID- 29234117 TI - Probing the growth and melting pathways of a decagonal quasicrystal in real-time. AB - How does a quasicrystal grow? Despite the decades of research that have been dedicated to this area of study, it remains one of the fundamental puzzles in the field of crystal growth. Although there has been no lack of theoretical studies on quasicrystal growth, there have been very few experimental investigations with which to test their various hypotheses. In particular, evidence of the in situ and three-dimensional (3D) growth of a quasicrystal from a parent liquid phase is lacking. To fill-in-the-gaps in our understanding of the solidification and melting pathways of quasicrystals, we performed synchrotron-based X-ray imaging experiments on a decagonal phase with composition of Al-15at%Ni-15at%Co. High flux X-ray tomography enabled us to observe both growth and melting morphologies of the 3D quasicrystal at temperature. We determined that there is no time reversal symmetry upon growth and melting of the decagonal quasicrystal. While quasicrystal growth is predominantly dominated by the attachment kinetics of atomic clusters in the liquid phase, melting is instead barrier-less and limited by buoyancy-driven convection. These experimental results provide the much-needed benchmark data that can be used to validate simulations of phase transformations involving this unique phase of matter. PMID- 29234115 TI - The glutamic residue at position 402 in the C-terminus of Newcastle disease virus nucleoprotein is critical for the virus. AB - The nucleocapsid proteins (NPs) of Newcastle disease virus (NDV) and other paramyxoviruses play an important functional role during genomic RNA replication. Our previous study showed that the NP-encoding gene significantly influenced viral replication. Here, we investigated the roles of certain amino acid residues in the NP C-terminus in viral replication and virulence. Results showed that the glutamic acid residue at position 402 (E402) in the C-terminus of the NP is critical for RNA synthesis in the NDV mini-genome system. Mutation of E402 resulted in larger viral plaques that appeared more quickly, and increased the virulence of NDV. Further study indicated that the mutant virus had increased RNA levels during the early stages of virus infection, but that RNA replication was inhibited at later time points. These findings increase our knowledge of viral replication and contribute to a more comprehensive understanding of the virulence factors associated with NDV. PMID- 29234118 TI - Young's double-slit interference with two-color biphotons. AB - In classical optics, Young's double-slit experiment with colored coherent light gives rise to individual interference fringes for each light frequency, referring to single-photon interference. However, two-photon double-slit interference has been widely studied only for wavelength-degenerate biphoton, known as subwavelength quantum lithography. In this work, we report double-slit interference experiments with two-color biphoton. Different from the degenerate case, the experimental results depend on the measurement methods. From a two-axis coincidence measurement pattern we can extract complete interference information about two colors. The conceptual model provides an intuitional picture of the in phase and out-of-phase photon correlations and a complete quantum understanding about the which-path information of two colored photons. PMID- 29234119 TI - Non-malignant epithelial cells preferentially proliferate from nasopharyngeal carcinoma biopsy cultured under conditionally reprogrammed conditions. AB - Nasopharyngeal carcinoma (NPC) is an invasive cancer with particularly high incidence in Southern China and Southeast Asia. The study of NPC is greatly hampered by the lack of reliable cell lines due to the loss of EBV genome and HeLa cell contamination. Conditional reprogramming (CR) cell culture technique has been reported for rapid and efficient establishment of patient-derived normal and tumor cell cultures. The purpose of this study was to assess this method to culture NPC patient-derived primary tumor cells. Using CR protocol, we demonstrated that epithelial cells could be efficiently cultured from normal (70%) and cancerous nasopharyngeal (46%) biopsies. However, by comparing with original tumors in terms of mutation and methylation profiles, epithelial cells derived from cancerous biopsy represented non-malignant cells. Further, they exhibited stem-like characteristics based on their cell surface proteins and could differentiate into pseudostratified epithelium in an air-liquid interface culture system. We conclude that CR method is a highly selective and useful method for growing non-malignant nasopharyngeal epithelial cells. PMID- 29234120 TI - Oral epithelial cell sheets engraftment for esophageal strictures after endoscopic submucosal dissection of squamous cell carcinoma and airplane transportation. AB - Endoscopic submucosal dissection (ESD) permits en bloc removal of superficial oesophageal squamous cell carcinoma (ESCC). However, post-procedure stricture is common after ESD for widespread tumours, and multiple endoscopic balloon dilation (EBD) procedures are required. We aimed to evaluate the safety and effectiveness of endoscopic transplantation of tissue-engineered autologous oral mucosal epithelial cell sheets that had been transported by air over a distance of 1200 km in controlling postprocedural oesophageal stricture. Ten patients who underwent complete circular or semicircular ESD for ESCC were transplanted with cell sheets. The safety of the entire process including cell sheet preparation, transport, ESD and cell sheet transplantation was assessed. The incidence of oesophageal stricture, number of EBD sessions, and time until epithelialization were investigated. Each ESD was successfully performed, with subsequent cell sheet engrafting carried out safely. Following cell sheet transplantation, the luminal stenosis rate was 40%, while the median number of EBD sessions was 0. The median post-ESD ulcer healing period was rather short at 36 days. There were no significant complications at any stage of the process. Cell sheet transplantation and preparation at distant sites and transportation by air could be a safe and promising regenerative medicine technology. PMID- 29234121 TI - In silico modelling to differentiate the contribution of sugar frequency versus total amount in driving biofilm dysbiosis in dental caries. AB - Dental caries is the most prevalent infection globally and a substantial economic burden in developed countries. Dietary sugars are the main risk factor, and drive increased proportions of acid-producing and acid-tolerating (aciduric) bacterial species within dental biofilms. Recent longitudinal studies have suggested that caries is most strongly correlated with total sugar intake, contrasting with the prevailing view that intake frequency is the primary determinant. To explore this possibility, we employed a computational model for supragingival plaque to systematically sample combinations of sugar frequency and total amount, allowing their independent contributions on the ratio of aciduric (i.e. cariogenic) to non aciduric bacteria to be unambiguously determined. Sugar frequency was found to be irrelevant for either very high or very low daily total amounts as the simulated biofilm was predicted to be always or never cariogenic, respectively. Frequency was a determining factor for intermediate total amounts of sugar, including the estimated average human consumption. An increased risk of caries (i.e. high prevalence of aciduric/non-aciduric species) was predicted for high intake frequencies. Thus, both total amount and frequency of sugar intake may combine to influence plaque cariogenicity. These findings could be employed to support public guidance for dietary change, leading to improved oral healthcare. PMID- 29234122 TI - Transcriptome-wide analysis of natural antisense transcripts shows their potential role in breast cancer. AB - Non-coding RNAs (ncRNA) represent 1/5 of the mammalian transcript number, and 90% of the genome length is transcribed. Many ncRNAs play a role in cancer. Among them, non-coding natural antisense transcripts (ncNAT) are RNA sequences that are complementary and overlapping to those of either protein-coding (PCT) or non coding transcripts. Several ncNATs were described as regulating protein coding gene expression on the same loci, and they are expected to act more frequently in cis compared to other ncRNAs that commonly function in trans. In this work, 22 breast cancers expressing estrogen receptors and their paired adjacent non malignant tissues were analyzed by strand-specific RNA sequencing. To highlight ncNATs potentially playing a role in protein coding gene regulations that occur in breast cancer, three different data analysis methods were used: differential expression analysis of ncNATs between tumor and non-malignant tissues, differential correlation analysis of paired ncNAT/PCT between tumor and non malignant tissues, and ncNAT/PCT read count ratio variation between tumor and non malignant tissues. Each of these methods yielded lists of ncNAT/PCT pairs that were enriched in survival-associated genes. This work highlights ncNAT lists that display potential to affect the expression of protein-coding genes involved in breast cancer pathology. PMID- 29234123 TI - DUSP1 regulates apoptosis and cell migration, but not the JIP1-protected cytokine response, during Respiratory Syncytial Virus and Sendai Virus infection. AB - The host antiviral response involves the induction of interferons and proinflammatory cytokines, but also the activation of cell death pathways, including apoptosis, to limit viral replication and spreading. This host defense is strictly regulated to eliminate the infection while limiting tissue damage that is associated with virus pathogenesis. Post-translational modifications, most notably phosphorylation, are key regulators of the antiviral defense implying an important role of protein phosphatases. Here, we investigated the role of the dual-specificity phosphatase 1 (DUSP1) in the host defense against human respiratory syncytial virus (RSV), a pathogenic virus of the Pneumoviridae family, and Sendai virus (SeV), a model virus being developed as a vector for anti-RSV vaccine. We found that DUSP1 is upregulated before being subjected to proteasomal degradation. DUSP1 does not inhibit the antiviral response, but negatively regulates virus-induced JNK/p38 MAPK phosphorylation. Interaction with the JNK-interacting protein 1 scaffold protein prevents dephosphorylation of JNK by DUSP1, likely explaining that AP-1 activation and downstream cytokine production are protected from DUSP1 inhibition. Importantly, DUSP1 promotes SeV induced apoptosis and suppresses cell migration in RSV-infected cells. Collectively, our data unveils a previously unrecognized selective role of DUSP1 in the regulation of tissue damage and repair during infections by RSV and SeV. PMID- 29234124 TI - Mechanistic Insights into the Reaction of Chlorination of Tryptophan Catalyzed by Tryptophan 7-Halogenase. AB - Tryptophan 7-halogenase catalyzes chlorination of free tryptophan to 7 chlorotryptophan, which is the first step in the antibiotic pyrrolnitrin biosynthesis. Many biologically and pharmaceutically active natural products contain chlorine and thus, an understanding of the mechanism of its introduction into organic molecules is important. Whilst enzyme-catalyzed chlorination is accomplished with ease, it remains a difficult task for the chemists. Therefore, utilizing enzymes in the synthesis of chlorinated organic compounds is important, and providing atomistic mechanistic insights about the reaction mechanism of tryptophan 7-halogenase is vital and timely. In this work, we examined a mechanism for the reaction of tryptophan chlorination, performed by tryptophan 7 halogenase, by calculating potential energy and free energy surfaces using two different Combined Quantum Mechanical/Molecular Mechanical (QM/MM) methods both employing Density Functional Theory (DFT) for the QM region. Both computational strategies agree on the nature of the rate-limiting step and provided close results for the reaction barriers of the two reaction steps. The calculations for both the potential energy and the free energy profiles showed very similar geometric features and hydrogen bonding interactions for the characterized stationary points. PMID- 29234125 TI - Comparison between dual-energy X-ray absorptiometry and skinfold thickness in assessing body fat in overweigh/obese adult patients with type-2 diabetes. AB - Percentage of body fat (%BF) is estimated in clinical practice using anthropometric equations, but little is known about their reliability in overweight/obese patients with type-2 diabetes. The aim of this study was to compare, in overweight/obese adults with type-2 diabetes, %BF estimated with several commonly used anthropometric equations and %BF measured with dual-energy X-ray absorptiometry (DXA, Hologic). The %BF was measured with DXA in 40 patients aged 40-68 years with type-2 diabetes (mean HbA1c, 7.3 +/- 0.9%). Body density was estimated in the same patients by means of four anthropometric equations and converted to %BF using the Siri and Brozek equations. Paired-sample t-test and the mean signed difference procedure were used to compare anthropometric equation derived %BF and DXA measurements. The coefficient of determination was computed. Bland-Altman analysis was used to test the agreement between methods. Among the four anthropometric equations, the Durnin-Womersley equation only showed close agreement with DXA in both female and male patients; the other equations significantly underestimated or overestimated %BF. Two new predictive equations were developed using DXA as the reference to predict total body and trunk %BF. Further comparative studies are required to confirm and refine the accuracy of practical, non-invasive methods for monitoring %BF in this population. PMID- 29234126 TI - Epidermal cornification is preceded by the expression of a keratinocyte-specific set of pyroptosis-related genes. AB - The homeostasis of the epidermis depends on keratinocyte differentiation and cornification, a mode of programmed cell death that does not elicit inflammation. Here, we report that cornification is associated with the expression of specific genes that control multiple steps of pyroptosis, another form of cell death that involves the processing and release of interleukin-1 family (IL1F) cytokines. Expression levels of pro-inflammatory IL1A and IL1B and of the pyroptotic pore forming gasdermin (GSDM) D were downregulated during terminal differentiation of human keratinocytes in vitro. By contrast, negative regulators of IL-1 processing, including NLR family pyrin domain containing 10 (NLRP10) and pyrin domain-containing 1 (PYDC1), the anti-inflammatory IL1F members IL-37 (IL1F7) and IL-38 (IL1F10), and GSDMA, were strongly induced in differentiated keratinocytes. In human tissues, these keratinocyte differentiation-associated genes are expressed in the skin at higher levels than in any other organ, and mammalian species, that have lost the epidermal cornification program during evolution, i.e. whales and dolphins, lack homologs of these genes. Together, our results suggest that human epidermal cornification is accompanied by a tight control of pyroptosis and warrant further studies of potential defects in the balance between cornification and pyroptosis in skin pathologies. PMID- 29234127 TI - Recent spread of Varroa destructor virus-1, a honey bee pathogen, in the United States. AB - RNA viruses impact honey bee health and contribute to elevated colony loss rates worldwide. Deformed wing virus (DWV) and the closely related Varroa destructor virus-1 (VDV1), are the most widespread honey bee viruses. VDV1 is known to cause high rates of overwintering colony losses in Europe, however it was unknown in the United States (US). Using next generation sequencing, we identified VDV1 in honey bee pupae in the US. We tested 603 apiaries the US in 2016 and found that VDV1 was present in 66.0% of them, making it the second most prevalent virus after DWV, which was present in 89.4% of the colonies. VDV1 had the highest load in infected bees (7.45*1012 +/- 1.62*1012 average copy number +/- standard error) compared to other tested viruses, with DWV second (1.04*1012 +/- 0.53*1012). Analysis of 75 colonies sourced in 2010 revealed that VDV1 was present in only 2 colonies (2.7%), suggesting its recent spread. We also detected newly emerged recombinants between the US strains of VDV1 and DWV. The presence of these recombinants poses additional risk, because similar VDV1-DWV recombinants constitute the most virulent honeybee viruses in the UK. PMID- 29234128 TI - States and traits of neural irregularity in the age-varying human brain. AB - Sensory representations, and thus human percepts, of the physical world are susceptible to fluctuations in brain state or "neural irregularity". Furthermore, aging brains display altered levels of neural irregularity. We here show that a single, within-trial, information-theoretic measure (weighted permutation entropy) captures neural irregularity in the human electroencephalogram as a proxy for both, trait-like differences between individuals of varying age, and state-like fluctuations that bias perceptual decisions. First, the overall level of neural irregularity increased with participants' age, paralleled by a decrease in variability over time, likely indexing age-related changes at structural and functional levels of brain activity. Second, states of higher neural irregularity were associated with optimized sensory encoding and a subsequently increased probability of choosing the first of two physically identical stimuli to be higher in pitch. In sum, neural irregularity not only characterizes behaviourally relevant brain states, but also can identify trait-like changes that come with age. PMID- 29234129 TI - Baseline Chloride Levels are Associated with the Incidence of Contrast-Associated Acute Kidney Injury. AB - Although hypo- and hyperchloremia have been associated with worsening renal outcomes, there has been no study that correlates hypo- and hyperchloremia and the incidence of contrast-associated acute kidney injury (CA-AKI). A total of 13,088 patients with less than 2.0 mg/dL of serum creatinine (Cr) who underwent contrast-enhanced abdominal CT (CECT) were included. Patients were divided into 3 groups based on Cl (the hypo-, normo- and hyperchloremia groups). Patients were also classified by baseline Cr (<1.2; the 'Normal Cr group' and 1.2-2.0 mg/dL; the 'Slightly increased Cr group'). Multivariate logistic regression analysis was used to reveal the association between Cl and CA-AKI. Among patients, 2,525 (19.3%) and 241 (1.8%) patients were classified in the hypo- and hyperchloremia group. The incidence of CA-AKI was significantly lower in the normochloremia group (4.0%) compared to the hypo- (5.4%) and hyperchloremia groups (9.5%). On multivariate logistic regression, hypochloremia was significantly associated with the incidence of CA-AKI compared with normochloremia (1.382, P = 0.002). Moreover, hypochloremia was still significantly associated with the incidence of CA-AKI in 'Normal Cr group' compared with normochloremia (1.314, P = 0.015), while hyperchloremia did not show significant association with CA-AKI incidence. In conclusion, hypochloremia might be associated with the incidence of CA-AKI even in patients who have normal-range Cr levels. PMID- 29234130 TI - A 6-DOF Navigation Method based on Iterative Closest Imaging Point Algorithm. AB - To achieve six degree-of-freedom autonomous navigation of an inboard spacecraft, a novel algorithm called iterative closest imaging point (ICIP) is proposed, which deals with the pose estimation problem of a vision navigation system (VNS). This paper introduces the basics of the ICIP algorithm, including mathematical model, algorithm architecture, and convergence theory. On this basis, a navigation method is proposed. This method realizes its initialization using a Gaussian mixture model-based Kalman filter, which simultaneously solves the 3D-to 2D point correspondences and the camera pose. The initial value sensitivity, computational efficiency, robustness, and accuracy of the proposed navigation method are discussed based on simulation results. A navigation experiment verifies that the proposed method works effectively. The three-axis Euler angle accuracy is within 0.19 degrees (1sigma), and the three-axis position accuracy is within 1.87 mm (1sigma). The ICIP algorithm estimates the full-state pose by merely finding the closest point couples respectively form the images obtained by the VNS and predicted at an initial value. Then the optimized solution of the imaging model is iteratively calculated and the full-state pose is obtained. Benefiting from the absence of a requirement for feature matching, the proposed navigation method offers advantages of low computational complexity, favorable stability, and applicability in an extremely simple environment in comparison with conventional methods. PMID- 29234131 TI - A gene expression study of ornamental fin shape in Neolamprologus brichardi, an African cichlid species. AB - The diversity of fin morphology within and across fish taxa offers great, but still largely unexplored, opportunities to investigate the proximate mechanisms underlying fin shape variation. Relying on available genetic knowledge brought forth mainly by the comprehensive study of the zebrafish caudal fin, we explored candidate molecular mechanisms for the maintenance and formation of the conspicuously elongated filaments adorning the unpaired fins of the East African "princess cichlid" Neolamprologus brichardi. Via qPCR assays, we detected expression differences of candidate genes between elongated and short regions of intact and regenerating fins. The identified genes include skeletogenic and growth factors (igf2b, fgf3, bmp2 and bmp4), components of the WNT pathway (lef1, wnt5b and wnt10) and a regulatory network determining fin ray segment size and junction (cx43, esco2 and sema3d), as well as other genes with different roles (mmp9, msxb and pea3). Interestingly, some of these genes showed fin specific expression differences which are often neglected in studies of model fish that focus on the caudal fin. Moreover, while the observed expression patterns were generally consistent with zebrafish results, we also detected deviating expression correlations and gene functions. PMID- 29234132 TI - MUMAPPS: a novel phasor approach to second harmonic analysis for in vitro-in vivo investigation of collagen microstructure. AB - Second Harmonic Generation (SHG) is a label-free imaging method used to monitor collagen organization in tissues. Due to its sensitivity to the incident polarization, it provides microstructural information otherwise unreachable by other intensity based imaging methods. We develop and test a Microscopic Multiparametric Analysis by Phasor projection of Polarization-dependent SHG (MUMAPPS) that maps the features of the collagen architecture in tissues at the micrometer scale. MUMAPPS retrieves pixel-by-pixel the collagen fibrils anisotropy and orientation by operating directly on two coupled phasor spaces, avoiding direct fitting of the polarization dependent SHG signal. We apply MUMAPPS to fixed tissue sections and to the study of the collagen microscopic organization in tumors ex-vivo and in-vivo. We develop a clustering algorithm to automatically group pixels with similar microstructural features. MUMAPPS can perform fast analyses of tissues and opens to future applications for in-situ diagnosis of pathologies and diseases that could assist histo-pathological evaluation. PMID- 29234133 TI - Multi-channel microfluidic chip coupling with mass spectrometry for simultaneous electro-sprays and extraction. AB - Considering the advantages and research status of microfluidic chip coupling with mass spectrometry (MS), a microfluidic chip-based multi-channel ionization (MCMCI) for the extraction of untreated compounds in complex matrices without sample pretreatments was developed. Quantitative analysis of human urine spiked with various rhodamine B concentrations was also performed, and good linearity was obtained. Comparing to the macro ionization device, MCMCI significantly improved the integration of ionization source, simplified the operation of such a device, and greatly increased the signal intensity with much lower gas pressure. Comparison of our MCMCI with two and three gas channels indicated that the liquid liquid extraction process before spraying and after spraying produced similar MS results. Moreover, this MCMCI with three gas channels also implemented simultaneous dual sprays with high DC voltages, the interference of two samples was minor and ion suppression effect was drastically alleviated. Such advantages may easily enable internal calibration for accurate mass measurement. Furthermore, dual extraction can be implemented by integrating such multi-spray configuration, which can improve the extracted signal intensity and sensitivity. These technologies open up new avenues for the application of microfluidic chip coupling with MS. PMID- 29234134 TI - Anatomical evidence for scent guided foraging in the turkey vulture. AB - The turkey vulture (Cathartes aura) is a widespread, scavenging species in the Western Hemisphere that locates carrion by smell. Scent guided foraging is associated with an expansion of the olfactory bulbs of the brain in vertebrates, but no such neuroanatomical data exists for vultures. We provide the first measurements of turkey vulture brains, including the size of their olfactory bulbs and numbers of mitral cells, which provide the primary output of the olfactory bulbs. Comparative analyses show that the turkey vulture has olfactory bulbs that are 4* larger and contain twice as many mitral cells as those of the sympatric black vulture (Coragyps atratus), despite having brains that are 20% smaller. The turkey vulture has the largest olfactory bulbs in absolute terms and adjusted for brain size among birds, but the number of mitral cells is proportional to the size of their olfactory bulbs. The combination of large olfactory bulbs, high mitral cell counts and a greatly enlarged nasal cavity likely reflects a highly sensitive olfactory system. We suggest that this sensitive sense of smell allowed the turkey vulture to colonize biomes that are suboptimal for scavenging birds and become the most widespread vulture species in the world. PMID- 29234135 TI - Comparative epidemiology of poliovirus transmission. AB - Understanding the determinants of polio transmission and its large-scale epidemiology remains a public health priority. Despite a 99% reduction in annual wild poliovirus (WPV) cases since 1988, tackling the last 1% has proven difficult. We identified key covariates of geographical variation in polio transmission patterns by relating country-specific annual disease incidence to demographic, socio-economic and environmental factors. We assessed the relative contributions of these variables to the performance of computer-generated models for predicting polio transmission. We also examined the effect of spatial coupling on the polio extinction frequency in islands relative to larger land masses. Access to sanitation, population density, forest cover and routine vaccination coverage were the strongest predictors of polio incidence, however their relative effect sizes were inconsistent geographically. The effect of climate variables on polio incidence was negligible, indicating that a climate effect is not identifiable at the annual scale, suggesting a role for climate in shaping the transmission seasonality rather than intensity. We found polio fadeout frequency to depend on both population size and demography, which should therefore be considered in policies aimed at extinction. Our comparative epidemiological approach highlights the heterogeneity among polio transmission determinants. Recognition of this variation is important for the maintenance of population immunity in a post-polio era. PMID- 29234136 TI - Study adherence in a tDCS longitudinal clinical trial with people with spinal cord injury. AB - STUDY DESIGN: Secondary analysis of a clinical trial. OBJECTIVES: To analyze adherence to 1-year transcranial Direct Current Stimulation (tDCS) clinical trial in people with chronic pain due to spinal cord injury (SCI). We also explore the association between dropout and several baseline variables such as age, depression levels, pain severity, number of days with pain in the last 7 days, walking ability, sleep, work, relationship with others, and enjoyment with life. SETTING: Boston, USA. METHODS: Forty-six participants were enrolled in this trial, and 33 participants were randomized to receive either active or sham tDCS. RESULTS: Using the full intention-to-treat (ITT) criteria, only 8 participants (24%) finished the study. The median time to dropout was seven (IQR:6,19) sessions (i.e., immediately after the first follow-up), regardless of the type of stimulation that participants received (active vs. sham tDCS) (chi2 = 0.025, p = 0.875). An exploratory analysis suggested that only the number of days with pain in the last 7 days was moderately associated with dropout, with people experiencing less pain being more prone to dropout from the study. CONCLUSIONS: Despite all the measures to improve study adherence (such as providing parking, flexibility to schedule sessions, follow-up with participants by phone), it seems that long follow-up periods may increase the likelihood of dropout. Given the need to understand long-term effects of interventions, longitudinal trials need to consider alternative designs or methods of treatment (for instance home treatment or home assessment) to decrease attrition rate. PMID- 29234138 TI - Effect of high-power-laser with and without graphite coating on bonding of resin cement to lithium disilicate ceramic. AB - The present study evaluated the effect of different high-power-laser surface treatments on the bond strength between resin cement and disilicate ceramic. Lithium disilicate ceramic specimens with truncated cones shape were prepared and divided into 5 groups: HF (hydrofluoric acid-etching), Er:YAG laser + HF, Graphite + Er:YAG laser + HF, Nd:YAG laser + HF, and Graphite + Nd:YAG laser + HF. The treated ceramic surfaces were characterized with scanning electron microscopy and surface roughness measurement. Hourglasses-shaped ceramic- resin bond specimens were prepared, thermomechanically cycled and stressed to failure under tension. The results showed that for both the factors "laser" and "graphite", statistically significant differences were observed (p < 0.05). Multiple-comparison tests performed on the "laser" factor were in the order: Er:YAG > Nd:YAG (p < 0.05), and on the "graphite" factor were in the order: graphite coating < without coating (p < 0.05). The Dunnett test showed that Er:YAG + HF had significantly higher tensile strength (p = 0.00). Higher surface roughness was achieved after Er:YAG laser treatment. Thus Er:YAG laser treatment produces higher bond strength to resin cement than other surface treatment protocols. Surface-coating with graphite does not improve bonding of the laser treated lithium disilicate ceramic to resin cement. PMID- 29234137 TI - Ratiometric Mass Spectrometry for Cell Identification and Quantitation Using Intracellular "Dual-Biomarkers". AB - This study proposed an easy-to-use method for cell identification and quantitation by ratiometric matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS). Two pairs of MS peaks in the molecular fingerprint of cells were selected as intracellular dual-biomarkers due to the stability and specificity of their ratio values in different types of hepatocellular cancer (HCC) cell lines. Five types of HCC cells can be thereafter differentiated based on these two pairs of intracellular peptides/proteins. Two types of HCC cells, Huh7 and LM3 were co-cultured as a model to test whether the method is feasible for cell quantitation. The results indicated that the ratiometric peak intensity of the two pair biomarkers exhibits linear relationship with the proportion of Huh7 cells. Furthermore, tumor heterogeneity was simulated by subcutaneously injecting the co-cultured cells into nude mice. The cell type and proportion in the section of grown tumor tissue can be discriminated using the ratiometric MALDI imaging approach. LC-MS/MS detection revealed that one of the biomarker pairs belongs to thymosin family, beta4 and beta10. The ratiometric MS spectral approach using intracellular dual-biomarkers might become a pervasive strategy for high-throughput cell identification and quantitation, which is vital in tumor heterogeneity study, clinical diagnosis and drug screening. PMID- 29234139 TI - Author Correction: Recovery of nearly 8,000 metagenome-assembled genomes substantially expands the tree of life. AB - In the original version of this Article, the authors stated that the archaeal phylum Parvarchaeota was previously represented by only two single-cell genomes (ARMAN-4_'5-way FS' and ARMAN-5_'5-way FS'). However, these are in fact unpublished, low-quality metagenome-assembled genomes (MAGs) obtained from Richmond Mine, California. In addition, the authors overlooked two higher-quality published Parvarchaeota MAGs from the same habitat, ARMAN-4 (ADCE00000000) and ARMAN-5 (ADHF00000000) (B. J. Baker et al., Proc. Natl Acad. Sci. USA 107, 8806 8811; 2010). The ARMAN-4 and ARMAN-5 MAGs are estimated to be 68.0% and 76.7% complete with 3.3% and 5.6% contamination, respectively, based on the archaeal specific marker sets of CheckM. The 11 Parvarchaeota genomes identified in our study were obtained from different Richmond Mine metagenomes, but are highly similar to the ARMAN-4 (ANI of ~99.7%) and ARMAN-5 (ANI of ~99.6%) MAGs. The highest-quality uncultivated bacteria and archaea (UBA) MAGs with similarity to ARMAN-4 and ARMAN-5 are 82.5% and 83.3% complete with 0.9% and 1.9% contamination, respectively. The Parvarchaeota represents only 0.23% of the archaeal genome tree and addition of the ARMAN-4 and ARMAN-5 MAGs do not change the conclusions of this Article, but do impact the phylogenetic gain for this phylum. This has now been corrected in all versions of the Article. An updated version of Fig. 5 has also been used to replace the previous version, with the row for Parvarchaeota removed, and Supplementary Table 15 and Supplementary Table 17 have both been replaced to reflect the availability of the two additional Parvarchaeota genomes. In addition, the Methods incorrectly stated that all metagenomes identified as being from studies where MAGs had previously been recovered were excluded from consideration. Metagenomes from studies where MAGs had previously been recovered were retained if the UBA MAGs provided appreciable improvements in genome quality or phylogenetic diversity. All versions of the Article have been updated to indicate the retention of such metagenomes. PMID- 29234140 TI - Altered Gut Microbiota Profiles in Sows and Neonatal Piglets Associated with Porcine Epidemic Diarrhea Virus Infection. AB - Porcine epidemic diarrhea virus (PEDV) is a devastating cause of diarrhea in pigs worldwide. Most of studies have focused on molecular and pathogenic characterization of PEDV, whereas there were limited studies in understanding the role of gut microbiota (GM) in viral-associated diarrhea. Here, using the Illumina MiSeq platform, we examined and compared the impact of PEDV infection on the GM of sows and their piglets less than 10 days old. Our results showed that PEDV caused alternations in the structure and abundance of GM from levels of phylum to genus, and even species. For sows, a significant decrease of observed species was found in diarrheal sows than that in healthy sows (p < 0.05). The unweighted and weighted UniFrac distances also revealed considerable segregations of GM structure among healthy, asymptomatic, and diarrheal sows. For piglets, Bacteroidetes, the dominant bacteria in healthy piglets, were replaced by Firmicutes in asymptomatic and diarrheal piglets. The abundances of Fusobacteria and Proteobacteria were also remarkably increased in asymptomatic piglets and diarrheal piglets when compared to those of the healthy piglets. Our findings demonstrated that PEDV infection caused severe perturbations of GM, reduced probiotic bacteria, and enriched pathogenic bacteria. PMID- 29234141 TI - Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. AB - Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders. However, the cell type specific mechanisms are unclear since the CB2R gene knockout mice are constitutive gene knockout. Therefore, we generated Cnr2-floxed mice that were crossed with DAT-Cre mice, in which Cre- recombinase expression is under dopamine transporter gene (DAT) promoter control to ablate Cnr2 gene in midbrain DA neurons of DAT-Cnr2 conditional knockout (cKO) mice. Using a novel sensitive RNAscope in situ hybridization, we detected CB2R mRNA expression in VTA DA neurons in wildtype and DAT-Cnr2 cKO heterozygous but not in the homozygous DAT Cnr2 cKO mice. Here we report that the deletion of CB2Rs in dopamine neurons enhances motor activities, modulates anxiety and depression-like behaviors and reduces the rewarding properties of alcohol. Our data reveals that CB2Rs are involved in the tetrad assay induced by cannabinoids which had been associated with CB1R agonism. GWAS studies indicates that the CNR2 gene is associated with Parkinson's disease and substance use disorders. These results suggest that CB2Rs in dopaminergic neurons may play important roles in the modulation of psychomotor behaviors, anxiety, depression, and pain sensation and in the rewarding effects of alcohol and cocaine. PMID- 29234142 TI - A molecular chaperone activity of CCS restores the maturation of SOD1 fALS mutants. AB - Superoxide dismutase 1 (SOD1) is an important metalloprotein for cellular oxidative stress defence, that is mutated in familiar variants of Amyotrophic Lateral Sclerosis (fALS). Some mutations destabilize the apo protein, leading to the formation of misfolded, toxic species. The Copper Chaperone for SOD1 (CCS) transiently interacts with SOD1 and promotes its correct maturation by transferring copper and catalyzing disulfide bond formation. By in vitro and in cell NMR, we investigated the role of the SOD-like domain of CCS (CCS-D2). We showed that CCS-D2 forms a stable complex with zinc-bound SOD1 in human cells, that has a twofold stabilizing effect: it both prevents the accumulation of unstructured mutant SOD1 and promotes zinc binding. We further showed that CCS-D2 interacts with apo-SOD1 in vitro, suggesting that in cells CCS stabilizes mutant apo-SOD1 prior to zinc binding. Such molecular chaperone function of CCS-D2 is novel and its implications in SOD-linked fALS deserve further investigation. PMID- 29234143 TI - Risk of glomerular filtration rate decline in patients with hypertrophic cardiomyopathy and obstructive sleep apnoea. AB - Sleep apnoea is associated with chronic kidney diseases. A high obstructive sleep apnoea (OSA) prevalence is shown in patients with hypertrophic cardiomyopathy (HCM). Whether the presence of OSA would affect the renal function of patients with HCM is unknown. Forty-five consecutive patients with HCM were divided into the HCM OSA- and OSA+ groups. Forty-three patients with OSA without HCM were recruited as controls. Clinical indices, including estimated glomerular filtration rate (eGFR) and urine 8-hydroxy-2-deoxyguanosine (8-OHdG), were measured. The eGFR was significantly lower in the HCM OSA+ group than in the HCM OSA- (P < 0.05) and OSA (P < 0.001) groups. Multivariate linear regression analysis identified that the apnoea-hypopnoea index was independently associated with eGFR in all patients with HCM (beta = -1.329, 95% confidence interval: 1.942, -0.717, P < 0.001). The urine 8-OHdG level, an oxidative stress marker, was significantly higher in the HCM OSA+ group than in the HCM OSA- (P < 0.001) and OSA (P < 0.001) groups and significantly correlated with the AHI (r = 0.467, P = 0.003) and eGFR (r = -0.457, P = 0.004) in all patients with HCM. Our study suggests a risk of eGFR decline in patients with HCM and OSA. PMID- 29234144 TI - Umbilical cord milking at birth for term newborns with acidosis: neonatal outcomes. AB - OBJECTIVE: To determine if umbilical cord milking is detrimental in compromised term/near-term infants. STUDY DESIGN: A retrospective analysis of infants with abnormal cord gases (cord arterial or venous pH of <= 7.1 or base deficit > -12). We collected maternal risk factors, cord management, birth, and neonatal outcomes during hospitalization. RESULT: We found 157 infants who met the criteria for abnormal cord gases. Thirty-six of those had umbilical cord milking at delivery. There was no significant difference in neonatal outcomes, but fewer infants in the cord milking group needed resuscitation (38 vs. 56%, p = 0.07) and ongoing respiratory support (19 vs. 31%, p = 0.16) compared to the immediate clamping group. CONCLUSIONS: While not significant, infants who received cord milking at birth needed less resuscitation and ongoing respiratory support. This study suggests that umbilical cord milking appears to be a safe therapy when acidosis is present and when resuscitation is needed. PMID- 29234145 TI - The Marshall Klaus Research Award and Tribute to a Trailblazing Neonatologist. PMID- 29234146 TI - Practices surrounding pulmonary hypertension and bronchopulmonary dysplasia amongst neonatologists caring for premature infants. AB - OBJECTIVE: Pulmonary hypertension (PH) is associated with bronchopulmonary dysplasia (BPD). Screening strategies, a thorough investigation of co morbidities, and multidisciplinary involvement prior to anti-PH medications have been advocated by recent guidelines. We sought to evaluate current practices of neonatologists caring for premature infants with PH. DESIGN: Electronic survey of American Academy of Pediatrics neonatology members. RESULTS: Among 306 neonatologist respondents, 38% had an institutional screening protocol for patients with BPD; 83% screened at 36 weeks for premature neonates on oxygen/mechanical ventilation. In those practicing more than 5 years, 54% noted increasing numbers of premature infants diagnosed with PH. Evaluation for PH in BPD patients included evaluations for micro-aspiration (41%), airways anomalies (29%), and catheterization (10%). Some degree of acquired pulmonary vein stenosis was encountered in 47%. A majority (90%) utilized anti-PH medications during the neonatal hospitalization. CONCLUSIONS: Screening for PH in BPD, and subsequent evaluation and management is highly variable. PMID- 29234148 TI - Quality improvement to reduce chronic lung disease rates in very-low birth weight infants: high compliance with a respiratory care bundle in a small NICU. AB - OBJECTIVE: Reduce chronic lung disease by 10% among very-low birth weight infants by implementing a consistent respiratory care bundle. STUDY DESIGN: Prospective quality improvement study of infants below 32 weeks gestation in a small neonatal intensive care unit. A respiratory care bundle to eliminate inter-provider variability and minimize use of mechanical ventilation was implemented. This included: defining delivery room management with use of continuous positive airway pressure/nasal intermittent positive pressure ventilation, uniform intubation/extubation criteria, and standardizing ventilation/post-extubation support. RESULTS: A total of 107 very-low birth weight infants were included in this project. Compliance with the respiratory care bundle was >90%. Chronic lung disease rates at 36 weeks postmenstrual age fell from 43 to 12% (P = 0.0006), rates of combined chronic lung disease/death decreased from 50 to 20% (P = 0.002, OR = 0.25, 95% CI 0.1-0.6), rates of severe intraventricular hemorrhage decreased from 13 to 0% (P = 0.005), and surgical ligation of patent ductus arteriosus decreased from 35 to 3% (P < 0.0001). CONCLUSION: High compliance with the respiratory care bundle was achieved and a 73% reduction in chronic lung disease rates in very-low birth weight infants occurred. PMID- 29234147 TI - Whole blood volumes associated with milking intact and cut umbilical cords in term newborns. AB - OBJECTIVE: The objective of this study is to determine placental transfusion blood volumes with intact and cut umbilical cord milking in term newborns. STUDY DESIGN: Sixty women at >=37 weeks' gestation were enrolled. Following delivery, the umbilical cord was immediately clamped and cut to separate the newborn. Either intact umbilical cord milking (I-UCM) of the placental-umbilical cord unit or cut umbilical cord milking (C-UCM) of the cut umbilical cord segment was performed. For I-UCM, the cord underwent milking three or four times while being attached to placental circulation. For C-UCM, a 10, 20, or 30 cm cord segment was cut separately and milked four times. Blood volumes were compared between I-UCM and C-UCM methods. RESULTS: Mean blood volume with I-UCM (*4) was increased compared to the 30 cm C-UCM technique (48.5 +/- 19.0 vs. 24.8 +/- 4.0 mL, P < 0.001). For C-UCM, blood volume increased proportionally to cord length and, by the second milking, 98.1 +/- 4.5% of blood volume was delivered. CONCLUSION: I UCM provides a greater blood volume than C-UCM. With C-UCM, milking the cord more than twice offers no additional advantage. PMID- 29234149 TI - Effect of maternal iron deficiency anemia on fetal neural development. AB - OBJECTIVE: Perinatal iron deficiency may have deleterious consequences on fetal neural development. The present study was conducted to determine the effect of maternal iron deficiency anemia (IDA) on fetal hippocampal morphogenesis and production of brain-derived neurotrophic factor (BDNF). STUDY DESIGN: Seventy term, singleton neonates born to mothers with IDA (hemoglobin <110g/L and serum ferritin <12 MUg/L) formed the study group. Twenty gestational age-matched neonates born to healthy mothers without IDA (hemoglobin >=110 g/L and serum ferritin >12 MUg/L) served as controls. Maternal and fetal inflammatory conditions, infections and neonates with perinatal asphyxia were excluded. Cord blood BDNF concentrations were estimated by enzyme-linked immunosorbent assay. Volumetric analysis of hippocampus (right, left and combined, corrected for total intracranial volume) was done by cranial magnetic resonance imaging on days 3-5 of life. RESULTS: In the study group, 24 mothers had mild (hemoglobin 100.0-109.0 g/L), 24 had moderate (hemoglobin 70.0-99.0 g/L), and 22 had severe (hemoglobin <70.0 g/L) anemia. Both hippocampal volumes and serum BDNF concentrations of neonates born to iron-deficient mothers were significantly reduced compared to controls. A progressive decline in hippocampal volumes and BDNF concentrations was observed with increasing severity of maternal anemia. Pearson correlation showed significant correlations among maternal and cord blood hemoglobin, iron indices, hippocampal volumes and BDNF concentrations. CONCLUSIONS: Maternal IDA adversely affects hippocampal morphogenesis and fetal production of BDNF. The degree of affection is proportional to the severity of maternal anemia. PMID- 29234150 TI - The shallow structure of Solfatara Volcano, Italy, revealed by dense, wide aperture seismic profiling. AB - Two active-source, high-resolution seismic profiles were acquired in the Solfatara tuff cone in May and November 2014, with dense, wide-aperture arrays. Common Receiver Surface processing was crucial in improving signal-to-noise ratio and reflector continuity. These surveys provide, for the first time, high resolution seismic images of the Solfatara crater, depicting a ~400 m deep asymmetrical crater filled by volcanoclastic sediments and rocks and carved within an overall non-reflective pre-eruptive basement showing features consistent with the emplacement of shallow intrusive bodies. Seismic reflection data were interpreted using the trace complex attributes and clearly display several steep and segmented collapse faults, generally having normal kinematics and dipping toward the crater centre. Fault/fracture planes are imaged as sudden amplitude drops that generate narrow low-similarity and high-dip attributes. Uprising fluids degassed by a magmatic source are the most probable cause of the small-scale amplitude reduction. Seismic data also support the interpretation of the shallow structure of the Solfatara crater as a maar. Our results provides a solid framework to constrain the near-surface geological interpretation of such a complex area, which improves our understanding of the temporal changes of the structure in relation with other geophysical and geochemical measurements. PMID- 29234152 TI - LncRNA SPRY4-IT was concerned with the poor prognosis and contributed to the progression of thyroid cancer. AB - Long non-coding RNAs (lncRNAs) have been demonstrated to be critical regulators in tumorigenesis. LncRNA SPRY4-IT1 has been identified as critical regulator for hepatocellular carcinoma and ovarian cancer. However, the potential role and clinical value of SPRY4-IT1 in human thyroid cancer (TC) still remain unclear and need to be uncovered. Our current study was aimed to ascertain the biological role of expression of SPRY4-IT1 in TC tissues and cells. Our findings revealed that the level of SPRY4-IT1 was significantly upregulated in TC tissues and cell lines, which was correlated with poor prognosis. And cellular experiments exhibited that silenced SPRY4-IT1 inhibited the proliferative and migratory abilities of TC cells. Mechanism assays noted that silenced SPRY4-IT1 could increase the levels of transforming growth factor-beta1 (TGF-beta1) and p-Smad2/3 and function mediated by si-SPRY4-IT1 could be rescued by the interference of TGF beta1. Generally speaking, these findings elucidated that SPRY4-IT1 might become a novel prognostic factor in the clinical behaviors of TC patients and participated in the progression of TC through targeting TGF-beta/Smad signaling pathway. PMID- 29234151 TI - SRGAP1, a crucial target of miR-340 and miR-124, functions as a potential oncogene in gastric tumorigenesis. AB - Slit-Robo GTPase-activating protein 1 (SRGAP1) functions as a GAP for Rho-family GTPases and downstream of Slit-Robo signaling. We aim to investigate the biological function of SRGAP1 and reveal its regulation by deregulated microRNAs (miRNAs) in gastric cancer (GC). mRNA and protein expression of SRGAP1 were examined by quantitative reverse transcription PCR (qRT-PCR) and western blot. The biological role of SRGAP1 was demonstrated through siRNA-mediated knockdown experiments. The regulation of SRGAP1 by miR-340 and miR-124 was confirmed by western blot, dual luciferase activity assays and rescue experiments. SRGAP1 is overexpressed in 9 out of 12 (75.0%) GC cell lines. In primary GC samples from TCGA cohort, SRGAP1 shows gene amplification in 5/258 (1.9%) of cases and its mRNA expression demonstrates a positive correlation with copy number gain. Knockdown of SRGAP1 in GC cells suppressed cell proliferation, reduced colony formation, and significantly inhibited cell invasion and migration. Luciferase reporter assays revealed that SRGAP1 knockdown significantly inhibited Wnt/beta catenin pathway. In addition, SRGAP1 was found to be a direct target of two tumor suppressive miRNAs, miR-340 and miR-124. Concordantly, these two miRNAs were downregulated in primary gastric tumors and these decreasing levels w5ere associated with poor outcomes. Expression of miR-340 and SRGAP1 displayed a reverse relationship in primary samples and re-expressed SRGAP1, rescued the anti cancer effects of miR-340. Taken together, these data strongly suggest that, apart from gene amplification and mutation, the activation of SRGAP1 in GC is partly due to the downregulation of tumor-suppressive miRNAs, miR-340 and miR 124. Thus SRGAP1 is overexpressed in gastric carcinogenesis and plays an oncogenic role through activating Wnt/beta-catenin pathway. PMID- 29234153 TI - Netrin-1 elicits metastatic potential of non-small cell lung carcinoma cell by enhancing cell invasion, migration and vasculogenic mimicry via EMT induction. AB - Ectopic expression of netrin-1 has been validated in several cancers including non-small cell lung cancer (NSCLC). Recent research confirms the critical role of netrin-1 in NSCLC growth and its prognostic value. Unfortunately, its contribution in NSCLC metastasis remains elusive. Here, netrin-1 had relatively high expression in NSCLC tissues and cells, especially in high metastatic groups. Notably, netrin-1 overexpression aggravated the malignant metastatic behavior of NSCLC cells, including cell invasion, migration, and vasculogenic mimicry (VM), whereas netrin-1 depression reversely dampened the metastatic potential. Mechanism analysis confirmed that elevation of netrin-1 induced the typical morphological changes of epithelial-to-mesenchymal transition (EMT) and increased the expression of EMT markers, including E-cadherin down-regulation and N cadherin up-regulation. Consistently, netrin-1 inhibition inversely antagonized the occurrence of EMT. Moreover, netrin-1 also activated the oncogenic pathways of PI3K/AKT and ERK signaling. More importantly, blocking these pathways with their antagonists LY294002 or U0126 reversed the effects of netrin-1 overexpression on cell invasion, migration, EMT, and VM formation. Collectively, the current data suggest that netrin-1 can act as a pro-metastatic factor in NSCLC by enhancing cell invasion, migration, and VM via PI3K/AKT and ERK-mediated EMT process, thereby implicating netrin-1 as a novel promising therapeutic target against aggressive NSCLC. PMID- 29234154 TI - LncRNA-SNHG16 predicts poor prognosis and promotes tumor proliferation through epigenetically silencing p21 in bladder cancer. AB - More and more evidences have ensured the crucial functions of long non-coding RNAs (lncRNAs) in multiple tumors. It has been discovered that lncRNA-SNHG16 is involved in many tumors. Even so, it is still necessary to study SNHG16 comprehensively in bladder cancer. In terms of our study, the level of SNHG16 both in the tumor tissues and cell lines was measured and the relationship among SNHG16, clinicopathological traits and prognosis was explored. Interference assays were applied to determine the biological functions of SNHG16. It was discovered that the level of SNHG16 was evidently enhanced both in tissues and cell lines of bladder cancer. Patients with highly expressed SNHG16 suffered from poor overall survival. Multivariable Cox proportional hazards regression analysis implied that highly expressed SNHG16 could be used as an independent prognostic marker. It could be known from functional assays that silenced SNHG16 impaired cell proliferation, owing to the effects of SNHG16 on cell cycle and apoptosis. Finally, mechanism experiments revealed that SNHG16 could epigenetically silence the expression of p21. The facts above pointed out that lncRNA-SNHG16 might be quite vital for the diagnosis and development of bladder cancer, and could even become an important therapeutic target for bladder cancer. PMID- 29234155 TI - Analysis of neuronal phosphoproteome reveals PINK1 regulation of BAD function and cell death. AB - PINK1 mutations that disrupt its kinase activity cause autosomal recessive early onset Parkinson's disease (PD). Although research in recent years has elucidated a PINK1-Parkin pathway of mitophagy activation that requires PINK1 kinase activity, mitophagy-independent functions of PINK1 and their possible roles in PD pathogenesis have been proposed. Using an unbiased quantitative mass spectrometry approach to analyze the phosphoproteome in primary neurons from wild type and Pink1 knockout mice after mitochondrial depolarization, we uncovered PINK1 regulated phosphorylation sites, which involve coordinated activation of multiple signaling pathways that control cellular response to stress. We further identified the pro-apoptotic protein BAD as a potential mitochondrial substrate of PINK1 both in vitro and in vivo, and found that cells more susceptible to a12poptosis induced by mitochondrial damage can be rescued by phosphorylation mimic BAD. Our results thus suggest that PINK1 kinase activity is important for pro-apoptotic protein function in regulation of cell death. PMID- 29234156 TI - Role of ATP Hydrolysis in Cyanobacterial Circadian Oscillator. AB - A cyanobacterial protein KaiC shows a stable oscillation in its phosphorylation level with approximately one day period when three proteins, KaiA, KaiB, and KaiC, are incubated in the presence of ATP in vitro. During this oscillation, KaiC hydrolyzes more ATP molecules than required for phosphorylation. Here, in this report, a theoretical model of the KaiABC oscillator is developed to elucidate the role of this ATP consumption by assuming multifold feedback relations among reactions and structural transition in each KaiC molecule and the structure-dependent binding reactions among Kai proteins. Results of numerical simulation showed that ATP hydrolysis is a driving mechanism of the phosphorylation oscillation in the present model, and that the frequency of ATP hydrolysis in individual KaiC molecules is correlated to the frequency of oscillation in the ensemble of many Kai molecules, which indicates that the coherent oscillation is generated through the coupled microscopic intramolecular and ensemble-level many-molecular regulations. PMID- 29234157 TI - Spatial genetic structure in American black bears (Ursus americanus): female philopatry is variable and related to population history. AB - Previously, American black bears (Ursus americanus) were thought to follow the pattern of female philopatry and male-biased dispersal. However, recent studies have identified deviations from this pattern. Such flexibility in dispersal patterns can allow individuals greater ability to acclimate to changing environments. We explored dispersal and spatial genetic relatedness patterns across ten black bear populations-including long established (historic), with known reproduction >50 years ago, and newly established (recent) populations, with reproduction recorded <50 years ago-in the Interior Highlands and Southern Appalachian Mountains, United States. We used spatially explicit, individual based genetic simulations to model gene flow under scenarios with varying levels of population density, genetic diversity, and female philopatry. Using measures of genetic distance and spatial autocorrelation, we compared metrics between sexes, between population types (historic and recent), and among simulated scenarios which varied in density, genetic diversity, and sex-biased philopatry. In empirical populations, females in recent populations exhibited stronger patterns of isolation-by-distance (IBD) than females and males in historic populations. In simulated populations, low-density populations had a stronger indication of IBD than medium- to high-density populations; however, this effect varied in empirical populations. Condition-dependent dispersal strategies may permit species to cope with novel conditions and rapidly expand populations. Pattern-process modeling can provide qualitative and quantitative means to explore variable dispersal patterns, and could be employed in other species, particularly to anticipate range shifts in response to changing climate and habitat conditions. PMID- 29234158 TI - pKWmEB: integration of Kruskal-Wallis test with empirical Bayes under polygenic background control for multi-locus genome-wide association study. AB - Although nonparametric methods in genome-wide association studies (GWAS) are robust in quantitative trait nucleotide (QTN) detection, the absence of polygenic background control in single-marker association in genome-wide scans results in a high false positive rate. To overcome this issue, we proposed an integrated nonparametric method for multi-locus GWAS. First, a new model transformation was used to whiten the covariance matrix of polygenic matrix K and environmental noise. Using the transferred model, Kruskal-Wallis test along with least angle regression was then used to select all the markers that were potentially associated with the trait. Finally, all the selected markers were placed into multi-locus model, these effects were estimated by empirical Bayes, and all the nonzero effects were further identified by a likelihood ratio test for true QTN detection. This method, named pKWmEB, was validated by a series of Monte Carlo simulation studies. As a result, pKWmEB effectively controlled false positive rate, although a less stringent significance criterion was adopted. More importantly, pKWmEB retained the high power of Kruskal-Wallis test, and provided QTN effect estimates. To further validate pKWmEB, we re-analyzed four flowering time related traits in Arabidopsis thaliana, and detected some previously reported genes that were not identified by the other methods. PMID- 29234159 TI - Evolution of reproductive parasites with direct fitness benefits. AB - Maternally inherited symbionts such as Wolbachia have long been seen mainly as reproductive parasites, with deleterious effects on host fitness. It is becoming clear, however, that, frequently, these symbionts also have beneficial effects on host fitness, either along with reproductive parasitism or not. Using the examples of cytoplasmic incompatibility (CI) and male-killing (MK), we here analyze the effect of direct fitness benefits on the evolution of reproductive parasites. By means of a simple theoretical framework, we synthesize and extend earlier modeling approaches for CI and MK, which usually ignore fitness benefits. Moreover, our framework is not restricted to a particular mechanism underlying the fitness benefit (e.g., protection against pathogens). We derive invasion conditions and equilibrium frequencies for the different infection scenarios. Our results demonstrate the importance of a symbiont's "effective fecundity" (i.e., the product of the relative fecundity of an infected female and her transmission efficiency) for a symbiont's invasion success. In particular, we adopt the concept of effective fecundity to scenarios where CI and MK co-occur in one host population. We confirm that direct fitness benefits substantially facilitate the invasion and spread of infections (for example, by lowering or removing the invasion threshold) or even make invasion possible in the first place (for example, if reproductive parasitism is weak or absent). Finally, we discuss the role of direct fitness benefits in long-term evolutionary dynamics of reproductive phenotypes and highlight their potential to resolve genetic conflicts between maternally inherited symbionts and their hosts. PMID- 29234160 TI - Inheritance patterns in metabolism and growth in diallel crosses of Arabidopsis thaliana from a single growth habitat. AB - Metabolism is a key determinant of plant growth and modulates plant adaptive responses. Increased metabolic variation due to heterozygosity may be beneficial for highly homozygous plants if their progeny is to respond to sudden changes in the habitat. Here, we investigate the extent to which heterozygosity contributes to the variation in metabolism and size of hybrids of Arabidopsis thaliana whose parents are from a single growth habitat. We created full diallel crosses among seven parents, originating from Southern Germany, and analysed the inheritance patterns in primary and secondary metabolism as well as in rosette size in situ. In comparison to primary metabolites, compounds from secondary metabolism were more variable and showed more pronounced non-additive inheritance patterns which could be attributed to epistasis. In addition, we showed that glucosinolates, among other secondary metabolites, were positively correlated with a proxy for plant size. Therefore, our study demonstrates that heterozygosity in local A. thaliana population generates metabolic variation and may impact several tasks directly linked to metabolism. PMID- 29234161 TI - Further clarifying the relationship between metformin, acute kidney injury and lactic acidosis. PMID- 29234162 TI - Acute kidney injury: Precision perioperative care protects the kidneys. PMID- 29234163 TI - Clarifying the relationship between metformin, acute kidney injury and lactic acidosis. PMID- 29234164 TI - Dyslipidaemia in nephrotic syndrome: mechanisms and treatment. AB - This corrects the article DOI: 10.1038/nrneph.2017.155. PMID- 29234165 TI - Short Physical Performance Battery for cardiovascular disease inpatients: implications for critical factors and sarcopenia. AB - We examined the relationship between Short Physical Performance Battery (SPPB) and clinical and laboratory factors and the effect of sarcopenia and sarcopenic obesity (SO) on clinical and laboratory factors for cardiovascular disease (CVD) inpatients. CVD male (n = 318) and female (n = 172) inpatients were recruited. A stepwise multiple-regression analysis was performed to predict total SPPB scores and assess clinical and laboratory factors (physical characteristics, functional and morphological assessments, etc.). Each test outcome were compared among sarcopenia, SO and non-sarcopenic groups. To predict total SPPB scores, the predicted handgrip, Controlling Nutritional Status score, % body fat, anterior mid-thigh muscle thickness, standing height and systolic blood pressure were calculated for males and anterior mid-thigh MTH, BMI, knee extension and fat mass were calculated for females. There were no differences in blood pressure, total SPPB scores and functional assessments between sarcopenia and SO groups for CVD male and female inpatients. In conclusion, the physical performance of CVD inpatients can be predicted by nutritional, functional, clinical and anthropometric variables, regardless the gender and the presence of sarcopenia. Furthermore, the presence of sarcopenia has a negative effect on the clinical and laboratory factors, but there is a difference in impact between sarcopenia and SO regardless the gender. PMID- 29234166 TI - The IICR (inverse instantaneous coalescence rate) as a summary of genomic diversity: insights into demographic inference and model choice. AB - Several inferential methods using genomic data have been proposed to quantify and date population size changes in the history of species. At the same time an increasing number of studies have shown that population structure can generate spurious signals of population size change. Recently, Mazet et al. (2016) introduced, for a sample size of two, a time-dependent parameter, which they called the IICR (inverse instantaneous coalescence rate). The IICR is equivalent to a population size in panmictic models, but not necessarily in structured models. It is characterised by a temporal trajectory that suggests population size changes, as a function of the sampling scheme, even when the total population size was constant. Here, we extend the work of Mazet et al. (2016) by (i) showing how the IICR can be computed for any demographic model of interest, under the coalescent, (ii) applying this approach to models of population structure (1D and 2D stepping stone, split models, two- and three-island asymmetric gene flow, continent-island models), (iii) stressing the importance of the sampling strategy in generating different histories, (iv) arguing that IICR plots can be seen as summaries of genomic information that can thus be used for model choice or model exclusion (v) applying this approach to the question of admixture between humans and Neanderthals. Altogether these results are potentially important given that the widely used PSMC (pairwise sequentially Markovian coalescent) method of Li and Durbin (2011) estimates the IICR of the sample, not necessarily the history of the populations. PMID- 29234167 TI - The SETDB2 locus: evidence for a genetic link between handedness and atopic disease. AB - The gene SETDB2, which mediates aspects of laterality in animal model systems, has recently been linked with human handedness as measured continuously on a scale from strong left to strong right. By contrast, it was marginally associated with a left-right dichotomous measure, and it showed no evidence of association with absolute handedness strength independent of direction. We genotyped the SETDB2 handedness-associated single nucleotide polymorphism, rs4942830, in a large healthy population likewise phenotyped for continuous, absolute, and dichotomous handedness variables. Our results demonstrated significant effects of rs4942830 genotype on continuous handedness, and weaker, marginal effects on dichotomous handedness, but no effects on absolute handedness. These results help to establish the locus marked by the SNP rs4942830 as a strong candidate for mediating human handedness. Intriguingly, rs4942830 is also in complete linkage disequilibrium with rs386770867, a polymorphism recently shown to affect human serum levels of IgE production and other atopic phenotypes. These findings implicate this locus in the longstanding links of handedness with asthma and other atopic diseases. PMID- 29234168 TI - Environmental and genetic determinants of transcriptional plasticity in Chinook salmon. AB - Variation in gene transcription is widely believed to be the mechanistic basis of phenotypically plastic traits; however, comparatively little is known about the inheritance patterns of transcriptional variation that would allow us to predict its response to selection. In addition, acclimation to different environmental conditions influences acute transcriptional responses to stress and it is unclear if these effects are heritable. To address these gaps in knowledge, we assayed levels of messenger RNA for 14 candidate genes at rest and in response to a 24-h confinement stress for 72 half-sib families of Chinook salmon reared in two different environments (hatchery and semi-natural stream channel). We observed extensive plasticity for mRNA levels of metabolic and stress response genes and demonstrated that mRNA level plasticity due to rearing environment affects mRNA level plasticity in response to stress. These effects have important implications for natural populations experiencing multiple stressors. We identified genotype by-environment interactions for mRNA levels that were dominated by maternal effects; however, mRNA level response to challenge also exhibited a non-additive genetic basis. Our results indicate that while plasticity for mRNA levels can evolve, predicting the outcome of selection will be difficult. The inconsistency in genetic architecture among treatment groups suggests there is considerable cryptic genetic variation for gene expression. PMID- 29234169 TI - Characterization of hybridization within a secondary contact region of the inshore fish, Bostrychus sinensis, in the East China Sea. AB - The northwest Pacific marginal seas are a primary center of phylogeographic and evolutionary research, because of their dynamic geographic history of falling and rising sea levels during the glaciations and interglaciations of the last one million years. Here we present new molecular and morphological data for geographic samples of the four-eyed sleeper (Bostrychus sinensis), which reinforce the evidence for secondary contact and hybridization between two phylogeographic lineages in the East China Sea. Specifically, we find that the secondary contact region is characterized by a low frequency of hybridization, where mitochondrial DNA introgression is relatively common, whereas F1 hybrids are correspondingly scarce. Furthermore, the adult standard lengths of the two phylogeographic lineages vary geographically in a manner that is consistent with reproductive character displacement. Collectively, the molecular and morphological data document that sleeper hybridization conforms to the classic "tension zone" model, where alleles are lost via reduced hybrid viability and/or positive assortative mating but are then replenished by dispersal from south of the secondary contact region. They also indicate that the two phylogeographic lineages are at an incipient stage of the speciation process. These results and conclusions for the four-eyed sleeper are presented as a case study for future research on the vicariance, secondary contact, and hybridization of marine groups in the northwest Pacific marginal seas. PMID- 29234171 TI - The mutational decay of male-male and hermaphrodite-hermaphrodite competitive fitness in the androdioecious nematode C. elegans. AB - Androdioecious Caenorhabditis have a high frequency of self-compatible hermaphrodites and a low frequency of males. The effects of mutations on male fitness are of interest for two reasons. First, when males are rare, selection on male-specific mutations is less efficient than in hermaphrodites. Second, males may present a larger mutational target than hermaphrodites because of the different ways in which fitness accrues in the two sexes. We report the first estimates of male-specific mutational effects in an androdioecious organism. The rate of male-specific inviable or sterile mutations is ?5 * 10-4/generation, below the rate at which males would be lost solely due to those kinds of mutations. The rate of mutational decay of male competitive fitness is ~ 0.17%/generation; that of hermaphrodite competitive fitness is ~ 0.11%/generation. The point estimate of ~ 1.5X faster rate of mutational decay of male fitness is nearly identical to the same ratio in Drosophila. Estimates of mutational variance (VM) for male mating success and competitive fitness are not significantly different from zero, whereas VM for hermaphrodite competitive fitness is similar to that of non-competitive fitness. Two independent estimates of the average selection coefficient against mutations affecting hermaphrodite competitive fitness agree to within two-fold, 0.33-0.5%. PMID- 29234170 TI - A missense point mutation in COL10A1 identified with whole-genome deep sequencing in a 7-generation Pakistan dwarf family. AB - Disease-associated variants in the human genome are continually being identified using DNA sequencing technologies that are especially effective for Mendelian disorders. Here we sequenced whole genome to high coverage (>30*) of 6 members of a 7-generation family with dwarfism from a consanguineous tribe in Pakistan to determine the causal variant(s). We identified a missense variant rs111033552 (c.2011T>C [p.Ser671Pro]) located in COL10A1 (encodes the alpha chain of type X collagen) as the most likely contributor to the dwarfism. We further confirmed the variant in 22 family members using Sanger sequencing. All affected individuals are heterozygous for the missense mutation rs111033552 and no individual homozygous was observed. Moreover, the mutation was absent in 69,985 individuals representing >150 global populations. Taking advantage of whole genome sequencing data, we also examined other variant forms, including copy number variation and insertion/deletion, but failed to identify such variants enriched in the affected individuals. Thus rs111033552 had priority for linkage with dwarfism. PMID- 29234172 TI - Influence of historical land use and modern agricultural expansion on the spatial and ecological divergence of sugarcane borer, Diatraea saccharalis (Lepidoptera: Crambidae) in Brazil. AB - Human-mediated changes in landscapes can facilitate niche expansion and accelerate the adaptation of insect species. The interaction between the evolutionary history of the sugarcane borer, Diatraea saccharalis Fabricius, and historical and modern agricultural activity in Brazil shaped its spatial genetic structure, facilitating ecological divergence and incipient host shifting. Based on microsatellite data, STRUCTURE analyses identified two (K = 2) and three (K = 3) significant genetic clusters that corresponded to: (a) a strong signal of spatial genetic structure and, (b) a cryptic signal of host differentiation. We inferred that K = 2 reflects the footprint of agricultural activity, such as expansion of crop production (sugarcane and maize), unintentional dispersion of pests, and management practices. In contrast, K = 3 indicated incipient host differentiation between larvae collected from sugarcane or maize. Our estimates of population size changes indicated that a historical bottleneck was associated with a reduction of sugarcane production ~200 years ago. However, a more recent population expansion was detected (>1950s), associated with agricultural expansion of large crop production into previously unfarmed land. Partial Mantel tests supported our hypothesis of incipient host adaptation, and identified isolation-by-environment (e.g., host plant) in Sao Paulo and Minas Gerais states, where sugarcane has been traditionally produced in Brazil. The impact of agricultural production on D. saccharalis may continue, as the current population structure may hinder the efficacy of refuge plants in delaying insect resistance evolution to Bt toxin. PMID- 29234173 TI - Porcine Y-chromosome variation is consistent with the occurrence of paternal gene flow from non-Asian to Asian populations. AB - Pigs (Sus scrofa) originated in Southeast Asia and expanded to Europe and North Africa approximately 1 MYA. Analyses of porcine Y-chromosome variation have shown the existence of two main haplogroups that are highly divergent, a result that is consistent with previous mitochondrial and autosomal data showing that the Asian and non-Asian pig populations remained geographically isolated until recently. Paradoxically, one of these Y-chromosome haplogroups is extensively shared by pigs and wild boars from Asia and Europe, an observation that is difficult to reconcile with a scenario of prolonged geographic isolation. To shed light on this issue, we genotyped 33 Y-linked SNPs and one indel in a worldwide sample of pigs and wild boars and sequenced a total of 9903 nucleotide sites from seven loci distributed along the Y-chromosome. Notably, the nucleotide diversity per site at the Y-linked loci (0.0015 in Asian pigs) displayed the same order of magnitude as that described for autosomal loci (~0.0023), a finding compatible with a process of sustained and intense isolation. We performed an approximate Bayesian computation analysis focused on the paternal diversity of wild boars and local pig breeds in which we compared three demographic models: two isolation models (I models) differing in the time of isolation and a model of isolation with recent unidirectional migration (IM model). Our results suggest that the most likely explanation for the extensive sharing of one Y-chromosome haplogroup between non-Asian and Asian populations is a recent and unidirectional (non-Asian > Asian) paternal migration event. PMID- 29234174 TI - Quality Assessment of Published Articles in Iranian Journals Related to Economic Evaluation in Health Care Programs Based on Drummond's Checklist: A Narrative Review. AB - Health economic evaluation research plays an important role in selecting cost effective interventions. The purpose of this study was to assess the quality of published articles in Iranian journals related to economic evaluation in health care programs based on Drummond's checklist in terms of numbers, features, and quality. In the present review study, published articles (Persian and English) in Iranian journals related to economic evaluation in health care programs were searched using electronic databases. In addition, the methodological quality of articles' structure was analyzed by Drummond's standard checklist. Based on the inclusion criteria, the search of databases resulted in 27 articles that fully covered economic evaluation in health care programs. A review of articles in accordance with Drummond's criteria showed that the majority of studies had flaws. The most common methodological weakness in the articles was in terms of cost calculation and valuation. Considering such methodological faults in these studies, it is anticipated that these studies would not provide an appropriate feedback to policy makers to allocate health care resources correctly and select suitable cost-effective interventions. Therefore, researchers are required to comply with the standard guidelines in order to better execute and report on economic evaluation studies. PMID- 29234175 TI - Reliability of Interaural Time Difference-Based Localization Training in Elderly Individuals with Speech-in-Noise Perception Disorder. AB - Background: Previous studies have shown that interaural-time-difference (ITD) training can improve localization ability. Surprisingly little is, however, known about localization training vis-a-vis speech perception in noise based on interaural time difference in the envelope (ITD ENV). We sought to investigate the reliability of an ITD ENV-based training program in speech-in-noise perception among elderly individuals with normal hearing and speech-in-noise disorder. Methods: The present interventional study was performed during 2016. Sixteen elderly men between 55 and 65 years of age with the clinical diagnosis of normal hearing up to 2000 Hz and speech-in-noise perception disorder participated in this study. The training localization program was based on changes in ITD ENV. In order to evaluate the reliability of the training program, we performed speech in-noise tests before the training program, immediately afterward, and then at 2 months' follow-up. The reliability of the training program was analyzed using the Friedman test and the SPSS software. Results: Significant statistical differences were shown in the mean scores of speech-in-noise perception between the 3 time points (P=0.001). The results also indicated no difference in the mean scores of speech-in-noise perception between the 2 time points of immediately after the training program and 2 months' follow-up (P=0.212). Conclusion: The present study showed the reliability of an ITD ENV-based localization training in elderly individuals with speech-in-noise perception disorder. PMID- 29234177 TI - The Effects of Piper Guineense versus Sesamum Indicum Aqueous Extracts on Lipid Metabolism and Antioxidants in Hypercholesterolemic Rats. AB - Background: Piper guineense (PG) and Sesamum indicum (SI) have been shown to be rich sources of antioxidants and other health benefits; hence, we evaluated the impact of its consumption in hypercholesterolemic model on lipid metabolism. Methods: Forty-eight animals were divided into eight groups of six rats each. Rats were given cholesterol (40 mg/0.3ml), PG and SI extract (100 and 200 mg/kg), and Questran (0.26 g/kg) orally, five times a week for 28 days. Lipid profile, hepatic antioxidant status, biomarkers of liver toxicity, and tissue histopathology were examined. Data were analyzed using one-way ANOVA and P<0.05 were considered statistically significant. Results: Cholesterol feeding caused 100% gain in weight, significantly increased AST, LPO (P=0.41 and 0.002) but significantly decreased SOD (P=0.003) compared to control. CHPG(1)/(2) and CHSI(1)/(2) caused a significant decrease (P=0.01, 0.005, 0.003, and 0.023) in cholesterol-induced body-weight gain and decreased serum total cholesterol by 20 30% compared to untreated-hypercholesterolemic rats. Triglyceride and LDL-c decreased with extract administration and specifically HDL-c increased significantly (P<0.001) by CHSI(1) compared to untreated-hypercholesterol rats. Furthermore, an increase in HDL-c was higher (P=0.04 and 0.002) by SI compared to PG at both doses. Conclusion: These results indicate that PG and SI exerts a hypolipidemic effect, reduces cholesterol intake induced body weight gain, and increases the body's antioxidant defense system in experimental hypercholesterolemia. PMID- 29234176 TI - Multilocus Sequence Typing of the Clinical Isolates of Salmonella Enterica Serovar Typhimurium in Tehran Hospitals. AB - Background: Salmonella enterica serovar Typhimurium is one of the most important serovars of Salmonella enterica and is associated with human salmonellosis worldwide. Many epidemiological studies have focused on the characteristics of Salmonella Typhimurium in many countries as well as in Asia. This study was conducted to investigate the genetic characteristics of Salmonella Typhimurium using multilocus sequence typing (MLST). Methods: Clinical samples (urine, blood, and stool) were collected from patients, who were admitted to 2 hospitals in Tehran between April and September, 2015. Salmonella Typhimurium strains were identified by conventional standard biochemical and serological testing. The antibiotic susceptibility patterns of the Salmonella Typhimurium isolates against 16 antibiotics was determined using the disk diffusion assay. The clonal relationship between the strains of Salmonella Typhimurium was analyzed using MLST. Results: Among the 68 Salmonella isolates, 31% (n=21) were Salmonella Typhimurium. Of the total 21 Salmonella Typhimurium isolates, 76% (n=16) were multidrug-resistant and showed resistance to 3 or more antibiotic families. The Salmonella Typhimurium isolates were assigned to 2 sequence types: ST19 and ST328. ST19 was more common (86%). Both sequence types were further assigned to 1 eBURST group. Conclusion: This is the first study of its kind in Iran to determine the sequence types of the clinical isolates of Salmonella Typhimurium in Tehran hospitals using MLST. ST19 was detected as the major sequence type of Salmonella Typhimurium. PMID- 29234178 TI - Combined Extract of Heated 4T1 and a Heat-Killed Preparation of Lactobacillus Casei in a Mouse Model of Breast Cancer. AB - Background: The adjuvanticity potential of Lactobacillus casei was first suggested in an old survey. The present study was designed to investigate the efficacy of a new immunotherapy against breast cancer made by mixing an extract of heated 4T1 mammary carcinoma cell line and a heat-killed preparation of Lactobacillus casei. Methods: Female BALB/c mice (6-8 weeks old, n=40) were challenged subcutaneously in the right flanks with 4T1 cells. When all the animals developed a palpable tumor, they were allocated to 4 equal groups and immunotherapy was initiated. The tumor-bearing mice in the experimental groups received the extract of heated 4T1 or heated Lactobacillus casei and/or a combination of both, twice at a 1-week interval. The mice in the control group received phosphate-buffered saline. One week after the last immunotherapy, one half of the mice were euthanized to determine the immune response profile. The remaining animals were kept until death occurred spontaneously. Results: The animals receiving the combined treatment significantly showed more favorable survival curves and slower rates of tumor development than the tumor-bearing mice receiving only the heated 4T1 and/or the negative control mice. The combined immunization significantly amplified the production of nitric oxide and the cytotoxicity of natural killer cells in the spleen cell culture of the tumor bearing mice. Moreover, the combined immunotherapy significantly increased the secretion of IFN-gamma and conversely diminished the secretion of IL-4 and TGF beta in the splenocyte population compared to the splenocytes from the other groups. Conclusion: The combined immunotherapy with heated 4T1 cells and heated Lactobacillus casei conferred beneficial outcomes in our mouse model of breast cancer. PMID- 29234179 TI - Vitamin E-Coated Polysulfone Membrane-Based Hemodiafiltration Attenuates Inflammation in a Rat Model of Lipopolysaccharide-Induced Systemic Inflammation. AB - Background: Acute blood purification (ABP) therapy is used regularly in the clinical setting and reportedly alleviates organ failure associated with severe systemic inflammatory responses, leading to reduced mortality. The present study aimed to determine whether there is a difference in efficacy between polysulfone (PS) membranes, which are currently used regularly in the clinical setting, and vitamin E-coated polysulfone (VEPS) membranes, which are anticipated to exhibit the antioxidant and anti-inflammatory properties of vitamin E. Methods: Male Wistar rats (n=15/group) were intravenously administered 10 mg/kg of lipopolysaccharide (LPS) to establish a systemic inflammatory response model. Six hours after LPS administration, hemodiafiltration (HDF) was performed for 30 minutes using a PS or VEPS membrane under general anesthesia. Blood was collected at various time points, lung tissue was evaluated histologically, and 24-hour survival was assessed. Results: The rats in the VEPS group tended to have a higher survival rate than those in the PS group when undergoing HDF, although the difference was not significant. With respect to lung tissue, the inflammatory response was suppressed to a greater extent in the VEPS group than the PS group. Serum interleukin (IL)-6 levels were reduced at an early stage, plasma antioxidant activity was increased, and oxidative stress was reduced in the VEPS group compared to the PS group. Conclusion: Relative to PS membrane-based HDF, the survival rate tended to improve and inflammation was subdued earlier due to the antioxidant activity and early attenuation of inflammation associated with VEPS membrane-based HDF. PMID- 29234180 TI - Role of the Nitrergic System of the Cuneiform Nucleus in Cardiovascular Responses in Urethane-Anesthetized Male Rats. AB - Background: The presence of nitric oxide (NO) in the cuneiform nucleus (CnF) has been previously shown. In this study, NG-nitro-L-arginine methyl ester (L-NAME) (an inhibitor of NO synthase), L-arginine (L-Arg) (a precursor of NO), and sodium nitroprusside (SNP) (a donor of NO) were microinjected into the CnF and cardiovascular responses were investigated. Methods: Seventy male rats were divided into 7 groups (n=10 each): 1) saline, 2 and 3) L-NAME (30 and 90 nmol), 4 and 5) L-Arg (20 and 60 nmol), and 6 and 7) SNP (9 and 27 nmol). After anesthesia, the femoral artery was cannulated and cardiovascular parameters were recorded using a PowerLab system. Time course changes in mean arterial pressure (DeltaMAP) and heart rate (DeltaHR) were calculated and compared with those in the control group (repeated measures ANOVA). Maximum ?MAP and ?HR were also compared with those in the control group (independent sample t test). Results: ?MAP with both doses of L-NAME (30: P=0.026 and 90: P=0.007) and ?HR with the higher dose (P=0.034) were significantly higher than those in the control group. Maximal ?MAP with both doses (P<0.01 and P<0.001, n=10) and maximal ?HR with the higher dose (P<0.01) were significantly higher than those in the control group. Changes in L-Arg with both doses were not significantly higher than those in the control group (P=0.26, n=8). ?MAP and ?HR of SNP only with the higher dose were significantly lower than those in the control group (P=0.006 and P=0.035), and maximal responses with the higher dose were lower than those in the control group (?MAP: P<0.01 and ? HR: P<0.05, n=7). Conclusion: Our results showed that the nitrergic system of the CnF had an inhibitory effect on central cardiovascular regulation. PMID- 29234181 TI - Urban-Rural Differences in the Prevalence of Self-Reported Diabetes and its Risk Factors: The WHO STEPS Iranian Noncommunicable Disease Risk Factor Surveillance in 2011. AB - The high prevalence of diabetes in Iran and other developing countries is chiefly attributed to urbanization. The objectives of the present study were to assess the prevalence of self-reported diabetes and to determine its associated risk factors. This study is a part of the national noncommunicable disease risk factor surveillance, conducted in 31 provinces of Iran in 2011. First, 10069 individuals, between 20 and 70 years old (3036 individuals from rural and 7033 from urban areas), were recruited. The major risk factors were studied using a modified WHO STEPS approach. Diabetes was considered based on self-reported diabetes. The prevalence of self-reported diabetes was 10% overall. The prevalence in the rural and urban settings was 7.4% and 11.1%, respectively. Moderate physical activity (OR=0.45, 95% CI=0.29-0.71) and family history of diabetes)OR=6.53, 95% CI=4.29-9.93) were the most important risk factors among the rural residents and systolic blood pressure (OR=1.01, 95% CI=1-1.02), waist circumference (OR=1.02, 95% CI=1.01-1.03), and overweight (OR=1.36, 95% CI= 1 1.84) were significantly associated with self-reported diabetes in the urban residents. The prevalence of self-reported diabetes in the urban setting was higher than that in the rural setting. Physical inactivity, abdominal obesity, and high blood pressure were the most important risk factors associated with self reported diabetes in Iran. PMID- 29234183 TI - Lymph Node Enlargement in Neck Filariasis as a Rare Cause: A Case Report. AB - Lymphatic filariasis is endemic to tropical countries and is the most common cause of acquired lymphedema in the world. Wuchereria bancrofti is the main etiological agent responsible. While the presentation of filariasis in limbs is common, isolated presentation as a single enlarged lymph node in the neck is very rare. We describe a 48-year-old Indian woman, who presented with a hard lymph node in the neck. There was no other significant lymph node enlargement. The overlying skin was erythematous, and no other findings were present on examination. Ultrasonography of the neck revealed a single enlarged lymph node in the left level 2 region, and fine-needle aspiration cytology showed microfilariae with surrounding inflammatory infiltrate. The patient was started on oral diethylcarbamazine and after 2 weeks of therapy, the lymph node enlargement in the neck subsided and the erythema was relieved. PMID- 29234182 TI - Interleukin-10 and Interferon-gamma Levels in Patients with Cutaneous Leishmaniasis Treated with Cryotherapy. AB - Pentavalent antimonials, as the 1st choice for the treatment of cutaneous leishmaniasis (CL), have various side effects. Also, there are some reports of drug resistance. Due to its safety, cryotherapy can be a good alternative or complementary treatment in CL. The aim of this study was to explore the possible systemic immunological mechanisms of cryotherapy besides its local effects in the treatment of CL. Twenty patients with CL were selected. The disease was confirmed via a direct smear. A venous blood sample was collected to determine IL-10 and IFN-gamma levels before starting cryotherapy. Then, 1 week after 8 sessions of cryotherapy were completed (i.e., 63 d), a 2nd venous sample was taken in order to compare the results with the pretreatment levels of these cytokines using the ELISA method. Cryotherapy resulted in no change in the levels of IL-10 and significantly increased the IFN-gamma levels in our patients with CL. Given these inconclusive or even mixed results, a larger sample size is needed in order to better assess the systemic immunological effects of cryotherapy. PMID- 29234184 TI - A Rare Case of Fixed Drug Eruption due to Ondansetron. AB - Fixed drug eruption (FDE) is a unique type of cutaneous drug reaction that typically recurs in the identical locations on re-exposure to the attributed drug. FDE is characterized by the appearance of a single or multiple sharply demarcated violaceous erythematous plaques which heal with residual hyperpigmentation. A 27-year-old woman presented with multiple dark patches over her eyelids, mouth, lips, and shoulders of 1 week's duration. These lesions followed multiple erythematous plaques over the same areas which appeared within 4 hours of the intake of an ondansetron tablet, 12 days previously. The case was diagnosed as post-inflammatory hyperpigmentation following ondansetron-induced FDE. There was an identical episode 1 year earlier due to the intake of the same drug. The causality assessment pointed toward a probable/likely association as per the Naranjo algorithm and the WHO-UMC scale. There have been only a few cases of FDE due to ondansetron in the reported literature. PMID- 29234185 TI - Ellis-van Creveld with an Unusual Dental Anomaly: A Case Report. AB - The Ellis-van Creveld (EVC) syndrome is a chondroectodermal dysplasia and is characterized by the cardinal features of disproportionate short stature, polydactyly, hidrotic ectodermal dysplasia, and congenital heart malformations, along with other skeletal and dental abnormalities. It is a rare condition, with very few cases reported in the medical literature. It is inherited as an autosomal recessive disorder with variable expressions, due to the mutation of the EVC syndrome 1 and 2 genes, which are located on chromosome 4p16. The present case report describes the EVC syndrome in a 14-year-old girl, who presented with a tetrad of all the cardinal features and other associated features. Additional unusual dental findings such as single-rooted funnel-shaped molars, reduced crown size, enamel hypoplasia, supernumerary teeth, dental fusion, taurodontism, abnormal occlusal anatomy with wide grooves, and atypical cusps have been reported in most previous cases of this syndrome. However, in our patient, surprisingly, the teeth present were relatively non-anomalous, both clinically and radiographically (i.e., with none of the usually found abnormalities mentioned above). The only abnormal dental findings were those of absent maxillary and mandibular incisors (including impacted permanent incisors) and mild malocclusion, a novel point of this case. PMID- 29234186 TI - Primary Leiomyosarcoma of the Mesentery: A Case Report. AB - Mesenteric masses are infrequent lesions ranging from benign cysts to aggressive malignancies and often present a diagnostic and therapeutic challenge. The mesentery is a frequent recipient of metastases from the gastrointestinal tract, pancreas, and biliary cancers. Primary mesenteric tumors are relatively rare, mostly mesenchymal in origin and benign in nature. Examples include gastrointestinal stromal tumors and smooth muscle tumors. We describe a 50-year old woman, who presented with a lump in the left hypochondrium along with altered bowel habits of 2 years' duration. Imaging revealed a cystic lesion, raising the differentials of a benign lesion. Exploratory laparotomy revealed a large cystic mass in the mesentery closely abutting the jejunal loops. This was followed by mass resection along with a segment of the jejunum. Histopathological examination revealed features of a leiomyosarcoma. Postoperatively, the patient developed a colocutaneous fistula, which was re-excised. At 6 months' follow-up, the patient is doing well. Our case demonstrates the diagnostic challenge posed by the atypical clinical and imaging features of this tumor at an unusual site. PMID- 29234187 TI - Efficacy of epsilon-Poly-L-lysine as an Antibacterial Additive for Platelets Stored at Room Temperature. PMID- 29234188 TI - Cranial Nerve Lymphomatosis Magnetic Resonance Imaging Findings in a Case of Mantle Cell Lymphoma. PMID- 29234189 TI - Inflammation, Immunity, and Cancer. PMID- 29234190 TI - Can Non-Selective Beta-Blockers (NSBBs) Prevent Enlargement of Small Esophageal Varices in Patients with Cirrhosis? A Meta-analysis. AB - Background: Non-selective beta-blockers (NSBBs) are recommended for prophylaxis of first variceal bleeding in patients of cirrhosis with large esophageal varices. However, the data is conflicting whether NSBBs can also prevent growth of small esophageal varices to large size. Aim: To perform a meta-analysis of the randomized clinical trials comparing NSBBs with placebo for prevention of development of large esophageal varices in patients of cirrhosis with small esophageal varices. Methods: The PubMed, EMBASE, Science Direct, and Cochrane library databases were searched for relevant papers. A meta-analysis was performed using risk ratios (RRs) with 95% confidence interval (CI) as the effect sizes. Results: Overall, 314 trials were initially retrieved from the database searches, of which five randomized controlled trials were included in the meta analysis. The incidence of development of large varices (RR = 0.91, 95%CI: 0.29 2.86; P = 0.87) was similar between NSBB and placebo groups. However, the heterogeneity among studies was significant (P < 0.01) with an I2 of 93%. The incidences of first variceal bleeding (RR = 0.72, 95%CI: 0.25-2.12; P = 0.55) and death (RR = 0.76, 95%CI: 0.50-1.15; P = 0.19) were also similar between NSBB and placebo groups; with no heterogeneity. The incidence of adverse events was significantly higher in the NSBB group compared with the placebo group (RR = 4.66, 95%CI: 1.36-15.91; P = 0.01). Conclusion: The results of this meta-analysis indicate that NSBBs are not effective in preventing growth of small varices and may lead to significant adverse effects. Hence, NSBBs should not be recommended for cirrhotic patients with small varices. PMID- 29234191 TI - Thromboelastography for Assessing the Risk of Bleeding in Patients With Cirrhosis Moving Closer. AB - Background and aims: Conventional coagulation tests (CCTs) in patients with cirrhosis only assess procoagulant factors and are poor predictors of bleeding risk. In spite of this knowledge, they are routinely used prior to invasive procedures, and attempts are made to correct these abnormalities before invasive procedures. These practices are not supported by the evidence and are harmful to the patients. Methods: This prospective study included 150 patients of cirrhosis undergoing invasive procedures. CCTs [bleeding time (BT), clotting time (CT), international normalized ratio (INR), activated partial thromboplastin time (aPTT) and platelet count], thromboplastin generation time (TGT) and thromboelastography (TEG) were done in all patients, and they were observed for post procedural bleeding. None of the patients received prophylactic transfusion before the procedure. Results: BT, CT and TGT were normal in all 150 patients. One of 150 patients developed clinically significant post procedural bleeding. No statistically significant association was seen among INR, aPTT, platelet count and Child class with bleeding. TEG values (R time and MA value) were normal in 61% and 75% patients respectively in spite of abnormal CCTs in most of them. Comparison of abnormal TEG values (R time and MA value) with INR and platelet count, respectively, in patients with no bleeding showed a statistically significant lower percentage of abnormal values of R time and MA value compared to INR and platelet count. Conclusion: Abnormal CCTs in patients of cirrhosis do not predict bleeding risk. TEG may be useful in patients undergoing invasive procedures to assess bleeding risk and prevents erroneous prophylactic transfusions. PMID- 29234192 TI - Impact of Acute Kidney Injury on Mortality of Patients Hospitalized for Complications of Cirrhosis. AB - Background/aims: The mortality of hospitalized patients for complications of cirrhosis is very high. We examined the independent predictors of mortality, particularly the impact of increments in creatinine, in 339 consecutive patients (636 admissions) who were admitted for complications of cirrhosis. Methods: Clinical characteristics, biochemical parameters including serum creatinine levels at various time intervals, and mortality data were recorded for all admissions. Data were analyzed for initial as well for all repeated admissions to identify independent predictors of mortality. Results: The in-hospital mortality, 30-day, 90-day, 180 days, and 365 days mortality were 6%, 15%, 23%, 30%, and 41% respectively. Those admitted with spontaneous bacterial peritonitis had the worst survival. Increase in creatinine was noted in 29% of patients and they had lower 30-day (78% vs.91%) and 90-day (73% vs. 82%) survival than those without increase in creatinine. Any increment in serum creatinine (>=0.1 mg/dL) within 48 h after admission (peak 48 h - admission) was associated with a step-wise increase in mortality, but only if peak creatinine reached above 1.2 mg/dL. If peak creatinine levels were below 1.2 mg/dL, increases in serum creatinine had no impact on survival. Cox regression analysis showed that increments in serum creatinine of 0.3 mg/dL or higher had the worst outcome (HR 2.51, CI 1.65-3.81). Etiology of cirrhosis or the use of PPI, beta blockers or rifaxamin did not predict mortality. Other independent predictors of mortality were age, reason for admission, hyponatremia, and INR. Conclusion: In patients with cirrhosis, any increment in serum creatinine within 48 h from hospitalization is associated with a higher mortality provided the peak serum creatinine within 48 h is above 1.2 mg/dL. PMID- 29234193 TI - Results of Portosystemic Shunt Embolization in Selected Patients with Cirrhosis and Recurrent Hepatic Encephalopathy. AB - Background: Large portosystemic shunts (PSSs) may lead to recurrent encephalopathy in patients with cirrhosis and embolization of these shunts may improve encephalopathy. Material and methods: Five patients underwent balloon occluded retrograde transvenous obliteration (BRTO) or plug-assisted retrograde transvenous obliteration (PARTO) of a large PSS at our center in last 2 years for recurrent hepatic encephalopathy (HE) at a tertiary care center at north India. Data are shown as number and mean +/- SD. None of these patients had Child's C cirrhosis or presence of large ascites/large varices. Results: Five patients (all males), aged 61 +/- 7 years, underwent BRTO or PARTO for recurrent HE and presence of lienorenal (n = 4) or mesocaval shunt (n = 1). The etiology of cirrhosis was cryptogenic/non-alcoholic steatohepatitis in 3, and alcohol and hepatitis B in one each. All patients had Child's B cirrhosis; Child's score was 8.6 +/- 0.5, model for end-stage liver disease (MELD) score was 13.4 +/- 2.3. One patient had mild ascites; 3 patients had small esophageal varices before procedure. Sclerosants (combination of air, sodium tetradecyl sulphate, and lipiodol) were used in two patients, endovascular occlusion plugs were used in two patients, and both sclerosants and endovascular occlusion plug were used in one patient. Embolization of minor outflow veins to allow for stable deposition sclerosants in dominant shunt was done using embolization coils and glue in two patients. One patient needed 2 sessions. The pre-procedure ammonia was 127 +/- 35 which decreased to 31 +/- 17 after the shunt embolization. There was no recurrence of encephalopathy in any of these patients. One patient was lost to follow-up at 6 months; others are doing well at 6 months (n = 2), 10 months (n = 1) and 2 years (n = 1). None of these patients developed further decompensation in the defined follow-up period. Conclusion: Good results can be obtained in selected patients after embolization of large PSS for recurrent HE. PMID- 29234194 TI - An Insight into Antibiotic Resistance to Bacterial Infection in Chronic Liver Disease. AB - Background: End stage liver disease leads to immune dysfunction which predisposes to infection. There has been a rise in antibiotic resistant infections in these patients. There is scanty data f from India or idea regarding the same. Aim of the study: The present study was undertaken to determine the type of infection acquired and the prevalence of antibiotic resistant infections in cirrhotic patients at a tertiary referral center in South India. Materials and methods: In this retrospective study, all consecutive cirrhotic patients hospitalized between 2011 and 2013 with a microbiologically-documented infection were enrolled. Details of previous admission and antibiotics if received were noted. In culture positive infections, the source of infection (ascites, skin, respiratory tract: sputum/endotracheal tube aspirate, pleural fluid; urine and blood) and microorganisms isolated and their antibiotic susceptibility was noted. Results: A total of 92 patients had 240 culture positive samples in the study period. Majority were Klebseilla followed by Escherichia coli and Enterococcus in nosocomial and health care associated infections. However, Enteroccocus was followed by E. coli and Klebsiella in community acquired infections. The antibiotic sensitivity pattern was analyzed for the major causative organisms such as E. coli, Klebsiella and Enterococcus. Most common resistant strains were extended spectrum beta lactamase producing enterobacteriacae (ESBL) followed by carbapenemase producing Klebsiella and methicillin resistant Staphylococcus aureus. Conclusion: Noscomial infection is the most common type, with Klebsiella and E. coli and there is significant rise in ESBL producing organism. PMID- 29234195 TI - Simple Anthropometric Indices are Useful for Predicting Non-alcoholic Fatty Liver Disease [NAFLD] in Asian Indians. AB - Background and aims: With the rising prevalence of obesity and metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common liver disorder in both developed and developing nations. Several studies on NAFLD have described waist circumference, a surrogate marker of visceral fat accumulation and waist height ratio as a better screening tool for NAFLD and metabolic syndrome than body mass index (BMI). We conducted this study to assess simple abdominal obesity indices as a predictor of NAFLD and determine the appropriate cut-off levels with reference to NAFLD. Methods: 1000 subjects with NAFLD detected ultrasonographically and 360 controls attending a Gastroenterology Clinic at Cuttack, Odisha were included in the study and subjected to detailed anthropometric measurements. The abdominal anthropometric cut offs were determined using ROC analysis. Statistical analysis was performed by using SPSS software version 16. Results: All receiver operating curve (ROC) curves of waist circumference, waist-height ratio and BMI were significantly above the diagonal line. There were no significant differences in the area under the curve values among these abdominal obesity indices in each gender. The appropriate cut-off point of waist circumference in screening for NAFLD was 89 cm for men and 84 cm for women and the optimal cut-off point of waist-height ratio was 0.53 for men and 0.57 for women and the cut-off point of waist to hip ratio was 0.94 for men and 0.87 for women with very good sensitivity and specificity. Conclusions: The simple anthropometric parameters, such as BMI, waist circumference, waist-hip ratio and waist-height ratio are useful for predicting NAFLD in Indian adults. The anthropometry cut offs would be very useful in setting target points of life style modification and weight reduction. Besides, our study also clearly demonstrated that a simple assessment of BMI is as efficacious as other anthropometry parameters in predicting NAFLD. PMID- 29234196 TI - Glycochenodeoxycholic Acid Does Not Increase Transforming Growth Factor-Beta Expression in Bile Duct Epithelial Cells or Collagen Synthesis in Myofibroblasts. AB - Background/Aims: Primary sclerosing cholangitis (PSC) is a chronic, progressive hepatobiliary disorder characterized by extensive fibrosis and stricturing of the intra- and/or extra-hepatic bile ducts: Previous studies have documented low phosphatylcholine (PC) concentrations in PSC bile. The aim of this study was to determine whether low PC levels in bile facilitate toxic bile acid induced injury of biliary tract epithelial cells resulting in enhanced transforming growth factor-beta (TGF-beta) expression and increased collagen synthesis by myofibroblasts. Methods: TGF-beta mRNA expression was documented in bile duct epithelial cells exposed to varying concentrations of the toxic bile acid; glycochenodeoxycholic acid (GCDCA) +/- PC. Results: In these experiments, as well as in co-culture experiments where bile duct epithelial cells were cultured with peripheral blood mononuclear cells and myofibroblasts, TGF-beta mRNA expression remained unaltered in the presence or absence of PC. Moreover, collagen type Ialpha1 mRNA expression by myofibroblasts also remained unaltered. Conclusion: The results of this study do not support the hypothesis that PC deficiency contributes to toxic bile acid-induced bile duct injury and/or myofibroblast activation. PMID- 29234197 TI - Echocardiographic and Electrocardiographic Predictors of Adverse Outcomes in Spontaneous Bacterial Peritonitis. AB - Background: Patients with cirrhosis who develop Spontaneous Bacterial Peritonitis (SBP) suffer from cirrhotic cardiomyopathy which is characterized by impaired contractility in response to stress despite a relatively normal resting cardiac output. We hypothesized that electrocardiographic and echocardiographic information would help prognosticate patients developing SBP in addition to existing scoring systems. Methods: Cirrhotic patients admitted to Einstein Medical Center from 01/01/2005 to 6/30/2012 for SBP, and did not receive a transplant within one year, were included. Patients were classified as QTc low vs. high, and E/E' low vs. high at cut points >=480 ms for QTc and >=10 for E/E' ratio. We estimated 1-year survival using Kaplan Meier curves. Regression analysis and Cox proportional hazards model were used for QTc and E/E' ratio, respectively, for assessing 1-year survival. Results: Among 112 patients with electrocardiogam, 78 were classified as QTc low. Among 64 patients with echocardiograms, 23 were classified as E/E' low. Higher QTc was associated with increased in-hospital acute kidney injury. QTc and E/E' ratio predicted worse 1 year survival (HR = 2.16, 95% CI 1.29-3.49; HR 2.65, 95% CI 1.31-5.35, respectively) on univariate and multivariate analysis (OR = 1.02, 95% CI 1.01 1.03; HR = 3.26, 95% CI 1.22-9.82 respectively) after adjusting for both Child Pugh stage, MELD score among other risk factors. Conclusion: In conclusion, cirrhotic patients with SBP who present with a prolonged QTc interval are at a greater risk for acute renal failure during hospitalization. High QTc duration and an E/E' ratio of >=10 independently predict increased mortality at 1-year follow-up. PMID- 29234198 TI - Long Term Outcomes of Patients with Significant Biliary Obstruction Due to Portal Cavernoma Cholangiopathy and Extra-Hepatic Portal Vein Obstruction (EHPVO) With No Shuntable Veins. AB - Aims: The natural history of portal cavernoma cholangiopathy (PCC) in patients with significant biliary obstruction (SBO) who cannot undergo shunt surgery, is not known. We therefore, analyzed data of patients of extra-hepatic portal venous obstruction (EHPVO) with PCC. Methods: Prospectively recorded details of 620 (age 21.2 [11.4] years; 400 [65%] males) patients with primary EHPVO were reviewed. Outcomes (hepatic decompensation/mortality) of patients with PCC and SBO without shuntable veins were noted at follow up of 7 [4-11] years. Results: Ninety-seven of 620 (15.6% [60 men]) EHPVO patients had PCC-SBO. Of these 57 did not have shuntable veins. The median duration from any index symptom to symptomatic PCC was 7 (0-24) years and from index bleed to symptomatic PCC was and 12 (5-24) years, respectively. Thirteen patients underwent endoscopic retrograde cholangiography; nine repeatedly over 7 (4-10) years. Decompensation was seen in 5 patients. Presentation other than variceal bleed was associated with hepatic decompensation (5/19 versus 0/38, P = 0.003). Conclusions: Majority of patients with PCC-SBO do not have shuntable veins, and may have good long-term outcomes. Patients presenting with variceal bleed have low chance of decompensation. Symptomatic PCC appears to be a late event in EHPVO. PMID- 29234199 TI - Prevalence and Characteristics of Hepatitis Delta Virus Infection in a Tertiary Hospital Setting in Cameroon. AB - Background/Aims: Hepatitis B virus (HBV) and hepatitis D virus (HDV) coinfection is associated with more severe liver disease than HBV alone. More knowledge on the epidemiology and clinical impact of HDV-infected individuals is needed in Cameroon.We aimed at determining the frequency of anti-HDV antibody testing in hepatitis B surface antigen (HBsAg) positive patients, the proportion of anti-HDV positivity, and the characteristics of anti-HDV positive compared to anti-HDV negative patients in a tertiary hospital setting in Cameroon. Methods: A cross sectional study was conducted. Clinical records of chronic HBV-infected patients attending the gastroenterology unit at the Douala General Hospital from 2010 to 2014 were reviewed. Results: Of 365 files of HBsAg-positive patients defined as chronic HBV infection, 80.5% (294) were tested for anti-HDV antibodies, among whom 10.5% (31/294) were positive. Median aspartate aminotransferase (P < 0.0001), alanine aminotransferase (P < 0.0001), and gamma glutaryl transpeptidase (P < 0.0001) were significantly higher while platelets count (P < 0.002) and prothrombin time (P < 0.0001) were significantly lower in anti-HDV positive compared to anti-HDV negative patients. Liver necroinflammation (P < 0.0001), fibrosis score (P < 0.0001), and decompensated cirrhosis (P < 0.0001) were also significantly associated with anti-HDV positivity. Conclusion: The proportion of anti-HDV antibody positivity remains high in this setting and was significantly associated with more severe liver disease compared to those who were anti-HDV negative. More studies are needed to evaluate rates of HDV testing in other centers in Cameroon and the subregion. Preventive strategies for HBV prevention, which also apply to HDV, must still be reinforced by healthcare providers and policy makers. PMID- 29234201 TI - Acute and Chronic Rejection After Liver Transplantation: What A Clinician Needs to Know. AB - While antibody mediated hyper-acute vasculitic rejection is rare in liver transplant recipients, acute and chronic rejection have clinical significance. The liver allograft behaves differently to other solid organ transplants as acute rejection generally does not impair graft survival and chronic rejection (CR) is uncommon. The incidence of acute and chronic rejection has declined in current era due to improved immunosuppressive regimens. Acute rejection generally improves with steroid boluses and steroid resistant rejection is uncommon. CR may improve with escalation of immunosuppression or may result in irreversible loss of graft function leading to retransplantation or death. The current review discusses diagnosis and management of acute and chronic liver allograft rejection. PMID- 29234202 TI - Matrix Metalloproteinases (MMPs) in Liver Diseases. AB - Matrix metalloproteinases (MMPs) are proteinases capable of degrading components of the extracellular matrix and numerous nonmatrix proteins. MMPs along with tissue inhibitors of MMPs, have been implicated in the pathogenesis of liver diseases. Although, the precise mechanism-of-actions of MMPs in various liver related disorders is largely unknown, however, data from diverse experimental models indicate that these proteinases influence cellular activities including proliferation and survival, gene expression, as well as multiple aspects of inflammation. Hence, MMP's are likely key players in the outcomes related to liver disease. PMID- 29234203 TI - Cholemic or Bile Cast Nephropathy in a Child with Liver Failure. AB - Cholemic or bile cast nephropathy is an under-reported entity characterized by acute renal dysfunction in patients with hepatic insult. Limited literature is available regarding its clinical presentation, pathogenesis and prognosis. We hereby present a pediatric case who presented with acute on chronic liver failure with renal dysfunction secondary to cholemic nephropathy. PMID- 29234204 TI - Middle Hepatic Vein Bleed During Donor Hepatectomy: Technique for Safe Practice. AB - Safe performance of donor hepatectomy is crucial for sustainability of a living donor liver transplantation (LDLT) program. Middle hepatic vein (MHV) is always encountered during parenchymal transection irrespective of right or left donor hepatectomies. Here we present a safe and effective technique for tackling MHV bleed during LDLT from a single centre experience. PMID- 29234206 TI - Large Heterogeneous Calcified Masses in Liver: A Diagnostic Dilemma. PMID- 29234205 TI - A Rare Case of Primary Sarcomatous Hepatocellular Carcinoma Without Previous Anticancer Therapy. AB - Primary sarcomatous hepatocellular carcinoma (PSHCC) is a rare and aggressive variety of hepatocellular carcinoma (HCC). The recent evidence suggests that anticancer therapy promotes the dedifferentiation of the carcinomatous component and is largely responsible for this aggressive variant of HCC. However, in the absence of any anticancer therapy, occurrence of PSHCC is extremely rare. Herein, we present a rare case report of a 65 year old male patient, with a hepatitis B positive status, presenting with PSHCC without any history of anticancer therapy. Detailed immunohistochemical evaluation of the tumor was performed with comparison of morphological and immunohistochemical features of the sarcomatous and carcinomatous components. This appears to be the first documented case of PSHCC from India, to the best of our knowledge. PMID- 29234200 TI - Nutrition and Muscle in Cirrhosis. AB - As the cirrhosis progresses, development of complication like ascites, hepatic encephalopathy, variceal bleeding, kidney dysfunction, and hepatocellular carcinoma signify increasing risk of short term mortality. Malnutrition and muscle wasting (sarcopenia) is yet other complications that negatively impact survival, quality of life, and response to stressors, such as infection and surgery in patients with cirrhosis. Conventionally, these are not routinely looked for, because nutritional assessment can be a difficult especially if there is associated fluid retention and/or obesity. Patients with cirrhosis may have a combination of loss of skeletal muscle and gain of adipose tissue, culminating in the condition of "sarcopenic obesity." Sarcopenia in cirrhotic patients has been associated with increased mortality, sepsis complications, hyperammonemia, overt hepatic encephalopathy, and increased length of stay after liver transplantation. Assessment of muscles with cross-sectional imaging studies has become an attractive index of nutritional status evaluation in cirrhosis, as sarcopenia, the major component of malnutrition, is primarily responsible for the adverse clinical consequences seen in patients with liver disease. Cirrhosis is a state of accelerated starvation, with increased gluconeogenesis that requires amino acid diversion from other metabolic functions. Protein homeostasis is disturbed in cirrhosis due to several factors such as hyperammonemia, hormonal, and cytokine abnormalities, physical inactivity and direct effects of ethanol and its metabolites. New approaches to manage sarcopenia are being evolved. Branched chain amino acid supplementation, Myostatin inhibitors, and mitochondrial protective agents are currently in various stages of evaluation in preclinical studies to prevent and reverse sarcopenia, in cirrhosis. PMID- 29234207 TI - Over-the-Counter Products In Line for User Fee Program. AB - Over-the-counter products in line for user fee program. PMID- 29234209 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 29234208 TI - EPINEPHrine for Anaphylaxis: Autoinjector or 1-mg Vial or Ampoule? AB - Epinephrine for anaphylaxis: Autoinjector or 1-mg vial or ampoule? PMID- 29234210 TI - Pharmaceutical Approval Update. AB - Secnidazole (Solosec) for the one-dose treatment of bacterial vaginosis; triamcinolone acetonide extended-release injection (Zilretta) for osteoarthritis knee pain; and insulin aspart injection (Fiasp), a rapidacting human insulin analogue for glycemic control in diabetes mellitus. PMID- 29234211 TI - Bezlotoxumab (Zinplava) for Clostridium Difficile Infection: The First Monoclonal Antibody Approved to Prevent the Recurrence of a Bacterial Infection. AB - Bezlotoxumab (Zinplava) to prevent the recurrence of Clostridium difficile infection. PMID- 29234212 TI - "Right to Try" Legislation Moving Through Congress: But Drug Companies and Some Patient Groups Want Changes. AB - State "Right to Try" laws, which allow terminally ill patients to seek investigational treatments under certain circumstances, have created pressure for Congress to follow up with a federal law. Though facing opposition from patient advocates and the drug industry, a bill passed by the Senate is now making its way to the House. PMID- 29234213 TI - Progress in Nanomedicine: Approved and Investigational Nanodrugs. AB - Nanomedicine is a relatively new and rapidly evolving field combining nanotechnology with the biomedical and pharmaceutical sciences.1-3 Nanoparticles (NPs) can impart many pharmacokinetic, efficacy, safety, and targeting benefits when they are included in drug formulations.1-5 Many nanodrugs have entered clinical practice, and even more are being investigated in clinical trials for a wide variety of indications.2 However, nanopharmaceuticals also face challenges, such as the need for better characterization, possible toxicity issues, a lack of specific regulatory guidelines, cost-benefit considerations, and waning enthusiasm among some health care professionals. 4,5 For these reasons, expectations regarding nanodrugs that are in early stages of development or clinical trials need to remain realistic.4. PMID- 29234214 TI - Clinical Practice Updates in the Management Of Immune Thrombocytopenia. AB - Immune thrombocytopenia (ITP), previously called idiopathic thrombocytopenia purpura, is an autoimmune disorder characterized by a severe reduction in peripheral blood platelet count. In healthy individuals, normal platelet count ranges from 150-450 * 109/L, while in thrombocytopenia counts fall to less than 100 * 109/L.1 In adults, the incidence of ITP is approximately two to four per 100,000.2,3 Bleeding risks, specifically hemorrhage and intracranial hemorrhage, represent the most serious complications for patients with ITP. Over the past decade, the understanding of ITP has expanded greatly, which has contributed to a number of updates in the diagnosis and treatment of the disorder.3 This article aims to briefly review the pathophysiology of ITP and summarize updates in ITP management and treatment options in the adult population. PMID- 29234215 TI - New Heart Failure Medications Aim To Fill Significant Gaps in Treatment. AB - Despite the many medications already available, patients with heart failure often have disease exacerbations, reduced quality of life, and increased mortality, highlighting the need for new treatment approaches. We explore drugs currently in development. PMID- 29234216 TI - Recommendations From the 2016 Guidelines for the Management of Adults With Hospital-Acquired or Ventilator-Associated Pneumonia. AB - Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) continue to represent the most common nosocomial-associated infections, resulting in significant attributable mortality, increased length of hospital stay, and financial burden.1 The updated Infectious Diseases Society of America (IDSA) guidelines provide guidance on the diagnosis and management of nonimmunocompromised hosts with HAP and VAP. PMID- 29234217 TI - Research Briefs. PMID- 29234219 TI - Concept and Design of a 3D Printed Support to Assist Hand Scanning for the Realization of Customized Orthosis. AB - In the rehabilitation field, the use of additive manufacturing techniques to realize customized orthoses is increasingly widespread. Obtaining a 3D model for the 3D printing phase can be done following different methodologies. We consider the creation of personalized upper limb orthoses, also including fingers, starting from the acquisition of the hand geometry through accurate 3D scanning. However, hand scanning procedure presents differences between healthy subjects and patients affected by pathologies that compromise upper limb functionality. In this work, we present the concept and design of a 3D printed support to assist hand scanning of such patients. The device, realized with FDM additive manufacturing techniques in ABS material, allows palmar acquisitions, and its design and test are motivated by the following needs: (1) immobilizing the hand of patients during the palmar scanning to reduce involuntary movements affecting the scanning quality and (2) keeping hands open and in a correct position, especially to contrast the high degree of hypertonicity of spastic subjects. The resulting device can be used indifferently for the right and the left hand; it is provided in four-dimensional sizes and may be also suitable as a palmar support for the acquisition of the dorsal side of the hand. PMID- 29234220 TI - Primary open-angle glaucoma in patients of Middle Eastern descent. PMID- 29234221 TI - Aflibercept in macular edema secondary to retinal vein occlusion: A real life study. AB - Purpose: To evaluate the real life outcomes of intravitreal aflibercept (IVAfl) treatment in patients with macular edema (ME) secondary to retinal vein occlusion (RVO) during the first year of treatment. Methods: Retrospective case series. Newly diagnosed or persistent ME patients secondary to RVO who were treated with IVAfl and had a follow-up period of at least 12 months were included. Twenty-two patients (54.8%) received 3 loading month loading doses IVAfl initially, whereas 20 patients (45.2%) did not receive. Then the patients were treated on an as needed treatment regimen. Primary outcome measures of this study included the change in best corrected visual acuity (BCVA) and central retinal thickness (CRT). Secondary outcome measures were the number of visits and injections. Results: Forty-two eyes of 42 patients were included. Fourteen patients (33.3%) had central RVO, and 28 (66.7%) had branch RVO. Mean BCVA at baseline and month 12 was 0.98 +/- 0.58 and 0.82 +/- 0.65 LogMAR, respectively (p = 0.04). Mean CRT at baseline and month 12 was 511 +/- 141 and 304 +/- 95 MUm, respectively (p < 0.0001). Mean number of visits was 5.9 +/- 2.1 (range 3-11) and injections was 3.2 +/- 1.7 (range 1-8) at month 12. Conclusion: In conclusion, IVAfl treatment seemed to be effective in patients with ME secondary to RVO with respect to visual and anatomical outcomes in real life. In this study the number of visits and injections was lower that randomized controlled trials, but the functional and anatomical outcomes are probably still acceptable. PMID- 29234222 TI - Anatomical and functional outcomes of retinectomies in retinal detachments complicated by proliferative vitreoretinopathy. AB - Purpose: To study anatomical and functional outcomes of retinectomies in rhegmatogenous retinal detachments complicated by proliferative vitreoretinopathy. Methods: This is a retrospective interventional consecutive case series of eyes with rhegmatogenous retinal detachments complicated by advanced proliferative vitreoretinopathy and managed by relaxing retinectomy over a period of seventeen years. Three-port pars plana vitrectomy included core vitrectomy and removal of all epi-retinal membranes. On failure to flatten, retina was cut and excised. Basal vitrectomy and removal of anterior flap of retina then followed. Silicone oil was used as temponade in majority of cases. The dependent variables were anatomical and functional outcomes. The statistical analysis was performed on SPSS 21. Results: Series included 370 eyes of 337 patients. Mean follow up was 39 months. Scleral explant was used in 90(24.39%) cases. Two hundred and nine (56.49%) eyes were operated with trans conjunctival sutureless vitrectomy technique. Procedure was bilateral in 33 patients (09.79%). Retina attached in 311(84.05%) eyes after initial surgery. Final re-attachment after one or more surgeries was achieved in 344(92.97%) eyes. Two hundred and eleven (57.02%) cases achieved visual acuity of 6/60 or better. Conclusion: Relaxing retinectomies have good and encouraging anatomical and functional outcomes. This surgery can be effectively carried out with trans conjunctival sutureless vitrectomy technique. PMID- 29234223 TI - Retinal nerve fiber layer thickness in children with beta-thalassemia major. AB - Purpose: To measure the retinal nerve fiber layer thickness (RNFLT) in children with beta-thalassemia major and to compare with healthy controls. Methods: A total of 47 patients with beta-thalassemia major and 51 healthy controls were included. Each subject underwent a standard ophthalmological examination. RNFLT measurements were performed using optical coherence tomography. Results: Mean age of the patient group and healthy controls were 13.7 +/- 2.1 and 14.3 +/- 2.2 years, respectively. Mean peripapillary RNFL thickness was 94 um in the patient group, and 100 um in the control group (p < 0.01). In patients with beta thalassemia major, RNFL was thinner in all quadrants than control subjects. Within the beta-thalassemia major group neither average RNFLT nor each four quadrant RNFLT were correlated with the age, serum ferritin or serum hemoglobin levels (p > 0.05). Conclusion: In this study, we observed RNFL was thinner in patients with beta-thalassemia major. Thinning of RNFL did not correlate with hemoglobin or ferritin levels. PMID- 29234224 TI - Chiasmal syndrome: Clinical characteristics in patients attending an ophthalmological center. AB - Purpose: To present the clinical characteristics of a group of patients with the diagnosis of chiasmal syndrome who attended a large ophthalmological institute. Methods: Retrospective, observational clinical study with the review of medical records of patients with a diagnosis of chiasmal syndrome. The following variables were assessed: demographic characteristics, chief complaint upon presentation, best-corrected visual acuity (BCVA), presence or absence of diplopia, pupillary responses, optic nerve head morphology, etiology, and results from the ancillary tests including Ishihara test, Goldmann visual field (GVF) perimetry and neuroimaging. Results: A total of 104 met the inclusion criteria, with a median age of 52 years (range 4-86 years). Fifty-four patients (51.9%) were referred to our institution with a diagnosis of a causative etiology for chiasmal syndrome, while in 50 (48.1%) the diagnosis was performed at our center. The most common presenting symptom was low visual acuity in 57 patients (54.8%), and the most common GVF defect was bitemporal hemianopsia in 39 patients (78 eyes, 39.8%). Pupillary abnormalities were present in 58 patients (55.7%), the optic nerve revealed pallor at any degree in 67 patients (64.4%) and the Ishihara test was affected in 65 patients (62.5%). The most common diagnosis was pituitary macroadenoma. Conclusion: The ophthalmologist participates in the diagnosis and rehabilitation of patients with chiasmal syndrome. Low visual acuity is the most common symptom at presentation, and bitemporal hemianopia the most frequent GVF defect. Examination of the optic nerve head and pupillary responses, and ancillary tests including Ishihara test and neuroimaging are relevant for diagnosis. PMID- 29234225 TI - A new surgical technique of intra-scleral tube fixation in Ahmed Glaucoma Valve implantation: 'Scleral Sleeve Method'. AB - Purpose: To present a new surgical technique 'Scleral Sleeve Method' which would reduce the risk of Ahmed Glaucoma Valve (AGV) tube related complications in patients undergoing AGV FP7 (New World Medical Inc., Rancho Cucamonga, CA) for refractory glaucoma. Design: Prospective, Non-Randomized, hospital based interventional case series. Subjects: A total of 16 eyes of adult patients (10 males and 6 females) with refractory glaucoma. Methods: Instead of using sutures to fix the AGV tube to sclera, we devised a novel method of intra-scleral tube fixation by creating a scleral tunnel fashioned in form of sleeve. Main outcome measure: Post-operative tube related complications. Result: There were no tube related complications such as exposure, extrusion or retraction in any of the cases. Conclusion: Use of scleral sleeve method for tube fixation, along with graft to cover the tube, will provide additional safety measure and reduce the risks of tube related complications. PMID- 29234226 TI - Patterns of ophthalmic emergencies presenting to a referral hospital in Medina City, Saudi Arabia. AB - Background: Data are required on ophthalmic cases that present to the emergency eye clinics in Madinah, Saudi Arabia for proper allocation of healthcare resources. Objectives: To determine the frequency and various diagnoses of patients presenting to the A&E at Ohud Hospital, Madinah, Saudi Arabia. Methods: Data was collected prospectively for all patients who presented to the A&E ophthalmology clinic from June 2014 to September 2014. The data was analyzed and presented using frequency of incidence and percentages. Chi-square tests were used to evaluate the diagnoses based on age, sex and nationality. P <= 0.05 indicated statistical significance. Results: The study sample included 868 patients. The male-to-female ratio was 1.1:1.0. The main age categories included patients >=45 years of age (256 patients) and 251 patients between the ages of 15 30 years. Various types of Conjunctivitis was the most common diagnosis, reported in 282 patients (32.5%), and followed by dry eye syndrome in 156 (18%) patients. Nasolacrimal duct obstruction in 156 patients (18%). Eyelid infections were detected in 102 patients (12%), corneal abrasion in 102 patients (9.3%). Various eye traumas was diagnosed in 30 patients (3.5%), increased intraocular pressure (IOP) in 17 patients (2%), ruptured globe in 2 patients (0.2%) and various other non-emergency pathologies in the remaining eyes. There were no significant differences in patient's characteristics and categories of diagnoses. Conclusion: Non-emergent ophthalmic cases were the most common reason for the ophthalmology emergency room visits. It was observed that most cases could be referred to outpatient departments and potentially be managed by primary healthcare providers. This would be more cost effective and will also allow for better management of vision threatening ocular emergencies. PMID- 29234227 TI - Eradicating primary congenital glaucoma from Saudi Arabia: The case for a national screening program. AB - The prevalence of primary congenital glaucoma (PCG) in Saudi Arabia is high and the condition is a cause of childhood blindness in the country. Children often present with severe disease, requiring multiple procedures and a lifetime of medical care. The social and economic burden of the condition is substantial. Presently, the mainstay of management is early diagnosis and treatment of PCG. Premarital screening, especially in recessive diseases, such as PCG can be immensely useful by detecting the presence of a defect in the causative gene, followed by genetic counseling to potential couples that will lead to eradication of the disease in future generations. The introduction of a national screening program similar to the one already functioning for thalassemia, could potentially eliminate childhood blindness from PCG in Saudi Arabia and is likely to prove cost-effective. PMID- 29234229 TI - Isolated bilateral congenital lacrimal gland agenesis - Report of two cases. AB - Congenital lacrimal gland agenesis, also called congenital alacrima, is a rare cause of dry eye and is characterized by aplasia or hypoplasia of lacrimal glands. We present two 5-year old children with congenital lacrimal gland agenesis. The two cases had the final diagnosis of isolated bilateral congenital lacrimal gland agenesis and we document the clinical aspects, treatment and present a literature review related to this rare condition. PMID- 29234228 TI - Purtscher-like retinopathy - A rare complication of acute myocardial infarction and a review of the literature. AB - Purtscher-like retinopathy is an uncommon condition with features similar to Purtscher retinopathy but have non-traumatic causes. Several pathogenic mechanisms have been put forth with differing views on treatment options. We describe for the first time, a case of Purtscher-like retinopathy which developed following a myocardial infarct and a transient ischemic attack. We present a review of the literature on this condition, describing the various clinical presentations, investigation findings, treatment options and prognosis. PMID- 29234231 TI - Spectral domain optical coherence tomography and en-face imaging in presumed ocular chalcosis. AB - A 35-year-old male, with a history of injury sustained three years back, underwent pars plana vitrectomy with intravitreal copper foreign body removal. Post-operatively, visual acuity improved; however, glistening refractile particles were seen at the macula. Spectral domain optical coherence tomography and en-face imaging were performed to localise the level of the deposits. To the best of our knowledge, this is the first such documentation in presumed ocular chalcosis. PMID- 29234230 TI - Traumatic eye ball luxation: A stepwise approach to globe salvage. AB - Craniofacial trauma is often associated with orbital and ocular injuries. We report a case of a 21-year-old male with motor vehicular accident, orbital roof blow-in fracture, cerebrospinal fluid (CSF) leak, and left sided globe luxation with corneal abrasion and complete conjunctival denuding. The patient was managed by a multispeciality team and the eyeball was protected by amniotic membrane graft (AMG) biological dressing with novel use of inverted sterile metallic bowl as mechanical protection till the patient stabilized. During surgery, eyeball was reposited and ocular surface was reconstructed using amniotic membrane and symblepharon ring. Surgical correction and plating of the facial fractures and dural repair with autologus tensor fascia lata was done. Post surgery ocular surface was intact, ocular motility was well preserved and the globe was prephthisical. Traumatic eyeball luxation is a rare, but dramatic presentation which may occur in a blow in fracture when the intra orbital volume reduces and expels the eye ball out of the socket. This may be associated with extra ocular muscle rupture or optic nerve avulsion. The visual prognosis is nil in majority cases. However, the management is targeted towards globe preservation in view of psychological benefit and ease of cosmetic or prosthetic rehabilitation. Knowing the mechanism of luxation helps to plan the management. A stepwise approach for globe salvage is recommended. Team efforts to take care of various morbidities with special steps to safeguard the eye help to optimize outcomes. PMID- 29234232 TI - Vitreous hemorrhage as a clue to late presenting Pulmonary Arterio Venous Malformation. AB - Retinal vasculature is frequently altered in systemic vascular disorders such as Diabetes and Hypertension. We present a rare case in which vitreous hemorrhage was the presenting sign of an underlying congenital cyanotic heart disease. PMID- 29234233 TI - Retinoblastoma presenting as total hyphema: Three year follow-up. AB - Retinoblastoma very rarely presents as total hyphema. Our patient presented at an early age of 7 months. Follow-up of 3 years shows that unilateral group E retinoblastoma was treated successfully with enucleation and adjuvant chemotherapy. The fellow eye remained normal during this period. The factors associated with delay in treatment are also described. Reports like the present case add to the information available about advanced staging of retinoblastoma at the time of presentation, seen in cases with spontaneous hyphema due to the tumor. PMID- 29234234 TI - Mini descemet membrane stripping (m-DMES) in patients with Fuchs' endothelial dystrophy: A new method. AB - We present two cases with focal corneal edema due to Fuchs' endothelial dystrophy that were successfully treated with mini Descemet membrane stripping (m-DMES) (diameter of 3-4 mm; at the area of preexisting focal corneal edema) without endothelial replacement during cataract surgery. Specular microscopy demonstrated Fuchs' endothelial dystrophy and histopathologic evaluation confirmed the diagnosis. Anterior segment optical coherence tomography and confocal microscopy were used for the evaluation of the corneal tissue recovery course after the surgical procedure. In both patients, we observed an initial aggravation of corneal edema in the area of DM removal for two months followed by gradual improvement. At four months postoperatively, corneal edema had completely regressed resulting in corneal clearance and visual acuity improvement in both cases. M-DMES without graft insertion represents a promising alternative surgical technique that could be applied in specific cases of Fuchs' endothelial dystrophy with focal corneal edema. PMID- 29234235 TI - Large symptomatic retinal astrocytic hamartoma in a child with tuberous sclerosis complex. PMID- 29234236 TI - Peripheral optical coherence tomography montage guided successful management of retinal detachment with sub retinal bands. PMID- 29234237 TI - Expression, Purification, and Characterization of (R)-Sulfolactate Dehydrogenase (ComC) from the Rumen Methanogen Methanobrevibacter millerae SM9. AB - (R)-Sulfolactate dehydrogenase (EC 1.1.1.337), termed ComC, is a member of an NADH/NADPH-dependent oxidoreductase family of enzymes that catalyze the interconversion of 2-hydroxyacids into their corresponding 2-oxoacids. The ComC reaction is reversible and in the biosynthetic direction causes the conversion of (R)-sulfolactate to sulfopyruvate in the production of coenzyme M (2 mercaptoethanesulfonic acid). Coenzyme M is an essential cofactor required for the production of methane by the methyl-coenzyme M reductase complex. ComC catalyzes the third step in the first established biosynthetic pathway of coenzyme M and is also involved in methanopterin biosynthesis. In this study, ComC from Methanobrevibacter millerae SM9 was cloned and expressed in Escherichia coli and biochemically characterized. Sulfopyruvate was the preferred substrate using the reduction reaction, with 31% activity seen for oxaloacetate and 0.2% seen for alpha-ketoglutarate. Optimal activity was observed at pH 6.5. The apparent KM for coenzyme (NADH) was 55.1 MUM, and for sulfopyruvate, it was 196 MUM (for sulfopyruvate the Vmax was 93.9 MUmol min-1 mg-1 and kcat was 62.8 s-1). The critical role of ComC in two separate cofactor pathways makes this enzyme a potential means of developing methanogen-specific inhibitors for controlling ruminant methane emissions which are increasingly being recognized as contributing to climate change. PMID- 29234239 TI - Polymorphism and Modulation of Para-Substituted l-Phenylalanine. AB - The crystal structure of para-methyl-l-phenylalanine at 230 K resembles that of the para-fluorinated analogue from the literature but is commensurately modulated with seven molecules in the asymmetric unit (Z' = 7). At 100 K, the superstructure loses its modulation, leading to a unit cell with Z' = 1, with clear disorder in the phenyl ring orientations. The methyl-substituent in para methyl-l-phenylalanine has, in contrast to fluorine, no polar interactions with protons of neighboring molecules, which might allow for the well-defined modulation of the crystal structure at 230 K. PMID- 29234238 TI - miR-155-5p modulates malignant behaviors of hepatocellular carcinoma by directly targeting CTHRC1 and indirectly regulating GSK-3beta-involved Wnt/beta-catenin signaling. AB - Background: Hepatocellular carcinoma (HCC) remains one of the most lethal cancers. MicroRNA-155 (miR-155) and collagen triple helix repeat containing 1 (CTHRC1) were found to be involved in hepatocarcinogenesis, but their detailed functions in HCC are unclear. Here, we aimed to investigate the underlying role of miR-155-5p and CTHRC1 in HCC. Methods: miR-155-5p and CTHRC1 expression levels were detected by qRT-PCR, IHC and WB in HCC patients and cell lines. Dual luciferase assay, qRT-PCR and WB were used to validate the target interaction between miR-155-5p and CTHRC1. Biological behaviors, including apoptosis, cell cycle progression, and cell proliferation, invasion and migration, were measured by flow cytometry, CCK-8 assay and Transwell tests. A xenograft model was established to examine the effects of miR-155-5p and CTHRC1 on tumor formation. WB was finally utilized to identify the role of GSK-3beta-involved Wnt/beta catenin signaling in HCC growth and metastasis. Results: Our results showed that miR-155-5p and CTHRC1 were down-regulated and up-regulated, respectively, in HCC patients and cell lines. Dual-luciferase assay verified that CTHRC1 was the direct target of miR-155-5p. Moreover, elevated miR-155-5p expression promoted apoptosis but suppressed cell cycle progression and cell proliferation, invasion and migration in vitro and facilitated tumor formation in vivo; elevated CTHRC1 expression abolished these biological effects. Additionally, miR-155-5p overexpression increased metastasis- and anti-apoptosis-related protein expression and decreased pro-apoptosis-related protein expression, while forced CTHRC1 expression conserved the expression of these proteins. Conclusion: Altogether, our data suggested that miR-155-5p modulated the malignant behaviors of HCC by targeting CTHRC1 and regulating GSK-3beta-involved Wnt/beta-catenin signaling; thereby, miR-155-5p and CTHRC1 might be promising therapeutic targets for HCC patients. PMID- 29234240 TI - Crystal Engineering in Continuous Plug-Flow Crystallizers. AB - Size, shape, and polymorphic form are the critical attributes of crystalline particles and represent the major focus of today's crystallization process design. This work demonstrates how crystal properties can be tuned efficiently in solution via a tubular crystallizer that facilitates rapid temperature cycling. Controlled crystal growth, dissolution, and secondary nucleation allow a precise control of the crystal size and shape distribution, as well as polymorphic composition. Tubular crystallizers utilizing segmented flow such as the one presented in our work can provide plug flow characteristics, fast heating and cooling, allowing for rapid changes of the supersaturation. This makes them superior for crystal engineering over common crystallizers. Characterization of particle transport, however, revealed that careful selection of process parameters, such as tubing diameter, flow rates, solvents, etc., is crucial to achieve the full benefits of such reactors. PMID- 29234241 TI - Preparation of Microcrystals of Piroxicam Monohydrate by Antisolvent Precipitation via Microfabricated Metallic Membranes with Ordered Pore Arrays. AB - Microcrystals of piroxicam (PRX) monohydrate with a narrow size distribution were prepared from acetone/PRX solutions by antisolvent crystallization via metallic membranes with ordered pore arrays. Crystallization was achieved by controlled addition of the feed solution through the membrane pores into a well-stirred antisolvent. A complete transformation of an anhydrous form I into a monohydrate form of PRX was confirmed by Raman spectroscopy and differential scanning calorimetry. The size of the crystals was 7-34 MUm and was controlled by the PRX concentration in the feed solution (15-25 g L-1), antisolvent/solvent volume ratio (5-30), and type of antisolvent (Milli-Q water or 0.1-0.5 wt % aqueous solutions of hydroxypropyl methyl cellulose (HPMC), poly(vinyl alcohol) or Pluronic P-123). The smallest crystals were obtained by injecting 25 g L-1 PRX solution through a stainless-steel membrane with a pore size of 10 MUm into a 0.06 wt % HPMC solution stirred at 1500 rpm using an antisolvent/solvent ratio of 20. HPMC provided better steric stabilization of microcrystals against agglomeration than poly(vinyl alcohol) and Pluronic P-123, due to hydrogen bonding interactions with PRX and water. A continuous production of large PRX monohydrate microcrystals with a volume-weighted mean diameter above 75 MUm was achieved in a continuous stirred membrane crystallizer. Rapid pouring of Milli-Q water into the feed solution resulted in a mixture of highly polydispersed prism shaped and needle-shaped crystals. PMID- 29234242 TI - Role of Molecular Recognition in l-Cystine Crystal Growth Inhibition. AB - l-Cystine kidney stones-aggregates of single crystals of the hexagonal form of l cystine-afflict more than 20 000 individuals in the United States alone. Current therapies are often ineffective and produce adverse side effects. Recognizing that the growth of l-cystine crystals is a critical step in stone pathogenesis, real-time in situ atomic force microscopy of growth on the (0001) face of l cystine crystals and measurements of crystal growth anisotropy were performed in the presence of prospective inhibitors drawn from a 31-member library. The most effective molecular imposters for crystal growth inhibition were l-cystine mimics (aka molecular imposters), particularly l-cystine diesters and diamides, for which a kinetic analysis revealed a common inhibition mechanism consistent with Cabrera-Vermilyea step pinning. The amount of inhibitor incorporated by l-cystine crystals, estimated from kinetic data, suggests that imposter binding to the {0001} face is less probable than binding of l-cystine solute molecules, whereas imposter binding to {1010} faces is comparable to that of l-cystine molecules. These estimates were corroborated by computational binding energies. Collectively, these findings identify the key structural factors responsible for molecular recognition between molecular imposters and l-cystine crystal kink sites, and the inhibition of crystal growth. The observations are consistent with the reduction of l-cystine stone burden in mouse models by the more effective inhibitors, thereby articulating a strategy for stone prevention based on molecular design. PMID- 29234243 TI - Random and independent sampling of endogenous tryptic peptides from normal human EDTA plasma by liquid chromatography micro electrospray ionization and tandem mass spectrometry. AB - Background: Normal human EDTA plasma samples were collected on ice, processed ice cold, and stored in a freezer at - 80 degrees C prior to experiments. Plasma test samples from the - 80 degrees C freezer were thawed on ice or intentionally warmed to room temperature. Methods: Protein content was measured by CBBR binding and the release of alcohol soluble amines by the Cd ninhydrin assay. Plasma peptides released over time were collected over C18 for random and independent sampling by liquid chromatography micro electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS) and correlated with X!TANDEM. Results: Fully tryptic peptides by X!TANDEM returned a similar set of proteins, but was more computationally efficient, than "no enzyme" correlations. Plasma samples maintained on ice, or ice with a cocktail of protease inhibitors, showed lower background amounts of plasma peptides compared to samples incubated at room temperature. Regression analysis indicated that warming plasma to room temperature, versus ice cold, resulted in a ~ twofold increase in the frequency of peptide identification over hours-days of incubation at room temperature. The type I error rate of the protein identification from the X!TANDEM algorithm combined was estimated to be low compared to a null model of computer generated random MS/MS spectra. Conclusion: The peptides of human plasma were identified and quantified with low error rates by random and independent sampling that revealed 1000s of peptides from hundreds of human plasma proteins from endogenous tryptic peptides. PMID- 29234244 TI - Genetic alterations in benign prostatic hyperplasia patients. AB - Background: Benign prostate hyperplasia (BPH) is a classical age-related disease of the prostate, present in 20% of men at the age of 40 years with progression to 70% by the age of 60 years. BPH is associated with various lower urinary tract symptoms, which affect their day-to-day life. Materials and methods: Our objective was to evaluate the association between HER-2/neu, c-myc, p53, and clinicopathological variables in 45 patients diagnosed with benign prostatic hyperplasia using fluorescence in situ hybridization (FISH). The patients underwent transurethral prostate resection to address their primary urological problem. All patients were evaluated by use of a comprehensive medical history and rectal digital examination. The preoperative evaluation also included serum prostate specific antigen (PSA) measurement and ultrasonographic measurement of prostate volume. Results: The mean (+/- standard deviation) age of the 45 patients was 69.65 +/- 8.97 years. The mean PSA value of the patients was 9.25 +/ 5.12 ng/mL. The mean prostate volume was 65.46 +/- 11.43 mL. Amplification of HER-2/neu was seen in 4/45 (8.9%) cases and amplification of c-myc was seen in 5 of 45 (11.1%) cases; both genes were not associated with adverse clinicopathological variables. Deletion of p53 was seen in 20/45 (44.4%) cases. p53 gene was significantly associated with a severe AUASI (American Urological Association Symptom Index) score. Conclusion: In this study, we discussed important genetic markers in benign prostatic hyperplasia patients which may, in the future, be used as markers for diagnosis and prognosis, as well as targets for therapeutic intervention. PMID- 29234245 TI - Are political views related to smoking and support for tobacco control policies? A survey across 28 European countries. AB - Background: General political views are rarely considered when discussing public support for tobacco control policies and tobacco use. The aim of this study was to explore potential associations between political views, smoking and support for tobacco control policies. Methods: We analysed responses from 22,313 individuals aged >=15 years from 28 European Union (EU) member states, who self reported their political views (far-left [1-2 on a scale 1-10]; centre-left (3 4); centre (5-6); centre-right (7-8); and far-right (9-10) in wave 82.4 of the Eurobarometer survey in 2014. We ran multi-level logistic regression models to explore associations between political views and smoking, as well as support for tobacco control policies, adjusting for socio-demographic factors. Results: Compared to those placing themselves at the political centre, people with far left political views were more likely to be current smokers (Odds Ratio [OR] = 1.13; 95% Confidence Interval [CI]: 1.01-1.26), while those in the centre-right were the least likely to smoke (OR = 0.84; 95% CI: 0.76-0.93). Similar associations were found for having ever been a smoker. Respondents on the left side of the political spectrum were more likely to support tobacco control policies and those on the centre-right were less likely to support them, as compared to those at the political centre, after controlling for smoking status. Conclusions: General political views may be associated not only with support for tobacco control policies, but even with smoking behaviours, which should be taken into account when discussing these issues at a population level. Further research is needed to explore the implications of these findings. PMID- 29234246 TI - Is There Still a Role for First-Line Single Agent Endocrine Therapy in HR+ and HER2- Advanced Breast Cancer? PMID- 29234247 TI - PI3K/mTOR Inhibitors in the Treatment of Luminal Breast Cancer. Why, When and to Whom? AB - Estrogen receptor (ER) signaling represents the main driver of tumor growth and survival in luminal breast cancer (BC). Despite the efficacy of endocrine agents, many patients with luminal BC do not respond to endocrine therapy and many others develop endocrine resistance over time, due to the activation of escape pathways such as the PI3K/AKT/mTOR signaling. Several clinical trials have demonstrated the efficacy of mTOR and PI3K inhibitors in overcoming endocrine resistance in hormone receptor-positive human epidermal growth factor receptor 2 (HER2) negative metastatic BC (MBC) patients. Nevertheless, to date, everolimus is the only agent targeting the PI3K/mTOR pathway that has been approved for clinical use. Recently, the introduction of CDK 4/6 inhibitors into clinical practice has significantly changed the therapeutic scenarios in luminal MBC. In the absence of direct comparisons among the new treatment combinations and predictive biomarkers of response, the choice of optimal therapeutic algorithms is very challenging. Future trials should focus on identifying more effective and safe combination therapies and defining the best treatment sequences in luminal BC. PMID- 29234248 TI - Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer. AB - After optimizing endocrine monotherapy modalities in the setting of advanced luminal breast cancer (BC), dual endocrine/targeted therapy combinations have been tested with positive results, and are transforming this BC subtype treatment landscape. Cell cycle deregulation is a hallmark of cancer that has become a key druggable target in hormone receptor (HR)-positive BC due to its role in endocrine resistance mechanisms. Cyclin dependent kinase (CDK)4/6 inhibitors have experienced a fast development in combination with endocrine therapy and have already been commercialized in some countries. In this review, we will summarize the development of these CDK4/6 inhibitors in luminal BC, from the preclinical data to the pivotal phase III trials that led to their approval, focusing on the efficacy and safety data for each of the treatment settings. Moreover, we will consider the challenges CDK4/6 inhibitors face in their positioning in the algorithm of treatment for advanced luminal BC and the considerations physicians should take into account when selecting these therapies for their patients. However, we are still in need of reliable predictive biomarkers in order to identify patients who will derive the greatest benefit from these drug combinations that are not exempt from toxicity. PMID- 29234249 TI - Mechanisms of Resistance to CDK4/6 Inhibitors in Breast Cancer and Potential Biomarkers of Response. AB - Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting. In addition, molecular mechanisms of acquired resistance to palbociclib have been analyzed only in preclinical studies. Here we review the current knowledge on the available preclinical data about the mechanisms of de novo and acquired resistance to CDK4/6 inhibitors in breast cancer, and clinical data about potential biomarkers of response. PMID- 29234250 TI - Are We Ready to Use ESR1 Mutations in Clinical Practice? AB - The recurrent ligand-binding domain ESR1 mutations are an important mechanism of endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer. These mutations evolve under the selective pressure of endocrine treatments and are rarely found in treatment-naive ER+ breast cancers. Preclinical studies showed that these mutations lead to ligand-independent activity facilitating resistance to aromatase inhibitors and relative resistance to tamoxifen and fulvestrant. Retrospective analyses of ESR1 mutations in baseline plasma circulating tumor DNA from clinical trials suggest that these mutations are prognostic of poor overall survival and predictive of resistance to aromatase inhibitors in metastatic disease. Larger datasets and prospective studies to confirm these results are lacking. In addition, response to other standard treatments for metastatic breast cancer in the presence of the ESR1 mutations is unknown, and studies to determine the optimal treatment combinations for patients with ESR1 mutations are also needed. PMID- 29234251 TI - Targeted Intraoperative Radiotherapy Tumour Bed Boost during Breast-Conserving Surgery after Neoadjuvant Chemotherapy. PMID- 29234252 TI - Targeted Intraoperative Radiotherapy Tumour Bed Boost during Breast-Conserving Surgery after Neoadjuvant Chemotherapy - a Subgroup Analysis of Hormone Receptor Positive HER2-Negative Breast Cancer. AB - Introduction: In a previous study our group showed a beneficial effect of targeted intraoperative radiotherapy (TARGIT-IORT) as an intraoperative boost on overall survival after neoadjuvant chemotherapy (NACT) compared to an external boost (EBRT). In this study we present the results of a detailed subgroup analysis of the hormone receptor (HR)-positive HER2-negative patients. Methods: In this cohort study involving 46 patients with HR-positive HER2-negative breast cancer after NACT, we compared the outcomes of 21 patients who received an IORT boost to those of 25 patients treated with an EBRT boost. All patients received whole breast radiotherapy. Results: Median follow-up was 49 months. Whereas disease-free-survival and breast cancer-specific mortality were not significantly different between the groups, the 5-year Kaplan-Meier estimate of overall mortality was significantly lower by 21% with IORT, p = 0.028. Non-breast cancer specific mortality was significantly lower by 16% with IORT, p = 0.047. Conclusion: Although our results have to be interpreted with caution, we have shown that the improved overall survival demonstrated previously could be reproduced in the HR-positive HER2-negative subgroup. These data give further support to the inclusion of such patients in the TARGIT-B (Boost) randomised trial that is testing whether IORT boost is superior to EBRT boost. PMID- 29234253 TI - Evaluation of Sentinel Lymph Node Biopsy and Axillary Lymph Node Dissection for Breast Cancer Treatment Concepts - a Retrospective Study of 1,214 Breast Cancer Patients. AB - Background: Most breast cancer patients require lumpectomy with axillary sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). The ACOSOG Z0011-trial failed to detect significant effects of ALND on disease-free and overall survival among patients with limited sentinel lymph node (SLN) metastases. Intense dose-dense chemotherapy and supraclavicular fossa radiation (SFR) are indicated for patients with extensive axillary metastases. In this multicentered study, we investigated the relevance of ALND after positive SLNB to determine adequate adjuvant therapy. Methods: We retrospectively analyzed data from 1,214 patients with clinically nodal negative T1-T2 invasive breast cancer undergoing surgery at Hanau City Hospital Breast cancer center. Results: 681 patients underwent ALND after SLNB. 20 patients (8.5%) from the group with 1 or 2 SLN metastases (n = 236) showed more than 3 lymph node metastases after ALND. 13 patients (31.7%) from the group with more than 2 SLN metastases (n = 41) were diagnosed with a minimum of 4 axillary lymph node metastases after ALND. Conclusions: In 8.5% of the patients with 1 or 2 SLN metastases, ALND detected more than 3 macrometastases, setting the indication for intense dose-dense chemotherapy and SFR. More than 2 SLN metastases, T stage and grading predict lymph node metastases. PMID- 29234254 TI - Prognostic Significance of Focal Adhesion Kinase in Node-Negative Breast Cancer. AB - Background: Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays an important role as a mediator of cell migration, invasion, proliferation and survival. Conflicting results for the prognostic role of FAK in breast cancer (BC) prompted us to determine its impact. Methods: Patients with node-negative BC entered this retrospective study. FAK expression was determined by immunohistochemistry (n = 335). The prognostic impact of FAK was examined with Cox regression analyses and Kaplan-Meier estimation in the whole cohort as well as in different molecular subtypes. Results: 151 (45.1%) had a FAK-positive BC. In univariate analyses, FAK expression showed a significant impact for shorter disease-free survival (DFS) (hazard ratio (HR) 1.54, 95% confidence interval (CI) 1.04-2.28, p = 0.030) but not for metastasis-free survival and overall survival. Significant prognostic relevance for DFS (HR 1.76, 95% CI 1.05-2.97, p = 0.033) was observed in particular in estrogen receptor-positive HER2-negative BC patients, most notably in luminal B-like tumors (HR 2.32, CI 1.20-4.48, p = 0.012). However, FAK lost its prognostic impact in multivariate Cox regression analysis. Conclusion: FAK was associated with impaired DFS in univariate analysis. Prognostic relevance for DFS was most pronounced in luminal B-like BC. However, FAK expression was not associated with an independent impact on survival for BC in multivariate analysis. PMID- 29234255 TI - Influence of Orally Administered Probiotic Lactobacillus Strains on Vaginal Microbiota in Women with Breast Cancer during Chemotherapy: A Randomized Placebo Controlled Double-Blinded Pilot Study. AB - Background: Due to chemotherapy and estrogen deprivation therapy, genitourinary syndrome of menopause is a common condition in breast cancer patients. We aimed to determine the effect of an orally administered Lactobacillus preparation on the vaginal microbiota in breast cancer patients. Methods: Postmenopausal breast cancer patients receiving chemotherapy, with vaginal atrophy and an intermediate vaginal microbiota (Nugent score 4-6), were either randomized to the intervention group receiving probiotic capsules of 4 Lactobacillus species or to the control group receiving placebo twice daily for 2 weeks. Consecutive vaginal swabs were taken at baseline, 1 day after administration of the last capsule (follow-up 1), and after 1 week (follow-up 2) in 22 patients (11 vs. 11). Results: We observed a positive influence on the vaginal microbiota in 7/11 (63%) women in the intervention group, and 4/11 (36%) women in the control group. There was a shift in Nugent score towards normal microbiota levels in the intervention group (-1.3 at follow-up 1, -0.45 at follow-up 2) and a significant deterioration of the Nugent score in the control group (+0.4 at follow-up 1, +2.5 at follow-up 2). Conclusion: The orally administered Lactobacillus preparation has the potential to improve the vaginal microbiota in women undergoing chemotherapy for breast cancer. PMID- 29234256 TI - Congenital Malformations of the Reproductive Tract in a Patient with Poland Syndrome: Is There a Connection? AB - Background: Poland syndrome and Mullerian duct agenesis (Mayer-Rokitansky-Kuster Hauser(MRKH)-like syndrome) are two rare congenital anomalies with unclear etiology. Case Report: An 18-year-old female presented with hypoplasia of the left pectoralis muscles and subcutaneous tissue, hypoplasia of the left breast and nipple, and dextrocardia, typical in those with a severe form of Poland syndrome. She also showed aplasia of the vagina and uterus, bilateral ovarian agenesis, and hyperandrogenism, presenting as MRKH-like syndrome. Conclusion: It is plausible to assume that these two congenital anomalies which arose from distant sites may be interrelated. More cases and further studies will certainly help delineate the pathogenesis of these syndromes. PMID- 29234257 TI - Dual HER2 Blockade. PMID- 29234258 TI - Toxicity, Adverse Events, and Quality of Life Associated with the Treatment of Metastatic Castration-Resistant Prostate Cancer. AB - Objectives: Among males, prostate cancer (PCa) is the most common cancer in Europe and the second most common cancer worldwide, especially in those aged > 70 years. With the advent of novel alternative treatments, survival in patients with advanced PCa has increased. PCa is now considered a chronic disease. Survival is an important endpoint in advanced PCa, as is quality of life (QoL). The effects of the disease and its treatment on patient health-related QoL must be taken into account when selecting the most appropriate treatment options. The present literature review aimed to provide an overview of metastatic castration-resistant prostate cancer treatment modalities, with an emphasis on side effect profiles and general health-related QoL. Methods: PubMed was searched using the keywords metastatic castration-resistant prostate cancer, docetaxel, cabazitaxel, enzalutamide, abiraterone acetate, and QoL. Conclusion: Based on the studies reviewed herein, abiraterone acetate and enzalutamide provide favorable outcomes, in terms of hematological adverse events. As enzalutamide and abiraterone acetate can be taken orally, they might have a positive effect on patient QoL. PMID- 29234259 TI - Simultaneous Measurements of Follicle Stimulating Hormone and Total Testosterone and Associations in Clinically Localized Prostate Cancer. AB - Objectives: To evaluate the potential relations of simultaneous measurements of basal levels of follicle stimulating hormone (FSH) and total testosterone (TT) in clinically localized prostate cancer (PCa). Materials and Methods: The study included 126 patients who had simultaneous measurements of prostate specific antigen (PSA), FSH, and TT before undergoing radical prostatectomy for clinically localized PCa. Correlations and independent associations between clinical and pathological factors were investigated by statistical methods. Results: The tumor volume (TV) was directly correlated to PSA and TT which was inversely related to FSH. Moreover, it was independently associated with both PSA and TT. In a multivariate linear regression model, FSH and TV were simultaneous independent factors associated with TT, and the association was inverse in the former and direct in the latter. In the patient population, the subset with FSH levels above the third quartile was related to lower median levels of TT that were associated with high grade cancer showing a lower TV. In localized PCa, basal levels of TT were associated with tumor parameters and inversely related to FSH levels, and the subset FSH levels above the third quartile were related to lower TT levels that were associated with high grade cancers showing a lower tumor load. Conclusion: Preoperative TT was associated with tumor parameters and inversely related to FSH levels. Patient with increased FSH levels was related to lower levels of TT, which was associated with high grade cancer. PMID- 29234260 TI - Can Anterior Prostatic Fat Harbor Prostate Cancer Metastasis? A Prospective Cohort Study. AB - Objectives: Traditionally anterior prostatic fat (APF) hasn't been included in pelvic lymph node (LN) dissection templates following radical prostatectomy. In this study we evaluate the incidence of lymphoid tissue in the APF and the incidence of LN metastasis in APF in patients who have undergone robotic-assisted laparoscopic radical prostatectomy (RALP). Methods: A prospective database of RALP has been maintained between January 2010 and September 2015. APF is routinely excised and sent separately for histopathological evaluation to identify lymphoid tissue and metastatic prostate cancer. Results: A total of 629 underwent RALP. Forty-six (7.3%) of the patients had lymphoid tissue on histopathological evaluation. Two patients had meta-static disease. Both patients with positive LNs were intermediate risk on pre-operative evolution (A-PSA 16.6 ng/ml, Gleason 3 + 4; B PSA 7.3 ng/ml, Gleason 4 + 3) and upgraded on final prostate pathological evaluation to high risk disease (A-Gleason 4 + 5, pT3b, B Gleason 4 + 3, pT4). Conclusion: There appears to be lymphatic drainage to the APF from the prostate. Hence APF should be included in pelvic LN dissection templates when lymphadenectomy is contemplated in patients undergoing radical prostatectomy. PMID- 29234261 TI - The Inverse Association between the Baseline Renal Function and Overall Survival in Patients with Metastatic Renal Cell Carcinoma Treated with Molecular-Targeted Agents. AB - Background: The objective of this study was to investigate the prognostic significance of the baseline renal function in metastatic renal cell carcinoma (mRCC) patients treated with molecular-targeted agents. Patients and Methods: This study included 408 consecutive mRCC patients receiving molecular-targeted therapy, consisting of 124 patients in group A and 284 patients in group B who had baseline estimated glomerular filtration rates >= 60 ml/min/1.73 m2 and < 60 ml/min/1.73 m2, respectively. Results: Compared with group A, group B was significantly less likely to have poor prognostic factors, such as a high proportion of patients without nephrectomy. The median overall survivals (OSs) after the initiation of targeted therapy in groups A and B were 21.4 and 35.8 months, respectively, and there was a significant difference in the OS between the 2 groups. However, multivariate analysis showed a lack of independent impact of the baseline renal function on the OS. Furthermore, when patients without a nephrectomy were excluded, no significant difference was noted in the OS between the 2 groups. Conclusion: These findings suggested that there was no adverse impact of an unfavorable baseline renal function on the efficacy of targeted agents against mRCC. Thus, molecular-targeted therapy should not be avoided in mRCC patients with an impaired baseline renal function. PMID- 29234262 TI - Physical Activity Decreases Kidney Cancer Mortality. AB - Background: To investigate associations of kidney cancer mortality with modifiable risk factors of obesity, physical activity, and smoking. Methods: We evaluate baseline data from US National Health Information Survey from 1998 through 2004 linked to mortality data reporting deaths through 2006. The primary outcome variable was kidney cancer-specific mortality and primary exposure variables were self-reported physical activity and body mass index (BMI). We utilized multivariable adjusted Cox proportional hazards regression models, with delayed entry to account for age at survey interview. Results: Among 222,163 individuals with complete follow-up data we identified 71 kidney cancer-specific deaths. In multivariate analyses, individuals who reported "any physical activity" were 50% less likely [adjusted hazard ratio (adjusted HR) 0.50, 95% CI 0.27-0.93, p = 0.028] to die of kidney cancer than non-exercisers, while obese individuals (BMI >= 30 kg/m2) were nearly 3 times more likely (adjusted HR 2.84, 95% CI 1.30-6.23, p = 0.009) compared to those of normal weight (BMI < 25 kg/m2). Compared to never smokers, former smokers were twice as likely to die of kidney cancer (adjusted HR 2.00, 95% CI 1.05-3.80, p = 0.034). Conclusion: Physical activity decreases and obesity increases the risk of kidney cancer mortality. PMID- 29234263 TI - Atypical Small Acinar Proliferation and High Grade Prostatic Intraepithelial Neoplasia: Should We Be Concerned? An Observational Cohort Study with a Minimum Follow-Up of 3 Years. AB - Introduction: Atypical small acinar proliferation (ASAP) and high grade prostatic intraepithelial neoplasia (HGPIN) are considered precancerous. We aimed to measure the rate of repeat biopsy and adenocarcinoma in patients with ASAP and HGPIN and identify any clinico-pathologic parameters at diagnosis of ASAP/HGPIN that are predictive of adenocarcinoma. Materials and Methods: Patients with a diagnosis of ASAP/HGPIN with no previous or concomitant cancer were identified. Prostate specific antigen (PSA) and magnetic resonance imaging (MRI) changes were monitored. Re-biopsy was at clinician discretion. Results: Nineteen were diagnosed with ASAP and 17 with HGPIN. Seven with ASAP (37%) and 6 with HGPIN (35%) underwent re-biopsy. Three (16%) with ASAP and 5 with HGPIN (29%) were diagnosed with adenocarcinoma. The difference in cancer detection rates between ASAP and HGPIN was not significant (p = 0.35). Five (14%) in total required definitive therapy for adenocarcinoma. Twenty-three (64%) did not undergo repeat biopsy. Parameters at diagnosis of HGPIN and ASAP, including PSA, prostate volume and PSA density, were compared between the cancer and non-cancer cohorts with none found to be predictive of adenocarcinoma. Conclusion: By monitoring PSA and MRI changes, we managed to spare re-biopsy in two-thirds of patients. Further evaluation is necessary to characterize a surveillance protocol in these populations. PMID- 29234264 TI - Use of a Modified Continent Ileovesicostomy in Adults with Prior Enterocystoplasty. AB - Background/Aims: To describe our initial experience with a novel modification of the Mitrofanoff conduit technique utilizing the Yang-Monti ileovesicostomy and the serosa lined extramural tunnel of the T-pouch to create a continent catheterizable stoma in patients with a prior enterocystoplasty. Methods: A 14 cm segment of bowel was harvested, and the distal 4 cm was divided and reconfigured utilizing the Yang-Monti technique. The remaining segment was folded into a U and secured with a serosal basting stitch. Half of the Yang-Monti tube is laid in the trough of the U-shaped segment and secured. Next, the U-shaped segment was incised along the anti-mesenteric border for the length of the tube. The newly created flaps adjacent to the tube was then laid over the tube and sutured together completing the serosa lined tunnel. The entire patch was anastomosed to a cystostomy through the previous enterocystoplasty. Finally, the proximal end of the tube was brought through the umbilicus and matured as a stoma. Results: Two patients with prior enterocystoplasties underwent the procedure described above. At follow-up of 18 and 24 months, both patients reported excellent continence. To date, there have been no revisions or significant complications. Conclusion: The construction of continent catheterizable stoma in adults with prior history of enterocystoplasty presents many technical challenges. The combination of the Yang Monti ileovesicostomy and the extramural tunnel of the T-pouch provides an effective option for creating a continent catheterizable stoma in adults with prior history of enterocystoplasty. PMID- 29234265 TI - The Benefit of a Surgical Resection of a Solitary Pulmonary Metastasis of Prostate Cancer after Radical Prostatectomy. AB - Historically, a solitary pulmonary metastasis of prostate cancer was considered as metastatic or disseminated disease and could only be treated systemically. However, some patients may benefit from surgical metastasectomy of a solitary pulmonary metastasis. We present an uncommon case of resection of a solitary pulmonary metastasis of prostate cancer after previous radical prostatectomy, resulting in un-detectable prostate specific antigen. PMID- 29234266 TI - Glomus Tumor of the Scrotum: A Case Report and Mini-Review. AB - Glomus tumor in the genital area is extremely rare, with an extensive search in the medical literature revealing only 1 case arising in the scrotum. They can be easily mistaken, both clinically and radiologically, for skin neoplasms or primary testicular tumors involving the scrotum. This report presents a case of a 54-year-old man who presented with a painful right scrotal swelling. Ultrasound suggested the possibility of an epidermal inclusion cyst. The excised mass was diagnosed as a benign glomus tumor. To the best of our knowledge, this is the second case of glomus tumor of the scrotum described in the literature. This report expands the differential diagnoses of scrotal neoplasms. Furthermore, essential guidelines necessary to distinguish glomus tumor from other lesions in the scrotum are discussed. PMID- 29234267 TI - Incidental Detection of Occult Thyroid Carcinoma with 11C-Choline PET/CT for High Risk Prostate Cancer. AB - We report a case of a 65-year-old male patient with high-risk prostate cancer, re staged with 11C-choline positron emission tomography/computed tomography (PET/CT) for prostate specific antigen recurrences 3 years after radical prostatectomy and adjuvant radiation therapy. In addition to 2 suspicious presacral lymph nodes which were resected and proven to be metastatic, PET/CT revealed a very high uptake in a calcified thyroid nodule. Evaluation with fine needle aspiration was suspicious for thyroid carcinoma and the patient underwent total thyroidectomy, confirming a non-metastatic encapsulated follicular variant of papillary thyroid carcinoma. To our knowledge, this is the first report of a thyroid cancer diagnosed with 11C-choline PET/CT for prostate cancer staging. PMID- 29234269 TI - Application of the Stockwell Transform to Electroencephalographic Signal Analysis during Gait Cycle. AB - The analysis of electroencephalographic signals in frequency is usually not performed by transforms that can extract the instantaneous characteristics of the signal. However, the non-steady state nature of these low voltage electrical signals makes them suitable for this kind of analysis. In this paper a novel tool based on Stockwell transform is tested, and compared with techniques such as Hilbert-Huang transform and Fast Fourier Transform, for several healthy individuals and patients that suffer from lower limb disability. Methods are compared with the Weighted Discriminator, a recently developed comparison index. The tool developed can improve the rehabilitation process associated with lower limb exoskeletons with the help of a Brain-Machine Interface. PMID- 29234268 TI - The Evidence for the Spread and Seeding Capacities of the Mutant Huntingtin Protein in in Vitro Systems and Their Therapeutic Implications. AB - Neurodegenerative disorders are not only characterized by specific patterns of cell loss but the presence and accumulation of various pathological proteins-both of which correlate with disease evolution. There is now mounting evidence to suggest that these pathological proteins present with toxic, at times prion-like, properties and can therefore seed pathology in neighboring as well remotely connected healthy neurons as they spread across the brain. What is less clear, at this stage, is how much this actually contributes to, and drives, the core pathogenic events. In this review, we present a comprehensive, up-to-date summary of the reported in vitro studies that support the spreading and seeding capacities of pathological proteins, with an emphasis on mutant huntingtin protein in the context of Huntington's disease, although in vivo work remains to be performed to validate this theory in this particular disease. We have further reviewed these findings in light of their potential implications for the development of novel therapeutic approaches. PMID- 29234271 TI - The Enigmatic Role of GBA2 in Controlling Locomotor Function. AB - The non-lysosomal glucosylceramidase GBA2 catalyzes the hydrolysis of glucosylceramide to glucose and ceramide. Loss of GBA2 function results in accumulation of glucosylceramide. Mutations in the human GBA2 gene have been associated with hereditary spastic paraplegia (HSP) and autosomal-recessive cerebellar ataxia (ARCA). Patients suffering from these disorders exhibit impaired locomotion and neurological abnormalities. GBA2 mutations found in these patients have been proposed to impair GBA2 function. However, the molecular mechanism underlying the occurrence of mutations in the GBA2 gene and the development of locomotor dysfunction is not well-understood. In this review, we aim to summarize recent findings regarding mutations in the GBA2 gene and their impact on GBA2 function in health and disease. PMID- 29234270 TI - Mouse Panx1 Is Dispensable for Hearing Acquisition and Auditory Function. AB - Panx1 forms plasma membrane channels in brain and several other organs, including the inner ear. Biophysical properties, activation mechanisms and modulators of Panx1 channels have been characterized in detail, however the impact of Panx1 on auditory function is unclear due to conflicts in published results. To address this issue, hearing performance and cochlear function of the Panx1-/- mouse strain, the first with a reported global ablation of Panx1, were scrutinized. Male and female homozygous (Panx1-/-), hemizygous (Panx1+/-) and their wild type (WT) siblings (Panx1+/+) were used for this study. Successful ablation of Panx1 was confirmed by RT-PCR and Western immunoblotting in the cochlea and brain of Panx1-/- mice. Furthermore, a previously validated Panx1-selective antibody revealed strong immunoreactivity in WT but not in Panx1-/- cochleae. Hearing sensitivity, outer hair cell-based "cochlear amplifier" and cochlear nerve function, analyzed by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recordings, were normal in Panx1+/- and Panx1-/- mice. In addition, we determined that global deletion of Panx1 impacts neither on connexin expression, nor on gap-junction coupling in the developing organ of Corti. Finally, spontaneous intercellular Ca2+ signal (ICS) activity in organotypic cochlear cultures, which is key to postnatal development of the organ of Corti and essential for hearing acquisition, was not affected by Panx1 ablation. Therefore, our results provide strong evidence that, in mice, Panx1 is dispensable for hearing acquisition and auditory function. PMID- 29234273 TI - Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Abeta Oligomer Induced Cognitive Impairments in Mice. AB - Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7 bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3 oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3beta (GSK3beta), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2.3-23.3 MUg/kg 7Bio effectively prevented beta-amyloid (Abeta) oligomer-induced impairments of spatial cognition and recognition without affecting bodyweight and motor functions in mice. Moreover, 7Bio potently inhibited Abeta oligomer-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Furthermore, 7Bio significantly prevented the decreased expression of synapsin-1 and PSD-95, biomarkers of pre-synaptic and post-synaptic proteins in Abeta oligomer-treated mice. The mean optical density (OD) with hyper-phosphorylated tau (pTau), glial fibrillary acidic protein (GFAP) and CD45 positive staining in the hippocampus of 7Bio-treated mice were significantly decreased compared to those of Abeta oligomer-treated mice. In addition, Western blotting analysis showed that 7Bio attenuated Abeta oligomer-decreased expression of pSer9 GSK3beta. Those results suggested that 7Bio could potently inhibit Abeta oligomer induced neuroinflammation, synaptic impairments, tau hyper-phosphorylation, and activation of astrocytes and microglia, which may contribute to the neuroprotective effects of 7Bio. Based on these findings, we expected that 7Bio might be developed as a novel anti-AD lead compound. PMID- 29234272 TI - Differential Roles of Glycogen Synthase Kinase 3 Subtypes Alpha and Beta in Cortical Development. AB - Glycogen synthase kinases 3 (GSK3) alpha and beta are expressed in the nervous system, and disruption of GSK3 signaling has been implicated in a wide range of neurodevelopmental and psychiatric disorders. Although several studies have established a role of GSK3 signaling in the nervous system, much less is known about isoform-specific functions. Here, we have examined the role of GSK3alpha and GSK3beta in the developing neocortex by performing in utero electroporation with specific small interfering RNAs targeting each isoform. We found that depletion of either GSK3alpha or GSK3beta commonly promoted the proliferation of neural progenitor cells in the ventricular zone, but at later stages, knocking down of each isoform resulted in distinct outcomes. In particular, the transformation of radial progenitors to intermediate progenitor cells was promoted in GSK3alpha-depleted cells, but markedly prevented in GSK3beta-depleted cells. Moreover, knocking down of GSK3beta but not GSK3alpha prevented the generation of upper-layer Cux1+ neurons. Consistent with the distinct outcomes, protein levels of c-Myc and beta-catenin, well-known substrates of GSK3, were differentially affected by depletion of GSK3alpha and GSK3beta. Together, these results suggest that GSK3alpha and GSK3beta might play distinct roles in the genesis and differentiation of neuronal lineage cells during neocortex development by differential regulation of downstream signaling pathways. PMID- 29234274 TI - Neuronal Nitric Oxide Synthase Contributes to PTZ Kindling Epilepsy-Induced Hippocampal Endoplasmic Reticulum Stress and Oxidative Damage. AB - Epilepsy is one of the most common chronic neurological disorders which provoke progressive neuronal degeneration. Endoplasmic reticulum (ER) stress has recently been recognized as pivotal etiological factors contributing to epilepsy-induced neuronal damage. However, the specific contribution of epilepsy made to ER stress remains largely elusive. Here we use pentylenetetrazole (PTZ) kindling, a chronic epilepsy model, to identify neuronal nitric oxide synthase (nNOS) as a signaling molecule triggering PTZ kindling epilepsy-induced ER stress and oxidative damage. By genetic deletion of nNOS gene, we further demonstrated that nNOS acts through peroxynitrite, an important member of reactive nitrogen species, to trigger hippocampal ER stress and oxidative damage in the PTZ-kindled mice. Our findings thus define a specific mechanism for chronic epilepsy-induced ER stress and oxidative damage, and identify a potential therapeutic target for neuroprotection in chronic epilepsy patients. PMID- 29234275 TI - Insulin Modulates Neural Activity of Pyramidal Neurons in the Anterior Piriform Cortex. AB - Insulin is an important peptide hormone that regulates food intake and olfactory function. While a multitude of studies investigated the effect of insulin in the olfactory bulb and olfactory epithelium, research on how it modulates higher olfactory centers is lacking. Here we investigate how insulin modulates neural activity of pyramidal neurons in the anterior piriform cortex, a key olfactory signal processing center that plays important roles in odor perception, preference learning, and odor pattern separation. In vitro we find from brain slice recordings that insulin increases the excitation of pyramidal neurons, and excitatory synaptic transmission while it decreases inhibitory synaptic transmission. In vivo local field potential (LFP) recordings indicate that insulin decreases both ongoing gamma oscillations and odor evoked beta responses. Moreover, recordings of calcium activity from pyramidal neurons reveal that insulin modulates the odor-evoked responses by an inhibitory effect. These results indicate that insulin alters olfactory signal processing in the anterior piriform cortex. PMID- 29234276 TI - Functional Reintegration of Sensory Neurons and Transitional Dendritic Reduction of Mitral/Tufted Cells during Injury-Induced Recovery of the Larval Xenopus Olfactory Circuit. AB - Understanding the mechanisms involved in maintaining lifelong neurogenesis has a clear biological and clinical interest. In the present study, we performed olfactory nerve transection on larval Xenopus to induce severe damage to the olfactory circuitry. We surveyed the timing of the degeneration, subsequent rewiring and functional regeneration of the olfactory system following injury. A range of structural labeling techniques and functional calcium imaging were performed on both tissue slices and whole brain preparations. Cell death of olfactory receptor neurons and proliferation of stem cells in the olfactory epithelium were immediately increased following lesion. New olfactory receptor neurons repopulated the olfactory epithelium and once again showed functional responses to natural odorants within 1 week after transection. Reinnervation of the olfactory bulb (OB) by newly formed olfactory receptor neuron axons also began at this time. Additionally, we observed a temporary increase in cell death in the OB and a subsequent loss in OB volume. Mitral/tufted cells, the second order neurons of the olfactory system, largely survived, but transiently lost dendritic tuft complexity. The first odorant-induced responses in the OB were observed 3 weeks after nerve transection and the olfactory network showed signs of major recovery, both structurally and functionally, after 7 weeks. PMID- 29234277 TI - Investigating the Usability and Acute Effects of a Bedside Video Console to Prefrontal Cortical Activity Alterations: A Preclinical Study in Healthy Elderly. AB - Elderly people at risk of developing cognitive decline; e.g., following surgery, may benefit from structured, challenging, and repetitive cognitive video training. This study assessed usability and acute effects of a newly developed bedside console (COPHYCON). Fifteen healthy elderly individuals performed a one time 80-min intervention, including cognitive video games aimed at improving awareness and selective attention. Perceived usefulness and perceived ease of use (Technology Acceptance Model) were assessed together with measures of the achieved game level, reaction times, (in-) correct responses during ALERT and SELECT game play. Further, prefrontal cortical involvement of the regional cerebral hemoglobin saturation (rS02%) assessed with functional near infrared spectroscopy (fNIRS) (n = 5) and EEG power (n = 10) was analyzed. All participants completed the study without any adverse events. Perceived usefulness and perceived ease of use (TAM scores range 1-7) of the system varied between 3.9 and 6.3. The game levels reached for awareness varied between 9 and 11 (initial score 8-10), for reaction speed between 439 and 469 ms, and for correct responses between 74.1 and 78.8%. The highest level for the selective attention games was 2 (initial score 1), where reaction speed varied between 439 and 469 ms, correct responses between 96.2 and 98.5%, respectively. The decrease of rS02% in the right prefrontal cortex during gameplay was significantly (p < 0.001) lower, compared to the left prefrontal cortex. Four participants yielded significant lower rS02% measures after exergaming with the ALERT games (p < 0.000), but not with the SELECT games. EEG recordings of theta power significantly decreased in the averaged ~0.25-0.75 time interval for the left prefrontal cortex sensor across the cognitive game levels between the ALERT 1 and SELECT 1, as well as between SELECT 1 and 2 games. Participants rated the usability of the COPHYCON training positively. Further results indicate that video gaming may be an effective measure to affect prefrontal cortical functioning in elderly. The results warrant a clinical explorative study investigating the feasibility of the COPHYCON in a clinical setting. PMID- 29234278 TI - Effects of Social Defeat Stress on Sleep in Mice. AB - Stress plays a key role in the development of psychiatric disorders and has a negative impact on sleep integrity. In mice, chronic social defeat stress (CSDS) is an ethologically valid model of stress-related disorders but little is known about its effects on sleep regulation. Here, we investigated the immediate and long-term effects of 10 consecutive days of social defeat (SD) on vigilance states in C57Bl/6J male mice. Social behavior was assessed to identify susceptible mice, i.e., mice that develop long-lasting social avoidance, and unsusceptible mice. Sleep-wake stages in mice of both groups were analyzed by means of polysomnographic recordings at baseline, after the first, third, and tenth stress sessions and on the 5th recovery day (R5) following the 10-day CSDS. In susceptible mice, each SD session produced biphasic changes in sleep-wake states that were preserved all along 10-day CSDS. These sessions elicited a short term enhancement of wake time while rapid eye-movement (REM) sleep was strongly inhibited. Concomitantly, delta power was increased during non REM (NREM) sleep. During the following dark period, an increase in total sleep time, as well as wake fragmentation, were observed after each analyzed SD session. Similar changes were observed in unsusceptible mice. At R5, elevated high-frequency EEG activity, as observed in insomniacs, emerged during NREM sleep in both susceptible and unsusceptible groups suggesting that CSDS impaired sleep quality. Furthermore, susceptible but not unsusceptible mice displayed stress-anticipatory arousal during recovery, a common feature of anxiety disorders. Altogether, our findings show that CSDS has profound impacts on vigilance states and further support that sleep is tightly regulated by exposure to stressful events. They also revealed that susceptibility to chronic psychological stress is associated with heightened arousal, a physiological feature of stress vulnerability. PMID- 29234279 TI - Long-Term Effects of Intermittent Adolescent Alcohol Exposure in Male and Female Rats. AB - Alcohol is a serious public health concern that has a differential impact on individuals depending upon age and sex. Patterns of alcohol consumption have recently changed: heavy episodic drinking-known as binge-drinking-has become most popular among the youth. Herein, we aimed to investigate the consequences of intermittent adolescent alcohol consumption in male and female animals. Thus, Wistar rats were given free access to ethanol (20% in drinking water) or tap water for 2-h sessions during 3 days, and for an additional 4-h session on the 4th day; every week during adolescence, from postnatal day (pnd) 28-52. During this period, animals consumed a moderate amount of alcohol despite blood ethanol concentration (BEC) did not achieve binge-drinking levels. No withdrawal signs were observed: no changes were observed regarding anxiety-like responses in the elevated plus-maze or plasma corticosterone levels (pnd 53-54). In the novel object recognition (NOR) test (pnd 63), a significant deficit in recognition memory was observed in both male and female rats. Western Blot analyses resulted in an increase in the expression of synaptophysin in the frontal cortex (FC) of male and female animals, together with a decrease in the expression of the CB2R in the same brain region. In addition, adolescent alcohol induced, exclusively among females, a decrease in several markers of dopaminergic and serotonergic neurotransmission, in which epigenetic mechanisms, i.e., histone acetylation, might be involved. Taken together, further research is still needed to specifically correlate sex-specific brain and behavioral consequences of adolescent alcohol exposure. PMID- 29234281 TI - Interleukin-6 Induces DEC1, Promotes DEC1 Interaction with RXRalpha and Suppresses the Expression of PXR, CAR and Their Target Genes. AB - Inflammatory burden is a primary cellular event in many liver diseases, and the overall capacity of drug elimination is decreased. PXR (pregnane X receptor) and CAR (constitutive androstane receptor) are two master regulators of genes encoding drug-metabolizing enzymes and transporters. DEC1 (differentiated embryonic chondrocyte-expressed gene 1) is a ligand-independent transcription factor and reportedly is induced by many inflammatory cytokines including IL-6. In this study, we used primary hepatocytes (human and mouse) as well as HepG2 cell line and demonstrated that IL-6 increased DEC1 expression and decreased the expressions of PXR, CAR, and their target genes. Overexpression of DEC1 had similar effect as IL-6 on the expression of these genes, and knockdown of DEC1 reversed their downregulation by IL-6. Interestingly, neither IL-6 nor DEC1 altered the expression of RXRalpha, a common dimerization partner for many nuclear receptors including PXR and CAR. Instead, DEC1 was found to interact with RXRalpha and IL-6 enhanced the interaction. These results conclude that DEC1 uses diverse mechanisms of action and supports IL-6 downregulation of drug-elimination genes and their regulators. PMID- 29234280 TI - Blunted Diurnal Cortisol Activity in Healthy Adults with Childhood Adversity. AB - Childhood adversity, such as neglect, or physical, emotional, or sexual abuse, is prevalent in the U.S. and worldwide, and connected to an elevated incidence of disease in adulthood. A pathway in this relationship might be altered hypothalamic-pituitary-adrenal (HPA) axis functioning, as a result of differential hippocampal development in early life. A blunted diurnal cortisol slope is a precursor for many disorders. While studies have focused on HPA reactivity in relation to childhood adversity, there has been markedly less research on basal HPA functioning in those with low-to-moderate adversity. Based on previous research, we hypothesized that adults with low-to-moderate childhood adversity would have altered HPA axis functioning, as evidenced by a blunted diurnal cortisol slope and altered cortisol awakening response (CAR). Healthy adults aged 18-65 (n = 61 adults; 31 males and 30 females) completed the Childhood Trauma Questionnaire. Participants provided at-home saliva samples on two consecutive days at wake-up, and 30 min, 1, 4, 9, and 13 h later; samples were averaged over the 2 days. We found that low-to-moderate childhood adversity predicted lower morning cortisol (beta = -0.34, p = 0.007, R2 = 0.21), as well as a blunted cortisol slope (beta = 2.97, p = 0.004, R2 = 0.22), but found no association with CAR (beta = 0.19, p = 0.14, R2 = 0.12). Overall, we found that in healthy participants, low-to-moderate adversity in childhood is associated with altered basal HPA activity in adulthood. Our findings indicate that even low levels of childhood adversity may predispose individuals to disease associated with HPA dysregulation in later life. PMID- 29234282 TI - Effect of Methanolic Extract of Dandelion Roots on Cancer Cell Lines and AMP Activated Protein Kinase Pathway. AB - Ethnomedicinal knowledge of plant-derived bioactives could help us in discovering new therapeutic compounds of great potential. Certainly, dandelion has been used in traditional ethno-medicinal systems (i.e., Chinese, Arabian, Indian, and Native American) to treat different types of cancer. Though, dandelion is highly vigorous, but the potential mode of action is still unclear. In the current study, the antiproliferative activity of methanolic extracts of dandelion root (MEDr) on cell viability of HepG2, MCF7, HCT116, and normal Hs27 was investigated. It was observed that MEDr (500 MUg/mL) drastically decreased the growth of HepG2 cell line, while the effect on MCF7 and HCT116 cell lines was less pronounced and no effect has been observed in Hs27 cell lines. The MEDr also enhanced the phosphorylation level of AMPK of HepG2 cells, which considered crucial in cancer treatment and other metabolic diseases. The AMPK activation by MEDr noticed in the current study has never been reported previously. The results regarding the number of apoptotic cells (HepG2 cells) were in line with the cell viability test. The current observations clearly demonstrated the potency of MEDr against liver cancer with validation that dandelion could control AMPK and thus cancer in the treated cell lines. PMID- 29234283 TI - High Fat Diet Decreases Neuronal Activation in the Brain Induced by Resistin and Leptin. AB - Resistin and leptin are adipokines which act in the brain to regulate metabolic and cardiovascular functions which in some instances are similar, suggesting activation of some common brain pathways. High-fat feeding can reduce the number of activated neurons observed following the central administration of leptin in animals, but the effects on resistin are unknown. The present work compared the distribution of neurons in the brain that are activated by centrally administered resistin, or leptin alone, and, in combination, in rats fed a high fat (HFD) compared to a normal chow diet (ND). Immunohistochemistry for the protein, Fos, was used as a marker of activated neurons. The key findings are (i) following resistin or leptin, either alone or combined, in rats fed the HFD, there were no significant increases in the number of activated neurons in the paraventricular and arcuate nuclei, and in the lateral hypothalamic area (LHA). This contrasted with observations in rats fed a normal chow diet; (ii) in the OVLT and MnPO of HFD rats there were significantly less activated neurons compared to ND following the combined administration of resistin and leptin; (iii) In the PAG, RVMM, and NTS of HFD rats there were significantly less activated neurons compared to ND following resistin. The results suggest that the sensitivity to resistin in the brain was reduced in rats fed a HFD. This has similarities with leptin but there were instances where there was reduced sensitivity to resistin with no significant effects following leptin. This suggests diet influences neuronal effects of resistin. PMID- 29234284 TI - The Efficacy of Wrestling-Style Compression Suits to Improve Maximum Isometric Force and Movement Velocity in Well-Trained Male Rugby Athletes. AB - Purpose: The prevalence of compression garment (CG) use is increasing with athletes striving to take advantage of the purported benefits to recovery and performance. Here, we investigated the effect of CG on muscle force and movement velocity performance in athletes. Methods: Ten well-trained male rugby athletes wore a wrestling-style CG suit applying 13-31 mmHg of compressive pressure during a training circuit in a repeated-measures crossover design. Force and velocity data were collected during a 5-s isometric mid-thigh pull (IMTP) and repeated countermovement jump (CMJ), respectively; and time to complete a 5-m horizontal loaded sled push was also measured. Results: IMTP peak force was enhanced in the CG condition by 139 +/- 142 N (effect size [ES] = 0.36). Differences in CMJ peak velocity (ES = 0.08) and loaded sled-push sprint time between the conditions were trivial (ES = -0.01). A qualitative assessment of the effects of CG wear suggested that the likelihood of harm was unlikely in the CMJ and sled push, while a beneficial effect in the CMJ was possible, but not likely. Half of the athletes perceived a functional benefit in the IMTP and CMJ exercises. Conclusion: Consistent with other literature, there was no substantial effect of wearing a CG suit on CMJ and sprint performance. The improvement in peak force generation capability in an IMTP may be of benefit to rugby athletes involved in scrummaging or lineout lifting. The mechanism behind the improved force transmission is unclear, but may involve alterations in neuromuscular recruitment and proprioceptive feedback. PMID- 29234285 TI - A Microarray Study of Carpet-Shell Clam (Ruditapes decussatus) Shows Common and Organ-Specific Growth-Related Gene Expression Differences in Gills and Digestive Gland. AB - Growth rate is one of the most important traits from the point of view of individual fitness and commercial production in mollusks, but its molecular and physiological basis is poorly known. We have studied differential gene expression related to differences in growth rate in adult individuals of the commercial marine clam Ruditapes decussatus. Gene expression in the gills and the digestive gland was analyzed in 5 fast-growing and five slow-growing animals by means of an oligonucleotide microarray containing 14,003 probes. A total of 356 differentially expressed genes (DEG) were found. We tested the hypothesis that differential expression might be concentrated at the growth control gene core (GCGC), i.e., the set of genes that underlie the molecular mechanisms of genetic control of tissue and organ growth and body size, as demonstrated in model organisms. The GCGC includes the genes coding for enzymes of the insulin/insulin like growth factor signaling pathway (IIS), enzymes of four additional signaling pathways (Raf/Ras/Mapk, Jnk, TOR, and Hippo), and transcription factors acting at the end of those pathways. Only two out of 97 GCGC genes present in the microarray showed differential expression, indicating a very little contribution of GCGC genes to growth-related differential gene expression. Forty eight DEGs were shared by both organs, with gene ontology (GO) annotations corresponding to transcription regulation, RNA splicing, sugar metabolism, protein catabolism, immunity, defense against pathogens, and fatty acid biosynthesis. GO term enrichment tests indicated that genes related to growth regulation, development and morphogenesis, extracellular matrix proteins, and proteolysis were overrepresented in the gills. In the digestive gland overrepresented GO terms referred to gene expression control through chromatin rearrangement, RAS-related small GTPases, glucolysis, and energy metabolism. These analyses suggest a relevant role of, among others, some genes related to the IIS, such as the ParaHox gene Xlox, CCAR and the CCN family of secreted proteins, in the regulation of growth in bivalves. PMID- 29234287 TI - Synergistic Effects of Proprioceptive Neuromuscular Facilitation and Manual Lymphatic Drainage in Patients with Mastectomy-Related Lymphedema. AB - Purpose: Manual lymphatic drainage (MLD) and proprioceptive neuromuscular facilitation (PNF) are potential therapeutic strategies to reduce mastectomy induced edema. The purpose of this study was to investigate whether the combination of these therapies would induce synergistic effects to treat lymphedema-related complications and to analyze a possible physiological mechanism involved in the observed effects. Methods: A total of 55 patients diagnosed with mastectomy-induced lymphedema were recruited and randomized into three experimental groups: PNF group (n = 17), MLD group (n = 20), and PNF + MLD group (n = 18). They were subjected to designated rehabilitation program three times a week for 16 weeks. ROM (flexion of the shoulder joint), edema size, arterial blood flow velocity, and degree of pain and depression were measured every 4 weeks over experimental period. Results: Lymphedema volume, VAS pain scale, and Beck depression scale were decreased in PNF and MLD groups for 16 weeks in a time-dependent manner. In combination, a greater reduction of these variables was observed over 16 weeks compared to each PNF and MLD. While axillary arterial blood circulation rate in the affected extremity was increased in both PNF and PNF + MLD groups over 16 weeks, this value was not increased in MLD group throughout the experimental period. A greater reduction of scales of VAS pain and Beck Depression Inventory (BDI) was observed in PNF + MLD group after the 16 week treatment, as compared to each PNF and MLD group. Pearson's coefficients test demonstrated that there are significant correlation of depression against pain (r = 0.616, p < 0.01), ROM (r = -0.478, p < 0.01), and lymphedema size (r = 0.492, p < 0.01). Conclusion: The combination of MLD and PNF induces potent synergistic effects on edema volume, shoulder range of motion (ROM), pain, and depression in patients with lymphedema. In addition, an increased rate of axillary arterial blood flow in PNF-treated patients provide a potential physiological mechanism by which local arterial pulsation in the affected extremity plays a positive role in the treatment of lymphedema. Therefore, it is suggested to incorporate an element of PNF into traditional MLD method to facilitate treatment process for patients with lymphedema. PMID- 29234286 TI - Identification of Biomarkers Correlated with the TNM Staging and Overall Survival of Patients with Bladder Cancer. AB - Objective: To identify candidate biomarkers correlated with clinical prognosis of patients with bladder cancer (BC). Methods: Weighted gene co-expression network analysis was applied to build a co-expression network to identify hub genes correlated with tumor node metastasis (TNM) staging of BC patients. Functional enrichment analysis was conducted to functionally annotate the hub genes. Protein protein interaction network analysis of hub genes was performed to identify the interactions among the hub genes. Survival analyses were conducted to characterize the role of hub genes on the survival of BC patients. Gene set enrichment analyses were conducted to find the potential mechanisms involved in the tumor proliferation promoted by hub genes. Results: Based on the results of topological overlap measure based clustering and the inclusion criteria, top 50 hub genes were identified. Hub genes were enriched in cell proliferation associated gene ontology terms (mitotic sister chromatid segregation, mitotic cell cycle and, cell cycle, etc.) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (cell cycle, Oocyte meiosis, etc.). 17 hub genes were found to interact with >=5 of the hub genes. Survival analysis of hub genes suggested that lower expression of MMP11, COL5A2, CDC25B, TOP2A, CENPF, CDCA3, TK1, TPX2, CDCA8, AEBP1, and FOXM1were associated with better overall survival of BC patients. BC samples with higher expression of hub genes were enriched in gene sets associated with P53 pathway, apical junction, mitotic spindle, G2M checkpoint, and myogenesis, etc. Conclusions: We identified several candidate biomarkers correlated with the TNM staging and overall survival of BC patients. Accordingly, they might be used as potential diagnostic biomarkers and therapeutic targets with clinical utility. PMID- 29234288 TI - Lipocalin-2 in Fructose-Induced Fatty Liver Disease. AB - The intake of excess dietary fructose most often leads to non-alcoholic fatty liver disease (NAFLD). Fructose is metabolized mainly in the liver and its chronic consumption results in lipogenic gene expression in this organ. However, precisely how fructose is involved in NAFLD progression is still not fully understood, limiting therapy. Lipocalin-2 (LCN2) is a small secreted transport protein that binds to fatty acids, phospholipids, steroids, retinol, and pheromones. LCN2 regulates lipid and energy metabolism in obesity and is upregulated in response to insulin. We previously discovered that LCN2 has a hepatoprotective effect during hepatic insult, and that its upregulation is a marker of liver damage and inflammation. To investigate if LCN2 has impact on the metabolism of fructose and thereby arising liver damage, we fed wild type and Lcn2-/- mice for 4 or 8 weeks on diets that were enriched in fructose either by adding this sugar to the drinking water (30% w/v), or by feeding a chow containing 60% (w/w) fructose. Body weight and daily intake of food and water of these mice was then measured. Fat content in liver sections was visualized using Oil Red O stain, and expression levels of genes involved in fat and sugar metabolism were measured by qRT-PCR and Western blot analysis. We found that fructose-induced steatosis and liver damage was more prominent in female than in male mice, but that the most severe hepatic damage occurred in female mice lacking LCN2. Unexpectedly, consumption of elevated fructose did not induce de novo lipogenesis or fat accumulation. We conclude that LCN2 acts in a lipid independent manner to protect the liver against fructose-induced damage. PMID- 29234289 TI - The Role of Perivascular Adipose Tissue in Non-atherosclerotic Vascular Disease. AB - Perivascular adipose tissue (PVAT) surrounds most large blood vessels and plays an important role in vascular homeostasis. PVAT releases various chemokines and adipocytokines, functioning in an endocrine and paracrine manner to regulate vascular signaling and inflammation. Mounting evidence suggests that PVAT plays an important role in atherosclerosis and hypertension; however, the role of PVAT in non-atherosclerotic vascular diseases, including neointimal formation, aortic aneurysm, arterial stiffness and vasculitis, has received far less attention. Increasing evidence suggests that PVAT responds to mechanical endovascular injury and regulates the subsequent formation of neointima via factors that promote smooth muscle cell growth, adventitial inflammation and neovascularization. Circumstantial evidence also links PVAT to the pathogenesis of aortic aneurysms and vasculitic syndromes, such as Takayasu's arteritis, where infiltration and migration of inflammatory cells from PVAT into the vascular wall may play a contributory role. Moreover, in obesity, PVAT has been implicated to promote stiffness of elastic arteries via the production of reactive oxygen species. This review will discuss the growing body of data and mechanisms linking PVAT to the pathogenesis of non-atherosclerotic vascular diseases in experimental animal models and in humans. PMID- 29234291 TI - The Role of Baseline Vagal Tone in Dealing with a Stressor during Face to Face and Computer-Based Social Interactions. AB - Facing a stressor involves a cardiac vagal tone response and a feedback effect produced by social interaction in visceral regulation. This study evaluated the contribution of baseline vagal tone and of social engagement system (SES) functioning on the ability to deal with a stressor. Participants (n = 70) were grouped into a minimized social interaction condition (procedure administered through a PC) and a social interaction condition (procedure administered by an experimenter). The State Trait Anxiety Inventory, the Social Interaction Anxiety Scale, the Emotion Regulation Questionnaire and a debriefing questionnaire were completed by the subjects. The baseline vagal tone was registered during the baseline, stressor and recovery phases. The collected results highlighted a significant effect of the baseline vagal tone on vagal suppression. No effect of minimized vs. social interaction conditions on cardiac vagal tone during stressor and recovery phases was detected. Cardiac vagal tone and the results of the questionnaires appear to be not correlated. The study highlighted the main role of baseline vagal tone on visceral regulation. Some remarks on SES to be deepen in further research were raised. PMID- 29234290 TI - The Potential Coordination of the Heat-Shock Proteins and Antioxidant Enzyme Genes of Aphidius gifuensis in Response to Thermal Stress. AB - Aphidius gifuensis is one of the most important aphid natural enemies and has been successfully used to control Myzys persicae and other aphid species. High temperature in summer is one of the key barriers for the application of A. gifuensis in the field and greenhouse. In this work, we investigated the biological performance of A. gifuensis and the response of heat-shock proteins and antioxidant enzymes under high temperature. The results showed that A. gifuensis could not survive at 40 degrees C and female exhibited a higher survival in 35 degrees C. Furthermore, the short term exposure to high temperature negatively affected the performance of A. gifuensis especially parasitism efficiency. Under short-term heating, the expression of AgifsHSP, Agifl(2)efl, AgifHSP70, AgifHSP70-4 and AgifHSP90 showed an increased trend, whereas AgifHSP10 initially increased and then decreased. In 35 degrees C, the expressions of Agifl(2)efl, AgifHSP70-4 and AgifHSP90 in female were higher than those in male, whereas the expression of AgifHSP70 exhibited an opposite trend. Besides the HSPs, we also quantified the expression levels of 11 antioxidant enzyme genes: AgifPOD, AgifSOD1, AgifSOD2, AgifSOD3, AgifCAT1, AgifCAT2, AgifGST1, AgifGST2, AgifGST3, AgifGST4 and AgifGST5. We found that the sex specific expression of AgifSOD2, AgifSOD3, AgifPOD, AgifGST1 and AgifGST3 were highly consistent with sex-specific heat shock survival rates at 35 degrees C. Furthermore, when the temperature was above 30 degrees C, the activities of GST, SOD, CAT and POD were significantly increased; however, there was no significant difference of the CAT activity between the male and female at 35 degrees C. Collectively, all of these results suggested that the protection of thermal damage is coordinated by HSPs and antioxidant enzymes in A. gifuensis. Based on the heat tolerance abilities of many aphid natural enemies, we also discussed an integrated application strategy of many aphid enemies in summer. PMID- 29234292 TI - Criterion and Divergent Validity of the Sexual Minority Adolescent Stress Inventory. AB - Sexual minority adolescents (SMA) consistently report health disparities compared to their heterosexual counterparts, yet the underlying mechanisms of these negative health outcomes remain unclear. The predominant explanatory model is the minority stress theory; however, this model was developed largely with adults, and no valid and comprehensive measure of minority stress has been developed for adolescents. The present study validated a newly developed instrument to measure minority stress among racially and ethnically diverse SMA. A sample of 346 SMA aged 14-17 was recruited and surveyed between February 2015 and July 2016. The focal measure of interest was the 64-item, 11-factor Sexual Minority Adolescent Stress Inventory (SMASI) developed in the initial phase of this study. Criterion validation measures included measures of depressive symptoms, suicidality and self-harm, youth problem behaviors, and substance use; the general Adolescent Stress Questionnaire (ASQ) was included as a measure of divergent validity. Analyses included Pearson and tetrachoric correlations to establish criterion and divergent validity and structural equation modeling to assess the explanatory utility of the SMASI relative to the ASQ. SMASI scores were significantly associated with all outcomes but only moderately associated with the ASQ (r = 0.13 to 0.51). Analyses revealed significant associations of a latent minority stress variable with both proximal and distal health outcomes beyond the variation explained by general stress. Results show that the SMASI is the first instrument to validly measure minority stress among SMA. PMID- 29234294 TI - The Mark of the Cognitive and the Coupling-Constitution Fallacy: A Defense of the Extended Mind Hypothesis. AB - Clark and Chalmers (1998) introduced the extended mind hypothesis, according to which some mental states can be realized by non-biological external resources. A lively debate has flourished around this hypothesis, connected with the issues of embodiment, embeddedness, situatedness and enaction (cf. Clark, 2008; Menary, 2010; Shapiro, 2011). Two of the main criticisms addressed to the functionalist version of the extended mind thesis have been the so-called "coupling constitution fallacy" and the alleged lack of a mark of the cognitive (Adams and Aizawa, 2001, 2005, 2009, 2010a,b). According to Adams and Aizawa, extended cognition is a logical possibility, but is not instantiated in our world. Following this view, they defend a "contingent intracranialism," based on a specific mark of the cognitive that they propose. In this paper I intend to show that neither criticism is effective against the extended cognition thesis. In particular: the mark of the cognitive proposed by Adams and Aizawa does not secure contingent intracranialism;the coupling-constitution fallacy criticizes extended cognition on precisely the point the theory was intended to defend: namely, that the best way to individuate cognitive systems, given a minimal mark of the cognitive, is to rely on coupling relations between agents and environmental resources. PMID- 29234293 TI - The Construction of Self in Relationships: Narratives and References to Mental States during Picture-Book Reading Interactions between Mothers and Children. AB - Previous studies showed that mothers vary in the way in which they discuss past experiences with their children, since they can exhibit narrative (elaborative) or paradigmatic (repetitive) styles to different extents. Given this background, the aim of the present study was to analyze differences in the mothers' use of narrative styles and mental state language (MSL), as a function of children's age and gender. Thirty dyads consisting of mothers and their 4- to 6-year-old children were observed during a picture-book reading interaction. Maternal utterances were coded according to the categories described by Tessler and Nelson (1994), classifying each mother as Narrative or Paradigmatic. Eight categories of MSL were analyzed: perceptual, emotional (positive and negative), volitional, cognitive, communicative, and moral. The results confirmed the existence of the two maternal styles observed in the earlier studies. Importantly, we found that the mothers of younger children were more narrative than paradigmatic, whereas the opposite pattern occurred for the mothers of older children (they were more paradigmatic than narrative). As concerns MSL, the results indicated that the use of communicative terms was significantly more frequent for narrative than for paradigmatic mothers, and decreased linearly with children's age. Lastly, the mothers of younger children referred their MSL more frequently to the book characters than to themselves or to the child. Taken together, these results support the idea that mothers adapt their narrative styles and MSL input to the growing abilities of their children, therefore contributing to the development of social understanding. PMID- 29234295 TI - Punish the Perpetrator or Compensate the Victim? Gain vs. Loss Context Modulate Third-Party Altruistic Behaviors. AB - Third-party punishment and third-party compensation are primary responses to observed norms violations. Previous studies mostly investigated these behaviors in gain rather than loss context, and few study made direct comparison between these two behaviors. We conducted three experiments to investigate third-party punishment and third-party compensation in the gain and loss context. Participants observed two persons playing Dictator Game to share an amount of gain or loss, and the proposer would propose unfair distribution sometimes. In Study 1A, participants should decide whether they wanted to punish proposer. In Study 1B, participants decided to compensate the recipient or to do nothing. This two experiments explored how gain and loss contexts might affect the willingness to altruistically punish a perpetrator, or to compensate a victim of unfairness. Results suggested that both third-party punishment and compensation were stronger in the loss context. Study 2 directly compare third-party punishment and third party compensation in the both contexts, by allowing participants choosing between punishment, compensation and keeping. Participants chose compensation more often than punishment in the loss context, and chose more punishments in the gain context. Empathic concern partly explained between-context differences of altruistic compensation and punishment. Our findings provide insights on modulating effect of context on third-party altruistic decisions. PMID- 29234296 TI - Grand Challenges for Personality and Social Psychology: Moving beyond the Replication Crisis. PMID- 29234297 TI - Commentary: Constructing nonhuman animal emotion. PMID- 29234298 TI - Editorial: Medical Image Perception: How Much Do We Understand It? PMID- 29234299 TI - Why People with More Emotion Regulation Difficulties Made a More Deontological Judgment: The Role of Deontological Inclinations. AB - Previous studies have demonstrated the key role of emotion in moral judgment, and explored the relationship between emotion regulation and moral judgment. The present study investigated the influence of individual differences in emotion regulation difficulties on moral judgment. Study 1 examined whether individuals with high emotion regulation difficulties made a more deontological judgment. Study 2 explored the underlying mechanism using a process-dissociation approach, examining whether deontological inclinations and utilitarian inclinations separately or jointly accounted for the association. The results indicated that individuals with high emotion regulation difficulties rated the utilitarian actions less morally appropriate, and one's deontological inclinations mediated the association between emotion regulation difficulties and moral judgment. PMID- 29234300 TI - Temporal Discrimination: Mechanisms and Relevance to Adult-Onset Dystonia. AB - Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test-retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis. PMID- 29234301 TI - Balance Screening of Vestibular Function in Subjects Aged 4 Years and Older: A Living Laboratory Experience. AB - To better understand the various individual factors that contribute to balance and the relation to fall risk, we performed the modified Romberg Test of Standing Balance on Firm and Compliant Support, with 1,174 participants between 4 and 83 years of age. This research was conducted in the Living Laboratory(r) at the Museum of Science, Boston. We specifically focus on balance test condition 4, in which individuals stand on memory foam with eyes closed, and must rely on their vestibular system; therefore, performance in this balance test condition provides a proxy for vestibular function. We looked for balance variations associated with sex, race/ethnicity, health factors, and age. We found that balance test performance was stable between 10 and 39 years of age, with a slight increase in the failure rate for participants 4-9 years of age, suggesting a period of balance development in younger children. For participants 40 years and older, the balance test failure rate increased progressively with age. Diabetes and obesity are the two main health factors we found associated with poor balance, with test condition 4 failure rates of 57 and 19%, respectively. An increase in the odds of having fallen in the last year was associated with a decrease in the time to failure; once individuals dropped below a time to failure of 10 s, there was a significant 5.5-fold increase in the odds of having fallen in the last 12 months. These data alert us to screen for poor vestibular function in individuals 40 years and older or suffering from diabetes, in order to undertake the necessary diagnostic and rehabilitation measures, with a focus on reducing the morbidity and mortality of falls. PMID- 29234302 TI - Home-Based Virtual Reality-Augmented Training Improves Lower Limb Muscle Strength, Balance, and Functional Mobility following Chronic Incomplete Spinal Cord Injury. AB - : Key factors positively influencing rehabilitation and functional recovery after spinal cord injury (SCI) include training variety, intensive movement repetition, and motivating training tasks. Systems supporting these aspects may provide profound gains in rehabilitation, independent of the subject's treatment location. In the present study, we test the hypotheses that virtual reality (VR) augmented training at home (i.e., unsupervised) is feasible with subjects with an incomplete SCI (iSCI) and that it improves motor functions such as lower limb muscle strength, balance, and functional mobility. In the study, 12 chronic iSCI subjects used a home-based, mobile version of a lower limb VR training system. The system included motivating training scenarios and combined action observation and execution. Virtual representations of the legs and feet were controlled via movement sensors. The subjects performed home-based training over 4 weeks, with 16-20 sessions of 30-45 min each. The outcome measures assessed were the Lower Extremity Motor Score (LEMS), Berg Balance Scale (BBS), Timed Up and Go (TUG), Spinal Cord Independence Measure mobility, Walking Index for Spinal Cord Injury II, and 10 m and 6 min walking tests. Two pre-treatment assessment time points were chosen for outcome stability: 4 weeks before treatment and immediately before treatment. At post-assessment (i.e., immediately after treatment), high motivation and positive changes were reported by the subjects (adapted Patients' Global Impression of Change). Significant improvements were shown in lower limb muscle strength (LEMS, P = 0.008), balance (BBS, P = 0.008), and functional mobility (TUG, P = 0.007). At follow-up assessment (i.e., 2-3 months after treatment), functional mobility (TUG) remained significantly improved (P = 0.005) in contrast to the other outcome measures. In summary, unsupervised exercises at home with the VR training system led to beneficial functional training effects in subjects with chronic iSCI, suggesting that it may be useful as a neurorehabilitation tool. Trial registration: Canton of Zurich ethics committee (EK-24/2009, PB_2016-00545), ClinicalTrials.gov: NCT02149186. Registered 24 April 2014. PMID- 29234303 TI - A Study of Super Refractory Status Epilepticus from India. AB - Background: Super refractory status epilepticus (SRSE) is an important and recently recognized neurological emergency. Purpose: In view of paucity of studies on SRSE, we report the frequency, etiology and outcome of SRSE. Methods: In a hospital-based observational study during 2013 to 2016, consecutive patients with SRSE [persistence of status epilepticus (SE) for 24 h or more, or recurrence of SE on weaning of intravenous anesthetic] were included. The demographic, clinical, and laboratory data were obtained and the severity of SE was defined using Status Epilepticus Severity Score (STESS). The outcome was defined as control of SE, hospital death, and functional status at the time of discharge. Results: Fourteen (13%) patients developed SRSE. Their median age was 27.5 (2-70) years and four were below 18 years of age. The etiology of SRSE was metabolic encephalopathy and encephalitis in five patients each, cerebral venous sinus thrombosis in one and miscellaneous disorders in three patients. Six (43%) patients died. The patients with SRSE had higher admission STESS (p = 0.04), and longer intensive care unit (p < 0.01) and hospital (p = 0.004) stay compared to non-SRSE group. The patients with treatable etiology had better outcome. Conclusion: SRSE occurred in 13% patients with SE and 43% of them died. The SRSE patients with treatable etiology had a better outcome. PMID- 29234304 TI - Hypothesis on the Role of Cryptochromes in Inflammation and Subarachnoid Hemorrhage Outcome. AB - We have recently found that the temperature variability (TV) in the day-night cycle may predict the mean intracranial pressure in the following 24 h (ICP24) in subarachnoid hemorrhage (SAH) patients under multimodality monitoring, sedation, and hypothermia (<35 degrees C). Specifically, we found that ICP24 = 6 (4 - TV) mmHg. TV is the ratio between the coefficient of variation of temperature during the nocturnal and the preceding diurnal periods. This result suggests that the circadian clock reflects brain plasticity mechanisms and its malfunctioning leads to deterioration of the neurologic status. The sleep-wake cycle is absent in these patients and their circadian clock can function properly only by environment light-independent mechanisms. One mechanism involves the circadian clock proteins named cryptochromes (CRYs). CRYs are highly preserved and widespread in the evolutionary tree, are expressed in different cell types in humans [type II CRYs, in two forms: human cryptochrome 1 and 2 (hCRY1 and hCRY2)], and in certain species, respond to blue light and play role in magnetoreception. Interestingly, SAH outcome seems to correlate with inflammation, and CRYs decrease inflammatory activity. Our hypothesis derived from these observations is that CRYs modulate the circadian oscillation of temperature even during therapeutic hypothermia and improve outcome in SAH through decrease in inflammation. A strategy to test this hypothesis is to measure periodically during the acute phase of high-grade SAH the level of CRYs in cerebrospinal fluid (CSF) and circulating white blood cells, and to correlate these levels with outcome, TV, ICP24, and pro- and anti-inflammatory markers in CSF and blood. If this hypothesis is true, the development of therapies targeting inflammation in SAH could take advantage of cryptochrome properties. It has been shown that blue light phototherapy increases the expression of CRYs in blood mononuclear cells in jaundiced neonates. Likewise, visual stimulus with flashing light improves Alzheimer's disease features in experimental model and there is a prominent expression of CRYs in the retina. Remarkably, recent evidence showed that hCRY2 responds to electromagnetic fields, which could be one elusive mechanism of action of transcranial magnetic stimulation and a reason for its use in SAH. PMID- 29234305 TI - Functional Components of Cognitive Impairment in Multiple Sclerosis: A Cross Sectional Investigation. AB - Background: Cognitive impairment is frequent and disabling in multiple sclerosis (MS). Changes in information processing speed constitute the most important cognitive deficit in MS. However, given the clinical and topographical variability of the disease, cognitive impairment may vary greatly and appear in other forms in addition to slower information processing speed. Our aim was to determine the frequency of cognitive impairment, the principal cognitive domains, and components involved in MS and to identify factors associated with presence of cognitive impairment in these patients in a large series of patients. Methods: Cross-sectional study of 311 patients with MS [236 with relapsing-remitting MS (RRMS), 52 with secondary progressive MS (SPMS), and 23 with primary progressive MS (PPMS)]. Patients' cognitive function was assessed with a comprehensive neuropsychological assessment protocol. Patients displaying deficits in 2 or more cognitive domains were considered to have cognitive impairment associated with MS. We conducted a principal component analysis to detect different cognitive patterns by identifying clusters of tests highly correlated to one another. Results: Cognitive impairment was detected in 41.5% of the sample, and it was more frequent in patients with SPMS and PPMS (P = 0.002). Expanded Disability Status Scale scores and education were independent predictors of cognitive impairment. Principal component analysis identified seven clusters: attention and basic executive function (including information processing speed), planning and high-level executive function, verbal memory and language, executive and visuospatial performance time, fatigue-depression, visuospatial function, and basic attention and verbal/visual working memory. Mean scoring of components 2 (high-order executive functioning) and 3 (verbal memory-language) was higher in patients with RRMS than in those with PPMS (component 2) and SPMS (component 3). Conclusion: MS is linked to multiple cognitive profiles and disturbances in different domains. This suggests that cognitive alterations in MS are heterogeneous and affect other domains in addition to information processing speed. PMID- 29234306 TI - Body Mass Index Influences the Prognostic Impact of Combined Nuclear Insulin Receptor and Estrogen Receptor Expression in Primary Breast Cancer. AB - The prognostic importance of tumor-specific nuclear insulin receptor (InsR) expression in breast cancer is unclear, while membrane and cytoplasmic localization of InsR is better characterized. The insulin signaling network is influenced by obesity and may interact with the estrogen receptor alpha (ERalpha) signaling. The purpose was to investigate the interplay between nuclear InsR, ER, body mass index (BMI), and prognosis. Tumor-specific expression of nuclear InsR was evaluated by immunohistochemistry in tissue microarrays from 900 patients with primary invasive breast cancer without preoperative treatment, included in a population-based cohort in Sweden (2002-2012) in relation to prognosis. Patients were followed for up to 11 years during which 107 recurrences were observed. Nuclear InsR+ expression was present in 214 patients (23.8%) and increased with longer time between surgery and staining (P < 0.001). There were significant effect modifications by ER status and BMI in relation to clinical outcomes. Nuclear InsR+ conferred higher recurrence-risk in patients with ER+ tumors, but lower risk in patients with ER- tumors (Pinteraction = 0.003). Normal-weight patients with nuclear InsR+ tumors had higher recurrence-risk, while overweight or obese patients had half the recurrence-risk compared to patients with nuclear InsR- tumors (Pinteraction = 0.007). Normal-weight patients with a nuclear InsR /ER+ tumor had the lowest risk for recurrence compared to all other nuclear InsR/ER combinations [HRadj 0.50, 95% confidence interval (CI): 0.25-0.97], while overweight or obese patients with nuclear InsR-/ER- tumors had the worst prognosis (HRadj 7.75, 95% CI: 2.04-29.48). Nuclear InsR was more prognostic than ER among chemotherapy-treated patients. In summary, nuclear InsR may have prognostic impact among normal-weight patients with ER+ tumors and in overweight or obese patients with ER- tumors. Normal-weight patients with nuclear InsR-/ER+ tumors may benefit from less treatment than normal-weight patients with other nuclear InsR/ER combinations. Overweight or obese patients with nuclear InsR-/ER- tumors may benefit from more tailored treatment or weight management. PMID- 29234307 TI - Thymoquinone Inhibits Virulence Related Traits of Cronobacter sakazakii ATCC 29544 and Has Anti-biofilm Formation Potential. AB - The aim of this study was to determine whether thymoquinone, the principal active ingredient in the volatile oil of Nigella sativa seeds, could suppress certain virulence traits of Cronobacter sakazakii ATCC 29544 which contribute to infection. Sub-inhibitory concentrations of thymoquinone significantly decreased motility, quorum sensing, and endotoxin production of C. sakazakii ATCC 29544 and biofilm formation of C. sakazakii 7-17. Thymoquinone substantially reduced the adhesion and invasion of C. sakazakii ATCC 29544 to HT-29 cells and decreased the number of intracellular bacterial cells within the RAW 264.7 macrophage cells. Thymoquinone also repressed the transcription of sixteen genes involved in the virulence. These findings suggest that thymoquinone could attenuated virulence related traits of C. sakazakii ATCC 29544, and its effects on other C. sakazakii strains and in vivo C. sakazakii infection need further investigation. PMID- 29234308 TI - Horizontal Transmission of Intracellular Insect Symbionts via Plants. AB - Experimental evidence is accumulating that endosymbionts of phytophagous insects may transmit horizontally via plants. Intracellular symbionts known for manipulating insect reproduction and altering fitness (Rickettsia, Cardinium, Wolbachia, and bacterial parasite of the leafhopper Euscelidius variegatus) have been found to travel from infected insects into plants. Other insects, either of the same or different species can acquire the symbiont from the plant through feeding, and in some cases transfer it to their progeny. These reports prompt many questions regarding how intracellular insect symbionts are delivered to plants and how they affect them. Are symbionts passively transported along the insect-plant-insect path, or do they actively participate in the process? How widespread are these interactions? How does symbiont presence influence the plant? And what conditions are required for the new infection to establish in an insect? From an ecological, evolutionary, and applied perspective, this mode of horizontal transmission could have profound implications if occurring frequently enough or if new stable symbiont infections are established. Transmission of symbionts through plants likely represents an underappreciated means of infection, both in terms of symbiont epidemiology and the movement of symbionts to new host species. PMID- 29234309 TI - Rokubacteria: Genomic Giants among the Uncultured Bacterial Phyla. AB - Recent advances in single-cell genomic and metagenomic techniques have facilitated the discovery of numerous previously unknown, deep branches of the tree of life that lack cultured representatives. Many of these candidate phyla are composed of microorganisms with minimalistic, streamlined genomes lacking some core metabolic pathways, which may contribute to their resistance to growth in pure culture. Here we analyzed single-cell genomes and metagenome bins to show that the "Candidate phylum Rokubacteria," formerly known as SPAM, represents an interesting exception, by having large genomes (6-8 Mbps), high GC content (66 71%), and the potential for a versatile, mixotrophic metabolism. We also observed an unusually high genomic heterogeneity among individual Rokubacteria cells in the studied samples. These features may have contributed to the limited recovery of sequences of this candidate phylum in prior cultivation and metagenomic studies. Our analyses suggest that Rokubacteria are distributed globally in diverse terrestrial ecosystems, including soils, the rhizosphere, volcanic mud, oil wells, aquifers, and the deep subsurface, with no reports from marine environments to date. PMID- 29234311 TI - The SlZRT1 Gene Encodes a Plasma Membrane-Located ZIP (Zrt-, Irt-Like Protein) Transporter in the Ectomycorrhizal Fungus Suillus luteus. AB - Zinc (Zn) is an essential micronutrient but may become toxic when present in excess. In Zn-contaminated environments, trees can be protected from Zn toxicity by their root-associated micro-organisms, in particular ectomycorrhizal fungi. The mechanisms of cellular Zn homeostasis in ectomycorrhizal fungi and their contribution to the host tree's Zn status are however not yet fully understood. The aim of this study was to identify and characterize transporters involved in Zn uptake in the ectomycorrhizal fungus Suillus luteus, a cosmopolitan pine mycobiont. Zn uptake in fungi is known to be predominantly governed by members of the ZIP (Zrt/IrtT-like protein) family of Zn transporters. Four ZIP transporter encoding genes were identified in the S. luteus genome. By in silico and phylogenetic analysis, one of these proteins, SlZRT1, was predicted to be a plasma membrane located Zn importer. Heterologous expression in yeast confirmed the predicted function and localization of the protein. A gene expression analysis via RT-qPCR was performed in S. luteus to establish whether SlZRT1 expression is affected by external Zn concentrations. SlZRT1 transcripts accumulated almost immediately, though transiently upon growth in the absence of Zn. Exposure to elevated concentrations of Zn resulted in a significant reduction of SlZRT1 transcripts within the first hour after initiation of the exposure. Altogether, the data support a role as cellular Zn importer for SlZRT1 and indicate a key role in cellular Zn uptake of S. luteus. Further research is needed to understand the eventual contribution of SlZRT1 to the Zn status of the host plant. PMID- 29234312 TI - Parallelized, Aerobic, Single Carbon-Source Enrichments from Different Natural Environments Contain Divergent Microbial Communities. AB - Microbial communities that inhabit environments such as soil can contain thousands of distinct taxa, yet little is known about how this diversity is maintained in response to environmental perturbations such as changes in the availability of carbon. By utilizing aerobic substrate arrays to examine the effect of carbon amendment on microbial communities taken from six distinct environments (soil from a temperate prairie and forest, tropical forest soil, subalpine forest soil, and surface water and soil from a palustrine emergent wetland), we examined how carbon amendment and inoculum source shape the composition of the community in each enrichment. Dilute subsamples from each environment were used to inoculate 96-well microtiter plates containing triplicate wells amended with one of 31 carbon sources from six different classes of organic compounds (phenols, polymers, carbohydrates, carboxylic acids, amines, amino acids). After incubating each well aerobically in the dark for 72 h, we analyzed the composition of the microbial communities on the substrate arrays as well as the initial inocula by sequencing 16S rRNA gene amplicons using the Illumina MiSeq platform. Comparisons of alpha and beta diversity in these systems showed that, while the composition of the communities that grow to inhabit the wells in each substrate array diverges sharply from that of the original community in the inoculum, these enrichment communities are still strongly affected by the inoculum source. We found most enrichments were dominated by one or several OTUs most closely related to aerobes or facultative anaerobes from the Proteobacteria (e.g., Pseudomonas, Burkholderia, and Ralstonia) or Bacteroidetes (e.g., Chryseobacterium). Comparisons within each substrate array based on the class of carbon source further show that the communities inhabiting wells amended with a carbohydrate differ significantly from those enriched with a phenolic compound. Selection therefore seems to play a role in shaping the communities in the substrate arrays, although some stochasticity is also seen whereby several replicate wells within a single substrate array display strongly divergent community compositions. Overall, the use of highly parallel substrate arrays offers a promising path forward to study the response of microbial communities to perturbations in a changing environment. PMID- 29234310 TI - Modulation of Lipid Droplet Metabolism-A Potential Target for Therapeutic Intervention in Flaviviridae Infections. AB - Lipid droplets (LDs) are endoplasmic reticulum (ER)-related dynamic organelles that store and regulate fatty acids and neutral lipids. They play a central role in cellular energy storage, lipid metabolism and cellular homeostasis. It has become evident that viruses have co-evolved in order to exploit host lipid metabolic pathways. This is especially characteristic of the Flaviviridae family, including hepatitis C virus (HCV) and several flaviviruses. Devoid of an appropriate lipid biosynthetic machinery of their own, these single-strand positive-sense RNA viruses can induce dramatic changes in host metabolic pathways to establish a favorable environment for viral multiplication and acquire essential components to facilitate their assembly and traffic. Here we have reviewed the current knowledge on the intracellular life cycle of those from the Flaviviridae family, with particular emphasis on HCV and dengue virus (DENV), and their association with the biosynthesis and metabolism of LDs, with the aim to identify potential antiviral targets for development of novel therapeutic interventions. PMID- 29234313 TI - Food Grade Pimenta Leaf Essential Oil Reduces the Attachment of Salmonella enterica Heidelberg (2011 Ground Turkey Outbreak Isolate) on to Turkey Skin. AB - Salmonella attached to the poultry skin is a major source of carcass contamination during processing. Once attached to the poultry skin, it is difficult to detach and inactivate Salmonella by commonly used antimicrobial agents since the pathogen is entrapped deeply in the feather follicles and the crevices on the skin. Essential oils could be natural, safe, and effective alternatives to synthetic antimicrobial agents during commercial and organic processing setup. The present study evaluated the efficacy of pimenta (Pimenta officinalis Lindl.) leaf essential oil (PEO), and its nanoemulsion in reducing Salmonella Heidelberg attachment on to turkey (Meleagris gallopavo) skin during simulated scalding (65 degrees C) and chilling (4 degrees C) steps in poultry processing. A multidrug resistant S. Heidelberg isolate from the 2011 ground turkey outbreak in the United States was used in the study. Results showed that PEO and the nanoemulsion resulted in significant reduction of S. Heidelberg attachment on turkey skin. Turkey skin samples treated with 1.0% PEO for 5 min resulted in >2 log10 CFU/sq. inch reduction of S. Heidelberg at 65 and 4 degrees C, respectively (n = 6; P < 0.05). Similarly, skin samples treated with 1.0% pimenta nanoemulsion (PNE) for 5 min resulted in 1.5- and 1.8- log10 CFU/sq. inch reduction of S. Heidelberg at 65 and 4 degrees C, respectively (n = 6; P < 0.05). In addition, PEO and PNE were effective in reducing S. Heidelberg on skin during short-term storage at 4 and 10 degrees C (temperature abuse) (n = 6; P < 0.05). No Salmonella was detected in the dipping solution containing 0.5 or 1.0% PEO or PNE, whereas a substantial population of the pathogen survived in the control dipping solution. The results were validated using scanning electron -, and confocal - microscopy techniques. PEO or PNE could be utilized as an effective antimicrobial agent to reduce S. Heidelberg attachment to turkey skin during poultry processing. PMID- 29234314 TI - Efficacy and Safety of a Bovine-Associated Staphylococcus aureus Phage Cocktail in a Murine Model of Mastitis. AB - Overuse of antibiotics is a major problem in the treatment of bovine mastitis, and antibiotic treatment is frequently non-curative, thus alternative treatments are necessary. The primary aim of this study was to evaluate the efficacy of a purified phage cocktail for treatment of bovine Staphylococcus aureus mastitis in a well-defined mouse model. Candidate phages were selected based on their in vitro performance and subsequently processed into an optimally composed phage cocktail. The highest scoring phages were further tested for efficacy and resistance suppression in broth and raw milk, with and without supplemental IgG. As these in vitro results displayed significant decreases in CFU, the cocktail was purified for testing in vivo. Lactating mice were intramammarily inoculated with S. aureus N305 (ATCC 29740), a clinical bovine mastitis isolate commonly used for experimental infection of dairy cows. The phage cocktail was applied via the same route 4 h post-inoculation. Treated mammary glands were graded for gross pathological appearance and excised for bacterial and phage load quantification as well as histopathology. Observation of gross macroscopic and histopathological changes and CFU quantification demonstrated that the phage cocktail treatment significantly improved mastitis pathology and decreased bacterial counts. Phage PFU quantification indicated that the tested phage cocktail treatment was able to maintain high intramammary phage titers without spreading systemically. The in vivo results complement the in vitro data and support our concept of phage therapy as an innovative alternative or supplementation therapy to antibiotics for the treatment of bovine mastitis. PMID- 29234315 TI - Food-Associated Lactobacillus plantarum and Yeasts Inhibit the Genotoxic Effect of 4-Nitroquinoline-1-Oxide. AB - Lactic acid bacteria and yeasts, representing the prevailing microbiota associated with different foods generally consumed without any cooking, were identified and characterized in vitro for some functional properties, such as acid-bile tolerance and antigenotoxic activity. In particular, 22 Lactobacillus plantarum strains and 14 yeasts were studied. The gastro-intestinal tract tolerance of all the strains was determined by exposing washed cell suspensions at 37 degrees C to a simulated gastric juice (pH 2.0), containing pepsin (0.3% w/v) and to a simulated small intestinal juice (pH 8.0), containing pancreatin (1 mg mL-1) and bile extract (0.5%), thus monitoring changes in total viable count. In general, following a strain-dependent behavior, all the tested strains persisted alive after combined acid-bile challenge. Moreover, many strains showed high in vitro inhibitory activity against a model genotoxin, 4-nitroquinoline-1 oxide (4-NQO), as determined by the short-term method, SOS-Chromotest. Interestingly, the supernatants from bacteria- or yeasts-genotoxin co-incubations exhibited a suppression on SOS-induction produced by 4-NQO on the tester strain Escherichia coli PQ37 (sfiA::lacZ) exceeding, in general, the value of 75%. The results highlight that food associated microorganisms may reach the gut in viable form and prevent genotoxin DNA damage in situ. Our experiments can contribute to elucidate the functional role of food-associated microorganisms general recognized as safe ingested with foods as a part of the diet. PMID- 29234316 TI - Delineating the Origins of Vibrio parahaemolyticus Isolated from Outbreaks of Acute Hepatopancreatic Necrosis Disease in Asia by the Use of Whole Genome Sequencing. AB - Acute hepatopancreatic necrosis disease (AHPND) is an emerging penaeid shrimp disease caused by Vibrio parahaemolyticus. Although V. parahaemolyticus has been isolated and sequenced from several Asia countries, the epidemiological links among the AHPND outbreaks in different locations remain unclear. In this study, we sequenced the genomes of nine strains isolated in China between 2014 and 2016 from four sampling sites in three provinces. Analysis of single nucleotide polymorphisms (SNPs) among the nine isolates yielded an average of 35,519 SNPs per isolate, ranging from 35,001 SNPs to 35,889 SNPs relative to the reference genome FDA_R31. To capture the genetic diversity of V. parahaemolyticus in Asia and Mexico, 93 published genomes were included in the analysis. Phylogenetic analysis divided the 102 isolates into 5 clades from I to V, with the majority belonging to Clade I and Clade II. There were at least 12 independent AHPND related clones. The results indicated that the clones recovered from AHPND affected shrimps in Asia were genomically distinct in various locations and there are no epidemiological links between Asian and Mexico outbreaks. Core genome analysis of pVA-1-like plasmid sequences from V. parahaemolyticus revealed that the AHPND-associated plasmids were also genetically diverse. Homology analysis of the publicly available microbial genomes showed that the conjugative transfer gene clusters of the plasmids in AHPND-causing strains were found in 27 V. parahaemolyticus strains and several other Vibrio sp. from 10 countries including five strains isolated prior to the first identification of AHPND outbreak, indicating that the backbone of AHPND- associated plasmid was widely distributed around the globe. In conclusion, at least 11 origins of AHPND outbreaks were identified; as AHPND-causing plasmid is widely distributed globally, prevention strategies for AHPND need to focus on microbial management in the aquaculture system and establishing ecological friendly aquaculture practices instead of detection of plasmid alone. However, more strains from other Asia countries as well as Mexico need to be included for whole genome sequencing (WGS) for reconstruction of the global transmission and the spread patterns of AHPND. PMID- 29234317 TI - Panton-Valentine Leucocidin (PVL) as a Potential Indicator for Prevalence, Duration, and Severity of Staphylococcus aureus Osteomyelitis. AB - Staphylococcus aureus is the most common cause of the difficult-to-treat osteomyelitis (OM). To better diagnose and manage S. aureus OM, especially for severe and long duration cases, indicators for risk prediction and severity evaluation are needed. Here, 139 clinical S. aureus isolates from orthopedic infections were divided into OM group (60 isolates from 60 OM patients) and non OM group (79 isolates from 79 non-OM patients). Molecular types, antimicrobial susceptibility, and virulence factor profiles were evaluated and compared between the two groups to identify potential indicators associated with the prevalence of S. aureus OM. Clinical manifestations and laboratory data were analyzed to identify indicators affecting OM duration and severity. We found that some sequence types were specific to OM infection. The pvl, bbp, and ebps genes were associated with S. aureus OM prevalence. The pvl, bbp, and sei genes were associated with relatively longer OM duration. Panton-Valentine leucocidin (PVL) positive S. aureus OM presented more serious inflammatory responses. Our results emphasize the significance of PVL in affecting the prevalence, duration, and severity of S. aureus OM. Diagnosing and monitoring PVL-related S. aureus OM may help direct better prognosis and treatment of these patients. PMID- 29234318 TI - Leprosy As a Complex Infection: Breakdown of the Th1 and Th2 Immune Paradigm in the Immunopathogenesis of the Disease. AB - Leprosy is a chronic infectious disease whose evolution involves complex immune mechanisms of the host that influence the clinical presentation of the disease. For many years, the main interpretation of the host defense response was based on characterization of the established immune paradigm between T helper (Th) 1 and Th2 lymphocytes. However, with advances in the knowledge of immunology, new approaches have emerged along with the development of new immunological pathways that have changed the interpretation of the long-established paradigm of the polar forms of the disease, especially with the identification of new subtypes of T lymphocytes such as Th9, Th17, Th22, and Tregs. Thus, this review discusses the role of these new subtypes of T helper lymphocytes and how the development of the immune response of these cells modifies the pattern of the Th1/Th2 response in the immunopathogenesis of leprosy. PMID- 29234322 TI - Corrigendum: Commentary: The Scavenger Receptor SSc5D Physically Interacts with Bacteria through the SRCR-Containing N-Terminal Domain. AB - [This corrects the article on p. 366 in vol. 8, PMID: 28396672.]. PMID- 29234321 TI - Viral Impact in Autoimmune Diseases: Expanding the "X Chromosome-Nucleolus Nexus" Hypothesis. AB - Viruses are suspected of significant roles in autoimmune diseases but the mechanisms are unclear. We get some insight by considering demands a virus places on host cells. Viruses not only require production of their own proteins, RNA and/or DNA, but also production of additional cellular machinery, such as ribosomes, to handle the increased demands. Since the nucleolus is a major site of RNA processing and ribonucleoprotein assembly, nucleoli are targeted by viruses, directly when viral RNA and proteins enter the nucleolus and indirectly when viruses induce increased expression of cellular polyamine genes. Polyamines are at high levels in nucleoli to assist in RNA folding. The size and activity of nucleoli increase directly with increases in polyamines. Nucleolar expansion due to abnormal increases in polyamines could disrupt nearby chromatin, such as the inactive X chromosome, leading to expression of previously sequestered DNA. Sudden expression of a large concentration of Alu elements from the disrupted inactive X can compete with RNA transcripts containing intronic Alu sequences that normally maintain nucleolar structural integrity. Such disruption of nucleolar activity can lead to misfolded RNAs, misassembled ribonucleoprotein complexes, and fragmentation of the nucleolus. Many autoantigens in lupus are, at least transiently, components of the nucleolus. Considering these effects of viruses, the "X chromosome-nucleolus nexus" hypothesis, which proposed disruption of the inactive X by the nucleolus during stress, is now expanded here to propose subsequent disruption of the nucleolus by previously sequestered Alu elements, which can fragment the nucleolus, leading to generation of autoantigens. PMID- 29234323 TI - Interferon (IFN)-lambda Takes the Helm: Immunomodulatory Roles of Type III IFNs. AB - Type III interferons (IFNs) (or IFN-lambda) are the latest addition to the IFN family. Even though they share little protein homology with type I IFN, both exhibit remarkable functional similarities: each can be induced in response to viral infections, and both lead to Janus kinases (JAK) and signal transducer and activator of transcription (STAT) activation. The JAK/STAT pathway induces antiviral responses and IFN-stimulated gene transcription. However, despite the similarities in their effector functions with type I IFNs, IFN-lambda also has a non-redundant role in protecting barrier organs: epithelial cells preferentially produce IFN-lambda rather than type I IFNs; and interferon lambda receptor 1 (IFNLR1), the specific receptor for IFN-lambda, is highly expressed on cells of epithelial lineage. Thus far, IFN-lambda has been considered mainly as an epithelial cytokine, which restricts viral replication in epithelial cells and constitutes an added layer of protection at mucosal sites. However, it is now increasingly recognized that IFNLR1 is expressed broadly, and that immune cells such as neutrophils and dendritic cells also respond to IFN-lambda. Moreover, in many in vivo models, IFN-lambda modulates immune cell functions and thereby configures itself less as a cytokine that is only specific to the epithelium, and more as a cytokine that directly controls the inflammatory response at mucosal sites. Here, we critically review the recent literature on immune modulatory roles for IFN-lambda, and distinguish between the direct and indirect effects of this IFN on immune cell functions in different inflammatory settings. PMID- 29234319 TI - They Are What You Eat: Can Nutritional Factors during Gestation and Early Infancy Modulate the Neonatal Immune Response? AB - The ontogeny of the human immune system is sensitive to nutrition even in the very early embryo, with both deficiency and excess of macro- and micronutrients being potentially detrimental. Neonates are particularly vulnerable to infectious disease due to the immaturity of the immune system and modulation of nutritional immunity may play a role in this sensitivity. This review examines whether nutrition around the time of conception, throughout pregnancy, and in early neonatal life may impact on the developing infant immune system. PMID- 29234324 TI - Long Non-Coding RNAs: Emerging and Versatile Regulators in Host-Virus Interactions. AB - Long non-coding RNAs (lncRNAs) are a class of non-protein-coding RNA molecules, which are involved in various biological processes, including chromatin modification, cell differentiation, pre-mRNA transcription and splicing, protein translation, etc. During the last decade, increasing evidence has suggested the involvement of lncRNAs in both immune and antiviral responses as positive or negative regulators. The immunity-associated lncRNAs modulate diverse and multilayered immune checkpoints, including activation or repression of innate immune signaling components, such as interleukin (IL)-8, IL-10, retinoic acid inducible gene I, toll-like receptors 1, 3, and 8, and interferon (IFN) regulatory factor 7, transcriptional regulation of various IFN-stimulated genes, and initiation of the cell apoptosis pathways. Additionally, some virus-encoded lncRNAs facilitate viral replication through individually or synergistically inhibiting the host antiviral responses or regulating multiple steps of the virus life cycle. Moreover, some viruses are reported to hijack host-encoded lncRNAs to establish persistent infections. Based on these amazing discoveries, lncRNAs are an emerging hotspot in host-virus interactions. In this review, we summarized the current findings of the host- or virus-encoded lncRNAs and the underlying mechanisms, discussed their impacts on immune responses and viral replication, and highlighted their critical roles in host-virus interactions. PMID- 29234320 TI - Increasing the Clinical Potential and Applications of Anti-HIV Antibodies. AB - Preclinical and early human clinical studies of broadly neutralizing antibodies (bNAbs) to prevent and treat HIV infection support the clinical utility and potential of bNAbs for prevention, postexposure prophylaxis, and treatment of acute and chronic infection. Observed and potential limitations of bNAbs from these recent studies include the selection of resistant viral populations, immunogenicity resulting in the development of antidrug (Ab) responses, and the potentially toxic elimination of reservoir cells in regeneration-limited tissues. Here, we review opportunities to improve the clinical utility of HIV Abs to address these challenges and further accomplish functional targets for anti-HIV Ab therapy at various stages of exposure/infection. Before exposure, bNAbs' ability to serve as prophylaxis by neutralization may be improved by increasing serum half-life to necessitate less frequent administration, delivering genes for durable in vivo expression, and targeting bNAbs to sites of exposure. After exposure and/or in the setting of acute infection, bNAb use to prevent/reduce viral reservoir establishment and spread may be enhanced by increasing the potency with which autologous adaptive immune responses are stimulated, clearing acutely infected cells, and preventing cell-cell transmission of virus. In the setting of chronic infection, bNAbs may better mediate viral remission or "cure" in combination with antiretroviral therapy and/or latency reversing agents, by targeting additional markers of tissue reservoirs or infected cell types, or by serving as targeting moieties in engineered cell therapy. While the clinical use of HIV Abs has never been closer, remaining studies to precisely define, model, and understand the complex roles and dynamics of HIV Abs and viral evolution in the context of the human immune system and anatomical compartmentalization will be critical to both optimize their clinical use in combination with existing agents and define further strategies with which to enhance their clinical safety and efficacy. PMID- 29234325 TI - The Future of Immunotherapy: A 20-Year Perspective. AB - Immunotherapy is the field of immunology that aims to identify treatments for diseases through induction, enhancement or suppression of an immune response. Immunotherapies designed to instigate or enhance an immune response are considered "activating immunotherapies" while those designed to repress an immune response are "suppressive immunotherapies." This perspective will focus on two areas of immunotherapy, activating immunotherapies for cancer and suppressive immunotherapies for autoimmunity both of which have seen a resurgence in interest in recent years and are likely to transform the treatment of many human diseases in the next 20 years. Effective immunotherapies for cancer, where the aim is to activate tumor-specific immune responses, will be totally different from those designed to suppress the immune response to self-antigens in autoimmune disease. Furthermore, the reader will appreciate that the degree to which side effects of immunotherapies are acceptable will differ drastically between life-threatening cancers and chronic, debilitating but not necessarily life-threatening autoimmune conditions. PMID- 29234326 TI - Toll-Like Receptor 4 on both Myeloid Cells and Dendritic Cells Is Required for Systemic Inflammation and Organ Damage after Hemorrhagic Shock with Tissue Trauma in Mice. AB - Trauma combined with hemorrhagic shock (HS/T) leads to systemic inflammation, which results in organ injury. Toll-like Receptor 4 (TLR4)-signaling activation contributes to the initiation of inflammatory pathways following HS/T but its cell-specific roles in this setting are not known. We assessed the importance of TLR4 on leukocytes of myeloid lineage and dendritic cells (DCs) to the early systemic inflammatory response following HS/T. Mice were subjected to HS/T and 20 inflammatory mediators were measured in plasma followed by Dynamic Bayesian Network (DBN) Analysis. Organ damage was assessed by histology and plasma ALT levels. The role of TLR4 was determined using TLR4-/-, MyD88-/-, and Trif-/- C57BL/6 (B6) mice, and by in vivo administration of a TLR4-specific neutralizing monoclonal antibody (mAb). The contribution of TLR4 expressed by myeloid leukocytes and DC was determined by generating cell-specific TLR4-/- B6 mice, including Lyz-Cre * TLR4loxP/loxP, and CD11c-Cre * TLR4loxP/loxP B6 mice. Adoptive transfer of bone marrow-derived TLR4+/+ or TLR4-/- DC into TLR4-/- mice confirmed the contribution of TLR4 on DC to the systemic inflammatory response after HS/T. Using both global knockout mice and the TLR4-blocking mAb 1A6 we established a central role for TLR4 in driving systemic inflammation. Using cell selective TLR4-/- B6 mice, we found that TLR4 expression on both myeloid cells and CD11chigh DC is required for increases in systemic cytokine levels and organ damage after HS/T. We confirmed the capacity of TLR4 on CD11chigh DC to promote inflammation and liver damage using adoptive transfer of TLR4+/+ conventional (CD11chigh) DC into TLR4-/- mice. DBN inference identified CXC chemokines as proximal drivers of dynamic changes in the circulating levels of cytokines/chemokines after HS/T. TLR4 on DC was found to contribute selectively to the elevations in these proximal drivers. TLR4 on both myeloid cells and conventional DC is required for the initial systemic inflammation and organ damage in a mouse model of HS/T. This includes a role for TLR4 on DC in promoting increases in the early inflammatory networks identified in HS/T. These data establish DC along with macrophages as essential to the recognition of tissue damage and stress following tissue trauma with HS. PMID- 29234328 TI - Forward and Reverse Signaling Mediated by Transmembrane Tumor Necrosis Factor Alpha and TNF Receptor 2: Potential Roles in an Immunosuppressive Tumor Microenvironment. AB - Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic inflammatory cytokine produced mainly by activated macrophages, lymphocytes and other cell types. Two distinct forms of TNF-alpha have been identified: soluble TNF-alpha (sTNF-alpha) and transmembrane TNF-alpha (mTNF-alpha). mTNF-alpha, which is the precursor of sTNF-alpha, can be cleaved by the TNF-alpha converting enzyme (TACE) and is released as sTNF-alpha. sTNF-alpha binds primarily to TNF receptor 1 (TNFR1) and plays an important role in the inflammatory immune response, whereas mTNF-alpha interacts primarily with TNF receptor 2 (TNFR2) and mediates the promotion of cellular proliferation and survival and other biological effects. It has been reported that the interaction between mTNF-alpha and TNFR2 induces bi-directional (forward and reverse) signaling in both mTNF-alpha- and TNFR2-expressing cells. Increasing evidence shows that the forward and reverse signaling mediated by mTNF alpha and TNFR2 might play a significant role in the tumor microenvironment. In this review, the role of the crosstalk between mTNF-alpha and TNFR2 in the tumor microenvironment will be discussed. PMID- 29234330 TI - Editorial: Interaction of Nanomaterials with the Immune System: Role in Nanosafety and Nanomedicine. PMID- 29234327 TI - Influence of Microbiota on Intestinal Immune System in Ulcerative Colitis and Its Intervention. AB - Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with chronic and recurrent characteristics caused by multiple reasons. Although the pathogenic factors have not been clarified yet, recent studies have demonstrated that intestinal microbiota plays a major role in UC, especially in the immune system. This review focuses on the description of several major microbiota communities that affect UC and their interactions with the host. In this review, eight kinds of microbiota that are highly related to IBD, including Faecalibacterium prausnitzii, Clostridium clusters IV and XIVa, Bacteroides, Roseburia species, Eubacterium rectale, Escherichia coli, Fusobacterium, and Candida albicans are demonstrated on the changes in amount and roles in the onset and progression of IBD. In addition, potential therapeutic targets for UC involved in the regulation of microbiota, including NLRPs, vitamin D receptor as well as secreted proteins, are discussed in this review. PMID- 29234329 TI - Neoantigens Generated by Individual Mutations and Their Role in Cancer Immunity and Immunotherapy. AB - Recent preclinical and clinical studies have proved the long-standing hypothesis that tumors elicit adaptive immune responses and that the antigens driving effective T-cell response are neoantigens, i.e., peptides that are generated from somatically mutated genes. Hence, the characterization of neoantigens and the identification of the immunogenic ones are of utmost importance for improving cancer immunotherapy and broadening its efficacy to a larger fraction of patients. In this review, we first introduce the methods used for the quantification of neoantigens using next-generation sequencing data and then summarize results obtained using these tools to characterize the neoantigen landscape in solid cancers. We then discuss the importance of neoantigens for cancer immunotherapy using checkpoint blockers, vaccination, and adoptive T-cell transfer. Finally, we give an overview over emerging aspects in cancer immunity, including tumor heterogeneity and immunoediting, and give an outlook on future prospects. PMID- 29234331 TI - RNA-Seq Profiling Shows Divergent Gene Expression Patterns in Arabidopsis Grown under Different Densities. AB - Plants growing under high-density (HD) conditions experience increased competition for water, nutrients, and light, possibly leading to changes in size, biomass, morphology, and productivity. However, no research has focused on the relationship between whole-genome expression patterns and growth density. Here, we performed whole-genome RNA sequencing to examine the gene expression patterns in Arabidopsis grown under low and high densities. Of the 20,660 detected genes, the expression levels of 98 were enhanced and 107 were repressed under HD growth. Further analysis revealed that changes in density influenced metabolism- and stimulus-related genes the most. Furthermore, HD growth led to a shade avoidance phenotype, represented by upward growth and a reduction in rosette leaves. Moreover, a cluster of glutaredoxin genes, GRXS3, 4, 5, 7, and 8, were significantly down-regulated under high density, suggesting that high density affects plant growth mainly by nitrate limitation. PMID- 29234332 TI - Mutations in the Arabidopsis AtMRS2-11/AtMGT10/VAR5 Gene Cause Leaf Reticulation. AB - In higher plants, the development of functional chloroplasts is essential for photosynthesis and many other physiological processes. With a long-term goal of elucidating the genetic regulation of chloroplast development, we identified two allelic leaf variegation mutants, variegated5-1 (var5-1) and var5-2. Both mutants showed a distinct leaf reticulation phenotype of yellow paraveinal regions and green interveinal regions, and the leaf reticulation phenotype correlated with photosynthetic defects. Through the identification of mutation sites in the two mutant alleles and the molecular complementation, we confirmed that VAR5 encodes a CorA family of Mg2+ transporters also known as AtMRS2-11/AtMGT10. Using protoplast transient expression and biochemical fractionation assays, we demonstrated that AtMRS2-11/AtMGT10/VAR5 likely localizes to the chloroplast envelope. Moreover, we established that AtMRS2-11/AtMGT10/VAR5 forms large molecular weight complexes in the chloroplast and the sizes of these complexes clearly exceed those of their bacterial counterparts, suggesting the compositions of CorA Mg2+ transporter complex is different between the chloroplast and bacteria. Our findings indicate that AtMRS2-11/AtMGT10/VAR5 plays an important role in the tissue specific regulation of chloroplast development. PMID- 29234334 TI - No Vegetative and Fecundity Fitness Cost Associated with Acetyl-Coenzyme A Carboxylase Non-target-site Resistance in a Black-Grass (Alopecurus myosuroides Huds) Population. AB - Attention should be devoted to weeds evolving herbicide resistance with non target-site resistance (NTSR) mechanism due to their unpredictable resistance patterns. Quantification of fitness cost can be used in NTSR management strategies to determine the long-term fate of resistant plants in weed populations. To our knowledge, this is the first report evaluating potential fecundity and vegetative fitness of a NTSR black-grass (Alopecurus myosuroides Huds), the most important herbicide resistant weed in Europe, with controlled genetic background. The susceptible (S) and NTSR sub-populations were identified and isolated from a fenoxaprop-P-ethyl resistant population by a plant cloning technique. Using a target-neighborhood design, competitive responses of S and NTSR black-grass sub-populations to increasing density of winter wheat were quantified for 2 years in greenhouse and 1 year in field. Fitness traits including potential seed production, vegetative biomass and tiller number of both sub-populations significantly decreased with increasing density of winter wheat. More importantly, no statistically significant differences were found in fitness traits between S and NTSR sub-populations either grown alone (no competition) or in competition with winter wheat. According to the results, the NTSR black-grass is probably to persist in field even in the cessation of fenoxaprop-P-ethyl. So, effective herbicide resistant management strategies are strongly suggested to prevent and stop the spread of the NTSR black-grass, otherwise NTSR loci conferring resistance to a range of herbicides in black-grass will persist in the gene pool even in the absence of herbicide application. Consequently, herbicide as an effective tool for control of black-grass will gradually be lost in fields infested by NTSR black-grass. PMID- 29234333 TI - Putative Microsatellite DNA Marker-Based Wheat Genomic Resource for Varietal Improvement and Management. AB - Wheat fulfills 20% of global caloric requirement. World needs 60% more wheat for 9 billion population by 2050 but climate change with increasing temperature is projected to affect wheat productivity adversely. Trait improvement and management of wheat germplasm requires genomic resource. Simple Sequence Repeats (SSRs) being highly polymorphic and ubiquitously distributed in the genome, can be a marker of choice but there is no structured marker database with options to generate primer pairs for genotyping on desired chromosome/physical location. Previously associated markers with different wheat trait are also not available in any database. Limitations of in vitro SSR discovery can be overcome by genome wide in silico mining of SSR. Triticum aestivum SSR database (TaSSRDb) is an integrated online database with three-tier architecture, developed using PHP and MySQL and accessible at http://webtom.cabgrid.res.in/wheatssr/. For genotyping, Primer3 standalone code computes primers on user request. Chromosome-wise SSR calling for all the three sub genomes along with choice of motif types is provided in addition to the primer generation for desired marker. We report here a database of highest number of SSRs (476,169) from complex, hexaploid wheat genome (~17 GB) along with previously reported 268 SSR markers associated with 11 traits. Highest (116.93 SSRs/Mb) and lowest (74.57 SSRs/Mb) SSR densities were found on 2D and 3A chromosome, respectively. To obtain homozygous locus, e-PCR was done. Such 30 loci were randomly selected for PCR validation in panel of 18 wheat Advance Varietal Trial (AVT) lines. TaSSRDb can be a valuable genomic resource tool for linkage mapping, gene/QTL (Quantitative trait locus) discovery, diversity analysis, traceability and variety identification. Varietal specific profiling and differentiation can supplement DUS (Distinctiveness, Uniformity, and Stability) testing, EDV (Essentially Derived Variety)/IV (Initial Variety) disputes, seed purity and hybrid wheat testing. All these are required in germplasm management as well as also in the endeavor of wheat productivity. PMID- 29234335 TI - Metabolite Profiling of Wheat Seedlings Induced by Chitosan: Revelation of the Enhanced Carbon and Nitrogen Metabolism. AB - Chitosan plays an important role in regulating growth and eliciting defense in many plant species. However, the exact metabolic response of plants to chitosan is still not clear. The present study performed an integrative analysis of metabolite profiles in chitosan-treated wheat seedlings and further investigated the response of enzyme activities and transcript expression related to the primary carbon (C) and nitrogen (N) metabolism. Metabolite profiling revealed that chitosan could induce significant difference of organic acids, sugars and amino acids in leaves of wheat seedlings. A higher accumulation of sucrose content was observed after chitosan treatment, accompanied by an increase in sucrose phosphate synthase (SPS) and fructose 1, 6-2 phosphatase (FBPase) activities as well as an up-regulation of relative expression level. Several metabolites associated with tricarboxylic acid (TCA) cycle, including oxaloacetate and malate, were also improved along with an elevation of phosphoenolpyruvate carboxylase (PEPC) and pyruvate dehydrogenase (PDH) activities. On the other hand, chitosan could also enhance the N reduction and N assimilation. Glutamate, aspartate and some other amino acids were higher in chitosan-treated plants, accompanied by the activation of key enzymes of N reduction and glutamine synthetase/glutamate synthase (GS/GOGAT) cycle. Together, these results suggested a pleiotropic modulation of carbon and nitrogen metabolism in wheat seedlings induced by chitosan and provided a significant insight into the metabolic mechanism of plants in response to chitosan for the first time, and it would give a basic guidance for the future application of chitosan in agriculture. PMID- 29234337 TI - Community Profiling of Fusarium in Combination with Other Plant-Associated Fungi in Different Crop Species Using SMRT Sequencing. AB - Fusarium head blight, caused by fungi from the genus Fusarium, is one of the most harmful cereal diseases, resulting not only in severe yield losses but also in mycotoxin contaminated and health-threatening grains. Fusarium head blight is caused by a diverse set of species that have different host ranges, mycotoxin profiles and responses to agricultural practices. Thus, understanding the composition of Fusarium communities in the field is crucial for estimating their impact and also for the development of effective control measures. Up to now, most molecular tools that monitor Fusarium communities on plants are limited to certain species and do not distinguish other plant associated fungi. To close these gaps, we developed a sequencing-based community profiling methodology for crop-associated fungi with a focus on the genus Fusarium. By analyzing a 1600 bp long amplicon spanning the highly variable segments ITS and D1-D3 of the ribosomal operon by PacBio SMRT sequencing, we were able to robustly quantify Fusarium down to species level through clustering against reference sequences. The newly developed methodology was successfully validated in mock communities and provided similar results as the culture-based assessment of Fusarium communities by seed health tests in grain samples from different crop species. Finally, we exemplified the newly developed methodology in a field experiment with a wheat-maize crop sequence under different cover crop and tillage regimes. We analyzed wheat straw residues, cover crop shoots and maize grains and we could reveal that the cover crop hairy vetch (Vicia villosa) acts as a potent alternative host for Fusarium (OTU F.ave/tri) showing an eightfold higher relative abundance compared with other cover crop treatments. Moreover, as the newly developed methodology also allows to trace other crop-associated fungi, we found that vetch and green fallow hosted further fungal plant pathogens including Zymoseptoria tritici. Thus, besides their beneficial traits, cover crops can also entail phytopathological risks by acting as alternative hosts for Fusarium and other noxious plant pathogens. The newly developed sequencing based methodology is a powerful diagnostic tool to trace Fusarium in combination with other fungi associated to different crop species. PMID- 29234336 TI - Evolution and Expansion of the Prokaryote-Like Lipoxygenase Family in the Brown Alga Saccharina japonica. AB - Lipoxygenase (LOX) plays important roles in fatty acid oxidation and lipid mediator biosynthesis. In this study, we give first insights into brown algal LOX evolution. Whole genome searches revealed four, three, and eleven LOXs in Ectocarpus siliculosus, Cladosiphon okamuranus, and Saccharina japonica, respectively. In phylogenetic analyses, LOXs from brown algae form a robust clade with those from prokaryotes, suggesting an ancestral origin and slow evolution. Brown algal LOXs were divided into two clades, C1 and C2 in a phylogenetic tree. Compared to the two species of Ectocarpales, LOX gene expansion occurred in the kelp S. japonica through tandem duplication and segmental duplication. Selection pressure analysis showed that LOX genes in brown algae have undergone strong purifying selection, while the selective constraint in the C2 clade was more relaxed than that in the C1 clade. Furthermore, within each clade, LOXs of S. japonica evolved under more relaxed selection constraints than E. siliculosus and C. okamuranus. Structural modeling showed that unlike LOXs of plants and animals, which contain a beta barrel in the N-terminal part of the protein, LOXs in brown algae fold into a single domain. Analysis of previously published transcriptomic data showed that LOXs in E. siliculosus are responsive to hyposaline, hypersaline, oxidative, and copper stresses. Moreover, clear divergence of expression patterns was observed among different life stages, as well as between duplicate gene pairs. In E. siliculosus, all four LOXs are male-biased in immature gametophytes, and mature gametophytes showed significantly higher LOX mRNA levels than immature gametophytes and sporophytes. In S. japonica, however, our RNA-Seq data showed that most LOXs are highly expressed in sporophytes. Even the most recently duplicated gene pairs showed divergent expression patterns, suggesting that functional divergence has likely occurred since LOX genes duplicated, which potentially contributes to the production of various oxylipins in brown algae. PMID- 29234338 TI - Transcript Profiling Identifies Gene Cohorts Controlled by Each Signal Regulating Trans-Differentiation of Epidermal Cells of Vicia faba Cotyledons to a Transfer Cell Phenotype. AB - Transfer cells (TCs) support high rates of membrane transport of nutrients conferred by a plasma membrane area amplified by lining a wall labyrinth comprised of an uniform wall layer (UWL) upon which intricate wall ingrowth (WI) papillae are deposited. A signal cascade of auxin, ethylene, extracellular hydrogen peroxide (H2O2) and cytosolic Ca2+ regulates wall labyrinth assembly. To identify gene cohorts regulated by each signal, a RNA- sequencing study was undertaken using Vicia faba cotyledons. When cotyledons are placed in culture, their adaxial epidermal cells spontaneously undergo trans-differentiation to epidermal TCs (ETCs). Expressed genes encoding proteins central to wall labyrinth formation (signaling, intracellular organization, cell wall) and TC function of nutrient transport were assembled. Transcriptional profiles identified 9,742 annotated ETC-specific differentially expressed genes (DEGs; Log2fold change > 1; FDR p <= 0.05) of which 1,371 belonged to signaling (50%), intracellular organization (27%), cell wall (15%) and nutrient transporters (9%) functional categories. Expression levels of 941 ETC-specific DEGs were found to be sensitive to the known signals regulating ETC trans-differentiation. Significantly, signals acting alone, or in various combinations, impacted similar numbers of ETC specific DEGs across the four functional gene categories. Amongst the signals acting alone, H2O2 exerted most influence affecting expression levels of 56% of the ETC-specific DEGs followed by Ca2+ (21%), auxin (18%) and ethylene (5%). The dominance by H2O2 was evident across all functional categories, but became more attenuated once trans-differentiation transitioned into WI papillae formation. Amongst the eleven signal combinations, H2O2/Ca2+ elicited the greatest impact across all functional categories accounting for 20% of the ETC-specific DEG cohort. The relative influence of the other signals acting alone, or in various combinations, varied across the four functional categories and two phases of wall labyrinth construction. These transcriptome data provide a powerful information platform from which to examine signal transduction pathways and how these regulate expression of genes encoding proteins engaged in intracellular organization, cell wall construction and nutrient transport. PMID- 29234339 TI - RNA Editing Responses to Oxidative Stress between a Wild Abortive Type Male Sterile Line and Its Maintainer Line. AB - RNA editing of mitochondrial gene transcripts plays a central role during plant development and evolutionary adaptation. RNA editing has previously been reported to differ between the rice cytoplasmic male sterile (CMS) line and its maintainer line, which has been suggested as a cause for their different performances under environmental stress. To specifically test this hypothesis, a wild abortive (WA) CMS line (Huhan-1A) and its maintainer line (Huhan-1B) were utilized to investigate performances in response to oxidative stress, as well as RNA editing efficiencies on transcripts of six selected mitochondrial genes. Compared to the maintainer line, Huhan-1A represented both lower plant height and total antioxidant capacity, possessed higher total soluble protein and chlorophyll contents, accumulated less H2O2 content on the 3rd day after treatment (DAT), and exhibited higher survival ratio after re-watering. Furthermore, a total of 90 editing sites were detected on transcripts of six mitochondrial genes (atp9, nad2, nad7, nad9, ccmB, and ccmC) in both Huhan-1A and Huhan-1B on the 0, 1st, and 3rd DAT. Forty-eight sites were furthermore determined as stress-responsive sites (SRS). Generally, in response to oxidative stress, SRS in Huhan-1A increased the resulting editing efficiencies, while SRS in Huhan-1B decreased the resulting editing efficiencies. In addition, 33 and 22 sites at ccmB and ccmC were differentially edited between Huhan-1A and Huhan-1B, respectively, on the 0, 1st, and 3rd DAT. Editing efficiencies of ccmB and ccmC were generally lower in Huhan-1A (ccmB, 37.3-47.8%; ccmC, 41.2-52.3%) than those in Huhan-1B (ccmB, 82.6 86.5%; ccmC, 81.0-82.9%). Deficiencies of RNA editing in Huhan-1A at ccmB and ccmC could lead to the loss of transmembrane domains in their protein structures. Consequently, differences in RNA editing at ccmB and ccmC between the WA-CMS line and its maintainer line partially explained their different performances under stress. Moreover, we detected differences in expressions of pentatricopeptide repeat (PPR) genes between both lines, as well as significant correlations with RNA editing. Our study indicated potential associations of RNA editing and PPR genes in rice tolerance to abiotic stresses. However, the underlying molecular mechanisms of stress-adaptation, which are attributed to RNA editing on transcripts of mitochondrial genes, require further investigation. PMID- 29234340 TI - Influence of Environmental Conditions and Genetic Background of Arabica Coffee (C. arabica L) on Leaf Rust (Hemileia vastatrix) Pathogenesis. AB - Global warming is a major threat to agriculture worldwide. Between 2008 and 2013, some coffee producing countries in South and Central America suffered from severe epidemics of coffee leaf rust (CLR), resulting in high economic losses with social implications for coffee growers. The climatic events not only favored the development of the pathogen but also affected the physiological status of the coffee plant. The main objectives of the study were to evaluate how the physiological status of the coffee plant modified by different environmental conditions impact on the pathogenesis of CLR and to identify indicators of the physiological status able to predict rust incidence. Three rust susceptible genotypes (one inbred line and two hybrids) were grown in controlled conditions with a combination of thermal regime (TR), nitrogen and light intensity close to the field situation before being inoculated with the rust fungus Hemileia vastatrix. It has been demonstrated that a TR of 27-22 degrees C resulted in 2000 times higher sporulation than with a TR of 23-18 degrees C. It has been also shown that high light intensity combined with low nitrogen fertilization modified the CLR pathogenesis resulting in huge sporulation. CLR sporulation was significantly lower in the F1 hybrids than in the inbred line. The hybrid vigor may have reduced disease incidence. Among the many parameters studied, parameters related to photosystem II and photosynthetic electron transport chain components appeared as indicators of the physiological status of the coffee plant able to predict rust sporulation intensity. Taken together, these results show that CLR sporulation not only depends on the TR but also on the physiological status of the coffee plant, which itself depends on agronomic conditions. Our work suggests that vigorous varieties combined with a shaded system and appropriate nitrogen fertilization should be part of an agro-ecological approach to disease control. PMID- 29234341 TI - Assuring Potato Tuber Quality during Storage: A Future Perspective. AB - Potatoes represent an important staple food crop across the planet. Yet, to maintain tuber quality and extend availability, there is a necessity to store tubers for long periods often using industrial-scale facilities. In this context, preserving potato quality is pivotal for the seed, fresh and processing sectors. The industry has always innovated and invested in improved post-harvest storage. However, the pace of technological change has and will continue to increase. For instance, more stringent legislation and changing consumer attitudes have driven renewed interest in creating alternative or complementary post-harvest treatments to traditional chemically reliant sprout suppression and disease control. Herein, the current knowledge on biochemical factors governing dormancy, the use of chlorpropham (CIPC) as well as existing and chemical alternatives, and the effects of pre- and post-harvest factors to assure potato tuber quality is reviewed. Additionally, the role of genomics as a future approach to potato quality improvement is discussed. Critically, and through a more industry targeted research, a better mechanistic understanding of how the pre-harvest environment influences tuber quality and the factors which govern dormancy transition should lead to a paradigm shift in how sustainable storage can be achieved. PMID- 29234342 TI - Melatonin Is Involved in Regulation of Bermudagrass Growth and Development and Response to Low K+ Stress. AB - Melatonin (N-acetyl-5-methoxytryptamine) plays critical roles in plant growth and development and during the response to multiple abiotic stresses. However, the roles of melatonin in plant response to K+ deficiency remain largely unknown. In the present study, we observed that the endogenous melatonin contents in bermudagrass were remarkably increased by low K+ (LK) treatment, suggesting that melatonin was involved in bermudagrass response to LK stress. Further phenotype analysis revealed that exogenous melatonin application conferred Bermudagrass enhanced tolerance to LK stress. Interestingly, exogenous melatonin application also promoted bermudagrass growth and development at normal condition. Furthermore, the K+ contents measurement revealed that melatonin-treated plants accumulated more K+ in both shoot (under both control and LK condition) and root tissues (under LK condition) compared with those of melatonin non-treated plants. Expression analysis indicated that the transcripts of K+ transport genes were significantly induced by exogenous melatonin treatment in bermudagrass under both control and LK stress conditions, especially under a combined treatment of LK stress and melatonin, which may increase accumulation of K+ content profoundly under LK stress and thereby contributed to the LK-tolerant phenotype. In addition, we investigated the role of melatonin in the regulation of photosystem II (PSII) activities under LK stress. The chlorophyll fluorescence transient (OJIP) curves were obviously higher in plants grown in LK with melatonin (LK+Mel) than those of plants grown in LK medium without melatonin application for 1 or 2 weeks, suggesting that melatonin plays important roles in PSII against LK stress. After a combined treatment of LK stress and melatonin, the values for performance indexes (PIABS, PITotal, and PICS), flux ratios (phiP0, PsiE0, and phiE0) and specific energy fluxes (ETO/RC) were significantly improved compared with those of LK stress alone, suggesting that melatonin plays positive roles in protecting PSII activity under LK stress. Collectively, this study reveals an important role of melatonin in regulating bermudagrass response to LK stress. PMID- 29234343 TI - Effects of Plant Functional Group Loss on Soil Microbial Community and Litter Decomposition in a Steppe Vegetation. AB - Globally, many terrestrial ecosystems are experiencing a rapid loss of biodiversity. Continued improvements in our understanding of interrelationships between plant diversity and soil microbes are critical to address the concern over the consequences of the decline in biodiversity on ecosystem functioning and services. By removing forbs, or grasses, or, to an extreme scenario, both forbs and grasses in a steppe vegetation in Inner Mongolia, we studied how plant functional group (PFG) loss affects soil microbial community composition using phospholipid fatty acid analysis (PLFA) and litter decomposition using a litter bag method. PFG loss significantly decreased above- and below-ground plant biomass, soil microbial biomass carbon (SMBC) and nitrogen (SMBN), but had no effect on the ratio of SMBC to SMBN. Although the ratio of fungal to bacterial PLFAs remained unaffected, PFG loss significantly reduced the amount of bacterial, fungal, and total PLFAs. PFG loss decreased litter monthly mass loss and decay constant, and such decrease was significant when both forbs and grasses were removed. Our results provide robust evidence that PFG loss in grassland ecosystem can lead to a rapid response of soil microbial activity which may affect litter decomposition and soil nutrient cycling, suggesting that the assessment of plant-microbe interactions in soils is an integral component of ecosystem response to biodiversity loss. PMID- 29234344 TI - LHP1 Could Act as an Activator and a Repressor of Transcription in Plants. AB - Polycomb group (PcG) proteins within the polycomb repressive complex 1 (PRC1) and PRC2 are significant epigenetic regulatory factors involved in important cellular and developmental processes in eukaryotes. In Arabidopsis, LIKE HETEROCHROMATIN PROTEIN 1 (LHP1), also known as TERMINAL FLOWER 2, has been proposed as a plant specific subunit of PRC1 that could bind the trimethylated lysine 27 of histone H3 (H3K27me3), which is established by PRC2 and is required for a functional plant PcG system. LHP1 not only interacts with PRC1 to catalyze monoubiquitination at lysine 119 of histone H2A but also functions with PRC2 to establish H3K27me3. This review is about the interaction of LHP1 with PRC1 and PRC2, in which LHP1 may act as a bridge between the two. Meantime, this review highlights that LHP1 could act as an activator and a repressor of transcription. PMID- 29234345 TI - A New Ala-122-Asn Amino Acid Change Confers Decreased Fitness to ALS-Resistant Echinochloa crus-galli. AB - Gene mutations conferring herbicide resistance may cause pleiotropic effects on plant fitness. Knowledge of these effects is important for managing the evolution of herbicide-resistant weeds. An Echinochloa crus-galli population resistant to acetolactate synthase (ALS) herbicides was collected in a maize field in north eastern Italy and the cross-resistance pattern, resistance mechanism and fitness costs associated to mutant-resistant plants under field conditions in the presence or absence of intra-specific competition were determined. The study reports for the first time the Ala-122-Asn amino-acid change in the ALS gene that confers high levels of cross-resistance to all ALS inhibitors tested. Results of 3-year growth analysis showed that mutant resistant E. crus-galli plants had a delayed development in comparison with susceptible plants and this was registered in both competitive (3, 7, and 20 plants m-2) and non-competitive (spaced plants) situations. The number of panicles produced by resistant plants was also lower (about 40% fewer panicles) than susceptible plants under no-intraspecific competition. Instead, with the increasing competition level, the difference in panicle production at harvest time decreased until it became negligible at 20 plants m-2. Evaluation of total dry biomass as well as biomass allocation in vegetative parts did not highlight any difference between resistant and susceptible plants. Instead, panicle dry weight was higher in susceptible plants indicating that they allocated more biomass than resistant ones to the reproductive organs, especially in no-competition and in competition situations at lower plant densities. The different fitness between resistant and susceptible phenotypes suggests that keeping the infestation density as low as possible can increase the reproduction success of the susceptible phenotype and therefore contribute to lowering the ratio between resistant and susceptible alleles. If adequately embedded in a medium or long-term integrated weed management strategy, the presence of R plants with a fitness penalty provides an opportunity to minimize or reverse herbicide resistance evolution through the implementation of integrated weed management, i.e., all possible control tools available. PMID- 29234346 TI - Involvement of Sodium Nitroprusside (SNP) in the Mechanism That Delays Stem Bending of Different Gerbera Cultivars. AB - Longevity of cut flowers of many gerbera cultivars (Gerbera jamesonii) is typically short because of stem bending; hence, stem bending that occurs during the early vase life period is a major problem in gerbera. Here, we investigated the effects of sodium nitroprusside (SNP) on the delay of stem bending in the gerbera cultivars, Alliance, Rosalin, and Bintang, by examining relative fresh weight, bacterial density in the vase solution, transcriptional analysis of a lignin biosynthesis gene, antioxidant activity, and xylem blockage. All three gerbera cultivars responded to SNP by delaying stem bending, compared to the controls; however, the responses were dose- and cultivar-dependent. Among the treatments, SNP at 20 mg L-1 was the best to delay stem bending in Alliance, while dosages of 10 and 5 mg L-1 were the best for Rosalin and Bintang, respectively. However, stem bending in Alliance and Rosalin was faster than in Bintang, indicating a discrepancy influenced by genotype. According to our analysis of the role of SNP in the delay of stem bending, the results revealed that SNP treatment inhibited bacterial growth and xylem blockage, enhanced expression levels of a lignin biosynthesis gene, and maintained antioxidant activities. Therefore, it is suggested that the cause of stem bending is associated with the above-mentioned parameters and SNP is involved in the mechanism that delays stem bending in the different gerbera cultivars. PMID- 29234347 TI - Ectopic Expression of Pumpkin NAC Transcription Factor CmNAC1 Improves Multiple Abiotic Stress Tolerance in Arabidopsis. AB - Drought, cold and salinity are the major environmental stresses that limit agricultural productivity. NAC transcription factors regulate the stress response in plants. Pumpkin (Cucurbita moschata) is an important cucurbit vegetable crop and it has strong resistance to abiotic stress; however, the biological functions of stress-related NAC genes in this crop are largely unknown. This study reports the function of CmNAC1, a stress-responsive pumpkin NAC domain protein. The CmNAC1-GFP fusion protein was transiently expressed in tobacco leaves for subcellular localization analysis, and we found that CmNAC1 is localized in the nucleus. Transactivation assay in yeast cells revealed that CmNAC1 functions as a transcription activator, and its transactivation domain is located in the C terminus. CmNAC1 was ubiquitously expressed in different organs, and its transcript was induced by salinity, cold, dehydration, H2O2, and abscisic acid (ABA) treatment. Furthermore, the ectopic expression (EE) of CmNAC1 in Arabidopsis led to ABA hypersensitivity and enhanced tolerance to salinity, drought and cold stress. In addition, five ABA-responsive elements were enriched in CmNAC1 promoter. The CmNAC1-EE plants exhibited different root architecture, leaf morphology, and significantly high concentration of ABA compared with WT Arabidopsis under normal conditions. Our results indicated that CmNAC1 is a critical factor in ABA signaling pathways and it can be utilized in transgenic breeding to improve the abiotic stress tolerance of crops. PMID- 29234349 TI - Genome-Wide Association Study of Piglet Uniformity and Farrowing Interval. AB - Piglet uniformity (PU) and farrowing interval (FI) are important reproductive traits related to production and economic profits in the pig industry. However, the genetic architecture of the longitudinal trends of reproductive traits still remains elusive. Herein, we performed a genome-wide association study (GWAS) to detect potential genetic variation and candidate genes underlying the phenotypic records at different parities for PU and FI in a population of 884 Large White pigs. In total, 12 significant SNPs were detected on SSC1, 3, 4, 9, and 14, which collectively explained 1-1.79% of the phenotypic variance for PU from parity 1 to 4, and 2.58-4.11% for FI at different stages. Of these, seven SNPs were located within 16 QTL regions related to swine reproductive traits. One QTL region was associated with birth body weight (related to PU) and contained the peak SNP MARC0040730, and another was associated with plasma FSH concentration (related to FI) and contained the SNP MARC0031325. Finally, some positional candidate genes for PU and FI were identified because of their roles in prenatal skeletal muscle development, fetal energy substrate, pre-implantation, and the expression of mammary gland epithelium. Identification of novel variants and candidate genes will greatly advance our understanding of the genetic mechanisms of PU and FI, and suggest a specific opportunity for improving marker assisted selection or genomic selection in pigs. PMID- 29234350 TI - Genetic Diversity and Connectivity in Maurolicus muelleri in the Bay of Biscay Inferred from Thousands of SNP Markers. AB - Mesopelagic fish are largely abundant poorly studied fish that are still intact, but which, due to their potentially great added value, will be imminently exploited by humans. Therefore, studies that provide information to anticipate the anthropogenic impact on this important resource are urgently needed. In particular, knowledge about their connectivity, potential adaptation and resilience are needed. This information can be obtained through the analysis of genome-wide markers which are now relatively easily and cost-efficiently discovered thanks to high-throughput sequencing technologies. Here, we have generated thousands of SNP markers in Maurolicus muelleri, based on the restriction-site associated DNA sequencing method, and preformed population connectivity and genetic diversity analyses in a subset of samples collected from the Bay of Biscay. Our study proves the method valid for obtaining genome-wide markers in this species and provides the first insights into the population genomics of M. muelleri. Importantly, the genomic resources developed here are made available for future studies and set the basics for additional endeavors on this issue. PMID- 29234348 TI - Diurnal Transcriptome and Gene Network Represented through Sparse Modeling in Brachypodium distachyon. AB - We report the comprehensive identification of periodic genes and their network inference, based on a gene co-expression analysis and an Auto-Regressive eXogenous (ARX) model with a group smoothly clipped absolute deviation (SCAD) method using a time-series transcriptome dataset in a model grass, Brachypodium distachyon. To reveal the diurnal changes in the transcriptome in B. distachyon, we performed RNA-seq analysis of its leaves sampled through a diurnal cycle of over 48 h at 4 h intervals using three biological replications, and identified 3,621 periodic genes through our wavelet analysis. The expression data are feasible to infer network sparsity based on ARX models. We found that genes involved in biological processes such as transcriptional regulation, protein degradation, and post-transcriptional modification and photosynthesis are significantly enriched in the periodic genes, suggesting that these processes might be regulated by circadian rhythm in B. distachyon. On the basis of the time series expression patterns of the periodic genes, we constructed a chronological gene co-expression network and identified putative transcription factors encoding genes that might be involved in the time-specific regulatory transcriptional network. Moreover, we inferred a transcriptional network composed of the periodic genes in B. distachyon, aiming to identify genes associated with other genes through variable selection by grouping time points for each gene. Based on the ARX model with the group SCAD regularization using our time-series expression datasets of the periodic genes, we constructed gene networks and found that the networks represent typical scale-free structure. Our findings demonstrate that the diurnal changes in the transcriptome in B. distachyon leaves have a sparse network structure, demonstrating the spatiotemporal gene regulatory network over the cyclic phase transitions in B. distachyon diurnal growth. PMID- 29234351 TI - Space and Time Resolved Detection of Platelet Activation and von Willebrand Factor Conformational Changes in Deep Suspensions. AB - Tracking cells and proteins' phenotypic changes in deep suspensions is critical for the direct imaging of blood-related phenomena in in vitro replica of cardiovascular systems and blood-handling devices. This paper introduces fluorescence imaging techniques for space and time resolved detection of platelet activation, von Willebrand factor (VWF) conformational changes, and VWF-platelet interaction in deep suspensions. Labeled VWF, platelets, and VWF-platelet strands are suspended in deep cuvettes, illuminated, and imaged with a high-sensitivity EM-CCD camera, allowing detection using an exposure time of 1 ms. In-house postprocessing algorithms identify and track the moving signals. Recombinant VWF eGFP (rVWF-eGFP) and VWF labeled with an FITC-conjugated polyclonal antibody are employed. Anti-P-Selectin FITC-conjugated antibodies and the calcium-sensitive probe Indo-1 are used to detect activated platelets. A positive correlation between the mean number of platelets detected per image and the percentage of activated platelets determined through flow cytometry is obtained, validating the technique. An increase in the number of rVWF-eGFP signals upon exposure to shear stress demonstrates the technique's ability to detect breakup of self-aggregates. VWF globular and unfolded conformations and self-aggregation are also observed. The ability to track the size and shape of VWF-platelet strands in space and time provides means to detect pro- and antithrombotic processes. PMID- 29234352 TI - Assessment of Osteoporosis in Injured Older Women Admitted to a Safety-Net Level One Trauma Center: A Unique Opportunity to Fulfill an Unmet Need. AB - Background: Older trauma patients often undergo computed tomography (CT) as part of the initial work-up. CT imaging can also be used opportunistically to measure bone density and assess osteoporosis. Methods: In this retrospective cohort study, osteoporosis was ascertained from admission CT scans in women aged >=65 admitted to the ICU for traumatic injury during a 3-year period at a single, safety-net, level 1 trauma center. Osteoporosis was defined by established CT based criteria of average L1 vertebral body Hounsfield units <110. Evidence of diagnosis and/or treatment of osteoporosis was the primary outcome. Results: The study cohort consisted of 215 women over a 3-year study period, of which 101 (47%) had evidence of osteoporosis by CT scan criteria. There were no differences in injury severity score, hospital length of stay, cost, or discharge disposition between groups with and without evidence of osteoporosis. Only 55 (59%) of the 94 patients with osteoporosis who survived to discharge had a documented osteoporosis diagnosis and/or corresponding evaluation/treatment plan. Conclusion: Nearly half of older women admitted with traumatic injuries had underlying osteoporosis, but 41% had neither clinical recognition of this finding nor a treatment plan for osteoporosis. Admission for traumatic injury is an opportunity to assess osteoporosis, initiate appropriate intervention, and coordinate follow-up care. Trauma and acute care teams should consider assessment of osteoporosis in women who undergo CT imaging and provide a bridge to outpatient services. PMID- 29234353 TI - Enteric Fever Caused by Salmonella enterica Serovars with Reduced Susceptibility of Fluoroquinolones at a Community Based Teaching Hospital of Nepal. AB - Enteric fever continues to be an important public health problem especially in developing countries of the tropical region including Nepal. In this study, we aimed to investigate the incidence of enteric fever associated with Salmonella enterica and determine its antimicrobial susceptibilities to therapeutic antimicrobials in a community based teaching hospital of Nepal. A total of 2,304 blood samples from suspected enteric fever patients attending Manmohan Memorial Teaching Hospital were processed with standard microbiological methods for the isolation and identification of bacterial pathogens. The Salmonella enterica clinical strains were subjected to antimicrobial susceptibility testing by Kirby Bauer disk diffusion method, and the results were interpreted according to the criteria suggested by the Clinical and Laboratory Standards Institute (CLSI). A total of 245 (10.6%) cases of enteric fever associated with Salmonella enterica were confirmed by blood culture. Out of them, 162 (66.1%) were caused by Salmonella Typhi and 83 (33.9%) by Salmonella Paratyphi. On Kirby-Bauer disk diffusion antimicrobial susceptibility testing, Salmonella isolates were highly susceptible to cefixime (100%), ceftriaxone (100%), ampicillin (97.9%), cotrimoxazole (94.6%), azithromycin (96.7%), tetracycline (95.5%), and chloramphenicol (97.5%), respectively. Two hundred twenty-six (92.2%) of Salmonella isolates were nalidixic acid resistant with reduced susceptibility to ciprofloxacin (36.7%) and ofloxacin (54.8%), respectively. Although the rate of MDR Salmonella strains was very low (<5%), their reduced susceptibility to fluoroquinolones has restricted their routine empirical use. Third generation cephalosporins are the safest choice for empirical use but ampicillin, cotrimoxazole, azithromycin, and chloramphenicol can be effective alternatives. PMID- 29234354 TI - Differential Microbial Diversity in Drosophila melanogaster: Are Fruit Flies Potential Vectors of Opportunistic Pathogens? AB - Drosophila melanogaster has become a model system to study interactions between innate immunity and microbial pathogens, yet many aspects regarding its microbial community and interactions with pathogens remain unclear. In this study wild D. melanogaster were collected from tropical fruits in Puerto Rico to test how the microbiota is distributed and to compare the culturable diversity of fungi and bacteria. Additionally, we investigated whether flies are potential vectors of human and plant pathogens. Eighteen species of fungi and twelve species of bacteria were isolated from wild flies. The most abundant microorganisms identified were the yeast Candida inconspicua and the bacterium Klebsiella sp. The yeast Issatchenkia hanoiensis was significantly more common internally than externally in flies. Species richness was higher in fungi than in bacteria, but diversity was lower in fungi than in bacteria. The microbial composition of flies was similar internally and externally. We identified a variety of opportunistic human and plant pathogens in flies such as Alcaligenes faecalis, Aspergillus flavus, A. fumigatus, A. niger, Fusarium equiseti/oxysporum, Geotrichum candidum, Klebsiella oxytoca, Microbacterium oxydans, and Stenotrophomonas maltophilia. Despite its utility as a model system, D. melanogaster can be a vector of microorganisms that represent a potential risk to plant and public health. PMID- 29234355 TI - Treatment of Community-Acquired Pneumonia: Are All Countries Treating Children in the Same Way? A Literature Review. AB - Background: Pneumonia represents an important threat to children's health in both developed and developing countries. In the last 10 years, many national and international guidelines on the treatment of pediatric CAP have been published, in order to optimize the prescription of antibiotics and limit their cost and side effects. However, the practical implementation of these guidelines is still limited. Main Text: We analyzed the current recommendations for the therapy of pediatric community-acquired pneumonia (CAP) that all converge on the identification of aminopenicillins and beta-lactams as the optimal treatment for CAP. We also conducted a review of the current literature on antibiotic regimens used for pediatric CAP to identify the current state of guidelines implementation in different settings. We selected 37 studies published from 2010 to 2016, including both retrospective and prospective studies, mainly cross-sectional and hospital based. The results show a global heterogeneity in the antibiotics prescription for pediatric CAP, with application of guidelines varying from 0% to more than 91% and with important differences even within the same country. Conclusions: Our review has demonstrated that the implementation of the guidelines is still limited but also that achieving the optimal prescription is possible and can be done in both developed and developing countries. PMID- 29234356 TI - The opportunities of virtual reality in the rehabilitation of children with attention deficit hyperactivity disorder: a literature review. AB - Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in childhood. This disorder, in addition to its main symptoms, creates significant difficulties in education, social performance, and personal relationships. Given the importance of rehabilitation for these patients to combat the above issues, the use of virtual reality (VR) technology is helpful. The aim of this study was to highlight the opportunities for VR in the rehabilitation of children with ADHD. This narrative review was conducted by searching for articles in scientific databases and e-Journals, using keywords including VR, children, and ADHD. Various studies have shown that VR capabilities in the rehabilitation of children with ADHD include providing flexibility in accordance with the patients' requirements; removing distractions and creating an effective and safe environment away from real-life dangers; saving time and money; increasing patients' incentives based on their interests; providing suitable tools to perform different behavioral tests and increase ecological validity; facilitating better understanding of individuals' cognitive deficits and improving them; helping therapists with accurate diagnosis, assessment, and rehabilitation; and improving working memory, executive function, and cognitive processes such as attention in these children. Rehabilitation of children with ADHD is based on behavior and physical patterns and is thus suitable for VR interventions. This technology, by simulating and providing a virtual environment for diagnosis, training, monitoring, assessment and treatment, is effective in providing optimal rehabilitation of children with ADHD. PMID- 29234357 TI - Neonatal arrhythmias: diagnosis, treatment, and clinical outcome. AB - Arrhythmias in the neonatal period are not uncommon, and may occur in neonates with a normal heart or in those with structural heart disease. Neonatal arrhythmias are classified as either benign or nonbenign. Benign arrhythmias include sinus arrhythmia, premature atrial contraction, premature ventricular contraction, and junctional rhythm; these arrhythmias have no clinical significance and do not need therapy. Supraventricular tachycardia, ventricular tachycardia, atrioventricular conduction abnormalities, and genetic arrhythmia such as congenital long-QT syndrome are classified as nonbenign arrhythmias. Although most neonatal arrhythmias are asymptomatic and rarely life-threatening, the prognosis depends on the early recognition and proper management of the condition in some serious cases. Precise diagnosis with risk stratification of patients with nonbenign neonatal arrhythmia is needed to reduce morbidity and mortality. In this article, I review the current understanding of the common clinical presentation, etiology, natural history, and management of neonatal arrhythmias in the absence of an underlying congenital heart disease. PMID- 29234358 TI - Hearing loss screening tool (COBRA score) for newborns in primary care setting. AB - Purpose: To develop and evaluate a simple screening tool to assess hearing loss in newborns. A derived score was compared with the standard clinical practice tool. Methods: This cohort study was designed to screen the hearing of newborns using transiently evoked otoacoustic emission and auditory brain stem response, and to determine the risk factors associated with hearing loss of newborns in 3 tertiary hospitals in Northern Thailand. Data were prospectively collected from November 1, 2010 to May 31, 2012. To develop the risk score, clinical-risk indicators were measured by Poisson risk regression. The regression coefficients were transformed into item scores dividing each regression-coefficient with the smallest coefficient in the model, rounding the number to its nearest integer, and adding up to a total score. Results: Five clinical risk factors (Craniofacial anomaly, Ototoxicity, Birth weight, family history [Relative] of congenital sensorineural hearing loss, and Apgar score) were included in our COBRA score. The screening tool detected, by area under the receiver operating characteristic curve, more than 80% of existing hearing loss. The positive-likelihood ratio of hearing loss in patients with scores of 4, 6, and 8 were 25.21 (95% confidence interval [CI], 14.69-43.26), 58.52 (95% CI, 36.26-94.44), and 51.56 (95% CI, 33.74-78.82), respectively. This result was similar to the standard tool (The Joint Committee on Infant Hearing) of 26.72 (95% CI, 20.59-34.66). Conclusion: A simple screening tool of five predictors provides good prediction indices for newborn hearing loss, which may motivate parents to bring children for further appropriate testing and investigations. PMID- 29234359 TI - Subtle inflammation: a possible mechanism of future cardiovascular risk in obese children. AB - Purpose: The risk of cardiovascular disease (CVD) has been shown to be associated with systemic inflammation in obese adults with metabolic syndrome (MetS). The aims of this study were to evaluate the prevalence of MetS and its relation to inflammatory markers in obese Thai children. Methods: A cross-sectional study was conducted. Children with history of endogenous obesity, chronic diseases, drug ingestion, and any acute illness within 2 weeks prior to enrollment were excluded. Their fasting blood glucose (FBG) levels, oral glucose tolerance tests, insulin, lipid profiles, and selected inflammatory markers, including interleukin 6, tumor necrosis factor-alpha, and high-sensitivity C-reactive protein (hs-CRP) levels, were tested. Results: In this study, 58 obese Thai children (female, 20; male, 38) with a mean body mass index z score of 5.1+/-2.2 were enrolled. The prevalence of MetS and prediabetes was 31% and 17.2%, respectively. None of the children had diabetes. FBG levels, 2-hour glucose levels, and lipid profiles were not statistically different between those with and without MetS. However, obese children with MetS had higher insulin levels and homeostasis model assessment of insulin resistance values. Elevated hs-CRP levels were found in 69% of the cases, although it was not statistically different between the 2 groups. Conclusion: We described a substantial prevalence of MetS in Thai obese children. Regardless of MetS status, two-thirds of the obese children had elevated hs-CRP level, indicating subtle ongoing inflammatory process. This chronic inflammation feasibly predisposes them to CVD in the future, even in children without MetS. PMID- 29234361 TI - A comparative study of established z score models for coronary artery diameters in 181 healthy Korean children. AB - Purpose: The aim of this study was to investigate the statistical properties of four previously developed pediatric coronary artery z score models in healthy Korean children. Methods: The study subjects were 181 healthy Korean children, whose age ranged from 1 month to 15 years. The diameter of each coronary artery was measured using 2-dimensional echocardiography and converted to the z score in the four models (McCrindle, Olivieri, Dallaire, and Japanese model). Descriptive statistical analyses and 1-sample t tests were performed. Results: All calculated z scores had P values of >=0.050 using the Kolmogorov-Smirnov test. The one sample t test showed that the mean z scores did not converge to zero except in 1 model, and the mean right coronary artery (RCA) z score was less than zero in all 4 models. The smaller RCA diameter in this study could be associated with the more distal measuring point used to avoid the conal branch. The percentage of subjects with extreme z score values (>=2.0 and >=2.5) for the left main coronary artery (LMCA) seems to be higher in the Dallaire (4.9% and 3.3%) and Japanese models (7.1% and 3.8%). Conclusion: All 4 models showed statistical feasibility of normal distribution. More precise instructions would be needed for the measurement of the RCA. The higher percentage of extreme z scores for the LMCA is compatible with the basic understanding of anatomic variation in the LMCA. PMID- 29234360 TI - Apoptosis and remodeling in adriamycin-induced cardiomyopathy rat model. AB - Purpose: The mechanism for the pathogenesis of adriamycin (ADR)-induced cardiomyopathy is not yet known. Different hypotheses include the production of free radicals, an interaction between ADR and nuclear components, and a disruption in cardiac-specific gene expression. Apoptosis has also been proposed as being involved in cardiac dysfunction. The purpose of this study was to determine if apoptosis might play a role in ADR-induced cardiomyopathy. Methods: Male Sprague-Dawley rats were separated into 2 groups: the control group (C group) and the experimental group (ADR 5 mg/wk for 3 weeks through intraperitoneal injections; A group). Echocardiographic images were obtained at week 3. Changes in caspase-3, B-cell leukemia/lymphoma (Bcl)-2, Bcl-2-associated X (Bax), interleukin (IL)-6, tumor necrosis factor-alpha, brain natriuretic peptide (BNP), troponin I, collagen 1, and collagen 3 protein expression from the left ventricle tissues of C and A group rats were determined by Western blot. Results: Ascites and heart failure as well as left ventricular hypertrophy were noted in the A group. Ejection fraction and shortening fraction were significantly lower in the A group by echocardiography. The expression of caspase 3, Bax, IL-6, BNP, collagen 1, and collagen 3 were significantly higher in the A group as compared with the C group. Protein expression of Bcl-2 decreased significantly in the A group compared with the C group. Conclusion: ADR induced an upregulation of caspase-3, Bax, IL-6, and collagen, as well as a depression in Bcl-2. Thus, apoptosis and fibrosis may play an important role in ADR-induced cardiomyopathy. PMID- 29234362 TI - Chinese Herbal Medicine as an Adjunctive Therapy Ameliorated the Incidence of Chronic Hepatitis in Patients with Breast Cancer: A Nationwide Population-Based Cohort Study. AB - We conducted a National Health Insurance Research Database-based Taiwanese nationwide population-based cohort study to evaluate whether Chinese herbal medicine (CHM) treatment decreased the incidence of chronic hepatitis in breast cancer patients receiving chemotherapy and/or radiotherapy. A total of 81171 patients were diagnosed with breast cancer within the defined study period. After randomly equal matching, data from 13856 patients were analyzed. Hazard ratios of incidence rate of chronic hepatitis were used to determine the influence and therapeutic potential of CHM in patients with breast cancer. The patients with breast cancer receiving CHM treatment exhibited a significantly decreased incidence rate of chronic hepatitis even across the stratification of age, CCI score, and treatments. The cumulative incidence of chronic hepatitis for a period of seven years after initial breast cancer diagnosis was also reduced in the patients receiving CHM treatment. The ten most commonly used single herbs and formulas were effective in protecting liver function in patients with breast cancer, where Hedyotis diffusa and Jia-Wei-Xiao-Yao-San were the most commonly used herbal agents. In conclusion, our study provided information that western medicine therapy combined with CHM as an adjuvant modality may have a significant impact on liver protection in patients with breast cancer. PMID- 29234363 TI - Shenfu Injection Adjunct with Platinum-Based Chemotherapy for the Treatment of Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis and Systematic Review. AB - Platinum-based chemotherapy is one of the standard treatments for non-small-cell lung cancer (NSCLC), while its high toxicity and limited clinical effects raise big concerns. Shenfu injection (SFI) has been commonly used as an adjutant chemotherapy drug for NSCLC in China. We ascertained the beneficial and adverse effects of SFI in combination with platinum-based chemotherapy for advanced NSCLC by using meta-analysis methods. The randomized controlled trials (RCTs) involving advanced NSCLC treatment with SFI plus platinum-based chemotherapy versus chemotherapy alone were searched on 6 medical databases up to February 2017. Cochrane handbook 5.1.0 was applied to assess the quality of included trials and RevMan 5.3 software was employed for data analysis. 23 RCTs including 1574 patients met our inclusion criteria. We evaluated the following outcome measures: objective tumor response (ORR), disease control rate (DCR), Karnofsky performance score (KPS), adverse effects, and indicators of cellular immune function. The meta-analysis indicated that SFI plus platinum-based chemotherapy may benefit the patients with NSCLC on attenuated synergies of chemotherapy. These findings need to be confirmed by further rigorously designed high-quality and large-scale RCTs. PMID- 29234364 TI - EGHB010, a Standardized Extract of Paeoniae Radix and Glycyrrhizae Radix, Inhibits VEGF-Induced Tube Formation In Vitro and Retinal Vascular Leakage and Choroidal Neovascularization In Vivo. AB - EGHB010 is a hot water extract of the rhizome mixture of Paeonia lactiflora Pallas and Glycyrrhiza uralensis Fisch. Choroidal neovascularization (CNV) and vascular leakage are the common pathophysiologies of age-related macular degeneration. In this study, we aimed to evaluate the effect of EGHB010 on retinal vascular leakage and laser-induced CNV in a rat model. Vascular endothelial growth factor- (VEGF-) induced tube formation was assayed in human retinal microvascular endothelial cells. Intravitreal VEGF-induced blood-retinal barrier breakdown was assayed in Sprague-Dawley rats. Experimental CNV was induced by laser photocoagulation in Brown Norway rats. EGHB010 (50 and 100 mg/kg/day) was administered orally for 10 days after laser photocoagulation. Choroidal flat mounts were prepared to measure the lesion size of CNV. Incubation of retinal vascular endothelial cells with EGHB010 (12.5 and 25 MUg/mL) resulted in the inhibition of VEGF-induced tube formation in a dose-dependent manner. VEGF mediated retinal vascular leakage was blocked by the oral administration of EGHB010. The CNV area was significantly lower in EGHB010-treated rats than in vehicle-treated rats. These results suggest that EGHB010 is a potent antiangiogenic agent. Thus, the oral administration of EGHB010 may have a beneficial effect in the treatment of vascular leakage and CNV in patients with age-related macular degeneration. PMID- 29234365 TI - Ethnopharmacological Uses, Phytochemistry, and Pharmacological Properties of Croton macrostachyus Hochst. Ex Delile: A Comprehensive Review. AB - Croton macrostachyus is widely used as herbal medicine by the indigenous people of tropical Africa. The potential of C. macrostachyus as herbal medicine, the phytochemistry, and pharmacological properties of its parts used as herbal medicines are reviewed. The extensive literature survey revealed that C. macrostachyus is traditionally used to treat or manage at least 81 human and animal diseases and ailments. The species is used as herbal medicine for diseases and ailments such as abdominal pains, cancer, gastrointestinal disorders, malaria, pneumonia, sexually transmitted infections, skin infections, typhoid, and wounds and as ethnoveterinary medicine. Multiple classes of phytochemicals such as alkaloids, amino acids, anthraquinones, carbohydrates, cardiac glycosides, coumarins, essential oil, fatty acids, flavonoids, phenolic compounds, phlobatannins, polyphenols, phytosteroides, saponins, sterols, tannins, terpenoids, unsaturated sterol, vitamin C, and withanoides have been isolated from the species. Pharmacological studies on C. macrostachyus indicate that it has a wide range of pharmacological activities such as anthelmintic, antibacterial, antimycobacterial, antidiarrhoeal, antifungal, anticonvulsant and sedative, antidiabetic, anti-inflammatory, antileishmanial, antioxidant, antiplasmodial, and larvicidal effects. Croton macrostachyus has potential as a possible source of a wide range of pharmaceutical products for the treatment of a wide range of both human and animal diseases and ailments. PMID- 29234366 TI - Antioxidant and Anti-Inflammatory Effects of Herbal Formula SC-E3 in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages. AB - SC-E3 is a novel herbal formula composed of five oriental medicinal herbs that are used to treat a wide range of inflammatory diseases in Korean traditional medicine. In this study, we sought to determine the effects of SC-E3 on free radical generation and inflammatory response in lipopolysaccharide- (LPS-) treated RAW 264.7 macrophages and the molecular mechanism involved. The ethanol extract of SC-E3 showed good free radical scavenging activity and inhibited LPS induced reactive oxygen species generation. SC-E3 significantly inhibited the production of the LPS-induced inflammatory mediators, nitric oxide and prostaglandin E2, by suppressing the expressions of inducible nitric oxide synthase and cyclooxygenase-2, respectively. SC-E3 also prevented the secretion of the proinflammatory cytokines, IL-1beta, TNF-alpha, and IL-6, and inhibited LPS-induced NF-kappaB activation and the mitogen-activated protein kinase (MAPK) pathway. Furthermore, SC-E3 induced the expression of heme oxygenase-1 (HO-1) by promoting the nuclear translocation and transactivation of Nrf2. Taken together, these results suggest that SC-E3 has potent antioxidant and anti-inflammatory effects and that these effects are due to the inhibitions of NF-kappaB and MAPK and the induction of Nrf2-mediated HO-1 expression in macrophages. These findings provide scientific evidence supporting the potential use of SC-E3 for the treatment and prevention of various inflammatory diseases. PMID- 29234367 TI - The Use of Herbal Remedies among Mothers of Young Children Living in the Central Appalachian Region. AB - Introduction: Women often use herbal remedies as a complement or alternative to traditional medicine. Guided by the Comprehensive Model of Information Seeking, this study examined use of herbal remedies among mothers of young children living in the Central Appalachian Region. Methods: A cross-sectional study was conducted among mothers of young children (n = 178). The outcome measure of interest was the use of any herbal remedy in the past six months. Two scales were developed to measure information seeking channels and to measure beliefs about the safety/efficacy of herbal remedies. Results: One-third reported using herbal remedies in the past six months, with fenugreek being the most common. Most reported using herbal remedies to increase breast milk production and to relieve cold/flu-like symptoms. Women scoring highest in information seeking channels were three times as likely to use herbal remedies. Women scoring highest in the beliefs about the safety/efficacy of herbal remedies were four times as likely to use herbal remedies. Conclusion: Herbal remedies are commonly used among women living in the Central Appalachian Region, a region with lower education and income level. Therefore, public health interventions about the types, safety, and efficacy of herbal remedies may improve health within this population. PMID- 29234368 TI - Mechanisms of P-Glycoprotein Modulation by Semen Strychni Combined with Radix Paeoniae Alba. AB - Semen Strychni has been extensively used as a Chinese herb, but its therapeutic window is narrowed by the strong toxicity of the compound, which limits its effectiveness. Radix Paeoniae Alba has been reported to reduce the toxic effects and increase the therapeutic effects of Semen Strychni, but the underlying mechanism remains unknown. This research aimed to explore the mechanism through which P-glycoprotein (P-gp) is modulated by Semen Strychni combined with Radix Paeoniae Alba in vitro. An MTT assay was used to study cytotoxicity in an MDCK MDR1 cell model. Rh123 efflux and accumulation were measured to assess P-gp function. The expression levels of MDR1 mRNA and P-gp protein in MDCK-MDR1 cells were investigated. A P-gp ATPase activity assay kit was applied to detect the effect on P-gp ATPase activity. Semen Strychni combined with Radix Paeoniae Alba could induce P-gp-mediated drug transport by inhibiting brucine and strychnine transport in MDCK-MDR1 cells, enhancing the P-gp efflux function, upregulating the P-gp expression and MDR1 mRNA levels, and stimulating P-gp ATPase activity. PMID- 29234369 TI - Bufei Yishen Granules Combined with Acupoint Sticking Therapy Suppress Inflammation in Chronic Obstructive Pulmonary Disease Rats: Via JNK/p38 Signaling Pathway. AB - The present study was initiated to explore the mechanism of the effects of Bufei Yishen granules combined with acupoint sticking therapy (Shu-Fei Tie) on inflammation regulated by c-Jun N-terminal kinase (JNK) and p38 MAPK signaling in COPD rats. Seventy-two rats were divided into healthy control (Control), Model, Bufei Yishen (BY), acupoint sticking (AS), Bufei Yishen + acupoint sticking (BY + AS), and aminophylline (APL) groups (n = 12 each). COPD rats were exposed to cigarette smoke and bacteria and were given the various treatments from weeks 9 through 20; all animals were sacrificed at the end of week 20. MCP-1, IL-2, IL-6, and IL-10 concentrations in BALF and lung tissue as well as JNK and p38 mRNA and protein levels in lung were measured. The results showed that all the four treatment protocols (BY, AS, BY + AS, and APL) markedly reduced the concentrations of IL-2, IL-6, and MCP-1 and levels of JNK and p38 MAPK mRNA, and the effects of Bufei Yishen granules combined with acupoint sticking therapy were better than acupoint sticking therapy only and aminophylline. In conclusion, the favorable effect of Bufei Yishen granules combined with Shu-Fei Tie may be due to decreased inflammation through regulation of the JNK/p38 signaling pathways. PMID- 29234370 TI - Electroacupuncture Improves Gastric Emptying in Critically Ill Neurosurgical Patients: A Pilot Study. AB - Objective: To compare the efficacy of combined electroacupuncture and metoclopramide treatment with that of metoclopramide only in improving gastric emptying in critically ill neurosurgical patients. Methods: In this prospective case-control pilot study, a total of 16 adult critically ill mechanically ventilated patients who were treated in the surgical intensive care unit were enrolled. Electrical stimulation was applied to 4 pairs of points (maximum intensity < 9.8 mA at 2 Hz). Patients in the control group received standard treatment with intravenous metoclopramide only. Patients in the experimental group received intravenous metoclopramide plus electroacupuncture treatment once daily for 6 consecutive days. Results: Gastric residual volume in the experimental group (n = 7) reduced gradually until the fourth day after treatment with electroacupuncture combined with routine metoclopramide administration. Beginning on the fourth day, residual volume was maintained at less than 200 ml per day for the following two days. In the control group (n = 9), there was a gradual reduction in residual volume during the first four days followed by a rebounding increase over the next two days. Conclusions: Electroacupuncture combined with intravenous metoclopramide is a more effective treatment for gastric emptying than metoclopramide alone in adult critically ill patients with impaired brain function. PMID- 29234371 TI - Correlation between Traditional Chinese Medicine Constitution and Dyslipidemia: A Systematic Review and Meta-Analysis. AB - Objective: To study the correlation between Traditional Chinese Medicine (TCM) constitution and dyslipidemia. Methods: CNKI, VIP, Wanfang database, CBMdisc, PubMed, and Embase were searched, and meta-analysis was performed by Review Manager 5.2 software. Results: Altogether 11 studies were included with 12890 individuals. The results showed that balanced constitution was a protective factor of dyslipidemia (OR = 0.62, 95% CI 0.47~0.82) while phlegm-dampness constitution was a risk factor of it (OR = 2.50, 95% CI 2.22~2.80), and the effect of phlegm-dampness constitution in South China (OR = 3.31, 95% CI 1.71~6.43) was more obvious than that in East (OR = 2.40, 95% CI 2.06~2.80) and North China (OR = 2.24, 95% CI 1.81~2.78). Conclusion: This study provides evidence for the prevention and treatment of dyslipidemia in TCM. However, most of the studies included are of moderate quality; more high quality, multicenter, large-sample studies are expected to provide higher level evidence. PMID- 29234372 TI - Hawthorn Leaf Flavonoids Protect against Diabetes-Induced Cardiomyopathy in Rats via PKC-alpha Signaling Pathway. AB - Objectives: DCM has become one of the main reasons of death in diabetic patients. In this study, we aimed to explore the hawthorn leaf flavonoids (HLF) protective effect against diabetes-induced cardiac injury and the underlying mechanisms in experimental rats. Methods: Experimental diabetic model was induced by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg) in rats after feeding with high-fat diet for 8 weeks. The diabetic rats received a 16-week treatment of different doses of HLF (50, 100, and 200). The morphological changes of myocardial cells were observed by light microscope; the concentration of antioxidant indicator and TNF-alpha and the expression of PKC-alpha mRNA, PKC alpha, and NF-kappaB proteins were assessed as well. Results: STZ-induced diabetes mellitus prompted blood glucose, cardiac injury, oxidative stress, and inflammation, accompanied with suppressed body weight. On the contrary, HLF administration improved body weight and blood glucose and attenuated myocardial structural abnormalities in diabetic rats. In addition, HLF decreased MDA level and enhanced SOD activities, inhibited TNF-alpha expression, and downregulated PKC-alpha mRNA, PKC-alpha, and NF-kappaB which were induced by diabetes. Conclusions: HLF has a protective effect against diabetic cardiomyopathy in rats. The mechanism may be involved in reducing oxidative stress and inflammation via inactivation of the PKC-alpha signaling pathway. PMID- 29234373 TI - Corrigendum to "Effect of Taichi Softball on Function-Related Outcomes in Older Adults: A Randomized Control Trial". AB - [This corrects the article DOI: 10.1155/2017/4585424.]. PMID- 29234375 TI - Kidney-Replenishing Herb Induces SOCS-3 Expression via ERK/MAPK Pathway and Improves Growth of the First-Trimester Human Trophoblast Cells. AB - Kidney-replenishing herb is a traditional medicine formula in China which has been widely used for clinical treatment of recurrent miscarriage. Our previous study showed that Kidney-replenishing herb could promote proliferation and inhibit apoptosis of the human first-trimester trophoblasts. In the present study, we further explored the potential mechanism and signal pathway of Kidney replenishing herb on human trophoblast cells. Our research showed that Kidney replenishing herb stimulated proliferation and reduced apoptosis of human trophoblast cells in vitro, and this appeared to be positive correlation with SOCS-3 transcription, suggesting that Kidney-replenishing herb regulated biological functions of human trophoblast cells by inducing SCOS-3 expression. Furthermore, the Kidney-replenishing herb treatment stimulated the phosphorylation of ERK1/2, and blocking the signaling pathway by mitogen activated protein MAPK (MEK) inhibitor, U0126, inhibited Kidney-replenishing herb induced SOCS-3 transcription, depressed proliferation, and promoted apoptosis of human trophoblasts. Kidney-replenishing herbs still induced ERK1/2 phosphorylation after SOCS-3 siRNA silence. Overexpression of SOCS-3 stimulated the proliferation of trophoblast. These findings suggest that SOCS-3 expression is induced by Kidney-replenishing herbs via activation of MAPK pathways, and this may possibly be involved in promoting human trophoblast cells growth which is contributed to embryo development. PMID- 29234374 TI - The Role of MAPK and Dopaminergic Synapse Signaling Pathways in Antidepressant Effect of Electroacupuncture Pretreatment in Chronic Restraint Stress Rats. AB - Acupuncture has demonstrated the function in ameliorating depressive-like behaviors via modulating PKA/CREB signaling pathway. To further confirm the antidepressant mechanism of EA on the mitogen-activated protein kinase (MAPK) and dopaminergic synapse signaling pathways, 4 target proteins were detected based on our previous iTRAQ analysis. Rats were randomly divided into control group, model group, and electroacupuncture (EA) group. Except for the control group, all rats were subjected to 28 days of chronic restraint stress (CRS) protocols to induce depression. In the EA group, EA pretreatment at Baihui (GV20) and Yintang (GV29) was performed daily (1 mA, 2 Hz, discontinuous wave, 20 minutes) prior to restraint. The antidepressant-like effect of EA was measured by body weight and open-field test. The protein levels of DAT, Th, Mapt, and Prkc in the hippocampus were examined by using Western blot. The results showed EA could ameliorate the depression-like behaviors and regulate the expression levels of Prkc and Mapt in CRS rats. The effect of EA on DAT and Th expression was minimal. These findings implied that EA pretreatment could alleviate depression through modulating MAPK signaling pathway. The role of EA on dopaminergic synapse signaling pathways needs to be further explored. PMID- 29234376 TI - Roles of Nitric Oxide and Prostaglandins in the Sustained Antihypertensive Effects of Acanthospermum hispidum DC. on Ovariectomized Rats with Renovascular Hypertension. AB - Although Acanthospermum hispidum is used in Brazilian folk medicine as an antihypertensive, no study evaluated its effects on a renovascular hypertension and ovariectomy model. So, this study investigated the mechanisms involved in the antihypertensive effects of an ethanol-soluble fraction obtained from A. hispidum (ESAH) using two-kidney-one-clip hypertension in ovariectomized rats (2K1C plus OVT). ESAH was orally administered at doses of 30, 100, and 300 mg/kg, daily, for 28 days, after 5 weeks of surgery. Enalapril (15 mg/kg) and hydrochlorothiazide (25 mg/kg) were used as standard drugs. Diuretic activity was evaluated on days 1, 7, 14, 21, and 28. Systolic, diastolic, and mean blood pressure and heart rate were recorded. Serum creatinine, urea, thiobarbituric acid reactive substances, nitrosamine, nitrite, aldosterone, vasopressin levels, and ACE activity were measured. The vascular reactivity and the role of nitric oxide (NO) and prostaglandins (PG) in the vasodilator response of ESAH on the mesenteric vascular bed (MVB) were also investigated. ESAH treatment induced an important saluretic and antihypertensive response, therefore recovering vascular reactivity in 2K1C plus OVT-rats. This effect was associated with a reduction of oxidative and nitrosative stress with a possible increase in the NO bioavailability. Additionally, a NO and PG-dependent vasodilator effect was observed on the MEV. PMID- 29234378 TI - Antibiofilm and Anti-Inflammatory Activities of Houttuynia cordata Decoction for Oral Care. AB - Dental biofilms that form in the oral cavity play a critical role in the pathogenesis of several infectious oral diseases, including dental caries, periodontal disease, and oral candidiasis. Houttuynia cordata (HC, Saururaceae) is a widely used traditional medicine, for both internal and external application. A decoction of dried HC leaves (dHC) has long been consumed as a health-promoting herbal tea in Japan. We have recently reported that a water solution of HC poultice ethanol extract (wHCP) exerts antimicrobial and antibiofilm effects against several important oral pathogens. It also exhibits anti-inflammatory effects on human keratinocytes. In our current study, we examined the effects of dHC on infectious oral pathogens and inflammation. Our results demonstrated that dHC exerts moderate antimicrobial effects against methicillin-resistant Staphylococcus aureus (MRSA) and other oral microorganisms. dHC also exhibited antibiofilm effects against MRSA, Fusobacterium nucleatum (involved in dental plaque formation), and Candida albicans and inhibitory effects on interleukin-8, CCL20, IP-10, and GROalpha productions by human oral keratinocytes stimulated by Porphyromonas gingivalis lipopolysaccharide (a cause of periodontal disease), without cytotoxic effects. This suggests that dHC exhibits multiple activities in microorganisms and host cells. dHC can be easily prepared and may be effective in preventing infectious oral diseases. PMID- 29234379 TI - The Instrument for Measuring the Implementation Situation of Traditional Chinese Medicine Guideline: Evaluation and Application. AB - Clinical practice guidelines play an important role in reducing the variations in clinical practices and improving the quality of care. To assess the real effect, measuring its implementation situation is needed. The implementation situation can be reflected by testing the consistency between the actual clinical practice and the guideline. We constructed an instrument to measure the implementation situation of Traditional Chinese Medicine (TCM) guideline through consistency testing. The main objectives of our study were to validate the instrument and evaluate the implementation situation of menopause syndrome guideline of TCM, using the data from the consistency test of comparing the medical records with the guideline. A total of 621 cases were included for data analysis. Cronbach's Alpha coefficient is 0.73. The model fit of 7 items in four dimensions was good (SRMR = 0.04; GFI = 0.97; NFI = 0.97; TLI = 0.96; CFI = 0.98; AGFI = 0.90). This instrument is of good reliability and validity. It can help the guideline developers to measure the implementation situation, find the reasons affecting the implementation, and revise the guideline. The method of using consistency test to measure the implementation situation may provide a sample for evaluating the guideline implementation in other fields. PMID- 29234377 TI - The Ethanol Extract of Licorice (Glycyrrhiza uralensis) Protects against Triptolide-Induced Oxidative Stress through Activation of Nrf2. AB - To investigate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2) in licorice ethanol extract (LEE) against triptolide- (TP-) induced hepatotoxicity, HepG2 cells were exposed to LEE (30, 60, and 90 mg.L-1) for 12 h and then treated with TP (50 nM) for 24 h. Besides, an acute liver injury model was established in ICR mice by a single dose of TP (1.0 mg.kg-1, i.p.). Relevant oxidant and antioxidant mediators were analyzed. TP led to an obvious oxidative stress as evidenced by increasing levels of ROS and decreasing GSH contents in HepG2 cells. In vitro results were likely to hold true in in vivo experiments. LEE protected against TP-induced oxidative stress in both in vitro and in vivo conditions. Furthermore, the decreased level of Nrf2 in the TP-treated group was observed. The mRNA levels of downstream genes decreased as well in ICR mice liver, whereas they increased in HepG2 cells. In contrast, LEE pretreatment significantly increased the level of Nrf2 and its downstream genes. LEE protects against TP-induced oxidative stress partly via the activation of Nrf2 pathway. PMID- 29234380 TI - Compression of the Fourth Ventricle Using a Craniosacral Osteopathic Technique: A Systematic Review of the Clinical Evidence. AB - Compression of the fourth ventricle (CV4) is a well-known osteopathic procedure, utilized by osteopaths, osteopathic physicians, craniosacral therapists, physical therapists, and manual therapists as part of their healthcare practice based on some evidence suggesting impact on nervous system functions. The main objective of the study was to identify randomized controlled trials (RCTs) assessing the clinical benefits of CV4 and to show the evidence supporting clinical prescriptions, guides, and advice in treating. A computerized search of the PubMed, CINAHL Complete, Scopus, Web of Science, and ScienceDirect databases was performed. Two filters were used (article type: RCTs; species: humans). The methodological quality of the trials was assessed using the Downs and Black quality checklist for healthcare intervention studies. Only six studies met the inclusion criteria, of which four were RCTs and two were observational studies. The Downs and Black score ranged from 17 to 24 points out of a maximum of 27 points. The present review revealed the paucity of CV4 research in patients with different clinical problems, as five out of six included studies investigated healthy adults. According to the results of the included studies, CV4 may be beneficial for patients with different functional problems. PMID- 29234382 TI - Biotechnological and Therapeutic Application of Useful Plants in Endocrinal Disorder. PMID- 29234381 TI - Antihyperglycemic, Antidiabetic, and Antioxidant Effects of Garcinia pedunculata in Rats. AB - The antihyperglycemic, antidiabetic, and antioxidant potentials of the methanolic extract of Garcinia pedunculata (GP) fruit in rats were investigated. The acute antihyperglycemic effect of different doses of GP was studied in normal male Wistar rats. Diabetes was induced by streptozotocin (STZ) injection in another cohort of male Wistar rats and they showed significantly higher blood glucose and glycated hemoglobin (HbA1c) levels, altered lipid profiles, and lower insulin levels compared to nondiabetic control animals. There were increased lipid peroxidation and reduced levels of cellular antioxidant enzymes in different tissues of diabetic rats. However, oral administration of GP extracts, especially the highest dose (1000 mg/kg), significantly ameliorated hyperglycemia (42%); elevated insulin levels (165%); decreased HbA1c (29.4%); restored lipid levels (reduction in TG by 25%, TC by 15%, and LDL-C by 75% and increase in HDL-C by 4%), liver and renal function markers, and lipid peroxidation (reduction by 52% in the liver, 39% in the kidney, 44% in the heart, and 46% in the pancreas); and stimulated tissue antioxidant enzymes to near normalcy. Overall, the findings suggest that GP fruit is effective against hyperglycemia and could be used in the treatment of diabetes and its complications and other oxidative stress-mediated pathological conditions. PMID- 29234383 TI - Goreisan Inhibits Upregulation of Aquaporin 4 and Formation of Cerebral Edema in the Rat Model of Juvenile Hypoxic-Ischemic Encephalopathy. AB - Secondary cerebral edema regulation is of prognostic significance in hypoxic ischemic encephalopathy (HIE), and aquaporin 4 (AQP4) plays an important role in the pathogenesis of cerebral edema. The traditional Japanese herbal medicine Goreisan relieves brain edema in adults; however, its effect and pharmacological mechanism in children are unknown. We investigated the effects of Goreisan on HIE associated brain edema and AQP4 expression in a juvenile rat model, established by combined occlusion of middle cerebral and common carotid arteries. Magnetic resonance imaging showed that the lesion areas were significantly smaller in the Goreisan- (2 g/kg) treated group than in the nontreated (saline) group at 24 and 48 h postoperatively. AQP4 mRNA levels in the lesion and nonlesion sides were significantly suppressed in the Goreisan group compared with the nontreated group 36 h postoperatively. Western blotting revealed that levels of AQP4 protein were significantly decreased in the Goreisan group compared with the nontreated group in the lesion side 72 h postoperatively, but not at 12 or 36 h. After 14 days, the Goreisan group had a significantly better survival rate. These findings suggest that Goreisan suppresses brain edema in HIE and improves survival in juvenile rats, possibly via regulation of AQP4 expression and function. PMID- 29234384 TI - Screening of Natural Bioactive Metabolites and Investigation of Antioxidant, Antimicrobial, Antihyperglycemic, Neuropharmacological, and Cytotoxicity Potentials of Litsea polyantha Juss. Ethanolic Root Extract. AB - This study was designed to identify some bioactive phytochemicals from ethanolic extract of roots of Litsea polyantha and to evaluate some of its pharmacological activities. Phytochemical tests indicated the presence of reducing sugar, combined reducing sugar, tannins, flavonoids, alkaloids, terpenoids, and phenol. In the antioxidant assay using 2-diphenyl-1-picryl-hydrazyl (DPPH) free radical scavenging method, the IC50 value was found to be 82.31 MUg/mL. Total content of phenolic compounds, flavonoid, and tannin was found to be 152.69 mg GAE/gm, 85.60 mg QE/gm, and 77.22 mg GAE/gm of dry extract, respectively. In disc diffusion antibacterial assay, the extract exhibited highest zone of inhibition up to 12.25 mm against Escherichia coli at the concentration of 500 MUg/disc. For brine shrimp lethality bioassay, the extract exhibited LC50 56.082 MUg/mL. In in vivo antihyperglycemic activity test by oral glucose tolerance test using Swiss Albino mice at the oral dose of 250 and 500 mg/kg, the extract showed statistically significant antihyperglycemic effect. Finally, in vivo, the extract exhibited the dose dependent CNS depressant effects by reducing the locomotors of Swiss Albino mice which was confirmed through three different neuropharmacological activity tests such as open field, hole cross, and hole board test. PMID- 29234385 TI - The Immediate Analgesic Effect of Acupuncture for Pain: A Systematic Review and Meta-Analysis. AB - Although acupuncture is gaining popularity for the treatment of nonspecific pain, the immediate analgesic effect of acupuncture has never been reviewed. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) on disease-related pain to critically evaluate the immediate effect of acupuncture for pain relief. The PubMed and Cochrane Central Register of Controlled Trials databases as well as three Chinese databases including the China National Knowledge Infrastructure (CNKI), Wanfang, and VIP platforms were searched through November 2016. The outcome was the extent of pain relief from baseline within 30 min of the first acupuncture treatment. We evaluated all RCTs comparing acupuncture with other interventions for disease-related pain. Real acupuncture showed statistically significantly greater pain relief effect compared to sham acupuncture (SMD, -0.56; 95% confidence interval [CI], -1.00 to 0.12; 9 RCTs) and analgesic injection (SMD, -1.33; 95% CI, -1.94 to -0.72; 3 RCTs). No serious adverse events were documented. Acupuncture was associated with a greater immediate pain relief effect compared to sham acupuncture and analgesic injections. Further RCTs with stricter design and methodologies are warranted to evaluate the immediate pain relief effect of acupuncture for more disease-related pain. PMID- 29234386 TI - Neuroprotective Effect of Modified Xijiao Dihuang Decoction against Oxygen Glucose Deprivation and Reoxygenation-Induced Injury in PC12 Cells: Involvement of TLR4-MyD88/NF-kappaB Signaling Pathway. AB - Modified Xijiao Dihuang (XJDH) decoction has been shown to exert powerful neuroprotective properties in clinical ischemic stroke treatment. It consists of 4 Chinese herbs: Buffalo Horn, Paeonia suffruticosa Andrews, Rehmannia glutinosa (Gaertn.) DC, and Paeonia lactiflora Pall. In the present study, the neuroprotective effect and specific mechanisms of XJDH in protecting PC12 cells from oxygen-glucose deprivation-induced injury were investigated. It was found that OGD/R significantly decreased the cell viability and lactate dehydrogenase (LDH) activity and increased the release of IL-1beta, IL-6, and TNF-alpha in PC12 cells, and these effects were suppressed by XJDH and one of its major active constituents, paeoniflorin. Additionally, XJDH inhibited caspase-3 activity and reduced cleaved caspase-3 level. Mechanistic studies showed that the expressions of TLR4, MyD88, TRAF6, and NF-kappaB p65 and phosphorylation of IkappaBalpha and p65 were significantly lower in the XJDH-treated group than in the OGD/R control group. Additionally, XJDH reversed the OGD/R-induced increases in p-JNK and p ERK1/2 expression. These results suggest that XJDH protects PC12 cells from oxygen-glucose deprivation-induced injury, which may be associated with the inhibition of the TLR4-MyD88/NF-kappaB signaling pathway. As an anti-inflammation factor, XJDH might be used as a neuronal protection strategy for the ischemia injury and related diseases. PMID- 29234387 TI - Antioxidant Activity of a Geopropolis from Northeast Brazil: Chemical Characterization and Likely Botanical Origin. AB - Geopropolis is a product containing wax, plant resin, and soil particles. It is elaborated by stingless bees of tribe Meliponini. Methanol extracts of sample of geopropolis produced by Scaptotrigona postica ("mandaguari") in the state of Rio Grande do Norte (RN, northeast Brazil) were analyzed for the determination of standard parameters (total phenols, total flavonoids, and radical scavenging activity) and chemical characterization by HPLC-DAD-MS/MS analysis. The sample analyzed has high contents of total phenols and flavonoids, as well as high antioxidant activity. The constituents characterized were mainly flavonols, such as quercetin methyl ethers, and methoxychalcones. Such chemical profile is similar to the composition of a green propolis from the same area of RN, which is produced by Africanized Apis mellifera, using shoot apices of Mimosa tenuiflora, popularly known as "jurema-preta." This finding provides evidence that "mandaguari" geopropolis and honeybee propolis have the same botanical origin in RN. The sharing of a plant resin source by phylogenetically distant bees (Apinae and Meliponinae) suggests that bee genetic factors play little role in the choice of plants for resin collection and that the availability of potential botanical sources plays a decisive role. PMID- 29234388 TI - The Effects of Aqueous Extract from Nardostachys chinensis Batalin on Blood Pressure and Cardiac Hypertrophy in Two-Kidney One-Clip Hypertensive Rats. AB - Aims: The aim of this study was to investigate the effects of the aqueous extract of Nardostachys chinensis Batalin (NCBAE) on blood pressure and cardiac hypertrophy using two-kidney one-clip (2K1C) hypertensive rats. Methods: 2K1C rat models were set up by clipping the left renal artery. Sham-operated rats underwent the same surgical procedure except for renal arterial clipping. 2K1C hypertensive rats were orally given NCBAE at doses of 210, 420, and 630 mg.kg-1.d 1 for 6 weeks. Twelve weeks after surgery, rat SBP and echocardiographic parameters were measured, cardiac histopathology was assessed, serum NO and LDH were detected, and the expression of Bcl-2 and caspase-3 of left ventricular tissue was assessed by western blot. Results: Treatment with NCBAE resulted in a decrease of SBP, LVPWd, LVPWs, IVSd, IVSs, LVW/BW ratio, and cardiomyocyte CSA, an increase of LVEF, and inhibition of 2K1C-induced reduction in serum NO and elevation of LDH compared with 2K1C group. NCBAE intervention also showed a significant increase of Bcl-2 expression and reduction of cleaved caspase-3 level dose-dependently in left ventricular tissue. Conclusion: Our data demonstrate that NCBAE has an antihypertensive property and protective effect on 2K1C-induced cardiac hypertrophy especially at the dose of 630 mg.kg-1.d-1. PMID- 29234389 TI - Rapid Screening of Chemical Constituents in Rhizoma Anemarrhenae by UPLC-Q-TOF/MS Combined with Data Postprocessing Techniques. AB - Rhizoma Anemarrhenae, a famous traditional Chinese medicine (TCM), is the dried rhizome of Anemarrhena asphodeloides Bge. (Anemarrhena Bunge of Liliaceae). The medicine presents anti-inflammatory, antipyretic, sedative, and diuretic effects. The chemical constituents of Rhizoma Anemarrhenae are complex and diverse, mainly including steroidal saponins, flavonoids, phenylpropanoids, benzophenones, and alkaloids. In this study, UPLC-Q-TOF/MS was used in combination with data postprocessing techniques, including characteristic fragments filter and neutral loss filter, to rapidly classify and identify the five types of substances in Rhizoma Anemarrhenae. On the basis of numerous literature reviews and according to the corresponding characteristic fragments produced by different types of compounds in combination with neutral loss filtering, we summarized the fragmentation patterns of the main five types of compounds and successfully screened and identified 32 chemical constituents in Rhizoma Anemarrhenae. The components included 18 steroidal saponins, 6 flavonoids, 4 phenylpropanoids, 2 alkaloids, and 2 benzophenones. The method established in this study provided necessary data for the study on the pharmacological effects of Rhizoma Anemarrhenae and also provided the basis for the chemical analysis and quality control of TCMs to promote the development of a method for chemical research on TCMs. PMID- 29234390 TI - Astragaloside IV Ameliorates Airway Inflammation in an Established Murine Model of Asthma by Inhibiting the mTORC1 Signaling Pathway. AB - Astragaloside IV (AS-IV), a main active constituent of Astragalus membranaceus, has been confirmed to have antiasthmatic effects. However, it remained unclear whether the beneficial effects of AS-IV on asthma were attributed to the mTOR inhibition; this issue was the focus of the present work. BALB/c mice were sensitized and challenged with ovalbumin followed with 3 weeks of rest/recovery and then reexposure to ovalbumin. AS-IV was administrated during the time of rest and reexposure. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokines (IL-4, IL-5, IL-13, IL-17, and INF gamma), and CD4+CD25+Foxp3+Treg cells in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling were examined. AS-IV markedly suppressed airway hyperresponsiveness and reduced IL-4, IL-5, and IL-17 levels and increased INF-gamma levels in the BALF. Histological studies showed that AS IV markedly decreased inflammatory infiltration in the lung tissues. Notably, AS IV inhibited mTORC1 activity, whereas it had limited effects on mTORC2, as assessed by phosphorylation of mTORC1 and mTORC2 substrates S6 ribosomal protein, p70 S6 Kinase, and Akt, respectively. CD4+CD25+Foxp3+Treg cells in BALF were not significantly changed by AS-IV. Together, these results suggest that the antiasthmatic effects of AS-IV were at least partially from inhibiting the mTORC1 signaling pathway. PMID- 29234391 TI - Antidiarrheal Activity of Dissotis multiflora (Sm) Triana (Melastomataceae) Leaf Extract in Wistar Rats and Subacute Toxicity Evaluation. AB - The present work was undertaken to evaluate antidiarrheal activity of ethanolic leaf extract of Dissotis multiflora (Sm) Triana (D. multiflora) on Shigella flexneri-induced diarrhea in Wistar rats and its subacute toxicity. Diarrhea was induced by oral administration of 1.2 * 109 cells/mL S. flexneri to rats. Antidiarrheal activity was investigated in rats with the doses of 111.42 mg/kg, 222.84 mg/kg, and 445.68 mg/kg. The level of biochemical parameters was assessed and organs histology examined by 14 days' subacute toxicity. S. flexneri stool load decreased significantly in dose-dependent manner. The level of ALT increased (p < 0.05) in male rats treated with the dose of 445.68 mg/kg while creatinine level increased in rats treated with both doses. In female rats, a significant decrease (p < 0.05) of the level of AST and creatinine was noted in rats treated with the dose of 222.84 mg/kg of D. multiflora. Histological exams of kidney and liver of treated rats showed architectural modifications at the dose of 445.68 mg/kg. This finding suggests that D. multiflora leaf extract is efficient against diarrhea caused by S. flexneri but the treatment with doses lower than 222.84 mg/kg is recommended while further study is required to define the exact efficient nontoxic dose. PMID- 29234392 TI - 1H NMR-Based Metabonomic Study of Functional Dyspepsia in Stressed Rats Treated with Chinese Medicine Weikangning. AB - 1H NMR-based metabolic profiling combined with multivariate data analysis was used to explore the metabolic phenotype of functional dyspepsia (FD) in stressed rats and evaluate the intervention effects of the Chinese medicine Weikangning (WKN). After a 7-day period of model establishment, a 14-day drug administration schedule was conducted in a WKN-treated group of rats, with the model and normal control groups serving as negative controls. Based on 1H NMR spectra of urine and serum from rats, PCA, PLS-DA, and OPLS-DA were performed to identify changing metabolic profiles. According to the key metabolites determined by OPLS-DA, alterations in energy metabolism, stress-related metabolism, and gut microbiota were found in FD model rats after stress stimulation, and these alterations were restored to normal after WKN administration. This study may provide new insights into the relationship between FD and psychological stress and assist in research into the metabolic mechanisms involved in Chinese medicine. PMID- 29234393 TI - Reduced MLH3 Expression in the Syndrome of Gan-Shen Yin Deficiency in Patients with Different Diseases. AB - Traditional Chinese medicine formulates treatment according to body constitution (BC) differentiation. Different constitutions have specific metabolic characteristics and different susceptibility to certain diseases. This study aimed to assess the characteristic genes of gan-shen Yin deficiency constitution in different diseases. Fifty primary liver cancer (PLC) patients, 94 hypertension (HBP) patients, and 100 diabetes mellitus (DM) patients were enrolled and classified into gan-shen Yin deficiency group and non-gan-shen Yin deficiency group according to the body constitution questionnaire to assess the clinical manifestation of patients. The mRNA expressions of 17 genes in PLC patients with gan-shen Yin deficiency were different from those without gan-shen Yin deficiency. However, considering all patients with PLC, HBP, and DM, only MLH3 was significantly lower in gan-shen Yin deficiency group than that in non-gen shen Yin deficiency. By ROC analysis, the relationship between MLH3 and gan-shen Yin deficiency constitution was confirmed. Treatment of MLH3 (-/- and -/+) mice with Liuweidihuang wan, classical prescriptions for Yin deficiency, partly ameliorates the body constitution of Yin deficiency in MLH3 (-/+) mice, but not in MLH3 (-/-) mice. MLH3 might be one of material bases of gan-shen Yin deficiency constitution. PMID- 29234394 TI - Predictors of Traditional Medical Practices in Illness Behavior in Northwestern Ethiopia: An Integrated Model of Behavioral Prediction Based Logistic Regression Analysis. AB - This study aimed at investigating traditional medical beliefs and practices in illness behavior as well as predictors of the practices in Gondar city, northwestern Ethiopia, by using the integrated model of behavioral prediction. A cross-sectional quantitative survey was conducted to collect data through interviewer administered structured questionnaires from 496 individuals selected by probability proportional to size sampling technique. Unadjusted bivariate and adjusted multivariate logistic regression analyses were performed, and the results indicated that sociocultural predictors of normative response and attitude as well as psychosocial individual difference variables of traditional understanding of illness causation and perceived efficacy had statistically significant associations with traditional medical practices. Due to the influence of these factors, majority of the study population (85%) thus relied on both herbal and spiritual varieties of traditional medicine to respond to their perceived illnesses, supporting the conclusion that characterized the illness behavior of the people as mainly involving traditional medical practices. The results implied two-way medicine needs to be developed with ongoing research, and health educations must take the traditional customs into consideration, for integrating interventions in the health care system in ways that the general public accepts yielding a better health outcome. PMID- 29234395 TI - The Effect of Dongeui Qigong for Prehypertension and Mild Essential Hypertension. AB - Although several previous studies have reported the effect of qigong on lowering blood pressure, rigorous trials are lacking. Studies evaluating the effect of qigong on prehypertension are also scarce. This study aimed to assess the effect of qigong on prehypertension and mild hypertension. Participants with prehypertension or mild hypertension were randomized to the Dongeui qigong group or a nontreated control group. In the qigong group, Dongeui qigong was administered 5 times/week for 12 weeks. The control group did not receive any intervention for blood pressure control. Fifty-two participants were included in this study. Even though diastolic blood pressure was significantly reduced in the qigong group after 8 weeks (p = 0.04) compared to baseline, the difference in change in blood pressure between the qigong and control groups was not significant. There were no significant differences in quality of life between the qigong and control groups. Dongeui qigong is not significantly effective in pre/mild hypertension compared with controls. This result could be due to a lack of effect of qigong or caused by other factors, such as the type of qigong, target symptoms, inappropriate sample size, and compliance of participants. Trial Registration. This trial is registered with KCT0001397 (Clinical Research Information Service). PMID- 29234396 TI - Analgesic Effect of Moxibustion with Different Temperature on Inflammatory and Neuropathic Pain Mice: A Comparative Study. AB - The aim of this study was to determine whether variation of temperature during moxibustion would generate division of analgesic effect. The moxibustion with different temperatures (37 degrees C, 42 degrees C, 47 degrees C, and 52 degrees C) was applied to ST36 acupoint for 30 minutes in chronic inflammatory or neuropathic pain mice. The analgesic effect was evaluated by thermal hyperalgesia test in chronic inflammatory pain and by mechanical allodynia in neuropathic pain, respectively. The results indicated that interventions of moxibustion with different temperature caused different analgesic effect on either chronic inflammatory induced by injection of complete Freund's adjuvant (CFA) or neuropathic pain induced by spared nerve injury (SNI). In chronic inflammatory pain, different moxibustion temperature generated different intensity of analgesic effect: the higher the better. In chronic neuropathic pain, stronger analgesic effect was found in moxibustion with temperature 47 degrees C or 52 degrees C other than 37 degrees C and 42 degrees C. However, there is no significant difference displayed between moxibustion temperatures 47 degrees C and 52 degrees C or 37 degrees C and 42 degrees C. It implies that the temperature should be taken into account for moxibustion treatment to chronic inflammatory or neuropathic pain. PMID- 29234397 TI - Artemisia iwayomogi plus Curcuma longa Synergistically Ameliorates Nonalcoholic Steatohepatitis in HepG2 Cells. AB - The combination of Artemisia iwayomogi and Curcuma longa radix is frequently prescribed for liver diseases in TKM. However, the synergic effects of the two herbs on nonalcoholic steatohepatitis (NASH) have not yet been studied. Therefore, we investigated the anti-NASH effects of the water extract of A. iwayomogi (AI), C. longa radix (CL), and combination of the two herbs (ACE). Hepatic steatosis and NASH were induced in HepG2 cells by treatment with palmitic acid (PA, for 6 h) with/without pretreatment of ACE (25 or 50 MUg/mL), AI (50 or 100 MUg/mL), CL (50 or 100 MUg/mL), curcumin (5 MUg/mL), or scopoletin (5 MUg/mL). The PA treatment (200 MUM) drastically altered intracellular triglyceride levels, total cholesterol, and expression levels of genes related to lipid metabolism (CD36, SREBP1c, PPAR-gamma, and PPAR-alpha), whereas pretreatment with ACE significantly attenuated these alterations. ACE also protected HepG2 cells from PA- (300 MUM-) induced endoplasmic reticulum (ER) stress and apoptosis and attenuated the related key molecules including GRP78, eIF2, and CHOP, respectively. In conclusion, we found synergic effects of A. iwayomogi and C. longa on NASH, supporting the clinical potential for fatty liver disorders. In addition, modulation of ER stress-relative molecules would be involved in its underlying mechanism. PMID- 29234398 TI - Review on Research about Traditional Chinese Medicine in Cancer Stem Cell. AB - Cancer stem cells (CSCs) are small subpopulations of neoplastic cells within a tumor, which have self-renewal and differentiation abilities and could generate new tumors with few cells. Researches have showed that CSCs are considered the most likely reason for cancer recurrence and metastasis. Accumulating evidences have showed that traditional Chinese medicine (TCM) has significant effect on CSCs. It could inhibit the proliferation, self-renew, and multidifferentiation of CSCs. We aimed to summarize the theories of CSCs in TCM, the inhibitory effect, and the pathway on CSCs of TCM. This review will provide potential new strategies and alternative perspectives for CSCs treatments and basic research into complementary and alternative medicine. PMID- 29234399 TI - Antimicrobial Activities and Time-Kill Kinetics of Extracts of Selected Ghanaian Mushrooms. AB - The rapid rise of antimicrobial resistance is a worldwide problem. This has necessitated the need to search for new antimicrobial agents. Mushrooms are rich sources of potential antimicrobial agents. This study investigated the antimicrobial properties of methanol extracts of Trametes gibbosa, Trametes elegans, Schizophyllum commune, and Volvariella volvacea. Agar well diffusion, broth microdilution, and time-kill kinetic assays were used to determine the antimicrobial activity of the extracts against selected test organisms. Preliminary mycochemical screening revealed the presence of tannins, flavonoids, triterpenoids, anthraquinones, and alkaloids in the extracts. Methanol extracts of T. gibbosa, T. elegans, S. commune, and V. volvacea showed mean zone of growth inhibition of 10.00 +/- 0.0 to 21.50 +/- 0.84, 10.00 +/- 0.0 to 22.00 +/- 1.10, 9.00 +/- 0.63 to 21.83 +/- 1.17, and 12.00 +/- 0.0 to 21.17 +/- 1.00 mm, respectively. The minimum inhibitory concentration of methanol extracts of T. gibbosa, T. elegans, S. commune, and V. volvacea ranged from 4.0 to 20, 6.0 to 30.0, 8.0 to 10.0, and 6.0 to 20.0 mg/mL, respectively. Time-kill kinetics studies showed that the extracts possess bacteriostatic action. Methanol extracts of T. gibbosa, T. elegans, S. commune, and V. volvacea exhibited antimicrobial activity and may contain bioactive compounds which may serve as potential antibacterial and antifungal agents. PMID- 29234400 TI - Effect of Acupotomy on FAK-PI3K Signaling Pathways in KOA Rabbit Articular Cartilages. AB - Objective: By observing the needle-knife of KOA rabbit morphology, knee joint cartilage p-FAK, p-PI3K, Aggrecan gene, and protein expression, to study the effect of needle-knife to promote cartilage cell synthesis metabolism mechanism. Method: 49 male New Zealand rabbits, randomly divided into normal group (Z), model group (M), model-inhibitors (MP), needle-knife group (D), needle-knife inhibitors group (DP), electroacupuncture group (E), and electroacupuncture inhibitors (EP). RT-PCR and Western Blot were used to test each animal cartilage p-FAK, p-PI3K, and Aggrecan gene and protein expression level. Results: Compared with N group, p-FAK and p-PI3K protein and mRNA expression of M group, D group, and E group increased (P < 0.05), while the protein and mRNA expression of Aggrecan reduced (P < 0.05). Compared with M group, p-FAK, p-PI3K, Aggrecan protein, and mRNA of E and D group increased (P < 0.05). Compared with E group, p FAK, p-PI3K, Aggrecan protein, and mRNA expression of D group increased (P < 0.05); after adding inhibitors, p-FAK, p-PI3K, Aggrecan protein, and mRNA expression reduced (P < 0.05). Conclusion: Needle-knife therapy can promote the repairment of cartilage cells by activating FAK-PI3K signaling pathways, promoting the synthesis of cartilage cell metabolism. PMID- 29234401 TI - trans-Cinnamaldehyde Inhibits Microglial Activation and Improves Neuronal Survival against Neuroinflammation in BV2 Microglial Cells with Lipopolysaccharide Stimulation. AB - Background: Microglial activation contributes to neuroinflammation and neuronal damage in neurodegenerative disorders including Alzheimer's and Parkinson's diseases. It has been suggested that neurodegenerative disorders may be improved if neuroinflammation can be controlled. trans-cinnamaldehyde (TCA) isolated from the stem bark of Cinnamomum cassia possesses potent anti-inflammatory capability; we thus tested whether TCA presents neuroprotective effects on improving neuronal survival by inhibiting neuroinflammatory responses in BV2 microglial cells. Results: To determine the molecular mechanism behind TCA-mediated neuroprotective effects, we assessed the effects of TCA on lipopolysaccharide- (LPS-) induced proinflammatory responses in BV2 microglial cells. While LPS potently induced the production and expression upregulation of proinflammatory mediators, including NO, iNOS, COX-2, IL-1beta, and TNF-alpha, TCA pretreatment significantly inhibited LPS-induced production of NO and expression of iNOS, COX-2, and IL 1beta and recovered the morphological changes in BV2 cells. TCA markedly attenuated microglial activation and neuroinflammation by blocking nuclear factor kappa B (NF-kappaB) signaling pathway. With the aid of microglia and neuron coculture system, we showed that TCA greatly reduced LPS-elicited neuronal death and exerted neuroprotective effects. Conclusions: Our results suggest that TCA, a natural product, has the potential of being used as a therapeutic agent against neuroinflammation for ameliorating neurodegenerative disorders. PMID- 29234402 TI - Extract of Fructus Cannabis Ameliorates Learning and Memory Impairment Induced by D-Galactose in an Aging Rats Model. AB - Hempseed (Cannabis sativa L.) has been used as a health food and folk medicine in China for centuries. In the present study, we sought to define the underlying mechanism by which the extract of Fructus Cannabis (EFC) protects against memory impairment induced by D-galactose in rats. To accelerate aging and induce memory impairment in rats, D-galactose (400 mg/kg) was injected intraperitoneally once daily for 14 weeks. EFC (200 and 400 mg/kg) was simultaneously administered intragastrically once daily in an attempt to slow the aging process. We found that EFC significantly increased the activity of superoxide dismutase, while lowering levels of malondialdehyde in the hippocampus. Moreover, EFC dramatically elevated the organ indices of some organs, including the heart, the liver, the thymus, and the spleen. In addition, EFC improved the behavioral performance of rats treated with D-galactose in the Morris water maze. Furthermore, EFC inhibited the activation of astrocytes and remarkably attenuated phosphorylated tau and suppressed the expression of presenilin 1 in the brain of D-galactose treated rats. These findings suggested that EFC exhibits beneficial effects on the cognition of aging rats probably by enhancing antioxidant capacity and anti neuroinflammation, improving immune function, and modulating tau phosphorylation and presenilin expression. PMID- 29234403 TI - Response Surface Optimisation for the Production of Antioxidant Hydrolysates from Stone Fish Protein Using Bromelain. AB - Protein hydrolysates produced from different food sources exhibit therapeutic potential and can be used in the management of chronic diseases. This study was targeted to optimise the conditions for the hydrolysis of stone fish protein to produce antioxidant hydrolysates using central composite design (CCD) by response surface methodology (RSM). The stone fish protein was hydrolysed under the optimum predicted conditions defined by pH (6.5), temperature (54 degrees C), E/S ratio (1.5%), and hydrolysis time (360 min). The hydrolysates were then evaluated for 2,2-diphenyl-1-picrylhydrazyl radical (DPPH*) scavenging activity and ferrous ion- (Fe2+-) chelating activity. Results validation showed no significant difference between the experimental values of DPPH* scavenging activity (48.94%) and Fe2+-chelating activity (25.12%) obtained at 54.62% degree of hydrolysis (DH) compared to their corresponding predicted values of 49.79% and 24.08% at 53.08% DH, respectively. The hydrolysates demonstrated non-Newtonian behavior (n < 1) with stronger shear-thinning effect and higher viscosities at increasing concentration. Thus, RSM can be considered as a promising strategy to optimise the production of stone fish protein hydrolysates containing antioxidant peptides. It is hoped that this finding will enhance the potential of stone fish protein hydrolysates (SHs) as therapeutic bioactive ingredient in functional foods development. PMID- 29234404 TI - Modernization Trends of Infertility Treatment of Traditional Korean Medicine. AB - Despite the development of assisted reproductive technology (ART), it is difficult to increase the implantation rate. In Korea, Traditional Korean Medicine, including herbal medicine, is an important component of infertility treatment. Korean medical doctors who are treating infertility often use herbal medicine to promote implantation. In this article, as one of the research works on modernization of Traditional Korean Medicine, we investigated the experimental studies to clarify the effects of herbal medicines that are traditionally used to promote pregnancy. We searched for experimental studies over the past 10 years of improvement of endometrial receptivity in herbal medicine using six domestic and international sites. We analyzed 11 studies that meet the selection criteria. We found that herbal medicines demonstrably improved endometrial receptivity and increased pregnancy rates. PMID- 29234405 TI - Qingchang Wenzhong Decoction Attenuates DSS-Induced Colitis in Rats by Reducing Inflammation and Improving Intestinal Barrier Function via Upregulating the MSP/RON Signalling Pathway. AB - Ulcerative colitis (UC) is a chronic, nonspecific, inflammatory disease for which an effective treatment is lacking. Our previous study found that Qingchang Wenzhong Decoction (QCWZD) can significantly improve the clinical symptoms of UC and ameliorate dextran sulphate sodium- (DSS-) induced ulcerative colitis in rats by downregulating the IP10/CXCR3 axis-mediated inflammatory response. The purpose of the present study was to further explore the mechanism of QCWZD for UC in rats models, which were established by 7-day administration of 4.5% dextran sulphate sodium solution. QCWZD was administered daily for 7 days; then we determined the serum macrophage-stimulating protein concentration (MSP) and recepteur d'origine nantais (RON) expression and its downstream proteins (protein kinase B [Akt], phosphorylated [p] Akt, occludin, zona occluden- [ZO-] 1, and claudin-2) in colon tissue using Western blotting and quantitative polymerase chain reaction. In DSS induced UC, QCWZD significantly alleviated colitis-associated inflammation, upregulated serum MSP expression and RON expression in the colon, reduced the pAkt levels, promoted colonic occluding and ZO-1 expression, and depressed claudin-2 expression. In conclusion, the MSP/RON signalling pathway plays an important role in the pathogenesis of UC by involving the inflammatory response and improving intestinal barrier function. QCWZD appears to attenuate DSS-induced UC in rats by upregulating the MSP/RON signalling pathway. PMID- 29234406 TI - Amelioration of Scopolamine-Induced Learning and Memory Impairment by alpha Pinene in C57BL/6 Mice. AB - Increasing evidence suggests that neurodegenerative disorders such as Alzheimer's disease (AD) are mediated via disruption of cholinergic neurons and enhanced oxidative stress. Therefore, attention has been focused on searching for antioxidant phytochemicals for the prevention and/or treatment of AD through their ability to fortify cholinergic function and antioxidant defense capacity. In this study, we have investigated the neuroprotective effect of alpha-pinene (APN) against learning and memory impairment induced by scopolamine (SCO, 1 mg/kg, i.p.), a muscarinic receptor antagonist in C57BL/6 mice. Administration of APN (10 mg/kg, i.p.) significantly improved SCO-induced cognitive dysfunction as assessed by Y-maze and passive avoidance tests. In Morris water-maze test, APN effectively shortened the mean escape latency to find the hidden platform during training days. To further elucidate the molecular mechanisms underlying the neuroprotective effect of APN, the expression of proteins involved in the acetylcholine metabolism and antioxidant system was examined. Particularly, APN treatment increased mRNA expression of choline acetyltransferase in the cortex and protein levels of antioxidant enzymes such as heme oxygenase-1 and manganese superoxide dismutase in the hippocampus via activation of NF-E2-related factor 2. These findings suggest the possible neuroprotective potentials of APN for the management of dementia with learning and memory loss. PMID- 29234407 TI - Jinhong Tablet Reduces Damage of Intestinal Mucosal Barrier in Rats with Acute Biliary Infection via Bcl-2/Bax mRNA and Protein Regulation. AB - Objective: To explore the effects and mechanism of Jinhong Tablet on intestinal mucosal barrier function and SIRS in rats with acute biliary infection. Methods: 36 SD male rats were divided into three groups: sham operation (control), acute biliary infection (ABI) model, and Jinhong Tablet (Jinhong) group. Jinhong group were force-fed with Jinhong Tablet, while the other two groups received oral saline. At days 3 and 5, morphological changes of intestinal mucosa were assessed. Serum diamine oxidase (DAO), D-lactate, and endotoxin levels were measured. And the genes bcl-2 and bax in intestinal tissues were tested by real time PCR and Western blotting. Results: Intestinal damage was significantly less severe in Jinhong group compared with ABI group, as indicated by Chiu's scoring, TUNEL analysis, and serum DAO, D-lactic acid, and endotoxin levels. Additionally, the expression of bax mRNA and protein was decreased and the ratio of bcl-2/bax mRNA and protein was increased compared with ABI group. Conclusion: Jinhong Tablet had a positive intervention on acute biliary infection through improving inflammation and intestinal mucosal barrier, inhibiting excessive apoptosis of intestinal epithelial cells via bax and bcl-2 gene, and protein regulation. PMID- 29234408 TI - Does the Fragrance of Essential Oils Alleviate the Fatigue Induced by Exercise? A Biochemical Indicator Test in Rats. AB - Objective: To study the effect of the essential oils of Citrus sinensis L., Mentha piperita L., Syzygium aromaticum L., and Rosmarinus officinalis L. on physical exhaustion in rats. Methods: Forty-eight male Wistar rats were randomly divided into a control group, a fatigue group, an essential oil mixture (EOM) group, and a peppermint essential oil (PEO) group. Loaded swimming to exhaustion was used as the rat fatigue model. Two groups were nebulized with EOM and PEO after swimming, and the others were nebulized with distilled water. After continuous inhalation for 3 days, the swimming time, blood glucose, blood lactic acid (BLA), blood urea nitrogen (BUN), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), and malondialdehyde (MDA) in blood were determined. Results: While an increased time to exhaustion and SOD activity were apparent in both the EOM and PEO groups, the BLA and MDA were lower in both groups, in comparison with the fatigue group, and the changes in the EOM group were more dramatic. Additionally, the EOM group also showed marked changes of the rise of blood glucose and the decrease of BUN and GSH-PX. Conclusion: The results suggested that the inhalation of an essential oil mixture could powerfully relieve exercise induced fatigue. PMID- 29234410 TI - Scorpion Venom Active Polypeptide May Be a New External Drug of Diabetic Ulcer. AB - Background: The epidermal growth factor (EGF) is recognized medicine of therapy in ulcer. However, its efficacy has been challenged. We compared scorpion venom active polypeptide and EGF of therapeutic effects in diabetic ulcer. Methods: The scorpion venom active polypeptide is made into gel. Fourteen diabetic SD rats were randomly divided into scorpion peptide gel group (SPG group) and EGF group. Before treatment, the rat model of diabetic ulcer was created. The levels of IL 1, IL-6, IL-8, and TNF-alpha in the wound tissue were measured at different time points during the treatment, secretions of wound were collected for bacterial culture, and the wound healing was recorded. Results: Wound healing was faster in SPG group compared to EGF group (3 weeks versus 5 weeks, t-test, p = 0.032). The levels of IL-1, IL-6, IL-8, and TNF-alpha were not statistically different when the wounds were formed but showed significant differences from the 2nd to the 5th week between two groups. The infection rate was higher in the EGF group (42.86% versus 0, Chi-square test, p = 0.025). Conclusions: Scorpion venom active polypeptide shortens wound healing with a stronger anti-inflammation and antibacterial effect and may be a new and effective topical drug for the treatment of diabetic ulcers. PMID- 29234409 TI - Antcin-H Isolated from Antrodia cinnamomea Inhibits Renal Cancer Cell Invasion Partly through Inactivation of FAK-ERK-C/EBP-beta/c-Fos-MMP-7 Pathways. AB - Antcin-H, a natural triterpene, is purified from a famous anticancer medicinal mushroom, Antrodia cinnamomea, in Taiwan. This study showed that antcin-H inhibited the growth of human renal carcinoma 786-0 cells; the IC50 value (for 48 h) was 170 MUM. Besides, the migration and invasion of 786-0 cells were suppressed by antcin-H under noncytotoxic concentrations (<100 MUM); these events were accompanied by inhibition of FAK and Src kinase activities, decrease of paxillin phosphorylation, impairment of lamellipodium formation, and upregulation of TIMPs and downregulation of MMPs, especially MMP-7 expression. Luciferase reporter assay showed that antcin-H repressed the MMP-7 promoter activity, in parallel to inhibiting c-Fos/AP-1 and C/EBP-beta transactivation abilities. Moreover, antcin-H suppressed the activity of ERK1/2 and decreased the binding ability of C/EBP-beta and c-Fos on the upstream/enhancer region of MMP-7 promoter. Overall, this study demonstrated that the anti-invasive effect of antcin-H in human renal carcinoma 786-0 cells might be at least in part by abrogating focal adhesion complex and lamellipodium formation through inhibiting the Src/FAK-paxillin signaling pathways and decreasing MMP-7 expression through suppressing the ERK1/2-AP-1/c-Fos and C/EBP-beta signaling axis. Our findings provide the evidence that antcin-H may be an active component existing in A. cinnamomea with anticancer effect. PMID- 29234411 TI - Kinematics Analysis of Cervical Rotation-Traction Manipulation Measured by a Motion Capture System. AB - Objectives: To analyze the kinematics of cervical rotation-traction manipulation (CRTM). Methods: An experimental study measuring the kinematics of CRTM was conducted. A total of 18 healthy volunteers participated in the study. A single manipulator operated the CRTM for all subjects. Motion capture technology was adopted to track the trajectory during the CRTM operation. Results: The manipulated side did not influence the cervical spine motion. The motion ranges obtained during CRTM were well below the active range of motion reported in the literature. The head rotation angle after thrusting was less than the angle of the rotary-position (P < 0.05). There was no significant difference in the head rotation angle between pretraction and upward-thrust. The thrust direction of CRTM was mainly upward. The thrust operation was of high-velocity and low amplitude (thrust velocity: 203.06 +/- 49.95 mm/s; thrust acceleration: 3836.27 +/- 1262.28 mm/s2; thrust displacement: 3.25 +/- 1.30 mm). Conclusions: CRTM has clear operation steps and repeatability that is suitable for clinical application. PMID- 29234412 TI - Genome-Wide Profiling Reveals That Herbal Medicine Jinfukang-Induced Polyadenylation Alteration Is Involved in Anti-Lung Cancer Activity. AB - Alternative polyadenylation (APA) plays an important role in regulation of genes expression and is involved in many biological processes. As eukaryotic cells receive a variety of external signals, genes produce diverse transcriptional isoforms and exhibit different translation efficiency. The traditional Chinese medicine (TCM) Jinfukang (JFK) has been effectively used for lung cancer treatment. In this study, we investigated whether JFK exerts its antitumor effect by modulating APA patterns in lung cancer cells. We performed a genome-wide APA site profiling analysis in JFK treated lung cancer cells A549 with 3T-seq approach that we reported previously. Comparing with those in untreated A549, in JFK treated A549 we observed APA-mediated 3' UTRs alterations in 310 genes including 77 genes with shortened 3' UTRs. In particular, we identified TMEM123, a gene involved in oncotic cell death, which produced transcripts with shortened 3' UTR and thus was upregulated upon JFK treatment. Taken together, our studies suggest that APA might be one of the antitumor mechanisms of JFK and provide a new insight for the understanding of TCM against cancer. PMID- 29234413 TI - Salidroside Protects against MPP+-Induced Neuronal Injury through DJ-1-Nrf2 Antioxidant Pathway. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder. We have found that salidroside (Sal) exhibited neuroprotective effects against MPP+ toxicity. However, the molecular mechanism is not fully understood. In this study, we found that Sal significantly prevented MPP+-induced decrease of mRNA and protein expression of Nrf2, GCLc, SOD1, and SOD2 in SH-SY5Y cells. Moreover, silencing of Nrf2 significantly inhibited Sal-induced increase in mRNA and protein expression of GCLc, SOD1, and SOD2. But Nrf2 silence did not significantly impact Sal-exhibited effects on DJ-1 expression. Silencing of Nrf2 significantly suppressed the decrease of apoptosis induced by Sal in MPP+-treated SH-SY5Y cells. Sal significantly prevented MPP+-induced decrease of the mRNA and protein expression of DJ-1 in SH-SY5Y cells. Moreover, silencing of DJ-1 significantly inhibited Sal-induced increase in mRNA and protein expression of Nrf2, GCLc, SOD1, and SOD2 in MPP+-treated SH-SY5Y cells. These results indicated that DJ-1 was an upstream regulator of Nrf2 in the neuroprotective effects of Sal. Furthermore, silencing of DJ-1 significantly suppressed the decrease of apoptosis induced by Sal in MPP+-treated SH-SY5Y cells. In conclusion, Sal prevented MPP+-induced neurotoxicity through upregulation of DJ-1-Nrf2 antioxidant pathway. Our findings provide novel insights into the neuroprotective effects of Sal against PD. PMID- 29234414 TI - A Systematic Review and Meta-Analysis of the Effect of Lifestyle Modification on Metabolic Control in Overweight Children. AB - Childhood obesity is associated with type 2 diabetes mellitus. We aimed to determine the effects of lifestyle modification programs on fasting plasma glucose (FPG) levels in overweight children. We queried six relevant electronic databases and manually searched for studies published before December 2016. Overweight/obese children who underwent a lifestyle modification for more than 6 months were included. A total of 3923 children from eight randomized controlled trials (RCTs) were included. Compared with the control group, the lifestyle modification group had significantly lower FPG levels by 1.3 mg/dL. The mean differences were significantly decreased for both secondary outcomes; BMI z-score decreased by 0.16 units and insulin levels decreased by 2.4 mU/L. The metaregression showed that the follow-up duration was associated with FPG levels and BMI and insulin levels and half year is a suitable follow-up duration for this population. This study showed that lifestyle modification programs may be effective in reducing the FPG levels of overweight/obese children. Further high quality RCTs with longer follow-up periods are needed to evaluate the long-term effect of this complementary approach for diabetes mellitus prevention on overweight/obese children. PMID- 29234415 TI - 1H-NMR Based Serum Metabolomics Study to Investigate Hepatoprotective Effect of Qin-Jiao on Carbon Tetrachloride-Induced Acute Hepatotoxicity in Rats. AB - Gentiana macrophylla Radix, commonly known as Qin-Jiao (QJ), was recorded alone to treat jaundice in Compendium of Materia Medica and has been frequently prescribed for treatment of liver disease in China. However, the underlying mechanism remains unknown. In the present work, QJ of 1,2 g/kg or silybin of 40 mg/kg (positive control) was orally given to rats for 7 days to verify the protective effect on acute liver damage induced by tetrachloride (CCl4). Together with serum biochemistry and histopathological examination, 1H-NMR based metabolomics work was carried out to investigate the efficacy. It turned out that QJ of 2 g/kg exerted comparable protective effect with positive control and partially recovered disturbed metabolism by CCl4. Multivariate analysis was conducted and metabolites altered significantly among groups were assigned and discussed, including betaine, glucose, lactate, creatine, and LDL/VLDL. Metabolic regulations involved in QJ or silybin treatment were as follows: tricarboxylic acid (TCA) cycle, synthesis of LDL/VLDL, and gluconeogenesis were enhanced, while betaine metabolism, glycolysis, creatine metabolism, synthesis of ketone bodies, amino acids metabolism, and beta-oxidation of fatty acids were suppressed. For the first time hepatoprotective effect of QJ on acute liver damage was revealed by 1H-NMR based metabolomics, prompting understanding of the underlying mechanism. PMID- 29234416 TI - Effects of Bedtime Periocular Warming on Sleep Status in Adult Female Subjects: A Pilot Study. AB - Several studies have reported that suitable manipulation of human skin or body temperature can lead to improved sleep. To clarify the effect of skin warming on human sleep, 38 female subjects, who occasionally had difficulty with falling asleep, were studied. The participants underwent two experimental sessions, which were carried out in two consecutive follicular phases and randomly crossed over. The participants wore hot or sham eye masks in one 14-day session. The first half of each 14-day session was designated the baseline period (BL) without any interventions and the later half was designated the intervention period (INT), in which they wore either the hot or sham eye mask for 10 minutes at bedtime. All the participants were instructed to keep a sleep diary every morning for the BL and INT. The results showed that the hot eye mask was significantly preferred over the sham one with respect to comfort and that feelings of restfulness and being refreshed upon wakening in the morning were significantly better with the hot eye mask than with the sham. These results suggest that bedtime periocular warming has favorable effects on subjective well-being on awakening, possibly due to the sense of comfort experienced at bedtime. PMID- 29234417 TI - A Molecular Basis for the Inhibition of Transient Receptor Potential Vanilloid Type 1 by Gomisin A. AB - Transient receptor potential (TRP) channel has critical actions as conditional sensors in primary afferent neurons. We studied the regulatory action of gomisin A on TRPV1 channel current in this report. Schisandra chinensis contains bioactive compounds such as the gomisin derivatives and their related compounds. Coapplication with gomisin A inhibited the capsaicin-mediated inward peak current. This inhibitory effect of gomisin A on capsaicin-induced inward current showed concentration-dependence and was reversible. The half maximal inhibitory concentration of gomisin A was 62.7 +/- 8.4 uM. In addition, this inhibition occurred in a noncompetition regulation mode and voltage insensitive manner. Furthermore, molecular docking studies of gomisin A on TRPV1 showed that it interacted predominantly with residues at cavities in the segments 1 and 2 of each subunit. Four potential binding sites for this ligand in the extracellular region at sensor domain of TRPV1 channel were identified. Point mutagenesis studies were undertaken, and gomisin A potency decreased for both the Y453A and N467A mutants. The double mutation of Y453 and N467 significantly attenuated inhibitory effects by gomisin A. In summary, this study revealed the molecular basis for the interaction between TRPV1 and gomisin A and provides a novel potent interaction ligand. PMID- 29234418 TI - Effects of Acupuncture on Alzheimer's Disease in Animal-Based Research. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by the accumulation of amyloid beta (Abeta) plaques, neurofibrillary tangles, and severe functional deficits in the brain. The pathogenesis and treatment of AD remain topics of investigation and significant global socioeconomic issues. The effect of complementary medicine has been investigated in managing AD. Acupuncture, a form of therapy practiced for more than 3000 years, has shown positive effects on several neurological disorders including AD. Animal studies have evaluated the specific utility and neuropathological mechanisms addressed by acupoint manipulation; however, no study has summarized the relationships among different acupoints and their therapeutic effects in the context of AD. Therefore, we reviewed the effects of acupuncture at different acupoints in animal models of AD. In general, acupuncture produced therapeutic benefits in rodent models of AD. Studies demonstrate the utility of GV20 as a valuable acupoint for electroacupuncture and manual acupuncture. GV20 stimulation suppresses Abeta generation, improves glucose metabolism, and attenuates neuropathological features in various disease models. However, a lack of sufficient evidence in preclinical and clinical studies makes these results controversial. Additional studies are required to confirm the exact utility of specific acupoints in clinically managing AD. PMID- 29234419 TI - Effect of Sheng-Jiang Powder on Obesity-Induced Multiple Organ Injuries in Rats. AB - Background and Aims: Obesity has become the main public health issue nowadays with poor control and has been associated with increased risk of multiorgan disease, but the specific mechanism and effective medication are still to be addressed. Sheng-jiang powder (SJP) showed great potential in preventing obesity in Chinese researches but has no trace in English reports. This study was designed to investigate the effect of SJP on obesity and obesity-mediated multiorgan injuries. Methods: Rats were randomized into normal group (NG), obese group (OG), and SJP treatment group (SG). Obesity was induced by high-fat diet feeding. Rats were gavaged with SJP/normal saline daily from the third week and all rats were sacrificed after 12 weeks' feeding. Tissues were obtained for cytokines tests. Results: Firstly, high-fat diet feeding led to significant obesity. Compared to NG, the level of SOD in the liver, spleen, lung, and kidney was much lower in OG (p < 0.05), while the pathological scores of pancreas, liver, spleen, lung, and kidney were much higher. SJP significantly increased SOD level in the liver, spleen, and lung and reduced the pathological scores of pancreas, liver, spleen, lung, and kidney correspondingly (p < 0.05). Conclusions: SJP ameliorates inflammatory response and mitigates obesity-induced multiple organ injuries. PMID- 29234420 TI - MMP-Inhibitory Effects of Flavonoid Glycosides from Edible Medicinal Halophyte Limonium tetragonum. AB - Limonium tetragonum has been well-known for its antioxidative properties as a halophyte. This study investigated the antimetastasis effect of solvent partitioned L. tetragonum extracts (LTEs) and isolated compounds on HT1080 mouse melanoma cell model with a focus on matrix metalloproteinase (MMP) activity and TIMP and MAPK pathways. Upregulation and stimulation of MMPs result in elevated degradation of extracellular matrix which is part of several complications such as metastasis, cirrhosis, and arthritis. The anti-MMP capacity of LTEs was confirmed by their MMP-inhibitory effects, regulation of MMP and TIMP expression, and suppression of MAPK pathway. Among all tested LTEs, 85% aq. MeOH and n-BuOH were found to be most active fractions which later yielded two known flavonoid glycosides, myricetin 3-galactoside and quercetin 3-o-beta-galactopyranoside. Anti-MMP potential of the compounds was confirmed by their ability to regulate MMP expression through inhibited MAPK pathway activation. These results suggested that L. tetragonum might serve as a potential source of bioactive substances with effective anti-MMP properties. PMID- 29234421 TI - Comparative Phytochemical Profiling and In Vitro Antioxidant Activity of Extracts from Raw Materials, Tissue-Cultured Plants, and Callus of Oroxylum indicum (L.) Vent. AB - Extracts from raw materials from different plant parts, tissue-cultured plants, and callus cultures of Oroxylum indicum were analyzed for in vitro antioxidant activities determined by DPPH radical scavenging assay and evaluated for phytochemical profiles by TLC and LC-MS methods. The results were analyzed by principal component analysis (PCA) to evaluate the similarity. Stalk, pedicel, flower, seed, and whole fruit and callus extracts promoted strong antioxidant activity with high total phenolic and total flavonoid contents. The main phytochemicals found in extracts were baicalin, baicalein, and chrysin. Baicalein and baicalin promoted strong antioxidant effects and existed in most extracts while chrysin, which promoted very low antioxidant activity, was a major flavonoid in the leaves and tissue-cultured plants. From PCA analysis by total phenolic and total flavonoid contents, four main clusters including callus and tissue-cultured plant groups from different growth stages, flower group, and whole fruit and leaf group could be organized. When the results were analyzed by PCA using antioxidant activity with total phenolic or total flavonoid contents, all O. indicum samples could be grouped together except the extracts from the root of tissue-cultured plants which separated from the rest due to their low phytochemical contents and weak antioxidant activities. PMID- 29234422 TI - Effect of Gelsemium elegans and Mussaenda pubescens, the Components of a Detoxification Herbal Formula, on Disturbance of the Intestinal Absorptions of Indole Alkaloids in Caco-2 Cells. AB - Gelsemium elegans (GE) is a kind of well-known toxic plant. It can be detoxified by Mussaenda pubescens (MP), but the detoxification mechanism is still unclear. Thus, a detoxification herbal formula (GM) comprising GE and MP was derived. The Caco-2 cells monolayer model was used to evaluate GM effects on transporting six kinds of indole alkaloids of GE. The bidirectional transport studies demonstrated that absorbance percentage of indole alkaloids in GE increased linearly over time. But in GM, Papp (AP->BL) values of the most toxic members, gelsenicine, humantenidine, and gelsevirine, were lower than that of Papp (BL->AP) (P < 0.05). The prominent analgesic effect members, gelsemine and koumine, were approximately 1.00 in gamma values. Nowhere was this increasing efflux more pronounced than in the case of indole alkaloids with N-O structure. In the presence of verapamil, the gamma values of humantenidine, gelsenicine, gelsevirine, and humantenine were decreased by 43.69, 41.42, 36.00, and 8.90 percent, respectively. The gamma values in presence of ciclosporin were homologous with a decrease of 42.32, 40.59, 34.00, and 15.07 percent. It suggested that the efflux transport was affected by transporters. Taken together, due to the efflux transporters participation, the increasing efflux of indole alkaloids from GM was found in Caco-2 cells. PMID- 29234423 TI - Antifungal Activity of Essential Oils against Candida albicans Strains Isolated from Users of Dental Prostheses. AB - Objective: The objective of this study was to analyze the antifungal activity of citral, selected by screening natural products, against Candida albicans isolates from subjects who use dental prostheses. Methodology: Screening of essential oils, including those from Mentha piperita L. (Briq), Origanum vulgare, and Zingiber officinale L., and the phytoconstituents citral and limonene, to select an appropriate natural product. Citral, which mediated the best antifungal response, was selected for biological assays. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) for citral and nystatin were determined by the microdilution method. Micromorphological analyses, time-kill curve, and modulation tests were performed. Results: The MIC and MFC of citral were established as 32 MUg/mL, consistent with fungicidal activity. The clinical strains were resistant to nystatin. Citral caused micromorphological alteration in the strains. In the time-kill curve, the growth of the clinical strain was reduction in growth equal to 3 log10 colony-forming units per milliliter after exposure to the MIC and MIC * 2 of citral for 2 h. Citral did not modulate the resistance of the studied strains to nystatin. Conclusion: This study revealed the potential of citral as a fungicidal agent and highlighted the resistance of clinical strains of C. albicans to nystatin. PMID- 29234424 TI - Anxiolytic Effect of Citrus aurantium L. in Crack Users. AB - The objective of this study was to investigate the anxiolytic effects of the essential oil (EO) of Citrus aurantium L. in patients experiencing crack withdrawal. This was developed with internal users in therapeutic communities in Paraiba, Brazil. The test population consisted of 51 volunteers, subdivided into three groups. To elicit anxiety, the Simulated Public Speaking (SPS) method was used. Physiological measures were assessed at specific phases during the experiment using appropriate equipment. Psychological measures of anxiety were assessed using the Trait-State Anxiety Inventory (IDATE) and the Analog Smoke Scale (HAS). EO was administered by nebulization. The experiment was developed in individual sessions and consolidated to four phases. The results demonstrated that the test subjects in the groups that were given the EO maintained controlled anxiety levels during SPS, when compared to the Control Group (no treatment). Subjects who used the EO also maintained levels of "discomfort" and "cognitive impairment" during SPS. It was concluded that individuals who are experiencing internal crack cocaine withdrawal present high anxiety traits and that nebulization of the EO of Citrus aurantium L. provided an acute anxiolytic effect in crack cocaine users exposed to SPS. PMID- 29234426 TI - A Study of Traditional Chinese Medicine Body Constitution Associated with Overweight, Obesity, and Underweight. AB - Objective: The aim of the study was to investigate the associations among the nine types of body constitution in traditional Chinese medicine (TCM) with the outcomes of overweight, obesity, and underweight. Method: Participants aged 30 to 90 years were recruited from communities in Shanghai and assessed using a self administered questionnaire pertaining to their demographics, lifestyles, and self reported medical history. The data of 3748 participants with complete information was available for the analysis. Multinomial logistic regression (MLR) analysis was performed to determine the associations among the TCM constitution variables and the health outcomes. Results: The standards of classification and determination of the constitution in TCM were used to gauge the patients' constitution type. MLR revealed independent and significant associations among the Qi_Deficient and Yang_Deficient groups with the outcomes of overweight, obesity, and underweight (P < 0.10 for all). MLR revealed independent and significant associations among the Qi_Deficient and Yang_Deficient groups with the outcomes of overweight, obesity, and underweight (P < 0.05 for all). Conclusion: Our study revealed significant negative correlations between the Qi_Deficient and Yang_Deficient groups with the outcomes of overweight, obesity, and underweight. On the other hand, positive correlations were found between Phlegm_Dampness and the outcomes of overweight and obesity. PMID- 29234425 TI - Systems Pharmacological Approach to the Effect of Bulsu-san Promoting Parturition. AB - Bulsu-san (BSS) has been commonly used in oriental medicine for pregnant women in East Asia. The purpose of this research was to elucidate the effect of BSS on ease of parturition using a systems-level in silico analytic approach. Research results show that BSS is highly connected to the parturition related pathways, biological processes, and organs. There were numerous interactions between most compounds of BSS and multiple target genes, and this was confirmed using herb compound-target network, target-pathway network, and gene ontology analysis. Furthermore, the mRNA expression of relevant target genes of BSS was elevated significantly in related organ tissues, such as those of the uterus, placenta, fetus, hypothalamus, and pituitary gland. This study used a network analytical approach to demonstrate that Bulsu-san (BSS) is closely related to the parturition related pathways, biological processes, and organs. It is meaningful that this systems-level network analysis result strengthens the basis of clinical applications of BSS on ease of parturition. PMID- 29234427 TI - A Chinese Herbal Formula, Gengnianchun, Ameliorates beta-Amyloid Peptide Toxicity in a Caenorhabditis elegans Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disorder, and the few drugs that are currently available only treat the symptoms. Traditional medicine or phytotherapy has been shown to protect against AD. In our previous studies, Gengnianchun (GNC), a traditional Chinese medicine formula with a prolongevity effect, protected against Abeta-induced cytotoxicity in pheochromocytoma cells (PC-12 cells) and hippocampal cells. Here, we investigated the effects and possible mechanisms by which GNC protected against Abeta toxicity using transgenic Caenorhabditis elegans CL4176. Our results showed that GNC effectively delayed the Abeta toxicity-triggered body paralysis of CL4176 worms. GNC decreased Abeta by reducing Abeta mRNA levels. Moreover, GNC significantly reduced reactive oxygen species in the AD model worms compared with the controls. In addition, GNC upregulated the daf-16, sod-3, hsp-16.2 genes, and enhanced DAF 16 translocation from the cytoplasm to the nuclei under oxidative stress conditions. GNC treatment of C. elegans strains lacking DAF-16 did not affect the paralysis phenotype. Taken together, these findings suggest that GNC could protect against Abeta-induced toxicity via the DAF-16 pathway in C. elegans. Further studies are required to analyze its effectiveness in more complex animals. PMID- 29234428 TI - Network Pharmacology-Based Approach to Investigate the Analgesic Efficacy and Molecular Targets of Xuangui Dropping Pill for Treating Primary Dysmenorrhea. AB - This study aimed to evaluate the clinical analgesic efficacy and identify the molecular targets of XGDP for treating primary dysmenorrhea (PD) by a network pharmacology approach. Analysis of pain disappearance rate of XGDP in PD treatment was conducted based on data from phase II and III randomized, double blind, double-simulation, and positive parallel controlled clinical trials. The bioactive compounds were obtained by the absorption, distribution, metabolism, and excretion processes with oral bioavailability (OB) and drug-likeness (DL) evaluation. Subsequently, target prediction, pathway identification, and network construction were employed to clarify the mechanisms of the analgesic effect of XGDP on PD. The pain disappearance rates in phase II and III clinical trials of XGDP in PD treatment were 62.5% and 55.8%, respectively, yielding a significant difference (P < 0.05) when compared with the control group using Tongjingbao granules (TJBG). Among 331 compounds, 53 compounds in XGDP were identified as the active compounds related to PD through OB, DL, and target prediction. The active compounds and molecular targets of XGDP were identified, and our study showed that XGDP may exert its therapeutic effects on PD through the regulation of the targets related to anti-inflammation analgesia and central analgesia and relieving smooth muscle contraction. PMID- 29234429 TI - Effects of Jiawei Shaoyao-Gancao Decoction and Its Drug-Containing Serum on Proliferation, Apoptosis, and Ultrastructure of Human Adenomyosis Foci Cells. AB - Objective: The present study aimed to investigate the effects of Jiawei Shaoyao Gancao Decoction (JSGD) and its drug-containing serum (CDS) on the proliferation, apoptosis, and ultrastructure of human adenomyosis foci cells. Methods: Primary cultures of human adenomyosis foci cells were prepared from hard uterine lesions of adenomyosis patients. The cells were treated with JSGD (10 and 20 mg/ml), CDS, and mifepristone (MIF) for 24 or 48 h. Cell proliferation was detected using CCK 8 assay, cell apoptosis was measured by flow cytometry, and the cell ultrastructure was observed by transmission electron microscopy (TEM). Results: JSGD and CDS significantly induced cell apoptosis and inhibited cell proliferation for 24 h or 48 h, in which the effects of JSGD were in a dose dependent manner. The effect of CDS for 24 h was higher than that of CDS for 48 h. Moreover, JSGD and CDS treatments induced marked apoptosis in adenomyosis foci cells, characterized by nucleus chromatin, condensation, fragmentation, mitochondria and endoplasmic swelling, and autophagy-lysosome. Conclusions: JSGD and CDS can suppress proliferation and induce apoptosis in adenomyosis foci cells, through altering their ultrastructure. The results provided support for JSGD and CDS in the treatment of adenomyosis and gained further insight into the effect of this prescription. PMID- 29234430 TI - Antidyslipidemic, Anti-Inflammatory, and Antioxidant Activities of Aqueous Leaf Extract of Dioscoreophyllum cumminsii (Stapf) Diels in High-Fat Diet-Fed Rats. AB - Dioscoreophyllum cumminsii (Stapf) Diels leaves are widely used in the treatment of diabetes, obesity, and cardiovascular related complications in Nigeria. This study investigates the anti-inflammatory and antiobesity effect of aqueous extract of Dioscoreophyllum cumminsii leaves in high-fat diet- (HFD-) induced obese rats. HFD-fed rats were given 100, 200, and 400 mgkg-1 body weight of aqueous extract of Dioscoreophyllum cumminsii leaves for 4 weeks starting from 9th week of HFD treatment. D. cumminsii leaves aqueous extract reversed HFD mediated decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glucose 6-phosphate dehydrogenase. Moreover, HFD-mediated elevation in the levels of conjugated dienes, lipid hydroperoxides, malondialdehyde, protein carbonyl, and DNA fragmentation in rats liver was lowered. HFD-mediated alterations in serum total cholesterol, triacylglycerol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol were significantly reversed by the extract. The treatment of HFD-fed rats reduced the levels of insulin, leptin, protein carbonyl, fragmented DNA, and tumour necrosis factor-alpha and interleukin- (IL-) 6 and IL- 8 and increased the adiponectin level. This study showed that aqueous extract of Dioscoreophyllum cumminsii leaves has potential antiobesity and anti-inflammatory effects through modulation of obesity-induced inflammation, oxidative stress, and obesity-related disorder in HFD-induced obese rats. PMID- 29234431 TI - Protective Effects of Total Flavones of Elaeagnus rhamnoides (L.) A. Nelson against Vascular Endothelial Injury in Blood Stasis Model Rats. AB - The aim was to evaluate the protective effects of total flavones of Elaeagnus rhamnoides (L.) A. Nelson (TFE) against vascular endothelial injury in blood stasis model rats and explore the potential mechanisms preliminarily. The model of blood stasis rat model with vascular endothelial injury was induced by subcutaneous injection of adrenaline combined with ice-water bath. Whole blood viscosity (WBV), histological examination, and prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen (FIB) were measured. Meanwhile, the levels of Thromboxane B2 (TXB2), 6-keto-PGF1alpha , von Willebrand factor (vWF), and thrombomodulin (TM) were detected. In addition, Quantitative Real-Time PCR (qPCR) was performed to identify PI3K, Erk2, Bcl-2, and caspase-3 gene expression. The results showed that TFE can relieve WBV, increase PT and APTT, and decrease FIB content obviously. Moreover, TFE might significantly downregulate the levels of TXB2, vWF, and TM in plasma and upregulate the level of 6-keto-PGF1alpha in plasma. Expressions of PI3K and Bcl-2 were increased and the expression of caspase-3 was decreased by TFE pretreatment in the rat model. Consequently, the study suggested that TFE may have the potential against vascular endothelial injury in blood stasis model rats induced by a high dose of adrenaline with ice-water bath. PMID- 29234432 TI - Ethanol Extract of Root of Prunus persica Inhibited the Growth of Liver Cancer Cell HepG2 by Inducing Cell Cycle Arrest and Migration Suppression. AB - Liver cancer is the second most lethal cancer and hepatocellular carcinoma (HCC) is the primary cancer subgroup. However, the current chemotherapy agents remain ineffective and present wide side effects for advanced HCC patient. In this study, we investigated the antitumor role of ethanol extract of root of peach tree (Prunus persica (L.) Batsch and hereafter designated as TSG in short of its Chinese name), which is an important ingredient in Chinese medicine prescription, in liver cancer cell HepG2. By cell viability assay, we showed that addition of TSG in the culture medium inhibited the cell growth of HepG2 cells in a dose and time-dependent way. Cell cycle analysis indicated that TSG caused sustained M/G2 phase arrest. The expression of mitosis-related protein Cdc25c was impaired upon TSG treatment. Furthermore, wound healing assay demonstrated that TSG treatment notably suppressed the migration of HepG2 cells and the expression of extracellular matrix metalloprotease, MMP3 and MMP9. Most significantly, administration of TSG inhibited in vivo tumor growth in nude mice. Our findings suggested that TSG may serve as a source to isolate anti-HCC therapeutic ingredients. PMID- 29234433 TI - Renoprotective Effects of Total Glucosides from Paeony against Nephrotoxicity Induced by Total Alkaloids from Semen Strychni. AB - Semen Strychni have been shown to have therapeutic effect in improving blood circulation, relieving rheumatic pain, and treating cancer. However, Semen Strychni could cause severe nephrotoxicity. The present study was designed to evaluate whether treatment with total glucosides from paeony (TGP) has renoprotective effect against nephrotoxicity induced by total alkaloids from Semen Strychni (TAS). The levels of blood urea nitrogen (BUN) and creatinine (Cr) were determined and histopathological changes were also examined to evaluate renal injury. Moreover, a HPLC-MS method was developed and validated to investigate the comparative toxicokinetics of strychnine and brucine in rats plasma after oral administration of TAS and pretreatment with TGP. Results demonstrated that the levels of BUN and Cr were significantly increased (p < 0.05) in TAS group, together with tubule epithelium cloudy swelling, degeneration, and glomerular atrophy in rats' kidneys. The TAS-induced kidney damage was alleviated after pretreatment with TGP. Besides, Tmax of strychnine and brucine were increased and T1/2 of strychnine and brucine were decreased after pretreatment with TGP. The toxicokinetics study showed that pretreatment with TGP could attenuate the absorption of strychnine and brucine, as well as accelerate their elimination. These results suggest that TGP possesses renoprotective effects. PMID- 29234434 TI - Prescription Function Prediction Using Topic Model and Multilabel Classifiers. AB - Determining a prescription's function is one of the challenging problems in Traditional Chinese Medicine (TCM). In past decades, TCM has been widely researched through various methods in computer science, but none concentrates on the prediction method for a new prescription's function. In this study, two methods are presented concerning this issue. The first method is based on a novel supervised topic model named Label-Prescription-Herb (LPH), which incorporates herb-herb compatibility rules into learning process. The second method is based on multilabel classifiers built by TFIDF features and herbal attribute features. Experiments undertaken reveal that both methods perform well, but the multilabel classifiers slightly outperform LPH-based method. The prediction results can provide valuable information for new prescription discovery before clinical test. PMID- 29234435 TI - Baduanjin Exercise for Type 2 Diabetes Mellitus: A Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - Objective: To investigate the effects of Baduanjin exercise for type 2 diabetes mellitus. Methods: Literature retrieval was performed in several databases, including PubMed, EMBASE, Cochrane Library, CNKI, Wanfang Data Information Site, CBM, and VIP from inception to April 2017. Randomized controlled trials on evaluating the effects of Baduanjin exercise were identified. The primary outcomes were glycosylated hemoglobin, fasting blood-glucose, and postprandial plasma glucose. Review Manager 5.2 (RevMan 5.2) and Stata V.13.0 software were conducted for data analysis. Results: The results of the meta-analysis indicated that the effects of type 2 diabetes mellitus were favoring Baduanjin plus conventional therapy, when compared with the routine treatment. Baduanjin plus conventional therapy lowered the level of glycosylated hemoglobin, fasting blood glucose, postprandial plasma glucose, TC, TG, and LDL-C and improved HDL-C. Adverse events were not mentioned in all included studies. No publication bias was detected by Begg's and Egger's test and no single study affected the overall result by influence analysis. Conclusions: Evidence from meta-analysis suggested that Baduanjin exercise plus conventional therapy has a positive effect on type 2 diabetes mellitus. However, more rigorously designed and large sample RCTs are required to confirm the efficacy and safety in further studies. PMID- 29234437 TI - Effects of Whole-Body Electromyostimulation on Low Back Pain in People with Chronic Unspecific Dorsal Pain: A Meta-Analysis of Individual Patient Data from Randomized Controlled WB-EMS Trials. AB - In order to evaluate the favorable effect of whole-body electromyostimulation (WB EMS) on low back pain (LBP), an aspect which is frequently claimed by commercial providers, we performed a meta-analysis of individual patient data. The analysis is based on five of our recently conducted randomized controlled WB-EMS trials with adults 60 years+, all of which applied similar WB-EMS protocols (1.5 sessions/week, bipolar current, 16-25 min/session, 85 Hz, 350 MUs, and 4-6 s impulse/4 s impulse-break) and used the same pain questionnaire. From these underlying trials, we included only subjects with frequent-chronic LBP in the present meta-analysis. Study endpoints were pain intensity and frequency at the lumbar spine. In summary, 23 participants of the underlying WB-EMS and 22 subjects of the control groups (CG) were pooled in a joint WB-EMS and CG. At baseline, no group differences with respect to LBP intensity and frequency were observed. Pain intensity improved significantly in the WB-EMS (p < .001) and was maintained (p = .997) in the CG. LBP frequency decreased significantly in the WB EMS (p < .001) and improved nonsignificantly in the CG (p = .057). Group differences for both LBP parameters were significant (p <= .035). We concluded that WB-EMS appears to be an effective training tool for reducing LBP; however, RCTs should further address this issue with more specified study protocols. PMID- 29234436 TI - Fraction n-Butanol of Radix Notoginseng Protects PC12 Cells from Abeta25-35 Induced Cytotoxicity and Alleviates Cognitive Deficits in SAMP8 Mice by Attenuating Oxidative Stress and Abeta Accumulation. AB - Chinese medicine has been used for Alzheimer's disease (AD) treatment for thousands of years with more effective and fewer side effects. Therefore, developing effective potential candidates from Chinese medicine against AD would be considered as critical and efficient therapy for AD treatment. This study was designed to evaluate the neuronal protective effect of fraction n-butanol (NB) of Radix Notoginseng on Abeta25-35-induced PC12 cells, explore the effect of the tested fraction on spatial learning and memory, and characterize the impacts of fraction NB on antioxidant enzymes, Abeta production, and APP and BACE1 expressions. The results revealed that fraction NB could promote proliferation of PC12 cells and protect and rescue PC12 cells from Abeta25-35-induced cell death. Moreover, fraction NB could improve spatial learning and memory impairments of senescence-accelerated prone8 (SAMP8) mice and attenuate oxidative stress and reduce the production of Abeta by inhibiting the expressions of APP and BACE1 in the brains of SAMP8 mice. The result of single dose acute toxicity assay showed that fraction NB had a mild toxicity in vivo. The pronounced actions against AD and in vivo low toxicity of fraction NB suggest that fraction NB may be a useful alternative to the current AD treatment. PMID- 29234438 TI - The Efficacy of Acupuncture on Anthropometric Measures and the Biochemical Markers for Metabolic Syndrome: A Randomized Controlled Pilot Study. AB - Background: Many previous studies have shown the potential therapeutic effect of acupuncture for metabolic syndrome (MetS). However, most of these studies were limited by short durations of observation and a lack of sham acupuncture as control. We designed a randomized controlled trial, used sham acupuncture as the control, and evaluated the efficacy over 12 weeks of treatment and 12 weeks of follow-up. Methods/Design: The study was designed as a multicentre, parallel group, randomized, double-blinded trial. 40 patients were randomly assigned to two groups: treatment group (treated with acupuncture) and control group (treated with sham acupuncture). Outcomes were measured at 4, 8, and 12 weeks and 3 months after treatment. Results: 33 participants (17 in acupuncture group and 16 in control group) completed the treatment and the follow-up. Decreases from baseline in mean waist circumference (WC) and weight at the end of treatment were 4.85 cm (95% CI [2.405,5.595]) and 4.00 kg (95% CI [1.6208,4.4498]) in acupuncture group and 1.62 cm and 1.64 kg in control group (P < 0.01). The changes in mean glycosylated haemoglobin (HbA1c), triglycerides (TG), total cholesterol (TC), and blood pressure in acupuncture group were greater than the changes in control group (P < 0.05, P < 0.01). Conclusion: Acupuncture decreases WC, HC, HbA1c, TG, and TC values and blood pressure in MetS. PMID- 29234439 TI - Herbal Medicine for the Treatment of Obesity: An Overview of Scientific Evidence from 2007 to 2017. AB - Obesity is a very common global health problem, and it is known to be linked to cardiovascular and cerebrovascular diseases. Western medical treatments for obesity have many drawbacks, including effects on monoamine neurotransmitters and the potential for drug abuse and dependency. The safety of these medications requires improvement. Herbal medicine has been used for treatment of disease for more than 2000 years, and it has proven efficacy. Many studies have confirmed that herbal medicine is effective in the treatment of obesity, but the mechanisms are not clear. This article will discuss the possible effects and mechanisms of herbal medicine treatments for obesity that have been reported in the past decade. PMID- 29234440 TI - Morinda Officinalis Polysaccharides Stimulate Hypothalamic GnRH Secretion in Varicocele Progression. AB - Varicoceles (VCs) are the predominant cause of male infertility and are a risk factor for chronic venous disease. Morinda officinalis (M. officinalis) is a traditional Chinese medicine used to tonify the kidney and strengthen yang. In this study, we evaluated the effects of water-soluble polysaccharides extracted from M. officinalis (MOPs) on gonadotropin-release hormone (GnRH) secretion in a classic experimental left VC (ELV) rat model. Intragastric administration of MOPs at a dose ranging from 50 mg kg-1 to 100 mg kg-1 facilitated improvements in sperm parameters and seminiferous epithelial structures, modulated serum hormone profiles, and stimulated GnRH synthesis and release in the hypothalamus. MOPs also promoted spinogenesis and functional spine maturation in the arcuate nuclei (Arc), wherein they acted mainly on Kiss1 and GnRH neurons. Moreover, MOP mediated Kisspeptin-GPR54 pathway upregulation and MAPK phosphorylation activation may have been responsible for increases in GnRH synthesis and release. Collectively, the findings of this study indicate that MOPs were effective in stimulating GnRH secretion, possibly by upregulating the Kiss1/GPR54 pathway and enhancing synaptic plasticity, and that MOPs can serve as a therapy for early VCs. PMID- 29234441 TI - Euphorbia kansui Attenuates Insulin Resistance in Obese Human Subjects and High Fat Diet-Induced Obese Mice. AB - Background: Obesity is a main cause of insulin resistance (IR), metabolic syndrome, and fatty liver diseases. This study evaluated Euphorbia kansui radix (Euphorbia) as a potential treatment option for obesity and obesity-induced IR in obese human and high-fat diet- (HFD-) induced obese mice. Methods: In the human study, we analyzed the body weight change of 14 patients who took a single dose of 6 g of Euphorbia powder. In the animal study, male mice were divided into three groups: normal chow, HFD, and Euphorbia (high-fat diet and 100 mg/Kg Euphorbia once per week). Body weight, epididymal fat pad weight, fasting blood glucose, fasting insulin, HOMA-IR, and oral glucose tolerance test were measured. Also, macrophage infiltration and expression of CD68, tumor necrosis factor- (TNF ) alpha, interferon- (IFN-) gamma, and interleukin- (IL-) 6 genes in the liver and adipose tissue were analyzed. Results: The human study showed that Euphorbia has a potential effect on body weight loss. In the in vivo study, body weight, epididymal fat weight, glucose level, IR, expression of CD68, TNF-alpha, IFN-r, and IL-6 genes, and macrophages in liver and adipose tissue were significantly reduced by Euphorbia. Conclusions: These results suggest that Euphorbia attenuates obesity and insulin resistance via anti-inflammatory effects. PMID- 29234442 TI - The Association of Quantitative Facial Color Features with Cold Pattern in Traditional East Asian Medicine. AB - Introduction: Facial diagnosis is a major component of the diagnostic method in traditional East Asian medicine. We investigated the association of quantitative facial color features with cold pattern using a fully automated facial color parameterization system. Methods: The facial color parameters of 64 participants were obtained from digital photographs using an automatic color correction and color parameter calculation system. Cold pattern severity was evaluated using a questionnaire. Results: The a* values of the whole face, lower cheek, and chin were negatively associated with cold pattern score (CPS) (whole face: B = -1.048, P = 0.021; lower cheek: B = -0.494, P = 0.007; chin: B = -0.640, P = 0.031), while b* value of the lower cheek was positively associated with CPS (B = 0.234, P = 0.019). The a* values of the whole face were significantly correlated with specific cold pattern symptoms including cold abdomen (partial rho = -0.354, P < 0.01) and cold sensation in the body (partial rho = -0.255, P < 0.05). Conclusions: a* values of the whole face were negatively associated with CPS, indicating that individuals with increased levels of cold pattern had paler faces. These findings suggest that objective facial diagnosis has utility for pattern identification. PMID- 29234443 TI - Psychotropic Effects of an Alcoholic Extract from the Leaves of Albizia zygia (Leguminosae-Mimosoideae). AB - Background: Albizia zygia is used in Ghanaian traditional medicine for the management of mental disorders. The present study tested the hypothesis that an extract of the leaves of Albizia zygia (AZE) may possess antipsychotic and antidepressant properties. Method: The novelty- and apomorphine-induced locomotor and rearing behaviours of AZE in mice were explored in an open-field observational test system. The effects of AZE in apomorphine-induced cage climbing test, extract-induced catalepsy, and haloperidol-induced catalepsy on mice were also investigated. Lastly, the forced swimming and tail suspension tests in mice were employed to screen the possible antidepressant effects of AZE. Results: AZE (100-3000 mg/kg) showed signs of central nervous system (CNS) depression under observation, with no lethality, 24 h after treatment in mice. AZE (100-1000 mg/kg) produced a significant decrease in the frequency of novelty- and apomorphine-induced locomotor activities in mice. The extract also significantly decreased the frequency and duration of apomorphine-induced climbing activities in mice. AZE, while failing to produce any cataleptic event in naive mice, significantly enhanced haloperidol-induced catalepsy at a dose of 1000 mg/kg. However, AZE did not produce any significant antidepressant effects in the test models employed. Conclusion: The extract of Albizia zygia exhibited an antipsychotic-like activity in mice. PMID- 29234444 TI - The Effects of Thai Herbal Ha-Rak Formula on COX Isoform Expression in Human Umbilical Vein Endothelial Cells Induced by IL-1beta. AB - Objective: To investigate the modulated effects of HRF on cyclooxygenase isoform expression and its activity, using the human umbilical vein endothelial cell (HUVEC) model induced by interleukin-1 beta (IL-1beta). Methods: Cells were treated with indomethacin (positive control), HRF, and its components at various concentrations prior to treatment with IL-1beta at 24 h. Cell viability was determined by MTT assay. Moreover, the anti-inflammatory effects of HRF and its components through mRNA and protein expression were established using real-time quantitative PCR and Western blot, respectively. COX activity was identified via exogenous and endogenous PGE2 productions using the EIA. Result: There was no cytotoxicity in HUVECs treated with HRF. None of the experimental conditions used in the study affected the expression of COX-1, but COX-2 protein expression was inhibited at concentrations under 10 ug/mL. Despite the significantly increased levels of exogenous PGE2, HRF had no effect on COX-2 mRNA expression. However, the production of PGE2 was lower at a concentration of 100 ug/mL HRF than at a concentration below 10 ug/mL. Interestingly, each component of HRF revealed different effects of the Ha-Rak formula. Conclusion: Our preliminary findings suggest that HRF and its components provide diverse modulation of COX-2 and PGE2 at the in vitro level. PMID- 29234445 TI - Bioactivity-Guided Fractionation of the Traditional Chinese Medicine Resina Draconis Reveals Loureirin B as a PAI-1 Inhibitor. AB - Thrombotic diseases have become a global burden due to morbidity, mortality, and disability. Traditional Chinese medicine has been proven effective in removing blood stasis and promoting blood circulation, but the exact mechanisms remain unclear. Plasminogen activator inhibitor-1 (PAI-1) is a natural inhibitor of tissue-type and urokinase-type plasminogen activators. In this study, we screened four fractions of Resina Draconis (a traditional Chinese medicine) extract for PAI-1 inhibitory activity. Bioactivity-guided purification and chromogenic substrate-based assay led to the identification of loureirin B as the major PAI-1 inhibitor, with an IC50 value of 26.10 MUM. SDS-PAGE analysis showed that formation of the PAI-1/uPA complex was inhibited by loureirin B, and the inhibitory effect of loureirin B on PAI-1 was also confirmed by clot lysis assay. In vivo studies showed that loureirin B significantly prolonged the tail bleeding time and reduced the weight and size of arterial thrombus, reduced hydroxyproline level, and partly cured liver fibrosis in mice. Taken together, the results revealed loureirin B as a PAI-1 inhibitor, adding a new pharmacological target for loureirin B and uncovering a novel mechanism underlying the antithrombotic property of Resina Draconis, which might be useful in the treatment of cardiovascular diseases such as thrombosis and fibrosis. PMID- 29234447 TI - Clinical Efficacy and Safety of Benjakul Remedy Extract for Treating Primary Osteoarthritis of Knee Compared with Diclofenac: Double Blind, Randomized Controlled Trial. AB - Background: The purpose of this study was to investigate the clinical efficacy and safety of Benjakul (BJK) extract for treating primary osteoarthritis (OA) of the knee compared with diclofenac. Methods: A phase 2, double blind, randomized, and controlled study was conducted. The BJK group received 300 mg of BJK extract per day, while another group received 75 mg of diclofenac per day. All patients were followed up at 14 and 28 days. The changing of visual analogue scale (VAS) for pain, 100-meter walking times, the modified Thai WOMAC index scores, and the global assessment were evaluated for efficacy. For safety issue, clinical signs and symptoms, complete physical examination, and renal and liver function were evaluated. Results: 39 and 38 patients for BJK extract group and diclofenac group were evaluated. For efficacy, all patients from both groups reported a decrease in the VAS pain score and 100-meter walking times but only the diclofenac group showed significant reduction of both measurements when compared with day 0. The modified Thai WOMAC scores of both groups were significantly reduced from baseline. However, all efficacy outcomes were not significantly different for both groups. For safety outcomes, the patients from both groups had no severe adverse events reported and only BJK had no toxicity in renal and liver functions. Conclusions: The BJK remedy extract showed equal clinical efficacy in relieving symptoms of OA knee when compared with diclofenac. PMID- 29234446 TI - Medicinal Plants from North and Central America and the Caribbean Considered Toxic for Humans: The Other Side of the Coin. AB - The consumption of medicinal plants has notably increased over the past two decades. People consider herbal products as safe because of their natural origin, without taking into consideration whether these plants contain a toxic principle. This represents a serious health problem. A bibliographic search was carried out using published scientific material on native plants from Mexico, Central America, and the Caribbean, which describe the ethnobotanical and toxicological information of medicinal plants empirically considered to be toxic. A total of 216 medicinal plants belonging to 77 families have been reported as toxic. Of these plants, 76 had been studied, and 140 plants lacked studies regarding their toxicological effects. The toxicity of 16 plants species has been reported in clinical cases, particularly in children. From these plants, deaths have been reported with the consumption of Chenopodium ambrosioides, Argemone mexicana, and Thevetia peruviana. In most of the cases, the principle of the plant responsible for the toxicity is unknown. There is limited information about the toxicity of medicinal plants used in Mexico, Central America, and the Caribbean. More toxicological studies are necessary to contribute information about the safe use of the medicinal plants cited in this review. PMID- 29234448 TI - Aristolochic Acid-Induced Autophagy Promotes Epithelial-to-Myofibroblast Transition in Human Renal Proximal Tubule Epithelial Cells. AB - Autophagy plays an essential role in cellular homeostasis in kidney. Previous studies have found that aristolochic acid (AA) can induce autophagy of renal tubular epithelial cells and epithelial-to-myofibroblast transition (EMT). However, the relationship between AA-induced autophagy and EMT is unclear. Our results showed that, after AA stimulation, the appearance of autophagy preceded EMT. Autophagy of HKC cells began to increase gradually from the 3rd hour, reached the peak at 12th hour, and then weakened gradually until 36th hour; the EMT process of HKC continued to increase from 6th hour to 36th hour after AA stimulation. The enhancement of autophagy using autophagy inducers, rapamycin or serum-free medium, led to an aggravation of EMT and upregulated expression of fibronectin, a component of extracellular matrix, in AA-treated HKC cells. In contrast, the inhibition of autophagy by autophagy inhibitor, 3-methyladenine, or by knockdown of Beclin 1 led to an attenuation of EMT and downregulated expression of fibronectin in AA-treated HKC cells. Taken together, our study suggests that, after AA stimulation, two types of cell responses of HKC cells, autophagy and EMT, will successively appear, and autophagy can promote EMT of HKC. PMID- 29234449 TI - The Phenomena of Naturopathic Practitioner: Predictors of a High Patient Throughput. AB - Objective. The aim of the current study was to evaluate which factors predicted a high patient throughput to add more evidence to the phenomena of naturopathic practitioners. Methods. The cross-sectional study was based on a questionnaire with a sample of 1,096 naturopathic practitioners in the German Federal State of Schleswig-Holstein. Besides, sociodemographic data and practice characteristics topics like job satisfaction and feeling for the job were evaluated. This was supplemented with an evaluation of patient traits which were perceived as challenging. Descriptive statistics and binary regression analysis were computed to identify potential predictors to a high patient throughput. Results. A response rate of 29.4% (322/1096 participants) was observed for the study. In general, our sample of the naturopathic practitioners was very satisfied with their job (mean = 6.38). Naturopathic practitioners described that 40% of their patients are challenging. The highest rate was for "aggressive patients." A high patient throughput was predicted with a higher satisfaction rate with the "opportunity to use abilities" and more direct contact with the patient. Conclusions. Therapeutic freedom and time with patients are important factors which are accountable for a high patient throughput. Moreover, our study provides evidence for the understanding of the phenomena of naturopathic practitioners. PMID- 29234450 TI - The Modulatory Effect of Acupuncture on the Activity of Locus Coeruleus Neuronal Cells: A Review. AB - The Locus Coeruleus (LC) is a small collection of noradrenergic neurons located in the pons. In the brain, noradrenaline (NE) is primarily produced by noradrenergic cell groups in the LC, which is the largest group of noradrenergic neurons in the central nervous system. Acupuncture, including the electroacupuncture which is a modified acupuncture method, is known to be effective in various kinds of diseases, and the involvement of noradrenergic system in the central nervous system has been reported by previous studies. However, on whether acupuncture can modulate the LC neuronal cells activities, results vary from studies to studies. In this paper, we included twelve articles, which observed the effect of acupuncture on the activities of LC in humans and animals. Our study shows that, among twelve included studies, six reported decrease of LC activities, whereas six showed increase of LC activities after acupuncture treatment. Although it is difficult to draw a firm conclusion, the authors suggest that the difference of frequencies may play an important role in the modulatory effect of acupuncture on LC. Further studies are needed to clarify the precise mechanism of acupuncture on LC, as it can lead to a new therapeutic method for various LC-NE related diseases. PMID- 29234451 TI - Moxibustion for Chemotherapy-Induced Nausea and Vomiting: A Systematic Review and Meta-Analysis. AB - Nausea and vomiting are distressing symptoms for patients receiving chemotherapy. Moxibustion, which involves the use of burning moxa to generate heat and stimulate acupoints, has been reported to potentially ameliorate chemotherapy induced side effects, particularly nausea and vomiting. This systematic review evaluated current evidence on the effectiveness of moxibustion against chemotherapy-induced nausea and vomiting (CINV). We searched eight online databases and two trial registries for relevant trials. The random-effects model was used to conduct a meta-analysis. Furthermore, the risk ratio (RR) and mean difference (MD) were used to explain dichotomous and continuous outcomes, respectively; the outcomes were within 95% confidence intervals (CIs). The results revealed that moxibustion might more favorably relieve the severity and frequency of CINV, compared with no treatment (RR: 2.04, 95% CI: 1.42-2.93); moxibustion might have stronger effects than antiemetic drugs (RR: 1.87, 95% CI: 1.27-2.76). There is no robust result that moxibustion could enhance the effects of antiemetic drugs administered as a complementary treatment. Actual moxibustion (8.10 +/- 10.98) may have more favorable effects than placebo moxibustion (46.67 +/- 23.32). However, the evidence obtained is not sufficient because of the lack of strict clinical trials. Protocol Registration. This trial is registered with PROSPERO CRD42016030037. PMID- 29234452 TI - Genetic variations of cholesteryl ester transfer protein and diet interactions in relation to lipid profiles and coronary heart disease: a systematic review. AB - Data on diet-genotype interactions in the prevention or treatment of dyslipidemia have increased remarkably. This systematic review aimed to assess nutrigenetic studies regarding the modulating effect of diet on cholesteryl ester transfer protein (CETP) polymorphisms in relation to metabolic traits. Data were collected through studies published between 2000 and SEP. 2016 using five electronic databases. The quality of eligible studies was assessed using a 12-item quality checklist, derived from the STrengthening the REporting of Genetic Association Studies (STREGA) statement. CETP variants that had associations with lipid profiles in previous studies were extracted for drawing of the linkage disequilibrium (LD) plot. Among CETP variants, the rs9989419 best represented this genome wide association signal across all populations, based on LD r2 estimates from 1000 genomes references. In the 23 found eligible studies (clinical trials and observational), the TaqIB and I405V polymorphisms were the two most intensively studied. Two studies reported the effect of interaction between rs3764261 and diet on lipid levels. Regarding the rs708272 (Taq1B), individuals with the B1 risk allele showed better responses to dietary interventions than those with B2B2 genotype, whereas with I405V, inconsistent results have been reported. Modest alcohol consumption was associated with decreased risk of coronary heart disease among B2 carriers of rs708272. It is concluded that variations in the CETP gene may modulate the effects of dietary components on metabolic traits. These results have been controversial, indicating complex polygenic factors in metabolic response to diet and lack of uniformity in the study conditions and designs. PMID- 29234453 TI - An association study of Taq1A ANKK1 and C957T and - 141C DRD2 polymorphisms in adults with internet gaming disorder: a pilot study. AB - Background: Though Internet gaming disorder (IGD) is considered to share similar genetic vulnerability with substance addictions, little has been explored about the role of the genetic variants on IGD. This pilot study was designed to investigate the association of the Taq1A polymorphism of the ankyrin repeat and kinase domain containing 1 (ANKK1) gene and C957T and - 141C of the dopamine D2 receptor (DRD2) with IGD and their role on the personality and temperament traits in IGD among adult population. Methods: Sixty-three subjects with IGD and 87 control subjects who regularly played Internet games were recruited. Self administered questionnaires on self-control, dysfunctional impulsivity, and temperament and character domains were done. The Taq1A ANKK1 and the C957T and - 141C ins/del from the DRD2 genes were genotyped using the specific TaqMan PCR assay. Results: The distributions of allele and genotype frequencies were not significantly different between the IGD and control groups in both genders. In male, excessive gaming and use of gaming to escape from a negative feeling were associated with the del- genotype of the - 141C. Among IGD, the del+ genotype was associated with higher novelty seeking. Logistic regression showed no predictive value of these polymorphisms for IGD when using age and gender as covariates. Conclusions: Though no direct association of the Taq1A ANKK1 and C957T DRD2 variants with IGD were observed, the - 141C polymorphism may play a role in IGD via mediating symptoms or temperament traits. PMID- 29234454 TI - Pulmonary injury associated with spray of a water-based nano-sized waterproofing product: a case study. AB - Background: In most reported cases of lung trauma with water proofing products, volatile organic compounds (VOC) have a prominent role. Here we report on a case involving ten workers exposed to a sprayed product containing nanoparticles in a water solution with only a few percent VOC. Case presentation: Ten workers suffered from respiratory symptoms following spray impregnation of hardwood furniture using a waterproofing product that contained positively charged fluorinated acrylate copolymer solid cores with a median diameter of 70 nm (1.3 w%) in aqueous suspension with 3.3 w% VOC and 0.3 w% quaternary ammonium. The worker who applied one liter of the product in a wood workshop, using an air mix spray gun, did not report any health complaints. Another worker, who entered the workshop 3 h later and had rolled and smoked two cigarettes, was hospitalized with severe chemical pneumonitis. A chest X-ray (CXR) showed bilateral infiltrative impairment in the lower lobe regions. On the next day a second CXR showed increased patchiness marking in all fields. A high-resolution Computer Tomography (CT)-scan demonstrated extensive bilateral areas of ground-glass opacities predominantly in the lower regions of the upper lobes, the right middle lobe and the apical regions of the lower lobes, compatible with severe chemical pneumonitis. On the following morning, nine workers in an adjacent workplace in the same building, experienced dry cough, chest tightness and substernal pain upon physical exercise. Reconstruction of the spray application in a climate chamber confirmed trimethyl silanol, glycol ethers and fluoroalkenes in the gas phase. Immediately after the spray application, aerosols were observed at a maximum concentration of 6.3 * 104 cm-3. Mass concentrations were 0.095 and 10 mg/m3 in the size ranges 5.6-560 nm and 0.22-30 MUm, respectively, decreasing to less than 10 MUg/m3 in both size ranges after 15 h. Conclusion: The hospitalized worker had smoked cigarettes contaminated with fluoropolymers which is a plausible explanation for the lung trauma. Respiratory symptoms in the nine workers may be caused by inhalation of particles that became airborne by resuspension from surfaces when workers entered the adjacent workplace the next day. A contribution from VOC appears less likely because measurements and modelling showed that concentrations in the mg/m3 range could have occurred only if the building was assumed to be completely airtight. PMID- 29234455 TI - Vibration thresholds in carpal tunnel syndrome assessed by multiple frequency vibrometry: a case-control study. AB - Background: Carpal tunnel syndrome (CTS) is the most common compression neuropathy, but there is no gold standard for establishing the diagnosis. The ability to feel vibrations in the fingertips is dependent on the function in cutaneous receptors and afferent nerves. Our aim was to investigate vibration perception thresholds (VPTs) in patients with CTS using multi-frequency vibrometry. Methods: Sixty-six patients (16 men and 50 women) with CTS, diagnosed from clinical signs and by electroneurography, and 66 matched healthy controls were investigated with multi-frequency vibrometry. The VPTs were assessed at seven frequencies (8, 16, 32, 64, 125, 250, and 500 Hz) in the index finger and little finger bilaterally. The severity of the CTS was graded according to Padua and the patient's subjective symptoms were graded according to the Boston carpal tunnel questionnaire. Touch thresholds were assessed using the Semmes-Weinstein monofilaments. Results: Patients with CTS had significantly higher VPTs at all frequencies in the index finger and in 6 out of 7 frequencies in the little finger compared to the controls. However, the VPT was not worse in patients with more severe CTS. Patients with unilateral CTS showed significantly higher VPTs in the affected hand. There were no correlations between VPTs and electrophysiological parameters, subjective symptoms, or touch threshold. Conclusions: Patients with CTS had impaired VPTs at all frequencies compared to the controls. Since the VPTs are dependent on function in peripheral receptors and their afferent nerves, multi-frequency vibrometry could possibly lead to diagnosis of CTS. PMID- 29234456 TI - "It's still a great adventure" - exploring offshore employees' working conditions in a qualitative study. AB - Background: Despite the particular demands inherent to offshore work, little is known about the working conditions of employees in the German offshore wind industry. To date, neither offshore employees' job demands and resources, nor their needs for improving the working conditions have been explored. Therefore, the aim of this study was to conduct a qualitative analysis to gain further insight into these topics. Methods: Forty-two semi-structured telephone interviews with German offshore employees (n = 21) and offshore experts (n = 21) were conducted. Employees and experts were interviewed with regard to their perceptions of their working conditions offshore. In addition, employees were asked to identify areas with potential need for improvement. The interviews were analysed in a deductive-inductive process according to Mayring's qualitative content analysis. Results: Employees and experts reported various demands of offshore work, including challenging physical labour, long shifts, inactive waiting times, and recurrent absences from home. In contrast, the high personal meaning of the work, regular work schedule (14 days offshore, 14 days onshore), and strong comradeship were highlighted as job resources. Interviewees' working conditions varied considerably, e.g. regarding their work tasks and accommodations. Most of the job demands were perceived in terms of the work organization and living conditions offshore. Likewise, employees expressed the majority of needs for improvement in these areas. Conclusions: Our study offers important insight into the working conditions of employees in the German offshore wind industry. The results can provide a basis for further quantitative research in order to generalize the findings. Moreover, they can be utilized to develop needs-based interventions to improve the working conditions offshore. PMID- 29234457 TI - Predictors and barriers to breastfeeding in north of Jordan: could we do better? AB - Background: Despite the ongoing recommendations for breastfeeding, we continue to see a decrease in exclusive breastfeeding among Jordanian women during infant follow up visits at the pediatric outpatient clinic. The purpose of our study is to determine the prevalence, predictors and barriers to exclusive breastfeeding in north of Jordan. Methods: We conducted a cross-sectional survey involving mothers with infants six to twelve months old, at two hospitals in Irbid city in north of Jordan, between December 2016 and March 2017. Questions included demographics, feeding pattern, and reasons for non-exclusive breastfeeding. Results: Five hundred women were included. Twenty four percent of women were employed and 87% initiated breastfeeding within three hours of birth. The proportion of women with any breastfeeding and exclusive breastfeeding at six months was 76 and 33%. After multivariate logistic regression analysis, predictors of exclusive breastfeeding at six months include the mother's previous experience (Adjusted Odds Ratio [AOR] 7.9, 95% CI 4.69, 13.36) and multiparity (AOR 2.26, 95% CI 1.2, 4.28), while barriers include maternal employment (AOR 0.4, 95% CI 0.22,0.72), Cesarean delivery (AOR 0.55, 95% CI 0.35, 0.86) and infant's hospitalization (AOR 0.44, 95% CI 0.23,0.82). Inadequate breastmilk supply and short maternity leave were the main reported reasons for non-exclusive breastfeeding. Conclusions: In north of Jordan, the majority of women initiate breastfeeding, half practice exclusive breastfeeding after birth while one third continue for six months, particularly those with previous experience. Cesarean delivery and infant's hospitalization, together with maternal employment are among the main barriers. Implementing educational programs and lactation consultant counselling together with work environment support, should be helpful to improve the breastfeeding practice among Jordanian women. PMID- 29234459 TI - A Structure Design Method for Reduction of MRI Acoustic Noise. AB - The acoustic problem of the split gradient coil is one challenge in a Magnetic Resonance Imaging and Linear Accelerator (MRI-LINAC) system. In this paper, we aimed to develop a scheme to reduce the acoustic noise of the split gradient coil. First, a split gradient assembly with an asymmetric configuration was designed to avoid vibration in same resonant modes for the two assembly cylinders. Next, the outer ends of the split main magnet were constructed using horn structures, which can distribute the acoustic field away from patient region. Finally, a finite element method (FEM) was used to quantitatively evaluate the effectiveness of the above acoustic noise reduction scheme. Simulation results found that the noise could be maximally reduced by 6.9 dB and 5.6 dB inside and outside the central gap of the split MRI system, respectively, by increasing the length of one gradient assembly cylinder by 20 cm. The optimized horn length was observed to be 55 cm, which could reduce noise by up to 7.4 dB and 5.4 dB inside and outside the central gap, respectively. The proposed design could effectively reduce the acoustic noise without any influence on the application of other noise reduction methods. PMID- 29234458 TI - Robust genetic transformation of sorghum (Sorghum bicolor L.) using differentiating embryogenic callus induced from immature embryos. AB - Background: Sorghum (Sorghum bicolor L.) is one of the world's most important cereal crops grown for multiple applications and has been identified as a potential biofuel crop. Despite several decades of study, sorghum has been widely considered as a recalcitrant major crop for transformation due to accumulation of phenolic compounds, lack of model genotypes, low regeneration frequency and loss of regeneration potential through sub-cultures. Among different explants used for genetic transformation of sorghum, immature embryos are ideal over other explants. However, the continuous supply of quality immature embryos for transformation is labour intensive and expensive. In addition, transformation efficiencies are also influenced by environmental conditions (light and temperature). Despite these challenges, immature embryos remain the predominant choice because of their success rate and also due to non-availability of other dependable explants without compromising the transformation efficiency. Results: We report here a robust genetic transformation method for sorghum (Tx430) using differentiating embryogenic calli (DEC) with nodular structures induced from immature embryos and maintained for more than a year without losing regeneration potential on modified MS media. The addition of lipoic acid (LA) to callus induction media along with optimized growth regulators increased callus induction frequency from 61.3 +/- 3.2 to 79 +/- 6.5% from immature embryos (1.5-2.0 mm in length) isolated 12-15 days after pollination. Similarly, the regeneration efficiency and the number of shoots from DEC tissue was enhanced by LA. The optimized regeneration system in combination with particle bombardment resulted in an average transformation efficiency (TE) of 27.2 or 46.6% based on the selection strategy, 25% to twofold higher TE than published reports in Tx430. Up to 100% putative transgenic shoots were positive for npt-II by PCR and 48% of events had < 3 copies of transgenes as determined by digital droplet PCR. Reproducibility of this method was demonstrated by generating ~ 800 transgenic plants using 10 different gene constructs. Conclusions: This protocol demonstrates significant improvements in both efficiency and ease of use over existing sorghum transformation methods using PDS, also enables quick hypothesis testing in the production of various high value products in sorghum. PMID- 29234460 TI - Generalized enhanced suffix array construction in external memory. AB - Background: Suffix arrays, augmented by additional data structures, allow solving efficiently many string processing problems. The external memory construction of the generalized suffix array for a string collection is a fundamental task when the size of the input collection or the data structure exceeds the available internal memory. Results: In this article we present and analyze [Formula: see text] [introduced in CPM (External memory generalized suffix and [Formula: see text] arrays construction. In: Proceedings of CPM. pp 201-10, 2013)], the first external memory algorithm to construct generalized suffix arrays augmented with the longest common prefix array for a string collection. Our algorithm relies on a combination of buffers, induced sorting and a heap to avoid direct string comparisons. We performed experiments that covered different aspects of our algorithm, including running time, efficiency, external memory access, internal phases and the influence of different optimization strategies. On real datasets of size up to 24 GB and using 2 GB of internal memory, [Formula: see text] showed a competitive performance when compared to [Formula: see text] and [Formula: see text], which are efficient algorithms for a single string according to the related literature. We also show the effect of disk caching managed by the operating system on our algorithm. Conclusions: The proposed algorithm was validated through performance tests using real datasets from different domains, in various combinations, and showed a competitive performance. Our algorithm can also construct the generalized Burrows-Wheeler transform of a string collection with no additional cost except by the output time. PMID- 29234461 TI - Discrimination of Radix Polygoni Multiflori from different geographical areas by UPLC-QTOF/MS combined with chemometrics. AB - Background: Nowadays, Radix Polygoni Multiflori (RPM, Heshouwu in Chinese) from different geographical origins were used in clinic. In order to characterize the chemical profiles of different geographical origins of RPM samples, ultra-high performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-QTOF/MS) combined with chemometrics (partial least squared discriminant analysis, PLS-DA) method was applied in the present study. Methods: The chromatography, chemical composition and MS information of RPM samples from 18 geographical origins were acquired and profiled by UPLC-QTOF/MS. The chemical markers contributing the differentiation of RPM samples were observed and characterized by supervised PLS-DA method of chemometrics. Results: The chemical composition differences of RPM samples derived from 18 different geographical origins were observed. Nine chemical markers were tentatively identified which could be used as specific chemical markers for the differentiation of geographical RPM samples. Conclusions: UPLC-QTOF/MS method coupled with chemometrics analysis has potential to be used for discriminating different geographical TCMs. Results will help to develop strategies for conservation and utilization of RPM samples. PMID- 29234462 TI - A precise and consistent assay for major wall polymer features that distinctively determine biomass saccharification in transgenic rice by near-infrared spectroscopy. AB - Background: The genetic modification of plant cell walls has been considered to reduce lignocellulose recalcitrance in bioenergy crops. As a result, it is important to develop a precise and rapid assay for the major wall polymer features that affect biomass saccharification in a large population of transgenic plants. In this study, we collected a total of 246 transgenic rice plants that, respectively, over-expressed and RNAi silenced 12 genes of the OsGH9 and OsGH10 family that are closely associated with cellulose and hemicellulose modification. We examined the wall polymer features and biomass saccharification among 246 transgenic plants and one wild-type plant. The samples presented a normal distribution applicable for statistical analysis and NIRS modeling. Results: Among the 246 transgenic rice plants, we determined largely varied wall polymer features and the biomass enzymatic saccharification after alkali pretreatment in rice straws, particularly for the fermentable hexoses, ranging from 52.8 to 95.9%. Correlation analysis indicated that crystalline cellulose and lignin levels negatively affected the hexose and total sugar yields released from pretreatment and enzymatic hydrolysis in the transgenic rice plants, whereas the arabinose levels and arabinose substitution degree (reverse xylose/arabinose ratio) exhibited positive impacts on the hexose and total sugars yields. Notably, near-infrared spectroscopy (NIRS) was applied to obtain ten equations for predicting biomass enzymatic saccharification and seven equations for distinguishing major wall polymer features. Most of the equations exhibited high R2/R2cv/R2ev and RPD values for a perfect prediction capacity. Conclusions: Due to large generated populations of transgenic rice lines, this study has not only examined the key wall polymer features that distinctively affect biomass enzymatic saccharification in rice but has also established optimal NIRS models for a rapid and precise screening of major wall polymer features and lignocellulose saccharification in biomass samples. Importantly, this study has briefly explored the potential roles of a total of 12 OsGH9 and OsGH10 genes in cellulose and hemicellulose modification and cell wall remodeling in transgenic rice lines. Hence, it provides a strategy for genetic modification of plant cell walls by expressing the desired OsGH9 and OsGH10 genes that could greatly improve biomass enzymatic digestibility in rice. PMID- 29234463 TI - Xylan extraction from pretreated sugarcane bagasse using alkaline and enzymatic approaches. AB - Background: New biorefinery concepts are necessary to drive industrial use of lignocellulose biomass components. Xylan recovery before enzymatic hydrolysis of the glucan component is a way to add value to the hemicellulose fraction, which can be used in papermaking, pharmaceutical, and food industries. Hemicellulose removal can also facilitate subsequent cellulolytic glucan hydrolysis. Results: Sugarcane bagasse was pretreated with an alkaline-sulfite chemithermomechanical process to facilitate subsequent extraction of xylan by enzymatic or alkaline procedures. Alkaline extraction methods yielded 53% (w/w) xylan recovery. The enzymatic approach provided a limited yield of 22% (w/w) but produced the xylan with the lowest contamination with lignin and glucan components. All extracted xylans presented arabinosyl side groups and absence of acetylation. 2D-NMR data suggested the presence of O-methyl-glucuronic acid and p-coumarates only in enzymatically extracted xylan. Xylans isolated using the enzymatic approach resulted in products with molecular weights (Mw) lower than 6 kDa. Higher Mw values were detected in the alkali-isolated xylans. Alkaline extraction of xylan provided a glucan-enriched solid readily hydrolysable with low cellulase loads, generating hydrolysates with a high glucose/xylose ratio. Conclusions: Hemicellulose removal before enzymatic hydrolysis of the cellulosic fraction proved to be an efficient manner to add value to sugarcane bagasse biorefining. Xylans with varied yield, purity, and structure can be obtained according to the extraction method. Enzymatic extraction procedures produce high-purity xylans at low yield, whereas alkaline extraction methods provided higher xylan yields with more lignin and glucan contamination. When xylan extraction is performed with alkaline methods, the residual glucan-enriched solid seems suitable for glucose production employing low cellulase loadings. PMID- 29234465 TI - Ten quick tips for machine learning in computational biology. AB - Machine learning has become a pivotal tool for many projects in computational biology, bioinformatics, and health informatics. Nevertheless, beginners and biomedical researchers often do not have enough experience to run a data mining project effectively, and therefore can follow incorrect practices, that may lead to common mistakes or over-optimistic results. With this review, we present ten quick tips to take advantage of machine learning in any computational biology context, by avoiding some common errors that we observed hundreds of times in multiple bioinformatics projects. We believe our ten suggestions can strongly help any machine learning practitioner to carry on a successful project in computational biology and related sciences. PMID- 29234464 TI - Production of isoprene, one of the high-density fuel precursors, from peanut hull using the high-efficient lignin-removal pretreatment method. AB - Background: Isoprene as the feedstock can be used to produce renewable energy fuels, providing an alternative to replace the rapidly depleting fossil fuels. However, traditional method for isoprene production could not meet the demands for low-energy consumption and environment-friendliness. Moreover, most of the previous studies focused on biofuel production out of lignocellulosic materials such as wood, rice straw, corn cob, while few studies concentrated on biofuel production using peanut hull (PH). As is known, China is the largest peanut producer in the globe with an extremely considerable amount of PH to be produced each year. Therefore, a novel, renewable, and environment-friendly pretreatment strategy to increase the enzymatic hydrolysis efficiency of cellulose and reduce the inhibitors generation was developed to convert PH into isoprene. Results: The optimal pretreatment conditions were 100 degrees C, 60 min, 10% (w/v) solid loading with a 2:8 volume ratio of phosphoric acid and of hydrogen peroxide. In comparison with the raw PH, the hemicellulose and lignin were reduced to 85.0 and 98.0%, respectively. The cellulose-glucose conversion of pretreated PH reached up to 95.0% in contrast to that of the raw PH (19.1%). Only three kinds of inhibitors including formic acid, levulinic acid, and a little furfural were formed during the pretreatment process, whose concentrations were too low to inhibit the isoprene yield for Escherichia coli fermentation. Moreover, compared with the isoprene yield of pure glucose fermentation (298 +/- 9 mg/L), 249 +/- 6.7 and 294 +/- 8.3 mg/L of isoprene were produced using the pretreated PH as the carbon source by the engineered strain via separate hydrolysis and fermentation and simultaneous saccharification and fermentation (SSF) methods, respectively. The isoprene production via SSF had a 9.8% glucose-isoprene conversion which was equivalent to 98.8% of isoprene production via the pure glucose fermentation. Conclusions: The optimized phosphoric acid/hydrogen peroxide combination pretreatment approach was proved effective to remove lignin and hemicellulose from lignocellulosic materials. Meanwhile, the pretreated PH could be converted into isoprene efficiently in the engineered Escherichia coli. It is concluded that this novel strategy of isoprene production using lignocellulosic materials pretreated by phosphoric acid/hydrogen peroxide is a promising alternative to isoprene production using traditional way which can fully utilize non-renewable fossil sources. PMID- 29234466 TI - The effect of variation in interpretation of the La Trobe radiographic foot atlas on the prevalence of foot osteoarthritis in older women: the Chingford general population cohort. AB - Background: The prevalence of foot osteoarthritis (OA) is much less understood than hip, knee and hand OA. The foot is anatomically complex and different researchers have investigated different joints with lack of methodological standardisation across studies. The La Trobe Foot Atlas (LFA) is the first to address these issues in providing quantitative assessment of radiographic foot OA, but has not been tested externally. The aim of this study was to evaluate three different interpretive approaches to using the LFA for grading OA when scoring is difficult due to indistinct views of interosseous space and joint contour. Methods: Foot radiographs of all remaining participants (n = 218) assessed in the Chingford Women Study 23 year visit (mean (SD) for age: 75.5 years (5.1)) were scored using the LFA defined protocol (Technique 1). Two revised scoring strategies were applied to the radiographs in addition to the standard LFA analyses. Technique 2 categorised joints that were difficult to grade as 'missing'. Technique 3 included joints that were difficult to grade as an over estimated score. Radiographic OA prevalence was defined for the foot both collectively and separately for individual joints. Results: When radiographs were scored using the LFA (Technique 1), radiographic foot OA was present in 89.9%. For Technique 2 the presence of radiographic foot OA was 83.5% and for Technique 3 it was 97.2%. At the individual joint level, using Technique 1, the presence of radiographic foot OA was higher with a wider range (18.3-74.3%) than Technique 2 (17.9-46.3%) and lower with a wider range (18.3-74.3%) than Technique 3 (39.9 79.4%). Conclusion: The three different ways of interpreting the LFA scoring system when grading of individual joints is technically difficult and result in very different estimates of foot OA prevalence at both the individual joint and global foot level. Agreement on the best strategy is required to improve comparability between studies. PMID- 29234467 TI - Reliability of doming and toe flexion testing to quantify foot muscle strength. AB - Background: Quantifying the strength of the intrinsic foot muscles has been a challenge for clinicians and researchers. The reliable measurement of this strength is important in order to assess weakness, which may contribute to a variety of functional issues in the foot and lower leg, including plantar fasciitis and hallux valgus. This study reports 3 novel methods for measuring foot strength - doming (previously unmeasured), hallux flexion, and flexion of the lesser toes. Methods: Twenty-one healthy volunteers performed the strength tests during two testing sessions which occurred one to five days apart. Each participant performed each series of strength tests (doming, hallux flexion, and lesser toe flexion) four times during the first testing session (twice with each of two raters) and two times during the second testing session (once with each rater). Intra-class correlation coefficients were calculated to test for reliability for the following comparisons: between raters during the same testing session on the same day (inter-rater, intra-day, intra-session), between raters on different days (inter-rater, inter-day, inter-session), between days for the same rater (intra-rater, inter-day, inter-session), and between sessions on the same day by the same rater (intra-rater, intra-day, inter-session). Results: ICCs showed good to excellent reliability for all tests between days, raters, and sessions. Average doming strength was 99.96 +/- 47.04 N. Average hallux flexion strength was 65.66 +/- 24.5 N. Average lateral toe flexion was 50.96 +/- 22.54 N. Conclusions: These simple tests using relatively low cost equipment can be used for research or clinical purposes. If repeated testing will be conducted on the same participant, it is suggested that the same researcher or clinician perform the testing each time for optimal reliability. PMID- 29234468 TI - Sulfation and amidinohydrolysis in the biosynthesis of giant linear polyenes. AB - Clethramycin from Streptomyces malaysiensis DSM4137, and mediomycins (produced together with clethramycin from Streptomyces mediocidicus), are near-identical giant linear polyenes apparently constructed from, respectively, a 4 guanidinobutanoate or 4-aminobutanoate starter unit and 27 polyketide extender units, and bearing a specific O-sulfonate modification at the C-29 hydroxy group. We show here that mediomycins are actually biosynthesised not by use of a different starter unit but by direct late-stage deamidination of (desulfo)clethramycin. A gene (slf) encoding a candidate sulfotransferase has been located in both gene clusters. Deletion of this gene in DSM4137 led to accumulation of desulfoclethramycin only, instead of a mixture of desulfoclethramycin and clethramycin. The mediomycin gene cluster does not encode an amidinohydrolase, but when three candidate amidinohydrolase genes from elsewhere in the S. mediocidicus genome were individually expressed in Escherichia coli and assayed, only one of them (medi4948), located 670 kbp away from the mediomycin gene cluster on the chromosome, catalysed the removal of the amidino group from desulfoclethramycin. Subsequent cloning of medi4948 into DSM4137 caused mediomycins A and B to accumulate at the expense of clethramycin and desulfoclethramycin, respectively, a rare case where an essential biosynthetic gene is not co-located with other pathway genes. Clearly, both desulfoclethramycin and clethramycin are substrates for this amidinohydrolase. Also, purified recombinant sulfotransferase from DSM4137, in the presence of 3' phosphoadenosine-5'-phosphosulfate as donor, efficiently converted mediomycin B to mediomycin A in vitro. Thus, in the final steps of mediomycin A biosynthesis deamidination and sulfotransfer can take place in either order. PMID- 29234469 TI - Exploring mechanochemistry to turn organic bio-relevant molecules into metal organic frameworks: a short review. AB - Mechanochemistry is a powerful and environmentally friendly synthetic technique successfully employed in different fields of synthetic chemistry. Application spans from organic to inorganic chemistry including the synthesis of coordination compounds. Metal-organic frameworks (MOFs) are a class of compounds with numerous applications, from which we highlight herein their application in the pharmaceutical field (BioMOFs), whose importance has been growing and is now assuming a relevant and promising domain. The need to find cleaner, greener and more energy and material-efficient synthetic procedures led to the use of mechanochemistry into the synthesis of BioMOFs. PMID- 29234470 TI - Asymmetric synthesis of propargylamines as amino acid surrogates in peptidomimetics. AB - The amide moiety of peptides can be replaced for example by a triazole moiety, which is considered to be bioisosteric. Therefore, the carbonyl moiety of an amino acid has to be replaced by an alkyne in order to provide a precursor of such peptidomimetics. As most amino acids have a chiral center at Calpha, such amide bond surrogates need a chiral moiety. Here the asymmetric synthesis of a set of 24 N-sulfinyl propargylamines is presented. The condensation of various aldehydes with Ellman's chiral sulfinamide provides chiral N-sulfinylimines, which were reacted with (trimethylsilyl)ethynyllithium to afford diastereomerically pure N-sulfinyl propargylamines. Diverse functional groups present in the propargylic position resemble the side chain present at the Calpha of amino acids. Whereas propargylamines with (cyclo)alkyl substituents can be prepared in a direct manner, residues with polar functional groups require suitable protective groups. The presence of particular functional groups in the side chain in some cases leads to remarkable side reactions of the alkyne moiety. Thus, electron-withdrawing substituents in the Calpha-position facilitate a base induced rearrangement to alpha,beta-unsaturated imines, while azide-substituted propargylamines form triazoles under surprisingly mild conditions. A panel of propargylamines bearing fluoro or chloro substituents, polar functional groups, or basic and acidic functional groups is accessible for the use as precursors of peptidomimetics. PMID- 29234472 TI - Herpetopanone, a diterpene from Herpetosiphon aurantiacus discovered by isotope labeling. AB - The genome of the predatory bacterium Herpetosiphon aurantiacus 114-95T harbors a number of biosynthesis genes, including four terpene cyclase genes. To identify the terpenes biosynthesized from H. aurantiacus 114-95T, we fed the strain with 13C-labeled glucose and, subsequently, searched for characteristic mass shifts in its metabolome. This approach led to the discovery of a new natural product, of which the isotope pattern is indicative for a diterpene originating from the methylerythritol phosphate pathway. After large-scale fermentation of H. aurantiacus 114-95T, the putative diterpene was isolated in sufficient quantity to enable NMR-based structure elucidation. The compound, for which the name herpetopanone is proposed, features a rare octahydro-1H-indenyl skeleton. Herpetopanone bears resemblance to cadinane-type sesquiterpenes from plants, but is structurally entirely unprecedented in bacteria. Based on its molecular architecture, a possible biosynthetic pathway is postulated. PMID- 29234471 TI - Hydrolysis, polarity, and conformational impact of C-terminal partially fluorinated ethyl esters in peptide models. AB - Fluorinated moieties are highly valuable to chemists due to the sensitive NMR detectability of the 19F nucleus. Fluorination of molecular scaffolds can also selectively influence a molecule's polarity, conformational preferences and chemical reactivity, properties that can be exploited for various chemical applications. A powerful route for incorporating fluorine atoms in biomolecules is last-stage fluorination of peptide scaffolds. One of these methods involves esterification of the C-terminus of peptides using a diazomethane species. Here, we provide an investigation of the physicochemical consequences of peptide esterification with partially fluorinated ethyl groups. Derivatives of N acetylproline are used to model the effects of fluorination on the lipophilicity, hydrolytic stability and on conformational properties. The conformational impact of the 2,2-difluoromethyl ester on several neutral and charged oligopeptides was also investigated. Our results demonstrate that partially fluorinated esters undergo variable hydrolysis in biologically relevant buffers. The hydrolytic stability can be tailored over a broad pH range by varying the number of fluorine atoms in the ester moiety or by introducing adjacent charges in the peptide sequence. PMID- 29234473 TI - Synthesis of naturally-derived macromolecules through simplified electrochemically mediated ATRP. AB - The flavonoid-based macroinitiator was received for the first time by the transesterification reaction of quercetin with 2-bromoisobutyryl bromide. In accordance with the "grafting from" strategy, a naturally-occurring star-like polymer with a polar 3,3',4',5,6-pentahydroxyflavone core and hydrophobic poly(tert-butyl acrylate) (PtBA) side arms was synthesized via a simplified electrochemically mediated ATRP (seATRP), utilizing only 78 ppm by weight (wt) of a catalytic CuII complex. To demonstrate the possibility of temporal control, seATRP was carried out utilizing a multiple-step potential electrolysis. The rate of the polymerizations was well-controlled by applying optimal potential values during preparative electrolysis to prevent the possibility of intermolecular coupling of the growing polymer arms. This appears to be the first report using on-demand seATRP for the synthesis of QC-(PtBA-Br)5pseudo-star polymers. The naturally-derived macromolecules showed narrow MWDs (D = 1.08-1.11). 1H NMR spectral results confirm the formation of quercetin-based polymers. These new flavonoid-based polymer materials may find applications as antifouling coatings and drug delivery systems. PMID- 29234474 TI - Diastereoselective Mannich reactions of pseudo-C2-symmetric glutarimide with activated imines. AB - As an extension of the boron enolate-based aldol reactions, the oxazolidinone installed bisimide 1a from 3-(trifluoromethyl)glutaric acid was employed for Mannich reactions with tosylated imines 2 as electrophiles to successfully obtain the corresponding adducts in a stereoselective manner. PMID- 29234475 TI - A permutation approach to the assignment of the configuration to diastereomeric tetrads by comparison of experimental and ab initio calculated differences in NMR data. AB - Scoring permutations of experimental chemical shift deviations and DFT/GIAO calculated deviations of isotropic shieldings for sets of four diastereomers can help to assign their relative configurations. This method was exercised on a set of diastereomeric Cinchona alkaloid derivatives, where 13C NMR data always identified the proper configuration. The presented approach is also an attempt to quantify the assignment by exclusion. PMID- 29234476 TI - Syntheses, structures, and stabilities of aliphatic and aromatic fluorous iodine(I) and iodine(III) compounds: the role of iodine Lewis basicity. AB - The title molecules are sought in connection with various synthetic applications. The aliphatic fluorous alcohols Rfn CH2OH (Rfn = CF3(CF2) n-1; n = 11, 13, 15) are converted to the triflates Rfn CH2OTf (Tf2O, pyridine; 22-61%) and then to Rfn CH2I (NaI, acetone; 58-69%). Subsequent reactions with NaOCl/HCl give iodine(III) dichlorides Rfn CH2ICl2 (n = 11, 13; 33-81%), which slowly evolve Cl2. The ethereal fluorous alcohols CF3CF2CF2O(CF(CF3)CF2O) x CF(CF3)CH2OH (x = 2 5) are similarly converted to triflates and then to iodides, but efforts to generate the corresponding dichlorides fail. Substrates lacking a methylene group, Rfn I, are also inert, but additions of TMSCl to bis(trifluoroacetates) Rfn I(OCOCF3)2 appear to generate Rfn ICl2, which rapidly evolve Cl2. The aromatic fluorous iodides 1,3-Rf6C6H4I, 1,4-Rf6C6H4I, and 1,3-Rf10C6H4I are prepared from the corresponding diiodides, copper, and Rfn I (110-130 degrees C, 50-60%), and afford quite stable Rfn C6H4ICl2 species upon reaction with NaOCl/HCl (80-89%). Iodinations of 1,3-(Rf6)2C6H4 and 1,3-(Rf8CH2CH2)2C6H4 (NIS or I2/H5IO6) give 1,3,5-(Rf6)2C6H3I and 1,2,4-(Rf8CH2CH2)2C6H3I (77-93%). The former, the crystal structure of which is determined, reacts with Cl2 to give a 75:25 ArICl2/ArI mixture, but partial Cl2 evolution occurs upon work-up. The latter gives the easily isolated dichloride 1,2,4-(Rf8CH2CH2)2C6H3ICl2 (89%). The relative thermodynamic ease of dichlorination of these and other iodine(I) compounds is probed by DFT calculations. PMID- 29234477 TI - One-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates using Togni's reagent. AB - A one-pot three-component route for the synthesis of S-trifluoromethyl dithiocarbamates by the reaction of secondary amines, carbon disulfide and Togni's reagent is described. The reactions proceed in moderate to good yields. A similar reaction using a primary aliphatic amine afforded the corresponding isothiocyanate in high yield. A variable temperature NMR study revealed a rotational barrier of 14.6, 18.8, and 15.9 kcal/mol for the C-N bond in the dithiocarbamate moiety of piperidine, pyrrolidine, and diethylamine adducts, respectively. In addition, the calculated barriers of rotation are in reasonable agreement with the experiments. PMID- 29234479 TI - First International Conference on Health Research, Hannover, Germany. PMID- 29234478 TI - Fructose ingestion impairs expression of genes involved in skeletal muscle's adaptive response to aerobic exercise. AB - Background: The inverse relationship between exercise capacity and its variation over time and both cardiovascular and all-cause mortality suggests the existence of an etiological nexus between cardiometabolic diseases and the molecular regulators of exercise capacity. Coordinated adaptive responses elicited by physical training enhance exercise performance and metabolic efficiency and possibly mediate the health benefits of physical exercise. In contrast, impaired expression of genes involved in mitochondrial biogenesis or protein turnover in skeletal muscle-key biological processes involved in adaptation to physical training-leads to insulin resistance and obesity. Ingestion of fructose has been shown to suppress the exercise-induced GLUT4 response in rat skeletal muscle. To evaluate in greater detail how fructose ingestion might blunt the benefits of physical training, we investigated the effects of fructose ingestion on exercise induction of genes that participate in regulation of mitochondrial biogenesis and protein turnover in rat's skeletal muscle. Methods: Eight-week-old Wistar rats were randomly assigned to sedentary (C), exercise (treadmill running)-only (E), fructose-only (F), and fructose + exercise (FE) groups and treated accordingly for 8 weeks. Blood and quadriceps femoris were collected for biochemistry, serum insulin, and gene expression analysis. Expression of genes involved in regulation of mitochondrial biogenesis and autophagy, GLUT4, and ubiquitin E3 ligases MuRF 1, and MAFbx/Atrogin-1 were assayed with quantitative real-time polymerase chain reaction. Results: Aerobic training improved exercise capacity in both E and FE groups. A main effect of fructose ingestion on body weight and fasting serum triglyceride concentration was detected. Fructose ingestion impaired the expression of PGC-1alpha, FNDC5, NR4A3, GLUT4, Atg9, Lamp2, Ctsl, Murf-1, and MAFBx/Atrogin-1 in skeletal muscle of both sedentary and exercised animals while expression of Erralpha and Ppardelta was impaired only in exercised rats. Conclusions: Our results show that fructose ingestion impairs the expression of genes involved in biological processes relevant to exercise-induced remodeling of skeletal muscle. This might provide novel insight on how a dietary factor contributes to the genesis of disorders of glucose metabolism. PMID- 29234480 TI - Which Benefits Are Mentioned Most Often in Drug Development Publications? AB - Objectives: The aim was to identify theoretically expected as well as actually reported benefits from drug development and the importance of individual patient benefits compared to the collective benefits to society in general. Background: Ethical guidelines require that clinical research involving humans offer the potential for benefit. A number of characteristics can be applied to define research benefit. Often benefit is categorized as being either direct or indirect. Indirect benefits can involve collective benefits for society rather than any benefits to the trial patient or subject. The purpose of this review was to examine which potential individual and societal benefits were mentioned as being expected in publications from government experts and which were mentioned in publications describing completed drug development trial results. Methods: Literature on research benefit was first identified by searching the PubMed database using several combinations of the key words benefit and clinical research. The search was limited to articles published in English. A Google search with the same combinations of key words but without any language limitation was then performed. Additionally, the reference lists of promising articles were screened for further thematically related articles. Finally, a narrative review was performed of relevant English- and German-language articles published between 1996 and 2016 to identify which of several potential benefits were either theoretically expected or which were mentioned in publications on clinical drug development trial results. Results: The principal benefits from drug development discussed included 2 main types of benefit, namely individual benefits for the patients and collective benefits for society. Twenty-one of an overall total of 26 articles discussing theoretically expected benefits focused on individual patient benefits, whereas 17 out of 26 articles mentioned collective benefits to society. In these publications, the most commonly mentioned theoretically expected individual patient benefit was the chance to receive up-to-date care (38.1%). A general increase in knowledge about health care, treatments, or drugs (70.6%) was the most commonly mentioned theoretically expected benefit for society. In contrast, all 13 publications reporting actual benefits of clinical drug development trials focused on personal benefits and only 1 of these publications also mentioned a societal benefit. The most commonly mentioned individual benefit was an increased quality of life (53.9%), whereas the only mentioned collective benefit to society was a general gain of knowledge (100.0%). Conclusions: Both theoretically expected and actually reported benefits in the majority of the included publications emphasized the importance of individual patient benefits from drug development rather than the collective benefits to society in general. The authors of these publications emphasized the right of each individual patient or subject to look for and expect some personal benefit from participating in a clinical trial rather than considering societal benefit as a top priority. From an ethical point of view, the benefits each individual patient receives from his or her participation in a clinical trial might also be seen as a societal benefit, especially when the drug or device tested, if approved for marketing, would eventually be made available for other similar patients from the country in which the clinical trial was conducted. PMID- 29234481 TI - In Defense of Pharmaceutically Enhancing Human Morality. AB - Purpose: I will discuss the prospect of pharmaceutically enhancing human morality and decision making in such a way as to eliminate morally unjustifiable choices and promote desirable ones. Background: Our species in the relatively short period since it has emerged has enormously advanced in knowledge, science, and technical progress. When it comes to moral development, the distance it has covered is almost negligible. What if we could medically accelerate our moral development? What if we could once and for all render our species totally immune to certain vices? Methodology: I will examine whether pharmaceutically intervening in human morality would compromise the autonomy of moral agents. I will argue that the argument from the autonomy of the moral agent is neither stable nor convincing. Conclusions: In the light of Kantian ethics we might consider moral enhancement by pharmaceutical means to be a perfect duty for moral agents. PMID- 29234482 TI - Roads to Health in Developing Countries: Understanding the Intersection of Culture and Healing. AB - Background: The most important attribute to which all human beings aspire is good health because it enables us to undertake different forms of activities of daily living. The emergence of scientific knowledge in Western societies has enabled scientists to explore and define several parameters of health by drawing boundaries around factors that are known to influence the attainment of good health. For example, the World Health Organization defined health by taking physical and psychological factors into consideration. Their definition of health also included a caveat that says, "not merely the absence of sickness." This definition has guided scientists and health care providers in the Western world in the development of health care programs in non-Western societies. Objective: However, ethnomedical beliefs about the cause(s) of illness have given rise to alternative theories of health, sickness, and treatment approaches in the developing world. Thus, there is another side to the story. Method: Much of the population in developing countries lives in rural settings where the knowledge of health, sickness, and care has evolved over centuries of practice and experience. The definition of health in these settings tends to orient toward cultural beliefs, traditional practices, and social relationships. Invariably, whereas biomedicine is the dominant medical system in Western societies, traditional medicine-or ethnomedicine-is often the first port of call for patients in developing countries. Results: The 2 medical systems represent, and are influenced by, the cultural environment in which they exist. On one hand, biomedicine is very effective in the treatment of objective, measurable disease conditions. On the other hand, ethnomedicine is effective in the management of illness conditions or the experience of disease states. Nevertheless, an attempt to supplant 1 system of care with another from a different cultural environment could pose enormous challenges in non-Western societies. Conclusion: In general, we, as human beings, are guided in our health care decisions by past experiences, family and friends, social networks, cultural beliefs, customs, tradition, professional knowledge, and intuition. No medical system has been shown to address all of these elements; hence, the need for collaboration, acceptance, and partnership between all systems of care in cultural communities. In developing countries, the roads to health are incomplete without an examination of the intersection of culture and healing. Perhaps mutual exclusiveness rather inclusiveness of these 2 dominant health systems is the greatest obstacle to health in developing countries. PMID- 29234483 TI - The Influence of Emerging Markets on the Pharmaceutical Industry. AB - Emerging markets represent an exceptional opportunity for the pharmaceutical industry. Although a precise definition is not yet available, economists define emerging markets as developing prosperous countries in which investment is expected to result in higher income despite high risks. Qualifying a market as emerging is not merely based on the economic status of the country, but also on several criteria that render the definition applicable to each country. Jim O'Neil, retired chairman of asset management at Goldman Sachs, identified leading economies of emerging markets: Brazil, Russia, India, and China (BRIC) and later Brazil, Russia, India, China, and South Africa (BRICS) and then Mexico, Indonesia, South Korea, and Turkey (MIST), which followed years later as the second tier of nations. Sales of the pharmaceutical markets in BRICS and MIST countries doubled in 5 years, reaching a market share of approximately 20%. The shift toward these new markets has been attributed to the large populations, growing prosperity, and increasing life expectancy in BRICS and MIST countries. In addition, companies are experiencing flattened growth of developed markets, expiration of patents leading to the up-selling of less expensive generic drugs, and tight regulations enforced in mature markets. Particular attention must therefore be given to these emerging markets. The strategies adopted by pharmaceutical companies that want to expand in these markets must be tailored to the pace of development of each country. These countries need drugs against infectious diseases and communicable diseases such as sexually transmitted diseases. They are readily exploitable territories for the innovative products of pharmaceuticals. Nevertheless, with the increase in wealth and longevity, a change of lifestyle is occurring. These changes accompany a shift in disease patterns. A disproportionally fast rise in the incidence of noncommunicable diseases such as cardiovascular illnesses, diabetes, and oncologic diseases has been observed in emerging markets, mimicking their Western counterparts. The incidence of diabetes and oncologic diseases is expected to grow by 20% or more by 2030. This shows that pharmaceutical industries will also be able to market their global products in these new countries. Conquering emerging markets can be challenging for industries. These challenges can be grouped into 3 categories: infrastructure development, cost-containment policies, and value-driven drug evaluation. Top strategies considered to overcome these challenges include adequate tailoring and a gain in market. PMID- 29234484 TI - Determining the Surface Structure of Silicated Alumina Catalysts via Isotopic Enrichment and Dynamic Nuclear Polarization Surface-Enhanced NMR Spectroscopy. AB - Isotopic enrichment of 29Si and DNP-enhanced NMR spectroscopy are combined to determine the detailed surface structure of a silicated alumina catalyst. The significant sensitivity enhancement provided by DNP is vital to the acquisition of multinuclear and multidimensional experiments that provide information on the atomic-level structure of the species present at the surface. Isotopic enrichment not only facilitates spectral acquisition, particularly given the low (1.5 wt %) Si loading, but also enables spectra with higher resolution than those acquired using DNP to be obtained. The unexpected similarity of conventional, CP, and DNP NMR spectra is attributed to the presence of adventitious surface water that forms a sufficiently dense 1H network at the silica surface so as to mediate efficient polarization transfer to all Si species regardless of their chemical nature. Spectra reveal the presence of Si-O-Si linkages at the surface (identified as Q4(3Al)-Q4(3Al)) and confirm that the anchoring of the surface overlayer with the alumina occurs through AlIV and AlV species only. This suggests the presence of Q3/Q4 Si at the surface affects the neighboring Al species, modifying the surface structure and making it less likely AlVI environments are in close spatial proximity. In contrast, Q1/Q2 species, bonded to the surface by fewer covalent bonds, have less of an effect on the surface, and more AlVI species are consequently found nearby. The combination of isotropic enrichment and DNP provides a definitive and fully quantitative description of the Si-modified alumina surface, and we demonstrate that almost one-third of the silicon at the surface is connected to another Si species, even at the low level of coverage used, lowering the propensity for the formation of Bronsted acid sites. This suggests that a variation in the synthetic procedure might be required to obtain a more even coverage for optimum performance. The work here will allow for more rigorous future investigations of structure-function relationships in these complex materials. PMID- 29234485 TI - Regulation of Sirtuin-Mediated Protein Deacetylation by Cardioprotective Phytochemicals. AB - Modulation of posttranslational modifications (PTMs), such as protein acetylation, is considered a novel therapeutic strategy to combat the development and progression of cardiovascular diseases. Protein hyperacetylation is associated with the development of numerous cardiovascular diseases, including atherosclerosis, hypertension, cardiac hypertrophy, and heart failure. In addition, decreased expression and activity of the deacetylases Sirt1, Sirt3, and Sirt6 have been linked to the development and progression of cardiac dysfunction. Several phytochemicals exert cardioprotective effects by regulating protein acetylation levels. These effects are mainly exerted via activation of Sirt1 and Sirt3 and inhibition of acetyltransferases. Numerous studies support a cardioprotective role for sirtuin activators (e.g., resveratrol), as well as other emerging modulators of protein acetylation, including curcumin, honokiol, oroxilyn A, quercetin, epigallocatechin-3-gallate, bakuchiol, tyrosol, and berberine. Studies also point to a cardioprotective role for various nonaromatic molecules, such as docosahexaenoic acid, alpha-lipoic acid, sulforaphane, and caffeic acid ethanolamide. Here, we review the vast evidence from the bench to the clinical setting for the potential cardioprotective roles of various phytochemicals in the modulation of sirtuin-mediated deacetylation. PMID- 29234486 TI - JNK-signaling: A multiplexing hub in programmed cell death. AB - Jun N-terminal kinases or JNKs have been shown to be involved in a wide array of signaling events underlying tumorigenesis and tumor progression. Through its interaction with a diverse set of signaling proteins and adaptors, JNKs regulate cell proliferation, invasive migration, therapy resistance, and programmed cell death. JNKs have been shown to play a role in apoptotic as well as non-apoptotic programmed cell death mechanisms including those of necroptosis, ferroptosis, pyroptosis, and autophagy. Most of the tumorigenic regulatory functions of JNKs can be related to their ability to module cell death via these programmed cell death mechanisms. JNKs stimulate or inhibit cell death in a context-dependent manner by stimulating the expression of specific genes as well as by modulating the activities of pro- and anti-apoptotic proteins through distinct phosphorylation events. This review summarizes our current understanding of the role of JNK in programmed cell death and its impact on cancer growth, progression, and therapy. PMID- 29234487 TI - Alcohol, stem cells and cancer. AB - Dosage, gender, and genetic susceptibility to the effects of alcohol remained only partially elucidated. In this review, we summarize the current knowledge of the mechanisms underlying the role of alcohol in liver and gastrointestinal cancers. In addition, two recent pathways- DNA repair and TGF-beta signaling which provide new insights into alcohol in the regulation of cancers and stem cells are also discussed here. PMID- 29234488 TI - SIRT6 histone deacetylase functions as a potential oncogene in human melanoma. AB - Melanoma is an aggressive skin cancer that can rapidly metastasize to become fatal, if not diagnosed early. Despite recent therapeutic advances, management of melanoma remains difficult. Therefore, novel molecular targets and strategies are required to manage this neoplasm. This study was undertaken to determine the role of the sirtuin SIRT6 in melanoma. Employing a panel of human melanoma cells and normal human melanocytes, we found significant SIRT6 mRNA and protein upregulation in melanoma cells. Further, using a tissue microarray coupled with quantitative Vectra analysis, we demonstrated significant SIRT6 overexpression in human melanoma tissues. Lentiviral short hairpin RNA-mediated knockdown of SIRT6 in A375 and Hs 294T human melanoma cells significantly decreased cell growth, viability, and colony formation, induced G1-phase arrest and increased senescence associated beta-galactosidase staining. As autophagy is important in melanoma and is associated with SIRT6, we used a qPCR array to study SIRT6 knockdown in A375 cells. We found significant modulation in several genes and/or proteins (decreases in AKT1, ATG12, ATG3, ATG7, BAK1, BCL2L1, CLN3, CTSB, CTSS, DRAM2, HSP90AA1, IRGM, NPC1, SQSTM1, TNF, and BECN1; increases in GAA, ATG10). Our data suggests that increased SIRT6 expression may contribute to melanoma development and/or progression, potentially via senescence-and autophagy-related pathways. PMID- 29234489 TI - Molecular insights: Suppression of EGFR and AKT activation by a small molecule in non-small cell lung cancer. AB - Epidermal growth factor receptor (EGFR) activation events and the mammalian target of rampamycin (mTOR) are considered important therapeutic targets in alleviating cancer conditions. The current treatment paradigm has shifted to personalized treatment strategies with tyrosine kinase inhibitors (TKIs) or anaplastic lymphoma kinase (ALK) inhibitors, due to low survival rates in non small cell lung cancer (NSCLC) in terms of the prevailing platinum-based therapy. In the present study, we examined the anticancer potential of Verrucarin J (VJ), a small molecule, in NSCLC cell lines (H460 and A549). The small molecule significantly inhibited cell growth, proliferation, colony forming ability, and induced apoptosis in both lung cancer cell lines. The inhibitory effects on EGFR (pEGFR -tyr1173) and AKT (pAKT Serine473) signaling, downregulates downstream pro survival signaling (mTOR and NF-kappaB) in cancer cell lines. In addition, VJ abrogated invasive and migratory potential of A549 and H460 cells. We also observed a downregulation of mesenchymal markers such as N-cadherin, Slug, beta catenin, and vimentin expression in both cell lines. Our results suggest that VJ inhibited cancer cell growth and could be a potent molecule to inhibit EGFR and AKT signaling in NSCLC. PMID- 29234490 TI - Geminin deficiency enhances survival in a murine medulloblastoma model by inducing apoptosis of preneoplastic granule neuron precursors. AB - Medulloblastoma is the most common malignant brain cancer of childhood. Further understanding of tumorigenic mechanisms may define new therapeutic targets. Geminin maintains genome fidelity by controlling re-initiation of DNA replication within a cell cycle. In some contexts, Geminin inhibition induces cancer selective cell cycle arrest and apoptosis and/or sensitizes cancer cells to Topoisomerase IIalpha inhibitors such as etoposide, which is used in combination chemotherapies for medulloblastoma. However, Geminin's potential role in medulloblastoma tumorigenesis remained undefined. Here, we found that Geminin is highly expressed in human and mouse medulloblastomas and in murine granule neuron precursor (GNP) cells during cerebellar development. Conditional Geminin loss significantly enhanced survival in the SmoA1 mouse medulloblastoma model. Geminin loss in this model also reduced numbers of preneoplastic GNPs persisting at one postnatal month, while at two postnatal weeks these cells exhibited an elevated DNA damage response and apoptosis. Geminin knockdown likewise impaired human medulloblastoma cell growth, activating G2 checkpoint and DNA damage response pathways, triggering spontaneous apoptosis, and enhancing G2 accumulation of cells in response to etoposide treatment. Together, these data suggest preneoplastic and cancer cell-selective roles for Geminin in medulloblastoma, and suggest that targeting Geminin may impair tumor growth and enhance responsiveness to Topoisomerase IIalpha-directed chemotherapies. PMID- 29234491 TI - Erratum: PRAJA is overexpressed in glioblastoma and contributes to neural precursor development. AB - [This corrects the article DOI: 10.18632/genesandcancer.151.]. PMID- 29234492 TI - No preliminary evidence of differences in astrocyte density within the white matter of the dorsolateral prefrontal cortex in autism. AB - Background: While evidence for white matter and astrocytic abnormalities exist in autism, a detailed investigation of astrocytes has not been conducted. Such an investigation is further warranted by an increasing role for neuroinflammation in autism pathogenesis, with astrocytes being key players in this process. We present the first study of astrocyte density and morphology within the white matter of the dorsolateral prefrontal cortex (DLPFC) in individuals with autism. Methods: DLPFC formalin-fixed sections containing white matter from individuals with autism (n = 8, age = 4-51 years) and age-matched controls (n = 7, age = 4-46 years) were immunostained for glial fibrillary acidic protein (GFAP). Density of astrocytes and other glia were estimated via the optical fractionator, astrocyte somal size estimated via the nucleator, and astrocyte process length via the spaceballs probe. Results: We found no evidence for alteration in astrocyte density within DLPFC white matter of individuals with autism versus controls, together with no differences in astrocyte somal size and process length. Conclusion: Our results suggest that astrocyte abnormalities within the white matter in the DLPFC in autism may be less pronounced than previously thought. However, astrocytic dysregulation may still exist in autism, even in the absence of gross morphological changes. Our lack of evidence for astrocyte abnormalities could have been confounded to an extent by having a small sample size and wide age range, with pathological features potentially restricted to early stages of autism. Nonetheless, future investigations would benefit from assessing functional markers of astrocytes in light of the underlying pathophysiology of autism. PMID- 29234494 TI - Company size, work-home interference, and well-being of self-employed entrepreneurs. AB - Background: The impact of working conditions on the health and well-being of workers of large enterprises has been widely described. This influence has not been studied as extensively in very small and medium-sized enterprises mainly due to methodological difficulties. Smaller organisations nevertheless constitute a reality that needs to be better understood. Methodology: The aim of this article is to better understand the working conditions of entrepreneurs in small and medium-sized enterprises, to describe the impact of these conditions on their health and well-being, and to learn how their work affects their private lives.This is why a study was conducted in 2015-2016 on a selected sample of entrepreneurs in the Brussels-Capital Region (n = 140). The survey form included questions pertaining to the work environment, motivations underlying the choice of activities, robustness of the business, work-home interference, work-related stress, work satisfaction, self-reported health indicators, and socio-demographic status. The results were compared with those from another survey on workers in small shops conducted between 2012 and 2015 within the same Region (n = 104). Results: The number of entrepreneurs who participated in the survey added up to 140, with an even distribution between men and women. Two results are highlighted. The first concerns the difficulties faced by entrepreneurs working with a small team (1 to 4 employees): they are more stressed, report having heavy workloads, describe their health more negatively, consume more sedatives, and claim to suffer from loneliness more often than those working with larger teams or alone. Comparatively, in the study on shopkeepers, business owners working alone found themselves in a worse situation regarding their health and well being.The second finding involves the difficulties entrepreneurs face when it comes to combining work and family life, and for which gender inequalities were noted. This phenomenon remains insufficiently explored amongst small business owners. Conclusion: In spite of the difficulties encountered at work, commitment to their chosen profession remains strong amongst entrepreneurs. Our results enable us underscore the aspects of entrepreneurial activity that should be taken into account whilst setting up support mechanisms or promoting entrepreneurship, especially amongst and for women. PMID- 29234495 TI - Response of letter to the editor on Procalcitonin: a promising diagnostic marker for sepsis and antibiotic therapy. AB - In a letter to the editor, Raineri SM et al. have given an insight of another dimension of procalcitonin (PCT) use as a diagnostic tool in invasive candidiasis. But based on our preliminary information, PCT is reported as unconventional modes of diagnosis approach which yet to prove its stand-alone biomarker properties for invasive candidiasis. PMID- 29234496 TI - Persistent diarrhoea in a 5-month-old baby carrying Vibrio cholerae nonO1/nonO139 producing Haitian cholera toxin. AB - Cholera toxin (CT) is the principal virulence factor of Vibrio cholerae for fatal cholera diarrhoea. Serogroups O1 and O139 harbour CT and are known to be epidemic strains. The remaining serogroups (nonO1/nonO139) are non-toxigenic and may be associated with mild disease. O1 serogroup emerged with a variant of CT known as Haitian cholera toxin (HCT). The HCT strains are hypervirulent and have been associated with severe cholera outbreaks in India, Western Africa and Haiti. Here, we report the presence of HCT (ctxB7) in a nonO1/nonO139 isolate causing persistent diarrhoea. PMID- 29234497 TI - Insertional inactivation of oprD in carbapenem-resistant Pseudomonas aeruginosa strains isolated from burn patients in Tehran, Iran. AB - In this study, we report the insertion sequence ISPpu21 in the oprD porin gene of carbapenem-resistant Pseudomonas aeruginosa isolates from burn patients in Tehran, Iran. Antibiotic susceptibility tests for P. aeruginosa isolates were determined. Production of metallo-beta-lactamases (MBLs) and carbapenemase was evaluated and the beta-lactamase-encoding and aminoglycoside-modifying enzyme genes were investigated by PCR and sequencing methods. The mRNA transcription level of oprD and mex efflux pump genes were evaluated by real-time PCR. The outer membrane protein profile was determined by SDS-PAGE. The genetic relationship between the P. aeruginosa isolates was assessed by random amplified polymorphic DNA PCR. In all, 10.52% (10/95) of clinical isolates of P. aeruginosa harboured the ISPpu21 insertion element in the oprD gene. The extended-spectrum beta-lactamase-encoding gene in ISPpu21-carrying isolates was blaTEM. PCR assays targeting MBL and carbapenemase-encoding genes were also negative in all ten isolates. The rmtA, aadA, aadB and armA genes were positive in all ISPpu21 harbouring isolates. The relative expression levels of the mexX, mexB, mexT and mexD genes in ten isolates ranged from 0.1- to 1.4-fold, 1.1- to 3.68-fold, 0.3- to 8.22-fold and 1.7- to 35.17-fold, respectively. The relative expression levels of the oprD in ten isolates ranged from 0.57- to 35.01-fold, which was much higher than those in the control strain P. aeruginosa PAO1. Evaluation of the outer membrane protein by SDS-PAGE suggested that oprD was produced at very low levels by all isolates. Using random amplified polymorphic DNA PCR genotyping, eight of the ten isolates containing ISPpu21 were shown to be clonally related. The present study describes a novel molecular mechanism, ISPpu21 insertion of the oprD gene, associated with carbapenem resistance in clinical P. aeruginosa isolates. PMID- 29234498 TI - Evaluation of the National Return of unwanted medicines (RUM) program in Australia: a study protocol. AB - Background: The National Return of Unwanted Medicines (NatRUM) program in Australia is one of the few nationally coordinated, free-to-consumer schemes to dispose of unwanted medicines globally. This scheme has been in operation since 1996, however, little is known about public awareness of the scheme and its effectiveness in reducing unsafe disposal practices. The study objectives are to undertake a review of (1) the current use of the NatRUM scheme by consumers; and (11) to investigate disposal practices and beliefs of the general population. Methods/design: A two-stage, mixed-methods study will be undertaken. Stage One will include a nation-wide audit of a representative sample of unwanted medicine bins, collected by community pharmacies, for incineration. The audit will detail the type and amount of unwanted medicines collected and if they are subsidised on the national formulary (Pharmaceutical Benefits Scheme). Stage Two will include: (i) a large, representative, general population survey; and (ii) more detailed interviews with a sub-set of this sample, who take five or more medications. Results will quantitatively describe the awareness of the NatRUM scheme, disposal practices and the volume of unwanted medicines stored in the home. It will qualitatively describe beliefs and perceptions about storage and disposal practices. Discussion: It is anticipated that this study will provide valuable insights about how Australians dispose of unwanted medicines, their awareness of the NatRUM scheme and how the scheme might be strengthened. Results will inform the Federal Department of Health and NatRUM Ltd. Board at a local level, as well as other countries who are yet to develop or implement coordinated disposal schemes. A number of challenges are expected, including ensuring the consistency of medicines terminology during the bin audit and recruiting a representative sample of Australians for the general population survey. Results of this study will be widely disseminated to support the translation of findings into practice. PMID- 29234493 TI - What are the risks of manual treatment of the spine? A scoping review for clinicians. AB - Background: Communicating to patients the risks of manual treatment to the spine is an important, but challenging element of informed consent. This scoping review aimed to characterise and summarise the available literature on risks and to describe implications for clinical practice and research. Method: A methodological framework for scoping reviews was followed. Systematic searches were conducted during June 2017. The quantity, nature and sources of literature were described. Findings of included studies were narratively summarised, highlighting key clinical points. Results: Two hundred and fifty articles were included. Cases of serious adverse events were reported. Observational studies, randomised studies and systematic reviews were also identified, reporting both benign and serious adverse events.Benign adverse events were reported to occur commonly in adults and children. Predictive factors for risk are unclear, but for neck pain patients might include higher levels of neck disability or cervical manipulation. In neck pain patients benign adverse events may result in poorer short term, but not long term outcomes.Serious adverse event incidence estimates ranged from 1 per 2 million manipulations to 13 per 10,000 patients. Cases are reported in adults and children, including spinal or neurological problems as well as cervical arterial strokes. Case-control studies indicate some association, in the under 45 years age group, between manual interventions and cervical arterial stroke, however it is unclear whether this is causal. Elderly patients have no greater risk of traumatic injury compared with visiting a medical practitioner for neuro-musculoskeletal problems, however some underlying conditions may increase risk. Conclusion: Existing literature indicates that benign adverse events following manual treatments to the spine are common, while serious adverse events are rare. The incidence and causal relationships with serious adverse events are challenging to establish, with gaps in the literature and inherent methodological limitations of studies. Clinicians should ensure that patients are informed of risks during the consent process. Since serious adverse events could result from pre-existing pathologies, assessment for signs or symptoms of these is important. Clinicians may also contribute to furthering understanding by utilising patient safety incident reporting and learning systems where adverse events have occurred. PMID- 29234499 TI - Removal of precursors and disinfection by-products (DBPs) by membrane filtration from water; a review. AB - Disinfection by-products (DBPs) have heterogeneous structures which are suspected carcinogens as a result of reactions between NOMs (Natural Organic Matter) and oxidants/disinfectants such as chlorine. Because of variability in DBPs characteristics, eliminate completely from drinking water by single technique is impossible. The current article reviews removal of the precursors and DBPs by different membrane filtration methods such as Microfiltration (MF), Ultrafiltration (UF), Nanofiltration (NF) and Reverse Osmosis (RO) techniques. Also, we provide an overview of existing and potentially Membrane filtration techniques, highlight their strengths and drawbacks. MF membranes are a suitable alternative to remove suspended solids and colloidal materials. However, NOMs fractions are effectively removed by negatively charged UF membrane. RO can remove both organic and inorganic DBPs and precursors simultaneously. NF can be used to remove compounds from macromolecular size to multivalent ions. PMID- 29234500 TI - Moving from information and collaboration to action: report from the 3rd International Dog Health Workshop, Paris in April 2017. AB - Background: Breed-related health problems in dogs have received increased focus over the last decade. Responsibility for causing and/or solving these problems has been variously directed towards dog breeders and kennel clubs, the veterinary profession, welfare scientists, owners, regulators, insurance companies and the media. In reality, all these stakeholders are likely to share some responsibility and optimal progress on resolving these challenges requires all key stakeholders to work together. The International Partnership for Dogs (IPFD), together with an alternating host organization, holds biennial meetings called the International Dog Health Workshops (IDHW). The Societe Centrale Canine (French Kennel Club) hosted the 3rd IDHW, in Paris, in April, 2017. These meetings bring together a wide range of stakeholders in dog health, science and welfare to improve international sharing of information and resources, to provide a forum for ongoing collaboration, and to identify specific needs and actions to improve health, well-being and welfare in dogs. Results: The workshop included 140 participants from 23 countries and was structured around six important issues facing those who work to improve dog health. These included individualized breed specific strategies for health and breeding, extreme conformations, education and communication in relation to antimicrobial resistance, behavior and welfare, genetic testing and population-based evidence. A number of exciting actions were agreed during the meeting. These included setting up working groups to create tools to help breed clubs accelerate the implementation of breed-health strategies, review aspects of extreme conformation and share useful information on behavior. The meeting also heralded the development of an online resource of relevant information describing quality measures for DNA testing. A demand for more and better data and evidence was a recurring message stressed across all themes. Conclusions: The meeting confirmed the benefits from inclusion of a diverse range of stakeholders who all play relevant and collaborative parts to improve future canine health. Firm actions were set for progress towards improving breed-related welfare. The next international workshop will be in the UK in 2019 and will be organized by the UK Kennel Club. PMID- 29234501 TI - Characterization of reproductive endocrinology and infertility (REI) fellowship applicants: guiding our mentees toward success. AB - Background: Advanced subspecialty training in reproductive endocrinology and infertility (REI) entails a competitive application process with many data points considered. It is not known what components weigh more heavily for applicants. Thus, we sought to study the REI fellow applicant and compare 1) those who apply but do not receive an interview, 2) those who receive an interview but do not match, and 3) those who successfully match. Methods: This retrospective cohort study was conducted at a single REI fellowship program from 2013 to 2017. Academic variables assessed included standardized test scores and total number of publications listed on their curriculum vitae. Logistic regression models were constructed to determine variables that were predictive of being offered an interview in our program and of matching in any program. Results: There were 270 applicants, of which 102 were offered interviews. Interviewed applicants had significantly higher mean USMLE 1 and CREOG scores, as well as total publications and total abstracts. There was no difference in Step 2 and Step 3 scores or in number of book chapters. Of those interviewed, USMLE scores remained predictive of matching in any program; however, publications and scientific abstracts were no longer predictive. Conclusions: The decision to offer applicants interviews appears to be influenced by objective standardized test scores, as well as a threshold of academic productivity. These items are less predictive of matching once the interview process begins, indicating that other factors, such as performance during the interview day, may be more heavily weighted. PMID- 29234502 TI - Nuchal cord and its implications. AB - Nuchal cord occurs when the umbilical cord becomes wrapped around the fetal neck 360 degrees. Nuchal cords occur in about 10-29% of fetuses and the incidence increases with advancing gestation age. Most are not associated with perinatal morbidity and mortality, but a few studies have shown that nuchal cord can affect the outcome of delivery with possible long-term effects on the infants. Nuchal cords are more likely to cause problems when the cord is tightly wrapped around the neck, with effects of a tight nuchal cord conceptually similar to strangulation. Umbilical cord compression due to tight nuchal cords may cause obstruction of blood flow in thin walled umbilical vein, while infant's blood continues to be pumped out of the baby through the thicker walled umbilical arteries causing hypovolemia, acidosis and anemia. Some of these infants have physical features secondary to tight nuchal cords that are distinct from those seen with birth asphyxia. The purpose of this article is to review the pathophysiology of tight nuchal cords and explore gaps in knowledge and research areas. PMID- 29234505 TI - Mental health law across the UK. AB - The criteria governing medical treatment without consent in the three legal jurisdictions of the UK - England and Wales, Scotland and Northern Ireland - is discussed. PMID- 29234503 TI - Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study). AB - Background: Clinical research has recently demonstrated that vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (PICU) and associated with worse clinical course. Multiple adult ICU trials have suggested that optimization of vitamin D status through high-dose supplementation may reduce mortality and improve other clinically relevant outcomes; however, there have been no trials of rapid normalization in the PICU setting. The objective of this study is to evaluate the safety and efficacy of an enteral weight-based cholecalciferol loading dose regimen in critically ill children with VDD. Methods/design: The VITdAL-PICU pilot study is designed as a multicenter placebo controlled phase II dose evaluation pilot randomized controlled trial. We aim to randomize 67 VDD critically ill children using a 2:1 randomization schema to receive loading dose enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or a placebo solution. Participants, caregivers and outcome assessors will be blinded to allocation. Eligibility criteria include ICU patient, aged 37 weeks to 18 years, expected ICU length of stay more than 48 h, anticipated access to bloodwork at 7 days, and VDD (blood total 25 hydroxyvitamin D < 50 nmol/L). The primary objective is to determine whether the dosing protocol normalizes vitamin D status, defined as a blood total 25(OH)D concentration above 75 nmol/L. Secondary objectives include an examination of the safety of the dosing regimen (e.g. hypercalcemia, hypercalciuria, nephrocalcinosis), measures of vitamin D axis function (e.g. calcitriol levels, immune function), and protocol feasibility (eligibility criteria, protocol deviations, blinding). Discussion: Despite significant observational literature suggesting VDD to be a modifiable risk factor in the PICU setting, there is no robust clinical trial evidence evaluating the benefits of rapid normalization. This phase II clinical trial will evaluate an innovative weight-based dosing regimen intended to rapidly and safely normalize vitamin D levels in critically ill children. Study findings will be used to inform the design of a multicenter phase III trial evaluating the clinical and economic benefits to rapid normalization. Recruitment for this trial was initiated in January 2016 and is expected to continue until November 30, 2017. Trial registration: Clinicaltrials.gov NCT02452762. PMID- 29234504 TI - The effects of low-intensity blood flow restricted exercise compared with conventional resistance training on the clinical outcomes of active UK military personnel following a 3-week in-patient rehabilitation programme: protocol for a randomized controlled feasibility study. AB - Background: A challenge for rehabilitation practitioners lies in designing optimal exercise programmes that facilitate musculoskeletal (MSK) adaptations whilst simultaneously accommodating biological healing and the safe loading of an injured limb. A growing body of evidence supports the use of resistance training at a reduced load in combination with blood flow restriction (BFR) to enhance hypertrophic and strength responses in skeletal muscle. In-patient rehabilitation has a long tradition in the UK Military, however, the efficacy of low intensity (LI) BFR training has not been tested in this rehabilitation setting. The aims of this study are to determine (1) the feasibility of a randomised controlled trial (RCT) investigating LI-BFR training in a residential, multidisciplinary treatment programme and (2) provide preliminary data describing the within and between group treatment effects of a LI-BFR intervention and a conventional resistance training group in military personnel. Methods: This is a single-blind randomised controlled feasibility study. A minimum of 28 lower-limb injured UK military personnel, aged 18 to 50 years, attending rehabilitation at the UK Defence Medical Rehabilitation Centre (DMRC) will be recruited into the study. After completion of baseline measurements, participants will be randomised in a 1:1 ratio to receive 3 weeks (15 days) of intensive multidisciplinary team (MDT) in patient rehabilitation. Group 1 will receive conventional resistance training 3 days per week. Group 2 will perform twice daily LI-BFR training. Both groups will also undertake the same common elements of the existing MDT programme. Repeat follow-up assessments will be undertaken upon completion of treatment. Group 2 participants will be asked to rate their pain response to LI-BFR training every five sessions. Discussion: The results will provide information on the feasibility of a full-scale RCT. Recommendations for an adequately powered study to determine the efficacy of LI-BFR training during in-patient rehabilitation can then be made. The study may also provide insights into the potential effectiveness of LI-BFR training as a novel exercise modality to induce muscle adaptations in the absence of high mechanical loading of the lower-limb. Trial registration: ISRCTN Reference: ISRCTN 63585315 dated 25 April 2017. PMID- 29234506 TI - Newspaper depictions of mental and physical health. AB - Aims and method Media portrayals of mental illness have long been recognised as being misleading and stigmatising. Following the campaigns of several advocacy groups to address this issue, we aimed to evaluate the impact on mental health reporting over time. We repeated a survey we did 15 years ago using the same methods. Nine UK daily newspapers were surveyed over a 4-week period and coded with a schema to analyse the reporting of mental health compared with physical health. Results In total, 963 articles - 200 on mental health and 763 on physical health - were identified. Over half of the articles on mental health were negative in tone: 18.5% indicated an association with violence compared with 0.3% of articles on physical health. However, there were more quotes from patients with mental disorders than physical disorders (22.5% v. 19.7%) and an equal mention of treatment and rehabilitation. Clinical implications Mental health in print media remains tainted by themes of violence, however some improvement in reporting in recent years is evident, in particular by providing a voice for people with mental illness. PMID- 29234507 TI - Implementation of a novel primary care pathway for patients with severe and enduring mental illness. AB - Aims and method New collaborative care models with an emphasis on primary care are required for long-term management of patients with severe and enduring mental illness (SMI). We conducted a descriptive evaluation of clinical outcomes of the first 3 years of a novel enhanced primary care (EPC) service. Data from 2818 patients and staff survey results were analysed. Results 2310 patients were discharged to EPC (508 not assessed as clinically suitable or patients/general practitioners declined the transfer); mean length of stay with secondary care service of the cohort was 9.8 years (range 0-24). 717 patients (31%) have been discharged to primary care only out of the EPC services and 233 patients (10%) have been transferred back to secondary care. Patient and staff satisfaction with the new EPC model was high. No severe untoward incidents were recorded. Clinical implications The data suggest that EPC can be safely provided for a significant proportion of patients with SMI, who traditionally received long-term secondary care support. The novel EPC model can be utilised as a template for the provision of cost-effective, recovery-oriented and non-stigmatising care in the community. PMID- 29234508 TI - National survey of training of psychiatrists on advance directives to refuse treatment in bipolar disorder. AB - Aims and method To determine features associated with better perceived quality of training for psychiatrists on advance decision-making in the Mental Capacity Act 2005 (MCA), and whether the quality or amount of training were associated with positive attitudes or use of advance decisions to refuse treatment (ADRTs) by psychiatrists in people with bipolar disorder. An anonymised national survey of 650 trainee and consultant psychiatrists in England and Wales was performed. Results Good or better quality of training was associated with use of case summaries, role-play, ADRTs, assessment of mental capacity and its fluctuation. Good or better quality and two or more sessions of MCA training were associated with more positive attitudes and reported use of ADRTs, although many psychiatrists would never discuss them clinically with people with bipolar disorder. Clinical implications Consistent delivery of better-quality training is required for all psychiatrists to increase use of ADRTs in people with bipolar disorder. PMID- 29234509 TI - Assessing the second-hand effects of a new no-smoking policy in an acute mental health trust. AB - Aims and method To examine whether a new no-smoking policy in an in-patient mental health setting had any effects outside of smoking cessation. Our hypothesis stated that a forced smoking ban for in-patients may result in an increased susceptibility for clinical incidents, aggression and lower admission rates. All patients admitted to adult in-patient mental health services in Coventry and Warwickshire Partnership NHS Trust were included in the analysis. Data 6 months post-implementation of the smoking policy (1 July 2015 to 1 January 2016) were compared with the same period 1 year prior (1 July 2014 to 1 January 2015). Patient demographics, admission rates, ward occupancy, average lengths of stay, numbers of reported incidents and use of the Mental Health Act 1983 (MHA) were compared. Results We analysed 4223 admissions. We found a significantly increased number of admissions under the MHA (P = 0.007), a significantly greater number of reported smoking-related incidents (P < 0.001) and aggression-related incidents in the psychiatric intensive care unit (P < 0.001). However, we found no significant difference in capacity of in-patient wards (P = 0.39), admission length (P = 0.34) or total aggression-related incidents (P = 0.86). Clinical implications Although further comparisons over longer time periods are necessary, our results suggest that enforced smoking cessation on acutely unwell psychiatric patients admitted to the most restricted environments may have some negative effects. Nicotine replacement therapy should be offered to all patients to minimise the risk of clinical incident. PMID- 29234511 TI - Weekend new patient reviews in psychiatry: evaluation of activity over 3 months. AB - Aims and method South West London and St George's Mental Health NHS Trust developed a system of weekend new patient reviews by higher trainees to provide senior medical input 7 days a week. To evaluate the effectiveness of these reviews, the notes for all patients admitted over 3 months were examined. The mean length of stay for patients before and after the introduction of the weekend new patient reviews were compared via unpaired t-test. Results A total of 88 patients were seen: 84.4% of patients were seen within 24 h of admission. Higher trainees instituted some changes in 78.9% of patients. The most frequent action was to modify medication, in 47.8%. The average length of stay after the introduction of weekend reviews was not significantly different. Clinical implications Weekend reviews of newly admitted patients by higher trainees is a feasible method for providing senior input to patients admitted out of hours. PMID- 29234510 TI - A service evaluation of outcomes in two in-patient recovery units. AB - Aims and method To evaluate outcomes for patients during their admission or in the first year of treatment in two in-patient recovery units. Changes in health and social functioning, service use and need (rated by patients and staff) were evaluated. Results In 43 patients treated, there was a large (30%) increase in patients discharged to their own tenancies, rather than supported accommodation. There was minimal change in Health of the Nation Outcome Scales (HoNOS) scores in the course of the admission but staff- and patient-rated unmet needs reduced and met needs increased. Needs changed mainly in domains relating to social functioning. Reductions in risk to self and others were rated by staff but not patients. There were no cases of patients being readmitted to acute hospital during the study period. Clinical implications Although these results offer some support to the treatment approach described in these in-patient recovery units, further research in larger samples is needed to identify how these services can best be deployed to help individuals with severe mental illness and complex needs. PMID- 29234512 TI - New models of care: a liaison psychiatry service for medically unexplained symptoms and frequent attenders in primary care. AB - Aims and method This paper describes the process of setting up and the early results from a new liaison psychiatry service in primary care for people identified as frequent general practice attenders with long-term conditions or medically unexplained symptoms. Using a rapid evidence synthesis, we identified existing service models, mechanisms to identify and refer patients, and outcomes for the service. Considering this evidence, with local contingencies we defined options and resources. We agreed a model to set up a service in three diverse general practices. An evaluation explored the feasibility of the service and of collecting data for clinical, service and economic outcomes. Results High levels of patient and staff satisfaction, and reductions in the utilisation of primary and secondary healthcare, with associated cost savings are reported. Clinical implications A multidisciplinary liaison psychiatry service integrated in primary care is feasible and may be evaluated using routinely collected data. PMID- 29234513 TI - Systematic review into factors associated with the recruitment crisis in psychiatry in the UK: students', trainees' and consultants' views. AB - Aims and method To review the literature to examine the factors that may be affecting recruitment into psychiatry in the UK. We systematically searched four databases to identify studies from 1974 to 2016 and identified 27 papers that met the specified inclusion criteria. Results Most papers (n = 24) were based on questionnaire surveys. The population in all studies comprised of 1879 psychiatrists, 6733 students and 220 746 trainees. About 4-7% of students opt for a career in psychiatry. Enrichment activities helped to attract students more towards psychiatry than just total time spent in the specialty. Job content in terms of the lack of scientific basis, poor prognosis and stigma towards psychiatry, work-related stress and problems with training jobs were common barriers highlighted among students and trainees, affecting recruitment. Job satisfaction and family-friendly status of psychiatry was rated highly by students, with lifestyle factors appearing to be important for trainees who tend to choose psychiatry. Clinical implications Negative attitudes and stigma towards psychiatry continue to persist. Teaching and training in psychiatry needs rethinking to improve student experience and recruitment into the specialty. PMID- 29234514 TI - Mental Capacity Act (Northern Ireland) 2016. AB - Mental health legislation in Northern Ireland has always been separate from legislation in the rest of the UK; the Mental Health (Northern Ireland) Order (MHO) had been in place since 1986. In common with other jurisdictions, this legislation utilises the presence of mental disorder and risk as criteria for detention and involuntary treatment. The MHO has been replaced by the Mental Capacity Act (Northern Ireland) 2016 (MCA), an example of 'fusion' legislation in which impairment of decision-making capacity and best interests are the only criteria to be used when making decisions across health and social care. In this paper, we outline the development of the MCA to date, and discuss its potential to improve mental healthcare by placing the treatment of mental illness within the same legislative framework as physical illnesses. PMID- 29234516 TI - Profile. The constant psychiatrist: an interview with Michael Kopelman. PMID- 29234515 TI - Measuring relational security in forensic mental health services. AB - Aims and method Relational security is an important component of care and risk assessment in mental health services, but the utility of available measures remains under-researched. This study analysed the psychometric properties of two relational security tools, the See Think Act (STA) scale and the Relational Security Explorer (RSE). Results The STA scale had good internal consistency and could highlight differences between occupational groups, whereas the RSE did not perform well as a psychometric measure. Clinical implications The measures provide unique and complimentary perspectives on the quality of relational security within secure services, but have some limitations. Use of the RSE should be restricted to its intended purpose; to guide team discussions about relational security, and services should refrain from collecting and aggregating this data. Until further research validates their use, relational security measurement should be multidimensional and form part of a wider process of service quality assessment. PMID- 29234517 TI - Clozapine withdrawal syndrome. PMID- 29234518 TI - Living with obsessional personality. PMID- 29234519 TI - 'Burnout syndrome' - from nosological indeterminacy to epidemiological nonsense. PMID- 29234520 TI - Soft diagnosis, guidelines and hard choices. PMID- 29234521 TI - Mental health difficulties and suicidal behaviours among young migrants: multicentre study of European adolescents. AB - Background: Migration has been reported to be associated with higher prevalence of mental disorders and suicidal behaviour. Aims: To examine the prevalence of emotional and behavioural difficulties, suicidal ideation and suicide attempts among migrant adolescents and their non-migrant peers. Method: A school-based survey was completed by 11 057 European adolescents as part of the Saving and Empowering Young Lives in Europe (SEYLE) study. Results: A previous suicide attempt was reported by 386 (3.6%) adolescents. Compared with non-migrants, first generation migrants had an elevated prevalence of suicide attempts (odds ratio (OR) 2.08; 95% CI 1.32-3.26; P=0.001 for European migrants and OR 1.86; 95% CI 1.06-3.27; P=0.031 for non-European migrants) and significantly higher levels of peer difficulties. Highest levels of conduct and hyperactivity problems were found among migrants of non-European origin. Conclusions: Appropriate mental health services and school-based supports are required to meet the complex needs of migrant adolescents. Declaration of interest: None. Copyright and usage: (c) The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID- 29234522 TI - Maternal mental health and child problem behaviours: disentangling the role of depression and borderline personality dysfunction. AB - Background: It is not known whether associations between child problem behaviours and maternal depression can be accounted for by comorbid borderline personality disorder (BPD) dysfunction. Aim: To examine the contributions of maternal depression and BPD symptoms to child problem behaviours. Method: Depression trajectories over the first-year postpartum were generated using repeated measurement from a general population sample of 997 mothers recruited in pregnancy. In a stratified subsample of 251, maternal depression and BPD symptoms were examined as predictors of child problem behaviours at 2.5 years. Results: Child problem behaviours were predicted by a high maternal depression trajectory prior to the inclusion of BPD symptoms. This association was no longer significant after the introduction of BPD symptoms. Conclusions: Risks for child problem behaviours currently attributed to maternal depression may arise from more persistent and pervasive difficulties found in borderline personality dysfunction. Declaration of interest: None. Copyright and usage: (c) The Royal College of Psychiatrists 2017, this is an open access article distributed under the terms of the Creative Commons Attribution (CC BY) license. PMID- 29234523 TI - Amlodipine Vs. hydrochlorothiazide: is there any disparity in its antihypertensive effect or not? AB - We have read the article "Comparison of effects between calcium channel blocker and diuretics in combination with angiotensin II receptor blocker on 24-h central blood pressure and vascular hemodynamic parameters in hypertensive patients: study design for a multicenter, double-blinded, active controlled, phase 4, randomized trial" by GC Oh., et al. and found it quite interesting to learn the testing of effectiveness between amlodipine and hydrochlorothiazide in combination with losartan. After 4 weeks of therapy, non-responders were exposed for dose titration of losartan/amlodipine 100/5 mg daily or losartan/hydrochlorothiazide 100/25 mg daily. However, authors didn't increase in the amlodipine dose from 5 to 10 mg from randomization. However, as per literature both drugs are non-significant in their blood pressure lowering effect. The clarification on above point will further allay the efficacy concerns of clinicians and result in wider usage of future published data. PMID- 29234524 TI - Viral Hepatitis Endemicity and Trends among an Asymptomatic Adult Population in Ho: A 5-Year Retrospective Study at the Ho Municipal Hospital, Ghana. AB - Background: Using prospective blood donors as a proxy, this study was aimed at estimating the burden and five-year (2012-2016) trend of viral hepatitis (HBV and HCV) infection among asymptomatic adult population in Ho. Materials and Methods: A retrospective analysis was done on secondary data extracted from the hospital archives comprising 4,180 prospective blood donors from January 2012 to December 2016. Demographic variables included age and sex, as well as place of residence. Screening results of serum infectious markers (HBV and HCV) were obtained. Results: The prevalence of asymptomatic viral hepatitis (HBV and HCV) infection in the general adult population was 6.94% and 1.84%, respectively. Females recorded a higher burden of HBV and HCV (8.3% and 5.0%) compared to their male peers (6.8% and 1.4%). A significant age variation in HBV antigenaemia was seen with HBV seropositivity peaking among the younger population (less than 20 years' group) at 11.24% and troughed among the older population (above 50 years' group) at 0.92%. Conclusion: Asymptomatic viral hepatitis among adult population in the Ho Municipality is estimated at the intermediate to high endemicity level. Preventive measures to reduce the burden are urgently needed and should be targeted at the younger generation. PMID- 29234525 TI - Invasive Candida Infection after Upper Gastrointestinal Tract Surgery for Gastric Cancer. AB - Upper gastrointestinal tract (GIT) surgical procedures are more likely to cause nosocomial Candida peritonitis than lower GIT procedures and they thus constitute an independent risk factor for mortality. Because of the severity of postsurgical fungal infections complications, intensivists and surgeons need to be extremely aware of their clinical importance in critically ill postsurgical intensive care unit (ICU) patients. We analyzed the clinical and microbiological data of 149 oncologic patients who were hospitalized in the ICU at Soroka Medical Center between January 2010 and January 2015 after undergoing upper GIT surgery for gastric cancer. Invasive fungal infections related to secondary peritonitis following oncologic upper GIT surgery had a higher mortality rate than patients with nonfungal postoperative infectious complications. The presence of gastroesophageal junction leakage and advanced age were found to be independent risk factors for invasive fungal infection after oncologic upper GIT surgery. PMID- 29234526 TI - Usefulness of Urea as a Means of Improving the Solubility of Poorly Water-Soluble Ascorbyl Palmitate. AB - The aim of this study was to evaluate complexes of L-ascorbyl palmitate (ASCP) and urea (UR). This evaluation involved differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), near infrared spectroscopy (NIR), a solubility test, a 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging test, and a mushroom tyrosinase inhibition assay. Physicochemical evaluation revealed that ASCP/UR complexes form at a molar ratio of 1/12. The solubility test revealed that ASCP/UR complexes had increased solubility compared to ASCP. The DPPH radical scavenging test and mushroom tyrosinase inhibition assay revealed that the activity of ASCP/UR complexes was not impaired by complex formation. These results are probably due to the tetragonal crystal system of UR changing to a hexagonal crystal system and interaction with the alkyl group of ASCP. PMID- 29234527 TI - Sphingosine 1-Phosphate Receptor 1 Modulates CNTF-Induced Axonal Growth and Neuroprotection in the Mouse Visual System. AB - The lack of axonal regeneration and neuronal cell death causes permanent neurological deficits in the injured CNS. Using the classical CNS injury model of optic nerve crush in mice, ciliary neurotrophic factor (CNTF) was found to stimulate retinal ganglion cell (RGC) survival and axonal growth, but in an incomplete fashion. The elucidation of molecular mechanisms impairing CNTF induced axonal regeneration is paramount to promote visual recovery. In the present study, we sought to evaluate the contribution of sphingosine 1-phosphate receptor 1 (S1PR1) to the neuroprotective and regenerative effects of CNTF. The transduction of retinal cells with adeno-associated viruses (AAV) allowed to activate CNTF/signal transducer and activator of transcription 3 (Stat3) signaling and to modulate S1PR1 expression in RGCs. Our results showed that CNTF/Stat3 prevented injury-induced S1PR1 downregulation. Silencing S1PR1 in RGCs significantly enhanced CNTF-induced axonal growth in the injured optic nerve. In contrast, RGC survival was markedly decreased when S1PR1 was repressed with viral vectors. The level of phosphorylated Stat3 (P-Stat3), an intracellular mediator of CNTF, did not fluctuate after S1PR1 inhibition and CNTF stimulation. Collectively, these results suggest that S1PR1 acts as a major regulator of retinal neuron survival and restricts the RGC growth response induced by CNTF. PMID- 29234529 TI - The effectiveness of ureteric metal stents in malignant ureteric obstructions: A systematic review. AB - Objective: To review the literature on the effectiveness, safety and long-term patency of ureteric metal mesh stents (MSs), as a variety of MSs have been used for managing malignant ureteric obstruction over the last three decades. Materials and methods: A systematic review using the search string; Ureter* AND (stent OR endoprosthesis) AND metal* was conducted on PubMed, Scopus, Web of science and Cochrane Library online databases in May 2016. Prospective, retrospective, and comparative studies including MSs were included. The primary endpoint was the patency rate and the secondary endpoint was complications. Results: In all, 324 publications were screened and 31 articles were included in the systematic review; 21 prospective and 10 retrospective studies. These studies reported the effectiveness of specific MSs in population studies, in comparative studies among different MSs, as well as among MSs and JJ stents. It should be noted that all comparative studies were retrospective. Conclusion: The experiences with vascular MSs, such as the WallstentTM (Boston Scientific/Microvasive, Natick, MA, USA), were related to high occlusion rates, due to endoluminal hyperplasia, and long-term disappointing patency. The use of covered MSs designed for the vascular system was also unfavourable. The Memokath 051TM (PNN Medical A/S, Kvistgaard, Denmark) had better patency rates, but also higher migration rates. The long-term results were acceptable and rendered the Memokath 051 as a viable option for the management of malignant ureteric obstruction. The UventaTM (Taewoong Medical, Seoul, Korea) and AlliumTM (Allium Medical Solutions Ltd, Caesarea, Israel) MSs, specifically designed for ureteric placement, provided promising results. Nevertheless, the wide acceptance of these MSs would require well-designed clinical studies and long-term follow-up. PMID- 29234528 TI - Critical appraisal of literature comparing minimally invasive extraperitoneal and transperitoneal radical prostatectomy: A systematic review and meta-analysis. AB - Objectives: To systematically review studies comparing extraperitoneal (E-RP) and transperitoneal minimally invasive radical prostatectomy (T-RP). Methods: The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in September 2015. Several databases were searched including Medline and Scopus. Only studies comparing E-RP and T-RP (either laparoscopic or robot-assisted approach) were evaluated. The follow-up of the included patients had to be >=6 months. Results: In all, 1256 records were identified after the initial database search. Of these 20 studies (2580 patients) met the inclusion criteria. The hospital stay was significantly lower in the E-RP cohort, with a mean difference of -0.30 days (95% confidence interval [CI] -0.35, -0.24) for the laparoscopic group and 1.09 days (95% CI -1.47, -0.70) for the robotic group (P < 0.001). Early continence rates favoured the E-RP group, although this was statistically significant only in the laparoscopic group (odds ratio [OR] 2.52, 95% CI 1.72, 3.70; P < 0.001). There was no statistically significant difference between the E-RP and T-RP cohorts for 12-month continence rates for both the laparoscopic (OR 1.55, 95% CI 0.89, 2.69; P = 0.12) and robotic groups (OR 3.03, 95% CI 0.54, 16.85; P = 0.21). The overall complication and ileus rates were significantly lower in the E-RP cohort for both the laparoscopic and robotic groups. The symptomatic lymphocele rate favoured the T-RP cohort, although this was statistically significant only in the laparoscopic group (OR 8.69, 95% CI 1.60, 47.17; P = 0.01). Conclusion: This review suggests that the extraperitoneal approach is associated with a shorter hospital stay, lower overall complication rate, and earlier return to continence when compared to the transperitoneal approach. The transperitoneal approach has a lower lymphocele rate. PMID- 29234530 TI - A prospective randomised double-blind placebo-controlled trial to assess the effect of diuretics on shockwave lithotripsy of calculi. AB - Objective: To assess the effect of diuretics with shockwave lithotripsy (SWL) on the treatment of renal and upper ureteric calculi. Patients and methods: Adult patients with a solitary non-obstructive radio-opaque renal or upper ureteric calculus with normal renal function were included. They were prospectively randomised to receive either SWL with placebo or SWL with diuretics (40 mg parenteral furosemide) in a double-blind manner with a sample size of 48 patients in each arm. The primary outcomes were the SWL success and failure rates. The secondary outcomes were the number of shocks and sessions. Results: Complete fragmentation was achieved in 89.6% of the patients in the furosemide arm as compared to 81.3% in the placebo arm. Clearance was achieved in 77.1% of the patients in the furosemide arm as compared to 70.8% in the placebo arm. The number of shocks and the number of sessions were higher in the placebo arm. These differences were not statistically significant. Conclusion: The use of diuretics along with SWL treatment of renal and upper ureteric calculi does not show a statistically significant improvement in fragmentation or clearance. PMID- 29234531 TI - Ultra-mini-percutaneous nephrolithotomy (PCNL) versus standard PCNL: A randomised clinical trial. AB - Objective: To assess the effectiveness and advantages of ultra-mini-percutaneous nephrolithotomy (UM-PCNL) versus standard PCNL (S-PCNL), as one of the most important differences between the various PCNL techniques is the size of the renal access, which contributes to the broad spectrum of complications and outcomes. Patients and methods: This clinical randomised trial was conducted in 2016. In all, 70 patients with renal or upper ureteric stones of 10-20 mm in diameter, who were candidates for PCNL, were divided equally into two groups. Group A, underwent UM-PCNL using a 9.8-F ureteroscope through a 16-F sheath; and Group B, underwent S-PCNL using a 24-F nephroscope through a 30-F sheath. The stones were fragmented by pneumatic lithotripsy. Any perioperative complications and need for analgesia were recorded, and postoperative pain was assessed in both groups using a visual analogue scale (VAS). Results: There were statistically significant differences in postoperative haemoglobin values, haemoglobin drop, transfusion rate, duration of hospitalisation and postoperative VAS pain score between the groups (P < 0.05). There were no significant differences in operation time, need for auxiliary procedures or stone-free rate. Conclusion: A minimally invasive UM-PCNL using a 9.8-F ureteroscope can play an important role in the treatment of symptomatic renal and upper ureteric stones of <20 mm in diameter with lesser blood loss, duration of hospitalisation, need of transfusion, and postoperative pain compared with S-PCNL. PMID- 29234532 TI - Bilateral same-session ureterorenoscopy: A feasible approach to treat pan-urinary stone disease. AB - Objectives: To assess treatment effectiveness and safety of bilateral same session ureterorenoscopy (BSSU) for the management of stone disease involving the entire urinary system. Patients and methods: We reviewed the records of 64 patients who underwent BSSU for the treatment of bilateral ureteric and/or kidney stones. Size, number, location per side, and the total burden of stones were recorded. Data on stenting, lithotripsy, and stone retrieval, and details of hospital stay and operation times were investigated. Treatment results were assessed using intraoperative findings and postoperative imaging. The outcome was considered successful in patients who were completely stone-free or who had only residual fragments of <=2 mm. Results: The outcome was successful in 82.8% of the patients who received BSSU (54.7% stone-free and 28.1% insignificant residual fragments). The success rate per renal unit was 89.8%. There were no adverse events in 73.4% of the patients. The most common intraoperative complication was mucosal injury (36%). The complications were Clavien-Dindo Grade I in 9.4% and Grade II in 7.8%. Grade IIIa and IIIb (9.4%) complications required re treatments. Statistical evaluation showed no association between complication grades and stone, patient, or operation features. Stone burden had no negative impact on BSSU results. The presence of impacted proximal ureteric stones was significantly related to unsuccessful outcomes. Conclusion: BSSU is safe and effective for the management of bilateral urolithiasis. BSSU can prevent recurrent surgeries, reduce overall hospital stay, and achieve a stone-free status and complication rates that are comparable to those of unilateral or staged bilateral procedures. PMID- 29234533 TI - Trends of intervention for paediatric stone disease over the last two decades (2000-2015): A systematic review of literature. AB - Objective: To ascertain the publication trends of interventions for paediatric kidney stone disease (KSD) we conducted a systematic review of literature over the last 16 years. Patients and methods: With a rise of paediatric KSD and related interventions, a systematic review using PubMed was done over the last 16 years for all published papers on 'Paediatric stone disease intervention - ureteroscopy (URS), shockwave lithotripsy (SWL), percutaneous nephrolithotomy (PCNL), open stone surgery, and laparoscopic stone surgery'. The search was limited to English language articles with a published abstract, whilst case reports, animal and laboratory studies, were excluded. We also analysed the data in two time periods, period-1 (2000-2007) and period-2 (2008-2015). Results: During the last 16-years, 339 papers were published on paediatric stone disease intervention on PubMed. This included papers on URS (95), PCNL (97), SWL (102), open stone surgery (34) and laparoscopic stone surgery (11). During period-1 and period-2 there were 30 and 65 papers on URS, 16 and 81 papers on PCNL, 33 and 60 papers on SWL, nine and 25 papers on open surgery, respectively. When comparing the two periods, there were 92 published papers for all interventions in period-1 and this had risen almost threefold to 247 papers in period-2. Conclusions: Our systematic review shows that intervention for KSD in the paediatric age group has risen over the last 8 years. Whilst URS, SWL, open surgery and laparoscopic surgery have all doubled, PCNL has risen fivefold reflecting an increase in the new minimally invasive PCNL techniques. PMID- 29234534 TI - Comparison of interrupted- and continuous-suture urethroplasty in tubularised incised-plate hypospadias repair: A prospective study. AB - Objective: To compare the effect of interrupted- and continuous-suture urethroplasty on complication rates in Snodgrass tubularised incised-plate (TIP) hypospadias repair. Patients and methods: This was a prospective randomised study comprising 100 boys (age range 1-5 years) with primary subcoronal, distal- and mid-penile hypospadias who underwent repair from October 2010 to March 2015 in a tertiary care hospital. Boys with glanular, recurrent, and proximal hypospadias were excluded from the study. The boys were prospectively randomised into two groups: Group A, comprised 50 boys who underwent interrupted subcuticular suture Snodgrass TIP urethroplasty; and Group B, comprised 50 boys who underwent continuous subcuticular suture Snodgrass TIP urethroplasty. Outcomes were assessed in terms of complication rates and aesthetic appearance during follow up. Results: There was no significant difference in the occurrence of complications between the groups. There were 21 complications, with 10 occurring in Group A and 11 in Group-B. Urethrocutaneous fistula was the most common complication in both groups (six in Group A and seven in Group B), the fistulae were <2 mm in nine patients and 3-5 mm in the remaining four. Partial glans dehiscence occurred in one patient in each group. One patient from each group also had superficial wound infection, meatal stenosis and urethral stricture respectively, all of which were managed conservatively. The resultant urinary stream was single and good in all patients of both groups. Conclusions: The type of suture technique had no significant effect on complication rates after Snodgrass hypospadias repair and thus the choice of technique depends on surgeon preference. PMID- 29234535 TI - Is transurethral incision better than upper pole partial nephrectomy for management of duplex system ureterocoele diagnosed in the first year of life? AB - Objective: To compare the outcomes of transurethral incision (TUI) and upper pole partial nephrectomy (PN) in patients with duplex system ureterocoele (DSU). Patients and methods: We retrospectively reviewed the medical charts of patients who presented with DSU in the first-year of life and were managed with either TUI or PN. Patients' demographics, ultrasonography examinations, voiding cystourethrogram studies, and dimercaptosuccinic acid scans were reviewed. Also, the postoperative vesico-ureteric reflux status and febrile urinary tract infection occurrences, and subsequent surgical interventions were identified. The outcomes for the DSU location (intravesical vs extravesical) were compared. Results: Between January 1995 and September 2015, 44 patients underwent TUI (31 patients) or PN (13). The TUI patients presented at a median age of 1.1 months and were followed-up for a median of 47.4 months, whilst those who underwent PN presented at a median age of 1.06 months and were followed-up for a median of 44.23 months. Postoperatively, in the TUI group, four of 15 units had improved renal function and 11 units had stable function. In the PN group, five of nine units had stable renal function and the remaining four had worsened function (P = 0.019). Furthermore, 15 of the 31 patients (48%) in the TUI group required second interventions compared with one of 13 patients in the PN group (P = 0.01). There was no significant difference between the outcomes of intravesical and extravesical DSUs after TUI and PN. Conclusion: This study shows significant renal function preservation with TUI compared to PN. However, secondary surgical interventions were higher with TUI. PMID- 29234536 TI - Role of urethral plate and fossa navicularis biopsies in the detection of balanitis xerotica obliterans in boys undergoing redo hypospadias repair. AB - Objectives: To evaluate the presence of balanitis xerotica obliterans (BXO), clinically and pathologically, in the urethra of boys with failed previous hypospadias repair and where surgical management was planned. Patients and methods: Between February 2010 and March 2015, boys with failed distal penile hypospadias repair who were planned for surgical management were evaluated for the presence of clinical and pathological evidence of BXO. Samples were obtained from the urethral plate and fossa navicularis, after obtaining informed consent and ethical approval. The samples were fixed, sectioned, and haematoxylin and eosin stained for light microscopic examination. Results: In all, 157 boys were enrolled in our study, with a mean (SD) age of 6.4 (2.8) years. All the boys had a history of failed hypospadias repair surgeries (once or more). The presentation was fistula in 34 boys (21.7%), meatal stenosis in 45 (28.7%), urethral stricture in 28 (17.8%), and total dehiscence in 50 (31.8%). BXO was detected clinically in 46 boys (29.3%). The total number of biopsies taken was 314, of which 124 (39.5%) were pathologically BXO-positive samples. Of the 157 boys, BXO-positive cases were clinically associated with fistula in seven boys (4.5%), meatal stenosis in 18 (10.8%), urethral stricture in seven (4.5%), and total dehiscence in 15 (9.6%). Of the 314 pathological samples, pathologically BXO-positive samples were associated with fistula in 20 samples (6.4%), meatal stenosis in 40 (12.7%), urethral stricture in 22 (7%), and total dehiscence in 42 (13.4%). Conclusions: In failed hypospadias cases BXO should be considered, especially for cases with multiple failures, meatal stenosis, and total dehiscence. Urethral plate and fossa navicularis biopsies are important in planning a proper approach for subsequent repair. PMID- 29234537 TI - Day care bipolar transurethral resection vs photoselective vaporisation under sedoanalgesia: A prospective, randomised study of the management of benign prostatic hyperplasia. AB - Objective: To conduct a prospective randomised study comparing the safety, effectiveness and treatment outcomes in patients undergoing bipolar transurethral resection of the prostate (bTURP) and photoselective vaporisation of the prostate (PVP) under sedoanalgesia, as sedoanalgesia is a safe and effective technique suitable for minimally invasive endourological procedures and although studies have confirmed that both TURP and PVP are feasible under sedoanalgesia there are none comparing the two. Patients and methods: Between November 2014 and April 2016, all patients satisfying the eligibility criteria underwent either bTURP or PVP under sedoanalgesia after randomisation. The groups were compared for functional outcomes, visual analogue scale (VAS) pain scores (range 0-10), perioperative variables and complications, with a follow-up of 3 months. Results: In all, 42 and 36 patients underwent bTURP and PVP under sedoanalgesia, respectively. The mean VAS pain score was <2 at any time during the procedure, with no conversions to general anaesthesia. PVP patients had a shorter operating time [mean (SD) 55.64 (12.8) vs 61.79 (14.2) min, P = 0.035], shorter duration of hospitalisation [mean (SD) 14.58 (2.81) vs 19.21 (2.82) h, P < 0.001] and a higher dysuria rate when compared to bTURP patients. However, the catheterisation time was similar and both intraoperative and postoperative complications were minimal and comparable. Improvements in the International Prostate Symptom Score, quality of life, prostate volume, maximum urinary flow rate and post-void residual urine volume at 3 months were similar in both groups. None of our patients required re-admission or re-operation. Conclusion: Both PVP and bTURP can be carried out safely under sedoanalgesia with excellent treatment outcomes. PMID- 29234538 TI - Can androgen-deprivation therapy obviate the need of channel transurethral resection of the prostate in advanced prostate cancer with urinary retention? A prospective study. AB - Objective: To evaluate the efficacy of androgen-deprivation therapy (ADT) in relieving urinary retention in patients with advanced prostate cancer presenting with urinary retention or a high post-void residual urine volume (PVR). Patients and methods: Patients with advanced prostate cancer with an indwelling catheter for acute/chronic urinary retention, or with a high PVR (>200 mL) who had not received any previous treatment were included in the study. Patients with localised prostate cancer eligible for receiving any therapy aimed at cure were excluded. All enrolled patients were managed by ADT (LHRH antagonist/agonist or orchidectomy) combined with alpha-adrenoceptor antagonist/combined therapy for at least 1 month to a maximum of 3 months; they were given their first trial of voiding without catheter after 1 month, and monthly thereafter. Results: A total of 101 patients received ADT of which 97 were able to void successfully at the end of 3 months. In all, 27 patients could void in the first month, followed by 50 in the second month, and an additional 20 in the third month. There was a significant decrease in prostate volume, PVR, and International Prostate Symptom Score, and maximum urinary flow rates improved with normalisation of renal functions and resolution of upper tract changes noted on ultrasonography. Conclusion: ADT can relieve retention and decrease PVR over a period of time obviating the need for channel transurethral resection of the prostate. PMID- 29234539 TI - Transurethral bipolar plasmakinetic vapo-enucleation of the prostate: Is it safe for patients on chronic oral anticoagulants and/or platelet aggregation inhibitors? AB - Objectives: To assess the safety and efficacy of bipolar plasmakinetic enucleation and resection of the prostate (PKERP) for the management of benign prostatic hyperplasia (BPH) in patients on oral anticoagulant (OAC) therapy and/or platelet aggregation inhibitors (PAIs). Patients and methods: In all, 91 patients were recruited and underwent PKERP whilst they were receiving PAIs (aspirin, 56 patients; clopidogrel, three; aspirin and clopidogrel, 11). In all, 15 patients were receiving an OAC drug perioperatively, whilst another six patients were on dual PAIs and OACs. The primary outcomes were the perioperative morbidity and mortality rates. The secondary outcomes were functional outcomes including maximum urinary flow rate (Qmax), International Prostate Symptoms Score (IPSS), and post-void residual urine volume (PVR). Results: The mean (SD) age of the patients was 65 (5.9) years, preoperative adenoma volume was 80.9 (30.4) mL, and the operative time was 67 (23) min. No patient developed serious perioperative cardiovascular complications. The mean (SD) duration of hospital stay was 1.79 (1) days and the postoperative catheterisation time was 1.14 (0.76) days. The mean (SD) haemoglobin drop was 0.74 (0.61) g/dL, blood transfusion rate was 2.2%, and the clot retention rate was 2.2%. The mean (SD) postoperative Qmax was 18.6 (4.37) mL/s as compared to 7.2 (3.2) mL/s preoperatively (P < 0.001), and the preoperative IPSS was reduced from 24.3 (6.1) to 5.7 (2.3) postoperatively (P < 0.05). Prostate volume measured by transrectal ultrasonography was significantly reduced from a mean (SD) of 80.9 (30.4) mL preoperatively to 29.5 (10.6) mL postoperatively (P < 0.001). Conclusion: Minimally invasive PKERP may be considered as a safe and effective treatment option for managing patients with BPH receiving OAC/PAI drugs. PMID- 29234540 TI - Bipolar plasma kinetic enucleation of non-muscle-invasive bladder cancer: Initial experience with a novel technique. AB - Objective: To assess the effectiveness and safety of bipolar plasma kinetic energy for en bloc enucleation of non-muscle-invasive bladder cancer (NMIBC). Patients and methods: In all, 46 patients diagnosed with suspected NMIBC were included. All patients were diagnosed using ultrasonography, computed tomography, and diagnostic cystoscopy, and then underwent bipolar plasma kinetic enucleation of bladder tumour (PKEBT). At the end of the procedure, all patients had a single dose (40 mg in 40 mL saline) intravesical installation of mitomycin C (<6 h after bipolar PKEBT). Follow-up diagnostic cystoscopy was performed at 3, 6, and 12 months. Results: The mean (SD) enucleation time was 17 (5.4) min, operative time was 27.9 (11.4) min, haemoglobin drop was 1.3 (0.9) g/dL, postoperative irrigation time was 1.7 (2.3) h, and hospital stay was 35.4 (13) h. There was intraoperative bleeding in three patients, with one requiring blood transfusion. There were no other perioperative complications. At the 1-month follow-up, six (13%) patients were diagnosed with residual tumour and underwent repeat bipolar PKEBT. The overall recurrence rate at 12 months' follow-up was 15.2%. Conclusion: Bipolar PKEBT is an effective procedure for managing NMIBC, as it preserves the entire lamina propria and detrusor muscle in well-intact specimens, with negligible perioperative complications. PMID- 29234541 TI - Radical cystectomy in the elderly - Is this a safe treatment option? AB - Objective: To determine if significant differences exist in the perioperative outcomes of patients aged >75 years treated with radical cystectomy (RC) compared to younger patients, as RC is frequently not offered to 'elderly' patients with bladder cancer because of supposed increased risks of complications. Patients and methods: We retrospectively analysed prospectively collected data of all patients that underwent RC in our centre from May 2013 to June 2015. In all, 81 consecutive RCs were identified and included in our study. Patients were divided into two age groups: Group A, aged <75 years (51 patients) and Group B, aged >=75 years (30). Co-morbidities and perioperative outcomes were compared between the groups. Fisher's exact test was used for statistical analysis. Results: In 68 patients RC was performed laparoscopically and the remaining 13 patients underwent open RC. The mean (range) age was 70.7 (36-85) years. There were 37 patients with muscle-invasive disease and 42 had non-muscle-invasive disease. The median hospital stay was not significantly different between the two age groups (10 vs 11 days). There was no significant difference in the preoperative Charlson co-morbidity index. The 30-day mortality rate was 4% for those aged <75 years and 6.6% for those aged >=75 years, with overall perioperative complication rates of 57% vs 66%, respectively. Most complications were minor (Clavien-Dindo Grade I II) and there was no statistically significant difference between the two cohorts. There was also no statistically significant difference in blood transfusion rates. Conclusion: RC in patients aged >=75 years has similar perioperative morbidity when compared with younger patients and can be offered in selected elderly patients. Thus, age should not be an absolute contraindication for RC. PMID- 29234542 TI - Demographics and sexual characteristics of sex-enhancing medication users: Study of a web-based cross-sectional sample of sexually active men. AB - Objectives: To evaluate the frequency of sex-enhancing medications (S-EM) use and to investigate the demographics and sexual characteristics of the S-EM users amongst a Saudi Arabian male population. Subjects and methods: A cross-sectional sample of 1176 Saudi Arabian men was recruited using a web-based survey between 1 January and 1 April 2015. The survey included multiple open and closed questions to assess the frequency of S-EM use; and demographics, clinical, and sexual characteristics of S-EM users, as well as their perceptions of S-EM. Results: Amongst the participants, 1008 were sexually active and included in the data analysis. Of the sexually active participants, 402 (39.9%) reported S-EM use in the form of herbal or phosphodiesterase type 5 inhibitors at some time in their lives. Comparing S-EM users with S-EM non-users, the S-EM users had a number of demographic and sexual characteristics including: higher education level, higher income, smoking, more than one sexual partner, longer sexual activity duration, higher frequency of sexual intercourse, and lower sexual satisfaction level. Most of the S-EM users (82.1%) bought S-EM without a medical prescription and 62.5% had used them recreationally. In all, 52% of respondents used S-EM to treat ED and 69% of those who used it recreationally reported enhancement of erection with S-EM usage. Conclusions: Demographic and sexual characteristics of S-EM users and the attitude of the users towards the S-EM were identified amongst a Saudi Arabian male population. PMID- 29234543 TI - A new tool for self-evaluation of adherence to antimuscarinic drugs treatment in patients with urinary incontinence. AB - Abstract objective: To evaluate the validity of the Medication Adherence Self Report Inventory (MASRI) questionnaire in determining antimuscarinic drugs adherence in patients with urinary incontinence (UI). Patients and methods: In all, 629 patients [355 (56.4%) women and 274 (43.6%) men], aged 18-65 years, were included. All patients were prescribed antimuscarinic drugs and treatment adherence was tested at the start, and after 4, 8 and 12 weeks using the MASRI. The standard of external monitoring was the Brief Medication Questionnaire (BMQ) and visual count of the remaining pills. The functional status of the lower urinary tract was tested using voiding diaries and uroflowmetry. Results: The correlation between indicators of adherence according to the MASRI and screen mode of the BMQ was r = 0.84 (P <= 0.01), r = 0.72 (P <= 0.01), r = 0.7 (P <= 0.05) at 4, 8 and 12 weeks of follow-up, respectively, which indicated a satisfactory competitive validity. In the study of the discriminant validity, we found that non-adherent patients were correctly identified according to the MASRI in 96.2%, 96.9% and 96.2% of cases at 4, 8 and 12 weeks of follow-up, respectively. The values of the positive likelihood ratio (7.92, 10.81, and 12.8 at 4, 8 and 12 weeks of follow-up, respectively) were quite acceptable for the adherence forecast. The receiver operating characteristic analysis revealed a failure of the null hypothesis of the excess/insufficient discrimination power of the MASRI. The correlation between the percentage of non-adherent patients and the percentage of patients with impaired lower urinary tract function according to uroflowmetry data was r = 0.55 (P <= 0.05) at 4 weeks; r = 0.59 (P <= 0.05) at 8 weeks; and r = 0.62 (P <= 0.01) at 12 weeks. Conclusion: The MASRI questionnaire is highly constructive, competitive, has discriminant validity, and is suitable for self-assessment of treatment adherence in patients with UI taking antimuscarinics. Using the MASRI is less costly and faster compared with other assessment tools. PMID- 29234544 TI - Impact of transobturator vaginal tape on female stress urinary incontinence and sexual function. AB - Objective: To evaluate the effect of vaginal transobturator tape (TOT) on female stress urinary incontinence (SUI) and sexual function. Patients and methods: In all, 145 patients with SUI underwent TOT repair using the 'outside-in' technique. All patients had been sexually active in the previous 6 months. Patients were evaluated by history, routine laboratory investigations, cough stress test, abdominopelvic ultrasonography, and full urodynamic studies. The preoperative data assessed included: age, parity, body mass index, menopausal status, and Stamey grade of SUI. The intraoperative data assessed included: operative time, blood loss, and hospital stay; intra- and postoperative complications were also assessed. At 2 weeks after discharge, patients were followed-up with a routine examination and cough stress test. After 6 months' patients were assessed by urodynamic studies, maximum urinary flow rate, post-void residual urine volume. The following questionnaires were completed before and at 6 months after TOT insertion: International Consultation of Incontinence Questionnaire-Short Form (ICIQ-SF), Urogenital Distress Inventory-Short Form (UDI-6), and Female Sexual Function Index (FSFI). Results: All sociodemographic data of the 145 patients were collected. According to ICIQ-SF scores, 122 patients were cured, 19 had improved, and four failed. There were significant improvements in the UDI-6 and FSFI scores, indicating that the women had significant improvement in their sexual life. There were six cases of urinary tract infection, five cases had a fever, and eight patients complained of groin or thigh pain postoperatively. Conclusions: Correction of SUI using TOT appears to have a positive effect on female sexual function. PMID- 29234545 TI - Minimal surgical management of penile paraffinoma after subcutaneous penile paraffin injection. AB - Objectives: To describe our reconstructive technique, without flap or graft use, after penile self-augmentation with injected substances, such as paraffin, which are still performed with unfortunate consequences. Patient and methods: Successful single-stage minimal surgical management of an already twice unsuccessfully managed ulcerative penile paraffinoma in a 38-year-old Greek man. Results: The patient was discharged with no postoperative complications, with a five-item version of the International Index of Erectile Function score of 23/25 (i.e. normal erectile function) and flaccid penile length of 5 cm. Conclusions: Penile paraffinoma is a serious complication that can be successfully managed with a single-stage minimal surgical procedure, with normal aesthetic and functional results. PMID- 29234546 TI - Repigmentation of Tenacious Vitiligo on Apremilast. AB - Vitiligo is a common pigment disorder characterized by acquired loss of function or absence of melanocytes, leading to distinct areas of depigmentation. Physical exam reveals sharply demarcated, depigmented macules or patches on otherwise normal skin. Vitiligo can present at any age, in any skin color. There is no specific serologic marker for diagnosis, but patients often have other autoimmune problems. Treatment options are limited and are difficult given the fact that the pathogenesis of the disease is not well elucidated. We present the case of a 52 year-old woman with vitiligo for over 2 decades. The patient's medical history reveals a lack of response to many different approaches. This case highlights the ability of apremilast, an FDA-approved drug for the treatment of psoriasis and psoriatic arthritis, to achieve repigmentation in a case a vitiligo that has been extremely recalcitrant. PMID- 29234547 TI - Testicular Cancer Presenting as Gastric Variceal Hemorrhage. AB - Testicular cancer is the most common solid malignancy affecting males between the ages of 15 and 35. The symptomatology caused by this tumor varies according to the site of metastasis. We present the case of a 26-year-old male who arrived to the emergency department with hematemesis. He had no previous medical history. On arrival, we noted enlargement of the left scrotal sac. There was also a mass in the left scrotum which provoked displacement of the penis and right testis. The serum alpha-fetoprotein level was 17,090 ng/mL, lactate dehydrogenase was 1480 U/L, and human chorionic gonadotropin was 287.4 IU/mL. Upper endoscopy revealed a type 1 isolated gastric varix, treated with cyanoacrylate. A CT scan showed extrinsic compression of the portal vein by lymphadenopathy along with splenic vein partial thrombosis, which caused left-sided portal hypertension. Neoadjuvant chemotherapy was started with etoposide and cisplatin, and seven days later the patient underwent left radical orchiectomy. A postoperative biopsy revealed a pure testicular teratoma. Noncirrhotic left portal hypertension with bleeding from an isolated gastric varix secondary to metastasic testicular cancer has not been described before. Clinicians must consider the possibility of malignancy in the differential diagnosis of a young man presenting with unexplained gastrointestinal bleeding. PMID- 29234548 TI - Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis Presenting with Fever and Confusion. AB - Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis (SREAT) is a diagnostic conundrum as it may present with a myriad of nonspecific clinical features and laboratory and neuroimaging investigations are not diagnostic. We report a case of a 65-year-old female who presented with an acute febrile illness associated with headache and confusion, tangential thoughts, and loose association. Based on neutrophil leukocytosis in the full blood count and elevated inflammatory markers, she was commenced on empirical intravenous antibiotics suspecting meningoencephalitis. Further evaluation found a very high titer of both anti-thyroid peroxidase (anti-TPO) antibodies and anti-thyroid globulin antibodies. She was clinically and biochemically euthyroid. EEG showed right sided frontal intermittent rhythmic delta activity (FIRDA). Cranial MRI revealed age related cerebral atrophy and nonspecific periventricular white matter changes. A diagnosis of SREAT was made and she was treated with intravenous methylprednisolone followed by oral prednisolone. Her condition improved dramatically within 48 hours of starting steroids. SREAT is a diagnosis of exclusion in patients with a central nervous system disorder. There are no specific clinical features or investigative findings. Elevated anti-TPO antibodies are considered a hallmark of SREAT and steroid responsiveness supports the diagnosis. Prompt diagnosis and treatment reverses the neurological dysfunction in most cases. PMID- 29234549 TI - Bilateral Mycobacterium chelonae Keratitis after Phacoemulsification Cataract Surgery. AB - The purpose of this manuscript is to report the case of an 81-year-old patient who presented with bilateral keratitis after phacoemulsification surgery. Cultures came back positive for Mycobacterium chelonae. Despite aggressive topical and systemic antimicrobial treatment, the patient developed a corneal perforation in both eyes, treated with corneal glue in the right eye and corneoscleral patch in the left eye. After two years of follow-up, patient was free of infection in the right eye with visual acuity of 20/200 and the left eye progressed to phthisis bulbi. We present an unusual case of bilateral Mycobacterium chelonae keratitis associated with phacoemulsification cataract surgery. This case represents the importance of making clinicians aware of this devastating infection and highlights the need for better management to improve outcomes. PMID- 29234550 TI - A Unique Case of Melorheostosis Presenting with Two Radiologically Distinct Lesions in the Shoulder. AB - Melorheostosis is a rare, nonhereditary, benign, mesenchymal condition of unknown aetiology affecting the bones and surrounding tissues. A male patient complaining of left shoulder pain, swelling, and mildly limited range of motion has an exclusive combination of the classic dripping wax lesion in the scapula and the myositis ossificans-like lesion in the deltoid muscle; this combination is the first to be reported in the shoulder. Both lesions showed typical findings of melorheostosis in radiographs, CT, MRI, and bone scan. This case has a stationary course over the follow-up period, and no specific treatment is needed in due course. PMID- 29234551 TI - Use of Insecticide-Treated Mosquito Net among Pregnant Women and Guardians of Children under Five in the Democratic Republic of the Congo. AB - Background: Insecticide-treated mosquito nets (ITNs) are one of the most effective tools for preventing malaria in sub-Saharan Africa. Objective: This study examined knowledge, attitude, and practice on the use of ITNs in the prevention of malaria among pregnant women and guardians of children under five in the Democratic Republic of the Congo. Methods: A total of 5,138 pregnant women and guardians of children under five were interviewed. Results: The majority of participants (>80%) knew the signs and symptoms of malaria; 81.6% reported having an ITN in the household, but 78.4% reported using it the night before the interview. Only 71.4% of pregnant women used ITN the night compared to 68.2% of children under five. In the Logistic Regression model, women who believed that it is normal to use ITNs were 1.9 times more likely to use it than those who did not (OR: 1.930); women who were confident in their abilities to use ITNs were 1.9 times more likely than those who were not confident (OR: 1.915); and women who had a good attitude towards ITNs were also more likely to use ITNs compared to those who did not (OR: 1.529). Conclusion: New and innovative evidence-based behavior change interventions are needed to increase the utilization of ITNs among vulnerable groups. PMID- 29234552 TI - Differentiation between 3,4- and 4,15-Epoxyeudesmanolides by Electrospray Ionization Tandem Mass Spectrometry. AB - We investigated the fragmentation of the eudesmanolide-type sesquiterpene lactones 1alpha-(4-hydroxymethacryloyloxy)-3alpha,4alpha-epoxy-8alpha hydroxyeudesm-11(13)-6alpha,12-olide (1) and 1alpha-(2,3-epoxyangeloyloxy) 4alpha,15-epoxy-8alpha-hydroxyeudesm-11(13)-6alpha,12-olide (2) by electrospray ionization tandem mass spectrometry (ESI-MS/MS). The elimination of the different ester substituent at C(1) directly from protonated 1 and 2 (A) led to the formation of two regioisomer product ions B (A - RCO2H). Further fragmentation of B resulted from consecutive eliminations of H2O and CO molecules. However, we identified four product ions that allowed for the differentiation between 3,4- and 4,15-epoxyeudesmanolides. The formation of these diagnostic ions was associated with the C(3)-O bond of compound 1, which propitiates the participation of the lone pair of the oxygen epoxide in the formation of B through a Grob-Wharton-type fragmentation, then resulting in an alternative fragmentation pathway. These data can be useful for the fast differentiation between epoxyeudesmanolide regioisomers directly from Dimerostemma extracts by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as an alternative to NMR, or even for quantitation studies of these compounds using multiple reaction monitoring (MRM) scan. PMID- 29234553 TI - GAIT DEFICITS UNDER DUAL - TASK CONDITIONS IN THE CONCUSSED ADOLESCENT AND YOUNG ATHLETE POPULATION: A SYSTEMATIC REVIEW. AB - Background: There are no current sport concussion assessments that capture the effects of dual-task conditions on gait. Multiple studies have evaluated changes, but none have comprehensively examined literature related to the adolescent and young adult population.Purpose: The purpose of this systematic review is to synthesize documented changes in gait under dual-task conditions in adolescents and young adults after sustaining a concussion.Study Design: Systematic Review. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was consulted to guide this systematic review. Six databases were searched: Cinahl, ProQuest, PubMed, Scopus, SPORTdiscus, and Web of Science. Concussion, gait, and dual-task, along with their synonymous terms were the search terms used. Inclusion criteria consisted of adolescent and young adult age groups, acute concussion, dual-tasking, and matched controls. Quality assessment was performed using The Joanna Briggs Institute Critical Appraisal Checklist for Case Control Studies. Results: Ten full-text articles were selected for inclusion. Concussed individuals demonstrated longer stride times with shorter stride lengths, increased mediolateral displacement with corresponding increases in sagittal and frontal plane peak velocity, and decreased sagittal plane Center of Mass (COM) and Center of Pressure (COP) displacement. The majority of included studies demonstrated moderate to large effect sizes in these gait characteristics. Conclusion: Concussed individuals demonstrated decreased gait stability while ambulating with a dual-task condition. Though statistically significant differences between concussed individuals and matched controls lasted only 72 hours, concussed individuals demonstrated continued improvements in gait for up to two months post-injury, which has the potential to affect an athlete's ability to perform. Further research is needed to determine if a gait examination with a dual-task condition is a realistic, reliable, and valid measure to be included in return to sport testing. Level of Evidence: 2a. PMID- 29234554 TI - THE INFLUENCE OF EXTRINSIC FACTORS ON KNEE BIOMECHANICS DURING CYCLING: A SYSTEMATIC REVIEW OF THE LITERATURE. AB - Background: The knee is susceptible to injury during cycling due to the repetitive nature of the activity while generating torque on the pedal. Knee pain is the most common overuse related injury reported by cyclists, and intrinsic and extrinsic factors can contribute to the development of knee pain. Purpose: Due to the potential for various knee injuries, this purpose of this systematic review of the literature was to determine the association between biomechanical factors and knee injury risk in cyclists. Study Design: Systematic review of the literature. Methods: Literature searches were performed using CINAHL, Ovid, PubMed, Scopus and SPORTDiscus. Quality of studies was assessed using the Downs and Black Scale for non-randomized trials. Results: Fourteen papers were identified that met inclusion and exclusion criteria. Only four studies included cyclists with knee pain. Studies were small with sample sizes ranging from 9-24 participants, and were of low to moderate quality. Biomechanical factors that may impact knee pain include cadence, power output, crank length, saddle fore/aft position, saddle height, and foot position. Changing these factors may lead to differing effects for cyclists who experience knee pain based on specific anatomical location. Conclusion: Changes in cycling parameters or positioning on the bicycle can impact movement, forces, and muscle activity around the knee. While studies show differences across some of the extrinsic factors included in this review, there is a lack of direct association between parameters/positioning on the cycle and knee injury risk due to the limited studies examining cyclists with and without pain or injury. The results of this review can provide guidance to professionals treating cyclists with knee pain, but more research is needed. Level of Evidence: 3a. PMID- 29234555 TI - SPINAL AND PERIPHERAL DRY NEEDLING VERSUS PERIPHERAL DRY NEEDLING ALONE AMONG INDIVIDUALS WITH A HISTORY OF LATERAL ANKLE SPRAIN: A RANDOMIZED CONTROLLED TRIAL. AB - Background: In addition to established interventions, dry needling may reduce impairments leading to greater functional abilities for individuals following ankle sprain. Hypothesis/Purpose: The purpose of this study was to compare effects of spinal and peripheral dry needling (DN) with peripheral DN alone on impairments and functional performance among individuals with a history of lateral ankle sprain. Study Design: Randomized controlled trial. Methods: Twenty individuals with a history of lateral ankle sprain (18 bilateral, 2 unilateral) participated in this study (4 males, 16 females; mean age 28.9 + /- 9.2 years). During the first of two sessions, participants completed the Foot and Ankle Disability Index (FADI) and the Cumberland Ankle Instability Tool (CAIT) and their strength, unilateral balance, and unilateral hop test performance was assessed. Participants were randomly assigned to a spinal and peripheral DN group (SPDN), or a peripheral only DN group (PDN). Participants in the SPDN site group received DN to bilateral L5 multifidi and fibularis longus and brevis muscles on the involved lower extremity. Participants in the PDN group received DN to the fibularis muscles alone. Participants' strength, balance and hop test performance were reassessed immediately following the intervention, and at follow-up 6-7 days later, all outcome measures were reassessed. Three-way mixed model ANOVAs and Mann-Whitney U tests assessed between group differences for outcome variables with normal distributions and non-normal distributions, respectively. Results: ANOVAs showed significant group by time interaction (p<0.05) for invertor strength, significant side by group and time by group interactions (p<0.05) for plantarflexor-evertor strength, no significant findings for dorsiflexor-invertor strength, significant side by time interaction (p<0.05) for unilateral balance, significant main effect of time (p<0.05) for triple hop for distance test, and significant main effect of side (p<0.05) for the CAIT. Mann-Whitney U tests showed no significance (p>0.05) for the side hop test or FADI. Conclusion: The results suggest that DN of the multifidi in addition to fibularis muscles does not result in improvements in strength, unilateral balance or unilateral hop test performance, compared to DN the fibularis muscles alone among individuals with a history of ankle sprain. PMID- 29234556 TI - TRANSVERSUS ABDOMINIS ACTIVATION AND TIMING IMPROVES FOLLOWING CORE STABILITY TRAINING: A RANDOMIZED TRIAL. AB - Background: Patients with non-specific low back pain (LBP) often present with a decrease in transversus abdominis (TrA) muscle activation and delayed onset of contraction with extremity movements, potentially contributing to recurrent LBP. Core stability is required for extremity movement and if the timing of when the TrA contracts is not corrected patients may continue to experience LBP. Hypothesis/Purpose: The purpose of this study was to assess the effects of a four week core stability rehabilitation program on TrA activation ratio and when the TrA initiates contraction during upper extremity movements in subjects with and without LBP. It was hypothesized that those with LBP would experience greater changes in TrA activation and onset of contraction by the TrA compared to the healthy group. Study Design: Randomized Clinical Trial. Methods: Forty-two participants volunteered (21 healthy and 21 LBP). Ultrasound imaging measured the TrA activation ratio and time of initial contraction of the TrA during upper extremity movement into flexion. Half of the healthy and LBP participants were assigned to the exercise group. Participants reported twice a week to the athletic training facility to complete an exercise progression of three exercises. After four weeks, all participants returned to have TrA activation and timing measured again. Results: Pertaining to demographics, there were no differences between the healthy and LBP participants. There was a group interaction for both TrA activation ratio (p=.049) and onset of initial contraction (p=.008). Those in the exercise group showed an increase in TrA activation ratio (1.85 +/- 0.09) compared to the control group (1.79 +/- 0.08), as well as an improvement in the onset of contraction (2.07 +/- 0.08 seconds) compared to the control group (2.23 +/- 0.09 seconds) after the four-week rehabilitation program. Strong effect sizes for TrA activation ratio (0.71 [0.06 1.35]) and initial onset of TrA contraction (-1.88 [-2.63 - -1.11]) were found indicating clinical differences related to the interventions. Conclusion: TrA activation and timing were altered following a four-week core stability program in people with and without LBP. Clinicians should consider incorporating these exercises for improving the function of the TrA. Level of Evidence: Therapy, level 2b. PMID- 29234557 TI - THE DIAGNOSTIC ACCURACY OF THE LEVER SIGN FOR DETECTING ANTERIOR CRUCIATE LIGAMENT INJURY. AB - Background: An alternative physical examination procedure for evaluating the integrity of the anterior cruciate ligament (ACL) has been proposed in the literature but has not been validated in a broad population of patients with a symptomatic complaint of knee pain for its diagnostic value. Purpose: To investigate the diagnostic accuracy of the Lever Sign to detect ACL tears and compare the results to Lachman testing in both supine and prone positions. Study design: Prospective, blinded, diagnostic accuracy study. Methods: Sixty-two consecutive patients with a complaint of knee pain were independently evaluated for the status of the ACL's integrity with the Lever Sign and the Lachman test in a prone and supine by a blinded examiner before any other diagnostic assessments were completed. Results: Twenty-four of the 60 patients included in the analysis had a torn ACL resulting in a prevalence of 40%. The sensitivity of the Lever Sign, prone, and supine Lachman tests were 38, 83, and 67 % respectively and the specificity was 72, 89, and 97% resulting in positive likelihood ratios of 1.4, 7.5, and 24 and negative likelihood ratios of 0.86, 0.19, and 0.34 respectively. The positive predictive values were 47, 83, and 94% and the negative predictive values were 63, 89, and 81% respectively. The diagnostic odds ratios were 1.6, 40, and 70 with a number needed to diagnose of 10.3, 1.4, and 1.6 respectively. Conclusions: The results of this study suggest that Lever Sign, in isolation, does not accurately detect the status of the ACL. During the clinical examination, the Lever Sign should be used as an adjunct to the gold standard assessment technique of anterior tibial translation assessment as employed in the Lachman tests in either prone or supine position. Level of Evidence: 2. PMID- 29234558 TI - LENGTH CHANGE OF THE SHORT EXTERNAL ROTATORS OF THE HIP IN COMMON STRETCH POSITIONS: A CADAVERIC STUDY. AB - Background: Stretching of the deep rotators of the hip is commonly employed in patients with lumbosacral, sacroiliac, posterior hip, and buttock pain. There is limited research demonstrating the effectiveness of common stretching techniques on the short external rotators of the hip. Purpose: The objective of this study was to evaluate length change during stretching of the superior and inferior fibers of the piriformis, superior gemellus, obturator internus, and inferior gemellus. Study Design: Repeated-measures laboratory controlled cadaveric study. Methods: Seventeen hip joints from nine embalmed cadavers (5 male; 4 female) with an age between 49-96 years were skeletonized. Polypropylene strings were attached from the origin to insertion sites of the short external rotators. The change of length (mm) noted by excursion of the strings was used as a proxy for change in muscle length, when the hip was moved from the anatomical position to four specific stretch positions: 1) 45 degrees internal rotation from hip neutral flexion/extension, 2) 45 degrees external rotation from 90 degrees hip and knee flexion, 3) 30 degrees adduction from 90 degrees of hip and knee flexion, and 4) 30 degrees of adduction with the hip and knee flexed so the lateral malleolus contacted the lateral femoral epicondyle of the contralateral limb , were recorded. Results: There was a significant effect on string displacement by stretch position, F (15,166) = 14.67, p < .0005; Wilk's L = .097, partial n2 = .540. The greatest displacement of the strings corresponding to the superior piriformis, inferior piriformis, and the superior gemellus occurred in 30 degrees adduction from 90 degrees of hip and knee flexion. The obturator internus and inferior gemellus had the largest string displacement with 45 degrees internal rotation from neutral flexion/extension. Conclusions: While all stretch positions caused a significant string displacement indicating length changes of the deep rotators of the hip, the three stretch positions that caused the greatest change were: 1) 30 degrees adduction from 90 degrees of hip and knee flexion, 2) 45 degrees internal rotation from neutral flexion/extension, and 3) 45 degrees external rotation with 90 degrees hip and knee flexion. Clinical Relevance: This study has clinical implications for the effectiveness of specific stretching techniques on the short external rotators of the hip with the potential to improve the validity of stretching protocols for patients with posterior hip or buttock pain. The piriformis and superior gemellus had a larger change in length when adducting the hip from 90 degrees degrees of hip and knee flexion. The obturator internus and inferior gemellus had a greater length change when internally rotating the hip from neutral flexion/extension. Level of Evidence: 3. PMID- 29234559 TI - CLINICAL MEASURES OF HIP RANGE OF MOTION DO NOT CORRELATE WITH THE DEGREE OF CAM MORPHOLOGY IN SEMI-ELITE AUSTRALIAN FOOTBALLERS: A CROSS-SECTIONAL STUDY. AB - Background: Clinical testing to determine the presence of a cam morphology is becoming more common however the correlation between hip range of motion and the degree of cam morphology remains controversial in the literature. The prevalence of a cam morphology in athletes has been reported as higher than in the general population but the prevalence of cam morphology has not been reported in Australian Football (AF). Purpose: The purpose of this study was to determine the correlation between hip range of motion and hip alpha angle and report the proportion of players with a cam morphology in a sample of AF players. Design: Cross-sectional Study. Methods: Twenty-one semi-elite AF players (42 hips) from the Peel Thunder Football Club were included in this study. A hip Flexion Internal Rotation (IR) test and a modified maximal squat test using the difference in depth of squat in hip internal and external rotation were used. These measures were then compared to alpha angles on 90 degree Dunn view x-rays. Results: Four of the 42 hips (9.5%) had a cam morphology (alpha angle > 60 degrees). There was no significant correlation between alpha angle and ROM in a Flexion IR test or the difference in modified maximal squat test depth within this sample of players. Conclusions: The proportion of cam morphology seems to be lower in this sample than the previously reported prevalence in other sports. The lack of correlations between hip range and hip alpha angle in players means that screening hips using clinical measures to detect cam morphology associated with poor hip range of motion may be inaccurate. Level of Evidence: Level 3a. PMID- 29234560 TI - COLLEGIATE MALE SOCCER PLAYERS EXHIBIT BETWEEN-LIMB SYMMETRY IN BODY COMPOSITION, MUSCLE STRENGTH, AND RANGE OF MOTION. AB - Background: Functional and structural asymmetries attributed to limb dominance are equivocal in soccer players. Previous authors hypothesize the existence of between-limb asymmetry secondary to the repetitive unilateral nature of kicking. However, symmetry is often present, particularly in measures of muscle strength. Purpose: The purpose of the present study was to determine if lateral dominance is accompanied by corresponding between-limb asymmetries in a comprehensive assessment of body composition, muscle strength, and range of motion in healthy soccer players. Study Design: Cross-sectional, observational. Methods: 17 healthy male NCAA Division One collegiate soccer players participated (age 19.6 +/- 1.5 years; BMI 23.9 +/- 1.4 kg/m2). Footedness was attained via participant self report. Lower limb muscle strength (hand held dynamometry), range of motion (goniometry), and body composition (dual energy x-ray absorptiometry scan) were measured. Lower-leg symmetry was analyzed comparing the dominant versus non dominant limb using paired t-tests. Results: Comparisons revealed no statistically different differences in outcomes, indicating remarkable symmetry in all measures of body composition, muscle strength, and range of motion (p>0.05) between the dominant and non-dominant lower limbs. Conclusions: The authors speculate the prevalence of running versus kicking, the longitudinal effects of playing careers, and/or functional compensation attenuates the expected asymmetries in healthy male collegiate soccer players. Level of Evidence: 2b. PMID- 29234561 TI - COMPARISON OF FUNCTIONAL ACTIVITIES ON STRUCTURAL CHANGES OF THE INFERIOR PATELLAR POLE. AB - Background: It is well known that eccentric and concentric exercise produce varied amounts of stress on the connective tissues. Diagnostic ultrasound has been used to measure these structural changes by observing fascicle length, angle, and thickness; however, there is a lack of evidence comparing the structural changes as it relates to eccentric, concentric, and stretching protocols. Purpose: The purpose of this study was to compare the acute effects of static stretching, eccentric, concentric, and a combination of eccentric/concentric exercises on structural changes of the muscle tendon unit at the inferior patellar pole utilizing the diagnostic ultrasound. Study Design: A repeated measures 2 * 4 within factorial study design with repeated measures on both factors was used to determine the differences in patellar tendon thickness within and between groups. Methods: Forty-seven healthy subjects were screened for any lower extremity deficits or orthopaedic pathology. Forty-four (N=44) subjects completed all four protocols; the attrition was due to injuries to the lower extremity, occurring unrelated to the study. A baseline measurement of the anterior inferior patellar tendon was performed with the diagnostic ultrasound prior to each participant completing one of the four interventions per week over a four-week period. Interventions completed by each participant included static stretching, concentric, eccentric, and combined concentric and eccentric exercises. Immediately following each intervention, a post-intervention inferior patellar tendon measurement was recorded using the diagnostic ultrasound. Results: Significant differences in anterior to posterior tendon thickness of the inferior patellar tendon were observed between pre (4.983 +/- 0.041mm) and post (5.198 +/- 0.055mm) measurements (p<0.0005) for the main effect of time. However, no differences in tendon thickness were noted comparing each intervention to one another (p=0.351). Conclusion: Differences in tendon thickness were noted acutely for pre- to post measurements across all interventions. Further research is needed to determine if differences in tendon thickness exist with a longer duration of exercise over time and with different types of intervention. PMID- 29234562 TI - ISOKINETIC KNEE MUSCLE STRENGTH PROFILE IN BRAZILIAN MALE SOCCER, FUTSAL, AND BEACH SOCCER PLAYERS: A CROSS-SECTIONAL STUDY. AB - Background: Anterior cruciate ligament injury is higher in soccer athletes as compared to athletes of other sports. Risk factors for anterior cruciate ligament injury include low knee hamstring/quadriceps strength ratio and bilateral strength deficits. Purpose: To investigate isokinetic thigh muscles strength, hamstring/quadriceps strength ratio, and bilateral strength comparisons in athletes who participate in professional soccer, futsal, and beach soccer. Study Design: Cross-sectional study. Methods: Brazilian professional soccer (n=70), futsal (n=30), and beach soccer (n=12) players were isokinetically assessed to examine strength of knee extensors and flexors at 60 degrees/second in concentric mode, to measure peak torque of dominant and non-dominant limbs. Results: In the dominant limb, for extensors muscles, futsal players presented significantly lower peak torque values (223.9 +/- 33.4 Nm) than soccer (250.9 +/- 43.0 Nm; p=0.02) and beach soccer players (253.1 +/- 32.4 Nm; p=0.03). Peak torque for extensor muscles in the non-dominant limb was significantly lower in futsal (224.0 +/- 35.8 Nm) than in beach soccer players (256.8 +/- 39.8 Nm; p=0.03). Hamstring/quadriceps strength ratio for dominant limbs for futsal (57.6 +/- 10.1%), soccer (53.5 +/- 8.8%), and beach soccer (56.3 +/- 8.4%) players presented no significant differences between groups; however, the mean values were lower than recommended values found in the literature. There were no strength deficits for any of the evaluated groups when compared bilaterally. Conclusions: Futsal athletes presented lower values for quadriceps strength than soccer and beach soccer athletes. Futsal, soccer, and beach soccer players presented no strength asymmetries, but they presented with strength imbalance in hamstring/quadriceps strength ratio. Level of Evidence: 3. PMID- 29234563 TI - POSTURAL ALTERATIONS IN PATIENTS WITH SUBACROMIAL IMPINGEMENT SYNDROME. AB - Background: An aberrant upper body posture has been proposed as one of the etiological factors contributing to the development of subacromial impingement syndrome (SAIS). Clinicians have translated this supposition into assessment and rehabilitation programs despite insufficient and conflicting evidence to support this approach. Purpose: The purpose of this study was to compare several postural variables between the SAIS patients and asymptomatic healthy controls. Study Design: Case-Control Study. Methods: A total of 75 participants including 39 patients (20 females; 19 males) and 36 healthy controls (15 females; 21 males) participated in the study. Study evaluated several postural variables including forward head posture (FHP), forward shoulder posture (FSP), thoracic kyphosis index (TKI), scapular index (SI), normalized scapular protraction (NSP), and the lateral scapular slide test (LSST). The variables were compared between patient and control groups according to sex. Results: Significant differences were observed in the female patients compared to asymptomatic controls for the FHP (49.38 + 9.6o vs 55.5o+8.38, p=0.03), FSP (45.58 + 10.1o vs 53.68 + 7.08, p=0.02), and LSST in third position (10.2 + 2.1cm vs 11.5 + 0.7cm, p=0.01). Male patients showed a significant difference only in the FSP compared to controls (61.9o+9.4o vs 49.78 + 9.28, p<0.001). Conclusions: While inadequate data on the relationship between dysfunctional posture and SAIS has led to broad variations in current rehabilitation strategies, the results of the present study revealed different patterns of postural aberrations in female and male patients with SAIS. This clarifies the need to develop individualized or sex-specific approaches for assessing posture in men and women with SAIS and rehabilitation programs based on the assessment results. Level of Evidence: 3b. PMID- 29234564 TI - SHOULDER EXTERNAL ROTATOR ECCENTRIC TRAINING VERSUS GENERAL SHOULDER EXERCISE FOR SUBACROMIAL PAIN SYNDROME: A RANDOMIZED CONTROLLED TRIAL. AB - Background: Shoulder pain affects up to 67% of the population at some point in their lifetime with subacromial pain syndrome (SAPS) representing a common etiology. Despite a plethora of studies there remains conflicting evidence for appropriate management of SAPS. Purpose: To compare outcomes, for individuals diagnosed with SAPS, performing a 6-week protocol of eccentric training of the shoulder external rotators (ETER) compared to a general exercise (GE) protocol. Study Design: Randomized controlled trial. Methods: Forty-eight individuals (mean age 46.8 years + /-17.29) with chronic shoulder pain, and a clinical diagnosis of SAPS were randomized into either an experimental group performing ETER or a control group performing a GE program. The intervention lasted for six weeks, and outcomes were measured after three weeks, six weeks, and again at six months post intervention. Results: The primary outcome of function, measured by the Western Ontario Rotator Cuff Index, demonstrated a significant interaction effect derived from a multilevel hierarchical model accounting for repeated measures favoring the experimental group at week 3: 14.65 (p=.003), Week 6: 17.04 (p<.001) and six months: 15.12 (p=.007). After six months, secondary outcome measures were improved for Numeric Pain Rating Scale levels representing pain at worst (p=.006) and pain on average (p=0.02), external rotator (p<.001), internal rotator (p=0.02), and abductor strength (p<.001). There were no statistically significant differences in secondary outcome measures of Global Rating of Change, Active Range of Motion, the Upper Quarter Y Balance Test and strength ratios after six months. Conclusion: An eccentric program targeting the external rotators was superior to a general exercise program for strength, pain, and function after six months. The findings suggest eccentric training may be efficacious to improve self-report function and strength for those with SAPS. Level of Evidence: 2b. PMID- 29234565 TI - RELIABILITY OF ANKLE-FOOT MORPHOLOGY, MOBILITY, STRENGTH, AND MOTOR PERFORMANCE MEASURES. AB - Background: Assessment of foot posture, morphology, intersegmental mobility, strength and motor control of the ankle-foot complex are commonly used clinically, but measurement properties of many assessments are unclear. Purpose: To determine test-retest and inter-rater reliability, standard error of measurement, and minimal detectable change of morphology, joint excursion and play, strength, and motor control of the ankle-foot complex. Design: Reliability study. Methods: 24 healthy, recreationally-active young adults without history of ankle-foot injury were assessed by two clinicians on two occasions, three to ten days apart. Measurement properties were assessed for foot morphology (foot posture index, total and truncated length, width, arch height), joint excursion (weight-bearing dorsiflexion, rearfoot and hallux goniometry, forefoot inclinometry, 1st metatarsal displacement) and joint play, strength (handheld dynamometry), and motor control rating during intrinsic foot muscle (IFM) exercises. Clinician order was randomized using a Latin Square. The clinicians performed independent examinations and did not confer on the findings for the duration of the study. Test-retest and inter-tester reliability and agreement was assessed using intraclass correlation coefficients (ICC2,k) and weighted kappa (Kw ). Results: Test-retest reliability ICC were as follows: morphology: .80 1.00, joint excursion: .58-.97, joint play: -.67-.84, strength: .67-.92, IFM motor rating: KW -.01-.71. Inter-rater reliability ICC were as follows: morphology: .81-1.00, joint excursion: .32-.97, joint play: -1.06-1.00, strength: .53-.90, and IFM motor rating: Kw .02-.56. Conclusion: Measures of ankle-foot posture, morphology, joint excursion, and strength demonstrated fair to excellent test-retest and inter-rater reliability. Test-retest reliability for rating of perceived difficulty and motor performance was good to excellent for short-foot, toe-spread-out, and hallux exercises and poor to fair for lesser toe extension. Joint play measures had poor to fair reliability overall. The findings of this study should be considered when choosing methods of clinical assessment and outcome measures in practice and research. Level of evidence: 3. PMID- 29234566 TI - THE REHABILITATION OF A RUNNER WITH ILIOPSOAS TENDINOPATHY USING AN ECCENTRIC BIASED EXERCISE-A CASE REPORT. AB - Background and Purpose: While there is much discussion about tendinopathy in the literature, there is little reference to the less common condition of iliopsoas tendinopathy, and no documentation of the condition in runners. The iliopsoas is a major decelerator of the hip and eccentric loading of the iliopsoas is an important component of energy transfer during running. Eccentric training is a thoroughly researched method of treating tendinopathy but has shown mixed results. The purpose of this case report is to describe the rehabilitation of a runner with iliopsoas tendinopathy, and demonstrate in a creative eccentric biased technique to assist with treatment. A secondary objective is to illustrate how evidence on intervention for other tendinopathies was used to guide rehabilitation of this seldom described condition. Case Description: The subject was a 39-year-old female middle distance runner diagnosed with iliopsoas tendinopathy via ultrasound, after sudden onset of left anterior groin pain. Symptoms began after a significant increase in running load, and persisted, despite rest, for three months. The intervention consisted of an eccentric-biased hip flexor exercise, with supportive kinetic chain exercises and progressive loading in a return to running program. Outcomes: The Copenhagen Hip and Groin Outcome Score, the Visual Analogue Scale, the Global Rating of Change Scale and manual muscle testing scores all improved after 12 weeks of intervention with further improvement at the five-year follow up. After 12 weeks of intervention, the subject was running without restriction and had returned to her pre-injury running mileage at the five-year follow up. Discussion: The eccentric-biased exercise in conjunction with exercises addressing the kinetic chain and a progressive tendon loading program, were successful in the rehabilitation of this subject with iliopsoas tendinopathy. This case report is the first to provide a description on the rehabilitation of iliopsoas tendinopathy, and offers clinicians suggestions and guidance for treatment and exercise choice in the clinical environment. Level of Evidence: 5. PMID- 29234567 TI - NERVE ENTRAPMENT IN THE HIP REGION: CURRENT CONCEPTS REVIEW. AB - : The purpose of this clinical commentary is to review the anatomy, etiology, evaluation, and treatment techniques for nerve entrapments of the hip region. Nerve entrapment can occur around musculotendinous, osseous, and ligamentous structures because of the potential for increased strain and compression on the peripheral nerve at those sites. The sequela of localized trauma may also result in nerve entrapment if normal nerve gliding is prevented. Nerve entrapment can be difficult to diagnose because patient complaints may be similar to and coexist with other musculoskeletal conditions in the hip and pelvic region. However, a detailed description of symptom location and findings from a comprehensive physical examination can be used to determine if an entrapment has occurred, and if so where. The sciatic, pudendal, obturator, femoral, and lateral femoral cutaneous are nerves that can be entrapped and serve a source of hip pain in the athletic population. Manual therapy, stretching and strengthening exercises, aerobic conditioning, and cognitive-behavioral education are potential interventions. When conservative treatment is ineffective at relieving symptoms surgical treatment with neurolysis or neurectomy may be considered. Level of Evidence: 5. PMID- 29234568 TI - Long-Term Quality of Life of Retroperitoneal Sarcoma Patients Treated with Pre Operative Radiotherapy and Surgery. AB - PURPOSE: Retroperitoneal sarcomas (RPS) are connective tissue cancers that are often large and anatomically in close proximity to critical and radiation sensitive normal structures and organs within the abdomen and pelvis. The management of RPS may include preoperative radiotherapy (RT) and surgery. We aimed to examine how treatment-related toxicities affect patient quality of life (QOL). Methods and materials: Within two prospective cohort studies, 48 RPS patients who were treated with preoperative RT from 1998-2012 were recruited and assessed for QOL (EORTC-QLQ-C30) and to determine toxicities potentially related to RT and surgery (graded using CTCAE V.4). Baseline and prospective QOL was available for 11 patients. In the other 37 patients, prospective data were obtained at different time points during their follow-up. Unless stated otherwise, all scores refer to the global QOL subscale. RESULTS: The patients' median age was 57 (38-82) and RT was administered to a median dose of 45 Gy (41.4 50.4). The median maximum tumor dimension was 16.0 cm (5.7-28) and the majority (35/48) were liposarcomas. The mean pre-RT QOL was 48.5/100. At one month post RT, the mean QOL improved to 54.2; however, the mean diarrhea symptom scale worsened from baseline (78.3 vs. 18.2, p<0.001). Correspondingly, 54% of patients had gastrointestinal toxicities (92% G1-2 and 8% G3) by the end of RT. At 36 months post-RT, 88% of patients had chronic toxicities (19% G3). RPS patients who survived and are free of recurrence >= 36 months had significantly (mean: 75.0; p=0.001) better QOL than at diagnosis. The number of toxicities was significantly (p=0.001) associated with QOL. RT dose, tumor size, patient age, and patient gender were not associated with 36-month QOL. Conclusions: Treatment toxicities seem to contribute to QOL recovery during the first 36 months. QOL at 36 months was better than at diagnosis. PMID- 29234569 TI - A Case of Localized Pulmonary Calcification Presenting as a Persistent Mass Lesion in an Immunosuppressed Patient Following Treatment of a Pseudomonas Pneumonia. AB - We report a case of a persistent right upper lobe opacity following treatment for a Pseudomonas infection in an immunosuppressed patient with a recent renal transplantation. The patient underwent a surgical lung biopsy for definitive diagnosis of the mass. The lesion was composed of extensive calcifications deposited throughout the lung with associated fibrosis. The patient had a history of a remote parathyroidectomy for hyperparathyroidism; however, the parathyroid hormone (PTH) and the calcium levels were still mildly elevated. No other calcified lung lesions had developed in a follow-up after the initial resection. Pulmonary calcification has been classically associated with varicella pneumonia; no viral cytopathic changes were identified for varicella or other viruses in this case. The calcification appears to be secondary to the recent Pseudomonas pneumonia. To our knowledge, this is the first report of a Pseudomonas pneumonia resulting in extensive localized pulmonary calcification. This is an important diagnostic consideration as this benign entity should be considered in patients with persistent opacities following treatment for pneumonia. PMID- 29234570 TI - Vaginal Cuff Closure in Minimally Invasive Hysterectomy: A Review of Training, Techniques, and Materials. AB - Hysterectomy is one of the most common surgeries performed each year and can be indicated for many gynecologic conditions. The development of minimally invasive surgery has transformed this procedure, resulting in improved outcomes, superior cosmesis, and quicker return to normal function. Vaginal cuff closure is a critical component of hysterectomy, with many variations in surgical technique and materials. This review provides an overview of intracorporeal suturing and knot-tying techniques at the level of a junior resident in obstetrics and gynecology and describes several validated models that have been developed to test resident skill level in vaginal cuff closure. We also provide a review of the literature regarding vaginal cuff closure techniques and suture materials, including knotless barbed sutures. Finally, a brief discussion of single-site surgery, the latest development in minimally invasive hysterectomy, will be provided. We hope to provide a better understanding of vaginal cuff closure for residents in the field of obstetrics and gynecology. PMID- 29234572 TI - Resection of a Pediatric Thalamic Juvenile Pilocytic Astrocytoma with Whole Brain Tractography. AB - The resection of deep-seated brain tumors has been associated with morbidity due to injury to critical neural structures during the approach. Recent technological advancements in navigation and stereotaxy, surgical planning, brain tractography and minimal-access brain ports present the opportunity to overcome such limitations. Here, we present the case of a pediatric patient with a left thalamic/midbrain juvenile pilocytic astrocytoma (JPA). The tumor displaced the corticospinal fibers posteriorly and resulted in hemiparesis. Using whole brain tractography to plan a corridor for the approach, neuronavigation, a tubular retractor and an exoscope for visualization, we obtained gross total resection of the tumor, while minimizing injury to white matter bundles, including the corticospinal fibers. We propose that surgical planning with whole brain tractography is essential for reducing morbidity while accessing deep-lying brain lesions via retractor tubes, by means of sparing critical fiber tracts. PMID- 29234571 TI - Measurement of Elevated IL-37 Levels in Acute Ischemic Brain Injury: A Cross sectional Pilot Study. AB - Interleukin (IL)-37 is a new member of the IL-1 cytokine family with a defined role as a negative feedback inhibitor of proinflammatory responses. IL-37 has yet to be evaluated in non-immune-mediated neurological diseases, such as ischemic or hemorrhagic strokes. This study aimed to measure urine and serum IL-37 levels in patients with ischemic stroke. Twelve patients consented for our study. Two sets of serum and urine samples were obtained and analyzed, one upon admission to the hospital and the second the next morning. The trends in serum levels of IL- 37 in six stroke patients and the trends in the urine levels of eight stroke patients were measured by real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Our pilot study showed IL-37 levels in urine in stroke patients ranging between 210 and 4,534. Serum IL-37 levels were in the range of 44 - 5,235 in patients with ischemic stroke. Three patients who presented within three hours of stroke onset had IL-37 serum levels of 2,655 pg/ml, 3,517 pg/ml, and 5,235 pg/ml, respectively. In all others, it ranged much less than that, with the trend of delayed presentation giving lower IL-37 levels. The study shows a rather stable early elevation of serum IL-37 levels post ischemic stroke. IL-37 plays a certain role in mediating post-stroke inflammation with a significant increase in serum levels of this novel cytokine observed in ischemic stroke patients. Further large-scale studies need to be done to establish its definite role. A prospective "CRISP" trial is registered with the ClinicalTrials.gov (Identifier: NCT03297827) to determine the role of IL-37 in modulating post-stroke inflammation. PMID- 29234573 TI - Development of a Dual Plasma Desorption/Ionization System for the Noncontact and Highly Sensitive Analysis of Surface Adhesive Compounds. AB - We developed a dual plasma desorption/ionization system using two plasmas for the semi-invasive analysis of compounds on heat-sensitive substrates such as skin. The first plasma was used for the desorption of the surface compounds, whereas the second was used for the ionization of the desorbed compounds. Using the two plasmas, each process can be optimized individually. A successful analysis of phenyl salicylate and 2-isopropylpyridine was achieved using the developed system. Furthermore, we showed that it was possible to detect the mass signals derived from a sample even at a distance 50 times greater than the distance from the position at which the samples were detached. In addition, to increase the intensity of the mass signal, 0%-0.02% (v/v) of hydrogen gas was added to the base gas generated in the ionizing plasma. We found that by optimizing the gas flow rate through the addition of a small amount of hydrogen gas, it was possible to obtain the intensity of the mass signal that was 45-824 times greater than that obtained without the addition of hydrogen gas. PMID- 29234574 TI - Robust procedure for creating and characterizing the atomic structure of scanning tunneling microscope tips. AB - Scanning tunneling microscopes (STM) are used extensively for studying and manipulating matter at the atomic scale. In spite of the critical role of the STM tip, procedures for controlling the atomic-scale shape of STM tips have not been rigorously justified. Here, we present a method for preparing tips in situ while ensuring the crystalline structure and a reproducibly prepared tip structure up to the second atomic layer. We demonstrate a controlled evolution of such tips starting from undefined tip shapes. PMID- 29234575 TI - Involvement of two uptake mechanisms of gold and iron oxide nanoparticles in a co exposure scenario using mouse macrophages. AB - Little is known about the simultaneous uptake of different engineered nanoparticle types, as it can be expected in our daily life. In order to test such co-exposure effects, murine macrophages (J774A.1 cell line) were incubated with gold (AuNPs) and iron oxide nanoparticles (FeO x NPs) either alone or combined. Environmental scanning electron microscopy revealed that single NPs of both types bound within minutes on the cell surface but with a distinctive difference between FeO x NPs and AuNPs. Uptake analysis studies based on laser scanning microscopy, transmission electron microscopy, and inductively coupled plasma optical emission spectrometry revealed intracellular appearance of both NP types in all exposure scenarios and a time-dependent increase. This increase was higher for both AuNPs and FeO x NPs during co-exposure. Cells treated with endocytotic inhibitors recovered after co-exposure, which additionally hinted that two uptake mechanisms are involved. Cross-talk between uptake pathways is relevant for toxicological studies: Co-exposure acts as an uptake accelerant. If the goal is to maximize the cellular uptake, e.g., for the delivery of pharmaceutical agents, this can be beneficial. However, co-exposure should also be taken into account in the case of risk assessment of occupational settings. The demonstration of co-exposure-invoked pathway interactions reveals that synergetic nanoparticle effects, either positive or negative, must be considered for nanotechnology and nanomedicine in particular to develop to its full potential. PMID- 29234576 TI - Comparing postdeposition reactions of electrons and radicals with Pt nanostructures created by focused electron beam induced deposition. AB - The ability of electrons and atomic hydrogen (AH) to remove residual chlorine from PtCl2 deposits created from cis-Pt(CO)2Cl2 by focused electron beam induced deposition (FEBID) is evaluated. Auger electron spectroscopy (AES) and energy dispersive X-ray spectroscopy (EDS) measurements as well as thermodynamics calculations support the idea that electrons can remove chlorine from PtCl2 structures via an electron-stimulated desorption (ESD) process. It was found that the effectiveness of electrons to purify deposits greater than a few nanometers in height is compromised by the limited escape depth of the chloride ions generated in the purification step. In contrast, chlorine atoms can be efficiently and completely removed from PtCl2 deposits using AH, regardless of the thickness of the deposit. Although AH was found to be extremely effective at chemically purifying PtCl2 deposits, its viability as a FEBID purification strategy is compromised by the mobility of transient Pt-H species formed during the purification process. Scanning electron microscopy data show that this results in the formation of porous structures and can even cause the deposit to lose structural integrity. However, this phenomenon suggests that the use of AH may be a useful strategy to create high surface area Pt catalysts and may reverse the effects of sintering. In marked contrast to the effect observed with AH, densification of the structure was observed during the postdeposition purification of PtC x deposits created from MeCpPtMe3 using atomic oxygen (AO), although the limited penetration depth of AO restricts its effectiveness as a purification strategy to relatively small nanostructures. PMID- 29234577 TI - Fabrication of CeO2-MO x (M = Cu, Co, Ni) composite yolk-shell nanospheres with enhanced catalytic properties for CO oxidation. AB - CeO2-MO x (M = Cu, Co, Ni) composite yolk-shell nanospheres with uniform size were fabricated by a general wet-chemical approach. It involved a non-equilibrium heat-treatment of Ce coordination polymer colloidal spheres (Ce-CPCSs) with a proper heating rate to produce CeO2 yolk-shell nanospheres, followed by a solvothermal treatment of as-synthesized CeO2 with M(CH3COO)2 in ethanol solution. During the solvothermal process, highly dispersed MO x species were decorated on the surface of CeO2 yolk-shell nanospheres to form CeO2-MO x composites. As a CO oxidation catalyst, the CeO2-MO x composite yolk-shell nanospheres showed strikingly higher catalytic activity than naked CeO2 due to the strong synergistic interaction at the interface sites between MO x and CeO2. Cycling tests demonstrate the good cycle stability of these yolk-shell nanospheres. The initial concentration of M(CH3COO)2.xH2O in the synthesis process played a significant role in catalytic performance for CO oxidation. Impressively, complete CO conversion as reached at a relatively low temperature of 145 degrees C over the CeO2-CuO x -2 sample. Furthermore, the CeO2-CuO x catalyst is more active than the CeO2-CoO x and CeO2-NiO catalysts, indicating that the catalytic activity is correlates with the metal oxide. Additionally, this versatile synthesis approach can be expected to create other ceria-based composite oxide systems with various structures for a broad range of technical applications. PMID- 29234578 TI - Au nanostructure fabrication by pulsed laser deposition in open air: Influence of the deposition geometry. AB - We present a fast and flexible method for the fabrication of Au nanocolumns. Au nanostructures were produced by pulsed laser deposition in air at atmospheric pressure. No impurities or Au compounds were detected in the resulting samples. The nanoparticles and nanoaggregates produced in the ablated plasma at atmospheric pressure led to the formation of chain-like nanostructures on the substrate. The dependence of the surface morphology of the samples on the deposition geometry used in the experimental set up was studied. Nanocolumns of different size and density were produced by varying the angle between the plasma plume and the substrate. The electrical, optical, and hydrophobic properties of the samples were studied and discussed in relation to their morphology. All of the nanostructures were conductive, with conductivity increasing with the accumulation of ablated material on the substrate. The modification of the electrical properties of the nanostructures was demonstrated by irradiation by infrared light. The Au nanostructures fabricated by the proposed technology are difficult to prepare by other methods, which makes the simple implementation and realization in ambient conditions presented in this work more ideal for industrial applications. PMID- 29234580 TI - Laser-assisted fabrication of gold nanoparticle-composed structures embedded in borosilicate glass. AB - We present results on laser-assisted formation of two- and three-dimensional structures comprised of gold nanoparticles in glass. The sample material was gold ion-doped borosilicate glass prepared by conventional melt quenching. The nanoparticle growth technique consisted of two steps - laser-induced defect formation and annealing. The first step was realized by irradiating the glass by nanosecond and femtosecond laser pulses over a wide range of fluences and number of applied pulses. The irradiation by nanosecond laser pulses (emitted by a Nd:YAG laser system) induced defect formation, expressed by brown coloration of the glass sample, only at a wavelength of 266 nm. At 355, 532 and 1064 nm, no coloration of the sample was observed. The femtosecond laser irradiation at 800 nm also induced defects, again observed as brown coloration. The absorbance spectra indicated that this coloration was related to the formation of oxygen deficiency defects. After annealing, the color of the irradiated areas changed to pink, with a corresponding well-defined peak in the absorbance spectrum. We relate this effect to the formation of gold nanoparticles with optical properties defined by plasmon excitation. Their presence was confirmed by high-resolution TEM analysis. No nanoparticle formation was observed in the samples irradiated by nanosecond pulses at 355, 532 and 1064 nm. The optical properties of the irradiated areas were found to depend on the laser processing parameters; these properties were studied based on Mie theory, which was also used to correlate the experimental optical spectra and the characteristics of the nanoparticles formed. We also discuss the influence of the processing conditions on the characteristics of the particles formed and the mechanism of their formation and demonstrate the fabrication of structures composed of nanoparticles inside the glass sample. This technique can be used for the preparation of 3D nanoparticle systems embedded in transparent materials with potential applications in the design of new optical components, such as metamaterials and in plasmonics. PMID- 29234579 TI - Strategy to discover full-length amyloid-beta peptide ligands using high efficiency microarray technology. AB - Although the formation of beta-amyloid (Abeta) fibrils in neuronal tissues is a hallmark of Alzheimer disease (AD), small-sized Abeta oligomers rather than mature fibrils have been identified as the most neurotoxic species. Therefore, the design of new inhibitors, able to prevent the aggregation of Abeta, is believed to be a promising therapeutic approach to AD. Unfortunately, the short lived intermediate structures that occur in a solution along the Abeta aggregation pathway escape conventional experimental investigations and there is urgent need of new tools aimed at the discovery of agents targeting monomeric Abeta and blocking the early steps of amyloid aggregation. Here, we show the combination of high-efficiency slides (HESs) with peptide microarrays as a promising tool for identifying small peptides that bind Abeta monomers. To this aim, HESs with two immobilized reference peptides, (i.e., KLVFF and Semax) with opposite behavior, were investigated for binding to fluorescently labeled Abeta peptide. Transmission electron microscopy was used to demonstrate Abeta fibrillar aggregates missing. The use of HESs was critical to ensure convenient output of the fluorescent microarrays. The resulting sensitivity, as well as the low sample consumption and the high potential for miniaturization, suggests that the proposed combination of peptide microarrays and highly efficient slides would be a very effective technology for molecule profiling in AD drug discovery. PMID- 29234581 TI - Towards molecular spintronics. PMID- 29234582 TI - Dynamic behavior of a nematic liquid crystal mixed with CoFe2O4 ferromagnetic nanoparticles in a magnetic field. AB - The dynamic behavior of a mixture of 4-cyano-4'-pentylbiphenyl (5CB) with 1% CoFe2O4 nanoparticles was analyzed. Experimental data indicate a high stability of the nematic director in the mixture compared to a reference 5CB sample in the magnetic field. The ferrite nanoparticles agglomerate forming long chains as observed in polarized microscopy images. These chains have a very high influence on the magneto-optic effect of the cell. When the magnetic field is applied on the mixture, the chains tend to align with the field direction but, due to their large size, they remain oriented obliquely between the support plates. Thus, the nematic molecules anchored on their surface can not reorient with the field and only a small distortion angle of the liquid crystal molecular director is observed. A comparison with a previously developed theoretical model confirms this small deviation. PMID- 29234583 TI - Synthesis of metal-fluoride nanoparticles supported on thermally reduced graphite oxide. AB - Metal-fluoride nanoparticles, (MF x -NPs) with M = Fe, Co, Pr, Eu, supported on different types of thermally reduced graphite oxide (TRGO) were obtained by microwave-assisted thermal decomposition of transition-metal amidinates, (M{MeC[N(iPr)]2} n ) or [M(AMD) n ] with M = Fe(II), Co(II), Pr(III), and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)europium, Eu(dpm)3, in the presence of TRGO in the ionic liquid (IL) 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIm][BF4]). The crystalline phases of the metal fluorides synthesized in [BMIm][BF4] were identified by powder X-ray diffraction (PXRD) to be MF2 for M = Fe, Co and MF3 for M = Eu, Pr. The diameters and size distributions of MF x @TRGO were from (6 +/- 2) to (102 +/- 41) nm. Energy-dispersive X-ray spectroscopy (EDX) and X-ray photoelectron spectroscopy (XPS) were used for further characterization of the MF x -NPs. Electrochemical investigations of the FeF2 NPs@TRGO as cathode material for lithium-ion batteries were evaluated by galvanostatic charge/discharge profiles. The results indicate that the FeF2 NPs@TRGO as cathode material can present a specific capacity of 500 mAh/g at a current density of 50 mA/g, including a significant interfacial charge storage contribution. The obtained nanomaterials show a good rate capacity as well (220 mAh/g and 130 mAh/g) at a current density of 200 and 500 mA/g, respectively. PMID- 29234584 TI - Adsorption of iron tetraphenylporphyrin on (111) surfaces of coinage metals: a density functional theory study. AB - The adsorption of the iron tetraphenylporphyrin (FeTPP) molecule in its deckchair conformation was investigated on Au(111), Ag(111) and Cu(111) surfaces by performing spin-polarized density functional theory (DFT) calculations taking into account both van der Waals (vdW) interaction and on-site Coulomb repulsion. The deckchair conformation of the molecule favours intermolecular pi-pi-type interactions in a less densely packed monolayer than the saddle conformation. The activation barrier between the two stable magnetic states (high spin, S = 2 and intermediate spin, S = 1) of the molecule in vacuum disappears upon adsorption on the metal surfaces. The high-spin state of physisorbed FeTPP is stable on all adsorption sites. This result reveals that an external permanent element such as a STM tip or an additional molecule is needed to use FeTPP or similar molecules as model system for molecular spin switches. PMID- 29234585 TI - Refractive index sensing and surface-enhanced Raman spectroscopy using silver gold layered bimetallic plasmonic crystals. AB - Herein we describe the fabrication and characterization of Ag and Au bimetallic plasmonic crystals as a system that exhibits improved capabilities for quantitative, bulk refractive index (RI) sensing and surface-enhanced Raman spectroscopy (SERS) as compared to monometallic plasmonic crystals of similar form. The sensing optics, which are bimetallic plasmonic crystals consisting of sequential nanoscale layers of Ag coated by Au, are chemically stable and useful for quantitative, multispectral, refractive index and spectroscopic chemical sensing. Compared to previously reported homometallic devices, the results presented herein illustrate improvements in performance that stem from the distinctive plasmonic features and strong localized electric fields produced by the Ag and Au layers, which are optimized in terms of metal thickness and geometric features. Finite-difference time-domain (FDTD) simulations theoretically verify the nature of the multimode plasmonic resonances generated by the devices and allow for a better understanding of the enhancements in multispectral refractive index and SERS-based sensing. Taken together, these results demonstrate a robust and potentially useful new platform for chemical/spectroscopic sensing. PMID- 29234586 TI - Aspergillus tamarii keratitis in a contact lens wearer. AB - Keratitis produced by Aspergillus tamarii has been previously described associated to an ocular injury. We report a case in a contact lens wearer with a history of previous bilateral myopic LASIK ablation, bilateral intracorneal rings and vitrectomy and scleral buckling in his left eye. The fungus could be quickly identified combining phenotype, microscopy and mass spectrometry. Treatment with intravenous amphotericin, oral voriconazole, and topical amphotericin and natamycin and voriconazole was needed for corneal preservation. PMID- 29234587 TI - Pulmonary papillary adenocarcinoma with Aspergillus versicolor infection in a dog. AB - Papillary adenocarcinoma of the lungs is the most common primary lung adenocarcinoma, with the feature of papillary-like structure formation by cells. A dog was presented with the primary complaint of vomiting, hyporexia and increased respiratory effort. Thoracic radiography revealed increased soft tissue radiopacity of the right cranial lung lobe suggestive of possible consolidation or collapsed lung lobe, with generalised miliary nodular pattern throughout the other lung fields. The dog was euthanized humanely and necropsy was performed. Histopathology confirmed the diagnosis of primary pulmonary lung neoplasm (papillary adenocarcinoma) with Aspergillus versicolor infection identified through fungal culture and PCR. There have been several reports on humans and dogs with fungal infections that often mimic or coexist with pulmonary neoplasm. This is the first documented report of A. versicolor isolated from a lung neoplasm in a dog in Malaysia. PMID- 29234588 TI - Emerging fluconazole resistance: Implications for the management of cryptococcal meningitis. AB - We present the case of an HIV-seropositive individual with cryptococcal meningitis who was found to have a fluconazole resistant strain of Cryptococcus neoformans. The individual required multiple rounds of amphotericin and fluconazole 800-1200 mg after several episodes of clinical relapse. Cerebrospinal fluid sterilization was achieved and maintained with high doses of fluconazole. This case demonstrates the emerging dilemma of increasing rates of fluconazole resistance in Cryptococcus and the clinical difficulties in meningitis management. PMID- 29234589 TI - Retrospective study of predictors of bone metastasis in colorectal cancer patients. AB - Background: We explored risk factors for bone metastasis (BMs) in colorectal cancer (CRC) to improve in early diagnosis and follow-up and to reduce bone metastasis. Methods: With a retrospective analysis of 2066 patients with CRC treated in our institution from January 2006 to January 2015, we assessed high risk variables associated with bone metastasis using univariate and multivariate analyses. Results: Of those subjects studied, 102 patients developed BMs, including 62 of 1014 the rectal cancer patients and 40 of the 1052 colon cancer patients. Lung metastases were accounting for 59.8% of the BMs (chi2 = 17.7, p<0.01) and hepatic metastases were accounting for 34.3% of BMs (chi2 = 3.06,p >0.05). BMs were diagnosed more rapidly in the presence of lung metastases(6.9 months versus 11.6 months for liver metastases). Univariate analysis revealed that BMs were associated with primary tumor location (p < 0.001), lung metastases (p < 0.001), initial stage (p = 0.001), radiotherapy (p < 0.001) and serum carcinoembryonic antigen (CEA) (p=0.001). Multivariate analysis revealed that primary tumor location (rectum), lung metastases, and serum CEA (>5 MUg/L) were statistically significant (p <0.05). Conclusions: BMs in rectal cancer occur more frequently than in colon cancer. Lung metastases predicted potential progression to bone in CRCs more than liver metastases. Primary rectal locations, lung metastases and serum CEA were independent risk factors for BMs in CRC. Thus, patients should receive early bones scanning when presenting with CRC. PMID- 29234590 TI - An integrative analysis of DNA methylation in osteosarcoma. AB - Background: The study aimed to analyze aberrantly methylated genes, relevant pathways and transcription factors (TFs) in osteosarcoma (OS) development. Methods: Based on the DNA methylation microarray data GSE36002 that were downloaded from GEO database, the differentially methylated genes in promoter regions were identified between OS and normal samples. Pathway and function enrichment analyses of differentially methylated genes was performed. Subsequently, protein-protein interaction (PPI) network was constructed, followed by identification of cancer-associated differentially methylated genes and significant differentially methylated TFs. Results: A total of 1379 hyper methylation regions and 169 hypo-methylation regions in promoter regions were identified in OS samples compared to normal samples. The differentially hyper methylated genes were significantly enriched in Neuroactive ligand-receptor interaction pathway, and Peroxisome proliferator activated receptor (PPAR) signaling pathway. The differentially hypo-methylated genes were significantly enriched in Toll-like receptor signaling pathway. In PPI network, signal transducers and activators of transcription (STAT3) had high degree (degree=21). MAX interactor 1, dimerization protein (MXI1), STAT3 and T-cell acute lymphocytic leukemia 1 (TAL1) were significant TFs enriched with target genes in OS samples. They were found to be cancer-associated and hyper-methylated in OS samples. Conclusion: Neuroactive ligand-receptor interaction, PPAR signaling, Toll-like receptor signaling pathways are implicated in OS. MXI1, STAT3, and TAL1 may be important TFs involved in OS development. PMID- 29234591 TI - Reproductive hormone analyses and effects of adjuvant zoledronic acid in early breast cancer - An AZURE (BIG 01/04) sub-study. AB - Purpose: Adjuvant bisphosphonates have been shown to improve disease outcomes in early breast cancer in women who are postmenopausal at the start of treatment. We explored the influence of pretreatment serum levels of reproductive hormones in the hypothalamic-pituitary-gonadal (HPG) axis from a subset of patients included in the AZURE trial to investigate their impact on disease recurrence and whether reproductive hormone measurements are of value in selecting patients for treatment with adjuvant zoledronic acid.Patients and methods; The AZURE trial is an academic, multi-centre, international phase III trial that randomised patients to standard adjuvant therapy (chemotherapy and/or endocrine therapy)+/ intravenous zoledronic acid, 4 mg for 5 years. Serum from 865 patients taken at randomisation was stored at -80 degrees C prior to central batch analysis for inhibin A, oestradiol and follicle stimulating hormone (FSH). We assessed the clinical value of pretreatment hormone levels for predicting invasive disease free survival (IDFS), skeletal recurrence and distant recurrence and response to treatment with zoledronic acid. Results: Oestradiol in the postmenopausal range (<50 pmol/l) was associated with a significantly shorter IDFS (HR 1.36 95%CI: 1.05-1.78 p=0.022), predominantly due to distant recurrence (HR 1.33 95%CI: 0.98 1.81 p=0.065), compared to oestradiol >=50pmol/l. In contrast, FSH in the postmenopausal range (>26 IU/l) was associated with a longer time to bone as first recurrence (HR 0.66 95%CI: 0.41-1.04 p=0.072) compared to an FSH <=26 IU/l. When all 3 hormone levels were within the assay specified postmenopausal range, a trend to improved IDFS was seen with addition of zoledronic acid in biochemically postmenopausal women only (postmenopausal HR=0.81; 95%CI: 0.54-1.22, non postmenopausal HR=0.99; 95%CI: 0.69-1.39) with risk reductions that mirrored the results of the main AZURE study, although the interaction between menopausal status and treatment effect was not statistically significant (p=0.47). Conclusion: Oestradiol and FSH may influence the pattern of disease recurrence with postmenopausal levels possibly creating a less conducive environment for the formation of bone metastases, therefore disseminated tumour cells could seek alternative niches outside of bone. Biochemical evaluation of a panel of reproductive hormones may be helpful to assist selection of patients for adjuvant zoledronic acid when menopausal status is unknown. PMID- 29234592 TI - Experience of total scapular excision for musculoskeletal tumor and reconstruction in eastern Asian countries. AB - Total scapulectomy and reconstruction has been performed for scapular tumor, however, most of the reconstruction methods have resulted in poor functional outcomes and there is still room for improvement. Most of the reports of reconstruction after scapulectomy are from a single institution. In the present study, we investigated functional outcomes after total scapulectomy in a multicenter study in The Eastern Asian Musculoskeletal Oncology Group (EAMOG). Thirty-three patients who underwent total scapulectomy were registered at EAMOG affiliated hospitals. The patients were separated into no reconstruction group (n=8), humeral suspension group (n=15) and prosthesis group (n=10). Functional outcome was assessed by the Enneking score. One-way ANOVA was used to compare parameters between the patient groups. Complications included five local recurrences, one superficial infection, one dislocation and one clavicle protrusion. The average follow-up period was 43.5 months. The average active flexion range was 45.8 degrees (0-120 degrees ), and 37.1 degrees in abduction (0-120 degrees ). The mean total functional score was 22.9 out of 30 (15-29), which is a satisfactory score following resection of the shoulder girdle. There were significant differences in reconstruction methods for active range of motion. Bony reconstruction provided better range of motion in this study. There was a variety of reconstruction methods after scapulectomy in the eastern Asian countries. Although better functional score was obtained using scapular prosthesis or recycled bone and prosthesis composite grafting, postoperative function is still lower than preoperative function. Modified designed prosthesis with or without combination of recycle bone or allograft would restore the lost shoulder function in the future. PMID- 29234593 TI - A new mode of ventilation for interventional pulmonology. A case with EBUS-TBNA and debulking. AB - Lung cancer is still underdiagnosed mainly due to lack of symptoms. Most patients are diagnosed in a late stage where unfortunately only systematic therapy can be applied. Fortunately in the last five years several novel therapies and combinations have emerged. However; in certain situations local therapeutics modalities have to be applied in order to solve emergency problems as in the case that we will present. Convex-EBUS probe was used along with a novel method of ventilation which keeps PCO2 concentration satisfyingly low. PMID- 29234594 TI - Successful use of linezolid for refractory Mycobacterium abcessus infection: A case report. AB - A 51-year-old male patient was receiving treatment for Mycobacterium abscessus infection for approximately 10 years. However, as his condition gradually progressed to type II respiratory insufficiency, he was referred to our hospital, which was near his home. Computed tomography on his first visit revealed an abscess in the right lower lobe. Because respiratory insufficiency was evident, he was admitted the same day. We began treatment with meropenem, amikacin, and clarithromycin, but his symptoms did not improve. In accordance with the 2007 American Thoracic Society/Infectious Diseases Society of America statement, we administered linezolid, which resulted in gradual improvement in his physical status and imaging findings. PMID- 29234595 TI - Ibrutinib as a bridge to transplant in high-risk chronic lymphocytic leukemia: A case report and review of the literature. AB - The treatment landscape of chronic lymphocytic leukemia (CLL) has been challenged by the advent of novel classes of drugs, such as B-cell receptor (BCR)-inhibitors and BCL-2 antagonists. In selected high-risk patients, the choice to start allogeneic hematopoietic stem cell transplantation (alloHCT) or continue these agents is a matter of debate. Furthermore, published data about the impact on the feasibility of alloHCT and the optimal timing of administration are limited. Here we present a case of relapsed TP53 mutated CLL treated with ibrutinib as a bridge to alloHCT, discussing risks and benefits of different treatment options in a "real life" situation. PMID- 29234596 TI - Exploring the multiple-hit hypothesis of preterm white matter damage using diffusion MRI. AB - Background: Preterm infants are at high risk of diffuse white matter injury and adverse neurodevelopmental outcome. The multiple hit hypothesis suggests that the risk of white matter injury increases with cumulative exposure to multiple perinatal risk factors. Our aim was to test this hypothesis in a large cohort of preterm infants using diffusion weighted magnetic resonance imaging (dMRI). Methods: We studied 491 infants (52% male) without focal destructive brain lesions born at < 34 weeks, who underwent structural and dMRI at a specialist Neonatal Imaging Centre. The median (range) gestational age (GA) at birth was 30+ 1 (23+ 2-33+ 5) weeks and median postmenstrual age at scan was 42+ 1 (38-45) weeks. dMRI data were analyzed using tract based spatial statistics and the relationship between dMRI measures in white matter and individual perinatal risk factors was assessed. We tested the hypothesis that increased exposure to perinatal risk factors was associated with lower fractional anisotropy (FA), and higher radial, axial and mean diffusivity (RD, AD, MD) in white matter. Neurodevelopmental performance was investigated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III) in a subset of 381 infants at 20 months corrected age. We tested the hypothesis that lower FA and higher RD, AD and MD in white matter were associated with poorer neurodevelopmental performance. Results: Identified risk factors for diffuse white matter injury were lower GA at birth, fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition, necrotizing enterocolitis and male sex. Clinical chorioamnionitis and patent ductus arteriosus were not associated with white matter injury. Multivariate analysis demonstrated that fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition were independently associated with lower FA values. Exposure to cumulative risk factors was associated with reduced white matter FA and FA values at term equivalent age were associated with subsequent neurodevelopmental performance. Conclusion: This study suggests multiple perinatal risk factors have an independent association with diffuse white matter injury at term equivalent age and exposure to multiple perinatal risk factors exacerbates dMRI defined, clinically significant white matter injury. Our findings support the multiple hit hypothesis for preterm white matter injury. PMID- 29234597 TI - A supervised framework with intensity subtraction and deformation field features for the detection of new T2-w lesions in multiple sclerosis. AB - Introduction: Longitudinal magnetic resonance imaging (MRI) analysis has an important role in multiple sclerosis diagnosis and follow-up. The presence of new T2-w lesions on brain MRI scans is considered a prognostic and predictive biomarker for the disease. In this study, we propose a supervised approach for detecting new T2-w lesions using features from image intensities, subtraction values, and deformation fields (DF). Methods: One year apart multi-channel brain MRI scans were obtained for 60 patients, 36 of them with new T2-w lesions. Images from both temporal points were preprocessed and co-registered. Afterwards, they were registered using multi-resolution affine registration, allowing their subtraction. In particular, the DFs between both images were computed with the Demons non-rigid registration algorithm. Afterwards, a logistic regression model was trained with features from image intensities, subtraction values, and DF operators. We evaluated the performance of the model following a leave-one-out cross-validation scheme. Results: In terms of detection, we obtained a mean Dice similarity coefficient of 0.77 with a true-positive rate of 74.30% and a false positive detection rate of 11.86%. In terms of segmentation, we obtained a mean Dice similarity coefficient of 0.56. The performance of our model was significantly higher than state-of-the-art methods. Conclusions: The performance of the proposed method shows the benefits of using DF operators as features to train a supervised learning model. Compared to other methods, the proposed model decreases the number of false-positives while increasing the number of true positives, which is relevant for clinical settings. PMID- 29234598 TI - Investigating structural and perfusion deficits due to repeated head trauma in active professional fighters. AB - Repeated head trauma experienced by active professional fighters results in various structural, functional and perfusion damage. However, whether there are common regions of structural and perfusion damage due to fighting and whether these structural and perfusion differences are associated with neuropsychological measurements in active professional fighters is still unknown. To that end, T1 weighted and pseudocontinuous arterial spin labeling MRI on a group of healthy controls and active professional fighters were acquired. Voxelwise group comparisons, in a univariate and multivariate sense, were performed to investigate differences in gray and white matter density (GMD, WMD) and cerebral blood flow (CBF) between the two groups. A significantly positive association between global GMD and WMD was obtained with psychomotor speed and reaction time, respectively, in our cohort of active professional fighters. In addition, regional WMD deficit was observed in a cluster encompassing bilateral pons, hippocampus, and thalamus in fighters (0.49 +/- 0.04 arbitrary units (a.u.)) as compared to controls (0.51 +/- 0.05a.u.). WMD in the cluster of active fighters was also significantly associated with reaction time. Significantly lower CBF was observed in right inferior temporal lobe with both partial volume corrected (46.9 +/- 14.93 ml/100 g/min) and non-partial volume corrected CBF maps (25.91 +/- 7.99 ml/100 g/min) in professional fighters, as compared to controls (65.45 +/- 22.24 ml/100 g/min and 35.22 +/- 12.18 ml/100 g/min respectively). A paradoxical increase in CBF accompanying right cerebellum and fusiform gyrus in the active professional fighters (29.52 +/- 13.03 ml/100 g/min) as compared to controls (19.43 +/- 12.56 ml/100 g/min) was observed with non-partial volume corrected CBF maps. Multivariate analysis with both structural and perfusion measurements found the same clusters as univariate analysis in addition to a cluster in right precuneus. Both partial volume corrected and non-partial volume corrected CBF of the cluster in the thalamus had a significantly positive association with the number of fights. In addition, GMD of the cluster in right precuneus was significantly associated with psychomotor speed in our cohort of active professional fighters. Our results suggest a heterogeneous pattern of structural and CBF deficits due to repeated head trauma in active professional fighters. This finding indicates that investigating both structural and CBF changes in the same set of participants may help to understand the pathophysiology and progression of cognitive decline due to repeated head trauma. PMID- 29234599 TI - Selecting the most relevant brain regions to discriminate Alzheimer's disease patients from healthy controls using multiple kernel learning: A comparison across functional and structural imaging modalities and atlases. AB - Background: Machine learning techniques such as support vector machine (SVM) have been applied recently in order to accurately classify individuals with neuropsychiatric disorders such as Alzheimer's disease (AD) based on neuroimaging data. However, the multivariate nature of the SVM approach often precludes the identification of the brain regions that contribute most to classification accuracy. Multiple kernel learning (MKL) is a sparse machine learning method that allows the identification of the most relevant sources for the classification. By parcelating the brain into regions of interest (ROI) it is possible to use each ROI as a source to MKL (ROI-MKL). Methods: We applied MKL to multimodal neuroimaging data in order to: 1) compare the diagnostic performance of ROI-MKL and whole-brain SVM in discriminating patients with AD from demographically matched healthy controls and 2) identify the most relevant brain regions to the classification. We used two atlases (AAL and Brodmann's) to parcelate the brain into ROIs and applied ROI-MKL to structural (T1) MRI, 18F-FDG-PET and regional cerebral blood flow SPECT (rCBF-SPECT) data acquired from the same subjects (20 patients with early AD and 18 controls). In ROI-MKL, each ROI received a weight (ROI-weight) that indicated the region's relevance to the classification. For each ROI, we also calculated whether there was a predominance of voxels indicating decreased or increased regional activity (for 18F-FDG-PET and rCBF SPECT) or volume (for T1-MRI) in AD patients. Results: Compared to whole-brain SVM, the ROI-MKL approach resulted in better accuracies (with either atlas) for classification using 18F-FDG-PET (92.5% accuracy for ROI-MKL versus 84% for whole brain), but not when using rCBF-SPECT or T1-MRI. Although several cortical and subcortical regions contributed to discrimination, high ROI-weights and predominance of hypometabolism and atrophy were identified specially in medial parietal and temporo-limbic cortical regions. Also, the weight of discrimination due to a pattern of increased voxel-weight values in AD individuals was surprisingly high (ranging from approximately 20% to 40% depending on the imaging modality), located mainly in primary sensorimotor and visual cortices and subcortical nuclei. Conclusion: The MKL-ROI approach highlights the high discriminative weight of a subset of brain regions of known relevance to AD, the selection of which contributes to increased classification accuracy when applied to 18F-FDG-PET data. Moreover, the MKL-ROI approach demonstrates that brain regions typically spared in mild stages of AD also contribute substantially in the individual discrimination of AD patients from controls. PMID- 29234601 TI - The characterization of an economic and portable LED-based photoacoustic imaging system to facilitate molecular imaging. AB - Photoacoustic imaging (PAI) is a non-invasive, high-resolution hybrid imaging modality that combines optical excitation and ultrasound detection. PAI can image endogenous chromophores (melanin, hemoglobin, etc.) and exogenous contrast agents in different medical applications. However, most current equipment uses sophisticated and complicated OPO lasers with tuning and stability features inconsistent with broad clinical deployment. As the number of applications of PAI in medicine increases, there is an urgent need to make the imaging equipment more compact, portable, and affordable. Here, portable light emitting diode - based photoacoustic imaging (PLED-PAI) was introduced and characterized in terms of system specifications, light source characterizations, photoacoustic spatial/temporal resolution, and penetration. The system uses two LED arrays attached to the sides of a conventional ultrasound transducer. The LED pulse repetition rate is tunable between 1 K Hz, 2 K Hz, 3 K Hz, and 4 K Hz. The axial resolution was 0.268 mm, and the lateral resolution was between 0.55 and 0.59 mm. The system could detect optical absorber (pencil lead) at a depth of 3.2 cm and the detection limits of indocyanine green (ICG) and methylene blue (MB) were 9 MUM and 0.78 mM. In vivo imaging of labeled human mesenchymal stem cells was achieved to confirm compatibility with small animal imaging. The characterization we report here may have value to other groups evaluating commercially available photoacoustic imaging equipment. PMID- 29234600 TI - Prediction of cognitive and motor development in preterm children using exhaustive feature selection and cross-validation of near-term white matter microstructure. AB - Background: Advanced neuroimaging and computational methods offer opportunities for more accurate prognosis. We hypothesized that near-term regional white matter (WM) microstructure, assessed on diffusion tensor imaging (DTI), using exhaustive feature selection with cross-validation would predict neurodevelopment in preterm children. Methods: Near-term MRI and DTI obtained at 36.6 +/- 1.8 weeks postmenstrual age in 66 very-low-birth-weight preterm neonates were assessed. 60/66 had follow-up neurodevelopmental evaluation with Bayley Scales of Infant Toddler Development, 3rd-edition (BSID-III) at 18-22 months. Linear models with exhaustive feature selection and leave-one-out cross-validation computed based on DTI identified sets of three brain regions most predictive of cognitive and motor function; logistic regression models were computed to classify high-risk infants scoring one standard deviation below mean. Results: Cognitive impairment was predicted (100% sensitivity, 100% specificity; AUC = 1) by near-term right middle temporal gyrus MD, right cingulate-cingulum MD, left caudate MD. Motor impairment was predicted (90% sensitivity, 86% specificity; AUC = 0.912) by left precuneus FA, right superior occipital gyrus MD, right hippocampus FA. Cognitive score variance was explained (29.6%, cross-validated R^2 = 0.296) by left posterior limb-of-internal-capsule MD, Genu RD, right fusiform gyrus AD. Motor score variance was explained (31.7%, cross-validated R^2 = 0.317) by left posterior limb-of-internal-capsule MD, right parahippocampal gyrus AD, right middle temporal gyrus AD. Conclusion: Search in large DTI feature space more accurately identified neonatal neuroimaging correlates of neurodevelopment. PMID- 29234602 TI - Neutralization of Naja naja venom induced lethality, edema and myonecrosis by ethanolic root extract of Coix lacryma-jobi. AB - Coix lacryma-jobi, commonly known as job's tear, is a tall grain-bearing tropical plant of the family Poaceae. The ethanolic root extract (ERE) of the plant was investigated for the first time for anti-venom activity against Indian cobra Naja naja venom. In-vitro studies were conducted to determine neutralization of phospholipase A2 (PLA2) activity of the Naja naja venom by the ERE. ERE showed significant inhibition of PLA2 activity, which was further confirmed from effective neutralization of human red blood cells (HRBC) lysis induced by the venom. In addition, venom-induced proteolysis, fibrinogenolysis, DNase activity were also neutralized by the ERE, which contained carbohydrates, glycolides, resins and tannins. Oral administration of ERE at doses levels 100, 200 and 400 mg/kg effectively inhibited Naja naja venom-induced lethality in mice. Myotoxicity induced by Naja naja venom, measured by creatine kinase activity in rats was significantly neutralized by the ERE at a dose of 200 mg/kg. Stigmasterol, as one of the component isolated from the ERE, was found to have venom phospholipase A2 inhibition potential, which was confirmed by molecular docking studies with PLA2. In summary, these studies indicate the ability of ERE of Coix lacryma-jobi to effectively neutralize the toxic effects of the venom is, in part, contributed by the inhibition of PLA2 activity among other venom-derived factors. PMID- 29234604 TI - Longitudinal survey of lead, cadmium, and copper in seagrass Syringodium filiforme from a former bombing range (Vieques, Puerto Rico). AB - Trace element composition in plant biomass could be used as an indicator of environmental stress, management practices and restoration success. A longitudinal study was conducted to compare Pb, Cd, and Cu content in seagrass Syringodium filiforme collected at a former bombing range in Puerto Rico with those of a Biosphere Reserve under similar geoclimatic conditions. Trace elements were measured by atomic absorption after dry-ashing of samples and extraction with acid. In general, levels of Pb, Cd, and Cu varied during 2001, 2003, 2005 2006, and 2013-2016. Results showed that bioaccumulated concentration of these trace elements were consistently higher, but not significant, at the bombing range site. As expected in polluted areas, greater variability in Pb and Cd content were observed in the military impacted site with levels up to 14 and 17 times higher than seagrass from the reference site, respectively. Although a decrease in Pb was observed after cessation of all military activities in 2003, the concentration in plant biomass was still above levels of ecological concern, indicating that natural attenuation is insufficient for cleanup of the site. PMID- 29234603 TI - A retrospective study of clinico-epidemiological profile of snakebite related deaths at a Tertiary care hospital in Midnapore, West Bengal, India. AB - Objective: Snakebite is one of the neglected tropical diseases that World Health Organization (WHO) aimed to eradicate. The objective of the study is to investigate the mortality and morbidity due to snakebite at Midnapore Medical College & Hospital in Paschim Medinipur district, West Bengal, India. Methods & materials: This is a record-based, retrospective, descriptive epidemiological study conducted from January 2012 to December 2016 at Midnapore Medical College and Hospital(MMCH), Paschim Medinipur district, West Bengal. The incidence and determinants of snakebite related mortality with reference to types of envenomation, age, sex, site of bite, clinical manifestations of snakebite, bite to hospital and bite to AVS treatment time, first aid and management of snakebite were investigated during the study. The data was analyzed by SPSS (Version 18) software.All results were expressed as percentage. Results: Total number of snakebite deaths in Midnapore Medical College and Hospital(MMCH) was 222 from the period 2012-2016. Number of males was 134(60.36%) and female 88 (39.63%). Maximum snakebite deaths occurred in the age group of 31-40 years during agricultural and outdoor activities. Most of the snakebites occurred during June-September. Out of the 222 cases of snakebite, 182(82%) cases were due to viper envenomation. Maximum number of cases(n = 162) were detected in the interval between 4.00 PM to 8.00 PM. The bite to hospital time was found to be 180 +/- 3.5 mins (n = 190 cases) and bite to AVS injection time was found to be 240 +/- 3.5 mins (n = 190 cases). The mean bleeding time was 12.55 +/- 3.2 min (n = 190 cases). The mean clotting time was found to be 20.1 +/- 2.55 min (n = 190 cases). The symptoms of envenomation included local signs of inflammation(100% cases), blisters and necrosis (45% cases), renal failure (20% cases), coagulopathies(57% cases), ptosis(10% cases), dysphagia(2%) and respiratory distress(15% cases). The WHO protocol for snakebite management was followed for treatment of snakebite victims. Conclusion: Snake bite is a neglected, life-threatening emergency in developing countries such as India and demands immediate anti-venom therapy. Hospital studies are a key source of information about snake bites. The ready availability and appropriate use of AVS, close monitoring of patients, the institution of ventilator support and if required, early referral to a larger hospital all help to reduce the mortality. Thus knowledge of the varied clinical manifestations of snake bite is important for effective management in hospitals by a complete health care team. PMID- 29234605 TI - Synthesis and biomedical applications of Cerium oxide nanoparticles - A Review. AB - A cerium oxide nanoparticles (nanoceria) has a wide range of applications in different fields, especially biomedical division. As a matter of concern, it has a major impact on the human health and environment. The aim of this review is to address the different ways of synthesis of nanoceria using chemical and green synthesis methods and characterization and the applications of nanoceria for antioxidant, anticancer, antibacterial activities and toxicological studies including the most recent studies carried out in vivo and in vitro to study the problems. We have exclusively discussed on the toxicology of nanoceria exposed to the general public along with recent advances in the studies of antimicrobial, toxicity and anti-oxidant activity. PMID- 29234606 TI - Complete genome sequence of N2-fixing model strain Klebsiella sp. nov. M5al, which produces plant cell wall-degrading enzymes and siderophores. AB - The bacterial strain M5al is a model strain for studying the molecular genetics of N2-fixation and molecular engineering of microbial production of platform chemicals 1,3-propanediol and 2,3-butanediol. Here, we present the complete genome sequence of the strain M5al, which belongs to a novel species closely related to Klebsiella michiganensis. M5al secretes plant cell wall-degrading enzymes and colonizes rice roots but does not cause soft rot disease. M5al also produces siderophores and contains the gene clusters for synthesis and transport of yersiniabactin which is a critical virulence factor for Klebsiella pathogens in causing human disease. We propose that the model strain M5al can be genetically modified to study bacterial N2-fixation in association with non legume plants and production of 1,3-propanediol and 2,3-butanediol through degradation of plant cell wall biomass. PMID- 29234607 TI - Lobectomy versus Sublobar Resection in Non-Lepidic Small-Sized Non-Small Cell Lung Cancer. AB - Background: Recently, many surgeons have chosen sublobar resection for the curative treatment of lung tumors with ground-glass opacity, which is a hallmark of lepidic lung cancer. The purpose of this study was to evaluate the oncological results of sublobar resection for non-lepidic lung cancer in comparison with lobectomy. Methods: We conducted a retrospective chart review of 328 patients with clinical N0 non-small cell lung cancer sized <=2 cm who underwent curative surgical resection from January 2009 to December 2014. The patients were classified on the basis of their lesions into non-lepidic and lepidic groups. The survival rates following lobectomy and sublobar resection were compared within each of these 2 groups. Results: The non-lepidic group contained a total of 191 patients. The 5-year recurrence-free survival rate was not significantly different between patients who received sublobar resection or lobectomy in the non-lepidic group (80.1% vs. 79.2%, p=0.822) or in the lepidic group (100% vs. 97.4%, p=0.283). Multivariate analysis indicated that only lymphatic invasion was a significant risk factor for recurrence in the non-lepidic group. Sublobar resection was not a risk factor for recurrence in the non-lepidic group. Conclusion: The oncological outcomes of sublobar resection and lobectomy in small sized non-small cell lung cancer did not significantly differ according to histological type. PMID- 29234608 TI - Location of Ruptured Bullae in Secondary Spontaneous Pneumothorax. AB - Background: The surgical treatment of secondary spontaneous pneumothorax (SSP) can be complicated by fragile lung parenchyma. The preoperative prediction of air leakage could help prevent intraoperative lung injury during manipulation of the lung. Common sites of bulla development and ruptured bullae were investigated based on computed tomography (CT) and intraoperative findings. Methods: The study enrolled 208 patients with SSP who underwent air leak control through video assisted thoracoscopic surgery (VATS). We retrospectively reviewed the sites of bulla development on preoperative CT and the rupture sites during VATS. Results: Of the 135 cases of right-sided SSP, the most common rupture site was the apical segment (31.9%), followed by the azygoesophageal recess (27.4%). Of the 75 cases on the left side, the most common rupture site was the apical segment (24.0%), followed by the anterior basal segment (17.3%). Conclusion: The azygoesophageal recess and parenchyma along the cardiac border were common sites of bulla development and rupture. Studies of respiratory lung motion to measure the pleural pressure at the lung surface could help to determine the relationship between cardiogenic and diaphragmatic movement and bulla formation or rupture. PMID- 29234609 TI - Outcomes of Open Repair of Mycotic Aortic Aneurysms with In Situ Replacement. AB - Background: Mycotic aortic aneurysms are rare and life-threatening. Unfortunately, no established guidelines exist for the treatment of patients with mycotic aortic aneurysms. The purpose of this study was to evaluate the midterm outcomes of the open repair of mycotic thoracic and thoracoabdominal aneurysms and suggest a therapeutic strategy. Methods: From 2006 to 2016, 19 patients underwent open repair for an aortic aneurysm. All infected tissue was extensively debrided and covered with soft tissue. We recorded the clinical findings, anatomic location of the aneurysm, bacteriology results, antibiotic therapy, morbidity, and mortality for these cases. Results: The median age was 62+/-7.2 years (range, 16 to 78 years), 13 patients (68%) were men, and the mean aneurysm size was 44.5+/-4.9 mm. The mean time from onset of illness to surgery was 14.5+/ 2.4 days. Aortic continuity was restored in situ with a Dacron prosthesis (79%), homograft (16%), or Gore-Tex graft (5%). Soft-tissue coverage of the prosthesis was performed in 8 patients. The mean follow-up time was 43.2+/-11.7 months. The early mortality rate was 10.5%, and the 5-year survival rate was 74.9%+/-11.5%. Conclusion: This study showed acceptable early and midterm outcomes of open repair of mycotic aneurysms. We emphasize that aggressive intraoperative debridement with soft-tissue coverage results in a high rate of success in these high-risk patients. PMID- 29234610 TI - A New Root-Strengthening Technique for Acute Aortic Dissection with a Weakened Aortic Root: The Neo-Adventitia Technique. AB - Background: Dissection flaps in acute type A aortic dissection typically extend into the root, most frequently into the non-coronary sinus (NCS). The weakened root can be susceptible not only to surgical trauma, but also to future dilatation because of its thinner layers. Herein, we describe a new technique that we named the "neo-adventitia" technique to strengthen the weakened aortic root. Methods: From 2012 to 2016, 27 patients with acute type A aortic dissection underwent supracommissural graft replacement using our neo-adventitia technique. After we applied biologic glue between the dissected layers, we wrapped the entire NCS and the partial left and right coronary sinuses on the outside using a rectangular Dacron tube graft that served as neo-adventitia to reinforce the dissected weakened wall. Then, fixation with subannular stitches stabilized the annulus of the NCS. Results: There were 4 cases of operative mortality, but all survivors were discharged with aortic regurgitation (AR) classified as mild or less. Follow-up echocardiograms were performed in 10 patients. Of these, 9 showed mild or less AR, and 1 had moderate AR without root dilatation. There were no significant differences in the size of the aortic annulus (p=0.57) or root (p=0.10) between before discharge and the last follow-up echocardiograms, and no reoperations on the aortic roots were required during the follow-up period. Conclusion: This technique is easy and efficient for reinforcing and stabilizing weakened roots. Furthermore, this technique may be an alternative for restoring and maintaining the geometry of the aortic root. An externally reinforced NCS could be expected to resist future dilatation. PMID- 29234612 TI - Near-Infrared Spectroscopy versus Transcranial Doppler-Based Monitoring in Carotid Endarterectomy. AB - Background: Proper monitoring of cerebral perfusion during carotid artery surgery is crucial for determining if a shunt is needed. We compared the safety and reliability of near-infrared spectroscopy (NIRS) with transcranial Doppler (TCD) for cerebral monitoring. Methods: This single-center, retrospective review was conducted on patients who underwent carotid endarterectomy (CEA) using selective shunt-based TCD or NIRS at Daegu Catholic University Medical Center from November 2009 to June 2016. Postoperative complications were the primary outcome, and the distribution of risk factors between the 2 groups was compared. Results: The medical records of 74 patients (45 TCD, 29 NIRS) were reviewed. The demographic characteristics were similar between the 2 groups. One TCD patient died within the 30-day postoperative period. Postoperative stroke (n=4, p=0.15) and neurologic complications (n=10, p=0.005) were only reported in the TCD group. Shunt usage was 44.4% and 10.3% in the TCD and NIRS groups, respectively (p=0.002). Conclusion: NIRS-based selective shunting during CEA seems to be safe and reliable for monitoring cerebral perfusion in terms of postoperative stroke and neurologic symptoms. It also reduces unnecessary shunt usage. PMID- 29234611 TI - Should We Remove the Retrievable Cook Celect Inferior Vena Cava Filter? Eight Years of Experience at a Single Center. AB - Background: The inferior vena cava filter (IVCF) is very effective for preventing pulmonary embolism in patients who cannot undergo anticoagulation therapy. However, if a filter is placed in the body permanently, it may lead to other complications. Methods: A retrospective study was performed of 159 patients who underwent retrievable Cook Celect IVCF implantation between January 2007 and April 2015 at a single center. Baseline characteristics, indications, and complications caused by the filter were investigated. Results: The most common underlying disease of patients receiving the filter was cancer (24.3%). Venous thrombolysis or thrombectomy was the most common indication for IVCF insertion in this study (47.2%). The most common complication was inferior vena cava penetration, the risk of which increased the longer the filter remained in the body (p=0.032, Exp(B)=1.004). Conclusion: If the patient is able to retry anticoagulation therapy and the filter is no longer needed, the filter should be removed, even if a long time has elapsed since implantation. If the filter cannot be removed, it is recommended that follow-up computed tomography be performed regularly to monitor the progress of venous thromboembolisms as well as any filter-related complications. PMID- 29234613 TI - Phlegmonous Esophagitis Treated with Internal Drainage and Feeding Jejunostomy. AB - We report the case of a 67-year-old woman presenting with epigastric pain. Computed tomography identified diffuse phlegmonous esophagitis. Esophagogastroduodenoscopy revealed multiple perforations in the mucosal layer of the esophagus. A large amount of pus was drained internally through the gut. The patient was treated with antibiotics and early jejunostomy feeding. Although phlegmonous esophagitis is a potentially fatal disease, the patient was successfully treated medically with only a minor complication (esophageal stricture). PMID- 29234614 TI - Delayed Iatrogenic Diaphragmatic Hernia after Left Lower Lobectomy. AB - A 66-year-old patient undergoing regular follow-up at Samsung Medical Center after left lower lobectomy visited the emergency department around 9 months postoperatively because of nausea and vomiting after routine esophagogastroduodenoscopy at a local clinic. Abdominal computed tomography showed the stomach herniating into the left thoracic cavity. We explored the pleural cavity via video-assisted thoracic surgery (VATS). Adhesiolysis around the herniated stomach and laparotomic reduction under video assistance were successfully performed. The diaphragmatic defect was repaired via VATS. The postoperative course was uneventful, and he was discharged with resolved digestive tract symptoms. PMID- 29234615 TI - Sterile Necrosis of the Sternum: A Rare Complication Following Coronary Artery Bypass Surgery. AB - We herein present the unique case of a 68-year-old male diabetic patient who developed sterile necrosis of the sternum 1 month after myocardial revascularization with the use of bilateral internal thoracic artery grafts. The sternum had been closed by the bilateral Robicsek wiring technique. The sternum was removed, and bilateral pectoralis major flaps were used to cover the defect. The patient had an uneventful recovery. PMID- 29234616 TI - Recurrent Mediastinal Sarcoma in the Aortic Arch. AB - As mediastinal sarcomas commonly present as large tumors invading adjacent vital structures, complete resection is frequently challenging. For such tumors, aggressive surgical strategies, such as the resection and reconstruction of the invaded vital structures under cardiopulmonary bypass, may be required to achieve complete resection and to improve survival. Herein, we report a case of recurrent mediastinal sarcoma invading the aortic arch and arch vessels that was successfully removed by total arch replacement. PMID- 29234617 TI - Transcatheter Mitral Valve Implantation in Open Heart Surgery: An Off-Label Technique. AB - Extensive mitral annulus calcifications are considered a contraindication for valve surgery. We describe the case of a 76-year-old female with severe mitral and aortic stenosis associated with extensive calcifications of the heart. The patient underwent an open mitroaortic valve replacement using transcatheter aortic valve implantation with an Edwards SAPIEN XT valve (Edwards Lifesciences Corp., Irvine, CA, USA) in the mitral position. The aortic valve was replaced using a stentless valve prosthesis (LivaNova SOLO; LivaNova PLC, London, UK). Postoperative echocardiography showed that the prosthetic valve was in the correct position and there were no paravalvular leaks. A bailout open transcatheter valve implantation can be considered a safe and effective option in selected cases with an extensively calcified mitral valve. PMID- 29234618 TI - Carney Complex: Eleven Open Heart Operations in a Single Family. AB - Herein, we report on a family with Carney complex. Four members of the family underwent a total of 11 open heart operations as well as 9 other operations to treat extrathoracic masses. All the family members met at least 2 major clinical criteria and 1 supplemental criterion. We analyzed their genomic loci, including the protein kinase A regulatory subunit 1 gene. The results revealed no specific mutations, except for a common single nucleotide polymorphism. This case series of Carney complex emphasizes the importance of close longitudinal follow-up because of the high rate of tumor recurrence irrespective of the site. Clinicians should not overlook the specific features of familial myxoma. PMID- 29234619 TI - Delayed Pulmonary Artery Rupture after Using BioGlue in Cardiac Surgery. AB - A 56-year-old woman, who underwent cardiac surgery 3 months previously, presented to the emergency room with pulmonary artery rupture due to the cytotoxic effects of BioGlue (CryoLife Inc., Kennesaw, GA, USA). She was successfully treated with surgical management. Although surgical glue can be effectively used for hemostasis, it can induce delayed vascular complications. Therefore, surgical glue should be used cautiously. PMID- 29234620 TI - What Are the Optimal Dose of Administration and Time of Drainage for Topical Tranexamic Acid in Patients Undergoing Cardiac Surgery? PMID- 29234622 TI - Impact of Serum TSH and Anti-Thyroglobulin Antibody Levels on Lymph Node Fine Needle Aspiration Thyroglobulin Measurements in Differentiated Thyroid Cancer Patients. AB - Background: Thyroglobulin measurements in the washout of fine needle aspiration (FNA-Tg) are an excellent tool to detect lymph node (LN) metastases of differentiated thyroid carcinoma (DTC). Nevertheless, how to define the best cutoffs and the influence of potential confounders are still being discussed. Objective: To evaluate the accuracy of FNA-Tg measurement to detect DTC metastases and the influence of thyroid status and anti-thyroglobulin antibodies (TgAb). Methods: One hundred thirty-eight patients with DTC and suspicious cervical LN were included. Patients underwent ultrasound (US)-guided FNA for cytological examination and FNA-Tg measurements. Final diagnoses were confirmed by histological examination or clinical and US follow-up for at least 1 year. Results: Data from 119 subjects with suspicious LN were evaluated. The median value of FNA-Tg in patients with metastatic LN (n = 65) was 3,263.0 ng/mL (838.55 12,507.5), while patients without LN metastasis (n = 54) showed levels of 0.2 ng/mL (0.2-0.2). According to the ROC curve analysis, the best cutoff value to predict metastasis was 4.41 ng/mL for FNA-Tg, with a sensitivity of 98% and specificity of 96%. There were no differences in the median of FNA-Tg measurements between those on (TSH 0.16 mUI/mL) and those off levothyroxine (TSH 99.41 mUI/mL) therapy (47.94 vs. 581.15 ng/mL, respectively; p = 0.79). Interestingly, the values of FNA-Tg in patients with LN metastasis (n = 65) did not differ between patients with positive and those with negative TgAb (88.8 vs. 3,263.0 ng/mL, respectively; p = 0.57). Conclusion: US-guided FNA-Tg proved to be a useful examination in the follow-up of patients with DTC, independently of TSH status and the presence of TgAb. PMID- 29234621 TI - Neonatal Exposure to 6-n-Propyl-Thiouracil, an Anti-Thyroid Drug, Alters Expression of Hepatic DNA Methyltransferases, Methyl CpG-Binding Proteins, Gadd45a, p53, and PCNA in Adult Male Rats. AB - Background: Neonatal 6-n-propyl-2-thiouracil (PTU) exposure to male rats is reported to impair liver function in adulthood. However, the mechanism by which the drug impairs liver function is not well known. Objectives: The objectives of the study were to investigate the effects of neonatal exposure of PTU on the expression of DNA methyltransferases (DNMTs), methyl-DNA binding proteins (MBDs), Gadd45a, p53, and proliferating cell nuclear antigen (PCNA) in adult rat liver. Methods: The effects of neonatal transient (from birth to 30 days of age) and persistent (from birth to 90 days of age) treatment of PTU on DNA damage and on the expression of p53, PCNA, DNMTs, and MBDs were investigated at transcriptional and translational levels in male adult liver. Results: Persistent exposure to PTU from birth caused significant downregulation of expression of DNMT1 and DNMT3a and upregulation of DNMT3b, MBD4, and Gadd45a without any damage to DNA. Although MeCp2 transcripts were significantly low in the liver of adult rats after persistent exposure to PTU compared to controls, its translated products were significantly higher than in controls. The expression of p53 and PCNA in PTU treated rats was significantly higher and lower, respectively, than that in control rats. Conclusion: The results suggest that neonatal exposure of male rats to PTU resulted in alteration in the expression of proteins that are associated with DNA methylation and genome stabilization in adult rat liver. PMID- 29234623 TI - Are Perinatal Events Risk Factors for Childhood Thyroid Autoimmunity? AB - Background: Environmental and genetic factors possibly trigger thyroid autoimmunity. Studies on perinatal risk factors for childhood thyroid autoimmunity are sparse. Objectives: The aim was to investigate if perinatal factors, family history of autoimmune diseases, and HLA-DQ genotypes contribute to thyroid autoimmunity in the Diabetes Prediction in Skane (DiPiS) study. Methods: Samples from 1,874 ten-year-old children were analyzed for autoantibodies to thyroid peroxidase (TPOAb), thyroglobulin (TGAb), and HLA-DQ genotypes. Information on perinatal events and family history of autoimmunity was gathered prospectively in questionnaires. Results: Thyroid autoimmunity was found in 6.9% of the children (TPOAb 4.4%, TGAb 5.8%, both autoantibodies 3.3%) and was overrepresented in girls. Prematurity was positively related to TGAb (OR: 2.4, p = 0.003, pc = 0.021). Autoimmune diseases in the family increased the risk of thyroid autoimmunity: TPOAb (OR: 2.2, p = 0.012), any autoantibody (OR: 1.7, p = 0.04), and both autoantibodies (OR: 2.2, p = 0.024). A first-degree relative (FDR) with thyroid disease increased the risk for TPOAb (OR: 2.4, p = 0.03) and both autoantibodies (OR: 2.6, p = 0.03), a FDR or sibling with celiac disease increased the risk for both autoantibodies (OR: 3.7, p = 0.03, and OR: 4.8, p = 0.003), a FDR or sibling with diabetes increased the risk for thyroid autoantibody (OR: 3.0, p = 0.01, and OR: 5.4, p = 0.032), and a father with rheumatic disease increased the risk for TPOAb (OR: 15.2, p = 0.017), TGAb (OR: 11.3, p = 0.029), any autoantibody (OR: 9.6, p = 0.038), and both autoantibodies (OR: 20, p = 0.01). Conclusions: Thyroid autoimmunity was found in 6.9% of the 10 year-old children who were being followed for their risk of type 1 diabetes. No relation to perinatal factors was found, with the exception of a possible association between prematurity and TGAb. Family history of autoimmune diseases increased the risk of thyroid autoimmunity. PMID- 29234624 TI - Thyroidectomy Improves Tracheal Anatomy and Airflow in Patients with Nodular Goiter: A Prospective Cohort Study. AB - Objective: A large goiter may cause compression of the trachea. The aim of this study was to investigate the impact of thyroidectomy on tracheal anatomy and airflow and to correlate this with changes in health-related quality of life (HRQoL) in patients with benign nodular goiter. Methods: Magnetic resonance images of the neck and respiratory flow-volume curves, including both inspiration and expiration, were performed prior to and 6 months following surgery. HRQoL was measured by selected scales from the thyroid-specific patient-reported outcome (ThyPRO). Cohen's effect size (ES) was calculated as mean change divided by standard deviation at baseline. ES of 0.2-0.5 were defined as small, 0.5-0.8 as moderate, and values >0.8 as large. Results: Sixty-five patients completed all examinations. Median goiter volume was 58 mL (range, 14-642 mL) before surgery with surgical removal of a median of 43 g (range, 8-607 g). Six months after surgery, tracheal narrowing and deviation were diminished by a median of 26% (ES = 0.67, p < 0.001) and 33% (ES = 0.61, p < 0.001), respectively. Correspondingly, each 10% decrease in goiter volume resulted in 1.0% less tracheal narrowing (p < 0.001). Concomitantly, a small improvement was seen in forced inspiratory flow at 50% of forced vital capacity (ES = 0.32, p < 0.001). A reduction in tracheal narrowing was associated with improvements in the Impaired Daily Life scale (0.33 points per 1% decrease in tracheal narrowing, p = 0.03) of the ThyPRO questionnaire. Conclusions: In patients with symptomatic benign nodular goiter, thyroidectomy resulted in substantial improvements in tracheal anatomy and improvements in inspiratory flow, which were followed by gains in HRQoL. This information is pertinent when counseling patients before choice of treatment. PMID- 29234625 TI - Insight into Differentiated Thyroid Cancer Gross Pathological Specimen Shrinkage and Its Influence on TNM Staging. AB - Introduction: This study aimed at comparing thyroid cancer staging when taking into account the differences between the "T" assessment" using ultrasound (US) and histopathological measurements. Material and Methods: This retrospective study included all consecutive differentiated follicular thyroid cancer (DTC) and medullary thyroid cancer (MTC) patients who underwent postoperative histopathological staging assessment at a single institution. Anaplastic thyroid carcinomas were excluded from the present study. Each malignant thyroid nodule was precisely evaluated by measuring its long axis using both US and gross specimen histopathological examination. T stage classification was attributed to each tumor as regards US (solely according to the tumor dimension) and histopathology: (1) solely according to the tumor dimension and (2) according to the tumor dimension and extrathyroidal extension features when present. Results: Retrospective comparison between US and histopathology size of the operated thyroid nodules showed a mean diminution of 7.52% of the tumor long axis. Tumors <=10 mm at histopathological examination showed a larger decrease in size of 13% (p = 0.054, statistically significant) compared to the US measurements. Ten out of 72 (13.8%) patients showed final T downstaging in comparison to US assessment: (US) T2 to T1b in 6 patients (1 MTC) and (US) T1b to T1a in 4 patients (1 MTC). Two (2.9%) DTC patients were downstaged from stage 2 to stage 1. Conclusion: Precise thyroid tumor US measurement may differ significantly from that obtained by histopathological assessment, which may result in a different TNM staging and subsequent patient management. PMID- 29234626 TI - Consumptive Hypothyroidism: Case Report of Hepatic Hemangioendotheliomas Successfully Treated with Vincristine and Systematic Review of the Syndrome. AB - Objectives: To provide a comprehensive description of consumptive hypothyroidism syndrome (CHS), a severe form of hypothyroidism that occurs due to the high expression levels of thyroid hormone inactivation enzyme type 3 deiodinase (D3) in tumors. Study Design: Case report and systematic review. Results: A 7-month old girl with a diagnosis of massive hepatic hemangioendotheliomas was treated with high doses of thyroid hormones and tumor-directed chemotherapy with vincristine. The tumor displayed excellent response, and euthyroid status was regained. A systematic review on the databases PubMed/Medline and Embase was performed, using the term "Consumptive AND "Hypothyroidism." From the 33 selected references, we extracted 42 case reports of CHS: 36 children and 6 adults. The laboratory profile at diagnosis displayed high TSH and low T4 and T3 serum levels. The serum reverse T3 and D3 activity levels were high in all patients tested. In children, 97% had vascular tumors, whereas in adults 33% were vascular tumors, 33% fibrous tumors, and 33% gastrointestinal stromal tumors. The conservative treatment was predominant in children, while in adults all cases were treated with surgery. Death occurred in 16% of children and 33% of adults. Conclusions: CHS is a rare form of hypothyroidism that occurs in children and adults, usually linked to hepatic vascular tumors. The condition is associated with high lethality. Prompt diagnosis, followed by high-dose thyroid hormone replacement and tumor-directed therapy are the keys to optimize outcomes. PMID- 29234628 TI - Adoption of Sorafenib for the Treatment of Advanced-Stage Hepatocellular Carcinoma in Oncology Practices in the United States. AB - Background: The adoption of sorafenib into oncology practice as a first-line systemic treatment for advanced hepatocellular carcinoma (HCC) is not well understood. We examined sorafenib use since Food and Drug Administration (FDA) approval in 2007 and associated survival for individuals diagnosed with advanced HCC, conducting a population-based evaluation of treatment patterns and outcomes for this newly approved drug in the US over time. Methods: We identified individuals diagnosed with Barcelona Clinic Liver Cancer Stage C from the 2007 and 2012 National Cancer Institute Patterns of Care study. We examined trends in use as well as patient and clinical factors associated with receiving sorafenib using multivariate logistic regression analysis. We then evaluated the association between sorafenib use and overall hazard of death using multivariate Cox proportional hazards regression. Results: Among 550 individuals diagnosed with advanced HCC, we found no significant increase in the proportion of patients treated with sorafenib from 2007 to 2012 (26.3 vs. 30.4%). After adjusting for patient and clinical characteristics, non-Hispanic Blacks (compared to non Hispanic Whites) and those with a lower Child-Pugh score remained more likely to receive sorafenib. Individuals receiving systemic chemotherapy only, radiation therapy only, or no treatment at all experienced a higher risk of death than those treated with sorafenib, while those receiving a transplant experienced a lower risk of death. Conclusions: Sorafenib has not been widely adopted into oncology practice since FDA approval for advanced HCC. Few factors apart from Child-Pugh score and race/ethnicity predict sorafenib use in clinical practice, although sorafenib treatment is associated with a lower risk of death. PMID- 29234629 TI - Lenvatinib in Advanced Hepatocellular Carcinoma. PMID- 29234627 TI - Imaging Diagnosis of Hepatocellular Carcinoma: Recent Advances of Contrast Enhanced Ultrasonography with SonoVue(r). AB - Due to the ability to detect the typical contrast-imaging pattern for hepatocellular carcinoma (HCC), that is hyperenhancement in the arterial phase and hypoenhancement in the late phase on a cirrhotic background, contrast enhanced ultrasonography (CEUS) was included in the American diagnostic algorithm for HCC in 2005. However, its role has been questioned because of the possibility of misdiagnosis of cholangiocarcinoma. The present review aims to describe the advantages and disadvantages of CEUS applications using Sonovue(r) for HCC. In particular there is focus on the accuracy of CEUS in detecting the typical HCC pattern, the CEUS patterns of intrahepatic cholangiocarcinoma (ICC), the risk of misdiagnosis with HCC, the diagnostic use of CEUS in cases of locoregional and systemic treatments, and the evaluation of response to antiangiogenic treatment using dedicated software. PMID- 29234630 TI - Consensus on Stereotactic Body Radiation Therapy for Small-Sized Hepatocellular Carcinoma at the 7th Asia-Pacific Primary Liver Cancer Expert Meeting. AB - Background: Stereotactic body radiation therapy (SBRT) is an advanced technique of external beam radiation therapy that delivers large ablative doses of radiation. In the past decade, many cancer centers have adopted SBRT as one mode of radically treating small-sized hepatocellular carcinoma (HCC), based on encouraging clinical outcomes. SBRT thus seems reasonable as first-line treatment of inoperable HCC confined to the liver. However, most of the clinical studies to date have been retrospective in nature, with key issues still under investigation. Summary: The above-mentioned publications were subjected to scrutiny, fueling discussions at the 7th Asia-Pacific Primary Liver Cancer Expert (APPLE 2016) Meeting on various clinical variables, such as indications for SBRT, therapeutic outcomes, treatment-related toxicities, doses prescribed, and specific techniques. The consensus reached should be of interest to all professionals active in the treatment of HCC, especially radiation oncologists. Key Messages: SBRT is a safe and effective therapeutic option for patients with small-sized HCC, offering substantial local control, improved overall survival, and low toxicity. PMID- 29234632 TI - An Ecological Study of the Association between Air Pollution and Hepatocellular Carcinoma Incidence in Texas. AB - Introduction: Primary liver cancer is a significant cause of cancer-related death in both the United States and the world at large. Hepatocellular carcinoma comprises 90% of these primary liver cancers and has numerous known etiologies. Evaluation of these identified etiologies and other traditional risk factors cannot explain the high incidence rates of hepatocellular carcinoma in Texas. Texas is home to the second largest petrochemical industry and agricultural industry in the nation; industrial activity and exposure to pathogenic chemicals have never been assessed as potential links to the state's increased incidence rate of hepatocellular carcinoma. Methods: The association between the county level concentrations of 4 air pollutants known to be linked to liver cancer, vinyl chloride, arsenic, benzene, and 1,3-butadiene, and hepatocellular carcinoma rates was evaluated using nonparametric generalized additive logistic regression and gamma regression models. Hepatocellular carcinoma incidence rates for 2000 2013 were evaluated in comparison to 1996 and 1999 pollution concentrations and hepatocellular carcinoma rates for the subset of 2006-2013 were evaluated in comparison to 2002 and 2005 pollution concentrations, respectively. Results: The analysis indicates that the relationship between the incidence of liver cancer and air pollution and risk factors is nonlinear. There is a consistent significant positive association between the incidence of liver cancer and hepatitis C prevalence rates (gamma all years, p < 0.05) and vinyl chloride concentrations (logistic 2002 and 2005, p < 0.0001; gamma 2002 and 2005, p < 0.05). Conclusions: This study suggests that vinyl chloride is a significant contributor to the incidence of liver cancer in Texas. The relationship is notably nonlinear. Further, the study supports the association between incidence of liver cancer and prevalence of hepatitis B. PMID- 29234631 TI - Sorafenib versus Hepatic Arterial Infusion Chemotherapy as Initial Treatment for Hepatocellular Carcinoma with Advanced Portal Vein Tumor Thrombosis. AB - Objective: To investigate the validity of hepatic arterial infusion chemotherapy with low-dose 5-fluorouracil and cisplatin (LFP) versus sorafenib as first-line treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (Vp3, Vp4). Patients and Methods: We retrospectively reviewed the cases of Child Pugh A advanced HCC with Vp3 or Vp4 treated with LFP or sorafenib between October 2002 and December 2013. Results: There were 32 patients in the LFP group and 14 patients in the sorafenib group. The objective response rate/disease control rate was 31.3/56.3% in the LFP group and 0/28.6% in the sorafenib group. The median survival time (MST) (309 vs. 120 days; p = 0.009) and the median time to treatment failure (109 vs. 37 days; p = 0.022) were significantly longer in the LFP group than in the sorafenib group. In the LFP group, a relatively favorable outcome (MST, 622 days) was obtained among the response cases. Among the nonresponse cases in the LFP group, at the time of cessation of LFP, 70.4% of cases were Child-Pugh A and 88.9% of cases maintained a score of <=7 points; of the cases in whom Child-Pugh A was maintained, the survival period from the time of LFP discontinuation was significantly longer in the cases in whom sorafenib was introduced as a secondary treatment after LFP than in the cases treated with best supportive care (220 vs. 89 days; p = 0.002). The main adverse event with LFP was grade 3 or higher cytopenia, which was manageable, and adverse event induced discontinuation was significantly lower as compared with sorafenib (p = 0.002). Conclusion: For the treatment of HCC with Vp3/Vp4, it is desirable to initially use LFP and then immediately change to sorafenib if no response is obtained. PMID- 29234633 TI - Clinical Factors Predicting Better Survival Outcome for Pulmonary Metastasectomy of Hepatocellular Carcinoma. AB - Background: In patients with lung metastasis of hepatocellular carcinoma (HCC), it remains uncertain how a better survival outcome can be predicted after metastasectomy. This study aims to identify clinical factors that may be used to guide patient selection for such a therapeutic modality. A total of 28 patients who received pulmonary metastasectomy for HCC between 1993 and 2012 were identified. All relevant clinical factors were extracted from medical records up to September 2015. Patients were classified into high- and low-risk groups according to survival outcome after metastasectomy. All pertinent clinical factors were analyzed for correlation with survival outcome. Summary: The overall survival of 28 patients after pulmonary metastasectomy was studied first. The survival curve was biphasic and reached a plateau at 40 months after metastasectomy. The results indicate the presence of 2 groups of patients with a different survival outcome. Among all clinical parameters, remission status in the liver before pulmonary metastasectomy and distant metastasis-free interval between the last treatment of HCC and the occurrence of lung metastasis were found to be significantly associated with excellent survival outcome after pulmonary metastasectomy (p = 0.019 and 0.007 by Fisher exact test, and p = 0.002 and 0.0002 by Cox regression analysis). PMID- 29234634 TI - Association of Serum Ferritin with Diabetes and Alcohol in Patients with Non Viral Liver Disease-Related Hepatocellular Carcinoma. AB - INTRODUCTION: Non-alcoholic fatty liver disease is a leading cause for hepatocellular carcinoma (HCC) in Sri Lanka. Diabetes mellitus, alcohol abuse, and liver inflammation are known to increase the risk of HCC. The present study evaluates serum ferritin levels in a cohort of patients with non-viral HCC (nvHCC). METHODOLOGY: Consecutive patients with nvHCC presenting to the Colombo North Liver transplant Service, Ragama, from January 2012 to July 2013 were investigated. All were negative for hepatitis B and C. At registration, 5 mL of serum was separated into plain tubes, stored at -80 degrees C and analysed for ferritin using an enzyme-linked immunosorbent assay. Correlation between the serum ferritin and patient risk factors, liver status, and tumour characteristics were analysed. RESULTS: There were 93 patients with nvHCC (median age 65 [12-82] years; 82 [88.2%] males). The median ferritin level was 246.2 MUg/L, and 38 (40.86%) patients had elevated ferritin. Non-diabetics (median 363.5 mg/L, p = 0.003) and alcohol abusers (median 261.2 mg/L, p = 0.018) had higher ferritin levels. On multiple-variable analysis, being non-diabetic (p = 0.013) and alcoholic (p = 0.046) was significantly associated with high serum ferritin. No association was found with body mass index, tumour stage, size, macrovascular invasion, number of nodules, alpha-fetoprotein, bilirubin, international normalized ratio, and survival. CONCLUSION: In patients with nvHCC, serum ferritin levels are higher in non-diabetics and alcoholics. PMID- 29234635 TI - Treatment Stage Migration Maximizes Survival Outcomes in Patients with Hepatocellular Carcinoma Treated with Sorafenib: An Observational Study. AB - Background: Level I evidence supports the use of sorafenib in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma, where heterogeneity in efficacy exists due to varying clinicopathologic features of the disease. Aim: We evaluated whether prior treatment with curative or locoregional therapies influences sorafenib-specific survival. Methods: From a prospective data set of 785 consecutive patients from international specialist centres, 264 patients (34%) were treatment naive (TN) and 521 (66%) were pre-treated (PT), most frequently with transarterial chemoembolization (n = 413; 79%). The primary endpoint was overall survival (OS) from sorafenib initiation with prognostic factors tested on uni- and multivariate analyses. Results: Median OS for the entire cohort was 9 months; the median sorafenib duration was 2.8 months, with discontinuation being secondary to progression (n = 454; 58%) or toxicity (n = 149; 19%). PT patients had significantly longer OS than TN patients (10.5 vs. 6.6 months; p < 0.001). Compared to TN patients, PT patients had a better Child-Pugh (CP) class (CP A: 57 vs. 47%; p < 0.001) and a lower BCLC stage (BCLC A-B, 40 vs. 30%; p = 0.007). PT status preserved an independent prognostic role (p = 0.002) following adjustment for BCLC stage, alpha-fetoprotein, CP class, aetiology, and post-sorafenib treatment status. PT patients were more likely to receive further anticancer treatment after sorafenib (31 vs. 9%; p < 0.001). Conclusion: Patients receiving sorafenib after having failed curative or locoregional therapies survive longer and are more likely to receive further treatment after sorafenib. This suggests an incremental benefit to OS from sequential exposure to multiple lines of therapy, justifying treatment stage migration in eligible patients. PMID- 29234636 TI - Validation and Potential of Albumin-Bilirubin Grade and Prognostication in a Nationwide Survey of 46,681 Hepatocellular Carcinoma Patients in Japan: The Need for a More Detailed Evaluation of Hepatic Function. AB - Background/Aim: Recently, albumin-bilirubin (ALBI) scoring/grading, consisting of only albumin and total bilirubin, has been proposed. We examined the efficacy of this grading system for determining hepatic function in patients with hepatocellular carcinoma (HCC). Methods/Materials: The prognoses of 46,681 HCC patients based on results obtained from a nationwide survey conducted in Japan from 2001 to 2007 were evaluated using (1) Japan Integrated Staging (JIS), consisting of Child-Pugh classification and TNM staging (TNM), (2) modified JIS (m-JIS), consisting of liver damage grading and TNM, and (3) ALBI-TNM (ALBI-T), consisting of ALBI grading and TNM, and the results were compared. A subanalysis was also performed to define a cutoff value for ALBI scores for a more detailed stratification of hepatic function. Results: ALBI-T, JIS, and m-JIS each showed good capacity for the stratification of prognoses. Although the Akaike information criterion for ALBI-T was nearly equal to that for JIS and m-JIS, the Kaplan-Meier curves and median survival times obtained with ALBI-T were always superior to the corresponding scores. When the indocyanine green retention test (<30%) was used as an additional cutoff value for ALBI score (-2.270, area under the curve 0.828) to divide ALBI grade into 4 levels (modified ALBI [mALBI] grade), mALBI grade was able to stratify the prognosis of patients at any TNM stage in order of grade. Modified ALBI-T (mALBI-T), using mALBI grading and TNM, produced a more detailed stratification for prognosis. Conclusion: The predictive value for prognosis of ALBI-T was found to be equal to that of JIS and m-JIS. In addition, mALBI grading and mALBI-T, as proposed in the present study, might provide a more detailed assessment of the hepatic function and prognosis of HCC patients. PMID- 29234637 TI - Efficacy and Safety of Systemic Therapies for Advanced Hepatocellular Carcinoma: A Network Meta-Analysis of Phase III Trials. AB - Aim/Background: After the introduction of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC), different studies tried to evaluate whether other systemic therapies can improve survival. To provide a comprehensive indirect treatment comparison of efficacy and safety of novel drugs, a network meta analysis (NMA) of phase III randomized controlled trials was performed. Methods: After pertinent literature search up to November 1, 2016, 6 studies were eligible for the analysis including 4,812 individual patients with advanced HCC: 2,454 received sorafenib, 577 received brivanib, 530 received sunitinib, 514 received linifanib, 358 received sorafenib + erlotinib and 379 received placebo. Frequentist NMA was used to compare treatments within a single analytical framework. Results: NMA showed that sorafenib alone, regardless of combination with erlotinib, and linifanib provide a significant survival advantage over placebo (p < 0.05) but without any significant difference between each other. Conversely, all regimens significantly ameliorate progression-free survival versus placebo (p < 0.05). The rank order of efficacy was: sorafenib +/- erlotinib, linifanib, brivanib, sunitinib, and placebo. Sorafenib +/- erlotinib was the regimen with the fewest number of adverse events that required discontinuation of treatment, whereas linifanib and brivanib resulted in the most adverse events. The risk-benefit summary identified one cluster of therapies with a similar balance between efficacy and safety which included sorafenib alone or in combination with erlotinib, having, at the same time, the highest efficacy and safety. Conclusions: Sorafenib remains the best systemic treatment for advanced HCC; linifanib also resulted in survival advantages over placebo but with a lower safety profile. PMID- 29234638 TI - Prospective Comparison of Gd-EOB-DTPA-Enhanced MRI with Dynamic CT for Detecting Recurrence of HCC after Radiofrequency Ablation. AB - Background: We prospectively compared the efficacy of gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) with that of dynamic multidetector computed tomography (MDCT) for detection of recurrent hypervascular hepatocellular carcinoma (HCC) after radiofrequency ablation (RFA). Methods: Institutional review board approval and written informed consent were obtained for this multicenter study. Ninety-seven HCC patients treated with curative RFA underwent both Gd-EOB-DTPA-enhanced MRI and dynamic MDCT every 3-4 months. HCC diagnosis was made based on the typical enhancement pattern of HCC on MRI and/or CT by on-site consensus reading. Two blinded observers independently assessed image datasets to compare diagnostic accuracy, sensitivity, specificity, and the areas under the receiver operating characteristic curve (AUROC). Results: Recurrence was observed in 48 of 97 patients. Among these, 22 were diagnosed by both Gd-EOB-DTPA-enhanced MRI and MDCT; the remainder were diagnosed by only one of these 2 modalities. Recurrence was diagnosed in more patients by Gd-EOB-DTPA-enhanced MRI than by MDCT (44 vs. 26 patients, p < 0.001). Patient-based analysis revealed that the accuracy, sensitivity, and AUROC of Gd-EOB-DTPA-enhanced MRI were significantly higher than those of MDCT for both observers (p < 0.005). The AUROC of Gd-EOB-DTPA- enhanced MRI and MDCT was 0.95 and 0.76 for observer 1 and 0.90 and 0.74 for observer 2, respectively. The kappa values for MRI and MDCT were 0.83 and 0.70, respectively. Conclusions: Compared with dynamic MDCT, Gd-EOB-DTPA-enhanced MRI had higher diagnostic accuracy and sensitivity for detection of recurrent hypervascular HCC and may be a better tool for following patients after RFA. PMID- 29234640 TI - ALBI Score as a Novel Tool in Staging and Treatment Planning for Hepatocellular Carcinoma: Is It Sufficient? PMID- 29234639 TI - Hepatocellular Carcinoma with Macrovascular Invasion: Defining the Optimal Treatment Strategy. AB - Background: Tumoral macrovascular invasion (MVI) of hepatic and/or portal vein branches is a common phenomenon in hepatocellular carcinoma (HCC) and is associated with poorer prognosis when compared to HCC without MVI. Summary: Current international guidelines for the management of HCC recommend sorafenib as the only treatment option in case of MVI. Despite guideline recommendations, several alternative options have been tested to manage HCC with MVI: surgery, transarterial chemoembolization, external or internal radiation, hepatic arterial infusion chemotherapy, percutaneous treatment, cryotherapy, or the combination of two or more of these strategies, with or without sorafenib. Here we will provide a comprehensive state-of-the-art review for the management of this challenging clinical entity based on the most recent available data. Key Messages: There is a growing body of evidence suggesting that alternative strategies to standard-of care sorafenib might improve survival in patients with advanced HCC with MVI but the level of evidence remains weak. Randomized phase III trials are ongoing and will hopefully provide information leading towards a more personalized treatment algorithm. PMID- 29234641 TI - ALBI Score as a Novel Tool in Staging and Treatment Planning for Hepatocellular Carcinoma: Advantage of ALBI Grade for Universal Assessment of Hepatic Function. PMID- 29234643 TI - The convoy continues its journey.... PMID- 29234642 TI - Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro Inflammation. AB - Background:Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation. Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4. Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-alpha, IL-1beta and IL-8 in term neonatal and adult monocytes (p < 0.01 and p < 0.05). Intracellular protein expression of TNF-alpha, IL-1beta and IL-8 in Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1beta in adult monocytes (Uu8: p < 0.05). Remarkably, ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1beta/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p < 0.01, vs. LPS). In contrast to LPS, both isolates induced TLR2 mRNA in neonatal and adult cells (p < 0.001 and p < 0.05) and suppressed TLR4 mRNA in adult monocytes (p < 0.05). Upon co-stimulation, Uu8 and Up3 inhibited LPS-induced intracellular IL-1beta (p < 0.001 and p < 0.05) and IL-8 in adult monocytes (p < 0.01), while LPS-induced neonatal cytokines were maintained or aggravated (p < 0.05). Conclusion: Our data demonstrate a considerable pro inflammatory capacity of Ureaplasma isolates in human monocytes. Stimulating pro inflammatory cytokine responses while hardly inducing immunomodulatory and anti inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of TLR2 and TLR4 expression may shape host susceptibility to inflammation. PMID- 29234645 TI - Bone graft in the treatment of nonunion of the scaphoid with necrosis of the proximal pole: a literature review. AB - Scaphoid fractures are the most common fractures of the carpal bones, corresponding to 60%. Of these, 10% progress to nonunion; moreover, 3% can present necrosis of the proximal pole. There are various methods of treatment using vascularized and non-vascularized bone grafts. To evaluate and compare the rate of scaphoid consolidation with necrosis of the proximal pole using different surgical techniques. The authors conducted a review of the literature using the following databases: PubMed and BIREME/LILACS, where 13 case series were selected (ten with use of vascularized bone grafts and three of non-vascularized bone grafts), according to inclusion and exclusion criteria. In most cases VBGs were used, especially those based on the 1,2 intercompartmental supraretinacular artery, due to greater reproducibility in performing the surgical technique. PMID- 29234644 TI - Prophylaxis with nasal decolonization in patients submitted to total knee and hip arthroplasty: systematic review and meta-analysis. AB - Despite the evolution of the total knee and hip arthroplasty surgery, high postoperative complication rates in the short and long term still persist. Infection is one of the most challenging complications; due to its gravity and treatment difficulties, prophylaxis protocols have been created to decrease its incidence. The objective of this study was to evaluate the impact of the prophylaxis protocol for methicillin-resistant Staphylococcus aureus decolonization of the nares in patients previously identified by swab cultures, who were to be submitted to a total joint arthroplasty. A systematic review with meta-analysis was conducted, following the PRISMA-2015 protocol, using the descriptors: "arthroplasty" and "nasal decolonization," or "joint arthroplasty" and "decolonization," or "joint arthroplasty" and "nasal decolonization," for final selection of four observational studies from 79 references identified. This study included a total sample of 10,179 patients, divided in two groups: the control group (4788 patients) and intervention group (5391 patients). It was observed that the intervention group, in which prophylaxis with nasal decolonization was used, 59 (1.09%) of the patients developed a surgical site infection, while in the control group there were 86 cases of surgical site infection (1.79%). This trend repeated itself in all articles, showing no publication biases, forming a homogeneous sample. The use of a prophylaxis protocol for decolonization of methicillin-resistant Staphylococcus aureus, reduced surgical site infection cases by approximately 39%. PMID- 29234646 TI - A retrospective analysis of surgically-treated complex proximal femur fractures with proximal femoral locking compression plate. AB - Objective: Analyze the outcomes of proximal femoral locking compression plate (PF LCP) in these complex fractures. Methods: This study retrospectively analyzed 21 proximal femoral fractures treated with PF-LCP from June 2013 to February 2015. There were 15 females (71%) and six males (29%) with an average age of 61.4 years (range: 34-80 years). The peritrochanteric fractures constituted by intertrochanteric and subtrochanteric fractures were classified by the Boyd and Griffin classification and Seinshemier's classification, respectively. Among them, 16 cases (76%) were of intertrochanteric and five cases (24%) were of subtrochanteric fracture pattern. The functional outcome was assessed by Harris Hip Score and the Parker Palmer mobility score one year post-surgery. Results: Among 21 patients, 19 patients obtained fracture union without further intervention; two patients required additional bone grafting. No cases of the hip screw cutting the femoral head were noted. There was no post-operative mortality in this study. The average Harris Hip Score was 84.5 (range: 83-94). The assessment by Parker and Palmar mobility score was 7.5 (range: 4-9). Conclusion: The PF-LCP is a good, stable alternative in the treatment of peritrochanteric femoral fractures. It provides good-to-excellent bone healing with reduced complications. PMID- 29234647 TI - Radiographic anatomy of the proximal femur: femoral neck fracture vs. transtrochanteric fracture. AB - Objective: To evaluate the correlation between radiographic parameters of the proximal femur with femoral neck fractures or transtrochanteric fractures. Methods: Cervicodiaphyseal angle (CDA), femoral neck width (FNW), hip axis length (HAL), and acetabular tear drop distance (ATD) were analyzed in 30 pelvis anteroposterior view X-rays of patients with femoral neck fractures (n = 15) and transtrochanteric fractures (n = 15). The analysis was performed by comparing the results of the X-rays with femoral neck fractures and with transtrochanteric fractures. Results: No statistically significant differences between samples were observed. Conclusion: There was no correlation between radiographic parameters evaluated and specific occurrence of femoral neck fractures or transtrochanteric fractures. PMID- 29234648 TI - Supination-external rotation ankle fractures: analysis of clinical results after syndesmotic screw removal. AB - Objective: To evaluate the postoperative results of patients with supination external rotation ankle fractures who underwent syndesmotic screw (SS) removal. Methods: Retrospective cohort study assessing the late postoperative results of 35 patients operated from January 2013 to June 2015. Patients undergoing treatment of rupture of the distal tibiofibular syndesmosis with SS fixation and who did not have any concomitant surgical injuries in sites other than the ankle were included. Patients who did not complete appropriate follow-up after surgery were excluded from the study. Results: There was no statistical significant difference in the evaluated outcomes among the patients who had their SS removed and those who remained with the SS. Conclusion: SS removal did not significantly alter the clinical results of patients surgically treated with SS for supination external rotation fractures. PMID- 29234649 TI - Total bilateral ruptures of the knee extensor apparatus. AB - Objective: Bilateral extensor tendon ruptures of the knee are rare and have only been published in the form of case reports or small series. Methods: Seven patients corresponding to 14 extensor tendon ruptures of the knee were evaluated by the same examiner after a minimum one year post-surgery. Clinical and radiographic evaluations were performed; for statistical analysis, the level of significance was set at 0.05. Results: The most common injury was patellar tendon rupture (n = 9; 64.29%) followed by quadriceps tendon rupture (n = 5, 35.71%). The intrasubstance was the most affected location (57.15%), followed by the myotendinous junction (21.43%) and the patellar bone insertions (21.43%). Quadriceps tendon ruptures were more prevalent in patients older than 50 years, while patellar tendon ruptures tended to occur in younger individuals. All but one patient had recognized risk factors for tendinous degeneration and rupture: 75% of the cases suffered from diseases, 50% had history of drug use and/or abuse, and 37.5% had both disease and drug use history. Mean attained values for flexion ROM were 124.64 degrees +/- 9.43 (110-140 degrees ) and 89.57 +/- 6.02 (78-94) for Kujala score. More than half of the patients complained of residual pain and quadriceps muscular weakness. Mean age was younger in the individuals who complained of residual pain. Conclusion: Bilateral tendon ruptures of the knee extensor apparatus ruptures are rare and serious injuries, mostly associated with risk factors. Early surgical repair and intensive rehabilitation program for bilateral extensor tendon ruptures of the knee may warrant satisfactory functional outcomes in the medium to long term, despite non-negligible levels of residual pain, quadriceps muscle weakness, and atrophy. PMID- 29234650 TI - Experience in fixation of infected non-union tibia by Ilizarov technique - a retrospective study of 42 cases. AB - Objective: The aim of the study is to evaluate the clinical and functional outcome in treatment of infected tibial nonunion by the Ilizarov method. Methods: The authors retrospectively analyzed 42 patients with infected tibial nonunion with bone loss; shortening and deformity treated at this institution during the period of February 2012 to April 2015 were included in the study. The results were evaluated according to Association for the Study and Application of the Methods of Ilizarov (ASAMI) criteria. Pin tract infections were assessed by Moore and Dahl score. Results: Bone results were excellent in 60% of patients (n = 25), good in 15% (n = 6), fair in 25% (n = 11), and poor in none. The functional results were excellent in 55% of patients, good in 30%, fair in 5%, and poor in 10%. The most common complication found in this study was pin tract infection. Conclusion: Ilizarov ring fixator still remains an excellent treatment modality for tibial nonunion, as it addresses the problems associated with the condition, although the procedure is cumbersome. PMID- 29234652 TI - Polypropylene prosthesis for the treatment of fingertip injuries. Description of surgical technique and results. AB - Objective: Report the results of treatment of fingertip injuries and describe this reproducible and low cost surgical technique, which utilizes a polypropylene prosthesis that temporarily replaces the nail and is placed on the area of injury, providing protection and encouragement for healing by secondary intention. Method: This study evaluated 22 patients with traumatic injuries of the fingertips in the period from January 2012 to December 2015. All procedures were performed by the same surgeon. The mean postoperative follow-up was 13 months, with a minimum follow-up of six months. For all statistical inferences, a p-value of 0.05 was considered. The software used was SPSS version 21.0 for Windows. Results: There were no cases of complications related to the polypropylene device. There was no significant difference between static two point discrimination and age, between discrimination and time between injury and surgery, or between discrimination and time to follow-up. The authors used a table of scores that includes three factors proposed by Jefferson for a better evaluation of the results. 72.7% (16 cases) of patients had good results, 22.7% (five cases) fair results, and only 4.5% (one case) poor result. Conclusion: This study presented a new technique for finger tip lesions, simple and easily reproducible, with satisfactory results and low complication rates. PMID- 29234651 TI - Dorsal capsulodesis associated with arthoscopy-assisted scapholunate ligament reconstruction using a palmaris longus tendon graft. AB - Objectives: To measure the quality of life, the time to work return, and clinical, functional, and radiographic parameters of patients treated with dorsal capsulodesis associated with scapholunate (SL) reconstruction, assisted by arthroscopy. Methods: From January 2015 to September 2016, 14 adult patients with SL dissociation underwent surgical treatment with the SL reconstruction procedure assisted by arthroscopy, using the new technique proposed in this study. All patients were assessed by the occupational therapy department at regular intervals after surgery and performed the same sequence of rehabilitation. The parameters analyzed were: range of motion (ROM), Disability of the Arm, Shoulder, and Hand (DASH), visual analog scale (VAS), and radiographic analysis to visualize the pre- and postoperative SL gap and the pre- and postoperative dorsal intercalated segment instability (DISI) deformity the. The complications and the time to return to work activities were described. Results: The follow-up time was 12 months (3-17). The ROM averaged 321 degrees (96.9% of the normal side). VAS was 1.79/10 (1-6). DASH was 6.50/100 (1-30). The time to work return work was 4.42 months (2-17). As for complications, one patient developed SLAC, and underwent four-corner fusion one year after ligament reconstruction. Currently, he has experienced pain relief, with a functional range of motion of the wrist, and has not yet returned to professional activities.The preoperative SL gap was 4.29 mm (2-7); in the postoperative period, it was 1.79 mm (1-4). The DISI deformity was present in ten patients with SL angle > 70 degrees (preoperative) and it was corrected after surgery, in all patients. SLAC stage I was identified in a patient. Arthroscopy was performed in all cases. The SL instability was classified as Geissler grade III in four cases and as grade IV in ten cases. Conclusion: The new approach (dorsal capsulodesis associated with SL reconstruction, assisted by arthroscopy) presented in this study is safe and effective in the treatment of SL dissociation, since it offers satisfactory clinical, radiographic and functional results, showing low rates of complications. For patients, it allows the return to their social and professional activities, and increases their life quality. PMID- 29234653 TI - Evaluation of the effectiveness of platelet-rich plasma in the bone consolidation of patients submitted to lumbar arthrodesis. AB - Objective: To determine whether the use of autograft associated with platelet rich plasma (PRP) increases bone healing in patients undergoing lumbar fusion. Method: This was a prospective, descriptive, and comparative study, which included 40 patients undergoing lumbar fusion, who were divided into two groups: group I, autograft only, and group II, autograft associated with PRP. After surgery, patients were followed-up on the first, third, and sixth month. The Molinari radiographic classification and Glassman tomographic classification were used as criteria to analyze the bone consolidation. Result: Comparing the group I with group II, according to the criteria of Molinari, bilateral fusion was observed in 27.5% of the patients in group I in the first month after surgery. In group II, the rate of bilateral fusion was 25.0% and 20% in the third and sixth months, respectively. The results of computed tomography scans performed at six months after surgery indicated, according to the criteria of Glassman, a rate of bilateral solid fusion of 15.0% and 10.0% in groups I and II, respectively. Conclusion: The use of PRP showed no significant difference in bone healing in cases of lumbar arthrodesis. PMID- 29234654 TI - Reconstruction of soft-tissue lesions of the foot with the use of the medial plantar flap. AB - Objective: To study use of the medial plantar flap for reconstruction of the heel and foot. Method: The authors share their clinical experience with the use of the medial plantar artery flap for coverage of tissue defects around the foot and heel after trauma. Twelve cases of medial plantar artery flap performed from January 2001 to December 2013 were included. Results: Of the 12 patients, ten were male and two were female. The indications were traumatic loss of the heel pad in ten cases and the dorsal foot in two cases. All the flaps healed uneventfully without major complications, except one case with partial flap loss. The donor site was covered with a split-thickness skin graft. The flaps had slightly inferior protective sensation compared with the normal side. Conclusion: From these results, the authors suggest that the medial plantar artery flap is a good addition to the existing armamentarium for coverage of the foot and heel. It is versatile flap that can cover defects on the heel, over the Achilles tendon and plantar surface, as well as the dorsal foot. It provides tissue to the plantar skin with a similar texture and intact protective sensation. PMID- 29234655 TI - Characterization, survival analysis, and expression of IGFR in tumor samples from patients diagnosed with Ewing family tumors treated at the Barretos Cancer Hospital. AB - Objectives: Study the clinical characteristics of patients diagnosed with Ewing family tumors (EFTs) and survival analysis based on risk criteria and expression of the surface protein known as insulin-like growth factor (IGFR). Methods: This was a retrospective cohort study based on clinical data from 77 patients diagnosed with EFTs treated by the Department of Pediatric Oncology at the Barretos Cancer Hospital in a period between 2003 and 2012. Biological samples of patients were examined for the presence of the surface receptor IGFR. Results: The overall survival rate (OSR) of patients included in the study was 45% at five years, and EFS was 30% at five years. Metastasis at diagnosis was present in 44.2% of the sample; 88.2% of the sample was male (p < 0.001). The evaluation of the expression of IGFR in biological samples of patients was associated with the variable metastasis at diagnosis (p < 0.001). Worse prognosis was observed in patients with extrapulmonary metastasis (p = 0.009). The local treatment of neoplasia presented better prognosis in patients undergoing local surgical treatment (p < 0.001). Conclusions: These results showed a higher incidence of metastasis at diagnosis in patients with EFTs treated at the Barretos Cancer Hospital (BCH). Extrapulmonary metastases were a negative prognostic factor in this study. Surgical treatment of the primary tumor was a factor for better prognosis. Strong expression of IGFR was more frequent in patients with metastases at diagnosis, but did not represent a prognostic factor for EFTs. PMID- 29234656 TI - Amputation risk after the revascularization procedures in sarcoma resections. AB - Objective: The objective of this study is to evaluate the efficacy of vascular reconstructive surgery after resection of bone and soft tissue tumors in extremities and the risk of progression to amputation. Methods: This is a retrospective, observational data collection from medical records of patients who underwent resection of bone and soft tissue tumors in the period of 2002-2015. Thirteen patients met the inclusion criteria, which evaluated the correlations between certain factors (gender, tumor type, location, reconstruction, revascularization and patency, infection) with amputation in the postoperative period. Results: In this study, of the 13 patients undergoing reconstruction, five (38.46%) evolved to amputation. All patients who progressed to amputation had the following in common: presence of bone sarcoma (p = 0.005), having undergone reconstruction with an orthopedic prosthesis (p = 0.005), lack of vascular patency in the revascularization site in the postoperative period (p = 0.032), and surgical site infection (p = 0.001). None of the patients with soft tissue sarcoma underwent amputation, and the only patient with bone sarcoma who did not undergo amputation had no infection and maintained vascular patency of the graft. Conclusion: The occurrence of infection appears to be one of the main risk factors for failure of revascularization, especially in cases of bone sarcoma in which vascular reconstruction is performed with placement of a non conventional joint prosthesis. PMID- 29234658 TI - Blood level changes in total knee arthroplasty with and without a tourniquet. AB - Objective: To evaluate the difference between the total blood loss in patients undergoing primary total knee arthroplasty with and without the use of tourniquet. Methods: A retrospective cohort study, with analysis of medical records of patients undergoing primary total knee arthroplasty in 2015, with and without the use of a tourniquet. Comparison was performed of hemoglobin (HB) and hematocrit (HT) variation in the complete blood count (CBC) during the pre- and post-operative period between the two groups. Results: There were 117 patients undergoing primary total knee arthroplasty included, minimum age of 33 and maximum of 86 years, with a mean of 67 years. 64.1% of the surgeries used a tourniquet and 35.9% did not. The mean preoperative HB in Group 1 was 13.08 and 12.97 in Group 2 (p = 0.435). The mean postoperative HB in Group 1 was 11.64 and 10.93 in Group 2 (p = 0.016). The variation of HB in Group 1 was 1.44 and 2.04 in Group 2 (p = 0.025). The mean preoperative HT in Group 1 was 38.96 and 39.01 in Group 2 (p = 0.898). The mean postoperative HT in Group 1 was 34.47 and 32.19 in Group 2 (p = 0.005). The variation of HT in Group 1 was 4.49 and 6.82 in Group 2 (p = 0.001). A total of 21 patients received transfusions RCC (red cell concentrates), as a result of HB below 8 g/dL or clinical symptoms, respectively, representing seven of Group 1 (9.3% of total intra-group) and 14 of Group 2 (33.3% of total intra-group), with p = 0.001. Conclusion: In patients undergoing primary total knee arthroplasty using a tourniquet, a lower variance in the hematimetric indices was observed and fewer blood transfusions were necessary. PMID- 29234657 TI - Social profile and cost analysis of deep infection following total hip replacement surgery. AB - Objective: To characterize the socio-economic and demographic profile of patients undergoing surgery for revision total hip arthroplasty regarding the diagnosis of deep prosthetic infection. Methods: Twenty patients were retrospectively studied, admitted in the period between 2009 and 2010 by the Hip Surgery Group with the diagnosis of deep prosthetic infection, whose proposed treatment was surgical. This study was carried out in the presence of the patient by completing two forms applied by the social worker of the Group. Results: In a 20-patient sample, 40% were male, 45% were working age, 50% of patients originated from the capital, 85% depended on benefits, 70% were retired, 60% of patients were from this hospital, and 40% were from other services. The average cost of patients to the public system was R$ 55,821.62 per patient and the total spent on treatment of patients in the study exceeded one million Brazilian reals, totalling R$ 1,116,432.40. Conclusion: Infection from total hip arthroplasty generates a major expense to the social security system and to the public healthcare system. Physicians must always be alert to the possible risk factors and perioperative care, striving to minimize this complication. PMID- 29234659 TI - Accessory muscle of the flexor digitorum superficialis and its clinical implications. AB - Anatomical variations of the flexor digitorum superficialis (FDS) muscle and tendon unit are frequently reported by anatomists and clinicians. Anatomical muscle variations of the FDS and its tendons may include variations of muscle belly, presence of accessory or duplicate tendons, abnormal tendon connections, and absence of muscle or tendon components. Such variations may or may not have clinical implications. This report presents a case not described previously: a unilateral accessory muscle of the flexor digitorum superficialis which was connected by a thick tendon to the flexor digitorum superficialis muscle; it was directed proximally to the insertion of the medial epicondyle of the humerus, next to the superficialis head of the pronator teres muscle. The belly of the accessory muscle was positioned anterior to the median and anterior interosseous nerve. This anatomical variation is known as type V in the classification of Elliot et al. The knowledge of these anatomical variations helps hand surgeons interpret the clinical examination, particularly in the evaluation of patients who have suffered tendon injuries or show sign s of possible peripheral nerve entrapment. PMID- 29234661 TI - Congenital syphilis with bone lesion: case report. AB - The authors report a case of congenital syphilis in a newborn with a bone lesion, resulting in left ankle periostitis. PMID- 29234660 TI - Monosegmental combined anterior posterior instrumentation for the treatment of a severe lumbar tuberculous spondylodiscitis: case report and literature review. AB - Spinal tuberculosis (Pott disease) can produce severe deformities when it is not properly treated. Long instrumentations through single or combined double approaches are usually required to prevent and correct the deformity. The authors present a case of severe deformity secondary to tuberculous spondylodiscitis in the lumbar spine treated with a monosegmental instrumentation through a double approach in a patient with idiopathic scoliosis. Deformity correction and infection resolution through debridement and arthrodesis is observed after one year of follow-up. PMID- 29234662 TI - Surgical treatment of rectus femoris injury in soccer playing athletes: report of two cases. AB - Muscle injury is the most common injury during sport practice. It represents 31% of all lesions in soccer, 16% in track and field, 10.4% in rugby, 17.7% in basketball, and between 22% and 46% in American football. The cicatrization with the formation of fibrotic tissue can compromise the muscle function, resulting in a challenging problem for orthopedics. Although conservative treatment presents adequate functional results in the majority of the athletes who have muscle injury, the consequences of treatment failure can be dramatic, possibly compromising the return to sport practice. The biarticular muscles with prevalence of type II muscle fibers, which are submitted to excentric contraction, present higher lesion risk. The quadriceps femoris is one example. The femoris rectus is the quadriceps femoris muscle most frequently involved in stretching injuries. The rupture occurs in the acceleration phase of running, jump, ball kicking, or in contraction against resistance. Although the conservative treatment shows good results, it is common that the patient has lower muscle strength, difficulty in return to sports, and a permanent and visible gap. Surgical treatment can be an option for a more efficient return to sports. PMID- 29234663 TI - Reconstruction with iliac pedestal cup and proximal femur tumor prosthesis after wide resection of chondrosarcoma - 10-year follow-up results. AB - Chondrosarcoma is a malignant cartilage-forming neoplasm. It is difficult to treat because of resistance to both chemotherapy and radiation, making wide local excision the only treatment. This report presents an active, 43 year-old man who was diagnosed with recurrent clear cell chondrosarcoma of the proximal left femur, previously reconstructed with a total hip prosthesis, extending to the weight-bearing dome of the acetabulum. Cancer staging study revealed no signs of tumor dissemination at distance. Given the excellent functional status of the patient, the authors performed a Enneking-Dunham type periacetabular pelvic resection and resected en bloc, with the total hip prosthesis including 22 cm of the femur and a portion of the hip abductor apparatus. Acetabular reconstruction was performed with a non-cemented pedestal cup prosthesis fixed at the iliac, and in-femur reconstruction utilized a cemented silver-coated proximal femur modular prosthesis. Today, after a 10-year follow-up, the patient is walking without crutches, he practices recreational cycling without assistance, and he is asymptomatic and free of tumoral disease. At present, no signs of relevant loosening, instability, infection, heterotopic ossification, or any other complications have been observed. Pelvic reconstructions are challenging and risky surgeries; however, the appearance of more functional implants, like the pedestal cup prosthesis, and its correct application and indication, may allow promising clinical and functional results with low complications rate. PMID- 29234664 TI - Perceptions of Important Characteristics of Physical Activity Facilities: Implications for Engagement in Walking, Moderate and Vigorous Physical Activity. AB - Background: Although few United States adults meet physical activity recommendations, those that do are more likely to access to physical activity facilities. Additionally, vigorous exercisers may be more likely to utilize a nearby physical activity facility, while light-to-moderate exercisers are less likely to do so. However, it is unclear what characteristics of those facilities are most important as well as how those characteristics are related to activity intensity. Purpose: This study examined relationships between self-reported leisure-time physical activities and the use of and perceived characteristics of physical activity facilities. Methods: Data were from a cross-sectional study in a major metropolitan area. Participants (N = 582; ages 18-74, mean age = 45 +/- 14.7 years) were more likely to be female (69.9%), Caucasian (65.6%), married (51.7%), and have some college education (72.8%). Household surveys queried leisure-time physical activity, regular physical activity facility use, and importance ratings for key facility characteristics. Results: Leisure-time physical activity recommendations were met by 41.0% of participants and 50.9% regularly used a physical activity facility. Regular facility use was positively associated with meeting walking (p = 0.036), moderate (p < 0.001), and vigorous (p < 0.001) recommendations. Vigorous exercisers were more likely to use a gym/fitness center (p = 0.006) and to place higher importance on facility quality (p = 0.022), variety of physical activity options offered (p = 0.003), and availability of special equipment and resources (p = 0.01). The facility characteristics of low or free cost (p = 0.02) and offering childcare (p = 0.028) were barriers for walking, and being where friends and family like to go were barriers for moderate leisure-time physical activity (p = 0.013). Conclusion: Findings offer insights for structuring interventions using the social ecological model as well as for improving existing physical activity facilities. PMID- 29234665 TI - Urinary Luteinizing Hormone Tests: Which Concentration Threshold Best Predicts Ovulation? AB - Objective: To study the best possible luteinizing hormone (LH) threshold to predict ovulation within the 24, 48, and 72 h. Design: Observational study. Setting: Multicenter collaborative study. Patients: A total of 107 women. Interventions: Women collected daily first morning urine for hormonal assessment and underwent serial ovarian ultrasound. This is a secondary analysis of 283 cycles. Main outcome measures: The sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were estimated for varying ranges of LH thresholds. Receiver operating characteristic curves and cost-benefit ratios were used to estimate the best thresholds to predict ovulation. Results: The best scenario to predict ovulation at random was within 24 h after the first single positive test. The false-positive rate was found to increase as (1) the cycle progressed or (2) two or three consecutive tests were used, or (3) ovulation was predicted within 48 or 72 h. Testing earlier in the cycle increases the predictive value of the test. The ideal thresholds to predict ovulation ranged between 25 and 30 mIU/ml with a PPV (50 60%), NPV (98%), LR+ (20-30), and LR- (0.5). At least, one day with LH >=25 mIU/ml followed by three negatives (LH <25) occurred before ovulation in 31% of all cycles. When used throughout the cycle and evaluated together, peak-fertility type mucus with a positive LH test >=25 mIU/ml provides a higher specificity than either mucus or LH testing alone (97-99 vs. 77-95 vs. 91%, respectively). Conclusion: We identified that beginning LH testing earlier in the cycle (day 7) with a threshold of 25-30 mIU/ml may present the best predictive value for ovulation within 24 h. However, prediction by LH testing alone may be affected negatively by several confounding factors so LH testing alone should not be used to define the end of the fertile window. Complementary markers should be further investigated to predict ovulation and identify the fertile window. The use of the peak cervical mucus along with an LH test may provide a higher specificity and predictive value than either of them alone. We recommend that manufacturers disclose their tests' threshold to the public. PMID- 29234666 TI - Technical Advances to Study Extracellular Vesicles. AB - Extracellular vesicles are a heterogeneous and dynamic group of lipid bilayer membrane nanoparticles that can be classified into three different groups depending on their cellular origin: exosomes, microvesicles, and apoptotic bodies. They are produced by different cell types and can be isolated from almost all body fluids. EVs contain a variety of proteins, lipids, nucleic acids, and metabolites which regulate a number of biological and pathological scenarios both locally and systemically. Different techniques have been described in order to determine EV isolation, release, uptake, and cargo. Although standard techniques such as immunoblotting, fluorescent microscopy, and electron microscopy are still being used to characterize and visualize EVs, in the last years, more fine-tuned techniques are emerging. For example, EV uptake can be specifically determined at a single cell level using the Cre reporter methodology and bioluminescence based methods reports have been employed to determine both EV release and uptake. In addition, techniques for cargo identification have also enormously evolved during these years. Classical mass spectrometry and next generation sequencing have been used in the past, but nowadays, advances in these tools have facilitated a more in depth characterization of the EV content. In this review, we aim to assess the standard and latest technical advances for studying EV biology in different biological systems. PMID- 29234667 TI - A Matter of Taste: Lineage-Specific Loss of Function of Taste Receptor Genes in Vertebrates. AB - Vertebrates can perceive at least five different taste qualities, each of which is thought to have a specific role in the evolution of different species. The avoidance of potentially poisonous foods, which are generally bitter or sour tasting, and the search for more nutritious ones, those with high-fat and high sugar content, are two of the most well-known examples. The study of taste genes encoding receptors that recognize ligands triggering taste sensations has helped to reconstruct several evolutionary adaptations to dietary changes. In addition, an increasing number of studies have focused on pseudogenes, genomic DNA sequences that have traditionally been considered defunct relatives of functional genes mostly because of the presence of deleterious mutations interrupting their open reading frames. The study of taste receptor pseudogenes has helped to shed light on how the evolutionary history of taste in vertebrates has been the result of a succession of gene gain and loss processes. This dynamic role in evolution has been explained by the "less-is-more" hypothesis, suggesting gene loss as a mechanism of evolutionary change in response to a dietary shift. This mini-review aims at depicting the major lineage-specific loss of function of taste receptor genes in vertebrates, stressing their evolutionary importance and recapitulating signatures of natural selection and their correlations with food habits. PMID- 29234668 TI - A genome-wide screen for FTY720-sensitive mutants reveals genes required for ROS homeostasis. AB - Fingolimod hydrochloride (FTY720), a sphingosine-1-phosphate (S1P) analogue, is an approved immune modulator for the treatment of multiple sclerosis (MS). Notably, in addition to its well-known mode of action as an S1P modulator, accumulating evidence suggests that FTY720 induces apoptosis in various cancer cells via reactive oxygen species (ROS) generation. Although the involvement of multiple signaling molecules, such as JNK (Jun N-terminal kinase), Akt (alpha serine/threonine-protein kinase) and Sphk has been reported, the exact mechanisms how FTY720 induces cell growth inhibition and the functional relationship between FTY720 and these signaling pathways remain elusive. Our previous reports using the fission yeast Schizosaccharomyces pombe as a model system to elucidate FTY720 mediated signaling pathways revealed that FTY720 induces an increase in intracellular Ca2+ concentrations and ROS generation, which resulted in the activation of the transcriptional responses downstream of Ca2+/calcineurin signaling and stress-activated MAPK signaling, respectively. Here, we performed a genome-wide screening for genes whose deletion induces FTY720-sensitive growth in S. pombe and identified 49 genes. These gene products are related to the biological processes involved in metabolic processes, transport, transcription, translation, chromatin organization, cytoskeleton organization and intracellular signal transduction. Notably, most of the FTY720-sensitive deletion cells exhibited NAC-remedial FTY720 sensitivities and dysregulated ROS homeostasis. Our results revealed a novel gene network involving ROS homeostasis and the possible mechanisms of the FTY720 toxicity. PMID- 29234669 TI - Aminoglycoside resistance profile and structural architecture of the aminoglycoside acetyltransferase AAC(6')-Im. AB - Aminoglycoside 6'-acetyltransferase-Im (AAC(6')-Im) is the closest monofunctional homolog of the AAC(6')-Ie acetyltransferase of the bifunctional enzyme AAC(6') Ie/APH(2")-Ia. The AAC(6')-Im acetyltransferase confers 4- to 64-fold higher MICs to 4,6-disubstituted aminoglycosides and the 4,5-disubstituted aminoglycoside neomycin than AAC(6')-Ie, yet unlike AAC(6')-Ie, the AAC(6')-Im enzyme does not confer resistance to the atypical aminoglycoside fortimicin. The structure of the kanamycin A complex of AAC(6')-Im shows that the substrate binds in a shallow positively-charged pocket, with the N6' amino group positioned appropriately for an efficient nucleophilic attack on an acetyl-CoA cofactor. The AAC(6')-Ie enzyme binds kanamycin A in a sufficiently different manner to position the N6' group less efficiently, thereby reducing the activity of this enzyme towards the 4,6 disubstituted aminoglycosides. Conversely, docking studies with fortimicin in both acetyltransferases suggest that the atypical aminoglycoside might bind less productively in AAC(6')-Im, thus explaining the lack of resistance to this molecule. PMID- 29234671 TI - A new role for the nuclear basket network. AB - Our view of the nuclear pore complexes (NPCs) as gateways between the nuclear and cytoplasmic compartments has been largely expanded in recent years. NPCs have now demonstrated roles in genome regulation and maintenance from single cells to multicellular organisms. Both NPC proteins as well as components of the NPC basket act as dynamic scaffolds for silencing factors, and chromatin and cell cycle regulators. Components of the NPC basket also couple mRNA production and export, and prevent the exit of unprocessed mRNAs from the nucleus. Our recent work describes a novel function of the fission yeast nuclear basket component - the translocated promoter region (TPR) nucleoporin Alm1 - in proper localization of the proteasome to the nuclear envelope. Here we discuss how regulation of proteasome localization to the nuclear envelope by Alm1 is key to maintain kinetochores homeostasis and proper chromosome segregation. PMID- 29234670 TI - Mitochondrial energy metabolism is required for lifespan extension by the spastic paraplegia-associated protein spartin. AB - Hereditary spastic paraplegias, a group of neurodegenerative disorders, can be caused by loss-of-function mutations in the protein spartin. However, the physiological role of spartin remains largely elusive. Here we show that heterologous expression of human or Drosophila spartin extends chronological lifespan of yeast, reducing age-associated ROS production, apoptosis, and necrosis. We demonstrate that spartin localizes to the proximity of mitochondria and physically interacts with proteins related to mitochondrial and respiratory metabolism. Interestingly, Nde1, the mitochondrial external NADH dehydrogenase, and Pda1, the core enzyme of the pyruvate dehydrogenase complex, are required for spartin-mediated cytoprotection. Furthermore, spartin interacts with the glycolysis enhancer phospo-fructo-kinase-2,6 (Pfk26) and is sufficient to complement for PFK26-deficiency at least in early aging. We conclude that mitochondria-related energy metabolism is crucial for spartin's vital function during aging and uncover a network of specific interactors required for this function. PMID- 29234672 TI - VAMP8 mucin exocytosis attenuates intestinal pathogenesis by Entamoeba histolytica. AB - The intestinal mucosa encounters a barrage of ingested insults within the host yet under homeostasis elegantly facilitates nutrient absorption and sustenance of the commensal microbiota. An essential defence mechanism employed by the host is limiting the spatial niche various microbes may occupy as executed by the fluid mucus layer. Pathogens that violate their restricted niche within the intestinal mucosa are first expelled by robust mucus secretion from goblet cells thus by passing the need for an immune response. Surprisingly, while many pathogens are known to exert hyper-secretion of mucus from goblet cells, the mechanisms governing this event remain elusive. In a recent report by Cornick et al (MBio 8: e01323-17), we nominate SNARE-mediated exocytosis as the putative mechanism responsible for pathogen-induced mucus secretion from goblet cells. The vesicle SNARE VAMP8 on mucin granules within goblet cells is specifically activated following infection with the protozoan parasite Entamoeba histolytica that is known to induce potent hyper-secretion and coordinates mucin exocytosis. This secretion event is critical in fending off a pathogen, as cells lacking VAMP8 are prone to increased E. histolytica colonization and cytolysis through apoptosis. Failing coordinated mucus exocytosis and subsequent epithelial barrier destruction, the host mounts an immune response as a last line of defence. PMID- 29234673 TI - Breathing training for dysfunctional breathing in asthma: taking a multidimensional approach. AB - Various breathing training programmes may be helpful for adults with asthma. The main therapeutic aim for many of these programmes is the correction of dysfunctional breathing. Dysfunctional breathing can be viewed practically as a multidimensional entity with the three key dimensions being biochemical, biomechanical and psychophysiological. The objectives of this review are to explore how each of these dimensions might impact on asthma sufferers, to review how various breathing therapy protocols target these dimensions and to determine if there is evidence suggesting how breathing therapy protocols might be optimised. Databases and reference lists of articles were searched for peer reviewed English language studies that discussed asthma or dysfunctional breathing and various breathing therapies. Biochemical, biomechanical and psychophysiological aspects of dysfunctional breathing can all potentially impact on asthma symptoms and breathing control. There is significant variation in breathing training protocols and the extent to which they evaluate and improve function in these three dimensions. The various dimensions of dysfunctional breathing may be of greater or lesser importance in different cases and the effectiveness of breathing training protocols is likely to be improved when all three dimensions are considered. Outcomes for breathing training for dysfunctional breathing in asthma may be most successful when the three key dimensions of dysfunctional breathing are evaluated at the start of treatment and monitored during treatment. This allows breathing training protocols to be adjusted as appropriate to ensure that treatment is sufficiently comprehensive and intensive to produce measurable improvements where necessary. PMID- 29234675 TI - Pharmacokinetics of Quercetin-Loaded Methoxy Poly(ethylene glycol)-b-poly(L lactic acid) Micelle after Oral Administration in Rats. AB - The purpose of this study was to evaluate the potential of micelle to change the pharmacokinetics of quercetin (QUT), with a primary goal of enhancing its oral bioavailability. QUT-loaded methoxy poly(ethylene glycol)-b-poly(L-lactic acid) micelle (QUT-loaded MPEG-b-PLLA micelle) was prepared by a thin-film hydration method, resulting in a particle size of 88.5 nm. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for determination of QUT in rat plasma. The chromatographic separation was performed on an Agilent Eclipse-C18 (4.6 mm * 50 mm, 3.5 MUm) with an isocratic mobile phase system consisting of water and methanol (30 : 70, v/v) at a flow rate of 0.4 mL/min. Calibration curves were linear over the concentration ranges of 2.5-2000 ng/mL for QUT. The micelle was orally administered at a single does in rats, and the pharmacokinetic parameters were evaluated and compared with that administered with the QUT aqueous suspension. The results show that the micelle was able to increase the QUT's oral bioavailability 9-fold compared to the QUT aqueous suspension. These results suggest that methoxy poly(ethylene glycol)-b-poly(L lactic acid) is a potential carrier for the oral delivery of QUT. PMID- 29234674 TI - MicroRNA in Glioblastoma: An Overview. AB - Glioblastoma is the most aggressive brain tumor and, even with the current multimodal therapy, is an invariably lethal cancer with a life expectancy that depends on the tumor subtype but, even in the most favorable cases, rarely exceeds 2 years. Epigenetic factors play an important role in gliomagenesis, are strong predictors of outcome, and are important determinants for the resistance to radio- and chemotherapy. The latest addition to the epigenetic machinery is the noncoding RNA (ncRNA), that is, RNA molecules that are not translated into a protein and that exert their function by base pairing with other nucleic acids in a reversible and nonmutational mode. MicroRNAs (miRNA) are a class of ncRNA of about 22 bp that regulate gene expression by binding to complementary sequences in the mRNA and silence its translation into proteins. MicroRNAs reversibly regulate transcription through nonmutational mechanisms; accordingly, they can be considered as epigenetic effectors. In this review, we will discuss the role of miRNA in glioma focusing on their role in drug resistance and on their potential applications in the therapy of this tumor. PMID- 29234676 TI - Healing and Antisecretory Effects of Aqueous Extract of Eremomastax speciosa (Acanthaceae) on Unhealed Gastric Ulcers. AB - Objective: This work investigated the healing and antisecretory effects of the aqueous extract of Eremomastax speciosa on "unhealed gastric ulcers" associated with gastric acid hypersecretion. Materials and Methods: "Unhealed gastric ulcers" were induced using indomethacin following the establishment of acetic acid-induced chronic gastric ulcers. The extract (200 and 400 mg/kg, per os) was administered concomitantly with indomethacin (1 mg/kg, subcutaneously). The effects of the extract on both basal and histamine-stimulated gastric acid secretion were determined. Mucus secretion and oxidative stress parameters were measured, and histological assessment of ulcer healing was carried out. Results: The extract significantly promoted the healing process in rats subjected to "unhealed gastric ulcers" (82.4-88.5% healing rates). Treatment with the extract significantly reduced the basal (25.95-49.51% reduction rates) and histamine stimulated (24.25-47.41%) acid secretions. The healing effect of the extract was associated with a significant (p < 0.05) increase of mucus secretion and concentrations of antioxidant enzymes compared with the controls. The extract at the highest dose showed normalization of the mucosa, without glandular destruction and with the disappearance of fibrosis and lymphocyte infiltration. Conclusion: The abilities of the extract to increase mucus secretion, to reinforce antioxidant status, and to inhibit acid secretion would be some of the mechanisms by which this extract would accelerate the healing process in "unhealed gastric ulcers." PMID- 29234677 TI - Metabolic Alterations of Thyroid Cancer as Potential Therapeutic Targets. AB - Thyroid cancer (TC) is the most frequent endocrine tumor with a growing incidence worldwide. Besides the improvement of diagnosis, TC increasing incidence is probably due to environmental factors and lifestyle modifications. The actual diagnostic criteria for TC classification are based on fine needle biopsy (FNAB) and histological examination following thyroidectomy. Since in some cases it is not possible to make a proper diagnosis, classical approach needs to be supported by additional biomarkers. Recently, new emphasis has been given to the altered cellular metabolism of proliferating cancer cells which require high amount of glucose for energy production and macromolecules biosynthesis. Also TC displays alteration of energy metabolism orchestrated by oncogenes activation and tumor suppressors inactivation leading to abnormal proliferation. Furthermore, TC shows significant metabolic heterogeneity within the tumor microenvironment and metabolic coupling between cancer and stromal cells. In this review we focus on the current knowledge of metabolic alterations of TC and speculate that targeting TC metabolism may improve current therapeutic protocols for poorly differentiated TC. Future studies will further deepen the actual understandings of the metabolic phenotype of TC cells and will give the chance to provide novel prognostic biomarkers and therapeutic targets in tumors with a more aggressive behavior. PMID- 29234678 TI - Follow-Up (Measurement) of Corrected QT Interval in Adult Patients before and after Lung Transplantation. AB - Background: Prolongation of the corrected QT (QTc) interval is well known for many drugs, some of which are an integral part of the therapeutic regimen after lung transplantation (LTX). Therefore, we investigated the QTc interval after LTX in the present study. Patients and Methods: The medical records of patients after LTX were studied for demographic data, indication of LTX, medication, and baseline and follow-up ECGs. The QT interval was corrected for the patient's heart rate using the different formulae of Bazett, Fridericia, Hodges, and Framingham. Results: Fifty-nine patients were included. The mean age +/- SD was 55.6 +/- 7.8 years (median 58 years). After LTX, QTc intervals showed no (relevant) changes during follow-up, even though all patients were treated with drugs (in combination) known to bear a risk of prolonged QTc interval and cortisone. The longest QTc intervals were obtained using Bazett's formula. Conclusion: The QTc interval did not increase under immunosuppressive medication after LTX in our cohort of patients. We speculate that the concurrent use of cortisone may shorten the QT(c) intervals or cancel out drug-induced prolongation of the QTc interval. PMID- 29234679 TI - Detection of Cryptosporidium and Cyclospora Oocysts from Environmental Water for Drinking and Recreational Activities in Sarawak, Malaysia. AB - Cryptosporidiosis and cyclosporiasis are caused by waterborne coccidian protozoan parasites of the genera Cryptosporidium and Cyclospora, respectively. This study was conducted to detect Cryptosporidium and Cyclospora oocysts from environmental water abstracted by drinking water treatment plants and recreational activities in Sarawak, Malaysia. Water samples (12 each) were collected from Sungai Sarawak Kanan in Bau and Sungai Sarawak Kiri in Batu Kitang, respectively. In addition, 6 water samples each were collected from Ranchan Recreational Park and UNIMAS Lake at Universiti Malaysia Sarawak, Kota Samarahan, respectively. Water physicochemical parameters were also recorded. All samples were concentrated by the iron sulfate flocculation method followed by the sucrose floatation technique. Cryptosporidium and Cyclospora were detected by modified Ziehl-Neelsen technique. Correlation of the parasites distribution with water physicochemical parameters was analysed using bivariate Pearson correlation. Based on the 24 total samples of environmental water abstracted by drinking water treatment plants, all the samples (24/24; 100%) were positive with Cryptosporidium, and only 2 samples (2/24; 8.33%) were positive with Cyclospora. Based on the 12 total samples of water for recreational activities, 4 samples (4/12; 33%) were positive with Cryptosporidium, while 2 samples (2/12; 17%) were positive with Cyclospora. Cryptosporidium oocysts were negatively correlated with dissolved oxygen (DO). PMID- 29234681 TI - Corrigendum to "Biomechanical Evaluation of a Tooth Restored with High Performance Polymer PEKK Post-Core System: A 3D Finite Element Analysis". AB - [This corrects the article DOI: 10.1155/2017/1373127.]. PMID- 29234682 TI - Chemical Compositions, Somatic Embryogenesis, and Somaclonal Variation in Cumin. AB - This is the first report evaluating the relationship between the chemical compositions of cumin seeds (based on the analysis of the content of catalase, ascorbate peroxidase, proline, protein, terpenic compounds, alcohol/phenols, aldehydes, and epoxides) and the induction efficiency of somatic embryogenesis in two Iranian superior cumin landraces (Golestan and North Khorasan). Cotyledons isolated from Golestan landrace seeds cultivated on MS medium supplemented with 0.1 mg/L kinetin proved to be the best primary explant for the induction of somatic embryogenesis as well as the regeneration of the whole plantlet. Results indicated that different developmental stages of somatic embryos were simultaneously observed on a callus with embryogenic potential. The high content of catalase, ascorbate peroxidase, proline, and terpenic hydrocarbons and low content of alcoholic and phenolic compositions had a stimulatory effect on somatic embryogenesis. Band patterns of RAPD markers in regenerated plants were different from those of the mother plants. This may be related to somaclonal variations or pollination system of cumin. Generally, measurement of chemical compositions can be used as a marker for evaluating the occurrence of somatic embryogenesis in cumin. Also, somaclonal variations of regenerated plants can be applied by the plant breeders in breeding programs. PMID- 29234680 TI - Myomas and Adenomyosis: Impact on Reproductive Outcome. AB - Among uterine structural abnormalities, myomas and adenomyosis represent two distinct, though frequently coexistent entities, with a remarkable prevalence in women of reproductive age. Various mechanisms have been proposed to explain the impact of each of them on reproductive outcome. In respect to myomas, current evidence implies that submucosal ones have an adverse effect on conception and early pregnancy. A similar effect yet is not quite clear and has been suggested for intramural myomas. Still, it seems reasonable that intramural myomas greater than 4 cm in diameter may negatively impair reproductive outcome. On the contrary, subserosal myomas do not seem to have a significant impact, if any, on reproduction. The presence of submucosal and/or large intramural myomas has also been linked to adverse pregnancy outcomes. In particular increased risk for miscarriage, fetal malpresentation, placenta previa, preterm birth, placenta abruption, postpartum hemorrhage, and cesarean section has been reported. With regard to adenomyosis, besides the tentative coexistence of adenomyosis and infertility, to date a causal relationship among these conditions has not been fully confirmed. Preterm birth and preterm premature rupture of membranes, uterine rupture, postpartum hemorrhage due to uterine atony, and ectopic pregnancy have all been reported in association with adenomyosis. Further research on the impact of adenomyosis on reproductive outcome is welcome. PMID- 29234683 TI - Antioxidant Potential of Selected Korean Edible Plant Extracts. AB - This study aimed to evaluate the antioxidant activity of various plant extracts. A total of 94 kinds of edible plant extracts obtained from the Korea Plant Extract Bank were screened for cytotoxicity, following which the total phenolic content of 24 shortlisted extracts was determined. Of these, extracts from three plants, namely, Castanea crenata (CC) leaf, Camellia japonica (CJ) fruit, and Viburnum dilatatum (VD) leaf, were examined for antioxidant capabilities by measuring radical scavenging activity, ferric reducing/antioxidant power, and lipid peroxidation inhibitory activity. In addition, cellular antioxidant activities of the three extracts were assessed by a cell-based dichlorofluorescein assay and antioxidant response element (ARE) reporter activity assay. The results demonstrated that all three extracts concentration dependently scavenged free radicals, inhibited lipid peroxidation, reduced the cellular level of reactive oxygen species, and increased ARE-luciferase activity, indicating antioxidant enzyme-inducing potential. In particular, CJ extract showed significantly greater antioxidative activity and antimigratory effect in a breast cancer cell line compared to CC and VD extracts. Hence, CJ extract deserves further study for its in vivo functionality or biologically active constituents. PMID- 29234684 TI - Changes in the Diaphragm Lipid Content after Administration of Streptozotocin and High-Fat Diet Regime. AB - The diaphragm is a dome-shaped skeletal muscle indispensable for breathing. Its activity contributes up to 70% of the total ventilatory function at rest. In comparison to other skeletal muscles, it is distinguished by an oxidative phenotype and uninterrupted cyclic contraction pattern. Surprisingly, the research regarding diaphragm diabetic phenotype particularly in the light of lipid-induced insulin resistance is virtually nonexistent. Male Wistar rats were randomly allocated into 3 groups: control, streptozotocin-induced (STZ) type-1 diabetes, and rodents fed with high-fat diet (HFD). Additionally, half of the animals from each group were administered with myriocin, a robust, selective inhibitor of ceramide synthesis and, therefore, a potent agent ameliorating insulin resistance. Diaphragm lipid contents were evaluated using chromatography. Fatty acid transporter expression was determined by Western blot. The STZ and HFD rats had increased concentration of lipids, namely, ceramides (CER) and diacylglycerols (DAG). Interestingly, this coincided with an increased concentration of long-chain (C >= 16) saturated fatty acid species present in both the aforementioned lipid fractions. The CER/DAG accumulation was accompanied by an elevated fatty acid transporter expression (FATP-1 in HFD and FATP-4 in STZ). Surprisingly, we observed a significantly decreased triacylglycerol content in the diaphragms of STZ-treated rats. PMID- 29234685 TI - Local and Systemic CD4+ T Cell Exhaustion Reverses with Clinical Resolution of Pulmonary Sarcoidosis. AB - Investigation of the Th1 immune response in sarcoidosis CD4+ T cells has revealed reduced proliferative capacity and cytokine expression upon TCR stimulation. In other disease models, such cellular dysfunction has been associated with a step wise, progressive loss of T cell function that results from chronic antigenic stimulation. T cell exhaustion is defined by decreased cytokine production upon TCR activation, decreased proliferation, increased expression of inhibitory cell surface receptors, and increased susceptibility to apoptosis. We characterized sarcoidosis CD4+ T cell immune function in systemic and local environments among subjects undergoing disease progression compared to those experiencing disease resolution. Spontaneous and TCR-stimulated Th1 cytokine expression and proliferation assays were performed in 53 sarcoidosis subjects and 30 healthy controls. PD-1 expression and apoptosis were assessed by flow cytometry. Compared to healthy controls, sarcoidosis CD4+ T cells demonstrated reductions in Th1 cytokine expression, proliferative capacity (p < 0.05), enhanced apoptosis (p < 0.01), and increased PD-1 expression (p < 0.001). BAL-derived CD4+ T cells also demonstrated multiple facets of T cell exhaustion (p < 0.05). Reversal of CD4+ T cell exhaustion was observed in subjects undergoing spontaneous resolution (p < 0.05). Sarcoidosis CD4+ T cells exhibit loss of cellular function during progressive disease that follows the archetype of T cell exhaustion. PMID- 29234688 TI - Superior semicircular canal dehiscence: A new perspective. AB - Objective: To determine the use of multi-detector computed tomography (MDCT) in the diagnostic interpretation of superior semicircular canal dehiscence (SSCD) or thinning and its association with ear pathologies and to find whether it is an acquired condition and its association with increase in age. Materials and methods: study was performed in a tertiary care institute present in a village, following approval of the institutional ethical committee. Retrospective review of temporal bone CT examinations performed between September 2016 and March 2017 was done. 1 mm interval axial images with sagittal and coronal reformatted images were reviewed for the presence of canal dehiscence and thinning by investigators. We characterised the Superior semicircular canal status as normal, frank dehiscence or thinning. Frank dehiscence was further classified anatomically as anterior limb, apex and posterior limb dehiscence.The patient list was then subcategorized into 5 age groups, and the prevalence of SSCD was calculated for each group. Results: Retrospective review yielded 80 positive cases which included SSC dehiscence (N = 39) and thinning (N = 41). 80 normal scans were selected as control group retrospectively. Statistical analysis was performed to assess for differences between the groups studied. Pearson chi-square test applied. there was a significant association of SSC pathologies prevalence with increasing age (p = < 0.001). No significant relationship was found between SSCD and presence of either CSOM or Cholesteatoma (p = 0.285). Vertigo rather than Tullio phenomenon was the statistically significant complaint (p = <0.001). which brought the patient to the hospital. Conclusions: The SSCD and thinning belong to the same spectrum and are acquired conditions. Increasing prevalence in old age suggests it to be an acquired condition rather than a congenital one. No significant association of these condition was seen with CSOM and cholesteatoma. Vertigo is the predominat symptom bringing the patient to hospital along with Tullio phenomenon. PMID- 29234687 TI - Delivery of CR2-fH Using AAV Vector Therapy as Treatment Strategy in the Mouse Model of Choroidal Neovascularization. AB - Complement activation plays a significant role in age-related macular degeneration (AMD) pathogenesis, and polymorphisms interfering with factor H (fH) function, a complement alternative pathway (AP) inhibitor, are associated with increased AMD risk. We have previously validated an AP inhibitor, a fusion protein consisting of a complement receptor 2 fragment linked to the inhibitory domain of fH (CR2-fH) as an efficacious treatment for choroidal neovascularization (CNV) when delivered intravenously. Here we tested an alternative approach of AAV-mediated delivery (AAV5-VMD2-CR2-fH or AAV5-VMD2 mCherry) using subretinal delivery in C57BL/6J mice. Secretion of CR2-fH was confirmed in polarized retinal pigment epithelium (RPE) cells. A safe concentration of AAV5-VMD2-CR2-fH was identified using electroretinography, optical coherence tomography (OCT), RPE morphology, and antibody profiling. One month after gene delivery, CNV was induced using argon laser photocoagulation. OCT assessment demonstrated reduced CNV with AAV5-VMD2-CR2-fH administration. Bioavailability studies revealed that gene-therapy delivered similar levels of CR2-fH to the RPE/choroid as treatment by intravenous injections, and C3a ELISA verified reduced CNV-associated ocular C3a production. These results contribute to existing data illustrating the importance of the AP of complement in CNV development and its potential role in AMD treatment. Demonstration of AAV-vector efficacy opens new avenues for the development of treatment strategies. PMID- 29234689 TI - Data supporting that adipose-derived mesenchymal stem/stromal cells express angiotensin II receptors in situ and in vitro. AB - This article contains results of analyses of angiotensin II receptors expression in human adipose tissue and stem/stromal cells isolated from adipose tissue. We also provide here data regarding the effect of angiotensin II on intracellular calcium mobilization in adipose tissue derived stem/stromal cells (ADSCs). Discussion of the data can be found in (Sysoeva et al., 2017) [1]. PMID- 29234686 TI - Therapeutic approaches for corneal neovascularization. AB - Angiogenesis refers to new blood vessels that originate from pre-existing vascular structures. Corneal neovascularization which can lead to compromised visual acuity occurs in a wide variety of corneal pathologies. A large subset of measures has been advocated to prevent and/or treat corneal neovascularization with varying degrees of success. These approaches include topical corticosteroid administration, laser treatment, cautery, and fine needle diathermy. Since the imbalance between proangiogenic agents and antiangiogenic agents primarily mediate the process of corneal neovascularization, recent therapies are intended to disrupt the different steps in the synthesis and actions of proangiogenic factors. These approaches, however, are only partially effective and may lead to several side effects. The aim of this article is to review the most relevant treatments for corneal neovascularization available so far. PMID- 29234690 TI - The dataset describes: Phenotypic changes induced by cholesterol loading in smooth muscle cells isolated from the aortae of C57BL/6 mice. AB - The data presented in this article is related to the research article entitled "ABCA1 and HDL3 are Required to Modulate Smooth Muscle Cells Phenotypic Switch after Cholesterol Loading" (Castiglioni et al., 2017) [1]. This data describes the characterization of the phenotypic changes induced by cholesterol loading in smooth muscle cells (SMCs) isolated from the aortae of C57BL/6 mice. Upon cholesterol loading, there is a significant and concentration-dependent decrease in the expression of Acta2 and a parallel increase in Mac-2, and ATP binding cassette (ABC) transporters Abca1 and Abcg1. Cholesterol incubation causes the transformation of SMCs into foam cells with a 3-fold increase in cellular total cholesterol content and a 2.5-fold stimulation of the activity of the esterifying enzyme Acyl-CoA:cholesterol acyltransferase (ACAT). The addition of the same amount of cholesterol, either dissolved in ethanol or as lipoprotein cholesterol (AcLDL or native LDL) only slightly induces the activity of the enzyme ACAT, and does not cause the accumulation of lipid droplets into SMCs. We describe also the knock down of ABCA1 expression by siRNA treatment in mouse smooth muscle cells. PMID- 29234691 TI - Diabetic Zucker rat Tibialis anterior muscle high-frequency electrical stimulation (HFES) data: Regulation of MAPKs associated proteins. AB - Anaerobic exercise has been advocated as a prescribed treatment for the management of diabetes: however, alterations in exercise-induced signaling remain largely unexplored in the diabetic muscle. Here, we compare the basal and the in situ contraction-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) ERK 1/2, p38, and JNK in the lean and obese (fa/fa) Zucker rat tibialus anterior (TA) muscle following a single bout of contractile stimuli. This article represents data associated with prior publications from our lab (Katta et al., 2009, Katta et al., 2009, Tullgren et al., 1991) [1-3] and concurrent Data in Brief articles (Ginjupalli et al., 2017, Rice et al., 2017, Rice et al., 2017, Rice et al., 2017) [4-7]. PMID- 29234692 TI - Characterization and isotherm data for adsorption of Cd2+ from aqueous solution by adsorbent from mixture of bagasse-bentonite. AB - The usage of wastes of baggase would be admirable from environmental and solid waste management point of view. Thus, herein, this data set present a facile method for providing an adsorbent from mixture of bagasse-bentonite. The prepared adsorbent was applied to remove Cd2+ from aqueous solution. The characterization data of the adsorbent were analyzed using XRF and FTIR methods. The XRF test results showed the changes of elemental content in adsorbent after the adsorption indicated that adsorbent can absorb Cd2+. The FTIR test results showed that adsorbent has a functional group that is useful in adsorption process. It was conducted in laboratory scale and the adsorption technique was batch technique. The information regarding isotherms of cadmium ions adsorption were listed. The Langmuir isotherm was suitable for correlation of equilibrium data. The acquired data indicated that the adsorption of Cd2+ by the adsorbent prepared from mixture of bagasse-bentonite is a promising technique for treating Cd-bearing wastewaters. PMID- 29234693 TI - Lean and Obese Zucker Rat Extensor Digitorum Longus Muscle high-frequency electrical stimulation (HFES) Data: Regulation of MAPKs Associated Proteins. AB - Anaerobic exercise has been advocated as a prescribed treatment for the management of diabetes: however, alterations in exercise-induced signaling remain largely unexplored in the diabetic muscle. Here, we compare the basal and the in situ contraction-induced phosphorylation of the mitogen-activated protein kinases (MAPKs) ERK 1/2, p38, and JNK in the lean and obese (fa/fa) Zucker rat extensor digitorum longus (EDL) muscle following a single bout of contractile stimuli. This article represents data associated with prior publications from our (Katta et al., 2009a, 2009b, 2008) [1-3] and concurrent Data in Brief articles (Ginjupalli et al., 2017a, 2017b; Rice et al., 2017a, 2017b) [4-7]. PMID- 29234694 TI - Contemporary data on treatment practices for low-density lipoprotein cholesterol in 3867 patients who had suffered an acute coronary syndrome across the world. AB - : DYSIS II ACS was a longitudinal, observational study in 3867 patients from 18 countries. They were being hospitalized after suffering an acute coronary syndrome. Evaluations were performed at the time of admission and again 120+/-15 days following the date of admission (the follow-up time point). 2521 patients were on active lipid lowering treatment (LLT) at admission. Mean atorvastatin dose was 22 mg per day and 2.7% received ezetimibe in combination with a statin. At discharge from hospital, 3767 patients received LLT expressed as a mean atorvastatin dose of 36 mg per day with 4.8% receiving ezetimibe on top of a statin. After 120 days, intensity in lipid lowering treatment was reduced to 32 mg per day with 4.9% of the patients receiving ezetimibe and a statin. Of note, during this 4-month follow up period, only 32% of all patients received laboratory lipid testing. 37% attained the low density lipoprotein cholesterol (LDL-C) target value of <70 mg/dl after 120 days. There are differences in the therapy administered as well as in the switch strategies when comparing the data from the respective countries studied. Conclusions: Only one in three patients achieved the LDL-C target value following only marginal improvements in atorvastatin dose or combination therapy after an ACS event. PMID- 29234695 TI - An improved draft of the pigeonpea (Cajanus cajan (L.) Millsp.) genome. AB - The first draft of the pigeonpea (Cajanus cajan (L.) Millsp. cv. Asha) genome with 511 Mbp of assembled sequence information has low genome coverage of about sixty percent. Here we present an improved version of this genome with 648.2 Mbp of assembled sequence of this popular pigeonpea variety, which is liked by the millers and has resistance to fusarium wilt and sterility mosaic diseases. With the addition of 137 Mb of assembled sequence information the present version has the highest available genome coverage of pigeonpea till date. We predicted 56,888 protein-coding genes of which 54,286 (96.7%) were functionally annotated. In the improved genome assembly we identified 158,432 SSR loci, designed flanking primers for 85,296 of these and validated them in-silico by e-PCR. The raw data used for the improvement of genome assembly are available in the SRA database of NCBI with accession numbers SRR5922904, SRR5922905, SRR5922906, SRR5922907. The genome sequence update has been deposited at DDBJ/EMBL/GenBank under the accession AFSP00000000, and the version described in this paper is the second version (AFSP02000000). PMID- 29234696 TI - Complete genome sequence of native Bacillus cereus strains isolated from intestinal tract of the crab Ucides sp. AB - Bacillus cereus is a gram positive bacterium with sporulation capacity. Here, we report the complete genome sequence of two native B. cereus strains (#25 and #29) isolated from intestinal tract of the crab Ucides sp. from Pacoti River in the State of Ceara, Brazil. The findings of this study might increase the molecular information for Bacillus strains. The data can be used in comparative analyses, origin and distribution, as well support for genetic engineering. PMID- 29234697 TI - Valorization of a plant beta-amylase: Immobilization and dataset on the kinetic process. AB - The data presented in this article are related to the research article titled "Immobilization nd topochemical mechanism of a new beta-amylase extracted from Pergularia tomentosa" (Lahmar et al., 2017) [1]. This article documented information on the determination of the molecular weight of the beta-amylase, the method of its immobilization and a comparison of the kinetic mechanism between the free and the immobilized forms by a mathematical method. Fresh Pergularia tomentosa was collected from Tunisia and a special method for beta-amylase extraction was followed (Yotova et al., 2000) [2]. Public dissemination of this dataset will allow further analyses of the data. PMID- 29234698 TI - Data on heavy metal and magnetic relationships in coastal sediments from South East Coast of Tamilnadu, India. AB - In this data, the heavy metal concentration and magnetic susceptibility in coastal sediment samples collected from Periyakalapet to Parangaipettai of East Coast of Tamilnadu using Energy Dispersive X-ray Fluorescence (EDXRF) technique and dual frequency susceptibility meter. We aimed to (i) determine the heavy metal concentration in the sediments from Periyakalapet to Parangaipettai of East Coast of Tamilnadu (ii) assess the magnetic mineral property of sediments (iii) study the correlation between heavy metal and magnetic susceptibility. The determined heavy metal concentration found in the order of Mn> Ba > V > Cr > Zn > La > Ni >Pb> Co > As > Cd > Cu > Al > Fe >Ca> Ti > K > Mg. The magnetic susceptibility (chilf) measurements show that they vary from 5.92*10-8 m3 kg-1to 29.06*10-8 m3 kg-1 with an average of 20.39*10-8 m3 kg-1. Analysed data confirmed that magnetic susceptibility has the potential tool to indicate the heavy metal pollution sources. PMID- 29234699 TI - Dataset on analysis of dyeing property of natural dye from Thespesia populnea bark on different fabrics. AB - The natural dyes separated from plants are of gaining interest as substitutes for synthetic dyes in food and cosmetics. Thespesia populnea (T. populnea) is widely grown plant and used in the treatment of various diseases. This study was aimed to separate natural dye from T. populnea bark and analysis of its dyeing property on different fabrics. In this investigation pharmacognostic study was carried out. The pharmacognostic study includes morphological study, microscopical examination, proximate analysis along with the phytochemical study. The dyeing of different fabric was done with a natural dye extracted from T. populnea bark. The fabrics like cotton, butter crep, polymer, chiken, lone, ulene and tarakasa were dye with plant extract. The various evaluation parameters were studied. It includes effect of washing with water, effect of soap, effect of sunlight, effect of alum, effect of Cupric sulphate, microscopical study of fabrics and visual analysis of dyeing by common people were studied. In results, natural dye isolated from T. populnea bark could be used for dyeing fabrics with good fastness properties. The studies reveals that, the dyeing property of fabrics after washing with water and soap, exposed to sunlight does not get affected. It was observed that cotton and tarakasa stains better as compared with other fabrics. It was concluded that the ethanolic extract having good dyeing property. PMID- 29234700 TI - Magnetic record of Mio-Pliocene red clay and Quaternary loess-paleosol sequence in the Chinese Loess Plateau. AB - This article presents magnetic data of a 300-m-thick Mio-Pliocene red clay and Quaternary loess-paleosol sequence near Chaona town in the Central Chinese Loess Plateau. Detailed magnetostratigraphy shows that the aeolian red clay began to accumulate at ca. 8.1 Ma. Here, we presented a high-resolution rock magnetic data at 20-40 cm intervals within 4.5-8 ka span per sample of this section, which has been published in Song et al. (2014) [1] and (2017) [2]. The dataset including the following magnetic parameters: mass magnetic susceptibility (chi), frequency dependent susceptibility (chifd), saturation magnetization (Ms), saturation remanent magnetization (Mrs), coercive force (Bc), remanent coercivity (Bcr), saturation isothermal remanent magnetization (SIRM) and S-ratio. Magnetic susceptibility and hysteresis parameters were measured at Lanzhou University and Kyoto University, respectively. This data provides a high-resolution rock magnetic evidences for understanding East Asia Monsoon change, Asian interior aridification and tectonic effect of the uplift of the Tibetan Plateau since middle Miocene period. PMID- 29234701 TI - Hysteresis data of planar perovskite solar cells fabricated with different solvents. AB - In this data article, we introduced the hysteresis of planar perovskite solar cells (PSCs) fabricated using dimethylformamide (DMF), gamma-butyrolactone (GBL), methyl-2-pyrrolidinone (NMP), dimethylsulfoxide (DMSO), DMF-DMSO, GBL-DMSO and NMP-DMSO as perovskite precursor solutions according to different scan directions, sweep times, and current stability. The hysteresis analyses of the planar PSCs prepared with a glass-ITO /NiOX/perovskite /PC61BM/BCP/Ag configuration were measured with Keithley 2400 source meter unit under 100 mW/cm2 (AM 1.5 G). The data collected in this article compares the hysteresis of PSCs with different solvents and is directly related to our research article "High Performance Planar Perovskite Solar Cells: Influence of Solvent upon Performance" (You-Hyun Seo et al., 2017 [1]). PMID- 29234702 TI - High-frequency electrical stimulation (HFES) data lean and obese Zucker rat tibialis anterior muscle: Regulation of glycogen synthase kinase 3 beta (GSK3B) associated proteins. AB - Anaerobic exercise has been advocated as a prescribed treatment for the management of diabetes: however, alterations in exercise-induced signaling remain largely unexplored in the diabetic muscle. Here, we compare the basal and the in situ contraction-induced phosphorylation of the AMPK, GSK3beta, and Shp2 in the lean and obese (fa/fa) Zucker rat tibialis anterior (TA) muscle following a single bout of contractile stimuli. This article represents data associated with prior publications from our lab (Katta et al., 2009; Katta et al., 2009; Tullgren et al., 1991) [1-3] and concurrent Data in Brief articles (Ginjupalli et al., 2017; Rice et al., 2017; Rice et al., 2017; Rice et al., 2017) [4-7]. PMID- 29234703 TI - Lean and Obese Zucker Rat Extensor Digitorum Longus Muscle high-frequency electrical stimulation (HFES) Data: Regulation of p70S6kinase Associated Proteins. AB - Anaerobic exercise has been advocated as a prescribed treatment for the management of diabetes: however, alterations in exercise-induced signaling remain largely unexplored in the diabetic muscle. Here, we compare the basal and the in situ contraction-induced phosphorylation of the AKT, GSK3beta, mTor, p70s6K, Pten, and Shp2 in the lean and obese (fa/fa) Zucker rat Extensor Digitorum Longus (EDL) muscle following a single bout of contractile stimuli. This article represents data associated with prior publications from our lab (Katta et al., 2009a, 2009b; Tullgren et al., 1991) [1-3] and concurrent Data in Brief articles (Ginjupalli et al., 2017a, 2017b; Rice et al., 2017a, 2017b) [4-7]. PMID- 29234704 TI - Experimental dataset on acid treated eggshell for removing cyanide ions from synthetic and industrial wastewaters. AB - The data current in this article are associated to the efficacy of acid treated eggshell as eggshell membrane (ESM) as an adsorbent for eliminating cyanide ion from synthetic and industrial wastewaters. This article describes the effects of selected factors such as pH (3-11), contact time (5-60 min), cyanide ion concentrations (50-150 mg/L), ESM dose (0.25-2 g/L), and solution temperature (20 50) on the removal cyanide ion from aqueous solution. The maximum cyanide ion removal obtained at a solution pH of 9-11. The kinetic data agreed with the pseudo-second-order kinetic. The equilibrium adsorption data at different temperatures well set through Langmuir equation. FTIR and thermodynamic data describe main adsorption phenomenon in cyanide ion onto ESM could be the ion exchange and chemisorption. PMID- 29234705 TI - The concentration data of heavy metals in Iranian grown and imported rice and human health hazard assessment. AB - The aim of this study was to review the prevalence of rice contamination to heavy metals in Iranian grown and imported rice brands by conducting a systematic review and assess the related human health risk. Multiple keywords such as "rice, heavy metals, and Iran" were used to search in related databases. The average concentration of Cd, Pb, As, Cu, Zn, Cr, Ni and Co for Iranian grown/imported rice were calculated as 0.16+/-0.08/0.13+/-0.05, 0.196+/-0.16/0.55+/-0.56, 0.046+/-0.002/0.057+/-0.0035,0.29+/-0.05/0.61+/-0.31, 26.13+/-10.3/3.46+/-2.49, 0.22+/-0.04/0.76+/-0.101, 16+/-7.3/2.08+/-0.34 and 0.29+/-0.047/0.29+/-0.07 mg kg 1, respectively. Except Co, there were significant differences between Iranian and imported rice brands. Estimated weekly intake for none of the metals exceeds the provisional tolerable weekly intake value. Accordingly, the rice types consumed in Iran have no health hazard for consumers. PMID- 29234706 TI - Adsorption of diclofenac onto different biochar microparticles: Dataset - Characterization and dosage of biochar. AB - Due to its wide occurrence in water resources and toxicity, pharmaceuticals and personal care products are becoming an emerging concern throughout the world. Application of residual/waste materials for water remediation can be a good strategy in waste management as well as in waste valorization. Herein, this dataset provides information on biochar application for the removal of emerging contaminant, diclofenac from water matrices. The data presented here is an extension of the research article explaining the mechanisms of adsorption diclofenac on biochars (Lonappan et al., 2017 [1]). This data article provides general information on the surface features of pine wood and pig manure biochar with the help of SEM and FTIR data. This dataset also provides information on XRD profiles of pine wood and pig manure biochars. In addition, different amounts of biochars were used to study the removal of a fixed concentration of diclofenac and the data is provided with this data set. PMID- 29234707 TI - Point of care testing of fecal calprotectin as a substitute for routine laboratory analysis. AB - Objectives: Fecal calprotectin (FC) is widely used to monitor the activity of inflammatory bowel disease (IBD) and to tailor medical treatment to disease activity. Laboratory testing of fecal samples may have a turnaround time of 1-2 weeks, whereas FC home testing allows results within hours and thus enables a rapid response to clinical deterioration. Design and methods: Fifty-five stool samples were analyzed by the IBDoc(r) Calprotectin Home Testing kit and the BUHLMANN fCAL(r) turbo assay on a Roche Cobas 6000 c501. The correlation between the assays was assessed using Spearman's Rho correlation coefficient and the intermediate imprecision of both assays was calculated. Results: We found a strong correlation coefficient of 0.887 between FC measured on IBDoc(r) and the laboratory assay BUHLMANN fCAL(r) turbo. The coefficients of variation (CVs) at three different FC levels were in the range 2.3-5.5% (BUHLMANN fCAL(r) turbo) and in the range of 4.8-26.6% (IBDoc(r)). Conclusions: This study suggests that IBDoc(r) is a suitable alternative for the assessment of disease activity in IBD patients. PMID- 29234708 TI - Simple and rapid validated HPLC-fluorescence determination of perampanel in the plasma of patients with epilepsy. AB - We present a simple and fast high-performance liquid chromatography method with fluorescence detection for the determination of the antiepileptic drug perampanel in human plasma. The chromatographic separation was performed on a Kinetex PFP (100 * 2.6 mm, 4.6 um) column, using a mobile phase of sodium acetate 0.03 M pH 3.7 and acetonitrile (40/60, v/v), at a flow rate of 0.8 mL/min. Total chromatography time for each run was 5 min. Sample preparation (250 uL) involved only one simple precipitation step by acetonitrile spiked with mirtazapine as internal standard. The method was validated over a concentration range of 20-1000 ng/mL and successfully applied to measure perampanel concentrations in plasma samples obtained from patients with epilepsy. This assay combines the high specificity of fluorescence detection with a very simple and fast sample pretreatment and can offer real advantages over existing methods in terms of simplicity and transferability to a therapeutic drug monitoring setting. PMID- 29234709 TI - Repeating platinum/bevacizumab in recurrent or progressive cervical cancer yields marginal survival benefits. AB - Our objective was to assess overall survival of cervical cancer patients following prior platinum/bevacizumab chemotherapy, comparing retreatment with platinum/bevacizumab with alternative therapies. A retrospective analysis was performed of women who received platinum/bevacizumab (PB) chemotherapy for cervical cancer at Washington University between July 1, 2005 and December 31, 2015. Wilcoxon rank-sum exact test and Fisher's exact test were used to compare the treatment groups, and Kaplan Meier curves were generated. Cox regression analyses were performed, with treatment free interval and prior therapy response included as covariates. Of 84 patients who received PB chemotherapy, 59 (70%) received no second line chemotherapy, as they did not recur, progressed without further chemotherapy, were lost to follow up, or expired. Of the remaining 25 patients, 9 were retreated with the combination of platinum/bevacizumab (PB), 6 were retreated with a platinum regimen without bevacizumab (P), and 10 were retreated with neither (not-P). The only long-term survivor was in the not-P group and was treated with an immunotherapy agent. Median overall survival of all patients was 7.1 months. There was a marginal difference in survival between women in the PB and not-PB groups (11.8 versus 5.7 months; HR 3.02, 95% CI, 0.98 9.28). There was no difference in survival based on platinum interval (HR 0.81; 95% CI, 0.27-2.45). Outcomes are grim for women retreated after platinum/bevacizumab therapy and are only marginally improved by retreatment with a platinum/bevacizumab regimen. Rather than additional PB therapy, women with cervical cancer who recur after platinum/bevacizumab should consider supportive care or clinical trials. PMID- 29234710 TI - Polypoid endometriosis mimicking invasive cancer in an obese, postmenopausal tamoxifen user. AB - Background: Tamoxifen is a medication often used for the treatment and prevention of breast cancer. It is classically associated with several gynecological side effects to include a thickened endometrial stripe, increased uterine polyp formation, and an increased risk of uterine cancer. Rarely tamoxifen use has been associated with proliferation of endometriosis often severe enough to mimic a late-stage gynecologic malignancy. Case: A 62-year-old Gravida 0 postmenopausal female with a medical history of severe obesity, infertility, and preventative tamoxifen use presented for evaluation of gross hematuria. A CT urogram was performed and demonstrated findings concerning for carcinomatosis, likely gynecologic in origin. Cervical cancer screening was up-to-date and she had a negative colonoscopy within the prior 2 years. Serum tumor markers were remarkable only for a mildly elevated CA125 of 37.6. Diagnostic laparoscopy demonstrated apparent operable carcinomatosis limited to the pelvis. The procedure was converted to an exploratory laparotomy, where radical tumor cytoreduction was performed to no gross residual disease. Frozen sections performed intraoperatively were unclear of origin but suggestive of low malignant potential. Final pathology resulted for endometriosis. Conclusion: This case illustrates a presentation of endometriosis in a postmenopausal woman mimicking advanced mullerian malignancy. The patient's estrogenic state from obesity in combination with the agonist action of the tamoxifen likely contributed to her rare presentation. While findings such as a thickened endometrial stripe are typical of tamoxifen use, such widespread proliferation of endometriosis resulting in a pelvic mass, genito-urinary obstruction, and plaque-like pelvic spread are not. Precis: Endometriosis is a benign estrogen dependent condition rarely problematic in a postmenopausal patient. Tamoxifen use in the setting of an obese patient may contribute to a proliferation of pre-existing endometriosis which resembles an aggressive late-stage gynecological malignancy. PMID- 29234711 TI - A study of the number of female editors-in-chief of dermatology journals. AB - Introduction: Over the past 50 years the proportion of women entering medical school has vastly increased, however there still exists a gender gap in top leadership positions, including within academic medicine. It is important to investigate the influence of women in this area, and assess change over time. The aim of the study was to assess the number of women who have acted as editors-in chief of prominent dermatology journals over the 20th and 21st centuries. Methods: A list of 25 journals was collated based on their impact factors and prominence. Information regarding previous and current editors was obtained, compiled and analysed. Results: Overall there have been 26 female editors and at least 128 male editors in the 25 dermatology journals, which means that less than 19% of editors-in-chief have been female. 45.8% of journals have not yet had a female editor. The percentage of female editors ranged from 0% to 100%, with only one journal having had all female editors (International Journal of Women's Dermatology). On average, the journals had female editorship for 27.2% of the total number of years in publication. Of the 13 journals that have had a female editor, 61.5% had their first female editor after the year 2000. Discussion and Conclusion: There are various factors that influence these numbers including age of the journals and length of each editorship. It is clear that over time there has been an increase in the number of women holding these prestigious positions however gender equity has not yet been reached. PMID- 29234713 TI - Promoting early detection of melanoma during the mammography experience. AB - Background: Invasive melanoma, a lethal form of skin cancer, is the seventh most common cancer in women. Factors such as a history of indoor tanning or sunburn and a personal or family history of skin cancer increase a woman's risk of developing a melanoma. Objective: Because the majority of melanomas occur in patients age 40 years or older, which is the age that is recommended for women to begin screening mammograms, the mammogram experience could be used to promote early detection of melanoma by introducing skin self-examinations (SSE) to a population of women who are already invested in preventive health. Methods: This was a pilot and feasibility study that was designed to promote the early detection of melanoma among women who undergo a mammogram at the Lynn Sage Breast Center at the Northwestern Medicine/Prentice Women's Hospital in Chicago, Illinois. The study was conducted in three phases: development of the materials, delivery of the program, and assessment of the program effectiveness. Results: Eighty six percent of women with scheduled mammogram appointments participated in the study (n = 560). Among these women, 68% noticed the SSE information in the changing rooms, 78% thought the information applied to them, and 68% identified with at least one of the risk factors for melanoma. Twenty percent of the patients checked their skin in the changing room, 13% noticed a concerning mole, and 60% of those women who noted a concerning lesion stated their intent to see a dermatologist for further evaluation. Conclusion: A large proportion of the women in our study had risk factors for developing a melanoma and noticed the SSE information in the screening center. Placing an intervention to encourage methods for the early detection of melanoma in an outpatient mammography environment is an effective strategy to increase awareness in a large proportion of at-risk women. PMID- 29234712 TI - The systemic management of cutaneous dermatomyositis: Results of a stepwise strategy. AB - Treatment of dermatomyositis (DM) is often achieved with a stepwise algorithm. However, the literature lacks quality evidence to support the use of this therapeutic strategy. The result of a stepwise therapeutic strategy in the management of skin-only DM is presented to better understand the clinical outcomes and allow for future studies. A cohort of 102 patients with DM, 41 of whom had skin-only disease, were seen between July 2009 and April 2013 at a referral-based connective tissue disease clinic. The Cutaneous Dermatomyositis Disease Area and Severity Index was used to prospectively assess disease severity and the outcomes in 41 adult patients with skin-only DM were analyzed. Of the 41 patients with skin-only DM, 23 patients (56.1%) received antimalarial medications alone and 18 patients (43.9%) received second- or third-line agents. Ten patients (24.4%) remained at the first level of the treatment algorithm and received only hydroxychloroquine. Prednisone was included in the treatment regimen for 11 patients with skin-only disease (26.8%). The results show that management of cutaneous DM often requires second-line agents because antimalarial medications alone are insufficient to treat most patients with skin-only disease. PMID- 29234714 TI - Bone mineral density is lower in male than female patients with plaque-type psoriasis in Iran. AB - Background: There are many similarities with regard to contributing cytokines in patients with psoriasis and osteoporosis. A theory of probable relationship between these two entities has been proposed but there is no concordant consensus. The aim of this study was to evaluate bone mineral density (BMD) in patients with psoriasis. Method and materials: This cross-sectional study of BMD was conducted with 64 eligible patients with psoriasis who were referred to the dermatology clinic of Razi hospital in Tehran, Iran in between 2011 and 2012. Results: The mean T score of femoral neck was -1.17 and -0.49 in men and women, respectively, which was statistically significant (p = .047). The mean T score of the lumbar spine was -0.93 and -0.30 in men and women, respectively, but not statistically significant (p = .058). In total except with the exclusion of the study site (femur or lumbar), men and women did not have a statistically significant difference with regard to osteoporosis or osteopenia in BMD (p = .114). The Pearson correlation coefficient demonstrated a moderate inverse relationship between age and T score of the femoral neck and lumbar spine (r = 0.419 and -.406, respectively), which was statistically significant (p = .001). Although there was no statistically significant relationship between the Psoriasis Area and Severity Index (PASI) and T scores of the femoral neck (p = .596), a positive and weak correlation was observed between the PASI and T scores for the lumbar spine, which was statistically significant (r = 0.269; p = .03). Conclusion: Patients with psoriasis had decreased bone density, which was more significant in men. Prevalence of osteoporosis showed no statistically significant difference when compared with the healthy population in Iran. PMID- 29234715 TI - Periocular dermatoses. AB - The periocular area may be affected by infectious or noninfectious diseases such as inflammatory dermatoses, systemic disease, drug reactions, benign and malignant lesions, traumatic lesions, and esthetic complications. We present a review of the most common periocular dermatoses. PMID- 29234717 TI - Vulvar lichen planus pemphigoides. AB - Lichen planus pemphigoides (LPP) is a rare blistering disease with features of both lichen planus and bullous pemphigoid. LPP typically appears on the extremities and occasionally involves the oral mucosa. Herein, we describe a case of LPP of the vulva of an 80-year-old woman, an uncommon location for this disease process. This clinical scenario can be confused with a number of similarly appearing entities such as erosive vulvar lichen planus, mucous membrane pemphigoid, and erosive lichen sclerosus et atrophicus. In fact, our patient carried a diagnosis of lichen sclerosus by an outside physician for 2 years prior to being properly diagnosed and treated. A detailed discussion of the epidemiology, clinical, and pathogenesis as well as the histologic and immunofluorescence characteristics of this uncommon diagnosis is presented. Our case emphasizes the necessity of microscopic analysis to differentiate lookalike disease states when making a diagnosis and choosing the correct therapeutics. PMID- 29234716 TI - Physiologic changes of pregnancy: A review of the literature. AB - Throughout pregnancy, the body undergoes a variety of physiologic changes. The cutaneous findings can be most noticeable and often worrisome to both physicians and patients. Obstetricians and dermatologists must be able to differentiate between changes that are benign and those that may be pathologic. Most physicians recognize benign changes that are commonly described in literature such as hyperpigmentation, melasma, striae gravidarum, and telogen effluvium; however, they may be unaware of changes that tend to be less frequently discussed. This comprehensive review provides a broad overview of the physiologic cutaneous changes that occur during pregnancy as described in the literature over the past 10 years. PMID- 29234718 TI - A case of multiple squamous cell carcinomas arising from red tattoo pigment. AB - Ornamental tattooing involves the administration of exogenous pigments into the skin to create a permanent design. Our case focuses on a 62-year-old woman who presented with an inflamed enlarging nodule on her right proximal calf, which arose within the red pigment of an ornamental tattoo. The nodule was diagnosed as squamous cell carcinoma (SCC) and subsequently excised. Over the course of the following year, the patient was diagnosed with a total of five additional SCCs that also arose within the red pigment of the tattoo. The increased popularity of tattooing and the lack of industry safety standards for tattoo ink production, especially metal-laden red pigments, may lead to more cases of skin cancer arising within tattoos among patients of all ages. PMID- 29234719 TI - Compression stockings as an effective treatment for erythema nodosum: Case series. AB - Erythema nodosum (EN) is a septal panniculitis that is characterized clinically by tender, erythematous, subcutaneous nodules that are predominately localized on the pretibial lower legs. EN affects women more than men and can be idiopathic or secondary to another disease process such as infection or an immune response. Treatment options for erythema nodosum are suboptimal and often involve significant side effects or require a change in lifestyle. We investigated the effects of moderate 20 mmHg to 30 mmHg compression stockings as an alternative treatment method in two female patients with recurrent erythema nodosum. In both cases, the patients wore the compression stockings daily. At the follow-up visit, the EN lesions were no longer tender to the touch, and postinflammatory hyperpigmentation changes had started. Both patients had a lasting clinical resolution. PMID- 29234720 TI - Radiation-induced circumscribed superficial morphea after brachytherapy for endometrial adenocarcinoma. AB - Radiation-induced morphea (RIM) is a rare and underrecognized complication of radiation therapy that most commonly occurs in women after treatment for breast cancer. Although not fully understood, RIM is hypothesized to arise from an increase in cytokines that stimulate collagen production and extracellular matrix formation. Most documented cases of RIM occur 1 year after radiation therapy and are localized to areas that were treated for breast cancer. We report on a case of a female patient with stage IB endometrial adenocarcinoma who was treated with 24 Gray of adjuvant brachytherapy. The patient developed a diffuse morpheaform, pruritic eruption only at distant sites from the brachytherapy treatment field. Although treatment for RIM is generally unsatisfactory, our patient experienced improvement in the pruritus and a regression of the lesions while applying topical 0.1% tacrolimus ointment and 0.1% triamcinolone creme. An early diagnosis of RIM can prevent extensive workup, guide treatment, and improve quality of life for patients. PMID- 29234721 TI - Nature, nurture, or nuisance: The ethical issues that surround alternative medicine. PMID- 29234722 TI - Physician-Industry Collaboration: Organizational Considerations for the Future of Innovation and Growth in Dermatology. AB - The U.S. medical environment continues to evolve with issues from Privacy to EMR, Insurance regulations, Physician Access and Healthcare Reform, and MACRA (Medicare Access and CHIP Reauthorization Act) on the discussion table. Not since the advent of Medicare and Medicaid in the mid 1960's, have we seen such widespread changes in the medical healthcare environment (Centers for Medicare and Medicaid Services). Physicians, industry, patients and consumers are affected by the changes. These four groups have historically worked as separate entities, but are now key stakeholders in the future of dermatology. As stakeholders collaborating in building a future together, the dermatologists/physicians will help to ensure and preserve the quality of patient care and best patient outcomes. In 2 Executive Forum meetings February 21-23, 2014 and June 3-4, 2016 the leaders from the Women's Dermatologic Society and Industry, explored several important areas, six of which will be reviewed in this article 1) A five-year outlook of Dermatology and Medicine; 2) The New Practice Environment; 3) Access of Industry to Dermatologists and Trainees; 4) Doing Things Differently; and 5) Female Leadership 6) Unmet Needs. The collaborative group explored solutions for our specialty and the patients we serve. PMID- 29234723 TI - Free and Cued Selective Reminding Test sensitivity. PMID- 29234724 TI - Lower cerebral blood flow in subjects with Alzheimer's dementia, mild cognitive impairment, and subjective cognitive decline using two-dimensional phase-contrast magnetic resonance imaging. AB - Introduction: In this cross-sectional study, we aimed to detect differences in cerebral blood flow (CBF) between subjects with Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD), using two dimensional phase-contrast magnetic resonance imaging. Methods: We included 74 AD patients (67 years, 51% female), 36 MCI patients (66 years, 33% female), and 62 patients with SCD (60 years, 32% female) from the Amsterdam Dementia Cohort. Patients with SCD are those who visited the memory clinic with subjective cognitive complaints without objective cognitive impairment. Whole-brain CBF (mL/100 g/min) was calculated using total volume flow measured with two dimensional phase-contrast magnetic resonance imaging and normalized for brain volume. Results: Mean CBF values (SD) were lower in AD compared to SCD (age and sex adjusted 70 +/- 26 vs. 82 +/- 24 mL/100 g/min, P < .05). Mean CBF values of MCI were comparable to AD. Across clinical groups, lower CBF was associated with lower scores on the Mini-Mental State Examination (age and sex adjusted stbeta = 0.19 per mL/100 g/min; P = .02). Discussion: Lower whole-brain CBF is seen in AD patients compared to SCD patients and is associated with worse cognitive function. PMID- 29234726 TI - Determinant of Implanon Discontinuation among Women Who Ever Used Implanon in Diguna Fango District, Wolayita Zone, Southern Ethiopia: A Community Based Case Control Study. AB - Background: A significant number of women make Implanon their first choice of contraception. However, they discontinue their Implanon before its expiry date was high, but factors that contribute to discontinuing their Implanon were poorly described in Ethiopia. Methods: A community based unmatched case control study was conducted. Then simple random sampling technique was used to select 340 women. Data was collected by nurses using face to face interview. Epi-Info version 7 and SPSS 20 software were used. Bivariate and multiple logistic regressions were performed with COR and AOR with 95% CI. Findings: Having preinsertion counseling (AOR: 0.36, 95% CI: 0.20-0.64), having follow-up appointment (AOR: 0.35, 95% CI: 0.2-0.62), age at insertion <20 years (AOR: 3, 95% CI: 1.16-7.8), women who had no formal education (AOR: 2.8, 95% CI: 1.31 6.11), women who had <=4 children (AOR: 1.8, 95% CI: 1.01-3.21), and women who had previous abortion history (AOR: 2.3, 95% CI: 1.10-4.63) were determinants of Implanon discontinuation. Conclusions: Policy makers and concerned bodies should take into account future intervention and also great emphasis should be given to follow-up appointment and counseling services, especially counseling on side effects, and informed choice for clients after Implanon insertion. PMID- 29234725 TI - Computerized cognitive training for older diabetic adults at risk of dementia: Study protocol for a randomized controlled trial. AB - Introduction: Older adults with type 2 diabetes are at high risk of cognitive decline and dementia and form an important target group for dementia risk reduction studies. Despite evidence that computerized cognitive training (CCT) may benefit cognitive performance in cognitively healthy older adults and those with mild cognitive impairment, whether CCT may benefit cognitive performance or improve disease self-management in older diabetic adults has not been studied to date. In addition, whether adaptive difficulty levels and tailoring of interventions to individuals' cognitive profile are superior to generic training remains to be established. Methods: Ninety community-dwelling older (age >= 65) diabetic adults are recruited and randomized into a tailored and adaptive computerized cognitive training condition or to a generic, nontailored, or adaptive CCT condition. Both groups complete an 8-week training program using the commercially available CogniFit program. The intervention is augmented by a range of behavior-change techniques, and participants in each condition are further randomized into a global or cognition-specific phone-based self-efficacy (SE) condition, or a no-SE condition. The primary outcome is global cognitive performance immediately after the intervention. Secondary outcomes include diabetes self-management, meta-memory, mood, and SE. Discussion: This pilot study is the first trial evaluating the potential benefits of home-based tailored and adaptive CCT in relation to cognitive and disease self-management in older diabetic adults. Methodological strengths of this trial include the double-blind design, the clear identification of the proposed active ingredients of the intervention, and the use of evidence-based behavior-change techniques. Results from this study will indicate whether CCT has the potential to lower the risk of diabetes-related cognitive decline. The outcomes of the trial will also advance our understanding of essential intervention parameters required to improve or maintain cognitive function and enhance disease self-management in this at-risk group. PMID- 29234728 TI - Nanocomposite capsules with directional, pulsed nanoparticle release. AB - The precise spatiotemporal delivery of nanoparticles from polymeric capsules is required for applications ranging from medicine to materials science. These capsules derive key performance aspects from their overall shape and dimensions, porosity, and internal microstructure. To this effect, microfluidics provide an exceptional platform for emulsification and subsequent capsule formation. However, facile and robust approaches for nanocomposite capsule fabrication, exhibiting triggered nanoparticle release, remain elusive because of the complex coupling of polymer-nanoparticle phase behavior, diffusion, phase inversion, and directional solidification. We investigate a model system of polyelectrolyte sodium poly(styrene sulfonate) and 22-nm colloidal silica and demonstrate a robust capsule morphology diagram, achieving a range of internal morphologies, including nucleated and bicontinuous microstructures, as well as isotropic and non-isotropic external shapes. Upon dissolution in water, we find that capsules formed with either neat polymers or neat nanoparticles dissolve rapidly and isotropically, whereas bicontinuous, hierarchical, composite capsules dissolve via directional pulses of nanoparticle clusters without disrupting the scaffold, with time scales tunable from seconds to hours. The versatility, facile assembly, and response of these nanocomposite capsules thus show great promise in precision delivery. PMID- 29234729 TI - A comprehensive study of eco-friendly natural pigment and its applications. AB - Actinomycetes, a large group of filamentous bacteria account for 70-80% of secondary metabolites available commercially. The present investigation was undertaken with an aim to identify and characterize pigment from actinomycetes. Actinomycetes were isolated from rhizosphere soil samples collected from different regions of Madhya Pradesh state. Out of 85 actinomycetes, only 5 actinomycetes showed pigment production and based on diffusible pigment production ability one actinomycete ARITM02 was selected. The extraction of pigment was done by solvent extraction method using methanol and purified by TLC and column chromatography. The pigment was characterized by UV-Vis spectroscopy which showed the lamda maximum of 277.44. FTIR spectroscopy suggested various functional groups like amino group, amide group, hydroxide, benzene and lactone group. The Mass spectroscopy and NMR spectroscopy showed that the molecular mass of pigment is 621.7 and molecular formula is C34H43N3O8. The pigment was also tested for Antimicrobial activity against broad spectrum human pathogens, antioxidant test and toxicity test for safe use as a natural colorant in cosmetic, food, pharmaceutical and textile industries. The conclusion of study suggested that this novel pigment could be a versatile natural, safe and multipurpose. PMID- 29234727 TI - The Dual Role of Bone Morphogenetic Proteins in Cancer. AB - Bone morphogenetic proteins (BMPs) are a diverse class of molecules with over 20 growth factor proteins that belong to the transforming growth factor-beta (TGF beta) family and are highly associated with bone formation and disease development. Aberrant expression of various BMPs has been reported in several cancer tissues. Biological function studies have elicited the dual role of BMPs in both cancer development and suppression. Furthermore, a variety of BMP antagonists, ligands, and receptors have been shown to reduce or enhance tumorigenesis and metastasis. Knockout mouse models of BMP signaling components have also revealed that the suppression of BMP signaling impairs cancer metastasis. Herein, we highlight the basic clinical background and involvement of BMPs in modulating cancer progression and their dynamic interactions (e.g., with microRNAs) in the tumor microenvironment in addition to their mutations and roles in chemoprevention. We also suggest that BMPs should be considered a powerful putative therapeutic target in tumorigenesis and bone metastasis. PMID- 29234730 TI - Spontaneous Superior Mesenteric Artery Branch Pseudoaneurysm: A Rare Case Report. AB - Background: Visceral arterial pseudoaneurysms (VAPAs) are rare vascular entities with serious consequences. Traditionally, they are associated with trauma, infection, and inflammatory disease, or they can arise as a post-operative complication. Report: An 87 year old man presented with abdominal pain and was found to have a spontaneous VAPA on a computed tomography angiogram. Serial imaging 4 months previously had demonstrated no aneurysm. Between scans, warfarin was changed to apixaban for aortic valve replacement, but he had no other changes to any other medications. He required urgent endovascular coiling of the pseudoaneurysm, with satisfactory recovery and outcome. Discussion: VAPAs are extremely rare, with splenic artery VAPAs the most commonly reported. Regardless, fewer than 250 cases of splenic artery pseudoaneurysm have been reported. Superior mesenteric artery (SMA) pseudoaneurysms are the rarest type of VAPAs. Early identification and urgent treatment are warranted because of the associated high mortality risk, with a 50% risk of rupture in any given VAPA. Treatment options range from open operation to endoscopic and endovascular procedures. Apixaban has been proposed to contribute to pseudoaneurysm formation by slow and continuous bleeding that results in the formation of the pseudoaneurysm. Conclusions: Spontaneous VAPAs are extremely rare and this is the first time a VAPA has been associated with the novel oral anticoagulant "apixaban". Urgent management of any VAPAs is important because of the high risk of rupture and potential life threatening haemorrhage. PMID- 29234731 TI - Endovascular "Intimal Flap Septostomy" for Safe Landing of a Stent Graft in an Anastomotic Pseudoaneurysm of Chronic Type B Aortic Dissection. AB - Objective/Background: The purpose of this report is to demonstrate a novel endovascular technique for gaining and producing the maximal landing zone for a thoracic stent graft in a patient with a chronic type B aortic dissection. Methods: The patient was a 64 year old man with chronic type B aortic dissection. He had developed acute type B aortic dissection and undergone descending thoracic replacement (Zone 2-Th10) 12 years earlier. During follow-up, he developed an anastomotic false aneurysm distally. In the initial operation, the distal anastomosis was performed with fenestration of the dissecting membrane. Computed tomography showed a pseudoaneurysm of 54 mm that was positioned 9 cm proximal to the coeliac artery. The landing zone was < 20 mm in the fenestrated area. At surgery, the true and false lumens were each cannulated from the femoral artery, and a pull through form was made just above the fenestrated flap. After the wire exchange, a 4 mm cutting balloon was positioned on the bottom of the flap, and the flap was gently sawed about 3.5 cm. Results: After stent graft placement no endoleak was observed. The patient was discharged without any complications. Conclusion: This technique was effective in producing a sufficient landing zone for endovascular aortic repair in a patient with an anastomotic pseudoaneurysm of chronic type B aortic dissection. PMID- 29234732 TI - Endovascular Aneurysm Repair (EVAR) of an Infrarenal Abdominal Aortic Aneurysm (AAA) in a Young Patient with Systemic Lupus Erythematosus (SLE). AB - Introduction: While hypertension, pericardial, myocardial, and coronary artery disease are common cardiovascular manifestations of systemic lupus erythematosus (SLE), aortic aneurysms (AA) are rare but increasingly diagnosed, with the true incidence unknown. Case report: A 40 year old female suffering from SLE with a 5.3 cm saccular eccentric infrarenal abdominal aortic aneurysm (AAA) was treated successfully with endovascular aneurysm repair (EVAR) using the Medtronic Endurant II bifurcated stent graft and followed up 2 years post-operatively. Pre operatively, open and EVAR options were offered and the latter was chosen by the patient. Discussion: Proposed mechanisms for AA formation in SLE including accelerated atherosclerosis brought about by chronic steroid use and SLE associated vasculitis and cystic medial degeneration (CMD) have been discussed in other case reports and series. To the authors' knowledge, the use of EVAR for AAA in SLE patients has not been reported in available literature. The need for earlier repair, screening, and detection as well as the long-term suitability, durability, and surveillance of EVAR remain unknown. The benefit of using the Ovation device in minimising late neck dilatation is also discussed. Conclusion: EVAR was demonstrated to be a suitable form of repair in a young female patient with SLE and AAA, followed up 2 years post-surgery. The ideal repair and the natural history of these aneurysms remains to be studied. PMID- 29234733 TI - Late Sterile Abscess Formation in Carotid Endarterectomy Following Use of BioGlue: A Word of Caution. AB - Introduction: BioGlue (CryoLife Inc., Kennesaw, GA) is a commonly used surgical adhesive, designed to achieve haemostasis following large vessel cardiovascular operations. Report: An 88-year-old female presents with an enlarging right sided neck mass 9 months after carotid endarterectomy with bovine pericardial patch repair which utilised BioGlue seal the patch suture line. Conclusion: BioGlue should be used properly and with caution. In cases of late wound complication following BioGlue use, simple drainage, debridement, and removal of BioGlue remnants may be a satisfactory approach. PMID- 29234734 TI - Endovascular Aneurysm Sealing for Management of Aortic Occlusive Disease. AB - Introduction: Endovascular management of aortic occlusive disease is an alternative to open surgery. This case describes the use of a Nellix graft to treat infrarenal aortic stenosis, outwith the graft indication for use. Case report: A 71 year old man with multiple comorbidities, presented with bilateral buttock claudication. A computed tomography angiogram (CTA) showed significant infrarenal aortic stenosis. Under local anaesthetic, using a percutaneous approach, Nellix grafts were inserted. The patient was discharged within 24 hours. His claudication improved significantly. A 6 month follow-up CT showed stent patency. Conclusion: Although further research is necessary, this case suggests that Nellix is safe and effective for primary stenting of the stenotic infrarenal aorta. PMID- 29234735 TI - The Case of the Neighbour's Cat Causing a Symptomatic (Mycotic) Aortic Aneurysm and an Infected Endograft. AB - Introduction: Aortic endograft infection is a rare but serious complication following endovascular aneurysm repair. An unusual presentation associated with an uncommon organism is reported. Case report: A 69 year old female was prescribed but failed to complete a full course of co-amoxiclav following a forearm cat bite. Nine days later she was admitted with pyrexia, left flank pain, and haematuria. Empiric treatment for a urinary tract infection was started. Pasteurella multocida was isolated from blood culture performed during this attendance. Imaging demonstrated hydronephrosis and a 5.5 cm aortic aneurysm with features of impending leak. Emergency endovascular repair was performed without immediate complication. Four weeks following stent graft insertion, the patient was readmitted with loss of consciousness. Imaging demonstrated an infected graft with an associated psoas abscess. The endograft was explanted and reconstruction performed with the femoral vein. Only at this point was the history of a cat bite and positive blood cultures elicited and recognised as relevant. Conclusion: Detailed history taking can expose unusual sources of infection. Ideally, an infected aortic endograft should be explanted and the septic focus eradicated prior to autogenous aortic reconstruction. PMID- 29234736 TI - Vein Patch Closure Using Below the Knee Greater Saphenous Vein for Femoral Endarterectomy Procedures is Not Always a Safe Choice. AB - Background: The complication of vein patch rupture is well described after carotid patch angioplasty; however, there is a paucity of data about the safety of vein patch closure in the setting of femoral endarterectomy. Methods/results: From May 2012 to May 2015, 115 femoral endarterectomies with patch closure were performed. A patch rupture occurred in three cases (2.6%) with a mortality rate of 66% (2/3). In all cases the greater saphenous vein below the knee was used as patch material. Discussion/conclusion: Vein patches, particularly from small calibre veins, should be excluded in femoral endarterectomy procedures as they pose a substantial risk of rupture. PMID- 29234737 TI - Hepatic toxicity assessment of cationic liposome exposure in healthy and chronic alcohol fed mice. AB - The utilisation of nanoparticles as the means of targeted delivery of therapeutics and/or imaging agents could greatly enhance the specific transport of biologically active payloads to target tissues while avoiding or reducing undesired side-effects. To allow for this to become a reality, the question of potential toxicological effects needs to be addressed. In the present investigation, a cationic liposome with prospective for medical applications was constructed and thoroughly assessed for any material-induced hepatic adverse effects in vivo - in healthy and alcoholic hepatic disease models and in vitro - (HepG2 cells). The data demonstrated that intravenous injection of liposomes did not cause any significant in vivo hepatic toxicity (inflammation, alterations in blood parameters, anti-oxidant depletion, acute phase response and histopathology) at doses of 200 MUg per mouse in either healthy or chronically alcohol fed mice. Additionally, the in vitro material-induced adverse effects (cytotoxicity, inflammation or albumin secretion) were all also minimal. The data from this study demonstrated that the intravenous injection of cationic liposomes does not cause hepatic toxicity. This investigation is important as it investigates the toxicity of a nano-sized material in a model of alcoholic hepatic disease in vitro and in vivo. This is an area of research in the field of nanotoxicology that is currently almost entirely overlooked. PMID- 29234738 TI - Redesigning axial-axial (biaxial) cruciform specimens for very high cycle fatigue ultrasonic testing machines. AB - The necessity to increase performances in terms of lifetime and security in mechanical components or structures is the motivation for intense research in fatigue. Applications range from aeronautics to medical devices. With the development of new materials, there is no longer a fatigue limit in the classical sense, where it was accepted that the fatigue limit is the stress level such that there is no fracture up to 1E7 cycles. The recent development of ultrasonic testing machines where frequencies can go as high as 20 kHz or over enabled tests to be extended to ranges larger than 1E9 in just a few days. This area of studies is now known as Very High Cycle Fatigue (VHCF). On the other hand, most of the existing test equipment in the market for both classical and VHCF are uniaxial test machines. However, critical components used in Engineering applications are usually subjected to complex multi-axial loading conditions. In this paper, it is presented the methodology to redesigning existing cruciform test specimens that can be used to create an in-plane biaxial state of stress when used in 'uniaxial' VHCF ultrasonic testing machines (in this case, the term 'uniaxial' is used not because of the state of stress created at the centre of the specimen, but because of the direction at which the load is applied). The methodology is explained in such a way that it can be expanded to other existing designs, namely cruciform designs, that are not yet used in VHCF. Also, although the approach is presented in simple and logical terms, it may not be that obvious for those who have a more focused approach on fatigue rather than on modal analysis. It is expected that by contributing to bridging the gap between the sciences of modal analysis and fatigue, this research will help and encourage others exploiting new capabilities in VHCF. PMID- 29234739 TI - Effects of cross-rearing with social peers on myelination in the medial prefrontal cortex of a mouse model with autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction, poor communication skills, and repetitive/restrictive behaviors. Recent studies have indicated that early rehabilitative intervention can alleviate the symptoms of individuals with ASD. However, it remains unknown whether rehabilitative intervention can restore brain structures such as myelin, which generally shows abnormalities in individuals with ASD. Therefore, in the present study, we used a mouse model of ASD (BTBR mice) that demonstrated asocial behaviors and hypomyelination in the medial prefrontal cortex (mPFC) to investigate whether interaction with social peers (C57BL/6J mice) has an effect on myelination. We found that housing with C57BL/6J mice after weaning through adulthood increased the myelin thickness in mPFC, but not in the motor cortex, of BTBR mice. There was no effect of cross-rearing with C57BL/6J mice on axon diameter in mPFC of BTBR mice. This finding suggests that early rehabilitative intervention may alleviate myelin abnormalities in mPFC as well as clinical symptoms in individuals with ASD. PMID- 29234740 TI - Gender influence on the number of roots and root canal system configuration in human permanent teeth of a Portuguese subpopulation. AB - OBJECTIVE: The aim of this study was to investigate in vivo, using cone beam computed tomography (CBCT), the differences between genders regarding the number of roots and root canal morphology. METHOD AND MATERIALS: An existing CBCT scan database was accessed and the scans were divided in two groups according to gender. Tooth inclusion and exclusion criteria were applied. The examined teeth were classified according to the number of roots, and the root canal system was classified according to Vertucci classification. Z-test for independent groups was used to detect differences between groups. RESULTS: In total, 12,325 teeth (4,597 from males and 7,728 from females) from 670 patients were analyzed. Females presented a lower number of roots per tooth in all groups of teeth, except for mandibular canine, the difference being statistically significant in the maxillary first premolar and both maxillary and mandibular second molars. Vertucci Type I configuration had a higher or equal prevalence in nine of the eleven groups of maxillary roots in females, with significance in both maxillary premolars. The same configuration was higher in females in five of the nine groups of mandibular roots, with significance in mandibular central incisor and first premolar. Eight of the nine root groups (maxillary and mandibular roots combined) that presented three-root canal system configurations, had a higher prevalence of that anatomy in males. CONCLUSION: Few differences were found between genders. It was possible to detect a lower number of roots per tooth and a higher number of Vertucci Type I configurations in females. The three-root canal system configurations were more common in males. PMID- 29234741 TI - Tooth hypersensitivity treatment trends among dental professionals. AB - OBJECTIVE: Tooth hypersensitivity is a common complaint of patients who present to the dental office. The aim of this study was to survey dental professionals in an effort to understand the current treatment trends for tooth hypersensitivity. METHOD AND MATERIALS: A questionnaire that addressed possible treatments for tooth hypersensitivity was developed and validated. The survey included a case presentation in which the responders were requested to list a first and second line of treatment. The questionnaire was distributed to dental professionals and analyzed statistically. RESULTS: A total of 106 questionnaires were collected. The most common first line treatments for tooth hypersensitivity included sensitivity toothpastes (38.7%) and desensitizers (40.6%). Referral for patients with tooth hypersensitivity was indicated by 12.0% of the responders. The most preferred products included sensitivity toothpaste (34.9%) and fluoride varnish (19.8%). In regards to the case presented in the survey, the most common first treatment recommendations for patients were to use a sensitivity toothpaste (37.7%), stop drinking cold water (13.2%), and apply a desensitizing agent (23.6%). Of the 106 responders, 7.5% would opt to graft the recession area and 29.2% would restore the area as the second line of treatment. CONCLUSION: This study suggests that more invasive treatment options such as grafting and restoring may be used too early in the treatment plan for tooth hypersensitivity. Providing continuing education programs that address simple and less aggressive or invasive modes of treatment will benefit patients and may also reduce the financial burden of the treatment. PMID- 29234742 TI - Tooth movement with elastic separators before ceramic veneer treatment: Rearranging asymmetric diastemas by managing the horizontal distance. AB - The treatment of diastemas should be conservative to preserve tooth structure, and porcelain veneers provide an esthetic solution with minimal tooth preparation. However, asymmetric diastemas can be difficult to treat and may require redistribution of spaces. Additionally, extensive proximal restorations may negatively impact periodontal health. Minor tooth movement with elastic separators can be used to redistribute the interdental spaces and provide space for the interdental papilla. The aim of this paper was to present a clinical treatment involving the movement of peg-shaped maxillary lateral incisors with elastic separators to rearrange the spaces of asymmetric diastemas, thereby managing the horizontal distance during rehabilitation of the smile with minimally invasive ceramic veneers. PMID- 29234744 TI - Editorial: Congratulations and thank you. PMID- 29234743 TI - Association of periodontal inflammation, systemic inflammation, and duration of menopausal years in postmenopausal women. AB - OBJECTIVE: The influence of menopause on vascular inflammation and systemic bone loss has been documented. The purpose of this cross-sectional study was to assess the periodontal status, high-sensitivity C-reactive protein (HsCRP) level, and estrogen level in women with early menopause and women with normal menopause. METHOD AND MATERIALS: A total of 103 participants comprising normal menopausal women (n = 53) and early menopausal women (n = 50) were examined. Periodontal parameters, anthropometric parameters, and metabolic parameters including serum levels of HsCRP and estrogen were recorded. RESULTS: Women with early menopause (age 49.02 +/- 2.70 years, postmenopausal period 5.86 +/- 2.48 years) had higher clinical attachment loss (CAL) and HsCRP along with increased sites with bleeding on probing (BOP) as compared with normal menopausal women (age 50.56 +/- 1.94 years; postmenopausal period 2.03 +/- 1.15). On partial correlation analysis after controlling for age, Plaque Index (PI), and body mass index (BMI), CAL correlated positively and significantly with HsCRP and duration of menopause (P = .000), and negatively with estradiol in pooled data. Multivariate linear regression analysis revealed that CAL (dependent variable) has significant association with HsCRP (P = .000, r2 = .343) and duration of menopause (P = .001, r2 = .343). Estrogen status also correlated with HsCRP. CONCLUSION: CAL and HsCRP were higher in women with early menopause. CAL was significantly correlated with postmenopausal period and HsCRP in the population studied. PMID- 29234746 TI - Short implants as an alternative to crestal sinus lift: a 3-year multicentre randomised controlled trial. AB - PURPOSE: To evaluate the efficacy of short (5 or 6 mm long) dental implants vs 10 mm or longer implants placed in crestally lifted sinuses. MATERIALS AND METHODS: Twenty partially edentulous patients with 5 to 7 mm of residual crestal height and at least 7 mm thickness below the maxillary sinuses as measured on computed tomography scans were randomised according to a parallel group design to receive either one to two 5 or 6 mm long implants (10 patients) or 10 mm long implants (10 patients) after crestal sinus lifting and grafting with anorganic bovine bone. Implants were left to heal submerged for 4 months and were loaded with reinforced acrylic provisional prostheses, replaced, after 4 months, by definitive provisionally cemented or screw-retained metal-ceramic or metal composite prostheses. Outcome measures were: prosthesis and implant failures, any complications, radiographic peri-implant marginal bone level changes, and patient's satisfaction assessed by blinded assessors, when possible. All patients were followed up to 3 years after loading. RESULTS: Two patients from the augmented group dropped out after the 1-year follow-up. No implant or prosthesis failure occurred. One short implant patient was affected by two complications vs one complication in the long implant group. There was no difference for patients experiencing complications between the two groups (difference in proportions = 0.03 %; 95%CI: -0.32 to 0.27; P = 1.000). Short implants lost 0.89 +/- 0.25 mm and long implants lost 1.08 +/- 0.29 mm of peri-implant marginal bone 3 years after loading, the difference between the two groups being not statistically significant (difference = -0.19 mm; 95%CI: -0.46 to 0.09; P = 0.165). All patients were fully or partially satisfied with function and fully satisfied with aesthetics. CONCLUSIONS: Both techniques achieved excellent results and no differences were observed between prostheses supported by one to two 5 or 6 mm long implants vs 10 mm long in posterior atrophic maxillae up to 3 years after loading; therefore it is up to clinicians to decide which procedure to use, although longer follow-ups with larger patient populations are needed to better understand if one of these procedures could be more effective in the long-term. Conflict of interest statement: this study was partially supported by Zimmer Biomet. However, data property belonged to the authors, and by no means did the manufacturer interfere with the conduct of the trial or the publication of its results. PMID- 29234745 TI - The influence of repeated abutment changes on peri-implant tissue stability: 3 year post-loading results from a multicentre randomised controlled trial. AB - PURPOSE: To evaluate the influence of at least three abutment disconnections in conventional loaded implants against placement of a definitive abutment in immediately non-occlusal loaded implants on hard and soft tissue changes. A secondary aim was to evaluate whether the presence of less than 2 mm of keratinised mucosa is associated with increased peri-implant marginal bone loss and soft tissue recessions. MATERIALS AND METHODS: Eighty patients requiring one single crown or one fixed partial prosthesis supported by a maximum of three implants were randomised, after implants were placed with more than 35 Ncm, according to a parallel group design to receive definitive abutments that were loaded immediately (definitive abutment or immediate loading group) or transmucosal abutments, which were delayed loaded after 3 months and removed at least three times: 1. At impression taking (3 months after implant placement); 2. When checking the zirconium core on titanium abutments at single crowns or the fitting the metal structure at prostheses supported by multiple implants; 3. At delivery of the definitive prostheses (repeated disconnection or conventional loading group). Patients were treated at four centres and each patient contributed to the study, with only one prosthesis followed for 3 years after initial loading. Outcome measures were: prosthesis failures, implant failures, complications, pink aesthetic score (PES), buccal recessions, patient satisfaction, peri-implant marginal bone level changes and height of the keratinised mucosa. RESULTS: Forty patients were randomly allocated to each group according to a parallel group design. Six patients from the definitive abutment group dropped out or died, and one left from the repeated disconnection group. One implant, from the repeated disconnection group, fractured (difference = 3%; CI 95%: -2%, 8%; P = 1). Four provisional crowns and one definitive single crown had to be remade because of poor fitting, and one definitive crown and one definitive prosthesis because of ceramic and implant fracture, respectively, in the repeated disconnection group vs one provisional prosthesis from the definitive abutment group due to frequent debondings (difference = 15%; CI 95%: 2%, 28%; P = 0.060). Five patients from the definitive abutment group and four patients from the repeated disconnection group were affected by complications (difference = 4%; CI 95%: -11%, 20%; P = 0.725). PES scores assessed at 3 years post-loading were 11.7 (standard deviation = 1.8) mm for the definitive abutment group and 11.3 (1.5) mm for the repeated abutment changes group (difference = 0.4; CI 95%: -0.4, 1.2; P = 0.315). However, there was a difference of 0.26 out of a maximum score of 2 in favour of the definitive abutment group for soft tissue contour only. Buccal recessions at 3 years post-loading amounted to -0.1 (0.8) mm for the definitive abutment group and -0.1 (1.2) mm for the repeated abutment changes group (it was actually a soft tissue gain; difference = 0.01 mm CI 95%: -0.48, 0.50; P = 0.965). All patients declared being very satisfied or satisfied with the function and aesthetics of the prostheses and said they would undergo the same procedure again, with the exception of one patient from the repeated disconnection group who was uncertain regarding function. Mean peri implant marginal bone loss 3 years after loading was 0.07 (0.18) mm for the definitive abutment group and 0.50 (0.93) mm for the repeated abutment changes group (difference = 0.43 mm; CI 95%: 0.13, 0.74; P = 0.007). The height of keratinised mucosa at 3 years post-loading was 2.8 (1.3) mm for the definitive abutment group and 2.8 (1.6) mm for the repeated abutment changes group (difference = 0.03; CI 95%: -0.67, 0.73; P = .926). Up to 3 years after initial loading there were no statistically significant differences between the two procedures, with the exception of 0.4 mm more marginal bone loss at implants subjected to three abutment disconnections. There were no significantly increased marginal bone loss (difference = 0.1 mm, CI 95%: -0.3, 0.5, P = 0.590) or buccal recessions (difference = 0.1 mm, CI 95%: -0.4, 0.7, P = 0.674) at implants with less than 2 mm of keratinised mucosa at loading. CONCLUSIONS: Three-year post loading data showed that repeated abutment disconnections significantly increased bone loss of 0.43 mm, but this difference may not be considered clinically relevant; therefore clinicians can use the procedure they find more convenient for each specific patient. Immediately non-occlusally loaded dental implants are a viable alternative to conventional loading and no increased bone loss or buccal recessions were noticed at implants with less than 2 mm of keratinised mucosa. Conflict of interest statement: This trial was partially funded by Dentsply Sirona Implants, the manufacturer of the implants and other products evaluated in this investigation. However, data belonged to the authors and by no means did the manufacturer interfere with the conduct of the trial or the publication of the results, with the exception of rejecting a proposal to change the protocol, after the trial was started, allowing the use of indexed abutments. PMID- 29234747 TI - Flapless vs flapped implant insertion in patients with controlled type 2 diabetes subjected to delayed loading: 1-year follow-up results from a randomised controlled trial. AB - PURPOSE: To compare the outcome of dental implants placed following full thickness flap surgery with flapless surgery in controlled type 2 diabetic patients. MATERIALS AND METHODS: A total of 92 controlled type 2 diabetic patients, who needed missing mandibular first molars to be replaced by implants, were selected for a single-centre, parallel group, double-blinded randomised controlled trial. Patients were randomly allocated into two groups: flap (46 patients) vs flapless (46 patients) implant placement. Implants were loaded with metal-ceramic crowns, 4 months after placement in both groups. OUTCOME MEASURES: Implant and crown success, complications, post-operative pain and swelling, plaque index, sulcular bleeding index, pocket depth and HbA1c level. Follow up examinations were made after 24 h, and on the third and seventh days for soft tissue healing, pain and swelling evaluation; then at 6 months and 12 months (after loading) for dental plaque, sulcular bleeding, pocket depth, and HbA1c level evaluation. RESULTS: After 16 months of implant placement, no dropouts occurred. Five implants failed, two in the flap group and three in the flapless group (4.34% vs 6.52%, McNemar test P = 1, difference = 0.4457, 95% CI of difference = 4.554 to 47.234). Seven prosthesis failures occurred, three in the flap group and four in the flapless group (McNemar test P = 1; difference = 0.4239; 95% CI of difference = 29.95 to 3.86). Two patients in each group were affected by complications. There were statistically insignificant differences in the incidence of complications between the groups (McNemar test P = 1; difference = 0.457; 95% CI of difference = 90.75 to 5.33). After 24 h, the flapped group patients showed significantly greater pain compared with the flapless group (24 h: P = 0.017, difference = 0.37 and 95% CI = 0.673 to -0.067). After the third and seventh postoperative days, the mean pain level in both groups decreased linearly after the treatments (third day: P = 0.183, difference = 0.19 and 95% CI = -0.472 to 0.092; seventh day: P = 0.225, difference = 0.09 and 95% CI = -0.237 to 0.056). The frequency of post-operative swelling "some + a lot" at the third day was significantly higher in the full thickness flap group compared with the flapless group (P = 0.002, difference = 0.1835 and 95% CI = -0.0409 to 0.4079). Most of the cases in either of the study groups demonstrated no swelling (P =1.00, difference = 0.00 and 95% CI = -0.3034 to 0.3034) on the seventh post operative day. The mean plaque index (6 months: 1.00 +/- 0.47 vs 0.83 +/- 0.79, P = 0.230, difference = 0.17 and 95% CI = -0.450 to 0.110 and 12 months: 1.30 +/- 0.67 vs 1.04 +/- 0.86, P = 0.123, difference = 0.26 and 95% CI = 0.593 to 0.073), mean sulcular bleeding index (6 months: 1.40 +/- 0.52 vs 1.04 +/- 0.83, P = 0.018, difference = 0.36 and 95% CI = 0.658 to 0.062 and 12 months: 1.90 +/- 0.48 vs 1.17 +/- 0.57, P = < 0.001, difference = -0.73 and 95% CI = -0.958 to -0.503) and pocket depth (6 months: 1.30 +/- 0.26 vs 1.17 +/- 0.25, P = 0.021, difference = -0.13 and 95% CI = - 0.240 to- 0.012 and 12 months: 1.95 +/- 0.28 vs 1.56 +/- 0.17, P = < 0.001, difference = -0.39 and 95% CI = -0.490 to -0.290) in both groups increased after the treatment and the increase was evident higher in full thickness flap group than flapless group. CONCLUSIONS: On the basis of these results, it was concluded that flapless surgical technique could be considered for dental implant placement in type 2 diabetic patients to reduce post-operative pain and swelling. PMID- 29234748 TI - Early loading of maxillary titanium implants with a nanostructured calcium incorporated surface (Xpeed): 5-year results from a multicentre randomised controlled trial. AB - PURPOSE: To evaluate clinical safety and effectiveness of a novel calcium incorporated titanium implant (Xpeed, MegaGen Implant Co. Limited, Gyeongbuk, South Korea). MATERIALS AND METHODS: In total, 60 patients were randomised to receive one to six titanium implants in the maxilla with either calcium incorporated (Xpeed) or control resorbable blasted media (RBM) surfaces, according to a parallel group design at two centres. Implants were submerged and exposed at three different endpoints in equal groups of 20 patients at 12, 10 and 8 weeks, respectively. Within 2 weeks, implants were functionally loaded with provisional or definitive prostheses. Outcome measures were prosthesis failures, implant failures, any complications and peri-implant marginal bone level changes. RESULTS: A total of 30 patients received 45 calcium-incorporated implants and 30 patients were given 42 control titanium implants. Five years after loading, eight patients dropped-out from the Xpeed group and nine left the RBM group. No prosthesis or implant failures occurred. Two patients were affected by three complications in the Xpeed group vs five patients from the RBM group, who experienced eight complications; the difference between groups being not statistically significant different (P = 0.187; difference in proportions = 14.7%; 95% CI: -10.7% to 39.4%). Five years after loading patients with Xpeed implants lost on average 1.19 +/- 0.48 mm of peri-implant marginal bone vs 1.43 +/- 0.98 mm of patients with RBM implants, the difference being not statistically significant (P = 0.35; mean difference: -0.23 mm; 95% CI: -0.73 to 0.27 mm). CONCLUSIONS: Both implant surfaces provided good clinical results and no significant difference was found when comparing titanium implants with a nanostructured calcium-incorporated surface with implants with an RBM surface. Conflict-of-interest statement: MegaGen partially supported this trial and donated the implants and prosthetic components. The study design was negotiated with MegaGen Implant Co, Gyeongbuk, South Korea, however, data property belonged to the authors and by no means did MegaGen interfere with the conduct of the trial or the publication of its results. PMID- 29234750 TI - Intraoral radiography lacks accuracy for the assessment of peri-implant bone level - a controlled clinical study. AB - PURPOSE: The aim of this study was to compare clinical and radiographic bone level assessments to intra-surgical bone level registration around implants with peri-implantitis and to identify the clinical variables rendering peri-implant bone level assessment accuracy. MATERIALS AND METHODS: The study sample included 50 implants with peri-implantitis in 23 patients. Registration methods included probing of the vertical distance between the implant/abutment interface and the bottom of the pocket (= VPD), intraoral radiography, bone sounding without flap elevation and intra-surgically assessed interproximal bone level. The latter was considered the true bone level (gold standard). Twenty clinicians evaluated all radiographs. RESULTS: VPD and intraoral radiography resulted in a significant underestimation of the true bone level by 1.0 mm (95% CI: 0.495-1.585; P < 0.001) and 2.3 mm (95% CI: 1.650-2.980; P < 0.013) respectively. Bone sounding without flap elevation did not differ significantly from the true bone level (mean difference 0.2 mm; 95% CI: -0.775 - 0.335; P = 0.429). Duplicate magnification registration of 50 implants resulted in excellent intra- and inter-rater reliability (ICC intra <= 0.99; ICC inter = 0.964; P < 0.001). Radiographic underestimation was significantly affected by defect depth (P < 0.001). Variation among clinicians was substantial (mean underestimation range 1.1 mm to 3.8 mm); however, clinical experience had no impact on radiographic underestimation (P = 0.796). CONCLUSIONS: Bone sounding without flap elevation was the best predictor of peri-implant bone level, whereas intraoral radiography was the most inferior. Consequently, peri-implantitis may be under-diagnosed if examination is only based on radiographs. Conflict-of-interest statement: Prof Hugo De Bruyn is associated with education and research collaboration agreements with Dentsply Sirona and Southern Implants, on behalf of Ghent University. Prof Cosyn has a collaboration agreement with Nobel Biocare. All other authors declare that they have no conflict of interest. PMID- 29234749 TI - Sinus lift grafting with anorganic bovine bone vs 50% autologous bone mixed with 50% anorganic bovine bone: 2 years after loading results from a randomised controlled trial. AB - PURPOSE: To compare the outcome of implants inserted in maxillary sinuses augmented with anorganic bovine bone (ABB) grafts vs mixed 50% ABB and 50% autologous bone graft, using a lateral window approach. MATERIALS AND METHODS: This study was designed as a randomised controlled trial of parallel groups. Patients in need of an implant-supported prosthesis in a maxillary posterior area with a residual alveolar bone height no greater than 4 mm (range 0-4 mm) were recruited for lateral sinus grafting. Patients were randomly allocated to receive 50% ABB and 50% autogenous bone (group A) or 100% ABB (group B). After 7 months, tapered implants were inserted with an insertion torque between 20 and 45 Ncm. After 3 months, implants were loaded with screw-retained temporary crowns. Definitive crowns were delivered 3 months later. Outcome measures were implant survival, complications, radiographic marginal bone-level changes, probing pocket depths (PPD) and bleeding on probing (BOP). Clinical data were collected at definitive prosthesis delivery, 1 and 2 years after loading. RESULTS: Thirty-two consecutive patients were treated with 32 sinus lift procedures (16 group A, 16 group B). A total of 46 implants were installed. No patient dropped out. No crown/implant failed by the end of the study. Three complications (one sinus membrane perforation and two chipping of the ceramic) were observed in three patients in group A, vs none in group B (RR 0.81; 95% CI 0.64 - 1.03 mm; P = 0.225). At the 2-year after final loading follow-up, the mean marginal bone loss was 1.18 +/- 0.50 mm (95% CI 0.95 - 1.45 mm) in group A and 1.28 +/- 0.48 mm (95% CI 0.97 - 1.43 mm) in group B, with no statistically significant differences between the two groups (difference 0.11 +/- 0.22 mm; 95% CI -0.06 - 0.16 mm; P = 0.586). At the same follow-up, the mean PPD value was 2.70 +/- 0.39 for group A and 2.54 +/- 0.66 for group B, with no statistically significant difference between groups (difference 0.17 +/- 0.39 mm; 95% CI 0.06 - 0.32 mm; P = 0.456), while the mean BOP value was 1.21 +/- 0.79 for group A and 1.28 +/- 0.68 for group B, (difference: 0.06 +/- 0.49 mm; 95% CI -0.23 - 0.25 mm; P = 0.297). CONCLUSIONS: Within the limitations of this study, the present data seem to confirm the hypothesis that the clinical outcome of implants inserted in sinuses grafted with ABB vs implants inserted in sinuses grafted with mixed 50% ABB and 50% autologous bone are comparable. Conflict-of-interest statement: This study was not supported by any company. All the authors declare no conflict of interest. PMID- 29234751 TI - Influence of horizontal dimensions around single gap and adjacent zirconia implants on the papilla - a cross-sectional survey. AB - PURPOSE: To evaluate a possible association between the inter-implant distance and the papilla deficit. Additionally, the effect of high or low contact points of the crowns on the papilla deficit was investigated. MATERIALS AND METHODS: Periapical radiographs taken 1 year after loading were used to assess the distance from the shoulder of the implant to the adjacent tooth or implant. On the clinical images, the interdental papilla height, soft tissue deficit and crown length were evaluated. The papilla crown proportion and the proportion of the height of the contact point to the crown length were assessed. RESULTS: Eighty-one patients, with a total of 104 zirconia implants and 208 measurements were involved in this cross-sectional survey. Considering patient means, the correlation between the papilla deficit and the interproximal distance, respectively inter-implant distance, was very low (r = -0.05220; P = 0.6435, N = 81). Logistic regression at implant-level showed that there was no significant difference in the likelihood for a papilla deficit between a high and a low contact point of the crowns with P = 0.8191 (Odds ratio: 1.106 with 95%CI 0.461; 2.654). CONCLUSIONS: Horizontal interproximal dimensions around zirconia implants showed very weak influence on the papilla height. A high or a low contact point position of the crowns did not affect the papilla deficit. Conflict of Interest and sources of funding: All authors reported no conflict of interest. There were no sources of funding for the research. PMID- 29234753 TI - Research in focus. AB - This section presents a brief review of articles on dental implants considered of special interest for the reader, in order to encourage the development of research, the interest for data analysis and the attention to scientific publications. Your comments are welcome. Please contact Dr Michele Nieri at michelenieri@gmail.com. PMID- 29234752 TI - Morphological and immunophenotypical differences between chronic periodontitis and peri-implantitis - a cross-sectional study. AB - PURPOSE: To examine differences in morphology and in immunophenotype subsets between chronic periodontitis (CP) and peri-implantitis (P-I) lesions and to test the diagnostic agreement (CP vs P-I) among three independent observers, based on histopathological features. MATERIALS AND METHODS: This observational cross sectional study included 15 gingival biopsies of CP lesions and 15 biopsies of P I lesions for double-blinded examination by three independent pathologists. Inflammatory infiltrate intensity was assessed semiquantitatively on a 4-point scale, determining the percentage of lymphocytes, plasma cells, monocytes/macrophages, and granulocytes and the presence/absence of bacterial colonies. Immunohistochemical analyses were performed to verify the inflammatory infiltrate subset data (CD45, CD38, CD68 and myeloperoxidase [MPO]-positive), and number of vessels. Kappa statistic was used to evaluate the degree of diagnostic concordance among examiners. RESULTS: Inflammatory infiltrate was significantly more severe in P-I cases (P = 0.01), which showed a significantly higher percentage of plasma cells (P = 0.004) than in CP cases. Immunohistochemically, the percentage of leukocyte subsets was generally lower in CP (CD38: 32.05%; CD68: 6.45% and MPO: 8.62%) than in P-I (CD38: 61.13%; CD68: 9.09% and MPO: 7.47%) (CD38 P = 0.001, P = 0.955 and P = 0.463, for remaining subsets, respectively; Mann-Whitney U-test). The inter-observer diagnostic agreement was poor or slight (kappa = -0.18 to 0.13). CONCLUSIONS: Despite the significantly more severe general inflammatory infiltrate and plasma cells in P-I cases, it proved difficult to detect reliable differential morphological features based on histopathological images of these CP and P-I soft-tissue samples, obtaining low inter-observer and intra-observer diagnostic agreement. Conflict of interest statement: This investigation was partially supported by Research Groups #CTS-138 and #CTS-583 (Junta de Andalucia, Spain). No conflict of interest. PMID- 29234754 TI - Durability of Resin Bonding to Lithium Disilicate and Zirconia Ceramic using a Self-etching Primer. AB - PURPOSE: The purpose of this in vitro study was twofold: 1. To evaluate the surface conditioning effect of a self-etching ceramic primer on lithium disilicate and zirconia ceramics; (2) to study the bond durability provided by the self-etching ceramic primer after artificial aging compared with conventional ceramic conditioning methods. MATERIALS AND METHODS: Lithium disilicate blocks (10 * 10 mm, 3.4 mm thick) and zirconia disks (8 mm diameter, 3.4 mm thick) were each divided into two groups. In group 1, the lithium disilicate disks (Li) were etched with hydrofluoric acid (HF), while zirconia (Zr) disks were treated with airborne-particle abrasion, both followed by application of a universal primer for restorative materials (MP; Monobond Plus, Ivoclar Vivadent). In group 2, Li disks were not etched with HF, while Zr disks were treated with airborne-particle abrasion, both followed by a self-etching primer (ME; Monobond Etch & Prime, Ivoclar Vivadent). Surface conditioning effects were evaluated using SEM. The specimens in both groups were bonded to a composite with a luting resin and divided into two subgroups. Subgroup 1 was stored in water (37 degrees C) for 3 days, and subgroup 2 was stored in water for 30 days before undergoing 7500 thermal cycles (5 degrees C to 55 degrees C). RESULTS: The self-etching ceramic primer had a significant effect only on the lithium disilicate surface topography. The mean initial bond strength of ME-Zr was relatively low (24.4 MPa) in comparison with all other material combinations (MP-Li: 34.3 MPa; ME-Li: 33.5 MPa; MP-Zr: 31.1 MPa). After 30 days of water storage and thermocycling, the bond strength decreased significantly in all groups. CONCLUSION: The self-etching primer provided bond strengths to lithium disilicate ceramic comparable with those of the well-established bonding method using hydrofluoric acid etching and a primer containing silane. To zirconia ceramic, however, it provided statistically significantly lower bond strength than did the established bonding method. PMID- 29234755 TI - Self-Etching Enamel Bonding Using Acidic Functional Monomers with Different length Carbon Chains and Hydrophilicity. AB - PURPOSE: To compare the enamel bonding performace of two commercial and three experimental two-step self-etch adhesives containing acidic functional monomers with different carbon-spacer length and hydrophilicity. The contact angle was also assessed to evaluate the wettability of each tested material. MATERIALS AND METHODS: Forty extracted human molars were sectioned into four parts (buccal, lingual, mesial, and distal) and divided into 5 groups, according to the adhesives used: Clearfil SE Bond (CSE), AdheSE (ADSE), 10-MDP (15 mol% 10 methacryloyldecylphosphate), CAP-P (15 mol% caprolactone phosphate), and MTEP (15 mol% methacryloyltetraethylene phosphate). Enamel specimens were bonded with each adhesive and submitted to microshear bond strength (MUSBS) testing after 24 h. The adhesives were applied onto additional enamel specimens without light curing to assess contact angle. Then the etching pattern was analyzed using SEM and confocal laser scanning microscopy (CLSM). The MUSBS and contact angle data were analyzed by one-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: 10-MDP showed the highest MUSBS of the tested groups (p < 0.05), followed by CAP-P and CSE (p < 0.05). MTEP and ADSE exhibited the lowest MUSBS (p < 0.05), but the difference between them was not significant. 10-MDP, CSE, and CAP-P exhibited lower contact angles (p < 0.05) than did ADSE and MTEP. The SEM and CLSM analyses showed that 10-MDP and CSE had the most pronounced etching patterns and deepest adhesive penetration. ADSE and MTEP exhibited weak etching ability and adhesive penetration, while CAP-P produced moderate etching and intermediate penetration. CONCLUSIONS: The length and hydrophilicity of the functional monomer spacer chain tested in this study influenced the enamel bonding performance. Functional monomers with longer chains and more hydrophobic properties, such as 10-MDP and CAP-P, may interact better with enamel and achieve higher enamel bond strength. PMID- 29234756 TI - Photon-mediated hybridization of molecular vibrational states. AB - Light-matter strong coupling is a promising route toward the modification of chemical and physical properties of molecules without formally changing their constituent atoms, bonds, or geometry. The photon-mediated hybridization of vibrational modes of two different molecules simultaneously dissolved in solution is demonstrated in a solution of hexacyanocobaltate(iii) and hexacyanoferrate(ii) ions. The formation of polaritons with tunable contributions from the bonds of each molecule is shown to be feasible within practical concentration ranges for cavity controlled chemistry. The resulting modified energy landscape of the two coupled molecules may have interesting effects on chemical processes. PMID- 29234757 TI - Water facilitates oxygen migration on gold surfaces. AB - The water-oxygen-gold interface is important in many surface processes and has potential influence on heterogeneous catalysis. Herein, it is shown that water facilitates the migration of atomic oxygen on Au(110), demonstrating the dynamic nature of surface adsorption. We demonstrate this effect for the first time, using in situ scanning tunnelling microscopy (STM), temperature-programmed reaction spectroscopy (TPRS) and first-principles theoretical calculations. The dynamic interaction of water with adsorbed O maintains a high dispersion of O on the surface, potentially creating reactive transient species. At low temperature and pressure, isotopic experiments show that adsorbed oxygen on the Au(110) surface exchanges with oxygen in H218O. The presence of water modulates local electronic properties and facilitates oxygen exchange. Combining experimental results and theory, we propose that hydroxyl is transiently formed via proton transfer from the water to adsorbed oxygen. Hydroxyl groups easily recombine to regenerate water and adsorbed oxygen atoms, the net result of which is migration of the adsorbed oxygen without significant change in its overall distribution on the surface. The presence of water creates a dynamic surface where mobile surface oxygen atoms and hydroxyls are present, which can lead to a better performance of gold catalysis in oxidation reactions. PMID- 29234758 TI - Polymorphism of griseofulvin: concomitant crystallization from the melt and a single crystal structure of a metastable polymorph with anomalously large thermal expansion. AB - Griseofulvin (GSF) is a classic antifungal drug that has been in clinical use for over 50 years, but its polymorphism was recognized only recently via melt crystallization. Here we report the structure of a single crystal of GSF form II which was unusually harvested from the supercooled melt. GSF form II exhibits an anomalously large thermal expansion coefficient. PMID- 29234759 TI - A SIMS study of cation and anion diffusion in tantalum oxide. AB - Ion transport in ceramics of the low-temperature phase of tantalum pentoxide, L Ta2O5, was examined by means of diffusion experiments and subsequent analysis of diffusion profiles with time-of-flight secondary ion mass spectrometry (ToF SIMS). 18O/16O isotope anneals were used to investigate oxygen diffusion, and oxygen tracer diffusion coefficients were obtained for the temperature range of 623 <= T/K <= 873 at an oxygen partial pressure of pO2 = 0.2 bar and for the oxygen partial pressure range of 10-2 <= pO2/bar <= 100 at a temperature of T = 723 K. Cation diffusion in Ta2O5 was probed by using chemically similar niobium as the diffusant (in the absence of stable tantalum isotopes). Thin films of Nb2O5 were deposited onto Ta2O5 ceramics; diffusion anneals yielded niobium diffusion coefficients for the temperature range of 1073 <= T/K <= 1223 at an oxygen partial pressure of pO2 = 0.2 bar. Comparison of the measured diffusion coefficients strongly suggests that oxygen is many orders of magnitude more mobile than niobium in L-Ta2O5 at these temperatures and at pO2 = 0.2 bar. The electrical conductivity was also determined in the range 950 <= T/K <= 1200 and 10-23 <= pO2/bar <= 10-2. Considered together with the measured diffusion coefficients, the conductivity data indicate that under oxidising conditions conduction is due to oxygen ions above T = 1090-1130 K and due to electron holes below this temperature range. Point-defect models are presented that are consistent with these transport data and with conductivity data in the literature. They suggest that under oxidising conditions oxygen interstitials are the majority ionic charge carriers in L-Ta2O5. The implications for resistive switching devices are discussed. PMID- 29234760 TI - Fast selective trapping and release of picoliter droplets in a 3D microfluidic PDMS multi-trap system with bubbles. AB - The selective manipulation and incubation of individual picoliter drops in high throughput droplet based microfluidic devices still remains challenging. We used a surface acoustic wave (SAW) to induce a bubble in a 3D designed multi-trap polydimethylsiloxane (PDMS) device to manipulate multiple droplets and demonstrate the selection, incubation and on-demand release of aqueous droplets from a continuous oil flow. By controlling the position of the acoustic actuation, individual droplets are addressed and selectively released from a droplet stream of 460 drops per s. A complete trapping and releasing cycle can be as short as 70 ms and has no upper limit for incubation time. We characterize the fluidic function of the hybrid device in terms of electric power, pulse duration and acoustic path. PMID- 29234761 TI - A density functional theory study of aldehydes and their atmospheric products participating in nucleation. AB - Aldehydes have been speculated as important precursor species in the formation of new atmospheric particles. In the present work, quantum chemical calculations were performed to investigate the hydrogen bonding interaction and the Gibbs free energy of formation (DeltaG) for clusters consisting of sulfuric acid and aldehydes as well as their atmospheric reaction products. Calculations were conducted at 298 K and 1 atm at the M06-2X/6-311+G(3df,3pd) level. The results show that the addition of aldehyde compounds to H2SO4 unlikely contributes to new particle formation. However, their products from aldol condensation, hydration, and polymerization reactions can promote new particle formation by stabilizing sulfuric acid in the first step of nucleation. Moreover, the favorability of the interaction in the absence of water between sulfuric acid and the addition products is as follows: the hydration products > aldol condensation > aldehydes, but the results may be changed if water molecules are added. In particular, the calculated DeltaG values imply that the monohydrate of glyoxal is more likely to nucleate with H2SO4 in comparison with ammonia in the presence or absence of water. PMID- 29234762 TI - Electronic and magnetic properties of monolayer alpha-RuCl3: a first-principles and Monte Carlo study. AB - Recent experiments revealed that monolayer alpha-RuCl3 can be obtained by a chemical exfoliation method and exfoliation or restacking of nanosheets can manipulate the magnetic properties of the materials. In this paper, the electronic and magnetic properties of an alpha-RuCl3 monolayer are investigated by combining first-principles calculations and Monte Carlo simulations. From first-principles calculations, we found that the spin configuration of FM corresponds to the ground state for alpha-RuCl3, however, the other excited zigzag oriented spin configuration has an energy of 5 meV per atom higher than the ground state. The energy band gap is found to be 3 meV using PBE functionals. When the spin-orbit coupling effect is taken into account, the corresponding energy gap is determined to be 57 meV. We also investigate the effect of the Hubbard U energy terms on the electronic band structure of the alpha-RuCl3 monolayer and revealed that the band gap increases approximately linearly with increasing U value. Moreover, spin-spin coupling terms (J1, J2, and J3) have been obtained using first-principles calculations. By benefiting from these terms, Monte Carlo simulations with a single site update Metropolis algorithm have been implemented to elucidate the magnetic properties of the considered system. Thermal variations of magnetization, susceptibility and also specific heat curves indicate that monolayer alpha-RuCl3 exhibits a phase transition between ordered and disordered phases at the Curie temperature of 14.21 K. We believe that this study can be utilized to improve two-dimensional magnetic materials. PMID- 29234768 TI - 3D-Printed seed planter and well array for high-throughput seed germination screening. AB - Seed germination is an important means of evaluating seed quality. In the present study, a well array for a seed germination experiment was designed and fabricated by 3D printing for the first time. Each hollow cone-shaped well can hold one seed, which not only prevented the seed from falling out of the well but also ensured that part of the seed was fully exposed to the sublayer of wet filter paper, allowing it to receive water for germination. Coupled with a 3D-printed seed planter, single seeds can be quickly placed into arrayed wells. Moreover, the number of sprouts could be automatically obtained from image analysis, which greatly improved the efficiency of the entire experiment. In summary, the high throughput, easy-to-use seed germination well array that we have developed has been shown to have potential applications in botanical seed research and agricultural production. PMID- 29234769 TI - Boosting the efficiency of inverted quantum dot light-emitting diodes by balancing charge densities and suppressing exciton quenching through band alignment. AB - We report an inverted and multilayer quantum dot light emitting diode (QLED) which boosts high efficiency by tuning the energy band alignment between charge transport and light emitting layers. The electron transport layer (ETL) was ZnO nanoparticles (NPs) with an optimized doping concentration of cesium azide (CsN3) to effectively reduce electron flow and balance charge injection. This is by virtue of a 0.27 eV upshift of the ETL's conduction band edge, which inhibits the quenching of excitons and preserves the superior emissive properties of the quantum dots due to the insulating characteristics of CsN3. The demonstrated QLED exhibits a peak current efficiency, power efficiency and external quantum efficiency of up to 13.5 cd A-1, 10.6 lm W-1 and 13.4% for the red QLED, and correspondingly 43.1 cd A-1, 33.6 lm W-1 and 9.1% for green, and 4.1 cd A-1, 2.0 lm W-1 and 6.6% for the blue counterparts. Compared with QLEDs without optimization, the performance of these modified devices shows drastic improvement by 95.6%, 39.4% and 36.7%, respectively. This novel device architecture with heterogeneous energy levels reported here offers a new design strategy for next generation high efficiency QLED displays and solid-state lighting technologies. PMID- 29234770 TI - Synthesis and structural investigation of a series of mannose-containing oligosaccharides using mass spectrometry. AB - A series of compounds associated with naturally occurring and biologically relevant glycans consisting of alpha-mannosides were prepared and analyzed using collision-induced dissociation (CID), energy-resolved mass spectrometry (ERMS), and 1H nuclear magnetic resonance spectroscopy. The CID experiments of sodiated species of disaccharides and ERMS experiments revealed that the order of stability of mannosyl linkages was as follows: 6-linked > 4-linked ? 2-linked > 3 linked mannosyl residues. Analysis of linear trisaccharides revealed that the order observed in disaccharides could be applied to higher glycans. A branched trisaccharide showed a distinct dissociation pattern with two constituting disaccharide ions. The estimation of the content of this ion mixture was possible using the disaccharide spectra. The hydrolysis of mannose linkages at 3- and 6 positions in the branched trisaccharide revealed that the 3-linkage was cleaved twice as fast as the 6-linkage. It was observed that the solution-phase hydrolysis and gas-phase dissociation have similar energetics. PMID- 29234771 TI - Thinking about Cognitive Frailty. PMID- 29234772 TI - Memory Brought to Mind. Five-Year Follow-Up of Case Finding and Intervention of Dementia in a Swedish Primary Health Care District. AB - BACKGROUND: In an urban/rural primary health care (PHC) district a five-year integrated project of early detection and management of cognitive disorders was made in collaboration between home care (HC) and family practice services using a single-item case-finding and intervention approach. OBJECTIVES: To assess feasibility, outcome and morbidity over a 5-year period. DESIGN, SETTING AND PARTICIPANT: In autumn 2008, the question "Have you experienced memory difficulties or been told of them by family members?" was mailed to all eligible persons > 75 years of age (n=367) in the urban/rural Valberg HC and PHC district (population = 5073). 320 (= 87%; 184 no and 136 yes) responded and 117 yes responders came for further examination. In the follow-up, all diagnoses up till November 2013 were collected and compared anonymously in both yes and no answerers. RESULTS: 114 completed examination. 29 showed low risk of cognitive impairment, 39 moderate and 46 high. Definitive diagnosis was obtained in 34 of the latter: 10 cognitive impairment, 16 Alzheimer's disease, 5 non-specific, 2 vascular and 1 alcoholic dementia. During follow-up no further dementia diagnoses occurred in the low, two in the moderate, and none in the high-risk group, versus 12 in the no responders. Age and mortality were significantly higher in the high risk group. Co-morbidity was very frequent but did not differ between the groups. CONCLUSIONS: Population response and compliance were excellent; the single-item direct question approach gave workable results with in particular high negative predictive power persisting over the five-year follow-up period, and can be applied in early case-finding, prevention and intervention of cognitive impairment in an integrated local HC, PHC and Hospital setting. PMID- 29234773 TI - Effect of Punicalagin and Resveratrol on Methionine Sulfoxide Reductase: A Possible Protective Contribution against Alzheimer's Disease. AB - Methionine sulfoxide reductase A (MsrA) has been postulated to act as a catalytic antioxidant system involved in the protection of oxidative stress-induced cell injury. MsrA has recently turned attention in coupling with the neurodegenerative disorders and in particular with Alzheimer disease. In fact this neurodegenerative disorder depends to a deposit of beta amyloid a peptide with an oxidizable methionine in position 35 which is proved able to modulate the expression to MsrA in neuronal cells. Here, we firstly provided evidence that pretreatment with Resveratrol and Punicalagin (a potent antioxidant extracted from pomegranate), up-regulate the expression and enzymatic activity of MsrA in human neuroblastoma IMR-32 cells with beta amyloid peptides. This effect determines a lowering of oxidative potential of the cells as demonstrated by the ROS measurement and a protective effect on cellular availability. Therefore we hypothesize a possible prevent role for these molecules in Alzheimer and in other neurodegenerative diseases. PMID- 29234774 TI - Interventions to Prevent Cognitive Decline and Dementia in Adults without Cognitive Impairment: A Systematic Review. AB - Without preventative strategies, the burden of dementia is likely to increase rapidly worldwide. Primary prevention approaches involve modifying risk factors before symptoms of cognitive impairment develop. This review systematically assesses Randomised Controlled Trials (RCTs) and reviews of RCTs for their effectiveness in primary prevention. We searched Medline, the Cochrane Library, Web of Science and Psych-Info for relevant studies using pre-determined keywords. Both non-pharmacological and pharmacological interventions were considered. Inclusion criteria were sample size greater or equal to 50, at least 6 months of follow-up, and participants with no cognitive impairment at baseline. Outcomes included dementia incidence, cognitive decline and cognitive function. Study quality was rated using the Jadad criteria. Thirty-nine studies, 17 non pharmacological and 22 pharmacological, were included. Results were heterogeneous across interventions and studies, with few significant effects. Studies investigating physical activity and calcium channel blocker treatment demonstrated significant effects in preventing cognitive decline. There were no conclusive results demonstrating overall capacity of assessed interventions to reduce risk of dementia. The review provides an overview of the current literature, and identifies areas in need of further research. PMID- 29234775 TI - Amyloid and Tau Biomarkers in CSF. AB - The number of failed Alzheimer's disease (AD) clinical trials on Abeta-targeting drugs is increasing. The explanation for this is most likely multi-factorial. An optimistic standpoint is that trials have to be on patients in an earlier stage of the disease, before neurodegeneration is too severe, to show efficacy, and probably also of longer duration. Further, there is a general agreement that enrolled patients have to be diagnosed based on combined clinical and biomarker criteria, to avoid noise from the large proportion (20%) of cases that are misdiagnosed if only clinical criteria are used. Last, the poor predictive power of translating an "anti-Abeta" or "anti-plaque" effect from AD transgenic animal models to AD patients also calls for biomarkers to verify target engagement in man, and to show downstream effects of Abeta-targeting drug candidates in AD patients. The focus of this review is on the possible role of cerebrospinal fluid (CSF) biomarkers in AD clinical trials for diagnostics, and thus patient enrichment, and for theragnostics, to provide evidence of target engagement of the drug on Abeta metabolism or aggregation, and of effects on the molecular pathology of the disease. PMID- 29234776 TI - Beyond the Controversy on Abeta Blood-Based Biomarkers. AB - Central biomarkers of Alzheimer's disease (AD) have been proven to have diagnostic and prognostic capacity. However, both amyloid positron emission tomography and cerebrospinal fluid collection studies present problems that limit their widespread acceptability in global clinical trials. Thus, development of other measures as potential surrogates of amyloid positivity should be pursued. Results from numerous experimental studies strongly suggest that the association between Abeta plasma levels, particularly the Abeta42/Abeta40 ratio, and AD diagnosis goes beyond what could be attributable to pure chance, although this association is still controversial. The aim of this review is to consider selected works that may help to improve the design of blood based biomarkers studies by controlling a number of confounding sources related to the clinical gold standard, the time-course of central and peripheral biomarkers, and the metabolism of Abeta in blood that may be blurring the presumptive association between Abeta blood levels and AD. Based on these data and to get pass the controversy, we tentatively postulate that at early stages of preclinical AD, blood Abeta levels and central Abeta biomarkers would follow parallel but temporally displaced trajectories. This association would become eventually lost as the disease progresses and the clearance mechanisms in the blood brain barrier are increasingly impaired. PMID- 29234777 TI - Physical Activity and beta-Amyloid Brain Levels in Humans: A Systematic Review. AB - Physical activity (PA) contributes to brain health and plasticity, which suggests that PA would protect against the development of Alzheimer's disease (AD). However, research on PA and AD biomarkers is very scarce. The objective of the present study was to perform a systematic review of studies that investigated the associations between PA and beta-amyloid brain deposition in humans. Electronic searches were performed in PubMed, Cochrane Library, SportDiscus, PEDro, and PsychInfo databases. Articles were eligible if they have assessed both PA and beta-amyloid brain deposition in humans. Five articles, published between 2010 and 2013, met eligibility criteria (study population varied across studies from 54 to 515, according with the beta-amyloid measure. All five studies assessed both PA and PET-amyloid; among them, two studies also assessed CSF Abeta42 levels). All studies were based on cross-sectional data, from non-demented populations. Among the five included studies, three found significant associations between PA and beta-amyloid brain deposition, and the other two did not find any significant association; limited evidence suggests that PA-amyloid plaques associations would be APOE epsilon4 allele-specific. In sum, no solid conclusions can be drawn on the associations between PA and human beta-amyloid brain deposition currently. Future research on this topic should particularly pay attention to the operationalisation of clinically relevant and valid PA variables and should include important confounders in multivariate analysis. More information is needed on the potential interactions between PA and other AD risk factors (e.g., cognitive activities, APOE epsilon4 status, nutrition, smoking) and their combined effects on AD biomarkers. PMID- 29234778 TI - Community-Based Intervention for Prevention of Dementia in Japan. AB - Population aging is accelerating, with prolonged life expectancy and a decrease in birth rate. As age is a significant risk factor for dementia, we are confronted with an ever-increasing prevalence of mild cognitive impairment (MCI)/dementia. Thus, the Japanese National Center for Geriatrics and Gerontology launched a project to promote community-based research, including the development of an effective screening system for high-risk groups and intervention for dementia prevention. This review introduces the project, the Obu Study of Health Promotion for the Elderly, with the following strategic triad: 1) Identification of the target population by population screening; we regarded patients with MCI as the target population, and developed a screening test battery to identify MCI in a population screening setting. 2) Scientific evaluation of community-based intervention; we developed an interventional method combining exercise and cognitive training ("cognicise"). In practical settings, "cognicise" is programmed into multicomponent exercise intervention, which was reported to have benefits of cognitive improvement and reduction of brain atrophy based on randomized controlled trials. 3) Standardization of the methods of population screening and community-based intervention for evidence-based policy making and widespread implementation. Dementia prevention, or at least delaying the onset of dementia and/or stopping/slowing the progression of dementia, should benefit the whole society as well as individuals. It is our continuing challenge to improve the screening system and community-based intervention for dementia prevention through accumulation of evidence. PMID- 29234779 TI - Evidence for Postmenopausal Hormone Therapy to Prevent Chronic Conditions: Success, Failure, and Lessons Learned. PMID- 29234780 TI - Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: Unfulfilled Expectations. PMID- 29234781 TI - Still Life With Flowers. PMID- 29234782 TI - Newborn Screening of Genetic Mutations in Common Deafness Genes With Bloodspot Based Gene Chip Array. AB - Purpose: This study screens for deafness gene mutations in newborns in the Northwest China population. Method: The 9 sites of 4 common deafness genes (GJB2, GJB3, SLC26A4, and mt 12S rRNA) were detected by bloodspot-based gene chip array in 2,500 newborns. Results: We detected mutations of the 4 genes in 101 (4.04%) newborns; particularly, 0.20% detected the double mutations. In the Hui population, 4.58% of the newborns tested positive for mutations, whereas 4.01% of Han newborns tested positive for mutations. The detective rates are as follows: 1.44% for GJB2 235delC, 1.08% for SLC26A4 IVS7-2A>G, 0.48% for GJB2 299_300delAT, 0.28% for SLC26A4 2168A>G, 0.2% for mt 12S rRNA 1555A>G, and 0.16% for GJB3 538C>T. The 31.25% (5/16) of infants with GJB2 235delC, 50% (3/6) with GJB2 299_300delAT, and 25% (3/12) with SLC26A4 IVS7-2A>G showed abnormal hearing when tested; only 1 double mutation case received the hearing test, and this infant showed abnormality in both ears on the hearing test. Conclusions: High mutation rates in the common deafness genes were detected in newborns in Northwest China. Our study is helpful in understanding the deafness genomic epidemiology and also provides evidence for prenatal and postnatal care as well as policy making on population health in the region. PMID- 29234783 TI - Monongahela Passing the Great Western, 1841. PMID- 29234784 TI - Corn Harvest Along the Brandywine. PMID- 29234785 TI - Rue Cortot, Montmartre. PMID- 29234788 TI - Point-of-Use Food Allergen Detector on the Horizon. PMID- 29234786 TI - The effects of delay duration on visual working memory for orientation. AB - We used a delayed-estimation paradigm to characterize the joint effects of set size (one, two, four, or six) and delay duration (1, 2, 3, or 6 s) on visual working memory for orientation. We conducted two experiments: one with delay durations blocked, another with delay durations interleaved. As dependent variables, we examined four model-free metrics of dispersion as well as precision estimates in four simple models. We tested for effects of delay time using analyses of variance, linear regressions, and nested model comparisons. We found significant effects of set size and delay duration on both model-free and model based measures of dispersion. However, the effect of delay duration was much weaker than that of set size, dependent on the analysis method, and apparent in only a minority of subjects. The highest forgetting slope found in either experiment at any set size was a modest 1.14 degrees /s. As secondary results, we found a low rate of nontarget reports, and significant estimation biases towards oblique orientations (but no dependence of their magnitude on either set size or delay duration). Relative stability of working memory even at higher set sizes is consistent with earlier results for motion direction and spatial frequency. We compare with a recent study that performed a very similar experiment. PMID- 29234789 TI - DNA Base Editing Could Reverse Most Disease-Causing Point Mutations. PMID- 29234790 TI - First Phase 1 Trial of a Prophylactic mRNA Vaccine Reported. PMID- 29234791 TI - Deep Learning Algorithms for Detection of Lymph Node Metastases From Breast Cancer: Helping Artificial Intelligence Be Seen. PMID- 29234792 TI - Menopausal Hormone Therapy for Primary Prevention of Chronic Disease. PMID- 29234793 TI - Using Free-Response Receiver Operating Characteristic Curves to Assess the Accuracy of Machine Diagnosis of Cancer. PMID- 29234795 TI - Five Ethical Values to Guide Health System Reform. PMID- 29234796 TI - The Banana Again. PMID- 29234797 TI - Availability of Pharmacist-Prescribed Contraception in California, 2017. PMID- 29234798 TI - Radiofrequency Denervation for Chronic Low Back Pain. PMID- 29234799 TI - Radiofrequency Denervation for Chronic Low Back Pain. PMID- 29234800 TI - Radiofrequency Denervation for Chronic Low Back Pain. PMID- 29234801 TI - Humane Language for People in the Criminal Justice System. PMID- 29234802 TI - Contact Precautions for Multidrug-Resistant Organisms. PMID- 29234803 TI - Radiofrequency Denervation for Chronic Low Back Pain-Reply. PMID- 29234804 TI - Humane Language for People in the Criminal Justice System-Reply. PMID- 29234805 TI - Contact Precautions for Multidrug-Resistant Organisms-Reply. PMID- 29234809 TI - Hormone Therapy for Primary Prevention of Chronic Conditions in Postmenopausal Women. PMID- 29234806 TI - Diagnostic Assessment of Deep Learning Algorithms for Detection of Lymph Node Metastases in Women With Breast Cancer. AB - Importance: Application of deep learning algorithms to whole-slide pathology images can potentially improve diagnostic accuracy and efficiency. Objective: Assess the performance of automated deep learning algorithms at detecting metastases in hematoxylin and eosin-stained tissue sections of lymph nodes of women with breast cancer and compare it with pathologists' diagnoses in a diagnostic setting. Design, Setting, and Participants: Researcher challenge competition (CAMELYON16) to develop automated solutions for detecting lymph node metastases (November 2015-November 2016). A training data set of whole-slide images from 2 centers in the Netherlands with (n = 110) and without (n = 160) nodal metastases verified by immunohistochemical staining were provided to challenge participants to build algorithms. Algorithm performance was evaluated in an independent test set of 129 whole-slide images (49 with and 80 without metastases). The same test set of corresponding glass slides was also evaluated by a panel of 11 pathologists with time constraint (WTC) from the Netherlands to ascertain likelihood of nodal metastases for each slide in a flexible 2-hour session, simulating routine pathology workflow, and by 1 pathologist without time constraint (WOTC). Exposures: Deep learning algorithms submitted as part of a challenge competition or pathologist interpretation. Main Outcomes and Measures: The presence of specific metastatic foci and the absence vs presence of lymph node metastasis in a slide or image using receiver operating characteristic curve analysis. The 11 pathologists participating in the simulation exercise rated their diagnostic confidence as definitely normal, probably normal, equivocal, probably tumor, or definitely tumor. Results: The area under the receiver operating characteristic curve (AUC) for the algorithms ranged from 0.556 to 0.994. The top-performing algorithm achieved a lesion-level, true-positive fraction comparable with that of the pathologist WOTC (72.4% [95% CI, 64.3% 80.4%]) at a mean of 0.0125 false-positives per normal whole-slide image. For the whole-slide image classification task, the best algorithm (AUC, 0.994 [95% CI, 0.983-0.999]) performed significantly better than the pathologists WTC in a diagnostic simulation (mean AUC, 0.810 [range, 0.738-0.884]; P < .001). The top 5 algorithms had a mean AUC that was comparable with the pathologist interpreting the slides in the absence of time constraints (mean AUC, 0.960 [range, 0.923 0.994] for the top 5 algorithms vs 0.966 [95% CI, 0.927-0.998] for the pathologist WOTC). Conclusions and Relevance: In the setting of a challenge competition, some deep learning algorithms achieved better diagnostic performance than a panel of 11 pathologists participating in a simulation exercise designed to mimic routine pathology workflow; algorithm performance was comparable with an expert pathologist interpreting whole-slide images without time constraints. Whether this approach has clinical utility will require evaluation in a clinical setting. PMID- 29234808 TI - Effect of Levothyroxine on Miscarriage Among Women With Normal Thyroid Function and Thyroid Autoimmunity Undergoing In Vitro Fertilization and Embryo Transfer: A Randomized Clinical Trial. AB - Importance: Presence of thyroid autoantibodies in women with normal thyroid function is associated with increased risk of miscarriage. Whether levothyroxine treatment improves pregnancy outcomes among women undergoing in vitro fertilization and embryo transfer (IVF-ET) is unknown. Objective: To determine the effect of levothyroxine on miscarriage among women undergoing IVF-ET who had normal thyroid function and tested positive for thyroid autoantibodies. Design, Setting, and Participants: An open-label, randomized clinical trial involving 600 women who tested positive for the antithyroperoxidase antibody and were being treated for infertility at Peking University Third Hospital from September 2012 to March 2017. Interventions: The intervention group (n = 300) received either a 25-MUg/d or 50-MUg/d dose of levothyroxine at study initiation that was titrated according to the level of thyroid-stimulating hormone during pregnancy. The women in the control group (n = 300) did not receive levothyroxine. All participants received the same IVF-ET and follow-up protocols. Main Outcomes and Measures: The primary outcome was the miscarriage rate (pregnancy loss before 28 weeks of gestation, which was calculated among women who became pregnant). The secondary outcomes were clinical intrauterine pregnancy rate (fetal cardiac activity seen at sonography observation on the 30th day after the embryo transfer), and live birth rate (at least 1 live birth after 28 weeks of gestation). Results: Among the 600 women (mean [SD] age, 31.6 [3.8] years) randomized in this trial, 567 women (94.5%) underwent IVF-ET and 565 (94.2%) completed the study. Miscarriage rates were 10.3% (11 of 107) in the intervention group and 10.6% (12 of 113) in the control group, with the absolute rate difference (RD) of -0.34% (95% CI, 8.65% to 8.12%) over the 4.5-year study period. Clinical intrauterine pregnancy rates were 35.7% (107 of 300) in the intervention group and 37.7% (113 of 300) in the control group, with an absolute RD of -2.00% (95% CI, -9.65% to 5.69%). Live birth rates were 31.7% (95 of 300) in the intervention group and 32.3% (97 of 300) in the control group, with an absolute RD of -0.67% (95% CI, -8.09% to 6.77%). Conclusions and Relevance: Among women in China who had intact thyroid function and tested positive for antithyroperoxidase antibodies and were undergoing IVF-ET, treatment with levothyroxine, compared with no levothyroxine treatment, did not reduce miscarriage rates or increase live-birth rates. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-TRC-13004097. PMID- 29234807 TI - Development and Validation of a Deep Learning System for Diabetic Retinopathy and Related Eye Diseases Using Retinal Images From Multiethnic Populations With Diabetes. AB - Importance: A deep learning system (DLS) is a machine learning technology with potential for screening diabetic retinopathy and related eye diseases. Objective: To evaluate the performance of a DLS in detecting referable diabetic retinopathy, vision-threatening diabetic retinopathy, possible glaucoma, and age-related macular degeneration (AMD) in community and clinic-based multiethnic populations with diabetes. Design, Setting, and Participants: Diagnostic performance of a DLS for diabetic retinopathy and related eye diseases was evaluated using 494 661 retinal images. A DLS was trained for detecting diabetic retinopathy (using 76 370 images), possible glaucoma (125 189 images), and AMD (72 610 images), and performance of DLS was evaluated for detecting diabetic retinopathy (using 112 648 images), possible glaucoma (71 896 images), and AMD (35 948 images). Training of the DLS was completed in May 2016, and validation of the DLS was completed in May 2017 for detection of referable diabetic retinopathy (moderate nonproliferative diabetic retinopathy or worse) and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse) using a primary validation data set in the Singapore National Diabetic Retinopathy Screening Program and 10 multiethnic cohorts with diabetes. Exposures: Use of a deep learning system. Main Outcomes and Measures: Area under the receiver operating characteristic curve (AUC) and sensitivity and specificity of the DLS with professional graders (retinal specialists, general ophthalmologists, trained graders, or optometrists) as the reference standard. Results: In the primary validation dataset (n = 14 880 patients; 71 896 images; mean [SD] age, 60.2 [2.2] years; 54.6% men), the prevalence of referable diabetic retinopathy was 3.0%; vision-threatening diabetic retinopathy, 0.6%; possible glaucoma, 0.1%; and AMD, 2.5%. The AUC of the DLS for referable diabetic retinopathy was 0.936 (95% CI, 0.925-0.943), sensitivity was 90.5% (95% CI, 87.3%-93.0%), and specificity was 91.6% (95% CI, 91.0%-92.2%). For vision-threatening diabetic retinopathy, AUC was 0.958 (95% CI, 0.956-0.961), sensitivity was 100% (95% CI, 94.1%-100.0%), and specificity was 91.1% (95% CI, 90.7%-91.4%). For possible glaucoma, AUC was 0.942 (95% CI, 0.929-0.954), sensitivity was 96.4% (95% CI, 81.7%-99.9%), and specificity was 87.2% (95% CI, 86.8%-87.5%). For AMD, AUC was 0.931 (95% CI, 0.928-0.935), sensitivity was 93.2% (95% CI, 91.1%-99.8%), and specificity was 88.7% (95% CI, 88.3%-89.0%). For referable diabetic retinopathy in the 10 additional datasets, AUC range was 0.889 to 0.983 (n = 40 752 images). Conclusions and Relevance: In this evaluation of retinal images from multiethnic cohorts of patients with diabetes, the DLS had high sensitivity and specificity for identifying diabetic retinopathy and related eye diseases. Further research is necessary to evaluate the applicability of the DLS in health care settings and the utility of the DLS to improve vision outcomes. PMID- 29234811 TI - A Fair Interpretation. PMID- 29234813 TI - Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Postmenopausal status coincides with increased risks for chronic conditions such as heart disease, osteoporosis, cognitive impairment, or some types of cancers. Previously, hormone therapy was used for the primary prevention of these chronic conditions. Objective: To update evidence for the US Preventive Services Task Force on the benefits and harms of hormone therapy in reducing risks for chronic conditions. Data Sources: MEDLINE, Cochrane Library, EMBASE, and trial registries from June 1, 2011, through August 1, 2016. Surveillance for new evidence in targeted publications was conducted through July 1, 2017. Study Selection: English-language randomized clinical trials reporting health outcomes. Data Extraction and Synthesis: Dual review of abstracts, full-text articles, and study quality; meta-analyses when at least 3 similar studies were available. Main Outcomes and Measures: Beneficial or harmful changes in risks for various chronic conditions. Results: Eighteen trials (n = 40 058; range, 142-16 608; mean age, 53 79 years) were included. Women using estrogen-only therapy compared with placebo had significantly lower risks, per 10 000 person-years, for diabetes (-19 cases [95% CI, -34 to -3]) and fractures (-53 cases [95% CI, -69 to -39]). Risks were statistically significantly increased, per 10 000 person-years, for gallbladder disease (30 more cases [95% CI, 16 to 48]), stroke (11 more cases [95% CI, 2 to 23]), venous thromboembolism (11 more cases [95% CI, 3 to 22]), and urinary incontinence (1261 more cases [95% CI, 880 to 1689]). Women using estrogen plus progestin compared with placebo experienced significantly lower risks, per 10 000 person-years, for colorectal cancer (-6 cases [95% CI, -9 to -1]), diabetes (-14 cases [95% CI, -24 to -3), and fractures (-44 cases [95% CI, -71 to -13). Risks, per 10 000 person-years, were significantly increased for invasive breast cancer (9 more cases [95% CI, 1 to 19]), probable dementia (22 more cases [95% CI, 4 to 53]), gallbladder disease (21 more cases [95% CI, 10 to 34]), stroke (9 more cases [95% CI, 2 to 19]), urinary incontinence (876 more cases [95% CI, 606 to 1168]), and venous thromboembolism (21 more cases [95% CI, 12 to 33]). Conclusions and Relevance: Hormone therapy for the primary prevention of chronic conditions in menopausal women is associated with some beneficial effects but also with a substantial increase of risks for harms. The available evidence regarding benefits and harms of early initiation of hormone therapy is inconclusive. PMID- 29234815 TI - Illicit Fentanyl Driving Opioid Overdose Deaths. PMID- 29234814 TI - Hormone Therapy for the Primary Prevention of Chronic Conditions in Postmenopausal Women: US Preventive Services Task Force Recommendation Statement. AB - Importance: Menopause occurs at a median age of 51.3 years, and the average US woman who reaches menopause is expected to live another 30 years. The prevalence and incidence of most chronic conditions, such as coronary heart disease, dementia, stroke, fractures, and breast cancer, increase with age; however, the excess risk for these conditions that can be attributed to menopause alone is uncertain. Since the publication of findings from the Women's Health Initiative that hormone therapy use is associated with serious adverse health effects in postmenopausal women, use of menopausal hormone therapy has declined. Objective: To update the 2012 US Preventive Services Task Force (USPSTF) recommendation on the use of menopausal hormone therapy for the primary prevention of chronic conditions. Evidence Review: The USPSTF reviewed the evidence on the benefits and harms of systemic (ie, oral or transdermal) hormone therapy for the prevention of chronic conditions in postmenopausal women and whether outcomes vary among women in different subgroups or by timing of intervention after menopause. The review did not address hormone therapy for preventing or treating menopausal symptoms. Findings: Although the use of hormone therapy to prevent chronic conditions in postmenopausal women is associated with some benefits, there are also well documented harms. The USPSTF determined that the magnitude of both the benefits and the harms of hormone therapy in postmenopausal women is small to moderate. Therefore, the USPSTF concluded with moderate certainty that combined estrogen and progestin has no net benefit for the primary prevention of chronic conditions for most postmenopausal women with an intact uterus and that estrogen alone has no net benefit for the primary prevention of chronic conditions for most postmenopausal women who have had a hysterectomy. Conclusions and Recommendation: The USPSTF recommends against the use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal women. (D recommendation) The USPSTF recommends against the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal women who have had a hysterectomy. (D recommendation). PMID- 29234816 TI - More Than 1 in 5 Working Adults Use Some Form of Tobacco. PMID- 29234817 TI - Neural plasticity and its initiating conditions in tinnitus. AB - BACKGROUND AND OBJECTIVE: Deafferentation caused by cochlear pathology (which can be hidden from the audiogram) activates forms of neural plasticity in auditory pathways, generating tinnitus and its associated conditions including hyperacusis. This article discusses tinnitus mechanisms and suggests how these mechanisms may relate to those involved in normal auditory information processing. MATERIALS AND METHODS: Research findings from animal models of tinnitus and from electromagnetic imaging of tinnitus patients are reviewed which pertain to the role of deafferentation and neural plasticity in tinnitus and hyperacusis. RESULTS: Auditory neurons compensate for deafferentation by increasing their input/output functions (gain) at multiple levels of the auditory system. Forms of homeostatic plasticity are believed to be responsible for this neural change, which increases the spontaneous and driven activity of neurons in central auditory structures in animals expressing behavioral evidence of tinnitus. Another tinnitus correlate, increased neural synchrony among the affected neurons, is forged by spike-timing-dependent neural plasticity in auditory pathways. Slow oscillations generated by bursting thalamic neurons verified in tinnitus animals appear to modulate neural plasticity in the cortex, integrating tinnitus neural activity with information in brain regions supporting memory, emotion, and consciousness which exhibit increased metabolic activity in tinnitus patients. DISCUSSION AND CONCLUSION: The latter process may be induced by transient auditory events in normal processing but it persists in tinnitus, driven by phantom signals from the auditory pathway. Several tinnitus therapies attempt to suppress tinnitus through plasticity, but repeated sessions will likely be needed to prevent tinnitus activity from returning owing to deafferentation as its initiating condition. PMID- 29234818 TI - Postrhinoplasty fibrotic syndrome. AB - BACKGROUND: Over the years there have been numerous anecdotal reports of nasal tip enlargement and loss of tip definition post rhinoplasty. Subsequent revisionary procedures not only failed to reduce the tip size but aggravated the problem causing an even larger and less defined nasal tip. The final result was often worse than the preop condition and uncorrectable. METHOD/RESULTS: Six patients who demonstrated an aggravation of the postop result with subsequent revisionary or secondary surgeries were evaluated to find common causes or circumstances. All patients had 1) worsening of nasal tip result with subsequent procedures, e. g., nasal tip enlargement and/or loss of tip definition with subsequent procedures 2) exhibited substantial postop edema at one or more surgeries and 3) extensive subcutaneous fibrous tissue noted at revisionary procedures. CONCLUSIONS: The nasal scenario described is referred to as postrhinoplasty fibrotic syndrome. It is recommended that if revision surgery is necessary by a surgeon, the scale of the surgery should be smaller than that of the primary operation. If yet another revision is necessary that surgery should be of an even smaller scale than the prior surgery. Augmentation rather than reduction rhinoplasty is clearly a better approach. With the surgical philosophy of smaller and/or less surgery with each revision (should it be necessary) the irreversible condition of postrhinoplasty fibrotic syndrome should be avoidable. PMID- 29234819 TI - [Optimized resource mobilization and quality of treatment of severely injured patients through a structured trauma room alarm system]. AB - BACKGROUND: The treatment of severely injured patients in the trauma resuscitation unit (TRU) requires an interdisciplinary and highly professional trauma team approach. The complete team needs to be waiting for the patient in the TRU on arrival. Treating severely injured patients in the TRU, the trauma team connects the initial preclinical emergency stabilization with the subsequent sophisticated treatment. Thus, the trauma team depends on concise information from the emergency personnel at the scene to provide its leader with further information as well as an accurate alarm including all departments necessary to stabilize the patient in the TRU. METHOD: Aiming at an accurate and most efficient trauma team alarm, this study was designed to provide and analyze an alarm system which mobilizes the trauma team in a stepwise fashion depending on the pattern of injuries and the threat to life. The trauma team alarm system was analyzed in a prospective data acquisition at a level I trauma center over a period of 12 months. Evaluation followed the acquisition phase and provided comparison to the status prior to the establishment of the alarm system. All items underwent statistical testing using t-tests (p < 0.05). RESULTS: The data of 775 TRU patients showed a significant reduction of false information on the patients status prior to arrival. It also showed an increase in punctual arrival in the TRU of the emergency teams. False alarms were significantly reduced (from 11.9% to 2.7%, p > 0.01). The duration from arrival of the patient in the TRU to the initial multislice computed tomography (CT) scan was reduced by 6 min while the total period of treatment in the TRU was reduced by 17 min. After the alarm system to gradually mobilize the trauma team was put into action, team members left the TRU if unneeded prior to finishing the initial treatment in only 4% of the cases. The patient fatality rate was 8.8% (injury severity score, ISS = 23 points) after establishment of the alarm system compared to 12.9% (ISS = 25 points) before. CONCLUSION: The implementation of an accurate and patient status based alarm system to mobilize the trauma team can improve the quality of treatment while the duration of treatment of the severely injured patients in the TRU can be decreased. It also provides a most efficient mobilization of personnel resources while sustaining patient safety. PMID- 29234820 TI - [Mesenchymal abdominal tumors in children]. AB - Mesenchymal tumors in childhood comprise benign and malign entities and differ regarding typical sites of manifestation, age peak and clinical symptoms. In some cases biopsy is mandatory. If nephroblastoma is a possible diagnosis, biopsy must be avoided by all means in order to avoid biopsy tract metastasis. Imaging is used to narrow the differential diagnosis, describe the exact extent of the lesion and deliver complete staging. In pediatric patients sonography and MRI are the most important imaging modalities. Low-dose CT of the thorax serves for assessment of possible pulmonary metastases. PMID- 29234821 TI - [Neuroendocrine tumors of the abdomen]. AB - CLINICAL/METHODICAL ISSUE: Gastroenteropancreatic neuroendocrine neoplasia (GEP NEN) are a heterogeneous group of complex tumors, which is often difficult to classify due to heterogeneity and varying locations. STANDARD RADIOLOGICAL METHODS: Ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and positron-emission tomography computed tomography (PET/CT) are available for the localization of NEN as well as for the staging. METHODOLOGICAL INNOVATIONS: In particular, nuclear medical examination methods with somatostatin analogues are of great importance since radioactively labeled receptor ligands make tumors visible with high sensitivity. PERFORMANCE: CT and MRT have high detection rates for GEP-NEN and have been further improved by developments such as diffusion weighted imaging. The nuclear medical methods, however, are superior in detection, especially in gastrointestinal NEN ACHIEVEMENTS: It is important for the radiologist to become acquainted with the NEN as they can occur ubiquitously in the abdomen and should be identified as such. PRACTICAL RECOMMENDATIONS: Since GEP-NEN are predominantly hypervascularized, a biphasic examination technique is obligatory for contrast-enhanced cross-sectional imaging. PET/CT with somatostatin analogs should be used for further diagnosis. PMID- 29234822 TI - [Acute vestibular syndrome : Clinical examination outperforms MRI in the detection of central lesions]. AB - A significant number of patients who seek medical treatment in an emergency department because of vertigo or dizziness, suffer from acute vestibular syndrome. This is characterized by sustained vertigo, horizontal or horizontal rotatory jerk nystagmus, and unsteady stance and gait. In the acute situation it is crucial to differentiate patients with a peripheral vestibular disorder from those with a central disease. A number of recent studies have shown that a structured clinical examination enables a reliable differential diagnosis of central or peripheral disorders. Such an examination includes the head impulse test, an alternating cover test to detect a skew deviation of the eyes, and observation of nystagmus in different positions of gaze and using Frenzel goggles. This examination is more sensitive for the detection of brainstem stroke than magnetic resonance imaging (MRI), at least within 48 h after symptom onset. As these facts are still little known, in practice there is an overuse of cost intensive imaging with computed tomography and MRI, and a number of patient brainstem strokes in the vertebrobasilar circulation may be missed. This paper describes the relevant studies on this topic. PMID- 29234823 TI - [Digital learning and teaching in medical education : Already there or still at the beginning?] AB - The current choice of digital teaching and learning formats in medicine is very heterogeneous. In addition to the widely used classical static formats, social communication tools, audio/video-based media, interactive formats, and electronic testing systems enrich the learning environment.For medical students, the private use of digital media is not necessarily linked to their meaningful use in the study. Many gain their experience of digital learning in the sense of "assessment drives learning", especially by taking online exams in a passive, consuming role. About half of all medical students can be referred to as "e-examinees" whose handling of digital learning is primarily focused on online exam preparation. Essentially, they do not actively influence their digital environment. Only a quarter can be identified as a "digital all-rounder", who compiles their individual learning portfolio from the broad range of digital media.At present, the use of digital media is not yet an integral and comprehensive component of the teaching framework of medical studies in Germany, but is rather used in the sense of a punctual teaching enrichment. Current trends in digital teaching and learning offerings are mobile, interactive, and personalized platforms as well as increasing the relevance of learning platforms. Furthermore, didactical concepts targeting the changed learning habits of the students are more successful regarding the acceptance and learning outcomes. In addition, digitalization is currently gaining importance as a component in the medical school curricula. PMID- 29234824 TI - [Comments on: Daytime variation of perioperative myocardial injury in cardiac surgery]. PMID- 29234825 TI - Bindarit Attenuates Pain and Cancer-Related Inflammation by Influencing Myeloid Cells in a Model of Bone Cancer. AB - C-C motif chemokine ligand 2 (CCL2) is a small cytokine that functions in inflammation and cancer development. Bindarit, a CCL2 inhibitor, is a small anti inflammatory molecule proven safe by phase II trials in type 2 diabetic nephropathy patients. As cancer-related inflammation is a cause of pain, we investigated whether Bindarit suppresses cancer-related inflammation and pain. We established a bone-cancer mouse model by inoculating cancer cells. After applying Bindarit, we preformed pain sensitivity tests and checked cancer development by X ray. Using flow cytometry and qRT-PCR assays, we assessed the effect of Bindarit on peripheral blood monocyte mobilization and M2 macrophage polarization. We also investigated the targets of Bindarit using western blotting and luciferase assay. Bindarit-treated mice performed better in pain sensitivity tests compare to control mice. X-ray imaging showed that Bindarit-treated mice had fewer cancer cell colonies and smaller overall tumor burden. Bindarit reduced the number of monocytes in peripheral blood and down-regulated the expression of M2 macrophage polarization makers. Bindarit also inhibited IKKbeta phosphorylation. Bindarit efficiently relieves cancer-related pain and suppresses cancer development. Bindarit inhibits monocyte mobilization in peripheral blood as well as M2 macrophage polarization. IKKbeta is identified as a target of Bindarit. PMID- 29234826 TI - Mental health impact of social capital interventions: a systematic review. AB - PURPOSE: Mental disorders are a major contributor to the global burden of disease and disability, and can be extremely costly at both individual and community level. Social capital, (SC) defined as an individual's social relationships and participation in community networks, may lower the risk of mental disorders while increasing resilience capacity, adaptation and recovery. SC interventions may be a cost-effective way of preventing and ameliorating these conditions. However, the impact of these SC interventions on mental health still needs research. METHODS: We conducted a systematic review of SC-based interventions to investigate their effect on mental health outcomes from controlled, quasi experimental studies or pilot trials. We searched twelve academic databases, three clinical trials registries, hand-searched references and contacted field experts. Studies' quality was assessed with the Cochrane Risk of Bias tools for randomized and non-randomized studies. RESULTS: Seven studies were included in the review, published between 2006 and 2016. There was substantial heterogeneity in the definitions of both SC and mental disorders among the studies, preventing us from calculating pooled effect sizes. The interventions included community engagement and educative programs, cognitive processing therapy and sociotherapy for trauma survivors, and neighbourhood projects. CONCLUSIONS: There are paucity of SC interventions investigating the effect on mental health outcomes. This study showed that both SC scores and mental health outcomes improved over time but there was little evidence of benefit compared to control groups in the long term. Further high-quality trials are needed, especially among adverse populations to assess sustainability of effect. PMID- 29234828 TI - [Failure to perform dermoscopy in melanoma-suspicious skin lesions in dermatological practice : Possible medical liability]. PMID- 29234827 TI - Transcriptome signatures of tomato leaf induced by Phytophthora infestans and functional identification of transcription factor SpWRKY3. AB - KEY MESSAGE: SpWRKY3 was identified as a resistance gene to Phytophthora infestans from Solanum pimpinellifolium L3708 and its transgenic tomato showed a significant resistance to P. infestans. This finding reveals the potential application of SpWRKY3 in future molecular breeding. Transcription factors (TFs) play crucial roles in the plant response to various pathogens. In this present study, we used comparative transcriptome analysis of tomatoes inoculated with and without Phytophthora infestans to identify 1103 differentially expressed genes. Seven enrichment GO terms (level 4) associated with the plant resistance to pathogens were identified. It was found that thirty-five selected TF genes from GO enriched term, sequence-specific DNA binding transcription factor activity (GO: 0003700), were induced by P. infestans. Of these TFs, the accumulation of a homologous gene of WRKY (SpWRKY3) was significantly changed after P. infestans induction, and it was also isolated form P. infestans-resistant tomato, Solanum pimpinellifolium L3708. Overexpression of SpWRKY3 in tomato positively modulated P. infestans defense response as shown by decreased number of necrotic cells, lesion sizes and disease index, while the resistance was impaired after SpWRKY3 silencing. After P. infestans infection, the expression levels of PR genes in transgenic tomato plants overexpressed SpWRKY3 were significantly higher than those in WT, while the number of necrotic cells and the reactive oxygen species (ROS) accumulation were fewer and lower. These results suggest that SpWRKY3 induces PR gene expression and reduces the ROS accumulation to protect against cell membrane injury, leading to enhanced resistance to P. infestans. Our results provide insight into SpWRKY3 as a positive regulator involved in tomato-P. infestans interaction, and its function may enhance tomato resistance to P. infestans. PMID- 29234829 TI - [Drug therapy of acne inversa]. AB - Acne inversa is a chronic inflammatory destructive skin disease that affects about 1% of the population. The therapy should be personalized and consists of surgical and conservative procedures. Antibiotics are administered either topically or systemically. Combination therapy with clindamycin and rifampicin for 10-12 weeks can be very effective. Furthermore, TNF-alpha inhibitors show adequate efficacy and can be recommended. Adalimumab is the only approved drug product for systemic treatment of acne inversa. The efficacy of retinoids is controversial. Isotretinoin cannot be recommended for the treatment of acne inversa; however, acitretin has been proven to be more effective. Immune modulating substances, like dapsone, cyclosporine A, methotrexate, colchicine, or corticosteroids, can be considered; however, the study data are insufficient for recommendation. Hormonal therapies can influence the course of the disease. Antiseptics are applied independent of the stage of disease. Patients should be informed about triggering factors. PMID- 29234830 TI - Temperature Dependent Adsorption-Desorption Behaviour of Pendimethalin in Punjab Soils. AB - This study shows the effect of soil type and temperature on the adsorption and desorption behaviour of pendimethalin using a batch equilibration technique. Adsorption kinetics followed pseudo-second-order-model (R2 > 0.99). The shape of adsorption curve for studied soils was S-type at 30 and 40 degrees C and L-type at 50 degrees C. The isotherms were nonlinear and were well described by Freundlich equation. Adsorption capacity ranged from 1.4 to 2.2 MUg1 - 1/n g-1 mL1/n and the order of adsorption was: clay loam > sandy loam > loamy sand indicating strong affinity of pendimethalin towards organic matter and clay content. Irrespective of soil type, the adsorption of pendimethalin increased with increase in temperature suggesting endothermic process. Freundlich desorption coefficient was greater than adsorption in all soils at studied temperatures indicating hysteresis. Thermodynamic parameters revealed spontaneous adsorption process which becomes more favourable at high temperature. The adsorption of pendimethalin was dominated by surface adsorption at lower equilibrium concentration and partition at high concentrations. PMID- 29234831 TI - Looking backwards and forward at the same time. PMID- 29234832 TI - How Flood Experience and Risk Perception Influences Protective Actions and Behaviours among Canadian Homeowners. AB - Canada is a country in the midst of a flood management policy transition that is shifting part of the flood damage burden from the state to homeowners. This transition-as well as the large financial losses resulting from flooding-have created a window of opportunity for Canada to implement strategies that increase property owners' capacity to avoid and absorb the financial and physical risks associated with flooding. This work presents foundational research into the extent to which Canadians' flood experience, perceptions of flood risks and socio demographics shape their intentions and adoption of property level flood protection (PLFP). A bilingual, national survey was deployed in Spring 2016 and was completed by 2300 respondents across all 10 Canadian provinces. The survey was developed using assumptions in existing literature on flood risk behaviours and the determinants of flood risk management in similar jurisdictions. The paper argues that property owners are not willing to accept greater responsibility for flood risk as envisioned by recent policy changes. This finding is consistent with other OECD jurisdictions, where flood risk engagement strategies have been developed that could be replicated in Canada to encourage risk-sharing behaviour. PMID- 29234833 TI - Towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data. AB - Physiologically based kinetic (PBK) modelling-based reverse dosimetry is a promising tool for the prediction of in vivo developmental toxicity using in vitro concentration-response data. In the present study, the potential of this approach to predict the dose-dependent increase of uterus weight in rats upon exposure to estrogenic chemicals was assessed. In vitro concentration-response data of 17beta-estradiol (E2) and bisphenol A (BPA) obtained in the MCF-7/BOS proliferation assay, the U2OS ER-CALUX assay and the yeast estrogen screen (YES) assay, were translated into in vivo dose-response data in rat, using a PBK model with a minimum number of in vitro and in silico determined parameter values. To evaluate the predictions made, benchmark dose (BMD) analysis was performed on the predicted dose-response data and the obtained BMDL10 values were compared with BMDL10 values derived from data on the effects of E2 and BPA in the uterotrophic assay reported in the literature. The results show that predicted dose-response data of E2 and BPA matched with the data from in vivo studies when predictions were made based on YES assay data. The YES assay-based predictions of the BMDL10 values differed 3.9-fold (E2) and 4.7- to 13.4-fold (BPA) from the BMDL10 values obtained from the in vivo data. The present study provides the proof-of-principle that PBK modelling-based reverse dosimetry of YES assay data using a minimum PBK model can predict dose-dependent in vivo uterus growth caused by estrogenic chemicals. In future studies, the approach should be extended to include other estrogens. PMID- 29234834 TI - Contributions of prolonged contingent and non-contingent cocaine exposure to escalation of cocaine intake and glutamatergic gene expression. AB - Similar to the pattern observed in people with substance abuse disorders, laboratory animals will exhibit escalation of cocaine intake when the drug is available over prolonged periods of time. Here, we investigated the contribution of behavioral contingency of cocaine administration on escalation of cocaine intake and gene expression in the dorsal medial prefrontal cortex (dmPFC) in adult male rats. Rats were allowed to self-administer intravenous cocaine (0.25 mg/infusion) under either limited cocaine-(1 h/day), prolonged cocaine-(6 h/day), or limited cocaine-(1 h/day) plus yoked cocaine-access (5 h/day); a control group received access to saline (1 h/day). One day after the final self-administration session, the rats were euthanized and the dmPFC was removed for quantification of mRNA expression of critical glutamatergic signaling genes, Homer2, Grin1, and Dlg4, as these genes and brain region have been previously implicated in addiction, learning, and memory. All groups with cocaine-access showed escalated cocaine intake during the first 10 min of each daily session, and within the first 1 h of cocaine administration. Additionally, the limited-access + yoked group exhibited more non-reinforced lever responses during self-administration sessions than the other groups tested. Lastly, Homer2, Grin1, and Dlg4 mRNA were impacted by both duration and mode of cocaine exposure. Only prolonged-access rats exhibited increases in mRNA expression for Homer2, Grin1, and Dlg4 mRNA. Taken together, these findings indicate that both contingent and non-contingent "excessive" cocaine exposure supports escalation behavior, but the behavioral contingency of cocaine-access has distinct effects on the patterning of operant responsiveness and changes in mRNA expression. PMID- 29234836 TI - Trans-Urethral Ureteral Stent Replacement Technique (TRUST): 10-Year Experience in 1168 Patients. AB - OBJECTIVES: To affirm technical success, clinical success and safety of fluoroscopically guided transurethral replacement of double-J (DJ) ureteral stents. METHODS: From January 2005 to December 2015, in a follow-up period ranging from 9 to 73 months, we replaced 6167 DJ ureteral stents in 3221 procedures in 1168 patients. All the procedures were performed in the angiography suite under fluoroscopic control. RESULTS: Technical success was achieved in 97.5% of the procedures. In eighty procedures, cystoscopic approach was necessary; time from previous procedure and side were significantly associated with technical success. Clinical success was reached in 95.7% of the procedures and was significantly lower in urological and gynaecological tumours (when compared to fibrosis and other causes) and in bilateral stents. No major complications were reported. In 90 cases, self-limiting transient minor haematuria occurred and in 160 procedures urinary tract infection responding to antibiotics were registered. Overall procedure time was 27 min. Mean fluoroscopic time was 6 min and 45 s. Mean radiation dose of the procedure was 38.40 Gy cm2. CONCLUSIONS: In patients that need routine replacement of DJ ureteral stent, transurethral fluoroscopically guided method may be the first choice; only in few cases of technical failure, cystoscopy may be considered. PMID- 29234837 TI - Injury severity in polytrauma patients is underestimated using the injury severity score: a single-center correlation study in air rescue. AB - PURPOSE: Prehospital estimation of injury severity is essential for prehospital therapy, deciding on the destination hospital and the associated emergency room care. The aim of this study was to compare prehospital estimates of the abbreviated injury scale (AIS) and the Injury Severity Score (ISS) by emergency physicians with the values of AIS and ISS of injury severity determined at the conclusion of diagnostics. METHODS: In this prospective study, the ISS was determined prehospital by emergency physicians. The validated AIS and ISS were analyzed based on final diagnoses. A Bland-Altman plot was used in analyzing the agreement between two different assays as well as sensitivity and specificity were determined. Confidence intervals were calculated for a Wilson score. Significance level was set at p <= 0.05. RESULTS: The prehospital ISS was estimated at 26.0 +/- 13.0 and was 34.7 +/- 16.3 (p < 0.001) after in-hospital validation. In addition, most of the AIS subgroups were significantly higher in the final calculation than preclinically estimated (p < 0.05). When analyzing subgroups of trauma patients (ISS < 16 vs. ISS >= 16), we were able to demonstrate a sensitivity of > 90% to identify a multiple-trauma patient. Diagnosing a higher injury severity group (ISS >= 25), sensitivity dropped to 61.1%. The Bland-Altman plot demonstrates that injury severity is underestimated in higher injury levels. CONCLUSION: Multiple-trauma patients can be identified using the ISS. Anatomic scores might be used for transport decisions; however, an accurate estimation of the injury severity should also be based on other criteria such as patient status, mechanism of injury, and other triage criteria. PMID- 29234841 TI - Pacemaker follow-up after device replacement. PMID- 29234838 TI - Clinical characteristics and prognosis of traumatic head injury following road traffic accidents admitted in ICU "analysis of 694 cases". AB - BACKGROUND: The aim of the present study is to analyze the clinical and epidemiological characteristics of Traumatic Brain Injury (TBI) following Road Traffic Accidents (RTAs). Moreover, we aim to evaluate the outcome of the TBI victims referred to our medico-surgical Intensive Care Unit (ICU), and to define predictive factors associated with poor prognosis. METHODS: A retrospective study over a 4-year period (2009 to 2012) of 694 patients with head injuries, incurred during road traffic accidents, admitted to the Intensive Care Unit (ICU) of a university hospital (Sfax-Tunisia). Basic demographic, clinical, biological, and radiological data were recorded on admission and during the ICU stay. RESULTS: There were 592 males (85.3%), and 102 female patients. The mean age was at 31.8 +/- 17.8 years (range 1-91). The mechanism of the accident was detailed in 666 patients (96%). The majority of the victims were motorcycle riders and/or passengers (40.5%), followed by pedestrians (29.1%). Extra-cranial pathology was present in 452 patients (65%). A total of 677 patients (97.6%) required intubation, mechanical ventilation, and sedation. Mean ICU stay was 16 +/- 17.4 days. A total of 187 patients (26.9%) died during their hospital stay. The GOS performed within a mean delay of 6 months after hospital discharge was as follows: 198 deaths (28.5%), 13 vegetative state (1.9%), and 349 (50.3%) good recovery and/or moderate disability. A multivariate analysis showed that the factors which correlated with a poor prognosis (mortality and severe disability) were: age > 38 years, Glasgow coma scale score < 8, subdural hematoma, and development of secondary systemic insults (respiratory, circulatory, and metabolic). CONCLUSION: In Tunisia, traumatic brain injury due to RTAs is a frequent cause of ICU admission, especially among young adults, and is associated with high mortality and morbidity rates. The majority of the victims were motorcycle riders and/or passengers and pedestrians. The factors associated with a poor outcome were: age > 38 years, Glasgow Coma Scale score < 8, subdural hematoma, and development of secondary systemic insults (respiratory, circulatory, and metabolic). As a consequence, prevention is highly warranted. PMID- 29234842 TI - [Patients with a wearable cardioverter-defibrillator (WCD) : Prescription, function and rehabilitation support]. AB - Assessment of a permanent risk of life-threatening ventricular arrhythmia in patients with severely reduced left ventricular ejection fraction (LVEF <35%), e. g. after myocarditis, dilated cardiomyopathy, acute myocardial infarction, in patients with postpartum cardiomyopathy or implantable cardioverter-defibrillator (ICD) and cardiac resynchronization treatment plus defibrillator (CRT-D) infection with temporary explantation of the system is a medical challenge. This is time-consuming and unsafe because life-threatening ventricular arrhythmias may occur during the time of risk assessment. During this phase of risk stratification, a wearable cardioverter-defibrillator (WCD) is indicated. The WCD, which is usually worn by the patient for several months, combines continuous retrievable electrocardiogram (ECG) recordings with a reliable defibrillation capability. The prescription of a WCD guarantees safe rehabilitation procedures for patients following acute inpatient treatment. Rehabilitation measures in patients with a WCD are indicated because of the underlying systolic cardiac insufficiency due to severe myocardial disease. In almost half of the patients, who are potentially threatened by ventricular tachyarrhythmias or sudden cardiac death (SCD), the LVEF and heart failure symptoms improve under controlled medication within a few months. Thus, the risk of SCD is lowered so that in many cases a first line ICD implantation is no longer necessary. The purpose of this article is to provide recommendations for rehabilitation procedures of patients with a WCD. A review of the currently available data on WCD publications was carried out with special emphasis on the current national and international guidelines. PMID- 29234843 TI - The right atrium in idiopathic hypereosinophilic syndrome : Insights from the 3D speckle tracking echocardiographic MAGYAR-Path Study. AB - BACKGROUND: Idiopathic hypereosinophilic syndrome is characterized by a persistent eosinophil blood count of >1.5 * 109 cells/l and organ damage, independent of the primary and secondary causes of eosinophilia. The purpose of the present study was to assess the three-dimensional speckle tracking echocardiography-derived right atrial volumetric and functional properties between hypereosinophilic syndrome patients and matched controls. METHODS: A total of 11 patients with idiopathic hypereosinophilic syndrome and 22 age- and gender-matched healthy controls were enrolled in the study. Three-dimensional speckle tracking echocardiography was used for calculation of right atrial volumes, volume-based functional properties, and strain parameters. RESULTS: Significantly increased right atrial maximum (68.7 +/- 33.1 ml vs. 40.3 +/- 12.1 ml, respectively; p = 0.001) and minimum volumes (48.3 +/- 31.0 ml vs. 28.3 +/- 9.4 ml, respectively; p = 0.009), as well as right atrial volume before atrial contraction (58.6 +/- 27.3 ml vs. 34.5 +/- 11.8 ml, respectively; p = 0.001), were found in hypereosinophilic syndrome patients compared with controls. Total and passive right atrial stroke volumes proved to be significantly increased in hypereosinophilic syndrome patients. However, global and mean segmental strain parameters did not differ significantly between the groups. CONCLUSION: Increased cyclic right atrial volumes and mild alterations in right atrial functional properties could be demonstrated in idiopathic hypereosinophilic syndrome patients. PMID- 29234844 TI - Speckle tracking imaging in hypertrophic cardiomyopathy : A powerful tool in search of an unfavorable substrate? PMID- 29234845 TI - EANM guideline for radionuclide therapy with radium-223 of metastatic castration resistant prostate cancer. AB - Radium Ra-223 dichloride (radium-223, Xofigo(r)) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up. PMID- 29234846 TI - FDG PET-CT as a powerful tool for diagnosing and monitoring treatment outcomes of relapsing polychondritis. PMID- 29234847 TI - Correction to: If You Detonate Dynamite, You Should Know Your Fish. AB - In the original article, the last paragraph erroneously states that author's upcoming study was going to be published in Diseases of the Colon and Rectum. PMID- 29234848 TI - The Assessment of Risk Factors for Difficult Intubation in Thyroid Patients. AB - OBJECTIVES: We aimed to assess possible risk factors related to difficult intubation in patients undergoing thyroid surgery. METHODS: We prospectively collected data of 200 patients scheduled for thyroid surgery. Clinical risk factors were defined as: Mallampati score, interincisor gap, thyromental distance, sternomental distance, range of neck motion, body mass index, neck circumference, goiter, the presence of radiological findings suggesting compression and thyroid weight. All evaluations were performed with Macintosh assessed for Cormack and Lehane (CL) classification and modified intubation difficulty scale (MIDS). RESULTS: It was observed that the proportion of patients with a thyroid weight >=40 g, goiter, a Macintosh CL score = 3-4 and the mean neck circumference were significantly higher in the group with a MIDS score >5 (p = 0.018, p = 0.011, p < 0.001, respectively). CONCLUSION: The presence of a palpable goiter, thyroid weight >=40 g and thyromental distance <6.5 cm were risk factors associated with difficult intubation in the multivariate regression model. PMID- 29234849 TI - Urbanization in Sub-Saharan Africa: Declining Rates of Chronic and Recurrent Infection and Their Possible Role in the Origins of Non-communicable Diseases. AB - BACKGROUND: Non-communicable diseases (NCDs), such as atherosclerosis and cancers, are a leading cause of death worldwide. An important, yet poorly explained epidemiological feature of NCDs is their low incidence in under developed areas of low-income countries and rising rates in urban areas. METHODS: With the goal of better understanding how urbanization increases the incidence of NCDs, we provide an overview of the urbanization process in sub-Saharan Africa, discuss gene expression differences between rural and urban populations, and review the current NCD determinant model. We conclude by identifying research priorities. RESULTS: Declining rates of chronic and recurrent infection are the hallmark of urbanization in sub-Saharan Africa. Gene profiling studies show urbanization results in complex molecular changes, with almost one-third of the peripheral blood leukocyte transcriptome altered. The current NCD determinant model could be improved by including a possible effect from declining rates of infection and expanding the spectrum of diseases that increase with urbanization. CONCLUSIONS: Urbanization in sub-Saharan Africa provides a unique opportunity to investigate the mechanism by which the environment influences disease epidemiology. Research priorities include: (1) studies to define the relationship between infection and risk factors for NCDs, (2) explaining the observed differences in the inflammatory response between rural and urban populations, and (3) identification of animal models that simulate the biological changes that occurs with urbanization. A better understanding of the biological changes that occur with urbanization could lead to new prevention and treatment strategies for some of the most common surgical diseases in high-income countries. PMID- 29234851 TI - Correction to: FDG uptake in cervical lymph nodes in children without head and neck cancer. AB - The original version of this article unfortunately contained a mistake. Author name Alaa Bakkari was incorrect. The correct spelling is given above. PMID- 29234850 TI - Normal magnetic resonance appearances of the temporomandibular joints in children and young adults aged 2-18 years. AB - BACKGROUND: Knowledge of normal appearances of the temporomandibular joint (TMJ) is paramount when assessing the joint for disease in juvenile idiopathic arthritis. Reliable features defining normal TMJs in children are limited. OBJECTIVE: To establish reliable normal standards for the TMJ at magnetic resonance imaging (MRI). MATERIALS AND METHODS: We included children and young adults aged 2-18 years undergoing a head MRI for reasons not believed to affect the TMJs. We assessed TMJ anatomy and contrast enhancement using a high resolution 3-D T1-weighted sequence. We noted joint fluid and bone marrow oedema based on a T2-weighted sequence. Three experienced radiologists read all examinations twice in consensus and defined intraobserver consensus agreement. RESULTS: We evaluated the TMJs in 101 children and young adults (45 female), mean age 10.7 years (range 2-18 years). The intraobserver consensus agreement for the assessment of anterior condylar inclination in the sagittal/oblique plane was moderate to good (Cohen kappa=0.7 for the right side). Cohen kappa for intraobserver consensus agreement for condylar shape in the coronal plane on a 0 2 scale was 0.4 for the right and 0.6 for the left. Intraobserver agreement for measurement of joint space height and assessment of bone marrow oedema was poor. There was a statistically significant increase in anterior inclination by age in the sagittal plane on a 0-2 scale (P<0.0001). Eighty percent of the condyles showed a rounded shape in the coronal plane while 20% showed mild flattening. Thirty-five of 36 right TMJs showed contrast enhancement (mild enhancement in 32 joints, moderate in 3 joints). CONCLUSION: Subjective assessment of the anterior condylar inclination in the sagittal/oblique plane and condylar flattening in the coronal plane can be considered precise features for describing TMJ anatomy in healthy children. There is an increasing anterior inclination by age. Mild contrast enhancement of the TMJs should be considered a normal finding. PMID- 29234852 TI - Correction to: Metabolic pathway of 6-aminohexanoate in the nylon oligomer degrading bacterium Arthrobacter sp. KI72: identification of the enzymes responsible for the conversion of 6-aminohexanoate to adipate. AB - The original publication of this paper contains mistakes for Tables 1 and 2 legends as well as the sublabels in Figs. 2, 4, 5, 6, and 7. PMID- 29234853 TI - Invited Commentary: Outcome of In Situ Septoplasty and Extracorporeal Subtotal Septal Reconstruction in Crooked Noses: A Randomized Self-Controlled Study. AB - Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29234854 TI - Commentary for the Article: "A Comparative Study of Full-Thickness Blepharotomy Versus Transconjunctival Eyelid Lengthening in the Correction of Upper Eyelid Retraction in Graves' Orbitopathy". PMID- 29234855 TI - Pedicle De-epithelialization in Reduction Mammoplasty: A Systematic Review of the Literature. AB - BACKGROUND: Reduction mammoplasty is among the most commonly performed plastic surgery procedures. The reduction pedicle is traditionally de-epithelialized. Many practitioners propose that preservation of the subdermal blood supply results in improved circulation for the nipple-areolar complex. However, this is a time-consuming step of the procedure. Presumed benefits have not been definitively demonstrated. OBJECTIVE: To evaluate current evidence regarding pedicle de-epithelialization in inferior pedicle reduction mammoplasty. METHODS: The MEDLINE database was searched for studies evaluating pedicle de epithelialization in reduction mammoplasty surgery. Studies reporting outcomes after reduction mammoplasty with pedicle de-epithelialization and deskinning were included. Additionally, reports detailing novel techniques or modification for pedicle de-epithelialization were evaluated and included. RESULTS: One hundred and thirty-eight articles were identified on a systematic review. Thirty-six articles met the study criteria. This includes 23 reporting outcomes after reduction mammoplasty procedures and 13 describing novel techniques for pedicle de-epithelialization. Of the 23 studies reporting outcomes, 6 studies evaluated deskinning of the pedicle. Two of the six studies directly compared deskinning and de-epithelialization. They reported no significant difference in outcomes. The remaining 17 articles described outcomes of inferior pedicle reduction mammoplasty with pedicle de-epithelialization. Studies evaluating deskinning reported ischemic nipple-areolar complex complication rates between 0 and 1.4%. Studies evaluating de-epithelialization reported ischemic nipple-areolar complex complication rates between 0 and 11.1%. CONCLUSIONS: Pedicle de-epithelialization is commonly performed despite limited definitive evidence evaluating its surgical necessity or benefits. Available evidence suggests deskinning may yield acceptable results; however, further investigation is necessary. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29234856 TI - Modified Island Technique for Prominent Ears. AB - There have been several methods described for the correction of prominent ears, including techniques that excise, bend, suture, score, or cut the auricular cartilage. The Island Technique, proposed by Pitanguy, is based on the creation of a cartilage island to define the antihelix and correct the conchoscaphal angle. Visibility of sharp edges has been the main criticism of this technique. To avoid them, we advise performing an internal bevel incision to round off the edges and achieve a more natural look. Also, sometimes prominent ears are asymmetric with different conchoscaphal angles, determining a residual but protruding upper pole, thus requiring different treatment on each side. For such cases, we propose the additional excision of a cartilage strip from the lower border of the auricular scapha, with a greater conchoscaphal angle. In this way, cartilage islands of similar width and identical antihelixes for both ears are created and a symmetric result is achieved. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29234857 TI - High frequency and wide range of human kidney papillary crystalline plugs. AB - Most of kidney stones are supposed to originate from Randall's plaque at the tip of the papilla or from papillary tubular plugs. Nevertheless, the frequency and the composition of crystalline plugs remain only partly described. The objective was to assess the frequency, the composition and the topography of papillary plugs in human kidneys. A total of 76 papillae from 25 kidneys removed for cancer and without stones were analysed by immunohistochemistry combined with Yasue staining, field emission-scanning electron microscopy and Fourier transformed infrared micro-spectroscopy. Papillary tubular plugs have been observed by Yasue staining in 23/25 patients (92%) and 52/76 papillae (68%). Most of these plugs were made of calcium phosphate, mainly carbonated apatite and amorphous calcium phosphate, and rarely octacalcium phosphate pentahydrate. Calcium and magnesium phosphate (whitlockite) have also been observed. Based upon immunostaining coupled to Yasue coloration, most of calcium phosphate plugs were located in the deepest part of the loop of Henle. Calcium oxalate monohydrate and dihydrate tubular plugs were less frequent and stood in collecting ducts. At last, we observed calcium phosphate plugs deforming and sometimes breaking adjacent collecting ducts. Papillary tubular plugging, which may be considered as a potential first step toward kidney stone formation, is a very frequent setting, even in kidneys of non-stone formers. The variety in their composition and the distal precipitation of calcium oxalate suggest that plugs may occur in various conditions of urine supersaturation. Plugs were sometimes associated with collecting duct deformation. PMID- 29234858 TI - Letter to the editor on "Dislocations after use of dual-mobility cups in cementless primary total hip arthroplasty: prospective multicentre series" by Hwang et al. PMID- 29234859 TI - Correction to: Good response to tolvaptan shortens hospitalization in patients with congestive heart failure. AB - In the original publication of the article, the values of blood urea nitrogen (BUN) and plasma renin activity (PRA) have been published incorrectly and the corrected values are as follows. PMID- 29234860 TI - Impact of right ventricular distensibility on congestive heart failure with preserved left ventricular ejection fraction in the elderly. AB - To elucidate involvement of age-related impairments of right ventricular (RV) distensibility in the elderly congestive heart failure (CHF), we examined the prevalence of less-distensible right ventricle in patients with preserved left ventricular ejection fraction (LVEF) over a wide range of ages. In 893 patients aged from 40 to 102 years, we simultaneously recorded electrocardiogram, phonocardiogram, and jugular venous pulse wave. Using signal-processing techniques, the prominent 'Y' descent of jugular pulse waveform was detected as a hemodynamic sign of a less-distensible right ventricle. Prevalence of less distensible right ventricle and elevated RV systolic pressure increased along with aging from the 50s to the 90s in an exponential fashion from 3.3 and 12% up to 33 and 61%, respectively (p < 0.001 for each). This age-dependent deterioration of ventricular distensibility was not observed for the left ventricle. Higher age and higher RV systolic pressure were independently associated with less-distensible right ventricle (Odds ratio, 1.05 per 1 year, p = 0.003; and 1.03 per 1 mmHg, p = 0.026, respectively). The elderly CHF was associated with high prevalence of the less-distensible right ventricle and higher RV systolic pressure, both of which were independent risk factors for CHF (Odds ratio, 5.27, p = 0.001, and 1.08 per 1 mmHg, p < 0.001, respectively). In elderly patients with preserved LVEF, the combination of a less-distensible right ventricle and a high RV systolic pressure seems to be related to developing CHF. The less-distensible right ventricle and elevated RV systolic pressure are closely associated with CHF with preserved LVEF in the elderly patients. PMID- 29234861 TI - Neural coding of sound envelope structure in songbirds. AB - Songbirds are a well-established animal model to study the neural basis of learning, perception and production of complex vocalizations. In this system, telencephalic neurons in HVC present a state-dependent, highly selective response to auditory presentations of the bird's own song (BOS). This property provides an opportunity to study the neural code behind a complex motor behavior. In this work, we explore whether changes in the temporal structure of the sound envelope can drive changes in the neural responses of highly selective HVC units. We generated an envelope-modified BOS (MOD) by reversing each syllable's envelope but leaving the overall temporal structure of syllable spectra unchanged, which resulted in a subtle modification for each song syllable. We conducted in vivo electrophysiological recordings of HVC neurons in anaesthetized zebra finches (Taeniopygia guttata). Units analyzed presented a high BOS selectivity and lower response to MOD, but preserved the profile response shape. These results show that the temporal evolution of the sound envelope is being sensed by the avian song system and suggest that the biomechanical properties of the vocal apparatus could play a role in enhancing subtle sound differences. PMID- 29234862 TI - Karl T. Neubuerger (1890-1972). PMID- 29234863 TI - Gait analysis in short-term follow-up of medial opening wedge high tibial osteotomy. AB - BACKGROUND: Biomechanical gait changes are proposed as adaptations to medial knee osteoarthritis (OA), and little is known about which parameters can be modified early by high tibial osteotomy (HTO) surgery. The aim of this study was to identify early gait changes in a postoperative period of 6 months as compared to a control group, in three different spatial planes. METHODS: Twenty-one patients with OA were submitted to three-dimensional gait analysis preoperatively and 6 months after HTO surgery. Sixteen healthy individuals were selected for the control group. RESULTS: Compared to the control group, OA patients walked more slowly, with a shorter stride length, and with a higher knee varus and flexion angles. The gait changes detected in the postoperative of 6 months were a significant reduction in knee varus angle and adductor moment in coronal plane; an important reduction in knee extension and an increased extensor moment in sagittal plane; also an increased foot external rotation angle in axial plane was observed. Flexion angle peak in swing phase, adductor and flexor moments were the gait parameters with postoperatively results that were closer to those of the control group. CONCLUSIONS: Even in a short follow-up of 6 months, HTO determines positive results in biomechanical gait, not only in the coronal plane but also in the sagittal and axial planes and should be taken into account during the rehabilitation process. PMID- 29234864 TI - 3D printing lunate prosthesis for stage IIIc Kienbock's disease: a case report. AB - Stage IIIc Kienbock's disease is a clinical challenge to treat collapse of the lunate bone. A new reconstructive surgery was described in one patient using 3D printing lunate prosthesis. The prosthesis shape was designed by tomographic image processing and segmentation using technology compared with the intact side matched by mirror symmetry and 3D post-processing technologies. The patient recovered nearly full range of motion of the wrist after 12 months. The visual analog scale scores and Cooney scores were 2 points and 91 points. We demonstrated that an anatomical reconstruction to Kienbock's Disease is possible using 3D printing lunate prosthesis. PMID- 29234865 TI - Electromechanical heterogeneity in the heart : A key to long QT syndrome? AB - In the healthy heart, physiological heterogeneities in structure and in electrical and mechanical activity are crucial for normal, efficient excitation and pumping. Alterations of heterogeneity have been linked to arrhythmogenesis in various cardiac disorders such as long QT syndrome (LQTS). This inherited arrhythmia disorder is caused by mutations in different ion channel genes and is characterized by (heterogeneously) prolonged cardiac repolarization and increased risk for ventricular tachycardia, syncope and sudden cardiac death. Cardiac electrical and mechanical function are not independent of each other but interact in a bidirectional manner by electromechanical and mechano-electrical coupling. Therefore, changes in either process will affect the other. Recent experimental and clinical evidence suggests that LQTS, which is primarily considered an "electrical" disorder, also exhibits features of disturbed mechanical function and heterogeneity, which in turn appears to correlate with the risk of arrhythmia in the individual patient. In this review, we give a short overview of the current knowledge about physiological and pathological, long QT-related electrical and mechanical heterogeneity in the heart. Also, their respective roles for future risk prediction approaches in LQTS are discussed. PMID- 29234867 TI - Photoconversion of DAPI and Hoechst dyes to green and red-emitting forms after exposure to UV excitation. AB - The fluorescent dye 4'-6-Diamidino-2-phenylindole (DAPI) is frequently used in fluorescence microscopy as a chromosome and nuclear stain because of its high specificity for DNA. Normally, DAPI bound to DNA is maximally excited by ultraviolet (UV) light at 358 nm, and emits maximally in the blue range, at 461 nm. Hoechst dyes 33258 and 33342 have similar excitation and emission spectra and are also used to stain nuclei and chromosomes. It has been reported that exposure to UV can convert DAPI and Hoechst dyes to forms that are excited by blue light and emit green fluorescence, potentially confusing the interpretation of experiments that use more than one fluorochrome. The work reported here shows that these dyes can also be converted to forms that are excited by green light and emit red fluorescence. This was observed both in whole tissues and in mitotic chromosome spreads, and could be seen with less than 10-s exposure to UV. In most cases, the red form of fluorescence was more intense than the green form. Therefore, appropriate care should be exercised when examining tissues, capturing images, or interpreting images in experiments that use these dyes in combination with other fluorochromes. PMID- 29234866 TI - Atrial thrombogenesis in atrial fibrillation : Results from atrial fibrillation models and AF-patients. AB - Atrial fibrillation (AF) is the most common cause of thromboembolic complications. The risk of suffering a thromboembolic complication depends on the accompanying cardiac risk factors and the patient's age. For patients who have an increased risk, which is now classified using the CHA2DS2-VASc score, initiation of long-term oral anticoagulation is the first-line treatment. In AF, thrombi arise in the left atrial appendage. The present review will summarize the basic pathophysiology of thrombogenesis in AF and will provide the molecular basis of a process called prothrombotic endocardial remodeling. Despite oral anticoagulation being a central component of therapy, the present results can be used to support concomitant therapy with statins, angiotensin II blockers, etc. to inhibit atrial thromogenesis. PMID- 29234868 TI - Is there a role for the international prognostic index in follicular lymphoma? PMID- 29234869 TI - A Controlled Trial of Inhaled Bronchodilators in Familial Dysautonomia. AB - BACKGROUND: Chronic lung disease is a leading cause of premature death in patients with familial dysautonomia (FD). A significant number of patients have obstructive airway disease, yet it is not known whether this is pharmacologically reversible. METHODS: We conducted a double-blind, placebo-controlled, randomized clinical trial comparing the beta 2 agonist albuterol with the muscarinic blocker ipratropium bromide in patients homozygous for the IKBKAP founder mutation. Albuterol, ipratropium bromide, and placebo were administered on 3 separate days via nebulizer in the seated position. Airway responsiveness was evaluated using spirometry and impulse oscillometry 30 min post dose. Cardiovascular effects were evaluated by continuous monitoring of blood pressure, RR intervals, cardiac output, and systemic vascular resistance. RESULTS: A total of 14 patients completed the trial. Neither active agent had significant detrimental effects on heart rate or rhythm or blood pressure. Albuterol and ipratropium were similar in their bronchodilator effectiveness causing significant improvement in forced expiratory volume in 1-s (FEV1, p = 0.002 and p = 0.030). Impulse oscillometry measures were consistent with a reduction in total airway resistance post nebulization (resistance at 5 Hz p < 0.006). CONCLUSION: Airway obstruction is pharmacologically reversible in a number of patients with FD. In the short term, both albuterol and ipratropium were well tolerated and not associated with major cardiovascular adverse events. PMID- 29234871 TI - [Curent aspects of dry eye syndrome]. PMID- 29234870 TI - [Good practice procedures for acquisition and preparation of cryopreserved human amniotic membranes from donor placentas]. AB - Within the framework of obtaining a valid authorization for tissue preparation of cryopreserved human amniotic membranes at the Paul Ehrlich Institute, pursuant to S 21a paragraph 1 of the German Medicines Act (AMG), parts of the existing good practice procedures for acquisition of cryopreserved human amniotic membranes from donor placentas were reviewed and supplemented by new knowledge. The present good practice procedures were formulated in cooperation with members of the section for tissue transplantation and biotechnology of the German Ophthalmological Society. The current revised version is presented in this article. PMID- 29234872 TI - [Multimodal imaging in Goldmann-Favre syndrome]. AB - Case report of a 23-year-old male patient suffering from Goldmann-Favre syndrome. The patient reported bilateral visual loss since 10 years of age and difficulties with dark adaptation for 2 years. Until recently a final diagnosis was not found. Multimodal imaging using multicolor fundus imaging (MCFI), optical coherence tomography (OCT), fundus autofluorescence (FAF), fluorescein angiography (FLA), electroretinography (ERG) and visual evoked potential (VEP) confirmed the diagnosis. We describe multimodal imaging of this rare hereditary retinal dystrophy. For diagnosis of Goldmann-Favre syndrome a multimodal examination is helpful. To confirm the diagnosis a genetic analysis is necessary. PMID- 29234873 TI - Predictors for incidence of increased time spent in hospital after ambulatory surgery in children: a retrospective cohort study. AB - PURPOSE: Recently, pediatric ambulatory surgery has become common. However, for some of these patients, unplanned admission or prolonged hospital stay is also necessary, which can increase the mental burden on these patients. The aim of this study was to identify the predictors of the incidence of increased time spent in hospitals associated with pediatric ambulatory surgery. METHODS: Data were obtained from the medical and anesthetic records of 1087 consecutive patients aged < 18 years who underwent ambulatory surgery under general anesthesia. We defined the incidence of increased time spent in a hospital as a composite outcome of unplanned admission and prolonged hospital stay. Multivariate logistic regression analysis was used to examine the associations between the incidence of increased time spent in a hospital and 14 parameters including patient characteristics, anesthesia, and operative factors. RESULTS: Multivariate analysis identified American Society of Anesthesiologist Physical Status (ASA-PS), type of regional block, intraoperative fluid volume, and type of surgery as predictors for the incidence of increased time spent in a hospital. Specifically, caudal block compared to no regional block [odds ratio (OR) (95% confidence interval (CI)) = 0.44 (0.22-0.90)]; increasing intraoperative fluid volume [OR (95% CI) = 0.71 (0.55-0.92) in every increment of 5 ml/kg/h); and ear, nose, and throat (ENT) and urology surgery compared to other types of surgery [OR (95% CI) = 0.13 (0.03-0.64), and 3.93 (1.99-7.77), respectively] were identified as strong predictors. CONCLUSIONS: This study found that the incidence of increased time spent in a hospital in pediatric ambulatory surgery was affected by the type of regional block, intraoperative fluid volume, type of surgery. Potentially modifiable factors, such as intraoperative fluid volume or type of regional block, should be further investigated in future prospective studies. PMID- 29234874 TI - MMAB, a novel candidate gene to be screened in the molecular diagnosis of Mevalonate Kinase Deficiency. AB - Mevalonate kinase deficiency (MKD) is an autosomal recessive inflammatory disease. Mutations in MVK gene are associated with MKD with modest genotype phenotype correlation. In spite of recent guidelines indicating specific MVK mutations for the more severe form or the milder one, little is known about MVK variability within and between populations. The aim of this work is to provide supplementary information about MVK variability useful in the molecular diagnosis of MKD, as well as to unravel the presence of novel genes potentially involved as involved in the clinical heterogeneity of MKD phenotype. We used a population based approach, coupled with Combined Annotation-Dependent Depletion (CADD) score, to analyze the level of genetic variability for common and putatively deleterious MVK variants. We also performed Exome screening with the Illumina Human Exome Bead Chip on 21 MKD patients to double-check our in silico findings. Haplotype block detection in different populations revealed the existence of two blocks in MVK; interestingly, the first haploblock comprises the promoter region shared with MMAB gene. Analyses of MMAB and MVK genetic variants in 21 MKD patients strengthen our observations showing a novel scenario in which the same mutations commonly associated with MKD are found coupled with different combination of MMAB rs7134594 SNP was already described as associated with HDL cholesterol level and present in the haploblock promoter region. The rs7134594 SNP is reported as an eQTL for MVK and MMAB. Hypothesizing the presence of genetic variants modulating the complex phenotypic spectrum of MKD, we suggest that future directions in screening for MKD pathogenic variants should focus both MMAB and MVK genes. PMID- 29234878 TI - 2nd European Conference on Brain Stimulation in Psychiatry (ECBSP): Individualizing Neuromodulation. PMID- 29234875 TI - Chronic disease list conditions in patients with rheumatoid arthritis in the private healthcare sector of South Africa. AB - INTRODUCTION: Little is known about the burden of rheumatoid arthritis (RA) in South Africa. The aim of this study was to establish the prevalence of RA and coexisting chronic disease list (CDL) conditions in the private health sector of South Africa. METHODS: A retrospective, cross-sectional analysis was performed on medicine claims data from 1 January 2014 to 31 December 2014 to establish the prevalence of RA. The cohort of RA patients was then divided into those with and those without CDL conditions, to determine the number and type of CDL conditions per patient, stratified by age group and gender. RESULTS: A total 4352 (0.5%) patients had RA, of whom 69.3% (3016) presented with CDL conditions. Patients had a median age of 61.31 years (3.38; 98.51), and 74.8% were female. Patients with CDL conditions were older than those patients without (p < 0.001; Cohen's d = 0.674). Gender had no influence on the presence of CDL conditions (p = 0.456). Men had relatively higher odds for hyperlipidemia (OR 1.83; CI 1.33-2.51; p < 0.001) and lower odds for asthma (OR 0.83; CI 0.48-1.42; p = 0.490) than women. In combination with hyperlipidemia, the odds for asthma were reversed and strongly increased (OR 6.74; CI 2.07-21.93; p = 0.002). The odds for men having concomitant hyperlipidemia, hypertension, type 2 diabetes mellitus and hypothyroidism were insignificant and low (OR 0.40; CI 0.16-1.02; p = 0.055); however, in the absence of hypothyroidism, the odds increased to 3.26 (CI 2.25 4.71; p < 0.001). CONCLUSION: Hypothyroidism was an important discriminating factor for comorbidity in men with RA. This study may contribute to the body of evidence about the burden of RA and coexisting chronic conditions in South Africa. PMID- 29234879 TI - Calcium phosphate in plant trichomes: the overlooked biomineral. AB - MAIN CONCLUSION: Calcium phosphate was unknown as a plant biomineral until recently reported in Neotropical Loasaceae. Here, we demonstrate its widespread occurrence in the trichomes of several plant families, including Brassicaceae. Calcium phosphate is the primary biomineral in, e.g., the bones and teeth of higher animals; in plants, it was only recently discovered in the stinging hairs and scabrid-glochidiate trichomes of South American Loasaceae (Ensikat et al. in Sci Rep UK 6:26073, 2016), where it appears to be deposited highly specifically, often replacing the common plant biomineral silica. We initiated a broader survey in a range of different plant orders to investigate a possibly wider distribution of calcium phosphate biomineralization in plants. Scanning electron microscopy with EDX element analysis and mapping was used for the detection of the biominerals: calcium phosphate, calcium carbonate, and silica in the trichomes of several common plant species of different orders. Results were authenticated with Raman spectroscopy. Calcium phosphate was found in the trichomes of several species in the orders Malpighiales, Rosales, Boraginales, and Brassicales. It occurred in trichome tips, replacing the more common silica, or together with silica and calcium carbonate at specific locations in the trichome cell walls. Most surprisingly, it was found in the trichomes of Arabidopsis thaliana, one of the most studied plant species-where it had been overlooked so far. The wide distribution of calcium phosphate as plant biomineral here demonstrated and the striking mineralization patterns with three different biominerals in the walls of single-celled trichomes underscore an unexpected complexity in plant biomineralization. PMID- 29234880 TI - Reorganization of wheat and rye genomes in octoploid triticale (* Triticosecale). AB - MAIN CONCLUSION: The analysis of early generations of triticale showed numerous rearrangements of the genome. Complexed transformation included loss of chromosomes, t-heterochromatin content changes and the emergence of retrotransposons in new locations. This study investigated certain aspects of genomic transformations in the early generations (F5 and F8) of the primary octoploid triticale derived from the cross of hexaploid wheat with the diploid rye. Most of the plants tested were hypoploid; among eliminated chromosomes were rye chromosomes 4R and 5R and variable number of wheat chromosomes. Wheat chromosomes were eliminated to a higher extent. The lower content of telomeric heterochromatin was also found in rye chromosomes in comparison with parental rye. Studying the location of selected retrotransposons from Ty1-copia and Ty3 gypsy families using fluorescence in situ hybridization revealed additional locations of these retrotransposons that were not present in chromosomes of parental species. ISSR, IRAP and REMAP analyses showed significant changes at the level of specific DNA nucleotide sequences. In most cases, the disappearance of certain types of bands was observed, less frequently new types of bands appeared, not present in parental species. This demonstrates the scale of genome rearrangement and, above all, the elimination of wheat and rye sequences, largely due to the reduction of chromosome number. With regard to the proportion of wheat to rye genome, the rye genome was more affected by the changes, thus this study was focused more on the rye genome. Observations suggest that genome reorganization is not finished in the F5 generation but is still ongoing in the F8 generation. PMID- 29234881 TI - PCR-DGGE Analysis on Microbial Community Structure of Rural Household Biogas Digesters in Qinghai Plateau. AB - To investigate contribution of environmental factor(s) to microbial community structure(s) involved in rural household biogas fermentation at Qinghai Plateau, we collected slurry samples from 15 digesters, with low-temperature working conditions (11.1-15.7 degrees C) and evenly distributed at three counties (Datong, Huangyuan, and Ledu) with cold plateau climate, to perform polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and further sequencing. The bacterial communities in the total 15 digesters were classified into 38 genera with Mangroviflexus (12.1%) as the first dominant, and the archaeal communities into ten genera with Methanogenium (38.5%) as the most dominant. For each county, the digesters with higher biogas production, designated as HP digesters, exclusively had 1.6-3.1 degrees C higher fermentation temperature and the unique bacterial structure composition related, i.e., unclassified Clostridiales for all the HP digesters and unclassified Marinilabiliaceae and Proteiniclasticum for Ledu HP digesters. Regarding archaeal structure composition, Methanogenium exhibited significantly higher abundances at all the HP digesters and Thermogymnomonas was the unique species only identified at Ledu HP digesters with higher-temperature conditions. Redundancy analysis also confirmed the most important contribution of temperature to the microbial community structures investigated. This report emphasized the correlation between temperature and specific microbial community structure(s) that would benefit biogas production of rural household digesters at Qinghai Plateau. PMID- 29234883 TI - Accuracy of thoracic pedicle screw placement in adolescent patients with severe spinal deformities: a retrospective study comparing drill guide template with free-hand technique. AB - PURPOSE: Patients with severe spinal deformities often have small pedicle diameters, and pedicle dimensions vary between segments and individuals. Free hand pedicle screw placement can be inaccurate. Individualized drill guide templates may be used, but the accuracy of pedicle screw placement in severe scoliosis remains unknown. The accuracy of drill guide templates and free-hand technique for the treatment of adolescent patients with severe idiopathic scoliosis are compared in this study. METHODS: This study included 37 adolescent patients (mean age 16.4 +/- 1.3 years) with severe idiopathic scoliosis treated surgically at a single spine center between January 2014 and June 2017. Spinal deformities were corrected using posterior pedicle screw fixation. Patients in group I were treated with rapid prototype drill guide template technique (20 patients; 396 screws) and patients in group II were treated with free-hand technique (17 patients; 312 screws). Outcomes that included operative time, correction rate, and the incidence and distribution of screw misplacement were evaluated. RESULTS: Operative time in group I was 283 +/- 22.7 min compared to 285 +/- 25.8 min in group II (p = 0.89). The scoliosis correction rate was 55.0% in group I and 52.9% in group II (p = 0.33). Based on both axial and sagittal reconstruction images, the accuracy rate of pedicle screw placement was 96.7% in group I and 86.9% in group II (p = 0.000). CONCLUSION: The drill guide template technique has potential to offer more accurate and thus safer placement of pedicle screws than free-hand technique in the treatment of severe scoliosis in adolescents. PMID- 29234882 TI - The impact of HLA-G, LILRB1 and LILRB2 gene polymorphisms on susceptibility to and severity of endometriosis. AB - Endometriosis is a disease in which endometriotic tissue occurs outside the uterus. Its pathogenesis is still unknown. The most widespread hypothesis claims that ectopic endometrium appears as a result of retrograde menstruation and its insufficient elimination by immunocytes. Some reports have shown expression of non-classical HLA-G molecules on ectopic endometrium. HLA-G is recognized by KIR2DL4, LILRB1 and LILRB2 receptors on natural killer (NK) and other cells. These receptors are polymorphic, which may affect their activity. In this study we investigated whether HLA-G, KIR2DL4, LILRB1 and LILRB2 polymorphisms may influence susceptibility to endometriosis and disease progression. We used polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism (PCR-RFLP) and allelic discrimination methods with TaqMan SNP Genotyping Assays for typing of 276 patients with endometriosis and 314 healthy fertile women. The HLA-G rs1632947:GG genotype was associated with protection against the disease and its severe stages; HLA-G rs1233334:CT protected against progression; LILRB1 rs41308748:AA and LILRB2 rs383369:AG predisposed to the disease and its progression. No effect of KIR2DL4 polymorphism was observed. These results support the role of polymorphisms of HLA-G and its receptors LILRB1 and LILRB2 in susceptibility to endometriosis and its progression. PMID- 29234884 TI - Management of persistent coccydynia with transrectal manipulation: results of a combined procedure. AB - OBJECTIVE: We compared the results of manual therapy combined with steroid injection with single steroid injection in the treatment of persistent coccydynia. PATIENTS AND METHODS: Combined therapy was performed in 21 patients (Group 1) and steroid injection in 23 patients (Group 2). We compared two groups and investigated the combined therapy group in details. Patients were classified according to the underlying cause, BMI, anatomic type of coccyx and duration of symptoms (< 6 or >= 6 months). RESULTS: Mean age was 30.5 years at the time of procedures. Mean followup time was 27.8 months. VAS scores were decreased in both groups but combined therapy group had much more better results. Complete pain relief was achieved in 61.9% of patients in Group 1 whereas it was only 17.4% in Group 2. In 23.8% of Group 1, the VAS score was significantly decreased but the feeling of uncomfortability persisted. This was 73.9% in Group 2. We had no relapse in Group 1 but in Group 2 the relapse rate was 56.5%. Underlying cause, body mass index, anatomic type of coccyx and duration of symptoms had no effect on results. CONCLUSION: Manual therapy combined with steroid injection would be an alternative method in case of persistent coccydynia. It is a safe and easy option before surgical treatment. PMID- 29234885 TI - The influence of related and unrelated co-infections on parasite dynamics and virulence. AB - Many parasitic infections increase the morbidity and mortality of host populations. Interactions between co-infecting parasites can influence virulence, the damage done to a host. Previous studies investigating the impacts of parasite co-infection on hosts have been limited by their inability to control parasite dosage, use consistent virulence metrics, or verify co-infection status. This study used molecular tools, known infection dosage, and multiple assessments over time to test whether parasite relatedness can predict virulence in co-infections, as well as whether competitive interactions between different parasite strains within a host are predictable over time. In addition, we examined the impacts of other parasite traits, such as infectivity, as alternative predictors of virulence and competition outcomes. Hosts with single-strain (related) parasite infections were found to have lower virulence in terms of host and parasite reproduction, supporting kin selection predictions. However, these infections also resulted in higher host mortality. We argue that mortality should not be used as a measurement of virulence in parasite systems that castrate hosts. Hosts were more susceptible to mixed strain (unrelated) parasite infections, indicating that co-infections may make resistance more costly to hosts. Co-infections were dynamic, with changes in parasite dominance over the course of the infection. The more infective parasite strain appeared to suppress the less infective strain, ultimately increasing host longevity. Our findings suggest that unrelated, or more diverse, parasite infections are associated with higher virulence, but that studies must consider their methodology and possible alternative explanations beyond kin selection to understand virulence outcomes. PMID- 29234886 TI - Recovery after intracorporeal anastomosis in laparoscopic right hemicolectomy: a systematic review and meta-analysis. AB - PURPOSE: Although intracorporeal anastomosis (IA) appears to guarantee a faster recovery compared to extracorporeal anastomosis (EA), the data are still unclear. Thus, we performed a systematic review of the literature with meta-analysis to evaluate the recovery benefits of intracorporeal anastomosis. MATERIALS AND METHODS: A systematic search was performed in electronic databases (PubMed, Web of Science, Scopus, EMBASE) using the following search terms in all possible combinations: "laparoscopic," "right hemicolectomy," "right colectomy," "intracorporeal," "extracorporeal," and "anastomosis." According to the pre specified protocol, all studies evaluating the impact of choice of intra- or extracorporeal anastomosis after right hemicolectomy on time to first flatus and stools, hospital stay, and postoperative complications according to Clavien-Dindo classification were included. RESULTS: Sixteen articles were included in the final analysis, including 1862 patients who had undergone right hemicolectomy: 950 cases (IA) and 912 controls (EA). Patients who underwent IA reported a significantly shorter time to first flatus (MD = - 0.445, p = 0.013, Z = - 2.494, 95% CI - 0.795, 0.095), to first stools (MD = - 0.684, p < 0.001, Z = - 4.597, 95% CI - 0.976, 0.392), and a shorter hospital stay (MD = - 0.782, p < 0.001, Z = -3.867, 95% CI - 1.178, - 0.385) than those who underwent EA. No statistically significant differences in complications between the IA and EA patients were observed in the Clavien-Dindo I-II group (RD = - 0.014, p = 0.797, Z = - 0.257, 95% CI - 0.117, 0.090, number needed to treat (NNT) 74) or in the Clavien-Dindo IV-V (RD = - 0.005, p = 0.361, Z = - 0.933, 95% CI - 0.017, 0.006, NNT 184). The IA procedure led to fewer complications in the Clavien-Dindo III group (RD = - 0.041, p = 0.006, Z = - 2.731, 95% CI - 0.070, 0.012, NNT 24). CONCLUSIONS: Although intracorporeal anastomosis appears to be safe in terms of postoperative complications and is potentially more effective in terms of recovery after surgery, further ad hoc randomized clinical trials are needed, given the heterogeneity of the data available in the current literature. PMID- 29234888 TI - Correction to: Plasma levels of hypoxia-regulated factors in patients with age related macular degeneration. AB - The original publication of this paper contains mistakes due to incorrect order of first and last names. PMID- 29234887 TI - iPS cells in the study of PD molecular pathogenesis. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease and its pathogenic mechanisms are poorly understood. The majority of PD cases are sporadic but a number of genes are associated with familial PD. Sporadic and familial PD have many molecular and cellular features in common, suggesting some shared pathogenic mechanisms. Induced pluripotent stem cells (iPSCs) have been derived from patients harboring a range of different mutations of PD-associated genes. PD patient-derived iPSCs have been differentiated into relevant cell types, in particular dopaminergic neurons and used as a model to study PD. In this review, we describe how iPSCs have been used to improve our understanding of the pathogenesis of PD. We describe what cellular and molecular phenotypes have been observed in neurons derived from iPSCs harboring known PD-associated mutations and what common pathways may be involved. PMID- 29234889 TI - Translaminar circuits formed by the pyramidal cells in the superficial layers of cat visual cortex. AB - Pyramidal cells in the superficial layers of the neocortex provide a major excitatory projection to layer 5, which contains the pyramidal cells that project to subcortical motor-related targets. Both structurally and functionally rather little is known about this interlaminar pathway, especially in higher mammals. Here, we made sparse ultrastructural reconstructions of the projection to layer 5 of three pyramidal neurons from layer 3 in cat V1 whose morphology, physiology, and synaptic connections with layers 2 and 3 were known. The dominant targets of the 74 identified synapses in layer 5 were the dendritic spines of pyramidal cells. The fractions of target spiny dendrites were 59, 61, and 84% for the three cells, with the remaining targets being dendrites of smooth neurons. These fractions were similar to the distribution of targets of unlabeled asymmetric synapses in the surrounding neuropil. Serial section reconstructions revealed that the target dendrites were heterogenous in morphology, indicating that different cell types are innervated. This new evidence indicates that the descending projection from the superficial layer pyramidal cells does not simply drive the output pyramidal cells that project to cortical and subcortical targets, but participates in the complex circuitry of the deep cortical layers. PMID- 29234891 TI - Geometry optimization of zirconium sulfophenylphosphonate layers by molecular simulation methods. AB - Classical molecular simulation methods were used for a detailed structural description of zirconium 4-sulfophenylphosphonate and zirconium phenylphosphonate 4-sulfophenylphosphonates with general formula Zr(HO3SC6H4PO3) x (C6H5PO3)2-x .yH2O (x = 0.7-2; y = 0 or 2). First, models describing the structure of zirconium 4-sulfophenylphosphonate (x = 2) were calculated for the hydrated (y = 2) and dehydrated (y = 0) compounds. Subsequently, models for two mixed zirconium phenylphosphonate 4-sulfophenylphosphonates (x = 1.3 and 0.7) were calculated. Optimized models suggest that the presence of water molecules between sulfo groups creates a water-sulfonate layer with a system of hydrogen bonds. We suppose that this arrangement is the reason for a higher proton conductivity of the hydrated samples compared to dehydrated samples. When the water molecules are removed, a small decrease in the basal spacing (around 0.06 A) is observed. This behavior is confirmed by the simulated models, where no significant changes in the structure on dehydration were observed except the absence of the water molecules and a lower number of hydrogen bonds between two adjacent sulfonate sheets. Due to the good crystallinity of the samples and the presence of sharp non-basal peaks in their X-ray diffraction patterns, Miller indices of the non basal peaks in the diffraction patterns calculated from the models can be compared with those found in the experimental data. This allowed us to precisely describe for example (15 5-2) planes, from which mutual distances of the phenyl rings were determined to be 2.62 A. Graphical Abstract Detailed ball and stick view into the interlayer structure of ZrSPhP1.3. PMID- 29234890 TI - Embryo-larvae and juvenile toxicity of Pb and Cd in Northern Chilean scallop Argopecten purpuratus. AB - This study aimed to investigate the effects of Cd and Pb on earlier stage of the commercially important scallop (Argopecten purpuratus) in the contamination context of Northern Chile where this specie is farmed, through acute exposure bioassays in embryo-larvae measuring cumulative abnormality (EC50) and juvenile cumulative mortality (LC50) as endpoints, based on environmentally detected concentrations and available toxicological data from similar species. Embryo larvae exposure indicates 48 h EC50 of 1.55 mg/L Cd, and 0.044 mg/L Pb. On the contrary, 96 h LC50 in juvenile scallops was 0.48 mg/L Cd and 1.47 mg/L Pb. Our results demonstrated differential toxicity between embryo and juvenile scallops that might relate to different primary defense mechanisms or effect in morphological development of individuals in each ontogenetic stage. Compared to similar bivalve metal toxicity tests, this study demonstrated that A. purpuratus embryos are more sensitive to Pb than most other bivalve species. Our results indicate that maximum permitted levels of Pb in marine waters and estuaries (according to Chilean regulation) could pose a risk for scallops' first stage of life (embryo-larvae) development, and needs to be reviewed. Furthermore, Chilean environmental regulations do not have quality standards for marine sediments (currently under discussion), where high levels of metals have been continuously reported. PMID- 29234892 TI - How accurate is the description of ligand-protein interactions by a hybrid QM/MM approach? AB - During the last decades, the application of hybrid quantum mechanical/molecular mechanical (QM/MM) methods has been extended to the field of drug design. In principle, the approximate QM/MM approach offers a more complete description of drug-receptor non-covalent interactions. This is especially true when charge or proton transfer, chelation of metal ions or strong polarization of ligand and protein or surface chemical groups are involved. The aim of this work was to assess the accuracy of calculated non-covalent ligand-protein interaction energies ([Formula: see text]) obtained by the hybrid QM/MM approach employed in QSite/Jaguar of Schrodinger's Small-Molecule Drug Discovery Suite on a set of small-molecule model systems when compared to rigorous QM calculations. The QM/MM approach was used at the density functional theory (DFT) level of theory with 6 31G* basis set, hybrid B3LYP functional and OPLS-2005 force field (DFT-B3LYP/6 31G*//OPLS-2005), a popular combination frequently used in studies on larger and complex biological systems such as drug-receptor complexes. In this work, we did not attempt to compute the most precise interaction energies of the model systems. We rather tried to assess the performance of the approximate QM/MM vs. full QM approach at the same computationally accessible level. For effective use of the QM/MM approach it is essential to select an appropriate QM region of the studied systems. To aid the selection of specific protein residues or functional groups to be included in the QM region, we evaluated the effect of its size, composition and symmetry on the accuracy of the QM/MM calculated [Formula: see text]. This was performed by means of a set of model clusters with well-defined configurations, which mimic the basic types of non-covalent interactions in proteins. Based on these systematic quantitative comparisons, recommendations for the addition of chemical groups or protein residues into the QM region are proposed for the popular DFT-B3LYP/6-31G*//OPLS-2005 QM/MM approach, leading to a more realistic description of ligand-protein interactions. These guidelines can have a significant bearing on computational drug or material research employing hybrid QM/MM methods by providing an estimate of the accuracy that can be expected from QM/MM studies. Graphical abstract An approximate hybrid QM/MM approach at the DFT-B3LYP/6-31G*//OPLS-2005 level was systematically assessed for the accuracy of description of non-covalent interactions on a series of six small molecule model systems using the QSite and Jaguar modules of Schrodinger. Guidelines for rational selection of receptor residues or function groups to be included in the QM region around the ligand were proposed based on the achieved accuracy of computed ligand-protein interaction energies obtained by QM/MM vs. the full QM approach. PMID- 29234893 TI - The clinical relevance of plasma CD147/basigin in biopsy-proven kidney diseases. AB - BACKGROUND: Precise understanding of kidney disease activity is needed to design therapeutic strategies. CD147/basigin is involved in the pathogenesis of acute kidney injury and renal fibrosis through inflammatory cell infiltration. The present study examined the clinical relevance of CD147 in biopsy-proven kidney diseases that lead to the progression of chronic kidney disease. METHODS: Kidney biopsy specimens and plasma and urine samples were obtained from patients with kidney diseases, including IgA nephropathy (IgAN), Henoch-Schonlein purpura nephritis (HSPN), diabetic kidney disease (DKD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN), who underwent renal biopsy between 2011 and 2014. Plasma and urinary CD147 levels were measured and evaluated for their ability to reflect histological features. Disease activity of IgAN tissues was evaluated according to the Oxford classification and the Japanese histological grading system. RESULTS: In biopsy tissues, CD147 induction was detected in injured lesions representing renal inflammation. Plasma CD147 values correlated with eGFR in patients with inflammation-related kidney diseases such as IgAN, HSPN, and DKD. Particularly in IgAN patients, plasma CD147 levels were correlated with injured regions comprising more than 50% of glomeruli or with tubular atrophy/interstitial injury in biopsy tissues. Proteinuria showed a closer correlation with urinary values of CD147 and L-FABP. Of note, plasma and urinary CD147 levels showed a strong correlation with eGFR or proteinuria, respectively, only in DKD patients. CONCLUSION: Evaluation of plasma and urinary CD147 levels might provide key insights for the understanding of the activity of various kidney diseases. PMID- 29234894 TI - Amputation neuroma mimicking lymph node metastasis of remnant gastric cancer: a case report. AB - BACKGROUND: Amputation neuromas (ANs) are reactive hyperplasia of nerve tissues that occur after a trauma or surgery involving the peripheral nerves. Only two previous reports of ANs occurring around the stomach and post gastrectomy have been reported. We report the case of a patient with AN near the remnant stomach who underwent distal gastrectomy for gastric cancer. CASE PRESENTATION: A 76-year old man underwent distal gastrectomy, D1+ lymphadenectomy, and Billroth-I reconstruction for early gastric cancer in another hospital at 63 years of age. A regular gastrointestinal endoscopic follow-up examination after gastrectomy revealed an ulcerative lesion on the lesser curvature of the remnant stomach, which was diagnosed as remnant gastric cancer based on the histopathological examination. Then, he was transferred to our hospital. An upper gastrointestinal series and endoscopy revealed an 18-mm Type 0-IIc lesion on the lesser curvature of the remnant stomach with an estimated depth within the mucosa (T1a). An abdominal contrast-enhanced computed tomography (CT) failed to detect the primary lesion; however, a slightly enhanced 13 * 10-mm nodule was detected near the lesser curvature of the remnant stomach. An endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) of the nodule showed no cancer cell; thus, endoscopic submucosal dissection (ESD) for the remnant gastric cancer was performed. Histopathological examination revealed noncurative resection due to T1b2 and UL (+). We planned an additional surgical resection. Before the resection, CT was performed, which had a 3-month interval with a previous CT, showing an enlargement of the nodule to 16 * 12 mm. We diagnosed the nodule as a lymph node metastasis and performed resection of the remnant stomach, D2 lymphadenectomy, splenectomy, and Roux-en-Y reconstruction. The nodule was later diagnosed as AN based on the histopathological examination. There was no residual cancer in the resected specimen. CONCLUSIONS: We report AN mimicking lymph node metastasis near the remnant stomach of a patient with remnant gastric cancer. When nodules appear in the previous operative field, the possibility of ANs should be considered, although the incidence may be quite low. PMID- 29234895 TI - Intestinal Stem Cells to Advance Drug Development, Precision, and Regenerative Medicine: A Paradigm Shift in Translational Research. AB - Recent advances in our understanding of the intestinal stem cell niche and the role of key signaling pathways on cell growth and maintenance have allowed the development of fully differentiated epithelial cells in 3D organoids. Stem cell derived organoids carry significant levels of proteins that are natively expressed in the gut and have important roles in drug transport and metabolism. They are, therefore, particularly relevant to study the gastrointestinal (GI) absorption of oral medications. In addition, organoids have the potential to serve as a robust preclinical model for demonstrating the effectiveness of new drugs more rapidly, with more certainty, and at lower costs compared with live animal studies. Importantly, because they are derived from individuals with different genotypes, environmental risk factors and drug sensitivity profiles, organoids are a highly relevant screening system for personalized therapy in both human and veterinary medicine. Lastly, and in the context of patient-specific congenital diseases, orthotopic transplantation of engineered organoids could repair and/or replace damaged epithelial tissues reported in various GI diseases, such as inflammatory bowel disease, cystic fibrosis, and tuft enteropathy. Ongoing translational research on organoids derived from dogs with naturally occurring digestive disorders has the potential to improve the predictability of preclinical models used for optimizing the therapeutic management of severe chronic enteropathies in human patients. PMID- 29234896 TI - Correction to: Multicenter phase II study of trastuzumab plus S-1 alone in elderly patients with HER2-positive advanced gastric cancer (JACCRO GC-06). AB - The correct name of the twelfth author should be ''Yasuhiro Yuasa", and not ''Yasuhiko Yuasa'' as given in the original publication of the article. PMID- 29234897 TI - Potential influence of the phthalates on normal liver function and cardiometabolic risk in males. AB - Phthalates are ubiquitous environmental contaminants, massively used in industry as plasticizers and additives in cosmetics, which may impair the human endocrine system inducing fertility problems, respiratory diseases, obesity, and neuropsychological disorders. The aim of this study was to examine the influence of the monoethyl phthalate (MEP) and mono-(2-ethylhexyl) phthalate (MEHP) on the liver function and cardiometabolic risk factors in males. In this research, 102 male participants (51 normal weight and 51 overweight/obese) were enrolled and examined for phthalate metabolites exposure in urine samples after 12 h of fasting. MEP was found in 28.43% (29/102) volunteers, while MEHP was detected among 20.59% (21/102) participants. Statistically significant increment in transaminase serum levels was observed in MEP-positive normal weight subgroup. Linear correlation was obtained between MEP concentration in urine samples and triglyceride (TG) serum levels (r 2 = 0.33; p < 0.01), visceral adiposity index (VAI) (r 2 = 0.41; p < 0.01), lipid accumulation product (LAP) (r 2 = 0.32; p < 0.01), and TG to high-density lipoprotein (HDL) ratio (r 2 = 0.40, p < 0.01) among the obese. The MEHP-positive normal weight volunteers had statistically significant increment of body mass index (p = 0.03) compared to MEHP-negative participants. Urine MEHP concentrations were negatively correlated with HDL serum levels (r 2 = 0.31; p < 0.05) in the normal weight subgroup. The phthalates exposure may be related to statistically significant ALT and AST serum levels increment as well as with increased BMI, while the phthalate levels in the urine may be correlated with increased TG and decreased HDL cholesterol serum levels and associated with indicators of cardiometabolic risk and insulin resistance as LAP and VAI. PMID- 29234899 TI - Correction to: Ten-year results of accelerated hypofractionated adjuvant whole breast radiation with concomitant boost to the lumpectomy cavity after conserving surgery for early breast cancer. AB - An error inadvertently occurred in the discussion of the original publication when citing the local relapse rates of the EORTC 22881-10882 trial ('boost vs no boost trial'). PMID- 29234900 TI - Trace lithium and mental health. AB - Lithium therapy is generally accepted as a first-line treatment for bipolar disorder, and it is also identified as one of the best augmenting options for treatment-resistant depression. Furthermore, lithium has been investigated in association with suicide, dementia and aggressiveness. In this review, we examined articles about the effects of very small amounts of lithium in treating suicide, dementia, bipolar disorder and temperament, to assess the present state of trace lithium's effect on mental state. The results indicate that trace lithium may be effective for suicide prevention but randomized, placebo controlled trials are required to draw a definite conclusion. Indications for using trace lithium in treating such conditions as dementia, bipolar disorder and temperament are supported by very limited evidence and such effects are yet to be determined. PMID- 29234898 TI - The detour paradigm in animal cognition. AB - In this paper, we review one of the oldest paradigms used in animal cognition: the detour paradigm. The paradigm presents the subject with a situation where a direct route to the goal is blocked and a detour must be made to reach it. Often being an ecologically valid and a versatile tool, the detour paradigm has been used to study diverse cognitive skills like insight, social learning, inhibitory control and route planning. Due to the relative ease of administrating detour tasks, the paradigm has lately been used in large-scale comparative studies in order to investigate the evolution of inhibitory control. Here we review the detour paradigm and some of its cognitive requirements, we identify various ecological and contextual factors that might affect detour performance, we also discuss developmental and neurological underpinnings of detour behaviors, and we suggest some methodological approaches to make species comparisons more robust. PMID- 29234901 TI - Upper limb function in children with attention-deficit/hyperactivity disorder (ADHD). AB - Upper limb function was investigated in children with ADHD using objective methods. We hypothesised that children with ADHD exhibit abnormal dexterity, force application during manipulation of a novel object, and movement rhythmicity. Two groups of age- and gender-matched children were investigated: 35 typically developing children (controls, 10.5 +/- 0.4 years, 32M-3F) and 29 children (11.5 +/- 0.5 years, 27M-2F) with formally diagnosed ADHD according to DSM-IV-TR criteria. Participants underwent a series of screening tests and tests of upper limb function while "off" medication. Objective quantification of upper limb function involved measurement of force during a grip and lift task, maximal finger tapping task, and maximal pinch grip. Acceleration at the index finger was also measured during rest, flexion and extension, and a postural task to quantify tremor. The Movement Assessment Battery for Children-2 (MABC-2) was also administered. Significant between-group differences were observed in movement rhythmicity, manipulation of a novel object, and performance of the MABC-2 dexterity and aiming and catching components. Children with ADHD lifted a novel object using a lower grip force (P = 0.036), and held the object with a more variable grip force (P = 0.003), than controls. Rhythmicity of finger tapping (P = 0.008) and performance on the dexterity (P = 0.007) and aiming and catching (P = 0.042) components of the MABC-2 were also significantly poorer in the ADHD group than controls. Movement speed, maximum pinch grip strength, and tremor were unaffected. The results of the study show for the first time that ADHD is associated with deficits in multiple, but not all domains of upper limb function. PMID- 29234902 TI - Correction to: Molecular imaging of advanced thyroid cancer: iodinated radiotracers and beyond. AB - The original version of this article unfortunately contained a mistake. The middle name of the author Steven B. Rowe is incorrect. The corrected name is Steven P. Rowe. PMID- 29234903 TI - Biodistribution and radiation dosimetry of [64Cu]copper dichloride: first-in human study in healthy volunteers. AB - BACKGROUND: In recent years, Copper-64 (T1/2 = 12.7 h) in the chemical form of copper dichloride ([64Cu]CuCl2) has been identified as a potential agent for PET imaging and radionuclide therapy targeting the human copper transporter 1, which is overexpressed in a variety of cancer cells. Limited human biodistribution and radiation dosimetry data is available for this tracer. The aim of this research was to determine the biodistribution and estimate the radiation dosimetry of [64Cu]CuCl2, using whole-body (WB) PET scans in healthy volunteers. Six healthy volunteers were included in this study (3 women and 3 men, mean age +/- SD, 54.3 +/- 8.6 years; mean weight +/- SD, 77.2 +/- 12.4 kg). After intravenous injection of the tracer (4.0 MBq/kg), three consecutive WB emission scans were acquired at 5, 30, and 60 min after injection. Additional scans were acquired at 5, 9, and 24 h post-injection. Low-dose CT scan without contrast was used for anatomic localization and attenuation correction. OLINDA/EXM software was used to calculate human radiation doses using the reference adult model. RESULTS: The highest uptake was in the liver, followed by lower and upper large intestine walls, and pancreas, in descending order. Urinary excretion was negligible. The critical organ was liver with a mean absorbed dose of 310 +/- 67 MUGy/MBq for men and 421 +/- 56 MUGy/MBq for women, while the mean WB effective doses were 51.2 +/ 3.0 and 61.8 +/- 5.2 MUSv/MBq for men and women, respectively. CONCLUSIONS: To the best of our knowledge, this is the first report on biodistribution and radiation dosimetry of [64Cu]CuCl2 in healthy volunteers. Measured absorbed doses and effective doses are higher than previously reported doses estimated with biodistribution data from patients with prostate cancer, a difference that could be explained not just due to altered biodistribution in cancer patients compared to healthy volunteers but most likely due to the differences in the analysis technique and assumptions in the dose calculation. PMID- 29234905 TI - Correction to: Combined gene expression and proteomic analysis of EGF induced apoptosis in A431 cells suggests multiple pathways trigger apoptosis. AB - The original version of this article unfortunately contained a mistake. The affiliation of first author Dr. Ibrahim Alanazi was incorrect. PMID- 29234904 TI - Post genomics era for orchid research. AB - Among 300,000 species in angiosperms, Orchidaceae containing 30,000 species is one of the largest families. Almost every habitats on earth have orchid plants successfully colonized, and it indicates that orchids are among the plants with significant ecological and evolutionary importance. So far, four orchid genomes have been sequenced, including Phalaenopsis equestris, Dendrobium catenatum, Dendrobium officinale, and Apostaceae shengen. Here, we review the current progress and the direction of orchid research in the post genomics era. These include the orchid genome evolution, genome mapping (genome-wide association analysis, genetic map, physical map), comparative genomics (especially receptor like kinase and terpene synthase), secondary metabolomics, and genome editing. PMID- 29234906 TI - Polyaniline-Coated Activated Carbon Aerogel/Sulfur Composite for High-performance Lithium-Sulfur Battery. AB - An activated carbon aerogel (ACA-500) with high surface area (1765 m2 g-1), pore volume (2.04 cm3 g-1), and hierarchical porous nanonetwork structure is prepared through direct activation of organic aerogel (RC-500) with a low potassium hydroxide ratio (1:1). Based on this substrate, a polyaniline (PANi)-coated activated carbon aerogel/sulfur (ACA-500-S@PANi) composite is prepared via a simple two-step procedure, including melt-infiltration of sublimed sulfur into ACA-500, followed by an in situ polymerization of aniline on the surface of ACA 500-S composite. The obtained ACA-500-S@PANi composite delivers a high reversible capacity up to 1208 mAh g-1 at 0.2C and maintains 542 mAh g-1 even at a high rate (3C). Furthermore, this composite exhibits a discharge capacity of 926 mAh g-1 at the initial cycle and 615 mAh g-1 after 700 cycles at 1C rate, revealing an extremely low capacity decay rate (0.480/00 per cycle). The excellent electrochemical performance of ACA-500-S@PANi can be attributed to the synergistic effect of hierarchical porous nanonetwork structure and PANi coating. Activated carbon aerogels with high surface area and unique three-dimensional (3D) interconnected hierarchical porous structure offer an efficient conductive network for sulfur, and a highly conductive PANi-coating layer further enhances conductivity of the electrode and prevents the dissolution of polysulfide species. PMID- 29234907 TI - Rheotropism of the dowser texture. AB - In spite of its metastability, the pseudo-planar texture of a nematic layer confined between surfaces with homeotropic anchoring can be preserved indefinitely in certain conditions. The pseudo-planar texture, dubbed "the dowser texture", is degenerated and therefore sensitive to perturbations. It has been shown recently that the dowser texture is cuneitropic, that is to say, has a tendency to follow thickness gradients. Here, we point out that the dowser texture is also rheotropic or, in other words, has a weathercock behavior: it tends to follow the direction of Poiseuille flows. We observed this behavior in two experiments. In the first one it appears as a deformation of a wound up dowser texture submitted to a slowly alternating linear Poiseuille flow. In the second one we study rheotropic effects of elliptical flow patterns generated by modulation of the gap thickness in a system made of a rigid lens and a flexible glass slide. We show that such elliptical flows can wind the dowser texture and therefore can be used in studies of generation and annihilation of nematic monopoles. PMID- 29234908 TI - Characterization of type IV antifreeze gene in Nile tilapia (Oreochromis niloticus) and influence of cold and hot weather on its expression and some immune-related genes. AB - The aim of this work is to study the effect of the thermal stress of ambient temperature during winter and summer on the expression of type IV antifreeze gene (ANF IV) in different tissues of Nile tilapia (Oreochromis niloticus) as well as some immune-related genes. At first, genomic ANF IV gene was characterized from one fish; 124 amino acids were identified with 92.7% similarity with that on the gene bank. Expression of ANF IV and immune-related genes were done twice, once at the end of December (winter sample, temperature 14 degrees C) and the other at August (summer sample, temperature 36 degrees C). Assessment of ANF IV gene expression in different organs of fish was done; splenic mRNA was used for assessment of immune-related gene transcripts (CXCl2 chemokine, cc-chemokine, INF 3A, and MHC IIbeta). Winter expression analysis of AFP IV in O. niloticus revealed significant upregulation of mRNA transcript levels in the intestine, gills, skin, spleen, liver, and brain with 324.03-, 170.06-, 107.63-, 97.61-, 94.35-, and 27.85-folds, respectively. Furthermore, upregulation in the gene was observed in some organs during summer: in the liver, gills, skin, intestine, and brain with lower levels compared with winter. The level of expression of immune related genes in winter is significantly higher than summer in all assessed genes. Cc-chemokine gene expression was the most affected in both winter and summer. Variable expression profile of ANF IV in different organs and in different seasons together with its amino acid similarity of N-terminal and C terminal with apolipoprotein (lipid binder) and form of high-density lipoprotein (HDL) suggests a different role for this protein which may be related to lipid metabolism. PMID- 29234909 TI - An era of biological treatment in systemic lupus erythematosus. PMID- 29234910 TI - Ultrasonography of occipital arteries to diagnose giant cell arteritis: a case series and literature review. AB - We describe four cases of giant cell arteritis (GCA) that presented with occipital headache in the last 6 months. Typical ultrasound features of GCA were found in the occipital arteries which helped to confirm the diagnosis. One patient had already suffered significant visual loss by the time the diagnosis was made, reflecting the similarity in prognosis to the more typical GCA patients. These cases prompted a review of the literature to evaluate the evidence regarding the use of occipital artery ultrasonography in the investigation of GCA. We searched PubMed, Google Scholar and Web of Science and identified 17 papers but only four of these were relevant studies. The studies available show that typical features of GCA can be detected in the occipital arteries using ultrasonography. They also suggest that ultrasonography can detect changes in the occipital arteries when temporal arteries are not involved. However, occipital artery abnormalities were less common than temporal artery abnormalities in GCA. We advocate maintaining a high index of suspicion for GCA in patients presenting with atypical features, such as occipital headache. Ultrasonography has a vital role to play in the diagnosis of these patients. We recommend priority imaging of the affected area to facilitate prompt and accurate diagnosis of GCA, especially when atypical vessels are involved. PMID- 29234911 TI - Increased DOT1L in synovial biopsies of patients with OA and RA. AB - The studies aimed to determine the changes of histone methylation in synovial tissues of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Synovial tissues were obtained from 30 patients including 12 OA, 16 RA, and 2 trauma that were used as control. A histone methyltransferase DOT1L of the tissues was examined for transcript level with quantitative RT-PCR and protein expression with western blot. Methylation status of DOT1L substrate, H3K79, was examined with immunohistochemistry and western blot. Two-tailed non-pair T test and chi-square test were applied for age/disease duration and gender distribution, respectively. Kruskal-Wallis test and Post hoc Dunn's test were used for examine the difference between control, OA and RA. Both transcript and protein levels of DOT1L appeared the highest in synovial tissues of RA patients and increased in that of OA patients compared to the controls with ratios of 13.8/4.7/1 and 15.5/11.2/1.0 for RA/OA/control, respectively. The changes between RA and control, and RA and OA patients were statistically significant. Both immunohistochemistry study and western blot showed an increased methylation of H3K79 in synovial tissues of OA and RA patients. Gene and protein expression of DOT1L was increased in synovial tissues of both OA and RA patients. A high level of di-methylated H3K79 was also observed in the patients. Considering the important functions of DOT1L and H3K79 contributing to the initiation and maintenance of active transcription in the genome, these unprecedented findings, although still unclear how to impact diseases, may provide novel insights to further explore pathological mechanism of OA and RA. PMID- 29234912 TI - Advanced CT acquisition protocol with a third-generation dual-source CT scanner and iterative reconstruction technique for comprehensive prosthetic heart valve assessment. AB - OBJECTIVES: Multidetector CT (MDCT) is a valuable tool for functional prosthetic heart valve (PHV) assessment. However, radiation exposure remains a concern. We assessed a novel CT-acquisition protocol for comprehensive PHV evaluation at limited dose. METHODS: Patients with a PHV were scanned using a third-generation dual-source CT scanner (DSCT) and iterative reconstruction technique (IR). Three acquisitions were obtained: a non-enhanced scan; a contrast-enhanced, ECG triggered, arterial CT angiography (CTA) scan with reconstructions at each 5 % of the R-R interval; and a delayed high-pitch CTA of the entire chest. Image quality was scored on a five-point scale. Radiation dose was obtained from the reported CT dose index (CTDI) and dose length product (DLP). RESULTS: We analysed 43 CT examinations. Mean image quality score was 4.1+/-1.4, 4.7+/-0.5 and 4.2+/-0.6 for the non-contrast-enhanced, arterial and delayed acquisitions, respectively, with a total mean image quality of 4.3+/-0.7. Mean image quality for leaflet motion was 3.9+/-1.4. Mean DLP was 28.2+/-17.1, 457.3+/-168.6 and 68.5+/-47.2 mGy.cm for the non-contrast-enhanced (n=40), arterial (n=43) and delayed acquisition (n=43), respectively. The mean total DLP was 569+/-208 mGy.cm and mean total radiation dose was 8.3+/-3.0 mSv (n=43). CONCLUSION: Comprehensive assessment of PHVs is possible using DSCT and IR at moderate radiation dose. KEY POINTS: * Prosthetic heart valve dysfunction is a potentially life-threatening condition. * Dual source CT can adequately assess valve leaflet motion and anatomy. * We assessed a comprehensive protocol with three acquisitions for PHV evaluation. * This protocol is associated with good image quality and limited dose. PMID- 29234913 TI - Prediction of the histopathologic findings of intrahepatic cholangiocarcinoma: qualitative and quantitative assessment of diffusion-weighted imaging. AB - OBJECTIVE: To correlate qualitative and quantitative diffusion weighted imaging (DWI) characteristics of intrahepatic cholangiocarcinoma (ICC) with histopathologic tumour grade and fibrosis content. METHODS: Fifty-one patients (21M/30F; mean age 61y) with ICC and MRI including DWI were included in this IRB approved multicentre retrospective study. Qualitative tumour features were assessed. Tumour apparent diffusion coefficient (ADC) mean, minimum, and normalized (nADCliver) values were computed. Tumour grade [well(G1), moderately(G2), or poorly differentiated(G3)] and tumour fibrosis content [minimal(1), moderate(2), or abundant(3)] were categorized pathologically. Imaging findings and ADC values were compared with pathologic measures. Utility of ADC values for predicting tumour grade was assessed using ROC analysis. RESULTS: 51 ICCs (mean size 6.5+/-1.1 cm) were assessed. 33/51(64%) of ICCs demonstrated diffuse hyperintensity and 15/51(29%) demonstrated target appearance on DWI. Infiltrative morphology (p=0.02) and tumour size (p=0.04) were associated with G3. ADCmean and nADCmean of G3 (1.32+/-0.47x10-3 mm2/sec and 0.97+/-0.95) were lower than G1+G2 (1.57+/-0.39x10-3 mm2/sec and 1.24+/-0.49; p=0.03 and p=0.04). ADCmean and nADCmean were inversely correlated with tumour grade (p<0.025). No correlation was found between ADC and tumour fibrosis content. AUROC, sensitivity and specificity of nADCmean for G3 versus G1+G2 were 0.71, 89.5% and 55.5%. CONCLUSION: ADC quantification has reasonable accuracy for predicting ICC grade. KEY POINTS: * ADC quantification was useful for predicting ICC tumour grade. * Infiltrative tumour morphology and size were associated with poorly differentiated ICCs. * ADC values depended more on ICC tumour grade than fibrosis content. * Ability to predict ICC tumour grade non-invasively could impact patient management. PMID- 29234914 TI - Discriminating MGMT promoter methylation status in patients with glioblastoma employing amide proton transfer-weighted MRI metrics. AB - OBJECTIVES: To explore the feasibility of using amide proton transfer-weighted (APTw) MRI metrics as surrogate biomarkers to identify the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status in glioblastoma (GBM). METHODS: Eighteen newly diagnosed GBM patients, who were previously scanned at 3T and had a confirmed MGMT methylation status, were retrospectively analysed. For each case, a histogram analysis in the tumour mass was performed to evaluate several quantitative APTw MRI metrics. The Mann-Whitney test was used to evaluate the difference in APTw parameters between MGMT methylated and unmethylated GBMs, and the receiver-operator-characteristic analysis was further used to assess diagnostic performance. RESULTS: Ten GBMs were found to harbour a methylated MGMT promoter, and eight GBMs were unmethylated. The mean, variance, 50th percentile, 90th percentile and Width10-90 APTw values were significantly higher in the MGMT unmethylated GBMs than in the MGMT methylated GBMs, with areas under the receiver operator-characteristic curves of 0.825, 0.837, 0.850, 0856 and 0.763, respectively, for the discrimination of MGMT promoter methylation status. CONCLUSIONS: APTw signal metrics have the potential to serve as valuable imaging biomarkers for identifying MGMT methylation status in the GBM population. KEY POINTS: * APTw-MRI is applied to predict MGMT promoter methylation status in GBMs. * GBMs with unmethylated MGMT promoter present higher APTw-MRI than methylated GBMs. * Multiple APTw histogram metrics can identify MGMT methylation status. * Mean APTw values showed the highest diagnostic accuracy (AUC = 0.825). PMID- 29234916 TI - Do acute effects of exercise on vascular function predict adaptation to training? AB - PURPOSE: No previous study has explored the importance of exercise-induced changes in vascular function to prolonged adaptations. Therefore, the purpose was to explore the within-subject relationship between the acute post-exercise change in brachial artery endothelial function (flow-mediated dilation, FMD) and the change in resting FMD after a 2-week exercise training in healthy volunteers. METHODS: Twenty one healthy, young men (24 +/- 5 years) underwent assessment of brachial artery FMD using high-resolution ultrasound before and after 30-min of moderate-intensity cycle exercise (80% maximal heart rate). Subsequently, subjects performed five 30-min cycle exercise bouts at 80% maximal heart rate across a 2-week period, followed by repeat assessment of resting brachial FMD post-training. RESULTS: Correcting for changes in diameter and shear, FMD did not change after the initial exercise bout (P = 0.26). However, a significant correlation was found between post-exercise changes in FMD and adaptation in resting FMD after training (r = 0.634, P = 0.002), where an acute decrease in post-exercise FMD resulted in a decrease in baseline FMD after 2 weeks and vice versa. We also found a positive correlation between antegrade shear rate during exercise and change in FMD% after acute exercise and after exercise training (r = 0.529 and 0.475, both P < 0.05). CONCLUSION: Our findings suggest that acute post exercise changes in vascular function are related to changes in resting FMD after a 2-week endurance exercise training period in healthy men, an effect that may be related to exercise-induced increases in antegrade shear rate. This provides further insight into the relevance of acute changes in shear and FMD for subsequent adaptation. PMID- 29234915 TI - The impact of exertional-heat stress on gastrointestinal integrity, gastrointestinal symptoms, systemic endotoxin and cytokine profile. AB - PURPOSE: The study aimed to determine the effects of exertional-heat stress on gastrointestinal integrity, symptoms, systemic endotoxin and inflammatory responses; and assess the relationship between changes in body temperature and gastrointestinal perturbations. METHODS: Ten endurance runners completed 2 h running at 60% [Formula: see text]O2max in hot (HOT: 35 degrees C) and temperate (TEMP: 22 degrees C)-ambient conditions. Rectal temperature (T re) and gastrointestinal symptoms were recorded every 10 min during exercise. Blood samples were collected pre- and post-exercise, and during recovery to determine plasma intestinal fatty acid binding protein (I-FABP), cortisol, bacterial endotoxin and cytokine profile. Calprotectin was determined from pre- and post exercise faecal samples. Urinary lactulose:L-rhamnose ratio was used to measure intestinal permeability. RESULTS: Compared with TEMP, HOT significantly increased T re (1.4 +/- 0.5 vs 2.4 +/- 0.8 degrees C, p < 0.001), cortisol (26 vs 82%, p < 0.001), I-FABP (127 vs 432%, p < 0.001), incidence (70 vs 90%) and severity (58 counts vs 720 counts, p = 0.008) of total gastrointestinal symptoms. Faecal calprotectin and circulating endotoxin increased post-exercise in both trials (mean increase 1.5 +/- 2.5 ug/g, p = 0.032, and 6.9 +/- 10.3 pg/ml, p = 0.047, respectively), while anti-endotoxin antibodies increased 28% post-exercise in TEMP and decreased 21% in HOT (p = 0.027). However, intestinal permeability did not differ between trials (p = 0.185). Inflammatory cytokines were greater on HOT compared to TEMP (p < 0.05). Increases in T re were positively associated with I FABP, IL-10, cortisol, nausea and urge to regurgitate (p < 0.05). CONCLUSIONS: Exertional-heat stress induces a thermoregulatory strain that subsequently injures the intestinal epithelium, reduces endotoxin clearance capacity, promotes greater cytokinaemia, and development of gastrointestinal symptoms. PMID- 29234917 TI - Cardiovascular and metabolic responses during indoor climbing and laboratory cycling exercise in advanced and elite climbers. AB - PURPOSE: To validate heart rate (f H) as an effective indicator of the aerobic demands of climbing, the f H vs oxygen uptake ([Formula: see text]) relationship determined during cycling exercise and climbing on a circular climbing treadwall was compared. Possible differences in maximum aerobic characteristics between advanced and elite climbers were also assessed. METHODS: Seven advanced and six elite climbers performed a discontinuous incremental test on a cycle ergometer and a similar test on a climbing treadwall. Cardiorespiratory and gas exchange parameters were collected at rest and during exercise. RESULTS: The f H vs [Formula: see text] relationship was steeper during cycling than climbing at submaximal exercise for both groups and during climbing in the elite climbers as compared to the advanced. At peak exercise, [Formula: see text] was similar during both cycling and climbing (3332 +/- 115 and 3193 +/- 129 ml/min, respectively). Despite similar [Formula: see text], the elite climbers had a higher peak workload during climbing (11.8 +/- 0.8 vs 9.2 +/- 0.3 m/min in elite and advanced climbers, respectively; P = .024) but not during cycling (291 +/- 13 and 270 +/- 12 W in elite and advanced climbers, respectively). CONCLUSIONS: Our findings indicate that care should be taken when energy expenditure during climbing is estimated from the f H vs [Formula: see text] relationship determined in the laboratory. The level of climbing experience significantly affects the energy cost of exercise. Last, the similar aerobic demands of cycling and climbing at peak exercise, suggest that maximum [Formula: see text]may play an important role in climbing performance. Specific training methodologies should be implemented to improve aerobic power in climbers. PMID- 29234918 TI - Patients with dementia in acute care hospitals : A cross-sectional study of physicians' experiences and attitudes. AB - BACKGROUND: Patients with dementia (PwD) are a vulnerable group and caring for these patients in acute care hospitals is challenging. Structural conditions and standardized treatment procedures in hospitals often do not correspond to the needs of this patient group. Physicians may not be well prepared for caring for PwD. OBJECTIVE: This study aimed to ascertain physicians' experiences and attitudes in caring for PwD or cognitive disorders and their subjective workload. This describes physicians' estimation of the share of the overall workload resulting from caring for PwD on the ward. Furthermore, we identified factors that are most likely to contribute to the workload. MATERIAL AND METHODS: An online survey was conducted using a self-developed standardized questionnaire with 29 questions based on a systematic literature review. The questionnaire was pretested in several steps and finally sent out via e-mail to 610 physicians in 9 hospitals in northern Germany. Aspects surveyed were: physicians' confidence in caring for PwD and resulting workload, challenges in caring for PwD, collaboration with relatives and other professionals and educational needs. Important influencing factors were determined by multiple linear regression analyses. RESULTS: A total of 192 hospital physicians completed the questionnaire (response rate 32%). According to respondents the proportion of PwD in acute care hospitals increased significantly during the last 3 years. Only one third of respondents reported feeling confident in caring for PwD and 65% stated that they do not feel confident in caring for PwD especially in situations of nutrition in cases of food refusal and distinguishing between delirium and dementia. The strongest influencing factors were increased efforts in terms of time and support needs, complex medical situations, difficult collaboration with relatives and lack of patient compliance. A successful collaboration with other professionals was associated with increased confidence in caring for PwD. Legal and ethical aspects as well as drug therapies were mentioned as desirable topics for educational programs. CONCLUSION: A relevant number of hospital physicians feel insecure and burdened in caring for PwD. The study provides important information for the design of educational programs and for potential changes in structural and procedural aspects. The results may be used as starting points for improving hospital care for PwD. PMID- 29234919 TI - [Soft skills : Somewhat different doping]. AB - Doping actually means the taking of illegal substances or the use of forbidden methods to increase or maintain performance. Diseases associated with age and functional decline can lead to constraints in the activities of daily living and this leads to loss of autonomy; therefore, doping in its different variations is used to try to achieve performance, which would not otherwise be possible. A somewhat different method is soft skills, i.e. personal, social and methodological competences, which are adopted to remain fit with the help of selection and compensation. One of the main cornerstones for healthy aging apart from medical interventions is physical activity and to keep training up to old age. An early beginning with sports activities and to continue practicing sport in a variety of forms into old age, plays a decisive role in healthy aging. There are also many recommendations for nutrition, such as changing eating habits and the composition of nourishment to counteract the process of aging. With increasing age the interests and life style also change and therefore early planning is absolutely necessary. Preservation of cognitive capabilities is one of the most important requirements to overcome aging. Not only the cognitive resources must be promoted but also attention must be paid to the resilience to deal with losses. Resilience plays a key role. People with a positive attitude to living with old age show less functional physical impairment and recover from illness more quickly. Humor, optimism and physical activity are crucial for successful aging. PMID- 29234921 TI - A phase II trial of Ifosfamide combination with recommended supportive therapy for recurrent SCLC in second-line and heavily treated setting. AB - PURPOSE: The response rate of ifosfamide (IFM) monotherapy for small-cell lung cancer (SCLC) is reported as 42.4% in Japanese package insert. However, these efficacy data are based on clinical studies conducted in 1970s. This phase II study evaluated the efficacy and safety of IFM combination with recommended current supportive therapy for recurrent SCLC in second-line and heavily treated setting. METHODS: Recurrent SCLC patients pretreated with one to three prior regimens received IFM monotherapy (1.5 g/m2 for 3 days every 3 weeks). Treatment was continued until disease progression or unacceptable toxicity. The primary end point was objective response rate. RESULTS: Twelve patients were enrolled in the study from June 2009 to January 2013. The study was early terminated at interim analysis due to futility stop. Patient characteristics were as follows: median age was 65 years, 11 were males (91.7%) and eight (66.7%) and four (33.3%) were Performance Status 0 and 1, respectively. Four patients (33.3%) enrolled in second-line setting were all refractory relapse SCLC and 8 (66.7%) were heavily treated patients. No patient showed objective response. Stable disease was observed in 3 patients. Median progression-free survival and overall survival were 0.9 months (95% CI, 0.3-1.5) and 4.8 months (95% CI, 1.6-9.9), respectively. Although one grade 4 amylase increase possibly related to IFM was observed, toxicity profile was totally favorable. CONCLUSIONS: IFM monotherapy should not be used for refractory relapse or heavily treated SCLC, and no further investigation is required in these populations. PMID- 29234922 TI - Pharmacokinetically-targeted dosed everolimus maintenance therapy in lymphoma patients. AB - BACKGROUND: Everolimus, an mTOR inhibitor, is active in refractory lymphomas. However, toxicity with flat dosing limits its usage. Speculatively, pharmacokinetically-targeted dosing could improve tolerability. Therefore, we studied serum-trough dosing with rituximab as maintenance after high-dose cyclophosphamide (HDC) consolidation in lymphoma patients. PATIENTS/METHODS: After HDC, everolimus was dosed to serum trough levels (goal 3-15 ng/mL), with quarterly rituximab infusions for 1 year while maintaining < grade II non hematologic and < grade III hematologic toxicities. Adult patients in first PR/CR with: mantle cell, transformed, double-hit, or high risk chronic lymphocytic leukemia or in second PR for any relapsed B cell lymphoma were eligible. Prophylaxis was given for encapsulated organisms, HSV and PCP. Serum IgG levels were maintained > 500 mg/dL. RESULTS: 49 patients, median age: 59.0 years enrolled; MCL (26), CLL (10), transformed lymphoma (7), and other histologies (6). During the life of the study, the most frequent everolimus dosing has been 2.5 mg daily or 2.5 mg every other day; at these doses, serum levels are within the therapeutic range and non-hematologic toxicity is rare. At a median follow-up of 27.1 months, three patients remain on active therapy. Two patients withdrew secondary to potentially-attributable adverse events including a bacterial pneumonia and a viral pneumonia; this low rate of discontinuation compares well to other long-term everolimus trials. While a 58 and 76% EFS at 30 months for the entire cohort and MCL cohort, respectively, compares similarly to previously published HDC/rituximab data, longer follow-up is required. CONCLUSIONS: Pharmacokinetically-targeted dosing appears to increase everolimus tolerability. This finding may be applicable to other patient populations. PMID- 29234924 TI - A new direction in anastomotic research: should we redesign the 'angle of sorrow'? AB - INTRODUCTION: Despite advances in oncological outcomes in colo-rectal surgery, rates of anastomotic leak have not improved. The precise mechanisms of anastomotic leak remain poorly understood. Current research has focused on anastomotic reinforcement to tackle anastomotic leak with little success. The 'Angle of Sorrow', the corner of the anastomosis is prone to anastomotic leak, but remains a persistent feature in the gastrointestinal anastomosis. The tendency for stress forces to concentrate in the vulnerable 'Angle of Sorrow' prompts the need for anastomotic design research. AIM: The aim of this study is to explore if redesigning the 'Angle of Sorrow' can reduce the stress forces in the ileocolic anastomosis. METHODS: A simulation-based experimental study compared two anastomotic designs: traditional Slit Enterotomy Anastomosis (SEA) vs a novel Radiused Enterotomy Anastomosis (REA). The finite element analysis simulations were performed using FEBIO to measure peak sheer stress in pressurised bowel. RESULTS: Tissue stress was found to concentrate at the 'Angles of Sorrow' in traditional anastomosis design while the REA design distributed sheer stress across the anastomosis. The SEA model had greater peak sheer stress factors than REA for the hand-sewn and stapled 'Barcelona' anastomosis (1.58 (k) vs 0.64 (k), 0.91 (k) vs 0.63 (k)). The REA anastomosis resulted in significantly less peak stress across all anastomotic experiments (p = 0.0047). The mucosa of the SEA model tended to unfavourably evert. CONCLUSION: Redesigning the 'Angle of Sorrow' decreased tissue stress concentration. The direction of future anastomotic research may involve going back to the drawing board, rather than attempting to reinforce a potentially flawed design. Despite advances in colorectal surgery, rates of anastomotic leak have not improved. The 'Angle of Sorrow', the corner of the anastomosis is prone to anastomotic leak, but remains a persistent feature in gastrointestinal anastomosis. The direction of future research may involve going back to redesign this vulnerable area. PMID- 29234925 TI - Modelling the effects of PSII inhibitor pulse exposure on two algae in co culture. AB - A weakness of standard testing procedures is that they do not consider interactions between organisms, and they focus only on single species. Furthermore, these procedures do not take into account pulse exposure. However, pulse exposure is of particular importance because in streams, after crop application and during and after precipitation, herbicide concentrations fluctuate widely and can exceed the Annual Average Environmental Quality Standards (AA-EQS), which aim to protect the aquatic environment. The sensitivity of the algae Scenedesmus vacuolatus and Pseudokirchneriella subcapitata in a co culture exposed to pulses is thus analysed in this study. As a first step, the growths of the algae in co-culture are investigated. For initial cell densities fixed, respectively, to 100,000 and 50,000 cells/mL, the growth of each alga is exponential over at least 48 h. S. vacuolatus seems to influence the growth of P. subcapitata negatively. Allelopathy is a possible explanation for this growth inhibition. The toxicity of the herbicide isoproturon is later tested on the algae S. vacuolatus and P. subcapitata cultured alone and in the co-culture. Despite the supplementary stress on the algae in the co-culture competing for nutrients, the toxicity of the herbicide is lower for the two algae when they are in the co-culture than when they are in separated culture. A model is adapted and used to predict the cell-density inhibition on the alga S. vacuolatus in the co culture with the alga P. subcapitata exposed to a pulse concentration of isoproturon. Four laboratory experiments are performed to validate the model. The comparison between the laboratory and the modelled effects shows good agreement. The differences can be considered minor most of time. For future studies, it is important to ensure that the cell count is precise, as it is used to determine the parameters of the model. The differences can be also induced by the fact that the cell number of the alga P. subcapitata re-suspended in a new OECD medium after the centrifugation process cannot be fixed. PMID- 29234923 TI - Non-inferiority multicenter prospective randomized controlled study of rectal cancer T2-T3s (superficial) N0, M0 undergoing neoadjuvant treatment and local excision (TEM) vs total mesorectal excision (TME). AB - PURPOSE: The standard treatment of rectal adenocarcinoma is total mesorectal excision (TME), in many cases requires a temporary or permanent stoma. TME is associated with high morbidity and genitourinary alterations. Transanal endoscopic microsurgery (TEM) allows access to tumors up to 20 cm from the anal verge, achieves minimal postoperative morbidity and mortality rates, and does not require an ostomy. The treatment of T2, N0, and M0 cancers remains controversial. Preoperative chemoradiotherapy (CRT) in association with TEM reduces local recurrence and increases survival. The TAU-TEM study aims to demonstrate the non inferiority of the oncological outcomes and the improvement in morbidity and quality of life achieved with TEM compared with TME. METHODS: Prospective, multicenter, randomized controlled non-inferiority trial includes patients with rectal adenocarcinoma less than 10 cm from the anal verge and up to 4 cm in size, staged as T2 or T3-superficial N0-M0. Patients will be randomized to two areas: CRT plus TEM or radical surgery (TME). Postoperative morbidity and mortality will be recorded and patients will complete the quality of life questionnaires before the start of treatment, after CRT in the CRT/TEM arm, and 6 months after surgery in both arms. The estimated sample size for the study is 173 patients. Patients will attend follow-up controls for local and systemic relapse. CONCLUSIONS: This study aims to demonstrate the preservation of the rectum after preoperative CRT and TEM in rectal cancer stages T2-3s, N0, M0 and to determine the ability of this strategy to avoid the need for radical surgery (TME). TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01308190. Numero de registro del Comite de Etica e Investigacion Clinica (CEIC) del Hospital universitario Parc Tauli: TAU TEM-2009-01. PMID- 29234926 TI - Association between PDE4D rs966221 polymorphism and risk of ischemic stroke: a systematic review and meta-analysis. AB - PDE4D polymorphism (SNP83/rs966221) was reported to be associated with the susceptibility to ischemic stroke (IS), however, the results were inconclusive. An electronic search of Embase, PubMed, CNKI and Wan Fang Date was performed to identify relevant studies published throughout April 2017. A total of 26 studies were enrolled in the analysis. No significant association between the rs9662221 polymorphism and IS was observed in the overall analysis. Nevertheless, in the subgroup analysis, our results showed a significant association between the SNP83 polymorphism and IS in CC+ CT vs. TT (OR = 1.19, 95% CI: 1.02-1.38), CT vs.TT (OR = 1.14, 95% CI: 1.01-1.29) and C vs. T (OR = 1.25, 95% CI: 1.06-1.48) in Asian population. But we did not found any association in CC vs. CT + TT (OR = 1.2, 95% CI: 0.9-1.61) and CC vs. TT (OR = 1.26, 95% CI: 0.91-1.75) in the Asian populations. Meantime, no significant correlations were observed under the five genetic model in Caucasian population (p > 0.05). In conclusion, our meta analysis demonstrated that the SNP83 polymorphism in the PDE4D gene might contribute to IS susceptibility especially in Asian populations. Whereas the relationship of the polymorphism to the disease in Caucasian population was still in controversial. In future, additional well designed studies with larger sample sizes are still required to further elucidate this association. PMID- 29234927 TI - Toward a Unified Integration Approach: Uniting Diverse Primary Care Strategies Under the Primary Care Behavioral Health (PCBH) Model. AB - Primary care continues to be at the center of health care transformation. The Primary Care Behavioral Health (PCBH) model of service delivery includes patient centered care delivery strategies that can improve clinical outcomes, cost, and patient and primary care provider satisfaction with services. This article reviews the link between the PCBH model of service delivery and health care services quality improvement, and provides guidance for initiating PCBH model clinical pathways for patients facing depression, chronic pain, alcohol misuse, obesity, insomnia, and social barriers to health. PMID- 29234929 TI - Can thyromental distance be measured accurately? AB - Using the thyromental distance (TMD) measured based on the ultrasonographic location of the thyroid cartilage prominence as the criterion, we investigated the accuracy of TMD measurement by surface landmark identification of the thyroid cartilage prominence. Twenty-nine anesthetist resident volunteers were recruited, including 10 first-year residents, 9 second-year residents and 10 third-year residents. Each volunteer measured the other 28 volunteers' TMD. Then, the thyroid cartilage prominence of each volunteer was identified by ultrasonography of the junction of the vocal cord and thyroid cartilage, and the TMD was measured precisely. The error of the TMD measurement was determined by the minimal detectable difference (MDD) compared to the ultrasound measurement. A difference of greater than 5.4 mm between the TMD measured by volunteers and that based on ultrasound localization was defined as a measurement error. The measurement error rate of females' TMD was significantly higher than that of males' (50 vs 10%, P < 0.001). The error rates of anesthetist residents of first-year, second-year and third-year were 34, 27, and 31%, respectively, and were not significantly different. The error of TMD measurement by surface landmark identification is often, especially for women. More clinic experience don't improve it. PMID- 29234928 TI - Alterations in acetylcholinesterase and butyrylcholinesterase activities in chronic obstructive pulmonary disease: relationships with oxidative and inflammatory markers. AB - This work focused on finding a relationship between acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities and the development and severity of COPD. The possible link of these enzymes to oxidative and inflammatory processes was also investigated. The study included 229 healthy controls and 153 COPD patients. Erythrocyte AChE and plasma BChE activities were determined using spectrophotometric methods. Markers related to the oxidative status including thiobarbituric acid-reactive substances (TBARS), total protein carbonyls (PCs), advanced oxidation protein products (AOPP), reduced glutathione, nitric oxide, and peroxynitrite were measured. We also evaluated the activity of glutathione peroxidase, catalase, and superoxide dismutase in the plasma and erythrocytes. Serum levels of IL-6 and TNF-alpha were measured by the enzyme-linked immunosorbent assay. COPD patients showed increased AChE and BChE activities in comparison to healthy controls. Interestingly, AChE activity was higher in COPD smokers than in nonsmokers, while no difference was revealed for BChE. In addition, our results showed an inverse correlation between AChE activity and the levels of IL-6 in COPD smokers. Positive correlations were found, in COPD smokers, between plasma BChE activity and the levels of several biomarkers of protein oxidative damage including AOPP and PC. Our findings suggest that the alterations in AChE and BChE activities may be related to the oxidative and inflammatory processes in COPD patients rendering these enzymes as markers of COPD disease. PMID- 29234930 TI - Brief Report: Factors Associated with Emergency Department Visits for Epilepsy Among Children with Autism Spectrum Disorder. AB - We examined how demographic and clinical characteristics differ between emergency department (ED) visits for epilepsy (EP cohort) and ED visits for other reasons (non-EP cohort) in children with ASD. The data were drawn from the 2009 and 2010 Nationwide Emergency Department Sample. We performed both univariate and multivariate analyses to compare and contrast similarities and differences between EP cohort and non-EP cohort among children with ASD. The results showed ED visits in EP cohort were more likely to occur among adolescents aged 13-17 years, less likely to occur among children with co-occurring psychiatric conditions, and were more likely to co-occur with injury. We discussed some unique challenges for managing children with both ASD and epilepsy. PMID- 29234931 TI - A Pilot Randomized Controlled Trial of the ACCESS Program: A Group Intervention to Improve Social, Adaptive Functioning, Stress Coping, and Self-Determination Outcomes in Young Adults with Autism Spectrum Disorder. AB - The purpose of this pilot randomized controlled trial was to investigate the acceptability and efficacy of the Acquiring Career, Coping, Executive control, Social Skills (ACCESS) Program, a group intervention tailored for young adults with autism spectrum disorder (ASD) to enhance critical skills and beliefs that promote adult functioning, including social and adaptive skills, self determination skills, and coping self-efficacy. Forty-four adults with ASD (ages 18-38; 13 females) and their caregivers were randomly assigned to treatment or waitlist control. Compared to controls, adults in treatment significantly improved in adaptive and self-determination skills, per caregiver report, and self-reported greater belief in their ability to access social support to cope with stressors. Results provide evidence for the acceptability and efficacy of the ACCESS Program. PMID- 29234932 TI - Emotion Coregulation Processes between Mothers and their Children With and Without Autism Spectrum Disorder: Associations with Children's Maladaptive Behaviors. AB - A dyadic microanalysis approach was used to examine emotion coregulation processes in mother-child interactions in relation to children's maladaptive behaviors. Seventy-two mother-child dyads (46 children with Autism Spectrum Disorder (ASD); 26 neurotypical children) were previously videotaped in a semi structured play procedure at home and mothers reported on children's internalizing and externalizing behaviors. Mother-child interactions were reliably coded in 5-second intervals and analyzed using Space State Grid software. Regression analyses supported moderation, whereby greater dyadic flexibility and more mutual-positive engagements were significantly associated with lower levels of maladaptive outcomes for children with ASD. Results have implications for initiating positive interactions and promoting effective parenting that help improve behavior in young children with ASD. PMID- 29234933 TI - MicroRNAs and metastasis: small RNAs play big roles. AB - MicroRNAs (miRNAs) are small non-coding RNAs regulating post-transcriptional gene expression. They play important roles in many biological processes under physiological or pathological conditions, including development, metabolism, tumorigenesis, metastasis, and immune response. Over the past 15 years, significant insights have been gained into the roles of miRNAs in cancer. Depending on the cancer type, miRNAs can act as oncogenes, tumor suppressors, or metastasis regulators. In this review, we focus on the role of miRNAs as components of molecular networks regulating metastasis. These miRNAs, termed metastamiRs, promote or inhibit metastasis through various mechanisms, including regulation of migration, invasion, colonization, cancer stem cell properties, epithelial-mesenchymal transition, and microenvironment. Some of these metastamiRs represent attractive therapeutic targets for cancer treatment. PMID- 29234934 TI - Early detection of left ventricular diastolic dysfunction using conventional and speckle tracking echocardiography in a large animal model of metabolic dysfunction. AB - Left ventricular (LV) diastolic dysfunction is one of the important mechanisms responsible for symptoms in patients with heart failure. The aim of the current study was to identify parameters that may be used to detect early signs of LV diastolic dysfunction in diabetic pigs on a high fat diet, using conventional and speckle tracking echocardiography. The study population consisted of 16 healthy Gottingen minipigs and 18 minipigs with experimentally induced metabolic dysfunction. Echocardiography measurements were performed at baseline and 3-month follow-up. The ratio of peak early (E) and late filling velocity (E/A ratio) and the ratio of E and the velocity of the mitral annulus early diastolic wave (E/Em ratio) did not change significantly in both groups. Peak untwisting velocity decreased in the metabolic dysfunction group (- 30.1 +/- 18.5 vs. - 23.4 +/- 15.5 degrees /ms) but not in controls (- 38.1 +/- 23.6 vs. - 42.2 +/- 23.0 degrees /ms), being significantly different between the groups at the 3-month time point (p < 0.05). In conclusion, whereas E/A ratio and E/Em ratio did not change significantly after 3 months of metabolic dysfunction, peak untwisting velocity was significantly decreased. Hence, peak untwisting velocity may serve as an important marker to detect early changes of LV diastolic dysfunction. PMID- 29234935 TI - Cardiac and respiratory-gated volumetric murine ultrasound. AB - Current cardiovascular ultrasound mainly employs planar imaging techniques to assess function and physiology. These techniques rely on geometric assumptions, which are dependent on the imaging plane, susceptible to inter-observer variability, and may be inaccurate when studying complex diseases. Here, we developed a gated volumetric murine ultrasound technique to visualize cardiovascular motion with high spatiotemporal resolution and directly evaluate cardiovascular health. Cardiac and respiratory-gated cine loops, acquired at 1000 frames-per-second from sequential positions, were temporally registered to generate a four-dimensional (4D) dataset. We applied this technique to (1) evaluate left ventricular (LV) function from both healthy mice and mice with myocardial infarction and (2) characterize aortic wall strain of angiotensin II induced dissecting abdominal aortic aneurysms in apolipoprotein E-deficient mice. Combined imaging and processing times for the 4D technique was approximately 2-4 times longer than conventional 2D approaches, but substantially more data is collected with 4D ultrasound and further optimization can be implemented to reduce imaging times. Direct volumetric measurements of 4D cardiac data aligned closely with those obtained from MRI, contrary to conventional methods, which were sensitive to transducer alignment, leading to overestimation or underestimation of estimated LV parameters in infarcted hearts. Green-Lagrange circumferential strain analysis revealed higher strain values proximal and distal to the aneurysm than within the aneurysmal region, consistent with published reports. By eliminating the need for geometrical assumptions, the presented 4D technique can be used to more accurately evaluate cardiac function and aortic pulsatility. Furthermore, this technique allows for the visualization of regional differences that may be overlooked with conventional 2D approaches. PMID- 29234937 TI - [Lysosomal acid lipase deficiency (LAL-D) : Diagnostic and therapeutic options in an underdiagnosed disease]. AB - BACKGROUND AND CLINICAL SETTING: Lysosomal acid lipase deficiency is an autosomal recessive storage disease caused by mutations in the LIPA gene. The accumulation of cholesteryl esters and triglycerides in hepatocytes lead to hepatomegaly with progressive fibrosis and liver cirrhosis. Characteristically, patients have a hepatomegaly combined with high serum levels of cholesterol, LDL-cholesterol and in some cases triglyceride, whereas HDL-cholesterol is decreased. Histologically, hepatocytes show a microvesicular steatosis with typically ballooned Kupffer cells. Even though histological morphology is typical, it is not characteristic. Therefore LAL-D is supposed to be an underdiagnosed disease with a high number of unreported cases misdiagnosed as uncharacteristic fatty liver disease (NASH, NAFLD, cryptogenic liver cirrhosis). Further, there is overlap with other storage diseases, complicating a correct diagnosis. THERAPY: Until recently, different therapeutic options could not prevent development of liver cirrhosis. Patients with Wolman's disease have an especially rapid progression and die within the first six months of life. With the recent development of a new enzyme replacement therapy with sebelipase alfa (Kanuma (r)), new therapeutic options with significant improvement of dyslipidemia and reduction of transaminases have become reality. Positive clinical results seem to have the potential to significantly raise life expectancy. CONCLUSION: These new therapeutic options warrant an increase in awareness of LAL-D by clinicians and pathologists. Correct diagnosis of LAL-D is important for effective therapy and long-term survival. PMID- 29234938 TI - Impact of incisional hernia development following abdominal operations on total healthcare cost. AB - BACKGROUND: Introduction of the category III CPT code (0437T) for prophylactic mesh augmentation (PMA) highlights efforts to reduce incisional hernia (IH). PMA's value in the context of value-based care requires understanding both the cost of IH development and the savings from prevention. We hypothesized large healthcare costs with IH development. Appreciating which subsets of patients are at highest risk for IH, and the subsets who have the costliest care is essential in targeting interventions for hernia prevention. METHODS: Retrospective cohort study utilizing data from Truven Health Analytic MarketScan Commercial Claims and Encounters Database from calendar years 2011-2014. Adults undergoing open abdominal operations with continued enrollment 3-year post-surgery were included. Inpatient and outpatient claims were tracked over 3 years to identify IH. Quantile regression estimated the association between conditional distribution of total cost and IH. A generalized linear model with gamma distribution estimated the association of conditional mean of total cost and IH. Models were adjusted for confounding cost covariates (e.g., age, gender, obesity, smoking, cancer). RESULTS: 14,290 patients were identified, 1294 (9.1%) developed IH, 48% within 1 year, 33% at 1-2 years, and 19% at 2-3 years post-surgery. 515 underwent stoma creation, 4579 colon resection, 2263 liver/kidney, 3890 peritoneal, 3043 other (foregut, appendectomy, cholecystectomy). Rate of IH formation was 25, 13, 5.9, 6.3, and 6.3%, respectively. The difference in median expenditures for IH development versus no IH was ostomies: $26,098, colorectal: $21,211, liver/kidney: $23,811, peritoneal: $25,554, others: $28,870 (p < 0.0.01). IH within 1 year was more expensive than within 3 years in the following categories: colorectal ($16,034, p = 0.0385), liver/kidney ($27,145, p = 0.0004), and ostomy ($18,992, p = 0.0035). CONCLUSION: IH is a common occurrence imposing significant healthcare burden. Higher costs occur when IH occurs within 1 year versus 3 years from the index-procedure. This highlights the importance of hernia prevention techniques and the question of whether temporizing closure adjuncts are appropriate in high-risk patients. PMID- 29234936 TI - A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim. AB - Proteins are an increasingly important class of drugs used as therapeutic as well as diagnostic agents. A generic physiologically based pharmacokinetic (PBPK) model was developed in order to represent at whole body level the fundamental mechanisms driving the distribution and clearance of large molecules like therapeutic proteins. The model was built as an extension of the PK-Sim model for small molecules incorporating (i) the two-pore formalism for drug extravasation from blood plasma to interstitial space, (ii) lymph flow, (iii) endosomal clearance and (iv) protection from endosomal clearance by neonatal Fc receptor (FcRn) mediated recycling as especially relevant for antibodies. For model development and evaluation, PK data was used for compounds with a wide range of solute radii. The model supports the integration of knowledge gained during all development phases of therapeutic proteins, enables translation from pre-clinical species to human and allows predictions of tissue concentration profiles which are of relevance for the analysis of on-target pharmacodynamic effects as well as off-target toxicity. The current implementation of the model replaces the generic protein PBPK model available in PK-Sim since version 4.2 and becomes part of the Open Systems Pharmacology Suite. PMID- 29234939 TI - The role of preoperative high resolution manometry in predicting dysphagia after laparoscopic Nissen fundoplication. AB - BACKGROUND: Laparoscopic fundoplication is an accepted surgical management of refractory gastro-esophageal reflux disease (GERD). The use of high resolution esophageal manometry (HRM) in preoperative evaluation is often applied to determine the degree of fundoplication to optimize reflux control while minimizing adverse sequela of postoperative dysphagia. OBJECTIVE: Assess the role of preoperative HRM in predicting surgical outcomes, specifically risk assessment of postoperative dysphagia and quality of life, among patients receiving laparoscopic Nissen fundoplication for GERD with immediate postoperative (< 4 weeks clinic), short-term (3-month clinic), and long-term (34 +/- 10.4 months of telephone) follow-up. METHODS: Retrospective analysis of 146 patients over the age of 18 who received laparoscopic Nissen fundoplication at University of Vermont Medical Center from July 1, 2011 through December 31, 2014 was completed, of which 52 patients with preoperative HRM met inclusion criteria. Exclusion criteria included history of: (a) named esophageal motility disorder or aperistalsis; (b) esophageal cancer; (c) paraesophageal hernia noted intraoperatively. RESULTS: Elevated basal integrated relaxation pressure (IRP), which is the mean of 4 s of maximal lower esophageal sphincter (LES) relaxation within 10 s of swallowing, was significantly correlated with worsened severity of post-fundoplication dysphagia (r = 0.572, p < 0.0001 with sensitivity and NPV of 100%) and poorer quality of life (r = 0.348, p = 0.018) at up to 3-years follow up. The presence of preoperative dysphagia was independently related to post fundoplication dysphagia at short-term (r = 0.403, p = 0.018) and long-term follow-up (r = 0.415, p = 0.005). Also, both elevated mean wave amplitude (r= 0.397, p = 0.006) and distal contractile integral (DCI) (r = - 0.294, p = 0.047) were significantly, inversely correlated to post-Nissen dysphagia. No significant association was demonstrated between other preoperative HRM parameters and surgical outcomes. CONCLUSIONS: Inadequacy of lower esophageal sphincter (LES) relaxation with swallowing as delineated by elevated IRP is significantly predictive of worse long-term postoperative outcomes including dysphagia and quality of life scores. Further assessment of tailoring anti-reflux surgical approach with partial vs. total fundoplication to functionally resistant LES is required. PMID- 29234941 TI - Short-term surgical outcomes of a randomized controlled trial comparing laparoscopic versus open gastrectomy with D2 lymph node dissection for advanced gastric cancer. AB - BACKGROUND: Laparoscopy-assisted gastrectomy (LAG) has gained acceptance as one of the best treatments for early gastric cancer. However, the application of LAG with D2 lymph node dissection in patients with locally advanced gastric cancer (AGC) remains controversial. METHODS: We launched a prospective randomized controlled trial comparing laparoscopic and open gastrectomy with D2 lymph node dissection for locally AGC to evaluate technical safety and oncologic feasibility. The postoperative morbidity and mortality rates were based on the modified intention-to-treat analysis. RESULTS: Between January 2010 and June 2012, a total of 328 patients with preoperative clinical stage T2-3N0-3M0 gastric cancer were enrolled in the trial. Six patients with unresected AGC were excluded, and the remaining 322 patients were randomized to the laparoscopic group (162 patients) or the open group (160 patients) for radical surgery. All patients underwent D2 lymph node dissection including 18 (5.59%) proximal gastrectomies, 196 (60.87%) distal gastrectomies, and 108 (33.54%) total gastrectomies. Six patients (3.70%) in the LAG group were converted to open procedures. The overall complication rate was 11.72% in the LAG group and 14.38% in the open group (P = 0.512). No mortality occurred in either group. CONCLUSIONS: The short-term results of the current study suggest that LAG with D2 lymph node dissection is a safe and feasible procedure in treating patients with locally AGC in experienced centers. PMID- 29234942 TI - Does hiatal repair affect gastroesophageal reflux symptoms in patients undergoing laparoscopic sleeve gastrectomy? AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has gained popularity as a treatment of choice for morbid obesity and associated comorbidities. There has been a concern about new onset or worsening of gastroesophageal reflux (GERD) following LSG. OBJECTIVE: The objective of the study was to evaluate the effect of surgically treating hiatal weakness on GERD symptoms in patients undergoing LSG. SETTING: Single tertiary referral institution, Sydney, Australia. METHODS: A prospective observational cohort study was conducted with consecutive patients undergoing LSG. Hiatal findings, patient demographics, medications and reflux score were recorded prospectively. Patients were followed up post-operatively for a minimum of 12 months and assessed using GERD-HRQL score to quantify reflux symptoms. RESULTS: Data from 100 patients with a minimum of 1-year follow-up were analysed. Mean follow-up was 18.9 months. Overall, GERD-HRQL improved from mean 4.5 +/- 5.8 pre-operatively to 0.76 +/- 1.5 after 18.9 months (p = 0.0001). For those with pre-operative reflux, GERD-HRQL improved from mean (SD) 8.43 +/- 6.26 pre-operatively to 0.94 +/- 1.55 (p = 0.0001). All the nine patients with troublesome daily reflux significantly improved. For those without pre-operative reflux, GERD-HRQL improved from 0.88 +/- 1.37 to 0.47 +/- 1.25 (p-ns) post operatively. On multivariate analysis, higher pre-operative reflux and dysphagia/bloat scores, younger age and lower percentage excess weight loss after 18.9 months were associated with GERD-HRQL improvement. CONCLUSION: In the medium term, GERD-HRQL improves following sleeve gastrectomy with meticulous hiatal assessment and repair of hiatal laxity and herniation. PMID- 29234940 TI - St.Gallen consensus on safe implementation of transanal total mesorectal excision. AB - BACKGROUND: The management of rectal cancer has evolved over the years, including the recent rise of Transanal Total Mesorectal Excision (TaTME). TaTME addresses the limitations created by the bony confines of the pelvis, bulky tumours, and fatty mesorectum, particularly for low rectal cancers. However, guidance is required to ensure safe implementation and to avoid the pitfalls and potential major morbidity encountered by the early adopters of TaTME. We report a broad international consensus statement, which provides a basis for optimal clinical practice. METHODS: Forty international experts were invited to participate based on clinical and academic achievements. The consensus statements were developed using Delphi methodology incorporating three successive rounds. Consensus was defined as agreement by 80% or more of the experts. RESULTS: A total of 37 colorectal surgeons from 20 countries and 5 continents (Europe, Asia, North and South America, Australasia) contributed to the consensus. Participation to the iterative Delphi rounds was 100%. An expert radiologist, pathologist, and medical oncologist provided recommendations to maximize relevance to current practice. Consensus was obtained on all seven different chapters: patient selection and surgical indication, perioperative management, patient positioning and operating room set up, surgical technique, devices and instruments, pelvic anatomy, TaTME training, and outcomes analysis. CONCLUSIONS: This multidisciplinary consensus statement achieved more than 80% approval and can thus be graded as strong recommendation, yet acknowledging the current lack of high level evidence. It provides the best possible guidance for safe implementation and practice of Transanal Total Mesorectal Excision. PMID- 29234944 TI - Investigating the mincing method for isolation of adipose-derived stem cells from pregnant women fat. AB - The success of stem cell application in regenerative medicine, usually require a stable source of stem or progenitor cells. Fat tissue represents a good source of stem cells because it is rich in stem cells and there are fewer ethical issues related to the use of such stem cells, unlike embryonic stem cells. Therefore, there has been increased interest in adipose-derived stem cells (ADSCs) for tissue engineering applications. Here, we aim to provide an easy processing method for isolating adult stem cells from human adipose tissue harvested from the subcutaneous fat of the abdominal wall during gynecologic surgery. We used a homogenizer to mince fat and compared the results with those obtained from the traditional cut method involving a sterile scalpel and forceps. Our results showed that our method provides another stable and quality source of stem cells that could be used in cases with a large quantity of fat. Furthermore, we found that pregnancy adipose-derived stem cells (P-ADSCs) could be maintained in vitro for extended periods with a stable population doubling and low senescence levels. P-ADSCs could also differentiate in vitro into adipogenic, osteogenic, chondrogenic, and insulin-producing cells in the presence of lineage-specific induction factors. In conclusion, like human lipoaspirates, adipose tissues obtained from pregnant women contain multipotent cells with better proliferation and showed great promise for use in both stem cell banking studies as well as in stem cell therapy. PMID- 29234943 TI - Enhanced recovery care versus traditional care after laparoscopic liver resections: a randomized controlled trial. AB - BACKGROUND: Enhanced recovery after surgery (ERAS), with several evidence-based elements, has been shown to shorten length of hospital stay and reduce perioperative hospital costs in many operations. This randomized clinical trial was performed to compare complications and hospital stay of laparoscopic liver resection between ERAS and traditional care. METHODS: A randomized controlled trial was performed for laparoscopic liver resection from August 2015 to August 2016. Patients were randomly divided into ERAS group and traditional care group. The primary outcome was length of hospital stay (LOS) after surgery. Second outcomes included postoperative complications, hospital cost, and 30-day readmissions. Elements used in ERAS group included more perioperative education, nurse navigators, nutrition support for liver diseases, respiratory therapy, oral carbohydrate 2 h before operation, early mobilization and oral intake, goal directed fluid therapy, less drainages, postoperative nausea and vomiting (PONV) prophylaxis and multimodal analgesia. RESULTS: The study included 58 (two conversion to laparotomy) patients in ERAS group and 61 (three conversion to laparotomy) patients in the traditional care group. Postoperative LOS was significantly shorter in the ERAS group than traditional care group (5 vs. 8 days; p < 0.001). ERAS program significantly reduced the hospital costs (CNY 45413.1 vs. 55794.1; p = 0.006) and complications (36.2 vs. 55.7%; p = 0.033). Duration till first flatus and PONV were significantly reduced in ERAS group. Pain control was better in ERAS (Visual analogue scale (VAS) POD1 (>= 4) 19.0 vs. 39.3%, p = 0.017; VAS POD1 2.5 vs. 3.1, p = 0.010). There was no difference in the rate of 30-day readmissions (6.9 vs. 8.2%; p = 1.000). CONCLUSION: ERAS protocol is feasible and safe for laparoscopic liver resection. Patients in ERAS group have less pain and complications. PMID- 29234946 TI - Comparison of published and unpublished phase I clinical cancer trials: an analysis of the CliniclTrials.gov database. AB - Introduction The role of phase I cancer trials is constantly evolving and they are increasingly being used in 'go/no' decisions in drug development. As a result, there is a growing need to ensure trials are published when completed. There are limited data on the publication rate and the factors associated with publication in phase I trials. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching publications published prior to April 1, 2017. Logistic regression was used to identify factors associated with unpublished trials. Linear regression was used to explore factors associated with time lag from study database lock to publication for published trials. Results The study cohort included 319 trials. 95 (30%) trials had no matching publication. Thirty (9%) trials were not published in abstract form as well. On multivariable analysis, the most significant factor associated with unpublished trials was industry funding (odds ratio 3.3, 95% confidence interval 1.7-6.6, p=0.019). For published trials, time lag between database lock and publication was longer by 10.9 months (standard error 3.6, p<0.001) for industry funded trials compared with medical center funded trials. Conclusions Timely publishing of early cancer clinical trials results remains unsatisfactory. Industry funded phase I cancer trials were more likely to remain unpublished, and were associated with a longer time lag from database lock to publication. Policies that promote transparency and data sharing in clinical trial research might improve accountability among industry and investigators and improve timely results publication. PMID- 29234945 TI - Clinical significance and functional validation of inorganic pyrophosphatase in diffuse large B cell lymphoma in humans. AB - Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin's lymphoma, displays marked heterogeneity. Although it is usually curable, 30-40% of patients die within 1-2 years due to refractory treatment or cancer relapse. In different types of cancer in humans, inorganic pyrophosphatase (PPA1) is deregulated, thereby contributing to tumorigenesis by supplying the tumor with an enormous energy source. However, the role of PPA1 in DLBCL is still unclear. Here, we analized PPA1 in 65 patients with DLBCL and 20 patients with reactive hyperplasia of the lymph nodes (control). The PPA1 level was significantly higher in patients with DLBCL than in control subjects (p < 0.05), and it is closely associated with B symptoms (i.e., fever, night sweats, and weight loss) and the IPI score (p < 0.05). Furthermore, PPA1 mRNA and protein levels were higher in most DLBCL cell lines than in the control HMy2.CIR cell line. Lastly, we investigated the effects of PPA1 knockdown on the proliferation and survival of the DLBCL cell line. We found that p53 and p21 expression decreased in PPA1 silenced DLBCL cells. In addition, cell proliferation decreased and cell apoptosis increased. In conclusion, PPA1 is a novel molecule that may be useful in the development and prognosis of DLBCL in the future. PMID- 29234947 TI - Correction to: NMR structure of the HIV-1 reverse transcriptase thumb subdomain. AB - In the original publication of the article, the given name and family name of the author P. Andrew Karplus was published incorrectly. The name should read as "P. Andrew" - Given name and "Karplus" - Family name. PMID- 29234948 TI - Assessing Documentation of Critical Imaging Result Follow-up Recommendations in Emergency Department Discharge Instructions. AB - To facilitate follow-up of critical test results across transitions in patient care settings, we implemented an electronic discharge module that enabled care providers to include follow-up recommendations in the discharge instructions. We assessed the impact of this module on documentation of follow-up recommendations for critical imaging findings in Emergency Department (ED) discharge instructions. We studied 240 patients with critical imaging findings discharged from the ED before (n = 80) and after (n = 160) implementation of the module. We manually reviewed hand-written forms and electronic discharge instructions to determine if follow-up recommendations were documented. Follow-up recommendations in ED discharge instructions increased from 60.0% (48/80) to 73.8% (118/160) post module implementation (p = 0.03), a relative increase of 23%. There was no significant change in the rate of documented critical imaging findings in the discharge instructions (77.5% [62/80] before the intervention and 76.9% [123/160] after the intervention; p = 0.91). Implementation of a discharge module was associated with increased documentation of critical imaging finding follow-up recommendations in ED discharge instructions. However, one in four patients still did not receive adequate follow-up recommendations, suggesting further opportunities for performance improvement exist. PMID- 29234949 TI - Curc-mPEG454, a PEGylated Curcumin Derivative, Improves Anti-inflammatory and Antioxidant Activities: a Comparative Study. AB - We previously demonstrated that a PEGylated curcumin (Curc-mPEG454) significantly inhibited cyclooxygenase 2 (COX-2) expression and improved the progression of liver fibrosis. The current study systematically evaluates its anti-inflammatory and antioxidant activities in vitro in a comparative study with curcumin, aspirin, NS-398, and vitamin C. RAW264.7 murine macrophages were pretreated with Curc-mPEG454, curcumin, aspirin, NS-398, or vitamin C at the indicated concentration for 2 h; then, the cells were stimulated with 1 MUg/mL lipopolysaccharide (LPS) for 24 h. The levels of pro-inflammatory cytokines and mediators, including IL-6, TNF-alpha, PGE2, NO, and GSH, and the activities of COX-2, SOD, and CAT, and the transcription factors involved in inflammation, such as NF-kappaB, c-Jun, and Nrf2, were measured. Curc-mPEG454 showed lower cytotoxicity (IC50 57.8 MUM) when compared with that of curcumin (IC50 32.6 MUM) and inhibited the release of the inflammatory cytokines IL-6, TNF-alpha, IL 1beta, and MCP-1 in a concentration-dependent manner. At 16 MUM, Curc-mPEG454 was most potent in the suppression of COX-2 expression at a transcriptional level rather than in the suppression of the catalytic activity of COX-2. Like curcumin, Curc-mPEG454 significantly reduced intracellular ROS production and enhanced the activities of SOD and CAT and the level of GSH to protect cells from LPS-induced oxidative injury. Further, its anti-inflammatory and antioxidation mechanisms are related to inhibition of NF-kappaB p65 nuclear translocation and c-Jun phosphorylation and to activation of Nrf2. Taken together, these findings indicate that PEGylation of curcumin not only improves its biological properties but also interferes with multiple targets involved in the inflammatory response. Curc-mPEG454 is a powerful and beneficial anti-inflammatory and antioxidant agent that merits further investigation. Graphical Abstract ?. PMID- 29234951 TI - Zinc-finger transcription factor Odd-skipped related 1 regulates cranial bone formation. AB - Knowledge of the molecular mechanisms of bone formation has been advanced by novel findings related to genetic control. Odd-skipped related 1 (Osr1) is known to play important roles in embryonic, heart, and urogenital development. To elucidate the in vivo function of Osr1 in bone formation, we generated transgenic mice overexpressing full-length Osr1 under control of its 2.8-kb promoter, which were smaller than their wild-type littermates. Notably, abnormalities in the skull of Osr1 transgenic mice were revealed by analysis of X-ray, skeletal preparation, and morphological findings, including round skull and cranial dysraphism. Furthermore, primary calvarial cells obtained from these mice showed increased proliferation and expression of chondrocyte markers, while expression of osteoblast markers was decreased. BMP2 reduced Osr1 expression and Osr1 knockdown by siRNA-induced alkaline phosphatase and osteocalcin expression in mesenchymal and osteoblastic cells. Together, our results suggest that Osr1 plays a coordinating role in appropriate skull closure and cranial bone formation by negative regulation. PMID- 29234950 TI - The evolution of endometrial carcinoma classification through application of immunohistochemistry and molecular diagnostics: past, present and future. AB - Uterine cancer was first subclassified based on anatomic site, separating those tumours arising from the endometrium from cervical cancers. There was then further subclassification of endometrial cancers based on cell type, and this correlated with the Type I and Type II categories identified through the epidemiological studies of Bokhman, with endometrioid carcinoma corresponding (approximately) to Type I and serous carcinoma to Type II. These histotypes are not clearly separable in practice, however, with considerable interobserver variability in histotype diagnosis, especially for high-grade tumours. There followed studies of immunomarkers and then mutational studies of single genes, in attempts to improve subclassification. While these have revealed significant differences in protein expression and mutation profiles between endometrioid and serous carcinomas, there is also considerable overlap, so that there remain challenges in subclassification of endometrial carcinoma. Gene panel testing, using next-generation sequencing, was applied to endometrial cancers and highlighted that there are tumours that show genetic alterations intermediate between classic Type I/endometrioid and Type II/serous carcinomas. The Cancer Genome Atlas studies of endometrioid and serous carcinoma offered revolutionary insight into the subclassification of endometrial carcinoma, i.e. that there are four distinct categories of endometrial carcinoma, rather than two, based on genomic architecture. In this review, we provide an overview of immunohistochemical and molecular markers in endometrial carcinoma and comment on the important future directions in endometrial carcinoma subclassification arising from The Cancer Genome Atlas results. PMID- 29234952 TI - Increased calcium uptake and improved trabecular bone properties in intestinal alkaline phosphatase knockout mice. AB - Previous studies have demonstrated a negative correlation between intestinal alkaline phosphatase (IAP) activity and calcium (Ca) absorption in the gut, as IAP acts as a protective mechanism inhibiting high Ca entry into enterocytes, preventing Ca overload. Here we evaluated Ca absorption and bone properties in knockout mice (KO) completely devoid of duodenal IAP (Akp3 -/- mice). Female C57BL/6 control mice (WT, n = 7) and KO mice (n = 10) were used to determine Ca absorption in vivo and by in situ isolated duodenal loops followed by histomorphometric analysis of duodenal villi and crypts. Bone mineral density, morphometry, histomorphometry and trabecular connectivity and biomechanical properties were measured on bones. We observed mild atrophy of the villi with lower absorption surface and a significantly higher Ca uptake in KO mice. While no changes were seen in cortical bone, we found better trabecular connectivity and biomechanical properties in the femurs of KO mice compared to WT mice. Our data indicate that IAP KO mice display higher intestinal Ca uptake, which over time appears to correlate with a positive effect on the biomechanical properties of trabecular bone. PMID- 29234953 TI - Involvement of microRNA-23b in TNF-alpha-reduced BMSC osteogenic differentiation via targeting runx2. AB - Elucidation of the molecular mechanism governing bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation is of great importance for improving the treatment of osteoporosis. TNF-alpha is a well-known inhibitory factor during osteogenic differentiation of BMSCs. In our experiment, we consistently observed that TNF-alpha significantly inhibited BMSC osteogenic differentiation, which was partially rescued by BAY 11-7082 (NF-kappaB inhibitor). In this study, we examined the potential roles of microRNAs (miRNAs) involved in TNF-alpha-mediated reduction of BMSC osteogenesis. We found that microRNA-23b (miR-23b) was dramatically induced under the stimulation of TNF-alpha, which was abolished by BAY 11-7082. Similar to the effect of TNF-alpha, miR-23b agonist (agomir-23b) obviously impaired BMSC osteogenic differentiation in vitro and in vivo. However, agomir-23b had no effect on osteoclast activity. Overexpression of miR-23b significantly reduced runx2, the master transcription factor during osteogenesis, suggesting that miR-23b acts as an endogenous attenuator of runx2 in BMSCs. Mutation of the putative miR-23b binding site in runx2 mRNA blocked miR-23b mediated repression of the runx2 3' untranslated region (3'UTR) luciferase reporter activity, suggesting that miR-23b directly binds to runx2 3'UTR. Furthermore, infection with Ad-runx2 (adenovirus carrying the entire CDS sequence of runx2) effectively rescued the inhibition of BMSC osteogenic differentiation in miR-23b-overexpressing cells, indicating that the inhibiting effect of miR-23b on osteogenesis is mediated by suppression of runx2. Moreover, caudal vein injection of agomir-23b notably caused severe osteoporosis in mice, and forced expression of runx2 by combined injecting Ad-runx2 attenuated the bone loss induced by miR-23b. Collectively, these data indicated that miR-23b was involved in TNF-alpha-mediated reduction of BMSC osteogenesis by targeting runx2. These findings may provide new insights into understanding the regulatory role of miR 23b in the process of BMSC osteogenic differentiation in inflammatory conditions and a novel therapeutic target for osteoporosis. PMID- 29234954 TI - Low versus high volume of culture medium during embryo transfer: a randomized clinical trial. AB - PURPOSE: The aim of this prospective randomized control trial was to evaluate if the use of two different volumes (20-25 vs 40-45 MUl) of media used for embryo transfer affects the clinical outcomes in fresh in vitro fertilization (IVF) cycles. METHODS: In total, 236 patients were randomized in two groups, i.e., "low volume" group (n = 118) transferring the embryos with 20-25 MUl of medium and "high volume" group (n = 118) transferring the embryos with 40-45 MUl of medium. The clinical pregnancy, implantation, and ongoing pregnancy rates were compared between the two groups. RESULTS: No statistically significant differences were observed in clinical pregnancy (46.8 vs 54.3%, p = 0.27), implantation (23.7 vs 27.8%, p = 0.30), and ongoing pregnancy (33.3 vs 40.0%, p = 0.31) rates between low and high volume group, respectively. CONCLUSION: Higher volume of culture medium to load the embryo into the catheter during embryo transfer does not influence the clinical outcome in fresh IVF cycles. TRIAL REGISTRATION NUMBER: NCT03350646. PMID- 29234955 TI - Predictors of Return to Work 6 Months After the End of Treatment in Patients with Common Mental Disorders: A Cohort Study. AB - Purpose Common mental disorders (CMDs) account for a large portion of sickness absence. Even after attending return to work (RTW) interventions, many patients with a CMD remain on sick leave. To identify people at risk of long-term work disability, more needs to be known about factors that predict RTW after treatment. Methods This was a prospective cohort study that followed 106 former patients at an RTW outpatient clinic for CMDs for 6 months after the end of treatment. Changes in work participation and mental health status between the end of treatment and the 6-month follow-up were analysed. Changes in work participation were used to identify patients with successful RTW. Patient characteristics and end-of-treatment measures of mental health status, work ability, generalized self-efficacy and expectations of future work ability, and changes in clinical outcome measures during treatment were included in logistic regression analyses to identify predictors of RTW at the 6-month follow-up. Results In the final model, high occupational status and higher work ability at the end of treatment predicted successful RTW at the 6-month follow-up. Further analyses showed that if the expectancy of future work ability improved or remained positive from before to the end of treatment, this was also strongly associated with RTW at the 6-month follow-up. Conclusions Among patients treated for CMDs, those with a low occupational status and who report lower work ability at the end of treatment are at risk of long-term disability. PMID- 29234956 TI - Work Participation Among Employees with Common Mental Disorders: A Meta synthesis. AB - Purpose The aim was to aggregate knowledge about the opportunities, challenges and need for support employees with common mental disorders experience in relation to work participation in order to develop recommendations for practice. Methods A meta-synthesis was conducted using a meta-aggregative approach to accurately and reliably present findings that could be used to meet our aim. Qualitative inductive content analysis was used to analyze and synthesize the findings. Results In all, 252 findings were extracted from 16 papers, and six categories were generated and aggregated into two synthesized findings. One synthesized finding indicates that a strong work identity and negative perceptions regarding mental disorders can impede work participation, creating an essential need for a supportive work environment. The other reveals that the diffuse nature of the symptoms of mental disorders causes instability in life and loss of control, but through the use of internal motivation and external support, employees may be able to regain control of their lives. However, external support is hampered by insufficient cooperation and coordination between vocational stakeholders. Conclusions Based on the synthesized findings, we recommended that the employer is involved in the rehabilitation process, and that rehabilitation professionals seek to strengthen the employee's ability to manage work-related stress. In addition, rehabilitation professionals should provide individualized and active support and ensure meaningful cooperation across the multidisciplinary disciplines involved in the rehabilitation process. PMID- 29234958 TI - The relationship between putamen-SMA functional connectivity and sensorimotor abnormality in ESRD patients. AB - The basal ganglia (BG) are composed of several nuclei involved in neural processing associated with integration of sensory and motor information. Recent neuroimaging studies implicated its key role in control of voluntary motor function. As the sensorimotor abnormality is common among the end-stage renal disease (ESRD) population, in the current study, we aimed to investigate the abnormal structure and functional connectivity patterns of BG in ESRD patients. Twenty-nine ESRD and twenty-nine age and gender-matched healthy controls (HC) were enrolled to compare the volume of the subsets in the BG (e.g., caudate nucleus, putamen and globus pallidus) by using the VBM analysis; resting-state functional connectivity was analyzed by a seed-based method. Compared with the HC group, ESRD patients had a smaller volume in the right putamen. Taking the right putamen as a seed region, we further found reduced functional connectivity in patients mainly between the putamen and supplementary motor area (SMA), insula, posterior mid-cingulate gyrus, and primary motor cortex. In ESRD group, the severity score of restless legs syndrome was negatively correlated with putamen SMA functional connectivity, while the hemoglobin level was positively correlated with functional connectivity degree between the putamen and SMA. Our results revealed an abnormal volume of the putamen and its decreased functional connectivity patterns during resting state in ESRD with sensorimotor abnormalities. These preliminary results indicated that the decreased functional connectivity in putamen-SMA was associated with sensorimotor abnormalities, and anemia was correlated with this abnormal functional pattern in ESRD patients. PMID- 29234959 TI - Olfactory cortex and Olfactory bulb volume alterations in patients with post infectious Olfactory loss. AB - Upper respiratory tract infection (URI) is one of the most common etiology of olfactory loss. Previous studies demonstrated that both olfactory bulb (OB) volume and sulcus (OS) depth decreased in patients with post-infectious olfactory loss (PIOL) compared to normal controls. The aim of our study was to observe alterations of central olfactory pathways in patients with PIOL. T1 weighted magnetic resonance images were acquired in 19 PIOL patients and 19 age- and sex matched control subjects on a 3 T scanner. Voxel-based morphometry (VBM) was performed using VBM8 toolbox and SPM8 in a Matlab environment. We also analyzed OB volume in coronal T2-weighted images. Whole-brain analysis revealed a significant gray matter volume loss in the right orbitofrontal cortex (OFC) in patients group. Further analysis with region of interest exhibited a significant negative correlation between gray matter volume in right OFC as well as OB volume and the duration of olfactory loss in these patients (r = -0.566 and r = -0.535 both P < 0.05, respectively). In conclusion, the morphological alterations in the right OFC and OB might contribute to the pathogenic mechanism of olfactory dysfunction after upper respiratory tract infection. PMID- 29234957 TI - Factors affecting the outcomes of direct pulp capping using Biodentine. AB - INTRODUCTION: This study aimed to evaluate the prognostic value of factors with regard to the treatment outcome of direct pulp capping using Biodentine (Septodont, Saint-Maur-des-Fosses, France), in permanent teeth in which the pulps were exposed during caries removal. METHODS: Between 2010 and 2014, 112 teeth with deep carious lesions underwent direct pulp capping. The patients were followed up at 2-3 months and 1-1.5 years with a routine examination on both recall visits. Periapical radiographs were taken at 1-1.5 years. Lack of patient complaints, positive reactions to cold and electric testing, no sensitivity to percussion, and no widening of the periapical ligament indicated success. The Fisher exact test was used for statistical analysis. The significance level was P = .05. RESULTS: Eighty-six teeth were available for 1-1.5 years follow-up. The overall success rate was 82.6%. Only age had a significant effect on the pulpal survival rate: the success rate was 90.9% in patients younger than 40 years and 73.8% in patients 40 years or older (P = .0480). Sex, initial or secondary caries treatment, occlusal or cervical/proximal caries, delayed placement of permanent filling, tooth position, and arch type did not influence the outcome. CONCLUSIONS: A patient's age influenced the outcome of direct pulp capping using this new calcium silicate cement. CLINICAL RELEVANCE: Asymptomatic vital permanent teeth with cariously exposed pulp can be treated successfully by direct pulp capping using Biodentine. PMID- 29234960 TI - A new postoperative pain management (intravenous acetaminophen: Acelio(r)) leads to enhanced recovery after esophagectomy: a propensity score-matched analysis. AB - PURPOSES: To investigate the efficacy of postoperative scheduled intravenous acetaminophen to reduce the opioid use and enhance the recovery after esophagectomy. METHODS: A propensity score-matched population was created using the 93 and 69 consecutive patients who underwent esophagectomy for esophageal cancer before and after the introduction of postoperative scheduled intravenous acetaminophen, and the short-term clinical outcomes were compared. RESULTS: Significant defervescence was demonstrated in the Acetaminophen group (A-group) compared with control group (C-group) during the perioperative period (p < 0.05), whereas no significant differences were observed in the postoperative inflammatory parameters. The incidence of postoperative complications was similar between the groups. The number of PCA pushes and the frequency of using other non opioid analgesics were significantly smaller in the A-group than in the C-group (p < 0.05). Both daily and cumulative opioid uses were significantly smaller in the A-group than in the C-group (p < 0.05). The time to first flatus was significantly shorter in the A-group than in the C-group (p < 0.001). The day of first walking after surgery was significantly earlier in the A-group than in the C-group (1.0 versus 2.0 days, p = 0.003). The ICU stay (2.86 versus 3.61 days, p < 0.001) and the hospital stay (21.5 versus 26.0 days, p = 0.061) tended to be shorter in the A-group than in the C-group. CONCLUSIONS: Postoperative scheduled intravenous acetaminophen decreased the rate of opioid use without increasing the intensity of postoperative pain and may be a feasible new pain management option in the enhanced recovery after surgery protocol following esophagectomy. PMID- 29234961 TI - Risk and incidence of perioperative deep vein thrombosis in patients undergoing gastric cancer surgery. AB - BACKGROUND AND PURPOSE: Venous thromboembolism (VTE) is a potentially fatal perioperative complication. Understanding the risk factors for deep vein thrombosis (DVT) and initiating appropriate prophylaxis is pivotal for reducing the risk of VTE. The purpose of this study was to clarify the perioperative risk factors for DVT in patients undergoing surgery for gastric cancer. METHODS: We reviewed the findings of lower limb ultrasonography performed in 160 patients who underwent gastrectomy for gastric cancer. RESULTS: The preoperative and postoperative incidence of DVT was 4.4% (7/160) and 7.2% (11/153), respectively. All postoperative DVTs were of the distal type, whereas preoperative DVTs were of the proximal (n = 3) and distal type (n = 4). None of the patients suffered symptomatic VTE. Multivariate analysis indicated that depth of invasion and D dimer concentration were independent risk factors for preoperative DVT and that gender and performance status were risk factors for postoperative DVT. Receiver operating characteristic analysis revealed that the optimal cut-off D-dimer concentration was 1.4 MUg/mL. CONCLUSIONS: The incidence of perioperative DVT was low for patients undergoing gastric cancer surgery. Therefore, the risk stratified application of perioperative pharmacologic thromboprophylaxis is thought to be more appropriate than routine pharmacologic thromboprophylaxis for Japanese patients undergoing surgery for gastric cancer. PMID- 29234962 TI - The functional outcome and factors influencing the quality of life after ileal pouch anal anastomosis in patients with ulcerative colitis. AB - PURPOSE: The aim of this study was to assess the bowel function and quality of life (QOL) in patients with ulcerative colitis (UC) after total proctocolectomy with ileal pouch anal anastomosis (IPAA). METHODS: Two questionnaires ["Questionnaire sheet on the bowel function" and "Inflammatory bowel disease questionnaire (Japanese IBDQ)"] were sent to 121 patients with UC who underwent IPAA at Tohoku University Hospital. Seventy-nine patients (65%) participated in the study. RESULTS: The median number of daily bowel movements was 6.5, which significantly decreased with postoperative time (<= 1, 1-5, 5-15 years) and increased with age (< 45, >= 45 years at colectomy). The ratio of patients who usually had bowel movements at night also significantly decreased with postoperative time and increased with age. The median total IBDQ score was 180. A multivariate analysis showed that "trip activity", "care about where the restroom is", and "bowel movements in the day" were significant independent risk factors for the daily life satisfaction score. CONCLUSIONS: The bowel function and QOL were acceptable in patients with UC after IPAA; however, patients with a short postoperative time or older age had a lower functional outcome than others. PMID- 29234963 TI - Financial Burden of Treatment of Transfusion Dependent Thalassemia. PMID- 29234964 TI - Pre-made consent for elective inguinal hernia repair: the need for standardisation-a survey of all UK NHS Trusts. AB - PURPOSE: Elective inguinal hernia repair (IHR) is one of the most commonly performed operations in the UK. As with all procedures, informed consent is essential. Pre-made consent forms have been suggested to improve consenting practice. This study aimed to assess the usage and quality of pre-made hernia specific consent forms (PCF) in the UK. METHODS: A freedom of information request was sent to all UK NHS Trusts asking: (1) does the trust perform IHRs; (2) do they have a PCF; and (3) to send a copy. Complications lists on received forms were reviewed and compared to those listed on the British Hernia Society (BHS) "patient information" webpage. RESULTS: 157/185 Trusts (85%) responded. 117/157 (75%) perform IHRs; 16/117 (14%) use PCFs. The number of reported risks was variable (range 4-18), as was the content of each form (28 different risks were listed). Quoted percentage risks were inconsistent (e.g. recurrence range < 1 5%). The frequency of each BHS-quoted risk was (open/laparoscopic): Bleeding 62/75%; infection 85/92%; seroma 31/42%; damage to testicular blood supply 69/75%; damage to abdominal contents NA/25%; haematoma 62/67%; venous thromboembolism 54/50%; recurrence 85/83%; chronic pain 77/58%; mesh infection 23/8%. Zero forms contained all BHS-quoted risks. CONCLUSIONS: Whilst the consent form only provides documentation of the consent process, this study suggests that PCFs do not improve the quality of consent as both the type and likelihood of quoted complications were highly variable between Trusts. As follow-up for elective procedures is rare, it is unlikely that this variability reflects actual measured outcomes. PMID- 29234965 TI - Psychological Science within a Three-Dimensional Ontology. AB - The present paper outlines the nature of a three-dimensional ontology and the place of psychological science within this ontology, in a way that is partly similar to and partly different from that of Perez-Alvarez. The first dimension is the material realities, and involves different levels (physical, chemical, biological, psychological, etc.), where each level builds on a lower level but also involves the development of new emergent properties, in accordance with Bunge's emergent materialism. Each level involves systems, with components, structures and mechanisms, and an environment. This dimension can be studied with natural scientific methods. The second dimension is the subjective-experiential realities, and refers to our subjective perspective on the world. In accordance with Husserl's phenomenology, it is argued that this subjectivity does not exist in the world (i.e., should not be reified as an object among other objects), but represents a perspective on the world that we enter in our capacity as conscious human beings. Essential characteristics of this subjectivity (such as intentionality, temporality, embodiment, and intersubjectivity) can be explored by phenomenological methods. The third dimension is the social-constructional realities, and includes social institutions, norms, categories, theories, and techniques. It is argued that psychological science spans over all three dimensions. Although almost all psychological research by necessity starts from a problem formulation where the subjective-experiential dimension plays an essential role (either explicitly or implicitly), most of present-day psychological research clearly emphasizes the material dimension. It is argued that a mature psychological science needs to integrate all three dimensions. PMID- 29234966 TI - Efficacy and feasibility of a collaborative multidisciplinary program for antibiotic prophylaxis in clean wound surgery. AB - Background Despite national and international guidelines and recommendations, inappropriate prophylactic antibiotic use for clean wound surgery remains a common phenomenon in many Chinese hospitals, causing higher medical costs and bacterial resistance. Objective To improve the prescribing behavior for antibiotic prophylaxis and decrease antibiotic abuse and/or misuse in clean wound surgery. Setting The teaching hospital of a medical university in Southwest China. Methods A collaborative multidisciplinary program involving educational, technical, and administrative strategies was undertaken. It was characterized by a monthly evaluation by clinical pharmacists for randomly selected cases of clean wound surgery, as well as a group discussion attended by correlative personnel, consisting of the administrative staff, experts from the Rational Drug Use Committee, clinical pharmacists and surgeons. Main outcome measure The overall incidence of antibiotic prophylaxis, appropriate antibiotics selection, appropriate initial dosage timing, proper drug combination and the duration of antibiotic prophylaxis were measured. Results from 2009 to 2014, the rate of antibiotic prophylaxis for clean wound surgery declined from nearly 100% to 20 30%. Improvements were also observed in drug selection, timing of the first dose, and dosage and duration for antibiotic prophylaxis. Broad-spectrum antibiotics and enzyme inhibitors have seldom been used after 2011. The medical cost for antibiotics also decreased. Conclusion A collaborative multidisciplinary program, together with a group discussion, is efficient for improving rational antibiotic prophylaxis for clean wound surgery. This study indicates that clinical pharmacists can play a pivotal role in providing the professional evaluation of medical cases, education, and intervention. PMID- 29234967 TI - Finding efficient swimming strategies in a three-dimensional chaotic flow by reinforcement learning. AB - We apply a reinforcement learning algorithm to show how smart particles can learn approximately optimal strategies to navigate in complex flows. In this paper we consider microswimmers in a paradigmatic three-dimensional case given by a stationary superposition of two Arnold-Beltrami-Childress flows with chaotic advection along streamlines. In such a flow, we study the evolution of point-like particles which can decide in which direction to swim, while keeping the velocity amplitude constant. We show that it is sufficient to endow the swimmers with a very restricted set of actions (six fixed swimming directions in our case) to have enough freedom to find efficient strategies to move upward and escape local fluid traps. The key ingredient is the learning-from-experience structure of the algorithm, which assigns positive or negative rewards depending on whether the taken action is, or is not, profitable for the predetermined goal in the long term horizon. This is another example supporting the efficiency of the reinforcement learning approach to learn how to accomplish difficult tasks in complex fluid environments. PMID- 29234968 TI - A cross-national analysis of the association between years of implementation of opioid substitution treatments and drug-related deaths in Europe from 1995 to 2013. AB - Data at the individual-level provide evidence that opioid substitution treatment (OST) programs protect against mortality for opioid dependent populations. Prior research has not examined the merits of national implementation of opioid substitution programs for reducing mortality at the country-level. This study elucidates longitudinal associations between country-level implementation of opioid substitution treatment programs on mortality rates of drug related deaths (DRD) from 1995 to 2013 in 30 European nations. Cases of DRD were measured using National Definitions for each country from official sources of data. Preliminary analysis of dispersion of cases of DRD using means and variances justified use of the negative binomial regression model with a population offset. Year and country level fixed effects negative binomial regression models investigated the association between years of implementation of methadone maintenance therapy (MMT), OST in prison, and high dose buprenorphine treatment (HDBT) implementation and mortality rates from drug related deaths after adjusting for unemployment rates, heroin seizures and per capita expenditures on health. Beta coefficients were converted to Incidence Rate Ratios (IRR) and standard errors bootstrapped using non-parametric methods to adjust for bias (SDbs). The mean mortality rate of DRD was 1.81 from 1995 to 2013. In adjusted models, each additional year of MMT (IRR = .61, SD = .04, p < .001; SDbs = .08, p < .001), prison OST (IRR = .90, SD = .01, p < .001; SDbs = .02, p < .001), and HDBT (IRR = .09, SD = .02, p < .001; SDbs = .02, p < .01) was significantly associated with lower rates of DRDs after adjusting for country and year fixed effects. Implementation of OST programs in the general population and in prison settings may have protected against mortality from drug use at the country-level in Europe from 1995 to 2013. PMID- 29234969 TI - Monoclonal Antibodies for Treatment of Eosinophilic Esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus affecting both children and adults, with debilitating and progressive symptoms. EoE has shown an explosive epidemiological rise in the past few decades. Many patients experience a poor level of disease control despite maximal use of available guideline-based therapies, which seriously hampers their quality of life. Diet restrictions and systemic and topical corticosteroids are the current mainstays of EoE therapy, but are associated with significant efficacy, treatment compliance, and safety issues such as oral or esophageal candidiasis, growth retardation, osteopenia, osteoporosis, glucose intolerance, and cataract formation. As EoE is a chronic inflammatory disease, immune cells and cytokines are responsible for the inflammatory response and symptoms. Monoclonal antibodies specifically targeting these pathophysiologic effectors offer more potent relief of histologic and clinical disease features while keeping off-target adverse effects to a minimum. Herein, we have reviewed the current evidence regarding efficacy and safety of monoclonal antibodies including mepolizumab (anti-IL-5), reslizumab (anti-IL-5), QAX576 (anti-IL-13), omalizumab (anti-immunoglobulin-E), and infliximab (anti-TNF-alpha) in treatment of EoE. Our review indicates that although the use of monoclonal antibodies for EoE treatment is safe with limited and reversible adverse events, however, it is not yet possible to reach a final verdict on the efficacy of mAbs in EoE. Future well-designed studies are needed to clarify the exact role of mAbs in EoE. PMID- 29234971 TI - Elective ambulatory surgical care in Ireland-why it needs to be better coded, classified and managed. AB - BACKGROUND: In the year to July 2017, surgical disciplines accounted for 73% of the total national inpatient and day case waiting list and, of these, day cases accounted for 72%. Their proper classification is therefore important so that patients can be managed and treated in the most suitable and efficient setting. AIMS: We set out to sub-classify the different elective surgical day cases treated in Irish public hospitals in order to assess their need to be managed as day cases and the consistency of practice between hospitals. METHODS: We analysed all elective day cases that came under the care of surgeons between January 2014 and December 2016 and sub-classified them into those that were (A) true day case surgical procedures; (B) minor surgery or outpatient procedures; (C) gastrointestinal endoscopies; (D) day case, non-surgical interventions and (E) unclassified or having no primary procedure identified. RESULTS: Of 813,236 day case surgical interventions performed over 3 years, 26% were adjudged to accord with group A, 41% with B, 23% with C, 5% with D and 5% with E. The ratio of A to B procedures did not vary significantly across the range of hospital types. However, there were some notable variations in coding and practices between hospitals. CONCLUSION: Our findings show that many day cases should have been performed as outpatient procedures and that there were variations in coding and practices between hospitals that could not be easily explained. Outpatient procedure coding and a better, more consistent, classification of day cases are both required to better manage this group of patients. PMID- 29234970 TI - Aortic valve reconstruction using autologous pericardium (Ozaki procedure) for active infective endocarditis: a case report. AB - Approximately one-third of patients with infective endocarditis require surgical treatment, but the ideal procedure that prevents infection ensures long durability and maintains quality of life remains unclear. A 21-year-old man who was diagnosed with aortic active infective endocarditis was referred to our hospital for surgical treatment. Echocardiography showed bicuspid aortic valve, severe aortic regurgitation, a large vegetation, and a paravalvular abscess. We planned to perform elective surgical treatment after antibiotic therapy; however, progression to heart failure required urgent operation. Aortic valve reconstruction (AVr) using autologous pericardium was performed. Perioperative and postoperative courses were uneventful. No recurrence of infection or adverse events were observed 4 years postoperatively. Considering prosthetic valve infection and redo operation, AVr may be considered among young patients. PMID- 29234972 TI - Staging, Treatment, and Future Approaches of Gallbladder Carcinoma. AB - BACKGROUND: Gallbladder cancer is the most common malignant cancer of the bile ducts and third most common gastrointestinal malignant in the world for public health. Its relatively low incidence and confused symptoms result in advanced disease at the time of presentation, contributing to poor prognosis and reduced survival associated with this disease. The main function of the gallbladder is to store excreted bile acids from the liver in preparation for a meal. Its main risk factor is prolonged exposure to biliary calculations, although bacterial infections and other inflammatory conditions are associated. Chronic inflammatory bowel conditions are associated with gallbladder cancer. T stage translates to identifying residual disease at reoperation for incidental gallbladder cancer and residual disease negatively affects survival. CONCLUSION: It is the most common cancer of gallbladder, gallbladder cancer remains a rare disease. Gallbladder cancer is a rare disease that can be accidentally diagnosed after cholecystectomy or accidentally, often with more advanced disease. The prognosis is generally extremely poor and improvements in surgical resection of this approach have to be re-evaluated, while the role of chemotherapy and radiotherapy remains controversial. PMID- 29234973 TI - Decompressive craniectomy in traumatic brain injury: usage and clinical outcome in a single centre. AB - BACKGROUND: Two randomised controlled trials (RCTs) of decompressive craniectomy (DC) in traumatic brain injury (TBI) have shown poor outcome, but there are considerations of how these protocols relate to real practice. The aims of this study were to evaluate usage and outcome of DC and thiopental in a single centre. METHOD: The study included all TBI patients treated at the neurointensive care unit, Akademiska sjukhuset, Uppsala, Sweden, between 2008 and 2014. Of 609 patients aged 16 years or older, 35 treated with DC and 23 treated with thiopental only were studied in particular. Background variables, intracranial pressure (ICP) measures and global outcome were analysed. RESULTS: Of 35 DC patients, 9 were treated stepwise with thiopental before DC, 9 were treated stepwise with no thiopental before DC and 17 were treated primarily with DC. Six patients received thiopental after DC. For 23 patients, no DC was needed after thiopental. Eighty-eight percent of our DC patients would have qualified for the DECRA study and 38% for the Rescue-ICP trial. Favourable outcome was 44% in patients treated with thiopental before DC, 56% in patients treated with DC without prior thiopental, 29% in patients treated primarily with DC and 52% in patients treated with thiopental with no DC. CONCLUSIONS: The place for DC in TBI management must be evaluated better, and we believe it is important that future RCTs should have clearer and less permissive ICP criteria regarding when thiopental should be followed by DC and DC followed by thiopental. PMID- 29234977 TI - Capsule Commentary on Lunney et al., Three Year Functional Trajectories Among Old Age Survivors and Decedents: Dying Eliminates a Racial Disparity. PMID- 29234976 TI - Assessment of bridge scour in the lower, middle, and upper Yangtze River estuary with riverbed sonar profiling techniques. AB - Riverbed scour of bridge piers can cause rapid loss in foundation strength, leading to sudden bridge collapse. This study used multi-beam echo sounders (Seabat 7125) to map riverbed surrounding the foundations of four major bridges in the lower, middle, and upper reaches of the 700-km Yangtze River Estuary (YRE) during June 2015 and September 2016. The high-resolution data were utilized to analyze the morphology of the bridge scour and the deformation of the wide-area riverbed (i.e., 5-18 km long and 1.3-8.3 km wide). In addition, previous bathymetric measurements collected in 1998, 2009, and 2013 were used to determine riverbed erosion and deposition at the bridge reaches. Our study shows that the scour depth surrounding the bridge foundations progressed up to 4.4-19.0 m in the YRE. Over the past 5-15 years, the total channel erosion in some river reaches was up to 15-17 m, possessing a threat to the bridge safety in the YRE. Tide cycles seemed to have resulted in significant variation in the scour morphology in the lower and middle YRE. In the lower YRE, the riverbed morphology displayed one long erosional ditch on both sides of the bridge foundations and a long-strip siltation area distributed upstream and downstream of the bridge foundations; in the middle YRE, the riverbed morphology only showed erosional morphology surrounding the bridge foundations. Large dunes caused deep cuts and steeper contours in the bridge scour. Furthermore, this study demonstrates that the high resolution grid model formed by point cloud data of multi-beam echo sounders can clearly display the morphology of the bridge scour in terms of wide areas and that the sonar technique is a very useful tool in the assessment of bridge scours. PMID- 29234974 TI - The impact of farnesol in combination with fluconazole on Candida albicans biofilm: regulation of ERG20, ERG9, and ERG11 genes. AB - Farnesol (FAR) has already demonstrated an inhibitory effect on Candida albicans biofilm. The aim of this work was to determine the effectiveness of externally added FAR in combination with fluconazole (FLC) on Candida albicans biofilm and on regulation of the ergosterol genes ERG20, ERG9, and ERG11. The effectiveness of compounds was determined by MTT assay and evaluated by the minimal inhibitory concentrations reducing a sessile biofilm to 50% activity (0.5 MUg/mL and 200 MUmol/L for FLC and FAR, respectively). These concentrations as well as 30 and 100 MUmol/L FAR were selected for a study of the effectiveness of the FAR/FLC combination. The reduction in biofilm robustness mainly caused by the presence of 200 MUmol/L FAR-alone or in combination with FLC-was accompanied by a significant inhibition of the yeast-to-hyphae transition that was observed by light microscopy and CLSM. Results from qRT-PCR indicated that while 30 MUmol/L FAR only slightly regulated the expression of all 3 genes in the 48-h biofilm, the presence of 200 MUmol/L FAR downregulated all the tested genes. However, the addition of 0.5 MUg/mL of FLC to the samples with 200 MUmol/L FAR restored the downregulation of the ERG20 and ERG11 genes to the control level. Moreover, the gene ERG9 was slightly upregulated. In summary, FAR acted via multiple effects on the C. albicans biofilm, but only a higher concentration of FAR proved to be effective. PMID- 29234975 TI - Adsorption isotherms and kinetic studies for the defluoridation from aqueous solution using eco-friendly raw marine green algae, Ulva lactuca. AB - The defluoridation from aquatic medium by raw marine algae, Ulva lactuca, was investigated. The element components and adsorbent's properties were determined. The influence of pH, contact period, and Ulva sp. weight on the deflouridation was achieved. The complete defluoridation of 10 mg F-/l solution was obtained within 10 min at definite pHs. Fourteen adsorption isotherms and four kinetic models (pseudo-first order and pseudo-second order, Elovich, and intraparticle diffusivity) were studied. The most adequate model was performed by using five error functions. The application of chi-squared test indicated that the nonlinear isotherm models (two and three parameters) were more applicable than the linear ones. The adsorption kinetic proceeded by pseudo-first-order model. The adsorption mechanism was very complex; thus, the solute distribution step was not the only dominant one during the process. The adsorption seemed to be a physical negative binding cooperative type with activation energy and free energy of 3.16 and - 1.672 kJ/mol, respectively. Thus, raw marine algae, Ulva lactuca, can be used as an adsorbent in solving the fluoridation problem in aquatic mediums throughout the world due to their fast procedure, high efficiency, low effort, and high economic value. PMID- 29234978 TI - From the Editors' Desk: Bias in Systematic Reviews-Let the Reader Beware. PMID- 29234979 TI - Neuroprotective effects of Moringa oleifera: Bio-guided GC-MS identification of active compounds in diabetic neuropathic pain model. AB - OBJECTIVES: To explore the phytotherapeutic-activities of Moringa oleifera (MO) seeds on painful diabetic neuropathy in alloxan-induced diabetic mice. METHODS: The bio-guided fractionation of MO utilizing column chromatography aided with GC MS was used to detect the most active constituent of MO. Hyperalgesia, using tail flick and hot-plate latency experiments, and mechanical-allodynia, utilizing von Frey filaments, were evaluated before and after 8 weeks of intraperitoneal alloxan administration (180 mg/kg). Serum catalase and insulin levels, body weight and blood glucose levels (BGL), alpha-glucosidase inhibition, lipid peroxidation and glycated hemoglobin (HbA1c) were measured to evaluate both alloxan-induced diabetes mellitus and diabetic painful neuropathy (DPN). RESULTS: Beta-sitosterol (BSL) was proved to be the most active constituent of MO. The administration of MO (40, 60 and 80 mg/kg) or BSL (18, 25 and 35 mg/kg) significantly attenuated hyperalgesia and tactile allodynia (P?0.05), compared with tramadol (10 mg/kg) acting as a positive control, in alloxan-treated animals (n=7 per group). Moreover, MO and BSL have improved insulin secretion, in vivo antioxidant catalase, lipid peroxidation, acute and subchronic BGL, and normalized alpha-glucosidase and HbA1c levels. CONCLUSIONS: The observed insulin secretagogue, alpha-glucosidase inhibition, hypoglycemic and antioxidant potentials might be responsible for MO and BSL antinociception and neuroprotective mechanism. MO and BSL have shown good glycemic-control and powerful neuroprotective properties which might serve as potential lead-compounds for further analysis. PMID- 29234980 TI - Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives. AB - CD4+CD25+Foxp3+ Treg is a functionally distinct subset of mature T cells with broad suppressive activity and has been shown to play an important role in the establishment of immune tolerance after HSCT. Altered cytokine environment in post-HSCT lymphopenia with a relative functional deficiency of IL-2 could hamper the reconstitution of Treg, leading to refractory GVHD. Based on the theory of low-dose IL-2 in which Treg can be selectively stimulated through the high affinity IL-2 receptor, clinical studies have been conducted and demonstrated that low-dose IL-2 administration can restore Treg homeostasis and promote the expansion of this subset on the polymorphic processes of Treg reconstitution after HSCT. The new therapeutic indication of IL-2 for immune tolerance has launched in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases. To further extend the indication of low-dose IL-2 to more patients with various immunological problems, the optimization of the timing and dosing of IL-2 intervention and the concomitant immune suppressive therapy according to each patient-based assessment are to be desired in the near future. Further prospective studies may facilitate the development of novel therapeutic algorithms for the effective and safe induction of immune tolerance after HSCT. PMID- 29234981 TI - Sarcopenia after induction therapy in childhood acute lymphoblastic leukemia: its clinical significance. AB - Muscle weakness is one of the most serious problems during chemotherapy for childhood hematological malignancies. It may be caused by long-term hospitalization, unfavorable physical conditions, and restricted activities. Although the concept of sarcopenia is becoming widely recognized, especially in geriatric medicine, there have been few reports about sarcopenia in pediatric patients with hematological malignancies. A total of 47 consecutive first-onset acute lymphoblastic leukemia (ALL) patients who underwent induction therapy between January 2011 and September 2016 were investigated. The cross-sectional psoas muscle area (PMA) was measured on computed tomography (CT) images. PMA changes were expressed as the Muscle Loss Index (MLI), which was calculated by dividing the post-treatment PMA by the pre-treatment PMA. In this study, patients with values less than the lowest quartile of MLI were classified into the sarcopenia group, and their basic and clinical factors were compared with those in the non-sarcopenia group. Muscle loss was observed in all patients after induction therapy, and severe adverse events during induction therapy were significantly more common in patients in the sarcopenia group. Furthermore, sarcopenia was found to be an independent prognostic factor for invasive fungal infection (IFI) that occurs after induction therapy. The evaluation of sarcopenia on CT images is easy and useful as a predictor of unfavorable events such as IFI in the treatment of childhood ALL. PMID- 29234982 TI - A Multicellular Model of Intestinal Crypt Buckling and Fission. AB - Crypt fission is an in vivo tissue deformation process that is involved in both intestinal homeostasis and colorectal tumourigenesis. Despite its importance, the mechanics underlying crypt fission are currently poorly understood. Recent experimental development of organoids, organ-like buds cultured from crypt stem cells in vitro, has shown promise in shedding light on crypt fission. Drawing inspiration from observations of organoid growth and fission in vivo, we develop a computational model of a deformable epithelial tissue layer. Results from in silico experiments show the stiffness of cells and the proportions of cell subpopulations affect the nature of deformation in the epithelial layer. In particular, we find that increasing the proportion of stiffer cells in the layer increases the likelihood of crypt fission occurring. This is in agreement with and helps explain recent experimental work. PMID- 29234983 TI - On a Volterra Cubic Stochastic Operator. AB - We consider a class of Volterra cubic stochastic operators. We describe the set of fixed points, the invariant sets and construct several Lyapunov functions to use them in the study of the asymptotical behavior of the given Volterra cubic stochastic operators. A complete description of the set of limit points is given, and we show that such operators have the ergodic property. PMID- 29234984 TI - BoBER: web interface to the base of bioisosterically exchangeable replacements. AB - We describe a novel freely available web server Base of Bioisosterically Exchangeable Replacements (BoBER), which implements an interface to a database of bioisosteric and scaffold hopping replacements. Bioisosterism and scaffold hopping are key concepts in drug design and optimization, and can be defined as replacements of biologically active compound's fragments with other fragments to improve activity, reduce toxicity, change bioavailability or to diversify the scaffold space. Our web server enables fast and user-friendly searches for bioisosteric and scaffold replacements which were obtained by mining the whole Protein Data Bank. The working of the web server is presented on an existing MurF inhibitor as example. BoBER web server enables medicinal chemists to quickly search for and get new and unique ideas about possible bioisosteric or scaffold hopping replacements that could be used to improve hit or lead drug-like compounds. PMID- 29234985 TI - Ponticoccus alexandrii sp. nov., a novel bacterium isolated from the marine toxigenic dinoflagellate Alexandrium minutum. AB - During an investigation of the biodiversity of the cultivable bacterial community associated with paralytic shellfish poisoning toxin-producing marine dinoflagellate, Alexandrium minutum a novel algal-associated bacterium, designated strain AT2-AT was isolated. 16S rRNA gene sequence similarity analysis showed that the strain is a member of the genus Ponticoccus, with high sequence similarity to Ponticoccus litoralis DSM 18986T (97.9%) and Ponticoccus lacteus JCM 30379T (96.0%). However, based on the data obtained for the physiological and biochemical characteristics, and low level of DNA-DNA relatedness analysis, the strain could be genotypically and phenotypically differentiated from two type strains of the genus Ponticoccus. Therefore, this algal-associated bacterial strain is concluded to represent a novel species of the genus Ponticoccus, for which the name Ponticoccus alexandrii sp. nov. is proposed. The type strain is AT2-AT (CCTCC AB 2016296T = KCTC 62340T) [corrected]. PMID- 29234986 TI - Exertional rhabdomyolysis leading to acute kidney injury: when genetic defects are diagnosed in adult life. AB - Rhabdomyolysis is a common cause of acute kidney injury (AKI) that is usually triggered by trauma. However, less common causes of rhabdomyolysis may precipitate AKI as well, possibly representing a diagnostic challenge even for the experienced nephrologist. Genetic defects of muscle metabolism represent one of these causes and can be overlooked in adults, since these diseases usually become apparent in childhood. We present here a case in which an adult patient with severe exertional rhabdomyolysis leading to AKI was finally diagnosed with a genetic defect of lipid metabolism. A 41-year-old patient was brought to our attention because of AKI and pigmenturia after strenuous physical effort. At admission, the patient was over-hydrated with a weight increase of 3 kg in few days. Laboratory examination showed creatinine of 8.7 mg/dl, along with increased myoglobin and CPK. Urinalysis was positive for haemoglobin and proteins, while urinary sediment analysis did not demonstrate any red blood cell but rather "muddy-brown" casts and tubular cells. Urine output was forced and the patient completely recovered renal function. Genetic analysis later demonstrated the presence of a common mutation of Carnitine Palmitoyl-Transferase II (CPTII). When facing rhabdomyolysis of obscure origin, nephrologists must keep in mind the possibility that even adult patients may have a genetic defect of energy metabolism. In these cases, patients usually experience rhabdomyolysis during exertion, fasting, or infection. CPTII deficiency often has a subtle presentation and might be unrecognized until AKI develops. Therefore, it is important to consider a genetic defect of muscle metabolism even in adult patients when a history of rhabdomyolysis of unclear origin is present. PMID- 29234988 TI - Identification, characterization and expression analysis of genes involved in steroidal saponin biosynthesis in Dracaena cambodiana. AB - Dracaena cambodiana is a traditional medicinal plant used for producing dragon's blood. The plants and dragon's blood of D. cambodiana contain a rich variety of steroidal saponins. However, little is known about steroidal saponin biosynthesis and its regulation in D. cambodiana. Here, 122 genes encoding enzymes involved in steroidal saponin biosynthesis were identified based on transcriptome data, with 29 of them containing complete open reading frames (ORF). Transcript expression analysis revealed that several genes related to steroidal saponin biosynthesis showed distinct tissue-specific expression patterns; the expression levels of genes encoding the key enzymes involved in the biosynthesis and early modification of steroidal saponins were significantly down-regulated in the stems in response to the inducer of dragon's blood, exhibiting positive correlations with the content of steroidal saponins. These results provide insights on the steroidal saponins biosynthetic pathway and mechanisms underlying induced formation of dragon's blood in D. cambodiana. PMID- 29234987 TI - Evaluation of microstructurally motivated constitutive models to describe age dependent tendon healing. AB - Tendon injuries are common to all ages. Injured tendons typically do not recover full functionality. The amount and organization of tendon constituents dictate their mechanical properties. The impact of changes in these constituents during (patho)physiologic processes (e.g., aging and healing) are not fully understood. Toward this end, microstructurally motivated strain energy functions (SEFs) offer insight into underlying mechanisms of age-dependent healing. Several SEFs have been adapted for tendon; however, most are phenomenological. Therefore, the aims of this study are: (1) evaluate the descriptive capability of SEFs in age dependent murine patellar tendon healing and (2) identify a SEF for implementation in a growth and remodeling (G&R) model. To accomplish these aims, models were fitted to patellar tendon tensile data from multiple age groups and post-injury timepoints. Model sensitivity to parameters and the determinability of the parameters were assessed. A two-way analysis of variance was used to identify changes in parameters and the feasibility of implementing each model into a G&R model is discussed. The evaluated SEFs exhibited adequate descriptive capability. Parameter determinability and sensitivity analysis, however, highlighted the need for additional data to inform and validate the models to increase physiologic relevance and enable G&R model formulation to determine underlying mechanisms of age-dependent healing. This work, as a first, evaluated changes in tendon mechanical properties both as functions of age and injury in an age-dependent manner using microstructurally motivated models, highlights inherent dependencies between parameters of widely used hyperelastic models, and identified unique post-injury behavior by the aging group compared to the mature and aged groups. PMID- 29234989 TI - Clinical Cardiovascular Genetic Counselors Take a Leading Role in Team-based Variant Classification. AB - We sought to delineate the genetic test review and interpretation practices of clinical cardiovascular genetic counselors. A one-time anonymous online survey was taken by 46 clinical cardiovascular genetic counselors recruited through the National Society of Genetic Counselors Cardiovascular Special Interest Group. Nearly all (95.7%) gather additional information on variants reported on clinical genetic test reports and most (81.4%) assess the classification of such variants. Clinical cardiovascular genetic counselors typically (81.0%) classify variants in collaboration with cardiologist and/or geneticist colleagues, with the genetic counselor as the team member who is primarily responsible. Variant classification is a relatively recent (mean 3.2 years) addition to practice. Most genetic counselors learned classification skills on the job from clinical and laboratory colleagues. Recent graduates were more likely to have learned this in graduate school (p < 0.001). Genetic counselors are motivated to take responsibility for the classification of variants because of prior experiences with variant reclassification, inconsistencies between laboratories, and incomplete laboratory reports. They are also driven by a sense of professional duty and their proximity to the clinical context. This practice represents a broadening of the skill set of clinical cardiovascular genetic counselors and a unique expertise that they contribute to the interdisciplinary teams in which they work. PMID- 29234992 TI - Beyond Trust: Plagiarism and Truth. AB - Academic misconduct distorts the relationship between scientific practice and the knowledge it produces. The relationship between science and the knowledge it produces is, however, not something universally agreed upon. In this paper I will critically discuss the moral status of an act of research misconduct, namely plagiarism, in the context of different epistemological positions. While from a positivist view of science, plagiarism only influences trust in science but not the content of the scientific corpus, from a constructivist point of view both are at stake. Consequently, I argue that discussions of research misconduct and responsible research ought to be explicitly informed by the authors' views on the relationship between science and the knowledge it produces. PMID- 29234990 TI - African Americans, African Immigrants, and Afro-Caribbeans Differ in Social Determinants of Hypertension and Diabetes: Evidence from the National Health Interview Survey. AB - In the United States (U.S.), Blacks have higher morbidity and mortality from cardiovascular disease (CVD) than other racial groups. The Black racial group includes African Americans (AAs), African immigrants (AIs), and Afro-Caribbeans (ACs); however, little research examines how social determinants differentially influence CVD risk factors in each ethnic subgroup. We analyzed the 2010-2014 National Health Interview Survey, a cross-sectional, nationally representative survey of non-institutionalized civilians. We included 40,838 Blacks: 36,881 AAs, 1660 AIs, and 2297 ACs. Age- and sex-adjusted hypertension prevalence was 37, 22, and 21% in AAs, ACs, and AIs, respectively. Age- and sex-adjusted diabetes prevalence was 12, 10, and 7% in AAs, ACs, and AIs, respectively. In the multivariable logistic regression analyses, social determinants of hypertension and diabetes differed by ethnicity. Higher income was associated with lower odds of hypertension in AAs (aOR 0.86, 95% CI 0.77-0.96) and ACs (aOR 0.55, 95% CI 0.37-0.83). In AAs, those with some college education (aOR 0.79, 95% CI 0.68 0.92) and college graduates (aOR 0.62, 95% CI 0.53-0.73) had lower odds of hypertension than those with < high school education. In AIs, having health insurance was associated with higher odds of hypertension (aOR 1.59, 95% CI 1.04 2.42) and diabetes (aOR 3.22, 95% CI 1.29-8.04) diagnoses. We observed that the social determinants associated with hypertension and diabetes differed by ethnicity. Socioeconomic factors of health insurance and income were associated with a disparate prevalence of hypertension by ethnic group. Future research among Blacks should stratify by ethnicity to adequately address the contributors to health disparities. PMID- 29234991 TI - Longitudinal Analysis of Particulate Air Pollutants and Adolescent Delinquent Behavior in Southern California. AB - Animal experiments and cross-sectional human studies have linked particulate matter (PM) with increased behavioral problems. We conducted a longitudinal study to examine whether the trajectories of delinquent behavior are affected by PM2.5 (PM with aerodynamic diameter <= 2.5 MUm) exposures before and during adolescence. We used the parent-reported Child Behavior Checklist at age 9-18 with repeated measures every ~2-3 years (up to 4 behavioral assessments) on 682 children from the Risk Factors for Antisocial Behavior Study conducted in a multi ethnic cohort of twins born in 1990-1995. Based on prospectively-collected residential addresses and a spatiotemporal model of ambient air concentrations in Southern California, monthly PM2.5 estimates were aggregated to represent long term (1-, 2-, 3-year average) exposures preceding baseline and cumulative average exposure until the last assessment. Multilevel mixed-effects models were used to examine the association between PM2.5 exposure and individual trajectories of delinquent behavior, adjusting for within-family/within-individual correlations and potential confounders. We also examined whether psychosocial factors modified this association. The results sMUggest that PM2.5 exposure at baseline and cumulative exposure during follow-up was significantly associated (p < 0.05) with increased delinquent behavior. The estimated effect sizes (per interquartile increase of PM2.5 by 3.12-5.18 MUg/m3) were equivalent to the difference in delinquency scores between adolescents who are 3.5-4 years apart in age. The adverse effect was stronger in families with unfavorable parent-to-child relationships, increased parental stress or maternal depressive symptoms. Overall, these findings sMUggest long-term PM2.5 exposure may increase delinquent behavior of urban-dwelling adolescents, with the resulting neurotoxic effect aggravated by psychosocial adversities. PMID- 29234993 TI - Narrative Identity in Third Party Reproduction: Normative Aspects and Ethical Challenges. AB - In the last few decades, assisted reproduction has introduced new challenges to the way people conceive and build their families. While the numbers of donor conceived (DC) individuals have increased worldwide, there are still many controversies concerning access to donor information. Is there a fundamental moral right to know one's genetic background? What does identity in DC families mean? Is there any relationship between identity formation and disclosure of genetic origins? These questions are addressed by analysing core regulatory discourse (ethical recommendations and codes of practice). This analysis shows that the notion of narrative identity is suitable for defining and answering these questions. This review analyses the meaning of resemblance in DC families and the way donors are selected following affinity-ties and discusses disclosure strategies and agreements. As a preliminary conclusion, it could be said that, in the field of third-party reproduction, knowing about the donor conception significantly contributes towards the development of a narrative identity and also serves as a moral basis for the child's right to know. PMID- 29234994 TI - How the physicality of space affects how we think about time. AB - Time is an abstract concept that may be better understood when mapped onto space. For English speakers, typically a timeline is used that runs horizontally from left (past) to right (future) (Boroditsky, Fuhrman, & McCormick, 2011) and can be separated into regions, past and future. However, it is unclear from prior research how these regions along the timeline are differentiated. In addition, although for English speakers time is typically thought of in terms of a left right axis, gestures and metaphors that conceptualize the past as behind and the future as ahead are prevalent, implicating the use of a front-back axis. In three experiments, participants made temporal judgments of pictures while holding their hands in various positions around their bodies, to assess whether the body or hands or both are used as anchors to differentiate regions and whether the front back axis can be used as a timeline. In Experiment 1 we found independent influences of the body and the hands in anchoring the left-right axis. In Experiment 2 we found support for the use of the front-back axis to map time, with independent influences of the body and the hands in anchoring this axis as well. In Experiment 3 we demonstrated that the timeline must be configured in a way that is consistent with underlying conceptualizations of time, by showing that the above-below axis is not used for English speakers. Together, these results indicate that time is mapped onto space, with this mapping being constrained by underlying conceptualizations of time. PMID- 29234995 TI - Correction to: Impact of age at onset and newborn screening on outcome in organic acidurias. AB - Due to an unfortunate error during the typesetting process, the collaborators were presented incorrectly. PMID- 29234996 TI - Retrieval practice after multiple context changes, but not long retention intervals, reduces the impact of a final context change on instrumental behavior. AB - Recent evidence from this laboratory suggests that a context switch after operant learning consistently results in a decrement in responding. One way to reduce this decrement is to train the response in multiple contexts. One interpretation of this result, rooted in stimulus sampling theory, is that conditioning of a greater number of common stimulus elements arising from more contexts causes better generalization to new contexts. An alternative explanation is that each change of context causes more effortful retrieval, and practice involving effortful retrieval results in learning that is better able to transfer to new situations. The current experiments were designed to differentiate between these two explanations for the first time in an animal learning and memory task. Experiment 1 demonstrated that the detrimental impact of a context change on an instrumental nose-poking response can be reduced by training the response in multiple contexts. Experiment 2 then found that a training procedure which inserted extended retention intervals between successive training sessions did not reduce the detrimental impact of a final context change. This occurred even though the inserted retention intervals had a detrimental impact on responding (and, thus, presumably retrieval) similar to the effect that context switches had in Experiment 1. Together, the results suggest that effortful retrieval practice may not be sufficient to reduce the negative impact of a context change on instrumental behavior. A common elements explanation which supposes that physical and temporal contextual cues do not overlap may account for the findings more readily. PMID- 29234997 TI - Learning epistatic interactions from sequence-activity data to predict enantioselectivity. AB - Enzymes with a high selectivity are desirable for improving economics of chemical synthesis of enantiopure compounds. To improve enzyme selectivity mutations are often introduced near the catalytic active site. In this compact environment epistatic interactions between residues, where contributions to selectivity are non-additive, play a significant role in determining the degree of selectivity. Using support vector machine regression models we map mutations to the experimentally characterised enantioselectivities for a set of 136 variants of the epoxide hydrolase from the fungus Aspergillus niger (AnEH). We investigate whether the influence a mutation has on enzyme selectivity can be accurately predicted through linear models, and whether prediction accuracy can be improved using higher-order counterparts. Comparing linear and polynomial degree = 2 models, mean Pearson coefficients (r) from [Formula: see text]-fold cross validation increase from 0.84 to 0.91 respectively. Equivalent models tested on interaction-minimised sequences achieve values of [Formula: see text] and [Formula: see text]. As expected, testing on a simulated control data set with no interactions results in no significant improvements from higher-order models. Additional experimentally derived AnEH mutants are tested with linear and polynomial degree = 2 models, with values increasing from [Formula: see text] to [Formula: see text] respectively. The study demonstrates that linear models perform well, however the representation of epistatic interactions in predictive models improves identification of selectivity-enhancing mutations. The improvement is attributed to higher-order kernel functions that represent epistatic interactions between residues. PMID- 29234998 TI - Reduction of Cardiopulmonary/Renal Complications with Serum BNP-Guided Volume Status Management in Posthepatectomy Patients. AB - BACKGROUND: After hepatectomy, over- and under-resuscitations induce cardiopulmonary complications and acute kidney injury, respectively, leading to significant perioperative morbidity and mortality. Unlike serum chemistries or urine output, serum brain natriuretic peptide (BNP) levels have been shown to accurately reflect current intravascular fluid balance without influence from alterations of hormonal axes. Based on these data, this study was designed to measure the impact of a serum BNP-guided hepatobiliary fluid protocol on the incidence of posthepatectomy cardiopulmonary/renal complications. METHODS: Hepatectomy patients registered in a single-institution American College of Surgeons-National Surgical Quality Improvement Program database between 2011 and 2016 were examined in real time for the development of cardiopulmonary/renal complications and divided into pre- (2011-2013) and postimplementation (2014 2016) of a BNP-guided hepatobiliary fluid protocol groups. In the postimplementation group, maintenance fluids were tapered on a set protocol. Bolus fluids, diuresis, and micro-adjustments in fluid rate were guided by daily BNP values. RESULTS: Four hundred sixty patients underwent hepatectomy in the study period with 251 patients in the pre- and 209 patients in the postprotocol implementation groups. Cardiopulmonary/renal complication rates were 4.0% in the preprotocol group and reduced to 0.9% after initiation of the BNP-guided hepatobiliary fluid protocol (p = 0.04). CONCLUSIONS: Despite low event rates, these data suggest that goal-directed postoperative fluid therapy with the combination of a hepatobiliary fluid protocol and serum BNP-guided volume management is superior to traditional chemistry and bedside volume assessment and can reduce posthepatectomy cardiopulmonary and renal complications. PMID- 29234999 TI - Prognostic Significance of Serum Inflammatory Markers in Gastric Cancer. AB - BACKGROUND: The aim of this study was to assess the relative prognostic value of biomarkers to measure the systemic inflammatory response (SIR) and improve prognostic modeling in a cohort of patients undergoing potentially curative surgery for gastric adenocarcinoma. The hypothesis was that a single SIR biomarker would be associated with the most prognostic value. METHODS: Consecutive 331 patients undergoing surgery for gastric cancer between 2004 and 2016 within a regional UK cancer network were identified. Serum measurements of hemoglobin, C-reactive protein, albumin, modified Glasgow Prognostic Score, and differential white cell counts were obtained before surgery, and correlated with histopathological factors (pTNM stage, differentiation, and vascular invasion) and survival. Primary outcome measures were disease-free (DFS) and overall survival (OS). RESULTS: Consecutive 331 patients were identified and 291 underwent potentially curative gastrectomy for adenocarcinoma. On univariable DFS analysis, female gender (p = 0.027), proximal location (p = 0.018), pT stage (p < 0.001), pN stage (p < 0.001), pTNM stage (p < 0.001), vascular invasion (p < 0.001), poor differentiation (p = 0.001), lymph node ratio (p < 0.001), R1 status (p < 0.001), platelet count (p = 0.038), and mGPS (p = 0.001) were significantly associated with poor survival. The mGPS was associated with advanced pT stage (p = 0.001), pTNM stage (p = 0.013), and poor differentiation (p = 0.030). On multivariable DFS analysis, mGPS [hazard ratio (HR) 2.51, 95% confidence interval (CI) 1.35-4.65, p = 0.011] was the only inflammatory marker to retain independent significance. Multivariable OS analysis revealed similar findings; mGPS (HR 2.75, (95% CI 1.65-4.59), p < 0.001). CONCLUSION: mGPS is an important and only SIR related prognostic biomarker independently associated with both DFS and OS in gastric cancer. PMID- 29235000 TI - Is Neoadjuvant Therapy Sufficient in Resected Pancreatic Cancer Patients? A National Study. AB - BACKGROUND: Despite the increasing use of neoadjuvant treatment, the question of whether preoperatively treated, successfully resected patients should receive additional postoperative adjuvant treatment remains unanswered. We evaluate the impact of adjuvant therapy following neoadjuvant treatment and pancreatectomy in pancreatic cancer patients in a large national study. METHODS: We used the National Cancer Data Base between 2006 and 2013 to identify resected, non metastatic pancreatic adenocarcinoma patients who received neoadjuvant chemo(radio)therapy followed by pancreatectomy. Kaplan-Meier and multivariate Cox proportional hazard regression analyses were performed to compare survival between groups. RESULTS: In total, 1357 patients were identified. Of the patients, 38.6% (n = 524) were treated with postoperative therapy. There was no difference in unadjusted median overall survival between patients who did and did not receive postoperative therapy (median survival, 27.5 vs. 27.1 months, log rank p = 0.5409). Postoperative therapy was not significantly associated with favorable prognosis in patients with positive resection margins (log-rank p = 0.6452) or positive lymph nodes (log-rank p = 0.6252). On multivariate analysis, receipt of postoperative therapy was not predictive of survival (hazard ratio 0.972; 95% CI 0.848-1.115; p = 0.6876). CONCLUSIONS: Our results using national data suggest that after receipt of neoadjuvant therapy and pancreatectomy, additional postoperative therapy may not provide additional survival benefit. These data warrant further prospective data collection and consideration for clinical trials. PMID- 29235001 TI - Diffuse Cystic Malformation with Early Gastric Cancer. PMID- 29235002 TI - The Added Diagnostic Value of 18F-Fluorodihydroxyphenylalanine PET/CT in the Preoperative Work-Up of Small Bowel Neuroendocrine Tumors. AB - BACKGROUND: The precise localization of the primary tumor and/or the identification of multiple primary tumors improves the preoperative work-up in patients with small bowel (SB) neuroendocrine tumor (NET). The present study assesses the diagnostic value of 18F-fluorodihydroxyphenylalanine (18F-FDOPA) positron emission tomography/computed tomography (PET/CT) during the preoperative wok-up of SB NETs. METHODS: Between January 2010 and June 2017, all consecutive patients with SB NETs undergoing preoperative 18F-FDOPA PET/CT and successive resection were analyzed. Preoperative work-up included computed tomography (CT), somatostatin receptor scintigraphy (SRS), and 18F-FDOPA PET/CT. Sensitivity and accuracy ratio for primary and multiple tumor detection were compared with data from surgery and pathology. RESULTS: There were 17 consecutive patients with SB NETs undergoing surgery. Nine patients (53%) had multiple tumors, 15 (88%) metastatic lymph nodes, 3 (18%) peritoneal carcinomatosis, and 9 patients (53%) liver metastases. A total of 70 SB NETs were found by pathology. Surgery identified the primary in 17/17 (100%) patients and recognized seven of 9 patients (78%) with multiple synchronous SB. Preoperatively, 18F-FDOPA PET/CT displayed a statistically significant higher sensitivity for primary tumor localization (100 vs. 23.5 vs. 29.5%) and multiple tumor detection (78 vs. 22 vs. 11%) over SRS and CT. Compared with pathology, 18F-FDOPA PET/CT displayed the highest accuracy ratio for number of tumor detected over CT and SRS (2.0 +/- 2.2 vs. 0.4 +/- 0.7 vs. 0.6 +/- 1.5, p = 0.0003). CONCLUSION: 18F-FDOPA PET/CT significantly increased the sensitivity and accuracy for primary and multiple SB NET identification. 18F-FDOPA PET/CT should be included systematically in the preoperative work-up of SB NET. PMID- 29235003 TI - Inflammatory Myofibroblastic Tumor of the Liver: Challenges in the Preoperative Diagnosis and Treatment. PMID- 29235004 TI - Surgical Resection vs. Ablative Therapies Through a Laparoscopic Approach for Hepatocellular Carcinoma: a Comparative Study. AB - BACKGROUND: When compatible with the liver functional reserve, laparoscopic hepatic resection remains the treatment of choice for hepatocellular carcinoma while laparoscopic ablation therapies appear as a promising less invasive alternative. The aim of the study is to compare two homogeneous groups of patients submitted to either hepatic resection or thermoablation for the treatment of single hepatocellular carcinoma (<= 3 cm). METHODS: We enrolled 264 cirrhotic patients out of 905 cases consecutively evaluated for hepatocellular carcinoma. We performed 59 hepatic resections and 205 thermoablations through a laparoscopic approach, and they were then followed for similar follow-up (41.7 +/ 31.5 months for laparoscopic hepatic resection vs. 38.7+/-32.3 for laparoscopic ablation therapy). Outcomes included short- and long-term morbidities, tumoral recurrence, and overall survival. RESULTS: Short-term morbidity was significantly higher in the resection group (but the two groups had similar rates for severe complications) while, during follow-up, recurrence was more frequent in patients treated with thermoablation, with a clear disadvantage in terms of survival. At multivariate analysis, only the type of surgical treatment was an independent predictor of disease recurrence, while plasmatic alpha-fetoprotein and Hb values, model for end-stage liver disease score, time to recurrence, and the type of surgical treatment were independent predictors of overall survival. CONCLUSION: Our data ultimately support some therapeutic advantages for hepatic resection in patients with a single nodule and preserved liver function. However, thermoablation is an adequate alternative in patients with nodules that would require complex surgical resections or imply a poor prognosis that might therefore better tolerate a less invasive procedure. PMID- 29235005 TI - Correction to: Metastasectomy for Tumor-Infiltrating Lymphocytes: An Emerging Operative Indication in Surgical Oncology. AB - In the original article the middle initial of Nicholas D. Klemen was inadvertently omitted. On the first page of the original article, under the heading A Novel Way to Fight Cancer, there was an error in the third sentence. The corrected text is as follows: For example, the presence of T cells within tumors of colorectal origin can be a superior predictor of patient survival compared with the standard histopathologic methods currently used to stage colorectal cancer.6,7. PMID- 29235006 TI - Intrinsic Contact Between T and N Classifications in Resected Well-Moderately Differentiated Locoregional Pancreatic Neuroendocrine Neoplasms. AB - BACKGROUND: The role of N classification is controversial in several prognostication systems proposed for pancreatic neuroendocrine neoplasms (pNENs). The widely accepted modified European Neuroendocrine Tumor Society (mENETS) system suggests this contradiction may be related to T classification. METHODS: Data were collected retrospectively from 981 patients in the Surveillance, Epidemiology, and End Results (SEER) database (1973-2012; cohort 1) and 140 patients from the Pancreatic Cancer Institute of Fudan University (2006-2016; cohort 2). All patients had resected well- to moderately differentiated locoregional pNENs, whereby the mENETS system was adopted. Factors related to N1 classification and the association between N and T classifications were analyzed, and N classification prognosis based on T classification was assessed. RESULTS: In cohorts 1 and 2, tumor size (2-4 cm: p < 0.001 and p = 0.037, respectively; > 4 cm: p < 0.001 and p = 0.012, respectively) and tumors extending beyond the pancreas (p < 0.001 and p = 0.016, respectively), which are factors for T classification, affected N1 classification. For tumors limited to the pancreas, the N1 classification was associated with tumor size (p < 0.001 and p = 0.046, respectively) and predicted poor disease-specific survival (DSS), while for tumors extending beyond the pancreas, the N1 classification did not affect patient outcomes. Findings obtained with data from the SEER database were reproducible with our institutional data. CONCLUSIONS: N classification is associated with T classification, limiting the value of N1 classification for the pNENs tumor-node-metastasis system. A new risk model is necessary to predict patient outcomes and guide clinical practice for the prognosis of pNENs. PMID- 29235008 TI - Oncological Assessment of Stent Placement for Obstructive Colorectal Cancer from Circulating Cell-Free DNA and Circulating Tumor DNA Dynamics. AB - BACKGROUND: The self-expanding metallic stent (SEMS) provides effective decompression for patients with malignant large bowel obstruction (MLBO); however, mechanical damage to malignant cells from insertion may negatively affect prognosis, similar to surgical manipulation, and its oncological safety is unclear. We examined mechanical damage from SEMS placement using circulating cell free DNA (cfDNA) and circulating tumor DNA (ctDNA). METHODS: Between 1 November 2014 and 30 June 2017, 35 MLBO patients were analyzed, comprising 25 SEMS patients and 10 transanal decompression tube (TDT) patients (control). Blood samples were collected before and after decompression on days 0, 1, 3, and 7. cfDNA, ctDNA, white blood cells, C-reactive protein, and lactate dehydrogenase were analyzed. RESULTS: The clinical success rates of SEMS and TDT were 88 and 90%, respectively (p = 1.0). The cfDNA concentration on day 7 was significantly higher in the SEMS group than in the TDT group (992 vs. 308 ng/mL; p = 0.005). A significant increase in ctDNA was observed in the SEMS group compared with the TDT group (83% vs. 22%; p = 0.002). The cfDNA concentration showed strong positive correlations with ctDNA and lactate dehydrogenase (R 2 = 0.838 and 0.593, respectively), and a weak positive correlation with C-reactive protein (R 2 = 0.263). CONCLUSIONS: Despite equivalent clinical success rates, SEMS placement increased plasma levels of cfDNA and ctDNA by tumor manipulation, but TDT did not. Colonic stenting showed oncological risk in terms of molecular analysis. PMID- 29235009 TI - Duodenal Exclusion but Not Sleeve Gastrectomy Preserves Insulin Secretion, Making It the More Effective Metabolic Procedure. AB - INTRODUCTION: There is an ongoing debate on which procedure provides the best treatment for type 2 diabetes. Furthermore, the pathomechanisms of diabetes improvement of partly anatomically differing operations is not fully understood. METHODS: A loop duodenojejunostomy (DJOS) with exclusion of one third of intestinal length, a sleeve gastrectomy (SG), or a combination of DJOS + SG was performed in 8-week-old male ZDF rats. One, three, and six months after surgery, an oral glucose tolerance test and measurements of GLP-1, GIP, insulin, and bile acids were conducted. RESULTS: After an initial (4 weeks) equal glucose control, DJOS and DJOS + SG showed significantly lower glucose levels than SG 3 and 6 months after surgery. There was sharp decline of insulin levels in SG animals over time, whereas insulin levels in DJOS and DJOS + SG were preserved. GIP levels were significantly larger in both groups containing a sleeve at all three time points, whereas GLP-1 was equal in all groups at all time. Bile acid levels were significantly higher in the DJOS compared to the SG group at all time points. Interestingly, the additional SG in the DJOS + SG group led to lower bile acid levels 1 and 6 months postoperatively. CONCLUSION: The effect of SG on glucose control was transient, whereas a duodenal exclusion was the more effective procedure in this model due to a sustained pancreatic function with a preserved insulin secretion. PMID- 29235010 TI - Metabolic Changes Up to 10 years After Gastric Bypass. AB - OBJECTIVE: The aim of this study was to investigate the lipid and glycemic profiles of patients up to 10 years after Roux-en-Y gastric bypass. METHOD: A retrospective, longitudinal study was conducted at a multidisciplinary center for the treatment of obesity in the state of Sao Paulo, Brazil. The study included 150 patients submitted to unbanded laparoscopic Roux-en-Y gastric bypass. The metabolic profile included total cholesterol and fractions, triglycerides, and fasting glucose. The patients were examined before and 3, 6, 12, 24, 48, 72, 96, and 120 months after surgery. Statistical analyses included the generalized estimating equations (GEE) and the Wilcoxon test at a significance level of 5%. RESULTS: All postoperative fasting glucose, total cholesterol, and triglyceride (p < 0.0001) test results were significantly lower than the preoperative test results. Low-density lipoprotein cholesterol (LDL-c) differed significantly in all but the 120-month follow-up (p = 0.0129). High-density lipoprotein cholesterol (HDL-c) was significantly higher 12, 24, 48, and 72 months after surgery (p < 0.001) and also 120 months after surgery (p = 0.0002). CONCLUSION: Gastric bypass promoted the control of metabolic diseases inherent to obesity as long as 10 years after surgery. PMID- 29235011 TI - Comparative Effectiveness of Laparoscopic Sleeve Gastrectomy on Morbidly Obese, Super-Obese, and Super-Super Obese Patients for the Treatment of Morbid Obesity. AB - BACKGROUNDS: The management of super-super obese patients is challenging for bariatric surgeons. Laparoscopic sleeve gastrectomy (LSG) is feasible as two stage treatment for high-risk patients. However, its efficacy as a stand-alone procedure in super-super obese (SSO) patients is controversial. The study objective was to demonstrate the safety and efficacy of LSG in super-obese (SO) and SSO patients. METHODS: A retrospective analysis was performed of consecutive patients undergoing LSG. The patients were classified into three groups: morbidly obese (MO), SO, and SSO. The patients' data, including each patient's characteristics, body mass index (BMI), preoperative comorbidities, postoperative complications, the resolution of comorbidities, percentage of excess weight loss (%EWL), and total weight loss (%TWL) were compared between groups. RESULTS: Of the 186 patients, 163 (87.6%) were followed up for 41.2 +/- 7.3 months (range 33 54 months). The mean BMI was 52.6 kg/m2. Eighty-three patients (50.9%) were MO, 52 (31.9%) were SO, and 28 (17.2%) were SSO. The groups were similar in terms of preoperative characteristics and postoperative complications. The mean %TWL were lower for the SSO group with no significant difference. The mean %TWL at 12, 24, 36, and 41.2 months postoperatively was 34.7, 34.4, 31.4, and 29.6% in SSO group, respectively. Also, the %EWL for the SSO group was significantly lower (48.3%) at the end of the follow-up period. However, the rate of significant improvement or complete resolution of comorbidities was similar in all groups. CONCLUSION: Although %EWL was lower in the SSO group, LSG was a feasible and safe stand-alone bariatric surgical procedure for the resolution of comorbidities in MO, SO, and SSO patients. PMID- 29235012 TI - Implications of Celiac Disease Among Patients Undergoing Gastric Bypass. AB - INTRODUCTION: Bariatric surgery is generally safe and effective, but co-existing malabsorptive processes may increase the risk of complications or nutritional deficiencies. Bariatric surgery has not been well studied in the setting of pre existing celiac disease. MATERIALS AND METHODS: Patients who underwent Roux-en-Y gastric bypass (RYGB) from January 2002 to December 2015 were retrospectively reviewed for either diagnosis of or serum testing for celiac disease. Identified patients were re-reviewed for adherence to American Gastroenterological Association (AGA) diagnostic criteria. Patient demographics, operative data, and post-operative weight loss and nutritional parameters were collected. RESULTS: Of the > 12,000 patients who underwent bariatric surgery during this study period, there were 342 patients that had abnormal serology or pathology results. Expert review confirmed three patients (0.8%) with celiac disease diagnosed before RYGB procedure. All were female, with an average age of 33 years and a mean BMI of 44.07 kg/m2. At the time of surgery, two of the three patients were following a gluten-free diet. At 6 months follow-up, mean % excess weight loss was 76.5%. The patients following a gluten-free diet preoperatively continued post-operatively. No patients were anemic nor had vitamin B12 or iron deficiencies at 12-month follow-up. Two patients had vitamin D insufficiencies and responded to daily oral supplementation. CONCLUSION: Though many bariatric patients may carry a presumptive diagnosis of celiac disease, a small percentage of these meet AGA diagnostic criteria. RYGB appears safe in this population with comparable weight loss in non-celiac counterparts. Increased attention to vitamin D levels may be warranted post-operatively. PMID- 29235007 TI - Snapshot Study on the Value of Omentoplasty in Abdominoperineal Resection with Primary Perineal Closure for Rectal Cancer. AB - BACKGROUND: Perineal wound complications are often encountered following abdominoperineal resection (APR). Filling of the pelvic space by omentoplasty (OP) might prevent these complications, but there is scant evidence to support its routine application. OBJECTIVE: The aim of this study was to evaluate the impact of OP on perineal wound complications. METHODS: All patients undergoing APR with primary perineal closure (PPC) for non-locally advanced rectal cancer in 71 Dutch centers in 2011 were selected from a cross-sectional snapshot study. Outcomes were compared between PPC with or without OP, which was based on variability in practice among surgeons. RESULTS: Of 639 patients who underwent APR for rectal cancer, 477 had a non-locally advanced tumor and PPC was performed. Of those, 172 (36%) underwent OP. Patients with OP statistically more often underwent an extralevator approach (32% vs. 14%). Median follow-up was 41 months (interquartile range 22-47). There were no significant differences with or without OP in terms of non-healing of the perineal wound at 30 days (47% vs. 48%), non-healing at the end of follow-up (9% vs. 5%), pelvic abscess (12% vs. 13%) or re-intervention for ileus (5% vs. 3%). Perineal hernia developed significantly more often after OP (13% vs. 7%), also by multivariable analysis (odds ratio 2.61, 95% confidence interval 1.271-5.364; p = 0.009). CONCLUSIONS: In contrast to previous assumptions, OP after APR with PPC appeared not to improve perineal wound healing and seemed to increase the occurrence of perineal hernia. These findings question the routine use of OP for primary filling of the pelvic space. PMID- 29235013 TI - Effects of Weight Loss on Acoustic Parameters After Bariatric Surgery. AB - BACKGROUND: Patients with morbid obesity may present vocal alterations, since large accumulation of fat in the vocal tract may interfere with voice production of these individuals. OBJECTIVE: Verify the neck circumference and the acoustic parameters of voice in obese women, before and after the bariatric surgery, and compare the results with a control group, with normal weight. METHODS: Observational, longitudinal, descriptive study with patients referred to the SCODE (Obesity Surgery and Related Disorders Center) in a university hospital. The sample consisted of 25 morbidly obese women, age range 28-43 years and 23 non obese women, aged 21-41 years control group. To measure the neck circumference, a tape measure was used and all participants were seated upright with the head positioned in the Frankfort horizontal plane. The fundamental frequency was calculated through the sustained emission of vowel [a] at usual intensity and pitch, to measure the fundamental frequency of the voice, that is, how much the vocal fold vibrates per second. After the recording, participants were prompted to produce vowels [a], [i], and [u] sustained at usual intensity and pitch, and a stopwatch was used to measure the maximum phonation time, to verify the balance between myoelastic and dynamic forces of the larynx. After 8 months post-surgery, the patients were recruited to be re-evaluated using the same pre-surgical data collection procedures. RESULTS: There was an increase in the mean value of f0. The maximum phonation time of all vowels increased after surgery. CONCLUSION: Obese individuals with post-surgery weight loss may present neck circumference, fundamental frequency, and maximum phonation time values closer to the mean values of normal weight individuals. In this study, weight loss was sufficient to adjust the acoustic parameter measurements. PMID- 29235014 TI - Increased Bile Acid Signals After Duodenal-Jejunal Bypass Improve Non-alcoholic Steatohepatitis (NASH) in a Rodent Model of Diet-Induced NASH. AB - BACKGROUND: The increasing incidence of non-alcoholic steatohepatitis (NASH) has resulted in it becoming a common cause of liver-related mortality; however, no efficient treatment has been established. It has been reported that bariatric surgery improves metabolic comorbidities, such as diabetes mellitus and NASH. Although the mechanism is unclear, it is thought that the changes in bile acid (BA) signaling via its nuclear receptor, farnesoid X receptor (FXR), produce various metabolic effects. We sought to investigate the effects and mechanisms of bariatric surgery on NASH improvement. METHODS: Male Sprague-Dawley rats were fed by a high-fat and high-fructose diet, which results in obesity, insulin resistance, and NASH. Rats underwent duodenal-jejunal bypass (DJB), which is a main component of bariatric procedures. The liver pathological findings and the expression level of mRNA of FXR were investigated. The plasma BA level was measured in peripheral and portal vein blood. RESULTS: DJB suppressed weight gain, improved insulin resistance, and ameliorated NASH mainly in a point of inflammation. The plasma BA level along with the expression of FXR and its target transcriptional factor, small heterodimer partner (SHP), in the liver were elevated. CONCLUSIONS: DJB has a direct effect on NASH improvement, and there is a possibility that an anti-inflammatory effect is functioning as a part of the mechanism. The increase of plasma bile acid level followed by the stimulation of FXR signaling may contribute to this phenomenon. PMID- 29235015 TI - Use of Self-Expandable Metal Stents in the Treatment of Leaks Complicating Laparoscopic Sleeve Gastrectomy: A Cohort Study. AB - BACKGROUND: Use of a self-expandable metal stent (SEMS) as an initial intervention for leaks after laparoscopic sleeve gastrectomy (LSG) has increased. We assessed the efficacy and safety of SEMS in the treatment of post-LSG leaks, and the determinants of repeated rounds of stenting. METHODS: A retrospective chart review was conducted at a university hospital in Saudi Arabia. The study included patients who developed leaks after undergoing LSG between October 2011 and April 2016. RESULTS: Sixty-four patients (mean age, 35.69 +/- 10.71 years) were included; 55% were males. The mean estimated size of the defect was 1.18 cm; partially covered SEMS and fully covered SEMS were used as the initial stents in 82.81 and 17.19% patients, respectively. One round of stenting was required in most patients (82.81%), two rounds in 10.94%, and three rounds in 6.25%. Clinical success was achieved in 93.75% patients, including 78.13% in the first round, 89.06% by the second round, and 93.75% by the third round. A higher proportion of patients who needed one round of stenting received a partially covered SEMS compared to those who needed two rounds (91.11 vs. 42.86%, p < 0.01). Additionally, the rate of migration in patients who underwent two rounds was higher than that in patients who underwent one round (42.86 vs. 5.26%, p < 0.01) of stenting. CONCLUSION: Repeated stenting for leaks after LSG is an effective and safe intervention. The efficacy of partially covered SEMS appears superior to that of the fully covered SEMS. PMID- 29235016 TI - Recent advances in toxicity assessment across taxa. PMID- 29235017 TI - Oral treatment with a rattlesnake native polypeptide crotamine efficiently inhibits the tumor growth with no potential toxicity for the host animal and with suggestive positive effects on animal metabolic profile. AB - The efficacy of crotamine as antitumoral was first demonstrated by daily intraperitoneal (IP) injections of low doses of this toxin in an animal model bearing melanoma tumors. Significant inhibition of tumor growth and increased lifespan of mice bearing tumor was also noticed after 21 consecutive days of this daily IP administration of crotamine. However, due to the limited acceptance of treatments by IP route in clinical conditions, herein, we evaluated the antitumor effect of this native polypeptide employing the oral route. The efficacy of crotamine in inhibiting the melanoma growth in vivo, even after passing through the gastrointestinal tract of the animal, was confirmed here. In addition, biochemical biomarkers and also histopathological analysis showed both the absence of any potential toxic effects in tissues or organs of the animal in which the highest accumulation of crotamine is expected. Interestingly, a reduction of weight gain was observed mainly in animals with tumor treated with crotamine by IP route, but not by oral administration. Albeit, oral administered crotamine was able to significantly decrease the body weight gain of healthy animals without tumor. Taking advantage of this same experimental animal models receiving crotamine by oral route, it was possible to show metabolic changes as the increased capacity of glucose clearance, which was accompanied by a reduction of the total cholesterol, and by increased high-density lipoprotein levels, both observed mainly in the absence of tumor. Triglycerides and low-density lipoprotein were also significantly decreased, but only in the absence of tumor. Taken together, these data suggest a clear trend for metabolic positive effects and mischaracterize unhealthy condition of animals, with or without tumors, treated with crotamine for 21 days. In addition, this study confirmed the efficacy of crotamine administered by oral route as antitumor agent, which besides the additional advantage of administration convenience and decreased risk of toxic effects, allowed the serendipitous observation of several positive metabolic effects on treated animals. PMID- 29235018 TI - Inverse correlation between maternal plasma asymmetric dimethylarginine (ADMA) and birthweight percentile in women with impaired placental perfusion: circulating ADMA as an NO-independent indicator of fetal growth restriction? AB - L-Arginine (Arg) is the enzymatic precursor of nitric oxide (NO) which has multiple biological functions. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of NO. We hypothesized that the ADMA and SDMA have additional biological functions in pregnancy, beyond NO synthesis, and may play a role in the regulation of birthweight (BW). To investigate this issue, we measured the plasma concentration of ADMA, SDMA, Arg and the NO metabolites nitrite and nitrate, at 23-25 weeks of gestation in women with normal placental function (Group 1) and in women with impaired placental perfusion; 19 of these women had normal outcome (Group 2), 14 had a fetus that was growth restricted (Group 3), and 10 women eventually developed preeclampsia (Group 4). BW percentile was found to inversely correlate with maternal plasma ADMA concentration in Group 3 (r = - 0.872, P < 0.001) and in Group 4 (r = - 0.800, P < 0.05). But, BW percentile did not correlate with the maternal plasma concentration of Arg, SDMA, nitrate or nitrite. Our results suggest that maternal plasma ADMA concentration is an important indicator of fetal growth restriction in women with impaired placental perfusion independent of NO. PMID- 29235019 TI - Investigation of the interaction of beta-methylamino-L-alanine with eukaryotic and prokaryotic proteins. AB - There is a strong body of evidence linking the non-protein amino acid (NPAA) beta methylamino-L-alanine (BMAA) to the development of a number of neurodegenerative diseases. BMAA has been found globally, is produced by a number of organisms including cyanobacteria, diatoms, and dinoflagellates; and has been shown to biomagnify through trophic levels. The role of BMAA in neurodegenerative disease is highlighted by its presence in the brains of a number of neurodegenerative disease patients, where it was found in a protein-bound form. We have previously shown that BMAA is bound to cell proteins, and results in the upregulation of the unfolded protein response, an endoplasmic reticulum stress response activated by the presence of misfolded proteins within the cell. Structurally aberrant proteins are features of a number of neurodegenerative diseases, and further investigation of how BMAA interacts with proteins is crucial to our understanding of its toxicity. Here we use radiolabelled BMAA to investigate the interaction and binding of BMAA to eukaryotic and prokaryotic proteins. We found differences in the presence and distribution of protein-bound BMAA between E. coli and neuroblastoma cells, with an increase in binding over time only seen in the eukaryotic cells. We also found that BMAA was unable to bind to pure proteins, or cell lysate in native or denaturing conditions, indicating that biological processing is required for BMAA to bind to proteins. PMID- 29235021 TI - Occurrence of antimicrobial agents, drug-resistant bacteria, and genes in the sewage-impacted Vistula River (Poland). AB - Antimicrobial agents (antimicrobials) are a group of therapeutic and hygienic agents that either kill microorganisms or inhibit their growth. Their occurrence in surface water may reveal harmful effects on aquatic biota and challenge microbial populations. Recently, there is a growing concern over the contamination of surface water with both antimicrobial agents and multidrug resistant bacteria. The aim of the study was the determination of the presence of selected antimicrobials at specific locations of the Vistula River (Poland), as well as in tap water samples originating from the Warsaw region. Analysis was performed using the liquid chromatography-electrospray ionization-tandem mass spectrometry method. In addition, the occurrence of drug-resistant bacteria and resistance genes was determined using standard procedures. This 2-year study is the first investigation of the simultaneous presence of antimicrobial agents, drug-resistant bacteria, and genes in Polish surface water. In Poland, relatively high concentrations of macrolides are observed in both surface and tap water. Simultaneous to the high macrolide levels in the environment, the presence of the erm B gene, coding the resistance to macrolides, lincosamides, and streptogramin, was detected in almost all sampling sites. Another ubiquitous gene was int1, an element of the 5'-conserved segment of class 1 integrons that encode site specific integrase. Also, resistant isolates of Enterococcus faecium and Enterococcus faecalis and Gram-negative bacteria were recovered. Multidrug resistant bacteria isolates of Gram-negative and Enterococcus were also detected. The results show that wastewater treatment plants (WWTP) are the main source of most antimicrobials, resistant bacteria, and genes in the aquatic environment, probably due to partial purification during wastewater treatment processes. PMID- 29235020 TI - Do GSTM1 and GSTT1 polymorphisms influence the risk of developing mitochondrial diseases in a Tunisian population? AB - Mitochondria play an essential role to supply the cell with metabolic energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). As a consequence, they are also the primary source of cellular reactive oxygen species (ROS) which can cause oxidative damage of individual respiratory chain complexes. Indeed, affected OXPHOS subunits result in decreases in ATP production and increases in ROS formation which generate oxidative phosphorylation deficiency leading to mitochondrial dysfunctions. It has been suggested that ROS play a vital role in the pathogenesis of mitochondrial diseases. To the best of our knowledge, this is the first study which aimed to investigate the genetic variant effect of the antioxidant enzymes GSTM1 and GSTT1 on mitochondrial disease among a Tunisian population. In this report, 109 patients with mitochondrial disease and 154 healthy controls were genotyped by multiplex PCR amplification, and data were analyzed by SPSS v20 software. The results showed that GSTM1 null genotype was found to be associated with mitochondrial disease with a protective effect; however, no significant association of GSTT1 polymorphism with mitochondrial disease risk was revealed. But, interestingly, our findings highlight that GSTM1 active and GSTT1 null genotype combination increased by three fold the risk of developing mitochondrial disease with p c = 0.020, notably mitochondrial myopathy with p c = 0.046 and Leigh syndrome with p c = 0.042. In conclusion, this study suggests that GSTM1 active and GSTT1 null genotype combination might be a risk factor in developing mitochondrial disease. PMID- 29235022 TI - Atmospheric heavy metal deposition in agro-ecosystems in China. AB - Atmospheric deposition has become one of the main sources of heavy metals in crops in developed and industrial zones in China for the past several years. However, lack of data of the agro-ecosystems on the vast areas of China makes it difficult to assess the impacts of air pollution on the heavy metal accumulation in crops. In this study, with deposit samples from 67 sites located at different agro-ecosystems (typical, factory nearby, town nearby, roadside, and remote) of four natural regions [Huanghuai (HH), Southeast (SE), Southwest (SW) and upper mid Yangzi River (Up-mid YR)], atmospheric heavy metal deposition in agro ecosystems on a large scale in China was studied. The results showed that during the growing season, the deposition fluxes of Cr, Ni, As, Cd, and Pb in typical agro-ecosystems were 0.60-36.86, 0.65-25.37, 0.05-8.88, 0.12-5.81, and 0.43-35.63 MUg m-2 day-1, respectively, which varied greatly between the four different regions. The average deposition fluxes of Cr, Ni, Cd, and Pb in the HH region, as well as the fluxes of As in the SW region, were significantly higher than those in the SE region. Heavy metal deposition rates among agro-ecosystems were very similar, except for the sites around cement factory in flat HH region. In mountainous SW region, however, deposition rates varied widely with sites nearby towns relatively higher and remote regions much lower. Higher correlation coefficients were observed between Cr, As, Pb, and Ni deposition rates, suggesting that they had similar sources. Samples from the SW and SE regions exhibited higher 207Pb/206Pb and 208Pb/206Pb ratios than those from the HH and Up mid YR regions. Airborne Pb in SW agro-ecosystems were mainly derived from vehicle exhaust and local smelting, whereas that in the HH region from burning of northern Chinese coal. PMID- 29235023 TI - Dinoflagellate cyst abundance is positively correlated to sediment organic carbon in Sydney Harbour and Botany Bay, NSW, Australia. AB - There is growing public concern about the global expansion of harmful algal bloom species (HABs), with dinoflagellate microalgae comprising the major portion of the harmful taxa. These motile, unicellular organisms have a lifecycle involving sexual reproduction and resting cyst formation whereby cysts can germinate from sediments and 'seed' planktonic populations. Thus, investigation of dinoflagellate cyst (dinocyst) distribution in sediments can provide significant insights into HAB dynamics and contribute to indices of habitat quality. Species composition and abundance of dinocysts in relation to sediment characteristics were studied at 18 stations in two densely populated temperate Australian estuaries, Sydney Harbour (Parramatta River/Port Jackson; PS) and Botany Bay (including Georges River; GB). Eighteen dinocyst taxa were identified, dominated by Protoceratium reticulatum and Gonyaulax sp.1 in the PS estuary, together with Archaeperidinium minutum and Gonyaulax sp.1 in the GB estuary. Cysts of Alexandrium catenella, which is one of the causative species of paralytic shellfish poisoning (PSP), were also detected in both estuaries. Out of the measured sediment characteristics (TOC, Cd, Cr, Cu, Fe, Pb, Mn, Ni, Zn and polycyclic aromatic hydrocarbons), TOC was the parameter explaining most of the variation in dinocyst assemblages and was positively correlated to most of the heavy metals. Given the significant relationship between sediment TOC and dinocyst abundance and heavy metal concentrations, this study suggests that sediment TOC could be broadly used in risk management for potential development of algal blooms and sediment contamination in these estuaries. PMID- 29235024 TI - Mill pond sediments as the indicator of the environment of the drainage area (an example of Liswarta River, Odra basin, Poland). AB - The geochemical characteristics of sediments deposited within a channel-type reservoir situated behind the weir of a water mill on the River Liswarta (southern Poland) were studied in relation to land use in the catchment. The catchment in question is an agricultural one with large forest areas. The contamination of sediments with trace elements was assessed using the geoaccumulation index. The sediments studied were moderately to heavily contaminated with As, Cu, Co, Ni and Ba. They were also heavily contaminated with Sr. Additionally, V and Cr contamination ranged from heavy to extreme. The basic composition of sediments and the trace elements present in them indicate both natural and anthropogenic sources of pollution. Mill impoundments provide zones where the sediments transported by rivers accumulate. Within the Liswarta catchment, their removal may cause the remobilisation of contaminated alluvial deposits. PMID- 29235025 TI - Effects of exposure to malathion on blood glucose concentration: a meta-analysis. AB - Exposure to malathion (an organophosphate pesticide widely used around the world) has been associated with alterations in blood glucose concentration in animal models. However, the results are inconsistent. The aim of this meta-analysis was to evaluate whether malathion exposure can disturb the concentrations of blood glucose in exposed rats. We performed a literature search of online databases including PubMed, EBSCO, and Google Scholar and reviewed original articles that analyzed the relation between malathion exposure and glucose levels in animal models. The selection of articles was based on inclusion and exclusion criteria. The database search identified thirty-five possible articles, but only eight fulfilled our inclusion criteria, and these studies were included in the meta analysis. The effect of malathion on blood glucose concentration showed a non monotonic dose-response curve. In addition, pooled analysis showed that blood glucose concentrations were 3.3-fold higher in exposed rats than in the control group (95% CI, 2-5; Z = 3.9; p < 0.0001) in a random-effect model. This result suggested that alteration of glucose homeostasis is a possible mechanism of toxicity associated with exposure to malathion. PMID- 29235026 TI - The N-shaped environmental Kuznets curve: an empirical evaluation using a panel quantile regression approach. AB - We evaluate the N-shaped environmental Kuznets curve (EKC) using panel quantile regression analysis. We investigate the relationship between CO2 emissions and GDP per capita for 74 countries over the period of 1994-2012. We include additional explanatory variables, such as renewable energy consumption, technological development, trade, and institutional quality. We find evidence for the N-shaped EKC in all income groups, except for the upper-middle-income countries. Heterogeneous characteristics are, however, observed over the N-shaped EKC. Finally, we find a negative relationship between renewable energy consumption and CO2 emissions, which highlights the importance of promoting greener energy in order to combat global warming. PMID- 29235027 TI - A study on the causal effect of urban population growth and international trade on environmental pollution: evidence from China. AB - This study seeks to contribute to the recent literature by empirically investigating the causal effect of urban population growth and international trade on environmental pollution of China, for the period 1980-2014. The Johansen cointegration confirmed a long-run cointegration association among the utilised variables for the case of China. The direction of causality among the variables was, consequently, investigated using the recent bootstrapped Granger causality test. This bootstrapped Granger causality approach is preferred as it provides robust and accurate critical values for statistical inferences. The findings from the causality analysis revealed the existence of a bi-directional causality between import and urban population. The three most paramount variables that explain the environmental pollution in China, according to the impulse response function, are imports, urbanisation and energy consumption. Our study further established the presence of an N-shaped environmental Kuznets curve relationship between economic growth and environmental pollution of China. Hence, our study recommends that China should adhere to stricter environmental regulations in international trade, as well as enforce policies that promote energy efficiency in the urban residential and commercial sector, in the quest to mitigate environmental pollution issues as the economy advances. PMID- 29235028 TI - Artificial intelligence and regression analysis for Cd(II) ion biosorption from aqueous solution by Gossypium barbadense waste. AB - In this study, batch biosorption experiments were conducted to determine the removal efficiency of Cd(II) ion from aqueous solutions by Gossypium barbadense waste. The biosorbent was characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) connected with energy dispersive X-ray (EDX). The sorption mechanism was described by complexation/chelation of Cd2+ with the functional groups of O-H, C=O, -COO-, and C-O, as well as, cation-exchange with Mg2+ and K+. At initial Cd(II) ion concentration (C o), 50 mg/L, the adsorption equilibrium of 89.2% was achieved after 15 min under the optimum experimental factors of pH 6.0, biosorbent dosage 10 g/L, and particle diameter 0.125-0.25 mm. Both Langmuir and Freundlich models fitted well to the sorption data, suggesting the co-existence of monolayer coverage along with heterogenous surface biosorption. Artificial neural network (ANN) with a structure of 5-10-1 was performed to predict the Cd(II) ion removal efficiency. The ANN model provided high fit (R 2 0.923) to the experimental data and indicated that C o was the most influential input. A pure-quadratic model was developed to determine the effects of experimental factors on Cd(II) ion removal efficiency, which indicated the limiting nature of pH and biosorbent dosage on Cd(II) adsorption. Based on the regression model (R 2 0.873), the optimum experimental factors were pH 7.61, biosorbent dosage 24.74 g/L, particle size 0.125-0.25 mm, and adsorption time 109.77 min, achieving Cd2+ removal of almost 100% at C o 50 mg/L. PMID- 29235029 TI - Impacts of integrated nutrient management on methane emission, global warming potential and carbon storage capacity in rice grown in a northeast India soil. AB - Rice soil is a source of emission of two major greenhouse gases (methane (CH4) and nitrous oxide (N2O)) and a sink of carbon dioxide (CO2). The effect of inorganic fertilizers in combination with various organics (cow dung, green manure (Sesbania aculeata) Azolla compost, rice husk) on CH4 emission, global warming potential, and soil carbon storage along with crop productivity were studied at university farm under field conditions. The experiment was conducted in a randomized block design for 2 years in a monsoon rice (cv. Ranjit) ecosystem (June-November, 2014 and 2015). Combined application of inorganic (NPK) with Sesbania aculeata resulted in high global warming potential (GWP) of 887.4 kg CO2 ha-1 and low GWP of 540.6 kg CO2 ha-1 was recorded from inorganic fertilizer applied field. Irrespective of the type of organic amendments, flag leaf photosynthesis of the rice crop increased over NPK application (control). There was an increase in CH4 emission from the organic amended fields compared to NPK alone. The combined application of NPK and Azolla compost was effective in the buildup of soil carbon (16.93 g kg-1) and capacity of soil carbon storage (28.1 Mg C ha-1) with high carbon efficiency ratio (16.9). Azolla compost application along with NPK recorded 15.66% higher CH4 emission with 27.43% yield increment over control. Azolla compost application significantly enhanced carbon storage of soil and improved the yielding ability of grain (6.55 Mg ha-1) over other treatments. PMID- 29235030 TI - Catalytic degradation of sulfaquinoxalinum by polyester/poly-4-vinylpyridine nanofibers-supported iron phthalocyanine. AB - Iron (II) phthalocyanine (FePc) supported on electrospun polyester/poly-4 vinylpyridine nanofibers (PET/P4VP NFs) was prepared by stirring in tetrahydrofuran. The resulting product was confirmed and characterized by ultraviolet-visible diffuse reflectance spectroscopy, attenuated total reflection Fourier transform infrared spectra, X-ray photoelectron spectroscopy, gas chromatography/mass spectrometry, and ultra-performance liquid chromatography. More than 95% of sulfaquinoxalinum (SQX) could be removed by the activation of hydrogen peroxide in the presence of FePc-P4VP/PET with a PET and P4VP mass ratio of 1:1. This system exhibited a high catalytic activity across a wide pH and temperature range. The degradation rates of SQX achieved 100, 95, and 78% at a pH of 3, 7, and 9, respectively, and the degradation rates of SQX are more than 80% at the temperature ranging from 35 to 65 degrees C. DMSO2 could be detected by gas chromatography/mass spectrometry after the addition of DMSO, suggesting the formation of the high-valent iron intermediates in this catalytic system. In addition, the electron paramagnetic resonance experiments proved that free radicals did not dominate the reaction in our system. Therefore, the high-valent iron intermediates were proposed to the main active species in the FePc P4VP/PET/hydrogen peroxide system. In summary, the heterogeneous catalytic processes with non-radical catalytic mechanism might have better catalytic performance for the removal of organic pollutants, which can potentially be used in wastewater treatment. PMID- 29235031 TI - The persistence and photostabilizing characteristics of benzotriazole and 5 methyl-1H-benzotriazole reduce the photochemical behavior of common photosensitizers and organic compounds in aqueous environments. AB - Benzotriazole (BT) and 5-methyl-1H-benzotriazole (5-MeBT) are broadly used in industrial applications, such as anti-icing fluids and dishwashing detergent, and act as the primary building blocks for UV absorbers and photostabilizers. This study examined the occurrence of these two compounds in the environment and their unique photochemical behavior affecting photosensitizers and other micro-organic pollutants in aqueous environments. BT and 5-MeBT were detected in all river water samples from the major rivers in Taipei City in the concentration ranges of 147 to 1560 ng/L and 22 to 235 ng/L, respectively, and both compounds persisted through a conventional wastewater treatment plant. The direct photolysis half lives of BT and 5-MeBT were 56.9 and 14.0 h, respectively. The half-life of photolysis in river water for BT was 44.2 h, whereas the half-life of 5-MeBT was 24.7 h. The long half-lives in real-water matrices resulted in their prevalence in water bodies, and these compounds were also found to minimize the photosensitizing ability of nitrate and dissolved organic matter (DOM) and increase the persistence of other micro-organic pollutant. With BT present, the production of .OH in nitrate photolysis was reduced, the degradation of DOM under sunlight was hindered, and the photodegradation of pharmaceutical residues in surface water, such as methotrexate, was completely impeded. This study suggests that in cases in which BT and 5-MeBT are highly concentrated, the effectiveness of natural attenuation process, i.e., photodegradation, in the aqueous environment is diminished, which increases the persistence of the pollutants as well as the risk of exposure. PMID- 29235033 TI - Metal pollution across the upper delta plain wetlands and its adjacent shallow sea wetland, northeast of China: implications for the filtration functions of wetlands. AB - Grain size and concentrations of organic carbon (Corg) and particulate metals (PMs) As, Cd, Cr, Cu, Hg, Pb, Zn, Al, Fe, and Mn of 373 surface sediment samples, salinities in 67 surface water samples, were analyzed in various environments, including the upper delta plain wetlands (UDPW), its adjacent shallow sea wetland (SSW) in the Liaodong Bay, and river channels that are running through the Liaohe Delta, to evaluate the spatial distribution, transportation environmental dynamics of metals, and the provenance of metal pollution and assess the filtration functions of wetlands. The concentrations of PMs for UDPW were generally higher by a factor of ~ 10-22% compared with its analogues in SSW, suggesting the accumulation of PMs within the UDPW indicates that the UDPW systems are efficiently physical and chemical traps for PMs of anthropogenic sources by retaining and storing pollutants flowing into the sea. However, there was sever sewage irrigation-induced Cd pollution with a geo-accumulation index of 0.62-3.11 in an area of ~ 86 km2 of the adjacent shallow sea wetland, where large amount wetlands were historically moved for agriculture in the UDPW. Remarkably, the distributions of PMs were controlled by salinity-induced desorption and re adsorption mechanisms and significantly dispersed the contamination coverage by the three-dimensional hydrodynamic and sedimentation processes that dominated by inputs of freshwater and ocean dynamics including NE-SW tidal currents and NE-E longshore drifts in the SSW of the Liaodong Bay. A high agreement between the UDPW and the SSW datasets in principal component analysis essentially reflects that the characteristics of PM sources in the SSW were actually inherited from that in the UDPW, with a much closer relationship among metals, organic matter, and fine particulates in SSW than that of UDPW, which was judged by their correlation coefficient range of 0.406-0.919 in SSW against those of 0.042-0.654 in UDPW. PMID- 29235032 TI - Monitoring and research of microcystins and environmental factors in a typical artificial freshwater aquaculture pond. AB - Freshwater aquaculture ponds are important artificially regulated aquatic ecosystems which provide a large number of freshwater fish products in China. The cyanobacteria bloom and microcystin (MC) pollution caused by anthropogenic eutrophication have attracted much attention due to their toxic effects. To provide an insight into the cyanobacterial problem in the ponds, the environmental parameters and MCs of a typical artificial pond in the Yangtze River Delta region of China were monitored and studied from May to December 2015. During the monitoring period, the ponds were in serious eutrophication with total phosphorus (TP) concentrations between 0.95 and 1.80 MUg/L, and total nitrogen (TN) concentrations between 1.1 and 4.86 MUg/L. High feed coefficient and high fish stock were the main reasons for the eutrophication. The results showed that the water temperature was the key factor that affected the cyanobacteria blooming in the pond. The chlorophyll a concentration was significantly positively correlated with the cyanobacteria density during the blooming season. MC-LR and MC-RR existed simultaneously and showed a significant positive correlation. The peak concentrations of dissolved MC-LR and MC-RR in the pond water were 40.6 and 4.7 MUg/L, respectively, which is considered highly toxic. Free MC-LR and MC-RR were also found in the aquaculture products. MC-LR concentrations in the bighead carp (Aristichthys nobilis) liver and shrimp (Macrobrachium nipponense) muscle were up to 2.64 and 4.17 MUg/kg, respectively. MC-RR concentration was up to 1.89 MUg/kg in the black carp (Mylopharyngodon piceus) liver. The results implied the potential health risks for citizens and pets caused by current artificial freshwater aquaculture pond systems. PMID- 29235034 TI - Assessment of the health status and risk of genotoxic and cytotoxic damage in Argentinian adolescents living near horticultural crops. AB - In some rural areas in Argentina, adolescents may be considered as a group indirectly exposed to agrochemicals because their parents plant small crops near their homes. This could become a health risk to children and adolescents who may be more sensitive to exposure to chemicals than adults. The objective of this study was to evaluate the health status of two different groups of Argentinian adolescents using biochemical parameters, dietary information, and cytogenetic biomarkers of genotoxicity and cytotoxicity. The study groups included 32 adolescents from Montecarlo, who were indirectly exposed to agrochemicals, and 30 unexposed adolescents from Exaltacion de la Cruz. The values of total cholesterol, LDL cholesterol, triglycerides, gamma glutamyltransferase, and butyrylcholinesterase (BuChE) were higher (p < 0.05) in males from Exaltacion de la Cruz compared with those from Montecarlo. The BuChE activity was also higher (p < 0.05) in females from this region. Furthermore, the consumption of citrus, vegetable-like fruits, tubers, and red meat was more frequent (p < 0.05) in Montecarlo. On the other hand, differences in frequency of biomarkers of genetic damage in lymphocytes were not found (p > 0.05). However, the cytome assay in buccal cells showed that karyorrhectic and pyknotic cells were more frequent (p < 0.05) in the Montecarlo group; whereas, the frequencies of cells with nuclear buds, condensed chromatin and karyolysis were higher (p < 0.05) in the Exaltacion de la Cruz group. Despite the differences between the parameters and biomarkers evaluated, the adolescents of Montecarlo did not present health impairment probably due to the type and level of exposure to agrochemicals. PMID- 29235035 TI - Is acupuncture actually not effective for polycystic ovary syndrome? : Analysis of the trial published in jama. AB - In recent years, acupuncture has been applied to treat more and more patients suffering from polycystic ovary syndrome (PCOS). On June 27, 2017 a paper titled "Effect of acupuncture and clomiphene in Chinese women with polycystic ovary syndrome: a randomized clinical trial" was published in Journal of the American Medical Association (JAMA). The results did not support acupuncture as an effective therapy for improving the live births in PCOS. The aim of this article was to analyze the therapeutic regimen and design of the clinical trial. The primary outcome and the conclusion of the paper were discussed as well. There are 5 doubts in the paper. (1) The therapeutic regimen decided by trigger points in the paper was different from that of the traditional Chinese acupuncture. (2) The live birth as the primary outcome was limited during the PCOS recovery. (3) In addition the period of the treatment was too short to reflect the therapeutic effect. (4) Although there was no significant difference between active acupuncture and control acupuncture, the conclusion that acupuncture was not effective for PCOS was not confirmed because the control acupuncture plus clomiphene was also more effective than that of clomiphene alone. (5) The proposal and the statistics were not in accordance with the one planned before. Therefore the result was worth to be discussed so as to provide some suggestions and references for improving the clinical research of acupuncture. PMID- 29235036 TI - Expression of DHA-Metabolizing Enzyme Alox15 is Regulated by Selective Histone Acetylation in Neuroblastoma Cells. AB - The omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA) is enriched in neural membranes of the CNS, and recent studies have shown a role of DHA metabolism by 15-lipoxygenase-1 (Alox15) in prefrontal cortex resolvin D1 formation, hippocampo-prefrontal cortical long-term-potentiation, spatial working memory, and anti-nociception/anxiety. In this study, we elucidated epigenetic regulation of Alox15 via histone modifications in neuron-like cells. Treatment of undifferentiated SH-SY5Y human neuroblastoma cells with the histone deacetylase (HDAC) inhibitors trichostatin A (TSA) and sodium butyrate significantly increased Alox15 mRNA expression. Moreover, Alox15 expression was markedly upregulated by Class I HDAC inhibitors, MS-275 and depsipeptide. Co-treatment of undifferentiated SH-SY5Y cells with the p300 histone acetyltransferase (HAT) inhibitor C646 and TSA or sodium butyrate showed that p300 HAT inhibition modulated TSA or sodium butyrate-induced Alox15 upregulation. Differentiation of SH-SY5Y cells with retinoic acid resulted in increased neurite outgrowth and Alox15 mRNA expression, while co-treatment with the p300 HAT inhibitor C646 and retinoic acid modulated the increases, indicating a role of p300 HAT in differentiation-associated Alox15 upregulation. Increasing Alox15 expression was found in primary murine cortical neurons during development from 3 to 10 days-in vitro, reaching high levels of expression by 10 days-in-vitro-when Alox15 was not further upregulated by HDAC inhibition. Together, results indicate regulation of Alox15 mRNA expression in neuroblastoma cells by histone modifications, and increasing Alox15 expression in differentiating neurons. It is possible that one of the environmental influences on the immature brain that can affect cognition and memory, may take the form of epigenetic effects on Alox15 and metabolites of DHA. PMID- 29235037 TI - Expression and Significance of Cytokeratin 7, a Squamocolumnar Junction Marker, in Head and Neck Squamous Cell Carcinoma. AB - The favorable features of high-risk human papillomavirus (HPV) in the head and neck are limited to those harboring transcriptionally-active HPV, which occur predominantly in the oropharynx (OP). Factors rendering the OP susceptible to HPV oncogenesis are largely unexplored. The role of cytokeratin 7 (CK7) in predisposition to HPV and cancer in the cervix has been evaluated. However, its significance in the H&N is unknown. CK7 immunohistochemistry was performed on a tissue microarray cohort of OP and non-oropharyngeal (NOP) squamous cell carcinomas (SCC) with known clinical follow-up and HPV E6/7 mRNA status. Expression was graded based on the distribution (1 <= 33%, 2 = 33-66%, 3 >= 66%) and intensity (1 = weak, 2 = strong) with combined score of >= 2 considered positive. Survival analysis was performed. Seventy-four NOPSCCs and 204 OPSCCs were studied. HPV was positive in 2.7% of NOPSCCs and 70.9% of OPSCCs. CK7 was positive in 23.0% of OPSCCs and 14.8% of NOPSCCs (p = 0.2), and in 24.1% of HPV positive versus 17.2% of negative patients (p = 0.2). There was no correlation with age, race, gender, HPV status, histologic type, tumor subsite, treatment, stage, or co-morbidities, and CK7 expression was not significantly associated with overall or disease specific survival. In our series, CK7 is positive in ~ 25% of H&N SCCs, although usually only focally. While CK7 has been suspected to be overexpressed selectively in HPV-related OPSCCs due to their origination from tonsillar crypt epithelium, we did not find any significant difference by anatomic H&N subsite, nor by HPV status, for its expression and found no association with patient survival. PMID- 29235038 TI - Simple Approach for De Novo Structural Identification of Mannose Trisaccharides. AB - Oligosaccharides have diverse functions in biological systems. However, the structural determination of oligosaccharides remains difficult and has created a bottleneck in carbohydrate research. In this study, a new approach for the de novo structural determination of underivatized oligosaccharides is demonstrated. A low-energy collision-induced dissociation (CID) of sodium ion adducts was used to facilitate the cleavage of desired chemical bonds during the dissociation. The selection of fragments for the subsequent CID was guided using a procedure that we built from the understanding of the saccharide dissociation mechanism. The linkages, anomeric configurations, and branch locations of oligosaccharides were determined by comparing the CID spectra of oligosaccharide with the fragmentation patterns based on the dissociation mechanism and our specially prepared disaccharide CID spectrum database. The usefulness of this method was demonstrated to determine the structures of several mannose trisaccharides. This method can also be applied in the structural determination of oligosaccharides larger than trisaccharides and containing hexose other than mannose if authentic standards are available. Graphical Abstract. PMID- 29235040 TI - Quantitative Peptidomics with Five-plex Reductive Methylation labels. AB - Quantitative peptidomics and proteomics often use chemical tags to covalently modify peptides with reagents that differ in the number of stable isotopes, allowing for quantitation of the relative peptide levels in the original sample based on the peak height of each isotopic form. Different chemical reagents have been used as tags for quantitative peptidomics and proteomics, and all have strengths and weaknesses. One of the simplest approaches uses formaldehyde and sodium cyanoborohydride to methylate amines, converting primary and secondary amines into tertiary amines. Up to five different isotopic forms can be generated, depending on the isotopic forms of formaldehyde and cyanoborohydride reagents, allowing for five-plex quantitation. However, the mass difference between each of these forms is only 1 Da per methyl group incorporated into the peptide, and for many peptides there is substantial overlap from the natural abundance of 13C and other isotopes. In this study, we calculated the contribution from the natural isotopes for 26 native peptides and derived equations to correct the peak intensities. These equations were applied to data from a study using human embryonic kidney HEK293T cells in which five replicates were treated with 100 nM vinblastine for 3 h and compared with five replicates of cells treated with control medium. The correction equations brought the replicates to the expected 1:1 ratios and revealed significant decreases in levels of 21 peptides upon vinblastine treatment. These equations enable accurate quantitation of small changes in peptide levels using the reductive methylation labeling approach. Graphical abstract ?. PMID- 29235039 TI - UV Lamp as a Facile Ozone Source for Structural Analysis of Unsaturated Lipids Via Electrospray Ionization-Mass Spectrometry. AB - Ozonolysis of alkene functional groups is a type of highly specific and effective chemical reaction, which has found increasing applications in structural analysis of unsaturated lipids via coupling with mass spectrometry (MS). In this work, we utilized a low-pressure mercury lamp (6 W) to initiate ozonolysis inside electrospray ionization (ESI) sources. By placing the lamp near a nanoESI emitter that partially transmits 185 nm ultraviolet (UV) emission from the lamp, dissolved dioxygen in the spray solution was converted into ozone, which subsequently cleaved the double bonds within fatty acyls of lipids. Solvent conditions, such as presence of water and acid solution pH, were found to be critical in optimizing ozonolysis yields. Fast (on seconds time scale) and efficient (50%-100% yield) ozonolysis was achieved for model unsaturated phospholipids and fatty acids with UV lamp-induced ozonolysis incorporated on a static and an infusion nanoESI source. The method was able to differentiate double bond location isomers and identify the geometry of the double bond based on yield. The analytical utility of UV lamp-induced ozonolysis was further demonstrated by implementation on a liquid chromatography (LC)-MS platform. Ozonolysis was effected in a flow microreactor that was made from ozone permeable tubing, so that ambient ozone produced by the lamp irradiation could diffuse into the reactor and induce online ozonolysis post-LC separation and before ESI-MS. Graphical Abstract ?. PMID- 29235041 TI - A Hybrid Constant and Oscillatory Field Ion Mobility Analyzer Using Structures for Lossless Ion Manipulations. AB - Here we explore the combination of constant and oscillatory fields applied in a single device to affect the continuous separation and filtering of ions based on their mobilities. The device explored allows confining and manipulating ions utilizing a combination of radio frequency (rf), direct current (DC) fields, and traveling waves (TW) in a structures for lossless ion manipulations (SLIM) module. We have investigated theoretically and experimentally a concept for continuous filtering of ions based on their mobilities where ions are mobility separated and selected by passage through two regions, both of which incorporated combined TW and constant fields providing opposing forces on the ions. The SLIM module was composed of two surfaces with mirror-image arrays of electrodes and had two regions where the different TW and opposing DC fields could be applied. The filtering capabilities are determined by the applied DC gradient and the TW parameters, such as speed, amplitude, and the TW sequence (i.e., the duty cycle of the traveling wave). The effects of different parameters on the sensitivity and the ion mobility (IM) resolution of the device have been investigated. By appropriately choosing the DC gradient and TW parameters for the two sections, it is possible to transmit ions of a selected mobility while filtering out others of both higher and lower mobility. The novel device described here provides a basis for the targeted analysis of compounds based upon the continuous selection of ions according to their mobility and without the need for high electric fields or pulsed injection. Graphical abstract ?. PMID- 29235042 TI - Rapid Quadrupole-Time-of-Flight Mass Spectrometry Method Quantifies Oxygen-Rich Lignin Compound in Complex Mixtures. AB - Complex mixture analysis is a costly and time-consuming task facing researchers with foci as varied as food science and fuel analysis. When faced with the task of quantifying oxygen-rich bio-oil molecules in a complex diesel mixture, we asked whether complex mixtures could be qualitatively and quantitatively analyzed on a single mass spectrometer with mid-range resolving power without the use of lengthy separations. To answer this question, we developed and evaluated a quantitation method that eliminated chromatography steps and expanded the use of quadrupole-time-of-flight mass spectrometry from primarily qualitative to quantitative as well. To account for mixture complexity, the method employed an ionization dopant, targeted tandem mass spectrometry, and an internal standard. This combination of three techniques achieved reliable quantitation of oxygen rich eugenol in diesel from 300 to 2500 ng/mL with sufficient linearity (R2 = 0.97 +/- 0.01) and excellent accuracy (percent error = 0% +/- 5). To understand the limitations of the method, it was compared to quantitation attained on a triple quadrupole mass spectrometer, the gold standard for quantitation. The triple quadrupole quantified eugenol from 50 to 2500 ng/mL with stronger linearity (R2 = 0.996 +/- 0.003) than the quadrupole-time-of-flight and comparable accuracy (percent error = 4% +/- 5). This demonstrates that a quadrupole-time-of-flight can be used for not only qualitative analysis but also targeted quantitation of oxygen-rich lignin molecules in complex mixtures without extensive sample preparation. The rapid and cost-effective method presented here offers new possibilities for bio-oil research, including: (1) allowing for bio oil studies that demand repetitive analysis as process parameters are changed and (2) making this research accessible to more laboratories. Graphical Abstract ?. PMID- 29235043 TI - Effects of physical exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy. AB - PURPOSE: Exercise has been shown to reduce fatigue during cancer treatment. Hypothesized mechanisms include inflammatory pathways. Therefore, we investigated effects of exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy. METHODS: We pooled data from two randomized controlled exercise intervention trials with breast cancer patients during adjuvant chemotherapy (n = 130), which had previously shown beneficial effects of exercise on fatigue. Exercise comprised a 12-week resistance training (BEATE study) or an 18-week combined resistance and aerobic training (PACT study). Serum IL-6, IL 1ra, and the IL-6/IL-1ra ratio were quantified at baseline, mid-intervention, post-intervention, and 6-9 months post-baseline. RESULTS: Mixed effect models showed significant increases in IL-6 and IL-6/IL-1ra ratio during chemotherapy and decreases afterwards. Differences between exercise and control group were not significant at any time point. Changes in total cancer-related fatigue were significantly correlated with changes in IL-6/IL-1ra ratio (partial correlation r = 0.23) and IL-6 (r = 0.21), and changes in physical cancer-related fatigue with changes in IL-6/IL-1ra ratio (r = 0.21). CONCLUSIONS: Changes in fatigue were slightly correlated with changes in inflammatory markers, and there was a strong inflammatory response to adjuvant chemotherapy. The supervised exercise training did not counteract this increase in inflammation, suggesting that beneficial effects of exercise on fatigue during adjuvant chemotherapy for breast cancer are not essentially mediated by IL-6, IL-1ra, or the IL-6/IL-1ra ratio. PMID- 29235044 TI - Worse survival after breast cancer in women with anorexia nervosa. AB - PURPOSE: A history of anorexia nervosa has been associated with a reduced risk of developing breast cancer. We investigated survival after breast cancer among women with a prior anorexia nervosa diagnosis compared with women in a population comparison group. METHODS: This register-based study included combined data from Sweden, Denmark and Finland. A total of 76 and 1462 breast cancer cases identified among 22,654 women with anorexia nervosa and 224,619 women in a population comparison group, respectively, were included in the study. Hazard ratios (HR) for overall and breast cancer-specific mortality after breast cancer diagnosis were estimated using Cox regression. Cause of death was available only for Swedish and Danish women; therefore, the analysis on breast cancer-specific mortality was restricted to these women. RESULTS: We observed 23 deaths after breast cancer among anorexia nervosa patients and 247 among population comparisons. The overall mortality after the breast cancer diagnosis was increased in women with a history of anorexia nervosa compared with population comparisons (HR 2.5, 95% CI 1.6-3.9) after adjustment for age, period and extent of disease. Results were similar for overall (HR 2.3, 95% CI 1.4-3.6) and breast cancer-specific mortality (HR 2.1, 95% CI 1.3-3.6) among Swedish and Danish women. CONCLUSIONS: We found that female breast cancer patients with a prior diagnosis of anorexia nervosa have a worse survival compared with other breast cancer patients. PMID- 29235046 TI - Efficiency of nitrogen metabolism in beef cattle grazing pasture and supplemented with different protein levels in the rainy season. AB - Supplementation of animals in the rainy season is essential to maximise weight gain. Thus, the objective was to evaluate the effects of supplementation with low , medium- and high-protein levels on nutritional parameters of grazing beef cattle in the rainy season. Eight rumen-cannulated Nellore bulls (437 kg body weight) were used in a 4 * 4 double Latin square design with four supplements and four experimental periods. The treatments were mineral supplement (ad libitum) and supplements with low-protein (LPSU), medium-protein (MPS) and high-protein (HPS) levels, providing 106, 408 and 601 g/day of crude protein (CP), respectively. There was no difference (P > 0.05) between treatments for dry matter and forage intake, ruminal pH, ruminal ammonia nitrogen (RAN) at time 0 (before supplementation) and microbial protein yield. Animals on MPS had a higher (P > 0.05) intake and digestibility of CP, higher RAN levels (3 and 6 h after supplementation), increased nitrogen intake and a better nitrogen balance than animals on LPSU. The HPS provided higher (P > 0.05) RAN at time 6 and a better nitrogen balance when compared with MPS. We therefore infer that the high-protein supplement positively impacts nitrogen metabolism and efficiency in grazing beef cattle during the rainy season. PMID- 29235045 TI - Axillary staging for breast cancer during pregnancy: feasibility and safety of sentinel lymph node biopsy. AB - BACKGROUND: Safety of sentinel lymph node (SLN) biopsy for breast cancer during pregnancy is insufficiently explored. We investigated efficacy and local recurrence rate in a large series of pregnant patients. PATIENTS AND METHODS: Women diagnosed with breast cancer who underwent SLN biopsy during pregnancy were identified from the International Network on Cancer, Infertility and Pregnancy, the German Breast Group, and the Cancer and Pregnancy Registry. Chart review was performed to record technique and outcome of SLN biopsy, locoregional and distant recurrence, and survival. RESULTS: We identified 145 women with clinically N0 disease who underwent SLN during pregnancy. The SLN detection techniques were as follows: 99mTc-labeled albumin nanocolloid only (n = 96; 66.2%), blue dye only (n = 14; 9.7%), combined technique (n = 15; 10.3%), or unknown (n = 20; 13.8%). Mapping was unsuccessful in one patient (0.7%) and she underwent an axillary lymph node dissection (ALND). Mean number of SLNs was 3.2 (interquartile range 1 3; missing n = 15). Positive SLNs were found in 43 (29.7%) patients and 34 subsequently underwent ALND. After a median follow-up of 48 months (range 1-177), 123 (84.8%) patients were alive and free of disease. Eleven patients experienced a locoregional relapse, including 1 isolated ipsilateral axillary recurrence (0.7%). Eleven (7.6%) patients developed distant metastases, of whom 9 (6.2%) died of breast cancer. No neonatal adverse events related to SLN procedure during pregnancy were reported. CONCLUSIONS: SLN biopsy during pregnancy has a comparably low axillary recurrence rate as in nonpregnant women. Therefore, this method can be considered during pregnancy instead of standard ALND for early stage, clinically node-negative breast cancer. PMID- 29235047 TI - Anthelmintic effects of indigenous multipurpose fodder tree extracts against Haemonchus contortus. AB - Condensed tannins (CT) extracted from Balanites aegyptiaca, Tamarindus indica, and Celtis toka browses were used to evaluate their anthelmintic effect on different developmental stages of Haemonchus contortus. To achieve this objective, various serial concentrations of each CT extract of the foliages were used to test adult motility, inhibition of egg hatchability, and larval development. The fodders were selected based on their multipurpose advantage and accessibility to use as fodder for livestock in the low lands of the Gambella region. The fastest and slowest adult motility rate was observed in 2-ml (4 min) and 0.125-ml dose of C. toka, respectively, which is better than that in ivermectin. Egg hatchability inhibition was observed with dose difference within species, but there is no difference between B. aegyptiaca and T. indica. The foliage extracts of the studied browses were observed to inhibit the larvae by 100% at 2 ml, which is similar to ivermectin. There is no significant difference observed in larvae development inhibition between the species and ivermectin (p > 0.05). CT extracts of studied plants have found to own significant anthelmintic activity in a dose-dependent manner. They could serve as anthelmintic economically and eco-friendly after further and series of in vivo experiments. PMID- 29235048 TI - Serum lipid, enzyme, and hematological responses of broilers fed Acacia angustissima leaf meal-based diets. AB - The objective of the study was to determine serum lipid, enzyme, and hematological responses of broilers to Acacia angustissima leaf meal. Acacia angustissima leaves were harvested at mid maturity, ground into a leaf meal, and included in broiler diets at 0, 5, and 10%. One hundred and fifty-day-old chicks of 41.7 +/- 1.560 g were randomly allocated to 15 groups of the three diets. Feed and water were provided ad libitum throughout the trial. At days 14, 28, and 42, 4 ml of blood were collected from the jugular vein in plain vacutainer tubes for alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol (TC) analyses. At the end of the experiment, 4 ml of blood were collected from two randomly selected birds of each replicate in sterilized bottles containing ethylene diamine tetra acetic acid (EDTA) for full blood count and packed cell volume assessment. Data was tested for normality and analyzed using the General Linear Model Procedure of SAS version 9.3 (SAS 2010). Comparison of means was done using Tukey's test. A. angustissima had no effect on serum ALP, AST, LDH, TC, HDL-C, LDL-C, TG, full blood count, and packed cell volume. Increasing levels of A. angustissima leaf meal increased the ALT in the serum (p < 0.05) at 4 and 6 weeks. However, serum ALT indices for birds on the control and 5% diet were not different. It was concluded that 5% A. angustissima leaf meal can be included in broiler diets without a negative effect on serum lipid and enzyme profile, production and proportions of white blood cells and packed cell volume. PMID- 29235049 TI - Age-specific reference values and cut-off points for anti-mullerian hormone in infertile women following a long agonist treatment protocol for IVF. AB - PURPOSE: The aims of this study were to determining the reference value of anti mullerian hormone (AMH) in infertile women and effect of AMH on different ovarian responses in the stratum of BMI categories. METHODS: Through a retrospective cohort study the information of 816 infertile patients referring to the referral infertility clinic of Mahdiyeh Hospital since the beginning of 2011 until the end of January 2016 were used. The normal-based method was undertaken to calculate age-specific AMH percentiles. To determine the effect of AMH on the outcomes of different ovarian responses following adjustment of associated variables, the multinomial regression model was used. RESULTS: Estimated reference intervals for AMH corresponding to the 2.5 and 97.5th0/00 in patients with normal ovarian response are from 0.096 to 6.2 ng/mL. These values for percentiles of 5, 10, 25, 50, 75, 90, and 95% are, respectively, 0.18, 0.33, 0.77, 1.68, 3.05, 4.45, and 5.36 ng/dL. Also the reference value for the 20-year-old participants has a maximum range (0.12-7.64), while for 43-year-old ones has the lowest range (0.08 5.3). Among participants under and above 35 years old, the optimal cut-off points for predicting normal ovarian response are, respectively, 1.5 and 1.2 ng/dL. With each unit increase in the log of AMH concentration, the odds of having excessive ovarian response in patients with normal weight compared to that of having normal ovarian response is 32% higher. CONCLUSIONS: Determining AMH reference values in IVF candidates allows specialists to measure only AMH plasma levels in IVF candidates so as to find whether or not the ovarian response is normal before applying other therapeutic measures; accordingly, they can adjust a treatment plan for each individual separately. PMID- 29235050 TI - Copeptin and insulin resistance: effect modification by age and 11 beta-HSD2 activity in a population-based study. AB - PURPOSE: Arginine vasopressin (AVP) may be involved in metabolic syndrome (MetS) by altering liver glycogenolysis, insulin and glucagon secretion, and pituitary ACTH release. Moreover, AVP stimulates the expression of 11beta-hydroxysteroid dehydrogenase-type 2 (11beta-HSD2) in mineralocorticosteroid cells. We explored whether apparent 11beta-HSD2 activity, estimated using urinary cortisol-to cortisone ratio, modulates the association between plasma copeptin, as AVP surrogate, and insulin resistance/MetS in the general adult population. METHODS: This was a multicentric, family-based, cross-sectional sample of 1089 subjects, aged 18-90 years, 47% men, 13.4% MetS, in Switzerland. Mixed multivariable linear and logistic regression models were built to investigate the association of insulin resistance (HOMA-IR)/fasting glucose and MetS/Type 2 Diabetes with copeptin, while considering potential confounders or effect modifiers into account. Stratified results by age and 11beta-HSD2 activity were presented as appropriate. RESULTS: Plasma copeptin was higher in men [median 5.2, IQR (3.7 7.8) pmol/L] than in women [median 3.0, IQR (2.2-4.3) pmol/L], P < 0.0001. HOMA IR was positively associated with copeptin after full adjustment if 11beta-HSD2 activity was high [beta (95% CI) = 0.32 (0.17-0.46), P < 0.001] or if age was high [beta (95% CI) = 0.34 (0.20-0.48), P < 0.001], but not if either 11beta-HSD2 activity or age was low. There was a positive association of type 2 diabetes with copeptin [OR (95% CI) = 2.07 (1.10-3.89), P = 0.024), but not for MetS (OR (95% CI) = 1.12 (0.74-1.69), P = 0.605), after full adjustment. CONCLUSIONS: Our data suggest that age and apparent 11beta-HSD2 activity modulate the association of copeptin with insulin resistance at the population level but not MeTS or diabetes. Further research is needed to corroborate these results and to understand the mechanisms underlying these findings. PMID- 29235051 TI - Development of the CNS TAP tool for the selection of precision medicine therapies in neuro-oncology. AB - The number of targeted therapies utilized in precision medicine are rapidly increasing. Neuro-oncology offers a unique challenge due to the varying blood brain barrier (BBB) penetration of each agent. Neuro-oncologists face a difficult task weighing the growing number of potential targeted therapies and their likelihood of BBB penetration. We developed the CNS TAP Working Group and performed an extensive literature review for the evidence-based creation of the CNS TAP tool, which was retrospectively validated by analyzing brain tumor patients who underwent therapy targeted based on genomic results from an academic sequencing study (MiOncoseq, n = 17) or private molecular profiling (Foundation One, n = 7). The CNS TAP tool scores relevant targeted agents by applying multiple variables (i.e., pre-clinical data, clinical data, BBB permeability) to patient specific genomic information and clinical trial availability. In the Michigan cohort, the CNS TAP tool predicted the selected agent 85.7% of the time. The CNS TAP tool predicted the agent independently selected by pediatric neuro oncologists in the Colorado cohort 50% of the time. Patients with recurrent brain tumors treated with agents predicted by the CNS TAP tool demonstrated a median progression-free survival of 4 months and four patients with recurrent high-grade glioma maintained ongoing partial responses of at least 6 months. The CNS TAP tool is a formalized algorithm to assist clinicians select the optimal targeted therapy for neuro-oncology patients. The CNS TAP tool has relatively high concordance with selected therapies and clinical outcomes in patients receiving targeted therapy in this heterogeneous retrospective cohort were promising. PMID- 29235052 TI - Salvage fractionated stereotactic re-irradiation (FSRT) for patients with recurrent high grade gliomas progressed after bevacizumab treatment. AB - Bevacizumab failure is a major clinical problem in the management of high grade gliomas (HGG), with a median overall survival (OS) of < 4 months. This study evaluated the feasibility and efficacy of fractionated stereotactic re irradiation (FSRT) for patients progressed after Bevacizumab treatment. Retrospective review was conducted of 36 patients treated with FSRT after progression on bevacizumab. FSRT was most commonly delivered in 3.5 Gy fractions to a total dose of 35 Gy. Survival from initial diagnosis, as well as from recurrence and re-irradiation, were utilized as study endpoints. Univariate and multivariate analysis was performed. The median time from initial bevacizumab treatment to FSRT was 8.5 months. The median plan target volume for FSRT was 27.5 cc. The median OS from FSRT was 4.8 months. FSRT treatment was well tolerated with no grade 3 or higher toxicity. Favorable outcomes were observed in patients with recurrent HGG who received salvage FSRT after bevacizumab failure. The treatment was well tolerated. Prospective study is warranted to further evaluate the efficacy of salvage FSRT for selected patients with recurrent HGG amenable to FSRT, who had failed bevacizumab treatment. PMID- 29235053 TI - Classification of C2C12 cells at differentiation by convolutional neural network of deep learning using phase contrast images. AB - In the field of regenerative medicine, tremendous numbers of cells are necessary for tissue/organ regeneration. Today automatic cell-culturing system has been developed. The next step is constructing a non-invasive method to monitor the conditions of cells automatically. As an image analysis method, convolutional neural network (CNN), one of the deep learning method, is approaching human recognition level. We constructed and applied the CNN algorithm for automatic cellular differentiation recognition of myogenic C2C12 cell line. Phase-contrast images of cultured C2C12 are prepared as input dataset. In differentiation process from myoblasts to myotubes, cellular morphology changes from round shape to elongated tubular shape due to fusion of the cells. CNN abstract the features of the shape of the cells and classify the cells depending on the culturing days from when differentiation is induced. Changes in cellular shape depending on the number of days of culture (Day 0, Day 3, Day 6) are classified with 91.3% accuracy. Image analysis with CNN has a potential to realize regenerative medicine industry. PMID- 29235054 TI - Exploring the relationship between nonalcoholic fatty liver disease and pancreatic cancer by computed tomographic survey. AB - Pancreatic cancer is difficult to diagnose in an early stage, and has the highest mortality of all types of cancer. Obesity, high body mass index, and increased abdominal girth are established risk factors. Some studies have postulated that there is a correlation between organ steatosis and pancreatic cancer. This study aims to explore whether nonalcoholic fatty liver disease (NAFLD) is a risk factor and a prognostic factor for pancreatic cancer. The study enrolled 557 patients (143 with and 414 without pancreatic cancer) who were diagnosed between January 2009 and December 2013. We reviewed the abdominal computed tomographic scans of the patients to confirm the diagnosis of NAFLD. Clinical parameters, laboratory data, and personal information were analyzed. NAFLD is an independent risk factor for pancreatic cancer according to adjusted multivariate logistic regression analysis (OR 2.63, 95% CI 1.24-5.58, p = 0.011). The Kaplan-Meier survival curve reveals that patients without NAFLD have longer survival than patients with NAFLD (p = 0.005, log-rank test). NAFLD is positively correlated with pancreatic cancer, a result suggesting that NAFLD may increase the incidence and risk of pancreatic cancer. Patients with pancreatic cancer and NAFLD have poorer overall survival than patients without NAFLD, perhaps, because dysregulated cytokine status leads to progression of pancreatic cancer. NAFLD may be a prognostic factor for pancreatic cancer. PMID- 29235055 TI - A finite element model to assess transtibial prosthetic sockets with elastomeric liners. AB - People with transtibial amputation often experience skin breakdown due to the pressures and shear stresses that occur at the limb-socket interface. The purpose of this research was to create a transtibial finite element model (FEM) of a contemporary prosthesis that included complete socket geometry, two frictional interactions (limb-liner and liner-socket), and an elastomeric liner. Magnetic resonance imaging scans from three people with characteristic transtibial limb shapes (i.e., short-conical, long-conical, and cylindrical) were acquired and used to develop the models. Each model was evaluated with two loading profiles to identify locations of focused stresses during stance phase. The models identified five locations on the participants' residual limbs where peak stresses matched locations of mechanically induced skin issues they experienced in the 9 months prior to being scanned. The peak contact pressure across all simulations was 98 kPa and the maximum resultant shear stress was 50 kPa, showing reasonable agreement with interface stress measurements reported in the literature. Future research could take advantage of the developed FEM to assess the influence of changes in limb volume or liner material properties on interface stress distributions. Graphical abstract Residual limb finite element model. Left: model components. Right: interface pressures during stance phase. PMID- 29235056 TI - Separating arterial pressure increases and decreases in assessing cardiac baroreflex sensitivity via sequence and bivariate phase-rectified signal averaging techniques. AB - Cardiac baroreflex (cBR) is activated by both arterial pressure (AP) increases and decreases. Sequence method, a widely utilized tool assessing cBR sensitivity (cBRS) from spontaneous heart period (HP) and systolic AP (SAP) variations, allows the separated computation of cBRS from positive and negative SAP variations. The recently proposed phase-rectified signal averaging (PRSA) method has the same feature but it has been applied so far solely to positive SAP variations. We adapted the PRSA method to compute cBRS over negative SAP variations and we compared the results with those derived from sequence method over two protocols: (i) graded head-up tilt (HUT) at 15, 30, 45, 60, and 75 degrees in 19 healthy subjects and (ii) general anesthesia induction in 118 patients undergoing coronary artery bypass graft surgery. Regardless of the sign of SAP changes and method, cBRS moved toward 0 during HUT. Only sequence method detected the cBRS decrease after general anesthesia induction. In both protocols, the correlation between the PRSA-based cBRSs derived from positive and negative SAP changes was higher than that obtained from analogous sequence-based cBRSs and correlation between equivalent cBRSs derived from different methods might be absent. We conclude that the two methods are not interchangeable in assessing cBRS. Graphical abstract Graphical representation of the baroreflex sensitivity (BRS) estimation procedures carried out using sequence (SEQ) and phase-rectified signal averaging (PRSA) techniques over spontaneous fluctuations of heart period (HP) and systolic arterial pressure (SAP). BRSSEQ and BRSPRSA was separately computed over positive (+) and negative (-) SAP variations. PMID- 29235057 TI - Design and Assessment of a Dynamic Perfusion Bioreactor for Large Bone Tissue Engineering Scaffolds. AB - Bioreactors can be used to apply fluid flow in vitro to scaffolds to improve mass transport of media and apply mechanical forces to cells. In this study, we developed and tested an autoclavable, modular perfusion bioreactor suitable for large scaffolds. We investigated the effects of fluid flow induced shear stress (FFSS) on osteogenic differentiation of human embryonic stem cell-derived mesenchymal progenitors (hES-MP cells) cultured on large polyurethane (PU) scaffolds (30 mm diameter * 5 mm thickness) in osteogenesis induction media (OIM). After seeding, scaffolds were either maintained in static conditions or transferred to the bioreactor 3 days post-seeding and a continuous flow rate of 3.47 mL/min was applied. Alkaline phosphatase activity (ALP) was used to evaluate osteogenic differentiation and resazurin salt reduction (RR) to measure metabolic activity after 10 days. Cultures subjected to flow contained significantly more metabolically active cells and higher total DNA content, as well as significantly higher ALP activity compared to scaffolds grown in static culture. These results confirm the responsiveness of hES-MP cells to fluid flow stimuli, and present a cost-effective, user-friendly bioreactor capable of supporting the growth and differentiation of mesenchymal progenitor cells within scaffolds capable of filling large bone defects. PMID- 29235059 TI - Quality of life after hip, vertebral, and distal forearm fragility fractures measured using the EQ-5D-3L, EQ-VAS, and time-trade-off: results from the ICUROS. AB - INTRODUCTION: The International Costs and Utilities Related to Osteoporotic fractures Study is a multinational observational study set up to describe the costs and quality of life (QoL) consequences of fragility fracture. This paper aims to estimate and compare QoL after hip, vertebral, and distal forearm fracture using time-trade-off (TTO), the EuroQol (EQ) Visual Analogue Scale (EQ VAS), and the EQ-5D-3L valued using the hypothetical UK value set. METHODS: Data were collected at four time-points for five QoL point estimates: within 2 weeks after fracture (including pre-fracture recall), and at 4, 12, and 18 months after fracture. Health state utility values (HSUVs) were derived for each fracture type and time-point using the three approaches (TTO, EQ-VAS, EQ-5D-3L). HSUV were used to estimate accumulated QoL loss and QoL multipliers. RESULTS: In total, 1410 patients (505 with hip, 316 with vertebral, and 589 with distal forearm fracture) were eligible for analysis. Across all time-points for the three fracture types, TTO provided the highest HSUVs, whereas EQ-5D-3L consistently provided the lowest HSUVs directly after fracture. Except for 13-18 months after distal forearm fracture, EQ-5D-3L generated lower QoL multipliers than the other two methods, whereas no equally clear pattern was observed between EQ-VAS and TTO. On average, the most marked differences between the three approaches were observed immediately after the fracture. CONCLUSIONS: The approach to derive QoL markedly influences the estimated QoL impact of fracture. Therefore the choice of approach may be important for the outcome and interpretation of cost-effectiveness analysis of fracture prevention. PMID- 29235060 TI - Sleep-related hypermotor epilepsy in a patient with mild Crouzon syndrome. PMID- 29235063 TI - Are the differences clinically relevant? The European Perspective. PMID- 29235062 TI - Retreatment with Vismodegib after Progression in Advanced Basal Cell Carcinoma: First-Time Report of a Single-Institution Experience. AB - Retreatment with vismodegib in advanced basal cell carcinoma (BCC) patients who previously discontinued the drug due to disease progression (PD) has not been reported yet. The objective of our report is to determine whether vismodegib is still active when used in BCC patients who progressed during a first vismodegib course (FVC). We conducted a retrospective study on six advanced BCC patients enrolled in a clinical trial (STEVIE, NCT01367665) who discontinued vismodegib due to PD and were then retreated with the same drug. All patients underwent intercurrent therapies between the FVC and the second vismodegib course (SVC). Disease control (complete response, CR; partial response, PR; and stable disease) was achieved in 100% and 80% of cases in FVC and SVC, respectively. The overall response rate was 80% for FVC (50% of CR) and 50% for SVC (only PR). Median treatment duration of FVC and SVC was 19.5 months (range: 13-35) and 8 months (range: 3-14+), respectively. G3-G4 AEs were reported only during SVC (two cases), leading to permanent discontinuation in one case. The median interval between FVC and SVC was 21.5 months (range: 13-30). After a median follow-up of 54 months (range: 46-63) only one patient with metastatic disease had rapid progression, discontinued vismodegib, and died. All other patients are still alive and two are currently on therapy. We concluded that vismodegib rechallenge is feasible and potentially active in advanced BCC patients who previously discontinued the drug due to disease progression. PMID- 29235061 TI - Differential expression of immune factor between patients with chronic prostatitis/chronic pelvic pain syndrome and the healthy volunteers. AB - PURPOSE: Immune mechanisms have been hypothesized to contribute to the development of CP/CPPS. In this study, we investigated the differential expression of immune factors between patients with CP/CPPS and healthy volunteers. METHODS: This study was registered in Australian New Zealand Clinical Trials Registry. Healthy volunteers and patients with CP/CPPS were enrolled in this study. The inclusion criteria for patients were below: (1) aged 18-45 years old; (2) prostatitis-related syndrome longer than 3 months; (3) normal routine urine culture and negative bacterial culture in prostatic fluid. Patients were further classified into two groups: types IIIA and IIIB CP/CPPS according to the results of EPS routine test. Serum immune markers include IgA, IgM, IgG, CD4+ and CD8+. RESULTS: There are total 23 CP/CPPS patients, including 12 type IIIB and 11 type IIIA. Relatively, there are 26 healthy volunteers. The serum levels of IgG were higher in CP/CPPS patients compared to healthy volunteers (1141.2 +/- 204.3 vs 1031.9 +/- 173.7 mg/L, p = 0.045), while the serum levels of CD8+ were lower in CP/CPPS patients compared to healthy volunteers (492.8 +/- 185.6 vs 640.0 +/- 246.8 cells/MUL, p = 0.021). Furthermore, serum levels of IgG were higher in patients with IIIA CP/CPPS compared to those with IIIB (1244.3 +/- 151.6 vs 1054.3 +/- 209.3 mg/L, p = 0.023). CONCLUSIONS: Differential levels of IgG and CD8+ between CPPS patients and healthy volunteers suggest a contributing role of immune mechanisms to the development of CP/CPPS; and IgG may play an important role in inflammatory CPPS. Clinical Study registration number ACTRN12613000792729. PMID- 29235064 TI - Induction of Neuroinflammatory Response and Histopathological Alterations Caused by Quinolinic Acid Administration in the Striatum of Glutaryl-CoA Dehydrogenase Deficient Mice. AB - Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase (GCDH) activity. Patients usually present progressive cortical leukodystrophy and commonly develop acute bilateral striatal degeneration mainly during infections that markedly worse their prognosis. A role for quinolinic acid (QA), a key metabolite of the kynurenine pathway, which is activated during inflammatory processes, on the pathogenesis of the acute striatum degeneration occurring in GA I was proposed but so far has not yet been evaluated. Therefore, we investigated whether an acute intrastriatal administration of quinolinic acid (QA) could induce histopathological alterations in the striatum of 30-day-old wild-type (WT) and GCDH knockout (Gcdh-/-) mice. Striatum morphology was evaluated by hematoxylin and eosin, T lymphocyte presence (CD3), and glial activation (GFAP and S100beta) by immunohistochemistry and 3-nitrotyrosine (YNO2) by immunofluorescence. QA provoked extensive vacuolation, edema, and especially lymphocyte infiltration in the striatum of Gcdh-/-. QA also enhanced CD3 staining and the number of YNO2 positive cells in Gcdh-/- mice, relatively to WT, indicating T lymphocyte infiltration and nitrosative stress, respectively. QA treated WT mice also showed an increase of GFAP and S100beta staining, which is indicative of reactive astrogliosis, whereas the levels of these astrocytic proteins were not changed in Gcdh-/- QA-injected mice. The present data indicate that QA significantly contributes to the histopathological changes observed in the striatum of Gcdh-/- mice. PMID- 29235065 TI - The intra-conduit release method is useful for avoiding migration of metallic stents during EUS-guided hepaticogastrostomy (with video). AB - PURPOSE: Although EUS-guided hepaticogastrostomy (EUS-HGS) with a covered self expandable metal stent (SEMS) is a useful procedure, it is associated with severe adverse events, including stent migration. We, therefore, developed an intra conduit release method, and investigated whether the technique yields a safer and more stable procedure. METHODS: The intra-conduit release method is a procedure to release the SEMS in the working channel conduit of the scope for anchoring between the liver and stomach to avoid stent migration. Forty-three patients who underwent EUS-HGS at two high-volume centers in Japan were enrolled in this retrospective study, and the safety and usefulness of this method were evaluated retrospectively. RESULTS: The intra-conduit release method was applied in 36 cases. The technical success rate of EUS-HGS with the intra-conduit release method was significantly higher in comparison with the conventional method. Additionally, the rate of early adverse events was significantly lower than that for the conventional method. CONCLUSION: The intra-conduit release method during EUS-HGS is useful for a stable procedure that avoids early adverse events. PMID- 29235066 TI - Dysthyroidism and Chronic Heart Failure: Pathophysiological Mechanisms and Therapeutic Approaches. AB - Among comorbidity in chronic heart failure (CHF), dysthyroidism represents a relevant problem especially in the ageing CHF patients worldwide. Thyroid greatly affects many cardiovascular activities and its dysfunction may worsen a CHF condition. In particular, hypothyroidism has a relative high prevalence in patients with heart failure and it plays a key role in influencing CHF onset, progression and prognosis. Hyperthyroidism, is less frequent in this clinical context but it necessitates of immediate treatment because of its negative effects on cardiovascular balance. Also, it must be considered that dysthyroism may also be iatrogenic and the main responsible drug is Amiodarone.Based on the best available evidence and our cumulative clinical experience, this manuscript analyzes the prevalence, the pathophysiology and the prognostic impact of thyroid disorders in chronic heart failure. PMID- 29235067 TI - Intermittent administration of PTH induces the expression of osteocalcin and BMP 2 on choroid plexus cells associated with suppression of sclerostin, TGF-beta1, and Na+K+ATPase. PMID- 29235071 TI - Computationally constructing a repository of compound remote associates test items in American English with comRAT-G. AB - The Remote Associates Test (RAT) has been used to measure creativity, however few repositories or standardizations of test items exist, like the normative data on 144 items provided by Bowden and Jung-Beeman. comRAT is a computational solver which has been used to solve the compound RAT in linguistic and visual forms, showing correlation to human performance over the normative data provided by Bowden and Jung-Beeman. This paper describes using a variant of comRAT, comRAT-G, to generate and construct a repository of compound RAT items for use in the cognitive psychology and cognitive modeling community. Around 17 million compound Remote Associates Test items are created from nouns alone, aiming to provide control over (i) frequency of occurrence of query items, (ii) answer items, (iii) the probability of coming up with an answer, (iv) keeping one or more query items constant and (v) keeping the answer constant. Queries produced by comRAT-G are evaluated in a study in comparison with queries from the normative dataset of Bowden and Jung-Beeman, showing that comRAT-G queries are similar to the established query set. PMID- 29235070 TI - PredPsych: A toolbox for predictive machine learning-based approach in experimental psychology research. AB - Recent years have seen an increased interest in machine learning-based predictive methods for analyzing quantitative behavioral data in experimental psychology. While these methods can achieve relatively greater sensitivity compared to conventional univariate techniques, they still lack an established and accessible implementation. The aim of current work was to build an open-source R toolbox - "PredPsych" - that could make these methods readily available to all psychologists. PredPsych is a user-friendly, R toolbox based on machine-learning predictive algorithms. In this paper, we present the framework of PredPsych via the analysis of a recently published multiple-subject motion capture dataset. In addition, we discuss examples of possible research questions that can be addressed with the machine-learning algorithms implemented in PredPsych and cannot be easily addressed with univariate statistical analysis. We anticipate that PredPsych will be of use to researchers with limited programming experience not only in the field of psychology, but also in that of clinical neuroscience, enabling computational assessment of putative bio-behavioral markers for both prognosis and diagnosis. PMID- 29235072 TI - A Bayesian approach to estimating variance components within a multivariate generalizability theory framework. AB - In many behavioral research areas, multivariate generalizability theory (mG theory) has been typically used to investigate the reliability of certain multidimensional assessments. However, traditional mG-theory estimation-namely, using frequentist approaches-has limits, leading researchers to fail to take full advantage of the information that mG theory can offer regarding the reliability of measurements. Alternatively, Bayesian methods provide more information than frequentist approaches can offer. This article presents instructional guidelines on how to implement mG-theory analyses in a Bayesian framework; in particular, BUGS code is presented to fit commonly seen designs from mG theory, including single-facet designs, two-facet crossed designs, and two-facet nested designs. In addition to concrete examples that are closely related to the selected designs and the corresponding BUGS code, a simulated dataset is provided to demonstrate the utility and advantages of the Bayesian approach. This article is intended to serve as a tutorial reference for applied researchers and methodologists conducting mG-theory studies. PMID- 29235073 TI - [Quality of life of nursing home residents with dementia before, during and after playing with a magic table]. AB - The 'Active Cues Magic Table' is a new game concept within nursing home care. It consists of light animations projected on a dining table and responding to movements of the players. The aim of this exploratory, quasi-experimental study was to examine the quality of life of nursing home residents with moderately severe or severe dementia before, during and after playing with this magic table. Quality of life was assessed with the Qualidem and the DS-DAT. Of the 34 nursing home residents included, 62% were female and mean age was 86.5 years (standard deviation 6.2). The Qualidem showed a small to moderate improvement in 'negative affect', 'restless tense behavior' and 'positive self-image' up to the week after playing (p <= 0.04). The DS-DAT showed a moderate improvement up to one hour after playing compared to a quarter of an hour before playing (p < 0.001). In conclusion, the quality of life of nursing home residents with moderately severe or severe dementia seems to improve up to the week after playing with the magic table. However, future research is needed to confirm the results of this exploratory study and to examine whether the improvements can truly be ascribed to the magic table. PMID- 29235068 TI - Migraine Treatment: Current Acute Medications and Their Potential Mechanisms of Action. AB - Migraine is a common and disabling primary headache disorder with a significant socioeconomic burden. The management of migraine is multifaceted and is generally dichotomized into acute and preventive strategies, with several treatment modalities. The aims of acute pharmacological treatment are to rapidly restore function with minimal recurrence, with the avoidance of side effects. The choice of pharmacological treatment is individualized, and is based on the consideration of the characteristics of the migraine attack, the patient's concomitant medical problems, and treatment preferences. Notwithstanding, a good understanding of the pharmacodynamic and pharmacokinetic properties of the various drug options is essential to guide therapy. The current approach and concepts relevant to the acute pharmacological treatment of migraine will be explored in this review. PMID- 29235074 TI - Twin-screw extrusion of sustained-release oral dosage forms and medical implants. AB - Most of published reviews of twin-screw extrusion focused on its application for enhancing the bioavailability of amorphous solid dispersions while few of them focused on its use for manufacturing sustained-release oral dosage forms and medical implants, despite the considerable interest and success this process has garnered both in academia and in the pharmaceutical industry. Compared to conventional batch processing, twin-screw extrusion offers the advantages of continuous processing and the ability to prepare oral dosage forms and medical implants that have unique physicochemical and drug release attributes. This review provides an in-depth analysis of the formulation composition and processing conditions of twin-screw extrusion and how these factors affect the drug release properties of sustained-release dosage forms. This review also illustrates the unique advantages of this process by presenting case studies of a wide variety of commercial sustained-release products manufactured using twin screw extrusion. PMID- 29235075 TI - PLLA-PHB fiber membranes obtained by solvent-free electrospinning for short-time drug delivery. AB - Fibers of poly(L-lactic acid) (PLLA)/polyhydroxybutyrate (PHB) with different concentrations of the drug dipyridamole (DPD) were prepared using solvent-free melt electrospinning to obtain a polymeric drug delivery system. The electrospun fibers were morphologically, structurally, thermally, and dynamically characterized. Crazes that resemble lotus root crevices were interestingly observed in the 7:3 PLLA/PHB fibers with 1% DPD. The crystallinity of PLLA slightly decreased as PHB was incorporated, and the addition of DPD significantly reduced the melting temperature of the composite. The interactions between PLLA and PHB mainly occurred at a proportion of 7:3, and drug encapsulation in the fibers was verified. The kinetic profiles of drug release demonstrated the predominant multiple patterns involving a diffusional stage in the short-term mode of release and kinetic process related to the hydrolysis of the biopolymers. Furthermore, the dynamic behavior of the polymer molecules was evaluated based on the segmental mobility using probe electron spin resonance spectroscopy. The segmental mobility in the amorphous fraction of PLLA decreased with increasing PLLA content. The 9:1 PLLA/PHB system was more resistant to polymer hydrolysis than to the 7:3 system and the rate of diffusion transport was approximately two times higher for the 7:3 PLLA/PHB fibers than for the 9:1 PLLA/PHB fibers. PMID- 29235077 TI - Metabolic syndrome and disability in Chinese nonagenarians and centenarians. AB - BACKGROUND: Little is known about the relationship between metabolic syndrome (MetS) and disability in the oldest old. AIMS: To investigate the possible association between MetS and disability among community-dwelling older adults aged >= 90 years. METHODS: This was a secondary analysis of a cross-sectional study. MetS was defined by the International Diabetes Federation Criteria. Activities of daily living (ADL) and instrumental activities of daily living (IADL) disabilities were evaluated using the physical self-maintenance scale and the Lawton-Brody IADL scale, respectively. RESULTS: We included 725 participants (mean age: 93.8 +/- 3.1 years). The prevalence of MetS was 13.0% in women and 9.8% in men, respectively. In women, ADL and IADL disabilities were more prevalent in the MetS group compared with the non-MetS group (ADL: 43.1 vs. 30.6%, p = 0.044; IADL: 73.8 vs. 59.8%, p = 0.030). After adjusting for relevant confounders, participants with MetS was associated with an increased risk of either ADL (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.22-3.45) or IADL disability (OR 2.12, 95% CI 1.31-4.78) compared with those without MetS. In men, similar results were found with respect to the prevalence of ADL or IADL disability and the adjusted ORs, but the results were not statistically significant. CONCLUSION: MetS is associated with an increased risk of either ADL or IADL disability in a study population of long-lived adults, especially in women. PMID- 29235076 TI - A comparison of the impact of physical exercise, cognitive training and combined intervention on spontaneous walking speed in older adults. AB - BACKGROUND: Spontaneous walking speed (SWS) is one of the most important indicators of health in older adults. Studies have shown benefits of physical trainings on SWS in older adults but the impact of cognitive training and multidomain interventions remains understudied. AIMS: This original study aimed at comparing the impact of aerobic/resistance exercise, computerized cognitive training and the combination of both interventions compared with active control conditions on SWS in healthy older adults. METHODS: Ninety community-dwelling older adults were randomly assigned to four different combinations composed of two active interventions: physical aerobic/resistance and cognitive dual-task trainings, and two active control conditions: stretching exercises and computer lessons. The four combinations were the following: (1) aerobic/resistance and cognitive dual task (n = 28), (2) aerobic/resistance and computer lessons (n = 21), (3) stretching exercises and cognitive dual task and (n = 23), (4) stretching exercises and computer lessons (n = 18). Training sessions were held three times/week for three months. SWS for 30 s was assessed before and after the intervention. RESULTS: Repeated-measures ANOVA showed a main effect of time and a significant three-way interaction suggesting differential improvement in SWS according to training combinations. A clinical meaningful improvement in SWS was observed in groups 1-3 (0.08-0.14 m/s; effect sizes: small to moderate) but not in the active control group 4. DISCUSSION: Results of this study suggest that aerobic/resistance exercise and computerized dual-task training are two non pharmacological interventions by which SWS, a functional vital sign, can be clinically improved in older adults. CONCLUSION: This original study pointed out different tools to prevent functional decline in older people. PMID- 29235078 TI - The Nutritional and Phytochemical Composition of the Indigenous Australian Pindan Walnut (Terminalia cunninghamii) Kernels. AB - Nutritional composition of the kernels of two types of Pindan walnut (Terminalia cunninghamii), a native nut consumed traditionally by Australian Indigenous peoples, is reported for the first time. Results showed that Pindan walnut kernels contained high levels of fat, protein and ash, approximately 50, 30 and 5% fresh basis, respectively. The levels of minerals in the kernels were much higher than common walnuts and macadamia nuts, especially those of phosphorus, magnesium and zinc. The high amounts of polyphenols in the kernels provided strong hydrophilic antioxidant capacities, of up to 2004 mg Trolox equivalents/100 g fresh basis using the hydrophilic oxygen radical absorbance capacity assay. Both free polyphenol content and hydrophilic antioxidant capacities of the kernels were higher than those of macadamia nuts, although the lipophilic oxygen radical absorbance capacity was lower. These preliminary studies indicate high potential for wider use of the Pindan walnut as a novel, nutritious and health-promoting food. PMID- 29235079 TI - Bacterial flagellar axial structure and its construction. AB - The bacterial flagellum is a motile organelle composed of thousands of protein subunits. The filamentous part that extends from the cell membrane is called the axial structure and consists of three major parts, the filament, hook, and rod, and other minor components. Each of the three main parts shares a similar self assembly mechanism and a common basic architecture of subunit arrangement while showing quite distinct mechanical properties to achieve its specific function. Structural and molecular mechanisms to produce these various mechanical properties of the axial structure, such as the filament, the hook, and the rod, have been revealed by the complementary use of X-ray crystallography and cryo electron microscopy. In addition, the mechanism of growth of the axial structure is beginning to be revealed based on the molecular structure. PMID- 29235080 TI - Light-induced chromophore and protein responses and mechanical signal transduction of BLUF proteins. AB - Photoreceptor proteins have been used to study how protein conformational changes are induced by alterations in their environments and how their signals are transmitted to downstream factors to dictate physiological responses. These proteins are attractive models because their signal transduction aspects and structural changes can be precisely regulated in vivo and in vitro based on light intensity. Among the known photoreceptors, members of the blue light-using flavin (BLUF) protein family have been well characterized with regard to how they control various light-dependent physiological responses in several microorganisms. Herein, we summarize our current understanding of their photoactivation and signal-transduction mechanisms. For signal transduction, we review recent studies concerning how the BLUF protein, PixD, transmits a light induced signal to its downstream factor, PixE, to modulate phototaxis of the cyanobacterium Synechocystis sp. PCC6803. PMID- 29235082 TI - My happy years of collaboration with Fumio Arisaka. PMID- 29235081 TI - Overview of the mechanism of cytoskeletal motors based on structure. AB - In the last two decades, a wealth of structural and functional knowledge has been obtained for the three major cytoskeletal motor proteins, myosin, kinesin and dynein, which we review here. The cytoskeletal motor proteins myosin and kinesin are structurally similar in the core architecture of their motor domains and have similar force-producing mechanisms that are coupled with the chemical cycles of ATP binding, hydrolysis, Pi release and subsequent ADP release. The force is generated through conformational changes in the motor domain during Pi release and ATP binding in myosin and kinesin, respectively, and then converted into the rotation of the lever arm or neck linker (referred to as a power stroke) through the common structural pathways. On the other hand, the dynein cytoskeletal motor is an AAA+ protein and has a different structure and power stroke mechanism from those of myosins and kinesins. The linker protruding from the AAA+ ring of dynein swings according to the ATPase states, which, presumably, generates force to carry cargos within a cell. The communication mechanism between the track-binding and ATPase domains of dynein is unique because the two helices that presumably slide with respect to each other work as coordinators for these domains. Details of the mechanism underlying the power stroke and interdomain communication were revealed through recent progress in the structural studies of myosin, kinesin and dynein. PMID- 29235083 TI - Molluscan hemocyanin: structure, evolution, and physiology. AB - Most molluscs have blue blood because their respiratory molecule is hemocyanin, a type-3 copper-binding protein that turns blue upon oxygen binding. Molluscan hemocyanins are huge cylindrical multimeric glycoproteins that are found freely dissolved in the hemolymph. With molecular masses ranging from 3.3 to 13.5 MDa, molluscan hemocyanins are among the largest known proteins. They form decamers or multi-decamers of 330- to 550-kDa subunits comprising more than seven paralogous functional units. Based on the organization of functional domains, they assemble to form decamers, di-decamers, and tri-decamers. Their structure has been investigated using a combination of single particle electron cryo-microsopy of the entire structure and high-resolution X-ray crystallography of the functional unit, although, the one exception is squid hemocyanin for which a crystal structure analysis of the entire molecule has been carried out. In this review, we explain the molecular characteristics of molluscan hemocyanin mainly from the structural viewpoint, in which the structure of the functional unit, architecture of the huge cylindrical multimer, relationship between the composition of the functional unit and entire tertiary structure, and possible functions of the carbohydrates are introduced. We also discuss the evolutionary implications and physiological significance of molluscan hemocyanin. PMID- 29235085 TI - Recurrence of atretic parietal cephalocele in adult: report a case and review of literature. AB - Common presentation of atretic parietal cephalocele (APC) is mostly seen in infants and young children. And, it is a palpable midline parietal soft tissue mass which is thought to represent involuted true cephalocele (meningocele or encephalocele)connected to dura mater via a fibrous stalk. The incidence of intracranial anomalies have increased with APC. Parietal cephaloceles comprise about 1% of all cerebrospinal congenital malformations and 10% of cephaloceles. We report here the case of an atretic parietal cephalocele with no associated brain malformations in adult. PMID- 29235086 TI - Endothelial expression of c-kit and CD68 in dental follicles of human impacted third molars. AB - Periodontal tissue remnants of odontogenesis constitute the dental follicle (DF) which is actually considered a stem niche in adults. However, potentialities of local endothelia within this niche seem overlooked. We thus aimed at testing the endothelial cells expression of c-kit, the progenitor cells marker, and CD68, commonly regarded as a monocyte/macrophage marker, in human DFs. We performed an immunohistochemical study using these two markers which were applied on samples collected from ten adult patients. The markers were positively expressed in endothelial cells, as well as in spindle-shaped stromal cells of the DF. The origin of DF stem or progenitor cells needs reviewing in the light of these findings, as endothelium could be a donor site for niche inhabitants. PMID- 29235084 TI - Toward an understanding of biochemical equilibria within living cells. AB - Four types of environmental effects that can affect macromolecular reactions in a living cell are defined: nonspecific intermolecular interactions, side reactions, partitioning between microenvironments, and surface interactions. Methods for investigating these interactions and their influence on target reactions in vitro are reviewed. Methods employed to characterize conformational and association equilibria in vivo are reviewed and difficulties in their interpretation cataloged. It is concluded that, in order to be amenable to unambiguous interpretation, in vivo studies must be complemented by in vitro studies carried out in well-characterized and controllable media designed to contain key elements of selected intracellular microenvironments. PMID- 29235087 TI - Quantitative prenatal growth of the cervical sympathetic trunk components in sheep (Ovis arise) during the foetal period. AB - BACKGROUND: Six liner measurements of constant cranial cervical ganglion (CCG), three inconstant main, first, second middle cervical ganglia (MG, MG1, MG2), and interganglionic branch (IGB) were taken to determine normal foetal growth rates and patterns of cervical sympathetic trunk (CST) components in different gestational ages. MATERIALS AND METHODS: Forty sheep foetuses of both sexes aged from 60 to 140 days were divided into four groups and 80 sides of foetuses were examined under a stereomicroscope using a digital calliper. RESULTS: Following findings were obtained: 1) There was no significant difference for the values between sex and body side among all age groups, although sex and laterality differences in CST length and laterality differences in IGB total length and MG1 width were found regardless of age groups. 2) Correlations between dimensions of CST components and crown-rump length (CRL) were always positive during foetal period and decreased with increasing foetal age. 3) The highest growth rate in CST components in foetal sheep took place in the youngest age group because of rapid growth rates in lengths of IGB and CCG. CONCLUSIONS: Based on these detailed findings, comparative prenatal growth rates and patterns of animal organs and body, embryological and histological data as well as neurovertebral relationships among cervical parts of sympathetic trunk, spinal cord, and vertebral column were discussed and compared with previous studies. Although allometric growth of CST in relation to CRL was constant between foetal sheep and pig, there were specific characteristics in prenatal growth of CST components in foetal sheep which were different from those of foetal pig. It seems that only growth pattern in length of CST in sheep during foetal period follows the same growth pattern of CRL, body weight, and length of cervical parts of spinal cord and vertebral column. PMID- 29235088 TI - Middle cerebral artery anatomical variations and aneurysms: a retrospective study based on computed tomography angiography findings. AB - BACKGROUND: Anatomical variations of the middle cerebral artery (MCA) are an important clinical issue, due to high prevalence of intracranial aneurysms. Anatomical variations of vessels can lead to higher shear stress, which is thought to be the main factor leading to aneurysm formation and consequently to higher prevalence of aneurysms. The aim of this study was to evaluate anatomy of the MCA; to classify MCA aneurysms using computed tomography angiography and to correlate anatomical variations of MCA and circle of Willis with prevalence of MCA aneurysms. MATERIALS AND METHODS: Two hundred and fifty patients without MCA aneurysms and 100 patients with unruptured MCA aneurysms were qualified for the study, with exclusion of patients after MCA clipping. Four aspects of MCA anatomy were evaluated: division point, its relation to the genu, distance to M1 division and the genu and domination of post-division trunks. RESULTS: Middle cerebral artery bifurcation was found in 86.2% and trifurcation in 13.8% of the cases. 78.4% of MCAs divided before the genu, 19.2% in the genu and 2.4% after the genu. Upper branch domination was seen in 26%, lower branch in 25.4%, middle branch in 4% and no domination in 44.6% of the cases. In the study group 116 aneurysms were found. 86.2% of the aneurysms were located in M1 division point, 6.9% in M2 segment, 3.4% near lenticulostriatae arteries and 3.4% near early cortical branches. The only anatomical variation, which had significantly higher prevalence in patients with left MCA aneurysms, was domination of upper post division trunk of MCA. No other statistically significant differences in circle of Willis and MCA variations were found between patients with aneurysms and without them. CONCLUSIONS: The most common configuration of MCA is bifurcation before the genu with no dominating post-division trunk. Incidence of MCA aneurysms is not correlated with anatomical variations of MCA and the circle of Willis. PMID- 29235089 TI - Early life adversity induced third ventricular enlargement in young adult male patients suffered from major depressive disorder: a study of brain morphology. AB - BACKGROUND: Early life adversity (ELA) is not uncommon in major depressive disorder (MDD) patients. Childhood trauma has been reported more frequently in adult MDD patients relative to healthy controls. Recent researches have demonstrated that ELA could result in changes in brain morphology which might be an aetiological factor of MDD development. MATERIALS AND METHODS: We recruited 40 young adult patients suffered from MDD and made computed tomography scan. Subjects were divided in two groups: MDD patients with ELA experience (E+D) vs. MDD patients without ELA experience (E-D) according to Chinese version-Childhood Trauma Questionnaire (CTQ). 17-item Hamilton Depression (HAMD) Scale and Neuropsychiatric Inventory (NPI) were also examined. Student's t-test was used to compare the HAMD scores, NPI scores, CTQ subcomponents scores, third ventricular (TV) width and volume of patients from E+D and E-D groups. RESULTS: Findings demonstrated that ELA might result in TV enlargement; furthermore, there was a correlation between physical neglect and TV volume. CONCLUSIONS: These findings supported the hypothesis that ELA could induce changes of structure around the TV, which might undermine the aetiology of MDD. PMID- 29235090 TI - Facial soft tissue thicknesses in Bulgarian adults: relation to sex, body mass index and bilateral asymmetry. AB - BACKGROUND: The aim of the study is to measure the facial soft tissue thicknesses (STTs) in Bulgarians, to evaluate the relation of the STTs to the nutritional status, sex and bilateral asymmetry, and to examine the correlations between the separate STTs as well as between the STTs and body weight, height, and body mass index (BMI). In the present study, the facial STTs were measured on computed tomography scans of the head of Bulgarian adults. MATERIALS AND METHODS: The STTs were measured at 7 midline and 9 bilateral landmarks. The measurements were performed in the free software InVesalius in the axial and sagittal planes. The mean, standard deviation, minimum and maximum values, median and coefficient of variation were reported for the STT at each landmark according to the sex and BMI category. The BMI, sex and bilateral differences were assessed for statistical significance. Pearson correlation analysis was applied to assess the strength and direction of the relationships between the STTs and body height, weight and BMI, as well as between separate STTs. RESULTS AND CONCLUSIONS: The facial soft tissues in Bulgarian adults changed in accordance with the nutritional status of the individual and in both sexes all STTs augmented with the increasing BMI. For both normal and overweight BMI categories, males had more soft tissue at the majority of facial points than females, as the only exceptions were observed in the cheek zone, where STTs were thicker in females. Significant bilateral differences were observed in either sex and BMI category. Stronger correlations were established for the STTs in the jaw region and between the cheek and jaw soft tissues. Besides, the correlations between the homologous bilateral landmarks were among the strongest ones. PMID- 29235091 TI - Upward displacement of the odontoid process into the foramen magnum: a paleopathological case. AB - An upward displacement of the odontoid process into the foramen magnum was observed in the skeletal remains of a young male unearthed from a 14th-17th century cemetery in the north-eastern Italy. Examination of skull bone vestiges and CT-SCAN analysis of the axis exhibited a clear-cut contact zone between the odontoid process and the anterior border of the foramen magnum. In addition, the odontoid process appeared backward deviated. Findings suggest a possible diagnosis of basilar impression/invagination. This anomalous contact may cause compression of neural and vascular structures with a multifaceted series of clinical symptoms. We are unable to set our finding into a complete presumptive diagnostic outline because there is no chance to estimate either the magnitude of the whole CVJ defect but we believe that the present case contributes to the general knowledge of the craniovertebral region and to bone pathology in ancient times. PMID- 29235092 TI - Bumetanide blocks the acquisition of conditioned fear in adult rats. AB - BACKGROUND AND PURPOSE: Bumetanide has anxiolytic effects in rat models of conditioned fear. As a loop diuretic, bumetanide blocks cation-chloride co transport and this property may allow bumetanide to act as an anxiolytic by modulating GABAergic synaptic transmission in the CNS. Its potential for the treatment of anxiety disorders deserves further investigation. In this study, we evaluated the possible involvement of the basolateral nucleus of the amygdala in the anxiolytic effect of bumetanide. EXPERIMENTAL APPROACH: Brain slices were prepared from Wistar rats. extracellular recording, stereotaxic surgery, fear potentiated startle response, locomotor activity monitoring and Western blotting were applied in this study. KEY RESULTS: Systemic administration of bumetanide (15.2 mg.kg-1 , i.v.), 30 min prior to fear conditioning, significantly inhibited the acquisition of the fear-potentiated startle response. Phosphorylation of ERK in the basolateral nucleus of amygdala was reduced after bumetanide administration. In addition, suprafusion of bumetanide (5 or 10 MUM) attenuated long-term potentiation in the amygdala in a dose-dependent manner. Intra-amygdala infusion of bumetanide, 15 min prior to fear conditioning, also blocked the acquisition of the fear-potentiated startle response. Finally, the possible off target effect of bumetanide on conditioned fear was excluded by side-by-side control experiments. CONCLUSIONS AND IMPLICATIONS: These results suggest the basolateral nucleus of amygdala plays a critical role in the anxiolytic effects of bumetanide. PMID- 29235093 TI - Role of clinical and laboratory parameters for treatment choice in patients with inherited FVII deficiency undergoing surgical procedures: evidence from the STER registry. AB - Perioperative bleeding is a major concern in patients with factor VII (FVII) deficiency. Evaluating data of 95 FVII-deficient patients undergoing 110 surgical procedures (61 major, 49 minor), we assessed the impact of type of surgery, bleeding phenotype and FVII coagulant activity (FVII:C) levels on perioperative replacement therapy (RT). Compared to those with higher FVII:C levels, patients with <3% FVII:C received a higher number of RT doses (8 vs. 2, P = 0.003) for a longer RT duration (3 days vs. 1 day, P = 0.001), with no difference in RT dose. Similarly, patients with a history of major bleeds received a higher number of RT doses (8.5 vs. 2-3, P = 0.013) for a longer RT duration (2 days vs. 1 day, P = 0.005) as compared to those with a history of minor bleeds or to asymptomatic patients. No difference in RT was found among major and minor surgical procedures. Overall, multivariate analysis showed that history of major bleeding was the only independent predictor of number of RT doses (beta = 0.352, P = 0.001) and RT duration (beta = 0.405, P = 0.018). Overall, a ~20 MUg/kg perioperative RT was efficacious in 95.5% of cases. The infusion should be repeated ~8 times in high-risk subsets (i.e. patients with a history of major bleeding). PMID- 29235094 TI - Effects of corilagin on alleviating cholestasis via farnesoid X receptor associated pathways in vitro and in vivo. AB - BACKGROUND AND PURPOSE: The aim of this study was to investigate the ameliorative effects of corilagin on intrahepatic cholestasis induced by regulating liver farnesoid X receptor (FXR)-associated pathways in vitro and in vivo. EXPERIMENTAL APPROACH: Cellular and animal models were treated with different concentrations of corilagin. In the cellular experiments, FXR expression was up-regulated by either lentiviral transduction or GW4064 treatment and down-regulated by either siRNA technology or treatment with guggulsterones. Real-time PCR and Western blotting were employed to detect the mRNA and protein levels of FXR, SHP1, SHP2, UGT2B4, BSEP, CYP7A1, CYP7B1, NTCP, MRP2 and SULT2A1. Immunohistochemistry was used to examine the expression of BSEP in liver tissues. Rat liver function and pathological changes in hepatic tissue were assessed using biochemical tests and haematoxylin and eosin staining. RESULTS: Corilagin increased the mRNA and protein levels of FXR, SHP1, SHP2, UGT2B4, BSEP, MRP2 and SULT2A1, and decreased those of CYP7A1, CYP7B1 and NTCP. After either up- or down-regulating FXR using different methods, corilagin could still increase the mRNA and protein levels of FXR, SHP1, SHP2, UGT2B4, BSEP, MRP2 and SULT2A1 and decrease the protein levels of CYP7A1, CYP7B1 and NTCP, especially when administered at a high concentration. Corilagin also exerted a notable effect on the pathological manifestations of intrahepatic cholestasis, BSEP staining in liver tissues and liver function. CONCLUSIONS AND IMPLICATIONS: Corilagin exerts a protective effect in hepatocytes and can prevent the deleterious activities of intrahepatic cholestasis by stimulating FXR-associated pathways. PMID- 29235095 TI - Immune cells regulate VEGF signalling via release of VEGF and antagonistic soluble VEGF receptor-1. AB - Vascular endothelial growth factor (VEGF) is an important regulator of physiological and pathological angiogenesis. Besides malignant and stromal cells, local immune cells shape VEGF signalling in the tumour microenvironment. Aminobisphosphonates such as zoledronic acid (Zol) are drugs known to inhibit osteoclast activity and bone resorption, but also have immunomodulatory and anti tumour effects. These properties have been linked previously to the down regulation of VEGF and interference with tumour neo-angiogenesis. It was therefore surprising to find that treatment with Zol in combination with low-dose interleukin (IL)-2 increased serum VEGF levels in cancer patients. In this study we aimed to characterize the effect of Zol and IL-2 on VEGF signalling of blood derived immune cells in vitro. Upon stimulation with IL-2, T cells and natural killer (NK) cells increase production of VEGF consecutively to the release of proinflammatory interferon (IFN)-gamma, and Zol accelerates this response specifically in gammadelta T cells. VEGF can, in turn, be antagonized by soluble VEGF receptor (sVEGFR)-1, which is released depending on stimulatory conditions and the presence of monocytes. Additionally, malignant cells represented by leukaemia and lymphoma cell lines produce VEGF and some release sVEGFR-1 simultaneously. Our findings indicate a mechanism by which the VEGF and the sVEGFR-1 production by immune cells regulates local VEGF signalling. Therefore, immunotherapeutic interventions may enable both pro- as well as anti-tumour effects via immune cell-mediated alterations of VEGF homeostasis. PMID- 29235096 TI - Effects of skeletal element identity, delipidation and demineralization on the analysis of stable isotope ratios of C and N in fish bone. AB - Stable isotope ratios of C and N in the bone tissue of three different skeletal elements (angular, cleithrum and vertebra) of three fish species from different evolutionary lineages (Clupeiformes, Atheriniformes and Notothenioidei) were determined before (delta13 Cbulk and delta15 Nbulk ) and after demineralization and delipidation (delta13 Cdml and delta15 Ndml ). One of the species had cellular bone and the other two had acellular bone. Results revealed that delta15 N and delta13 C values from different skeletal elements were interchangeable in species with acellular bone, but caution was needed in species with cellular bone, as delta15 N values varied among skeletal elements. Furthermore, delta15 Nbulk values were significantly lower than delta15 Ndml values in the three species, thus suggesting that they are not comparable. This difference is probably because delta15 Nbulk refers to total bone protein and delta15 Ndml to collagen only. PMID- 29235097 TI - Activation of astrocytic PAR1 receptors in the rat nucleus of the solitary tract regulates breathing through modulation of presynaptic TRPV1. AB - KEY POINTS: In the rat nucleus of the solitary tract (NTS), activation of astrocytic proteinase-activated receptor 1 (PAR1) receptors leads to potentiation of neuronal synaptic activity by two mechanisms, one TRPV1-dependent and one TRPV1-independent. PAR1-dependent activation of presynaptic TRPV1 receptors facilitates glutamate release onto NTS neurons. The TRPV1-dependent mechanism appears to rely on astrocytic release of endovanilloid-like molecules. A subset of NTS neurons excited by PAR1 directly project to the rostral ventral respiratory group. The PAR1 initiated, TRPV1-dependent modulation of synaptic transmission in the NTS contributes to regulation of breathing. ABSTRACT: Many of the cellular and molecular mechanisms underlying astrocytic modulation of synaptic function remain poorly understood. Recent studies show that G-protein coupled receptor-mediated astrocyte activation modulates synaptic transmission in the nucleus of the solitary tract (NTS), a brainstem nucleus that regulates crucial physiological processes including cardiorespiratory activity. By using calcium imaging and patch clamp recordings in acute brain slices of wild-type and TRPV1-/- rats, we show that activation of proteinase-activated receptor 1 (PAR1) in NTS astrocytes potentiates presynaptic glutamate release on NTS neurons. This potentiation is mediated by both a TRPV1-dependent and a TRPV1-independent mechanism. The TRPV1-dependent mechanism appears to require release of endovanilloid-like molecules from astrocytes, which leads to subsequent potentiation of presynaptic glutamate release via activation of presynaptic TRPV1 channels. Activation of NTS astrocytic PAR1 receptors elicits cFOS expression in neurons that project to respiratory premotor neurons and inhibits respiratory activity in control, but not in TRPV1-/- rats. Thus, activation of astrocytic PAR1 receptor in the NTS leads to a TRPV1-dependent excitation of NTS neurons causing a potent modulation of respiratory motor output. PMID- 29235098 TI - Hepcidin and DNA promoter methylation in hepatocellular carcinoma. AB - BACKGROUND: The liver hormone hepcidin regulates iron homoeostasis that is often altered in hepatocellular carcinoma (HCC). Epigenetic phenomena control gene expression through a dynamic fashion; therefore, considering the plasticity of both iron homoeostasis and epigenetic mechanisms and their role in liver carcinogenesis, we investigated whether hepcidin gene (HAMP) expression is modulated by DNA methylation, thus affecting iron status in human HCC. MATERIALS AND METHODS: Thirty-two patients affected by nonviral HCC were enrolled, and their main clinical and biochemical characteristics were obtained. Neoplastic and homologous non-neoplastic liver tissues were analysed for HAMP promoter DNA methylation, for HAMP gene expression and for iron content. An in vitro demethylation assay with a human hepatocarcinoma cell line was performed to evaluate the role of DNA methylation on HAMP transcriptional repression. RESULTS: Gene expression and DNA methylation analyses on tissues showed that HAMP was transcriptionally repressed in HCC tissues consensually with a promoter hypermethylation. Furthermore, patients with HCC had low serum hepcidin concentrations, and HCC tissues had relative iron depletion as compared to non neoplastic liver tissues. The cell culture model showed the functional role of DNA hypermethylation by downregulating HAMP gene expression. Through a quantitative methylation analysis on HCC tissues, we then proved that methylation at definite CpG sites within consensus sequences for specific transcription factors is possibly the mechanism underlying HAMP repression. CONCLUSIONS: This study highlights a novel role for HAMP downregulation through DNA promoter hypermethylation and emphasises the significance of epigenetics in the regulation of iron metabolism in HCC. PMID- 29235099 TI - Variations from morning to afternoon of middle cerebral and umbilical artery blood flow, and fetal heart rate variability, and fetal characteristics in the normally developing fetus. AB - OBJECTIVE: To determine if there are changes in maternal uterine blood flow, fetal brain blood flow, fetal heart rate variability, and umbilical blood flow between morning (AM) and afternoon (PM) in healthy, uncomplicated pregnancies. STUDY DESIGN: In this prospective study, 68 uncomplicated singleton pregnancies (mean 35 + 0.7 weeks gestation) underwent a standard observational protocol at both 08:00 (AM) and 13:30 (PM) of the same day. This protocol included Doppler measurements of uterine, umbilical, and fetal middle cerebral artery (MCA) volume flow parameters (flow, HR, peak systolic velocity [PSV], PI, and RI) followed by computerized cardiotocography. Standard descriptive statistics, chi2 and t tests were used where appropriate. P < .05 was considered significant. RESULTS: A significant increase in MCA flow and MCA PSV was observed in the PM compared to the AM. This was accompanied by a fall in MCA resistance. Higher umbilical artery resistance indices were also observed in the PM compared to AM. In contrast, fetal heart rate characteristics, maternal uterine artery Doppler flow and resistance indices did not vary significantly between the AM and PM. CONCLUSION: In normal pregnancies, variations in fetal cerebral and umbilical blood flow parameters were observed between AM and PM independent of other fetal movements or baseline fetal heart rate. In contrast, uterine flow parameters remained stable across the day. These findings may have implications for the use of serial Doppler parameters used to guide clinical management in high-risk pregnancies. PMID- 29235101 TI - Aquatic food-web dynamics following incorporation of nutrients derived from Atlantic anadromous fishes. AB - Changes in the isotopic composition (delta13 C and delta15 N) in biofilm, macro invertebrates and resident salmonids were used to characterize temporal dynamics of marine derived nutrients (MDNs) incorporation between stream reaches with and without MDN inputs. Five Atlantic rivers were chosen to represent contrasting MDN subsidies: four rivers with considerable numbers of anadromous fishes; one river with little MDN input. Rainbow smelt Osmerus mordax, alewife Alosa pseudoharengus, sea lamprey Petromyzon marinus and Atlantic salmon Salmo salar, were the primary anadromous species for the sampled rivers. Regardless of the spatial resolution or the pathway of incorporation, annual nutrient pulses from spawning anadromous fishes had a positive effect on isotopic enrichment at all trophic levels (biofilm, 1.2-5.40/00; macro-invertebrates, 0.0-6.80/00; fish, 1.2 2.60/00). Community-wide niche space shifted toward the marine-nutrient source, but the total ecological niche space did not always increase with MDN inputs. The time-integrated marine-nutrient resource contribution to the diet of S. salar parr and brook trout Salvelinus fontinalis ranged between 16.3 and 36.0% during anadromous fish-spawning periods. The high degree of spatio-temporal heterogeneity in marine-nutrient subsidies from anadromous fishes lead to both direct and indirect pathways of MDN incorporation into stream food webs. This suggests that organisms at many trophic levels derive a substantial proportion of their energy from marine resources when present. The current trend of declining anadromous fish populations means fewer nutrient-rich marine subsidies being delivered to rivers, diminishing the ability to sustain elevated riverine productivity. PMID- 29235100 TI - Embryonic exposure to valproic acid affects the histaminergic system and the social behaviour of adult zebrafish (Danio rerio). AB - BACKGROUND AND PURPOSE: Histamine modulates several behaviours and physiological functions, and its deficiency is associated with neuropsychiatric disorders. Gestational intake of valproic acid (VPA) is linked to autism spectrum disorder (ASD), characterized by impaired sociability and stereotypies. VPA effects on the neurochemistry and functional morphology of the histaminergic system in ASD are unclear. Zebrafish are highly social, and given the similarities between zebrafish and human neurotransmitter systems, we have studied the effects of VPA on histamine in zebrafish. EXPERIMENTAL APPROACH: Histaminergic, dopaminergic and noradrenergic systems of larval and adult zebrafish exposed to VPA from the end of gastrulation until neural tube formation were studied using HPLC, quantitative PCR, immunocytochemistry and in situ hybridization. Sociability, dark-flash response and locomotion were also studied. KEY RESULTS: Zebrafish larvae exposed to VPA showed decreased locomotion and an abnormal dark-flash response. Additionally, a reduced number of histaminergic neurons, low histamine and altered mRNA expression of key genes of the monoaminergic systems were also detected. The reduced mRNA expression of genes of the studied systems persisted until adulthood. Furthermore, adult VPA-exposed animals presented lower brain levels of noradrenaline and 3,4-dihydroxyphenylacetic acid, along with impaired sociability. CONCLUSIONS AND IMPLICATIONS: VPA exposure in early development causes molecular and neurochemical alterations in zebrafish, which persist into adulthood and accompany impaired sociability. These findings will highlight the possible involvement of the histaminergic system in outcomes related to neuropsychiatric disorders. Furthermore, it supports zebrafish as a tool to investigate mechanisms underlying these disorders. PMID- 29235102 TI - Eukaryotic elongation factor 2 kinase upregulates the expression of proteins implicated in cell migration and cancer cell metastasis. AB - Eukaryotic elongation factor 2 kinase (eEF2K) negatively regulates the elongation phase of mRNA translation and hence protein synthesis. Increasing evidence indicates that eEF2K plays an important role in the survival and migration of cancer cells and in tumor progression. As demonstrated by two-dimensional wound healing and three-dimensional transwell invasion assays, knocking down or inhibiting eEF2K in cancer cells impairs migration and invasion of cancer cells. Conversely, exogenous expression of eEF2K or knocking down eEF2 (the substrate of eEF2K) accelerates wound healing and invasion. Importantly, using LC-HDMSE analysis, we identify 150 proteins whose expression is decreased and 73 proteins which are increased upon knocking down eEF2K in human lung carcinoma cells. Of interest, 34 downregulated proteins are integrins and other proteins implicated in cell migration, suggesting that inhibiting eEF2K may help prevent cancer cell mobility and metastasis. Interestingly, eEF2K promotes the association of integrin mRNAs with polysomes, providing a mechanism by which eEF2K may enhance their cellular levels. Consistent with this, genetic knock down or pharmacological inhibition of eEF2K reduces the protein expression levels of integrins. Notably, pharmacological or genetic inhibition of eEF2K almost completely blocked tumor growth and effectively prevented the spread of tumor cells in vivo. High levels of eEF2K expression were associated with invasive carcinoma and metastatic tumors. These data provide the evidence that eEF2K is a new potential therapeutic target for preventing tumor metastasis. PMID- 29235103 TI - Dietary patterns and risk of recurrence and progression in non-muscle-invasive bladder cancer. AB - The association of dietary factors with urinary bladder cancer prognosis has scarcely been investigated, and results of studies conducted to date are inconsistent. We investigated whether empirically derived dietary patterns are associated with risks of recurrence and progression in non-muscle-invasive bladder cancer (NMIBC) patients. Data from 595 newly diagnosed NMIBC patients from an ongoing prospective cohort study were used to derive dietary patterns using exploratory factor analysis. Factor scores were calculated and then categorized in sex-specific tertiles. Multivariable-adjusted proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals for the associations between tertiles of adherence to the dietary patterns and risks of recurrence and progression. We identified four dietary patterns: "fruits and vegetables," "Western," "low-fat," and "Tex-Mex." Patients in the highest tertile of adherence to the Western pattern experienced a 1.48 times higher risk of recurrence (95% CI 1.06-2.06) compared to patients in the lowest tertile. No statistically significant associations of a Western diet with risk of progression or of the other dietary patterns with risk of recurrence and progression were found. Overall, we found that adherence to a Western diet was associated with a higher risk of recurrence but further studies are needed to confirm our findings. PMID- 29235104 TI - Chaos and the (un)predictability of evolution in a changing environment. AB - Among the factors that may reduce the predictability of evolution, chaos, characterized by a strong dependence on initial conditions, has received much less attention than randomness due to genetic drift or environmental stochasticity. It was recently shown that chaos in phenotypic evolution arises commonly under frequency-dependent selection caused by competitive interactions mediated by many traits. This result has been used to argue that chaos should often make evolutionary dynamics unpredictable. However, populations also evolve largely in response to external changing environments, and such environmental forcing is likely to influence the outcome of evolution in systems prone to chaos. We investigate how a changing environment causing oscillations of an optimal phenotype interacts with the internal dynamics of an eco-evolutionary system that would be chaotic in a constant environment. We show that strong environmental forcing can improve the predictability of evolution by reducing the probability of chaos arising, and by dampening the magnitude of chaotic oscillations. In contrast, weak forcing can increase the probability of chaos, but it also causes evolutionary trajectories to track the environment more closely. Overall, our results indicate that, although chaos may occur in evolution, it does not necessarily undermine its predictability. PMID- 29235105 TI - Correction. PMID- 29235106 TI - WNT signalling: mechanisms and therapeutic opportunities. AB - : This themed section of the British Journal of Pharmacology stems from the EMBO Conference: Wnt Meeting 2016 held from the 14th to 16th September 2016 in Brno, Czech Republic. LINKED ARTICLES: This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc. PMID- 29235107 TI - Headache Characteristics and Clinical Features of Elderly Migraine Patients. AB - OBJECTIVE: To investigate the headache characteristics and clinical features of elderly migraine patients at a tertiary headache center. METHODS: We retrospectively reviewed 239 records of migraine patients, over the age of 64 at the first visit, who had migraine as defined by the International Classification of Headache Disorders 3rd edition (beta version) from 2006 to 2015 based on the Marseille registry at Timone Hospital. RESULTS: 13.8% (33/239) patients had migraine with aura only, 13.0% (31/239) had both diagnoses. Of the patients who presented with migraine with aura, 13.4% (32/239) presented with aura without headache. Unilateral pain location was reported by 58.6% (140/239) of patients and the throbbing type of pain was present in 50.2% (120/239) of our study group. Photo- and phonophobia were observed in 77.4% (185/239) and 79.5% (190/239) of patients. Seventy-nine out of 239 (30.1%) patients were found to have probable medication overuse. Within this group, 31.65% (25/79) overused triptan and 70.9% (56/79) overused combination analgesics. We found higher frequencies of migraine for patients whose age at onset of migraine was younger than 18 years, and low frequency migraine was reported more frequently in the later onset group (P = .0357). DISCUSSION: We assess the headache characteristics of elderly migraine patients who were seen at our tertiary headache center and report the high frequency of probable medication overuse headache in this study group. Finally, we suggest that age of onset is an important factor in the clinical profile of these patients. PMID- 29235108 TI - Initial results of population based cervical cancer screening program using HPV testing in one million Turkish women. AB - To evaluate the Turkey's nationwide HPV DNA screening program on the basis of first 1 million screened women. Women over age 30 were invited for population based screening via HPV DNA and conventional cytology. Samples were collected by family physicians and the evaluations and reports had been performed in the National Central HPV laboratories. The acceptance rate for HPV based cervical cancer screening after first invitation was nearly 36.5%. Since HPV DNA tests have been implemented, cervical cancer screening rates have shown 4-5-fold increase in primary level. Through the evaluation of all, HPV positivity was seen in 3.5%. The commonest HPV genotypes were 16, followed by 51, 31, 52 and 18. Among the 37.515 HPV positive cases, cytological abnormality rate was 19.1%. Among HPV positive cases, 16.962 cases had HPV 16 or 18 or other oncogenic HPV types with abnormal cytology (>ASC-US). These patients were referred to colposcopy. The colposcopy referral rate was 1.6%. Among these, final clinico pathological data of 3.499 patients were normal in 1.985 patients, CIN1 in 708, CIN2 in 285, CIN3 in 436 and cancer in 85 patients and only pap-smear program could miss 45.9% of >=CIN3 cases. The results of 1 million women including the evaluation of 13 HPV genotypes with respect to prevalence, geographic distribution and abnormal cytology results shows that HPV DNA can be used in primary level settings to have a high coverage rated screening program and is very effective compared to conventional pap-smear. PMID- 29235110 TI - Corrigendum. PMID- 29235109 TI - "Double-duty" conventional dendritic cells in the amphibian Xenopus as the prototype for antigen presentation to B cells. AB - Two populations of dendritic cells (DCs) are found in mammals, one derived from hematopoietic precursors (conventional/cDC), and another derived from mesenchymal precursors, the follicular DC (FDC); the latter is specialized for antigen presentation to B cells, and has only been definitively demonstrated in mammals. Both cDC and FDC are necessary for induction of germinal centers (GC) and GC dependent class switch recombination (CSR) and somatic hypermutation (SHM). We demonstrate that in Xenopus, an amphibian in which immunoglobulin CSR and SHM occur without GC formation, a single type of DC has properties of both cDC and FDC, including high expression of MHC class II for the former and display of native antigen at the cell surface for the latter. Our data confirm that the advent of FDC functionality preceded emergence of bona fide FDC, which was in turn crucial for the development of GC formation and efficient affinity maturation in mammals. PMID- 29235114 TI - Editorial: Allee effects in ecology and evolution. PMID- 29235113 TI - Postnatal effects of intrauterine treatment of the growth-restricted ovine fetus with intra-amniotic insulin-like growth factor-1. AB - KEY POINTS: Fetal growth restriction increases the risk of fetal and neonatal mortality and morbidity, and contributes to increased risk of chronic disease later in life. Intra-amniotic insulin-like growth factor-1 (IGF1) treatment of the growth-restricted ovine fetus improves fetal growth, but postnatal effects are unknown. Here we report that intra-amniotic IGF1 treatment of the growth restricted ovine fetus alters size at birth and mechanisms of early postnatal growth in a sex-specific manner. We also show that maternal plasma C-type natriuretic peptide (CNP) products are related to fetal oxygenation and size at birth, and hence may be useful for non-invasive monitoring of fetal growth restriction. Intrauterine IGF1 treatment in late gestation is a potentially clinically relevant intervention that may ameliorate the postnatal complications of fetal growth restriction. ABSTRACT: Placental insufficiency-mediated fetal growth restriction (FGR) is associated with altered postnatal growth and metabolism, which are, in turn, associated with increased risk of adult disease. Intra-amniotic insulin-like growth factor-1 (IGF1) treatment of ovine FGR increases growth rate in late gestation, but the effects on postnatal growth and metabolism are unknown. We investigated the effects of intra-amniotic IGF1 administration to ovine fetuses with uteroplacental embolisation-induced FGR on phenotypical and physiological characteristics in the 2 weeks after birth. We measured early postnatal growth velocity, amino-terminal propeptide of C-type natriuretic peptide (NTproCNP), body composition, tissue-specific mRNA expression, and milk intake in singleton lambs treated weekly with 360 MUg intra amniotic IGF1 (FGRI; n = 13 females, 19 males) or saline (FGRS; n = 18 females, 12 males) during gestation, and in controls (CON; n = 15 females, 22 males). There was a strong positive correlation between maternal NTproCNP and fetal oxygenation, and size at birth in FGR lambs. FGR lambs were ~20% lighter at birth and demonstrated accelerated postnatal growth velocity. IGF1 treatment did not alter perinatal mortality, partially abrogated the reduction in newborn size in females, but not males, and reduced accelerated growth in both sexes. IGF1 mediated upregulation of somatotrophic genes in males during the early postnatal period could suggest that treatment effects are associated with delayed axis maturation, whilst treatment outcomes in females may rely on the reprogramming of nutrient-dependent mechanisms of growth. These data suggest that the growth restricted fetus is responsive to intra-amniotic intervention with IGF1, and that sex-specific somatotrophic effects persist in the early postnatal period. PMID- 29235112 TI - Heat shock protein 70 and tumor-infiltrating NK cells as prognostic indicators for patients with squamous cell carcinoma of the head and neck after radiochemotherapy: A multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). AB - Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre-activated NK cells. In our retrospective study the expression of Hsp70 was determined in relation to tumor-infiltrating CD56+ NK cells in formalin-fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N = 145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin-based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3-4) showed significantly decreased overall survival (OS; p = 0.008), local progression-free survival (LPFS; p = 0.034) and distant metastases-free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0-2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16- (p = 0.001), p53- (p = 0.0003) and HPV16 DNA-negative (p = 0.001) tumors. The absence or low numbers of tumor-infiltrating CD56+ NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor-infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers. PMID- 29235115 TI - The mechanistic basis of demographic Allee effects: The search for mates. AB - In Focus: Berec, L., Kremer, A.M., Bernhauverova, V., & Drake, J.M. (2017). Density-dependent selection on mate-finding Allee effects. Journal of Animal Ecology, 87, 24-35. https://doi.org/10.1111/1365-2656.12662 In Focus: Shaw, A.K., Kokko, H., & Neubert, M.G. (2017). Details of mate finding drive dynamics of sex structured invasions. Journal of Animal Ecology, 87, 36-46. https://doi.org/10.1111/1365-2656.12658 Lowered population growth ability at low abundances is called the demographic Allee effect. The difficulty of finding mates in a sparse population is the best documented pathway through which a demographic Allee effect might arise. The articles in focus here aim to establish the mechanistic links between mate search component Allee effects and the emergent demographic Allee effect manifested at the level of population growth rate. The authors discover that limitations in the time invested in mate searching generates demographic Allee effects and that the population level adaptations of mate search time are likely to be dependent on the prevailing population density. Trade-offs between mate search, survival and reproductive outputs are key in understanding optimal mate search strategies and their fitness consequences. The present studies provide guidelines to identify populations at risk of experiencing demographic Allee effects at low abundances. PMID- 29235116 TI - Transparency and open processes in Journal of Animal Ecology. PMID- 29235117 TI - Greater pollination generalization is not associated with reduced constraints on corolla shape in Antillean plants. AB - Flowers show important structural variation as reproductive organs but the evolutionary forces underlying this diversity are still poorly understood. In animal-pollinated species, flower shape is strongly fashioned by selection imposed by pollinators, which is expected to vary according to guilds of effective pollinators. Using the Antillean subtribe Gesneriinae (Gesneriaceae), we tested the hypothesis that pollination specialists pollinated by one functional type of pollinator have maintained more similar corolla shapes through time due to more constant and stronger selection constraints compared to species with more generalist pollination strategies. Using geometric morphometrics and evolutionary models, we showed that the corolla of hummingbird specialists, bat specialists, and species with a mixed-pollination strategy (pollinated by hummingbirds and bats; thus a more generalist strategy) have distinct shapes and that these shapes have evolved under evolutionary constraints. However, we did not find support for greater disparity in corolla shape of more generalist species. This could be because the corolla shape of more generalist species in subtribe Gesneriinae, which has evolved multiple times, is finely adapted to be effectively pollinated by both bats and hummingbirds. These results suggest that ecological generalization is not necessarily associated with relaxed selection constraints. PMID- 29235118 TI - Erratum: "Experimental verification of EGSnrc Monte Carlo calculated depth doses within a realistic parallel magnetic field in a polystyrene phantom" [Med. Phys. Vol 44 (9), 4804 - 4815 (2017)]. PMID- 29235119 TI - V-set and Ig domain-containing 4 (VSIG4)-expressing hepatic F4/80+ cells regulate oral antigen-specific responses in mouse. AB - Oral tolerance can prevent unnecessary immune responses against dietary antigens. Members of the B7 protein family play critical roles in the positive and/or negative regulation of T cell responses to interactions between APCs and T cells. V-set and Ig domain-containing 4 (VSIG4), a B7-related co-signaling molecule, has been known to act as a co-inhibitory ligand and may be critical in establishing immune tolerance. Therefore, we investigated the regulation of VSIG4 signaling in a food allergy and experimental oral tolerance murine models. We analyzed the contributions of the two main sites involved in oral tolerance, the mesenteric lymph node (MLN) and the liver, in VSIG4-mediated oral tolerance induction. Through the comparative analysis of major APCs, dendritic cells (DCs) and macrophages, we found that Kupffer cells play a critical role in inducing regulatory T cells (Tregs) and establishing immune tolerance against oral antigens via VSIG4 signaling. Taken together, these results suggest the possibility of VSIG4 signaling-based regulation of orally administered antigens. PMID- 29235120 TI - Two-dimensional antiscatter grid: A novel scatter rejection device for Cone-beam computed tomography. AB - PURPOSE: Scattered radiation remains to be a major cause of image quality degradation in Flat Panel Detector (FPD)-based Cone-beam computed tomography (CBCT). We have been investigating a novel two-dimensional antiscatter grid (2D ASG) concept to reduce scatter intensity, and hence improve CBCT image quality. We present the first CBCT imaging experiments performed with the 2D-ASG prototype, and demonstrate its efficacy in improving CBCT image quality. METHODS: A 2D-ASG prototype with septa focused to x-ray source was additively manufactured from tungsten and mounted on a Varian TrueBeam CBCT system. CBCT projections of phantoms were acquired with an offset detector geometry using TrueBeam's "developer" mode. To minimize the effect of gantry flex, projections were gain corrected on angle-specific bases. CBCT images were reconstructed using a filtered backprojection algorithm and image quality improvement was quantified by measuring contrast-to-noise ratio (CNR) and CT number accuracy in images acquired with no antiscatter grid (NO-ASG), conventional one dimensional antiscatter grid (1D-ASG), and the 2D-ASG prototype. RESULTS: A significant improvement in contrast resolution was achieved using our 2D-ASG prototype compared to results of 1D-ASG and NO-ASG acquisitions. Compared to NO-ASG and 1D-ASG experiments, the CNR of material inserts improved by as much as 86% and 54% respectively. Using 2D ASG, CT number underestimation in water equivalent material section of the phantom was reduced by up to 325 HU when compared to NO-ASG and up to 179 HU when compared to 1D-ASG. CONCLUSION: We successfully performed the first CBCT imaging experiments with a 2D-ASG prototype. 2D-ASG provided significantly higher CT number accuracy, higher CNR, and diminished scatter-induced image artifacts in qualitative evaluations. We strongly believe that utilization of a 2D-ASG may potentially lead to better soft tissue visualization in CBCT and may enable novel clinical applications that require high CT number accuracy. PMID- 29235121 TI - A simple and rapid HPLC-UV method for the determination of retigabine in human plasma. AB - A simple and rapid high-performance liquid chromatographic method with ultraviolet detection was developed for the quantitative determination of retigabine, known also as ezogabine, in human plasma. The assay uses a simple solid-phase extraction for sample preparation and direct injection of the extract into the chromatograph. Flupirtine is used as an internal standard. Chromatographic separation is achieved on a C18 Chromolith column (Chromolith Performance, 100 * 4.6 mm i.d.), using as mobile phase water/acetonitrile/methanol (72:18:10 v/v/v) mixed with 0.1% of 85% phosphoric acid. Isocratic elution is conducted at a flow rate of 1.5 mL min-1 . The total duration of a chromatographic run is 7 min. Calibration curves are linear over the 25-2000 ng mL-1 concentration range, with a limit of quantitation of 25 ng mL 1 . Other performance characteristics include high precision (intra- and inter day coefficients of variation <=12.6%) and high accuracy (99.7%-108.7%). The method is suitable for the investigation of concentration-response relationships in patients receiving therapeutic doses of retigabine. PMID- 29235122 TI - Simultaneous determination of isochamaejasmin, neochamaejasmin A and aphnoretinin rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study of Stellera chamaejasme L. extract. AB - Isochamaejasmin, neochamaejasmin A and daphnoretin derived from Stellera chamaejasme L. are important because of their reported anticancer properties. In this study, a sensitive UPLC-MS/MS method for the determination of isochamaejasmin, neochamaejasmin A and daphnoretin in rat plasma was developed. The analyte and IS were separated on an Acquity UPLC HSS T3 column (100 * 2.1 mm, 1.8 MUm) using gradient elution with the mobile phase of aqueous solution (methanol-water, 1:99, v/v, containing 1 mm formic acid) and organic solution (methanol-water, 99:1, v/v, containing 1 mm formic acid) at a flow rate of 0.3 mL/min. Multiple reaction monitoring mode with negative electrospray ionization interface was carried out to detect the components. The method was validated in terms of specificity, linearity, accuracy, precision, stability, etc. Excellent linear behavior was observed over the certain concentration ranges with the correlation coefficient values >0.99. Intra- and inter-day precisions (RSD) were <6.7% and accuracy (RE) ranged from -7.0 to 12.0%. The validated method was successfully applied to investigate the pharmacokinetics of three chemical ingredients after oral administration of S. chamaejasme L. extract to rats. PMID- 29235123 TI - Proof of principle of helium-beam radiography using silicon pixel detectors for energy deposition measurement, identification, and tracking of single ions. AB - PURPOSE: Hadron therapy has the capability to provide a high dose conformation to tumor regions. However, it requires an accurate target positioning. Thus, the precise monitoring of the patient's anatomical positioning during treatment is desirable. For this purpose, hadron-beam radiography with protons (pRad) and ions (iRad) could be an attractive tool complementing the conventional imaging technologies. On the pathway to an envisaged clinical application, several challenges have to be addressed. Among them are achieving the desired spatial resolution in the presence of multiple Coulomb scattering (MCS), performing radiographs with a sufficient thickness resolution at clinically applicable dose levels, and the search for combinations of particularly suitable hadrons and detectors. These topics are investigated in this work for a detection system based on silicon pixel detectors. METHODS: A method of iRad based on energy deposition measurements in thin layers is introduced. It exploits a detection system consisting of three parallel silicon pixel detectors, which also enables particle tracking and identification. Helium ions, which exhibit less pronounced MCS than protons, were chosen as imaging radiation. A PMMA phantom with a mean water-equivalent thickness (WET) of 192 mm, containing maximal WET-variations of +/-6 mm, was imaged with a 173 MeV/u helium ion beam at the Heidelberg Ion-Beam Therapy Center. WET-differences in form of 2.3 mm * 2.3 mm steps were aimed to be visualized and resolved in images of the energy deposition measured behind the phantom. The detection system was placed downstream of the imaged object in order to detect single ions leaving it. The combination of the measured information on energy deposition, ion type, and the track behind the phantom was used for the image formation, employing a self-developed data-processing procedure. RESULTS: It was shown that helium-beam radiography is feasible with the reported detection system. The introduced data preprocessing purified the detector signal from detector artifacts and improved the image quality. Additionally, the rejection of hydrogen ions originating from nuclear interactions was shown to increase the contrast-to-noise ratio (CNR) by at least a factor of 2.5. This enabled the resolution of relative thickness differences of 1.2% at a dose level typical for diagnostic x-ray images. The spatial resolution was improved by taking into account the direction of single helium ions leaving the phantom. A spatial resolution (MTF10% ) of at least 1.15p mm-1 for the presented experimental set-up was achieved. CONCLUSION: A successful feasibility study of helium-beam radiography with the introduced detection system was conducted. The methodology of iRad was based on energy deposition measurements in thin silicon layers. The tracking of single ions and the method of the ion identification was shown to be important for helium-beam radiography in terms of spatial resolution and CNR. PMID- 29235124 TI - Silver nanoparticles increase connexin43-mediated gap junctional intercellular communication in HaCaT cells through activation of reactive oxygen species and mitogen-activated protein kinase signal pathway. AB - Silver nanoparticles (AgNPs) are widely used in health and consumer products that routinely contact skin. However, the biological effects and possible mechanisms of AgNPs on skin remain unclear. Gap junctional intercellular communication (GJIC) plays a critical role in multicellular organisms to maintain tissue homeostasis. The aim of this study is to examine if non-coated AgNPs affect GJIC in human keratinocytes (HaCaT cells), and to identify the possible molecular mechanisms responsible for the effects. GJIC, connexin (Cx)43 protein and mRNA expression, and the effect of siRNA-mediated knockdown of Cx43 on GJIC were assessed. HaCaT cells exposed to non-coated AgNPs at different doses after a 24 hour exposure. To explore further the underlying mechanism, reactive oxygen species and mitogen-activated protein kinase pathway were evaluated after 2, 6, 12 and 24 hours. Our results revealed that non-coated AgNP exposure at subcytotoxic doses increase GJIC partially via Cx43 upregulation. Reactive oxygen species and extracellular signal-regulated kinase and activation of c-Jun N terminal kinase were involved in the AgNP-induced upregulation of Cx43. This study provides new insight into the potential mechanism of AgNP biological activity. PMID- 29235125 TI - Nasal epithelial barrier disruption by particulate matter <=2.5 MUm via tight junction protein degradation. AB - Upper airway diseases including sinonasal disorders may be caused by exposure to fine particulate matter (<=2.5 MUm; PM2.5), as proven by epidemiological studies. PM2.5 is a complex entity whose chemical constituents and physicochemical properties are not confined to a single, independent "particle" but which in this study means a distinctive environmental "toxin." The mechanism whereby PM2.5 induces nasal epithelial barrier dysfunction leading to sinonasal pathology remains unknown. In the present study, human nasal epithelial cells were exposed to non-cytotoxic doses of PM2.5 to examine how PM2.5 affects the nasal epithelial barrier. Tight junction (TJ) integrity and function were assessed by transepithelial electric resistance and paracellular permeability. The expression levels of TJ proteins such as zona occludens-1, occludin and claudin-1 were assessed by immunofluorescence staining and western blot. PM2.5 exposure induced epithelial barrier dysfunction as reflected by increased paracellular permeability and decreased transepithelial electric resistance. TJ proteins zona occludens-1, occludin and claudin-1 were found to be downregulated. Pretreatment with N-acetyl-l-cysteine alleviated PM2.5-mediated reactive oxygen species generation in RPMI 2650 cells, further preventing barrier dysfunction and attenuating the degradation of TJ proteins. These results suggest that PM2.5 induces nasal epithelial barrier disruption via oxidative stress, and N-acetyl-l cysteine counteracts this PM2.5-mediated effect. Thus, nasal epithelial barrier disruption caused by PM2.5, which leads to sinonasal disease, may be prevented or treated through the inhibition of reactive oxygen species. PMID- 29235126 TI - Relationships of serum 25-hydroxyvitamin D, ionized calcium and parathyroid hormone after obesity surgery. AB - OBJECTIVE: The high prevalence of secondary hyperparathyroidism (SHPT) after obesity surgery is a concern for long-term bone health. Limited knowledge exists about optimal vitamin D and suppression of parathyroid hormone (PTH) after these procedures. The aim of this study was to investigate the prevalence of SHPT and its relation to vitamin D status. DESIGN: A cross-sectional study at Oslo University Hospital, Norway. PATIENTS: A total of 502 consecutive patients, age 22-64 years, attending 2-year follow-up after Roux-en-Y gastric bypass. MEASUREMENTS: A serum intact PTH >7.0 pmol/L in the absence of elevated serum ionized calcium (iCa) was considered as SHPT. Vitamin D status was defined by serum concentrations of 25-hydroxyvitamin D (S-25(OH)D). RESULTS: Altogether, 171 patients (34%) had SHPT. The prevalence of SHPT varied across the range of S 25(OH)D (P < 0.001), being highest (71%) with S-25(OH)D < 25 nmol/L. Compared with S-25(OH)D < 50 nmol/L, the prevalence of SHPT was lower with S-25(OH)D >= 50 nmol/L (29.0%; RR = 0.64 (95%-CI:0.50-0.81)) and S-25(OH)D >= 75 nmol/L (27.7%; RR = 0.61 (95%-CI:0.44-0.84)). S-25(OH)D >= 100 nmol/L was associated with the lowest PTH and the lowest prevalence of SHPT (16.0%; RR = 0.35 (95%-CI:0.14-0.88) compared with S-25(OH)D < 50 nmol/L) and the most normal calcium distribution. These associations were most pronounced with iCa in the lower range. A synergistic association was found for S-25(OH)D and iCa on SHPT. CONCLUSIONS: Vitamin D deficient patients had the highest prevalence of SHPT 2 years after gastric bypass. PTH and the prevalence of SHPT were notably lower with S-25(OH)D >= 100 nmol/L, compared with lower target levels. PMID- 29235127 TI - Joint modeling of multiple ordinal adherence outcomes via generalized estimating equations with flexible correlation structure. AB - Adherence to medication is critical in achieving effectiveness of many treatments. Factors that influence adherence behavior have been the subject of many clinical studies. Analyzing adherence is complicated because it is often measured on multiple drugs over a period, resulting in a multivariate longitudinal outcome. This paper is motivated by the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C study, where adherence is measured on two drugs as a bivariate ordinal longitudinal outcome. To analyze such outcome, we propose a joint model assuming the multivariate ordinal outcome arose from a partitioned latent multivariate normal process. We also provide a flexible multilevel association structure covering both between and within outcome correlation. In simulation studies, we show that the joint model provides unbiased estimators for regression parameters, which are more efficient than those obtained through fitting separate model for each outcome. The joint method also yields unbiased estimators for the correlation parameters when the correlation structure is correctly specified. Finally, we analyze the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C adherence data and discuss the findings. PMID- 29235128 TI - 'Love builds brains': representations of attachment and children's brain development in parenting education material. AB - A focus on early brain development has come to dominate expert child rearing advice over the past two decades. Recent scholars have noted a reinvigoration of the concept of attachment in this advice and changes in the ways that attachment is framed and understood. The extent to which the concept of attachment is drawn on, the way it is framed, and the consequences for mothers, families and parent child relationships is examined through a discursive analysis of a current Canadian parental education campaign. Findings support the argument that attachment is receiving a great deal of attention in brain-based parenting education programmes as children's emotional development becomes increasingly prioritized. Attachment is presented as needing to be actively and continually built through expert-guided empathetic and responsive parental behaviour, and is framed as crucial for the development of brain pathways that promote emotional strength and self-regulation in children. Attachment-building is also presented as requiring highly intensive parenting that falls overwhelmingly to mothers. The parent-child relationship that is envisioned is one that is instrumental, lacking in affect and conducive to the creation of ideal self-regulating neo-liberal citizens. PMID- 29235129 TI - Association of gene polymorphisms of pattern-recognition receptor signaling pathway with the risk and severity of hand, foot, and mouth disease caused by enterovirus 71 in Chinese Han population. AB - Hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) presents with a wide variety of clinical manifestations. Host immune response is a factor that influences disease susceptibility and severity. We investigated the potential association of gene polymorphisms in the pattern recognition receptor (PRR) pathway with the risk and severity of EV71 infection. A total of 180 EV71 HFMD cases (108 severe case; 72 mild cases) were enrolled. A group of 201 sex- and age-matched children was included as a control. All subjects were genotyped for the most common single-nucleotide polymorphisms (SNPs) in the PRR and the PRR signaling pathway using the SNPscan multiple SNP typing method. Binary logistic regression analysis revealed statistically significant differences in polymorphism of RIG-1 between patients and controls (rs3739674 G vs C: OR = 1.502, 95%CI: 1.120-2.014; rs9695310 G vs C: OR = 1.782, 95%CI: 1.312-2.419). Polymorphisms of RIG-1 rs3739674 (G vs C: OR = 2.047, 95%CI: 1.307-3.205) and TLR3 rs5743305 (A vs T: OR = 0.346, 95%CI: 0.212-0.566) were found to be associated with disease severity. The results indicated that RIG-1 (rs3739674 and rs9695310) polymorphisms are associated with an increased risk of EV71-induced HFMD in Chinese children, whereas RIG-1 rs3739674 and TLR3 rs5743305 polymorphisms are associated with disease severity. These findings support an important role of innate immune mechanism in EV71 infection. PMID- 29235130 TI - Melt Electrospun Bilayered Scaffolds for Tissue Integration of a Suture-Less Inflow Cannula for Rotary Blood Pumps. AB - Implantation of left ventricular assist devices typically requires cardiopulmonary bypass support, which is associated with postoperative complications. A novel suture-less inflow cannula, which can be implanted without bypass, uses mild myocardial compression to seal the interface, however, this may lead to necrosis of the myocardium. To circumvent this issue, a bilayered scaffold has been developed to promote tissue growth at the interface between cannula and myocardium. The bilayered scaffold consists of a silicone base layer, which mimics the seal, and a melt electrospun polycaprolactone scaffold to serve as a tissue integration layer. Biocompatibility of the bilayered scaffolds was assessed by analyzing cell viability, morphology, and metabolic activity of human foreskin fibroblasts cultured on the scaffolds for up to 14 days. There was no evidence of cytotoxicity and the cells adhered readily to the bilayered scaffolds, revealing a cell morphology characteristic of fibroblasts, in contrast to the low cell adhesion observed on flat silicone sheets. The rate of cell proliferation on the bilayered scaffolds rose over the 14-day period and was significantly greater than cells seeded on the silicone sheets. This study suggests that melt electrospun bilayered scaffolds have the potential to support tissue integration of a suture-less inflow cannula for cardiovascular applications. Furthermore, the method of fabrication described here and the application of bilayered scaffolds could also have potential uses in a diverse range of biomedical applications. PMID- 29235131 TI - Measured and Monte Carlo simulated surface dose reduction for superficial X-rays incident on tissue with underlying air or bone. AB - PURPOSE: Measurement of surface dose reduction effects for superficial x-rays incident on tissue with underlying air or bone and comparison with Monte Carlo simulations of such effects. Further to investigate the correlation between surface dose reduction and changes in Compton backscatter spectra with tissue bone separation. METHODS: An Advanced Markus chamber with entrance window facing downstream on the surface of a solid water phantom was used to investigate changes in surface dose with an underlying air or bone interface located at various depths below the surface. Chamber readings were obtained for interface depths ranging from 1 to 100 mm using the 50 kV, 100 kV and 150 kV beams of an Xstrahl 150 x-ray unit, with field diameters (phi) = 2.5 cm and 5 cm. For each beam quality and field size the dose correction factor, DCF(t), namely the ratio of measured dose (t) to dose (t = 100 mm) was determined. Monte Carlo simulations of DCF(t) for air and bone interfaces in tissue are used to validate corresponding measured data. For a given beam and field size, the difference between simulated spectra with an air or bone interface at t = 3 mm was used to determine the Compton backscatter from bone at the surface. RESULTS: For air, DCF(t < 40 mm) is less than unity and for a given t DCF(t) decreases as beam energy increases from 50 kV to 150 kV. Conversely for bone DCF(t < 40 mm) increases for a given t with increasing beam energy. In particular for t = 1 mm, phi = 5 cm, DCF for air(bone) are 0.90(0.92) and 0.86(0.96) for 50 kV and 150 kV, respectively. For the same tube potentials corresponding factors, phi = 2.5 cm, for air(bone) are 0.94(0.96) and 0.92(0.99). Calculated DCF(t) based on Monte Carlo simulations are consistent with experimental observations to within 2%. Monte Carlo simulations of x-ray spectra demonstrate the presence of Compton backscatter from underlying bone in tissue. With bone at 3 mm depth calculated backscatter spectra at the tissue surface suggest that surface dose is influenced by the proximity of bone and that this effect depends on beam quality. CONCLUSIONS: This work demonstrates the feasibility of using an Advanced Markus chamber with entrance window facing downstream to investigate surface dose reduction with underlying air or bone in tissue. As the field size decreases and beam quality increases surface dose with underlying bone tends to full backscatter values even though tissue thicknesses are below those normally associated with full backscatter. Conversely with underlying bone close to the surface dose will increasingly fall below full backscatter values as the beam energy is reduced and field size is increased. PMID- 29235132 TI - Mitochondrial donation, patient engagement and narratives of hope. AB - This article develops the sociology of hope and patient engagement by exploring how patients' perceptions and actions are shaped by narratives of hope surrounding the clinical introduction of novel reproductive techniques. In 2015, after extensive public debates, the UK became the first country to legalise a mitochondrial donation technique aimed at preventing the transmission of inherited disorders. The article draws on the accounts of twenty-two women of reproductive age who are at risk of having a child with mitochondrial disease and would be the potential target of the technique. We explore the extent to which our participants engaged with the public debates and how they accounted for their support of mitochondrial donation. We show that while the majority of our participants were in favour of legalisation, they did not necessarily wish to use the technique themselves. We found that hope was multi-faceted, involving hope for self, hope for family and hope for society. We conclude by considering the implications of hope narratives for patients and families and the important but potentially limited role that patients can play as advocates for technology. PMID- 29235133 TI - Operating (on) the self: transforming agency through obesity surgery and treatment. AB - In this article, I describe the processes through which patients diagnosed with 'morbid obesity' become active subjects through undergoing obesity surgery and an empowerment lifestyle programme in a Dutch obesity clinic. Following work in actor-network theory and material semiotics that complicates the distinction between active and passive subjects, I trace how agency is configured and re distributed throughout the treatment trajectory. In the clinic's elaborate care assemblage - consisting of dieticians, exercise coaches and psychologists - the person is not only actively involved in his/her own change, the subject of intervention is the self as 'actor': his/her material constitution, inclinations and feelings. The empirical examples reveal that a self becomes capable of self care only after a costly and laborious conditioning through which patients are completely transformed. In this work, the changed body, implying a new, potentially disruptive reality that patients must learn to cope with, is pivotal to what the patient can do and become. Rather than striving to be disembodied, self-contained liberal subjects that make sensible decisions for their body, patients become empowered through submission and attachment and by arranging support. PMID- 29235134 TI - Sex hormone-binding globulin is associated with androgen deficiency features independently of total testosterone. AB - OBJECTIVE: It is recognized that total testosterone (TT) does not sufficiently describe androgen status when sex hormone-binding globulin (SHBG) is altered. However, in humans, evidence supporting the existence of a hypogonadism due to low T bioactivity is scanty. The aim of the study was to assess whether changes in SHBG levels, independently of TT, are associated with subjective and objective androgen-dependent parameters. DESIGN: Cross-sectional observation. PATIENTS: Two thousand six hundred and twenty-two men (aged 51.1 +/- 13.5 years) attending a Sexual Medicine and Andrology Outpatient Clinic for sexual dysfunctions. MEASUREMENTS: All patients underwent a standardized diagnostic protocol before starting any treatment. Clinical and biochemical parameters have been collected. Higher ANDROTEST score has been used as a comprehensive marker of more severe hypogonadal symptoms. Prostate-specific antigen (PSA) and haematocrit have been used as objective surrogate markers of T bioactivity. RESULTS: After adjusting for TT and lifestyle, SHBG showed a significant positive association with ANDROTEST score (B = 0.79 [0.61; 0.96], P < .0001). Conversely, higher SHBG, independently of TT, was negatively related to PSA (B = -0.86 [-0.83; -0.89]; P < .0001) and haematocrit (B = -0.64 [-0.88; -0.40]; P < .0001), after adjustment for the aforementioned confounders along with age and body mass index. Furthermore, a relationship between SHBG and lipids or blood pressure was found, with lower SHBG levels associated with a worse metabolic profile, independently of TT. CONCLUSIONS: Higher SHBG, independently of TT, is associated with either subjective or objective androgen deficiency features. This indicates that besides a hypogonadism due to an impaired T production, a hypogonadism due to a lower biological activity of T does exist. PMID- 29235135 TI - The determination of polycyclic aromatic hydrocarbons in human urine by high resolution gas chromatography-mass spectrometry. AB - Polycyclic aromatic hydrocarbons (PAHs), organic compounds formed by at least two condensed aromatic rings, are ubiquitous environmental pollutants that are produced by incomplete combustion of organic materials. PAHs have been classified as carcinogenIC to humans by the International Agency for Research on Cancer, because they can bind to DNA, causing mutations. Therefore, the levels of PAHs in human urine can be used as an indicator for potential carcinogenesis and cell mutation. An analytical method was developed for the accurate measurement of PAHs in urine using high-resolution gas chromatography-mass spectrometry. Urine samples were extracted by an Oasis HLB extraction cartridge after enzymatic hydrolysis with a beta-glucuronidase/arylsulfatase cocktail. The 18 PAHs were separated using an Agilent DB-5 MS capillary column (30 m * 0.25 mm, 0.25 MUm) and monitored by time-of-flight mass spectrometry. Under the optimized method, the linearity of calibration curves was >0.994. The limits of detection at a signal-to-noise ratio of 3 were 10-100 ng/L. The coefficients of variation were in the range of 0.4-9.0%. The present method was highly accurate for simultaneous determination of 18 PAHs in human urine and could be applied to monitoring and biomedical investigations to check exposure of PAHs. PMID- 29235136 TI - Reluctance to express emotion explains relation between cognitive distortions and social competence in anxious children. AB - Guided by social information processing and affective social competence models, the focal objective of this research was to examine the relations among anxious children's cognitive distortions, social skill competence, and reluctance to express emotion. In addition, we explored whether children's attention control played any meaningful role. Using a sample of 111 anxious children (Mage = 9.63, SD = 0.73; 75.7% girls; 56% Hispanic/Latino), we found that cognitive distortions were negatively related to social competence. In addition, tests of moderated mediation showed that the negative association between cognitive distortions and social skill competence was indirect via reluctance to express emotion, but this only was the case for anxious children with high attention control and for distortions in the academic domain. The findings of this study may set the stage for new ways to conceptualize the role of higher attention control among anxious youth. Statement of contribution What is already known on this subject? Cognitive errors are prevalent in anxious youth Anxious children show socio-emotion deficits What does this study add? Cognitive errors are related to socio-emotion deficits in anxious youth Relations depend on attention control. PMID- 29235137 TI - Development of HPLC with fluorescent detection using NBD-F for the quantification of colistin sulfate in rat plasma and its pharmacokinetic applications. AB - Colistin sulfate, composed of a mixture of colistin A sulfate (CLA) and colistin B sulfate (CLB), is available for treating life-threatening infections caused by multidrug-resistant Gram-negative bacteria. In this study, the CLA and CLB were quantified separately. Colistin sulfate was extracted from rat plasma with a solid-phase extraction C18 cartridge and reacted with 4-fluoro-7-nitro-2,1,3 benzoxadiazole (NBD-F), and the fluorescent derivatives were subjected to reversed-phase high-performance liquid chromatography analysis and used to investigate the pharmacokinetics of CLA and CLB in rat plasma. The recovery rates of CLA and CLB were 41.2 +/- 4.4 and 45.5 +/- 3.1%, respectively. The recovery rate calculated from the total area of CLA and CLB was 43.9 +/- 3.6%. When 2 mm NBD-F and 10 mm boric acid buffer (pH 9.5) were added to colistin sulfate, the highest recovery rate was obtained. The best heating time was 5 min at 60 degrees C. The lower limits of quantification for CLA, CLB and the total area of CLA and CLB were 0.05, 0.05 and 0.1 MUg/mL; the coefficients of variations were 13.5, 14.5 and 14.1%, respectively. This method was found to have acceptable linearity, precision and accuracy, and has been successfully applied to a pharmacokinetic study in rat plasma. PMID- 29235138 TI - Biomedical Chromatography 2018. PMID- 29235139 TI - Association of serum testosterone levels and testicular volume in adult patients. AB - A retrospective observational study was undertaken to gain new insight into the relationship between total testicular volume and levels of serum testosterone, luteinising hormone, follicle-stimulating hormone, prolactin and clinical variables. A total of 312 men with sexual dysfunction or infertility were divided into groups A and B (156 each) on the basis of basal plasma testosterone <=5 nmol/L of >=12 nmol/L respectively. Group A was subclassified in A1 (primary hypogonadism) and A2 (secondary hypogonadism). There were significant differences in total testicular volume between group A (15.33 +/- 11.94 ml) and group B (36.74 +/- 6.9; p < .001) and also between subgroup A1 (11.07 +/- 8.49 ml) and subgroup A2 (23.62 +/- 13.04 ml; p < .001). Only 13.5% of patients in group B had a total testicular volume <30 ml. Differences in all studied parameters were found between group A and group B. There were no variations when comparing age, body mass index and testosterone in groups A1 and A2 . The use of total testicular volume and body mass index together for predicting testosterone levels yields a sensitivity and specificity of 85.3% and 86.5% respectively. Logistic regression analysis, univariate and multivariate models, using the measurement of total testicular volume resulted in a high capacity to predict testosterone levels. PMID- 29235140 TI - The Changing Role of Sound-Symbolism for Small Versus Large Vocabularies. AB - Natural language contains many examples of sound-symbolism, where the form of the word carries information about its meaning. Such systematicity is more prevalent in the words children acquire first, but arbitrariness dominates during later vocabulary development. Furthermore, systematicity appears to promote learning category distinctions, which may become more important as the vocabulary grows. In this study, we tested the relative costs and benefits of sound-symbolism for word learning as vocabulary size varies. Participants learned form-meaning mappings for words which were either congruent or incongruent with regard to sound-symbolic relations. For the smaller vocabulary, sound-symbolism facilitated learning individual words, whereas for larger vocabularies sound-symbolism supported learning category distinctions. The changing properties of form-meaning mappings according to vocabulary size may reflect the different ways in which language is learned at different stages of development. PMID- 29235141 TI - Pseudomesotheliomatous carcinoma of the pleura: an autopsy case of metastasis from a G-CSF-producing anaplastic carcinoma of the pancreas. AB - Pseudomesotheliomatous carcinoma is a malignant tumor that extends along the pleura mimicking malignant mesothelioma. An 81-year-old male patient presented to our hospital with epigastralgia, and abdominal computed tomography (CT) showed a 36-mm tumor in the pancreatic tail. The laboratory data revealed a high leukocyte count (>44 000/MUL). Chest CT showed left pleural thickening with pleural effusion. The cancer showed a poor response to chemotherapy, and the patient died of respiratory failure at 5 months after the onset of disease. Autopsy showed solid tumor with hemorrhage, measuring 6 cm in diameter, in the pancreatic tail, with wide invasion to the stomach, left adrenal gland, spleen, and diaphragm. The left pleura, which was circumferentially thickened by the involved tumor, macroscopically resembled pleural mesothelioma. Histologically, the primary pancreatic tumor was diagnosed as anaplastic carcinoma, due to the absence of glandular structures or other features that would indicate a definite direction of differentiation. The primary lesion and carcinoma involving the left pleura were all positive for G-CSF. We recently experienced an autopsy case of G-CSF producing anaplastic carcinoma with pseudomesotheliomatous spread. PMID- 29235142 TI - Assessment of data-assisted prediction by inclusion of crosslinking/mass spectrometry and small angle X-ray scattering data in the 12th Critical Assessment of protein Structure Prediction experiment. AB - Integrative modeling approaches attempt to combine experiments and computation to derive structure-function relationships in complex molecular assemblies. Despite their importance for the advancement of life sciences, benchmarking of existing methodologies is rather poor. The 12th round of the Critical Assessment of protein Structure Prediction (CASP) offered a unique niche to benchmark data and methods from two kinds of experiments often used in integrative modeling, namely residue-residue contacts obtained through crosslinking/mass-spectrometry (CLMS), and small-angle X-ray scattering (SAXS) experiments. Upon assessment of the models submitted by predictors for 3 targets assisted by CLMS data and 11 targets by SAXS data, we observed no significant improvement when compared to the best data-blind models, although most predictors did improve relative to their own data-blind predictions. Only for target Tx892 of the CLMS-assisted category and for target Ts947 of the SAXS-assisted category, there was a net, albeit mild, improvement relative to the best data-blind predictions. We discuss here possible reasons for the relatively poor success, which point rather to inconsistencies in the data sources rather than in the methods, to which a few groups were less sensitive. We conclude with suggestions that could improve the potential of data integration in future CASP rounds in terms of experimental data production, methods development, data management and prediction assessment. PMID- 29235143 TI - Allostatic load but not medical burden predicts memory performance in late-life bipolar disorder. AB - OBJECTIVE: Older patients with bipolar disorder (BD) present with variable degrees of cognitive impairment. Over time, stress, mood episodes, and comorbidities increase the body's allostatic load. We assessed the extent to which allostatic load vs more traditional measures of medical burden account for the heterogeneity in cognition in this population. METHODS: Thirty-five older euthymic patients with BD and 30 age-equated, gender-equated, and education equated comparison participants were administered a comprehensive assessment including a neuropsychological battery, and 9 physiological measures to determine allostatic load. The relationship among allostatic load, medical burden, and cognition was assessed. RESULTS: Compared with the mentally healthy comparators, patients were impaired globally, and in 4 cognitive domains-information processing speed / executive functioning, delayed memory, language, and visuomotor ability, and presented with greater medical burden but not a different allostatic load. Allostatic load, but not medical burden, was associated with delayed memory performance both in a correlational analysis and in a multivariate regression analysis. CONCLUSION: Euthymic older patients with BD are impaired on several cognitive domains and have high medical burden. Their memory performance is more strongly associated with allostatic load than with traditional measures of medical burden. These findings need to be replicated and extended longitudinally. PMID- 29235145 TI - Macrolide and fluoroquinolone resistance in Mycoplasma genitalium in two Swedish counties, 2011-2015. AB - Mycoplasma genitalium, causing non-gonococcal non-chlamydial urethritis and associated with cervicitis, has developed antimicrobial resistance (AMR) to both the macrolide azithromycin (first-line treatment) and the fluoroquinolone moxifloxacin (second-line treatment). Our aim was to estimate the prevalence of resistance, based on genetic AMR determinants, to these antimicrobials in the M. genitalium population in two Swedish counties, Orebro and Halland, 2011-2015. In total, 672 M. genitalium positive urogenital samples were sequenced for 23S rRNA and parC gene mutations associated with macrolide and fluoroquinolone resistance, respectively. Of the samples, 18.6% and 3.2% in Orebro and 15.2% and 2.7% in Halland contained mutations associated with macrolide and fluoroquinolone resistance, respectively. The predominating resistance-associated mutations in the 23S rRNA gene was A2059G (n = 39) in Orebro and A2058G (n = 13) and A2059G (n = 13) in Halland. The most prevalent possible resistance-associated ParC amino acid alterations were S83I (n = 4) in Orebro and S83N (n = 2) in Halland. Resistance-associated mutations to both macrolides and fluoroquinolones were found in 0.7% of samples. Our findings emphasize the need for routine AMR testing, at a minimum for macrolide resistance, of all M. genitalium-positive samples and regular national and international surveillance of AMR in M. genitalium, to ensure effective patient management and rational antimicrobial use. PMID- 29235144 TI - Histological assessment of the liver explant in transplanted hepatitis C virus patients achieving sustained virological response with direct-acting antiviral agents. AB - AIMS: The use of direct-acting anti-viral agents (DAAs) has resulted in extremely high sustained virological response (SVR) rates in patients being treated while on liver transplantation (LT) waiting lists. The aim of this study was to evaluate the histological findings of hepatitis C virus (HCV) patients who achieved SVR after receiving DAA treatment [SVR(+)] prior to LT, and compare them with HCV patients who had not achieved SVR [SVR(-)]. METHODS AND RESULTS: Fifty eight adult HCV patients who underwent LT at our institution from 2014 to 2016 were included in the study. Two pathologists, blinded to SVR status, simultaneously evaluated the histological sections. Assessment included the Histology Activity Index (HAI/modified Knodell score), fibrosis stage (Ishak score), and Laennec cirrhosis stage. The study group comprised 25 SVR(+) patients (56% male; mean age, 63.8 years), and the control group comprised 33 SVR(-) patients (69% male; mean age, 61.7 years). There was no significant difference in HAI between the groups (P = 0.414). Patients who achieved SVR also did not show less portal inflammation (P = 0.787), interface hepatitis (P = 0.999), confluent necrosis (P = 0.627) or spotty necrosis (P = 0.093) than the control group. There was a trend towards a higher degree of inflammation in patients who achieved SVR in <24 weeks (P = 0.07). The degree of focal lytic necrosis/apoptosis and portal inflammation was more prominent in SVR(+) patients with shorter SVR-LT intervals. CONCLUSIONS: Our study is the first to report persistent inflammation in HCV patients who received DAAs prior to LT. This supports the notion that inflammation is immunologically driven and that inflammation persists despite the absence of virus. PMID- 29235146 TI - Development of METAL-ACTIVE SITE and ZINCCLUSTER tool to predict active site pockets. AB - The advent of whole genome sequencing leads to increasing number of proteins with known amino acid sequences. Despite many efforts, the number of proteins with resolved three dimensional structures is still low. One of the challenging tasks the structural biologists face is the prediction of the interaction of metal ion with any protein for which the structure is unknown. Based on the information available in Protein Data Bank, a site (METALACTIVE INTERACTION) has been generated which displays information for significant high preferential and low preferential combination of endogenous ligands for 49 metal ions. User can also gain information about the residues present in the first and second coordination sphere as it plays a major role in maintaining the structure and function of metalloproteins in biological system. In this paper, a novel computational tool (ZINCCLUSTER) is developed, which can predict the zinc metal binding sites of proteins even if only the primary sequence is known. The purpose of this tool is to predict the active site cluster of an uncharacterized protein based on its primary sequence or a 3D structure. The tool can predict amino acids interacting with a metal or vice versa. This tool is based on the occurrence of significant triplets and it is tested to have higher prediction accuracy when compared to that of other available techniques. PMID- 29235147 TI - Transapical mitral valve-in-valve ring implantation with the Edwards Sapien 3 prosthesis. AB - We present the case of a high-risk patient with symptomatic severe mitral regurgitation following a surgical annuloplasty ring. An inverted aortic Edwards Sapien 3 bioprosthesis (Edwards Lifesciences, Irvine, CA) was successfully implanted through a transapical approach inside the previously implanted annuloplasty ring. PMID- 29235148 TI - Structural analysis of protein tyrosine phosphatase 1B reveals potentially druggable allosteric binding sites. AB - Catalytic proteins such as human protein tyrosine phosphatase 1B (PTP1B), with conserved and highly polar active sites, warrant the discovery of druggable nonactive sites, such as allosteric sites, and potentially, therapeutic small molecules that can bind to these sites. Catalyzing the dephosphorylation of numerous substrates, PTP1B is physiologically important in intracellular signal transduction pathways in diverse cell types and tissues. Aberrant PTP1B is associated with obesity, diabetes, cancers, and neurodegenerative disorders. Utilizing clustering methods (based on root mean square deviation, principal component analysis, nonnegative matrix factorization, and independent component analysis), we have examined multiple PTP1B structures. Using the resulting representative structures in different conformational states, we determined consensus clustroids and used them to identify both known and novel binding sites, some of which are potentially allosteric. We report several lead compounds that could potentially bind to the novel PTP1B binding sites and can be further optimized. Considering the possibility for drug repurposing, we discovered homologous binding sites in other proteins, with ligands that could potentially bind to the novel PTP1B binding sites. PMID- 29235149 TI - International Young Investigator Award 2016. PMID- 29235150 TI - Efficacy and tolerability of antidepressants in Parkinson's disease: A systematic review and network meta-analysis. AB - OBJECTIVE: To systematically review and analyze the efficacy and tolerability of different antidepressant pharmacologic treatments for depressive symptoms in Parkinson's disease (PD) METHODS: We searched PubMed, EMBASE, Cochrane database (CENTRAL), clinicaltrials.gov, and bibliographies for randomized controlled trials investigating the efficacy of antidepressant medications versus a non treatment, placebo, or active treatment groups for depressive symptoms in PD. Twenty of 3191 retrieved studies (1893 patients) were included, but not all could be meta-analyzed. We used a random-effects model meta-analysis to compare depression scores between an active drug and placebo or control group then used a network meta-analysis to compare the effectiveness of different antidepressant classes. The primary outcome was the efficacy of different classes of antidepressant medications in PD patients with depressive symptoms, measured by standardized mean difference (SMD) in depression score from baseline compared with control. RESULTS: Pairwise meta-analysis suggested that type B-selective monoamine oxidase inhibitors (SMD = -1.28, CI = -1.68, -0.88), selective serotonin reuptake inhibitors (SMD = -0.49, CI = -0.93, -0.05), and tricyclics (SMD = -0.83, CI = -1.53, -0.13) are effective antidepressants in PD. Network meta-analysis showed that monoamine oxidase inhibitors had the largest effect on depression in PD (SMD (vs selective serotonin reuptake inhibitors) = -0.78, CI = 1.55, -0.01), but these might not be considered traditional antidepressants given their type B selectivity. CONCLUSIONS: Although limited by few data, this review suggests that multiple antidepressant classes are potentially efficacious in the treatment of depression in PD, but that further comparative efficacy and tolerability research is needed. PMID- 29235151 TI - One-stage ascending-to-abdominal aortic bypass with concomitant aortic valve procedures for aortic coarctation combined with aortic valve pathology in adult patients. AB - OBJECTIVE: This study aims to evaluate the results of one-stage ascending-to abdominal aortic bypass and aortic valve replacement for concomitant aortic coarctation combined with aortic valve pathology. METHODS: From June 2009 to March 2017, 28 consecutive adult patients (23 males and five females) with aortic coarctation combined with aortic valve pathology underwent one-stage ascending-to abdominal aorta bypass and aortic valve replacement or a Bentall procedure. Patients were followed for a mean of 45.5 +/- 26.5 months (range 3-96 months). RESULT: All patients successfully underwent the one-stage procedure. No early deaths were recorded. The mean aortic cross-clamp and cardiopulmonary bypass times were 71 +/- 23 and 113 +/- 37 mins, respectively. Re-exploration for bleeding was performed on one patient (3.6%). The average post-operative hospital stay was 15.9 +/- 4.9 days and the average operation time was 5.2 h. No paraplegia or stroke was observed. The blood pressure gradient of the upper and lower extremities significantly decreased (P < 0.001). Systolic blood pressure decreased from 158 +/- 36 mmHg pre-operatively to 121 +/- 18 mmHg post operatively. No deaths or significant gradients between the upper and lower extremities occurred during follow-up. No death and complications of bypass grafts occurred during follow-up. CONCLUSION: Ascending-to-abdominal aortic bypass and concomitant aortic valve procedures are a suitable therapeutic option for severe aortic coarctation combined with aortic valve pathology in adult patients. PMID- 29235152 TI - Radial arteriovenous fistula following coronary angiography. PMID- 29235153 TI - Acral melanoma foot lesions. Part 2: clinical presentation, diagnosis, and management. AB - Acral melanoma (AM) is a rare subtype of cutaneous malignant melanoma found on acral skin, primarily on the soles of the feet. Although rare, it is the most common subtype of melanoma found in patients of African or Asian ethnicity and has a poor prognosis, often because of the more advanced stage of presentation at diagnosis. In the second of this two-part series, we review the clinical presentation, histopathology, diagnosis and management of AM. Clinically, AM presents as a variegated lesion with blue-black pigment and irregular borders on acral skin. A parallel-ridge pattern is a very specific dermoscopic finding for AM. The differential diagnoses of AM include acral naevus, pyoderma gangrenosum, pyogenic granuloma, verrucous carcinoma and peripheral neuropathy-induced foot ulcers. If there is a clinical suspicion of AM, an excisional biopsy should be taken. Once diagnosis is confirmed by histology, surgical excision is the standard treatment. Overall, dermoscopy and histopathology are key tools in the diagnosis of AM. A greater emphasis on melanoma screening and awareness is essential in minority populations to improve survival outcomes in AM. PMID- 29235154 TI - Left atrial myxoma induced acute ST-segment elevation myocardial infarction. PMID- 29235155 TI - Effects of force fields on the conformational and dynamic properties of amyloid beta(1-40) dimer explored by replica exchange molecular dynamics simulations. AB - The conformational space and structural ensembles of amyloid beta (Abeta) peptides and their oligomers in solution are inherently disordered and proven to be challenging to study. Optimum force field selection for molecular dynamics (MD) simulations and the biophysical relevance of results are still unknown. We compared the conformational space of the Abeta(1-40) dimers by 300 ns replica exchange MD simulations at physiological temperature (310 K) using: the AMBER ff99sb-ILDN, AMBER-ff99sb*-ILDN, AMBER-ff99sb-NMR, and CHARMM22* force fields. Statistical comparisons of simulation results to experimental data and previously published simulations utilizing the CHARMM22* and CHARMM36 force fields were performed. All force fields yield sampled ensembles of conformations with collision cross sectional areas for the dimer that are statistically significantly larger than experimental results. All force fields, with the exception of AMBER-ff99sb-ILDN (8.8 +/- 6.4%) and CHARMM36 (2.7 +/- 4.2%), tend to overestimate the alpha-helical content compared to experimental CD (5.3 +/- 5.2%). Using the AMBER-ff99sb-NMR force field resulted in the greatest degree of variance (41.3 +/- 12.9%). Except for the AMBER-ff99sb-NMR force field, the others tended to under estimate the expected amount of beta-sheet and over estimate the amount of turn/bend/random coil conformations. All force fields, with the exception AMBER-ff99sb-NMR, reproduce a theoretically expected beta sheet-turn-beta-sheet conformational motif, however, only the CHARMM22* and CHARMM36 force fields yield results compatible with collapse of the central and C terminal hydrophobic cores from residues 17-21 and 30-36. Although analyses of essential subspace sampling showed only minor variations between force fields, secondary structures of lowest energy conformers are different. PMID- 29235156 TI - IFN-gamma against the 38-kDa antigen of Mycobacterium tuberculosis discriminates pulmonary tuberculosis from infection and infection from exposure: evidence from a study of human population in a high endemic setting. AB - Mycobacterium tuberculosis (Mtb) 38-kDa antigen is an immunogenic lipoprotein that induces strong T-cell responses in experimental animals. However, there is limited information on the role of this antigen in human population. In this article, we present the dynamics of pro-inflammatory (IFN-gamma and TNF-alpha) and anti-inflammatory cytokine (IL-10) against the 38 kDa in cohorts of pulmonary TB (PTB) patients, household contacts (HHCs), and community controls (CCs) in a high endemic setting. Whole blood assay was used to determine the levels of cytokines in 149 patients, 149 HHCs, and 68 CCs at baseline, 6 months, and 12 months. At baseline, the level of IFN-gamma was significantly (p < 0.0001) higher in CCs and HHCs than in untreated patients. CCs had significantly (p < 0.05) higher level of IFN-gamma than HHCs. There was no significant difference between treated and untreated patients, and there was no significant change in HHCs over 12 months. At baseline, the levels of IL-10 and TNF-alpha were significantly (p < 0.0001) higher in patients than in HHCs and CCs. No significant change was observed between treated patients and untreated patients and HHCs over time. The study shows that IFN-gamma against the 38 kDa discriminates clinical TB from infection and infection from exposure, suggesting its potential for immune protection and diagnosis. PMID- 29235157 TI - Dietary intake in people consuming a low-carbohydrate diet in the UK Biobank. AB - BACKGROUND: Low-carbohydrate diets are becoming increasingly popular, although their dietary quality outside of clinical studies is unknown. A previous study analysed the dietary intake in people consuming a reduced-carbohydrate diet (<40% calories). However, it is not clear what foods people consume when carbohydrate is reduced to below 26% of total calories. METHODS: In the present cross sectional study, the dietary and nutrient intake collected via up to five consecutive 24-h dietary recalls and a food frequency questionnaire of 444 individuals (aged 46-79 years) consuming <26% of calories from carbohydrate (LCHO) was compared with that of 131 897 individuals consuming >=45% calories from carbohydrate (NCHO) using the UK Biobank Dataset. Absolute cut-offs to define the low-carbohydrate group (<130 g day-1 ; n = 1953 versus >=225 g day-1 , n = 113 036) were also used. RESULTS: Both NCHO (>45% calories and >=225 g) groups consumed significantly more high-sugar, high-fat snacks [median 6.0, interquartile range (IQR) = 2.0-11.0 and median 6.0, IQR = 3.0-11.8, respectively) compared to the LCHO (<26% calories and <130 g) groups (median 0, IQR = 0-2.8 and median 1, IQR = 0-3.8, respectively) (P < 0.0001). Both LCHO groups reported consuming significantly more red meat, oily fish, nuts and seeds but fewer fruits, vegetables and pulses compared to the NCHO groups. In general, the consumption of oily fish, nuts, seeds and pulses was low across the whole cohort and differences in intake between the LCHO and NCHO groups were small. After adjusting for socio-economic status, most differences remained. CONCLUSIONS: Carbohydrate restriction is associated with both beneficial and potentially deleterious dietary changes compared to a normal carbohydrate intake. PMID- 29235158 TI - Single-staged implant placement using bone ring technique with and without membrane placement: An experimental study in the Beagle dog. AB - AIM: To evaluate the impact of a collagen membrane on bone remodeling and osseointegration of implants placed simultaneously with a bone ring technique. MATERIAL AND METHODS: Standardized, vertical alveolar bone defects in the mandibles of six dogs were created. Tapered dental implants designed for two stage subcrestal placement were inserted simultaneously with a bone ring technique. On one side of the mandible, the augmented sites were covered with a collagenous membrane. Implants with (M Group) and without membranes (NM Group) were left for an osseointegration period of 3 and 6 months, respectively. Block biopsies of the implants with surrounding bone were harvested and analyzed histologically. RESULTS: Implant exposure was a common finding (2/3) concomitantly with loss of healing caps. It appeared to be related to advanced bone loss around the implants. Exposure of implants was more frequent in M Group, however, without significant differences when compared to NM Group. The total bone area within the region of the bone ring was greater in the NM Group compared to the M Group. Moreover, in the region of the pristine bone of the M Group, the total bone was greater than at the corresponding NM Group sites at both observation periods. A nonparametric analysis of variance (ANOVA) revealed no significant effects of membrane placement or healing period on the total area of the bone. The total bone-to-implant contact (BIC) for the two groups was similar at each observation time point. However, BIC increased significantly at 6-month compared with 3-month observation period (p = .0088) in both groups. CONCLUSIONS: In vertical bone augmentation applying the bone ring technique, the disruption of soft tissue was a frequent complication. Membrane placement yielded no significant advantage on the osseointegration (BIC) of implants or bone characteristics. PMID- 29235159 TI - The effect of green tea ointment on episiotomy pain and wound healing in primiparous women: A randomized, double-blind, placebo-controlled clinical trial. AB - The delayed healing of episiotomy wound and its associated pain is a major problem in obstetrics. Because green tea has analgesic and wound-healing properties, the present study was conducted to determine the effect of green tea ointment on episiotomy pain and wound-healing. The green tea extract was also standardized by measuring its Phenolic and flavonoid compounds, antioxidant activity, and one of its active components, that is, Epigallocatechin gallate. The present clinical trial was conducted on 99 primiparous women visiting Afzalipour Hospital in Kerman in 2015. The subjects were randomly divided into 3 groups, including a green tea ointment group, a placebo ointment group, and a routine care group. The 2 ointment groups smeared 2 cm of the green tea or placebo ointments onto their sutured area twice daily for a total of 10 days. The severity of pain was assessed in the subjects using the visual pain scale and wound-healing using the Redness, Edema, Ecchymosis, Discharge, Approximation (REEDA) scale before the intervention and on the 5th and 10th days after delivery. To standardize the extract, Epigallocatechin gallate was measured by high-performance liquid chromatography (HPLC). Phenolic and flavonoid compounds, as well as antioxidant activity of the extract were also determined by spectrometry methods. Before the intervention, no significant differences were observed between the 3 groups in terms of their personal and obstetric details (p > .05), the severity of pain (p = .118), and the REEDA score (p = .212). On the 5th and 10th days after delivery, the severity of pain was significantly lower in the green tea group than in the other 2 groups (p < .0001). The mean REEDA score on the 5th and 10th days showed a better and faster healing in the green tea group compared to the other 2 groups (p < .0001). Total content of phenolic and flavonoids contents of green tea were 74.2 mg/g Gallic acid equivalent and 16.3 mg/g Rutin equivalent, respectively, and its antioxidant capacity was 46% of b carotene. Green tea ointment appears to be effective in relieving episiotomy pain and improving wound-healing in this study. Further studies are recommended to be conducted on the effectiveness and safety of the different doses of green tea ointment. PMID- 29235160 TI - Photoprotection by sunscreen depends on time spent on application. AB - BACKGROUND: To be effective, sunscreens must be applied in a sufficient quantity and reapplication is recommended. No previous study has investigated whether time spent on sunscreen application is important for the achieved photoprotection. AIM: To determine whether time spent on sunscreen application is related to the amount of sunscreen used during a first and second application. METHODS: Thirty one volunteers wearing swimwear applied sunscreen twice in a laboratory environment. Time spent and the amount of sunscreen used during each application was measured. Subjects' body surface area accessible for sunscreen application (BSA) was estimated from their height, weight and swimwear worn. The average applied quantity of sunscreen after each application was calculated. RESULTS: Subjects spent on average 4 minutes and 15 seconds on the first application and approximately 85% of that time on the second application. There was a linear relationship between time spent on application and amount of sunscreen used during both the first and the second application (P < .0001). Participants applied 2.21 grams of sunscreen per minute during both applications. After the first application, subjects had applied a mean quantity of sunscreen of 0.71 mg/cm2 on the BSA, and after the second application, a mean total quantity of 1.27 mg/cm2 had been applied. CONCLUSION: We found that participants applied a constant amount of sunscreen per minute during both a first and a second application. Measurement of time spent on application of sunscreen on different body sites may be useful in investigating the distribution of sunscreen in real life settings. PMID- 29235161 TI - Management of actinic keratosis at specific body sites in patients at high risk of carcinoma lesions: expert consensus from the AKTeamTM of expert clinicians. AB - Actinic keratoses (AK) arise on sun-exposed regions of the skin. If left untreated, AK may progress to invasive squamous cell carcinoma (SCC), although the rate of progression is low. A practical treatment algorithm for the treatment of AK in standard situations has been published by the AKTeamTM expert panel. However, management of particular situations of AK with increasing/higher carcinoma risk or AK progressing into carcinomas with increased aggressiveness due to their anatomical location (risky areas), or in patients with an increased risk of SCC requires further discussion. These include AK on the dorsal hands, forearms, legs, periorbital region, eyelids, ears, or lips, and organ transplant recipients, patients undergoing treatment with carcinogenic agents and patients with chronic lymphocytic leukaemia. The main objective was to propose therapeutic strategies for the treatment of AK located in risky areas and in patients with more invasive/aggressive lesions and a higher risk of progression to SCC. A systematic review of the literature was initially performed, and results were discussed by the experts to propose best management practices in specific situations. Finally, adapted management strategies for AK occurring in risky areas and in high-risk patients are presented, taking into account the experts' own clinical experience and current guidelines. In most of these 'at-risk' situations, patients can be treated according to the AKTeamTM treatment algorithm. Difficult-to-treat lesions should be treated more aggressively due to their higher risk of transformation. For patients with skin that is highly susceptible to actinic damage, monitoring and sun protection strategies are mandatory, and patients should undergo more regular follow-up. Further assessment of newer therapies in clinical trials is necessary to determine optimal treatment conditions. This expert consensus provides guidance for the management of AK in risky body sites and in patients with an increasing/higher risk for SCCs. PMID- 29235162 TI - Iron-chelating effect of silymarin in patients with beta-thalassemia major: A crossover randomised control trial. AB - This study aimed to determine the potential iron-chelating effects of silymarin in patients with beta-thalassemia major receiving standard iron-chelation therapy. We evaluated whether addition of silymarin to standard iron-chelation therapy could improve iron burden markers and liver and cardiac function in these patients, via a placebo-controlled, crossover clinical study. Silymarin (140 mg) or placebo were administered thrice daily to all patients (n = 82) for 12 weeks, and after a 2-week washout period, patients were crossed over to the other groups. Silymarin efficacy was assessed by measuring serum iron level, ferritin level, total iron-binding capacity and liver and cardiac function on magnetic resonance imaging. Silymarin treatment resulted in a negative change in the serum iron and ferritin levels and a positive change in the total iron-binding capacity levels (treatment effect, p < .001, p = .06, and p = .05, respectively). Silymarin treatment led to positive changes in cardiac and liver function in both treatment sequences of study; however, this was not statistically significant. There was a negative change in liver iron concentration in both treatment sequences (treatment effect, p = .02). In conclusion, combined iron-chelation and silymarin therapy was effective for improving the iron-burden status in patients with beta-thalassemia major. PMID- 29235163 TI - Ultraviolet B eye irradiation aggravates atopic dermatitis via adrenocorticotropic hormone and NLRP3 inflammasome in NC/Nga mice. AB - BACKGROUND: Ultraviolet (UV) B irradiation has been shown to improve atopic dermatitis (AD). However, the relationship between UVB eye irradiation and AD is not known. This issue was addressed using a mouse model of AD. METHODS: The eyes of NC/Nga mice were irradiated with UVB at a dose of 1.0 kJ/m2 using a 20SE sunlamp for the duration of the experimental period. RESULTS: AD symptoms deteriorated upon UVB eye irradiation. The levels of adrenocorticotropic hormone (ACTH) in the plasma and nucleotide-binding domain and leucine-rich-containing family, pyrin domain-containing (NLRP)3 and neutrophil markers in the skin were increased in UVB-irradiated mice. Treatment with inhibitors of ACTH, caspase-1, interleukin-18, and thymic stromal lymphopoietin (TSLP) partly reversed the effects of irradiation, with the greatest improvement observed upon ACTH inhibition. The NLRP3 inflammasome was implicated in the effects of UVB irradiation. CONCLUSIONS: UVB eye irradiation causes AD symptom deterioration, which is likely mediated by ACTH and the activity of the inflammasome. PMID- 29235164 TI - Boosting Bifunctional Oxygen Electrocatalysis with 3D Graphene Aerogel-Supported Ni/MnO Particles. AB - Electrocatalysts for oxygen-reduction and oxygen-evolution reactions (ORR and OER) are crucial for metal-air batteries, where more costly Pt- and Ir/Ru-based materials are the benchmark catalysts for ORR and OER, respectively. Herein, for the first time Ni is combined with MnO species, and a 3D porous graphene aerogel supported Ni/MnO (Ni-MnO/rGO aerogel) bifunctional catalyst is prepared via a facile and scalable hydrogel route. The synthetic strategy depends on the formation of a graphene oxide (GO) crosslinked poly(vinyl alcohol) hydrogel that allows for the efficient capture of highly active Ni/MnO particles after pyrolysis. Remarkably, the resulting Ni-MnO/rGO aerogels exhibit superior bifunctional catalytic performance for both ORR and OER in an alkaline electrolyte, which can compete with the previously reported bifunctional electrocatalysts. The MnO mainly contributes to the high activity for the ORR, while metallic Ni is responsible for the excellent OER activity. Moreover, such bifunctional catalyst can endow the homemade Zn-air battery with better power density, specific capacity, and cycling stability than mixed Pt/C + RuO2 catalysts, demonstrating its potential feasibility in practical application of rechargeable metal-air batteries. PMID- 29235165 TI - Melaleuca alternifolia and its application against dental plaque and periodontal diseases: A systematic review. AB - This is a systematic review of clinical and laboratory studies evaluating the effect of Melaleuca alternifolia on periodontopathogens, dental plaque, gingivitis, periodontitis, and inflammatory responses. The PubMed, Cochrane, Web of science, Bireme, Lilacs, Prospero, Open Grey, and Clinical Trials databases were searched to identify potentially eligible studies through October 2016. Of 1,654 potentially eligible studies, 25 were included in the systematic review. Their methodology was evaluated through the Cochrane Handbook for clinical studies and the GRADE system for in vivo/in vitro studies. Although clinical studies must be interpreted with caution due to methodological limitations, laboratory studies have found promising results. In vitro evidences showed that M. alternifolia has bactericidal and bacteriostatic effects against the most prevalent periodontopathogens. Clinical studies found comparable effects to chlorhexidine 0.12% in reducing gingival inflammation, although the antiplaque effect was lower. M. alternifolia also showed antioxidant properties, which are beneficial to the host, allied to the reduction on immune-inflammatory responses to pathogens. This systematic review suggests that the M. alternifolia has potential anti-inflammatory and antimicrobial properties, which can be easily applied to the periodontal tissues. However, further clinical trials are needed to elucidate the clinical relevance of its application. PMID- 29235166 TI - The South African universal preschool year: a case study of policy development and implementation. AB - BACKGROUND: South Africa is the first sub-Saharan African country to legislate, fund and implement free preschool education. Human rights and restitution were at the forefront of the political struggle for democracy in South Africa. Levelling the playing fields by improving the school readiness of children disadvantaged by the racist policies of Apartheid is essential to the transformation of South African society. METHODS: A review of published and unpublished documents on Grade R was undertaken, and access and enrolment data come from the National Department of Basic Education's Education Management Information System (EMIS). RESULTS: A decade after initiation in 2005, 79% of 5-year-olds was enrolled in a preschool class; the vast majority of them in free public schools. Grade R is near universal and on track to becoming compulsory. It is part of the Foundation Phase (Grades 1-3) of schooling, falling under the Department of Basic Education, but also part of a broader national strategy to improve early child development under the direction of an Inter-Departmental Steering. Evaluations demonstrate wide access to Grade R and high uptake, especially in the poorest areas. However, the quality of Grade R provision in these areas is not up to standard because of low levels of funding; inadequate training, supervision, remuneration and retention of Grade R teachers; insufficient learner support materials; and inadequate monitoring and quality assurance. CONCLUSIONS: Lack of quality, amongst other factors, contributes to a widening school performance gap between children from more and less privileged areas. Quality of Grade R as well as earlier learning and subsequent years of schooling must be improved to achieve South Africa's aim to reduce poverty and inequality through, amongst others, parent and family involvement, learning in the home and preschool preparation. PMID- 29235167 TI - Care for Child Development: an intervention in support of responsive caregiving and early child development. AB - BACKGROUND: An estimated 43% of children younger than 5 years of age are at elevated risk of failing to achieve their human potential. In response, the World Health Organization and UNICEF developed Care for Child Development (CCD), based on the science of child development, to improve sensitive and responsive caregiving and promote the psychosocial development of young children. METHODS: In 2015, the World Health Organization and UNICEF identified sites where CCD has been implemented and sustained. The sites were surveyed, and responses were followed up by phone interviews. Project reports provided information on additional sites, and a review of published studies was undertaken to document the effectiveness of CCD for improving child and family outcomes, as well as its feasibility for implementation in resource-constrained communities. RESULTS: The inventory found that CCD had been integrated into existing services in diverse sectors in 19 countries and 23 sites, including child survival, health, nutrition, infant day care, early education, family and child protection and services for children with disabilities. Published and unpublished evaluations have found that CCD interventions can improve child development, growth and health, as well as responsive caregiving. It has also been reported to reduce maternal depression, a known risk factor for poor pregnancy outcomes and poor child health, growth and development. Although CCD has expanded beyond initial implementation sites, only three countries reported having national policy support for integrating CCD into health or other services. CONCLUSIONS: Strong interest exists in many countries to move beyond child survival to protect and support optimal child development. The United Nations Sustainable Development Goals depend on children realizing their potential to build healthy and emotionally, cognitively and socially competent future generations. More studies are needed to guide the integration of the CCD approach under different conditions. Nevertheless, the time is right to provide for the scale-up of CCD as part of services for families and children. PMID- 29235168 TI - Scaling up early childhood development programmes in low and middle-income countries. PMID- 29235169 TI - Chile Crece Contigo: Implementation, results, and scaling-up lessons. AB - BACKGROUND: Chile Crece Contigo (ChCC) is defined as a comprehensive, intersectoral, and multicomponent policy that aims to help all children reach their full potential for development, regardless of their socio-economic status. METHODS: This case study was developed on the basis of grey literature review and key informants' interviews. RESULTS: ChCC behaves as a complex adaptive system that combines universal and targeted benefits for the more vulnerable starting since gestation and until the children are 4 years old. Three key ministries are involved in ChCC management: health, education, and social development. Studies show adequate programme implementation and positive effects of ChCC on child development. In addition, it was found that the more families use ChCC benefits and the longer the subsystem has been operating in the commune, the greater the positive effects. CONCLUSIONS: Strong political support based on principles of equity and child rights combined with strong evidence and funding commitment from government has been central to emergence, scaling up, and sustainability of ChCC. Further sustainability of ChCC will rely on firmly establishing a well-trained and compensated cadre of early child development professionals and paraprofessionals as well as an improved management and evaluation decentralized system. PMID- 29235170 TI - Scaling up Integrated Early Childhood Development programs: lessons from four countries. AB - BACKGROUND: There is still limited knowledge regarding the translation of early child development (ECD) knowledge into effective policies and large-scale programmes. A variety of frameworks that outline the key steps in scaling up exist, but we argue that taking a complex adaptive systems (CAS) approach assists in understanding the complex, dynamic processes that result in programmes being taken to scale. OBJECTIVES: The objective of this study is to examine the process of scaling up four major country-level ECD programmes through the application of a CAS framework. METHODS: Nine key informants with a deep knowledge of how each ECD programme was established and brought to scale were interviewed via Skype or phone by using open-ended interviews. The interviews were tape recorded and then transcribed verbatim for subsequent coding by using CAS domains. The coding and integration of the results to identify unique and common CAS scaling up features across the case studies involved an iterative process of reaching consensus. RESULTS: The scaling up of all four programmes behaved as a CAS including as follows: (i) positive feedback loops (five themes) and negative feedback loops (two themes); (ii) scale-free networks (two themes); (iii) phase transitions (four themes); (iv) path dependence (two themes); and (v) emergent behaviour (six themes). Five additional themes were identified for sustainability, which was repeatedly mentioned as an important consideration when deciding how to scale up programmes. CONCLUSIONS: CAS analysis is likely to improve our understanding of how effective ECD programmes become scaled up. Prospective CAS implementation research is needed to continue advancing the knowledge in the field. PMID- 29235171 TI - India's integrated child development services scheme: challenges for scaling up. AB - BACKGROUND: India had around 158 million children under the age of 6 and about 26 million births in 2015. In the same year, India's Integrated Child Development Services Scheme served about 82 million children under 6 years and over 19 million pregnant women and lactating mothers. These 102 million beneficiaries received services in about 1.3 million centres. METHOD: This paper reviews the growth of the Scheme and considers challenges to scaling up quality with equity based on results of large-scale national or multistate studies. RESULTS: The Scheme is associated with decreased malnutrition and better child development. The size and diversity of the country, the policy context, funding mode and lack of community awareness and engagement have hindered scaling up access while the approach to service delivery, low institutional capacity and poor infrastructure have impeded scaling up of implementation quality. CONCLUSIONS: This review illustrates the challenges associated with scaling-up access and implementation quality of a multicomponent, integrated early childhood programme in a large, diverse country. The future success of the Integrated Child Development Services will depend on how well it adheres to quality standards and how well it evolves to address current weaknesses. PMID- 29235172 TI - Scaling up child development centres in Bangladesh. AB - BACKGROUND: Child Development Centres (CDCs) have been established within government medical college tertiary hospitals across Bangladesh. Services entail a parent-professional partnership in a child and family friendly environment with a focus on assessment, diagnosis, and management of a range of neurodevelopmental disorders in children and adolescents 0-16 years of age. Services are provided by a multidisciplinary team of professionals (child health physician, child psychologist, and developmental therapist) who emphasize quality of services over the numbers of children seen. METHODS: In 2008, Dhaka Shishu (Children's) Hospital was given the mandate by the government to conceptualize, train, and monitor CDCs nationwide. Here, we describe the rationale and processes for the establishment of the national network of CDCs and discuss lessons learned on scaling up early childhood development services in a low resource setting. RESULTS: Fifteen CDCs were established in major government hospitals across Bangladesh and have recorded 208,866 patient visits. The majority (79%) of children were from the lowest and middle-income families, and about one third (30%) were < 2 years of age at first presentation. Two thirds of children seen in follow-up demonstrated improvements in functional skills since their first visit, 77% in their adaptive behaviour (i.e., activities of daily living) and 70% in cognitive functions. CONCLUSIONS: CDCs are expanding coverage for child neurodevelopment services across Bangladesh through a tiered system of home-based screening, community- and clinic-based functional assessment, and CDC-based diagnosis, support, and referral. Vulnerable populations-the lowest income groups and younger children-comprised the majority of patients, among whom there is high unmet need for psychological services that is being met for the first time. Innovative human resource development, including a 3-month training for the multidisciplinary teams, enabled wide coverage for assessment and diagnosis of a range of neurodevelopmental problems. Demand for services is growing, especially among non-government and private hospitals. PMID- 29235174 TI - Big Data and medicine: a big deal? AB - Big Data promises huge benefits for medical research. Looking beyond superficial increases in the amount of data collected, we identify three key areas where Big Data differs from conventional analyses of data samples: (i) data are captured more comprehensively relative to the phenomenon under study; this reduces some bias but surfaces important trade-offs, such as between data quantity and data quality; (ii) data are often analysed using machine learning tools, such as neural networks rather than conventional statistical methods resulting in systems that over time capture insights implicit in data, but remain black boxes, rarely revealing causal connections; and (iii) the purpose of the analyses of data is no longer simply answering existing questions, but hinting at novel ones and generating promising new hypotheses. As a consequence, when performed right, Big Data analyses can accelerate research. Because Big Data approaches differ so fundamentally from small data ones, research structures, processes and mindsets need to adjust. The latent value of data is being reaped through repeated reuse of data, which runs counter to existing practices not only regarding data privacy, but data management more generally. Consequently, we suggest a number of adjustments such as boards reviewing responsible data use, and incentives to facilitate comprehensive data sharing. As data's role changes to a resource of insight, we also need to acknowledge the importance of collecting and making data available as a crucial part of our research endeavours, and reassess our formal processes from career advancement to treatment approval. PMID- 29235175 TI - Acetate provokes mitochondrial stress and cell death in Ustilago maydis. AB - The fungal pathogen Ustilago maydis causes disease on maize by mating to establish an infectious filamentous cell type that invades the host and induces tumours. We previously found that beta-oxidation mutants were defective in virulence and did not grow on acetate. Here, we demonstrate that acetate inhibits filamentation during mating and in response to oleic acid. We therefore examined the influence of different carbon sources by comparing the transcriptomes of cells grown on acetate, oleic acid or glucose, with expression changes for the fungus during tumour formation in planta. Guided by the transcriptional profiling, we found that acetate negatively influenced resistance to stress, promoted the formation of reactive oxygen species, triggered cell death in stationary phase and impaired virulence on maize. We also found that acetate induced mitochondrial stress by interfering with mitochondrial functions. Notably, the disruption of oxygen perception or inhibition of the electron transport chain also influenced filamentation and mating. Finally, we made use of the connections between acetate and beta-oxidation to test metabolic inhibitors for an influence on growth and virulence. These experiments identified diclofenac as a potential inhibitor of virulence. Overall, these findings support the possibility of targeting mitochondrial metabolic functions to control fungal pathogens. PMID- 29235173 TI - Type IV secretion in Gram-negative and Gram-positive bacteria. AB - Type IV secretion systems (T4SSs) are versatile multiprotein nanomachines spanning the entire cell envelope in Gram-negative and Gram-positive bacteria. They play important roles through the contact-dependent secretion of effector molecules into eukaryotic hosts and conjugative transfer of mobile DNA elements as well as contact-independent exchange of DNA with the extracellular milieu. In the last few years, many details on the molecular mechanisms of T4SSs have been elucidated. Exciting structures of T4SS complexes from Escherichia coli plasmids R388 and pKM101, Helicobacter pylori and Legionella pneumophila have been solved. The structure of the F-pilus was also reported and surprisingly revealed a filament composed of pilin subunits in 1:1 stoichiometry with phospholipid molecules. Many new T4SSs have been identified and characterized, underscoring the structural and functional diversity of this secretion superfamily. Complex regulatory circuits also have been shown to control T4SS machine production in response to host cell physiological status or a quorum of bacterial recipient cells in the vicinity. Here, we summarize recent advances in our knowledge of 'paradigmatic' and emerging systems, and further explore how new basic insights are aiding in the design of strategies aimed at suppressing T4SS functions in bacterial infections and spread of antimicrobial resistances. PMID- 29235177 TI - Preparation of tri(ethylene glycol) grafted core-shell type polymer support for solid-phase peptide synthesis. AB - A core-shell type polymer support for solid-phase peptide synthesis has been developed for high coupling efficiency of peptides and versatile applications such as on-bead bioassays. Although various kinds of polymer supports have been developed, they have their own drawbacks including poor accessibility of reagents and incompatibility in aqueous solution. In this paper, we prepared hydrophilic tri(ethylene glycol) (TEG) grafted core-shell type polymer supports (TEG SURE) for efficient solid-phase peptide synthesis and on-bead bioassays. TEG SURE was prepared by grafting TEG derivative on the surface of AM PS resin via biphasic diffusion control method and subsequent acetylation of amine groups which are located at the core region of AM PS resin. The performance of TEG SURE was evaluated by synthesizing several peptides. Three points can be highlighted: (1) easy control of loading level of TEG, (2) improved efficiency of peptide synthesis compared with the conventional resins, and (3) applicability of on-bead bioassays. PMID- 29235176 TI - Roles of elusive translational GTPases come to light and inform on the process of ribosome biogenesis in bacteria. AB - Protein synthesis relies on several translational GTPases (trGTPases), related proteins that couple the hydrolysis of GTP to specific molecular events on the ribosome. Most bacterial trGTPases, including IF2, EF-Tu, EF-G and RF3, play well known roles in translation. The cellular functions of LepA (also termed EF4) and BipA (also termed TypA), conversely, have remained enigmatic. Recent studies provide compelling in vivo evidence that LepA and BipA function in biogenesis of the 30S and 50S subunit respectively. These findings have important implications for ribosome biogenesis in bacteria. Because the GTPase activity of each of these proteins depends on interactions with both ribosomal subunits, some portion of 30S and 50S assembly must occur in the context of the 70S ribosome. In this review, we introduce the trGTPases of bacteria, describe the new functional data on LepA and BipA, and discuss the how these findings shape our current view of ribosome biogenesis in bacteria. PMID- 29235179 TI - SNP g.1007A>G within the porcine DNAL4 gene affects sperm motility traits and percentage of midpiece abnormalities. AB - The flagellar beating of a spermatozoa's axoneme is caused by the varying activation and inactivation of dynein molecules. Dynein, axonemal, light chain 4 (DNAL4) is a functional candidate gene for sperm motility as it encodes a small subunit of the dyneins. We resequenced the porcine DNAL4 using three artificial insemination (AI) boars each with high (>68%) or low (<60%) motility, and detected 23 SNP. These were then genotyped for 82 AI boars. Using spermatological records, significantly negative genetic correlations between ejaculate volume (VOL) and the further spermatological parameters concentration (CONC) (r = -.43), motility of undiluted semen (MOTUD) (r = -.09), motility after 24 h (MOT1) (r = .17) and after 48 hr (MOT2) (r = -.23) were estimated. Significantly positive correlations existed between CONC and MOT1 (r = .07) as well as MOT2 (r = .10), between MOTUD and MOT1 (r = .33), between MOTUD and MOT2 (r = .36), and finally between MOT1 and MOT2 (r = .70). Significantly negatively correlated were all motility traits with the parameters abnormal acrosome (AA) (MOTUD r = -.06; MOT1 r = -.08, and MOT2 r = -.1) and presence of cytoplasmic droplet (CD) (MOTUD r = .07; MOT1 r = -.08; MOT2 r = -.07). Association analyses (single marker regression model; SMR) propose that SNP g.1007A>G, located in the second intron, reduces motility significantly (MOTUD -4.59%; MOT1 -10.33%; MOT2 -19.37%). According to the dominant-recessive model (DRM), genotype AA is always superior compared to genotypes AG and GG (i.e. MOTUD 67.67%, 64.16% and 53.91%; MOT1 54.17%, 43.75% and 28.44%; MOT2 44.12%, 24.91% and 4.97%). The average effect of gene substitution (g.1007A>G) on abnormal midpiece (AM) was 0.71%, the genotypic values-as expressed by LSmeans-were 0.1 (AA) and 0.81 (AG). PMID- 29235180 TI - The effects of hypoglycemia and weight loss of total lignans from Fructus Arctii in KKAy mice and its mechanisms of the activity. AB - Fructus Arctii (great burdock achene) is the dried ripe fruit of Arctium lappa L. (family Asteraceae) and is included in the Chinese pharmacopoeia. It has been reported that the clinical use of Fructus Arctii resulted in a satisfactory hypoglycemic effect in diabetic patients. This study aimed to investigate antidiabetic activity and mechanism of total lignans from Fructus Arctii (TLFA) in KKAy mice, a spontaneous Type 2 diabetic rodent model that exhibits marked obesity. In this study, KKAy mice were gavaged once daily with solvents (0.5% sodium carboxymethyl cellulose), TLFA (250 and 125 mg/kg), or metformin (200 mg/kg) for 11 weeks, and C57BL/6J mice treated with saline solution (0.9%, w/v) were used as normal control. The results indicate that TLFA has dual effects of hypoglycemia and weight loss, and administration of TLFA in KKAy mice could decrease fasting blood glucose, glycated hemoglobin, and body weight; improve oral glucose tolerance; increase high density lipoprotein cholesterol; and decrease triglycerides and free fatty acid in mice serum. Its efficacy may associate with multiple mechanisms of action such as stimulation of insulin secretion, activation of phosphatidylinositol 3-kinase/protein kinase B, and adenosine-monophosphate-activated protein kinase signaling pathway, decreasing leptin. PMID- 29235178 TI - The gp130 Cytokine Interleukin-11 Regulates Engraftment of Vav1-/- Hematopoietic Stem and Progenitor Cells in Lethally Irradiated Recipients. AB - During bone marrow transplantation, hematopoietic stem and progenitor cells (HSPCs) respond to signals from the hematopoietic microenvironment by coordinately activating molecular pathways through Rho GTPases, including Rac. We have previously shown that deletion of Vav1, a hematopoietic-specific activator of Rac, compromises engraftment of transplanted adult HSPCs without affecting steady-state hematopoiesis in adult animals. Here, we show that Vav1-/- fetal HSPCs can appropriately seed hematopoietic tissues during ontogeny but cannot engraft into lethally irradiated recipients. We demonstrate that the engraftment defect of Vav1-/- HSPCs is abrogated in the absence of irradiation and demonstrate that Vav1 is critical for the response of HSPCs to the proinflammatory cytokine interleukin-11 (IL-11) that is upregulated in the marrow of irradiated recipients. Vav1-/- HSPCs display abnormal proliferative responses to IL-11 in vitro and dysregulated activation of pathways critical to engraftment of HSPCs. The engraftment of Vav1-/- HSPCs can be partially rescued in irradiated recipients treated with an anti-IL-11 antibody. These data suggest that HSPCs may respond to different functional demands by selective usage of the IL-11-Vav-Rac pathway, contextualizing further the recent view that HSPCs capable of reconstituting the blood system following transplantation might be distinct from those supporting hematopoiesis during homeostatic conditions. Stem Cells 2018; 36:446-457. PMID- 29235181 TI - Fuzheng Huayu capsule as an adjuvant treatment for HBV-related cirrhosis: A systematic review and meta-analysis. AB - Fuzheng Huayu (FZHY) capsule, a formulated traditional Chinese medicine product with 6 Chinese herbs, is widely used for HBV-related cirrhosis as an adjuvant treatment. However, the efficacy of FZHY capsule for HBV-induced cirrhosis did not be comprehensively proved by systematic analysis. Our current analysis was aimed to assess the efficacy and safety of FZHY capsule by an evidence-based method. Databases, including China National Knowledge Infrastructure, Wangfang, VIP medicine information system, Pubmed, Embase, and Cochrane Library, were searched, and the randomized controlled trials of FZHY capsule were used for the treatment of HBV-associated liver cirrhosis. Meta-analysis was performed by Review Manager 5.3. The efficacy rate, alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), albumin (ALB), Procollagen III protein (PIIIP), hyaluronic acid (HA), laminin (LN), Collagen C Type IV (IV-C), Child-Pugh score, portal vein diameter, spleen thickness, HBeAg negative conversion rate, and HBV-DNA negative conversion rate were systematically assessed. The Cochrane Risk of Bias tool was used to evaluate the methodological quality of eligible studies. Nineteen studies with 1,769 patients were included in the meta-analysis. Compared to conventional treatment, FZHY capsule was effective by increasing the efficacy. FZHY capsule was more efficient in improving ALT, AST, TBIL, PIIIP, HA, LN, IV-C, Child-Pugh grading score, portal vein diameter, spleen thickness, and HBV-DNA negative conversion rate with no serious adverse reactions. Nevertheless, a variety of well-designed randomized controlled trials are needed to confirm these findings since small samples were applied in the previous studies. PMID- 29235182 TI - Spinal cord injury-induced cardiomyocyte atrophy and impaired cardiac function are severity dependent. AB - NEW FINDINGS: What is the central question of this study? How does the severity of spinal cord injury affect left ventricular mechanics, function and the underlying cardiomyocyte morphology? What is the main finding and its importance? Here, we show that severe, but not moderate, spinal cord injury causes cardiomyocyte atrophy, altered left ventricular mechanics and impaired cardiac function. The principal aim of the present study was to assess how the severity of spinal cord injury (SCI) affects left ventricular (LV) mechanics, function and underlying cardiomyocyte morphology. Here, we used different severities of T3 spinal cord contusions (MODERATE, 200 kdyn contusion; SEVERE, 400 kdyn contusion; SHAM) and combined standard echocardiography with speckle tracking analyses to investigate in vivo cardiac function and deformation (contractility) after experimental SCI in the Wistar rat. In addition, we investigated changes in the intrinsic structure of cardiac myocytes ex vivo. We demonstrate that SEVERE SCI induces a characteristic decline in LV chamber size and a reduction in in vivo LV deformation (i.e. radial strain) throughout the entire systolic portion of the cardiac cycle [25.6 +/- 3.0 versus 44.5 +/- 8.1% (Pre-injury); P = 0.0029]. SEVERE SCI also caused structural changes in cardiomyocytes, including decreased length [115.6 +/- 7.63 versus 125.8 +/- 6.75 MUm (SHAM); P = 0.0458], decreased width [7.78 +/- 0.71 versus 10.78 +/- 1.08 MUm (SHAM); P = 0.0015] and an increase in the length/width ratio [14.88 +/- 0.66 versus 11.74 +/- 0.89 (SHAM); P = 0.0018], which was significantly correlated with LV flow-generating capacity after SCI (i.e. stroke volume, R2 = 0.659; P = 0.0013). Rats with MODERATE SCI exhibited no changes in any metric versus SHAM. This is the first study to demonstrate that the severity of SCI determines the course of changes in the intrinsic structure of cardiomyocytes, which are directly related to contractile function of the LV. PMID- 29235183 TI - A Preview of Selected Articles. PMID- 29235184 TI - Rethinking contact lens discomfort. PMID- 29235185 TI - The intraparietal sulcus governs multisensory integration of audiovisual information based on task difficulty. AB - Object recognition benefits maximally from multimodal sensory input when stimulus presentation is noisy, or degraded. Whether this advantage can be attributed specifically to the extent of overlap in object-related information, or rather, to object-unspecific enhancement due to the mere presence of additional sensory stimulation, remains unclear. Further, the cortical processing differences driving increased multisensory integration (MSI) for degraded compared with clear information remain poorly understood. Here, two consecutive studies first compared behavioral benefits of audio-visual overlap of object-related information, relative to conditions where one channel carried information and the other carried noise. A hierarchical drift diffusion model indicated performance enhancement when auditory and visual object-related information was simultaneously present for degraded stimuli. A subsequent fMRI study revealed visual dominance on a behavioral and neural level for clear stimuli, while degraded stimulus processing was mainly characterized by activation of a frontoparietal multisensory network, including IPS. Connectivity analyses indicated that integration of degraded object-related information relied on IPS input, whereas clear stimuli were integrated through direct information exchange between visual and auditory sensory cortices. These results indicate that the inverse effectiveness observed for identification of degraded relative to clear objects in behavior and brain activation might be facilitated by selective recruitment of an executive cortical network which uses IPS as a relay mediating crossmodal sensory information exchange. PMID- 29235186 TI - Improving quit rates of web-delivered interventions for smoking cessation: full scale randomized trial of WebQuit.org versus Smokefree.gov. AB - BACKGROUND AND AIMS: Millions of people world-wide use websites to help them quit smoking, but effectiveness trials have an average 34% follow-up data retention rate and an average 9% quit rate. We compared the quit rates of a website using a new behavioral approach called Acceptance and Commitment Therapy (ACT; WebQuit.org) with the current standard of the National Cancer Institute's (NCI) Smokefree.gov website. DESIGN: A two-arm stratified double-blind individually randomized trial (n = 1319 for WebQuit; n = 1318 for Smokefree.gov) with 12-month follow-up. SETTING: United States. PARTICIPANTS: Adults (n = 2637) who currently smoked at least five cigarettes per day were recruited from March 2014 to August 2015. At baseline, participants were mean [standard deviation (SD)] age 46.2 years (13.4), 79% women and 73% white. INTERVENTIONS: WebQuit.org website (experimental) provided ACT for smoking cessation; Smokefree.gov website (comparison) followed US Clinical Practice Guidelines for smoking cessation. MEASUREMENTS: The primary outcome was self-reported 30-day point prevalence abstinence at 12 months. FINDINGS: The 12-month follow-up data retention rate was 88% (2309 of 2637). The 30-day point prevalence abstinence rates at the 12-month follow-up were 24% (278 of 1141) for WebQuit.org and 26% (305 of 1168) for Smokefree.gov [odds ratio (OR) = 0.91; 95% confidence interval (CI) = 0.76, 1.10; P = 0.334] in the a priori complete case analysis. Abstinence rates were 21% (278 of 1319) for WebQuit.org and 23% (305 of 1318) for Smokefree.gov (OR = 0.89 (0.74, 1.07; P = 0.200) when missing cases were imputed as smokers. The Bayes factor comparing the primary abstinence outcome was 0.17, indicating 'substantial' evidence of no difference between groups. CONCLUSIONS: WebQuit.org and Smokefree.gov had similar 30-day point prevalence abstinence rates at 12 months that were descriptively higher than those of prior published website delivered interventions and telephone counselor-delivered interventions. PMID- 29235187 TI - The clinical utility of fluorodeoxyglucose-positron emission tomography for investigation of fever in immunocompromised children. AB - AIM: Fever in immunocompromised children presents significant challenges. We aimed to determine the clinical impact of fluorodeoxyglucose-positron emission tomography (FDG-PET) in combination with computed tomography (CT) in children with malignancy or following haematopoietic stem cell transplantation with prolonged or recurrent fever. METHODS: Immunocompromised children who underwent FDG-PET/CT for investigation of prolonged or recurrent fever were identified from hospital databases. The clinical impact of the FDG-PET/CT was considered 'high' if it contributed to any of the following: diagnosis of a new site infection/inflammation, change to antimicrobials or chemotherapy, or additional investigations or specialist consult contributing to final diagnosis. RESULTS: Fourteen patients underwent an FDG-PET/CT for prolonged or recurrent fever. Median age was 11 years and 46% had diagnosis of acute lymphoblastic leukaemia. The median absolute neutrophil count on the day of FDG-PET/CT was 0.47 cells/MUL. The clinical impact of FDG-PET/CT was 'high' in 11 (79%) patients, contributing to rationalisation of antimicrobials in three, and cessation of antimicrobials in five. Compared to conventional imaging, FDG PET/CT identified seven additional sites of clinically significant infection/inflammation in seven patients. Of the 10 patients who had a cause of fever identified, FDG-PET/CT contributed to the final diagnosis in six (60%). CONCLUSION: This study has identified potential utility for FDG-PET/CT in immunocompromised children with prolonged or recurrent fever. Further prospective studies are needed to compare FDG-PET/CT versus conventional imaging, to identify the optimal timing of FDG-PET/CT and to study the role of subsequent scans to monitor response to therapy. PMID- 29235188 TI - Evaluation of the psychometric properties of "the Norwegian screening test for dyslexia". AB - The aim of this study was to develop and investigate the psychometric properties of a screening protocol for Norwegian students in upper secondary school. The protocol was designed to assess skills that are at stake in dyslexia. It was administered to 232 students. In the absence of a "gold standard," comparisons were made between students who reported normal literacy skills (n = 184) and literacy problems (n = 48). Significant group differences were found across all areas. Logistic regression and receiver operating characteristic curve analyses demonstrated good discriminatory power. The screening protocol met the standards for reliability and validity. It has the potential to be a useful tool for teachers to identify students at risk for dyslexia and who thus need to be referred to a full diagnostic investigation. PMID- 29235189 TI - Predictors of smoking cessation during pregnancy: a systematic review and meta analysis. AB - AIM: To identify factors found in the research literature to be associated with smoking cessation in pregnancy. METHODS: Electronic searches of the bibliographic databases of PubMed, EMBASE, PsycINFO, Elsevier, Scopus and ISI Web of Science were conducted to April 2017. All studies reporting factors associated with smoking cessation or continuing smoking during pregnancy were included and reviewed systematically, irrespective of study design. The Newcastle-Ottawa Quality Assessment Scale was used to assess the study quality. The DerSimonian & Laird random-effects model was used to conduct meta-analyses, and where effect estimates were reported for factors included in at least three studies. RESULTS: Fifty-four studies, including 505 584 women globally who smoked before pregnancy, 15 clinical trials and 40 observational studies, were included in the review and 36 (65.5%) were considered to be of high quality. This review identified 11 socio demographic, seven socially related, 19 smoking behaviour-related, five pregnancy related, six health-related and six psychological factors that were associated significantly with smoking cessation during pregnancy. The most frequently observed significant factors associated with cessation were: higher level of education, pooled odds ratio (OR), 95% confidence interval (CI) = 2.16 (1.80 2.84), higher socio-economic status: 1.97 (1.20-3.24), overseas maternal birth: 2.00 (1.40-2.84), Medicaid coverage or private insurance: 1.54 (1.29-1.85), living with partner or married: 1.49 (1.38-1.61), partner/other members of the household do not smoke: 0.42 (0.35-0.50), lower heaviness of smoking index score: 0.45 (0.27-0.77, lower baseline cotinine level: 0.78 (0.64-0.94), low exposure to second-hand smoking: 0.45 (0.20-1.02), not consuming alcohol before and/or during pregnancy: 2.03 (1.47-2.80), primiparity: 1.85 (1.68-2.05), planned breastfeeding:1.99 (1.94-2.05), perceived adequate pre-natal care: 1.74 (1.38 2.19), no depression: 2.65 (1.62-4.30) and low stress during pregnancy: 0.58 (0.44-0.77). CONCLUSION: A wide range of socio-demographics, relationship, social, smoking-related, pregnancy-related, health and psychological factors have been found to predict smoking cessation in pregnancy. PMID- 29235191 TI - The effect of Cyanidin-3-o-glucoside on UVA-induced damage in human dermal fibroblasts. AB - BACKGROUND/PURPOSE: Ultraviolet-A (UVA) radiation can induce photoaging and skin cancer, but means to prevent or treat UVA-induced skin damage require further study. We investigated the effects of cyanidin-3-o-glucoside (C3G), a monomer of anthocyanin, on UVA-induced damage in primary human dermal fibroblasts (HDFs), and we identify possible mechanisms underlying the protective effects of this compound. METHODS: Primary HDFs were pretreated with 80 MUmol/L C3G for 2 hours and UVA irradiated at 12 J/cm2 . The cells were then incubated with 80 MUmol/L C3G for 12 hours after irradiation. HDFs were randomly divided into control, UVA treatment, C3G, and UVA treatment plus C3G pretreatment groups. RESULTS: C3G increased the cell viability of primary HDFs and decreased UVA-induced ROS production and apoptosis rate. Compared to the UVA group, the UVA plus pretreatment with C3G group displayed increased Bcl-2 expression and Bcl-2/Bax ratio, decreased cleaved caspase-3 and p-P38 levels, and increased ERK phosphorylation; no significant effect on p-JNK levels was observed. CONCLUSION: C3G reduced UVA-induced HDF oxidative damage and apoptosis, likely be related to the down-regulation of p-P38, up-regulation of ERK protein phosphorylation. PMID- 29235192 TI - Influence of Implant Position in Implant-Assisted Removable Partial Denture: A Three-Dimensional Finite Element Analysis. AB - PURPOSE: To determine the ideal position of a dental implant to assist a posterior extended partial removable dental prosthesis (PRDP), through stress values, displacement values, and deformation of periodontal ligament (PDL). MATERIALS AND METHODS: A finite element analysis of different implant positions was analyzed using a 3D mandible model from a human patient. Test models were created: model A (implant in second molar area), model B (implant in the first molar area), and model C (implant in premolar area). A control model without implant support was also created. Overall displacement values, von Mises stress distribution maps, and nonlinear deformations were evaluated. RESULTS: Some differences could be observed between test models. The introduction of an implant in the edentulous area, unlike a conventional removable partial denture without implant support, decreases stress values in the biological structures such as: mandible, tooth, soft tissue, and PDL. Placing the implant in the first molar area resulted in improved displacement values, and reduced maximum stress values at the peri-implant bone area, metal structure, and implant were observed. CONCLUSIONS: Within the limitations of this study we can conclude that placing the implant in the position of the first molar improves biomechanical behavior of implant-assisted PRDPs. PMID- 29235193 TI - Chronic musculoskeletal pain in European older adults: Cross-national and gender differences. AB - BACKGROUND: In an ageing Europe, chronic pain is a major public health problem, but robust epidemiological data are scarce. This study aimed to analyse the prevalence of and factors associated with chronic musculoskeletal pain by gender in older adults of 14 European countries. METHODS: A cross-sectional study was performed from wave 5 of the Survey of Health, Ageing and Retirement in Europe (SHARE). The study included people >=50 years residing in Austria, Belgium, Czech Republic, Denmark, Estonia, France, Germany, Italy, Luxembourg, the Netherlands, Slovenia, Spain, Sweden and Switzerland. Chronic pain was defined as being bothered by joint and/or back pain for the previous 6 months. Multivariable Poisson regression models with robust variance were performed to analyse prevalence ratio by covariates, stratified by sex. RESULTS: A total of 61,157 participants were included. Overall prevalence of chronic musculoskeletal pain was 35.7% (28.8-31.7), ranging from 18.6% (17.1-20.1) for Switzerland to 45.6% (43.3-47.8) for France. Prevalence was higher in women than in men: 41.3% (40.2 42.4) versus 29.1% (28.0-30.3). Chronic musculoskeletal pain was lower in men aged >75 years (PR = 0.82; 0.72-0.92) than the younger (50-59) group. Separated/divorced status presented opposite effects among men (PR = 0.85; 0.76 0.96) and women (PR = 1.12; 1.03-1.21) compared with married, and unemployment was a significant factor in men (PR = 1.21; 95% CI 1.02-1.43) compared with employed. CONCLUSIONS: Musculoskeletal pain in older European adults is very frequent, especially in women, with large differences depending on the country of residence. Health policy makers should prioritize strategies aimed at improving the prevention and management of chronic musculoskeletal pain in Europe. SIGNIFICANCE: This study provides epidemiological data of chronic musculoskeletal pain in older adults. Reported differences contribute to highlight the relevance of considering a gender perspective in chronic musculoskeletal pain research. Cross-national comparison also offers a map of differences that improves the knowledge of this chronic condition in Europe. PMID- 29235190 TI - Intrinsic functional connectivity of the central extended amygdala. AB - The central extended amygdala (EAc)-including the bed nucleus of the stria terminalis (BST) and central nucleus of the amygdala (Ce)-plays a critical role in triggering fear and anxiety and is implicated in the development of a range of debilitating neuropsychiatric disorders. Although it is widely believed that these disorders reflect the coordinated activity of distributed neural circuits, the functional architecture of the EAc network and the degree to which the BST and the Ce show distinct patterns of functional connectivity is unclear. Here, we used a novel combination of imaging approaches to trace the connectivity of the BST and the Ce in 130 healthy, racially diverse, community-dwelling adults. Multiband imaging, high-precision registration techniques, and spatially unsmoothed data maximized anatomical specificity. Using newly developed seed regions, whole-brain regression analyses revealed robust functional connectivity between the BST and Ce via the sublenticular extended amygdala, the ribbon of subcortical gray matter encompassing the ventral amygdalofugal pathway. Both regions displayed coupling with the ventromedial prefrontal cortex (vmPFC), midcingulate cortex (MCC), insula, and anterior hippocampus. The BST showed stronger connectivity with the thalamus, striatum, periaqueductal gray, and several prefrontal territories. The only regions showing stronger functional connectivity with the Ce were neighboring regions of the dorsal amygdala, amygdalohippocampal area, and anterior hippocampus. These observations provide a baseline against which to compare a range of special populations, inform our understanding of the role of the EAc in normal and pathological fear and anxiety, and showcase image registration techniques that are likely to be useful for researchers working with "deidentified" neuroimaging data. PMID- 29235196 TI - Influence of Particle and Air-Abrasion Moment on Y-TZP Surface Characterization and Bond Strength. AB - PURPOSE: To evaluate the influence of particle and air-abrasion on the surface characterization and shear bond strength (SBS) of a Y-TZP ceramic with a resin cement. MATERIALS AND METHODS: Y-TZP specimens were air-abraded with 50 MUm alumina particles; 120 MUm alumina particles; 30 MUm silica-coated alumina particles (Rocatec Soft); 110 MUm silica-coated alumina particles (Rocatec Plus). Air-abrasion was performed before (BS); after (AS); before and after (BAS) zirconia sintering. Surface characterization included roughness (n = 10), wettability (n = 10), morphology (n = 2), and elemental composition (n = 2). For SBS (n = 11), composite resin discs were bonded to the air-abraded and silane treated zirconia surface, with the resin cement RelyX ARC. Failure mode was determined. Roughness, wettability, and SBS data were analyzed by two-way ANOVA with pairwise interaction and Tukey's test (alpha = 0.05). RESULTS: Air-abrasion performed with coarser particles at BS and BAS moments provided the highest roughness values, while the lowest roughness values were observed with particles combined with AS moment (p < 0.01). Rocatec Plus provided lower contact angle than the 120 MUm alumina particles (p = 0.013), and BAS exhibited lower contact angle than BS (p = 0.002). The combinations 120 MUm/BS and the silica-coated alumina particles/AS and /BAS showed the highest SBS (p < 0.05). The combination of each particle/BAS was statistically similar to the same particle/AS. Failure mode was 100% adhesive for all groups. The interaction particle size/air-abrasion moment determined the morphological pattern. Silicon was observed only in the Rocatec groups. CONCLUSIONS: Roughness was influenced by the particle size and was higher when the zirconia was air-abraded in its green stage. The particle composition played an important role in the wettability and both studied air abrasion moments provided similar wettability than the one in which air-abrasion is usually performed. The highest SBS values were observed in the three moments, by using certain particles for each moment. PMID- 29235194 TI - Dual-Sensitivity Multiple Sclerosis Lesion and CSF Segmentation for Multichannel 3T Brain MRI. AB - BACKGROUND AND PURPOSE: A pipeline for fully automated segmentation of 3T brain MRI scans in multiple sclerosis (MS) is presented. This 3T morphometry (3TM) pipeline provides indicators of MS disease progression from multichannel datasets with high-resolution 3-dimensional T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery (FLAIR) contrast. 3TM segments white (WM) and gray matter (GM) and cerebrospinal fluid (CSF) to assess atrophy and provides WM lesion (WML) volume. METHODS: To address nonuniform distribution of noise/contrast (eg, posterior fossa in 3D-FLAIR) of 3T magnetic resonance imaging, the method employs dual sensitivity (different sensitivities for lesion detection in predefined regions). We tested this approach by assigning different sensitivities to supratentorial and infratentorial regions, and validated the segmentation for accuracy against manual delineation, and for precision in scan-rescans. RESULTS: Intraclass correlation coefficients of .95, .91, and .86 were observed for WML and CSF segmentation accuracy and brain parenchymal fraction (BPF). Dual sensitivity significantly reduced infratentorial false-positive WMLs, affording increases in global sensitivity without decreasing specificity. Scan-rescan yielded coefficients of variation (COVs) of 8% and .4% for WMLs and BPF and COVs of .8%, 1%, and 2% for GM, WM, and CSF volumes. WML volume difference/precision was .49 +/- .72 mL over a range of 0-24 mL. Correlation between BPF and age was r = .62 (P = .0004), and effect size for detecting brain atrophy was Cohen's d = 1.26 (standardized mean difference vs. healthy controls). CONCLUSIONS: This pipeline produces probability maps for brain lesions and tissue classes, facilitating expert review/correction and may provide high throughput, efficient characterization of MS in large datasets. PMID- 29235197 TI - Superoxide dismutase from Helicobacter pylori suppresses the production of pro inflammatory cytokines during in vivo infection. AB - BACKGROUND: Helicobacter pylori has undergone considerable adaptation to allow chronic persistence within the gastric environment. While H. pylori-associated diseases are driven by an excessive inflammation, severe gastritis is detrimental to colonization by this pathogen. Hence, H. pylori has developed strategies to minimize the severity of gastritis it triggers in its host. Superoxide dismutase (SOD) is well known for its role in protecting against oxidative attack; less recognized is its ability to inhibit immunity, shown for SOD from mammalian sources and those of some bacterial species. This study examined whether H. pylori SOD (HpSOD) has the ability to inhibit the host immune response to these bacteria. MATERIALS AND METHODS: The ability of recombinant HpSOD to modify the response to LPS was measured using mouse macrophages. A monoclonal antibody against HpSOD was generated and injected into H. pylori-infected mice. RESULTS: Addition of HpSOD to cultures of mouse macrophages significantly inhibited the pro-inflammatory cytokine response to LPS stimulation. A monoclonal antibody was generated that was specific for SOD from H. pylori. When injected into mice infected with H. pylori for 3 months, this antibody was readily detected in both sera and gastric tissues 5 days later. While treatment with anti-HpSOD had no effect on H. pylori colonization at this time point, it significantly increased the levels of a range of pro-inflammatory cytokines in the gastric tissues. This did not occur with antibodies against other antioxidant enzymes. CONCLUSIONS: SOD from H. pylori can inhibit the production of pro-inflammatory cytokine during in vivo infection. PMID- 29235195 TI - Concise Review: Human Pluripotent Stem Cells to Produce Cell-Based Cancer Immunotherapy. AB - Human pluripotent stem cells (PSCs) provide a promising resource to produce immune cells for adoptive cellular immunotherapy to better treat and potentially cure otherwise lethal cancers. Cytotoxic T cells and natural killer (NK) cells can now be routinely produced from human PSCs. These PSC-derived lymphocytes have phenotype and function similar to primary lymphocytes isolated from peripheral blood. PSC-derived T and NK cells have advantages compared with primary immune cells, as they can be precisely engineered to introduce improved anti-tumor activity and produced in essentially unlimited numbers. Stem Cells 2018;36:134 145. PMID- 29235199 TI - Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models. AB - The bone marrow stroma maintains hematopoiesis and coordinately regulates regenerative responses through dynamic interactions with hematopoietic stem and progenitor cells. Recent studies indicate that stromal components in the bone marrow of leukemia patients undergo a process of successive adaptation that in turn exerts dramatic effects on the hematopoietic stem cell compartment and promotes leukemic drug resistance. Therefore, functional changes in discrete marrow stromal populations can be considered an aspect of leukemia biogenesis in that they create an aberrant, self-reinforcing microenvironment. In this review, we will describe the current understanding of the remodeling of the hematopoietic stem cell niche following invasion by leukemia cells. We place emphasis on existing evidence of how mesenchymal stem cells and their progeny facilitate neoplastic growth and describe available models and analytical techniques to understand the conversion of the niche toward disease persistence. Stem Cells 2018;36:304-312. PMID- 29235201 TI - Assessment of Bone Dimensions in the Anterior Maxilla: A Cone Beam Computed Tomography Study. AB - PURPOSE: To evaluate labial and palatal bone thickness at the maxillary anterior teeth as well as distance from cemento-enamel junction (CEJ) to bone crest using cone beam computed tomography (CBCT). MATERIALS AND METHODS: Measurements were obtained for maxillary anterior teeth of 120 subject CBCT volumes including thickness of labial and palatal plates of bone (coronal, middle, and apical thirds), and distance between CEJ and alveolar bone crest mid-labially, mesially, and distally. RESULTS: The mean value of bone thickness at coronal, middle, and apical thirds of the labial side for central incisor roots were respectively: 0.73, 0.69, 0.60 (mm), for lateral incisors: 0.70, 0.61, 0.49 (mm), and for canines: 0.74, 0.53, 040 (mm). The thickness of palatal bone was significantly larger. The mean distance between CEJ and mid-labial bone crest for all sites was 2.16 mm. CONCLUSION: Labial bone thickness is thin in the vast majority of maxillary anterior teeth. Use of CBCT facilitates planning for immediate implant placement and is helpful in the decision-making process when further bone augmentation is needed. PMID- 29235200 TI - Concise Review: The Cellular Conspiracy of Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is incurable and devastating. A dearth of therapies has galvanized experimental focus onto the cellular and molecular mechanisms that both initiate and subsequently drive motor neuron degeneration. A traditional view of ALS pathogenesis posits that disease-specific injury to a subtype of neurons is mechanistically cell-autonomous. This "neuron-centric" view has biased past research efforts. However, a wealth of accumulating evidence now strongly implicates non-neuronal cells as being major determinants of ALS. Although animal models have proven invaluable in basic neuroscience research, a growing number of studies confirm fundamental interspecies differences between popular model organisms and the human condition. This may in part explain the failure of therapeutic translation from rodent preclinical models. It follows that integration of a human experimental model using patient-specific induced pluripotent stem cells may be necessary to capture the complexity of human neurodegeneration with fidelity. Integration of enriched human neuronal and glial experimental platforms into the existing repertoire of preclinical models might prove transformational for clinical trial outcomes in ALS. Such reductionist and integrated cross-modal approaches allow systematic elucidation of cell-autonomous and non-cell-autonomous mechanisms of disease, which may then provide novel cellular targets for therapeutic intervention. Stem Cells 2018;36:293-303. PMID- 29235198 TI - Substrate interaction defects in histidyl-tRNA synthetase linked to dominant axonal peripheral neuropathy. AB - Histidyl-tRNA synthetase (HARS) ligates histidine to cognate tRNA molecules, which is required for protein translation. Mutations in HARS cause the dominant axonal peripheral neuropathy Charcot-Marie-Tooth disease type 2W (CMT2W); however, the precise molecular mechanism remains undefined. Here, we investigated three HARS missense mutations associated with CMT2W (p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly). The three mutations localize to the HARS catalytic domain and failed to complement deletion of the yeast ortholog (HTS1). Enzyme kinetics, differential scanning fluorimetry (DSF), and analytical ultracentrifugation (AUC) were employed to assess the effect of these substitutions on primary aminoacylation function and overall dimeric structure. Notably, the p.Tyr330Cys, p.Ser356Asn, and p.Val155Gly HARS substitutions all led to reduced aminoacylation, providing a direct connection between CMT2W-linked HARS mutations and loss of canonical ARS function. While DSF assays revealed that only one of the variants (p.Val155Gly) was less thermally stable relative to wild-type, all three HARS mutants formed stable dimers, as measured by AUC. Our work represents the first biochemical analysis of CMT-associated HARS mutations and underscores how loss of the primary aminoacylation function can contribute to disease pathology. PMID- 29235202 TI - Three-Dimensional Static Articulation Accuracy of Virtual Models - Part I: System Trueness and Precision. AB - PURPOSE: To evaluate the 3D static articulation accuracy of 3 model scanner-CAD systems (Ceramill Map400 [AG], inEos X5 [SIR], Scanner S600 Arti [ZKN]) using a coordinate measuring machine (CMM). Trueness and precision for each system will be reported in Part I. MATERIALS AND METHODS: The master model simulated a single crown opposing a 3-unit fixed dental prosthesis. Five mounted stone cast sets were prepared, and one set was randomly selected. Reference values were obtained by measuring interarch and interocclusal reference features with the CMM. The stone cast set was scanned 5 times consecutively and articulated virtually with each system (3 test groups, n = 5). STL files of the virtual models were measured with CMM software. dRR , dRC , and dRL , represented interarch global distortions at right, central, and left sides, respectively, while dRM , dXM , dYM , and dZM represented interocclusal global and linear distortions between preparations. RESULTS: For trueness values, mean interarch global distortions ranged from 13.1 to 40.3 MUm for dRR , -199.0 to -48.1 MUm for dRC , and -114.1 to -47.7 MUm for dRL . Mean percentage error of interarch distortion did not exceed 0.6%. Mean interocclusal distortions ranged from 16.0 to 117.0 MUm for dRM , -33.1 to 101.3 MUm for dXM , 32.9 to 49.9 MUm for dYM and -32.0 to 133.1 MUm for dZM. ANOVA of trueness found statistically significant differences for dRC , dRL , dRM , dXM , and dZM . For precision values, absolute mean difference between the 10 superimposition combinations ranged from 25.3 to 91.0 MUm for dRR , 21.5 to 85.5 MUm for dRC , 24.8 to 70.0 MUm for dRL . Absolute mean difference ranged from 49.9 to 66.1 MUm for dRM , 20.7 to 92.1 MUm for dXM , 86.8 to 96.0 MUm for dYM , and 36.5 to 100.0 MUm for dZM . ANOVA of precision of all test groups found statistically significant differences for dRR , dRC , dRL , dXM and dZM , and the SIR group was the least precise. CONCLUSION: The overall interarch global distortion of all three model scanner-CAD systems was low and did not exceed 0.6%. Variations in scanner technology, virtual articulation algorithm, and use of physical articulators contributed to the differences in distortion observed among all three groups. PMID- 29235203 TI - Selective C-H Halogenation with a Highly Fluorinated Manganese Porphyrin. AB - The selective C-H functionalization of aliphatic molecules remains a challenge in organic synthesis. While radical chain halogenation reactions provide efficient access to many halogenated molecules, the use of typical protocols for the selective halogenation of electron-deficient and strained aliphatic molecules is rare. Herein, we report selective C-H chlorination and fluorination reactions promoted by an electron-deficient manganese pentafluorophenyl porphyrin catalyst, Mn(TPFPP)Cl. This catalyst displays superior properties for the aliphatic halogenation of recalcitrant, electron-deficient, and strained substrates with unique regio- and stereoselectivity. UV/Vis analysis during the course of the reaction indicated that an oxo-MnV species is responsible for hydrogen-atom abstraction. The observed stereoselectivity results from steric interactions between the bulky porphyrin ligand and the intermediate substrate radical in the halogen rebound step. PMID- 29235205 TI - The Effect of Surface Treatment on Shear Bond Strength between Y-TZP and Veneer Ceramic: A Systematic Review and Meta-Analysis. AB - PURPOSE: The objective of this systematic review with meta-analysis was to evaluate surface treatment in yttria-stabilized tetragonal zirconia polycrystal ceramic (Y-TZP) on the shear bond strength (SBS) values between Y-TZP (core ceramic) and veneer ceramic, compared to untreated specimens. MATERIALS AND METHODS: This review was registered at PROSPERO platform under the number CRD42016036493. The systematic review of the extracted publications was performed to compare the effect of surface treatment on SBS between Y-TZP ceramic and veneering ceramic. A comprehensive review of the literature from the earliest available dates through January 2017 was performed in the PubMed/Medline, Embase, Scopus, and Cochrane Library databases. RESULTS: A total of 15 studies were identified for the inclusion of data, with only in vitro studies. A random-effect model found statistically significant differences between untreated and treated surfaces of Y-TZP (p < 0.00001; MD: 2.84; 95% CI: 2.19 to 3.49). In another analysis, a random-effect model found statistically significant differences between the groups that only performed the associations of treatments and control group (p < 0.00001; MD: 3.19; 95% CI: 2.11 to 4.28). CONCLUSIONS: Surface treatment in Y-TZP improved the values of SBS between the Y-TZP and veneer ceramic. The associations between two or more treatments also showed positive effect on the bond strength due the cumulative effect of the treatments. PMID- 29235204 TI - Plasma-activated medium (PAM) kills human cancer-initiating cells. AB - Medical non-thermal plasma (NTP) treatments for various types of cancers have been reported. Cells with tumorigenic potential (cancer-initiating cells; CICs) are few in number in many types of tumors. CICs efficiently eliminate anti-cancer chemicals and exhibit high-level aldehyde dehydrogenase (ALDH) activity. We previously examined the effects of direct irradiation via NTP on cancer cells; even though we targeted CICs expressing high levels of ALDH, such treatment affected both non-CICs and CICs. Recent studies have shown that plasma-activated medium (PAM) (culture medium irradiated by NTP) selectively induces apoptotic death of cancer but not normal cells. Therefore, we explored the anti-cancer effects of PAM on CICs among endometrioid carcinoma and gastric cancer cells. PAM reduced the viability of cells expressing both low and high levels of ALDH. Combined PAM/cisplatin appeared to kill cancer cells more efficiently than did PAM or cisplatin alone. In a mouse tumor xenograft model, PAM exerted an anti cancer effect on CICs. Thus, our results suggest that PAM effectively kills both non-CICs and CICs, as does NTP. Therefore, PAM may be a useful new anti-cancer therapy, targeting various cancer cells including CICs. PMID- 29235206 TI - Sperm storage influences the potential for spontaneous acrosome reaction of the sperm in the newt Cynops pyrrhogaster. AB - Sperm storage is supposed to influence sperm quality, although the details remain unclear. In the present study, we found that sperm stored in a sperm storage site, the vas deferens of Cynops pyrrhogaster, spontaneously undergo acrosome reaction following incubation in Steinberg's salt solution (ST). Percentages of acrosome-reacted sperm increased time-dependently to about 60% in 24 hr. The concentration of cyclic adenosine monophosphate (cAMP) was elevated after incubating sperm in ST, while dibutylyl cAMP induced an acrosome reaction. Chelating of extracellular Ca2+ suppressed the dibutylyl cAMP-induced acrosome reaction as well as spontaneous acrosome reaction in ST. These results suggest that cAMP elevation driven by Ca2+ influx can be a cue for spontaneous acrosome reaction. Relatively low Ca2+ concentration and pH in the vas deferens were sufficient to suppress spontaneous acrosome reaction within 1 hr. In addition, the cysteine rich secretory protein 2 gene was expressed in the vas deferens, indicating that it may be involved in the continuous suppression of spontaneous acrosome reaction. Sperm that underwent spontaneous acrosome reaction in ST was significantly increased when stored in the vas deferens for longer periods, or by males experiencing temperatures in excess of 12 degrees C during hibernation conditions. Percentages of the spontaneously acrosome-reacted sperm were found to differ among males even though they were of identical genetic background. Taken together, C. pyrrhogaster sperm possess the potential for spontaneous acrosome reaction that does not become obvious in the vas deferens, unless promoted in correlation with sperm storage. PMID- 29235207 TI - Discriminating movements of liquid and gas in the rabbit colon with impedance manometry. AB - BACKGROUND: High-resolution impedance manometry is a technique that is well established in esophageal motility studies for relating motor patterns to bolus flow. The use of this technique in the colon has not been established. METHODS: In isolated segments of rabbit proximal colon, we recorded motor patterns and the movement of liquid or gas boluses with a high-resolution impedance manometry catheter. These detected movements were compared to video recorded changes in gut diameter. Using the characteristic shapes of the admittance (inverse of impedance) and pressure signals associated with gas or liquid flow we developed a computational algorithm for the automated detection of these events. KEY RESULTS: Propagating contractions detected by video were also recorded by manometry and impedance. Neither pressure nor admittance signals alone could distinguish between liquid and gas transit, however the precise relationship between admittance and pressure signals during bolus flow could. Training our computational algorithm upon these characteristic shapes yielded a detection accuracy of 87.7% when compared to gas or liquid bolus events detected by manual analysis. CONCLUSIONS & INFERENCES: Characterizing the relationship between both admittance and pressure recorded with high-resolution impedance manometry can not only help in detecting luminal transit in real time, but also distinguishes between liquid and gaseous content. This technique holds promise for determining the propulsive nature of human colonic motor patterns. PMID- 29235209 TI - Contrasting above- and belowground organic matter decomposition and carbon and nitrogen dynamics in response to warming in High Arctic tundra. AB - Tundra regions are projected to warm rapidly during the coming decades. The tundra biome holds the largest terrestrial carbon pool, largely contained in frozen permafrost soils. With warming, these permafrost soils may thaw and become available for microbial decomposition, potentially providing a positive feedback to global warming. Warming may directly stimulate microbial metabolism but may also indirectly stimulate organic matter turnover through increased plant productivity by soil priming from root exudates and accelerated litter turnover rates. Here, we assess the impacts of experimental warming on turnover rates of leaf litter, active layer soil and thawed permafrost sediment in two high-arctic tundra heath sites in NE-Greenland, either dominated by evergreen or deciduous shrubs. We incubated shrub leaf litter on the surface of control and warmed plots for 1 and 2 years. Active layer soil was collected from the plots to assess the effects of 8 years of field warming on soil carbon stocks. Finally, we incubated open cores filled with newly thawed permafrost soil for 2 years in the active layer of the same plots. After field incubation, we measured basal respiration rates of recovered thawed permafrost cores in the lab. Warming significantly reduced litter mass loss by 26% after 1 year incubation, but differences in litter mass loss among treatments disappeared after 2 years incubation. Warming also reduced litter nitrogen mineralization and decreased the litter carbon to nitrogen ratio. Active layer soil carbon stocks were reduced 15% by warming, while soil dissolved nitrogen was reduced by half in warmed plots. Warming had a positive legacy effect on carbon turnover rates in thawed permafrost cores, with 10% higher respiration rates measured in cores from warmed plots. These results demonstrate that warming may have contrasting effects on above- and belowground tundra carbon turnover, possibly governed by microbial resource availability. PMID- 29235208 TI - Optical coherence tomography for assessment of epithelialization in a human ex vivo wound model. AB - The ex vivo human skin wound model is a widely accepted model to study wound epithelialization. Due to a lack of animal models that fully replicate human conditions, the ex vivo model is a valuable tool to study mechanisms of wound reepithelialization, as well as for preclinical testing of novel therapeutics. The current standard for assessment of wound healing in this model is histomorphometric analysis, which is labor intensive, time consuming, and requires multiple biological and technical replicates in addition to assessment of different time points. Optical coherence tomography (OCT) is an emerging noninvasive imaging technology originally developed for noninvasive retinal scans that avoids the deleterious effects of tissue processing. This study investigated OCT as a novel method for assessing reepithelialization in the human ex vivo wound model. Excisional ex vivo wounds were created, maintained at air-liquid interface, and healing progression was assessed at days 4 and 7 with OCT and histology. OCT provided adequate resolution to identify the epidermis, the papillary and reticular dermis, and importantly, migrating epithelium in the wound bed. We have deployed OCT as a noninvasive tool to produce, longitudinal "optical biopsies" of ex vivo human wound healing process, and we established an optimal quantification method of re-epithelialization based on en face OCT images of the total wound area. Pairwise statistical analysis of OCT and histology based quantifications for the rate of epithelialization have shown the feasibility and superiority of OCT technology for noninvasive monitoring of human wound epithelialization. Furthermore, we have utilized OCT to evaluate therapeutic potential of allogeneic adipose stem cells revealing their ability to promote reepithelialization in human ex vivo wounds. OCT technology is promising for its applications in wound healing and evaluation of novel therapeutics in both the laboratory and the clinical settings. PMID- 29235210 TI - Usefulness of cytological analysis in the diagnosis of pancreatic undifferentiated rhabdoid carcinoma. PMID- 29235211 TI - Pretransplant serum procalcitonin level for prediction of early post-transplant sepsis in living donor liver transplantation. AB - AIM: Infection is a frequent cause of in-hospital mortality after liver transplantation (LT). Elimination of possible risks in the pretransplant period, early diagnosis of post-transplant sepsis, and prompt treatment with antimicrobial agents are important. The objectives of this study were to analyze the impact of early post-transplant sepsis on outcomes and to clarify the value of predictive factors for early post-transplant sepsis. METHODS: The study included 136 patients who underwent initial living donor LT (LDLT) at our institute between April 2009 and December 2016. Sepsis was defined using the third international consensus criteria. The results of biochemical tests at the introduction of anesthesia before LDLT were collected for pretransplant evaluation. RESULTS: Post-transplant sepsis was found in 37 patients (27.2%). More patients had a pre-transplant serum procalcitonin (PCT) level >0.5 ng/mL in the sepsis group than in the non-sepsis group (11 [29.7%] vs 10 [10.1%]; P = 0.007). The 1-year survival rate in the sepsis group was significantly lower than in the non-sepsis group (53.8% vs 87.2%; P < 0.001). Multivariate analysis identified pretransplant serum PCT >0.5 ng/mL (odds ratio, 3.8; 95% confidence interval, 1.3-10.9; P = 0.01) as the only independent risk factor for post transplant sepsis. CONCLUSIONS: Survival of patients with early post-transplant sepsis was poor and the incidence of sepsis was associated with the pretransplant serum PCT level. Re-evaluation of the general condition and rescheduling of LT should be considered in a patient with pretransplant serum PCT >0.5 ng/mL. PMID- 29235212 TI - High-Performance As-Cast Nonfullerene Polymer Solar Cells with Thicker Active Layer and Large Area Exceeding 11% Power Conversion Efficiency. AB - In this work, a nonfullerene polymer solar cell (PSC) based on a wide bandgap polymer donor PM6 containing fluorinated thienyl benzodithiophene (BDT-2F) unit and a narrow bandgap small molecule acceptor 2,2'-((2Z,2'Z)-((4,4,9,9-tetrahexyl 4,9-dihydro-s-indaceno[1,2-b:5,6-b']dithiophene-2,7 diyl)bis(methanylylidene))bis(3-oxo-2,3-dihydro-1H-indene-2,1 diylidene))dimalononitrile (IDIC) is developed. In addition to matched energy levels and complementary absorption spectrum with IDIC, PM6 possesses high crystallinity and strong pi-pi stacking alignment, which are favorable to charge carrier transport and hence suppress recombination in devices. As a result, the PM6:IDIC-based PSCs without extra treatments show an outstanding power conversion efficiency (PCE) of 11.9%, which is the record value for the as-cast PSC devices reported in the literature to date. Moreover, the device performances are insensitive to the active layer thickness (~95-255 nm) and device area (0.20-0.81 cm2 ) with PCEs of over 11%. Besides, the PM6:IDIC-based flexible PSCs with a large device area of 1.25 cm2 exhibit a high PCE of 6.54%. These results indicate that the PM6:IDIC blend is a promising candidate for future roll-to-roll mass manufacturing and practical application of highly efficient PSCs. PMID- 29235213 TI - Models meet data: Challenges and opportunities in implementing land management in Earth system models. AB - As the applications of Earth system models (ESMs) move from general climate projections toward questions of mitigation and adaptation, the inclusion of land management practices in these models becomes crucial. We carried out a survey among modeling groups to show an evolution from models able only to deal with land-cover change to more sophisticated approaches that allow also for the partial integration of land management changes. For the longer term a comprehensive land management representation can be anticipated for all major models. To guide the prioritization of implementation, we evaluate ten land management practices-forestry harvest, tree species selection, grazing and mowing harvest, crop harvest, crop species selection, irrigation, wetland drainage, fertilization, tillage, and fire-for (1) their importance on the Earth system, (2) the possibility of implementing them in state-of-the-art ESMs, and (3) availability of required input data. Matching these criteria, we identify "low hanging fruits" for the inclusion in ESMs, such as basic implementations of crop and forestry harvest and fertilization. We also identify research requirements for specific communities to address the remaining land management practices. Data availability severely hampers modeling the most extensive land management practice, grazing and mowing harvest, and is a limiting factor for a comprehensive implementation of most other practices. Inadequate process understanding hampers even a basic assessment of crop species selection and tillage effects. The need for multiple advanced model structures will be the challenge for a comprehensive implementation of most practices but considerable synergy can be gained using the same structures for different practices. A continuous and closer collaboration of the modeling, Earth observation, and land system science communities is thus required to achieve the inclusion of land management in ESMs. PMID- 29235214 TI - The effect of administration of copper nanoparticles to chickens in their drinking water on the immune and antioxidant status of the blood. AB - The aim of this experiment was to determine what dosage of copper (Cu) nanoparticles, added to a standard dietary supplementation with copper sulfate, would improve antioxidant and immune defense in chickens. The experiment was conducted with 126 broiler chickens assigned to seven treatments with three pens per treatment and six broiler chickens per pen. The basal-diet treatment did not receive Cu nanoparticles (nano-Cu) and as shown by analyses it was Cu-deficient ( 29% vs. National Research Council (NRC) recommendations; 5.7 vs. 8 mg/kg). Broiler chickens received nano-Cu (0.5, 1.0 or 1.5 mg/kg body weight per day) via a tube into the crop over three 3-day periods (days 8-10, 22-24 and 36-38) or three 7-day periods (days 8-14, 22-28 and 36-42). As a result, in the nano-Cu treated broilers the total experimental Cu intake was from -11% to +96% versus NRC recommendations. At the age of 42 days of broilers, their blood indices were determined. The obtained results showed that correction of the deficient basal diet of chickens with nano-Cu to a level of copper exceeding the NRC recommendation by 54% increased the antioxidant potential of the organism and inhibited lipid peroxidation. At the dosage of +96% versus NRC, some symptoms of a deterioration in antioxidant status appeared (a decrease in the level of glutathione plus glutathione disulfide and an increase in superoxide dismutase, catalase and ceruloplasmin activity and in lipid hydroperoxide content). Additionally, +7% versus the recommended Cu dietary level was followed by unfavorable results, indicating a deterioration in red blood cell parameters and stimulation of the immune system (an increase in interleukin-6, immunoglobulin A (IgA), IgM and IgY). To conclude, it was shown that it is possible to simultaneously increase antioxidant and immune defense of chickens by supplementing their diets with nano-Cu - up to 12 mg per bird during 6 weeks of feeding, that is to a level no more than 7% over the NRC recommendation for growing broiler chickens. PMID- 29235215 TI - Cloning-free template DNA preparation for cell-free protein synthesis via two step PCR using versatile primer designs with short 3'-UTR. AB - Cell-free protein synthesis (CFPS) systems largely retain the endogenous translation machinery of the host organism, making them highly applicable for proteomics analysis of diverse biological processes. However, laborious and time consuming cloning procedures hinder progress with CFPS systems. Herein, we report the development of a rapid and efficient two-step polymerase chain reaction (PCR) method to prepare linear DNA templates for a wheat germ CFPS system. We developed a novel, effective short 3'-untranslated region (3'-UTR) sequence that facilitates translation. Application of the short 3'-UTR to two-step PCR enabled the generation of various transcription templates from the same plasmid, including fusion proteins with N- or C-terminal tags, and truncated proteins. Our method supports the cloning-free expression of target proteins using an mRNA pool from biological material. The established system is a highly versatile platform for in vitro protein synthesis using wheat germ CFPS. PMID- 29235216 TI - Surface Molding of Microscale Hydrogels with Microactuation Functionality. AB - This work describes the fabrication of numerous hydrogel microstructures (MU gels) via a process called "surface molding." Chemically patterned elastomeric assembly substrates were used to organize and manipulate the geometry of liquid prepolymer microdroplets, which, following photo-initiated crosslinking, maintained the desired morphology. By adjusting the state of strain during the crosslinking process, a continua of structures could be created using one pattern. These arrays of MU-gels have stimuli-responsive properties that are directly applicable to actuation where the basis shape and array geometry of the MU-gels can be used to rationally generate microactuators with programmed motions. As a method, "surface molding," represents a powerful addition to the soft-lithographic toolset that can be readily applied to the simultaneous synthesis of large numbers of geometrically and functionally distinct polymeric microstructures. PMID- 29235217 TI - Heterologous Protein Expression in Pichia pastoris: Latest Research Progress and Applications. AB - Pichia pastoris is a well-known platform strain for heterologous protein expression. Over the past five years, different strategies to improve the efficiency of recombinant protein expression by this yeast strain have been developed; these include a patent-free protein expression kit, construction of the P. pastoris CBS7435Ku70 platform strain with its high efficiency in site specific recombination of plasmid DNA into the genomic DNA, the design of synthetic promoters and their variants by combining different core promoters with multiple putative transcription factors, the generation of mutant GAP promoter variants with various promoter strengths, codon optimization, engineering the alpha-factor signal sequence by replacing the native glutamic acid at the Kex2 cleavage site with the other 19 natural amino acids and the addition of mammalian signal sequence to the yeast signal sequence, and the co-expression of single chaperones, multiple chaperones or helper proteins that aid in recombinant protein folding. Publically available high-quality genome data from multiple strains of P. pastoris GS115, DSMZ 70382, and CBS7435 and the continuous development of yeast expression kits have successfully promoted the metabolic engineering of this strain to produce carotenoids, xanthophylls, nootkatone, ricinoleic acid, dammarenediol-II, and hyaluronic acid. The cell-surface display of enzymes has obviously increased enzyme stability, and high-level intracellular expression of acyl-CoA and ethanol O-acyltransferase, lipase and d-amino acid oxidase has opened up applications in whole-cell biocatalysis for producing flavor molecules and biodiesel, as well as the deracemization of racemic amino acids. High-level expression of various food-grade enzymes, cellulases, and hemicellulases for applications in the food, feed and biorefinery industries is in its infancy and needs strengthening. PMID- 29235218 TI - Efficacy and safety of rifaximin in Japanese patients with hepatic encephalopathy: A phase II/III, multicenter, randomized, evaluator-blinded, active-controlled trial and a phase III, multicenter, open trial. AB - AIM: The efficacy and safety of rifaximin in the treatment of hepatic encephalopathy (HE) are widely known, but they have not been confirmed in Japanese patients with HE. Thus, two prospective, randomized studies (a phase II/III study and a phase III study) were carried out. METHODS: Subjects with grade I or II HE and hyperammonemia were enrolled. The phase II/III study, which was a randomized, evaluator-blinded, active-comparator, parallel-group study, was undertaken at 37 institutions in Japan. Treatment periods were 14 days. Eligible patients were randomized to the rifaximin group (1200 mg/day) or the lactitol group (18-36 g/day). The phase III study was carried out in the same patients previously enrolled in the phase II/III study, and they were all treated with rifaximin (1200 mg/day) for 10 weeks. RESULTS: In the phase II/III study, 172 patients were enrolled. Blood ammonia (B-NH3 ) concentration was significantly improved in the rifaximin group, but the difference between the two groups was not significant. The portal systemic encephalopathy index (PSE index), including HE grade, was significantly improved in both groups. In the phase III study, 87.3% of enrolled patients completed the treatment. The improved B-NH3 concentration and PSE index were well maintained from the phase II/III study during the treatment period of the phase III study. Adverse drug reactions (ADRs) were seen in 13.4% of patients who received rifaximin, but there were no severe ADRs leading to death. CONCLUSION: The efficacy of rifaximin is sufficient and treatment is well tolerated in Japanese patients with HE and hyperammonemia. PMID- 29235220 TI - Not Oligomers but Amyloids are Cytotoxic in the Membrane-Mediated Amyloidogenesis of Amyloid-beta Peptides. AB - The formation of neurotoxic aggregates by amyloid-beta peptide (Abeta) is considered to be a key step in the onset of Alzheimer's disease. It is widely accepted that oligomers are more neurotoxic than amyloid fibrils in the aqueous phase aggregation of Abeta. Membrane-mediated amyloidogenesis is also relevant to the pathology, although the relationship between the aggregate size and cytotoxicity has remained elusive. Here, aggregation processes of Abeta on living cells and cytotoxic events were monitored by fluorescence techniques. Abeta formed amyloids after forming oligomers composed of ~10 Abeta molecules. The formation of amyloids was necessary to activate apoptotic caspase-3 and reduce the ability of the cell to proliferate; this indicated that amyloid formation is a key event in Abeta-induced cytotoxicity. PMID- 29235221 TI - Liver transplant for metastatic pancreatoblastoma: 7-year event-free survival after chemotherapy, pancreatectomy, complete hepatectomy, and liver transplant. AB - Pancreatoblastoma is a rare malignant tumor in children. Surgical resection of the tumor is necessary for cure; however, due to its aggressive nature, it is often unresectable at presentation due to tumor size, local invasion, and/or metastasis. Because it is a rare tumor, there is currently no standard treatment regimen. We report a case of a 4-year-old boy who presented with metastatic pancreatoblastoma with multiple large metastases involving all four sectors of the liver. We began treatment with chemotherapy (cisplatin, 5FU, vincristine, and doxorubicin), which significantly reduced the tumor burden in both the pancreas and liver. We then performed a staged subtotal pancreatectomy, complete hepatectomy, and living donor left lateral segment liver transplant. This was followed by postoperative adjuvant chemotherapy. Our patient is alive and healthy and has now been tumor-free for 7 years with no tumor relapse. PMID- 29235219 TI - Neonatal morbidity due to maternal use of two antidepressant drugs. PMID- 29235222 TI - Profile of advanced nursing practice in Spain: A cross-sectional study. AB - In this study, we described the profile of advanced nursing practice in Spain. A cross-sectional study design was used to explore the extent and patterns of advanced nursing practice activity within the domains of expert care planning, integrated care, interprofessional collaboration, education, research, evidence based practice, and professional leadership. Data were collected in 2015/2016. Purposive sampling yielded a sample of 165 specialist and expert nurses employed by a dual tertiary and community hospital in an urban setting. The study included specialist and expert nurses who had a higher practice profile than registered general nurses. The performance of activities according to age, current position, years of experience, nursing grade, and education was compared. Practice domains were more strongly influenced by the predictors of nursing position and professional career ladder. Age and experience predictors were found to be weak predictors of advanced practice domains. This study offers essential information of the nursing workforce, and clarifies both the advanced nursing practice profile and nomenclature in the context of study. PMID- 29235223 TI - Carbon Monoxide Oxidation on Metal-Supported Monolayer Oxide Films: Establishing Which Interface is Active. AB - Ultrathin (monolayer) films of transition metal oxides grown on metal substrates have recently received considerable attention as promising catalytic materials, in particular for low-temperature CO oxidation. The reaction rate on such systems often increases when the film only partially covers the support, and the effect is commonly attributed to the formation of active sites at the metal/oxide boundary. By studying the structure and reactivity of FeO(111) films on Pt(111), it is shown that, independent of the film coverage, CO oxidation takes place at the interface between reduced and oxidized phases in the oxide film formed under reaction conditions. The promotional role of a metal support is to ease formation of the reduced phase by reaction between CO adsorbed on metal and oxygen at the oxide island edge. PMID- 29235224 TI - Cobalt(II)-based Metalloradical Activation of 2-(Diazomethyl)pyridines for Radical Transannulation and Cyclopropanation. AB - A new catalytic method for the denitrogenative transannulation/cyclopropanation of in-situ-generated 2-(diazomethyl)pyridines is described using a cobalt catalyzed radical-activation mechanism. The method takes advantage of the inherent properties of a CoIII -carbene radical intermediate and is the first report of denitrogenative transannulation/cyclopropanation by a radical activation mechanism, which is supported by various control experiments. The synthetic benefits of the metalloradical approach are showcased with a short total synthesis of (+/-)-monomorine. PMID- 29235225 TI - No change in type 2 diabetes prevalence in children and adolescents over 10 years: Update of a population-based survey in South Germany. AB - Objective of this study was to analyze prevalence changes in type 2 diabetes (T2D) among children and adolescents over the last 10 years. We performed a cross sectional survey in Baden-Wurttemberg (BW), Germany, by using a written questionnaire and comparing these results with T2D prevalence data from the same area retrieved in 2004/2005. In 2016, 50 patients with T2D under 20 years of age were registered in BW, Germany, which corresponds to a prevalence rate of 2.42 per 100 000 (95% confidence interval [CI]: 1.75-3.09). The prevalence rate found in the same geographic area 10 years prior was 2.30 per 100 000 (95% CI: 1.70 2.90). Overall, 70% of T2D patients of this age group were treated by adult diabetologists. Concisely the prevalence of T2D in children and adolescents is still low in South Germany, remaining practically unchanged over the past decade. PMID- 29235226 TI - Reduced therapeutic effect of antiviral drugs in patients with hepatitis B virus reactivation after hematopoietic stem cell transplantation. AB - AIM: Patients with resolved hepatitis B virus (HBV) infection following hematopoietic stem cell transplantation (HSCT) are potentially at high risk of HBV reactivation. Although antiviral drug therapy is recommended when HBV DNA reappears in the serum, drug efficacy after HBV reactivation remains unclear. METHODS: Host immune response against HBV was investigated by immunological analyses at 12 months after entecavir (ETV) treatment in six HSCT-treated and five non-HSCT-treated patients with HBV reactivation, and 18 patients with chronic hepatitis B (CHB). Peripheral HBV-specific CD8+ T cells were analyzed for total numbers by flow cytometry and tetramer staining, as was intracellular gamma interferon (IFN-gamma) production and CD107a expression in response to HBV peptides. Interleukin-10 (IL-10)-expressing CD19+ B-cell count and serum inflammatory cytokine levels were also analyzed. RESULTS: Serum HBV DNA was detectable in HSCT-treated patients with HBV reactivation at 12 months compared with other groups, indicating insufficient ETV efficacy against HBV. The HBV specific CD8+ T-cell counts in HSCT-treated patients with HBV reactivation were significantly lower compared with those in non-HSCT patients. Additionally, IFN gamma production and CD107a expression by CD8+ T cells after incubation with HBV peptides was significantly reduced in HSCT-treated compared with CHB patients at 12 months after ETV treatment. Conversely, HSCT-treated patient serum IL-10 levels were significantly elevated compared with those in non-HSCT patients. Finally, IL-10-producing CD19+ B-cell counts were increased in HSCT-treated compared with CHB patients. CONCLUSION: After HBV reactivation, ETV efficacy was impaired in HSCT-treated patients as evidenced by low HBV-specific CD8+ T-cell counts and high B-cell IL-10 production. PMID- 29235227 TI - Peptide-Based Fluorescent Probes for Deacetylase and Decrotonylase Activity: Toward a General Platform for Real-Time Detection of Lysine Deacylation. AB - Histone deacetylases regulate the acetylation levels of numerous proteins and play key roles in physiological processes and disease states. In addition to acetyl groups, deacetylases can remove other acyl modifications on lysines, the roles and regulation of which are far less understood. A peptide-based fluorescent probe for single-reagent, real-time detection of deacetylase activity that can be readily adapted for probing broader lysine deacylation, including decrotonylation, is reported. Following cleavage of the lysine modification, the probe undergoes rapid intramolecular imine formation that results in marked optical changes, thus enabling convenient detection of deacylase activity with good statistical Z' factors for both absorption and fluorescence modalities. The peptide-based design offers broader isozyme scope than that of small-molecule analogues, and is suitable for probing both metal- and nicotinamide adenine dinucleotide (NAD+ )-dependent deacetylases. With an effective sirtuin activity assay in hand, it is demonstrated that iron chelation by Sirtinol, a commonly employed sirtuin inhibitor, results in an enhancement in the inhibitory activity of the compound that may affect its performance in vivo. PMID- 29235228 TI - Experiences of Singapore nurses as second victims: A qualitative study. AB - Nurses, like other healthcare professionals, such as physicians, pharmacists, and therapists, are susceptible to unanticipated patient harm, in which they suffer as second victims due to the immense personal and professional impact from the adverse event. The aim of the present study was to explore the psychological responses, coping strategies, and support needs of Singapore nurses as second victims of adverse events. A descriptive qualitative study was adopted. Eight participants (6 women and 2 men) who had been involved in an adverse event were interviewed and audio-recorded. Thematic analysis was performed to analyze the data. Seven themes emerged from the thematic analysis: responding psychologically after the event, feeling others' prejudice, having intrusive thoughts, drawing valuable lessons from the event, coping to recover after the event, taking responsibility for the mistakes made, and finding self-identity. The harmful effects of adverse events on nurses are long lasting. Second-victim nurses adopted various coping strategies to recover. The findings from the present study will guide the development of effective second-victim support programs. PMID- 29235229 TI - Self-imposed pressure or organizational norms? Further examination of the construct of workplace telepressure. AB - Information and communication technologies (ICTs) are rapidly becoming indispensable organizational tools. Though the benefits of such technologies have been trumpeted, recent research has examined the unique pressures that may be introduced through the lens of a construct called workplace telepressure, defined as an urge for and preoccupation with quickly responding to ICTs (e.g., email). The current study further explores the workplace telepressure construct as a unique contributor to measures of workplace well-being over and above perceived workplace demands and individual differences, introducing new constructs into the study of workplace telepressure. Furthermore, the study critically evaluates the term "telepressure" as applied to the underlying construct, as "pressure" may connote a perception of external force being placed on an individual, whereas the definition offered by past research identifies a preoccupation and urge to respond immediately to ICT messages, which may be internally generated. Finally, the ability of workplace telepressure to account for unique variance in workplace subjective well-being measures is investigated. PMID- 29235230 TI - Multidimensional factors associated with the loss of independence: A population based longitudinal study. AB - AIM: To clarify the factors associated with loss of independence multidimensionally over a 3-year period among community-dwelling older adults. METHODS: The survey was exclusively carried out by the local government for people aged >65 years who were independent at baseline living in H-City, a mid sized urban city in Japan. The participants completed a self-administered postal questionnaire, and we obtained data regarding their loss of independence from administrative records 3 years later. RESULTS: A total of 22 328 participants completed the follow up (baseline mean age 71.6 years). At follow up, 998 (4.3%) participants were categorized as dependent, with 606 requiring partial support in toileting, bathing and so on (mild loss of independence), and 392 requiring complete support (severe loss). Factors independently associated with mild loss of independence after 3 years for both men and women were advanced age, low physical function, low nutritional status, low cognitive function and high depression risk. In contrast, factors independently associated with severe loss of independence were advanced age, low physical function and high depression risk in men, and advanced age, and low physical and cognitive function in women. CONCLUSIONS: We clarified the variety of factors associated with loss of independence according to its severity, and the strength of those independent associations was different in the whole city longitudinal study. The present study's findings have important clinical implications for the development of better preventive medicine to establish a society of healthy longevity. Geriatr Gerontol Int 2018; 18: 448-455. PMID- 29235231 TI - Influencing factors in quantitative measurement using activated platelet levels and platelet-activating capacity for the assessment of thrombosis in pre metabolic syndrome and type 2 diabetes mellitus. AB - Activated platelet levels and platelet-activating capacity are well recognized as useful index parameters for the physiological and pharmacological prediction of thrombotic events. Recently, quantitative measurements for platelet functions using a flow cytometer have been increasing gradually. However, the relation of physiological factors, such as sex, aging, and laboratory tests, to platelet functions has not been well documented. We conducted a blood analysis of people with normal/pre-metabolic syndrome and patients with type 2 diabetes mellitus to clarify the pathological factors. The levels of basal (non-stimulated)-activated, platelet-expressed P-selectin and activated platelet stimulated by agonists were measured by a flow cytometer, and ratios of platelet-activating capacity were also calculated. Statistical analyses indicated significantly high basal activated platelet in pre-metabolic syndrome, and basal-activated platelet was positively associated with hyperlipidemia and hepatic damage. Platelet-activating capacity was significantly low in aging and hyperlipidemia, but high in hyperglycemia, and was negatively associated with hyperlipidemia and hepatic damage. Aging and high nutrient condition impaired platelet functions. Quantitative measurements of basal-activated platelet and platelet-activating capacity are precise parameters for the prediction of thrombotic events. PMID- 29235232 TI - Signs of electrocochleography on endolymphatic sac decompression for patients with Meniere's Disease: Our experience in 12 patients. PMID- 29235233 TI - Sodium 4-mercaptophenolate capped CdSe/ZnS quantum dots as a fluorescent probe for pH detection in acidic aqueous media. AB - Development of the fluorescent pH detection method is promising due to the sensitivity, easy operation, and low-cost, etc. However, traditional organic fluorophores have still some disadvantages such as the tedious preparation and purification as well as low photostability and water solubility, which limits the rapid detection application. Semiconductor quantum dots (QDs) have recently risen to prominence as an alternative for organic fluorophores in fluorescence analysis by virtue of their convenient synthesis and superior optical properties. In this study, we report on sodium 4-mercaptophenolate functionalized CdSe/ZnS QDs (denoted as - OPhS-QDs), which can serve as a selective "on-off" fluorescence probe for aqueous media pH. - OPhS-QDs exhibit strong fluorescence in near neutral medium. As a Lewis organic base, - OPhS- moieties on QDs surface easily binds to proton under acidic conditions to yield 4-mercaptophenol capped QDs (i.e. HOPhS-QDs), which acts as an efficient hole trapper. As a result, the QDs photoluminescence (PL) is switched off. Under optimal conditions, the present probe exhibits a good linear relationship between fluorescence response and pH values in the pH range 3.0-5.2. Furthermore, the present probe exhibits a high selectivity for proton over other common cations and has been successfully used for pH detection in real water samples. PMID- 29235234 TI - 'Holding on to life': An ethnographic study of living well at home in old age. AB - In recent years, much attention has been paid to how older people living at home can remain independent and manage their illness themselves, while less attention has been given to those who have become frail and need assistance with challenges of everyday life. In this article, I drew on Latimer's formulation of care for frail older people as relational and world-making and on Foucault's work related to the care of the self in developing an understanding of how frail older persons manage to live well at home in the final years of their lives. I use data from an ethnographic study of home care nursing in the homes of 15 frail older people to develop an understanding of how their care at home can be developed. The participants were holding on to life, which reflected their vitality and vulnerability as well as agency in continuing to explore ways to preserve and build their world at home. With declining ability and stamina relations with material things, relatives and official care workers become of central importance in holding on to life. Home care services can be thought of as part of life, as world-forming, where workers contribute to daily activities that support living well at home. PMID- 29235235 TI - Review article: Best practice management of common ankle and foot injuries in the emergency department (part 2 of the musculoskeletal injuries rapid review series). AB - Ankle and foot injuries are the most common musculoskeletal injuries presenting to Australian EDs and are associated with a large societal and economic impact. The quality of ED care provided to patients with ankle and foot fractures or soft tissue injuries is critical to ensure the best possible outcomes for the patient. This rapid review investigated best practice for the assessment and management of common ankle and foot injuries in the ED. Databases including PubMed, CINAHL, EMBASE, TRIP and the grey literature, including relevant organisational websites, were searched in 2017. Primary studies, systematic reviews and guidelines were considered for inclusion. English language articles published in the last 12 years that addressed the acute assessment, management or prognosis in the ED were included. Data extraction of included articles was conducted, followed by quality appraisal to rate the level of evidence where possible. The search revealed 1242 articles, of which 71 were included in the review (n = 22 primary articles, n = 35 systematic reviews and n = 14 guidelines). This rapid review provides clinicians managing fractures and soft tissue injuries of the ankle and foot in the ED a summary of the best available evidence to enhance the quality of care for optimal patient outcomes. Following a thorough history and physical examination, including the application of the Ottawa ankle rules, ED clinicians should not only provide a diagnosis, but rate the severity of soft tissue injuries, or stability of fractures and dislocations, which are the pivotal decision points in guiding ED treatment, specialist referral and the follow-up plan. PMID- 29235236 TI - Copper Catalysis and Organocatalysis Showing the Way: Synthesis of Selenium Containing Highly Functionalized 1,2,3-Triazoles. AB - This article provides a comprehensive overview of reported methods - particularly copper- and organocatalyzed reactions - for the regioselective syntheses of selenium-containing 1,2,3-triazoles systems. These chemical entities are prevalent cores in biologically active compounds and functional materials. In view of their unique properties, substantial efforts have been paid for the design and development of practical approaches for the synthesis of these scaffolds. PMID- 29235237 TI - Community-based preventive activities in the Public Dental Service in Norway. AB - OBJECTIVES: The purpose of this study was to describe community-based preventive interventions undertaken by the dental team outside the dental clinics in Norway, from the dental hygienists' and the dentists' perspective, with the main focus on target groups and existing guidelines and routines for these activities. A secondary aim was to identify the personnel responsible for developing the local guidelines and the knowledge sources for the guidelines. METHODS: With the assistance of the Chief Dental Officers in 15 Public Dental Service (PDS) regions, questionnaires were emailed to the local clinics (n = 421). In each, the most experienced dental hygienist and dentist were asked to respond; 215 dentists and 166 and dental hygienists responded (60%). RESULTS: Almost 40% of the respondents reported that their clinic had guidelines on community-based activities conducted outside the clinics. Dental hygienists and local chief dentists were responsible for planning them. The main target groups were young children and the dependent elderly; the majority of the activities were carried out at child welfare centres and for personnel at nursing homes or for home care nurses. CONCLUSION: At the regional and local level, a more strategic and coordinated approach to the provision of community-based activities is needed, including assessment of oral health needs among population groups. Continuous documentation and evaluation of results are necessary for optimal use of available resources and to facilitate an evidence-based approach. PMID- 29235238 TI - Study of the controlled assembly of DNA gated PEI/Chitosan/SiO2 fluorescent sensor. AB - In this paper, polyethylenimine (PEI) and Chitosan were simultaneously one-step doped into silicon dioxide (SiO2 ) nanoparticles to synthesize PEI/Chitosan/SiO2 composite nanoparticles. The polymer PEI contained a large amount of amino groups, which can realize the amino functionalized SiO2 nanoparticles. And, the good pore forming effect of Chitosan was introduced into SiO2 nanoparticles, and the resulting composite nanoparticles also had a porous structure. In pH 7.4 phosphate buffer solution (PBS), the amino groups of PEI had positive charges, and therefore the fluorescein sodium dye molecule can be loaded into the channels of PEI/Chitosan/SiO2 composite nanoparticles by electrostatic adsorption. Furthermore, utilizing the diversity of DNA molecular conformation, we designed a high sensitive controllable assembly of DNA gated fluorescent sensor based on PEI/Chitosan/SiO2 composite nanoparticles as loading materials. The factors affecting the sensing performance of the sensor were investigated, and the sensing mechanism was also further studied. PMID- 29235240 TI - Gender differences in first self-perceived signs and symptoms in patients with an at-risk mental state and first-episode psychosis. AB - AIM: Gender differences in the current symptomatology of patients with psychotic disorders have previously been described in the literature. However, it has not yet been investigated whether gender differences exist in the very first self perceived signs or symptoms of illness onset. The aim of this study was to investigate this aspect in at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. METHODS: ARMS and FEP were recruited via the early detection of psychosis (FePsy) clinic Basel, Switzerland. The Basel Interview for Psychosis (BIP) was used to retrospectively assess the first 3 self-perceived signs and symptoms at illness onset. Differences between gender and patient groups on single item and symptom cluster levels were analysed using logistic regression models. RESULTS: One-hundred-thirty six ARMS (91 men, 45 women) and 89 FEP patients (63 men, 26 women) could be recruited for this study. On a single item level, women more frequently reported "unusual anxiety, fears" and men (at a trend level) "social withdrawal" as being among their 3 first self-perceived symptoms, independent of diagnostic group. On the symptom cluster level, women more frequently reported "increased worrying/anxiety" and (sub-threshold) "hallucinations", independent of diagnostic group. Problems with "thinking, concentration" were reported more frequently by men in the ARMS group only. CONCLUSION: Our results suggest that only few and relatively small gender differences exist in the first self-perceived signs and symptoms. While men initially mainly notice negative/cognitive symptoms, women first notice (sub threshold) positive and affective symptoms. PMID- 29235241 TI - Risky sex behaviours among college students: The psychosocial profile. AB - AIMS: Risky sex behaviours among college students are a growing public health concern. However, few studies have profiled these behaviours using a large range of psychosocial correlates. METHODS: Participants were 6874 undergraduate and postgraduate students (64.7% female, age range 17-25 years, M = 20.43 years, SD = 1.86 years) drawn from 13 higher-level institutions in Ireland. RESULTS: Regarding prevalence, 75% of the sample report that they have been, or are currently sexually active. Of this sexually active cohort (n = 5111), 27.2% report early sexual initiation, 29.5% report 5 or more lifetime sexual partners and 12.1% report 2 or more sexual partners in the past 3 months. In addition, 47.7% of students report inconsistent condom use and 39.5% report inconsistent use of other contraceptive methods in the past 3 months. Using multivariate logistic regression analyses, significant correlates of risky sex behaviour are identified across 5 groups of psychosocial predictors (demographic, sexuality and relationships, substance use, mental well-being and personal resources). Differences between males and females and between different sexual orientations are highlighted. CONCLUSIONS: Suggestions are made for sexual education and intervention programs to specifically target subgroups of the student population. PMID- 29235239 TI - Familial risks in urolithiasis in the population of Sweden. AB - OBJECTIVE: To assess detailed familial risks for medically diagnosed urolithiasis (UL, urinary tract stone disease) based on nationwide hospital and population records. PATIENTS/SUBJECTS AND METHODS: Subjects were identified from the Swedish Multigeneration Register in which there were 211 718 patients with UL. Standardised incidence ratios (SIRs) were calculated by comparison to individuals without a family history of UL. RESULTS: The highest familial SIRs were invariably found for the same (concordant) type of UL: 2.18 for kidney, 2.20 for ureter, and 1.93 for bladder. SIRs increased from 1.84, when one parent was affected, to 3.54 when both parents were affected, which was a multiplicative interaction. The SIR was 1.79 when one sibling was affected but it increased to 24.91 when two siblings were affected. Such excessive risks (5.2% of familial cases) are probably explained by high-penetrant genes. A low SIR of 1.29 between spouses suggested a minor contribution by shared environmental factors on the familial risk. CONCLUSIONS: The results point to underlying genetic causes for the observed familial clustering and establish the genetic landscape of UL. Family histories should be taken in UL diagnostics and prevention could follow guidelines recommended for recurrent UL. PMID- 29235242 TI - The effect of an educational intervention, based on clinical simulation, on the diagnosis of rheumatoid arthritis and osteoarthritis. AB - OBJECTIVE: The aim of the present study was to evaluate the effectiveness of an educational tool for general physicians, based on rheumatological clinical simulation, for the diagnosis of rheumatoid arthritis and osteoarthritis. METHODS: A randomized clinical study was carried out, in which the physician research subjects were assigned to one of two groups: the experimental group (educational intervention for rheumatoid arthritis with clinical simulation) or the control group (educational intervention for the basic aspects of the diagnosis and treatment of osteoporosis). Four weeks after the educational intervention, the members of both groups completed an examination that included four clinical cases with real patients, two clinical cases with two clinical simulation models and six virtual clinical cases. In this examination, the participants noted clinical findings, established a diagnosis and defined the complementary tests they would request, if necessary, to corroborate their diagnosis. RESULTS: A total of 160 doctors participated (80 in the active educational intervention for rheumatoid arthritis and 80 in the control group), of whom 89 were women (56%). The mean age was 35 (standard deviation 7.7) years. Success was defined as a physician correctly diagnosing at least 10 of the 12 cases presented. A significant difference of 81.3% (95% confidence interval 72 90%; p < 0.001) in success was found in favour of the active group (88.8% versus 7.5%). A greater number of correct answers was found in the active group compared with the control group in the detection of clinical findings and in the number of complementary tests requested (p < 0.001). CONCLUSIONS: The study showed the effectiveness of an educational intervention based on clinical simulation to improve the diagnostic approach to rheumatoid arthritis and osteoarthritis. The results open a new horizon in the teaching of rheumatology. PMID- 29235243 TI - A waiting time of 7 min is sufficient to reduce bleeding in oculoplastic surgery following the administration of epinephrine together with local anaesthesia. AB - OBJECTIVE: The time taken to reach maximal haemostatic effect following local anaesthesia with epinephrine is generally believed to be <10 min. This is based on clinical experience and indirect measurements of perfusion using methods such as laser Doppler flowmetry and oxygen spectroscopy. However, the only study in which bleeding has been measured quantitatively in an intra-operative setting in humans showed that the full haemostatic effect was not achieved until 30 min after anaesthesia. The aim of this study was to determine the time taken to reach maximum haemostatic effect when using epinephrine for local anaesthesia in oculoplastic surgery. METHODS: Intra-operative bleeding following infiltration anaesthesia with either lidocaine 20 mg/ml (2%) or lidocaine + epinephrine 12.5 MUg/ml (1:80 000) was measured after 7, 15 and 30 min in the eyelids of 16 patients undergoing upper eyelid blepharoplasty. RESULTS: Bleeding was decreased by 74.6% (with 95% CI, 6.16-87.6%) 7 min after the injection of lidocaine + epinephrine (p = 0.0048) compared with lidocaine without epinephrine. There was no further decrease in bleeding after 15 or 30 min (p = n.s.). CONCLUSION: The optimal time for skin incision in eyelid surgery is within 7 min of injection of lidocaine with epinephrine. Waiting longer does not lead to a further decrease in bleeding. PMID- 29235245 TI - Corrigendum: Trace H2 O2 -Assisted High-Capacity Tungsten Oxide Electrochromic Batteries with Ultrafast Charging in Seconds. PMID- 29235247 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 51/2017. PMID- 29235246 TI - Corrigendum: Copper-Catalyzed Synthesis of gamma-Amino Acids Featuring Quaternary Stereocenters. PMID- 29235244 TI - Exercise and heart failure: an update. AB - The present update is dedicated to the evolution of the interaction between heart failure (HF) and exercise and how the scientific community has handled it. Indeed, on the one hand, HF is a leading cause of morbidity and mortality with a stable prevalence from 1998 onward varying between 6.3% and 13.3%. On the other hand, exercise is seen as a diagnostic and prognostic tool as well as a therapeutic intervention in chronic HF. More precisely, the knowledge, the clinical application, and the research interest on the mutual interactions between exercise and HF have different phases in disease progression: Before HF onset (past): exercise provides protective benefit in preventing HF (primary prevention). With HF present: exercise improvement with training provides benefits in HF (secondary prevention). The prediction of future in HF patients: exercise impairment, as a leading characteristic of HF, is used as a prognostic factor. PMID- 29235248 TI - Smoking and pregnancy: getting dads 'on the bus'. PMID- 29235249 TI - Anticancer effects of resveratrol in canine hemangiosarcoma cell lines. AB - Hemangiosarcoma (HSA) is a highly malignant tumour with aggressive biological behaviour. HSAs are more common in dogs than other domestic animals. The median survival time of dogs with HSA remains short, even with chemotherapy and surgery. Therefore, there is a critical need to improve the adjuvant chemotherapeutic regimens to improve clinical outcomes in dogs with HSA. Resveratrol has been shown to possess strong anti-proliferative and/or pro-apoptotic properties in human cancer cell lines. Nevertheless, the potential anticancer effects of resveratrol have not been reported in canine HSAs. The objective of this study is to determine the growth inhibitory effects of resveratrol in HSA cells when used alone or in combination with doxorubicin, a commonly used chemotherapeutic agent. Frog and DD-1 canine HSA cell lines were treated with varying concentrations of resveratrol with and without doxorubicin. Cell viability was measured by the MTT assay. The expression of apoptotic proteins, activation of p38 mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) were assessed by western blotting. Similar to human cancer cell lines, resveratrol markedly inhibited the growth and induced apoptosis in both HSA cell lines. Mechanistically, resveratrol activated p38 MAPK, but did not affect the AMPK or the ERK1/2 pathways. Additional experiments showed that resveratrol augmented the growth-inhibitory and apoptotic effects of doxorubicin in both HSA cell lines. These findings suggest that resveratrol has pro-apoptotic effects in canine HSA cells; therefore, its use as a potential adjunct therapy in canine HSA patients warrants further investigation. PMID- 29235250 TI - Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma. AB - Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium-throughput 20 000-compound screen of a diverse subset of 1 000 000 compounds to identify cytotoxic small molecules. Cytotoxic compounds were screened for PDI inhibition, and, from the screen, 35G8 emerged as the most cytotoxic inhibitor of PDI. Bromouridine labeling and sequencing (Bru-seq) of nascent RNA revealed that 35G8 induces nuclear factor like 2 (Nrf2) antioxidant response, endoplasmic reticulum (ER) stress response, and autophagy. Specifically, 35G8 upregulated heme oxygenase 1 and solute carrier family 7 member 11 (SLC7A11) transcription and protein expression and repressed PDI target genes such as thioredoxin-interacting protein 1 (TXNIP) and early growth response 1 (EGR1). Interestingly, 35G8-induced cell death did not proceed via apoptosis or necrosis, but by a mixture of autophagy and ferroptosis. Cumulatively, our data demonstrate a mechanism for a novel PDI inhibitor as a chemical probe to validate PDI as a target for brain cancer. PMID- 29235251 TI - The score distribution and factor structure of the Community Assessment of Psychic Experiences-Positive Scale (CAPE-P15) in a Canadian sample. AB - AIM: Psychotic-like experiences (PLEs) share several risk factors with psychotic disorders and confer greater risk of developing a psychotic disorder. Thus, individuals with PLEs not only comprise a valuable population in which to study the aetiology and premorbid changes associated with psychosis, but also represent a high-risk population that could benefit from clinical monitoring or early intervention efforts. METHOD: We examined the score distribution and factor structure of the current 15-item Community Assessment of Psychic Experiences Positive Scale (CAPE-P15) in a Canadian sample. The CAPE-P15, which measures current PLEs in the general population, was completed by 1741 university students. RESULTS: The distribution of total scores was positively skewed, and confirmatory factor analysis indicated that a 3-factor structure produced the best fit. CONCLUSION: The CAPE-P15 has a similar score distribution and consistently measures three types of positive PLEs: persecutory ideation, bizarre experiences and perceptual abnormalities when administered in Canada vs Australia. PMID- 29235252 TI - Closure of the cystic duct orifice in laparoscopic subtotal cholecystectomy for severe cholecystitis. AB - INTRODUCTION: Laparoscopic subtotal cholecystectomy (LSC) has been recognized as an alternative to conversion to laparotomy for severe cholecystitis. However, it may be associated with an increased risk of recurrent stones in the gallbladder remnant. The objective of this study was to evaluate the safety and feasibility of the complete removal of the gallbladder cavity in LSC for severe cholecystitis using the cystic duct orifice suturing (CDOS) technique. METHODS: In a consecutive series of 412 laparoscopic cholecystectomies that were performed from January 2015 to June 2017, 12 patients who underwent LSC with CDOS were enrolled in this retrospective study. In this procedure, Hartmann's pouch was carefully identified, and the infundibulum-cystic duct junction was transected while the posterior wall adherent to Calot's triangle was left behind. The clinical records, including the operative records and outcomes, were analyzed. RESULTS: The median operating time and blood loss were 158 min and 20 mL, respectively. In all cases, LSC with CDOS was completed without conversion to open surgery. No injuries to the bile duct or vessels were experienced. The median postoperative hospital stay was 6 days. Postoperative complications occurred in two patients (bile leakage, n = 1: common bile duct stones, n = 1) and were successfully treated by endoscopic management. A gallbladder remnant was not delineated by postoperative imaging in any of the cases. CONCLUSION: These results suggest that LSC with CDOS is a promising approach that can avoid dissection of Calot's triangle and achieve the complete removal of the gallbladder cavity in patients with severe cholecystitis. PMID- 29235253 TI - An attempt at revisiting the factor structure of the Dysexecutive Questionnaire in the Chinese setting. AB - This study examined the factor structure of the Chinese version of the Dysexecutive Questionnaire (DEX) in a large nonclinical sample of college students (n = 1,586). All participants completed the self-report version of the DEX. An exploratory factor analysis was first performed on a sub-sample (randomly split, n = 766) and produced a four-factor model (Volition, Intentionality, Inhibition, and Abstract Problem-Solving), which was similar to previous models reported in Western samples. In addition, a series of confirmatory factor analyses was conducted on the remaining sample (n = 820). The findings suggested that a four-factor solution of the self-report DEX might better explain the latent structure in the present healthy Chinese sample. PMID- 29235254 TI - Mesenchymal stem cells: A double-edged sword in radiation-induced lung injury. AB - Radiation therapy is an important treatment modality for multiple thoracic malignancies. However, radiation-induced lung injury (RILI), which is the term generally used to describe damage to the lungs caused by exposure to ionizing radiation, remains a critical issue affecting both tumor control and patient quality of life. Despite tremendous effort, there is no current consensus regarding the optimal treatment approach for RILI. Because of a number of functional advantages, including self-proliferation, multi-differentiation, injury foci chemotaxis, anti-inflammation, and immunomodulation, mesenchymal stem cells (MSCs) have been a focus of research for many years. Accumulating evidence indicates the therapeutic potential of transplantation of MSCs derived from adipose tissue, umbilical cord blood, and bone marrow for inflammatory diseases, including RILI. However, reports have also shown that MSCs, including fibrocytes, lung hematopoietic progenitor cells, and ABCG2+ MSCs, actually enhance the progression of lung injuries. These contradictory results suggest that MSCs may have dual effects and that caution should be taken when using MSCs to treat RILI. In this review, we present and discuss recent evidence of the double-edged function of MSCs and provide comments on the prospects of these findings. PMID- 29235255 TI - Immune response profiling of primary monocytes and oral keratinocytes to different Tannerella forsythia strains and their cell surface mutants. AB - The oral pathogen Tannerella forsythia possesses a unique surface (S-) layer with a complex O-glycan containing a bacterial sialic acid mimic in the form of either pseudaminic acid or legionaminic acid at its terminal position. We hypothesize that different T. forsythia strains employ these stereoisomeric sugar acids for interacting with the immune system and resident host tissues in the periodontium. Here, we show how T. forsythia strains ATCC 43037 and UB4 displaying pseudaminic acid and legionaminic acid, respectively, and selected cell surface mutants of these strains modulate the immune response in monocytes and human oral keratinocytes (HOK) using a multiplex immunoassay. When challenged with T. forsythia, monocytes secrete proinflammatory cytokines, chemokines and vascular endothelial growth factor (VEGF) with the release of interleukin-1beta (IL-1beta) and IL-7 being differentially regulated by the two T. forsythia wild-type strains. Truncation of the bacteria's O-glycan leads to significant reduction of IL-1beta and regulates macrophage inflammatory protein-1. HOK infected with T. forsythia produce IL-1Ra, chemokines and VEGF. Although the two wild-type strains elicit preferential immune responses for IL-8, both truncation of the O-glycan and deletion of the S-layer result in significantly increased release of IL-8, granulocyte-macrophage colony-stimulating factor and monocyte chemoattractant protein-1. Through immunofluorescence and confocal laser scanning microscopy of infected HOK we additionally show that T. forsythia is highly invasive and tends to localize to the perinuclear region. This indicates, that the T. forsythia S layer and attached sugars, particularly pseudaminic acid in ATCC 43037, contribute to dampening the response of epithelial tissues to initial infection and hence play a pivotal role in orchestrating the bacterium's virulence. PMID- 29235257 TI - Erratum. PMID- 29235256 TI - Automated refraction is stable 1 week after uncomplicated cataract surgery. AB - PURPOSE: To compare automated refraction 1 week and 1 month after uncomplicated cataract surgery. METHODS: In this prospective cohort study, we recruited patients in a 2-month period and included consecutive patients scheduled for bilateral small-incision phacoemulsification cataract surgery. The exclusion criteria were (i) corneal and/or retinal pathology that could lead to automated refraction miscalculation and (ii) surgery complications. Automated refraction was measured 1 week and 1 month after surgery. RESULTS: Ninety-five patients met the in- and exclusion criteria and completed follow-up. The mean refractive shift in spherical equivalent was -0.02 dioptre (D) between 1 week and 1 month after surgery and not statistical significant (p = 0.78, paired t-test). The magnitude of refractive shift in either myopic or hyperopic direction was neither correlated to age, preoperative corneal astigmatism, axial length nor phacoemulsification energy used during surgery (p > 0.05 for all variables, regression analysis). The refractive target was missed with 1.0 D or more in 11 (12%) patients. In this subgroup, the mean refractive shift in spherical equivalent was 0.49 D between 1 week and 1 month after surgery with a trend towards statistical significance (p = 0.07, paired t-test). There was no difference in age, preoperative corneal astigmatism, axial length or phacoemulsification energy used during surgery compared to the remainder of the patients (p > 0.05 for all variables, unpaired t-test). CONCLUSION: Automated refraction is stabile 1 week after uncomplicated cataract surgery, but there is a trend towards instability, if the refractive target is missed with 1.0 D or more. PMID- 29235259 TI - What if there were no universities? AB - To a large extent, the pursuit of science takes place in universities. In this essay, I ask the following questions. Supposing there were no universities, and that all the knowledge mankind has ever collected and generated is somehow accessible, would we invent universities to make this knowledge available to address the problems humanity faces? What should those universities perform, and what role would science play in such universities? To look for answers to those questions, I consider the nature of the problems dealt with by science, the knowledge needed to address those problems, the gap between the two, the need for interdisciplinarity and the need to educate the leaders of the future, and finally, the boundaries of scientific knowledge. PMID- 29235260 TI - Functional polymorphisms of innate immunity receptors are not risk factors for the non-SBP type bacterial infections in cirrhosis. AB - BACKGROUND & AIMS: Pattern recognition receptors (PRRs) have a key role in the innate host defense. Functional polymorphisms of various PRRs have been established to contribute to an increased susceptibility to spontaneous bacterial peritonitis (SBP). Their role in the development of cirrhosis-associated bacterial infections (BI), beyond SBP or progressive disease course related to pathological bacterial translocation (BT) remains unknown. METHODS: Three hundred and forty-nine patients with cirrhosis were genotyped for common NOD2 (R702W, G908R and L1007PfsinsC), TLR2 (-16934T>A), and TLR4 (D299G) variants. Incidence of BIs, decompensating events and liver-related death were assessed in a 5-year follow-up observational study. Pathological BT was assessed based on the presence of antimicrobial antibodies or lipopolysaccharide-binding protein (LBP) level. RESULTS: In patients with ascites (n = 88) only NOD2 gene variants were associated with an increased cumulative probability of SBP (76.9% +/- 19.9%) compared to wild-type (30.9% +/- 6.9%, PLogRank = .047). Individual or combined PRR genetic profiles were associated with the risk of non-SBP type BI. Advanced disease stage (HR [95% CI]: 2.11 [1.38-3.25]) and prior history of a BI episode (HR: 2.42 [1.58-3.72]) were the major clinical risk factors of a subsequent BI. The risk of a non-SBP type BI in patients with advanced disease and a prior BI was even higher (HR: 4.74 [2.68-8.39]). The frequency of antimicrobial antibodies and LBP levels did not differ between various PRR genotypes. Correspondingly, PRR genetic profile was not able to predict the long-term disease course. CONCLUSIONS: In cirrhosis, functional polymorphisms of PRRs did not improve the identification of patients with high risk of BI beyond SBP or progressive diseases course. PMID- 29235262 TI - Corrugated Bruch's membrane in high myopia. AB - PURPOSE: To assess the appearance of Bruch's membrane (BM) in axially elongated eyes. METHODS: The light-microscopical investigation included histological anterior-posterior sections of human eyes. Using a light microscope, we assessed whether BM in the posterior segment was straight or locally corrugated. Corrugation of BM was defined as an elevation of BM with a height >20 MUm over a basis of 50 MUm without collateral proliferations of retinal pigment epithelium or choroidal swelling. RESULTS: The investigation included 85 eyes (age: 62.0 +/- 14.1 years; axial length: 26.7 +/- 3.5 mm). In multivariate analysis, the presence of a corrugated BM, detected in eight eyes (9.4%), was strongly associated with the presence of macular BM defects [p = 0.001; odds ratio (OR): 418; 95% confidence interval (CI): 1 215 000], but not with axial length (p = 0.54). Bruch's membrane (BM) corrugation was detected in seven (54%) of 13 eyes with macular BM defects. The single eye with BM corrugation and without macular BM defect showed the corrugated BM located in the parapapillary region at the peripheral end of a large parapapillary gamma zone. CONCLUSION: Bruch's membrane (BM) corrugation can be present in the vicinity of macular BM defects in highly myopic eyes, perhaps due to differences in the tension within BM in various regions at the margin of the BM defect. Bruch's membrane (BM) corrugation may also develop at the papillary end of BM in eyes with a large parapapillary gamma zone, potentially due to a disinsertion of BM at the end of the peripapillary choroidal border tissue of Jacoby. The observation of BM corrugation may help elucidating the aetiology of axial myopia. PMID- 29235261 TI - Interferon alpha2 and interferon gamma induce the degranulation independent production of VEGF-A and IL-1 receptor antagonist and other mediators from human mast cells. AB - BACKGROUND: Mast cells are resident immune effector cells, often studied in the context of allergic disease. Found in substantial numbers at sites of potential infection they are increased at sites of angiogenesis and can be pivotal for the sensing and clearance of a variety of pathogens. Interferons (IFNs) are cytokines that are critical for host defence against intracellular pathogens. Increased levels of IFNs are observed during viral infection and in autoimmune diseases. IFNs are also widely used therapeutically and have been examined in the therapy of severe asthma. OBJECTIVE: To define the selective human mast cell cytokine and chemokine response following activation with type I or type II IFN's. METHODS: The ability of both IFNalpha2 and IFNgamma to induce cytokine production by human cord blood-derived mast cells was examined in vitro. Cytokine and chemokine production at 6 and 24 h was assessed by multiplex protein analysis. Degranulation was assessed by beta-hexosaminidase release. Mast cells were also treated with reovirus or respiratory syncytial virus and their production of CXCL10, IL-1 receptor antagonist (IL-1Ra), and vascular endothelial growth factor (VEGF) examined after 24 h. RESULTS: In addition to increased expression of classical IFN response genes, such as CXCL10, small but significant increases in CCL5 and IL-17 production were observed following IFN activation. Notably, human mast cells produced both VEGF and IL-1Ra in a dose dependent manner. These responses occurred in the absence of mast cell degranulation by a mechanism consistent with classical IFN signaling. Both reovirus and respiratory syncytial virus infection of mast cells, were also associated with IFN-dependent IL-1Ra expression. CONCLUSION AND CLINICAL RELEVANCE: Our findings demonstrate that IFNs have profound impact on cytokine and chemokine expression by human mast cells, alone or in the context of viral infection. Mast cell VEGF and IL-1Ra responses to IFNs could impact the regulation of local inflammatory responses and subsequent tissue remodeling. PMID- 29235263 TI - Detection and genetic characterization of diverse Bartonella genotypes in the small mammals of Singapore. AB - Bartonella species are arthropod-borne bacterial pathogens that infect numerous mammalian species. Small mammals play an important role as natural reservoirs of many Bartonella species, maintaining the greatest diversity of Bartonella described to date. Although Bartonella research has been conducted in Southeast Asia, no studies have been undertaken on small mammals in Singapore. Here, we report the detection and description of Bartonella in small mammals in Singapore during the period of November 2011 to May 2014. BartonellaDNA was detected in 20.8% (22/106) of small mammal spleens with a PCR amplifying the beta subunit of bacterial RNA polymerase (rpoB) gene. Commensal species Rattus norvegicus and Rattus tanezumi had the highest prevalence, 75% (3/4) and 34,5% (10/29), followed by Suncus murinus 30% (6/20), Tupaia glis 16,7% (1/6) and Mus castaneus 13.3% (2/15). Phylogenetic analysis of 18 rpoB gene sequences revealed five Bartonella genotypes circulating in the small mammals of Singapore. Bayesian tip significance testing demonstrated strong structuring in the geographical signal, indicating that distribution of Bartonella species is correlated to the distribution of their hosts. Major deforestation and fragmentation in Singapore favour synanthropic species that traverse habitats and increase the possibility of spillover to incidental hosts. PMID- 29235264 TI - Reconceptualizing motivation for smoking cessation among people with rheumatoid arthritis as incentives and facilitators. AB - OBJECTIVES: Smokers with rheumatoid arthritis (RA) may have different motivations for, and barriers to, quitting. Understanding the motivations of smokers and ex smokers with RA will help in the design and implementation of targeted smoking cessation interventions for people with RA that are not based solely on extrapolation from the general population or populations with other chronic illnesses. METHODS: Twenty-nine smokers and 10 recent ex-smokers with RA participated in semi-structured interviews via telephone 18 months after being offered a smoking cessation intervention in Aotearoa/New Zealand. The sample consisted of 27 women and 12 men (age range 32-78 years), of whom 14 had received the intervention, 14 had been in the control group and 11 had declined participation in the trial. RESULTS: Thematic analysis led to the formulation of four "incentives" to quit and five "facilitators" of quitting for people with RA. Desiring improvements to health (overall and specific to arthritis), social relationships and avoiding costs were incentives to quit. Coping with stress without smoking, commitment, mental preparedness, willpower and interventions were facilitators of quitting. CONCLUSIONS: Becoming aware of the effects of smoking on arthritis provides an important motivation to quit smoking that may counter RA-specific barriers to smoking cessation. Further research is needed to test whether similar incentives and facilitators of smoking cessation exist in other chronic illnesses, and how to develop interventions to address these motivational processes. PMID- 29235265 TI - Synthesis of alpha-Branched Acyclic Nucleoside Phosphonates as Potential Inhibitors of Bacterial Adenylate Cyclases. AB - Inhibition of Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF), key virulence factors with adenylate cyclase activity, represents a potential method for treating or preventing toxemia related to whooping cough and anthrax, respectively. Novel alpha-branched acyclic nucleoside phosphonates (ANPs) having a hemiaminal ether moiety were synthesized as potential inhibitors of bacterial adenylate cyclases. ANPs prepared as bisamidates were not cytotoxic, but did not exhibit any profound activity (IC50 >10 MUm) toward ACT in J774A.1 macrophages. The apparent lack of activity of the bisamidates is speculated to be due to the inefficient formation of the biologically active species (ANPpp) in the cells. Conversely, two 5 haloanthraniloyl-substituted ANPs in the form of diphosphates were shown to be potent ACT and EF inhibitors with IC50 values ranging from 55 to 362 nm. PMID- 29235266 TI - Host genetic variations associated with disease progression in chronic hepatitis C virus infection. AB - Treatment with recently developed interferon-free oral regimens combining direct acting antiviral agents (DAAs) results in the elimination of hepatitis C virus (HCV) in almost all chronic hepatitis C (CHC) patients. In the era of DAAs, surveillance of hepatocellular carcinoma (HCC) after eradication of HCV by anti HCV therapy is particularly important. As is well known, an advanced state of hepatic fibrosis is the major risk factor for developing HCC. Therefore, an increased understanding of various factors associated with disease progression and development of HCC in CHC patients is essential for implementing personalized treatment and surveillance of disease progression and HCC. Recent genome-wide association studies (GWAS) have identified several host genetic variants influencing treatment efficacy or clinical course in HCV infection. This review focuses on these host genetic variations recently identified, mainly by GWAS, which are associated with the clinical course of chronic HCV infection, especially disease progression and hepatocarcinogenesis. PMID- 29235268 TI - Corrigendum: Human Variation in Pelvic Shape and the Effects of Climate and Past Population History. PMID- 29235267 TI - Nitrate Esters of Heteroaromatic Compounds as Candida albicans CYP51 Enzyme Inhibitors. AB - Four heteroaromatic compounds bearing nitrate esters were selected using a virtual-screening procedure as putative sterol 14alpha-demethylase (CYP51) Candida albicans inhibitors. Compounds were examined for their inhibition on C. albicans growth and biofilm formation as well as for their toxicity. NMR spectroscopy studies, in silico docking, and molecular dynamics simulations were used to investigate further the selectivity of these compounds to fungal CYP51. All compounds exhibited good antimicrobial properties, indicated with low minimal inhibitory concentrations and ability to inhibit formation of fungal biofilm. Moreover, all of the compounds had the ability to inhibit growth of C. albicans cells. N-(2-Nitrooxyethyl)-1Eta-indole-2-carboxamide was the only compound with selectivity on C. albicans CYP51 that did not exhibit cytotoxic effect on cells isolated from liver and should be further investigated for selective application in new leads for the treatment of candidiasis. PMID- 29235269 TI - Application of Generative Autoencoder in De Novo Molecular Design. AB - A major challenge in computational chemistry is the generation of novel molecular structures with desirable pharmacological and physiochemical properties. In this work, we investigate the potential use of autoencoder, a deep learning methodology, for de novo molecular design. Various generative autoencoders were used to map molecule structures into a continuous latent space and vice versa and their performance as structure generator was assessed. Our results show that the latent space preserves chemical similarity principle and thus can be used for the generation of analogue structures. Furthermore, the latent space created by autoencoders were searched systematically to generate novel compounds with predicted activity against dopamine receptor type 2 and compounds similar to known active compounds not included in the trainings set were identified. PMID- 29235270 TI - Lamellar keratoplasty using position-guided surgical needle and M-mode optical coherence tomography. AB - Deep anterior lamellar keratoplasty (DALK) is an emerging surgical technique for the restoration of corneal clarity and vision acuity. The big-bubble technique in DALK surgery is the most essential procedure that includes the air injection through a thin syringe needle to separate the dysfunctional region of the cornea. Even though DALK is a well-known transplant method, it is still challenged to manipulate the needle inside the cornea under the surgical microscope, which varies its surgical yield. Here, we introduce the DALK protocol based on the position-guided needle and M-mode optical coherence tomography (OCT). Depth resolved 26-gage needle was specially designed, fabricated by the stepwise transitional core fiber, and integrated with the swept source OCT system. Since our device is feasible to provide both the position information inside the cornea as well as air injection, it enables the accurate management of bubble formation during DALK. Our results show that real-time feedback of needle end position was intuitionally visualized and fast enough to adjust the location of the needle. Through our research, we realized that position-guided needle combined with M mode OCT is a very efficient and promising surgical tool, which also to enhance the accuracy and stability of DALK. PMID- 29235271 TI - Wide field of view common-path lateral-shearing digital holographic interference microscope. AB - Quantitative three-dimensional (3-D) imaging of living cells provides important information about the cell morphology and its time variation. Off-axis, digital holographic interference microscopy is an ideal tool for 3-D imaging, parameter extraction, and classification of living cells. Two-beam digital holographic microscopes, which are usually employed, provide high-quality 3-D images of micro objects, albeit with lower temporal stability. Common-path digital holographic geometries, in which the reference beam is derived from the object beam, provide higher temporal stability along with high-quality 3-D images. Self-referencing geometry is the simplest of the common-path techniques, in which a portion of the object beam itself acts as the reference, leading to compact setups using fewer optical elements. However, it has reduced field of view, and the reference may contain object information. Here, we describe the development of a common-path digital holographic microscope, employing a shearing plate and converting one of the beams into a separate reference by employing a pin-hole. The setup is as compact as self-referencing geometry, while providing field of view as wide as that of a two-beam microscope. The microscope is tested by imaging and quantifying the morphology and dynamics of human erythrocytes. PMID- 29235272 TI - Real-time detection of antibiotic activity by measuring nanometer-scale bacterial deformation. AB - Diagnosing antibiotic-resistant bacteria currently requires sensitive detection of phenotypic changes associated with antibiotic action on bacteria. Here, we present an optical imaging-based approach to quantify bacterial membrane deformation as a phenotypic feature in real-time with a nanometer scale (~9 nm) detection limit. Using this approach, we found two types of antibiotic-induced membrane deformations in different bacterial strains: polymyxin B induced relatively uniform spatial deformation of Escherichia coli O157:H7 cells leading to change in cellular volume and ampicillin-induced localized spatial deformation leading to the formation of bulges or protrusions on uropathogenic E. coli CFT073 cells. We anticipate that the approach will contribute to understanding of antibiotic phenotypic effects on bacteria with a potential for applications in rapid antibiotic susceptibility testing. PMID- 29235273 TI - [Current status and challenging of direct target study of traditional Chinese medicine complex system based on solid coupling beads]. AB - Traditional Chinese medicine(TCM) is a complex system with multiple chemical compositions. The most significant character of TCM is that the chemical compositions interact with each other by multi-target synergism to treat diseases. Previous reports mainly focused on the investigation of single signaling pathway detection or the phenotypic analysis of proteomics difference; however, no studies have been conducted on the identification of direct targets of TCM. Therefore, it is difficult to analyze the molecular mechanism of traditional Chinese medicine from the target source, and it is difficult to explain its traditional efficacy scientifically, thus seriously affecting its clinical application and internationalization. In this article, we discussed the methodology for the identification of direct TCM targets(groups), and presented the strategy for preparation of TCM chemical composition solid coupling beads, as well as of enrichment and identification strategy of target proteins based on photosensitive coupling technique. We also discussed the advantages and limitations of this strategy, and put forward some new ideas for the future developments. We hope this article can provide some guidance and reference significance for the researchers on TCM pharmacology study, especially on target identification. PMID- 29235274 TI - [Identification and function analysis of target group for cardioprotection of Baoyuan decoction]. AB - Baoyuan decoction (BYD) is a well-known traditional Chinese medicine formula for coronary heart disease with Qi deficiency. However, the detailed pharmacological mechanism of BYD is still unknown because of its complicated chemical compositions. In this study, we synthesized a kind of solid beads with benzophenone groups on its surface. Benzophenone can be activated and chemically cross-linked with the C-H bonds of the chemical compositions in BYD (BYD beads) under UV activation. We thus captured all the target proteins from mouse heart tissue lysates by using BYD beads. Based on proteomics analysis, we discovered totally 46 potential binding target proteins, most of which were located in mitochondria. KEGG analysis revealed that these target proteins were mainly associated with TCA cycle and amino acid metabolism signaling pathways, suggesting that the cardioprotection of BYD might be associated with regulating mitochondrial function and energy production. Moreover, JC-1 staining analysis also confirmed the protective effect of BYD on mitochondrial damage. In summary, our findings elucidated the potential mechanism of BYD on cardioprotection through "target fishing" strategy, and further explained its traditional efficacy in the molecular level. In addition, we also provide an approach for investigating the target group of complicated compositions in Chinese herbal formula. This novel method may provide a methodological reference for exploring the pharmacological mechanism of traditional Chinese formula in the future. PMID- 29235276 TI - [Anti-tumor target identification and molecular mechanism study of total saponins from Albizia julibrissin]. AB - Dried stem bark from Albizia julibrissin(AJ) is a common traditional Chinese herb with several therapy effects including insomnia, anxiety and anti-tumor. Recently, the anti-tumor effect and mechanism studies of AJ have drawn much attention; however, there are still some troubles in chemical composition separation, which leads to the difficulties in pharmacological research of AJ. In this study, we firstly confirmed the proliferation inhibitory effect of total saponins from AJ(TSAJ)on human hepatocarcinoma(HepG2) cells, and also tested the apoptosis induction effect of TSAJ. Then, we successfully captured the potential target proteins from HepG2 lysates by using TSAJ-modified solid beads, and identified the target proteins by LC-MS/MS. Finally, we confirmed 5 target proteins including Exportin-2, Beta-actin-like protein 2, Myosin-9, Protein transport protein Sec61 subunit beta,and Cytochrome c oxidase copper chaperone, which are responsible forcell apoptosis, proliferation, differentiation andmigration. In summary, our findings elucidate the potential anti-tumor mechanism of TSAJ from the direct target proteins, and provide a new insight for exploring the pharmacological mechanism of traditional Chinese medicine. PMID- 29235275 TI - [Identification and function analysis of neuroprotective targets group of modified Wuzi Yanzong pill]. AB - Targets group identification in complex Chinese medicine system is a key step for revealing the potential mechanism of Chinese medicine. The solid beads with magnetic core and benzophenone-modified surface were made in our study, and then benzophenone was activated and cross-linked with the C-H bonds of chemical compositions in Chinese medicines under UV excitation. Thus the chemical compositions of modified Wuzi Yanzong pill(MWP) were linked to the solid bead surface, and enriched the neuroprotective targets group of MWP after being co incubated with nerve cell lysate. We performed proteomics analysis on these targets and discovereda total of 32 potential binding targets. KEGG analysis revealed that these targets were mainly associated with Hippo and Cell cycle signaling pathways, suggesting that MWP might be involved in regulating the proliferation and differentiation of neural stem cells. Our findings elucidate the potential targets and mechanism of MWP on anti-dementia and neuroprotection, and further providean approach for investigating the targets group in complex Chinese medicine system. This novel method may provide methodological references for exploring the pharmacological mechanism of Chinese medicinal formulae in the future. PMID- 29235277 TI - [Targets identification and mechanism analysis for macrophage activation of low molecular weight saccharides from Cistanche deserticola based on molecular affinity chromatography]. AB - This study aims to investigate the targets and targets-involved mechanism for the macrophage activation of low molecular weight saccharides from Cistanche deserticola (LMSC). The phagocytic activity and NO release of RAW264.7 cells were detected, and results showed that LMSC exerts immune activation effect by significantly increasing the phagocytic activity and NO release. LMSC-conjugated epoxy-activated sepharose beads were prepared as affinity reagent to capture the target proteins. Twenty-four proteins such as Eef2 were identified by LC-MS/MS analysis. Pathway enrichment analysis showed LMSC activated RAW264.7 cells by regulating Fcgamma receptor dependent phagocytosis, TNF-alpha NF-kappaB signaling pathway, glycolysis/gluconeogenesis and the citric acid cycle and respiratory electron transport pathway. PMID- 29235278 TI - [Guideline principle and technical requirement for preparing traditional Chinese medicine reference drug]. AB - Traditional Chinese medicine (TCM) reference drug is a new form of TCM standard reference substance. The purpose of this guideline is to guide the establishment of the reference drug and standardize its investigation and application in national drug standards. Definition of TCM reference drug was specified and relating guideline and technical requirement were introduced in this paper. Its application in quality control of TCM was analyzed and the developing train was proposed. There is a wide prospect for the application of reference drug in quality control of TCM. Thus it has practical significance to explore and conduct the quality evaluation system by using TCM reference drug as the reference substance. PMID- 29235279 TI - [Advance of a representative traditional Tibetan medicine Meconopsis horridula on its phytochemical and pharmacological aspects]. AB - Meconopsis horridula is one of alpine plants belonging to family Papaveraceae, mainly distributed in Himalaya Range area. M. horridula is a rare alpine flower, and is a kind of traditional Tibetan medicine, which has been included in more than 40 compound formulae, having efficacies of clearing away heat and alleviating pain, activating blood circulation to remove stasis, traditionally used for the treatment of fractures, injuries, and chest and back pains. Modern research shows that the whole plant of M. horridula contains alkaloids, flavonoids, and terpenes, and its pharmacological activities including antitumor, antivirus and myocardial protection etc. However, due to various factors, the current research of M.horridula still faces many challenges. This paper summaries herein a progress of MH on its ecological resources, traditional uses, and studies on chemical constituents and pharmacological effects, hopefully to provide a useful reference for the ecological protection and applications. PMID- 29235281 TI - [Research & development and evaluation of oral films]. AB - Oral film is a new type of oral preparation. Due to portability, simple preparation process and good clinical compliance, oral films have become the focus of novel drug delivery system in recent years. Meanwhile, oral films have been gradually used in the development of Chinese medicine preparations. According to the application and approval situation of different types of oral films both at home and abroad in recent years, their research and development status was analyzed, including the basic concept, formulation, manufacturing process and quality control, as well as related progress and development prospects of oral films applied in traditional Chinese medicine. Some suggestions on the technical evaluation of oral films were put forward by considering specific requirements from regulatory agencies. This paper could provide some references for the development and evaluation of oral films. Due to the complexity of the drug substances and the particularity of the drug product, the development and application of oral films in traditional Chinese medicine are still faced with opportunity and challenges. PMID- 29235280 TI - [Advances on chemical constituents of Tibetan Salvia genus]. AB - Salvia is the largest genus of Labiatae family, and there are more than 1 000 species around the world. Our country is rich in the resources of Salvia plants. The plants of this genus contain multiple chemical components, including sesquiterpenoids, diterpenoids, triterpenoids and phenols, et al. In order to develop better Tibetan plants of Salvia genus, this article reviewed and summarized the constituents from Tibetan Salvia genus. PMID- 29235282 TI - [Research progress of puerarin and its derivatives on anti-inflammatory and anti gout activities]. AB - The research progress of puerarin and its derivatives in anti-inflammatory and anti-gout activities was reviewed in this paper. Puerarin possesses anti inflammatory activity by affecting immunocyte, inflammation cytokines and signaling pathway. Puerarin also has anti-gout activity through inhibition of xanthine oxidase, promoting the excretion of uric acid to reduce serum uric acid level. Although its ability in reducing uric acid level was lower than that of allopurinol in clinical application, puerarin can also enhance the total antioxidant and free radical scavenging with stronger anti-inflammatory effect, so it will be a promising research direction to find new drugs with better anti gout activity and less side effects by modifying the chemical structure of puerarin. PMID- 29235283 TI - [Effect of proinflammatory factors TNF-alpha,IL-1beta, IL-6 on neuropathic pain]. AB - Cytokines can be divided into two types: proinflammatory cytokines and anti inflammatory cytokines. Proinflammatory cytokines are a kind of small molecular peptides synthesized and excreted by immune and non-immune cells, which can regulate a variety of physiological functions and play an important role in the process of trauma, pain and infection. Proinflammatory cytokines include TNF, IL 1, IL-6 and IL-8. More and more evidences suggest that proinflammatory cytokines(PICs), such as interleukin-1beta(IL-1beta), interleukin-6(IL-6) and tumor necrosis factor-alpha(TNF-alpha), are induced in the spinal cord(SC) and dorsal root ganglion (DRG) under various injury conditions, and contribute to pain hypersensitivity. In recent years, with the deepening of studies on neuropathic pain mechanism and the increasing expansion of the neuroinflammation study field, the action mechanisms of cytokines and molecules in regulating cytokines in neuropathic pain are expected to provide new targets for the development of analgesic drugs. This review aims to provide an overview of inflammatory mechanisms for proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, with a focus on neuropathic pain. PMID- 29235284 TI - [Recent research progress in immunomodulatory effects of Chinese herbal medicine on asthma treatment]. AB - Asthma is a kind of chronic respiratory inflammation, commonly with breathlessness, chest tightness, coughing, recurrent episodes of wheezing and airflow obstruction, severely affecting human health. A variety of immunocytes are involved in this chronic disease. Chinese herbal medicine(CHM) has a long history in the treatment of asthma. A large number of studies have shown that CHM could ameliorate asthma symptoms through regulating cellular immune responses. This paper reviewed the studies of CHM on the regulation of immunocytes and their mechanisms in recent years, including the count of inflammatory cells, maturation of dendritic cells, balance of helper T cell subtypes, induction of regulatory T cells and intracellular signaling pathways. We also proposed the future research directions about the effects of CHM on asthma treatment. PMID- 29235285 TI - [Study on calibration standard for reference drug of Lonicera japonica cultivated in Xinmi]. AB - The calibration technical specification for reference drug of Lonicera japonica cultivated in Xinmi (Mi Yin Hua) established in this study can be used as the theoretical basis and technical standard for internal quality control and evaluation of reference drug of Mi Yin Hua and for modern research and characteristics identification of Dao-di herbs. Based on the quality standard of L. japonica in Chinese Pharmacopoeia (version 2015), 10 batches samples of Mi Yin Hua also conformed to the stipulation. The LC-MS fingerprint common mode of Mi Yin Hua was obtained, and a total of 23 characteristic peaks were selected as the common fingerprint peaks, and eight common chromatographic peaks in the fingerprint was identified based on standard substances and references. The similarities of 10 batches samples were greater than 0.95. Seven core primers were used to construct SSR fingerprint and the ten batches samples were only 0 or 1 site disaccord with the standard diagram of Jianshan Damaohua germplasm from Xinmi. This paper constructed the first calibration standard of Dao-di herbals by combination of macroscopical identification, SSR fingerprint and LC-MS fingerprint, and the calibration standard provide theoretical basis and technical standard for evaluation system of Dao-di herbals. PMID- 29235286 TI - [Growth rings in roots of seven Sect. Paeonia species and its application on identification of Paeoniae Radix Rubra]. AB - The growth years of medicinal materials are closely related to their quality, and "Herb-chronology" has been used to determine the growth years of perennial dicotyledonous plants in recent years. On the basis of conventional paraffin section and freehand section, the anatomical study on roots of seven Sect. Paeonia species and main roots of cultivated Paeonia lactiflora was conducted in this paper. The results showed that, there existed some differences in microstructure of the seven species such as P. lactiflora, P. obovata, P. veitchii, P. mairei, P. anomala, P. sinjiangensis and P. anomala var. intermedia, and this could be used to distinguish different species. In the roots of seven Sect. Paeonia species, distinct growth rings were formed because that the different diameters or density of xylem vessels in the secondary xylem formed clusters and arranged interrupted rings in tangential direction. There were growth rings in the main roots of P. lactiflora cultivated 1-4 years in Siping, Jilin, which were all consistent with their growth years. Due to the similar growth characteristics between wild Sect. Paeonia species and cultivated P. lactiflora, the growth rings can provide a basis for the age identification and lay the foundation for the quality evaluation of Paeoniae Radix Rubra. PMID- 29235287 TI - [Analysis of commercial grades of Schisandrae Sphenantherae Fructus based on schisantherin]. AB - Schisandrae Sphenantherae Fructus, from different producing areas, were collected and divided into three grades. The moisture content and total ash were determined on the basis of the pharmacopoeia method, and schisantherin was determined by UPLC. The study is aimed to find the commercial specifications and grades of Schisandrae Sphenantherae Fructus based on schisantherin content. The results showed that the content of water, total ash and schisantherin of Schisandrae Sphenantherae Fructus from different producing areas qualified. There was no significant difference between different grades of schisandrin content, but the second-class were the highest, first-class and third-class were lower. It means that schisandrin content is not positive correlation to commercial grade. The study will be helpful to the production, management and clinical practice of Schisandrae Sphenantherae Fructus. PMID- 29235288 TI - [Prokaryotic expression, functional identification of squalene synthase in Alisma orientale and its immunoassay study]. AB - Squalene synthase of Alisma orientale catalyzes farnesyl diphosphate (FPP) to form squalene, which is the key regulatory enzyme of the carbon source flow to protostane triterpenes biosynthesis. For further research on the function and expression of AoSS gene, the open reading frame (ORF) of squalene synthase gene (accession no. JX866770) from A. orientale was subcloned into a prokaryotic expression vector pCzn1 and induced the expression of AoSS gene in Escherichia coli BL21(Roseta). The fusion protein was mainly in the form of inclusion bodies and purified to obtain high purity protein. By verifying its functionality through vitro enzymatic reaction, the results showed that the catalytic protein had the catalytic activity of FPP into squalene. In order to research the expression of AoSS in A. orientale, the purified protein was used to immunized rabbits to prepare polyclonal antibody which was then purified, the titer of the antibody was greater than 1?51 200 by ELISA detection, and displayed good specificity by Western blotting. The prepared antibody was used for immunoassay of AoSS in different organs of A. orientale, and the results showed that the AoSS expression level was the highest in tubers, followed by leaves, and lowest in root. Successful construction of prokaryotic expression vector, validation of gene functions and establishment of rapid immunoassay lay the foundation for further researches on the function and regulation of AoSS gene, and also provide scientific basis on the application of the protostane triterpenes of A. orientale in the field of synthetic biology. PMID- 29235289 TI - [Effects of drug-oil properties on fabrication of drug nanocrystalline self stabilizied Pickering emulsions]. AB - To investigate the effects of drug and oil properties on the formation and stability of drug nanocrystalline self-stabilizied Pickering emulsions (NSSPE). Three insoluble Chinese medicine components (puerarin, tanshinone IIA and ferulic acid) were selected as model drugs, and Capmul C8, Fabrafil M 1944 CS, isopropyl myristate, Pzechwan Lovage Rhizome oil, and olive oil were used as oil phase. NSSPEs were developed by high pressure homogenization method and were evaluated for their appearance, centrifugal stability, droplet size and drug content changes in emulsion layer after storing at room temperature for 14 d. Then the properties of the oil (surface tension and viscosity) and properties of the drugs (surface energy, oil-water partition coefficient, size and Zeta potential of nanocrystalline and drug-water-oil contact angle) on the formation and stability of NSSPE were analyzed. The emulsification property and stability of five samples prepared with ferulic acid nanocrystals and different oils were significantly lower than those of puerarin and tanshinone IIA; the particle size of ferulic acid nanocrystals was 3.90 MUm, extremely higher than 305 nm of puerarin and 406 nm of tanshinone IIA (P<0.05); the zeta potential of ferulic acid nanocrystals was -0.018 0 mV, significantly lower than -29.1 mV of puerarin and -42.6 mV of tanshinone IIA (P<0.05). Three samples prepared with isopropyl myristate and different drugs were not emulsions and the viscosity of isopropyl myristate was 4.67 mPa*s, significantly lower than that of the other oils (P<0.01). Puerarin NSSPEs prepared with Pzechwan Lovage Rhizome oil showed best emulsification property and stability; the contact angle of puerarin in Pzechwan Lovage Rhizome oil-water was 69.7 degrees , close to 90 degrees , significantly higher than other contact angles. NSSPEs made by tanshinone IIA-Capmul C8-water, tanshinone IIA-Labrafil M 1944 CS-water showed highest stability, with a contact angle of 99.2 degrees and 112 degrees respectively, more close to 90 degrees than other oils. The results indicated that viscosity, size and Zeta potential of nanocrystalline and three-phase contact angle had great influence on the formation and stability of NSSPE; surface tension of oil, surface energy of drug and oil-water partition coefficient may not be related to the construction of NSSPE. PMID- 29235290 TI - [Preparation and evaluation of dioscin nanostructured lipid carriers]. AB - In this report, a heat and high-pressure homogenization method was used to prepare dioscin nanostructured lipid carriers, and the formulation of dioscin nanostructured lipid carriers was optimized by central composite design-response surface methodology. In vitro evaluation data showed that the preparation of dioscin nanostructured lipid carriers under optimal process by central composite design-response surface methodology had a spherical shape and homogeneous size distribution, with a particle size of (90.9+/-0.6) nm, a polydispersity index of (0.253+/-0.07), Zeta potential of (-45.7+/-0.5) mV, encapsulation efficiency of (90.2+/-0.5)%, and the drug loading of (23.30+/-0.10)%. These results clearly indicate that the preparation of dioscin nanostructured lipid carriers made with the heat and high-pressure homogenization method have very good physical and chemical properties, suitable for therapeutic applications. PMID- 29235291 TI - [Rapid determination of nine components in the first extraction process of Xingnaojing injection by using ultraviolet spectroscopy]. AB - In this study, an analytical method based on ultraviolet spectroscopy was established for the rapid determination of nine components including isophorone, 4-methylene-isophorone, curcumenone, curcumenol, curdione, curzerenone, furanodienone, curcumol and germacrone in the first extraction process of Xingnaojing injection. 166 distillate samples of Gardeniae Fructus and Radix Curcumae were collected in the first extraction process of Xingnaojing injection. The ultraviolet spectra of these samples were collected, and the contents of the nine components in these samples were determined by high performance liquid chromatography. Least squares support vector machine and radial basis function artificial neural network were used to establish the multivariate calibration models between the ultraviolet spectra and the contents of the nine components. The results showed that the established ultraviolet spectrum analysis method can determine the contents of the nine components in the distillates accurately, with root mean square error of prediction of 0.068, 0.147, 0.215, 0.319, 1.01, 1.27, 0.764, 0.147, 0.610 mg*L-1, respectively. This proposed method is a rapid, simple and low-cost tool for the monitoring and endpoint determination of the extraction process of Xingnaojing injection to reduce quality defects and variations. PMID- 29235292 TI - [A new naphthalene derivative from Aloe vera and its antibacterial activity]. AB - A new naphthalene derivative has been isolated from Aloe vera by using various chromatographic techniques, including silica gel, sephadex, MCI-gel resin, and RP HPLC. The new compound was determined as 3-hydroxy-1-(1,7-dihydroxy-3,6 dimethoxynaphthalen-2-yl)propan-1-one (1). In the biological activity assay, compound 1 disglayed prominent antibacterial activity with a MIC90 value of (48+/ 4) mg*L-1 for methicillin resistant Staphylococcus aureus (MRSA) strain which was stronger than that of the positive control levofloxacin with a MIC90 value (58+/ 5) mg*L-1. PMID- 29235293 TI - [Chemical constituents from petroleum ether fraction of Swertia chirayita and their activities in vitro]. AB - The present work is to study the chemical constituents from petroleum ether fraction of Tibetan medicine Swertia chirayita by column chromatography and recrystallization. The structures were identified by physical and chemical properties and spectral data as swerchirin (1), decussatin (2), 1,8-dihydroxy 3,5,7-trimethoxyxanthone (3), 1-hydroxy-3,5,7,8-tetramethoxyxanthone (4), bellidifolin (5), 1-hydroxy-3, 7-dimethoxyxanthone (6), methylswertianin (7), 1 hydroxy-3,5-dimethoxyxanthone (8), erythrodiol (9), oleanolic acid (10), gnetiolactone (11), scopoletin (12), sinapaldehyde (13), syringaldehyde (14), and beta-sitosterol (15). Compounds 3, 4, 9, 11-14 were isolated from S. chirayita for the first time. Compounds 9 and 12 were firstly isolated from the genus Swertia. The cytotoxic activities of compounds 1, 2, 5, 7 and 8 against human pancreatic cancer cell lines SW1990 and BxPC-3,and the protective effects of these compounds against hydrogen peroxide (H2O2)-induced oxidative stress in human endothelium-derived EA.hy926 were investigated in vitro. The results showed no obvious effect at the high concentration of 50 MUmol*L-1. PMID- 29235294 TI - [Simultaneous determination of sixteen mycotoxins contaminants in cogon rootstalk by QuEChERS-UPLC-QqQ mass spectrometry]. AB - A method for the simultaneous determination of sixteen mycotoxins in cogon rootstalk was developed using ultra-performance liquid chromatography coupled with triple quadropole mass spectrometry(UPLC-QqQ-MS/MS). The samples were extracted with acetonitrile contained 1% acetic acid and purified by QuEChERS method. The separation was performed on an Agilent Eclipse Plus C18column by gradient elution using methanol and 0.01% aqueous formic acid as mobile phase. The targeted compounds were detected in MRM mode by mass spectrometry with electrospray ionization(ESI)source operated in positive ionization mode. The linear relationships of the sixteen mycotoxins were good in their respective linear ranges. The correlation coefficients(r)ranged among 0.996 2-1.000. The LOQs of the sixteen mycotoxins were between 0.03 and 186.68 MUg*kg -1. The average recoveries ranged from 60.28% to 129.2% with relative standard deviations(RSDs)within 0.29%-11%. The results demonstrated that the proposed method was sensitive and accurate, and suitable for the mycotoxins quantification in cogon rootstalk. PMID- 29235295 TI - [Study on correlation between color and effective components contents of Glycyrrhiza uralensis]. AB - To explore the correlation between color of Glycyrrhiza uralensis and its quality evaluation,the colors of root bark and transverse section were determined by Precision Color Reader and Visual Analyzer,and the contents of six flavonoids and two saponins in G.uralensis were determined by high performance liquid chromatography(HPLC).The partial least squares regression(PLSR)method was employed to correlate the colors with component contents in G.uralensis. The results showed that there were no significant differences in the colors of root bark but significant or very significant differences(P<0.05,P<0.01)in the colors of transverse section between the wild and cultivated G. uralensis. Compared with those in the cultivated G. uralensis, the contents of liquiritin, isoliquiritin isoliquiritigenin and the contents of ammonium glycyrrhizinate, glycyrrhetinic acid were obviously significant or remarkably significant in the wild G. uralensis.The correlation results showed that there was a significant or very significant correlation between the colors and the effective component contents. This study provides a scientific basis to evaluate the quality of G.uralensis by color and a new reference for the traditional evaluation methods for Chinese drugs. PMID- 29235296 TI - [Effect of astragaloside IV combined with Panax notoginseng saponins on cerebral ischemia-reperfusion injury and study of pharmacokinetics in rats]. AB - The aim is to study the effect of astragaloside IV (AST IV) combined with Panax notoginseng saponins (PNS) on cerebral ischemia-reperfusion injury, and to probe the synergistic mechanism through the pharmacokinetics of the four major components such as AST IV, ginsenoside Rg1 (Rg1), ginsenoside Rb1 (Rb1), notoginsenoside R1 (R1) in cerebral ischemia-reperfusion rats. Following the establishment of cerebral ischemia/reperfusion model in rats by modified suture method, neurological function score, cerebral infarction area and pathomorphology were used to evaluate the pharmacological effect that the combination of AST IV and PNS antagonized cerebral ischemia-reperfusion injury; the contents of AST IV, Rg1, Rb1, R1 in rat plasma of different time points were determined with ultra performance liquid chromatography tandem massspectrometry (UPLC-MS/MS), pharmacokinetic parameters were calculated and pharmacokinetics changes of the main effective components were analyzed. The results showed that AST IV, PNS alone and their combination could reduce the cerebral infarction area of rats, relieve the behavioral scores of neurologic deficit, improve the pathological changes after cerebral ischemia, the effects of the combination were better. Among AST IV, Rg1, Rb1, R1, the area under the curve (AUC) was significantly increased, the mean residence time of (MRT0-t) was delayed, the peak concentration (Cmax) was significantly raised, the apparent volume of distribution (Vz/F) was reduced, and the clearance rate in vivo was significantly slowed. It suggested that AST IV combined with PNS has synergistic enhancement on anti-cerebral ischemia/reperfusion injury, moreover, make the pharmacokinetic behavior of the main effective components change, the mechanism may be associated with prolonging the retention time of the effective components in cerebral ischemia condition, elevating the bioavailability. PMID- 29235297 TI - [Simultaneous determination of 8 constituents of Desmodii Styracifolii Herba in rat bile with HPLC-MS/MS and their excretion pharmacokinetics]. AB - To establish a HPLC-MS/MS quantitative method for analysis of 8 constituents in rat bile. The method was applied in the biliary excretion study after oral administration of Desmodii Styracifolii Herba extract. The rat bile samples were collected during 0-1, 1-2, 2-4, 4-6, 6-8, 8-12, 12-24 h. Diamonsil C18column (4.6 mm*150 mm, 5 MUm) was adopted and eluted with methanol and 0.01% acetic acid in a gradient mode. The flow rate was 0.8 mL*min-1, and the column temperature was set at 40 C. The detection was carried out by a triple quadrupole linearion trap mass spectrometer in the negative ion mode with an electrospray source. Multiple reactions monitoring (MRM) mode was employed. The calibration curves showed a good linearity, with correlation coefficients (r>=0.991 5) for all of the analytes within the concentration range. The intra-day and inter-day precisions (RSD) were both less than 15%, and the accuracies (RE) ranged from -15% to 15%. The method had a good stability, and was suitable for the content determination of 8 constituents in rat bile. The extraction recoveries of the 8 analytes were more than 63.2%, and the RSD of IS-normalized matrix factors were no more than 15%, which met the requirements for analysis. According to the biliary excretion study, the bile excretion rates of the 8 analytes were relatively low, with great difference among the individuals. The results showed that the established method was simple, selective and specific, thus could be applied in the biliary excretion study of the 8 analytes in rat bile. PMID- 29235299 TI - [Prescription regularity of famous veteran traditional Chinese medicine Doctor Yu Guoyou for treating gastrointestinal failure based ondata mining]. AB - Gastrointestinal failure is a kind of severe systemic inflammatory response, and often complicated with multiple organ dysfunction syndrome. Integrated traditional Chinese and Western medicine have a better curative effect in treating it. This study collected the famous veteran TCM physician Yu Guoyou's 175 prescriptions for treating 89 cases of gastrointestinal failure, calculated the frequency of traditional Chinese medicines and their categories, and analyzed the medication regularity with system clustering method, so as to summarize Yu's frequently used drugs and prescriptions. The results showed the top three most frequently used drugs aremagnolia bark, bitter orange, and rhubarb, which are components of Xiaochengqi decoction; Among the traditional Chinese medicines, medicines of tonifying deficiency, regulating qi, clearing heat, eliminating phlegm and dissipating dampness are most commonly used. Among the tonic medicines, those for tonifying Qi accounted for 2/3, which was the largest proportion; At the same time, some new prescriptions and new drug combinations were excavated and could be used as the reference for clinical medication. According to the findings, when differentiating syndromes of gastrointestinal failure, Yu regards the spleen and stomach Qi deficiency as the root cause and the heat toxin, blood stasis, Qi stagnation and dampness as the symptoms. In the treatment of gastrointestinal function failure, Yu gives priority to strengthening spleen, regulating Qi and purgation, prescribes medicines for dissolving blood stasis and detoxication, dissipating dampness, clearing heat and eliminating phlegm according to syndrome types. In other words, the treatment is based on syndrome differentiation, and the prescription is modified according to symptoms. In particular, Yu attaches importance to stomach-Qi recuperation and gastrointestinal function recovery in the process of treatment. PMID- 29235298 TI - [Effect of Saposhnikoviae Radix on pharmacokinetics and tissue distributions of active components in Tongxie Yaofang in rats]. AB - Tongxie Yaofang (TXYF) is a famous formula that has been used for treating gastrointestinal diseases in traditional Chinese medicine(TCM). Saposhnikoviae Radix is considered as a meridian guiding drug in TXYF and could enhance the effectiveness of prescription. However, the scientific evidence for this effect is still not clear. To reveal the interactions of Saposhnikoviae Radix with other herbs, we conducted this study on the pharmacokinetic profile and tissue distribution of active ingredients of TXYF in rats. The concentrations of four components in blood and tissues were determined by UPLC-MS/MS after oral administration with TXYF. The detection was carried out by electrospray ionization mass spectrometry in the multiple reaction monitoring (MRM) mode. The positive and negative ion switching technique was performed in the same analysis. The results revealed that Saposhnikoviae Radix could enhance Cmax, AUC0-t, and AUC0-infinity of paeoniflorin and hesperidin, and increase the distribution of atractylenolide-I, paeoniflorin and hesperidin in liver, spleen, brain and small intestine. Saposhnikoviae Radix increased the ratio of brain to blood concentrations of atractylenolide-I, paeoniflorin and hesperidin. Meanwhile, it reduced the ratio of lung to blood concentrations of atractylenolide-I and paeoniflorin. Saposhnikoviae Radix, and may enhance the effectiveness of prescriptions by promoting distribution of other herbs in brain. PMID- 29235300 TI - [Clinical observation on treatment of type 2 cardiac and kidney syndrome by combination of traditional Chinese and Western medicines]. AB - Clinical observation on treatment of type 2 cardiac and kidney syndrome by combination of traditional Chinese and Western medicine. The patients were divided into two groups: the simple Western medicine treatment group (control group) and the traditional Chinese medicine and Western medicine treatment group (treatment group). The patients in the two groups were treated with conventional western medicine.The treatment group was given based on Buxin Yishen decoction, a total of three courses of treatment to observe the two groups of patients before and after treatment of total efficacy, cardiac function indicators, changes in renal function indicators. The total efficacy of the treatment group and the control group were 91.80% and 72.41%, respectively. There were significant differences between the two groups (P<0.01). The cardiac function indexes and renal function indexes of the treatment group and the control group before and after treatment (P<0.01). Compared with the two groups, the left ventricular function, Hematuria natriuretic peptide, serum creatinine, urea nitrogen, cystatin-C were improved, and the treatment group (P<0.05~0.01). The results showed that the combination of traditional Chinese and Western medicine treatment can improve the clinical efficacy of type 2 heart and kidney syndrome, significantly improve heart and kidney function, better than conventional Western medicine treatment, and has good safety. PMID- 29235301 TI - [Advantages and problems of traditional Chinese medicine in treatment of acute pharyngitis]. AB - This paper systematically studies relevant literatures at home and abroad in recent years. China National Knowledge Internet (CNKI) was used to collect the literatures for acute pharyngitis treated with traditional Chinese medicine from January 1, 2006, to December 31, 2016, and the bibliometric method was employed for statistical analysis. A total of 493 papers were preliminarily selected. According to the inclusion criteria and exclusion criteria, 182 eligible articles were selected. According to the evaluation and analysis of the literatures, the Guidelines for Clinical Research of New Drugs is currently used as the common standards for the diagnosis and treatment of acute pharyngitis; Chinese patent medicines are the main traditional Chinese medicine for treating this disease; Decoctions for treatment of this disease include Lonicerae Japonicae Flos, Scutellariae Radix, Platycodonis Radix, Forsythiae Fructus, Glycyrrhizae Radix et Rhizoma, Scrophdlariae Radix, Isatidis Radix, and Ophiopogonis Radix; The bloodletting puncture is the common external therapy. Traditional Chinese medicine and Western medicine have their own characteristics in the treatment of this disease. Western medicine for the treatment of acute pharyngitis are mainly antiviral, antibiotic and glucocorticoid drugs, whose disadvantages are toxicity, side effects, drug resistance and double infections. Traditional Chinese medicine doctors have rich experiences in the treatment of the disease, which is characterized by treatment determination based on syndrome differentiation, safe and reliable medication, significant curative effect, low drug resistance, and wide varieties of traditional Chinese medicine forms, convenient portability and taking, low price, and low toxic and side effects. It is an arduous and significant task to explore traditional Chinese medicine, and study and develop new-type effective drugs. PMID- 29235302 TI - [Status, problems and warranty strategy of quality uniformity for traditional Chinese medicine preparations]. AB - The quality uniformity of traditional Chinese medicine (TCM) preparation is the base for guaranteeing the safety and effectiveness of clinical medication. At present, the quality of TCM preparation is uneven. At present, the same TCM preparation in different manufacturers, TCM preparations in the same manufacturer, and even different batches of a same TCM preparation in the same manufacturer have great differences in quality, which can not reach stability and uniformity. This paper would discuss the possible factors that influence the uniformity of quality in the whole process of pharmacy by means of consulting relevant literature on quality control of Chinese herbal preparations and analyzing the present situation and problems of the quality of TCM preparation. In addition, some strategies such as standardization of cultivation of TCM, processing standardization, standardization of pharmaceutical equipment, mixed batch feeding, and Quality by Design would be also put forward to provide references for the quality uniformity of TCM preparation. PMID- 29235303 TI - [Varieties textual research, resource investigation and identification of commercial drugs on Cuscutae Semen]. AB - Through the textual research, resource investigation, literature reviews (including Flora of China, municipal Flora, pharmacopoeia of China and municipal drug standards) and identification of commercial drugs on Cuscutae Semen, it was found the species described in the herbal textual was Cuscuta chinensis, with good quality from Shandong and Henan Province. The identification of commodities showed the majority drugs were from C. australis, varied from the ancient herbal textuals .Mordern literature reviews indicate that it was necessary to strengthen the research on Cuscutae Semen from C. australis, C. chinensis and C. japonica because of their differences in resources, macroscopical and microscopical characters, while wrong descriptions in some literatures. It was suggested that the two species (C. australis and C. chinensis) should be separated in pharmacopoeia of China. The study provides scientific basis for the development and utilization of Cuscutae Semen. PMID- 29235304 TI - [Exploration and thoughts about zoological origin and macroscopical identification of Chinese material medica "Haima" in China Pharmacopoeia]. AB - "Haima" (Hippocampus) has a long history in China as an important traditional animal medicine, but many closely-related members of the Hippocampus genus are also used as Haima in particular regions. To investigate the real origin of "Haima", a herbalogical studies, particularly inpictures and photographs of the ancient literature are corroborated with seahorse specimens in museum, we confirm Chinese material medica "Haima" in China Pharmacopoeia is origin from H. kelloggi, 1901, H.spinosissimus, 1913, H. kuda, 1852, H. trimaculatus, 1814, or H. mohnikei, 1853. The so-called "Ci Haima" is H. spinosissimus, instead of H. histrix, 1856. The paper also suggests to revise of "macroscopical identification" item and add identification methods of "Haima" in China Pharmacopoeia, which may improve quality controls tandards of "Haima". PMID- 29235305 TI - [Discussion on related problems of model species of fungus: Paecilomyces hepialid]. AB - Paecilomyces hepiali is a new species of fungus isolated from a field collection of Ophiocordyceps sinensis from Baima snow mountain, Diqing Tibetan Autonomous Prefecture, Yunnan Province by the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences. The specimen was identified and named as Paecilomyces hepiali by Qing-Tao Chen, the professor of the Institute of Microbiology, Chinese Academy of Sciences (Paecilomyces hepiali) (2008), who identified a dried culture of living strain 82-2 as the holotype. Until now, the holotype (the voucher specimen) was deposited in the Herbarium of the Institute of Chinese Materia Medica (HICMM), China Academy of Chinese Medical Sciences, Beijing. The P. hepiali neotype designated by the paper "Neotypification of P. hepiali (Hypocreales)" published in TAXON 64 (1) by Yao Yi-Jian et al. in February 2015 is untenable. PMID- 29235307 TI - Oral Cancer Awareness Month. PMID- 29235306 TI - Comparison of everolimus-eluting bioresorbable vascular scaffolds and metallic stents: three-year clinical outcomes from the ABSORB China randomised trial AB - Aims: Absorb bioresorbable vascular scaffolds (BVS) and XIENCE cobalt-chromium everolimus-eluting stents (CoCr-EES) had comparable angiographic and clinical outcomes up to one year in patients enrolled in the ABSORB China randomised trial. Whether these favourable results with BVS continue beyond one year up to three years is unknown. In this study we sought to analyse the outcomes from the trial up to three-year follow-up. Methods and results: ABSORB China was a prospective, open-label, multicentre trial in which 480 patients with one or two native coronary artery lesions were randomised 1:1 to BVS (N=241) vs. CoCr-EES (N=239). Clinical endpoints included target lesion failure (TLF; cardiac death, target vesselrelated myocardial infarction or ischaemia-driven target lesion revascularisation), its components, and definite/probable stent/scaffold thrombosis (ST). There were no significant differences in clinical outcomes in patients treated with BVS and CoCr-EES up to three years, including TLF (5.5% vs. 4.7%, p=0.68) and definite/probable ST (0.9% vs. 0.0%, p=0.50). STs in the BVS arm consisted of one probable subacute event at 15 days and one definite very late event at 622 days. Among 32 BVS patients with a reference vessel diameter between 2.25 and 3.75 mm by quantitative coronary angiography and in whom post dilatation was performed at >16 atm with a balloon:scaffold diameter >1:1 and balloon <=scaffold diameter 0.5 mm, no TLF or ST events occurred within three years. Conclusions: In the ABSORB China trial, BVS and CoCr-EES had similar results up to three-year follow-up, the time at which the scaffold has completely resorbed. BVS outcomes may be further optimised by appropriate lesion selection and implantation technique. PMID- 29235308 TI - Periodontal Treatment Versus Antibiotics. PMID- 29235309 TI - Focus On: Oral Cancer Screening Devices. PMID- 29235310 TI - New Trends in Endodontics and Treatment Planning. PMID- 29235311 TI - Excellent Canal Cleansing, Minimal Root Weakening. PMID- 29235312 TI - Basics of Platelet-Rich Fibrin Therapy. PMID- 29235313 TI - The Implant Practice. PMID- 29235314 TI - Are You Placing Implants? PMID- 29235315 TI - Design Enhances Soft-Tissue Architecture. PMID- 29235316 TI - Aesthetic Mandibular Anterior Alignment: A Quick and Affordable Prerestorative Option. PMID- 29235317 TI - Bruxism, Botox, and Dental Implants. PMID- 29235318 TI - A Zirconia Option for Anterior Restorations. PMID- 29235319 TI - Hydrolytic enzymes expressivity in different parts of the Rapana digestive system. AB - The relevance of comprehensive studies of the Rapana vital functions is determined by its considerab-le negative impact on the ecosystem of the Black Sea. The aim of the work was to find out the polymorphism and activity of the main hydrolases in the different parts of the digestive system of Rapana. Hydrolases (proteases, amylases, esterases, lipases and phosphatases) in glandular structures of the Rapana digestive system were studied by electrophoresis. It was found that different sets of hydrolytic enzymes are functioning in certain parts of the Rapana digestive tract. The gland of Leiblein and hepatopancreas played the most important role in the digestion of food components. The salivary glands had the significant influence on proteolysis. PMID- 29235320 TI - Prospectively Engineered Implant Placement. PMID- 29235321 TI - Isolation and purification of Bacillus thuringiensis var. israelensis IMV V-7465 peptidase with specificity toward elastin and collagen. AB - Peptidase of Bacillus thuringiensis var. israelensis IMV V-7465 was isolated from culture supernatant using consecutive fractionations by an ammonium sulphate (60% saturation), ion-exchange chromatography and gel-filtration on the TSK-gels Toyoperl HW-55 and DEAE 650(M). Specific elastase (442 U?mg of protein-1) and collagenase (212.7 U?mg of protein-1) activities of the purified enzyme preparation were 8.0- and 6.1-fold, respectively higher than ones of the culture supernatant. Peptidase yields were 33.5% for elastase activity and 30.1% for collagenase activity. It was established that the enzyme is serine metal dependent alkaline peptidase with Mr about 37 kDa. Maximal hydrolysis of elastin and collagen occurs at the optimum pH 8.0 and t degrees - 40 and 50 degrees S, respectively. The purified preparation has high stability at pH in the range of 7.0 to 10.0 and 40-50 degrees S. PMID- 29235322 TI - Kinetic parameters of polyreactive immunoglobulins interaction with antigens in the presence of protamine. AB - The discovered earlier phenomenon of the enhancment of polyreactive immunoglobulines (PRIGs) binding to antigens in the presence of protamine and Tween 20 was investigated in more details. The comparative analysis of PRIGs reaction dynamics with immobilized antigen was provided. In addition, the rate constants for the reaction and the affinity constants of PRIGs-antigen binding in the presence or absence of optimal protamine concentration were determined. The rate constant of PRIGs-antigen reaction did not increase in the presence of protamine optimal concentration and was even reduced approximately twice. However, in the presence of protamine the concentration of reactive PRIGs molecules, that were able to interact with antigen, increased approximately 30 times, and this led to strong reaction rate increase. Protamine also influenced the affinity constant of PRIGs-antigen binding, which increased approximately three times. The suggestion was made that such protamine effect was due to its influence on the PRIGs molecules special structure, and, as a result of the conformational change PRIGs became able to bind more effectively to the antigens. PMID- 29235323 TI - Plasminogen fragments K 1-3 and K 5 bind to different sites in fibrin fragment DD. AB - Specific plasminogen-binding sites of fibrin molecule are located in Aalpha148 160 regions of C-terminal domains. Plasminogen interaction with these sites initiates the activation process of proenzyme and subsequent fibrin lysis. In this study we investigated the binding of plasminogen fragments K 1-3 and K 5 with fibrin fragment DD and their effect on Glu-plasminogen interaction with DD. It was shown that the level of Glu-plasminogen binding to fibrin fragment DD is decreased by 50-60% in the presence of K 1-3 and K 5. Fragments K 1-3 and K 5 have high affinity to fibrin fragment DD (Kd is 0.02 for K 1-3 and 0.054 MUM for K 5). K 5 interaction is independent and K 1-3 is partly dependent on C-terminal lysine residues. K 1-3 interacts with complex of fragment DD-immobilized K 5 as well as K 5 with complex of fragment DD-immobilized K 1-3. The plasminogen fragments do not displace each other from binding sites located in fibrin fragment DD, but can compete for the interaction. The results indicate that fibrin fragment DD contains different binding sites for plasminogen kringle fragments K 1-3 and K 5, which can be located close to each other. The role of amino acid residues of fibrin molecule Aalpha148-160 region in interaction with fragments K 1-3 and K 5 is discussed. PMID- 29235324 TI - Loach embryos prooxidant-antioxidant status under the influence of amide derivatives of 1,4-naphthoquinone. AB - The mechanisms of disorders in cell functions induced by 1,4-naphthoquinone amide derivatives are not clarified yet. The article is dedicated to the study of features of these substances influence on loach Misgurnus fossilis L. embryos pro/antioxidant homeostasis during early embryogenesis. The aim of this work was to study the effect of 2-chloro-3-hydroxy-1,4-naphthoquinone, 2-chloro-3-(3-oxo-3 (piperidine-1-yl)propylamine)-1,4-naphthoquinone (FO-1), 2-chloro-3-(3 (morpholine-4-yl)-3-oxopropylamine)-1,4-naphthoquinone (FO-2 at concentrations of 10-3, 10-5, 10-7 M on the content of TBA-reactive substances (a byproduct of lipid peroxidation) and the activities of superoxide dismutase and catalase in loach embryos. It was established that 1,4-naphthoquinone amide derivatives and 2 chloro-3-hydroxy-1,4-naphthoquinone decreased the content of lipid peroxidation products in embryo cells in a dose-dependent manner. The investigated compounds cause an increase in superoxide dismutase and catalase activities compared with the control value. The results of the two-factor ANOVA test indicate that 2 chloro-3-hydroxy-1,4-naphthoquinone and 1,4-naphthoquinone amide derivatives (FO 1, FO-2) have predominant influence on the TBA-reactive substances content and superoxide dismutase activity. However, the time of loach embryos development has a more pronounced effect on catalase activity than the studied 1,4-naphthoquinone derivatives. PMID- 29235325 TI - Interest in Implant Dentistry Grows. PMID- 29235326 TI - Effect of hypoxia on the expression of nuclear genes encoding mitochondrial proteins in U87 glioma cells. AB - We have studied the effect of hypoxia on the expression of nuclear genes encoding mitochondrial proteins in U87 glioma cells under the inhibition of IRE1 (inositol requiring enzyme-1), which controls cell proliferation and tumor growth as a central mediator of endoplasmic reticulum stress. It was shown that hypoxia down regulated gene expression of malate dehydrogenase 2 (MDH2), malic enzyme 2 (ME2), mitochondrial aspartate aminotransferase (GOT2), and subunit B of succinate dehydrogenase (SDHB) in control (transfected by empty vector) glioma cells in a gene specific manner. At the same time, the expression level of mitochondrial NADP+-dependent isocitrate dehydrogenase 2 (IDH2) and subunit D of succinate dehydrogenase (SDHD) genes in these cells does not significantly change in hypoxic conditions. It was also shown that the inhibition of IRE1 signaling enzyme function in U87 glioma cells decreases the effect of hypoxia on the expression of ME2, GOT2, and SDHB genes and introduces the sensitivity of IDH2 gene to hypoxia. Furthermore, the expression of all studied genes depends on IRE1 mediated endoplasmic reticulum stress signaling in gene specific manner, because IRE1 knockdown significantly decreases their expression in normoxic conditions, except for IDH2 gene, which expression level is strongly up-regulated. Therefore, changes in the expression level of nuclear genes encoding ME2, MDH2, IDH2, SDHB, SDHD, and GOT2 proteins possibly reflect metabolic reprogramming of mitochondria by hypoxia and IRE1-mediated endoplasmic reticulum stress signaling and correlate with suppression of glioma cell proliferation under inhibition of the IRE1 enzyme function. PMID- 29235327 TI - Prophy or Perio Patient: What is your why? PMID- 29235328 TI - Focus On: Lasers for Disinfection. PMID- 29235329 TI - Expression of IGFBP6, IGFBP7, NOV, CYR61, WISP1 and WISP2 genes in U87 glioma cells in glutamine deprivation condition. AB - We have studied gene expression of insulin-like growth factor binding proteins in U87 glioma cells upon glutamine deprivation depending on the inhibition of IRE1 (inositol requiring enzyme-1), a central mediator of endoplasmic reticulum stress. We have shown that exposure of control glioma cells upon glutamine deprivation leads to down-regulation of NOV/IGFBP9, WISP1 and WISP2 gene expressions and up-regulation of CYR61/IGFBP10 gene expression at the mRNA level. At the same time, the expression of IGFBP6 and IGFBP7 genes in control glioma cells was resistant to glutamine deprivation. It was also shown that the inhibition of IRE1 modifies the effect of glutamine deprivation on the expression of all studied genes. Thus, the inhibition of IRE1 signaling enzyme enhances the effect of glutamine deprivation on the expression of CYR61 and WISP1 genes and suppresses effect of the deprivation on WISP2 gene expression in glioma cells. Moreover, the inhibition of IRE1 introduces sensitivity of the expression of IGFBP6 and IGFBP7 genes to glutamine deprivation and removes this sensitivity to NOV gene. We have also demonstrated that the expression of all studied genes in glioma cells growing with glutamine is regulated by IRE1 signaling enzyme, because the inhibition of IRE1 significantly down-regulates IGFBP6 and NOV genes and up-regulates IGFBP7, CYR61, WISP1, and WISP2 genes as compared to control glioma cells. The present study demonstrates that glutamine deprivation condition affects most studied IGFBP and WISP gene expressions in relation to IRE1 signaling enzyme function and possibly contributes to slower glioma cell proliferation upon inhibition of IRE1. PMID- 29235330 TI - Implant Fixtures and Abutment Considerations. PMID- 29235331 TI - The impact of hydroxycitric acid on the lipid metabolism profile under experimental insulin resistance syndrome of Syrian hamsters. AB - The syndrome of insulin resistance (IR) is one of the leading reasons for the increased risk of cardiovascular diseases and their complications. Among the key components of IR are obesity and dyslipidemia. Hydroxycitric acid (HCA), an inhibitor of a key enzyme of lipogenesis ATP citrate lyase (ACLY) is a promising obesity treatment agent. The aim of this work was to investigate the effect of HCA on lipid and lipoproteins content in the blood serum, as well as lipid content and activity of some lipid metabolism enzymes in the liver of hamsters with IR. IR was modeled by keeping animals on high-fat diet with addition of fructose. Lipid content was determined by using standard reagent kits, the level of lipoproteins, the activity of glucose 6-phosphate dehydrogenase and ACLY - spectrophotometrically, lysosomal lipase activity - fluorimetrically. Development of hyperlipidemia and atherogenic dyslipidemia, lipid accumulation in the liver, activation of lysosomal lipase and ACLY and reduction of glucose 6-phosphate dehydrogenase activity were shown under IR. The treatment by HCA reduces the manifestations of hyperlipidemia, but enhances the lipid accumulation in the liver. PMID- 29235332 TI - Technology Expands the Scope of the General Practice. PMID- 29235333 TI - Effect of curcumin on accumulation in mononuclear cells and secretion in incubation medium of Abeta(40) and cytokines under local excess of Abeta(42) homoaggregates. AB - The aim of the work was to investigate accumulation of endogenous Abeta40 and cytokines (IL-1beta, TNFalpha, IL-6, IL-10) in mononuclear cells and their secretion into incubation medium under Abeta42-aggregates' toxicity and anti inflammatory effects of curcumin. Mononuclear cells were isolated in Ficoll Urografin density gradient from venous blood of healthy donors, resuspended and used for testing of homoaggregates of Abeta42 (15 nM), curcumin (54 pM) and their combinations on various timescales (0, 1, 2, 3, 6 and 24 hours). Endogenous Abeta40 and cytokines were detected in mononuclear cells and (separately) in incubation medium by ELISA. We demonstrated for the first time that homoaggregates of Abeta42 cause rapid accumulation of endogenous Abeta40 in mononuclear cells and accelerate its secretion into incubation medium. We found increased concentration of TNFalpha after 3 hours of incubation, and no changes in IL-1beta concentration due to secretion of these pro-inflammatory factors into incubation medium. The concentrations of IL-6 in mononuclear cells were increased under effects of Abeta42 homoaggregates, and it was being secreted profoundly into incubation medium. Abeta42 did not affect IL-10 secretion, yet caused an increase in its intracellular concentration after 1 hour of incubation, which was subsequently suppressed. Curcumin prevented the increase in Abeta40 concentration in mononuclear cells and significantly decreased its secretion resulting from Abeta42 toxicity. Curcumin negated the activating effect of Abeta42 on pro inflammatory cytokines, starting immediately for IL-1beta and on 3-6 hours for TNFalpha, which resulted in decreased extracellular concentrations of these cytokines. The polyphenol also potentiated repleni-shing of intracellular IL-6 and IL-10 concentrations and their secretion into incubation medium. PMID- 29235334 TI - Fatty acids composition of inner mitochondrial membrane of rat cardiomyocytes and hepatocytes during hypoxia-hypercapnia. AB - We studied the influence of hypoxic-hypercapnic environment under the effect of hypothermia (artificial hibernation) on fatty acids spectrum of inner mitochondrial membrane (IMM) lipids of rat cardiomyocytes and hepatocytes. Specific for cellular organelles redistribution of IMM fatty acids was determined. It led to the reduction of total amount of saturated fatty acids (SFAs) and increase of unsaturated fatty acids (UFAs) in cardiomyocytes and to the increase of SFAs and decrease of UFAs in hepatocytes. The decrease in the content of oleic acid and increased content of arachidonic and docosahexaenoic acids in IMM were shown. This may be due to their role in the regulatory systems during hibernation, as well as following exit therefrom. It is assumed that artificial hibernation state is characterized by the stress reaction leading to optimal readjustment of fatty acids composition of membrane lipids, which supports functional activity of mitochondria in hepatocytes and cardiomyocytes. PMID- 29235335 TI - Hepatotoxicity of bisphenol A under conditions of differential supplementation with retinoids. AB - Classical xenoestrogenic in vivo effects of bisphenol A (2,2-bis(4 hydroxyphenyl)propane, BPA) are well-described in the literature, however the molecular mechanisms of BPA-induced hepatotoxicity are not fully characterized. The work is aimed to assess biochemical markers of BPA induced hepatotoxicity under conditions of differential supplementation with retinoids. We demonstrate that the absence of hepatic retinyl esters as the main form of vitamin A storage provides for a resistance to BPA induced liver damage. Retinoid supplementation increases the hepatotoxic effects of bisphenol A, evidenced in higher indexes of oxidative damage of lipids, proteins and non-protein thiol groups as well as increase of serum alanine aminotransferase activity and myeloperoxidase activity in liver parenchyma. The absence of hepatotoxicity signs when hepatic retinoid stores are depleted and their presence during normal or excessive retinoid supplementation suggest that hepatic retinoid availability is one of the factors determining the hepatotoxicity of bisphenol A. PMID- 29235337 TI - Considerations in Abutment Selection. PMID- 29235336 TI - [Inventive activity of the Departments of Protein Structure and Function, and Molecular Immunology of the Palladin Institute of Biochemistry of NAS of Ukraine. Part II. National breakthrough in the study and diagnostics of human hemostasis system]. AB - The scientists of Protein Structure and Function, and Molecular Immunology Departments of the Palladin Institute of Biochemistry (NAS of Ukraine) under the supervision of member of NASU and NAMSU, prof. S. V. Komisarenko and corresponding member of NASU prof. E. V. Lugovskoy have made the real breakthrough in the field of research of the mechanisms of fibrin polymerization and formation of fibrin framework of thrombi. The immunodiagnostic test-systems for the evaluation of the risk of thrombus formation were developed for the first time. Researches have obtained the monoclonal antibodies to fibrinogen, fibrin, D-dimer and their fragments. These monoclonal antibodies were used as molecular probes for the localization of newly detected fibrin polymerization sites. Obtained antibodies with high affinity interact with fibrinogen, D-dimer and soluble fibrin - main markers of the risk of thrombus formation. They were used for the development of the immunodiagnostic test-systems to quantify these markers in human blood plasma for the evaluation of the state of haemostasis system, detection of prethrombotic states, disseminated intravascular coagulation, detection of thrombosis and monitoring of antithrombotic and fibrinolytic therapy. The successful trial of developed test-systems was carried out in clinics of Ukraine, and the State registration was obtained for the implementation of them into the clinical practice. Presented works were awarded State prize of Ukraine in Science and technology. PMID- 29235338 TI - Three Impression Material Classifications: A Comparison. PMID- 29235340 TI - Visible-Light-Promoted Synthesis of Dibenzofuran Derivatives. AB - Dibenzofurans are naturally occurring molecules that have received considerable attention for a variety of practical applications, such as in pharmaceuticals and electronic materials. Herein, an efficient and eco-friendly method for the synthesis of dibenzofuran derivatives via intramolecular C-O bond formation, which involves the in situ production of a diazonium salt, is described. The transformation requires a diazotizing agent and is promoted by the use of an organic photosensitizer under visible-light irradiation. PMID- 29235339 TI - Ca(2+)-dependent regulation of the Ca(2+) concentration in the myometrium mitochondria. I. Trifluoperazine effects on mitochondria membranes polarization and [Ca(2+)](m). AB - Sa2+-dependent regulation of Ca2+ exchange in mitochondria is carried out with participation of calmodulin. We have shown previously that calmodulin antagonists reduced the level of mitochondrial membrane polarization and induced increase of the ionized Sa concentration in both the mitochondrial matrix and cell cytoplasm. The concentration-dependent influence of trifluoperazine on the level of polarization of mitochondrial membranes has been shown in this work. The coordinates of the Hill graphs were used to calculate the constant K0.5 and the Hill coefficient. K0.5 was 24.4 +/- 5 MUM (n = 10). The Hill coefficient was 2.0 +/- 0.2, indicating the presence of two centers of the trifluoperazine binding. We have also studied [Ca2+]m changes, when incubating mitochondria in mediums of different composition: without ATP and ions of Mg (0-medium), in the presence of 3 mM Mg (Mg-medium) and 3 mM Mg + 3 mM ATP (Mg,ATP-medium). It was shown that the composition of the incubation medium affected the [Ca2+]m values in the absence of exogenous Ca2+ and did not affect them in the presence of the latter. Preincubation of mitochondria in mediums of different composition with 25 MUM trifluoperazine did not affect the [Ca2+]m values both before and after the addition of 100 uM Sa2+ to the incubation medium. It was concluded, that trifluoperazine depolarized myometrial mitochondria membranes in concentration dependent manner. However, mitochondria preincubation with 25 MUM trifluope razine accompanied by 50% decrease in membrane polarization did not affect the [Ca2+]m values. PMID- 29235341 TI - Group-Assisted Purification Chemistry for Asymmetric Mannich-type Reaction of Chiral N-Phosphonyl Imines with Azlactones Leading to Syntheses of alpha Quaternary alpha,beta-Diamino Acid Derivatives ?. AB - An asymmetric Mannich-type reaction between chiral N-phosphonyl imines and azlactones [oxazol-5(4H)-ones] has been established under convenient conditions at room temperature. The reaction was performed without using any bases, additives, or catalysts to achieve up to excellent chemical yields and diastereoselectivity for 32 examples. The alpha-quaternary syn-alpha,beta-diamino acid products were purified simply by washing the crude mixtures with cosolvents, following the group-assisted purification chemistry/technology, without involving traditional chromatography or recrystallization methods. The auxiliary can be readily removed and recycled for reuse. The absolute configuration was unambiguously assigned by X-ray structural analysis. PMID- 29235342 TI - Noble-Metal-Free Co0.6Fe2.4O4 Nanocubes Self-Assembly Monolayer for Highly Sensitive Electrochemical Detection of As(III) Based on Surface Defects. AB - Nanocrystals generally suffer from agglomeration because of the spontaneous reduction of the system surface energy, resulting in blocking the active sites from reacting with target ions, and then severely reducing the electrochemical sensitivity. In this article, a highly ordered self-assembled monolayer array is successfully constructed using ~14 nm Co0.6Fe2.4O4 nanocubes uniformly and controllably distributed on the surface of a working electrode (glass carbon plate). The large area and high exposure of the surface defects on Co0.6Fe2.4O4 nanocubes are clearly characterized by high-resolution transmission electron microscopy (HRTEM) and atomic-resolution high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM). Expectedly, a considerable sensitivity of 2.12 MUA ppb-1 and a low limit of detection of 0.093 ppb are achieved for As(III) detection on this highly homogeneous sensing interface; this excellent electroanalysis performance is even better than that of noble metals electrodes. Most importantly, this approach of uniformly distributing the small sized defective nanoparticles on the electrode surface provides a new opportunity for modifying the electrodes, as well as the realization of their applications in the field of environmental electroanalysis for heavy metal ions. PMID- 29235343 TI - N-Glucosides of Fairy Chemicals, 2-Azahypoxanthine and 2-Aza-8-oxohypoxanthine, in Rice. AB - Plant growth stimulators, 2-azahypoxanthine (AHX) and 2-aza-8-oxohypoxanthine (AOH), were isolated from the fairy-ring-forming fungus, Lepista sordida, and AHX treated rice, respectively. Further metabolites of AHX were detected in AHX treated rice by HPLC, and the metabolites 1-4 were isolated from the rice. The structures of 1-4 were determined by spectroscopic analysis and synthesis. Compounds 1-4 exhibited no significant activity against rice, indicating that rice regulates the activity of AHX and AOH by converting them into their glucosides. PMID- 29235344 TI - High Dynamic Range (Deltan) Two-Stage Photopolymers via Enhanced Solubility of a High Refractive Index Acrylate Writing Monomer. AB - Holographic photopolymers capable of high refractive index modulation (Deltan) on the order of 10-2 are integral for the fabrication of functional holographic optical elements that are useful in a myriad of optical applications. In particular, to address the deficiency of suitable high refractive index writing monomers for use in two-stage holographic formulations, here we report a novel high refractive index writing monomer, 1,3-bis(phenylthio)-2-propyl acrylate (BPTPA), simultaneously possessing enhanced solubility in a low refractive index (n = 1.47) urethane matrix. When examined in comparison to a widely used high refractive index monomer, 2,4,6-tribromophenyl acrylate, BPTPA exhibited superior solubility in a stage 1 urethane matrix of approximately 50% with a 20% higher refractive index increase per unit amount of the writing monomer for stage 2 polymerizations. Formulations with 60 wt % loading of BPTPA exhibit a peak-to mean holographic Deltan ~ 0.029 without obvious deficiencies in transparency, color, or scatter. To the best of our knowledge, this value is the highest reported in the peer-reviewed literature for a transmission hologram. The capabilities and versatility of BPTPA-based formulations are demonstrated at varying length scales via demonstrative refractive index gradient structure examples including direct laser write, projection mask lithography of a 1" diameter Fresnel lens, and ~100% diffraction efficiency volume transmission holograms with a 1 MUm fringe spacing in 11 MUm thick samples. PMID- 29235345 TI - Mucus and Cell-Penetrating Nanoparticles Embedded in Nano-into-Micro Formulations for Pulmonary Delivery of Ivacaftor in Patients with Cystic Fibrosis. AB - Here, mucus-penetrating nanoparticles (NPs) for pulmonary administration of ivacaftor in patients with cystic fibrosis (CF) were produced with the dual aim of enhancing ivacaftor delivery to the airway epithelial cells, by rapid diffusion through the mucus barrier, and at the same time, promoting ivacaftor lung cellular uptake. Pegylated and Tat-decorated fluorescent nanoparticles (FNPs) were produced by nanoprecipitation, starting from two synthetic copolymers, and showed nanometric sizes (~70 nm), a slightly negative zeta potential, and high cytocompatibility toward human bronchial epithelium cells. After having showed the significant presence of poly(ethylene glycol) chains and Tat protein onto the FNP surface, the FNP mucus-penetrating ability, ivacaftor release profile, and lung cellular uptake were studied in the presence of CF artificial mucus as a function of the FNP surface chemical composition. Moreover, microparticle-based pulmonary drug-delivery systems composed of mucus-penetrating FNPs loaded with ivacaftor and mannitol were prepared by using the nano-into micro strategy and realized by spray-drying, thereby providing optimal preservation and stabilization of FNP technological and fluorescence properties. PMID- 29235346 TI - Pathways of Amyloid-beta Aggregation Depend on Oligomer Shape. AB - One of the main research topics related to Alzheimer's disease is the aggregation of the amyloid-beta peptide, which was shown to follow different pathways for the two major alloforms of the peptide, Abeta40 and the more toxic Abeta42. Experimental studies emphasized that oligomers of specific sizes appear in the early aggregation process in different quantities and might be the key toxic agents for each of the two alloforms. We use transition networks derived from all atom molecular dynamics simulations to show that the oligomers leading to the type of oligomer distributions observed in experiments originate from compact conformations. Extended oligomers, on the other hand, contribute more to the production of larger aggregates thus driving the aggregation process. We further demonstrate that differences in the aggregation pathways of the two Abeta alloforms occur as early as during the dimer stage. The higher solvent-exposure of hydrophobic residues in Abeta42 oligomers contributes to the different aggregation pathways of both alloforms and also to the increased cytotoxicity of Abeta42. PMID- 29235347 TI - Nano-electromechanical Switch Based on a Physical Unclonable Function for Highly Robust and Stable Performance in Harsh Environments. AB - A physical unclonable function (PUF) device using a nano-electromechanical (NEM) switch was demonstrated. The most important feature of the NEM-switch-based PUF is its use of stiction. Stiction is one of the chronic problems associated with micro- and nano-electromechanical system (MEMS/NEMS) devices; however, here, it was utilized to intentionally implement a PUF for hardware-based security. The stiction is caused by capillary and van der Waals forces, producing strong adhesion, which can be utilized to design a highly robust and stable PUF. The probability that stiction will occur on either of two gates in the NEM switch is the same, and consequently, the occurrence of the stiction is random and unique, which is critical to its PUF performance. This uniqueness was evaluated by measuring the interchip Hamming distance (interchip HD), which characterizes how different responses are made when the same challenge is applied. Uniformity was also evaluated by the proportion of "1" or "0" in the response bit-string. The reliability of the proposed PUF device was assessed by stress tests under harsh environments such as high temperature, high dose radiation, and microwaves. PMID- 29235348 TI - Carbon Dots with Red Emission for Sensing of Pt2+, Au3+, and Pd2+ and Their Bioapplications in Vitro and in Vivo. AB - Red emissive carbon dots (CDs) have drawn more and more attention due to their good organ penetration depth and slight biological tissue photodamage. Herein, the fluorescent CDs with red emission were synthesized by the facile one-pot hydrothermal treatment of citric acid and neutral red and they show red fluorescence both in aqueous solution and solid state. The solution of CDs exhibits the quantum yield of 12.1%, good stability against photobleaching, and low cytotoxicity. As-prepared CDs can be used as a fluorescent probe for peculiar detection of Pt2+, Au3+, and Pd2+. Furthermore, the CDs show excellent biocompatibility, which were successfully used as hopeful bioimaging and biosensing of noble metal ions in PC12 cells and zebrafish. PMID- 29235349 TI - Improving Uniformity and Reproducibility of Hybrid Perovskite Solar Cells via a Low-Temperature Vacuum Deposition Process for NiOx Hole Transport Layers. AB - Recently, the trend in inverted hybrid perovskite solar cells (PVSCs) has been to utilize NiOx as hole transport layers. However, the majority of reported solution processed NiOx films require a high-temperature thermal annealing process, which is unfavorable for large-scale manufacturing and suffers from lack of uniformity. We report, for the first time, e-beam evaporation as a low-temperature vacuum process for the deposition of NiOx hole transport layers for PVSCs. Device characterization shows that efficiency is on par with solution-processed methods, the highest efficiency at 15.4% with no obvious hysteresis. Differences are found to be due to the presence of more Ni3+ in e-beam evaporated NiOx, which are responsible for a lower transmittance but higher conductivity. Most importantly, e-beam-evaporated NiOx-based PVSCs show greater uniformity and reproducibility compared to spin-coated NiOx-based PVSCs. Finally, e-beam-evaporated NiOx has the additional advantage of being produced by a low-temperature deposition process and applicable over large areas. This work, therefore, represents a significant step toward large-area PVSCs, where e-beam evaporation can be used for the low temperature uniform deposition of charge-transport layers, such as NiOx. PMID- 29235350 TI - Spatial Confinement of the Optical Sensitizer to Realize a Thin Film Organic Photodetector with High Detectivity and Thermal Stability. AB - A thin film planar heterojunction organic photodetector (PHJ-OPD) is demonstrated. Different from a conventional sensitizer-doped photodetector, the limited spatial distribution of sensitizer in a PHJ-OPD enables significantly reduced thickness of the active layer without allowing the formation of unnecessary trap sites and electron percolation pathways. As a result, peak external quantum efficiency (EQE) of 120 700% and detectivity over 1013 Jones are demonstrated with thin active layer thickness of 150 nm, which can be a significant benefit for high-resolution image sensor application. Furthermore, the operating voltage can be decreased to -5 V while maintaining high detectivity over 1012 Jones. Remarkable thermal stability is also observed with minor change in detectivity for 2 h of continuous operation at 60 degrees C due to morphological robustness of PHJ. This work opens up a possibility of using a thin film PHJ-OPD as a key unit of high-resolution image sensor. PMID- 29235351 TI - A Metal-Free Route to Heterocyclic Trifluoromethyl- and Fluoroalkylselenolated Molecules. AB - A metal-free methodology to easily synthesize various CF3Se-containing heterocyclic compounds has been developed through intramolecular ring closures of alkynes promoted with CF3SeCl. Moreover, this strategy has also been extended to other fluoroalkylselenyl groups. PMID- 29235353 TI - Sensing Parts per Million Level Ammonia and Parts per Billion Level Acetic Acid in the Gas Phase by Common Black Film with a Fluorescent pH Probe. AB - Relying on the nanometer-thick water core and large surface area-to-volume ratio (~2 * 108 m-1) of common black film (CBF), we are able to use a pH-sensitive dye (carboxy-seminaphthorhodafluor-1, SNARF-1) to detect ammonia and acetic acid gas adsorption into the CBF, with the limit of detection reaching 0.8 ppm for NH3 gas and 3 ppb for CH3COOH gas in the air. Data analysis reveals that fluorescence signal change is linearly proportional to the gas concentration up to 15 ppm and 65 ppb for NH3 and CH3COOH, respectively. PMID- 29235352 TI - Systems Approaches to Understanding and Designing Allosteric Proteins. AB - The study of allostery has a central place in biology because of the myriad roles of allosteric proteins in cellular function. As technologies for probing the spatiotemporal resolution of biomolecules have become increasingly sophisticated, so has our understanding of the diverse structural and molecular mechanisms of allosteric proteins. Studies have shown that the allosteric signal is transmitted a through a network of residue-residue interactions connecting distal sites on a protein. Linking structural and dynamical changes to the functional role of individual residues will give a more complete molecular view of allostery. In this work, we highlight new mutational technologies that enable a systems-level, quantitative description of allostery that dissect the role of individual residues through large-scale functional screens. A molecular model for predicting allosteric hot spots can be developed by applying statistical tools on the resulting large sequence-structure-function data sets. Design of allosteric proteins with new function is essential for engineering biological systems. Previous design efforts demonstrate that the allosteric network is a powerful functional constraint in the design of novel or enhanced allosteric proteins. We discuss how a priori knowledge of an allosteric network could improve rational design by facilitating better navigation of the design space. Understanding the molecular "rules" governing allostery would elucidate the molecular basis of dysfunction in disease-associated allosteric proteins, provide a means for designing tailored therapeutics, and enable the design of new sensors and enzymes for synthetic biology. PMID- 29235354 TI - Ultralow-Carbon Nanotube-Toughened Epoxy: The Critical Role of a Double-Layer Interface. AB - Understanding the chemistry and structure of interfaces within epoxy resins is important for studying the mechanical properties of nanofiller-filled nanocomposites as well as for developing high-performance polymer nanocomposites. Despite the intensive efforts to construct nanofiller/matrix interfaces, few studies have demonstrated an enhanced stress-transferring efficiency while avoiding unfavorable deformation due to undesirable interface fractures. Here, we report an optimized method to prepare epoxy-based nanocomposites whose interfaces are chemically modulated by poly(glycidyl methacrylate)-block-poly(hexyl methacrylate) (PGMA-b-PHMA)-functionalized multiwalled carbon nanotubes (bc@fMWNTs) and also offer a fundamental explanation of crack growth behavior and the toughening mechanism of the resulting nanocomposites. The presence of block copolymers on the surface of the MWNT results in a promising double-layered interface, in which (1) the outer-layered PGMA segment provides good dispersion in and strong interface bonding with the epoxy matrix, which enhances load transfer efficiency and debonding stress, and (2) the interlayered rubbery PHMA segment around the MWNT provides the maximum removable space for nanotubes as well as triggering cavitation while promoting local plastic matrix deformation, for example, shear banding to dissipate fracture energy. An outstanding toughening effect is achieved with only a 0.05 wt % carbon nanotube loading with the bc@fMWNT, that is, needing only a 20-times lower loading to obtain improvements in fracture toughness comparable to epoxy-based nanocomposites. The enhancements of their corresponding ultimate mode-I fracture toughnesses and fracture energies are 4 times higher than those of pristine MWNT-filled epoxy. These results demonstrate that a MWNT/epoxy interface could be optimized by changing the component structure of grafted modifiers, thereby facilitating the transfer of both mechanical load and energy dissipation across the nanofiller/matrix interface. This work provides a new route for the rational design and development of polymer nanocomposites with exceptional mechanical performance. PMID- 29235355 TI - Facile Fabrication of Electrically Conductive Low-Density Polyethylene/Carbon Fiber Tubes for Novel Smart Materials via Multiaxial Orientation. AB - Electromechanical sensors are indispensable components in functional devices and robotics application. However, the fabrication of the sensors still maintains a challenging issue that high percolation threshold and easy failure of conductive network are derived from uniaxial orientation of conductive fillers in practical melt processing. Herein, we reported a facile fabrication method to prepare a multiaxial low-density polyethylene (LDPE)/carbon fibers (CFs) tube with bidirectional controllable electrical conductivity and sensitive strain responsive performance via rotation extrusion technology. The multidimensional helical flow is confirmed in the reverse rotation extrusion, and the CFs readily respond to the flow field leading to a multiaxial orientation in the LDPE matrix. In contrast to uniaxial LDPE/CF composites, which perform a "head to head" conjunction, multiaxial-orientated CF networks exhibit a unique multilayer structure in which the CFs with distinct orientation direction intersect in the interface, endowing the LDPE/CF composites with a low percolation threshold (15 wt %) to those of the uniaxial ones (~35 wt %). The angles between two axes play a vital role in determining the density of the conductive networks in the interface, which is predominant in tuning the bending-responsive behaviors with a gauge factor range from 12.5 to 56.3 and the corresponding linear respond region from ~15 to ~1%. Such a superior performance of conductive LDPE/CF tube confirms that the design of multiaxial orientation paves a novel way to facile fabrication of advanced cost-effective CF-based smart materials, shedding light on promising applications such as smart materials and intelligent engineering monitoring. PMID- 29235356 TI - Biomimetic Total Syntheses of Clavine Alkaloids. AB - Biomimetic total syntheses of either enantiomers of a number of ergot alkaloids, chanoclavine I (1b), chanoclavine I aldehyde (1c), pyroclavine (1e), festuclavine (1f), pibocin A (1g), 9-deacetoxyfumigaclavine C (1h), and fumigaclavine G (1i), have been achieved from seco-agroclavine (1a). The advanced intermediate for seco agroclavine (1a) was synthesized via a key thiourea-catalyzed intramolecular nitronate addition onto alpha,beta-unsaturated ester. PMID- 29235357 TI - Synthesis, characterization and biological screening of pyrazole-conjugated benzothiazole analogs. AB - AIM: Benzothiazole and pyrazoles are two important pharmacophores, the activity can be enhanced by conjugating them. Here, two novel series of the pyrazole conjugated benzothiazole derivatives were synthesized. RESULTS: Synthesized compounds were characterized by Fourier-transform infrared, LC-MS, 1H NMR and 13C NMR spectroscopic techniques. Synthesized compounds exhibited moderate antimicrobial, antioxidant and excellent anti-TB activities. In in vitro anti-TB activity, 4d and 4e exhibited 1.6 MUg/ml minimum inhibitory concentration value. In order to rationalize the anti-TB activity, molecular docking studies were carried out and they were correlated with the in vitro results. CONCLUSION: Compounds containing electron donating groups show the promising antimicrobial and antioxidant activities, compounds with CH3 and Cl substitution show excellent anti-TB activity. Synthesized molecules may become potential candidates for the clinical trials. PMID- 29235358 TI - Case report of a suspected pheochromocytoma co-presenting with a glioblastoma multiforme: case report and review of the literature. AB - The combination of a pheochromocytoma with any brain neoplasm is a rare occurrence, to our knowledge, this is the first reported case of a glioblastoma multiforme co-presenting with undiagnosed pheochromocytoma. PMID- 29235359 TI - Unusual cranial infection caused by Citrobacter Koseri. AB - A 60-year-old female had a frontal bone intraosseous meningioma resected 10 years previously. On follow up CT head, an enlarging intraosseous frontal bone lesion was noted. This was thought to be a recurrent frontal meningioma. Intraooperatively, she was found to have an abscess deep to the cranioplasty. PMID- 29235361 TI - The elusive search for the public voice in health policy: the case for 'systems thinking'. PMID- 29235360 TI - HALO-109-301: a Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. AB - The outlook for patients with advanced pancreatic cancer remains poor, despite significant advances in our understanding of pancreatic tumor biology. One emerging theme highlights the distinct composition of the pancreatic tumor microenvironment. Hyaluronic acid is a hydrophilic glycosaminoglycan whose production within the tumor leads to increased interstitial tumor pressure, thereby limiting the access of potentially effective circulating anticancer drugs via reduced tumor perfusion. PEGylated rHuPH20 is a multiply PEGylated recombinant human hyaluronidase that has shown promising efficacy in preclinical models and early phase clinical trials in pancreatic cancer patients. Here, we discuss these findings, and the rationale for the ongoing randomized Phase III trial (HALO-109-301), which seeks to definitively define the efficacy of PEGylated rHuPH20 alongside gemcitabine and nab-paclitaxel in previously untreated, hyaluronic acid-high, stage IV pancreatic cancer. PMID- 29235363 TI - Phenotypic screening approaches for Chagas disease drug discovery. AB - INTRODUCTION: Chagas disease, caused by the parasite Trypanosoma cruzi, is a global public health issue. Current treatments targeting the parasite are limited to two old nitroheterocyclic drugs with serious side effects. The need for new and safer drugs has prompted numerous drug discovery efforts to identify compounds suitable for parasitological cure in the last decade. Areas covered: Target-based drug discovery has been limited by the small number of well validated targets - the latest example being the failure of azoles, T. cruzi CYP51 inhibitors, in proof-of-concept clinical trials; instead phenotypic-based drug discovery has become the main pillar of Chagas R&D. Rather than focusing on the technical features of these screening assays, the authors describe the different assays developed and available in the field, and provide a critical view on their values and limitations in the screening cascade for Chagas drug development. Expert opinion: The application of technological advances to the field of Chagas disease has led to a variety of phenotypic assays that have not only changed the disease discovery landscape but have also helped us to gain a better understanding of parasite/host interactions. Recent examples of target resolution from phenotypic hits will uncover new opportunities for drug discovery for Chagas disease. PMID- 29235362 TI - Reconsidering the causality of TIA1 mutations in ALS. PMID- 29235364 TI - Patient-reported safety incidents as a new source of patient safety data: an exploratory comparative study in an acute hospital in England. AB - Objectives To compare a new co-designed, patient incident reporting tool with three established methods of detecting patient safety incidents and identify if the same incidents are recorded across methods. Method Trained research staff collected data from inpatients in nine wards in one university teaching hospital during their stay. Those classified as patient safety incidents were retained. We then searched for patient safety incidents in the corresponding patient case notes, staff incident reports and reports to the Patient Advice and Liaison Service specific to the study wards. Results In the nine wards, 329 patients were recruited to the study, of which 77 provided 155 patient reports. From these, 68 patient safety incidents were identified. Eight of these were also identified from case note review, five were also identified in incident reports, and two were also found in the records of a local Patient Advice and Liaison Service. Reports of patients covered a range of events from their immediate environment, involving different health professionals and spanning the entire spectrum of care. Conclusion Patient safety incidents reported by patients are unlikely to be found through other established methods of incident detection. When hospitalized patients are asked about their care, they can provide a unique perspective on patient safety. Co-designed, real-time reporting could be a helpful addition to existing methods of gathering patient safety intelligence. PMID- 29235365 TI - A phase III, open-label, multicenter study to evaluate the safety and efficacy of long-term triple combination therapy with azilsartan, amlodipine, and hydrochlorothiazide in patients with essential hypertension. AB - PURPOSE: Patients with essential hypertension who are receiving treatment with an angiotensin II receptor blocker and a calcium channel blocker often develop inadequate blood pressure (BP) control and require the addition of a diuretic. This study aimed to evaluate the long-term safety and efficacy of a triple combination therapy with 20 mg azilsartan (AZL), 5 mg amlodipine (AML) and 12.5 mg hydrochlorothiazide (HCTZ). MATERIALS AND METHODS: The phase III, open-label, multicenter study (NCT02277691) comprised a 4-week run-in period and 52-week treatment period. Patients with inadequate BP control despite AZL/AML therapy (n = 341) received 4 weeks' treatment with AZL/AML (combination tablet) + HCTZ (tablet) and 4 weeks' treatment with AZL/AML/HCTZ (combination tablet) in a crossover manner, followed by AZL/AML/HCTZ (combination tablet) from Week 8 of the treatment period up to Week 52. The primary and secondary endpoints were long term safety and BP (office and home), respectively. RESULTS: Most adverse events (AEs) were mild or moderate in intensity, and no deaths or treatment-related serious AEs were reported. The triple therapy provided consistent BP-lowering effects in both office and home measurements. CONCLUSIONS: The triple combination therapy with AZL/AML/HCTZ was well tolerated and effective for 52 weeks in Japanese patients with essential hypertension. PMID- 29235366 TI - Assessing the public health impact of using poison center data for public health surveillance. AB - CONTEXT: The National Poison Data System (NPDS) is a database and surveillance system for US poison centers (PCs) call data. The Centers for Disease Control and Prevention (CDC) and American Association of Poison Control Centers (AAPCC) use NPDS to identify incidents of potential public health significance. State health departments are notified by CDC of incidents identified by NPDS to be of potential public health significance. Our objective was to describe the public health impact of CDC's notifications and the use of NPDS data for surveillance. METHODS: We described how NPDS data informed three public health responses: the Deepwater Horizon incident, national exposures to laundry detergent pods, and national exposures to e-cigarettes. Additionally, we extracted survey results of state epidemiologists regarding NPDS incident notification follow-up from 1 January 2015 to 31 December 2016 to assess current public health application of NPDS data using Epi Info 7.2 and analyzed data using SAS 9.3. We assessed whether state health departments were aware of incidents before notification, what actions were taken, and whether CDC notifications contributed to actions. DISCUSSION: NPDS data provided evidence for industry changes to improve laundry detergent pod containers safety and highlighted the need to regulate e-cigarette sale and manufacturing. NPDS data were used to improve situational awareness during the 2010 Deepwater Horizon oil spill. Of 59 health departments and PCs who responded to CDC notifications about anomalies (response rate = 49.2%), 27 (46%) reported no previous awareness of the incident, and 20 (34%) said that notifications contributed to public health action. CONCLUSIONS: Monitoring NPDS data for anomalies can identify emerging public health threats and provide evidence-based science to support public health action and policy changes. PMID- 29235367 TI - What has health technology assessment ever done for us? AB - Health technology assessment (HTA) has over the past three decades become a well established part of decisions about allocation of resources in many countries. Despite this, little is known about HTA's impact on health systems. Few studies have evaluated the benefits of HTA for health outcomes, for access to care or for public budgets. In contrast, HTA has relatively clear upfront costs, which could potentially discourage policy-makers from establishing HTA agencies, especially in low income countries with restricted resources. It may be premature, though, to dismiss this approach altogether, as less tangible modernizing goals are still significant. PMID- 29235368 TI - Antischistosomal agents: state of art and perspectives. AB - Praziquantel has remained the drug of choice for schistosomiasis chemotherapy for almost 40 years. The pressing need to develop a new antischistosomal drug may necessitate exploring and filtering chemotherapeutic history to search for the most promising ones. In this context, this review attempts to summarize all progress made in schistosomiasis chemotherapy from the early 20th century (mid 1910s) to 2016. We gathered almost 100 compounds providing information on therapeutic action, specifically covering at least first in vivo studies in animal model and in vitro. Pharmacokinetic and toxicity profiles of antischistosomal agents were also described. Preclinical studies indicate a handful of promising future candidates. PMID- 29235369 TI - Academic chartered data safety committees versus industry sponsored data safety committees: The need for different recommendations. PMID- 29235370 TI - Factors determining perceptions of fairness in access to hospital outpatient departments in Taiwan. AB - Objectives To investigate the effects of four factors on perceptions of fairness in access to outpatient services: proportions of walk-in versus scheduled registration, consultation queues, regulations for late patients and particular categories of patients getting better access. Methods A total of 124 young adults were asked to consider nine different scenarios and report their views of the fairness of each one. Results As regards the balance of types of patients, 60% walk-in registration was seen as fair to both walk-in and scheduled patients. The fairness to both types of patients was higher in the queue with a 1:1 ratio of walk-in to scheduled patients. The policy that a late patient should wait for three on-time patients to be seen was considered to be fair to both on-time and late patients. Immediate consultation for some particular categories of patient (e.g. the elderly) was fair, but for other categories was unfair (e.g. paying an addition amount). Conclusions Fairness in outpatient care is based on equality and need principles. Shorter waiting time does not mean patients view the system as fairer. PMID- 29235371 TI - Hybrid 2D/3D-quantitative structure-activity relationship and modeling studies perspectives of pepstatin A analogs as cathepsin D inhibitors. AB - AIM: Cathepsin D, one of the attractive targets in the treatment of breast cancer, has been implicated in HIV neuropathogenesis with potential proteolytic effects on chemokines. Methodology/result: Diverse modeling tools were used to reveal the key structural features affecting the inhibitory activities of 78 pepstatin A analogs. Analyses were performed to investigate the stability, rationality and fluctuation of the analogs. Results showed a clear correlation between the experimental and predicted activities of the analogs as well as the variation in their activities relative to structural modifications. CONCLUSION: The insight gained from this study offers theoretical references for understanding the mechanism of action of cathepsin D and will aid in the design of more potent and clinically-relevant drugs. Graphical abstract [Formula: see text]. PMID- 29235372 TI - Strengthening stakeholder involvement in health workforce governance: why we need to talk about power. AB - There is now widespread agreement on the benefits of an integrated, people centred health workforce, but the implementation of new models is difficult. We argue that we need to think about stakeholders and power, if we want to ensure change in the health workforce. We discuss these issues from a governance perspective and suggest a critical approach to stakeholder involvement as an indicator of good governance. Three models of involving stakeholders in health workforce governance can be identified: corporatist professional involvement either in a continental European model of conservative corporatism or in a Nordic model of public corporatism; managerialist and market-centred involvement of professions as organizational agents; and a more inclusive, network-based involvement of plural professional experts at different levels of governance. The power relations embedded in these models of stakeholder involvement have different effects on capacity building for an integrated health workforce. PMID- 29235373 TI - Pro-inflammatory cytokine-induced lipolysis after an episode of acute pancreatitis. AB - CONTEXT: Pro-inflammatory cytokine-stimulated lipolysis is one of the mechanisms underlying the pathogenesis of type 2 diabetes. However, whether it plays a role in the pathogenesis of post-pancreatitis diabetes mellitus (PPDM) remains unknown. OBJECTIVE: To investigate the associations between markers of lipid metabolism and pro-inflammatory cytokines in individuals after acute pancreatitis (AP) in general, and in individuals with abnormal glucose metabolism (AGM) following AP in particular. METHODS: Fasting blood samples were collected to measure markers of lipid metabolism (apolipoprotein-B, cholesterol, free fatty acids (FFA), glycerol, high and low-density lipoproteins, triglycerides) and cytokines (interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and tumour necrosis factor (TNF) alpha). Linear regression analysis was conducted. Four statistical models were used to adjust for patient- and pancreatitis-related characteristics. RESULTS: A total of 83 patients were recruited. IL-6 was significantly associated with glycerol in all models (p < .05), with glycerol levels increasing by 106% in individuals with AGM after AP (p <.05) compared to a 30.3% increase in individuals with normal glucose metabolism (NGM) (p >.05). TNFalpha was significantly associated with FFA (p = .015) in individuals with AGM after AP in the most adjusted model, with FFA levels increasing by 314% in these individuals compared to a 162% decrease in individuals with NGM after AP (p >.05). CONCLUSIONS: Lipolysis appears to be an important pathogenetic mechanism in glucose derangements after diseases of the exocrine pancreas. IL-6 and TNFalpha are the driving forces behind lipolysis in individuals with AGM after AP. Modulation of lipolysis may be a promising therapeutic modality. PMID- 29235374 TI - Computational modeling in glioblastoma: from the prediction of blood-brain barrier permeability to the simulation of tumor behavior. AB - The integrated in silico-in vitro-in vivo approaches have fostered the development of new treatment strategies for glioblastoma patients and improved diagnosis, establishing the bridge between biochemical research and clinical practice. These approaches have provided new insights on the identification of bioactive compounds and on the complex mechanisms underlying the interactions among glioblastoma cells, and the tumor microenvironment. This review focuses on the key advances pertaining to computational modeling in glioblastoma, including predictive data on drug permeability across the blood-brain barrier, tumor growth and treatment responses. Structure- and ligand-based methods have been widely adopted, enabling the study of dynamic and evolutionary aspects of glioblastoma. Their potential applications as predictive tools and the advantages over other well-known methodologies are outlined. Challenges regarding in silico approaches for predicting tumor properties are also discussed. PMID- 29235375 TI - Chitosan nanoparticles loaded hydrogels promote skin wound healing through the modulation of reactive oxygen species. AB - This study developed a novel bioactive chitosan nanoparticle loaded calcium alginate hydrogel to regulate inflammation and neovascularization for accelerated wound healing in vivo. It was found that chitosan nanoparticles loaded calcium alginate hydrogel exhibited remarkable antibacterial activity. Through the modulation of generation of ROS, it promoted the synthesis and secretion of IL-6 in vascular endothelial cell (VEC), suggesting its potential proinflammatory activation. Further, it promoted VEC invasion, metastasis and neovascularization to accelerate wound healing. PMID- 29235376 TI - Matteucens I-J, phenolics from the rhizomes of Matteuccia orientalis. AB - Two new phenolics, named matteucens I-J (1-2), were isolated from the 60% EtOH extract of the rhizomes of Matteuccia orientalis (HOOK.) TREV. Their structures were elucidated by means of extensive spectroscopic analysis (HRESIMS, NMR). PMID- 29235377 TI - How important is information and communication technology in enabling interprofessional collaboration? PMID- 29235379 TI - Corrigendum. PMID- 29235378 TI - The Hexane Fraction of Bursera microphylla A. Gray Induces p21-Mediated Anti Proliferative and Pro-Apoptotic Effects in Human Cancer-Derived Cell Lines. AB - Bursera microphylla (BM), one of the common elephant trees, is widely distributed in the Sonoran Desert in Mexico. The Seri ethnic group in the Sonoran Desert uses BM as an anti-inflammatory and painkiller drug for the treatment of sore throat, herpes labialis, abscessed tooth, and wound healing. Dried stems and leaves of BM are used in a tea to relieve painful urination and to stimulate bronchial secretion. Furthermore, BM is used for fighting venereal diseases. To investigate the effects of the hexane fraction of resin methanol extract (BM-H) on cell growth, the acute myeloid cell line (OCI-AML3) was treated with 250, 25, or 2.5 ug/mL of BM-H. The first 2 concentrations were able to significantly decrease OCI AML3 cell number. This reduced cell number was associated with decreased S-phase, blockade of the G2/M phase of the cell cycle, and increased cell death. Similar results were obtained on all tested tumor cell lines of different origins. We found that blockade of the cell cycle was due to upregulation of p21 protein in a p53-independent way. Increase of p21 was possibly due to upstream upregulation of p-ERK (which stabilizes p21 protein) and downregulation of p-38 (which promotes its degradation). Regarding cell death, activation of caspase-3, but not of caspase-8 or -9, was detectable after BM-H treatment. In conclusion, these data suggest that the BM's hexane fraction inhibited proliferation of cell lines mainly by a p21-dependent, p53-independent mechanism and promoted apoptosis through activation of caspase-3, but not caspase-8 or -9. PMID- 29235381 TI - Welcome to the 13th volume of Future Microbiology. PMID- 29235380 TI - Pharmacokinetic drug evaluation of ixazomib citrate for the treatment of multiple myeloma. AB - INTRODUCTION: multiple myeloma (MM) is a plasma cell disorder that represents the second most frequent hematologic cancer. Although MM is still an incurable disease, prognosis has improved in the last decades thanks to the introduction of novel agents such as proteasome inhibitors (PIs), immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. Areas covered: ixazomib is the first oral PI recently approved by Food and Drug Administration (FDA) and European Medicine Agency (EMA) in combination with lenalidomide and dexamethasone as salvage therapy in MM patients. In this paper, we focus on its pharmacokinetics features, as well as its safety and efficacy in clinical studies. Expert opinion: ixazomib can be considered an oral analogue of bortezomib, with 9.5-day half-life, 58% of oral bioavailability, and a large distribution volume of 543L. These features make it a versatile molecule, potentially useful both in combination and as single agent. Oral route of administration and good efficacy/safety profile are its winning characteristics, providing the rationale for a future role also in the maintenance setting. PMID- 29235382 TI - Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer. AB - INTRODUCTION: Mutations in genes associated with splicing have been found in hematologic malignancies, but also in solid cancers. Aberrant cancer specific RNA splicing either results from mutations or misexpression of the spliceosome genes directly, or from mutations in splice sites of oncogenes or tumor suppressors. Areas covered: In this review, we present molecular targets of aberrant splicing in various malignancies, information on existing and emerging therapeutics against such targets, and strategies for future drug development. Expert opinion: Alternative splicing is an important mechanism that controls gene expression, and hence pharmacologic and genetic control of aberrant alternative RNA splicing has been proposed as a potential therapy in cancer. To identify and validate aberrant RNA splicing patterns as therapeutic targets we need to (1) characterize the most common genetic aberrations of the spliceosome and of splice sites, (2) understand the dysregulated downstream pathways and (3) exploit in-vivo disease models of aberrant splicing. Antisense oligonucleotides show promising activity, but will benefit from improved delivery tools. Inhibitors of mutated splicing factors require improved specificity, as alternative and aberrant splicing are often intertwined like two sides of the same coin. In summary, targeting aberrant splicing is an early but emerging field in cancer treatment. PMID- 29235383 TI - Advances in Biomechanical Preparation. PMID- 29235384 TI - Technique for Fenestrated Stent-Graft Implantation as a Proximal Extension to a Previous Fenestrated Endovascular Repair for Abdominal Aortic Aneurysm. AB - PURPOSE: To describe planning and a technique for fenestrated endovascular repair of a large Crawford type IV thoracoabdominal aortic aneurysm after previous 2 fenestration endovascular aneurysm repair (FEVAR). TECHNIQUE: The first FEVAR procedure performed at another center implanted a standard Zenith device with 2 fenestrations and 1 scallop for a juxtarenal abdominal aortic aneurysm. The diameter of the Crawford type IV thoracoabdominal aortic aneurysm had progressed from 68 to 75 mm within a year after the FEVAR. Since the celiac trunk was already occluded, a 3-fenestration 22-*172-mm stent-graft was chosen to extend the existing stent-graft further proximally. A tapered 38/22-*179-mm Zenith custom-made device was designed for the thoracic component. The technique addresses several issues that arise during a FEVAR-in-FEVAR case, such as the orientation of the new stent-graft and its fenestrations, the absence of space between the 2 devices for maneuvers, and the difficulty in catheterizing target vessels with existing bridging stents, for which a bailout "snare-ride" maneuver is described. CONCLUSION: FEVAR after previous FEVAR is a feasible and efficient treatment option. The modified "snare-ride" technique can be used to catheterize target vessels in the absence of an Indy snare. PMID- 29235385 TI - Selling in a Dying Business: An Analysis of Trends During a Period of Major Market Transition in the Funeral Industry. AB - As a result of recent economic changes in the United States and cultural changes among the population, the funeral industry has experienced a "legitimation crisis." The objective of this research is to examine new advertising and marketing strategies engaged in by professionals in the funeral industry to respond to market and cultural changes that have affected both the funeral industry at large and the role of the funeral director as a participant in this industry. A meta-analysis of articles from issues of the industry trade journal American Funeral Director for the years 2008 through 2015 was conducted. Two major themes emerged from the data. First, that funeral home owners should respond to market changes by using their assets for diverse reasons and second that forms of community engagement can create feelings of goodwill that will increase usage and loyalty from families. Within each of these major themes, a variety of subthemes emerged from the data. PMID- 29235386 TI - How is palliative care understood in the context of dementia? Results from a massive open online course. AB - BACKGROUND: A palliative approach to the care of people with dementia has been advocated, albeit from an emergent evidence base. The person-centred philosophy of palliative care resonates with the often lengthy trajectory and heavy symptom burden of this terminal condition. AIM: To explore participants' understanding of the concept of palliative care in the context of dementia. The participant population took an online course in dementia. DESIGN: The participant population took a massive open online course on 'Understanding Dementia' and posted answers to the question: 'palliative care means ...' We extracted these postings and analysed them via the dual methods of topic modelling analysis and thematic analysis. SETTING/PARTICIPANTS: A total of 1330 participants from three recent iterations of the Understanding Dementia Massive Open Online Course consented to their posts being used. Participants included those caring formally or informally for someone living with dementia as well as those with a general interest in dementia Results: Participants were found to have a general awareness of palliative care, but saw it primarily as terminal care, focused around the event of death and specialist in nature. Comfort was equated with pain management only. Respondents rarely overtly linked palliative care to dementia. CONCLUSIONS: A general lack of palliative care literacy, particularly with respect to dementia, was demonstrated by participants. Implications for dementia care consumers seeking palliative care and support include recognition of the likely lack of awareness of the relevance of palliative care to dementia. Future research could access online participants more directly about their understandings/experiences of the relationship between palliative care and dementia. PMID- 29235387 TI - Work-life integration in neuropsychology: a review of the existing literature and preliminary recommendations. AB - OBJECTIVE: The purpose of the current review paper is to identify and describe challenges to work-life integration in neuropsychology, and from this review extrapolate an initial set of recommendations and present a set of scenarios in which the recommendations might apply in the hopes of improving quality of life for current and prospective neuropsychologists. Specific areas of focus include diversity, early and mid-career transitions, and potential barriers to advancement in specific practice settings. METHOD: A broad review was conducted of extant literature on work-life integration. There is scant scientific literature in this area that is specific to neuropsychologists, or even psychology as a whole. Subsequently, the majority of this review was collected from more developed literatures in business and medical fields. The authors then provided recommendations based on experiences in their respective careers. Attempts were made to promote generalizability of recommendations for neuropsychologists in different settings. RESULTS: Evidence supports a potentially adverse impact on quality of life and overall life satisfaction when work and personal lives conflict. CONCLUSION: This manuscript identifies some of the potential risks when work and life responsibilities are not well integrated. It is anticipated this will serve as a catalyst for future studies on work-life integration in the field of neuropsychology, specifically. PMID- 29235388 TI - Early Outcomes of the t-Branch Off-the-Shelf Multibranched Stent-Graft in Urgent Thoracoabdominal Aortic Aneurysm Repair. AB - PURPOSE: To assess the short-term outcomes of the multibranched off-the-shelf t Branch stent-graft for urgent thoracoabdominal aortic aneurysm (TAAA) repair and to evaluate the impact on outcomes of the learning curve and adherence to the instruction for use (IFU). METHODS: Between 2014 and 2017, 42 patients (mean age 73.3+/-7 years; 26 men) underwent urgent TAAA treatment using the t-Branch stent graft [18 in the early (2014-2015) period and 24 in the late (2016-2017) period]. Nearly half the patients were symptomatic (n=18) and 12 had contained rupture. Aneurysm diameter >80 mm was present in 12 (mean diameter 77.7+/-13.2 mm). Nineteen patients did not meet the IFU for the t-Branch due to target vessel anatomy. The primary endpoints were spinal cord ischemia (SCI), renal function impairment, and 30-day mortality. Target vessel patency and endoleak incidence were assessed at 30 days. Multivariate analyses examined associations between perioperative variables and outcomes; the results are presented as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: The technical success rate was 93% (39/42). Successful catheterization was achieved in 150/155 target vessels (97%). The postoperative SCI rate was 21% (5 paraplegia/4 transient paraparesis) and was correlated with age (OR 1.26, 95% CI 1.01 to 1.56, p=0.04). The renal function impairment rate was 23% (10/42; 2 temporary, 2 permanent dialysis) and was correlated with early experience (OR 7.74, 95% CI 1.3 to 43.9, p=0.019). The 30-day mortality was 14% (no intraoperative deaths); no factor was associated with mortality. During the first month, the incidences of type I, II, and III endoleaks were 0%, 43%, and 0%, respectively; branch patency was 99% (150/151). Procedure time decreased in the later experience (479+/-333 vs 407+/-25 minutes, p=0.09), though it was increased in cases outside the IFU (497+/-135 vs 389+/-118 minutes, p=0.009), along with fluoroscopy time (121+/-48 vs 92+/-33 minutes, p=0.036). CONCLUSION: Endovascular repair of urgent TAAA using the t-Branch is a feasible treatment option with acceptable 30-day mortality and morbidity in terms of SCI and renal function impairment. Adherence to the IFU prolonged procedure time but had no effect on outcomes. Increased experience of such cases over time may improve outcomes. PMID- 29235389 TI - Extracellular genomic biomarkers of osteoarthritis. AB - INTRODUCTION: Osteoarthritis (OA), a chronic, debilitating and degenerative disease of the joints, is the most common form of arthritis. The seriousness of this prevalent and chronic disease is often overlooked. Disease modifying OA drug development is hindered by the lack of soluble biomarkers to detect OA early. The objective of OA biomarker research is to identify early OA prior to the appearance of radiographic signs and the development of pain. Areas covered: This review has focused on extracellular genomic material that could serve as biomarkers of OA. Recent studies have examined the expression of extracellular genomic material such as miRNA, lncRNA, snoRNA, mRNA and cell-free DNA, which are aberrantly expressed in the body fluids of OA patients. Changes in genomic content of peripheral blood mononuclear cells in OA could also function as biomarkers of OA. Expert commentary: There is an unmet need for soluble biomarkers for detecting and then monitoring OA disease progression. Extracellular genomic material research may also reveal more about the underlying pathophysiology of OA. Minimally-invasive liquid biopsies such as synovial fluid and blood sampling of genomic material may be more sensitive over radiography in the detection, diagnosis and monitoring of OA in the future. PMID- 29235390 TI - MiR-122 and other microRNAs as potential circulating biomarkers of drug-induced liver injury. AB - INTRODUCTION: Drug-induced liver injury (DILI) is a severe adverse drug reaction which is of major concern to patients, clinicians and the pharmaceutical industry. Accurate and rapid detection of DILI is important for patient stratification and treatment in the clinic and benefits preclinical drug design and risk assessment. MicroRNAs (miRNAs) offer a potential new and improved class of circulating biomarkers of DILI over the current gold standard biomarkers. Areas covered: This review highlights the shortcomings of the currently used panel of biomarkers and how miRNAs, primarily miR-122, show an improved level of specificity and sensitivity in the prediction of DILI. Furthermore, the use of miRNAs as potential markers of progression of DILI and specific zonated damage within the liver is discussed. Expert commentary: MiRNAs offer more sensitive and specific markers over the current biomarkers for DILI. Combinations of different miRNAs may be able to relay the location of DILI and the progression of disease. More studies using different hepatotoxins apart from acetaminophen will ultimately strengthen the case for the clinical introduction of miRNAs as biomarkers of DILI. PMID- 29235391 TI - Association between vitamin D, oestradiol and interferon-gamma in female patients with inactive systemic lupus erythematosus: A cross-sectional study. AB - Objectives To investigate possible associations between 25-hydroxyvitamin D3 (25(OH)D3), oestradiol (E2) and IFN-gamma (IFNgamma) in female patients with inactive systemic lupus erythematosus (SLE). Methods Female patients with inactive SLE and age-matched healthy controls were recruited into this cross sectional study. Serum concentrations of 25(OH)D3, E2 and IFNgamma were measured by radioimmunoassay with gamma-counters and enzyme-linked immunosorbent assay. Results 36 patients and 37 controls were enrolled. In patients with SLE, the concentration of 25(OH)D3 was lower and E2 was higher compared with controls. In vitamin D deficient (i.e., 25(OH)D3<=20 ng/ml) patients, IFNgamma was 150% higher compared with patients with 25(OH)D3>20 ng/ml and controls. The concentration of E2 was higher in all patients compared with controls independently of the vitamin D level. A difference was found between patients and controls in the correlation of 25(OH)D3 with E2 and a positive correlation was found between E2 and IFNgamma in all participants. Conclusions Our results suggest that E2 may have a strong modulating effect on vitamin D function which is significant only at low concentration of E2. PMID- 29235392 TI - Re-evaluating osteoporosis and fracture risk in Crohn's disease patients in the era of TNF-alpha inhibitors. AB - INTRODUCTION: Patients with Crohn's disease (CD) are at increased risk for osteoporosis and fractures as compared to the general population. Recently, various cytokines including tumor necrosis factor (TNF)-alpha are found to play a major role in bone health. In this study, we aimed to gain a better understanding of the risk factors for osteoporosis and vitamin D deficiency in the era of TNF alpha inhibitors. METHODS: We conducted a retrospective review of 464 consecutive patients with CD in our GI clinic between 2008 and 2015. Statistical analysis was performed using the student t-test and chi-square test. RESULTS: CD patients treated with TNF-alpha inhibitors (TNF) and those who are anti-TNF naive (NB) had similar rates of vitamin D deficiency, insufficiency and normal vitamin D-25-OH levels. Similarly, rates of osteoporosis (16% vs 18%), osteopenia (53% vs 57%) and normal bone density (31% vs 25%) were comparable between the TNF and NB groups respectively. However, Z-scores at the spine (-0.47 vs -0.05) were significantly lower in the TNF group (p = .03). Interestingly, rates of osteoporosis in the NB group were drastically different before and after age 60 (3.6% vs 30%) with no major difference in the TNF group (15% vs 18%). Bone density was positively correlated with BMI (Pearson's R = 0.39) and negatively correlated with age and smoking status (R= -0.25). CONCLUSIONS: TNF group patients were diagnosed with osteoporosis from an earlier age compared to NB group but with a smaller increase in osteoporosis after menopause. Further prospective studies are necessary to further determine the role of anti-TNF medications in osteoporosis. PMID- 29235393 TI - Needs of people with advanced dementia in their final phase of life: A multi perspective qualitative study in nursing homes. AB - BACKGROUND: People with advanced dementia present an important target group for palliative care. They suffer a range of symptoms, and their verbal communication abilities are highly restricted. At present, little is known about their needs in the final phase of life. AIM: To identify the needs of people with advanced dementia in their final phase of life and to explore the aspects relevant to first recognize and then meet these needs. DESIGN: Multi-perspective qualitative study using grounded theory methodology conducting group discussions, individual interviews, and participant observation. SETTING/PARTICIPANTS: The study encompassed nursing homes and involved health professionals, relatives, and residents with advanced dementia. RESULTS: Data were collected in six nursing homes. Nine group discussions and three individual interviews were conducted comprising 42 health professionals and 14 relatives. Participant observations aided in giving the perspective of 30 residents with advanced dementia. Data analysis generated a total of 25 physical, psychosocial, and spiritual needs divided into 10 categories. Physical needs were classified as follows: "food intake," "physical well-being," and "physical activity and recovery." Categories of psychosocial needs were classified as follows: "adaptation of stimuli," "communication," "personal attention," "participation," "familiarity and safety," as well as "self-determination." Spiritual needs addressed "religion." The results revealed a multitude of key aspects for recognizing and meeting these needs, stressing the importance of personhood. CONCLUSION: People with advanced dementia in their final phase of life have a multitude of individual and complex needs. This evidence contributes to narrowing the current research gap, offering an orientation framework for research and practice. PMID- 29235394 TI - Follow-up magnetic resonance imaging in spine infection: details which matter most. PMID- 29235395 TI - Adjuvant activity of ethanol extract of Hippophae rhamnoides leaves with inactivated rabies virus antigen. AB - CONTEXT: Hippophae rhamnoides L. (Elaeagnaceae), commonly known as seabuckthorn (SBT), is known for its medicinal and nutritional properties. OBJECTIVE: Evaluation of in vivo adjuvant activity of SBT leaf extract (SBTE) with inactivated rabies virus antigen (Rb). MATERIALS AND METHODS: Swiss albino mice were immunized with aqueous-alcoholic SBTE (100 mg/kg body weight) or algel (aluminium hydroxide gel) with or without Rb (5% v/v). After priming, booster was administered on day 14. Rabies virus neutralizing antibody (RVNA) titers were estimated by rapid fluorescent focus inhibition test in sera samples collected on days 7, 14, 21, 28 and 35. Effect of adjuvant administration on cytotoxic T lymphocytes (CTLs), memory T cells, plasma and CD11c+ cells was studied by flow cytometry. In vitro hemolysis was assayed in human RBC. RESULTS: RVNA titers were significantly enhanced (p < 0.05) after booster administration in mice immunized with SBTE + Rb as compared to the controls. In combination, SBTE, algel and Rb, enhanced the RVNA titers. CTLs significantly increased (p < 0.05) in SBTE + Rb immunized mice. Memory T cells and plasma cells were 27.9 and 15.9%, respectively, in SBTE + Rb immunized mice as compared to that of 20.3 and 11.3%, respectively, in Rb immunized group. SBTE + Rb enhanced peritoneal CD11c+ cells (25.8%) as compared to 9.4% cells in Rb immunized mice, showed 3.2-fold increment in LPS induced IL-1beta. No RBC hemolysis was observed with SBTE. CONCLUSIONS: This study demonstrates the potential adjuvant activity of SBTE with Rb by increasing RVNA titers and CTL response. PMID- 29235396 TI - Brain-derived neurotrophic factor (BDNF) serum level in women with first-episode depression, correlation with clinical and metabolic parameters. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) influences neuron differentiation during development, as well as the synaptic plasticity and neuron survival in adulthood. BDNF has been implicated in the pathogenesis of psychiatric disorders and its serum level is a potential biomarker for depression. The aim of this study was to examine serum levels of BDNF in first episode depression and its correlation with clinical and metabolic parameters. MATERIALS AND METHODS: The study was performed on a group of 60 women: 30 diagnosed with a first-episode of depression and 30 healthy controls. 17-Item Hamilton Depression Rating Scale (HDRS-17) was used to assess the severity of depression. Patients were randomly chosen for treatment with sertraline or venlafaxine. BDNF serum levels and metabolic parameters: fasting serum glucose, cholesterol, triglyceride (TG), high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C) were measured at baseline and week 8 of treatment. RESULTS: There were no differences between BDNF level in depressed patients compared with the healthy controls. Lack of differences in medication effect of sertraline or venlafaxine on HDRS-17 scores during 8 weeks of treatment was observed. Correlation of BDNF at baseline and fasting serum glucose at baseline and week 8 was detected. CONCLUSIONS: Correlations of BDNF serum levels with metabolic parameters were observed. PMID- 29235397 TI - Leptospira interrogans outer membrane protein LipL21 is a potent inhibitor of neutrophil myeloperoxidase. AB - Leptospirosis is a widespread zoonotic and neglected infectious disease of human and veterinary concern that is caused by pathogenic Leptospira species. After entrance in the host, pathogenic leptospires evade the host natural defense mechanisms in order to propagate and disseminate to multiple organs. Myeloperoxidase is an enzyme stored in neutrophils azurophilic granules, and is released upon neutrophil activation to produce mainly hypochlorous acid, a strong oxidant and potent antimicrobial agent. In the present investigation, we studied the modulation of myeloperoxidase activity by L. interrogans serovar Copenhageni. We show that leptospires and their culture supernatants are able to inhibit both peroxidase and chlorination activities of myeloperoxidase, without interfering with neutrophil degranulation. By leptospiral outer membrane protein extraction and fractionation, we identified the proteins LipL21 and LipL45 as myeloperoxidase inhibitors, constituting new Leptospira virulence factors. Accordingly, we propose a function for the protein LipL21, one of the most expressed leptospiral outer membrane proteins. Our results show a novel innate immune evasion mechanism by which leptospires interfere with the host response in order to cope with the host oxidative stress and efficiently achieve dissemination and colonization. PMID- 29235398 TI - Antipsychotic treatment of community-dwelling and institutionalised patients with dementia in Germany. AB - OBJECTIVE: A restrictive use of antipsychotic drugs in patients with Alzheimer's disease (AD) is recommended due to an increased risk of cerebrovascular events and mortality. We hypothesise that the prescription of antipsychotics is associated with the patients' socio-demographic and clinical status (e.g., dementia severity). METHODS: The prescription of antipsychotics was cross sectionally evaluated in 272 community-dwelling and 123 institutionalised patients with AD across all severity stages of dementia. The patients' clinical characteristics covered the cognitive status, neuropsychiatric symptoms, daily activities, and quality of life (HrQoL). To determine associations with the use of antipsychotics bivariate and logistic regression analyses were conducted. RESULTS: Totally, 25% of the patients were treated with antipsychotics. significantly less frequently than nursing home inhabitants (15.1% vs. 45.5%). Severely demented patients (MMSE 0-9) received antipsychotics most often (51.5%). Additionally, multiple regression analyses revealed a higher chance of prescription for participants with depressive symptoms (OR 2.3, 95% CI: 1.019 5.160) and those treated by neuropsychiatric specialists (OR 3.4, 95% CI: 1.408 8.328). CONCLUSIONS: Further longitudinal studies are required to assess the appropriateness of indications for antipsychotics and the reasons for a higher use in nursing home inhabitants and patients with severe dementia and depression. PMID- 29235399 TI - Reviewing the use of ventricular assist devices in the elderly: where do we stand today? AB - INTRODUCTION: Implantation of left ventricular assist devices (LVADS) in older patients appears to be an attractive option in the wake of donor shortage and increasing incidence and prevalence of end stage heart failure. Since the inception of the artificial heart program half a century ago tremendous progress in research and development has led to utilization of more sophisticated devices. VADs have therefore emerged as a successful therapy for extending life with meaningful quality. Areas covered: This review will address the use of LVADS as a bridge to transplantation, destination therapy and comparison of LVAD therapy with alternate list heart transplantation in the elderly population. Expert commentary: Age >70 years is an important aspect when assessing LVAD risk, but other characteristics appear to be better predictors of LVAD survival. Elevated pre-operative creatinine, bilirubin and ischemic etiology predispose to a higher risk of mortality. Creatinine has been shown to be a very powerful predictor in post LVAD survival. Based on the existing literature, the authors suggest an algorithm which could be useful when evaluating patients for LVAD implantation. PMID- 29235401 TI - What do human rights bring to discussions of power and politics in health policy and systems? AB - Scholarly interrogations of power and politics are not endemic to the disciplines primarily tasked with exploring health policy and planning in the domestic or global domains. Scholars in these domains have come late to investigating power, prompted in part by the growing focus in domestic and global health research on the intersections between governance, globalization and health inequities. Recent prominent reports in this area increasingly point to human rights as important norms capable of responding in part to power differentials that sustain and exacerbate health inequities. Yet human rights law is not traditionally incorporated into health policy scholarship or education, despite offering important normative and strategic frameworks for public and global health, with distinctive contributions in relation to identifying and challenging certain forms of power disparity. This paper overviews two of these reports and how they see power functioning to sustain health inequities. It then turns to investigate what human rights and the right to health in particular may offer in addressing and challenging power in the health policy context. PMID- 29235400 TI - Role of bevacizumab in the management of the patient with malignant pleural effusion: more questions than answers. AB - INTRODUCTION: Malignant pleural effusion (MPE) is a feature of metastatic cancer associated with significant morbidity and cost. The typical management of MPE is systemic chemotherapy and mechanical intervention. Vascular endothelial growth factor (VEGF), an inducer of vascular permeability, has been shown to mediate fluid formation. Therefore, bevacizumab, an inhibitor of VEGF, offers theoretical promise for abolishing fluid formation in MPE. Areas covered: This review begins with a summary of VEGF physiology and evidence of its role in MPE pathogenesis. This is followed by an overview of bevacizumab and major trials that put it on the map of non-small cell lung cancer (NSCLC). The majority of the article is devoted to a review of the current evidence base for the use of bevacizumab for MPE control in metastatic pleural malignancy. The review concludes with considerations of patient selection and toxicity. Expert commentary: Evidence in support of bevacizumab administration for MPE management remains flawed. Small studies suggest efficacy of both intravenous and intrapleural routes, but their design raises bias concerns. Bevacizumab appears to be safe in properly selected cases. The future of MPE management may de-emphasize VEGF inhibition in favor of precise molecular therapeutics that could address the root cause of tumorigenesis. PMID- 29235402 TI - Biofilm-related disease. AB - INTRODUCTION: Biofilm formation represents a protected mode of growth that renders bacterial cells less susceptible to antimicrobials and to killing by host immune effector mechanisms and so enables the pathogens to survive in hostile environments and also to disperse and colonize new niches. Biofilm disease includes device-related infections, chronic infections in the absence of a foreign body, and even malfunction of medical devices. Areas covered: This review puts forward a new medical entity that represents a major public health issue, which we have named 'biofilm-related disease'. We highlight the characteristics of biofilm disease including its pathogenesis, microbiological features, clinical presentation, and treatment challenges. Expert commentary: The diversity of biofilm-associated infections is increasing over time and its impact may be underestimated. This peculiar form of development endows associated bacteria with a high tolerance to conventional antimicrobial agents. A small percentage of persister cells developing within the biofilm is known to be highly tolerant to antibiotics and has typically been involved in causing relapse of infections. Knowledge of the pivotal role played by biofilm-growing microorganisms in related infections will provide new treatment dynamics for this biofilm-related disease. PMID- 29235404 TI - Understanding the interactions of different substrates with wild-type and mutant acylaminoacyl peptidase using molecular dynamics simulations. AB - Acylaminoacylpeptidase (AAP) belongs to peptidase protein family, which can degrade amyloid beta-peptide forms in the brains of patients, and hence leads to Alzheimer's disease. And so, AAP is considered to be a novel target in the design of drugs against Alzheimer's disease. In this investigation, six molecular dynamics simulations were used to find that the interaction between the wild-type and R526V AAP with two different substrates (p-nitrophenylcaprylate and Ac-Leu-p nitroanilide). Our results were as follows: firstly, Ac-Leu-p-nitroanilide bound to R526V AAP to form a more disordered loop (residues 552-562) in the alpha/beta hydrolase fold like of AAP, which caused an open and inactive AAP domain form, secondly, binding p-nitrophenylcaprylate and Ac-Leu-p-nitroanilide to AAP can decrease the flexibility of residues 225-250, 260-270, and 425-450, in which the ordered secondary structures may contain the suitable geometrical structure and so it is useful to serine attack. Our theoretical results showed that the binding of the two substrates can induce specific conformational changes responsible for the diverse AAP catalytic specificity. These theoretical substrate-induced structural diversities can help explain the abilities of AAPs to recognize and hydrolyze extremely different substrates. PMID- 29235406 TI - Acquiring clinical modesty. PMID- 29235405 TI - Mapping the Balint groups to the Accreditation Council for Graduate Medical Education family medicine competencies. AB - : Introduction Balint group discussions provide learning opportunities for many of the competencies and milestones put forward by the Accreditation Council for Graduate Medical Education. The current literature is mixed concerning the effect of Balint groups on communication skills and professionalism. Aim To map the content of the Balint discussion to the competencies and milestones put forward by the Accreditation Council for Graduate Medical Education. METHODOLOGY: A group who were both experts in Balint and members of the clinical competency committee of residency programs rated narratives that summarized Balint group discussions. Credentialed Leaders of the American Balint Society were invited via email to submit narratives (250 words) about Balint groups that they have led, or were leading, with residents. Results Only four narratives were submitted. Additional cases were recruited through literature review of published Balint discussion cases. A total of 25 cases were rated by the committee. There was agreement between three out of four raters on at least one core milestone in every case. The most frequent milestones were C1 (develops meaningful therapeutic relationships with patients and families), C2 (communicated effectively with patients, families, and public), Prof1 (completes a process of professionalization), and Prof3 (demonstrates humanism and cultural proficiency). Balint groups provided a learning opportunity for a subset of milestones in at least 36% of the cases. Conclusion This pilot research suggests that Balint groups and the discussions of complex and challenging cases provide learning opportunities for multiple family medicine milestones, mainly communication skills and professionalism. Further research is needed to refine the methodology and the rating system. PMID- 29235407 TI - Creation of a curriculum for the Balint Group Leader Education Fellowship. PMID- 29235408 TI - Balint work and the creation of medical knowledge. AB - Michael Balint's pioneering work in primary care was not simply the application of psychodynamic theory to the complex problems and relationships encountered by clinicians. Rather, Balint's work was part of a wider conversation in Western epistemology that had already begun to break down the enlightenment rationalist agenda. Since the time of Descartes, we sought to find certain truth through decontextualizing and abstracting problems, and through separation of the observer from the thing observed, with a focus on finding universal timeless laws that could be generalized. By the mid-1950s, it was clear that this agenda was insufficient to answer important questions about what it means to be human and to live a healthy and happy life. Balint's experiment was a return to a method of knowledge creation that is case based, narrative, local, timely, particular, and especially considers specific contexts for finding solutions to problems. For current healthcare reform efforts to be effective, we must include Balint's focus on the context of the doctor, patient, and their relationship, as well as development of practical wisdom (i.e. Aristotelian phronesis) that we know in medicine as professional judgment. The case study method of the Balint group is one of the few and best formal methods to teach and practice this way of knowing. PMID- 29235409 TI - Engaging indigenous Maori and inward migrating Asian professionals into a Pakeha (White European)-dominated Balint community in New Zealand. AB - This inquiry began with two questions: How can the established predominately Pakeha/Caucasian (White European) Balint community in New Zealand more successfully engage both indigenous populations of both Maori and Pacifica origin into Balint work? And what is the existing Balint community doing to address the lack of Asian members of the Balint community in New Zealand, at a time when Asian health professionals are being recruited into the health sector at an increasingly high rate in comparison to White European entrants to the profession? These questions, and their preliminary answers presented here, invite the reader to reflect on both the challenges and opportunities in reaching out to groups different from our own. The author hopes readers may begin to see what can be done to allow new entrants to benefit from all that participation in Balint work offers while not losing sight of the uniqueness which each person can bring. It is hoped that sharing such questions and their subsequent explorations will help Balint leaders feel more confident in reaching out to a wider ethic and cultural mix within their local populations and encouraging them to enter the exciting world of the Balint group. PMID- 29235410 TI - Diversity: The hidden ABS core value-Emerging conversations and strategic actions. PMID- 29235411 TI - Traffic safety science: research agenda for the way forward. PMID- 29235413 TI - Facile and large-scale synthesis of curcumin/PVA hydrogel: effectively kill bacteria and accelerate cutaneous wound healing in the rat. AB - The complicated synthesis procedure and limited preparation size of hydrogel inhibit its clinical application. Therefore, a facile preparation method for large-size hydrogel is required. In this study, a series of curcumin (Cur)/polyvinyl alcohol (PVA) hydrogel in a large size with different Cur concentrations is prepared by a facile physical-chemical crosslinking. The physicochemical properties, antibacterial performance and accelerating wound healing ability are evaluated with the aim of attaining a novel and effective wound dressing. The results show that the as-prepared hydrogel with the optimal Cur to PVA volume ratio of 1:5 (20% Cur/PVA) exhibits the best antibacterial abilities to E. coli (85.6%) and S. aureus (97%) than other hydrogels. When the volume ratio of Cur to PVA is 1:10 (10% Cur/PVA), the hydrogel can significantly accelerate the wound healing in rats, and successfully reconstruct intact and thickened epidermis during 14 day of healing of impaired wounds after histological examination. In one word, the present approach can shed new light on designing new type of hydrogels with promising applications in wound dressing. PMID- 29235414 TI - ZikaPLAN: Zika Preparedness Latin American Network. AB - The ongoing Zika virus (ZIKV) outbreak in Latin America, the Caribbean, and the Pacific Islands has underlined the need for a coordinated research network across the whole region that can respond rapidly to address the current knowledge gaps in Zika and enhance research preparedness beyond Zika. The European Union under its Horizon 2020 Research and Innovation Programme awarded three research consortia to respond to this need. Here we present the ZikaPLAN (Zika Preparedness Latin American Network) consortium. ZikaPLAN combines the strengths of 25 partners in Latin America, North America, Africa, Asia, and various centers in Europe. We will conduct clinical studies to estimate the risk and further define the full spectrum and risk factors of congenital Zika virus syndrome (including neurodevelopmental milestones in the first 3 years of life), delineate neurological complications associated with ZIKV due to direct neuroinvasion and immune-mediated responses in older children and adults, and strengthen surveillance for birth defects and Guillain-Barre Syndrome. Laboratory-based research to unravel neurotropism and investigate the role of sexual transmission, determinants of severe disease, and viral fitness will underpin the clinical studies. Social messaging and engagement with affected communities, as well as development of wearable repellent technologies against Aedes mosquitoes will enhance the impact. Burden of disease studies, data-driven vector control, and vaccine modeling as well as risk assessments on geographic spread of ZIKV will form the foundation for evidence-informed policies. While addressing the research gaps around ZIKV, we will engage in capacity building in laboratory and clinical research, collaborate with existing and new networks to share knowledge, and work with international organizations to tackle regulatory and other bottlenecks and refine research priorities. In this way, we can leverage the ZIKV response toward building a long-term emerging infectious diseases response capacity in the region to address future challenges. PMID- 29235415 TI - Decisional control preferences among patients with advanced cancer: An international multicenter cross-sectional survey. AB - BACKGROUND: Understanding patients' decision control preferences is important in providing quality cancer care. Patients' decisional control preference can be either active (patients prefer to make decisions themselves), shared (collaborative between patient, their physician, and/or family), or passive (patients prefer that the decisions are made by either the physician and/or their family). AIM: To determine the frequency and predictors of passive decision control preferences among advanced cancer patients. We also determined the concordance between actual decision-making and decision control preferences and its association with patient satisfaction. DESIGN: In this cross-sectional survey of advanced cancer patients referred to palliative care across 11 countries, we evaluated sociodemographic variables, Control Preference Scale, and satisfaction with the decisions and care. RESULTS: A total of 1490 participants were evaluable. Shared, active, and passive decision control preferences were 33%, 44%, and 23%, respectively. Passive decision control preferences (odds ratio, p value) was more frequent in India (4.34, <0.001), Jordan (3.41, <0.001), and France (3.27, <0.001). Concordance between the actual decision-making and decision control preferences was highest in the United States ( k = 0.74) and lowest in Brazil (0.34). Passive decision control preference was significantly associated with (odds ratio per point, p value) better performance status (0.99/point, 0.017), higher education (0.64, 0.001), and country of origin (Brazil (0.26, <0.0001), Singapore (0.25, 0.0003), South Africa (0.32, 0.0002), and Jordan (2.33, 0.0037)). CONCLUSION: Passive decision control preferences were less common (23%) than shared and active decision control preference even among developing countries. Significant predictors of passive decision control preferences were performance status, education, and country of origin. PMID- 29235416 TI - Skeletal muscle cell contraction reduces a novel myokine, chemokine (C-X-C motif) ligand 10 (CXCL10): potential roles in exercise-regulated angiogenesis. AB - Accumulating evidence indicates that skeletal muscle secrets proteins referred to as myokines and that exercise contributes to their regulation. In this study, we propose that chemokine (C-X-C motif) ligand 10 (CXCL10) functions as a novel myokine. Initially, we stimulated differentiated C2C12 myotubes with or without electrical pulse stimulation (EPS) to identify novel myokines. Cytokine array analysis revealed that CXCL10 secretion was significantly reduced by EPS, which was further confirmed by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction analysis. Treadmill experiments in mice identified significant reduction of Cxcl10 gene expression in the soleus muscle. Additionally, contraction-dependent p38 MAPK activation appeared to be involved in this reduction. Furthermore, C2C12 conditioned medium obtained after applying EPS could induce survival of MSS31, a vascular endothelial cell model, which was partially attenuated by the addition of recombinant CXCL10. Overall, our findings suggest CXCL10 as a novel exercise-reducible myokine, to control endothelial cell viability. PMID- 29235417 TI - South-South cross-border patient travel to South Africa. AB - This paper explores intra-regional South-South cross-border patient travel within the context of Southern Africa. South Africa, in particular, has been widely touted as one of the emerging destinations of high-end patients from the Global North alongside other destinations such as Brazil, India, Costa Rica and Thailand. Using South Africa as a case study, the paper demonstrates that South South cross-border patient travel is far more significant than North-South patient travel both in numerical and financial terms. Every year, thousands of patients from neighbouring countries travel to South Africa in search of medical treatment for procedures that are not offered in their own countries. Despite its size and importance, the South-South flow of patients in Southern Africa is not fully understood and requires further scholarly research. PMID- 29235418 TI - Dying persons' perspectives on, or experiences of, participating in research: An integrative review. AB - BACKGROUND: Conducting research with dying persons can be controversial and challenging due to concerns for the vulnerability of the dying and the potential burden on those who participate with the possibility of little benefit. AIM: To conduct an integrative review to answer the question 'What are dying persons' perspectives or experiences of participating in research? DESIGN: A structured integrative review of the empirical literature was undertaken. DATA SOURCES: Cumulative Index Nursing and Allied Health Complete, PsycINFO, MEDLINE, Informit and Embase databases were searched for the empirical literature published since inception of the databases until February 2017. RESULTS: From 2369 references, 10 papers were included in the review. Six were qualitative studies, and the remaining four were quantitative. Analysis revealed four themes: value of research, desire to help, expression of self and participation preferences. Dying persons value research participation, regarding their contribution as important, particularly if it provides an opportunity to help others. Participants perceived that the potential benefits of research can and should be measured in ways other than life prolongation or cure. Willingness to participate is influenced by study type or feature and degree of inconvenience. CONCLUSION: Understanding dying persons' perspectives of research participation will enhance future care of dying persons. It is essential that researchers do not exclude dying persons from clinically relevant research due to their prognosis, fear or burden or perceived vulnerability. The dying should be afforded the opportunity to participate in research with the knowledge it may contribute to science and understanding and improve the care and treatment of others. PMID- 29235419 TI - An observational study of patient handover communications among nurses on an oncology critical care unit. AB - BACKGROUND: Breakdown in communication is a common cause of errors in hospitals. Aim/Objectives: To evaluate the feasibility and utilization of evidence-based recommendations for nurse-to-nurse shift handover on an oncology critical care unit. DESIGN: Observational study. METHODS: Nurses were provided education that integrated evidence-based recommendations for handover of care. Nursing shift report was observed for one month in 2015 and for one month in 2016. Results were evaluated for inclusion of 24 evidence-based essential elements for handover communication. RESULTS: Total completeness of handover increased with 86.64% (N = 38) in 2015 and 88.68% (N = 35) in 2016. Interruptions during handover were positively correlated with length of handover (r = 0.587, n = 18, p = .010), thus confirming the need for structured, more effective handover methods. CONCLUSIONS: Providing education, mentoring, and real-time feedback to motivated staff may lead to improvements in handover communication methods, yielding positive patient outcomes. PMID- 29235420 TI - A self-care, problem-solving and mindfulness intervention for informal caregivers of people with motor neurone disease: A pilot study. AB - BACKGROUND: Informal caregivers of people with motor neurone disease (MND) take on an extensive role. Caregivers are at increased risk of experiencing psychological distress and burden, yet, there is a lack of intervention programmes to support them. AIM: The aim of this study was to investigate the feasibility and acceptability of a therapeutic group intervention promoting self care, problem-solving and mindfulness to informal caregivers of people with MND. DESIGN: Pilot study that utilised a one-arm pre- and post-design. Acceptability of the intervention was assessed 2 weeks post intervention with a questionnaire designed specifically for this study. Feasibility was assessed with consent, adherence and reasons for non-participation, refusal and attrition. Participants completed baseline and follow-up (6-week post intervention) questionnaires for psychological morbidity, burden, problem-solving, mindfulness and preparedness. Settings/participants: Caregivers of people with a diagnosis of MND within the past 12 months who were 18 years or older; who could speak, read and write in English and who were attending a progressive neurological diseases clinic were eligible. RESULTS: A total of 13 caregivers participated in one of three group intervention sessions which were focused on self-care, problem-solving and mindfulness. The intervention appeared to be feasible and acceptable. All participants stated that they would recommend the intervention to others. The group format appeared to be highly valued. There was no significant change in measures between pre-intervention and 6 weeks post intervention. CONCLUSION: This pilot serves as an initial step for examining interventions for MND caregivers, with the hope of identifying effective, efficient and sustainable strategies to best support this group. PMID- 29235421 TI - How should we talk about palliative care, death and dying? A qualitative study exploring perspectives from caregivers of people with advanced cancer. AB - BACKGROUND: Health professionals commonly underestimate caregiver needs for information about palliative care, death and dying and may feel poorly prepared to discuss these issues. Few studies have sought caregiver perspectives of these communication practices. AIM: To explore caregiver perspectives on communication about death, dying and the introduction to palliative care, with a view towards a series of caregiver-informed recommendations for use in clinical practice. DESIGN: Cross-sectional, prospective, exploratory qualitative design, involving narrative-style interviews and underpinned by an interpretative phenomenological framework. SETTING/PARTICIPANTS: Purposively sampled, English-speaking, adult caregivers of people with advanced cancer ( n = 25) recruited from cancer services at a tertiary metropolitan hospital in Melbourne, Australia. RESULTS: Caregivers reported wanting routinely available written resources about palliative care, supplemented by conversations that are ideally staged overtime. Education about the tasks of palliative care should be separated from referral process, allowing time for gradual adjustment, and re-visiting discussion to enable patients and families to take some control in the process of transition. Once death is imminent, carers wanted health professionals to clarify how much they want to know about the dying process; provide spoken acknowledgement when death is close; include the words 'death' and 'dying'; use direct language, avoiding euphemisms; and communicate about death with patient present. CONCLUSION: This study is among the first to directly address caregiver perspectives of communication about death, dying and the introduction to palliative care. The recommendations derived from caregiver perspectives build upon existing guidelines and offer health professionals some preliminary considerations around how to undertake these important communication tasks in future. PMID- 29235422 TI - 'The importance of planning for the future': Burden and unmet needs of caregivers' in advanced heart failure: A mixed methods study. AB - BACKGROUND: While studies have evaluated caregiver outcomes in heart failure, the burden and support needs when caring for someone with advanced heart failure at the end of life have yet to be outlined. AIM: To identify psychosocial factors associated with caregiver burden and evaluate the support needs of caregivers in advanced heart failure. DESIGN: A sequential mixed methods study comprising two phases: (1) postal survey with advanced heart failure patients and their caregivers and (2) interviews with current and bereaved caregivers. Correlation, chi-square, t test, regression and thematic analysis were undertaken on the data. PARTICIPANTS: Advanced heart failure patients ( n = 112) and their caregivers ( n = 84) were recruited from secondary care settings across the United Kingdom and Ireland. For phase 2 interviews, current caregivers ( n = 20) were purposively recruited from phase 1, and bereaved caregivers ( n = 10) were purposively recruited via voluntary organisation, social media and email. RESULTS: More than half the caregivers (53%) had levels of distress associated with depression (Zarit Burden score >24). Caregiver depression score, preparedness for caregiving and patients' depression score predicted caregiver burden. Qualitative analysis identified an overarching theme of lack of future care planning and four subthemes: (1) seeking emotional support from someone who understands, (2) want information on prognostication, (3) lack of knowledge on how to and where to get support and (4) require knowledge on what to expect at the end of life. CONCLUSION: Caregivers have unmet needs and feel unprepared for the future. Implementation of future care planning by clinical teams should address patient and caregiver support needs and in turn alleviate caregiver burden. PMID- 29235423 TI - Review of a commercially available hybrid closed-loop insulin-delivery system in the treatment of Type 1 diabetes. AB - Type 1 diabetes is an important medical condition causing significant burden and morbidity to those persons affected by it. Improvements in insulin products, insulin delivery and glucose monitoring technology have all contributed to reductions in long-term complications and hypoglycemia. This article reviews the Medtronic 670G device and summarizes the data supporting how this product reduces the burden and increases the safety of insulin dosing in Type 1 diabetes. PMID- 29235424 TI - Fundamental Movement Skills of Children Living in England: The Role of Ethnicity and Native English Language. AB - The development of fundamental movement skills (FMS) has been associated with children's general health, and, while there is evidence to suggest that age, gender, physical activity, and socioeconomic status relate to FMS, the relationship of ethnicity and language barriers to FMS competence has been underexplored. These factors may be of particular interest for South Asian (SA) children who have lower physical activity and increased risk of metabolic disease. This cross-sectional study examined ethnic and language differences in FMS among 218 ethnically diverse five-year-old children (61 White ethnic background, 91 SA, 29 Black ethnic background, and 37 other), some with English as a native language ( n = 90) and some with English as an additional language ( n = 75), all recruited from within central England. Each child was assessed performing five locomotor skills (run, gallop, hop, leap, and jump) and six object skills (catch, kick, bounce, strike, underarm roll, and overarm throw) on the Test of Gross Motor Development-2 . A 2 (gender) * 4 (ethnicity) factor analysis of covariance assessed differences in the locomotor and object composite scores and total FMS score, while controlling for body mass index. A two-factor analysis of covariance assessed native language differences in their impact on FMS. We found ethnic and gender differences in FMS ( p < .05) in that SA children had poorer total FMS and locomotor scores than children of either White or Black ethnic backgrounds ( p = .004, p = .001, and p = .008, p = .002, respectively). Girls had poorer total ( p = .001) and locomotor FMS skills ( p < .001). Children with English as an additional language had similar FMS scores compared to children whose native language was English ( p > .05). The findings of low FMS competency in SA children and girls, irrespective of body mass index, suggest that developmentally appropriate interventions targeting SA children and girls are needed in early years. We discuss some unclear factors related to these differences. PMID- 29235425 TI - Antibacterial Effect of 2R,3R-dihydromyricetin on the Cellular Functions of Staphylococcus aureus. AB - The C-3-OH, C-4 carbonyl oxygen and hydrogenation of C2=C3 bond on the C-ring of 2R,3R-dihydromyricetin (DMY) proved to be not necessary for the antibacterial activity against Staphylococcus aureus. DMY significantly decreased the intracellular ATP of S. aureus cells but had few effects on pHin, proline oxidation, succinate dehydrogenase activity or malate dehydrogenase activity. PMID- 29235426 TI - CpdA is involved in amino acid metabolism in Shewanella oneidensis MR-1. AB - Cyclic 3',5'-adenosine monophosphate (cAMP) phosphodiesterase (CPD) is an enzyme that catalyzes the hydrolysis of cAMP, a signaling molecule affecting diverse cellular and metabolic processes in bacteria. Some CPDs are also known to function in cAMP-independent manners, while their physiological roles remain largely unknown. Here, we investigated physiological roles of CPD in Shewanella oneidensis MR-1, a model environmental bacterium, and report that CPD is involved in amino-acid metabolism. We found that a CPD-deficient mutant of MR-1 (DeltacpdA) showed decreased expression of genes for the synthesis of methionine, S-adenosylmethionine, and histidine and required these three compounds to grow in minimal media. Interestingly, deletion of adenylate cyclases in DeltacpdA did not restore the ability to grow in minimal media, indicating that the amino acid requirements were not due to the accumulation of cAMP. These results suggest that CPD is involved in the regulation of amino acid metabolism in MR-1 in a cAMP independent manner. PMID- 29235427 TI - Dengue hospitalisations in Brazil: annual wave from West to East and recent increase among children. AB - The number of dengue epidemics in Brazil has increased dramatically in the last 15 years. In this study, we analysed the seasonal patterns in the incidence of hospitalisations due to dengue across the different states of Brazil and compared these with the corresponding climatic patterns. We discovered that the seasonality of dengue hospitalisations in Brazil has a clear zonal gradient, characterised by the progression of primary peaks from West to East during the first half of the year, which may be associated with the increased vapour pressure and rainfall during this period, leading to increased mosquito abundance and activity. We also found that the proportion of children among hospitalised individuals was especially high during the peak outbreaks in 2007/2008 and 2010. This may be due to the emergence and spread of the new DENV-2 Southeast Asian genotype lineage II from 2007, which has probably arrived from the Caribbean and may have caused an increase in incidence and severity of the disease, particularly among children. Our findings may allow health systems to improve control interventions and contribute to reducing dengue morbidity and mortality by using integrated vector control in conjunction with early diagnosis and prompt supportive care. PMID- 29235429 TI - Evolution and future directions for the concept of mild cognitive impairment. AB - The term mild cognitive impairment has been associated with a varying degree of clinical utility and controversy. The concept has been introduced to try and define a pre-dementia period associated with underlying neurodegenerative pathology and a higher likelihood of the person developing a dementia syndrome. As scientific understanding improves then the definition of MCI rightly adapts, meaning that the MCI concept is prone quite rightly to frequent evolution. We consider that we are a long way away from the concept having evolved to a point where it can be embedded with confidence in clinical practice as a diagnosis but should remain as a term primarily for use in research. PMID- 29235430 TI - Prevalence and risk factors for delirium diagnosis in patients followed in general practices in Germany. AB - : ABSTRACTBackground:The aim of this study is to identify the prevalence and risk factors of documented delirium in general practices in Germany. METHODS: The present study includes 2,194 patients over the age of 65 years with delirium and 2,194 controls without delirium from a sample of 6,180,042 patients from 1,262 general practices. Multivariate logistic regression models were fitted with delirium as a dependent variable and other disorders and drugs as potential predictors. RESULTS: A five-year-prevalence of 0.08% and an average of 0.7 (SD: 1.5) patients per practice per year were found. Among the study participants, 43.0% were men, and the mean age was 82.2 years (SD = 7.1 years). 24.2% of delirium patients and 10.3% of controls lived in nursing homes. Delirium was found to be positively associated with nursing home residence (OR: 1.69), dementia (OR = 3.45), epilepsy (OR = 2.16), stroke (OR = 1.80), Parkinson's disease (OR = 1.78), sleep disorder (OR = 1.64), renal insufficiency (OR = 1.57), fractures (OR = 1.56), and the prescription of benzodiazepines (OR = 1.62) and antiepileptics (OR = 1.53). Finally, the number of different drug classes prescribed within one year prior to the index date was positively associated with a risk of delirium. Compared to patients without medication therapy, the OR for delirium was 3.21 when more than four drug classes were prescribed. CONCLUSIONS: In primary care, neuropsychiatric risk factors and polymedication were particularly important for the diagnosis of delirium compared to inpatient care. The methodological limitations of the analysis of data from routine care must be considered. Delirium is rarely diagnosed in primary care. Risk factors in primary care differ from those found in inpatient care. The reasons for this need to be further investigated. PMID- 29235428 TI - Does smallpox vaccination modify HIV disease progression among ART-naive people living with HIV in Africa? AB - We examined the association between a history of smallpox vaccination and immune activation (IA) in a population of antiretroviral therapy-naive people living with HIV (PLHIV). A cross-sectional study was conducted in Senegal from July 2015 to March 2017. Smallpox vaccination was ascertained by the presence of smallpox vaccine scar and IA by the plasma level of beta-2-microglobulin (beta2m). The association was analysed using logistic regression and linear regression models. The study population comprised 101 PLHIV born before 1980 with a median age of 47 years (interquartile range (IQR) = 42-55); 57.4% were women. Smallpox vaccine scar was present in 65.3% and the median beta2m level was 2.59 mg/l (IQR = 2.06 3.86). After adjustment, the presence of smallpox vaccine scar was not associated with a beta2m level ?2.59 mg/l (adjusted odds ratio 0.94; 95% confidence interval 0.32-2.77). This result was confirmed by the linear regression model. Our study does not find any association between the presence of smallpox vaccine scar and the beta2m level and does not support any association between a previous smallpox vaccination and HIV disease progression. In this study, IA is not a significant determinant of the reported non-targeted effect of smallpox vaccination in PLHIV. PMID- 29235431 TI - Using targeted solution tools as an initiative to improve hand hygiene: challenges and lessons learned. AB - The Joint Commission Centre for Transforming Healthcare's Web-based Targeted Solutions Tool (TST) for improving hand hygiene was implemented to elucidate contributing factors to low compliance rates of hand hygiene. Monitoring of compliance was done by trained unknown and known observers and rates of hospital acquired infections were tracked and correlated against the changes in hand hygiene compliance. In total, 5669 of hand hygiene observations were recorded by the secret observers. The compliance rate increased from 75.4% at baseline (May August 2014) to 88.6% during the intervention (13 months) and the control periods (P < 0.0001). Reductions in healthcare-associated infection rates were recorded for Clostridium difficle infections from 7.95 (CI 0.8937-28.72) to 1.84 (CI 0.02411-10.26) infections per 10 000 patient-days (P = 0.23), central line associated blood-stream infections from 5.9 (CI 1.194-17.36) to 2.9 (0.7856 7.475) per 1000 device days (P = 0.37) and catheter-associated urinary tract infections from 5.941 (CI 1.194-17.36) to 0 per 1000 device days (P = 0.42). The top contributing factors for non-compliance were: improper use of gloves, hands full of supplies or medications and frequent entry or exit in isolation areas. We conclude that the application of TST allows healthcare organisations to improve hand hygiene compliance and to identify the factors contributing to non compliance. PMID- 29235432 TI - Impact of informal caregiving on cognitive function and well-being in Canada. AB - : ABSTRACTBackground:With a rise in the aging population and a consequential rise in persons diagnosed with dementia comes an increase in the number of informal caregivers who are caring for a loved one. The objective of the proposed study was to assess the neurocognitive and psychological effects of caring for a person with dementia or a related neurodegenerative disease in a sample of Canadian informal caregivers. METHODS: Fifty-seven informal caregivers of a person with dementia or a related neurodegenerative disease (mean age = 66.26, SD = 7.55) and 97 non-caregivers (mean age = 69.16, SD = 4.84) were recruited. Neuropsychological measures of attention, cognitive flexibility, verbal learning, delayed recall, and verbal fluency were examined, and questionnaires related to perceived stress, quality of life, mood, and self-esteem were administered. RESULTS: Caregivers made more errors on a measure of cognitive flexibility (p = 0.02), generated fewer words on measures of phonemic fluency (p < 0.01) and semantic fluency (p < 0.001), and learned significantly fewer words on a list learning task (p < 0.01). Caregivers also reported experiencing significantly more perceived stress (p < 0.001), lower quality of life (p < 0.001), and were more likely to meet the cut-off for clinically significant depressive symptoms on a self-report scale (p < 0.001). CONCLUSION: These data contribute to a growing body of literature that consistently points to the need for immediate action to improve the welfare of caregivers. PMID- 29235434 TI - IgE to alpha-Gal in Foresters and Forest Workers From La Rioja, North of Spain. AB - OBJECTIVE: To investigate the prevalence of and factors associated with the presence of alpha-gal-specific IgE in a risk group of foresters and forest workers from La Rioja, Spain and in a control group. METHODS: The study population comprised 169 workers and 100 individuals who did not recall having had tick bites. A questionnaire including demographic data and number of tick bites per year was completed by a physician. alpha-Gal sIgE was assessed using ImmunoCAP with serum samples that had been taken in 2010. In 2015, second serum specimens were taken from all but 1 of the workers, who had positive specific IgE to alpha-gal in 2010. These new samples were tested for IgE to the alpha-gal epitope and to mammalian meat. RESULTS: The prevalence of positive sIgE to alpha gal was 15% in the risk population and 4% in the control population. alpha-Gal sIgE positivity was associated with the number of tick bites per year and with seniority. Thirteen out of 21 patients sensitized to alpha-gal in 2010 showed positive specific IgE to alpha-gal in serum samples from 2015. Eleven had specific IgE to mammalian meat, but none reported symptoms of meat allergy. CONCLUSIONS: The prevalence of alpha-gal sIgE antibodies in this risk population was higher than in the control group and was associated with the number of tick bites per year and with seniority. None of the workers sensitized to mammalian meat developed meat allergy, possibly owing to the low levels of sIgE to alpha gal. PMID- 29235433 TI - Annual prevalence and economic burden of genital warts in Korea: Health Insurance Review and Assessment (HIRA) service data from 2007 to 2015. AB - This study evaluated the annual prevalence of anogenital warts (AGW) caused by human papillomavirus (HPV) and analysed the trend in annual per cent changes (APC) by using national claims data from the Health Insurance Review and Assessment of Korea, 2007-2015. We also estimated the socio-economic burden and co-morbidities of AGW. All analyses were performed based on data for primary A63.0, the specific diagnosis code for AGW. The socio-economic cost of AGW was calculated based on the direct medical cost, direct non-medical cost and indirect cost. The overall AGW prevalence and socio-economic burden has increased during the last 9 years. However, the prevalence of AGW differed significantly by sex. The female prevalence increased until 2012, and decreased thereafter (APC + 3.6%). It would fall after the introduction of routine HPV vaccination, principally for females, in Korea. The male prevalence increased continuously over time (APC + 11.6%), especially in those aged 20-49 years. Referring to the increasing AGW prevalence and its disease burden, active HPV infection control surveillance and prevention in males are worth consideration. PMID- 29235435 TI - Transcatheter aortic valve-in-valve treatment in prior Sorin Freedom Solo valve. PMID- 29235436 TI - Bioprosthetic aortic valve leaflet thrombosis detected by multidetector computed tomography is associated with adverse cerebrovascular events: a meta-analysis of observational studies. AB - AIMS: Leaflet thrombosis (LT) has become increasingly recognised following transcatheter and surgical aortic bioprosthetic valve (ABV) replacement and can be reliably identified by multidetector computed tomography (MDCT). However, it is an ongoing debate whether MDCT-defined LT is associated with adverse cerebrovascular outcomes. We sought to perform a systematic review and meta analysis in order to assess the incidence and clinical outcomes associated with MDCT-defined leaflet thrombosis following (ABV) replacement. METHODS AND RESULTS: Electronic databases were searched for studies that performed mandatory MDCT imaging following ABV replacement. The primary endpoint was the incidence of cerebrovascular events, defined as a composite of stroke or transient ischaemic attack (TIA). Secondary endpoints included major adverse cerebrovascular and cardiovascular events (MACCE), stroke, TIA, death or myocardial infarction. In total, six studies met the inclusion criteria with 11.6% (198/1,704) of patients having MDCT-defined LT. The prevalence of LT following transcatheter and surgical ABV replacement was 13.2% and 3.6%, respectively. Cerebrovascular events were significantly increased in patients with LT (odds ratio [OR] 3.38, 95% CI: 1.78 6.41, p<0.001). The risk of MACCE (OR 2.10, 95% CI: 1.21-3.64, p<0.001) and TIA (OR 5.86, 95% CI: 2.05-16.75, p<0.001) was also increased in patients with LT, although there were no differences in the incidence of stroke (OR 2.43, 95% CI: 1.00-5.93, p=0.05), death (OR 0.92, 95% CI: 0.42-2.03, p=0.84) or myocardial infarction (OR 1.72, 95% CI: 0.34-9.78, p=0.54) between groups. CONCLUSIONS: MDCT defined LT following ABV replacement is associated with a significantly increased risk of adverse cerebrovascular events. Further prospective studies are required to ascertain whether LT can be prevented or treated with pharmacological strategies. PMID- 29235437 TI - Impact of a in situ laboratory on physician expectancy. AB - Biological examinations are essential for clinicians' medical care. The aim of this study is to assess clinicians' expectations in healthcare facilities and their perception of medical biology in different types of organization. We performed a prospective transversal study by electronic questionnaire conducted among 242 practitioners in four healthcare facilities. The aspects explored were as follows: quality, reliability, rendering time of examination results and biology platform support. Analyses were conducted after rectification of the sample by weight. Sixty one clinicians responded (25.2% [19.7-30.7]). The rendering time of examination is the main criterion mentioned with a requirement of less than one hour in case of emergency (81.5% [71.8-91.2] of the answers) to less than 72 hours for specialized examinations (81.5% [71.8-91.2] of the answers). Better collaboration with biologists is expected by clinicians (54.7% [50.9-58.5]). Satisfaction with the biology platform support and rendering time of emergency cases results was significantly (p <0.005) lower in facilities without an on-site laboratory. In conclusion, although medical biology performance is generally satisfactory within medical facilities, it remains nonetheless affected when the laboratory is not on site. The rendering time of examination, depending on the biology platform support functions and the proximity of the laboratory, remains the main criterion. Clinician-biologist collaboration, which increases of the medico-economic efficiency of patient's healthcare, appears as an essential criterion in a structural conception of medical biology. PMID- 29235438 TI - Acoustic stimulation can induce a selective neural network response mediated by piezoelectric nanoparticles. AB - OBJECTIVE: We aim to develop a novel non-invasive or minimally invasive method for neural stimulation to be applied in the study and treatment of brain (dys)functions and neurological disorders. APPROACH: We investigate the electrophysiological response of in vitro neuronal networks when subjected to low intensity pulsed acoustic stimulation, mediated by piezoelectric nanoparticles adsorbed on the neuronal membrane. MAIN RESULTS: We show that the presence of piezoelectric barium titanate nanoparticles induces, in a reproducible way, an increase in network activity when excited by stationary ultrasound waves in the MHz regime. Such a response can be fully recovered when switching the ultrasound pulse off, depending on the generated pressure field amplitude, whilst it is insensitive to the duration of the ultrasound pulse in the range 0.5 s-1.5 s. We demonstrate that the presence of piezoelectric nanoparticles is necessary, and when applying the same acoustic stimulation to neuronal cultures without nanoparticles or with non-piezoelectric nanoparticles with the same size distribution, no network response is observed. SIGNIFICANCE: We believe that our results open up an extremely interesting approach when coupled with suitable functionalization strategies of the nanoparticles in order to address specific neurons and/or brain areas and applied in vivo, thus enabling remote, non invasive, and highly selective modulation of the activity of neuronal subpopulations of the central nervous system of mammalians. PMID- 29235439 TI - Theoretical analysis of angular distribution of scattering in nozzle components using a response-function method for proton spot-scanning therapy. AB - In spot-scanning proton therapy, highly precise beam control is required in the treatment nozzle such that the proton beam does not spread out during transportation by restraining the divergence of the beam angle and spot size, simultaneously. In order to evaluate the beam-broadening behaviour induced by passing through the various nozzle components, we have developed a new method to calculate the angular divergence profile of a proton beam in the nozzle. The angular divergence of the proton beam for each nozzle component is calculated by the Monte Carlo simulation code, Geant4, assuming that the initial beam has no divergence. The angular divergence profiles generated in the various nozzle components are then fitted by the analytic function formula with triple Gaussian distributions. The fitted profiles can be treated like analytic response functions and the angular divergence profile in the nozzle can be easily and systematically calculated by using a convolution theorem. The beam-broadening behaviour during transportation in the nozzle is carefully evaluated. The beam profiles are well-characterized by the proposed angular divergence analysis, i.e. triple Gaussian profile analysis. The primary Gaussian part of the beam profile is mainly generated by air and dose monitors with plate electrode components. The secondary and tertiary Gaussian parts are so-called wide-angle scattering and generated mainly by spot-position and profile monitors with metal window and wire components. The scattering of the nozzle component can be analysed using the proposed response function method for the angular distribution. Multiple convolved angular scattering can be determined from the response function of the individual nozzle components. The angular distribution from small to large angle regions can then be quantitatively evaluated by the proposed method. The method is quite simple and generalized, and is a straightforward way to understand the nozzle and component characteristics related to the beam-broadening behaviour. PMID- 29235440 TI - Leveraging multi-layer imager detector design to improve low-dose performance for megavoltage cone-beam computed tomography. AB - While megavoltage cone-beam computed tomography (CBCT) using an electronic portal imaging device (EPID) provides many advantages over kilovoltage (kV) CBCT, clinical adoption is limited by its high doses. Multi-layer imager (MLI) EPIDs increase DQE(0) while maintaining high resolution. However, even well-designed, high-performance MLIs suffer from increased electronic noise from each readout, degrading low-dose image quality. To improve low-dose performance, shift-and-bin addition (ShiBA) imaging is proposed, leveraging the unique architecture of the MLI. ShiBA combines hardware readout-binning and super-resolution concepts, reducing electronic noise while maintaining native image sampling. The imaging performance of full-resolution (FR); standard, aligned binned (BIN); and ShiBA images in terms of noise power spectrum (NPS), electronic NPS, modulation transfer function (MTF), and the ideal observer signal-to-noise ratio (SNR)-the detectability index (d')-are compared. The FR 4-layer readout of the prototype MLI exhibits an electronic NPS magnitude 6-times higher than a state-of-the-art single layer (SLI) EPID. Although the MLI is built on the same readout platform as the SLI, with each layer exhibiting equivalent electronic noise, the multi stage readout of the MLI results in electronic noise 50% higher than simple summation. Electronic noise is mitigated in both BIN and ShiBA imaging, reducing its total by ~12 times. ShiBA further reduces the NPS, effectively upsampling the image, resulting in a multiplication by a sinc2 function. Normalized NPS show that neither ShiBA nor BIN otherwise affects image noise. The LSF shows that ShiBA removes the pixilation artifact of BIN images and mitigates the effect of detector shift, but does not quantifiably improve the MTF. ShiBA provides a pre sampled representation of the images, mitigating phase dependence. Hardware binning strategies lower the quantum noise floor, with 2 * 2 implementation reducing the dose at which DQE(0) degrades by 10% from 0.01 MU to 0.004 MU, representing 20% improvement in d'. PMID- 29235441 TI - Memristive effects in oxygenated amorphous carbon nanodevices. AB - Computing with resistive-switching (memristive) memory devices has shown much recent progress and offers an attractive route to circumvent the von-Neumann bottleneck, i.e. the separation of processing and memory, which limits the performance of conventional computer architectures. Due to their good scalability and nanosecond switching speeds, carbon-based resistive-switching memory devices could play an important role in this respect. However, devices based on elemental carbon, such as tetrahedral amorphous carbon or ta-C, typically suffer from a low cycling endurance. A material that has proven to be capable of combining the advantages of elemental carbon-based memories with simple fabrication methods and good endurance performance for binary memory applications is oxygenated amorphous carbon, or a-CO x . Here, we examine the memristive capabilities of nanoscale a CO x devices, in particular their ability to provide the multilevel and accumulation properties that underpin computing type applications. We show the successful operation of nanoscale a-CO x memory cells for both the storage of multilevel states (here 3-level) and for the provision of an arithmetic accumulator. We implement a base-16, or hexadecimal, accumulator and show how such a device can carry out hexadecimal arithmetic and simultaneously store the computed result in the self-same a-CO x cell, all using fast (sub-10 ns) and low energy (sub-pJ) input pulses. PMID- 29235442 TI - The effect of RNA stiffness on the self-assembly of virus particles. AB - Under many in vitro conditions, some small viruses spontaneously encapsidate a single stranded (ss) RNA into a protein shell called the capsid. While viral RNAs are found to be compact and highly branched because of long distance base-pairing between nucleotides, recent experiments reveal that in a head-to-head competition between an ssRNA with no secondary or higher order structure and a viral RNA, the capsid proteins preferentially encapsulate the linear polymer! In this paper, we study the impact of genome stiffness on the encapsidation free energy of the complex of RNA and capsid proteins. We show that an increase in effective chain stiffness because of base-pairing could be the reason why under certain conditions linear chains have an advantage over branched chains when it comes to encapsidation efficiency. While branching makes the genome more compact, RNA base pairing increases the effective Kuhn length of the RNA molecule, which could result in an increase of the free energy of RNA confinement, that is, the work required to encapsidate RNA, and thus less efficient packaging. PMID- 29235443 TI - Integrating radiation protection criteria for radioactive waste management into remediation procedures in existing exposure situations after a nuclear accident. AB - Experience after the accident at the Fukushima Daiichi nuclear power station has shown that there is a need to establish radiation protection criteria for radioactive waste management consistent with the criteria adopted for the remediation of existing exposure situations. A stepwise approach to setting such criteria is proposed. Initially, a reference level for the annual effective dose from waste management activities in the range 1-10 mSv should be set, with the reference level being less than the reference level for the ambient dose. Subsequently, the reference level for the annual effective dose from waste management activities should be reduced in one or more steps to achieve a final target value of 1 mSv. The dose criteria at each stage should be determined with relevant stakeholder involvement. Illustrative case studies show how this stepwise approach might be applied in practice. PMID- 29235444 TI - Contact guidance for cardiac tissue engineering using 3D bioprinted gelatin patterned hydrogel. AB - Here, we have developed a 3D bioprinted microchanneled gelatin hydrogel that promotes human mesenchymal stem cell (hMSC) myocardial commitment and supports native cardiomyocytes (CMs) contractile functionality. Firstly, we studied the effect of bioprinted microchanneled hydrogel on the alignment, elongation, and differentiation of hMSC. Notably, the cells displayed well defined F-actin anisotropy and elongated morphology on the microchanneled hydrogel, hence showing the effects of topographical control over cell behavior. Furthermore, the aligned stem cells showed myocardial lineage commitment, as detected using mature cardiac markers. The fluorescence-activated cell sorting analysis also confirmed a significant increase in the commitment towards myocardial tissue lineage. Moreover, seeded CMs were found to be more aligned and demonstrated synchronized beating on microchanneled hydrogel as compared to the unpatterned hydrogel. Overall, our study proved that microchanneled hydrogel scaffold produced by 3D bioprinting induces myocardial differentiation of stem cells as well as supports CMs growth and contractility. Applications of this approach may be beneficial for generating in vitro cardiac model systems to physiological and cardiotoxicity studies as well as in vivo generating custom designed cell impregnated constructs for tissue engineering and regenerative medicine applications. PMID- 29235445 TI - Direct three-dimensional printing of polymeric scaffolds with nanofibrous topography. AB - Three-dimensional (3D) printing is a powerful manufacturing tool for making 3D structures with well-defined architectures for a wide range of applications. The field of tissue engineering has also adopted this technology to fabricate scaffolds for tissue regeneration. The ability to control architecture of scaffolds, e.g. matching anatomical shapes and having defined pore size, has since been improved significantly. However, the material surface of these scaffolds is smooth and does not resemble that found in natural extracellular matrix (ECM), in particular, the nanofibrous morphology of collagen. This natural nanoscale morphology plays a critical role in cell behaviour. Here, we have developed a new approach to directly fabricate polymeric scaffolds with an ECM like nanofibrous topography and defined architectures using extrusion-based 3D printing. 3D printed tall scaffolds with interconnected pores were created with disparate features spanning from nanometres to centimetres. Our approach removes the need for a sacrificial mould and subsequent mould removal compared to previous methods. Moreover, the nanofibrous topography of the 3D printed scaffolds significantly enhanced protein absorption, cell adhesion and differentiation of human mesenchymal stem cells when compared to those with smooth material surfaces. These 3D printed scaffolds with both defined architectures and nanoscale ECM-mimicking morphologies have potential applications in cartilage and bone regeneration. PMID- 29235446 TI - Optimized programming algorithm for cylindrical and directional deep brain stimulation electrodes. AB - OBJECTIVE: Deep brain stimulation (DBS) is a growing treatment option for movement and psychiatric disorders. As DBS technology moves toward directional leads with increased numbers of smaller electrode contacts, trial-and-error methods of manual DBS programming are becoming too time-consuming for clinical feasibility. We propose an algorithm to automate DBS programming in near real time for a wide range of DBS lead designs. APPROACH: Magnetic resonance imaging and diffusion tensor imaging are used to build finite element models that include anisotropic conductivity. The algorithm maximizes activation of target tissue and utilizes the Hessian matrix of the electric potential to approximate activation of neurons in all directions. We demonstrate our algorithm's ability in an example programming case that targets the subthalamic nucleus (STN) for the treatment of Parkinson's disease for three lead designs: the Medtronic 3389 (four cylindrical contacts), the direct STNAcute (two cylindrical contacts, six directional contacts), and the Medtronic-Sapiens lead (40 directional contacts). MAIN RESULTS: The optimization algorithm returns patient-specific contact configurations in near real-time-less than 10 s for even the most complex leads. When the lead was placed centrally in the target STN, the directional leads were able to activate over 50% of the region, whereas the Medtronic 3389 could activate only 40%. When the lead was placed 2 mm lateral to the target, the directional leads performed as well as they did in the central position, but the Medtronic 3389 activated only 2.9% of the STN. SIGNIFICANCE: This DBS programming algorithm can be applied to cylindrical electrodes as well as novel directional leads that are too complex with modern technology to be manually programmed. This algorithm may reduce clinical programming time and encourage the use of directional leads, since they activate a larger volume of the target area than cylindrical electrodes in central and off-target lead placements. PMID- 29235447 TI - Electrical conductivity of In2O3 and Ga2O3 after low temperature ion irradiation; implications for instrinsic defect formation and charge neutrality level. AB - The evolution of sheet resistance of n-type In2O3 and Ga2O3 exposed to bombardment with MeV 12C and 28Si ions at 35 K is studied in situ. While the sheet resistance of Ga2O3 increased by more than eight orders of magnitude as a result of ion irradiation, In2O3 showed a more complex defect evolution and became more conductive when irradiated at the highest doses. Heating up to room temperature reduced the sheet resistivity somewhat, but Ga2O3 remained highly resistive, while In2O3 showed a lower resistance than as deposited samples. Thermal admittance spectroscopy and deep level transient spectroscopy did not reveal new defect levels for irradiation up to [Formula: see text] cm-2. A model where larger defect complexes preferentially produce donor like defects in In2O3 is proposed, and may reveal a microscopic view of a charge neutrality level within the conduction band, as previously proposed. PMID- 29235448 TI - How do the reference montage and electrodes setup affect the measured scalp EEG potentials? AB - OBJECTIVE: Human scalp electroencephalogram (EEG) is widely applied in cognitive neuroscience and clinical studies due to its non-invasiveness and ultra-high time resolution. However, the representativeness of the measured EEG potentials for the underneath neural activities is still a problem under debate. This study aims to investigate systematically how both reference montage and electrodes setup affect the accuracy of EEG potentials. APPROACH: First, the standard EEG potentials are generated by the forward calculation with a single dipole in the neural source space, for eleven channel numbers (10, 16, 21, 32, 64, 85, 96, 128, 129, 257, 335). Here, the reference is the ideal infinity implicitly determined by forward theory. Then, the standard EEG potentials are transformed to recordings with different references including five monopolar references (Left earlobe, Fz, Pz, Oz, Cz), and three re-references (Linked Mastoids (LM), Average Reference (AR) and Reference Electrode Standardization Technique (REST)). Finally, the relative errors between the standard EEG potentials and the transformed ones are evaluated in terms of channel number, scalp regions, electrodes layout, dipole source position and orientation, as well as sensor noise and head model. MAIN RESULTS: Mono-polar reference recordings are usually of large distortions; thus, a re-reference after online mono-polar recording should be adopted in general to mitigate this effect. Among the three re-references, REST is generally superior to AR for all factors compared, and LM performs worst. REST is insensitive to head model perturbation. AR is subject to electrodes coverage and dipole orientation but no close relation with channel number. SIGNIFICANCE: These results indicate that REST would be the first choice of re-reference and AR may be an alternative option for high level sensor noise case. Our findings may provide the helpful suggestions on how to obtain the EEG potentials as accurately as possible for cognitive neuroscientists and clinicians. PMID- 29235449 TI - Evaluation of skin absorbed doses during manipulation of radioactive sources: a comparison between the VARSKIN code and Monte Carlo simulations. AB - The evaluation of skin doses during manipulation of radioactive sources can be a critical issue for which the most accurate calculation strategies available should be used. The aim of this work was to compare the results of the analytical approach used in VARSKIN with the simulation of radiation transport and interaction by Monte Carlo calculations in GAMOS (GEANT4-based Architecture for Medicine-Oriented Simulations), and to provide an accurate and versatile tool for the evaluation of skin doses from radionuclide sources of any realistic shape (e.g. cylindrical, parallelepiped), even in the presence of multiple interposed absorber layers. A set of 20 radionuclides (pure beta, beta-gamma, Auger and gamma emitters) from among the most frequently employed in nuclear medicine and laboratory practices were selected for comparison. We studied a point-like and a cylindrical source, in the presence of varying thicknesses of absorbing layers. We found a general agreement for most nuclides when the source was directly in contact with skin or in the presence of a thin layer of absorbing material. However, when the thickness of the absorber increased, significant differences were found for several nuclides. In these cases, the proposed method based on a dedicated Monte Carlo simulation could give more accurate results in a reasonable time, which could optimise accuracy when assessing skin doses in routine as well as incidental exposure scenarios. PMID- 29235450 TI - Si-H induced synthesis of Si/Cu2O nanowire arrays for photoelectrochemical water splitting. AB - We report a facile and low-cost method to synthesize Si/Cu2O heterojunction nanowire arrays, without SiOx, at the Si/Cu2O interface. The reductive Si-H bonds on the surface of Si nanowires plays a key role in situ by reducing Cu(II) ions to Cu2O nanocubes and avoiding the SiOx interface layer. Different pH values would vary the electrochemical potential of reactions and as a result, different products would be formed. Utilized as a photoanode for water splitting, Si/Cu2O nanowire arrays exhibit good photoelectrochemical performance. PMID- 29235451 TI - Towards a theoretical clarification of biomimetics using conceptual tools from engineering design. AB - Many successful examples of biomimetic products are available, and most research efforts in this emerging field are directed towards the development of specific applications. The theoretical and conceptual underpinnings of the knowledge transfer between biologists, engineers and architects are, however, poorly investigated. The present article addresses this gap. We use a 'technomorphic' approach, i.e. the application of conceptual tools derived from engineering design, to better understand the processes operating during a typical biomimetic research project. This helps to elucidate the formal connections between functions, working principles and constructions (in a broad sense)-because the 'form-function-relationship' is a recurring issue in biology and engineering. The presented schema also serves as a conceptual framework that can be implemented for future biomimetic projects. The concepts of 'function' and 'working principle' are identified as the core elements in the biomimetic knowledge transfer towards applications. This schema not only facilitates the development of a common language in the emerging science of biomimetics, but also promotes the interdisciplinary dialogue among its subdisciplines. PMID- 29235452 TI - Comparison of external doses between radio-contaminated areas and areas with high natural terrestrial background using the individual dosimeter 'D-shuttle' 75 months after the Fukushima Daiichi nuclear power plant accident. AB - After the Fukushima Daiichi nuclear power plant accident, the air dose gradually decreases every year due to the physical decay of radioactive materials and environmental changes, as well as countermeasures. However, there is little information on personal behavioural patterns and individual dose from external exposure among the inhabitants around the nuclear power plant. To evaluate the dose from external exposure in Minamisoma city, and compare the differences with outside Fukushima Prefecture, we started the external dose assessment project in cooperation with city officials in Minamisoma and three other cities in Japan where the natural terrestrial background radiation level is relatively high. In these four cities, external dose was measured every hour for two weeks using an individual electronic dosimeter D-shuttle. The places of activity of participants were recorded every hour to compare and evaluate the dose from external exposure, and to clarify whether there is a difference in the exposure dose by behaviour. The annual effective doses from external exposure for 100 participants from four municipalities ranged from 0.566 to 1.295 with a mean value of 0.784 mSv, which was below the level where it is necessary to initiate further remedial actions. Mean external dose in Minamisoma city (0.820 mSv/year) was comparable to those in municipalities with a relatively high natural radiation background in Japan (0.793, 0.806, and 0.718 mSv/year in Fukuyama, Nanto, and Tajimi, respectively). The time spent at home and in the workplace accounted for most of the time of the participants, and this also contributed to the majority of the total dose from external exposure. The amount of exposure at times other than while at home or in the workplace was very small regardless of the indoor or outdoor location in the city. For future dose reduction and radiation protection, continuous dosimetry and countermeasures at home and in the workplace are important for individuals who present high values. PMID- 29235453 TI - Potential impact of thermal effects during ultrasonic neurostimulation: retrospective numerical estimation of temperature elevation in seven rodent setups. AB - In the past decade, a handful but growing number of groups have reported worldwide successful low intensity focused ultrasound induced neurostimulation trials on rodents. Its effects range from movement elicitations to reduction of anesthesia time or reduction of the duration of drug induced seizures. The mechanisms underlying ultrasonic neuromodulation are still not fully understood. Given the low intensities used in most of the studies, a mechanical effect is more likely to be responsible for the neuromodulation effect, but a clear description of the thermal and mechanical effects is necessary to optimize clinical applications. Based on five studies settings, we calculated the temperature rise and thermal doses in order to evaluate its implication in the neuromodulation phenomenon. Our retrospective analysis shows thermal rise ranging from 0.002 degrees C to 0.8 degrees C in the brain for all setups, except for one setup for which the temperature increase is estimated to be as high as 7 degrees C. We estimate that in the latter case, temperature rise cannot be neglected as a possible cause of neuromodulation. Simulations results were supported by temperature measurements on a mouse with two different sets of parameters. Although the calculated temperature is compatible with the absence of visible thermal lesions on the skin, it is high enough to impact brain circuits. Our study highlights the usefulness of performing thermal simulations prior to experiment in order to fully take into account not only the impact of the peak intensity but also pulse duration and pulse repetition. PMID- 29235454 TI - A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure. AB - Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, a leading cause of blindness. IOP heritability has been estimated to up to 67%, and to date only 11 IOP loci have been reported, accounting for 1.5% of IOP variability. Here, we conduct a genome-wide association study of IOP in 69,756 untreated individuals of European, Latino, Asian, and African ancestry. Multiple longitudinal IOP measurements were collected through electronic health records and, in total, 356,987 measurements were included. We identify 47 genome-wide significant IOP-associated loci (P < 5 * 10-8); of the 40 novel loci, 14 replicate at Bonferroni significance in an external genome-wide association study analysis of 37,930 individuals of European and Asian descent. We further examine their effect on the risk of glaucoma within our discovery sample. Using longitudinal IOP measurements from electronic health records improves our power to identify new variants, which together explain 3.7% of IOP variation. PMID- 29235455 TI - Atmospheric pressure mass spectrometric imaging of live hippocampal tissue slices with subcellular spatial resolution. AB - We report a high spatial resolution mass spectrometry (MS) system that allows us to image live hippocampal tissue slices under open-air atmospheric pressure (AP) and ambient temperature conditions at the subcellular level. The method is based on an efficient desorption process by femtosecond (fs) laser assisted with nanoparticles and a subsequent ionization step by applying nonthermal plasma, termed AP nanoparticle and plasma assisted laser desorption ionization (AP nanoPALDI) MS method. Combining the AP-nanoPALDI with microscopic sample scanning, MS imaging with spatial resolution of 2.9 um was obtained. The observed AP-nanoPALDI MS imaging clearly revealed the differences of molecular composition between the apical and basal dendrite regions of a hippocampal tissue. In addition, the AP-nanoPALDI MS imaging showed the decrease of cholesterol in hippocampus by treating with methyl beta-cyclodextrin, which exemplifies the potential of AP-nanoPALDI for live tissue imaging for various biomedical applications without any chemical pretreatment and/or labeling process. PMID- 29235456 TI - Infection via mosquito bite alters Zika virus tissue tropism and replication kinetics in rhesus macaques. AB - Mouse and nonhuman primate models now serve as useful platforms to study Zika virus (ZIKV) pathogenesis, candidate therapies, and vaccines, but they rely on needle inoculation of virus: the effects of mosquito-borne infection on disease outcome have not been explored in these models. Here we show that infection via mosquito bite delays ZIKV replication to peak viral loads in rhesus macaques. Importantly, in mosquito-infected animals ZIKV tissue distribution was limited to hemolymphatic tissues, female reproductive tract tissues, kidney, and liver, potentially emulating key features of human ZIKV infections, most of which are characterized by mild or asymptomatic disease. Furthermore, deep sequencing analysis reveals that ZIKV populations in mosquito-infected monkeys show greater sequence heterogeneity and lower overall diversity than in needle-inoculated animals. This newly developed system will be valuable for studying ZIKV disease because it more closely mimics human infection by mosquito bite than needle-based inoculations. PMID- 29235458 TI - The ideal harvest time for seeds of hybrid maize (Zea mays L.) XY335 and ZD958 produced in multiple environments. AB - To identify the ideal harvest time (IHT) for the seed production of XY335 and ZD958, six seed-related traits were evaluated in seeds harvested at 11 harvest stages in 8 environments. Standard germination (SG), accelerated aging germination (AAG) and cold test germination (CTG) were vigor traits; hundred-seed weight (HSW) and seed moisture content (SMC) were physiological traits; and >=10 degrees C accumulated temperature from pollination to harvest (AT10ph) was an ecological trait. All the traits were significantly affected by harvest stage. The responses of SG, AAG, CTG and HSW to postponing harvest stage fit quadratic models, while SMC and AT10ph fit linear models. The IHT (indicated by the last date to reach maximum SG, AAG and CTG) were 57.97 DAP and 56.80 DAP for XY335 and ZD958, respectively. SMC and AT10ph at IHT were 33.15% and 1234 degrees C for XY335, and 34.98% and 1226 degrees C for ZD958, respectively. The period to reach the maximum HSW was 5 days later than the IHT. Compared to HSW and SMC, AT10ph had a closer relationship to the seed vigor traits. Together with the fact that AT10ph was less affected by environment, these results suggested that AT10ph may be a novel indicator for determining the IHT. PMID- 29235457 TI - Serum Metabolic Profile Alteration Reveals Response to Platinum-Based Combination Chemotherapy for Lung Cancer: Sensitive Patients Distinguished from Insensitive ones. AB - Most lung cancers are diagnosed at fairly advanced stages due to limited clinical symptoms. Platinum-based chemotherapy, either as single regimen or in combination with radiation, is one of the major recommendations for the patients. Earlier evaluation of the effectiveness of the chemotherapies is critical for developing better treatment plan given the toxicity of the chemotherapeutic reagents. Drug efficacy could be reflected in the systemic metabolism characteristics though knowledge about which remains scarce. In this study, serum metabolism influence of three types of commonly used platinum-based combination chemotherapy regimens, namely cisplatin with gemcitabine, vinorelbine or docetaxel, were studied using pattern recognition coupled with nuclear magnetic resonance techniques. The treated patients were divided into sensitive or insensitive subgroups according to their response to the treatments. We found that insensitive subjects can be identified from the sensitive ones with up-regulation of glucose and taurine but reduced alanine and lactate concentrations in serum. The combination chemotherapy of lung cancer is accompanied by disturbances of multiple metabolic pathways such as energy metabolism, phosphatidylcholine biosynthesis, so that the treated patients were marginally discriminated from the untreated. Serum metabolic profile of patients shows potential as an indicator of their response to platinum based combination chemotherapy. PMID- 29235459 TI - PI3Kdelta activates E2F1 synthesis in response to mRNA translation stress. AB - The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein-Barr virus (EBV)-encoded EBNA1, results in PI3Kdelta-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation. Treatment with a specific PI3Kdelta inhibitor Idelalisib (CAL-101) suppresses E2F1 and c-Myc levels and causes cell death in EBNA1-induced B cell lymphomas. Suppression of PI3Kdelta prevents E2F1 activation also in non-EBV-infected cells. These data illustrate an mRNA translation stress-response pathway for E2F1 activation that is exploited by EBV to promote cell growth and proliferation, offering new strategies to treat EBV carrying cancers. PMID- 29235460 TI - Structural insight into catalytic mechanism of PET hydrolase. AB - PET hydrolase (PETase), which hydrolyzes polyethylene terephthalate (PET) into soluble building blocks, provides an attractive avenue for the bioconversion of plastics. Here we present the structures of a novel PETase from the PET-consuming microbe Ideonella sakaiensis in complex with substrate and product analogs. Through structural analyses, mutagenesis, and activity measurements, a substrate binding mode is proposed, and several features critical for catalysis are elucidated. PMID- 29235461 TI - Oxytocin enhances observational fear in mice. AB - Empathy is fundamental to human relations, but its neural substrates remain largely unknown. Here we characterize the involvement of oxytocin in the capacity of mice to display emotional state-matching, an empathy-like behavior. When exposed to a familiar conspecific demonstrator in distress, an observer mouse becomes fearful, as indicated by a tendency to freeze and subsequent efforts to escape. Both intranasal oxytocin administration and chemogenetic stimulation of oxytocin neurons render males sensitive to the distress of an unfamiliar mouse. Acute intranasal oxytocin penetrates the brain and enhances cellular activity within the anterior cingulate cortex, whereas chronic administration produces long-term facilitation of observational fear and downregulates oxytocin receptor expression in the amygdala. None of these manipulations affect fear acquired as a result of direct experience with the stressor. Hence, these results implicate oxytocin in observational fear in mice (rather than fear itself) and provide new avenues for examining the neural substrates of empathy. PMID- 29235462 TI - Atomic-resolution three-dimensional hydration structures on a heterogeneously charged surface. AB - Local hydration structures at the solid-liquid interface around boundary edges on heterostructures are key to an atomic-level understanding of various physical, chemical and biological processes. Recently, we succeeded in visualising atomic scale three-dimensional hydration structures by using ultra-low noise frequency modulation atomic force microscopy. However, the time-consuming three-dimensional map measurements on uneven heterogeneous surfaces have not been achieved due to experimental difficulties, to the best of our knowledge. Here, we report the local hydration structures formed on a heterogeneously charged phyllosilicate surface using a recently established fast and nondestructive acquisition protocol. We discover intermediate regions formed at step edges of the charged surface. By combining with molecular dynamics simulations, we reveal that the distinct structural hydrations are hard to observe in these regions, unlike the charged surface regions, possibly due to the depletion of ions at the edges. Our methodology and findings could be crucial for the exploration of further functionalities. PMID- 29235463 TI - Exposure to Magnetic Field Non-Ionizing Radiation and the Risk of Miscarriage: A Prospective Cohort Study. AB - Magnetic field (MF) non-ionizing radiation is widespread and everyone is exposed to some degree. This prospective cohort study of 913 pregnant women examined the association between high MF exposure and miscarriage risk. Cox (proportional hazards) regression was used to examine the association. After controlling for multiple other factors, women who were exposed to higher MF levels had 2.72 times the risk of miscarriage (hazard ratio = 2.72, 95% CI: 1.42-5.19) than those with lower MF exposure. The increased risk of miscarriage associated with high MF was consistently observed regardless of the sources of high MF. The association was much stronger if MF was measured on a typical day of participants' pregnancies. The finding also demonstrated that accurate measurement of MF exposure is vital for examining MF health effects. This study provides fresh evidence, directly from a human population, that MF non-ionizing radiation could have adverse biological impacts on human health. PMID- 29235464 TI - SYK kinase mediates brown fat differentiation and activation. AB - Brown adipose tissue (BAT) metabolism influences glucose homeostasis and metabolic health in mice and humans. Sympathetic stimulation of beta-adrenergic receptors in response to cold induces proliferation, differentiation, and UCP1 expression in pre-adipocytes and mature brown adipocytes. Here we show that spleen tyrosine kinase (SYK) is upregulated during brown adipocyte differentiation and activated by beta-adrenergic stimulation. Deletion or inhibition of SYK, a kinase known for its essential roles in the immune system, blocks brown and white pre-adipocyte proliferation and differentiation in vitro, and results in diminished expression of Ucp1 and other genes regulating brown adipocyte function in response to beta-adrenergic stimulation. Adipocyte-specific SYK deletion in mice reduces BAT mass and BAT that developed consisted of SYK expressing brown adipocytes that had escaped homozygous Syk deletion. SYK inhibition in vivo represses beta-agonist-induced thermogenesis and oxygen consumption. These results establish SYK as an essential mediator of brown fat formation and function. PMID- 29235466 TI - Ultrathin graphene oxide-based hollow fiber membranes with brush-like CO2-philic agent for highly efficient CO2 capture. AB - Among the current CO2 capture technologies, membrane gas separation has many inherent advantages over other conventional techniques. However, fabricating gas separation membranes with both high CO2 permeance and high CO2/N2 selectivity, especially under wet conditions, is a challenge. In this study, sub-20-nm thick, layered graphene oxide (GO)-based hollow fiber membranes with grafted, brush-like CO2-philic agent alternating between GO layers are prepared by a facile coating process for highly efficient CO2/N2 separation under wet conditions. Piperazine, as an effective CO2-philic agent, is introduced as a carrier-brush into the GO nanochannels with chemical bonding. The membrane exhibits excellent separation performance under simulated flue gas conditions with CO2 permeance of 1,020 GPU and CO2/N2 selectivity as high as 680, demonstrating its potential for CO2 capture from flue gas. We expect this GO-based membrane structure combined with the facile coating process to facilitate the development of ultrathin GO-based membranes for CO2 capture. PMID- 29235465 TI - Molecular basis of differential 3' splice site sensitivity to anti-tumor drugs targeting U2 snRNP. AB - Several splicing-modulating compounds, including Sudemycins and Spliceostatin A, display anti-tumor properties. Combining transcriptome, bioinformatic and mutagenesis analyses, we delineate sequence determinants of the differential sensitivity of 3' splice sites to these drugs. Sequences 5' from the branch point (BP) region strongly influence drug sensitivity, with additional functional BPs reducing, and BP-like sequences allowing, drug responses. Drug-induced retained introns are typically shorter, displaying higher GC content and weaker polypyrimidine-tracts and BPs. Drug-induced exon skipping preferentially affects shorter alternatively spliced regions with weaker BPs. Remarkably, structurally similar drugs display both common and differential effects on splicing regulation, SSA generally displaying stronger effects on intron retention, and Sudemycins more acute effects on exon skipping. Collectively, our results illustrate how splicing modulation is exquisitely sensitive to the sequence context of 3' splice sites and to small structural differences between drugs. PMID- 29235468 TI - Prognostic impact of gene mutations in myelodysplastic syndromes with ring sideroblasts. PMID- 29235467 TI - In situ functional dissection of RNA cis-regulatory elements by multiplex CRISPR Cas9 genome engineering. AB - RNA regulatory elements (RREs) are an important yet relatively under-explored facet of gene regulation. Deciphering the prevalence and functional impact of this post-transcriptional control layer requires technologies for disrupting RREs without perturbing cellular homeostasis. Here we describe genome-engineering based evaluation of RNA regulatory element activity (GenERA), a clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 platform for in situ high-content functional analysis of RREs. We use GenERA to survey the entire regulatory landscape of a 3'UTR, and apply it in a multiplex fashion to analyse combinatorial interactions between sets of miRNA response elements (MREs), providing strong evidence for cooperative activity. We also employ this technology to probe the functionality of an entire MRE network under cellular homeostasis, and show that high-resolution analysis of the GenERA dataset can be used to extract functional features of MREs. This study provides a genome editing based multiplex strategy for direct functional interrogation of RNA cis regulatory elements in a native cellular environment. PMID- 29235469 TI - Dielectric anomalies and interactions in the three-dimensional quadratic band touching Luttinger semimetal Pr2Ir2O7. AB - Dirac and Weyl semimetals with linearly crossing bands are the focus of much recent interest in condensed matter physics. Although they host fascinating phenomena, their physics can be understood in terms of weakly interacting electrons. In contrast, more than 40 years ago, Abrikosov pointed out that quadratic band touchings are generically strongly interacting. We have performed terahertz spectroscopy on the films of the conducting pyrochlore Pr2Ir2O7, which has been shown to host a quadratic band touching. A dielectric constant as large as [Formula: see text] is observed at low temperatures. In such systems, the dielectric constant is a measure of the relative scale of interactions, which are therefore in our material almost two orders of magnitude larger than the kinetic energy. Despite this, the scattering rate exhibits a T 2 dependence, which shows that for finite doping a Fermi liquid state survives-however, with a scattering rate close to the maximal value allowed. PMID- 29235470 TI - Upregulation of B7-H4 promotes tumor progression of intrahepatic cholangiocarcinoma. AB - Recent reports show that B7-H4 is highly expressed in a variety of tumor cells, functions as a negative regulator of T cells and then promotes tumor progression. However, its expression and role in intrahepatic cholangiocarcinoma (ICC) remain unclear. In present study, B7-H4 expression in ICC and peritumoral tissues was determined at the level of mRNA and protein, and its bioactivity in ICC cells was studied after modification of B7-H4 expression. Then, the mechanism related to tumor progression induced by B7-H4 expression in ICC cells was explored. Finally, clinical significance of B7-H4 expression in ICC patients was further analyzed. The results showed that B7-H4 expression in ICC was much higher than that in peritumoral tissues at the level of both mRNA and protein. The high level of B7 H4 in ICC cells induced epithelial-to-mesenchymal transitions and promoted invasion and metastasis of tumor cells through activation of ERK1/2 signaling. The elevated B7-H4 expression was associated with the downregulated Bax, upregulated Bcl-2 expression, and activation of caspase-3. Clinically, high B7-H4 expression in tumor samples was significantly related to malignant phenotype, such as lymph node metastasis, high tumor stage, and poor differentiation. ICC patients with high expression of B7-H4 had shorter overall survival (OS) and disease-free survival. Moreover, the B7-H4 expression was an independent prognostic factor for predicting OS and tumor recurrence of ICC patients after operation. In conclusion, high expression of B7-H4 promotes tumor progression of ICC and may be a novel therapeutic target for ICC patients. PMID- 29235472 TI - A pH-gated conformational switch regulates the phosphatase activity of bifunctional HisKA-family histidine kinases. AB - Histidine kinases are key regulators in the bacterial two-component systems that mediate the cellular response to environmental changes. The vast majority of the sensor histidine kinases belong to the bifunctional HisKA family, displaying both kinase and phosphatase activities toward their substrates. The molecular mechanisms regulating the opposing activities of these enzymes are not well understood. Through a combined NMR and crystallographic study on the histidine kinase HK853 and its response regulator RR468 from Thermotoga maritima, here we report a pH-mediated conformational switch of HK853 that shuts off its phosphatase activity under acidic conditions. Such a pH-sensing mechanism is further demonstrated in the EnvZ-OmpR two-component system from Salmonella enterica in vitro and in vivo, which directly contributes to the bacterial infectivity. Our finding reveals a broadly conserved mechanism that regulates the phosphatase activity of the largest family of bifunctional histidine kinases in response to the change of environmental pH. PMID- 29235471 TI - CTCF driven TERRA transcription facilitates completion of telomere DNA replication. AB - Telomere repeat DNA forms a nucleo-protein structure that can obstruct chromosomal DNA replication, especially under conditions of replication stress. Transcription of telomere repeats can initiate at subtelomeric CTCF-binding sites to generate telomere repeat-encoding RNA (TERRA), but the role of transcription, CTCF, and TERRA in telomere replication is not known. Here, we have used CRISPR/Cas9 gene editing to mutate CTCF-binding sites at the putative start site of TERRA transcripts for a class of subtelomeres. Under replication stress, telomeres lacking CTCF-driven TERRA exhibit sister-telomere loss and upon entry into mitosis, exhibit the formation of ultra-fine anaphase bridges and micronuclei. Importantly, these phenotypes could be rescued by the forced transcription of TERRA independent of CTCF binding. Our findings indicate that subtelomeric CTCF facilitates telomeric DNA replication by promoting TERRA transcription. Our findings also demonstrate that CTCF-driven TERRA transcription acts in cis to facilitate telomere repeat replication and chromosome stability. PMID- 29235473 TI - Metasurface-assisted phase-matching-free second harmonic generation in lithium niobate waveguides. AB - The phase-matching condition is a key aspect in nonlinear wavelength conversion processes, which requires the momenta of the photons involved in the processes to be conserved. Conventionally, nonlinear phase matching is achieved using either birefringent or periodically poled nonlinear crystals, which requires careful dispersion engineering and is usually narrowband. In recent years, metasurfaces consisting of densely packed arrays of optical antennas have been demonstrated to provide an effective optical momentum to bend light in arbitrary ways. Here, we demonstrate that gradient metasurface structures consisting of phased array antennas are able to circumvent the phase-matching requirement in on-chip nonlinear wavelength conversion. We experimentally demonstrate phase-matching free second harmonic generation over many coherent lengths in thin film lithium niobate waveguides patterned with the gradient metasurfaces. Efficient second harmonic generation in the metasurface-based devices is observed over a wide range of pump wavelengths (lambda = 1580-1650 nm). PMID- 29235474 TI - Engineering cell signaling using tunable CRISPR-Cpf1-based transcription factors. AB - The catalytically dead Cpf1 endonuclease from Acidaminococcus sp. BV3L6 (dAsCpf1) has been used to construct effective transcriptional repressors in bacteria and plants. However, it is still unclear if dAsCpf1 can function in human cells as a transcriptional regulator or a signal conductor. Here, we repurpose the dAsCpf1 system in human cells for a variety of functions, including the activation or repression of gene transcription. Moreover, we construct programmable ligand controlled dAsCpf1 systems either by coupling crRNAs with engineered riboswitches or by fusing dAsCpf1 proteins with G protein-coupled receptors. These generalizable approaches allow us to regulate the transcription of endogenous genes in response to diverse classes of ligands, thus constructing artificial signaling pathways with rewired cellular input-output behaviors. The systems exhibit signal amplification, an important feature in cell signaling, when multiple crRNAs are processed from a single transcript. The results provide a robust and efficient platform for engineering customized cell signaling circuits. PMID- 29235475 TI - Structural and functional dissection of the DH and PH domains of oncogenic Bcr Abl tyrosine kinase. AB - The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To provide a molecular rationale for these observations, we study the Dbl-homology (DH) and Pleckstrin-homology (PH) domains of Bcr-Abl p210, which constitute the only structural differences to p190. Here we report high-resolution structures of the DH and PH domains and characterize conformations of the DH-PH unit in solution. Our structural and functional analyses show no evidence that the DH domain acts as a guanine nucleotide exchange factor, whereas the PH domain binds to various phosphatidylinositol phosphates. PH-domain mutants alter subcellular localization and result in decreased interactions with p210-selective interaction partners. Hence, the PH domain, but not the DH domain, plays an important role in the formation of the differential p210 and p190 Bcr-Abl signaling networks. PMID- 29235476 TI - Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7. AB - Metastasis is the main cause of death in cancer patients. TGF-beta is pro metastatic for malignant cancer cells. Here we report a loss-of-function screen in mice with metastasis as readout and identify OTUD1 as a metastasis-repressing factor. OTUD1-silenced cancer cells show mesenchymal and stem-cell-like characteristics. Further investigation reveals that OTUD1 directly deubiquitinates the TGF-beta pathway inhibitor SMAD7 and prevents its degradation. Moreover, OTUD1 cleaves Lysine 33-linked poly-ubiquitin chains of SMAD7 Lysine 220, which exposes the SMAD7 PY motif, enabling SMURF2 binding and subsequent TbetaRI turnover at the cell surface. Importantly, OTUD1 is lost in multiple types of human cancers and loss of OTUD1 increases metastasis in intracardial xenograft and orthotopic transplantation models, and correlates with poor prognosis among breast cancer patients. High levels of OTUD1 inhibit cancer stemness and shut off metastasis. Thus, OTUD1 represses breast cancer metastasis by mitigating TGF-beta-induced pro-oncogenic responses via deubiquitination of SMAD7. PMID- 29235477 TI - Nucleotide- and Mal3-dependent changes in fission yeast microtubules suggest a structural plasticity view of dynamics. AB - Using cryo-electron microscopy, we characterize the architecture of microtubules assembled from Schizosaccharomyces pombe tubulin, in the presence and absence of their regulatory partner Mal3. Cryo-electron tomography reveals that microtubules assembled from S. pombe tubulin have predominantly B-lattice interprotofilament contacts, with protofilaments skewed around the microtubule axis. Copolymerization with Mal3 favors 13 protofilament microtubules with reduced protofilament skew, indicating that Mal3 adjusts interprotofilament interfaces. A 4.6-A resolution structure of microtubule-bound Mal3 shows that Mal3 makes a distinctive footprint on the S. pombe microtubule lattice and that unlike mammalian microtubules, S. pombe microtubules do not show the longitudinal lattice compaction associated with EB protein binding and GTP hydrolysis. Our results firmly support a structural plasticity view of microtubule dynamics in which microtubule lattice conformation is sensitive to a variety of effectors and differently so for different tubulins. PMID- 29235478 TI - Sexual recombination and increased mutation rate expedite evolution of Escherichia coli in varied fitness landscapes. AB - Sexual recombination and mutation rate are theorized to play different roles in adaptive evolution depending on the fitness landscape; however, direct experimental support is limited. Here we examine how these factors affect the rate of adaptation utilizing a "genderless" strain of Escherichia coli capable of continuous in situ sexual recombination. The results show that the populations with increased mutation rate, and capable of sexual recombination, outperform all the other populations. We further characterize two sexual and two asexual populations with increased mutation rate and observe maintenance of beneficial mutations in the sexual populations through mutational sweeps. Furthermore, we experimentally identify the molecular signature of a mating event within the sexual population that combines two beneficial mutations to generate a fitter progeny; this evidence suggests that the recombination event partially alleviates clonal interference. We present additional data suggesting that stochasticity plays an important role in the combinations of mutations observed. PMID- 29235479 TI - Dynamic cortical representations of perceptual filling-in for missing acoustic rhythm. AB - In the phenomenon of perceptual filling-in, missing sensory information can be reconstructed via interpolation or extrapolation from adjacent contextual cues by what is necessarily an endogenous, not yet well understood, neural process. In this investigation, sound stimuli were chosen to allow observation of fixed cortical oscillations driven by contextual (but missing) sensory input, thus entirely reflecting endogenous neural activity. The stimulus employed was a 5 Hz frequency-modulated tone, with brief masker probes (noise bursts) occasionally added. For half the probes, the rhythmic frequency modulation was moreover removed. Listeners reported whether the tone masked by each probe was perceived as being rhythmic or not. Time-frequency analysis of neural responses obtained by magnetoencephalography (MEG) shows that for maskers without the underlying acoustic rhythm, trials where rhythm was nonetheless perceived show higher evoked sustained rhythmic power than trials for which no rhythm was reported. The results support a model in which perceptual filling-in is aided by differential co-modulations of cortical activity at rates directly relevant to human speech communication. We propose that the presence of rhythmically-modulated neural dynamics predicts the subjective experience of a rhythmically modulated sound in real time, even when the perceptual experience is not supported by corresponding sensory data. PMID- 29235480 TI - Vocal learning promotes patterned inhibitory connectivity. AB - Skill learning is instantiated by changes to functional connectivity within premotor circuits, but whether the specificity of learning depends on structured changes to inhibitory circuitry remains unclear. We used slice electrophysiology to measure connectivity changes associated with song learning in the avian analog of primary motor cortex (robust nucleus of the arcopallium, RA) in Bengalese Finches. Before song learning, fast-spiking interneurons (FSIs) densely innervated glutamatergic projection neurons (PNs) with apparently random connectivity. After learning, there was a profound reduction in the overall strength and number of inhibitory connections, but this was accompanied by a more than two-fold enrichment in reciprocal FSI-PN connections. Moreover, in singing birds, we found that pharmacological manipulations of RA's inhibitory circuitry drove large shifts in learned vocal features, such as pitch and amplitude, without grossly disrupting the song. Our results indicate that skill learning establishes nonrandom inhibitory connectivity, and implicates this patterning in encoding specific features of learned movements. PMID- 29235482 TI - Ratiometric fluorescence imaging of cell surface pH by poly(ethylene glycol) phospholipid conjugated with fluorescein isothiocyanate. AB - Various physiological and pathological processes are accompanied with the alteration of pH at extracellular juxtamembrane region. Accordingly, the methods to analyze the cell surface pH have been demanded in biological and medical sciences. In this study, we have established a novel methodology for cell surface pH imaging using poly(ethylene glycol)-phospholipid (PEG-lipid) as a core structure of ratiometric fluorescent probes. PEG-lipid is a synthetic amphiphilic polymer originally developed for the cell surface modification in transplantation therapy. Via its hydrophobic alkyl chains of the phospholipid moiety, PEG-lipid is, when applied extracellularly, spontaneously inserted into the plasma membrane and retained at the surface of the cells. We have demonstrated that the PEG-lipid conjugated with fluorescein isothiocyanate (FITC-PEG-lipid) can be used as a sensitive and reversible cell-surface-anchored pH probe between weakly alkaline and acidic pH with an excellent spatiotemporal resolution. The remarkably simple procedure for cell-surface labeling with FITC-PEG-lipid would also be advantageous when considering its application to high-throughput in vitro assay. This study further indicates that various probes useful for the investigation of juxtamembrane environments could also be developed by using PEG-lipid as the core structure for bio-membrane anchoring. PMID- 29235484 TI - Paper-based MoS2 nanosheet-mediated FRET aptasensor for rapid malaria diagnosis. AB - There has been growing interest in the development of paper-based biosensors because their simplicity and low cost are attractive for point-of-care diagnosis, especially in low-resource areas. However, only a limited range of paper materials - primarily chromatography papers - have been incorporated into diagnostics thus far. Here, we investigate the performance of different types of paper in order to develop an aptamer- and MoS2 nanosheet-based sensor relying on fluorescence resonance energy transfer (FRET) to signal the presence of a target protein. An aptamer which binds to a malarial biomarker, Plasmodium lactate dehydrogenase (pLDH), is chosen for this study, as point-of-care diagnostics would be especially advantageous in low-resource areas, such as those where malaria is prevalent. We observe that of all papers tested, a measurable and specific fluorescence recovery can only be produced on the sensor created with printer paper, while no significant fluorescence recovery is generated on sensors made from other types of paper, including chromatography, lens, and filter papers. Therefore, our findings demonstrate the importance of careful material selection for the development of a paper-based diagnostic test, and suggest that commercially-available products such as printer paper may serve as viable materials to develop cost-effective and simple diagnostics. PMID- 29235485 TI - Quantification of interacting cognate odorants with olfactory receptors in nanovesicles. AB - This study aims to improve our understanding of the interaction between olfactory receptors and odorants to develop highly selective biosensing devices. Natural nanovesicles (NVs) from Saccharomyces cerevisiae, ~100 nm in diameter, carrying either the human OR17-40 or the chimpanzee OR7D4 olfactory receptor (OR) tagged with the c-myc epitope at their N-terminus, are presented as model systems to quantify the interaction between odorant and olfactory receptors. The level of expression of olfactory receptors was determined at individual NVs using a novel competitive ELISA immunoassay comparing the values obtained against those from techniques involving the solubilization of cell membrane proteins and the identification of c-myc-carrying receptors. Surface Plasmon Resonance (SPR) measurements on L1 Biacore chips indicate that cognate odorants bind to their Ors, thereby quantifying the approximate number of odorants that interact with a given olfactory receptor. The selectivity of OR17-40-carrying NVs towards helional and OR7D4-carrying NVs towards androstenone has been proven in cross check experiments with non-specific odorant molecules (heptanal and pentadecalactone, respectively) and in control receptors. PMID- 29235483 TI - A novel type I cystatin of parasite origin with atypical legumain-binding domain. AB - Parasite inhibitors of cysteine peptidases are known to influence a vast range of processes linked to a degradation of either the parasites' own proteins or proteins native to their hosts. We characterise a novel type I cystatin (stefin) found in a sanguinivorous fish parasite Eudiplozoon nipponicum (Platyhelminthes: Monogenea). We have identified a transcript of its coding gene in the transcriptome of adult worms. Its amino acid sequence is similar to other stefins except for containing a legumain-binding domain, which is in this type of cystatins rather unusual. As expected, the recombinant form of E. nipponicum stefin (rEnStef) produced in Escherichia coli inhibits clan CA peptidases - cathepsins L and B of the worm - via the standard papain-binding domain. It also blocks haemoglobinolysis by cysteine peptidases in the worm's excretory-secretory products and soluble extracts. Furthermore, we had confirmed its ability to inhibit clan CD asparaginyl endopeptidase (legumain). The presence of a native EnStef in the excretory-secretory products of adult worms, detected by mass spectrometry, suggests that this protein has an important biological function at the host-parasite interface. We discuss the inhibitor's possible role in the regulation of blood digestion, modulation of antigen presentation, and in the regeneration of host tissues. PMID- 29235481 TI - Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. AB - Effective therapy of acute myeloid leukemia (AML) remains an unmet need. DNA methylcytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML. Through a series of data analysis and drug screening, we identified two compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5-hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML), including AML carrying t(11q23)/MLL-rearrangements and t(8;21) AML. NSC-311068 and especially NSC-370284 significantly repressed TET1-high AML progression in vivo. UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold. NSC-370284 and UC-514321 both directly target STAT3/5, transcriptional activators of TET1, and thus repress TET1 expression. They also exhibit strong synergistic effects with standard chemotherapy. Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment. PMID- 29235486 TI - Free-Breathing 3D Liver Perfusion Quantification Using a Dual-Input Two Compartment Model. AB - The purpose of this study is to test the feasibility of applying a dual-input two compartment liver perfusion model to patients with different pathologies. A total of 7 healthy subjects and 11 patients with focal liver lesions, including 6 patients with metastatic adenocarcinoma and 5 with hepatocellular carcinoma (HCC), were examined. Liver perfusion values were measured from both focal liver lesions and cirrhotic tissues (from the 5 HCC patients). Compared to results from volunteer livers, significantly higher arterial fraction, fractional volume of the interstitial space, and lower permeability-surface area product were observed for metastatic lesions, and significantly higher arterial fraction and lower vascular transit time were observed for HCCs (P < 0.05). Significantly lower arterial fraction and higher vascular transit time, fractional volume of the vascular space, and fractional volume of the interstitial space were observed for metastases in comparison to HCCs (P < 0.05). For cirrhotic livers, a significantly lower total perfusion, lower fractional volume of the vascular space, higher fractional volume of the interstitial space, and lower permeability surface area product were noted in comparison to volunteer livers (P < 0.05). Our findings support the possibility of using this model with 3D free-breathing acquisitions for lesion and diffuse liver disease characterization. PMID- 29235487 TI - Long-term nitrogen addition affects the phylogenetic turnover of soil microbial community responding to moisture pulse. AB - How press disturbance (long-term) influences the phylogenetic turnover of soil microbial communities responding to pulse disturbances (short-term) is not fully known. Understanding the complex connections between the history of environmental conditions, assembly processes and microbial community dynamics is necessary to predict microbial response to perturbation. We started by investigating phylogenetic spatial turnover (based on DNA) of soil prokaryotic communities after long-term nitrogen (N) deposition and temporal turnover (based on RNA) of communities responding to pulse by conducting short-term rewetting experiments. The results showed that moderate N addition increased ecological stochasticity and phylogenetic diversity. In contrast, high N addition slightly increased homogeneous selection and decreased phylogenetic diversity. Examining the system with higher phylogenetic resolution revealed a moderate contribution of variable selection across the whole N gradient. The moisture pulse experiment showed that high N soils had higher rates of phylogenetic turnover across short phylogenetic distances and significant changes in community compositions through time. Long term N input history influenced spatial turnover of microbial communities, but the dominant community assembly mechanisms differed across different N deposition gradients. We further revealed an interaction between press and pulse disturbances whereby deterministic processes were particularly important following pulse disturbances in high N soils. PMID- 29235488 TI - Nomogram for cirrhosis in patients with chronic hepatitis B: A simple self assessed scale for individual risk of cirrhosis. AB - The aim of this retrospective study was to establish a simple self-assessed scale for individual risk of cirrhosis in patients with chronic hepatitis B. A total of 1808 consecutive patients were enrolled and analyzed. According to the results of multivariate logistic regression analysis, a simple nomogram was calculated for cirrhosis. The area under receiver operating characteristic curves (AUROCs) were calculated to compare the diagnostic accuracy of nomogram with aspartate aminotransferase to platelet ratio index (APRI), fibrosis index based on the four factors (FIB-4), and S index. The AUROCs of nomogram for cirrhosis were 0.807 (adjusted AUROC 0.876) in model group and 0.794 (adjusted AUROC0.866) in validation group. DeLong's test and Brier Score further demonstrated that nomogram was superior to APRI, FIB-4 and S index in both model group and validation group. The patients with nomogram <0.07 could be defined as low risk group with cirrhosis prevalence lower than 4.3% (17/397). The patients with nomogram >0.52 could be defined as high risk group with cirrhosis prevalence higher than 73.0% (119/163). In conclusion, as a self-assessed style, simple, non invasive, economical, convenient, and repeatable scale, nomogram is suitable to serve as a massive health screening tool for cirrhosis in CHB patients and further external validation is needed. PMID- 29235489 TI - The Zn12O12 cluster-assembled nanowires as a highly sensitive and selective gas sensor for NO and NO2. AB - Motivated by the recent realization of cluster-assembled nanomaterials as gas sensors, first-principles calculations are carried out to explore the stability and electronic properties of Zn12O12 cluster-assembled nanowires and the adsorption behaviors of environmental gases on the Zn12O12-based nanowires, including CO, NO, NO2, SO2, NH3, CH4, CO2, O2 and H2. Our results indicate that the ultrathin Zn12O12 cluster-assembled nanowires are particularly thermodynamic stable at room temperature. The CO, NO, NO2, SO2, and NH3 molecules are all chemisorbed on the Zn12O12-based nanowires with reasonable adsorption energies, but CH4, CO2, O2 and H2 molecules are only physically adsorbed on the nanowire. The electronic properties of the Zn12O12-based nanowire present dramatic changes after the adsorption of the NO and NO2 molecules, especially their electric conductivity and magnetic properties, however, the other molecules adsorption hardly change the electric conductivity of the nanowire. Meanwhile, the recovery time of the nanowire sensor at T = 300 K is estimated at 1.5 MUs and 16.7 MUs for NO and NO2 molecules, respectively. Furthermore, the sensitivities of NO and NO2 are much larger than that of the other molecules. Our results thus conclude that the Zn12O12-based nanowire is a potential candidate for gas sensors with highly sensitivity for NO and NO2. PMID- 29235491 TI - Full-scale experimental investigation of deposition and corrosion of pre protector and 3rd superheater in a waste incineration plant. AB - Municipal solid waste (MSW) incineration is widely adopted as a waste management strategy and for the energy production. However, this technology experience grave deposition and corrosion of the boiler tubes due to high chlorine (~1.09wt.%) and alkali metal (Na, K) content in MSW. Little is known about the concentration profile of these corrosive elements in the deposits at different boiler locations. Therefore, a full-scale experimental investigation was conducted to determine the concentration profile of Cl, K, Na, S, and Ca in the deposits at pre-protector and compare with those at 3rd superheater during MSW combustion at a 36 MWe waste incineration plant (WIP) in Chengdu, China. The deposit samples were analyzed using wet chemical techniques, scanning electron microscope coupled with energy dispersive spectroscopy (SEM/EDS), and X-ray diffraction (XRD). The concentrations of Na, K, and Cl were high in the deposits at pre-protector while S and Ca concentrations were high on the 3rd superheater. The pre-protector was severely corroded than the 3rd superheater. The governing mechanisms for the deposition and corrosion on these boiler locations were elucidated. PMID- 29235490 TI - Fibroblasts play a potential role in bone destruction via osteopontin related caldesmon expression and polymerization in human non-functioning pituitary adenomas. AB - Non-functioning pituitary adenomas (NFPAs) are the most frequent pituitary tumors. The elucidation of the mechanisms of aggressive NFPAs in bone destruction is required in order to guide the clinical diagnosis and treatment of NFPAs. In the present study, we investigated the differential proteomics of fibroblasts isolated from clinical specimens of NFPAs with or without bone destruction. Proteomic analysis revealed a group of molecules associated with cytoskeleton organization, including caldesmon, were differentially expressed between fibroblasts isolated from bone destruction NFPAs (BD-NFPAs) and fibroblasts isolated from non-bone destruction NFPAs (NBD-NFPAs). The secreted proteins analysis found that osteopontin was significantly upregulated in BD-NFPAs fibroblasts. Furthermore, immunohistochemical staining of the NFPAs clinical samples showed that the expression of caldesmon in stromal cells and the expression of osteopontin in both tumor cells and stroma were significantly increased in BD-NFPAs. Taken together, our results indicate a possible way that osteopontin secreted from both NFPA cells and surrounding fibroblasts modify caldesmon expression and polymerization in fibroblasts, which may contribute to bone destruction in NFPA patients. PMID- 29235492 TI - Proteome-wide Analysis of Lysine 2-hydroxyisobutyrylation in Developing Rice (Oryza sativa) Seeds. AB - Lysine 2-hydroxyisobutyrylation is a recently identified protein post translational modification that is known to affect the association between histone and DNA. However, non-histone protein lysine 2-hydroxyisobutyrylation remains largely unexplored. Utilizing antibody-based affinity enrichment and nano HPLC/MS/MS analyses of 2-hydroxyisobutyrylation peptides, we efficaciously identified 9,916 2-hydroxyisobutyryl lysine sites on 2,512 proteins in developing rice seeds, representing the first lysine 2-hydroxyisobutyrylome dataset in plants. Functional annotation analyses indicated that a wide variety of vital biological processes were preferably targeted by lysine 2-hydroxyisobutyrylation, including glycolysis/gluconeogenesis, TCA cycle, starch biosynthesis, lipid metabolism, protein biosynthesis and processing. Our finding showed that 2 hydroxyisobutyrylated histone sites were conserved across plants, human, and mouse. A number of 2-hydroxyisobutyryl sites were shared with other lysine acylations in both histone and non-histone proteins. Comprehensive analysis of the lysine 2-hydroxyisobutyrylation sites illustrated that the modification sites were highly sequence specific with distinct motifs, and they had less surface accessibility than other lysine residues in the protein. Overall, our study provides the first systematic analysis of lysine 2-hydroxyisobutyrylation proteome in plants, and it serves as an important resource for future investigations of the regulatory mechanisms and functions of lysine 2 hydroxyisobutyrylation. PMID- 29235493 TI - Small molecules related to adrenomedullin reduce tumor burden in a mouse model of colitis-associated colon cancer. AB - To investigate the contribution of adrenomedullin (AM) and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), to the progression and potential treatment of colon cancer we studied the effects of four small molecules (SM) related to AM and PAMP on a mouse model of colon cancer. For each SM, four experimental groups of male mice were used: (i) Control group; (ii) SM group; (iii) DSS group (injected with azoxymethane [AOM] and drank dextran sulfate sodium [DSS]); and (iv) DSS + SM group (treated with AOM, DSS, and the SM). None of the mice in groups i and ii developed tumors, whereas all mice in groups iii and iv developed colon neoplasias. No significant differences were found among mice treated with PAMP modulators (87877 and 106221). Mice that received the AM negative modulator, 16311, had worse colitis symptoms than their control counterparts, whereas mice injected with the AM positive modulator, 145425, had a lower number of tumors than their controls. SM 145425 regulated the expression of proliferation marker Lgr5 and had an impact on microbiota, preventing the DSS-elicited increase of the Bacteroides/Prevotella ratio. These results suggest that treatment with AM or with positive modulator SMs may represent a novel strategy for colon cancer. PMID- 29235494 TI - Molecular cloning and expression analysis of two key genes, HDS and HDR, in the MEP pathway in Pyropia haitanensis. AB - The 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate synthase (HDS) gene and the 1 hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate reductase (HDR) gene are two important genes in the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway. In this study, we reported the isolation and characterization of full-length HDS (MF101802) and HDR (MF159558) from Pyropia haitanensis. Characteristics of 3-D structures of the PhHDS and PhHDR proteins were analysed respectively. The results showed that the full-length cDNA of PhHDS, which is 1801 bp long, contained a 1455 bp open reading frame (ORF) encoding a putative 484 amino acid residue protein with a predicted molecular mass of 51.60 kDa. Meanwhile, the full length cDNA of PhHDR was 1668 bp and contained a 1434 bp ORF encoding a putative 477 amino acid 2 residue protein with a predicted molecular mass of 51.49 kDa. The expression levels of the two genes were higher in conchocelis than that in leafy thallus. Additionally, the expression levels could be influenced by light, temperature and salinity and induced by methyl jasmonate (MJ) and salicylic acid (SA). This study contributed to our in-depth understanding of the roles of PhHDS and PhHDR in terpenoid biosynthesis in Pyropia haitanensis and the regulation of the two genes by external environments. PMID- 29235495 TI - Identification of nonsense-mediated mRNA decay pathway as a critical regulator of p53 isoform beta. AB - Human TP53 gene encodes the tumor suppressor p53 and, via alternative splicing, the p53beta and gamma isoforms. Numerous studies have shown that p53beta/gamma can modulate p53 functions and are critically involved in regulation of cellular response to stress conditions. However, it is not fully understood how the beta and gamma isoforms are regulated following splicing. Using gene targeting and RNAi, we showed that depletion of the nonsense-mediated mRNA decay (NMD) factor SMG7 or UPF1 significantly induced p53beta but had minimal effect on p53gamma. Sequence analysis reveals the presence of unique features - key hallmarks of NMD targets in the p53beta transcript, which was further confirmed in NMD reporter gene assays. By manipulating splicing components, we found that NMD activities are crucial to control p53beta levels under conditions that favor its splicing. Our data demonstrate that the NMD and alternative splicing pathways regulate p53beta in a synergistic manner, and NMD plays a critical role in the determination of the p53beta following its splicing. As aberrant p53beta expression and dysfunctional NMD are both implicated in cancers, our studies may provide a novel insight into the regulation of p53beta in tumorigenic settings. PMID- 29235496 TI - Involvement of TRPM2 and TRPV1 channels on hyperalgesia, apoptosis and oxidative stress in rat fibromyalgia model: Protective role of selenium. AB - Fibromyalgia (FM) results in pain characterized by low selenium (Se) levels, excessive Ca2+ influx, reactive oxygen species (ROS) production, and acidic pH. TRPM2 and TRPV1 are activated by ROS and acid; nevertheless, their roles have not been elucidated in FM. Therefore, we investigated the contribution of TRPM2 and TRPV1 to pain, oxidative stress, and apoptosis in a rat model of FM and the therapeutic potential of Se. Thirty-six rats were divided into four groups: control, Se, FM, and FM + Se. The Se treatment reduced the FM-induced increase in TRPM2 and TRPV1 currents, pain intensity, intracellular free Ca2+, ROS, and mitochondrial membrane depolarization in the sciatic (SciN) and dorsal root ganglion (DRGN) neurons. Furthermore, Se treatment attenuated the FM-induced decrease in cell viability in the DRGN and SciN, glutathione peroxidase, and reduced glutathione and alpha-tocopherol values in the DRGN, SciN, brain, muscle, and plasma; however, lipid peroxidation levels were decreased. Se also attenuated PARP1, caspase 3, and 9 expressions in the SciN, DRGN, and muscle. In conclusion, Se treatment decreased the FM-induced increase in hyperalgesia, ROS, apoptosis, and Ca2+ entry through TRPM2 and TRPV1 in the SciN and DRGN. Our findings may be relevant to the elucidation and treatment of FM. PMID- 29235498 TI - Computational exploration of the chemical structure space of possible reverse tricarboxylic acid cycle constituents. AB - The reverse tricarboxylic acid (rTCA) cycle has been explored from various standpoints as an idealized primordial metabolic cycle. Its simplicity and apparent ubiquity in diverse organisms across the tree of life have been used to argue for its antiquity and its optimality. In 2000 it was proposed that chemoinformatics approaches support some of these views. Specifically, defined queries of the Beilstein database showed that the molecules of the rTCA are heavily represented in such compound databases. We explore here the chemical structure "space," e.g. the set of organic compounds which possesses some minimal set of defining characteristics, of the rTCA cycle's intermediates using an exhaustive structure generation method. The rTCA's chemical space as defined by the original criteria and explored by our method is some six to seven times larger than originally considered. Acknowledging that each assumption in what is a defining criterion making the rTCA cycle special limits possible generative outcomes, there are many unrealized compounds which fulfill these criteria. That these compounds are unrealized could be due to evolutionary frozen accidents or optimization, though this optimization may also be for systems-level reasons, e.g., the way the pathway and its elements interface with other aspects of metabolism. PMID- 29235497 TI - Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage. AB - Higher stages of central auditory processing compensate for a loss of cochlear nerve synapses by increasing the gain on remaining afferent inputs, thereby restoring firing rate codes for rudimentary sound features. The benefits of this compensatory plasticity are limited, as the recovery of precise temporal coding is comparatively modest. We reasoned that persistent temporal coding deficits could be ameliorated through modulation of voltage-gated potassium (Kv) channels that regulate temporal firing patterns. Here, we characterize AUT00063, a pharmacological compound that modulates Kv3.1, a high-threshold channel expressed in fast-spiking neurons throughout the central auditory pathway. Patch clamp recordings from auditory brainstem neurons and in silico modeling revealed that application of AUT00063 reduced action potential timing variability and improved temporal coding precision. Systemic injections of AUT00063 in vivo improved auditory synchronization and supported more accurate decoding of temporal sound features in the inferior colliculus and auditory cortex in adult mice with a near complete loss of auditory nerve afferent synapses in the contralateral ear. These findings suggest modulating Kv3.1 in central neurons could be a promising therapeutic approach to mitigate temporal processing deficits that commonly accompany aging, tinnitus, ototoxic drug exposure or noise damage. PMID- 29235499 TI - Relation between Fractal Inhomogeneity and In/Nb-Arrangement in Pb(In1/2Nb1/2)O3. AB - Relaxor ferroelectrics show substantial responses to electric fields. The key difference from normal ferroelectrics is a temperature-dependent inhomogeneous structure and its dynamics. The lead-based complex perovskite Pb(In1/2Nb1/2)O3 is an intriguing system in which the inhomogeneous structure can be controlled by thermal treatment. Herein, we report investigations of the phase transitions in single crystals of Pb(In1/2Nb1/2)O3 via changing the degree of randomness in which In and Nb occupy the B site of the ABO3 perovskite structure. We studied the dynamic properties of the structure using inelastic light scattering and the static properties using diffuse X-ray scattering. These properties depend on the degree of randomness with which the B site is occupied. When the distribution of occupied In/Nb sites is regular, the antiferroelectric phase is stabilised by a change in the collective transverse-acoustic wave, which suppresses long-range ferroelectric order and the growth of the inhomogeneous structure. However, when the B site is occupied randomly, a fractal structure grows as the temperature decreases below T *~475 K, and nanosized ferroelectric domains are produced by the percolation of self-similar and static polar nanoregions. PMID- 29235501 TI - Room-Temperature Performance of Poly(Ethylene Ether Carbonate)-Based Solid Polymer Electrolytes for All-Solid-State Lithium Batteries. AB - Amorphous poly(ethylene ether carbonate) (PEEC), which is a copolymer of ethylene oxide and ethylene carbonate, was synthesized by ring-opening polymerization of ethylene carbonate. This route overcame the common issue of low conductivity of poly(ethylene oxide)(PEO)-based solid polymer electrolytes at low temperatures, and thus the solid polymer electrolyte could be successfully employed at the room temperature. Introducing the ethylene carbonate units into PEEC improved the ionic conductivity, electrochemical stability and lithium transference number compared with PEO. A cross-linked solid polymer electrolyte was synthesized by photo cross-linking reaction using PEEC and tetraethyleneglycol diacrylate as a cross-linking agent, in the form of a flexible thin film. The solid-state Li/LiNi0.6Co0.2Mn0.2O2 cell assembled with solid polymer electrolyte based on cross-linked PEEC delivered a high initial discharge capacity of 141.4 mAh g-1 and exhibited good capacity retention at room temperature. These results demonstrate the feasibility of using this solid polymer electrolyte in all-solid state lithium batteries that can operate at ambient temperatures. PMID- 29235500 TI - The development of spontaneous facial responses to others' emotions in infancy: An EMG study. AB - Viewing facial expressions often evokes facial responses in the observer. These spontaneous facial reactions (SFRs) are believed to play an important role for social interactions. However, their developmental trajectory and the underlying neurocognitive mechanisms are still little understood. In the current study, 4- and 7-month old infants were presented with facial expressions of happiness, anger, and fear. Electromyography (EMG) was used to measure activation in muscles relevant for forming these expressions: zygomaticus major (smiling), corrugator supercilii (frowning), and frontalis (forehead raising). The results indicated no selective activation of the facial muscles for the expressions in 4-month-old infants. For 7-month-old infants, evidence for selective facial reactions was found especially for happy (leading to increased zygomaticus major activation) and fearful faces (leading to increased frontalis activation), while angry faces did not show a clear differential response. These results suggest that emotional SFRs may be the result of complex neurocognitive mechanisms which lead to partial mimicry but are also likely to be influenced by evaluative processes. Such mechanisms seem to undergo important developments at least until the second half of the first year of life. PMID- 29235502 TI - Stress-induced release of the S100A8/A9 alarmin is elevated in coronary artery disease patients with impaired cortisol response. AB - Psychological stress is thought to be an important trigger of cardiovascular events, yet the involved pathways and mediators are largely unknown. Elevated systemic levels of the pro-inflammatory alarmin S100A8/A9 correlate with poor prognosis in coronary artery disease (CAD) patients. Here, we investigated the links between S100A8/A9 release and parameters of anti-inflammatory glucocorticoid secretion in two different cohorts subjected to a psychological stress test. In the first cohort of 60 CAD patients, psychological stress induced a rapid increase of circulating S100A8/A9. This rapid S100A8/A9 response strongly correlated with elevated evening saliva cortisol levels, suggesting an association with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. In the second cohort of 27 CAD patients and 28 controls, elevated S100A8/A9 levels were still detectable 24 h after stress in 40% of patients and 36% of controls, with a tendency for higher levels in patients. The sustained S100A8/A9 response was associated with a poor rapid cortisol release after stress in patients, but not in the control group. Our findings reveal for the first time that acute psychological stress induces elevated levels of S100A8/A9. We also provide hypothesis-generating evidence that dysregulated cortisol secretion in CAD patients might be associated with an exaggerated pro-inflammatory S100A8/A9 response. PMID- 29235503 TI - Inactivation of the dnaK gene in Clostridium difficile 630 Deltaerm yields a temperature-sensitive phenotype and increases biofilm-forming ability. AB - Clostridium difficile infection is a growing problem in healthcare settings worldwide and results in a considerable socioeconomic impact. New hypervirulent strains and acquisition of antibiotic resistance exacerbates pathogenesis; however, the survival strategy of C. difficile in the challenging gut environment still remains incompletely understood. We previously reported that clinically relevant heat-stress (37-41 degrees C) resulted in a classical heat-stress response with up-regulation of cellular chaperones. We used ClosTron to construct an insertional mutation in the dnaK gene of C. difficile 630 Deltaerm. The dnaK mutant exhibited temperature sensitivity, grew more slowly than C. difficile 630 Deltaerm and was less thermotolerant. Furthermore, the mutant was non-motile, had 4-fold lower expression of the fliC gene and lacked flagella on the cell surface. Mutant cells were some 50% longer than parental strain cells, and at optimal growth temperatures, they exhibited a 4-fold increase in the expression of class I chaperone genes including GroEL and GroES. Increased chaperone expression, in addition to the non-flagellated phenotype of the mutant, may account for the increased biofilm formation observed. Overall, the phenotype resulting from dnaK disruption is more akin to that observed in Escherichia coli dnaK mutants, rather than those in the Gram-positive model organism Bacillus subtilis. PMID- 29235504 TI - The beta-fibrinogen gene 455G/A polymorphism associated with cardioembolic stroke in atrial fibrillation with low CHA2DS2-VaSc score. AB - Previous work has suggested that ischemic stroke (IS) may be more likely to occur in individuals with a genetic predisposition. In this study, we investigated the potential association of IS-relevant genetic risk factors with cardioembolic stroke (CES) in atrial fibrillation (AF) patients with low CHA2DS2-VaSc score. Genotyping was performed using the GenomeLab SNPstream genotyping platform for five IS-relevant SNPs (MMP-9 C1562T, ALOX5AP SG13S114A/T, MTHFR 677 C/T, FGB 455 G/A, and eNOS G298A) in 479 AF patients with CES and 580 age and sex-matched AF patients without CES. The multivariate analysis adjusted for potential confounders and demonstrated that FGB 455 G/A was independently associated with increased risk of CES in AF patients and the significance remained after Bonferroni correction in the additive, dominant, and recessive models with ORs of 1.548 (95% CI: 1.251-1.915, P = 0.001), 1.588 (95% CI: (1.226-2.057, P = 0.003), and 2.394 (95% CI: 1.357-4.223, P = 0.015), respectively. Plasma fibrinogen levels were significantly higher in patients with the A allele compared with patients with genotype of GG (3.29 +/- 0.38 mg/dl vs. 2.87 +/- 0.18 mg/dl, P < 0.001). We found for the first time that the A allele of FGB 455 G/A was a risk factor for CES in AF patients, probably by elevating the level of plasma fibrinogen. PMID- 29235505 TI - Comprehensive analysis of the catalytic and structural properties of a mu-class glutathione s-transferase from Fasciola gigantica. AB - Glutathione S-transferases (GSTs) play an important role in the detoxification of xenobiotics. They catalyze the nucleophilic addition of glutathione (GSH) to nonpolar compounds, rendering the products water-soluble. In the present study, we investigated the catalytic and structural properties of a mu-class GST from Fasciola gigantica (FgGST1). The purified recombinant FgGST1 formed a homodimer composed of 25 kDa subunit. Kinetic analysis revealed that FgGST1 displays broad substrate specificity and shows high GSH conjugation activity toward 1-chloro-2,4 dinitrobenzene, 4-nitroquinoline-1-oxide, and trans-4-phenyl-3-butene-2-one and peroxidase activity towards trans-2-nonenal and hexa-2,4-dienal. The FgGST1 was highly sensitive to inhibition by cibacron blue. The cofactor (GSH) and inhibitor (cibacron blue) were docked, and binding sites were identified. The molecular dynamics studies and principal component analysis indicated the stability of the systems and the collective motions, respectively. Unfolding studies suggest that FgGST1 is a highly cooperative molecule because, during GdnHCl-induced denaturation, a simultaneous unfolding of the protein without stabilization of any partially folded intermediate is observed. The protein is stabilized with a conformational free energy of about 10 +/- 0.3 kcal mol-1. Additionally, the presence of conserved Pro-53 and structural motifs such as N-capping box and hydrophobic staple, further aided in the stability and proper folding of FgGST1. PMID- 29235506 TI - Differential contributions of the middle frontal gyrus functional connectivity to literacy and numeracy. AB - Literacy and numeracy equally affect an individual's success in and beyond schools, but these two competencies tend to be separately examined, particularly in neuroimaging studies. The current resting-state fMRI study examined the neural correlates of literacy and numeracy in the same sample of healthy adults. We first used an exploratory "Multivariate Distance Matrix Regression" (MDMR) approach to examine intrinsic functional connectivity (iFC), highlighting the middle frontal gyrus (MFG) for both competencies. Notably, there was a hemispheric asymmetry in the MDMR-based MFG findings, with literacy associated with the left MFG, whereas numeracy associated with the right MFG (R.MFG). Results of post-hoc seed-based correlation analyses further strengthened differential contributions of MFG connections to each competency. One of the most striking and novel findings from the present work was that numeracy was negatively related to R.MFG connections with the default network, which has been largely overlooked in the literature. Our results are largely consistent with prior neuroimaging work showing distinct neural mechanisms underlying literacy and numeracy, and also indicate potentially common iFC profiles to both competencies (e.g., R.MFG with cerebellum). Taken together, our iFC findings have a potential to provide novel insights into neural bases of literacy, numeracy, and impairments in these competencies. PMID- 29235507 TI - Blood-Brain Glucose Transfer in Alzheimer's disease: Effect of GLP-1 Analog Treatment. AB - There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral metabolic rate for glucose (CMRglc) in AD, and GLP-1 may serve to raise transporter numbers. We hypothesized that the GLP-1 analog liraglutide would prevent the decline of CMRglc in AD by raising blood-brain glucose transfer, depending on the duration of disease. We randomized 38 patients with AD to treatment with liraglutide (n = 18) or placebo (n = 20) for 6 months, and determined the blood-brain glucose transfer capacity (T max) in the two groups and a healthy age matched control group (n = 6). In both AD groups at baseline, T max estimates correlated inversely with the duration of AD, as did the estimates of CMRglc that in turn were positively correlated with cognition. The GLP-1 analog treatment, compared to placebo, highly significantly raised the T max estimates of cerebral cortex from 0.72 to 1.1 umol/g/min, equal to T max estimates in healthy volunteers. The result is consistent with the claim that GLP-1 analog treatment restores glucose transport at the BBB. PMID- 29235508 TI - Genetic adaptation of microbial populations present in high-intensity catfish production systems with therapeutic oxytetracycline treatment. AB - Microbial communities that are present in aquaculture production systems play significant roles in degrading organic matter, controlling diseases, and formation of antibiotic resistance. It is important to understand the diversity and abundance of microbial communities and their genetic adaptations associated with environmental physical and chemical changes. Here we collected water and sediment samples from a high-intensity catfish production system and its original water reservoir. The metagenomic analysis showed that Proteobacteria, Actinobacteria, Bacteroidetes, Cyanobacteria, and Firmicutes were the top five phyla identified from all samples. The aquaculture production system significantly changed the structure of aquatic microbial populations. Substantial changes were also observed in SNP patterns among four sample types. The gene specific sweep was found to be more common than genome-wide sweep. The selective sweep analysis revealed that 21 antibiotic resistant (AR) genes were under selection, with most belonging to antibiotic efflux pathways. Over 200 AR gene gains and losses were determined by changes in gene frequencies. Most of the AR genes were characterized as ABC efflux pumps, RND efflux pumps, and tetracycline MFS efflux pumps. Results of this study suggested that aquaculture waste, especially waste containing therapeutic antibiotics, has a significant impact on microbial population structures and their genetic structures. PMID- 29235510 TI - Acoustic Waveguide Eigenmode Solver Based on a Staggered-Grid Finite-Difference Method. AB - A numerical method of solving for the elastic wave eigenmodes in acoustic waveguides of arbitrary cross-section is presented. Operating under the assumptions of linear, isotropic materials, it utilizes a finite-difference method on a staggered grid to solve for the acoustic eigenmodes (field and frequency) of the vector-field elastic wave equation with a given propagation constant. Free, fixed, symmetry, and anti-symmetry boundary conditions are implemented, enabling efficient simulation of acoustic structures with geometrical symmetries and terminations. Perfectly matched layers are also implemented, allowing for the simulation of radiative (leaky) modes. The method is analogous to that in eigenmode solvers ubiquitously employed in electromagnetics to find waveguide modes, and enables design of acoustic waveguides as well as seamless integration with electromagnetic solvers for optomechanical device design. The accuracy of the solver is demonstrated by calculating eigenfrequencies and mode shapes for common acoustic modes across four orders of magnitude in frequency in several simple geometries and comparing the results to analytical solutions where available or to numerical solvers based on more computationally expensive methods. The solver is utilized to demonstrate a novel type of leaky-guided acoustic wave that couples simultaneously to two independent radiation channels (directions) with different polarizations - a 'bi leaky' mode. PMID- 29235509 TI - In vivo metabolic imaging of Traumatic Brain Injury. AB - Complex alterations in cerebral energetic metabolism arise after traumatic brain injury (TBI). To date, methods allowing for metabolic evaluation are highly invasive, limiting our understanding of metabolic impairments associated with TBI pathogenesis. We investigated whether 13C MRSI of hyperpolarized (HP) [1-13C] pyruvate, a non-invasive metabolic imaging method, could detect metabolic changes in controlled cortical injury (CCI) mice (n = 57). Our results show that HP [1 13C] lactate-to-pyruvate ratios were increased in the injured cortex at acute (12/24 hours) and sub-acute (7 days) time points after injury, in line with decreased pyruvate dehydrogenase (PDH) activity, suggesting impairment of the oxidative phosphorylation pathway. We then used the colony-stimulating factor-1 receptor inhibitor PLX5622 to deplete brain resident microglia prior to and after CCI, in order to confirm that modulations of HP [1-13C] lactate-to-pyruvate ratios were linked to microglial activation. Despite CCI, the HP [1-13C] lactate to-pyruvate ratio at the injury cortex of microglia-depleted animals at 7 days post-injury remained unchanged compared to contralateral hemisphere, and PDH activity was not affected. Altogether, our results demonstrate that HP [1-13C] pyruvate has great potential for in vivo non-invasive detection of cerebral metabolism post-TBI, providing a new tool to monitor the effect of therapies targeting microglia/macrophages activation after TBI. PMID- 29235511 TI - Production of lignin based insoluble polymers (anionic hydrogels) by C. versicolor. AB - Unlike previous lignin biodegradation studies, white rot fungi were used to produce functional biopolymers from Kraft lignin. Lignin-based polymers (hydrogel precursors) partially soluble in both aqueous and organic solvents were produced employing a relatively fast (6 days) enzymation of Kraft lignin with basidiomycetes, primarily Coriolus versicolor, pre-grown on kenaf/lignin agar followed by either vacuum evaporation or acid precipitation. After drying followed by a treatment with alkaline water, this intermediate polymer became a pH-sensitive anionic hydrogel insoluble in either aqueous or organic solvents. The yield of this polymer increased from 20 to 72 wt% with the addition of 2% dimethylsulfoxide to distilled water used as a medium. The mechanical stability and buffering capacity of this hydrogel can be adjusted by washing the intermediate polymer/hydrogel precursor prior to drying with solvents of different polarity (water, methanol or ethanol). Any of these polymers featured a significant thermal resilience assessed as a high thermostable "coked" fraction in thermal carbon analysis, apparently resulting from significant covalent cross linking that occurs during the treatment of their intermediate precursors. PMID- 29235512 TI - A Multimodal Biomicroscopic System based on High-frequency Acoustic Radiation Force Impulse and Multispectral Imaging Techniques for Tumor Characterization Ex vivo. AB - We report a multimodal biomicroscopic system which offers high-frequency ultrasound B-mode, acoustic radiation force impulse (ARFI), and multispectral imaging for qualitative tumor characterization ex vivo. Examinations of resected tissues from diseased regions such as tumors are crucial procedures during surgical operations to treat cancer. Particularly, if tiny tumors remain at surgical sites after tumor resection, such tumors can result in unwanted outcomes, such as cancer recurrence or metastasis to other organs. To avoid this, accurate characterizations of tumors resected during surgery are necessary. To this end, we devised a multimodal biomicroscopic system including high-frequency ultrasound B-mode, ARFI, and multispectral imaging modalities to examine resected tumors with high levels of accuracy. This system was evaluated with tissue mimicking phantoms with different mechanical properties. In addition, colorectal tumors excised from cancer patients were examined. The proposed system offers highly resolved anatomical, mechanical, chemical information pertaining to tumors, thus allowing the detection of tumor regions from the surface to deep inside tissues. These results therefore suggest that the multimodal biomicroscopic system has the potential to undertake qualitative characterizations of excised tumors ex vivo. PMID- 29235513 TI - Metabolic engineering of the pentose phosphate pathway for enhanced limonene production in the cyanobacterium Synechocysti s sp. PCC 6803. AB - Isoprenoids are diverse natural compounds, which have various applications as pharmaceuticals, fragrances, and solvents. The low yield of isoprenoids in plants makes them difficult for cost-effective production, and chemical synthesis of complex isoprenoids is impractical. Microbial production of isoprenoids has been considered as a promising approach to increase the yield. In this study, we engineered the model cyanobacterium Synechocystis sp. PCC 6803 for sustainable production of a commercially valuable isoprenoid, limonene. Limonene synthases from the plants Mentha spicata and Citrus limon were expressed in cyanobacteria for limonene production. Production of limonene was two-fold higher with limonene synthase from M. spicata than that from C. limon. To enhance isoprenoid production, computational strain design was conducted by applying the OptForce strain design algorithm on Synechocystis 6803. Based on the metabolic interventions suggested by this algorithm, genes (ribose 5-phosphate isomerase and ribulose 5-phosphate 3-epimerase) in the pentose phosphate pathway were overexpressed, and a geranyl diphosphate synthase from the plant Abies grandis was expressed to optimize the limonene biosynthetic pathway. The optimized strain produced 6.7 mg/L of limonene, a 2.3-fold improvement in productivity. Thus, this study presents a feasible strategy to engineer cyanobacteria for photosynthetic production of isoprenoids. PMID- 29235515 TI - Discrete and continuous character-based disparity analyses converge to the same macroevolutionary signal: a case study from captorhinids. AB - The relationship between diversity and disparity during the evolutionary history of a clade provides unique insights into evolutionary radiations and the biological response to bottlenecks and to extinctions. Here we present the first comprehensive comparison of diversity and disparity of captorhinids, a group of basal amniotes that is important for understanding the early evolution of high fiber herbivory. A new fully resolved phylogeny is presented, obtained by the inclusion of 31 morphometric characters. The new dataset is used to calculate diversity and disparity through the evolutionary history of the clade, using both discrete and continuous characters. Captorhinids do not show a decoupling between diversity and disparity, and are characterized by a rather symmetric disparity distribution, with a peak in occupied morphospace at about the midpoint of the clade's evolutionary history (Kungurian). This peak represents a delayed adaptive radiation, identified by the first appearance of several high-fiber herbivores in the clade, along with numerous omnivorous taxa. The discrete characters and continuous morphometric characters indicate the same disparity trends. Therefore, we argue that in the absence of one of these two possible proxies, the disparity obtained from just one source can be considered robust and representative of a general disparity pattern. PMID- 29235514 TI - Substrate stiffness influences phenotype and function of human antigen-presenting dendritic cells. AB - Dendritic cells (DCs) are specialized immune cells that scan peripheral tissues for foreign material or aberrant cells and, upon recognition of such danger signals, travel to lymph nodes to activate T cells and evoke an immune response. For this, DCs travel large distances through the body, encountering a variety of microenvironments with different mechanical properties such as tissue stiffness. While immune-related pathological conditions such as fibrosis or cancer are associated with tissue stiffening, the role of tissue stiffness in regulating key functions of DCs has not been studied yet. Here, we investigated the effect of substrate stiffness on the phenotype and function of DCs by conditioning DCs on polyacrylamide substrates of 2, 12 and 50 kPa. Interestingly, we found that C type lectin expression on immature DCs (iDCs) is regulated by substrate stiffness, resulting in differential antigen internalization. Furthermore, we show that substrate stiffness affects beta2 integrin expression and podosome formation by iDCs. Finally, we demonstrate that substrate stiffness influences CD83 and CCR7 expression on mature DCs, the latter leading to altered chemokine directed migration. Together, our results indicate that DC phenotype and function are affected by substrate stiffness, suggesting that tissue stiffness is an important determinant for modulating immune responses. PMID- 29235516 TI - Leveraging ectopic Hsp90 expression to assay the presence of tumor cells and aggressive tumor phenotypes in breast specimens. AB - Hsp90 has been studied extensively as a therapeutic target in breast cancer in pre-clinical and clinical trials, demonstrating a variety of roles in metastatic progression. The evidence to date suggests a compelling opportunity to leverage attributes of Hsp90 expression beyond therapeutics with potential applications in breast cancer diagnosis, prognosis, and recurrence risk assessment. In this study, we developed a completely non-destructive strategy using HS-27, a fluorescently-tethered Hsp90 inhibitor, to assay Hsp90 expression on intact tissue specimens with comparable contrast to in vivo administration routes, and demonstrate the feasibility of our approach in breast cancer patients. In addition to Hsp90 inhibition being most effective in glycolytic tumors, we found ectopic Hsp90 expression to be highest in glycolytic tumors reinforcing its role as an indicator of aggressive disease. This work sets the stage for immediately using Hsp90 to improve outcomes for breast cancer patients without affecting traditional care pathways. PMID- 29235517 TI - Enhanced Removal of Arsenic from Water by Synthetic Nanocrystalline Iowaite. AB - Nanocrystalline iowaite, a Mg/Fe-based layered double hydroxide (LDH) intercalated with chloride, was synthesized to evaluate its performance for arsenic removal from water and to investigate the contributing dearsenication mechanisms. It is characterized by fast arsenic sorption rates and has a much higher arsenic uptake capacity than other LDHs that are commonly used for water dearsenication. The surface adsorption of the solution arsenic onto the iowaite samples and the anion exchange of the arsenic in solution with chloride, which is originally in the iowaite interlayers, are the primary mechanisms for the uptake of arsenic by iowaite. In addition to the Coulombic attraction between arsenate/arsenite and positively charged layers of iowaite, the inner-sphere complexation of arsenic with Fe (instead of Mg) in the iowaite layers is responsible for the formation of more stable and stronger arsenic bonds, as indicated by both XPS and EXAFS analyses. Specifically, bidentate-binuclear and monodentate-mononuclear As-Fe complexes were detected in the arsenate removal experiments, whereas bidentate-mononuclear, bidentate-binuclear, and monodentate mononuclear As-Fe complexes were present for the arsenite-treated iowaite samples. This study shows that nanocrystalline iowaite is a promising, low-cost material for arsenic removal from natural arsenic-rich waters or contaminated high-arsenic waters. PMID- 29235518 TI - The efficacy of intensity modulated radiation therapy in treating thyroid associated ophthalmopathy and predictive factors for treatment response. AB - The study evaluated clinical efficacy of intensity modulated radiation therapy (IMRT) in treating patients with thyroid-associated ophthalmopathy (TAO) and defined predictive factors that associated with treatment response. A total of 178 TAO patients were treated with retro-orbital IMRT with radiation dose of 20 Gy in 10 fractions. The immediate and long-term treatment response and complications were evaluated. Besides, logistic-regression analysis was conducted to identify possible predictive factors. TAO symptom score significantly fell from the initiation to 6-month post-treatment (P < 0.001). 134 patients (73.2%) had mild to significant response to IMRT, and 172 patients (96.6%) achieved stabilization of TAO without future progression. Current smoker (OR 2.88, 95% CI 1.32-6.29; P = 0.008) and symptom duration longer than 18 months (OR 3.33, 95% CI 1.24-8.93; P = 0.017) were identified as independent predictive factors for non response of TAO to retro-orbital IMRT. Immediate complications were slight and self-limited, and long-term complications mainly included chronic xerophthalmias in12 patients (6.74%) and cataract formation in 4 patients (2.25%). The study suggested that IMRT was a viable option for treating TAO patients, with a satisfactory symptom control ability and acceptable post-treatment complications. PMID- 29235519 TI - Strengthening face centered cubic crystals by annealing induced nano-twins. AB - Usually, cold working strengthen metals and alloys by introducing large population of dislocations, whereas annealing of cold worked metal recovers the structure, annihilates dislocations, forms new strain-free grains, and results loss of strength. Here, we report annealing-hardening at temperature well below stress relieving and recrystallization temperatures in contrast to the typical behavior. A large amount of structural defects, such as dislocations, grain boundaries, twins, and stacking faults, have been introduced in nanostructured alpha-brass by cryorolling. The interaction and rearrangement of these defects upon annealing at 165-200 degrees C have been monitored at an interval of 1 minute. Large increase of the yield strength up to 578 MPa has been achieved in annealed specimens, which is 23% higher than that of as-cryorolled, and 425% higher than that of as-cast brass due to the evolution of nano-twins. Our approach shows a new avenue on strengthening fcc crystals by incorporating annealing induced nano-twins. PMID- 29235520 TI - Ubiquitin-conjugating enzyme E2T (UBE2T) and denticleless protein homolog (DTL) are linked to poor outcome in breast and lung cancers. AB - Protein ubiquitination and degradation represent druggable vulnerabilities of cancer cells. We used gene expression and functional annotation analyses to identify genes in the ubiquitin pathway which are differentially expressed between normal breast and basal-like tumors. With this approach we identified 16 ubiquitin related genes overexpressed in basal-like breast cancers compared with normal breast. We then explored the association between these genes and outcomes using the KMPlotter online tool. Two genes, the ubiquitin-conjugating enzyme E2T (UBE2T) and the denticleless protein homolog (DTL) were overexpressed and linked with detrimental outcome in basal-like and luminal breast cancer patients. Furthermore, we found that UBE2T and DTL were amplified in around 12% of breast tumors based on data contained at cBioportal. In non-small cell lung adenocarcinomas, UBE2T and DTL were also amplified in around 7% of cases and linked with disease recurrence after surgical resection. No significant molecular alterations or a clear trend for clinical outcome was observed for these genes in ovarian serous cystadenocarcinoma, esophagus-stomach cancer or non-small squamous cell carcinoma. Our data suggest that UBE2T and DTL may have a role in the pathophysiology of breast and lung tumors, opening avenues for future clinical evaluation of agents targeting those proteins or their pathways. PMID- 29235521 TI - Infrared actuation-induced simultaneous reconfiguration of surface color and morphology for soft robotics. AB - Cephalopods, such as cuttlefish, demonstrate remarkable adaptability to the coloration and texture of their surroundings by modulating their skin color and surface morphology simultaneously, for the purpose of adaptive camouflage and signal communication. Inspired by this unique feature of cuttlefish skins, we present a general approach to remote-controlled, smart films that undergo simultaneous changes of surface color and morphology upon infrared (IR) actuation. The smart film has a reconfigurable laminated structure that comprises an IR-responsive nanocomposite actuator layer and a mechanochromic elastomeric photonic crystal layer. Upon global or localized IR irradiation, the actuator layer exhibits fast, large, and reversible strain in the irradiated region, which causes a synergistically coupled change in the shape of the laminated film and color of the mechanochromic elastomeric photonic crystal layer in the same region. Bending and twisting deformations can be created under IR irradiation, through modulating the strain direction in the actuator layer of the laminated film. Furthermore, the laminated film has been used in a remote-controlled inchworm walker that can directly couple a color-changing skin with the robotic movements. Such remote-controlled, smart films may open up new application possibilities in soft robotics and wearable devices. PMID- 29235523 TI - Selectable phase formation in VAlN thin films by controlling Al+ subplantation depth. AB - We report on a thin film synthesis technique which allows for unprecedented control over the crystalline phase formation in metastable transition metal nitride based layers. For the model material system of V0.26Al0.74N, a complete transition from hexagonal to supersaturated cubic structure is achieved by tuning the incident energy, hence subplantation depth, of Al+ metal ions during reactive hybrid high power impulse magnetron sputtering of Al target and direct current magnetron sputtering of V target in Ar/N2 gas mixture. These findings enable the phase selective synthesis of novel metastable materials that combine excellent mechanical properties, thermal stability, and oxidation resistance. PMID- 29235522 TI - An optogenetic arrhythmia model to study catecholaminergic polymorphic ventricular tachycardia mutations. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a condition of abnormal heart rhythm (arrhythmia), induced by physical activity or stress. Mutations in ryanodine receptor 2 (RyR2), a Ca2+ release channel located in the sarcoplasmic reticulum (SR), or calsequestrin 2 (CASQ2), a SR Ca2+ binding protein, are linked to CPVT. For specific drug development and to study distinct arrhythmias, simple models are required to implement and analyze such mutations. Here, we introduced CPVT inducing mutations into the pharynx of Caenorhabditis elegans, which we previously established as an optogenetically paced heart model. By electrophysiology and video-microscopy, we characterized mutations in csq-1 (CASQ2 homologue) and unc-68 (RyR2 homologue). csq-1 deletion impaired pharynx function and caused missed pumps during 3.7 Hz pacing. Deletion mutants of unc 68, and in particular the point mutant UNC-68(R4743C), analogous to the established human CPVT mutant RyR2(R4497C), were unable to follow 3.7 Hz pacing, with progressive defects during long stimulus trains. The pharynx either locked in pumping at half the pacing frequency or stopped pumping altogether, possibly due to UNC-68 leakiness and/or malfunctional SR Ca2+ homeostasis. Last, we could reverse this 'worm arrhythmia' by the benzothiazepine S107, establishing the nematode pharynx for studying specific CPVT mutations and for drug screening. PMID- 29235524 TI - Multibit memory operation of metal-oxide bi-layer memristors. AB - Emerging nanoionic memristive devices are considered as the memory technology of the future and have been winning a great deal of attention due to their ability to perform fast and at the expense of low-power and -space requirements. Their full potential is envisioned that can be fulfilled through their capacity to store multiple memory states per cell, which however has been constrained so far by issues affecting the long-term stability of independent states. Here, we introduce and evaluate a multitude of metal-oxide bi-layers and demonstrate the benefits from increased memory stability via multibit memory operation. We propose a programming methodology that allows for operating metal-oxide memristive devices as multibit memory elements with highly packed yet clearly discernible memory states. These states were found to correlate with the transport properties of the introduced barrier layers. We are demonstrating memory cells with up to 6.5 bits of information storage as well as excellent retention and power consumption performance. This paves the way for neuromorphic and non-volatile memory applications. PMID- 29235525 TI - Novel fabrication of a robust superhydrophobic PU@ZnO@Fe3O4@SA sponge and its application in oil-water separations. AB - We report a novel superhydrophobic material based on commercially available polyurethane (PU) sponge with high porosity, low density and good elasticity. The fabrication of a superhydrophobic sponge capable of efficiently separating oil from water was achieved by imitating or mimicking nature's designs. The original PU sponge was coated with zinc oxide (ZnO), stearic acid (SA) and iron oxide particles (Fe3O4) via a facile and environmentally friendly method. After each treatment, the properties of the modified sponge were characterized, and the changes in wettability were examined. Water contact angle (WCA) measurements confirmed the excellent superhydrophobicity of the material withhigh static WCA of 161 degrees andlow dynamic WCA (sliding WCA of 7 degrees and shedding WCA of 8 degrees ). The fabricated sponge showed high efficiency in separation (over 99%) of different oils from water. Additionally, the fabricated PU@ZnO@Fe3O4@SA sponge could be magnetically guided to quickly absorb oil floating on the water surface. Moreover, the fabricated sponge showed excellent stability and reusability in terms of superhydrophobicity and oil absorption capacity. The durable, magnetic and superhydrophobic properties of the fabricated sponge render it applicable to the cleanup of marine oil spills and other oil-water separation issues, with eco-friendly recovery of the oil by simple squeezing process. PMID- 29235526 TI - Plasma acylcarnitine concentrations reflect the acylcarnitine profile in cardiac tissues. AB - Increased plasma concentrations of acylcarnitines (ACs) are suggested as a marker of metabolism disorders. The aim of the present study was to clarify which tissues are responsible for changes in the AC pool in plasma. The concentrations of medium- and long-chain ACs were changing during the fed-fast cycle in rat heart, muscles and liver. After 60 min running exercise, AC content was increased in fasted mice muscles, but not in plasma or heart. After glucose bolus administration in fasted rats, the AC concentrations in plasma decreased after 30 min but then began to increase, while in the muscles and liver, the contents of medium- and long-chain ACs were unchanged or even increased. Only the heart showed a decrease in medium- and long-chain AC contents that was similar to that observed in plasma. In isolated rat heart, but not isolated-contracting mice muscles, the significant efflux of medium- and long-chain ACs was observed. The efflux was reduced by 40% after the addition of glucose and insulin to the perfusion solution. Overall, these results indicate that during fed-fast cycle shifting the heart determines the medium- and long-chain AC profile in plasma, due to a rapid response to the availability of circulating energy substrates. PMID- 29235527 TI - Assessment of low concentration wastewater treatment operations with dewatered alum sludge-based sequencing batch constructed wetland system. AB - Competition of volatile fatty acids between anoxic denitrification and anaerobic phosphorus release is prominent. Therefore, low concentration wastewater has restricted effects on nitrogen and phosphorus removal. The purpose of this study is to treat dormitory sewage with a biochemical oxygen demand (BOD) ranging from 50 to 150 mg/L using dewatered alum sludge-based sequencing batch constructed wetland system. Vegetation in the wetland system was chosen to be Phragmites australis. Three parallel cases were carried out to assess impacts due to different hydraulic retention time (HRT) and artificial aeration. The results showed that this system is effective in removing total nitrogen (TN), ammonia nitrogen (NH3-N) and total phosphorus (TP) under different HRT. However, nitrous oxide (N2O) emission poses to be the greatest challenge in the high HRT cases. Artificial aeration could reduce N2O emission but is associated with high operational cost. Results indicate that dewatered alum sludge-based sequencing batch constructed wetland system is a promising bio-measure in the treatment of low concentration wastewater. PMID- 29235528 TI - Identification of Newly Committed Pancreatic Cells in the Adult Mouse Pancreas. AB - Multipotent epithelial cells with high Aldehyde dehydrogenase activity have been previously reported to exist in the adult pancreas. However, whether they represent true progenitor cells remains controversial. In this study, we isolated and characterized cells with ALDH activity in the adult mouse or human pancreas during physiological conditions or injury. We found that cells with ALDH activity are abundant in the mouse pancreas during early postnatal growth, pregnancy, and in mouse models of pancreatitis and type 1 diabetes (T1D). Importantly, a similar population of cells is found abundantly in healthy children, or in patients with pancreatitis or T1D. We further demonstrate that cells with ALDH activity can commit to either endocrine or acinar lineages, and can be divided into four sub populations based on CD90 and Ecadherin expression. Finally, our in vitro and in vivo studies show that the progeny of ALDH1+/CD90-/Ecad- cells residing in the adult mouse pancreas have the ability to initiate Pancreatic and duodenal homeobox (Pdx1) expression for the first time. In summary, we provide evidence for the existence of a sortable population of multipotent non-epithelial cells in the adult pancreas that can commit to the pancreatic lineage following proliferation and mesenchymal to epithelial transition (MET). PMID- 29235529 TI - Identification of MYLK3 mutations in familial dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is a primary cause of heart failure, life threatening arrhythmias, and cardiac death. Pathogenic mutations have been identified at the loci of more than 50 genes in approximately 50% of DCM cases, while the etiologies of the remainder have yet to be determined. In this study, we applied whole exome sequencing in combination with segregation analysis to one pedigree with familial DCM, and identified a read-through mutation (c.2459 A > C; p.*820Sext*19) in the myosin light chain kinase 3 gene (MYLK3). We then conducted MYLK3 gene screening of 15 DCM patients (7 familial and 8 sporadic) who were negative for mutation screening of the previously-reported cardiomyopathy-causing genes, and identified another case with a MYLK3 frameshift mutation (c.1879_1885del; p.L627fs*41). In vitro experiments and immunohistochemistry suggested that the MYLK3 mutations identified in this study result in markedly reduced levels of protein expression and myosin light chain 2 phosphorylation. This is the first report that MYLK3 mutations can cause DCM in humans. The clinical phenotypes of DCM patients were consistent with MYLK3 loss-of-function mouse and zebrafish models in which cardiac enlargement and heart failure are observed. Our findings highlight an essential role for cardiac myosin light chain kinase in the human heart. PMID- 29235531 TI - Circulating bone morphogenetic protein-9 in relation to metabolic syndrome and insulin resistance. AB - Our objective is to determine circulating Bone morphogenetic protein-9(BMP-9) levels in subjects with Metabolic Syndrome (MetS) and examine the relationship between BMP-9 and conventional markers for MetS and insulin resistance (IR). A total of 362 newly diagnosed patients with MetS along with healthy controls were recruited for this cross-sectional study. Circulating BMP-9 levels were measured by ELISA. Circulating BMP-9 levels were significantly lower in MetS patients compared to those of the healthy controls. BMP-9 was associated negatively with Waist hip ratio (WHR), fasting blood glucose (FBG), 2-hour blood glucose after glucose overload (2h-OGTT), HbA1c, triglyceride (TG) levels and HOMA-IR and positively with free fatty acid (FFA) and HDL after control for age and sex. In a multiple linear regression, BMP-9 was independently associated with type 2 diabetes mellitus (T2DM), HOMA-IR and FFA. Binary logistic regression showed that plasma BMP-9 concentrations were significantly associated with MetS even after controlling for anthropometric variables and lipid profiles. In addition, circulating BMP-9 levels reduced progressively with an increasing number of MetS components. The best cutoff values for circulating BMP-9 to predict MetS was 56.6 ng/L. Circulating BMP-9 levels were associated with the key components of MetS and IR. PMID- 29235530 TI - TRI Microspheres prevent key signs of dry eye disease in a murine, inflammatory model. AB - Dry eye disease (DED) is a highly prevalent, ocular disorder characterized by an abnormal tear film and ocular surface. Recent experimental data has suggested that the underlying pathology of DED involves inflammation of the lacrimal functional unit (LFU), comprising the cornea, conjunctiva, lacrimal gland and interconnecting innervation. This inflammation of the LFU ultimately results in tissue deterioration and the symptoms of DED. Moreover, an increase of pathogenic lymphocyte infiltration and the secretion of pro-inflammatory cytokines are involved in the propagation of DED-associated inflammation. Studies have demonstrated that the adoptive transfer of regulatory T cells (Tregs) can mediate the inflammation caused by pathogenic lymphocytes. Thus, as an approach to treating the inflammation associated with DED, we hypothesized that it was possible to enrich the body's own endogenous Tregs by locally delivering a specific combination of Treg inducing factors through degradable polymer microspheres (TRI microspheres; TGF-beta1, Rapamycin (Rapa), and IL-2). This local controlled release system is capable of shifting the balance of Treg/T effectors and, in turn, preventing key signs of dry eye disease such as aqueous tear secretion, conjunctival goblet cells, epithelial corneal integrity, and reduce the pro-inflammatory cytokine milieu in the tissue. PMID- 29235532 TI - Investigation of the effects of the CFTR potentiator ivacaftor on human P glycoprotein (ABCB1). AB - Ivacaftor is a potentiator of the CFTR chloride channel and is in worldwide clinical use for the chronic treatment of cystic fibrosis in patients. There is evidence that the bioavailability of ivacaftor in the body may be influenced by the multi-drug exporter P-glycoprotein. Here we have employed purified and reconstituted P-glycoprotein to study its interaction with ivacaftor as well as the ability of the drug to compete with a known transported substrate of the protein. We find that ivacaftor stimulates the ATPase activity of the purified protein and can compete with the transport of the fluorescent substrate Hoechst 33342. These findings lead us to conclude that ivacaftor is very likely an efficiently transported substrate of P-glycoprotein. Evidence for state-dependent binding of ivacaftor was obtained using a fluorescent, cysteine-reactive reporter dye. The quiescent, nucleotide-free state in the P-glycoprotein transport cycle appears to bind ivacaftor strongly. PMID- 29235533 TI - A generic standard additions based method to determine endogenous analyte concentrations by immunoassays to overcome complex biological matrix interference. AB - We describe a novel generic method to derive the unknown endogenous concentrations of analyte within complex biological matrices (e.g. serum or plasma) based upon the relationship between the immunoassay signal response of a biological test sample spiked with known analyte concentrations and the log transformed estimated total concentration. If the estimated total analyte concentration is correct, a portion of the sigmoid on a log-log plot is very close to linear, allowing the unknown endogenous concentration to be estimated using a numerical method. This approach obviates conventional relative quantification using an internal standard curve and need for calibrant diluent, and takes into account the individual matrix interference on the immunoassay by spiking the test sample itself. This technique is based on standard additions for chemical analytes. Unknown endogenous analyte concentrations within even 2-fold diluted human plasma may be determined reliably using as few as four reaction wells. PMID- 29235534 TI - Direct Generation and Detection of Quantum Correlated Photons with 3.2 um Wavelength Spacing. AB - Quantum correlated, highly non-degenerate photons can be used to synthesize disparate quantum nodes and link quantum processing over incompatible wavelengths, thereby constructing heterogeneous quantum systems for otherwise unattainable superior performance. Existing techniques for correlated photons have been concentrated in the visible and near-IR domains, with the photon pairs residing within one micron. Here, we demonstrate direct generation and detection of high-purity photon pairs at room temperature with 3.2 um wavelength spacing, one at 780 nm to match the rubidium D2 line, and the other at 3950 nm that falls in a transparent, low-scattering optical window for free space applications. The pairs are created via spontaneous parametric downconversion in a lithium niobate waveguide with specially designed geometry and periodic poling. The 780 nm photons are measured with a silicon avalanche photodiode, and the 3950 nm photons are measured with an upconversion photon detector using a similar waveguide, which attains 34% internal conversion efficiency. Quantum correlation measurement yields a high coincidence-to-accidental ratio of 54, which indicates the strong correlation with the extremely non-degenerate photon pairs. Our system bridges existing quantum technology to the challenging mid-IR regime, where unprecedented applications are expected in quantum metrology and sensing, quantum communications, medical diagnostics, and so on. PMID- 29235535 TI - Seasonal pattern of influenza activity in a subtropical city, China, 2010-2015. AB - Influenza seasonality study is critical for policy-makers to choose an optimal time for influenza vaccination campaign, especially for subtropical regions where influenza seasonality and periodicity are unclear. In this study, we explored the seasonality and periodicity of influenza in Hefei, China during 2010 to 2015 using five proxies originated from three data sources of clinical surveillance of influenza-like illness (ILI), laboratory surveillance of influenza and death registration of pneumonia and influenza. We combined both wavelets analysis and de-linear-trend regression with Fourier harmonic terms to estimate seasonal characteristics of epidemic phase, peak time, amplitude, ratio of dominant seasonality. We found both annual cycle of influenza epidemics peaking in December-February and semi-annual cycle peaking in December-February and June July in subtropical city Hefei, China. Compared to proxies developed by ILI and death registration data separately, influenza proxies incorporated laboratory surveillance data performed better seasonality and periodicity, especially in semi-annual periodicity in Hefei. Proxy of ILI consultation rate showed more timeliness peak than other proxies, and could be useful in developing the early warning model for influenza epidemics. Our study suggests to integrate clinical and laboratory surveillance of influenza for future influenza seasonality studies in subtropical regions. PMID- 29235536 TI - Genetically unmatched human iPSC and ESC exhibit equivalent gene expression and neuronal differentiation potential. AB - The potential uniformity between differentiation and therapeutic potential of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) remains debatable. We studied the gene expression profiles, pathways analysis and the ability to differentiated into neural progenitor cells (NPCs) and motor neurons (MNs) of genetically unmatched integration-free hiPSC versus hESC to highlight possible differences/similarities between them at the molecular level. We also provided the functional information of the neurons derived from the different hESCs and hiPSCs lines using the Neural Muscular Junction (NMJ) Assay. The hiPSC line was generated by transfecting human epidermal fibroblasts (HEF) with episomal DNAs expressing Oct4, Sox2, Klf4, Nanog, L-Myc and shRNA against p53. For the hESCs line, we used the NIH-approved H9 cell line. Using unsupervised clustering both hESCs and hiPSCs were clustered together implying homogeneous genetic states. The genetic profiles of hiPSCs and hESCs were clearly similar but not identical. Collectively, our data indicate close molecular similarities between genetically unmatched hESCs and hiPS in term of gene expression, and signaling pathways. Moreover, both cell types exhibited similar cholinergic motor neurons differentiation potential with marked ability of the differentiated hESCs and hiPSCs-derived MNs to induce contraction of myotubes after 4 days of co-culture. PMID- 29235537 TI - Optical sparse aperture imaging with faint objects using improved spatial modulation diversity. AB - The next generation of optical sparse aperture systems will provide high angular resolution for astronomical observations. Spatial modulation diversity (SMD) is a newly developed post-processing technique for such telescopes, faced with challenges of imaging faint objects, which are very attractive for astronomers but always make raw diversity images suffer serious photon noise. In this paper, we propose an improved SMD with denoising reprocessing embedded to address the problem. The blocking-matching and 3D filtering algorithm, a state-of-the-art denoising technique, is first employed to process the diversity images with low photon intensities generated by spatial modulation, specifically switching off each sub-aperture sequentially. SMD algorithm then can be applied to estimate wavefront and digitally restore images. It is demonstrated by both simulations and experiments that the proposed method outperforms the previous SMD in terms of reconstructions of wavefront and imagery from the raw images of faint objects corrupted seriously by photon noise. The reported method may provide an alternative approach to acquire high-quality images of faint objects for astronomical observations of the future segmented mirrors or telescope arrays. PMID- 29235538 TI - Preoperative neutrophil-to-lymphocyte ratio and tumor-related factors to predict lymph node metastasis in nonfunctioning pancreatic neuroendocrine tumors. AB - The lymph node (LN) status is very important for the survival in pancreatic neuroendocrine tumors (PNETs). Therefore, the investigation of factors related to LN metastases has a great clinical significance. The aim of this study was to evaluate the predictive value of the preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and possible clinical parameters on the LN metastases in nonfunctional PNETs (NF-PNETs). A retrospective review of 101 NF PNET patients following curative resection and lymphadenectomy was conducted. The associations between clinicopathological factors and LN metastases and prognosis were determined. Twenty-seven (26.7%) patients had LN metastases. LN metastases was independently associated with disease-free survival (P = 0.009). Ideal cutoff values for predicting LN metastases were 1.80 for NLR, 168.25 for PLR and 2.5 cm for tumor size according to the receiver operating characteristic curve. On multivariable analysis, NLR (P = 0.017), symptomatic diagnosis (P = 0.028) and tumor size (P = 0.020) were associated with LN metastases. These results indicate that preoperative NLR >= 1.80, tumor size >=2.5 cm and symptomatic diagnosis are independently associated with LN metastases for patients undergoing resection of NF-PNETs. It is anticipated that these findings are useful for further planning of lymphadenectomy before surgery. PMID- 29235539 TI - First-principle study of structural, electronic and magnetic properties of (FeC)n (n = 1-8) and (FeC)8TM (TM = V, Cr, Mn and Co) clusters. AB - The structural, electronic and magnetic properties of the (FeC)n (n = 1-8) clusters are studied using the unbiased CALYPSO structure search method and density functional theory. A combination of the PBE functional and 6-311 + G* basis set is used for determining global minima on potential energy surfaces of (FeC)n clusters. Relatively stabilities are analyzed via computing their binding energies, second order difference and HOMO-LUMO gaps. In addition, the origin of magnetic properties, spin density and density of states are discussed in detail, respectively. At last, based on the same computational method, the structures, magnetic properties and density of states are systemically investigated for the 3d (V, Cr, Mn and Co) atom doped (FeC)8 cluster. PMID- 29235540 TI - Characteristic dysmorphic features in congenital disorders of glycosylation type IIb. AB - Over 100 types of congenital disorders of glycosylation (CDG) have been reported and the number is rapidly increasing. However, each type is very rare and is problematic to diagnose. Mannosyl-oligosaccharide glucosidase (MOGS)-CDG (CDG type IIb) is an extremely rare CDG that has only been reported in three patients from two unrelated families. Using targeted exome sequencing, we identified another patient affected by this condition. This patient had increased serum trisialotransferrin levels. Importantly, a review of the features of all four patients revealed the recognizable clinical hallmarks of MOGS-CDG. The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency. PMID- 29235541 TI - Biodegradable Bisvinyl Sulfonemethyl-crosslinked Gelatin Conduit Promotes Regeneration after Peripheral Nerve Injury in Adult Rats. AB - In our previous study, we found that gelatin-based materials exhibit good conductivity and are non-cytotoxic. In this study, gelatin was cross-linked with bisvinyl sulfonemethyl (BVSM) to fabricate a biodegradable conduit for peripheral nerve repair. First, BVSM on the prepared conduit was characterized to determine its mechanical properties and contact angle. The maximum tensile strength and water contact angle of the gelatin-BVSM conduits were 23 +/- 4.8 MPa and 74.7 +/- 9 degrees , which provided sufficient mechanical strength to resist muscular contraction; additionally, the surface was hydrophilic. Cytotoxicity and apoptosis assays using Schwann cells demonstrated that the gelatin-BVSM conduits are non-cytotoxic. Next, we examined the neuronal electrophysiology, animal behavior, neuronal connectivity, macrophage infiltration, calcitonin gene-related peptide localization and expression, as well as the expression levels of nerve regeneration-related proteins. The number of fluorogold-labelled cells and histological analysis of the gelatin-BVSM nerve conduits was similar to that observed with the clinical use of silicone rubber conduits after 8 weeks of repair. Therefore, our results demonstrate that gelatin-BVSM conduits are promising substrates for application as bioengineered grafts for nerve tissue regeneration. PMID- 29235542 TI - Bone mineral density measurements in vertebral specimens and phantoms using dual layer spectral computed tomography. AB - To assess whether phantomless calcium-hydroxyapatite (HA) specific bone mineral density (BMD) measurements with dual-layer spectral computed tomography are accurate in phantoms and vertebral specimens. Ex-vivo human vertebrae (n = 13) and a phantom containing different known HA concentrations were placed in a semi anthropomorphic abdomen phantom with different extension rings simulating different degrees of obesity. Phantomless dual-layer spectral CT was performed at different tube current settings (500, 250, 125 and 50 mAs). HA-specific BMD was derived from spectral-based virtual monoenergetic images at 50 keV and 200 keV. Values were compared to the HA concentrations of the phantoms and conventional qCT measurements using a reference phantom, respectively. Above 125 mAs, errors for phantom measurements ranged between -1.3% to 4.8%, based on spectral information. In vertebral specimens, high correlations were found between BMD values assessed with spectral CT and conventional qCT (r ranging between 0.96 and 0.99; p < 0.001 for all) with different extension rings, and a high agreement was found in Bland Altman plots. Different degrees of obesity did not have a significant influence on measurements (P > 0.05 for all). These results suggest a high validity of HA-specific BMD measurements based on dual-layer spectral CT examinations in setups simulating different degrees of obesity without the need for a reference phantom, thus demonstrating their feasibility in clinical routine. PMID- 29235543 TI - Purification of replicating pancreatic beta-cells for gene expression studies. AB - beta-cell proliferation is a rare event in adult pancreatic islets. To study the replication-related beta-cell biology we designed a replicating beta-cells sorting system for gene expression experiments. Replicating beta-cells were identified by EdU incorporation and purified by flow cytometry. For beta-cell separation islet cells were sorted by size, granularity and Newport Green fluorescence emission that was combined with emitted fluorescence for EdU labelled replicating cells sorting. The purity of the resulting sorted populations was evaluated by insulin staining and EdU for beta-cell identification and for replicating cells, respectively. Total RNA was isolated from purified cell-sorted populations for gene expression analysis. Cell sorting of dispersed islet cells resulted in 96.2% purity for insulin positivity in the collected beta-cell fraction and 100% efficiency of the EdU-based cell separation. RNA integrity was similar between FACS-sorted replicating and quiescent beta-cells. Global transcriptome analysis of replicating vs quiescent beta-cells showed the expected enrichment of categories related to cell division and DNA replication. Indeed, key genes in the spindle check-point were the most upregulated genes in replicating beta-cells. This work provides a method that allows for the isolation of replicating beta-cells, a very scarce population in adult pancreatic islets. PMID- 29235544 TI - Relationship of corneal hysteresis and optic nerve parameters in healthy myopic subjects. AB - The association between corneal biomechanical properties and glaucoma is an area of much interest. We determined the relationship between corneal hysteresis (CH) and optic nerve parameters in healthy myopic subjects in the current study. CH was measured with Reichert Ocular Response Analyzer in 108 eyes from 108 healthy myopic subjects. All subjects received retinal nerve fiber layer and optic disc imaging Cirrus HD-OCT, GDx ECC, and Heidelberg Retina Tomograph II. None of the tested optic nerve parameters showed statistical significance with CH by using correlation analysis. For RNFL parameters, there was a negative but not statistically significant correlation between CH and average RNFL thickness obtained with OCT (r = -0.15, p = 0.13). For optic disc parameters, there was a negative but not statistically significant correlation between CH and rim area measured with OCT (r = -0.10, p = 0.29). The current study did not find any statistically significant relationship between CH and optic nerve parameters as measured by all three imaging modalities in healthy myopic eyes. Therefore, the relationship observed previously in glaucoma subjects is likely coming to fruition as optic nerve damage is caused by the disease. PMID- 29235545 TI - One-plasmid double-expression His-tag system for rapid production and easy purification of MS2 phage-like particles. AB - MS2 phage-like particles (MS2 PLP) are artificially constructed pseudo-viral particles derived from bacteriophage MS2. They are able to carry a specific single stranded RNA (ssRNA) sequence of choice inside their capsid, thus protecting it against the effects of ubiquitous nucleases. Such particles are able to mimic ssRNA viruses and, thus, may serve as the process control for molecular detection and quantification of such agents in several kinds of matrices, vaccines and vaccine candidates, drug delivery systems, and systems for the display of immunologically active peptides or nanomachines. Currently, there are several different in vivo plasmid-driven packaging systems for production of MS2 PLP. In order to combine all the advantages of the available systems and to upgrade and simplify the production and purification of MS2 PLP, a one-plasmid double-expression His-tag system was designed. The described system utilizes a unique fusion insertional mutation enabling purification of particles using His tag affinity. Using this new production system, highly pure MS2 PLP can be quickly produced and purified by a fast performance liquid chromatography (FPLC) approach. The system can be easily adapted to produce other MS2 PLP with different properties. PMID- 29235546 TI - Experimental model: A new mouse model of Alagille syndrome. PMID- 29235547 TI - Stem cells: Stem cell therapy for liver cirrhosis unREALISTIC? PMID- 29235548 TI - Developmental biology: Stable epigenetic signatures in intestinal organoids. PMID- 29235550 TI - Biliary tract: MMP7 - a diagnostic biomarker for biliary atresia. PMID- 29235549 TI - Treatment for unresectable or metastatic oesophageal cancer: current evidence and trends. AB - Approximately half of the patients diagnosed with oesophageal cancer present with unresectable or metastatic disease. Treatment for these patients aims to control dysphagia and other cancer-related symptoms, improve quality of life and prolong survival. In the past 25 years, modestly improved outcomes have been achieved in the treatment of patients with inoperable non-metastatic cancer who are medically not fit for surgery or have unresectable, locally advanced disease. Concurrent chemoradiotherapy offers the best outcomes in these patients. In distant metastatic oesophageal cancer, several double-agent or triple-agent chemotherapy regimens have been established as first-line treatment options. In addition, long term results of multiple large randomized phase III trials using additional targeted therapies have been published in the past few years, affecting contemporary clinical practice and future research directions. For the local treatment of malignant dysphagia, various treatment options have emerged, and self-expandable metal stent (SEMS) placement is currently the most widely applied method. Besides the continuous search for improved SEMS designs to minimize the risk of associated complications, efforts have been made to develop and evaluate the efficacy of antireflux stents and irradiation stents. This Review outlines the current evidence and ongoing trends in the different modern-day, multidisciplinary interventions for patients with unresectable or metastatic oesophageal cancer with an emphasis on key randomized trials. PMID- 29235551 TI - Interleukin-1beta induces human cementoblasts to support osteoclastogenesis. AB - Injury of the periodontium followed by inflammatory response often leads to root resorption. Resorption is accomplished by osteoclasts and their generation may depend on an interaction with the cells in direct contact with the root, the cementoblasts. Our study aimed to investigate the role of human cementoblasts in the formation of osteoclasts and the effect of interleukin (IL)-1beta hereupon. Extracted teeth from healthy volunteers were subjected to sequential digestion by type I collagenase and trypsin. The effect of enzymatic digestion on the presence of cells on the root surface was analyzed by histology. Gene expression of primary human cementoblasts (pHCB) was compared with a human cementoblast cell line (HCEM). The pHCBs were analyzed for their expression of IL-1 receptors as well as of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG). In a co-culture system consisting of osteoclast precursors (blood monocytes) and pHCBs, the formation of osteoclasts and their resorptive activity was assessed by osteo-assay and ivory slices. The cells obtained after a 120 min enzyme digestion expressed the highest level of bone sialoprotein, similar to that of HCEM. This fraction of isolated cells also shared a similar expression pattern of IL-1 receptors (IL1-R1 and IL1-R2). Treatment with IL-1beta potently upregulated RANKL expression but not of OPG. pHCBs were shown to induce the formation of functional osteoclasts. This capacity was significantly stimulated by pretreating the pHCBs with IL-1beta prior to their co-culture with human blood monocytes. Our study demonstrated that cementoblasts have the capacity to induce osteoclastogenesis, a capacity strongly promoted by IL-1beta. These results may explain why osteoclasts can be formed next to the root of teeth. PMID- 29235552 TI - Zika virus evolution on the edges of the Pacific ocean. PMID- 29235553 TI - Pro-inflammatory gene expression profile in obese adults with high plasma GIP levels. AB - BACKGROUND: Glucose-dependent insulinotropic peptide (GIP) provides a novel link between the immune system and the gut, although results from different experimental and observational studies are contradictory, ranging from anti inflammatory, through neutral to pro-inflammatory action of GIP. Thus, the aim of this study was to analyze inflammatory pathways on the level of gene expression and circulating inflammatory markers in relation to plasma GIP level. SUBJECTS/METHODS: The study included 128 obese adults. Two groups of obese subjects were created according to fasting GIP levels, with cutoff point at the 66th percentile and compared in respect with molecular and circulating markers of inflammation. GIP, interleukin (IL)-6 and adipokines: leptin, adiponectin, visfatin were measured by enzyme-linked immunosorbent assay. Inflammatory markers: monocyte chemoattractant protein-1 (MCP-1), sE-Selectin, sVCAM-1, sPECAM 1 were studied at fasting and after nutrient challenges. Gene expression in blood cells was determined by human gene microarray. RESULTS: Obese patients with high GIP levels had elevated fasting glucose (Q2 (Q1-Q3): 5.6 (5.0-6.0) vs 5.0 (4.8 5.4), P<0.001), homeostasis model assessment of insulin resistance (Q2 (Q1-Q3): 3.68 (2.72-5.42) vs 2.70 (2.13-4.33), P=0.021), thus increased markers of insulin resistance as well as elevated inflammatory markers Il-6 (Q2 (Q1-Q3): 1.34 (1.0 2.04) vs 1.12 (0.76-1.64), P=0.045), MCP-1 (Q2 (Q1-Q3): 363 (287-447) vs 323 (263 389), P=0.026). Leptin to adiponectin ratio was significantly associated with fasting plasma GIP levels (beta (95% CI): 0.84 (0.10-1.59)) independently of glucose levels. sE-Selectin was found to be a factor influencing GIP response to oral glucose intake (beta (95% CI): 0.47 (0.14-0.81)) and sVCAM was found to be a factor influencing GIP response to high-fat meal intake (beta (95% CI): 0.19 (0.01-0.37)). We identified 32 genes of inflammatory pathways differentially expressed in subjects with a high plasma GIP level compared to low GIP. Most upregulated genes play a role in leukocyte chemotaxis and tissue infiltration. CONCLUSIONS: These findings support the hypothesis that increased GIP signaling has a role in chronic low-grade inflammation. PMID- 29235555 TI - Brown rice compared to white rice slows gastric emptying in humans. AB - BACKGROUND/OBJECTIVES: Consumption of whole vs. refined grain foods is recommended by nutrition or dietary guideline authorities of many countries, yet specific aspects of whole grains leading to health benefits are not well understood. Gastric emptying rate is an important consideration, as it is tied to nutrient delivery rate and influences glycemic response. Our objective was to explore two aspects of cooked rice related to gastric emptying, (1) whole grain brown vs. white rice and (2) potential effect of elevated levels of slowly digestible starch (SDS) and resistant starch (RS) from high-amylose rice. SUBJECTS/METHODS: Ten healthy adult participants were recruited for a crossover design study involving acute feeding and testing of 6 rice samples (50 g available carbohydrate). Gastric emptying rate was measured using a 13C-labeled octanoic acid breath test. A rice variety (Cocodrie) with high-amylose content was temperature-cycled to increase SDS and RS fractions. RESULTS: In vitro starch digestibility results showed incremental increase in RS in Cocodrie after two temperature cycles. For low-amylose varieties, SDS was higher in the brown rice form. In human subjects, low-amylose and high-amylose brown rice delayed gastric emptying compared to white rices regardless of amylose content or temperature cycling (p < 0.05). CONCLUSIONS: Whole grain brown rice had slower gastric emptying rate, which appears to be related to the physical presence of the bran layer. Extended gastric emptying of brown rice explains in part comparably low glycemic response observed for brown rice. PMID- 29235554 TI - Morning and afternoon appetite and gut hormone responses to meal and stress challenges in obese individuals with and without binge eating disorder. AB - BACKGROUND: Eating late in the day is common, and stress can induce eating. Little is understood about how time of day and stress interact to affect appetite and thereby body weight. These may be particularly important influences in binge eaters, who tend to binge in the evening, and in response to stress. METHOD: Obese participants with (n=16) and without (n=16) binge eating disorder (BED) participated in two identical test protocols beginning either in the morning or the afternoon (AM condition/PM condition), each following an 8 h fast. For each protocol, they first received a standardized liquid meal (0900/1600 hours), then a stress test (Socially Evaluated Cold Pressor Test, 1110/1810 hours), and then a multi-item ad libitum buffet meal (1140/1840 hours) while rating appetite and stress and having blood drawn for hormone measures. RESULTS: Appetite at baseline was greater in the PM than in the AM condition (higher hunger, lower fullness). Following the liquid meal, area under the curve (AUC) values for hunger and ghrelin were greater and AUC values for peptide YY lower in the PM than in the AM condition. Only those with BED showed lower fullness AUC in the PM condition, as well as a pattern of higher initial PM and lower initial AM ghrelin. Following the stress test, cortisol and ghrelin increased in both the AM and PM conditions, but higher ghrelin AUC and lower cortisol AUC were observed in the PM condition. Again, only participants with BED showed lower fullness AUC in the PM condition. Buffet meal intake was similar across groups and conditions but those with BED reported greater loss of control and binge resemblance than those without. CONCLUSIONS: Afternoon/evening may be a high-risk period for overeating, particularly when paired with stress exposure, and for those with binge eating. PMID- 29235556 TI - Mortality due to refeeding syndrome? You only find what you look for, and you only look for what you know. PMID- 29235557 TI - Timing, duration, and severity of iron deficiency in early development and motor outcomes at 9 months. AB - BACKGROUND/OBJECTIVES: Poorer motor development is reported in infants with iron deficiency (ID). The role of timing, duration and severity is unclear. We assessed relations between ID timing, duration, and severity and gross motor scores, neurological integrity, and motor behavior quality at 9 months. SUBJECTS/METHODS: Iron status was determined at birth and 9 months in otherwise healthy term Chinese infants. The 9-month motor evaluation included the Peabody Developmental Motor Scale (PDMS-2), Infant Neurological International Battery (INFANIB), and motor quality factor. Motor outcomes were analyzed by ID timing (fetal-neonatal, infancy), duration, and severity. For severity, we also considered maternal iron status. RESULTS: The data were available for 1194 infants. Iron status was classified as fetal-neonatal and infancy ID (n = 253), fetal-neonatal ID (n = 256), infancy ID (n = 288), and not ID (n = 397). Compared with not ID, infants with fetal-neonatal or infancy ID had lower locomotion scores (effect size ds = 0.19, 0.18) and those with ID in both periods (longer duration) had lower locomotion and overall PDMS-2 gross motor scores (ds = 0.20, 0.18); ID groups did not differ. More severe ID in late pregnancy was associated with lower INFANIB Vestibular function (p = 0.01), and total score (p = 0.03). More severe ID in infancy was associated with lower scores for locomotion (p = 0.03), overall gross motor (p = 0.05). CONCLUSIONS: Fetal-neonatal and/or infancy ID was associated with lower overall gross motor development and locomotion test scores at 9 months. Associations with ID severity varied by ID timing: more severe ID in late pregnancy, poorer neurological integrity; more severe ID in infancy, poorer gross motor development. PMID- 29235558 TI - Dietary copper restriction in Wilson's disease. AB - Dietary copper restriction has long been considered an important aspect of treatment for Wilson's disease (WD). However, evidence supporting this approach is limited. There are no published randomised controlled trials examining this recommendation due to rarity of the disease and variable presentation. This review summarises current knowledge on the absorption and regulation of copper in humans and its relevance to patients with WD. Studies have demonstrated that as the level of dietary copper increases, the proportion absorbed decreases. This observation implies that 'high copper' foods that WD patients are generally advised to avoid would need to be consumed in large amounts to impact markedly on the quantity absorbed. Dietary copper restriction is unlikely to reduce the amount absorbed significantly and is not only difficult to manage but restricts food groups unnecessarily, detracting from the provision of substrates essential for improving nutritional status in a nutritionally compromised group. Medical management for WD is effective in compliant patients, allowing stabilisation of the liver disease. Based on current evidence, dietary copper restrictions in stable WD patients who are adherent to medical therapy are unnecessary with two food exceptions (shellfish and liver). PMID- 29235559 TI - Body size modifies the relationship between maternal serum 25-hydroxyvitamin D concentrations and gestational diabetes in high-risk women. AB - Obesity increases the risk of low 25-hydroxyvitamin D (25(OH)D) concentrations and gestational diabetes (GDM). We explored whether the association between GDM and change in 25(OH)D concentrations measured in the first (7-18 wk) and second (20-27 wk) trimesters of pregnancy is dependent on maternal BMI. The study was a prospective study of 219 women with BMI of >=30 kg/m2, a history of GDM, or both. The participants were stratified by first-trimester BMI: BMI of <25.0, 25.0-29.9, 30.0-34.9, and >=35 kg/m2. In the BMI group >=35 kg/m2, those who did not develop GDM during the follow-up showed higher increase in serum 25(OH)D concentrations compared with women who developed GDM (43.2 vs. 11.5%; P < 0.001). No associations between 25(OH)D concentrations and GDM were observed in other BMI groups. These findings give an important aspect of the role of maternal body size in the association between vitamin D and GDM in high-risk women. PMID- 29235560 TI - Effect of high milk and sugar-sweetened and non-caloric soft drink intake on insulin sensitivity after 6 months in overweight and obese adults: a randomized controlled trial. AB - BACKGROUND/OBJECTIVES: Milk contributes with saturated fat, but randomized controlled trials (RCT) on the effects of dairy on the risk of type 2 diabetes (T2D) where dairy is given as whole foods are scarce. The objective of our study was to investigate the long-term effects of semi-skimmed milk on insulin sensitivity and further to compare milk with sugar-sweetened soft drinks (SSSD). SUBJECTS/METHODS: A secondary analysis of a 6-month RCT with 60 overweight and obese subjects randomly assigned to 1 L/d of either milk (1.5 g fat/100 mL), SSSD, non-calorie soft drink (NCSD), or water was conducted. Insulin sensitivity was evaluated by oral glucose tolerance test (OGTT) and plasma free fatty acids. Second, fasting blood lipids, blood pressure, and concentration of plasminogen activator inhibitor-1 were assessed. RESULTS: There were no differences between milk, SSSD, NCSD, and water on insulin sensitivity assessed by OGTT (Matsuda Index, fasting, and area under the curve glucose, insulin and homeostasis model assessment values). SSSD increased total cholesterol compared to NCSD (P = 0.007), and triacylglycerol compared to NCSD and water (P = 0.045 and 0.045, respectively). None of the other parameters differed significantly between the groups. CONCLUSIONS: In conclusion, there were no differences in effect between intake of milk, SSSD, NCSD, and water (1 L/d) for 6-month on risk markers of T2D in overweight and obese adults. As a secondary analysis, these results need confirmation in future studies. PMID- 29235561 TI - Fruit and vegetable intake and cognitive impairment: a systematic review and meta analysis of observational studies. AB - BACKGROUND/OBJECTIVES: Epidemiological studies investigating the association between fruit and vegetable consumption and cognitive function have produced inconclusive findings. The aim of this review was to systematically investigate if increased fruit and vegetable consumption is linked with decreased risk of cognitive impairment (CI). METHODS: We conducted a systematic literature search using four databases (PubMed, Embase, Cochrane Library, and Scopus) in October 2016 and identified cohort and cross-sectional studies, which estimated the risk of CI for fruit and vegetable consumption. The pooled odds ratio (OR) and 95% confidence interval (CI) were estimated by using a random effects model. RESULTS: The six studies meeting inclusion criteria offered 10 effect sizes and the total of 17,537 participants in the analysis. Increased fruit and vegetable intake was associated with reduced risk of CI (OR: 0.79; 95% CI: 0.67-0.93; P = 0.006). The subgroup analysis demonstrated that in studies conducted in China (but not in Western countries), the corresponding reduction in risk of CI risk was significant (OR: 0.74; 95% CI: 0.61, 0.89; P = 0.002) and the relationship between fruits, vegetables, and CI did not differ by study design, type of exposure, and gender. CONCLUSION: Increased fruit and vegetable consumption is associated with the reduced risk of CI; however, such association might be dependent on the geographical region. Further prospective studies specifically designed to compare vegetables and fruit varieties, and also to determine the recommended amounts to prevent CI are warranted. PMID- 29235563 TI - Cell and molecular biology: a new section joins the fight against cancer. PMID- 29235562 TI - Targeting the Raf kinases in human cancer: the Raf dimer dilemma. AB - The Raf protein kinases are key intermediates in cellular signal transduction, functioning as direct effectors of the Ras GTPases and as the initiating kinases in the ERK cascade. In human cancer, Raf activity is frequently dysregulated due to mutations in the Raf family member B-Raf or to alterations in upstream Raf regulators, including Ras and receptor tyrosine kinases. First-generation Raf inhibitors, such as vemurafenib and dabrafenib, have yielded dramatic responses in malignant melanomas containing B-Raf mutations; however, their overall usefulness has been limited by both intrinsic and acquired drug resistance. In particular, issues related to the dimerisation of the Raf kinases can impact the efficacy of these compounds and are a primary cause of drug resistance. Here, we will review the importance of Raf dimerisation in cell signalling as well as its effects on Raf inhibitor therapy, and we will present the new strategies that are being pursued to overcome the 'Raf Dimer Dilemma'. PMID- 29235564 TI - Influence of induction chemotherapy in trimodality therapy-eligible oesophageal cancer patients: secondary analysis of a randomised trial. AB - BACKGROUND: A randomised phase 2 trial of trimodality with or without induction chemotherapy (IC) in oesophageal cancer (EC) patients showed no advantage in overall survival (OS) or pathologic complete response rate. To identify subsets that might benefit from IC, a secondary analysis was done. METHODS: The trial had accrued 126 patients (NCT 00525915). Recursive partitioning and proportional hazards regression with interactions were performed. RESULTS: The median follow up of surviving patients was 6.7 years and the median OS duration was 3.8 years (95% confidence interval (CI), 2.6-5.8 years). OS was associated with tumour length (P=0.03), cT (P=0.02), cN (P=0.04), clinical stage (P=0.01), and tumour grade (P<0.001). The effect of IC differed according to tumour grade. Among patients with well or moderately differentiated (WMD) ECs (n=59), the 5-year survival rate was 74% with IC and 50% without IC, P=0.001. IC had no effect on OS of patients with poorly differentiated (PD) ECs (31% and 28%, respectively; interaction, P=0.04; IC, P=0.03). In the multivariate reduced model, WMD with IC was an independent prognosticator for better OS (HR=0.41, 95% CI, 0.25-0.67; P=<0.001). The following four EC phenotypes emerged for OS: (1) very high risk (PD, cN2/N3), (2) high risk (PD, cN0/N1, stage cIII), (3) moderate risk (PD, cN0/N1, stage cI/II or WMD without IC), and (4) low risk (WMD with IC). The 5 year survival rates were 11%, 27%, 48%, and 74%, respectively (P<0.001). CONCLUSIONS: Our data show that IC significantly prolonged OS of WMD EC patients who undergo trimodality; prospective evaluation is needed. PMID- 29235565 TI - Anthropometric measurements and survival after a prostate cancer diagnosis. AB - BACKGROUND: Evidence regarding the role of anthropometrics in prostate cancer survival is inconsistent. We examined the associations between anthropometric measures and survival outcomes. METHODS: Men diagnosed with prostate cancer (n=987) were recruited into a population-based case-control study between 1997 and 2000 then a prospective cohort study between 2000 and 2002 where anthropometric measurements (weight, height, body mass index, waist circumference, waist-hip ratio) were taken and participants were followed up to 19 years for survival outcomes. Cox proportional hazards were used to examine these associations. RESULTS: Survival analyses suggested no clear pattern of associations between post-diagnosis anthropometric measurements and all-cause mortality, prostate-specific mortality, first recurrence/progression or new primary cancer. CONCLUSIONS: We did not find a significant trend relating anthropometrics to survival outcomes after prostate cancer diagnosis. Continued assessment of objective measurements of body composition over the life-course is warranted to determine true associations between anthropometrics and survival after prostate cancer. PMID- 29235566 TI - Long-term survival outcomes of triple-receptor negative breast cancer survivors who are disease free at 5 years and relationship with low hormone receptor positivity. AB - BACKGROUND: We counsel our triple-negative breast cancer (TNBC) patients that the risk of recurrence is highest in the first 5 years after diagnosis. However, there are limited data with extended follow-up on the frequency, characteristics, and predictors of late events. METHODS: We queried the MD Anderson Breast Cancer Management System database to identify patients with stage I-III TNBC who were disease free at 5 years from diagnosis. The Kaplan-Meier method was used to estimate yearly recurrence-free interval (RFI), recurrence-free survival (RFS), and distant relapse-free survival (DRFS), as defined by the STEEP criteria. Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We identified 873 patients who were disease free at least 5 years from diagnosis with median follow-up of 8.3 years. The 10 year RFI was 97%, RFS 91%, and DRFS 92%; the 15-year RFI was 95%, RFS 83%, and DRFS 84%. On a subset of patients with oestrogen receptor and progesterone receptor percentage recorded, low hormone receptor positivity conferred higher risk of late events on multivariable analysis for RFS only (RFI: HR=1.98, 95% CI=0.70-5.62, P-value=0.200; RFS: HR=1.94, 95% CI=1.05-3.56, P-value=0.034; DRFS: HR=1.72, 95% CI=0.92-3.24, P-value=0.091). CONCLUSIONS: The TNBC survivors who have been disease free for 5 years have a low probability of experiencing recurrence over the subsequent 10 years. Patients with low hormone receptor positive cancers may have a higher risk of late events as measured by RFS but not by RFI or DRFS. PMID- 29235567 TI - Alcohol and oestrogen metabolites in postmenopausal women in the Women's Health Initiative Observational Study. AB - BACKGROUND: Alcohol consumption is associated with an increased risk of several cancers. Potential mechanisms include altered oestrogen metabolism. Parent oestrogens metabolise into alternate pathways of oestrogen metabolites that may have variable effects on cancer pathogenesis. We examined associations of alcohol consumption with circulating oestrogen/oestrogen metabolites in postmenopausal women in the Women's Health Initiative (WHI)-Observational Study (OS). METHODS: We conducted a cross-sectional analysis of prediagnosis ovarian/endometrial cancer case-control data within WHI-OS (N=1864). Alcohol consumption was measured by validated food frequency questionnaire. Fasting serum parent oestrogens/oestrogen metabolites were assayed using liquid chromatography tandem mass-spectrometry. Geometric mean analyte concentrations (GM, pmol l-1) were calculated by alcohol category using inverse-probability weighted linear regression, adjusting for venepuncture age/year, race, smoking, body mass index, years since menopause, oral contraceptive duration, caffeine intake, and physical activity. RESULTS: There was evidence for a positive association between alcohol consumption and oestrone, oestradiol and 2-hydroxylation oestrogen metabolite concentrations among menopausal hormone therapy (MHT) users. We observed an association between liquor consumption and parent oestrogens among non-MHT users, who consumed larger doses of liquor than MHT users. CONCLUSIONS: Among postmenopausal women, the association between alcohol intake and parent oestrogen, but not oestrogen metabolite concentrations, may be influenced by MHT and type of alcohol. PMID- 29235568 TI - ALDH1A3 affects colon cancer in vitro proliferation and invasion depending on CXCR4 status. AB - BACKGROUND: Aldehyde dehydrogenase (ALDH) has been widely used as a marker of cancer stem cells (CSCs). However, the ALDH family includes 19 members, and the most relevant isoforms and their biological functions in cancer biology are still controversial. METHODS: We examined ALDH enzyme activity and the mRNA expression of 19 ALDH members in 58 human cell lines. The biological effect and mechanism of knocking down ALDH1A3 with siRNA and shRNA in cell lines were explored. Finally, the relationship between ALDH1A3 and CXCR4 was analysed in a large panel of cell lines. RESULTS: ALDH1A3 is the key isoform that contributed to Aldefluor positivity in cell lines. Knocking down ALDH1A3 in different cancer cells conferred opposite phenotypes due to differential effects on CXCR4 expression. There was a significant negative correlation between ALDH1A3 and CXCR4 in 58 human cell lines. CONCLUSIONS: ALDH1A3 was the main contributor to Aldefluor positivity in human cell lines, and its contrasting effects might arise from differences in CXCR4 expression. PMID- 29235569 TI - S-1 chemotherapy and intensity-modulated radiotherapy after D1/D2 lymph node dissection in patients with node-positive gastric cancer: a phase I/II study. AB - BACKGROUND: This phase I/II clinical trial investigated S-1 administered with intensity-modulated radiotherapy (IMRT) as adjuvant therapy for node-positive gastric cancer. Patients had undergone radical resection and D1/D2 lymph node dissection. METHODS: In phase I, patients received adjuvant chemoradiotherapy of IMRT (45 Gy in 25 fractions) with concurrent S-1 administered on a dose escalation schedule to determine the recommended dose (RD). In phase II, the safety and efficacy of the RD of S-1 combined with IMRT were assessed. RESULTS: We consecutively enrolled 73 patients (56 men; median age, 53 years; range, 29-73 years) and the phase I portion of the study included 27 patients. The RD of S-1 administered concomitantly with IMRT was 80 mg m-2 day-1 orally, twice daily. The phase II analysis included 52 patients (46 new patients plus 6 from phase I). 8 patients (15.4%) developed grade 3 or 4 toxicities. There were 21 recurrence events and 15 deaths (1 bowel obstruction, 14 gastric cancer). Three-year disease free survival and overall survival were 62.2% (95% confidence interval (CI), 48.5 75.9) and 70.0% (95% CI, 56.3-83.7), respectively. The median time to recurrence was 17.5 months (range, 3.8-42.0). The median time from recurrence to death was 7.0 months (range, 1.5-28.7). CONCLUSIONS: S-1 combined with IMRT adjuvant chemoradiotherapy is safe and efficacious for advanced gastric cancer. PMID- 29235570 TI - Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma. AB - BACKGROUND: Cutaneous melanoma is the most serious skin malignancy and new therapeutic strategies are needed for advanced melanoma. TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma. Here, we investigated the WIP1 inhibitor, GSK2830371, and MDM2-p53 binding antagonists (nutlin-3, RG7388 and HDM201) alone and in combination treatment in cutaneous melanoma cell lines and explored the mechanistic basis of these responses in relation to the genotype and induced gene expression profile of the cells. METHODS: A panel of three p53WT (A375, WM35 and C8161) and three p53MUT (WM164, WM35-R and CHL-1) melanoma cell lines were used. The effects of MDM2 and WIP1 inhibition were evaluated by growth inhibition and clonogenic assays, immunoblotting, qRT-PCR gene expression profiling and flow cytometry. RESULTS: GSK2830371, at doses (?10 MUM) that alone had no growth-inhibitory or cytotoxic effects on the cells, nevertheless significantly potentiated the growth-inhibitory and clonogenic cell killing effects of MDM2 inhibitors in p53WT but not p53MUT melanoma cells, indicating the potentiation worked in a p53-dependent manner. The siRNA-mediated knockdown of p53 provided further evidence to support the p53 dependence. GSK2830371 increased p53 stabilisation through Ser15 phosphorylation and consequent Lys382 acetylation, and decreased ubiquitination and proteasome-dependent degradation when it was combined with MDM2 inhibitors. These changes were at least partly ATM mediated, shown by reversal with the ATM inhibitor (KU55933). GSK2830371 enhanced the induction of p53 transcriptional target genes, cell cycle arrest and apoptosis. CONCLUSIONS: GSK2830371, a WIP1 inhibitor, at doses with no growth inhibitory activity alone, potentiated the growth-inhibitory and cytotoxic activity of MDM2 inhibitors by increasing phosphorylation, acetylation and stabilisation of p53 in cutaneous melanoma cells in a functional p53-dependent manner. PMID- 29235572 TI - A Shared Understanding: Managing Aesthetic Treatment Imperfection. PMID- 29235571 TI - The hypoxia marker CAIX is prognostic in the UK phase III VorteX-Biobank cohort: an important resource for translational research in soft tissue sarcoma. AB - BACKGROUND: Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial. METHODS: Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1alpha, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan-Meier and Cox regression. RESULTS: Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44-3.59, P<0.001). Hypoxia-inducible factor-1alpha and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis. CONCLUSIONS: The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity. PMID- 29235573 TI - Constitutively elevated levels of SOCS1 suppress innate responses in DF-1 immortalised chicken fibroblast cells. AB - The spontaneously immortalised DF-1 cell line is rapidly replacing its progenitor primary chicken embryo fibroblasts (CEFs) for studies on avian viruses such as avian influenza but no comprehensive study has as yet been reported comparing their innate immunity phenotypes. We conducted microarray analyses of DF-1 and CEFs, under both normal and stimulated conditions using chicken interferon-alpha (chIFN-alpha) and the attenuated infectious bursal disease virus vaccine strain PBG98. We found that DF-1 have an attenuated innate response compared to CEFs. Basal expression levels of Suppressor of Cytokine Signalling 1 (chSOCS1), a negative regulator of cytokine signalling in mammals, are 16-fold higher in DF-1 than in CEFs. The chSOCS1 "SOCS box" domain (which in mammals, interacts with an E3 ubiquitin ligase complex) is not essential for the inhibition of cytokine induced JAK/STAT signalling activation in DF-1. Overexpression of SOCS1 in chIFN alpha-stimulated DF-1 led to a relative decrease in expression of interferon stimulated genes (ISGs; MX1 and IFIT5) and increased viral yield in response to PBG98 infection. Conversely, knockdown of SOCS1 enhanced induction of ISGs and reduced viral yield in chIFN-alpha-stimulated DF-1. Consequently, SOCS1 reduces induction of the IFN signalling pathway in chicken cells and can potentiate virus replication. PMID- 29235575 TI - Ageing: Pol III inhibition: new promise of longevity. PMID- 29235577 TI - Out-of-hospital cardiac arrest. AB - Out-of-hospital cardiac arrest (OHCA) is a leading cause of death in developed industrial countries. The global worldwide average of OHCA incidence in adults is 95.9/100,000/year. European incidences vary according to source from 16 to 119/100,000/year. The aim of this study was to provide an overview of current information on OHCA. The incidences in various populations are discussed, along with the factors affecting the prognosis and outcome of these patients. The etiology and pathophysiological mechanisms are also described, especially in relation to the most common causes - acute and chronic forms of coronary artery disease and cardiomyopathies. Measures that could improve survival rates are discussed, with emphasis on the role of the general public and deployment of automatic external defibrillators. PMID- 29235576 TI - The unfolded protein response impacts melanoma progression by enhancing FGF expression and can be antagonized by a chemical chaperone. AB - The mechanisms hallmarking melanoma progression are insufficiently understood. Here we studied the impact of the unfolded protein response (UPR) - a signalling cascade playing ambiguous roles in carcinogenesis - in melanoma malignancy. We identified isogenic patient-derived melanoma cell lines harboring BRAFV600E mutations as a model system to study the role of intrinsic UPR in melanoma progression. We show that the activity of the three effector pathways of the UPR (ATF6, PERK and IRE1) was increased in metastatic compared to non-metastatic cells. Increased UPR-activity was associated with increased flexibility to cope with ER stress. The activity of the ATF6- and the PERK-, but not the IRE-pathway, correlated with poor survival in melanoma patients. Using whole-genome expression analysis, we show that the UPR is an inducer of FGF1 and FGF2 expression and cell migration. Antagonization of the UPR using the chemical chaperone 4-phenylbutyric acid (4-PBA) reduced FGF expression and inhibited cell migration and viability. Consistently, FGF expression positively correlated with the activity of ATF6 and PERK in human melanomas. We conclude that chronic UPR stimulates the FGF/FGF receptor signalling axis and promotes melanoma progression. Hence, the development of potent chemical chaperones to antagonize the UPR might be a therapeutic approach to target melanoma. PMID- 29235578 TI - Are we any closer to screening for colorectal cancer using microbial markers?A critical review. AB - The role of gut microbiota in the development of sporadic colorectal cancer (CRC) is supported by a number of studies, however, the conclusiveness of published metagenomic studies is questioned by technical pitfalls and limited by small cohort sizes. In this review, we evaluate the current knowledge critically and outline practical solutions. We also list candidate CRC risk markers that are - in our opinion - well supported by available data and thus deserve clinical validation. Last but not least, we summarise available knowledge useful for improving care for patients immediately. PMID- 29235579 TI - The presence of gasping predicts long-term survival in out-of-hospital cardiac arrest patients. AB - BACKGROUND: The presence of gasping in out-of-hospital cardiac arrest (OHCA) patients predicts short-term prognosis. We performed a retrospective study to evaluate whether the presence of gasping at the time of Emergency Medical Service (EMS) arrival in the case OHCA patients of presumed cardian origin has any impact on six-month survival and/or sustained return of spontaneous circulation (ROSC). METHODS: We collected and analyzed Utstein Style data for all patients resuscitated for OHCA of presumed cardiac origin by the EMS of the Central Bohemian Region from July 1st, 2013 to June 30th, 2014. RESULTS: During the data collection period, 565 cases of OHCA of presumed cardiac origin were reported. Gasping at the time of EMS arrival was identified in 23.9%. The presence of gasping was associated with a significantly increased frequency of sustained ROSC (48.1 versus 20.7%, P<0.001) and six-month survival (40.7 versus 16.7%, P<0.001) than in non-breathing patients. Presence of gasping upon EMS arrival has been found to be an independent positive predictor of sustained ROSC (OR 2.51, CI 95% 1.59-3.98, P<0.001). The occurrence of gasping at the time of EMS arrival at the scene was significantly related to response time from EMS activation to arrival. CONCLUSION: The presence of gasping upon arrival of the EMS for the patient with OHCA of presumed cardiac origin predicts both improves short-term and long-term prognoses. PMID- 29235574 TI - Ten principles of heterochromatin formation and function. AB - Heterochromatin is a key architectural feature of eukaryotic chromosomes, which endows particular genomic domains with specific functional properties. The capacity of heterochromatin to restrain the activity of mobile elements, isolate DNA repair in repetitive regions and ensure accurate chromosome segregation is crucial for maintaining genomic stability. Nucleosomes at heterochromatin regions display histone post-translational modifications that contribute to developmental regulation by restricting lineage-specific gene expression. The mechanisms of heterochromatin establishment and of heterochromatin maintenance are separable and involve the ability of sequence-specific factors bound to nascent transcripts to recruit chromatin-modifying enzymes. Heterochromatin can spread along the chromatin from nucleation sites. The propensity of heterochromatin to promote its own spreading and inheritance is counteracted by inhibitory factors. Because of its importance for chromosome function, heterochromatin has key roles in the pathogenesis of various human diseases. In this Review, we discuss conserved principles of heterochromatin formation and function using selected examples from studies of a range of eukaryotes, from yeast to human, with an emphasis on insights obtained from unicellular model organisms. PMID- 29235580 TI - Corrigendum: Interleukin-7 Induces Osteoclast Formation via STAT5, Independent of Receptor Activator of NF-kappaB Ligand. AB - [This corrects the article on p. 1376 in vol. 8, PMID: 29104576.]. PMID- 29235581 TI - Erratum: Inter-Facility Transport on Extracorporeal Life Support: Clinical Outcomes and Comparative Analysis with In-house Patients. AB - [This corrects the article on p. 363 in vol. 50, PMID: 29124028.]. PMID- 29235582 TI - Commentary: Evolution of UCP1 Transcriptional Regulatory Elements Across the Mammalian Phylogeny. PMID- 29235584 TI - Erratum: A short telephone-call reminder improves bowel preparation, quality indicators and patient satisfaction with first colonoscopy. AB - [This corrects the article DOI: 10.1055/s-0043-117954.]. PMID- 29235583 TI - Pregnancy-induced alterations in mitochondrial function in euthyroid pregnant women and pregnant women with subclinical hypothyroidism; relation to adverse outcome. AB - Background: It is well documented that overt hypothyroidism is associated with adverse pregnancy outcomes, but studies of subclinical hypothyroidism have demonstrated conflicting results. Objective: Thyroid hormones are known to regulate mitochondrial function, and the aim of this study was to examine the possible relationship of subclinical hypothyroidism and mitochondrial dysfunction to adverse pregnancy outcomes in pregnant women. Methods: Women in their third trimester of pregnancy (n = 113) who did not receive thyroid medication were included in this cross-sectional study. All participants were interviewed, and their thyroid status was determined. All participants had concentrations of thyroid hormones (fT4 and tT3) within the reference range. In addition to thyroid status, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were measured by flow cytometry. To establish a reference range of MMP and ROS, a group of euthyroid, nonpregnant women were used as euthyroid controls. Adverse pregnancy outcome was defined as preterm delivery, preeclampsia, placental abruption, Apgar score <7 points 1 minute after birth, or postpartum hemorrhage. Results: The prevalence of subclinical hypothyroidism among pregnant women was 17% (n = 19), and the number of overall adverse pregnancy outcomes was increased (p = 0.02) compared with that in euthyroid pregnant women. Preeclampsia, poor Apgar score, and postpartum hemorrhage were more frequent in the subclinical hypothyroidism group than in the euthyroid group (p = 0.04, p = 0.001 and p = 0.03, respectively), and more women showed prolonged gestation and gave birth later than 41 weeks of gestation than in the euthyroid group (p = 0.04). Compared with euthyroid, nonpregnant controls, a physiological upregulation of mitochondrial function was observed in euthyroid pregnant women. This was impaired in pregnant women with subclinical hypothyroidism. Compared with euthyroid, nonpregnant controls, pregnant women had increased ROS regardless of their thyroid status. Conclusion: We speculate that the unfavorable effects on mitochondrial function in women with subclinical hypothyroidism may be associated with higher prevalence of adverse pregnancy outcomes. PMID- 29235585 TI - Corrigendum to "Antihypercholesterolemic Effects of Fruit Aqueous Extract of Copernicia prunifera (Miller) H. E. Moore in Mice Diet-Induced Hypercholesterolemia". AB - [This corrects the article DOI: 10.1155/2017/6376173.]. PMID- 29235586 TI - Exploring glycosuria as a mechanism for weight and fat mass reduction. A pilot study with remogliflozin etabonate and sergliflozin etabonate in healthy obese subjects. AB - Inhibitors of sodium-dependent glucose co-transporter 2 (SGLT2) increase glucose excretion in the urine and improve blood glucose in Type 2 diabetes mellitus. Glycosuria provides an energy and osmotic drain that could alter body composition. We therefore conducted a pilot study comparing the effects on body composition of two SGLT2 inhibitors, remogliflozin etabonate (RE) 250 mg TID (n = 9) and sergliflozin etabonate (SE) (1000 mg TID) (n = 9), with placebo (n = 12) in obese non-diabetic subjects. Both drugs were well tolerated during 8 weeks of dosing, and the most common adverse event was headache. No urinary tract infections were observed, but there was one case of vaginal candidiasis in the RE group. As expected, RE and SE increased urine glucose excretion, with no change in the placebo group. All the subjects lost weight over 8 weeks, irrespective of treatment assignment. There was a reduction in TBW measured by D2O dilution in the RE group that was significantly greater than placebo (1.4 kg, p = 0.029). This was corroborated by calculation of fat-free mass using a quantitative magnetic resonance technique. All but one subject had a measurable decrease in fat mass. There was significant between-subject variability of weight and fat loss, and no statistically significant differences were observed between groups. Despite a lack of a difference in weight and fat mass loss, the leptin/adiponectin ratio, a measure of insulin resistance, was significantly decreased in the RE group when compared to placebo and SE, suggesting that this SGTL-2 inhibitor may improve metabolic health independent of a change in fat mass. PMID- 29235587 TI - Retinopathy in subjects with type 2 diabetes at a tertiary diabetes clinic in Durban, South Africa: Clinical, biochemical and genetic factors. AB - Aim: To determine the prevalence of clinical and laboratory variables and genetic polymorphisms in association with diabetic retinopathy (DR) in subjects with type 2 diabetes attending a tertiary referral diabetes clinic in Durban, South Africa. Methods: Cross-sectional study on 292 Indian and African patients with type 2 diabetes (71.5% women). The presence of DR was determined by direct ophthalmoscopy. Clinical and laboratory data were collected and polymorphisms in the NOS3 (rs61722009, rs2070744, rs1799983) and VEGF (rs35569394, rs2010963) genes were determined. Results: DR was present in 113 (39%) subjects. Those with DR were older (60.6 +/- 9.6 vs. 55.4 +/- 12.9 years, p = 0.005), had longer duration diabetes (18.5 +/- 8.8 vs. 11.9 +/- 9.2 years, p < 0.0001), higher HbA1c (9.2 +/- 1.8 vs. 8.8 +/- 1.7%, p = 0.049), serum creatinine (106.3 +/- 90.2 vs. 75.2 +/- 33.4 MUmol/l), triglycerides (2.1 +/- 1.2 vs. 1.9 +/- 1.6 mmol/l, p = 0.042), proteinuria (72% vs. 28%, p = 0.001), and used more insulin (78% vs. 39% p = 0.0001), anti-hypertensive (95% vs. 80%, p = 0.0003) and lipid-lowering therapy (70% vs. 56%, p = 0.023). There was no association between DR and any of the NOS3 or VEGF gene polymorphisms studied, although there were ethnic differences. After adjustment, diabetes duration (OR 1.05, 95% CI 1.01-1.08), presence of proteinuria (OR 4.15, 95% CI 1.70-10.11) and use of insulin therapy (OR 3.38, 95% CI 1.60-7.12) were associated with DR. Conclusion: Hyperglycemia, duration of diabetes and proteinuria are associated with DR in Indian and African patients in South Africa, whereas NOS3 and VEGF gene polymorphisms were not associated with DR. PMID- 29235588 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000463377.]. PMID- 29235589 TI - Corrigendum to "Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions". AB - [This corrects the article DOI: 10.1155/2017/5491812.]. PMID- 29235590 TI - Unravelling the hydrophobicity of urea in water using thermodiffusion: implications for protein denaturation. AB - Urea is widely used as a protein denaturant in aqueous solutions. Experimental and computer simulation studies have shown that it dissolves in water almost ideally at high concentrations, introducing little disruption in the water hydrogen bonded structure. However, at concentrations of the order of 5 M or higher, urea induces denaturation in a wide range of proteins. The origin of this behaviour is not completely understood, but it is believed to stem from a balance between urea-protein and urea-water interactions, with urea becoming possibly hydrophobic at a specific concentration range. The small changes observed in the water structure make it difficult to connect the denaturation effects to the solvation properties. Here we show that the exquisite sensitivity of thermodiffusion to solute-water interactions allows the identification of the onset of hydrophobicity of urea-water mixtures. The hydrophobic behaviour is reflected in a sign reversal of the temperature dependent slope of the Soret coefficient, which is observed, both in experiments and non-equilibrium computer simulations at ~5 M concentration of urea in water. This concentration regime corresponds to the one where abrupt changes in the denaturation of proteins are commonly observed. We show that the onset of hydrophobicity is intrinsically connected to the urea-water interactions. Our results allow us to identify correlations between the Soret coefficient and the partition coefficient, log P, hence establishing the thermodiffusion technique as a powerful approach to study hydrophobicity. PMID- 29235591 TI - BEAMing LAMP: single-molecule capture and on-bead isothermal amplification for digital detection of hepatitis C virus in plasma. AB - A novel dNAD platform (BEAMing LAMP) by combining emulsion micro-reactors, single molecule magnetic capture and on-bead loop-mediated isothermal amplification has been developed for DNA detection, which enables absolute and high-precision quantification of a target with a detection limit of 300 copies. PMID- 29235592 TI - Effect of immobilization site on the orientation and activity of surface-tethered enzymes. AB - Tethering peptides and proteins to abiotic surfaces has the potential to create biomolecule-functionalized surfaces with useful properties. Commonly used methods of immobilization lack control over the orientation in which biological molecules are covalently or physically bound to the surface, leading to sub-optimal materials. Here we use an engineered beta-galactosidase that can be chemically immobilized on a surface with a well-defined orientation through unique surface accessible cysteine residues. A combined study using sum frequency generation (SFG) vibrational spectroscopy and coarse grained molecular dynamics (MD) simulations was performed to determine the effects of enzyme immobilization site and abiotic surface chemistry on enzyme surface orientation, surface coverage, and catalytic activity. Two beta-galactosidase variants that were immobilized through cysteine introduced at positions 227 and 308 were studied. In both cases, when the abiotic surface was made more hydrophilic, the enzyme surface coverage decreased, but the activity increased. MD simulations indicated that this is due to the weakened interactions between the immobilized enzyme and the more hydrophilic surface. These studies provide improved understanding of how enzyme surface interactions can be optimized to maximize the catalytic activity of surface tethered enzymes. PMID- 29235594 TI - Salivary endocannabinoids and N-acylethanolamines upon mastication of a semisolid food: implications in fat taste, appetite and food liking. AB - This study aimed to evaluate whether salivary endocannabinoid (EC) and N acylethanolamine (NAE) concentrations upon mastication of a semisolid food were involved in the sensory perception of fat taste, food liking and appetite in humans. A fat-enriched (FEP) and a low-fat control (CP) pudding were developed and used in a randomized cross-over study with 19 healthy volunteers. The study protocol combined a Modified Sham-Feeding (MSF) with a multiple-spoon Temporal Dominance of Sensations method. Subjects masticated and expectorated 10 spoons of the pudding and selected the dominant sensations among a list of attributes. Saliva samples, appetite and food liking scores were collected at baseline, immediately after the MSF of the pudding and every 5 min until 20 min after MSF. Salivary concentrations of all monitored ECs and NAEs increased during pudding mastication compared to baseline (except for palmitoylethanolamide with FEP). The raise was lower with FEP than with CP for all compounds except for 2 arachidonoylglycerol whose increase was higher than the other compounds and independent of pudding type. Salivary N-arachidonoylethanolamine, linoleoylethanolamide and palmitoylethanolamide were significantly lower at 10 and 20 min after MSF of FEP than CP. Fatty taste at the 2nd spoon and creaminess at the 5th spoon were perceived as dominant with FEP whereas only wateriness was dominant with CP at the 2nd spoon. No difference between puddings for individual appetite or food liking over the 20 min of the protocol was recorded. During mastication of a semisolid fat-enriched food, the fatty taste and the creaminess were perceived as dominant. Salivary ECs and NAEs were not associated with the individual perception of fatty taste, pudding liking and appetite sensations. PMID- 29235598 TI - The stimulation of GLP-1 secretion and delivery of GLP-1 agonists via nanostructured lipid carriers. AB - Nanoparticulate based drug delivery systems have been extensively studied to efficiently encapsulate and deliver peptides orally. However, most of the existing data mainly focus on the nanoparticles as a drug carrier, but the ability of nanoparticles having a biological effect has not been exploited. Herein, we hypothesize that nanostructured lipid carriers (NLCs) could activate the endogenous glucagon-like peptide-1 (GLP-1) secretion and also act as oral delivery systems for GLP-1 analogs (exenatide and liraglutide). NLCs effectively encapsulated the peptides, the majority of which were only released under the intestinal conditions. NLCs, with and without peptide encapsulation, showed effective induction of GLP-1 secretion in vitro from the enteroendocrinal L-cells (GLUTag). NLCs also showed a 2.9-fold increase in the permeability of exenatide across the intestinal cell monolayer. The intestinal administration of the exenatide and liraglutide loaded NLCs did not demonstrate any glucose lowering effect on normal mice. Further, ex vivo studies depicted that the NLCs mainly adhered to the mucus layer. In conclusion, this study demonstrates that NLCs need further optimization to overcome the mucosal barrier in the intestine; nonetheless, this study also presents a promising strategy to use a dual-action drug delivery nanosystem which synergizes its own biological effect and that of the encapsulated drug molecule. PMID- 29235599 TI - Modelling oral up-take of hydrophobic and super-hydrophobic chemicals in fish. AB - We have extended a recently published toxicokinetic model for fish (TK-fish) towards the oral up-take of contaminants. Validation with hydrophobic chemicals revealed that diffusive transport through aqueous boundary layers in the gastro intestinal tract and in the blood is the limiting process. This process can only be modelled correctly if facilitated transport by albumin or bile micelles through these boundary layers is accounted for. In a case study we have investigated the up-take of a super hydrophobic chemical, Dechlorane Plus. Our results suggest that there is no indication of a hydrophobicity or size cut-off in the bioconcentration of this chemical. Based on an extremely high, but mechanistically sound facilitation factor we received model results in good agreement with experimental values from the literature. The results also indicate that established experimental procedures for BCF determination cannot cover the very slow up-take and clearance kinetics that are to be expected for such a chemical. PMID- 29235601 TI - Ruthenium(ii) arene NSAID complexes: inhibition of cyclooxygenase and antiproliferative activity against cancer cell lines. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of molecules which have been found to be active against cancer cells with chemopreventive properties by targeting cyclooxygenase (COX-1 and COX-2) and lipoxygenase (LOX), commonly upregulated (particularly COX-2) in malignant tumors. Arene ruthenium(ii) complexes with a pseudo-octahedral coordination environment containing different ancillary ligands have shown remarkable activity against primary and metastatic tumors as reported earlier. This work describes the synthesis of four novel ruthenium(ii)-arene complexes viz. [Ru(eta6-p-cymene)(nap)Cl] 1 [Hnap = naproxen or (S)-2-(6-methoxy-2-naphthyl)propionic acid], [Ru(eta6-p-cymene)(diclo)Cl] 2 [Hdiclo = diclofenac or 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, [Ru(eta6-p-cymene)(ibu)Cl] 3 [Hibu = ibuprofen or 2-(4-isobutylphenyl)propanoic acid] and [Ru(eta6-p-cymene)(asp)Cl] 4 [Hasp = aspirin or 2-acetoxy benzoic acid] using different NSAIDs as chelating ligands. Complexes 1-3 have shown promising antiproliferative activity against three different cell lines with GI50 (concentration of drug causing 50% inhibition of cell growth) values comparable to adriamycin. At the concentration of 50 MUM, complex 3 is more effective in the inhibition of cyclooxygenase and lipooxygenase enzymes, followed by complex 2 and complex 1 in comparison to their respective free NSAID ligands indicating a possible correlation between the inhibition of COX and/or LOX and anticancer properties. Molecular docking studies with COX-2 reveal that complexes 1 and 2 having naproxen and diclofenac ligands exhibit stronger interactions with COX-2 than their respective free NSAIDs and these results are in good agreement with their relative experimentally observed COX inhibition as well as anti proliferative activities. PMID- 29235603 TI - A graphene mesh as a hybrid electrode for foldable devices. AB - A graphene mesh with arrays of micro-holes was fabricated on a polymer substrate using photolithography for use as an electrode in flexible devices. The optimal mesh structure with high optical transmittance and electrical conductivity was designed using a finite element method, in which the conductivity of the mesh was simulated as a function of structure, size, and periodicity of the hole array. The sheet resistance of the graphene mesh was lowered to that of a graphene monolayer by chemical doping and found to be 330 Omega Sq-1 at 98.5% transparency. The figure of merit of the doped graphene mesh was calculated to be 106 at 98% transmittance, a value that has not yet been reported for any conventional transparent electrode material. Due to strong bonding between the polymer and substrate, the hybrid electrode composed of a silver nanowire (AgNW)/graphene mesh coated with an over-coating layer exhibited more stable electrical characteristics during mechanical fatigue deformation compared to a hybrid film composed of a AgNW/graphene sheet. The AgNW/graphene sheet underwent breakdown at less than 20 000 cycles in cyclic bending tests with 6.5% strain, but the AgNW/graphene mesh showed a 38% increase in resistance at 20 000 cycles and no breakdown even at 100 000 cycles. Therefore, in this study, we propose a hybrid structure composed of a AgNW/graphene mesh, which is optically and mechanically superior to AgNW/graphene sheets, and therefore suitable for application as a transparent electrode in foldable devices with long-term stability. PMID- 29235605 TI - Flexible integrated diode-transistor logic (DTL) driving circuits based on printed carbon nanotube thin film transistors with low operation voltage. AB - Fabrication and application of hybrid functional circuits have become a hot research topic in the field of printed electronics. In this study, a novel flexible diode-transistor logic (DTL) driving circuit is proposed, which was fabricated based on a light emitting diode (LED) integrated with printed high performance single-walled carbon nanotube (SWCNT) thin-film transistors (TFTs). The LED, which is made of AlGaInP on GaAs, is commercial off-the-shelf, which could generate free electrical charges upon white light illumination. Printed top gate TFTs were made on a PET substrate by inkjet printing high purity semiconducting SWCNTs (sc-SWCNTs) ink as the semiconductor channel materials, together with printed silver ink as the top-gate electrode and printed poly(pyromellitic dianhydride-co-4,4'-oxydianiline) (PMDA/ODA) as gate dielectric layer. The LED, which is connected to the gate electrode of the TFT, generated electrical charge when illuminated, resulting in biased gate voltage to control the TFT from "ON" status to "OFF" status. The TFTs with a PMDA/ODA gate dielectric exhibited low operating voltages of +/-1 V, a small subthreshold swing of 62-105 mV dec-1 and ON/OFF ratio of 106, which enabled DTL driving circuits to have high ON currents, high dark-to-bright current ratios (up to 105) and good stability under repeated white light illumination. As an application, the flexible DTL driving circuit was connected to external quantum dot LEDs (QLEDs), demonstrating its ability to drive and to control the QLED. PMID- 29235608 TI - Extra green light induced ZnO ultraviolet lasing enhancement assisted by Au surface plasmons. AB - We observed the dramatic enhancement of the intrinsic spontaneous and stimulated emission as well as the ensuing suppression of defect-related green emission in Au-decorated ZnO microrods. A series of spectral experiments and theoretical analysis demonstrated an electron transfer assisted process by surface plasmon (SP) resonant coupling between the Au nanoparticles and ZnO. The mechanism indicates an approach to enhance the UV emission of ZnO through an extra excitation of visible light similar to that for the defect emission of ZnO. Based on the coupling mechanism, the externally enhanced ultraviolet lasing was further improved from 1.5 to 2.8-fold by adjusting the pumping power of the green light intensity in the Au/ZnO hybrid cavity. This research not only further confirms the SPR-assisted electron transfer process but also offers an approach to improve the intrinsic UV emission even for heavily-defected ZnO through visible light excitation via a nonlinear process. PMID- 29235611 TI - Primary Renal Neuroendocrine Tumour Presenting as an Enormous Cystic Lesion. PMID- 29235612 TI - Cellular Myxoma of the Vocal Cord: A Case Report and Review of the Literature. AB - Myxomas are rare in the vocal cords. A 69-year-old man was admitted with one-year history of progressive dysphonia. Laryngoscopy revealed a polypoid mass on the right vocal cord. The diagnosis was cellular myxoma. A review of the literature including the present case revealed eleven reported cases of myxoma. Ten cases were classic myxoma. To the best of our knowledge, cellular myxoma has not been previously reported in the vocal cord. Hypercellularity does not affect the behavior of cellular myxoma. However, its recognition is important to prevent confusion with the group of low-grade myxoid sarcomas. Cellular myxoma should be considered in the differential diagnosis of any vocal cord mass. PMID- 29235614 TI - Techniques for Maximizing the Performance of Molecular Pathology Testing: Responsibilities of All Pathologists. AB - Molecular pathological analysis has an expanding role in patient diagnosis and management. The performance of these techniques relies on excellent laboratory procedures. However, the crucial step is obtaining the best samples for molecular analysis. Archiving and selection of these are the responsibilities of all pathologists even if they are not working at a center with molecular pathological facilities. This review focuses on the features of different types of materials for molecular pathological analysis. Many steps that might affect the results, including communication between the pathologist and the oncology team, features of different types of materials (cytological, tissue blocks, biopsy, circulating tumor cells (CTCs) and cell-free circulating nucleic acids), effects of tissue processing, methods for selecting the best material, and tissue saving and tumor enrichment methods are discussed. The procedures for referral to a center for molecular pathological analysis are also mentioned. Awareness of the importance of the cytopathological and histopathological material of the patients for future molecular pathological analysis by pathologists is of the utmost importance. PMID- 29235613 TI - Can GATA3 Immunocytochemistry be Utilized as a Reliable Diagnostic Marker for Metastatic Breast Carcinoma in Cytological Materials? A Comparative Study with Mammaglobin and GCDFP-15 Expression. AB - OBJECTIVE: Cytomorphologic differentiation of metastatic breast carcinoma from non breast metastases in cytological materials can be difficult. Current breast immunocytochemical markers have low sensitivities. Transcription factor GATA 3 is a promising marker for detecting breast differentiation in cytological materials. The aim of the study was to assess the diagnostic value of GATA 3 as a breast differentiation marker in metastatic cytological materials and to compare it with expression of mammaglobin and gross cystic disease fluid protein-15 (GCDFP-15). MATERIAL AND METHOD: We retrospectively retrieved 133 cases of metastatic breast carcinoma from the archive the of Cytology Unit between December 2013 and June 2015. They included 77 fine needle aspiration and 56 serous effusion samples. Forty-five cytological materials from non mammary metastatic tumors were used as a control. Immunostaining was performed on cell blocks for the presence of GATA 3, mammaglobin and GCDFP-15. RESULTS: GATA 3 nuclear staining was detected in 82.7% of metastatic breast carcinomas, and 11.1% of metastatic non mammary adenocarcinomas (p < 0.001). GATA 3 sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 82.7%, 88.9%, 95.7%, 63.5% and 84.3%, respectively. Mammaglobin and GCDFP-15 staining of metastatic breast carcinoma cases was positive in 70.7% and 47.1%, respectively. GATA 3 staining was significantly higher compared with mammaglobin and GCDFP-15 (p < 0.001). CONCLUSION: GATA 3 is more sensitive marker than mammaglobin and GCDFP-15 for diagnosing metastatic breast carcinoma in cytological cell block materials. Adding mammaglobin to GATA 3 resulted in improvement in its sensitivity. GATA 3 was occasionally positive in some metastatic non mammary carcinoma that may cause misdiagnosis. PMID- 29235615 TI - [Music therapy as a non-pharmacological treatment in Alzheimer's disease. A systematic review]. AB - INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease which involves, among other manifestations, a progressive deterioration of memory and language, as well as behavioral disorders. In addition to non-curative pharmacological therapies, for the last years, music therapy has been developed as an effective non-pharmacological therapy in order to relieve many of these manifestations. AIM: To analyze the recent scientific evidence about the effect of music therapy on cognitive and behavioral symptoms in patients with AD. PATIENTS AND METHODS: A systematic review has been carried out by means of a bibliographical research using the database PubMed and Science Direct. The key words used for this search were 'Alzheimer's disease' and 'music therapy', as well as the boolean operator 'AND'. We selected those publications between January 2006 and December 2016 and after inclusion criteria, 21 publications were selected. RESULTS: This systematic review has demonstrated the beneficial impact of music therapy on cognition (memory, attention, language), emotion and behavior (anxiety, depression and agitation) in AD patients. CONCLUSIONS: Music therapy constitutes a non-pharmacological therapy effective for some cognitive, emotional and behavioral symptoms in patients with AD. However, further investigations and more evidence in this field are needed to claim conclusively the impact of music therapy on this disease. PMID- 29235616 TI - [Social cognition in Parkinson's disease dementia and behavioral variant of frontotemporal dementia]. AB - AIM: To study the presence of alterations in social cognition in Parkinson's disease dementia (PDD) and behavioral variant frontotemporal dementia (bvFTD), to compare the levels of involvement, and to analyze their relevance as a tool to distinguish between both demential profile. SUBJECTS AND METHODS: For this purpose, 34 patients diagnosed with PDD, 21 men and 13 women, with an average age of 70 years and 8 years of education, and 26 patients diagnosed with bvFTD, 9 men and 17 women, with an average age of 68 years and 6 years of education, were assessed. The control group consisted of 30 healthy subjects, with a mean of 66 years of age and 8 of schooling. Reading the Mind in the Eyes was use as an emotional Theory of Mind (ToM) test; First-Order False Belief as a cognitive ToM test; Faux Pas as mixed test, considering their emotional (FPec) and cognitive (FPcc) components; and Iowa Gambling Task for social decision-making. RESULTS: Both groups of patients showed alterations in all tests compared to the control group. A significant difference between PDD and bvFTD was also observed for Reading the Mind in the Eyes test, Faux Pas total score, FPec and FPcc, with lower means and medians for PDD patients on all scores except for FPcc. CONCLUSIONS: This findings suggests that emotional ToM would be most affected PDD patients, while the use of cognitive ToM and social decision-making tests would be restrain tools to differentiate between a type of dementia or another. PMID- 29235617 TI - [Predictors of seizure related injuries in adult patients with epilepsy in Colombia: a case-control study]. AB - AIM: To identify predictors of seizure related injuries in adult patients with epilepsy in Colombia. SUBJECTS AND METHODS: Case-control study. Patients with a diagnosis of epilepsy aged 16 years and older who attended the Neurocentro epilepsy center between 2013-2016 and were attended by a specialist in epilepsy were included. Patients with seizure related injuries were defined as the case. The control group was conformed by those without seizure related injuries. Odds ratios and 95% confidence intervals were calculated. A logistic regression was performed. RESULTS: A total of 101 (28.5%) patients were cases and 253 (71.5%) were controls. Patients with seizure related injuries were significantly younger than controls at the age of onset of epilepsy (9 vs 12 years; p = 0.017). The significant variables in the bivariate analysis were: some degree of cognitive impairment, drug resistant epilepsy, abnormal neurological examination, and seizures related with changes in the lunar phases. No protective factors were identified. In the multivariate analysis, two variables remained significant: drug resistant epilepsy and some degree of cognitive impairment. CONCLUSION: Drug resistant epilepsy and cognitive impairment were predictors of seizure related injuries in adult patients with epilepsy. Adequate pharmacological control of epileptic seizures and prevention recommendations may reduce the risk of seizure related injuries in these patients. PMID- 29235618 TI - [Direct current electrical stimulation in the treatment of aphasia]. AB - INTRODUCTION: Ictus is a medical condition with a high prevalence in Spanish population. One of its most common consequences is aphasia. Nowadays, aphasia is treated with both neuropsychological and pharmacological therapy. However, in recent years, transcranial direct current stimulation has been presented as a complement to classical therapies. AIMS: To familiarize the reader with transcranial direct current stimulation and to critically review the evidence on the benefits of this technique in aphasia rehabilitation. DEVELOPMENT: The first part of this paper describes what transcranial electrical stimulation is. Subsequently, an analysis of the efficacy of this technique in the treatment of aphasia is presented. To achieve this, we searched in PubMed database and found 19 different scientific papers, published between 2008 and 2016, which used transcranial electrical stimulation in the treatment of aphasia. CONCLUSIONS: These studies suggest that, when it is used in conjunction with speech therapy, transcranial direct current electrical stimulation is effective in the treatment of aphasia. In addition, its benefits are observed when a minimum of five sessions with intensities higher than 1 mA, stimulating perilesional areas, and in those patients with fluent aphasias. However, the reviewed studies also suggest that this technique is not a substitutive of speech therapy, but a way to prime the brain to it. PMID- 29235620 TI - [XV Reunion Anual de la Asociacion Madrilena de Neurologia. Communications]. PMID- 29235619 TI - [Spasticity and progressive ataxia due to vanishing white matter]. PMID- 29235621 TI - [Early onset epileptic encephalopathy in a patient with mutation in SCN8A]. PMID- 29235622 TI - [Valproate-induced hyperammonemic encephalopathy]. PMID- 29235624 TI - DISTRIBUTION AND DIAGNOSIS OF DIROFILARIASIS AND TOXOCARIASIS IN AUSTRALIA. AB - The prevalence of Dirofilaria immitis infection in dogs continues to increase in the temperate east coast zone of Australia (and is extending further south into New South Wales and Victoria). However, the infection rate has not changed in the tropics over the past 10 years where it would appear that a maximum infection rate of 90% occurs in a given Australian dog population. Twelve percent of Brisbane dogs had occult dirofilariasis and it is suggested that the proportion of occult infections was probably higher in the tropics. Dogs of all breeds appear equally susceptible to D. immitis with infection being more common in older male dogs. The level of microfilaraemia was, occasionally, proportional to the number of heartwprms per dog. Toxocara canis was present in about 75% of dogs from all areas studied except in Central Australia where the level of infection was much lower. Immunodiagnosis of D. immitis and T. canis with high specificity and sensitivity was achieved by cyanogen bromide indirect fluorescent antibody and cell-mediated immunity tests using parasite antigens purified by affinity chromatography. These tests enabled occult dirofilariasis to be differentiated from unrelated canine cardiac and pulmonary failure. Such immunodiagnosis can aid in the early diagnosis of dirofilariasis particularly in situations where no circulating microfilariae can be detected. The prevalence of serum antibody in man to purified Dirofilaria and Toxocara antigens was proportional to the incidence of respective canine infections at each location. PMID- 29235623 TI - [Borderline phenotype of Pelizaeus-Merzbacher disease]. PMID- 29235625 TI - ELECTROCARDIOGRAPHY, HEART SCORE AND HAEMATOLOGY OF HORSES COMPETING IN AN ENDURANCE RIDE. AB - Thirty-one horses competing in a 100 kilometre endurance ride had electrocardiograms recorded before and after the ride from which the heart score of each horse was calculated. Blood was also taken to determine the packed cell volume (PCV) and total plasma protein (TPP) before the ride, after 60 kilometres (mid-ride) and at completion of the ride. Statistical analysis of the heart scores showed that a faster group of horses had significantly higher heart scores than either a slower group or those eliminated due to inadequate recovery of heart rate. No horses developed electrocardiogram abnormalities as a result of the ride. Analysis of the results of PCV and TPP showed that horses became dehydrated during the ride. The faster group of horses had significantly higher PCV values and heart rates at both the mid-ride and end of ride sampling times. However, the TPP values indicated no significant differences in the amount of dehydration between the 2 groups. PMID- 29235627 TI - GRADUATE TRAINING IN PREVENTIVE VETERINARY MEDICINE IN THE SCHOOL OF VETERINARY MEDICINE OF THE UNIVERSITY OF CALIFORNIA. PMID- 29235626 TI - DEATHS IN CATTLE AFTER ADMINISTRATION OF LARGE DOSES OF THIABENDAZOLE. PMID- 29235628 TI - TREATMENT OF OVINE ANNUAL RYEGRASS TOXICITY WITH CHLORDIAZEPOXIDE. AB - The results of pen trials indicate that sheep affected by annual ryegrass toxicity can be treated successfully with chlordiazepoxide. In the first experiment, 87% of chlordiazepoxide-treated animals survived a lethal dose of toxic ryegrass. In the second experiment, 90% of chlordiazepoxide treated animals survived compared with a 10% recovery of control animals. PMID- 29235629 TI - THE ROLE OF EQUIPMENT THAT HAS DIRECT CONTACT WITH THE CARCASE IN THE SPREAD OF SALMONELLA IN A BEEF ABATTOIR. AB - Counts of Salmonella were performed by the most probable number technique on 16 articles of abattoir equipment having direct contact with the carcase. Forty samples were collected from each article over 21 months. The contamination rate of these articles with salmonellae varied from nil % for a saw used to quarter the sides to 47.5% for stainless steel tables and hooks. Mesh gloves were also highly contaminated, salmonellae being isolated from 32.5% of gloves on the slaughter floor and 40% of those in the boning room. Salmonella counts ranged from 1.0 to 3,663 organisms per article. Mesh gloves, cutting boards and stainless steel tables were found to have counts that were at times of greater than 1,000 salmonellae per article. PMID- 29235630 TI - REPRODUCTIVE PERFORMANCE OF BEEF CATTLE IN NORTHWESTERN QUEENSLAND. AB - The reproductive performance of beef cattle in 5 herds mated all year round in north-west Queensland was examined from 1970 to 1973. Conception rates, conception patterns and branding rates were used to assess annual reproductive performance. The level of loss between the times of confirmed pregnancy and branding was defined. The mean annual conception rate was 83.1% with individual property means ranging from 75.4 to 90.9%. Conception rates for heifers, first calf cows and mature cows were 83.9%, 80.6% and 84.7% respectively. Conception patterns were influenced by seasonal conditions, 68.1% of conceptions occurring in the wet season, between December and May. In this region, conception patterns were highly correlated with rainfall during the previous month. Losses between the times of confirmed pregnancy and branding ranged from 5.9 to 27.7%. Body condition of animals varied and was dependent upon lactation, seasonal and parity effects. PMID- 29235631 TI - CONGENITAL PROGRESSIVE OVINE MUSCULAR DYSTROPHY IN WESTERN AUSTRALIA. PMID- 29235632 TI - EXPERIMENTAL SURGERY FOR WEIGHT LOSS? PMID- 29235633 TI - CONGENITAL MITRAL INCOMPETENCE. PMID- 29235634 TI - NON-SURGICAL STERILISATION OF RAMS USING A SCLEROSING AGENT. AB - Injection of 0.25 ml of a solution of 3.6% formaldehyde in 90% ethanol direct into the caudae epididymides caused sterility in the rams treated. No live sperm were seen in ejaculates collected 35, 57, 91 and 196 days post-injection. The rams retained their libido and were mated to ewes between 2 and 3 months post injection with no pregnancy ensuing. The technique offers a simple, safe, quick and effective method of sterilising rams. Attempts to produce sterilisation by injection of the sclerosing agent into the yas deferens were not successful. PMID- 29235635 TI - YERSINIA PSEUDOTUBERCULOSIS INFECTION IN A LION. PMID- 29235636 TI - HAEMATOLOGICAL INVESTIGATION OF A MULTIPLE CASE LEUCOSIS HERD. AB - Adult cattle in a Queensland dairy herd with a history of deaths from lymphosarcoma were sampled regularly over a 4 year period for the identification of animals with persistent lymphocytosis (PL). Twenty-one of 94 animals that were sampled at least 6 times had PL. At the initial sampling 27% of the animals had lymphocytosis. Culling of haematologically positive animals in the first 18 months of the investigation reduced this to 5.3%, but cessation of the culling programme resulted in a gradual increase in the percentage of animals with lymphocytosis. Four deaths from lymphosarcoma occurred in adult animals, but only in the first 18 months of the investigation. Two of these animals had lymphocytosis and two lymphoblastic leukaemia. The Calf of one of the latter cows developed lymphoblastic leukaemia and lymphosarcoma by the time it was 6 months of age. Although histological evidence of lymphosarcoma was lacking in a number of clinically normal animals with lymphocytosis, haematological investigation identified a group of animals within the herd that may develop lymphosarcoma. PMID- 29235637 TI - OBITUARY. PMID- 29235638 TI - HAEMOLYTIC ANAEMIA IN TWO DOGS SUSPECTED TO HAVE BEEN INDUCED BY LEVAMISOLE. PMID- 29235640 TI - XII BIENNIAL CONFERENCE OF THE CARIBBEAN VETERINARY ASSOCIATION. PMID- 29235639 TI - NON-SUPPURATIVE MYOCARDITIS IN YOUNG DOGS. PMID- 29235641 TI - DIAGNOSTIC TESTS, SENSITIVITY, SPECIFICITY, EFFICIENCY AND PREVALENCE. PMID- 29235642 TI - COMPARISON OF THE EFFICIENCY OF TWO DOSES OF BOVINE PPD TUBERCULIN IN SINGLE CAUDAL FOLD TESTS ON AUSTRALIAN CATTLE. AB - The sensitivity and specificity of 0.2 mg and 0.4 mg doses of bovine PPD tuberculin were compared in Northern Territory beef cattle from tuberculous herds and herds with a prevalence of tuberculosis of less than 0.1%. Reactions were interpreted subjectively by observation and palpation, and were also measured to the nearest mm with calipers at 24 h, 48 h, 72 h and 96 h after injection of tuberculin. All cattle were examined post mortem for the presence of macroscopic and microscopic tuberculous lesions. The apparent specificity of caudal fold tests with 0.2 mg and 0.4 mg doses was determined in cattle in Victoria from tuberculosis-free dairy and beef herds. Victorian cattle reacting to the caudal fold tests were subjected to a comparative intradermal test with 0.1 mg bovine PPD and 2,500 IU avian PPD not less than 42 days later. Tests with the 0.2 mg dose achieved the highest level of sensitivity of 95.6% at 48 h, 72 h and 96 h, while in tests with 0.4 mg the maximum reached was 94.7% at 72 h. The specificity of tests in Northern Territory cattle ranged from 85.0% to 88.3% with the 0.2 mg dose and from 80.6% to 82.3% with the 0.4 mg dose. The highest specificity was achieved with both doses at 96 h. The apparent specificity of 0.2 and 0.4 mg doses of bovine PPD in tuberculosis-free herds in Victoria was high, a false positive reactor rate of only 0.6% occurring with caudal fold tests. All false positive reactions were shown to be non-specific or due to previous experimental sensitisation. PMID- 29235643 TI - EXPERIMENTAL SURGERY FOR WEIGHT LOSS? PMID- 29235645 TI - WELLCOME TRUST EXTENDS TRAVEL GRANT SCHEMES. PMID- 29235644 TI - POISONING OF CHICKENS AND DUCKS BY PYRROLIZIDINE ALKALOIDS OF HELIOTROPIUM EUROPAEUM. AB - The disease produced by feeding chickens and ducks a commercial poultry feed containing heliotrine and lasiocarpine, pyrrolizidine alkaloids of Heliotropium europaeum, is described. Illthrift, ascites and degenerative lesions in the liver were the major findings. Similar lesions occurred in chickens fed a diet containing H. europaeum. The source of the alkaloids in commercial poultry feed was probably the seeds of H. europaeum harvested with wheat. PMID- 29235646 TI - CHINESE AGRICULTURALISTS VISIT TO AUSTRALIA. PMID- 29235647 TI - EVIDENCE FOR A PARVOVIRUS AS THE AETIOLOGIC AGENT IN MYOCARDITIS OF PUPPIES. PMID- 29235648 TI - Anatomical map of the cranial vasculature and sensory ganglia. AB - There is growing evidence of a direct influence of vasculature on the development of neurons in the brain. The development of the cranial vasculature has been well described in zebrafish but its anatomical relationship with the adjacent developing sensory ganglia has not been addressed. Here, by 3D imaging of fluorescently labelled blood vessels and sensory ganglia, we describe for the first time the spatial organization of the cranial vasculature in relation to the cranial ganglia during zebrafish development. We show that from 24 h post fertilization (hpf) onwards, the statoacoustic ganglion (SAG) develops in direct contact with two main blood vessels, the primordial hindbrain channel and the lateral dorsal aortae (LDA). At 48 hpf, the LDA is displaced medially, losing direct contact with the SAG. The relationship of the other cranial ganglia with the vasculature is evident for the medial lateral line ganglion and for the vagal ganglia that grow along the primary head sinus (PHS). We also observed that the innervation of the anterior macula runs over the PHS vessel. Our spatiotemporal anatomical map of the cranial ganglia and the head vasculature indicates physical interactions between both systems and suggests a possible functional interaction during development. PMID- 29235649 TI - Letter to the Editor: Unreported statistics lead to unverifiable results in study of vitamin D supplementation in children with autism spectrum disorder - Comment regarding Saad, K., et al. (2016). PMID- 29235650 TI - Letter to the author from Editor-in-Chief seeking clarifications. PMID- 29235651 TI - 'The way we do the things we do' - decision making transparency at the Journal of Child Psychology and Psychiatry. AB - As in life generally, so in scholarly publishing, the turn of the year inevitably encourages editors to reflect soberly and take honest stock of the progress their journals have made over the previous 12 months. In this frame of mind, my own thoughts turned to our beloved Journal of Child Psychology and Psychiatry. Of course I say ours because we who currently work at the journal, know it actually belongs to you, the world-wide community of child and adolescent psychologists and psychiatrists: We are only its stewards. We hold it in trust for the whole field. We understand the important role that it has served, in shaping the field of scientific child psychology and psychiatry. We know it has a special place in both your intellectual and working lives. We are aware how important it is to you that the journal continues, on your behalf, to help drive the promotion of science-driven and evidence-based solutions to the great, and, in some aspects, growing, burden of suffering imposed by childhood mental and neuro-developmental disorders. It is vital that we have your confidence that we do this in a transparent and fair way - without fear or favour - not letting our own preconceptions, prejudices or vested interests influence the content of what we publish - unless it is our prejudice towards, and vested interest in, finding out 'the truth of the matter'. We are acutely aware of the responsibility that all this places on our shoulders - a yoke we feel privileged to bear. PMID- 29235652 TI - Response to letters: Randomized controlled trial of vitamin D supplementation in children with autism spectrum disorder - correction and additional information. PMID- 29235653 TI - Letter to the Editor: Unreported statistics lead to unverifiable results in study of vitamin D supplementation in children with autism spectrum disorder - Comment regarding Saad, K., et al. (2016). PMID- 29235654 TI - Case of Penicillium marneffei infection in a non-AIDS patient. PMID- 29235656 TI - Nonalcoholic fatty liver disease in patients with psoriasis: a consequence of systemic inflammatory burden? AB - Patients with psoriasis are at an increased risk for nonalcoholic fatty liver disease (NAFLD) compared with the general population. However, the pathophysiology underlying this comorbidity and elucidation of effective treatment strategies are unclear. This review provides insights into the possible role of chronic, low-grade inflammation in the pathogenesis of NAFLD in patients with psoriasis. Both conditions are associated with increased levels of proinflammatory adipokines (such as tumour necrosis factor-alpha and interleukin 6) and hepatokines, and decreased levels of adiponectin, an anti-inflammatory adipokine. This imbalance in inflammatory mediators could result in insulin resistance and, thereby, facilitate the occurrence and progression of NAFLD in a multistep manner. All patients with psoriasis should, therefore, be considered candidates for NAFLD screening and managed accordingly. Given the common aetiology of inflammation between these conditions, it is hypothesized that biological therapies for psoriasis may attenuate the systemic inflammatory process and progression of NAFLD in patients with psoriasis. PMID- 29235655 TI - Dermoscopic features distinctive for extraocular sebaceous carcinoma. AB - We examined dermoscopic features of three cases of extraocular sebaceous carcinoma and reviewed the literatures. The yellowish structures, polymorphous vessels and ulceration were common findings in our cases and all cases of the previous reports. The appearance of whitish-pink areas has not been described previously. Our results suggested that the combination of four dermoscopic features, whitish-pink areas, yellowish structures, polymorphous vessels and ulceration might be distinctive in extraocular sebaceous carcinoma. PMID- 29235657 TI - Electric double layer electrostatics of lipid-bilayer-encapsulated nanoparticles: Toward a better understanding of protocell electrostatics. AB - Lipid-bilayer-encapsulated nanoparticles (LBLENPs) or NP-supported LBL systems, such as protocells (which are lipid bilayer encapsulated mesoporous silica nanoparticles or MSNPs) have received extensive attention for applications like targeted drug and gene deliveries, multimodal diagnostics, characterization of membrane-geometry sensitive molecules, etc. Very often electrostatic-mediated interactions have been hypothesized to play key roles in the functioning of these LBLENPs. Despite that, very little has been done to theoretically quantify the fundamental electric double layer (EDL) electrostatics of such LBLENPs. In this study, we develop an EDL theory to describe the electrostatics of such LBLENPs. We show that the electrostatics is a manifestation of the charged/dielectric nature of the NP, LBL structure and charging, and the ionic environment in which the LBLENPs are present. We also establish that for certain conditions of charging of the NP one witnesses a most remarkable charge inversion like electrostatics within the LBL membrane or the NP itself. We anticipate that our findings will provide an extremely useful platform for better understanding the fabrication and functioning of such LBLENPs and discuss examples where our theory can be useful. PMID- 29235658 TI - Baseline Characteristics and Outcomes of Older Adults Seeking Care in Ambulatory Urgent Care Clinics. AB - OBJECTIVES: To determine the most common clinical conditions associated with older adults visiting Urgent care centers (UCCs) and the potential need for further resource use. DESIGN: Cross-sectional retrospective study. SETTING: Nonprofit academic medical center with campuses and multiple satellite offices in Ohio and Florida. PARTICIPANTS: Individuals aged 55 and older who visited UCCs between August 2014 and March 2015 (N = 9,445; average age 63.1 +/- 10.1, 64% female). Of those, 2,445 had at least one encounter within the same healthcare system within 30 days after the index visit and were included in our final analysis. MEASUREMENTS: 30-day ED visits and hospitalizations. RESULTS: Of the 2,445 patients, 578 (23.6%) visited the emergency department (ED) or were hospitalized, 974 (39.8%) returned to the UCC, and 895 (63.4%) visited their primary care physician's office. A significantly higher proportion (38.4%, n = 68/177) of individuals aged 85 and older visited the ED or were hospitalized within 30 days (P < .010) than of those younger than 65 (20.0%, n = 273/1,367). Diabetes mellitus (odds ratio (OR) = 1.73, 95% confidence interval (CI) = 1.40 2.15, P < .001), coronary artery disease or cerebrovascular disease (OR = 2.45 CI 1.95-3.09, P < .001), chronic obstructive pulmonary disorder or asthma (OR = 1.57, 95% CI = 1.23-2.01, P < .001), polypharmacy (OR = 1.45, 95% CI = 1.18-1.78, P = .004), and cognitive impairment (OR = 2.74, 95% CI = 1.74-4.31, P < .010) were associated with higher rates of ED visits or hospitalizations within 30 days of the UCC visit. CONCLUSION: Older adults (especially those aged >=85) and those with conditions such as polypharmacy and dementia are at higher risk of being hospitalized or visit the ED after seeking care at UCCs than younger adults and those without these conditions. PMID- 29235660 TI - Courses and Conferences. PMID- 29235661 TI - Association of Higher Daptomycin Dose (7 mg/kg or Greater) with Improved Survival in Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia. AB - STUDY OBJECTIVE: Current guidelines recommend higher daptomycin doses than the daptomycin label dose of 6 mg/kg for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia; however, the evidence supporting this recommendation is from in vitro and case series studies. This study evaluated the comparative effectiveness of the daptomycin label dose versus higher daptomycin doses in patients with MRSA bacteremia. DESIGN: Retrospective national cohort study. SETTING: Veterans Affairs medical centers. PATIENTS: A total of 371 adults with MRSA bacteremia who were admitted between 2002 and 2015 and treated initially with vancomycin within 24 hours of initial culture collection and then switched to daptomycin therapy within 7 days; 138 patients (37.2%) received daptomycin doses higher than the daptomycin label dose (7 mg/kg or greater), and 233 (62.8%) received the daptomycin label dose (6 mg/kg). MEASUREMENTS AND MAIN RESULTS: Clinical outcomes were compared among those who received the daptomycin label dose and those who received the higher dose using propensity score-matched Cox proportional hazards regression models. To identify dose partitioning associated with optimal survival, classification and regression tree (CART) analysis was used among patients, controlling for confounding with a 30-day mortality disease risk score. Propensity score-matched 30-day mortality was 8.6% (6/70 patients) among the higher dose group versus 18.6% (13/70 patients) among the label dose group (hazard ratio 0.31, 95% confidence interval 0.10-0.94). No significant differences were observed in inpatient mortality, length of stay, 30-day readmission, or 30-day S. aureus reinfection between groups. CART analysis resulted in doses of 7 mg/kg or greater providing benefit only among patients with higher (more than 51%) predicted probabilities of 30-day mortality (p<0.001). CONCLUSION: To our knowledge, this is the first comparative effectiveness study of daptomycin doses in patients with MRSA bacteremia. Survival benefits were observed with doses higher than the daptomycin label dose (7 mg/kg or greater) for the treatment of MRSA bacteremia. These data suggest that higher doses than the daptomycin label dose may be preferred over the label dose for improving clinical outcomes in patients with MRSA bacteremia. PMID- 29235662 TI - Aural haematoma in Guinea pig (Cavia porcellus). PMID- 29235659 TI - Effect of Metabolic Syndrome on Late-Life Depression: Associations with Disease Severity and Treatment Resistance. AB - BACKGROUND/OBJECTIVES: Metabolic syndrome (MetS) is the co-occurrence of obesity and metabolic derangements. Prior research implicates MetS in prolongation of the course of depression in older adults, but its effect on antidepressant response is unknown in this population. The objective was to determine whether MetS and related metabolic dyscrasias are associated with decreased rate of remission from depression in older adults treated pharmacologically for depression. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: Three academic medical centers in North America. PARTICIPANTS: Adults aged 60 and older (mean age 69.1) with major depressive disorder (MDD) (N = 435). INTERVENTION: Open label, protocolized treatment with extended-release venlafaxine for 12 or more weeks. MEASUREMENTS: Time to remission from depression, with remission defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 10 or less at last two visits. RESULTS: Two hundred twenty-two participants (51%) met criteria for MetS at baseline; MetS was associated with greater severity (MADRS score) and chronicity of depression at baseline. Remission was achieved in 182 participants (42%). In the unadjusted analysis, MetS was associated with prolonged time to remission (hazard ratio for remission = 0.71, 95% confidence interval = 0.52 0.95), but this relationship was not significant in the adjusted model; greater number of MetS components and lower high-density lipoprotein cholesterol had similar effects. Only diastolic blood pressure (DBP) was a significant predictor of time to remission before and after adjustment, with higher DBP predicting longer time to remission. Insulin sensitivity did not predict time to remission. CONCLUSION: The presence of MetS in older adults with depression was associated with greater symptom severity and chronicity of depression, which appears to have accounted for the poorer antidepressant response observed in those with MetS. Additionally, our preliminary finding of an association between higher DBP and poorer antidepressant response bears further examination and replication. PMID- 29235663 TI - Digital Screen Time Limits and Young Children's Psychological Well-Being: Evidence From a Population-Based Study. AB - There is little empirical understanding of how young children's screen engagement links to their well-being. Data from 19,957 telephone interviews with parents of 2- to 5-year-olds assessed their children's digital screen use and psychological well-being in terms of caregiver attachment, resilience, curiosity, and positive affect in the past month. Evidence did not support implementing limits (< 1 or < 2 hr/day) as recommended by the American Academy of Pediatrics, once variability in child ethnicity, age, gender, household income, and caregiver educational attainment were considered. Yet, small parabolic functions linked screen time to attachment and positive affect. Results suggest a critical cost-benefit analysis is needed to determine whether setting firm limits constitutes a judicious use of caregiver and professional resources. PMID- 29235664 TI - An observer-blinded randomized controlled pilot trial comparing localized immersion psoralen-ultraviolet A with localized narrowband ultraviolet B for the treatment of palmar hand eczema. AB - BACKGROUND: Hand eczema is a common inflammatory dermatosis that causes significant patient morbidity. Previous studies comparing psoralen-ultraviolet A (PUVA) with narrowband ultraviolet B (NB-UVB) have been small, nonrandomized and retrospective. OBJECTIVES: To conduct an observer-blinded randomized controlled pilot study using validated scoring criteria to compare immersion PUVA with NB UVB for the treatment of chronic hand eczema unresponsive to topical steroids. METHODS: Sixty patients with hand eczema unresponsive to clobetasol propionate 0.05% were randomized to receive either immersion PUVA or NB-UVB twice weekly for 12 weeks with assessments at intervals of 4 weeks. The primary outcome measure was the proportion of patients achieving 'clear' or 'almost clear' Physician's Global Assessment (PGA) response at 12 weeks. Secondary outcome measures included assessment of the modified Total Lesion and Symptom Score (mTLSS) and the Dermatology Life Quality index (DLQI). RESULTS: In both treatment arms, 23 patients completed the 12-week assessment for the primary outcome measure. In the PUVA group, five patients achieved 'clear' and eight 'almost clear' [intention-to treat (ITT) response rate 43%]. In the NB-UVB group, two achieved 'clear' and five 'almost clear' (ITT response rate 23%). For the secondary outcomes, median mTLSS scores were similar between groups at baseline (PUVA 9.5, NB-UVB 9) and at 12 weeks (PUVA 3, NB-UVB 4). Changes in DLQI were similar, with improvements in both groups. CONCLUSIONS: In this randomized pilot trial recruitment was challenging. After randomization, there were acceptable levels of compliance and safety in each treatment schedule, but lower levels of retention. Using validated scoring systems - PGA, mTLSS and DLQI - as measures of treatment response, the trial demonstrated that both PUVA and NB-UVB reduced the severity of chronic palmar hand eczema. PMID- 29235665 TI - Metastatic adenocarcinoma with osseous metaplasia in the pelvic limb musculature of a cat. PMID- 29235666 TI - Complete regression of crateriform verruca after partial biopsy: Another type of epithelial crateriform tumor or a subtype of keratoacanthoma? PMID- 29235667 TI - Case of lichenoid-lichen scrofulosorum: A rare variety of lichen scrofulosorum mimicking lichen planus in an elderly patient. PMID- 29235668 TI - A diaper bank and home visiting partnership: Initial exploration of research and policy questions. AB - OBJECTIVES: The cost of diapering an infant can place a significant financial strain on families living in poverty. Partnerships between diaper banks and home visiting programs for young families may offer an innovative solution to expanding the reach and impact of diaper banks in low-income communities. The purpose of this pilot study was to uncover preliminary information about the functions of diaper distribution through home visiting programs, and to inform future research and policy questions regarding diaper distribution to families in need. DESIGN AND SAMPLE: In this descriptive qualitative pilot study, semi structured interviews were conducted with 6 home visitors from Minding the Baby(r) (MTB), a home visiting intervention for young parents. MTB clinicians routinely distribute diapers in partnership with The Diaper Bank in Connecticut. We used directed content analysis to code and analyze interview transcripts. RESULTS/CONCLUSION: These preliminary findings indicate that partnerships between home visiting programs and diaper banks may benefit families by improving diaper access, reducing stigma, and fostering trusting relationships with home visitors. Home visiting program benefits including engagement or re-engagement with families may need to be balanced with potential effects on clinical and therapeutic relationships. Recommendations for next steps in research and related policy questions are discussed. PMID- 29235669 TI - Portable negative-pressure wound therapy for pyoderma gangrenosum: Report of two cases. AB - Pyoderma gangrenosum is a chronic non-infectious neutrophilic dermatosis that causes undermining ulcers. Topical therapies for the deep ulcers of pyoderma gangrenosum have not been established. To investigate whether negative-pressure wound therapy is effective for a pyoderma gangrenosum ulcer, we used the PICO single use negative-pressure wound therapy system (Smith & Nephew, London, UK) for two pyoderma gangrenosum patients. In these cases, the ulcers decreased in size and necrolytic tissue was removed notably. Moreover, there were no secondary infections nor was there Koebner phenomena. Our cases suggest that portable negative-pressure wound therapy can be a treatment option for deep, intractable ulcers caused by pyoderma gangrenosum. Because portable negative-pressure wound therapy devices afford increased mobility to patients, they can give the patient a better quality of life than standard negative-pressure wound therapy systems do. PMID- 29235670 TI - Presumptive migrating gall bladder mucocoele in two dogs with gall bladder rupture. AB - A 10-year-old neutered female soft-coated wheaten terrier and a 10-year-old, entire female Pomeranian were presented for vomiting and anorexia. Using ultrasound, an oval structure with a stellate, kiwifruit-like appearance typical of a gall bladder mucocoele was observed in the caudal abdomen of the soft-coated wheaten terrier and adjacent to the liver in the Pomeranian. There was also a moderate volume of abdominal effusion in both dogs. Cytology of the peritoneal fluid indicated a sterile exudative process but varied between the two dogs, with an absence of bile pigment in the soft-coated wheaten terrier and marked bile peritonitis in the Pomeranian. An entire free-floating ectopic mucocoele was confirmed via exploratory laparotomy with concomitant gall bladder rupture and common bile duct obstruction. Both dogs recovered completely after surgery. This is the first report of cases of gall bladder rupture with entire free-floating gall bladder mucocoeles in dogs. PMID- 29235672 TI - Psoriasis verrucosa complicated by generalized pustular psoriasis. PMID- 29235671 TI - TADEA-PCR is a highly efficient method of amplifying unknown flanking fragments of T-DNA transformants. AB - Forward genetic analysis, widely used to find new gene functions, benefits from the availability of mutants. At present, based on Agrobacterium-mediated plant transformation technology, many transfer (T)-DNA transformants have been created. However, cloning their T-DNA insertion sites, which enables identification of the mutated genes, is still challenging. In this study, we improved adapter ligation mediated polymerase chain reaction (A-PCR), which mainly utilizes the Thermal Asymmetric interlaced reaction and Degenerate sequence-recognizing restriction Endonucleases (TADE). Using the new method TADE-mediated A-PCR (TADEA-PCR), we successfully cloned 22 of all the 24 junction sites in 10 Arabidopsis thaliana L. transformants that contained 12 T-DNA insertions in total, giving a success rate of 91.7%. In most cases, the two junction sites resulting from a single T-DNA insertion were simultaneously cloned. In addition, TADEA-PCR was able to clone more than two junction sites present in one transformant containing several T-DNA insertions. Overall, TADEA-PCR is a powerful technique for cloning T-DNA insertion sites. PMID- 29235673 TI - Long-term administration of oral macrolides for acne treatment increases macrolide-resistant Propionibacterium acnes. AB - Macrolide-resistant Propionibacterium acnes are frequently isolated from patients with acne vulgaris, and the most resistant isolates (>90% resistance) have the 23S rRNA mutation. An increase in resistant P. acnes with this mutation is thought to be caused by the inappropriate use of antimicrobials. Therefore, we studied the mutation frequency of macrolide resistance in P. acnes in vitro. When P. acnes mutants were exposed to clarithromycin after being incubated in broth without antimicrobials, resistant mutants with the 23S rRNA mutation were not isolated. However, the mutants were obtained at the frequency of 10-6 after being pre-incubated with 0.03 MUg/mL of antimicrobials. This is the estimated epidermal concentration of clarithromycin after p.o. administration. The resistant mutants had the 23S rRNA mutations A2058G, A2059G and C2611G. When pre-incubated with clarithromycin, C2611G mutants which showed resistance to clarithromycin were obtained 32.1% more often than pre-incubated with clindamycin (P < 0.01). By contrast, when pre-incubated with clindamycin, A2058G mutants, which show high level resistance to both clarithromycin and clindamycin, were more frequently obtained than pre-incubated with clarithromycin (87.5%, P < 0.01). No difference in the isolation rate of A2059G mutants, which show high-level resistance to macrolides but low-level resistance to clindamycin, was found with either treatment. These results indicate the possibility that long-term use of oral macrolides for acne treatment facilitate the increase of macrolide-resistant P. acnes. PMID- 29235674 TI - Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) has a very poor prognosis because of its highly invasive nature, and the 5-year survival rate has not changed appreciably for the past 30 years. Although cylindromatosis (CYLD), a deubiquitinating enzyme, is thought to be a potent tumour suppressor, its biological and clinical significance in OSCC is largely unknown. This study aimed to clarify the roles of CYLD in OSCC progression. Our immunohistochemical analyses revealed significantly reduced CYLD expression in invasive areas in OSCC tissues, whereas CYLD expression was conserved in normal epithelium and carcinoma in situ. Furthermore, downregulation of CYLD by siRNA led to the acquisition of mesenchymal features and increased migratory and invasive properties in OSCC cells and HaCaT keratinocytes. It is interesting that CYLD knockdown promoted transforming growth factor-beta (TGF-beta) signalling by inducing stabilization of TGF-beta receptor I (ALK5) in a cell autonomous fashion. In addition, the response to exogenous TGF beta stimulation was enhanced by CYLD downregulation. The invasive phenotypes induced by CYLD knockdown were completely blocked by an ALK5 inhibitor. In addition, lower expression of CYLD was significantly associated with the clinical features of deep invasion and poor overall survival, and also with increased phosphorylation of Smad3, which is an indicator of activation of TGF-beta signalling in invasive OSCC. These findings suggest that downregulation of CYLD promotes invasion with mesenchymal transition via ALK5 stabilization in OSCC cells. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29235676 TI - Diagnostic criteria, severity classification and guidelines of eosinophilic fasciitis. AB - We established diagnostic criteria and severity classification of eosinophilic fasciitis because there is no established diagnostic criteria or widely accepted severity classification of the disease. Also, there has been no clinical guideline for eosinophilic fasciitis, so we established its clinical guideline ahead of all over the world. In particular, the clinical guideline was established by clinical questions based on evidence-based medicine according to the New Minds Clinical Practice Guideline Creation Manual (version 1.0). We aimed to make the guideline easy to use and reliable based on the newest evidence, and to present guidance as specific as possible for various clinical problems in treatment of eosinophilic fasciitis. PMID- 29235677 TI - MICHEL DE M'UZAN AND ORIGINS OF IDENTITY. AB - Michel de M'Uzan describes a way to think about identity in which two distinct sources of our sense of identity must be considered. His innovation is the concept of the vital-identital, which he suggests is equally foundational with the sense of identity derived from the early human environment. The term endogenous identity is used to unify under one heading the ideas that de M'Uzan employs to build his concept of vital-identital. The author summarizes de M'Uzan's earlier work, elaborates on his more recent ideas, and illustrates the use of de M'Uzan's ideas with a cultural and a clinical example. PMID- 29235675 TI - Evidence for a hierarchical transcriptional circuit in Drosophila male germline involving testis-specific TAF and two gene-specific transcription factors, Mod and Acj6. AB - To analyze transcription factors involved in gene regulation by testis-specific TAF (tTAF), tTAF-dependent promoters were mapped and analyzed in silico. Core promoters show decreased AT content, paucity of classical promoter motifs, and enrichment with translation control element CAAAATTY. Scanning of putative regulatory regions for known position frequency matrices identified 19 transcription regulators possibly contributing to tTAF-driven gene expression. Decreased male fertility associated with mutation in one of the regulators, Acj6, indicates its involvement in male reproduction. Transcriptome study of testes from male mutants for tTAF, Acj6, and previously characterized tTAF-interacting factor Modulo implies the existence of a regulatory hierarchy of tTAF, Modulo and Acj6, in which Modulo and/or Acj6 regulate one-third of tTAF-dependent genes. PMID- 29235679 TI - FROM EXTENSION TO REVOLUTIONARY CHANGE IN CLINICAL PSYCHOANALYSIS: THE RADICAL INFLUENCE OF BION AND WINNICOTT. AB - This paper addresses the radical departure of late Bion's and Winnicott's clinical ideas and practices from traditional psychoanalytic work, introducing a revolutionary change in clinical psychoanalysis. The profound significance and implications of their thinking are explored, and in particular Bion's conception of transformation in O and Winnicott's clinical-technical revision of analytic work, with its emphasis on regression in the treatment of more disturbed patients. The author specifically connects the unknown and unknowable emotional reality-O with unthinkable breakdown (Winnicott) and catastrophe (Bion). The author suggests that the revolutionary approach introduced by the clinical thinking of late Bion and Winnicott be termed quantum psychoanalysis. She thinks that this approach can coexist with classical psychoanalysis in the same way that classical physics coexists with quantum physics. PMID- 29235680 TI - THE STORIED ANALYST: DESIRE AND PERSUASION IN THE CLINICAL VIGNETTE. AB - Beginning with the quintessentially psychoanalytic tales of Freud, the case history has held a privileged position in the history and practice of psychoanalysis. Psychoanalysts grow up with, grow into, and grow out of these narratives as clinical practitioners. Alongside the representational aspects of these case histories, there is a rhetorical or persuasive force that significantly influences us. The author contends that the theory of narrative and rhetoric can inform the how, the why, and the "so what?" of our relationship to these stories of psychoanalysis. PMID- 29235681 TI - ON THE BIRTH AND DEVELOPMENT OF PSYCHOANALYTIC FIELD THEORY, PART 2. AB - Advances in Contemporary Psychoanalytic Field Theory: Concept and Further Development. Edited by S. Montana Katz, Roosevelt Cassorla, and Giuseppe Civitarese. London/New York: Routledge, 2017. 212 pp. PMID- 29235683 TI - TRANSFERENCE BEFORE TRANSFERENCE. AB - This paper is predominantly a clinical presentation that describes the transmigration of one patient's transference to another, with the analyst functioning as a sort of transponder. It involves an apparently accidental episode in which there was an unconscious intersection between two patients. The author's aim is to show how transference from one case may affect transference in another, a phenomenon the author calls transference before transference. The author believes that this idea may serve as a tool for understanding the unconscious work that takes place in the clinical situation. In a clinical example, the analyst finds himself caught up in an enactment involving two patients in which he becomes the medium of what happens in session. PMID- 29235684 TI - ON BECOMING ABLE TO PLAY: INDIVIDUAL CHILD PSYCHOANALYTIC PSYCHODRAMA AND THE DEVELOPMENT OF SYMBOLIZATION. AB - In this paper, the authors analyze the relevance and transformative potential of individual psychoanalytic psychodrama in the treatment of children with severe impairments in symbolization. Central features of this modality, including promoting the representation of early traumatic experiences, are presented and discussed. Specific features include double-envelope containment of the co therapists' group and play leader, consequent diffraction of the transference determining portrayal, gradual integration, and initial figuration of coexisting split-off fragments. Drawing on in-depth clinical material, the authors show how psychodrama tempers the potentially traumatic effects of the encounter with the object, allowing these patients to access the transitional area of play. PMID- 29235686 TI - THE MISSING FATHER FUNCTION IN PSYCHOANALYTIC THEORY AND TECHNIQUE: THE ANALYST'S INTERNAL COUPLE AND MATURING INTIMACY. AB - This paper argues that recovering the "missing" paternal function in analytic space is essential for the patient's achievement of mature object relations. Emerging from the helpless infant's contact with primary caregivers, mature intimacy rests on establishing healthy triadic functioning based on an infant with-mother-and-father. Despite a maternocentric bias in contemporary clinical theory, the emergence of triangularity and the inclusion of the paternal third as a separating element is vital in the analytic dyad. Effective technique requires the analyst's balanced interplay between the paternal, investigative and the maternal, maximally receptive modes of functioning-the good enough analytic couple within the analyst-to serve as the separating element that procreatively fertilizes the capacity for intimacy with a differentiated other. A clinical example illustrates how treatment is limited when the paternal function is minimized within more collusive, unconsciously symbiotic dyads. PMID- 29235689 TI - Adduction of ammonium to polylactides to modify their dissociation behavior in collision-induced dissociation. AB - RATIONALE: The goal of this work was to modify the dissociation pathways of polylactide (PLA) holding benzyl and hydroxyl terminations, in order to circumvent coincidence of product ions generated during collisional activation of sodiated chains, which prevented their reliable characterization. METHODS: Benzyl , hydroxyl-terminated PLAs were ionized as ammonium adducts in positive ion mode electrospray and subjected to collision-induced dissociation (CID). Tandem mass spectrometry (MS/MS) experiments were conducted in a quadrupole time-of-flight (QTOF) instrument for safe assignment of product ions based on their elemental composition derived from accurate mass measurements. RESULTS: Adduction of ammonium to PLAs was found to induce chain fragmentation via charge-assisted processes, in great contrast to the charge-remote mechanisms experienced by sodiated molecules. The main reaction produced ions containing the omega termination only, hence allowing straightforward end-group determination. Other minor pathways were studied in detail to establish dissociation rules for ammoniated PLAs. Some reactions were found to be end-group specific, highlighting the higher reactivity of ammonium than alkali ion adducts. CONCLUSIONS: Changing the usually employed sodium-cationizing agent to ammonium was shown to induce dramatic changes in the CID behavior of PLAs. This was a simple and efficient approach to address issues encountered for end-group analysis of the particular PLA studied here. PMID- 29235690 TI - Improving alcohol and mental health treatment for lesbian, bisexual and queer women: Identity matters. AB - OBJECTIVE: Lesbian, bisexual and queer (LBQ) women experience substantial unmet alcohol and mental health treatment needs. This paper explores the way in which sexual identity shapes experience, and needs, in relation to alcohol and mental health treatment, and presents key messages for improving treatment. METHODS: Twenty-five in-depth interviews were undertaken with same-sex attracted Australian women, aged 19-71. Interview transcripts were analysed thematically. RESULTS: Key messages offered by participants focused on language, disclosure and practitioner training. Variation in sexual identity did not alter treatment expectations or needs; however, we noted an important difference with respect to identity salience, with high LBQ identity salience linked with preference for disclosure and acknowledgement of sexual identity in treatment interactions, and low identity salience linked with a preference not to disclose and for sexual identity not to require acknowledgement in treatment. CONCLUSIONS: Treatment providers may find it useful to gather information about the centrality of sexual identity to LBQ women as a means of overcoming treatment barriers related to heteronormative conventions and discrimination, language and disclosure. Implications for public health: Treatment providers should adopt more inclusive language, seek information about identity salience and the importance of sexual identity to the current treatment, and regularly pursue LBQ-related professional development upskilling. PMID- 29235691 TI - RNA interference-mediated functional characterization of aquaporin genes in Tribolium castaneum. AB - An obvious challenge faced by most terrestrial insects is maintaining water homeostasis in an arid environment. Current research suggests aquaporins may be evolved to meet the challenge. However, up to now, this suggestion has not been verified in any insect that feeds upon solid food with mandibulate mouthparts. In the present paper, nine putative aquaporin genes [Tribolium castaneum big brain, T. castaneum Drosophila integral protein (TcDrip), T. castaneum Pyrocoelia rufa integral protein (TcPrip), T. castaneum aquaporin 12-like, T. castaneum entomoglyceroporin 1 (TcEglp1), TcEglp2, TcEglp3, TcEglp4 and TcEglp5] were identified in T. castaneum. The transcripts of the nine genes were easily detectable in the foregut, midgut, hindgut-Malpighian tubule complex, fat body and carcass (except gut and fat body). Amongst them TcDrip, TcPrip, TcEglp1, TcEglp3 and TcEglp5 were highly transcribed in the hindgut-Malpighian tubule complex; TcEglp4 was abundantly expressed in both the fat body and hindgut Malpighian tubule complex. RNA interference (RNAi)-mediated knockdown of TcEglp3 caused a grey larval cuticle, in contrast to a smooth and bright cuticle in control larvae. Approximately 40% of the TcEglp3 RNAi larvae had their hindguts protruding from the anus; their fresh wet faeces were attached to the hindgut. Another 20% of these treated larvae did not defaecate normally; wet brown faeces were adhered to the anal area. As a result, the larval growth was inhibited and about 60% larval lethality occurred. Silencing of TcEglp4 or TcDrip exhibited similar but weaker defective phenotypes as those of the TcEglp3-silenced larvae. Therefore, Eglp3, Eglp4 and Drip may contribute to the conductance of water in the alimentary canal and Malpighian tubules in T. castaneum. PMID- 29235692 TI - Incidence of left atrial thrombus prior to catheter ablation of atrial fibrillation: Is it time for atrial cardiomyopathy evaluation? PMID- 29235693 TI - Porcine intestinal yeast species, Kazachstania slooffiae, a new potential protein source with favourable amino acid composition for animals. AB - There is little information about Kazachstania slooffiae which dominates among other yeasts in the pigs' intestine. Therefore, the aims of this study were to characterise the yeast cell contents and to investigate which nitrogen sources, organic acids and alcohols may be utilised or produced by this species. The results showed that, K. slooffiae could use urea, ammonium sulphate, peptides and single amino acids and produce thereby ethanol and formic acid. However, this yeast did not metabolise amino acids, lactic, butyric, propionic and acetic acids as sole carbon source. Using a global metabolite profiling approach employing gas chromatography and high-resolution liquid chromatography mass spectrometry, was found that the amount of peptides and dehydroascorbic acid considerably increased in the fermentation residues after yeast cultivation. It is noteworthy that the cells of K. slooffiae had higher contents of nitrogen and total amino acids (especially lysine) than the cells of nutritional yeast (Saccharomyces cerevisiae). This study indicates that due to potential production of peptides and formic acid in the intestinal tract, K. slooffiae might have an impact on the gut health. Moreover, from a nutritional standpoint, the cells of this yeast can be a good source of protein with useful amino acid composition for animal. PMID- 29235694 TI - Calling all archaeologists: guidelines for terminology, methodology, data handling, and reporting when undertaking and reviewing stable isotope applications in archaeology. AB - Stable isotope analysis has been utilized in archaeology since the 1970s, yet standardized protocols for terminology, sampling, pretreatment evaluation, calibration, quality assurance and control, data presentation, and graphical or statistical treatment still remain lacking in archaeological applications. Here, we present recommendations and requirements for each of these in the archaeological context of: bulk stable carbon and nitrogen isotope analysis of organics; bulk stable carbon and oxygen isotope analysis of carbonates; single compound stable carbon and nitrogen isotope analysis on amino acids in collagen and keratin; and single compound stable carbon and hydrogen isotope analysis on fatty acids. The protocols are based on recommendations from the Commission on Isotopic Abundances and Atomic Weights of the International Union of Pure and Applied Chemistry (IUPAC) as well as an expanding geochemical and archaeological science experimental literature. We hope that this will provide a useful future reference for authors and reviewers engaging with the growing number of stable isotope applications and datasets in archaeology. PMID- 29235696 TI - Beyond Hydrofunctionalisation: A Well-Defined Calcium Compound Catalysed Mild and Efficient Carbonyl Cyanosilylation. AB - Organocalcium compounds have been reported as efficient catalysts for various transformations, for cases in which one of the substrates contained an E-H (E=B, N, Si, P) bond. Here, we look at the possibility of employing an organocalcium compound for a transformation in which none of the precursors has a polar E-H bond. This study demonstrates the utilization of a well-defined amidinatocalcium iodide, [PhC(NiPr)2 CaI] (1) for cyanosilylation of a variety of aldehydes and ketones with Me3 SiCN under ambient conditions without the need of any co catalyst. The reaction mechanism involves a weak adduct formation between 1 and Me3 SiCN leading to the activation of the Si-C bond, which subsequently undergoes sigma-bond metathesis with a C=O moiety. Such a mechanistic pathway is unprecedented in alkaline earth metal chemistry. Experimental and computational studies support the mechanism. PMID- 29235695 TI - Enzymatic characterization of two epsilon-class glutathione S-transferases of Spodoptera litura. AB - Two cDNAs encoding glutathione S-transferase (GST) of the tobacco cutworm, Spodoptera litura, were cloned by reverse transcriptase-polymerase chain reaction. The deduced amino acid sequences of the resulting clones revealed 32 51% identities to the epsilon-class GSTs from other organisms. The recombinant proteins were functionally overexpressed in Escherichia coli cells in soluble form and were purified to homogeneity. The enzymes were capable of catalyzing the bioconjugation of glutathione with 1-chloro-2,4-dinitrobenzene, 1,2-epoxy-3-(4 nitrophenoxy)-propane, and ethacrynic acid. A competition assay revealed that the GST activity was inhibited by insecticides, suggesting that it could be conducive to insecticide tolerance in the tobacco cutworm. PMID- 29235697 TI - Remote sampling mass spectrometry for dry samples: Sheath-flow probe electrospray ionization (PESI) using a gel-loading tip inserted with an acupuncture needle. AB - RATIONALE: Probe electrospray ionization (PESI) is only applicable to liquid or wet samples. In this study, a sheath-flow PESI method for remote sampling mass spectrometry that can be applied to dry samples was developed. METHODS: An acupuncture needle (0.12 mm outer diameter, 700 nm tip diameter) was inserted into a gel-loading tip with a 0.1 mm protrusion out of the tip. Analytes were extracted by filling the latter tip with solvent and softly touching the sample surface for a short time (<1 s). A high voltage was applied to the acupuncture needle, and mass spectra of analytes were obtained by self-aspirating electrospray. RESULTS: Dry samples, such as lines of ballpoint pen ink on paper, pharmaceutical tablets, instant coffee, brown rice, and narcotics, gave strong ion signals. The sample carryover was negligible. The sequential electrospray was observed to be similar to conventional PESI. The limits of detection (LODs) for morphine and rhodamine B were found to be of the order of picograms. CONCLUSIONS: Because of its simplicity and versatility, sheath-flow PESI is a promising technique for on-site and nondestructive profile analysis of dry samples with bulky and complicated shapes, with a spatial resolution of ~0.3 mm. PMID- 29235698 TI - Retracted: Metallothionein I+II expression and their role in experimental autoimmune encephalomyelitis. AB - Following on from the Expression of Concern (10.1002/glia.22466) previously published by GLIA, the following Original Article has been retracted by the journal Editors and Publisher: Metallothionein I+II expression and their role in experimental autoimmune encephalomyelitis By Milena Penkowa and Juan Hidalgo GLIA (2000), 32(3), 247-263 DOI: 10.1002/1098-1136(200012)32:3<247::AID GLIA50>3.0.CO;2-T Discrepancies in the type and number of animals used in experiments performed by Milena Penkowa and reported in Table 1, identified during the course of investigations into Ms Penkowa's research, render the data and conclusions drawn from them unreliable. PMID- 29235699 TI - Pizza, burgers and booze: online marketing and promotion of food and drink to university students. PMID- 29235700 TI - Comments on "Wi-Fi radiation exposures to children in kindergartens and schools - results should lessen parental concerns". PMID- 29235702 TI - In Vitro Evaluation of Resilient Liner after Brushing with Conventional and Experimental Ricinus communis-Based Dentifrices. AB - PURPOSE: To evaluate the effect of experimental (Ricinus communis) and commercial dentifrices used for denture cleaning on abrasiveness (gravimetric method; roughness), hardness, and color stability of a resilient relining material. MATERIALS AND METHODS: Sixty circular (15 * 3 mm) specimens were distributed into four groups: C (control; brushing with water); CO (brushing with Colgate - for natural teeth); CB (brushing with Corega Brite - for complete dentures); RC (brushing with experimental dentifrice). Brushing was performed in a toothbrushing machine with a soft brush and a dentifrice suspension for 50 minutes, calculated to correspond to 1 year of regular brushing. Variables were measured initially and after the trial period. For the gravimetric method, the difference in mass was considered. The surface roughness was measured by a rugosimeter, and the hardness test was performed by a Shore A durometer. Color changes (DeltaE; CIE L*a*b* and NBS systems) were measured by a portable spectrophotometer. Results were analyzed by ANOVA/Tukey's test (alpha = 0.05). RESULTS: The largest mass variation (MUg; p < 0.0001) occurred in C (-6.21 +/- 3.18). Concerning roughness, CB (0.26 +/- 0.04) showed the lowest value, followed by RC (0.29 +/- 0.08) and CO (0.34 +/- 0.24) (p < 0.0001). Group C produced the greatest surface roughness (0.72 +/- 0.25). Hardness values decreased after brushing with water (p = 0.014). No significant differences were found among RC (50.31 +/- 1.03), CO (49.11 +/- 1.31), CB (49.17 +/- 1.23), and C (48.02 +/- 1.26). Color stability was similar in all groups (p = 0.135; C: 2.3 +/- 0.77; CO: 2.6 +/- 0.54; CB: 2.2 +/- 0.44; RC: 2.9 +/- 1.56). CONCLUSIONS: The use of experimental dentifrice could be indicated, as it showed similar results to the specific dentifrice, keeping the resilient material properties within acceptable values. PMID- 29235701 TI - Relation of child, caregiver, and environmental characteristics to childhood injury in an urban Aboriginal cohort in New South Wales, Australia. AB - OBJECTIVE: Despite being disproportionately affected by injury, little is known about factors associated with injury in Aboriginal children. We investigated factors associated with injury among urban Aboriginal children attending four Aboriginal Community Controlled Health Services in New South Wales, Australia. METHODS: We examined characteristics of caregiver-reported child injury, and calculated prevalence ratios of 'ever-injury' by child, family, and environmental factors. RESULTS: Among children in the cohort, 29% (n=373/1,303) had ever broken a bone, been knocked out, required stitches or been hospitalised for a burn or poisoning; 40-78% of first injuries occurred at home and 60-91% were treated in hospital. Reported ever-injury was significantly lower (prevalence ratio <=0.80) among children who were female, younger, whose caregiver had low psychological distress and had not been imprisoned, whose family experienced few major life events, and who hadn't experienced alcohol misuse in the household or theft in the community, compared to other cohort members. CONCLUSIONS: In this urban Aboriginal child cohort, injury was common and associated with measures of family and community vulnerability. Implications for public health: Prevention efforts targeting upstream injury determinants and Aboriginal children living in vulnerable families may reduce child injury. Existing broad-based intervention programs for vulnerable families may present opportunities to deliver targeted injury prevention. PMID- 29235703 TI - Characteristics of healthy weight advertisements in three countries. AB - OBJECTIVE: High rates of population obesity have resulted in the dissemination of mass media campaigns that focus on achieving and maintaining a healthy weight. The aim of the present study was to analyse advertising techniques used in such campaigns to identify common and differential approaches in three countries with similar cultures and rates of obesity (Australia, the United Kingdom and the United States). METHODS: An Internet search was conducted to identify healthy weight television advertisements aired in the three countries. Seventy-two advertisements were located and coded according to the advertising techniques employed. RESULTS: Despite the cultural similarity and comparable obesity rates of the three countries, there were few consistencies in advertising techniques employed. A main focus of the ads was diet, but disparate approaches were used to convey the message in each country. CONCLUSIONS: The identified wide variation in advertising techniques may suggest that campaign managers would benefit from greater certainty about which advertising approaches are most effective in encouraging lifestyle behaviours associated with a healthy weight. Implications for public health: A more robust evidence base would be useful to guide the development of healthy weight campaigns. PMID- 29235704 TI - Industry-Academia Partnership: The Synthesis and Solid-State Pharmaceutical Centre (SSPC) as a Collaborative Approach from Molecule to Medicine. AB - A marriage made in Ireland! The Synthesis and Solid-State Pharmaceutical Centre (SSPC) transcends company and academic boundaries and is one of the largest research collaborations of its type globally. Trust, a culture of inclusivity and commitment to mutual benefit are just some of the factors that have led to the success of the SSPC. Fostering these ideals within its industry-academia, and inter-company collaborations remains crucial to further development. PMID- 29235705 TI - Facile Synthesis of Ultrahigh-Surface-Area Hollow Carbon Nanospheres and their Application in Lithium-Sulfur Batteries. AB - Hollow carbon nanospheres (HCNs) with specific surface areas up to 2949 m2 g-1 and pore volume up to 2.9 cm3 g-1 were successfully synthesized from polyaniline co-polypyrrole hollow nanospheres by carbonization and CO2 activation. The cavity diameter and wall thickness of HCNs can be easily controlled by activation time. Owing to their large inner cavity and enclosed structure, HCNs are desirable carriers for encapsulating sulfur. To better understand the effects of pore characteristics and sulfur contents on the performances of lithium-sulfur batteries, three composites of HCNs and sulfur are prepared and studied in detail. The composites of HCNs with moderate specific surface areas and suitable sulfur content present a better performance. The first discharge capacity of this composite reaches 1401 mAh g-1 at 0.2 C. Even after 200 cycles, the discharge capacity remains at 626 mAh g-1 . PMID- 29235706 TI - A conserved tad pilus promotes Vibrio vulnificus oyster colonization. AB - Vibrio vulnificus has the highest death rate (>35%) and per-case economic burden ($3.3 million) of any foodborne pathogen in the United States. Infections occur via open wounds or following ingestion of contaminated seafood, most infamously oysters. We isolated a 1000th generation descendant, designated NT that exhibited increased biofilm and aggregate formation relative to its parent. We identified two significant causal changes underlying these phenotypes. First, the entire 24 kb capsular polysaccharide biosynthesis locus, which is essential for virulence but inhibits biofilm formation, had been purged from the genome. However, NT formed more extensive biofilms and aggregates than a defined cps mutant, suggesting that additional factor(s) contributed to its phenotypes. Second, the expression of a tight adherence (tad) pilus locus was elevated in NT. Deletion of the associated pilin (flp) decreased NT biofilm and aggregate formation. Furthermore, NTDeltaflp strains were deficient relative to NT in an oyster colonization model, demonstrating a positive correlation between the biofilm and aggregation phenotypes associated with Tad pilus production and efficient bacterial retention by feeding oysters. Despite being widely distributed in the Vibrionaceae, this is the first demonstration of a bona fide physiological role for a Tad pilus in this bacterial family. PMID- 29235707 TI - Tales from the tomb: the microbial ecology of exposed rock surfaces. AB - Although a broad diversity of eukaryotic and bacterial taxa reside on rock surfaces where they can influence the weathering of rocks and minerals, these communities and their contributions to mineral weathering remain poorly resolved. To build a more comprehensive understanding of the diversity, ecology and potential functional attributes of microbial communities living on rock, we sampled 149 tombstones across three continents and analysed their bacterial and eukaryotic communities via marker gene and shotgun metagenomic sequencing. We found that geographic location and climate were important factors structuring the composition of these communities. Moreover, the tombstone-associated microbial communities varied as a function of rock type, with granite and limestone tombstones from the same cemeteries harbouring taxonomically distinct microbial communities. The granite and limestone-associated communities also had distinct functional attributes, with granite-associated bacteria having more genes linked to acid tolerance and chemotaxis, while bacteria on limestone were more likely to be lichen associated and have genes involved in photosynthesis and radiation resistance. Together these results indicate that rock-dwelling microbes exhibit adaptations to survive the stresses of the rock surface, differ based on location, climate and rock type, and seem pre-disposed to different ecological strategies (symbiotic versus free-living lifestyles) depending on the rock type. PMID- 29235708 TI - Chlorantraniliprole resistance and its biochemical and new molecular target mechanisms in laboratory and field strains of Chilo suppressalis (Walker). AB - BACKGROUND: The rice striped stem borer (SSB), Chilo suppressalis (Walker), is one of the most economically important and destructive rice pests in China. To date, the efficiency of conventional insecticides has decreased greatly because of the development of high resistance. Since the introduction of chlorantraniliprole in 2008, SSB has presented resistance issues. RESULTS: In this study, laboratory resistant strains R1 and R2 [resistance ratio (RR) of 38.8 and 110.4, respectively] were established and a field population HR (RR of 249.6) was collected. Synergist assessment and enzyme activity data suggested the potential involvement of P450s and esterases in the resistance mechanism. No target (ryanodine receptor, RyR) mutation was found in R1, but a novel mutation Y4667D was found in R2. At the same position of RyR in HR strain, Y4667D and Y4667C were observed at low frequencies. In addition, the conserved mutation I4758M was found with a frequency of 94.4%. RyR mRNA expression was significantly lower in R1, R2 and HR than in S. When treated with chlorantraniliprole, RyR mRNA expression in all four strains was downregulated to ~ 50%. CONCLUSIONS: A comprehensive analysis, including biochemical, target mutations and target mRNA expression, was conducted in an attempt to interpret the chlorantraniliprole resistance mechanism in both laboratory and field SSB strains. (c) 2017 Society of Chemical Industry. PMID- 29235709 TI - Dynamic environments of fungus-farming termite mounds exert growth-modulating effects on fungal crop parasites. AB - This study investigated for the first time the impact of the internal mound environment of fungus-growing termites on the growth of fungal crop parasites. Mounds of the termite Odontotermes obesus acted as (i) temperature and relative humidity (RH) 'stabilisers' showing dampened daily variation and (ii) 'extreme environments' exhibiting elevated RH and CO2 levels, compared to the outside. Yet, internal temperatures exhibited seasonal dynamics as did daily and seasonal CO2 levels. During in situ experiments under termite-excluded conditions within the mound, the growth of the crop parasite Pseudoxylaria was greater inside than outside the mound, i.e., Pseudoxylaria is 'termitariophilic'. Also, ex situ experiments on parasite isolates differing in growth rates and examined under controlled conditions in the absence of termites revealed a variable effect with fungal growth decreasing only under high CO2 and low temperature conditions, reflecting the in situ parasite growth fluctuations. In essence, the parasite appears to be adapted to survive in the termite mound. Thus the mound microclimate does not inhibit the parasite but the dynamic environmental conditions of the mound affect its growth to varying extents. These results shed light on the impact of animal-engineered structures on parasite ecology, independent of any direct role of animal engineers. PMID- 29235710 TI - Localized high abundance of Marine Group II archaea in the subtropical Pearl River Estuary: implications for their niche adaptation. AB - Marine Group II archaea are widely distributed in global oceans and dominate the total archaeal community within the upper euphotic zone of temperate waters. However, factors controlling the distribution of MGII are poorly delineated and the physiology and ecological functions of these still-uncultured organisms remain elusive. In this study, we investigated the planktonic MGII associated with particles and in free-living forms in the Pearl River Estuary (PRE) over a 10-month period. We detected high abundance of particle-associated MGII in PRE (up to ~108 16S rRNA gene copies/l), which was around 10-fold higher than the free-living MGII in the same region, and an order of magnitude higher than previously reported in other marine environments. 100/00 salinity appeared to be a threshold value for these MGII because MGII abundance decreased sharply below it. Above 100/00 salinity, the abundance of MGII on the particles was positively correlated with phototrophs and MGII in the surface water was negatively correlated with irradiance. However, the abundances of those free-living MGII showed positive correlations with salinity and temperature, suggesting the different physiological characteristics between particle-attached and free-living MGIIs. A nearly completely assembled metagenome, MGIIa_P, was recovered using metagenome binning methods. Compared with the other two MGII genomes from surface ocean, MGIIa_P contained higher proportions of glycoside hydrolases, indicating the ability of MGIIa_P to hydrolyse glycosidic bonds in complex sugars in PRE. MGIIa_P is the first assembled MGII metagenome containing a catalase gene, which might be involved in scavenging reactive oxygen species generated by the abundant phototrophs in the eutrophic PRE. Our study presented the widespread and high abundance of MGII in the water columns of PRE, and characterized the determinant abiotic factors affecting their distribution. Their association with heterotrophs, preference for particles and resourceful metabolic traits indicate MGII might play a significant role in metabolising organic matters in the PRE and other temperate estuarine systems. PMID- 29235711 TI - An assessment of Australian school physical activity and nutrition policies. AB - OBJECTIVE: This study's objective was to identify and assess existing physical activity and nutrition policies for Australian schools. METHODS: Policies were identified through a search of the websites of national and state/territory education departments and school associations, and were subsequently assessed against specific criteria. RESULTS: Policies were identified for government schools, but only for one non-government school association. Physical activity policies were identified at the national level and for six of eight state/territories. The national policy was mandated, and most state/territory physical activity policies were mandated and consistent with the national policy. Several physical activity policies did not meet expert recommendations for time and instructor qualifications. Nutrition policies were identified at the national level and all eight states/territories. The national policy was not mandated, but all state/territory nutrition policies were mandated and consistent with the national policy and relevant guidelines. Most physical activity and nutrition policies lacked information about implementation monitoring. CONCLUSIONS: To improve school practices, policies are needed that are mandated and consistent with expert recommendations, use clear language, and specify monitoring and accountability mechanisms. Implications for public health: Improvements in school policies can promote physical activity and healthy eating behaviours to positively influence student outcomes across Australia. PMID- 29235712 TI - Paroxysmal bradyarrhythmias are frequent among heart transplant recipients with unexplained syncope: a study based on implantable loop recorders. PMID- 29235713 TI - The Ideal Ionic Liquid Salt Bridge for the Direct Determination of Gibbs Energies of Transfer of Single Ions, Part I: The Concept. AB - Described is a procedure for the thermodynamically rigorous, experimental determination of the Gibbs energy of transfer of single ions between solvents. The method is based on potential difference measurements between two electrochemical half cells with different solvents connected by an ideal ionic liquid salt bridge (ILSB). Discussed are the specific requirements for the IL with regard to the procedure, thus ensuring that the liquid junction potentials (LJP) at both ends of the ILSB are mostly canceled. The remaining parts of the LJPs can be determined by separate electromotive force measurements. No extra thermodynamic assumptions are necessary for this procedure. The accuracy of the measurements depends, amongst others, on the ideality of the IL used, as shown in our companion paper Part II. PMID- 29235714 TI - Formate hydrogenlyase and formate secretion ameliorate H2 inhibition in the hyperthermophilic archaeon Thermococcus paralvinellae. AB - Some hyperthermophilic heterotrophs in the genus Thermococcus produce H2 in the absence of S degrees and have up to seven hydrogenases, but their combined physiological roles are unclear. Here, we show which hydrogenases in Thermococcus paralvinellae are affected by added H2 during growth without S degrees . Growth rates and steady-state cell concentrations decreased while formate production rates increased when T. paralvinallae was grown in a chemostat with 65 uM of added H2(aq) . Differential gene expression analysis using RNA-Seq showed consistent expression of six hydrogenase operons with and without added H2 . In contrast, expression of the formate hydrogenlyase 1 (fhl1) operon increased with added H2 . Flux balance analysis showed H2 oxidation and formate production using FHL became an alternate route for electron disposal during H2 inhibition with a concomitant increase in growth rate relative to cells without FHL. T. paralvinellae also grew on formate with an increase in H2 production rate relative to growth on maltose or tryptone. Growth on formate increased fhl1 expression but decreased expression of all other hydrogenases. Therefore, Thermococcus that possess fhl1 have a competitive advantage over other Thermococcus species in hot subsurface environments where organic substrates are present, S degrees is absent and slow H2 efflux causes growth inhibition. PMID- 29235715 TI - Ronald Breslow (1931-2017). AB - Ronald Breslow, Samuel Latham Mitchill Professor of Chemistry at Columbia University, passed away on October 25, 2017, at the age of 86. Breslow made remarkable contributions to the fields of physical-organic and bioorganic chemistry, including biological and biomimetic transformations, and the use of molecular recognition to control reaction selectivity. PMID- 29235716 TI - Authors' response to 2017-199 LtoEd. PMID- 29235717 TI - Direct Asymmetric Michael Reaction of alpha,beta-Unsaturated Aldehydes and Ketones Catalyzed by Two Secondary Amine Catalysts. AB - A direct asymmetric Michael reaction of alpha,beta-unsaturated aldehydes and ketones proceeded in the presence of two pyrrolidine-type catalysts, a diphenylprolinol silyl ether and hydroxyproline, to afford synthetically useful delta-keto aldehydes with excellent diastereo- and enantioselectivity. Although there are several iminium ions and enamines in the reaction mixture, the iminium ion generated by the former catalyst reacts preferentially with the enamine generated by the latter catalyst. PMID- 29235718 TI - Letter from the Editor. PMID- 29235719 TI - Prevalence and sociodemographic correlates of routine breast cancer screening practices among migrant-Australian women. AB - OBJECTIVE: To evaluate breast cancer screening (BCS) practice and explore the relationship between sociodemographic factors and breast awareness (BA), clinical breast examination (CBE) and mammography in migrant-Australian women. METHOD: Secondary analysis was performed on the pooled sample (n=1,744) from five cross sectional studies of BCS rates among immigrant-Australian women, and the associated sociodemographic factors. RESULTS: Only 19% of women participated in routine BA, 27.4% of women in the target group of >40 year presented for an annual CBE, and 60.6% of women in the target group of 50-74 years received a biennial mammogram. Associated sociodemographic factors differed by modality except for length of Australian residency. In multivariable analysis, age, length of Australian residency, marital status, and employment status accounted for more than 50% of the variance in regular BA and CBE. CONCLUSION: These findings indicate suboptimal BCS rates persist among migrant-Australian women, and suggest the importance of certain sociodemographic factors in BCS practice. Implications for public health: Further education is required for BA and CBE practice in immigrant-Australian women, especially for those who have resided in Australia less than 12 years without a partner. PMID- 29235721 TI - The Ideal Ionic Liquid Salt Bridge for Direct Determination of Gibbs Energies of Transfer of Single Ions, Part II: Evaluation of the Role of Ion Solvation and Ion Mobilities. AB - An important intermediate goal to evaluate our concept for the assumption-free determination of single-ion Gibbs transfer energies Deltatr G degrees (i, S1 ->S2 ) is presented. We executed the crucial steps a) and b) of the methodology, described in Part I of this treatise, exemplarily for Ag+ and Cl- with S1 being water and S2 being acetonitrile. The experiments showed that virtually all parts of the liquid junction potentials (LJPs) at both ends of a salt bridge cancel, if the bridge electrolyte is an "ideal" ionic liquid, that is, one with nearly identical diffusion of anion and cation. This ideality holds for [N2225 ]+ [NTf2 ]- in the pure IL, but also in water and acetonitrile solution. Electromotive force measurements of solvation cells between S1 and S2 demonstrated Nernstian behavior for Ag+ concentration cells and constant like cell potentials for solutions with five tested Ag+ counterions. PMID- 29235720 TI - Chimeric mice with humanized liver as a model for testing organophosphate and carbamate pesticide exposure. AB - BACKGROUND: Diagnosis of acute intoxication with organophosphate (OP) or carbamate (CM) pesticides in humans is achieved by measuring plasma butyrylcholinesterase (BuChE) activity. However, BuChE activity is not an ideal biomarker in experimental animal models. The aim of this study was to establish an experimental mouse model for evaluating exposure to OP and CM pesticides by monitoring BuChE activity using chimeric mice in which the liver was reconstituted with human hepatocytes. RESULTS: A single oral administration of acephate (300 mg/kg), chlorpyrifos (10 mg/kg), fenobucarb (300 mg/kg) or molinate (250 mg/kg) in chimeric mice led to inhibition of >95%, > 95%, 28% and 60% of plasma BuChE activity after 7, 0.5, 0.5 and 7 h, respectively. Dose-dependent decreases in plasma BuChE activity were also observed for acephate and chlorpyrifos. A 5-day repeated-dose study with 10 or 30 mg/kg acephate found a constitutive reduction in plasma BuChE activity to 80% and 70% of pre-dose levels, respectively. CONCLUSION: Changes in plasma BuChE activity in chimeric mice with humanized liver clearly reflected the exposure levels of OP and CM pesticides. These results suggest that the humanized-liver mouse model may be suitable for estimating levels of exposure to these pesticides in humans. (c) 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29235722 TI - Alterations in ventricular pumping in patients with atrial septal defect at rest, during dobutamine stress and after defect closure. AB - BACKGROUND: Regional ventricular pumping mechanisms in patients with volume loaded right ventricles (RV) are altered, but the cause is unknown. The aim was to determine whether these changes in ventricular pumping mechanisms are influenced by the RV dilatation itself or the aetiology behind it. METHODS: Seventeen patients with atrial septal defects (ASD) and 10 healthy controls underwent cardiovascular magnetic resonance (CMR) at rest and during dobutamine/atropine stress. Sixteen patients underwent transcutaneous ASD closure. Follow-up CMR at rest was performed the following day. Thirty patients with RV overload due to pulmonary regurgitation (PR) underwent CMR at rest. Cine images were used to measure left ventricular (LV) and RV volumes as well as septal, longitudinal and lateral contributions to LV and RV stroke volume (SV). RESULTS: At rest, septal contribution to LVSV was lower in ASD patients than controls (-1% versus 7%, P<0.05), but there was no difference in longitudinal or lateral contribution to SV. Patients with PR had lower longitudinal contribution to RV with increased lateral and septal contribution. During dobutamine stress, longitudinal contribution to LV and RVSV decreased and lateral contribution increased for ASD patients and controls. The day after ASD closure, septal contribution to LVSV was 6%, longitudinal contribution had increased for RVSV (P<0.05) and decreased for LVSV (P<0.01). CONCLUSION: Pumping mechanisms in patients with RV volume overload depend on the aetiology for the RV dilation and not the size of the RV. PMID- 29235723 TI - Cyclopentanone Derivatives from 5-Hydroxymethylfurfural via 1-Hydroxyhexane-2,5 dione as Intermediate. AB - An efficient strategy for the conversion of biomass derived 5 hydroxymethylfurfural (HMF) into 2-hydroxy-3-methylcyclopent-2-enone (MCP) by an intramolecular aldol condensation of 1-hydroxyhexane-2,5-dione (HHD) has been developed. Further transformations of MCP towards the diol, enol acetate, levulinic acid and N-heterocyclic compounds are also reported. PMID- 29235724 TI - Electrobiorefineries: Unlocking the Synergy of Electrochemical and Microbial Conversions. AB - An integrated biobased economy urges an alliance of the two realms of "chemical production" and "electric power". The concept of electrobiorefineries provides a blueprint for such an alliance. Joining the forces of microbial and electrochemical conversions in electrobiorefineries allows interfacing the production, storage, and exploitation of electricity as well as biobased chemicals. Electrobiorefineries are a technological evolution of biorefineries by the addition of (bio)electrochemical transformations. This interfacing of microbial and electrochemical conversions will result in synergies affecting the entire process line, like enlarging the product portfolio, increasing the productivity, or exploiting new feedstock. A special emphasis is given to the utilization of oxidative and reductive electroorganic reactions of microbially produced intermediates that may serve as privileged building blocks. PMID- 29235725 TI - Low-temperature chemotaxis, halotaxis and chemohalotaxis by the psychrophilic marine bacterium Colwellia psychrerythraea 34H. AB - A variety of ecologically important processes are driven by bacterial motility and taxis, yet these basic bacterial behaviours remain understudied in cold habitats. Here, we present a series of experiments designed to test the chemotactic ability of the model marine psychrophilic bacterium Colwellia psychrerythraea 34H, when grown at optimal temperature and salinity (8 degrees C, 35 ppt) or its original isolation conditions (-1 degrees C, 35 ppt), towards serine and mannose at temperatures from -8 degrees C to 27 degrees C (above its upper growth temperature of 18 degrees C), and at salinities of 15, 35 and 55 ppt (at 8 degrees C and -1 degrees C). Results indicate that C. psychrerythraea 34H is capable of chemotaxis at all temperatures tested, with strongest chemotaxis at the temperature at which it was first grown, whether 8 degrees C or -1 degrees C. This model marine psychrophile also showed significant halotaxis towards 15 and 55 ppt solutions, as well as strong substrate-specific chemohalotaxis. We suggest that such patterns of taxis may enable bacteria to colonize sea ice, position themselves optimally within its extremely cold, hypersaline and temporally fluctuating microenvironments, and respond to various chemical signals therein. PMID- 29235726 TI - Chemical Immobilization Effect on Lithium Polysulfides for Lithium-Sulfur Batteries. AB - Despite great progress in lithium-sulfur batteries (LSBs), great obstacles still exist to achieve high loading content of sulfur and avoid the loss of active materials due to the dissolution of the intermediate polysulfide products in the electrolyte. Relationships between the intrinsic properties of nanostructured hosts and electrochemical performance of LSBs, especially, the chemical interaction effects on immobilizing polysulfides for LSB cathodes, are discussed in this Review. Moreover, the principle of rational microstructure design for LSB cathode materials with strong chemical interaction adsorbent effects on polysulfides, such as metallic compounds, metal particles, organic polymers, and heteroatom-doped carbon, is mainly described. According to the chemical immobilizing mechanism of polysulfide on LSB cathodes, three kinds of chemical immobilizing effects, including the strong chemical affinity between polar host and polar polysulfides, the chemical bonding effect between sulfur and the special function groups/atoms, and the catalytic effect on electrochemical reaction kinetics, are thoroughly reviewed. To improve the electrochemical performance and long cycling life-cycle stability of LSBs, possible solutions and strategies with respect to the rational design of the microstructure of LSB cathodes are comprehensively analyzed. PMID- 29235727 TI - MnCo2 O4 /MoO2 Nanosheets Grown on Ni foam as Carbon- and Binder-Free Cathode for Lithium-Oxygen Batteries. AB - Carbon is usually used as cathode material for Li-O2 batteries. However, the discharge product, such as Li2 O2 and LiO2 , could react with carbon to form an insulating lithium carbonate layer, resulting in cathode passivation and capacity fading. To solve this problem, the development of non-carbon cathodes is highly desirable. Herein, we successfully synthesized MnCo2 O4 (MCO) nanoparticles anchored on porous MoO2 nanosheets that are grown on Ni foam (current collector) (MCO/MoO2 @Ni), acting as a carbon- and binder-free cathode for Li-O2 batteries, in an attempt to improve the electrical conductivity, electrocatalytic activity, and durability. This MCO/MoO2 @Ni electrode delivers excellent cyclability (more than 400 cycles) and rate performance (voltage gap of 0.75 V at 5000 mA g-1 ). Notably, the battery with this electrode exhibits a high energy efficiency (higher than 85 %). The advanced electrochemical performance of MCO/MoO2 @Ni can be attributed to its high electrical conductivity, excellent stability, and outstanding electrocatalytic activity. This work offers a new strategy to fabricate high-performance Li-O2 batteries with non-carbon cathode materials. PMID- 29235728 TI - Semicontinuous sophorolipid fermentation using a novel bioreactor with dual ventilation pipes and dual sieve-plates coupled with a novel separation system. AB - Sophorolipids (SLs) are biosurfactants with widespread applications. The yield and purity of SLs are two important factors to be considered during their commercial large-scale production. Notably, SL accumulation causes an increase in viscosity, decrease in dissolved oxygen and product inhibition in the fermentation medium. This inhibits the further production and purification of SLs. This describes the development of a novel integrated system for SL production using Candida albicans O-13-1. Semicontinuous fermentation was performed using a novel bioreactor with dual ventilation pipes and dual sieve plates (DVDSB). SLs were separated and recovered using a newly designed two-stage separation system. After SL recovery, the fermentation broth containing residual glucose and oleic acid was recycled back into the bioreactor. This novel approach considerably alleviated the problem of product inhibition and accelerated the rate of substrate utilization. Production of SLs achieved was 477 g l-1 , while their productivity was 1.59 g l-1 h-1 . Purity of SLs improved by 23.3%, from 60% to 74%, using DVDSB with the separation system. The conversion rate of carbon source increased from 0.5 g g-1 (in the batch fermentation) to 0.6 g g-1 . These results indicated that the integrated system could improve the efficiency of production and purity of SLs. PMID- 29235729 TI - Conductive Tough Hydrogel for Bioapplications. AB - Biocompatible conductive tough hydrogels represent a new class of advanced materials combining the properties of tough hydrogels and biocompatible conductors. Here, a simple method, to achieve a self-assembled tough elastomeric composite structure that is biocompatible, conductive, and with high flexibility, is reported. The hydrogel comprises polyether-based liner polyurethane (PU), poly(3,4-ethylenedioxythiophene) (PEDOT) doped with poly(4-styrenesulfonate) (PSS), and liquid crystal graphene oxide (LCGO). The polyurethane hybrid composite (PUHC) containing the PEDOT:PSS, LCGO, and PU has a higher electrical conductivity (10*), tensile modulus (>1.6*), and yield strength (>1.56*) compared to respective control samples. Furthermore, the PUHC is biocompatible and can support human neural stem cell (NSC) growth and differentiation to neurons and supporting neuroglia. Moreover, the stimulation of PUHC enhances NSC differentiation with enhanced neuritogenesis compared to unstimulated cultures. A model describing the synergistic effects of the PUHC components and their influence on the uniformity, biocompatibility, and electromechanical properties of the hydrogel is presented. PMID- 29235730 TI - SMART Design of a Bulk-Capped Supramolecular Segment for the Assembly into Organic Interdigital Lipid Bilayer-Like (ILB) Nanosheets. AB - Rational molecular design for the organic nanocrystal morphology still remains a challenge due to the structural diversity and complicated weak intermolecular interactions. In this work, a typical attractor-repulsor molecule N,N-diphenyl-4 (9-phenyl-fluoren-9-yl) phenylamine (TPA-PF) is designed to explore a general assembly strategy for 2D nanocrystals. Via an interdigital lipid bilayer-like (ILB) molecular packing mode, large-sized lamellar 2D nanosheets are obtained with a length:width:thickness ratio as ~2500:1000:1. The d-spacing of the largest (001) plane is 1.32 nm, which equals to the thickness of a single interdigital stacking layer. The synergetic effect of the attractive supramolecular segment (TPA) and the repulsive bulky group (PF) is supposed to be the critical factor for the ILB packing that leads to the 2D structures. The attractor-repulsor molecule design is expected to be an effective strategy for the growth of 2D nanocrystals based on small organic molecules. PMID- 29235731 TI - Collaborative model for training and credentialing point-of-care ultrasound: 6 year experience and quality outcomes. AB - INTRODUCTION: Point-of-care ultrasound (PoCUS) is a rapidly growing area, providing physicians with a valuable diagnostic tool for patient assessment. This paper describes a collaborative model, utilising radiology department ultrasound expertise, to train and credential physicians in PoCUS. A 6-year experience of the implementation and outcomes of the programme established within the emergency departments of a large, multi-campus hospital network are presented. METHODS: A collaborative model was initially developed and implemented between radiology and emergency departments. Key elements of the programme included hospital executive support, close collaboration with stakeholders, resource allocation, appointment of a sonographer educator, clear scope of practise and robust quality processes. RESULTS: Participation grew from 36 emergency physicians in 2011 to 96 physicians in 2016. A total 11064 scans were logged with the programme in the 6-year period. Routine quality audit of 61.8% (6836/11064) of all scans included 2836 Focussed Assessment by Sonography in Trauma (FAST) and 1422 Abdominal Aortic Aneurysm (AAA) examinations. False-positive or false-negative diagnoses occurred in 3.6% (102/2836) FAST and 1.3% (19/1422) AAA cases. No adverse clinical outcomes were reported to involve programme-compliant scans. CONCLUSION: A collaborative model to train and credential physicians in PoCUS has been successfully implemented. The programme grew significantly, produced excellent quality outcomes and resolved many issues of potential conflict related to PoCUS. PMID- 29235733 TI - Intraoperative Parathyroid Aspiration and Parathyroid Hormone Assay During Parathyroidectomy for Primary Hyperparathyroidism. AB - BACKGROUND: Direct aspiration from suspected pathological tissue and rapid parathyroid hormone analysis may offer a reliable, cost effective alternative to currently used "gold standard" tests. OBJECTIVES: To validate the accuracy of intraoperative measurements of parathyroid hormone levels in parathyroid adenomas. METHODS: A prospective study included 22 patients diagnosed with primary hyperparathyroidism who underwent parathyroidectomy due to an adenoma or hyperplasia. Aspirations of tissues extracted from three adjacent areas (the pathological parathyroid, thyroid, and muscle tissues) were sent for rapid parathyroid hormone analysis. The assay values of these tissue aspirates were compared to the results of the pathology report based on frozen section analysis and the final pathology report. RESULTS: All assay results were significantly higher for parathyroid tissue 16,800 to 1,097,986 pmol/L (median 26,600), than for either thyroid 1.7 to 415 pmol/L (median 6.5), P < 0.001, or muscle tissue 1.1 to 1230 pmol/L, (median 11.3), P < 0.001. All tissues showing high parathyroid assay values were also verified by pathology examinations: 7 had adenomas and 15 had a differential diagnosis of adenoma or hyperplasia. The frozen section identified all but one (false negative). Rapid intraoperative parathyroid levels > 1500 predicted parathyroid tissue with a 99% level of confidence, while levels between 1000 and 1500 predicted it with 95% confidence. The intraoperative parathyroid hormone assay showed > 70% decrease in 15/21 cases. CONCLUSIONS: Rapid intraoperative parathyroid hormone analysis is a reliable and precise technique, equally accurate for frozen section analysis in predicting with high certainty intraoperative parathyroid tissue. PMID- 29235734 TI - Comparison of the Long-Term Oncological Outcomes of Stent as a Bridge to Surgery and Surgery Alone in Malignant Colonic Obstruction. AB - BACKGROUND: Self-expanding metallic stents (SEMS) insertion is an alternative to emergency surgery in malignant colonic obstruction. However, the long-term oncological outcome of stents as a bridge to surgery is limited and controversial. OBJECTIVES: To determine the long-term oncological outcome of stents as a bridge to surgery. METHODS: Data of patients who underwent emergency surgery and endoscopic stent insertion as a bridge to surgery due to obstructing colon cancer at Soroka Medical Center during a 14 year period were collected retrospectively. Preoperative data, tumor staging, and oncological outcomes in terms of local recurrence, metastatic spread, and overall survival of the patients were compared. RESULTS: Sixty-four patients (56% female, mean age 72 years) were included in the study: 43 (67%) following emergency surgery, 21 stent inserted prior to surgery. A stent was inserted within 24-48 hours of hospital admission. The mean time between SEMS insertion and surgery was 15 days (range 0 30). Most of the patients had stage II (41%) and stage III (34%) colonic cancer. There was no difference in tumor staging and localization between groups. There was no significant difference in disease recurrence between SEMS and surgery groups, 24% and 32%, respectively. Disease-free survival rates were similar between the SEMS group (23.8%) and surgery group (22%). Four year and overall survival rates were 52.4% vs. 47.6%, 33.3% vs. 39.5%, respectively. CONCLUSIONS: SEMS as a bridge to surgery in patients with obstructing colon cancer provide an equivalent long-term oncological outcome to surgery alone. PMID- 29235732 TI - Weed resistance to synthetic auxin herbicides. AB - Herbicides classified as synthetic auxins have been most commonly used to control broadleaf weeds in a variety of crops and in non-cropland areas since the first synthetic auxin herbicide (SAH), 2,4-D, was introduced to the market in the mid 1940s. The incidence of weed species resistant to SAHs is relatively low considering their long-term global application with 30 broadleaf, 5 grass, and 1 grass-like weed species confirmed resistant to date. An understanding of the context and mechanisms of SAH resistance evolution can inform management practices to sustain the longevity and utility of this important class of herbicides. A symposium was convened during the 2nd Global Herbicide Resistance Challenge (May 2017; Denver, CO, USA) to provide an overview of the current state of knowledge of SAH resistance mechanisms including case studies of weed species resistant to SAHs and perspectives on mitigating resistance development in SAH tolerant crops. (c) 2017 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29235735 TI - Homemade Hypertonic Saline: Essential Treatment Can Be Available and Affordable. AB - BACKGROUND: Nebulized hypertonic saline (HS) treatment is unavailable to large populations worldwide. OBJECTIVES: To determine the bacterial contamination and electrolyte concentrations in homemade (HM-HS) vs. pharmacy made (PM-HS). METHODS: We conducted three double-blind consecutive trials: 50 boiled-water homemade 3%-HS (B-HM-HS) bottles and 50 PM-HS. The bottles were cultured after 48 hours. Electrolyte concentrations were measured in 10 bottles (5 per group). Forty bottles (20 per group) were distributed to volunteers for simulation of realistic treatment by drawing 4 ml HS three times daily. From each bottle, 4 ml samples were cultured after 1, 5, and 7 days. Volunteers prepared 108 bottles containing 3%-HS, sterilizing them using a microwave oven (1100-1850W). These bottles were cultured 24 hours, 48 hours, and 1 month after preparation. RESULTS: Contamination rates of B-HM-HS and PM-HS after 48 hours were 56% and 14%, respectively (P = 0.008). Electrolyte concentrations were similar: 3.7% +/- 0.4 and 3.5% +/- 0.3, respectively (P = NS). Following a single day of simulation B HM-HS bottles were significantly more contaminated than PM-HS bottles: 75% vs. 20%, respectively (P < 0.01). By day 7, 85% of PM-HS bottles and 100% of B-HM-HS bottles were contaminated (P = 0.23). All 108 microwave-oven prepared bottles (MICRO-HS) were sterile, which was significantly better than the contamination rate of B-HM-HS and PM-HS (P < 0.001). Calculated risk for a consecutive MICRO-HS to be infected was negligible. CONCLUSIONS: Microwave preparation provides sterile HS with adequate electrolyte concentrations, and is a cheap, fast, and widely available method to prepare HS. PMID- 29235736 TI - Primary and Secondary Antibiotic Resistance of Helicobacter pylori in Israeli Children and Adolescents. AB - BACKGROUND: Empiric treatment for Helicobacter pylori is influenced by antibiotic susceptibility of infecting strains. A rise in the resistance rate to clarithromycin and metronidazole has been reported in pediatric populations. OBJECTIVES: To assess the primary and secondary antibiotic resistance of H. pylori isolates in Israeli children and adolescents. METHODS: A retrospective review of H. pylori isolates cultured from antral biopsies of consecutive children aged 1 to 18 years, who were referred to the Pediatric Gastroenterology Unit, Kaplan Medical Center, over a 2.8 year period, was performed. Antibiotic susceptibility to clarithromycin, metronidazole, amoxicillin, tetracycline, and levofloxacin was determined by E-test. Data on the age of the patient, indication for endoscopy, and antibiotic treatment for H. pylori in previously treated children was collected. RESULTS: Cultures for H. pylori yielded 123 isolates. In children not previously treated (n=95), the primary global resistance was 38% with resistance to clarithromycin 9.5%, metronidazole 32.6 %, and to both 4.2%. Respective rates of resistance in previously treated children (n=28) were 71% (P = 0.002), 29% (P = 0.02), and 61% (P = 0.007). Simultaneous resistance to both drugs was found in 18% (P = 0.02). All H. pylori strains were susceptible to amoxicillin, tetracycline, and levofloxacin. Past eradication treatment was the only independent risk factor for antibiotic resistance in multivariate analysis. CONCLUSIONS: Significantly higher resistance rates were found in previously treated patients, stressing the need to refrain from empiric treatment using the "test and treat strategy." Culture-based treatment strategy should be considered in all previously treated children. PMID- 29235737 TI - Long-Term Survival of Discharged Patients Admitted to Intensive Coronary Care Unit after Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: Survival of patients who were discharged from the hospital following out-of-hospital cardiac arrest (OHCA) has not been well defined. OBJECTIVES: To verify predictor variables for prognosis of patients following OHCA who survived hospitalization. METHODS: We retrospectively reviewed clinical, demographic, and outcome data of consecutive patients who were hospitalized from January 1, 2009, through December 31, 2014, into the intensive coronary care unit (ICCU) after aborted OHCA and discharged alive. The patients were followed until December 31, 2015. RESULTS: Of the 180 patients who were admitted into ICCU after OHCA, 64 were discharged alive (59.3%): 55 were male (85.9%), 14 died 16.5 +/- 18 months after their discharge. During 1 year follow-up, nine patients (14.1%) died after a median period of 5.5 months and 55 patients (85.9 %) survived. Diabetes mellitus and chronic renal failure (CRF) were more frequent in patients who died within 1 year after their hospital discharge than those who survived. Ventricular fibrillation, such as initial arrhythmia, and opening of occluded infarct related artery were more frequent in survivors. CONCLUSIONS: Most of the patients who were discharged after OHCA were alive at the 1 year follow-up. The risk of death of cardiac arrest survivors is greatest during the first year after discharge. CRF remains a poor long-term prognostic factor beyond the patients' discharge. Ventricular fibrillation, as initial arrhythmia, and opening of occluded infarct related artery have a positive impact on long-term survival. PMID- 29235738 TI - Twenty Year Trends of Survival after In-Hospital Cardiac Arrest. AB - BACKGROUND: In 2006, the Israeli Ministry of Health distributed guidelines for improving cardiopulmonary resuscitation (CPR) knowledge among hospital staff. The impact of these guidelines on survival after in-hospital cardiac arrest (IHCA) is unclear. OBJECTIVES: To compare rates of incidence and survival to discharge after IHCA, preceding and subsequent to issuance of the guidelines: 1995-2005 and 2006-2015. METHODS: Data were retrieved from the computerized records of patients who had an IHCA and underwent CPR. In addition, we retrieved data available from the hospital's resuscitation committee that included number, type, methods of training in CPR refresher courses, type and number of audits carried out during the past 10 years, and type of CPR quality assessments. RESULTS: From 1995 to 2015, IHCA incidence increased from 0.7 to 1.7 per 1000 admissions (P < 0.001), while survival rate did not increase (P = 0.37). Survival for shockable rhythms increased from 15.4 to 30.2% (P = 0.05) between the two time periods. The ratio of non-shockable to shockable rhythms increased from 2.4 to 4.6 (P = 0.01) between the two time periods. CONCLUSIONS: Overall IHCA survival did not improve following the issuance of guidelines requiring CPR refresher courses, although survival improved for patients with initial shockable dysrhythmia. A decrease of events with initial shockable dysrhythmia, an increase with acute renal failure, and a decrease occurring in intensive care units contributed to understanding the findings. We found that CPR refresher courses were helpful, although an objective measure of their effectiveness is lacking. PMID- 29235739 TI - Assistance of Medical Clowns Improves the Physical Examinations of Children Aged 2-6 Years. AB - BACKGROUND: A good physical exam is necessary to help pediatricians make the correct diagnosis and can save unnecessary imaging or invasive procedures. Distraction by medical clowns may create the optimal conditions for a proper physical examination. METHODS: Children aged 2-6 years who required physical examination in the pediatric emergency department were recruited and randomly assigned to one of two groups: physical exam by a pediatrician in the presence of caregivers vs. physical exam with the assistance of a medical clown. Outcome measures consisted of the level of child's discomfort, anxiety, and the quality of the physical examination. RESULTS: Ninety three children participated. Mean age was 3.3 +/- 3.6 years (range 2-6). The duration of the physical exam was similar between the clown and control groups (4.6 +/- 1.4 minutes vs. 4.5 +/- 1.1 minutes (P = 0.64). The duration of discomfort was shorter in the clown group (0.2 +/- 0.6 minutes) than the control group(1.6 +/- 2.0 minutes, P = 0.001). In the medical clown group, 94% of pediatricians reported that the medical clown improved their ability to perform a complete physical examination. A trend of less hospitalization in the medical clown group was also noticed (11.3% in the medical clown group vs. 18.3% in the control group, P = 0.1); however, further study is required to verify this observation. CONCLUSIONS: Integration of a medical clown in physical examination improves the overall experience of the child and the caregivers and helps the pediatrician to perform a complete physical examination. PMID- 29235740 TI - Thalassemia Major and Intermedia in Patients Older than 35 Years: A Single Center Experience. AB - BACKGROUND: During the past decades, beta thalassemia major (TM) and beta thalassemia intermedia (TI) have transformed from a universally fatal disease at a young age into a chronic disease. This advancement is attributed to improved chelation therapy as well as enhanced management strategies, with focused attention on disease and treatment-related complications. OBJECTIVES: To describe characteristics of adults with thalassemia as well as treatment modalities, disease and treatment-related complications, and socioeconomic information of the patients. METHODS: We preformed a retrospective analysis of 14 adult patients > 35 years of age with TM and TI who were treated at our institute, a single center specializing in the care of adult thalassemia patients living in Israel, between the years 2006 and 2016. RESULTS: The median age of patients was 37 years and most patients were transfusion-dependent. The median number of chelation therapeutic lines was three, and 85.7% of patients were treated at one point by combination chelation therapy. Most patients suffered from at least some form of endocrine dysfunction (n=12), and four patients developed overt heart failure. Of the patients, 85% had completed at least a high school education, 78% were employed, and 64.2% were married. CONCLUSIONS: Prolonged survival of thalassemia patients in recent years has been accompanied by a new set of challenges for both the patients and the treating staff. Further research is warranted to improve both medical management and the socioeconomic well-being of this unique group of adult thalassemia patients. PMID- 29235741 TI - A Picture is Worth a Thousand Words: Art and Medicine. AB - BACKGROUND: Medical practice is a form of art, with each complex detail essential to the welfare of the individuals in the care of the physician. Art and medicine have shared a close relationship in a variety of ways for centuries, as demonstrated by anatomical drawings and textbooks from the 16th century. Leonardo da Vinci, driven by his fascination with the details of the human body and how it functioned, succeeded in creating an anatomical model of the cerebral ventricles and the aorta using molten wax and a glass structure, respectively (Heart and Its Blood Vessels). By using water that contained grass seeds, this experiment enabled him to study blood flow. da Vinci's engrossment with the complexity of the human body is reflected in many of his drawings, including the famous depiction of the human physique in his drawing of the Vitruvian Man. This drawing, which defines the ideal proportions of the human body and their correlation with geometry, is an example of how artistic and scientific objectives integrate with each other. PMID- 29235742 TI - Metastatic Collecting (Bellini) Duct Carcinoma Presented in a Young Patient: A Case Report and Review of the Literature. PMID- 29235744 TI - Rheumatology and Autoimmunity in The Israel Medical Association Journal (IMAJ): 2017. PMID- 29235743 TI - Severe cognitive Disorders after Bilateral Infarction in the Cerebellum. PMID- 29235745 TI - Hypertonic Saline for Inhalation: A Do It Yourself Recipe. PMID- 29235746 TI - Clinical Problem Solving: A Tobacco Merchant Who Can't Spit. AB - BACKGROUND: A 47 year old man presented with a combination of dry mouth and lightheadedness while standing. His medical background was unremarkable except for cigarette smoking and hyperlipidemia. Sjogren's syndrome was ruled out, and he was referred for evaluation of orthostatic hypotension, which by then included syncopal episodes and injuries. Additional symptoms included dry eyes, constipation, reduced sweating, and erectile dysfunction. After excluding medications and structural cardiac abnormalities as causes of orthostatic hypotension, a clinical autonomic evaluation was performed. The pattern of beat to-beat blood pressure associated with performance of the Valsalva maneuver, and a low plasma norepinephrine level that did not increase in response to standing, established that the orthostatic hypotension was neurogenic. Treatment with an alpha-adrenoceptor agonist and fludrocortisone yielded partial improvement. After systemic diseases involving autonomic failure were excluded, cardiac sympathetic neuroimaging was performed by 123I-metaliodobenzylguanidine (MIBG) scanning. The normal uptake seen in the heart indicated intact post ganglionic sympathetic innervation. There were no signs of central neurodegeneration or peripheral neuropathy. Because of symptoms and signs of both parasympathetic and sympathetic failure without denervation, an autonomic ganglionopathy was considered. A high titer of antibody to the neuronal nicotinic receptor, which mediates ganglionic neurotransmission, was obtained. The diagnosis of autoimmune autonomic ganglionopathy (AAG) was made, and the management strategy shifted to first lowering the antibody burden by plasma exchanges and then instituting chronic anti-autoimmune treatment with rituximab and a low dose of cortiosteroid. The patient showed remarkable improvement. PMID- 29235747 TI - Glass Ionomers in Modern Clincial Practice. PMID- 29235748 TI - Implementing a Systematic Digital Workflow. PMID- 29235749 TI - Restoration of a Lateral Incisor With Dens Invaginatus. PMID- 29235751 TI - The Innovation Engine. PMID- 29235750 TI - Proud Defenders of Dentistry. PMID- 29235752 TI - The mechanism of VEGF-mediated endothelial cells survival and proliferation in conditions of unfed-culture. AB - The mechanisms of VEGF-mediated effects on endothelial cells during cancer development and progression is not clear. In present study the biological effects of VEGF, VEGF-rich culture medium of peritoneal macrophages from mice with Lewis lung carcinoma were studied on MAEC cell line under conditions of unfed culture. We have shown that VEGF increased cell proliferation by the 5th day of culturing vs control and anti-VEGF-treated cells. This effect was associated with increased consumption of glucose and NO production by the 2nd day while decreased - on the 5th day of cell culturing. VEGF-mediated NO production was dependent on Ca2+ ions. Block of Ca2+-channels (LaCl3) had more pronounced inhibitory effect vs chelator of Ca2+ ions (EDTA). It was shown that peritoneal macrophages are the main suppliers of VEGF at tumor angiogenesis, as evidenced by the data obtained on model system of endothelial cells synchronized in G0/G1 phase. PMID- 29235754 TI - Focus On: Silver Diamine Fluoride. PMID- 29235753 TI - The influence of heavy metal ions, spermine and sodium nitroprusside on ATP hydrolases of cell membranes of rat colon smooth muscle. AB - The specific features of functional lability of the rat colon smooth muscle (CSM) ATR-hydrolases were studied. Na+,K+-ATRase activity is effectively inhibited by divalent ions of both transition (>= 0,1 uM) and nontransition (>= 1 uM) heavy metals in succession by efficiency: Cu2+ > Fe2+ >= Cd2+ (10 uM). Polyamine spermine (0,5-1,0 mM) is a weak Na+,K+-ATRase inhibitor at saturation concentrations of ions and substrate. Sodium nitroprusside (1 mM) as nitric oxide generating compound exhibits weak Na+,K+-ATRase inhibition only after prolonged preincubation with membranes. Mg2+-ATR-hydrolase activity in all cases is much more resistant to studied agents. Considering the example of the CSM Na+,K+ ATRase it is assumed that enzyme has specific biochemical features that contribute to its role as a potential target and redox-sensor, mediating the pathological mechanisms of heavy metal intoxication and cell oxidative damage. PMID- 29235755 TI - Changes in oxidative stress intensity in blood of tumor-bearing rats following different modes of administration of rhenium-platinum system. AB - Effects of the different modes of administration of dichlorotetra-MU isobutyratodirhenium(III) - I - (in water solution, liposomes, nanoliposomes and together with cisplatin - in the rhenium-platinum system) on the intensity of lipid peroxidation (LP) in blood plasma and the activity of the erythrocyte antioxidant enzymes were investigated on the model of tumor growth. A decrease in the concentration of TBA-active substances caused by dirhenium compounds was shown to be independent of the administration mode and the extent of the tumor growth inhibition. I was four-times more effective in inhibition of the LP burst than any known antioxidant. I induced the increasing activity of erythrocyte superoxide dismutase and decreasing activity of catalase. In vitro experiments with native superoxide dismutase, the interaction of I with following activation of the active center of the enzyme was confirmed and the superoxide dismutase activity of I was shown, that may contribute to the enhancement of the enzyme activity in vivo. The cluster rhenium compounds may be promising nontoxic potent antioxidants capable of deactivating superoxide radicals. PMID- 29235756 TI - Materials and Instruments: Has Anything Changed? PMID- 29235759 TI - A One-Visit Option: An Alternative to Traditional Ceramic Restorations. PMID- 29235757 TI - A Multidisciplinary Approach to Cosmetic Rehabilitation. PMID- 29235760 TI - Overdenture Design to Maximize Stability and Function. PMID- 29235762 TI - Locating Canals: Strategies, Armamentarium, and Techniques. PMID- 29235761 TI - The effect of perioperative analgesic drugs omnopon and dexketoprofen on the functional activity of immune cells in murine model of tumor surgery. AB - We aimed to investigate the effect of perioperative analgesia with nonselective cyclooxygenase-2 inhibitor dexketoprofen and opioid drug omnopon on the functional activity of immune cells in tumor excision murine model. Lewis lung carcinoma cells were transplanted into hind paw of C57/black mice. On the 23th day tumor was removed. Analgesic drugs were injected 30 min before and once a day for 3 days after the surgery. Biological material was obtained a day before, 1 day and 3 days after the tumor removal. IFN-gamma, IL-4, IL-10 and TGF-beta mRNA levels in splenic cells were assessed by quantitative real-time RT-PCR. Cytotoxic activity of splenocytes was estimated by flow cytometry. We found that in splenocytes of mice received opioid analgesia IL-10 mRNA level was increased 2.3 times on day one after the surgery compared to preoperative level (P < 0.05), while in dexketoprofen group this parameter did not change. IFN-gamma gene expression level on day 3 after tumor removal was 40% higher in splenocytes of dexketoprofen treated mice as compared with omnopon treated animals (P < 0.05). Cytotoxic activity of splenocytes on day 3 postsurgery was (62.2 +/- 2.4)% in dexketoprofen against (50.2 +/- 3.3)% in omnopon group. In conclusion, perioperative analgesia with cyclooxygenase inhibitor dexketoprofen in contrast to opioid analgesia with omnopon preserves higher functional activity of murine immune cells in the experimental model of tumor surgery. PMID- 29235763 TI - Biocompatible Quadrant Dentistry for Overall Health. PMID- 29235764 TI - Monooxygenase system in Guerin's carcinoma of rats under conditions of omega-3 polyunsaturated fatty acids administration. AB - The aim of the study was to determine the variations of function in components of monooxygenase system (MOS) of rat Guerin's carcinoma under omega-3 polyunsaturated fatty acids (PUFAs) administration. The activity of Guerin's carcinoma microsomal NADH-cytochrome b5 reductase, the content and the rate of cytochrome b5 oxidation-reduction, the content and the rate of cytochrome R450 oxidation-reduction have been investigated in rats with tumor under conditions of omega-3 PUFAs administration. omega-3 PUFAs supplementation before and after transplantation of Guerin's carcinoma resulted in the increase of NADH-cytochrome b5 reductase activity and decrease of cytochrome b5 level in the Guerin's carcinoma microsomal fraction in the logarithmic phases of carcinogenesis as compared to the tumor-bearing rats. Increased activity of NADH-cytochrome b5 reductase facilitates higher electron flow in redox-chain of MOS. Under decreased cytochrome b5 levels the electrons are transferred to oxygen, which leads to heightened generation of superoxide (O2*-) in comparison to control. It was shown, that the decrease of cytochrome P450 level in the Guerin's carcinoma microsomal fraction in the logarithmic phases of oncogenesis under omega-3 PUFAs administration may be associated with its transition into an inactive form - cytochrome P420. This decrease in cytochrome P450 coincides with increased generation of superoxide by MOS oxygenase chain. PMID- 29235765 TI - QSAR studies and antimicrobial potential of 1,3-thiazolylphosphonium salts. AB - The regression QSAR models were built to predict the antimicrobial activity of new thiazole derivatives. Compounds with high predicting activity were synthesized and evaluated against Gram-positive and Gram-negative bacteria and fungi. 1,3-Thiazole-4-ylphosphonium salts 4 and 5 displayed good antibacterial properties and high antifungal activity. The predictions are in a good agreement with the experiment results, which indicate the good predictive power of the created QSAR models. PMID- 29235766 TI - An Improved Glass Ionomer Restorative System: Stress-Bearing Class I and II Indications. PMID- 29235769 TI - Corporate Healthcare Important Contracts. PMID- 29235768 TI - Optimism Rings in the New Year. PMID- 29235767 TI - Severe Xerostomia Secondary to Anticholinergic Drug Therapy: Case Report. PMID- 29235770 TI - Focus On: Continuing Education. PMID- 29235771 TI - Schedules of Controlled Substances: Placement of MT-45 Into Schedule I. Final order. AB - With the issuance of this final order, the Administrator of the Drug Enforcement Administration places the substance MT-45 (Systematic IUPAC Name: 1-cyclohexyl-4 (1,2-diphenylethyl)piperazine), including its salts, isomers, and salts of isomers into schedule I of the Controlled Substances Act. This scheduling action is pursuant to the Controlled Substances Act and is required in order for the United States to discharge its obligations under the Single Convention on Narcotic Drugs, 1961. This action imposes the regulatory controls and administrative, civil, and criminal sanctions applicable to schedule I controlled substances on persons who handle (manufacture, distribute, import, export, engage in research or conduct instructional activities with, or possess), or propose to handle, MT-45. PMID- 29235772 TI - Dental Implants in the Aesthetic Zone. PMID- 29235773 TI - Implants in the Aesthetic Zone: Clinical Guidelines. PMID- 29235774 TI - Achieving Natural Tissue Contours: A Predictable and Simplified Technique. PMID- 29235775 TI - Screw-Retained Versus Cement-Retained Restorations: Aesthetic Zone Options. PMID- 29235776 TI - Questions to Ask Prior to Root Canal Treatment. PMID- 29235777 TI - Aesthetics and Strength With One Restorative Material. PMID- 29235778 TI - The Seven Deadly Sins of Traditional Class II Restorations. PMID- 29235779 TI - Laser Troughing to Improve Scanning and Impressions. PMID- 29235780 TI - Hypertension and the Dental Patient. PMID- 29235781 TI - Addressing the Social Determinants of Health Through Medicaid Managed Care. AB - Issue: With its emphasis on coordinated care and prevention, managed care should be tailor-made to tackle social determinants of health. But various challenges discourage Medicaid health plans and providers from assisting beneficiaries with nonmedical concerns such as housing insecurity or parenting skills that are integral to improving health outcomes and lowering costs. To better address these social factors, the Centers for Medicare and Medicaid Services (CMS) updated its Medicaid managed care rule in early 2016. Goal: To explore the impact of several provisions of the new regulation that influence states' ability to address social determinants of health through managed care. Findings and Conclusions: Several provisions in the new Medicaid managed care rule signal CMS's intent to increase access to high-value nonmedical interventions. For instance, the regulation financially incentivizes health plans to address these needs by allowing certain nonclinical services to be included as covered services when calculating the capitated rate and medical loss ratios. In addition, the regulation encourages states to improve care coordination, adopt alternative payment models, and provide long-term services and supports in the home and community for beneficiaries with functional limitations. PMID- 29235782 TI - Survey says... PMID- 29235783 TI - Growth in nursing workforce unlikely to keep up with demand for seniors care. PMID- 29235784 TI - Federal budget removes one of the legislative barriers to NP practice. PMID- 29235785 TI - The Evolution of Private Plans in Medicare. AB - Issue: Since the 1980s, private plans have played an increasingly important role in the Medicare program. While initially created with the goals of reducing costs, improving choice, and enhancing quality, risk-based plans--now known as Medicare Advantage plans--have undergone significant policy changes since their inception; these changes have not always aligned with the original policy objectives. Goal: To examine major policy changes to Medicare risk plans and the effects of these policies on plan participation, enrollment, average premiums and cost-sharing, total costs to Medicare, and quality of care. Methods: Review of key policy documents, reports, position statements, and academic studies. Findings and Conclusions: Private plans have changed considerably since their introduction into Medicare. Enrollment has risen to 33 percent of all Medicare beneficiaries; 99 percent of beneficiaries have access to private plans in 2017. Recent policies have improved risk-adjustment methods, rewarded plans' performance on quality of care, and reduced average payments to private plans to 100 percent of traditional Medicare spending. As enrollment in private plans continues to grow and as health care costs rise, policymakers should enhance incentives for private plans to meet intended goals for higher-quality care at lower cost. PMID- 29235787 TI - Artificial intelligence, automation and the future of nursing. PMID- 29235786 TI - Adopting national nursing data standards in Canada. PMID- 29235788 TI - Editorial. PMID- 29235789 TI - The use of the Petri net method in the simulation modeling of mitochondrial swelling. AB - Using photon correlation spectroscopy, which allows investigating changes in the hydrodynamic dia-meter of the particles in suspension, it was shown that ultrahigh concentrations of Ca2+ (over 10 mM) induce swelling of isolated mitochondria. An increase in hydrodynamic diameter was caused by an increase of non-specific mitochondrial membrane permeability to Ca ions, matrix Ca2+ overload, activation of ATP- and Ca2+-sensitive K+-channels, as well as activation of cyclosporin-sensitive permeability transition pore. To formalize the experimental data and to assess conformity of experimental results with theoretical predictions we developed a simulation model using the hybrid functional Petri net method. PMID- 29235791 TI - Empowered by technology. PMID- 29235790 TI - A mathematical model of the metabolic process of atherosclerosis. AB - A mathematical model of the metabolic process of atherosclerosis is constructed. The functioning of the polyenzymatic prostacyclin-thromboxane system of blood and the influence of a level of "bad cholesterol", namely low density lipoproteins (LDL), on it are studied. With the help of the numerical experiment, we analyze the influence of the concentration of molecules of fat on hemostasis of blood in blood vessels. The kinetic curves for components of the system, phase-periodic bifurcation diagrams, attractors for various modes, and Poincare cross-section and image of a strange attractor are constructed. The complete spectra of Lyapunov's exponents, divergencies, KS-entropies, predictability horizons, and Lyapunov dimensions of the fractality of strange attractors are calculated. Conclusions about the structural-functional connections, which determine the dependence of hemostasis of a circulatory system on the level of cholesterol in blood are drawn. PMID- 29235793 TI - Wanted: A new role as a clinical nurse philosopher. PMID- 29235792 TI - [Inventive activity of the Departments of Chemistry and Biochemistry of Enzymes, and Protein Structure and Function of the Palladin Institute of Biochemistry of NAS of Ukraine. Part III. Diagnostic test-systems for analysis of fibrinolysis blood system and novel approaches to thrombosis treatment]. AB - This article continues analysis of scientific achievements of the Institute of Biochemistry in the study of hemostasis system. Two previous articles were focused on the studies of blood coagulation proteins and development of the immune-enzyme test-systems for evaluation of the risk of thrombosis upon various pathologies. This article highlights the research on the blood fibrinolysis system and new approaches to thrombosis treatment, which were developed (and are under development) in the Palladin Institute of Biochemistry of the NAS of Ukraine, in particular, in the Department of Chemistry and Biochemistry of Enzymes headed previously by Dr.Sci.(Biol.) S. O. Kudinov and now by Dr.Sci.(Biol.) T .V. Grinenko, and also in the Department of Protein Structure and Function headed by Dr.Biol.Sci. E. M. Makogonenko. The fundamental knowledge of protein molecule functions and mechanisms of regulation of blood coagulation and fibrinolysis opens up new opportunities to diagnose hemostasis disorders and control the effectiveness of the cardiovascular disease treatment and also contributes to development of new techniques for isolation of new proteins - promising therapeutic agents. PMID- 29235794 TI - TAKING THE LEAD. NURSES, MIDWIVES AND LEADERSHIP. PMID- 29235795 TI - So much not known about Muslim nurses in Canada. PMID- 29235796 TI - The role of the TNF receptors and apoptosis inducing ligands in tumor growth. AB - Tumor necrosis factor (TNF) superfamily receptors and TNF apoptosis inducing ligands play an important role in the realization of TNF function and control tumor growth. The TNF-related pathways are controlled by endoplasmic reticulum stress signaling, which has a crucial role in the control of cell proliferation and tumor growth. Furthermore, the inhibition of IRE1 (inositol requiring enzyme 1), which is a central mediator of endoplasmic reticulum stress sand mainly responsible for cell proliferation and apoptosis, leads to suppression of tumor growth through specific changes in the expression of genes encoding transcription factors, tumor suppressors, angiogenesis and apoptosis related proteins, including TNF superfamily receptors and TNF apoptosis inducing ligands. Therefore, changes in the expression level of TNF-related genes encoding TNF superfamily receptors and apoptosis inducing ligands possibly reflect metabolic reprogramming of cancer cells upon inhibition of IRE1-mediated endoplasmic reticulum stress signaling and correlate with suppression of glioma cell proliferation. PMID- 29235798 TI - Review of the National Registration and Accreditation Scheme. PMID- 29235797 TI - Harm reduction in the addiction continuum of care. PMID- 29235800 TI - Non-probability sampling. PMID- 29235799 TI - Prednisolone and vitamin D(3) modulate oxidative metabolism and cell death pathways in blood and bone marrow mononuclear cells. AB - The study was designed to evaluate reactive oxygen species (ROS)/nitric oxide (NO) formation and apoptotic/necrotic cell death elicited by prednisolone in peripheral blood and bone marrow mononuclear cells and to define the efficacy of vitamin D3 to counter glucocorticoid (GC)-induced changes. It was shown that prednisolone (5 mg per kg of female Wistar rat's body weight for 30 days) evoked ROS and NO overproduction by blood mononuclear cells (monocytes and lymphocytes) that correlated with increased cell apoptosis and necrosis. In contrast, prednisolone did not affect ROS/NO levels in bone marrow mononuclear cells that corresponded to lower level of cell death than in the control. Alterations of prooxidant processes revealed in mononuclear cells and associated with GC action were accompanied by vitamin D3 deficiency in animals, which was assessed by the decreased level of blood serum 25-hydroxivitamin D3 (25OHD3). Vitamin D3 administration (100 IU per rat daily for 30 days, concurrently with prednisolone administration) completely restored 25OHD3 content to the control values and significantly reversed ROS and NO formation in blood mononuclear cells, thus leading to decreased apoptosis. In bone marrow, vitamin D3 activated ROS/NO production and protein nitration that may play a role in prevention of prednisolone-elicited increase in bone resorption. We conclude that vitamin D3 shows a profound protection against GC-associated cellular damage through regulating intracellular ROS/NO formation and cell death pathways. PMID- 29235802 TI - Resolving to be healthier. PMID- 29235803 TI - Licensure Portability. PMID- 29235801 TI - Calix[4]arene C-90 and its analogs activate ATPase of the myometrium myosin subfragment-1. AB - Numerous female reproductive abnormalities are consequences of disorders in uterus smooth muscle (myometrium) contractile function. In this work, we described activators of ATPase, which could be used for development of effective treatments for correcting this dysfunction. Myosin ATPase localized in the catalytic domain of myosin subfragment-1 transforms a chemical energy deposited in macroergic bonds of ATP into mechanical movement. It was shown that salix[4]arene C-90 and its structural analogs functionalized at the upper rim of macrocycle with four or at least two N-phenylsulfonultrifluoroacetamidine groups, are able to activate ATP hydrolysis catalyzed by myometrium myosin subfragment-1. It was shown with the method of computer modeling that N phenylsulfonultrifluoroacetamidine groups of calix[4]arene C-90 interact with responsible for binding, coordination and the hydrolysis of ATP amino acid residues of myosin subfragment-1. The results can be used for further research aimed at using calix[4]arene C-90 and its analogs as pharmacological compounds that can effectively normalize myometrium contractile hypofunction. PMID- 29235804 TI - An alternative approach for dealing with workplace grievances. PMID- 29235806 TI - The nurse practitioner. PMID- 29235805 TI - Buying Snake Heads. PMID- 29235807 TI - The Conservative leadership hopefuls: Where they stand on health care. PMID- 29235809 TI - The making of the MAID framework. PMID- 29235808 TI - Prostate Cancer. PMID- 29235810 TI - Probability sampling. PMID- 29235812 TI - Uncovering a cover up. PMID- 29235811 TI - Mycobacterium tuberculosis antigens MPT63 and MPT83 increase phagocytic activity of murine peritoneal macrophages. AB - Macrophages (MPhi) are the most described and characterized target and host of mycobacteria. Like other cells of innate immunity MPhi have a wide range of receptor molecules which interact with different pathogen associated molecular patterns (PAMPs). Immunodominant proteins MPT63 and MPT83 that are synthesized in abundance by Mycobacterium bovis or Mycobacterium tuberculosis strains could be involved in development of tuberculosis infection. The aim of this study was to search for effects of these mycobacterial antigens on target cells. For this aim full-sized sequences of MPT83 (rMPT83full) and MPT63 antigens were cloned into plasmid pET24a(+). The increase of phagocytic activity of murine peritoneal macrophages was demonstrated, but not of macrophage-like cells from J774 cell line, which were treated by rMPT63 and rMPT83full proteins for 24 h. This effect of such antigens can be considered as a way to facilitate the consumption of mycobacterial cells by macrophages to avoid other effector mechanisms of innate and adaptive immunity. PMID- 29235813 TI - Revisions in the works for Canada's Food Guide. PMID- 29235814 TI - Mutation of katG in a clinical isolate of Mycobacterium tuberculosis: effects on catalase-peroxidase for isoniazid activation. AB - Mutations in katG gene are often associated with isoniazid (INH) resistance in Mycobacterium tuberculosis strain. This research was perfomed to identify the katG mutation in clinical isolate (L8) that is resistant to INH at 1 MUg/ml. In addition to characterize the catalase-peroxidase of KatG L8 and perform the ab initio structural study of the protein to get a more complete understanding in drug activation and the resistan-ce mechanism. The katG gene was cloned and expressed in Escherichia coli, then followed by characterization of catalase peroxidase of KatG. The structure modelling was performed to know a basis of alterations in enzyme activity. A substitution of A713G that correspond to Asn238Ser replacement was found in the L8 katG. The Asn238Ser modification leads to a decline in the activity of catalase-peroxidase and INH oxidation of the L8 KatG protein. The catalytic efficiency (Kcat/KM) of mutant KatGAsn238Ser respectively decreases to 41 and 52% for catalase and peroxidase. The mutant KatGAsn238Ser also shows a decrease of 62% in INH oxidation if compared to a wild type KatG (KatGwt). The mutant Asn238Ser might cause instability in the substrate binding- site of KatG, because of removal of a salt bridge connecting the amine group of Asn238 to the carbo-xyl group of Glu233, which presents in KatGwt. The lost of the salt bridge in the substrate binding site in mutant KatGAsn238Ser created changes unfavorable for enzyme activities, which in turn emerge as INH resistan-ce in the L8 isolate of M. tuberculosis. PMID- 29235815 TI - Effect of nitric oxide donor SNAP on GABA release from rat brain nerve terminals. AB - In this work we investigated the effect of nanomolar concentrations of nitric oxide on the release of gamma-aminobutyric acid (GABA) from rat brain nerve terminals using a radioisotope method with [3H]GABA and a spectrofluorimetric method with Ca2+-sensitive probe Fluo-4 AM. It was shown that in the presen-ce of dithiothreitol (DTT), nitric oxide donor SNAP at concentration, in which it produces NO in the nanomolar range, caused Ca2+-independent [3H]GABA release from nerve terminals. The applications of 4-aminopyridine (4-AP) and nipecotic acid (NA), as the inducers of GABA release from vesicular and cytoplasmic pools, showed that the maximum of SNAP/+DTT-induced [3H]GABA release was registered at 10th min of incubation and coincided in time with significant increase (almost double) in NA-induced [3H]GABA release. At this time point, 4-AP-induced release of [3H]GABA was drastically reduced. At the 15th min of incubation of nerve terminals with SNAP/+DTT, the opposite picture was observed: the decrease in NA- and increase in 4-AP-induced [3H]GABA release. Thus, nitric oxide in the form of S-nitrosothiols at nanomolar concentrations causes Ca2+-independent GABA leakage from synaptic vesicles into cytosol with subsequent release from nerve terminals. The reuptake of the neurotransmitter and its re-accumulation in synaptic vesicles occur later. PMID- 29235816 TI - Food for thought. PMID- 29235818 TI - Legalizing and regulating cannabis: Designing a framework. PMID- 29235817 TI - Protein kinase Akt activity in human thyroid tumors. AB - We studied the expression and activation of the main effector protein kinase of phosphatidylinositol-3-kinase cascade (PI3K) - Akt in conventionally normal tissues, benign and highly differentiated (with and without metastases) human thyroid tumors. There was a difference in the Akt1 amount in tumor tissue compared with normal tissue in papillary carcinomas and tissue of multinodular goiter. Akt expression both in tumor and conventionally normal tissues of follicular adenoma was significantly lower than in follicular carcinoma. The lowest level of Akt expression was observed in tissues of multinodular goiter. Total activity of all three isoforms of Akt1/2/3 was lower in tumors compared to conventionally normal tissue. Thus, Akt activity (according to Thr308 phosphorylation) is not associated with proliferative processes in the tumor tissue of the thyroid. Apoptosis level detected in these tissues was not associated with the protein kinase activity either. Possible mechanisms of signaling cascade PI3K/Akt inhibition in thyroid tumors are discussed. PMID- 29235820 TI - What mask to use? AB - The type of face mask used in the clinical setting needs to be determined dependent on the reasons for wearing it, whether it be for droplet or airborne precautions. PMID- 29235819 TI - Determination of frequencies of alleles, associated with the pseudodeficiency of lysosomal hydrolases, in population of Ukraine. AB - The pseudodeficiency of lysosomal hydrolases described as a significant reduction in enzyme activi-ty in vitro in clinically healthy individuals, can lead to diagnostic errors in the process of biochemical analysis of lysosomal storage disease in case of its combination with pathology of another origin. Pseudodeficiency is mostly caused by some non-pathogenic changes in the corresponding gene. These changes lead to the in vitro lability of the enzyme molecule, whereas in vivo the enzyme retains its functional activity. To assess the prevalence of the most common lysosomal hydrolases pseudodeficiency alleles in Ukraine, we have determined the frequency of alleles c.1055A>G and c.* 96A>G in the ARSA gene, substitutions c.739C>T (R247W) and c.745C>T (R249W) in the HEXA gene, c.1726G>A (G576S) and c.2065G>A (E689K) in the GAA gene, c.937G>T (D313Y) in the GLA1 gene and c.898G>A (A300T) in the IDUA gene in a group of 117 healthy individuals from different regions of the country and 14 heterozygous carriers of pathogenic mutations in the HEXA gene (parents of children with confirmed diagnosis of Tay-Sachs disease). The total frequency of haplotypes, associated with arylsulfatase A pseudodeficiency, in healthy people in Ukraine (c.1055G/c.*96G and c.1055G/c.*96A haplotypes) was 10.3%. The frequency of c.739C>T (R247W) allele, associated with hexo-saminidase A pseudodeficiency, among Tay-Sachs carriers from Ukraine was 7.1%. The total frequency of alpha glucosidase pseudodeficiency haplotypes in healthy individuals in Ukraine (c.1726A/c.2065A and c.1726G/c.2065A haplotypes) was 2.6%. No person among examined individuals with the substitution c.937G>T (D313Y) in the GLA1 gene and c.898G>A (A300T) in the IDUA gene was found. The differential diagnostics of lysosomal storage diseases requires obligatory determination of the presence of the pseudodeficiency alleles, particularly the ones with high incidence in the total population. Ignoring phenomenon of pseudodeficiency may lead to serious diagnostic errors. PMID- 29235821 TI - Needle fear and insulin self-injection. PMID- 29235822 TI - Measurement of methionine level with the LC-ESI-MS/MS method in schizophrenic patients. AB - The purpose of this study was to evaluate plasma methionine levels by using liquid chromatography electrospray ionization-tandem mass spectroscopy (LC-ESI MS/MS) in schizophrenic patients. A twelve-point standard graph was drawn, and the recovery rate, the intra-day and inter-day coefficients of variation (CV), the limit of detection (LOD), and the limit of quantification (LOQ) were evaluated. The y and R2 values of the standard graph equation were determined as 0.011x + 0.0179 and 0.9989, respectively, and the graph remained linear until the 200 umol/l level. The intra-day coefficients of variation of the samples (n = 10) containing 8, 28, and 58 umol/l methionine were determined as 2.68, 3.10, and 3.79%, respectively; while their inter-day coefficients of variation were determined as 2.98, 3.19, and 3.84%. The LOD and LOQ values were determined as 0.04 and 0.1 umol/l, respectively, while the mean recovery rates were determined as 101.7 and 99.3%. Plasma methionine values were measured as 21.5 (19.5-24,6) umol/l for the patient group, 17.8 (16.3-20.1) umol/l for the control group, and the difference between the two groups was statistically significant (p = 0.03). LC-ESI-MS/MS method represents a fairly sensitive, economic, and rapid analysis that requires very little sample and is suitable for measuring methionine levels in schizophrenic patients. PMID- 29235823 TI - A home care palliative sedation simulation program. PMID- 29235824 TI - Larger investment needed in student nutrition. PMID- 29235825 TI - [Inventive activity of the Department of Molecular Immunology of the Palladin Institute of Biochemistry of NAS of Ukraine]. AB - The article is devoted to the inventive activity of the Department of Molecular Immunology of the Palladin Institute of Biochemistry of NAS of Ukraine in the context of the history of its inception, development and in the context of scholarly and organizational activities of Sergii Vasyl'ovych Komisarenko. This autumn marks 50th anniversary since young Sergii Komisarenko (now - Academician of NAS and NAMS of Ukraine, Dr. Biol. Sci., Professor) has joined the Palladin Institute of Biochemistry, has completed all stages of the academic carrier from PhD student to Head of the Institute. He is the first in Ukraine who started the new branch of research - molecular immunology, created a strong scientific school, which earned worldwide acclaim and made significant contribution to finding solutions to current problems in human health sciences. S.V. Komisarenko was among those, who were first in the USSR to use immunoenzyme and flow cytofluometric assays, hybridoma technology for producing monoclonal antibodies and immunochemical assay of proteins, which became the basis for development of highly sensitive and highly specific immunodiagnostic systems, which are of high necessity in medicine, veterinary, development of immunotechnologies, environment monitoring, etc. Under his leadership the Department has made a series of important discoveries and developments including relating to antitumour immunotoxins, effects of low dose radiation on the immune system of Chernobyl liquidators, immunochemical structure of neurotoxin apamine, cytochrom c, fibrinogen and fibrin molecules at different stages of polymerization, diphtheria toxin and its receptor, tuberculosis causing micobacterium, roles of protease activated receptors (PARs) and nicotinic acetylcholine receptors of lymphocytes, nature of polyreactive immunoglobulins (PRIGs), among other important scientific contributions. S.V. Komisarenko and his colleagues also hold numerous (more than 80) author's certificates and patents in Ukraine and USSR. PMID- 29235826 TI - Promoting health, one strategy at a time. PMID- 29235827 TI - Nursing memes at odds with our values. PMID- 29235828 TI - Personal Development is Professional Development. Taking care of the wellbeing of our nurses. PMID- 29235829 TI - Clinical nurse specialist. PMID- 29235830 TI - Beating to the sound of an HIV men's health drum. AB - The recent international AIDS 2014 conference, which attracted a record 14,000 delegates to Melbourne, put a bright spotlight not only on the challenges facing the medical profession, but also on the passion, commitment and dedication of nurses and carers to help those living with and affected by HIV. PMID- 29235832 TI - Expanding our understanding of suicidal men's help-seeking practices. AB - There is a striking gender difference in suicide rates in Australia and worldwide with men accounting for approximately 80% of all deaths (World Health Organization (WHO), 2011; Australian Bureau of Statistics (ABS), 2012). Yet research data suggests suicidal men are less likely than women to access professional help (Booth & Owens, 2,000). PMID- 29235831 TI - Chemical structure and properties of low-molecular furin inhibitors. AB - The review is devoted to the analysis of the relationship between a chemical structure and properties of low-molecular weight inhibitors of furin, the most studied proprotein convertase, which is involved in the development of some pathologies, such as oncologic diseases, viral and bacterial infections, etc. The latest data concerning the influence of peptides, pseudo-peptides, aromatic and heterocyclic compounds, some natural ones such as flavonoids, coumarins, and others on enzyme inactivation are considered. The power of furin inhibition is shown to rise with the increasing number of positively charged groups in the structure of these compounds. Peptidomimetics (Ki = 5-8 pM) are shown to be the most effective furin inhibitors. The synthesized substances, however, have not been used in practical application yet. Nowadays it is very important to find more selective inhibitors, improve their stability, bioavailability and safety for the human organism. PMID- 29235833 TI - Purification and properties of lipoxygenase from wheat seedlings infected by Fusarium graminearum and treated by salicylic acid. AB - Lipoxygenase from wheat seedlings in normal conditions, infected by Fusarium graminearum and treated by salicylic acid was isolated. The isolated enzyme was purified by the methods of salting-out (60% ammonium sulphate), dialysis, gel filtration and ion-exchange chromatography. Specific activity of the purified enzyme was 8.0-12.5 DeltaE234/mg of protein, degree of purification - 11.6-15.3 times. The enzyme yield was 18.3-27.9%. Molecular mass of lipoxygenase is 90 kDa, amino acid composition is distinguished by a high content of glutamic acid, proline, valine, isoleucine, leucine and low level of histidine, tyrosine, phenylalanine, threonine, tryptophan, cystein. Research of lipoxygenase substrate dependence indicated that the enzyme catalysed with the maximum velocity of the reaction of arachidonic acid oxidation at a substrate concentration of 4.5 mM at pH 7.2, the reaction of linoleic acid oxidation at a substrate concentration of 4.5 mM at pH 7.2 and the reaction of linolenic acid oxidation at a substrate concentration of 9.0 mM at pH 8.0. The change of wheat lipoxygenase activity depending on genotype resistance to Fusarium graminearum and millieu of germination was shown. One of the manifestations of the protective effect of salicylic acid is its ability to induce changes of lipoxygenase activity. PMID- 29235835 TI - Redistribution of DNA loop domains in human lymphocytes under blast transformation with interleukin 2. AB - At higher order levels chromatin fibers in interphase nuclei are organized into loop domains. Gene regulatory elements (promoters and enhancers) are often located near the sites of loop attachments. Therefore, loop domains play a key role in regulation of cell transcriptional activity. We investigated the kinetics of DNA loop exit during single cell gel electrophoresis (the comet assay) of nucleoids obtained from two cell types that differ in their synthetic activity - human lymphocytes and lymphoblasts. Lymphocyte activation and transformation into lymphoblasts (blast transformation) was performed with interleukin 2. The results obtained suggest that a rearrangement of the loops occurs after lymphocyte activation. After blast transformation we observed an increase of the amount of loop domains on the surface of nucleoids against a decrease of the inner loop fraction. Therefore, the comet assay can be used for detection of large-scale changes in the cell nucleus that follow changes in cell functional state. PMID- 29235834 TI - Carbohydrate composition of rat intestine surface mucus layer after ceftriaxone treatment. AB - The epidemiological studies have shown that antibiotic treatment increases the susceptibility to inflammatory bowel disease development. The disturbance of mucus layer integrity might be one of the possible mechanisms. The aim of the present study was to investigate the effect of antibiotic ceftriaxone treatment on glycoproteins level and its carbohydrate composition in surface mucus layer of rat intestine. The study was done on male Wistar rats (140-160 g). Ceftriaxone (300 mg/kg, i.m.) was administered once a day for 14 days. The surface mucus from terminal ileum and colon were collected on the 15th, 29th and 72nd days of the experiment. Total level of mucus glycoproteins, hexoses, hexosamines, fucose and sialic acids were measured. Ceftriaxone administration did not affect the levels of glycoproteins in rat ileum. In the colon, the levels of glycoprotein were 1.3 fold decreased (R < 0.05) on the 72nd day of the experiment. These changes were accompanied by the 1.2-fold decrease of hexoses (R < 0.05) and 3.1-fold (R < 0.05) decrease of fucose level and 1.5-fold (R < 0.05) increase of the levels of sialic acids in the surface mucus of the rat colon. Thus, ceftriaxone administration induces the long-term changes in the levels of glycoproteins and carbohydrates composition in the rat colon surface mucus. This could potentially explain the susceptibility to inflammatory bowel disea-ses development. PMID- 29235837 TI - Monodisperse Palladium Sulfide as Efficient Electrocatalyst for Oxygen Reduction Reaction. AB - In this study, we report a colloidal synthesis of palladium sulfides (including Pd16S7, Pd4S, and PdS) via a facile one-pot hot-solution synthetic route and their promising application as electrocatalyst for the oxygen reduction reaction (ORR). Among the different palladium sulfides tested, monodisperse Pd4S nanoparticles exhibit the best electrocatalytic activity toward ORR in alkaline medium, with the half-wave potential ca. 47 mV more positive than that of the state-of-the-art Pt/C catalyst. Density functional theory calculations indicate the existence of oxygen absorption sites in Pd4S surface result in optimized oxygen-binding ability for the four-electron oxygen reduction. PMID- 29235836 TI - Hypoxic regulation of MYBL1, MEST, TCF3, TCF8, GTF2B, GTF2F2 and SNAI2 genes expression in U87 glioma cells upon IRE1 inhibition. AB - We investigated the impact of IRE1/ERN1 (inositol requiring enzyme 1/endoplasmic reticulum to nucleus signaling 1) knockdown on hypoxic regulation of the expression of a subset of proliferation and migration-related genes in U87 glioma cells. It was shown that hypoxia leads to up-regulation of the expression of MEST and SNAI2, to down-regulation - of MYBL1, TCF8 and GTF2F2 genes at the mRNA level in control glioma cells. At the same time hypoxia did not affect the expression of TCF3 and GTF2B transcription factor genes. In turn, inhibition of IRE1 modified the effect of hypoxia on the expression of all studied genes, except MYBL1 and GTF2B. For instance, IRE1 knockdown decreased sensitivity to hypoxia of the expression of MEST, TCF8 and SNAI2 genes and increased sensitivity to hypoxia of GTF2F2 expression. At the same time, IRE1 inhibition introduced sensitivity to hypoxia of the expression of TCF3 gene in glioma cells. The present study demonstrated that the inhibition of IRE1 in glioma cells affected the hypoxic regulation of the expression of studied genes in various directions, though hypoxic conditions did not abolish the effect of IRE1 inhibition on the expression of respective genes. To the contrary, in case of SNAI2, GTF2F2 and MEST hypoxic conditions magnified the effect of IRE1 inhibition on the expression of respective genes in glioma cells. PMID- 29235838 TI - Hydrogel with Ultrafast Self-Healing Property Both in Air and Underwater. AB - Self-healing hydrogels have a great potential application in 3D printing, soft robotics, and tissue engineering. There have been a large number of successful strategies for developing hydrogels that exhibit rapid and autonomous recovery. However, developing a gel with an excellent self-healing performance within several seconds is still an enormous challenge. Here, an ultrafast self-healing hydrogel based on an agarose/PVA double network (DN) is presented. The gel utilizing a dynamic borate bond exhibits 100% cure in strength and elongation after healing for 10 s in air, and this hydrogel shows an excellent self-healing property underwater as well. In addition, the agarose/PVA DN hydrogel exhibits a smart self-healing property for an in situ priority recovery, ensuring that the shape and the function are the same as those of the original one. With the combination of self-healing properties, such a hydrogel could be applied to a board range of areas. PMID- 29235839 TI - Room-Temperature-Processed Flexible Amorphous InGaZnO Thin Film Transistor. AB - A room-temperature flexible amorphous indium-gallium-zinc oxide thin film transistor (a-IGZO TFT) technology is developed on plastic substrates, in which both the gate dielectric and passivation layers of the TFTs are formed by an anodic oxidation (anodization) technique. While the gate dielectric Al2O3 is grown with a conventional anodization on an Al:Nd gate electrode, the channel passivation layer Al2O3 is formed using a localized anodization technique. The anodized Al2O3 passivation layer shows a superior passivation effect to that of PECVD SiO2. The room-temperature-processed flexible a-IGZO TFT exhibits a field effect mobility of 7.5 cm2/V.s, a subthreshold swing of 0.44 V/dec, an on-off ratio of 3.1 * 108, and an acceptable gate-bias stability with threshold voltage shifts of 2.65 and -1.09 V under positive gate-bias stress and negative gate-bias stress, respectively. Bending and fatigue tests confirm that the flexible a-IGZO TFT also has a good mechanical reliability, with electrical performances remaining consistent up to a strain of 0.76% as well as after 1200 cycles of fatigue testing. PMID- 29235840 TI - Newly Designed Covalent Triazine Framework Based on Novel N-Heteroaromatic Building Blocks for Efficient CO2 and H2 Capture and Storage. AB - In this article, a set of novel covalent triazine frameworks (CTFs) were prepared by trimerization of 4,4',4",4'''-(1,4-phenylenebis(pyridine-4,2,6 triyl))tetrabenzonitrile in molten ZnCl2 under ionothermal conditions. The influence of several parameters such as the ZnCl2/monomer ratio and reaction temperature on the structure and porosity of the resulting frameworks was systematically examined. After a thorough characterization, their performance in H2 and CO2 adsorption as well as their selectivity of CO2 over N2 was assessed. Notably, the CTF obtained using 20 molar equiv of ZnCl2 at a reaction temperature of 400 degrees C (CTF-20-400) exhibits an excellent CO2 adsorption capacity of 3.48 mmol/g at 1 bar and 273 K as well as a significantly high H2 uptake of 1.5 wt % at 1 bar and 77 K. These values belong to the top levels for all the CTFs measured under identical conditions to date. In addition, the obtained CTFs also present a relatively high CO2/N2 selectivity (up to 36 at 298 K), making them promising adsorbents for gas sorption and separation. PMID- 29235841 TI - p-p Heterojunction of Nickel Oxide-Decorated Cobalt Oxide Nanorods for Enhanced Sensitivity and Selectivity toward Volatile Organic Compounds. AB - The utilization of p-p isotype heterojunctions is an effective strategy to enhance the gas sensing properties of metal-oxide semiconductors, but most previous studies focused on p-n heterojunctions owing to their simple mechanism of formation of depletion layers. However, a proper choice of isotype semiconductors with appropriate energy bands can also contribute to the enhancement of the gas sensing performance. Herein, we report nickel oxide (NiO) decorated cobalt oxide (Co3O4) nanorods (NRs) fabricated using the multiple-step glancing angle deposition method. The effective decoration of NiO on the entire surface of Co3O4 NRs enabled the formation of numerous p-p heterojunctions, and they exhibited a 16.78 times higher gas response to 50 ppm of C6H6 at 350 degrees C compared to that of bare Co3O4 NRs with the calculated detection limit of approximately 13.91 ppb. Apart from the p-p heterojunctions, increased active sites owing to the changes in the orientation of the exposed lattice surface and the catalytic effects of NiO also contributed to the enhanced gas sensing properties. The advantages of p-p heterojunctions for gas sensing applications demonstrated in this work will provide a new perspective of heterostructured metal-oxide nanostructures for sensitive and selective gas sensing. PMID- 29235842 TI - Mussel-Inspired Synthesis of NIR-Responsive and Biocompatible Ag-Graphene 2D Nanoagents for Versatile Bacterial Disinfections. AB - Pathogenic bacterial infection has been becoming a global threat toward people's health, especially the massive usage of antibiotics due to the lack of antibacterial agents with less side effects. Developing new nanoagents to fight pathogenic bacteria has provided enormous new possibilities in the treatment of bacterial infections, such as graphene-based two-dimensional (2D) antibacterial nanoagents with different bacterial inhibition capabilities; however, mussel inspired design of near-infrared (NIR)-responsive and biocompatible Ag-graphene nanoagents possessing efficient and versatile bacterial disinfection activities have rarely been reported. In this study, we developed a new kind of antibacterial nanoagent, dopamine-conjugated polysaccharide sulfate-anchored and protected Ag-graphene (Ag@G-sodium alginate sulfate ((SAS)) nanocomposite, to combat bacterial infection and contamination in different application fields. Ag@G-SAS exhibited robust antibacterial activity toward both Escherichia coli and Staphylococcus aureus; notably, the nanoagent can significantly inhibit S. aureus infection on wounded pig skin without or with NIR laser. Besides wound disinfection, the 2D Ag@G-SAS can also serve as a good layer-by-layer (LbL) building block for the construction of self-sterilizing coatings on biomedical devices. All of the results verified that the LbL-assembled Ag@G-SAS coating exhibited favorable bactericidal activity, extraordinary blood compatibilities, and good promotion ability for cell proliferation. Owing to the shielding effects of heparin-like polysaccharide sulfates, the Ag@G-SAS nanoagent showed limited cytotoxicity toward mammalian cells. Combining all of the advantages mentioned above, it is believed that the proposed Ag@G-SAS nanoagent and its LbL-assembled coatings may have versatile application potentials to avoid bacterial contaminations in different fields, such as wounded skin, disinfection of biomedical implants and devices, and food packaging sterilization. PMID- 29235843 TI - Self-Sterilizing and Regeneratable Microchip for the Precise Capture and Recovery of Viable Circulating Tumor Cells from Patients with Cancer. AB - Cancer cells metastasize and are transported in the bloodstream, easily reaching any site in the body through the blood circulation. A method designed to assess the number of circulating tumor cells (CTCs) should be validated as a clinical tool for predicting the response to therapy and monitoring the disease progression in patients with cancer. Although CTCs are detectable in many cases, they remain unavailable for clinic usage because of their high testing cost, tedious operation, and poor clinical relevance. Herein, we developed a regeneratable microchip for isolating CTCs, which is available for robust cell heterogeneity assays on-site without the need for a sterile environment. The ivy like hierarchical roughened zinc oxide (ZnO) nanograss interface was synthesized and directly integrated into the microfluidic devices and enables effective CTC capture and flexible, nontoxic CTC release during incubation in a mildly acidic solution, thus enabling cellular and molecular analyses. The microchip can be regenerated and recycled to capture CTCs with the remaining ZnO without affecting the efficiency, even after countless cycles of cell release. Moreover, microbial infection is avoided during its storage, distribution, and even in the open space usage, which ideally appeals to the demands of point-of-care (POC) and home testing and meets to the requirements for blood examinations in undeveloped or resource-limited settings. Furthermore, the findings generated using this platform based on the cocktail of antiepithelial cell adhesion molecule and antivimentin antibodies indicate that CTC capture was more precise and reasonable for patients with advanced cancer. PMID- 29235844 TI - Injectable and Degradable pH-Responsive Hydrogels via Spontaneous Amino-Yne Click Reaction. AB - Injectable hydrogels have attracted increasing attention in tissue regeneration and local drug delivery applications. Current click reactions for preparing injectable hydrogels often require a photoinitiator or catalyst, which may be toxic and may involve complex synthesis of precursors. Here, we report a facile and inexpensive method to prepare injectable and degradable hydrogels via spontaneous amino-yne click reaction without using any initiator or catalyst under physiological conditions based on telechelic electron-deficient dipropiolate ester of polyethylene glycol and water-soluble commercially available carboxymethyl chitosan (CMC). The gelation time, mechanical property, and degradation rate of the hydrogels could be adjusted by varying CMC concentrations and stoichiometric ratios. The reversible pH-induced sol-gel transitions of the hydrogel are presented and the pH-controlled drug release behaviors are demonstrated, of which the mechanism is discussed. In vitro cytotoxicity assays and in vivo in situ injection study of the CMC-based hydrogels showed favorable gel formation, nontoxicity, and good tissue biocompatibility. Therefore, these biodegradable and injectable hydrogels prepared by spontaneous amino-yne click reaction hold potential for tissue engineering and other biomedical applications. PMID- 29235846 TI - Cu(II)-Doped Polydopamine-Coated Gold Nanorods for Tumor Theranostics. AB - Gold nanorods (AuNRs) are potentially useful in tumor theranostics, but the poor stability, high toxicity, and rapid removal by the immune system seriously limit their theranostic applications. In our study, we demonstrate the fabrication of Cu(II)-doped polydopamine-coated AuNR (AuNR@CuPDA), which significantly improves the potentials in tumor theranostics. Besides the improvement of physiological stability and biocompatibility, the PDA shell increases the photothermal performance and prolongs the blood circulation time of AuNRs. The half-life of AuNRs during blood circulation increases from 0.7 to 4.5 h after PDA coating, and the injected dose per gram of tumor tissue is 4.6% ID g-1 for AuNR@CuPDA. In addition to computer tomography imaging, the loading of Cu(II) in PDA shell endows AuNR@CuPDA with magnetic resonance imaging function. Cu(II) doped in PDA shell also exhibits chemotherapeutic behavior, and the tumor inhibitor rate is 31.2%. Further combining 808 nm laser-driven photothermal therapy, tumors were completely ablated, and no recurrence was observed. Liver and renal functions tests and histological analysis of major organs confirm that AuNR@CuPDA is in good safety. PMID- 29235847 TI - Enhanced Electrocatalytic Hydrogen Evolution from Large-Scale, Facile-Prepared, Highly Crystalline WTe2 Nanoribbons with Weyl Semimetallic Phase. AB - Tungsten ditellurium (WTe2) is one of most important layered transition metal dichalcogenides (TMDs) and exhibits various prominent physical properties. All the present methods for WTe2 preparation need strict conditions such as high temperature or cannot be applied in large scale, which limits its practical applications. In addition, most studies on WTe2 focus on its physical properties, whereas its electrochemical properties are still illusive with little investigation. Here, we develop a facile and scalable two-step method to synthesize high-quality WTe2 nanoribbon crystals with 1T' Weyl semimetal phase for the first time. Highly crystalline 1T'-WTe2 nanoribbons can be obtained on a large scale through this two-step method. In addition, the electrochemical tests show that WTe2 nanoribbons exhibit smaller overpotential and much better hydrogen evolution reaction catalytic performance than other tungsten-based sulfide and selenide (WS2, WSe2) nanoribbons of same morphology and under same preparation conditions. WTe2 nanoribbons show a Tafel slope of 57 mV/dec, which is one of best values for TMD catalysts and about 2 and 4 times smaller than that for 2H WS2 nanoribbons (135 mV/dec) and 2H-WSe2 nanoribbons (213 mV/dec), respectively. 1T'-WTe2 nanoribbons also show ultrahigh stability in 5000 cycles and 20 h at 10 mA/cm2. The better performance is attributed to high conductivity of semimetallic 1T'-phase-stable WTe2 nanoribbons with one or two order higher charge-transfer rate than normally semiconducting 2H-stable WS2 and WSe2 nanoribbons. These results open the door for electrochemical applications of Weyl semimetallic TMDs. PMID- 29235845 TI - Structure-Based Identification of HIV-1 Nucleocapsid Protein Inhibitors Active against Wild-Type and Drug-Resistant HIV-1 Strains. AB - HIV/AIDS is still one of the leading causes of death worldwide. Current drugs that target the canonical steps of the HIV-1 life cycle are efficient in blocking viral replication but are unable to eradicate HIV-1 from infected patients. Moreover, drug resistance (DR) is often associated with the clinical use of these molecules, thus raising the need for novel drug candidates as well as novel putative drug targets. In this respect, pharmacological inhibition of the highly conserved and multifunctional nucleocapsid protein (NC) of HIV-1 is considered a promising alternative to current drugs, particularly to overcome DR. Here, using a multidisciplinary approach combining in silico screening, fluorescence-based molecular assays, and cellular antiviral assays, we identified nordihydroguaiaretic acid (6), as a novel natural product inhibitor of NC. By using NMR, mass spectrometry, fluorescence spectroscopy, and molecular modeling, 6 was found to act through a dual mechanism of action never highlighted before for NC inhibitors (NCIs). First, the molecule recognizes and binds NC noncovalently, which results in the inhibition of the nucleic acid chaperone properties of NC. In a second step, chemical oxidation of 6 induces a potent chemical inactivation of the protein. Overall, 6 inhibits NC and the replication of wild-type and drug-resistant HIV-1 strains in the low micromolar range with moderate cytotoxicity that makes it a profitable tool compound as well as a good starting point for the development of pharmacologically relevant NCIs. PMID- 29235848 TI - Dual Data-Independent Acquisition Approach Combining Global HCP Profiling and Absolute Quantification of Key Impurities during Bioprocess Development. AB - Host cell proteins (HCP) are a major class of impurities derived from recombinant protein production processes. While HCP are usually monitored by ELISA, mass spectrometry (MS)-based approaches are emerging as promising orthogonal methods. Here, we developed an original method relying on data-independent acquisition (DIA) coupling global HCP amount estimation (Top 3) and absolute quantification with isotope dilution (ID). The method named Top 3-ID-DIA was benchmarked against ELISA and a gold-standard selected reaction monitoring assay (ID-SRM). Various samples generated at different steps and conditions of the purification process, including different culture durations, harvest procedures, and purification protocols were used to compare the methods. Overall, HCP were quantified over 5 orders of magnitude and down to the sub-ppm level. The Top 3-ID-DIA strategy proved to be equivalent to the gold-standard ID-SRM in terms of sensitivity (1-10 ppm), accuracy, and precision. Moreover, 81% of the Top 3 estimations were accurate within a factor of 2 when compared to ID-SRM. Thus, our approach aggregates global HCP profiling for comprehensive process understanding with absolute quantification of key HCP within a single analysis and provides an improved support for bioprocess development and product purity assessment. PMID- 29235850 TI - Digital Protocol for Chemical Analysis at Ultralow Concentrations by Surface Enhanced Raman Scattering. AB - Single molecule surface-enhanced Raman spectroscopy (SM-SERS) has the potential to revolutionize quantitative analysis at ultralow concentrations (less than 1 nM). However, there are no established protocols to generalize the application of this technique in analytical chemistry. Here, a protocol for quantification at ultralow concentrations using SM-SERS is proposed. The approach aims to take advantage of the stochastic nature of the single-molecule regime to achieved lower limits of quantification (LOQ). Two emerging contaminants commonly found in aquatic environments, enrofloxacin (ENRO) and ciprofloxacin (CIPRO), were chosen as nonresonant molecular probes. The methodology involves a multivariate resolution curve fitting known as non-negative matrix factorization with alternating least-squares algorithm (NMF-ALS) to solve spectral overlaps. The key element of the quantification is to realize that, under SM-SERS conditions, the Raman intensity generated by a molecule adsorbed on a "hotspot" can be digitalized. Therefore, the number of SERS event counts (rather than SERS intensities) was shown to be proportional to the solution concentration. This allowed the determination of both ENRO and CIPRO with high accuracy and precision even at ultralow concentrations regime. The LOQ for both ENRO and CIPRO were achieved at 2.8 pM. The digital SERS protocol, suggested here, is a roadmap for the implementation of SM-SERS as a routine tool for quantification at ultralow concentrations. PMID- 29235849 TI - All-Small-Molecule Solar Cells Incorporating NDI-Based Acceptors: Synthesis and Full Characterization. AB - A series of naphthalene diimide (NDI)-based small molecules were synthesized as nonfullerene acceptors and incorporated in all-small-molecule solar cells. Three NDI-based small molecules, NDICN-T, NDICN-BT, and NDICN-TVT, were designed with different linkers between two NDI units to induce the different conjugation length and modulate the geometric structures of the NDI dimers. The small NDI based dimer electron acceptors with slip-stacked structures that facilitate pi-pi stacking interactions and/or hinder excessive aggregation exhibited different morphological behaviors, such as miscibility or crystallinity in bulk heterojunction blends with 7,7'-(4,4-bis(2-ethylhexyl)-4H-silolo[3,2-b:4,5 b']dithiophene-2,6-diyl)bis(6-fluoro-4-(5'-hexyl-[2,2'-bithiophen]-5 yl)benzo[c][1,2,5]thiadiazole) (DTS-F) electron donors. The photovoltaic devices prepared with NDICN-TVT gave the highest power conversion efficiency (PCE) of 3.01%, with an open-circuit voltage (Voc) of 0.75 V, a short-circuit current density (Jsc) of 7.10 mA cm-2, and a fill factor of 56.2%, whereas the DTS F:NDICN-T and DTS-F:NDICN-BT devices provided PCEs of 1.81 and 0.13%, respectively. Studies of the charge-generation properties, charge-transfer dynamics, and charge-transport properties for understanding the structure property relations revealed that DTS-F:NDICN-TVT blend films with well-developed domains and well-ordered crystalline structures performed well, whereas an excessive miscibility between DTS-F and NDICN-BT disrupted the crystallinity of the material and yielded a poor device performance. PMID- 29235851 TI - Semi-Interpenetrating Polymer Network Composite Gel Electrolytes Employing Vinyl Functionalized Silica for Lithium-Oxygen Batteries with Enhanced Cycling Stability. AB - A major challenge of lithium-oxygen batteries is to develop a stable electrolyte not only to suppress solvent evaporation and lithium dendrite growth, but also to resist the attack by superoxide anion radical formed at the positive electrode. The present study demonstrates the enhancement of cycling stability by addressing the above challenges through the use of three-dimensional semi-interpenetrating polymer network (semi-IPN) composite gel polymer electrolyte when fabricating the lithium-oxygen cell. The semi-IPN composite gel electrolyte synthesized from poly(methyl methacrylate), divinylbenzene, and vinyl-functionalized silica effectively encapsulated electrolyte solution and exhibited stable interfacial characteristics toward lithium electrodes. Matrix polymers in the semi-IPN composite gel electrolyte also retained high stability without any decomposition by superoxide anion radicals during cycling. The lithium-oxygen cell employing semi-IPN composite gel polymer electrolyte was shown to cycle with good capacity retention at 0.25 mAh cm-2. The semi-IPN composite gel electrolyte is one of the promising electrolytes for the stable lithium-oxygen battery with high energy density. PMID- 29235853 TI - General Synthetic Route toward Highly Dispersed Ultrafine Pd-Au Alloy Nanoparticles Enabled by Imidazolium-Based Organic Polymers. AB - Bimetallic Pd-Au nanoparticles (NPs) usually show superior catalytic performances over their single-component counterparts, the general and facile synthesis of subnanometer-scaled Pd-Au NPs still remains a great challenge, especially for electronegative ultrafine bimetallic NPs. Here, we develop an anion-exchange strategy for the synthesis of ultrafine Pd-Au alloy NPs. Simple treatment of main chain imidazolium-based organic polymer (IOP) with HAuCl4 and Na2PdCl4, followed by reduction with NaBH4 generated Pd-Au alloy NPs (Pd-Au/IOP). These NPs possess an unprecedented tiny size of 1.50 +/- 0.20 nm and are uniformly dispersed over IOP. The electronic structure of the surface Pd and Au atoms is optimized via electron exchange during alloying, a net charge flowing resulting from counteranions is injected into Au and Pd to form a strong ensemble effect, which is responsible for a remarkably higher catalytic activity of Pd-Au/IOP in the hydrolytic dehydrogenation of ammonia borane than those of monometallic counterparts. PMID- 29235852 TI - In Situ Alloying of Thermally Conductive Polymer Composites by Combining Liquid and Solid Metal Microadditives. AB - Room-temperature liquid metals (LMs) are attractive candidates for thermal interface materials (TIMs) because of their moderately high thermal conductivity and liquid nature, which allow them to conform well to mating surfaces with little thermal resistance. However, gallium-based LMs may be of concern due to the gallium-driven degradation of many metal microelectronic components. We present a three-component composite with LM, copper (Cu) microparticles, and a polymer matrix, as a cheaper, noncorrosive solution. The solid copper particles alloy with the gallium in the LM, in situ and at room temperature, immobilizing the LM and eliminating any corrosion issues of nearby components. Investigation of the structure-property-process relationship of the three-component composites reveals that the method and degree of additive blending dramatically alter the resulting thermal transport properties. In particular, microdispersion of any combination of the LM and Cu additives results in a large number of interfaces and a thermal conductivity below 2 W m-1 K-1. In contrast, a shorter blending procedure of premixed LM and Cu particle colloid into the polymer matrix yields a composite with polydispersed filler and effective intrinsic thermal conductivities of up to 17 W m-1 K-1 (effective thermal conductivity of up to 10 W m-1 K-1). The LM-Cu colloid alloying into CuGa2 provides a limited, but practical, time frame to cast the uncured composite into the desired shape, space, or void before the composite stiffens and cures with permanent characteristics. PMID- 29235854 TI - Noncentrosymmetric Cubic Cyanurate K6Cd3(C3N3O3)4 Containing Isolated Planar pi Conjugated (C3N3O3)3- Groups. AB - Single crystals of K6Cd3(C3N3O3)4 (1) were successfully grown via a solid-state cyclotrimerization reaction method from CdCl2 and KOCN. To our best knowledge, it is the first inorganic compound containing isolated six-membered-ring (6-MR) anionic groups that crystallizes in the cubic system. In the structure, the basic 6-MR anionic unit is a planar pi-conjugated (C3N3O3)3- group that is isoelectronic with the (B3O6)3- group, as observed in the benchmark nonlinear optical (NLO) crystal beta-BaB2O4 with strong second-harmonic-generation response. In addition, the electronic structure and linear-optical and NLO properties for 1 were also investigated by the first-principles calculation. The NLO coefficient (d14 = 1.17 pm/V) of 1 is about 3 times that of KH2PO4. PMID- 29235855 TI - Zinc-Ligand Swapping Mediated Complex Formation and Sulfur Transfer between SufS and SufU for Iron-Sulfur Cluster Biogenesis in Bacillus subtilis. AB - SufU is a zinc-containing protein involved in mobilization of sulfur from SufS for iron-sulfur cluster biogenesis of Bacillus subtilis. Structural basis for the sulfur transfer in SufS-SufU complex was revealed. A zinc-ligand exchange reaction upon SufS-SufU complexation provides a free thiol from Cys41 of SufU as a sulfur acceptor. PMID- 29235856 TI - A Machine-Driven Hunt for Global Reaction Coordinates of Azobenzene Photoisomerization. AB - Azobenzene is a very important system that is often studied for better understanding light-activated mechanical transformations via photoisomerization. The central C-N?N-C dihedral angle is widely recognized as the primary reaction coordinate for changing cis- to trans-azobenzene and vice versa. We report on a global reaction coordinate (containing all internal coordinates) to thoroughly describe the reaction mechanism for azobenzene photoisomerization. Our global reaction coordinate includes all of the internal coordinates of azobenzene contributing to the photoisomerization reaction coordinate. We quantify the contribution of each internal coordinate of azobenzene to the overall reaction mechanism. Finally, we provide a detailed mapping on how each significantly contributing internal coordinate changes throughout the energy profile (from trans to transition state and subsequently to cis). In our results, the central C N?N-C dihedral remains the primary internal coordinate responsible for the reaction coordinate; however, we also conclude that the disputed inversion assisted rotation is half as important to the overall reaction mechanism and the inversion-assisted rotation is driven by four adjacent dihedral angles C-C-N?N with very little change to the adjacent C-C-N angles. PMID- 29235857 TI - Second-Sphere Effects in Dinuclear FeIIIZnII Hydrolase Biomimetics: Tuning Binding and Reactivity Properties. AB - Herein, we report the synthesis and characterization of two dinuclear FeIIIZnII complexes [FeIIIZnIILP1] (1) and [FeIIIZnIILP2] (2), in which LP1 and LP2 are conjugated systems containing one and two pyrene groups, respectively, connected via the diamine -HN(CH2)4NH- spacer to the well-known N5O2-donor H2L ligand (H2L = 2-bis{[(2-pyridylmethyl)aminomethyl]-6-[(2-hydroxybenzyl)(2 pyridylmethyl)]aminomethyl}-4-methylphenol). The complex [FeIIIZnIIL1] (3), in which H2L was modified to H2L1, with a carbonyl group attached to the terminal phenol group, was included in this study for comparison purposes.1 Both complexes 1 and 2 were satisfactorily characterized in the solid state and in solution. Extended X-ray absorption fine structure data for 1 and 3 in an acetonitrile solution show that the multiply bridged structure seen in the solid state of 3 is retained in solution. Potentiometric and UV-vis titration of 1 and 2 show that electrostatic interaction between the protonated amino groups and coordinated water molecules significantly decreases the pKa of the iron(III)-bound water compared to those of 3. On the other hand, catalytic activity studies using 1 and 2 in the hydrolysis of the activated substrate bis(2,4-dinitrophenyl)phosphate (BDNPP) resulted in a significant increase in the association of the substrate (Kass ? 1/KM) compared to that of 3 because of electrostatic and hydrophobic interactions between BDNPP and the side-chain diaminopyrene of the ligands H2LP1 and H2LP2. In addition, the introduction of the pyrene motifs in 1 and 2 enhanced their activity toward DNA and as effective antitumor drugs, although the biochemical mechanism of the latter effect is currently under investigation. These complexes represent interesting examples of how to promote an increase in the activity of traditional artificial metal nucleases by introducing second coordination-sphere effects. PMID- 29235858 TI - Self-Assembly of Chiral Metal-Organic Tetartoid. AB - Chiral coordination cages feature both chirality and defined inner space, providing advanced molecular materials. A series of chiral 20-nucleus cobalt imidazolate cages were synthesized by self-assembly of 72 subcomponents, featuring a novel tetartoid (tetragonal pentagonal dodecahedron) structure. Spontaneous resolution of racemic tetartoidal cages (Delta and Lambda) into a conglomerate of homochiral crystals are observed, while both homochiral Delta and Lambda tetartoidal cages can be obtained through chiral induction of (d)- and (l) enantiomers of menthol, respectively. The 2-methyl substituent on imidazolyl is critical to the formation of a tetartoidal cage, and the absence of such steric effect will switch the final structure to a cubic cage. PMID- 29235859 TI - The Rise and Fall of a Scaffold: A Trend Analysis of Scaffolds in the Medicinal Chemistry Literature. AB - Scaffolds are a core concept in medicinal chemistry, and they can be the focus of multiple independent development efforts over an extended period. Thus, scaffold associated properties can vary over time, possibly showing consistently increasing or decreasing trends. We posit that such trends characterize the attention that the community pays to a scaffold. In this study, we employed data from ChEMBL20 to examine the evolution of scaffold features, such as enumerated compounds, biological activity, and liabilities, over 17 years. Our analysis highlights that certain properties such as enumerated compounds, but not liabilities, show statistically significant increasing trends for some scaffolds. We also attempt to explain why a scaffold receives more attention over time and highlight that obvious aspects such as synthetic feasibility do not explicitly drive attention. In summary, trend analyses of scaffold properties could support scaffold selection and prioritization in small molecule development projects. PMID- 29235860 TI - Origin of Both Right- and Left-Handed Helicities in a Supramolecular Gel with and without Ni2+ at the Supramolecular Level. AB - We demonstrate the different origins of helical directions in polymeric gels derived from a hydrazone reaction in the absence and presence of Ni2+. The right handed helicity of polymeric gels without Ni2+ originates from the enantiomeric d form alanine moiety embedded in the building block. However, the right-handed helicity is inverted to a left-handed helicity upon the addition of Ni2+, indicating that added Ni2+ greatly affects the conformation of the polymeric gel by overcoming the influence of the enantiomer embedded in the building block on the helicity at the supramolecular level. More interestingly, the ratio of the right-toleft-handed helical fibers varies with the concentration of Ni2+, which converts from 100% right-handed helical fiber to 90% left-handed helical fiber. In the presence of Ni2+, both right- and left-handed helical fibers coexist at the supramolecular level. Some fibers also exhibit both right- and left-handed helicities in a single fiber. PMID- 29235861 TI - KRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation. AB - KRAS switch loop movements play a crucial role in regulating RAS signaling, and alteration of these sensitive dynamics is a principal mechanism through which disease-associated RAS mutations lead to aberrant RAS activation. Prior studies suggest that despite a high degree of sequence similarity, the switches in KRAS are more dynamic than those in HRAS. We determined X-ray crystal structures of the rare tumorigenic KRAS mutants KRASD33E, in switch 1 (SW1), and KRASA59G, in switch 2 (SW2), bound to GDP and found these adopt nearly identical, open SW1 conformations as well as altered SW2 conformations. KRASA59G bound to a GTP analogue crystallizes in the same conformation. This open conformation is consistent with the inactive "state 1" previously observed for HRAS bound to GTP. For KRASA59G, switch rearrangements may be regulated by increased flexibility in the 57DXXGQ61 motif at codon 59. However, loss of interactions between side chains at codons 33 and 35 in the SW1 33DPT35 motif drives changes for KRASD33E. The 33DPT35 motif is conserved for multiple members of the RAS subfamily but is not found in RAB, RHO, ARF, or Galpha families, suggesting that dynamics mediated by this motif may be important for determining the selectivity of RAS-effector interactions. Biochemically, the consequence of altered switch dynamics is the same, showing impaired interaction with the guanine exchange factor SOS and loss of GAP-dependent GTPase activity. However, interactions with the RBD of RAF are preserved. Overall, these observations add to a body of evidence suggesting that HRAS and KRAS show meaningful differences in functionality stemming from differential protein dynamics independent of the hypervariable region. PMID- 29235862 TI - Characterization of the B-Center Defect in Diamond through the Vibrational Spectrum: A Quantum-Mechanical Approach. AB - The B-center in diamond, which consists of a vacancy whose four first nearest neighbors are nitrogen atoms, has been investigated at the quantum-mechanical level with an all-electron Gaussian-type basis set, hybrid functionals, and the periodic supercell approach. To simulate various defect concentrations, four cubic supercells have been considered, containing (before the creation of the vacancy) 64, 216, 512, and 1000 atoms, respectively. Whereas the B-center does not affect the Raman spectrum of diamond, several intense peaks appear in the IR spectrum, which should permit us to identify this defect. It turns out that of the seven peaks proposed by Sutherland in 1954, located at 328, 780, 1003, 1171, 1332, 1372, and 1426 cm-1, and frequently mentioned as fingerprints of the B center, the first one and the last three do not appear in the simulated spectrum at any concentration. The graphical animation of the modes confirms the attribution of the remaining three and also permits investigation of the nature of the full set of modes. PMID- 29235863 TI - Entrance Effects Induced Rectified Ionic Transport in a Nanopore/Channel. AB - The nanofluidic diode, as one of the emerging nanofluidic logic devices, has been used in many fields such as biosensors, energy harvesting, and so on. However, the entrance effects of the nanofluidic ionic conductance were less discussed, which can be a crucial factor for the ionic conduction. Here we calculate the ionic conductance as a function of the length-to-pore ratio (L/r), which has a clear boundary between nanopore (surface dominated) and nanochannel (geometry dominated) electrically in diluted salt solution. These entrance effects are even more obvious in the rectified ionic conduction with oppositely charged exterior surfaces of a nanopore. We build three models-Exterior Charged Surface model (ECS), Inner Charged Surface model (ICS), and All Charged Surface model (ACS)-to discuss the entrance effects on the ionic conduction. Our results demonstrate, for a thin nanopore, that the ECS model has a larger ionic rectification factor (Q) than that of ICS model, with a totally reversed tendency of Q compared to the ICS and ACS models as L/r increases. Our models predict an alternative option of building nanofluidic biosensors that only need to modify the exterior surface of a nanopore, avoiding the slow diffusion of molecules in the nanochannel. PMID- 29235864 TI - Effective Anisotropic Interactions in Spin Pairs Containing High-Spin Ions with Large Zero-Field Splitting. AB - Analytic and numeric derivations are made of the effective exchange and dipolar magnetic interactions between spin pairs containing S = 3/2 ions, such as high spin Co(II), S = 5/2 ions, such as high-spin Fe(III) ions, experiencing zero field splittings much larger than the interion interactions, or J = 15/2 ions such as Dy(III) with crystal-field splittings much larger than the interion interaction. These formulas allow for a simpler analysis of the magnetic properties of dimers containing high-spin ions. PMID- 29235865 TI - Synergetic Catalysis of Copper and Iron in Oxidation of Reduced Keggin Heteropolytungstates by Dioxygen. AB - Polyoxometalates (POMs) and in particularly Keggin heteropolytungstates are much studied and commercially important catalysts for dioxygen-based oxidation processes. The rate-limiting step in many POM-catalyzed O2-based oxidations is reoxidation of the reduced POM by O2. We report here that this reoxidation process, as represented by the one-electron-reduced Keggin complexes POMred (alpha-PW12O404- and alpha-SiVW11O406-) reacting with O2, is efficiently catalyzed by a combination of copper and iron complexes. The reaction kinetics and mechanism have been comprehensively studied in sulfate and phosphate buffer at pH 1.8. The catalytic pathway includes a reversible reaction between Cu(II) and Fe(II), followed by a fast oxidation of POMred by Fe(III) and Cu(I) by O2 to regenerate Fe(II) and Cu(II). The proposed reaction mechanism quantitatively describes the experimental kinetic curves over a wide range of experimental conditions. Since the oxidized forms, alpha-PW12O403- and alpha-SiVW11O405-, are far better oxidants of organic substrates than the previously studied POMs, alpha SiW12O404- and alpha-AlW12O405-, this synergistic Fe/Cu cocatalysis of reduced POM reoxidation could well facilitate significant new O2/air-based processes. PMID- 29235866 TI - Total Synthesis of (+/-)-Aspergilline A. AB - The total synthesis of (+/-)-aspergilline A (1) is described. Key features of the synthesis include pyrrolinone formation via reaction of an intermediate propargyl amine with a methyl malonyl chloride derived ammonium enolate and a formal [3+2] cycloaddition between an imidate and cyclopropenone. PMID- 29235867 TI - NFGAIL Amyloid Oligomers: The Onset of Beta-Sheet Formation and the Mechanism for Fibril Formation. AB - The hexapeptide NFGAIL is a highly amyloidogenic peptide, derived from the human islet amyloid polypeptide (hIAPP). Recent investigations indicate that presumably soluble hIAPP oligomers are one of the cytotoxic species in type II diabetes. Here we use thioflavin T staining, transmission electron microscopy, as well as ion mobility-mass spectrometry coupled to infrared (IR) spectroscopy to study the amyloid formation mechanism and the quaternary and secondary structure of soluble NFGAIL oligomers. Our data reveal that at neutral pH NFGAIL follows a nucleation dependent mechanism to form amyloid fibrils. During the lag phase, highly polydisperse, polymorph, and compact oligomers (oligomer number n = 2-13) as well as extended intermediates (n = 4-11) are present. IR secondary structural analysis reveals that compact conformations adopt turn-like structures, whereas extended oligomers exhibit a significant amount of beta-sheet content. This agrees well with previous molecular dynamic simulations and provides direct experimental evidence that unordered off-pathway NFGAIL aggregates up to the size of at least the 13-mer as well as partially folded beta-sheet containing oligomers are coexisting. PMID- 29235869 TI - Correction to "Organocatalytic Enantioselective Cross-Aldol Reaction of o Hydroxyarylketones and Trifluoromethyl Ketones". PMID- 29235868 TI - Metabolomic Signature of Endometrial Cancer. AB - Endometrial cancer (EC) is the most common cancer of the female reproductive tract in developed countries. At the moment, no effective screening system is available. Here, we evaluate the diagnostic performance of a serum metabolomic signature. Two enrollments were carried out, one consisting of 168 subjects: 88 with EC and 80 healthy women, was used for building the classification models. The second (used to establish the performance of the classification algorithm) was consisted of 120 subjects: 30 with EC, 30 with ovarian cancer, 10 with benign endometrial disease, and 50 healthy controls. Two ensemble models were built, one with all EC versus controls (Model I) and one in which EC patients were aggregated according to their histotype (Model II). Serum metabolomic analysis was conducted via gas chromatography-mass spectrometry, while classification was done by an ensemble learning machine. Accuracy ranged from 62% to 99% for the Model I and from 67% to 100% for the Model II. Ensemble model showed an accuracy of 100% both for Model I and II. The most important metabolites in class separation were lactic acid, progesterone, homocysteine, 3-hydroxybutyrate, linoleic acid, stearic acid, myristic acid, threonine, and valine. The serum metabolomics signature of endometrial cancer patients is peculiar because it differs from that of healthy controls and from that of benign endometrial disease and from other gynecological cancers (such as ovarian cancer). PMID- 29235870 TI - Plasmonic Substrates Do Not Promote Vibrational Energy Transfer at Solid-Liquid Interfaces. AB - Intermolecular vibrational energy transfer in monolayers of isotopically mixed rhenium carbonyl complexes at solid-liquid interfaces is investigated with the help of ultrafast 2D Attenuated Total Reflectance Infrared (2D ATR IR) spectroscopy in dependence of plasmonic surface enhancement effects. Dielectric and plasmonic materials are used to demonstrate that plasmonic effects have no impact on the vibrational energy transfer rate in a regime of moderate IR surface enhancement (enhancement factors up to ca. 30). This result can be explained with the common image-dipole picture. The vibrational energy transfer rate thus can be used as a direct observable to determine intermolecular distances on surfaces, regardless of their plasmonic properties. PMID- 29235872 TI - Correction to "Isolation of Notoamide S and Enantiomeric 6-epi-Stephacidin A from the Terrestrial Fungus Aspergillus amoenus: Biogenetic Implications". PMID- 29235871 TI - Increased Levels of Circulating Fatty Acids Are Associated with Protective Effects against Future Cardiovascular Events in Nondiabetics. AB - Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide, particularly in individuals with diabetes. The current study objective was to determine the circulating metabolite profiles associated with the risk of future cardiovascular events, with emphasis on diabetes status. Nontargeted metabolomics analysis was performed by LC-HRMS in combination with targeted quantification of eicosanoids and endocannabinoids. Plasma from 375 individuals from the IMPROVE pan-European cohort was included in a case-control study design. Following data processing, the three metabolite data sets were concatenated to produce a single data set of 267 identified metabolites. Factor analysis identified six factors that described 26.6% of the variability in the given set of predictors. An association with cardiovascular events was only observed for one factor following adjustment (p = 0.026). From this factor, we identified a free fatty acid signature (n = 10 lipids, including saturated, monounsaturated, and polyunsaturated fatty acids) that was associated with lower risk of future cardiovascular events in nondiabetics only (OR = 0.65, 0.27-0.80 95% CI, p = 0.030), whereas no association was observed among diabetic individuals. These observations support the hypothesis that increased levels of circulating omega-6 and omega-3 fatty acids are associated with protective effects against future cardiovascular events. However, these effects were only observed in the nondiabetic population, further highlighting the need for patient stratification in clinical investigations. PMID- 29235873 TI - Esterase Sensitive Self-Immolative Sulfur Dioxide Donors. AB - A series of cell-permeable esterase-sensitive sulfonates that undergo self immolation to produce sulfur dioxide (SO2), a gaseous pollutant with new and emerging biological roles, is reported. These compounds should facilitate the study SO2 biology and will lay the platform for newer stimuli-responsive donors of this gas. PMID- 29235874 TI - Effect of Wetting on Drop Splashing of Newtonian Fluids and Blood. AB - We investigate the impact velocity beyond which the ejection of smaller droplets from the main droplet (splashing) occurs for droplets of different liquids impacting different smooth surfaces. We examine its dependence on the surface wetting properties and droplet surface tension. We show that the splashing velocity is independent of the wetting properties of the surface but increases roughly linearly with increasing surface tension of the liquid. A preexisting splashing model and simplification are considered that predict the splashing velocity by incorporating the air viscosity. Both the splashing model and simplification give a good prediction of the splashing velocity for each surface and liquid, demonstrating the robustness of the splashing model. We also show that the splashing model can also predict the splashing velocity of blood, a shear-thinning fluid. PMID- 29235875 TI - Coalescence-Induced Jumping of Nanodroplets on Textured Surfaces. AB - Conducting experimental studies on nanoscale droplet coalescence using traditional microscopes is a challenging research topic, and views differ as to whether the spontaneous removal can occur in the coalescing nanodroplets. Here, a molecular dynamics simulation is carried out to investigate the coalescence process of two equally sized nanodroplets. On the basis of atomic coordinates, we compute the liquid bridge radii for various cases, which is described by a power law of spreading time, and these nanodroplets undergo coalescence in the inertially limited-viscous regime. Moreover, coalescence-induced jumping is also possible for the nanodroplets, and the attraction force between surface and water molecules plays a crucial role in this process, where the merged nanodroplets prefer to jump away from those surfaces with lower attraction force. When the solid-liquid interaction intensity and surface structure parameters are varied, the attraction force is shown to decrease with decreasing surface wettability intensity and solid fraction. PMID- 29235876 TI - Suppressing Polysulfide Dissolution via Cohesive Forces by Interwoven Carbon Nanofibers for High-Areal-Capacity Lithium-Sulfur Batteries. AB - Nanostructural design renders several breakthroughs for the construction of high performance materials and devices including energy-storage systems. Although attempts made toward electrode engineering have improved the existing drawbacks, nanoengineering is still hindered by some issues. To achieve practical applications of lithium-sulfur (Li-S) batteries, it is difficult to attain a high areal capacity with stable cycling. Physical encapsulation via nanostructural design not only can resolve the issue of lithium polysulfide dissolution during the electrochemical cycling, but also can offer significant contact resistance, which in turn can decrease the kinetics, particularly at a high sulfur loading. Thus, we demonstrate an electrospun carbon nanofiber (CNF) matrix for a sulfur cathode. This simple design enables a high mass loading of 10.5 mg cm-2 with a high specific capacity and stable cycling. The CNF-sulfur complex can deliver a high areal capacity of greater than 7 mAh cm-2, which is related to the excellent electrical conductivity of one-dimensional species. Moreover, we have observed that the reacted sulfur species have adhered well to the junction of the CNF network with specific wetting angles, which are induced by the cohesive force between the narrow gaps in the matrix that trapped the viscous polysulfides during cycling. The results of this study open new avenues for the design of high areal-capacity Li-S batteries. PMID- 29235877 TI - Cooperative Pd/Cu Catalysis: Multicomponent Synthesis of Tetrasubstituted Imidazolones from Methyl alpha-Isocyanoacetates, Primary Amines, and Aryl(vinyl) Iodides. AB - Three-component reaction of methyl alpha,alpha-disubstituted alpha isocyanoacetates, primary amines, and aryl(vinyl) halides in the presence of Pd(OAc)2 (0.05 equiv) and Cu2O (1.0 equiv) provided 2,3,5,5-tetrasubstituted imidazolones via the formation of three chemical bonds. A copper-mediated migratory insertion of the isocyano group into the N-H bond of the amine followed by lactamization and Pd-catalyzed cross-coupling of the in situ generated amidinyl copper species with aryl(vinyl) halides accounted for the reaction outcome. PMID- 29235878 TI - Literature Review for Office-Based Anesthesia. PMID- 29235879 TI - Experimental studies on artifacts and tumor enhancement on gadoxetic acid enhanced arterial phase liver MRI in a rabbit VX2 tumor model. AB - Background Rapid injection of gadoxetic acid is reported to produce more frequent artifacts and lower vascular enhancement on arterial phase liver magnetic resonance imaging (MRI). However, its effect on tumor enhancement and the mechanism of the artifacts remain unclear. Purpose To evaluate the effect of rapid injection of gadoxetic acid on artifacts and tumor enhancement during arterial phase liver MRI, and on arterial blood gases (ABGs) which may explain the cause of the artifacts. Material and Methods ABG analysis was performed in 13 free-breathing rabbits after rapid injection (1 mL/s; injection time = 0.6-0.8 s) of gadoxetic acid (0.025 mmol/kg). Dynamic liver MRI was performed in six anesthetized rabbits with VX2 tumors under a ventilation stoppage after rapid and slow injection (0.25 mL/s; injection time = 2.4-3.2 s) of gadoxetic acid. Artifacts and signal enhancement on arterial phase imaging were compared with those obtained after rapid injection of gadopentetic acid (Gd-DTPA, 0.1 mmol/kg) using a Friedman test or Kruskal-Wallis test. Results ABG analysis did not find any significant changes. Artifacts were not related to injection protocols ( P = 0.95). Aortic enhancement with slow injection of gadoxetic acid was significantly higher than that with rapid injection ( P < 0.05), and was comparable to that with Gd-DTPA injection. Tumor enhancement obtained with gadoxetic acid was not significantly different between rapid and slow injection, and was significantly lower than that with Gd-DTPA injection ( P < 0.05). Conclusion Rapid injection of gadoxetic acid did not affect ABGs and may not be the cause of the artifacts. It lowered vascular enhancement but not arterial tumor enhancement. PMID- 29235880 TI - A Critical Review of Physicochemical Properties and Analytical Methods Applied to Quantitative Determination of Ebastine. AB - Allergic diseases are the most common conditions in children and the second most frequent in adults. Currently, there are two well-defined generations of antihistamines, those belonging to first generation, with inherent side effects such as drowsiness and anticholinergic effects. These side effects are often attributed to their high lipophilicity and high affinity for brain H1 receptors. The ebastine is a modern antihistaminic drug belongs to the second generation and has lower lipophilicity, which diminish the undesirable side effects. To ensure the quality, efficacy, safety, and effectiveness of ebastine drug products, efficient and reliable analytical methods are mandatory. Besides official compendial methods, alternative methods are often developed and used in quality control of pharmaceuticals as well as in pharmacokinetic studies. In this work, we present a critical review on characteristics, physicochemical properties, and analytical methods applied in the analysis of ebastine. PMID- 29235881 TI - Prediction of pancreatic cancer risk and therapeutic response with next generation sequencing. PMID- 29235882 TI - Early warning systems for the management of chronic heart failure: a systematic literature review of cost-effectiveness models. AB - INTRODUCTION: Describing the general and methodological characteristics of decision-analytical models used in the economic evaluation of early warning systems for the management of chronic heart failure patients and performing a quality assessment of their methodological characteristics is expected to provide concise and useful insight to inform the future development of decision analytical models in the field of heart failure management. Areas covered: The literature on decision-analytical models for the economic evaluation of early warning systems for the management of chronic heart failure patients was systematically reviewed. Nine electronic databases were searched through the combination of synonyms for heart failure and sensitive filters for cost effectiveness and early warning systems. Expert commentary: The retrieved models show some variability with regards to their general study characteristics. Overall, they display satisfactory methodological quality, even though some points could be improved, namely on the consideration and discussion of any competing theories regarding model structure and disease progression, identification of key parameters and the use of expert opinion, and uncertainty analyses. A comprehensive definition of early warning systems and further research under this label should be pursued. To improve the transparency of economic evaluation publications, authors should make available detailed technical information regarding the published models. PMID- 29235884 TI - Cost per successfully treated patient for vortioxetine versus duloxetine in adults with major depressive disorder: an analysis of the complete symptoms of depression and functional outcome. AB - OBJECTIVE: To determine the cost-effectiveness of vortioxetine vs duloxetine in adults with moderate-to-severe major depressive disorder (MDD) in Norway using a definition of a successfully treated patient (STP) that incorporates improvement in both mood symptoms and functional capacity. METHODS: Using the population of patients who completed the 8-week CONNECT study, the cost-effectiveness of vortioxetine (n = 168) (10-20 mg/day) vs duloxetine (n = 176) (60 mg/day) was investigated for the treatment of adults in Norway with moderate-to-severe MDD and self-reported cognitive dysfunction over an 8-week treatment period. Cost effectiveness was assessed in terms of cost per STP, defined as improvement in mood symptoms (>=50% decrease from baseline in Montgomery-Asberg Depression Rating Scale total score) and change in UCSD [University of California San Diego] performance-based skills assessment [UPSA] score of >=7. The base case analysis utilized pharmacy retail price (apotek utsalgspris (AUP)) for branded vortioxetine (Brintellix) and branded duloxetine (Cymbalta). RESULTS: After 8 weeks of antidepressant therapy, there were more STPs with vortioxetine than with duloxetine (27.4% vs 22.5%, respectively). The mean number needed to treat for each STP was 3.6 for vortioxetine and 4.4 for duloxetine, resulting in a lower mean cost per STP for vortioxetine (NOK [Norwegian Kroner] 3264) than for duloxetine (NOK 3310) and an incremental cost per STP of NOK 3051. The use of a more challenging change in the UPSA score from baseline (>=9) resulted in a mean cost per STP of NOK 3822 for vortioxetine compared with NOK 3983 for duloxetine and an incremental cost per STP of NOK 3181. CONCLUSIONS: Vortioxetine may be a cost-effective alternative to duloxetine, owing to its superior ability to improve functional capacity. The dual-response STP concept introduced here represents a more comprehensive analysis of the cost-effectiveness of antidepressants. PMID- 29235883 TI - Nitric oxide modulates the responses of osteoclast formation to static magnetic fields. AB - Nitric oxide (NO) is involved in osteoclast differentiation. Our previous studies showed that static magnetic fields (SMFs) could affect osteoclast differentiation. The inhibitory effects of 16 T of high SMF (HiMF) on osteoclast differentiation was correlated with increased production of NO. We raised the hypothesis that NO mediated the regulatory role of SMFs on osteoclast formation. In this study, 500 nT of hypomagnetic field (HyMF), 0.2 T of moderate SMF (MMF) and 16 T of high SMF (HiMF) were utilized as SMF treatment. Under 16 T, osteoclast formation was markedly decreased with enhanced NO synthase (NOS) activity, thus producing a high level of NO. When treated with NOS inhibitor N Nitro-L-Arginine Methyl Ester (L-NAME), NO production could be inhibited, and osteoclast formation was restored to control group level in a concentration dependent manner. However, 500 nT and 0.2 T increased osteoclast formation with decreased NOS activity and NO production. When treated with NOS substrate L Arginine (L-Arg) or NO donor sodium nitroprusside (SNP), the NO level in the culture medium was obviously elevated, thus inhibiting osteoclast differentiation in a concentration-dependent manner under 500 nT or 0.2 T. Therefore, these findings indicate that NO mediates the regulatory role of SMF on osteoclast formation. PMID- 29235885 TI - Is there a relation between the manipulative activity of Toxoplasma and personalized medicine? PMID- 29235886 TI - Effect of Induced Vertical Disparity on Horizontal Fusional Reserves. AB - PURPOSE: The aim of this study was to investigate the effects of induced vertical disparity on horizontal fusional reserves at near. MATERIALS AND METHODS: In 170 healthy subjects wearing best corrective refraction, the negative and positive horizontal fusional reserves were measured with base-in (BI) and base-out (BO) prisms, respectively, in the presence of 0.5 prism diopters (?) and 1? vertical prisms placed in trial frames in front of the right eye. The prism power was slowly increased step by step until the subject reported sustained blur, break, and recovery. These were compared to horizontal fusional reserves in the same subjects without a vertical prism. Data were analyzed in SPSS.17 software using a repeated measures ANOVA. RESULTS: Induced vertical disparity decreased negative fusional reserves (NFR) horizontally and was more significant with 1? vertical disparity (P<0.001). There were significant differences between the blur (P<0.001), break (P<0.001), and recovery (P<0.001) for NFR before and after induced vertical disparity and no significant difference between blur (P=0.173) and recovery points (P=0.261) with a marginal difference for break points (P=0.045) for the positive fusional reserves (PFR). CONCLUSION: Inducing vertical disparity even with small magnitudes affects all 3 aspects (blur, break, and recovery) of horizontal negative fusional reserves while only break is affected in positive fusional reserves. These changes are statistically significant but do not seem to be clinically significant except for cases accompanied by symptoms. PMID- 29235887 TI - Novel 4-methylsulfonylphenyl derivatives as NSAIDS with preferential COX-2 inhibition. AB - AIM: There has been an enormous commercial development following the introduction of selective COX-2 inhibitors. Efforts are continuously done to discover efficient and safe COX-2 inhibitors. RESULTS: A series of 4-methylsulfonylphenyl derivatives was designed, synthesized and screened for preferential inhibition of COX-2 over COX-1 isoforms and in vivo anti-inflammatory activity using the rat paw edema method. The most active ones were investigated via ulcerogenic liability and molecular docking. Physicochemical parameters were calculated for all the newly synthesized compounds. CONCLUSION: The new compounds showed clear preferential COX-2 over COX-1 inhibition. Selective indices for compounds 4, 6b and 6e were 124, 131 and 119, respectively. Compound 4 reached 71% in vivo anti inflammatory inhibition. The compounds obeyed 'Lipinski's rule of five'. PMID- 29235888 TI - Validation of the eighth clinical American Joint Committee on Cancer stage grouping for esophageal cancer. AB - AIM: To validate the American Joint Committee on Cancer (AJCC) clinical staging system for esophageal cancer using Surveillance, Epidemiology and End Results database. METHODS: Cancer-specific survival analyses for clinically-staged patients with esophageal cancer according to both seventh and eighth editions were conducted through Kaplan-Meier analysis. RESULTS: For cancer-specific survival according to both seventh and eighth clinical systems, p-values for pairwise comparisons were nonsignificant in many comparisons. C-index for adenocarcinoma was: 0.671 according to the seventh AJCC and 0.671 according to the clinical eighth AJCC. C-index for squamous cell carcinoma according to the seventh AJCC was: 0.634 and 0.643 according to clinical eighth AJCC. CONCLUSION: Minimal improvement was achieved by the eighth clinical AJCC staging system for esophageal cancer. PMID- 29235889 TI - Effects of coating layer and release medium on release profile from coated capsules with Eudragit FS 30D: an in vitro and in vivo study. AB - The aim of the present research was to evaluate the impact of coating layers on release profile from enteric coated dosage forms. Capsules were coated with Eudragit FS 30D using dipping method. The drug profile was evaluated in both phosphate buffer and Hank's solutions. Utilization X-ray imaging, gastrointestinal transmission of enteric coated capsules was traced in rats. According to the results, no release of the drug was found at pH 1.2, and the extent of release drug in pH 6.8 medium was decreased by adding the coating layers. The results indicated single-layer coated capsules in phosphate buffer were significantly higher than that in Hank's solution. However, no significant difference was observed from capsules with three coating layers in two different dissolution media. X-ray imaging showed that enteric coated capsules were intact in the stomach and in the small intestine, while disintegrated in the colon. PMID- 29235890 TI - Low-density lipoprotein cholesterol and suicidal behaviour in a large sample of first-episode psychosis patients. AB - OBJECTIVES: Our aims were to confirm the relationship between lipid and lipoprotein concentrations and suicidal behaviour in first-episode psychosis (FEP) patients. METHODS: Suicidal behaviour was explored in a large FEP sample (N = 383). Baseline lipid profile was compared between those who attempted or completed suicide and those who not presented suicidal behaviour. RESULTS: Low density lipoprotein cholesterol (LDL-c) (OR = 0.99, 95% CI= 0.98-1.00) and depressive symptoms (OR = 1.15, 95% CI = 1.06-1.24) were significantly related with suicidal behaviour. CONCLUSIONS: Lipid profile test may be considered in the assessment of suicide risk in psychosis and LDL-c an important biological marker. PMID- 29235891 TI - Lipid biomarkers for the peroxisomal and lysosomal disorders: their formation, metabolism and measurement. AB - Lipid biomarkers play important roles in the diagnosis of and monitoring of treatment in peroxisomal disorders and lysosomal storage disorders. Today, a variety of lipids, including very long chain fatty acids, glycolipids, bile acids and the oxidation products of cholesterol, have been considered as biomarkers for these disorders. In this brief review, the authors summarized the recent advances regarding these lipid biomarkers in terms of their formation, metabolism and measurement in these disorders. An understanding of these biomarkers will offer a key to the development of novel diagnoses and help create more effective therapies in the future. PMID- 29235892 TI - Changes in technical efficiency of the broiler production in Poland, 1994-2013. AB - 1. The effects of changes in technical efficiency on the increase of broiler production are presented for the period 1994-2013 based on the panel data from seven farms located in southern and central Poland. A total of 766 cycles were analysed. 2. The Cobb-Douglas production function was used to assess the changes of output elasticities as well as technical changes in broiler production, for 5 year sub-periods separately. 3. Technical indices of broiler production significantly improved between years 1994-2013: feed conversion ratio decreased from 2.50 kg/kg to 1.78 kg/kg, mortality rate from 8.8% to 4.0% and daily weight gain increased from 37.1 g/d to 58.7 g/d, respectively. 4. Before accession to the EU, there was a substantial increase of fixed capital connected with modernisation of buildings and equipment. In the period 1994-2013, inputs of fixed capital per kilogram of livestock increased by 72% and at the same time the input of labour decreased by 56%. 5. Technical changes in years 1994-1998 contributed to a rapid production increase at a rate of 4.6% annually and only by up to 0.7% annually during 2009-2013. The slowdown of production rate increase after 2009 was partially caused by decreasing the stocking density. PMID- 29235893 TI - Construction of some cytotoxic agents with aurone and furoaurone scaffolds. AB - AIM: In spite of the availability of different chemotherapies for cancer treatment, there is still a need for new candidates with higher efficacy and lower toxicity. METHODOLOGY: Aurones 7a-f, 8a-f and furoaurones 13a-f, 16a-c were synthesized. Some compounds were selected by the National Cancer Institute, USA, for cytotoxicity screening. RESULTS & DISCUSSION: The furoaurone derivative, 13a was the most active one exhibiting promising growth inhibition against leukemia, K562 and melanoma, MDA-MB-435 cells at concentration of 10 MUM. It induced apoptosis in both cell lines by activation of CASP3 and inhibition of CDK2. Additionally, 13a showed good selectivity over normal kidney and liver cells. Simulation docking study was undertaken to gain insight into the possible binding mode of 13a in the CDK2 enzyme. CONCLUSION: The furoaurone 13a can be considered as a scaffold for further optimization to obtain more active hits. Graphical abstract [Formula: see text]. PMID- 29235894 TI - Pacritinib and its use in the treatment of patients with myelofibrosis who have thrombocytopenia. AB - The treatment landscape for myelofibrosis (MF) has reached the molecular era by targeting different pathways that are implied in this myeloproliferative neoplasm. A few years ago, the first-in-class JAK1/JAK2 inhibitor ruxolitinib, demonstrated reductions in both constitutional symptoms and splenomegaly, leading to the US FDA approval. The development or worsening of cytopenias in patients receiving ruxolitinib uncovered an unmet need that has been addressed by alternative approaches. Pacritinib, a dual JAK2 and FLT3 inhibitor which also inhibits IRAK1, has demonstrated the ability to favorably impact MF-associated splenomegaly and symptom burden, while having limited myelosuppression with manageable gastrointestinal toxicity. Herein, we provide an overview of pacritinib, from early preclinical studies to the latest and ongoing PAC203 trial, as an emerging therapy for MF. PMID- 29235895 TI - Drug Repurposing Patent Applications July-September 2017. PMID- 29235896 TI - Drug Repurposing Patent Applications April-June 2017. PMID- 29235897 TI - Old Compounds, New Uses, New Ways: Many Ways. PMID- 29235898 TI - Flash Glucose Measurements in Children with Type 1 Diabetes in Real-Life Settings: To Trust or Not to Trust? AB - BACKGROUND AND AIMS: To evaluate the clinical accuracy of a flash glucose monitoring device FreeStyle Libre (FSL) among children with type 1 diabetes in real-world settings during a summer camp. MATERIALS AND METHODS: During a summer camp, children with type 1 diabetes (n = 79, aged 8-18 years) were provided with FSLs for 12 days. On days 3, 7, and 11 of the study, they underwent supervised glucose testing at 8 timepoints. Glycemia was estimated by using FSL and measured with a personal glucometer within a period of 2 min. The glucose trend arrows were recorded. RESULTS: The study was completed by 78 children (median: age 12.8 years, diabetes duration 5.8 years, HbA1c 58.5 mmol/mol). Mean absolute relative difference (MARD) between the FSL and the glucometer was 13.5% +/- 12.9%. FSL was the most accurate in stable glycemic conditions: MARD 11.4% +/- 10.4%, less accurate when glycemia was falling >2 mg/(dL.min) [0.111 mmol/(L.min)-MARD 22.6% +/- 18.6%; P < 0.001 vs. stable conditions] and when the device could not determine the glucose trends (16.5% +/- 16.3%, P = 0.01 vs. stable conditions). The FSL demonstrated lower accuracy during the day than the night [MARD 14.9% +/- 14% vs. 11.2% +/- 10.6%, P < 0.0001]. Out of 1655 data pairs of glucometer and FSL, using the Surveillance Error Grid methodology we determined that 80.36% of FSL readings were associated with no clinical risk, 18.73% with slight risk and only one high-risk measurement was detected. CONCLUSION: FSL is accurate in children, but its accuracy depends on the glucose trend. Results flagged by the rapid fall flag and "trend undetermined" should be verified by blood glucose measurements. PMID- 29235899 TI - Metabolic profiles of corydaline in rats by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. AB - 1. Corydaline, an isoquinoline alkaloid obtained from the rhizomes of Corydalis yanhusuo, exhibits anti-acetylcholinesterase, anti-angiogenic, anti-allergic and gastric-emptying activities. In this study, a rapid and reliable ultra performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) method was developed and employed for the comprehensive study of the metabolites of corydaline in rats. 2. Altogether, 43 metabolites were identified in the plasma (11), bile (9), urine (34) and feces (21) of rats after oral administration of corydaline at a dose of 4.5mg/kg. 3. It was demonstrated that demethylation, hydroxylation, sulfation and glucuronidation were the major metabolic transformation pathways. Among these, two metabolites were identified as tetrahydropalmatine and isocorybulbine, and 33 phase I and phase II products were inferred to be new metabolites arising from the in vivo metabolism of corydaline. 4. Importantly, this research provides scientific and reliable support for full understanding of the metabolic profiles of corydaline and the results could help to elucidate its safety and efficacy. PMID- 29235900 TI - Treatment and discharge patterns among patients hospitalized with non-valvular atrial fibrillation transitioning from the inpatient to outpatient setting. AB - OBJECTIVE: To evaluate inpatient oral anticoagulant (OAC) treatment, discharge location, and post-discharge OAC treatment for patients hospitalized with non valvular atrial fibrillation (NVAF). RESEARCH DESIGN AND METHODS: Retrospective study using claims data linked to hospital electronic health records (EHR). Patients (n = 2,484) were hospitalized with a primary (38%) or secondary (62%) diagnosis of AF without evidence of mitral valvular heart disease or valve replacement between January 2009 and September 2013. Inpatient OAC treatment was identified from EHR data. MAIN OUTCOME MEASURES: Inpatient and post-discharge OAC treatment [direct OAC (DOAC; apixaban, rivaroxaban, dabigatran), warfarin, no OAC] and discharge location (long-term care, home health-care, home self-care). RESULTS: Mean age was 72.6 years, 61.2% were male, and 89.5% had a CHA2DS2-VASc score >=2. Overall, 6.4% received a DOAC, 38.0% warfarin, and 55.6% no OAC during hospitalization. Compared to other treatment groups, patients receiving DOAC were younger and more likely to be male. The majority (72.2%) were discharged to home health-care, 13.2% home self-care, and 6.0% long-term care. Among patients who were treated with warfarin during hospitalization, 40.3% filled a warfarin prescription within 30 days post-discharge, whereas among patients who were treated with a DOAC, 52.4% filled a DOAC prescription within 30 days post discharge. Some NVAF patients not treated with an OAC during hospitalization filled a prescription for warfarin (18.0%) or DOAC (1.9%) within 30 days post discharge. Results were similar among patients with CHA2DS2-VASc score >=2. CONCLUSIONS: Most patients hospitalized for NVAF were discharged to home support, and the majority did not have OAC treatment during hospitalization or the 30 days post-discharge. Additional investigation should be conducted on trends beyond 30 days post-hospitalization, and the reasons for not receiving anticoagulation therapy in patients at moderate-to-severe risk of stroke or systemic embolism. Helping to avoid preventable strokes is an important goal for public health. PMID- 29235901 TI - A novel mixed polymeric micelle for co-delivery of paclitaxel and retinoic acid and overcoming multidrug resistance: synthesis, characterization, cytotoxicity, and pharmacokinetic evaluation. AB - In the current study, retinoic acid (RA) was conjugated to Pluronic F127 (PF127) through an esterification process. Mixed micelles were formed with tocopheryl polyethylene glycol 1000 (TPGS) for co-delivery of paclitaxel (PTX) and RA to the cancer cells. Mixed micelles of RA-PF127 and TPGS in different weight ratios (10:0, 7:3, 5:5, 3:7, 0:10 w/w) were prepared and physicochemical properties including, particle size, zeta potential, critical micelle concentration (CMC), drug loading content, entrapment efficiency, drug release, cellular uptake and in vitro cytotoxicity, were investigated in details. Furthermore, the pharmacokinetics of PTX-loaded optimized mixed micelles were evaluated in Sprague Dawley rats and compared with Stragen(r) (PTX in Cremophor EL(r)). Particle sizes and zeta potentials of the drug-loaded micelles were in the range of 102.6-223.5 nm and -5.3 to -9.6 mV, respectively. The 7:3 and 5:5 micellar combinations had lower CMC values (0.034-0.042 mg/mL) than 0:10 (0.124 mg/mL). The entrapment efficiencies of 10:0, 7:3, and 5:5 were 53.4 +/- 9.3%, 61.3 +/- 0.5%, and 78.7 +/ 1.66%, respectively. The release rates of PTX from 7:3 and 5:5 mixed micelles were significantly slower than other formulations. Cytotoxicity assay demonstrated increased cytotoxic activity of PTX-loaded mixed micelles compared to free PTX. The Vd and t1/2beta of PTX-loaded RA-PF127/TPGS (7:3) were increased by 2.61- and 1.27-fold, respectively, while the plasma area under the curve (AUC) of the micelles was 2.03-fold lower than those of Stragen(r). Therefore, these novel mixed micelles could be effectively used for delivery of PTX and RA to the cancer cells. Moreover, TPGS as part of micelle composition could enhance the therapeutic effect of PTX and reduce side effects. PMID- 29235902 TI - Storage of Unfed and Leftover Mothers' Own Milk. AB - OBJECTIVE: The objective was to examine the bacteriological and immunological properties of freshly expressed, previously frozen, and leftover mothers' own milk during storage. MATERIALS AND METHODS: In the first of two pilot studies, 12 mother-infant dyads participated. The milk studied included freshly expressed unfed and freshly expressed leftover milk. Milk samples were stored at 24 degrees C, 4 degrees C, or -20 degrees C. In the second pilot study, 11 mother-infant dyads participated. The milk studied included milk that had been previously frozen, including previously frozen leftover milk. Milk samples were stored at 24 degrees C and 4 degrees C. After storage in both studies, the milk was analyzed for bacteriological and immunological properties. RESULTS: Bacteriological and immunological characteristics of freshly expressed unfed and freshly expressed leftover milk and previously frozen unfed and previously frozen leftover milk remained stable during storage at 4 degrees C for at least 6 days. The quality of all groups of mothers' milk declined when stored at 24 degrees C for longer than 3 hours. CONCLUSIONS: While this study provides evidence that human milk might be safe at longer storage times, storage guidelines should not be revised until more research is performed. This study serves as a call to action for more research on the topic of human milk storage, specifically leftover human milk. The study provides information to inform future study designs on the topic of unpasteurized human milk storage. More research is needed regarding leftover human milk storage with a greater number of participants, determination of the quality of human milk, and the storage of human milk in a real-life setting. PMID- 29235903 TI - Brain-targeted intranasal zaleplon solid dispersion in hydrophilic carrier system; 23 full-factorial design and in vivo determination of GABA neurotransmitter. AB - Intranasal zaleplon solid dispersion was formulated to enhance the solubility, bioavailability and deliver an effective therapy. Zaleplon belongs to Class II drugs, and undergoes extensive first-pass metabolism after oral absorption exhibiting 30% bioavailability. A 23 full-factorial design was chosen for the investigation of solid dispersion formulations. The effects of different variables include drug to carrier ratio (1:1 and 1:2), carrier type (polyethylene glycol 4000 and poloxamer 407), and preparation method (solvent evaporation and freeze drying) on different dissolution parameters were studied. The dependent variables determined from the in vitro characterization and their constraints were set as follows: minimum mean dissolution time, maximum dissolution efficiency and maximum percentage release. Numerical optimization was performed according to the constraints set based on the utilization of desirability functions. Differential scanning calorimetry, infrared spectroscopy, X-ray diffraction and scanning electron microscopy were performed. Ex vivo estimation of nasal cytotoxicity and assessment of the gamma-aminobutyric acid level in plasma and brain 1 h after nasal SD administration in rabbits compared to the oral market product were conducted. The selected ZP-SD, with a desirability 0.9, composed of poloxamer 407 at drug to carrier ratio 1:2 successfully enhanced the bioavailability showing 44% increase in GABA concentration than the marketed tablets. PMID- 29235905 TI - The Thrombectomy challenge in Neuro-radiology. PMID- 29235904 TI - Molecular modeling and docking studies of the oxytocin receptor. AB - AIM: Low oxytocin (OT) level is involved in a number of psychiatric diseases, indicating that OT could be used to aid treating these disorders. OT itself is unable to cross the blood-brain barrier, and development of new small nonpeptide drugs targeting the OT receptor (OXTR) may be beneficial for treating mental disorders. Results & methodology: Three OXTR models were constructed based on crystallized homologous proteins (Protein Data Bank [PDB]: 2Y00, PDB: 4BVN and PDB: 4LDE). The abilities of the models to discriminate between true binders and decoys were analyzed using receiver operating characteristics curves, and the 4LDE-based model gave the best result. CONCLUSION: The present study demonstrates that the 4LDE-based model may be suitable as a tool for the development of novel drugs targeting OXTR. PMID- 29235907 TI - A validation study of Fitbit Charge 2TM compared with polysomnography in adults. AB - We evaluated the performance of a consumer multi-sensory wristband (Fitbit Charge 2TM), against polysomnography (PSG) in measuring sleep/wake state and sleep stage composition in healthy adults. In-lab PSG and Fitbit Charge 2TM data were obtained from a single overnight recording at the SRI Human Sleep Research Laboratory in 44 adults (19-61 years; 26 women; 25 Caucasian). Participants were screened to be free from mental and medical conditions. Presence of sleep disorders was evaluated with clinical PSG. PSG findings indicated periodic limb movement of sleep (PLMS, > 15/h) in nine participants, who were analyzed separately from the main group (n = 35). PSG and Fitbit Charge 2TM sleep data were compared using paired t-tests, Bland-Altman plots, and epoch-by-epoch (EBE) analysis. In the main group, Fitbit Charge 2TM showed 0.96 sensitivity (accuracy to detect sleep), 0.61 specificity (accuracy to detect wake), 0.81 accuracy in detecting N1+N2 sleep ("light sleep"), 0.49 accuracy in detecting N3 sleep ("deep sleep"), and 0.74 accuracy in detecting rapid-eye-movement (REM) sleep. Fitbit Charge 2TM significantly (p < 0.05) overestimated PSG TST by 9 min, N1+N2 sleep by 34 min, and underestimated PSG SOL by 4 min and N3 sleep by 24 min. PSG and Fitbit Charge 2TM outcomes did not differ for WASO and time spent in REM sleep. No more than two participants fell outside the Bland-Altman agreement limits for all sleep measures. Fitbit Charge 2TM correctly identified 82% of PSG-defined non REM-REM sleep cycles across the night. Similar outcomes were found for the PLMS group. Fitbit Charge 2TM shows promise in detecting sleep-wake states and sleep stage composition relative to gold standard PSG, particularly in the estimation of REM sleep, but with limitations in N3 detection. Fitbit Charge 2TM accuracy and reliability need to be further investigated in different settings (at-home, multiple nights) and in different populations in which sleep composition is known to vary (adolescents, elderly, patients with sleep disorders). PMID- 29235908 TI - Sometimes, I'd rather play poker. PMID- 29235906 TI - Synthesis and molecular modeling of new benzimidazoles as glutathione S transferase inhibitors and anticancer agents. AB - AIM: Synthesis of novel glutathione S-transferases (GSTs) inhibitors constitutes a promising strategy in cancer treatment. Results & methodology: A new set of benzimidazoles clubbed with various heterocycles as GST inhibitors and anticancer agents were synthesized. The biological results proved the potential of the new compounds as GST inhibitors, specifically compounds 7 and 14 which produced more potency than ethacrynic acid by three- and tenfold, respectively. Most compounds exhibited promising cytotoxic activity against breast and colon cancer cell lines. Molecular modeling studies revealed that compounds 7 and 14 showed good binding with the amino acids of the GST protein. CONCLUSION: Both compounds 7 and 14 fulfilled the Lipinski's rule of five suggesting them as new promising GST inhibitors and anticancer agents. PMID- 29235909 TI - The role of Balint group training in the professional and personal development of family medicine residents. AB - This paper presents a study based on the participation of PGY2 and PGY3 family medicine residents in Balint seminars that occurred twice monthly for 24 months. Balint groups were cofacilitated by leader pairs experienced with the Balint method. Prior to residency graduation, 18 of 19 eligible resident physicians (94.5%) completed 30- to 60-min semistructured interviews conducted by a research assistant. Resident physicians were told that these individual interviews concerned "...how we teach communication in residency." The deidentified transcripts from these interviews formed the raw data that were coded for positive (n = 9) and negative (n = 3) valence themes by four faculty coders utilizing an iterative process based on grounded theory. The consensus positive themes included several elements that have previously been discussed in published literature concerning the nature of Balint groups (e.g., being the doctor that the patient needs, reflection, empathy, blind spots, bonding, venting, acceptance, perspective taking, and developing appreciation for individual experiences). The negative themes pointed to ways of possibly improving future Balint offerings in the residency setting ( repetitive, uneasiness, uncertain impact). These findings appear to have consistency with seminal writings of both Michael and Enid Balint regarding the complex nature of intrapsychic and interpersonal skills required to effectively manage troubling doctor-patient relationships. The implications of findings for medical education (curriculum) development as well as future research efforts are discussed. PMID- 29235911 TI - Short notes on short reports. PMID- 29235910 TI - Best practices and new directions. PMID- 29235912 TI - Multiplex one-step real-time PCR detection for influenza viruses, AH1pdm09, AH3 and B. PMID- 29235913 TI - Should We Regulate Digital Platforms? PMID- 29235914 TI - Improving Predictive Accuracy in Elections. AB - The problem of accurately predicting vote counts in elections is considered in this article. Typically, small-sample polls are used to estimate or predict election outcomes. In this study, a machine-learning hybrid approach is proposed. This approach utilizes multiple sets of static data sources, such as voter registration data, and dynamic data sources, such as polls and donor data, to develop individualized voter scores for each member of the population. These voter scores are used to estimate expected vote counts under different turnout scenarios. The proposed technique has been tested with data collected during U.S. Senate and Louisiana gubernatorial elections. The predicted results (expected vote counts, predicted several days before the actual election) were accurate within 1%. PMID- 29235915 TI - Social Bots: Human-Like by Means of Human Control? AB - Social bots are currently regarded an influential but also somewhat mysterious factor in public discourse and opinion making. They are considered to be capable of massively distributing propaganda in social and online media, and their application is even suspected to be partly responsible for recent election results. Astonishingly, the term social bot is not well defined and different scientific disciplines use divergent definitions. This work starts with a balanced definition attempt, before providing an overview of how social bots actually work (taking the example of Twitter) and what their current technical limitations are. Despite recent research progress in Deep Learning and Big Data, there are many activities bots cannot handle well. We then discuss how bot capabilities can be extended and controlled by integrating humans into the process and reason that this is currently the most promising way to realize meaningful interactions with other humans. This finally leads to the conclusion that hybridization is a challenge for current detection mechanisms and has to be handled with more sophisticated approaches to identify political propaganda distributed with social bots. PMID- 29235917 TI - Computational Propaganda and Political Big Data: Moving Toward a More Critical Research Agenda. PMID- 29235916 TI - Harvesting Social Signals to Inform Peace Processes Implementation and Monitoring. AB - Peace processes are complex, protracted, and contentious involving significant bargaining and compromising among various societal and political stakeholders. In civil war terminations, it is pertinent to measure the pulse of the nation to ensure that the peace process is responsive to citizens' concerns. Social media yields tremendous power as a tool for dialogue, debate, organization, and mobilization, thereby adding more complexity to the peace process. Using Colombia's final peace agreement and national referendum as a case study, we investigate the influence of two important indicators: intergroup polarization and public sentiment toward the peace process. We present a detailed linguistic analysis to detect intergroup polarization and a predictive model that leverages Tweet structure, content, and user-based features to predict public sentiment toward the Colombian peace process. We demonstrate that had proaccord stakeholders leveraged public opinion from social media, the outcome of the Colombian referendum could have been different. PMID- 29235918 TI - Detecting Bots on Russian Political Twitter. AB - Automated and semiautomated Twitter accounts, bots, have recently gained significant public attention due to their potential interference in the political realm. In this study, we develop a methodology for detecting bots on Twitter using an ensemble of classifiers and apply it to study bot activity within political discussions in the Russian Twittersphere. We focus on the interval from February 2014 to December 2015, an especially consequential period in Russian politics. Among accounts actively Tweeting about Russian politics, we find that on the majority of days, the proportion of Tweets produced by bots exceeds 50%. We reveal bot characteristics that distinguish them from humans in this corpus, and find that the software platform used for Tweeting is among the best predictors of bots. Finally, we find suggestive evidence that one prominent activity that bots were involved in on Russian political Twitter is the spread of news stories and promotion of media who produce them. PMID- 29235919 TI - Fake News: A Technological Approach to Proving the Origins of Content, Using Blockchains. AB - In this article, we introduce a prototype of an innovative technology for proving the origins of captured digital media. In an era of fake news, when someone shows us a video or picture of some event, how can we trust its authenticity? It seems that the public no longer believe that traditional media is a reliable reference of fact, perhaps due, in part, to the onset of many diverse sources of conflicting information, via social media. Indeed, the issue of "fake" reached a crescendo during the 2016 U.S. Presidential Election, when the winner, Donald Trump, claimed that The New York Times was trying to discredit him by pushing disinformation. Current research into overcoming the problem of fake news does not focus on establishing the ownership of media resources used in such stories the blockchain-based application introduced in this article is technology that is capable of indicating the authenticity of digital media. Put simply, using the trust mechanisms of blockchain technology, the tool can show, beyond doubt, the provenance of any source of digital media, including images used out of context in attempts to mislead. Although the application is an early prototype and its capability to find fake resources is somewhat limited, we outline future improvements that would overcome such limitations. Furthermore, we believe that our application (and its use of blockchain technology and standardized metadata) introduces a novel approach to overcoming falsities in news reporting and the provenance of media resources used therein. However, while our application has the potential to be able to verify the originality of media resources, we believe that technology is only capable of providing a partial solution to fake news. That is because it is incapable of proving the authenticity of a news story as a whole. We believe that takes human skills. PMID- 29235920 TI - New insights into HEATR1 functions. PMID- 29235921 TI - Tannic acid for remediation of historically arsenic-contaminated soils. AB - Soil washing effectively and permanently decreases soil pollution. Thus, it can be considered for the removal of the most toxic elements, for example arsenic (As). In this study, historically As-contaminated soils (2041-4294 mg/kg) were remediated with tannic acid (TA) as the washing agent. The scope of this study included optimization of the operational conditions of As removal, determination of As distribution in soil before and after double soil washing, and measurement of TA loss during washing. The optimum conditions for As removal were 4% TA, pH 4 and 24 h washing time. The average As removal after single and double washings was 38% and 63%, respectively. TA decreased As content in amorphous and poorly crystalline oxides by >90%. Although TA increased the amount of As in the easily mobilizable As fraction, the stability of As in washed soils increased, with reduced partition indexes of 0.52-0.66 after washing. The maximum capacity of the soils to adsorb TA (qmax) was 50.2-70.4 g C/kg. TA sorption was higher at alkaline than at acidic conditions. Only TA removes As from soils effectively if the proportion of As in amorphous and poorly crystalline oxides is high. Thus, it can be considered for remediation of historically contaminated soils. PMID- 29235922 TI - DNA methylation reprogramming of human cancer cells by expression of a plant 5 methylcytosine DNA glycosylase. AB - Patterns of DNA methylation, an important epigenetic modification involved in gene silencing and development, are disrupted in cancer cells. Understanding the functional significance of aberrant methylation in tumors remains challenging, due in part to the lack of suitable tools to actively modify methylation patterns. DNA demethylation caused by mammalian DNA methyltransferase inhibitors is transient and replication-dependent, whereas that induced by TET enzymes involves oxidized 5mC derivatives that perform poorly understood regulatory functions. Unlike animals, plants possess enzymes that directly excise unoxidized 5mC from DNA, allowing restoration of unmethylated C through base excision repair. Here, we show that expression of Arabidopsis 5mC DNA glycosylase DEMETER (DME) in colon cancer cells demethylates and reactivates hypermethylated silenced loci. Interestingly, DME expression causes genome-wide changes that include both DNA methylation losses and gains, and partially restores the methylation pattern observed in normal tissue. Furthermore, such methylome reprogramming is accompanied by altered cell cycle responses and increased sensibility to anti tumor drugs, decreased ability to form colonospheres, and tumor growth impairment in vivo. Our study shows that it is possible to reprogram a human cancer DNA methylome by expression of a plant DNA demethylase. PMID- 29235923 TI - Oncogenic BRAF mutation induces DNA methylation changes in a murine model for human serrated colorectal neoplasia. AB - Colorectal cancer is a major cause of cancer death and approximately 20% arises within serrated polyps, which are under-recognized and poorly understood. Human serrated colorectal polyps frequently exhibit both oncogenic BRAF mutation and widespread DNA methylation changes, which are important in silencing genes restraining neoplastic progression. Here, we investigated whether in vivo induction of mutant Braf is sufficient to result in coordinated promoter methylation changes for multiple cancer-related genes. The BrafV637E mutation was induced in murine intestine on an FVB;C57BL/6J background and assessed for morphological and DNA methylation changes at multiple time points from 10 days to 14 months. Extensive intestinal hyperplasia developed by 10 days post-induction of the mutation. By 8 months, most mice had murine serrated adenomas with dysplasia and invasive cancer developed in 40% of mice by 14 months. From 5 months onwards, Braf mutant mice showed extensive, gene-specific increases in DNA methylation even in hyperplastic mucosa without lesions. This demonstrates that persistent oncogenic Braf signaling is sufficient to induce widespread DNA methylation changes. This occurs over an extended period of time, mimicking the long latency followed by rapid progression of human serrated neoplasia. This study establishes for the first time that DNA methylation arises slowly in direct response to prolonged oncogenic Braf signaling in serrated polyps; this finding has implications both for chemoprevention and for understanding the origin of DNA hypermethylation in cancer generally. PMID- 29235924 TI - Unplanned stents in thoracic endovascular aortic repair for type B aortic dissection: A 16-year single-center report. AB - Background Unplanned stents in thoracic endovascular aortic repair mean additional stents implantation beyond the preoperative planning to achieve operation success. This study aimed to reveal the prevalence and consequences of unplanned stents in thoracic endovascular aortic repair for type B aortic dissection and explore the reasons, risk factors and solutions for unplanned stents. Methods Retrospectively analysis consecutive patients diagnosed as type B aortic dissection with initial tear originating distal from the left subclavian artery and underwent thoracic endovascular aortic repair from September 1998 to June 2014 in our center. Results Under the criteria, this study enrolled 322 patients, with 83 (25.8%) patients in unplanned group. The incidence rate of unplanned stents in thoracic endovascular aortic repair for type B aortic dissection in each year demonstrates as a bimodal curve. The curve showed that, 2003 and, 2004 was the first and highest peak and 2007 was the second peak. There was no difference in five-year survival rate between planned and unplanned patients (log-rank test, p = 0.994). The unplanned group had higher hospitalization expenses (142,699.08 +/- 78,446.75 yuan vs. 175,238.58 +/- 34,838.01 yuan; p = 0.019), longer operation time (104.50 +/- 93.24 min vs. 179.08 +/- 142.47 min; p < 0.001) and hospitalization time (17.07 +/- 16.62 d vs. 24.00 +/- 15.34 d; p = 0.001). The reasons for unplanned stents were type Ia endoleak (46 patients, 55.4%), bird beak (25 patients, 30.1%), and inappropriate shaping of stent (9 patients, 10.8%). Asymptomatic aortic dissection patients had higher incidence of unplanned stents. Short proximal neck length (2.66 +/- 0.59 mm vs. 2.50 +/- 0.51 mm; p = 0.016), short stent coverage length (154.62 +/- 41.12 mm vs. 133.60 +/- 44.33 mm; p = 0.002), and large distal stent oversize (75.44+/-10.77% vs. 82.68+/-15.80%; p <0.001) were risk factors for unplanned stents in thoracic endovascular aortic repair. Conclusion There are some special risk factors and reasons for unplanned stents in thoracic endovascular aortic repair for type B aortic dissection. Knowing these can we reduce the utilization of unplanned stents with appropriate methods. PMID- 29235925 TI - Left atrial remodelling may predict exercise capacity in obstructive sleep apnoea patients. AB - BACKGROUND: Left atrial volume (LAV) and LA deformation has been proposed as a good marker of exercise performance in patients with diastolic dysfunction (DD). As DD is more prevalent in obstructive sleep apnoea (OSA) we aimed to evaluate the influence of LAV and LA deformation parameters on exercise performance in varying severity of OSA. MATERIALS AND METHODS: OSA was diagnosed after polysomnography. Fifty-five OSA patients were enrolled in the study. OSA patients were divided into two groups with apnoea-hypopna-index (AHI) > 30 and <30. LAV was calculated. LA strain and LA strain rates were assessed with speckle tracking echocardiography (STE). Exercise capacity was evaluated by treadmill exercise test. RESULTS: MET values were lower in group II compared to group I (p < .05). Echocardiographic findings: Comparison within groups: In both groups E/E', LA stain, LA strain rate S and LA strain rate E were higher after exercise than before (p < .05). In group I LA strain rate A was higher after exercise than before (p < .05). Comparison between groups: LA strain, LA strain rate S, LA strain rate E and LA strain rate A were lower and E/E' and LAVI were higher in group II compared to group I before and after exercise (p < .05). Correlation with METs: AHI, LVEDV, E/E' and LAVI were negatively and LA strain was positively correlated with METs (p < .05). CONCLUSIONS: Left ventricular diastolic dysfunction is more prevalent in severe OSA and is associated with impaired exercise performance. Additionally, LA remodelling may predict exercise capacity in this subgroup of patients. PMID- 29235926 TI - Effect of powdered activated carbon dosage on sludge properties and membrane bioreactor performance in a hybrid MBR-PAC system. AB - An improved insight into the effect of powdered activated carbon (PAC) on membrane fouling is crucial to the MBR performance. Sludge key property, soluble microbial products (SMP) and transmembrane pressure (TMP) were monitored. The membrane fouling rate in the MBRs was also analyzed based on TMP profile and resistance-in-series model. PAC reduced the membrane filtration resistance and significantly decreased the fouling rate. The sludge filterability was improved by extending the filtration time by almost twofold. PAC affected the SMP release and protein/polysaccharide (carbohydrate) was in a lower ratio. Fourier transform infrared (FTIR) analysis indicated that PAC decreased the impact of organic carbon, and reduced the proteins' and polysaccharides' absorption and deposition on the membrane surface and in the pores. The degree of reversible and irreversible fouling was related to the PAC content added into the MBRs. At the optimum dosage of 2 g/L, the results signified the PAC potential as a mitigation strategy of membrane fouling. PMID- 29235928 TI - Hydrogen and syngas production by catalytic gasification of algal biomass (Cladophora glomerata L.) using alkali and alkaline-earth metals compounds. AB - The steam gasification of algal biomass (Cladophora glomerata L.) in presence of alkali and alkaline-earth metal compounds catalysts was studied to enhance the yield of syngas and reduce its tar content through cracking and reforming of condensable fractions. The commercial catalysts used include NaOH, KHCO3, Na3PO4 and MgO. The gasification runs carried out with a research scale, biomass gasification unit, show that the NaOH has a strong potential for production of hydrogen, along with the added advantages of char converting and tar destruction, allowing enhancement of produced syngas caloric value. When the temperature increased from 700 degrees C to 900 degrees C, the tar content in the gas sharply decreased, while the hydrogen yield increased. Increasing steam/biomass ratio significantly increased hydrogen yield and tar destruction; however, the particle size in the range of 0.5-2.5 mm played a minor role in the process. PMID- 29235927 TI - Risk factors for hospital death in conditions needing palliative care: Nationwide population-based death certificate study. AB - BACKGROUND: Most people would prefer to die at home as opposed to hospital; therefore, understanding mortality patterns by place of death is essential for health resources allocation. AIM: We examined trends and risk factors for hospital death in conditions needing palliative care in a country without integrated palliative care. DESIGN: This is a death certificate study. We examined factors associated with hospital death using logistic regression. SETTING/PARTICIPANTS: All adults (1,045,381) who died between 2003 and 2012 in Portugal were included. We identified conditions needing palliative care from main causes of death: cancer, heart/cerebrovascular, renal, liver, respiratory and neurodegenerative diseases, dementia/Alzheimer's/senility and HIV/AIDS. RESULTS: Conditions needing palliative care were responsible for 70.7% deaths ( N = 738,566, median age 80); heart and cerebrovascular diseases (43.9%) and cancer (32.2%) accounted for most. There was a trend towards hospital death (standardised percentage: 56.3% in 2003, 66.7% in 2012; adjusted odds ratio: 1.04, 95% confidence interval: 1.04-1.04). Hospital death risk was higher for those aged 18-39 years (3.46, 3.25-3.69 vs aged 90+), decreasing linearly with age; lower in dementia/Alzheimer's/senility versus cancer (0.13, 0.13-0.13); and higher for the married and in HIV/AIDS (3.31, 3.00-3.66). Effects of gender, working status, weekday and month of death, hospital beds availability, urbanisation level and deprivation were small. CONCLUSION: The upward hospital death trend and fact that being married are risk factors for hospital death suggest that a reliance on hospitals may coexist with a tradition of extended family support. The sustainability of this model needs to be assessed within the global transition pattern in where people die. PMID- 29235929 TI - The nomological network of emotion knowledge and emotion understanding in adults: evidence from two new performance-based tests. AB - Emotion understanding, which can broadly be defined as expertise in the meaning of emotion, is a core component of emotional intelligence and facilitates better intra- and interpersonal outcomes. However, to date only very few standard tests to measure emotion understanding in healthy adults exist. Here, we present two new performance-based tests that were developed and are scored based on componential emotion theory and large-scale cross-cultural empirical findings. These instruments intend to measure facets of emotion understanding that are not included in existing tests. The first test (Geneva EMOtion Knowledge test - Blends; GEMOK-Blends) measures the ability to understand and label emotional experiences of a target person from a description of emotion features covering five emotion components (appraisal, feeling, action tendencies, expression, and physiology) embedded in a written vignette. The second test (GEMOK-Features) measures semantic knowledge about which features from each component are characteristic of emotion episodes described by a specific emotion label. In four studies, we found evidence for the good internal consistency and construct validity of these tests. Both tests were positively correlated with other emotional abilities and cognitive ability and showed meaningful associations with a variety of personality and demographic variables. PMID- 29235930 TI - Author's Response. PMID- 29235931 TI - Impact of poly dimethyldiallylammonium chloride on membrane fouling mitigation in a membrane bioreactor. AB - Poly dimethyldiallylammonium chloride (PDMDAAC) was applied in a membrane bioreactor (MBR) to study its effects on mitigation of MBR membrane fouling. Floc size, zeta potential, soluble microbial substances (SMP) and extracellular polymeric substances (EPS) secretion were studied with respect to PDMMAAC-dosing operations. Results demonstrated that a sustainable filtration cycle extended 3.3 times with the optimal PDMDAAC dosage of 90 mg L-1. The addition of PDMDAAC could increase zeta potential of sludge floc, which led to the decrease in repulsive electrostatic interactions between flocs, as well as the facilitation of flocs-to flocs aggregation. With the optimal dosage of PDMDAAC, the mean size of sludge was 3.23 +/- 0.55 times higher than the control group, resulting in higher impact resistance and better adaptive capacity to the changing environment, which led to less SMP secretion. Moreover, a high contaminants removal rate was achieved in the reactor that was dosed with PDMDAAC. The average effluent concentrations of chemical oxygen demand and total nitrogen were less than 45.6 +/- 2.85 and 5.23 +/- 0.61 mg L-1, respectively, and the corresponding removal rates were 93.1 +/- 5.81% and 89.1 +/- 9.61%. PMID- 29235932 TI - Retrospective study of the presentation, diagnosis and management of 16 cats with otitis media not due to nasopharyngeal polyp. AB - OBJECTIVES: The aim of this study was to analyse retrospectively cats diagnosed with otitis media (OM) not due to nasopharyngeal polyp, and to review the clinical outcome with surgical and medical management. METHODS: Patient records were searched for cats diagnosed with OM. The diagnosis of OM was based on the presence of clinical signs, including neurological signs, respiratory signs and signs of otitis externa, and on the basis of evidence of thickened or irregular bullae walls, or the presence of fluid within the tympanic cavity in those that had diagnostic imaging. In those that did not have imaging, the diagnosis was made on the basis of the presence of fluid in the bulla or organisms cultured using myringotomy. These records were analysed retrospectively. RESULTS: Of 16 cats, one had a total ear canal ablation, five had ventral bulla osteotomy surgery and 11 were medically managed. Of the cats that were medically managed, using either topical products, systemic antimicrobials or a combination of both, eight had complete resolution of clinical signs. CONCLUSIONS AND RELEVANCE: This small cohort shows that some cats with OM can be successfully managed medically. Surgery is invasive and may not necessarily be required if appropriate medical management is undertaken. This is the first study of OM treatment in cats and provides the basis for further studies, which should aim to establish specific infectious causes of OM and how they can potentially be managed with medical therapies. PMID- 29235934 TI - Learning from guidelines on the sexual healthcare of men who have sex with men. AB - The British Association for Sexual Health and HIV (BASHH) United Kingdom national guideline on the sexual health care of men who have sex with men (MSM) was published in electronic format in this journal in 2018. In common with other BASHH guidelines, the document fulfils the dual role of scrutinising and evaluating the available evidence according to the accredited Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, as well as the often more challenging job of codifying and summarising expert opinion in areas where the evidence base is incomplete or lacking. In addition to the learning gained from developing the recommendations included in the final document, further benefit was derived from the process through a number of learning and development actions for the writing group and through this the MSM special interest group and the wider sexual health community. PMID- 29235933 TI - Faster ticking rate of the epigenetic clock is associated with faster pubertal development in girls. AB - Epigenetic age is an indicator of biological aging, capturing the impact of environmental and behavioral influences across time on cellular function. Deviance between epigenetic age and chronological age (AgeAccel) is a predictor of health. Pubertal timing has similarly been associated with cancer risk and mortality rate among females. We examined the association between AgeAccel and pubertal timing and adolescent breast composition in the longitudinal Growth and Obesity Cohort Study. AgeAccel was estimated in whole blood using the Horvath method at breast Tanner 2 (B2) and 4 (B4). Total breast volume, absolute fibro glandular volume (FGV), and %FGV were evaluated at B4 using dual X-ray absorptiometry. The impact of AgeAccel (mean: 0; SD: 3.78) across puberty on the time to breast development (thelarche), menarche, and pubertal tempo (thelarche to menarche) was estimated using accelerated failure time models; generalized estimating equations were used to evaluate associations with breast density. A five-year increase in average adolescent AgeAccel was associated with a significant decrease in time to menarche [hazard ratio (HR): 1.37; 95% confidence interval (CI): 1.04, 1.80] adjusting for birth weight, maternal pre-pregnancy body mass index, maternal height, maternal education, B2 height, fat percentage, and cell composition. AgeAccel displayed a stronger inverse association with pubertal tempo (HR: 1.48; 95% CI: 1.10, 1.99). A five-year increase in AgeAccel was associated with 5% greater %FGV, adjusting for B4 percent body fat, and maternal traits (95% CI: 1.01, 1.10). Our study provides unique insight into the influence of AgeAccel on pubertal development in girls, which may have implications for adult health. PMID- 29235935 TI - Interplay of Gravicentric, Egocentric, and Visual Cues About the Vertical in the Control of Arm Movement Direction. AB - Our perception of the vertical corresponds to the weighted sum of gravicentric, egocentric, and visual cues. Here we evaluate the interplay of those cues not for the perceived but rather for the motor vertical. Participants were asked to flip an omnidirectional switch down while their egocentric vertical was dissociated from their visual-gravicentric vertical. Responses were directed mid-between the two verticals; specifically, the data suggest that the relative weight of congruent visual-gravicentric cues averages 0.62, and correspondingly, the relative weight of egocentric cues averages 0.38. We conclude that the interplay of visual-gravicentric cues with egocentric cues is similar for the motor and for the perceived vertical. Unexpectedly, we observed a consistent dependence of the motor vertical on hand position, possibly mediated by hand orientation or by spatial selective attention. PMID- 29235936 TI - Ego involvement increases doping likelihood. AB - Achievement goal theory provides a framework to help understand how individuals behave in achievement contexts, such as sport. Evidence concerning the role of motivation in the decision to use banned performance enhancing substances (i.e., doping) is equivocal on this issue. The extant literature shows that dispositional goal orientation has been weakly and inconsistently associated with doping intention and use. It is possible that goal involvement, which describes the situational motivational state, is a stronger determinant of doping intention. Accordingly, the current study used an experimental design to examine the effects of goal involvement, manipulated using direct instructions and reflective writing, on doping likelihood in hypothetical situations in college athletes. The ego-involving goal increased doping likelihood compared to no goal and a task-involving goal. The present findings provide the first evidence that ego involvement can sway the decision to use doping to improve athletic performance. PMID- 29235937 TI - The impact of Genetically Modified (GM) crops in modern agriculture: A review. AB - Genetic modification in plants was first recorded 10,000 years ago in Southwest Asia where humans first bred plants through artificial selection and selective breeding. Since then, advancements in agriculture science and technology have brought about the current GM crop revolution. GM crops are promising to mitigate current and future problems in commercial agriculture, with proven case studies in Indian cotton and Australian canola. However, controversial studies such as the Monarch Butterfly study (1999) and the Seralini affair (2012) along with current problems linked to insect resistance and potential health risks have jeopardised its standing with the public and policymakers, even leading to full and partial bans in certain countries. Nevertheless, the current growth rate of the GM seed market at 9.83-10% CAGR along with promising research avenues in biofortification, precise DNA integration and stress tolerance have forecast it to bring productivity and prosperity to commercial agriculture. PMID- 29235938 TI - Free radical behaviours during methylene blue degradation in the Fe2+/H2O2 system. AB - Behaviours of the free radicals during the methylene blue (MB) oxidation process in the Fe2+/H2O2 system were studied to reveal the reason for the low utilization efficiency of H2O2. The roles of [Formula: see text], [Formula: see text] and [Formula: see text] radicals were proven to be different in the MB oxidation process. The results showed that [Formula: see text] radicals had a strong ability to oxidize MB; however, they were not the main active substances for MB degradation due to the low concentration in the traditional Fe2+/H2O2 system. [Formula: see text] radicals could not oxidize MB. [Formula: see text] radicals were the main active substances for MB oxidation. In the short initial stage, the utilization efficiency of H2O2 was high, because the generation rate of [Formula: see text] was much higher than that of [Formula: see text]. More [Formula: see text] radicals were involved in the MB oxidation reaction. In the long deceleration stage (after the short initial stage), a large amount of H2O2 was consumed, but the amount of oxidized MB was very small. Most of the [Formula: see text] radicals were consumed via the rapid useless reaction between [Formula: see text] and [Formula: see text] in this stage, resulting in the serious useless consumption of H2O2. It is a feasible method to improve the utilization efficiency of H2O2 by adding suitable additives into the Fe2+/H2O2 system to weaken the useless reaction between [Formula: see text] and [Formula: see text]. PMID- 29235939 TI - Are shoulder counter rotation and hip shoulder separation angle representative metrics of three-dimensional spinal kinematics in cricket fast bowling? AB - This study aimed to investigate the relationship between shoulder counter rotation (SCR), hip shoulder separation (HSS) and three-dimensional spinal kinematics during fast bowling in cricket. Thirty five elite male fast bowlers were analysed using three-dimensional inertial sensors on the spine. Lumbar, thoracic and thoracolumbar kinematics were determined during the delivery stride. Spearman's pairwise correlations displayed significant associations between SCR, thoracic and thoracolumbar lateral flexion between the back foot impact and max contralateral rotation phase of the delivery stride (rs = -.462 and -.460). HSS and thoracolumbar lateral flexion displayed a significant correlation between back foot impact and max contralateral rotation (rs = -.552). No other significant correlations were observed. These results suggest SCR and HSS are modestly related to lateral flexion, leaving a large component of SCR and HSS unrelated to specific three-dimensional spinal kinematics. It is possible that this represents changes in whole spinal orientation and not resultant spinal motion. Despite this, SCR remains the only metric currently related to injury and therefore is important; however it is only a very modest proxy for more traditional descriptions of spinal motion. PMID- 29235941 TI - Ethical Challenges in Community-Based Participatory Research: A Scoping Review. AB - Ethical challenges in community-based participatory research (CBPR) are of increasing interest to researchers; however, it is not known how widespread these challenges are or how extensively the topic has been explored. Using Arksey and O'Malley's scoping review method, studies on ethical challenges in CBPR were mapped. Findings indicate that researchers continue to raise questions about ethics associated with CBPR. Our purpose in this article is to present a thematic summary of international ethical challenges as a guide for researchers interested in community participatory approaches and to better prepare them for qualitative health research with communities. PMID- 29235940 TI - SLC9B1 methylation predicts fetal intolerance of labor. AB - Fetal intolerance of labor is a common indication for delivery by Caesarean section. Diagnosis is based on the presence of category III fetal heart rate tracing, which is an abnormal heart tracing associated with increased likelihood of fetal hypoxia and metabolic acidemia. This study analyzed data from 177 unique women who, during their prenatal visits (7-15 weeks and/or 24-32 weeks) to Atlanta area prenatal care clinics, consented to provide blood samples for DNA methylation (HumanMethylation450 BeadChip) and gene expression (Human HT-12 v4 Expression BeadChip) analyses. We focused on 57 women aged 18-36 (mean 25.4), who had DNA methylation data available from their second prenatal visit. DNA methylation patterns at CpG sites across the genome were interrogated for associations with fetal intolerance of labor. Four CpG sites (P value <8.9 * 10 9, FDR <0.05) in gene SLC9B1, a Na+/H+ exchanger, were associated with fetal intolerance of labor. DNA methylation and gene expression were negatively associated when examined longitudinally during pregnancy using a linear mixed effects model. Positive predictive values of methylation of these four sites ranged from 0.80 to 0.89, while negative predictive values ranged from 0.91 to 0.92. The four CpG sites were also associated with fetal intolerance of labor in an independent cohort (the Johns Hopkins Prospective PPD cohort). Therefore, fetal intolerance of labor could be accurately predicted from maternal blood samples obtained between 24-32 weeks gestation. Fetal intolerance of labor may be accurately predicted from maternal blood samples obtained between 24-32 weeks gestation by assessing DNA methylation patterns of SLC9B1. The identification of pregnant women at elevated risk for fetal intolerance of labor may allow for the development of targeted treatments or management plans. PMID- 29235942 TI - The Process of Adaptation Following a New Diagnosis of Type 1 Diabetes in Adulthood: A Meta-Synthesis. AB - While Type 1 diabetes (T1D) is generally associated with childhood, half of all cases occur in adulthood. The adaptive strategies individuals employ during the initial adaptive phase may have an important impact on their risk of future diabetes complications and their psychosocial well-being. We conducted a systematic review of six databases and included nine qualitative studies in a meta-synthesis, the aims of which were to develop a better understanding of how adults newly diagnosed with T1D experience the diagnosis and the phenomena associated with the early process of adaptation to life with diabetes. The meta synthesis identified five constructs that shaped and influenced the early adaptive process: disruption, constructing a personal view of diabetes, reconstructing a view of self, learning to live with diabetes, and behavioral adaptations. The adaptive processes of adults to a diabetes diagnosis are highly referenced to prior life experiences, social habitus, and psychological orientation. PMID- 29235943 TI - "Trapped in an Empty Waiting Room"-The Existential Human Core of Loneliness in Old Age: A Meta-Synthesis. AB - Loneliness in old age has a negative influence on quality of life, health, and survival. To understand the phenomenon of loneliness in old age, the voices of lonely older adults should be heard. Therefore, the purpose of this meta synthesis was to synthesize scientific studies of older adults' experiences of loneliness. Eleven qualitative articles that met the inclusion criteria were analyzed and synthesized according to Noblit and Hare's meta-ethnographic approach. The analysis revealed the overriding meaning of the existential human core of loneliness in old age expressed through the metaphor "trapped in an empty waiting room." Four interwoven themes were found: (a) the negative emotions of loneliness, (b) the loss of meaningful interpersonal relationships, (c) the influence of loneliness on self-perception, and (d) the older adults' endeavors to deal with loneliness. The joint contribution of family members, health care providers, and volunteers is necessary to break the vicious circle of loneliness. PMID- 29235945 TI - In Nurses We Trust. PMID- 29235944 TI - Experience of Touch in Health Care: A Meta-Ethnography Across the Health Care Professions. AB - Touch mediates health professionals' interactions with patients. Different professionals have reported their practices but what is currently lacking is a well-theorized, interprofessional synthesis. We systematically searched eight databases, identified 41 studies in seven professions-nursing (27), medicine (4), physiotherapy (5), osteopathy (1), counseling (2), psychotherapy (1), dentistry (1)-and completed a meta-ethnographic line-of-argument synthesis. This found that touch is caring, exercises power, and demands safe space. Different professions express care through the medium of touch in different ways. They all, however, expect to initiate touch rather than for patients to do so. Various practices negotiate boundaries that define safe spaces between health care professions and patients. A metaphor-the waltz-integrates the practice of touch. Health care professionals connect physically with patients in ways that form strong relationships between them while "dance steps" help manage the risk that is inherent in such an intimate form of connection. PMID- 29235947 TI - Betrayal in Teaching-Learning: A Sword in the Heart. AB - In this article, the human experience of betrayal is explored within teaching learning, where trust might be expected and the notion of betrayal might seem counterintuitive. To gain insight into this experience, the unique perspectives of an undergraduate student, a graduate student, and a new faculty are considered through the stories they shared with the author about betrayal in teaching learning. The humanbecoming paradigm provided a unique perspective to view these stories and explore the unlimited possibilities emerging when human dignity and freedom to choose are honored. PMID- 29235948 TI - Integrative Literature Review on Shame. AB - Shame is a universal living experience that is just beginning to be explored within the discipline of nursing. Development of a broad understanding of shame is needed to aid nurse researchers in clarifying this phenomenon from a nursing perspective. Pursuant to this goal, the author in this article reviews the extant literature on shame from the disciplines of nursing, psychology, sociology, philosophy, and theology. Three themes that emerged from the scholarly literature were (a) shame propels miring in paralysis, (b) shame captures the illusionary seen-unseen, and PMID- 29235949 TI - Will Nursing Continue as the Most Trusted Profession? An Ethical Overview. AB - Trust-mistrust is a paradoxical rhythm found in all healthcare disciplines. The discipline of nursing has traditionally been regarded as the most trusted. What are the ethical obligations for professional nurses in establishing community relationships of trust according to societal needs and desires? Specifically, the author seeks to conceptualize and discern potential implications for fiduciary trust and the future of nursing as a healthcare discipline. PMID- 29235950 TI - Thoughts About Advancement of the Discipline: Dark Clouds and Bright Lights. AB - In this essay, several nurse scholars who are particularly concerned about the contemporary state of nursing science present their specific concerns (dark clouds) about the advancement of our discipline and the ways in which the concerns have been addressed (bright lights). This essay is the first of two essays that were catalyzed by Barrett's paper, "Again, What Is Nursing Science?" The second essay will be published in the next issue Nursing Science Quarterly. PMID- 29235951 TI - With A Kiss: Betrayal. AB - The author in this article explores theoretical perspectives on the humanbecoming ethical tenet of betrayal. Perspectives on betrayal include betrayal as a breach of promise, a betrayal continuum, betrayal as incidental and intentional, betrayal as moral injury, betrayal trauma, and the humanbecoming perspective of betrayal linked to feeling disappointed. PMID- 29235952 TI - Public Dialogue in Nursing and Healthcare. AB - Dialogue between two scholars on the importance of engagement with consumers as well as professionals. Social media is emphasized as a critical mode of communication. PMID- 29235953 TI - Persistent Pain: Nursing Perspectives. AB - Pain has diligently been regarded by scholars of different disciplines, and yet the experience of pain for patients and families can be minimized and relegated to a more perfunctory place. Pain, particularly persistent pain, warrants attention and to not fully attend to pain betrays and does not honor human dignity warranted by patients and families cared for within nursing and the larger healthcare community. PMID- 29235954 TI - Persistent Pain in Older Adults: Roy's Adaptation Model. AB - Persistent pain in older adults is difficult to assess and therefore address consistently. The experience of pain is individual, and therefore a comprehensive way to assess pain is required. Roy's adaptation model offers a systematic way of evaluating pain in the older adult. In this column, the author shares some statistics about persistent pain and a case study using Roy's model as a system for assessment. PMID- 29235955 TI - What's New With NSQ? PMID- 29235956 TI - The Experience of Korean Nurses During the Middle East Respiratory Syndrome Outbreak. AB - The authors in this article explore the experiences of eight South Korean nurses during an outbreak of the Middle East Respiratory Syndrome (MERS), which took place in the fall of 2015. These nurses were mandated to remain in isolation in an intensive care unit (ICU) dedicated to the treatment of the patients with the MERS virus for 7 days. Parse's humanbecoming theory was used to frame the discussion. Three themes found in the nurse's stories are discussed: feeling hopeless and cut off, feeling shame and overworked, and feeling pride in fulfilling a duty. The nurses discuss how they overcame the difficulties of their situation, which ultimately reinforced their identities as nurses. PMID- 29235957 TI - Feeling Peaceful: A Universal Living Experience. AB - The purpose of this study was to investigate the living experience of feeling peaceful. Parse's research method was used to answer the question: What is the structure of the living experience of feeling peaceful? Twelve participants living in a community consented to partake in the study. The central finding of the study is the structure: feeling peaceful is contentedness amid tribulation, as unburdening surfaces with devout involvements. The findings are discussed in relation to the humanbecoming school of thought and extant literature. PMID- 29235958 TI - Caring Science or Science of Caring. AB - The concepts caring science and science of caring have different meanings; however, they are often used interchangeably. The purpose of this paper is to present an overview of the synthesis of the scholarly literature on the definitions of the science of caring and caring science and to affirm the authors' perspective relating to the language of caring science. Caring science advances the epistemology and ontology of caring. Ideas related to caring science inquiry are presented, and the authors acknowledge the future of caring science as unitary caring science. PMID- 29235959 TI - Rediscovering the Art of Nursing to Enhance Nursing Practice. AB - There is wide agreement that nursing practice is a combination of art and science. While the science is easily found in nursing education, research, and practice, the art is overshadowed. Philosophical and theoretical discussions on the art of nursing are plentiful, but research demonstrating its importance to nursing practice is lacking. In this article, the nature of nursing is explored separate from science, and a comprehensive exploration of the literature on the art of nursing is presented. Three themes concerning the art of nursing are identified and discussed, including implications for research, practice, and education. PMID- 29235960 TI - The Living Experience of Suffering: Lakota Voices. AB - Suffering, as a universal humanuniverse living experience, was explored utilizing the Parsesciencing mode of inquiry. Ten Lakota historians engaged in discussion to answer the question, "What is your experience of suffering?" The discovery revealed the discerning extant moment of suffering as follows: Suffering is burdening anguish amid uplifting aspirations surfacing in persevering with divergent encounters. PMID- 29235961 TI - Big Data: Its Meaning. PMID- 29235962 TI - Perspectives on Policy and the Value of Nursing Science in a Big Data Era. AB - As data volume explodes, nurse scientists grapple with ways to adapt to the big data movement without jeopardizing its epistemic values and theoretical focus that celebrate while acknowledging the authority and unity of its body of knowledge. In this article, the authors describe big data and emphasize ways that nursing science brings value to its study. Collective nursing voices that call for more nursing engagement in the big data era are answered with ways to adapt and integrate theoretical and domain expertise from nursing into data science. PMID- 29235963 TI - Prevent Betrayal by Predatory Publishers: Trust But Verify. AB - In this column, the concept of betrayal is considered as it relates to publishing. The definition of betrayal is discussed, followed by information regarding the cost of publishing and why this led to the formation of open access publishing as a remedy. The Gold and Green Open Access models are examined along with why they may have inadvertently set the stage for predatory publishing practices. Finally, information will be provided on how to spot and avoid betrayal on the part of predatory publishers. PMID- 29235964 TI - Star Light, Star Bright. PMID- 29235965 TI - Philosophical Issues and Nursing Science. AB - The author of this article introduces a new column that will explore philosophical issues of concern to nurse scientists. In this initial column, I review the general terrain of philosophy in nursing science and explore some philosophical issues relevant to theory development. One conclusion is that inquiry into philosophical issues may help expand our repertoire of conceptual tools useful in building scientific knowledge and facilitating theoretical progress. PMID- 29235966 TI - The characteristics of antibodies of mice immunized by human unconventional myosin 1c. AB - Specific antibodies produced against a protein of interest are invaluable tools for monitoring the protein structure, intracellular location and biological activity. Inoculation of murine lymphoma cells into the peritoneal cavity of immunized mice provides generation of ascitic fluid containing a significant amount of antibody with desired antigen specificity. Here we demonstrated that the intraperitoneal administration of murine lymphoma NK/Ly cells in mice immunized with 48 kDa isoform of human blood serum unconventional myosin 1c leads to generation of ascitic fluid that contained specific IgG-antibodies. These antibodies were capable of binding of the unconventional myosin 1c isolated from blood serum of patients with multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosis, and could be used for diagnostics of several autoimmune diseases, the multiple sclerosis in particular. PMID- 29235967 TI - Effect of alternating postures on cognitive performance for healthy people performing sedentary work. AB - Prolonged sitting is a risk factor for several diseases and the prevalence of worksite-based interventions such as sit-to-stand workstations is increasing. Although their impact on sedentary behaviour has been regularly investigated, the effect of working in alternating body postures on cognitive performance is unclear. To address this uncertainty, 45 students participated in a two-arm, randomised controlled cross-over trial under laboratory conditions. Subjects executed validated cognitive tests (working speed, reaction time, concentration performance) either in sitting or alternating working postures on two separate days (ClinicalTrials.gov Identifier: NCT02863731). MANOVA results showed no significant difference in cognitive performance between trials executed in alternating, standing or sitting postures. Perceived workload did not differ between sitting and alternating days. Repeated measures ANOVA revealed significant learning effects regarding concentration performance and working speed for both days. These results suggest that working posture did not affect cognitive performance in the short term. Practitioner Summary: Prior reports indicated health-related benefits based on alternated (sit/stand) body postures. Nevertheless, their effect on cognitive performance is unknown. This randomised controlled trial showed that working in alternating body postures did not influence reaction time, concentration performance, working speed or workload perception in the short term. PMID- 29235968 TI - Mycobacterial blood culture as the only means of diagnosis of disseminated tuberculosis in advanced HIV infection. AB - The diagnosis of disseminated tuberculosis (TB) in advanced HIV infection is often delayed because of difficulty in obtaining suitable specimens for culture. A total of 32 such patients from South India with positive mycobacterial blood cultures were studied over ten years. Almost all (90%) had a febrile illness and the majority (68.7%) had clinical lung involvement, but only 27.3% had positive sputum smears. Liver biopsy yielded a positive diagnosis in only 1/7. Cytopenia was almost universal (96.9%). Bone marrow cultures were, however, positive in 54.8%, of whom one-quarter grew atypical mycobacteria. Mycobacterial blood culture is therefore a useful adjunct test to diagnose TB in advanced HIV. PMID- 29235970 TI - DIRECTING DRUG EVOLUTION. AB - Directed evolution is poised to change small molecule discovery and provide greater access to "drug space." Sarah Webb looks into the evolving drug discovery landscape. PMID- 29235969 TI - Chikungunya-dengue co-infection during pregnancy requiring preterm Caesarean section: first case report from Bangladesh. AB - We report the first case of chikungunya-dengue co-infection during pregnancy requiring emergency Caesarean section (CS) because of fetal distress in a Bangladeshi primigravida. Though previously unreported, this situation may become increasingly common. PMID- 29235971 TI - Western blot analysis of cells encapsulated in self-assembling peptide hydrogels. AB - Continuous optimization of in vitro analytical techniques is ever more important, especially given the development of new materials for tissue engineering studies. In particular, isolation of cellular components for downstream applications is often hindered by the presence of biomaterials, presenting a major obstacle in understanding how cell-matrix interactions influence cell behavior. Here, we describe an approach for western blot analysis of cells that have been encapsulated in self-assembling peptide hydrogels (SAPHs), which highlights the need for complete solubilization of the hydrogel construct. We demonstrate that both the choice of buffer and multiple cycles of sonication are vital in obtaining complete solubilization, thereby enabling the detection of proteins otherwise lost to SAP aggregation. Moreover, we show that the presence of self assembling peptides (SAPs) does not interfere with the standard immunoblotting technique, offering the potential for use in more full-scale proteomic studies. PMID- 29235972 TI - Decoding DNA labels by melting curve analysis using real-time PCR. AB - Synthetic DNA has been used as an authentication code for a diverse number of applications. However, existing decoding approaches are based on either DNA sequencing or the determination of DNA length variations. Here, we present a simple alternative protocol for labeling different objects using a small number of short DNA sequences that differ in their melting points. Code amplification and decoding can be done in two steps using quantitative PCR (qPCR). To obtain a DNA barcode with high complexity, we defined 8 template groups, each having 4 different DNA templates, yielding 158 (>2.5 billion) combinations of different individual melting temperature (Tm) values and corresponding ID codes. The reproducibility and specificity of the decoding was confirmed by using the most complex template mixture, which had 32 different products in 8 groups with different Tm values. The industrial applicability of our protocol was also demonstrated by labeling a drone with an oil-based paint containing a predefined DNA code, which was then successfully decoded. The method presented here consists of a simple code system based on a small number of synthetic DNA sequences and a cost-effective, rapid decoding protocol using a few qPCR reactions, enabling a wide range of authentication applications. PMID- 29235973 TI - Linear array of multi-substrate tracts for simultaneous assessment of cell adhesion, migration, and differentiation. AB - Cell migration, which is central to a wide variety of life processes, involves integration of the extracellular matrix (ECM) with the internal cytoskeleton and motor proteins via receptors spanning the plasma membrane. Cell migration can be induced by a variety of signals, including gradients of external soluble molecules, differences in ECM composition, or electrical gradients. Current in vitro methods to study cell migration only test one substrate at a time. Here, we present a method for assessing cell adhesion, migration, and differentiation in up to 20 different test conditions simultaneously, using only minute amounts of target substrate. Our system, which we call the linear array of multi-substrate cell migration assay (LAMA), has two configurations for direct comparison of one or two cell types in response to an array of ECM constituents under the same culture conditions. This culture model utilizes only nanogram amounts of test substrates and a minimal number of cells, which maximizes the use of limited and expensive test reagents. Moreover, LAMA can also be used for high-throughput screening of potential pharmaceuticals that target ECM-dependent cell behavior and differentiation. PMID- 29235975 TI - Preparing thin cross sections of Arabidopsis roots without embedding. AB - Here, we describe a method for obtaining thin cross sections of Arabidopsis thaliana roots without fixation and embedding. Roots were grown in pinholes made in a solidified growth medium, and cross sections were prepared without pretreatment. Using this method, we detected unique distributions of two polar localized proteins-green fluorescent protein (GFP)-tagged BOR1 and NIP5;1-with less sample preparation time than conventional methods. This method is simple, rapid, and yields high-quality cross-section images that are free from artifacts commonly associated with embedding or the sample preparation procedures used in many conventional methods. PMID- 29235974 TI - Processing fixed and stored adipose-derived stem cells for quantitative protein array assays. AB - Accurately characterizing cellular subpopulations is essential for elucidating the mechanisms underlying normal and pathological biology. Isolation of specific cell types can be accomplished by labeling unique cell-associated proteins with fluorescent antibodies. Cell fixation is commonly used to prepare these samples and allow for long-term storage, but this poses challenges for subsequent protein analysis. We previously established the FITSAR (formaldehyde-fixed intracellular target-sorted antigen retrieval) method, in which protein can be isolated and characterized from fixed, enriched cell subpopulations. Here, we improve on this method by allowing compatibility with highly sensitive multiplex protein arrays and demonstrating applicability to long-term stored samples. Feasibility experiments demonstrated parallel detection of cell adhesion molecules (CAMs) using an enzyme-linked immunosorbent assay (ELISA) panel with human adipose derived stem cells (ASCs) stored for up to 1 month. PMID- 29235976 TI - Litoribrevibacter euphylliae sp. nov., isolated from the torch coral Euphyllia glabrescens. AB - Strain Eup a-2T, isolated from the torch coral Euphyllia glabrescens, was characterized using a polyphasic taxonomy approach. Cells of strain Eup a-2T were Gram-negative, aerobic and motile by three polar flagella and formed translucent colonies. Optimal growth occurred at 25 degrees C, pH 6-8 and in the presence of 2-4 % NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Eup a-2T belonged to the genus Litoribrevibacter and showed the highest levels of sequence similarity with respect to Litoribrevibacter albus Y32T (97.8 %). Strain Eup a-2T contained summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C16 : 0 as the predominant fatty acids. The predominant isoprenoid quinone was Q-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphophatidylglycerol. Genomic DNA G+C content of strain Eup a-2T was 49.1 mol%. The DNA-DNA hybridization value for strain Eup a-2T with L. albus Y32T was less than 30 %. Differential phenotypic properties, together with the phylogenetic inference, demonstrate that strain Eup a-2T should be classified as a novel species of the genus Litoribrevibacter, for which the name Litoribrevibactereuphylliae sp. nov. is presented. The type strain is Eup a-2T (=BCRC 81004T=LMG 29725T=KCTC 52438T). PMID- 29235977 TI - Proprotein convertase subtilisin/kexin type 9 inhibits hepatitis C virus replication through interacting with NS5A. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease actively involved in regulating lipid homeostasis. Although PCSK9 has been shown to inhibit hepatitis C virus (HCV) entry and replication, the underlying mechanisms have not been thoroughly characterized. Moreover, whether PCSK9 regulates HCV translation and assembly/secretion has not been determined. We therefore further studied the effects of PCSK9 on the HCV life cycle. We showed that PCSK9 did not affect HCV translation or assembly/secretion. Overexpression of PCSK9 inhibited HCV replication in HCV genomic replicon cells in a dose dependent manner and after cell culture-derived HCV (HCVcc) infection. Knocking down PCSK9 increased HCV replication. The gain-of-function (D374Y) or loss-of function (Deltaaa. 31-52) PCSK9 mutants for low-density lipoprotein receptor (LDLR) degradation had no effect on HCV replication, suggesting that HCV replication inhibition by PCSK9 was not due to LDLR degradation. The uncleaved ProPCSK9, but not cleaved PCSK9, down-regulated HCV replication, suggesting that the auto-cleavage of PCSK9 affected HCV replication. We also found that PCSK9 interacted with NS5A through NS5A aa. 95-215, and this region played an important role in NS5A dimerization, NS5A-RNA binding and was essential for HCV replication. More importantly, NS5A dimerization and NS5A-RNA binding were suppressed by PCSK9 upon interaction. These results suggested that PCSK9 inhibited HCV replication through interaction with NS5A. Our study should help optimize anti-HCV treatment regimen in patients with abnormal lipid profiles. PMID- 29235978 TI - Rigid amphipathic fusion inhibitors demonstrate antiviral activity against African swine fever virus. AB - Rigid amphipathic fusion inhibitors (RAFIs) are a family of nucleoside derivatives that inhibit the infectivity of several enveloped viruses by interacting with virion envelope lipids and inhibiting fusion between viral and cellular membranes. Here we tested the antiviral activity of two RAFIs, 5 (Perylen-3-ylethynyl)-arabino-uridine (aUY11) and 5-(Perylen-3-ylethynyl)uracil-1 acetic acid (cm1UY11) against African swine fever virus (ASFV), for which no effective vaccine is available. Both compounds displayed a potent, dose-dependent inhibitory effect on ASFV infection in Vero cells. The major antiviral effect was observed when aUY11 and cm1UY11 were added at early stages of infection and maintained during the complete viral cycle. Furthermore, virucidal assay revealed a significant extracellular anti-ASFV activity for both compounds. We also found decrease in the synthesis of early and late viral proteins in Vero cells treated with cm1UY11. Finally, the inhibitory effect of aUY11 and cm1UY11 on ASFV infection in porcine alveolar macrophages was confirmed. Overall, our study has identified novel anti-ASFV compounds with potential for future therapeutic developments. PMID- 29235979 TI - Aminipila butyrica gen. nov., sp. nov., a strictly anaerobic, arginine decomposing bacterium isolated from a methanogenic reactor of cattle waste. AB - A strictly anaerobic bacterial strain (FH042T) was isolated from a methanogenic reactor treating waste from cattle farms. Cells were stained Gram-positive, straight to gently curved rods with polar flagella. The strain was asaccharolytic. The strain fermented amino acids (l-arginine, l-lysine and l serine) as growth substrates and produced acetate and butyrate. The optimum temperature for growth was 30 degrees C and the optimum pH was 6.1-6.8. Oxidase, catalase and nitrate-reducing activities were negative. Hydrogen sulfide was produced. The genomic DNA G+C content of strain FH042T was 44.7+/-0.2 mol%. The major cellular fatty acids were C18 : 1omega9c DMA, C17 : 2/C17 : 1omega9c (as summed feature), C16 : 0 DMA and C14 : 0. The cell-wall peptidoglycan contained meso-diaminopimelic acid as a diagnostic amino acid. The most closely related described species on the basis of 16S rRNA gene sequences was Anaerovorax odorimutans in the family XIII Incertae Sedis in the order Clostridiales of the class Clostridia with sequence similarity of 95.1 %. Based on the distinct differences in phylogenetic and phenotypic characteristics between strain FH042T and related species, Aminipila butyrica gen. nov., sp. nov. is proposed to accommodate the strain. Type strain is FH042T (=JCM 31555T=DSM 103574T). PMID- 29235980 TI - Restoration of glycoprotein Erns dimerization via pseudoreversion partially restores virulence of classical swine fever virus. AB - The classical swine fever virus (CSFV) represents one of the most important pathogens of swine. The CSFV glycoprotein Erns is an essential structural protein and an important virulence factor. The latter is dependent on the RNase activity of this envelope protein and, most likely, its secretion from the infected cell. A further important feature with regard to its function as a virulence factor is the formation of disulfide-linked Erns homodimers that are found in virus infected cells and virions. Mutant CSFV lacking cysteine (Cys) 171, the residue responsible for intermolecular disulfide bond formation, were found to be attenuated in pigs (Tews BA, Schurmann EM, Meyers G. J Virol 2009;83:4823-4834). In the course of an animal experiment with such a dimerization-negative CSFV mutant, viruses were reisolated from pigs that contained a mutation of serine (Ser) 209 to Cys. This mutation restored the ability to form disulphide-linked Erns homodimers. In transient expression studies Erns mutants carrying the S209C change were found to form homodimers with about wt efficiency. Also the secretion level of the mutated proteins was equivalent to that of wt Erns. Virus mutants containing the Cys171Ser/Ser209Cys configuration exhibited wt growth rates and increased virulence when compared with the Cys171Ser mutant. These results provide further support for the connection between CSFV virulence and Erns dimerization. PMID- 29235982 TI - Estimated Prevalence of Children With Diagnosed Developmental Disabilities in the United States, 2014-2016. AB - Developmental disabilities are a set of heterogeneous disorders characterizedby difficulties in one or more domains, including but not limited to, learning,behavior, and self-care. This report provides the latest prevalence estimatesfor diagnosed autism spectrum disorder, intellectual disability, and otherdevelopmental delay among children aged 3-17 years from the 2014 2016National Health Interview Survey (NHIS). Estimates are also presented forany developmental disability, defined as having had one or more of these threediagnoses. Prevalence estimates are based on parent or guardian report of everreceiving a diagnosis of each developmental disability from a doctor or otherhealth care professional. PMID- 29235981 TI - Paenibacillus limicola sp. nov., isolated from tidal flat sediment. AB - An aerobic, Gram-staining-variable, rod-shaped, endospore-forming and motile bacterial strain, designated CJ6T, was isolated from a tidal flat on Ganghwa Island, South Korea. The isolate was characterized based on a polyphasic taxonomy approach. Strain CJ6T grew optimally on R2A agar media at 30 degrees C and pH 7. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that strain CJ6T belonged to the genus Paenibacillus, displaying the highest sequence similarity to Paenibacillus vulneris CCUG 53270T (97.0 %) and clearly defined strain CJ6T as a novel species within the genus. The G+C content of the genomic DNA was 49.9 mol%. The major polar lipid contents of strain CJ6T were phosphatidylmonomethylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and unidentified glycolipids. MK-7 was detected as the major respiratory quinone. The dominant fatty acid was anteiso-C15 : 0. Analyses of phylogenetic, phenotypic, biochemical and chemotaxonomic characteristics indicated that strain CJ6T was distinguishable from its closely related type strains. Therefore, strain CJ6T represents a novel species in the genus Paenibacillus, for which name Paenibacilluslimicola sp. nov. is proposed; the type strain is CJ6T (=KACC 19303T=JCM 32079T). PMID- 29235983 TI - Characteristics of Office-based Physician Visits, 2014. AB - In 2014, most Americans had a usual place to receive health care (86% ofadults and 97% of children) (1,2). A majority of children and adults listed adoctor's office as the usual place they received care (1,2). In 2014, there werean estimated 885 million office-based physician visits in the United States(3,4). This report examines office-based physician visit rates by age and sex.It also examines visit characteristics, including insurance status, reasonfor visit, and services, by age. Estimates use data from the 2014 NationalAmbulatory Medical Care Survey (NAMCS). PMID- 29235984 TI - Deaths: Leading Causes for 2015. AB - Objectives-This report presents final 2015 data on the 10 leading causes of death in the United States by age, sex, race, and Hispanic origin. Leading causes of infant, neonatal, and postneonatal death are also presented. This report supplements "Deaths: Final Data for 2015," the National Center for Health Statistics' annual report of final mortality statistics. Methods-Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia in 2015. Causes of death classified by the International Classification of Diseases, Tenth Revision (ICD-10) are ranked according to the number of deaths assigned to rankable causes. Cause-of-death statistics are based on the underlying cause of death. Results-In 2015, the 10 leading causes of death were, in rank order: Diseases of heart; Malignant neoplasms; Chronic lower respiratory diseases; Accidents (unintentional injuries); Cerebrovascular diseases; Alzheimer's disease; Diabetes mellitus; Influenza and pneumonia; Nephritis, nephrotic syndrome and nephrosis; and Intentional self-harm (suicide). They accounted for 74% of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2015 were, in rank order: Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Newborn affected by maternal complications of pregnancy; Accidents (unintentional injuries); Newborn affected by complications of placenta, cord and membranes; Bacterial sepsis of newborn; Respiratory distress of newborn; Diseases of the circulatory system; and Neonatal hemorrhage. Important variations in the leading causes of infant death are noted for the neonatal and postneonatal periods. PMID- 29235985 TI - Deaths: Final Data for 2015. AB - Objectives-This report presents final 2015 data on U.S. deaths, death rates, life expectancy, infant mortality, and trends, by selected characteristics such as age, sex, Hispanic origin and race, state of residence, and cause of death. Methods-Information reported on death certificates, which are completed by funeral directors, attending physicians, medical examiners, and coroners, is presented in descriptive tabulations. The original records are filed in state registration offices. Statistical information is compiled in a national database through the Vital Statistics Cooperative Program of the National Center for Health Statistics. Causes of death are processed in accordance with the International Classification of Diseases, Tenth Revision. Results-In 2015, a total of 2,712,630 deaths were reported in the United States. The age-adjusted death rate was 733.1 deaths per 100,000 U.S. standard population, an increase of 1.2% from the 2014 rate. Life expectancy at birth was 78.8 years, a decrease of 0.1 year from 2014. Life expectancy decreased from 2014 to 2015 for non-Hispanic white males (0.2 year), non-Hispanic white females (0.1), non-Hispanic black males (0.4), non-Hispanic black females (0.1), Hispanic males (0.1), and Hispanic females (0.2). Age-specific death rates increased in 2015 from 2014 for age groups 5-14, 15-24, 25-34, 35-44, 55-64, 65-74, and 85 and over. The 15 leading causes of death in 2015 remained the same as in 2014. The infant mortality rate, 5.90 infant deaths per 1,000 live births in 2015, did not change significantly from the rate of 5.82 in 2014. Conclusions-The age-adjusted death rate increased for the first time since 2005. Life expectancy for the total population decreased for the first time since 1993. PMID- 29235986 TI - Managing diabetes in people with dementia: a realist review. AB - BACKGROUND: Dementia and diabetes mellitus are common long-term conditions that coexist in a large number of older people. People living with dementia and diabetes may be at increased risk of complications such as hypoglycaemic episodes because they are less able to manage their diabetes. OBJECTIVES: To identify the key features or mechanisms of programmes that aim to improve the management of diabetes in people with dementia and to identify areas needing further research. DESIGN: Realist review, using an iterative, stakeholder-driven, four-stage approach. This involved scoping the literature and conducting stakeholder interviews to develop initial programme theories, systematic searches of the evidence to test and develop the theories, and the validation of programme theories with a purposive sample of stakeholders. PARTICIPANTS: Twenty-six stakeholders (user/patient representatives, dementia care providers, clinicians specialising in dementia or diabetes and researchers) took part in interviews and 24 participated in a consensus conference. DATA SOURCES: The following databases were searched from 1990 to March 2016: MEDLINE (PubMed), Cumulative Index to Nursing and Allied Health Literature, Scopus, The Cochrane Library (including the Cochrane Database of Systematic Reviews), Database of Abstracts of Reviews of Effects, the Health Technology Assessment (HTA) database, NHS Economic Evaluation Database, AgeInfo (Centre for Policy on Ageing - UK), Social Care Online, the National Institute for Health Research (NIHR) portfolio database, NHS Evidence, Google (Google Inc., Mountain View, CA, USA) and Google Scholar (Google Inc., Mountain View, CA, USA). RESULTS: We included 89 papers. Ten papers focused directly on people living with dementia and diabetes, and the rest related to people with dementia or diabetes or other long-term conditions. We identified six context-mechanism-outcome (CMO) configurations that provide an explanatory account of how interventions might work to improve the management of diabetes in people living with dementia. This includes embedding positive attitudes towards people living with dementia, person-centred approaches to care planning, developing skills to provide tailored and flexible care, regular contact, family engagement and usability of assistive devices. A general metamechanism that emerges concerns the synergy between an intervention strategy, the dementia trajectory and social and environmental factors, especially family involvement. A flexible service model for people with dementia and diabetes would enable this synergy in a way that would lead to the improved management of diabetes in people living with dementia. LIMITATIONS: There is little evidence relating to the management of diabetes in people living with dementia, although including a wider literature provided opportunities for transferable learning. The outcomes in our CMOs are largely experiential rather than clinical. This reflects the evidence available. Outcomes such as increased engagement in self-management are potential surrogates for better clinical management of diabetes, but this is not proven. CONCLUSIONS: This review suggests that there is a need to prioritise quality of life, independence and patient and carer priorities over a more biomedical, target-driven approach. Much current research, particularly that specific to people living with dementia and diabetes, identifies deficiencies in, and problems with, current systems. Although we have highlighted the need for personalised care, continuity and family-centred approaches, there is much evidence to suggest that this is not currently happening. Future research on the management of diabetes in older people with complex health needs, including those with dementia, needs to look at how organisational structures and workforce development can be better aligned to the needs of people living with dementia and diabetes. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015020625. FUNDING: The NIHR HTA programme. PMID- 29235987 TI - Gene-free methodology for cell fate dynamics during development. AB - Models of cell function that assign a variable to each gene frequently lead to systems of equations with many parameters whose behavior is obscure. Geometric models reduce dynamics to intuitive pictorial elements that provide compact representations for sparse in vivo data and transparent descriptions of developmental transitions. To illustrate, a geometric model fit to vulval development in Caenorhabditis elegans, implies a phase diagram where cell-fate choices are displayed in a plane defined by EGF and Notch signaling levels. This diagram defines allowable and forbidden cell-fate transitions as EGF or Notch levels change, and explains surprising observations previously attributed to context-dependent action of these signals. The diagram also reveals the existence of special points at which minor changes in signal levels lead to strong epistatic interactions between EGF and Notch. Our model correctly predicts experiments near these points and suggests specific timed perturbations in signals that can lead to additional unexpected outcomes. PMID- 29235988 TI - Optimal transformations leading to normal distributions of positron emission tomography standardized uptake values. AB - : The statistical analysis of positron emission tomography (PET) standardized uptake value (SUV) measurements is challenging due to the skewed nature of SUV distributions. This limits utilization of powerful parametric statistical models for analyzing SUV measurements. An ad-hoc approach, which is frequently used in practice, is to blindly use a log transformation, which may or may not result in normal SUV distributions. This study sought to identify optimal transformations leading to normally distributed PET SUVs extracted from tumors and assess the effects of therapy on the optimal transformations. METHODS: The optimal transformation for producing normal distributions of tumor SUVs was identified by iterating the Box-Cox transformation parameter (lambda) and selecting the parameter that maximized the Shapiro-Wilk P-value. Optimal transformations were identified for tumor SUVmax distributions at both pre and post treatment. This study included 57 patients that underwent 18F-fluorodeoxyglucose (18F-FDG) PET scans (publically available dataset). In addition, to test the generality of our transformation methodology, we included analysis of 27 patients that underwent 18F-Fluorothymidine (18F-FLT) PET scans at our institution. RESULTS: After applying the optimal Box-Cox transformations, neither the pre nor the post treatment 18F-FDG SUV distributions deviated significantly from normality (P > 0.10). Similar results were found for 18F-FLT PET SUV distributions (P > 0.10). For both 18F-FDG and 18F-FLT SUV distributions, the skewness and kurtosis increased from pre to post treatment, leading to a decrease in the optimal Box Cox transformation parameter from pre to post treatment. There were types of distributions encountered for both 18F-FDG and 18F-FLT where a log transformation was not optimal for providing normal SUV distributions. CONCLUSION: Optimization of the Box-Cox transformation, offers a solution for identifying normal SUV transformations for when the log transformation is insufficient. The log transformation is not always the appropriate transformation for producing normally distributed PET SUVs. PMID- 29235989 TI - Motion vector field phase-to-amplitude resampling for 4D motion-compensated cone beam CT. AB - We propose a phase-to-amplitude resampling (PTAR) method to reduce motion blurring in motion-compensated (MoCo) 4D cone-beam CT (CBCT) image reconstruction, without increasing the computational complexity of the motion vector field (MVF) estimation approach. PTAR is able to improve the image quality in reconstructed 4D volumes, including both regular and irregular respiration patterns. The PTAR approach starts with a robust phase-gating procedure for the initial MVF estimation and then switches to a phase-adapted amplitude gating method. The switch implies an MVF-resampling, which makes them amplitude specific. PTAR ensures that the MVFs, which have been estimated on phase-gated reconstructions, are still valid for all amplitude-gated reconstructions. To validate the method, we use an artificially deformed clinical CT scan with a realistic breathing pattern and several patient data sets acquired with a TrueBeamTM integrated imaging system (Varian Medical Systems, Palo Alto, CA, USA). Motion blurring, which still occurs around the area of the diaphragm or at small vessels above the diaphragm in artifact-specific cyclic motion compensation (acMoCo) images based on phase-gating, is significantly reduced by PTAR. Also, small lung structures appear sharper in the images. This is demonstrated both for simulated and real patient data. A quantification of the sharpness of the diaphragm confirms these findings. PTAR improves the image quality of 4D MoCo reconstructions compared to conventional phase-gated MoCo images, in particular for irregular breathing patterns. Thus, PTAR increases the robustness of MoCo reconstructions for CBCT. Because PTAR does not require any additional steps for the MVF estimation, it is computationally efficient. Our method is not restricted to CBCT but could rather be applied to other image modalities. PMID- 29235990 TI - The Fokker-Planck equation for coupled Brown-Neel-rotation. AB - Calculating the dynamic properties of magnetization of single-domain particles is of great importance for the tomographic imaging modality known as magnetic particle imaging (MPI). Although the assumption of instantaneous thermodynamic equilibrium (Langevin function) after application of time-dependent magnetic fields is sufficient for understanding the fundamental behavior, it is essential to consider the finite response times of magnetic particles for optimizing or analyzing various aspects, e.g. interpreting spectra, optimizing MPI sequences, developing new contrasts, and evaluating simplified models. The change in magnetization following the application of the fields is caused by two different movements: the geometric rotation of the particle and the rotation of magnetization with respect to the fixed particle axes. These individual rotations can be well described using the Langevin equations or the Fokker-Planck equation. However, because the two rotations generally exhibit interdependence, it is necessary to consider coupling between the two equations. This article shows how a coupled Fokker-Planck equation can be derived on the basis of coupled Langevin equations. Two physically equivalent Fokker-Planck equations are derived and transformed by means of an appropriate series expansion into a system of ordinary differential equations, which can be solved numerically. Finally, this system is also used to specify a system of differential equations for various limiting cases (Neel, Brown, uniaxial symmetry). Generally, the system exhibits a sparsely populated matrix and can therefore be handled well numerically. PMID- 29235991 TI - Imaging of monochromatic beams by measuring secondary electron bremsstrahlung for carbon-ion therapy using a pinhole x-ray camera. AB - A feasibility study on the imaging of monochromatic carbon-ion beams for carbon ion therapy was performed. The evaluation was based on Monte Carlo simulations and beam-irradiation experiments, using a pinhole x-ray camera, which measured secondary electron bremsstrahlung (SEB). The simulation results indicated that the trajectories of the carbon-ion beams with injection energies of 278, 249 and 218 MeV/u in a water phantom, were clearly imaged by measuring the SEB with energies from 30 to 60 keV, using a pinhole camera. The Bragg-peak positions for these three injection energies were located at the positions where the ratios of the counts of SEB acquisitions to the maximum counts were approximately 0.23, 0.26 and 0.29, respectively. Moreover, we experimentally demonstrated that it was possible to identify the Bragg-peak positons, at the positions where the ratios coincided with the simulation results. However, the estimated Bragg-peak positions for the injection energies of 278 and 249 MeV/u were slightly deeper than the expected positions. In conclusion, for both the simulations and experiments, we found that the 25 mm shifts in the Bragg-peak positions can be observed by this method. PMID- 29235992 TI - Avoiding neuromuscular stimulation in liver irreversible electroporation using radiofrequency electric fields. AB - Electroporation-based treatments typically consist of the application of high voltage dc pulses. As an undesired side effect, these dc pulses cause electrical stimulation of excitable tissues such as motor nerves. The present in vivo study explores the use of bursts of sinusoidal voltage in a frequency range from 50 kHz to 2 MHz, to induce irreversible electroporation (IRE) whilst avoiding neuromuscular stimulation. A series of 100 dc pulses or sinusoidal bursts, both with an individual duration of 100 us, were delivered to rabbit liver through thin needles in a monopolar electrode configuration, and thoracic movements were recorded with an accelerometer. Tissue samples were harvested three hours after treatment and later post-processed to determine the dimensions of the IRE lesions. Thermal damage due to Joule heating was ruled out via computer simulations. Sinusoidal bursts with a frequency equal to or above 100 kHz did not cause thoracic movements and induced lesions equivalent to those obtained with conventional dc pulses when the applied voltage amplitude was sufficiently high. IRE efficacy dropped with increasing frequency. For 100 kHz bursts, it was estimated that the electric field threshold for IRE is about 1.4 kV cm-1 whereas that of dc pulses is about 0.5 kV cm-1. PMID- 29235993 TI - Raman micro-spectroscopy analysis of human lens epithelial cells exposed to a low dose-range of ionizing radiation. AB - Recent findings in populations exposed to ionizing radiation (IR) indicate dose related lens opacification occurs at much lower doses (<2 Gy) than indicated in radiation protection guidelines. As a result, research efforts are now being directed towards identifying early predictors of lens degeneration resulting in cataractogenesis. In this study, Raman micro-spectroscopy was used to investigate the effects of varying doses of radiation, ranging from 0.01 Gy to 5 Gy, on human lens epithelial (HLE) cells which were chemically fixed 24 h post-irradiation. Raman spectra were acquired from the nucleus and cytoplasm of the HLE cells. Spectra were collected from points in a 3 * 3 grid pattern and then averaged. The raw spectra were preprocessed and principal component analysis followed by linear discriminant analysis was used to discriminate between dose and control for 0.25, 0.5, 2, and 5 Gy. Using leave-one-out cross-validation accuracies of greater than 74% were attained for each dose/control combination. The ultra-low doses 0.01 and 0.05 Gy were included in an analysis of band intensities for Raman bands found to be significant in the linear discrimination, and an induced repair model survival curve was fit to a band-difference-ratio plot of this data, suggesting HLE cells undergo a nonlinear response to low-doses of IR. A survival curve was also fit to clonogenic assay data done on the irradiated HLE cells, showing a similar nonlinear response. PMID- 29235994 TI - Pressure-induced structural change in liquid GeI4. AB - The similarity in the shape of the melting curve of GeI4 to that of SnI4 suggests that a liquid-liquid transition as observed in liquid SnI4 is also expected to occur in liquid GeI4. Because the slope of the melting curve of GeI4 abruptly changes at around 3 GPa, in situ synchrotron diffraction measurements were conducted to examine closely the structural changes upon compression at around 3 GPa. The reduced radial distribution functions of the high- and low-pressure liquid states of GeI4 share the same feature inherent in the high-pressure (high density) and low-pressure (low-density) radial distribution functions of liquid SnI4. This feature allows us to introduce local order parameters that we may use to observe the transition. Unlike the transition in liquid SnI4, the transition from the low-pressure to the high-pressure structure seems sluggish. We speculate that the liquid-liquid critical point of GeI4 is no longer a thermodynamically stable state and is slightly located below the melting curve. As a result, the structural change is said to be a crossover rather than a transition. The behavior of the local-order parameters implies a metastable extension of the liquid-liquid phase boundary with a negative slope. . PMID- 29235995 TI - Spin dynamics of FeGa3-xGex studied by Electron Spin Resonance. AB - The intermetallic semiconductor FeGa3 acquires itinerant ferromagnetism upon electron doping by a partial replacement of Ga with Ge. We studied the electron spin resonance (ESR) of high-quality single crystals of FeGa3-xGex for x from 0 up to 0.162 where ferromagnetic order is observed. For x = 0 we observed a well-defined ESR signal, indicating the presence of pre-formed magnetic moments in the semiconducting phase. Upon Ge doping the occurrence of itinerant magnetism clearly affects the ESR properties below ~ 40 K whereas at higher temperatures an ESR signal as seen in FeGa3 prevails independent on the Ge-content. The present results show that the ESR of FeGa3-xGex is an appropriate and direct tool to investigate the evolution of 3d-based itinerant magnetism. PMID- 29235996 TI - Research on a soft measurement model of sewage treatment based on a case-based reasoning approach. AB - In this paper, the measurement of biochemical oxygen demand (BOD) in a wastewater treatment process is analyzed and an intelligent integrated prediction method based on case-based reasoning (CBR) is proposed in order to overcome difficulties. Due to the fact that there are many factors that influence the accuracy of the prediction model, the radial basis function, which is a neural network with a 3 layer feedforward network, is employed to reduce the dimension of input values. Under these circumstances, a back propagation neural network combining with a nearest neighbor retrieval strategy is adopted to match case. Then, the measurement of BOD in wastewater treatment process is analyzed. Finally, the validity of the improved CBR in sewage treatment is demonstrated by using numerical results. PMID- 29235997 TI - Effective biosorption of phenol by the thermophilic cyanobacterium Phormidium sp. AB - The use of microbial biomass as biosorbent for phenol removal has been extensively studied, but its removal by biosorption by thermophilic cyanobacterium Phormidium sp. has not been investigated to the best of our knowledge. In the present study, some important parameters for biosorption process were optimized, starting with testing the effects of different pH values ranging from 1 to 12, and then initial phenol concentrations of 45.1, 115.3, 181.4, 243.3, 339.9 mg/L on phenol uptake. The efficiency of removal from aqueous solution was higher within the pH 6-8 range, with the maximum of 100% at pH 7 after 24 hours of adsorption time. The highest specific rate was observed as 165.1 mg/g in the presence of 339.9 mg/l initial phenol concentration. The Freundlich adsorption models were fitted to the equilibrium data, which indicated that phenol ions were favourably adsorbed by Phormidium sp. PMID- 29235998 TI - Enhanced degradation of micropollutants by zero-valent aluminum activated persulfate: assessment of toxicity and genotoxic activity. AB - Advanced oxidation of the aqueous TritonTM X-45 (TX-45), iopamidol (IOPA), ciprofloxacin (CIP) and bisphenol A (BPA) solutions via activation of persulfate (PS) with zero-valent aluminum (ZVA) was investigated. The study aimed at assessing the effectiveness of the PS/ZVA process in terms of target micropollutants (MPs) and toxicity abatements in raw surface water (RSW) and distilled water (DW). TX-45, CIP and BPA were completely degraded after 90 minute, 120-minute and 40-minute treatment, respectively, with PS/ZVA in DW, whereas 95% IOPA removal was achieved after 120-minute (MPs = 2 mg/L; ZVA = 1 g/L; PS = 0.25 mM for CIP and BPA; PS = 0.50 mM for TX-45 and IOPA; pH = 3). TX 45 (59%), IOPA (29%), CIP (73%) and BPA (46%) removal efficiencies decreased after 120-minute PS/ZVA treatment in RSW. In DW, Vibrio fischeri toxicities of original (untreated) MPs were found as: CIP (51%) > BPA (40%) > TX-45 (15%) > IOPA (1%), and as BPA (100%) > CIP (66%) > IOPA (62%) > TX-45 (35%) in RSW. Acute toxicities of MPs and their degradation products fluctuated during PS/ZVA treatment both in DW and RSW samples and resulted in different relative inhibition values after 120-minute. The original and PS/ZVA-treated TX-45, IOPA and BPA in DW exhibited neither cytotoxic nor genotoxic effects, whereas CIP oxidation ended up in degradation products with genotoxic effects. PMID- 29235999 TI - Life cycle assessment study on polishing units for use of treated wastewater in agricultural reuse. AB - A life cycle assessment (LCA) approach was used in the assessment of environmental impacts of some polishing units for reuse of wastewater treatment plant effluents in agricultural irrigation. These alternative polishing units were assessed: (1) microfiltration and ultraviolet (UV) disinfection, (2) cartridge filter and ultrafiltration (UF), and (3) just UV disinfection. Two different energy sources, electric grid mix and natural gas, were considered to assess the environmental impacts of them. Afterwards, the effluent of each case was evaluated against the criteria required for irrigation of sensitive crops corresponding to Turkey regulations. Evaluation of environmental impacts was carried out with GaBi 6.1 LCA software. The overall conclusion of this study is that higher electricity consumption causes higher environmental effects. The results of the study revealed that cartridge filter and UF in combination with electric grid mix has the largest impact on the environment for almost all impact categories. In general, the most environmentally friendly solution is UV disinfection. The study revealed environmental impacts for three alternatives drawing attention to the importance of the choice of the most appropriate polishing processes and energy sources for reuse applications. PMID- 29236000 TI - The effect of different mesophilic temperatures during anaerobic digestion of sludge on the overall performance of a WWTP in Sweden. AB - This project was initiated to evaluate the effect of alternative process temperatures to 38 degrees C at the anaerobic digestion step in a Swedish wastewater treatment plant (WWTP) treating mixed sludge. The efficiency of the different temperatures was evaluated with respect to biogas production, volume of sludge produced and nutrient content in the reject water to find the optimum temperature for the WWTP as a whole. Three temperatures, 34 degrees C, 38 degrees C and 42 degrees C, were compared in laboratory scale. Increasing the process temperature to 42 degrees C resulted in process instability, reduced methane yield, accumulation of volatile fatty acids and higher treatment costs of the reject water. By decreasing the temperature to 34 degrees C, slightly higher sludge mass was observed and a lower gas production rate, while the specific methane produced remained unchanged compared to 38 degrees C but foaming was observed at several occasions. In summary 38 degrees C was proved to be the most favourable temperature for the anaerobic digestion process treating mixed sludge when the evaluation included effects such as foaming, sludge mass and quality of the reject water. PMID- 29236001 TI - Optimization analysis of separation conditions of washed water containing a lead complex and characterization of the precipitation products. AB - Presently, the large amount of industrial leaded wastewater creates a great challenge to both environmental governance and wastewater recycling. Lead complexes in washed water must be removed mostly before the washed water can be recycled. This paper reports the mechanism and factors of removing Pb complexes in simulated washed water by the sulfide precipitation method. The reaction time, sodium sulfide dosage, pH, and polymeric aluminum chloride (PAC) dosage were analyzed and the optimal conditions were explored. The composition of the reaction products was also verified by scanning electron microscopy (SEM) and X ray diffraction (XRD). Additionally, the kinetics of the precipitation reaction of sodium sulfide and Pb-EDTA were studied. These results showed that the Pb removal efficiency reached 91.7% under the optimal process conditions which were as follows: the dosages of Na2S and PAC were 188 mg/L (Na2S/Pb2+ molar ratio of 5:1) and 30 mg/L, respectively, the reaction time was 40 min, and the pH was 9. It was demonstrated using SEM and XRD that the reaction product in the separation process was PbS and the precipitation process was fitted to the following first order reaction kinetics equation: Ct = 89.1e-0.1047t + 10.1 (R2 = 0.9929; Ct is Pb concentration at reaction time t). PMID- 29236002 TI - Anodic oxidation of slaughterhouse wastewater on boron-doped diamond: process variables effect. AB - A non-sacrificial boron-doped diamond electrode was prepared in the laboratory and used as a novel anode for electrochemical oxidation of poultry slaughterhouse wastewater. This wastewater poses environmental threats as it is characterized by a high content of recalcitrant organics. The influence of several process variables, applied current density, initial pH, supporting electrolyte nature, and concentration of electrocoagulant, on chemical oxygen demand (COD) removal, color removal, and turbidity removal was investigated. Results showed that raising the applied current density to 3.83 mA/cm2 has a positive effect on COD removal, color removal, and turbidity removal. These parameters increased to 100%, 90%, and 80% respectively. A low pH of 5 favored oxidants generation and consequently increased the COD removal percentage to reach 100%. Complete removal of COD had occurred in the presence of NaCl (1%) as supporting electrolyte. Na2SO4 demonstrated lower efficiency than NaCl in terms of COD removal. The COD decay kinetics follows the pseudo-first-order reaction. The simultaneous use of Na2SO4 and FeCl3 decreased the turbidity in wastewater by 98% due to electrocoagulation. PMID- 29236003 TI - Treatment of high strength aqueous wastes in a thermophilic aerobic membrane reactor (TAMR): performance and resilience. AB - In the present work, the thermophilic aerobic membrane reactor technology was studied for the treatment of high strength aqueous wastes mainly containing dyes, surfactants and solvents. The thermophilic biomass resilience and the process stability under critical conditions (such as rapid rise of the mixed liquor pH, oxygen supply interruption, etc.) were also evaluated. The experimental work was carried out with the use of a pilot plant at semi-industrial scale, which was managed throughout for 14 months; the operation temperature was 49 degrees C and the organic loading rate was increased from 3 to 12 kgCOD m-3 d-1. Critical conditions, especially the interruption of oxygen supply, affected the pilot plant performance but did not cause a complete system break down. After the temporary reduction of process performance, also proven by the decrease in the oxygen consumption, the normal working conditions were restored. Moreover, the longer non-aerated phase involved a significant reduction (40%) of volatile suspended solids concentration in the biological reactor and the increase of 30% in foaming power; nevertheless, once the oxygen supply was reactivated, optimal conditions were rapidly restored. Therefore, the study showed the high resilience of the thermophilic biomass, which was able to recover full functionality after critical events. PMID- 29236004 TI - Novel insights into the coagulation process for pharmaceutical wastewater treatment with fluorescence EEMs-PARAFAC. AB - In this study, coagulation process was applied to treat the effluent of pharmaceutical wastewater using polymeric ferric sulfate as a coagulant. Three dimensional excitation-emission matrix fluorescence spectroscopy coupled with parallel factor analysis (EEMs-PARAFAC) was applied to investigate the fluorescent characteristics of dissolved organic matter (DOM) from pharmaceutical wastewater and the reduction of contaminant and fluorescent variations in the coagulation process. It shows that coagulation was effective to remove contaminants in the effluent of pharmaceutical wastewater, and the optimum coagulate dosage was 0.5 g/L, where the removal efficiency of total organic matter (TOC), UV254, turbidity and NH4+-N were achieved 44.2%, 43.3%, 87.0% and 10.27%, respectively. Five fluorescence components were identified by EEMs PARAFAC, including one fulvic-like component (C1), one xenobiotic-like component (C2), two humic-like components (C3 and C5) and one protein-like component (C4); DOM of pharmaceutical wastewater was dominated by C3, C4 and C2. Under the optimum coagulation condition, the decreasing order of removal efficiencies was C5 (49.92%), C3 (40.95%), C4 (10.58%), C2 (9.68%) and C1 (5.05%). Principal component analysis (PCA) showed C3, C5 had remarkable correlations with TOC and UV254, suggesting that C3 and C5 may be a good indicator for the reduction of TOC and UV254. PCA indicated that the EEM-PARAFAC could be successfully applied to the evaluation of the coagulation efficiency for pharmaceutical wastewater treatment. PMID- 29236005 TI - Good servant, bad master: sulfide influence on partial nitritation of sewage. AB - When applying partial nitritation (PN) to anaerobically pre-treated sewage, ammonium oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) will be exposed to dissolved sulfide and methane. Both sulfide and methane may inhibit nitrification. To gain knowledge necessary for sustaining PN under these conditions, we exposed an AOB enrichment and a mixed nitrifying culture to dissolved sulfide and methane. In the mixed nitrifying culture, sulfide selectively inhibited NOB activity (KI,AOB1 = 150 mg-S L-1, KI,NOB = 10 mg-S L-1) which shows that sulfide may help establish PN. The AOB enrichment showed similar KI,AOB2 (130 mg-S L-1), but nitritation activity lagged longer than the time necessary to remove sulfide from the liquid. This demonstrates that feeding of sulfide into established PN should be avoided. Methane inhibition of AOB enrichment was assessed in batch assays with 10 mg-CH4 L-1. As compared to control without methane, AOB enrichment activity was identical. Up to 51% of methane was converted to methanol, thus reducing the greenhouse gas emissions. PMID- 29236006 TI - Electricity generation through a photo sediment microbial fuel cell using algae at the cathode. AB - Sediment microbial fuel cells (SMFCs) are bio-electrochemical devices generating electricity from redox gradients occurring across the sediment-water interface. Sediment microbial carbon-capture cell (SMCC), a modified SMFC, uses algae grown in the overlying water of sediment and is considered as a promising system for power generation along with algal cultivation. In this study, the performance of SMCC and SMFC was evaluated in terms of power generation, dissolved oxygen variations, sediment organic matter removal and algal growth. SMCC gave a maximum power density of 22.19 mW/m2, which was 3.65 times higher than the SMFC operated under similar conditions. Sediment organic matter removal efficiencies of 77.6 +/ 2.1% and 61.0 +/- 1.3% were obtained in SMCC and SMFC, respectively. With presence of algae at the cathode, a maximum chemical oxygen demand and total nitrogen removal efficiencies of 63.3 +/- 2.3% (8th day) and 81.6 +/- 1.2% (10th day), respectively, were observed. The system appears to be favorable from a resources utilization perspective as it does not depend on external aeration or membranes and utilizes algae and organic matter present in sediment for power generation. Thus, SMCC has proven its applicability for installation in an existing oxidation pond for sediment remediation, algae growth, carbon conversion and power generation, simultaneously. PMID- 29236007 TI - Treatment of oilfield wastewater by combined process of micro-electrolysis, Fenton oxidation and coagulation. AB - In this study, a combined process was developed that included micro-electrolysis, Fenton oxidation and coagulation to treat oilfield fracturing wastewater. Micro electrolysis and Fenton oxidation were applied to reduce chemical oxygen demand (COD) organic load and to enhance organic components gradability, respectively. Orthogonal experiment were employed to investigate the influence factors of micro electrolysis and Fenton oxidation on COD removal efficiency. For micro electrolysis, the optimum conditions were: pH, 3; iron-carbon dosage, 50 mg/L; mass ratio of iron-carbon, 2:3; reaction time, 60 min. For Fenton oxidation, a total reaction time of 90 min, a H2O2 dosage of 12 mg/L, with a H2O2/Fe2+ mole ratio of 30, pH of 3 were selected to achieve optimum oxidation. The optimum conditions in coagulation process: pH, cationic polyacrylamide dosage, mixing speed and time is 4.3, 2 mg/L, 150 rpm and 30 s, respectively. In the continuous treatment process under optimized conditions, the COD of oily wastewater fell 56.95%, 46.23%, 30.67%, respectively, from last stage and the total COD removal efficiency reached 83.94% (from 4,314 to 693 mg/L). In the overall treatment process under optimized conditions, the COD of oily wastewater was reduced from 4,314 to 637 mg/L, and the COD removal efficiency reached 85.23%. The contribution of each stage is 68.45% (micro-electrolysis), 24.07% (Fenton oxidation), 7.48% (coagulation), respectively. Micro-electrolysis is the uppermost influencing process on COD removal. Compared with the COD removal efficiency of three processes on raw wastewater under optimized conditions: the COD removal efficiency of single micro-electrolysis, single Fenton oxidation, single coagulation is 58.34%, 44.88% and 39.72%, respectively. Experiments proved the effect of combined process is marvelous and the overall water quality of the final effluent could meet the class III national wastewater discharge standard of petrochemical industry of China (GB8978-1996). PMID- 29236008 TI - Denitrification processes and microbial communities in a sequencing batch reactor treating nanofiltration (NF) concentrate from coking wastewater. AB - A biological denitrifying process was employed for the treatment of nanofiltration (NF) concentrate with high conductivity, which was generated from coking wastewater in a sequencing batch reactor (SBR). The results showed that the average removal efficiencies of chemical oxygen demand (COD), total nitrogen (TN) and nitrate were 47.6%, 61.1% and 94.6%, respectively. Different microbial communities were identified by sequencing the V1-V3 region of the 16S rRNA gene using the MiSeq platform, showing that the most abundant bacterial phylum in the SBR system was Proteobacteria, with the subclasses beta-Proteobacteria and alpha Proteobacteria being dominant. The key microorganisms responsible for denitrification belonged to the genera Thauera, Hyphomicrobium, Methyloversatilis, Hydrogenophaga, Ignavibacterium, Rubrivivax and Parvibaculum. Quantitative real-time polymerase chain reaction was used to assess the absolute abundance of microbial genera, using 16S rRNAs and denitrifying genes such as narG, nirS, nirK, nosZ, in both SBR start-up and stable operation. The abundances of narG, nirK and nosZ were lower during stable operation than those during the start-up period. The abundance of nirS at a level of 104-105copies/ng in DNA was much higher than that of nirK, thus being the dominant functional gene in nitrite reduction. PMID- 29236009 TI - Carbon recovery from screenings for energy-efficient wastewater treatment. AB - The energy content of screenings from six municipal wastewater treatment plants (WWTPs) was examined. Hourly samples of separated screenings were taken over 24 hours at three of the plants to illustrate diurnal variations. To recover the chemical energy, which usually leaves the WWTP with the screenings, a screenings wash press was used to transfer organic matter from the solid into the liquid phase. The chemical energy of raw and compacted washed screenings as well as the chemical energy of washing water were determined by measuring the chemical oxygen demand (COD) for the six WWTPs. A mass weighted average of 1.35 gCOD/gdm (dm: dry matter) was found in the raw screenings of three WWTPs. The overall recovered energy from screenings was found to range from 0.27 to 0.62 gCOD/gdm. This washed out COD found in the washing water could be sent for anaerobic digestion or to the wastewater treatment process as a carbon source for denitrification. PMID- 29236010 TI - A novel biochar derived from cauliflower (Brassica oleracea L.) roots could remove norfloxacin and chlortetracycline efficiently. AB - The biochar was prepared by pyrolyzing the roots of cauliflowers, at a temperature of 500 degrees C under oxygen-limited conditions. The structure and characteristics of the biochar were examined using scanning electron microscopy, an energy dispersive spectrometer, a zeta potential analyzer, and Fourier transform infrared spectroscopy. The effects of the temperature, the initial pH, antibiotic concentration, and contact time on the adsorption of norfloxacin (NOR) and chlortetracycline (CTC) onto the biochar were investigated. The adsorption kinetics of NOR and CTC onto the biochar followed the pseudo-second-order kinetic and intra-particle diffusion models. The adsorption isotherm experimental data were well fitted to the Langmuir and Freundlich isotherm models. The maximum adsorption capacities of NOR and CTC were 31.15 and 81.30 mg/g, respectively. There was little difference between the effects of initial solution pH (4.0-10.0) on the adsorption of NOR or CTC onto the biochar because of the buffering effect. The biochar could remove NOR and CTC efficiently in aqueous solutions because of its large specific surface area, abundant surface functional groups, and particular porous structure. Therefore, it could be used as an excellent adsorbent material because of its low cost and high efficiency and the extensive availability of the raw materials. PMID- 29236011 TI - Hydraulic retention time influence on azo dye and sulfate removal during the sequential anaerobic-aerobic treatment of real textile wastewater. AB - In the present study, we evaluate the behavior of real textile wastewater treatment using a system composed of two sequential pilot-scale reactors (anaerobic followed by aerobic) during 622 days. The work focused on the competition between color and sulfate removal processes, when the hydraulic retention time (HRT) was increased in the anaerobic/aerobic reactors from 16/12 hours in phase I (PI) to 4/3 days in phase II (PII). The organic matter was successfully removed in both phases through the system, and the highest efficiency (75%) was achieved in PII. The increase in the HRT did not improve azo dye degradation under anaerobic conditions. Instead, it favored sulfate reduction, which removal efficiency increased from 26% in PI to 75% in PII. Aromatic amines were detected in the anaerobic reactor effluent and removed in the aerobic reactor. PMID- 29236012 TI - Organic matter degradation in a greywater recycling system using a multistage moving bed biofilm reactor (MBBR). AB - Greywater is an important non-conventional water resource which can be treated and recycled in buildings. A decentralized greywater recycling system for 223 inhabitants started operating in 2006 in Berlin, Germany. High load greywater undergoes advanced treatment in a multistage moving bed biofilm reactor (MBBR) followed by sand filtration and UV disinfection. The treated water is used safely as service water for toilet flushing. Monitoring of the organic matter degradation was pursued to describe the degradation processes in each stage and optimize the system. Results showed that organic matter reduction was achieved for the most part in the first three reactors, whereas the highest reduction rate was observed in the third reactor in terms of COD (chemical oxygen demand), dissolved organic carbon and BOD7 (biological oxygen demand). The results also showed that the average loading rate entering the system was 3.7 kg COD/d, while the removal rate was 3.4 kg COD/d in a total bioreactor volume of 11.7 m3. In terms of BOD, the loading rate was 2.8 kg BOD/d and it was almost totally removed. This system requires little space (0.15 m2/person) and maintenance work of less than one hour per month and it shows operational stability under peak loads. PMID- 29236013 TI - Characteristics, distribution and sources of polychlorinated biphenyls (PCBs) in coastal sediments from the heavily industrialized area of Asalouyeh, Iran. AB - In this research, the levels of polychlorinated biphenyls (PCBs) were investigated in the marine sediments of Asaluyeh harbor, in the Persian Gulf. The samples were taken from industrial, semi-industrial and urban regions. The mean concentration levels of total (Sigma) 18 detected PCBs were 514.32, 144.67 and 31.6 pg/g dw for the industrial, semi-industrial and urban sampling stations, respectively. Based on a multivariate statistical analysis, it was found that high contamination levels of PCBs in sediments collected along the Persian Gulf were associated with releases from local industries. Total organic carbon (TOC) content was significantly and positively correlated with the concentrations of PCB congeners. World Health Organization toxic equivalents (TEQs) for PCBs ranged from 0.04 to 2.66 pg TEQ/g dry weight (dw) in the coastal sediments. The TEQ values in this study were higher than many reported worldwide in the literature for sediments. This suggests that there are high levels of contamination in the area due to industrial and other human activities. PMID- 29236014 TI - Identification of potential sewer mining locations: a Monte-Carlo based approach. AB - Rapid urbanization affecting demand patterns, coupled with potential water shortages due to supply side impacts of climatic changes, has led to the emergence of new technologies for water and wastewater reuse. Sewer mining (SM) is a novel decentralized option that could potentially provide non-potable water for urban uses, including for example the irrigation of urban green spaces, providing a mid-scale solution to effective wastewater reuse. SM is based on extracting wastewater from local sewers and treatment at the point of demand and entails in some cases the return of treatment residuals back to the sewer system. Several challenges are currently in the way of such applications in Europe, including public perception, inadequate regulatory frameworks and engineering issues. In this paper we consider some of these engineering challenges, looking at the sewer network as a system where multiple physical, biological and chemical processes take place. We argue that prior to implementing SM, the dynamics of the sewer system should be investigated in order to identify optimum ways of deploying SM without endangering the reliability of the system. Specifically, both wastewater extraction and sludge return could result in altering the biochemical process of the network, thus unintentionally leading to degradation of the sewer infrastructure. We propose a novel Monte-Carlo based method that takes into account both spatial properties and water demand characteristics of a given area of SM deployment while simultaneously accounting for the variability of sewer network dynamics in order to identify potential locations for SM implementation. The outcomes of this study suggest that the method can provide rational results and useful guidelines for upscale SM technologies at a city level. PMID- 29236015 TI - Ammonium removal by native microbes and activated sludge within the Jialu River basin and the associated microbial community structures. AB - To explore the availability of native microbes and activated sludge for ammonium removal, the native microbes and activated sludge in Jialu River basin were investigated in terms of ammonium-removing activities and their microbial communities using spectrophotometry and high-throughput sequencing. NH4+-N and total nitrogen (TN) in the targeted river ranged from 2.45 +/- 1.76 to 8.56 +/- 2.54 mg/L and from 3.42 +/- 2.79 to 13.49 +/- 5.06 mg/L, respectively. Both the native microbes and activated sludge had strong ammonium-removing activities with the removal efficiencies of more than 94%. High-throughput sequencing results indicated that, after five batches of operation, the class Gammaproteobacteria (28.55%), Alphaproteobacteria (14.55%), Betaproteobacteria (13.89%), Acidobacteria (8.82%) and Bacilli (7.04%) were dominated in native community, and there was a predominance of Gammaproteobacteria (21.57%), Betaproteobacteria (16.33%), Acidobacteria (12.41%), Alphaproteobacteria (10.01%), Sphingobacteriia (6.92%) and Bacilli (6.66%) in activated sludge. These two microbial sources were able to remove ammonium, while activated sludge was more cost-effective. PMID- 29236016 TI - Synthesis of MnFe2O4 and Mn3O4 magnetic nano-composites with enhanced properties for adsorption of Cr(VI): artificial neural network modeling. AB - This study reports adsorptive removal of Cr(VI) by magnetic manganese ferrite and manganese oxide nano-particles (MnF-MO-NPs) composite from aqueous media. The X ray diffraction pattern of MnF-MO-NPs revealed a polycrystalline nature with nanoscale crystallite size. The prepared adsorbent with high Brunauer-Emmett Teller specific surface area of 100.62 m2/g and saturation magnetization of 30.12 emu/g exhibited maximum Cr(VI) removal at solution pH 2.0 and was easily separated from water under an external magnetic field. Adsorption capacity as much as 91.24 mg/g is reported and electrostatic interaction between positively charged adsorbent surface and anionic metal ion species is the main driving force in this adsorption. Adsorption experimental data followed Langmuir isotherm and second order kinetics. Partial involvement of intra-particle diffusion was also observed due to the mesoporous nature of MnF-MO-NPs. The thermodynamic studies revealed that the process was favorable, spontaneous and exothermic in nature. An artificial neural network model was developed for accurate prediction of Cr(VI) ions removal with minimum mean squared error (MSE) of 15.4 * 10-4 and maximum R2 of 0.98. Owing to large surface to volume ratio, advantage of easy magnetic separation, and high adsorption capacity towards Cr(VI), the reported MnF-MO-NPs appear to be a potential candidate in Cr(VI) contaminated wastewater remediation. PMID- 29236017 TI - Macroalgae of Iridaea cordata as an efficient biosorbent to remove hazardous cationic dyes from aqueous solutions. AB - In the present work, Iridaea cordata (IC), a red marine macroalgae, was used as an efficient biosorbent for the removal of crystal violet (CV) and methylene blue (MB) dyes from aqueous solutions. The effects of pH (5, 7, and 9) and IC concentration (1, 3, and 5 g L-1) on the biosorption were studied through a 32 full factorial design. Under the optimal conditions (pH: 7, biosorbent concentration: 1 g L-1), biosorption kinetic studies were developed and the obtained experimental data were evaluated by pseudo-first order and pseudo-second order models. The results showed that the pseudo-second order model was in agreement with the experimental kinetic data for both dyes. Equilibrium studies were also carried out, and results exhibited good concordance with the Brunauer Emmett-Teller isotherm. The biosorption capacities were 36.5 and 45.0 mg g-1 for CV and MB dyes, respectively. The dye removal percentages were around 75% for CV and 90% for MB. Thermodynamically, the biosorption process proved to be exothermic, spontaneous, and favorable. These results showed that IC biomass is a promising biosorbent for removal of CV and MB dyes from aqueous solutions. PMID- 29236018 TI - Urban stormwater inundation simulation based on SWMM and diffusive overland-flow model. AB - With rapid urbanization, inundation-induced property losses have become more and more severe. Urban inundation modeling is an effective way to reduce these losses. This paper introduces a simplified urban stormwater inundation simulation model based on the United States Environmental Protection Agency Storm Water Management Model (SWMM) and a geographic information system (GIS)-based diffusive overland-flow model. SWMM is applied for computation of flows in storm sewer systems and flooding flows at junctions, while the GIS-based diffusive overland flow model simulates surface runoff and inundation. One observed rainfall scenario on Haidian Island, Hainan Province, China was chosen to calibrate the model and the other two were used for validation. Comparisons of the model results with field-surveyed data and InfoWorks ICM (Integrated Catchment Modeling) modeled results indicated the inundation model in this paper can provide inundation extents and reasonable inundation depths even in a large study area. PMID- 29236019 TI - Degradation of amyl xanthate by manganese dioxide. AB - Amyl xanthate (AX), a widely used reagent in sulfide mineral flotation, has caused serious environmental problems. Manganese dioxides (MnO2), ubiquitous in natural soils and sediments, are one kind of important oxidant or catalyst in facilitating organic pollutant decomposition. In this study, the oxidative degradation of AX by MnO2 was investigated in batch experiments. It was found that up to 90% AX was decomposed by MnO2 in 30 min and the removal efficiency of AX depended strongly on the loading of MnO2 and pH value in the solution where the reactions closely followed a pseudo-first-order model. The reaction orders with respect to the initial AX concentration, MnO2 concentration and pH value were 0.4573, 0.2034, and -0.1701, respectively. Coexisting metal ions, such as Mn2+, Fe3+, Ca2+ and Mg2+, displayed suppressive effects and the inhibitive capacity of the metal ions followed the order Mn2+ > Fe3+ > Ca2+ > Mg2+. However, the effect of humic acid (HA) on reaction rates was significant only at higher concentrations. This study provided meaningful information to elucidate the oxidative degradation of AX by MnO2. PMID- 29236020 TI - Application of response surface methodology as a new PID tuning method in an electrocoagulation process control case. AB - In this work the application of response surface methodology (RSM) to proportional-integral-derivative (PID) controller parameter tuning for electrocoagulation (EC) treatment of pulp and paper mill wastewater was researched. Dynamic data for two controlled variables (pH and electrical conductivity) were obtained under pseudo random binary sequence (PRBS) input signals applied to manipulated variables (acid and supporting electrolyte flow rates). Third order plus time delay model parameters were evaluated through System Identification ToolboxTM in MATLAB(r). Four level full factorial design was applied to form a design matrix for three controller tuning parameters as factors and to evaluate statistical analysis of the system in terms of integral of square error (ISE), integral of absolute error (IAE), integral of time square error (ITSE) and integral of time absolute error (ITAE) performance criteria as response. Numerical values of the responses for the runs in the design matrices were determined using closed-loop PID control system simulations designed in Simulink(r). Optimum proportional gain, integral action and derivative action values for electrical conductivity control were found to be 1,500 s, 0 s and 16.4636 s respectively. Accordingly, the same optimization scheme was followed for pH control and optimum controller parameters were found to be -8.6970 s, 0.0211 s and 50 s, respectively. Theoretically optimized controller parameters were applied to batch experimental studies. Chemical oxygen demand (COD) removal efficiency and energy consumption of pulp and paper mill wastewater treatment by EC under controlled action of pH at 5.5 and electrical conductivity at 2.72 mS/cm was found to be 85% and 3.87 kWh/m3 respectively. Results showed that multi input multi output (MIMO) control action increased removal efficiency of COD by 15.41% and reduced energy consumption by 6.52% in comparison with treatment under uncontrolled conditions. PMID- 29236021 TI - Enhanced bacterial quorum aggregation on a zeolite capping layer for sustainable inhibition of ammonium release from contaminated sediment. AB - The main objective of this study was to investigate how signal molecules enhance bacterial quorum aggregation on a zeolite capping layer for sustainable inhibition of ammonium release from contaminated sediment. Sediment remediation experiments were carried out by using nitrifying bacteria (WGX10, WGX18), denitrifying bacteria (HF3, HF7) and two kinds of signal molecules (OHHL, C8 HSL). The results showed that nitrifying bacteria and denitrifying bacteria could significantly aggregate on zeolite after adding 1.0 MUM OHHL at a C/N ratio of 7. The maximum ammonium removal of five times the amount of ammonium adsorbed was achieved when 1.0 MUM OHHL was added at the C/N ratio of 7 (the bio-regeneration rate was up to 88.32%), which was 1.24-2.02 times the ammonium removal amount at C/N ratios of 3, 5, 9. The concentration of total nitrogen in the overlying water was no more than 0.8 mg/L during four rounds of sediment remediation experiments. In addition, the bio-regeneration rate was up to 71.20%, which achieved sustainable inhibition of ammonium release from contaminated sediment. PMID- 29236022 TI - Synthesis of zeolites with different chemical and textural properties for metal ions removal from aqueous solutions. AB - In this study beta-zeolite, ferrierite and partially delaminated PREFER (precursor of ferrierite) zeolites with several chemical and textural properties were synthesized for the removal of zinc and lead ion metals from their respective solutions. Adsorption experiments involving the suspension of tiny amounts of these solids in aqueous solutions containing either Zn2+ or Pb2+ showed that the removal of these metals at a considerable extent may be attained. Among the studied materials, beta-zeolite displayed the better performance in metal ion removal, which may be ascribed to its higher aluminum content, surface area and external surface area, that allows a greater density and availability of ion adsorption active sites. Kinetic data from a pseudo-second-order model indicate that the chemical interaction among metal ions and active sites is the rate-limiting step. Furthermore, the better performance of the beta-zeolite displayed in reusability testing makes it a potential adsorbent for future applications in the treatment of effluents containing toxic metals. PMID- 29236023 TI - Effect of COD/N ratio on N2O production during nitrogen removal by aerobic granular sludge. AB - N2O-production was investigated during nitrogen removal using aerobic granular sludge (AGS) technology. A pilot sequencing batch reactor (SBR) with AGS achieved an effluent in accordance with national discharge limits, although presented a nitrite accumulation rate of 95.79% with no simultaneous nitrification denitrification. N2O production was 2.06 mg L-1 during the anoxic phase, with N2O emission during air pulses and the aeration phase of 1.6% of the nitrogen loading rate. Batch tests with AGS from the pilot reactor verified that at the greatest COD/N ratio (1.55), the N2O production (1.08 mgN2O-N L-1) and consumption (up to 0.05 mgN2O-N L-1), resulted in the lowest remaining dissolved N2O (0.03 mgN2O-N L 1), stripping the minimum N2O gas (0.018 mgN2O-N L-1). Conversely, the carbon supply shortage, under low C/N ratios, increased N2O emission (0.040 mgN2O-N L 1), due to incomplete denitrification. High abundance of ammonia-oxidizing and low abundance of nitrite-oxidizing bacteria were found, corroborating the fact of partial nitrification. A denitrifying heterotrophic community, represented mainly by Pseudoxanthomonas, was predominant in the AGS. Overall, the AGS showed stable partial nitrification ability representing capital and operating cost savings. The SBR operation flexibility could be advantageous for controlling N2O emissions, and extending the anoxic phase would benefit complete denitrification in cases of low C/N influents. PMID- 29236024 TI - Heterotrophic nitrogen removal in Bacillus sp. K5: involvement of a novel hydroxylamine oxidase. AB - An aerobic denitrifying bacterium isolated from a bio-trickling filter treating NOx, Bacillus sp. K5, is able to convert ammonium to nitrite, in which hydroxylamine oxidase (HAO) plays a critical role. In the present study, the performance for simultaneous nitrification and denitrification was investigated with batch experiments and an HAO was purified by an anion-exchange and gel filtration chromatography from strain K5. The purified HAO's molecular mass was determined by SDS-PAGE and its activity by measuring the change in the concentration of ferricyanide, the electron acceptor. Results showed that as much as 87.8 mg L-1 ammonium-N was removed without nitrite accumulation within 24 hours in the sodium citrate medium at C/N of 15. The HAO isolated from the strain K5 was approximately 71 KDa. With hydroxylamine (NH2OH) as a substrate and potassium ferricyanide as an electron acceptor, the enzyme was capable of oxidizing NH2OH to nitrite in vitro when the pH varied from 7 to 9 and temperature ranged from 25 degrees C to 40 degrees C. This is the first time that an HAO has been purified from the Bacillus genus, and the findings revealed that it is distinctive in its molecular mass and enzyme properties. PMID- 29236026 TI - Corrigendum: Water Science and Technology 76 (5), 1011-1021: Removal of lead (II) from aqueous solutions using rice straw, Hayam Amer, Ahmed El-Gendy and Salah El Haggar, doi: 10.2166/wst.2017.249. PMID- 29236025 TI - Treatment performance, nitrous oxide production and microbial community under low ammonium wastewater in a CANON process. AB - To investigate the characteristics of anaerobic ammonia oxidation for treating low-ammonium wastewater, a continuous-flow completely autotrophic nitrogen removal over nitrite (CANON) biofilm reactor was studied. At a temperature of 32 +/- 1 degrees C and a pH between 7.5 and 8.2, two operational experiments were performed: the first one fixed the hydraulic retention time (HRT) at 10 h and gradually reduced the influent ammonium concentrations from 210 to 50 mg L-1; the second one fixed the influent ammonium concentration at 30 mg L-1 and gradually decreased the HRT from 10 to 3 h. The results revealed that the total nitrogen removal efficiency exceeded 80%, with a corresponding total nitrogen removal rate of 0.26 +/- 0.01 kg N m-3 d-1 at the final low ammonium concentration of 30 mg L 1. Small amounts of nitrous oxide (N2O) up to 0.015 +/- 0.004 kg m-3 d-1 at the ammonium concentration of 210 mg L-1 were produced in the CANON process and decreased with the decrease in the influent ammonium loads. High-throughput pyrosequencing analysis indicated that the dominant functional bacteria 'Candidatus Kuenenia' under high influent ammonium levels were gradually succeeded by Armatimonadetes_gp5 under low influent ammonium levels. PMID- 29236029 TI - Fracture Assessment of PEEK under Static Loading by Means of the Local Strain Energy Density. AB - Polyetheretherketone (PEEK) has gained interest in many industrial applications due to its high strength-to-weight ratio, excellent heat tolerance and high corrosion resistance. Stress concentrators such as notches and geometrical discontinuities are present in many such components necessitating the reliable assessment of notch sensitivity of PEEK in monotonic tension. Here we evaluate the applicability of the strain energy density (SED) approach for the assessment of the fracture strength of experimentally tested notched geometries subject to corrosion. The fracture behavior of neat, circumferentially razor-grooved dog bone specimens and circumferentially U-notched specimens with different notch radii can be predicted with a discrepancy lower than +/-10%. Reliable predictions are shown on two previously published datasets employing both computed and published mechanical properties as inputs for the SED calculations. This report presents the first successful application of SED for PEEK as well as the successful prediction of tensile behavior in corrosive environments. This opens the road towards future applications of PEEK in fields its compliant use is of growing popularity. PMID- 29236028 TI - Beyond Disaster Preparedness: Building a Resilience-Oriented Workforce for the Future. AB - Enhancing citizens' and communities' resilience is critical to adapt successfully to ongoing challenges faced by communities, as well as acute shocks resulting from disasters. While significant progress has been made in this area, several research and practice gaps remain. A crucial next step to advance resilience is the development of a resilience-oriented workforce. This narrative review examines existing literature to determine key components of a resilience-oriented workforce, with a focus on organizational structures, training and education, and leadership models. Reviewed articles spanned a variety of study types, including needs assessments of existing workforce, program evaluations, and reviews/commentaries. A resilience-oriented workforce spans many disciplines and training programs will need to reflect that. It requires a collaborative organizational model that promotes information sharing structures. Leadership models should foster a balance between workforce autonomy and operation as a collective entity. Optimal strategies to develop a resilience-oriented workforce have yet to be realized and future research will need to collect and synthesize data to promote and evaluate the growth of this field. PMID- 29236027 TI - Simvastatin Inhibits Cell Proliferation and Migration in Human Anaplastic Thyroid Cancer. AB - Malignant human anaplastic thyroid cancer (ATC) is pertinacious to conventional therapies. The present study investigated the anti-cancer activity of simvastatin and its underlying regulatory mechanism in cultured ATC cells. Simvastatin (0-20 MUM) concentration-dependently reduced cell viability and relative colony formation. Depletions of mevalonate (MEV) and geranylgeranyl pyrophosphate (GGpp) by simvastatin induced G1 arrest and increased apoptotic cell populations at the sub-G1 phase. Adding MEV and GGpp prevented the simvastatin-inhibited cell proliferation. Immunoblotting analysis illustrated that simvastatin diminished the activation of RhoA and Rac1 protein, and this effect was prevented by pre treatment with MEV and GGpp. Simvastatin increased the levels of p21cip and p27kip proteins and reduced the levels of hyperphosphorylated-Rb, E2F1 and CCND1 proteins. Adding GGpp abolished the simvastatin-increased levels of p27kip protein, and the GGpp-caused effect was abolished by Skp2 inhibition. Introduction of Cyr61 siRNA into ATC cells prevented the epidermal growth factor (EGF)-enhanced cell migration. The EGF-induced increases of Cyr61 protein expression and cell migration were prevented by simvastatin. Taken together, these results suggest that simvastatin induced ATC proliferation inhibition through the deactivation of RhoA/Rac1 protein and overexpression of p21cip and p27kip, and migration inhibition through the abrogation of Cyr61 protein expression. PMID- 29236030 TI - The Tumor Suppressor p53 in Mucosal Melanoma of the Head and Neck. AB - Despite worldwide prevention programs, the incidence for cutaneous melanoma is continuously increasing. Mucosal melanoma (MM) represents a rare but highly aggressive phenotype of common melanoma with predilection in the sinonasal system. Far away from ultraviolet sun exposure, the molecular mechanisms underlying tumorigenesis and the highly aggressive clinical behavior are poorly understood. In many solid malignomas of the head and neck region, p53 tumor suppressor functions as oncogene due to p53 protein stabilizing mutation. Interestingly, the vast majority of MM demonstrates constitutively expressed p53 protein, with protein stabilizing mutations being rare. Abrogated activation of p53 target genes results in derogation of the apoptotic signal cascade and contributes to the strong resistance against chemotherapeutic agents activating p53 dependent apoptosis. The current review illustrates the role of p53 and its pathway in MM. PMID- 29236031 TI - SACFIR: SDN-Based Application-Aware Centralized Adaptive Flow Iterative Reconfiguring Routing Protocol for WSNs. AB - Smart reconfiguration of a dynamic networking environment is offered by the central control of Software-Defined Networking (SDN). Centralized SDN-based management architectures are capable of retrieving global topology intelligence and decoupling the forwarding plane from the control plane. Routing protocols developed for conventional Wireless Sensor Networks (WSNs) utilize limited iterative reconfiguration methods to optimize environmental reporting. However, the challenging networking scenarios of WSNs involve a performance overhead due to constant periodic iterative reconfigurations. In this paper, we propose the SDN-based Application-aware Centralized adaptive Flow Iterative Reconfiguring (SACFIR) routing protocol with the centralized SDN iterative solver controller to maintain the load-balancing between flow reconfigurations and flow allocation cost. The proposed SACFIR's routing protocol offers a unique iterative path selection algorithm, which initially computes suitable clustering based on residual resources at the control layer and then implements application-aware threshold-based multi-hop report transmissions on the forwarding plane. The operation of the SACFIR algorithm is centrally supervised by the SDN controller residing at the Base Station (BS). This paper extends SACFIR to SDN-based Application-aware Main-value Centralized adaptive Flow Iterative Reconfiguring (SAMCFIR) to establish both proactive and reactive reporting. The SAMCFIR transmission phase enables sensor nodes to trigger direct transmissions for main value reports, while in the case of SACFIR, all reports follow computed routes. Our SDN-enabled proposed models adjust the reconfiguration period according to the traffic burden on sensor nodes, which results in heterogeneity awareness, load-balancing and application-specific reconfigurations of WSNs. Extensive experimental simulation-based results show that SACFIR and SAMCFIR yield the maximum scalability, network lifetime and stability period when compared to existing routing protocols. PMID- 29236032 TI - Accurate Sample Time Reconstruction of Inertial FIFO Data. AB - In the context of modern cyber-physical systems, the accuracy of underlying sensor data plays an increasingly important role in sensor data fusion and feature extraction. The raw events of multiple sensors have to be aligned in time to enable high quality sensor fusion results. However, the growing number of simultaneously connected sensor devices make the energy saving data acquisition and processing more and more difficult. Hence, most of the modern sensors offer a first-in-first-out (FIFO) interface to store multiple data samples and to relax timing constraints, when handling multiple sensor devices. However, using the FIFO interface increases the negative influence of individual clock drifts introduced by fabrication inaccuracies, temperature changes and wear-out effects onto the sampling data reconstruction. Furthermore, additional timing offset errors due to communication and software latencies increases with a growing number of sensor devices. In this article, we present an approach for an accurate sample time reconstruction independent of the actual clock drift with the help of an internal sensor timer. Such timers are already available in modern sensors, manufactured in micro-electromechanical systems (MEMS) technology. The presented approach focuses on calculating accurate time stamps using the sensor FIFO interface in a forward-only processing manner as a robust and energy saving solution. The proposed algorithm is able to lower the overall standard deviation of reconstructed sampling periods below 40 MU s, while run-time savings of up to 42% are achieved, compared to single sample acquisition. PMID- 29236033 TI - Mast Cells Interact with Endothelial Cells to Accelerate In Vitro Angiogenesis. AB - Angiogenesis is a complex process that involves interactions between endothelial cells and various other cell types as well as the tissue microenvironment. Several previous studies have demonstrated that mast cells accumulate at angiogenic sites. In spite of the evidence suggesting a relationship between mast cells and angiogenesis, the association of mast cells and endothelial cells remains poorly understood. The present study aims to investigate the relationship between mast cells and endothelial cells during in vitro angiogenesis. When endothelial cells were co-cultured with mast cells, angiogenesis was stimulated. Furthermore, there was direct intercellular communication via gap junctions between the two cell types. In addition, the presence of mast cells stimulated endothelial cells to release angiogenic factors. Moreover, conditioned medium from the co-cultures also stimulated in vitro angiogenesis. The results from this investigation demonstrate that mast cells have both direct and indirect proangiogenic effects and provide new insights into the role of mast cells in angiogenesis. PMID- 29236034 TI - Gastric Emptying and Gastrointestinal Transit Compared among Native and Hydrolyzed Whey and Casein Milk Proteins in an Aged Rat Model. AB - Little is known about how milk proteins affect gastrointestinal (GI) transit, particularly for the elderly, in whom digestion has been observed to be slowed. We tested the hypothesis that GI transit is faster for whey than for casein and that this effect is accentuated with hydrolysates, similar to soy. Adult male rats (18 months old) were fed native whey or casein, hydrolyzed whey (WPH) or casein (CPH), hydrolyzed blend (HB; 60% whey:40% casein), or hydrolyzed soy for 14 days then treated with loperamide, prucalopride, or vehicle-control for 7 days. X-ray imaging tracked bead-transit for: gastric emptying (GE; 4 h), small intestine (SI) transit (9 h), and large intestine (LI) transit (12 h). GE for whey was 33 +/- 12% faster than that for either casein or CPH. SI transit was decreased by 37 +/- 9% for casein and 24 +/- 6% for whey compared with hydrolyzed soy, and persisted for casein at 12 h. Although CPH and WPH did not alter transit compared with their respective intact counterparts, fecal output was increased by WPH. Slowed transit by casein was reversed by prucalopride (9-h), but not loperamide. However, rapid GE and slower SI transit for the HB compared with intact forms were inhibited by loperamide. The expected slower GI transit for casein relative to soy provided a comparative benchmark, and opioid receptor involvement was corroborated. Our findings provide new evidence that whey slowed SI transit compared with soy, independent of GE. Increased GI transit from stomach to colon for the HB compared with casein suggests that including hydrolyzed milk proteins in foods may benefit those with slowed intestinal transit. PMID- 29236035 TI - Short-Communication: A Comparison of the In Vitro Angiotensin-1-Converting Enzyme Inhibitory Capacity of Dairy and Plant Protein Supplements. AB - The consumption of supplements based on dairy or plant proteins may be associated with bioactive potential, including angiotensin-1-converting enzyme inhibitory (ACE-1i) activity, which is linked with blood pressure reduction in vivo. To gain insight into this proposed mechanism, the ACE-1i potential of protein-based supplements, including a selection of dairy (n = 10) and plant (n = 5) proteins were in vitro digested. The total digest was filtered and permeate and retentate were obtained. ACE-1i activity was measured as the ability of proteins (pre digestion, 'gastric', permeate, and retentate) to decrease the hydrolysis of furanacroloyl-Phe-Glu-Glu (FAPGG) substrate for the ACE-1 enzyme. Permeate and retentate of dairy proteins exerted a significantly higher ACE-1i activity (mean of 10 proteins: 27.05 +/- 0.2% and 20.7 +/- 0.2%, respectively) compared with pre digestion dairy proteins (16.7 +/- 0.3%). Plant protein exhibited high ACE-1i in 'gastric' and retentate fractions (mean of five proteins: 54.9 +/- 0.6% and 35.7 +/- 0.6%, respectively). The comparison of the in vitro ACE-1i activity of dairy and plant proteins could provide valuable knowledge regarding their specific bioactivities, which could inform their use in the formulation of specific functional supplements that would require testing for blood pressure control in human randomly-controlled studies. PMID- 29236036 TI - Efficient Enzymatic Routes for the Synthesis of New Eight-membered Cyclic beta Amino Acid and beta-Lactam Enantiomers. AB - Efficient enzymatic resolutions are reported for the preparation of new eight membered ring-fused enantiomeric beta-amino acids [(1R,2S)-9 and (1S,2R)-9] and beta-lactams [(1S,8R)-3, (1R,8S)-3 (1S,8R)-4 and (1R,8S)-7], through asymmetric acylation of (+/-)-4 (E > 100) or enantioselective hydrolysis (E > 200) of the corresponding inactivated (+/-)-3 or activated (+/-)-4 beta-lactams, catalyzed by PSIM or CAL-B in an organic solvent. CAL-B-catalyzed ring cleavage of (+/-)-6 (E > 200) resulted in the unreacted (1S,8R)-6, potential intermediate for the synthesis of enantiomeric anatoxin-a. The best strategies, in view of E, reaction rate and product yields, which underline the importance of substrate engineering, are highlighted. PMID- 29236037 TI - Calibration of Binocular Vision Sensors Based on Unknown-Sized Elliptical Stripe Images. AB - Most of the existing calibration methods for binocular stereo vision sensor (BSVS) depend on a high-accuracy target with feature points that are difficult and costly to manufacture and. In complex light conditions, optical filters are used for BSVS, but they affect imaging quality. Hence, the use of a high-accuracy target with certain-sized feature points for calibration is not feasible under such complex conditions. To solve these problems, a calibration method based on unknown-sized elliptical stripe images is proposed. With known intrinsic parameters, the proposed method adopts the elliptical stripes located on the parallel planes as a medium to calibrate BSVS online. In comparison with the common calibration methods, the proposed method avoids utilizing high-accuracy target with certain-sized feature points. Therefore, the proposed method is not only easy to implement but is a realistic method for the calibration of BSVS with optical filter. Changing the size of elliptical curves projected on the target solves the difficulty of applying the proposed method in different fields of view and distances. Simulative and physical experiments are conducted to validate the efficiency of the proposed method. When the field of view is approximately 400 mm * 300 mm, the proposed method can reach a calibration accuracy of 0.03 mm, which is comparable with that of Zhang's method. PMID- 29236038 TI - Adverse Effects of Amoxicillin for Acute Lower Respiratory Tract Infection in Primary Care: Secondary and Subgroup Analysis of a Randomised Clinical Trial. AB - A European placebo-controlled trial of antibiotic treatment for lower respiratory tract infection (LRTI) conducted in 16 primary care practices networks recruited participants between November 2007 and April 2010, and found adverse events (AEs) occurred more often in patients prescribed amoxicillin compared to placebo. This secondary analysis explores the causal relationship and estimates specific AEs (diarrhoea, nausea, rash) due to amoxicillin treatment for LRTI, and if any subgroup is at increased risk of any or a specific AE. A total of 2061 patients were randomly assigned to amoxicillin (1038) and placebo (1023); 595 (28%) were 60 and older. A significantly higher proportion of any AEs (diarrhoea or nausea or rash) (OR = 1.31, 95% CI 1.05-1.64, number needed to harm (NNH) = 24) and of diarrhoea (OR 1.43 95% CI 1.08-1.90, NNH = 29) was reported in the amoxicillin group during the first week after randomisation. Subgroup analysis showed rash was significantly more often reported in males prescribed amoxicillin (interaction term 3.72 95% CI 1.22-11.36; OR of amoxicillin in males 2.79 (95% CI 1.08-7.22). No other subgroup at higher risk was identified. Although the study was not powered for subgroup analysis, this analysis suggests that most patients are likely to be equally harmed when prescribed antibiotics. PMID- 29236039 TI - Teacher Rated School Ethos and Student Reported Bullying-A Multilevel Study of Upper Secondary Schools in Stockholm, Sweden. AB - School ethos refers to the school leadership's purposive efforts to shape and direct the attitudes, values and behaviors needed in order to promote an active learning environment and to prevent the emergence of undesirable behaviors by creating shared meaning and common goals for the school. The aim of this study was to examine how teacher rated aspects of school ethos are linked with manifestations of bullying among 11th grade students. Five teacher-rated sub dimensions of school ethos (staff stability, teacher morale, structure-order, student focus, and academic atmosphere) were examined in relation to student reported perpetration of and exposure to traditional school bullying and cyberbullying. The data material combines student and teacher information from two separate data collections performed in 2016, comprising teachers and students in 58 upper secondary schools in Stockholm. Analyses showed that bullying was associated with all but one of the five sub-dimensions of school ethos, namely structure and order for dealing with bullying behaviors at the school. Results are discussed in light of this counter-intuitive finding. Our findings nevertheless lend support to the idea that the social organization of schools, as reflected in their teacher-rated ethos, can affect individual students' attitudes in a way that prevents the emergence of bullying behavior among students. PMID- 29236040 TI - Impacts of the 2015 Heat Waves on Mortality in the Czech Republic-A Comparison with Previous Heat Waves. AB - This study aimed to assess the impacts of heat waves during the summer of 2015 on mortality in the Czech Republic and to compare them with those of heat waves back to the previous record-breaking summer of 1994. We analyzed daily natural-cause mortality across the country's entire population. A mortality baseline was determined using generalized additive models adjusted for long-term trends, seasonal and weekly cycles, and identified heat waves. Mortality deviations from the baseline were calculated to quantify excess mortality during heat waves, defined as periods of at least three consecutive days with mean daily temperature higher than the 95th percentile of annual distribution. The summer of 2015 was record-breaking in the total duration of heat waves as well as their total heat load. Consequently, the impact of the major heat wave in 2015 on the increase in excess mortality relative to the baseline was greater than during the previous record-breaking heat wave in 1994 (265% vs. 240%). Excess mortality was comparable among the younger age group (0-64 years) and the elderly (65+ years) in the 1994 major heat wave while it was significantly larger among the elderly in 2015. The results suggest that the total heat load of a heat wave needs to be considered when assessing its impact on mortality, as the cumulative excess heat factor explains the magnitude of excess mortality during a heat wave better than other characteristics such as duration or average daily mean temperature during the heat wave. Comparison of the mortality impacts of the 2015 and 1994 major heat waves suggests that the recently reported decline in overall heat-related mortality in Central Europe has abated and simple extrapolation of the trend would lead to biased conclusions even for the near future. Further research is needed toward understanding the additional mitigation measures required to prevent heat-related mortality in the Czech Republic and elsewhere. PMID- 29236041 TI - The Facile Synthesis of Branch-Trunk Ag Hierarchical Nanostructures and Their Applications for High-Performance H2O2 Electrochemical Sensors. AB - A novel branch-trunk Ag hierarchical nanostructure was synthesized via a galvanic replacement reaction combined with microwave-assisted synthesis using Te nanowire as a sacrificial template. The Te nanowire was synthesized via a hydrothermal process. We further investigated the potential application of the obtained hierarchical nanostructures in electrochemical sensor analysis. The results showed that the as-prepared sensor exhibited a wide linear range with 0.05 uM to 1.925 mM (R = 0.998) and the detection limit was estimated to be 0.013 uM (S/N = 3). These results indicate the branch-truck Ag hierarchical nanostructures are an excellent candidate material for sensing applications. PMID- 29236042 TI - Single Channel EEG Artifact Identification Using Two-Dimensional Multi-Resolution Analysis. AB - As a diagnostic monitoring approach, electroencephalogram (EEG) signals can be decoded by signal processing methodologies for various health monitoring purposes. However, EEG recordings are contaminated by other interferences, particularly facial and ocular artifacts generated by the user. This is specifically an issue during continuous EEG recording sessions, and is therefore a key step in using EEG signals for either physiological monitoring and diagnosis or brain-computer interface to identify such artifacts from useful EEG components. In this study, we aim to design a new generic framework in order to process and characterize EEG recording as a multi-component and non-stationary signal with the aim of localizing and identifying its component (e.g., artifact). In the proposed method, we gather three complementary algorithms together to enhance the efficiency of the system. Algorithms include time-frequency (TF) analysis and representation, two-dimensional multi-resolution analysis (2D MRA), and feature extraction and classification. Then, a combination of spectro temporal and geometric features are extracted by combining key instantaneous TF space descriptors, which enables the system to characterize the non stationarities in the EEG dynamics. We fit a curvelet transform (as a MRA method) to 2D TF representation of EEG segments to decompose the given space to various levels of resolution. Such a decomposition efficiently improves the analysis of the TF spaces with different characteristics (e.g., resolution). Our experimental results demonstrate that the combination of expansion to TF space, analysis using MRA, and extracting a set of suitable features and applying a proper predictive model is effective in enhancing the EEG artifact identification performance. We also compare the performance of the designed system with another common EEG signal processing technique-namely, 1D wavelet transform. Our experimental results reveal that the proposed method outperforms 1D wavelet. PMID- 29236043 TI - Stress-Induced Endocrine and Immune Dysfunctions in Caregivers of People with Eating Disorders. AB - Caregivers have to cope repeatedly with acute stressors in their daily lives, and this is associated with disturbances in the hypothalamic-pituitary-adrenal (HPA) axis and the immune system. Such disturbances could contribute to the development of health problems in informal caregivers of people with chronic illnesses, such as eating disorders (EDs). The main objective of this study was to examine endocrine (salivary cortisol levels (Csal)), immune (immunoglobulin-A (IgA)), and psychological (anxiety, mood, and anger feelings) responses to an acute psychological stressor in a sample of informal caregivers of individuals with EDs compared to a sample of non-caregivers. In addition, it also aimed to analyze the potential relationship of the aforementioned endocrine and immune response parameters with psychological variables in the caregivers. Caregivers had lower Csal and IgA levels at all assessment points except baseline. Moreover, they also exhibited lower Csal and IgA responses and greater worsening of mood in response to acute psychosocial stress than the non-caregivers, which suggests that caregivers had dampened endocrine and immune reactivity to acute stress. On the other hand, endocrine and immune parameters were unrelated to psychological variables. These findings advance our understanding of how a chronically stressed population reacts to acute stress, and should be considered for the development of effective interventions focused on stress management that could help caregivers to reduce their stress levels, which, in turn, would improve their health. PMID- 29236044 TI - Effect of Guar Gum with Sorbitol Coating on the Properties and Oil Absorption of French Fries. AB - This paper investigated the effects of guar gum with sorbitol coating on the oil absorption of French fries by combined dye oil methods, confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). The results showed that pretreatment of blanching with calcium ions and coating with guar gum and sorbitol could significantly reduce the structural oil (STO) and penetrated surface oil (PSO) of French fries and have no negative effects on its texture and also effectively control the final moisture content (p < 0.05). Compared with control or samples coated with guar gum (blanching with or without calcium ions), the total oil (TO) of French fries with guar gum and sorbitol reduced by 50.8%, 33.1% and 30.6%, respectively. CLSM photographs confirmed that STO significantly reduced after coating with guar gum and sorbitol, followed by PSO. In the process of frying, the coatings of guar gum or guar gum with sorbitol could effectively prevent oil from infiltrating the potato tissue, which can be seen in the SEM photographs. The barrier properties of French fries were enhanced by coating guar gum, and sorbitol was added to avoid pores and cracks. Blanching with calcium ion can significantly reduce the final moisture content of coating French fries. PMID- 29236045 TI - Clodronate as a Therapeutic Strategy against Osteoarthritis. AB - Osteoarthritis (OA), the most prevalent musculoskeletal pathology, is mainly characterized by the progressive degradation of articular cartilage due to an imbalance between anabolic and catabolic processes. Consequently, OA has been associated with defects in the chondrocitic differentiation of progenitor stem cells (PSCs). In addition, SOX9 is the transcription factor responsible for PSCs chondrogenic commitment. To evaluate the effects of the non-amino bisphosphonate clodronate in OA patients we investigated SOX9 gene expression in circulating progenitor cells (CPCs) and in an in vitro OA model. We evaluated pain intensity, mental and physical performance in OA patients, as well as serum biomarkers related to bone metabolism. In addition, in order to improve therapeutic strategies, we assayed nanoparticle-embedded clodronate (NPs-clo) in an in vitro model of chondrogenic differentiation. Our data showed upregulation of SOX9 gene expression upon treatment, suggesting an increase in chondrocytic commitment. Clodronate also reduced osteoarticular pain and improved mental and physical performance in patients. Furthermore, NPs-clo stimulated SOX9 expression more efficaciously than clodronate alone. Clodronate may therefore be considered a good therapeutic tool against OA; its formulation in nanoparticles may represent a promising challenge to counteract cartilage degeneration. PMID- 29236048 TI - Adaptive Wavelet Coding Applied in a Wireless Control System. AB - Wireless control systems can sense, control and act on the information exchanged between the wireless sensor nodes in a control loop. However, the exchanged information becomes susceptible to the degenerative effects produced by the multipath propagation. In order to minimize the destructive effects characteristic of wireless channels, several techniques have been investigated recently. Among them, wavelet coding is a good alternative for wireless communications for its robustness to the effects of multipath and its low computational complexity. This work proposes an adaptive wavelet coding whose parameters of code rate and signal constellation can vary according to the fading level and evaluates the use of this transmission system in a control loop implemented by wireless sensor nodes. The performance of the adaptive system was evaluated in terms of bit error rate (BER) versus E b / N 0 and spectral efficiency, considering a time-varying channel with flat Rayleigh fading, and in terms of processing overhead on a control system with wireless communication. The results obtained through computational simulations and experimental tests show performance gains obtained by insertion of the adaptive wavelet coding in a control loop with nodes interconnected by wireless link. These results enable the use of this technique in a wireless link control loop. PMID- 29236047 TI - hASC and DFAT, Multipotent Stem Cells for Regenerative Medicine: A Comparison of Their Potential Differentiation In Vitro. AB - Adipose tissue comprises both adipose and non-adipose cells such as mesenchymal stem cells. These cells show a surface antigenic profile similar to that of bone marrow-derived MSC. The cells derived from the dedifferentiation of mature adipocytes (DFAT) are another cell population with characteristics of stemness. The aim of this study is to provide evidence of the stemness, proliferation, and differentiation of human adipose stem cells (hASC) and DFAT obtained from human subcutaneous AT and evaluate their potential use in regenerative medicine. Cell populations were studied by histochemical and molecular biology techniques. Both hASC and DFAT were positive for MSC markers. Their proliferative capacity was similar and both populations were able to differentiate into osteogenic, chondrogenic, and adipogenic lineages. DFAT were able to accumulate lipids and their lipoprotein lipase and adiponectin gene expression were high. Alkaline phosphatase and RUNX2 gene expression were greater in hASC than in DFAT at 14 days but became similar after three weeks. Both cell populations were able to differentiate into chondrocytes, showing positive staining with Alcian Blue and gene expression of SOX9 and ACAN. In conclusion, both hASC and DFAT populations derived from AT have a high differentiation capacity and thus may have applications in regenerative medicine. PMID- 29236046 TI - Advances in Proteomic Techniques for Cytokine Analysis: Focus on Melanoma Research. AB - Melanoma is a skin cancer with permanently increasing incidence and resistance to therapies in advanced stages. Reports of spontaneous regression and tumour infiltration with T-lymphocytes makes melanoma candidate for immunotherapies. Cytokines are key factors regulating immune response and intercellular communication in tumour microenvironment. Cytokines may be used in therapy of melanoma to modulate immune response. Cytokines also possess diagnostic and prognostic potential and cytokine production may reflect effects of immunotherapies. The purpose of this review is to give an overview of recent advances in proteomic techniques for the detection and quantification of cytokines in melanoma research. Approaches covered span from mass spectrometry to immunoassays for single molecule detection (ELISA, western blot), multiplex assays (chemiluminescent, bead-based (Luminex) and planar antibody arrays), ultrasensitive techniques (Singulex, Simoa, immuno-PCR, proximity ligation/extension assay, immunomagnetic reduction assay), to analyses of single cells producing cytokines (ELISpot, flow cytometry, mass cytometry and emerging techniques for single cell secretomics). Although this review is focused mainly on cancer and particularly melanoma, the discussed techniques are in general applicable to broad research field of biology and medicine, including stem cells, development, aging, immunology and intercellular communication. PMID- 29236049 TI - Effect of Monthly, High-Dose, Long-Term Vitamin D on Lung Function: A Randomized Controlled Trial. AB - Although observational studies suggest positive vitamin D-lung function associations, randomized trials are inconsistent. We examined effects of vitamin D supplementation on lung function. We recruited 442 adults (50-84 years, 58% male) into a randomized, double-blinded, placebo-controlled trial. Participants received, for 1.1 years (median; range = 0.9-1.5 years), either (1) vitamin D3 200,000 IU, followed by monthly 100,000 IU doses (n = 226); or (2) placebo monthly (n = 216). At baseline and follow-up, spirometry yielded forced expiratory volume in 1 s (FEV1; primary outcome). Mean (standard deviation) 25 hydroxyvitamin D increased from 61 (24) nmol/L at baseline to 119 (45) nmol/L at follow-up in the vitamin D group, but was unchanged in the placebo group. There were no significant lung function improvements (vitamin D versus placebo) in the total sample, vitamin D-deficient participants or asthma/chronic obstructive pulmonary disease (COPD) participants. However, among ever-smokers (n = 217), the mean (95% confidence interval) FEV1 increase in the vitamin D versus placebo was 57 (4, 109) mL (p = 0.03). FEV1 increases were larger among vitamin D-deficient ever-smokers (n = 54): 122 (8, 236) mL (p = 0.04). FEV1 improvements were largest among ever-smokers with asthma/COPD (n = 60): 160 (53, 268) mL (p = 0.004). Thus, vitamin D supplementation did not improve lung function among everyone, but benefited ever-smokers, especially those with vitamin D deficiency or asthma/COPD. PMID- 29236051 TI - Synchrotron-Based Pencil Beam Scanning Nozzle with an Integrated Mini-Ridge Filter: A Dosimetric Study to Optimize Treatment Delivery. AB - A mini-ridge filter is often used to widen the Bragg peak in the longitudinal direction at low energies but not high energies. To facilitate the clinical use of a mini-ridge filter, we performed a planning study for the feasibility of a mini-ridge filter as an integral part of the synchrotron nozzle (IMRF). Dose models with and without IMRF were commissioned in a commercial Treatment planning system (TPS). Dosimetric characteristics in a homogenous water phantom were compared between plans with and without IMRF for a fixed spread-out Bragg peak width of 4 cm with distal ranges varying from 8 to 30 g/cm2. Six clinical cases were then used to compare the plan quality between plans. The delivery efficiency was also compared between plans in both the phantom and the clinical cases. The Bragg peak width was increased by 0.18 cm at the lowest energy and by only about 0.04 cm at the highest energy. The IMRF increased the spot size (sigma) by up to 0.1 cm at the lowest energy and by only 0.02 cm at the highest energy. For the phantom, the IMRF negligibly affected dose at high energies but increased the lateral penumbra by up to 0.12 cm and the distal penumbra by up to 0.06 cm at low energies. For the clinical cases, the IMRF slightly increased dose to the organs at risk. However, the beam delivery time was reduced from 18.5% to 47.1% for the lung, brain, scalp, and head and neck cases, and dose uniformities of target were improved up to 2.9% for these cases owing to the reduced minimum monitor unit effect. In conclusion, integrating a mini-ridge filter into a synchrotron nozzle is feasible for improving treatment efficiency without significantly sacrificing the plan quality. PMID- 29236050 TI - Molecular Markers for Interspecies Transmission of Avian Influenza Viruses in Mammalian Hosts. AB - In the last decade, a wide range of avian influenza viruses (AIVs) have infected various mammalian hosts and continuously threaten both human and animal health. It is a result of overcoming the inter-species barrier which is mostly associated with gene reassortment and accumulation of mutations in their gene segments. Several recent studies have shed insights into the phenotypic and genetic changes that are involved in the interspecies transmission of AIVs. These studies have a major focus on transmission from avian to mammalian species due to the high zoonotic potential of the viruses. As more mammalian species have been infected with these viruses, there is higher risk of genetic evolution of these viruses that may lead to the next human pandemic which represents and raises public health concern. Thus, understanding the mechanism of interspecies transmission and molecular determinants through which the emerging AIVs can acquire the ability to transmit to humans and other mammals is an important key in evaluating the potential risk caused by AIVs among humans. Here, we summarize previous and recent studies on molecular markers that are specifically involved in the transmission of avian-derived influenza viruses to various mammalian hosts including humans, pigs, horses, dogs, and marine mammals. PMID- 29236053 TI - Cut-Off Values of Hematologic Parameters to Predict the Number of Alpha Genes Deleted in Subjects with Deletional Alpha Thalassemia. AB - Most alpha-thalassemia cases are caused by deletions of the structural alpha globin genes. The degree of microcytosis and hypochromia has been correlated with the number of affected alpha-globin genes, suggesting a promising role of hematologic parameters as predictive diagnostic tools. However, cut-off points for these parameters to discriminate between the different subtypes of alpha thalassemia are yet to be clearly defined. Six hematologic parameters (RBC, Hb, MCV, MCH, MCHC and RDW) were evaluated in 129 cases of deletional alpha thalassemia (56 heterozygous alpha+ thalassemia, 36 homozygous alpha+ thalassemia, 29 heterozygous alpha0 thalassemia and 8 cases of Hb H disease). A good correlation between the number of deleted alpha genes and MCV (r = -0.672, p < 0.001), MCH (r = -0.788, p < 0.001) and RDW (r = 0.633, p < 0.001) was observed. The presence of an alpha0 allele should be discarded in individuals with microcytosis without iron deficiency and normal values of Hb A2 and Hb F with MCH < 23.40 pg. Furthermore, MCH < 21.90 pg and/or MCV < 70.80 fL are strongly suggestive of the presence of one alpha0 allele. Finally, an accurate presumptive diagnosis of Hb H disease can be made if both RDW >= 20% and MCH < 19 pg are seen. PMID- 29236054 TI - Genome-Wide Profiling of Small RNAs and Degradome Revealed Conserved Regulations of miRNAs on Auxin-Responsive Genes during Fruit Enlargement in Peaches. AB - Auxin has long been known as a critical phytohormone that regulates fruit development in plants. However, due to the lack of an enlarged ovary wall in the model plants Arabidopsis and rice, the molecular regulatory mechanisms of fruit division and enlargement remain unclear. In this study, we performed small RNA sequencing and degradome sequencing analyses to systematically explore post transcriptional regulation in the mesocarp at the hard core stage following treatment of the peach (Prunus persica L.) fruit with the synthetic auxin alpha naphthylacetic acid (NAA). Our analyses identified 24 evolutionarily conserved miRNA genes as well as 16 predicted genes. Experimental verification showed that the expression levels of miR398 and miR408b were significantly upregulated after NAA treatment, whereas those of miR156, miR160, miR166, miR167, miR390, miR393, miR482, miR535 and miR2118 were significantly downregulated. Degradome sequencing coupled with miRNA target prediction analyses detected 119 significant cleavage sites on several mRNA targets, including SQUAMOSA promoter binding protein-like (SPL), ARF, (NAM, ATAF1/2 and CUC2) NAC, Arabidopsis thaliana homeobox protein (ATHB), the homeodomain-leucine zipper transcription factor revoluta(REV), (teosinte-like1, cycloidea and proliferating cell factor1) TCP and auxin signaling F-box protein (AFB) family genes. Our systematic profiling of miRNAs and the degradome in peach fruit suggests the existence of a post-transcriptional regulation network of miRNAs that target auxin pathway genes in fruit development. PMID- 29236052 TI - microRNAs in Parkinson's Disease: From Pathogenesis to Novel Diagnostic and Therapeutic Approaches. AB - Parkinson's disease (PD) is the most prevalent central nervous system (CNS) movement disorder and the second most common neurodegenerative disease overall. PD is characterized by the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc) within the midbrain, accumulation of alpha-synuclein (alpha-SYN) in Lewy bodies and neurites and excessive neuroinflammation. The neurodegenerative processes typically begin decades before the appearance of clinical symptoms. Therefore, the diagnosis is achievable only when the majority of the relevant DAergic neurons have already died and for that reason available treatments are only palliative at best. The causes and mechanism(s) of this devastating disease are ill-defined but complex interactions between genetic susceptibility and environmental factors are considered major contributors to the etiology of PD. In addition to the role of classical gene mutations in PD, the importance of regulatory elements modulating gene expression has been increasingly recognized. One example is the critical role played by microRNAs (miRNAs) in the development and homeostasis of distinct populations of neurons within the CNS and, in particular, in the context of PD. Recent reports demonstrate how distinct miRNAs are involved in the regulation of PD genes, whereas profiling approaches are unveiling variations in the abundance of certain miRNAs possibly relevant either to the onset or to the progression of the disease. In this review, we provide an overview of the miRNAs recently found to be implicated in PD etiology, with particular focus on their potential relevance as PD biomarkers, as well as their possible use in PD targeted therapy. PMID- 29236055 TI - Hyaluronan Production by Renomedullary Interstitial Cells: Influence of Endothelin, Angiotensin II and Vasopressin. AB - The content of hyaluronan (HA) in the interstitium of the renal medulla changes in relation to body hydration status. We investigated if hormones of central importance for body fluid homeostasis affect HA production by renomedullary interstitial cells in culture (RMICs). Simultaneous treatment with vasopressin and angiotensin II (Ang II) reduced HA by 69%. No change occurred in the mRNA expressions of hyaluronan synthase 2 (HAS2) or hyaluronidases (Hyals), while Hyal activity in the supernatant increased by 67% and CD44 expression reduced by 42%. The autocoid endothelin (ET-1) at low concentrations (10-10 and 10-8 M) increased HA 3-fold. On the contrary, at a high concentration (10-6 M) ET-1 reduced HA by 47%. The ET-A receptor antagonist BQ123 not only reversed the reducing effect of high ET-1 on HA, but elevated it to the same level as low concentration ET-1, suggesting separate regulating roles for ET-A and ET-B receptors. This was corroborated by the addition of ET-B receptor antagonist BQ788 to low concentration ET-1, which abolished the HA increase. HAS2 and Hyal2 mRNA did not alter, while Hyal1 mRNA was increased at all ET-1 concentrations tested. Hyal activity was elevated the most by high ET-1 concentration, and blockade of ET-A receptors by BQ123 prevented about 30% of this response. The present study demonstrates an important regulatory influence of hormones involved in body fluid balance on HA handling by RMICs, thereby supporting the concept of a dynamic involvement of interstitial HA in renal fluid handling. PMID- 29236056 TI - The Potential of Frog Skin-Derived Peptides for Development into Therapeutically Valuable Immunomodulatory Agents. AB - The aim of this article is to review the immunoregulatory actions of frog skin derived peptides in order to assess their potential as candidates for immunomodulatory or anti-inflammatory therapy. Frog skin peptides with demonstrable immunomodulatory properties have been isolated from skin secretions of a range of species belonging to the families Alytidae, Ascaphidae, Discoglossidae, Leptodactylidae, Pipidae and Ranidae. Their effects upon production of inflammatory and immunoregulatory cytokines by target cells have been evaluated ex vivo and effects upon cytokine expression and immune cell activity have been studied in vivo by flow cytometry after injection into mice. The naturally-occurring peptides and/or their synthetic analogues show complex and variable actions on the production of proinflammatory (TNF-alpha, IL-1beta, IL-12, IL-23, IL-8, IFN-gamma and IL-17), pleiotropic (IL-4 and IL-6) and immunosuppressive (IL-10 and TGF-beta) cytokines by peripheral and spleen cells, peritoneal cells and/or isolated macrophages. The effects of frenatin 2.1S include enhancement of the activation state and homing capacity of Th1-type lymphocytes and NK cells in the mouse peritoneal cavity, as well as the promotion of their tumoricidal capacities. Overall, the diverse effects of frog skin derived peptides on the immune system indicate their potential for development into therapeutic agents. PMID- 29236058 TI - Exploring the Optical and Morphological Properties of Ag and Ag/TiO2 Nanocomposites Grown by Supersonic Cluster Beam Deposition. AB - Nanocomposite systems and nanoparticle (NP) films are crucial for many applications and research fields. The structure-properties correlation raises complex questions due to the collective structure of these systems, often granular and porous, a crucial factor impacting their effectiveness and performance. In this framework, we investigate the optical and morphological properties of Ag nanoparticles (NPs) films and of Ag NPs/TiO2 porous matrix films, one-step grown by supersonic cluster beam deposition. Morphology and structure of the Ag NPs film and of the Ag/TiO2 (Ag/Ti 50-50) nanocomposite are related to the optical properties of the film employing spectroscopic ellipsometry (SE). We employ a simple Bruggeman effective medium approximation model, corrected by finite size effects of the nano-objects in the film structure to gather information on the structure and morphology of the nanocomposites, in particular porosity and average NPs size for the Ag/TiO2 NP film. Our results suggest that SE is a simple, quick and effective method to measure porosity of nanoscale films and systems, where standard methods for measuring pore sizes might not be applicable. PMID- 29236057 TI - Development of Houttuynia cordata Extract-Loaded Solid Lipid Nanoparticles for Oral Delivery: High Drug Loading Efficiency and Controlled Release. AB - Houttuynia cordata (H. cordata) has been used for diuresis and detoxification in folk medicine as well as a herbal medicine with antiviral and antibacterial activities. H. cordata extract-loaded solid lipid nanoparticles (H-SLNs) were prepared with various concentration of poloxamer 188 or poloxamer 407 by a hot homogenization and ultrasonication method. H-SLNs dispersion was freeze-dried with or without trehalose as a cryoprotectant. The physicochemical characteristics of H-SLNs were evaluated by dynamic laser scattering (DLS), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). Additionally, the in vitro release and in vitro cytotoxicity of H-SLNs were measured. Encapsulation efficiencies of H-SLNs (as quercitrin) were 92.9-95.9%. The SEM images of H-SLNs showed that H-SLNs have a spherical morphology. DSC and FT-IR showed that there were no interactions between ingredients. The increased extent of particle size of freeze-dried H-SLNs with trehalose was significantly lower than that of H-SLNs without trehalose. H-SLNs provided sustained release of quercitrin from H. cordata extracts. Cell viability of Caco-2 cells was over 70% according to the concentration of various formulation. Therefore, it was suggested that SLNs could be good carrier for administering H. cordata extracts. PMID- 29236059 TI - The Toxicity of Nanoparticles Depends on Multiple Molecular and Physicochemical Mechanisms. AB - Nanotechnology is an emerging discipline that studies matters at the nanoscale level. Eventually, the goal is to manipulate matters at the atomic level to serve mankind. One growing area in nanotechnology is biomedical applications, which involve disease management and the discovery of basic biological principles. In this review, we discuss characteristics of nanomaterials, with an emphasis on transition metal oxide nanoparticles that influence cytotoxicity. Identification of those properties may lead to the design of more efficient and safer nanosized products for various industrial purposes and provide guidance for assessment of human and environmental health risk. We then investigate biochemical and molecular mechanisms of cytotoxicity that include oxidative stress-induced cellular events and alteration of the pathways pertaining to intracellular calcium homeostasis. All the stresses lead to cell injuries and death. Furthermore, as exposure to nanoparticles results in deregulation of the cell cycle (i.e., interfering with cell proliferation), the change in cell number is a function of cell killing and the suppression of cell proliferation. Collectively, the review article provides insights into the complexity of nanotoxicology. PMID- 29236061 TI - The Microstructure of Nanocrystalline TiB2 Films Prepared by Chemical Vapor Deposition. AB - Nanocrystalline titanium diboride (TiB2) ceramics films were prepared on a high purity graphite substrate via chemical vapor deposition (CVD). The substrate was synthesized by a gas mixture of TiCl4, BCl3, and H2 under 1000 degrees C and 10 Pa. Properties and microstructures of TiB2 films were also examined. The as deposited TiB2 films had a nano-sized grain structure and the grain size was around 60 nm, which was determined by X-ray diffraction, field emission scanning electron microscopy, and transmission electron microscopy. Further research found that a gas flow ratio of TiCl4/BCl3 had an influence on the film properties and microstructures. The analyzed results illustrated that the grain size of the TiB2 film obtained with a TiCl4/BCl3 gas flow ratio of 1, was larger than the grain size of the as-prepared TiB2 film prepared with a stoichiometric TiCl4/BCl3 gas flow ratio of 0.5. In addition, the films deposited faster at excessive TiCl4. However, under the condition of different TiCl4/BCl3 gas flow ratios, all of the as-prepared TiB2 films have a preferential orientation growth in the (100) direction. PMID- 29236060 TI - The Use of Poly-d,l-lactic Acid (PDLLA) Devices for Bone Augmentation Techniques: A Systematic Review. AB - Poly-d,l-lactic acid (PDLLA) has been proposed in dentistry for regenerative procedures in the form of membranes, screws, and pins. The aim of this review was to evaluate the efficacy of bone augmentation techniques using PDLLA devices. A literature search was carried out by two independent and calibrated reviewers. All interventional and observational studies assessing the efficacy of bone augmentation techniques using PDLLA devices were included. Six studies were included. The relevant variability of design and methods impeded any qualitative or quantitative comparison. Ease of handling, absence of a re-entry phase, moldability of foils, and good soft-tissue response were appreciated characteristics of PDLLA devices. Some drawbacks such as the risk of membrane exposition, a prolonged adsorbability, and a tendency to a fibrous encapsulation of the PDLLA devices have been described, although the clinical significance of these findings is unclear. Clinical data about PDLLA devices for bone regeneration are very scarce and heterogenous. Well-designed randomized controlled trials comparing the use of PDLLA foils and pins with conventional membranes for bone regeneration are strongly encouraged in order to understand the real clinical benefits/drawbacks of this technique. PMID- 29236062 TI - Measuring Activity Performance of Older Adults Using the activPAL: A Rapid Review. AB - Current measures of physical activity and sedentary behaviors such as questionnaires and functional assessments are insufficient to provide comprehensive data on older adults. In response, the use of activity monitors has increased. The purpose of this review was to summarize and assess the quality of observational literature on activity measuring of older adults using the activPAL activity monitor. Seventeen databases and a bibliography, compiled by the activPAL creators, were searched. Articles were included if they were in English, were peer-reviewed, included people 65 years or older, measured activity using the activPAL and reported at least one of the following outcomes: step count, hours upright, hours sitting/lying, hours stepping, or hours standing. The search revealed 404 titles; after exclusions 24 were included in the final review. Of these studies, one examined older adults from residential aged care, six from hospital in-patient clinics, nine from outpatient clinics and eight examined community-dwellers. Mean age ranged from 66.0 to 84.2 years. Not all studies reported similar outcome variables, preventing data pooling. The review found a lack of high quality articles. There may be limitations to using the activPAL among older adults but further research is required to examine its use in this population. PMID- 29236065 TI - Performance Analysis of Cluster Formation in Wireless Sensor Networks. AB - Clustered-based wireless sensor networks have been extensively used in the literature in order to achieve considerable energy consumption reductions. However, two aspects of such systems have been largely overlooked. Namely, the transmission probability used during the cluster formation phase and the way in which cluster heads are selected. Both of these issues have an important impact on the performance of the system. For the former, it is common to consider that sensor nodes in a clustered-based Wireless Sensor Network (WSN) use a fixed transmission probability to send control data in order to build the clusters. However, due to the highly variable conditions experienced by these networks, a fixed transmission probability may lead to extra energy consumption. In view of this, three different transmission probability strategies are studied: optimal, fixed and adaptive. In this context, we also investigate cluster head selection schemes, specifically, we consider two intelligent schemes based on the fuzzy C means and k-medoids algorithms and a random selection with no intelligence. We show that the use of intelligent schemes greatly improves the performance of the system, but their use entails higher complexity and selection delay. The main performance metrics considered in this work are energy consumption, successful transmission probability and cluster formation latency. As an additional feature of this work, we study the effect of errors in the wireless channel and the impact on the performance of the system under the different transmission probability schemes. PMID- 29236063 TI - Recent Advances in the Role of SLC39A/ZIP Zinc Transporters In Vivo. AB - Zinc (Zn), which is an essential trace element, is involved in numerous mammalian physiological events; therefore, either a deficiency or excess of Zn impairs cellular machineries and influences physiological events, such as systemic growth, bone homeostasis, skin formation, immune responses, endocrine function, and neuronal function. Zn transporters are thought to mainly contribute to Zn homeostasis within cells and in the whole body. Recent genetic, cellular, and molecular studies of Zn transporters highlight the dynamic role of Zn as a signaling mediator linking several cellular events and signaling pathways. Dysfunction in Zn transporters causes various diseases. This review aims to provide an update of Zn transporters and Zn signaling studies and discusses the remaining questions and future directions by focusing on recent progress in determining the roles of SLC39A/ZIP family members in vivo. PMID- 29236064 TI - Recent Advances in Marine Algae Polysaccharides: Isolation, Structure, and Activities. AB - Marine algae have attracted a great deal of interest as excellent sources of nutrients. Polysaccharides are the main components in marine algae, hence a great deal of attention has been directed at isolation and characterization of marine algae polysaccharides because of their numerous health benefits. In this review, extraction and purification approaches and chemico-physical properties of marine algae polysaccharides (MAPs) are summarized. The biological activities, which include immunomodulatory, antitumor, antiviral, antioxidant, and hypolipidemic, are also discussed. Additionally, structure-function relationships are analyzed and summarized. MAPs' biological activities are closely correlated with their monosaccharide composition, molecular weights, linkage types, and chain conformation. In order to promote further exploitation and utilization of polysaccharides from marine algae for functional food and pharmaceutical areas, high efficiency, and low-cost polysaccharide extraction and purification methods, quality control, structure-function activity relationships, and specific mechanisms of MAPs activation need to be extensively investigated. PMID- 29236066 TI - Avid 18F-FDG Uptake in Idiopathic Tumoral Calcinosis Mimicking Lymph Node Metastasis. AB - Tumoral calcinosis is a benign condition characterized by periarticular calcified lesions that is frequently observed in patients with chronic renal failure. Tumoral calcinosis often presents with subcutaneous masses and joint swelling. We present a case of tumoral calcinosis with dramatically increased 18F-fluoro-2 deoxy-d-glucose (18F-FDG) uptake on positron emission tomography/computed tomography (PET/CT) that mimicked lymphoma or lymph node metastases. PMID- 29236067 TI - How Well Do Health-Mediation Programs Address the Determinants of the Poor Health Status of Roma? A Longitudinal Case Study. AB - In Central and Eastern Europe (CEE), health-mediation programs (HMPs) have become central policy instruments targeting health inequities between segregated Roma and general populations. Social determinants of health (SDH) represent the root causes behind health inequities. We therefore evaluated how an HMP based in Slovakia addressed known SDH in its agenda and its everyday implementation. To produce descriptive data on the HMP's agenda and everyday implementation we observed and consulted 70 program participants across organizational levels and 30 program recipients over the long-term. We used a World Health Organization framework on SDH to direct data acquisition and consequent data content analysis, to structure the reporting of results, and to evaluate the program's merits. In its agenda, the HMP did not address most known SDH, except for healthcare access and health-related behaviours. In the HMP's everyday implementation, healthcare access facilitation activities were well received, performed as set out and effective. The opposite was true for most educational activities targeting health related behaviours. The HMP fieldworkers were proactive and sometimes effective at addressing most other SDH domains beyond the HMP agenda, especially material conditions and psychosocial factors, but also selected local structural aspects. The HMP leaders supported such deliberate engagement only informally, considering the program inappropriate by definition and too unstable institutionally to handle such extensions. Reports indicate that the situation in other CEE HMPs is similar. To increase the HMPs' impact on SDH, their theories and procedures should be adapted according to the programs' more promising actual practice regarding SDH. PMID- 29236068 TI - In Silico Screening and In Vitro Activity Measurement of Javamide Analogues as Potential p38 MAPK Inhibitors. AB - p38 Mitogen-activated protein kinase (p38 MAPK) is a protein kinase critically involved in the progress of inflammation/stress-associated diseases. Our data suggested that javamide analogues may contain strong anti-inflammation activities, but there is little information about their effects on p38 MAPK. Therefore, in this paper, the effects of thirty javamide analogues on p38 MAPK were investigated using in silico screening and in vitro p38 MAPK assay methods. The javamide analogues were synthesized and their chemical structures were confirmed using nuclear magnetic resonance (NMR) spectroscopic methods. Then, the javamide analogues were screened using an in silico modeling program. The screened analogues demonstrated a wide range of binding energy (DeltaE; -20 to 39) and several analogues with DeltaE; -34 to -39 showed strong binding affinity to p38 MAPK. In vitro p38 MAPK assay, the kinase was significantly inhibited by the analogues with great binding energy (DeltaE; -34 to -39) and in silico scores (Avg. score; -27.5 to -29.3). Furthermore, the comparative analysis of both assays showed a positive correlation between the in silico scores and p38 MAPK inhibition. In fact, the javamide analogues with top five in silico scores (Avg. score; -27.5 to -29.3) were found to inhibit p38 MAPK by 27-31% (p < 0.05) better than those with less scores (DeltaE < -27.0). Especially, javamide-II-O-ethyl ester with relatively high in silico score (Avg. score; -29.2) inhibited p38 MAPK (IC50 = 9.9 MUM) a little better than its methyl ester with best in silico score (Avg. score; -29.3). To support the ability to inhibit p38 MAPK, the treatment of javamide-II-ethyl and -methyl esters could suppress the production of IL-8 and MCP-1 protein significantly by 22-73% (p < 0.05) in the differentiated THP-1 cells, and the inhibition was slightly stronger by the ethyl ester than the methyl ester. Altogether, this study suggests that javamide-II-O-ethyl ester may be a most potent p38 MAPK inhibitor among the tested compounds and the combining in silico and in vitro assay approach may be a useful and efficient solution as a functional screening approach in searching new lead compounds for targeted molecules. PMID- 29236069 TI - A Portrait of the Sialyl Glycan Receptor Specificity of the H10 Influenza Virus Hemagglutinin-A Picture of an Avian Virus on the Verge of Becoming a Pandemic? AB - Pandemic influenza is a constant global threat to human health. In particular, the pandemic potential of novel avian influenza viruses such as the H10N7 and H10N8 avian strains, which recently managed to cross the species barrier from birds to humans, are always of great concern as we are unlikely to have any prior immunity. Human and avian isolates of H10 influenza display the ability to rapidly adapt to replication in mammalian hosts. Fortunately, so far there is no evidence of efficient human-to-human transmission of any avian influenza virus. This review examines all of the available clinical and biological data for H10 influenza viruses with an emphasis on hemagglutinin as it is a major viral antigen that determines host range and immunity. The available glycan binding data on the influenza H10 hemagglutinin are discussed in a structure-recognition perspective. Importantly, this review raises the question of whether the emerging novel avian H10 influenza viruses truly represents a threat to global health that warrants close monitoring. PMID- 29236070 TI - LC-MS/MS Tandem Mass Spectrometry for Analysis of Phenolic Compounds and Pentacyclic Triterpenes in Antifungal Extracts of Terminalia brownii (Fresen). AB - Decoctions and macerations of the stem bark and wood of Terminalia brownii Fresen. are used in traditional medicine for fungal infections and as fungicides on field crops and in traditional granaries in Sudan. In addition, T. brownii water extracts are commonly used as sprays for protecting wooden houses and furniture. Therefore, using agar disc diffusion and macrodilution methods, eight extracts of various polarities from the stem wood and bark were screened for their growth-inhibitory effects against filamentous fungi commonly causing fruit, vegetable, grain and wood decay, as well as infections in the immunocompromised host. Ethyl acetate extracts of the stem wood and bark gave the best antifungal activities, with MIC values of 250 ug/mL against Nattrassia mangiferae and Fusarium verticillioides, and 500 ug/mL against Aspergillus niger and Aspergillus flavus. Aqueous extracts gave almost as potent effects as the ethyl acetate extracts against the Aspergillus and Fusarium strains, and were slightly more active than the ethyl acetate extracts against Nattrassiamangiferae. Thin layer chromatography, RP-HPLC-DAD and tandem mass spectrometry (LC-MS/MS), were employed to identify the chemical constituents in the ethyl acetate fractions of the stem bark and wood. The stem bark and wood were found to have a similar qualitative composition of polyphenols and triterpenoids, but differed quantitatively from each other. The stilbene derivatives, cis- (3) and trans- resveratrol-3-O-beta-galloylglucoside (4), were identified for the first time in T. brownii. Moreover, methyl-(S)-flavogallonate (5), quercetin-7-beta-O-di glucoside (8), quercetin-7-O-galloyl-glucoside (10), naringenin-4'-methoxy-7 pyranoside (7), 5,6-dihydroxy-3',4',7-tri-methoxy flavone (12), gallagic acid dilactone (terminalin) (6), a corilagin derivative (9) and two oleanane type triterpenoids (1) and (2) were characterized. The flavonoids, a corilagin derivative and terminalin, have not been identified before in T. brownii. We reported earlier on the occurrence of methyl-S-flavogallonate and its isomer in the roots of T. brownii, but this is the first report on their occurrence in the stem wood as well. Our results justify the traditional uses of macerations and decoctions of T. brownii stem wood and bark for crop and wood protection and demonstrate that standardized extracts could have uses for the eco-friendly control of plant pathogenic fungi in African agroforestry systems. Likewise, our results justify the traditional uses of these preparations for the treatment of skin infections caused by filamentous fungi. PMID- 29236071 TI - The Multi-Attribute Group Decision-Making Method Based on Interval Grey Trapezoid Fuzzy Linguistic Variables. AB - With respect to multi-attribute group decision-making (MAGDM) problems, where attribute values take the form of interval grey trapezoid fuzzy linguistic variables (IGTFLVs) and the weights (including expert and attribute weight) are unknown, improved grey relational MAGDM methods are proposed. First, the concept of IGTFLV, the operational rules, the distance between IGTFLVs, and the projection formula between the two IGTFLV vectors are defined. Second, the expert weights are determined by using the maximum proximity method based on the projection values between the IGTFLV vectors. The attribute weights are determined by the maximum deviation method and the priorities of alternatives are determined by improved grey relational analysis. Finally, an example is given to prove the effectiveness of the proposed method and the flexibility of IGTFLV. PMID- 29236072 TI - Environmental Concerns, Environmental Policy and Green Investment. AB - Environmental regulators often use environmental policy to induce green investment by firms. However, if an environmental policy fails to exert a long run effect on regulating the economic agents' behavior, it may be more reasonable to think of the firm as the leader in the game, since the investment in green technology is usually a strategic decision. In this paper, we consider a three stage Stackelberg game to address the interaction between a profit-maximizing firm (Stackelberg leader) facing emission-dependent demand, and the environmental regulator (Stackelberg follower). The firm decides on the green technology level in the first stage of the game based on its understanding of the regulator's profits function, especially an environmental concern that is introduced as an exogenous variable. In the current research, we show that high levels of the regulator's environmental concerns do not necessarily lead to the choice of green technology by the firm, and green investment level depends on the combined effects of the market and operational factors for a given level of the regulator's environmental concerns. The result also shows that increasing environmental awareness amongst the consumers is an effective way to drive the firm's green investment. PMID- 29236074 TI - Morphological and Optical Characteristics of Chitosan(1-x):Cuox (4 <= x <= 12) Based Polymer Nano-Composites: Optical Dielectric Loss as an Alternative Method for Tauc's Model. AB - In this work, copper (Cu) nanoparticles with observable surface plasmonic resonance (SPR) peaks were synthesized by an in-situ method. Chitosan host polymer was used as a reduction medium and a capping agent for the Cu nanoparticles. The surface morphology of the samples was investigated through the use of scanning electron micrograph (SEM) technique. Copper nanoparticles appeared as chains and white specks in the SEM images. The strong peaks due to the Cu element observed in the spectrum of energy dispersive analysis of X-rays. For the nanocomposite samples, obvious peaks due to the SPR phenomena were obtained in the Ultraviolet-visible (UV-vis) spectra. The effect of Cu nanoparticles on the host band gap was understood from absorption edges shifting of absorption edges to lower photon energy. The optical dielectric loss parameter obtained from the measurable quantities was used as an alternative method to study the band structure of the samples. Quantum mechanical models drawbacks, in the study of band gap, were explained based on the optical dielectric loss. A clear dispersion region was able to be observed in refractive indices spectra of the composite samples. A linear relationship with a regression value of 0.99 was achieved between the refractive index and volume fractions of CuI content. Cu nanoparticles with various sizes and homogenous dispersions were also determined from transmission electron microscope (TEM) images. PMID- 29236073 TI - Reduced Educational Outcomes Persist into Adolescence Following Mild Iodine Deficiency in Utero, Despite Adequacy in Childhood: 15-Year Follow-Up of the Gestational Iodine Cohort Investigating Auditory Processing Speed and Working Memory. AB - There is increasing evidence that even mild gestational iodine deficiency (GID) results in adverse neurocognitive impacts on offspring. It's unclear, however, if these persist long-term and whether they can be ameliorated by iodine sufficiency in childhood. We followed a unique cohort (Gestational Iodine Cohort, n = 266) where gestation occurred during a period of mild population iodine deficiency, with children subsequently growing-up in an iodine replete environment. We investigated whether associations between mild GID and reductions in literacy outcomes, observed at age 9-years, persisted into adolescence. Comparisons were made between offspring of mothers with gestational urinary iodine concentrations (UICs) >= 150 MUg/L and < 150 MUg/L. Educational outcomes were measured using Australian National Assessment Program-Literacy and Numeracy (NAPLAN) tests. Children whose mothers had UICs < 150 MUg/L exhibited persistent reductions in spelling from Year 3 (10%, -41.4 points (95% Confidence Interval -65.1 to -17.6, p = 0.001)) to Year 9 (5.6%, -31.6 (-57.0 to -6.2, p = 0.015)) compared to children whose mothers had UICs >= 150 MUg/L. Associations remained after adjustment for biological factors, socioeconomic status and adolescent UIC. Results support the hypothesis that mild GID may impact working memory and auditory processing speed. The findings have important public health implications for management of iodine nutrition in pregnancy. PMID- 29236075 TI - Risks and Benefits of Increased Nut Consumption: Cardiovascular Health Benefits Outweigh the Burden of Carcinogenic Effects Attributed to Aflatoxin B1 Exposure. AB - Nuts are rich in nutrients and mounting evidence shows that consumption reduces cardiovascular disease (CVD) incidence. Nuts may also be a major source of aflatoxin B1, a potent liver carcinogen and the risk/benefit balance is unknown. Based on national statistics and data from the PREDIMED intervention trial, we estimated the potential CVD-reduction if Swedes aged 55-79 consumed 30 g nuts/day, instead of the current national average of five grams per day. We also assessed the reduction in disability-adjusted life years (DALYs) due to myocardial infarction (MI) and stroke. We estimated the aflatoxin B1 exposure from nuts and calculated the margin of exposure. The approximation that one nanogram aflatoxin B1/kg body weight/day results in one additional liver cancer case/10 million person-years was used to estimate the number of liver cancer cases. The increased nut consumption scenario prevented more than 7000 CVDs in 2013 (306/100,000 person-years) and contributed to about 55,000 saved DALYs for stroke and 22,000 for MI. The concomitant increase in aflatoxin B1 exposure caused an estimated zero to three additional cases of liver cancer, corresponding to 159 DALYs spent, emphasizing the associated risks. Increased nut consumption, as part of a varied healthy diet, is warranted even when aflatoxin B1 exposure is taken into account. However, efforts to reduce aflatoxin exposure from food are essential. PMID- 29236077 TI - A Pilot Study of Children's Blood Lead Levels in Mount Isa, Queensland. AB - Mount Isa, Queensland, is one of three Australian cities with significant lead emissions due to nonferrous mining and smelting. Unlike the two other cities with lead mines or smelters, Mount Isa currently has no system of annual, systematic, community-wide blood lead level testing; and testing rates among Indigenous children are low. In previous screenings, this group of children has been shown to have higher average blood lead levels than non-Indigenous children. The first aim of this study was to assess whether parents and children would participate in less invasive, rapid point-of-care capillary testing. The second aim was to measure blood lead levels among a range of children that roughly reflected the percentage of the Indigenous/non-Indigenous population. This pilot study is based on a convenience sample of children between the ages of 12 and 83 months who were recruited to participate by staff at a Children and Family Centre. Over three half-days, 30 children were tested using capillary blood samples and the LeadCare II Point-of-Care testing system. Rapid point-of-care capillary testing was well tolerated by the children. Of 30 children tested, 40% (n = 12) had blood lead levels >=5 ug/dL and 10% had levels >=10 ug/dL. The highest blood lead level measured was 17.3 ug/dL. The percentage of children with blood lead levels >=5 ug/dL was higher among Indigenous children compared to non-Indigenous (64.2% compared to 18.8%) as was the geometric mean level (6.5 (95% CI, 4.7, 9.2) versus 2.4 (95% CI, 1.8, 3.1)), a statistically significant difference. Though based on a small convenience sample, this study identified 12 children (40%) of the sample with blood lead levels >=5 ug/dL. Due to historical and ongoing heavy metal emissions from mining and smelting in Mount Isa, we recommend a multi-component program of universal blood lead level testing, culturally appropriate follow-up and intervention for children who are identified with blood lead levels >=5 ug/dL. We further recommend focused outreach and assistance to the Indigenous community, and further control of emissions and remediation of existing environmental lead contamination in children's play and residential areas. PMID- 29236076 TI - Nucleobase-Guanidiniocarbonyl-Pyrrole Conjugates as Novel Fluorimetric Sensors for Single Stranded RNA. AB - We demonstrate here for the first time that a guanidiniocarbonyl-pyrrole (GCP) unit can be applied for the fine recognition of single stranded RNA sequences-an intuitively unexpected result since so far binding of the GCP unit to ds-DNA or ds-RNA relied strongly on minor or major groove interactions, as shown in previous work. Two novel nucleobase-GCP isosteric conjugates differing in the flexibility of GCP unit revealed a fluorimetric recognition of various single stranded RNA, which could be additionally regulated by pH. The more rigid conjugate showed a specific fluorescence increase for poly A only at pH 7, whereby this response could be reversibly switched-off at pH 5. The more flexible derivative revealed selective fluorescence quenching by poly G at pH 7 but no change for poly A, whereas its recognition of poly AH+ can be switched-on at pH 5. The computational analysis confirmed the important role of the GCP fragment and its protonation states in the sensing of polynucleotides and revealed that it is affected by the intrinsic dynamical features of conjugates themselves. Both conjugates showed a negligible response to uracil and cytosine ss-RNA as well as ds-RNA at pH 7, and only weak interactions with ds-DNA. Thus, nucleobase-GCP conjugates can be considered as novel lead compounds for the design of ss-RNA or ss-DNA selective fluorimetric probes. PMID- 29236078 TI - An Artificial Neural Network for Movement Pattern Analysis to Estimate Blood Alcohol Content Level. AB - Impairments in gait occur after alcohol consumption, and, if detected in real time, could guide the delivery of "just-in-time" injury prevention interventions. We aimed to identify the salient features of gait that could be used for estimating blood alcohol content (BAC) level in a typical drinking environment. We recruited 10 young adults with a history of heavy drinking to test our research app. During four consecutive Fridays and Saturdays, every hour from 8 p.m. to 12 a.m., they were prompted to use the app to report alcohol consumption and complete a 5-step straight-line walking task, during which 3-axis acceleration and angular velocity data was sampled at a frequency of 100 Hz. BAC for each subject was calculated. From sensor signals, 24 features were calculated using a sliding window technique, including energy, mean, and standard deviation. Using an artificial neural network (ANN), we performed regression analysis to define a model determining association between gait features and BACs. Part (70%) of the data was then used as a training dataset, and the results tested and validated using the rest of the samples. We evaluated different training algorithms for the neural network and the result showed that a Bayesian regularization neural network (BRNN) was the most efficient and accurate. Analyses support the use of the tandem gait task paired with our approach to reliably estimate BAC based on gait features. Results from this work could be useful in designing effective prevention interventions to reduce risky behaviors during periods of alcohol consumption. PMID- 29236079 TI - Unexpected Binding Mode of a Potent Indeno[1,2-b]indole-Type Inhibitor of Protein Kinase CK2 Revealed by Complex Structures with the Catalytic Subunit CK2alpha and Its Paralog CK2alpha'. AB - Protein kinase CK2, a member of the eukaryotic protein kinase superfamily, is associated with cancer and other human pathologies and thus an attractive drug target. The indeno[1,2-b]indole scaffold is a novel lead structure to develop ATP competitive CK2 inhibitors. Some indeno[1,2-b]indole-based CK2 inhibitors additionally obstruct ABCG2, an ABC half transporter overexpressed in breast cancer and co-responsible for drug efflux and resistance. Comprehensive derivatization studies revealed substitutions of the indeno[1,2-b]indole framework that boost either the CK2 or the ABCG2 selectivity or even support the dual inhibition potential. The best indeno[1,2-b]indole-based CK2 inhibitor described yet (IC50 = 25 nM) is 5-isopropyl-4-(3-methylbut-2-enyl-oxy)-5,6,7,8 tetrahydroindeno[1,2-b]indole-9,10-dione (4p). Herein, we demonstrate the membrane permeability of 4p and describe co-crystal structures of 4p with CK2alpha and CK2alpha', the paralogs of human CK2 catalytic subunit. As expected, 4p occupies the narrow, hydrophobic ATP site of CK2alpha/CK2alpha', but surprisingly with a unique orientation: its hydrophobic substituents point towards the solvent while its two oxo groups are hydro-gen-bonded to a hidden water molecule. An equivalent water molecule was found in many CK2alpha structures, but never as a critical mediator of ligand binding. This unexpected binding mode is independent of the interdomain hinge/helix alphaD region conformation and of the salt content in the crystallization medium. PMID- 29236080 TI - Three-Dimensional Analysis of the Interactions between hLDH5 and Its Inhibitors. AB - Inhibitors of human lactate dehydrogenase (hLDH5)-the enzyme responsible for the conversion of pyruvate to lactate coupled with oxidation of NADH to NAD+-are promising therapeutic agents against cancer because this enzyme is generally found to be overexpressed in most invasive cancer cells and is linked to their vitality especially under hypoxic conditions. Consequently, significant efforts have been made for the identification of small-molecule hLDH5 inhibitors displaying high inhibitory potencies. X-ray structure of hLDH5 complexes as well as molecular modeling studies contribute to identify and explain the main binding modes of hLDH5 inhibitors reported in literature. The purpose of this review is to analyze the main three-dimensional interactions between some of the most potent inhibitors and hLDH5, in order to provide useful suggestions for the design of new derivatives. PMID- 29236082 TI - Low Cost Plastic Optical Fiber Pressure Sensor Embedded in Mattress for Vital Signal Monitoring. AB - The aim of this paper is to report the design of a low-cost plastic optical fiber (POF) pressure sensor, embedded in a mattress. We report the design of a multipoint sensor, a cheap alternative to the most common fiber sensors. The sensor is implemented using Arduino board, standard LEDs for optical communication in POF (lambda = 645 nm) and a silicon light sensor. The Super ESKA(r) plastic fibers were used to implement the fiber intensity sensor, arranged in a 4 * 4 matrix. During the breathing cycles, the force transmitted from the lungs to the thorax is in the order of tens of Newtons, and the respiration rate is of one breath every 2-5 s (0.2-0.5 Hz). The sensor has a resolution of force applied on a single point of 2.2-4.5%/N on the normalized voltage output, and a bandwidth of 10 Hz, it is then suitable to monitor the respiration movements. Another issue to be addressed is the presence of hysteresis over load cycles. The sensor was loaded cyclically to estimate the drift of the system, and the hysteresis was found to be negligible. PMID- 29236081 TI - Pharmacogenomics Guided-Personalization of Warfarin and Tamoxifen. AB - The use of pharmacogenomics to personalize drug therapy has been a long-sought goal for warfarin and tamoxifen. However, conflicting evidence has created reason for hesitation in recommending pharmacogenomics-guided care for both drugs. This review will provide a summary of the evidence to date on the association between cytochrome P450 enzymes and the clinical end points of warfarin and tamoxifen therapy. Further, highlighting the clinical experiences that we have gained over the past ten years of running a personalized medicine program, we will offer our perspectives on the utility and the limitations of pharmacogenomics-guided care for warfarin and tamoxifen therapy. PMID- 29236083 TI - Non-Linear Relationship between Economic Growth and CO2 Emissions in China: An Empirical Study Based on Panel Smooth Transition Regression Models. AB - The non-linear relationship between provincial economic growth and carbon emissions is investigated by using panel smooth transition regression (PSTR) models. The research indicates that, on the condition of separately taking Gross Domestic Product per capita (GDPpc), energy structure (Es), and urbanisation level (Ul) as transition variables, three models all reject the null hypothesis of a linear relationship, i.e., a non-linear relationship exists. The results show that the three models all contain only one transition function but different numbers of location parameters. The model taking GDPpc as the transition variable has two location parameters, while the other two models separately considering Es and Ul as the transition variables both contain one location parameter. The three models applied in the study all favourably describe the non-linear relationship between economic growth and CO2 emissions in China. It also can be seen that the conversion rate of the influence of Ul on per capita CO2 emissions is significantly higher than those of GDPpc and Es on per capita CO2 emissions. PMID- 29236085 TI - Performance Evaluation of Bluetooth Low Energy: A Systematic Review. AB - Small, compact and embedded sensors are a pervasive technology in everyday life for a wide number of applications (e.g., wearable devices, domotics, e-health systems, etc.). In this context, wireless transmission plays a key role, and among available solutions, Bluetooth Low Energy (BLE) is gaining more and more popularity. BLE merges together good performance, low-energy consumption and widespread diffusion. The aim of this work is to review the main methodologies adopted to investigate BLE performance. The first part of this review is an in depth description of the protocol, highlighting the main characteristics and implementation details. The second part reviews the state of the art on BLE characteristics and performance. In particular, we analyze throughput, maximum number of connectable sensors, power consumption, latency and maximum reachable range, with the aim to identify what are the current limits of BLE technology. The main results can be resumed as follows: throughput may theoretically reach the limit of ~230 kbps, but actual applications analyzed in this review show throughputs limited to ~100 kbps; the maximum reachable range is strictly dependent on the radio power, and it goes up to a few tens of meters; the maximum number of nodes in the network depends on connection parameters, on the network architecture and specific device characteristics, but it is usually lower than 10; power consumption and latency are largely modeled and analyzed and are strictly dependent on a huge number of parameters. Most of these characteristics are based on analytical models, but there is a need for rigorous experimental evaluations to understand the actual limits. PMID- 29236086 TI - Multiscale Analyses of Surface Failure Mechanism of Single-Crystal Silicon during Micro-Milling Process. AB - This article presents an experimental investigation on ductile-mode micro-milling of monocrystalline silicon using polycrystalline diamond (PCD) end mills. Experimental results indicate that the irregular fluctuation of cutting force always induces machined surface failure, even in ductile mode. The internal mechanism has not been investigated so far. The multiscale discrete dislocation plasticity framework was used to predict the dislocation structure and strain evolution under the discontinuous cutting process. The results showed that a mass of dislocations can be generated and affected in silicon crystal. The dislocation density, multiplication rate, and microstructure strongly depend on the milling conditions. In particular, transient impulse load can provide a great potential for material strength by forming dislocations entanglement structure. The continuous irregular cutting process can induce persistent slip bands (PSBs) in substrate surface, which would result in stress concentration and inhomogeneous deformation within grains. PMID- 29236084 TI - Phylodynamic and Genetic Diversity of Canine Parvovirus Type 2c in Taiwan. AB - Canine parvovirus type 2c (CPV-2c) emerged in 2000 and is known for causing a more severe disease than other CPV-2 variants in puppies. In 2015, the emerging CPV-2c variant was isolated in Taiwan and it subsequently became the predominant variant. To trace the evolution of Taiwanese CPV-2c, we compared complete VP2 genes of CPV-2c from Taiwan and sequences obtained from GenBank. The evolutionary rate of CPV-2c was estimated to be 4.586 * 10-4 substitutions per site per year (95% highest posterior density (HPD) was 3.284-6.076 * 10-4). The time to the most recent common ancestor (TMRCA) dated to 1990 (95% HPD: 1984-1996) and 2011 (95% HPD: 2010-2013) for the CPV-2c variant and Taiwanese isolates, respectively. The CPV-2c variant isolated from Taiwan was clustered with CPV-2c from China. This phylogenetic clade began to branch off in approximately 2010 (95% HPD was 3.823-6.497). Notably, two unique mutations of Taiwanese CPV-2c were found, Q383R and P410L. In summary, this is the first report on the genome evolution of CPV-2c in Taiwan, revealing that this CPV-2c variant shares a common evolutionary origin with strains from China. The demographic history inferred by the Bayesian skyline plot showed that the effective population of CPV-2c increased until 2006 and then slowly declined until 2011. PMID- 29236087 TI - Fiber Fabry-Perot Force Sensor with Small Volume and High Performance for Assessing Fretting Damage of Steam Generator Tubes. AB - Measuring the radial collision force between the steam generator tube (SGT) and the tube support plate (TSP) is essential to assess the fretting damage of the SGT. In order to measure the radial collision force, a novel miniaturized force sensor based on fiber Fabry-Perot (F-P) was designed, and the principle and characteristics of the sensor were analyzed in detail. Then, the F-P force sensor was successfully fabricated and calibrated, and the overall dimensions of the encapsulated fiber F-P sensor were 17 mm * 5 mm * 3 mm (L * W * H). The sensor works well in humid, high pressure (10 MPa), high temperature (350 degrees C), and vibration (40 kHz) environments. Finally, the F-P force sensors were installed in a 1:1 steam generator test loop, and the radial collision force signals between the SGT and the TSP were obtained. The experiments indicated that the F-P sensor with small volume and high performance could help in assessing the fretting damage of the steam generator tubes. PMID- 29236088 TI - Dicationic Imidazolium-Based Ionic Liquid Coatings on Zirconia Surfaces: Physico Chemical and Biological Characterization. AB - In the present work, dicationic imidazolium-based ionic liquids (ILs) were investigated as multi-functional coatings on a zirconia (ZrO2) surface to prevent biofilm formation and enhance the wear performance of zirconia while maintaining the material's compatibility with host cells. ILs containing phenylalanine and methionine were synthesized and deposited on zirconia. Intermolecular interactions driving IL deposition on zirconia were studied using X-ray photoelectron spectroscopy (XPS). Anti-biofilm activity and cell compatibility were evaluated in vitro after one and seven days, and wear performance was tested using a pin-on-disk apparatus. ILs were observed to form strong hydrogen bonds with zirconia. IL containing phenylalanine formed a stable film on the surface after one and seven days in phosphate-buffered saline (PBS) and artificial saliva and showed excellent anti-biofilm properties against Streptococcussalivarius and Streptococcussanguinis. Compatibility with gingival fibroblasts and pre osteoblasts was maintained, and conditions for growth and differentiation were preserved. A significantly lower coefficient of friction and wear volume loss were observed for IL-coated surfaces as compared to non-coated substrates. Overall, zirconia is an emerging alternative to titanium in dental implants systems, and this study provides additional evidence of the materials' behavior and IL coatings as a potential surface treatment technology for improvement of its properties. PMID- 29236089 TI - Sequential Combination of Microwave- and Ultrasound-Assisted Extraction of Total Flavonoids from Osmanthus fragrans Lour. Flowers. AB - Microwave-assisted and ultrasound-assisted extraction assays were used to isolate total flavonoids (TF) from Osmanthus fragrans flowers. The effects of the solid liquid ratio, ethanol concentration, microwave power, microwave extraction time, ultrasonic power and ultrasonic extraction time on the yield of TF were studied. A sequential combination of microwave- and ultrasound-assisted extraction (SC MUAE) methods was developed, which was subsequently optimized by Box-Behnken design-response surface methodology (BBD-RSM). The interaction effects of the ethanol concentration (40-60%), microwave extraction time (5-7 min), ultrasonic extraction time (8-12 min) and ultrasonic power (210-430 W) on the yield of TF were investigated. The optimum operating parameters for the extraction of TF were determined to be as follows: ethanol concentration (48.15%), microwave extraction time (6.43 min), ultrasonic extraction time (10.09 min) and ultrasonic power (370.9 W). Under these conditions, the extraction yield of TF was 7.86 mg/g. PMID- 29236090 TI - Novel Hydrogel-Advanced Modified Clay Nanocomposites as Possible Vehicles for Drug Delivery and Controlled Release. AB - Present study refers to the synthesis of new advanced materials based on poly(methacrylic acid) (PMAA) with previously reported own advanced modified clays by edge covalent bonding. This will create the premises to obtain nanocomposite hydrogels with combined hydrophilic-hydrophobic behavior absolutely necessary for co-delivery of polar/nonpolar substances. For the synthesis, N,N' methylenebisacrylamide was used as cross-linker and ammonium persulphate as initiator. As a consequence of the inclusion of clay into the polymer matrix and the intercalation of PMAA between the layers as well as the presence of hydrophobic interactions occurred between partners, the final hydrogel nanocomposites possessed greater swelling degrees, slower de-swelling process and enhanced mechanical properties depending on the clay type in comparison with pure hydrogel. In vitro MTS ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl) 2-(4-sulfophenyl)-2H-tetrazolium, inner salt]) colorimetric assay showed that direct exposure with PMMA-clay-based constructs did not affect cell viability and proliferation in time (24 and 48 h) on either normal or adenocarcinoma cell lines. PMID- 29236092 TI - Paternal smoking and maternal protective behaviors at home on infant's saliva cotinine levels. AB - BackgroundWe investigated the association between paternal smoking, avoidance behaviors and maternal protective actions and smoke-free home rules with infant's saliva cotinine in Hong Kong.MethodsSix hundred and seventy-five non-smoking mothers (mean age 32.6 years) who attended the maternal-child health clinics with their newborns aged <=18 months completed a questionnaire about paternal smoking and avoidance behaviors, maternal protective actions, smoke-free rules at home, and infant's second-hand smoke (SHS) exposure. Three hundred and eighty-nine infants provided saliva sample and its cotinine was tested.ResultsThe geometric mean of infant's saliva cotinine was 1.07 ng/ml (95% confidence interval (CI): 0.98, 1.16). Infants living in smoking families with SHS exposure had significantly higher cotinine level than in non-smoking families (adjusted beta=0.25, 95% CI: 0.16, 0.33). Paternal smoking near infants (within 1.5 m) was associated with higher cotinine level (adjusted beta=0.60, 95% CI: 0.22, 0.98), which was not reduced by avoidance behaviors (e.g., smoking in kitchen or balcony). Even fathers smoking >=3 m away from infants was associated with higher cotinine level than non-smoking families (adjusted beta=0. 09, 95% CI: 0.01, 0.16). Maternal protective actions and smoke-free home rules were not significantly associated with reduced cotinine level.ConclusionPaternal smoking avoidance, maternal protective actions, and smoke-free policy at home did not reduce infant's saliva cotinine. PMID- 29236091 TI - Noncoding copy-number variations are associated with congenital limb malformation. AB - PurposeCopy-number variants (CNVs) are generally interpreted by linking the effects of gene dosage with phenotypes. The clinical interpretation of noncoding CNVs remains challenging. We investigated the percentage of disease-associated CNVs in patients with congenital limb malformations that affect noncoding cis regulatory sequences versus genes sensitive to gene dosage effects.MethodsWe applied high-resolution copy-number analysis to 340 unrelated individuals with isolated limb malformation. To investigate novel candidate CNVs, we re-engineered human CNVs in mice using clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing.ResultsOf the individuals studied, 10% harbored CNVs segregating with the phenotype in the affected families. We identified 31 CNVs previously associated with congenital limb malformations and four novel candidate CNVs. Most of the disease-associated CNVs (57%) affected the noncoding cis-regulatory genome, while only 43% included a known disease gene and were likely to result from gene dosage effects. In transgenic mice harboring four novel candidate CNVs, we observed altered gene expression in all cases, indicating that the CNVs had a regulatory effect either by changing the enhancer dosage or altering the topological associating domain architecture of the genome.ConclusionOur findings suggest that CNVs affecting noncoding regulatory elements are a major cause of congenital limb malformations. PMID- 29236094 TI - Hospital Perceptions of Medicare's Sepsis Quality Reporting Initiative. AB - BACKGROUND: In October 2015, the Centers for Medicare and Medicaid Services (CMS) implemented the Sepsis CMS Core Measure (SEP-1) program, requiring hospitals to report data on the quality of care for their patients with sepsis. OBJECTIVE: We sought to understand hospital perceptions of and responses to the SEP-1 program. DESIGN: A thematic content analysis of semistructured interviews with hospital quality officials. SETTING: A stratified random sample of short-stay, nonfederal, general acute care hospitals in the United States. PATIENTS: Hospital quality officers, including nurses and physicians. MEASUREMENTS: We completed 29 interviews before reaching content saturation. RESULTS: Hospitals reported a variety of actions in response to SEP-1, including new efforts to collect data, improve sepsis diagnosis and treatment, and manage clinicians' attitudes toward SEP-1. These efforts frequently required dedicated resources to meet the program's requirements for treatment and documentation, which were thought to be complex and not consistently linked to patient-centered outcomes. Most respondents felt that SEP-1 was likely to improve sepsis outcomes. At the same time, they described specific changes that could improve its effectiveness, including allowing hospitals to focus on the treatment processes most directly associated with improved patient outcomes and better aligning the measure's sepsis definitions with current clinical definitions. CONCLUSIONS: Hospitals are responding to the SEP-1 program across a number of domains and in ways that consistently require dedicated resources. Hospitals are interested in further revisions to the program to alleviate the burden of the reporting requirements and help them optimize the effectiveness of their investments in quality improvement efforts. PMID- 29236093 TI - Trends in Troponin-Only Testing for AMI in Academic Teaching Hospitals and the Impact of Choosing Wisely(r). AB - BACKGROUND: Identifying hospitals that are both early and consistent adopters of high-value care can help shed light on the culture and practices at those institutions that are necessary to promote high-value care nationwide. The use of troponin to diagnose acute myocardial infarction (AMI), and not to test for myoglobin or creatine kinase-MB (CK-MB), is a high-value recommendation of the Choosing Wisely(r) campaign. OBJECTIVE: To examine the variation in cardiac biomarker testing and the effect of the Choosing Wisely(r) troponin-only recommendation for the diagnosis of AMI. DESIGN: A retrospective observational study using administrative ordering data from Vizient's Clinical Database/Resource Manager. SETTING: Ninety-one academic medical centers from the fourth quarter of 2013 through the third quarter of 2016. PATIENTS: Hospitalized patients with a principal discharge diagnosis of AMI. INTERVENTION: The Choosing Wisely(r) recommendation to order troponin-only testing to diagnose AMI was released during the first quarter of 2015. RESULTS: In 19 hospitals, troponin only testing was consistently ordered to diagnose AMI before the Choosing Wisely(r) recommendation and throughout the study period. In 34 hospitals, both troponin and myoglobin/CK-MB were ordered to diagnose AMI even after the Choosing Wisely(r) recommendation. In 26 hospitals with low rates of troponin-only testing before the Choosing Wisely(r) recommendation, the release of the recommendation was associated with a statistically significant increase in the rate of troponin only testing to diagnose AMI. CONCLUSIONS: In institutions with low rates of troponin-only testing prior to the Choosing Wisely(r) recommendation, the recommendation was associated with a significant increase in the rate of troponin only testing. PMID- 29236095 TI - Health Literacy and Hospital Length of Stay: An Inpatient Cohort Study. AB - BACKGROUND: Associations between low health literacy (HL) and adverse health outcomes have been well documented in the outpatient setting; however, few studies have examined associations between low HL and in-hospital outcomes. OBJECTIVE: To compare hospital length of stay (LOS) among patients with low HL and those with adequate HL. DESIGN: Hospital-based cohort study. SETTING: Academic urban tertiary-care hospital. PATIENTS: Hospitalized general medicine patients. MEASUREMENTS: We measured HL using the Brief Health Literacy Screen. Severity of illness and LOS were obtained from administrative data. Multivariable linear regression controlling for illness severity and sociodemographic variables was employed to measure the association between HL and LOS. RESULTS: Among 5540 participants, 20% (1104/5540) had low HL. Participants with low HL had a longer average LOS (6.0 vs 5.4 days, P < 0.001). Low HL was associated with an 11.1% longer LOS (95% confidence interval [CI], 6.1%-16.1%; P < 0.001) in multivariate analysis. This effect was significantly modified by gender (P = 0.02). Low HL was associated with a 17.8% longer LOS among men (95% CI, 10.0%-25.7%; P < 0.001), but only a 7.7% longer LOS among women (95% CI, 1.9%-13.5%; P = 0.009). CONCLUSIONS: In this single-center cohort study, low HL was associated with a longer hospital LOS. The findings suggest that the adverse effects of low HL may extend into the inpatient setting, indicating that targeted interventions may be needed for patients with low HL. Further work is needed to explore these negative consequences and potential mitigating factors. PMID- 29236096 TI - How Exemplary Teaching Physicians Interact with Hospitalized Patients. AB - BACKGROUND: Effectively interacting with patients defines the consummate clinician. OBJECTIVE: As part of a broader study, we examined how 12 carefully selected attending physicians interacted with patients during inpatient teaching rounds. DESIGN: A multisite study using an exploratory, qualitative approach. PARTICIPANTS: Exemplary teaching physicians were identified using modified snowball sampling. Of 59 potential participants, 16 were contacted, and 12 agreed to participate. Current and former learners of the participants were also interviewed. Participants were from hospitals located throughout the United States. INTERVENTION: Two researchers-a physician and a medical anthropologist conducted 1-day site visits, during which they observed teaching rounds and patient-physician interactions and interviewed learners and attendings. MEASUREMENTS: Field notes were taken during teaching rounds. Interviews were recorded and transcribed, and code reports were generated. RESULTS: The attendings generally exhibited the following 3 thematic behaviors when interacting with patients: (1) care for the patient's well-being by being a patient advocate and forming a bond with the patient; (2) consideration of the "big picture" of the patient's medical and social situation by anticipating what the patient may need upon discharge and inquiring about the patient's social situation; and (3) respect for the patient through behaviors such as shaking hands with the patient and speaking with the patient at eye level by sitting or kneeling. CONCLUSIONS: The key findings of our study (care for the patient's well being, consideration of the "big picture," and respect for the patient) can be adopted and honed by physicians to improve their own interactions with hospitalized patients. PMID- 29236097 TI - A Randomized Cohort Controlled Trial to Compare Intern Sign-Out Training Interventions. AB - BACKGROUND: Although previous studies have investigated the efficacy of specific sign-out protocols (such as the illness severity, patient summary, action list, situation awareness and contingency planning, and synthesis by reviewer [I-PASS] bundle), the implementation of a bundle can be time consuming and costly. We compared 4 sign-out training pedagogies on sign-out quality. OBJECTIVE: To evaluate training interventions that best enhance multidimensional sign-out quality measured by information exchange, task accountability, and personal responsibility. INTERVENTION: Four general internal medicine firms were randomly assigned into 1 of the following 4 training interventions: didactics (control), I PASS, policy mandate on task accountability, and Plan-Do-Study-Act (PDSA). SETTING: First-year interns at a large, Mid-Atlantic internal medicine residency program. MEASUREMENTS: Eight trained observers examined 10 days each in the pre- and postintervention periods for each firm using a standardized sign-out checklist. RESULTS: Pre- and postintervention differences showed significant improvements in the transfer of patient information, task accountability, and personal responsibility for the I-PASS, policy mandate, and PDSA groups, respectively, in line with their respective training foci. Compared to the control, I-PASS reported the best improvements in sign-out quality, although there was room to improve in task accountability and responsibility. CONCLUSIONS: Different training emphases improved different dimensions of sign-out quality. A combination of training pedagogies is likely to yield optimal results. PMID- 29236098 TI - A Strong Diagnosis of Weakness. PMID- 29236099 TI - Inpatient Management of Diabetic Foot Infections: A Review of the Guidelines for Hospitalists. AB - Diabetic foot infections (DFIs) are common and represent the leading cause for hospitalization among diabetic complications. Without proper management, DFIs may lead to amputation, which is associated with a decreased quality of life and increased mortality. However, there is currently significant variation in the management of DFIs, and many providers fail to perform critical prevention and assessment measures. In this review, we will provide an overview of the diagnosis, management, and discharge planning of hospitalized patients with DFIs to guide hospitalists in the optimal inpatient care of patients with this condition. PMID- 29236100 TI - Reconsidering Hospital Readmission Measures. AB - Current hospital readmission measures are part of the Centers for Medicare & Medicaid Services Five-Star Quality Rating System but are inadequate for reporting hospital quality. We review potential biases in the readmission measures and offer policy recommendations to address these biases. Hospital readmission rates are influenced by multiple sources of variation (eg, mix of patients served, bias in the performance measure); true differences in quality of care are often a much smaller source of this variation. Thus, variation from caring for large proportions of socioeconomically disadvantaged or tertiary-care patients will bias a hospital's ratings. Ratings aside, readmission measures may indirectly harm patients because low readmission rates do not correlate with reduced mortality, yet the Five-Star Quality Rating System weighs readmission equally with mortality. We propose that hospital quality rankings not use readmission measures as currently constructed. PMID- 29236101 TI - Cardiac Biomarkers-Are We Testing Wisely? PMID- 29236103 TI - Improving Handoffs: Teaching beyond "Watch One, Do One". PMID- 29236102 TI - Keeping It Simple in Sepsis Measures. PMID- 29236104 TI - A precursor method for the synthesis of new Ce(iv) MOFs with reactive tetracarboxylate linkers. AB - A precursor method has been developed to synthesize Ce(iv) MOFs that could not be prepared directly from Ce(iv) salts. Starting from Ce6 clusters, two Ce-UiO-66 analogues and four tetracarboxylate-based Ce(iv) MOFs could be synthesized. The applied method facilitates framework formation by evading reactive individual Ce(iv)-ions thereby paving the way for further development of Ce-MOFs. PMID- 29236105 TI - A new potential energy surface of the OH2+ system and state-to-state quantum dynamics studies of the O+ + H2 reaction. AB - A new global potential energy surface (PES) of the O+ + H2 system was constructed with the permutation invariant polynomial neural network method, using about 63 000 ab initio points, which were calculated by employing the multi-reference configuration interaction method with aug-cc-pVTZ and aug-cc-pVQZ basis sets. For improving the accuracy of the PES, the basis set was extrapolated to the complete basis set limit by the two-point extrapolation method. The root mean square error of fitting was only 5.28 * 10-3 eV. The spectroscopic constants of the diatomic molecules were calculated and compared with previous theoretical and experimental results, which suggests that the present results agree well with the experiment. On the newly constructed PES, reaction dynamics studies were performed using the time-dependent wave packet method. The calculated integral cross sections (ICSs) were compared with the available theoretical and experimental results, where a good agreement with the experimental data was seen. Significant forward and backward scatterings were observed in the whole collision energy region studied. At the same time, the differential cross sections biased the forward scattering, especially at higher collision energies. PMID- 29236106 TI - A general and facile strategy for precisely controlling the crystal size of monodispersed metal-organic frameworks via separating the nucleation and growth. AB - A novel and facile strategy was proposed for precisely controlling the crystal size of ZIF-8, ZnCo bimetallic ZIFs and also NPs@ZIF-8 by separating the nucleation and growth. The fundamentals of crystallization of this strategy were elaborately investigated, and the size effect on the internal diffusion was explored for a series of Pt@ZIF-8 catalysts. PMID- 29236107 TI - Uncovering the impact of 'capsule' shaped amine-type ligands on Am(iii)/Eu(iii) separation. AB - Separation of trivalent actinides (An(iii)) and lanthanides (Ln(iii)) in spent nuclear fuel reprocessing is extremely challenging mainly owing to their similar chemical properties. Two amine-type reagents, tetrakis(2-pyridyl-methyl)-1,2 ethylenediamine (TPEN) and its hydrophobic derivative N,N,N',N'-tetrakis((4 butoxypyridin-2-yl)methyl)-ethylenediamine (TBPEN), have been identified to possess a selectivity for Am(iii) over Eu(iii). In this work, the structures, bonding nature, and thermodynamic behaviors of the Am(iii) and Eu(iii) complexes with these two ligands have been systematically studied via scalar relativistic density functional theory (DFT) calculations. According to Mayer bond order and the quantum theory of atoms in molecules (QTAIM) analyses, interactions between the ligands and metal cations exhibit some degree of covalent character with relatively more covalency for Am(iii) complexes. In comparison with TPEN, TBPEN has better extractability but worse separation ability for Am(iii) and Eu(iii). Four nitrogen atoms in pyridine moieties may be responsible for the different extraction abilities of TPEN and TBPEN, while two nitrogen atoms in amine chains of these ligands appear to play more important roles in the separation of Am(iii)/Eu(iii). These different extraction behaviors may be attributed to the longer and thinner 'capsule' shaped TBPEN ligand compared to TPEN. Our study might provide new insights into understanding the selectivity of the amine-type ligands toward minor actinides, and pave the way for designing new TPEN derivatives for extraction and separation of An(iii)/Ln(iii). PMID- 29236108 TI - Palladium pincer-type complexes and zwitterionic sulfur adducts of pyridine bridged bis(1,2,3-triazolin-5-ylidenes): syntheses, characterizations and catalytic applications. AB - Four pyridine-bridged bis(1,2,3-triazoles) A/B and C/D have been prepared by "click" reactions. Methylations/ethylations of A/B and C/D employing Meerwein's salts led to the formation of the corresponding dicationic salts 1/2 and 3/4 with pyridine moieties surviving from the alkylations. Interestingly, the reactions of "N-linked" salts 1/2 with K2CO3 in the presence of elemental sulfur did not yield the mesoionic carbene-sulfur betaine adducts but unexpectedly afforded 1,5 disubstituted triazoles 5/6, which may produce pyridine thioaldehydes as by products. In contrast, in the case of "C-linked" salts 3/4, the reactions to synthesize carbene-sulfur zwitterions 9/10 proceeded smoothly. Employing a silver carbene transfer protocol with salt 3 as the precursor, the [CNC]-type palladium pincer complex 8 was synthesized, the solid-state structure of which was determined by X-ray diffraction analysis. Complex 8 underwent ligand substitutions with silver carboxylates producing the acetato complex 11 and trifluoroacetato complex 12. All newly synthesized pincer complexes were employed to test their catalytic activities in Mizoroki-Heck reactions. Positive mercury drop tests implied that the pincer-type complexes do not survive under the conditions of catalysis, owing to which no conclusions can be drawn regarding the catalyst variation or substrate scope. PMID- 29236109 TI - Correction: Geobacter sulfurreducens pili support ohmic electronic conduction in aqueous solution. AB - Correction for 'Geobacter sulfurreducens pili support ohmic electronic conduction in aqueous solution' by Nicole L. Ing et al., Phys. Chem. Chem. Phys., 2017, 19, 21791-21799. PMID- 29236110 TI - Simultaneous monitoring of different vitrification solution components permeating into tissues. AB - Cryopreservation can be used for long-term preservation of tissues and organs. It relies on using complex mixtures of cryoprotective agents (CPAs) to reduce the damaging effects of freezing, but care should be taken to avoid toxic effects of CPAs themselves. In order to rationally design cryopreservation strategies for tissues, it is important to precisely determine permeation kinetics of the protectants that are used to ensure maximum permeation, while minimizing the exposure time and toxicity effects. This is particularly challenging with protectant solutions consisting of multiple components each with different physical properties and diffusing at a different rate. In this study, we show that an attenuated total reflection-Fourier transform infrared spectroscopy (ATR FTIR) setup can be used to simultaneously monitor diffusion of multiple components in a mixture into tissues in real time. Diffusion studies were done with decellularized heart valves using a sucrose-DMSO mixture as well as vitrification solution VS83. To assess diffusion kinetics of different solutes in mixtures, the increase in specific infrared absorbance bands was monitored during diffusion through the tissue. Solute specific wavenumber ranges were selected, and the calculated area was assumed to be proportional to the CPA concentration in the tissue. A diffusion equation based on Fick's second law of diffusion fitted the experimental data quite well, and clear differences in permeation rates were observed among the different mixture components dependent on molecular size and physical properties. PMID- 29236111 TI - Palladium-catalyzed carbene/alkyne metathesis with enynones as carbene precursors: synthesis of fused polyheterocycles. AB - An unprecedented palladium-catalyzed novel carbene/alkyne metathesis cascade reaction of alkyne-tethered enynones is described. This reaction affords fused polyheterocycles in moderate to good yields. The transformation begins with Pd catalyzed 5-exo-dig cyclization of the enynone to form the donor/donor metal carbene, which then undergoes metathesis with the alkyne followed by electrophilic aromatic substitution. PMID- 29236112 TI - Interfacial and thermal energy driven growth and evolution of Langmuir-Schaefer monolayers of Au-nanoparticles. AB - Structures of Langmuir-Schaefer (LS) monolayers of thiol-coated Au-nanoparticles (DT-AuNPs) deposited on H-terminated and OTS self-assembled Si substrates (of different hydrophobic strength and stability) and their evolution with time under ambient conditions, which plays an important role for their practical use as 2D nanostructures over large areas, were investigated using the X-ray reflectivity technique. The strong effect of substrate surface energy (gamma) on the initial structures and the competitive role of room temperature thermal energy (kT) and the change in interfacial energy (Deltagamma) at ambient conditions on the evolution and final structures of the DT-AuNP LS monolayers are evident. The strong-hydrophobic OTS-Si substrate, during transfer, seems to induce strong attraction towards hydrophobic DT-AuNPs on hydrophilic (repulsive) water to form vertically compact partially covered (with voids) monolayer structures (of perfect monolayer thickness) at low pressure and nearly covered buckled monolayer structures (of enhanced monolayer thickness) at high pressure. After transfer, the small kT-energy (in absence of repulsive water) probably fluctuates the DT AuNPs to form vertically expanded monolayer structures, through systematic exponential growth with time. The effect is prominent for the film deposited at low pressure, where the initial film-coverage and film-thickness are low. On the other hand, the weak-hydrophobic H-Si substrate, during transfer, appears to induce optimum attraction towards DT-AuNPs to better mimic the Langmuir monolayer structures on it. After transfer, the change in the substrate surface nature, from weak-hydrophobic to weak-hydrophilic with time (i.e. Deltagamma-energy, apart from the kT-energy), enhances the size of the voids and weakens the monolayer/bilayer structure to form a similar expanded monolayer structure, the thickness of which is probably optimized by the available thermal energy. PMID- 29236113 TI - Visual detection of a nerve agent simulant using chemically modified paper strips and dye-assembled inorganic nanocomposite. AB - Chromogenic probe with oxidized bis-indolyl scaffold has been synthesized for the detection of a nerve gas mimicking agent, DCNP (diethyl cyanophosphonate) at pH 8.0 in water. The mechanism of interaction was proposed as the release of cyanide ion through the indole group mediating the hydrolysis of phosphorous-hetero atom bond and, thereafter, the Michael addition of the liberated CN- ion to the electron deficient C[double bond, length as m-dash]C bond of the bis-indolyl moiety. The reaction featured a remarkable change in color from red to colorless at ambient condition. Then, low-cost and portable paper strips were designed for a rapid and on-site vapor phase detection of DCNP without involving any sophisticated instrument or skilled personnel. Finally, a dye assembled inorganic nanocomposite material was devised to achieve a more sensitive 'turn-on' detection of DCNP in water. PMID- 29236114 TI - Stereodynamics of electron-induced dissociative ionization of N2 studied by (e, e+ion) spectroscopy. AB - We report an (e, e+ion) spectroscopy study on electron-induced dissociative ionization of N2. Vector correlation between the scattered electron and N+ ion has been measured for inner-valence ionization of N2 at an incident electron energy of 1.4 keV and scattering angles of 2.2 degrees , 4.2 degrees , and 8.2 degrees . By analyzing the experimental data, partial ion yield spectra have been obtained for transitions to the C 2Sigma, F 2Sigma, and 2sigma ion states, showing that the individual transitions depend on the momentum transferred to the target, K, in different ways. The molecular-orientation dependence of the ionization cross section has subsequently been examined for the F 2Sigma ionization. To account for the angular anisotropy of the scattering cross section, a compact analytical form has been developed. It is elucidated that for small K the F 2Sigma ionization preferentially takes place when the molecule has its axis aligned parallel to the momentum transfer vector due to sigmau shape resonance, while the angular distribution drastically changes with K, indicating strong influences of non-dipole interaction on the ionization dynamics. It has been shown that the present method provides a powerful means to explore K dependent stereodynamics in electron-induced dissociative ionization of molecules. PMID- 29236117 TI - Liquid crystal elastomer foams with elastic properties specifically engineered as biodegradable brain tissue scaffolds. AB - Tissue regeneration requires 3-dimensional (3D) smart materials as scaffolds to promote transport of nutrients. To mimic mechanical properties of extracellular matrices, biocompatible polymers have been widely studied and a diverse range of 3D scaffolds have been produced. We propose the use of responsive polymeric materials to create dynamic substrates for cell culture, which goes beyond designing only a physical static 3D scaffold. Here, we demonstrated that lactone- and lactide-based star block-copolymers (SBCs), where a liquid crystal (LC) moiety has been attached as a side-group, can be crosslinked to obtain Liquid Crystal Elastomers (LCEs) with a porous architecture using a salt-leaching method to promote cell infiltration. The obtained SmA LCE-based fully interconnected porous foams exhibit a Young modulus of 0.23 +/- 0.07 MPa and a biodegradability rate of around 20% after 15 weeks both of which are optimized to mimic native environments. We present cell culture results showing growth and proliferation of neurons on the scaffold after four weeks. This research provides a new platform to analyse LCE scaffold-cell interactions where the presence of liquid crystal moieties promotes cell alignment paving the way for a stimulated brain-like tissue. PMID- 29236119 TI - Estimation of the bioaccessibility and bioavailability of Fe, Mn, Cu, and Zn in Chinese vegetables using the in vitro digestion/Caco-2 cell model: the influence of gut microbiota. AB - The influence of the human gut microbiota on the bioaccessibility and bioavailability of trace elements in vegetables has barely been studied. An in vitro digestion model combining the physiologically based extraction test (PBET) and the Simulator of Human Intestinal Microbial Ecosystem (SHIME) was applied. Results showed that the gut microbiota increased the bioaccessibility of iron (Fe) in ten test vegetables by 1.3-1.8 times, but reduced the bioaccessibility of manganese (Mn), copper (Cu), and zinc (Zn) in vegetables in the colon phase by 3.7% to 89.6%, 24.8% to 100.0%, and 59.9% to 100.0%, respectively. Using the Caco 2 cell model to simulate the human absorption process, the bioavailable contents and the bioavailability of the trace elements were further determined. Swamp cabbage was the best source of Fe and Cu; spinach and lettuce provided the highest amounts of bioavailable Mn and Zn, respectively. Referring to the daily reference intakes of trace elements, the obtained data provide a scientific basis for both reasonable ingestion of vegetables in diets and diversification of diets. PMID- 29236123 TI - Converting colour to length based on the coffee-ring effect for quantitative immunoassays using a ruler as readout. AB - We report a method for converting the colorimetric results of an enzyme-linked immunosorbent assay (ELISA) into length based on the coffee-ring effect, so that the quantitative detection of analytes can be carried out simply using a ruler. The influence of the shape and lamination of the paper strip on the test results is studied. As a demonstration, human IgG is quantitatively analyzed. It is found that the width of the colored stains correlates with the concentration of the analyte which can be measured for quantitative analysis. The method is promising for quantitative point-of-care detection of biomarkers under resource-limited settings. PMID- 29236124 TI - ? PMID- 29236125 TI - [Laser treatment of basal cell carcinoma]. AB - With a clear increase in the incidence and a continuously earlier onset, the main risk factors for the development of basal cell carcinoma are still exposure to sunlight, fair skin, immunosuppression, carcinogens such as arsenic, chronic irritations and certain genodermatoses. Treatment options for localized resectionable basal cell carcinoma include micrographically controlled surgery, simple excision, curettage, laser ablation, cryosurgery, imiquimod, 5 fluorouracil, photodynamic treatment and radiotherapy. Non-surgical treatment options are more suited for cases in which surgical procedures lead to disfigurement or functional impairments or for patients with a high surgical risk. Laser treatment, ablative and non-ablative as monotherapy or in combination can represent a meaningful treatment option in selected cases. In recent years there has been an increase in knowledge about the indications and effects of laser treatment of basal cell carcinoma; nevertheless, further studies with a high level of evidence are necessary. PMID- 29236126 TI - [Structural damage after shoulder dislocation and development of surgical treatment from a historical perspective]. AB - In the nineteenth century there was a high incidence of habitual shoulder instability caused by epileptic seizures and accompanied by therapeutic dilettantism, which led to socioeconomic problems in the working population. In the preradiography era the pathomechanism of shoulder dislocation was only known on the basis of cadaver studies and autopsy findings. The underlying structural disorders of habitual shoulder instability in the Bismarck era were published by Malgaigne, Broca and Hartmann. In1898 the first surgical reconstructive stabilization procedure for habitual shoulder dislocation was performed by Wilhelm Muller in Rostock. At the beginning of the twentieth century Perthes introduced the anatomical reconstruction of the capsulolabral complex, which was copied in the English speaking area by Bankart. Surgical wrong tracks through extra-anatomical procedures, capsulorrhaphy and tendon transfer, were followed by bone block procedures according to Eden-Hybinette and a modification of this procedure by Lange. In the French speaking area Latarjet introduced the transfer of the coracoid process in the middle of the 1950s, which brought the advantage of simultaneous dynamic stabilization to bony augmentation of the glenoidacetabulum . PMID- 29236127 TI - [Basic knowledge on the efficacy of hearing aids depending on the type of hearing impairment for Ear, Nose & Throat specialists]. AB - For Ear, Nose & Throat specialists, the physiological and psychoacoustical deficits related to hearing impairment and the compensatory capabilities of hearing aids are topics of prime importance. In conductive hearing loss, the foremost deficit is decreased audibility, for which hearing aids can compensate almost entirely through the use of level independent gain. In the instance of sensorineural hearing loss, however, the irreversible loss of outer and inner hair cells causes a distorted sound perception, which is particularly troublesome when trying to understand speech in noisy environments. Unfortunately, this distortion cannot be compensated through the use of hearing aids. Nevertheless, in particular listening environments, its effects can be lessened by reducing background noise levels through the use of directional microphones and, to a lesser extent, digital noise reduction. Noise reduction is in many cases also the main effect to improve speech discrimination in retrocochlear hearing loss. PMID- 29236128 TI - NK and NKT-Like Cells in Patients with Recurrent Furunculosis. AB - To analyze changes in the number and percentage of NK and NKT-like cells in relation to other immune cells as well as to examine associations between increased susceptibility to infections and NK and NKT-like status in patients with recurrent furunculosis (RF) and healthy controls. Thirty patients with RF and 20 healthy age- and sex-matched volunteers were recruited. Blood samples were examined. Lymphocyte count and cytometric analyses were conducted. For statistical analysis, the Student's t test, F test, and Brown-Forsythe test were used for comparison between groups of variables. Associations were assessed with Pearson coefficient. Patients with RF had lower lymphocyte count than controls. Additionally, they presented with the following changes in the blood picture: a significant increase in the number of NK cells with a CD3+CD16+CD56+ phenotype; a proportional increase in the number and percentage of NKT-like cells with a CD3+CD16+CD56+ phenotype; a significant decrease in the number and percentage of T CD3+ cells. The number of NK cells was strongly positively correlated with the number of CD3 cells (r = 0.6162). The number of NKT cells was strongly positively correlated with CD3 cells (r = 0.6885) and CD3CD8 cells (r = 0.5465). Periodic exacerbations in RF are associated with the development of furuncles, which are a result of many already discovered as well as just being examined mechanisms. One of them is a significant increase in the number and most likely activation of NK and NKT-like cells during the formation of the inflammatory process and furuncles. PMID- 29236129 TI - [Accidental poisoning with aconite napel (monkshood) : Simultaneous treatment of two patients]. AB - The unintentional poisoning with aconite in a 32-year-old healthy woman led to life-threatening neurological and cardiovascular effects with cardiac arrest and need for resuscitation. The combined administration of magnesium and amiodarone was able to stabilize heart rhythm and circulation. Organ damage was not recognized in the follow-up. PMID- 29236130 TI - Referees 2017. PMID- 29236131 TI - Trends in incidence and long-term outcomes of myelomeningocele in British Columbia. AB - PURPOSE: Myelomeningocele is typically a disabling condition that results in neurologic, orthopedic, and urologic morbidity. The aim of this study was to examine the trends over time in both incidence and outcomes of myelomeningocele (MMC) in British Columbia (BC). METHODS: A retrospective chart review was performed of all children with MMC followed in the British Columbia Children's Hospital (BCCH) Spinal Cord Clinic between 1971 and 2016. The incidence of new MMC cases and the long-term outcomes of MMC were compared between two 10-year cohorts. The first cohort comprised children born with MMC between 1971 and 1981, and the second cohort comprised children born with MMC between 1996 and 2006. RESULTS: A total of 309 children with MMC were followed in the BCCH Spinal Cord Clinic between 1971 and 2016. There were 101 and 46 children with MMC in the two time cohorts, respectively. Between the earlier and later cohorts, there was a significant difference in the following: MMC incidence [2.5/10,000 births vs 1.1/10,000 births, respectively (p = 0.0002)], mortality [18 vs 0% (p = 0.0009)], and the proportion of cases repaired in under 48 h [56 vs 98% (p < 0.0001)]. For surviving children, the proportion of children attending special classes was significantly different between the earlier and later cohorts [16 vs 46%, respectively (p = 0.0002)], whereas all other outcome measures, including the proportion with hydrocephalus, kyphoscoliosis, Chiari II surgery, bowel and bladder continence, recreation participation, obesity, and ambulation, were not significantly different. CONCLUSIONS: In BC, the incidence of new cases of MMC has decreased between 1971 and 2016, while the probability of survival for these patients has increased. Despite earlier and more universal post-natal repair, long-term outcomes have not improved significantly over time. Future research should focus on developing ways of reducing disability and improving quality of life for MMC patients and their families. PMID- 29236132 TI - Brentuximab-vedotin maintenance following chemotherapy without irradiation for primary intracranial embryonal carcinoma in down syndrome. AB - BACKGROUND: Germ cell tumors (GCT) are the most common central nervous system (CNS) tumors in individuals with Down syndrome. Patients with Down syndrome treated with CNS irradiation are at increased risk of developing cerebrovascular complications such as moyamoya disease. Embryonal carcinoma components are recognized to be more resistant to conventional chemotherapy and radiotherapy and confer a very poor prognosis. CD30 is a member of the tumor necrosis factor receptor superfamily. CD30+ has a limited expression in normal cells but is the defining marker for embryonal carcinoma. Brentuximab-vedotin is a novel antibody drug conjugate consisting of the chimeric anti-CD30 antibody conjugated to an anti-tubulin synthetic analog monomethyl auristatin E. METHODS: A retrospective review of the patient's records was conducted in September 2017. RESULTS: We report upon our management of a teenage girl with Down syndrome and a suprasellar pure embryonal carcinoma utilizing an intensive chemotherapy regimen followed by brentuximab-vedotin without irradiation. The patient received two cycles of carboplatin and etoposide interspersed with one cycle of cyclophosphamide and etoposide for induction followed by three cycles of marrow-ablative thiotepa and carboplatin rescued by autologous hematopoietic stem cell. Finally, She received six cycles of intravenous brentuximab-vedotin. The patient continues without evidence of recurrent tumor by MRI and tumor marker surveillance 24 months since diagnosis, with no adverse sequelae of her treatment. CONCLUSIONS: Brentuximab vedotin may provide a selective and safe alternative (or adjunct) to radiotherapy in the management of patients with CD30-positive CNS embryonal carcinoma, especially for those patients at high risk of developing irradiation-related complications. PMID- 29236133 TI - Pesticide analysis by pulsed flow modulation GCxGC-MS with Cold EI-an alternative to GC-MS-MS. AB - We explored the use of pulsed flow modulation (PFM) two-dimensional comprehensive gas chromatography (GCxGC) mass spectrometry with supersonic molecular beams (SMB) (also named Cold electron ionization (EI)) for achieving universal pesticide analysis in agricultural products. The use of GCxGC serves as an alternative to MS-MS in the needed reduction of matrix interference while enabling full-scan MS operation for universal pesticide analysis with reduced number of false negatives. Matrix interference is further reduced with Cold EI in view of the enhancement of the molecular ions. Pulsed flow modulation is a simple GCxGC modulator that does not consume cryogenic gases while providing tuneable second GCxGC column injection time for enabling the use of quadrupole-based mass spectrometry regardless its limited scanning speed. PFM-GCxGC-MS with Cold EI combines improved separation of GCxGC with Cold EI benefits of tailing-free ultra fast ion source response time and enhanced molecular ions for the provision of increased sample identification information and reduced matrix interference. Consequently, PFM GCxGC-MS with Cold EI also improved NIST library identification probabilities of the spiked pesticides. PFM GCxGC is further characterized by largely increased second column sample and matrix capacity that as a result performs much better than thermal modulation GCxGC-MS with standard EI in the suppression of matrix interference. In a comparison with standard GC-MS, we measured with PFM GCxGC-MS with Cold EI an average total ion count matrix interference reduction factor of 32 for 12 pesticides in two matrices of baby leaves mixture and lettuce. In addition, Cold EI further increases the range of pesticides amenable for GC-MS analysis and its response is relatively uniform hence with it the need for pesticides specific calibration is reduced. Graphical abstract Pulsed flow modulation GCxGC-MS with Cold EI significantly reduces matrix interference and improves sample identification. PMID- 29236135 TI - [Retinal dystrophy with kidney disease]. PMID- 29236134 TI - Determination of halogenated flame retardants by GC-API-MS/MS and GC-EI-MS: a multi-compound multi-matrix method. AB - The extensive application of halogenated flame retardants has led to their widespread distribution in the environment. Recently, concerns emerged regarding their potential persistence, (bio)accumulation, and/or toxicity. Particularly halogenated flame retardants based on norbornene structures, like Dechlorane Plus as well as other brominated PBDE replacements, generically called emerging, novel, or alternative flame retardants, are in the focus of interest. A comprehensive analytical method for the determination of 21 halogenated flame retardants (HFRs) of different substance classes (dechloranes, brominated aromates, brominated ethers, cyclic BFR) in a broad variety of matrices (tree leaves, fish fillet, birds eggs, suspended particles) was developed in order to assess their environmental levels as well as temporal trends, especially for the use within environmental specimen banks (ESBs). In addition to the alternative HFRs, a set of 24 PBDEs were measured in the same samples, however using GC-EI-MS for detection. Samples were extracted using accelerated solvent extraction (ASE) with dichloromethane:hexane (exception: soxhlet extraction for suspended particles) followed by a multi column clean-up. Quantification was performed by API-GC-MS/MS as a modern, gentle, and sensitive technique for simultaneous detection of compounds throughout a wide range of masses and fragmentation characteristics (exception: PBDE detection using GC-EI-MS). With the exception of BDE 209, instrumental precisions of target compounds ranged from 1% to 16 % (at levels of 2 pg injection-1 for HFR, 20 pg injection-1 for DBDPE, 7-36 pg injection-1 for PBDEs). Interday precisions of the entire analytical method including extraction and clean-up were mostly below 25% for all validation matrices at spiked levels of 100 pg sample-1 for HFR (DBDPE: 1000 pg sample-1) and 1200-6000 pg sample-1 for PBDEs. The majority of analytes were investigated with expanded measurement uncertainties of less than 50%. Graphical abstract A new approach to HFR analysis in multiple environmental matrices. PMID- 29236137 TI - [Knee pain in a female marathon runner]. PMID- 29236136 TI - Occupational class and the changing patterns of hospitalization for affective and neurotic disorders: a nationwide register-based study of the Finnish working-age population, 1976-2010. AB - PURPOSE: This study aimed to examine the long-term changes and socioeconomic disparities in hospitalization for affective and neurotic disorders among the Finnish working-age population from 1976 to 2010. METHODS: Register-based study, consisting of a 5-year follow-up of 3,223,624 Finnish working-age (18-64-year old) individuals in seven consecutive cohorts. We calculated the hazard ratios of psychiatric hospitalization for different occupational classes using Cox regression models. RESULTS: The risk of hospitalization for affective and neurotic disorders increased in all occupational classes after the economic recession in the 1990s, and then decreased in the 2000s. Before the 2000s, the risk was the highest among manual workers. In the 2000s the disparities between upper-level non-manual employees and other occupational classes increased. Hospitalization rates remained high among female manual workers and non-manual lower-level employees. CONCLUSIONS: This study revealed important similarities and differences between occupational classes in terms of long-term changes in hospitalization for affective and neurotic disorders. The results suggest that the labor market changes and healthcare reforms during the 1990s and 2000s in Finland have been more beneficial for higher than for lower occupational classes. PMID- 29236138 TI - [Inflammatory and infectious abdominal peritoneal and mesenterial processes]. AB - BACKGROUND: Mesenterial and peritoneal inflammation represents a major clinical challenge regarding differential diagnosis. In this review article, a systematic overview of the most common causes such as autoimmune reaction, infarction with consecutive necrosis and infection caused by protozoa or bacteria is provided. RESULTS: The common clinical features of all inflammatory peritoneal and mesenterial diseases are the nonspecific abdominal symptoms. Even in radiological imaging an overlap of imaging features such as lymphadenopathy and nodular mesenteric structures is typical. Frequently the radiologist can narrow the differential diagnosis based on clinical information and anamnesis resulting in an optimized clinical outcome. CONCLUSION: Having a huge spectrum of etiologies for inflammatory peritoneal and mesenterial conditions the radiologist has to consider autoimmune diseases (IgG4-associated disease), acute infarction with necrosis and bacterial or protozoan infection. PMID- 29236139 TI - [Notochordal tumors : Benign notochordal tumors and chordomas]. AB - Benign notochordal tumors (BNCT) and chordomas are primary bone tumors of the spine with a predominant localization in the sacrum and clival region followed by the vertebral bodies. Besides the most common variant (NOS [not otherwise specified] with hepatoid or renal carcinoma cell-like differentiation) chordomas with chondroid, and polymorphic to anaplastic morphology are described. An unfavorable variant are pediatric chordomas with a loss of INI-1. BNCT and chordomas are characterized by the following immunohistological profile: vimentin+, cytokeratin+/-, epithelial membrane antigen (EMA)+/-, S100 protein+/-, brachyury+. This profile helps to distinguish these tumors from other lesions such as chondrosarcoma, chordoid meningioma, and metastases of carcinoma. PMID- 29236140 TI - Letter to the Editor concerning "Can standard anterior Smith-Robinson supramanubrial approach be utilized for approach down to T2 or T3?" by Singhatanadgige W, Zebala LP, Luksanapruksa P, Riew KD [Eur Spine J (2017) 26:2357-2362]. PMID- 29236141 TI - Annual Meeting Abstracts of the Society of Skeletal Radiology (SSR) 2018, Austin, Texas, USA. PMID- 29236142 TI - Frequency-dependent growth in class-structured populations: continuous dynamics in the limit of weak selection. AB - In this paper we consider class-structured populations in discrete time in the limit of weak selection and with the inverse of the intensity of selection as unit of time. The aim is to establish a continuous model that approximates the discrete model. More precisely, we study frequency-dependent growth in an infinite haploid population structured into a finite number of classes such that individuals in each class contribute to a given subset of classes from one time step to the next. These contributions take the form of generalized fecundity parameters with perturbations of order 1 / N that depends on the class frequencies of each type and the type frequencies. Moreover, they satisfy some mild conditions that ensure mixing in the long run. The dynamics in the limit as [Formula: see text] with N time steps as unit of time is considered first in the case of a single type, and second in the case of multiple types. The main result is that the type frequencies as [Formula: see text] obey the replicator equation with instantaneous growth rates for the different types that depend only on instantaneous equilibrium class frequencies and reproductive values. An application to evolutionary game theory complemented by simulation results is presented. PMID- 29236143 TI - [Bulbar urethral strictures : A trivial urological disease or a surgical challenge?] AB - Urethral strictures are often located in the bulbar urethra, and bulbar strictures are commonly due to urethral trauma. Diagnosis is confirmed by radiographic imaging of the urethra. In cases of short primary bulbar strictures, a simple internal urethrotomy may be curative. In contrast, open surgery should be performed in long segment or recurrent strictures because recurrence rates are near 100% in these cases. Depending of the actual findings and comorbidities, end to-end anastomosis, graft urethroplasty, flap urethroplasty, or perineal urethrostomy may be used. If definitive treatment using open surgery is delayed and multiple endoscopic treatments are tried, urethroplasty becomes more complex and success rates of definitive treatment decline. PMID- 29236144 TI - Technological properties assessment and two component systems distribution of Streptococcus thermophilus strains isolated from fermented milk. AB - Streptococcus thermophilus is one of the economically most representatives of lactic acid bacteria, which is widely used as a starter to produce fermented milk products. In this study, 22 S. thermophilus strains were isolated from 26 fermented milk samples. Most isolates showed the ability to ferment a broad range of carbohydrates. Interestingly, eight strains are galactose positive, which is a desirable property in various industrial dairy fermentations. Four different nucleotide sequences were found in the galR-galK intergenic regions. The 16S-23S intergenic spacer region sequences of most isolates were determined as ITS-St-II type, which are related with protease positive and fast acidification. CS18 presented excellent technological performances, and showed potential as a promising starter candidate. To gain a comprehensive view of stress response mechanisms of strains, the distribution of all the two-component systems (TCSs) in strains were investigated. TCS analysis indicated that the nucleotide sequence of TCSs have obvious differences in different strains. And the strains with the special nucleotide sequences of TCS have distinctive traits. Therefore, it was speculated that there is a certain connection between the traits' difference and the TCS difference of strains. PMID- 29236145 TI - [Non-coding RNA : Innovative regulators with therapeutic perspective]. AB - As a result of the Human Genome Project it became evident that only 1-3% of all gene transcripts encode proteins. The vast majority of gene transcripts are in fact characterized as non-coding RNAs (ncRNAs). These ncRNAs have a huge impact on diverse physiological and pathological mechanisms within an organism. In particular, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), which are differentiated by their size and function, are involved in the regulation and development of many illnesses. In the context of heart and cardiovascular diseases numerous ncRNAs have also already been described in some detail. As these molecules represent therapeutic target structures, ncRNAs provide a completely new level for the discovery of promising therapeutic approaches. Many approaches have already been developed aimed at influencing the expression levels of specific ncRNAs in order to induce beneficial effects on pathological processes. In fact, first medications based on miRNAs have already achieved approval. Additionally, ncRNAs contained in plasma can serve as new non-invasive diagnostic markers for the detection of diseases. PMID- 29236146 TI - [Atherothrombosis : Novel therapeutic strategies]. AB - Despite intensive scientific research over the past decades, atherosclerosis and atherothrombosis are the leading cause of mortality worldwide. During the recent past it has become clear that atherosclerosis is not merely a lipid-driven disease but a multifactorial process involving chronic inflammation of large arteries. This review article briefly outlines the mechanistic nature of atherosclerosis, presents a synopsis of the current state of the art treatment strategies and finally outlines several therapeutic options, which are in clinical and experimental testing. PMID- 29236147 TI - [Platelet inhibition in elderly patients]. AB - Single antiplatelet therapy (SAPT) using predominantly acetylsalicylic acid (ASA) is the baseline anti-thrombotic therapy in primary as well as secondary prevention of atherosclerotic disease. Dual antiplatelet therapy (DAPT) is the cornerstone of maintenance medication following elective percutaneous coronary interventions or acute coronary syndromes (ST elevation myocardial infarction, non-ST elevation myocardial infarction and unstable angina pectoris). In the past the duration of DAPT in particular has been frequently discussed. Current recommendations, such as the "Focused Update DAPT 2017" of the European Society of Cardiology (ESC) emphasize the importance of strategies aiming to reduce an increased risk of bleeding based on clinical predictors. In this case older age is an important factor relevant for bleeding. In this article, the evidence for SAPT or DAPT is summarized with a special focus on patients aged >=75 years. PMID- 29236148 TI - Dual antiplatelet therapy after percutaneous coronary intervention for stable CAD or ACS : Redefining the optimal duration of treatment. AB - The duration and combination of dual antiplatelet therapy after coronary stent implantation, consisting of aspirin and a P2Y12 inhibitor, is among the most intensely investigated therapeutic strategies in cardiovascular medicine. While initial studies have mainly focused on the efficacy and safety of individual antithrombotic agents, the increased need for a personalized, risk-based approach to define the optimal duration of antithrombotic treatment according to the estimated ischemic and bleeding risk was then recognized. Recent recommendations for the optimal duration of antithrombotic combination therapies following coronary stent implantation in various clinical scenarios have substantially changed. The aim of the present article is to discuss the recent evidence from randomized clinical trials and observational studies with respect to antithrombotic treatment regimens in patients undergoing coronary artery stenting for stable coronary artery disease (CAD) or an acute coronary syndrome (ACS). We will focus on optimal treatment duration and a personalized approach based on ischemic and bleeding risk assessment. PMID- 29236149 TI - Transcatheter aortic valve replacement with balloon-expandable valve : Analysis of initial experience in China. AB - BACKGROUND: Transcatheter aortic valve replacement (TAVR) is widely applied for the treatment of severe aortic stenosis (AS) in developed countries; however, in China, it is still in the early stage of utilization. On the basis of previous studies, this work explored the feasibility of TAVR in patients with severe AS in China and analyzed the cause of death in four cases. METHODS: This retrospective study included 20 patients who had severe AS and underwent TAVR with a balloon expandable system (Edwards SAPIEN XT) in our hospital from January 2011 to June 2016. The valve and heart functions of 16 survivors before and after the TAVR procedure were compared. TAVR endpoints, device success, and adverse events were assessed according to the definitions of the Valve Academic Research Consortium-2 (VARC-2). RESULTS: There were 13 male and seven female patients aged 65-81 years (average, 73.15) who underwent TAVR. The TAVR approach was transfemoral in 19 patients and transapical in one patient. Four patients died (two of coronary artery occlusion and two of aortic annulus rupture) during the TAVR procedure or shortly after; six patients had mild paravalvular leakage, and the rest of the patients showed a significant improvement in cardiac function. During the follow up period (2-62 months), one patient died of lung cancer 13 months after the TAVR procedure. CONCLUSION: TAVR with a balloon-expandable system is safe and effective and can be used for patients with severe AS in China. It requires careful patient selection and preoperative assessment so as to reduce the 30-day postoperative mortality rate. PMID- 29236150 TI - Correction to: Impact of surgeon experience on routine prolapse operations. AB - The article "Impact of surgeon experience on routine prolapse operations", written by Emil Nussler, Jacob Kjaer Eskildsen, Emil Karl Nussler, Marie Bixo, and Mats Lofgren, was originally published without open access. PMID- 29236152 TI - Transport pathway and source area for Artemisia pollen in Beijing, China. AB - Artemisia pollen is an important allergen responsible for allergic rhinitis in Beijing, China. To explore the transport pathways and source areas of Artemisia pollen, we used Burkard 7-day traps to monitor daily pollen concentrations in 2016 in an urban and suburban locality. Backward trajectories of 24- and 96-h and their cluster analysis were performed to identify transport pathways of Artemisia pollen using the HYSPLIT model on 0.5 degrees * 0.5 degrees GADS meteorological data. The potential source contribution function (PSCF) and concentration weighted trajectory (CWT) were calculated to further identify the major potential source areas at local, regional, and long-range scales. Our results showed significant differences in Artemisia pollen concentration between urban and suburban areas, attributed to differences in plant distribution and altitude of the sampling locality. Such differences arisen from both pollen emission and air mass movements, hence pollen dispersal. At local or regional scales, source area of northwestern parts of Beijing City, Hebei Province and northern and northwestern parts of Inner Mongolia influenced the major transport pathways of Artemisia pollen. Transport pathway at a long-range scale and its corresponding source area extended to northwestern parts of Mongolia. The regional-scale transport affected by wind and altitude is more profound for Artemisia pollen at the suburban than at the urban station. PMID- 29236151 TI - The effects of HAP and macrophage cells to the expression of inflammatory factors and apoptosis in HK-2 cells of vitro co-cultured system. AB - This study developed an in vitro system by co-culturing HK-2 cells with different concentration of hydroxyapatite (HAP) and/or macrophage cells to simulate the internal environment of urolithiasis as far as possible, investigating the regulatory effects of macrophage cells on HAP-induced expression of relative inflammatory factors of HK-2 cells. The control group (H group) was only comprised of HK-2 cells. Experimental groups included co-culturing HK-2 cells and macrophage cells (H + M group), co-culturing HK-2 cells and HAP (H + A group), co culturing macrophage cells and HAP (M + A group), and co-culturing HK-2 cells and macrophage cells with HAP (H + M + A group). In the H + A, M + A, and H + M + A group, we set the concentration of HAP as 5 MUg/cm2 (A1) and 10 MUg/cm2 (A2). After co-culturing for 2, 4, and 6 h, we detected the expression of CCL-2 in the liquid by ELISA. We tested the expression of LDH and ROS to evaluate the damage of HK-2 cells. We assessed the apoptosis of HK-2 cells using DAPI staining assay, flow cytometry, and the rate of BAX/BCL-2. Western Blotting detected OPN, Fetuin A, BAX, and BCL-2 of HK-2 cells. The expression of CCL-2 in the medium of H + A1 and H + A2 group increased significantly compared with the control (P < 0.05); CCL-2 of M + A1 and M + A2 group was higher than the H + A1 and H + A2 group (P < 0.05). The expression of CCL-2 in H + M + A1 and H + M + A2 group was also higher than M + A1 and M + A2 group (P < 0.05). Compared with control, the expression of OPN, LDH release, the ratio of BAX/BCL-2, and the generation of ROS in HK-2 cells increased in a dose- and time-dependent manner. Compared with the control, the expression of Fetuin-A decreased in various degrees at different incubation periods. Especially when co-culturing for 6 h, Fetuin-A decreased most seriously in the H + M + A1 group. (1) The HAP can induce the HK-2 cells oxidative stress and inflammatory damage and apoptosis, when adding the macrophages to co-culture, macrophage cells can aggravate the damage and apoptosis of the HK-2 cells. (2) After the stimulation of HAP, the expression of OPN in HK-2 cells increased in a time- and dose-dependent manner; macrophage cells can aggravate the increase of OPN in HK-2 cells. (3) In the HAP and HK-2 cells co-cultured system, the low level Fetuin-A of HK-2 cells may be related to the excessive consumption of Fetuin-A in the process of HAP-induced renal tubular epithelial cell excessive oxidative stress, inflammatory injury, and cell apoptosis. When adding macrophage cells to co-culture, Fetuin-A decreased even more seriously, it reminds us that macrophage cells can slightly regulate the expression of Fetuin-A in the HK-2 cells. PMID- 29236153 TI - Insufficient vaccination rates in patients with systemic lupus erythematosus in a German outpatient clinic. AB - BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at an increased risk of acquiring infections due to the disease itself and the immunosuppressive therapy. Furthermore, infections largely contribute to overall SLE mortality. Vaccinations against preventable diseases are therefore of particular importance for these patients. AIMS: To estimate vaccination frequencies among patients with SLE, we studied patients in a survey and calculated vaccination rates based on their vaccination documents. Patients were recruited from our outpatient clinic during one of their routine visits. For the statistical analysis, they have been stratified by age (>=60 vs. <60 years) for further subgroup analysis due to age related recommendations for some vaccines. RESULTS: Among the patients studied (n = 68) we found rather low vaccination rates in particular for the strongly recommended vaccines against pneumococcus and influenza (21% and 49%, respectively). Furthermore, protection rates for important basic vaccinations were found to be low, e. g. pertussis protection for 31% of patients. Beside these findings, we saw age-dependant differences for a variety of vaccines: while the pneumococcus vaccination was more often given to patients >=60 years, measles, pertussis, diphtheria and hepatitis B vaccinations were found significantly more often in younger patients. CONCLUSIONS: Vaccination rates have to be improved among SLE patients, in particular for vaccines protecting from respiratory tract infections such as pneumococcus and influenza. PMID- 29236155 TI - Oxidative Stress Response Induced by Butachlor in Zebrafish Embryo/Larvae: The Protective Effect of Vitamin C. AB - The widespread contamination and persistence of the herbicide butachlor in the environment resulted in the exposure of non-target organisms. The present study investigated the toxicity effect of butachlor (1-15 umol/L) and the protective effect of vitamin C (VC) against butachlor-induced toxicity in zebrafish. It was found that butachlor significantly increased the mortality and malformation rates in a dose-dependent manner, which caused elevation in reactive oxygen species (ROS) and malondialdehyde (MDA) after 72 h exposure. Compared with butachlor treatment group, the protective effect of VC against butachlor-induced toxicity were observed after adding 40, 80 mg/L VC respectively. VC significantly decreased the mortality, malformation rates, ROS, MDA, and normalized antioxidant enzymes activities of zebrafish after 72 h exposure. The result shows VC has mitigative effect on butachlor-induced toxicity and it can be used as an effective antioxidant in aquaculture. PMID- 29236156 TI - Experimental Infection and Clearance of Coccidian Parasites in Mercury-Exposed Zebra Finches. AB - Mercury is a globally distributed, persistent environmental contaminant that affects the health of many taxa. It can suppress the immune system, which often plays a role in defense against parasites. However, there have been few investigations of whether mercury affects the abilities of animals to resist parasitic infection. Here, we exposed zebra finches to a lifetime dietary exposure of methylmercury (1.2 MUg/g wet weight) and experimentally infected them with coccidian parasites to examine the effect of methylmercury exposure on parasitic infection. The mercury-exposed birds did not have an altered immune response (heterophil:lymphocyte ratio) nor a reduced ability to clear the infection. However, mercury-exposed birds tended to have higher parasite loads at the time when we expected the greatest immune response (2-3 weeks post infection). Although mercury did not greatly influence the infection-course of this parasite in captivity, responses may be more accentuated in the wild where birds face additional immune challenges. PMID- 29236154 TI - Calcium dynamics in tomato pollen tubes using the Yellow Cameleon 3.6 sensor. AB - KEY MESSAGE: In vitro tomato pollen tubes show a cytoplasmic calcium gradient that oscillates with the same period as growth. Pollen tube growth requires coordination between the tip-focused cytoplasmic calcium concentration ([Ca2+]cyt) gradient and the actin cytoskeleton. This [Ca2+]cyt gradient is necessary for exocytosis of small vesicles, which contributes to the delivery of new membrane and cell wall at the pollen tube tip. The mechanisms that generate and maintain this [Ca2+]cyt gradient are not completely understood. Here, we studied calcium dynamics in tomato (Solanum lycopersicum) pollen tubes using transgenic tomato plants expressing the Yellow Cameleon 3.6 gene under the pollen specific promoter LAT52. We use tomato as an experimental model because tomato is a Solanaceous plant that is easy to transform, and has an excellent genomic database and genetic stock center, and unlike Arabidopsis, tomato pollen is a good system to do biochemistry. We found that tomato pollen tubes showed an oscillating tip-focused [Ca2+]cyt gradient with the same period as growth. Then, we used a pharmacological approach to disturb the intracellular Ca2+ homeostasis, evaluating how the [Ca2+]cyt gradient, pollen germination and in vitro pollen tube growth were affected. We found that cyclopiazonic acid (CPA), a drug that inhibits plant PIIA-type Ca2+-ATPases, increased [Ca2+]cyt in the subapical zone, leading to the disappearance of the Ca2+ oscillations and inhibition of pollen tube growth. In contrast, 2-aminoethoxydiphenyl borate (2-APB), an inhibitor of Ca2+ released from the endoplasmic reticulum to the cytoplasm in animals cells, completely reduced [Ca2+]cyt at the tip of the tube, blocked the gradient and arrested pollen tube growth. Although both drugs have antagonistic effects on [Ca2+]cyt, both inhibited pollen tube growth triggering the disappearance of the [Ca2+]cyt gradient. When CPA and 2-APB were combined, their individual inhibitory effects on pollen tube growth were partially compensated. Finally, we found that GsMTx-4, a peptide from spider venom that blocks stretch-activated Ca2+ channels, inhibited tomato pollen germination and had a heterogeneous effect on pollen tube growth, suggesting that these channels are also involved in the maintenance of the [Ca2+]cyt gradient. All these results indicate that tomato pollen tube is an excellent model to study calcium dynamics. PMID- 29236157 TI - Isoprene Emissions and Ozone Formation in Urban Conditions: A Case Study in the City of Rio de Janeiro. AB - The potential role of isoprene oxidative processes, as well as the possible impact of air pollution on isoprene emissions, are more important in tropical cities, surrounded by rainforests. In this study, the contribution of isoprene to ozone formation was determined considering different scenarios, mainly volatile organic compounds/NO x (VOC/NO x ) ratios, and typical atmospheric conditions for the city of Rio de Janeiro, where more than 36% of the urbanized area is covered by vegetation. Ozone isopleths and incremental reactivity coefficients (IR) were evaluated to understand the direct contribution of isoprene to ground-level ozone formation and the negative impact of anthropogenic NO x emissions on the natural atmospheric balance. Although isoprene accounted for only 2.7% of the total VOC mass, excluding the isoprene concentration from the model reduced the maximum ozone value by 14.1%. The calculated IR coefficient (grams of O3 formed per gram of added isoprene) was 2.2 for a VOC/NO x ratio of 8.86. PMID- 29236158 TI - Nitrate Concentration Patterns Over Space and Time in a Regionally Sloping Sedimentary Aquifer, Texas, USA. AB - Nitrate concentrations in a regionally sloping sedimentary aquifer were compiled every 4 years from 1999 to 2015. Sampled wells ranged from 14.6 m deep in the outcrop zone to 1031.4 m deep in the confined zone, with a median depth of 192.1 m. Approximately 3.6% of 138 samples collected in 2015 exceeded the drinking water standard of 44.3 mg/L; while low, this percentage was highest among five sampling years. All observed exceedances were in relatively shallow wells in the outcrop zone. Generally, the spatial pattern of nitrate occurrence persisted through time. Shallow wells tended to have higher nitrate concentrations, in addition to larger increases or decreases in concentration over time. Maximum concentrations ranged from 30.5 mg/L in 1999 to 100.5 mg/L in 2015. Over any 4 year period, the maximum concentration increase was 42.1 mg/L, and the maximum decrease was 41.0 mg/L, both occurring in wells in the outcrop zone. This study has land management implications for sloping sedimentary aquifers. Practices that alter nitrogen inputs and dilution processes in unconfined zones may produce large fluctuations in nitrate concentration over short time periods. PMID- 29236159 TI - Rapid Detection of Sublethal Toxicity Using Locomotor Activity of Rainbow Trout Juveniles. AB - This study examined changes in locomotor activity of the rainbow trout (Oncorhynchus mykiss) juveniles exposed to sublethal concentrations of hexavalent chromium (Cr6+) (as a single pollutant) and landfill leachate (as an complex mixture of mainly organic compounds, including trace amounts of metals). Fish were first examined for baseline behavior patterns for 3 h to determine the appropriate duration of acclimation and the control level. The average velocity of fish was found to be the most informative among other endpoints throughout the 3 h long acclimation. Under the effect of both test substances, fish locomotor activity significantly increased after 5 min reaching maximum values after 10 min of exposure. The juveniles exposed to leachate were more responsive than those exposed to Cr6+. However, in this study we did not succeed in identifying pollutants from the elicited fish behavioral response patterns. PMID- 29236160 TI - Ethanol and Cytokines in the Central Nervous System. AB - The innate immune system plays a critical role in the ethanol-induced neuroimmune response in the brain. Ethanol initiates the innate immune response via activation of the innate immune receptors Toll-like receptors (TLRs, e.g., TLR4, TLR3, TLR7) and NOD-like receptors (inflammasome NLRs) leading to a release of a plethora of chemokines and cytokines and development of the innate immune response. Cytokines and chemokines can have pro- or anti-inflammatory properties through which they regulate the immune response. In this chapter, we will focus on key cytokines (e.g., IL-1, IL-6, TNF-alpha) and chemokines (e.g., MCP-1/CCL2) that mediate the ethanol-induced neuroimmune responses. In this regard, we will use IL-1beta, as an example cytokine, to discuss the neuromodulatory properties of cytokines on cellular properties and synaptic transmission. We will discuss their involvement through a set of evidence: (1) changes in gene and protein expression following ethanol exposure, (2) association of gene polymorphisms (humans) and alterations in gene expression (animal models) with increased alcohol intake, and (3) modulation of alcohol-related behaviors by transgenic or pharmacological manipulations of chemokine and cytokine systems. Over the last years, our understanding of the molecular mechanisms mediating cytokine- and chemokine-dependent regulation of immune responses has advanced tremendously, and we review evidence pointing to cytokines and chemokines serving as neuromodulators and regulators of neurotransmission. PMID- 29236162 TI - Bisphosphonates prevent age-related weight loss in Japanese postmenopausal women. AB - Decline of body weight with aging is a major risk factor for frailty, osteoporosis and fracture, suggesting that treatment for osteoporosis may affect body composition. Recently, we have shown that 5-year treatment with raloxifene prevented age-related weight loss, suggesting some other drugs for osteoporosis may also prevent a decrease in body weight with aging. The present study aimed to identify the relationship between bisphosphonate treatment and body composition markers. We measured bone mineral density (BMD), body composition, and bone remodeling markers in 551 Japanese postmenopausal women with bisphosphonate treatment, which included risedronate or alendronate treatment (BP-treatment group; N = 193) and without treatment by any osteoporosis drug (no-treatment group; N = 358) for 4-7 years (mean observation periods; 5.5 years) and analyzed the relationship of these with BMD, body mass index (BMI), body weight, and biochemical markers. The mean (SD) age of the participants was 68.6 (9.8) years in the BP-treatment group and 63.7 (10.6) years in the no-treatment group. Percent changes in body weight and BMI were significantly different between the BP-treatment and no-treatment groups (P < 0.01 and P < 0.01, respectively). In multiple linear regression analysis, bisphosphonate treatment was a significant independent determinant of percent changes in body weight and BMI (P < 0.01 and P = 0.01, respectively). Long-term use of bisphosphonates prevented reductions in BMI and body weight, usually observed in elderly women. Our results suggest that bisphosphonate treatment not only reduces the risk for incident osteoporotic fractures but also for frailty in the elderly. PMID- 29236161 TI - Genetic analysis of adults heterozygous for ALPL mutations. AB - Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity. PMID- 29236163 TI - Evaluation of pain perception associated with use of the magnetic-end ureteric double-J stent for short-term ureteric stenting. AB - PURPOSE: To investigate the morbidity, complication rate, and pain perception during removal of a novel ureteric stent with a magnetic end using a-traumatic retrieval catheter. METHODS: Between November 2013 and July 2015, 151 consecutive patients who underwent semirigid ureterorenoscopy (URS) for stone removal were prospectively enrolled. Stent removal was performed under local anesthesia using a special magnetic-end stent remover 1 week following URS. At follow-up, we obtained patients' medical history, urine culture result, renal ultrasonogram, and visual analog scale (VAS) score regarding stent irritation (VAS 1) and pain during removal (VAS 2). RESULTS: Pain perception during stent removal was significantly less painful in patients with a magnet stent than in those with a regular stent (p < 0.001). Stent irritation was slightly higher in patients with an indwelling magnet stent than in those with a regular stent (p < 0.001). No significant differences in stent irritations were found in patients who had a magnetic stent for 4 weeks after laparoscopic pyeloplasty (p = 0.20). Patients with a magnetic stent experienced significantly less pain during removal with a median VAS 2 score of 2.5 and a mean VAS 2 score of 2.58 [standard deviation (SD) +/- 0.90] than those without a magnetic stent a median VAS 2 of 6 and a mean VAS 2 of 5.88 (SD +/- 1.43). The stent length correlated with stent irritation (p = 0.05), and it significantly correlated with pain during removal (p < 0.001). CONCLUSION: The magnetic-end ureteric double-J stent is a safe option associated with less pain, particularly for male patients requiring short-term ureteric stenting. PMID- 29236164 TI - The influence of isoflavone for denervation-induced muscle atrophy. AB - PURPOSE: Decrease in activity stress induces skeletal muscle atrophy. A previous study showed that treatment with a high level (20%) of isoflavone inhibits muscle atrophy after short-term denervation (at 4 days) in mice. The present study was designed to elucidate whether the dietary isoflavone aglycone (AglyMax) at a 0.6% prevents denervation-mediated muscle atrophy, based on the modulation of atrogin 1- or apoptosis-dependent signaling. METHODS: Mice were fed either a normal diet or 0.6% AglyMax diet. One week later, the right sciatic nerve was cut. The wet weight, mean fiber area, amount of atrogin-1 and cleaved caspase-3 proteins, and the percentages of apoptotic nuclei were examined in the gastrocnemius muscle at 14 days after denervation. RESULTS: The 0.6% AglyMax diet significantly attenuated denervation-induced decreases in fiber atrophy but not the muscle wet weight. In addition, dietary isoflavone suppressed the denervation-induced apoptosis in spite of there being no significant changes in the amount of cleaved caspase-3 protein. In contrast, the 0.6% AglyMax diet did not significantly modulate the protein expression of atrogin-1 in the denervated muscle of mice. CONCLUSIONS: The isoflavone aglycone (AglyMax) at a 0.6% significantly would modulate muscle atrophy after denervation in mice, probably due to the decrease in apoptosis-dependent signaling. PMID- 29236165 TI - Polyphenol-rich curry made with mixed spices and vegetables benefits glucose homeostasis in Chinese males (Polyspice Study): a dose-response randomized controlled crossover trial. AB - PURPOSE: To investigate acute effects of two doses of a polyphenol-rich curry made with seven different spices and four base vegetables, eaten with white rice, on 24 h glucose response, postprandial insulinemia, triglyceridemia and 24 h urinary total polyphenol excretion (TPE). METHODS: Randomized, controlled, dose response crossover trial in healthy, Chinese men [n = 20, mean +/- standard deviation (SD) age 23.7 +/- 2.30 years, BMI 23.0 +/- 2.31 kg/m2] who consumed test meals matched for calories, macronutrients and total vegetables content, consisting either Dose 0 Control (D0C) or Dose 1 Curry (D1C) or Dose 2 Curry (D2C) meal. 24 h glucose concentration was measured using continuous glucose monitoring (CGM), together with postprandial plasma insulin and triglyceride for up to 7 h. Total polyphenol content (TPC) of test meals and urinary TPE were measured using the Folin-Ciocalteu assay. RESULTS: TPC for D0C, D1C and D2C were 130 +/- 18, 556 +/- 19.7 and 1113 +/- 211.6 mg gallic acid equivalent (GAE) per portion served, respectively (p < 0.0001). Compared with D0C meal, we found significant linear dose-response reductions in the 3-h postprandial incremental AUC (iAUC) for CGM glucose of 19% and 32% during D1C and D2C meals respectively (p < 0.05) and non-significant linear dose response reductions in iAUC of insulin (p = 0.089). Notably, we found significant dose-dependent increases in postprandial triglyceride with increasing curry doses (p < 0.01). Significant increases in TPE with increasing curry doses were also observed (p < 0.01). CONCLUSION: Polyphenol-rich curry intake can improve postprandial glucose homeostasis. The longer term effects remain to be established. PMID- 29236166 TI - Correction to: Expression of matrix metalloproteinase 12 is highly specific for non-proliferating invasive trophoblasts in the first trimester and temporally regulated by oxygen-dependent mechanisms including HIF-1A. AB - In the original publication, the contribution of Dr. Christian Eyth as equal first author was not indicated. This has been corrected confirming that U. Hidden and C. Eyth contributed equally to this work. PMID- 29236167 TI - Evaluation of the yield of 24-h close observation in patients with mild traumatic brain injury on anticoagulation therapy: a retrospective multicenter study and meta-analysis. AB - BACKGROUND/AIMS: Patients with mild traumatic brain injury (mTBI) on anticoagulants have an increased risk of intracranial hemorrhage (ICH). However, consensus is lacking on whether to admit them after normal initial cranial CT. We evaluated the yield of 24-h neurological observation. METHODS: Retrospective multicenter study including adult patients admitted over a 5-year period with mTBI on anticoagulation [therapeutic dose heparin, direct oral anticoagulant, or vitamin K antagonist (VKA) with international normalized ratio (INR) >= 1.7] and reportedly normal cranial CT obtained within 24 h after trauma. Primary endpoint was symptomatic ICH within 24 h of injury. Literature on delayed ICH in patients with mTBI and anticoagulation use was reviewed. RESULTS: Of 17.643 mTBI patients, 905 met the inclusion criteria (median age 82 years). 97% used VKA (median INR 2.9). None developed delayed ICH within 24 h. Nine patients deteriorated neurologically due to ICH, four within 24 h (0.4%, 95% CI 0.1-1.2) and five on day 2, 18, 22, 36 and 52, respectively. In six patients, including all four that developed symptoms within 24 h, ICH was found upon reevaluation of initial imaging. The meta-analysis comprised of 9 studies with data from 2885 patients. The estimated pooled proportion of symptomatic delayed ICH or delayed diagnosis of ICH within 24 h was 0.2% (95% CI 0.0-0.5). CONCLUSIONS: Delayed (diagnosis of) ICH within 24 h is very rare in mTBI patients on anticoagulants after reportedly normal initial CT. Routine hospitalization of these patients seems unwarranted when the initial cranial CT is scrupulously evaluated. PMID- 29236168 TI - Clinical and magnetic resonance imaging features of elderly onset dentatorubral pallidoluysian atrophy. AB - Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar ataxia caused by CAG triplet expansion in atrophin 1 and is frequently associated with cerebral white matter lesions. To elucidate the clinical features of elderly onset DRPLA and the key radiological findings for differentiating DRPLA from physiological white matter lesions in healthy elderly subjects, we reviewed the clinical and magnetic resonance imaging (MRI) features of ten patients with elderly onset genetically confirmed DRPLA (> 60 years) and compared their MRI findings with those of age- and sex-matched ten healthy subjects with asymptomatic cerebral white matter lesions. The initial symptom was cerebellar ataxia in all DRPLA patients, and five of them did not have any symptoms other than ataxia at the time of MRI examination. Atrophy of the brainstem, superior cerebellar peduncle, and cerebellum was detected in all DRPLA patients and none of the healthy subjects. Abnormal signals in the brainstem (inferior olive, pons, and midbrain), thalamus, and cerebellar white matter were frequently observed in elderly onset DRPLA patients but not in healthy subjects. In conclusion, elderly onset DRPLA presents as cerebellar ataxia alone in the early stage of disease. Atrophy of the brainstem, superior cerebellar peduncle, and cerebellum and abnormal signals in the brainstem, cerebellum, and thalamus are key findings for differentiating elderly onset DRPLA from asymptomatic cerebral white matter lesions in healthy subjects. PMID- 29236170 TI - Response to the Letter to the Editor by Dr. Junaid Rafi. PMID- 29236169 TI - Current treatment of central retinal artery occlusion: a national survey. AB - BACKGROUND: Central retinal artery occlusion (CRAO) is an ophthalmological emergency, the retinal analog of a stroke. To date there is no consensus or national guidelines on how this disorder should be managed. As academic neurologists and ophthalmologists treat CRAO frequently, we set out to understand how these clinicians approach patients with CRAO with a national survey. METHODS: We identified university-associated teaching hospitals offering vascular neurology, neuro-ophthalmology and/or retina fellowships in the US and asked the directors of the programs to respond to questions in an open response format to profile the acute management of CRAO at their institution. RESULTS: We found remarkable heterogeneity in the approach to acute treatment of patients with CRAO among the 45 institutions that responded to the survey. Only 20% had a formal policy, guideline or white paper to standardize the approach to treatment. The primary treating physician was an ophthalmologist, neurologist, or neuro ophthalmologist 44, 27, and 4% of the time, respectively; 24% were co-managed acutely by neurology and ophthalmology. Intravenous fibrinolysis was offered to selected patients in 53% of institutions, and was the preferred initial treatment in 36%. When the acute treatment team involved a vascular neurologist, fibrinolysis was more likely to be considered a first-line treatment (p < 0.05). Anterior chamber paracentesis, ocular massage and hyperbaric oxygen therapy were offered 42, 66 and 7% of the time, respectively, while 9% of institutions offered no treatment. Anterior chamber paracentesis was more likely to be offered at programs where neurologists were not involved in treating CRAOs (p < 0.001). At 35% of institutions, patients with acute CRAO were not routinely referred to a general emergency room for initial evaluation and treatment. Carotid imaging was routinely obtained by 89% of programs, magnetic resonance imaging of the brain by 69%, echocardiogram by 62%, laboratory screening for an inflammatory state by 27% and retinal angiography by 30%. The thoroughness of vascular risk factors' screening was greater in programs that routinely referred acute CRAO cases to the emergency department. CONCLUSIONS: This survey shows that there is significant variability in treatment practices for acute CRAO in the US. Because of the high cerebrovascular and cardiovascular risk reported in this population of patients, it is notable that the approach to risk factor screening is also highly variable and many programs do not routinely refer patients to an emergency department for urgent evaluation. Finally, there appears to be equipoise among treatment teams regarding the efficacy of systemic fibrinolysis, as 53% of programs report a willingness to treat at least some patients with this modality. PMID- 29236171 TI - Uterine fibroid size modifications during pregnancy and puerperium: evidence from the first systematic review of literature. AB - PURPOSE: The influence of pregnancy on uterine fibroid size still remains an unsolved dilemma. Basing on current knowledge, physicians are not able to inform patients about the likelihood of uterine fibroids to modify their size during pregnancy. Study aim was to summarize available evidence concerning the size modifications of uterine fibroids during each trimester of pregnancy and during puerperium. METHODS: The review was reported following the PRISMA guidelines and registered in PROSPERO (registration number: CRD42017071117). A literature search was conducted in electronic database (PubMed, Embase, Sciencedirect, the Cochrane library and Clinicaltrials.gov) until July 2017. All studies evaluating fibroids' changes during pregnancy and puerperium by ultrasound or magnetic-resonance imaging were included. Descriptive characteristics of studies and patients were collected. The modifications of uterine fibroid diameter and volume were the outcome measures. RESULTS: Concerning the first trimester of pregnancy, all authors reported a significant growth of uterine fibroids. Contradictory evidence was found about uterine fibroid modifications during the second and third trimesters, mainly supporting a slowdown during mid pregnancy and a subsequent size reduction during late pregnancy. Concerning the overall modifications during pregnancy and puerperium, poor evidence quality suggests that uterine fibroids do not modify their volume/slightly enlarge during pregnancy and subsequently reduce in size during puerperium. CONCLUSIONS: Uterine fibroids seem to be subject to a non-linear trend of modifications during pregnancy and puerperium, which may vary from myoma to myoma. Adequate evidence supports uterine fibroid systematic enlargement during the first trimester of pregnancy, while inconsistent evidence is available about the changes of uterine fibroids during second and third trimesters. In addition, the overall modifications of myomas during pregnancy and puerperium remain unclear. PMID- 29236172 TI - The Society of European Robotic Gynaecological Surgery (SERGS) Pilot Curriculum for robot assisted gynecological surgery. AB - PURPOSE: To set forth experiences in the context of the SERGS Pilot Curriculum the first standardized educational program for robotic use in gynecological surgery-in terms of feasibility, effectiveness and potential for certification. METHODS: The Society of European Robotic Gynecological Surgery (SERGS) outlined a Pilot Curriculum for standardized education in robot-assisted laparoscopic gynecological surgery. Its feasibility and acceptance were checked in the form of a fellowship pilot program conducted at four European Centers of Excellence for robot-assisted surgery. Results and conclusions derived from this pilot program are presented. RESULTS: The SERGS Pilot Curriculum defines criteria for a standardized training and assessment of performance, boosts the learning curve of the candidate and increases contentment at work. Regarding face validity, it proves valuable as finally all candidates could perform the outlined procedure safely and efficiently without supervision. CONCLUSION: Due to the immense increase of robotic procedures in gynecology standardized training curricula are indispensable. This seems highly necessary to ensure patients' safety and surgical outcome. The SERGS Pilot Curriculum sets standards for a stepwise theoretical and practical training in gynecological robotic procedures. It seems feasible as instrument for accreditation as gynecologic robotic surgeon. Though as a general applicable guideline for systematic training in robot-assisted surgery, a definite curriculum should have a more definite timeline and implementation of a structured assessment of performance. PMID- 29236173 TI - Is surgical plume developing during routine LEEPs contaminated with high-risk HPV? A pilot series of experiments. AB - INTRODUCTION: Growing evidence shows a causal role of high-risk humane papillomavirus (HPV) infections in the development of head and neck cancer. A recent case report shows two patients suffering from tonsillar cancer without any risk factors apart from their work as gynecologists doing laser ablations and loop electrosurgical excision procedures (LEEP). The aim of the present investigation is to evaluate whether surgical plume resulting from routine LEEPs of HSIL of the cervix uteri might be contaminated with the DNA of high-risk HPV. MATERIALS AND METHODS: The prospective pilot study is done at the Department of Gynecology and Obstetrics of the University of Lubeck, Germany. The primary outcome was defined as HPV subtype in resected cone and in surgical plume resulting from LEEPs of HSIL of the cervix uteri. Plume resulting from LEEPs was analyzed using a Whatman FTA Elute Indicating Card which was placed in the tube of an exhaust suction device used to remove the resulting aerosols. For detection of HPV and analysis of its subtype, the novel EUROArray HPV test was performed. Resected cones of LEEPs were evaluated separately for HPV subtypes. RESULTS: Four samples of surgical plume resulting from routine LEEPs indicated contamination with high-risk HPV and showed the same HPV subtype as identified in the resected cones. CONCLUSION: Surgical plume resulting from routine LEEPs for HSIL of the cervix uteri has the risk of contamination with high-risk HPV. Further investigations of infectiousness of surgical plume are necessary for evaluation of potential hazards to involved healthcare professionals. PMID- 29236174 TI - Oncotype DX(r) in breast cancer patients: clinical experience, outcome and follow up-a case-control study. AB - PURPOSE: Breast cancer is the leading cause of death from cancer in women and the most common cancer in the world [1]. To date, many patients with estrogen receptor-positive (ER+) breast cancer are overtreated with chemotherapy when the rationale for adjuvant chemotherapy is based on clinicopathologic parameters. Different studies were able to demonstrate that a 21-gene expression assay (Oncotype DX(r) Genomic Health, Redwood City, CA) can predict the benefit from adjuvant chemotherapy in ER+ breast cancers [2, 3] and provide additional prognostic information independent of clinicopathological features [4]. RESULTS: Data from all patients with ER+ Her2neu- breast cancer undergoing Oncotype DX(r) testing between 2011 and 2014 at a tertiary referral center in Germany were analyzed. Oncotype DX(r) was performed in 69 cases, in 2 cases data were missing and in 3 cases Oncotype DX(r) could not be performed by the company. The results showed a low risk in 39 cases, an intermediate risk in 22 cases and a high risk in 3 cases. Based on Oncotype results, treatment recommendations were changed in 39 of 64 patients (61%). Before Oncotype DX(r) testing, chemotherapy was recommended in 67 patients, afterwards only in 25 patients. Data from 44 of 67 patients were matched to controls for stage, tumor grade, menopausal and hormone receptor status. Within a mean observation time of 19.7 months, cancer recurrence was observed in two patients. CONCLUSIONS: Oncotype DX(r) testing can be recommended for risk-tailored chemotherapy. Results should be validated in larger prospective studies. PMID- 29236175 TI - An assessment of metal-humus complexes in river waters of the Upper Amur basin, Russia. AB - The dissolved metal concentrations have been assessed for Co, Cr, Cu, Fe, Mn, Ni, V, Zn, Ca, Mg, and Cd, and their complex compounds with humic substances (Me-HS complexes) in river waters of the Upper Amur basin using the inductively coupled plasma-mass spectrometry technique. The study shows an increase in the amount of Me-HS complexes from the southwestern steppe and forest-steppe to the northeastern mountainous taiga areas. In alkali waters of the steppe and forest steppe areas with low concentrations of HS, the amount of Zn-HS complexes increases considerably. The observed general regularity in the distribution of metals is as follows: Fe > Cu >= Zn > Cr > V > Ni > So >= Mn > Ca > Mg > Cd. In acidic and neutral waters of the taiga rivers containing high concentrations of HS, 50% of metals are complexed with HS. Metals are arranged in the following order: Fe > Cu > Ni > Cr > V > Zn > So > Mn > Ca > Mg > Cd. Quantitative characteristics and a correlation matrix show that Me-HS complexes are dominant among toxic metals (Ni, Cu, Zn, Cr, Fe, and V) and account for 40-55% of total dissolved forms. This allows us to evaluate the important role of Me-HS complexes in satisfactory ecological situation in rivers of the Upper Amur basin. However, toxicity may increase in separate watercourses (Chita and Argun rivers) due to high concentrations of dissolved Zn, Cu, and Cr, which indicate local and transboundary sources of pollution. PMID- 29236176 TI - Na18F accumulates on the compressive side of peri-implant bone under immediate loading. AB - This study aimed to examine the dynamic change in bone metabolism by immediate loading in several sites around implants using high-resolution Na18F-PET scan. Two titanium implants (O 1.2 mm) were inserted parallel to each other in the right tibiae of Wistar rats (n = 4). The left tibia was set as control side. One day after insertion, closed coil springs of 4.0 N were attached to the expose superior portions of the implants to apply a continuous mechanical stress. The rats with fluorine-18 (18F) ion (5 mCi/rat) intravenously injected were scanned by PET scanner at 4, 7, 14, 28 days after load application. Round region of interests (ROIs) were set around the distal implant of the right tibia (loaded side) and same site (control) of the left tibia. Furthermore, four rectangular ROIs were set at the superior and inferior parts of traction side (mesial) and opposite side (distal) of the distal implant. Longitudinal dynamic changes in bone metabolism were evaluated by examination of the accumulation count of 18F ion at each ROI. The uptake values of ROIs (loaded side) initially increased until 7 days, and they gradually decreased from the peak level to the pre-loading level despite a static force being applied to the implants. In cancellous bone, the uptake values at the superior part of traction side and inferior part of opposite side showed significantly high value compared with those at other parts. In conclusion, immediate loading to the implant initially enhanced bone metabolism around it, especially at the part with compressive stress. Peri implant bone metabolism varies according to different loading conditions. PMID- 29236177 TI - Effect of Er:YAG laser enamel conditioning and moisture on the microleakage of a hydrophilic sealant. AB - For a given sealant, successful pit and fissure sealing is principally governed by the enamel conditioning technique and the presence of moisture contamination. A new generation of hydrophilic resin sealants is reported to tolerate moisture. This study investigates the impact of Er:YAG laser pre-conditioning and moisture contamination on the microleakage of a recent hydrophilic sealant. Occlusal surfaces of extracted human molars were either acid etched (n = 30), or successively lased and acid etched (n = 30). Ten teeth from each group were either air-dried, water-contaminated, or saliva-contaminated prior to sealing with UltraSeal XT(r) hydroTM. Samples were inspected for penetration of fuchsin dye following 3000 thermocycles between 5 and 50 degrees C, and the enamel sealant interfaces were observed by scanning electron microscopy (SEM). Significant differences in microleakage were evaluated using the Mann-Whitney U test with Bonferroni adjustment (p = 0.05). Laser pre-conditioning significantly reduced dye penetration irrespective of whether the enamel surface was moist or dry. Microleakage of water-contaminated acid etched teeth was significantly greater than that of their air-dried or saliva-contaminated counterparts. SEM analysis demonstrated good adaptation in all groups with the exception of water contaminated acid etched teeth which exhibited relatively wide gaps. In conclusion, this hydrophilic sealant tolerates the presence of saliva, although water was found to impair its sealing ability. Laser pre-conditioning significantly decreases microleakage in all cases. PMID- 29236179 TI - Effects of glucose and ethylene on root hair initiation and elongation in lettuce (Lactuca sativa L.) seedlings. AB - Root hair formation occurs in lettuce seedlings after transfer to an acidic medium (pH 4.0). This process requires cortical microtubule (CMT) randomization in root epidermal cells and the plant hormone ethylene. We investigated the interaction between ethylene and glucose, a new signaling molecule in plants, in lettuce root development, with an emphasis on root hair formation. Dark-grown seedlings were used to exclude the effect of photosynthetically produced glucose. In the dark, neither root hair formation nor the CMT randomization preceding it occurred, even after transfer to the acidic medium (pH 4.0). Adding 1 aminocyclopropane-1-carboxylic-acid (ACC) to the medium rescued the induction, while adding glucose did not. Although CMT randomization occurred when glucose was applied together with ACC, it was somewhat suppressed compared to that in ACC treated seedlings. This was not due to a decrease in the speed of randomization, but due to lowering of the maximum degree of randomization. Despite the negative effect of glucose on ACC-induced CMT randomization, the density and length of ACC induced root hairs increased when glucose was also added. The hair-cell length of the ACC-treated seedlings was comparable to that in the combined-treatment seedlings, indicating that the increase in hair density caused by glucose results from an increase in the root hair number. Furthermore, quantitative RT-PCR revealed that glucose suppressed ethylene signaling. These results suggest that glucose has a negative and positive effect on the earlier and later stages of root hair formation, respectively, and that the promotion of the initiation and elongation of root hairs by glucose may be mediated in an ethylene-independent manner. PMID- 29236180 TI - Diagnosis, medical treatment, and stepwise mechanical circulatory support for fulminat myocarditis. AB - Fulminant myocarditis is one of the most challenging diseases. We sought to examine the outcomes of our multidisciplinary treatment strategy for fulminant myocarditis. A retrospective review of consecutive 30 patients with fulminant myocarditis was conducted. Of the 30 patients, 25 required mechanical circulatory support (MCS). Percutaneous extracorporeal membrane oxygenation (ECMO) was the first-line therapy to rescue the patients and inserted in 23 of them. The other 2 were implanted with temporary ventricular assist device (t-VAD) with extracorporeal centrifugal pump(s). Sixteen of the ECMO-supported patients were later transitioned to t-VAD. Of the 18 patients who underwent t-VAD support, heart function recovered and the VAD was explanted in 10. Four patients were bridged to long-term VAD and the other 4 died on t-VAD. Two patients were directly bridged to long-term VAD by ECMO. Heart function recovered only with ECMO in 4 patients and 1 died on ECMO. Overall survival rate was 83.3%. The duration of ECMO support significantly correlated with total bilirubin level, which was a significant risk factor for mortality. Pathologically, 7 patients (23.3%) had eosinophilic myocarditis and 1 (3.3%) had giant-cell myocarditis, and all the 8 patients underwent immunosuppressive therapy including steroids. Heart function recovered to normal level in 7 of them (87.5%). Timely conversion from the percutaneous ECMO to the temporary VAD before elevation of total bilirubin level is crucial for improving the clinical outcomes. Endomyocardial biopsy is needed to be done as soon as possible, because immunosuppressive therapy carries promising outcomes in certain etiologies. PMID- 29236181 TI - Ultrasound-based logistic regression model LR2 versus magnetic resonance imaging for discriminating between benign and malignant adnexal masses: a prospective study. AB - BACKGROUND: The diagnostic performances of the International Ovarian Tumor Analysis (IOTA) ultrasound-based logistic regression model (LR2) and magnetic resonance imaging (MRI) in discriminating between benign and malignant adnexal masses have not been directly compared in a single study. METHODS: Using the IOTA LR2 model and subjective interpretation of MRI findings by experienced radiologists, 265 consecutive patients with adnexal masses were preoperatively evaluated in two hospitals between February 2014 and December 2015. Definitive histological diagnosis of excised tissues was used as a gold standard. RESULTS: From the 265 study subjects, 54 (20.4%) tumors were histologically diagnosed as malignant (including 11 borderline and 3 metastatic tumors). Preoperative diagnoses of malignant tumors showed 91.7% total agreement between IOTA LR2 and MRI, with a kappa value of 0.77 [95% confidence interval (CI), 0.68-0.86]. Sensitivity of IOTA LR2 (0.94, 95% CI, 0.85-0.98) for predicting malignant tumors was similar to that of MRI (0.96, 95% CI, 0.87-0.99; P = 0.99), whereas specificity of IOTA LR2 (0.98, 95% CI, 0.95-0.99) was significantly higher than that of MRI (0.91, 95% CI, 0.87-0.95; P = 0.002). Combined IOTA LR2 and MRI results gave the greatest sensitivity (1.00, 95% CI, 0.93-1.00) and had similar specificity (0.91, 95% CI, 0.86-0.94) to MRI. CONCLUSIONS: The IOTA LR2 model had a similar sensitivity to MRI for discriminating between benign and malignant tumors and a higher specificity compared with MRI. Our findings suggest that the IOTA LR2 model, either alone or in conjunction with MRI, should be included in preoperative evaluation of adnexal masses. PMID- 29236182 TI - Effect of Engineered Nanoparticles on Exopolymeric Substances Release from Marine Phytoplankton. AB - Engineered nanoparticles (ENPs), products from modern nanotechnologies, can potentially impact the marine environment to pose serious threats to marine ecosystems. However, the cellular responses of marine phytoplankton to ENPs are still not well established. Here, we investigate four different diatom species (Odontella mobiliensis, Skeletonema grethae, Phaeodactylum tricornutum, Thalassiosira pseudonana) and one green algae (Dunaliella tertiolecta) for their extracellular polymeric substances (EPS) release under model ENP treatments: 25 nm titanium dioxide (TiO2), 10-20 nm silicon dioxide (SiO2), and 15-30 nm cerium dioxide (CeO2). We found SiO2 ENPs can significantly stimulate EPS release from these algae (200-800%), while TiO2 ENP exposure induced the lowest release. Furthermore, the increase of intracellular Ca2+ concentration can be triggered by ENPs, suggesting that the EPS release process is mediated through Ca2+ signal pathways. With better understanding of the cellular mechanism mediated ENP induced EPS release, potential preventative and safety measures can be developed to mitigate negative impact on the marine ecosystem. PMID- 29236183 TI - Awake mapping is not an additional surgical technique but an alternative philosophy in the management of low-grade glioma patients. PMID- 29236184 TI - Hybrid UV-Ozone-Treated rGO-PEDOT:PSS as an Efficient Hole Transport Material in Inverted Planar Perovskite Solar Cells. AB - Inverted planar perovskite solar cells (PSCs), which are regarded as promising devices for new generation of photovoltaic systems, show many advantages, such as low-temperature film formation, low-cost fabrication, and smaller hysteresis compared with those of traditional n-i-p PSCs. As an important carrier transport layer in PSCs, the hole transport layer (HTL) considerably affects the device performance. Therefore, HTL modification becomes one of the most critical issues in improving the performance of PSCs. In this paper, we report an effective and environmentally friendly UV-ozone treatment method to enhance the hydrophilia of reduced graphene oxide (rGO) with its excellent electrical performance. The treated rGO was applied to doped poly(3,4-ethylenedioxythiophene) poly(styrene sulfonate) (PEDOT:PSS) as HTL material of PSCs. Consequently, the performance of rGO/PEDOT:PSS-doped PSCs was improved significantly, with power conversion efficiency (PCE) of 10.7%, Jsc of 16.75 mA/cm2, Voc of 0.87 V, and FF of 75%. The PCE of this doped PSCs was 27% higher than that of the PSCs with pristine PEDOT:PSS as HTL. This performance was attributed to the excellent surface morphology and optimized hole mobility of the solution-processable rGO-modified PEDOT:PSS. PMID- 29236185 TI - Genome-wide identification and cadmium induced expression profiling of sulfate transporter (SULTR) genes in sorghum (Sorghum bicolor L.). AB - Sulfur is an essential element for all living organisms. Plants can convert inorganic sulfur into organic sulfur compounds by complex enzymatic steps. In this study, we conducted a genome-wide analysis of sulfate transporter genes (SULTRs) in the sorghum (Sorghum bicolor) genome and examined expression profiles of SbSULTR genes under 200 uM cadmium (Cd) exposure. As a result of sorghum genome analysis, 11 SULTR genes were identified, including SbSULTR1;1, SbSULTR1;2, SbSULTR1;3, SbSULTR2;1, SbSULTR2;2, SbSULTR3;1, SbSULTR3;2, SbSULTR3;3, SbSULTR3;4, SbSULTR3;5, and SbSULTR4. Given names are based on phylogeny and chromosomal locations. Except SbSULTR4, all SbSULTR proteins contained Sulfate_transp (PF00916), STAS (PF01740) domains and 12 trans-membrane domains. Phylogenetic analysis revealed that four major groups were identified such as SULTR1, 2, 3, and 4 groups and SULTR4 group was separated to other SULTR groups. In promotor sequences of SbSULTR genes, many diverse cis-acting elements were found mainly related with physiological processes such as light, stress and hormone responsiveness. The expression profiles of SbSULTR genes showed that SULTR1;2, 1;3, 3;3, and 3;5 genes up-regulated in root, while expression level of SULTR4 decreased under 200 uM Cd exposure. The predicted 3D structures of SULTR proteins showed some conformational changes, suggesting functional diversities of SbSULTRs. Finally, results of this study may contribute towards understanding SbSULTR genes and their regulations and roles in Cd stress in sorghum. PMID- 29236186 TI - Establishment of pathological quantitative method for determining undifferentiated component ratio in patients with differentiated/undifferentiated mixed-type early gastric cancer and clinical significance of this ratio. AB - PURPOSES: The purpose of this study was to establish a pathological quantitative method for determining the undifferentiated components ratio (UCR) in patients with differentiated/undifferentiated mixed-type (Mixed-type) early gastric cancer (EGC) and to examine the clinical significance. METHODS: The subjects were 410 patients who underwent surgical resection for EGC with the invasion limited to m or sm1. Analysis 1: In 12 randomly selected patients with Mixed-type cancer, we calculated the area ratio and the ratio of the length ratio using ImageJ and analyzed the correlation between them. Analysis 2: We generated ROC curves, and determined the cutoff UCR on the basis of the predictive risk factors for lymph node metastasis (LNM). Analysis 3: We analyzed the relationship between clinicopathological factors including UCR/length of undifferentiated component (LUC = maximum dimensions of tumor * UCR) and LNM. RESULTS: Analysis 1: The length ratio can be used as a substitute parameter for the UCR (r = 0.996). Analysis 2: The cutoff UCR as a risk factor for LNM was 58% (sensitivity = 1, 1 - specificity = 0.404). Analysis 3: Lymphovascular invasion (p < 0.0001), UCR >=58% (p = 0.023), and LUC >=25 mm (p = 0.005) were identified as significant risk factors for LNM. No LNM was observed in patients with invasion limited to m or sm1 and negativity for lymphovascular invasion and UCR <58% (0/215). CONCLUSIONS: In the patients with Mixed-type EGC, the length ratio of undifferentiated components can be a substitute parameter for the UCR. LNM rarely occurs in patients without lymphovascular invasion and with an UCR <58%. The analysis of the UCR has great significance in determining whether additional surgical resection is required after endoscopic resection. PMID- 29236187 TI - Mixed poorly differentiated adenocarcinoma in undifferentiated-type early gastric cancer predicts endoscopic noncurative resection. AB - BACKGROUND: Comparisons between surgical cases of mixed poorly differentiated adenocarcinoma and pure signet ring cell carcinoma have revealed higher frequencies of lymph node metastasis and submucosal invasion in the former. However, this comparison has not been reported for endoscopically treated cases. Therefore, we compared cases of curative and noncurative resection in patients who underwent endoscopic submucosal dissection to determine what factors could influence the curative resection rate. METHODS: We analyzed 268 undifferentiated type early gastric cancers in 264 patients treated with endoscopic submucosal dissection in our hospital between March 2005 and March 2017, involving 229 and 39 cases of curative and noncurative resection, respectively. Treatment results were compared between 129 lesions of pure signet ring cell carcinoma and 139 lesions of mixed poorly differentiated adenocarcinoma. RESULTS: The overall curative resection rate was 85.4% (229/268). On comparing noncurative and curative resection cases, after excluding factors that determine curative resection (e.g., tumor diameter), we found that the former was associated with older age and significantly more mixed poorly differentiated adenocarcinomas, with odds ratios of 1.052 [95% confidence interval (CI), 1.017-1.089] and 2.746 (95% CI, 1.162-6.485), respectively, on multivariate analysis. The curative resection rate was significantly higher in pure signet ring cell carcinoma than in mixed poorly differentiated adenocarcinoma (93.8% vs. 77.7%, respectively). CONCLUSION: Advanced age and mixed poorly differentiated adenocarcinoma predicted endoscopic noncurative resection. PMID- 29236188 TI - Contributors to nonsuicidal self-injury in incarcerated youth. AB - BACKGROUND: Despite elevations in risks associated with self-injurious behavior among community adolescents, the degree to which these features are associated with self-injury among incarcerated youth has rarely been examined. Although the DSM-5 recently proposed a distinct category of nonsuicidal self-injury (NSSI), most studies of youths in forensic settings have not distinguished between subtypes of self-harming individuals. METHODS: Demographic, offense, and disorder contributors to NSSI in incarcerated youths of both genders (N = 358) were examined via a computerized self-report instrument (VISA), largely consistent with DSM-5. RESULTS: Nonsuicidal self-injurers (vs. non-injurers) were almost three times as likely to be white, slightly younger, and more than seven times as likely to have also made a suicide attempt. While males and females reported different rates of exposure to different types of assaultive violence, both nonsexual assault and forced sexual activity were approximately twice as likely among those reporting NSSI in both genders. CONCLUSION: Finding support standardized, universal screening for nonsuicidal self-injury in juvenile justice secure care facilities. PMID- 29236190 TI - As the first sign of multiple sclerosis, eight-and-a-half syndrome. PMID- 29236189 TI - Manure and mineral fertilization change enzyme activity and bacterial community in millet rhizosphere soils. AB - Fertilization is a key agricultural practice for increasing millet yields and influencing soil properties, enzyme activities and rhizosphere bacterial communities. High throughput Illumina sequencing of the 16S rDNA was applied to compare the bacterial community structures and diversities among six different soil samples. The experiments involved the following: no fertilizer (CK), phosphate (P) and potassium (K) plus organic manure (M) (PKM), nitrogen (N) and K plus M (NKM), NPM, NPK and NPKM fertilization. The results showed that the NPKM fertilization of the millet field had a maximal yield of 3617 kg ha-1 among the six different treatments. The abundances of the Actinobacteria and Bacteroidetes phyla, especially the Devosia, Mycobacterium, Opitutus and Chitinophaga genera, were higher in NPKM than those in the other samples. Redundancy analysis showed that the soil organic matter (SOM), available phosphorus (AP), and urease (UR) activity were significantly correlated with bacterial communities, while SOM and AP were strongly correlated with soil enzyme activities. Pearson's correlation showed that the available nitrogen was strongly correlated with Devosia and Mycobacterium, and SOM was strongly correlated with Opitutus and Chitinophaga. Besides, catalase was significantly related to Iamia, the UR was significantly related to Devosia, phosphatase was significantly related to Luteimonas and Chitinophaga. Based on the soil quality and millet yield, NPKM treatment was a better choice for the millet field fertilization practices. These findings provide a better understanding of the importance of fertilization in influencing millet yield, soil fertility and microbial diversity, and they lead to a choice of scientific fertilization practices for sustainable development of the agroecosystem. PMID- 29236191 TI - Engineering genome-reduced Bacillus subtilis for acetoin production from xylose. AB - OBJECTIVES: To investigate the capacity of a genome-reduced Bacillus subtilis strain as chassis cell for acetoin production from xylose. RESULTS: To endow the genome-reduced Bacillus subtilis strain BSK814 with the ability to utilize xylose, we inserted a native xyl operon into its genome and deleted the araR gene. The resulting strain BSK814A2 produced 2.94 g acetoin/l from 10 g xylose/l, which was 39% higher than control strain BSK19A2. The deletion of the bdhA and acoA genes further improved xylose utilization efficiency and increased acetoin production to 3.71 g/l in BSK814A4. Finally, BSK814A4 produced up to 23.3 g acetoin/l from 50 g xylose/l, with a yield of 0.46 g/g xylose. Both the titer and yield were 39% higher than those of control strain BSK19A4. CONCLUSIONS: As a chassis cell, genome-reduced B. subtilis showed significantly improved capacity for the production of the overflow product acetoin from xylose compared with wild type strain. PMID- 29236192 TI - Inhibitory effect of streptococci on the growth of M. catarrhalis strains and the diversity of putative bacteriocin-like gene loci in the genomes of S. pneumoniae and its relatives. AB - S. pneumoniae is a facultative human pathogen causing a wide range of infections including the life-threatening pneumoniae or meningitis. It colonizes nasopharynx as well as its closest phylogenetic relatives S. pseudopneumoniae and S. mitis. Both the latter, despite the considerable morphological and phenotypic similarity with the pneumococcus, are considerably less pathogenic for humans and cause infections mainly in the immunocompromized hosts. In this work, we compared the inhibitory effect of S. pneumoniae and its relatives on the growth of Moraxella catarrhalis strains using the culture-based antagonistic test. We observed that the inhibitory effect of S. mitis strains is kept when a hydrogen peroxide produced by cells is inactivated by catalase, and even when the live cells are killed in chloroform vapors, in contrast to the pneumococcus whose inhibiting ability disappeared when the cells die. It was suggested that this effect may be due to the production of bacterial antimicrobial peptides by S. mitis, so we examined the genomes of our strains for the presence of bacteriocin-like peptides encoding genes. We observed that a set of bacteriocin-like genes in the genome of S. mitis is greatly poorer in comparison with S. pneumoniae one; moreover, in one S. mitis strain we found no bacteriocin-like genes. It could mean that there are probably some additional opportunities of S. mitis to inhibit the growth of competing neighbors which are still have to be discovered. PMID- 29236193 TI - Ammonium removal using algae-bacteria consortia: the effect of ammonium concentration, algae biomass, and light. AB - In this study, the effects of ammonium nitrogen concentration, algae biomass concentration, and light conditions (wavelength and intensity) on the ammonium removal efficiency of algae-bacteria consortia from wastewater were investigated. The results indicated that ammonium concentration and light intensity had a significant impact on nitrification. It was found that the highest ammonia concentration (430 mg N/L) in the influent resulted in the highest ammonia removal rate of 108 +/- 3.6 mg N/L/days, which was two times higher than the influent with low ammonia concentration (40 mg N/L). At the lowest light intensity of 1000 Lux, algae biomass concentration, light wavelength, and light cycle did not show a significant effect on the performance of algal-bacterial consortium. Furthermore, the ammonia removal rate was approximately 83 +/- 1.0 mg N/L/days, which was up to 40% faster than at the light intensity of 2500 Lux. It was concluded that the algae-bacteria consortia can effectively remove nitrogen from wastewater and the removal performance can be stabilized and enhanced using the low light intensity of 1000 Lux that is also a cost-effective strategy. PMID- 29236194 TI - Synergetic Effect of Dy2O3 and Ca Co-Dopants towards Enhanced Coercivity of Rare Earth Abundant RE-Fe-B Magnets. AB - Low coercivity is the main disadvantage of RE-Fe-B permanent magnets containing highly abundant rare earths (RE: La, Ce) from the application point of view, even though they exhibit many cost and resource advantages. In this work, an industrial mixed rare earth alloy (RE100 = La30.6Ce50.2Pr6.4Nd12.8) with a high amount of the more abundant elements was adopted to fabricate RE-Fe-B permanent magnets by means of mechanical alloying accompanied by post-annealing. A synergetic effect towards enhancing the coercivity was observed after co-doping with Dy2O3 and Ca, with the coercivity increasing from 2.44 kOe to 11.43 kOe for co-dopant percentages of 7 wt.% Dy2O3 + 2.3 wt.% Ca. Through analysis of the phase constituents and microstructure, it was determined that part of the Dy atoms entered the matrix of RE2Fe14B phase to enhance the magnetocrystalline anisotropy; due to the reductive effect of Ca on Dy2O3, nanocrystals of Dy-rich RE2Fe14B were present throughout the matrix, which could increase the resistance to domain wall movement. These are the dominant factors behind the improvement of the coercivity of the RE-Fe-B magnets with highly abundant RE elements. PMID- 29236195 TI - Measures of subclinical cardiac dysfunction and increased filling pressures associate with pulmonary arterial pressure in the general population: results from the population-based Rotterdam Study. AB - Pulmonary hypertension is associated with increased mortality and morbidity in the elderly population. Heart failure is a common cause of pulmonary hypertension. Yet, the relation between left heart parameters reflective of subclinical cardiac dysfunction and increased filling pressures, and pulmonary arterial pressures in the elderly population remains elusive. Within the population-based Rotterdam Study, 2592 unselected participants with a mean age of 72.6 years (61.4% women) had complete echocardiography data available. We studied the cross-sectional associations of left heart structure and systolic and diastolic function with echocardiographically measured pulmonary artery systolic pressure. Mean pulmonary artery systolic pressure was 25.4 mmHg. After multivariable-adjustment measures of both structure and function were independently associated with pulmonary artery systolic pressure: E/A ratio [0.63 mmHg (95% CI 0.35-0.91) per 1-SD increase], left atrial diameter [0.79 mmHg (0.50 1.09) per 1-SD increase], E/E' ratio [1.27 mmHg (0.92-1.61) per 1-SD increase], left ventricular volume [0.62 mmHg (0.25-0.98) per 1-SD increase], fractional shortening [0.45 mmHg (0.17-0.74) per 1-SD increase], aortic root diameter [- 0.43 mmHg (- 0.72 to - 0.14) per 1-SD increase], mitral valve deceleration time [ 0.31 mmHg (- 0.57 to - 0.05) per 1-SD increase], and E' [1.04 mmHg (0.66-1.42) per 1-SD increase]. Results did not materially differ when restricting the analyses to participants free of symptoms of shortness of breath. Structural and functional echocardiographic parameters of subclinical cardiac dysfunction and increased filling pressures are associated with pulmonary arterial pressures in the unselected general ageing population. PMID- 29236196 TI - Thoracoabdominal aortic mural and floating thrombus extending into superior mesenteric artery. AB - Thrombus in the thoracic aorta not related to aneurysm or atherosclerosis is a rare clinical entity with a limited number of cases reported. Floating thrombus is defined as non-adherent part of the thrombus floating within the aortic lumen. Herein, we present a 48-year-old woman who presented with progressive midline dull, aching abdominal pain of 2-day duration. Thoracoabdominal computed tomography revealed a free floating thrombus extending from the aortic arch into the superior mesenteric artery. Transesophageal echocardiography confirmed the findings of a thrombus extending through the aortic arch. Floating thrombus within the aortic lumen in a morphologically normal descending thoracic and abdominal aorta is a rare entity. PMID- 29236197 TI - Nearly complete TME quality conundrum. PMID- 29236199 TI - Caspase cleavage of transcription factor Sp1 enhances apoptosis. AB - Sp1 is a ubiquitous transcription factor that regulates many genes involved in apoptosis and senescence. Sp1 also has a role in the DNA damage response; at low levels of DNA damage, Sp1 is phosphorylated by ATM and localizes to double-strand break sites where it facilitates DNA double-strand-break repair. Depletion of Sp1 increases the sensitivity of cells to DNA damage, whereas overexpression of Sp1 can drive cells into apoptosis. In response to a variety of stimuli, Sp1 can be regulated through proteolytic cleavage by caspases and/or degradation. Here, we show that activation of apoptosis through DNA damage or TRAIL-mediated activation of the extrinsic apoptotic pathway induces caspase-mediated cleavage of Sp1. Cleavage of Sp1 was coincident with the appearance of cleaved caspase 3, and produced a 70 kDa Sp1 product. In vitro analysis revealed a novel caspase cleavage site at aspartic acid 183. Mutation of aspartic acid 183 to alanine conferred resistance to cleavage, and ectopic expression of the Sp1 D183A rendered cells resistant to apoptotic stimuli, indicating that Sp1 cleavage is involved in the induction of apoptosis. The 70 kDa product resulting from caspase cleavage of Sp1 comprises amino acids 184-785. This truncated form, designated Sp1-70C, which retains transcriptional activity, induced apoptosis when overexpressed in normal epithelial cells, whereas Sp1D183A induced significantly less apoptosis. Together, these data reveal a new caspase cleavage site in Sp1 and demonstrate for the first time that caspase cleavage of Sp1 promotes apoptosis. PMID- 29236198 TI - SDF-1 induces TNF-mediated apoptosis in cardiac myocytes. AB - Chemokines are small secreted proteins with chemoattractant properties that play a key role in inflammation. One such chemokine, Stromal cell-derived factor-1 (SDF-1) also known as CXCL12, and its receptor, CXCR4, are expressed and functional in cardiac myocytes. SDF-1 both stimulates and enhances the cellular signal which attracts potentially beneficial stem cells for tissue repair within the ischemic heart. Paradoxically however, this chemokine is known to act in concert with the inflammatory cytokines of the innate immune response which contributes to cellular injury through the recruitment of inflammatory cells during ischemia. In the present study, we have demonstrated that SDF-1 has dose dependent effects on freshly isolated cardiomyocytes. Using Tunnel and caspase 3 activation assays, we have demonstrated that the treatment of isolated adult rat cardiac myocyte with SDF-1 at higher concentrations (pathological concentrations) induced apoptosis. Furthermore, ELISA data demonstrated that the treatment of isolated adult rat cardiac myocyte with SDF-1 at higher concentrations upregulated TNF-alpha protein expression which directly correlated with subsequent apoptosis. There was a significant reduction in SDF-1 mediated apoptosis when TNF-alpha expression was neutralized which suggests that SDF-1 mediated apoptosis is TNF-alpha-dependent. The fact that certain stimuli are capable of driving cardiomyocytes into apoptosis indicates that these cells are susceptible to clinically relevant apoptotic triggers. Our findings suggest that the elevated SDF-1 levels seen in a variety of clinical conditions, including ischemic myocardial infarction, may either directly or indirectly contribute to cardiac cell death via a TNF-alpha mediated pathway. This highlights the importance of this receptor/ligand in regulating the cardiomyocyte response to stress conditions. PMID- 29236201 TI - Can we implant left ventricle pacing lead in a patient with coronary sinus reducer? PMID- 29236200 TI - Electrophysiologic features of protected channels in late postinfarction patients with and without spontaneous ventricular tachycardia. AB - PURPOSE: Protected channels of surviving myocytes in late postinfarction ventricular scar predispose to ventricular tachycardia (VT). However, only a few patients develop VT spontaneously. We studied differences in electric remodeling and protected channels in late postinfarction patients with and without spontaneous VT. METHODS: Patients with ischemic cardiomyopathy (ICM) with recurrent sustained monomorphic VT (n = 22) were compared with stable ICM patients without spontaneous VT (control group; n = 5). Left ventricular mapping was performed with a 20-pole catheter. Detailed pace mapping was used to identify channels of protected conduction, and confirmed, when feasible, by entrainment. Anatomical and electrophysiological properties of VT channels and non-VT channels in VT patients and channels in controls were evaluated. RESULTS: Seventy-three (median 3) VTs were inducible in VT patients compared to two (median 0) in controls. The VT channels in VT patients (n = 57, 3 +/- 1 per patient) were lengthier (mean +/- SEM 53 +/- 5 vs. 33 +/- 4 vs. 24 +/- 8 mm), had longer S-QRS (73 +/- 4 vs. 63 +/- 3 vs. 44 +/- 8 ms), longer conduction time (103 +/- 13 vs. 33 +/- 4 vs. 24 +/- 8 ms), and slower conduction velocity (CV) (0.85 +/- 0.21 vs. 1.39 +/- 0.20 vs. 1.31 +/- 0.41 m/s) than non-VT channels in VT patients (n = 183, 8 +/- 6 per patient) (p <= 0.01) and channels in controls (n = 46, 9 +/- 8 per patient) (p <= 0.01). Additionally, non-VT channels in VT patients had longer S-QRS (p = 0.02); however, they were similar in length, conduction time, and CV compared to channels in controls. CONCLUSIONS: Channels supporting VT are lengthier, with longer conduction times and slower CV compared to channels in patients without spontaneous VT. These observations may explain why some ICM patients have spontaneous VT and others do not. PMID- 29236202 TI - Sentinel Lymph Node Biopsy and Management of Regional Lymph Nodes in Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Clinical Practice Guideline Update. AB - PURPOSE: To update the American Society of Clinical Oncology (ASCO)-Society of Surgical Oncology (SSO) guideline for sentinel lymph node (SLN) biopsy in melanoma. METHODS: An ASCO-SSO panel was formed, and a systematic review of the literature was conducted regarding SLN biopsy and completion lymph node dissection (CLND) after a positive sentinel node in patients with melanoma. RESULTS: Nine new observational studies, two systematic reviews and an updated randomized controlled trial (RCT) of SLN biopsy, as well as two randomized controlled trials of CLND after positive SLN biopsy, were included. RECOMMENDATIONS: Routine SLN biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions < 0.8 mm in Breslow thickness). SLN biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or <0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure. SLN biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of >1.0 to 4.0 mm). SLN biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm. In the case of a positive SLN biopsy, CLND or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathological factors. For higher risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND. Important qualifying statements outlining relevant clinicopathological factors, and details of the reference patient populations are included within the guideline. PMID- 29236203 TI - Work Outcomes in Patients Who Stay at Work Despite Musculoskeletal Pain. AB - Purpose To assess self-reported work impacts and associations between psychosocial risk factors and work impairment amongst workers seeking care for musculoskeletal pain while continuing to work. Methods Patients were recruited from Musculoskeletal Assessment Clinics at 5 hospitals across Ireland. Participants completed questionnaires including assessments of work impairment (Work Productivity and Activity Impairment Questionnaire), work ability (single item from the Work Ability Index) and work performance (Work Role Functioning Questionnaire; WRFQ). Logistic and hierarchical regressions were conducted to analyse the relation between psychosocial variables and work outcomes. Results 155 participants (53.5% female; mean age = 46.50 years) who were working at the time of assessment completed the questionnaires. Absenteeism was low, yet 62.6% were classified as functioning poorly according to the WRFQ; 52.3% reported having poor work ability. Logistic regression analyses indicated that higher work role functioning was associated with higher pain self-efficacy (OR 1.51); better work ability was associated with older age (OR 1.063) and lower functional restriction (OR 0.93); greater absenteeism was associated with lower pain self efficacy (OR 0.65) and poorer work expectancy (OR 1.18). Multiple regression analysis indicated that greater presenteeism was associated with higher pain intensity (beta = 0.259) and lower pain self-efficacy (beta = - 0.385). Conclusions While individuals continue to work with musculoskeletal pain, their work performance can be adversely affected. Interventions that target mutable factors, such as pain self-efficacy, may help reduce the likelihood of work impairment. PMID- 29236204 TI - The burden of pure anisometropic amblyopia: a cross-sectional study on 2800 Iranians. AB - PURPOSE: To assess the proportion of pure anisometropic amblyopia in a sample Iranian (white) population. METHODS: A total of 2800 consecutive individuals who presented at a referral eye clinic for any reason were examined for the presence of pure anisometropic amblyopia. Anisometropia was reported when a spherical equivalent refraction difference of at least 1.0 D with or without a cylinder refraction difference of at least 1.0 D was present between the two eyes. Amblyopia was defined as the best-corrected visual acuity of 20/30 or worse or a two-line interocular visual acuity difference between eyes that could not be attributed to any structural ocular pathology or visual pathway abnormality. RESULTS: Subjects were 1528 females and 1272 males with a mean age of 30.25 +/- 14.93 years (range, 5-65). Amblyopia was diagnosed in 192 cases (6.9%), significantly more frequent among females (7.9 vs. 5.7%, p = 0.02). Pure anisometropic amblyopia was present in 6.1% of the study population, significantly more common in patients with spherical hyperopic anisometropia (37.7%) compared to patients with spherical myopic anisometropia (21.3%), cylindrical myopic anisometropia (4.1%), and cylindrical hyperopic anisometropia (15%) (p < 0.001). CONCLUSIONS: Pure anisometropic amblyopia is a common finding in Caucasians seeking eye care, particularly when anisometropia is of spherical hyperopic subtype. PMID- 29236205 TI - A novel fibrin-based artificial ovary prototype resembling human ovarian tissue in terms of architecture and rigidity. AB - PURPOSE: The aim of this study is to optimize fibrin matrix composition in order to mimic human ovarian tissue architecture for human ovarian follicle encapsulation and grafting. METHODS: Ultrastructure of fresh human ovarian cortex in age-related women (n = 3) and different fibrin formulations (F12.5/T1, F30/T50, F50/T50, F75/T75), rheology of fibrin matrices and histology of isolated and encapsulated human ovarian follicles in these matrices. RESULTS: Fresh human ovarian cortex showed a highly fibrous and structurally inhomogeneous architecture in three age-related patients, but the mean +/- SD of fiber thickness (61.3 to 72.4 nm) was comparable between patients. When the fiber thickness of four different fibrin formulations was compared with human ovarian cortex, F50/T50 and F75/T75 showed similar fiber diameters to native tissue, while F12.5/T1 was significantly different (p value < 0.01). In addition, increased concentrations of fibrin exhibited enhanced storage modulus with F50/T50, resembling physiological ovarian rigidity. Excluding F12.5/T1 from further analysis, only three remaining fibrin matrices (F30/T50, F50/T50, F75/T75) were histologically investigated. For this, frozen-thawed fragments of human ovarian tissue collected from 22 patients were used to isolate ovarian follicles and encapsulate them in the three fibrin formulations. All three yielded similar follicle recovery and loss rates soon after encapsulation. Therefore, based on fiber thickness, porosity, and rigidity, we selected F50/T50 as the fibrin formulation that best mimics native tissue. CONCLUSIONS: Of all the different fibrin matrix concentrations tested, F50/T50 emerged as the combination of choice in terms of ultrastructure and rigidity, most closely resembling human ovarian cortex. PMID- 29236206 TI - Management of Slipped Gastric Bands via Creation of a De Novo Tunnel and Band Replacement: a Single-Centre Experience. AB - BACKGROUND: A lack of clarity remains over the optimal strategy for the management of laparoscopic adjustable gastric band (LAGB) slippage, which, although rare (around 3% in our experience), can when acute result in obstruction, gastric erosion or ischaemia. Typically, slipped bands are removed acutely. The aim of this study was to explore outcomes following immediate or delayed resiting of slipped LAGBs in a single centre, comparing simple repositioning with retunnelling and replacement. METHODS: A retrospective analysis of computerised records, notes and prospectively maintained bariatric databases was undertaken to identify all patients with a slipped LAGB in a single centre. RESULTS: Thirty-two patients required operative intervention following a diagnosis of slipped LAGB (median time from initial LAGB insertion to slippage 2.9 years). Two (6%) patients underwent band removal and 30 (94%), band revision surgery (25 immediately and five at a planned but expedited procedure).Twenty four (77%) patients underwent insertion of a new LAGB via a de novo retrogastric tunnel, five (21%) of which required further future operative intervention; whereas, six (23%) patients underwent repositioning of the existing LAGB within the same tunnel, five (83%) of which underwent further operative intervention (log-rank test p = 0.0001). Following LAGB revision, there was no significant further change in BMI (median + 1 kg/m2; range - 13 to + 10 kg/m2). CONCLUSION: Resiting of slipped LAGBs is safe and maintains weight loss. Although a significant risk of future operative intervention remains, this can be reduced via the creation of a de novo retrogastric tunnel for band resiting. PMID- 29236207 TI - Factors related to disagreement in implant size between preoperative CT-based planning and the actual implants used intraoperatively for total hip arthroplasty. AB - PURPOSE: In total hip arthroplasty, prediction of the optimal implant size is important in order to prevent perioperative complications. However, it is not easy to achieve complete agreement between the planned size and the actual size required appropriate implant fit. No previous report has adequately discussed the factors related to mismatch between predicted and actual implant sizes. The purpose was to report the results of a single surgeon case series of patients undergoing THA using computed tomography (CT)-based templating and the possible factors related to implant size mismatch. METHODS: The study included 141 hips of 126 patients who underwent primary total hip arthroplasty with CT-based navigation. We retrospectively reviewed the planned and actual implant sizes used in these patients. Cup position, cup orientation and stem alignment were evaluated as surgical factors that could possibly be related to mismatch in implant size. Cortical index and canal flare index were also evaluated as morphological factors. RESULTS: The final inclusions in this study were 124 hips of 111 patients including 82% of those were developmental dysplasia of the hip. Agreement in implant size was seen for 94.4% of cups and 85.5% of stems, respectively. No related factors were found for cup size mismatch. Stem alignment in the sagittal and coronal planes showed significant differences between the size-matched stem group and the smaller stem group ([Formula: see text]). CONCLUSIONS: Implant size agreement rates between the three-dimensional plan and the actual implants used intraoperatively were high. However, broach alignment should be checked in the coronal and sagittal planes if the intraoperative broach is smaller than the planned size. PMID- 29236208 TI - Effects of photosynthetic photon flux density, frequency, duty ratio, and their interactions on net photosynthetic rate of cos lettuce leaves under pulsed light: explanation based on photosynthetic-intermediate pool dynamics. AB - Square-wave pulsed light is characterized by three parameters, namely average photosynthetic photon flux density (PPFD), pulsed-light frequency, and duty ratio (the ratio of light-period duration to that of the light-dark cycle). In addition, the light-period PPFD is determined by the averaged PPFD and duty ratio. We investigated the effects of these parameters and their interactions on net photosynthetic rate (P n) of cos lettuce leaves for every combination of parameters. Averaged PPFD values were 0-500 umol m-2 s-1. Frequency values were 0.1-1000 Hz. White LED arrays were used as the light source. Every parameter affected P n and interactions between parameters were observed for all combinations. The P n under pulsed light was lower than that measured under continuous light of the same averaged PPFD, and this difference was enhanced with decreasing frequency and increasing light-period PPFD. A mechanistic model was constructed to estimate the amount of stored photosynthetic intermediates over time under pulsed light. The results indicated that all effects of parameters and their interactions on P n were explainable by consideration of the dynamics of accumulation and consumption of photosynthetic intermediates. PMID- 29236209 TI - Adverse Events under Tacrolimus and Cyclosporine in the First 3 Years Post-Renal Transplantation in Children. AB - BACKGROUND: Progress in immunosuppression has reduced acute rejection, graft loss and mortality after renal transplantation. Adverse drug reactions are well described in adults but few data are available in children. Our objectives were to analyse the adverse events reported in the first 3 years post-transplantation in children receiving tacrolimus or cyclosporine-based immunosuppression and compare them with the information of the Summary of Product Characteristics. METHODS: This retrospective study included all children who underwent a renal transplant at Hospital Robert Debre between 2002 and 2015. Initial immunosuppression was based on induction, calcineurin inhibitor, mycophenolate mofetil and corticosteroids. Adverse events were collected from medical records and coded using the Medical Dictionary for Regulatory Activities and the implications of tacrolimus and cyclosporine analysed. Statistical analyses were performed using SAS 9.4. RESULTS: One hundred and twenty-five children were included. During the observation period [2.7 years (0.6-4.3)], 105 patients received tacrolimus and 39 received cyclosporine. The incidence rate for gastrointestinal disorders was 0.128 and 0.056 by patient-years of exposure (p < 0.05), under tacrolimus and cyclosporine schedules. For neutropenia, it was 0.064 and 0.014 (p < 0.05). The frequencies of toxic nephropathy and gastrointestinal pain were higher than those in the Summary of Product Characteristics of tacrolimus (> 20%) and cyclosporine (> 10%). Cosmetic events for cyclosporine and neutropenia for tacrolimus were frequently observed (18 and 14.3%, respectively), although uncommon in the Summary of Product Characteristics. CONCLUSIONS: The exposure-adjusted incidence rate of gastrointestinal disorders and neutropenia was higher in children under the tacrolimus schedule. Our findings contribute to the evaluation of the benefit-risk balance of immunosuppressive therapy following paediatric renal transplantation. PMID- 29236210 TI - Perceptions of Physical Activity Participation Among Adolescents with Autism Spectrum Disorders: A Conceptual Model of Conditional Participation. AB - Adolescents with an autism spectrum disorder (ASD) are less physically active compared to typically developing peers. The reasons for not being physically active are complex and depend on several factors, which have not been comprehensively described from the adolescent's perspective. Therefore, the aim was to describe how adolescents with an ASD perceive, experience and reflect on their participation in physical activity. Interviews with 24 adolescents diagnosed with high-functioning ASD, aged 12-16 years, were analysed with qualitative content analysis with an inductive approach. They expressed a variety of reasons determining their willingness to participate, which were conceptualized as: Conditional participation in physical activities. The present study presents an alternative perspective on participation in physical activity, with impact on intervention design. PMID- 29236211 TI - Association of Whole Blood Tacrolimus Concentrations with Kidney Injury in Heart Transplantation Patients. AB - BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) is frequently observed after heart transplantation and is associated with morbidity and mortality. However, many confounding factors also contribute to the development of AKI in heart transplants. We hypothesized that supratherapeutic whole-blood tacrolimus trough concentrations are associated with AKI. METHODS: In a retrospective observational cohort from April 2005 to December 2012, all adult heart transplantation patients were included. AKI was assessed in the first 2 weeks after transplantation as classified by the Kidney Disease Improving Global Outcomes Network (KDIGO). Whole blood tacrolimus trough concentrations were determined from day 1 to day 14 and at 1, 3, 6 and 12 months post-transplantation. The therapeutic range was 9 to 15 ng/ml in the first 2 months and tapered to 5-8 ng/ml thereafter. The relationship between supratherapeutic tacrolimus trough concentrations and AKI was evaluated. The impact of various potentially confounding factors on tacrolimus concentrations and AKI was considered. RESULTS: We included 110 patients. AKI occurred in 57% of patients in the first week. Recovery from AKI was seen in 24%. The occurrence of chronic kidney disease (CKD) was 19% at 1 year. Whole-blood tacrolimus trough concentrations were often supratherapeutic and, despite correction for confounding factors, independently associated with AKI (OR 1.66; 95% CI 1.20-2.31). CONCLUSIONS: Supratherapeutic whole-blood tacrolimus trough concentrations are independently associated with the development of AKI in adult heart transplantation patients. More stringent dosing of tacrolimus early after transplantation may be critical in preserving the kidney function. PMID- 29236212 TI - Post-operative Refractive Prediction Error After Phacovitrectomy: A Retrospective Study. AB - INTRODUCTION: Many authors have reported on a myopic post-operative refractive prediction error when combining phacoemulsification with pars plana vitrectomy (phacovitrectomy). In this study we evaluate the amount of this error in our facility and try to elucidate the various factors involved. METHODS: This was a retrospective study which included 140 patients who underwent phacovitrectomy (39 with macular holes, 88 with puckers, and 13 with floaters). Post-operative refractive error was defined as the difference between the actual spherical equivalent (SEQ) and expected SEQ based on the SRK/T and Holladay-II formulas. Both univariate (paired t test, independent t test, one-way analysis of variance, or Mann-Whitney test) and multivariate (regression analysis) statistical analyses were performed. RESULTS: Overall, a refractive error of - 0.13 dpt (p = 0.033) and - 0.26 dpt (p < 0.01) were found in the SRK/T and Holladay-II formulas, respectively. For the independent diagnoses, only macular holes showed a myopic error with the SRK/T (- 0.31 dpt; p < 0.01) and Holladay-II (- 0.44 dpt; p < 0.01) formulas. In univariate analysis, significant factors involved in myopic refractive error were macular hole as diagnosis (p < 0.01 for SRK/T and Holladay II), gas tamponade (SRK/T p = 0.024; Holladay-II p = 0.025), pre-operative myopia (p < 0.01 for SRK/T), and optical technique for axial length measurement (SRK/T and Holladay-II p < 0.01). In the multivariate analysis, pre-operative axial length (p = 0.026), optical technique for axial length measurement (p < 0.01), and pre-operative SEQ (p < 0.01) were independent predictors for myopic refractive error in the SRK/T formula. For the Holladay-II formula, optical technique for axial length measurement (p < 0.01) and pre-operative SEQ (p = 0.04) were predictive. CONCLUSION: Various factors are involved in determining the myopic refractive error after phacovitrectomy. Not every factor seems to be as important in each individual patient, suggesting a more tailored approach is warranted to overcome this problem. PMID- 29236213 TI - Structural Probing, Screening and Structure-Based Drug Repositioning Insights into the Identification of Potential Cox-2 Inhibitors from Selective Coxibs. AB - The rate-limiting enzyme cyclooxygenase-2 (COX-2) is considered as an insightful prognostic target for non-small cell lung cancer (NSCLC) therapy. Now, administration and prolonged utilization of selective COX-2 inhibitors (COXIBs) towards moderating the NSCLC has been associated with different side effects. In the present study, we focused on the structure-based drug repositioning approaches for predicting therapeutic potential de novo candidates for human COX 2. Due to discrepancies in the eminence of x-ray diffraction structures, creates a big barrier in drug discovery approach. Hence, the adaptable COX-2 structure was investigated using multi-template modeling method. Next, a dataset of twenty six celebrex-associated optimized scaffolds were screened from ZINC database. Comparative docking approaches were then utilized to identify five compounds as best binders to the active site of COX-2 structures and strongly agree with enormous experimental consequences. MD simulations of regarded protein-ligand complexes reveals that lead molecules were stabilized dynamically in inside the cyclooxygenase site by forming potential salt bridges with Tyr348, Tyr385 and Ser530 residues. These significant results revealed that, identified druggables could prevent the tyrosyl radicals and prostaglandin production that reduces NSCLC progression. Furthermore, pharmacokinetics assets of respected ligands were analyzed, which incorporates similarity ensemble approach, druglikeness and ADMET properties. Finally, the identified novel candidates could serve as COX-2 inhibitors for NSCLC therapy, and coxibs are the best choices for designing new scaffolds to treat cyclooxygenases regard disorders. PMID- 29236214 TI - Neural Network Modeling of AChE Inhibition by New Carbazole-Bearing Oxazolones. AB - Acetylcholine esterase (AChE) is one of the targeted enzymes in the therapy of important neurodegenerative diseases such as Alzheimer's disease. Many studies on carbazole- and oxazolone-based compounds have been conducted in the last decade due to the importance of these compounds. New carbazole-bearing oxazolones were synthesized from several carbazole aldehydes and p-nitrobenzoyl glycine as AChE inhibitors by the Erlenmeyer reaction in the present study. The inhibitory effects of three carbazole-bearing oxazolone derivatives on AChE were studied in vitro and the experimental results were modeled using artificial neural network (ANN). The developed ANN provided sufficient correlation between several dependent systems, including enzyme inhibition. The inhibition data for AChE were modeled by a two-layered ANN architecture. High correlation coefficients were observed between the experimental and predicted ANN results. Synthesized carbazole-bearing oxazolone derivatives inhibited AChE under in vitro conditions, and further research involving in vivo studies is recommended. An ANN may be a useful alternative modeling approach for enzyme inhibition. PMID- 29236216 TI - Long-term outcomes of a Caucasian cohort presenting with acute coronary syndrome and/or out-of-hospital cardiac arrest caused by coronary spasm. AB - BACKGROUND: Coronary artery spasm may be the underlying mechanism in up to 10% of cases of acute coronary syndrome (ACS) and sudden cardiac death. Asian individuals exhibit a 3-times greater incidence of spasm than Caucasians; this is likely due to different types of mechanisms. Consequently, solid data is limited about the long-term prognosis in Caucasian patients presenting with ACS and/or out-of-hospital cardiac arrest (OHCA) caused by coronary spasm. METHODS: Between 2002 and 2015, thirty Caucasian patients with coronary artery spasm presenting with ACS (N = 29) and/or OHCA (N = 11) were enrolled in this prospective registry. Follow-up, consisting of regular outpatient visits, was conducted with a mean follow-up period of 7.5 +/- 3.3 years. Outcomes included presence of stable angina pectoris, recurrence of ACS, occurrence of implantable cardioverter defibrillator (ICD) shocks and death. RESULTS: The majority of patients (60%) remained asymptomatic during the entire follow-up period. At the end of the follow-up period only 3 patients still experienced stable angina (10%). Only 2 patients (7%) had a recurrent cardiac event, in which the ICD provided appropriate shock therapy. Half of the patients treated with stenting (N = 6), required re-interventions. CONCLUSION: Coronary spasm with ACS and/or OHCA in a Caucasian patient cohort has a relatively benign prognosis in the majority of patients in long-term follow-up, if treated appropriately with medical therapy. Both the role of ICD in OHCA secondary to coronary spasm, and the efficacy of stenting to treat vasospastic angina, warrant further study in large-sized prospective clinical trials. PMID- 29236215 TI - Phylogenetic comparison of the VP7, VP4, VP6, and NSP4 genes of rotaviruses isolated from children in Nizhny Novgorod, Russia, 2015-2016, with cogent genes of the Rotarix and RotaTeq vaccine strains. AB - Group A rotaviruses (RVA) are one of the leading causes of gastroenteritis in young children worldwide. The introduction of universal mass vaccination around the world has contributed to a reduction in hospitalizations and outpatient visits associated with rotavirus infection. Continued surveillance of RVA strains is needed to determine long-term effects of vaccine introduction. In the present work, we carried out the analysis of the genotypic diversity of RVA strains isolated in Nizhny Novgorod (Russia) during the 2015-2016 epidemic season. Also we conducted a comparative analysis of the amino acid sequences of T-cell epitopes of wild-type and vaccine (RotaTeq and Rotarix) strains. In total, 1461 samples were examined. RVAs were detected in 30.4% of cases. Rotaviruses with genotype G9P[8] (40.5%) dominated in the 2015-16 epidemic season. Additionally, RVAs with the following genotypes were detected: G4P[8] (25.4%), G1P[8] (13%), G2P[4] (3.2%). Rotaviruses with genotypes G3P[9], G6P[9], and G1P[9] totaled 3%. The number of partially typed and untyped RVA samples was 66 (14.9%). The findings of a RVA of G6P[9] genotype in Russia were an original observation. Our analysis of VP6 and NSP4 T-cell epitopes showed highly conserved amino acid sequences. The found differences seem not to be caused by the immune pressure but were rather related to the genotypic affiliations of the proteins. Vaccination against rotavirus infection is not included in the national vaccination schedule in Russia. Monitoring of the genotypic and antigenic diversity of contemporary RVA will allow providing a comparative analysis of wild-type strains in areas with and without vaccine campaign. PMID- 29236217 TI - The association between medical diagnosis and caregiver burden: a cross-sectional study of recipients of informal support and caregivers from the general population study 'Good Aging in Skane', Sweden. AB - BACKGROUND: Different kinds of chronic diseases might imply different dimensions of caregiver burden, not previously described among the caregivers to recipients from the general elder population. AIM: The main objective was to examine differences in burden between the 343 caregivers to persons with different diagnoses. METHODS: A group of elderly recipients of informal care (n = 343) from the general population study 'Good Aging in Skane' (GAS) Sweden, were divided into five diagnostic groups: dementia (n = 90), heart and lung diseases (n = 48), stroke (n = 62), fractures (n = 66), depression (n = 40) and the group "other", consisting of different diagnoses (n = 37) according to ICD-10. Differences in burden were analyzed using the Caregiver Burden Scale (CBS), a 22-item scale consisting of five dimensions: general strain, isolation, disappointment, emotional involvement and environmental burden. A total burden index comprises the mean of all the 22 items and a higher score indicates a higher burden. RESULTS: The most common diagnosis associated to caregiving was dementia and fracture and the median hours weekly for informal support with instrumental ADL for the five diagnostic groups ranged from 7 to 45 h for spouses and from 4 to 7 h for parents. The highest proportion of caregivers scoring high total burden was seen among recipients with dementia (50%) and depression (38%); the OR for high total burden for the dementia group was 4.26 (2.29-7.92) and depression group 2.38 (1.08-5.24) adjusted for covariates like age, gender and ADL and these two groups had higher self-perception of burden in all the dimensions, especially the dimension's emotional burden and strain. CONCLUSION: Informal support constitutes a substantial time for instrumental ADL for the diseased elders. Caregivers to persons with dementia and depression experience high burden. PMID- 29236218 TI - The dangers of the "Head Down" position in patients with untreated pituitary macroadenomas: case series and review of literature. AB - PURPOSE: Cavernous sinus syndrome is a rare phenomenon, characterized by simultaneous neuropathies of cranial nerves III-VI. Various pathological processes have been reported as precipitating etiologies, including infection, inflammation, vascular lesions, and neoplasms. PURPOSE: We report a unique case series of cavernous sinus syndrome attributable to prolonged Trendelenburg or prone positioning during non-cranial procedures and review the pertinent literature to enlighten on this rare but catastrophic phenomenon. METHODS: Retrospective case series. RESULTS: In the past year we encountered two patients who presented with acute cavernous sinus syndrome upon awakening from non-cranial operations. One patient underwent an extensive urologic resection of a bladder malignancy positioned in Trendelenburg for approximately 4 h. The second patient underwent a lumbar laminectomy and discectomy in prone position. Both patients were discovered to have infarcted large pituitary macroadenomas as the etiology of their acute ophthalmoplegias, and transnasal, transsphenoidal resection was performed acutely to decompress the cavernous sinus contents. Pathologic analysis of the resected specimens in each case confirmed necrotic, infarcted pituitary adenoma. Both patients made a complete recovery with no evidence of residual or recurrent tumor in short term follow-up. CONCLUSION: We report a brief case series of acute cavernous sinus syndrome resulting from dependent positioning during non-cranial operations in patients with pituitary macroadenoma. Although rare, this highlights a potential danger of "head down" positioning in patients with intracranial pathology-particularly in or around the sella and cavernous sinus. Despite multiple cranial neuropathies upon presentation, both patients made complete recovery following surgical decompression of the cavernous sinuses. PMID- 29236219 TI - Radioresistant Sf9 insect cells readily undergo an intrinsic mode of apoptosis in response to histone deacetylase (HDAC) inhibition. AB - Insect cell lines have been utilized as an important higher eukaryotic model system to decipher stress responses and cell death mechanisms. Lepidopteran Sf9 cells (derived from the ovaries of Spodoptera frugiperda) display nearly 100 times higher resistance to ionizing radiation in contrast to mammalian cells, which is partly contributed by an unusually high HDAC activity. However, their response to HDAC inhibition remains to be evaluated. In the present study, the effects of HDAC inhibitor (NaBt) on Sf9 cellular/nuclear morphology, cell cycle progression, DNA damage/repair, redox status, and mitochondrial perturbations were evaluated. NaBt-induced apoptosis was evident at 18 h in Sf9 cells at 2 mM concentration, primarily through mitochondrial induction of oxidative stress and subsequent DNA damage. Cell cycle analysis revealed appearance of sub-G1 DNA content at 12 h onwards and DNA fragmentation by 18 h. Initial few hours of treatment caused significant loss in MMP through oxidation of mitochondrial inner membrane protein, i.e., cardiolipin. HDAC inhibition-mediated apoptosis was associated with increased Bax/Bcl2 ratio, mitochondrial cytochrome-c release, and caspase-3 activation. The study thus infers that Sf9 cells, which can withstand very high radiation doses, are quite sensitive to the increase in the chromatin acetylation levels. In addition, HDAC inhibition also sensitized Sf9 cells to radiation-induced DNA damage, further corroborating our recent finding that chromatin compactness contributes significantly to their radioresistance. Therefore, the study demonstrates prominence of prevailing DNA/chromatin protective mechanisms in Lepidopteran insect cells. PMID- 29236220 TI - Automatic lung segmentation in functional SPECT images using active shape models trained on reference lung shapes from CT. AB - OBJECTIVE: Image segmentation is an essential step in quantifying the extent of reduced or absent lung function. The aim of this study is to develop and validate a new tool for automatic segmentation of lungs in ventilation and perfusion SPECT images and compare automatic and manual SPECT lung segmentations with reference computed tomography (CT) volumes. METHODS: A total of 77 subjects (69 patients with obstructive lung disease, and 8 subjects without apparent perfusion of ventilation loss) performed low-dose CT followed by ventilation/perfusion (V/P) SPECT examination in a hybrid gamma camera system. In the training phase, lung shapes from the 57 anatomical low-dose CT images were used to construct two active shape models (right lung and left lung) which were then used for image segmentation. The algorithm was validated in 20 patients, comparing its results to reference delineation of corresponding CT images, and by comparing automatic segmentation to manual delineations in SPECT images. RESULTS: The Dice coefficient between automatic SPECT delineations and manual SPECT delineations were 0.83 +/- 0.04% for the right and 0.82 +/- 0.05% for the left lung. There was statistically significant difference between reference volumes from CT and automatic delineations for the right (R = 0.53, p = 0.02) and left lung (R = 0.69, p < 0.001) in SPECT. There were similar observations when comparing reference volumes from CT and manual delineations in SPECT images, left lung (bias was - 10 +/- 491, R = 0.60, p = 0.005) right lung (bias 36 +/- 524 ml, R = 0.62, p = 0.004). CONCLUSION: Automated segmentation on SPECT images are on par with manual segmentation on SPECT images. Relative large volumetric differences between manual delineations of functional SPECT images and anatomical CT images confirms that lung segmentation of functional SPECT images is a challenging task. The current algorithm is a first step towards automatic quantification of wide range of measurements. PMID- 29236221 TI - DPP-4 Inhibitor-Induced Rheumatoid Arthritis Among Diabetics: A Nested Case Control Study. AB - INTRODUCTION: The risk of rheumatoid arthritis (RA) associated with dipeptidyl peptidase-4 inhibitor (DPP-4i) use is unclear. This study assesses the RA risk associated with DPP-4i use among a diabetic cohort initiating second-line therapy. METHODS: This was a nested case-control study, using the adult diabetic population starting second-line antidiabetic therapy from IMS LifeLink Plus(r) database (2006-2015). Cases were those with two or more RA diagnosis, at least one prescription, and 180 days enrollment prior to the event date (earliest of the two: first RA diagnosis, first RA prescription). Controls were drawn from the nest after matching (1:15) with cases on index date (+/- 90 days), age (+/- 5 years), sex, and event date (imputed to have the same time difference between cohort entry and event date as the matched case). Exposure and covariate information was gathered from the 180-day period prior to event date. Conditional logistic regression was used to assess exposure among cases and controls. Adjusted analysis was carried out after controlling for important medications and comorbidities. RESULTS: The final sample consists of 790 cases and 11,850 controls; of these, 151 cases (19.11%) and 2177 controls (18.37%) had DPP-4i claims during the exposure assessment period. DPP-4i therapy was not significantly associated with the development of RA after adjusting for covariates (OR = 1.156, 95% CI 0.936-1.429). Changing the exposure definition or exposure window to 1 year and subgroup analyses yielded similar results except for the non-insulin-using subgroup (OR = 1.299, 95% CI 1.001-1.985) which showed a significant positive association. CONCLUSION: DPP-4i were not significantly associated with the risk of RA compared with other second-line antidiabetic therapies. PMID- 29236222 TI - An Indirect Comparison of Changes in the Impact of Weight on Quality of Life Among Subjects with Type 2 Diabetes Treated with Antihyperglycemic Agents in Dual Therapy with Metformin. AB - INTRODUCTION: It is important to capture the patient experience with a diabetes treatment in clinical trials; however, use of instruments to assess patient reported outcomes (PROs) in diabetes trials is inconsistent and results may not be reported alongside primary efficacy data. In lieu of head-to-head data, indirect comparisons can be used to compare competing interventions. In this study, we used indirect comparison methods to assess differences in PRO score changes between canagliflozin and other antihyperglycemic agents as add-on to metformin. METHODS: Literature searches were performed to identify studies that reported the same PRO instruments that were collected across four trials of canagliflozin in dual or triple therapy. Extensive searches identified only one study that was sufficiently similar in design and reported common PRO results using the Impact of Weight on Quality of Life-Lite (IWQoL-Lite): the DURATION-2 study of exenatide once-weekly (QW) versus sitagliptin and pioglitazone. This study was compared with the CANTATA-D study of canagliflozin versus sitagliptin. Bayesian indirect comparisons were performed to assess mean change in IWQoL-Lite total score. A fixed-effects model with noninformative priors was used to estimate between-treatment differences. Sensitivity analyses examined differences in trial populations. RESULTS: In the primary analysis, the probability that canagliflozin treatment results in greater improvement in IWQoL-Lite total score versus exenatide, sitagliptin, and pioglitazone was 60.0%, 89.9%, and 99.5%, respectively. When the CANTATA-D population was restricted using DURATION-2 inclusion/exclusion criteria, canagliflozin was also associated with a higher probability of having greater improvement in IWQoL-Lite than exenatide, sitagliptin, and pioglitazone. CONCLUSIONS: These findings suggest that improvements in the impact of weight on health-related quality of life may be greater with canagliflozin than exenatide, sitagliptin, and pioglitazone. This analysis also demonstrates the application of indirect comparison methodology to PRO data and provides examples of advantages and challenges associated with performing indirect comparisons of PRO data. PMID- 29236223 TI - Transit and lifespan in neutrophil production: implications for drug intervention. AB - A comparison of the transit compartment ordinary differential equation modelling approach to distributed and discrete delay differential equation models is studied by focusing on Quartino's extension to the Friberg transit compartment model of myelosuppression, widely relied upon in the pharmaceutical sciences to predict the neutrophil response after chemotherapy, and on a QSP delay differential equation model of granulopoiesis. An extension to the Quartino model is provided by considering a general number of transit compartments and introducing an extra parameter that allows for the decoupling of the maturation time from the production rate of cells. An overview of the well established linear chain technique, used to reformulate transit compartment models with constant transit rates as distributed delay differential equations (DDEs), is then given. A state-dependent time rescaling of the Quartino model is performed to apply the linear chain technique and rewrite the Quartino model as a distributed DDE, yielding a discrete DDE model in a certain parameter limit. Next, stability and bifurcation analyses are undertaken in an effort to situate such studies in a mathematical pharmacology context. We show that both the original Friberg and the Quartino extension models incorrectly define the mean maturation time, essentially treating the proliferative pool as an additional maturation compartment. This misspecification can have far reaching consequences on the development of future models of myelosuppression in PK/PD. PMID- 29236224 TI - Two new aromatic glycosides, elengiosides A and B, from the flowers of Mimusops elengi. AB - Two new aromatic glycosides, elengiosides A (1) and B (2), were isolated from the methanolic extract of the flowers of Mimusops elengi (Sapotaceae) together with 26 known compounds. Their stereostructures were elucidated based on their spectroscopic properties and chemical evidence. Among the isolates, a phenylethanoid glycoside, undatuside C (14), was found to exhibit hyaluronidase inhibitory activity. PMID- 29236225 TI - Enhanced ultrasound-assisted enzymatic hydrolysis extraction of quinolizidine alkaloids from Sophora alopecuroides L. seeds. AB - Quinolizidine alkaloids are the main bioactive components in Sophora alopecuroides L. This study reports a novel ultrasound-assisted enzymatic hydrolysis method for the extraction of these important alkaloids. Box-Behnken design, a widely used response surface methodology, was used to investigate the effects of process variables on ultrasound bath-assisted enzymatic hydrolysis (UAEH) extraction. Four independent variables, pH, extraction temperature ( degrees C), extraction time (min) and solvent-to-material ratio (mL/g), were studied. For the extraction of sophocarpine, oxysophocarpine, oxymatrine, matrine, sophoramine, sophoridine and cytisine, the optimal UAEH condition was found to be a pH of 5, extraction temperature of 54 degrees C, extraction time of 60 min and solvent-to-material ratio of 112 mL/g. The experimental values obtained under optimal conditions were fairly consistent with the predicted values. UAEH extraction was then compared with reflux heating, enzymatic extraction and ultrasound-assisted extraction. Of these extraction methods, UAEH extraction under optimal conditions produced the highest yield for seven types of alkaloids. In addition, UAEH extraction resulted in lower ingredient degradation than reflux heating extraction. PMID- 29236226 TI - Evaluation of left ventricular diastolic function: state of the art after 35 years with Doppler assessment. AB - Left ventricular (LV) diastolic function can be evaluated by echocardiographic indices of LV relaxation/restoring forces, diastolic compliance, and filling pressure. By using a combination of indices, diastolic function can be graded and LV filling pressure estimated with high feasibility and good accuracy. Evaluation of diastolic function is of particular importance in patients with unexplained exertional dyspnea or other symptoms or signs of heart failure which cannot be attributed to impaired LV systolic function and to assess filling pressure in patients with heart failure and reduced LV ejection fraction. Furthermore, grading of diastolic dysfunction can be used for risk assessment in asymptomatic subjects and in patients with heart disease. PMID- 29236227 TI - Loss of vascular expression of nucleoside triphosphate diphosphohydrolase-1/CD39 in hypertension. AB - Ectonucleoside triphosphate diphosphohydrolase-1, the major vascular/immune ectonucleotidase, exerts anti-thrombotic and immunomodulatory actions by hydrolyzing extracellular nucleotides (danger signals). Hypertension is characterized by vascular wall remodeling, endothelial dysfunction, and immune infiltration. Here our aim was to investigate the impact of arterial hypertension on CD39 expression and activity in mice. Arterial expression of CD39 was determined by reverse transcription quantitative real-time PCR in experimental models of hypertension, including angiotensin II (AngII)-treated mice (1 mg/kg/day, 21 days), deoxycorticosterone acetate-salt mice (1% salt and uninephrectomy, 21 days), and spontaneously hypertensive rats. A decrease in CD39 expression occurred in the resistance and conductance arteries of hypertensive animals with no effect on lymphoid organs. In AngII-treated mice, a decrease in CD39 protein levels (Western blot) was corroborated by reduced arterial nucleotidase activity, as evaluated by fluorescent (etheno)-ADP hydrolysis. Moreover, serum-soluble ADPase activity, supported by CD39, was significantly decreased in AngII-treated mice. Experiments were conducted in vitro on vascular cells to determine the elements underlying this downregulation. We found that CD39 transcription was reduced by proinflammatory cytokines interleukin (IL) 1beta and tumor necrosis factor alpha on vascular smooth muscle cells and by IL-6 and anti-inflammatory and profibrotic cytokine transforming growth factor beta 1 on endothelial cells. In addition, CD39 expression was downregulated by mechanical stretch on vascular cells. Arterial expression and activity of CD39 were decreased in hypertension as a result of both a proinflammatory environment and mechanical strain exerted on vascular cells. Reduced ectonucleotidase activity may alter the vascular condition, thus enhancing arterial damage, remodeling, or thrombotic events. PMID- 29236228 TI - Population Pharmacokinetic-Pharmacodynamic Modeling of Ropivacaine in Spinal Anesthesia. AB - BACKGROUND: Ropivacaine is frequently used in spinal anesthesia but the relationship between plasma concentrations and sensory block level remains unknown. OBJECTIVE: The aim of this study was to assess the relationship between plasma ropivacaine concentrations and effects during spinal anesthesia. METHODS: Sixty patients aged between 18 and 82 years were included in this study after providing written informed consent. Patients were randomly assigned to receive intrathecal administration of ropivacaine 15, 20 or 25 mg. Blood samples were drawn to determine ropivacaine concentrations, and sensory blockade was assessed using pinprick testing. Ropivacaine plasma concentrations and sensory block level were analyzed using a nonlinear mixed-effects modeling approach with Monolix 4.2.2. Uncertainty of parameters was estimated by bootstrapping. RESULTS: Overall, 216 plasma ropivacaine values and 407 sensory block-related data were available for pharmacokinetic-pharmacodynamic (PK-PD) model evaluation. A two compartment open model connected to a spinal compartment was selected to describe the PKs of ropivacaine. Sensory block modeling was performed using a sigmoid E max model assuming an equilibration delay between the amount in the depot or spinal compartment and at the effect site. Using multiple linear regression analysis, we were able to demonstrate the importance of dose, age and weight as major predictors of sensory block-level kinetics. CONCLUSIONS: This first population PK-PD model for ropivacaine in spinal anesthesia confirms the relationship between plasma ropivacaine concentrations and effect. We also clarify the relationship between the spread of sensory block level and dose, age and, for the first time, weight. STUDY REGISTRATION: This study was approved by the Reims University Hospital Ethics Committee (protocol: PHRC-2005; registered at Agence Nationale de Securite du Medicament et des Produits de Sante ANSM: D60890). This was an open, prospective, monocentric study conducted in the University Hospital of Reims (France). PMID- 29236229 TI - Model-Based Therapeutic Drug Monitoring of Infliximab Using a Single Serum Trough Concentration. AB - BACKGROUND AND OBJECTIVES: The pharmacokinetics of infliximab are highly variable and influence clinical response in chronic inflammatory diseases. The goal of this study was to build a Bayesian model allowing predictions of upcoming infliximab concentrations and dosing regimen adjustment, using only one concentration measurement and information regarding the last infliximab infusion. METHODS: This retrospective study was based on data from 218 patients treated with infliximab in Tours University Hospital who were randomly assigned to learning (two-thirds) or validation (one-third) data subsets. One-compartment pharmacokinetic and time since last dose (TLD) models were built and compared using learning and validation subsets. From these models, Bayesian pharmacokinetic and TLD models using one concentration measurement (1C-PK and 1C TLD) were designed. The predictive performances of the 1C-TLD model were tested on two external validation cohorts. RESULTS: Pharmacokinetic and TLD models described the data satisfactorily and provided accurate parameter estimations. Comparable predictions of infliximab concentrations were obtained from pharmacokinetic versus TLD models, as well as from Bayesian 1C-PK versus 1C-TLD models. The 1C-TLD model showed satisfactory prediction of future infliximab concentrations and provided satisfactory predictions of infliximab steady-state concentration for up to three upcoming visits after a blood sample. CONCLUSIONS: Accurate individual concentration predictions can be obtained using a single infliximab concentration measurement and information regarding only the last infusion. The 1C-TLD model may help to optimize the dosing regimen of infliximab in routine therapeutic drug monitoring. PMID- 29236230 TI - Gene Patents in Canada: Is There a New Legal Landscape? AB - In 2016, the Children's Hospital of Eastern Ontario (CHEO) announced the settlement of its patent lawsuit against US-based Transgenomic, Inc. At issue in the case was CHEO's ability to test for gene mutations associated with long QT syndrome (LQTS) that are described in Transgenomic's patents. CHEO challenged the patents as invalid, and Transgenomic ultimately agreed to license them on a royalty-free basis to CHEO and other healthcare institutions for LQTS testing and research. While widely celebrated in the media, the ethical rhetoric surrounding the settlement has at times obscured the practical and legal context in which it was made and will operate. Here, we provide a nuanced account of the events surrounding the settlement and its implications for research and clinical care. Although the settlement is remarkable for the transparency of its terms and its inclusion of a license intended to benefit unaffiliated test providers, we conclude that another significant implication of the settlement may be its elimination of the opportunity to clarify an increasingly confused area of Canadian law against a backdrop of continued international controversy surrounding the patenting of genes and gene-based diagnostic and therapeutic methods. PMID- 29236231 TI - Dimethyl Fumarate: A Review in Moderate to Severe Plaque Psoriasis. AB - Fumaric acid esters (FAEs) have been used in the treatment of psoriasis in some European countries for over 20 years, and are recommended in the European guidelines for the management of moderate to severe plaque psoriasis. Dimethyl fumarate (Skilarence(r); hereafter referred to as DMF) is an orally administered FAE indicated for the treatment of moderate to severe plaque psoriasis in adults in need of systemic medicinal therapy; unlike other available FAEs, it is not formulated in combination with monoethyl fumarate salts. EU approval was based on results of the phase III BRIDGE trial, and supported by previous publications of FAE preparations, including a combination of FAEs containing dimethyl fumarate and monoethyl fumarate salts (DMF/MEF; Fumaderm(r)). In the BRIDGE trial, DMF was superior to placebo in terms of the proportion of patients achieving a >= 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) and a Physician Global Assessment score of 0 (clear) or 1 (almost clear) at week 16. DMF was also noninferior to DMF/MEF for PASI 75 at week 16. Patients receiving DMF also reported clinically meaningful improvements in body surface area involvement and health-related quality of life. The safety profile of DMF was similar to that of DMF/MEF, and no major or unexpected safety concerns were identified. The most common adverse events (flushing and gastrointestinal disorders) occurred mainly during the first few weeks of treatment. Currently available data indicate that DMF is an effective oral systemic treatment option for patients with moderate to severe plaque psoriasis. PMID- 29236232 TI - beta-(1->6)-D-glucan secreted during the optimised production of exopolysaccharides by Paecilomyces variotii has immunostimulatory activity. AB - Paecilomyces variotii is a filamentous fungus that occurs worldwide in soil and decaying vegetation. Optimization of the fermentation process for exopolysaccharide (EPS) production from the fungus P. variotii, structure determination and immuno-stimulating activity of EPS were performed. Response surface methodology (RSM) coupled with central composite design (CCD) was used to optimize the physical and chemical factors required to produce EPS in submerged fermentation. Preliminary investigations to choose the three factors for the present work were made using a factorial experimental design. Glucose, ammonium nitrate (NH4NO3) and pH were used as variables for which, with constant temperature of 28 degrees C and agitation of 90 rpm, the optimal process parameters were determined as glucose values of 0.96%, NH4NO3 0.26% and pH 8.0. The three parameters presented significant effects. In this condition of culture, the main composition of the isolated EPS was a linear beta-(1 -> 6)-linked-D glucan, as determined by Nuclear Magnetic Resonance (NMR) and methylation analysis. This polysaccharide is a very unusual as an EPS from fungi, especially a filamentous fungus such as P. variotii. Murine peritoneal macrophages cultivated with beta-glucan for 6 and 48 h showed an increase in TNF-alpha, IL-6 and nitric oxide release with increased polysaccharide concentrations. Therefore, we conclude that the beta-(1 -> 6)-linked-D-glucan produced in optimised conditions of P. variotii cultivation has an immune-stimulatory activity on murine macrophages. PMID- 29236233 TI - Thauera sinica sp. nov., a phenol derivative-degrading bacterium isolated from activated sludge. AB - A bacterial strain, K11T, capable of degrading phenol derivatives was isolated from activated sludge of a sewage treatment plant in China. This strain, which can degrade more than ten phenol derivatives, was identified as a Gram-stain negative, rod-shaped, asporogenous, facultative anaerobic bacterium with a polar flagellum. The strain was found to grow in tryptic soy broth in the presence of 0 2.5% (w/v) NaCl (optimum 0-1%), at 4-43 degrees C (optimum 30-35 degrees C) and pH 4.5-10.5 (optimum 7.5-8). Comparative analysis of nearly full-length 16S rRNA gene sequences showed that this strain belongs to the genus Thauera. The 16S rRNA gene sequence was found to show high similarity (97.5%) to that of Thauera chlorobenzoica 3CB-1T, with lesser similarity to other recognised Thauera strains. The G+C content of the DNA of the strain was determined to be 67.8 mol%. The DNA-DNA hybridization value between K11T and Thauera aromatica DSM6984T was 10.4 +/- 4.5%. The genomic OrthoANI values of K11T with the other nine type strains of genus Thauera were less than 81.1%. Chemotaxonomic analysis of strain K11T revealed that Q-8 is the predominant quinone; the polar lipids contain phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, two unidentified phospholipids and five uncharacterised lipids; the major cellular fatty acid was identified as summed feature 3 (C16:1 omega7c and/or iso-C15:0 2 OH; 45.9%), followed by C16:0 (20.5%) and C18:1 omega7c (15.8%). Based on the phenotypic and phylogenetic evidence, DNA-DNA hybridisation, OrthoANI, chemotaxonomic analysis and results of the physiological and biochemical tests, a new species named Thauera sinica sp. nov. is proposed with strain K11T (= CGMCC 1.15731T = KACC 19216T) designated as the type strain. PMID- 29236234 TI - Assessment of the functional impact of germline BRCA1/2 variants located in non coding regions in families with breast and/or ovarian cancer predisposition. AB - PURPOSE: The molecular mechanism of breast and/or ovarian cancer susceptibility remains unclear in the majority of patients. While germline mutations in the regulatory non-coding regions of BRCA1 and BRCA2 genes have been described, screening has generally been limited to coding regions. The aim of this study was to evaluate the contribution of BRCA1/2 non-coding variants. METHODS: Four BRCA1/2 non-coding regions were screened using high-resolution melting analysis/Sanger sequencing or next-generation sequencing on DNA extracted from index cases with breast and ovarian cancer predisposition (3926 for BRCA1 and 3910 for BRCA2). The impact of a set of variants on BRCA1/2 gene regulation was evaluated by site-directed mutagenesis, transfection, followed by Luciferase gene reporter assay. RESULTS: We identified a total of 117 variants and tested twelve BRCA1 and 8 BRCA2 variants mapping to promoter and intronic regions. We highlighted two neighboring BRCA1 promoter variants (c.-130del; c.-125C > T) and one BRCA2 promoter variants (c.-296C > T) inhibiting significantly the promoter activity. In the functional assays, a regulating region within the intron 12 was found with the same enhancing impact as within the intron 2. Furthermore, the variants c.81-3980A > G and c.4186-2022C > T suppress the positive effect of the introns 2 and 12, respectively, on the BRCA1 promoter activity. We also found some variants inducing the promoter activities. CONCLUSION: In this study, we highlighted some variants among many, modulating negatively the promoter activity of BRCA1 or 2 and thus having a potential impact on the risk of developing cancer. This selection makes it possible to conduct future validation studies on a limited number of variants. PMID- 29236235 TI - Potential biomarkers of CDK4/6 inhibitors in hormone receptor-positive advanced breast cancer. AB - PURPOSE: Cyclin D/cyclin-dependent kinase 4/6 (CDK4/6) complex inhibitors have recently been proven effective when combined with endocrine therapy in clinical trials. However, the clinical benefit from CDK4/6 inhibitor varied from different patients. In order to optimize the clinical application of CDK4/6 inhibitors, this review focuses on the potential biomarkers applicable to identify patients who will benefit the most from CDK4/6 inhibition. METHODS: We have summarized the clinical trials about addition of CDK4/6 inhibitors to endocrine therapy and reviewed literature currently available on the potential biomarkers in predicting efficacy of CDK4/6 inhibitors. The primary objective was to determine the predictors. The secondary objective was to optimize the combination therapeutics for patients with estrogen receptor (ER)-positive breast cancer. RESULTS: We reviewed clinical trials on antiestrogen agents combined with the CDK4/6 inhibitor (Palbociclib, Ribociclib, or Abemaciclib) in ER-positive breast cancer. It was confirmed that the addition of CDK4/6 inhibitors was associated with an improved efficacy. More importantly, we discussed potential biomarkers for identifying the subpopulations of breast cancer patients who would derive the greatest benefit from CDK4/6 inhibitors. CONCLUSIONS: We have found that although CDK4/6 inhibitors combined with endocrine therapy were potent, the toxicity and financial burden also increased. To maximize the effect of the combinations and select patients that best response to such combinations, further experiments and trials are expected to confirm these molecules as reliable biomarkers. PMID- 29236236 TI - The Co-evolution of Bullying Perpetration, Homophobic Teasing, and a School Friendship Network. AB - Bullying and homophobic teasing behaviors affect the lives of many school aged children, often co-occur, and tend to peak in middle school. While bullying and homophobic teasing behaviors are known to be peer group phenomena, studies typically examine the associations at the individual or school levels. An examination of these behaviors at the peer group level can aid in our understanding of the formation and maintenance of peer groups that engage in these forms of aggressive behavior (selection), and the extent to which friends and the peer group impact individual rates of these aggressive behaviors (influence). In this longitudinal study, we assess the co-evolution of friendship networks, bullying perpetration, and homophobic teasing among middle school students (n = 190) using a Stochastic Actor-Based Model (SABM) for longitudinal networks. Data were collected from 6-8th-grade students (Baseline age 12-15; 53% Female; 47% Male) across three waves of data. The sample was diverse with 58% African American, 31% White, and 11% Hispanic. Since bullying and homophobic teasing behaviors are related yet distinct forms of peer aggression, to capture the unique and combined effects of these behaviors we ran models separately and then together in a competing model. Results indicated that on average individuals with higher rates of bullying perpetration and homophobic teasing were associated with becoming increasingly popular as a friend. However, the effects were not linear, and individuals with the highest rates of bullying perpetration and homophobic teasing were less likely to receive friendship nominations. There was no evidence that bullying perpetration or homophobic teasing were associated with the number of friendship nominations made. Further, there was a preference for individuals to form or maintain friendships with peers who engaged in similar rates of homophobic name-calling; however, this effect was not found for bullying perpetration. Additionally, changes in individual rates of bullying perpetration were not found to be predicted by the bullying perpetration of their friends; however, changes in adolescent homophobic teasing were predicted by the homophobic teasing behaviors of their friends. In a competing model that combined bullying perpetration and homophobic teasing, we found no evidence that these behaviors were associated with popularity. These findings are likely due to the high association between bullying perpetration and homophobic teasing combined with the small sample size. However, friendship selection was based on homophobic name-calling, such that, there was a preference to befriend individuals with similar rates of homophobic teasing. We also examined several risk factors (dominance, traditional masculinity, impulsivity, femininity, positive attitudes of bullying, and neighborhood violence), although, impulsivity was the only covariate that was associated with higher levels of bullying perpetration and homophobic teasing. More specifically, youth with higher rates of impulsivity engaged in higher rates of bullying perpetration and homophobic teasing over time. The findings suggest bullying perpetration and homophobic teasing have important influences on friendship formation, and close friendships influence youth's engagement in homophobic teasing. Implications for prevention and intervention efforts are discussed in terms of targeting peer groups and popular peers to help reduce rates of these aggressive behaviors. PMID- 29236237 TI - Outcome of children and adolescents with central nervous system tumors in phase I trials. AB - Central nervous system (CNS) tumors are a leading cause of death in pediatric oncology. New drugs are desperately needed to improve survival. We evaluated the outcome of children and adolescents with CNS tumors participating in phase I trials within the Innovative Therapies for Children with Cancer (ITCC) consortium. Patients with solid tumors aged < 18 years at enrollment in their first dose-finding trial between 2000 and 2014 at eight ITCC centers were included retrospectively. Survival was evaluated using univariate/multivariate analyses. Overall, 114 patients were included (109 evaluable for efficacy). Median age was 10.2 years (range 1.0-17.9). Main diagnoses included: medulloblastoma/primitive neuroectodermal tumors (32.5%) and high-grade gliomas (23.7%). Complete/partial responses (CR/PR) were reported in 7.3% patients and stable disease (SD) in 23.9%. Performance status of 90-100%, school/work attendance, normal ALT/AST and CR/PR/SD correlated with better overall survival (OS) in the univariate analysis. No variables assessable at screening/enrollment were associated with OS in the multivariate analysis. Five patients (4.5%) were discontinued from study due to toxicity. No toxic deaths occurred. Median OS was 11.9 months with CR/PR, 14.5 months with SD and 3.7 months with progressive disease (p < 0.001). The enrollment of children and adolescents with CNS tumors in phase I trials is feasible, safe and offers potential benefit for the patients. Sustained disease stabilization has a promising role as a marker of anti-tumor activity in children with CNS tumors participating in phase I trials. PMID- 29236238 TI - Internet-based guided self-help for glioma patients with depressive symptoms: a randomized controlled trial. AB - Depressive symptoms are common in glioma patients, and can negatively affect health-related quality of life (HRQOL). We performed a nation-wide randomized controlled trial to evaluate the effects of an online guided self-help intervention for depressive symptoms in adult glioma patients. Glioma patients with depressive symptoms were randomized to a 5-week online course based on problem-solving therapy, or a waiting list control group. After having received the intervention, the glioma patient groups combined were compared with patients with cancer outside the central nervous system (non-CNS cancer controls), who also received the intervention. Sample size calculations yielded 63 participants to be recruited per arm. The primary outcome [depressive symptoms (CES-D)] and secondary outcomes [fatigue (Checklist Individual Strength (CIS)) and HRQOL (Short Form-36)], were assessed online at baseline, post-intervention, and 3 and 12 months follow-up. In total, 89 glioma patients (intervention N = 45; waiting list N = 44) and 26 non-CNS cancer controls were included, of whom 35 and 54% completed the intervention, respectively. Recruitment could not be extended beyond 3.5 years due to funding. On depression, no statistically significant differences between the groups were found. Fatigue decreased post-treatment in the glioma intervention group compared with the waiting list group (p = 0.054, d = 0.306). At 12 months, the physical component summary (HRQOL) remained stable in glioma patients, while scores improved in non-CNS cancer controls (p = 0.035, d = 0.883). In this underpowered study, no evidence for the effectiveness of online guided self-help for depression or HRQOL in glioma patients was found, but it may improve fatigue. Trial registration Netherlands Trial Register NTR3223. PMID- 29236239 TI - Abdominal aorta and pelvic artery calcifications on plain radiographs may predict mortality in chronic kidney disease, hemodialysis and renal transplantation. AB - PURPOSE: Vascular calcification is common in chronic kidney disease (CKD) and predicts poor patient outcomes. While computed tomography is the gold standard for evaluation of vascular calcification, plain radiograph offers a simpler and less costly alternative. The calcification of abdominal aorta, iliac and femoral arteries has been evaluated by plain radiograph, but the data on their outcome predictabilities are still limited. The present study investigated the role of abdominal aortic calcification (AAC) and pelvic arterial calcification (PAC) in predicting overall morality in non-dialysis CKD stages 2-5 (CKD 2-5), maintenance hemodialysis (HD) and long-term kidney transplant (KT) patients. METHODS: Four hundred and nineteen patients were included. Lateral abdominal and pelvic radiographs were obtained. The degree of AAC and PAC was evaluated according to the methods described previously by Kaupplia et al. and Adragao et al. Patients were followed prospectively for 5 years. RESULTS: AAC and PAC scores correlated well with the correlation coefficients of 0.442 for CKD 2-5, 0.438 for HD and 0.586 for KT (p < 0.001). Patients with AAC score > 6 or PAC score > 1 were older, showed higher prevalence of DM and had higher serum phosphate and PTH but lower serum albumin and eGFR. A more severe degree of AAC was associated with an increase in KT duration, whereas a more severe degree of PAC was associated with worsening kidney function and prolonged dialysis vintage. Kaplan-Meier survival curves revealed AAC score > 6 as a significant predictor of all-cause mortality in CKD 2-5 but not in HD or KT, whereas PAC score > 1 was a significant predictor of all-cause mortality in all three populations. After adjusting for age, the predictability of AAC was lost, whereas PAC remained an independent predictor of mortality in all three populations. Adjustments for cardiovascular and CKD risk factors including age, gender, BMI, DM, serum albumin, calcium and phosphate attenuated the predictability of PAC in HD but not in CKD 2-5 or KT patients. CONCLUSION: PAC was better than AAC in predicting mortality in CKD, HD and KT patients. PMID- 29236241 TI - Set organic pollution as an impact category to achieve more comprehensive evaluation of life cycle assessment in wastewater-related issues. AB - For wastewater-related issues (WRI), life cycle assessment (LCA) is often used to evaluate environmental impacts and derive optimization strategies. To promote the application of LCA for WRI, it is critical to incorporate local impact of water pollutants. Organic pollution, a main type of water pollution, has not been given much consideration in current LCA systems. This paper investigates the necessity of setting a regionalized impact category to reflect the local impact of organic pollution. A case study is conducted concerning an upgraded wastewater treatment plant (WWTP) in China, which is assumed to meet different sewage control strategies. Chemical oxygen demand (COD) is selected to represent the organic pollution and treated as an individual impact category. CML 2002 is used to quantify the environmental impacts of different strategies. Results show that abnormal LCA results are generated with the traditional eutrophication impact category, and after the introduction of COD, more reasonable LCA results are obtained, making the entire comparison of different control strategies more meaningful and compelling. Moreover, BEES, Ecovalue 08, and Chinese factors are adopted here as different weighting methods. Different weighting results exhibited various trade-offs for the increasingly strict control strategies; the results of BEES and Ecovalue08 underlined the potential environmental burden, but the results of Chinese factors only emphasized the local environmental improvement. It is concluded that setting regionalized impact category for organic pollution can make LCA results more reasonable in wastewater treatment, especially in evaluating Chinese cases because of the serious water pollution caused by large quantities of COD emission. PMID- 29236240 TI - Effects of small molecules water that may retard kidney stone formation. AB - PURPOSE: Water intake is important for preventing kidney stones. Small molecules water is a more active restructured water under magnetic field. Here, we studied the relation between small molecules water and crystal formation in the rat kidney. MATERIALS: The small molecules water was prepared by a water machine providing a 0.8-T magnetic field. Calcium oxalate crystals were induced by 0.75% EG (ethylene glycol) in male Sprague-Dawley rats by drinking small molecules water and plain water for up to 6 weeks, respectively. Urinary ions were assayed. Osteopontin mRNA expression and urinary LDH were detected. Crystals were observed using a light microscope and a polarizing microscope. RESULTS: A significantly reduced urinary calcium and phosphorus excretion occurred in the 2nd and the 4th week after treatment of small molecules water. Crystals were initially detected in 40% of the experimental rats in the small molecules water group at the 6th week, later than the control group in which crystals were detected in 60% of rats at the 4th week. After 6 weeks of treatment, crystals were observed to form in renal cortex, medulla and papilla in the control group, whereas only to form in renal medulla and papilla in the small molecules water group. OPN mRNA expression significantly increased earlier in the 2nd week after treatment of the small molecules water compared to the control (P = 0.016). CONCLUSIONS: Small molecules water may retard crystal formation, reduce urinary calcium and phosphorus excretion and promote earlier OPN mRNA expression in the rat kidney. PMID- 29236242 TI - Study of different environmental matrices to access the extension of metal contamination along highways. AB - Metals are indicators of contamination by anthropic activities, such as road traffic. To assess the extent of the metal contamination, more comprehensive studies analyzing different environmental matrices, such as soils, dust, and plants, collected in different sites that are potential sources of these pollutants along the highways, must be prioritized. Samples of soils, dust, and plants were collected alongside the highways of Brazil at 20 sites selected in strategic locations of metal accumulation (Cr, Pb, Zn, As, and Sb) or different situations of the high ways during two rain conditions (wet and dry weeks of sampling): nearby gutters and water supplies, tolls, petrol stations, a federal road police station, and areas associated with agriculture (yearly culture planting upstream of the highway). The geoaccumulation index (metal concentration in the sample of interest/background) varied from 0 to 6, and the decreasing order of contamination by metals during the wet and dry periods were, respectively: Zn > As > Pb = Sb > Cr and Zn > As > Pb > Cr > Sb. In the soils near the highways, the highest concentrations of metals were as follows (mg kg 1): As = 15.6, Cr = 81.9, Pb = 39.7, Sb = 5.0, and Zn = 379.3. The highest amounts of these elements in the most superficial layer in soils indicated their addition through atmospheric emissions. The most prominent metal was Sb, whose concentration was greater than the quality limits for soils. The concentration of Sb in soils was higher in the wet week than in the dry week. The emissions from road traffic promoted the increase in metals in the dust on the track, especially Zn and Pb. The highest metal concentrations in grasses (Brachiaria) were found in the roots, except for Sb and Zn, which suggests leaf absorption of atmospheric deposition. Metal contamination was widespread in all studied matrices along the highways. PMID- 29236243 TI - Application potential of aerobic denitrifiers coupled with a biostimulant for nitrogen removal from urban river sediment. AB - Aerobic denitrifiers coupled with a denitrification agent were applied in the sediment of an urban river for the bioremediation of nitrogen pollution. The results revealed that 14.7% of the total nitrogen in the sediment was removed after 115 days of treatment and the nitrate nitrogen concentration removal rate was enhanced in the overlying water. Compared with the control, the total transferable nitrogen in the sediment increased from 0.097 to 0.166 mg/g, indicating that more nitrogen is likely to be involved in the biogeochemical cycling of nitrogen. Increased urease activity indicated the possible further potential of nitrogen biodegradation, while the decreased protease pointed to the low concentration of protein remaining in the sediment. Sequencing revealed that the bacterial community diversity in the sediment increased significantly after 43 days of treatment and that the effect persisted. Compared with other microcosms, the dominant phyla in the sediment after 43 days were Firmicutes, Elusimicrobia, Spirochaetae and Fibrobacteres; whereas, after 115 of treatment, the dominant bacteria were Nitrospirae, Deferribacteres and Chloroflexi. The dominant bacteria in the sediment are mainly associated with nitrogen cycling and thus contributed considerably to nitrogen removal in the sediment. Overall, the direction of species succession was similar to natural succession; namely, there were no undesirable ecological risks involved. This study highlights the possible benefits and feasibility of using bioaugmentation technology coupled with biostimulation to remediate nitrogen-polluted sediments. PMID- 29236244 TI - Evaluation of disinfection by-product formation during chlor(am)ination from algal organic matter after UV irradiation. AB - This study evaluated the effect of low-pressure ultraviolet (UV) irradiation on the formation of disinfection by-products (DBPs) from algal organic matter of Microcystis aeruginosa during subsequent chlorination and chloramination. The algal organic matter includes extracellular organic matter (EOM) and intracellular organic matter (IOM). The fluorescence excitation-emission matrix spectra indicated that the humic/fulvic acid-like organics of EOM and the protein like organics of IOM may be preferentially degraded by UV treatment. UV irradiation with low specific UV absorbance values was effective in reducing the formation of trihalomethanes and dichloroacetic acid from EOM and IOM during the subsequent chlorination. During the UV-chloramine process, higher UV dose (1000 mJ/cm2) led to the decrease of the formation of dichloroacetic acid, trichloroacetic acid, and haloketones from IOM by an average of 24%. Furthermore, UV irradiation can slightly increase the bromine substitution factors (BSFs) of haloacetic acids from EOM during chlorination, including dihaloacetic acids and trihaloacetic acids in the presence of bromide (50 MUg/L). However, UV irradiation did not shift the formation of DBPs from IOM to more brominated species, since the BSFs of trihalomethanes, dihaloacetic acids, trihaloacetic acids, and dihaloacetonitriles almost kept unchanged during UV-chlorine process. As for UV-chloramine process, UV irradiation decreased the BSFs of trihalomethanes, while increased the BSFs of dihaloacetic acid for both EOM and IOM. Overall, the UV pretreatment process is a potential technology in treating algae-rich water. PMID- 29236245 TI - [Relevance of type of diagnosis and occupational status for the results of psychiatric rehabilitation]. AB - OBJECTIVE: The specific effectiveness of psychiatric rehabilitation has been confirmed in numerous studies. Of particular interest is to what extend different results can be observed regarding the occupational status and type of mental illness of patients. Unemployment at the start of treatment is generally deemed to be a disadvantage for treatment outcome. Weaker treatment effects have also been reported for some types of mental illnesses, such as pain- und somatoform disorders. METHODS: Results from the evaluation of a sample of 2260 patients form the psychiatric rehabilitation clinic Gars am Kamp were analyzed, with regard to the occupational status and type of mental illness of patients. Changes in general symptom severity, quality of life and functioning were assessed. RESULTS: Regarding the occupational status, overall unemployed patients suffered from higher degrees of global symptom severity and the lower levels of global quality of life compared to employed and retired patients. However, improvements in the course of rehabilitative treatment could be observed regardless of the occupational status of patients. Regarding the type of mental illness, overall patients with burnout (Z73.0) reported the lowest levels of global symptom severity and highest degree of global quality of life. In comparison patients with somatoform disorders (F45) showed the lowest degree of global quality of life. However, positive treatment effects regarding general symptom severity and health related quality of life could be observed regardless of the type of mental illness (diagnosis) of patients. In respect to the improvement of global functioning small differences in absolute treatment effects were detected depending on the type of diagnosis of patients. However, relative treatment effects in respect to global functioning were comparable for all types of diagnosis. CONCLUSIONS: Improvements in the course of rehabilitative treatment regarding general symptom severity, quality of life and global functioning can be obtained independent of occupational status and type of mental illness of patients. PMID- 29236246 TI - Multimycotoxin analysis of South African Aspergillus clavatus isolates. AB - Aspergillus clavatus poisoning is a neuromycotoxicosis of ruminants that occurs sporadically across the world after ingestion of infected feedstuffs. Although various toxic metabolites are synthesized by the fungus, it is not clear which specific or group of mycotoxins induces the syndrome. A. clavatus isolates were deposited in the culture collection of the Biosystematics Division, Plant Protection Research Institute, Agricultural Research Council during incidences of livestock poisoning (1988-2016). Six isolates were still viable and these plus three other South African isolates that were also previously deposited in the collection were positively identified as A. clavatus based on morphology and beta tubulin sequence data. The cultures were screened for multiple mycotoxins using a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Twelve A. clavatus metabolites were detected. The concentrations of the tremorgenic mycotoxins (i.e., tryptoquivaline A and its related metabolites deoxytryptoquivaline A and deoxynortryptoquivaline) were higher than patulin and cytochalasin E. Livestock owners should not feed A. clavatus-infected material to ruminants as all the South African A. clavatus isolates synthesized the same compounds when cultured under similar conditions. PMID- 29236247 TI - 5'-Bromouridine IP Chase (BRIC)-Seq to Determine RNA Half-Lives. AB - Analysis of RNA stability at genome-wide level is an advanced method in RNA biology that examines the half-life of each transcript. In particular, a pulse labeling method using uridine analogs enables the determination of half-life of each transcript under physiologically undisturbed conditions. The technique involves pulse labeling of endogenous RNAs in mammalian cells with 5' bromouridine (BrU), followed by measuring the chronological decrease of BrU labeled RNAs using deep sequencing (BRIC-seq). Here, we describe a detailed protocol and technical tips for BRIC-seq. PMID- 29236248 TI - Determining mRNA Decay Rates Using RNA Approach to Equilibrium Sequencing (RATE Seq). AB - RATE-seq is a 4-thiouracil (4-tU)-based method that enables the in vivo measurement of transcriptome-wide RNA degradation rates. 4-tU is an analog of uracil that is rapidly incorporated into newly synthesized RNA and facilitates the conjugation of a biotinylated molecule containing a reactive thiol group. The biotinylated RNA can then be fractionated from the unlabeled RNA with streptavidin magnetic beads. By adding 4-tU to a culture of cells growing in steady-state conditions, fractionating the labeled population of RNA at multiple time points following 4-tU addition, and quantifying the abundance of newly transcribed RNAs using RNAseq, it is possible to estimate the degradation rates of all transcripts in a single experiment. The analysis of the RATE-seq data entails normalization of RNAseq libraries to thiolated RNA spike-ins and nonlinear model fitting to estimate the degradation rate constant for each RNA species. PMID- 29236249 TI - Metabolic Labeling of Newly Synthesized RNA with 4sU to in Parallel Assess RNA Transcription and Decay. AB - The development of genome-wide RNA profiling technologies greatly facilitates the global analysis of gene expression. However, such technologies alone could not distinguish the contribution to cellular RNA abundance by transcription versus decay. To overcome such limitation, metabolic labeling of newly synthesized RNA with 4-thiouridine (4sU) combined with genome-wide RNA profiling was used to in parallel measure RNA transcription and decay. Here, we describe the detailed protocol for using metabolic labeling with 4sU to separate newly synthesized RNA from the preexisting RNA in mammalian cells. PMID- 29236250 TI - Measuring mRNA Decay in Budding Yeast Using Single Molecule FISH. AB - Cellular mRNA levels are determined by the rates of mRNA synthesis and mRNA decay. Typically, mRNA degradation kinetics are measured on a population of cells that are either chemically treated or genetically engineered to inhibit transcription. However, these manipulations can affect the mRNA decay process itself by inhibiting regulatory mechanisms that govern mRNA degradation, especially if they occur on short time-scales. Recently, single molecule fluorescent in situ hybridization (smFISH) approaches have been implemented to quantify mRNA decay rates in single, unperturbed cells. Here, we provide a step by-step protocol that allows quantification of mRNA decay in single Saccharomyces cerevisiae using smFISH. Our approach relies on fluorescent labeling of single cytoplasmic mRNAs and nascent mRNAs found at active sites of transcription, coupled with mathematical modeling to derive mRNA half-lives. Commercially available, single-stranded smFISH DNA oligonucleotides (smFISH probes) are used to fluorescently label mRNAs followed by the quantification of cellular and nascent mRNAs using freely available spot detection algorithms. Our method enables quantification of mRNA decay of any mRNA in single, unperturbed yeast cells and can be implemented to quantify mRNA turnover in a variety of cell types as well as tissues. PMID- 29236251 TI - PAR-CLIP for Discovering Target Sites of RNA-Binding Proteins. AB - RNA-binding proteins (RBPs) establish posttranscriptional gene regulation (PTGR) by coordinating the maturation, editing, transport, stability, and translation of cellular RNAs. A variety of experimental approaches have been developed to characterize the RNAs associated with RBPs in vitro as well as in vivo. Our laboratory developed Photoactivatable-Ribonucleoside-Enhanced Cross-Linking and Immunoprecipitation (PAR-CLIP), which in combination with next-generation sequencing enables the identification of RNA targets of RBPs at a nucleotide level resolution. Here we present an updated and condensed step-by-step PAR-CLIP protocol followed by the description of our RNA-seq data analysis pipeline. PMID- 29236252 TI - Characterizing mRNA Sequence Motifs in the 3'-UTR Using GFP Reporter Constructs. AB - GFP reporter constructs are widely used as an expression system for studying the function of regulatory sequence motifs (cis elements) within the 3'-UTRs (3' untranslated regions) of mRNAs. Here we provide details on the characterization of individual sequence motifs, which typically regulate mRNA decay and translation. In addition, we describe methods to identify trans factors required for the function of such elements. To facilitate efficient identification of novel functional 3'-UTR motifs, we describe a screening approach based on dual color fluorescence reporter constructs. Such screening approaches can be used to test large collections of defined sequence or libraries of random sequences. PMID- 29236254 TI - Integration of ENCODE RNAseq and eCLIP Data Sets. AB - During the last decade, the study of mRNA decay has largely benefited from an increasing number of high-throughput assays that emerged from developments in next generation sequencing (NGS) technologies as well as mass spectrometry. While assay-specific data analysis is often reported and software made available many researchers struggle with the overwhelming challenge of integrating data from diverse assays, different sources, and of different formats.We here use Python, R, and bash to analyze and integrate RNAseq and eCLIP data publicly available from ENCODE. Annotation is performed with biomart, motif analysis with MEME and finally a functional enrichment analysis using DAVID. This analysis is centered on KHSRP eCLIP data from K562 cell as well as RNAseq data from KHSRP knockdown and respective mock controls. PMID- 29236253 TI - iCLIP of the PIWI Protein Aubergine in Drosophila Embryos. AB - Piwi-interacting RNAs (piRNAs) are a class of small noncoding RNAs bound to specific Argonaute proteins, the PIWI proteins. piRNAs target mRNAs by complementarity to silence them; they play an important role in the repression of transposable elements in the germ line of many species. piRNAs and PIWI proteins are also involved in diverse biological processes through their role in the regulation of cellular mRNAs. In the Drosophila embryo, they contribute to the maternal mRNA decay occurring during the maternal-to-zygotic transition. CLIP (UV cross-linking and immunoprecipitation) techniques have been used to identify target mRNAs of Argonaute proteins. Here we describe the iCLIP (individual nucleotide resolution CLIP) protocol that we have adapted for the PIWI protein Aubergine in Drosophila embryos. PMID- 29236255 TI - Identifying miRNA Targets Using AGO-RIPseq. AB - microRNAs (miRNA) are small, noncoding RNAs that bind to messenger RNAs (mRNAs) and regulate their activity. They are, therefore, important posttranscriptional regulators. In recent years it has become clear that miRNAs regulate large genetic networks, rather than single genes, and that one gene can be targeted by several miRNAs. To understand the role of miRNAs in cells or tissues, it is therefore important to analyze the targetome of miRNAs. Here, we present a technique called Argonaute-RNA Immunoprecipitation (AGO-RIP) which takes advantages of the fact that miRNAs and their targets are directly bound by the Argonaute protein family. With this approach quantitative, genome-wide analysis of miRNA targets is possible. In this chapter we describe the RIP-methodology and provide advice for RNA sequencing and bioinformatic analyses. PMID- 29236256 TI - Integrated Analysis of miRNA and mRNA Expression Profiles to Identify miRNA Targets. AB - miRNAs are involved in various biological processes and different diseases through interacting with their target mRNAs. Therefore, deciphering miRNA targets is important for diagnostics and therapeutics. However, it is still complex and expensive to do large scale screening for miRNA alterations and identify their downstream miRNA targets. Recently, integrating analysis of miRNA expression profiles and mRNA expression levels has been used to successfully identify the most prominent interactions. Here, we present a protocol that combines both expression data and computational prediction to refine the microarray result for identifying the miRNA targets. Many details are also provided to help researchers choose more appropriate tools and methods for a given type of application. Available web-based resources and experimental conditions for functional enrichment and validation of miRNA targets are also summarized. PMID- 29236257 TI - Identifying RISC Components Using Ago2 Immunoprecipitation and Mass Spectrometry. AB - Complex immunoprecipitation (Co-IP) is a powerful technique for precipitating an intact protein complex out of solution and cell lysates using an antibody that specifically binds to a particular protein in a large complex of proteins. Mass spectrometry (MS) is used to identify, sequence, and quantify proteins. RNA induced silencing complexes (RISCs), Ago2 centered protein assemblies, are essential for miRNA mediated RNA decay and gene expression regulation; however, the complete list of RISCs is unknown. Here we describe methods used to combine IP and MS to identify new components of RISCs. PMID- 29236258 TI - Using Tet-Off Cells and RNAi Knockdown to Assay mRNA Decay. AB - Cellular mRNA levels are determined by the competing forces of transcription and decay. A wide array of cellular mRNA decay pathways carry out RNA turnover either on a constitutive basis or in response to changing cellular conditions. Here, we outline a method to investigate mRNA decay that employs RNAi knockdown of known or putative decay factors in commercially available Tet-off cell systems. Reporter mRNAs of interest are expressed under the control of a tetracycline regulated promoter, allowing pulse-chase mRNA decay assays to be conducted. Levels of reporter and constitutively expressed control RNAs throughout the decay assay time course are detected by traditional northern blot analysis and used to calculate mRNA half-lives. We describe the utility of this approach to study nonsense-mediated mRNA decay substrates and factors, but it can be readily adapted to investigate key mechanistic features that dictate the specificity and functions of any mRNA decay pathway. PMID- 29236259 TI - Identifying Cellular Nonsense-Mediated mRNA Decay (NMD) Targets: Immunoprecipitation of Phosphorylated UPF1 Followed by RNA Sequencing (p-UPF1 RIP Seq). AB - Recent progress in the technology of transcriptome-wide high-throughput sequencing has revealed that nonsense-mediated mRNA decay (NMD) targets ~10% of physiologic transcripts for the purpose of tuning gene expression in response to various environmental conditions. Regardless of the eukaryote studied, NMD requires the ATP-dependent RNA helicase upframeshift 1 (UPF1). It was initially thought that cellular NMD targets could be defined by their binding to steady state UPF1, which is largely hypophosphorylated. However, the propensity for steady-state UPF1 to bind RNA nonspecifically, coupled with regulated phosphorylation of UPF1 on an NMD target serving as the trigger for NMD, made it clear that it is phosphorylated UPF1 (p-UPF1), rather than steady-state UPF1, that can be used to distinguish cellular NMD targets from cellular RNAs that are not. Here, we describe the immunoprecipitation of p-UPF1 followed by RNA sequencing (p-UPF1 RIP-seq) as a transcriptome-wide approach to define physiologic NMD targets. PMID- 29236261 TI - Reactivation Assay to Identify Direct Targets of the Nonsense-Mediated mRNA Decay Pathway in Drosophila. AB - Transcriptome analysis provides a snapshot of cellular gene expression and is used to determine how cells and organisms respond to genetic or environmental changes. Identifying the transcripts whose expression levels are regulated directly by the manipulation being examined from those whose expression changes as a secondary cause from the primary changes requires additional analyses. Here we present a technique used to distinguish direct targets of the nonsense mediated mRNA decay (NMD) pathway in Drosophila from secondary gene expression effects caused by loss of this pathway. This technique uses pulsed reexpression of an essential NMD gene in Drosophila lacking this NMD factor, followed by analysis of the transcriptome over time. In this way, RNAs with a rapid reduction in expression upon reactivation of NMD activity, corresponding to primary NMD targets, can be identified. This technique could potentially be modified to identify direct targets of other mRNA decay mechanisms in Drosophila or other organisms. PMID- 29236260 TI - Generation of Cell Lines Stably Expressing a Fluorescent Reporter of Nonsense Mediated mRNA Decay Activity. AB - Nonsense-mediated mRNA decay (NMD) is a mechanism of mRNA surveillance ubiquitous among eukaryotes. Importantly, NMD not only removes aberrant transcripts with premature stop codons, but also regulates expression of many normal genes. A recently introduced dual-color fluorescent protein-based reporter enables analysis of NMD activity in live cells. In this chapter we describe the method to generate stable transgenic cell lines expressing the splicing-dependent NMD reporter using consecutive steps of lentivirus transduction and Tol2 transposition. PMID- 29236262 TI - Studying Nonsense-Mediated mRNA Decay in Mammalian Cells Using a Multicolored Bioluminescence-Based Reporter System. AB - The nonsense-mediated mRNA decay (NMD) pathway degrades aberrant transcripts containing premature translation termination codons (PTCs) and also regulates the levels of many normal mRNAs containing NMD-inducing features. The activity of this pathway varies considerably in different cell types and can change in response to developmental and environmental cues. Modulating NMD activity represents a potential therapeutic avenue for certain genetic disorders and cancers. Simple reporter systems capable of faithfully assessing NMD activity in mammalian cells greatly facilitate both basic and translational research on NMD. Here we describe a simple and effective method for assaying NMD specifically and quickly in live mammalian cells using a multicolored bioluminescence-based reporter system. This reporter can be transiently or stably introduced into cultured cells as well as animals, and NMD activity can be accurately assessed by bioluminescence imaging, western blot, or RT-qPCR. PMID- 29236263 TI - 2-D to 3-D conversion: The future of medical imaging. PMID- 29236264 TI - Skin necrosis in a magnet-based bone-conduction implant. PMID- 29236265 TI - Nasopharyngeal papillary adenocarcinoma. PMID- 29236266 TI - Proliferative pilomatricoma of the eyebrow in a 94-year-old patient. PMID- 29236268 TI - Presbycusis-peripheral and central. PMID- 29236267 TI - Myeloid sarcoma of the thyroid. PMID- 29236269 TI - The value of ASSR threshold-based bilateral hearing aid fitting in children with difficult or unreliable behavioral audiometry. AB - We conducted an analysis to assess the relative contribution of auditory brainstem response (ABR) testing and auditory steady-state response (ASSR) testing in providing appropriate hearing aid fitting in hearing-impaired children with difficult or unreliable behavioral audiometry. Of 150 infants and children who had been referred to us for hearing assessment as part of a neonatal hearing screening and cochlear implantation program, we identified 5 who exhibited significant discrepancies between click-ABR and ASSR testing results and difficult or unreliable behavioral audiometry. Hearing aid fitting in pediatric cochlear implant candidates for a trial period of 3 to 6 months is a common practice in many implant programs, but monitoring the progress of the amplified infants and providing appropriate hearing aid fitting can be challenging. If we accept the premise that we can assess the linguistic progress of amplified infants with an acceptable degree of certainty, the auditory behavior that we are monitoring presupposes appropriate bilateral hearing aid fitting. This may become very challenging in young children, or even in older children with difficult or unreliable behavioral audiometry results. This challenge can be addressed by using data from both ABR and ASSR testing. Fitting attempts that employ data from only ABR testing provide amplification that involves the range of spoken language but is not frequency-specific. Hearing aid fitting should also incorporate and take into account ASSR data because reliance on ABR testing alone might compromise the validity of the monitoring process. In conclusion, we believe that ASSR threshold-based bilateral hearing aid fitting is necessary to provide frequency-specific amplification of hearing and appropriate propulsion in the prelinguistic vocalizations of monitored infants. PMID- 29236270 TI - Endoscopic endonasal management of recurrent maxillary mucoceles using biliary T tube stenting. AB - Mucoceles of the paranasal sinus can be managed endoscopically with an extremely low recurrence rate. Frontal sinus mucoceles can sometimes be prevented from closing and reforming by stenting, which to the best of our knowledge has not yet been reported in the maxillary sinus. We describe the cases of 5 patients-3 men and 2 women, aged 47 to 75 years (mean: 59.6)-with a recurrent and intractable maxillary sinus mucocele that was managed with biliary T-tube stenting. The indications for stenting included recurrent episodes of mucocele with or without a lateral location with a relatively thick bony wall. A latex rubber pediatric biliary T-tube was endoscopically inserted through a window opening into the marsupialized mucocele. The stent was removed 6 to 14 months postoperatively in 4 cases; in the other case, the stent remained adequately positioned for 35 months. None of the patients experienced signs or symptoms of recurrence. We conclude that a T-tube stent can be used successfully to maintain long-term patency in patients with a recurrent and intractable maxillary mucocele, with patency being maintained even after removal of the stent. PMID- 29236271 TI - Changes in abnormal muscle tension pattern after fiberoptic injection laryngoplasty. AB - We performed a retrospective chart review to compare the presence and types of abnormal muscle tension patterns (MTPs) in patients who had been diagnosed with glottal insufficiency before and after fiberoptic injection laryngoplasty. The main cause of glottal insufficiency had been unilateral vocal fold paralysis. Our review included an analysis of the medical records and laryngeal videostroboscopic recordings of 16 patients-9 men and 7 women, aged 25 to 87 years (mean: 59). Stroboscopic frames were analyzed for the presence of one or more types of abnormal MTP. Statistical analysis was performed to determine the significance of the change in scores for type II and type III MTP before injection and 1 month after injection. Before injection laryngoplasty, 15 of the 16 patients exhibited evidence of an abnormal MTP; 10 patients had MTP II only, 2 had MTP III only, and 3 patients had both. The mean percentage of frames showing MTP (i.e., MTP score) in patients with MTP II was 66.2% before the injection and 28.9% 1 month after; the decrease was statistically significant (p = 0.001). For MTP III, the corresponding figures were 71.6 and 37.7% (p = 0.043). We conclude that injection laryngoplasty has a positive effect on reducing muscle tension in patients with glottal insufficiency. PMID- 29236272 TI - Medical malpractice and transoral robotic surgery: Evaluation and some preemptive thoughts. AB - Medical malpractice is costly and disruptive, and it is important to prevent. We conducted a study with the objective to look at medical malpractice in robotic surgery overall, to evaluate reasons for litigation, and to comment on possible strategies to avoid litigation with transoral robotic surgery. We used the Westlaw computerized database to identify all state and federal verdict summaries in medical malpractice cases. We found 17 cases alleging malpractice that involved the use of robotic surgery. In all, the plaintiffs in 6 cases (35%) contended that an open rather than a robotic approach should have been used, 5 (29%) alleged negligent credentialing, 4 (24%) alleged training deficiencies, 2 (12%) alleged manufacturing problems, and 1 (6%) charged that robotic surgery should have been performed instead of open surgery (1 case involved two of these allegations). In 11 cases (65%), plaintiffs charged that robotic surgery contributed to an undesirable outcome, and in 6 cases (35%) they raised concerns about informed consent. In all, only 5 of the 17 lawsuits (29%) resulted in plaintiff verdicts or settlements; damages ranged from $95,000 to $7.5 million. We believe the courts should not play a major role in establishing safety guidelines for the introduction of new technology such as robotic surgery. Instead, training and credentialing guidelines should be established by appropriate national associations and societies to assist hospitals in doing so. PMID- 29236273 TI - Prognosticating hearing outcome in patients with idiopathic sudden sensorineural hearing loss by means of otoacoustic emissions and auditory brainstem response. AB - This is an analytic-descriptive study, parallel with a randomized, controlled trial performed at Amir'Alam Hospital, a tertiary referral center, with the aim of evaluating the correlation between otoacoustic emission (OAE) and auditory brainstem response (ABR) findings with hearing outcome after treatment of idiopathic sudden sensorineural hearing loss (SSNHL). Sixty patients with idiopathic SSNHL who presented to the emergency services and otology clinics between 2012 and 2014, and whose symptoms had begun <10 days previously, enrolled in this study. Before commencing treatment, distortion-product OAE (DP-OAE) and ABR were performed for all patients. They also underwent magnetic resonance imaging +/- gadolinium. Therapeutic intervention was done in a parallel randomized, controlled trial, and responders to the medical therapy were selected for our final analysis. There was no significant correlation between the OAE record and responsiveness to treatment, but there was a correlation between ABR presence and the probability of responsiveness in patients with profound hearing loss who responded to medical therapy and had at least wave V ABR. However, in those who had no recorded wave, the response to treatment was variable. In conclusion, in patients with profound hearing loss, studying the waves of ABR could be a factor in predicting hearing loss resolution after treatment. PMID- 29236274 TI - Outcomes of adenotonsillectomy in severe pediatric obstructive sleep apnea. AB - We conducted a retrospective chart review to examine the efficacy of adenotonsillectomy for the treatment of severe obstructive sleep apnea (OSA) in children. Our study population was made up of 85 patients-58 boys and 27 girls, aged 1 to 17 years (mean: 6.9 +/- 4.4)-with severe OSA who had undergone adenotonsillectomy and pre- and postoperative attended polysomnography (PSG) over a 4-year period. Severe OSA was defined as an apnea-hypopnea index (AHI) of >10 events per hour of sleep. Patients who had an underlying genetic or craniofacial anomaly were excluded. In addition to demographic and PSG data, we compiled information on selected characteristics of patients according to postoperative residual AHIs of <=5 and >5. Finally, information on body mass index z score was available on 72 patients; the mean score was 1.55 +/- 1.51, with 36 patients (50.0%) fulfilling the criteria for obesity. In the group as a whole, we found that adenotonsillectomy resulted in a significant reduction in AHI from 35.4 to 7.1 (p < 0.001). We also found an improvement in mean oxygen saturation nadir from 75.2 to 85.5 (p < 0.001). Postoperatively, only 8 patients (9.4%) achieved an AHI of <=1; AHIs were >1 to <=5 in 39 patients (45.9%), >5 to <=10 in 24 patients (28.2%), and >10 in 14 patients (16.5%). A significantly higher proportion of boys had a residual AHI of >5 after surgery compared with those whose postoperative AHI was <=5 (78.9 vs. 59.6%; p = 0.04). We conclude that adenotonsillectomy leads to a significant improvement in sleep-disordered breathing in children with severe OSA, but residual disease is common so close postoperative follow-up is essential. PMID- 29236275 TI - Multidisciplinary management of a giant cervico-mediastinal liposarcoma: A case report and literature review. AB - Liposarcomas are rare mesenchymal tumors that usually develop in lower extremities or retroperitoneum; cervico-mediastinal presentation is quite uncommon. These neoplasms are commonly diagnosed at a late stage because they remain asymptomatic until nearby structures are compressed. This makes radical excision particularly challenging. To date, alternative chemoradiotherapy protocols have not yet been standardized. We report a case of a 55-year-old man with a right laterocervical mass and without substantial symptoms. Fine-needle aspiration cytology results were compatible with a well-differentiated liposarcoma. Contrast-enhanced magnetic resonance imaging revealed the magnitude of the mass, which was expanding into the mediastinum; displacing the trachea, esophagus, cervical neurovascular bundle, and thoracic aorta; and encasing the brachiocephalic artery. Compression of the left brachiocephalic vein resulted in a focal enhancement spot in the fourth liver segment, the expression of superior vena cava compression, which can promote the development of collateral venous pathways, such as the caval-mammary-phrenic-hepatic capsule-portal venous pathway. The mass was successfully excised by a team of surgical subspecialists (otorhinolaryngologists and thoracic, cardiac, and vascular surgeons). Adjuvant tomotherapy was administered to increase local disease control. The patient remained disease-free 38 months postoperatively. This case underlines the importance of accurate preoperative radiologic evaluation in patients presenting with neck masses but without substantial symptoms. Because of the involvement of many critical structures, the cooperation of many surgical subspecialties is mandatory to achieve a satisfying oncologic outcome. PMID- 29236276 TI - 5-HT7 receptors are over-expressed in patients with nasal polyps. AB - Nasal polyposis (NP) is an inflammatory disease of the paranasal sinuses and nasal cavity. The primary purpose of our study is to determine the expression of 5-HT7 receptors both in nasal polyps and in healthy tissue in the nasal cavity. The subsequent aim is to compare the expression of 5-HT7 receptors in patients with NP and in inferior turbinate tissue (control). The study included 60 participants (40 with NP and 20 controls) aged 35 to 62 years. Nasal polyp samples were collected from all patients and relative 5-HT7 receptor expression analyses were performed. Reverse transcription polymerase chain reaction analysis of nasal polyps and control tissue identified 5-HT7 receptor expression in the nasal cavities of controls. This expression was approximately 67 times higher in nasal polyp tissue than in healthy tissue. Our study identifies the expression of 5-HT7 receptors in the nasal cavity for the first time and the first demonstration of increased 5-HT7 receptor expression in tissue from nasal polyps, which occur in the paranasal sinuses and nasal cavity. PMID- 29236277 TI - Clouds of different colors: A prospective look at head and neck surgical resident call experience. AB - Graduate medical education programs typically set up call under the assumption that residents will have similar experiences. The terms black cloud and white cloud have frequently been used to describe residents with more difficult (black) or less difficult (white) call experiences. This study followed residents in the department of head and neck surgery during call to determine whether certain residents have a significantly different call experience than the norm. It is a prospective observational study conducted over 16 months in a tertiary care center with a resident training program in otolaryngology. Resident call data on total pages, consults, and operative interventions were examined, as well as subjective survey data about sleep and perceived difficulty of resident call. Analysis showed no significant difference in call activity (pages, consults, operative interventions) among residents. However, data from the resident call surveys revealed perceived disparities in call difficulty that were significant. Two residents were clearly labeled as black clouds compared to the rest. These residents did not have the highest average number of pages, consults, or operative interventions. This study suggests that factors affecting call perception are outside the objective, absolute workload. These results may be used to improve resident education on sleep training and nighttime patient management in the field of otolaryngology and may influence otolaryngology residency programs. PMID- 29236278 TI - Head and neck surgical reconstruction in Operation Iraqi Freedom and Operation Enduring Freedom-Afghanistan: A systematic review. AB - Historically, head and neck injuries constituted 16 to 20% of all nonfatal combat injuries. However, advances in body and vehicle armor in the context of the use of ambushes and improvised explosive devices by enemy combatants have resulted in fewer fatalities from head and neck wounds, and thus the incidence of nonfatal head and neck injuries has risen to as high as 52%. Despite this increase, data regarding specific injury distributions, surgical cases, and approaches to repair are lacking in the current literature. We conducted a study to systematically review the current literature regarding head and neck injuries and reconstructions during Operation Iraqi Freedom and Operation Enduring Freedom Afghanistan. We found 44 articles that met our inclusion criteria. These articles covered 17,461 head and neck wounds sustained by 12,105 patients. Superficial soft-tissue facial injuries were most common wounds (31.7% of cases), followed by wounds to the neck (25.2%) and midface (17.9%). The 44 articles listed 5,122 discrete surgical reports covering 5,758 procedures. Of these procedures, simple facial laceration repairs (25.2%) and ophthalmologic surgeries (12.1%) were the most common soft-tissue repairs, and mandibular reconstructions (11.3%) were the most common type of bony reconstruction. Major flap reconstructions for coverage were required in only 0.4% of procedures. This information will be valuable for educating those involved in otolaryngology training programs, as well as civilian otolaryngologists regarding the types of injury patterns they should expect to see and treat in the returning veteran population. PMID- 29236279 TI - The maxillary nerve block for in-office hybrid balloon sinus dilation procedures: A preliminary study. AB - Transitioning of rhinologic procedures from the operating room to the office setting in selected patients is a rising trend. An effective pain-control, patient-preparation protocol is essential, especially with advanced in-office rhinologic procedures such as hybrid balloon sinus dilation (BSD), in which other procedures such as ethmoidectomy, turbinate reduction, and other procedures are concomitantly performed. A regimen using oral sedation, topical tetracaine gel, topical tetracaine/epinephrine-soaked cottonoid packs, and intranasal local infiltrative anesthesia can vary significantly in effectiveness and be suboptimal at times (as determined by using treated patients as historical controls). A modification of this regimen was subsequently used, incorporating the maxillary nerve block, and qualitative differences were then assessed retrospectively between the two regimens. Twenty-five consecutive patients were retrospectively studied who underwent hybrid BSD procedures in the office setting using the maxillary nerve-block regimen modification. All patients underwent BSD of the sphenoid, frontal, and maxillary sinuses with anterior and partial posterior ethmoidectomies. Five patients also underwent septoplasty, and 18 patients underwent inferior turbinate reduction procedures. Twenty-four patients received oral sedation, and all patients received topical tetracaine/epinephrine-soaked cottonoid packs. The topical tetracaine gel was dropped after 5 patients because it was not felt to be needed anymore. No intranasal local infiltrative anesthesia was used. Several qualitative differences were observed after modifying the patient-preparation regimen incorporating the maxillary nerve block. The most important observation seen with this modification was a consistently reproducible, dense anesthesia coverage over the entire nasal cavity with good paranasal sinus coverage. This modification eliminated intranasal bleeding and swelling associated with intranasal local anesthetic injections. No complications were encountered. This preliminary study provides support for use and further evaluation of the maxillary nerve block for in-office rhinologic procedures. If the trend continues to rise in performing advanced in-office rhinologic procedures in selected patients, the maxillary nerve block may find a place in the patient-preparation protocol. PMID- 29236280 TI - Intracranial abscess formation following sphenoid sinus occlusion with nasoseptal flap skull base reconstruction: A cautionary tale. AB - The formation of an intracranial abscess secondary to sphenoid sinus occlusion after nasoseptal flap skull base reconstruction has not been previously described. We report such a case that occurred at our institution in a 23-year old man who underwent flap reconstruction for a cerebrospinal fluid leak. We determined that occlusion of the sphenoid sinus outflow might have played a role in this complication. The patient was treated via a combined surgical and medical approach that entailed a bur-hole craniotomy and endoscopic debridement followed by administration of an intravenous antibiotic. The patient recovered without long-term deficit. When closing a defect of the posterior ethmoid and sphenoid skull base, especially with a pedicled graft, care must be taken to reduce the potential for retention of secretions and blood because this may lead to an intracranial complication. PMID- 29236281 TI - Preoperative evaluation and intraoperative protection of the facial nerve in congenital aural atresia. AB - We conducted a prospective study to assess the value of high-resolution computed tomography (HRCT) in identifying facial nerve variations in patients with congenital aural atresia and to determine how they affect otologic reconstruction surgery. Our study population was made up of 65 patients (69 ears) aged 6 to 22 years (mean: 13.7) without regard to sex. They were classified into three groups according to their scores on the Jahrsdoerfer grading scale: 46 ears scored 8 or more, 18 had a score of 6 or 7, and 5 scored 5 or less. The course of each facial nerve as determined intraoperatively was compared with the preoperative HRCT findings. HRCT revealed that in most of the facial nerves, the tympanic segments overlapped the oval window partly or completely; this was confirmed by surgical findings in most cases. Three of the 69 facial nerves (4.3%) were bifurcated. It is interesting that in 1 ear in which the facial nerve completely covered the oval window, the angle of the second genu was acute, exhibiting a "sharp turn." We conclude that HRCT is undoubtedly of value in identifying the course of the facial nerve and is of critical importance in helping surgeons make correct decisions in otologic reconstruction surgery. PMID- 29236282 TI - Where am I? Transnasal esophagoscopy outside the normal esophagus. PMID- 29236284 TI - Endoscopic view of an acutely inflamed maxillary sinus. PMID- 29236283 TI - Retropharyngeal hematoma following botulinum toxin injection for abductor spasmodic dysphonia. PMID- 29236285 TI - Functioning of nitric oxide cycle in gastric mucosa of rats under excessive combined intake of sodium nitrate and fluoride. AB - In the article the function of nitric oxide (.NO) cycle in rat's gastric mucosa was assessed under excessive combined chronic fluoride and nitrate intake during 30 days. It was estimated that general nitric oxide synthase activity (NOS) was increased during excessive sodium fluoride intake meanwhile influence on gene-ral nitrate reduction was not statistically significant, but general nitrite reduction was increased. General arginase activity decreased. Excessive sodium nitrate intake decreased NOS activity, but increased nitrate, nitrite reduction and general arginase activity. Combined sodium nitrate and fluoride intake increased NOS by 18.9%, nitrate reduction by 71.7%, nitrite by 161.5%, arginase activity increase by 61.4%. The highest amounts of peroxynitrite were obtained from excessive sodium fluoride intake group, excessive sodium nitrate intake showed the lowest levels and combined excessive sodium nitrate and fluoride intake levels had intermediate results. Summarizing the data obtained, the authors have made a conclusion that combined excessive sodium nitrate and fluoride intake creates optimal conditions for functioning of nitrate-nitrite reductases. PMID- 29236286 TI - Corticosteroids for pneumonia. AB - BACKGROUND: Pneumonia is a common and potentially serious illness. Corticosteroids have been suggested for the treatment of different types of infection, however their role in the treatment of pneumonia remains unclear. This is an update of a review published in 2011. OBJECTIVES: To assess the efficacy and safety of corticosteroids in the treatment of pneumonia. SEARCH METHODS: We searched the Cochrane Acute Respiratory Infections Group's Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS on 3 March 2017, together with relevant conference proceedings and references of identified trials. We also searched three trials registers for ongoing and unpublished trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed systemic corticosteroid therapy, given as adjunct to antibiotic treatment, versus placebo or no corticosteroids for adults and children with pneumonia. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently assessed risk of bias and extracted data. We contacted study authors for additional information. We estimated risk ratios (RR) with 95% confidence intervals (CI) and pooled data using the Mantel-Haenszel fixed-effect model when possible. MAIN RESULTS: We included 17 RCTs comprising a total of 2264 participants; 13 RCTs included 1954 adult participants, and four RCTs included 310 children. This update included 12 new studies, excluded one previously included study, and excluded five new trials. One trial awaits classification.All trials limited inclusion to inpatients with community-acquired pneumonia (CAP), with or without healthcare-associated pneumonia (HCAP). We assessed the risk of selection bias and attrition bias as low or unclear overall. We assessed performance bias risk as low for nine trials, unclear for one trial, and high for seven trials. We assessed reporting bias risk as low for three trials and high for the remaining 14 trials.Corticosteroids significantly reduced mortality in adults with severe pneumonia (RR 0.58, 95% CI 0.40 to 0.84; moderate quality evidence), but not in adults with non-severe pneumonia (RR 0.95, 95% CI 0.45 to 2.00). Early clinical failure rates (defined as death from any cause, radiographic progression, or clinical instability at day 5 to 8) were significantly reduced with corticosteroids in people with severe and non-severe pneumonia (RR 0.32, 95% CI 0.15 to 0.7; and RR 0.68, 95% CI 0.56 to 0.83, respectively; high-quality evidence). Corstocosteroids reduced time to clinical cure, length of hospital and intensive care unit stays, development of respiratory failure or shock not present at pneumonia onset, and rates of pneumonia complications.Among children with bacterial pneumonia, corticosteroids reduced early clinical failure rates (defined as for adults, RR 0.41, 95% CI 0.24 to 0.70; high-quality evidence) based on two small, clinically heterogeneous trials, and reduced time to clinical cure.Hyperglycaemia was significantly more common in adults treated with corticosteroids (RR 1.72, 95% CI 1.38 to 2.14). There were no significant differences between corticosteroid-treated people and controls for other adverse events or secondary infections (RR 1.19, 95% CI 0.73 to 1.93). AUTHORS' CONCLUSIONS: Corticosteroid therapy reduced mortality and morbidity in adults with severe CAP; the number needed to treat for an additional beneficial outcome was 18 patients (95% CI 12 to 49) to prevent one death. Corticosteroid therapy reduced morbidity, but not mortality, for adults and children with non-severe CAP. Corticosteroid therapy was associated with more adverse events, especially hyperglycaemia, but the harms did not seem to outweigh the benefits. PMID- 29236287 TI - Characterization of a Norovirus-specific monoclonal antibody that exhibits wide spectrum binding activities. AB - Noroviruses (NoVs) are increasingly recognized as the leading cause of acute non bacterial gastroenteritis worldwide. To screen for NoV-specific monoclonal antibodies (mAbs) with wide spectrum binding activities that could be used for the development of NoV-related detection reagents, we immunized mice with a combination of virus like particles (VLPs) derived from eight different genotypes (two from genogroup I and six from genogroup II), of which two (GI.7 and GII.2) were newly produced VLPs. Indirect enzyme-linked immunosorbent assay (ELISA) confirmed that two mAbs (8D8 and 10B11) bound to all eight major capsid proteins (VP1) with varied binding abilities. Epitope mapping using short peptides covering the N-terminal half of GII.3 VP1 indicated that the binding site of mAb 8D8 was located between amino acid 31 and 60. Multiple amino acid sequence alignment of VP1 suggested that this site harbors conservative sequences across all genogroups. Indirect and sandwich ELISA indicated that mAb 8D8 was unable bind intact VLPs. In summary, we successfully produced GI.7 and GII.2 VLPs using recombinant baculovirus expression system and a cross-reactive mAb by immunizing mice with eight different VLPs that might be useful in the studying and detecting NoVs. PMID- 29236288 TI - Disaster Preparedness: Biological Threats and Treatment Options. AB - Biological disasters can be natural, accidental, or intentional. Biological threats have made a lasting impact on civilization. This review focuses on agents of clinical significance, bioterrorism, and national security, specifically Category A agents (anthrax, botulism, plague, tularemia, and smallpox), as well as briefly discusses other naturally emerging infections of public health significance, Ebola virus (also a Category A agent) and Zika virus. The role of pharmacists in disaster preparedness and disaster response is multifaceted and important. Their expertise includes clinical knowledge, which can aid in drug information consultation, patient-specific treatment decision making, and development of local treatment plans. To fulfill this role, pharmacists must have a comprehensive understanding of medical countermeasures for these significant biological threats across all health care settings. New and reemerging infectious disease threats will continue to challenge the world. Pharmacists will be at the forefront of preparedness and response, sharing knowledge and clinical expertise with responders, official decision makers, and the general public. PMID- 29236289 TI - Assessment of cellular and serum proteome from tongue squamous cell carcinoma patient lacking addictive proclivities for tobacco, betel nut, and alcohol: Case study. AB - The intriguing molecular pathways involved in oral carcinogenesis are still ambiguous. The oral squamous cell carcinoma (OSCC) ranks as the most common type constituting more than 90% of the globally diagnosed oral cancers cases. The elevation in the OSCC incidence rate during past 10 years has an alarming impression on human healthcare. The major challenges associated with OSCC include delayed diagnosis, high metastatic rates, and low 5-year survival rates. The present work foundations on reverse genetic strategy and involves the identification of genes showing expressional variability in an OSCC case lacking addictive proclivities for tobacco, betel nut, and/or alcohol, major etiologies. The expression modulations in the identified genes were analyzed in 16 patients comprising oral pre-cancer and cancer histo-pathologies. The genes SCCA1 and KRT1 were found to down regulate while DNAJC13, GIPC2, MRPL17, IG-Vreg, SSFA2, and UPF0415 upregulated in the oral pre-cancer and cancer pathologies, implicating the genes as crucial players in oral carcinogenesis. PMID- 29236291 TI - Dysregulation of microRNA biogenesis machinery and microRNA/RNA ratio in skeletal muscle of amyotrophic lateral sclerosis mice. AB - INTRODUCTION: The pathology of amyotrophic lateral sclerosis (ALS) is associated with impaired RNA processing and microRNA (miRNA) dysregulation. Here we investigate the regulation of the members of the miRNA biogenesis pathways and total miRNA levels at different stages of the disease. METHODS: Muscle, brain, and spinal cord tissue were obtained from presymptomatic, symptomatic, and end stage superoxide dismutase 1 (SOD1)G93A mice. miRNA and transcript levels were measured by quantitative polymerase chain reaction. RESULTS: As the diseases progresses, several genes involved in miRNA biogenesis as well as the miRNA/total RNA (totRNA) ratio increased in the tibialis anterior (TA) muscle but not in the soleus or in neural tissue. DISCUSSION: We propose that a dysregulation in the miRNA/totRNA ratio in the TA muscle from SOD1G93A mice reflects a pathological increase in miRNA biogenesis machinery. Alterations in the miRNA/totRNA ratio influence the levels of reference noncoding RNAs and may therefore potentially compromise the accuracy of commonly used miRNA normalization strategies. Muscle Nerve 57: 838-847, 2018. PMID- 29236290 TI - An 8-generation family with X-linked Charcot-Marie-Tooth: Confirmation Of the pathogenicity Of a 3' untranslated region mutation in GJB1 and its clinical features. AB - INTRODUCTION: Mutations in gap junction protein beta 1 (GJB1) on the X chromosome represent one of the most common causes of hereditary neuropathy. We assessed manifestations associated with a rare 3' untranslated region mutation (UTR) of GJB1 in a large family with X-linked Charcot-Marie-Tooth disease (CMTX). METHODS: Clinical, electrophysiological, and molecular genetic analyses were performed on an 8-generation family with CMTX. RESULTS: There were 22 affected males and 19 symptomatic females, including an 83-year-old woman followed for 40 years. Electrophysiological studies showed a primarily axonal neuropathy. The c.*15C>T mutation in the GJB1 3' UTR was identified in 4 branches of the family with a log of odds (LOD) of 4.91. This created a BstE II enzyme recognition site that enabled detection by restriction digestion. DISCUSSION: The c.*15C>T mutation in the GJB1 3' UTR segregates with CMTX1 in 8 generations. Penetrance in males and females is essentially complete. A straightforward genetic method to detect this mutation is described. Muscle Nerve 57: 859-862, 2018. PMID- 29236292 TI - A novel report of MiR-4301 induces cell apoptosis by negatively regulating DRD2 expression in human breast cancer cells. AB - In several cancers, microRNA (miRNAs) play vital roles in tumor initiation, drug resistance, and metastasis. The aim of this study was to examine the expression levels of miR-4301 in human breast cancer and investigate whether its potential roles involved targeting Dopamine receptor D2 (DRD2). Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was also used to examine the expression levels of miR-4301 in human breast cancer cell lines MDA MB-231, MCF-7, and SKBR3. In these cell lines, MTT assay, immunofluorescence staining, caspase assay, proliferation assay, and flow cytometry were conducted to explore the potential functions of miR-4301. The effects of modulating miR 4301 on transcription levels of DRD2 were subsequently confirmed via qRT-PCR. miR 4301 expression levels were significantly decreased in human breast cancer specimens and cell lines (P < 0.05). Transfection of miR-4301 in breast cancer cells suppressed cell proliferation and induced apoptosis. Expression analysis indicated that miR-4301 was inversely correlated with DRD2 expression in breast cancer specimens. qRT-PCR showed that miR-4301 negatively regulated DRD2 expression. Downregulation of DRD2 expression in MDA-MB-231, MCF-7, and SKBR3 cells suppressed cell proliferation and promoted apoptosis. PMID- 29236293 TI - Real time PCR to evaluate HSV-2 shedding from anal and genital samples among men who have sex with men, living with HIV. AB - This study shows the relative quantification of HSV-2 by qPCR, using the MIQE Guidelines. The reaction efficiency was evaluated, and the relative quantification used the R = 2-DeltaCq method. The relative quantification of HSV 2 was conducted with anal and genital samples from men who have sex with men (MSM), living with HIV. The presence of a single amplification product was validated with a dissociation curves profile and the determination of the melting temperature. The limit of detection for beta-globin was determined as 3.3 * 10-5 ng/MUL, and for HSV-2 at 6.0 * 10-6 ng/MUL. The efficiency for beta-globin was 100.2% and for HSV-2 was 106.8%. From 336 MSM, 2.1% and 3.9% individuals presented anal or genital HSV-2 shedding, respectively. The HSV-2 viral load was 9.2 RU, individuals with fewer CD4+ presented higher HSV-2 viral load. The qPCR method is reproducible and has optimal reaction efficiency. PMID- 29236294 TI - Acute myeloid leukemia and myelodysplastic syndrome after adjuvant chemotherapy: A population-based study among older breast cancer patients. AB - BACKGROUND: Chemotherapy for early breast cancer is associated with a small risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The aim of this study was to determine the risk of developing AML or MDS after modern adjuvant chemotherapy in older breast cancer patients and to further define the risk of individual chemotherapy regimens. METHODS: Patients diagnosed with stage I to III breast cancer from 2003 to 2009 were identified in the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry Medicare linked databases. The development of AML/MDS, chemotherapy use, and comorbidities were identified with International Classification of Diseases, Ninth Revision and Healthcare Common Procedure Coding System codes. Analyses included descriptive statistics, cumulative incidences, and Cox proportional hazards models to estimate the hazard of AML/MDS after adjustments for clinically relevant covariates. RESULTS: In all, 92,110 patients were included; after a median follow-up of 85 months, the overall rates per 1000 person-years were 0.65 for AML and 1.56 for MDS. Patients who received an anthracycline (A) or anthracycline and taxane (A+T) regimen were more likely to develop AML (hazard ratio [HR] for A, 1.70; 95% confidence interval [CI], 1.16-2.50; HR for A+T, 1.68; 95% CI, 1.22-2.30) or MDS (HR for A, 2.18; 95% CI, 1.70-2.80; HR for A+T, 1.62; 95% CI, 1.29-2.03) than patients who did not receive chemotherapy. Patients using docetaxel and cyclophosphamide (TC) were not at increased risk for AML or MDS. CONCLUSIONS: Adjuvant chemotherapy is associated with a small but significant increase in the risk of AML and MDS, especially with regimens that include A. Longer follow-up is needed to confirm that risk is not increased with the recently adopted TC regimen. Cancer 2018;124:899-906. (c) 2017 American Cancer Society. PMID- 29236295 TI - Supporting Behaviour, Not Sex: The Women in Science Debate Re-Framed.... PMID- 29236297 TI - MRI change metrics of facioscapulohumeral muscular dystrophy: Stir and T1. AB - INTRODUCTION: MRI evaluation in facioscapulohumeral muscular dystrophy (FSHD) demonstrates fatty replacement and inflammation/edema in muscle. Our previous work demonstrated short T1 inversion recovery (STIR)-hyperintense (STIR+) signal in muscle 2 years before fatty replacement. We evaluated leg muscle STIR changes and fatty replacement within 14 months. METHODS: FSHD subjects received 2 MRI scans of thigh and calf over a 6.9- to 13.8-month interval. Quality of life measures were collected. One Radiologist rated muscle changes on a semi quantitative scale. RESULTS: Fifteen subjects completed longitudinal imaging. Four STIR + muscles and 3 STIR-normal (STIR-) muscles were rated as progressing to fatty tissue over the study period. DISCUSSION: STIR + muscles with confluent regions of fat at baseline increased more in fat, while STIR- muscles had increases in septal-fat over the study period. These changes may reflect two phases of FSHD, demonstrating MRI sensitivity is weighted toward gross pathological phases of the disease. Muscle Nerve 57: 905-912, 2018. PMID- 29236298 TI - Leptin: A new therapeutic target for treatment of diabetes mellitus. AB - Leptin is an endogenous protein having 167 amino acids and is derived from adipocytes. It has tertiary structure that resembles with that of the pro inflammatory cytokines family. The fundamental role of leptin is to maintain the energy homeostasis with the aid of its counter hormone called ghrelin, known as the "hunger hormone." Small quantities of leptin are also present in various tissues like ovary, placenta, pituitary gland, mammary gland, skeletal muscle, stomach, and lymphoid tissue. Expression of leptin is strongly associated with various inflammatory responses and immune system, and plays crucial role in the pathophysiology of obesity and development of diabetes mellitus (DM) and insulin resistance. The metabolic action of leptin is equally important as that of insulin in the pathophysiology of obesity and DM. Thereby, this review article tends to discuss the diverse and complicated role of leptin in the pathogenesis of DM. Furthermore, this article will highlight the signifying role of leptin as a therapeutic target by indicating the targeted treatment of DM through the appropriate understanding of advanced therapeutic approaches using leptin as a treatment strategy for DM. PMID- 29236296 TI - RNA Decay Factor UPF1 Promotes Protein Decay: A Hidden Talent. AB - The RNA-binding protein, UPF1, is best known for its central role in the nonsense mediated RNA decay (NMD) pathway. Feng et al. now report a new function for UPF1 it is an E3 ubiquitin ligase that specifically promotes the decay of a key pro muscle transcription factor: MYOD. UPF1 achieves this through its RING-like domain, which confers ubiquitin E3 ligase activity. Feng et al. provide evidence that the ability of UPF1 to destabilize MYOD represses myogenesis. In the future, it will be important to define other protein substrates of UPF1-driven ubiquitination and to determine whether this biochemical activity is responsible for some of UPF1's previously defined biological functions, including in development and stress responses. The exciting findings presented by Feng et al. open up the possibility that protein turnover and RNA turnover are coupled processes. PMID- 29236299 TI - Potential role of salt-bridges in the hinge-like movement of apicomplexa specific beta-hairpin of Plasmodium and Toxoplasma profilins: A molecular dynamics simulation study. AB - Profilin is one of the actin-binding proteins that regulate dynamics of actin polymerization. It plays a key role in cell motility and invasion. It also interacts with several other proteins notably through its poly-L-proline (PLP) binding site. Profilin in apicomplexa is characterized by a unique mini-domain consisting of a large beta-hairpin extension and an acidic loop which is relatively longer in Plasmodium species. Profilin is essential for the invasive blood stages of Plasmodium falciparum. In the current study, unbound profilins from Plasmodium falciparum (Pf), Toxoplasma gondii (Tg), and Homo sapiens (Hs) were subjected to molecular dynamics (MD) simulations for a timeframe of 100 ns each to understand the conformational dynamics of these proteins. It was found that the beta-hairpin of profilins from Pf and Tg shows a hinge-like movement. This movement in Pf profilin may possibly be driven by the loss of a salt-bridge within profilin. The impact of this conformational change on actin binding was assessed by docking three dimensional (3D) structures of profilin from Pf and Tg with their corresponding actins using ClusPro2.0. The stability of docked Pf profilin-actin complex was assessed through a 50 ns MD simulation. As Hs profilin I does not have the apicomplexa specific mini-domain, MD simulation was performed for this protein and its dynamics was compared to that of profilins from Pf and Tg. Using an immunoinformatics approach, potential epitope regions were predicted for Pf profilin. This has a potential application in the design of vaccines as they mapped to its unique mini-domain. PMID- 29236300 TI - Creepiness Creeps In: Uncanny Valley Feelings Are Acquired in Childhood. AB - The uncanny valley posits that very human-like robots are unsettling, a phenomenon amply demonstrated in adults but unexplored in children. Two hundred forty 3- to 18-year-olds viewed one of two robots (machine-like or very human like) and rated their feelings toward (e.g., "Does the robot make you feel weird or happy?") and perceptions of the robot's capacities (e.g., "Does the robot think for itself?"). Like adults, children older than 9 judged the human-like robot as creepier than the machine-like robot-but younger children did not. Children's perceptions of robots' mental capacities predicted uncanny feelings: children judge robots to be creepy depending on whether they have human-like minds. The uncanny valley is therefore acquired over development and relates to changing conceptions about robot minds. PMID- 29236301 TI - Synergistic effect of carnosine on browning of adipose tissue in exercised obese rats; a focus on circulating irisin levels. AB - The recent appreciation of the energy burning capacity of brown adipose tissue turns it to an attractive target for anti-obesity therapy. We sought to evaluate the effect of L-carnosine on browning of white adipose tissue in exercised obese rats. Sixty adult male Wistar albino rats, 7-8 week-old weighing 130-150 g, were allocated into six groups; with 10 rats in each, for an experimentation period of 12 weeks: (i) normal control rats fed a standard fat diet (SFD/control), (ii) normal control rats fed a standard diet and injected with L-carnosine (250 mg/kg, i.p,) for 6 weeks (SFD/CAR), (iii) high-fat diet (HFD)-induced obese rats for 12 weeks, (iv) HFD rats subjected to exercise training (HFD/EXE) for 6 weeks, (v) HFD rats injected with L-carnosine (250 mg/kg,i.p.) for 6 weeks (HFD/CAR) and, (vi) HFD rats subjected to exercise training and L-carnosine (HFD/EXE/CAR). At the end of the 12-week-experiment, the body weights and the serum levels of lipid profile, oxidative stress, and inflammatory markers as well as circulating myokines were investigated. Gastrocnemius muscles and inguinal adipose tissues were excised for the measurement of gene expression of muscle irisin, adipose tissue uncoupling protein1 (UCP1), CD137 and the protein level of p38MAPK. In addition, histopathological examination for the studied groups was performed. Both exercise training for 6 weeks and carnosine treatment significantly decreased body weight gain, ameliorated obesity-induced dyslipidemia, reduced the thiobarbituric acid reactive species (TBARS) and TNF-alpha, while increased total antioxidant capacity and IL-10. Furthermore, increases in serum irisin levels and the expression of adipose uncoupling protein-1 (UCP-1), adipose CD137, p38 MAPK, and muscular fibronectin type III domain-containing protein 5(FNDC5), the precursor of irisin gene expression, were correlated with these carnosine- and exercise-induced physiological improvements. The highest improvement was evident in the combined exercise and carnosine group which indicates that their beneficial effects in obese animals were synergistic. These findings suggest that L-carnosine may induce browning of adipose tissue through irisin stimulation, a phenomenon that could be related to its antioxidant, anti-inflammatory, and anti obesity effects. PMID- 29236302 TI - Recovery of hepatitis C specific T-cell responses after rituximab therapy in hepatitis C mixed cryoglobulinemic vasculitis. AB - Mixed cryoglobulinemic vasculitis is associated with monoclonal B cell expansion in patients with chronic hepatitis C (HCV) infection. B cell depletion therapy using rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from symptomatic disease. This study investigated whether B cell depletion therapy has an impact on activation of HCV-specific T cell phenotype and function. Nineteen patients with Hepatitis C mixed cryoglobulinemic vasculitis were treated with 4 cycles of rituximab (375 mg/m2 ) and variables were measured 6 months after therapy. Using flow cytometry and Enzyme-Linked Immunospot assay, the number of activated and tissue-like B cells and number of T cells expressing Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and multiple cytokines were measured before and after rituximab therapy. B cell depletion therapy is associated with a significant (P < 0.0001) decline in peripheral T cells with exhaustive phenotype, from pre-therapy to post-therapy-of rituximab (mean +/- standard error): CD4+ (16.9 +/- 0.9% to 8.9 +/- 1.0%) and CD8+ (6.8 +/- 0.6% to 3.0 +/- 0.5%) T cells expressing PD-1 and CD4+ (11.0 +/- 1.0% to 6.1 +/- 0.8%) and CD8+ (12.7 +/- 0.7% to 6.4 +/- 0.4%) T cells expressing TIM-3. In addition, there was a significantly higher percentage of peripheral CD8+ T cells responding to HCV peptide stimulation in vitro secreting IFN-gamma (4.55 +/- 0.3 to 9.6 +/- 1.0 IFN gamma/106 PBMCs, P < 0.0001), and more than one cytokine (1.3 +/- 0.1% to 3.8 +/- 0.2%, P < 0.0001) after therapy compared to pre-therapy. B cell depletion therapy results in recovery of T cell exhaustion and function in patients with HCV cryoglobulinemic vasculitis. PMID- 29236303 TI - Impact of antimicrobial stewardship programme on hospitalized patients at the intensive care unit: a prospective audit and feedback study. AB - AIMS: Inappropriate use of antibiotics is one of the most important factors contributing to the emergence of drug resistant pathogens. The purpose of this study was to measure the clinical impact of antimicrobial stewardship programme (ASP) interventions on hospitalized patients at the Intensive care unit at Palestinian Medical Complex. METHODS: A prospective audit with intervention and feedback by ASP team within 48-72 h of antibiotic administration began in September 2015. Four months of pre-ASP data were compared with 4 months of post ASP data. Data collected included clinical and demographic data; use of antimicrobials measured by defined daily doses, duration of therapy, length of stay, readmission and all-cause mortality. RESULTS: Overall, 176 interventions were made the ASP team with an average acceptance rate of 78.4%. The most accepted interventions were dose optimization (87.0%) followed by de-escalation based on culture results with an acceptance rate of 84.4%. ASP interventions significantly reduces antimicrobial use by 24.3% (87.3 defined daily doses/100 beds vs. 66.1 defined daily doses/100 beds P < 0.001). The median (interquartile range) of length of stay was significantly reduced post ASP [11 (3-21) vs. 7 (4 19) days; P < 0.01]. Also, the median (interquartile range) of duration of therapy was significantly reduced post-ASP [8 (5-12) days vs. 5 (3-9); P = 0.01]. There was no significant difference in overall 30-day mortality or readmission between the pre-ASP and post-ASP groups (26.9% vs. 23.9%; P = 0.1) and (26.1% vs. 24.6%; P = 0.54) respectively. CONCLUSIONS: Our prospective audit and feedback programme was associated with positive impact on antimicrobial use, duration of therapy and length of stay. PMID- 29236304 TI - Enterovirus detection in patients with acute gastroenteritis in Switzerland. AB - Acute gastroenteritis (GE) has a major impact on morbidity and mortality worldwide, yet comprehensive data regarding infectious agents including enteroviruses are scarce. We hypothesized that enteroviruses constitute a significant cause of acute GE. We analyzed 677 stool samples from 504 patients, which had been submitted for suspected infectious GE. 0.2 mL of stool suspension was extracted using the Abbott m2000sp robot and analysed by multiplex nucleic acid testing (NAT) using the Luminex xTAG gastrointestinal pathogen panel (GPP) as well as by specific NATs detecting enteroviruses and polioviruses. Median age of the patients was 6.6 years (IQR 1.1-50.6; pediatric <18 years). 292 of 677 (43%) samples were positive for at least one pathogen. Enterovirus was detected in 5.3% (36/677) as sole pathogen (67%), and more frequently in children (P = 0.0054). Only rotavirus (18.6%) and norovirus (12.1%) were more frequent. Clostridium difficile and Campylobacter jejuni were detected in 5.5% and 2.2% of stools, respectively. Adenovirus, E. coli O157, Salmonella, Shiga toxin-producing E. coli (STEC), Shigella, Giardia lamblia, Cryptosporidium, and Entamoeba histolytica were rare (<1% of samples). Vibrio cholerae, Yersinia enterocolitica, enterotoxigenic E. coli (ETEC) and poliovirus were not detected. Thus, non-polio enteroviruses are the third most frequent pathogen in acute GE suggesting that enteroviruses may play an important role in GE even in developed, industrial health care settings. PMID- 29236305 TI - Electrochromatographic performance of graphene and graphene oxide modified silica particles packed capillary columns. AB - Graphene oxide functionalized silica microspheres (GO@SiO2 ) were synthesized based on condensation reaction between amino from aminosilica particles and carboxyl groups from GO. Reduction of GO@SiO2 with hydrazinium hydroxide generated graphene modified silica particles (G@SiO2 ). GO@SiO2 and G@SiO2 packed capillary columns for capillary electrochromatography were thereafter fabricated by pressure slurry packing with single-particle frits. GO of 0.3 mg/mL in dispersion solution for GO@SiO2 synthesis was considered as a compromise between retaining and column efficiency whereas GO@SiO2 of 20 mg/mL in slurries for column packing was chosen for a homogenous and tight bed. Optimum mobile phases were acquired considering both electroosmotic flow and resolution at an applied voltage of -6 kV as the following: acetonitrile/phosphate buffer (10 mM, pH 7.0), 75:25 (v/v) for polycyclic aromatic hydrocarbons and 50:50 (v/v) for aromatic compounds. A comparison was made between electrochromatographic performances for three PAHs (naphthalene, fluorene and phenanthrene) and three aromatic compounds of various polarities (toluene, aniline and phenol) on bare aminosilica, GO@SiO2 and G@SiO2 packed columns, which proved the contribution of alone or combinational actions of solvophobic effect and pi-pi electron stacking as well as hydrogen bonds to retaining behaviors by GO@SiO2 and G@SiO2 . Well over-run, over-day and over-column precisions (retention time: 0.3-1.4, 1.1-3.8 and 2.8 5.2%, respectively; peak area: 2.6-6.5, 4.8-8.3 and 6.5-12.6%, respectively) of GO@SiO2 packed columns were a powerful proof for good reproducibility. Analytical characteristics of GO@SiO2 packed capillary columns in CEC analysis of fresh water were evaluated with respect to linearity (R2 = 0.9961-0.9989) over the range 0.1 to 100 mg/L and detection limits of 9.5 for naphthalene, 12.6 for fluorene and 16.2 MUg/L for phenanthrene. Further application to fresh water increased the visibility of the proposed material, where good spike recoveries in the range 89-96% were offered. PMID- 29236306 TI - Rs4705342 polymorphism is involved in the tumorigenesis of HBV positive HCC by altering the binding affinity of HBV induced NF-kB with the promoter region of microRNA-143. AB - The objective of this study was to explore the role of rs4705342 located in the miR-143 promoter in relation to the control of HBV positive HCC and the underlying molecular mechanism. A luciferase assay was performed to explore the factors which influenced miR-143 transcription activity and the target gene of miR-143. This would further be confirmed by ChIP assay. Western blot and real time PCR were performed to identify the relationship between miR-143 and ORP8. Luciferase activity of miR-143 SNP was increased with the presence of C allele. The presence of T allele partially restored the transcription ability. NF-kappaB displayed a much higher degree of luciferase activity in relation to the cells transfected with vectors containing either T or C allele rather than control cells with a greater extent in C allele group than T allele group. At the same time, ChIP assay indicated that the affinity of NF-KappaB in the miR-143 promoter was higher in C/C cells. The over-expression of HBX promotes NF-kB expression thus increasing the extent of binding of NF-kB on the CC allele of the miR-143 promoter. The binding is also abolished by NF-kB siRNA. ORP8 was proven to be a target gene of miR-143 using bioinformatics algorithm analysis. It was further confirmed by the luciferase assay that miR-143 substantially inhibited luciferase activities of wild-type ORP8. However, it did not affect the mutant ORP8. HBx induced by HBV infection up-regulated miR-143 expression. NF- kB can partially abolish the promotion effect of HBx on the miR-143 level in cells genotyped as CC but not in cells genotyped as TT. Tissues derived from participants genotyped as CC exhibited a higher level of miR-143, but a lower level of ORP8. The presence of the minor allele of rs4705342 in the promoter of miR-143 attenuated the transcription ability. This promoted ORP8 expression and could be a factor contributing to the oncogenesis in HBV positive HCC. PMID- 29236307 TI - Interleukin-4 induces a CD44high /CD49bhigh PC3 subpopulation with tumor initiating characteristics. AB - Pro- and anti-inflammatory cytokines may influence proliferation, migration, invasion, and other cellular events of prostate cancer (PCa) cells. The hyaluronan receptor CD44, which is regulated by Interleukin (IL)-4, is a prostate basal cell marker. CD44high /CD49bhigh expressing cells have been demonstrated to have tumor-initiating characteristics. Here, we aimed to analyze the effects of long-term IL-4 treatment on CD44/CD49b expression, migration, proliferation, and clonogenic potential of basal-like PCa cells. To this end PC3 cells were treated over 30 passages with 5 ng/mL IL-4 (PC3-IL4) resulting in an increased population of CD44high expressing cells. This was concurrent with a clonal outgrowth of cuboid-shaped cells, with increased size and light absorbance properties. Flow cytometry revealed that the PC3-IL4 CD44high expressing subpopulation corresponds to the CD49bhigh population. Isolation of the PC3-IL4 CD44high /CD49bhigh subpopulation via fluorescence-associated cell sorting showed increased migrative, proliferative, and clonogenic potential compared to the CD44low /CD49blow subpopulation. In conclusion, IL-4 increases a PC3 subpopulation with tumor-initiating characteristics. Thus, IL-4, similar to other cytokines may be a regulator of tumor-initiation and hence, may present a suitable therapy target in combination with current treatment options. PMID- 29236308 TI - Database of transcription factors in lung cancer (DBTFLC): A novel resource for exploring transcription factors associated with lung cancer. AB - Lung cancer is considered as the most prevalent form of cancer and it is found to be frequent cause of cancer related death. Even though, approved molecular targeted therapies other than chemotherapy are currently unavailable, the mechanism of pathogenesis in lung cancer remains still unclear. Transcription factors (TFs) play a critical role in cancer cell processes, such as cell proliferation, apoptosis, migration, and regulate gene expression. Thus, the identification and characterization of transcription factors involved in lung cancer would provide valuable information for further elucidation of the mechanism(s) underlying pathogenesis and the identification of potential therapeutic target types, which are critical for the development of therapeutic strategies. Through an extensive literature survey, we have identified 349 transcription factors noted for their strong involvement in lung cancer. Database of Transcription Factors in Lung Cancer (DBTFLC) was constructed as a data repository and analytical platform for systematic collection, curation of TFs and their interacting partners. The database includes all pertinent information such as lung cancer related TFs, chromosomal location, family, lung cancer type, references, TF-TF interaction(s), and TF-target gene interaction(s); thus, it could serve as a valuable resource for therapeutic studies in lung cancer. The database is freely available at http://www.vit.ac.in/files/database/Home.php. PMID- 29236309 TI - Leptin induces MMP1/13 and ADAMTS 4 expressions through bone morphogenetic protein-2 autocrine effect in human chondrocytes. AB - The induction of bone morphogenetic protein (BMP)2 in injured and arthritis articular cartilage has been proposed, but the precise mechanism has not been clearly clarified. Our previous study has found that leptin could stimulate the BMP2 autocrine effect to increase the anabolic collagen II expression when it initiates the catabolic response in human chondrocytes. It has been suggested that this BMP2 autocrine effect contributes to a reparative role in leptin stimulated human chondrocytes. In this study, we further determined whether this BMP2 autocrine effect also affect the expressions of catabolic matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS). Human primary and SW1353 chondrocytes were used in this study. It was shown that leptin could induce the expressions of MMP1, 3, and 13 and ADAMTS4 and 5 in both human primary and SW1353 chondrocytes. Leptin increased MMP1/13 (not MMP3) and ADAMTS4 (not ADAMTS5) expressions were affected by the leptin-upregulated BMP2 and its specific downstream Smad1/5 signaling. Moreover, both HDAC3 and 4 are involved in regulating leptin-induced BMP2 upregulation and then affect MMP1 and 13 and ADAMTS4 expression. Both HDAC3 and 4 also affect leptin-increased MMP3 mRNA expression but not through BMP2 autocrine effect of leptin induction. Our results further elucidated the role of BMP2 autocrine effect in matrix-degrading enzymes expressions under leptin stimulation. The findings in this study provide new insights into the possible mechanism of BMP2 induction in leptin-stimulated chondrocytes and in leptin induced OA development. PMID- 29236310 TI - Insulin induces an EMT-like process in mammary epithelial cells MCF10A. AB - Diabetes mellitus has been related with an increased risk of breast cancer, whereas it has been suggested that links between diabetes mellitus and cancer are hyperinsulinemia, insulin resistance, hyperglycemia, and chronic inflammation induced by adipose tissue. Contribution of hyperinsulinemia to carcinogenesis is mediated through resistance to endogenous insulin and by exogenous insulin used in treatment. Epithelial to mesenchymal transition (EMT) is a process by which epithelial cells are transdifferentiated to a mesenchymal state that has been implicated in cancer progression. However, the role of insulin in EMT process has not been studied in detail. In the present study, we demonstrate that insulin induces downregulation of E-cadherin expression, accompanied with an increase of N-cadherin and vimentin expression, and an increase of MMP-2 and -9 secretions. Insulin also induces FAK activation, an increase of NFkappaB DNA binding activity, migration, and invasion of mammary non-tumorigenic epithelial cells MCF10A. In addition, migration requires the activity of insulin receptors and insulin-like growth factor receptor 1 (IGF1R). In summary, our results demonstrate that insulin induces an EMT-like process in MCF10A cells. PMID- 29236311 TI - miR-221 negatively regulates inflammation and insulin sensitivity in white adipose tissue by repression of sirtuin-1 (SIRT1). AB - It is well known that obesity-induced white adipose tissue inflammation is an important reason for insulin-resistance and type 2 diabetes mellitus. Sirtuin-1 (SIRT1) is an important regulator of inflammtion response pathways in white adipose tissue. Here, we found that miR-221 negatively regulated SIRT1 in white adipose tissue during inflammation and HFD-induced obesity. MiR-221 is a putative oncogene which has been found overexpressed in a number of human tumors. Recently, it has also found that miR-221 was increased in obese adipose tissue and may be involved in inflammation and insulin-resistance. However the specific mechanism remains to be elucidated. In our present study, we found that overexpression of miR-221 decreased the protein abundance of SIRT1 and caused inflammation and insulin-resistance in differentiated 3T3-L1 cells. Conversely, miR-221 inhibition increased the protein levels, ameliorated inflammation, and improved insulin sensitivity. Moreover, inhibition of SIRT1 by EX527 significantly diminished the downregulation of the inflammation and insulin resistance levels induced by the miR-221 inhibitor. In conclusion, our data suggest that miR-221 promotes white adipose tissue inflammation and decreases insulin sensitivity in obesity, at least in part, through suppressing SIRT1. PMID- 29236312 TI - Hazard assessment of the pesticides KRAFT 36 EC and SCORE in a tropical natural soil using an ecotoxicological test battery. AB - Pesticides are widely used in agricultural fields to control plant diseases, weeds, and pests; however, the unforeseeable consequences of releasing these compounds into the soil and their effects on terrestrial invertebrates are matters of grave concern. The aim of the present study was to determine the direct impact of 2 pesticides, KRAFT(r) 36 EC (an insecticide; a.i. abamectin) and SCORE(r) (a fungicide; a.i. difenoconazole), on nontarget terrestrial invertebrates. Ecotoxicological tests were performed to evaluate the chronic and acute toxicity of these compounds to a potworm (Enchytraeus crypticus), a collembolan (Folsomia candida), and a mite (Hypoaspis aculeifer). The results showed that, for both pesticides, the collembolan F. candida was the most sensitive species, followed by the enchytraeid E. crypticus and the mite H. aculeifer. Effect concentrations at 50% of organisms' reproduction calculated for F. candida, E. crypticus, and H. aculeifer were 0.06, 2.8, and >32 mg of abamectin/kg dry weight soil and 28.9, 125, and 145.5 mg of difenoconazole/kg dry weight soil, respectively. Environmentally relevant concentrations of both pesticides significantly affected the collembolan species. The existence of a potential risk from abamectin and difenoconazole for soil invertebrates even at recommended doses could be identified. Environ Toxicol Chem 2018;37:2919-2924. (c) 2017 SETAC. PMID- 29236313 TI - MicroRNAs and exosomes in depression: Potential diagnostic biomarkers. AB - Depression is known as one of important psychiatric disorders which could be associated with disability among various populations. Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV) and international statistical classification of diseases and related health problems (ICD-10) could be used as subjective diagnostic schemes for identification of mental disorders such as depression. Utilization of subjective diagnostic schemes are associated with limitations. Hence, it seems that employing of new diagnosis platforms is required. Multiple lines of evidence indicated that measurement of several biomarkers could be useful for detection patients with depression. Among of various types of biomarkers, microRNAs (miRNAs) have been emerged as powerful tools for diagnosis patients with depression. MiRNAs are small non-coding RNAs which act as epigenetic regulators. It has been showed that these molecules have critical roles in pathogenesis of many diseases such as depression. These molecules exert their effects via targeting a variety of cellular and molecular pathways involved in initiation and progression of depression. Hence, miRNAs could be used as diagnostic and therapeutic biomarkers in patients with depression. Besides miRNAs, exosomes as nano- carriers could have been emerged as diagnostic biomarkers in several diseases such as depression. These vesicles are able to carry several cargos such as DNAs, proteins, mRNAs, and miRNAs to recipient cells. Here, we summarized several miRNAs involved in pathogenesis and response to treatment of depression which could be used as diagnostic biomarkers. Moreover, we highlighted exosomes as new diagnostic biomarkers for patients with depression. PMID- 29236314 TI - IL-1beta-induced miR-34a up-regulation inhibits Cyr61 to modulate osteoarthritis chondrocyte proliferation through ADAMTS-4. AB - Osteoarthritis (OA) is the most prevalent degenerative joint disease with multifactorial etiology caused by risk factors. The degradation of aggrecan by upregulated ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is the key event in the development of OA. ADAMTS-4 contributes to aggrecan degradation in human OA. Cysteine-rich angiogenic inducer 61 (Cyr61), which is associated with diseases related to chronic inflammation, is found in articular cartilage from patients with osteoarthritis and appears to suppress ADAMTS-4 activity, possibly leading to chondrocyte cloning. Herein, we first revealed that Cyr61 and ADAMTS-4 protein levels were remarkably increased in OA cartilage tissues and OA chondrocytes, and verified Cyr61 regulation of ADAMTS-4 in normal and OA chondrocyte. Further, we revealed that Cyr61 could promote OA chondrocyte proliferation through inhibiting ADAMTS-4. Overproduction of inflammatory cytokines plays a vital role in the pathological development of OA; herein, we demonstrated that IL-1beta inhibited Cyr61, while promoted ADAMTS-4 expression. By using online tools and luciferase assays, we confirmed that miR 34a, a regulatory miRNA of chondrocyte proliferation, could directly bind to the 3'-UTR of Cyr61 to inhibit its expression; further, IL-1beta regulated Cyr61 and ADAMTS-4 expression through miR-34a. In OA cartilage tissues, miR-34a, and IL 1beta mRNA expression was up-regulated and positively correlated; miR-34a and Cyr61 mRNA was positively correlated, further indicating that suppressing miR-34a expression might rescue IL-1beta-induced Cyr61 suppression, and promote OA chondrocyte proliferation. Taken together, we provided novel experimental basis for rescuing OA chondrocyte proliferation through miR-34a/Cyr61 axis. PMID- 29236315 TI - Lnc RNA SNHG20 participated in proliferation, invasion, and migration of breast cancer cells via miR-495. AB - To explore the mechanism of lnc SNHG20 in the regulation of proliferation, invasion, and migration of breast cancer cells. mRNA levels of SNHG20, miR-495, and HER2 were detected by qRT-PCR. Protein level of HER2 was measured by Western blot. Cell proliferation, invasion, and migration were detected by CCK-8 assay, Boyden chamber assay, and Transwell assay. The combination between SNHG20 and miR 495 was confirmed by RNA pull down assay. The combination between miR-495 and HER2 was confirmed by luciferase report assays. We also established breast cancer bearing mice model and analyzed tumor volumes. Our data showed SNHG20 expression was significantly upregulated, miR-495 expression was significantly downregulated, and HER2 expression was significantly upregulated in breast cancer tissues and cell lines. Besides, SNHG20 promoted the proliferation, invasion, and migration of breast cancer cells. We also found SNHG20 negatively regulated miR 495, and miR-495 could negatively regulate HER2. Moreover, we discovered that SNHG20 regulated HER2 via miR-495. SNHG20 regulated proliferation, invasion, and migration of breast cancer cells via miR-495/HER2. Finally, we confirmed the mechanism of SNHG20 in the regulation of proliferation, invasion, and migration in breast cancer-bearing mice model. SNHG20 regulates HER2 via miR-495 to promote proliferation, invasion, and migration of breast cancer cells. PMID- 29236316 TI - 2,5-hexanedione induces bone marrow mesenchymal stem cell apoptosis via inhibition of Akt/Bad signal pathway. AB - 2,5-Hexanedione (HD) is an important bioactive metabolite of n-hexane and mediates the neurotoxicity of parent compound. Studies show that HD induces apoptotic death of neural progenitor cells. However, its underlying mechanism remains unknown. Mesenchymal stem cells (MSCs) are multipotential stem cells with the ability to differentiate into various cell types and have been used as cell model for studying the toxic effects of chemicals on stem cells. In this study, we exposed rat bone marrow MSCs to 0, 10, 20, and 40 mM HD in vitro. Apoptosis and disruption of mitochondrial transmembrane potential were estimated by immunochemistry staining. The expression of Akt, Bad, phosphorylated Akt (p-Akt), and Bad (p-Bad) as well as cytochrome c in mitochondria and cytosol were examined by Western blot. Moreover, caspase 3 activity, viability, and death of cells were measured by spectrophotometry. Our results showed that HD induced cell apoptosis and increased caspase 3 activity. HD down-regulated the expression levels of p Akt, p-Bad and induced MMP depolarization, followed by cytochrome c release. Moreover, HD led to a concentration-dependent increase in the MSCs death, which was relative to MSCs apoptosis. However, these toxic effects of HD on the MSCs were significantly mitigated in the presence of IGF, which could activate PI3 K/Akt pathway. These results indicated that HD induced mitochondria-mediated apoptosis in the MSCs via inhibiting Akt/Bad signaling pathway and apoptotic death of MSCs via the signaling pathway. These results might provide some clues for studying further the mechanisms of HD-induced stem cell apoptosis and adverse effect on neurogenesis. PMID- 29236317 TI - Association of rno-miR-183-96-182 cluster with diethyinitrosamine induced liver fibrosis in Wistar rats. AB - Chronic liver injury due to various etiological factors including environmental carcinogens results in development of liver fibrosis. Numerous studies showed role of miRNAs in liver fibrosis. In the present study, we determined the rno-miR 183-96-182 cluster expression during hepatic fibrosis induced by diethylnitrosamine (DEN) treated Wistar rats and its association with plasma levels of circulating rno-miR-96, rno-miR-182, rno-miR-183, liver function test and lipid profile, aiming to identify their potential for histological stratification and early diagnosis of liver fibrosis. We found significant upregulation in the hepatic expression of rno-miR-183-96-182 cluster upon development of fibrosis in a DEN treated rats. Interestingly, the hepatic expression of this miRNA cluster correlates positively with the progression of fibrosis. Univariate analysis showed that hepatic expression of rno-miR-182-5p and rno-miR-183-5p and plasma activity of ALT are significant predictors of fibrosis. Multivariate logistic regression analysis revealed a panel of rno-miR 182-5p and ALT that can discriminate F2-F3 from F0-F1 (AUC = 0.87; P-value < 0.001), F4-F5-F6 from F0 to F1 (AUC = 0.981; P-value < 0.001), and F4-F5-F6 from F2 to F3 (AUC = 0.824; P-value < 0.001). A significant positive correlation of rno-miR-183-96-182 cluster members was also observed with plasma activities of ALT, AST, ALP, and levels of total cholesterol, HDLc and LDLc during fibrosis progression in DEN treated Wistar rats. Thus, it can be concluded that rno-miR 183-96-182 cluster being significantly up regulated and associated with chronic liver disease might play a role in fibrosis maintenance and progression. A panel of rno-miR-182-5p and ALT being significant predictors of fibrosis might improve histological stratification of fibrosis staging. PMID- 29236318 TI - Proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes following signal transducer and activator of transcription 3 RNA interference delivery. AB - OBJECTIVE: In this study, we investigated the effects of delivering small interfering RNA (siRNA) for efficient STAT3 downregulation on propagation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). METHODS: The FLSs were transfected with three different siRNAs. RNAi-1 was selected for further experiments. The expression levels of both STAT3 messenger RNA (mRNA) and its protein were detected by a real-time polymerase chain reaction and Western blot analysis. The proliferation of FLSs was examined by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide assay. The apoptosis of FLSs was examined by flow cytometry. The expression levels of cell apoptotic-related genes Bcl-2, Bax, and caspase-3 were detected by Western blot analysis. RESULTS: RNAi-1 was selected as the RNAi group for its lowest expression levels of STAT3 mRNA. In RNAi group, the proliferation of synoviocytes was much lower and the apoptosis rate was significantly higher. FLSs of RNAi-1 group showed significantly lower expression level of apoptotic-inhibiting gene Bcl-2 and significantly higher expression levels of proapoptotic gene Bax and apoptotic protease caspase-3. CONCLUSION: Transfection with targeted STAT3 recombinant plasmids effectively inhibited the expression of STAT3 mRNA and its protein in RA-FLSs. RNAi-mediated silencing of STAT3 reduced the proliferation and promoted the apoptosis of FLSs. PMID- 29236319 TI - Effects of long non-coding RNA HOST2 on cell migration and invasion by regulating MicroRNA let-7b in breast cancer. AB - The study intends to investigate the effects of long non-coding RNA HOST2 (lncRNA HOST2) on cell migration and invasion by regulating microRNA let-7b (let-7b) in breast cancer. Breast cancer and adjacent normal tissues were collected from 98 patients with breast cancer. Breast cancer MCF-7 cells were divided into the blank, negative control (NC), pcDNA3-Mock, siHOST2, let-7b inhibitor, pcDNA3 HOST2, let-7b mimic, pcDNA3-HOST2 + let-7b mimic, and siHOST2 + let-7b inhibitor groups. RT-qPCR was used to detect the mRNA expressions of HOST2, let-7b, and c Myc. Western blotting was conducted to measure the c-Myc expression. Scratch test and Transwell assay were applied to detect the cell motility, migration, and invasion. Xenograft tumor in nude mice was performed to evaluate the effect of different transfection on the tumor growth. Compared with adjacent normal tissues, HOST2 expression was higher but let-7b expression lower in breast cancer tissues. HOST2 expression in breast cancer cells was remarkably increased compared with that in the normal breast epithelial MCF-10A cells. In MCF-7 cells, in comparison with the blank and NC groups, expressions of HOST2 and c-Myc were reduced, but let-7b expression was remarkably elevated in the siHOST2 and let-7b mimic groups; the let-7b inhibitor group exhibited higher expressions of HOST2 and c-Myc but lower let-7b expression. Overexpression of HOST2 could promote cell motility, migration and invasion, thus enhancing the growth of breast cancer tumor. By inhibiting HOST2, opposite trends were found. LncRNA HOST2 promotes cell migration and invasion by inhibiting let-7b in breast cancer patients. PMID- 29236320 TI - Analgesic effects of microRNA-129-5p against bone cancer pain through the EphB1/EphrinB2 signaling pathway in mice. AB - The study aims to investigate the analgesic effects of microRNA-129-5p (miR-129 5p) on bone cancer pain (BCP) by targeting Eph receptor B1 (EphB1) through the EphB1/EphrinB2 signaling pathway. BCP mice models were established, and C3H/HeJ female mice were classified into the normal, blank, negative control (NC), miR 129-5p mimics, miR-129-5p inhibitors, EphB1 knockout (KO), and miR-129-5p inhibitors + EphB1 KO groups. Quantitative reverse transcription polymerase chain reaction and Western blot analysis were used to evaluate the miR-129-5p expression, and messenger RNA (mRNA) and protein expressions of EphB1, p-EphB1, EphrinB2, and p-EphrinB2. EphB1 and EphrinB2 were highly activated in the tibias of BCP mice 7 days after the operation. EphB1 is a target gene of miR-129-5p. The mechanical withdrawal threshold increased in the miR-129-5p mimics, EphB1 KO and miR-129-5p inhibitors + EphB1 KO groups, but decreased in the miR-129-5p inhibitors group. Compared with the blank and the NC groups, the expression of miR-129-5p was significantly increased in the miR-129-5p mimics group, and the mRNA and protein expressions of EphrinB2, p-EphrinB2, EphB1, and p-EphB1 were significantly decreased, while in the miR-129-5p inhibitors group, the results were opposite (all P < 0.05); the mRNA and protein expressions of EphrinB2, p EphrinB2, EphB1, and p-EphB1 were significantly decreased in the EphB1 KO group (all P < 0.05); the expression of miR-129-5p was significantly decreased in the miR-129-5p inhibitors + EphB1 KO group ( P < 0.05), while the mRNA and protein expressions of EphrinB2 and p-EphrinB2 were not significantly different ( P > 0.05). The results indicated that upregulated miR-129-5p alleviate BCP via downregulation of the EphB1/EphrinB2 signaling pathway. PMID- 29236321 TI - Murine models of osteosarcoma: A piece of the translational puzzle. AB - Osteosarcoma (OS) is the most common cancer of bone in children and young adults. Despite extensive research efforts, there has been no significant improvement in patient outcome for many years. An improved understanding of the biology of this cancer and how genes frequently mutated contribute to OS may help improve outcomes for patients. While our knowledge of the mutational burden of OS is approaching saturation, our understanding of how these mutations contribute to OS initiation and maintenance is less clear. Murine models of OS have now been demonstrated to be highly valid recapitulations of human OS. These models were originally based on the frequent disruption of p53 and Rb in familial OS syndromes, which are also common mutations in sporadic OS. They have been applied to significantly improve our understanding about the functions of recurrently mutated genes in disease. The murine models can be used as a platform for preclinical testing and identifying new therapeutic targets, in addition to testing the role of additional mutations in vivo. Most recently these models have begun to be used for discovery based approaches and screens, which hold significant promise in furthering our understanding of the genetic and therapeutic sensitivities of OS. In this review, we discuss the mouse models of OS that have been reported in the last 3-5 years and newly identified pathways from these studies. Finally, we discuss the preclinical utilization of the mouse models of OS for identifying and validating actionable targets to improve patient outcome. PMID- 29236322 TI - microRNA-383 suppresses the PI3K-AKT-MTOR signaling pathway to inhibit development of cervical cancer via down-regulating PARP2. AB - This study aims to evaluate the effect of the regulatory relationship between microRNA-383 (miR-383) and PARP2 in the cell migration and invasion in human with cervical cancer (CC) via the PI3K-AKT-MTOR signaling pathway. Cancerous tissues and corresponding paracancerous tissues were collected from 115 patients with CC. The positive expression rate of PARP2 was detected by immunohistochemistry. HeLa cells with highest miR-383 expression were selected and assigned into the blank, negative control (NC), miR-383 mimic, miR-383 inhibitor, si-PARP2, and miR-383 inhibitor + si-PARP2 groups. qRT-PCR and Western blot were performed to evaluate the expression of miR-383, PI3K, AKT, mTOR, PARP2, and p70S6K. MTT assay were utilized to measure cell viability. Transwell assay were applied to evaluate cell invasion and metastasis. Dual luciferase reporter assay identified that PARP2 is a target gene of miR-383. Cancerous tissues manifested higher expression of PI3K, AKT, mTOR, PARP2, and p70S6K but lower miR-383 expression than paracancerous tissues. Compared with the blank and NC groups, the miR-383 mimic and si-PARP2 groups had decreased expression of PI3K, AKT, mTOR, PARP2, and p70S6K mRNA and protein. In the miR-383 mimic and si-PARP2 groups, the cell viability, migration, and invasion were descended, in comparison to the blank and NC groups. All above parameters showed an opposite trend in the miR-383 inhibitor group when compared with the blank and NC groups. This study demonstrates that miR-383 could down regulate PARP2 to protect against CC by inhibiting PI3K-AKT-MTOR signaling pathway. PMID- 29236323 TI - Effects of microRNA-330 on vulnerable atherosclerotic plaques formation and vascular endothelial cell proliferation through the WNT signaling pathway in acute coronary syndrome. AB - This study is designed to investigate the effects of microRNA (miR)-330 on atherosclerotic plaques formation and vascular endothelial (VE) cell proliferation by targeting MAPK8 through the WNT signaling pathway in rats with acute coronary syndrome (ACS). Expression of hemodynamic variables were tested. Rats were allocated into control, blank, negative control (NC), miR-330 mimic, miR-330 inhibitor, DDK-1, miR-330 inhibitor + DDK-1 groups. ELISA was used to evaluate the expression of TC, TG, LDL-C, hs-CRP, IL-6, IL-10, TNF-alpha, and SAA. Immunohistochemistry, reverse transcription quantitative polymerase chain reaction and Western blotting were used for expression of VEGF, MAPK8, WNT1, beta catenin, GSK-3beta, p-GSK-3beta, CyclinD1, MMP-9, IL-6, and IL-8. MTT assay and flow cytometry for cell proliferation and apoptosis. Compared with the control group, other groups had lower levels of SBP, DBP, MBP, LVSP, and miR-330, higher levels of HR, LVEDP, TC, TG, LDC-C, hs-CRP, IL-6, IL-10, TNF-alpha, SAA, higher positive protein expression rates of MAPK8, VEGF, and MMP-9, elevated WNT1, beta catenin, GSK-3beta and CyclinD1, and reduced cell proliferation. MAPK8-3'-UTR was targeted by miR-330. Compared with the blank group, the miR-330 mimic and DDK-1 groups had higher levels of SBP, DBP, MBP, LVSP, lower levels of HR, LVEDP, TC, TG, LDC-C, hs-CRP, IL-6, TNF-alpha, SAA, elevated IL-10, decreased positive protein expression rates of MAPK8 and VEGF, raised cell proliferation and reduced cell apoptosis rates. We conclude that overexpressed miR-330 suppresses atherosclerotic plaques formation while promotes VE cell proliferation by targeting MAPK8 through the WNT signaling pathway in ACS rats. PMID- 29236324 TI - Silencing of phospholipase C gamma 2 promotes proliferation of rat hepatocytes in vitro. AB - The management of hepatic failure is undoubtedly difficult, and poor results have led to the search for novel therapeutic approaches. Nowadays, anti-apoptotic gene therapy is considered as an ideal approach. It has been proved that phospholipase Cgamma2 (PLCgamma2) is involved in the apoptosis of immune cells and tumor cells; however, whether this gene is related to hepatocyte death is still unclear. This study examined the role of PLCgamma2 by inhibiting its expression in rat hepatocytes with siRNA. We also further analyzed the cellular mechanism by which the expression inhibition of PLCgamma2 induces cell death. Silencing PLCgamma2 gene by adenovirus vector expressing PLCgamma2-targeted siRNA caused the great decline in the number of G1- and G2/M phase cells, the significant increase in the number of S phase cells, and the obvious reduction in apoptosis index. In addition, silencing PLCgamma2 gene relieved the rat hepatocyte damage, such as the cell shrinkage and chromatin condensation, nuclear fragmentation. Further analysis of Ad-PLCgamma2 siRNA-transfected hepatocytes demonstrated that suppression of PLCgamma2 gene expression could cause the caspase dependent cell death by inhibiting the signal pathway MEKK1/MKK4/JNK1/2/c-Jun. In conclusion, these findings suggest that interference with PLCgamma2 expression could relieve the inhibitory effect of PLCgamma2 on hepaocyte apoptosis, thus, promote proliferation through inactivating PKCdelta-mediated JNK1/2 signaling pathway. PMID- 29236325 TI - AML1/ETO trans-activates c-KIT expression through the long range interaction between promoter and intronic enhancer. AB - The AML1/ETO onco-fusion protein is crucial for the genesis of t(8;21) acute myeloid leukemia (AML) and is well documented as a transcriptional repressor through dominant-negative effect. However, little is known about the transactivation mechanism of AML1/ETO. Through large cohort of patient's expression level data analysis and a series of experimental validation, we report here that AML1/ETO transactivates c-KIT expression through directly binding to and mediating the long-range interaction between the promoter and intronic enhancer regions of c-KIT. Gene expression analyses verify that c-KIT expression is significantly high in t(8;21) AML. Further ChIP-seq analysis and motif scanning identify two regulatory regions located in the promoter and intronic enhancer region of c-KIT, respectively. Both regions are enriched by co-factors of AML1/ETO, such as AML1, CEBPe, c-Jun, and c-Fos. Further luciferase reporter assays show that AML1/ETO trans-activates c-KIT promoter activity through directly recognizing the AML1 motif and the co-existence of co-factors. The induction of c-KIT promoter activity is reinforced with the existence of intronic enhancer region. Furthermore, ChIP-3C-qPCR assays verify that AML1/ETO mediates the formation of DNA-looping between the c-KIT promoter and intronic enhancer region through the long-range interaction. Collectively, our data uncover a novel transcriptional activity mechanism of AML1/ETO and enrich our knowledge of the onco-fusion protein mediated transcription regulation. PMID- 29236326 TI - Knockdown of Ski decreased the reactive astrocytes proliferation in vitro induced by oxygen-glucose deprivation/reoxygenation. AB - Glia scar is a pathological marker in late phase of brain ischemia disease, which constitutes a major physical biochemical barrier to impede axonal regrowth. Astrocytes are known to be critically involved in the formation of glial scar. However, their response to ischemia and their role in neuroprotection after central nervous system (CNS) injury are not completely clear. Recently, we have demonstrated for the first time that Ski was up-regulated in reactive astrocytes after spinal cord injury in vivo and in vitro, which indicates Ski may be a new molecule that control astrocytes biologic properties after CNS injury. However, its role in the process of reactive astrogliosis after cerebral ischemia and its definite mechanism still remains unknown. This study is to elucidate the role of Ski in reactive astrocytes induced by oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro. The expression of Ski was proved to be up-regulated in OGD/R model. Meanwhile, Up-regulation of Ski was accompanied with high ratio of EdU (+) cells and up-expression of related proteins including GFAP, PCNA, CDK4, and CyclinD1, which demonstrated the distinct activation and proliferation of astrocytes after stimulation by OGD/R. Astrocytes were transfected with Ski specific siRNA to knockdown Ski expression and subsequently attenuated OGD induced astrocyte proliferation. Our results also showed that Ski down-regulation could suppress the activity of the Ras-Raf-ERK1/2 signaling pathway. Together, knockdown of Ski can effectively inhibit the proliferation of reactive astrogliosis via suppressing the Ras-Raf-ERK1/2 pathway. These findings indicated that maybe Ski is a promising therapeutic target for cerebral ischemic injury. PMID- 29236327 TI - PI3K inhibitors IC87114 inhibits the migration and invasion of thyroid cancer cell in vitro and in vivo. AB - Thyroid cancer is currently the most common endocrine malignancies, and PI3K/Akt pathway play an important role during its initiation and development. IC87114 is an inhibitor of PI3K/Akt pathway. Little is known about the role of IC87114 in the initiation and progression of thyroid cancer. Here, we demonstrated that IC87114 significantly inhibited both the migration and invasion of thyroid cancer cells, which can be mediated by inhibition of PI3K/Akt pathway. These results suggest that application of IC87114 may prove to be a particularly effective treatment for thyroid cancer. PMID- 29236328 TI - MiRNALet-7a mediates prostate cancer PC-3 cell invasion, migration by inducing epithelial-mesenchymal transition through CCR7/MAPK pathway. AB - Prostate cancer is one of the most common malignancies in older men. Recent evidence has demonstrated microRNA (miRNA) Let-7a expression decreased in prostate cancer, while the expression of C?C chemokine receptor type 7 (CCR7) increased. In this study, we investigated whether CCR7 overexpression was associated with a decrease in the expression of miRNA Let-7a in invasion and metastasis of prostate cancer cell. Synthetic Let-7a mimics and Let-7a inhibitors were transfected into prostate cancer PC-3 cells, respectively. Then Western blot was used to detect the expression of CCR7, ERK, p38, MMP-9, and Epithelial Mesenchymal Transition (EMT)-related proteins. Matrigel invasion assays were performed to assess the migratory and invasive activities of PC3 cells. To confirm the fact that 3'UTR of CCR7 is a direct target of Let-7a, a luciferase assay for the reporter gene expressing the Let-7a binding sites of CCR7 3'UTR was used. Synthetic Let-7a mimics decreased prostate cancer cell migration and invasion, as well as the expression of CCR7, phospho-p38, phospho-ERK1/2, MMP-9, N-cadherin, and Snail in PC-3 cells. The Let-7a inhibitors reversed the effects of Let-7a on PC-3 cells. The 3'UTR of CCR7 was confirmed as a direct target of Let-7a by using the luciferase assay. All findings demonstrated that Let-7a/CCR7 axis regulated EMT progress in prostate cancer cells and mediated the tumor cell invasion and migration process via activation of P38/ERK signal pathway. Our results suggested that the therapeutic potential of Let-7a as an antitumor and antimetastatic manager in prostate cancer and CCR7 may be regarded as a therapeutic target for the prostate cancer treatment. PMID- 29236329 TI - Predicting the bioavailability of sediment-bound uranium to the freshwater midge (Chironomus dilutus) using physicochemical properties. AB - Assessment of uranium (U)-contaminated sediment is often hindered by the inability to accurately account for the physicochemical properties of sediment that modify U bioavailability. The present goal was to determine whether sediment associated U bioavailability could be predicted over a wide range of conditions and sediment properties using simple regressions and a geochemical speciation model, the Windermere Humic Aqueous Model (WHAM7). Data from a U-contaminated field sediment bioaccumulation test, along with previously published bioaccumulation studies with U-spiked field and formulated sediments, were used to examine the models. Observed U concentrations in Chironomus dilutus larvae exposed to U-spiked and U-contaminated sediments correlated well (r2 > 0.74, p < 0.001) with the WHAM-calculated concentration of U bound to humic acid, indicating that humic acid may be a suitable surrogate for U binding sites (biotic ligands) in C. dilutus larvae. Subsequently, the concentration of U in C. dilutus was predicted with WHAM7 by numerically optimizing the equivalent mass of humic acid per gram of organism. The predicted concentrations of U in C. dilutus larvae exposed to U-spiked and U-contaminated field sediment compared well with the observed values, where one of the regression models provided a slightly better fit (mean absolute error = 18.1 mg U/kg dry wt) than WHAM7 (mean absolute error = 34.2 mg U/kg dry wt). The regression model provides a predictive capacity with a minimal number of variables, whereas WHAM7 provides additional complementary insight into the chemical variables influencing the speciation, sorption, and bioavailability of U in sediment. The present results indicate that physicochemical properties of sediment can be used to account for variability in U bioavailability as measured through bioaccumulation in chironomids exposed to U contaminated sediments. Environ Toxicol Chem 2018;37:1146-1157. (c) 2017 SETAC. PMID- 29236330 TI - Exploring the usefulness of key green physicochemical properties: Quantitative structure-activity relationship for solvents from biomass. AB - In recent decades there has been a growing interest in the development of new solvents from biomass. Some of these new solvents have been classified as green because of their renewable and sustainable source. However, characterization from the ecotoxicological and physicochemical points of view is needed to categorize them as green solvents. We have selected several key physicochemical properties that can reflect environmental features (density, boiling point, critical aggregation concentration, and log p) and explored their usefulness for preliminarily assessing the green character of the studied solvents. Specifically, we have studied several solvents from biomass: lactate family (methyl, ethyl, and butyl lactate), furfural family (furfural, 5-methylfurfural, furfuryl alcohol, and tetrahydrofurfuryl alcohol), and levulinate family (methyl, ethyl, and butyl levulinate). To fill the gaps and complete some toxicity data for the environment, we have measured the ecotoxicity using 2 of the most common and versatile biomodels, bacteria Vibrio fischeri and crustacean Daphnia magna, for furfural- and lactate-derived compounds. The results indicate that solvents from biomass can be categorized as green because their toxicity for the environment is low. Finally, a quantitative structure-activity relationship (QSAR) study was performed with the selected key properties and the ecotoxicological information. Despite the different structure of the chemicals under study, good correlations were found for the studied organisms. It seems that log p and critical aggregation concentration reflect the greatest part of the ecotoxic behavior, whereas density and boiling point cannot reflect toxicity signals. However, these properties are rather useful for assessing the final environmental fate of the studied chemicals. Environ Toxicol Chem 2018;37:1014 1023. (c) 2017 SETAC. PMID- 29236331 TI - Reduction of two histone marks, H3k9me3 and H3k27me3 by epidrug induces neuroendocrine differentiation in prostate cancer. AB - Neuroendocrine prostate cancer (NE PCa) is an aggressive malignancy, often presenting with advanced metastasis. We previously reported that reduction of histone marks regulated by DNMT1 following epidrug (5-Azacitidine, 5-Aza) treatment controls induction of epithelial to mesenchymal (EMT) and a cancer stem cell (CSC) phenotype, which facilitates tumorigenesis in PCa cells. Here, we use the epidrug 5-Aza as a model for how histone marks may regulate the reprogramming of prostate adenocarcinoma into NE phenotypic cells. First, we observed that 5 Aza treatment of PCa cells in vitro induces a neuron-like phenotype. In addition, significant increases in the expression of the NE markers N-Myc downstream regulated gene 1 (NDRG1), enolase-2 (ENO2), and synaptophysin were observed. Critically, a high density of NE cells with synaptophysin expression was found in tumors generated by 5-Aza pretreatment of PCa cells. Importantly, induction of NE differentiation of PCa cells was associated with an enhancement of NDRG1 expression by reduction of two histone marks, H3K9me3 and H3K27me3. Further, more NDRG1 expression was detected in the subset of PCa cells with reduced expression of H3K9me3 or H3K27me3 in the tumors generated by 5-Aza pretreated PCa cells and critically, these biological differences are also observed in small cell carcinoma in advanced stage of human primary PCa tumors. Our results suggest that reduction of histone marks regulated by the epidrug 5-Aza may control induction of a NE phenotype, which facilitates PCa progression. These studies suggest a strong rationale for developing therapeutics, which target epigenetic regulation. PMID- 29236333 TI - Effect and mechanism of lncRNA HOTAIR on occurrence and development of gastric cancer. AB - OBJECTIVE: In this study, we aimed at looking for the lncRNA abnormally expressed in gastric cancer (GC) tissues, and analyzing the association of its expression level with the clinicopathological feature and patient prognosis. The biological function of this lncRNA in occurrence and development of GC was studied in vivo and in vitro. The underlying molecular mechanism was further discussed. METHODS: We investigated the lncRNA expression level in GC tissues and normal gastric mucosa tissues by lncRNA chips analysis. The expression of lncRNA HOTAIR was detected by qRT-PCR. The relationship between HOTAIR expression level and prognosis was investigated by analyzing clinical samples. The influence of HOTAIR down-regulation on GC cell proliferation, chemosensitivity, apoptosis and invasion were determined by BrdU incorporation assay, flow cytometry analysis and transwell assay. Tumor xenograft model was developed to study the influence of down-regulated HOTAIR on tumor growth and metastasis. RESULTS: lncRNA HOTAIR had an extremely high expression level in GC cells, and predicted poor prognosis in patients. Down-regulation of HOTAIR could promote chemosensitivity, induce apoptosis of GC cells, and significantly inhibit GC cell proliferation, invasion and metastasis in vivo and in vitro. CONCLUSION: It was proved that HOTAIR played a positive role in GC occurrence and development according to the study in its mechanism, function and clinical manifestation, so that it could be expected to become a new target in GC prevention and treatment. This article is protected by copyright. All rights reserved. PMID- 29236332 TI - A New Mechanism for beta-Lactamases: Class D Enzymes Degrade 1beta-Methyl Carbapenems through Lactone Formation. AB - beta-Lactamases threaten the clinical use of carbapenems, which are considered antibiotics of last resort. The classical mechanism of serine carbapenemase catalysis proceeds through hydrolysis of an acyl-enzyme intermediate. We show that class D beta-lactamases also degrade clinically used 1beta-methyl substituted carbapenems through the unprecedented formation of a carbapenem derived beta-lactone. beta-Lactone formation results from nucleophilic attack of the carbapenem hydroxyethyl side chain on the ester carbonyl of the acyl-enzyme intermediate. The carbapenem-derived lactone products inhibit both serine beta lactamases (particularly class D) and metallo-beta-lactamases. These results define a new mechanism for the class D carbapenemases, in which a hydrolytic water molecule is not required. PMID- 29236335 TI - Current antibiotic prophylaxis for cataract surgery in Sydney: comment. PMID- 29236334 TI - Post-transfusion changes in serum hepcidin and iron parameters in preterm infants. AB - BACKGROUND: Packed red blood cell transfusion is common in preterm neonates. Hepcidin acts as a negative feedback iron regulator. Iron parameters such as immature reticulocyte fraction (IRF) and high-light-scatter reticulocytes (HLR) are used to clarify iron metabolism. Very little is known about the regulation of hepcidin in preterm infants because most reports have evaluated prohepcidin. The aim of this study was therefore to evaluate serum hepcidin and establish hematological parameters in preterm infants after transfusion. METHODS: The subjects consisted of 19 newborns (10 boys) with mean gestational age 29.1 +/- 2.0 weeks, who had been transfused at the chronological age of 44.84 +/- 19.61 days. Blood sample was collected before the transfusion and thereafter at 5 days and at 1 month. Serum hepcidin and other iron parameters were evaluated. RESULTS: Mean serum hepcidin before and 5 days after transfusion was significantly different (5.5 +/- 5.1 vs 10 +/- 7.9 ng/mL respectively, P = 0.005). IRF and % HLR were also decreased significantly, 5 days after transfusion (0.4 +/- 0.2 vs 0.2 +/- 0.1, P = 0.009; 1.4 +/- 1.5% vs 0.5 +/- 0.4%, P = 0.012, respectively). Changes in hepcidin 5 days after transfusion were correlated significantly with changes in mean corpuscular hemoglobin (beta, 0.13; SE, 0.05; P = 0.017), total iron binding capacity (beta, 3.74; SE, 1.56; P = 0.016) and transferrin (beta, 2.9, SE, 1.4; P = 0.039). CONCLUSIONS: Serum hepcidin concentration, along with IRF and HLR, are potentially useful in estimating pre- and post-transfusion iron status. Larger studies are needed to evaluate the sensitivity and specificity of hepcidin compared with ordinary iron parameters in premature infants. PMID- 29236337 TI - Homonuclear decoupling in the 13 C indirect dimension of HSQC experiments for 13 C-enriched compounds. AB - The two most compelling methods for broadband homonuclear decoupling currently available, Zangger-Sterk (ZS) and pure shift yielded by chirp excitation (PSYCHE), were successfully adapted and tested on the 13 C isotope. When applied during the indirect carbon evolution in the HSQC experiment, they both entirely eliminated the extended carbon-carbon multiplet structures observed in this dimension of a non-decoupled HSQC spectrum of 13 C-enriched cholesterol. The optimized selective pulse modulated using novel non-equidistant scheme for multisite refocusing (ZS) and the small flip angle saltire chirps (PSYCHE) both proved to be robust and efficient in providing decoupled spectra with a sensitivity of about 25% that of the non-decoupled HSQC spectra with improved quality compared to earlier results. PMID- 29236336 TI - Anionic Hosts for the Incorporation of Cationic Guests. AB - Pentaphosphaferrocene [Cp*Fe(eta5 -P5 )] (1 a) represents an excellent building block for the template-directed synthesis of spherical supramolecules. Here, the self-assembly of 1 a with CuI and CuII halides in the presence of the template complexes [FeCp2 ][PF6 ], [CoCp2 ][PF6 ] and [CoCp2 ] is reported, testifying to the redox behavior of the formed supramolecules. The oxidation or reduction capacity of these reactive complexes does not inhibit their template impact and, for the first time, the cationic metallocene [CoCp2 ]+ is enclosed in unprecedented anionic organometallic hosts. Furthermore, the large variety of structural motifs, as icosahedral, trigonal antiprismatic, cuboidal and tetragonal antiprismatic arrangements of 1 a units are realized in the supramolecules [FeCp2 ]@[{1 a}12 (CuBr)17.3 ] (3), [CoCp2 ]+3 {[CoCp2 ]+ @[{1 a}8 Cu24.25 Br28.25 (CH3 CN)6 ]4- } (4), {[Cp2 Co]+ @[{1 a}8 (CuI)28 (CH3 CN)9.8 ]}{[Cp2 Co]+ @[{1 a)}8 Cu24.4 I26.4 (CH3 CN)8 ]2- } (5), and [{1 a}3 {(1 a)2 NH}3 Cu16 I10 (CH3 CN)7 ] (6), respectively. PMID- 29236338 TI - Inflammatory cytokine and C-reactive protein concentrations in dogs with systemic inflammatory response syndrome. AB - OBJECTIVE: To evaluate C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) kinetics in dogs with a systemic inflammatory response syndrome (SIRS) presented to an emergency service. We hypothesized serum CRP concentrations would increase and vary during hospitalization, and would correlate with plasma IL-6 and TNF-alpha concentrations, vary in magnitude according to the underlying disease, and predict survival. DESIGN: Prospective, observational, clinical study. SETTING: University emergency department. ANIMALS: Sixty-nine dogs with SIRS weighing over 5 kg who could tolerate the blood sampling. INTERVENTIONS: Serum and plasma were collected (and stored at -80 degrees C) at presentation (T0), after 6 (T6), 12 (T12), 24 (T24), and 72 (T72) hours, and at a follow-up visit at least 1 month after discharge (T1m). Underlying diseases were categorized as infection (I), neoplasia (N), trauma (T), gastric-dilation and volvulus (GDV), other gastrointestinal (GI), renal (R), and miscellaneous (M) disease. MEASUREMENTS AND MAIN RESULTS: Serum CRP concentration was measured using a canine-specific immunoturbidimetric assay. Biologically active plasma IL-6 and TNF-alpha concentrations were assessed using bioassays. Forty-four dogs survived, 8 died, and 17 were euthanized. Nineteen dogs had follow-up visits. At T0, serum CRP concentration was above the reference interval in 73.1% (49/67), and was within the reference interval (0-141.9 nmol/L) throughout hospitalization in only 6% (4/67). Serum CRP concentrations were significantly higher (P < 0.0001) at T0 (882.9 +/- 1082.9 nmol/L) and at all time points during hospitalization (P < 0.0001) compared to T1m, with highest concentrations observed at T24 (906. 7 +/- 859.0 nmol/L). At T1m, serum CRP concentrations were within the reference interval (22.9 +/- 42.9 nmol/L) in 95% (18/19) of dogs. Logarithmic concentrations of serum CRP and plasma IL-6 were significantly correlated (P < 0.001, r = 0.479). None of the measured cytokines were associated with disease category or outcome. CONCLUSIONS: Serum CRP concentration is increased in dogs with SIRS, and decreases during treatment and hospitalization. Serum CRP, plasma IL-6, and plasma TNF-alpha concentrations cannot predict outcome in dogs with SIRS. PMID- 29236339 TI - Physical activity level among children recovering from severe acute malnutrition. AB - OBJECTIVE: To assess the level and predictors of physical activity at discharge among children recovering from severe acute malnutrition (SAM). METHODS: We conducted a prospective study among 69 children 6-59 months of age admitted with SAM for nutritional rehabilitation at Mulago National Referral Hospital, Uganda. Using hip-mounted triaxial accelerometers, we measured physical activity expressed as counts per minute (cpm) during the last three days of hospital treatment. As potential predictors, we assessed clinical and background characteristics, duration to transition phase and duration of hospitalisation, serum C-reactive protein and whole-blood docosahexaenoic acid (DHA). Multiple linear regression analyses were used to identify predictors of physical activity. RESULTS: The median (IQR) age was 15.5 (12.6; 20.5) months. At discharge, the mean (SD) movement was 285 (126) cpm. Physical activity was 43 (19; 67) cpm higher for each unit increase in weight-for-height z-score (WHZ) and 72 (36; 108) cpm higher for each centimetre increase in MUAC. Whole-blood DHA on admission was also a positive predictor of physical activity, whereas duration to transition phase and duration of hospitalisation were both negative predictors. CONCLUSION: The level of physical activity at discharge among children treated for SAM was low. WHZ, MUAC and DHA on admission were positive predictors of physical activity, whereas duration of stabilisation and hospitalisation was negative predictors of physical activity. These results suggest that assessment of physical activity may be used as a marker of recovery. PMID- 29236341 TI - NMR Lineshapes and Scalar Relaxation of the Water-Endofullerene H217 O@C60. AB - The 17 O isotopomer of the water-endofullerene H2 O@C60 displays a remarkable proton NMR spectrum, with six well resolved peaks. These peaks are due to the J coupling between the water protons and the 17 O nucleus, which has spin-5/2. The resolution of these peaks is enabled by the suppression of water proton exchange by the fullerene cage. The six peaks display an unusual pattern of linewidths, which we model by a Liouville-space treatment of scalar relaxation due to quadrupolar relaxation of the 17 O nuclei. The data are consistent with rotational diffusion of the water molecules on the sub-picosecond timescale. PMID- 29236340 TI - Flow cytometry: a versatile technology for specific quantification and viability assessment of micro-organisms in multistrain probiotic products. AB - AIMS: Classical microbiology techniques are the gold standard for probiotic enumeration. However, these techniques are limited by parameters of time, specificity and incapacity to detect viable but nonculturable (VBNC) micro organisms and nonviable cells. The aim of the study was to evaluate flow cytometry as a novel method for the specific quantification of viable and nonviable probiotics in multistrain products. METHODS AND RESULTS: Custom polyclonal antibodies were produced against five probiotic strains from different species (Bifidobacterium bifidum R0071, Bifidobacterium longum ssp. infantis R0033, Bifidobacterium longum ssp. longum R0175, Lactobacillus helveticus R0052 and Lactobacillus rhamnosus R0011). Evaluation of specificity confirmed that all antibodies were specific at least at the subspecies level. A flow cytometry method combining specific antibodies and viability assessment with SYTO(r) 24 and propidium iodide was applied to quantify these strains in three commercial products. Analyses were conducted on two flow cytometry instruments by two operators and compared with classical microbiology using selective media. Results indicated that flow cytometry provides higher cell counts than classical microbiology (P < 0.05) in 73% of cases highlighting the possible presence of VBNC. Equivalent performances (repeatability and reproducibility) were obtained for both methods. CONCLUSIONS: This study showed that flow cytometry methods can be applied to probiotic enumeration and viability assessment. Combination with polyclonal antibodies can achieve sufficient specificity to differentiate closely related strains. SIGNIFICANCE AND IMPACT OF THE STUDY: Flow cytometry provides absolute and specific quantification of viable and nonviable probiotic strains in a very short time (<2 h) compared with classical techniques (>48 h), bringing efficient tools for research and development and quality control. PMID- 29236342 TI - Longitudinal assessment of rabbit renal fibrosis induced by unilateral ureteral obstruction using two-dimensional susceptibility weighted imaging. AB - BACKGROUND: Previous studies indicated that two-dimensional-susceptibility weighted imaging (2D-SWI) could serve as a useful biomarker for differentiating the grade of liver fibrosis. PURPOSE: To evaluate the feasibility of 2D-SWI in the dynamic quantification of renal fibrosis in a rabbit model. STUDY TYPE: Longitudinal study. ANIMAL MODEL: Twenty-Four New Zealand White Rabbits including control group (n = 4); and renal fibrosis group (n = 20), by means of a unilateral ureteral obstruction (UUO) model. FIELD STRENGTH/SEQUENCE: The 3.0 T SWI using a 2D gradient-echo sequence. ASSESSMENT: The relative SWI signal ratio(r) of cortical and medulla (r = SIrenal /SImuscle ) was longitudinally assessed before ligation and on weeks 2, 4, 6, and 8 following ligation. Sirius Red staining was used to assess the degree of fibrosis in five high-power fields. STATISTICAL TESTS: The repeated measures of analysis of variance and linear regression analysis. RESULTS: Both the cortical and medullary r values were significantly higher in the UUO kidneys at week 2 compared with the kidneys before ligation. Over the course of UUO progression, significant changes occurred in the cortical and medullary r values in vivo and fibrosis scores in vitro (all P values < 0.05). The r values gradually decreased, while the fibrosis scores gradually increased over 8 weeks following ligation. The linear regression analysis showed a strong and significant correlation between cortical and medullary r values and the pathologic fibrosis scores (R2 = 0.91, 0.81, respectively). DATA CONCLUSION: The SWI sequence could provide a quantitative evaluation of renal fibrosis during UUO progression. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:1572-1577. PMID- 29236343 TI - Relationship between reticular pseudodrusen and choroidal thickness in intermediate age-related macular degeneration. AB - IMPORTANCE: Reticular pseudodrusen (RPD) is strongly associated with late age related macular degeneration (AMD) but their aetiology remains unknown. RPD have been associated with reduced choroidal thickness (ChT) but most studies are limited by small sample size and varying severity of AMD. BACKGROUND: To investigate the relationship between choroidal thickness and RPD in eyes with intermediate AMD (iAMD), controlling for variables known to influence ChT. DESIGN: Retrospective cohort study. PARTICIPANTS: Participants were recruited from Centre for Eye Research Australia. METHODS: Colour fundus photographs, fundus auto fluorescence, near-infrared and spectral-domain ocular coherence tomography (OCT) were graded for RPD. ChT was measured from enhanced-depth imaging OCT scans at the centre of fovea, 1500 and 3000 MUm nasal, temporal, superior and inferior from centre of fovea. MAIN OUTCOME MEASURES: ChT between RPD and non-RPD group. RESULTS: A total of 297 eyes from 152 subjects were included. A total of 84 (28%) had RPD and were older than non-RPD group (75.1 +/- 5.4 years and 68.7 +/- 6.9 years, respectively; P < 0.001). In unadjusted analysis, the RPD group was significantly associated with thinner choroids across all measured locations (P <= 0.022). After adjustment for variables, the presence of RPD was no longer associated with ChT (P >= 0.132 for all locations) but age (P < 0.001) and refractive error (P = 0.002) remained significantly associated with ChT. CONCLUSIONS AND RELEVANCE: Age and refractive error, rather than RPD, was significantly associated with reduced ChT in eyes with iAMD. Choroidal insufficiency may be a less important variable in RPD aetiology than previously considered. PMID- 29236344 TI - Association between Urologic Malignancies and End-stage Renal Disease: A Meta Analysis. AB - OBJECTIVE: Previous studies have suggested a higher incidence of urologic malignancies in end-stage renal disease (ESRD) patients. However, incidence trends of urologic malignancies in ESRD patients remain unclear. The study's aims were 1) to investigate the pooled incidence/incidence trends and 2) to assess the risk of urologic malignancies in ESRD patients. METHODS: A literature search was conducted using MEDLINE, EMBASE and Cochrane Database from inception through April 2017. Studies that reported incidence or odd ratios of urologic malignancies among ESRD patients were included. Pooled odds ratios (OR) and 95%CI were calculated using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017067687). RESULTS: Nineteen observational studies with 1,931,073 ESRD patients were enrolled. The pooled estimated incidence of kidney cancer and urothelial cancers (carcinomas of the bladder, ureters, and renal pelvis) in ESRD patients were 0.3% (95%CI: 0.2%-0.5%) and 0.5% (95%CI: 0.3% 0.8%), respectively. Meta-regression showed significant positive correlation between incidence of urologic malignancies in ESRD patients and year of study (slopes = +0.05 and +0.07, p <0.001 for kidney cancer and urothelial cancers, respectively). Compared to non-ESRD status, ESRD was significantly associated with both kidney cancer (pooled OR 6.04; 95% CI 4.70-7.77) and urothelial cancers (pooled OR 4.37; 95% CI 2.40-7.96). CONCLUSION: Our study demonstrates a significant association between ESRD and urologic malignancies. The overall estimated incidence rates of kidney cancer and urothelial cancers are 0.4% and 0.5%, respectively. There is a significant positive correlation between the incidence of urologic malignancies and year of study. PMID- 29236345 TI - Ferrocene-Alkynyl Conjugated Molecular Wires: Synthesis, Characterization, and Conductance Properties. AB - A novel series of 1,2,3-substituted ferrocene-based wires a1-a2 and b4-b5 have been synthesized by using an iterative Pd-mediated Sonogashira cross-coupling methodology. The molecular structures of a2 and b3 were determined by single crystal X-ray analysis. Electrochemical data showed that there was a strong electronic communication among the ferrocenyl moieties in b1-b5. The UV absorption spectra indicated that replacing the 1,1'-substituted ferrocene unit with a 1,2,3-substituted ferrocene moiety causes delocalization of electrons in the extended pi orbitals. The self-assembled monolayers of wire a1 and a2 on Au surfaces have been comprehensively characterized by electrochemistry and scanning tunneling microscopy break junction. The data demonstrated that 1,2,3-substituted ferrocene-based wires reduced the intermolecular pi-pi stacking, and furthermore solved the rotation problem in the 1,1'-substituted ferrocene-based wires. PMID- 29236346 TI - Therapy-related acute myeloid leukaemia and myelodysplastic syndrome in Victoria, Australia 2003-2014. AB - BACKGROUND: The burden of therapy-related acute myeloid leukaemia (tAML)/therapy related myelodysplastic syndrome (tMDS) in Australia has not been characterised. AIMS: To provide insights into the incidence, associated cancers, latency and survival outcomes of patients with tAML/tMDS in Victoria, Australia, based on a state-wide cancer registry and to assess if these features are different in tAML/tMDS compared with de novo AML/MDS. METHODS: We analysed adults aged >=20 years at diagnosis of AML/MDS reported to the Victorian Cancer Registry (VCR) between 2003 and 2014. RESULTS: In total, 73 of 3120 (2.3%) AML cases were classified tAML. tAML patients were younger than non-tAML patients at diagnosis (median age 66 vs 71 years, P = 0.000). Median overall survival was similar (6 months). Median latency to tAML was 82 months, with two incidence peaks at 1-4 and 7-8 years. In total, 59 of 73 patients had recorded cancers, the most frequent being non-Hodgkin lymphoma (NHL, 32.2%) and breast cancer (16.9%). In total, 532 of 3120 (14.1%) additional AML cases had >=1 prior cancer (confirmation of chemoradiotherapy unavailable). tAML incidence increased (0.0/100 000 persons in 2003, 0.5/100 000 persons in 2014), as did the incidence of non-tAML with previous cancer (0.8/100 000 persons in 2003, 1.1/100 000 persons in 2014). In total, 101 of 4435 (2.3%) MDS cases were classified tMDS. Although tMDS incidence fluctuated (range 0-0.4/100 000 persons/year), the incidence of non-tMDS with prior cancer rose (1.4/100 000 persons in 2003, 1.9/100 000 persons in 2014). Compared to tAML, the tMDS cohort was older (median age 70 vs 66 years, P = 0.007). Median latency to tMDS was 42.5 months. NHL was also the most common cancer preceding tMDS, but the second most common cancer was myeloma (17.8%). In total, 1287 of 5061 (20.3%) non-tMDS patients had a prior cancer. CONCLUSIONS: The burden of tAML/tMDS in Victoria is likely to be underestimated. Linkage between VCR and clinical registries is needed to provide more accurate insights. PMID- 29236347 TI - Full blood count as an ancillary test to support the diagnosis of giant cell arteritis. AB - BACKGROUND: Temporal artery biopsy is considered the investigation of choice to diagnose definitively giant cell arteritis (GCA) in patients with compatible symptoms. However it is invasive and not completely sensitive. Serum markers, particularly erythrocyte sedimentation rate (ESR), can be supportive, but are not definitive in individual cases. AIMS: To investigate whether indices derived from the full blood count, including neutrophil-to-lymphocyte ratio (NLR) and platelet to-lymphocyte ratio (PLR) were associated with a positive biopsy in patients with suspected GCA. METHODS: The clinical and pathological details of 537 patients undergoing temporal artery biopsy at our institution from 1992 to 2015 were reviewed. RESULTS: In univariate analysis high platelets (odds ratio (OR) 4.44, P < 0.001), NLR (OR 1.81, P = 0.02), PLR (OR 3.25, P < 0.001), C-reactive protein (CRP) (OR 3.00, P < 0.001), ESR (OR 3.62, P < 0.001) and increased age (OR 1.03, P = 0.006) were strongly associated with a positive biopsy. In multivariate modelling only high platelets (P < 0.001) and ESR (P = 0.049) maintained significance. CONCLUSIONS: We conclude that the presence of thrombocytosis and high NLR, PLR, ESR and CRP can all be used clinically to support the diagnosis of GCA prior to biopsy. Of particular note, in multivariate modelling the presence of thrombocytosis is a stronger predictor of a positive temporal artery biopsy than ESR. Therefore, careful consideration of the findings in a full blood count can be used to predict the likelihood of a positive temporal artery biopsy in patients with suspected GCA. PMID- 29236348 TI - Isolation of a Reactive Tricoordinate alpha-Oxo Gold Carbene Complex. AB - The [(P,P)Au=C(Ph)CO2 Et]+ complex 3 [where (P,P) is an o-carboranyl diphosphine ligand] was prepared by diazo decomposition at -40 degrees C. It is the first alpha-oxo gold carbene complex to be characterized. Its crystallographic structure was determined and DFT calculations have been performed, unraveling the key influence of the chelating (P,P) ligand. The gold center is tricoordinate and the electrophilicity of the carbene center is decreased. Complex 3 mimics transient alpha-oxo gold carbenes in a series of catalytic transformations, and provides support for the critical role of electrophilicity in the chemoselectivity of phenol functionalization (O-H vs. C-H insertion). PMID- 29236349 TI - Direct and Enantioselective Synthesis of N-H-Free 1,5-Benzodiazepin-2-ones by an N-Heterocyclic Carbene Catalyzed [3+4] Annulation Reaction. AB - An NHC-catalyzed formal [3+4] annulation of alpha,beta-unsaturated acylazoliums with protecting-group-free aryl 1,2-diamines was developed for a direct and highly enantioselective synthesis of 4-aryl N-H-free 1,5-benzodiazepin-2-ones. This methodology offers an efficient and rapid access to a wide range of enantioenriched target compounds from easily accessible starting materials. The protocol is also scalable and the desired products can easily undergo subsequent N-functionalization to afford diverse N-substituted derivatives. Additionally, a mechanism was proposed to explain the high enantioselectivity in this process. PMID- 29236350 TI - ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and related disorders part 3 - data analysis, reporting and case studies. AB - Over the past several years, a diverse group of physicians and other laboratory scientists have developed various recommendations and guidelines regarding best practices for PNH testing. This manuscript is based on these previous recommendations as well as various other relevant publications of experts in the area of PNH testing. The goal is to provide flow cytometry laboratories with an updated consensus approach to analysis and reporting of PNH results and to address the most common analytical challenges for accurate reporting of this rare disease. A comprehensive case library is included in this section. (c) 2017 International Clinical Cytometry Society. PMID- 29236352 TI - ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and related disorders part 1 - clinical utility. AB - Paroxysmal nocturnal hemoglobinuria (PNH) arises as a consequence of the non malignant clonal expansion of one or more hematopoietic stem cells with an acquired somatic mutation of the PIGA gene (Brodsky RA. Blood 113 (2009) 6522 6527). Progeny of affected stem cells are deficient in glycosyl phosphatidylinositol-anchored proteins (GPI-APs). This deficiency is readily detected by flow cytometry. Though this seems straightforward, the clinical utility of this testing requires that the ordering clinician understand not only the characteristics of the test, but also the biology of the underlying disease, and the clinical and laboratory manifestations in the individual patient. When interpreted correctly, the results from PNH flow cytometry testing, including presence and size of the clonal populations and the cell types involved, can allow the clinician to classify the disease appropriately; evaluate the risk of disease progression; and subsequently monitor response to therapy. In these guidelines, we discuss the evaluation of a patient with suspected PNH or other bone marrow failure disorders, with specific emphasis on the contribution of this testing to the diagnosis, classification, and monitoring of patients. For convenience we will commonly refer to these flow cytometry studies as "PNH testing" recognizing that an abnormal result is not diagnostic of PNH; rather both laboratory and clinical features are used to establish this diagnosis. (c) 2017 International Clinical Cytometry Society. PMID- 29236353 TI - ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and related disorders part 2 - reagent selection and assay optimization for high-sensitivity testing. AB - Since publication in 2010 of the International Clinical Cytometry Society (ICCS) Consensus Guidelines for detection of Paroxysmal nocturnal hemoglobinuria (PNH) by flow cytometery, a great deal of work has been performed to develop, optimize, and validate a number of high-sensitivity assays to detect PNH phenotypes in both red blood cells (RBCs) and white blood cells (WBCs, neutrophils, and monocytes). This section (Part 2) of the updated ICCS PNH Consensus Guidelines will focus on specific instrument setup for these PNH assays, the identification and proper testing of appropriate antibody conjugates and combinations therof, and basic assay design. (c) 2017 International Clinical Cytometry Society. PMID- 29236351 TI - Adipocytes role in the bone marrow niche. AB - Adipocyte infiltration in the bone marrow follows chemotherapy or irradiation. Previous studies indicate that bone marrow fat cells inhibit hematopoietic stem cell function. Recently, Zhou et al. (2017) using state-of-the-art techniques, including sophisticated Cre/loxP technologies, confocal microscopy, in vivo lineage-tracing, flow cytometry, and bone marrow transplantation, reveal that adipocytes promote hematopoietic recovery after irradiation. This study challenges the current view of adipocytes as negative regulators of the hematopoietic stem cells niche, and reopens the discussion about adipocytes' roles in the bone marrow. Strikingly, genetic deletion of stem cell factor specifically from adipocytes leads to deficiency in hematopoietic stem cells, and reduces animal survival after myeloablation, The emerging knowledge from this research will be important for the treatment of multiple hematologic disorders. (c) 2017 International Society for Advancement of Cytometry. PMID- 29236354 TI - How comprehensive are research studies investigating the efficacy of technology enhanced learning resources in anatomy education? A systematic review. AB - Anatomy education is at the forefront of integrating innovative technologies into its curricula. However, despite this rise in technology numerous authors have commented on the shortfall in efficacy studies to assess the impact such technology-enhanced learning (TEL) resources have on learning. To assess the range of evaluation approaches to TEL across anatomy education, a systematic review was conducted using MEDLINE, the Educational Resources Information Centre (ERIC), Scopus, and Google Scholar, with a total of 3,345 articles retrieved. Following the PRISMA method for reporting items, 153 articles were identified and reviewed against a published framework-the technology-enhanced learning evaluation model (TELEM). The model allowed published reports to be categorized according to evaluations at the level of (1) learner satisfaction, (2) learning gain, (3) learner impact, and (4) institutional impact. The results of this systematic review reveal that most evaluation studies into TEL within anatomy curricula were based on learner satisfaction, followed by module or course learning outcomes. Randomized controlled studies assessing learning gain with a specific TEL resource were in a minority, with no studies reporting a comprehensive assessment on the overall impact of introducing a specific TEL resource (e.g., return on investment). This systematic review has provided clear evidence that anatomy education is engaged in evaluating the impact of TEL resources on student education, although it remains at a level that fails to provide comprehensive causative evidence. Anat Sci Educ 11: 303-319. (c) 2017 American Association of Anatomists. PMID- 29236355 TI - B cell-specific protein FCRLA is expressed by plasmacytoid dendritic cells in humans. AB - BACKGROUND: Fc receptor-like A (FCRLA) is a unique member of a family of Fc receptor like-molecules that lacks a transmembrane region and is an ER-resident protein. In mice and humans, FCRLA has been known as a B cell specific protein. We report here that, in humans, FCRLA is also expressed in a subpopulation of plasmacytoid dendritic cells (pDCs). METHODS: Human peripheral blood mononuclear cells (PBMC), splenocytes, and tonsillar cells were stained for lineage markers followed by fixation/saponin permeabilization and intracellular staining for FCRLA, and then analyzed by flow cytometry with CD123 and CD303 used as pDC markers. RESULTS: We conducted an extensive flow cytometric analysis of a rare population of CD19-FCRLA+ cells found for the first time in human lymphoid tissues that we assigned to pDCs as they were lin-/CD123+/CD303+. FCRLA expression in human pDCs was further confirmed by the RT-PCR analysis of cDNA of pDCs isolated from the peripheral blood of a healthy donor. FCRLA-positive pDCs expressed a lower level of HLA-DR than their FCRLA-negative counterparts. CONCLUSIONS: FCRLA has long been viewed as a B cell specific protein, and this is the first time its expression has also been shown in human pDCs. (c) 2017 International Clinical Cytometry Society. PMID- 29236356 TI - Proteomics in Pathology. AB - Proteomic approaches are of growing importance in the biologist's toolbox. It greatly benefited from past and recent advances in sampling, chemical processing, mass spectrometry (MS) instrumentation, and data processing. MS-based analysis of proteins is now in the process of being translated in pathology for objective diagnoses. In this viewpoint, we present the workflows that we think are the most promising for applications in pathology. We also comment what we think are prerequisites for a successful translational implementation. PMID- 29236357 TI - Live attenuated influenza virus vaccine reduces virus shedding of newborn piglets in the presence of maternal antibody. AB - BACKGROUND: Influenza A virus in swine (IAV-S) causes an acute respiratory disease of swine which results in great economic losses in pig production. Major control strategies include the use of killed vaccines (KV) in breeding females to confer passive immunity to their offspring. A bivalent H1N1 and H3N2 NS1 truncated live attenuated IAV-S vaccine have recently become available, which showed promising results in young pigs. OBJECTIVE: The aim of this study was to investigate the effect of an intranasal vaccination of newborn pigs with or without maternally derived antibodies (MDA) on virus shedding (via nasal swabs tested by virus isolation). METHODS: The study was performed as intratracheal challenge experiments with either a heterologous H1N2 or H3N2 viruses. RESULTS AND CONCLUSION: The results of this study showed a significant decrease in the incidence and duration of shedding viable virus for vaccinated newborn piglets with or without MDA, providing strong evidence that intranasal vaccination is overcoming passively acquired maternal immunity. This study indicates that intranasal vaccination with a truncated NS1 live attenuated IAV-S vaccine of newborn piglets with maternal antibodies can be a valuable tool for reducing the prevalence of heterologous H1N2 and H3N2 IAV-S in pig herds. PMID- 29236358 TI - In vivo imaging the motility of monocyte/macrophage during inflammation in diabetic mice. AB - Diabetes, as a chronic metabolic disease, can impair the immune function of monocytes/macrophages (MMs). However, it is unclear how MM immune response to inflammation with the development of diabetes, and whether immune response around the inflammatory foci depends on the depth in tissue. Footpad provides a classical physiological site for monitoring cellular behavior during inflammation, but limited to the superficial dermis due to the strong scattering of footpad. Herein, we used confocal microscopy to monitor the motility of MMs in deeper tissue around inflammatory foci with the development of type 1 diabetic (T1D) mice through a switchable footpad skin optical clearing window. Delayed type hypersensitivity (DTH) model was elicited on the footpad of T1D. Results demonstrated that progressive T1D led to the gradually potentiated MM recruitment and increased expression of monocyte chemoattractant protein-1 during DTH, but MM migration displacement, motion velocity and motility coefficient were significantly attenuated. Besides, MMs from the deeper dermis had a much larger migration displacement than those from superficial dermis at early stages of DTH but an opposite tendency at late stages for non-T1D, while progressive T1D obscured this difference gradually. This study will be helpful for investigating the influences of progressive metabolic diseases on immune response. MM motion trajectory at depth of superficial dermis and the deeper dermis at AOVA (heat aggregated ovalbumin)-4 hours and AOVA-72 hours on non-T1D (A) and T1D-4 weeks (B). Mean motility coefficient (C) at the 2 depths. Data were pooled from 6 mice per group. *P < .05 and **P < .01 compared among different T1D disease durations. #P < .05 compared between different depths. PMID- 29236359 TI - The relationship between student engagement with online content and achievement in a blended learning anatomy course. AB - Blended learning has become increasingly common in higher education. Recent findings suggest that blended learning achieves better student outcomes than traditional face-to-face teaching in gross anatomy courses. While face-to-face content is perceived as important to learning there is less evidence for the significance of online content in improving student outcomes. Students enrolled in a second-year anatomy course from the physiotherapy (PT), exercise physiology (EP), and exercise science (ES) programs across two campuses were included (n = 500). A structural equation model was used to evaluate the relationship of prior student ability (represented by grade in prerequisite anatomy course) and final course grade and whether the relationship was mediated by program, campus or engagement with the online elements of the learning management system (LMS; proportion of documents and video segments viewed and number of interactions with discussion forums). PT students obtained higher grades and were more likely to engage with online course materials than EP and ES students. Prerequisite grade made a direct contribution to course final grade (P < 0.001) but was also mediated by engagement with LMS videos and discussion forums (P < 0.001). Student learning outcomes in a blended anatomy course can be predicted the by level of engagement with online content. Anat Sci Educ 11: 471-477. (c) 2017 American Association of Anatomists. PMID- 29236360 TI - Low risk of avian influenza A (H5N6) transmission to depopulation workers in Korea. AB - An outbreak of highly pathogenic avian influenza A (H5N6) virus occurred between November 20, 2016, and March 1, 2017 in poultry farms, in the Gyeonggi Province, Republic of Korea. To identify the risk of transmission of H5N6 to depopulation workers, active and passive surveillance was conducted. Virological testing of respiratory swabs with real-time reverse transcription-polymerase chain reaction was performed for workers who reported respiratory symptoms. Among 4633 depopulation workers, 22 reported respiratory symptoms, but all tested negative for H5N6. Personal protective equipment in addition to antiviral prophylaxis was adequate to limit transmission of H5N6 from poultry to humans. PMID- 29236361 TI - New Metabolites Produced by Cylindrocarpon sp. SY-39 from a Driftwood. AB - Four novel compounds, cylindropyrone A (1), 10'-hydroxyilicicolinic acid D (3), cylindrolactones A (4) and B (5), together with known dihydroinfectopyrone (2) were isolated from the culture of Cylindrocarpon sp. SY-39 from a driftwood. Their structures were elucidated using 1D- and 2D-NMR spectroscopy. Compound 3 showed antimicrobial activity against Staphylococcus aureus with MIC value of 5.0 MUg/mL. PMID- 29236363 TI - Diabetic Status Influences the Storage of Melatonin in Human Salivary Glands. AB - Recently we reported on the detailed localization of melatonin (and its receptors) in human salivary glands, revealing that serous cells are able to store and secrete melatonin into saliva. Since we found that type 2 diabetic patients display reduced melatonin content in saliva, our next step was to examine the presence of melatonin in salivary glands removed from type 2 diabetic subjects. The resulting data were compared with those previously obtained by identical procedures in non-diabetics, to establish if the diabetic status may affect melatonin distribution. Bioptic samples of diabetic parotid and submandibular glands were fixed, dehydrated, embedded in Epon Resin and processed to demonstrate melatonin reactivity by the immunogold staining method. The labeling density (expressed as the number of gold particles per MUm2 /granule) and the percentage of melatonin-positive granules were assessed in diabetic samples. These values were compared with those in non-diabetic samples and differences were evaluated. In parotid and submandibular diabetic glands the reactivity for melatonin was specifically associated with secretory granules and small vesicles in serous cells. Melatonin reactivity was higher in parotid than in submandibular glands. Our data were in line with those obtained in our previous study on non-diabetic glands. Diabetic salivary glands showed a higher labeling density and a lower number of melatonin-positive granules compared to non-diabetic glands. Taken together, these data might explain the decreased salivary melatonin content and the associated oral problems observed in diabetics. Anat Rec, 301:711-716, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29236362 TI - Implementation of repeat HIV testing during pregnancy in southwestern Kenya: progress and missed opportunities. AB - INTRODUCTION: Repeat HIV testing during the late antenatal period is crucial to identify and initiate treatment for pregnant women with incident HIV infection to prevent perinatal HIV transmission and keep mothers alive. In 2012, the Kenya Ministry of Health adopted international guidelines suggesting that pregnant women be offered retesting three months after an initial negative HIV test. Our objectives were to determine the current rate of antenatal repeat HIV testing; identify successes, missed opportunities and factors associated with retesting; and estimate the incidence of HIV during pregnancy. METHODS: Retrospective analysis of longitudinal data was conducted for a cohort of 2145 women attending antenatal care clinic at a large district hospital in southwestern Kenya. Data were abstracted from registers for all women who attended the clinic from the years 2011 to 2014. RESULTS: Although 90.2% of women first came to clinic prior to their third trimester and 27.5% had at least four clinic visits, 58.0% of all women went to delivery without a retest. Missed opportunities for retesting included not returning to clinic at all, not returning when eligible, or late gestational age (>28 weeks) at first clinic visit making them ineligible for retesting (accounting for 14.2%, 26.8% and 9.6% of all clinic attendees respectively); and failure to be retested even when eligible at one or more visits (accounting for 73.2% of eligible returnees). Being unmarried and aged 20 or younger was associated with an increase in mean gestational age of first visit by 2.52 weeks (95% CI: 1.56, 3.48) and a 2.59 increased odds (95% CI: 1.90, 3.54) of failing to return to clinic, compared to those who were married and over 20 years of age. On retest, two women tested HIV positive, suggesting an incidence rate of 4.4 per 100 person-years. After adjusting for potential confounders, only later year of last menstrual period (2013 vs. 2012 and 2011) was associated with retesting. CONCLUSIONS: Adoption of retesting guidelines in 2012 appears to have successfully increased retesting rates, but missed opportunities to identify incident HIV infection during pregnancy may contribute to continuing high rates of perinatal HIV transmission in southwestern Kenya. PMID- 29236364 TI - Intraflagellar transporter protein 140 (IFT140), a component of IFT-A complex, is essential for male fertility and spermiogenesis in mice. AB - Intraflagellar transport (IFT) is a conserved mechanism essential for the assembly and maintenance of most eukaryotic cilia and flagella. However, little is known about its role in sperm flagella formation and male fertility. IFT140 is a component of IFT-A complex. In mouse, it is highly expressed in the testis. Ift140 gene was inactivated specifically in mouse spermatocytes/spermatids. The mutant mice did not show any gross abnormalities, but all were infertile and associated with significantly reduced sperm number and motility. Multiple sperm morphological abnormalities were discovered, including amorphous heads, short/bent flagella and swollen tail tips, as well as vesicles along the flagella due to spermiogenesis defects. The epididymides contained round bodies of cytoplasm derived from the sloughing of the cytoplasmic lobes and residual bodies. Knockout of Ift140 did not significantly affect testicular expression levels of selective IFT components but localization of IFT27 and IFT88, two components of IFT-B complex, was changed. Our findings demonstrate that IFT140 is a key regulator for male fertility and normal spermiogenesis in mice. It not only plays a role in sperm flagella assembling, but is also involved in critical assembly of proteins that interface between the germ cell plasma and the Sertoli cell. PMID- 29236366 TI - ? PMID- 29236367 TI - ? PMID- 29236368 TI - ? PMID- 29236369 TI - ? PMID- 29236365 TI - Species Differences in the Organization of the Ventral Cochlear Nucleus. AB - The mammalian cochlear nuclei (CN) consist of two major subdivisions, the dorsal (DCN) and ventral (VCN) nuclei. We previously reported differences in the structural and neurochemical organization of the human DCN from that in several other species. Here we extend this analysis to the VCN, considering both the organization of subdivisions and the types and distributions of neurons. Classically, the VCN in mammals is composed of two subdivisions, the anteroventral (VCA) and posteroventral cochlear nuclei (VCP). Anatomical and electrophysiological data in several species have defined distinct neuronal types with different distributions in the VCA and VCP. We asked if VCN subdivisions and anatomically defined neuronal types might be distinguished by patterns of protein expression in humans. We also asked if the neurochemical characteristics of the VCN are the same in humans as in other mammalian species, analyzing data from chimpanzees, macaque monkeys, cats, rats and chinchillas. We examined Nissl- and immunostained sections, using antibodies that had labeled neurons in other brainstem nuclei in humans. Nissl-stained sections supported the presence of both VCP and VCA in humans and chimpanzees. However, patterns of protein expression did not differentiate classes of neurons in humans; neurons of different soma shapes and dendritic configurations all expressed the same proteins. The patterns of immunostaining in macaque monkey, cat, rat, and chinchilla were different from those in humans and chimpanzees and from each other. The results may correlate with species differences in auditory function and plasticity. Anat Rec, 301:862 886, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29236370 TI - ? PMID- 29236371 TI - ? PMID- 29236372 TI - ? PMID- 29236373 TI - ? PMID- 29236374 TI - ? PMID- 29236375 TI - ? PMID- 29236376 TI - The relationship between serum ferritin levels and serum lipids and HDL function with respect to age and gender. AB - Elevated serum ferritin (SFer) levels have been associated with chronic diseases such as coronary heart disease and diabetes mellitus type 2. The aim of this study was to examine the relationship between SFer levels and serum lipid parameters, and how this relation changes in terms of age and gender. Additionally, we investigated a possible relationship between SFer levels and high-density lipoprotein (HDL) function. SFer levels and lipid panel (total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and HDL-C) of 4205 people (3139 women, 1066 men) were examined retrospectively. Study population was classified according to age and gender. Separately, 100 subjects (52 women, 48 men) were randomly recruited to investigate the relation between SFer levels, and HDL dependent paraoxonase-1 (PON1) and arylesterase (ARE) activities. In all age groups, women's SFer levels were found to be significantly lower and HDL-C levels significantly higher compared to men. In the 50-70 ages range, TC and LDL-C levels of women were found to be significantly higher than those of men (P < 0.01). SFer levels tended to increase with age in women. Correlation analyses revealed a negative correlation between levels of SFer and HDL-C, while positive correlations existed between levels of SFer, and TC, TG and LDL-C. There was no significant correlation between SFer levels and PON1 or ARE activities. The finding that increased SFer levels are accompanied by increased serum TC, TG and LDL-C levels may help us to explain the increased risk of metabolic disorders and cardiovascular disease in postmenopausal women. PMID- 29236377 TI - Xpey' Relational Environments: an analytic framework for conceptualizing Indigenous health equity. AB - INTRODUCTION: Both health equity research and Indigenous health research are driven by the goal of promoting equitable health outcomes among marginalized and underserved populations. However, the two fields often operate independently, without collaboration. As a result, Indigenous populations are underrepresented in health equity research relative to the disproportionate burden of health inequities they experience. In this methodological article, we present Xpey' Relational Environments, an analytic framework that maps some of the barriers and facilitators to health equity for Indigenous peoples. METHODS: Health equity research needs to include a focus on Indigenous populations and Indigenized methodologies, a shift that could fill gaps in knowledge with the potential to contribute to 'closing the gap' in Indigenous health. With this in mind, the Equity Lens in Public Health (ELPH) research program adopted the Xpey' Relational Environments framework to add a focus on Indigenous populations to our research on the prioritization and implementation of health equity. The analytic framework introduced an Indigenized health equity lens to our methodology, which facilitated the identification of social, structural and systemic determinants of Indigenous health. To test the framework, we conducted a pilot case study of one of British Columbia's regional health authorities, which included a review of core policies and plans as well as interviews and focus groups with frontline staff, managers and senior executives. CONCLUSION: ELPH's application of Xpey' Relational Environments serves as an example of the analytic framework's utility for exploring and conceptualizing Indigenous health equity in BC's public health system. Future applications of the framework should be embedded in Indigenous research methodologies. PMID- 29236379 TI - Alcohol consumption and low-risk drinking guidelines among adults: a cross sectional analysis from Alberta's Tomorrow Project. AB - INTRODUCTION: Moderate to heavy alcohol consumption is a risk factor for all cause mortality and cancer incidence. Although cross-sectional data are available through national surveys, data on alcohol consumption in Alberta from a large prospective cohort were not previously available. The goal of these analyses was to characterize the levels of alcohol consumption among adults from the Alberta's Tomorrow Project in the context of cancer prevention guidelines. Furthermore, we conducted analyses to examine the relationships between alcohol consumption and other high-risk or risk-related behaviours. METHODS: Between 2001 and 2009, 31 072 men and women aged 35 to 69 years were enrolled into Alberta's Tomorrow Project, a large provincial cohort study. Data concerning alcohol consumption in the past 12 months were obtained from 26 842 participants who completed self administered health and lifestyle questionnaires. We conducted cross-sectional analyses on daily alcohol consumption and cancer prevention guidelines for alcohol use in relation to sociodemographic factors. We also examined the combined prevalence of alcohol consumption and tobacco use, obesity and comorbidities. RESULTS: Approximately 14% of men and 12% of women reported alcohol consumption exceeding recommendations for cancer prevention. Higher alcohol consumption was reported in younger age groups, urban dwellers, those with higher incomes and those who consumed more red meat. Moreover, volume of daily alcohol consumption was positively associated with current tobacco use in both men and women. Overall, men were more likely to fall in the moderate and high-risk behavioural profiles and show higher daily alcohol consumption patterns compared to women. CONCLUSION: Despite public health messages concerning the adverse impact of alcohol consumption, a sizeable proportion of Alberta's Tomorrow Project participants consumed alcohol in excess of cancer prevention recommendations. Continued strategies to promote low-risk drinking among those who choose to drink could impact future chronic disease risk in this population. PMID- 29236378 TI - Urinary bisphenol A and obesity in adults: results from the Canadian Health Measures Survey. AB - INTRODUCTION: Exposure to bisphenol A (BPA) has been shown to affect lipid metabolism and promote weight gain in animal studies. Recent epidemiological studies also support a link between BPA and obesity in human populations, although many were limited to a single adiposity measure or have not considered potential confounding by dietary factors. The purpose of this study is to examine associations between urinary BPA and adiposity measures in a nationally representative sample of Canadian adults. METHODS: We performed analyses using biomonitoring and directly measured anthropometric data from 4733 adults aged 18 to 79 years in the Canadian Health Measures Survey (2007-2011). We used multinomial and binary logistic regression models to estimate associations of urinary BPA with body mass index (BMI) categories (overweight vs. under/normal weight; obesity vs. under/normal weight) and elevated waist circumference (males: >= 102 cm; females: >= 88 cm), respectively, while controlling for potential confounders. Linear regression analyses were also performed to assess associations between urinary BPA and continuous BMI and waist circumference measures. RESULTS: Urinary BPA was positively associated with BMI-defined obesity, with an odds ratio of 1.54 (95% confidence interval [CI]: 1.002-2.37) in the highest (vs. lowest) BPA quartile (test for trend, p = .041). Urinary BPA was not associated with elevated waist circumference defined using standard cut-offs. Additionally, each natural-log unit increase in urinary BPA concentration was associated with a 0.33 kg/m2 (95% CI: 0.10- 0.57) increase in BMI and a 1.00 cm (95% CI: 0.34-1.65) increase in waist circumference. CONCLUSION: Our study contributes to the growing body of evidence that BPA is positively associated with obesity. Prospective studies with repeated measures are needed to address temporality and improve exposure classification. PMID- 29236380 TI - Generation of optimized preparations of bone morphogenetic proteins for bone regeneration. AB - Correction of inherited skeletal abnormalities, traumas affecting wide bone areas and non-healing fractures require efficient bone formation and regeneration. Bone morphogenetic proteins (BMPs) are signa-ling molecules that play a crucial role in bone and cartilage formation and regeneration. Osteoinductive properties of existing hydroxyapatite-based osteoplastic materials are frequently insufficient for efficient bone regeneration, thus raising a requirement for novel matrices involving BMPs for highly efficient local induction of bone formation at the area of the bone defect. The aim of this study was conducting in vitro optimization of osteoinductive properties of recombinant BMPs preparations to be used in bone regenerative practice. Recombinant BMPs were produced in human embryonic kidney 293 cells upon their transfection or co-transfection with plasmids expressing BMP2 and BMP7 at different ratios. A quality of BMP preps was validated based on their ability to induce in vitro osteoblast differentiation of C2C12 cells. Alkaline phosphatase that is widely used as a marker of osteoblast differentiation was measured spectrophotometrically. We found that the most effective inducer of osteoblast differentiation was recombinant BMP preparation produced upon cotransfection of 85% of BMP2 and 15% of BMP7 plasmids, that is most likely due to generation of conditions most favorable for formation of BMP2/7 heterodimers. Frozen BMP2/7 preparations stored for 3 h in experimental setup and for several weeks in routine work do not lose their osteoinductive properties compared with freshly prepared BMP2/7 preparations and can be successfully used for generation of highly efficient bone regenerative matrices. PMID- 29236381 TI - Nobel laureate Ilya I. Metchnikoff (1845-1916). Life story and scientific heritage. AB - A century of science after I. Metchnikoff's death demonstrated the truth in many of his views and judgments in the field of immunology, pathology, bacteriology, zoology and comparative embryology. Today Metchnikoff is deservedly called the father of the theory of cellular immunity, and also a harbinger of the theo-ry of natural immunity. His work in the field of lactic acid bacteria formed the basis for an entire industry of probiotics. Metchnikoff's doctrine of the possibility of extending human life is still relevant. This publication is one more attempt to tie the biography of the scientist with his creative legacy and his contribution in the world treasury of biological science. PMID- 29236382 TI - [Inventive activity of the Department of Metabolism Regulation of the Palladin Institute of Biochemistry of NAS of Ukraine]. AB - The article is devoted to the inventive activity of the Department of Metabolism Regulation of the Palladin Institute of Biochemistry of NAS of Ukraine in the context of the history of its inception, development and the research activities of its founder, academician of NAS of Ukraine M. F. Guly as well as his students and followers. It briefly tells about practical achievements of M. F. Guly which were as significant, immense and diverse as his scientific accomplishments. The paper analyses in detail the practical results of scientific research of his students and followers aimed to solve practical problems of medicine, food processing, agriculture, and which are essentially a continuation of the ideas and projects of M. F. Guly. PMID- 29236383 TI - Black men and utilisation of healthcare services. AB - Health disparities is described as inequalities signified by differences in environment, access, utilization, quality of care, health status, or particular health outcomes. On a variety of health measures, healthcare access and other social determinants of health, minority men fare worse than white men. Nurses have the responsibility to eliminate health disparities among people from diverse racial, ethnic, and cultural backgrounds. To do this, nurses must become more knowledgeable about the health disparities among the racial and ethnic groups they serve. PMID- 29236384 TI - Research project supports the emotional wellbeing of young fathers during the perinatal journey in parenthood. AB - In Australia, mental health problems carry the highest burden of disease in 18-25 year olds, with males representing 23% of those affected (Australian Institute of health and Welfare [AIHW] 2011). PMID- 29236385 TI - Lipoxygenases and their metabolites in formation of plant stress tolerance. AB - The review focuses on the analysis of new information concerning molecular enzymology of lipoxygenases - proteins involved in lipid peroxidation and found in animals and plants. Modern concept of structural features, catalytic characteristics and functions of lipoxygenase family enzymes as well as products of their catalytic activity in plants have been discussed and summarized. Issues of enzyme localization in plant cells and tissues, evolution and distribution of lipoxygenases, involvement in production of signaling substances involved in formation of adaptation response to abiotic and biotic stress factors and in regulation of lipoxygenase signal system activity are highlighted. Participants of the elements signaling of LOX-pathway reception and transduction into genome are considered. Special attention is given to jasmonates, metabolites of the allene oxide synthase branch of the lipoxygenase cascade, because these metabolites have high biological activity, are ubiquitously present in all plant organisms, and are involved in regulation of vitally important processes. Data concerning lipoxygenase phylogeny, possible occurrence of a common predecessor for modern isoforms of the enzyme in pro- and eukaryote have been examined. Some results of our studies that open up possibilities of using the lipoxygenase catalytic activity characteristics as biological markers in plant stress tolerance researches are given. PMID- 29236386 TI - Characteristics of enzyme-linked immunosorbent assay for detection of IgG antibodies specific to Shlamydia trachomatis heat shock protein (HSP-60) AB - The goal of this work was to study sensitivity and specificity of the developed ELISA set for the identification of IgG antibodies against Chlamydia trachomatis HSP-60 (using biotinylated tyramine-based signal amplification system). The study was conducted using a panel of characterized sera, as well as two reference ELISA sets of similar purpose. According to the results of ELISA informative value parameters, the ELISA we have developed showed the highest specificity and sensitivity parameters (no false negative or false positive results were registered). In 4 out of 15 intralaboratory panel serum samples initially identified as negative, anti-HSP-60 IgG-antibodies test result in reference ELISA sets upon dilution changed from negative to positive. The nature of titration curves of false negative sera and commercial monoclonal antibodies A57-V9 against C. trachomatis HSP-60 after incubation for 24 h was indicative of the presence of anti-idiotypic antibodies in these samples. Upon sera dilution, idiotypic-anti idiotypic complexes dissociated, which caused the change of test result. High informative value of the developed ELISA set for identification of IgG antibodies against C. trachomatis HSP-60 has been proven. Anti-idiotypic antibodies possessing C. trachomatis anti-HSP-60 activity and being one of the causes of false negative results of the relevant ELISA-based tests have been identified in blood sera of individuals infected with chlamydial genitourinary infection agents. PMID- 29236387 TI - Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction. AB - Biochemical properties of 3-substituted 1,4-benzodiazepine determined by the characteristics of their chemical structure. Influence of 3-substituted 1,4 benzodiazepin-2-ones on maximal normalized rate and amplitudes of isometric smooth muscle contraction in rats was investigated. Compounds MX-1775 and MX-1828 demonstrated the similar inhibition effect on bradykinin-induced contraction of smooth muscle like competitive inhibitor des-arg9-bradykinin-acetate to bradykinin B2-receptors. MX-1626 demonstrated unidirectional changes of maximal normalized rate and force of smooth muscle that proportionally depended on bradykinin concentration in the range 10-10-10-6 M. MX-1828 has statistically significant decrease of normalized rate of smooth muscle contraction for bradykinin concentrations 10-10 and 10-9 M by 20.7 and 8.6%, respectively, but for agonist concentration 10-6 M, this parameter increased by 10.7% and amplitude was reduced by 29.5%. Compounds MX-2011, MX-1785 and MX-2004 showed no natural effect on bradykinin-induced smooth muscle contraction. Compounds MX-1775, MX 1828, MX-1626 were selected for further research of their influence on kinin kallikrein system and pain perception. PMID- 29236388 TI - Inhibition of IRE1 modifies hypoxic regulation of G6PD, GPI, TKT, TALDO1, PGLS and RPIA genes expression in U87 glioma cells. AB - We have studied the effect of hypoxia on the expression level of mRNA of the basic enzymes of pentose-phosphate cycle (G6PD, TKT, TALDO1, PGLS and RPIA) and glucose-6-phosphate isomerase (GPI) in U87 glioma cells in relation to inhibition of IRE1 (inositol requiring enzyme 1). It was shown that hypoxia leads to up regulation of the expression of GPI and PGLS genes and to down-regulation of TALDO1 and RPIA genes in control glioma cells. Changes for GPI gene were more significant than for other genes. At the same time, inhibition of IRE1 modified the effect of hypoxia on the expression of all studied genes. In particular, it increased sensitivity to hypoxia of G6PD and TKT genes expression and suppressed the effect of hypoxia on the expression of GPI and RPIA genes. Additionally, inhibition of IRE1 eliminated hypoxic regulation of PGLS gene and did not change significantly effect of hypoxia on the expression of TALDO1 gene in glioma cells. Present study demonstrated that hypoxia, which often contributes to tumor growth, affects the expression of most studied genes and inhibition of IRE1 modified the hypoxic regulation of pentose-phosphate cycle gene expressions in a gene specific manner and thus possibly contributes to slower glioma growth, but several aspects of this regulation warrant further investigation. PMID- 29236389 TI - Fecal short-chain fatty acids at different time points after ceftriaxone administration in rats. AB - Short-chain fatty acids (SCFAs) are major products of the microbial fermentation of dietary fiber in the colon. Recent studies suggest that these products of microbial metabolism in the gut act as signaling molecules, influence host energy homeostasis and play major immunological roles. In the present study, defined the long-term effects of ceftriaxone administration on the fecal SCFAs concentration in Wistar rats. Ceftriaxone (300 mg/kg, i.m.) was administered daily for 14 days. Rats were euthanized in 1, 15 and 56 days after ceftriaxone withdrawal. Caecal weight and fecal concentration of SCFAs by gas chromatography were measured. Ceftriaxone administration induced time-dependent rats' caecal enlargement through accumulation of undigestable substances. In 1 day after ceftriaxone withdrawal, the concentrations of acetic, propionic, butyric acids and total SCFAs were decreased 2.9-, 13.8-, 8.5-, 4.8-fold (P < 0.05), respectively. Concentration of valeric, isovaleric and caproic acids was below the detectable level. That was accompanied by decreased 4.3-fold anaerobic index and increased the relative amount of acetic acid (P < 0.05). In 56 days, concentration of SCFAs was still below control value but higher than in 1 day (except propionic acid). Anaerobic index was lower 1.3-fold (P < 0.05) vs. control. Conclusion: antibiotic therapy induced long-term disturbance in colonic microbiota metabolic activity. PMID- 29236390 TI - Serum glycomarkers of endoplasmic reticulum and lysosomal-endosomal system stress in human healthy aging and diseases. AB - To verify the idea that extracellular free oligosaccharides might be able to reflect the functional status of the endoplasmic reticulum (ER) and lysosomal endosomal system, HPLC-profiles of serum-derived free oligosaccharides (FOS) in human healthy aging, acute myeloproliferative neoplasms, and cardiovascular pathologies were compared with intracellular glycans. After plasma deproteinization and FOS purification the oligosaccharides were labelled with anthranilic acid, separated into the neutral and charged with QAE Sephadex (Q25 120) chromatography and analysed using high-performance liquid chromatography (HPLC). The charged FOS were digested with a sialidase and compared with free oligosaccharides from transferrin for structural decoding. HPLC-profiles of serum derived FOS revealed mild delay of the dolichol phosphate cycle in ER, moderate intensification of ER-associated degradation (ERAD) and degradation in endosomal lysosomal system with aging; an inhibition of the dolichol phosphate cycle, intensification of ERAD and increasing of lysosomal exocytosis in acute myeloproliferative neoplasms; intensification of ERAD and glycocojugate degradation with endosomal-lysosomal system in cardiovascular diseases. As serum free oligosaccharides are able to reflect specifically perturbations in ER and endosomal-lysosomal system under wide range of stressors they can serve as extracellular markers of functionality of these organelles. PMID- 29236391 TI - Age-related changes phospholipids of sterlet in liver and dorsal muscles. AB - Study of phospholipids changes peculiarities in the liver and dorsal muscles of sterlet (Acipenser ruthenus Linnaeus) may be important to determine the etiology and pathogenesis of fatty liver. We established that the content of total phospholipids in tissues of the liver and dorsal muscles of three-year-old sterlet was less than for two-year-old fish by 15% and 20% (P <= 0.01), respectively. The amount of phosphatidylcholine (P <= 0.05), phosphatidylethanolamine, phosphatidylserine (P <= 0.01), phosphatidylinositol (P <= 0.01) and cardiolipin in the liver of 3-year-old sterlet was lower than for the 2-year-old fish, while quantitative indices for lysophosphatidylcholine and sphingomyelin were slightly increased. Similarly, in the cells of the dorsal muscles, the amount of phospholipid components (except lysophosphatidylcholine) was decreased with age. A decrease in the amount of phosphatidylethanolamine and phosphatidylserine in the dorsal muscles of 3-year-old sterlet was significant. The major phospholipids respective distribution was stable, except for phosphatidylethanolamine and particularly sphingomyelin. PMID- 29236393 TI - Validation of biological activity testing procedure of recombinant human interleukin-7. AB - Validation procedure for method of monitoring the biological activity of resombinant human interleukin-7 has been developed and conducted according to the requirements of national and international recommendations. This method is based on the ability of recombinant human interleukin-7 to induce proliferation of T lymphocytes. It has been shown that to control the biological activity of recombinant human interleukin-7 peripheral blood mononuclear cells (PBMCs) derived from blood or cell lines can be used. Validation charac-teristics that should be determined depend on the method, type of product or object test/measurement and biological test systems used in research. The validation procedure for the method of control of biological activity of recombinant human interleukin-7 in peripheral blood mononuclear cells showed satisfactory results on all parameters tested such as specificity, accuracy, precision and linearity. PMID- 29236392 TI - Effect of preparations Methyure and Ivine on Sa(2+)-ATPases activity in plasma and vacuolar membrane of corn seedling roots under salt stress conditions. AB - Ca2+-ATPases regulate the functioning of Ca2+-dependent signaling pathway SOS which provides removal of Na+ from the cytoplasm of cells via Na+/H+-antiporters in saline conditions. The influence of synthetic preparations Methyure and Ivine on the Ca2+-ATPase activity was investigated. It was shown that exposition of corn seedlings in the presence of 0.1 M NaCl rather enhanced hydrolytic than transport activity of Ca2+-ATPases in plasma and vacuolar membrane of root cells. It was found that seed treatment with such preparations, especially Methyure, caused intensification of the both activities of Ca2+-ATPases, mainly in vacuolar membrane. The results indicate than salt protective activity of preparations, especially Methyure, is associated with increased Ca2+-ATPase activity, which regulates the functioning of Na+/H+-antiporters. PMID- 29236394 TI - [Scientific and practical activity of the Department of Muscle Biochemistry of the Palladin Institute of Biochemistry of NAS of Ukraine]. AB - The article focuses on scientific and practical activity of the Department of Muscle Biochemistry of the Palladin Institute of Biochemistry of NAS of Ukraine in the context of its foundation and development. Main findings and practical achievements in the area of muscle biochemistry are summarized and discussed. PMID- 29236395 TI - Being brave enough to ask. PMID- 29236396 TI - Consultations lead to national home care action plan. PMID- 29236397 TI - Dementia-friendly care models added to resource. PMID- 29236398 TI - Toward a National Dementia Strategy. PMID- 29236399 TI - How to better serve an aging population. PMID- 29236400 TI - Being uprooted, finding her place. PMID- 29236401 TI - Education on grief, loss and dementia for family caregivers. PMID- 29236402 TI - Redrawing the nursing identity. PMID- 29236403 TI - Canada's long-term care funding crisis. PMID- 29236404 TI - Exploring the decline of narrow networks on the 2017 ACA marketplaces. AB - The prevalence of narrow provider networks on the ACA Marketplace is trending down. In 2017, 21% of plans had narrow networks, down from 25% in 2016. The largest single factor was that 70% of plans from National carriers exited the market and these plans had narrower networks than returning plans. Exits account for more than half of the decline in the prevalence of narrow networks, with the rest attributed to broadening networks among stable plans, particularly among Blues carriers. The narrow network strategy is expanding among traditional Medicaid carriers and remains steady among provider-based carriers and regional/local carriers. PMID- 29236405 TI - Will health ministers craft a health accord that delivers for Canadians? PMID- 29236406 TI - Recommendations for federal budget, health accord and home care top Hill Day agenda. PMID- 29236407 TI - Editorial. PMID- 29236408 TI - Continuing improvements being made to certification program. PMID- 29236409 TI - CNA leads development of first nursing list for Choosing Wisely Canada. PMID- 29236410 TI - First steps in creating a national action plan on post-traumatic stress injury/disorder. PMID- 29236412 TI - Introduction to research sampling. PMID- 29236411 TI - Boosting Social and Emotional Development In and Out of School. AB - (1) Illinois' state ESSA plan reflects the state's whole-child approach, adding references to the social, emotional and behavioral needs of students, along with high expectations for student achievement. (2) Massachusetts' state ESSA plan lists supporting socialemotional learning, health and safety as among the state's core educational strategies. (3) South Carolina's ESSA plan develops a framework identifying self-direction, perseverance, global perspective and interpersonal skills to be among thecharacteristics that every student should have when he or she graduates from high school. PMID- 29236413 TI - The fentanyl crisis. PMID- 29236414 TI - Conference and summit tackle opioid crisis. PMID- 29236415 TI - The challenges of medical cannabis research. PMID- 29236416 TI - Cannabis for medical purposes: Legal implications for nurses. PMID- 29236417 TI - Understanding Crohn's Disease. AB - The following excerpt is from the Understanding Crohn's Disease course available on the ANMF's Body Systems Training Room. The complete course is approximately 70 minutes in duration and will introduce you to the disease state and clinical management of Crohn's disease. This excerpt gives you 30 minutes of CPD toward your annual requirements. PMID- 29236418 TI - Building bridges to enhance interpersonal relationships. PMID- 29236420 TI - Navigating a bill of rights for Australia. PMID- 29236419 TI - Optimizing the role. PMID- 29236421 TI - Promoting direct human contact. PMID- 29236422 TI - Lessons from the U.K. about vitamin D supplementation. PMID- 29236423 TI - GMOs, genetically modified organisms or genuinely mixed opinions? A reasonable Consumer's understanding of the terms "GMO" and "non-GMO," and the struggle to set a Standard.? PMID- 29236425 TI - Review of a home nursing injection service: SHINE. AB - The SHINE home injection service is part of a patient support program run by Novartis. SHINE is for people prescribed octreotide long-acting release (Sandostatin LAR) for neuroendocrine tumours (NETs) and acromegaly. SHINE has been running in Australia since 2009. The service is run by a third-party and administered by homecare (SHINE) nurses. Five hundred people with NETs or acromegaly have been involved since the service started. We review our collective experience of the benefits of SHINE, and make recommendations for future development. We hope this review provides guidance for developing future home injection service. PMID- 29236427 TI - Sharing, samples, and generics: an antitrust framework. AB - Rising drug prices are in the news. By increasing price, drug companies have placed vital, even life-saving, medicines out of the reach of consumers. In a recent development, brand firms have prevented generics even from entering the market. The ruse for this strategy involves risk-management programs known as Risk Evaluation and Mitigation Strategies ("REMS"). Pursuant to legislation enacted in 2007, the FDA requires REMS when a drug's risks (such as death or injury) outweigh its rewards. Brands have used this regime, intended to bring drugs to the market, to block generic competition. Regulations such as the federal Hatch-Waxman Act and state substitution laws foster widespread generic competition. But these regimes can only be effectuated through generic entry. And that entry can take place only if a generic can use a brand's sample to show that its product is equivalent. More than 100 generic firms have complained that they have not been able to access needed samples. One study of 40 drugs subject to restricted access programs found that generics' inability to enter cost more than $5 billion a year. Brand firms have contended that antitrust law does not compel them to deal with their competitors and have highlighted concerns related to safety and product liability in justifying their refusals. This Article rebuts these claims. It highlights the importance of samples in the regulatory regime and the FDA's inability to address the issue. It shows how a sharing requirement in this setting is consistent with Supreme Court caselaw. And it demonstrates that the brands' behavior fails the defendant-friendly "no economic sense" test because the conduct literally makes no sense other than by harming generics. Brands' denial of samples offers a textbook case of monopolization. In the universe of pharmaceutical antitrust behavior, other conduct--such as "pay for delay" settlements between brands and generics and "product hopping" from one drug to a slightly modified version--has received the lion's share of attention. But sample denials are overdue for antitrust scrutiny. This Article fills this gap. Given the failure of Congress and the FDA to remedy the issue, antitrust can play a crucial role in ensuring generic access to samples, affirming a linchpin of the pharmaceutical regime. PMID- 29236429 TI - Editorial. PMID- 29236430 TI - PROTECTING MOTHERS AND BABIES ABROAD. AB - A 28-year-old mother who had just given birth to her fourth child when she suffered a postpartum haemorrhage confirms the profound impact of a bustling maternity service established in one of the poorest neighbourhoods in Afghanistan's capital Kabul. PMID- 29236431 TI - GROUND ZERO. STANDING UP AGAINST VIOLENCE IN OUR HEALTHCARE SECTOR. AB - Occupational violence and aggression is rife within the healthcare sector. The impact of verbal and physical assault can leave psychological scars that lead many to question their place in the workforce. Growing public awareness, harsher penalties for perpetrators, and improved safety strategies mark a shift towards a culture of zero tolerance and collective attitude that enough is enough. Robert Fedele investigates. PMID- 29236432 TI - ASSISTING WOMEN TO CONCEIVE: A CLINICAL UPDATE ON FERTILITY-AWARENESS. AB - This update on fertility-awareness has two principle aims. First, to highlight the gaps in women's understanding of when in the menstrual cycle it is possible to conceive and second, to outline the accurate use of fertility-awareness methods to ensure correctly timed intercourse for a pregnancy. Nurses and midwives who provide sexual and reproductive healthcare services will find this clinical practice update particularly helpful. PMID- 29236433 TI - TIME TO MAKE YOUR VOICE HEARD IN THE VOLUNTARY EUTHANASIA DEBATE. PMID- 29236434 TI - WE MAKE A DIFFERENCE. AB - Back in 2009 Julianne used this column to raise the issue of the importance of language 'in the way we describe ourselves as nurses and midwives, what it is that we do and what that means to both ourselves and others'. Her assertion was that when attempting to define nursing or midwifery, or the role of a nurse or a midwife, the definition never seems to adequately address all that a nurse or midwife is, or does. We are not 'just a nurse' or 'just a midwife'. PMID- 29236435 TI - BREAKING THE SILENCE--THE TERMINALLY ILL MENTAL HEALTH CLIENT. AB - Both mental illness and terminal disease require an adjustment of expectations from both therapist and client if management of either condition is to be achieved. When mental illness is present in the terminal patient, these adjustments are both radical and very difficult. Which beckons the question, does this provide a basis for integrated mental health services within palliative care? PMID- 29236436 TI - FAILING TO IDENTIFY AND RESPOND TO THE DETERIORATING PATIENT: A CASE FOR THE CORONER. AB - The Coroners Court is a unique court that fulfills an important function in our legal system--determining the manner and cause of death of those who have died in unexpected or unexplained circumstances. With broad powers of investigation the Coroner through the coronial process will make findings and recommendations regarding the death or suspected deaths of individuals in their particular circumstances. PMID- 29236437 TI - FALLS PREVENTION. AB - The following excerpt on Falls Prevention is from the newest addition to the topics list on the Continuing Professional Education (CPE) website. The tutorial covers falls risk, contributing factors, screening and assessment tools, strategies to reduce falls and the nurses and midwives role in prevention and treatment. The ANMF falls prevention tutorial is relevant to all levels of nurses and midwives. PMID- 29236438 TI - A REGISTERED NURSE IN 20 WEEKS? AB - This paper raises concerns and issues related to the adequacy of nursing students' clinical placement hours. PMID- 29236463 TI - Interface-Induced Enhancement of Ferromagnetism in Insulating LaMnO3 Ultrathin Films. AB - Engineering ferromagnetism, by modulating its magnitude or anisotropy, is an important topic in the field of magnetism and spintronics. Among different types of magnetic materials, ferromagnetic insulators, in which magnetic moment unusually coexists with localized electrons, are of particular interest. Here, we report a remarkable interfacial enhancement of the ferromagnetism by adding one unit-cell LaAlO3 adjacent to an insulating LaMnO3 ultrathin film. The enhancement of ferromagnetism is explained in terms of charge transfer at the interface, as evidenced by X-ray absorption spectroscopy and ab initio calculations. This study demonstrates an effective and dramatic approach to modulate the functionality of ferromagnetic insulators, contributing to the arsenal of engineering techniques for future spintronics. PMID- 29236464 TI - Interpreting the Combustion Process for High-Performance ZrNiSn Thermoelectric Materials. AB - The ZrNiSn alloy, a member of the half-Heusler family of thermoelectric materials, shows great potential for mid-to-high-temperature power generation applications due to its excellent thermoelectric properties, robust mechanical properties, and good thermal stability. The existing synthesis processes of half Heusler alloys are, however, rather time and energy intensive. In this study, single-phase ZrNiSn bulk materials were prepared by self-propagating high temperature synthesis (SHS) combined with spark plasma sintering (SPS) for the first time. The analysis of thermodynamic and kinetic processes shows that the SHS reaction in the ternary ZrNiSn alloy is different from the more usual binary systems. It consists of a series of SHS reactions and mass transfers triggered by the SHS fusion of the binary Ni-Sn system that eventually culminates in the formation of single-phase ternary ZrNiSn in a very short time, which reduced the synthesis period from few days to less than an hour. Moreover, the nonequilibrium feature induces Ni interstitials in the structure, which simultaneously enhances the electrical conductivity and decreases the thermal conductivity, which is favorable for thermoelectric properties. The maximum thermoelectric figure of merit ZT of the SHS + SPS-processed ZrNiSn1-xSbx alloy reached 0.7 at 870 K. This study opens a new avenue for the fast and low-cost fabrication of half-Heusler thermoelectric materials. PMID- 29236465 TI - G-Quadruplex Induction by the Hairpin Pyrrole-Imidazole Polyamide Dimer. AB - The G-quadruplex (G4) is one type of higher-order structure of nucleic acids and is thought to play important roles in various biological events such as regulation of transcription and inhibition of DNA replication. Pyrrole-imidazole polyamides (PIPs) are programmable small molecules that can sequence-specifically bind with high affinity to the minor groove of double-stranded DNA (dsDNA). Herein, we designed head-to-head hairpin PIP dimers and their target dsDNA in a model G4-forming sequence. Using an electrophoresis mobility shift assay and transcription arrest assay, we found that PIP dimers could induce the structural change to G4 DNA from dsDNA through the recognition by one PIP dimer molecule of two duplex-binding sites flanking both ends of the G4-forming sequence. This induction ability was dependent on linker length. This is the first study to induce G4 formation using PIPs, which are known to be dsDNA binders. The results reported here suggest that selective G4 induction in native sequences may be achieved with PIP dimers by applying the same design strategy. PMID- 29236466 TI - Honokiol-Inspired Analogs as Inhibitors of Oral Bacteria. AB - The oral microbiome is a complex ecological niche where both commensal and pathogenic bacteria coexist. Previous reports have cited that the plant isolate honokiol is a potent inhibitor of S. mutans biofilms. Herein we report a cross coupling method that provides access to a concise library of honokiol-inspired analogs. Through this work we determined that the inhibitory activity of honokiol is highly dependent on the growth conditions. Further, we identify a series of analogs that display significant potency against oral bacteria leading to the discovery of a potent antimicrobial. PMID- 29236468 TI - Assessment of Eco-friendly Gases for Electrical Insulation to Replace the Most Potent Industrial Greenhouse Gas SF6. AB - Gases for electrical insulation are essential for the operation of electric power equipment. This Review gives a brief history of gaseous insulation that involved the emergence of the most potent industrial greenhouse gas known today, namely sulfur hexafluoride. SF6 paved the way to space-saving equipment for the transmission and distribution of electrical energy. Its ever-rising usage in the electrical grid also played a decisive role in the continuous increase of atmospheric SF6 abundance over the last decades. This Review broadly covers the environmental concerns related to SF6 emissions and assesses the latest generation of eco-friendly replacement gases. They offer great potential for reducing greenhouse gas emissions from electrical equipment but at the same time involve technical trade-offs. The rumors of one or the other being superior seem premature, in particular because of the lack of dielectric, environmental, and chemical information for these relatively novel compounds and their dissociation products during operation. PMID- 29236467 TI - Recent Advances in Enzymatic Complexity Generation: Cyclization Reactions. AB - Enzymes in biosynthetic pathways, especially in plant and microbial metabolism, generate structural and functional group complexity in small molecules by conversion of acyclic frameworks to cyclic scaffolds via short, efficient routes. The distinct chemical logic used by several distinct classes of cyclases, oxidative and non-oxidative, has recently been elucidated by genome mining, heterologous expression, and genetic and mechanistic analyses. These include enzymes performing pericyclic transformations, pyran synthases, tandem acting epoxygenases, and epoxide "hydrolases", as well as oxygenases and radical S adenosylmethionine enzymes that involve rearrangements of substrate radicals under aerobic or anaerobic conditions. PMID- 29236469 TI - Synthetic Phenolic Antioxidants Cause Perturbation in Steroidogenesis in Vitro and in Vivo. AB - Synthetic phenolic antioxidants (SPAs) are closely correlated with human life due to their extensive usages, and increasing concerns have been raised on their biosafety. The previous controversial findings caused continuous debates on their potential endocrine disrupting effects. In the present study, four commonly used SPAs, including butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butyl hydroquinone (TBHQ) and 2,2'-methylenebis(6-tert-butyl-4-methylphenol) (AO2246), were investigated for their estrogenic effects, and the results from in vitro screening assays showed SPAs themselves had negligible estrogen receptor binding affinities. Nevertheless, significant increase in E2 secretion was observed in H295R cells treated with SPAs, especially for BHA. The transcriptional levels of steroidogenic enzymes, including StAR, 3betaHSD, CYP11B1, and CYP11B2 were up-regulated via the mediation of protein kinase A (PKA) signaling pathway. In vivo experiment confirmed that waterborne exposure to BHA disturbed E2 and testosterone (T) levels in zebrafish gonad, thus causing potential estrogenic effects through the regulation of hypothalamic-pituitary gonadal-liver axis (HPGL-axis). Accordingly, this study has provided new insights for SPA-induced endocrine disrupting effects. Considering the allowable maximum level of individual BHA or in combination with TBHQ and BHT in foodstuffs (200 mg kg-1), the perturbation in steroidogenesis observed for relatively low concentrations of SPAs would need more public attention. PMID- 29236470 TI - A Case Study Application of the Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) Frameworks to Facilitate the Integration of Human Health and Ecological End Points for Cumulative Risk Assessment (CRA). AB - Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from multiple stressors. While CSMs may encompass multiple species, evaluating end points across taxa can be challenging due to data availability and physiological differences among organisms. Adverse outcome pathways (AOPs) describe biological mechanisms leading to adverse outcomes (AOs) by assembling causal pathways with measurable intermediate steps termed key events (KEs), thereby providing a framework for integrating data across species. In this work, we used a case study focused on the perchlorate anion (ClO4-) to highlight the value of the AOP framework for cross-species data integration. Computational models and dose-response data were used to evaluate the effects of ClO4- in 12 species and revealed a dose-response concordance across KEs and taxa. The aggregate exposure pathway (AEP) tracks stressors from sources to the exposures and serves as a complement to the AOP. We discuss how the combined AEP-AOP construct helps to maximize the use of existing data and advances CRA by (1) organizing toxicity and exposure data, (2) providing a mechanistic framework of KEs for integrating data across human health and ecological end points, (3) facilitating cross-species dose-response evaluation, and (4) highlighting data gaps and technical limitations. PMID- 29236471 TI - Lifelong Exposure to PCBs in the Remote Norwegian Arctic Disrupts the Plasma Stress Metabolome in Arctic Charr. AB - Lake Ellasjoen on the remote Norwegian island of Bjornoya is populated by Arctic charr (Salvelinus alpinus) having 20-fold higher body burdens of polychlorinated biphenyls (PCB) compared to charr from the neighboring Lake Laksvatn. This provides a natural setting to test the hypothesis that lifelong exposure to PCBs compromises the energy metabolism in this northernmost living salmonid. To test this, blood was sampled from charr from both lakes immediately after capture and following a 1 h handling and confinement stressor to assess possible differences in their energy metabolism and energy substrate mobilization, respectively. The plasma metabolome of charr was assessed by metabolite detection/separation with LC-MS. Plasma metabolite profiles revealed differences in key pathways involved in amino acid metabolism between charr from each lake, underscoring an impact of PCBs on energy metabolism in Arctic charr residing in Lake Ellasjoen. Subjecting charr from either lake to an acute stressor altered the plasma metabolite profiles and revealed distinct stress metabolome in Lake Ellasjoen charr, suggesting a reduced metabolic capacity. Taken together, lifelong exposure to PCBs in Ellasjoen charr disrupts the plasma metabolome, and may impair the adaptive metabolic response to stressors, leading to a reduced fitness. PMID- 29236472 TI - Analyzing the n-Doping Mechanism of an Air-Stable Small-Molecule Precursor. AB - Efficient n-doping of organic semiconductors requires electron-donating molecules with small ionization energies, making such n-dopants usually sensitive to degradation under air exposure. A workaround consists in the usage of air-stable precursor molecules containing the actual n-doping species. Here, we systematically analyze the doping mechanism of the small-molecule precursor o-MeO DMBI-Cl, which releases a highly reducing o-MeO-DMBI radical upon thermal evaporation. n-Doping of N,N-bis(fluoren-2-yl)-naphthalene tetracarboxylic diimide yields air-stable and highly conductive films suitable for application as electron transport layer in organic solar cells. By photoelectron spectroscopy, we determine a reduced doping efficiency at high doping concentrations. We attribute this reduction to a change of the precursor decomposition mechanism with rising crucible temperature, yielding an undesired demethylation at high evaporation rates. Our results do not only show the possibility of efficient and air-stable n-doping, but also support the design of novel air-stable precursor molecules of strong n-dopants. PMID- 29236473 TI - Modeling the Toxicokinetics of Multiple Metals in the Oyster Crassostrea hongkongensis in a Dynamic Estuarine Environment. AB - Metal contamination is a major problem in many estuaries. Toxicokinetic models are useful tools for predicting metal accumulation in estuarine organisms and managing the associated ecological risks. However, obtaining toxicokinetic parameter values with sufficient predictive power is challenging for dynamic estuarine waters. In this study, we determined the toxicokinetics of multiple metals in the oyster Crassostrea hongkongensis in a dynamic estuary polluted by metals using a 48 day transplant experiment. During the experiment, metal concentrations in oysters, water, and suspended particles were intensively monitored at 3 day intervals. The toxicokinetic parameters were then estimated using the Markov chain Monte Carlo (MCMC) method. The calibrated model was capable of successfully simulating the time-course of metal bioaccumulation in oysters and was further validated by predicting the bioaccumulation at another site in the estuary. Furthermore, the model was used to assess the relative importance of different pathways in metal bioaccumulation. With the MCMC method, distributions instead of single values were assigned to model parameters. This method makes the model predictions probabilistic with clearly defined uncertainties, and they are thus particularly useful for the risk assessment of metals in aquatic systems. PMID- 29236474 TI - Surface Characteristics of Microporous and Mesoporous Carbons Functionalized with Pentafluorophenyl Groups. AB - The in situ diazonium reduction reaction is a reliable and well-known approach for the surface modification of carbon materials for use in a range of applications, including in energy conversion, as chromatography supports, in sensors, etc. Here, this approach was used for the first time with mesoporous colloid-imprinted carbons (CICs), materials that contain ordered monodisperse pores (10-100 nm in diameter) and are inherently highly hydrophilic, using a common microporous carbon (Vulcan carbon (VC)), which is relatively more hydrophobic, for a comparison. The ultimate goal of this work was to modify the CIC wettability without altering its nanostructure and also to lower its susceptibility to oxidation, as required in fuel cell and battery electrodes, by the attachment of pentafluorophenyl (-PhF5) groups onto their surfaces. This was shown to be successful for the CIC, with the -PhF5 groups uniformly coating the inner pore walls at a surface coverage of ca. 90% and allowing full solution access to the mesopores, while the -PhF5 groups deposited only on the outer VC surface, likely blocking its micropores. Contact angle kinetics measurements showed enhanced hydrophobicity, as anticipated, for both the -PhF5 modified CIC and VC materials, even revealing superhydrophobicity at times for the CIC materials. In contrast, water vapor sorption and cyclic voltammetry suggested that the micropores remained hydrophilic, arising from the deposition of smaller N- and O-containing surface groups, caused by a side reaction during the in situ diazonium functionalization process. PMID- 29236475 TI - Electron-Deficient Pyridylimines: Versatile Building Blocks for Functional Metallosupramolecular Chemistry. AB - Metallosupramolecular systems heavily rely on the correct choice of ligands to obtain materials with desired properties. Engaging this problem, we present three ligand systems and six of their mono- and dinuclear complexes, based on the subcomponent self-assembly approach using electron-deficient pyridylcarbaldehyde building blocks. The properties are examined in solution by NMR and UV-vis spectroscopy and CV measurements as well as in solid state by single crystal X ray diffraction analysis. Ultimately, the choice of ligands allows for fine tuning of the electronic properties of the metal centers, complex-to-complex transformations, as well as establishing distinct anion-pi-interaction motifs. PMID- 29236476 TI - Oxygen-Self-Produced Nanoplatform for Relieving Hypoxia and Breaking Resistance to Sonodynamic Treatment of Pancreatic Cancer. AB - Hypoxia as one characteristic hallmark of solid tumors has been demonstrated to be involved in cancer metastasis and progression, induce severe resistance to oxygen-dependent therapies, and hamper the transportation of theranostic agents. To address these issues, an oxygen-self-produced sonodynamic therapy (SDT) nanoplatform involving a modified fluorocarbon (FC)-chain-mediated oxygen delivery protocol has been established to realize highly efficient SDT against hypoxic pancreatic cancer. In this nanoplatform, mesopores and FC chains of FC chain-functionalized hollow mesoporous organosilica nanoparticle carriers can provide sufficient storage capacity and binding sites for sonosensitizers (IR780) and oxygen, respectively. In vitro and in vivo experiments demonstrate the nanoplatform involving this distinctive oxygen delivery protocol indeed breaks the hypoxia-specific transportation barriers, supplies sufficient oxygen to hypoxic PANC-1 cells especially upon exposure to ultrasound irradiation, and relieves hypoxia. Consequently, hypoxia-induced resistance to SDT is inhibited and sufficient highly reactive oxygen species (ROS) are produced to kill PANC-1 cells and shrink hypoxic PANC-1 pancreatic cancer. This distinctive FC-chain mediated oxygen delivery method provides an avenue to hypoxia oxygenation and holds great potential in mitigating hypoxia-induced resistance to those oxygen depleted therapies, e.g., photodynamic therapy, radiotherapy, and chemotherapy. PMID- 29236478 TI - Coexistence of Multilayered Phases of Confined Water: The Importance of Flexible Confining Surfaces. AB - Flexible nanoscale confinement is critical to understanding the role that bending fluctuations play on biological processes where soft interfaces are ubiquitous or to exploit confinement effects in engineered systems where inherently flexible 2D materials are pervasively employed. Here, using molecular dynamics simulations, we compare the phase behavior of water confined between flexible and rigid graphene sheets as a function of the in-plane density, rho2D. We find that both cases show commensurate mono-, bi-, and trilayered states; however, the water phase in those states and the transitions between them are qualitatively different for the rigid and flexible cases. The rigid systems exhibit discontinuous transitions between an (n)-layer and an (n+1)-layer state at particular values of rho2D, whereas under flexible confinement, the graphene sheets bend to accommodate an (n)-layer and an (n+1)-layer state coexisting in equilibrium at the same density. We show that the flexible walls introduce a very different sequence of ice phases and their phase coexistence with vapor and liquid phases than that observed with rigid walls. We discuss the applicability of these results to real experimental systems to shed light on the role of flexible confinement and its interplay with commensurability effects. PMID- 29236477 TI - Plasma-Assisted Large-Scale Nanoassembly of Metal-Insulator Bioplasmonic Mushrooms. AB - Large-scale plasmonic substrates consisting of metal-insulator nanostructures coated with a biorecognition layer can be exploited for enhanced label-free sensing by utilizing the principle of localized surface plasmon resonance (LSPR). Most often, the uniformity and thickness of the biorecognition layer determine the sensitivity of plasmonic resonances as the inherent LSPR sensitivity of nanomaterials is limited to 10-20 nm from the surface. However, because of time consuming nanofabrication processes, there is limited work on both the development of large-scale plasmonic materials and the subsequent surface functionalizing with biorecognition layers. In this work, by exploiting properties of reactive ions in an SF6 plasma environment, we are able to develop a nanoplasmonic substrate containing ~106/cm2 mushroom-like structures on a large sized silicon dioxide substrate (i.e., 2.5 cm by 7.5 cm). We further investigate the underlying mechanism of the nanoassembly of gold on glass inside the plasma environment, which can be expanded to a variety of metal-insulator systems. By incorporating a novel microcontact printing technique, we deposit a highly uniform biorecognition layer of proteins on the nanoplasmonic substrate. The bioplasmonic assays performed on these substrates achieve a limit of detection of 10-17 g/mL (~66 zM) for biomolecules such as antibodies (~150 kDa). Our simple nanofabrication procedure opens new opportunities in fabricating versatile bioplasmonic materials for a wide range of biomedical and sensing applications. PMID- 29236479 TI - Pathways to Mesoporous Resin/Carbon Thin Films with Alternating Gyroid Morphology. AB - Three-dimensional (3D) mesoporous thin films with sub-100 nm periodic lattices are of increasing interest as templates for a number of nanotechnology applications, yet are hard to achieve with conventional top-down fabrication methods. Block copolymer self-assembly derived mesoscale structures provide a toolbox for such 3D template formation. In this work, single (alternating) gyroidal and double gyroidal mesoporous thin-film structures are achieved via solvent vapor annealing assisted co-assembly of poly(isoprene-block-styrene-block ethylene oxide) (PI-b-PS-b-PEO, ISO) and resorcinol/phenol formaldehyde resols. In particular, the alternating gyroid thin-film morphology is highly desirable for potential template backfilling processes as a result of the large pore volume fraction. In situ grazing-incidence small-angle X-ray scattering during solvent annealing is employed as a tool to elucidate and navigate the pathway complexity of the structure formation processes. The resulting network structures are resistant to high temperatures provided an inert atmosphere. The thin films have tunable hydrophilicity from pyrolysis at different temperatures, while pore sizes can be tailored by varying ISO molar mass. A transfer technique between substrates is demonstrated for alternating gyroidal mesoporous thin films, circumventing the need to re-optimize film formation protocols for different substrates. Increased conductivity after pyrolysis at high temperatures demonstrates that these gyroidal mesoporous resin/carbon thin films have potential as functional 3D templates for a number of nanomaterials applications. PMID- 29236480 TI - Manipulation of Origin of Life Molecules: Recognizing Single-Molecule Conformations in beta-Carotene and Chlorophyll-a/beta-Carotene Clusters. AB - Carotenoids and chlorophyll are essential parts of plant leaves and are involved in photosynthesis, a vital biological process responsible for the origin of life on Earth. Here, we investigate how beta-carotene and chlorophyll-a form mixed molecular phases on a Au(111) surface using low-temperature scanning tunneling microscopy and molecular manipulation at the single-molecule level supported by density functional theory calculations. By isolating individual molecules from nanoscale molecular clusters with a scanning tunneling microscope tip, we are able to identify five beta-carotene conformations including a structure exhibiting a three-dimensional conformation. Furthermore, molecular resolution images enable direct visualization of beta-carotene/chlorophyll-a clsuters, with intimate structural details highlighting how they pair: beta-carotene preferentially positions next to chlorophyll-a and induces switching of chlorophyll-a from straight to several bent tail conformations in the molecular clusters. PMID- 29236481 TI - Exploring the Nanotoxicology of MoS2: A Study on the Interaction of MoS2 Nanoflakes and K+ Channels. AB - Molybdenum disulfide (MoS2) nanomaterial has recently found various applications in the biomedical field mainly due to its outstanding physicochemical properties. However, little is known about its interactions with biological systems at the atomic level, which intimately relates to the biocompatibility of the material. To provide insights into the effects of MoS2 in biological entities, we investigated the interactions of MoS2 with proteins from a functionally important membrane family, the ubiquitous potassium (K+) channels. Here, we study four representative K+ channels-KcsA, Kir3.2, the Kv1.2 paddle chimera, and K2P2-to investigate their interactions with a triangular MoS2 nanoflake using Molecular Dynamics (MD) simulations combined with electrophysiology experiments. These particular K+ channels were selected based on the diversity in their structure; that is, although these K+ channels display similar structural motifs, they also contain significant differences related to their particular function. Our results indicate that the MoS2 nanoflake is able to stably bind to three out of the four channels, albeit through distinct binding modes. The binding mode between each channel and MoS2 underlies the specific deleterious influence on the channel's basic physiological function: For KcsA, MoS2 binds on the extracellular loops, which indirectly destroys the delicate structure of the selectivity filter causing a strong leak of K+ ions. In the binding mode with Kir3.2, the MoS2 nanoflake completely covers the entrance to the channel pore affecting the normal ion conduction. For the Kv1.2 chimera, the MoS2 nanoflake prefers to bind into a crevice located at the extracellular side of the Voltage Sensor Domain (VSD). Interestingly, the crevice involves the N-terminal segment of S4, a crucial transmembrane helix which directly controls the gating process of the Kv1.2 chimera channel by electromechanical coupling the VSD to the transmembrane electric field. MoS2 in contact with S4 from the Kv1.2 chimera, potentially influences the channel's gating process from open to closed states. In all three systems, the van der Waals contribution to the total energy dominates the binding interactions; also, hydrophobic residues contribute the most contact points, which agrees with the strong hydrophobic character of the MoS2 nanomaterial. Electrophysiology recordings using two-electrode voltage-clamp show that currents of Kir3.2 and Kv1.2 are both blocked by the MoS2 nanoflakes in a concentration dependent way. While the background K+ channel, K2P2 (TREK-1), identified as a negative control, is not blocked by the MoS2 nanoflakes. The large and rigid extracellular domain of K2P2 appears to protect the channel from disturbance by the nanoflakes. Intrinsic chemical properties of MoS2, together with the specific features of the channels, such as the electrostatic character and complex surface architecture, determine the critical details of the binding events. These findings might shed light on the potential nanotoxicology of MoS2 nanomaterials and help us to understand the underlying molecular mechanism. PMID- 29236482 TI - Use of Cysteine Aminoethylation To Identify the Hypervariable Peptides of an Antibody. AB - Aminoethylation of cysteines can provide enzymatically cleavable sites. The ability to obtain peptides containing antibody complementarity determining regions (CDRs) with aminoethylated cysteines was investigated. Because cysteines are often located N-terminal to CDRs, digestion with Lys-N enables acquisition of peptides with CDRs. Lys-N peptides containing an aminoethylated cysteine at the N terminus were also amidinated. Subsequent collisional activation yields a unique loss of 118 Da that originates from this modified residue, providing a signature ion for cysteine-containing peptides. The relative cleavage efficiencies for Lys N and trypsin are also compared. PMID- 29236483 TI - Biological Limitations of Dechlorination of cis-Dichloroethene during Transport in Porous Media. AB - We applied a mathematical model to data from experimental column studies to understand the dynamics of successful and unsuccessful reductive dechlorination of chlorinated ethenes in groundwater under different flow conditions. In laboratory column experiments (reported previously), it was observed that complete dechlorination of cis-dichloroethene to ethene was sustained at high flow velocity (0.51 m/d), but that dechlorination failed at medium or low flow velocity (0.080 or 0.036 m/d). The mathematical model applied here accounts for transport of chlorinated ethenes in flowing groundwater, mass transfer of chlorinated ethenes between mobile groundwater and stationary biofilms, and diffusion and biodegradation within the biofilms. Monod kinetics with competitive inhibition are used to describe biodegradation. Nearly all parameters needed to solve the model are estimated independently from batch and nonreactive transport experiments. Comparing the model predictions to the experimental results permits the evaluation of three hypothesized biological limitations: insufficient supply of electron donor, decay of dechlorinators' biomass, and reduction in bacterial metabolism rates. Any of these three limitations are able to adequately describe observed experimental data, but insufficient supply of electron donor is the most plausible explanation for failure of dechlorination. Therefore, an important conclusion of this investigation is that insufficient hydrogen production occurs if groundwater flow is too slow to provide adequate flux of electron donor. Model simulations were in good agreement with experimental results for both successful and unsuccessful dechlorination, suggesting the model is a valid tool for describing transport and reductive dechlorination. An implication of our findings is that in engineered or natural bioremediation of chloroethene-contaminated groundwater, not only must the proper dechlorinating organisms be present, but also proper groundwater flow conditions must be maintained or else dechlorination may fail. PMID- 29236484 TI - Constructing Grids for Molecular Quantum Dynamics Using an Autoencoder. AB - A challenge for molecular quantum dynamics (QD) calculations is the curse of dimensionality with respect to the nuclear degrees of freedom. A common approach that works especially well for fast reactive processes is to reduce the dimensionality of the system to a few most relevant coordinates. Identifying these can become a very difficult task, because they often are highly unintuitive. We present a machine learning approach that utilizes an autoencoder that is trained to find a low-dimensional representation of a set of molecular configurations. These configurations are generated by trajectory calculations performed on the reactive molecular systems of interest. The resulting low dimensional representation can be used to generate a potential energy surface grid in the desired subspace. Using the G-matrix formalism to calculate the kinetic energy operator, QD calculations can be carried out on this grid. In addition to step-by-step instructions for the grid construction, we present the application to a test system. PMID- 29236485 TI - Valence State of Eu and Superconductivity in Se-Substituted EuSr2Bi2S4F4 and Eu2SrBi2S4F4. AB - Recently, we reported the synthesis and investigations of EuSr2Bi2S4F4 and Eu2SrBi2S4F4. We have now been able to induce superconductivity in EuSr2Bi2S4F4 by Se substitution at the S site (isovalent substitution) with Tc = 2.9 K in EuSr2Bi2S2Se2F4. The other compound, Eu2SrBi2S4F4, shows a significant enhancement of Tc. In Se-substituted Eu2SrBi2S4-xSexF4, we find Tc = 2.6 K for x = 1.5 and Tc = 2.8 K for x = 2, whereas Tc = 0.4 K in the Se-free sample. In addition to superconductivity, an important effect associated with Se substitution is that it gives rise to remarkable changes in the Eu valence. Our 151Eu Mossbauer and X-ray photoemission spectroscopic measurements show that Se substitution in both of the compounds Eu2SrBi2S4F4 and EuSr2Bi2S4F4 gives rise to an increase in the Eu2+ component in the mixed-valence state of Eu. PMID- 29236486 TI - Regioselective IBX-Mediated Synthesis of Coumarin Derivatives with Antioxidant and Anti-influenza Activities. AB - Different catechol and pyrogallol derivatives have been synthesized by oxidation of coumarins with 2-iodoxybenzoic acid (IBX) in DMSO at 25 degrees C. A high regioselectivity was observed in accordance with the stability order of the incipient carbocation or radical benzylic-like intermediate. The oxidation was also effective in water under heterogeneous conditions by using IBX supported on polystyrene. The new derivatives showed improved antioxidant effects in the DPPH test and inhibitory activity against the influenza A/PR8/H1N1 virus. These data represent a new entry for highly oxidized coumarins showing an antiviral activity possibly based on the control of the intracellular redox value. PMID- 29236487 TI - The Connection between NHC Ligand Count and Photophysical Properties in Fe(II) Photosensitizers: An Experimental Study. AB - Four homo- and heteroleptic complexes bearing both polypyridyl units and N heterocyclic carbene (NHC) donor functions are studied as potential noble metal free photosensitizers. The complexes [FeII(L1)(terpy)][PF6]2, [FeII(L2)2][PF6]2, [FeII(L1)(L3)][PF6]2, and [FeII(L3)2][PF6]2 (terpy = 2,2':6',2" terpyridine, L1 = 2,6-bis[3-(2,6-diisopropylphenyl)imidazol-2-ylidene]pyridine, L2 = 2,6-bis[3 isopropylimidazol-2-ylidene]pyridine, L3 = 1-(2,2'-bipyridyl)-3-methylimidazol-2 ylidene) contain tridentate ligands of the C^N^C and N^N^C type, respectively, resulting in a Fe-NHC number between two and four. Thorough ground state characterization by single crystal diffraction, electrochemistry, valence-to-core X-ray emission spectroscopy (VtC-XES), and high energy resolution fluorescence detected X-ray absorption near edge structure (HERFD-XANES) in combination with ab initio calculations show a correlation between the geometric and electronic structure of these new compounds and the number of the NHC donor functions. These results serve as a basis for the investigation of the excited states by ultrafast transient absorption spectroscopy, where the lifetime of the 3MLCT states is found to increase with the NHC donor count. The results demonstrate for the first time the close interplay between the number of NHC functionalities in Fe(II) complexes and their photochemical properties, as revealed in a comparison of the activity as photosensitizers in photocatalytic proton reduction. PMID- 29236488 TI - Sesqui- and Diterpenoids from the Radix of Curcuma aromatica. AB - Eight new sesquiterpenoids (1-8), two new diterpenoids (9 and 10), and 17 known sesqui- and diterpenoids (11-27) were isolated from the radix of Curcuma aromatica. Among these compounds, 1 is an unprecedented guaiane with unique cyclopropane and furan functionalities, and 9 is the first atisane diterpenoid isolated from a Curcuma species. Their 2D and 3D structures were established using HRESIMS and spectroscopic methods, including ECD and IECD data. The antioxidant activities of compounds 1-27 were evaluated based on their ability to protect PC12 cells against H2O2-induced damage, with 1, 2, 5-8, 11, 12, 14, 16, 18, and 19 exhibiting notable antioxidant effects on oxidative injury induced by H2O2. PMID- 29236489 TI - Magnesium Catalyzed Polymerization of End Functionalized Poly(propylene maleate) and Poly(propylene fumarate) for 3D Printing of Bioactive Scaffolds. AB - The ring-opening copolymerization of maleic anhydride and propylene oxide, using a functionalized primary alcohol initiator and magnesium 2,6-di-tert-butyl phenoxide as a catalyst, was investigated in order to produce high end-group fidelity poly(propylene maleate). Subsequent isomerization of the material into 3D printable poly(propylene fumarate) was utilized to produce thin films and scaffolds possessing groups that can be modified with bioactive groups postpolymerization and postprinting. The surface concentration of these modifiable groups was determined to be 30.0 +/- 3.3 pmol.cm-2, and copper mediated azide-alkyne cycloaddition was used to attach a small molecule dye and cell adhesive GRGDS peptides to the surface as a model system. The films were then studied for cytotoxicity and found to have high cell viability before and after surface modification. PMID- 29236490 TI - Lipid-Controlled Stabilization of Charge-Separated States (P+QB-) and Photocurrent Generation Activity of a Light-Harvesting-Reaction Center Core Complex (LH1-RC) from Rhodopseudomonas palustris. AB - The photosynthetic light-harvesting-reaction center core complex (LH1-RC) is a natural excitonic and photovoltaic device embedded in a lipid membrane. In order to apply LH1-RCs as a biohybrid energy-producing material, some important issues must be addressed, including how to make LH1-RCs function as efficiently as possible. In addition, they should be characterized to evaluate how many active LH1-RCs efficiently work in artificial systems. We report here that an anionic phospholipid, phosphatidylglycerol (PG), stabilizes the charge-separated state (a photooxidized electron donor and reduced quinone pair, P+QB-) of LH1-RC (from Rhodopseudomonas palustris) and enhances its activity in photocurrent generation. Steady-state fluorometric analysis demonstrated that PG enhances the formation of the P+QB- state at lower irradiances. The photocurrent generation activity was analyzed via Michaelis-Menten kinetics, revealing that 38% of LH1-RCs reconstituted into the PG membrane generated photocurrent at a turnover frequency of 46 s-1. PG molecules, which interact with LH1-RC in vivo, play the role of an active effector component for LH1-RC to enhance its function in the biohybrid system. PMID- 29236491 TI - Short-Chain Fatty Acids Suppress Inflammatory Reactions in Caco-2 Cells and Mouse Colons. AB - Short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate, play an important role in the maintenance of intestinal homeostasis. In the present study, anti-inflammatory effects of SCFAs were examined in human intestinal Caco 2 cells and mouse colonic cultures. Stimulation of Caco-2 cells with tumor necrosis factor (TNF)-alpha induced interleukin (IL)-8 (TNF-alpha, 17.1 +/- 7.2 vs Control, 1.00 +/- 0.26, P < 0.01) and IL-6 expression (TNF-alpha, 21.7 +/- 10.0 vs Control, 1.00 +/- 0.28, P < 0.01) through the activation of nuclear factor kappaB p65, spleen tyrosine kinase, and mitogen-activated protein kinase pathways. Pretreatment of cells with acetate (5 mM, IL-8 1.23 +/- 0.40, IL-6 2.19 +/- 0.92, P < 0.01 ), propionate (2.5 mM, IL-8 2.45 +/- 2.10, IL-6 2.19 +/- 0.92, P < 0.01), or butyrate (0.625 mM, IL-8 1.44 +/- 0.70, IL-6 2.31 +/- 0.32, P < 0.01) suppressed inflammatory responses induced by TNF-alpha. Pharmacological inhibition of monocarboxylate transporter (MCT)-1 attenuated the suppression of inflammatory signals by SCFAs. High expression levels of CXC motif chemokine ligand 2 (CXCL2, an IL-8 homologue, DSS, 31.7 +/- 9.8 vs Control, 1.00 +/- 0.70, P < 0.01) and IL-6 (DSS, 17.5 +/- 7.2 vs Control, 1.00 +/- 0.68, P < 0.01) were observed in BALB/c mouse colonic cultures exposed to dextran sodium sulfate, whereas treatments with mixtures of SCFAs decreased these elevated expression levels (CXCL2 4.14 +/- 2.88, IL-6 0.58 +/- 0.28, P < 0.01). Our results suggest that SCFAs transported by MCT-1 suppress TNF-alpha-induced inflammatory signaling in intestinal cells. PMID- 29236492 TI - Pimentelamines A-C, Indole Alkaloids Isolated from the Leaves of the Australian Tree Flindersia pimenteliana. AB - Three members of a new class of ascorbic acid-adduct indole alkaloids (1-3), a new prenylated indole alkaloid (4), and five known compounds (5-9) were isolated from the leaves of Flindersia pimenteliana. The structures of 1-4 were elucidated on the basis of their (+)-HRESIMS and 2D NMR spectroscopic data. Antiplasmodial activity was also reported for the natural products against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum with IC50 values ranging from 0.19 to 3.6 MUM. PMID- 29236493 TI - Polarizable QM/Classical Approaches for the Modeling of Solvation Effects on UV Vis and Fluorescence Spectra: An Integrated Strategy. AB - Hybrid methods combining quantum chemistry and classical models are largely used to describe solvent effects in absorption and emission processes of solvated chromophores. Here we compare three different formulations of these hybrid approaches, using a continuum, an atomistic, or a mixed description of the solvent. In all cases mutual polarization effects between the quantum and the classical subsystems are taken into account. As a molecular probe, 3 hydroxyflavone has been selected due to its rich photophysics, which involves different tautomeric and anionic forms. We show that a clear assignment of the measured spectroscopic signals to each specific form can be achieved by combining the different solvation models into an integrated and cost-effective strategy. Previously proposed mechanisms for the excited-state proton transfer (ESIPT), specific solvent perturbation effects on ESIPT, and solvent-assisted anion formation are also validated in terms of short- and long-range solvation effects. PMID- 29236494 TI - Theoretical Study on Elementary Reaction Steps in Thermal Decomposition Processes of Syringol-Type Monolignol Compounds. AB - This paper theoretically investigated a large number of reaction pathways and kinetics to describe the vapor-phase pyrolytic behavior of several syringol-type monolignol compounds that are derived from the primary pyrolysis of lignin: 1-(4 hydroxy-3,5-dimethoxyphenyl)prop-2-en-1-one (HDPP), sinapyl alcohol, 3-hydroxy-1 (4-hydroxy-3,5-dimethoxyphenyl)propan-1-one (HHDPP), 1-(4-hydroxy-3,5 dimethoxyphenyl)propane-1,3-diol (HDPPD), and syringol. The possible pyrolytic pathways involving unimolecular decomposition, addition, and abstraction reactions were investigated by comparing the energy barriers calculated at the B3LYP/6-311++G(d,p) level. In the proposed pathways, all syringol-type monolignols containing a side chain undergo its cleavage to form syringol through the formation of syringaldehyde or 4-vinylsyringol. Syringol is then converted into two products: (a) pyrogallol via the homolysis of the O-CH3 bond and hydrogenation or (b) guaiacol via addition of an H atom with a carbon bearing methoxyl group in syrignol and the subsequent demethoxylation. The pyrolytic pathways of pyrogallol are classified into two processes: (a) the concerted dehydrogenation of the two hydroxyl H atoms and the unimolecular decomposition to produce acetylene (C2H2), ethynol (C2HOH), and CO or (b) the displacement of an OH with H to produce catechol and resorcinol. Additionally, HDPP undergoes O-CH3 bond cleavage to form but-1-en-3-yne. The high-pressure limit rate constants for all the proposed elementary reaction steps were evaluated on the basis of transition state theory. PMID- 29236496 TI - Experimental and Theoretical Study of the Kinetics and Mechanism of the Reaction of Chlorine Atoms with CH3CHClCH3 and CD3CDClCD3. AB - The overall rate constants for H-abstraction (kH) from CH3CHClCH3 and D abstraction (kD) from CD3CDClCD3 by chlorine atoms in the temperature range 298 528.5 K were determined and are described by the expressions: kH = (3.52 +/- 0.21) * 10-11 exp(-184 +/- 19/T) cm3 molecule-1 s-1 and kD = (1.91 +/- 0.16) * 10 11 exp(-185 +/- 31/T) cm3 molecule-1 s-1 respectively. The results of the experiment show that the value of the kinetic isotope effect (kH/kD) for the overall rate constants is temperature independent and is equal to 1.85 +/- 0.17. A theoretical examination of these reaction mechanisms revealed some unusual properties, such as negative values of the activation energy for the H abstraction reaction from the secondary carbon atom. Moreover, it was proved that in the radical process of H-abstraction from the primary carbon atom of 2 chloropropane the created R-Cl...Cl complex is the most stable structure responsible for the value of the activation energy of this transformation. PMID- 29236495 TI - A Stable Heroin Analogue That Can Serve as a Vaccine Hapten to Induce Antibodies That Block the Effects of Heroin and Its Metabolites in Rodents and That Cross React Immunologically with Related Drugs of Abuse. AB - An improved synthesis of a haptenic heroin surrogate 1 (6-AmHap) is reported. The intermediate needed for the preparation of 1 was described in the route in the synthesis of 2 (DiAmHap). A scalable procedure was developed to install the C-3 amido group. Using the Boc protectng group in 18 allowed preparation of 1 in an overall yield of 53% from 4 and eliminated the necessity of preparing the diamide 13. Hapten 1 was conjugated to tetanus toxoid and mixed with liposomes containing monophosphoryl lipid A as an adjuvant. The 1 vaccine induced high anti-1 IgG levels that reduced heroin-induced antinociception and locomotive behavioral changes following repeated subcutaneous and intravenous heroin challenges in mice and rats. Vaccinated mice had reduced heroin-induced hyperlocomotion following a 50 mg/kg heroin challenge. The 1 vaccine-induced antibodies bound to heroin and other abused opioids, including hydrocodone, oxycodone, hydromorphone, oxymorphone, and codeine. PMID- 29236497 TI - Discovery of LY3104607: A Potent and Selective G Protein-Coupled Receptor 40 (GPR40) Agonist with Optimized Pharmacokinetic Properties to Support Once Daily Oral Treatment in Patients with Type 2 Diabetes Mellitus. AB - As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate. PMID- 29236498 TI - Enhancement of Anti-Inflammatory Properties of Nobiletin in Macrophages by a Nano Emulsion Preparation. AB - Lots of active substances are hydrophobic materials at ambient and body temperatures, decreasing their bioavailability and posing great challenges to successful incorporation into medication and functional foods. The goal of this research was to develop a nanoemulsion delivery system containing a hydrophobic crystalline bioactive component (nobiletin) to improve the anti-inflammatory activity. Nobiletin was incorporated into the oily phase, and the nanoemulsions were fabricated using high-speed and high-pressure homogenization. Particle size, polydispersity index (PDI), and zeta potential were evaluated by a commercial laser light scattering instrument. The anti-inflammatory activities were performed in LPS-stimulated RAW 264.7 cells. The developed nobiletin nanoemulsion had an average droplet size of 168.6 +/- 3.8 nm and a PDI of 0.168, while the average diameter of the blank nanoemulsion was 157.3 +/- 1.9 nm and its PDI was 0.161. The zeta potential values of nobiletin nanoemulsion and blank nanoemulsion were -68.45 +/- 0.64 and -62.75 +/- 0.21 mV, respectively. All obtained nanoemulsions kept physically stable during storage at 4, 25, and 37 degrees C. A nobiletin-loaded nanoemulsion showed an enhanced anti-inflammatory activity in LPS-induced macrophages, with a decrease in pro-inflammatory mediators and cytokines. The findings suggested that the nanoemulsion would be used as an effective delivery system for nobiletin to improve its anti-inflammatory activity. PMID- 29236499 TI - Mutual Interaction of Phenolic Compounds and Microbiota: Metabolism of Complex Phenolic Apigenin-C- and Kaempferol-O-Derivatives by Human Fecal Samples. AB - Human colonic bacteria have an important impact on the biotransformation of flavonoid glycosides and their conversion can result in the formation of bioactive compounds. However, information about the microbial conversion of complex glycosylated flavonoids and the impact on the gut microbiota are still limited. In this study, in vitro fermentations with selected flavonoid O- and C glycosides and three different fecal samples were performed. As a result, all flavonoid glycosides were metabolized via their aglycones yielding smaller substances. Main metabolites were 3-(4-hydroxyphenyl)propionic acid, 3 phenylpropionic acid, and phenylacetic acid. Differences in the metabolite formation due to different time courses between the donors were determined. Therefore, from all fermentations, the ones with a specific donor were always slower resulting in a lower number of metabolites compared to the others. For example, tiliroside was totally degraded from 0 h (105 +/- 13.2 MUM) within the first 24 h, while in the fermentations with fecal samples from other donors, tiliroside (107 +/- 52.7 MUM at 0 h) was not detected after 7 h anymore. In general, fermentation rates of C-glycosides were slower compared to the fermentation rates of O-glycosides. The O-glycoside tiliroside was degraded within 4 h while the gut microbiota converted the C-glycoside vitexin within 13 h. However, significant changes (p < 0.05) in the microbiota composition and short chain fatty acid levels as products of carbohydrate fermentation were not detected between incubations with different phenolic compounds. Therefore, microbiota diversity was not affected and a significant prebiotic effect of phenolic compounds cannot be assigned to flavonoid glycosides in food-relevant concentrations. PMID- 29236500 TI - Structural Insights into the Thermophilic Adaption Mechanism of Endo-1,4-beta Xylanase from Caldicellulosiruptor owensensis. AB - Xylanases (EC 3.2.1.8) are a kind of enzymes degrading xylan to xylooligosaccharides (XOS) and have been widely used in a variety of industrial applications. Among them, xylanases from thermophilic microorganisms have distinct advantages in industries that require high temperature conditions. The CoXynA gene, encoding a glycoside hydrolase (GH) family 10 xylanase, was identified from thermophilic Caldicellulosiruptor owensensis and was overexpressed in Escherichia coli. Recombinant CoXynA showed optimal activity at 90 degrees C with a half-life of about 1 h at 80 degrees C and exhibited highest activity at pH 7.0. The activity of CoXynA activity was affected by a variety of cations. CoXynA showed distinct substrate specificities for beechwood xylan and birchwood xylan. The crystal structure of CoXynA was solved and a molecular dynamics simulation of CoXynA was performed. The relatively high thermostability of CoXynA was proposed to be due to the increased overall protein rigidity resulting from the reduced length and fluctuation of Loop 7. PMID- 29236501 TI - Tunneling Hot Spots in Ferroelectric SrTiO3. AB - Strontium titanate (SrTiO3) is the "silicon" in the emerging field of oxide electronics. While bulk properties of this material have been studied for decades, new unexpected phenomena have recently been discovered at the nanoscale, when SrTiO3 forms an ultrathin film or an atomically sharp interface with other materials. One of the striking discoveries is room-temperature ferroelectricity in strain-free ultrathin films of SrTiO3 driven by the TiSr antisite defects, which generate a local dipole moment polarizing the surrounding nanoregion. Here, we demonstrate that these polar defects are not only responsible for ferroelectricity, but also propel the appearance of highly conductive channels, "hot spots", in the ultrathin SrTiO3 films. Using a combination of scanning probe microscopy experimental studies and theoretical modeling, we show that the hot spots emerge due to resonant tunneling through localized electronic states created by the polar defects and that the tunneling conductance of the hot spots is controlled by ferroelectric polarization. Our finding of the polarization controlled defect-assisted tunneling reveals a new mechanism of resistive switching in oxide heterostructures and may have technological implications for ferroelectric tunnel junctions. It is also shown that the conductivity of the hot spots can be modulated by mechanical stress, opening a possibility for development of conceptually new electronic devices with mechanically tunable resistive states. PMID- 29236502 TI - Redox Conditions Affect Ultrafast Exciton Transport in Photosynthetic Pigment Protein Complexes. AB - Pigment-protein complexes in photosynthetic antennae can suffer oxidative damage from reactive oxygen species generated during solar light harvesting. How the redox environment of a pigment-protein complex affects energy transport on the ultrafast light-harvesting time scale remains poorly understood. Using two dimensional electronic spectroscopy, we observe differences in femtosecond energy transfer processes in the Fenna-Matthews-Olson (FMO) antenna complex under different redox conditions. We attribute these differences in the ultrafast dynamics to changes to the system-bath coupling around specific chromophores, and we identify a highly conserved tyrosine/tryptophan chain near the chromophores showing the largest changes. We discuss how the mechanism of tyrosine/tryptophan chain oxidation may contribute to these differences in ultrafast dynamics that can moderate energy transfer to downstream complexes where reactive oxygen species are formed. These results highlight the importance of redox conditions on the ultrafast transport of energy in photosynthesis. Tailoring the redox environment may enable energy transport engineering in synthetic light-harvesting systems. PMID- 29236503 TI - Droplet Demulsification Using Ultralow Voltage-Based Electrocoalescence. AB - Demulsification of droplets stabilized with surfactant is very challenging due to their low surface energy. We report ultralow voltage-based electrocoalescence phenomenon for the demulsification of aqueous droplets with an aqueous stream. In the absence of electric field, due to the disjoining pressure resulting from the tail-tail interaction between the surfactant molecules present on the aqueous droplets and interface, coalescence of aqueous droplets with the aqueous stream is prevented. However, above a critical electric field, the electrical stress overcomes the disjoining pressure, thus leading to the droplet coalescence. The influence of surfactant concentration, droplet diameter, and velocity on the electrocoalescence phenomena is studied. The macroscopic contact between the aqueous droplet with the aqueous stream enables droplet coalescence at much lower voltage (10 to 90 V), which is at least two orders of magnitude smaller than voltages used in prior works (1.0 to 3.0 kV). The electrocoalescence phenomena is used for the extraction of microparticles encapsulated in aqueous droplets into the aqueous stream and size-based selective demulsification. A new paradigm of droplet electrocoalescence and content extraction is presented that would find significant applications in chemistry and biology. PMID- 29236504 TI - Atomristor: Nonvolatile Resistance Switching in Atomic Sheets of Transition Metal Dichalcogenides. AB - Recently, two-dimensional (2D) atomic sheets have inspired new ideas in nanoscience including topologically protected charge transport,1,2 spatially separated excitons,3 and strongly anisotropic heat transport.4 Here, we report the intriguing observation of stable nonvolatile resistance switching (NVRS) in single-layer atomic sheets sandwiched between metal electrodes. NVRS is observed in the prototypical semiconducting (MX2, M = Mo, W; and X = S, Se) transitional metal dichalcogenides (TMDs),5 which alludes to the universality of this phenomenon in TMD monolayers and offers forming-free switching. This observation of NVRS phenomenon, widely attributed to ionic diffusion, filament, and interfacial redox in bulk oxides and electrolytes,6-9 inspires new studies on defects, ion transport, and energetics at the sharp interfaces between atomically thin sheets and conducting electrodes. Our findings overturn the contemporary thinking that nonvolatile switching is not scalable to subnanometre owing to leakage currents.10 Emerging device concepts in nonvolatile flexible memory fabrics, and brain-inspired (neuromorphic) computing could benefit substantially from the wide 2D materials design space. A new major application, zero-static power radio frequency (RF) switching, is demonstrated with a monolayer switch operating to 50 GHz. PMID- 29236505 TI - Confined Chemical Fluid Deposition of Ferromagnetic Metalattices. AB - A magnetic, metallic inverse opal fabricated by infiltration into a silica nanosphere template assembled from spheres with diameters less than 100 nm is an archetypal example of a "metalattice". In traditional quantum confined structures such as dots, wires, and thin films, the physical dynamics in the free dimensions is typically largely decoupled from the behavior in the confining directions. In a metalattice, the confined and extended degrees of freedom cannot be separated. Modeling predicts that magnetic metalattices should exhibit multiple topologically distinct magnetic phases separated by sharp transitions in their hysteresis curves as their spatial dimensions become comparable to and smaller than the magnetic exchange length, potentially enabling an interesting class of "spin-engineered" magnetic materials. The challenge to synthesizing magnetic inverse opal metalattices from templates assembled from sub-100 nm spheres is in infiltrating the nanoscale, tortuous voids between the nanospheres void-free with a suitable magnetic material. Chemical fluid deposition from supercritical carbon dioxide could be a viable approach to void-free infiltration of magnetic metals in view of the ability of supercritical fluids to penetrate small void spaces. However, we find that conventional chemical fluid deposition of the magnetic late transition metal nickel into sub-100 nm silica sphere templates in conventional macroscale reactors produces a film on top of the template that appears to largely block infiltration. Other deposition approaches also face difficulties in void-free infiltration into such small nanoscale templates or require conducting substrates that may interfere with properties measurements. Here we report that introduction of "spatial confinement" into the chemical fluid reactor allows for fabrication of nearly void-free nickel metalattices by infiltration into templates with sphere sizes from 14 to 100 nm. Magnetic measurements suggest that these nickel metalattices behave as interconnected systems rather than as isolated superparamagnetic systems coupled solely by dipolar interactions. PMID- 29236506 TI - Association Behavior of Poly(ethylene oxide)-Poly(propylene oxide) Alternating Multiblock Copolymers in Water toward Thermally Induced Phase Separation. AB - Thermal changes in the association behavior of poly(ethylene oxide) poly(propylene oxide) alternating multiblock (PEO-PPO AMB) copolymers in water are investigated by the use of transmittance and light scattering measurements. Two PEO-PPO AMB copolymers with a different weight fraction of PEO, (EO220PO33)8 and (EO68PO33)9, are prepared. The weight-average molecular weights of (EO220PO33)8 and (EO68PO33)9 estimated by static light scattering measurements are 1.3 * 105 and 4.1 * 104 g mol-1, respectively. The number of PEO-PPO repeating pairs is over 8. It is found that the aqueous solution of (EO220PO33)8 undergoes phase separation with a lower critical solution temperature (LCST) of around 58 degrees C at 0.3 wt %. For the aqueous (EO68PO33)9 solution, the LCST is estimated to be ca. 42 degrees C. The critical solution concentration for (EO68PO33)9 is not clear because of a small concentration dependence of Tc at a higher concentration range. Dynamic light scattering measurements indicate that a micellelike aggregate is formed below the LCST. From the Debye plot, it is elucidated that the second virial coefficient, A2, starts going down at around 32 degrees C for (EO220PO33)8 and below 15 degrees C for (EO68PO33)9. The A2 value of (EO220PO33)8 approaches 0 near 50 degrees C, whereas that of (EO68PO33)9 approaches 0 at around 35 degrees C. At a high temperature, the attractive interaction among the copolymers becomes dominant, thereby inducing the formation of micellelike aggregates. PMID- 29236507 TI - Phonon Hydrodynamic Heat Conduction and Knudsen Minimum in Graphite. AB - In the hydrodynamic regime, phonons drift with a nonzero collective velocity under a temperature gradient, reminiscent of viscous gas and fluid flow. The study of hydrodynamic phonon transport has spanned over half a century but has been mostly limited to cryogenic temperatures (~1 K) and more recently to low dimensional materials. Here, we identify graphite as a three-dimensional material that supports phonon hydrodynamics at significantly higher temperatures (~100 K) based on first-principles calculations. In particular, by solving the Boltzmann equation for phonon transport in graphite ribbons, we predict that phonon Poiseuille flow and Knudsen minimum can be experimentally observed above liquid nitrogen temperature. Further, we reveal the microscopic origin of these intriguing phenomena in terms of the dependence of the effective boundary scattering rate on momentum-conserving phonon-phonon scattering processes and the collective motion of phonons. The significant hydrodynamic nature of phonon transport in graphite is attributed to its strong intralayer sp2 hybrid bonding and weak van der Waals interlayer interactions. More intriguingly, the reflection symmetry associated with a single graphene layer is broken in graphite, which opens up more momentum-conserving phonon-phonon scattering channels and results in stronger hydrodynamic features in graphite than graphene. As a boundary sensitive transport regime, phonon hydrodynamics opens up new possibilities for thermal management and energy conversion. PMID- 29236508 TI - Size Matters: Cocatalyst Size Effect on Charge Transfer and Photocatalytic Activity. AB - Hybrid semiconductor-metallic nanostructures play an important role in a wide range of applications and are key components in photocatalysis. Here we reveal that the nature of a nanojunction formed between a semiconductor nanorod and metal nanoparticle is sensitive to the size of the metal component. This is reflected in the activity toward hydrogen production, emission quantum yields, and the efficiency of charge separation which is determined by transient absorption spectroscopy. A set of Ni decorated CdSe@CdS nanorods with different tip size were examined, and an optimal metal domain size of 5.2 nm was obtained. Remarkably, charge separation time constants were found to be nonvariant with metal tip size. It is proposed that electron transfer mechanism encompasses two consecutive but separate processes: slow charge migration along the rod toward the interface, followed by fast interface crossing of the electron from the semiconductor into the metal phase. The first migration step dominates the time constant for the charge separation process and is not affected by the metal size. The efficiency of charge separation on the other hand was found to be sensitive to metal size. It is suggested that Coulomb blockade charging energy and a size dependent Schottky barrier contribute to the metal size effect on charge transfer probability across the semiconductor-metal nanojunction. These two opposing trends result in an optimal metal size domain for the cocatalyst. This work is expected to benefit a broad range of applications utilizing semiconductor-metal nanocomposites. PMID- 29236509 TI - Tetrahydrobenzo[c]thieno[2,1-e]isothiazole 4-Oxides: Three-Dimensional Heterocycles as Cross-Coupling Building Blocks. AB - Unprecedented three-dimensional heterocycles are introduced, and their scaffold functionalization is described. A robust synthetic method utilizing cheap commercially available starting materials leads to a wide range of products on gram scale. The product portfolio can be expanded by applying newly devised building blocks with relevance for automated parallel synthesis in cross-coupling reactions. PMID- 29236511 TI - Substrate-Induced Structure and Molecular Dynamics in a Lipid Bilayer Membrane. AB - The solid-substrate-dependent structure and dynamics of molecules in a supported lipid bilayer (SLB) were directly investigated via atomic force microscopy (AFM) and single particle tracking (SPT) measurements. The appearance of either vertical or horizontal heterogeneities in the SLB was found to be strongly dependent on the underlying substrates. SLB has been widely used as a biointerface with incorporated proteins and other biological materials. Both silica and mica are popular substrates for SLB. Using single-molecule dynamics, the fluidity of the upper and lower membrane leaflets was found to depend on the substrate, undergoing coupling and decoupling on the SiO2/Si and mica substrates, respectively. The anisotropic diffusion caused by the locally destabilized structure of the SLB at atomic steps appeared on the Al2O3(0001) substrate because of the strong van der Waals interaction between the SLB and the substrate. Our finding that the well-defined surfaces of mica and sapphire result in asymmetry and anisotropy in the plasma membrane is useful for the design of new plasma-membrane-mimetic systems. The application of well-defined supporting substrates for SLBs should have similar effects as cell membrane scaffolds, which regulate the dynamic structure of the membrane. PMID- 29236510 TI - Sn Wears Super Skin: A New Design for Long Cycling Batteries. AB - Searching for new anode alternatives in lieu of graphite for lithium-ion batteries that can deliver better electrochemical performance to meet the emerging energy/power demands in electric vehicles becomes particularly challenging. We report a rationally designed hybrid composite as anode in LIB that exhibits a greatly improved gravimetric capacity of 727 mAh/g with a Coulombic efficiency of >99.8% after 3000 cycles at 1.0 C. A capacity of 662 mAh/g at a high rate of 5.0 C was obtained after impressively long 10 000 cycles. From the 50th to 10 000th cycle under 5.0 C, the capacity retention is >97% with a negligible decay of <0.00026% per cycle. The excellence in electrochemistry is attributed to the efficient stress relax, accommodable space, lack of agglomeration, and solid-electrolyte interphase consuming Li+ of a delicate composite configuration that is composed of a Sn kernel wearing adjustable TiO2 "skin". PMID- 29236512 TI - Exhaled breath condensate as an alternative sample for drug monitoring. PMID- 29236514 TI - Past Methylphenidate Exposure and Stress Fractures in Combat Soldiers: A Case Control Study. AB - BACKGROUND: Previous research has revealed decreased bone mineral density (BMD) among children and adolescents who receive methylphenidate (MP) treatment for attention deficit hyperactivity disorder (ADHD). These findings have major clinical implications given that the prevalence of medication-treated ADHD is on the rise worldwide. We decided to investigate the clinical effect of MP exposure on the incidence of stress fractures, for which a low BMD is a risk factor. HYPOTHESIS: Exposure to MP is a risk factor for stress fractures. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: This is a case-control study of combat soldiers who served in the military for 3 years between 2005 and 2015. The case group included 2400 soldiers with at least 1 stress fracture diagnosed by a bone scan. The control group comprised 6187 combat soldiers without a diagnosis of a stress fracture. The use of MP was determined by an automated text search of medical records and manual sorting of the results. Other study variables included age; sex; weight; height; body mass index (BMI); place of birth; and characterization of fractures by location, side, and grade. Odds ratios of stress fractures, the attributable proportion among the exposed, and the population attributable fraction were calculated using standard contingency tables. Logistic regression was fitted after adjusting for covariates. RESULTS: The previous use of MP was associated with a higher risk of stress fractures (odds ratio, 1.15 [95% CI, 1.07-1.24]). The attributable proportion was 13.2%, and the population attributable fraction was 0.3%. Logistic regression demonstrated an increased risk of stress fractures associated with past MP use, preserved after adjusting for BMI, sex, and place of birth ( P = .005). Female sex, BMI <=20 kg/m2, and 20 < BMI <=25 kg/m2 were independent positive predictors of a stress fracture, while African origin was a negative predictor. Most participants who used MP had only 1 fracture (77.8%), while the majority of participants who did not use MP in the past had >=2 coincident fractures (53.5%) ( P = .003). CONCLUSION: This study supports the hypothesis that an MP-associated reduction in BMD has a clinical effect in the form of an increased incidence of stress fractures. The high percentage of fractures attributed to MP use may serve as a basis for risk stratification, that is, the referral of patients with a history of MP use to BMD measurements. PMID- 29236513 TI - Depletion of Airway Submucosal Glands and TP63+KRT5+ Basal Cells in Obliterative Bronchiolitis. AB - RATIONALE: Obliterative bronchiolitis (OB) is a major cause of mortality after lung transplantation. Depletion of airway stem cells (SCs) may lead to fibrosis in OB. OBJECTIVES: Two major SC compartments in airways are submucosal glands (SMGs) and surface airway p63 (also known as TP63 [tumor protein 63])-positive/K5 (also known as KRT5 [keratin 5])-positive basal cells (BCs). We hypothesized that depletion of these SC compartments occurs in OB. METHODS: Ferret orthotopic left lung transplants were used as an experimental model of OB, and findings were corroborated in human lung allografts. Morphometric analysis was performed in ferret and human lungs to evaluate the abundance of SMGs and changes in the expression of phenotypic BC markers in control, lymphocytic bronchiolitis, and OB airways. The abundance and proliferative capacity of proximal and distal airway SCs was assessed using a clonogenic colony-forming efficiency assay. MEASUREMENTS AND MAIN RESULTS: Ferret allografts revealed significant loss of SMGs with development of OB. A progressive decline in p63+/K5+ and increase in K5+/K14+ and K14+ BC phenotypes correlated with the severity of allograft rejection in large and small ferret airways. The abundance and proliferative capacity of basal SCs in large allograft airways declined with severity of OB, and there was complete ablation of basal SCs in distal OB airways. Human allografts mirrored phenotypic BC changes observed in the ferret model. CONCLUSIONS: SMGs and basal SC compartments are depleted in large and/or small airways of lung allografts, and basal SC proliferative capacity declines with progression of disease and phenotypic changes. Global airway SC depletion may be a mechanism for pulmonary allograft failure. PMID- 29236515 TI - Novel LC-MS/MS method for the quantification of silodosin and its metabolites in human plasma. PMID- 29236516 TI - Trace minerals intake: Risks and benefits for cardiovascular health. AB - Minerals play a major role in regulating cardiovascular function. Imbalances in electrolyte minerals are frequent and potentially hazardous occurrences that may lead to the development of cardiovascular diseases (CVDs). Transition metals, such as iron, zinc, copper and selenium, play a major role in cell metabolism. However, there is controversy over the effects of dietary and supplemental intake of these metals on cardiovascular risk factors and events. Since their pro oxidant or antioxidant functions can have different effects on cardiovascular health. While deficiency of these trace elements can cause cardiovascular dysfunction, several studies have also shown a positive association between metal serum levels and cardiovascular risk factors and events. Thus, a J- or U-shaped relationship between the transition minerals and cardiovascular events has been proposed. Given the existing controversies, large, well-designed, long-term, randomized clinical trials are required to better examine the effects of trace mineral intake on cardiovascular events and all-cause mortality in the general population. In this review, we discuss the role of dietary and/or supplemental iron, copper, zinc, and selenium on cardiovascular health. We will also clarify their clinical applications, benefits, and harms in CVDs prevention. PMID- 29236517 TI - Epidemiology of Hypersensitivity Pneumonitis among an Insured Population in the United States: A Claims-based Cohort Analysis. AB - RATIONALE: Hypersensitivity pneumonitis is a complex lung disease resulting from repeated inhalation of a variety of antigens. Limited data exist regarding its epidemiology. OBJECTIVES: To describe the trends in the annual incidence and prevalence of hypersensitivity pneumonitis in the United States. METHODS: We developed novel claims-based coding algorithms to identify hypersensitivity pneumonitis, chronic hypersensitivity pneumonitis, and fibrotic hypersensitivity pneumonitis cases using the 2004 to 2013 MarketScan Commercial and Medicare Supplemental healthcare claims databases. Algorithm validity and reliability were assessed with clinical data from National Jewish Health. We calculated yearly cumulative incidence and prevalence overall and by age. For the subgroup with vital status, Kaplan-Meier methods were used to analyze survival stratified by evidence of fibrosis. RESULTS: We identified 7,498 cases that met our hypersensitivity pneumonitis definition over the 10-year study period, including 3,902 with chronic hypersensitivity pneumonitis and 1,852 with fibrotic hypersensitivity pneumonitis. On the basis of the clinical-radiological adjudication of the validation sample, 38 cases (95%) were confirmed as hypersensitivity pneumonitis. The mean age was 52 years, and 58% were women. The 1-year prevalence rates for hypersensitivity pneumonitis ranged from 1.67 to 2.71 per 100,000 persons, and 1-year cumulative incidence rates ranged from 1.28 to 1.94 per 100,000 persons. The prevalence increased with age, ranging from 0.95 per 100,000 among 0- to 9-year-olds to 11.2 per 100,000 among those aged 65 years and older. Between 56 and 68% of hypersensitivity pneumonitis cases in each year were classified as chronic hypersensitivity pneumonitis (prevalence, 0.91-1.70 per 100,000 persons; cumulative incidence, 0.63-1.08 per 100,000 persons). Fewer had fibrotic hypersensitivity pneumonitis (prevalence, 0.41-0.80 per 100,000 persons; cumulative incidence: 0.29-0.43 per 100,000 persons). Most cases (74%) were classified as unspecified hypersensitivity pneumonitis. Older age, male sex, and fibrosis were associated with higher mortality rates in unadjusted analyses. CONCLUSIONS: Using U.S. administrative claims-based data, we developed an algorithm with a high sensitivity and specificity for hypersensitivity pneumonitis. Between 2004 and 2013, hypersensitivity pneumonitis was more common among women and those older than 65 years. Most cases were classified as chronic hypersensitivity pneumonitis. Approximately one-fourth met our criteria for fibrotic hypersensitivity pneumonitis, which was associated with a higher mortality rate. PMID- 29236518 TI - Reservations about Permissive Underfeeding in Low versus High NUTRIC Patients? PMID- 29236519 TI - Supercritical fluid chromatography: a promising alternative to current bioanalytical techniques. AB - During the last years, chemistry was involved in the worldwide effort toward environmental problems leading to the birth of green chemistry. In this context, green analytical tools were developed as modern Supercritical Fluid Chromatography in the field of separative techniques. This chromatographic technique knew resurgence a few years ago, thanks to its high efficiency, fastness and robustness of new generation equipment. These advantages and its easy hyphenation to MS fulfill the requirements of bioanalysis regarding separation capacity and high throughput. In the present paper, the technical aspects focused on bioanalysis specifications will be detailed followed by a critical review of bioanalytical supercritical fluid chromatography methods published in the literature. PMID- 29236520 TI - Reply to Compher et al.: Reservations about Permissive Underfeeding in Low versus High NUTRIC Patients? PMID- 29236521 TI - Korean dentists' perceptions and attitudes regarding radiation safety and protection. AB - OBJECTIVES: To investigate dentists' perceptions and attitudes regarding radiation safety in dental practices in Korea. METHODS: 207 dentists participated in this study. An anonymous survey was conducted regarding the following areas: years of practice, characteristics of the radiography equipment, knowledge of diagnostic reference levels, prescription of dental radiographs, use of radiation protection procedures and participation in the radiation safety program. Data were evaluated according to frequency distribution; the chi test; and Fisher's exact test, which was used to investigate statistical significances (p < 0.05) between those with less than 10 years of experience in practice vs those with 10 years of experience or more. RESULTS: Approximately 83% of the dentists who responded to our survey participated in the radiation safety program, but only 58% were satisfied with it. There were statistically significant differences in the installation of X-ray units, learning pathway of diagnostic reference levels, prescription of dental radiography for new adult patients, use of personnel radiation monitoring systems and participation in the radiation safety program between those with less than 10 years of experience in practice vs those with 10 years of experience or more (p < 0.05). CONCLUSIONS: Dentists with less than 10 years of experience were less attentive to radiation protection procedures. Therefore, taking both the duration of experience of dentists and the installed X ray equipment into consideration, continuous and efficient education for both dental workers and patients regarding radiation safety and protection is recommended. PMID- 29236522 TI - Risky Sex, Drugs, Sensation Seeking, and Callous Unemotional Traits in Justice Involved Male Adolescents. AB - The current study examined whether callous-unemotional (CU) traits predicted risky sexual behavior (i.e., unprotected sex, casual sex) and whether substance use and sensation seeking mediated this relationship over 24 months in justice involved young men. Participants (N = 1,216) were an ethnically and racially diverse sample (46.3% White Latino, 38% Black, 15.7% White non-Latino) of first time offending male adolescents (ages 13-17 years) from 3 U.S. cities. Participants completed 5 self-reported interviews at 6-month intervals over 2 years. Bootstrapped mediation analyses were conducted to test direct effects of CU traits on risky sexual behaviors, as well as indirect effects through substance use and sensation seeking. CU traits at baseline were positively associated with risky sexual behavior 18-24 months later. CU traits were also associated with the hypothesized mediators, sensation seeking and substance use, measured 6-12 months after baseline. CU traits exerted direct effects on later unprotected sex and casual sex, as well as indirect effects through substance use but not sensation seeking. These effects were largely unchanged when accounting for the youth's level of self-reported delinquency. These findings demonstrate that CU traits predict later risky sexual outcomes, and this is at least partly explained by substance use. Further, the findings highlight the importance of CU traits for several outcomes that are of significant public health concern among justice-involved adolescents, namely, risky sexual behavior and substance use. PMID- 29236523 TI - Associations between inflammatory bowel diseases and vitamin D. AB - Inflammatory Bowel Diseases (IBD) are increasing sharply, and the common medications are not effective for most patients. Vitamin D (VD) has been considerate to reduce inflammatory processes and may be helpful in IBD. The aim of this review was to perform an update on the potential role of VD in the IBD. We performed a search for articles associating VD and IBD published in MEDLINE PubMed and EMBASE. The focused question used for the search was "What is the association between Inflammatory Bowel Disease and Vitamin D?" The exclusion criteria for this search were studies not in English, editorials, case reports, or poster presentations. VD prevents the inflammatory process such as negatively interfering with the release of Interleukin (IL)-1, IL-6, and Tumour Necrosis Factor-alpha; enhancing the function of the intestinal epithelial barrier; decreasing the occurrence of apoptosis; stimulating Toll-Like Receptor-4; inducing the production of an antimicrobial peptide in Paneth cells. Furthermore, deficiency of VD is related to the severity of the symptoms and increased the risk of cancer and surgery. In conclusion, VD shows a potential role in the management of IBD, the supplementation is inexpensive, safe, and leads to improvement of the quality of life. PMID- 29236524 TI - The Impact of the Professional Qualifications of the Prenatal Care Provider on Breastfeeding Duration. AB - BACKGROUND: A prenatal commitment to breastfeed is a strong predictor for breastfeeding success. Prenatal care providers have the opportunity to educate and promote breastfeeding. However, differences in education and training between healthcare providers such as physicians and midwives may result in differing breastfeeding outcomes. This study explores whether breastfeeding initiation and duration differ by prenatal care provider. MATERIALS AND METHODS: Longitudinal data from the Infant Feeding Practices Survey II were analyzed (N = 2,832 women). Prenatal care providers were categorized as obstetrician, family/other physician, and midwife/nurse-midwife. Breastfeeding initiation was dichotomized (yes; no). Breastfeeding duration and exclusive breastfeeding duration were reported in weeks. Logistic regression was used to investigate the relationship between prenatal care provider and breastfeeding initiation. Cox proportional hazard models provided crude and adjusted hazard ratios and 95% confidence limits to determine the relationship between type of prenatal care provider and breastfeeding duration. RESULTS: After adjusting for confounders, women who received care from a midwife were 68% less likely to never breastfed than women whose prenatal care was provided by an obstetrician. Women whose prenatal care was provided by a midwife had 14% lower risk of discontinuing breastfeeding and 23% lower risk of discontinuing exclusive breastfeeding. No significant association was found between women whose prenatal care was provided by a family physician or other type of physician and breastfeeding initiation and duration. CONCLUSION: Findings highlight the importance of prenatal care providers on breastfeeding duration. Future studies should examine factors (i.e., training, patient-provider interaction) that contribute to differences in breastfeeding outcomes by type of prenatal care provider. PMID- 29236525 TI - Convergence in Reports of Adolescents' Psychopathology: A Focus on Disorganized Attachment and Reflective Functioning. AB - Although convergence in parent-youth reports of adolescent psychopathology is critical for treatment planning, research documents a pervasive lack of agreement in ratings of adolescents' symptoms. Attachment insecurity (particularly disorganized attachment) and impoverished reflective functioning (RF) are 2 theoretically implicated predictors of low convergence that have not been examined in the literature. In a cross-sectional investigation of adolescents receiving inpatient psychiatric treatment, we examined whether disorganized attachment and low (adolescent and parent) RF were associated with patterns of convergence in adolescent internalizing and externalizing symptoms. Compared with organized adolescents, disorganized adolescents had lower parent-youth convergence in reports of their internalizing symptoms and higher convergence in reports of their externalizing symptoms; low adolescent self-focused RF was associated with low convergence in parent-adolescent reports of internalizing symptoms, whereas low adolescent global RF was associated with high convergence in parent-adolescent reports of externalizing symptoms. Among adolescents receiving inpatient psychiatric treatment, disorganized attachment and lower RF were associated with weaker internalizing symptom convergence and greater externalizing symptom convergence, which if replicated, could inform assessment strategies and treatment planning in this setting. PMID- 29236526 TI - Effects of Varying Color, Imagery, and Text of Cigarette Package Warning Labels among Socioeconomically Disadvantaged Middle School Youth and Adult Smokers. AB - The U.S. Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) of 2009 paved the way for the Food and Drug Administration (FDA) to propose nine different graphic warning labels (GWLs) intended for prominent placement on the front and back of cigarette packs and on cigarette advertisements. Those GWLs were adjudicated as unconstitutional on the ground that they unnecessarily infringed tobacco companies' free speech without sufficiently advancing the government's public health interests. This study examines whether less extensive alternatives to the original full-color GWLs, including black-and-white GWLs and text-only options, have similar or divergent effects on visual attention, negative affect, and health risk beliefs. We used a mobile media research lab to conduct a randomized experiment with two populations residing in socioeconomically disadvantaged communities: biochemically confirmed adult smokers (N = 313) and middle school youth (N = 340). Results indicate that full color GWLs capture attention for longer than black-and-white GWLs among both youth and adult smokers. Among adults, packages with GWLs (in either color or black-and-white) engendered more negative affect than those with text-only labels, while text-only produced greater negative affect than the packages with brand imagery only. Among youth, GWLs and text-only labels produced comparable levels of negative affect, albeit more so than brand imagery. We thus offer mixed findings related to the claim that a less extensive alternative could satisfy the government's compelling public health interest to reduce cigarette smoking rates. PMID- 29236528 TI - Role of clinical neuropsychology in deep brain stimulation: Review of the literature and considerations for clinicians. AB - Deep Brain Stimulation (DBS) is an effective surgical therapy for several neurological movement disorders. The clinical neuropsychologist has a well established role in the neuropsychological evaluation and selection of surgical candidates. In this article, we argue that the clinical neuropsychologist's role is much broader, when considered in relation to applied psychologists' core competencies. We consider the role of the clinical neuropsychologist in DBS in relation to: assessment, formulation, evaluation and research, intervention or implementation, and communication. For each competence the relevant evidence-base was reviewed. Clinical neuropsychology has a vital role in presurgical assessment of cognitive functioning and psychological, and emotional and behavioral difficulties. Formulation is central to the selection of surgical candidates and crucial to intervention planning. Clinical neuropsychology has a well-established role in postsurgical assessment of cognitive functioning and psychological, emotional, and behavioral outcomes, which is fundamental to evaluation on an individual and service level. The unique contribution clinical neuropsychology makes to pre- and postsurgical interventions is also highlighted. Finally, we discuss how clinical neuropsychology can promote clear and effective communication with patients and between professionals. PMID- 29236527 TI - Paradoxical Effects of Intranasal Oxytocin on Trust in Inpatient and Community Adolescents. AB - Research suggests that oxytocin, a neuropeptide implicated in attachment, is a promising clinical tool because it increases affiliation and attachment behaviors, which are reduced in a range of psychiatric disorders. Oxytocin has been recommended as a psychiatric treatment for adolescents, but this remains largely unstudied. Skepticism is warranted, based on mixed findings in adults and absence of data across development. The objective of this study was to examine the effect of intranasal oxytocin on attachment-related and non-attachment related trust in an interactive game, determining how this effect differs among inpatient adolescents and healthy controls and whether this effect is moderated by attachment security. There were 122 adolescents (ages 12-17; n = 75 inpatient, 70% female, 37% Black, 24% Hispanic, 20% White, and 20% multiracial; n = 46 control, 55% female, 75% Caucasian) randomized to receive self-administered intranasal oxytocin or a placebo and play a trust game with their mother and a stranger over the Internet. Oxytocin only affected the trust game behavior of adolescents when attachment security was moderate or low. At these levels, oxytocin increased the trust of patients, such that their behavior was equivalent to that of healthy controls. Paradoxically, oxytocin reduced the investments of healthy control subjects. This study takes a first step toward determining whether, and for whom, oxytocin may have a trust-enhancing effect and challenges simplistic notions of oxytocin as the attachment-chemical of the brain-pointing instead to differential oxytocin effects based upon clinical status (patient vs. control) and attachment security. PMID- 29236529 TI - The Effects of Varying Electronic Cigarette Warning Label Design Features On Attention, Recall, and Product Perceptions Among Young Adults. AB - This study was a 3 (Brand: Blu, MarkTen, Vuse) by 3 (Warning Size: 20%, 30%, or 50% of advertisement surface) by 2 (Warning Background: White, Red) experimental investigation of the effects of electronic cigarette (e-cigarette) warning label design features. Young adults aged 18-30 years (n = 544) were recruited online, completed demographic and tobacco use history measures, and randomized to view e cigarette advertisements with warning labels that varied by the experimental conditions. Participants completed a task assessing self-reported visual attention to advertisements with a-priori regions of interest defined around warning labels. Warning message recall and perceived addictiveness of e cigarettes were assessed post-exposure. Approximately half of participants reported attending to warning labels and reported attention was greater for warnings on red versus white backgrounds. Recall of the warning message content was also greater among those reporting attention to the warning label. Overall, those who viewed warnings on red backgrounds reported lower perceived addictiveness than those who viewed warnings on white backgrounds, and e cigarette users reported lower perceived addictiveness than non-users. Among e cigarette users, viewing warnings on white backgrounds produced perceptions more similar to non-users. Greater recall was significantly correlated with greater perceived addictiveness. This study provides some of the first evidence that e cigarette warning label design features including size and coloring affect self reported attention and content recall. PMID- 29236531 TI - Communication Regulatory Science: Mapping a New Field. AB - Communication regulatory science is an emerging field that uses validated techniques, tools, and models to inform regulatory actions that promote optimal communication outcomes and benefit the public. In the opening article to this special issue on communication and tobacco regulatory science, we 1) describe Food and Drug Administration (FDA) regulation of tobacco products in the US; 2) introduce communication regulatory science and provide examples in the tobacco regulatory science realm; and 3) describe the special issue process and final set of articles. Communication research on tobacco regulatory science is a burgeoning area of inquiry, and this work advances communication science, informs and potentially guides the FDA, and may help to withstand legal challenges brought by the tobacco industry. This research has the potential to have a major impact on the tobacco epidemic and population health by helping implement the most effective communications to prevent tobacco initiation and increase cessation. This special issue provides an example of 10 studies that exemplify tobacco regulatory science and demonstrate how the health communication field can affect regulation and benefit public health. PMID- 29236530 TI - Ethnic and Socioeconomic Disparities in Recalled Exposure to and Self-Reported Impact of Tobacco Marketing and Promotions. AB - The role of tobacco marketing in tobacco use, particularly among the vulnerable ethnic and socioeconomic sub-populations is a regulatory priority of the U.S. Food and Drug Administration. There currently exist both ethnic and socioeconomic disparities in the use of tobacco products. Monitoring such inequalities in exposure to tobacco marketing is essential to inform tobacco regulatory policy that may reduce known tobacco-related health disparities. We use data from the Population Assessment of Tobacco and Health (PATH) Wave 1 youth survey to examine (1) recalled exposure to and liking of tobacco marketing for cigarettes, non large cigars, and e-cigarettes, (2) self-reported exposure to specific tobacco marketing tactics, namely coupons, sweepstakes, and free samples, and (3) self reported impact of tobacco marketing and promotions on product use. Findings indicate that African Americans and those of lower SES were more likely to recall having seen cigarette and non-large cigar ads. Reported exposure to coupons, sweepstakes and free samples also varied ethnically and socioeconomically. African Americans and those of lower SES were more likely than other respondents to report that marketing and promotions as played a role in their tobacco product use. Better understanding of communication inequalities and their influence on product use is needed to inform tobacco regulatory action that may reduce tobacco company efforts to target vulnerable groups. Tobacco education communication campaigns focusing on disproportionately affected groups could help counter the effects of targeted industry marketing. PMID- 29236532 TI - Correction to: Breastfeed Med 2015; 11(2):70-74. DOI: 10.1089/bfm.2015.0134. PMID- 29236533 TI - A History of Social Work in Public Health. AB - Social work is a core health profession with origins deeply connected to the development of contemporary public health in the United States. Today, many of the nation's 600 000 social workers practice broadly in public health and in other health settings, drawing on a century of experience in combining clinical, intermediate, and population approaches for greater health impact. Yet, the historic significance of this long-standing interdisciplinary collaboration-and its current implications-remains underexplored in the present era. This article builds on primary and contemporary sources to trace the historic arc of social work in public health, providing examples of successful collaborations. The scope and practices of public health social work practice are explored, and we articulate a rationale for an expanded place for social work in the public health enterprise. PMID- 29236534 TI - Health Outcomes and Costs of Social Work Services: A Systematic Review. AB - BACKGROUND: Efforts to reduce expensive health service utilization, contain costs, improve health outcomes, and address the social determinants of health require research that demonstrates the economic value of health services in population health across a variety of settings. Social workers are an integral part of the US health care system, yet the specific contributions of social work to health and cost-containment outcomes are unknown. The social work profession's person-in-environment framework and unique skillset, particularly around addressing social determinants of health, hold promise for improving health and cost outcomes. OBJECTIVES: To systematically review international studies of the effect of social work-involved health services on health and economic outcomes. SEARCH METHODS: We searched 4 databases (PubMed, PsycINFO, CINAHL, Social Science Citation Index) by using "social work" AND "cost" and "health" for trials published from 1990 to 2017. SELECTION CRITERIA: Abstract review was followed by full-text review of all studies meeting inclusion criteria (social work services, physical health, and cost outcomes). DATA COLLECTION AND ANALYSIS: Of the 831 abstracts found, 51 (6.1%) met criteria. Full text review yielded 16 studies involving more than 16 000 participants, including pregnant and pediatric patients, vulnerable low-income adults, and geriatric patients. We examined study quality, health and utilization outcomes, and cost outcomes. MAIN RESULTS: Average study quality was fair. Studies of 7 social work-led services scored higher on quality ratings than 9 studies of social workers as team members. Most studies showed positive effects on health and service utilization; cost-savings were consistent across nearly all studies. CONCLUSIONS: Despite positive overall effects on outcomes, variability in study methods, health problems, and cost analyses render generalizations difficult. Controlled hypothesis-driven trials are needed to examine the health and cost effects of specific services delivered by social workers independently and through interprofessional team-based care. Public Health Implications. The economic and health benefits reported in these studies suggest that the broad health perspective taken by the social work profession for patient, personal, and environmental needs may be particularly valuable for achieving goals of cost containment, prevention, and population health. Novel approaches that move beyond cost savings to articulate the specific value-added of social work are much needed. As health service delivery focuses increasingly on interprofessional training, practice, and integrated care, more research testing the impact of social work prevention and intervention efforts on the health and well-being of vulnerable populations while also measuring societal costs and benefits is essential. PMID- 29236536 TI - Public Health Social Work: An Uncertain Future. PMID- 29236535 TI - A Social Work Approach to Policy: Implications for Population Health. AB - The substantial disparities in health and poorer outcomes in the United States relative to peer nations suggest the need to refocus health policy. Through direct contact with the most vulnerable segments of the population, social workers have developed an approach to policy that recognizes the importance of the social environment, the value of social relationships, and the significance of value-driven policymaking. This approach could be used to reorient health, health care, and social policies. Accordingly, social workers can be allies to public health professionals in efforts to eliminate disparities and improve population health. PMID- 29236538 TI - Health in All Social Work Programs: Findings From a US National Analysis. AB - OBJECTIVES: To establish a baseline of health content in 4 domains of US social work education-baccalaureate, master's, doctoral, and continuing education programs-and to introduce the Social Work Health Impact Model, illustrating social work's multifaceted health services, from clinical to wide-lens population health approaches. METHODS: We analyzed US social work programs' Web site content to determine amount and types of health content in mission statements, courses, and specializations. Coding criterion determined if content was (1) health or health-related (HHR) and (2) had wide-lens health (WLH) emphasis. A second iteration categorized HHR and WLH courses into health topics. RESULTS: We reviewed 4831 courses. We found broad HHR content in baccalaureate, master's, and continuing education curricula; doctoral programs had limited health content. We identified minimal WLH content across all domains. Topical analysis indicated that more than 50% of courses concentrated on 3 areas: mental and behavioral health, abuse and violence, and substance use and addictions. CONCLUSIONS: As a core health profession, social work must strengthen its health and wide-lens content to better prepare graduates for integrated practice and collaboration in the changing health environment. PMID- 29236537 TI - Social Work's Role in Medicaid Reform: A Qualitative Study. AB - OBJECTIVES: To critically analyze social work's role in Medicaid reform. METHODS: We conducted semistructured interviews with 46 stakeholders from 10 US states that use a range of Medicaid reform approaches. We identified participants using snowball and purposive sampling. We gathered data in 2016 and analyzed them using qualitative methods. RESULTS: Multiple themes emerged: (1) social work participates in Medicaid reform through clinical practice, including care coordination and case management; (2) there is a gap between social work's practice-level and systems-level involvement in Medicaid innovations; (3) factors hindering social work's involvement in systems-level practice include lack of visibility, insufficient clarity on social work's role and impact, and too few resources within professional organizations; and (4) social workers need more training in health transformation payment models and policy. CONCLUSIONS: Social workers have unique skills that are valuable to building health systems that promote population health and reduce health inequities. Although there is considerable opportunity for social work to increase its role in Medicaid reform, there is little social work involvement at the systems level. PMID- 29236539 TI - No Equity, No Triple Aim: Strategic Proposals to Advance Health Equity in a Volatile Policy Environment. AB - Health professionals, including social workers, community health workers, public health workers, and licensed health care providers, share common interests and responsibilities in promoting health equity and improving social determinants of health-the conditions in which people live, work, play, and learn. We summarize the underlying causes of health inequity and comparatively poor health outcomes in the United States. We describe barriers to realizing the hope embedded in the 2010 Patient Protection and Affordable Care Act, that moving away from fee-for service payments will naturally drive care upstream as providers respond to greater financial risk by undertaking greater prevention efforts for the health of their patients. We assert that health equity should serve as the guiding framework for achieving the Triple Aim of health care reform and outline practical opportunities for improving care and promoting stronger efforts to address social determinants of health. These proposals include developing a dashboard of measures to assist providers committed to health equity and community-based prevention and to promote institutional accountability for addressing socioeconomic factors that influence health. PMID- 29236541 TI - Social Work and Public Health: Charting the Course for Innovation. PMID- 29236540 TI - Advancing Social Work Education for Health Impact. AB - Social work education plays a critical role in preparing social workers to lead efforts that improve health. Because of the dynamic health care landscape, schools of social work must educate students to facilitate health care system improvements, enhance population health, and reduce medical costs. We reviewed the existing contributions of social work education and provided recommendations for improving the education of social workers in 6 key areas: aging, behavioral health, community health, global health, health reform, and health policy. We argue for systemic improvement in the curriculum at every level of education, including substantive increases in content in health, health care, health care ethics, and evaluating practice outcomes in health settings. Schools of social work can further increase the impact of the profession by enhancing the curricular focus on broad content areas such as prevention, health equity, population and community health, and health advocacy. PMID- 29236543 TI - Rorschach Assessment of Two Distinctive Personality States of a Person With Dissociative Identity Disorder. AB - This case study used test data from a patient with Dissociative Identity Disorder (DID; American Psychiatric Association, 2013 ) to illustrate how two main personality states of the patient ("Ann" and "Ben") seemed to function. The Rorschach Performance Assessment System (R-PAS; Meyer, Viglione, Mihura, Erard, & Erdberg, 2011 ) and the Inventory of Interpersonal Problems-Circumplex (IIP-64; Horowitz, Alden, Wiggins, & Pincus, 2000 ), administered to Ann and Ben in separate settings, exposed two diverse R-PAS and IIP-64 profiles. Ann's R-PAS profile suggested an intellectualized style of information processing with few indications of psychological problems. Ben's profile indicated severe perceptual, cognitive, and interpersonal difficulties combined with suspicion and anxiety. Ann's IIP-64 profile suggested minor interpersonal problems, whereas Ben's indicated serious relational difficulties. The findings were discussed in relation to the theory of trauma-related structural dissociation of the personality (van der Hart, Nijenhuis, & Steele, 2006 ), which implies an enduring split in the organization of the personality with more or less separate entities with their own sense of self, perception of the world, and ways of organizing emotional, cognitive, and social functions. The DID personality structure is seen as a defense strategy and as a pathway in the personality development producing serious psychological pain and symptoms. PMID- 29236542 TI - Systematic Review of Health Communication for Non-Cigarette Tobacco Products. AB - The Food and Drug Administration, which now has regulatory authority over all tobacco products meeting the statutory definition, is tasked with communicating the risks of these products to the public through health warnings and public education. However, there have been no attempts to summarize what is known about non-cigarette tobacco product (NCTP) health messaging. We conducted a systematic review to examine the existing literature on health communication for NCTPs and identify key research gaps. A total of 45 unique studies were retrieved and coded, with the majority focused on messaging for smokeless tobacco (SLT, k = 32, 71.1%), followed by waterpipe tobacco (WT, k = 9, 20%), electronic nicotine delivery systems (ENDS, k = 2, 4.4%), cigars (k = 2, 4.4%), and a potentially reduced exposure product (k = 1, 2.2%). Studies most commonly examined tobacco product warnings (k = 26, 57.8%) and public education (k = 19, 42.2%), which included mass media campaigns. Most studies examined knowledge, attitudes, and beliefs as outcomes (k = 27, 60%), while behavior was an outcome in the minority of studies (k = 8, 17.8%). Pictorial warnings and public education about NCTPs demonstrated positive impact in some studies, although the literature is nascent. Given the increasing use of NCTPs such as ENDS, WT, and cigars, particularly among adolescents and young adults, more research is needed on effective ways to communicate product risk to those audiences most at risk. PMID- 29236545 TI - Nurses' Perceptions of Quality of Life for Adolescents with Congenital Heart Disease. AB - The purpose of this study was to understand nurses' perceptions and experiences regarding Quality of Life (QOL) of adolescents with complex congenital heart disease (CHD). Interpretive, hermeneutic, phenomenology was used to explore the perceptions and experiences of nurses who care for adolescents with complex CHD. The participants included 6 female registered nurses with experience taking care of adolescents with complex CHD. Data were collected using semi-structured interviews. Data analysis revealed 4 themes: QOL depends on how the psychological and social issues are interwoven with the physical; finding that balance between overprotection and too much freedom; setting goals to envision a future; and not being defined by a CHD. These results indicate that understanding nurses' perspectives and experiences may contribute to effective guidance for adolescents with complex CHD transitioning into adulthood. PMID- 29236544 TI - Gene therapy for Cystic Fibrosis: Improved delivery techniques and conditioning with lysophosphatidylcholine enhance lentiviral gene transfer in mouse lung airways. AB - : Purpose/Aim: Cystic fibrosis (CF) is the most common, fatal recessive genetic disease among the Caucasian population. Gene therapy has the potential to treat CF long term, however physiological barriers can prevent VSV-G pseudotyped lentiviral (LV) vectors from efficiently accessing the relevant receptors on the basolateral membrane of airway epithelial cells. The aims of this experiment were to use our new dose delivery techniques to determine whether conditioning the mouse lung conducting airways with lysophosphatidylcholine (LPC) improves the level of airway gene expression. MATERIALS AND METHODS: Anaesthetised normal C57Bl/6 mice were intubated with an endotracheal cannula to non-invasively facilitate airway access. The airways were conditioned with 0.1% LPC, 0.3% LPC, or PBS (control) instilled via the ET tube. One hour later a VSV-G pseudotyped LV vector carrying the LacZ transgene was delivered. LacZ expression was measured by X-gal staining of the excised lungs 3 months after gene delivery. RESULTS: Endotracheal intubation enabled precise dose delivery to the trachea and conducting airways. The cartilaginous airways of the groups conditioned with 0.1% and 0.3% LPC contained significantly larger numbers of LacZ positive cells compared to the PBS control group. In the LPC conditioned groups the majority of cell transduction was in ciliated epithelial cells. CONCLUSION: LPC conditioning prior to LV vector delivery, substantially enhanced the level of conducting airway gene expression after a single gene vector delivery. These results extend the previously established effectiveness of this protocol for producing gene expression in the nasal airways to the lung airways, the primary site of deleterious pathophysiology in CF individuals. PMID- 29236546 TI - The International Parenting Survey: Rationale, Development, and Potential Applications. AB - The quality of parent-child interactions and family relationships has a powerful influence on children's development and well-being. The International Parenting Survey (IPS) is a brief, web-based survey developed to provide a cross-national, community-level, population snapshot of the experiences of parents related to raising children. The IPS was developed as a planning tool to assist policy makers and community agencies plan, implement, and evaluate parenting programs and as a tracking tool to evaluate parenting support programs in different countries. We report the preliminary psychometric properties of the IPS on various domains of measurement in an international sample of over 9,000 parents. Moderate to high reliabilities were obtained for all domains of measurement. High internal consistency reliabilities (alpha = .88-.97) were obtained for the domains of children's behavior and emotional maladjustment, for parental self efficacy, parental distress and parental beliefs. Moderate levels of reliabilities (alpha = .52-.83) were obtained for domains of parental consistency, coercive parenting, positive encouragements, and parent-child relationships. Overall, the measure appears to have satisfactory reliability justifying further psychometric validation studies in population level studies of parenting. Examples of uses of the IPS are described and directions for future research and policy explored. PMID- 29236547 TI - The Impact of Smokeless Tobacco Risk Information on Smokers' Risk Perceptions and Use Intentions: A News Media Experiment. AB - Little research exists on the impact of risk information comparing smokeless tobacco (SLT) use, particularly snus, to cigarette smoking. This study explored this topic using a communication channel where smokers may be exposed to such information-the news media. We randomly assigned 1008 current smokers to read one of three constructed news stories or to a control group (no article). The "favorable" story framed snus as a "safer" smoking alternative while the "cautious" story described snus risks. The "mixed" version described potential risks and harm-reduction benefits. Participants completed a post-article survey with snus risk and harm perception and use intention measures. Article condition was significantly associated with perceived harm of daily snus use relative to smoking (1 = a lot less harmful - 5 = a lot more harmful; p < .0001), and mean ratings of snus harm in the favorable (2.46) and mixed conditions (2.66) were significantly lower than those of the cautious (2.96) and control conditions (2.98). Mean interest in trying snus in the next 6 months was low, but significantly higher for those in the favorable (1.55) and mixed conditions (1.32) versus those in the cautious (1.17) and control conditions (1.16)(1 = not at all - 5 = extremely interested, p < .0001). There were no significant differences by group in terms of the story's perceived interestingness, importance, or relevance. Exposure to reduced-risk news messages about SLT and snus relative to cigarettes may impact smokers' SLT harm perceptions and use intentions. Tobacco control professionals and FDA officials should consider the potential impact of the news media when communicating about tobacco risks. PMID- 29236548 TI - Budesonide instillation immediately after reperfusion ameliorates ischemia/reperfusion-induced injury in the transplanted lung of rat. AB - PURPOSE: Lung ischemia-reperfusion injury (LIRI) after lung transplantation can lead to primary graft dysfunction. Budesonide can improve endothelial function to reduce lung injury. This study was aimed to examine the effects of budesonide on LIRI and potential mechanisms. METHODS: Wistar rats were randomized and transplanted with syngeneic left lung or received the sham surgery. The recipients were instilled with saline or budesonide immediately after reperfusion. The mean arterial pressure (MAP), blood gas, and lung histology were analyzed. The ratios of wet to dry lung weights, the levels of total proteins, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10, and neutrophil elastase in bronchoalveolar lavage fluid (BALF) were measured. The levels of malondialdehyde (MDA), myeloperoxidase (MPO), and xanthine oxidase (XO) in the lung, and the levels of plasma lymphocyte function-associated antigen (LFA)-1 and P-selectin were determined. RESULTS: Compared with the saline group, treatment with budesonide significantly increased blood PaO2, but reduced PaCO2, and mitigated lung damages after reperfusion, the levels of BALF proteins, and the ratios of wet to dry lung weights in rats. Furthermore, treatment with budesonide significantly decreased the levels of MDA, MPO, and XO in the lung and the levels of TNF-alpha, IL-1beta, IL-6, and neutrophil elastase, but increased IL-10 in the BALF, accompanied by significantly reduced levels of serum P selectin and LFA-1 in rats. CONCLUSIONS: Budesonide effectively mitigated LIRI and ameliorated the lung function by attenuating oxidative stress and inflammation following syngeneic lung transplantation. PMID- 29236549 TI - Does Seeking e-Cigarette Information Lead to Vaping? Evidence from a National Longitudinal Survey of Youth and Young Adults. AB - Youth and young adults (YYAs) are vulnerable populations for e-cigarette use or vaping. This study examined the effect of YYAs' health information seeking behavior (HISB) around e-cigarette use and vaping on their subsequent vaping behavior. We conducted a nationally representative longitudinal phone survey of 13-25 year olds from June 2014 to September 2016, with 2,413 respondents who completed a baseline and follow-up survey six months later. The results from lagged logistic regressions and mediation analyses showed a) that information seeking predicted higher likelihood of vaping six months later even after controlling for baseline smoking and vaping status, intention to vape, and demographics, and b) that information seeking partially mediated the relationship between intention to vape and subsequent vaping behavior. Theoretical and regulatory implications are discussed. PMID- 29236550 TI - Effects of e-Cigarette Advertisements on Adolescents' Perceptions of Cigarettes. AB - This study examined the effect of exposure to "cigalike" (products resembling cigarettes) e-cigarette advertisements on adolescents' perceptions of cigarettes. A nationally representative sample of 802 adolescents (13-17 years old) was randomly assigned to watch three e-cigarette or three control advertisements. Never-smokers who saw the e-cigarette advertisements (n = 352) reported significantly lower perceived risks of smoking than those in the control condition (n = 320). Ever-smokers (n = 130) did not show significant differences across the conditions. In subgroup analyses, current smokers (reported smoking in the past 30 days, n = 31) in the e-cigarette condition reported significantly lower perceived benefits of smoking than those in the control condition. E cigarette advertisements can affect adolescents' perceptions of cigarettes. Many advertisements, especially the ones promoting "cigalikes," depict e-cigarettes as being similar to cigarettes (e.g., look, flavor) but also as a solution for cigarettes' shortcomings (e.g., bad smell). While the advertisements include messages about problems posed by cigarettes, proposing e-cigarettes as a solution may decrease the perceived risks of smoking among never-smokers. It may also not be clear to adolescents whether advertisements are for cigarettes or e cigarettes. Regulating e-cigarette advertisements to minimize adolescents' exposure may prevent potential harmful effects on never-smokers' perception of smoking. PMID- 29236551 TI - The Association Between Index of Nutritional Quality (INQ) and Glioma and Evaluation of Nutrient Intakes of These Patients: A Case-Control Study. AB - INTRODUCTION: Glioma is the most common adult brain tumors. Dietary factors may play a role in the etiology of glioma. The Index of Nutritional Quality (INQ) provides a general overview for the nutrient content of a food or a diet. This study aimed to investigate the association between INQ and glioma and nutrient intakes. MATERIAL AND METHODS: This study was included 128 patients and 256 controls. Dietary intakes of the subjects were evaluated by a food frequency questionnaire (FFQ) and FFQ-derived dietary data were used to calculate INQ scores. Logistic regression was used to calculate the odds ratios and 95% confidence intervals. RESULTS: Cases had higher intake of total fat, saturated fatty acid (SFA), meats, hydrogenated oils and controls had higher intake of monounsaturated fatty acid, polyunsaturated fatty acid, calcium, dairy, fruits, and nuts. Only the INQ of vitamin C, vitamin E, calcium, and fiber are higher in controls. An inverse association was observed between glioma and INQ of calcium, vitamin E, vitamin C, and fiber. CONCLUSION: The results of this study propose a healthy diet such as high intake of vitamins C and E, calcium, fiber, food groups like fruits and vegetables, and low-fat milk and nuts; and low consumption of total fat, SFA, and red meat may be protective against glioma. PMID- 29236552 TI - Website Designs for Communicating About Chemicals in Cigarette Smoke. AB - The Family Smoking Prevention and Tobacco Control Act requires the US government to inform the public about the quantities of toxic chemicals in cigarette smoke. A website can accomplish this task efficiently, but the site's user interface must be usable to benefit the general public. We conducted online experiments with national convenience samples of 1,451 US adult smokers and nonsmokers to examine the impact of four interface display elements: the chemicals, their associated health effects, quantity information, and a visual risk indicator. Outcomes were perceptions of user experience (perceived clarity and usability), motivation (willingness to use), and potential impact (elaboration about the harms of smoking). We found displaying health effects as text with icons, providing quantity information for chemicals (e.g., ranges), and showing a visual risk indicator all improved the user experience of a webpage about chemicals in cigarette smoke (all p < .05). Displaying a combination of familiar and unfamiliar chemicals, providing quantity information for chemicals, and showing a visual risk indicator all improved motivation to use the webpage (all p < .05). Displaying health effects or quantity information increased the potential impact of the webpage (all p < .05). Overall, interface designs displaying health effects of chemicals in cigarette smoke as text with icons and with a visual risk indicator had the greatest impact on the user experience, motivation, and potential impact of the website. Our findings provide guidance for accessible website designs that can inform consumers about the toxic chemicals in cigarette smoke. PMID- 29236553 TI - Progesterone suppresses the lipopolysaccharide-induced pro-inflammatory response in primary mononuclear cells isolated from human placental blood. AB - Progesterone is an essential hormone that induces deep immune adaptations favoring pregnancy maintenance. We aimed at evaluating the effects of progesterone on the synthesis of pro- and anti-inflammatory cytokines by mononuclear cells isolated from human placental blood stimulated with lipopolysaccharide, emulating an infection-inflammation environment. Mononuclear cells isolated form human placental blood were obtained from nine women undergoing elective cesarean delivery at term (not in labor), isolated by density gradient sedimentation, cultured and co-stimulated with lipopolysaccharide (500 ng/ml) from Escherichia coli in the presence or not of progesterone (0.01, 0.1, or 1.0 uM) for 24 h. Culture supernatants were assayed for pro-inflammatory (IL 1beta, TNFalpha, IL-6), anti-inflammatory (IL-10) cytokines, chemokines (IL-8, MIP-1alpha) and total MMP-9 by ELISA. In comparison with basal conditions, lipopolysaccharide treatment induced IL-1beta, TNFalpha, IL-6, IL-8, MIP-1alpha, and MMP-9 synthesis. lipopolysaccharide co-treatment with progesterone significantly decreased the bacterial endotoxin-induced IL-1beta, TNF-alpha, IL 6, IL-8, and MIP-1alpha secretion. In contrast, co-treatment with progesterone increased the level of IL-10 secreted to the culture medium. The present results support the concept that progesterone can modulate--partially--the inflammatory response of professional immune cells isolated from placental blood. Therefore, progesterone might be part of the natural compensatory mechanism that limits the cytotoxic effects associated with an intrauterine infection process during gestation. PMID- 29236554 TI - Just a Spoonful of Sugar Helps the Messages Go Down: Using Stories and Vicarious Self-Affirmation to Reduce e-Cigarette Use. AB - While prior research has demonstrated the benefits of self-affirming individuals prior to exposing them to potentially threatening health messages, the current study assesses the feasibility of inducing self-affirmation vicariously through the success of a character in a narrative. In Study 1, college-age participants who regularly use e-cigarettes (N = 225) were randomly assigned to read one of two versions of a story depicting a college student of their own gender. The versions were identical except in the vicarious self-affirmation (VSA) condition, the main character achieves success (i.e., honored with a prestigious award) before being confronted by a friend about the dangers associated with their e cigarette use; whereas in the vicarious control condition, the achievement is mentioned after the risk information. Results of the posttest and 10-day follow up demonstrated that VSA reduced messages derogation, while increasing self appraisal and perceived risk. The effect of VSA on e-cigarette outcomes was moderated by frequency of use, with heavier users benefiting the most. Study 2 (N = 152) confirmed that traditional value affirmation works with our stimuli on a comparable population. PMID- 29236555 TI - Assessing Private and Public Need for Uniqueness: Validation of French Versions of the Need for Uniqueness (NfU) and Self-Attributed Need for Uniqueness (SANU) Scales. AB - Need for uniqueness represents the need for people to feel different and distinguish themselves from others. Two major scales exist that measure this need: the Need for Uniqueness scale (NfU; Snyder & Fromkin, 1977 ) and the Self Attributed Need for Uniqueness scale (SANU; Lynn & Harris, 1997b ). We propose here a French version of both scales. Through a dual approach of exploratory and confirmatory factorial analyses, we investigated the scales' structure in student samples from two French-speaking countries (France and Switzerland, N = 1,348) as well as measures of internal and external validity. Both scales presented good psychometric properties in French. Additionally, we investigated differences between the scales, as literature suggests that the NfU relies mostly on public and risky displays of uniqueness, whereas the SANU focuses on private and more socially acceptable means to acquire a feeling of uniqueness. Differences arose in the links with several personality characteristics (emotionality, extraversion, agreeableness, sensation seeking, and self-consciousness), suggesting that the NfU corresponds rather to a need to demonstrate uniqueness through public displays and the SANU to a need to feel unique through more private means. We discuss implications for research and provide advice on choosing by the scale most appropriate to the researcher's aims. PMID- 29236556 TI - Mechanisms of Change for Children Participating in Therapeutic Horse Riding: A Grounded Theory. AB - AIM: To develop a model for understanding mechanisms of change in health outcomes for riders with disabilities participating in therapeutic horse riding (THR). METHODS: Using grounded theory methods we collected and analyzed data from interviews with 16 child riders and 18 caregivers, teachers and primary therapists, and from participant-observation during THR sessions. RESULTS: The central concept underpinning the model illustrating mechanisms of change was "gaining the tools to go on." Riders' experiences suggested the THR landscape (i.e., "where the tools are gathered") allowed for an expanded range of experiences in which riders could participate. Riders experienced an expansion of self-concept by learning to move, succeed, connect, and adapt (i.e., "the tools gathered") within the THR landscape. Riders then iteratively translated an expanded view of self into other environments, reflecting "how and where the tools are used." CONCLUSION: Findings suggest that positive changes in health arise from riders' experiences of learning and agency within the THR therapeutic landscape, and from the influence of these experiences on a child's developing self-concept. This article considers the wider impact of THR on children's health, beyond a focus on changes in physical outcomes. PMID- 29236557 TI - Complications and posttreatment care following invasive laser skin resurfacing: A review. AB - OBJECTIVE: Laser skin resurfacing (LSR) has been used for facial rejuvenation for the last 20 years. Posttreatment care after LSR is essential to decrease the risk of complications. Currently, no unified standards or criteria exist for invasive LSR posttreatment care. We aimed to identify the optimal wound care timing and choice of specific local, systemic, and general medical measures required to decrease complications. METHODS: We performed a systematic search of the PubMed/MEDLINE electronic databases and included only articles written and published in the English language, with no restrictions on the publication time (year). RESULTS: The search yielded 316 potentially relevant articles, 133 of which met our review criteria. Most of the studies on this topic have focused on wound care during the early stage, typically the first 2 weeks. Closed dressings may offer a more ideal, moist wound environment. The use of medications must be judicious. The ongoing emergence of new methods and products warrants evaluation in future large clinical trials. SUMMARY: Familiarity with the complications following invasive LSR and the provision of optimal, effective, and timely posttreatment care may substantially decrease the risks associated with the treatment modality. PMID- 29236558 TI - The paradox of adaptive responses and iso-effect per fraction. AB - PURPOSE: Despite decades of research into radiation-induced adaptive responses, where prior irradiation changes the response to subsequent irradiations, the field of radiation oncology relies upon models of tumor control that assume that each radiation therapy fraction reproduces the same effect, known as iso-effect per fraction. Can these radiobiology principles both be true, forming a paradox or is only one of them right? Here, the apparent coexistence of these two contradictory observations is considered, examining how adaptive responses might apply in radiotherapy scenarios that are inconsistent with the majority of adaptive response experimental designs. CONCLUSION: While the iso-effect per fraction assumption would preclude the observation of adaptive responses for cells survival after radiotherapy fractions, this does not preclude the observation of adaptive responses for other endpoints. Adaptive responses for cell survival might also manifest without invalidating the iso-effect principle in practical terms. It may also be the case that instances of both phenomena can be observed under different conditions, but not at the same time. PMID- 29236560 TI - Examining the nature of interprofessional practice: An initial framework validation and creation of the InterProfessional Activity Classification Tool (InterPACT). AB - The practice of, and research on interprofessional working in healthcare, commonly referred to as teamwork, has been growing rapidly. This has attracted international policy support flowing from the growing belief that patient safety and quality of care can only be achieved through the collective effort of the multiple professionals caring for a given patient. Despite the increasing policy support, the evidence for effectiveness lags behind: while there are supporting analytic epidemiological studies, few reliable intervention studies have been published and so we have yet to confirm a causal link. We argue that this lag in evidence development may be because interprofessional terms (e.g. teamwork, collaboration) remain conceptually unclear, with no common terminology or definitions, making it difficult to distinguish interventions from each other. In this paper, we examine published studies from the last decade in order to elicit current usage of terms related to interprofessional working; and, in so doing, undertake an initial empirical validation of an existing conceptual framework by mapping its four categories (teamwork, collaboration, coordination and networking) against the descriptions of interprofessional interventions in the included studies. We searched Medline and Embase for papers describing interprofessional interventions using a standard approach. We independently screened papers and classified these under set categories following a thematic approach. Disagreements were resolved through consensus. Twenty papers met our inclusion criteria. Identified interprofessional work interventions fall into a range, from looser to tighter links between members. Definitions are inconsistently and inadequately applied. We found the framework to be a helpful and practical tool for classifying such interventions more consistently. Our analysis enabled us to scrutinise the original dimensions of the framework, confirm their usefulness and consistency, and reveal new sub-categories. We propose a slightly revised typology and a classification tool (InterPACT) for future validation, with four mutually exclusive categories: teamwork, collaboration, coordination and networking. Consistent use, further examination and refinement of the new typology and tool may lead to greater clarity in definition and design of interventions. This should support the development of a reliable and coherent evidence base on interventions to promote interprofessional working in health and social care. PMID- 29236561 TI - Substance Use among Sexual Minorities: Has it Actually Gotten Better? AB - BACKGROUND: Despite efforts to decrease substance use, rates among sexual minority youth (SMY) remain higher than among heterosexuals. Substance use is a leading contributor to morbidity and mortality in adulthood, and SMY's use of substances is related to poorer mental and emotional health. OBJECTIVES: We sought to document the trends in substance use for a large sample of youth over 14 years with special attention to SMY. In addition, we tested whether there were disparities in substance use behaviors between SMY and heterosexual youth. Last, we examined changes in disparities over time in substance use among SMY. METHODS: We analyzed data from 8 waves of the Massachusetts YRBS (N = 26,002, Mage = 16), from 1999 to 2013, to investigate trends and disparities in current tobacco, alcohol, and cannabis use for heterosexual youth and SMY. We used logistic regression interaction models to test whether these disparities have widened or narrowed for SMY, as compared to heterosexuals, over the span of 14 years. RESULTS: In absolute terms, substance use rates decreased for nearly all youth between 1999 and 2013. There were striking disparities in substance use between heterosexual youth and all sexual minority subgroups. These disparities in substance use narrowed among males but remained unchanged or worsened among females. Conclusions/Importance: Trends in substance use are changing over time, but not in the same ways for all sexual minority subgroups. Patterns are worsening for females. These findings suggest that we need to address the needs of LGB populations in novel ways. PMID- 29236562 TI - From Narcotic to Normalizer: The Misperception of Methadone Treatment and the Persistence of Prejudice and Bias. AB - This article concentrates on methadone maintenance as a normalizer for the impairments of opioid addiction, and the misunderstandings of it as a substitute for heroin that continues an opiate addiction. Methadone treatment was developed by Drs. Dole, Nyswander, and Kreek. Their cutting-edge theory transformed the way that opioid addiction is perceived and their work changed methadone from a narcotic to withdraw addicts to a medication that is a maintenance normalizer for a chronic condition. Their extensive research involved the physiological and sociological normalizing effects of methadone and medical safety of the medication (Dole & Nyswander, 1967). PMID- 29236563 TI - Feasibility of a Modified Ride-on Car Intervention on Play Behaviors during an Inclusive Playgroup. AB - AIMS: Children with mobility related disabilities often experience limited participation and access to social interactions. An emerging pediatric powered mobility device are modified ride-on cars that provide self-directed mobility experiences to children with disabilities. This study aimed to determine: (1) the feasibility of a modified ride-on car intervention during an inclusive playgroup, (2) the effect of a modified ride-on car intervention on the play behaviors of children with and without mobility related disabilities. METHOD: A single-subject research design was implemented. Thirteen children participated in a weekly inclusive playgroup. The five children with mobility related disabilities were provided modified ride-on cars during the intervention. Children's play behaviors were classified with Howes' Peer Play Scale. Intervention effects were examined using nonoverlap of all pairs (NAP). RESULTS: The intervention was feasible based on participants' good attendance, retention rates, and successful use of modified ride-on cars. Overall children did not experience significant changes in play behaviors, with a few exceptions for decreased solitary, and increased parallel play, and/or direct peer interaction, among children with mobility related disabilities. Future research could examine modified ride-on car use by children with mobility related disabilities focusing on changes in unique play interactions between children with and without disabilities. PMID- 29236564 TI - Views from the field: Medical student experiences and perceptions of interprofessional learning and collaboration in rural settings. AB - Exploring the perceived environment where students are educated, as well as where they practice, is particularly important for educators and practitioners working in situations of interprofessional rural and remote health. In this study, we explored the perceptions of undergraduate medical students regarding interprofessionalism across their four-year undergraduate program which focuses on rural health. A thematic content analysis of the text-data was conducted on a convenience sample of 47 student responses to essay questions across four cohorts of a four-year undergraduate medical program. The medical program has an explicit social accountability mandate for responsiveness to the needs of a rural population and thus students have multiple opportunities to experience interprofessional education and collaboration in rural contexts. Participants reported (a) blurring and flexibility of roles in a primarily positive manner, (b) participating in unstructured interprofessional learning and collaboration, (c) experiencing the importance of social connections to interprofessional collaboration and learning, and (d) realisations that interprofessional collaboration is a means of overcoming barriers in rural areas. We discuss our findings using the socio-material perspective of complexity theory. These findings may be used to inform undergraduate programs in re-defining, re creating, developing, and fostering interprofessional learning opportunities for medical students in rural communities as well as to support clinical faculty through ongoing professional development. PMID- 29236565 TI - Developing a Point-of-Sale Health Communication Campaign for Cigarillos and Waterpipe Tobacco. AB - Adolescents and young adults smoke waterpipe tobacco (WT) and cigarillos, at least in part, based on erroneous beliefs that these products are safer than cigarettes. To address this challenge, we used a systematic, three-phase process to develop a health communication campaign to discourage WT and cigarillo smoking among at-risk (tobacco users and susceptible non-users) 16- to 25-year-olds. In Phase 1, we used a national phone survey (N = 896) to determine salient message beliefs. Participants reported constituents (i.e., harmful chemicals) emitted by the products were worrisome. In Phase 2, we developed and evaluated four message executions, with varying imagery, tone, and unappealing products with the same constituents, using focus groups (N = 38). Participants rated one execution highly, resulting in our development of a campaign where each message: (1) identified a tobacco product and constituent in the smoke; (2) included an image of an unappealing product containing the constituent (e.g., pesticides, gasoline) to grab attention; and (3) used a humorous sarcastic tone. In Phase 3, we tested the campaign messages (17 intervention and six control) with a nationally representative online survey (N = 1,636). Participants rated intervention and control messages highly with few differences between them. Exposure to messages resulted in significant increases in all risk beliefs from pre to post (p < 0.05). For WT, intervention messages increased beliefs about addiction more than control messages (p < 0.05). This systematic, iterative approach resulted in messages that show promise for discouraging WT and cigarillo use. PMID- 29236567 TI - Sexual Harassment in Medicine - #MeToo. PMID- 29236566 TI - Genome profile in a extremely rare case of pulmonary sclerosing pneumocytoma presenting with diffusely-scattered nodules in the right lung. AB - BACKGROUND: Pulmonary sclerosing pneumocytoma (PSP) typically presents solitary and peripheral mass, while only rarely cases display unusual multiple lesions. We reported a extremely rare case of PSP with diffusely-scattered nodules in the right lung. CASE PRESENTATION: Diffusely round-shaped nodular shadows in the right lung were found by CT scan in a 31-year-old Chinese woman. The patient undergone the right pneumnectomy. Grossly, numerous small nodules, up to 2.5 cm in greatest dimension were identified in the upper, middle and lower lobes of the right lung. Histologically, the tumor presented the typical features of PSP, with a variable proportion of solid, sclerotic and papillary patterns. Immunohistochemical staining further revealed that cuboidal surface epithelial cells were positive for TTF-1, EMA, AE1/3 and vimentin (partially), and round or polygonal cells expressed TTF-1, vimentin, EMA (weakly), synaptophysin (partially), progesterone receptor (partially), and estrogen receptor (scatteredly). The patient has been followed up for 83 months after surgery by annual chest CT and no new lesions are detected in her left lung and other organs. The whole-exome sequencing identified 15 somatic mutations genes (MEGF6, DNAH5, AKT1, GPRIN2, PIK3AP1, FBXO40, HERC1, VPS16, MORN1, ZNF474, CTNNB1, ZNF251, TSC1, ATM, KDR). Pathway analysis showed possible pathways like the components of CTNNB1, AKT1, and TSC1 mutations in the PI3K/AKT signalings and AKT1, KDR and ATM in VEGF signaling pathway and AKT1 activation seemed closely related with these pathways. CONCLUSION: According to our and previous data, PSP with diffuse or multiple lesions is very rare, and the patients are most commonly seen in women in Asian countries. The misdiagnosis rate by clinical and intraoperative frozen-section assessment is high because of the multiple nodules in the lung and its confusing histological features. Long time follow up indicates surgical resection should not be considered as the preferred strategy for treating multiple PSP in the intralobar sites. AKT1 activation may contribute to the development of PSP while the pathogenesis of diffuse or multiple PSP still needs to be further analyzed. PMID- 29236568 TI - Richard Bright's observations on diseases of the nervous system due to inflammation. AB - This study examines case reports of brain diseases attributed to inflammation in Richard Bright's Reports of Medical Cases, Volume II. The rationale for the belief that these cases were due to inflammation is discussed in light of theories of inflammation that were current in Bright's time. The consequences of these theories for the therapy of brain diseases are evaluated. The value of Bright's reports lies in the accuracy of the descriptions of a number of brain diseases, featuring descriptions of symptoms or conditions that were novel or not well known in the early nineteenth century. They provided a conception of diseases that constituted "typical condition of many patients," rather than "disorderly condition of a particular patient." Many cases are illustrated by remarkable images of pathological specimens. PMID- 29236569 TI - Lactation Advice through Texting Can Help: An Analysis of Intensity of Engagement via Two-Way Text Messaging. AB - Rates of breastfeeding initiation and duration among women who attend the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) are dramatically lower than nonparticipants. Innovative solutions are needed to improve breastfeeding rates in this population. The Lactation Advice through Texting Can Help (LATCH) study was one such approach, designed to augment and reinforce the WIC breastfeeding peer counseling process. The purpose of the present study was to examine engagement via two-way text messaging in a sample of women attending the WIC breastfeeding peer counseling program and enrolled in LATCH. The objectives were to: (1) describe text message engagement in the context of LATCH; and (2) assess the association between engagement variables and exclusive breastfeeding status. Text messaging data were first coded qualitatively by two independent researchers and engagement variables created. An analysis of engagement was conducted using descriptive statistics for normally distributed data and binary logistic regression. In the multivariable model, intensity of engagement during the first 2 weeks post partum was the single strongest predictor of exclusive breastfeeding status. LATCH is an innovative intervention designed to enhance the capacity of breastfeeding peer counselors and holds much potential for improving exclusive breastfeeding rates in this population. PMID- 29236570 TI - Streamlining Adverse Events Reporting in Oncology: An American Society of Clinical Oncology Research Statement. PMID- 29236571 TI - Soaring Cost of Cancer Treatment: Moving Beyond Sticker Shock. PMID- 29236572 TI - Radical Treatment of the Primary Tumor in Metastatic Bladder Cancer: Potentially Dangerous Findings From Observational Data. PMID- 29236573 TI - Massachusetts' Proposed Medicaid Reforms - Cheaper Drugs and Better Coverage? PMID- 29236574 TI - Genetic Diversity of KPC-Producing Escherichia coli, Klebsiella oxytoca, Serratia marcescens, and Citrobacter freundii Isolates from Argentina. AB - The predominance of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae was caused by the spread of ST258 clone. In Latin America, KPC was reported in 2006, with the isolation of genetically unrelated K. pneumoniae in Colombia. Since then, the expansion of blaKPC in either K. pneumoniae ST258 or other Enterobacteriaceae (ETB) species was increasingly reported. In this study, we characterized 89 KPC-producing Escherichia coli, Klebsiella oxytoca, Serratia marcescens, and Citrobacter freundii that were received between 2010 and 2014. The results revealed that all isolates harbored blaKPC-2. Moreover, the dissemination of KPC by non-K. pneumoniae was mainly caused by the dispersion of ETB mostly genetically unrelated. E. coli is a community pathogen that may serve as the vehicle for the spread of KPC into community settings. Recently, KPC was detected in E. coli ST131, an international epidemic and multidrug-resistant clone. We found that 5/29 KPC-producing E. coli belonged to ST131 and four were blaCTXM-15 producers. The detection of blaKPC in ST131 should be closely monitored to prevent further dissemination. The blaKPC is generally located within Tn4401 transposon capable of mobilization through transposition found in plasmids in ST258. Less is known about the diversity of blaKPC genetic elements that disseminate horizontally among other species of ETB. We found that 16/29 E. coli and 2/18 S. marcescens harbored blaKPC-2 in Tn4401a. In 71 isolates, blaKPC 2 was located amidst diverse Tn3-derived genetic elements bearing non-Tn4401 structure. Further studies on the plasmids that encode blaKPC-2 in these clinical isolates may provide additional insight into its transmission mechanisms. PMID- 29236575 TI - Comparing different nanofat procedures on scars: role of the stromal vascular fraction and its clinical implications. AB - AIM: Recently, a new fat grafting technique termed 'nanofat grafting' was proposed which improved tissue repair by the stem cells contained in the stromal vascular fraction (SVF) of nanofat. Here, we reported the clinical outcomes of different nanofat procedures in the treatment of scars in relation with SVF cell yield. METHODS: Three different modified nanofat grafting procedures (supercharged-, evo- and centrifuged-modified nanofat) were compared with the classic nanofat method, and histological analysis was performed to assess skin regeneration. Residual nanofat samples were analyzed to determine SVF immunophenotype and yield from each procedure. RESULTS: Supercharged-modified nanofat gave the best results in terms of clinical outcome and SVF yield. Histological analysis revealed similar skin regeneration in all treatments. CONCLUSION: This work suggested a positive correlation between SVF yield and clinical outcomes in the nanofat treatment of scars. PMID- 29236577 TI - A Focal Cooling Method for the Cervical Spinal Cord: A Percutaneous Approach to the Dorsal Neck in Dogs. AB - For the treatment of acute cervical spinal cord injuries, a local epidural cooling system using a percutaneous technique was proposed. In this animal study, regional low temperature was obtained stably in the cervical epidural space (CED) without decreasing temperatures at the rectum and the thoracic epidural space. Three stainless steel tubes were inserted percutaneously using the lateral approach into 3 serial interspinous spaces of the neck of 12 beagles under radiographic guidance. Two temperature probes were inserted into the CEDs at the level of the middle cooling tube. A third temperature probe was inserted into the epidural space at the Th13 level. A fourth temperature probe was placed in the rectum as a control. Iced water was circulated in the cooling tubes for 60 minutes. Temperatures were monitored every 10 seconds for 90 minutes, with the minimum temperatures during the period being recorded. The mean minimum temperatures recorded in the dorsal CED (min-CED-dorsal), the lateral CED (min CED-lateral), the Th13 epidural space (min-T13ED), and the rectum (min-rectum), were 16.0 +/- 0.6 degrees C, 22.6 +/- 1.6 degrees C, 35.4 +/- 0.2 degrees C, and 35.5 +/- 0.2 degrees C, respectively. There was a statistically significant difference between the mean min-CED-dorsal and min-rectum temperatures (p < 0.0001). The method introduced above was effective in reducing cervical epidural temperature selectively. PMID- 29236578 TI - The Effect of Cane Use on Attentional Demands During Walking. AB - We investigated the effects of cane use, lateral walking stability, and cane use practice on attentional demands during walking. Attentional demands were assessed using dual-task methodology with a reaction time (RT) task. Sixteen healthy young subjects performed the RT task during walking, before and after cane use practice under four conditions: with/without cane use while wearing normal/unstable shoes. Among normal shoe conditions, cane use resulted in longer RTs. In contrast, RTs were similar regardless of cane use in the unstable shoe conditions. Among conditions without cane use, unstable shoes resulted in longer RTs. In contrast, RTs were similar regardless of shoe type in the cane use conditions. This study suggests that using a cane during walking requires additional attention; however, the resulting attentional demands depend on walking stability. PMID- 29236576 TI - Destination memory accuracy and confidence in younger and older adults. AB - : Background/Study Context: Nascent research on destination memory-remembering to whom we tell particular information-suggested that older adults have deficits in destination memory and are more confident on inaccurate responses than younger adults. This study assessed the effects of age, attentional resources, and mental imagery on destination memory accuracy and confidence in younger and older adults. METHODS: Using computer format, participants told facts to pictures of famous people in one of four conditions (control, self-focus, refocus, imagery). RESULTS: Older adults had lower destination memory accuracy than younger adults, driven by a higher level of false alarms. Whereas younger adults were more confident in accurate answers, older adults were more confident in inaccurate answers. Accuracy across participants was lowest when attention was directed internally but significantly improved when mental imagery was used. Importantly, the age-related differences in false alarms and high-confidence inaccurate answers disappeared when imagery was used. CONCLUSION: Older adults are more likely than younger adults to commit destination memory errors and are less accurate in related confidence judgments. Furthermore, the use of associative memory strategies may help improve destination memory across age groups, improve the accuracy of confidence judgments in older adults, and decrease age-related destination memory impairment, particularly in young-old adults. PMID- 29236579 TI - Dimensions of ethnic identity as protective factors for substance use and sexual risk behaviors in African American college students. AB - OBJECTIVE: To examine ethnic identity and ethnic socialization as potential protective factors for risk behaviors among US college students. PARTICIPANTS: Participants were 398 African American and Afro-Caribbean students recruited from 30 colleges and universities during September 2008-October 2009. METHODS: Data on hazardous alcohol use, substance use, sexual behaviors, ethnic identity, and ethnic/racial socialization were collected. Hierarchical linear and negative binomial regression analyses were conducted to determine the degree to which ethnic identity and ethnic/racial socialization predicted the risk behaviors. RESULTS: Ethnic Identity affirmation, belonging, and commitment (EI-ABC) significantly predicted lower substance use and hazardous alcohol use. Ethnic/racial socialization was not a significant predictor of substance use or sexual risk behaviors. CONCLUSIONS: Components of ethnic identity are potentially protective against alcohol and substance use behaviors. Additional research is recommended to determine effective intervention strategies. PMID- 29236580 TI - Measures of emergency preparedness contributing to nursing home resilience. AB - Resilience approaches have been successfully applied in crisis management, disaster response, and high reliability organizations and have the potential to enhance existing systems of nursing home disaster preparedness. This study's purpose was to determine how the Center for Medicare and Medicaid Services (CMS) "Emergency Preparedness Checklist Recommended Tool for Effective Health Care Facility Planning" contributes to organizational resilience by identifying the benchmark resilience items addressed by the CMS Emergency Preparedness Checklist and items not addressed by the CMS Emergency Preparedness Checklist, and to recommend tools and processes to improve resilience for nursing homes. The CMS Emergency Preparedness Checklist items were compared to the Resilience Benchmark Tool items; similar items were considered matches. Resilience Benchmark Tool items with no CMS Emergency Preparedness Checklist item matches were considered breaches in nursing home resilience. The findings suggest that the CMS Emergency Preparedness Checklist can be used to measure some aspects of resilience, however, there were many resilience factors not addressed. For nursing homes to prepare and respond to crisis situations, organizations need to embrace a culture that promotes individual resilience-related competencies that when aggregated enable the organization to improve its resiliency. Social workers have the skills and experience to facilitate this change. PMID- 29236582 TI - Heavy metals in eggs and chicken and the associated human health risk assessment in the mining areas of Singhbhum copper belt, India. AB - Metal contamination was studied in locally rearing chicken and eggs in the environs of mining areas of Singhbhum copper belt. Concentrations of metals were below Indian standards except for Cu, Ni and Zn in the case of chicken at some locations. Estimated daily intake (EDI) and target hazard quotient (THQ) suggested that the metals did not pose risk individually. However, considering the geometric mean of the metals, hazard index (HI) was above unity. Cu, Pb and Co were the key components contributing to a potential noncarcinogenic risk. The HI varied from 0.62 to 1.66 among the locations indicating a considerable heath risk to the consumers of locally reared chicken and eggs around the mining areas. Higher HIs were found at the locations in close vicinity to copper mining and processing units compared to other locations. PMID- 29236581 TI - Esophageal Cooling Device Versus Other Temperature Modulation Devices for Therapeutic Normothermia in Subarachnoid and Intracranial Hemorrhage. AB - Achieving and maintaining normothermia (NT) after subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH) often require temperature modulating devices (TMD). Shivering is a common adverse effect of TMDs that can lead to further costs and complications. We evaluated an esophageal TMD, the EnsoETM (Attune Medical, Chicago, IL), to compare NT performance, shiver burden, and cost of shivering interventions with existing TMDs. Patients with SAH or ICH and refractory fever were treated with the EnsoETM. Patient demographics, temperature data, shiver severity, and amounts and costs of medications used for shiver management were prospectively collected. Controls who received other TMDs were matched for age, gender, and body surface area to EnsoETM recipients, and similar retrospective data were collected. All patients were mechanically ventilated. Fever burden was calculated as areas of curves of time spent above 37.5 degrees C or 38 degrees C. Demographics, temperature data, and costs of EnsoETM recipients were compared with recipients of other TMDs. Eight EnsoETM recipients and 24 controls between October 2015 and November 2016 were analyzed. There were no differences between the two groups in demographics or patient characteristics. No difference was found in temperature at initiation (38.7 degrees C vs. 38.5 degrees C, p = 0.4) and fever burden above 38 degrees C (-0.44 degrees C * hours vs. -0.53 degrees C * hours, p = 0.47). EnsoETM recipients showed a nonsignificant trend in taking longer to achieve NT than other TMDs (5.4 hours vs. 2.9 hours, p = 0.07). EnsoETM recipients required fewer shiver interventions than controls (14 vs. 30, p = 0.02). EnsoETM recipients incurred fewer daily costs than controls ($124.27 vs. $232.76, p = 0.001). The EnsoETM achieved and maintained NT in SAH and ICH patients and was associated with less shivering and lower pharmaceutical costs than other TMDs. Further studies in larger populations are needed to determine the EnsoETM's efficacy in comparison to other TMDs. PMID- 29236583 TI - The Raven. PMID- 29236584 TI - Shyness, Loneliness Avoidance, and Internet Addiction: What are the Relationships? AB - Given that shyness has been consistently linked to Internet addiction in youth, an examination into the mediating effect of a desire to avoid loneliness on the shyness-Internet addiction link could offer potential insights into a possible explanatory mechanism as well as directions for Internet addiction prevention and intervention in young adulthood. Thus, the aim of this study is to investigate the mediating role of loneliness avoidance in the relationship between shyness and Internet addiction among 286 youth Internet users. Shyness was significantly and positively correlated with loneliness avoidance and Internet addiction. In addition, loneliness avoidance was significantly and positively correlated with Internet addiction. Most importantly, loneliness avoidance may predispose shy youth to become addicted to the Internet. Theoretical and practical implications of the research findings for youth wellness are addressed in this study. PMID- 29236585 TI - Impact of meningococcal C conjugate vaccination programs with and without catch up campaigns in adolescents: Lessons learned from Bahia, Brazil. AB - The significant increase in the incidence rates and ongoing outbreaks of serogroup C meningococcal (MenC) disease, associated with the sequence type-103 complex, motivated the incorporation of the meningococcal C conjugate (MCC) vaccine in the routine immunization program in the State of Bahia, Brazil in early 2010, targeting children younger than 5 years of age. In its capital, Salvador, the program also included a catch-up campaign for individuals 10-24 years of age. We performed an observational, ecological study, analyzing data collected from 2007 to 2015, to compare the impact of these two immunization strategies on meningococcal disease incidence and mortality rates. In Salvador, following the vaccination program, a dramatic early impact on MenC disease and mortality rates could be observed, with significant reductions in incidence rates of MenC disease in all age groups, including individuals that were too old to have been vaccinated, indicating the presence of herd protection. Compared to the pre-vaccine period, a virtual disappearance of MenC disease was observed in 2015. However, in the state of Bahia (excluding the city of Salvador), no herd protection could be observed, with significant impact only among vaccine-eligible children within 5 years of introduction of the MCC vaccination program. These results highlight the importance of catch-up campaigns, including adolescents and young adults, to induce herd protection compared to immunization strategies restricted to infants and young children. This information is crucial for identifying optimal immunization policies and future strategies, focused on adolescents, to optimize the impact of MCC vaccination programs. PMID- 29236586 TI - Erratum. PMID- 29236589 TI - Tactile-Based Pantomime Grasping: Knowledge of Results is Not Enough to Support an Absolute Calibration. AB - Tactile-based pantomime-grasping requires that a performer use their right hand to 'grasp' a target previously held in the palm of their opposite hand - a task examining how mechanoreceptive (i.e., tactile) feedback informs the motor system about an object property (i.e., size). Here, we contrasted pantomime-grasps performed with (H+) and without (H-) haptic feedback (i.e., thumb and forefinger position information derived from the grasping hand touching the object) with a condition providing visual KR (VKR) related to absolute target object size. Just noticeable-difference (JND) scores were computed to determine whether responses adhered to - or violated - Weber's law. JNDs for H+ trials violated the law, whereas H- and VKR trials adhered to the law. Accordingly, results demonstrate that haptic feedback - and not KR - supports an absolute tactile-haptic calibration. PMID- 29236588 TI - Topical Glycyrrhizin Is Therapeutic for Pseudomonas aeruginosa Keratitis. AB - PURPOSE: Glycyrrhizin (GLY), an inhibitor of high-mobility group box 1 (HMGB1) protects prophylactically against Pseudomonas aeruginosa keratitis. However, the therapeutic potential of GLY to enhance an antibiotic has not been tested and is our purpose. METHODS: C57BL/6 mice (B6) were infected with a clinical isolate (KEI 1025) of P. aeruginosa and treated topically at 6 h postinfection (p.i.) with GLY or phosphate-buffered saline (PBS). Clinical scores, photography with a slit lamp, enzyme-linked immunosorbent assay, myeloperoxidase assay, bacterial plate counts, histopathology, reactive oxygen/nitrogen species (ROS/RNS) assays, and in vitro macrophage (Mphi) stimulation assays were used to assess effects of GLY treatment. In separate similar experiments, the ability of GLY to bioenhance the antibiotic, tobramycin (TOB), was assessed. RESULTS: In vivo, GLY versus PBS topical treatment began at 6 h p.i., improved disease outcome by significantly reducing clinical scores, proinflammatory proteins (HMGB1, RAGE, TLR4, TNF-alpha, and CXCL2), neutrophil infiltrate, bacterial load, ROS/RNS, and nitric oxide. In vitro, GLY downregulated iNOS and COX-2 expression (mRNA) in both mouse and human (THP-1) Mphi. At 6 and 24 h p.i., treatment with GLY enhanced the effects of TOB compared with TOB alone by significantly reducing corneal bacterial load and/or protein levels of cytokines CXCL2 and IL-1beta. CONCLUSIONS: Data provide evidence that GLY is not only therapeutic for Pseudomonas keratitis through its ability to reduce HMGB1, bacterial load, and oxidative damage but also through its bioenhancement of an antibiotic, even when treatment is initiated at 24 h after infection. PMID- 29236590 TI - A Novel Nonelectrosurgical Technique for Incising the Pylorus in Laparoscopic Pyloromyotomy. AB - OBJECTIVE: Since the loss of the protected arthrotomy knife several years ago, pediatric surgeons have struggled to find a safe, reliable, and inexpensive way to incise the pyloric serosa before spreading the muscle. The most widely accepted method of cutting the serosa is with electrocautery, although some still question its safety. We introduce a novel technique of incising the serosa with a percutaneously inserted needle without the use of electrocautery. DESCRIPTION: In this case series, we describe the experience of a single surgeon with a novel technique of incising the serosa. A retrospective chart review was conducted between January 2012 and September of 2015. In 6 patients, the serosal incision on the pylorus was made using a percutaneously inserted 18 gauge needle to cut the serosa and the superficial hypertrophied muscle fibers. As the body of the needle is not sharp, it protects the mucosa from being lacerated as the incision is carried out given a fixed depth of cut. RESULTS: The last 6 patients with hypertrophic pyloric stenosis underwent this technique. There were no conversions to open. In addition, there were no perforations and no complications related to the alteration in technique. CONCLUSIONS: Although many manufacturers pursue both disposable and nondisposable solutions to this problem, we believe this is a safe, reliable, and very inexpensive solution to this simple problem. PMID- 29236592 TI - Sequencing of Postoperative Radiotherapy and Chemotherapy for Locally Advanced or Incompletely Resected Non-Small-Cell Lung Cancer. AB - Purpose Although several feasibility studies have demonstrated the safety of adjuvant concurrent chemoradiotherapy (CRT) for locally advanced or incompletely resected non-small-cell lung cancer (NSCLC), it remains uncertain whether this approach is superior to sequential chemotherapy followed by postoperative radiotherapy (C->PORT). We sought to determine the most effective treatment sequence. Patients and Methods Using the National Cancer Database, we selected two cohorts of patients with nonmetastatic NSCLC who had received at least a lobectomy followed by multiagent chemotherapy and radiotherapy; cohort one included patients with R0 resection and pN2 disease, whereas cohort two included patients with R1-2 resection regardless of nodal status. Overall survival (OS) was examined using a propensity score-matched analysis with a shared frailty Cox regression. Results A total of 747 patients in cohort one and 277 patients in cohort two were included, with a median follow-up of 32.8 and 27.9 months, respectively. The median OS was 58.8 months for patients who received C->PORT versus 40.4 months for patients who received CRT in cohort one (log-rank P < .001). For cohort two, the median OS was 42.6 months for patients who received C >PORT versus 38.5 months for patients who received CRT (log-rank P = .42). After propensity score matching, C->PORT remained associated with improved OS compared with CRT in cohort one (hazard ratio, 1.35; P = .019), and there was no statistical difference in OS between the sequencing groups for cohort two (hazard ratio, 1.35; P = .19). Conclusion Patients with NSCLC who undergo R0 resection and are found to have pN2 disease have improved outcomes when adjuvant chemotherapy is administered before, rather than concurrently with, radiotherapy. For patients with positive margins after surgery, there is not a clear association between treatment sequencing and survival. PMID- 29236594 TI - Reply to M.C. Chamberlain. PMID- 29236595 TI - ERRATA. PMID- 29236596 TI - Genomic Assays and Individualized Treatment of Ductal Carcinoma In Situ in the Era of Value-Based Cancer Care. PMID- 29236597 TI - Immunochemotherapy, the New Standard of Care for Primary CNS Lymphoma: However, Which One? PMID- 29236598 TI - ERRATA. PMID- 29236593 TI - Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017. AB - Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease. PMID- 29236600 TI - Benefit of Intraoperative Neurophysiological Monitoring in a Pediatric Patient with Spinal Dysmorphism, Split Cord Malformation, and Scoliosis. AB - Intraoperative neurophysiological monitoring (IONM) consists of a group of neurodiagnostic techniques that assess the nervous system's functional integrity during surgical operations. A retrospective analysis of a pediatric female patient was conducted who underwent 12 operations for the correction of scoliosis, tethered cord, and split spinal cord wherein IONM played an important role. From age 3 to 6, she underwent six procedures including a release of the tethered cord, resection of the filum terminale, removal of a T11-T12 bony spur, release of L3 adhesions, repair of subcutaneous meningocele, and correction of scoliosis with a vertical expandable prosthetic titanium rod (VEPTR) technique without the use of IONM. However, a multimodality IONM protocol with somatosensory evoked potentials, transcranial electrical motor evoked potentials (TCeMEP), and an electromyogram was utilized during the later procedures. At age 6 (the seventh procedure), a VEPTR expansion was performed, with loss and recovery of the lower extremity motor evoked potentials. The postoperative magnetic resonance imaging (MRI) showed a partial split cord malformation with retethering of the spinal cord. We repaired her split cord malformation and tethered cord while employing IONM. Using IONM for her operation was crucial because a sudden significant loss of TCeMEP resulted in a cancellation of the procedure; the MRI showed a thick remnant attached to the spinal cord. If the procedure was performed without IONM, we could have missed the underlying pathology, an error that may have resulted in paraplegia. We strongly recommend using IONM during high-risk surgical procedures to help significantly reduce the risk of permanent postoperative complications. PMID- 29236602 TI - The Trustees Award. PMID- 29236601 TI - Optimal Reference Electrode Positioning for Electroneurography at the Orbicularis Oculi: A Case Report and Short Review. AB - Electroneurography is one of the most useful tests for evaluating facial nerve function. Because many patients with peripheral facial palsy complain of difficulty with eye closure, recording compound muscle action potentials (CMAPs) of the orbicularis oculi (OC) is important. However, electromyographers often encounter OC CMAPs that have an initial positivity. In the present study, facial motor potentials of a healthy subject were recorded using an electrode on the acromion and electrical activities over the facial muscles were evaluated.The contralateral OC electrode was the most inactive. A CMAP recorded using two electrodes on the ipsilateral OC showed an initial positivity. It is assumed that the onset discrepancy between electrical activities of the two electrodes on the OC results in an initial positivity. Thus, the authors recommend that electromyographers avoid using a reference electrode on the ipsilateral OC for recording its CMAP. The bilateral OC montage could be useful for recording OC CMAPs. PMID- 29236603 TI - The Maureen Berkeley Award. PMID- 29236605 TI - ASET-CEU Quiz. PMID- 29236604 TI - Intraoperative Neuromonitoring Alarms: Relationship of the Surgeon's Decision to Intervene (or Not) and Clinical Outcomes in a Subset of Spinal Surgical Patients with a New Postoperative Neurological Deficit. AB - BACKGROUND: The goal of intraoperative neurophysiologic monitoring (IONM) is to minimize neurologic injury during surgery, yet patients still emerge with postoperative deficits. Few studies focus on outcomes relative to IONM alarms and interventions in this population. The authors sought to analyze the influence of IONM alarms with and without surgical intervention on patient outcome in spinal surgical patients who suffered immediate postoperative neurologic deficits. METHODS: Of 62,038 spinal surgeries with multimodality IONM, 90 patients with new or worsened postoperative neurologic deficits and whose outcomes were reported immediate to the surgery and at discharge were analyzed. Outcomes at discharge were compared for surgeries in which an IONM alarm versus no alarm occurred. Outcomes where surgical intervention was performed versus not performed were also compared. RESULTS: By discharge, 48 (53.3%) of 90 patients had complete or partial recovery of their postoperative deficit. Patients with IONM alarms and surgical interventions had an 80% (39/49) recovery rate overall versus only 26% (7/27) recovery rate of patients with IONM alarms but no interventions, and only 14% (2/14) of patients without IONM alarms and without interventions (P < 0.001). CONCLUSIONS: These data showed significantly more patients recovered by the time of discharge when a surgical intervention was precipitated by an IONM alarm versus when it was not. The authors conclude that surgical interventions based on IONM alarms do improve patient outcomes despite immediate postoperative deficit. PMID- 29236606 TI - ASET 58th Annual Conference Proceedings. PMID- 29236609 TI - Volume 57 Contents. PMID- 29236608 TI - Credentialing Organizations. PMID- 29236612 TI - Staff Response Times in the Epilepsy Monitoring Unit: A Study of Diurnal/Nocturnal Variability. AB - Although inpatient epilepsy monitoring units (EMUs) are generally safe, seizures in this setting can still produce significant morbidity. The MORTEMUS (MORTality in Epilepsy Monitoring Unit Study) study revealed that the most feared consequence of an unattended seizure-sudden unexpected death in epilepsy (SUDEP) does occur rarely in the EMU. Nearly all cases identified in that study occurred in the evening. The hypothesis for this study is that unwitnessed seizures would be more likely to occur during the night shift, and that response times to seizures would be slower at night, due to multiple variables. A retrospective video-EEG review of all seizures captured in our EMU during a 4-week period in 15 patients admitted was conducted. The time between seizure onset and the arrival of an attendant at the bedside was measured. There were 16 diurnal and 14 nocturnal seizures identified. The median response time during the day shift was approximately 22 +/- 28 (0-80) seconds during the day shift, and 49 +/- 93 (0 360) during the night shift (Mann-Whitney U test, P = 0.03). There were six seizures that were subclinical or showed subtle clinical signs (head turning or eyes opening), including one prolonged seizure lasting nearly 18 minutes, which all occurred in the evening, went unattended, and were excluded from the statistical analysis. These preliminary findings indicate a statistically significant delay in nursing response times to seizures in the EMU during the night shift. All unattended seizures occurred in the evening. More research is needed to study human factors, systems issues, or patient-related/physiological factors that slow response times. PMID- 29236613 TI - Postretirement work and volunteering by poverty groups informed by role theory. AB - This study uses role theory to examine the association between postretirement work and volunteering among retirees and to determine whether this association varies across poverty status. Data came from the 2012 wave of the Health and Retirement Study (HRS). The sample was restricted to respondents of older retirees (N = 6,619). We found that postretirement work positively influenced volunteering. However, poverty can be a risk factor of volunteering among older retirees. The positive effect of post-retirement work was found to be more significant in the near-poverty group. We provide an empirical foundation to help inform volunteer programs for retirees. PMID- 29236614 TI - Depression among older Japanese Americans: The impact of functional (ADL & IADL) and cognitive status. AB - PURPOSE: The objective of this article is to investigate the relationship between activities of daily living, instrumental activities of daily living, cognitive impairment, and depression among Japanese American elders. METHODS: A cross sectional study of 207 older Japanese Americans (68 years and older) was conducted in Los Angeles, California and Honolulu, Hawaii. Independent variables included activities of daily living, instrumental activities of daily living, and cognitive functioning. Age, gender, marital status, and income were also identified. Depression was the dependent variable. RESULTS: Descriptive analyses were done to show group differences in terms of gender, age and marital status. Gender (male) and marital status (married) were the determinants of lower rates of depression. Lower rates of IADL and cognitive functioning were significant determinants of higher rates of depression among older Japanese Americans. CONCLUSIONS: This study provides empirical evidence that physical and cognitive functioning are directly associated with depression in older Japanese Americans. Social workers need to provide the services of ethnic-based via formal agencies in order to prevent depression of older Japanese Americans. Also, it is important to have sensitivity and competency to assess depressive symptoms and refer elders to an appropriate mental health agency. PMID- 29236615 TI - Visual Feedback of Target Position Affects Accuracy of Sequential Movements at Even Spaces. AB - The role of visual feedback during movement is attributed to its accuracy, but findings regarding the utilization of this information are inconsistent. We developed a novel dot-placing task to investigate the role of vision in arm movements. Participants conducted pointing-like movements between two target stimuli at even spaces. In Experiment 1, visual feedback of targets and response positions was manipulated. Although visual loss of target stimuli hindered accuracy of movements, the absence of the position of previously placed dots had little effect. In Experiment 2, the effect of movement time on accuracy was assessed, as the relationship between these has been traditionally understood as a speed/accuracy trade-off. Results revealed that duration of movement did not impact movement accuracy. PMID- 29236616 TI - Reply to M. Loberg et al. PMID- 29236617 TI - How Does One Decide Which Tyrosine Kinase Inhibitor To Use for the Initial Treatment of Chronic-Phase Chronic Myeloid Leukemia? PMID- 29236618 TI - Reply to K.R. Hoffman. PMID- 29236619 TI - Aspirin, Colorectal Cancer, and Cause of Death: A Complex Landscape. PMID- 29236620 TI - ERRATUM. PMID- 29236621 TI - Helping Hispanic Dementia Caregivers Cope with Stress Using Technology-based Resources. AB - OBJECTIVES: The objectives of this study were to develop and evaluate a culturally appropriate intervention for Hispanic/Latino caregivers of individuals with dementia, using a structured online program without professional involvement to improve well-being, decrease stress, and reduce depression. METHODS: The Webnovela Mirela, an online Spanish-language telenovela, was designed specifically to teach caregivers how to cope with dementia caregiving. A prototype of Webnovela Mirela was tested in a pilot study with 25 Hispanic/Latino dementia caregivers, 19 of whom completed the study. RESULTS: Data were analyzed using paired-samples t-tests. Results indicated a significant decrease from pre- to post-treatment in levels of stress and symptoms of depression (p = .045). CONCLUSIONS: The pilot study indicated high potential of the Webnovela Mirela to help the target population and demonstrated that the telenovela format is acceptable and helpful for Hispanic dementia caregivers. CLINICAL IMPLICATIONS: Study outcomes suggested that self-paced approaches with culturally relevant content in an appealing format for the target population have the potential to implement effective interventions. Furthermore, technology enables support programs to reach a broader audience in a cost-effective manner. Of note is the fact that minimal professional and/or personal assistance was required for caregivers to complete this intervention. PMID- 29236622 TI - European Social Work Research Association SIG to Study Decisions, Assessment, and Risk. AB - PURPOSE: The increasing interest in professional judgement and decision making is often separate from the discourse about "risk," and the time-honored focus on assessment. METHOD: The need to develop research in and across these topics was recognized in the founding of a Decisions, Assessment, and Risk Special Interest Group (DARSIG) by the European Social Work Research Association in 2014. RESULTS: The Group's interests include cognitive judgements; decision processes with clients, families, other professionals and courts; assessment tools and processes; the assessment, communication, and management of risk; and legal, ethical, and emotional aspects of these. This article outlines the founding and scope of DARSIG; gives an overview of decision making, assessment, and risk for practice; illustrates connections between these; and highlights future research directions. DISCUSSION: Professional knowledge about decision making, assessment, and risk complements knowledge about effectiveness of interventions. CONCLUSION: DARSIG promises to be a useful mechanism for the purpose. PMID- 29236623 TI - Group-based Acceptance and Commitment Therapy (ACT) for Older Veterans: Findings from a Quality Improvement Project. AB - OBJECTIVES: The purpose of this project was to develop, implement, and evaluate a 12-session Acceptance and Commitment Therapy (ACT) for Older Veterans group protocol. METHODS: The Plan-Do-Study-Act (PDSA) quality improvement model was the foundational process for this project. Veterans age 55 years and older participated in an ACT for Older Veterans group in an outpatient geropsychology clinic at a Veterans Affairs Medical Center. Study methods included analysis of participant feedback gathered in a focus group, process measures (i.e., number of sessions attended and number of early terminations), and outcome measures (i.e., depressive symptoms, anxiety symptoms, and psychological flexibility). RESULTS: Seventeen participants completed an average of ten sessions. Less than 25% of participants terminated early. Depressive symptoms improved, though there were no statistically significant changes in anxiety symptoms and psychological flexibility. The focus group yielded several recommendations that were implemented in subsequent groups. CONCLUSIONS: The PDSA model helped in the development of a group therapy intervention that is both relevant and beneficial to older Veterans presenting with a variety of biopsychosocial issues. Results provide support for further research investigation of ACT for Older Veterans Group. CLINICAL IMPLICATIONS: ACT used in a group format is a feasible and acceptable psychotherapy for older Veterans. PMID- 29236624 TI - A Socio-Ecological Examination of Treatment Access, Uptake and Adherence Issues Encountered By HIV-Positive Women in Rural North-Central Nigeria. AB - BACKGROUND: In spite of the global decline in HIV infections, sub-Saharan Africa still accounts for a non-proportional majority of global new infections. While many studies have documented the importance of facilitating access to anti retroviral therapy (ART) as a means of reducing infections, the relationship between interpersonal, community, healthcare facility, and policy-level factors and treatment adherence in Africa have not been well-described. The authors examined these factors in the context of prevention of mother-to-child transmission (PMTCT) of HIV in rural north-central Nigeria, where HIV burden is high and service coverage is low. METHODS: Eleven focus groups (n = 105) were conducted among PMTCT clients, male partners, young women, and other community members from 39 rural and semi-rural communities to explore factors related to HIV and antenatal care service use. Data were analyzed using the Constant Comparative Method. RESULTS: Irrespective of HIV status, participants reported barriers to access including long clinic wait times, transportation availability and cost, and the lack of HIV treatment medications. For HIV-positive women, stigma from family members, providers, and the local community affected their ability to obtain care and remain ART-adherent. In the face of these barriers, these women reflected on the importance of peer and community support, as well as the passage of laws to combat barriers to treatment access, uptake, and adherence. CONCLUSIONS: Facilitating treatment adherence may require not only focusing on the medical treatment needs of these women but also structural issues, such as the availability of providers and drugs, and systemic stigmatization of HIV-positive patients. PMID- 29236626 TI - Personal and contextual factors in substance abuse treatment among racial and ethnic minorities: Studies from the NIDA clinical trials network. PMID- 29236627 TI - Structural factors affecting Asians and Pacific Islanders in community-based substance use treatment: Treatment provider perspectives. AB - Asians and Pacific Islanders (API) have large disparities in utilization of substance use treatment compared to other racial groups. In this study, we analyzed factors that shape API experiences accessing and engaging in community based treatment from the perspective of treatment providers. We conducted semi structured interviews with 40 treatment providers who work with API clients in treatment programs in San Francisco and Los Angeles. We analyzed the transcribed interview data in ATLAS.ti using a content analysis approach. There were three main findings. First, treatment providers found the API category itself is too broad and heterogeneous to meaningfully explain substance use patterns. Second, beyond race/ethnicity, structural factors such as poverty, neighborhood, housing, and age had an impact on API substance use. Third, factors such as family, immigration status, religion, language, stigma played complex roles in API treatment experiences, contingent on how client, programs, and providers attended to differences in these categories. PMID- 29236629 TI - The Fate of FDA Postapproval Studies. PMID- 29236628 TI - Outcomes of a Coaching-Based WHO Safe Childbirth Checklist Program in India. AB - BACKGROUND: The prevalence of facility-based childbirth in low-resource settings has increased dramatically during the past two decades, yet gaps in the quality of care persist and mortality remains high. The World Health Organization (WHO) Safe Childbirth Checklist, a quality-improvement tool, promotes systematic adherence to practices that have been associated with improved childbirth outcomes. METHODS: We conducted a matched-pair, cluster-randomized, controlled trial in 60 pairs of facilities across 24 districts of Uttar Pradesh, India, testing the effect of the BetterBirth program, an 8-month coaching-based implementation of the Safe Childbirth Checklist, on a composite outcome of perinatal death, maternal death, or maternal severe complications within 7 days after delivery. Outcomes - assessed 8 to 42 days after delivery - were compared between the intervention group and the control group with adjustment for clustering and matching. We also compared birth attendants' adherence to 18 essential birth practices in 15 matched pairs of facilities at 2 and 12 months after the initiation of the intervention. RESULTS: Of 161,107 eligible women, we enrolled 157,689 (97.9%) and determined 7-day outcomes for 157,145 (99.7%) mother newborn dyads. Among 4888 observed births, birth attendants' mean practice adherence was significantly higher in the intervention group than in the control group (72.8% vs. 41.7% at 2 months; 61.7% vs. 43.9% at 12 months; P<0.001 for both comparisons). However, there was no significant difference between the trial groups either in the composite primary outcome (15.1% in the intervention group and 15.3% in the control group; relative risk, 0.99; 95% confidence interval, 0.83 to 1.18; P=0.90) or in secondary maternal or perinatal adverse outcomes. CONCLUSIONS: Birth attendants' adherence to essential birth practices was higher in facilities that used the coaching-based WHO Safe Childbirth Checklist program than in those that did not, but maternal and perinatal mortality and maternal morbidity did not differ significantly between the two groups. (Funded by the Bill and Melinda Gates Foundation; Clinical Trials number, NCT02148952 .). PMID- 29236630 TI - Kidney Diseases Associated with Human Immunodeficiency Virus Infection. PMID- 29236631 TI - Molecular Drug-Susceptibility Test for Tuberculosis. PMID- 29236632 TI - Noninvasive Ablation of Ventricular Tachycardia. PMID- 29236633 TI - Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. PMID- 29236634 TI - Improving Birth Outcomes in Low- and Middle-Income Countries. PMID- 29236635 TI - Rosai-Dorfman Disease with Activating KRAS Mutation - Response to Cobimetinib. PMID- 29236636 TI - Coupling Policymaking with Evaluation - The Case of the Opioid Crisis. PMID- 29236637 TI - Genetic Associations with Spontaneous Preterm Birth. PMID- 29236638 TI - Third Dose of MMR Vaccine for Mumps Control. PMID- 29236640 TI - Drug Companies' Liability for the Opioid Epidemic. PMID- 29236641 TI - Case 38-2017. A 20-Year-Old Woman with Seizures and Progressive Dystonia. PMID- 29236643 TI - Tubular Opacities in the Gastrointestinal Tract. PMID- 29236644 TI - The Less-Is-More Crusade - Are We Overmedicalizing or Oversimplifying? PMID- 29236642 TI - Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia. AB - BACKGROUND: Recent advances have enabled noninvasive mapping of cardiac arrhythmias with electrocardiographic imaging and noninvasive delivery of precise ablative radiation with stereotactic body radiation therapy (SBRT). We combined these techniques to perform catheter-free, electrophysiology-guided, noninvasive cardiac radioablation for ventricular tachycardia. METHODS: We targeted arrhythmogenic scar regions by combining anatomical imaging with noninvasive electrocardiographic imaging during ventricular tachycardia that was induced by means of an implantable cardioverter-defibrillator (ICD). SBRT simulation, planning, and treatments were performed with the use of standard techniques. Patients were treated with a single fraction of 25 Gy while awake. Efficacy was assessed by counting episodes of ventricular tachycardia, as recorded by ICDs. Safety was assessed by means of serial cardiac and thoracic imaging. RESULTS: From April through November 2015, five patients with high-risk, refractory ventricular tachycardia underwent treatment. The mean noninvasive ablation time was 14 minutes (range, 11 to 18). During the 3 months before treatment, the patients had a combined history of 6577 episodes of ventricular tachycardia. During a 6-week postablation "blanking period" (when arrhythmias may occur owing to postablation inflammation), there were 680 episodes of ventricular tachycardia. After the 6-week blanking period, there were 4 episodes of ventricular tachycardia over the next 46 patient-months, for a reduction from baseline of 99.9%. A reduction in episodes of ventricular tachycardia occurred in all five patients. The mean left ventricular ejection fraction did not decrease with treatment. At 3 months, adjacent lung showed opacities consistent with mild inflammatory changes, which had resolved by 1 year. CONCLUSIONS: In five patients with refractory ventricular tachycardia, noninvasive treatment with electrophysiology-guided cardiac radioablation markedly reduced the burden of ventricular tachycardia. (Funded by Barnes-Jewish Hospital Foundation and others.). PMID- 29236639 TI - A Bivalent Meningococcal B Vaccine in Adolescents and Young Adults. AB - BACKGROUND: MenB-FHbp is a licensed meningococcal B vaccine targeting factor H binding protein. Two phase 3 studies assessed the safety of the vaccine and its immunogenicity against diverse strains of group B meningococcus. METHODS: We randomly assigned 3596 adolescents (10 to 18 years of age) to receive MenB-FHbp or hepatitis A virus vaccine and saline and assigned 3304 young adults (18 to 25 years of age) to receive MenB-FHbp or saline at baseline, 2 months, and 6 months. Immunogenicity was assessed in serum bactericidal assays that included human complement (hSBAs). We used 14 meningococcal B test strains that expressed vaccine-heterologous factor H-binding proteins representative of meningococcal B epidemiologic diversity; an hSBA titer of at least 1:4 is the accepted correlate of protection. The five primary end points were the proportion of participants who had an increase in their hSBA titer for each of 4 primary strains by a factor of 4 or more and the proportion of those who had an hSBA titer at least as high as the lower limit of quantitation (1:8 or 1:16) for all 4 strains combined after dose 3. We also assessed the hSBA responses to the primary strains after dose 2; hSBA responses to the 10 additional strains after doses 2 and 3 were assessed in a subgroup of participants only. Safety was assessed in participants who received at least one dose. RESULTS: In the modified intention-to-treat population, the percentage of adolescents who had an increase in the hSBA titer by a factor of 4 or more against each primary strain ranged from 56.0 to 85.3% after dose 2 and from 78.8 to 90.2% after dose 3; the percentages of young adults ranged from 54.6 to 85.6% and 78.9 to 89.7%, after doses 2 and 3, respectively. Composite responses after doses 2 and 3 in adolescents were 53.7% and 82.7%, respectively, and those in young adults were 63.3% and 84.5%, respectively. Responses to the 4 primary strains were predictive of responses to the 10 additional strains. Most of those who received MenB-FHbp reported mild or moderate pain at the vaccination site. CONCLUSIONS: MenB-FHbp elicited bactericidal responses against diverse meningococcal B strains after doses 2 and 3 and was associated with more reactions at the injection site than the hepatitis A virus vaccine and saline. (Funded by Pfizer; ClinicalTrials.gov numbers, NCT01830855 and NCT01352845 ). PMID- 29236645 TI - Caterpillar Sign in Infantile Hypertrophic Pyloric Stenosis. PMID- 29236647 TI - Assessing the marks of change: how psychotherapy alters the brain structure in women with borderline personality disorder. AB - BACKGROUND: There is increasing evidence that psychotherapy can alter the function of the brain of patients with borderline personality disorder (BPD). However, it is not known whether psychotherapy can also modify the brain structure of patients with BPD. METHODS: We used structural MRI data of female patients with BPD before and after participation in 12 weeks of residential dialectical behavioural therapy (DBT) and compared them to data from female patients with BPD who received treatment as usual (TAU). We applied voxel-based morphometry to study voxel-wise changes in grey matter volume over time. RESULTS: We included 31 patients in the DBT group and 17 in the TAU group. Patients receiving DBT showed an increase of grey matter volume in the anterior cingulate cortex, inferior frontal gyrus and superior temporal gyrus together with an alteration of grey matter volume in the angular gyrus and supramarginal gyrus compared with patients receiving TAU. Furthermore, therapy response correlated with increase of grey matter volume in the angular gyrus. LIMITATIONS: Only women were investigated, and groups differed in size, medication (controlled for) and intensity of the treatment condition. CONCLUSION: We found that DBT increased grey matter volume of brain regions that are critically implicated in emotion regulation and higher-order functions, such as mentalizing. The role of the angular gyrus for treatment response may reside in its cross-modal integrative function. These findings enhance our understanding of psychotherapy mechanisms of change and may foster the development of neurobiologically informed therapeutic interventions. PMID- 29236646 TI - Evaluation of bone mineral density (BMD) and indicators of bone turnover in patients with hemophilia. AB - A decrease in bone mass is observed in hemophilic patients. The aim of this study was to evaluate bone mineral density (BMD), parathyroid hormone (PTH), 25-hydroxy vitamin D (vitamin D), and a bone formation and resorption marker, procollagen type I N-terminal propeptide (PINP) and urinary N-terminal telopeptide (uNTX) respectively, in hemophilic patients and healthy controls. Laboratory parameters related to the pathogenesis of bone loss such as neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were also evaluated. Thirty-five men over 18 years of age, with severe hemophilia (A and B) and receiving secondary prophylaxis, were included in the study. The same number of age-, sex-, and ethnicity-matched healthy controls were evaluated. Anthropometric, biochemical, and hormonal parameters were determined in both groups. No significant difference in anthropometric parameters was found between the two groups. The BMD was low in 34% of hemophilic patients. Vitamin D, calcium, and free testosterone levels were significantly lower (p < 0.001, p = 0.011, p < 0.001, respectively), while PTH, PINP, and activated partial thromboplastin time (aPTT) levels were significantly higher (p < 0.014, p = 0.043, p < 0.001, respectively), in hemophilic patients compared to controls. There was no significant difference between the two groups in NLR, PLR, phosphorus, thyroid-stimulating hormone, and uNTX level. The reduction of bone mass in hemophilic patients may be evaluated using the markers of bone formation and resorption, enabling early detection and timely treatment. PMID- 29236648 TI - A putative electrophysiological biomarker of auditory sensory memory encoding is sensitive to pharmacological alterations of excitatory/inhibitory balance in male macaque monkeys. AB - BACKGROUND: The amplitude of the auditory evoked N1 component that can be derived from noninvasive electroencephalographic recordings increases as a function of time between subsequent tones. N1 amplitudes in individuals with schizophrenia saturate at a lower asymptote, thus giving rise to a reduced dynamic range. Reduced N1 dynamic range is a putative electrophysiological biomarker of altered sensory memory function in individuals with the disease. To date, it is not clear what determines N1 dynamic range and what causes reduced N1 dynamic range in individuals with schizophrenia. Here we test the hypothesis that reduced N1 dynamic range results from a shift in excitatory/inhibitory (E/I) balance toward an excitation-deficient or inhibition-dominant state. METHODS: We recorded auditory-evoked potentials (AEPs) while 4 macaque monkeys passively listened to sequences of sounds of random pitch and stimulus-onset asynchrony (SOA). Three independent experiments tested the effect of the N-methyl-d-aspartate receptor channel blockers ketamine and MK-801 as well as the gamma-aminobutyric acid (GABA) A receptor-positive allosteric modulator midazolam on the dynamic range of a putative monkey N1 homologue and 4 other AEP components. RESULTS: Ketamine, MK 801 and midazolam reduced peak N1 amplitudes for the longest SOAs. Other AEP components were also affected, but revealed distinct patterns of susceptibility for the glutamatergic and GABA-ergic drugs. Different patterns of susceptibility point toward differences in the circuitry maintaining E/I balance of individual components. LIMITATIONS: The study used systemic pharmacological interventions that may have acted on targets outside of the auditory cortex. CONCLUSION: The N1 dynamic range may be a marker of altered E/I balance. Reduced N1 dynamic range in individuals with schizophrenia may indicate that the auditory cortex is in an excitation-deficient or inhibition-dominant state. This may be the result of an incomplete compensation for a primary deficit in excitatory drive. PMID- 29236649 TI - Deadly Sphenoid Fungus-Isolated Sphenoid Invasive Fungal Rhinosinusitis: A Case Report. AB - INTRODUCTION: Acute invasive fungal rhinosinusitis (AIFRS) is a potentially fatal infection, usually affecting immunocompromised patients. Isolated sphenoid sinus involvement is rare and has been reported in only a few cases. We discuss the clinical characteristics, histopathologic features, and differential diagnosis of AIFRS of the sphenoid sinus. CASE PRESENTATION: A 57-year-old man with a history of refractory non-Hodgkin lymphoma and neutropenia presented with a 1-week duration of left-sided headache and ipsilateral cheek paresthesia. Nasal endoscopy showed mucoid drainage from the sphenoethmoidal recess. Magnetic resonance imaging demonstrated left sphenoid mucosal thickening and enhancement along the adjacent skull base. The patient underwent endoscopic sinus surgery with extended sphenoidotomy and debridement. The lateral wall and recess of the left sphenoid sinus demonstrated pale mucosa and fungal debris. Pathologic analysis demonstrated necrotic tissue and fungal hyphae with angioinvasion. Microbiology studies isolated Aspergillus fumigatus. The right maxillary sinus contained a synchronous fungal ball, which was removed during surgery; there was no evidence of tissue necrosis or invasive fungus in the maxillary sinus. He was treated with long-term voriconazole therapy, and 6-month follow-up showed disease resolution. DISCUSSION: AIFRS should be considered in the differential diagnosis of immunocompromised patients with nonspecific sinonasal symptoms. Usually, AIFRS is diffuse with multiple sinus involvement; however, isolated sphenoid AIFRS can occur. This is one of the few cases of AIFRS demonstrating isolated sphenoid involvement and is thought to be the first case showing a synchronous noninvasive fungal ball of another sinus cavity. Prompt recognition and surgical treatment may be curative and lifesaving. PMID- 29236650 TI - Perspective on Publishing Quality Improvement Efforts. AB - Quality improvement (QI) activities are critical to achieve the Triple Aim and to the Institute of Medicine's six "Aims for Quality Improvement": Safe, Effective, Patient-Centered, Timely, Efficient, and Equitable. These QI activities are essential to create a learning health care system. Academic publishing is critical to foster continuous QI and sharing, and yet it tends to favor more traditional research articles. Publishing QI activities has great value, encourages greater rigor, and helps facilitate greater willingness to share improvement opportunities. PMID- 29236651 TI - Recognizing a Rare Phenomenon of Angiotensin-Converting Enzyme Inhibitors: Visceral Angioedema Presenting with Chronic Diarrhea-A Case Report. AB - INTRODUCTION: Peripheral angioedema of the face and upper airways is a well-known phenomenon of angiotensin-converting enzyme inhibitors occurring in only 0.1% to 0.7% of patients. We describe a case of the even less-common manifestation of visceral angioedema, which causes symptoms of chronic and intractable diarrhea. CASE PRESENTATION: A 68-year-old white woman presented with large-volume diarrhea, caused by visceral angioedema secondary to lisinopril therapy. Initial imaging studies were significant for distended small bowel loops, with subsequent unremarkable findings on colonoscopy and biopsy studies. After an exhaustive laboratory work-up, her diarrhea resolved only after the discontinuation of lisinopril. DISCUSSION: Use of angiotensin-converting enzyme inhibitors is increasing, making the recognition of visceral angioedema important in preventing significant morbidity and avoiding invasive and costly studies. PMID- 29236652 TI - Image Diagnosis: Nasal Furunculosis-A Dangerous Nose Infection. PMID- 29236654 TI - Access to Affordable Housing Promotes Health and Well-Being and Reduces Hospital Visits. AB - Clinical interventions can only partially mitigate homelessness and housing insecurity, which are threats to health and well-being. Clinicians have several opportunities to address these problems: They can refer patients who are homeless or housing insecure to support services, advocate for their employer or care group to commit resources to end homelessness and housing insecurity, and/or work with government and private sector community organizations to address and eliminate these problems. Citing examples from around the US, we will illustrate how clinics, hospitals, health plans, and public health organizations work to engage in initiatives to end homelessness and housing insecurity. PMID- 29236653 TI - Rectal Cancer Survivors' Participation in Productive Activities. AB - CONTEXT: Rectal cancer and its treatment impair survivors' productivity. OBJECTIVE: To assess determinants of market and nonmarket employment, job search, volunteering, and homemaking among survivors five years or longer after diagnosis. DESIGN: We mailed questionnaires to 1063 survivors who were members of Kaiser Permanente (Northern California, Northwest) during 2010 and 2011. MAIN OUTCOME MEASURES: Productive activities, functional health status, and bowel management at the time of the survey. RESULTS: Response rate was 60.5% (577/953). Higher comorbidity burdens were associated with lower productivity for men and women rectal cancer survivors. Productive survivors were younger and had lower disease stage and age at diagnosis, higher household income and educational attainment, and fewer comorbidity burdens and workplace adjustments than did nonproductive survivors (p < 0.05 each; 2-sided). Productive rectal cancer survivors were evenly split by sex. CONCLUSION: Staying productive is associated with better mental health for rectal cancer survivors. Rectal cancer survivors with multiple chronic conditions, higher disease stage, lower productive activities, and older age need better access to medical care and closer monitoring of the quality of their care, including self-care. To capture the full extent of the involvement of survivors in all types of productive activities, research should routinely include measures of employment, searching for employment, homemaking, and volunteering. Counting market and nonmarket productive activities is innovative and recognizes the continuum of contributions survivors make to families and society. Health care systems should routinely monitor rectal cancer survivors' medical care access, comorbidities, health related quality of life, and productive activities. PMID- 29236655 TI - Association of Proteinuria with Central Venous Catheter Use at Initial Hemodialysis. AB - CONTEXT: Central venous catheter (CVC) use is associated with increased mortality and complications in hemodialysis recipients. Although prevalent CVC use has decreased, incident use remains high. OBJECTIVE: To examine characteristics associated with CVC use at initial dialysis, specifically looking at proteinuria as a predictor of interest. DESIGN: Retrospective cohort of 918 hemodialysis recipients from Kaiser Permanente Northwest who started hemodialysis from January 1, 2004, to January 1, 2014. MAIN OUTCOME MEASURES: Multivariable logistic regression was used to examine an association of proteinuria with the primary outcome of CVC use. RESULTS: More than one-third (36%) of patients in our cohort started hemodialysis with an arteriovenous fistula, and 64% started with a CVC. Proteinuria was associated with starting hemodialysis with a CVC (likelihood ratio test, p < 0.001) after adjustment for age, peripheral vascular disease, congestive heart failure, diabetes, sex, race, and length of predialysis care. However, on pairwise comparison, only patients with midgrade proteinuria (0.5-3.5 g) had lower odds of starting hemodialysis with a CVC (odds ratio = 0.39, 95% confidence interval = 0.24-0.65). CONCLUSION: Proteinuria was associated with use of CVC at initial hemodialysis. However, a graded association did not exist, and only patients with midgrade proteinuria had significantly lower odds of CVC use. Our findings suggest that proteinuria is an explanatory finding for CVC use but may not have pragmatic value for decision making. Patients with lower levels of proteinuria may have a higher risk of starting dialysis with a CVC. PMID- 29236656 TI - Secondary Syphilis Associated with Membranous Nephropathy and Acute Hepatitis in a Patient with HIV: A Case Report. AB - INTRODUCTION: We present a case of membranous nephropathy associated with a secondary syphilis infection in a patient with HIV. CASE PRESENTATION: A 37-year old white man with HIV who was receiving highly active antiretroviral therapy presented to the Emergency Department with 6 weeks of rectal pain. He had a CD3 CD4 count of 656 cells/mm3 and an undetectable viral load. On admission, he was found to have an anal ulcer, a serum creatinine of 1.4 mg/dL (baseline 0.7 to 1.0 mg/dL), elevated transaminases, positive rapid plasmin reagin, and a urine protein/creatinine ratio revealing nephrotic-range proteinuria. Renal biopsy demonstrated membranous nephropathy with features suggestive of a secondary cause. Our patient was treated with penicillin for secondary syphilis, with normalization of renal function, resolution of the nephrotic syndrome, and improvement of his elevated transaminases. DISCUSSION: This case is a reminder that patients with HIV are not infrequently coinfected with Treponema pallidum and that secondary syphilis can have systemic manifestations, including elevated transaminases and nephrotic syndrome. Prompt diagnosis and treatment will result in resolution of these problems. PMID- 29236657 TI - Psoriasiform Hailey-Hailey Disease Presenting as Erythematous Psoriasiform Plaques Throughout the Body: A Case Report. AB - INTRODUCTION: Hailey-Hailey disease is an adult-onset skin condition characterized by lesions in the intertriginous regions of the body. The lesions can be pruritic, painful, and associated with physical and social impairment. CASE PRESENTATION: We present a case of psoriasiform Hailey-Hailey disease in a 60-year-old white woman who exhibited erythematous psoriasiform plaques in many areas of her body. The patient's condition was successfully treated with a twice daily regimen of doxycycline, mometasone, and clindamycin. DISCUSSION: It is important to recognize this variant of Hailey-Hailey disease so it can be diagnosed and treated promptly. Hailey-Hailey disease can be treated with topical corticosteroids and antibiotics and usually is associated with a positive prognosis. PMID- 29236658 TI - How Using Generative Learning Strategies Improved Medical Student Self-Competency in End-of-Life Care. AB - During a mandatory fourth-year core geriatric medicine rotation at our medical school, we discovered that our medical students were struggling with end-of-life (EOL) issues both personally and professionally. We implemented curriculum changes to assist them in developing emotional awareness about death and dying, and to help develop their ability to respond personally and professionally to patients and their families during EOL experiences.In our new curriculum, a seasoned ethicist at our university conducts 2 educational sessions addressing EOL issues. Students complete self-study content before the first session, in which they have a discussion about their own experience with death and dying. Our ethicist facilitates these discussions with a small group (10-14 medical students), allowing the students to explore their own experiences, case studies, and others' experiences in EOL. Before the second session, students prepare a self-reflective narrative essay about an EOL experience. Our facilitator, by using a generative learning strategy, has a rich interaction that attempts to connect previous experiences, present training, and how the student physicians may need to adjust behaviors in order to be advocates for their patients in EOL situations in the future. Students complete a pre- and post-self-assessment in the didactic. Results show significant improvement in their perceived competence in EOL issues. In addition, the students' self-reflection essays reveal intriguing themes for future study. PMID- 29236659 TI - The Harmony of Disequilibrium. PMID- 29236660 TI - Migraine Headache Treated with Famciclovir and Celecoxib: A Case Report. AB - INTRODUCTION: Herpes simplex virus (HSV) has been speculated to play a role in migraine headache pathophysiology. We present the first successful migraine headache treatment with therapy specifically targeting HSV infection. CASE PRESENTATION: A previously healthy 21-year-old white woman presented with a severe headache and was diagnosed with severe migraine headache disorder. She initially was treated with standard migraine headache medications without symptomatic improvement. She was then given famciclovir and celecoxib. The patient fully recovered within days and continues to enjoy significant reduction in severity and frequency of symptoms. DISCUSSION: Famciclovir and celecoxib may work synergistically against HSV. The virus may play a role in the pathophysiology of migraine headaches, and this is the first case report of successful migraine headache treatment with these medications. Further studies are needed to elucidate the efficacy of these medications in treating migraine disorder. PMID- 29236661 TI - WITHDRAWN: Efficacy of thermobalancing therapy for chronic prostatitis/chronic pelvic pain syndrome, confirmed by clinical study, may suggest etiology and pathophysiology of this disease. PMID- 29236662 TI - [Mechanics of inner cell mass formation]. AB - During the very first days of mammalian development, the embryo forms a structure called the blastocyst. The blastocyst consists of two cell types: the trophectoderm (TE), which implants the embryo in the uterus and the inner cell mass (ICM), which gives rise to all cells of the mammalian body. Previous works identified how cells differentiate according to their position within the embryo: TE for surface cells and ICM for internal cells. It is therefore essential to understand how cells acquire their position in the first place. During the formation of the blastocyst, cells distort and relocate as a consequence of forces that are generated by the cells themselves. Recently, several important studies have identified the forces and cellular mechanisms leading to the shaping of the ICM. Here, I describe how these studies led us to understand how contractile forces shape the mammalian embryo to position and differentiate the ICM. PMID- 29236663 TI - [Antibiotic transport and membrane permeability: new insights to fight bacterial resistance]. AB - A main challenge in medicinal chemistry is to determine the parameters modulating the in cellulo drug concentration needed for a therapeutic action. In Gram negative antibacterial research, the concern is to evaluate the antibiotic permeation across the outer and inner membranes, that delineate the periplasm surrounding the bacterial cytoplasm. Passing through the membrane barrier to reach the inhibitory concentration inside the bacterium is the first pivotal step for antibiotics. The research and the development of new antimicrobials mostly rely on their capacity to reach critical concentrations in the vicinity of their intracellular target. Despite several decades of studies focused on antibiotic/drug activity against bacterial cells using different approaches, no consensus regarding the analysis of the kinetics and accumulation in individual bacterium and in bacterial populations is available to understand the drug translocation into living bacteria as a first step of drug action. Our TRANSLOCATION consortium supports the development of reliable and robust methods to quantify penetration and efflux processes in Gram-negative bacteria and recently we have developed a reliable and efficient method to determine the intra bacterial concentration of fluorescent antibiotics. By using these powerful approaches, new concepts, "Resident Time Concentration Close to Target" (RTC2T) and "Structure Intracellular Concentration Activity Relationship" (SICAR), have been proposed in order to link chemical and structural aspects with the bacterial membrane and transport aspects. Using RTC2T and SICAR indexes, a new dissection of antibiotic translocation-transport can be obtained to better understand and improve the antibiotic pharmacophoric groups that are related to permeation and efflux. PMID- 29236664 TI - ? PMID- 29236665 TI - [Claude Bernard - then and now]. AB - The early life of Claude Bernard - dreamer and frustrated playwright - reveals no indication of his future scientific aptitude. Cartesian doubt, a principle that he would adhere to lifelong, clouded a failed pharmacy apprenticeship that led to medical studies in Paris - but without great success. Research was his only aim, it was made possible only by a lucrative but unsuccessful arranged marriage. His passion for work and over-riding principles of truth and proof would ultimately allow him to stand out from his peers with recognition by multiple French professional societies - and the wider scientific world. In today's world, the two centuries-long practice of homeopathy illustrates his abhorrence of ''practice without proof'': a dominance by economic factors that is apparent in cancer chemotherapy, where new drug approval is often based on statistics rather than genuine clinical benefit. Bernard was indeed sceptical about the (ab)use of statistics - a caution even more necessary today. His experimental method stands out as a signal principle in research. This was cleverly taken out of context by Emile Zola, who used it to support his ideas on the literary naturalism that appeared in his Rougon-Macquart cycle of books - and that led him to dedicate his book, Le Roman Experimental, to Claude Bernard himself. PMID- 29236666 TI - [Louis Pasteur and Claude Bernard: about a posthumous controversy]. AB - Claude Bernard and Louis Pasteur will meet on various occasions, scientific prizes were awarded by Claude Bernard to Louis Pasteur, Claude Bernard's lessons were followed by Louis Pasteur at the Faculty of Science or at the College de France, and friendly relationship were established. But the essential lies in a posthumous controversy where Claude Bernard, denying the role of microbes in the fermentation, seems to criticize Pasteur's assertions and, later, his method and vision. We shall report here the exchanges which concern these two scientists and, beyond that, the scientific approach. PMID- 29236667 TI - [Diabetes: What are the key targets and the objectives? Preserving and protecting a functional pancreatic beta cell mass]. AB - Diabetes is characterized by chronic hyperglycemia. Type 2 diabetes, which represents 90% of diabetes cases, is the consequence of an insulin resistance and pancreatic beta cell dysfunction combination. Since the beta cells are the only cells of the organism to synthesize and to secrete insulin, it is essential to maintain and to protect their function and survival. It is currently proposed that an ideal and innovative treatment of type 2 diabetes should be based on an approach targeting pancreatic beta-cell dysfunction and death. It is now well described that chronic hyperglycemia is critically involved in the development of beta-cell dysfunction and apoptotic death (Glucotoxicity). Reducing the chronic hyperglycemia is a key objective in the treatment of type 2 diabetes, to attenuate not only the development of micro and macrovascular complications, but also the deleterious effects exerted on the pancreatic beta cells. PMID- 29236668 TI - [Claude Bernard and nicotinic receptors: from the neuromuscular junction to tobacco weaning]. AB - Claude Bernard (1813-1878) was fascinated by the pharmacological mechanisms of poisons. In particular, using a huge amount of ingenious and robust experiments, he demonstrated the peripheral toxic action of the natural compound curare. His work generated controversies in a period where scientific methodology and technical development followed the progression of concepts and ideas. From his intense debates with Albert Vulpian emerged the location of curare's toxicity at the neuromuscular junction. These two fascinating scientists could not imagine how important were these discoveries which allowed John Langley to propose the concept of receptor early in the 20th century. At the same time, the German immunologist Paul Ehrlich suggested that these receptors could be targeted by so called "magic bullets", i.e., drugs that act on receptors, in order to treat patients. The molecular substrate of curare's activity was identified many years later as the nicotinic receptor of the motor end-plate. We now have curare molecules belonging to various chemical families that block receptors during anaesthesia. Suggamadex is the antidote for two of them, a drug that Claude Bernard perhaps dreamt of. We also have the recently marketed varenicline that acts as a partial agonist of nicotinic receptors in the central nervous system to treat patients from tobacco addiction. This rich story shows that biomedical research needs collaborations, imagination, perspicacity but also all results that it can have many years later, therefore challenging researchers about consequences of their discoveries. PMID- 29236669 TI - [Optically dissecting brain nicotinic receptor function with photo-controllable designer receptors]. AB - Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels widely expressed in the central nervous system and the periphery. They play an important modulatory role in learning, memory and attention, and have been implicated in various diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, schizophrenia and addiction. These receptors are activated by the endogenous neurotransmitter acetylcholine, or by nicotine, the alkaloid found in tobacco leaves. Both molecules open the ion channel and cause the movement of cations across the membrane, which directly affects neuronal excitability and synaptic plasticity. nAChRs are very heterogeneous in their subunit composition (alpha2-10 et beta2-4), in their brain distribution (cortex, midbrain, striatum...) and in their sub-cellular localization (pre- vs post-synaptic, axonal, dendritic...). This heterogeneity highly contributes to the very diverse roles these receptors have in health and disease. The ability to activate or block a specific nAChR subtype, at a defined time and space within the brain, would greatly help obtaining a clearer picture of these various functions. To this aim, we are developing novel optogenetic pharmacology strategies for optically controlling endogenous nAChR isoforms within the mouse brain. The idea is to tether a chemical photoswitch on the surface of a cysteine-modified nAChR, and use light for rapidly and reversibly turning that receptor mutant on and off. Here we will discuss the history of optogenetic pharmacology, and the recent advances for the optical control of brain nicotinic receptors in vivo. PMID- 29236670 TI - [Insulinoresistancy in Man: from mechanisms to nutritional interference]. AB - Obesity is presently regarded as the "the first non-infectious epidemic outbreak" in the history of Humanity. It is a multifactorial pathology, that contributes to the emergence of insulinoresistancy. Some obese individuals display an obesity qualified as metabolically sound, i.e., non-associated with metabolical anomalies. The present paper reviews the different possible mechanisms responsible for insulin-resistancy. PMID- 29236671 TI - ? PMID- 29236672 TI - Setting Up the Perimeter of Tolerance: Insights into mTEC Physiology. AB - Medullary thymic epithelial cells (mTECs) play a central role in T cell tolerance. However, how the mTEC compartment is maintained remains elusive. We review recent discoveries on new transcription factors involved in mTEC homeostasis and discuss the possibility that their actions might be facilitated by the unique biology of mTECs. PMID- 29236675 TI - Selected Extended Papers of the 11th International Conference on Practical Applications of Computational Biology and Bioinformatics (PACBB). PMID- 29236674 TI - Citrullus colocynthis Linn. Fruit extract ameliorates cisplatin-induced hepato renal toxicity in rats. AB - Background Cisplatin-induced acute liver and kidney injuries are serious problems in cancer patients during treatment of solid tumours. Objective This study sought to investigate possible protective effect of ethanolic fruit extract of Citrullus colocynthis (CC) against cisplatin-induced hepato-renal toxicity in rats. Methods Thirty male albino rats (150-200 g) were divided into five groups (n=6) and treated as follows: group 1: vehicle (10 mL/kg, p.o.; normal control); group 2: vehicle (10 mL/kg); groups 3-5: CC (100, 200 or 400 mg/kg, p.o.), respectively, for 10 days. Cisplatin (7.5 mg/kg; i.p.) was administered on the 7th day to animals in groups (2-5) 1 h after pretreatment. The animals were euthanized on day 10 for haematological, biochemical and histological analysis. Results Cisplatin induced a significant increase in the serum levels of ALT, ALP, creatinine and blood urea nitrogen indicative of hepato-renal injury. More so, cisplatin caused marked increase in granulocyte, lymphocyte and platelets counts which were ameliorated by CC (100-400 mg/kg) treatment. In addition, cisplatin induced marked increase in MDA and nitrite levels coupled with deficits in glutathione, catalase and superoxide dismutase activities which were attenuated by CC administration. In vitro assay showed that CC scavenged DPPH and nitrite radicals (69.50 and 64.50 ug/mL, respectively). Total antioxidant capacity, phenolic and flavonoid contents are 24.27+/-0.09 mg QUE/g, 17.14+/-0.12 mg GAE/g and 10.20+/-0.09 mg QUE/g, respectively. CC preserved the liver and kidney histoarchitecture. Conclusions This study showed that C. colocynthis possesses hepatoprotective and nephroprotective actions possibly through enhancement of antioxidant defence system. Thus, it could be a potential adjuvant in cisplatin based chemotherapy. PMID- 29236673 TI - ZBP1: Innate Sensor Regulating Cell Death and Inflammation. AB - Z-DNA-binding protein 1 (ZBP1), initially reported as an interferon (IFN) inducible tumor-associated protein, harbors nucleic acid-binding domains for left handed helix (Z-form) and receptor-interacting protein homotypic interaction motif (RHIM) domains for protein homotypic interactions. Recent studies have identified ZBP1 as an innate sensor of viral infections and a target of viral evasion strategies, regulating cell death, inflammasome activation, and proinflammatory responses. ZBP1 also functions during development and can trigger perinatal lethality when its RHIM-dependent interactions are not restricted. Here we review the history and emergence of ZBP1 as a pathogen sensor and a central regulator of cell death and inflammatory responses. We also discuss the gaps in our knowledge regarding the regulation and functions of ZBP1 and highlight potential avenues for future research. PMID- 29236676 TI - Supervised Learning and Knowledge-Based Approaches Applied to Biomedical Word Sense Disambiguation. AB - Word sense disambiguation (WSD) is an important step in biomedical text mining, which is responsible for assigning an unequivocal concept to an ambiguous term, improving the accuracy of biomedical information extraction systems. In this work we followed supervised and knowledge-based disambiguation approaches, with the best results obtained by supervised means. In the supervised method we used bag of-words as local features, and word embeddings as global features. In the knowledge-based method we combined word embeddings, concept textual definitions extracted from the UMLS database, and concept association values calculated from the MeSH co-occurrence counts from MEDLINE articles. Also, in the knowledge-based method, we tested different word embedding averaging functions to calculate the surrounding context vectors, with the goal to give more importance to closest words of the ambiguous term. The MSH WSD dataset, the most common dataset used for evaluating biomedical concept disambiguation, was used to evaluate our methods. We obtained a top accuracy of 95.6 % by supervised means, while the best knowledge-based accuracy was 87.4 %. Our results show that word embedding models improved the disambiguation accuracy, proving to be a powerful resource in the WSD task. PMID- 29236677 TI - A Chemometrics Approach for Nuclear Magnetic Resonance Data to Characterize the Partial Metabolome Banana Peels from Southern Brazil. AB - Banana peels are well recognized as a source of important bioactive compounds, such as phenolics, carotenoids, biogenic amines, among others. As such, they have recently started to be used for industrial purposes. However, its composition seems to be strongly affected by biotic or abiotic ecological factors. Thus, this study aimed to investigate banana peels chemical composition, not only to get insights on eventual metabolic changes caused by the seasons, in southern Brazil, but also to identify the most relevant metabolites for these processes. To achieve this, a Nuclear magnetic resonance (NMR)-based metabolic profiling strategy was adopted, followed by chemometrics analysis, using the specmine package for the R environment, and metabolite identification. The results showed that the metabolomic approach adopted allowed identifying a series of primary and secondary metabolites in the aqueous extracts investigated. Besides, over the seasons the metabolic profiles of the banana peels showed to contain biologically active compounds relevant to the skin wound healing process, indicating the biotechnological potential of that raw material. PMID- 29236678 TI - Protein-Protein Interaction Article Classification Using a Convolutional Recurrent Neural Network with Pre-trained Word Embeddings. AB - Curation of protein interactions from scientific articles is an important task, since interaction networks are essential for the understanding of biological processes associated with disease or pharmacological action for example. However, the increase in the number of publications that potentially contain relevant information turns this into a very challenging and expensive task. In this work we used a convolutional recurrent neural network for identifying relevant articles for extracting information regarding protein interactions. Using the BioCreative III Article Classification Task dataset, we achieved an area under the precision-recall curve of 0.715 and a Matthew's correlation coefficient of 0.600, which represents an improvement over previous works. PMID- 29236679 TI - Assessing Public Metabolomics Metadata, Towards Improving Quality. AB - Public resources need to be appropriately annotated with metadata in order to make them discoverable, reproducible and traceable, further enabling them to be interoperable or integrated with other datasets. While data-sharing policies exist to promote the annotation process by data owners, these guidelines are still largely ignored. In this manuscript, we analyse automatic measures of metadata quality, and suggest their application as a mean to encourage data owners to increase the metadata quality of their resources and submissions, thereby contributing to higher quality data, improved data sharing, and the overall accountability of scientific publications. We analyse these metadata quality measures in the context of a real-world repository of metabolomics data (i.e. MetaboLights), including a manual validation of the measures, and an analysis of their evolution over time. Our findings suggest that the proposed measures can be used to mimic a manual assessment of metadata quality. PMID- 29236680 TI - UV-Vis and CIELAB Based Chemometric Characterization of Manihot esculenta Carotenoid Contents. AB - Vitamin A deficiency is a prevalent health problem in many areas of the world, where cassava genotypes with high pro-vitamin A content have been identified as a strategy to address this issue. In this study, we found a positive correlation between the color of the root pulp and the total carotenoid contents and, importantly, showed how CIELAB color measurements can be used as a non destructive and fast technique to quantify the amount of carotenoids in cassava root samples, as opposed to traditional methods. We trained several machine learning models using UV-visible spectrophotometry data, CIELAB data and a low level data fusion of the two. Best performance models were obtained for the total carotenoids contents calculated using the UV-visible dataset as input, with R2 values above 90 %. Using CIELAB and fusion data, values around 60 % and above 90 % were found. Importantly, these results demonstrated how data fusion can lead to a better model performance for prediction when comparing to the use of a single data source. Considering all these findings, the use of colorimetric data associated with UV-visible and HPLC data through statistical and machine learning methods is a reliable way of predicting the content of total carotenoids in cassava root samples. PMID- 29236681 TI - Electrical resistivity and wave character of free electrons in amorphous and nanoglass Sc75Fe25. AB - The residual electrical resistivity of metallic amorphous alloys, rho 0, is typically in the range 50 uOmega cm < rho 0 < 310 uOmega cm corresponding to a mean free path of conduction electrons of order a few interatomic distances. In crystalline metals with low defect levels such as Cu however, the residual electrical resistivity is about rho 0 ~ 1.54 * 10-2 uOmega cm, leading to extensive progression of free electrons through the crystalline material, of typically up to 4 * 106 nm. The relatively 'high' values for the electrical resistivity of distorted Sc75Fe25 alloys are discussed here within the framework of the wave character of electrons. The present investigation of amorphous and nanoglass Sc75Fe25 over the temperature range 1.9-320 K, focuses on clarification of the temperature dependence of the resistivity, rho(T). These alloys systems, which show a range of behaviours for temperature dependent resistivity-including temperature independent residual resistivity, as well as positive and negative polarities for the slope drho(T)/dT-are examined in detail. PMID- 29236682 TI - Is it Beneficial to Reuse the Balloon in Percutaneous Kyphoplasty for the Treatment of Non-Neoplastic Vertebral Compression Fractures? AB - BACKGROUND Percutaneous kyphoplasty (PKP) has been widely used to treat vertebral compression fractures (VCFs). Bilateral percutaneous punctures are always performed to access the fractured vertebrae. However, the procedure has expensive clinical costs, especially the cost for the device, which creates a heavy financial burden for patients. MATERIAL AND METHODS Data from 49 patients who have single-level non-neoplastic vertebral compression fracture (VCF) were collected for 12 months after treated by PKP, including 21 cases that used bilateral puncture with single balloon (S group) and 28 cases that used bilateral puncture with double balloon (D group). We assessed the clinical (visual analogue scale, VAS) and radiological (vertebral height and kyphotic angle, KA) outcomes. Cost data (gross medical cost, cost for the device and cost for drugs) were obtained from the medical bill of each patient. RESULTS Baseline patient variables were similar between the two groups except the compensation (S group = 25kg/m2) occurred in 63% of women aged between 15 and 49 years. It was associated with increasing age, high gravidity and parity, and full time employment (p<0.001). Of those with high BMI, 5.5% were diabetic, 19.3% hypertensive and 2.8% were both diabetic and hypertensive. Obesity was recorded in 10.5% of maternal deaths, with higher proportions of deaths due to hypertension in pregnancy (27.5%), circulatory/ cardiovascular disorders (13.0%), and diabetes (4.3%) compared to 21.9%, 6.9% and 2.6% respectively in non-obese women. CONCLUSIONS: This is one of a few studies from a middle-income setting to explore maternal burden of obesity during pregnancy, which contributes to improving the knowledge base, identifying the gaps in information and increasing awareness of the growing problem of maternal overweight and obesity. While survey diagnostic conditions require cautious interpretation of findings, it is clear that obesity and related medical conditions present a substantial public health problem for emerging LMICs like Jamaica. There is an urgent need for global consensus on routine measures of the burden and risk factors associated with obesity and development of culturally appropriate interventions. PMID- 29236712 TI - Automatic detection and decoding of honey bee waggle dances. AB - The waggle dance is one of the most popular examples of animal communication. Forager bees direct their nestmates to profitable resources via a complex motor display. Essentially, the dance encodes the polar coordinates to the resource in the field. Unemployed foragers follow the dancer's movements and then search for the advertised spots in the field. Throughout the last decades, biologists have employed different techniques to measure key characteristics of the waggle dance and decode the information it conveys. Early techniques involved the use of protractors and stopwatches to measure the dance orientation and duration directly from the observation hive. Recent approaches employ digital video recordings and manual measurements on screen. However, manual approaches are very time-consuming. Most studies, therefore, regard only small numbers of animals in short periods of time. We have developed a system capable of automatically detecting, decoding and mapping communication dances in real-time. In this paper, we describe our recording setup, the image processing steps performed for dance detection and decoding and an algorithm to map dances to the field. The proposed system performs with a detection accuracy of 90.07%. The decoded waggle orientation has an average error of -2.92 degrees (+/- 7.37 degrees ), well within the range of human error. To evaluate and exemplify the system's performance, a group of bees was trained to an artificial feeder, and all dances in the colony were automatically detected, decoded and mapped. The system presented here is the first of this kind made publicly available, including source code and hardware specifications. We hope this will foster quantitative analyses of the honey bee waggle dance. PMID- 29236711 TI - Magnetic resonance imaging of the hand and wrist in a randomized, double-blind, multicenter, placebo-controlled trial of infliximab for rheumatoid arthritis: Comparison of dynamic contrast enhanced assessments with semi-quantitative scoring. AB - The objective of this study was to compare the scope and the discriminative power of Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) to those of semi-quantitative MRI scoring for evaluating treatments for rheumatoid arthritis (RA) in multicenter randomized clinical trials (RCTs). Sixty-one patients with active RA participated in a double-blind, parallel group, randomized, multicenter methodology study receiving infliximab or placebo through 14 weeks. The most symptomatic wrist and metacarpophalangeal joints (MCPs) were imaged using MRI. In addition to clinical assessments with DAS28(CRP), the severity of inflammation was measured as synovial leak of gadolinium based contrast agent (GBCA) using DCE MRI (Ktrans, primary endpoint) at weeks 0, 2, 4, and 14. Two radiologists independently scored synovitis, osteitis and erosion using RA MRI Score (RAMRIS) and cartilage loss using a 9-point MRI scale (CARLOS). Infliximab showed greater decrease from baseline in DAS28(CRP), DCE-MRI Ktrans of wrist and MCP synovium, and RAMRIS synovitis and osteitis at all visits compared with placebo (p<0.001). Treatment effect sizes of infliximab therapy were similar for DAS28(CRP) (1.08; 90% CI (0.63-1.53)) and MRI inflammation endpoints: wrist Ktrans (1.00 (0.55 1.45)), RAMRIS synovitis (0.85 (0.38-1.28)) and RAMRIS osteitis (0.99 (0.52 1.43)). Damage measures of bone erosion (RAMRIS) and cartilage loss (CARLOS) were reduced with infliximab compared to with placebo at 14 weeks (p<=0.025). DCE-MRI and RAMRIS were equally sensitive and responsive to the anti-inflammatory effects of infliximab. RAMRIS and CARLOS showed suppression of erosion and cartilage loss, respectively, at 14 weeks. (ClinicalTrials.gov registration: NCT01313520). PMID- 29236713 TI - Sirt3 deficiency does not affect venous thrombosis or NETosis despite mild elevation of intracellular ROS in platelets and neutrophils in mice. AB - Inflammation is a common denominator in chronic diseases of aging. Yet, how inflammation fuels these diseases remains unknown. Neutrophils are the primary leukocytes involved in the early phase of innate immunity and inflammation. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs have been shown to induce tissue injury and thrombosis. Here, we demonstrated that Sirt3, a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, an enzyme linked to human longevity, was expressed in mouse neutrophils and platelets. Using Sirt3-/- mice as a model of accelerated aging, we investigated the effects of Sirt3 deficiency on NETosis and platelet function, aiming to detect enhancement of thrombosis. More mitochondrial reactive oxygen species (ROS) were generated in neutrophils and platelets of Sirt3-/- mice compared to WT, when stimulated with a low concentration of phorbol 12-myristate 13-acetate (PMA) and a high concentration of thrombin, respectively. There were no differences in in vitro NETosis, with or without stimulation. Platelet aggregation was mildly augmented in Sirt3-/- mice compared to WT mice, when stimulated with a low concentration of collagen. The effect of Sirt3 deficiency on platelet and neutrophil activation in vivo was examined by the venous thrombosis model of inferior vena cava stenosis. Elevation of plasma DNA concentration was observed after stenosis in both genotypes, but no difference was shown between the two genotypes. The systemic response to thrombosis was enhanced in Sirt3-/- mice with significantly elevated neutrophil count and reduced platelet count. However, no differences were observed in incidence of thrombus formation, thrombus weight and thrombin-antithrombin complex generation between WT and Sirt3-/- mice. We conclude that Sirt3 does not considerably impact NET formation, platelet function, or venous thrombosis in healthy young mice. PMID- 29236715 TI - Fungal communities in ancient peatlands developed from different periods in the Sanjiang Plain, China. AB - Peatlands in the Sanjiang Plain could be more vulnerable to global warming because they are located at the southernmost boundary of northern peatlands. Unlike bacteria, fungi are often overlooked, even though they play important roles in substance circulation in the peatland ecosystems. Accordingly, it is imperative that we deepen our understanding of fungal community structure and diversity in the peatlands. In this study, high-throughput Illumina sequencing was used to study the fungal communities in three fens in the Sanjiang Plain, located at the southern edge of northern peatlands. Peat soil was collected from the three fens which developed during different periods. A total of 463,198 fungal ITS sequences were obtained, and these sequences were classified into at least six phyla, 21 classes, more than 60 orders and over 200 genera. The fungal community structures were distinct in the three sites and were dominated by Ascomycota and Basidiomycota. However, there were no significant differences between these three fens in any alpha-diversity index (p > 0.05). Soil age and the carbon (C) accumulation rate, as well as total carbon (TC), total nitrogen (TN), C/N ratio, and bulk density were found to be closely related to the abundance of several dominant fungal taxa. We captured a rich fungal community and confirmed that the dominant taxa were those which were frequently detected in other northern peatlands. Soil age and the C accumulation rate were found to play important roles in shaping the fungal community structure. PMID- 29236714 TI - Non-invasive identification of protein biomarkers for early pregnancy diagnosis in the cheetah (Acinonyx jubatus). AB - Approximately 80% of cheetahs living in typical zoological collections never reproduce. In more than 60% of breedings, the female is confirmed to ovulate, but parturition fails to occur. It is unknown if these non-pregnant intervals of elevated progesterone (deemed luteal phases) are conception failures or a pregnancy terminating in embryonic/fetal loss. There have been recent advances in metabolic profiling and proteome analyses in many species with mass spectrometry used to identify 'biomarkers' and mechanisms indicative of specific physiological states (including pregnancy). Here, we hypothesized that protein expression in voided cheetah feces varied depending on pregnancy status. We: 1) identified the expansive protein profile present in fecal material of females; and 2) isolated proteins that may be candidates playing a role in early pregnancy establishment and diagnosis. Five hundred and seventy unique proteins were discovered among samples from pregnant (n = 8), non-pregnant, luteal phase (n = 5), and non ovulatory control (n = 5) cheetahs. Four protein candidates were isolated that were significantly up-regulated and two were down-regulated in samples from pregnant compared to non-pregnant or control counterparts. One up-regulated candidate, immunoglobulin J chain (IGJ; an important component of the secretory immune system) was detected using a commercially available antibody via immunoblotting. Findings revealed that increased IGJ abundance could be used to detect pregnancy successfully in >80% of 23 assessed females within 4 weeks after mating. The discovery of a novel fecal pregnancy marker improves the ability to determine reproductive, especially gestational, status in cheetahs managed in an ex situ insurance and source population. PMID- 29236716 TI - Design, characterization and control of thermally-responsive and magnetically actuated micro-grippers at the air-water interface. AB - The design and control of untethered microrobotic agents has drawn a lot of attention in recent years. This technology truly possesses the potential to revolutionize the field of minimally invasive surgery and microassembly. However, miniaturization and reliable actuation of micro-fabricated grippers are still challenging at sub-millimeter scale. In this study, we design, manufacture, characterize, and control four similarly-structured semi-rigid thermoresponsive micro-grippers. Furthermore, we develop a closed loop-control algorithm to demonstrate and compare the performance of the said grippers when moving in hard to-reach and unpredictable environments. Finally, we analyze the grasping characteristics of three of the presented designs. Overall, not only does the study demonstrate motion control in unstructured dynamic environments-at velocities up to 3.4, 2.9, 3.3, and 1 body-lengths/s with 980, 750, 250, and 100 MUm-sized grippers, respectively-but it also aims to provide quantitative data and considerations to help a targeted design of magnetically-controlled thin micro-grippers. PMID- 29236717 TI - Burrow characteristics of the mud shrimp Austinogebia edulis, an ecological engineer causing sediment modification of a tidal flat. AB - The mud shrimp Austinogebia edulis, being abundant in the intertidal zone of western Taiwan, constructs deep burrows (>1 m). This study highlights the potential of mud shrimps to modify sediment characteristics of the tidal flat by its burrowing behavior. We studied the structure of the burrow wall, compared the difference in the sediment composition of the burrow and the background sediment, and compared the organic content inside the burrow wall. This study was carried out from September 2015 to November 2016 in three areas of the western coast of Taiwan, namely Shengang, Hanbow, and Wangong. The present study found significant differences between burrow wall and the burrow lumen. The diameter of the burrow wall was double as wide as the inner burrow lumen at the opening and gradually increased to 10 times of the burrow lumen at 30 cm depth. The burrow wall of A. edulis showed low permeability and increased the sheer strength. Statistically, a significant difference was noticed in the comparison between the sediment composition of the burrow wall and the background (p < 0.05, Student's t-test). An accumulation of 3.63 for fine sand (t = -5.22, p < 0.001, fine sand) and 9 for clay (t = -25.01, p < 0.001, clay) was found in the upper burrow wall of A. edulis. This indicated that they somehow chose finer particles to build burrows. This will gradually change the sediment distribution-vertically and horizontally. The burrow wall consisted of a 24 times higher organic matter content than one individual of mud shrimp. The burrow may provide organic material as a potential food source. The mud shrimp thus transforms the sediment characteristics as an ecological engineer, which is expected to have a significant ecological impact on the ecosystem. PMID- 29236718 TI - Particle swarm optimization-based automatic parameter selection for deep neural networks and its applications in large-scale and high-dimensional data. AB - In this paper, we propose a new automatic hyperparameter selection approach for determining the optimal network configuration (network structure and hyperparameters) for deep neural networks using particle swarm optimization (PSO) in combination with a steepest gradient descent algorithm. In the proposed approach, network configurations were coded as a set of real-number m-dimensional vectors as the individuals of the PSO algorithm in the search procedure. During the search procedure, the PSO algorithm is employed to search for optimal network configurations via the particles moving in a finite search space, and the steepest gradient descent algorithm is used to train the DNN classifier with a few training epochs (to find a local optimal solution) during the population evaluation of PSO. After the optimization scheme, the steepest gradient descent algorithm is performed with more epochs and the final solutions (pbest and gbest) of the PSO algorithm to train a final ensemble model and individual DNN classifiers, respectively. The local search ability of the steepest gradient descent algorithm and the global search capabilities of the PSO algorithm are exploited to determine an optimal solution that is close to the global optimum. We constructed several experiments on hand-written characters and biological activity prediction datasets to show that the DNN classifiers trained by the network configurations expressed by the final solutions of the PSO algorithm, employed to construct an ensemble model and individual classifier, outperform the random approach in terms of the generalization performance. Therefore, the proposed approach can be regarded an alternative tool for automatic network structure and parameter selection for deep neural networks. PMID- 29236719 TI - Neighbourhood socioeconomic deprivation and health-related quality of life: A multilevel analysis. AB - OBJECTIVE: To assess the relationship between socioeconomic deprivation and health-related quality of life in urban neighbourhoods, using a multilevel approach. METHODS: Of the population-based cohort EPIPorto, 1154 georeferenced participants completed the 36-Item Short-Form Health Survey. Neighbourhood socioeconomic deprivation classes were estimated using latent-class analysis. Multilevel models measured clustering and contextual effects of neighbourhood deprivation on physical and mental HRQoL. RESULTS: Residents from the least deprived neighbourhoods had higher physical HRQoL. Neighbourhood socioeconomic deprivation together with individual-level variables (age, gender and education) and health-related factors (smoking, alcohol consumption, sedentariness and chronic diseases) explained 98% of the total between-neighbourhood variance. Neighbourhood socioeconomic deprivation was significantly associated with physical health when comparing least and most deprived neighbourhoods (class 2 beta coefficient: -0.60; 95% confidence interval:-1.76;-0.56; class 3 -beta coefficient: -2.28; 95% confidence interval:-3.96;-0.60), and as neighbourhood deprivation increases, a decrease in all values of physical health dimensions (physical functioning, role physical, bodily pain and general health) was also observed. Regarding the mental health dimension, no neighbourhood clustering or contextual effects were found. However, as neighbourhood deprivation increases, the values of vitality and role emotional dimensions significantly decreased. CONCLUSION: Neighbourhood socioeconomic deprivation is associated with HRQoL, affecting particularly physical health. This study suggests that to improve HRQoL, people and places should be targeted simultaneously. PMID- 29236720 TI - Topical use and systemic action of green and roasted coffee oils and ground oils in a cutaneous incision model in rats (Rattus norvegicus albinus). AB - INTRODUCTION: Wounds are a common health problem. Coffee is widely consumed and its oil contains essential fatty acids. We evaluated the local (skin) and systemic effects associated with the topical use of coffee oils in rats. METHODS: Punch skin wounds (6 mm) incisions were generated on the backs of 75 rats. Saline (SS), mineral oil (MO), green coffee oil (GCO), roasted coffee oil (RCO), green coffee ground oil (GCGO) or roasted coffee ground oil (RCGO) were topically applied to the wounds. Healing was evaluated by visual and histological/morphometric optical microscopy examination; second harmonics generation (SHG) microscopy, wound tissue q-PCR (values in fold-change) and blood serum (ELISA, values in pg/mL). RESULTS: RCO treated animals presented faster wound healing (0.986 vs. 0.422), higher mRNA expression of IGF-1 (2.78 vs. 1.00, p = 0.01), IL-6 (10.72 vs. 1.00, p = 0.001) and IL-23 (4.10 vs. 1.2, p = 0.05) in early stages of wound healing; higher IL-12 (3.32 vs. 1.00, p = 0.05) in the later stages; and lower serum levels of IFN-gamma (11.97 vs. 196.45, p = 0.01). GCO treatment led to higher mRNA expression of IL-6 (day 2: 7.94 vs. 1.00, p = 0.001 and day 4: 6.90 vs. 1.00, p = 0.01) and IL-23 (7.93 vs. 1.20, p = 0.001) in the early stages. The RCO treatment also produced higher serum IFN-alpha levels throughout the experiment (day 2: 52.53 vs. 21.20; day 4: 46.98 vs.21.56; day 10: 83.61 vs. 25.69, p = 0.05) and lower levels of IL-4 (day 4: 0.9 vs.13.36, p = 0.01), adiponectin (day 10: 8,367.47 vs. 16,526.38, p = 0.001) and IFN-gamma (day 4: 43.03 vs.196.45, p = 0.05). The SHG analysis showed a higher collagen density in the RCO and GCO treatments (p = 0.05). CONCLUSION: Topical treatment with coffee oils led to systemic actions and faster wound healing in rats. Further studies should be performed are necessary to assess the safety of topical vegetal oil use for skin lesions. PMID- 29236721 TI - Survey on open peer review: Attitudes and experience amongst editors, authors and reviewers. AB - Open peer review (OPR) is a cornerstone of the emergent Open Science agenda. Yet to date no large-scale survey of attitudes towards OPR amongst academic editors, authors, reviewers and publishers has been undertaken. This paper presents the findings of an online survey, conducted for the OpenAIRE2020 project during September and October 2016, that sought to bridge this information gap in order to aid the development of appropriate OPR approaches by providing evidence about attitudes towards and levels of experience with OPR. The results of this cross disciplinary survey, which received 3,062 full responses, show the majority (60.3%) of respondents to be believe that OPR as a general concept should be mainstream scholarly practice (although attitudes to individual traits varied, and open identities peer review was not generally favoured). Respondents were also in favour of other areas of Open Science, like Open Access (88.2%) and Open Data (80.3%). Among respondents we observed high levels of experience with OPR, with three out of four (76.2%) reporting having taken part in an OPR process as author, reviewer or editor. There were also high levels of support for most of the traits of OPR, particularly open interaction, open reports and final-version commenting. Respondents were against opening reviewer identities to authors, however, with more than half believing it would make peer review worse. Overall satisfaction with the peer review system used by scholarly journals seems to strongly vary across disciplines. Taken together, these findings are very encouraging for OPR's prospects for moving mainstream but indicate that due care must be taken to avoid a "one-size fits all" solution and to tailor such systems to differing (especially disciplinary) contexts. OPR is an evolving phenomenon and hence future studies are to be encouraged, especially to further explore differences between disciplines and monitor the evolution of attitudes. PMID- 29236722 TI - Does a decision aid improve informed choice in mammography screening? Results from a randomised controlled trial. AB - BACKGROUND: Decision aids can support informed choice in mammography screening, but for the German mammography screening programme no systematically evaluated decision aid exists to date. We developed a decision aid for women invited to this programme for the first time based on the criteria of the International Patient Decision Aids Standards Collaboration. OBJECTIVE: To determine whether a decision aid increases informed choice about mammography screening programme participation. METHODS: A representative sample of 7,400 women aged 50 was drawn from registration offices in Westphalia-Lippe, Germany. Women were randomised to receive usual care (i.e., the standard information brochure sent with the programme's invitation letter) or the decision aid. Data were collected online at baseline, post-intervention, and 3 months follow-up. The primary outcome was informed choice. Secondary outcomes were the constituents of informed choice (knowledge, attitude, intention/uptake), decisional conflict, decision regret, and decision stage. Outcomes were analysed using latent structural equation models and chi2-tests. RESULTS: 1,206 women participated (response rate of 16.3%). The decision aid increased informed choice. Women in the control group had lower odds to make an informed choice at post-intervention (OR 0.26, 95% CI 0.18-0.37) and at follow-up (OR 0.66, 95% CI 0.46-0.94); informed choices remained constant at 30%. This was also reflected in lower knowledge and more decisional conflict. Post-intervention, the uptake intention was higher in the control group, whereas the uptake rate at follow-up was similar. Women in the control group had a more positive attitude at follow-up than women receiving the decision aid. Decision regret and decision stage were not influenced by the intervention. CONCLUSION: This paper describes the first systematic evaluation of a newly developed decision aid for the German mammography screening programme in a randomised controlled trial. Our decision aid proved to be an effective tool to enhance the rate of informed choice and was made accessible to the public. TRIAL REGISTRATION: German Clinical Trials Register DRKS00005176. PMID- 29236723 TI - Reproductive performance parameters in a large population of game-ranched white rhinoceroses (Ceratotherium simum simum). AB - The population of free-roaming white rhinoceroses (Ceratotherium simum) is under serious threat. Captive breeding of this species is therefore becoming more important, but this is challenging and often not successful. Obtaining reproductive reference values is a crucial aspect of improving these breeding results. In this study performed between 2008 and 2016, reproductive performance was analysed in 1,354 animals kept in a 8000 hectares game-ranched environment. Descriptive statistics of this captive population showed an average annual herd growth (%) of 7 .0+/-0.1 (min -9 -max 15). Average calving rates were calculated as an annual calving rate of 20% and biennial calving rate of 37% adult females calving per year. Females had a median age of 83.2 months at first calving (IQR 72.9-110.7) and inter-calving intervals of 29.2 (IQR 24.6-34.8) months. Furthermore, translocations of animals did not interfere with reproductive success in terms of inter-calving periods or age at first calving. Multivariate models showed a clear seasonal calving pattern with a significant increase of the number of calvings during December-April when compared to April-December. Our results did not show any significant skewed progeny sex ratios. Weather observations showed no significant influence of rain or season on sex ratios of the calves. PMID- 29236725 TI - Roles of children and their parents in the reduction of radiation risk after the 2011 Fukushima Daiichi Nuclear Power Plant accident. AB - INTRODUCTION: On March 11, 2011, Japan experienced its largest recorded earthquake with a magnitude of 9.0. The resulting tsunami caused massive damage to the Fukushima Daiichi Nuclear Power Plant reactors, and the surrounding environment was contaminated with radioactive materials. During this period, some residents were exposed to high levels of radiation (up to 5 millisieverts [mSv]), but since then, many residents have been exposed to low levels of radiation (<1 mSv). This study was conducted to assess the effects of lifestyle and attitude factors on external radiation exposure among Fukushima residents. METHODS: This community-based, cross-sectional study was conducted in Nihonmatsu City of the Fukushima Prefecture from May to July 2014. The population survey targeted 6,884 children between the ages of 0-15 years, and a personal radiation badge and questionnaire were administered to each of the residences. Multiple linear regression analysis was used to assess the impact of lifestyle and attitude factors on external radiation dose. RESULTS: The study participants (population size [n] = 4,571) had an additional mean radiation dose of 0.65 mSv/year, which is small as compared to the mean radiation dose 6 months after the disaster (1.5 mSv/year), in 2012 (1.5 mSv/year), and in 2013 (1.0 mSv/year). External radiation doses statistically varied by socio-demographic and lifestyle factors. Participants living in wooden residences (p-value<0.001) and within 100 meters of a forest (p = 0.001) had higher radiation exposure. Conversely, participants with a cautious attitude towards radiation had lower radiation exposure (beta [b] = 0.124, p = 0.003). CONCLUSION: Having a cautious attitude towards radiation and being aware of exposure risks proved to be significant in the reduction of external radiation dose. Therefore, in the event of future radiation disasters, attitudes towards and awareness of radiation should be considered in the reduction of exposure risk and implementation of radiation protection. PMID- 29236726 TI - Demographic monitoring of wild muriqui populations: Criteria for defining priority areas and monitoring intensity. AB - Demographic data are essential to assessments of the status of endangered species. However, establishing an integrated monitoring program to obtain useful data on contemporary and future population trends requires both the identification of priority areas and populations and realistic evaluations of the kinds of data that can be obtained under different monitoring regimes. We analyzed all known populations of a critically endangered primate, the muriqui (genus: Brachyteles) using population size, genetic uniqueness, geographic importance (including potential importance in corridor programs) and implementability scores to define monitoring priorities. Our analyses revealed nine priority populations for the northern muriqui (B. hypoxanthus) and nine for the southern muriqui (B. arachnoides). In addition, we employed knowledge of muriqui developmental and life history characteristics to define the minimum monitoring intensity needed to evaluate demographic trends along a continuum ranging from simple descriptive changes in population size to predictions of population changes derived from individual based life histories. Our study, stimulated by the Brazilian government's National Action Plan for the Conservation of Muriquis, is fundamental to meeting the conservation goals for this genus, and also provides a model for defining priorities and methods for the implementation of integrated demographic monitoring programs for other endangered and critically endangered species of primates. PMID- 29236724 TI - The role of cortical oscillations in a spiking neural network model of the basal ganglia. AB - Although brain oscillations involving the basal ganglia (BG) have been the target of extensive research, the main focus lies disproportionally on oscillations generated within the BG circuit rather than other sources, such as cortical areas. We remedy this here by investigating the influence of various cortical frequency bands on the intrinsic effective connectivity of the BG, as well as the role of the latter in regulating cortical behaviour. To do this, we construct a detailed neural model of the complete BG circuit based on fine-tuned spiking neurons, with both electrical and chemical synapses as well as short-term plasticity between structures. As a measure of effective connectivity, we estimate information transfer between nuclei by means of transfer entropy. Our model successfully reproduces firing and oscillatory behaviour found in both the healthy and Parkinsonian BG. We found that, indeed, effective connectivity changes dramatically for different cortical frequency bands and phase offsets, which are able to modulate (or even block) information flow in the three major BG pathways. In particular, alpha (8-12Hz) and beta (13-30Hz) oscillations activate the direct BG pathway, and favour the modulation of the indirect and hyper-direct pathways via the subthalamic nucleus-globus pallidus loop. In contrast, gamma (30 90Hz) frequencies block the information flow from the cortex completely through activation of the indirect pathway. Finally, below alpha, all pathways decay gradually and the system gives rise to spontaneous activity generated in the globus pallidus. Our results indicate the existence of a multimodal gating mechanism at the level of the BG that can be entirely controlled by cortical oscillations, and provide evidence for the hypothesis of cortically-entrained but locally-generated subthalamic beta activity. These two findings suggest new insights into the pathophysiology of specific BG disorders. PMID- 29236727 TI - Mental health, behavioural problems and treatment seeking among students commencing university in Northern Ireland. AB - Mental health and behavioural problems are common among students commencing university. University life can be stressful and problems often exacerbate during their course of study, while others develop disorders for the first time. The WHO World Mental Health Surveys International College Student Project aims to conduct longitudinal research to examine and monitor student mental health and wellbeing. The Ulster University Student Wellbeing study, which commenced in September 2015 in Northern Ireland (NI), was conducted as part of this initiative (wave 1, n = 739), using the WMH-CIDI to examine psychopathology. Baseline prevalence rates of lifetime and 12-month mental health and substance disorders, ADHD and suicidality were high, with more than half of new undergraduate students reporting any lifetime disorder. Co-morbidity was common with 19.1% of students experiencing three or more disorders. Logistic regression models revealed that females, those over 21, non-heterosexual students, and those from a lower SES background were more likely to have a range of mental health and behavioural problems. Overall, 10% of new entry students received treatment for emotional problems in the previous year. However, 22.3% of students with problems said they would not seek help. The study provides important information for universities, policy makers and practice, on mental health and wellbeing in young people generally but particularly for students commencing university. The findings will assist in the development and implementation of protection and prevention strategies in the university setting and beyond. PMID- 29236728 TI - Catch-up growth in stunted children: Definitions and predictors. AB - This paper examines the incidence and correlates of linear growth catch up in early childhood among stunted children, using a range of definitions of catch up. Catch-up growth between two and five years of age is defined in both absolute terms (i.e. the centimetre height deficit from the healthy reference population mean is reduced) and relative terms (the height-for-age z-score improved or passed the -2SD or -1SD cut-off points). Data from a cohort study from urban South Africa are used to estimate the percentage of children who caught up and the predictors of catch-up growth according to these varying definitions. The results show that our sample of stunted children exhibits catch-up growth regardless of the definition used, however prevalence of catch up is highly sensitive to the way catch up is classified, ranging from 19%-93%. Of the biological, early growth, socioeconomic status and maternal reproductive variables included in the multivariate probit regressions, only a few were found to be consistent predictors of the incidence of catch-up growth. Mother's height was positively correlated with the incidence of catch-up growth and early stunting at one year was associated with a lower likelihood of subsequent catch up. PMID- 29236729 TI - Genome-wide analysis of Atlantic salmon (Salmo salar) mucin genes and their role as biomarkers. AB - The aim of this study was to identify potential mucin genes in the Atlantic salmon genome and evaluate tissue-specific distribution and transcriptional regulation in response to aquaculture-relevant stress conditions in post-smolts. Seven secreted gel-forming mucin genes were identified based on several layers of evidence; annotation, transcription, phylogeny and domain structure. Two genes were annotated as muc2 and five genes as muc5. The muc2 genes were predominantly transcribed in the intestinal region while the different genes in the muc5 family were mainly transcribed in either skin, gill or pyloric caeca. In order to investigate transcriptional regulation of mucins during stress conditions, two controlled experiments were conducted. In the first experiment, handling stress induced mucin transcription in the gill, while transcription decreased in the skin and intestine. In the second experiment, long term intensive rearing conditions (fish biomass ~125 kg/m3) interrupted by additional confinement led to increased transcription of mucin genes in the skin at one, seven and fourteen days post-confinement. PMID- 29236730 TI - Treatment following myocardial infarction in patients with schizophrenia. AB - BACKGROUND: A correlation between excess mortality from myocardial infarctions (MI) and schizophrenia has already been established. What remains unclear is whether the initial communication between the treating doctor and the corresponding patient contributes to this excess mortality. AIM: The aim of this study is to investigate whether a patient with schizophrenia receives the same offers for examination and treatment following a MI compared to a psychiatric healthy control (PHC). METHODS: This cohort study includes patients diagnosed with schizophrenia at the time of their first MI (n = 47) in the years between 1995-2015 matched 1:2 to psychiatric healthy MI patients on gender, age and year of first MI. All existing hospital files for the 141 patients were thoroughly reviewed and the number of offered and accepted examinations and treatments were extracted for comparisons between the two groups. RESULTS: In general patients with schizophrenia were less likely to be offered and accept examination and at the same time be offered and accept treatment as compared to PHCs (p<0.01). In addition, there was a statistical trend towards patients with schizophrenia being more likely to decline examination (p = 0.10) and decline treatment (p = 0.09) compared to PHCs, while being offered examination and being offered treatment both contributed statistically insignificantly to the overall discrepancy between the two patient groups. CONCLUSIONS: Being diagnosed with schizophrenia limits the treatment received following a first MI compared to PHCs. However, we are unable to pinpoint, whether Physician bias, patient's unwillingness to receive health care or both contribute to the excess mortality seen in these comorbid patients. PMID- 29236731 TI - The effect of exposure to farmed salmon on piscine orthoreovirus infection and fitness in wild Pacific salmon in British Columbia, Canada. AB - The disease Heart and Skeletal Muscle Inflammation (HSMI) is causing substantial economic losses to the Norwegian salmon farming industry where the causative agent, piscine orthoreovirus (PRV), is reportedly spreading from farmed to wild Atlantic salmon (Salmo salar) with as yet undetermined impacts. To assess if PRV infection is epidemiologically linked between wild and farmed salmon in the eastern Pacific, wild Pacific salmon (Oncorhynchus sp.) from regions designated as high or low exposure to salmon farms and farmed Atlantic salmon reared in British Columbia (BC) were tested for PRV. The proportion of PRV infection in wild fish was related to exposure to salmon farms (p = 0.0097). PRV was detected in: 95% of farmed Atlantic salmon, 37-45% of wild salmon from regions highly exposed to salmon farms and 5% of wild salmon from the regions furthest from salmon farms. The proportion of PRV infection was also significantly lower (p = 0.0008) where wild salmon had been challenged by an arduous return migration into high-elevation spawning habitat. Inter-annual PRV infection declined in both wild and farmed salmon from 2012-2013 (p <= 0.002). These results suggest that PRV transfer is occurring from farmed Atlantic salmon to wild Pacific salmon, that infection in farmed salmon may be influencing infection rates in wild salmon, and that this may pose a risk of reduced fitness in wild salmon impacting their survival and reproduction. PMID- 29236732 TI - Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. AB - The efficacy and accepted regimen of antibiotic treatment for Lyme disease has been a point of significant contention among physicians and patients. While experimental studies in animals have offered evidence of post-treatment persistence of Borrelia burgdorferi, variations in methodology, detection methods and limitations of the models have led to some uncertainty with respect to translation of these results to human infection. With all stages of clinical Lyme disease having previously been described in nonhuman primates, this animal model was selected in order to most closely mimic human infection and response to treatment. Rhesus macaques were inoculated with B. burgdorferi by tick bite and a portion were treated with recommended doses of doxycycline for 28 days at four months post-inoculation. Signs of infection, clinical pathology, and antibody responses to a set of five antigens were monitored throughout the ~1.2 year study. Persistence of B. burgdorferi was evaluated using xenodiagnosis, bioassays in mice, multiple methods of molecular detection, immunostaining with polyclonal and monoclonal antibodies and an in vivo culture system. Our results demonstrate host-dependent signs of infection and variation in antibody responses. In addition, we observed evidence of persistent, intact, metabolically-active B. burgdorferi after antibiotic treatment of disseminated infection and showed that persistence may not be reflected by maintenance of specific antibody production by the host. PMID- 29236733 TI - Evolutionary design optimization of traffic signals applied to Quito city. AB - This work applies evolutionary computation and machine learning methods to study the transportation system of Quito from a design optimization perspective. It couples an evolutionary algorithm with a microscopic transport simulator and uses the outcome of the optimization process to deepen our understanding of the problem and gain knowledge about the system. The work focuses on the optimization of a large number of traffic lights deployed on a wide area of the city and studies their impact on travel time, emissions and fuel consumption. An evolutionary algorithm with specialized mutation operators is proposed to search effectively in large decision spaces, evolving small populations for a short number of generations. The effects of the operators combined with a varying mutation schedule are studied, and an analysis of the parameters of the algorithm is also included. In addition, hierarchical clustering is performed on the best solutions found in several runs of the algorithm. An analysis of signal clusters and their geolocation, estimation of fuel consumption, spatial analysis of emissions, and an analysis of signal coordination provide an overall picture of the systemic effects of the optimization process. PMID- 29236734 TI - Freeze-dried Lactobacillus plantarum 299v increases iron absorption in young females-Double isotope sequential single-blind studies in menstruating women. AB - BACKGROUND: The probiotic strain Lactobacillus plantarum 299v has earlier been shown to increase iron absorption when added to foods. However, it is not known if the same probiotic strain in a freeze-dried format included in a capsule increases the iron absorption. OBJECTIVE: The aim of this study was to test the hypotheses that non-heme iron absorption from a light meal is promoted by a simultaneous intake of freeze-dried Lactobacillus plantarum 299v (Lp299v, DSM 9843). STUDY DESIGN: With a single blinded placebo controlled sequential design, iron absorption from a light breakfast meal administered with or without capsules containing 1010 cfu freeze-dried Lp299v was studied in healthy female volunteers of fertile age. The methodology used was a double isotope technique (59Fe and 55Fe). Two studies were performed using the same protocol. RESULTS: In study 1, the absorption of iron from a meal without Lp299v was found to be 17.4 +/- 13.4%, and from an identical meal with Lp299v was found to be 22.4 +/- 17.3% (mean +/- SD). This difference was statistically significant (p = 0.040, n = 14). In study 2, the absorption of iron from a meal without Lp299v was found to be 20.9 +/- 13.1%, and from an identical meal with Lp299v found to be 24.5 +/- 12.0% (mean +/ SD, n = 28), which again was statistically significant (p = 0.003). CONCLUSION: Freeze-dried Lp299v enhances the absorption of iron when administered together with a meal with a high iron bioavailability. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02131870. PMID- 29236735 TI - Hypertension in rats is associated with an increased permeability of the colon to TMA, a gut bacteria metabolite. AB - An increased blood trimethylamine N-oxide (TMAO) has emerged as a marker of cardiovascular mortality, however, the mechanisms of the increase are not clear. We evaluated if hypertension was associated with changes in the colon permeability to trimethylamine (TMA), a TMAO precursor. We did experiments on male, 24-26-week-old normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and SHR treated with enalapril, an antihypertensive drug (SHR-E). To check the colon permeability and liver TMA clearance, blood was collected from the portal vein and hepatic veins confluence, at baseline and after the intracolonic administration of TMA. Arterial blood pressure (BP) and intestinal blood flow (IBF) recordings and histological assessment of the colon were performed. SHR showed an increased gut-blood barrier permeability to TMA. Namely, at baseline SHR had a higher BP and portal blood TMA, but a lower IBF than WKY. After the intracolonic administration of TMA, SHR had a significantly higher portal blood TMA and higher TMA liver clearance than WKY. In SHR the arteriolar walls of the colon mucosa were significantly thicker than in WKY. Furthermore, SHR showed a significant decrease in the height of the mucosa. In contrast, SHR-E had lower portal blood TMA, lower BP and smaller thickness of arteriolar walls, but higher IBF than SHR, which indicates improved function of the gut-blood barrier in SHR-E. All groups had similar immunostaining of occludin and zonula occludens-1, markers of tight junctions. In conclusion, hypertensive rats show an increased permeability of the colon to TMA, which is accompanied by morphological and hemodynamic alterations in the colon. Therefore, cardiovascular diseases may be characterized by an increased permeability of the gut-blood barrier to bacterial metabolites such as TMA. PMID- 29236736 TI - Functions for fission yeast splicing factors SpSlu7 and SpPrp18 in alternative splice-site choice and stress-specific regulated splicing. AB - Budding yeast spliceosomal factors ScSlu7 and ScPrp18 interact and mediate intron 3'ss choice during second step pre-mRNA splicing. The fission yeast genome with abundant multi-intronic transcripts, degenerate splice signals and SR proteins is an apt unicellular fungal model to deduce roles for core spliceosomal factors in alternative splice-site choice, intron retention and to study the cellular implications of regulated splicing. From our custom microarray data we deduce a stringent reproducible subset of S. pombe alternative events. We examined the role of factors SpSlu7 or SpPrp18 for these splice events and investigated the relationship to growth phase and stress. Wild-type log and stationary phase cells showed ats1+ exon 3 skipped and intron 3 retained transcripts. Interestingly the non-consensus 5'ss in ats1+ intron 3 caused SpSlu7 and SpPrp18 dependent intron retention. We validated the use of an alternative 5'ss in dtd1+ intron 1 and of an upstream alternative 3'ss in DUF3074 intron 1. The dtd1+ intron 1 non canonical 5'ss yielded an alternative mRNA whose levels increased in stationary phase. Utilization of dtd1+ intron 1 sub-optimal 5' ss required functional SpPrp18 and SpSlu7 while compromise in SpSlu7 function alone hampered the selection of the DUF3074 intron 1 non canonical 3'ss. We analysed the relative abundance of these splice isoforms during mild thermal, oxidative and heavy metal stress and found stress-specific splice patterns for ats1+ and DUF3074 intron 1 some of which were SpSlu7 and SpPrp18 dependent. By studying ats1+ splice isoforms during compromised transcription elongation rates in wild-type, spslu7-2 and spprp18-5 mutant cells we found dynamic and intron context-specific effects in splice-site choice. Our work thus shows the combinatorial effects of splice site strength, core splicing factor functions and transcription elongation kinetics to dictate alternative splice patterns which in turn serve as an additional recourse of gene regulation in fission yeast. PMID- 29236738 TI - Genetic relatedness of previously Plant-Variety-Protected commercial maize inbreds. AB - The emergence of high-throughput, high-density genotyping methods combined with increasingly powerful computing systems has created opportunities to further discover and exploit the genes controlling agronomic performance in elite maize breeding populations. Understanding the genetic basis of population structure in an elite set of materials is an essential step in this genetic discovery process. This paper presents a genotype-based population analysis of all maize inbreds whose Plant Variety Protection certificates had expired as of the end of 2013 (283 inbreds) as well as 66 public founder inbreds. The results provide accurate population structure information and allow for important inferences in context of the historical development of North American elite commercial maize germplasm. Genotypic data was obtained via genotyping-by-sequencing on 349 inbreds. After filtering for missing data, 77,314 high-quality markers remained. The remaining missing data (average per individual was 6.22 percent) was fully imputed at an accuracy of 83 percent. Calculation of linkage disequilibrium revealed that the average r2 of 0.20 occurs at approximately 1.1 Kb. Results of population genetics analyses agree with previously published studies that divide North American maize germplasm into three heterotic groups: Stiff Stalk, Non-Stiff Stalk, and Iodent. Principal component analysis shows that population differentiation is indeed very complex and present at many levels, yet confirms that division into three main sub-groups is optimal for population description. Clustering based on Nei's genetic distance provides an additional empirical representation of the three main heterotic groups. Overall fixation index (FST), indicating the degree of genetic divergence between the three main heterotic groups, was 0.1361. Understanding the genetic relationships and population differentiation of elite germplasm may help breeders to maintain and potentially increase the rate of genetic gain, resulting in higher overall agronomic performance. PMID- 29236737 TI - Comparison of sequential multiplex PCR, sequetyping and whole genome sequencing for serotyping of Streptococcus pneumoniae. AB - Streptococcus pneumoniae is one of the major causes of pneumonia, meningitis and other pneumococcal infections in young children and elders. Determination of circulating S. pneumoniae serotypes is an essential service by public health laboratories for the monitoring of putative serotype replacement following the introduction of pneumococcal conjugate vaccines (PCVs) and of the efficacy of the immunization program. The Quellung method remains the gold standard for typing S. pneumoniae. Although this method is very effective, it is also costly, time consuming and not totally reliable due to its subjective nature. The objectives of this study were to test and evaluate the efficiency of 3 different molecular methods compared to the Quellung method. Sequential multiplex PCR, sequetyping and whole genome sequencing (WGS) were chosen and tested using a set of diverse S. pneumoniae. One-hundred and eighteen isolates covering 83 serotypes were subjected to multiplex PCR and sequetyping while 88 isolates covering 53 serotypes were subjected to WGS. Sequential multiplex PCR allowed the identification of a significant proportion (49%) of serotypes at the serogroup or subset level but only 27% were identified at the serotype level. Using WGS, 55% to 60% of isolates were identified at the serotype level depending on the analysis strategy used. Finally, sequetyping demonstrated the lowest performance, with 17% of misidentified serotypes. The use of Jin cpsB database instead of the GenBank database slightly improved results but did not significantly impact the efficiency of sequetyping. Although none of these molecular methods may currently replace the Quellung method, WGS remains the most promising molecular pneumococcal serotyping method. PMID- 29236739 TI - Correlations between human mobility and social interaction reveal general activity patterns. AB - A day in the life of a person involves a broad range of activities which are common across many people. Going beyond diurnal cycles, a central question is: to what extent do individuals act according to patterns shared across an entire population? Here we investigate the interplay between different activity types, namely communication, motion, and physical proximity by analyzing data collected from smartphones distributed among 638 individuals. We explore two central questions: Which underlying principles govern the formation of the activity patterns? Are the patterns specific to each individual or shared across the entire population? We find that statistics of the entire population allows us to successfully predict 71% of the activity and 85% of the inactivity involved in communication, mobility, and physical proximity. Surprisingly, individual level statistics only result in marginally better predictions, indicating that a majority of activity patterns are shared across our sample population. Finally, we predict short-term activity patterns using a generalized linear model, which suggests that a simple linear description might be sufficient to explain a wide range of actions, whether they be of social or of physical character. PMID- 29236740 TI - Evidence of behavior-based utilization by the Asian citrus psyllid of a combination of UV and green or yellow wavelengths. AB - The Asian citrus psyllid, Diaphorina citri, vectors huanglongbing (HLB), the most serious disease affecting citrus globally. D. citri and HLB have spread to the major citrus growing regions of North America causing billions of dollars of damage in Florida alone. The visual behavior of D. citri is not well characterized and more knowledge is needed to improve attractive traps for monitoring and control of the D. citri. Bioassays were conducted to evaluate attraction to light transmitted through different colored filters. The addition of ultra-violet light (< 400 nm) enhanced attraction of D. citri to transparent visual targets made of green or yellow filters. However, attraction to blue targets was unaffected by UV light. This is the first study to demonstrate a phytophagous insect responding to a hue that is a combination of long and short wavelengths. Further testing is needed to determine how D. citri uses such discriminatory powers in the field. Our results further imply that D. citri utilize color vision, as the less intense yellow and green hues were chosen over white light. In summary, this research provides an increased understanding of D. citri visual behavior and can be used for the development of a more attractive D. citri trap than those currently available. PMID- 29236741 TI - Social determinants of adult mortality from non-communicable diseases in northern Ethiopia, 2009-2015: Evidence from health and demographic surveillance site. AB - INTRODUCTION: In developing countries, mortality and disability from non communicable diseases (NCDs) is rising considerably. The effect of social determinants of NCDs-attributed mortality, from the context of developing countries, is poorly understood. This study examines the burden and socio economic determinants of adult mortality attributed to NCDs in eastern Tigray, Ethiopia. METHODS: We followed 45,982 adults implementing a community based dynamic cohort design recording mortality events from September 2009 to April 2015. A physician review based Verbal autopsy was used to identify the most probable causes of death. Multivariable Cox proportional hazards regression was performed to identify social determinants of NCD mortality. RESULTS: Across the 193,758.7 person-years, we recorded 1,091 adult deaths. Compared to communicable diseases, NCDs accounted for a slightly higher proportion of adult deaths; 33% vs 34.5% respectively. The incidence density rate (IDR) of NCD attributed mortality was 194.1 deaths (IDR = 194.1; 95% CI = 175.4, 214.7) per 100,000 person-years. One hundred fifty-seven (41.8%), 68 (18.1%) and 34 (9%) of the 376 NCD deaths were due to cardiovascular disease, cancer and renal failure, respectively. In the multivariable analysis, age per 5-year increase (HR = 1.35; 95% CI: 1.30, 1.41), and extended family and non-family household members (HR = 2.86; 95% CI: 2.05, 3.98) compared to household heads were associated with a significantly increased hazard of NCD mortality. Although the difference was not statistically significant, compared to poor adults, those who were wealthy had a 15% (HR = 0.85; 95% CI: 0.65, 1.11) lower hazard of mortality from NCDs. On the other hand, literate adults (HR = 0.35; 95% CI: 0.13, 0.9) had a significantly decreased hazard of NCD attributed mortality compared to those adults who were unable to read and write. The effect of literacy was modified by age and its effect reduced by 18% for every 5-year increase of age among literate adults. CONCLUSION: In summary, the study indicates that double mortality burden from both NCDs and communicable diseases was evident in northern rural Ethiopia. Public health intervention measures that prioritise disadvantaged NCD patients such as those who are unable to read and write, the elders, the extended family and non-family household co-residents could significantly reduce NCD mortality among the adult population. PMID- 29236742 TI - Route of infection alters virulence of neonatal septicemia Escherichia coli clinical isolates. AB - Escherichia coli is the leading cause of Gram-negative neonatal septicemia in the United States. Invasion and passage across the neonatal gut after ingestion of maternal E. coli strains produce bacteremia. In this study, we compared the virulence properties of the neonatal E. coli bacteremia clinical isolate SCB34 with the archetypal neonatal E. coli meningitis strain RS218. Whole-genome sequencing data was used to compare the protein coding sequences among these clinical isolates and 33 other representative E. coli strains. Oral inoculation of newborn animals with either strain produced septicemia, whereas intraperitoneal injection caused septicemia only in pups infected with RS218 but not in those injected with SCB34. In addition to being virulent only through the oral route, SCB34 demonstrated significantly greater invasion and transcytosis of polarized intestinal epithelial cells in vitro as compared to RS218. Protein coding sequences comparisons highlighted the presence of known virulence factors that are shared among several of these isolates, and revealed the existence of proteins exclusively encoded in SCB34, many of which remain uncharacterized. Our study demonstrates that oral acquisition is crucial for the virulence properties of the neonatal bacteremia clinical isolate SCB34. This characteristic, along with its enhanced ability to invade and transcytose intestinal epithelium are likely determined by the specific virulence factors that predominate in this strain. PMID- 29236743 TI - Risk factors associated with adverse events during endoscopic ultrasound-guided tissue sampling. AB - BACKGROUND AND AIM: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is commonly used to obtain tissue external to the gastrointestinal tract. EUS-FNA is relatively safe, but occasionally adverse events have been reported. There is scarcity of data on risk factors of adverse events. The aim of this study is to identify risk factors associated with EUS-FNA. METHODS: In this multicenter case control study, we retrospectively reviewed 4,097 cases between 2009 and 2012 at 15 hospitals in Korea. Among the patients there were 104 cases (2.5%) who had adverse events of which 12 (0.29%) were severe. We matched 520 controls (1:5 ratios) stratified by hospital to analyze the potential risk factors. RESULTS: The most common adverse events were pancreatitis (45/104, 43.3%) and infection (46/104, 44.2%). Endoscopic retrograde cholangiopancreatography (ERCP) on the same day was a risk factor of all adverse events [OR = 2.41, 95% CI (1.41, 4.12)], pancreatitis [OR = 2.31, 95% CI (1.02, 5.25)], and infection [OR = 2.75, 95% CI (1.31, 5.78)]. More than 15 to-and-fro movements during puncture increased the risk of pancreatitis [OR = 2.30, 95% CI (1.11, 4.77)] and infection [OR = 3.65, 95% CI (1.55, 8.59)]. A higher number of punctures was positively correlated with pancreatitis [OR = 1.34, 95% CI (1.08, 1.67)] but negatively correlated with infection [OR = 0.66, 95% CI (0.48, 0.89)]. CONCLUSIONS: EUS-FNA is a safe procedure in which serious adverse events are rare. We define some risk factors of adverse events during EUS-FNA, including ERCP on the same day, a higher number of punctures, and more than 15 to-and-fro movements. PMID- 29236744 TI - Multilayer perceptron architecture optimization using parallel computing techniques. AB - The objective of this research was to develop a methodology for optimizing multilayer-perceptron-type neural networks by evaluating the effects of three neural architecture parameters, namely, number of hidden layers (HL), neurons per hidden layer (NHL), and activation function type (AF), on the sum of squares error (SSE). The data for the study were obtained from quality parameters (physicochemical and microbiological) of milk samples. Architectures or combinations were organized in groups (G1, G2, and G3) generated upon interspersing one, two, and three layers. Within each group, the networks had three neurons in the input layer, six neurons in the output layer, three to twenty-seven NHL, and three AF (tan-sig, log-sig, and linear) types. The number of architectures was determined using three factorial-type experimental designs, which reached 63, 2 187, and 50 049 combinations for G1, G2 and G3, respectively. Using MATLAB 2015a, a logical sequence was designed and implemented for constructing, training, and evaluating multilayer-perceptron-type neural networks using parallel computing techniques. The results show that HL and NHL have a statistically relevant effect on SSE, and from two hidden layers, AF also has a significant effect; thus, both AF and NHL can be evaluated to determine the optimal combination per group. Moreover, in the three study groups, it is observed that there is an inverse relationship between the number of processors and the total optimization time. PMID- 29236745 TI - Facultative parthenogenesis validated by DNA analyses in the green anaconda (Eunectes murinus). AB - In reptiles, the mode of reproduction is typically sexual. However, facultative parthenogenesis occurs in some Squamata, such as Komodo dragon (Varanus komodoensis) and Burmese python (Python bivittatus). Here, we report facultative parthenogenesis in the green anaconda (Eunectes murinus). We found two fully developed female neonates and 17 undeveloped eggs in the oviduct of a female anaconda isolated from other individuals for eight years and two months at Ueno Zoo, Japan. To clarify the zygosity of the neonates, we analyzed 18 microsatellite markers of which 16 were informative. We observed only maternal alleles and no paternal alleles for all 16 markers. To examine the possibility of the long-term sperm storage, we estimated allele frequencies in a putative parental stock by genotyping five unrelated founders. If all founders, including the mother, are originated from a single Mendelian population, then the probability that the neonates were produced by sexual reproduction with an unrelated male via long-term sperm storage was infinitesimally small (2.31E-32 per clutch). We also examined samples from two additional offspring that the mother delivered eight years before her death. We consistently observed paternal alleles in these elder offspring, indicating that the mother had switched from sexual reproduction to asexual reproduction during the eight years of isolation. This is the first case of parthenogenesis in Eunectes to be validated by DNA analysis, and suggests that facultative parthenogenesis is widespread in the Boidae. PMID- 29236746 TI - Root-derived carbon and nitrogen from beech and ash trees differentially fuel soil animal food webs of deciduous forests. AB - Evidence is increasing that soil animal food webs are fueled by root-derived carbon (C) and also by root-derived nitrogen (N). Functioning as link between the above- and belowground system, trees and their species identity are important drivers structuring soil animal communities. A pulse labeling experiment using 15N and 13C was conducted by exposing beech (Fagus sylvatica) and ash (Fraxinus excelsior) seedlings to 13CO2 enriched atmosphere and tree leaves to 15N ammonium chloride solution in a plant growth chamber under controlled conditions for 72 h. C and N fluxes into the soil animal food web of beech, associated with ectomycorrhizal fungi (EMF), and ash, associated with arbuscular mycorrhizal fungi (AMF), were investigated at two sampling dates (5 and 20 days after labeling). All of the soil animal taxa studied incorporated root-derived C, while root-derived N was only incorporated into certain taxa. Tree species identity strongly affected C and N incorporation with the incorporation in the beech rhizosphere generally exceeding that in the ash rhizosphere. Incorporation differed little between 5 and 20 days after labeling indicating that both C and N are incorporated quickly into soil animals and are used for tissue formation. Our results suggest that energy and nutrient fluxes in soil food webs depend on the identity of tree species with the differences being associated with different types of mycorrhiza. Further research is needed to prove the generality of these findings and to quantify the flux of plant C and N into soil food webs of forests and other terrestrial ecosystems. PMID- 29236747 TI - A 'meta-analysis' of effects of post-hatch food and water deprivation on development, performance and welfare of chickens. AB - A 'meta-analysis' was performed to determine effects of post-hatch food and water deprivation (PHFWD) on chicken development, performance and welfare (including health). Two types of meta-analysis were performed on peer-reviewed scientific publications: a quantitative 'meta-analysis' (MA) and a qualitative analysis (QA). Previously reported effects of PHFWD were quantified in the MA, for variables related to performance, mortality and relative yolk sac weight. The QA counted the number of studies reporting (non-)significant effects when five or more records were available in the data set (i.e. relative heart, liver and pancreas weight; plasma T3, T4 and glucose concentrations; relative duodenum, jejunum and ileum weight; duodenum, jejunum and ileum length; and villus height and crypt depth in duodenum, jejunum and ileum). MA results indicated that 24 hours of PHFWD (i.e. >=12-36 hours) or more resulted in significantly lower body weights compared to early-fed chickens up to six weeks of age. Body weights and food intake were more reduced as durations of PHFWD (24, 48, 72, >=84 hours) increased. Feed conversion rate increased in chickens up to 21 and 42 days of age after >=84 hours PHFWD in comparison with chickens fed earlier. Total mortality at day 42 was higher in chickens after 48 hours PHFWD compared to early fed chickens or chickens after 24 hours PHFWD. First week mortality was higher in chickens after >=84 hours PHFWD than in early fed chickens. The MA for relative yolk sac weight was inconclusive for PHFWD. The QA for plasma T3, T4 and glucose concentrations indicated mainly short-term decreases in T3 and glucose in PHFWD chickens compared to early fed chickens, and no effects of PHFWD on T4 concentrations. Relative weights of liver, pancreas and heart were lower after PHFWD, but only in the first week of life. A retarded development of gut segments (duodenum, jejunum and ileum) was found in the first week of life, measured as shorter, lower relative weight, and lower villus height and crypt depth. It is concluded that 48 hours (>=36-60 hours) PHFWD leads to lower body weights and higher total mortality in chickens up to six weeks of age, the latter suggesting compromised chicken welfare, but effects of PHFWD on organ development and physiological status appear to be mainly short-term. PMID- 29236748 TI - The diagnostic use of choroidal thickness analysis and its correlation with visual field indices in glaucoma using spectral domain optical coherence tomography. AB - PURPOSE: To evaluate the quantitative characteristics of choroidal thickness in primary open-angle glaucoma (POAG), normal tension glaucoma (NTG) and in normal eyes using spectral-domain optical coherence tomography (SD-OCT). To evaluate the diagnostic ability of choroidal thickness in glaucoma and to determine the correlation between choroidal thickness and visual field parameters in glaucoma. METHODS: A total of 116 subjects including 40 POAG, 30 NTG and 46 healthy subjects were enrolled in this study. Choroidal thickness measurements were acquired in the macular and peripapillary regions using SD-OCT. All subjects underwent white-on-white (W/W) and blue-on-yellow (B/Y) visual field tests using Humphrey Field Analyzer. The receiver operating characteristic (ROC) curve and the area under curve (AUC) were generated to assess the discriminating power of choroidal thickness for glaucoma. Pearson's correlation coefficients were calculated to assess the structure function correlation for glaucoma patients. RESULTS: No significant differences were observed for macular choroidal thickness among the different groups (all P > 0.05). Regarding the peripapillary choroidal thickness (PPCT), significant differences were observed among the three groups (all P < 0.05). Post hoc tests for multiple comparisons revealed a significant difference in the NTG-normal comparison group (all P < 0.01). The inferior and temporal PPCT in POAG patients were significantly thinner than those in normal subjects (P = 0.007, P = 0.002, respectively). Different parameters of PPCT showed significantly low diagnostic values to detect POAG from normal subjects (AUC: 0.555 to 0.652) and to discriminate NTG from POAG (AUC: 0.462 to 0.702), but moderate diagnostic power to detect NTG from normal subjects (AUC: 0.708 to 0.771). Regarding the diagnosis of early glaucoma, different parameters of PPCT showed relatively low diagnostic power (AUC: 0.606 to 0.698). In all the glaucoma subjects, PPCT was not significantly correlated with W/W mean deviation (MD) (all P > 0.05), but showed significant correlations with B/Y MD (all P < 0.05). In the early glaucomatous eyes, PPCT showed significant correlations with W/W MD and B/Y MD (all P < 0.05). CONCLUSIONS: In our study, peripapillary choroidal thickness measured on OCT showed a low to moderate but statistically significant diagnostic power and a significant correlation with blue-on-yellow visual field indices in glaucoma. This may indicate a potential adjunct for peripapillary choroidal thickness in glaucoma diagnosis. PMID- 29236750 TI - Identification of GAD65 AA 114-122 reactive 'memory-like' NK cells in newly diagnosed Type 1 diabetic patients by HLA-class I pentamers. AB - Type 1 diabetes is an autoimmune disease, in which pancreatic beta cells are destroyed by autoreactive T cells in genetically predisposed individuals. Serum beta cell autoantibody specificities have represented the mainstay for classifying diabetes as autoimmune-mediated and for stratifying risk in first degree relatives. In recent years, approaches were attempted to solve the difficult issue of detecting rare antigen-specific autoreactive T cells and their significance to etiopathogenesis such as the use of the MHC multimer technology. This tool allowed the specific detection of increased percentages of GAD65 autoreactive T cells by means of HLA A*02:01 GAD65 AA 114-122 pentamers in newly diagnosed diabetics. Here we provide evidence that GAD65 AA 114-122 pentamers can depict a GAD65 AA114-122 peptide expandable population of functionally and phenotypically skewed, preliminary characterized CD3-CD8dullCD56+ 'memory-like' NK cells in PBMC of newly diagnosed diabetics. Our data suggest that the NK cell subset could bind the HLA class I GAD65 AA 114-122 pentamer through ILT2 inhibitory receptor. CD107a expression revealed increased degranulation of CD3 CD8dullCD56+ NK cells in GAD65 AA 114-122 and FLU peptide expanded peripheral blood mononuclear cells of diabetics following GAD65 AA 114-122 peptide HLA A*02:01 presentation in respect to the unpulsed condition. CD107a expression was enriched in ILT2 positive NK cells. As opposite to basal conditions where similar percentages of CD3-CD56+ILT2+ cells were detected in diabetics and controls, CD3 CD56+CD107a+ and CD3-CD56+ILT2+CD107a+ cells were significantly increased in T1D PBMC either GAD65 AA 114-122 or FLU peptides stimulated after co-culture with GAD65 AA 114-122 pulsed APCs. As control, healthy donor NK cells showed similar degranulation against both GAD65 AA 114-122 pulsed and unpulsed APCs. The pathogenetic significance of the CD3-CD8dullCD56+ 'memory-like NK cell subset' with increased response upon secondary challenge in diabetics remains to be elucidated. PMID- 29236749 TI - Transcriptomic analysis of chicken Myozenin 3 regulation reveals its potential role in cell proliferation. AB - Embryonic muscle development and fibre type differentiation has always been a topic of great importance due to its impact on both human health and farm animal financial values. Myozenin3 (Myoz3) is an important candidate gene that may regulate these processes. In the current study, we knocked down and overexpressed Myoz3 in chicken embryonic fibroblasts (CEFs) and chicken myoblasts, then utilized RNA-seq technology to screen genes, pathways and biological processes associated with Myoz3. Multiple differentially expressed genes were identified, including MYH10, MYLK2, NFAM1, MYL4, MYL9, PDZLIM1; those can in turn regulate each other and influence the development of muscle fibres. Gene ontology (GO) terms including some involved in positive regulation of cell proliferation were enriched. We further validated our results by testing the activity of cells by cell counting kit-8(CCK-8) and confirmed that under the condition of Myoz3 overexpression, the proliferation rate of CEFs and myoblasts was significantly upregulated, in addition, expression level of fast muscle specific gene was also significantly upregulated in myoblasts. Pathway enrichment analysis revealed that the PPAR (Peroxisome Proliferator-Activated Receptor) pathway was enriched, suggesting the possibility that Myoz3 regulates muscle fibre development and differentiation through the PPAR pathway. Our results provide valuable evidence regarding the regulatory functions of Myoz3 in embryonic cells by screening multiple candidate genes, biological processes and pathways associated with Myoz3. PMID- 29236751 TI - Lysophosphatidic acid receptor mRNA levels in heart and white adipose tissue are associated with obesity in mice and humans. AB - BACKGROUND: Lysophosphatidic acid (LPA) receptor signaling has been implicated in cardiovascular and obesity-related metabolic disease. However, the distribution and regulation of LPA receptors in the myocardium and adipose tissue remain unclear. OBJECTIVES: This study aimed to characterize the mRNA expression of LPA receptors (LPA1-6) in the murine and human myocardium and adipose tissue, and its regulation in response to obesity. METHODS: LPA receptor mRNA levels were determined by qPCR in i) heart ventricles, isolated cardiomyocytes, and perigonadal adipose tissue from chow or high fat-high sucrose (HFHS)-fed male C57BL/6 mice, ii) 3T3-L1 adipocytes and HL-1 cardiomyocytes under conditions mimicking gluco/lipotoxicity, and iii) human atrial and subcutaneous adipose tissue from non-obese, pre-obese, and obese cardiac surgery patients. RESULTS: LPA1-6 were expressed in myocardium and white adipose tissue from mice and humans, except for LPA3, which was undetectable in murine adipocytes and human adipose tissue. Obesity was associated with increased LPA4, LPA5 and/or LPA6 levels in mice ventricles and cardiomyocytes, HL-1 cells exposed to high palmitate, and human atrial tissue. LPA4 and LPA5 mRNA levels in human atrial tissue correlated with measures of obesity. LPA5 mRNA levels were increased in HFHS-fed mice and insulin resistant adipocytes, yet were reduced in adipose tissue from obese patients. LPA4, LPA5, and LPA6 mRNA levels in human adipose tissue were negatively associated with measures of obesity and cardiac surgery outcomes. This study suggests that obesity leads to marked changes in LPA receptor expression in the murine and human heart and white adipose tissue that may alter LPA receptor signaling during obesity. PMID- 29236752 TI - The combined fatigue effects of sequential exposure to seated whole body vibration and physical, mental, or concurrent work demands. AB - Many occupations in agriculture, construction, transportation, and forestry are non-routine, involving non-cyclical tasks, both discretionary and non discretionary work breaks, and a mix of work activities. Workers in these industries are exposed to seated whole body vibration (WBV) and tasks consisting of physical, mental, or a combination of demands. Risk assessment tools for non routinized jobs have emerged but there remains a need to understand the combined effects of different work demands to improve risk assessment methods and ultimately inform ergonomists and workers on optimum work arrangement and scheduling strategies. The objective of this study was to investigate fatigue related human responses of WBV sequentially combined with physical, mental, or concurrent physical and mental demands. Sixteen healthy participants performed four conditions on four separate days: (1) physically demanding work, (2) mentally demanding work, (3) concurrent work, and (4) control quiet sitting. For each condition, participants performed two 15-minute bouts of the experimental task, separated by 30-minutes of simulated WBV based on realistic all-terrain vehicle (ATV) riding data. A test battery of fatigue measures consisting of biomechanical, physiological, cognitive, and sensorimotor measurements were collected at four interval periods: pre-session, after the first bout of the experimental task and before WBV, after WBV and before the second bout of the experimental task, and post-session. Nine measures demonstrated statistically significant time effects during the control condition; 11, 7, and 12 measures were significant in the physical, mental, and concurrent conditions, respectively. Overall, the effects of seated WBV in combination with different tasks are not additive but possibly synergistic or antagonistic. There appears to be a beneficial effect of seated ATV operation as a means of increasing task variation; but since excessive WBV may independently pose a health risk in the longer-term, these beneficial results may not be sensible as a long-term solution. PMID- 29236754 TI - Methodological comparison of alpine meadow evapotranspiration on the Tibetan Plateau, China. AB - Estimation of evapotranspiration (ET) for alpine meadow areas in the Tibetan Plateau (TP) is essential for water resource management. However, observation data has been limited due to the extreme climates and complex terrain of this region. To address these issues, four representative methods, Penman-Monteith (PM), Priestley-Taylor (PT), Hargreaves-Samani (HS), and Mahringer (MG) methods, were adopted to estimate ET, which were then compared with ET measured using Eddy Covariance (EC) for five alpine meadow sites during the growing seasons from 2010 to 2014. And each site was measured for one growing season during this period. The results demonstrate that the PT method outperformed at all sites with a coefficient of determination (R2) ranging from 0.76 to 0.94 and root mean square error (RMSE) ranging from 0.41 to 0.62 mm d-1. The PM method showed better performance than HS and MG methods, and the HS method produced relatively acceptable results with higher R2 (0.46) and lower RMSE (0.89 mm d-1) compared to MG method with R2 of 0.16 and RMSE of 1.62 mm d-1, while MG underestimated ET at all alpine meadow sites. Therefore, the PT method, being the simpler approach and less data dependent, is recommended to estimate ET for alpine meadow areas in the Tibetan Plateau. The PM method produced reliable results when available data were sufficient, and the HS method proved to be a complementary method when variables were insufficient. On the contrary, the MG method always underestimated ET and is, thus, not suitable for alpine meadows. These results provide a basis for estimating ET on the Tibetan Plateau for annual data collection, analysis, and future studies. PMID- 29236753 TI - Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine. AB - BACKGROUND: Ranitidine (Zantac(r)) is a H2-receptor antagonist commonly used for the treatment of acid-related gastrointestinal diseases. Ranitidine was reported to be a substrate of the organic cation transporters OCT1 and OCT2. The hepatic transporter OCT1 is highly genetically variable. Twelve major alleles confer partial or complete loss of OCT1 activity. The effects of these polymorphisms are highly substrate-specific and therefore difficult to predict. The renal transporter OCT2 has a common polymorphism, Ala270Ser, which was reported to affect OCT2 activity. AIM: In this study we analyzed the effects of genetic polymorphisms in OCT1 and OCT2 on the uptake of ranitidine and on its potency to inhibit uptake of other drugs. METHODS AND RESULTS: We characterized ranitidine uptake using HEK293 and CHO cells stably transfected to overexpress wild type OCT1, OCT2, or their naturally occurring allelic variants. Ranitidine was transported by wild-type OCT1 with a Km of 62.9 MUM and a vmax of 1125 pmol/min/mg protein. Alleles OCT1*5, *6, *12, and *13 completely lacked ranitidine uptake. Alleles OCT1*2, *3, *4, and *10 had vmax values decreased by more than 50%. In contrast, OCT1*8 showed an increase of vmax by 25%. The effects of OCT1 alleles on ranitidine uptake strongly correlated with the effects on morphine uptake suggesting common interaction mechanisms of both drugs with OCT1. Ranitidine inhibited the OCT1-mediated uptake of metformin and morphine at clinically relevant concentrations. The inhibitory potency for morphine uptake was affected by the OCT1*2 allele. OCT2 showed only a limited uptake of ranitidine that was not significantly affected by the Ala270Ser polymorphism. CONCLUSIONS: We confirmed ranitidine as an OCT1 substrate and demonstrated that common genetic polymorphisms in OCT1 strongly affect ranitidine uptake and modulate ranitidine's potential to cause drug-drug interactions. The effects of the frequent OCT1 polymorphisms on ranitidine pharmacokinetics in humans remain to be analyzed. PMID- 29236755 TI - Genomic features of "Candidatus Venteria ishoeyi", a new sulfur-oxidizing macrobacterium from the Humboldt Sulfuretum off Chile. AB - The Humboldt Sulfuretum (HS), in the productive Humboldt Eastern Boundary Current Upwelling Ecosystem, extends under the hypoxic waters of the Peru-Chile Undercurrent (ca. 6 degrees S and ca. 36 degrees S). Studies show that primeval sulfuretums held diverse prokaryotic life, and, while rare today, still sustain species-rich giant sulfur-oxidizing bacterial communities. We here present the genomic features of a new bacteria of the HS, "Candidatus Venteria ishoeyi" ("Ca. V. ishoeyi") in the family Thiotrichaceae.Three identical filaments were micro manipulated from reduced sediments collected off central Chile; their DNA was extracted, amplified, and sequenced by a Roche 454 GS FLX platform. Using three sequenced libraries and through de novo genome assembly, a draft genome of 5.7 Mbp, 495 scaffolds, and a N50 of 70 kbp, was obtained. The 16S rRNA gene phylogenetic analysis showed that "Ca. V. ishoeyi" is related to non-vacuolate forms presently known as Beggiatoa or Beggiatoa-like forms. The complete set of genes involved in respiratory nitrate-reduction to dinitrogen was identified in "Ca. V. ishoeyi"; including genes likely leading to ammonification. As expected, the sulfur-oxidation pathway reported for other sulfur-oxidizing bacteria were deduced and also, key inorganic and organic carbon acquisition related genes were identified. Unexpectedly, the genome of "Ca. V. ishoeyi" contained numerous CRISPR repeats and an I-F CRISPR-Cas type system gene coding array. Findings further show that, as a member of an eons-old marine ecosystem, "Ca. V. ishoeyi" contains the needed metabolic plasticity for life in an increasingly oxygenated and variable ocean. PMID- 29236756 TI - Stability evaluation of reference genes for gene expression analysis by RT-qPCR in soybean under different conditions. AB - Real-time quantitative reverse transcription PCR is a sensitive and widely used technique to quantify gene expression. To achieve a reliable result, appropriate reference genes are highly required for normalization of transcripts in different samples. In this study, 9 previously published reference genes (60S, Fbox, ELF1A, ELF1B, ACT11, TUA5, UBC4, G6PD, CYP2) of soybean [Glycine max (L.) Merr.] were selected. The expression stability of the 9 genes was evaluated under conditions of biotic stress caused by infection with soybean mosaic virus, nitrogen stress, across different cultivars and developmental stages. DeltaCt and geNorm algorithms were used to evaluate and rank the expression stability of the 9 reference genes. Results obtained from two algorithms showed high consistency. Moreover, results of pairwise variation showed that two reference genes were sufficient to normalize the expression levels of target genes under each experimental setting. For virus infection, ELF1A and ELF1B were the most stable reference genes for accurate normalization. For different developmental stages, Fbox and G6PD had the highest expression stability between two soybean cultivars (Tanlong No. 1 and Tanlong No. 2). ELF1B and ACT11 were identified as the most stably expressed reference genes both under nitrogen stress and among different cultivars. The results showed that none of the candidate reference genes were uniformly expressed at different conditions, and selecting appropriate reference genes was pivotal for gene expression studies with particular condition and tissue. The most stable combination of genes identified in this study will help to achieve more accurate and reliable results in a wide variety of samples in soybean. PMID- 29236758 TI - Distinctive Collembola communities in the Mesovoid Shallow Substratum: First data for the Sierra de Guadarrama National Park (Central Spain) and a description of two new species of Orchesella (Entomobryidae). AB - Two new species of the genus Orchesella Templeton, 1836 have been identified following intensive sampling in the Colluvial Milieu Souterrain Superficiel (Mesovoid Shallow Substratum, or MSS) of the Sierra de Guadarrama using Subterranean Sampling Devices (SSD). The data were obtained from the first extraction of the traps between May and October of 2015. During a study of the Collembola taxon, 32 different genera (61 species) were identified. The highest representative genus presence in almost all traps was Orchesella, with two new species. One of the two species described had been misidentified until this study was carried out, indicating that their preferential habitat had not been sampled; the second species had never been identified. The community of the Orchesella species in the Colluvial MSS was investigated, leading to the conclusion that this environment has its own assemblage of characteristic species. The opportunity to study specimens that belong to five species of the genus Orchesella, including three previously recollected, has allowed for obtaining reliable information regarding their macrochaetotaxy. A part of this chaetotaxy is proposed as a useful diagnostic tool for the species of the genus. In conclusion, it can be affirmed that this study has demonstrated that the Colluvial Mesovoid Shallow Substratum (Colluvial MSS) has its own fauna, and it supports the hypothesis that it constitutes a new biotope, at least for Collembola. PMID- 29236757 TI - High genetic structure and low mitochondrial diversity in bottlenose dolphins of the Archipelago of Bocas del Toro, Panama: A population at risk? AB - The current conservation status of the bottlenose dolphin (Tursiops truncatus) under the IUCN is 'least concern'. However, in the Caribbean, small and localized populations of the 'inshore form' may be at higher risk of extinction than the 'worldwide distributed form' due to a combination of factors including small population size, high site fidelity, genetic isolation, and range overlap with human activities. Here, we study the population genetic structure of bottlenose dolphins from the Archipelago of Bocas del Toro in Panama. This is a small population characterized by high site fidelity and is currently heavily-impacted by the local dolphin-watching industry. We collected skin tissue samples from 25 dolphins to study the genetic diversity and structure of this population. We amplified a portion of the mitochondrial Control Region (mtDNA-CR) and nine microsatellite loci. The mtDNA-CR analyses revealed that dolphins in Bocas del Toro belong to the 'inshore form', grouped with the Bahamas-Colombia-Cuba-Mexico population unit. They also possess a unique haplotype new for the Caribbean. The microsatellite data indicated that the Bocas del Toro dolphin population is highly structured, likely due to restricted movement patterns. Previous abundance estimates obtained with mark-recapture methods reported a small population of 80 dolphins (95% CI = 72-87), which is similar to the contemporary effective population size estimated in this study (Ne = 73 individuals; CI = 18.0 - infinity; 0.05). The combination of small population size, high degree of genetic isolation, and intense daily interactions with dolphin-watching boats puts the Bocas del Toro dolphin to at high risk of extinction. Despite national guidelines to regulate the dolphin-watching industry in Bocas del Toro and ongoing educational programs for tour operators, only in 2012 seven animals have died due to boat collisions. Our results suggest that the conservation status of bottlenose dolphins in Bocas del Toro should be elevated to 'endangered' at the national level, as a precautionary measure while population and viability estimates are conducted. PMID- 29236759 TI - Collaborative representation-based classification of microarray gene expression data. AB - Microarray technology is important to simultaneously express multiple genes over a number of time points. Multiple classifier models, such as sparse representation (SR)-based method, have been developed to classify microarray gene expression data. These methods allocate the gene data points to different clusters. In this paper, we propose a novel collaborative representation (CR) based classification with regularized least square to classify gene data. First, the CR codes a testing sample as a sparse linear combination of all training samples and then classifies the testing sample by evaluating which class leads to the minimum representation error. This CR-based classification approach is remarkably less complex than traditional classification methods but leads to very competitive classification results. In addition, compressive sensing approach is adopted to project the high-dimensional gene expression dataset to a lower dimensional space which nearly contains the whole information. This compression without loss is beneficial to reduce the computational load. Experiments to detect subtypes of diseases, such as leukemia and autism spectrum disorders, are performed by analyzing the gene expression. The results show that the proposed CR based algorithm exhibits significantly higher stability and accuracy than the traditional classifiers, such as support vector machine algorithm. PMID- 29236760 TI - Distribution of circulating T follicular helper cell subsets is altered in immunoglobulin A vasculitis in children. AB - BACKGROUND: Immunoglobulin A vasculitis (IgAV) is the most common vasculitis in children. Previously, we demonstrated that patients with IgAV show abnormal proliferation of cluster of differentiation (CD)4+C-X-C chemokine receptor type (CXCR)5+ follicular helper T (Tfh) cells. Here, we explored the status of Tfh cell subsets and plasma cytokine levels in patients with IgAV. METHODS: CD4+CXCR5+CD45RA-, CD45RA-CXCR3+CCR6-, CD45RA-CXCR3-CCR6-, CD45RA-CXCR3-CCR6+, and CD45RA-CXCR3+CCR6+ Tfh cell fractions and plasma concentrations of interferon gamma, interleukin (IL)-4, and IL-17A were evaluated by flow cytometry and a flow cytometric bead array, respectively, in 30 patients with IgAV and 15 healthy controls (HCs). RESULTS: Tfh2 and Tfh17 cell fractions were larger and the Tfh2+Tfh17/Tfh1 ratio and plasmaIL-4 and -17A levels were higher in patients with IgAV than in the HCs. Only Tfh1 cell counts were reduced in the abdominal subtype. The elevations in Tfh2 and Tfh17 cell counts and plasma IL-4 levels were abrogated by treatment. Tfh2 cell number was positively correlated with serum IgA and plasma IL-4 levels, but negatively correlated with the serum C4 concentration, while Tfh17 cell number was positively correlated with the serum IgA level and Tfh2 cell counts. CONCLUSIONS: Abnormally high numbers of Tfh2 and Tfh17 cells are linked to the occurrence and development of IgAV, but are not specific to the abdominal type. Only Tfh1 cells play a critical role in abdominal type IgAV. PMID- 29236761 TI - Knowledge about human papillomavirus and prevention of cervical cancer among women of Arkhangelsk, Northwest Russia. AB - BACKGROUND: Knowledge about cervical cancer (CC) risk factors and benefits of CC prevention motivates women to participate in its screening. However, several studies show that there is a significant knowledge deficit worldwide about human papillomavirus (HPV). The current study explores the level of knowledge about HPV and CC prevention in the context of sociodemographic and behavioral characteristics of women who visited an antenatal clinic in Arkhangelsk, Russia. METHODS: This cross-sectional study was conducted in the city of Arkhangelsk, which seats the administrative center of Arkhangelsk County, Northwest Russia. It included women who consulted a gynecologist for any reason between January 1, 2015 and April 30, 2015, were residents of Arkhangelsk, 25 to 65 years of age and sexually active (N = 300). Student's t-test for continuous variables and Pearson's chi2 test for categorical variables were used in the comparisons of women grouped as having either poor or sufficient knowledge. Linear regression analysis was also employed. RESULTS: The level of knowledge about HPV and CC prevention was associated with education, parity, age of initiating of intercourse, and sources of information. After adjustment, women with university education were more likely to have higher knowledge about HPV and CC prevention compared to those with lower education. CONCLUSIONS: We observed that most participants had a sufficient level of knowledge. Educational gaps were identified that potentially could be used to tailor interventions in CC prevention. PMID- 29236762 TI - Quantifying male and female pheromone-based mate choice in Caenorhabditis nematodes using a novel microfluidic technique. AB - Pheromone cues are an important component of intersexual communication, particularly in regards to mate choice. Caenorhabditis nematodes predominant rely on pheromone production for mate finding and mate choice. Here we describe a new microfluidic paradigm for studying mate choice in nematodes. Specifically, the Pheromone Arena allows for a constant flow of odorants, including pheromones and other small molecules, to be passed in real time from signaling worms to those making a choice without any physical contact. We validated this microfluidic paradigm by corroborating previous studies in showing that virgin C. remanei and C. elegans males have a strong preference for virgin females over mated ones. Moreover, our results suggest that the strength of attraction is an additive effect of male receptivity and female signal production. We also explicitly examine female choice and find that females are more attracted to virgin males. However, a female's mate choice is strongly dependent on her mating status. PMID- 29236763 TI - Identification of potential antimicrobials against Salmonella typhimurium and Listeria monocytogenes using Quantitative Structure-Activity Relation modeling. AB - The shelf-life of fresh carcasses and produce depends on the chemical and physical properties of antimicrobials currently used for treatment. For many years the gold standard of these antimicrobials has been Cetylpyridinium Chloride (CPC) a quaternary ammonium compound (QAC). CPC is very effective at removing bacterial pathogens from the surface of chicken but has not been approved for other products due to a toxic residue left behind after treatment. Currently there is also a rising trend in QAC resistant bacteria. In order to find new compounds that can combat both antimicrobial resistance and the toxic residue we have developed two Quantitative Structure-Activity Relationship (QSAR) models for Salmonella typhimurium and Listeria monocytogenes. These models have been shown to be accurate and reliable through multiple internal and external validation techniques. In processing these models we have also identified important descriptors and structures that may be key in producing a viable compound. With these models, development and testing of new compounds should be greatly simplified. PMID- 29236764 TI - Dexamethasone inhibits activation of monocytes/macrophages in a milieu rich in 27 oxygenated cholesterol. AB - Molecular mechanisms underlying the decreased number of macrophages and T cells in the arteries of cholesterol-fed-rabbits following dexamethasone administration are unknown. We investigated the possibility that dexamethasone could affect activation of monocytic cells induced by oxygenated derivatives of cholesterol (oxysterols) using THP-1 monocyte/macrophage cells. 27-Hydroxycholesterol (27OHChol), an oxysterol elevated with hypercholesterolemia, enhanced production of CCL2, known as MCP1, chemokine from monocytes/macrophages and migration of the monocytic cells, but the CCL2 production and the cell migration were reduced by treatment with dexamethasone. Dexamethasone inhibited superproduction of CCL2 induced by 27OHChol plus LPS and attenuated transcription of matrix metalloproteinase 9 as well as secretion of its active gene product induced by 27OHChol. The drug downregulated cellular and surface levels of CD14 and blocked release of soluble CD14 without altering transcription of the gene. Dexamethasone also inhibited expression and phosphorylation of the NF-kappaB p65 subunit enhanced by 27OHChol. Collectively, these results indicate that dexamethasone inhibits activation of monocytes/macrophages in response to 27OHChol, thereby leading to decreased migration of inflammatory cells in milieu rich in oxygenated derivatives of cholesterol. PMID- 29236766 TI - Influences of micro-geomorphology on the stoichiometry of C, N and P in Chenier Island soils and plants in the Yellow River Delta, China. AB - Studies have indicated that consistent or well-constrained (relatively low variability) carbon:nitrogen:phosphorus (C:N:P) ratios exist in large-scale ecosystems, including both marine and terrestrial ecosystems. Little is known about the C, N and P stoichiometric ratios that exist in the soils and plants of Chenier Island in the Yellow River Delta (YRD). We examined the distribution patterns and relationships of C, N and P stoichiometry in the soils and plants of Chenier Island, as well as the potential influences of the island's micro geomorphology. Based on a study of four soil profile categories and Phragmites australis and Suaeda heteroptera plant tissues, our results showed that micro geomorphology could leave a distinct imprint on the soil and plant elemental stoichiometry of Chenier Island; significant variation in the atomic C:N:P ratios (RCNP) existed in soils and plants, indicating that the RCNP values in both the soil and plants are not well constrained at the Chenier Island scale. RCN and RCP in Chenier Island soils were high, whereas the RNP values were comparatively low, indicating that the ecosystems of Chenier Island are nutrient-limited by N and P. However, the RNP values in P. australis and S. heteroptera plant tissues were high, suggesting that the plants of Chenier Island are nutrient-limited by P. Finally, we suggest that soil and plant N:P ratios may be good indicators of the soil and plant nutrient status during soil development and plant growth, which could be a useful reference for restoring the degraded soils of Chenier Island. PMID- 29236765 TI - Chondrocytes and stem cells in 3D-bioprinted structures create human cartilage in vivo. AB - Cartilage repair and replacement is a major challenge in plastic reconstructive surgery. The development of a process capable of creating a patient-specific cartilage framework would be a major breakthrough. Here, we described methods for creating human cartilage in vivo and quantitatively assessing the proliferative capacity and cartilage-formation ability in mono- and co-cultures of human chondrocytes and human mesenchymal stem cells in a three-dimensional (3D) bioprinted hydrogel scaffold. The 3D-bioprinted constructs (5 * 5 * 1.2 mm) were produced using nanofibrillated cellulose and alginate in combination with human chondrocytes and human mesenchymal stem cells using a 3D-extrusion bioprinter. Immediately following bioprinting, the constructs were implanted subcutaneously on the back of 48 nude mice and explanted after 30 and 60 days, respectively, for morphological and immunohistochemical examination. During explantation, the constructs were easy to handle, and the majority had retained their macroscopic grid appearance. Constructs consisting of human nasal chondrocytes showed good proliferation ability, with 17.2% of the surface areas covered with proliferating chondrocytes after 60 days. In constructs comprising a mixture of chondrocytes and stem cells, an additional proliferative effect was observed involving chondrocyte production of glycosaminoglycans and type 2 collagen. This clinically highly relevant study revealed 3D bioprinting as a promising technology for the creation of human cartilage. PMID- 29236767 TI - Comparing the temporal dynamics of thematic and taxonomic processing using event related potentials. AB - We report the results of a study comparing the temporal dynamics of thematic and taxonomic knowledge activation in a picture-word priming paradigm using event related potentials. Although we found no behavioral differences between thematic and taxonomic processing, ERP data revealed distinct patterns of N400 and P600 amplitude modulation for thematic and taxonomic priming. Thematically related target stimuli elicited less negativity than taxonomic targets between 280-460 ms after stimulus onset, suggesting easier semantic processing of thematic than taxonomic relationships. Moreover, P600 mean amplitude was significantly increased for taxonomic targets between 520-600 ms, consistent with a greater need for stimulus reevaluation in that condition. These results offer novel evidence in favor of a dissociation between thematic and taxonomic thinking in the early phases of conceptual evaluation. PMID- 29236768 TI - Autophagy induction by Mycobacterium indicus pranii promotes Mycobacterium tuberculosis clearance from RAW 264.7 macrophages. AB - Mycobacterium indicus pranii (MIP) is a potent vaccine candidate against tuberculosis (TB) as it has demonstrated significant protection in animal models of tuberculosis as well as in clinical trials. Higher protective efficacy of MIP against TB as compared to BCG provoked the efforts to gain insight into the molecular mechanisms underlying MIP mediated protection against Mycobacterium tuberculosis (M.tb). Autophagy, initially described as a cell survival mechanism during starvation, also plays a key role in host resistance to M.tb. Virulent mycobacteria like M.tb, suppresses host autophagy response to increase its survival in macrophages. Since mycobacterial species have been shown to vary widely in their autophagy-inducing properties, in the present study, we examined the autophagy inducing efficacy of MIP and its role in MIP-mediated protection against M.tb. MIP was found to be potent inducer of autophagy in macrophages. Induced autophagy was responsible for reversal of the phagosome maturation block and phagolysosome fusion inhibition in M.tb infected macrophages, which ultimately lead to significantly enhanced clearance of M.tb from the macrophages. This is an important study which further delineated the underlying mechanisms for significant immunotherapeutic activity observed in TB patients / animal models of tuberculosis, given MIP therapy along with chemotherapy. PMID- 29236769 TI - Creating infinite contrast in fluorescence microscopy by using lanthanide centered emission. AB - The popularity of fluorescence microscopy arises from the inherent mode of action, where the fluorescence emission from probes is used to visualize selected features on a presumed dark background. However, the background is rarely truly dark, and image processing and analysis is needed to enhance the fluorescent signal that is ascribed to the selected feature. The image acquisition is facilitated by using considerable illumination, bright probes at a relatively high concentration in order to make the fluorescent signal significantly more intense than the background signal. Here, we present two methods for completely removing the background signal in spectrally resolved fluorescence microscopy. The methodology is applicable for all probes with narrow and well-defined emission bands (Full width half-maximum < 20 nm). Here, we use two lanthanide based probes exploiting the narrow emission lines of europium(III) and terbium(III) ions. We used a model system with zeolites doped with lanthanides immobilized in a polymer stained with several fluorescent dyes regularly used in bioimaging. After smoothing the spectral data recorded in each pixel, they are differentiated. Method I is based on the direct sum of the gradient, while method II resolves the fluorescent signal by subtracting a background calculated via the gradient. Both methods improve signal-to-background ratio significantly and we suggest that spectral imaging of lanthanide-centered emission can be used as a tool to obtain absolute contrast in bioimaging. PMID- 29236770 TI - Association between preoperative peripheral blood mononuclear cell gene expression profiles, early postoperative organ function recovery potential and long-term survival in advanced heart failure patients undergoing mechanical circulatory support. AB - BACKGROUND: Multiorgan dysfunction syndrome contributes to adverse outcomes in advanced heart failure (AdHF) patients after mechanical circulatory support (MCS) implantation and is associated with aberrant leukocyte activity. We tested the hypothesis that preoperative peripheral blood mononuclear cell (PBMC) gene expression profiles (GEP) can predict early postoperative improvement or non improvement in patients undergoing MCS implantation. We believe this information may be useful in developing prognostic biomarkers. METHODS & DESIGN: We conducted a study with 29 patients undergoing MCS-surgery in a tertiary academic medical center from 2012 to 2014. PBMC samples were collected one day before surgery (day -1). Clinical data was collected on day -1 and day 8 postoperatively. Patients were classified by Sequential Organ Failure Assessment score and Model of End stage Liver Disease Except INR score (measured eight days after surgery): Group I = improving (both scores improved from day -1 to day 8, n = 17) and Group II = not improving (either one or both scores did not improve from day -1 to day 8, n = 12). RNA-sequencing was performed on purified mRNA and analyzed using Next Generation Sequencing Strand. Differentially expressed genes (DEGs) were identified by Mann-Whitney test with Benjamini-Hochberg correction. Preoperative DEGs were used to construct a support vector machine algorithm to predict Group I vs. Group II membership. RESULTS: Out of 28 MCS-surgery patients alive 8 days postoperatively, one-year survival was 88% in Group I and 27% in Group II. We identified 28 preoperative DEGs between Group I and II, with an average 93% prediction accuracy. Out of 105 DEGs identified preoperatively between year 1 survivors and non-survivors, 12 genes overlapped with the 28 predictive genes. CONCLUSIONS: In AdHF patients following MCS implantation, preoperative PBMC-GEP predicts early changes in organ function scores and correlates with long-term outcomes. Therefore, gene expression lends itself to outcome prediction and warrants further studies in larger longitudinal cohorts. PMID- 29236771 TI - Neuropsychological performance in solvent-exposed vehicle collision repair workers in New Zealand. AB - OBJECTIVES: To assess whether contemporary solvent exposures in the vehicle collision repair industry are associated with objectively measured neuropsychological performance in collision repair workers. METHODS: The RBANS battery and additional tests were administered to 47 vehicle collision repair and 51 comparison workers randomly selected from a previous questionnaire study. RESULTS: Collision repair workers performed lower on tests of attention (digit span backwards: -1.5, 95% CI -2.4, -0.5; digit span total: -1.7, CI -3.3, -0.0; coding: -6.1, CI -9.9, -2.8; total attention scale: -9.3, CI -15.9, -2.8) and the RBANS total scale (-5.1, CI -9.1, -1.2). Additional tests also showed deficits in visual attention and reaction time (Trails B: -11.5, CI -22.4, -0.5) and motor speed/dexterity (coin rotation dominant hand & non-dominant: -2.9, CI -5.3, -0.4 and -3.1, CI -5.6, -0.7 respectively). The strongest associations were observed in panel beaters. Applying dichotomised RBANS outcomes based on the lowest percentile scores of a normative comparison group showed strongly increased risks for attention (5th percentile: OR 20.1, 95% CI 1.5, 263.3; 10th percentile: 8.8, CI 1.7, 46.2; and 20th percentile: 5.1, CI 1.5, 17.6, respectively). Those employed in the industry for <= 17 years (the median work duration) generally had lower scores in the attention domain scale and RBANS total scale compared to those employed >17 years suggesting a healthy worker survivor bias, but trends were inconsistent for other domains. CONCLUSIONS: This study has found significant deficits in cognitive performance in collision repair workers despite low current airborne exposures in New Zealand. PMID- 29236772 TI - Age-related reduction of adaptive brain response during semantic integration is associated with gray matter reduction. AB - While aging is associated with increased knowledge, it is also associated with decreased semantic integration. To investigate brain activation changes during semantic integration, a sample of forty-eight 25-75 year-old adults read sentences with high cloze (HC) and low cloze (LC) probability while functional magnetic resonance imaging was conducted. Significant age-related reduction of cloze effect (LC vs. HC) was found in several regions, especially the left middle frontal gyrus (MFG) and right inferior frontal gyrus (IFG), which play an important role in semantic integration. Moreover, when accounting for global gray matter volume reduction, the age-cloze correlation in the left MFG and right IFG was absent. The results suggest that brain structural atrophy may disrupt brain response in aging brains, which then show less brain engagement in semantic integration. PMID- 29236773 TI - First insights into a type II toxin-antitoxin system from the clinical isolate Mycobacterium sp. MHSD3, similar to epsilon/zeta systems. AB - A putative type II toxin-antitoxin (TA) system was found in the clinical isolate Mycobacterium sp. MHSD3, a strain closely related to Mycobacterium chelonae. Further analyses of the protein sequences of the two genes revealed the presence of domains related to a TA system. BLAST analyses indicated the presence of closely related proteins in the genomes of other recently published M. chelonae strains. The functionality of both elements of the TA system was demonstrated when expressed in Escherichia coli cells, and the predicted structure of the toxin is very similar to those of well-known zeta-toxins, leading to the definition of a type II TA system similar to epsilon/zeta TA systems in strains that are closely related to M. chelonae. PMID- 29236774 TI - EphrinA1-Fc attenuates myocardial ischemia/reperfusion injury in mice. AB - EphrinA1, a membrane-bound receptor tyrosine kinase ligand expressed in healthy cardiomyocytes, is lost in injured cells following myocardial infarction. Previously, we have reported that a single intramyocardial injection of chimeric ephrinA1-Fc at the time of ischemia reduced injury in the nonreperfused myocardium by 50% at 4 days post-MI by reducing apoptosis and inflammatory cell infiltration. In a clinically relevant model of acute ischemia (30min)/reperfusion (24hr or 4 days) injury, we now demonstrate that ephrinA1-Fc reduces infarct size by 46% and completely preserves cardiac function (ejection fraction, fractional shortening, and chamber dimensions) in the short-term (24hrs post-MI) as well as long-term (4 days). At 24 hours post-MI, diminished serum inflammatory cell chemoattractants in ephrinA1-Fc-treated mice reduces recruitment of neutrophils and leukocytes into the myocardium. Differences in relative expression levels of EphA-Rs are described in the context of their putative role in mediating cardioprotection. Validation by Western blotting of selected targets from mass spectrometry analyses of pooled samples of left ventricular tissue homogenates from mice that underwent 30min ischemia and 24hr of reperfusion (I/R) indicates that ephrinA1-Fc administration alters several regulators of signaling pathways that attenuate apoptosis, promote autophagy, and shift from FA metabolism in favor of increased glycolysis to optimize anaerobic ATP production. Taken together, reduced injury is due a combination of adaptive metabolic reprogramming, improved cell survival, and decreased inflammatory cell recruitment, suggesting that ephrinA1-Fc enhances the capacity of the heart to withstand an ischemic insult. PMID- 29236777 TI - How lizards fly: A novel type of wing in animals. AB - Flying lizards of the genus Draco are renowned for their gliding ability, using an aerofoil formed by winglike patagial membranes and supported by elongated thoracic ribs. It remains unknown, however, how these lizards manoeuvre during flight. Here, I present the results of a study on the aerial behaviour of Dussumier's Flying Lizard (Draco dussumieri) and show that Draco attaches the forelimbs to the leading edge of the patagium while airborne, forming a hitherto unknown type of composite wing. The attachment of the forelimbs to the patagium suggests that that aerofoil is controlled through movements of the forelimbs. One major advantage for the lizards is that the forelimbs retain their complete range of movement and functionality for climbing and running when not used as a part of the wing. These findings not only shed a new light on the flight of Draco but also have implications for the interpretation of gliding performance in fossil species. PMID- 29236776 TI - An adenylyl cyclase like-9 gene (NlAC9) influences growth and fecundity in the brown planthopper, Nilaparvata lugens (Stal) (Hemiptera: Delphacidae). AB - The cAMP/PKA intracellular signaling pathway is launched by adenylyl cyclase (AC) conversion of adenosine triphosphate (ATP) to 3', 5'-cyclic AMP (cAMP) and cAMP dependent activation of PKA. Although this pathway is very well known in insect physiology, there is little to no information on it in some very small pest insects, such as the brown planthopper (BPH), Nilaparvata lugens Stal. BPH is a destructive pest responsible for tremendous crop losses in rice cropping systems. We are investigating the potentials of novel pest management technologies from RNA interference perspective. Based on analysis of transcriptomic data, the BPH AC like-9 gene (NlAC9) was up-regulated in post-mating females, which led us to pose the hypothesis that NlAC9 is a target gene that would lead to reduced BPH fitness and populations. Targeting NlAC9 led to substantially decreased soluble ovarian protein content, yeast-like symbiont abundance, and vitellogenin gene expression, accompanied with stunted ovarian development and body size. Eggs laid were decreased and oviposition period shortened. Taken together, our findings indicated that NlAC9 exerted pronounced effects on female fecundity, growth and longevity, which strongly supports our hypothesis. PMID- 29236775 TI - Active site-targeted covalent irreversible inhibitors of USP7 impair the functions of Foxp3+ T-regulatory cells by promoting ubiquitination of Tip60. AB - Accumulation of Foxp3+ T-regulatory (Treg) cells in the tumor microenvironment is associated with tumor immune evasion and poor patient outcome in the case of many solid tumors. Current therapeutic strategies for blocking Treg functions are not Treg-specific, and display only modest and transient efficacy. Recent studies revealed that ubiquitin-specific protease 7 (USP7) is essential for Treg functions by stabilizing expression of Tip60 and Foxp3, which together are central to the development and maintenance of the Treg cell lineage. Pharmacological inhibition of USP7 is therefore a promising strategy for suppressing Treg functions and promoting anti-tumor immunity. Previously, we reported the P5091 series of small molecule USP7 inhibitors and demonstrated their direct anti-tumor activity in vivo using xenograft models. However, the precise mechanism of action of these compounds was not well defined. In this study, we report the development and characterization of P217564, a second generation USP7 inhibitor with improved potency and selectivity. P217564 selectively targets the catalytic cleft of USP7 and modifies its active site cysteine (C223) by forming a covalent adduct. Irreversible inhibition of USP7 results in durable downstream biological responses in cells, including down regulation of Tip60 and consequent impairment of Treg suppressive function. In addition, we demonstrate that both USP7 and various USP7 substrates are subjected to Lys48-mediated ubiquitin modification, consistent with increased proteasomal degradation of these proteins because of USP7 inhibition. PMID- 29236778 TI - Interaction of porcine reproductive and respiratory syndrome virus proteins with SUMO-conjugating enzyme reveals the SUMOylation of nucleocapsid protein. AB - SUMOylation is a reversible post-translational modification that regulates the function of target protein. In this study, we first predicted by software that the multiple proteins of porcine reproductive and respiratory syndrome virus (PRRSV) could be sumoylated. Next, we confirmed that Nsp1beta, Nsp4, Nsp9, Nsp10 and nucleocapsid (N) protein of PRRSV could interact with the sole SUMO E2 conjugating enzyme Ubc9, and Ubc9 could be co-localized with Nsp1beta, Nsp4, Nsp9 and Nsp10 in the cytoplasm, while with N protein in both the cytoplasm and nucleus. Finally, we demonstrated that N protein could be sumoylated by either SUMO1 or SUMO2/3. In addition, the overexpression of Ubc9 could inhibit viral genomic replication at early period of PRRSV infection and the knockdown of Ubc9 by siRNA could promote the virus replication. These findings reveal the SUMOylation property of PRRSV N protein and the involvement of Ubc9 in PRRSV replication through interaction with multiple proteins of PRRSV. To our knowledge, this is the first study indicating the interplay between SUMO modification system and PRRSV. PMID- 29236779 TI - Detection and molecular characterization of the novel recombinant norovirus GII.P16-GII.4 Sydney in southeastern Brazil in 2016. AB - Noroviruses are the leading cause of acute gastroenteritis (AGE) in all age groups worldwide. Despite the high genetic diversity of noroviruses, most AGE outbreaks are caused by a single norovirus genotype: GII.4. Since 1995, several different variants of norovirus GII.4 have been associated with pandemics, with each variant circulating for 3 to 8 years. The Sydney_2012 variant was first reported in Australia and then in other countries. A new variant, GII.P16-GII.4, was recently described in Japan and South Korea and then in the USA, France, Germany and England. In our study, 190 faecal specimens were collected from children admitted to a paediatric hospital and a public health facility during a surveillance study of sporadic cases of AGE conducted between January 2015 and July 2016. The norovirus was detected by RT-qPCR in 51 samples (26.8%), and in 37 of them (72.5%), the ORF1-2 junction was successfully sequenced. The new recombinant GII.P16-GII.4 Sydney was revealed for the first time in Brazil in 2016 and predominated among other strains (9 GII.Pe-GII.4, 3 GII.P17-GII.17, 1 GII.Pg-GII.1, 1 GII.P16-GII.3 and 1 GII.PNA-GII.4). The epidemiological significance of this new recombinant is still unknown, but continuous surveillance studies may evaluate its impact on the population, its potential to replace the first recombinant GII.Pe-GII.4 Sydney 2012 variant, and the emergence of new recombinant forms of GII.P16. PMID- 29236780 TI - The role of phytochromes in regulating biosynthesis of sterol glycoalkaloid in eggplant leaves. AB - Glycoalkaloids are toxic compounds that are synthesized by many Solanum species. Glycoalkaloid biosynthesis is influenced by plant genetic and environmental conditions. Although many studies have shown that light is an important factor affecting glycoalkaloid biosynthesis, the specific mechanism is currently unknown. Chlorophyll and carotenoid biosynthesis depend on light signal transduction and share some intermediate metabolites with the glycoalkaloid biosynthetic pathway. Here, we used virus-induced gene silencing to silence genes encoding phytoene desaturase (PDS) and magnesium chelatase (CHLI and CHLH) to reduce chlorophyll and carotenoid levels in eggplant leaves. Quantification of carotenoid and chlorophyll levels is analyzed by LC/PDA/APCI/MS and semipolar metabolite profiling by LC/HESI/MS. Notably, the resulting lines showed decreases in glycoalkaloid production. We further found that the expression of some genes involved in the production of glycoalkaloids and other metabolites were suppressed in these silenced lines. Our results indicate that photosynthetic pigment accumulation affects steroidal glycoalkaloid biosynthesis in eggplant leaves. This finding lays the foundation for reducing the levels of endogenous antinutritional compounds in crops. PMID- 29236781 TI - Chitosan coating as an antibacterial surface for biomedical applications. AB - BACKGROUND AND OBJECTIVES: A current public health issue is preventing post surgical complications by designing antibacterial implants. To achieve this goal, in this study we evaluated the antibacterial activity of an animal-free chitosan grafted onto a titanium alloy. METHODS: Animal-free chitosan binding on the substrate was performed by covalent link via a two-step process using TriEthoxySilylPropyl Succinic Anhydride (TESPSA) as the coupling agent. All grafting steps were studied and validated by means of X-ray Photoelectron Spectroscopy (XPS), Time-of-Flight secondary ion mass spectrometry (ToF-SIMS) analyses and Dynamic-mode Secondary Ion Mass Spectrometry (DSIMS). The antibacterial activity against Escherichia coli and Staphylococcus aureus strains of the developed coating was assessed using the number of colony forming units (CFU). RESULTS: XPS showed a significant increase in the C and N atomic percentages assigned to the presence of chitosan. A thick layer of polymer deposit was detected by ToF-SIMS and the results obtained by DSIMS measurements are in agreement with ToF-SIMS and XPS analyses and confirms that the coating synthesis was a success. The developed coating was active against both gram negative and gram positive tested bacteria. CONCLUSION: The success of the chitosan immobilization was proven using the surface characterization techniques applied in this study. The coating was found to be effective against Escherichia coli and Staphylococcus aureus strains. PMID- 29236783 TI - Nutrition label experience, obesity, high blood pressure, and high blood lipids in a cohort of 42,750 Thai adults. AB - INTRODUCTION: Nutrition labels have been promoted for nearly two decades in Thailand to educate people about healthy eating and to combat nutrient-related non-communicable diseases (NCDs). But little is known about how nutrition labels are experienced and whether they are linked with better health. Our objective was to investigate the associations between nutrition label experience, obesity and nutrient-related NCDs in Thai consumers. METHODS: A cross-sectional study was undertaken with a nationwide cohort of 42,750 distance learning Thai adult students enrolled in an Open University in 2013. We measured exposure as nutrition label experience (read, understand, use). Health outcomes were high blood pressure, high blood lipids, and high Body Mass Index (overweight at risk and obesity). Multivariate logistic regression was used to determine the association between nutrition label experience and health outcome adjusting for sociodemographic attributes, physical activity, smoking, and alcohol intake. RESULTS: Frequent nutrition label use varied by cohort attributes and health outcomes and was least for those with low physical activity and high blood pressure. Being male, older, an urban resident or with low physical activity was associated with increasing high blood pressure and high blood lipids. Compared to those who read, understand and use nutrition labels, participants who did not (read, understand, and use), were more likely to report high blood pressure (Adjusted Odds Ratio 1.33; 1.17-1.51), high blood lipids (AOR 1.26; 1.14-1.39), and obesity (AOR 1.23; 1.13-1.33), but were not more likely to be overweight at risk (AOR 1.06; 0.97-1.16). CONCLUSIONS: We found cross-sectional associations between low nutrition label experience and increased likelihood of high blood pressure, high blood lipids, and obesity among Thai adults. Nutrition label education should be promoted as part of a public health approach to appropriate food choices and better lifestyles to reduce obesity and nutrient-related NCDs. PMID- 29236782 TI - Interleukin-35 mitigates the function of murine transplanted islet cells via regulation of Treg/Th17 ratio. AB - Pancreatic islet transplantation is a promising treatment for type 1 diabetes (T1D). Interleukin-35 (IL-35) is a recently discovered cytokine that exhibits potent immunosuppressive functions. However, the role of IL-35 in islet transplant rejection remains to be elucidated. In this study, we isolated islet cells of BALB/c mouse and purified CD4+ T cell subsets of a C57BL/6 mouse. The model for islet transplantation was established in vitro by co-culture of the islet cells and CD4+ T cells. IL-35 (20 ng/ml) was administered every other day. Following co-culture, the islet function and Treg/Th17 ratio were analyzed on days 1, 3, and 5. Furthermore, the Th17/Treg ratio was modulated (1:0-2), and the function of islet cells as well as proliferation of Th17 cells were analyzed. T cell sorting was performed using the magnetic bead sorting method; Treg and Th17 count using flow cytometry; cell proliferation detection using the carboxyfluorescein diacetate succinimidyl ester (CFSE) method, and islet function test using the sugar stimulation test. Results showed that Th17 counts increased in the co-culture system. However, after administration of IL-35, the number of Treg cells increased significantly compared to that in the control group (50.7% of total CD4+ T cells on day 5 in IL-35 group vs. 9.5% in control group) whereas the proliferation rate of Th17 cells was significantly inhibited (0.3% in IL-35 group vs. 7.2% in control group on day 5). Reducing the Th17/Treg ratio significantly improved the function of transplanted islets. Treg inhibited Th17 proliferation and IL-35 enhanced this inhibitory effect. IL-35 mitigates the function of murine transplanted islet cells via regulation of the Treg/Th17 ratio. This might serve as a potential therapeutic strategy for in-vivo islet transplant rejection and T1D. PMID- 29236784 TI - Preperimetric Glaucoma Prospective Observational Study (PPGPS): Design, baseline characteristics, and therapeutic effect of tafluprost in preperimetric glaucoma eye. AB - PURPOSE: There is no consensus on the diagnosis or treatment policy for Preperimetric Glaucoma (PPG) because the pathogenesis of PPG is not clear at this time. Preperimetric Glaucoma Prospective Observational Study (PPGPS) is a first multicenter, prospective, observational study to clarify the pathogenesis of PPG. This article indicates study design, patient baseline characteristics, and analysis focused on optic nerve head (ONH) blood flow in PPG, as well as the intraocular pressure (IOP) -lowering effect and ONH blood flow-improving effects of Tafluprost. METHOD: In this study, 122 eyes from 122 subjects (mean age: 53.1 +/- 14.3) newly diagnosed as PPG were enrolled. The circumpapillary retinal nerve fiber layer thickness (cpRNFLT) was evaluated with optical coherence tomography (OCT). The ONH blood flow was measured with laser speckle flowgraphy. The therapeutic effect of Tafluprost was evaluated at Month 0 (ONH blood flow improving effect) and Month 4 (IOP-lowering effect). RESULTS: The untreated IOP, cpRNFLT, and baseline Mean deviation (MD) value was 16.4 +/- 2.5 mmHg, 80.4 +/- 8.2 MUm, and -0.48 +/- 1.29 dB, respectively. In the site-specific visual field evaluation using the sector map, there was no appreciable site-specific visual field defect in the eye with PPG. The inferior region of cpRNFLT in 4-quadrant OCT sector analysis and 6 o'clock region in 12-o'clock OCT sector analysis was the highest rate of abnormality in PPG eyes. Topical administration of Tafluprost significantly reduced IOP from 16.4 +/- 2.5 mmHg at baseline to 14.5 +/- 2.3 mmHg at Month 4 (P < 0.001, paired t-test). In the linear regression analysis, there was a significant relationship between the increase of ONH blood flow and baseline value. CONCLUSION: PPGPS is a first prospective study focusing on the pathology of PPG. This study is expected to elucidate the pathology of PPG, with evidence useful for determining a treatment strategy for PPG. PMID- 29236786 TI - Theoretical proposal of a low-loss wide-bandwidth silicon photonic crystal fiber for supporting 30 orbital angular momentum modes. AB - We propose a novel four-ring hollow-core silicon photonic crystal fiber (PCF), and we systematically and theoretically investigate the properties of their vector modes. Our PCF can stably support 30 OAM states from the wavelength of 1.5 MUm to 2.4 MUm, with a large effective refractive index separation of above 1*10 4. The confinement loss is less than 1*10-9 dB/m at the wavelength of 1.55 MUm, and the average confinement loss is less than 1*10-8 dB/m from the wavelength of 1.2 MUm to 2.4 MUm. Moreover, the curve of the dispersion tends to flatten as the wavelength increases. In addition, we comparably investigate PCFs with different hole spacing. This kind of fiber structure will be a potential candidate for high capacity optical fiber communications and OAM sensing applications using fibers. PMID- 29236785 TI - The soluble mannose receptor (sMR) is elevated in alcoholic liver disease and associated with disease severity, portal hypertension, and mortality in cirrhosis patients. AB - BACKGROUND AND AIMS: Hepatic macrophages (Kupffer cells) are involved in the immunopathology of alcoholic liver disease (ALD). The mannose receptor (MR, CD206), expressed primarily by macrophages, mediates endocytosis, antigen presentation and T-cell activation. A soluble form, sMR, has recently been identified in humans. We aimed to study plasma sMR levels and its correlation with disease severity and survival in ALD patients. METHODS: We included 50 patients with alcoholic hepatitis (AH), 68 alcoholic cirrhosis (AC) patients (Child-Pugh A (23), B (24), C (21)), and 21 healthy controls (HC). Liver status was described by the Glasgow Alcoholic Hepatitis Score (GAHS), Child-Pugh (CP) and MELD-scores, and in AC patients the hepatic venous pressure gradient (HVPG) was measured by liver vein catheterisation. We used Kaplan-Meier statistics for short-term survival (84-days) in AH patients and long-term (4 years) in AC patients. We measured plasma sMR by ELISA. RESULTS: Median sMR concentrations were significantly elevated in AH 1.32(IQR:0.69) and AC 0.46(0.5) compared to HC 0.2(0.06) mg/L; p<0.001 and increased in a stepwise manner with the CP-score (p<0.001). In AC sMR predicted portal hypertension (HVPG >=10 mmHg) with an area under the Receiver Operator Characteristics curve of 0.86 and a high sMR cut-off (>0.43 mg/l) was associated with increased mortality (p = 0.005). CONCLUSION: The soluble mannose receptor is elevated in alcoholic liver disease, especially in patients with AH. Its blood level predicts portal hypertension and long-term mortality in AC patients. PMID- 29236787 TI - Efficient enhancement of information in the prefrontal cortex during the presence of reward predicting stimuli. AB - The prefrontal cortex (PFC) is a key brain structure for decision making, behavioural flexibility and working memory. Neurons in PFC encode relevant stimuli through changes in their firing rate, although the metabolic cost of spiking activity puts strong constrains to neural codes based on firing rate modulation. Thus, how PFC neural populations code relevant information in an efficient way is not clearly understood. To address this issue we made single unit recordings in the PFC of rats performing a GO/NOGO discrimination task and analysed how entropy between pairs of neurons changes during cue presentation. We found that entropy rises only during reward-predicting cues. Moreover, this change in entropy occurred along an increase in the efficiency of the whole process. We studied possible mechanisms behind the efficient gain in entropy by means of a two neuron leaky integrate-and-fire model, and found that a precise relationship between synaptic efficacy and firing rate is required to explain the experimentally observed results. PMID- 29236789 TI - Characterization of Mycosphaerellaceae species associated with citrus greasy spot in Panama and Spain. AB - Greasy spot of citrus, caused by Zasmidium citri-griseum (= Mycosphaerella citri), is widely distributed in the Caribbean Basin, inducing leaf spots, premature defoliation, and yield loss. Greasy spot-like symptoms were frequently observed in humid citrus-growing regions in Panama as well as in semi-arid areas in Spain, but disease aetiology was unknown. Citrus-growing areas in Panama and Spain were surveyed and isolates of Mycosphaerellaceae were obtained from citrus greasy spot lesions. A selection of isolates from Panama (n = 22) and Spain (n = 16) was assembled based on their geographical origin, citrus species, and affected tissue. The isolates were characterized based on multi-locus DNA (ITS and EF-1alpha) sequence analyses, morphology, growth at different temperatures, and independent pathogenicity tests on the citrus species most affected in each country. Reference isolates and sequences were also included in the analysis. Isolates from Panama were identified as Z. citri-griseum complex, and others from Spain attributed to Amycosphaerella africana. Isolates of the Z. citri-griseum complex had a significantly higher optimal growth temperature (26.8 degrees C) than those of A. africana (19.3 degrees C), which corresponded well with their actual biogeographical range. The isolates of the Z. citri-griseum complex from Panama induced typical greasy spot symptoms in 'Valencia' sweet orange plants and the inoculated fungi were reisolated. No symptoms were observed in plants of the 'Ortanique' tangor inoculated with A. africana. These results demonstrate the presence of citrus greasy spot, caused by Z. citri-griseum complex, in Panama whereas A. africana was associated with greasy spot-like symptoms in Spain. PMID- 29236788 TI - Aflatoxin and viral hepatitis exposures in Guatemala: Molecular biomarkers reveal a unique profile of risk factors in a region of high liver cancer incidence. AB - Liver cancer is an emerging global health issue, with rising incidence in both the United States and the economically developing world. Although Guatemala experiences the highest rates of this disease in the Western hemisphere and a unique 1:1 distribution in men and women, few studies have focused on this population. Thus, we determined the prevalence and correlates of aflatoxin B1 (AFB1) exposure and hepatitis virus infection in Guatemalan adults. Healthy men and women aged >=40 years (n = 461), residing in five departments of Guatemala, were enrolled in a cross-sectional study from May-October of 2016. Serum AFB1 albumin adducts were quantified using isotope dilution mass spectrometry. Multivariate linear regression was used to assess relationships between AFB1 albumin adduct levels and demographic factors. Biomarkers of hepatitis B virus and hepatitis C virus infection were assessed by immunoassay and analyzed by Fisher's exact test. AFB1-albumin adducts were detected in 100% of participants, with a median of 8.4 pg/mg albumin (range, 0.2-814.8). Exposure was significantly higher (p<0.05) in male, rural, low-income, and less-educated participants than in female, urban, and higher socioeconomic status participants. Hepatitis B and C seropositivity was low (0.9% and 0.5%, respectively). Substantial AFB1 exposure exists in Guatemalan adults, concurrent with low prevalence of hepatitis virus seropositivity. Quantitatively, AFB1 exposures are similar to those previously found to increase risk for liver cancer in Asia and Africa. Mitigation of AFB1 exposure may reduce liver cancer incidence and mortality in Guatemala, warranting further investigation. PMID- 29236790 TI - SCREENING FOR MENTAL HEALTH PROBLEMS IN PRESCHOOLERS AT PRIMARY HEALTH CARE SETTINGS. AB - OBJECTIVE: To study the applicability of the Strength and Difficulties Questionnaire (SDQ 2,4-p) as a screening tool for mental health problems in preschoolers, in the context of Primary Health Care; to evaluate the mental health problems of the sample, comparing data from SDQ (2,4-p) and from the Child Behavior Check List (CBCL 11/2-5 years). METHODS: Cross-sectional observational study with a convenience sample of 31-50-month-old children, whose caretakers provided informational reports. In the first stage, professionals from the primary care health unit have applied the SDQ (2,4-p) during routine appointments. Subsequently, the CBCL (11/2-5) was applied by a professional experienced in infant mental health. The SDQ and CBCL results were compared and the correlation between the scales was tested. RESULTS: Among 280 questionnaires available to the health professionals, 48 were filled out and the CBCL was applied to 40 of the participants. Among the problems found with the SDQ, 18 cases (37.6% out of 48) have shown abnormal score in the "Total Difficulties" and 38 (80.9% out of 48) have shown normal score in the "Impact of Difficulty". Behavioral issues were highlighted by the percentage of abnormal scores (47.9%). The correlation between SQD and CBCL was positive for all scales, except for the pro-social behavior. CONCLUSIONS: Clinically important mental health problems were found in preschool children. Variables of the SDQ discriminate normal and abnormal scores according to the CBCL parameters, thus functioning as a good screening tool. PMID- 29236791 TI - Spatial and temporal variations in fish assemblage: testing the zonation concept in small reservoirs. AB - Large reservoirs usually present spatial gradients in fish assemblage, distinguishing three strata (littoral, pelagic, and bathypelagic) along the vertical and horizontal axes, and three zones (fluvial, transitional, and lacustrine) along the longitudinal axis. The main objective of this study was to assess if small reservoirs also present the spatial gradients in fish assemblage attributes and structure as already observed in large reservoirs. Fish surveys were conducted quarterly, from 2003 to 2008, in the Mourao Reservoir (Mourao River, Parana, Brazil), using gillnets with different mesh sizes, arranged in all strata of all three zones. Community attributes (species richness and evenness) were calculated for each sample, and differences were tested using three-way ANOVA (factors: zone, strata, year). Community composition was summarized using Correspondence Analysis (CA) and differences were tested with three-way ANOVA for each axis, controlling the same three factors. Because of the high variability in reservoir water level through time, all analyses were made considering temporal variations. Species richness presented a decreasing trend from fluvial to lacustrine zones, and higher values in littoral strata, possibly because upper reaches and littoral regions provide better conditions for fish to feed and to reproduce. Evenness was considerably low, presenting high variability, and no evident pattern. The expected longitudinal gradient was not found in this study indicating longitudinal similarity, contrary to observed in large reservoirs. Vertical and horizontal gradients were observed in all sampling stations, indicating that abiotic and biotic conditions are influencing fish distributions within the reservoir. PMID- 29236792 TI - Specificities of presentation of Crohn's disease in childhood. AB - The incidence of inflammatory bowel disease in the pediatric population has increased in the last years. The most common form of inflammatory bowel disease is Crohn's disease and, according to its form and age of presentation, it is possible to predict the evolution of the disease. PMID- 29236793 TI - Diagnosis and treatment of anaphylaxis: there is an urgent needs to implement the use of guidelines. AB - Anaphylaxis is a severe, life-threatening generalized or systemic hypersensitivity reaction that requires rapid and adequate care. This study aimed to obtain an integrated view of the level of physicians' knowledge related with treatment of anaphylaxis in studies published within the last 5 years. Sixteen studies were found and four points were identified as of the great interest to the authors: (1) emergency pharmacological treatment, (2) epinephrine auto injectors prescription, (3) knowledge of the main signs of anaphylaxis, and (4) admission of the patient to verify biphasic reactions. Concern about the use of intramuscular adrenaline as the first choice in relation with anaphylaxis was evident in most studies, rather than its use in the comparison dial, and especially low in a study that included data from Brazil, in which the frequency of its use was 23.8%. An adrenaline autoinjector is highly recommended among specialists for patients at risk of anaphylaxis, however, its use is still infrequent among non-specialists and in countries that this agent is not available. Intervention studies have shown improved medical knowledge of anaphylaxis following disclosure of the information contained in the international guidelines. The analysis of these studies reinforces the need to disseminate international guidelines for diagnosis and treatment of anaphylaxis, as well as providing an adrenaline autoinjector, to improve management and to prevent a fatal outcome. PMID- 29236794 TI - Qualitative analysis of the viability of autogenous fat grafts grafted in different environments of interstitial pressure. Preliminary results and description of a new experimental model in mini-pigs. AB - PURPOSE: To evaluate the feasibility of an experimental model of autologous fat graft (AFG) in different interstitial pressure (IP) environments. METHODS: Three mini-pigs(Minipig-BR) with age of 8 months (weight: 25-30 kg) were used. AFG were collected from the bucal fat pad, and grafted in the intramuscular pocket (biceps femoralis muscle). IP model was based on a fusiform ressection followed by primary closure "under tension". A blood pressure catheter located in the intramuscular region connected to a pressure module was applied to quantify IP. RESULTS: The mean operative time was 236 min (210 - 272 min). All the AFG and muscular segments were removed successfully. Average interstitial pressure CP and H were 3 and 10.6 mmHg respectively. The AFG were biopsied for histopathological analysis 30 days after graft. Hematoxylin-eosin staining and immunohistochemical analyzes (TNF-alpha, CD31 and Perilipine with monoclonal antibodies) were employed. CONCLUSION: The data show that minipigs model could be used as a recipient site for autologous fat graft techniques and allow the development of studies to explore the AFG intake and pathophysiology response. PMID- 29236795 TI - Comparative study of intraperitoneal adhesions related to light-weight polypropylene mesh and type I polymerized and purified bovine collagen coated light-weight polypropylene mesh in rabbits. AB - PURPOSE: To compare the effectiveness of light-weight polypropylene mesh coated with polymerized and purified bovine type I collagen (Surgidry HNB) in the treatment of abdominal wall defect and the degree of adhesion formation. METHODS: Two types of polypropylene mesh were implanted after creation of defect measuring 6.0cm X 5.5cm in the anterior abdominal wall of 32 male New Zealand breed rabbits, divided in two groups (n = 32): (1) light-weigh macroporous polypropylene, (2) type I polymerized and purified bovine collagen coated light weigh macroporous polypropylene. These animals were further accessed for adhesions, histological evaluation of inflammation and wall's thickness. RESULTS: The percentage of the area adhered in group 1 (62.31 +/- 16.6) was higher compared to group 2 (22.19 +/- 14.57) (p <0.05). There was an association between the percentage of the covered area by adhesions and the type of adhesion, toughness and the scores obtained by the adhesion score by correlation analysis (p <0.05). There was no difference between the groups in any variables in relation to the degree of inflammation. CONCLUSION: The purified type I bovine collagen coated light-weigh polypropylene mesh showed to be effective in the repair of abdominal wall defects and reducing adhesion formation. PMID- 29236796 TI - Hyperbaric oxygenation and the genic expression related to oxidative stress in the heart of mice during intestinal ischemia and reperfusion. AB - PURPOSE: To investigate the effects of hyperbaric oxygenation (HBO) on intestinal ischemia and reperfusion (IR) injury, we evaluated the expression of 84 genes related to oxidative stress and the antioxidant response in mouse hearts. METHODS: Four groups were subjected to 60 minutes of intestinal ischemia followed by 60 minutes of reperfusion: IRG, ischemia and reperfusion group without HBO; HBO-IG, which received HBO during ischemia; HBO-RG, which received HBO during reperfusion; and HBO-IRG, which received HBO during ischemia and reperfusion. The control group (CG) underwent anesthesia and laparotomy and was observed for 120 minutes. The (RT-qPCR) method was applied. Genes with expression levels three times below or above the threshold cycle were considered significantly hypoexpressed or hyperexpressed, respectively (Student's t-test p<0.05). RESULTS: Eight genes (9.52%) were hyperexpressed in the IRG. When the HBO groups were compared to the IRG, we found a decrease in the expression of eight genes in the HBO-IG, five genes in the HBO-RG, and seven genes in the HBO-IRG. CONCLUSION: The reduction in the expression of genes related to oxidative stress and antioxidant defense following HBO in mouse hearts resulting from intestinal IR injury was more favorable during the ischemic period than during the reperfusion period. PMID- 29236797 TI - Nandrolone decanoate appears to increase bone callus formation in young adult rats after a complete femoral fracture. AB - PURPOSE: To evaluate the influence of nandrolone decanoate on fracture healing and bone quality in normal rats. METHODS: Male rats were assigned to four groups (n=28/group): Control group consisting of animals without any intervention, Nandrolone decanoate (DN) group consisting of animals that received intramuscular injection of nandrolone decanoate, Fracture group consisting of animals with a fracture at the mid-diaphysis of the femur, and Fracture and nandrolone decanoate group consisting of animals with a femur fracture and treatment with nandrolone decanoate. Fractures were created at the mid-diaphysis of the right femur by a blunt trauma and internally fixed using an intramedullary steel wire. The DN was injected intramuscularly twice per week (10 mg/kg of body mass). The femurs were measured and evaluated by densitometry and mechanical resistance after animal euthanasia. The newly formed bone and collagen type I levels were quantified in the callus. RESULTS: The treated animals had longer femurs after 28 days. The quality of the intact bone was not significantly different between groups. The bone callus did show a larger mass in the treated rats. CONCLUSION: The administration of nandrolone decanoate did not affect the quality of the intact bone, but might have enhanced the bone callus formation. PMID- 29236798 TI - The expression of endothelial and inducible nitric oxide synthase and apoptosis in intestinal ischemia and reperfusion injury under the action of ischemic preconditioning and pentoxifylline. AB - PURPOSE: To investigate the expression of nitric oxide synthase (NOS) and apoptosis associated with ischemic preconditioning (IPC) and pentoxifylline (PTX) in intestinal ischemia (I) and reperfusion (R) injury. METHODS: Thirty male rats were assigned to 5 groups: (CG), no clamping of the superior mesenteric artery (90 minutes); (IR-SS) saline + ischemia (30 minutes) + reperfusion (60 minutes); (IR-PTX) PTX + ischemia (30 minutes) + reperfusion (60 minutes); (IPC-IR-SS) 5 minutes of ischemia + 5 minutes of reperfusion (IPC) + saline + I(30 minutes)+R(60 minutes); and (IPC-IR-PTX) IPC + PTX + I(30 minutes)+ R(60 minutes). RESULTS: The application of IPC and PTX showed a significantly lower immunohistochemistry reaction for active caspase-3 (P<0.05) compared to IR+SS. The number of cells immunoreactive to BCL-2 was higher in the IR-PTX group (P>0.05). The NOS-2 expression (qRTPCR) in the IR-PTX group (P<0.05) was higher than the values for the IPC+IR-SS and IPC-IR-PTX groups. The NOS-3 expression was significantly upper in the IPC-IR-PTX group than in the CG (P<0.05), the IR-SS (P<0.05) and the IR-PTX (P<0.05) groups. CONCLUSIONS: The BCL-2 and active caspase-3 showed beneficial effects on PTX and IPC. The expression of NOS-2 and NOS-3 in the IPC and IPC-PTX groups showed no synergistic effect. PMID- 29236799 TI - Perconditioning associated to hypertonic saline solution on liver function improvement after ischemia/reperfusion injury. AB - PURPOSE: To evaluate the effects of hypertonic saline solution associated to remote ischemic perconditioning in liver ischemia/reperfusion injury in rats. METHODS: 25 male rats (Wistar) were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of liver ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during liver ischemia; Hypertonic saline solution group (HSS) treated with hypertonic saline solution (4ml/kg); Remote ischemic perconditioning + Hypertonic saline solution group (Per+HSS) with both treatments. RESULTS: Per+HSS group showed a lower degree of liver dysfunction in relation to I/R group, whereas the technique of remote ischemic perconditioning isolated or associated with saline solution significantly improved liver function and reduced histological damage. CONCLUSION: Remote ischemic perconditioning associated or not to saline solution promoted reduction of acute liver injury induced by ischemia/reperfusion. PMID- 29236800 TI - Topical action of Buriti oil (Mauritia flexuosa L.) in myositis induced in rats. AB - PURPOSE: To analyze the topical effects of Buriti oil (Mauritia flexuosa L.) in induced myositis in rats. METHODS: Thirty six male rats divided into three groups: Control group (C), induced myositis group (MI) and induced myositis group reated with Mauritia flexuosa L. (MT). After inducing myositis with 1% acetic acid, was topically applied 0.5 ml of Mauritia flexuosa L.extract on the posterior region of the right gastrocnemius muscle in animals belonging to group MT, for 7 and 14 days. RESULTS: The neutrophil number there was statistically significant difference, after 7 and 14 days, between groups C and MI (p <0.001) (p<0.01). The group MT there was a significant difference in relation to MI group in both experimental times with (p<0.001). The number of fibroblasts in the 14 days showed that when comparing the groups M and MT the differences were also significant (p<0.001). As for the DLL, in 7 days, there was a significant difference between group C and MI group (p <0.001). When considering the MT group, there was a significant difference in relation to the MI group (p <0.001). CONCLUSION: The extract of Mauritia flexuosa L. leaves lessened acute and chronic inflammation, increased fibroblast proliferation and reduced macroscopically edema. PMID- 29236802 TI - Tadalafil protector effect during ischemia-reperfusion in rats. AB - PURPOSE: To evaluate histological parameters in rat renal tissue after tadalafil use during hot ischemia for 45 minutes and reperfusion for 24 hours. METHODS: Twenty rats were divided into 2 groups. In the experimental group 10 mg/kg of tadalafil was used per gavage before the procedure. All cases underwent left partial nephrectomy, followed by 45 minutes of warm ischemia. Left nephrectomy of the remaining kidney was performed after 24 hours from the initial procedure. The histological parameters analyzed were: detachment of tubular cells, accumulation of desquamated cells in the proximal tubule, loss of brush border, tubular cylinders, interstitial edema, leukocyte infiltration, capillary congestion, vacuolization, tubular dilatation, necrosis and collapse of the capillary tuft. RESULTS: Two rats from each group died and were excluded from the study. Tadalafil significantly reduced leukocyte infiltration (p = 0.036). The remaining histological parameters did not show statistical difference between the groups. CONCLUSION: The use of tadalafil during warm ischemia and reperfusion demonstrates statistically significant reduction of leukocyte infiltration in the renal interstitium. PMID- 29236801 TI - Effect of atenolol pre-treatment in heart damage in a model of intestinal ischemia-reperfusion. AB - PURPOSE: To investigate the effects of atenolol in inflammatory mediator and oxidative stress in a myocardial injury by intestinal ischemia/reperfusion in rat model. METHODS: Adult Wistar male rats were randomly (n=8), anesthetized and divided in: Sham: submitted to operation only; group SS+IR: intravenous saline infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); group AT+IR: intravenous atenolol infusion (2 mg/kg) following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); and group AT+I+AT+R: intravenous atenolol infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and in the time 45 minutes other atenolol doses were administrated and the artery was open for 120 minutes (reperfusion), all animals were submitted to muscular relaxation for mechanical ventilation. In the end of experiment the animals were euthanized and the hearts tissue were morphology analyzed by histology and malondialdehyde by ELISA, and the plasma were analyzed for tumor necrosis factor-alpha by ELISA. RESULTS: The group SS+IR demonstrated the higher malondialdehyde levels when compared with the atenolol treated-groups (p=0.001) in the heart tissue. The tumor necrosis factor-alpha level in plasma decrease in the treated groups when compared with SS+IR group (p=0.001). Histology analyses demonstrate pyknosis, edema, cellular vacuolization, presence of inflammatory infiltrate and band contraction in the heart tissue of the rats. CONCLUSION: Atenolol significantly reduce the degree of cardiac damage after intestinal ischemia-reperfusion. PMID- 29236803 TI - Aldefluor protocol to sort keratinocytes stem cells from skin. AB - PURPOSE: To investigate the use Aldefluor(r) and N, N - Dimethylaminobenzaldehyde (DEAB) to design a protocol to sort keratinocyte stem cells from cultured keratinocytes from burned patients. METHODS: Activated Aldefluor(r) aliquots were prepared and maintained at temperature between 2 to 8 degrees C, or stored at -20 degrees C. Next, the cells were collected following the standard protocol of sample preparation. RESULTS: Best results were obtained with Aldefluor(r) 1.5ul and DEAB 15 ul for 1 x 106 cells, incubated at 37 degrees C for 15 minutes. Flow cytometer range for keratinocyte stem cells separation was evaluated. There were 14.8% of stem cells separated in one sample of keratinocyte culture used to pattern the protocol. After being defined the ideal concentration, the same test pattern was performed in other keratinocyte samples. We observed a final mean of 10.8%. CONCLUSION: Aldefluor(r) has been shown as a favorable marking of epidermal keratinocyte stem cells for subsequent separation on a flow cytometer, with detection of 10.8% of epidermal keratinocyte stem cells, in this protocol. PMID- 29236804 TI - Psy cultures: psychoanalysis, subjectivity and politics. PMID- 29236805 TI - Psychoanalysis as a belief system: a research program outline. AB - This article lays out an agenda for research on the establishment of psy cultures in Latin America. It begins by analyzing some of the debates on the nature of psychoanalysis, a discipline located between the sciences, philosophy and common sense. It argues that the place of psy cultures needs to be problematized as emerging out of modernity in a cultural space like Latin America, where the very concept of modernity differs greatly from that of central countries. PMID- 29236806 TI - The circulation of psychoanalytical knowledge and practice in the social sciences. AB - A concise but broad-based review is presented of the circulation of knowledge and practices from psychoanalysis in the social sciences, especially anthropology. The different contexts in which the concepts and conceptions of psychoanalysis have been read, refuted, or appropriated by different national schools of thought and intellectual traditions and the ways psychoanalysis itself has interacted with anthropological knowledge and its incorporations of psychoanalytical knowledge are explored. The interpretations of these two major groups of knowledge are referred to as participating in a common cultural horizon with a common epistemological orientation, and the sources of the frequent mistaken beliefs occurring in this interplay are also addressed. PMID- 29236807 TI - The ritualization of life and the expansion of psy cultures in Colombia: the local and the barely transnational. AB - This paper exposes the status of psy cultures in Colombia. It is shown how the country's official health system has transformed biomedical psychiatry and cognitive behavioral psychology into the dominant and hegemonic psy culture. However, far from being hegemonic, as presented, both serve to foster and sustain the existence of different "religious" or "sacred" therapeutic systems and practices that denaturalize human existential and psychological suffering. In general, the latter are ritual practices with a strong spiritualist, anti materialist and antimonist content, that deal freely with a wide range of cosmologies, beliefs and symbols, even including the same concepts and practices of a biomedical origin. The result is a hyper-ritualization of daily life in the country. PMID- 29236808 TI - Psychoanalysis and the transition to democracy in Spain. AB - This article studies the links between psychoanalysis and the transition to democracy in Spain. It examines the major changes that characterized the spread of psychoanalysis in the years after Franco's death, in particular the rise of the Lacanian movement, the impact of this phenomenon on the sociocultural sphere and, in broader terms, its role in the re-emergence of psychoanalysis as a cultural object in the country. The article also analyzes factors linked to the history of psychoanalysis during the Franco dictatorship; factors that, together with the arrival of Oscar Masotta and numerous Argentinian analysts in Spain, help explain the new vision of the field that emerged during the transition. PMID- 29236809 TI - The discourse of "neutrality": attitudes of psychoanalysts during the military dictatorship. AB - This article examines the position of psychanalytical societies and Brazilian psychoanalysts affiliated to the International Psychoanalytical Association during the military dictatorship in the 1970s. It shows that the period was a time of extended ideas, featuring a large investment in private clinics and a resulting "marginalization" of the social universe doctrine. Through the writings of certain important members of the movement, it seeks to show how, based on the notions of "neutrality", of the primacy of internal reality to the detriment of external reality, and of investment in the "here and now" of the setting, these psychoanalysts chose to allow psychoanalysis to be divorced from politics. It concludes with arguments in support of the importance of the involvement of such professionals in political society. PMID- 29236810 TI - The saga of psychoanalysis in Eastern Europe: repression and rebirth in Hungary, and in former Czechoslovakia and Yugoslavia. AB - The paper shortly presents the early roles of Budapest, Prague, and Belgrade in the development of psychoanalytic movement in Central-Europe before the Second World War. Mapping this historical heritage, it suggests how psychoanalysts of former Soviet Bloc countries could restore their own psychoanalytic communities. The study investigates the consequences of these dictatorial and authoritarian regimes for psychoanalysis and for psychoanalysts focusing on similarities and differences in Hungary, in former Czechoslovakia, and Yugoslavia. Furthermore, it emphasizes the contribution of the international professional organizations - the International Psychoanalytic Association, and the European Psychoanalytic Federation - for reintegration of Budapest, Prague, and Belgrade to the international psychoanalytic community. PMID- 29236811 TI - An Italian peculiarity? Psychoanalysis, modernization and the sociology of consumption in 1960s Italy. AB - Psychoanalysis experienced a remarkable boom in 1960s Italy. One of the areas where psychoanalytic theory disseminated was the world of marketing and the sociology of consumption. Based on the case of the sociologist Francesco Alberoni, we can examine the impact of the theories of Melanie Klein for understanding the behavior of consumers. Similarly, Alberoni's work shows the concerns and uncertainties on the social modernization of Italy, and also raises questions on the specificities of the growing importance of psychoanalysis in Italy in the 1960s. PMID- 29236812 TI - "Freud for all:" psychoanalysis and mass culture in Chile, 1920-1950. AB - This article deals with the circulation and early spread of Freudianism in mass culture in Chilean society at the turn of the twentieth century. It documents the first references to Sigmund Freud in the Chilean media, the announcement of Freudian-style self-help classes, the appearance of psychoanalysts as characters in some fantasy novels, and the open lectures on psychoanalysis given by the first juvenile court judge in Santiago, the lawyer Samuel Gajardo Contreras. It explores the expectations projected onto Freudianism by the Chilean elite, and how Freud's theories contributed to a rethinking of childhood, the family and emotional life in Chile from 1920-1950. PMID- 29236813 TI - Psychoanalysis and neurosciences: fuzzy outlines? Notes on the notion of cerebral plasticity. AB - "Psychoanalysis versus psychiatry" and "unconscious versus brain" are classic oppositions between different perspectives on the human being and mental suffering. This article draws on certain elements of this discussion and reflects on how new ideas about the brain and biology favor closer interaction between psychoanalysis and the neurosciences. These questions are redefined through the notion of cerebral plasticity, by which the brain is open to interaction with the social environment and the influence of psychoanalytical therapy. Conceiving of the brain as a plastic organ allows for the possibility of interchange between psychoanalysis and the neurosciences. PMID- 29236814 TI - From psychic to somatic: notes on the reframing of the contemporary self. AB - This exploration of the shift from a psychological understanding of the self to a somatic/cerebral one centers on the duality between the Enlightened, rationalist worldview and the so-called Romantic worldview, characteristic of modern Western culture. The discussion seeks to show how physicalism draws support from a reframing of what L.F. Duarte has called a "relentless tension" between these two worldviews. It finds basis in examples where biotechnological interventions are linked to heavy affective, emotional investment in bodily experiences and puts forward the notion of a contemporary "vitalism," where the category "life" is understood as something that, while anchored in biological materialism, moves beyond it, meshing with fluid categories like happiness and well-being or with feelings and emotions that resist objective definition. PMID- 29236815 TI - [The reception of psychoanalysis in Rio de Janeiro: input for the debates on hysteria, nervousness and sexuality, 1908-1919]. AB - The research note presents the initial reception of psychoanalytic theory by psychiatric physicians in Rio de Janeiro in the first decades of the twentieth century before it became an institutionalized scientific tool. To understand the specificities of its reception, it examines, from the standpoint of the circulation of scientific knowledge and the process of adaptation to the local context, how the perceptions of psychiatrists regarding psychoanalytic theory were embedded in the then prevailing scientific theories and assumptions, initially in the dabates on the hysteria and nervousness categories. It also suggests that psychoanalytic theory should be used to deeply understand other debates of the time, such as sexuality and nervous diseases. PMID- 29236816 TI - Limb apraxia and aphasia. PMID- 29236817 TI - Progression of spinocerebellar ataxia type 2. What do we need to know? PMID- 29236818 TI - Limb apraxia in aphasic patients. AB - Limb apraxia is usually associated with left cerebral hemisphere damage, with numerous case studies involving aphasic patients. The aim of this study was to verify the occurrence of limb apraxia in aphasic patients and analyze its nature. This study involved 44 healthy volunteers and 28 aphasic patients matched for age and education. AH participants were assessed using a limb apraxia battery comprising subtests evaluating lexical-semantic aspects related to the comprehension/production of gestures as well as motor movements. Aphasics had worse performances on many tasks related to conceptual components of gestures. The difficulty found on the imitation of dynamic gesture tasks also indicated that there were specific motor difficulties in gesture planning. These results reinforce the importance of conducting limb apraxia assessment in aphasic patients and also highlight pantomime difficulties as a good predictor for semantic disturbances. PMID- 29236819 TI - Impact of disease duration on functional status of patients with spinocerebellar ataxia type 2. AB - OBJECTIVE: To correlate disease duration in spinocerebellar ataxia type 2 (SCA2) with disease severity, balance and functionality. METHOD: Sixteen SCA2 patients were analyzed for: disease duration, disease severity (SARA score), balance (Berg balance scale score) and functionality (FIM and Lawton scores). RESULTS: Greater severity was correlated with worse functionality (Lawton: r = -0.0561, FIM: r = 0.6402) and balance (r = -0.7188). Longer disease duration was correlated with greater severity (p = 0.0002) and reduced functionality (FIM: p = 0.005; Lawton: p = 0.0402) and balance (p = 0.0036). A year increase in disease duration corresponded to a 0.8-point increase on the SARA scale, a 1.38-point decrease in FIM score, a 2.30-point decrease on the Berg balance scale and a 0.45-point decrease on the Lawton scale. CONCLUSION: Longer disease duration in this series of SCA2 patients was correlated with greater disease severity, worse balance and greater functional dependency. PMID- 29236820 TI - Integrity of white matter structure is related to episodic memory performance in the low-educated elderly. AB - : The low-educated elderly are a vulnerable population in whom studying the role of white matter integrity on memory may provide insights for understanding how memory declines with aging and disease. METHODS: Thirty-one participants (22 women), 23 cognitively healthy and eight with cognitive impairment-no dementia, aged 80.4 +/- 3.8 years, with 2.2 +/- 1.9 years of education, underwent an MRI scan with diffusion tensor imaging (DTI) acquisition. We verified if there were correlations between the performance on the Brief Cognitive Screening Battery (BCSB) and the Rey Auditory Verbal Learning Test (RAVLT) with DTI parameters. RESULTS: The BCSB delayed recall task correlated with frontotemporoparietal connection bundles, with the hippocampal part of the cingulum bilaterally and with the right superior longitudinal fasciculus. The RAVLT learning and delayed recall scores also correlated with the hippocampal part of the cingulum bilaterally. CONCLUSIONS: Although preliminary, our study suggests that the integrity of white matter frontotemporoparietal fasciculi seems to play a role in episodic memory performance in the low-educated elderly. This finding opens opportunities to study potential targets for memory decline prevention in vulnerable populations. PMID- 29236821 TI - The critical influence of nocturnal breathing complaints on the quality of sleep after stroke: the Pittsburgh Sleep Quality Index and STOP-BANG. AB - In stroke patients particularly, many factors, such as sleep-related respiratory disturbances, can impair sleep. Cheap and easy-to-use tools have been created to identify sleep quality and sleep disturbances in patients after stroke. This study described the scores of the sleep apnea screening questionnaire - STOP-BANG - in patients after a stroke, and correlated the findings with sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI). The scores of the STOP BANG and PSQI were 4.3 +/- 1.8 and 76 +/- 3.9, respectively. The STOP-BANG scores were higher in poor sleepers (4.5 +/- 1.6 versus 3.5 +/- 1.9; p = 0.032). Logistic regression analysis was used to identify predictors of subjective sleep quality (PSQI) and the STOP-BANG as a predictor of poor quality sleep, with a relative risk of 1.6, controlled for age and sex. This study indicated that sleep quality was largely influenced by sleep breathing problems, which were well identified by the STOP-BANG, especially in younger stroke patients. PMID- 29236823 TI - Good sensory recovery of the hand in brachial plexus surgery using the intercostobrachial nerve as the donor. AB - OBJECTIVE: Restoration of the sensitivity to sensory stimuli in complete brachial plexus injury is very important. The objective of our study was to evaluate sensory recovery in brachial plexus surgery using the intercostobrachial nerve (ICBN) as the donor. METHODS: Eleven patients underwent sensory reconstruction using the ICBN as a donor to the lateral cord contribution to the median nerve, with a mean follow-up period of 41 months. A protocol evaluation was performed. RESULTS: Four patients perceived the 1-green filament. The 2-blue, 3-purple and 4 red filaments were perceptible in one, two and three patients, respectively. According to Highet's scale, sensation recovered to S3 in two patients, to S2+ in two patients, to S2 in six patients, and S0 in one patient. CONCLUSION: The procedure using the ICBN as a sensory donor restores good intensity of sensation and shows good results in location of perception in patients with complete brachial plexus avulsion. PMID- 29236822 TI - The relative frequency of common neuromuscular diagnoses in a reference center. AB - : The diagnostic procedure in neuromuscular patients is complex. Knowledge of the relative frequency of neuromuscular diseases within the investigated population is important to allow the neurologist to perform the most appropriate diagnostic tests. OBJECTIVE: To report the relative frequency of common neuromuscular diagnoses in a reference center. METHODS: A 17-year chart review of patients with suspicion of myopathy. RESULTS: Among 3,412 examinations, 1,603 (46.98%) yielded confirmatory results: 782 (48.78%) underwent molecular studies, and 821 (51.21%) had muscle biopsies. The most frequent diagnoses were: dystrophinopathy 460 (28.70%), mitochondriopathy 330 (20.59%), spinal muscular atrophy 158 (9.86%), limb girdle muscular dystrophy 157 (9.79%), Steinert myotonic dystrophy 138 (8.61%), facioscapulohumeral muscular dystrophy 99 (6.17%), and other diagnoses 261 (16.28%). CONCLUSION: Using the presently-available diagnostic techniques in this service, a specific limb girdle muscular dystrophy subtype diagnosis was reached in 61% of the patients. A neuromuscular-appropriate diagnosis is important for genetic counseling, rehabilitation orientation, and early treatment of respiratory and cardiac complications. PMID- 29236824 TI - Transtemporal amygdalohippocampectomy: a novel minimally-invasive technique with optimal clinical results and low cost. AB - : Mesial temporal sclerosis creates a focal epileptic syndrome that usually requires surgical resection of mesial temporal structures. OBJECTIVE: To describe a novel operative technique for treatment of temporal lobe epilepsy and its clinical results. METHODS: Prospective case-series at a single institution, performed by a single surgeon, from 2006 to 2012. A total of 120 patients were submitted to minimally-invasive keyhole transtemporal amygdalohippocampectomy. RESULTS: Of the patients, 55% were male, and 85% had a right-sided disease. The first 70 surgeries had a mean surgical time of 2.51 hours, and the last 50 surgeries had a mean surgical time of 1.62 hours. There was 3.3% morbidity, and 5% mild temporal muscle atrophy. There was no visual field impairment. On the Engel Outcome Scale at the two-year follow-up, 71% of the patients were Class I, 21% were Class II, and 6% were Class III. CONCLUSION: This novel technique is feasible and reproducible, with optimal clinical results. PMID- 29236826 TI - Hereditary spastic paraplegia from 1880 to 2017: an historical review. AB - The authors have constructed a brief timeline of major clinical research related to hereditary spastic paraplegia (HSP). This timeline summarizes the evolution of HSP research, from the first clinical descriptions by Adolf von Strumpell in 1880 to the present day, with the transformation of these diseases into a rapidly growing and heterogeneous group of neurogenetic diseases. PMID- 29236825 TI - The number of burr holes and use of a drain do not interfere with surgical results of chronic subdural hematomas. AB - : Burr hole evacuation has been the most frequently-used procedure for the treatment of chronic subdural hematomas (CSDH). OBJECTIVE: To evaluate whether the use of a drain and/or the number of burr holes for treatment of CSDH modifies the rates of recurrence and complications. METHODS: A retrospective review of 142 patients operated on because of CSDH, between 2006 and 2015, analyzing recurrence and complications of the use of one or two burr holes with or without the use of a drain. RESULTS: Thirty-seven patients had bilateral CSDH (26%) and 105 (73.9%) patients had unilateral CSDH. Twenty-two (59.4%) patients were given a drain and 15 (40.6%) were not. A total number of recurrences occurred in 22 (15.5%) patients and the total number of complications was in six (4.2%) patients. Mean follow-up time was 7.67 months. CONCLUSIONS: The number of burr holes and the use of the drain did not alter the rates of recurrence and complications in the treatment of CSDH. PMID- 29236827 TI - Conservative therapeutic management of carpal tunnel syndrome. AB - Carpal tunnel syndrome is the most prevalent nerve compression and can be clinically or surgically treated. In most cases, the first therapeutic alternative is conservative treatment but there is still much controversy regarding the most effective modality of this treatment. In this study, we critically evaluated the options of conservative treatment for carpal tunnel syndrome, aiming to guide the reader through the conventional options used in this therapy. PMID- 29236828 TI - Mary Broadfoot Walker: 83 years since a historical discovery. AB - Mary Broadfoot Walker was a Scottish physician who, in 1935, described in great detail the effect of an anticholinesterase drug (physostigmine) on the signs and symptoms of myasthenia gravis. An original five-minutes movie is available online and the skepticism of her contemporary British medical doctors is understandable when the drastic effect of the treatment is shown in this movie. What Mary Walker taught us, more than eight decades ago, about myasthenia gravis continues to be the basis of a pharmacological diagnostic test and treatment of this disease. PMID- 29236829 TI - Requiem for a neurologist: the funeral rites of Jean-Martin Charcot. AB - Jean-Martin Charcot, the founder of modern neurology and leading figure in international neurology in the 19th century, died on August 16, 1893, in the province of Morvan in the French countryside, at the age of 67. The funeral service was held in Paris at the La Salpetriere Hospital, and Charcot was buried in Montmartre cemetery in the same city. PMID- 29236830 TI - The charming physician (El medico encantador): neurological conditions in a short story by Silvina Ocampo. AB - The Argentinian author Silvina Ocampo (1903-1993) left us a vast body of works which are considered outstanding in many ways. In 1960, she published a short story, entitled "El medico encantador" (The Charming Physician), in the renowned literary magazine Sur. The central character of this piece is a family doctor named Albino Morgan, who had a secret truth: in any house he visited, all variety of disease also entered. He brought with him the viruses he disseminated. The narrator of this short story-one of his patients-describes four of Morgan's diseases. These imaginary neurological conditions allowed Ocampo to explore improbable situations in everyday life. PMID- 29236831 TI - Pontine calcification in late stage cerebellar multiple system atrophy: a marker of synucleinopathy neurodegeneration? PMID- 29236832 TI - Abnormal tongue features as a clinical clue for late-onset Pompe's disease. PMID- 29236833 TI - Terson's syndrome in the context of intracranial hemorrhage. PMID- 29236834 TI - Decompressive craniectomy for stroke in Brazil. PMID- 29236835 TI - Prospective studies on decompressive craniotomy for malignant MCA infarctions in Brazil: ready for prime time. PMID- 29236836 TI - Psychological aspects of patients with intestinal stoma: integrative review. AB - OBJECTIVE: to analyze evidences of psychological aspects of patients with intestinal stoma. METHOD: integrative review with search of primary studies in the PsycINFO, PubMed, CINAHL and WOS databases and in the SciELO periodicals portal. Inclusion criteria were: primary studies published in a ten-year period, in Portuguese, Spanish or English, available in full length and addressing the theme of the review. RESULTS: after analytical reading, 27 primary studies were selected and results pointed out the need to approach patients before surgery to prevent the complications, anxieties and fears generated by the stoma. The national and international scientific production on the experience of stomized patients in the perioperative moments is scarce. CONCLUSION: it is recomendable that health professionals invest in research on interventions aimed at the main psychological demands of stomized patients in the perioperative period, respecting their autonomy on the decisions to be made regarding their health/illness state and treatments. PMID- 29236837 TI - Construction and validation of a nursing care protocol in anesthesia. AB - OBJECTIVE: To construct and validate a nursing care protocol in anesthesia. METHOD: methodological study of face and content validation, judging clarity, relevance, pertinence and comprehensiveness of a care protocol, elaborated from the integrative review of previous literature and based on the conceptual model of assistance perioperative nursing of Castellanos and Jouclas. The protocol was evaluated by five anesthesiologists and nurses from the surgical center. The results were analyzed through the content validity index. RESULTS: among the 119 items assessed by experts, 11 (9.2%) instrument items presented content validity index of <80% and were changed. The items with disagreement were related to the selection and availability of materials and equipment, especially before anesthetic induction. The content validity index, obtained for the different items, proposed after the amendments mentioned, ranged from 80 to 100%, in the three periods of anesthesia, indicating the proper validity of the proposed content. CONCLUSION: the nursing care protocol in anesthesia was considered valid. PMID- 29236838 TI - Birth plan compliance and its relation to maternal and neonatal outcomes. AB - OBJECTIVE: to know the degree of fulfillment of the requests that women reflect in their birth plans and to determine their influence on the main obstetric and neonatal outcomes. METHOD: retrospective, descriptive and analytical study with 178 women with birth plans in third-level hospital. Inclusion criteria: low risk gestation, cephalic presentation, single childbirth, delivered at term. Scheduled and urgent cesareans without labor were excluded. A descriptive and inferential analysis of the variables was performed. RESULTS: the birth plan was mostly fulfilled in only 37% of the women. The group of women whose compliance was low (less than or equal to 50%) had a cesarean section rate of 18.8% and their children had worse outcomes in the Apgar test and umbilical cord pH; while in women with high compliance (75% or more), the percentage of cesareans fell to 6.1% and their children had better outcomes. CONCLUSION: birth plans have a low degree of compliance. The higher the compliance, the better is the maternal and neonatal outcomes. The birth plan can be an effective tool to achieve better outcomes for the mother and her child. Measures are needed to improve its compliance. PMID- 29236839 TI - Ostomy patients' perception of the health care received. AB - AIM: to describe ostomy patient's perception about health care received, as well as their needs and suggestions for healthcare system improvement. METHOD: qualitative phenomenological study was conducted, involving individual and semi structured interviews on the life experiences of 21 adults who had a digestive stoma. Participants were selected following a purposive sampling approach. The analysis was based on the constant comparison of the data, the progressive incorporation of subjects and triangulation among researchers and stoma therapy nurses. The software Atlas.ti was used. RESULTS: perception of health care received is closely related to the information process, as well as training for caring the stoma from peristomal skin to diet. It is worthy to point out the work performed by stoma care nurses ensuring support during all stages of the process. CONCLUSION: findings contribute to address the main patients' needs (better prepared nurses, shorter waiting lists, information about sexual relation, inclusion of family members all along the process) and recommendations for improving health care to facilitate their adaptation to a new status of having a digestive stoma. PMID- 29236840 TI - Clinical information systems for the management of tuberculosis in primary health care. AB - OBJECTIVE: to analyze the clinical information systems used in the management of tuberculosis in Primary Health Care. METHOD: descriptive, quantitative cross sectional study with 100 health professionals with data collected through a questionnaire to assess local institutional capacity for the model of attention to chronic conditions, as adapted for tuberculosis care. The analysis was performed through descriptive and inferential statistics. RESULTS: Nurses and the Community Health Agents were classified as having fair capacity with a mean of 6.4 and 6.3, respectively. The city was classified as having fair capacity, with a mean of 6.0 and standard deviation of 1.5. Family Health Units had higher capacity than Basic Health Units and Mixed Units, although not statistically relevant. Clinical records and data on tuberculosis patients, items of the clinical information systems, had a higher classification than the other items, classified as having fair capacity, with a mean of 7.3 and standard deviation of 1.6, and the registry of TB patients had a mean of 6.6 and standard deviation of 2.0. CONCLUSION: clinical information systems are present in the city, mainly in clinical records and patient data, and they have the contribution of professionals linked with tuberculosis patients. PMID- 29236841 TI - The utility of the records medical: factors associated with the medication errors in chronic disease. AB - OBJECTIVE: This study describes the development of the medication history of the medical records to measure factors associated with medication errors among chronic diseases patients in Diamantina, Minas Gerais. METHODS: retrospective, descriptive observational study of secondary data, through the review of medical records of hypertensive and diabetic patients, from March to October 2016. RESULTS: The patients the mean age of patient was 62.1 +/- 14.3 years. The number of basic nursing care (95.5%) prevailed and physician consultations were 82.6%. Polypharmacy was recorded in 54% of sample, and review of the medication lists by a pharmacist revealed that 67.0% drug included at least one risk. The most common risks were: drug-drug interaction (57.8%), renal risk (29.8%), risk of falling (12.9%) and duplicate therapies (11.9%). Factors associated with medications errors history were chronic diseases and polypharmacy, that persisted in multivariate analysis, with adjusted RP chronic diseases, diabetes RP 1.55 (95%IC 1.04-1.94), diabetes/hypertension RP 1.6 (95%CI 1.09-1.23) and polypharmacy RP 1.61 (95%IC 1.41-1.85), respectively. CONCLUSION: Medication errors are known to compromise patient safety. This has led to the suggestion that medication reconciliation an entry point into the systems health, ongoing care coordination and a person focused approach for people and their families. PMID- 29236842 TI - The moderator effect of sex on attitude toward communication, emotional intelligence, and empathy in the nursing field. AB - OBJECTIVES: to analyze differences in the variables for the object of this study (attitude toward communication, emotional intelligence, and empathy) according to sex; verify correlations among variables between men and women and analyze regression models according to sex. METHOD: the ATC was used to measure attitudes toward communication; the Jefferson Scale of Empathy was used to measure empathy; and the Trait Meta Mood Scale 24 was used to measure emotional intelligence. The sample was composed of 450 nurses working in 7 hospitals located in Valencia, Spain. The t-test for independent samples was used to verify whether there were statistically significant differences, together with a prior application of the Levene test to assess the equality of variances. The correlations were analyzed using Person's coefficient. Finally, the Beta coefficients of variables predicting ATC's dimensions were verified using hierarchical multiple linear regression according to sex. RESULTS: There are statistically significant differences based on sex for the variables, correlations and power of prediction. CONCLUSIONS: This study presents evidence on how the levels of variables (attitudes toward communication, EI, and empathy) vary among nurses according to sex, as well as the relationships established among such variables. PMID- 29236843 TI - Weakness acquired in the intensive care unit. Incidence, risk factors and their association with inspiratory weakness. Observational cohort study. AB - OBJECTIVE: This paper sought to determine the accumulated incidence and analyze the risk factors associated with the development of weakness acquired in the intensive care unit and its relationship to inspiratory weakness. METHODS: We conducted a prospective cohort study at a single center, multipurpose medical surgical intensive care unit. We included adult patients who required mechanical ventilation >= 24 hours between July 2014 and January 2016. No interventions were performed. Demographic data, clinical diagnoses, the factors related to the development of intensive care unit -acquired weakness, and maximal inspiratory pressure were recorded. RESULTS: Of the 111 patients included, 66 developed intensive care unit -acquired weakness, with a cumulative incidence of 40.5% over 18 months. The group with intensive care unit-acquired weakness were older (55.9 +/- 17.6 versus 45.8 +/- 16.7), required more mechanical ventilation (7 [4 - 10] days versus 4 [2 - 7.3] days), and spent more time in the intensive care unit (15.5 [9.2 - 22.8] days versus 9 [6 - 14] days). More patients presented with delirium (68% versus 39%), hyperglycemia > 3 days (84% versus 59%), and positive balance > 3 days (73.3% versus 37%). All comparisons were significant at p < 0.05. A multiple logistic regression identified age, hyperglycemia >= 3 days, delirium, and mechanical ventilation > 5 days as independent predictors of intensive care unit-acquired weakness. Low maximal inspiratory pressure was associated with intensive care unit-acquired weakness (p < 0.001), and the maximum inspiratory pressure cut-off value of < 36cmH2O had sensitivity and specificity values of 31.8% and 95.5%, respectively, when classifying patients with intensive care unit-acquired weakness. CONCLUSION: The intensive care unit acquired weakness is a condition with a high incidence in our environment. The development of intensive care unit-acquired weakness was associated with age, delirium, hyperglycemia, and mechanical ventilation > 5 days. The maximum inspiratory pressure value of >= 36cmH2O was associated with a high diagnostic value to exclude the presence of intensive care unit -acquired weakness. PMID- 29236844 TI - Functional evaluation of pediatric patients after discharge from the intensive care unit using the Functional Status Scale. AB - OBJECTIVE: To evaluate the functional status of pediatric patients after discharge from the pediatric intensive care unit using the Functional Status Scale and to compare the time of invasive mechanical ventilation, length of stay in the pediatric intensive care unit, and Pediatric Index of Mortality 2 results among individuals with different degrees of functional impairment. METHODS: A cross-sectional study was conducted on patients who were discharged from a pediatric intensive care unit. The functional evaluation by the Functional Status Scale was performed on the first day after discharge from the unit, and the Pediatric Index of Mortality 2 was used to predict the mortality rate at the time of admission to the pediatric intensive care unit. RESULTS: The sample consisted of 50 individuals, 60% of which were male, with a median age of 19 [6 - 61] months. The overall score of the Functional Status Scale was 11.5 [7 - 15], and the highest scores were observed in the "motor function" 3 [1 - 4] and "feeding" 4 [1 - 4] domains. Compared to patients who were not readmitted to the pediatric intensive care unit, patients who were readmitted presented a worse overall score (p = 0.01), worse scores in the "motor function" (p = 0.01), "feeding" (p = 0.02), and "respiratory" (p = 0.036) domains, and a higher mortality rate according to the Pediatric Index of Mortality 2 (p = 0.025). CONCLUSION: Evaluation of the functional status using the Functional Status Scale indicated moderate impairment in patients after discharge from the pediatric intensive care unit, mainly in the "motor function" and "feeding" domains; patients who were readmitted to the pediatric intensive care unit demonstrated worse overall functional, motor function, feeding and respiratory scores. Individuals with greater functional impairment had longer times of invasive mechanical ventilation and hospitalization in the pediatric intensive care unit. PMID- 29236845 TI - Comparison between conventional protective mechanical ventilation and high frequency oscillatory ventilation associated with the prone position. AB - OBJECTIVE: To compare the effects of high-frequency oscillatory ventilation and conventional protective mechanical ventilation associated with the prone position on oxygenation, histology and pulmonary oxidative damage in an experimental model of acute lung injury. METHODS: Forty-five rabbits with tracheostomy and vascular access were underwent mechanical ventilation. Acute lung injury was induced by tracheal infusion of warm saline. Three experimental groups were formed: healthy animals + conventional protective mechanical ventilation, supine position (Control Group; n = 15); animals with acute lung injury + conventional protective mechanical ventilation, prone position (CMVG; n = 15); and animals with acute lung injury + high-frequency oscillatory ventilation, prone position (HFOG; n = 15). Ten minutes after the beginning of the specific ventilation of each group, arterial gasometry was collected, with this timepoint being called time zero, after which the animal was placed in prone position and remained in this position for 4 hours. Oxidative stress was evaluated by the total antioxidant performance assay. Pulmonary tissue injury was determined by histopathological score. The level of significance was 5%. RESULTS: Both groups with acute lung injury showed worsening of oxygenation after induction of injury compared with the Control Group. After 4 hours, there was a significant improvement in oxygenation in the HFOG group compared with CMVG. Analysis of total antioxidant performance in plasma showed greater protection in HFOG. HFOG had a lower histopathological lesion score in lung tissue than CMVG. CONCLUSION: High-frequency oscillatory ventilation, associated with prone position, improves oxygenation and attenuates oxidative damage and histopathological lung injury compared with conventional protective mechanical ventilation. PMID- 29236846 TI - Neutral detergent fibre in piglet diets: digestibility, performance, and deposition of body nutrients. AB - A total 120 piglets with an average live weight of 7.00 kg, weaned at 21 days, were used to evaluate the effect of neutral detergent fibre levels on the digestibility of nutrients and energy from the diets, productive performance, and the composition and rate of deposition of nutrients and energy in the bodies of piglets in the nursery phase. The animals were distributed according to a randomized-block design into five treatments, which consisted of neutral detergent fibre levels, with six replicates and four animals per plot. A quadratic effect was detected for the digestibility coefficients of nutrients and energy, feed intake and weight gain. The increase in fibre level promoted a linear increase in fat content in the carcass, blood, and body, whereas the energy in the carcass, organs, and body showed an inverse response. The results showed a quadratic effect on the nutrient deposition rate in the carcass, organs and body. In conclusion, the best digestibility of nutrients and energy from the diet is obtained with 10-11.5% neutral detergent fibre, as higher weight gain and greater protein deposition in the body are achieved at neutral detergent fibre levels of 10.6% and 10.3%, respectively. PMID- 29236847 TI - Protocol for chromosome-specific probe construction using PRINS, micromanipulation and DOP-PCR techniques. AB - Chromosome-specific probes have been widely used in molecular cytogenetics, being obtained with different methods. In this study, a reproducible protocol for construction of chromosome-specific probes is proposed which associates in situ amplification (PRINS), micromanipulation and degenerate oligonucleotide-primed PCR (DOP-PCR). Human lymphocyte cultures were used to obtain metaphases from male and female individuals. The chromosomes were amplified via PRINS, and subcentromeric fragments of the X chromosome were microdissected using microneedles coupled to a phase contrast microscope. The fragments were amplified by DOP-PCR and labeled with tetramethyl-rhodamine-5-dUTP. The probes were used in fluorescent in situ hybridization (FISH) procedure to highlight these specific regions in the metaphases. The results show one fluorescent red spot in male and two in female X chromosomes and interphase nuclei. PMID- 29236848 TI - Histopatology of the reproductive tract of Nellore pubertal heifers with genital ureaplasmosis. AB - In order to study and characterize the lesions in the reproductive tract of Nellore heifers naturally infected with Ureaplasma diversum and presenting granular vulvovaginitis syndrome (GVS), fragments of uterine tube, uterus, cervix, vagina and vulva of 20 animals were evaluated. The macroscopic lesions of the vulvovaginal mucosa were classified in scores of "1" mild, until "4", severe inflammation and pustular or necrotic lesions. The histopathological evaluation was performed using scores of "1" to "4", according to the inflammatory alterations. The fragments with severe microscopic lesions (3 and 4) were from the uterine tubes and uterus, which showed leukocytes infiltration and destruction and/or necrosis of epithelium. Alterations in the lower reproductive tract fragments were mild, but characteristics of acute inflammatory processes. The histopathological findings of the reproductive tract of females naturally infected with Ureaplasma diversum are consistent with injuries that compromise the environment from the local where spermatozoa acquires ability to fertilize an oocyte until those where the oocyte is fertilized. Therefore, animals with GVS should be identified early in the herd, because, besides the reduction in the fertility rates caused by tissue damages, they can contribute to disseminate the microorganism. Key words: bovine, tissue evaluation, reproduction, Ureaplasma diversum. PMID- 29236849 TI - Natural decomposition of hornbeam wood decayed by the white rot fungus Trametes versicolor. AB - The impacts of white-rot fungi on altering wood chemistry have been studied mostly in vitro. However, in vivo approaches may enable better assessment of the nature of interactions between saprotrophic fungi and host tree in nature. Hence, decayed and sound wood samples were collected from a naturally infected tree (Carpinus betulus L.). Fruiting bodies of the white rot fungus Trametes versicolor grown on the same tree were identified using rDNA ITS sequencing. Chemical compositions (cellulose and lignin) of both sound and infected wood were studied. FT-IR spectroscopy was used to collect spectra of decayed and un-decayed wood samples. The results of chemical compositions indicated that T. versicolor reduced cellulose and lignin in similar quantities. Fungal activities in decayed wood causes serious decline in pH content. The amount of alcohol-benzene soluble extractives was severely decreased, while a remarkable increase was found in 1% sodium hydroxide soluble and hot water extractive contents in the decayed wood samples, respectively. FT-IR analyses demonstrated that T. versicolor causes simultaneous white rot in the hornbeam tree in vivo which is in line with in vitro experiments. PMID- 29236850 TI - Bioethanol production with different dosages of the commercial Acrylamide polymer compared to a Bioextract in clarifying sugarcane juice. AB - One of the most important steps is to clarify the juice, which are added synthetic polymer acrylamide base, aiming the fast settling of impurities present in the juice. However, this input is expensive and may have carcinogenic and neurotoxic actions to humans. The search for new natural flocculants that have similarity with the commercial product is of great value. A bioextract that may be promising and has coagulant action is the Moringa oleifera Lam. In this context, the objective of the research was to evaluate the consequences of the use of moringa seed extracts and various concentrations of commercial polymer, such as sedimentation aids in clarifying sugarcane juice in the ethanol production, comparing the efficiency of the bioextract moringa. In the treatment of the juice, excessive addition of flocculants can result in reduction of sugars. The bioflocculant moringa was similar in technological features and the fermentative viability compared to usual dose of commercial polymer in Brazil. The fermentation efficiency was also higher for this flocculant, followed by moringa extract. The results obtained in this research indicate potential to the moringa bioextract, particularly in countries where the doses of flocculants are higher than 5 mg.L-1. PMID- 29236851 TI - Tannic extract potential as natural wood preservative of Acacia mearnsii. AB - High toxicity of the preservatives most frequently used in wood treatment and the resulting risks of handling pose a threat to small producers and to the environment. In an attempt to mitigate these problems, the present study was conducted with the objective of evaluating the preservative effect of tannic extract on biodeterioration of Acacia mearnsii wood. For this purpose, untreated and preserved specimens, some with tannin extract and some with a preservative mixture based on CCB (Chromated Copper Borate), were submitted to accelerated rotting trials with the fungus that causes white rot (Pycnoporus sanguineus) for 16 weeks. The evaluations were made with a basis on weight loss and chemical components analysis, and they showed that the natural resistance of Acacia wood is moderate when exposed to the white rot fungus. The tannin concentrations showed similar effects to those of the CBB mixture in all evaluations, i.e., they significantly increased the biological resistance of the material, which started to be classified as very resistant to the fungus. Overall, the results suggest that tannin can be considered as a potential natural preservative product. PMID- 29236852 TI - Antifungal activities of the essential oil and its fractions rich in sesquiterpenes from leaves of Casearia sylvestris Sw. AB - Casearia genus (Salicaceae) is found in sub-tropical and tropical regions of the world and comprises about 160-200 species. It is a medicinal plant used in South America, also known as "guacatonga", "erva-de-tiu", "cafezinho-do-mato". In Brazil, there are about 48 species and 12 are registered in the State of Rio de Janeiro, including Casearia sylvestris Sw. There are many studies related to the chemical profile and cytotoxic activities of extracts from these plants, although few studies about the antifungal potential of the essential oil have been reported. In this work, we have studied the antifungal properties of the essential oil of C. sylvestris leaves, as well as of their fractions, against four yeasts (Saccharomyces cerevisae, Candida albicans, C. glabrata and C. krusei) for the first time. The chemical analysis of the essential oil revealed a very diversified (n = 21 compounds) volatile fraction composed mainly of non oxygenated sesquiterpenes (72.1%). These sesquiterpenes included alpha-humulene (17.8%) and alpha-copaene (8.5%) and the oxygenated sesquiterpene spathulenol (11.8%) were also identified. Monoterpenes were not identified. The fractions are mainly composed of oxygenated sesquiterpenes, and the most active fraction is rich in the sesquiterpene 14-hydroxy -9-epi-beta-caryophyllene. This fraction was the most effective in inhibiting the growth of three yeast strains. PMID- 29236853 TI - Pollen morphology and viability in Bromeliaceae. AB - Pollen morphology characterization is important in taxonomy, conservation and plant breeding, and pollen viability studies can support breeding programs. This study investigated pollen morphology and male fertility in 18 species of Bromeliaceae with ornamental potential. For morphological characterization, pollen grains were acetolyzed and characterization of exine was done using scanning and transmission electron microscopy. Pollen viability was investigated by in vitro germination and histochemical tests. Species belonging to Aechmea and Ananas genera presented medium size pollen, except for Ae. fasciata, with large pollen. Al. nahoumii, P. sagenarius and the Vriesea species analyzed showed large pollen, except for V. carinata, with very large pollen. Pollen of Aechmea, Ananas and P. sagenarius presented bilateral symmetry, diporate, exine varying from tectate to semitectate. Al. nahoumii and Vriesea species presented pollen with bilateral symmetry, monocolpate; exine was semitectate, reticulate and heterobrochate. Germination percentage and tube growth were greater in SM and BKM media. Histochemical tests showed pollen viability above 70% for all species, except for Ananas sp. (40%). Pollen morphology is important for the identification of species, especially in this family, which contains a large number of species. High rates of viability favor fertilization and seed production, essential for efficient hybrid production and conservation. PMID- 29236854 TI - A Novel Porous Diamond - Titanium Biomaterial: Structure, Microstructure, Physico Mechanical Properties and Biocompatibility. AB - With the aim of introducing permanent prostheses with main properties equivalent to cortical human bone, Ti-diamond composites were processed through powder metallurgy. Grade 1 titanium and mixtures of Ti powder with 2%, 5% and 10 wt% diamond were compacted at 100MPa, and then sintered at 1250 degrees C/2hr/10 6mbar. Sintered samples were studied in the point of view of their microstructures, structures, yield strength and elastic modulus. The results showed that the best addition of diamonds was 2 wt%, which led to a uniform porosity, yield strength of 370MPa and elastic modulus of 13.9 GPa. Samples of Ti and Ti-2% diamond were subjected to in vitro cytotoxicity test, using cultures of VERO cells, and it resulted in a biocompatible and nontoxic composite material. PMID- 29236855 TI - Biting midges (Diptera: Ceratopogonidae) from an urban forest fragment in Central Amazon (Brazil): Effects of opening areas on abundance, richness, and composition. AB - We assessed the immature stages of Ceratopogonidae (Diptera) in artificial containers in an urban forest fragment in Manaus (Brazil), including their behavioral, biological and ecological information. In addition, we evaluated the effects of deforestation in an open and forested area on Ceratopogonidae communities. Immatures were sampled between August 2012 and July 2014 in artificial containers installed in both habitat types. We collected 685 immatures of seven morpho-species of Bezzia Kieffer, Culicoides Latreille, Dasyhelea Kieffer, Forcipomyia Meigen, and Palpomyia Meigen. In the open area, we recorded higher temperature and electrical conductivity values than in the forested area; however, these variables did not differ between seasons. Water volume was higher in open area and in rainy season, while pH was similar in both areas and seasons. Species richness was higher in forested area, but did not differ between seasons. We did not record differences in abundance between areas or seasons. Community composition differed between areas, but not between seasons. We provide the first records of Culicoides (Hoffmania) insignis Lutz and C. (Haematomyidium) quasiparaensis Clastrier in artificial containers from the state of Amazonas. Our results suggest that the preservation of forested areas in Amazonas is fundamental for the maintenance of the life cycle of some species of Ceratopogonidae. PMID- 29236856 TI - Bird diversity along a gradient of fragmented habitats of the Cerrado. AB - Understanding the factors that affect biodiversity is of central interest to ecology, and essential to species conservation and ecosystems management. We sampled bird communities in 17 forest fragments in the Cerrado biome, the Central West region of Brazil. We aimed to know the communities structure pattern and the influence of geographical distance and environmental variables on them, along a gradient of fragmented habitats at both local and landscape scales. Eight structural variables of the fragments served as an environmental distance measurement at the local scale while five metrics served as an environmental distance measurement at the landscape scale. Species presence-absence data were used to calculate the dissimilarity index. Beta diversity was calculated using three indices (betasim, betanes and betasor), representing the spatial species turnover, nestedness and total beta diversity, respectively. Spatial species turnover was the predominant pattern in the structure of the communities. Variations in beta diversity were explained only by the environmental variables of the landscape with spatial configuration being more important than the composition. This fact indicates that, in Cerrado of Goias avian communities structure, deterministic ecological processes associated to differences in species responses to landscape fragmentation are more important than stochastic processes driven by species dispersal. PMID- 29236857 TI - Post-fire regeneration in seasonally dry tropical forest fragments in southeastern Brazil. AB - Seasonally dry tropical forest is one of the highly threatened biome. However, studies on the effect of fire on these tree communities are still scarce. In this context, a floristic and structural survey in three forest areas in the southeast of Brazil that were affected by fire between 14 and 25 years ago was performed with the objective of evaluating post-fire regeneration. In each site, five systematically placed plots (25 m x 25 m each) were established. The more recently burnt site had significantly lower values of richness and diversity than the other two sites. However, the sites did not differ in density and basal area. Annona dolabripetala, Astronium concinnum, Joannesia princeps and Polyandrococos caudescens were within the 10 most important species for the three sites. Comparing these data with adjacent mature forests, the results indicated differences both in structural and floristic aspects, suggesting that the time after fire was not sufficient for recuperation of these areas. The recovery process indicate at least 190 years for areas return to basal area values close to those observed in mature forests nearby. PMID- 29236859 TI - Mentha pulegium crude extracts induce thiol oxidation and potentiate hemolysis when associated to t-butyl hydroperoxide in human's erythrocytes. AB - Mentha pulegium (Lamiaceae) tea has been used as a traditional medicine; however, the modulatory effect of M. pulegium extracts on damage to human erythrocytes associated to t-butyl hydroperoxide (t-BHP) exposure remains to be investigated. Accordingly, we perform this study in order to test the hypothesis that aqueous and ethanolic extracts of M. pulegium could modulate the hemolysis associated to t-BHP exposure, non-protein thiol (NPSH) oxidation and lipid peroxidation (measured as thiobarbituric acid reactive substances - TBARS) in human erythrocytes. Samples were co-incubated with t-BHP (4 mmol/L) and/or aqueous or ethanolic extracts (10-1000 mg/mL) during 120 min to further analysis. We found that both extracts, when associated to t-BHP, potentiate NPSH oxidation and hemolysis. Moreover, both extracts significantly prevents against t-BHP-induced TBARS production. A significant correlation among hemolysis and NPSH levels was found. Taking together, our data points that the association of M. pulegium extracts with t-BHP culminates in toxic effect to exposed erythrocytes, besides its protective effect against t-BHP-induced TBARS production. So, we infer that the use of this extract may exert negative effect during painful crisis in sickle cell anemia. However, more studies are still necessary to better investigate/understand the mechanism(s) involved in the toxic effect resultant from this association. PMID- 29236858 TI - Effects of temperature on the feeding behavior of Alabama argillacea (Hubner) (Lepidoptera: Noctuidae) on Bt and non-Bt cotton plants. AB - The host acceptance behavior and environmental factors as temperature affect the feeding behavior of Lepidoptera pests. Thus, they must be considered in studies about the risk potential of resistance evolution. The current study sets the differences in the feeding behavior of neonate Alabama argillacea (Hubner) (Lepidoptera: Noctuidae) larvae exposed to Bt and non-Bt cotton plants, under different temperatures and time gap after hatching. Two cotton cultivars were used: the Bt (DP 404 BG - bollgard) and the non-transformed isoline, DP 4049. We found that the feeding behavior of neonate A. argillacea is significantly different between Bt and non-Bt cotton. Based on the number of larvae with vegetal tissue in their gut found on the plant and in the organza as well as on the amount of vegetal tissue ingested by the larvae. A. argillacea shows feeding preference for non-Bt cotton plants, in comparison to that on the Bt. However, factors such as temperature and exposure time may affect detection capacity and plant abandonment by the larvae and it results in lower ingestion of vegetal tissue. Such results are relevant to handle the resistance of Bt cotton cultivars to A. argillacea and they also enable determining how the cotton seeds mix will be a feasible handling option to hold back resistance evolution in A. argillacea populations on Bt cotton, when it is compared to other refuge strategies. The results can also be useful to determine which refuge distribution of plants is more effective for handling Bt cotton resistance to A. argillacea. PMID- 29236860 TI - Scale insects (Hemiptera: Coccoidea) associated with arabica coffee and geographical distribution in the neotropical region. AB - Coffee is one of the most important Brazilian agricultural commodities exported, and Minas Gerais and Espirito Santo States are the main coffee producers. Scale insects are important coffee pests, and 73 species of Cerococcidae (3), Coccidae (18), Diaspididae (6), Eriococcidae (1), Ortheziidae (3), Pseudococcidae (21), Putoidae (2) and Rhizoecidae (19) have been associated with roots, branches, leaves, flowers and fruits of Arabica coffee in the Neotropics. Eight species were found associated with Arabica coffee in Minas Gerais and Espirito Santo States in this study, and Coccidae was the most frequent family. Coccus alpinus, Cc. celatus, Cc. lizeri, Cc. viridis, and Saissetia coffeae (Coccidae) were found in both states; Alecanochiton marquesi, Pseudaonidia trilobitiformis (Diaspididae), and Dysmicoccus texensis (Pseudococcidae) were only found in Minas Gerais. Alecanochiton marquesi and P. trilobitiformis are first reported in Minas Gerais, and Cc. alpinus in Espirito Santo, on Arabica coffee. All scale insect species were associated with coffee leaves and branches, except D. texensis, associated with coffee roots. Fourty seven scale insect species have been found occurring in Brazilian Arabica coffee, and in Espirito Santo (28) and Minas Gerais (23). Widespread and geographical distribution of each species found are discussed. PMID- 29236861 TI - Plant species diversity in a Neotropical wetland: patterns of similarity, effects of distance, and altitude. AB - The Brazilian Pantanal is an extensive wetland with heterogeneous habitats, primarily due to the river-floodplain system and plants with differential adaptations and reproductive strategies. Factors such as altitude, distance among plant formations, and flood pulse must be considered to better understand its diversity. Aiming to assess the influence of biogeographic patterns in this system, we analyzed the floristic composition of six areas along the Paraguay River, including residual relieves, verifying the pattern of similarity, and effects of distance and altitude. We recorded 356 species in 87 families, mostly perennial (75%), and some annuals (15%) and pluriannuals (5%). Herbaceous plants were the most represented (48%), followed by arboreal (23%), shrubby (15%) and epiphytic (14%) habits, only 12% being endemic to Brazil. The studied areas showed low floristic similarity, but higher resemblance of species between neighboring areas, and no relation with altitude. The upper Paraguay River is diverse, with high spatial variability of species, predominantly perennial. The river-floodplain connectivity may be a determinant factor in species richness and occurrence of endemic species. PMID- 29236862 TI - Ecology and biotechnological potential of bacterial community from three marine sponges of the coast of Rio de Janeiro, Brazil. AB - Marine sponges has been a large reservoir of microbial diversity, with the presence of many species specific populations as well as producing biologically active compounds, which has attracted great biotechnological interest. In order to verify the influence of the environment in the composition of the bacterial community present in marine sponges and biotechnological potential of bacteria isolated from these organisms, three species of sponges and the waters surrounding them were collected in different beaches of Rio de Janeiro, Brazil. The profile of the bacterial community present in sponges and water was obtained by PCR-DGGE technique and the biotechnological potential of the strains isolated by producing amylase, cellulase, protease and biosurfactants. The results showed that despite the influence of the environment in the composition of the microbial community, studied marine sponges shown to have specific bacterial populations, with some, showing potential in the production of substances of biotechnological applications. PMID- 29236863 TI - Evaluation of phenolic compounds and lipid-lowering effect of Morus nigra leaves extract. AB - Morus nigra L. (Moraceae) is a tree known as black mulberry and the leaves are used in folk medicine in the treatment of diabetes, high cholesterol and menopause symptoms. The aim of this study was to evaluate the M. nigra leaves phytochemical profile in different extractions and the hypolipidemic effect of the infusion comparing to the fenofibrate. Morus nigra infusion (MN) showed higher amounts of phenolics and flavonoids (83.85 mg/g and 79.96 ug/g, respectively), as well as antioxidant activity (83.85%) than decoction or hydromethanolic extracts. Although, decoction showed the best result for ascorbic acid (4.35 mg/100 g) than hydromethanolic or infusion (2.51 or 2.13 mg/100 g, respectively). The phenolic acids gallic, chlorogenic and caffeic and the flavonoids quercetin, rutin and catechin were found in the M. nigra extracts. Hyperlipidemic rats treated with 100, 200 or 400 mg/kg of MN decreased serum cholesterol, triglycerides and normalized lipoproteins. Furthermore, MN inhibited lipid peroxidation in liver, kidney and brain of hyperlipidemic rats. This study provides evidence that M. nigra leaves extracts are rich in polyphenols, mainly chlorogenic acid, which normalized hyperlipidemic disturbance. The results suggest a potential therapeutic effect of the M. nigra leaves infusion on dislipidemic condition and related oxidative stress. PMID- 29236864 TI - Biomarkers as predictors of mortality in critically ill patients with solid tumors. AB - Biochemical markers produced by the affected organ or body in response to disease have gained high clinical value due to assess disease development and being excellent predictors of morbidity and mortality. The aim of this study is to analyze different biochemical markers in critically cancer patients and to determine which of them can be used as predictors of mortality. This is a prospective, cross-sectional study conducted at a University Hospital in Porto Alegre - RS. Screening was done to include patients in the study. Serum biochemical markers obtained in the first 24 hours of Intensive Care Unit hospitalization were analyzed. A second review of medical records occurred after three months objected to identify death or Unit discharged. A sample of 130 individuals was obtained (control group n = 65, study group n = 65). In the multivariate model, serum magnesium values OR = 3.97 (1.17; 13.5), presence of neoplasia OR = 2.68 (95% CI 1.13; 6.37) and absence of sepsis OR = 0.31 (95% CI 0.12; 0.79) were robust predictors of mortality. The association of solid tumors, sepsis presence and alteration in serum magnesium levels resulted in an increased chance of mortality in critically ill patients. PMID- 29236865 TI - Microscopic aspects of electrosensory system on the partially euryhaline lesser guitarfish. AB - The electrosensory system on elasmobranchs consists of subcutaneous electroreceptor organs known as ampullae of Lorenzini. The present study investigated the ampullae of Lorenzini morphology of the lesser guitarfish Zapteryx brevirostris, using light microscopy and scanning electron microscopy. The pore number found in the ventral skin surface is much higher than that found in the dorsal portion, characteristic of species that inhabit the euphotic zone. Under light microscopy it was possible to observe that the wall canal consists of a single layer of squamous epithelial cells. The canal features distal expansion, where the ampullae are located with up to six alveoli. The sensory epithelium of ampullae is composed by cubic cells, with oval nucleus, restricted to the interior of the alveoli. With analysis the clusters under scanning electron microscopy, it was possible to observe the structure and the random arrangement of individual ampullae, canals and nerves. The distribution of dorsal and ventral pores and ampullae in Z. brevirostris resembled those of the same family. The number of alveoli per ampullae was similar to that found in euryhaline elasmobranchs species, suggesting that the morphological organization in Z. brevirostris is linked to its possible evolutionary transitory position among batoids. PMID- 29236866 TI - Thiol/disulfide status regulates the activity of thiol-containing kinases related to energy homeostasis in rat kidney. AB - Considering that thiol-containing enzymes like kinases are critical for several metabolic pathways and energy homeostasis, we investigated the effects of cystine dimethyl ester and/or cysteamine administration on kinases crucial for energy metabolism in the kidney of Wistar rats. Animals were injected twice a day with 1.6 umol/g body weight cystine dimethyl ester and/or 0.26 umol/g body weight cysteamine from the 16th to the 20th postpartum day and euthanized after 12 hours. Pyruvate kinase, adenylate kinase, creatine kinase activities and thiol/disulfide ratio were determined. Cystine dimethyl ester administration reduced thiol/disulfide ratio and inhibited the kinases activities. Cysteamine administration increased the thiol/disulfide ratio and co-administration with cystine dimethyl ester prevented the inhibition of the enzymes. Regression between the thiol/disulfide ratio, and the kinases activities were significant. These results suggest that redox status may regulate energy metabolism in the rat kidney. If thiol-containing enzymes inhibition and oxidative stress occur in patients with cystinosis, it is possible that lysosomal cystine depletion may not be the only beneficial effect of cysteamine administration, but also its antioxidant and thiol-protector effect. PMID- 29236867 TI - Karyotype analysis in Bignonieae (Bignoniaceae): chromosome numbers and heterochromatin. AB - Chromosome numbers and heterochromatin banding pattern variability have been shown to be useful for taxonomic and evolutionary studies of different plant taxa. Bignonieae is the largest tribe of Bignoniaceae, composed mostly by woody climber species whose taxonomies are quite complicated. We reviewed and added new data concerning chromosome numbers in Bignonieae and performed the first analyses of heterochromatin banding patterns in that tribe based on the fluorochromes chromomycin A3 (CMA) and 4'-6-diamidino-2-phenylindole (DAPI). We confirmed the predominant diploid number 2n = 40, as well as variations reported in the literature (dysploidy in Mansoa [2n = 38] and polyploidy in Dolichandra ungis cati [2n = 80] and Pyrostegia venusta [2n = 80]). We also found a new cytotype for the genus Anemopaegma (Anemopaegma citrinum, 2n = 60) and provide the first chromosome counts for five species (Adenocalymma divaricatum, Amphilophium scabriusculum, Fridericia limae, F. subverticillata, and Xylophragma myrianthum). Heterochromatin analyses revealed only GC-rich regions, with six different arrangements of those bands. The A-type (one large and distal telomeric band) were the most common, although the presence and combinations of the other types appear to be the most promising for taxonomic studies. PMID- 29236868 TI - Richness and structure of ant assemblies (Hymenoptera: Formicidae) in Atlantic forest in southern Brazil. AB - Ant diversity is influenced by the structural complexity of the environment. Ants are thus an ecologically important group due to their potential to serve as indicators of environmental quality. The objective of this study was to evaluate ant diversity in areas with different land use histories and thus, within different stages of regeneration in the Permanent Preservation Area of the Foz do Chapeco Hydroelectric Plant reservoir. Ant assemblies among sample sites were compared using rarefaction analysis, and estimated richness, frequency of occurrence, and relative abundance were calculated. Associations between species and sample sites were evaluated using Principal Component Analysis (PCA). We identified 55 species in total from 24 genera, distributed among seven subfamilies. Eight species had positive associations with sample sites. Estimates indicated that ant richness may be up to 21.4% greater than that observed. This study presents an inventory of species capable of colonizing environments undergoing natural regeneration processes, and aids our understanding of ecological recovery dynamics in protected areas near hydroelectric plant reservoirs southern Brazil. PMID- 29236869 TI - Interactive effects of genotype x environment on the live weight of GIFT Nile tilapias. AB - In this paper, the existence of a genotype x environment interaction for the average daily weight in GIFT Nile tilapia (Oreochromis niloticus) in different regions in the state of Parana (Brazil) was analyzed. The heritability results were high in the uni-characteristic analysis: 0.71, 0.72 and 0.67 for the cities of Palotina (PL), Floriano (FL) and Diamond North (DN), respectively. Genetic correlations estimated in bivariate analyzes were weak with values between 0.12 for PL-FL, 0.06 for PL and 0.23 for DN-FL-DN. The Spearman correlation values were low, which indicated a change in ranking in the selection of animals in different environments in the study. There was heterogeneity in the phenotypic variance among the three regions and heterogeneity in the residual variance between PL and DN. The direct genetic gain was greater for the region with a DN value gain of 198.24 g/generation, followed by FL (98.73 g/generation) and finally PL (98.73 g/generation). The indirect genetic gains were lower than 0.37 and greater than 0.02 g/generation. The evidence of the genotype x environment interaction was verified, which indicated the phenotypic heterogeneity of the variances among the three regions, weak genetic correlation and modified rankings in the different environments. PMID- 29236870 TI - Accuracy of linear measurements performed with two imaging software in cone-beam computed tomography scans of dry human mandibles. AB - The present study aimed to assess the accuracy of linear measurements performed with two software packages in multislice (MSCT) and cone beam (CBCT) computed tomography (CT) images. The sample consisted of 10 human mandibles marked standardly 8 times with metallic orthodontic wires. The mandibles underwent both MSCT and CBCT scanning and were measured linearly and digitally with two software packages, namely Studio 3.1(r) (Anne Solutions(r), SP, Brazil) (ST) and Implant Viewer 2.817(r) (Anne Solutions(r), SP, Brazil) (IV). The linear measurements were the mandibular height (MH) and width (MW), and the distance from the alveolar ridge to the mandibular canal (AC). To validate the measurements, the mandibles were sectioned in the marked regions and measured with a digital caliper. Statistically significant differences were not observed between the measurements (MH, MW, and AC) taken digitally with the two software packages from images obtained from the two scanning modalities (MSCT and CBCT) and the measurements taken manually with a digital caliper (p>0.05). MSCT and CBCT images measured digitally with ST and IV software packages resulted in reliable outcomes when compared to measurements obtained manually. Both software and imaging modalities are reliably useful for planning surgical procedure in the dental practice. PMID- 29236871 TI - Evaluation of anaerobic threshold in non-pregnant and pregnant rats. AB - Several studies present different methodologies and results about intensity exercise, and many of them are performed in male rats. However, the impact of different type, intensity, frequency and duration of exercise on female rats needs more investigation. From the analysis of blood lactate concentration during lactate minimum test (LacMin) in the swimming exercise, the anaerobic threshold (AT) was identified, which parameter is defined as the transition point between aerobic and anaerobic metabolism. LacMin test is considered a good indicator of aerobic conditioning and has been used in prescription of training in different exercise modalities. However, there is no evidence of LacMin test in female rats. The objective was to determine AT in non-pregnant and pregnant Wistar rats. The LacMin test was performed and AT defined for mild exercise intensity was from a load equivalent to 1% of body weight (bw), moderate exercise as carrying 4% bw and severe intensity as carrying 7% bw. In pregnant rats, the AT was reached at a lower loading from 5.0% to 5.5% bw, while in non-pregnant the load was from 5.5% to 6.0% bw. Thus, this study was effective to identify exercise intensities in pregnant and non-pregnant rats using anaerobic threshold by LacMin test. PMID- 29236872 TI - Photosynthetic capacity and water use efficiency in Ricinus communis (L.) under drought stress in semi-humid and semi-arid areas. AB - Castor bean is one of the crops with potential to provide raw material for production of oils for biodiesel. This species possess adaptive mechanisms for maintaining the water status when subjected to drought stress. A better understanding these mechanisms under field conditions can unravel the survival strategies used by this species. This study aimed to compare the physiological adaptations of Ricinus communis (L.) in two regions with different climates, the semi-arid and semi-humid subject to water stress. The plants showed greater vapor pressure deficit during the driest hours of the day, which contributed to higher values of the leaf temperature and leaf transpiration, however, the VPD(leaf-air) had the greatest effect on plants in the semi-arid region. In both regions, between 12:00 p.m. and 2:00 p.m., the plants presented reduction in the rates of photosynthesis and intracellular CO2 concentration in response to stomatal closure. During the dry season in the semi-arid region, photoinhibition occurred in the leaves of castor bean between 12:00 p.m. and 2:00 p.m. These results suggest that castor bean plants possess compensatory mechanisms for drought tolerance, such as: higher stomatal control and maintenance of photosynthetic capacity, allowing the plant to survive well in soil with low water availability. PMID- 29236873 TI - Lychee (Litchi chinensis Sonn.) peel flour: effects on hepatoprotection and dyslipidemia induced by a hypercholesterolemic diet. AB - Dyslipidemias are associated with the incidence of cardiovascular diseases, obesity, diabetes, hypertension and hepatic steatosis, being the cause of morbidity and mortality. This study investigated the effects of lychee peel flour (PF) on serum levels of total cholesterol (TC), low-density lipoprotein (LDL-c), triacylglycerols (TAG) and various parameters related to obesity, in rats fed a hypercholesterolemic diet. Therefore, 20 male rats were used. In the first 21 days, the animals were fed a hypercholesterolemic diet, except for control group. In the following 21 days, their diets were modified, and they received a standard diet (Control); hypercholesterolemic (Hyper); hypercholesterolemic + 5% PF (PF5) and hypercholesterolemic + 10% PF (PF10). The results revealed that PF intake attenuated weight gain, reduced body mass index, glucose and the levels of TAG, TC, LDL-c, hepatic enzymes and leptin, besides the percentage of hepatic lipids, liver lipid peroxidation and frequency of severe steatosis. Histological studies of the aorta did not show the formation of the atheromatous plaque. These results reinforce its potential to reduce the risk of diseases associated with obesity. PMID- 29236874 TI - Physiological response and productivity of safflower lines under water deficit and rehydration. AB - Water deficit is one of the major stresses affecting plant growth and productivity worldwide. Plants induce various morphological, physiological, biochemical and molecular changes to adapt to the changing environment. Safflower (Carthamus tinctorius L.), a potential oil producer, is highly adaptable to various environmental conditions, such as lack of rainfall and temperatures. The objective of this work was to study the physiological and production characteristics of six safflower lines in response to water deficit followed by rehydration. The experiment was conducted in a protected environment and consisted of 30 days of water deficit followed by 18 days of rehydration. A differential response in terms of photosynthetic pigments, electrolyte leakage, water potential, relative water content, grain yield, oil content, oil yield and water use efficiency was observed in the six lines under water stress. Lines IMA 04, IMA 10, IMA 14 showed physiological characteristics of drought tolerance, with IMA 14 and IMA 16 being the most productive after water deficit. IMA 02 and IMA 21 lines displayed intermediate characteristics of drought tolerance. It was concluded that the lines responded differently to water deficit stress, showing considerable genetic variation and influence to the environment. PMID- 29236875 TI - Quality of the record of data on fatal workplace injuries in Brazil. AB - OBJECTIVE: To evaluate the quality of the data on fatal workplace injuries in Brazil, in the Mortality Information System (SIM) and the Information System of Notifiable Diseases (SINAN-AT), analyzing the spatial and temporal distribution between 2007 and 2012. METHODS: We identified fields related to fatal workplace injuries, which were examined for completeness and the use of the "ignored" option. From the SIM, we extracted the records of deaths from external causes, which require the completing of the field about their relation with work. From the SINAN, we analyzed the field, which allows us to identify fatal cases among s severe workplace injuries. RESULTS: In the SIM, from 469,121 records, the field was left unfilled or filled as ignored in 84.2% of them; the Brazilian region with the highest proportion was the Northeast (79.1%), from which the state of Alagoas (94.4%) had the highest amount. There was a 5.5% decreasing trend between 2007 (86.6%) and 2012 (81.8%). Among the 251,681 records found in the SINAN-AT, 28.3% had unfilled or ignored responses for , varying from 39.7% in 2007 to 23.2% in 2012, a 41.6% decrease. CONCLUSIONS: The quality of the records on the fields of interest needed to identify fatal workplace injuries is poor in the SIM, but gradually improving. Recording quality was better for SINAN-AT, which has also been strongly getting better lately. PMID- 29236876 TI - The process of implementation of emergency care units in Brazil. AB - OBJECTIVE: To analyze the process of implementation of emergency care units in Brazil. METHODS: We have carried out a documentary analysis, with interviews with twenty-four state urgency coordinators and a panel of experts. We have analyzed issues related to policy background and trajectory, players involved in the implementation, expansion process, advances, limits, and implementation difficulties, and state coordination capacity. We have used the theoretical framework of the analysis of the strategic conduct of the Giddens theory of structuration. RESULTS: Emergency care units have been implemented after 2007, initially in the Southeast region, and 446 emergency care units were present in all Brazilian regions in 2016. Currently, 620 emergency care units are under construction, which indicates expectation of expansion. Federal funding was a strong driver for the implementation. The states have planned their emergency care units, but the existence of direct negotiation between municipalities and the Union has contributed with the significant number of emergency care units that have been built but that do not work. In relation to the urgency network, there is tension with the hospital because of the lack of beds in the country, which generates hospitalizations in the emergency care unit. The management of emergency care units is predominantly municipal, and most of the emergency care units are located outside the capitals and classified as Size III. The main challenges identified were: under-funding and difficulty in recruiting physicians. CONCLUSIONS: The emergency care unit has the merit of having technological resources and being architecturally differentiated, but it will only succeed within an urgency network. Federal induction has generated contradictory responses, since not all states consider the emergency care unit a priority. The strengthening of the state management has been identified as a challenge for the implementation of the urgency network. PMID- 29236877 TI - Aedes aegypti breeding site in an underground rainwater reservoir: a warning. AB - We describe the discovery of Aedes aegypti underground breeding site in the Pinheiros neighborhood of Sao Paulo, SP, during an entomological survey program performed in 2016. Even with intense surveillance and vector control, large numbers of mosquitoes were present in this area. A detailed investigation allowed for the detection of Ae. aegypti in an underground reservoir used for rainwater storage. After the implementation of protection screens in the accesses, the presence of the vector was no longer detected. In this study, we discuss the frequent use of this type of reservoir structure and its risk for mosquito production. PMID- 29236878 TI - Analysis of possible factors of vocal interference during the teaching activity. AB - OBJECTIVE: To measure the risk of dysphonia in teachers, as well as investigate whether the perceptual-auditory and acoustic aspects of the voice of teachers in situations of silence and noise, the signal-to-noise ratio, and the noise levels in the classroom are associated with the presence of dysphonia. METHODS: This is an observational cross-sectional research with 23 primary and secondary school teachers from a private school in the municipality of Sao Paulo, Brazil, divided into the groups without dysphonia and with dysphonia. We performed the following procedures: general Dysphonia Risk Screening Protocol (General-DRSP) and complementary to speaking voice - teacher (Specific-DRSP), voice recording during class and in an individual situation in a silent room, and measurement of the signal-to-noise ratio and noise levels of classrooms. RESULTS: We have found differences between groups regarding physical activity (General-DRSP) and particularities of the profession (Specific-DRSP), as well as in all aspects of the perceptual-auditory vocal analysis. We have found signs of voice wear in the group without dysphonia. Regarding the vocal resources in the situations of noise and silence, we have identified a difference for the production of abrupt vocal attack and the tendency of a more precise speech in the situation of noise. Both the signal-to-noise ratio and the room noise levels during class were high in both groups. CONCLUSIONS: Teachers in both groups are at high risk for developing dysphonia and have negative vocal signals to a greater or lesser extent. Signal to-noise ratio was inadequate in most classrooms, considering the standards for both children with normal hearing and with hearing loss, as well as equivalent noise levels. PMID- 29236879 TI - Integrality of the therapeutic and pharmaceutical care: a necessary debate. AB - The controversy surrounding the different interpretations on the integrality of therapeutic and pharmaceutical care has led to the delimitation of its scope by a law, but the issue has not been completely pacified. As a contribution to this debate, we aim to discuss the challenges to ensure the integrality of the therapeutic and pharmaceutical care, based on a conceptual approach on the meanings of integrality in the Brazilian Unified Health System (SUS). We identified important challenges to ensure the integrality of the therapeutic and pharmaceutical care in the SUS. These challenges are related to professional practices, the organization of actions and services, and the governmental response to health problems or to the treatment of specific population groups. For this end, governments need to carry out structuring actions and be efficient in using available resources so that existing problems can be overcome. PMID- 29236880 TI - Urban violence is the biggest cause of fatal work-related accidents in Brazil. AB - OBJECTIVE: To quantify the occurrence of deaths directly associated with urban violence among fatal work-related accidents. METHODS: Verbal autopsies were performed with the relatives and coworkers of residents of Campinas, state of Sao Paulo, Brazil, who died from external causes in 2015. We have also analyzed police reports and reports of the Legal Medical Institute related to these deaths. RESULTS: We have identified 82 fatal work-related accidents in Campinas in 2015, of which 25 were murders, 35 were traffic accidents not directly related to work activities, and three were suicides at work. The proportional mortality rate for homicides, traffic accidents, and suicides among fatal work-related accidents was estimated at 30.5%, 42.7%, and 3.7%, respectively. CONCLUSIONS: Urban violence accounted for three-fourths of the fatal work-related accidents recorded in the period studied. PMID- 29236881 TI - Public policies on healthcare-associated infections: a Brazil and UK case study. AB - To summarize the historical events and drivers underlying public policy for the prevention and control of healthcare-associated infections in Brazil and in the United Kingdom. In doing so, the article aims to identify lessons and recommendations for future development of public policy. The analysis is based on a historical overview of national healthcare-associated infections programs taken from previously published sources. Findings highlight how the development of healthcare-associated infections prevention and control policies followed similar trajectories in Brazil and the United Kingdom. This can be conceptualized around four sequential phases: Formation, Consolidation, Standardization, and Monitoring and Evaluation. However, while we identified similar phases of development in Brazil and the United Kingdom, it can be seen that the former entered each stage around 20 years after the latter. PMID- 29236882 TI - Narratives of family members on the suicide of older adults in an Amazonian metropolis. AB - OBJECTIVE: To analyze the narratives of family members on the suicide of older adults in Manaus, State of Amazonas, Brazil. METHODS: This is a qualitative study of the narratives of eight older adults, who committed suicide in the period of 2001-2012. In the analytic-interpretative process, we have tried to perform the hermeneutic double exercise: to interpret the interpretation of narrators. We have used as theoretical references authors who have investigated suicide from the perspective of gender and its correlations with the sociofamiliar context and with mental disorders. RESULTS: The family members would conceive the suicide of the older adults as related to losses, which would occur in a strained sociofamiliar scenario, leading to the appearance of psychopathological situations that, if not properly followed, would result in death. There would also be something inexorable in this sequence of events. The older adults, by the very time of their life, would tend to accumulate losses of different aspects in their trajectory. Their rigor and other relational limitations would simultaneously stress family relationships, favoring conflicts, and hinder adherence to treatment. This model of understanding, which has a wide support in the hegemonic medical-psychological discourse, in a sense minimizes possible self or heteroaccusations directed at family members. CONCLUSIONS: Special attention should be given to identify the older adults who present losses, family conflicts, and signs of psychopathology and who do not follow-up psychosocial care services. Strategies to help older adults handle family conflicts and losses, empowering them, should be developed and made available by intersectoral actions. The adequate treatment of psychopathological conditions should be implanted in a context in which active search mechanisms also existed for older adults who abandoned follow-up. The implementation of these actions is a challenge to be faced in Manaus, State of Amazonas, Brazil, where there is a low availability of psychosocial care services, which are not articulated with specialized care services in tertiary medical conditions, and there is still low coverage by the basic care. PMID- 29236883 TI - Violence in public transportation: an approach based on spatial analysis. AB - OBJECTIVE: To carry out a spatial analysis of the occurrence of acts of violence (specifically robberies) in public transportation, identifying the regions of greater incidence, using geostatistics, and possible causes with the aid of a multicriteria analysis in the Geographic Information System. METHODS: The unit of analysis is the traffic analysis zone of the survey named Origem-Destino, carried out in Salvador, state of Bahia, in 2013. The robberies recorded by the Department of Public Security of Bahia in 2013 were located and made compatible with the limits of the traffic analysis zones and, later, associated with the respective centroids. After determining the regions with the highest probability of robbery, we carried out a geographic analysis of the possible causes in the region with the highest robbery potential, considering the factors analyzed using a multicriteria analysis in a Geographic Information System environment. RESULTS: The execution of the two steps of this study allowed us to identify areas corresponding to the greater probability of occurrence of robberies in public transportation. In addition, the three most vulnerable road sections (Estrada da Liberdade, Rua Pero Vaz, and Avenida General San Martin) were identified in these areas. In these sections, the factors that most contribute with the potential for robbery in buses are: F1 - proximity to places that facilitate escape, F3 - great movement of persons, and F2 - absence of policing, respectively. CONCLUSIONS: Indicator Kriging (geostatistical estimation) can be used to construct a spatial probability surface, which can be a useful tool for the implementation of public policies. The multicriteria analysis in the Geographic Information System environment allowed us to understand the spatial factors related to the phenomenon under analysis. PMID- 29236884 TI - Prevalence of common mental disorders among sugarcane workers. AB - OBJECTIVE: To estimate the prevalence of common mental disorders and to analyze the associated factors in migrant and sugarcane workers. METHODS: This is a cross sectional study carried out with 110 workers. Common mental disorders were evaluated using the Self-Reporting Questionnaire (SRQ-20), and sociodemographic, occupational, and lifestyle variables were studied. The CAGE questionnaire was used to detect the abuse of alcoholic beverages. RESULTS: The prevalence of common mental disorders affected 40% of the workers and the association showed statistical significance for the positive result of the CAGE test, sickness, absence from work, and medical care during the harvest period. CONCLUSIONS: The suspected cases of problem drinkers and the control mechanisms used by the mill for workers who miss work or become ill are factors that can cause common mental disorders. PMID- 29236885 TI - Arquivos de Neuro-Psiquiatria has new Editors. PMID- 29236886 TI - Educational status influences cognitive-motor learning in older adults: going to university provides greater protection against aging than going to high school. AB - OBJECTIVE: To investigate if middle-aged and older adults with a higher education would differ from those with an average education in cognitive-motor tasks involving lower limb function. METHODS: A walking version of the Trail Making Test (Walking Executive Function Task, [WEFT]) was used. Eighty volunteers (40: 50-65 years; 40: 66-80 years) were subdivided into average (6-11years of education) and higher education (12-17 years). They received two training sessions (session 1: eight repetitions, session 2: four repetitions), with a one week-interval between them. The Timed Up and Go (TUG) test was performed before and after the training. RESULTS: Volunteers with an average education showed longer times on the WEFT than those with a higher education. Older adults showed lower retention than middle-aged adults (p < 0.001). The TUG was faster after the WEFT training (p < 0.001). CONCLUSION: The impact of education was observed when locomotion was associated with cognitive tasks. Average education resulted in poorer performance and learning than higher education, mainly in older adults. Gait speed increased after training. PMID- 29236888 TI - Convexity subarachnoid hemorrhage: clinical features and etiology of an Argentinian cohort. AB - : Nontraumatic convexity subarachnoid hemorrhage is an increasingly recognized subtype of subarachnoid bleeding. OBJECTIVE: Our aim was to describe the etiology and clinical features of a cohort of patients with convexity subarachnoid hemorrhage. METHODS: We retrospectively analyzed all cases of convexity subarachnoid hemorrhage admitted to our hospital between January 2012 and April 2017. Demographic features, clinical characteristics, complementary investigations, etiology and mortality were assessed. Twenty patients (65% females) were identified. Mean age: 53 years (range, 15-86 years). RESULTS: Symptoms on admission: headache (65%), sensory and/or motor symptoms (50%) and seizures (35%). Commonest causes: cerebral vein thrombosis (20%), reversible cerebral vasoconstriction syndrome (20%) and cerebral amyloid angiopathy (20%). Two patients died. CONCLUSION: Convexity subarachnoid hemorrhage may be related to a wide spectrum of etiologies. In our patients, an increased prevalence of cerebral vein thrombosis was observed. Mortality was low and not related to the bleeding itself. PMID- 29236887 TI - Pilates and aerobic training improve levels of depression, anxiety and quality of life in overweight and obese individuals. AB - OBJECTIVE: To compare the effects of Pilates and walking on quality of life, depression, and anxiety levels. METHODS: Sixty-three overweight/obese participants were randomly divided into: control (n = 20), walking (n = 21), and Pilates (n = 22) groups. Pilates and walking groups attended eight weeks of 60 minute exercise sessions three times per week. Quality of life, depression, and state- and trait-anxiety levels were evaluated before and after eight weeks of training. RESULTS: Scores of quality of life, depression, and trait-anxiety improved in the Pilates and walking groups. State-anxiety levels improved only in the walking group. CONCLUSION: Pilates and walking positively impact quality of life, depression and anxiety. The Pilates method could be used as an alternative to improve mood disorders in overweight/obese individuals. PMID- 29236889 TI - Syndromic craniosynostosis: neuropsycholinguistic abilities and imaging analysis of the central nervous system. AB - OBJECTIVE: To characterize patients with syndromic craniosynostosis with respect to their neuropsycholinguistic abilities and to present these findings together with the brain abnormalities. METHODS: Eighteen patients with a diagnosis of syndromic craniosynostosis were studied. Eight patients had Apert syndrome and 10 had Crouzon syndrome. They were submitted to phonological evaluation, neuropsychological evaluation and magnetic resonance imaging of the brain. The phonological evaluation was done by behavioral observation of the language, the Peabody test, Token test and a school achievement test. The neuropsychological evaluation included the WISC III and WAIS tests. RESULTS: Abnormalities in language abilities were observed and the school achievement test showed abnormalities in 66.67% of the patients. A normal intelligence quotient was observed in 39.3% of the patients, and congenital abnormalities of the central nervous system were observed in 46.4% of the patients. CONCLUSION: Abnormalities of language abilities were observed in the majority of patients with syndromic craniosynostosis, and low cognitive performance was also observed. PMID- 29236890 TI - Phrenic nerve conduction studies: normative data and technical aspects. AB - OBJECTIVE: The aim of the present study was to define normative data of phrenic nerve conduction parameters of a healthy population. METHODS: Phrenic nerve conduction studies were performed in 27 healthy volunteers. RESULTS: The normative limits for expiratory phrenic nerve compound muscle action potential were: amplitude (0.47 mv - 0.83 mv), latency (5.74 ms - 7.10 ms), area (6.20 ms/mv - 7.20 ms/mv) and duration (18.30 ms - 20.96 ms). Inspiratory normative limits were: amplitude (0.67 mv - 1.11 mv), latency (5.90 ms - 6.34 ms), area (5.62 ms/mv - 6.72 ms/mv) and duration (13.77 ms - 15.37 ms). CONCLUSION: The best point of phrenic nerve stimulus in the neck varies among individuals between the medial and lateral border of the clavicular head of the sternocleidomastoid muscle and stimulation of both sites, then choosing the best phrenic nerve response, seems to be the appropriate procedure. PMID- 29236891 TI - High expression of XIAP and Bcl-2 may inhibit programmed cell death in glioblastomas. AB - : Glioblastoma (GBM) is the most malignant glioma and represents 29% of all brain tumors. Tumorigenesis is intimately connected with characteristics acquired in the physiologic pathway of cellular death. OBJECTIVE: In the present study, the expression of anti-apoptotic (XIAP and Bcl-2) and apoptotic (cytochrome C, caspase 9, APAF-1), caspase 3 and the Smac/DIABLO genes related to the apoptosis pathway were evaluated in 30 samples of glioblastoma. METHODS: The gene expression was evaluated in 30 glioblastomas (WHO grade IV) and compared to 10 white matter control samples with real-time PCR. RESULTS AND CONCLUSION: There were higher expressions of XIAP (p = 0.0032) and Bcl-2 (p = 0.0351) in the glioblastoma samples compared to the control samples of normal brain. These results raise the question of whether Bcl-2 and XIAP genes can be responsible for the inhibition of programmed cell death in glioblastomas. Moreover, they provide additional information capable of allowing the development of new target therapy strategies. PMID- 29236892 TI - Joinville stroke biobank: study protocol and first year's results. AB - : Aiming to contribute to studies that use detailed clinical and genomic information of biobanks, we present the initial results of the first Latin American Stroke Biobank. METHODS: Blood samples were collected from patients included in the Joinville Stroke Registry and four Brazilian cities. Demographic socio-economic data, cardiovascular risk factors, Causative Classification System for Ischemic Stroke, Trial of Org 10172 in Acute Stroke Treatment and National Institutes of Health scores, functional stroke status (modified Rankin) and brain images were recorded. Additionally, controls from both geographic regions were recruited. High-molecular-weight genomic DNA was obtained from all participants. RESULTS: A total of 2,688 patients and 3,282 controls were included. Among the patients, 76% had ischemic stroke, 12% transient ischemic attacks, 9% hemorrhagic stroke and 3% subarachnoid hemorrhage. Patients with undetermined ischemic stroke were most common according the Trial of Org 10172 in Acute Stroke Treatment (40%) and Causative Classification System for Ischemic Stroke (47%) criteria. A quarter of the patients were under 55 years of age at the first-ever episode. CONCLUSIONS: We established the Joinville Stroke Biobank and discuss its potential for contributing to the understanding of the risk factors leading to stroke. PMID- 29236893 TI - Pan, Syrinx and syringomyelia. AB - Many myths and legends have had a deep influence on modern language, and on modern medical vernacular. The terms "syrinx" and "panic"are two of the most characteristic examples and their use in neurology and other specialties is well known. This article reviews the history of these words in Greek mythology and their use in modern medicine. It is known by very few that clinical symptoms or conditions, such as syringomyelia and panic attacks, have a mythological origin in their definition and naming. PMID- 29236894 TI - What do Flaubert, Dostoevsky and Machado de Assis have in common with neurology? AB - The Frenchman Gustave Flaubert, the Russian Fyodor Dostoevsky and the Brazilian Machado de Assis are known for their immeasurable contributions to literature. However, what most people do not know is that all three authors suffered from epilepsy and were affected by their neurological condition in different ways. We offer a short description of how epilepsy influenced their lives, how they dealt with it and how their neurological condition was present in their novels and correspondence. Their lives are excellent examples of how intimately neurology can be entwined in art and history, and provide an important perspective on patients with epilepsy. PMID- 29236895 TI - Multiple sporadic cerebral cavernous malformations. PMID- 29236896 TI - Sulcal hyperintensity mimicking subarachnoid hemorrhage in the context of hemiplegic migraine. PMID- 29236897 TI - Central nervous system vasculitis in a patient with HIV infection: a diagnostic challenge. PMID- 29236898 TI - In vitro analysis of a local polymeric device as an alternative for systemic antibiotics in Dentistry. AB - The development of a biodegradable material with antimicrobial properties for local applications is required in the prevention and treatment of infectious diseases. The objective of this study was to produce blends of poly-L-lactide acid (PLLA) synthetic polymer associated with several antimicrobials, as an alternative in the prevention and treatment of infections, as well as to evaluate its cytotoxicity, release of antimicrobials and inhibit bacteria growth. Blends of PLLA added with 20% Amoxicillin, Metronidazole, Clindamycin or Azithromicyn were used to produce Films (F) or Meshs (M) by casting and electrospinning methods, respectively. Standardized discs of the films and meshs were stored in buffer solutions (pH 5 or 7.4) and aliquots were analyzed by high performance chromatography (HPLC) during 168 hours. Cytotoxicity on human gingival fibroblasts was tested after 24, 48 and 72h by MTT reaction. The antimicrobial capacity was determined against P. gingivalis and S. pyogenes. The specimens were weighed after 3 and 6 months of storage for degradation analysis. SEM was performed to control interfaces and degradation. Antimicrobials presented a continuous and exponential drug release. Analysis showed that both M and F were able to inhibit S. pyogenes and P. gingivalis growth, indicating the release of active antimicrobial agents. The products were not toxic to the fibroblasts. Amoxicillin-film showed more degradation than PLLA at both pHs (p < 0.05), whereas Azithromycin-meshes were more degraded than PLLA at pH 7.4 (p < 0.05). PLLA association with antimicrobials is biocompatible and may represent a potential tool for the local delivery of antimicrobials. PMID- 29236899 TI - Mechanical behavior of yttria-stabilized tetragonal zirconia polycrystal: Effects of different aging regimens. AB - This study aimed to characterize and compare the effect of different aging regimens on surface characteristic (topography and roughness), structural stability (phase transformation) and mechanical performance (Weibull analysis) of a Y-TZP ceramic. Discs (15 * 1.2 mm; VITA In-Ceram YZ) were prepared according to ISO 6872-2015 for biaxial flexural strength testing and randomly assigned into five groups (n = 30): as-sintered, no aging treatment (CTRL); 20 h in autoclave at 134 degrees C, 2 bar pressure (AUT); intermittent mechanical loading at 20 Hz/106 load pulses (MechLoad); AUT followed by MechLoad (AUT+MechLoad); and storage in distilled water at 37 degrees C, for 1 year (STO). The following analyses were performed: roughness (n = 30), surface topography (n = 2), phase transformation (n = 2) and biaxial flexure strength (n = 30). Phase transformation (increase of m-phase content) was shown to be a spontaneous, unavoidable and time-dependent process, occurring even under ambient conditions (dry storage after 1 year = 6.0% increase), and is considerably accelerated in the presence of moisture (STO = 17.6%; AUT= 63.1%; and AUT+MechLoad = 59.9%). For roughness parameters, only Ra was affected by aging, and the highest values were observed for AUT+MechLoad (0.25 +/- 0.07 um). For Weibull analysis, structural reliability (Weibull moduli) and characteristic strength were not impaired after aging, and some aging conditions led to increased values (highest weibull moduli in AUT, and highest characteristic strength in STO). Phase transformation proves to be a time-dependent spontaneous mechanism that is accelerated in the presence of different stimuli. However, none of the aging regimens had a negative effect on the characteristic strength and structural reliability of Y-TZP ceramic. PMID- 29236900 TI - Influence of implantoplasty on stress distribution of exposed implants at different bone insertion levels. AB - This study evaluated the effect of implantoplasty on different bone insertion levels of exposed implants. A model of the Bone Level Tapered implant (Straumann Institute, Waldenburg, Switzerland) was created through the Rhinoceros software (version 5.0 SR8, McNeel North America, Seattle, WA, USA). The abutment was fixed to the implant through a retention screw and a monolithic crown was modeled over a cementation line. Six models were created with increasing portions of the implant threads exposed: C1 (1 mm), C2 (2 mm), C3 (3 mm), C4 (4 mm), C5 (5 mm) and C6 (6 mm). The models were made in duplicates and one of each pair was used to simulate implantoplasty, by removing the threads (I1, I2, I3, I4, I5 and I6). The final geometry was exported in STEP format to ANSYS (ANSYS 15.0, ANSYS Inc., Houston, USA) and all materials were considered homogeneous, isotropic and linearly elastic. To assess distribution of stress forces, an axial load (300 N) was applied on the cusp. For the periodontal insert, the strains increased in the peri-implant region according to the size of the exposed portion and independent of the threads' presence. The difference between groups with and without implantoplasty was less than 10%. Critical values were found when the inserted portion was smaller than the exposed portion. In the exposed implants, the stress generated on the implant and retention screw was higher in the models that received implantoplasty. For the bone tissue, exposure of the implant's thread was a damaging factor, independent of implantoplasty. Implantoplasty treatment can be safely used to control peri-implantitis if at least half of the implant is still inserted in bone. PMID- 29236901 TI - Collagen sponge and rhBMP-2 improve socket healing in rats treated with zoledronic acid. AB - The aim of the present study was to evaluate the possible use of a commercial absorbed collagen sponge and bone morphogenetic protein (BMP) for the prevention of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in rats. Twenty rats received intraperitoneal injections of 0.1-mg/kg of zoledronic acid three times a week for eight weeks before the extraction of both maxillary first molars after eight weeks. A collagen sponge (experimental group 1) and a collagen sponge with recombinant human BMP-2 (experimental group 2) were applied to the right extraction sockets of ten rats each. The 20 left extraction sockets (control groups 1 and 2) were left unprotected. After eight weeks, all rats were euthanized. Macroscopic analysis, micro-computed tomography (CT) analysis, and histological analysis were performed. There was a significant difference in the bone density between the control and experimental groups on micro-CT analysis. Impaired healing of the extraction sockets, indicating BRONJ, was observed in 80% of control group 1, 90% of control group 2, 30% of experimental group 1, and 20% of experimental group 2. The collagen sponge with/without BMP used for protecting the extraction socket had the potential for a positive effect in reducing the incidence of bisphosphonate-related osteonecrosis of the jaw in rats. PMID- 29236902 TI - Evaluation of speech-language pathology care in the family health strategy from user perspective. AB - PURPOSE: To evaluate the satisfaction of users assisted by speech-language pathologists during their Multi-professional Residency in Family Health, considering the structural, organizational and relational categories. METHODS: Qualitative assessment conducted with 30 Family Health Strategy (FHS) users. Data were analyzed using Bardin's content analysis. RESULTS: The organizational category presented aspects associated with the organization of speech-language pathology (SLP) services, describing the specific practice and role of speech language therapists in the FHS, as well as referral and waiting time for care, speech-language therapy actions, clarification of problems, and promotion of self care. The relational category showed the relationship between residents and users, with emphasis on humanized care and bonding. The structural category described the dimensioning of speech-language pathologists in the FHS and the aspects related to the resources available in the health unit. CONCLUSION: User satisfaction was associated with the rapid access to the service and the humanized care provided by the residents, promoting a welcoming service and bonding between residents and community. User dissatisfaction was associated with the reduced number of speech-language pathologists available at FHS. PMID- 29236903 TI - Ultrasound analysis of tongue contour for the sound [j] in adults and children. AB - PURPOSE: Analyze and compare the mean tongue contours and articulatory gestures in the production of the sound [j] in adults and children with typical and atypical speech development. The children with atypical development presented speech sound disorders. METHODS: The diagnosis was determined by speech assessments. The study sample was composed of 90 individuals divided into three groups: 30 adults with typical speech development aged 19-44 years (AT), 30 children with typical speech development (CT), and 30 children with speech sound disorders, named as atypical in this study, aged four years to eight years and eleven months (CA). Ultrasonography assessment of tongue movements was performed for all groups. Mean tongue contours were compared between three groups in different vocalic contexts following the sound [j]. The maximum elevation of the tongue tip was considered for delimitation of gestures using the Articulate Assistant Advanced (AAA) software and images in sagittal plane/Mode B. The points that intercepted the language curves were analyzed by the statistical tool R. The graphs of tongue contours were obtained adopting a 95% confidence interval. After that, the regions with significant statistical differences (p<0.05) between the CT and CA groups were obtained. RESULTS: The mean tongue contours demonstrated the gesture for the sound [j] in the comparison between typical and atypical children. For the semivowel [j], there is an articulatory gesture of tongue and dorsum towards the center of the hard palate, with significant differences observed between the children. CONCLUSION: The results showed differences between the groups of children regarding the ability to refine articulatory gestures. PMID- 29236904 TI - Retrocochlear impairments in systemic sclerosis: a case report study. AB - PURPOSE: To report three cases of patients with Systemic Sclerosis (SSc) and retrocochlear impairments. METHODS: This is a case report of three individuals with SSc and retrocochlear impairments assisted at a rheumatology outpatient clinic. All individuals underwent Brainstem Auditory Evoked Potential (BAEP) and, when necessary, audiometry. RESULTS: All three individuals presented sensorineural hearing loss. Although no retrocochlear impairment was identified in the basic audiologic evaluation, the BAEP results were altered. CONCLUSION: Retrocochlear impairments were present in the individuals under study, both in the absolute latencies and interpeak interval, thereby demanding the attention of rheumatologists and speech-language pathologists to such changes during the monitoring of SSc patients. The results also show a need for epidemiological studies on the theme. PMID- 29236905 TI - Nijmegen Cochlear Implant Questionnaire (NCIQ): translation, cultural adaptation, and application in adults with cochlear implants. AB - PURPOSE: Cross-cultural adaptation and translation of the Nijmegen Cochlear Implant Questionnaire (NCIQ) into Brazilian Portuguese and analysis of quality of life (QoL) results in adults with cochlear implant (CI). METHODS: The NCIQ instrument was translated into Brazilian Portuguese and culturally adapted. After that, a cross-sectional and clinical QoL evaluation was conducted with a group of 24 adults with CI. RESULTS: The questionnaire title in Brazilian Portuguese is 'Questionario Nijmegen de Implantes Cocleares' (NCIQ-P). The version of the NCIQ questionnaire translated into Brazilian Portuguese presented good internal consistency (0.78). The social and physical domains presented the highest scores, with the basic and advanced sound perception subdomains achieving the highest scores. No correlation between gender and time of device use was found for the questionnaire domains and subdomains. CONCLUSION: The cross-cultural adaptation and translation of the NCIQ into Brazilian Portuguese suggests that this instrument is reliable and useful for clinical and research purposes in Brazilian adults with CI. PMID- 29236906 TI - Auditory-perceptual and acoustic analysis of voices of HIV-infected children. AB - PURPOSE: To compare vocal and acoustic parameters of HIV-infected children and non-HIV-infected children. METHODS: Vocal samples were submitted to auditory perceptual and acoustic analysis. Samples of the sustained vowel /epsilon/ and continuous speech of 74 children between 6 and incomplete 12 years old were analyzed, divided into two groups: 37 HIV-infected children (GHIV) and 37 non-HIV infected children, the control group (CG), age and gender-matched and without previous vocal evaluation; they were all prepubescent by the Tanner Stages (MS, 2014). The children had their voices recorded and analyzed by VoxMetria 5.1, in the period between 2014 and 2015. The auditory-perceptual analysis assessed the overall degree of the vocal quality and was performed using a 100-point visual analogue scale, transformed into a 4 point numerical scale (0 = no vocal deviation and 4 = severe vocal deviation). The acoustic evaluation was based on the analysis of the vocal sample distribution in the Phonatory Deviation Diagram (PDD). The research was approved by the Ethics Committee under the number 122.746. RESULTS: In the auditory-perceptual analysis, most children of both groups were evaluated as with no vocal deviation. No difference between the groups was found in the acoustic analysis using the PDD; most voice samples were within the normality area, in the quadrant 1, with a spread density distribution and a vertical shape. CONCLUSION: HIV-infected children presented similar vocal quality to children without the illness, both for the perceptual-auditory and acoustic evaluation. PMID- 29236907 TI - Effect of delayed auditory feedback on stuttering with and without central auditory processing disorders. AB - PURPOSE: To verify the effect of delayed auditory feedback on speech fluency of individuals who stutter with and without central auditory processing disorders. METHODS: The participants were twenty individuals with stuttering from 7 to 17 years old and were divided into two groups: Stuttering Group with Auditory Processing Disorders (SGAPD): 10 individuals with central auditory processing disorders, and Stuttering Group (SG): 10 individuals without central auditory processing disorders. Procedures were: fluency assessment with non-altered auditory feedback (NAF) and delayed auditory feedback (DAF), assessment of the stuttering severity and central auditory processing (CAP). Phono Tools software was used to cause a delay of 100 milliseconds in the auditory feedback. The "Wilcoxon Signal Post" test was used in the intragroup analysis and "Mann Whitney" test in the intergroup analysis. RESULTS: The DAF caused a statistically significant reduction in SG: in the frequency score of stuttering-like disfluencies in the analysis of the Stuttering Severity Instrument, in the amount of blocks and repetitions of monosyllabic words, and in the frequency of stuttering-like disfluencies of duration. Delayed auditory feedback did not cause statistically significant effects on SGAPD fluency, individuals with stuttering with auditory processing disorders. CONCLUSION: The effect of delayed auditory feedback in speech fluency of individuals who stutter was different in individuals of both groups, because there was an improvement in fluency only in individuals without auditory processing disorder. PMID- 29236908 TI - Translation and cultural adaptation of the Aguado Syntax Test (AST) into Brazilian Portuguese. AB - PURPOSE: To perform the translation and cultural adaptation of the Aguado Syntax Test (AST) into Brazilian Portuguese considering the linguistic and cultural reality of the language. METHODS: The AST assesses the early morphosyntactic development in children aged 3 to 7 in terms of understanding and expression of various types of structures such as sentences, pronouns, verbal voices, comparisons, prepositions and verbal desinence as to number, mode and tense. The process of translation and cultural adaptation followed four steps: 1) preparation of two translations; 2) synthesis of consensual translations; 3) backtranslation; and 4) verification of equivalence between the initial translations and backtranslations that resulted in the final translated version. RESULTS: The whole process of translation and cultural adaptation revealed the presence of equivalence and reconciliation of the translated items and an almost complete semantic equivalence between the two translations and the absence of consistent translation difficulties. CONCLUSION: The AST was translated and culturally adapted into Brazilian Portuguese, constituting the first step towards validation and standardization of the test. PMID- 29236909 TI - Sudden unexpected death in Parkinson's disease (SUDPAR): a review of publications since the decade of the brain. PMID- 29236910 TI - Role of T. cruzi exposure in the pattern of T cell cytokines among chronically infected HIV and Chagas disease patients. AB - OBJECTIVES: The impact of Chagas disease (CD) in HIV-infected patients is relevant throughout the world. In fact, the characterization of the adaptive immune response in the context of co-infection is important for predicting the need for interventions in areas in which HIV and Chagas disease co-exist. METHODS: We described and compared the frequency of cytokine-producing T cells stimulated with soluble antigen of Trypanosoma cruzi (T. cruzi) using a cytometric assay for the following groups: individuals with chronic Chagas disease (CHR, n=10), those with Chagas disease and HIV infection (CO, n=11), those with only HIV (HIV, n=14) and healthy individuals (C, n=15). RESULTS: We found 1) a constitutively lower frequency of IL-2+ and IFN-gamma+ T cells in the CHR group compared with the HIV, CO and healthy groups; 2) a suppressive activity of soluble T. cruzi antigen, which down-regulated IL-2+CD4+ and IFN-gamma+CD4+ phenotypes, notably in the healthy group; 3) a down-regulation of inflammatory cytokines on CD8+ T cells in the indeterminate form of Chagas disease; and 4) a significant increase in IL-10+CD8+ cells distinguishing the indeterminate form from the cardiac/digestive form of Chagas disease, even in the presence of HIV infection. CONCLUSIONS: Taken together, our data suggest the presence of an immunoregulatory response in chronic Chagas disease, which seems to be driven by T. cruzi antigens. Our findings provide new insights into immunotherapeutic strategies for people living with HIV/AIDS and Chagas disease. PMID- 29236911 TI - Assessment of the quality of life, muscle strength, and dynamic balance of elderly Kendo players. AB - OBJECTIVE: To compare Kendo players with active elderly adults in terms of quality of life, functional aspects (muscle strength, postural balance) and body composition. METHODS: This was a controlled cross-sectional study. Twenty elderly individuals were divided into two groups: the Kendo group, with an average age of 71.8 (5.4) years, and the Control group, with an average age of 73.1 (4.8) years. Quality of life was evaluated using a questionnaire (WHOQOL-bref and WHOQOL-old); body composition was evaluated with a bioimpedance scale (InBody230); hand-grip strength was assessed with a portable manual dynamometer (Jamar SH 5001); flexor and extensor muscle strength of the knees was evaluated with an isokinetic device (Biode(r) System 3 model Biodex Multi Joint System, BIODEX); and dynamic balance was assessed using a force platform (Balance Master System, Neurocom International, Inc.,(r) Clackamas County, Oregon, USA). RESULTS: The groups were statistically homogeneous in terms of socio-demographic characterization, body composition, muscle strength, and dynamic balance, but the Control group was faster in the sit-to-stand test (p=0.03). The Kendo group had a statistically significantly better quality of life; in the WHOQOL-bref, these differences were present in the physical (p<=0.001) and environment (p=0.004) domains, and in the WHOQOL-old, these differences were present in social participation (p=0.001) and in past, present, and future activities (p=0.019). CONCLUSION: The results suggest that Kendo is a health-promoting activity that improves the quality of life, functional aspects (muscle strength and postural balance) and body composition of players. PMID- 29236912 TI - Cardiorespiratory performance of coronary artery disease patients on land versus underwater treadmill tests: a comparative study. AB - OBJECTIVE: To compare responses to a cardiopulmonary exercise test on land versus on an underwater treadmill, to assess the cardiorespiratory performance of coronary artery disease patients while immersed in warm water and to compare with the performance of healthy individuals. METHODS: The sample population consisted of 40 subjects, which included 20 coronary artery disease patients aged 63.7+/ 8.89 years old, functional class I and II, according to the New York Hearth Association, and 20 healthy subjects aged 64.7+/-7.09 years old. The statistical significances were calculated through an ANOVA test with a (1 - beta) power of 0.861. ClinicalTrials.gov: NCT00989248 (22). RESULTS: Significant differences were uncovered in coronary artery disease group regarding the variables heart beats (HB), (p>0.01), oxygen consumption (VO2), (p>0.01) and carbon dioxide production (VCO2) (p<0.01). Also, for the same group, in relation to the environment, water versus on land for HB, VO2, VCO2 and oxygen for each heart beat (VO2/HB) all of than (p<0.01). The stages for data collected featured the subject's performance throughout the experiment, and within the given context, variables rating of perceived exertion (RPE), HB, VO2, VCO2 and VO2/HB (p<0.01) showed significant interactions between test stages and environment. Additionally, there was a significant interaction between the etiology and the test stages for the variables HB, VO2 and VCO2 (p<0.01). Electrocardiographic changes compatible with myocardial ischemia or arrhythmia were not observed. The subjects exhibited lower scores on Borg's perceived exertion scale in the water than at every one of the test stages on land (p<0.01). CONCLUSION: This study show that a cardiopulmonary exercise test can be safely conducted in subjects in immersion and that the procedures, resources and equipment used yielded replicable and reliable data. Significant differences observed in water versus on land allow us to conclude that coronary artery disease patients are able to do physical exercise in water and that the physiological effects of immersion do not present any risk for such patients, as exercise was well tolerated by all subjects. PMID- 29236913 TI - Impact of the delay to start treatment in patients with lung cancer treated in a densely populated area of Brazil. AB - OBJECTIVES: The aim of this study is to evaluate the access of patients with lung cancer in a densely populated area of Sao Paulo to the Brazilian Public Health System, focusing on the time spent from symptom onset or initial diagnosis until the beginning of treatment. METHODS: We retrospectively reviewed 509 patients with malignant lung neoplasms who were admitted to a single reference oncology center of the public health system between July 2008 and December 2014. Patients were considered eligible for this study if they were older than 18 years and had not undergone any previous oncology treatment when they were admitted to the institution. The following data were collected from all patients: age, gender, smoking status, tumor staging, time from the when the first symptoms were experienced by the patient to when the patient was diagnosed with cancer, time from the first appointment to cancer diagnosis, and time from when the patient was diagnosed with cancer to the initiation of treatment. RESULTS: The median time from symptom onset to diagnosis was three months. From the first appointment to diagnosis, the median time interval was one month; however, 79% of patients were diagnosed in up to two months. The median time from diagnosis to the start of treatment was one month, but most patients (82.5%) started treatment in up to two months. CONCLUSION: In our highly populated region with preferential access to the public health system, patients are required to wait a relatively long time to effectively begin treatment for lung cancer. This type of study is important to alert medical societies and government health agencies. PMID- 29236914 TI - Dental status, oral prosthesis and chewing ability in an adult and elderly population in southern Brazil. AB - OBJECTIVE: The objective of this study was to explore the factors associated with inadequate chewing in an adult and elderly population of a city in the southern region of Brazil. METHODS: This was a cross-sectional study based on a population home-based inquiry (DCH-POP) in southern Brazil. Individuals were interviewed by trained interviewers to create a standardized procedure. In a pilot study, the Questionnaire of Human Communication Disorders (DCH-POP) was created and validated to identify self-reported speech and language, swallowing and hearing disorders. The outcome was dichotomized into either having adequate chewing or not, as assessed by a series of questions about chewing ability. Analyses of absolute and relative frequencies were measured according to the studied variables. A Poisson regression was applied at a significance level of 5%. RESULTS: A total of 1,246 people were interviewed. Inadequate chewing was found in 52 (5.6%) individuals, with a higher prevalence in the elderly (11.8%) than in adults (5.2%). In the final model, the following factors were associated with inadequate chewing: being 61 years of age or older (prevalence ratio or PR=9.03; 95% CI: 1.20-67.91), loss of teeth and use of unadjusted prosthesis (PR=3.50; 95% CI: 1.54-7.95), preference for foods of soft consistency (PR=9.34; 95% CI:4.66 8.70) and difficulty in nasal breathing (PR=2.82; 95% CI: 1.31-6.06). CONCLUSION: Age, oral health status through dental prosthesis, preference for foods of soft consistency and difficulty breathing through the nose were factors associated with chewing inability in adults and the elderly. PMID- 29236915 TI - Prognostic factors of the short-term outcomes of patients with hepatitis B virus associated acute-on-chronic liver failure. AB - OBJECTIVE: To investigate the impact of the baseline status of patients with hepatitis B virus-associated acute-on-chronic liver failure on short-term outcomes. METHODS: A retrospective study was conducted that included a total of 138 patients with hepatitis B virus-associated acute-on-chronic liver failure admitted to the Department of Infectious Diseases, Taihe Hospital, Hubei University of Medicine, from November 2013 to October 2016. The patients were divided into a poor prognosis group (74 patients) and a good prognosis group (64 patients) based on the disease outcome. General information, clinical indicators and prognostic scores of the patients' baseline status were analyzed, and a prediction model was established accordingly. RESULTS: Elder age, treatment with artificial liver support systems and the frequency of such treatments, high levels of white blood cells, neutrophils, neutrophil count/lymphocyte count ratio, alanine aminotransferase, gamma-glutamyl transferase, total bilirubin, urea, and prognostic scores as well as low levels of albumin and sodium were all significantly associated with the short-term outcomes of hepatitis B virus associated acute-on-chronic liver failure. The predictive model showed that logit (p) = 3.068 + 1.003 * neutrophil count/lymphocyte count ratio - 0.892 * gamma glutamyl transferase - 1.138 * albumin - 1.364 * sodium + 1.651 * artificial liver support therapy. CONCLUSION: The neutrophil count/lymphocyte count ratio and serum levels of gamma-glutamyl transferase, albumin and sodium were independent risk factors predicting short-term outcomes of hepatitis B virus associated acute-on-chronic liver failure, and the administration of multiple treatments with artificial liver support therapy during the early stage is conducive to improved short-term outcomes. PMID- 29236916 TI - Videofluoroscopic analysis of different volumes of liquid bolus swallowing in healthy individuals: comparison between height and sex. AB - OBJECTIVE: The volume of swallowed bolus affects the pharyngeal transit duration. The sex and corporal height of individuals may likely influence this effect. The aim of this investigation was to determine the influence of sex and corporal height on the pharyngeal transit modification produced by the swallowed bolus volume. METHODS: Forty healthy volunteers, 20 men and 20 women, including tall (10 men and 10 women, corporal height: 1.71--2.07m) and short (10 men and 10 women, corporal height: 1.52--1.70m) persons, ranging in age between 20 and 50 years, were included in the study. Videofluoroscopic evaluation of swallowing was performed with the subjects in the sitting position. Each individual swallowed three 5 mL and three 10 mL boluses of liquid barium in a random sequence. The durations of oral transit, pharyngeal transit, pharyngeal clearance, hyoid movement, upper esophageal sphincter opening and oral-pharyngeal transit were evaluated. RESULTS: In men and women, and in taller and shorter individuals, the increase of the swallowed liquid bolus volume from 5 mL to 10 mL causes a faster transit of the bolus tail from the oral-pharyngeal transition to the upper esophageal sphincter and an increase in the duration of the upper esophageal sphincter opening, with similar alteration in men and women and in taller and shorter individuals. CONCLUSION: An increase in the swallowed liquid bolus volume from 5 mL to 10 mL causes a faster pharyngeal bolus transit and a longer bolus transit through the upper esophageal sphincter, with similar alterations in men and women and in shorter and taller individuals. PMID- 29236918 TI - Peri-implant assessment via cone beam computed tomography and digital periapical radiography: an ex vivo study. AB - OBJECTIVES: This research evaluated detail registration in peri-implant bone using two different cone beam computer tomography systems and a digital periapical radiograph. METHODS: Three different image acquisition protocols were established for each cone beam computer tomography apparatus, and three clinical situations were simulated in an ex vivo fresh pig mandible: buccal bone defect, peri-implant bone defect, and bone contact. Data were subjected to two analyses: quantitative and qualitative. The quantitative analyses involved a comparison of real specimen measures using a digital caliper in three regions of the preserved buccal bone - A, B and E (control group) - to cone beam computer tomography images obtained with different protocols (kp1, kp2, kp3, ip1, ip2, and ip3). In the qualitative analyses, the ability to register peri-implant details via tomography and digital periapical radiography was verified, as indicated by twelve evaluators. Data were analyzed with ANOVA and Tukey's test (alpha=0.05). RESULTS: The quantitative assessment showed means statistically equal to those of the control group under the following conditions: buccal bone defect B and E with kp1 and ip1, peri-implant bone defect E with kp2 and kp3, and bone contact A with kp1, kp2, kp3, and ip2. Qualitatively, only bone contacts were significantly different among the assessments, and the p3 results differed from the p1 and p2 results. The other results were statistically equivalent. CONCLUSIONS: The registration of peri-implant details was influenced by the image acquisition protocol, although metal artifacts were produced in all situations. The evaluators preferred the Kodak 9000 3D cone beam computer tomography in most cases. The evaluators identified buccal bone defects better with cone beam computer tomography and identified peri-implant bone defects better with digital periapical radiography. PMID- 29236917 TI - A novel body mass index reference range - an observational study. AB - OBJECTIVE: To generate a new body mass index curve of reference values and ranges for body mass index and weight gain during pregnancy and to compare the new curve and weight gain ranges with the currently used references. METHODS: A prospective observational study was conducted with a total of 5,656 weight and body mass index measurements in 641 women with single pregnancy who attended their first prenatal visit before 12 weeks. All the women were over 18 years old and had no medical conditions that would influence body mass index. Data were collected using prenatal charts and medical records during hospitalization for childbirth. A linear regression method was used for standard curve smoothing in the general population and for specific curves according to the baseline body mass index classification. Curves were obtained for the 5th, 10th, 50th, 85th, 90th and 95th percentiles. Concordance between the classification of women using the newly generated and currently used curves was evaluated by percentages and kappa coefficients. The weight gain was compared with the reference values of the Institute of Medicine using Student's T test. The data were analyzed using SAS software version 9.2, and the significance level was set at 5%. RESULTS: A general reference curve of percentiles of body mass index by gestational age was established. Additionally, four specific curves were generated according to the four baseline body mass index categories. The new general curve offered percentile limits for women according to their initial body mass index and according to the Centers for Disease Control and Prevention limits, showing poor agreement with the currently used curve (48.3%). Women who were overweight or obese when starting prenatal care had higher weight gain than the Institute of Medicine recommendation. CONCLUSIONS: The new proposed curve for body mass index during pregnancy showed weak agreement with the currently used curve. The new curve provided more information regarding body mass index increase using percentiles for general and specific groups of body mass index. Overweight pregnant women showed an upward body mass index trend throughout pregnancy that increased more dramatically than those of other groups of pregnant women, and they also presented a major mean difference between weight gain and the Institute of Medicine recommendation. PMID- 29236919 TI - Evidence of progenitor cells in the adult human cochlea: sphere formation and identification of ABCG2. AB - OBJECTIVES: The aim of this study was to search for evidence of stem or progenitor cells in the adult human cochlea by testing for sphere formation capacity and the presence of the stem cell marker ABCG2. METHODS: Cochleas removed from patients undergoing vestibular schwannoma resection (n=2) and from brain-dead organ donors (n=4) were dissociated for either flow cytometry analysis for the stem cell marker ABCG2 or a sphere formation assay that is widely used to test the sphere-forming capacity of cells from mouse inner ear tissue. RESULTS: Spheres were identified after 2-5 days in vitro, and the stem cell marker ABCG2 was detected using flow cytometric analysis after cochlear dissociation. CONCLUSIONS: Evidence suggests that there may be progenitor cells in the adult human cochlea, although further studies are required. PMID- 29236920 TI - Brazilian version of the Cognitive Failures Questionnaire (CFQ): cross-cultural adaptation and evidence of validity and reliability. AB - OBJECTIVE: Cognitive failures are simple mistakes in routine activities, such as forgetting commitments and experiencing difficulty concentrating. The Cognitive Failures Questionnaire (CFQ) was designed to assess the frequency of these errors in everyday life. Although widely used in psychiatry and psychology, both in clinical and research settings, it has not been adapted for use in Brazil. Our objective was to perform cross-cultural adaptation of the CFQ for the Brazilian reality and assess its validity and reliability. METHODS: The original version of the CFQ was translated into Brazilian Portuguese by two independent researchers, analyzed by a multidisciplinary board of experts, and back-translated into English. The final version was administered to 225 adults. Validity was assessed by correlation with the Self Reporting Questionnaire-20 (SRQ-20) and the Adult Attention Deficit/Hyperactivity Disorder Self-Report Scale (ASRS-18). Reliability was analyzed by calculating internal consistency and test-retest stability. RESULTS: The adapted version of the CFQ showed significant correlations with SRQ 20 (r = -0.311), ASRS-18 inattention (r = 0.696), and hyperactivity/impulsivity (r = 0.405) scores. Reliability analysis suggests high internal consistency (0.906) and temporal stability (0.813). CONCLUSION: The Brazilian Portuguese version of the CFQ showed moderate correlations with other measures of mental health, as well as adequate reliability. PMID- 29236921 TI - Intermittent theta-burst transcranial magnetic stimulation for autism spectrum disorder: an open-label pilot study. AB - OBJECTIVE: Theta-burst stimulation (TBS) modulates synaptic plasticity more efficiently than standard repetitive transcranial magnetic stimulation delivery and may be a promising modality for neuropsychiatric disorders such as autism spectrum disorder (ASD). At present there are few effective interventions for prefrontal cortex dysfunction in ASD. We report on an open-label, pilot study of intermittent TBS (iTBS) to target executive function deficits and restricted, repetitive behaviors in male children and adolescents with ASD. METHODS: Ten right-handed, male participants, aged 9-17 years with ASD were enrolled in an open-label trial of iTBS treatment. Fifteen sessions of neuronavigated iTBS at 100% motor threshold targeting the right dorsolateral prefrontal cortex were delivered over 3 weeks. RESULTS: Parent report scores on the Repetitive Behavior Scale Revised and the Yale-Brown Obsessive Compulsive Scale demonstrated improvements with iTBS treatment. Participants demonstrated improvements in perseverative errors on the Wisconsin Card Sorting Test and total time for the Stroop test. The iTBS treatments were well tolerated with no serious adverse effects. CONCLUSION: These preliminary results suggest that further controlled interventional studies of iTBS for ASD are warranted. PMID- 29236922 TI - Effects of N-acetylcysteine on amphetamine-induced sensitization in mice. AB - OBJECTIVE: N-acetylcysteine (NAC) is beneficial in psychiatric conditions, including schizophrenia. Patients with schizophrenia exhibit mesolimbic dopamine hyperfunction consequent to an endogenous sensitization process. This sensitization can be modeled in rodents by repeated exposure to psychostimulants, provoking an enduring amplified response at subsequent exposure. The aim of this study was to investigate the effects of NAC on amphetamine sensitization in mice. METHODS: D-amphetamine was administered to C57BL/6 mice three times a week for 3 weeks; the dose was increased weekly from 1 to 3 mg/kg. NAC (60 mg/kg) or saline was administered intraperitoneally before saline or amphetamine during the second and third weeks. After a 4-week washout period, latent inhibition (LI) and the locomotor response to amphetamine 2 mg/kg were assessed. RESULTS: Sensitization disrupted LI and amplified the locomotor response; NAC disrupted LI in control mice. In sensitized animals, NAC attenuated the enhanced locomotion but failed to prevent LI disruption. CONCLUSION: NAC warrants consideration as a candidate for early intervention in ultra-high risk subjects due to its safety profile and the relevance of its mechanism of action. Supplementing this proposition, we report that NAC attenuates sensitization-induced locomotor enhancement in mice. The finding that NAC disrupted LI incites a cautionary note and requires clarification. PMID- 29236923 TI - Whole-genome sequencing of Leptospira interrogans from southern Brazil: genetic features of a highly virulent strain. AB - BACKGROUND Leptospirosis is the most widespread zoonotic disease. It is caused by infection with pathogenic Leptospira species, of which over 300 serovars have been described. The accurate identification of the causative Leptospira spp. is required to ascertain the pathogenic status of the local isolates. OBJECTIVES This study aimed to obtain the complete genome sequence of a virulent Leptospira interrogans strain isolated from southern Brazil and to describe its genetic features. METHODS The whole genome was sequenced by next-generation sequencing (Ion Torrent). The genome was assembled, scaffolded, annotated, and manually reviewed. Mutations were identified based on a variant calling analysis using the genome of L. interrogans strain Fiocruz L1-130 as a reference. FINDINGS The entire genome had an average GC content of 35%. The variant calling analysis identified 119 single nucleotide polymorphisms (SNPs), from which 30 led to a missense mutation. The structural analyses identified potential evidence of genomic inversions, translocations, and deletions in both the chromosomes. MAIN CONCLUSIONS The genome properties provide comprehensive information about the local isolates of Leptospira spp., and thereby, could facilitate the identification of new targets for the development of diagnostic kits and vaccines. PMID- 29236924 TI - Ecological characterisation and infection of Anophelines (Diptera: Culicidae) of the Atlantic Forest in the southeast of Brazil over a 10 year period: has the behaviour of the autochthonous malaria vector changed? AB - BACKGROUND In southeastern Brazil, autochthonous cases of malaria can be found near Atlantic Forest fragments. Because the transmission cycle has not been completely clarified, the behaviour of the possible vectors in those regions must be observed. A study concerning the entomological aspects and natural infection of anophelines (Diptera: Culicidae) captured in the municipalities of the mountainous region of Espirito Santo state was performed in 2004 and 2005. Similarly, between 2014 and 2015, 12 monthly collections were performed at the same area of the study mentioned above. METHODS Center for Disease Control (CDC) light traps with CO2 were set in open areas, at the edge and inside of the forest (canopy and ground), whereas Shannon traps were set on the edge. FINDINGS A total of 1,414 anophelines were collected from 13 species. Anopheles (Kerteszia) cruzii Dyar and Knab remained the most frequently captured species in the CDC traps set in the forest canopy, as well as being the vector with the highest prevalence of Plasmodium vivax/simium infection, according to molecular polymerase chain reaction techniques. CONCLUSIONS P. vivax/simium was found only in abdomens of the mosquitoes of the subgenus Nyssorhynchus, weakening the hypothesis that this subgenus also plays a role in malaria transmission in this specific region. PMID- 29236925 TI - Increased thiol levels in antimony-resistant Leishmania infantum isolated from treatment-refractory visceral leishmaniasis in Brazil. AB - BACKGROUND Treatment-refractory visceral leishmaniasis (VL) has become an important problem in many countries. OBJECTIVES We evaluated the antimony resistance mechanisms of Leishmania infantum isolated from VL patients refractory or responsive to treatment with pentavalent antimony. METHODS Strains isolated from antimony-refractory patients (in vitro antimony-resistant isolates) and antimony-responsive patients (in vitro antimony-sensitive isolates) were examined. Morphological changes were evaluated by transmission electron microscopy after trivalent antimony exposure. P-glycoprotein (P-gp) efflux pump activity was evaluated using the pump-specific inhibitor verapamil hydrochloride, and the role of thiol in trivalent antimony resistance was investigated using the enzymatic inhibitor L-buthionine sulfoximine. FINDINGS Antimony treatment induced fewer alterations in the cellular structure of L. infantum resistant isolates than in that of sensitive isolates. P-gp efflux activity was not involved in antimony resistance in these isolates. Importantly, the resistant isolates contained higher levels of thiol compared to the sensitive isolates, and inhibition of thiol synthesis in the resistant isolates recovered their sensitivity to trivalent antimony treatment, and enhanced the production of reactive oxygen species in promastigotes exposed to the drug. MAIN CONCLUSIONS Our results demonstrate that isolates from patients with antimony-refractory VL exhibited higher thiol levels than antimony-sensitive isolates. This indicates that redox metabolism plays an important role in the antimony-resistance of New World VL isolates. PMID- 29236926 TI - Genome of Leptospira borgpetersenii strain 4E, a highly virulent isolate obtained from Mus musculus in southern Brazil. AB - A previous study by our group reported the isolation and characterisation of Leptospira borgpetersenii serogroup Ballum strain 4E. This strain is of particular interest because it is highly virulent in the hamster model. In this study, we performed whole-genome shotgun genome sequencing of the strain using the SOLiD sequencing platform. By assembling and analysing the new genome, we were able to identify novel features that have been previously overlooked in genome annotations of other strains belonging to the same species. PMID- 29236927 TI - Making the invisible visible: searching for human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) in Brazilian patients with viral hepatitis B and C. AB - With this study, the authors hope to alert clinicians regarding the presence of human T-cell lymphotropic virus type 1 and 2 (HTLV-1/-2) infections in patients with viral hepatitis B and C in Brazil. HTLV-1/-2 were detected in 1.3% of hepatitis B virus (HBV)- and 5.3% of hepatitis C virus (HCV)-infected blood samples sent for laboratory viral load measurements. A partial association of human immunodeficiency virus (HIV)-1 and HTLV-1/-2 infection was detected in patients with HCV (HIV+, 27.3%), whereas this association was almost 100% in HBV infected patients (HIV+, all except one). The high prevalence of HTLV-1/-2 infection among patients with hepatitis C was of concern, as HTLV-1/-2 could change the natural course of subsequent liver disease. The authors suggest including HTLV-1/-2 serology in the battery of tests used when following patients with viral hepatitis in Brazil, regardless of the HIV status. PMID- 29236928 TI - Leishmanicidal compounds of Nectria pseudotrichia, an endophytic fungus isolated from the plant Caesalpinia echinata (Brazilwood). AB - BACKGROUND In a screen of extracts from plants and fungi to detect antileishmanial activity, we found that the ethyl acetate extract of the fungus Nectria pseudotrichia, isolated from the tree Caesalpinia echinata (Brazilwood), is a promising source of bioactive compounds. OBJECTIVES The aims of this study were to isolate and determine the chemical structures of the compounds responsible for the antileishmanial activity of the organic extract from N. pseudotrichia. METHODS Compounds were isolated by chromatographic fractionation using semi-preparative high-performance liquid chromatography, and their chemical structures were determined by analytical and spectral data and by comparison with published data. The antileishmanial activity of the isolated compounds was evaluated in intracellular amastigote forms of Leishmania (Viannia) braziliensis expressing firefly luciferase as reporter gene, and cytotoxicity was determined in Vero and THP-1 mammalian cell lines by MTT assay. FINDINGS Fractionation of the extract yielded seven compounds: 10-acetyl trichoderonic acid A (1), 6' acetoxy-piliformic acid (2), 5',6'-dehydropiliformic acid (3), piliformic acid (4), hydroheptelidic acid (5), xylaric acid D (6), and cytochalasin D (7). Compounds 1, 2 and 3 are reported here for the first time. Compounds 1, 2, and 5 were more active, with IC50 values of 21.4, 28.3, and 24.8 uM, respectively, and showed low toxicity to Vero and THP-1 cells. MAIN CONCLUSIONS N. pseudotrichia produces secondary metabolites that are more toxic to intracellular amastigote forms of L. (V.) braziliensis than to mammalian cells. PMID- 29236929 TI - Towards a standard protocol for antimony intralesional infiltration technique for cutaneous leishmaniasis treatment. AB - BACKGROUND Despite its recognised toxicity, antimonial therapy continues to be the first-line drug for cutaneous leishmaniasis (CL) treatment. Intralesional administration of meglumine antimoniate (MA) represents an alternative that could reduce the systemic absorption of the drug and its side effects. OBJECTIVES This study aims to validate the standard operational procedure (SOP) for the intralesional infiltration of MA for CL therapy as the first step before the assessment of efficacy and safety related to the procedure. METHODS The SOP was created based on 21 trials retrieved from the literature, direct monitoring of the procedure and consultation with experts. This script was submitted to a formal computer-aided inspection to identify readability, clarity, omission, redundancy and unnecessary information (content validation). For criterion and construct validations, the influence of critical condition changes (compliance with the instructions and professional experience) on outcome conformity (saturation status achievement), tolerability (pain referred) and safety (bleeding) were assessed. FINDINGS The median procedure length was 12 minutes and in 72% of them, patients classified the pain as mild. The bleeding was also classified as mild in 96.6% of the procedures. Full compliance with the SOP was observed in 66% of infiltrations. Despite this, in 100% of the inspected procedures, lesion saturation was observed at the end of infiltration, which means that it tolerates some degree of modification in its execution (robustness) without prejudice to the result. CONCLUSIONS The procedure is reproducible and can be used by professionals without previous training with high success and safety rates. PMID- 29236930 TI - Anophelines species and the receptivity and vulnerability to malaria transmission in the Pantanal wetlands, Central Brazil. AB - BACKGROUND Studies on malaria vectors in the Pantanal biome, Central Brazil, were conducted more than half a century ago. OBJECTIVES To update anopheline records and assess receptivity and vulnerability to malaria transmission. METHODS Five day anopheline collections were conducted bimonthly in Salobra, Mato Grosso do Sul state, for one year. Indoors, mosquitoes were collected from their resting places, while in open fields, they were captured using protected human-baited and horse-baited traps near the house and at the Miranda River margin, respectively. Hourly biting activity outdoors was also assessed. Secondary data were collected on the arrival of tourists, economic projects, and malaria cases. FINDINGS A total of 24,894 anophelines belonging to 13 species were caught. The main Brazilian malaria vector Anopheles darlingi was the predominant species, followed by An. triannulatus s.l. Hourly variation in anopheline biting showed three main peaks occurring at sunset, around midnight, and at sunrise, the first and last being the most prominent. The highest density of all species was recorded near the river margin and during the transition period between the rainy and early dry seasons. This coincides with the time of main influx of outsider workers and tourists, whose activities mostly occur in the open fields and frequently start before sunrise and last until sunset. Some of these individuals originate from neighbouring malaria-endemic countries and states, and are likely responsible for the recorded imported and introduced malaria cases. MAIN CONCLUSION Pantanal is a malaria-prone area in Brazil. Surveillance and anopheline control measures must be applied to avoid malaria re-emergence in the region. PMID- 29236931 TI - Comparative genomics of pathogenic Leptospira interrogans serovar Canicola isolated from swine and human in Brazil. AB - Leptospira interrogans serovar Canicola is one of the most important pathogenic serovars for the maintenance of urban leptospirosis. Even though it is considered highly adapted to dogs, serovar Canicola infection has already been described in other animals and even a few human cases. Here, we present the genomic characterisation of two Brazilian L. interrogans serovar Canicola strains isolated from slaughtered sows (L0-3 and L0-4) and their comparison with human strain Fiocruz LV133. It was observed that the porcine serovar Canicola strains present the genetic machinery to cause human infection and, therefore, represent a higher risk to public health. Both human and porcine serovar Canicola isolates also presented sequences with high identity to the Chinese serovar Canicola published plasmids pGui1 and pGui2. The plasmids identification in the Brazilian and Chinese serovar Canicola strains suggest that extra-chromosomal elements are one more feature of this serovar that was previously unnoticed. PMID- 29236932 TI - Alternative splicing originates different domain structure organization of Lutzomyia longipalpis chitinases. AB - BACKGROUND The insect chitinase gene family is composed by more than 10 paralogs, which can codify proteins with different domain structures. In Lutzomyia longipalpis, the main vector of visceral leishmaniasis in Brazil, a chitinase cDNA from adult female insects was previously characterized. The predicted protein contains one catalytic domain and one chitin-binding domain (CBD). The expression of this gene coincided with the end of blood digestion indicating a putative role in peritrophic matrix degradation. OBJECTIVES To determine the occurrence of alternative splicing in chitinases of L. longipalpis. METHODS We sequenced the LlChit1 gene from a genomic clone and the three spliced forms obtained by reverse transcription polymerase chain reaction (RT-PCR) using larvae cDNA. FINDINGS We showed that LlChit1 from L. longipalpis immature forms undergoes alternative splicing. The spliced form corresponding to the adult cDNA was named LlChit1A and the two larvae specific transcripts were named LlChit1B and LlChit1C. The B and C forms possess stop codons interrupting the translation of the CBD. The A form is present in adult females post blood meal, L4 larvae and pre-pupae, while the other two forms are present only in L4 larvae and disappear just before pupation. Two bands of the expected size were identified by Western blot only in L4 larvae. MAIN CONCLUSIONS We show for the first time alternative splicing generating chitinases with different domain structures increasing our understanding on the finely regulated digestion physiology and shedding light on a potential target for controlling L. longipalpis larval development. PMID- 29236933 TI - Intramural duodenal hematoma secondary to pancreatitis: case report and review of the literature. AB - CONTEXT: Spontaneous intramural duodenal hematoma is uncommon and is usually associated with coagulopathy, anticoagulant therapy and endoscopic procedures. The aim here was to describe a case of intramural duodenal hematoma caused by chronic exacerbation of pancreatitis. CASE REPORT: A 46-year-old male with chronic alcoholic pancreatitis was admitted to hospital due to abdominal pain, melena and low hemoglobin. An intramural duodenal hematoma with active bleeding was detected and selective angioembolization was warranted. The patient evolved with a perforated duodenum and underwent laparotomy with exclusion of the pylorus and Roux-en-Y gastrojejunostomy. He was discharged nine days later. CONCLUSION: Intramural duodenal hematoma is a rare complication of pancreatitis. Selective embolization is the preferred treatment for hemorrhagic complications of pancreatitis. However, the risk of visceral ischemia and perforation should be considered. PMID- 29236934 TI - Sensory-motor training versus resistance training among patients with knee osteoarthritis: randomized single-blind controlled trial. AB - BACKGROUND: Osteoarthritis of the knee is defined as a progressive disease of the synovial joints and is characterized by failure of joint damage repair. The objective here was to compare the effectiveness of sensory-motor training versus resistance training among patients with knee osteoarthritis. DESIGN AND SETTING: Randomized, single-blinded controlled trial conducted at the outpatient service of the University of Santo Amaro. METHODS: A total of 64 patients were randomly assigned to sensory-motor training or resistance training. The evaluations were performed at baseline and 16 weeks after the intervention and included pain evaluation on a visual analogue scale, isometric quadriceps femoris force measurement using a dynamometer, Timed Up and Go test, Tinetti balance scale, Western Ontario and McMaster Universities osteoarthritis index, and the SF-36 quality-of-life questionnaire. Data analysis was performed using analysis of variance with repeated measurements and Cohen's effect size. RESULTS: Sensory motor training may be a plausible alternative and showed a small effect on pain and a medium effect on maximal voluntary isometric contraction. Resistance training showed a small effect on balance and a medium effect on mobility. CONCLUSION: Resistance training and sensory motor training for the lower limbs among patients with knee osteoarthritis seemed to present similar effects on pain and function. However, because there was a considerable risk of type 2 error, further randomized clinical trials are still needed to provide a sound conclusion. PMID- 29236937 TI - Why the US Centers for Medicare and Medicaid Services (CMS) should have required a randomized trial of Foundation Medicine (F1CDx) before paying for it. PMID- 29236935 TI - Translation and cultural adaptation of the revised foot function index for the Portuguese language: FFI-R Brazil. AB - BACKGROUND: The revised foot function index (FFI-R) is used to evaluate the functionality of patients with conditions that affect the feet. The objective here was to produce the Brazilian Portuguese version of this index. DESIGN AND SETTING: Translation and validation study conducted at the Federal University of Sao Paulo, Brazil. METHODS: The translation and cultural adaptation process involved translation by two independent translators, analysis by an expert committee, back translation into the original language, analysis by the expert committee again and a pretest. The Portuguese-language version was administered to 35 individuals with plantar fasciitis and metatarsalgia to determine their level of understanding of the assessment tool. RESULTS: Changes were made to the terms and expressions of some original items to achieve cultural equivalence. Terms not understood by more than 10% of the sample were altered based on the suggestions of the patients themselves. CONCLUSION: The translation and cultural adaptation of the FFI-R for the Portuguese language were completed and the Brazilian version was obtained. PMID- 29236936 TI - Report of a rare case and review of adult intestinal duplication at the opposite side of mesenteric margin. AB - CONTEXT: To study the previously discovered clinical entity of adult intestinal duplication and its treatment, and propose an extension to its existing classification. CASE REPORT: We report the case of an adult male with abdominal pain, constipation and vomiting. This patient underwent surgical separation of adhesions, reduction of torsion and intestinal decompression. Postoperative pathological findings confirmed the rare diagnosis of intestinal duplication. CONCLUSION: Adult intestinal duplication is quite rare. Its clinical manifestations are nonspecific. From this finding of intestinal duplication originating at the opposite side of the mesenteric margin, a further extension of the existing anatomical classification is proposed. PMID- 29236938 TI - Ten thousand attentive hours, rapid learning, dissemination of knowledge and the future of experience-based care in germ-cell tumors. PMID- 29236939 TI - A proposal to explain how the circatidal rhythm of the Arabidopsis thaliana root elongation rate could be mediated by the lunisolar gravitational force: a quantum physical approach. AB - Background and Aims: Roots of Arabidopsis thaliana exhibit a 24.8 h oscillation of elongation rate when grown under free-running conditions. This growth rhythm is synchronized with the time course of the local lunisolar tidal acceleration. The present study aims at a physiological/physical model to describe the interaction of weak gravitational fields with cellular water dynamics that mediate rhythmic root growth profiles. Methods: Fundamental physical laws are applied to model the water dynamics within single plant cells in an attempt to mimic the 24.8 h oscillations in root elongation growth. In particular, a quantum gravitational description of the time course in root elongation is presented, central to which is the formation of coherent assemblies of mass due to the lunisolar gravitational field. Mathematical equations that characterize lunisolar gravity-induced coherent assemblies of water molecules are derived and related to the mass of cellular water within roots of A. thaliana. Key Results: The derived physical model of gravitationally modulated water assemblies is capable of accounting for the experimentally observed arabidopsis root growth kinetics under free-running conditions. The close analogy between the derived time-dependent lunisolar effect upon coherent molecular states of water within single cells and the coherent assemblies of electrons that characterize the quantum Hall effect is emphasized. Conclusions: The dynamics of the lunisolar-induced variation in coherent water assemblies provide a possible mechanism to describe the observed 24.8 h oscillation of root growth rate of A. thaliana. Therefore, this mechanism could function as an independent timekeeper to control cell elongation. PMID- 29236940 TI - Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. AB - Background: While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known. Patients and methods: We identified patients who had pre- and post-genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors. Genotyping was carried out in tumor tissue or blood collected before start of CDK 4/6 inhibitor and after disease progression on CDK 4/6 inhibitor, covering more than 90% of the coding region in RB1. Results: We identified detectable acquired RB1 mutations in circulating tumor DNA (ctDNA) after exposure to CDK4/6 inhibitor (palbociclib, palbociclib, ribociclib) for 5, 8, and 13 months, respectively, in three patients. The RB1 mutations included substitution in donor splicing site of exon 8 of the RB1 gene in patient #1; substitution in donor splicing site of exon 22 of RB1 gene, exon 19 deletion, exon 3 insertion in patient #2; and RB1 exon 16 H483Y mutation in patient #3. None of these RB1 mutations were present in the pre CDK 4/6 specimen highlighting these molecular alterations, which lead to functional loss of Rb1, likely emerged under selective pressure from the CDK4/6 inhibitor potentially confering therapeutic resistance. Conclusion: This is the first clinical report to describe the emergence of somatic RB1 mutations after exposure to palbociclib or ribociclib, in patients with metastatic breast cancer. Further research is needed to validate these findings, identify how these mutations temporally emerge under selective pressure of CDK 4/6 inhibitor, and develop rational therapeutic strategies. PMID- 29236941 TI - TAQ1A1 Allele of the DRD2 Gene Region Contribute to Shorter Survival Time in Alcohol Dependent Individuals When Controlling for the Influence of Age and Gender. A Follow-up Study of 18 Years. AB - Aims: To investigate the influence of the A1 allele of the TAQ1A polymorphism in the dopamine D2 receptor (DRD2) gene region on mortality in adult individuals with alcohol dependence. Methods: The study sample consisted of 359 alcohol dependent individuals treated for severe alcohol withdrawal symptoms in 1997. Years of survival was studied in an 18-year follow-up. In the analyses, gender and age were controlled for. Results: At the 18-year follow-up, 53% individuals had deceased. The analyses showed that older age (P < 0.001), male gender (P < 0.05) and carrying the A1 allele (P < 0.01) all significantly and independently contributed to shorten years of survival. Among the deceased individuals, the genotype A1+ was the only significant contributor to shorten years of survival. Conclusions: An important contribution of the present study is that in alcohol dependence the Taq1A1 allele of the DRD2 gene region is a risk factor for premature death of similar importance as the well-known risk factors of age and gender. Short Summary: We investigated the influence of A1 allele of the TAQ1A polymorphism in DRD2 receptor gene region on mortality in alcohol-dependent individuals in an 18-year follow-up. Age, gender and the A1 allele contributed to shorten years of survival. Among the deceased, the A1+ was the only contributor to shorten years of survival. PMID- 29236942 TI - Anaesthetics stop diverse plant organ movements, affect endocytic vesicle recycling and ROS homeostasis, and block action potentials in Venus flytraps. AB - Background and Aims: Anaesthesia for medical purposes was introduced in the 19th century. However, the physiological mode of anaesthetic drug actions on the nervous system remains unclear. One of the remaining questions is how these different compounds, with no structural similarities and even chemically inert elements such as the noble gas xenon, act as anaesthetic agents inducing loss of consciousness. The main goal here was to determine if anaesthetics affect the same or similar processes in plants as in animals and humans. Methods: A single lens reflex camera was used to follow organ movements in plants before, during and after recovery from exposure to diverse anaesthetics. Confocal microscopy was used to analyse endocytic vesicle trafficking. Electrical signals were recorded using a surface AgCl electrode. Key Results: Mimosa leaves, pea tendrils, Venus flytraps and sundew traps all lost both their autonomous and touch-induced movements after exposure to anaesthetics. In Venus flytrap, this was shown to be due to the loss of action potentials under diethyl ether anaesthesia. The same concentration of diethyl ether immobilized pea tendrils. Anaesthetics also impeded seed germination and chlorophyll accumulation in cress seedlings. Endocytic vesicle recycling and reactive oxygen species (ROS) balance, as observed in intact Arabidopsis root apex cells, were also affected by all anaesthetics tested. Conclusions: Plants are sensitive to several anaesthetics that have no structural similarities. As in animals and humans, anaesthetics used at appropriate concentrations block action potentials and immobilize organs via effects on action potentials, endocytic vesicle recycling and ROS homeostasis. Plants emerge as ideal model objects to study general questions related to anaesthesia, as well as to serve as a suitable test system for human anaesthesia. PMID- 29236943 TI - A randomized trial of induction docetaxel-cisplatin-5FU followed by concomitant cisplatin-RT versus concomitant cisplatin-RT in nasopharyngeal carcinoma (GORTEC 2006-02). AB - Background: Concomitant chemotherapy (CT)-radiotherapy (RT) is a standard of care in locally advanced nasopharyngeal carcinoma (NPC) and a role for induction CT is not established. Methods: Patients with locally advanced NPC, WHO type 2 or 3, were randomized to induction TPF plus concomitant cisplatin-RT or concomitant cisplatin-RT alone. The TPF regimen consisted of three cycles of Docetaxel 75 mg/m2 day 1; cisplatin 75 mg/m2 day 1; 5FU 750 mg/m2/day days 1-5. RT consisted of 70 Gy in 7 weeks plus concomitant cisplatin 40 mg/m2 weekly. Results: A total of 83 patients were included in the study. Demographics and tumour characteristics were well balanced between both arms. Most of the patients (95%) in the TPF arm received three cycles of induction CT. The rate of grade 3-4 toxicity and the compliance (NCI-CTCAE v3) during cisplatin-RT were not different between both arms. With a median follow-up of 43.1 months, the 3-year PFS rate was 73.9% in the TPF arm versus 57.2% in the reference arm [hazard ratio (HR) = 0.44; 95% confidence interval (CI): 0.20-0.97, P = 0.042]. Similarly the 3 years overall survival rate was 86.3% in the TPF arm versus 68.9% in the reference arm (HR = 0.40; 95% CI: 0.15-1.04, P = 0.05). Conclusion: In conclusion, several important aspects can be emphasized: the compliance to induction TPF was good and TPF did not compromise the tolerance of the concomitant RT-cisplatin phase. The improved PFS and overall survival rates needs to be confirmed by further trials. PMID- 29236944 TI - Transplantation for Alcohol-related Liver Disease: Is It Fair? AB - Aims: Alcohol-related liver disease (ALD) is the second leading cause of liver transplantation performed in the USA and Europe. We aimed to provide a narrative review of the major ethical issues governing transplantation for ALD. Methods: We performed a narrative review of the ethical concepts in organ allocation for ALD, including alcoholic hepatitis. Results: Ethical concerns regarding organ allocation for ALD involve issues of urgency, utility and justice. Post transplant outcomes for ALD patients are good and ethical considerations limiting organs solely because of alcohol etiology do not bear scrutiny. Conclusion: ALD will continue to be a major cause for liver failure. The main criteria for transplant in ALD should be the patient's risk of return to harmful drinking, alongside standard assessments of physical and psychosocial fitness for transplant. PMID- 29236945 TI - The Effect of Increasing Age on the Concentric and Eccentric Contractile Properties of Isolated Mouse Soleus and Extensor Digitorum Longus Muscles. AB - There is currently a limited amount of literature investigating the age-related changes in eccentric muscle function in vitro. The present study uniquely uses the work loop (WL) technique, to better replicate in vivo muscle function, in the assessment of the age- and muscle-specific changes in acute and sustained concentric and eccentric power and recovery. Whole soleus or extensor digitorum longus (EDL) muscles were isolated from 10-week and 78-week-old mice and acute and sustained concentric and eccentric WL power assessed. Despite an age-related increase in body and muscle mass, peak absolute power for both muscles was unaffected by age. Peak concentric power normalized to muscle mass declined significantly for each muscle, while peak normalized eccentric power declined only for soleus. Fatigue resistance and recovery for the soleus did not differ between age or contraction type. Older EDL was less resistant to concentric fatigue, but was better able to withstand sustained eccentric activity than young EDL. We have shown that age-related changes in muscle quality are more limited for eccentric function than concentric function. A greater bodily inertia is likely to further reduce in vivo locomotor performance in older animals. PMID- 29236946 TI - Reply: POLR3A variants in hereditary spastic paraplegia and ataxia. PMID- 29236947 TI - Earliness traits in rapeseed (Brassica napus): SNP loci and candidate genes identified by genome-wide association analysis. AB - Life cycle timing is critical for yield and productivity of Brassica napus (rapeseed) cultivars grown in different environments. To facilitate breeding for earliness traits in rapeseed, SNP loci and underlying candidate genes associated with the timing of initial flowering, maturity and final flowering, as well as flowering period (FP) were investigated in two environments in a diversity panel comprising 300 B. napus inbred lines. Genome-wide association studies (GWAS) using 201,817 SNP markers previously developed from SLAF-seq (specific locus amplified fragment sequencing) revealed a total of 131 SNPs strongly linked (P < 4.96E-07) to the investigated traits. Of these 131 SNPs, 40 fell into confidence intervals or were physically adjacent to previously published flowering time QTL or SNPs. Phenotypic effect analysis detected 35 elite allelic variants for early maturing, and 90 for long FP. Candidate genes present in the same linkage disequilibrium blocks (r2>0.6) or in 100 kb regions around significant trait associated SNPs were screened, revealing 57 B. napus genes (33 SNPs) orthologous to 39 Arabidopsis thaliana flowering time genes. These results support the practical and scientific value of novel large-scale SNP data generation in uncovering the genetic control of agronomic traits in B. napus, and also provide a theoretical basis for molecular marker-assisted selection of earliness breeding in rapeseed. PMID- 29236949 TI - Seipin deficiency leads to increased endoplasmic reticulum stress and apoptosis in mammary gland alveolar epithelial cells during lactation. AB - Seipin is an integral endoplasmic reticulum (ER) membrane protein encoded by Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2/Bscl2) gene. Most litters (59%) from Bscl2-/- dams mated with wild type (WT) (Bscl2+/+) males did not survive postnatal day 5 (PND5) and pups (Bscl2+/-) lacked milk in their stomachs. The survived litters had reduced pup survival rate at PND21. It was hypothesized that seipin was critical for lactation. Bscl2 was upregulated and highly detected in the lactation day 1 (LD1) WT mammary gland alveolar epithelial cells. LD1 Bscl2-/- mammary glands lacked adipocytes and alveolar clusters and had varied alveolar morphology: from interconnected mammary gland alveoli with dilated lumen and sloughed epithelial cells to undifferentiated mammary gland alveoli with unexpanded lumen. Comparable levels of whey acidic protein (WAP, a major component in rodent milk) staining and Nile Red lipid droplet staining between WT and Bscl2-/- LD1 alveolar epithelial cells indicated normal milk protein synthesis and lipid syntheses in LD1 Bscl2-/- mammary glands. Significantly reduced percentage of larger lipid droplets was detected in LD1 Bscl2-/- alveoli with unexpanded lumen. There was no obviously impaired proliferation detected by PCNA staining but increased apoptosis detected by cleaved caspase-3 staining in LD1 Bscl2-/- alveolar epithelial cells. Increased expression of protein disulfide isomerase and binding immunoglobulin protein in the LD1 Bscl2-/- mammary gland alveolar epithelial cells indicated increased ER stress. This study demonstrates increased ER stress and apoptosis in LD1 Bscl2-/- mammary gland alveolar epithelial cells and reveals a novel in vivo function of seipin in lactation. PMID- 29236948 TI - TarHunter, a tool for predicting conserved microRNA targets and target mimics in plants. AB - Summary: In plants, the targets of deeply conserved microRNAs (miRNAs) were comprehensively studied. Evidence is emerging that targets of less conserved miRNAs, endogenous target mimics (eTM) and non-canonical targets play functional roles. Existing plant miRNA prediction tools lack a cross-species conservation filter and eTM prediction function. We developed a tool named TarHunter that features a strict cross-species conservation filter and capability of predicting eTMs. TarHunter has higher recall or precision rate as compared with other tools, and the conservation filter effectively increases prediction precision. TarHunter prediction combined with degradome analysis uncovered previously neglected miRNA targets including non-canonical target sites from various plant species, which are available at the TarHunter website (http://tarhunter.genetics.ac.cn/). Availability and implementation: The code of TarHunter is available on Github (https://github.com/XMaBio). Contact: xuemei.chen@ucr.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29236950 TI - Discrimination and Chemical Phylogenetic Study of Four Pulsatilla Herbs Using UPLC-ESI-MS/MS Combined with Hierarchical Cluster Analysis. AB - A tissue-smashing based ultra-rapid extraction coupled with ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method was developed to determine 10 major triterpenoid saponins from Pulsatilla herbs. Compound 4 was characterized as betulinic acid glycoside 3-O-alpha-arabinopyranosyl-28-O-beta glucopyranosyl-23-hydroxy with HR-ESI-MS, 1H-NMR and 13C-NMR experiment. The MS spectra result showed that the ionization of compound 4 was more efficient in the positive mode. Meanwhile, the ions at m/z 789.6 and m/z 627.5 were selected as precursor and product ion for the determination, respectively. The chromatographic separation was carried out on a Phenomenex Kinetex C18 column using a gradient mobile phase system composed of 0.1% formic acid both in methanol and water at a flow rate of 0.4 mL/min. The detection was performed by multiple reaction monitoring mode, using electrospray ionization in the positive and negative mode. The total run time was 6 min. The calibration curves possessed good linearity with all coefficients higher than 0.9987. The intra- and interday precisions were no more than 4.9%, and the average recoveries were from 97.6% to 103.4% with RSD <4.7%. Moreover, hierarchical cluster analysis was performed to compare and discriminate the Pulsatilla herbs based on the quantitative data. The hierarchical cluster analysis results demonstrated that Pulsatilla chinensis, Pulsatilla cernua, Pulsatilla dahurica, Pulsatilla turczainovii samples could be easily discriminated from each other based on the contents of triterpenoid saponins and the established method is feasible for quality control of Pulsatilla herbs. PMID- 29236951 TI - Epicardial adipose tissue volume assessed by computed tomography and coronary artery disease: a systematic review and meta-analysis. AB - To conduct a systematic review and meta-analysis on the crude and adjusted associations between epicardial adipose tissue (EAT) volume determined by computed tomography (CT) and coronary artery disease (CAD). MEDLINE, Scopus, and Web of Science databases were screened for all observational studies assessing the association between EAT volume and CAD. We calculated pooled odds ratio (OR) or hazard ratio (HR) and 95% confidence intervals (CI) for the association per 10 cm3 variation of EAT by five different definitions of CAD: obstructive or significant coronary stenosis (luminal narrowing >=50% and >=70%, respectively), presence of coronary artery calcification (CAC), myocardial ischaemia, and major adverse cardiovascular events (MACE) using DerSimonian and Laird random-effects models. Seventy studies were identified comprising 41 534 subjects, mainly derived from community-based or hospital-based low-to-intermediate pretest probability of CAD populations. Participants with any outcome of CAD had a higher mean volume of EAT than those without. Accordingly, the analysis of crude associations showed that EAT volume was associated with obstructive stenosis, significant stenosis, any CAC, and MACE. Based on the analysis of adjusted associations, although attenuated, EAT volume remained associated with obstructive stenosis (OR 1.055, 95% CI 1.033-1.078; I2 = 63.5%), significant stenosis (OR 1.514, 95% CI 1.262-1.815; I2 = 51.8%), myocardial ischaemia (OR 1.062, 95% CI 1.006-1.122; I2 = 86.9%), and MACE (HR 1.040, 95% CI 1.024-1.056; I2 = 64.7%) but was only borderline significant with CAC (OR 1.007, 95% CI 1.000 1.011; I2 = 75.8%). In low-to-intermediate cardiovascular risk subjects, EAT volume was independently associated with coronary artery stenosis, myocardial ischaemia, and MACE. PMID- 29236952 TI - Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine. AB - Aims: Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. Creatine levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) in the kidney catalyses both the first step in creatine biosynthesis as well as homoarginine (HA) synthesis. AGAT-/- mice fed a creatine-free diet have a whole body creatine-deficiency. We hypothesized that AGAT-/- mice would develop cardiac dysfunction and rescue by dietary creatine would imply causality. Methods and results: Withdrawal of dietary creatine in AGAT-/- mice provided an estimate of myocardial creatine efflux of ~2.7%/day; however, in vivo cardiac function was maintained despite low levels of myocardial creatine. Using AGAT-/- mice naive to dietary creatine we confirmed absence of phosphocreatine in the heart, but crucially, ATP levels were unchanged. Potential compensatory adaptations were absent, AMPK was not activated and respiration in isolated mitochondria was normal. AGAT-/- mice had rescuable changes in body water and organ weights suggesting a role for creatine as a compatible osmolyte. Creatine-naive AGAT-/- mice had haemodynamic impairment with low LV systolic pressure and reduced inotropy, lusitropy, and contractile reserve. Creatine supplementation only corrected systolic pressure despite normalization of myocardial creatine. AGAT-/- mice had low plasma HA and supplementation completely rescued all other haemodynamic parameters. Contractile dysfunction in AGAT-/- was confirmed in Langendorff perfused hearts and in creatine-replete isolated cardiomyocytes, indicating that HA is necessary for normal cardiac function. Conclusions: Our findings argue against low myocardial creatine per se as a major contributor to cardiac dysfunction. Conversely, we show that HA deficiency can impair cardiac function, which may explain why low HA is an independent risk factor for multiple cardiovascular diseases. PMID- 29236953 TI - Applications of cardiac computed tomography in electrophysiology intervention. AB - Cardiac electrophysiology is an evolving specialty that has seen rapid advances in recent years. Concurrently, there has been much progress in the field of cardiac imaging. Electrophysiologists are increasingly requesting cross-sectional imaging in advance of many procedures. Pulmonary vein isolation and left atrial appendage (LAA) occlusion are now an established treatment options for atrial fibrillation. In patients undergoing pulmonary vein isolation, applications of computed tomography (CT) include evaluating the left atrial and pulmonary venous anatomy, excluding LAA thrombus and assessing for pulmonary vein stenosis. In those undergoing LAA occlusion, CT may be of value in assessing the size, position, and morphology of the LAA as well as for determining correct positioning of the device and evaluating for peri-device leak. Implantable cardiac devices are now commonly used in the management of cardiac failure and cardiac arrhythmias. Applications of CT prior to device implantation include detecting myocardial scar, evaluating for mechanical dyssynchrony as well as visualising the coronary venous anatomy. PMID- 29236954 TI - NGLview-interactive molecular graphics for Jupyter notebooks. AB - Summary: NGLview is a Jupyter/IPython widget to interactively view molecular structures as well as trajectories from molecular dynamics simulations. Fast and scalable molecular graphics are provided through the NGL Viewer. The widget supports showing data from the file-system, online data bases and from objects of many popular analysis libraries including mdanalysis, mdtraj, pytraj, rdkit and more. Availability and implementation: The source code is freely available under the MIT license at https://github.com/arose/nglview. Python packages are available from PyPI and bioconda. NGLview uses Python on the server-side and JavaScript on the client. The integration with Jupyter is done through the ipywidgets package. The NGL Viewer is embedded client-side to provide WebGL accelerated molecular graphics. Contact: asr.moin@gmail.com. PMID- 29236955 TI - Clustering single cells: a review of approaches on high-and low-depth single-cell RNA-seq data. AB - Advances in single-cell RNA-sequencing technology have resulted in a wealth of studies aiming to identify transcriptomic cell types in various biological systems. There are multiple experimental approaches to isolate and profile single cells, which provide different levels of cellular and tissue coverage. In addition, multiple computational strategies have been proposed to identify putative cell types from single-cell data. From a data generation perspective, recent single-cell studies can be classified into two groups: those that distribute reads shallowly over large numbers of cells and those that distribute reads more deeply over a smaller cell population. Although there are advantages to both approaches in terms of cellular and tissue coverage, it is unclear whether different computational cell type identification methods are better suited to one or the other experimental paradigm. This study reviews three cell type clustering algorithms, each representing one of three broad approaches, and finds that PCA-based algorithms appear most suited to low read depth data sets, whereas gene clustering-based and biclustering algorithms perform better on high read depth data sets. In addition, highly related cell classes are better distinguished by higher-depth data, given the same total number of reads; however, simultaneous discovery of distinct and similar types is better served by lower-depth, higher cell number data. Overall, this study suggests that the depth of profiling should be determined by initial assumptions about the diversity of cells in the population, and that the selection of clustering algorithm(s) subsequently based on the depth of profiling will allow for better identification of putative transcriptomic cell types. PMID- 29236956 TI - Stability-Indicating Liquid Chromatographic Methods with Photodiode Array Detection and Light Scattering Detection for Simultaneous Determination of Candesartan and Hydrochlorothiazide. AB - Development, validation and comparison of two stability-indicating LC methods, one with photodiode array detector (DAD) and the other with evaporative light scattering detector (ELSD), were performed for simultaneous determination of candesartan cilexetil (CANC) and hydrochlorothiazide (HCTZ), in pharmaceutical samples. A RP-18 column (125 mm * 4 mm, 5 MUm) was used for separation of CANC, HCTZ and its major degradation products, using acetonitrile and phosphate buffer (pH 6.0) for DAD method and acetonitrile and water with acetic acid and triethylamine (pH 4.1) for ELSD method, as mobile phase in a gradient mode. The response with ELSD was fitted to a power function and the DAD response by a linear model over a range of 32-160 MUg/mL for CANC and 25-125 MUg/mL for HCTZ. The precision and accuracy of the methods were similar, with RSD below 3.0% and recovery between 98.1% and 103.9%. The drugs were subjected to stress conditions of hydrolysis, oxidation, photolysis, humidity and temperature. The degradation products were satisfactory separated from the main peaks and from each other. Both drugs mainly degrade by hydrolysis, showing the formation of one degradation product for HCTZ and two for CANC; its identification was conducted by LC/MS/MS. The methods were successfully applied to the analysis of CANC and HCTZ in combined commercial tablets. The performance of DAD and ELSD methods are comparable, therefore both methods are suitable for stability study and determination of CANC and HCTZ in pharmaceutical samples. PMID- 29236957 TI - Pharmacogenomics: time to rethink its role in precision medicine. PMID- 29236958 TI - Patterns of Alcohol Use in Italian Emerging Adults: A Latent Class Analysis Study. AB - Aims: The goals of the current study were to identify latent classes of alcohol users among Italian emerging adults (18-33 years), examine differences in the class solution based on socio-demographic characteristics, and examine whether differences exist across classes in experiencing different types of alcohol related negative consequences. Methods: Participants (N = 5955; 62.72% female; mean age 27.19 years) were drawn from a pre-recruited Web panel designed to be representative of the Italian young adults (18-33 years) population. Latent class analysis (LCA) was used to identify common patterns of alcohol use. Results: Four classes of drinking patterns were identified: (a) Current Nondrinkers (15%); (b) Weekend Non-Risky Drinkers (51%); (c) Weekend Risky Drinkers (20%); and (d) Daily Drinkers (13%). The number and type of classes did not differ across several demographic variables, although proportions within classes varied by sex, age, occupation status and geographic area. Weekend Risky Drinkers experienced the greatest number of alcohol-related negative consequences. Conclusions: The great majority of the sample displayed drinking patterns with relatively infrequent involvement in risky drinking. Preventive interventions should, instead, target those who drink alcohol on weekends only, but show the greatest negative consequences. Short Summary: Four classes of drinking patterns were identified in a large representative sample of Italian young adults. The great majority of the sample displayed drinking patterns with relatively little involvement in risky drinking, though those misusing alcohol at weekends were at greatest risk to experience alcohol-related negative consequences. PMID- 29236959 TI - Aging Decreases Chorda-Tympani Nerve Responses to NaCl and Alters Morphology of Fungiform Taste Pores in Rats. AB - Sensory processing is susceptible to decline with age. The sense of taste is, however, generally thought to be resistant to aging. We investigated how chorda tympani nerve responses and fungiform-taste pores are affected by aging in the Sprague-Dawley rat, a model system for salt taste. First, we measured chorda tympani nerve responses to NH4Cl and NaCl solutions in young (3-5 months old) and aged (14-15 months old) rats. Aged rats had significantly attenuated chorda tympani responses to 0.01, 0.03, 0.1, and 0.3 M NaCl, whereas responses to NH4Cl were statistically similar between age groups. Second, we investigated if fungiform papillae, which harbor taste buds innervated by the chorda-tympani nerve, were affected by aging in "young" (4-7 months old) and "aged" ("aged1" 18 months old and "aged2" 24-28 months old) rats. Using scanning electron microscopy, we found that aging significantly reduced morphological characteristics associated with intact fungiform-taste pores (hillock, rim, pore presence, and open pore). We conclude that the structure and function of the peripheral-taste system may not be as resistant to aging as previously reported. PMID- 29236960 TI - MicroRNA-128-3p-mediated depletion of Drosha promotes lung cancer cell migration. AB - Alteration in microRNAs (miRNAs) expression is a frequent finding in human cancers. In particular, widespread miRNAs down-regulation is a hallmark of malignant transformation. In the present report, we showed that the miR-128-3p, which is up-regulated in lung cancer tissues, has Drosha and Dicer, two key enzymes of miRNAs processing, as the main modulation targets leading to the widespread down-regulation of miRNA expression. We observed that the miRNAs downregulation induced by miR-128-3p contributed to the tumorigenic properties of lung cancer cells. In particular, miR-128-3p-mediated miRNAs down-regulation contributed to aberrant SNAIL and ZEB1 expression thereby promoting the epithelial-to-mesenchymal transition (EMT) program. Drosha also resulted to be implicated in the control of migratory phenotype as its expression counteracted miR-128-3p functional effects. Our study provides mechanistic insights into the function of miR-128-3p as a key regulator of the malignant phenotype of lung cancer cells. This also enforces the remarkable impact of Drosha and Dicer alteration in cancer, and in particular it highlights a role for Drosha in non small-cell lung cancer cells migration. PMID- 29236961 TI - Outlier detection for improved differential splicing quantification from RNA-Seq experiments with replicates. AB - Motivation: A key component in many RNA-Seq-based studies is contrasting multiple replicates from different experimental conditions. In this setup, replicates play a key role as they allow to capture underlying biological variability inherent to the compared conditions, as well as experimental variability. However, what constitutes a 'bad' replicate is not necessarily well defined. Consequently, researchers might discard valuable data or downstream analysis may be hampered by failed experiments. Results: Here we develop a probability model to weigh a given RNA-Seq sample as a representative of an experimental condition when performing alternative splicing analysis. We demonstrate that this model detects outlier samples which are consistently and significantly different compared with other samples from the same condition. Moreover, we show that instead of discarding such samples the proposed weighting scheme can be used to downweight samples and specific splicing variations suspected as outliers, gaining statistical power. These weights can then be used for differential splicing (DS) analysis, where the resulting algorithm offers a generalization of the MAJIQ algorithm. Using both synthetic and real-life data, we perform an extensive evaluation of the improved MAJIQ algorithm in different scenarios involving perturbed samples, mislabeled samples, same condition groups, and different levels of coverage, showing it compares favorably to other tools. Overall, this work offers an outlier detection algorithm that can be combined with any splicing pipeline, a generalized and improved version of MAJIQ for DS detection, and evaluation metrics with matching code and data for DS algorithms. Availability and implementation: Software and data are accessible via majiq.biociphers.org/norton_et_al_2017/. Contact: yosephb@upenn.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29236962 TI - Anastomosis of the thoracic duct and the azygos vein for the treatment of recurrent chylothoraxes. AB - Thoracic duct ligation is a widely accepted treatment option for chylothorax. This case report describes another treatment approach for recurrent chylothoraxes after thoracic duct ligation. A 40-year-old woman had chylothoraxes after thoracic duct ligation. She underwent a secondary surgery to ligate the thoracic duct. Three days later, the number of chylothoraxes increased compared with presurgery, and we anastomosed the thoracic duct and azygos vein after releasing the thoracic duct ligation. The patient recovered smoothly and was followed up for 2 years. This case shows that anastomosis of the thoracic duct and azygos vein is an alternative surgical approach to treat recurrent chylothoraxes. PMID- 29236964 TI - Erratum. PMID- 29236963 TI - Stearic acid supplementation in high protein to carbohydrate (P:C) ratio diet improves physiological and mitochondrial functions of Drosophila melanogaster parkin null mutants. AB - Optimizing dietary macronutrients benefits the prevention and management of many human diseases but there is conflicting dietary advice for Parkinson's disease (PD), and no single strategy is universally recommended. Recently, it was shown that dietary stearic acid (C18:0) improves survival and mitochondrial functions in the parkin null Drosophila model of PD. Here we incorporate stearic acid into high protein and high carbohydrate diets and study survival, climbing ability, mitochondrial membrane potential, respiration, basal reactive oxygen species and conduct lipidomics assays. We observed parkin null flies showed improvement in all assays tested when stearic acid was added to high protein but not to the high carbohydrate diet. When lipid proportion was examined we observed higher levels in flies fed the high protein diet with stearic acid and the high carbohydrate diet. Unexpectedly, free levels of fatty acids exhibited opposite trend. Combined, these data suggest that dietary Protein: Carbohydrate ratio and stearic acid influences levels of bound fatty acids. The mechanisms that influence free and bound fatty-acid levels remain to be explored, but one possible explanation is that breakdown products can bind to membranes and improve the mitochondrial functions of parkin null flies. PMID- 29236965 TI - Management errors in adults with congenital heart disease: prevalence, sources, and consequences. AB - Aims: Improved survival has resulted in increasing numbers and complexity of adults with congenital heart disease (ACHD). International guidelines recommend specialized care but many patients are still not managed at dedicated ACHD centres. This study analysed referral sources and appropriateness of management for patients referred to our tertiary ACHD Centre over the past 3 years. Methods and results: We compared differences in care between patients referred from paediatric/ACHD-trained vs. general adult cardiologists, according to Adherence (A) or Non-Adherence (NA) with published guidelines. Non-Adherent cases were graded according to the severity of adverse outcome or risk of adverse outcome. Of 309 consecutively referred patients (28 +/- 14 years, 51% male), 134 (43%) were from general cardiologists (19% highly complex CHD) and 115 (37%) were from paediatric cardiology or ACHD specialists (33% highly complex CHD). Sixty referrals (20%) were from other medical teams and of those, 31 had been lost to follow-up. Guideline deviations were more common in referrals from general compared to CHD-trained cardiologists (P < 0.001). Of general cardiology referrals, 49 (37%) were NA; 18 had catastrophic or major complications (n = 2, 16 respectively). In contrast, only 12 (10%) of the paediatric/ACHD referrals were NA, but none of these were catastrophic and only 3 were major. Simple, moderate, and highly complex CHD patients were at increased risk of adverse outcome when not under specialized CHD cardiology care (P = 0.04, 0.009, and 0.002, respectively). Conclusion: Non-adherence with guidelines was common in the ACHD population, and this frequently resulted in important adverse clinical consequences. These problems were more likely in patients who had not been receiving specialized CHD care. Configuring healthcare systems to optimize 'whole of life' care for this growing population is essential. PMID- 29236967 TI - Postoperative analgesia after pulmonary resection with a focus on video-assisted thoracoscopic surgery. AB - Video-assisted thoracoscopic surgery is a widespread technique that has been linked to improved postoperative respiratory function, reduced hospital length of stay and a higher level of tolerability for the patients. Acute postoperative pain is of considerable significance, and the late development of neuropathic pain syndrome is also an issue. As anaesthesiologists, we have investigated the available evidence to optimize postoperative pain management. An opioid-sparing multimodal approach is highly recommended. Loco-regional techniques such as the thoracic epidural and peripheral blocks can be performed. Several adjuvants have been employed with varying degrees of success both intravenously and in combination with local anesthetics. Opioids with different pharmacodynamic and pharmacokinetic profiles can be used, either through continuous infusion or on demand. Non-opioid analgesics are also beneficial. Finally, perioperative gabapentinoids may be implemented to prevent the onset of chronic neuropathic pain. PMID- 29236968 TI - Use of ultrasound for the palpable undescended testis: a wasteful practice. AB - Background: Many primary care physicians order an ultrasound (US) before referral to specialist care for suspected undescended testis; however, the value of this practice is questionable. Objective: To determine the proportion of boys referred for suspected undescended testis who had accompanying US, the cost of this practice and the accuracy of US for testis localization when compared with physical examination by a pediatric urologist. Methods: This was a retrospective chart review at a pediatric urology service, including all patients referred for suspected undescended testis from 2008 to 2012. We determined the cost of US ordered, and calculated Cohen's kappa, sensitivity and specificity, and positive and negative predictive value. Results: We identified 894 eligible patients; 32% (289/894) were accompanied by US. In 77% (223/289), the urologist was able to palpate the testis: 51% (147/289) had a normal/retractile testis and 26% (76/289) had a palpable undescended testis. At a cost of 71.10 CAD per US, 20 547.90 CAD was expended on this practice. Of the 223 patients with palpable testes, we were able to gather detailed US and physical examination results for 214 patients. Cohen's kappa was 0.06 (95% CI -0.005, 0.11; P = 0.10). US had 92.8% sensitivity (95% CI 84.1, 96.9%) and 15.2% specificity (95% CI 10.2, 21.9%) to detect an undescended testis. The positive predictive value was 34.2% (95% CI 27.8, 41.3%), while the negative predictive value was 81.5% (95% CI 63.3, 91.8%). Conclusions: Referral of patients for suspected undescended testis should not be accompanied by an US study as US is not useful in these cases. PMID- 29236969 TI - DaMiRseq-an R/Bioconductor package for data mining of RNA-Seq data: normalization, feature selection and classification. AB - Summary: RNA-Seq is becoming the technique of choice for high-throughput transcriptome profiling, which, besides class comparison for differential expression, promises to be an effective and powerful tool for biomarker discovery. However, a systematic analysis of high-dimensional genomic data is a demanding task for such a purpose. DaMiRseq offers an organized, flexible and convenient framework to remove noise and bias, select the most informative features and perform accurate classification. Availability and implementation: DaMiRseq is developed for the R environment (R >= 3.4) and is released under GPL (>=2) License. The package runs on Windows, Linux and Macintosh operating systems and is freely available to non-commercial users at the Bioconductor open-source, open-development software project repository (https://bioconductor.org/packages/DaMiRseq/). In compliance with Bioconductor standards, the authors ensure stable package maintenance through software and documentation updates. Contact: luca.piacentini@ccfm.it. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29236966 TI - Neuronal inhibition and synaptic plasticity of basal ganglia neurons in Parkinson's disease. AB - Deep brain stimulation of the subthalamic nucleus is an effective treatment for Parkinson's disease symptoms. The therapeutic benefits of deep brain stimulation are frequency-dependent, but the underlying physiological mechanisms remain unclear. To advance deep brain stimulation therapy an understanding of fundamental mechanisms is critical. The objectives of this study were to (i) compare the frequency-dependent effects on cell firing in subthalamic nucleus and substantia nigra pars reticulata; (ii) quantify frequency-dependent effects on short-term plasticity in substantia nigra pars reticulata; and (iii) investigate effects of continuous long-train high frequency stimulation (comparable to conventional deep brain stimulation) on synaptic plasticity. Two closely spaced (600 um) microelectrodes were advanced into the subthalamic nucleus (n = 27) and substantia nigra pars reticulata (n = 14) of 22 patients undergoing deep brain stimulation surgery for Parkinson's disease. Cell firing and evoked field potentials were recorded with one microelectrode during stimulation trains from the adjacent microelectrode across a range of frequencies (1-100 Hz, 100 uA, 0.3 ms, 50-60 pulses). Subthalamic firing attenuated with >=20 Hz (P < 0.01) stimulation (silenced at 100 Hz), while substantia nigra pars reticulata decreased with >=3 Hz (P < 0.05) (silenced at 50 Hz). Substantia nigra pars reticulata also exhibited a more prominent increase in transient silent period following stimulation. Patients with longer silent periods after 100 Hz stimulation in the subthalamic nucleus tended to have better clinical outcome after deep brain stimulation. At >=30 Hz the first evoked field potential of the stimulation train in substantia nigra pars reticulata was potentiated (P < 0.05); however, the average amplitude of the subsequent potentials was rapidly attenuated (P < 0.01). This is suggestive of synaptic facilitation followed by rapid depression. Paired pulse ratios calculated at the beginning of the train revealed that 20 Hz (P < 0.05) was the minimum frequency required to induce synaptic depression. Lastly, the average amplitude of evoked field potentials during 1 Hz pulses showed significant inhibitory synaptic potentiation after long train high frequency stimulation (P < 0.001) and these increases were coupled with increased durations of neuronal inhibition (P < 0.01). The subthalamic nucleus exhibited a higher frequency threshold for stimulation-induced inhibition than the substantia nigra pars reticulata likely due to differing ratios of GABA:glutamate terminals on the soma and/or the nature of their GABAergic inputs (pallidal versus striatal). We suggest that enhancement of inhibitory synaptic plasticity, and frequency-dependent potentiation and depression are putative mechanisms of deep brain stimulation. Furthermore, we foresee that future closed loop deep brain stimulation systems (with more frequent off stimulation periods) may benefit from inhibitory synaptic potentiation that occurs after high frequency stimulation. PMID- 29236970 TI - Seen through the patients' eyes: quality of chronic illness care. AB - Background: Most well-developed healthcare systems are facing the challenge of managing the increasing prevalence of patients with chronic diseases. Comprehensive frameworks, such as the chronic care model (CCM), receive widespread acceptance for improving care processes, clinical outcomes and costs. Objective: The purpose of this study was to explore chronic patients' perceptions of the quality of chronic care and the alignment with the CCM. Since previous research indicated that a patient's assessment may depend on socio-demographic or disease-related characteristics, the relationship between the mean Patient Assessment of Chronic Illness Care (PACIC) score and possible aforementioned predictors was also explored. Methods: An observational, cross-sectional study design was applied, and participants were recruited from the Flemish Patients' Platform (Belgium). An online questionnaire was designed to assess chronic patients' socio-demographic characteristics, medical consumption, quality of life (EuroQol-5D survey) and the perspective of chronic illness care PACIC survey. Results: The mean overall PACIC score was 2.87 on a maximum score of 5. The highest mean score for the PACIC subscales was found for 'patient activation' (3.26), followed by 'delivery system design/decision support' (3.23), 'problem solving/contextual counselling' (2.86), 'goal setting/tailoring' (2.70) and 'follow-up/coordination' (2.59). Quality of life, as measured by the EuroQol Visual Analogue Scale, had a significantly positive correlation with the mean PACIC score (P = 0.005). Conclusion: The CCM is considered an important step towards improved care for patients with chronic diseases. However, the findings of this study showed that elements from the CCM have not yet been fully implemented. Aspects such as dealing with problems which interfered with achieving predefined goals, helping patients to set specific goals for their care delivery and arranging follow-ups are less common in today's care of chronic diseases. PMID- 29236972 TI - Evaluation of diastolic function by echocardiography: important progression, but issues to be resolved. PMID- 29236971 TI - New algorithms to represent complex pseudoknotted RNA structures in dot-bracket notation. AB - Motivation: Understanding the formation, architecture and roles of pseudoknots in RNA structures are one of the most difficult challenges in RNA computational biology and structural bioinformatics. Methods predicting pseudoknots typically perform this with poor accuracy, often despite experimental data incorporation. Existing bioinformatic approaches differ in terms of pseudoknots' recognition and revealing their nature. A few ways of pseudoknot classification exist, most common ones refer to a genus or order. Following the latter one, we propose new algorithms that identify pseudoknots in RNA structure provided in BPSEQ format, determine their order and encode in dot-bracket-letter notation. The proposed encoding aims to illustrate the hierarchy of RNA folding. Results: New algorithms are based on dynamic programming and hybrid (combining exhaustive search and random walk) approaches. They evolved from elementary algorithm implemented within the workflow of RNA FRABASE 1.0, our database of RNA structure fragments. They use different scoring functions to rank dissimilar dot-bracket representations of RNA structure. Computational experiments show an advantage of new methods over the others, especially for large RNA structures. Availability and implementation: Presented algorithms have been implemented as new functionality of RNApdbee webserver and are ready to use at http://rnapdbee.cs.put.poznan.pl. Contact: mszachniuk@cs.put.poznan.pl. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29236973 TI - The role of financial strain and self-control in explaining health behaviours: the GLOBE study. AB - Background: Why lower socioeconomic groups behave less healthily can only partly be explained by direct costs of behaving healthily. We hypothesize that low income increases the risk of facing financial strain. Experiencing financial strain takes up cognitive 'bandwidth' and leads to less self-control, and subsequently results in more unhealthy behaviour. We therefore aim to investigate (i) whether a low income increases the likelihood of experiencing financial strain and of unhealthy behaviours, (ii) to what extent more financial strain is associated with less self-control and, subsequently, (iii) whether less self control is related to more unhealthy behaviour. Methods: Cross-sectional survey data were obtained from participants (25-75 years) in the fifth wave of the Dutch GLOBE study (N = 2812) in 2014. The associations between income, financial strain, self-control and health-behaviour-related outcomes (physical inactivity in leisure-time, obesity, smoking, excessive alcohol intake, and weekly fruit and vegetable intake) were analysed with linear regression and generalized linear regression models (log link). Results: Experiencing great compared with no financial strain increased the risk of all health-behaviour-related outcomes, independent of income. Low self-control, as compared with high self-control, also increased the risk of an unhealthy lifestyle. Taking self-control into account slightly attenuated the associations between financial strain and the outcomes. Conclusion: Great financial strain and low self-control are consistently associated with unhealthy behaviours. Self-control may partly mediate between financial strain and unhealthy behaviour. Interventions that relieve financial strain may free up cognitive bandwidth and improve health behaviour. PMID- 29236974 TI - Diabetes as an independent predictor of left ventricular longitudinal strain reduction at rest and during dobutamine stress test in patients with significant coronary artery disease. AB - Aims: Diabetes (DM) is a strong cardiovascular risk factor modifying also the left ventricular (LV) function that may be objectively assessed with echocardiographic strain analysis. Although the impact of isolated DM on myocardial deformation has been already studied, few data concern diabetics with coronary artery disease (CAD), especially in all stages of dobutamine stress echocardiography (DSE). We compared LV systolic function during DSE in CAD with and without DM using state-of-the art speckle-tracking quantification and assessed the impact of DM on LV systolic strain. Methods and results: DSE was performed in 250 patients with angina who afterwards had coronarography with >=50% stenosis in the left main artery and >=70% in other arteries considered as significant. In this analysis, we included 127 patients with confirmed CAD: 42 with DM [DM(+); mean age 64 +/- 9 years] and 85 patients without DM [DM(-); mean age 63 +/- 9 years]. The severity of CAD and LV ejection fraction (EF) were similar in both groups. Global and regional LV peak systolic longitudinal strain (PSLS) revealed in all DSE phases lower values in DM(+) group: 14.5 +/- 3.6% vs. 17.4 +/- 4.0% at rest; P = 0.0001, 13.8 +/- 3.9% vs. 16.7 +/- 4.0% at peak stress; P = 0.0002, and 14.2 +/- 3.1% vs. 15.5 +/- 3.5% at recovery; P = 0.0432 for global parameters, although dobutamine challenge did not enhance further resting differences. LV EF, body surface area, and diabetes were independent predictors for strain in 16-variable model (R2 = 0, 51, P < 0.001). Conclusion: PSLS although diminished in both groups with CAD was lower in diabetics at all DSE stages, and DM was an independent predictor of this impairment. However, the dobutamine challenge did not deepen the resting differences, suggesting that the direct impact of coronary stenoses effaces the influence of DM during DSE. The comparison with our previous data revealed synergistic, detrimental effect of coexisting CAD and DM on myocardial strain. PMID- 29236975 TI - IndeCut evaluates performance of network motif discovery algorithms. AB - Motivation: Genomic networks represent a complex map of molecular interactions which are descriptive of the biological processes occurring in living cells. Identifying the small over-represented circuitry patterns in these networks helps generate hypotheses about the functional basis of such complex processes. Network motif discovery is a systematic way of achieving this goal. However, a reliable network motif discovery outcome requires generating random background networks which are the result of a uniform and independent graph sampling method. To date, there has been no method to numerically evaluate whether any network motif discovery algorithm performs as intended on realistically sized datasets-thus it was not possible to assess the validity of resulting network motifs. Results: In this work, we present IndeCut, the first method to date that characterizes network motif finding algorithm performance in terms of uniform sampling on realistically sized networks. We demonstrate that it is critical to use IndeCut prior to running any network motif finder for two reasons. First, IndeCut indicates the number of samples needed for a tool to produce an outcome that is both reproducible and accurate. Second, IndeCut allows users to choose the tool that generates samples in the most independent fashion for their network of interest among many available options. Availability and implementation: The open source software package is available at https://github.com/megrawlab/IndeCut. Contact: megrawm@science.oregonstate.edu or david.koslicki@math.oregonstate.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29236976 TI - 'Highest risk-highest benefit' strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. PMID- 29236977 TI - gene2drug: a computational tool for pathway-based rational drug repositioning. AB - Motivation: Drug repositioning has been proposed as an effective shortcut to drug discovery. The availability of large collections of transcriptional responses to drugs enables computational approaches to drug repositioning directly based on measured molecular effects. Results: We introduce a novel computational methodology for rational drug repositioning, which exploits the transcriptional responses following treatment with small molecule. Specifically, given a therapeutic target gene, a prioritization of potential effective drugs is obtained by assessing their impact on the transcription of genes in the pathway(s) including the target. We performed in silico validation and comparison with a state-of-art technique based on similar principles. We next performed experimental validation in two different real-case drug repositioning scenarios: (i) upregulation of the glutamate-pyruvate transaminase (GPT), which has been shown to induce reduction of oxalate levels in a mouse model of primary hyperoxaluria, and (ii) activation of the transcription factor TFEB, a master regulator of lysosomal biogenesis and autophagy, whose modulation may be beneficial in neurodegenerative disorders. Availability and implementation: A web tool for Gene2drug is freely available at http://gene2drug.tigem.it. An R package is under development and can be obtained from https://github.com/franapoli/gep2pep. Contact: dibernardo@tigem.it. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29236979 TI - Relevance of low miR-30c-5p levels in atherogenesis: a promising predictive biomarker and potential therapeutic target. PMID- 29236978 TI - Impact of the 2016 ASE/EACVI recommendations on the prevalence of diastolic dysfunction in the general population. AB - Aims: Diastolic dysfunction (DD) is frequent in the general population; however, the assessment of diastolic function remains challenging. We aimed to evaluate the impact of the recent 2016 American Society of Echocardiography (ASE)/European Association of Cardiovascular Imaging (EACVI) recommendations in the prevalence and grades of DD compared with the 2009 guidelines and the Canberra Study Criteria (CSC). Methods and results: Within a population-based cohort, a total of 1000 individuals, aged >=45 years, were evaluated retrospectively. Patients with previously known cardiac disease or ejection fraction <50% were excluded. Diastolic function was assessed by transthoracic echocardiography. DD prevalence and grades were determined according to the three classifications. The mean age was 62.0 +/- 10.5 years and 37% were men. The prevalence of DD was 1.4% (n = 14) with the 2016 recommendations, 38.1% (n = 381) with the 2009 recommendations, and 30.4% (n = 304) using the CSC. The concordance between the updated recommendations and the other two was poor (from k = 0.13 to k = 0.18, P < 0.001). Regarding the categorization in DD grades, none of the 14 individuals with DD by the 2016 guidelines were assigned to Grade 1 DD, 64% were classified as Grade 2, 7% had Grade 3, and 29% had indeterminate grade. Conclusion: The application of the new 2016 ASE/EACVI recommendations resulted in a much lower prevalence of DD. The concordance between the classifications was poor. The updated algorithm seems to be able to diagnose only the most advanced cases. PMID- 29236980 TI - Simultaneous Determination of Tizanidine, Nimesulide, Aceclofenac and Paracetamol in Tablets and Biological Fluids Using Micellar Liquid Chromatography. AB - A simple, sensitive and rapid micellar liquid chromatographic method was developed and validated for simultaneous determination of four drugs, namely, paracetamol (PAR), tizanidine (TZD), aceclofenac (ACF) and nimesulide (NMD). Good chromatographic separation was achieved using Cyano column and micellar mobile phase consisting of 120 mM sodium dodecyl sulfate, 25 mM phosphate buffer and 10% (V/V) butanol. The pH was adjusted to three using phosphoric acid. The total retention time was below 10 min. The analysis was performed at a flow rate of 1 mL/min and a column temperature of 40 degrees C with direct UV detection at 230 nm. Diclofenac sodium was used as the internal standard. The proposed method was validated according to the ICH guidelines and was successfully applied to the analysis of these drugs in their tablet dosage forms with high accuracy. Limits of detection were found to be 0.03, 0.07, 0.033 and 0.11 MUg/mL for PAR, ACF, TZD and NMD, respectively. The high sensitivity of developed method permitted its application to the in-vitro determination of the cited drugs in spiked human plasma and urine samples, and the obtained results were satisfactory. However, PAR could not be determined in spiked human urine because its peak overlapped with that of the urine peak. PMID- 29236981 TI - Electrophysiology testing for risk stratification of patients with ischaemic cardiomyopathy: a call for action. AB - Current guidelines recommendations, based on the results of primary sudden cardiac death prevention trials, use the left ventricular ejection fraction (LVEF) as a sole criterion for the indication of implantable cardioverter defibrillator therapy for primary prevention purposes. In this article, we review the sensitivity and specificity of LVEF for predicting arrhythmic vs. non arrhythmic cardiac death and examine existing evidence on the use of electrophysiology testing for risk stratification of ischaemic patients with reduced left ventricular function. PMID- 29236982 TI - Primary care providers' willingness to continue gender-affirming hormone therapy for transgender patients. AB - Background: Most transgender individuals either use or are interested in using gender-affirming hormone therapy (HT). Making gender-affirming HT available in primary care is critical for quality care to this vulnerable population. The barriers that transgender patients experience to accessing this treatment may be exacerbated if primary care providers (PCPs) will not provide it. Little is known about PCPs' willingness to administer HT to transgender patients. Objective: To examine whether PCPs are willing to continue prescribing HT for transgender patients and the factors that predict such willingness. Methods: An online survey of internal and family medicine physicians and residents practising in a large integrated Midwest health system (n = 308); 158 responded to the relevant questions (51.3%). Results: Approximately 50% of respondents were willing to continue HT for transgender patients. Most participants had previously met a transgender person (77%), and approximately half of them had cared for a transgender patient in the past 5 years. Multivariate logistic regression results indicate that attending physicians had lower odds of willingness to continue HT compared with medical residents, and those who reported perceived capability of providing routine care to transgender patients had higher odds of willingness. Conclusions: Only about half of PCPs surveyed were willing to continue HT for transgender patients. Our study indicates that both personal and clinical factors play a role. Future research should address ways to increase PCPs' willingness and comfort related to continuing HT for transgender patients. PMID- 29236983 TI - Cardioprotective anti-hyperglycaemic medications: a review of clinical trials. AB - Despite extensive clinical efforts to achieve stricter glycaemic control over the past few decades, cardiovascular (CV) disease remains the leading cause of death among diabetic patients. Recently, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor (GLP-1-R) agonists have gained attention due to their apparent effects in reducing CV mortality. Four CV randomized controlled trials: EMPA-REG, CANVAS, LEADER, and SUSTAIN-6, found a decrease in CV events among patients with type 2 diabetes on empagliflozin, canagliflozin, liraglutide, and semaglutide, respectively. In light of this data, the US Food and Drug Administration has recently approved empagliflozin for CV mortality reduction in type 2 diabetic patients, making it the first diabetes medication approved for such an indication. The purpose of this review is to summarize the results of novel anti-hyperglycaemic medication trials, and shed light on their mode of action and cardioprotective pathways. PMID- 29236984 TI - Longitudinal Association Between Brain Amyloid-Beta and Gait in the Mayo Clinic Study of Aging. AB - Background: The longitudinal association between cerebral amyloid-beta (Abeta) and change in gait, and whether this association is mediated by cortical thickness, has yet to be determined. Methods: We included 439 clinically normal (CN) participants, aged 50-69 years and enrolled in the Mayo Clinic Study of Aging with cerebral Abeta, cortical thickness, and gait measurements. Cerebral Abeta deposition was assessed by Pittsburgh Compound B (PiB)-PET in multiple regions of interest (ROIs) (ie, frontal, orbitofrontal, parietal, temporal, anterior cingulate, posterior cingulate/precuneus, and motor). Cortical thickness was assessed on 3T MRI in corresponding ROIs. Gait parameters (gait speed, cadence, stride length, double support time, and covariance of stance time) were measured with GAITRite. Multivariate-adjusted two level structural equation models were used to examine the longitudinal association between PiB-PET, cortical thickness, and change in gait over a median 15.6 months. Results: Higher PiB-PET in all ROIs was associated with decreasing cadence and increasing double support time, and in the temporal ROI was associated with declining gait speed. In sex-stratified analyses, higher PiB-PET in all ROIs was associated with declining performance on all gait parameters among women. In contrast, among men, the only association was with higher orbitofrontal ROI PiB-PET and declining cadence. None of the associations were mediated by cortical thickness or attenuated after adjustment of baseline cognition. Conclusion: Higher PiB-PET was associated with declining gait, particularly among women in this middle-aged CN cohort, independent of cortical thickness and baseline cognitive. Elevated brain Abeta may play a critical role in age-related mobility decline. PMID- 29236985 TI - How can male rates of HIV testing be increased? Recommendations from a mixed methods study in southern Malawi. AB - Background: In southern Malawi, 12.8% of adults are HIV positive. Men are less likely to have been tested than women. We investigated men's HIV knowledge and the attitudes, influencers, facilitators and barriers affecting HIV testing. Methods: We conducted an explanatory mixed-methods study with analysis of secondary quantitative data from 425 rural men collected in January 2014 (time 1) and April 2015 (time 2) and qualitative interviews with 50 men in September 2015. All respondents lived in villages receiving HIV education and testing. Results: Quantitative data revealed that comprehensive HIV knowledge increased and was associated with having been tested by time 2. Educational level was positively associated with having been tested. Men's reasons for not getting tested were fear of learning their HIV status, fear of rejection by partners and wives and fear of discrimination. Wives influenced men's opinions about healthcare. The qualitative results demonstrated that men feared being seen at test sites and feared discrimination. Wives had the greatest reported influence on male testing. Men perceived services as female-oriented and stigmatizing. They preferred door to-door testing. Conclusions: Providers can improve uptake by increasing men's HIV knowledge, leveraging the influence of spouses and offering door-to-door testing with male health workers. PMID- 29236986 TI - Training in cardiac computed tomography: EACVI certification process. PMID- 29236987 TI - Extragonadal Actions of FSH: A Critical Need for Novel Genetic Models. AB - Follicle-stimulating hormone (FSH) is critical for ovarian folliculogenesis and essential for female fertility. FSH binds to FSH receptors (FSHRs) and regulates estrogen production in ovarian granulosa cells to orchestrate female reproductive physiology. Ovarian senescence that occurs as a function of aging results in loss of estrogen production, and this is believed to be the major reason for bone loss in postmenopausal women. Although conflicting, studies in rodents and humans during the last decade have provided genetic, pharmacological, and physiological evidence that elevated FSH levels that occur in the face of normal or declining estrogen levels directly regulate bone mass and adiposity. Recently, an efficacious blocking polyclonal FSHbeta antibody was developed that inhibited ovariectomy-induced bone loss and triggered white-to-brown fat conversion accompanied by mitochondrial biogenesis in mice. Moreover, additional nongonadal targets of FSH action have been identified, and these include the female reproductive tract (endometrium and myometrium), the placenta, hepatocytes, and blood vessels. In this mini-review, I summarize these studies in mice and humans and discuss critical gaps in our knowledge, yet unanswered questions, and the rationale for developing novel genetic models to unambiguously address the extragonadal actions of FSH. PMID- 29236988 TI - Diagnostic and prognostic value of myocardial blood flow quantification as non invasive indicator of cardiac allograft vasculopathy. AB - Aims: Cardiac allograft vasculopathy (CAV) is a leading cause of death in orthotopic heart transplant (OHT) survivors. Effective non-invasive screening methods are needed. Our aim was to investigate the added diagnostic and prognostic value of myocardial blood flow (MBF) to standard myocardial perfusion imaging (MPI) with positron emission tomography (PET) for CAV detection. Methods and results: We studied 94 OHT recipients (prognostic cohort), including 66 who underwent invasive coronary angiography and PET within 1 year (diagnostic cohort). The ISHLT classification was used as standard definition for CAV. Positron emission tomography evaluation included semiquantitative MPI, quantitative MBF (mL/min/g), and left ventricular ejection fraction (LVEF). A PET CAV severity score (on a scale of 0-3) was modelled on the ISHLT criteria. Patients were followed for a median of 2.3 years for the occurrence of major adverse events (death, re-transplantation, acute coronary syndrome, and hospitalization for heart failure). Sensitivity, specificity, positive, and negative predictive value of semiquantitative PET perfusion alone for detecting moderate-severe CAV were 83% [52-98], 82% [69-91], 50% [27-73], and 96% [85-99], respectively {receiver operating characteristic (ROC area: 0.82 [0.70-0.95])}. These values improved to 83% [52-98], 93% [82-98], 71% [42-92], and 96% [97-99], respectively, when LVEF and stress MBF were added (ROC area: 0.88 [0.76-0.99]; P = 0.01). There were 20 major adverse events during follow-up. The annualized event rate was 5%, 9%, and 25% in patients with normal, mildly, and moderate-to severely abnormal PET CAV grading (P < 0.001), respectively. Conclusion: Multiparametric cardiac PET evaluation including quantification of MBF provides improved detection and gradation of CAV severity over standard myocardial perfusion assessment and is predictive of major adverse events. PMID- 29236989 TI - Swiss cheese heart. PMID- 29236990 TI - Outcome reporting for surgical treatment of degenerative mitral valve disease: a systematic review and critical appraisal. AB - OBJECTIVES: Standardized outcome reporting is of critical importance for performance monitoring, improvement of existing techniques and introduction of novel technologies. Whether outcome reporting for surgical treatment of degenerative mitral valve disease complies with the guidelines has not been assessed to date. METHODS: A systematic review of PubMed, EMBASE, Web of Science and the Cochrane Library was conducted for articles published between 1 January 2009 and 7 March 2016. Inclusion criteria were adult patient population (n >= 200) and surgical intervention for degenerative mitral valve disease. The quality of reported outcome was compared with the standard recommended by the guidelines on reporting morbidity and mortality after cardiac valve interventions. RESULTS: Forty-two non-randomized clinical studies were included: 4 provided early and 38 provided early and late outcome data. Early echocardiographic outcome was reported in 49% of studies. Freedom from reintervention, the indication for reintervention and the follow-up echocardiographic outcome were reported in 97%, 59% and 79% of studies providing late outcome data, respectively. The Kaplan Meier method was used to assess the freedom from recurrent mitral regurgitation in 60% (18/30) of studies, whereas 7% (2/30) of studies applied a longitudinal data analysis. Recurrent mitral regurgitation was most commonly defined as moderate (Grade 2+; 60%) or severe (Grade 4+; 37%) regurgitation. CONCLUSIONS: There is a significant discordance between the guidelines-based recommendations and actual reporting of outcome for surgical treatment of degenerative mitral valve disease. Better adherence to the guidelines would raise the quality and generalizability of clinical data reporting. PMID- 29236991 TI - Neurochemical changes in the medial wall of the brain in chronic migraine. AB - Migraine chronification is associated with a dysfunctional thalamocortical pathway. The present study addressed whether abnormal concentrations of neurochemicals exist in key brain regions of this pathway in chronic migraine. Magnetic resonance spectroscopic imaging of the bilateral medial walls of the brain was used to measure choline, creatine, glutamate and glutamine, myo inositol, and N-acetyl-aspartate in chronic migraine patients and in matched groups of episodic migraine patients and healthy controls. A region of interest analysis was conducted to examine whether N-acetyl-aspartate, a marker of neuronal integrity, was reduced in the thalamus, occipital cortex and anterior cingulate cortex in chronic migraine. Interregional N-acetyl-aspartate correlations among these regions of interest were also examined. Additionally, statistical mapping was performed for all the metabolites throughout the medial walls. Chronic migraine was associated with N-acetyl-aspartate reductions in the bilateral thalami and in the right anterior cingulate. The N-acetyl-aspartate reduction in the right thalamus correlated with disease duration. Compared with healthy controls, patients with chronic migraine had altered interregional N acetyl-aspartate correlations between the right thalamus-anterior cingulate and thalamus-occipital cortex, and between the left and right anterior cingulate. N acetyl-aspartate concentrations and interregional correlations in patients with episodic migraine were between those of healthy controls and chronic migraine patients. The unconstrained analyses revealed a reduction of myo-inositol in the left anterior and posterior cingulate in both patient groups as well as a negative association with depression scores for the anterior cingulate in the combined patient group. In addition, migraine patients with headache on the scan day (irrespective of diagnosis) had reduced N-acetyl-aspartate and total creatine concentrations in the right dorsal anterior cingulate. Reduced N-acetyl-aspartate metabolism and altered interregional N-acetyl-aspartate correlations lend support to the role of thalamocortical dysfunction in migraine chronification. It remains to be established if the pattern of changes within the N-acetyl-aspartate network is specific to chronic migraine or can be found in other chronic pain conditions. PMID- 29236993 TI - Balanced nutrition and hand hygiene for children in South Africa. AB - Globally, ~5.9 million children under the age of 5 years died in 2015, with the challenges of child mortality and morbidity being common in developing countries. Many of these deaths are preventable and poor nutritional and hygienic practices contribute greatly to these rates. The spread of infectious disease through unhygienic practices, such as inadequate hand hygiene, remains high due to lack of education regarding hygienic infection control practices at home and in the workplace. The aim of this research was to design and implement a participatory health promotion intervention for caregivers at the Rhodes Day Care Centre (RDCC) that highlighted these important public health issues. We conducted a pre intervention group feedback discussion with caregivers at the RDCC to identify current practices and to establish the current baseline knowledge of the caregivers. Health workshops with caregivers was facilitated by the researcher, and health information leaflets (HILs) were designed for and used during these workshops. Caregivers at RDCC exhibited fair baseline knowledge on the importance of providing nourishing meals to the infants, including the need for exclusive breastfeeding, and the importance of hand hygiene in preventing the spread of disease. This basic knowledge was positively built upon in the two health promotion intervention workshops. This initiative, held at RDCC, was able to catalyse the development of health knowledge that could have a substantial impact on the understanding of health literacy of the caregivers and on the promotion of adequate child health in the community. PMID- 29236992 TI - The Effects of Aging on the Regulation of T-Tubular ICa by Caveolin in Mouse Ventricular Myocytes. AB - Aging is associated with diminished cardiac function in males. Cardiac excitation contraction coupling in ventricular myocytes involves Ca influx via the Ca current (ICa) and Ca release from the sarcoplasmic reticulum, which occur predominantly at t-tubules. Caveolin-3 regulates t-tubular ICa, partly through protein kinase A (PKA), and both ICa and caveolin-3 decrease with age. We therefore investigated ICa and t-tubule structure and function in cardiomyocytes from male wild-type (WT) and caveolin-3-overexpressing (Cav-3OE) mice at 3 and 24 months of age. In WT cardiomyocytes, t-tubular ICa-density was reduced by ~50% with age while surface ICa density was unchanged. Although regulation by PKA was unaffected by age, inhibition of caveolin-3-binding reduced t-tubular ICa at 3 months, but not at 24 months. While Cav-3OE increased cardiac caveolin-3 protein expression ~2.5-fold at both ages, the age-dependent reduction in caveolin-3 (WT ~35%) was preserved in transgenic mice. Overexpression of caveolin-3 reduced t tubular ICa density at 3 months but prevented further ICa loss with age. Measurement of Ca release at the t-tubules revealed that the triggering of local Ca release by t-tubular ICa was unaffected by age. In conclusion, the data suggest that the reduction in ICa density with age is associated with the loss of a caveolin-3-dependent mechanism that augments t-tubular ICa density. PMID- 29236994 TI - Group G Streptococcus Induces an Autoimmune Carditis Mediated by Interleukin 17A and Interferon gamma in the Lewis Rat Model of Rheumatic Heart Disease. AB - Acute rheumatic fever and rheumatic heart disease (ARF/RHD) have long been described as autoimmune sequelae of Streptococcus pyogenes or group A streptococcal (GAS) infection. Both antibody and T-cell responses against immunodominant GAS virulence factors, including M protein, cross-react with host tissue proteins, triggering an inflammatory response leading to permanent heart damage. However, in some ARF/RHD-endemic regions, throat carriage of GAS is low. Because Streptococcus dysgalactiae subspecies equisimilis organisms, also known as beta-hemolytic group C streptococci and group G streptococci (GGS), also express M protein, we postulated that streptococci other than GAS may have the potential to initiate or exacerbate ARF/RHD. Using a model initially developed to investigate the uniquely human disease of ARF/RHD, we have discovered that GGS causes interleukin 17A/interferon gamma-induced myocarditis and valvulitis, hallmarks of ARF/RHD. Remarkably the histological, immunological, and functional changes in the hearts of rats exposed to GGS are identical to those exposed to GAS. Furthermore, antibody cross-reactivity to cardiac myosin was comparable in both GGS- and GAS-exposed animals, providing additional evidence that GGS can induce and/or exacerbate ARF/RHD. PMID- 29236995 TI - A prospective 5-year follow-up study after limited resection for lung cancer with ground-glass opacity. AB - OBJECTIVES: The incidence of small-sized pulmonary adenocarcinomas with ground glass opacity (GGO) has recently increased, with excellent postoperative prognosis. The limited resection of such cancers has been deemed to be acceptable based on retrospective studies. We conducted a prospective multi-institutional study evaluating the validity of limited resection for small-sized pulmonary adenocarcinoma with GGO. METHODS: The inclusion criteria were 25-80 years of age, no prior treatment, a maximum tumour diameter of 8-20 mm, a GGO ratio of >= 80%, clinical T1N0M0, lower 18F-fluorodeoxyglucose accumulation than the mediastinum, resectable by sublobar resection, pulmonary lobectomy tolerable and an intraoperative pathological diagnosis of bronchiloalveolar carcinoma. Wedge resection was preferred, but segmentectomy was permitted. Disease-specific survival and overall survival were analysed. RESULTS: From November 2006 to April 2012, 73 patients were enrolled from 13 institutions. One patient was ineligible, and the remaining 72 patients were preregistered. The tumours of 3 and 14 patients were intraoperatively diagnosed as benign lesions and adenocarcinomas with mixed subtype, respectively. Intraoperative cytological/histological examination of surgical margin was not performed in 2 patients, and the remaining 53 patients were ultimately eligible for this study. The mean tumour size was 14.0 mm and the mean GGO ratio was 95.9%. Thirty-nine and 14 patients underwent wedge resection and segmentectomy, respectively. Although all tumours were intraoperatively diagnosed as bronchioloalveolar carcinomas, 6 were ultimately diagnosed as adenocarcinoma with a mixed subtype. No completion lobectomy was performed. As of 1 May 2017, no recurrence of the original lung cancer was observed during 60.0-126.3 months after surgery. Two patients died from other diseases. The 5-year disease-specific and overall survival rates were 100% and 98.1%, respectively. The reduction in the pulmonary function after limited resection was minimal. CONCLUSIONS: With these criteria, limited resection was performed safely without any recurrence, and the postoperative pulmonary function was well preserved. The outcomes of limited resection for small-sized lung cancer with GGOs that met the criteria of this study were satisfactory. PMID- 29236996 TI - Entamoeba Species in South Africa: Correlations With the Host Microbiome, Parasite Burdens, and First Description of Entamoeba bangladeshi Outside of Asia. AB - Background: Diarrhea is frequent in communities without clean water, which include low-income South African populations in Giyani and Pretoria. In these populations, the amount of diarrhea caused by Entamoeba histolytica, inclusive of all ages, sexes, and human immunodeficiency virus status, is uncertain. Infection with E. histolytica can modulate the host microbiota, and a key species indicative of this is the Prevotella copri pathobiont. Methods: A cross-sectional study of patients attending gastroenterology clinics was conducted to determine the frequency and burden of 4 Entamoeba species and P. copri. Results: Entamoeba species were present in 27% of patients (129/484), with E. histolytica detected in 8.5% (41), E. dispar in 8% (38), E. bangladeshi in 4.75% (23), and E. moshkovskii in 0%. This is the first description of E. bangladeshi outside Bangladesh. In E. histolytica-positive samples, the levels of both the parasite and P. copri were lower in nondiarrheal samples, validating the results of a study in Bangladesh (P = .0034). By contrast, in E. histolytica-negative samples positive for either of the nonpathogenic species E. dispar or E. bangladeshi, neither P. copri nor Entamoeba levels were linked to gastrointestinal status. Conclusions: Nonmorphologic identification of this parasite is essential. In South Africa, 3 morphologically identical Entamoeba were common, but only E. histolytica was linked to both disease and changes in the microbiota. PMID- 29236997 TI - Impact of Fire Suit Ensembles on Firefighter PAH Exposures as Assessed by Skin Deposition and Urinary Biomarkers. AB - Over the past 10 years, a number of safety measures for reducing firefighters' exposure to combustion particles have been introduced in Sweden. The most important measure was the reduction in the time firefighters wear suits and handle contaminated equipment after turn-outs involving smoke diving. This study was divided into two parts, those being to investigate the level of protection obtained by multiple garment layers and to assess exposure during a standardized smoke diving exercise. First, realistic work protection factors (WPFs) were calculated by comparing air concentrations of the full suite of gaseous and particle-bound polycyclic aromatic hydrocarbons (PAHs) inside and outside structural ensembles, including jacket and thick base layer, during a tough fire extinguishing exercise using wood as the fuel. Second, during a standardized smoke diving exercise, exposure was assessed by measuring PAH skin deposition and levels of eight urinary PAH metabolites in 20 volunteer student firefighters before and after the exercise. The average WPF for the sum of 22 PAHs was 146 +/- 33 suggesting a relatively high protective capacity but also indicating a substantial enrichment of contaminants with a risk of prolonged dermal exposure. Accordingly, in the second exercise, the median levels of skin-deposited Sigma14 PAHs and urinary 1-hydroxypyrene significantly increased 5-fold (21 to 99 ng/wipe) and 8-fold (0.14 to 1.1 umol mol-1 creatinine), respectively, post exposure. Among the PAH metabolites investigated, 1-hydroxypyrene proved to be the most useful indicator of exposure, with significantly elevated urinary levels at both 6 h and 20 h after the exercise and with the strongest correlation to dermal exposure. Metabolites from two-ring and three-ring PAHs were eliminated faster while levels of 3-hydroxy-benzo[a]pyrene did not meet the detection criteria. The results from correlation studies indicated that dermal uptake was a major route of exposure in accordance with previous findings. To summarize, this study shows that some of the newly adopted protective measures were correctly implemented, and should continue to be followed and be more widely adopted. PMID- 29236998 TI - Extensive myocardial calcification in septic shock and precursor B-cell acute lymphoblastic leukaemia. PMID- 29236999 TI - Weight loss to rejuvenate the heart. PMID- 29237000 TI - Denitrifying haloarchaea: sources and sinks of nitrogenous gases. AB - Haloarchaea thrive under saline and hypersaline conditions and often dominate microbial communities in saltmarshes, salted lakes/soils and some oceanic areas. Some of the predominant species show denitrifying capabilities, although it remains unclear whether they are complete or partial denitrifiers. As complete denitrifiers, they could play important roles buffering ecosystems in which nitrate and nitrite appear as contaminants. However, partial denitrifying haloarchaea could contribute to the emission of nitrogenous gasses, thus acting as drivers of climate change and ozone depletion. In this review, we summarise some recent results on denitrification in haloarchaea, discuss the environmental implications and outline possible applications in mitigation. Finally, we list questions to be addressed in the near future, facilitating increased understanding of the role of these organisms in N turnover in arid and hypersaline environments. PMID- 29237002 TI - Corrigendum to: Quantitative deformation analysis differentiates ischaemic and non-ischaemic cardiomyopathy: sub-group analysis of the VINDICATE trial. PMID- 29237001 TI - Beneficial effect of body weight control on left ventricular diastolic function in the general population: an analysis of longitudinal data from a health check up clinic. AB - Aims: Left ventricular (LV) diastolic dysfunction may lead to heart failure. A high body mass index (BMI) is associated with worse LV diastolic function. However, knowledge of the longitudinal relation between changes in BMI and LV diastolic function is limited. Methods and results: We retrospectively identified 165 asymptomatic individuals (aged 60 +/- 10 years, 55% male) with preserved LV ejection fraction, who underwent repeated health check-ups (median interval: 365 days) at our hospital between 2009 and 2012. The longitudinal data were analysed using a linear mixed-effects model adjusted for important clinical variables at baseline to evaluate the associations between changes in BMI and LV diastolic function from one visit to the next. Baseline characteristics were BMI, 23 +/- 3 kg/m2; E/E' ratio, 9 +/- 2; E' velocity, 8 +/- 2 cm/s; and left atrial (LA) volume index, 26 +/- 8 mL/m2. Eighty-two of our participants had baseline LV diastolic dysfunction. In multivariable analyses, a BMI change was associated with a change in LV diastolic function. A one-unit decrease in BMI between consecutive visits corresponded to an average decrease in LA volume index of 0.80 mL/m2 (95% confidence interval: 0.38, 1.23; P < 0.001), a decrease in E/E'ratio of 0.11 (-0.015, 0.23; P = 0.086), and an increase in E' velocity of 0.11 cm/s (0.18, 0.031; P = 0.006). Conclusion: Our study showed that there was an association between changes in BMI and LV diastolic function. A decrease in BMI corresponded to a significant decrease in LA volume index and a significant increase in E' velocity. PMID- 29237003 TI - Illumina short-read and MinION long-read WGS to characterize the molecular epidemiology of an NDM-1 Serratia marcescens outbreak in Romania. AB - Background and Objectives: Serratia marcescens is an emerging nosocomial pathogen, and the carbapenemase blaNDM has been reported in several surveys in Romania. We aimed to investigate the molecular epidemiology of S. marcescens in two Romanian hospitals over 2010-15, including a neonatal NDM-1 S. marcescens outbreak. Methods: Isolates were sequenced using Illumina technology together with carbapenem-non-susceptible NDM-1-positive and NDM-1-negative Klebsiella pneumoniae and Enterobacter cloacae to provide genomic context. A subset was sequenced with MinION to fully resolve NDM-1 plasmid structures. Resistance genes, plasmid replicons and ISs were identified in silico for all isolates; an annotated phylogeny was reconstructed for S. marcescens. Fully resolved study NDM 1 plasmid sequences were compared with the most closely related publicly available NDM-1 plasmid reference. Results: 44/45 isolates were successfully sequenced (S. marcescens, n = 33; K. pneumoniae, n = 7; E. cloacae, n = 4); 10 with MinION. The S. marcescens phylogeny demonstrated several discrete clusters of NDM-1-positive and -negative isolates. All NDM-1-positive isolates across species harboured a pKOX_NDM1-like plasmid; more detailed comparisons of the plasmid structures demonstrated a number of differences, but highlighted the largely conserved plasmid backbones across species and hospital sites. Conclusions: The molecular epidemiology is most consistent with the importation of a pKOX_NDM1-like plasmid into Romania and its dissemination amongst K. pneumoniae/E. cloacae and subsequently S. marcescens across hospitals. The data suggested multiple acquisitions of this plasmid by S. marcescens in the two hospitals studied; transmission events within centres, including a large outbreak on the Targu Mures neonatal unit; and sharing of the pKOX_NDM1-like plasmid between species within outbreaks. PMID- 29237004 TI - Surrogacy families headed by gay men: relationships with surrogates and egg donors, fathers' decisions over disclosure and children's views on their surrogacy origins. AB - STUDY QUESTION: How do gay father families experience surrogacy in terms of their relationships with surrogates and egg donors, fathers' disclosure decisions and children's views on their surrogacy origins? SUMMARY ANSWER: More families had a relationship with the surrogate than the egg donor, and almost all had started to disclose to their children, the majority of whom expressed limited interest in their surrogacy conception. WHAT IS KNOWN ALREADY: Gay fathers tend to report greater contact with the surrogate than the egg donor and to disclose only the use of a surrogate (omitting discussion of the egg donor and the respective fathers' genetic relatedness). Children's views on their surrogacy conception to gay fathers are not known. STUDY DESIGN, SIZE, DURATION: Thirty-one children and 80 fathers were interviewed as part of a larger in-depth investigation of 40 Italian gay father surrogacy families. Multiple strategies were used to recruit participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: Children were aged 6-12 years and had been born to gay fathers through gestational surrogacy. Semi structured interviews were conducted in participants' homes with each family member, separately. Fathers' interviews were presented from the perspective of the father who identified as being most involved with the child on a day-to-day basis. Qualitative content analysis was performed and quotations illustrating the findings were reported. Where appropriate, comparisons were conducted using chi2 or Fisher's exact tests. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 31 children in 24 families were interviewed. Most families reported a harmonious relationship with the surrogate (n = 20, 57.1%) and a distant relationship with the donor (n = 10, 66.7%) (chi2(1) = 23.33, P < 0.001). Before the child was aged 4 years, almost all families (n = 34, 85%) had started to disclose their use of a surrogate, with 16 families (n = 16, 40%) also disclosing their use of a donated egg, and only 4 (10%) disclosing which father's sperm had been used. Of the 31 children interviewed, most (n = 17, 54.8%) showed a clear understanding of their conception. About 19 (61.3%) expressed limited interest in their conception, 11 (35.5%) felt positive and 1 child (3.2%) was unsure how he felt. Children differed in their feelings towards their surrogate and egg donor (Fisher's exact test, P = 0.002). Of the 31 children who were aware of the surrogate, the majority felt grateful towards her (n = 22, 71%), while of the 25 children who were also aware of the egg donation, 11 (44%) showed limited interest in their donor. LIMITATIONS, REASONS FOR CAUTION: The sample's convenience nature and the gay father families' high income limited the representativeness of the findings. Further, some children belonged to the same family, and this could have biased the results, as these children may have had similar experiences. WIDER IMPLICATIONS OF THE FINDINGS: Prior to this study, the voice of children conceived by gay fathers through surrogacy had not been heard. Future research on factors influencing children's desired contact with-or interest in-the surrogate and/or egg donor and their feelings when contact is not possible will be important in preparing families for such events. STUDY FUNDING/COMPETING INTEREST(S): Support was obtained from a Sapienza Starting Grant for Research to the first author (grant number AR11715C77EB56B2). None of the authors has any conflict of interest. PMID- 29237005 TI - Beta-blockers for the treatment of heart failure with a mid-range ejection fraction: deja-vu all over again? PMID- 29237006 TI - Letter to the Editor in response to "Online physician ratings fail to predict actual performance on measures of quality, value, and peer review". PMID- 29237007 TI - A nationwide serosurvey of hepatitis E virus antibodies in the general population of Portugal. AB - Background: Evidence has shown that Hepatitis E virus (HEV) genotype 3 is autochthonous in industrialized countries due to zoonotic transmission through direct contact or consumption of raw or undercooked meat from domestic swine or wild boar. As there is lack of data on seroprevalence of HEV in the general Portuguese population, a wide survey was conducted as part of the HEPeCONTROL project (60DT2), under EEA grants funding. Methods: Sera from a representative sample of the Portuguese population (n = 1656) at different geographic locations (30 territorial units), and age (0-99 years) were collected between July 2015 and February 2016. The sera were tested for the presence of anti-HEV IgG and IgM by EIA using one of the two most commonly used commercial immunoassays in Europe. Results: The overall HEV IgG seroprevalence was found to be 16.3% increasing with age (P < 0.05) from 0.6% in the 0-9 years group to 30.1% in people older than 70 years. The seroprevalence also varied geographically with generally higher seropositivities (25-30%) in the most rural areas of Portugal. However, the geographical differences were not statistically significant (P > 0.05). Out of 1656 samples, 8 were positive for anti-HEV IgM indicating current of recent HEV infection but no significant differences were found concerning age groups, regions and sex. Conclusions: The present nation-wide survey provides insight in the epidemiology of HEV in Portugal and confirms that HEV is endemic in the Portuguese population. PMID- 29237008 TI - Pharmacokinetics of darunavir/cobicistat and etravirine alone and co-administered in HIV-infected patients. AB - Objectives: To determine the effect of etravirine on the pharmacokinetics of darunavir/cobicistat and vice versa. Safety and tolerability of this combination were also evaluated. Methods: Open-label, fixed-sequence trial in two cohorts of HIV-infected patients on therapy with darunavir/cobicistat 800/150 mg once daily (DRV cohort; n = 15) or etravirine 400 mg once daily (ETR cohort; n = 15). Etravirine or darunavir/cobicistat were added on days 1-14 and 1-7 in participants in the DRV or ETR cohort, respectively. Full pharmacokinetic profiles were obtained on days 0 and 14 in the DRV cohort, and on days 0 and 7 in the ETR cohort. Darunavir, cobicistat and etravirine pharmacokinetic parameters [AUC0-24, Cmax and trough concentrations in plasma (C24)] were calculated for each individual by non-compartmental analysis and were compared using linear mixed-effects models. Adverse events and HIV-1 RNA in plasma were monitored. Results: Etravirine co-administration decreased cobicistat AUC0-24, Cmax and C24 by 30%, 14% and 66%, respectively. Although darunavir AUC0-24 and Cmax were unchanged by etravirine, darunavir C24 was 56% lower for darunavir/cobicistat co administered with etravirine relative to darunavir/cobicistat alone. Etravirine pharmacokinetics were unchanged by darunavir/cobicistat. Treatments were well tolerated, and HIV-1 RNA remained undetectable in all participants. Conclusions: Although etravirine pharmacokinetics was unchanged by darunavir/cobicistat, there was a significant decrease in cobicistat exposure and in darunavir C24 when darunavir/cobicistat was co-administered with etravirine. Boosting darunavir with ritonavir instead of with cobicistat may be preferred if darunavir is to be combined with etravirine in clinical practice. PMID- 29237009 TI - Recent Trends in Chemotherapy Use and Oncologists' Treatment Recommendations for Early-Stage Breast Cancer. AB - Background: There is growing concern about overtreatment of breast cancer as outcomes have improved over time. However, little is known about how chemotherapy use and oncologists' recommendations have changed in recent years. Methods: We surveyed 5080 women (70% response rate) diagnosed with breast cancer between 2013 and 2015 and accrued through two Surveillance, Epidemiology, and End Results registries (Georgia and Los Angeles) about chemotherapy receipt and their oncologists' chemotherapy recommendations. We surveyed 504 attending oncologists (60.3% response rate ) about chemotherapy recommendations in node-negative and node-positive case scenarios. We conducted descriptive statistics of chemotherapy use and patients' report of oncologists' recommendations and used a generalized linear mixed model of chemotherapy use according to time and clinical factors. All statistical tests were two-sided. Results: The analytic sample was 2926 patients with stage I-II, estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. From 2013 to 2015, keeping other factors constant, chemotherapy use was estimated to decline from 34.5% (95% confidence interval [CI] = 30.8% to 38.3%) to 21.3% (95% CI = 19.0% to 23.7%, P < .001). Estimated decline in chemotherapy use was from 26.6% (95% CI = 23.0% to 30.7%) to 14.1% (95% CI = 12.0% to 16.3%) for node-negative/micrometastasis patients and from 81.1% (95% CI = 76.6% to 85.0%) to 64.2% (95% CI = 58.6% to 69.6%) for node-positive patients. Use of the 21-gene recurrence score (RS) did not change among node-negative/micrometastasis patients, and increasing RS use in node-positive patients accounted for one-third of the chemotherapy decline. Patients' report of oncologists' recommendations for chemotherapy declined from 44.9% (95% CI = 40.2% to 49.7%) to 31.6% (95% CI = 25.9% to 37.9%), controlling for other factors. Oncologists were much more likely to order RS if patient preferences were discordant with their recommendations (67.4%, 95% CI = 61.7% to 73.0%, vs 17.5%, 95% CI = 13.1% to 22.0%, concordant), and they adjusted recommendations based on patient preferences and RS results. Conclusions: For both node-negative/micrometastasis and node-positive patients, chemotherapy receipt and oncologists' recommendations for chemotherapy declined markedly over time, without substantial change in practice guidelines. Results of ongoing trials will be essential to confirm the quality of this approach to breast cancer care. PMID- 29237010 TI - CRISPR/Cas9-mediated modulation of splicing efficiency reveals short splicing isoform of Xist RNA is sufficient to induce X-chromosome inactivation. AB - Alternative splicing of mRNA precursors results in multiple protein variants from a single gene and is critical for diverse cellular processes and development. Xist encodes a long noncoding RNA which is a central player to induce X chromosome inactivation in female mammals and has two major splicing variants: long and short isoforms of Xist RNA. Although a differentiation-specific and a female-specific expression of Xist isoforms have been reported, the functional role of each Xist RNA isoform is largely unexplored. Using CRISPR/Cas9-mediated targeted modification of the 5' splice site in Xist intron 7, we create mutant female ES cell lines which dominantly express the long- or short-splicing isoform of Xist RNA from the inactive X-chromosome (Xi) upon differentiation. Successful execution of CRISPR/Cas-based splicing modulation indicates that our CRISPR/Cas based targeted modification of splicing sites is a useful approach to study specific isoforms of a transcript generated by alternative splicing. Upon differentiation of splicing-mutant Xist female ES cells, we find that both long and short Xist isoforms can induce X-chromosome inactivation normally during ES cell differentiation, suggesting that the short splicing isoform of Xist RNA is sufficient to induce X-chromosome inactivation. PMID- 29237011 TI - Back to Bed: From Hospital to Home Obstetrics in the City of Chicago. AB - This article analyzes the role of doctors and activists in Chicago who successfully redefined the practice and politics of childbirth both locally and ultimately nationwide. It begins with the story of Joseph DeLee's Chicago Maternity Center, responsible for supervising over 100,000 home births between 1932 and 1972. Most of the mothers cared for by the Center were nonwhite, poor, and had little or no access to prenatal care, yet their babies had a far higher survival rate than the nationwide average. Thousands of medical students from all over the Midwest experienced their first deliveries not in hospitals, but in these homes. The article then addresses a very different demographic: a rising number of middle-class white families in the suburbs of Chicago who, beginning in the 1950s, opted for out-of-hospital births. Many of them learned about home birth through their involvement in La Leche League, the breastfeeding organization formed in a Chicago suburb in 1956. Seemingly separated by class, race, and locale, the link between these two groups of home birthers was the philosophy and training in place at the Chicago Maternity Center. PMID- 29237013 TI - Outcome quality and long-term (>=15 years) stability after Class II:2 Herbst multibracket appliance treatment in comparison to untreated Class I controls. AB - Aim: To investigate the outcome quality and the long-term (>=15 years) post treatment (Tx) changes after Class II:2 Herbst-multibracket appliance (MBA) Tx. Subjects and Methods: In this longitudinal observational study, a recall of Class II:2 patients who had been treated by a Herbst-MBA during adolescence was conducted. Study models from before and after active Tx, after retention and after recall were assessed using standard occlusal variables and the peer assessment rating index (PAR). These data were compared to historical untreated Class I controls. Results: Twenty out of 33 patients (61%) could be located and participated at age 33.9 +/- 2.7 years. When comparing their data to the 13 patients who did not participate, the pre- and post-Tx occlusal findings did not differ systematically; however, the PAR scores of the non-participants were by 3.3-8.2 points higher at all times and the non-participants were 2.1-2.5 years older. Pre-Tx at age 14.4 +/- 2.7 years, the participants showed the following mean values: PAR = 15.0 +/- 7.0, Class II molar relationship (MR) = 0.8 +/- 0.3 cusp widths (cw), overbite = 5.3 +/- 1.3 mm. After Tx, a PAR score of 2.9 +/- 1.3 and a super Class I MR (-0.1 +/- 0.1 cw) with normal overbite (1.2 +/- 0.8 mm) existed. At recall, a PAR score increase to 5.9 +/- 3.6 points had occurred, mainly caused by an increase of overbite to 2.5 +/- 1.5 mm. The average MR remained Class I (0.0 +/- 0.2 cw). For all variables, the untreated controls exhibited similar findings. Conclusion: The occlusal outcome of Class II:2 Herbst MBA Tx exhibited very good long-term stability. While mild post-Tx changes occurred, the long-term findings are similar to untreated Class I controls. PMID- 29237012 TI - Clinical implications of Plasmodium resistance to atovaquone/proguanil: a systematic review and meta-analysis. AB - Background: Atovaquone/proguanil, registered as Malarone(r), is a fixed-dose combination recommended for first-line treatment of uncomplicated Plasmodium falciparum malaria in non-endemic countries and its prevention in travellers. Mutations in the cytochrome bc1 complex are causally associated with atovaquone resistance. Methods: This systematic review assesses the clinical efficacy of atovaquone/proguanil treatment of uncomplicated malaria and examines the extent to which codon 268 mutation in cytochrome b influences treatment failure and recrudescence based on published information. Results: Data suggest that atovaquone/proguanil treatment efficacy is 89%-98% for P. falciparum malaria (from 27 studies including between 18 and 253 patients in each case) and 20%-26% for Plasmodium vivax malaria (from 1 study including 25 patients). The in vitro P. falciparum phenotype of atovaquone resistance is an IC50 value >28 nM. Case report analyses predict that recrudescence in a patient presenting with parasites carrying cytochrome b codon 268 mutation will occur on average at day 29 (95% CI: 22, 35), 19 (95% CI: 7, 30) days longer than if the mutation is absent. Conclusions: Evidence suggests atovaquone/proguanil treatment for P. falciparum malaria is effective. Late treatment failure is likely to be associated with a codon 268 mutation in cytochrome b, though recent evidence from animal models suggests these mutations may not spread within the population. However, early treatment failure is likely to arise through alternative mechanisms, requiring further investigation. PMID- 29237014 TI - The effect of stochasticity on repair of DNA double strand breaks throughout non homologous end joining pathway. AB - DNA double strand breaks (DSBs) are the most lethal lesions of DNA induced by ionizing radiation, industrial chemicals and a wide variety of drugs used in chemotherapy. In the context of DNA damage response system modelling, uncertainty may arise in several ways such as number of induced DSBs, kinetic rates and measurement error in observable quantities. Therefore, using the stochastic approaches is imperative to gain further insight into the dynamic behaviour of DSBs repair process. In this article, a continuous-time Markov chain (CTMC) model of the non-homologous end joining (NHEJ) mechanism is formulated according to the DSB complexity. Additionally, a Metropolis Monte Carlo method is used to perform maximum likelihood estimation of the kinetic rate constants. Here, the effects of fluctuating kinetic rates and DSBs induction rate of the NHEJ mechanism are investigated. The stochastic realizations of the total yield of simple and complex DSBs ligation are simulated to compare their asymptotic dynamics. Furthermore, it has been proved that the total yield of DSBs has a normal distribution for sufficiently large number of DSBs. In order to estimate the expected duration of repairing DSBs, the probability distribution of DSBs lifetime is calculated based on the CTMC NHEJ model. Moreover, the variability of total yield of DSBs during constant low-dose radiation is evaluated in the presented model. The findings indicate that in stochastic NHEJ model, when there is no new DSBs induction through the repair process, all DSBs are eventually repaired. However, when DSBs are induced by constant low-dose radiation, a number of DSBs remains un-repaired. PMID- 29237016 TI - Evaluation of cefazolin antimicrobial prophylaxis during cardiac surgery with cardiopulmonary bypass. AB - Objectives: Although clinical practice guidelines recommend standard cefazolin antimicrobial prophylaxis (AP) dosing for cardiac surgery, limited data exist as to whether adequate concentrations are achieved in this patient population. The goal of our study was to characterize intraoperative cefazolin concentrations particularly at wound closure with regards to maintaining target cefazolin closure concentrations >=40 mg/L. Methods: Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) and receiving cefazolin AP according to protocol were studied. Blood samples were collected after the preoperative cefazolin dose, prior to intraoperative cefazolin doses and at wound closure. Intraoperative trough and closure concentrations were characterized and evaluated against a target threshold of >= 40 mg/L (>=8 mg/L unbound, assuming 80% protein binding). Results: Fifty-five subjects (64.9 +/- 10.4 years, 89.7 +/- 16.5 kg, CLCR >50 mL/min/72 kg) completed the study. Total cefazolin concentrations were <40 mg/L in 40% (12 of 30) of intraoperative trough samples and 9.8% (5 of 51) of closure samples. Below-target concentrations at some time during surgery were documented in 30.9% (17 of 55) of subjects. In multivariate analyses, lower body weight (P = 0.027) and shorter duration of surgery (P = 0.045) were significant predictors of closure concentrations <40 mg/L. A total cefazolin exposure (preoperative and intraoperative doses) of >= 7.6 mg/kgdosing weight for every hour of surgery (intermittent dosing) was required to achieve target closure concentrations. Conclusions: The standard cefazolin AP regimen was not reliable in maintaining target closure concentrations >=40 mg/L in patients with normal renal function undergoing elective cardiac surgery with CPB. The findings supported a cefazolin AP regimen consisting of at least 2 g preoperatively and every 3 h during surgery. PMID- 29237015 TI - Perceval Less Invasive Aortic Replacement Register: multicentric Spanish experience with the Perceval S bioprosthesis in moderate-high-risk aortic surgery. AB - OBJECTIVES: The development of new percutaneous and surgical techniques has reduced the risk associated with aortic valve replacement procedures. We present the results of a Spanish register after initiating a programme for sutureless prostheses in moderate-high-risk patients. METHODS: This prospective multicentre study was carried out from November 2013 to November 2016. Data were obtained from 448 patients in whom a Perceval S prosthesis was implanted. RESULTS: The mean age was 79.24 (standard deviation [SD] 4.1) years, and 61.2% were women. The estimated EuroSCORE I log risk was 11.15% (SD 7.6), with an observed mortality of 4.4% (20 patients). Isolated aortic valve replacement was performed on 69.26% of patients, with 64% involving ministernotomy. The incidence of neurological events was 2%, with 2 permanent cerebrovascular accidents, and 41 (9.2%) patients were implanted with a permanent endocavitary pacemaker. At discharge, 12 (2.6%) patients presented minimal periprosthetic leakage, and 4 (0.89%) patients had moderate leakage. There were 3 reinterventions during follow-up (2 endocarditis and 1 dysfunction due to periprosthetic leak progression). The mean gradient at discharge, 6 months and 1 year was 12.94 (SD 5.3) mmHg, 12.19 (SD 4.7) mmHg and 11.77 (SD 4.7) mmHg, respectively; 59.4% of the patients were octogenarians, with a survival rate of 98% at both 6 months and 1 year at discharge. There was neither valve migration nor early structural degeneration. The mean follow-up was 12 +/- 3 months. The 6-month and 1-year mortality was 1.4% and 2.1%, respectively. CONCLUSIONS: This is a prospective multicentric study on the largest cohort of patients with sutureless valves conducted in Spain to date. It is a reproducible procedure that has enabled surgery on patients with a moderate high risk with low morbidity and mortality, providing good haemodynamic results. PMID- 29237017 TI - Double-orifice Barlow's mitral valve. PMID- 29237018 TI - Social costs of illicit financial flows in low- and middle-income countries: the case of infant vaccination coverage. AB - The liberalization of capital flows is generally associated with prospects of higher growth. However, in developing countries, opening the capital account may also facilitate the flow of capital out of the country through illicit financial flows (IFFs). Given that IFFs drain the scarce public resources available to finance the provision of public goods and services, the extent of illicit capital flows from developing countries is serious cause for concern. In this context, as a first step in analysing the social costs of IFFs in developing countries, this article studied the relationship between IFFs and infant immunization coverage rates. Data for 56 low- and middle-income countries for the period 2002-13 were used in the empirical analysis. The main result was that the relative level of IFFs to total trade negatively impacted vaccination coverage but only in the case of countries with very high levels of perceived corruption. In this case, the total effect of an annual 1 p.p. increase in the ratio of IFFs to total trade was to reduce the level of vaccination coverage rates over the coming years by 0.19 p.p. Given that there was an annual average of 18 million infants in this cluster of 25 countries, this result suggests that at least 34 000 children may not receive this basic health care intervention in the future as a consequence of this increase in IFFs in any particular year. PMID- 29237019 TI - Swimming Against the Stream: Non-normative Family Transitions and Loneliness in Later Life Across 12 Nations. AB - Background and Objectives: Relatively little research investigated whether experiences during young adulthood have long-lasting consequences for older age loneliness. This article examines whether deviations from culturally based scripts regarding family transitions represent risk factors for later-life loneliness. Moreover, it analyzes whether and in which conditions long-term associations between family transitions and loneliness differ across nations. Research Design and Methods: The analyses use micro-level data from the Generations and Gender Survey Wave 1 for 12 European countries. The sample comprises 61,082 individuals aged 50-85. The research questions are addressed using a step-wise approach based on linear regression analyses, meta-analyses, and meta-regressions. Results: Results show that never having lived with a partner and childlessness are most strongly related to later-life loneliness. Whereas early transitions are unrelated to later-life loneliness, the postponement of partnership, and parenthood are associated with higher levels of loneliness compared to having experienced these transitions "on-time". Childlessness is more strongly associated with later-life loneliness in more traditionalist countries than in less traditionalist ones. Discussion and Implications: This study reveals that individuals with non-normative family transitions are more exposed to loneliness in old age, and that this exposure is related to societal context. In traditionalist contexts, where people rely on families for support, older adults who have experienced non-normative family behavior, and childlessness in particular, may be particularly at risk of loneliness. PMID- 29237020 TI - Extrinsic compression of left main coronary artery by aneurysmal pulmonary artery in severe pulmonary hypertension: its correlates, clinical impact, and management strategies. AB - Aims: Although left main coronary artery (LMCA) compression (Co) by pulmonary artery (PA) aneurysm (A) has been reported in some pulmonary hypertension (PH) series, clinical importance and management of this complication remain to be determined. In this single-centre prospective study, we evaluated correlates, clinical impact, and management strategies of LMCA-Co in patients with PH. Methods and results: Our study group comprised 269 (female 166, age 52.9 +/- 17.3 years) out of 498 patients with confirmed PH who underwent coronary angiography (CA) because of the PAA on echocardiography, angina or incidentally detected LMCA Co during diagnostic evaluation with multidetector computed tomography. The LMCA Co >= 50% was documented in 22 patients (8.2%) who underwent CA, and stenosis were between 70% and 90% in 14 of these. Univariate comparisons revealed that a younger age, a D-shaped septum, a higher PA systolic, diastolic, and mean pressures and pulmonary vascular resistance, a larger PA diameter, a smaller aortic diameter and pulmonary arterial hypertension associated with patent-ductus arteriosus, atrial or ventricular septal defects were significantly associated with LMCA-Co. Bare-metal stents were implanted in 12 patients and 1 patient underwent PAA and atrial septal defect surgery and another one declined LMCA stenting procedure. Conclusion: Our study demonstrates that LMCA-Co is one of the most important and potentially lethal complications of severe PH, and alertness for this risk seems to be necessary in specific circumstances related with PAA. However, long-term benefit from stenting in this setting remains as a controversy. PMID- 29237022 TI - Life in the Emergency Department. PMID- 29237021 TI - Human-specific subcellular compartmentalization of P-element induced wimpy testis like (PIWIL) granules during germ cell development and spermatogenesis. AB - STUDY QUESTION: What is the dynamics of expression of P-element induced wimpy testis-like (PIWIL) proteins in the germline during human fetal development and spermatogenesis? SUMMARY ANSWER: PIWIL1, PIWIL2, PIWIL3 and PIWIL4 were expressed in a sex-specific fashion in human germ cells (GC) during development and adulthood. PIWILs showed a mutually exclusive pattern of subcellular localization. PIWILs were present in the intermitochondrial cement and a single large granule in meiotic GC and their expression was different from that observed in mice, highlighting species-differences. WHAT IS KNOWN ALREADY: In mice, PIWIL proteins play prominent roles in male infertility. PIWIL mouse mutants show either post-meiotic arrest at the round spermatid stage (PIWIL1) or arrest at the zygotene-pachytene stage of meiosis I (PIWIL2 and PIWIL4) in males, while females remain fertile. Recent studies have reported a robust piRNA pool in human fetal ovary. STUDY DESIGN, SIZE, DURATION: This is a qualitative analysis of PIWILs expression in paraffin-embedded fetal human male (N = 8), female gonads (N = 6) and adult testes (N = 5), and bioinformatics analysis of online available single cell transcriptomics data of human fetal germ cells (n = 242). PARTICIPANTS/MATERIALS, SETTING, METHODS: Human fetal gonads from elective abortion without medical indication and adult testes biopsies were donated for research with informed consent. Samples were fixed, paraffin-embedded and analyzed by immunofluorescence to study the temporal and cellular localization of PIWIL1, PIWIL2, PIWIL3 and PIWIL4. MAIN RESULTS AND THE ROLE OF CHANCE: PIWIL1, PIWIL2 and PIWIL4 showed a mutually exclusive pattern of subcellular localization, particularly in female oocytes. To our surprise, PIWIL1 immunostaining revealed the presence of a single dense paranuclear body, resembling the chromatoid body of haploid spermatocytes, in meiotic oocytes. Moreover, in contrast to mice, PIWIL4, but not PIWIL2, localized to the intermitochondrial cement. PIWIL3 was not expressed in GC during development. The upregulation of PIWIL transcripts correlated with the transcription of markers associated with piRNAs biogenesis like the TDRDs and HENMT1 in fetal GC. LARGE SCALE DATA: Non-applicable. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the restricted number of samples and consequently stages analyzed. WIDER IMPLICATIONS OF THE FINDINGS: In the germline, PIWILs ensure the integrity of the human genome protecting it from 'parasitic sequences'. This study offers novel insights on the expression dynamics of PIWILs during the window of epigenetic remodeling and meiosis, and highlights important differences between humans and mice, which may prove particularly important to understand causes of infertility and improve both diagnosis and treatment in humans. STUDY FUNDING/COMPETING INTEREST(S): M.G.F. was funded by Fundacao para a Ciencia e Tecnologia (FCT) [SFRH/BD/78689/2011]; N.H. by China Scholarship Council (CSC) [No. 201307040026] and F.W. by Medical Personnel Training Abroad Project of Henan Province [No. 2015022] and S.M.C.d.S.L. by the Netherlands Organization of Scientific Research (NWO) [ASPASIA 015.007.037] and the Interuniversity Attraction Poles-Phase VII [IUAP/PAI P7/14]. The authors have no conflicts of interest to declare. PMID- 29237023 TI - Strategies to manage cardiovascular risk in chronic kidney disease. PMID- 29237024 TI - Comparative analysis of neutropenia in patients receiving prolonged treatment with ceftaroline. AB - Objectives: Ceftaroline is often used in durations greater than that studied in clinical trials. Several retrospective, non-comparative studies have suggested a higher than anticipated incidence of neutropenia in patients receiving prolonged treatment with ceftaroline. We sought to determine if ceftaroline was associated with neutropenia by comparing the incidence with ceftaroline treatment with treatment with several comparative antibiotics. Methods: Patients receiving 14 or more consecutive days of treatment with ceftaroline were compared with patients receiving cefazolin, daptomycin, linezolid, nafcillin or vancomycin (control group). The primary outcome was the development of neutropenia. Multivariate logistic regression and propensity score weighting using inverse probability weights with regression adjustment were used to control for confounding variables. Results: A total of 753 patients were included (53 that received ceftaroline and 700 that received a comparative antibiotic). Ceftaroline was associated with a greater incidence of neutropenia as compared with the control group (17.0% versus 3.9%, P < 0.001). Several covariates were also associated with neutropenia and included younger age, lower baseline absolute neutrophil count, liver disease and bone and joint infections. After controlling for these confounders, receipt of ceftaroline continued to be associated with the development of neutropenia (adjusted OR 3.97, P = 0.003). Analysis after propensity score weighting confirmed this finding. Conclusions: The results of this study suggest that prolonged treatment with ceftaroline is associated with a greater incidence of neutropenia as compared with other antibiotics that are often used for treatment of staphylococcal infections. Careful monitoring of absolute neutrophil count is recommended in patients receiving >14 days of ceftaroline. PMID- 29237025 TI - Rasmussen's aneurysm. PMID- 29237026 TI - How do external donors influence national health policy processes? Experiences of domestic policy actors in Cambodia and Pakistan. AB - Although concerns have historically been raised about the influence of external donors on health policy process in recipient countries, remarkably few studies have investigated perspectives and experiences of domestic policymakers and advisers. This study examines donor influence at different stages of the health policy process (priority setting, policy formulation, policy implementation and monitoring and evaluation) in two aid-dependent LMICs, Cambodia and Pakistan. It identifies mechanisms through which asymmetries in influence between donors and domestic policy actors emerge. We conducted 24 key informant interviews-14 in Pakistan and 10 in Cambodia-with high-level decision-makers who inform or authorize health priority setting, allocate resources and/or are responsible for policy implementation, identifying three routes of influence: financial resources, technical expertise and indirect financial and political incentives. We used both inductive and deductive approaches to analyse the data. Our findings indicate that different routes of influence emerged depending on the stage of the policy process. Control of financial resources was the most commonly identified route by which donors influenced priority setting and policy implementation. Greater (perceived) technical expertise played an important role in donor influence at the policy formulation stage. Donors' power in influencing decisions, particularly during the final (monitoring and evaluation) stage of the policy process, was mediated by their ability to control indirect financial and political incentives as well as direct control of financial resources. This study thus helps unpack the nuances of donor influence over health policymaking in these settings, and can potentially indicate areas that require attention to increase the ownership of domestic actors of their countries' health policy processes. PMID- 29237027 TI - Poverty-related diseases: factors that predict coping in two Cameroonian settings. AB - In this paper, we explore the connection between poverty and health (poverty related diseases: PRDs) by investigating the factors that play a role in how two groups of people in Cameroon cope with health challenges: workers in a large agro industrial organization (living in 'camps') and students in two major universities (living on 'campuses'). We investigated factors reported in the literature as being associated with coping, summarized under the 'salutogenic umbrella', as well as demographic, social and environmental factors. A total of 509 respondents from camps and campuses participated in this study. We used a combination of standardized and un-standardized survey instruments to measure coping. We used chi2 and ANOVA tests to investigate bivariate differences and multiple logistic regression analysis to determine which significant survey factors predicted coping. Our results showed expected and unexpected differences between the settings. Individual dispositional factors such as sense of coherence (SOC), self-efficacy (SE), subjective wellbeing and self-rated health differed significantly between the settings. Expected coping resources such as income and SE did not differ between non-copers and copers. Two factors emerged as predictors of coping: living environment (setting) and SOC. Our results highlight the need for a multidimensional perspective on poverty and also the need to apply the salutogenic approach in PRD research. In particular, the emphasis this approach puts on stressors and the capacity to employ a variety of resources to overcome stressors is a fruitful way to better understand PRDs and the importance of location-specific circumstances where poverty, health and diseases are connected. PMID- 29237028 TI - Response to Letter to the Editor. PMID- 29237029 TI - Organization of Vascular Cells in the Haustorium of the Parasitic Flowering Plant Cuscuta japonica. AB - The stem parasite dodder, Cuscuta japonica, has evolved a specialized root-like organ, the haustorium, which is differentiated from the stem. In order to take up water and nutrients, C. japonica reprograms haustorial cells to vascular cells, connecting the host's vascular system to its own. However, little is known about vascular differentiation in haustoria. In this study, we first confirmed the temporal and spatial expression profiles of vascular cell type-specific genes, CjAPL, CjSEOR1, CjWOX4 and CjTED7, to examine whether phloem companion cells, developing sieve elements, procambial cells and differentiating xylem cells, respectively, are present in the haustoria. CjAPL and CjSEOR1 decreased, and CjWOX4 showed a transient increase before the onset of xylem vessel formation, and then decreased. CjTED7 increased coincidentally with xylem vessel formation. In situ hybridization demonstrated that CjWOX4-expressing cells and phloem conducting cells are in close proximity, and occupied a domain distinguishable from xylem vessels, suggesting differentiation of a phloem/procambial domain and a xylem domain in the haustorium. Secondly, expression of regulatory genes that are involved in determination of the fate of procambial cells was investigated. Expression patterns of CjCLE41, CjGSK3 and CjBES1suggested that TDIF-TDR-GSK3 mediated signaling is activated in haustoria. The natural antisense transcript of CjCLE41 was detected in haustoria, implying the sense regulation of CjCLE41. Expression profiles of the regulatory genes, combined with those of cell type specific marker genes, suggest that reprogramming of haustorial cells to vascular cells is regulated in a way that allows the immediate formation of xylem vessels by alleviating inhibition of xylem differentiation. PMID- 29237031 TI - Controlling alcohol availability through local policy: an observational study to evaluate Cumulative Impact Zones in a London borough. AB - Background: Cumulative impact zones (CIZs) are a discretionary policy lever available to local government, used to restrict the availability of alcohol in areas deemed already saturated. Despite little evidence of their effect, over 200 such zones have been introduced. This study explores the impact of three CIZs on the licensing of venues in the London Borough of Southwark. Methods: Using 10 years of licensing data, we examined changes in the issuing of licences on the introduction of three CIZs within Southwark, relative to control areas. The number of licence applications made (N = 1110), the number issued, and the proportion objected to, were analysed using negative binomial regression. Results: In one area tested, CIZ implementation was associated with 119% more licence applications than control areas (incidence rate ratios (IRR) = 2.19, 95% confidence intervals (CI): 1.29-3.73, P = 0.004) and 133% more licences granted (IRR = 2.33, 95% CI: 1.31-4.16, P = 0.004). No significant effect was found for the other two areas. CIZs were found to have no discernible effect on the relative proportion of licence applications receiving objections. Conclusions: CIZs are proposed as a key lever to limit alcohol availability in areas of high outlet density. We found no evidence that CIZ establishment reduced the number of successful applications in Southwark. PMID- 29237030 TI - Natural variation reveals that OsSAP16 controls low-temperature germination in rice. AB - Low temperature affects seed germination in plants, and low-temperature germination (LTG) is an important agronomic trait. Natural variation of LTG has been reported in rice, but the molecular basis for this variation is largely unknown. Here we report the phenotypic analysis of LTG in 187 rice natural accessions and a genome-wide association study (GWAS) of LTG in this collection. A total of 53 quantitative trait loci (QTLs) were found to be associated with LTG, of which 20 were located in previously reported QTLs. We further identified Stress-Associated Protein 16 (OsSAP16), coding for a zinc-finger domain protein, as a causal gene for one of the major LTG QTLs. Loss of OsSAP16 function reduces germination while greater expression of OsSAP16 enhances germination at low temperature. In addition, accessions with extremely high and low LTG values have correspondingly high and low OsSAP16 expression at low temperatures, suggesting that variation in expression of the OsSAP16 gene contributes to LTG variation. As the first case of identification of an LTG gene through GWAS, this study indicates that GWAS of natural accessions is an effective strategy in genetically dissecting LTG processes and gaining molecular understanding of low-temperature response and germination. PMID- 29237032 TI - The development and pilot testing of the marijuana retail surveillance tool (MRST): assessing marketing and point-of-sale practices among recreational marijuana retailers. AB - As recreational marijuana expands, it is critical to develop standardized surveillance measures to study the retail environment. To this end, our research team developed and piloted a tool assessing recreational marijuana retailers in a convenience sample of 20 Denver retailers in 2016. The tool assesses: (i) compliance and security (e.g. age-of-sale signage, ID checks, security cameras); (ii) marketing (i.e. promotions, product availability and price) and (iii) contextual and neighborhood features (i.e. retailer type, facilities nearby). Most shops (90.0%) indicated the minimum age requirement, all verified age. All shops posted interior ads (M = 2.6/retailer, SD = 3.4), primarily to promote edibles and other non-smoked products. Price promotions were common in shops (73.7%), 57.9% used social media promotions and 31.6% had take-away materials (e.g. menus, party promotions). Nearly half of the shops (42.1%) advertised health claims. All shops offered bud, joints, honey oil, tinctures, kief, beverages, edibles and topicals; fewer sold clones and seeds. Six shops (31.6%) sold shop-branded apparel and/or paraphernalia. Prices for bud varied within and between stores ($20-$45/'eighth', ~3.5 g). Twelve were recreational only, and eight were both recreational and medicinal. Liquor stores were commonly proximal. Reliability assessments with larger, representative samples are needed to create a standardized marijuana retail surveillance tool. PMID- 29237033 TI - Colchicine for Prevention of Perioperative Atrial Fibrillation in patients undergoing lung resection surgery: a pilot randomized controlled study. AB - OBJECTIVES: We carried out a pilot randomized controlled study to determine the feasibility of a large trial evaluating the impact of colchicine versus placebo on postoperative atrial fibrillation or atrial flutter (POAF) among patients undergoing lung resection surgery. METHODS: Patients >=55 years of age undergoing lung resection surgery were randomly assigned to receive colchicine 0.6 mg or placebo starting a few hours before surgery. Postoperatively, patients received colchicine 0.6 mg or placebo twice daily for an additional 9 days. Our feasibility outcomes included the period of time required to recruit 100 patients, the completeness of follow-up and compliance with the study drug. The primary efficacy outcome was POAF within 30 days of randomization. RESULTS: One hundred patients were randomized (49 to colchicine and 51 to placebo) over a period of 12 months at 2 centres in Canada. All patients completed the 30-day follow-up. The mean staff time required to recruit and to follow-up each patient was 165 min. In all, 71% of patients completed the study drug course without interruption. Patient refusal to continuing taking the study drug was the main reason for permanent drug discontinuation. New POAF occurred in 5 (10.2%) patients in the colchicine group and 7 (13.7%) patients in the placebo group (adjusted hazard ratio 0.69, 95% confidence interval 0.20-2.34). CONCLUSIONS: These results show the feasibility of a trial evaluating Colchicine for the prevention of perioperative Atrial Fibrillation in patients undergoing lung resection surgery. This pilot study will serve as the foundation for the large multicentre COP-AF trial. PMID- 29237034 TI - Long-term Care Provision and the Well-Being of Spousal Caregivers: An Analysis of 138 European Regions. AB - Objectives: The individual burden of caring for one's relatives not only depends on care characteristics but is also related to contextual factors. The objective of this study is to determine whether regional formal long-term care provision is linked to the well-being of spousal caregivers introducing the concept of "control" as central pathway to explain this link. Method: We applied multilevel analysis using data from the Survey of Health, Ageing and Retirement in Europe (SHARE) from over 29,000 Europeans and 1,800 spousal caregivers located in 138 regions in 11 countries to analyze the effects of regional contexts on caregiver well-being. The provision of formal care in a region was measured by the number of long-term care beds in nursing and residential homes among the older population. Results: We found that spousal caregivers' well-being, measured in terms of life satisfaction, loneliness, and depression, was positively linked to the regional availability of formal care, which is partly due to higher perceived control in regions with more formal care provision. Discussion: Our results suggest that formal care supply is essential not only for care recipients but also for caregivers: perceived alternatives to the private care arrangement go along with greater well-being of informal caregivers. PMID- 29237036 TI - A Commentary on Research on Death and End of Life Issues. PMID- 29237035 TI - Adjuvant Chemotherapy for ER+ Breast Cancer: A Sea Change is Underway. PMID- 29237039 TI - Development of a Brief Version of the Current Opioid Misuse Measure (COMM): The COMM-9. AB - Objective: The Current Opioid Misuse Measure (COMM) is a commonly used self report instrument to identify and monitor aberrant opioid-related behavior in chronic pain patients on opioid therapy. However, the length of the COMM may limit its clinical utility. Additionally, this paper-and-pencil screener requires hand scoring, which increases paperwork and staff burden. Therefore, the current study presents development of the "COMM-9," a brief electronically administered form of the COMM. Methods: Patients (N = 517) with chronic noncancer pain on opioid therapy completed the COMM. Patients were classified as either being positive or negative for aberrant drug-related behavior based on self-report data from a structured interview, physician-report data, and urine toxicology screen (the Aberrant Drug Behavior Index [ADBI]). COMM items with the strongest classification accuracy were identified using the LASSO method as the selection criterion in conjunction with the leave-one-out cross-validation method as the stop criterion. A sub-set of patients (n=55) completed a second administration of the COMM one week later to evaluate test-retest reliability. Results: Nine items were identified before the selection criterion stopped, and logistic regression was utilized to predict probabilities of positive ADBI from the 9 COMM items using all data and the cross-validation procedure. Receiver operating characteristic curves revealed high levels of classification accuracy that were essentially equivalent to the full COMM. Cut-points were identified to classify patients as having no/low risk, moderate risk, and high risk for aberrant opioid related behavior. Test-retest reliability of the COMM-9 was comparable to the full 17-item COMM. Conclusions: This study presents the successful development of a brief electronic screener to identify current aberrant opioid-related behavior in chronic pain patients on long-term opioid therapy. PMID- 29237038 TI - Analysis of abbreviations used by residents in admission notes and discharge summaries. AB - Background: There are abbreviations that are used daily such as BP for blood pressure and ECG for electrocardiogram, but many of the abbreviations found in medical documents are unclear. Aim: The purpose of this study was to assess the frequency, type and comprehension of abbreviations in admission notes and discharge letters composed by orthopedic surgery and medical residents. Methods: Abbreviations were extracted from discharge letters and admission notes composed by residents from orthopedic surgery and medical wards. The frequency of use of the abbreviations was determined. Additionally, the fifty commonest abbreviations from each specialty were graded by three medical and three orthopedic surgery senior physicians as 1. understandable or 2. Ambiguous or unknown. Results: The number of abbreviations found in the documents composed by medical and orthopedic surgery residents was 1525 with 80 different abbreviations and 493 with 51 different abbreviations respectively (9.3% and 4.9% of the total word number respectively). Analysis revealed that 14% of the abbreviations from medical ward documents were graded as ambiguous or unknown by medical senior physicians compared with 25% by senior orthopedic surgeons. When abbreviations from orthopedic surgery documents were presented to both groups, senior orthopedic surgeons graded 8% as ambiguous or unknown compared with 21% by the medical senior physicians. Conclusion: In order to prevent impairment of patient care, only standard abbreviations should be used in medical documents. Measures should be taken to decrease the use of non standard abbreviations such as the incorporation of authorized abbreviations to the electronic medical record. PMID- 29237040 TI - Conceptual and computational framework for logical modelling of biological networks deregulated in diseases. AB - Mathematical models can serve as a tool to formalize biological knowledge from diverse sources, to investigate biological questions in a formal way, to test experimental hypotheses, to predict the effect of perturbations and to identify underlying mechanisms. We present a pipeline of computational tools that performs a series of analyses to explore a logical model's properties. A logical model of initiation of the metastatic process in cancer is used as a transversal example. We start by analysing the structure of the interaction network constructed from the literature or existing databases. Next, we show how to translate this network into a mathematical object, specifically a logical model, and how robustness analyses can be applied to it. We explore the visualization of the stable states, defined as specific attractors of the model, and match them to cellular fates or biological read-outs. With the different tools we present here, we explain how to assign to each solution of the model a probability and how to identify genetic interactions using mutant phenotype probabilities. Finally, we connect the model to relevant experimental data: we present how some data analyses can direct the construction of the network, and how the solutions of a mathematical model can also be compared with experimental data, with a particular focus on high throughput data in cancer biology. A step-by-step tutorial is provided as a Supplementary Material and all models, tools and scripts are provided on an accompanying website: https://github.com/sysbio-curie/Logical_modelling_pipeline. PMID- 29237037 TI - Insights into the evolutionary conserved regulation of Rio ATPase activity. AB - Eukaryotic ribosome biogenesis is a complex dynamic process which requires the action of numerous ribosome assembly factors. Among them, the eukaryotic Rio protein family members (Rio1, Rio2 and Rio3) belong to an ancient conserved atypical protein kinase/ ATPase family required for the maturation of the small ribosomal subunit (SSU). Recent structure-function analyses suggested an ATPase dependent role of the Rio proteins to regulate their dynamic association with the nascent pre-SSU. However, the evolutionary origin of this feature and the detailed molecular mechanism that allows controlled activation of the catalytic activity remained to be determined. In this work we provide functional evidence showing a conserved role of the archaeal Rio proteins for the synthesis of the SSU in archaea. Moreover, we unravel a conserved RNA-dependent regulation of the Rio ATPases, which in the case of Rio2 involves, at least, helix 30 of the SSU rRNA and the P-loop lysine within the shared RIO domain. Together, our study suggests a ribosomal RNA-mediated regulatory mechanism enabling the appropriate stimulation of Rio2 catalytic activity and subsequent release of Rio2 from the nascent pre-40S particle. Based on our findings we propose a unified release mechanism for the Rio proteins. PMID- 29237041 TI - Seroprevalence of rabies virus antibodies in bats from high risk areas in Brazilian Amazonia between 2013 and 2015. AB - Background: The outbreaks of human rabies that occurred between 2004 and 2005 in the Brazilian Amazon highlight the importance of bats in the transmission of this zoonosis. Ten years after, this region is still considered to be a risk area. Methods: Serum and brain tissue samples were obtained from bats captured between 2013 and 2015. The sera were tested for the presence of rabies antibodies, using the rapid fluorescent focus inhibition test, and the brain tissue samples were tested for the presence of the rabies antigen by the direct immunofluorescence method and intracerebral inoculation in mice. Results: A total of 64% (148/230) of the serum samples were seropositive, although none of the brain samples were positive for rabies infection. The seroprevalence was significantly higher in the second year of the study (p<0.001). This figure was detected in all variables (sex, age, season) and in most of the bat species. Conclusions: Our results indicate the possible occurrence of a recent peak in infection by the rabies virus in these bat populations, which represents an important alert, given that attacks by hematophagous bats are a constant threat in the study area, contributing to the probability of the occurrence of new cases of rabies. PMID- 29237042 TI - Dual antiplatelet therapy after coronary artery bypass surgery: is there an increase in bleeding risk? A meta-analysis. AB - OBJECTIVES: There is increasing evidence that dual antiplatelet therapy (DAPT) when compared with single antiplatelet therapy may improve venous graft patency after coronary artery bypass graft. However, it is not yet known whether postoperative administration of DAPT may increase the potential risk of bleeding, especially in the early postoperative period. METHODS: We searched studies on PubMed, Embase, Web of Science and the Cochrane Central Register of Controlled Trials. Relative risk (RR) was pooled with 95% confidence intervals (CIs) for dichotomous data. Prior subgroup analyses were performed to look for potential heterogeneity. RESULTS: Thirteen studies involving 23 591 participants were included. Our meta-analysis showed that DAPT does not increase the risk of major bleeding (randomized controlled trials group: RR = 1.28, 95% CI 0.95-1.71; cohort studies group: RR = 0.99, 95% CI 0.66-1.51) and minor bleeding (randomized controlled trials group: RR = 1.15, 95% CI 0.73-1.81; cohort studies group: RR = 0.84, 95% CI 0.37-1.93) when compared with single antiplatelet therapy. Meanwhile, DAPT does not increase the incidence of major bleeding events during hospitalization (randomized controlled trials group: RR = 1.27, 95% CI 0.91-1.78; cohort studies group: RR = 0.50, 95% CI 0.12-2.09). Sensitivity analyses showed that our results are stable, and there was no evidence of publication bias. CONCLUSIONS: DAPT does not increase the risk of major bleeding and minor bleeding when compared with single antiplatelet therapy. Postoperative administration of DAPT is considered to be safe in patients after coronary artery bypass graft, even in the early postoperative period. PMID- 29237043 TI - Veratramine modulates AP-1-dependent gene transcription by directly binding to programmable DNA. AB - Because the transcription factor activator protein-1 (AP-1) regulates a variety of protein-encoding genes, it is a participant in many cellular functions, including proliferation, transformation, epithelial mesenchymal transition (EMT), and apoptosis. Inhibitors targeting AP-1 have potential use in the treatment of cancer and other inflammatory diseases. Here, we identify veratramine as a potent natural modulator of AP-1, which selectively binds to a specific site (TRE 5' TGACTCA-3') of the AP-1 target DNA sequence and regulates AP-1-dependent gene transcription without interfering with cystosolic signaling cascades that might lead to AP-1 activation. Moreover, RNA-seq experiments demonstrate that veratramine does not act on the Hedgehog signaling pathway in contrast to its analogue, cyclopamine, and likely does not harbor the same teratogenicity and toxicity. Additionally, veratramine effectively suppresses EGF-induced AP-1 transactivation and transformation of JB6 P+ cells. Finally, we demonstrate that veratramine inhibits solar-ultraviolet-induced AP-1 activation in mice. The identification of veratramine and new findings in its specific regulation of AP-1 down stream genes pave ways to discovering and designing regulators to regulate transcription factor. PMID- 29237045 TI - Informing antimicrobial stewardship: factors associated with inappropriate antimicrobial prescribing in primary care. AB - Background: Antimicrobial stewardship (AS) programs promote the optimal use of antimicrobials and safe patient care. With most antimicrobials prescribed in the ambulatory setting, establishing benchmark data is imperative to gauge the impact of future AS initiatives. Objectives: To determine the frequency of potentially inappropriate antimicrobial prescribing in primary care practices in Manitoba, Canada and to assess the association between potentially inappropriate antimicrobial prescribing and patient, prescriber and practice-related factors. Methods: A retrospective cohort study using the Manitoba Primary Care Research Network repository of de-identified Electronic Medical Records from consenting primary care practices. Descriptive statistics and logistic regressions detailed patients with bacterial or viral infections of interest and antimicrobial prescriptions. Results: Eighteen percent (n = 35 574) of primary care visits for common infections were associated with a potentially inappropriate antimicrobial prescription. Among antimicrobials prescribed to patients diagnosed with bacterial infections, 37.8% (n = 2168) had a potentially inappropriate antimicrobial prescribed and 19.6% (n = 1126) had an antimicrobial prescribed for a duration outside of guideline-based ranges. Female patients, younger age and less office visits were associated with potentially inappropriate antimicrobial prescribing for bacterial infections. Among physician visits for viral infection, 15.9% (n = 29 833) were associated with an antimicrobial prescription. Older patients, those with more comorbidity, more office visits and those who were seen in larger or rural practices, were associated with potentially inappropriate antimicrobial prescribing for viral infections. Conclusions: High frequency of potentially inappropriate antimicrobial prescribing, especially in certain patient populations, suggests the need for coordinated community-based AS programs to optimize prescribing and improve patient care. PMID- 29237044 TI - Comparison of MOLLI, shMOLLLI, and SASHA in discrimination between health and disease and relationship with histologically derived collagen volume fraction. AB - Aims: To determine the bioequivalence of several T1 mapping sequences in myocardial characterization of diffuse myocardial fibrosis. Methods and results: We performed an intra-individual sequence comparison of three types of T1 mapping sequences [MOdified Look-Locker Inversion recovery (MOLLI), Shortened MOdified Look-Locker Inversion recovery ((sh)MOLLI), and SAturation recovery single-SHot Acquisition (SASHA)]. We employed two model diseases of diffuse interstitial fibrosis [patients with non-ischaemic dilated cardiomyopathy (NIDCM), n = 32] and aortic stenosis [(AS), n = 25)]. Twenty-six healthy individuals served as controls. Relationship with collagen volume fraction (CVF) was assessed using endomyocardial biopsies (EMB) intraoperatively in 12 AS patients. T2 mapping (GraSE) was also performed. Myocardial native T1 with MOLLI and shMOLLI showed, firstly, an excellent discriminatory accuracy between health and disease [area under the curves (P-value): 0.94 (0.88-0.99); 0.87 (0.79-0.94); 0.61 (0.49 0.72)], secondly, relationship between histological CVF [native T1 MOLLI vs. shMOLLI vs. SASHA: r = 0.582 (P = 0.027), r = 0.524 (P = 0.046), r = 0.443 (P = 0.150)], and thirdly, with native T2 [r = 0.628(P < 0.001), r = 0.459 (P = 0.003), r = 0.211 (P = 0.083)]. The respective relationships for extracellular volume fraction with CVF [r = 0.489 (P = 0.044), r = 0.417 (0.071), r = 0.353 (P = 0.287)] were significant for MOLLI, but not other sequences. In AS patients, native T2 was significantly higher compared to controls, and associated with levels of C-reactive protein and troponin. Conclusion: T1 mapping sequences differ in their bioequivalence for discrimination between health and disease as well as associations with diffuse myocardial fibrosis. PMID- 29237046 TI - Exposure to contrast media in the perioperative period confers no additional risk of acute kidney injury in surgical patients. AB - Background: Iodinated contrast media (CM) used in angiography and computed tomography (CT) scans is an important cause of acute kidney injury (AKI) in hospitalized patients undergoing surgery. Contrast-induced nephropathy leads to AKI soon after CM administration. The aim of the study was to determine whether the timing of contrast media exposure related to diagnostic imaging during the immediate perioperative period influences the risk of post-operative AKI. Methods: All patients aged 18 years or above who underwent diagnostic imaging within 7 days of non-cardiac surgery between 1 January 2003 and 31 December 2013 in the Tayside region of Scotland, UK were included in the analysis. The primary outcome of AKI was defined using the Kidney Disease: Improving Global Outcomes creatinine-based criteria. Multiple logistic regressions were performed to identify predictors for AKI. Results: Of 9300 patients, 6224 were exposed to CM in the immediate perioperative period and 3076 were not. Post-operative AKI occurred in 678 (10.9%) of the 6224 patients who were exposed to CM. On multiple logistic regression, independent predictors of post-operative AKI were increasing age, male gender, lower baseline renal function and treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Timing of CM exposure did not affect risk of developing AKI, odds ratio 0.972 (95% confidence interval 0.935-1.010), P = 0.146. Conclusions: For patients who have either just had or are soon to undergo general surgical procedures there appears to be no need to limit CT scan quality by avoiding the administration of CM. These patients may benefit from the increased diagnostic utility of contrast-enhanced CT scans without increasing their risk of perioperative AKI. PMID- 29237048 TI - Latent Profiles of Physical Activity and Sedentary Behavior in Elementary School Age Youth:Associations With Health-Related Quality of Life. AB - Objective: The objectives were to identify and describe profiles of elementary school-age youth based on objective measurements of total time spent in moderate to-vigorous physical activity (MVPA) and sedentary behavior (SB) and in bouts of the activities, to examine predictors of profiles, and to examine whether profiles were differentially associated with physical and psychosocial health related quality of life (HRQOL). Methods: Participants included 204 youth (aged 8 11 years) who wore accelerometers to gather objective activity data. The average proportion of time in MVPA and SB and average proportion of time in MVPA and SB bouts were used for analyses. Participants completed a self-report measure of HRQOL. Latent variable mixture modeling was conducted. Results: Overall, participants did not meet the MVPA guideline (M = 50.7 min) and spent 47% of waking hours in SB, indicating that elementary school is a critical developmental period to study activity levels. Three profiles emerged: "Active," "Inactive," and "Moderate." Boys were significantly more likely to be in the Active profile than the other profiles, and older youth were significantly more likely to be in the Inactive profile. After controlling for child sex and age, participants in the Active profile reported significantly higher psychosocial HRQOL than the participants in the other profiles; however, no significant differences were found in physical HRQOL. Conclusions: Identification of these naturally occurring profiles suggests need for interventions early in development focused on increasing the intensity of physical activity from light to moderate-to-vigorous for at least 60 min per day as way to improve psychosocial HRQOL. PMID- 29237049 TI - The comet assay in human biomonitoring: cryopreservation of whole blood and comparison with isolated mononuclear cells. AB - The comet assay is often applied in human biomonitoring. Most of the time the assay is performed with isolated peripheral blood mononuclear cells (PBMC). However, using whole blood instead of isolated cells reduces processing time, and only 20 ul is sufficient for analysis. In this study, a cryopreservation protocol for human whole blood for application in the comet assay was optimised by removing excess plasma before adding freezing medium. Cryopreservation of whole blood samples (n = 30) did not increase the detected level of strand breaks and formamidopyrimidine DNA glycosylase (FPG)-sensitive sites. Although there was no significant correlation with breaks measured in fresh whole blood, strand breaks detected in frozen whole blood were significantly correlated with breaks measured in frozen PBMC (Pearson correlation r = 0.54, P < 0.01). This correlation was however not observed for FPG-sensitive sites. Since we do not yet know the full extent to which cryopreservation might influence the blood cell population, care should be taken to ensure a similar cell type and storage conditions for all samples in one study. PMID- 29237047 TI - Correlates of high-impact physical activity measured objectively in older British adults. AB - Background: Exposure to higher magnitude vertical impacts is thought to benefit bone health. The correlates of this high-impact physical activity (PA) in later life are unknown. Methods: Participants were from the Cohort for Skeletal Health in Bristol and Avon, Hertfordshire Cohort Study and MRC National Survey of Health and Development. Associations of demographic, behavioural, physiological and psychological factors with vertical acceleration peaks >=1.5 g (i.e. high-impact PA) from 7-day hip-worn accelerometer recordings were examined using linear regression. Results: A total of 1187 participants (mean age = 72.7 years, 66.6% females) were included. Age, sex, education, active transport, self-reported higher impact PA, walking speed and self-rated health were independently associated with high-impact PA whereas BMI and sleep quality showed borderline independent associations. For example, differences in log-high-impact counts were 0.50 (P < 0.001) for men versus women and -0.56 (P < 0.001) for worst versus best self-rated health. Our final model explained 23% of between-participant variance in high impacts. Other correlates were not associated with high-impact activity after adjustment. Conclusions: Besides age and sex, several factors were associated with higher impact PA in later life. Our findings help identify characteristics of older people that might benefit from interventions designed to promote osteogenic PA. PMID- 29237050 TI - Serum Levels of IL-6, IL-8, TNF-alpha, and TGF-beta in Chronic HBV-Infected Patients: Effect of Depression and Anxiety. AB - Objective: To assess the effects of depression and anxiety on serum cytokine levels in patients with chronic hepatitis B (CHB) infection. Methods: In this cross-sectional study, 60 healthy control individuals and 60 patients with CHB participated after filling out standard questionnaires. We examined their serum interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, and TGF-beta levels using enzyme-linked immunosorbent assay (ELISA) techniques. Results: In patients with CHB compared with healthy controls, serum levels of IL-8 were significantly increased, whereas IL-6 and TGF-beta levels were significantly decreased. Serum levels of TGF-beta were significantly decreased in the patients with CHB who had mild depression, compared with patients with CHB without depression and with moderate and severe depression. Conclusions: Downregulation of IL-8 and TGF-beta, respectively, is a corresponding mechanism for induction of chronic inflammation in patients with CHB. Depression also seems to induce inflammation via downregulation of TGF-beta in these patients. PMID- 29237051 TI - Pharmacist participation in antimicrobial stewardship in Australian and French hospitals: a cross-sectional nationwide survey. AB - Background: Hospital pharmacists are an integral part of antimicrobial stewardship (AMS) programmes globally. Currently, little is known as to how hospital pharmacists see their role and involvement within the AMS framework. Objectives: To assess the current level of involvement of Australian and French hospital pharmacists in AMS programmes and identify barriers limiting their involvement in AMS. Methods: Hospital pharmacists throughout Australia and France were invited to participate in a nationwide online survey throughout March-May 2016. The survey was promoted through the national hospital pharmacists' association in Australia, while a stratified sampling method was used in France to invite pharmacists working in a variety of hospital settings. Results: Invitations to participate in this survey were sent to 334 Australian pharmacists and 482 French pharmacists. Responses from 133 Australian and 126 French pharmacists were included for analysis. A total of 78.4% (203/259) of pharmacists reported the presence of an AMS programme. Pharmacists were most likely to be involved in AMS through assessing total antibiotic consumption and participating in AMS committee meetings. Barriers to participating in AMS included a lack of time and substantial non-clinical activities limiting involvement in AMS. Differences in responses were found between the two countries. Conclusions: While the majority of pharmacists reported the presence of an AMS programme, multiple barriers to participation were identified by pharmacists in both countries. Further research should consider how to overcome the identified barriers to optimize the involvement of pharmacists in AMS. PMID- 29237052 TI - Multimode drug inducible CRISPR/Cas9 devices for transcriptional activation and genome editing. AB - Precise investigation and manipulation of dynamic biological processes often requires molecular modulation in a controlled inducible manner. The clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) has emerged as a versatile tool for targeted gene editing and transcriptional programming. Here, we designed and vigorously optimized a series of Hybrid drug Inducible CRISPR/Cas9 Technologies (HIT) for transcriptional activation by grafting a mutated human estrogen receptor (ERT2) to multiple CRISPR/Cas9 systems, which renders them 4-hydroxytamoxifen (4-OHT) inducible for the access of genome. Further, extra functionality of simultaneous genome editing was achieved with one device we named HIT2. Optimized terminal devices herein delivered advantageous performances in comparison with several existing designs. They exerted selective, titratable, rapid and reversible response to drug induction. In addition, these designs were successfully adapted to an orthogonal Cas9. HIT systems developed in this study can be applied for controlled modulation of potentially any genomic loci in multiple modes. PMID- 29237054 TI - ESTIMATION OF FEMALE RADIATION DOSES AND BREAST CANCER RISK FROM CHEST CT EXAMINATIONS. AB - Breast organ doses, effective doses and lifetime attributable risk (LAR) of breast cancer from chest CT scans are presented for 200 female patients surveyed from 10 hospitals in the West Bank and Gaza Strip, Palestine. Patient data were collected and organized in a database from May to November 2016. Data include age (15-80 years), weight, height, and calculated body mass index. Exposure data were also recorded for every examination. Exposure data includes milliampere-second (mAs), X-ray tube kilovoltage (kVp), computed tomography dose index, dose length product, manufacturer, name and type of operated CT scanner. Organ and effective doses were evaluated using a web-based commercially available Monte Carlo software: VirtualDoseTMCT, a product of Virtual Phantoms, Inc. The software utilizes male and female tissue equivalent phantoms of all ages and sizes including pregnant patients. The corresponding phantom was selected for every patient according to patient's tomographic parameters. Calculated organ doses were used to estimate the LAR of breast cancer according to BEIR VII Phase 2 report. It was found that radiation doses resulting from the same exam vary widely between different hospitals, depending on the parameters used and the type of scanner. For all patients, the breast organ dose ranged from 6.5 to 28 mGy per examination, with an average breast organ dose of 15 mGy. The effective dose from chest CT scan per examination ranged from 3 to 14.7 mSv with an average of 7 mSv. For younger females (15-29 years), the LAR of breast cancer risk was estimated to be around 0.05%. For older female patients (60-79 years), the risk was ~0.001%. It was found that LAR decreases remarkably with patient's age. Values obtained in this study vary between hospitals, they are generally low and consistent with other studies reported worldwide. PMID- 29237053 TI - Beyond sleep duration: Bidirectional associations between chronotype, social jetlag, and drinking behaviors in a longitudinal sample of US high school students. AB - Clinical Trial Registration: Health Behavior in School-Aged Children: NEXT Longitudinal Study 2009-2013, https://clinicaltrials.gov/ct2/show/NCT01031160?term=Simons-Morton&rank=3, NCT01031160. PMID- 29237055 TI - The epigenetic control of transposable elements and imprinted genes in newborns is affected by the mode of conception: ART versus spontaneous conception without underlying infertility. AB - STUDY QUESTION: Do assisted reproductive technologies alter DNA methylation and/or transcription of transposable elements and imprinted genes in cord blood and placenta? SUMMARY ANSWER: After ART, DNA methylation and/or transcription changes of some transposable elements and imprinted genes were found in placenta samples while transcription modifications for some transposable elements were also discovered in cord blood. WHAT IS KNOWN ALREADY: Recent studies have confirmed the increased risk of placenta-related adverse pregnancy outcomes and the excess of imprinted disorders with abnormal methylation patterns after ART, which raises the issue of a potential ART-induced epigenetic risk. STUDY DESIGN, SIZE, DURATION: A total of 51 IVF/ICSI (15 conventional and 36 ICSI) singleton pregnancies were prospectively included from January 2013 to April 2015 and compared to 48 spontaneously conceived singleton pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: The DNA methylation and transcription of three imprinted loci (H19/IGF2, KCNQ1OT1 and SNURF DMRs) and four transposon families (LINE-1, ERVFRD, AluYa5 and ERVW) in cord blood and placenta obtained at birth were assessed by pyrosequencing and quantitative RT-PCR, respectively. All data were adjusted for gestational age at delivery, sex of the newborn, parity and maternal age. MAIN RESULTS AND THE ROLE OF CHANCE: DNA methylation levels of H19/IGF2, KCNQ1OT1, LINE-1Hs and ERVFRD-1 were significantly lower in IVF/ICSI placentas than in control placentas, while there was no difference for cord blood. Moreover, the expression of ERVFRD-1 and LINE-1 ORF2 in cord blood and ERVFRD-1 in placenta was lower in the IVF/ICSI group than in controls. The expression of ERVFRD-1 in placenta correlated positively with birth weight and placenta weight, but only in the control group, thus pointing to the potential deregulation of syncytin function after ART. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The control group of fertile couples having conceived within 1 year prevented us from deciphering the distinct roles of ART and infertility. WIDER IMPLICATIONS OF THE FINDINGS: These novel findings of ERVFRD (syncytin-2) expression correlating with birth weight and placenta weight suggest that more research on syncytins and pregnancy-associated diseases could lead to them being used as biomarkers or even as therapeutic targets. The epigenetic modifications in placenta for sequences involved in foetal development raise the question of their potential effects on pregnancy and future life. These results should encourage us to analyse the exact causes and consequences of epigenetic changes and strive to minimize these variations in the interests of epigenetic safety after ART. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by a grant from Besancon and Dijon University Hospitals. The authors have no conflicts of interest to declare. PMID- 29237057 TI - Diabetic retinopathy: in need of multi-dimensional pharmacotherapy. PMID- 29237056 TI - The plant membrane surrounding powdery mildew haustoria shares properties with the endoplasmic reticulum membrane. AB - Many filamentous plant pathogens place specialized feeding structures, called haustoria, inside living host cells. As haustoria grow, they are believed to manipulate plant cells to generate a specialized, still enigmatic extrahaustorial membrane (EHM) around them. Here, we focused on revealing properties of the EHM. With the help of membrane-specific dyes and transient expression of membrane associated proteins fused to fluorescent tags, we studied the nature of the EHM generated by barley leaf epidermal cells around powdery mildew haustoria. Observations suggesting that endoplasmic reticulum (ER) membrane-specific dyes labelled the EHM led us to find that Sar1 and RabD2a GTPases bind this membrane. These proteins are usually associated with the ER and the ER/cis-Golgi membrane, respectively. In contrast, transmembrane and luminal ER and Golgi markers failed to label the EHM, suggesting that it is not a continuum of the ER. Furthermore, GDP-locked Sar1 and a nucleotide-free RabD2a, which block ER to Golgi exit, did not hamper haustorium formation. These results indicated that the EHM shares features with the plant ER membrane, but that the EHM membrane is not dependent on conventional secretion. This raises the prospect that an unconventional secretory pathway from the ER may provide this membrane's material. Understanding these processes will assist future approaches to providing resistance by preventing EHM generation. PMID- 29237058 TI - Evolution and Function of the Populus SABATH Family Reveal That a Single Amino Acid Change Results in a Substrate Switch. AB - Evolutionary mechanisms of substrate specificities of enzyme families remain poorly understood. Plant SABATH methyltransferases catalyze methylation of the carboxyl group of various low molecular weight metabolites. Investigation of the functional diversification of the SABATH family in plants could shed light on the evolution of substrate specificities in this enzyme family. Previous studies identified 28 SABATH genes from the Populus trichocarpa genome. In this study, we re-annotated the Populus SABATH gene family, and performed molecular evolution, gene expression and biochemical analyses of this large gene family. Twenty-eight Populus SABATH genes were divided into three classes with distinct divergences in their gene structure, expression responses to abiotic stressors and enzymatic properties of encoded proteins. Populus class I SABATH proteins converted IAA to methyl-IAA, class II SABATH proteins converted benzoic acid (BA) and salicylic acid (SA) to methyl-BA and methyl-SA, while class III SABATH proteins converted farnesoic acid (FA) to methyl-FA. For Populus class II SABATH proteins, both forward and reverse mutagenesis studies showed that a single amino acid switch between PtSABATH4 and PtSABATH24 resulted in substrate switch. Our findings provide new insights into the evolution of substrate specificities of enzyme families. PMID- 29237059 TI - Utility and justice in public health. AB - Background: Many public health practitioners and organizations view themselves as engaged in the promotion or achievement of equity. However, discussions around public health frequently assume that practitioners and policy-makers take a utilitarian approach to this work. Methods: I argue that public health is better understood as a social justice endeavor. I begin by presenting the utility view of public health and then discuss the equity view. This is a theoretical argument, which should help public health to justify interventions for communicable and non-communicable diseases equally, and which contributes to breaking down the 'old/new' public health divide. Results: This argument captures practitioners' views of the work they are engaged in and allows for the moral and policy justification of important interventions in communicable and non communicable diseases. Systemic interventions are necessary to remedy high rates of disease among certain groups and, generally, to improve the health of entire populations. Conclusions: By viewing diseases as partly the result of failures of health protective systems in society, public health may justify interventions in communicable and non-communicable diseases equally. Public health holds a duty to improve the health of the worst-off in society; by prioritizing this group, the health of the whole community may improve. PMID- 29237060 TI - News from the PUB: plant U-box type E3 ubiquitin ligases. AB - Plant U-box type E3 ubiquitin ligases (PUBs) are well known for their functions in a variety of stress responses, including immune responses and the adaptation to abiotic stresses. First linked to pollen self-incompatibility, their repertoire of roles has grown to encompass also the regulation of developmental processes. Notably, new studies provide clues to their mode of action, underline the existence of conserved PUB-kinase modules, and suggest new links to G-protein signalling, placing PUBs at the crossroads of major signalling hubs. The frequent association with membranes, by interacting and/or targeting membrane proteins, as well as through a recently reported direct interaction with phospholipids, indicates a general function in the control of vesicle transport and their cargoes. This review aims to give an overview of the most significant advances in the field, while also trying to identify common themes of PUB function. PMID- 29237061 TI - Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines in Preventing Postinfluenza Deaths. PMID- 29237062 TI - Rumpel-Leede phenomenon associated with blood flow restriction training. PMID- 29237063 TI - Spectrum of Pig-a mutations in T lymphocytes of rats treated with procarbazine. AB - Procarbazine is a primary component of antineoplastic combination chemotherapy often used for the treatment of Hodgkin's lymphoma. It is believed that cytostatic and cytotoxic properties of procarbazine are mediated via its interaction with genomic DNA. Procarbazine is a carcinogen in animal models; it is classified as Group 2A compound by IARC. Also it is known as an in vitro and in vivo mutagen and genotoxicant. However, the molecular mechanism by which procarbazine induces mutations is not thoroughly understood and the spectrum of procarbazine-induced in vivo mutations is described insufficiently. We employed flow cytometry-based erythrocyte and T lymphocyte assays in order to quantify the frequencies of cells deficient in glycosylphosphatidyl inositol-anchored surface markers CD59 and CD48 (presumed mutants in the endogenous X-linked Pig-a gene) in rats. The rats were treated once daily with 100 mg/kg procarbazine HCl for 3 days. In addition, we sorted mutant-phenotype spleen T cells and immediately analysed their Pig-a gene using next generation sequencing of dual-indexed multiplex libraries and error-correcting data filtering. More than 100-fold increase in the frequencies of CD59-deficient RBCs was observed at Day 29 after the last administration, and a 10-fold increase in the frequency of CD48 deficient T cells was observed at Days 45 to 50. Sequencing revealed that, in T cells from procarbazine-treated rats, mutations in the Pig-a gene occurred predominantly at A:T basepairs when A was located on the non-transcribed DNA strand. A->T transversion was the most common mutation. Our results suggest that, at least for the transcribed X-linked Pig-a gene, in vivo methyl guanine adducts are not the major contributors to mutations induced by procarbazine. PMID- 29237064 TI - Relationship between pemphigus and American tegumentary leishmaniasis: insights from serological and genetic profiles. AB - Background: Antibodies against Leishmania peptides (Lbr-peps) and desmogleins (Dsgs) have been reported in pemphigus foliaceus (PF) and leishmaniasis patients, respectively. We aimed to compare serological and genetic features in a Brazilian region endemic for American tegumentary leishmaniasis (ATL) and pemphigus. Methods: Commercial anti-Dsg ELISA and in-house ELISA with Lbr-peps were used to determine the serological profile, in addition to immunoblotting (IB) and indirect immunofluorescence (IIF) assays. HLA-DRB1 and -DQA1/DQB1 alleles were characterized by PCR combined with sequence-specific oligonucleotide probes (PCR SSOP). The serological and genetic profiles were compared using 78 PF, 62 pemphigus vulgaris (PV) and 58 ATL patients against 163 and 1592 healthy controls, respectively. Results: Some ATL patients showed positive results for anti-Dsg1 and/or anti-Dsg3 antibodies. They also revealed 130, 160 and/or 230 kDa epidermal peptides in IB. Moreover, some ATL samples exhibited pemphigus or a bullous pemphigoid pattern in IIF. ELISA and IB assays showed Lbr-peps in pemphigus patients. HLA-DQA1*01 and -DQA1*01:02 were protective and susceptibility alleles for ATL, respectively, but the opposite for pemphigus. Conclusions: Anti-Dsgs in ATL may represent epiphenomena. Anti-Lbr-pep antibodies in pemphigus suggest a previous infection. A differential association of the HLA profile may contribute to the lack of co-association between pemphigus and ATL. PMID- 29237065 TI - Methicillin-resistant Staphylococcus aureus in Papua New Guinea: a community nasal colonization prevalence study. AB - Background: There are few epidemiological data available to inform a national response to community-acquired methicillin-resistant Staphylococcus aureus (MRSA) in Papua New Guinea (PNG). Methods: We performed a cross-sectional survey to determine the pattern of MRSA nasal colonization and the diversity of circulating MRSA clones among adults and adolescents in Madang Province, PNG. Results: S. aureus nasal colonization was confirmed in 44 (17.1%) of 257 participants. Four (9.1%) isolates were methicillin resistant. Resistance to other antimicrobial agents was uncommon. Detailed molecular typing of three MRSA isolates demonstrated multiple MRSA clones in this community, of which two carried the Panton-Valentin leukocidin-associated virulence genes. Conclusions: MRSA is likely to account for a clinically important proportion of staphylococcal disease in PNG. There are multiple MRSA clones in PNG. Ongoing surveillance of community and invasive isolates is a critical component of an effective response to the challenge of community-acquired MRSA in this and many other resource-limited contexts. PMID- 29237066 TI - Early Motor Developmental Milestones and Schizotypy in the Northern Finland Birth Cohort Study 1966. AB - Delayed motor developmental milestones have been reported to be associated with schizophrenia in previous studies, but no study has examined the relationship between early motor developmental milestones and schizotypy. We have examined this relationship in a prospective birth cohort.In the Northern Finland Birth Cohort 1966, data on 9 early motor developmental milestones were collected prospectively from visits to child welfare centers, and data on adult schizotypy were collected through a questionnaire (N = 4557-4674). Positive schizotypy was measured by the Perceptual Aberration Scale (PAS), negative schizotypy was measured by Physical Anhedonia Scale (PhAS) and Social Anhedonia Scale (SAS). Three related scales were included: Schizoidia Scale (SCHD), Hypomanic Personality Scale (HPS), and Bipolar II Scale (BIP2). We examined the milestone schizotypy associations before and after excluding cases of schizophrenia from this population-based sample. Hierarchical regression analyses adjusted for covariates and separately for both genders were performed. In men, each extra month of delay in achievement of touching thumb with index finger, sitting unsupported, standing up, walking with support, or walking unsupported was associated with an increase in PAS, PhAS, or SCHD scores, or decrease in BIP2 score (P < .05). In women, each extra month of delay in achievement of turning from back to tummy was associated with an increase in PhAS and SAS scores (P < .05). Schizotypy is associated with delayed motor developmental milestones in early-life, but there is some heterogeneity with regards to types of milestones and gender. These findings suggest delayed motor development confers risk across the continuum of schizophrenia syndrome. PMID- 29237067 TI - EXPERIMENTAL AND MONTE CARLO INVESTIGATIONS OF BCF-12 SMALL-AREA PLASTIC SCINTILLATION DETECTORS FOR NEUTRON PINHOLE CAMERA. AB - Plastic organic scintillators such as the blue-emitting BCF-12 are versatile and inexpensive tools. Recently, BCF-12 scintillators have been foreseen for investigation of the spatial distribution of neutrons emitted from dense magnetized plasma. For this purpose, small-area (5 mm * 5 mm) detectors based on BCF-12 scintillation rods and Hamamatsu photomultiplier tubes were designed and constructed at the Institute of Nuclear Physics. They will be located inside the neutron pinhole camera of the PF-24 plasma focus device. Two different geometrical layouts and approaches to the construction of the scintillation element were tested. The aim of this work was to determine the efficiency of the detectors. For this purpose, the experimental investigations using a neutron generator and a Pu-Be source were combined with Monte Carlo computations using the Geant4 code. PMID- 29237068 TI - Screening for frailty in older emergency department patients: the utility of the Survey of Health, Ageing and Retirement in Europe Frailty Instrument. AB - Background: Greater numbers of older patients are accessing hospital services. Specialist geriatric input at presentation may improve outcomes for at-risk patients. The Survey of Health, Ageing and Retirement in Europe Frailty Instrument (SHARE-FI) frailty measure, developed for use in the community, has also been used in the emergency department (ED). Aim: To measure frailty, review its prevalence in older patients presenting to ED and compare characteristics and outcomes of frail patients with their non-frail counterparts. Design: Patient characteristics were recorded using symphony(r) electronic data systems. SHARE-FI assessed frailty. Cognition, delirium and 6 and 12 months outcomes were reviewed. Methods: A prospective cohort study was completed of those aged >=70 presenting to ED over 24 h, 7 days a week. Results: Almost half of 198 participants (46.7%, 93/198) were classified as frail, but this was not associated with a significant difference in mortality rates (OR 0.89, 95% CI 0.58-1.38, P = 0.614) or being alive at home at 12 months (OR 1.07, 95% CI 0.72-1.57, P = 0.745). Older patients were more likely to die (OR 2.34, 95% CI 1.30-4.21, P = 0.004) and less likely to be alive at home at 12 months (OR 0.49, 95% CI 0.23-0.83, P = 0.009). Patients with dementia (OR 0.24, P = 0.005) and on >=5 medications (OR 0.37, 95% CI 0.16 0.87, P = 0.022) had a lower likelihood of being alive at home at 12 months. Conclusions: Almost half of the sample cohort was frail. Older age was a better predictor of adverse outcomes than frailty as categorized by the SHARE-FI. SHARE FI has limited predictability when used as a frailty screening instrument in the ED. PMID- 29237070 TI - Rolling circle amplification shows a sinusoidal template length-dependent amplification bias. AB - Biophysical properties of DNA such as its longitudinal and torsional persistence length govern many processes and phenomena in biology, DNA nanotechnology and biotechnology. It has, for example, long been known that the circularization efficiency of short DNA fragments shows a periodic pattern where fragments with integer helical turns circularize much more efficiently than those with odd helical half turns due to stronger stacking of duplex ends. Small DNA circles can serve as templates for rolling circle amplification (RCA), which is a common and extremely robust amplification mechanism for nucleic acids. We discovered a strong template length-dependent amplification efficiency bias of RCA with the same periodicity as B-DNA. However, stacking cannot explain the mechanism behind this bias as the presence of the polymerase in the bifurcation fork inhibits base stacking of ends. Instead, coarse-grained molecular dynamics simulations imply that different amplification efficiencies come from a varying fraying probability of the last two downstream base pairs. We conclude that an increased strain promoted fraying probability can increase the polymerization rate compared to a relaxed template. PMID- 29237071 TI - Measuring Type 2 diabetes mellitus knowledge and perceptions of risk in middle class African Americans. AB - There is a paucity in the literature examining the African American middle-class. Most studies of African Americans and Type 2 Diabetes Mellitus (T2DM) have concentrated on lower-SES individuals, or make no distinction between African Americans of varying socio-economic positions. Middle-class African Americans are vulnerable in ways often overlooked by researchers. This study quantitatively examines specific T2DM knowledge and perceptions of risk in middle-class African Americans (N = 121). The majority of respondents, 70.2%, were unable to correctly identify all the warning signs of T2DM development. Only 3.3% of respondents correctly identified all risk factors provided as 'possible causes' of T2DM development. The difference between those participants who considered themselves to be at risk for T2DM development and their level of risk, according to the American Diabetes Associations' risk assessment, was not statistically significant (P = 0.397). However, there were statistically significant differences between participants' perceptions of their weight and clinical definitions of overweight, a major risk factor in T2DM development, based on BMI (P = 0.000). Middle-class African Americans are not inherently protected or exempt from developing T2DM. This study demonstrates gaps in knowledge and overall incongruent levels of perceived susceptibility, suggesting a need for additional research and health education in this segment of the population. PMID- 29237072 TI - Appropriate choice of stress modality in patients undergoing myocardial perfusion scintigraphy with a cardiac camera equipped with solid-state detectors: the role of diabetes mellitus. AB - Aims: To evaluate the impact of diabetes mellitus (DM) on the accuracy of myocardial perfusion scintigraphy (MPS) in detecting coronary artery disease (CAD). Methods and results: Two hundred and sixteen patients with DM and 432 matched controls were submitted to MPS on a dedicated cardiac camera equipped with cadmium-zinc-telluride (CZT) detectors and coronary angiography. Exercise stress was performed in 442 (68%) patients, while the remainders underwent vasodilator stress. Exercise level was determined as the percentage of the predicted maximal workload that was attained (%Wattmax). The summed difference score was derived from CZT images. A coronary stenosis >70% was considered obstructive. The prevalence of obstructive CAD was 59.7% in patients with DM and 56.2% in controls (P = NS). The accuracy of MPS in detecting CAD was similar in patients with and without DM [area under the ROC curve (AUC) 0.77 vs. 0.78, P = NS]. An interaction between the accuracy of MPS and cardiac stress-protocol was revealed. In fact, in patients with DM exercise stress CZT had a lower accuracy than vasodilator-stress (AUC 0.70 vs. 0.89, P < 0.001), because of a lower specificity (45% vs. 69%), while in the control group the accuracy of MPS was similar regardless of the stress-protocol adopted. Patients with DM attained a significantly lower %Wattmax during exercise than controls (76 +/- 27% vs. 82 +/- 26%, P = 0.038), which resulted an independent predictor of reduced specificity (P = 0.026). Conclusion: The accuracy of CZT imaging in patients with DM is elevated, and it is quite comparable to the one obtained in patients without DM. However, a reduced specificity can be expected in the case of exercise stress CZT, because of an impaired exercise capacity. PMID- 29237069 TI - Auxin signaling: a big question to be addressed by small molecules. AB - Providing a mechanistic understanding of the crucial roles of the phytohormone auxin has been an important and coherent aspect of plant biology research. Since its discovery more than a century ago, prominent advances have been made in the understanding of auxin action, ranging from metabolism and transport to cellular and transcriptional responses. However, there is a long road ahead before a thorough understanding of its complex effects is achieved, because a lot of key information is still missing. The availability of an increasing number of technically advanced scientific tools has boosted the basic discoveries in auxin biology. A plethora of bioactive small molecules, consisting of the synthetic auxin-like herbicides and the more specific auxin-related compounds, developed as a result of the exploration of chemical space by chemical biology, have made the tool box for auxin research more comprehensive. This review mainly focuses on the compounds targeting the auxin co-receptor complex, demonstrates the various ways to use them, and shows clear examples of important basic knowledge obtained by their usage. Application of these precise chemical tools, together with an increasing amount of structural information for the major components in auxin action, will certainly aid in strengthening our insights into the complexity and diversity of auxin response. PMID- 29237073 TI - Frequencies of borderline pulmonary hypertension before and after the DETECT algorithm: results from a prospective systemic sclerosis cohort. AB - Objective: The DETECT algorithm was developed for screening patients with SSc at high risk of pulmonary arterial hypertension (PAH). We evaluated the impact of this algorithm in a SSc population. Methods: Patients from the unselected, prospective Oslo University Hospital SSc study were divided into the Early and DETECT cohorts, respectively, depending on whether an incident right heart catheterization (RHC) was performed before (2009-13) or after (2014-17) the DETECT algorithm was instituted. A PAH diagnosis and patient risk stratification (low, intermediate and high risk) were performed according to 2015 European Society of Cardiology guidelines. Results: At the time of the incident RHC, PAH frequency was similar between the DETECT (15/84 with PAH; 18%) and Early (16/77; 21%) cohorts, but more patients had borderline pulmonary hypertension (PH) in the DETECT (31%) than in the Early (17%) cohort. PAH risk levels were distributed differently. In the DETECT cohort, 27% and 27% were at low and high risk, respectively, at the time of PAH diagnosis. In the Early cohort, 19 and 44% were at low and high risk, respectively. A follow-up RHC, performed after [mean (SD)] 2.4 (1.8) years, showed that 39% of patients with borderline PH in the Early cohort had developed PAH. Conclusion: The DETECT algorithm did not alter PAH incidence in this unselected SSc population. However, it appeared to affect the risk distribution at the time of PAH diagnosis and increased the frequency of borderline PH cases. These findings may translate into novel opportunities for earlier PAH treatment and, possibly, prevention. PMID- 29237074 TI - MEASUREMENT AND EVALUATION OF ELECTRIC FIELD STRENGTH LEVELS IN PRIMARY AND SECONDARY SCHOOLS IN A PILOT REGION. AB - In this study, in order to evaluate the exposed radiofrequency electromagnetic field (RF-EMF) levels, and to control their compliance with the limits determined by International Commission on Non-Ionizing Radiation Protection (ICNIRP), extensive short-term/band-selective and long-term RF-EMF measurements were conducted at 92 primary and secondary schools in the Ilkadim district of Samsun/Turkey. The measurements were performed once each in May, June, October and December in 2016, using the PMM-8053 EMF meter. It was seen from the measurement results that the maximum average electric field strength (Eavg) was recorded, 2.34 V/m, in October, when students were at school. It was concluded from the measurement results that the measured Eavg levels recorded at 92 schools were below the limits determined by ICNIRP. According to the band-selective measurement results performed using a Narda SRM-3006 EMF meter, the five main electric field strength (E) sources that had the most contribution in total E were LTE800, GSM900, GSM1800, UMTS2100 and WLAN services. With the use of these main E sources, an empirical model was then proposed that helps to determine the total E with 99.6% accuracy. It was also concluded from the long-term broadband measurement result that the number of active users affected the total E in the medium directly, and that the measured E levels were significantly higher in daytime than those of recorded in night-time. In the final stage of the study, all measurement results were transferred on scaled color maps. The use of these maps helped to determine and maintain control on the levels of RF-EMF exposure at schools using, or intending to install, such systems, and also to take measures for future precautions. PMID- 29237075 TI - Bimodal evolutionary developmental miRNA program in animal embryogenesis. AB - miRNAs play essential roles in the mechanics of gene regulation, however, on an organismal-scale, the processes in which they are deployed are not well understood. Here, we adopt an evolutionary developmental approach to study miRNA function by examining their expression throughout embryogenesis in both C. elegans and D. melanogaster. We find that, in both species, miRNA transcriptomic shifts in a punctuated fashion during the mid-developmental transition, specifying two dominant modes of early and late expression profiles. Strikingly, late-expressed miRNAs are enriched for phylogenetic conservation and function by fine-tuning the expression of their targets, implicating a role in the canalization of cell-types during differentiation. In contrast, early-expressed miRNAs are inversely expressed with their targets suggesting strong target inhibition. Taken together, our work exposes a bimodal role for miRNA function during animal development, involving late-expressed physiological roles and early expressed repressive roles. PMID- 29237076 TI - RECOMBINATION CHAMBERS-DO THE OLD IDEAS REMAIN USEFUL? AB - Recombination methods were invented almost contemporaneously with the introduction of the ICRU/ICRP concept of a radiation quality factor expressed in terms of linear energy transfer. Since then, recombination chambers and related methodologies have been extensively developed, along with new concepts of dosimetry and radiation protection. This article briefly presents the main features of recombination chambers and their possible applications in practical systems for measuring dosimetric quantities. PMID- 29237077 TI - Commercial Heritage as Democratic Action: Historicizing the 'Save the Market' Campaigns in Bradford and Chesterfield, 1969-76. AB - This article argues that the traditional retail market-a ubiquitous commercial feature of British towns and cities-produced a particular strand of heritage politics in late 1960s and early 1970s Britain. In recovering the activists involved in two campaigns to 'save the market' from redevelopment-one unsuccessful campaign in Bradford and one successful campaign in Chesterfield-I make the case for thinking through local urban heritage movements in comparative terms, focusing on how place-based citizenship collided with a nascent, national 'anti-development' mood in the early 1970s. The campaigns in Bradford and Chesterfield defended the transhistorical 'publicness' of the retail market-its spatial centrality, its collective ownership, and its relief of town or city rates-as a critique of contemporary, undemocratic privatization of communal space. Combining the archives of civic amenity, community action, and heritage societies with subjective attitudes towards preservation and redevelopment found in local 'letters to the editor' pages, this article reads the market as one physical nexus where local 'politics' and 'publics' collided and permutated in early 1970s provincial Britain. This focus on the lived heritage of socio economic place has bearing on public history, the history of urban social movements, and architecture and planning historiography. PMID- 29237078 TI - Determinants of Peripheral Muscle Strength and Activity in Daily Life in People With Bronchiectasis. AB - Background: Bronchiectasis is characterized by a progressive structural lung damage, recurrent infections and chronic inflammation which compromise the exertion tolerance, and may have an impact on skeletal muscle function and physical function. Objective: The purpose of this study was to compare peripheral muscle strength, exercise capacity, and physical activity in daily life between participants with bronchiectasis and controls and to investigate the determinants of the peripheral muscle strength and physical activity in daily life in bronchiectasis. Design: This study used a cross-sectional design. Methods: The participants' quadriceps femoris and biceps brachii muscle strength was measured. They performed the incremental shuttle walk test (ISWT) and cardiopulmonary exercise testing, and the number of steps/day was measured by a pedometer. Results: Participants had reduced quadriceps femoris muscle strength (mean difference to control group = 7 kg, 95% CI = 3.8-10.1 kg), biceps brachii muscle strength (2.1 kg, 95% CI = 0.7-3.4 kg), ISWT (227 m, 95% CI = 174-281 m), peak VO2 (6.4 ml/Kg/min, 95% CI = 4.0-8.7 ml/Kg/min), and number of steps/day (3,332 steps/day, 95% CI = 1,758-4,890 steps/day). A lower quadriceps femoris strength is independently associated to an older age, female sex, lower body mass index (BMI), higher score on the modified Medical Research Council scale, and shorter distance on the ISWT (R2 = 0.449). Biceps brachii strength is independently associated with sex, BMI, and dyspnea (R2 = 0.447). The determinants of number of daily steps were dyspnea and distance walked in ISWT, explaining only 27.7% of its variance. Limitations: Number of steps per day was evaluated by a pedometer. Conclusions: People with bronchiectasis have reduced peripheral muscle strength, and reduced aerobic and functional capacities, and they also are less active in daily life. Modifiable variables such as BMI, dyspnea, and distance walked on the ISWT are associated with peripheral muscle strength and physical activity in daily life. PMID- 29237080 TI - Cardiopulmonary coupling spectrogram as an ambulatory clinical biomarker of sleep stability and quality in health, sleep apnea and insomnia. AB - Study Objectives: Ambulatory tracking of sleep and sleep pathology is rapidly increasing with the introduction of wearable devices. The objective of this study was to evaluate a wearable device which used novel computational analysis of the electrocardiogram (ECG), collected over multiple nights, as a method to track the dynamics of sleep quality in health and disease. Methods: This study used the electrocardiogram as a primary signal, a wearable device, the M1, and an analysis of cardiopulmonary coupling to estimate sleep quality. The M1 measures trunk movements, the ECG, body position, and snoring vibrations. Data from three groups of patients were analyzed, healthy subjects, sleep apnea, and insomnia patients, obtained from multiple nights of recording. Analysis focused on summary measures and night-to-night variability, specifically the intra-class coefficient. Results: Data was collected from 10 healthy, 18 positive pressure treated sleep apnea, and 20 insomnia patients, 128, 65 and 121 nights respectively. In any subject, all nights were consecutive. High frequency coupling, the signal biomarker of stable breathing and stable sleep, showed high ICC's in healthy subjects and sleep apnea patients (0.83, 0.89) but only 0.66 in insomnia subjects. The only statistically significant difference between weekday vs. weekend in healthy subjects was HFC duration: 242.8 +/- 53.8 vs. 275.8 +/- 57.1 minutes (89 vs. 39 total nights), F(1,126)=9.86, p: 0.002. Conclusions: The M1 and similar wearable devices provide new opportunities to measure sleep in dynamic ways not possible before. These measurements can yield new biological insights, and aid clinical management. PMID- 29237079 TI - Fine-tuning of the setting of critical day length by two casein kinases in rice photoperiodic flowering. AB - Many short-day plants have a critical day length that fixes the schedule for flowering time, limiting the range of natural growth habitats (or growth and cultivation areas). Thus, fine-tuning of the critical day-length setting in photoperiodic flowering determines ecological niches within latitudinal clines; however, little is known about the molecular mechanisms controlling the fine tuning of the critical day-length setting in plants. Previously, we determined that florigen genes are regulated by day length, and identified several key genes involved in setting the critical day length in rice. Using a set of chromosomal segment substitution lines with the genetic background of an elite temperate japonica cultivar, we performed a series of expression analyses of flowering-time genes to identify those responsible for setting the critical day-length in rice. Here, we identified two casein kinase genes, Hd16 and Hd6, which modulate the expression of florigen genes within certain restricted ranges of photoperiod, thereby fine-tuning the critical day length. In addition, we determined that Hd16 functions as an enhancer of the bifunctional action of Hd1 (the Arabidopsis CONSTANS ortholog) in rice. Utilization of the natural variation in Hd16 and Hd6 was only found among temperate japonica cultivars adapted to northern areas. Therefore, this fine-tuning of the setting of the critical day length may contribute to the potential northward expansion of rice cultivation areas. PMID- 29237081 TI - 131I INTERNAL CONTAMINATION AND COMMITTED DOSE ASSESSMENT AMONG NUCLEAR MEDICINE MEDICAL PERSONNEL. AB - This study presents 131I thyroid activity measurements of 56 employees of the Department of Nuclear Medicine and Endocrine Oncology, Centre for Oncology in Gliwice. The research instrument was a whole-body spectrometer. In 44 out of 56 examined staff members, the determined 131I activity was found to be above the detection limit. The measured activities ranged from 6 +/- 2 to 457 +/- 118 Bq. The maximum estimated committed effective dose reached was 1.5 mSv/y. The results were compared with previous measurements conducted in another Polish nuclear medical unit. From this comparison, we can see that radiological safety among nuclear medicine personnel can be improved by appropriate work organisation. Reducing exposure of workers can be achieved by properly organised turnovers concerning the most vulnerable worksites. In addition, to lower the radiation risk, it is essential to comply strictly with the isolation regime for the patients. PMID- 29237082 TI - ADVANCED SURVEILLANCE OF ENVIROMENTAL RADIATION IN AUTOMATIC NETWORKS. AB - The objective of this study is the verification of the operation of a radiation monitoring network conformed by several sensors. The malfunction of a surveillance network has security and economic consequences, which derive from its maintenance and could be avoided with an early detection. The proposed method is based on a kind of multivariate distance, and the verification for the methodology has been tested at CIEMAT's local radiological early warning network. PMID- 29237083 TI - Relationship between patient-reported outcomes and clinical outcomes in metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-301 and COU-AA-302. AB - Background: Patient-reported outcomes (PROs) are used to assess benefit-risk in drug development. The relationship between PROs and clinical outcomes is not well understood. We aim to elucidate the relationships between changes in PRO measures and clinical outcomes in metastatic castration-resistant prostate cancer (mCRPC). Patients and methods: We investigated relationships between changes in self reported fatigue, pain, functional well-being (FWB), physical well-being (PWB) and prostate cancer-specific symptoms with overall survival (OS) and radiographic progression-free survival (rPFS) after 6 and 12 months of treatment in COU-AA-301 (N = 1195) or COU-AA-302 (N = 1088). Eligible COU-AA-301 patients had progressed after docetaxel and had Eastern Cooperative Oncology Group performance status (ECOG PS) <= 2. Eligible COU-AA-302 patients had no prior chemotherapy and ECOG PS 0 or 1. Patients were treated with abiraterone acetate (1000 mg/day) plus prednisone (10 mg/day) or prednisone alone daily. Association between self reported fatigue, pain and functional status, and OS and/or rPFS, using pooled data regardless of treatment, was assessed. Cox proportional hazard regression modeled time to death or radiographic progression. Results: In COU-AA-301 patients, PRO improvements were associated with longer OS and longer time to radiographic progression versus worsening or stable PROs (P < 0.0001). In multivariate models, all except pain intensity remained associated with OS. Pain intensity, PWB and FWB improvements remained associated with rPFS. In COU-AA-302 patients, worsening PROs were associated with higher likelihood of radiographic progression (P <= 0.025) compared with improved or stable PROs. In multivariate models, worsening PWB remained associated with worse rPFS. The 12-month analysis confirmed the 6-month results. Conclusions: PROs are significantly associated with clinically relevant time-to-event efficacy outcomes in clinical trials and may complement and help predict traditional clinical practice methods for monitoring patients for disease progression. PMID- 29237084 TI - New dimensions in circadian clock function: the role of biological sex. PMID- 29237085 TI - Corrigendum. PMID- 29237086 TI - Enterobacteriaceae producing OXA-48-like carbapenemases in Poland, 2013-January 2017. AB - Objectives: To analyse OXA-48 (OXA-48/181)-type carbapenemase-producing Enterobacteriaceae reported in Poland from 2013 until January 2017. Methods: Bacterial isolates were typed by PFGE and MLST. Genes coding for OXA-48/181 types and other beta-lactamases were amplified and sequenced. Mobile elements with blaOXA-48/181-like genes were PCR mapped. blaOXA-48/181-carrying plasmids were characterized by nuclease S1-hybridization profiling, transfer assays and PCR based replicon typing, while the chromosomal location of the genes was confirmed by the I-CeuI analysis. Results: Fifty-four isolates from 52 patients in 20 hospitals (14 cities) were included, in 14 cases having probable foreign origins indicated. The organisms were genetically diverse and represented numerous pandemic clones, including Klebsiella pneumoniae ST395 (n = 23), ST11, ST15 and ST101, Escherichia coli ST38, ST410 and ST648, and Enterobacter cloacae complex ST78. These produced OXA-48 (n = 49), OXA-181 (n = 4) or OXA-232 (n = 1). One of five K. pneumoniae ST395 pulsotypes caused a multicentre outbreak with 18 cases, which significantly contributed to the total number of patients. Depending on the variant, the blaOXA-48/181-like genes were parts of the Tn1999-, Tn2013- or Tn2016-like transposons, with blaOXA-48 found in an ISEcp1-associated module (Tn2016-like) for the first time. Three genotypes, including E. coli ST38, had chromosomal blaOXA-48 genes, while others carried transmissible IncL (~60 kb; blaOXA-48; n = 30), IncM (~80-95 kb; blaOXA-48; n = 4), IncX3 (~50 kb; blaOXA 181; n = 4) or non-typeable (~90-160 kb; blaOXA-48 or blaOXA-232) plasmids. Conclusions: Even though OXA-48/181 producers seem to occur infrequently in Poland, their epidemiology has been marked by various phenomena, namely multiple imports, several limited transmissions plus one larger clonal outbreak, and possible plasmid transfers. PMID- 29237087 TI - Type, Frequency, and Spatial Distribution of Immune Cell Infiltrates in CNS Germinomas: Evidence for Inflammatory and Immunosuppressive Mechanisms. AB - Central nervous system germinomas are characterized by a massive immune cell infiltrate. We systematically characterized these immune cells in 28 germinomas by immunophenotyping and image analysis. mRNA expression was analyzed by Nanostring technology and in situ RNA hybridization. Tumor infiltrating lymphocytes (TILs) were composed of 61.8% +/- 3.1% (mean +/- SE) CD3-positive T cells, including 45.2% +/- 3.5% of CD4-positive T-helper cells, 23.4% +/- 1.5% of CD8-positive cytotoxic T cells, 5.5% +/- 0.9% of FoxP3-positive regulatory T cells, and 11.9% +/-1.3% PD-1-positive TILs. B cells accounted for 35.8% +/- 2.9% of TILs and plasma cells for 9.3% +/- 1.6%. Tumor-associated macrophages consisted of clusters of activated PD-L1-positive macrophages and interspersed anti-inflammatory macrophages expressing CD163. Germinoma cells did not express PD-L1. Expression of genes encoding immune cell markers and cytokines was high and comparable to mRNA levels in lymph node tissue. IFNG and IL10 mRNA was detected in subfractions of TILs and in PD-L1-positive macrophages. Taken together, the strong immune reaction observed in germinomas involves inflammatory as well as various suppressive mechanisms. Expression of PD-1 and PD-L1 and infiltration of cytotoxic T cells are biomarkers predictive of response to anti PD-1/PD-L1 therapies, constituting a rationale for possible novel treatment approaches. PMID- 29237088 TI - Hemoglobin concentration and the risk of hemorrhagic and ischemic stroke in patients undergoing hemodialysis: the Q-cohort study. AB - Background: The contribution of the hemoglobin concentration to the incidence of hemorrhagic or ischemic stroke in patients undergoing hemodialysis is unclear. Methods: In total, 3436 patients undergoing prevalent hemodialysis were followed up for 4 years. The primary outcome was the first development of hemorrhagic or ischemic stroke. The baseline hemoglobin concentration was divided into quartiles [hemoglobin (g/dL): Q1, <=9.7; Q2, 9.8-10.5; Q3, 10.6-11.1; Q4, >=11.2]. The association between the hemoglobin concentration and each type of stroke was examined using the Kaplan-Meier method and a Cox proportional hazards model. Results: During the follow-up period, 76 (2.2%) patients developed hemorrhagic stroke and 139 (4.0%) developed ischemic stroke. The 4-year incidence rate of hemorrhagic stroke was significantly higher in patients with lower hemoglobin concentrations. Compared with the quartile of patients with the highest hemoglobin concentrations (Q4), the multivariable-adjusted hazard ratios for hemorrhagic stroke were 1.18 (95% confidence interval, 0.56-2.51), 1.59 (0.82 3.21) and 2.31 (1.16-4.73) in patients in Q3, Q2 and Q1, respectively. No association was identified between the 4-year incidence rate of ischemic stroke and the hemoglobin concentration. Compared with the quartile of patients with the lowest hemoglobin concentrations (Q1), the multivariable-adjusted hazard ratios for ischemic stroke were 1.17 (95% confidence interval, 0.73-1.89), 0.88 (0.51 1.51) and 1.10 (0.66-1.83) in patients in Q2, Q3 and Q4, respectively. Conclusions: Our results suggest that low hemoglobin concentrations are associated with a high risk of hemorrhagic stroke, but not of ischemic stroke, in patients undergoing hemodialysis. PMID- 29237089 TI - Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis. AB - Background/Introduction: Sarcoidosis is a multi-systemic disorder of unknown etiology, characterized by the presence of non-caseating granulomas in target organs. In 90% of cases, there is thoracic involvement. Fifty to seventy percent of pulmonary sarcoidosis patients will experience acute, self-limiting disease. For the subgroup of patients who develop persistent disease, no targeted therapy is currently available. Aim: To investigate the potential of the single nucleotide polymorphism (SNP), Toll-like receptor 3 Leu412Phe (TLR3 L412F; rs3775291), as a causative factor in the development of and in disease persistence in pulmonary sarcoidosis. To investigate the functionality of TLR3 L412F in vitro in primary human lung fibroblasts from pulmonary sarcoidosis patients. Design: SNP-genotyping and cellular assays, respectively, were used to investigate the role of TLR3 L412F in the development of persistent pulmonary sarcoidosis. Methods: Cohorts of Irish sarcoidosis patients (n = 228), healthy Irish controls (n = 263) and a secondary cohort of American sarcoidosis patients (n = 123) were genotyped for TLR3 L412F. Additionally, the effect of TLR3 L412F in primary lung fibroblasts from pulmonary sarcoidosis patients was quantitated following TLR3 activation in the context of cytokine and type I interferon production, TLR3 expression and apoptotic- and fibroproliferative-responses. Results: We report a significant association between TLR3 L412F and persistent clinical disease in two cohorts of Irish and American Caucasians with pulmonary sarcoidosis. Furthermore, activation of TLR3 in primary lung fibroblasts from 412 F-homozygous pulmonary sarcoidosis patients resulted in reduced IFN-beta and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients. Discussion/Conclusion: This study identifies defective TLR3 function as a previously unidentified factor in persistent clinical disease in pulmonary sarcoidosis and reveals TLR3 L412F as a candidate biomarker. PMID- 29237090 TI - Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patients. AB - BACKGROUND: Identification of myositis-specific autoantibodies (MSAs) for dermatomyositis (DM) could allow the characterization of an antibody-associated clinical phenotype. OBJECTIVE: We sought to define the clinical phenotype of DM and the risk of cancer, interstitial lung disease (ILD) and calcinosis based on MSA. METHODS: A 3.5-year multicentre prospective study of adult DM patients was conducted to determine the clinical phenotype associated with MSAs and the presence of cancer, ILD and calcinosis. RESULTS: MSAs were detected in 47.1% of 117 included patients. Patients with antimelanoma differentiation-associated protein-5 antibodies (13.7%) had significantly more palmar violaceous macules/papules [odds ratio (OR) 9.9], mechanic's hands (OR 8), cutaneous necrosis (OR 3.2), articular involvement (OR 15.2) and a higher risk of ILD (OR 25.3). Patients with antitranscriptional intermediary factor-1 antibodies (11.1%), antinuclear matrix protein-2 antibodies (6.8%) and antiaminoacyl transfer RNA synthetase (5.1%) had, respectively, significantly more poikiloderma (OR 5.9), calcinosis (OR 9.8) and articular involvement (OR 15.2). Cutaneous necrosis was the only clinical manifestation significantly associated with cancer (OR 3.1). CONCLUSION: Recognition of the adult DM phenotype associated with MSAs would allow more accurate appraisal of the risk of cancer, ILD and calcinosis. PMID- 29237091 TI - Epidermodysplasia verruciformis in an adult patient with a germline Interleukin-2 inducible T-Cell Kinase mutation and lymphoma: the case of inherited versus acquired. PMID- 29237092 TI - Artificial Cysteine S-Glycosylation Induced by Per-O-Acetylated Unnatural Monosaccharides during Metabolic Glycan Labeling. AB - The unexpected, non-enzymatic S-glycosylation of cysteine residues in various proteins by per-O-acetylated monosaccharides is described. This artificial S glycosylation greatly compromises the specificity and validity of metabolic glycan labeling in living cells by per-O-acetylated azido and alkynyl sugars, which has been overlooked in the field for decades. It is demonstrated that the use of unacetylated unnatural sugars can avoid the artifact formation and a corrected list of O-GlcNAcylated proteins and O-GlcNAc sites in HeLa cells has been assembled by using N-azidoacetylgalactosamine (GalNAz). PMID- 29237094 TI - Dermoscopy for discriminating between Trichophyton and Microsporum infections in tinea capitis. PMID- 29237093 TI - Serum androgens and prostate-specific antigen levels in androgenetic alopecia: is there a difference between frontal and vertex baldness? AB - BACKGROUND: Androgenetic alopecia (AGA) seems to be a marker of increased risk of prostate cancer (PCa). OBJECTIVE: We sought to investigate potential pathophysiological differences between frontal and vertex balding that might have the impact on the incidence of PCa. METHODS: Serum concentrations of testosterone (T), dihydrotestosterone (DHT) and prostate-specific antigen (PSA) were measured in 88 subjects with AGA. RESULTS: We have examined sixty patients with frontal baldness and 28 patients with vertex baldness. The subgroups did not differ significantly in age, BMI and as regards age of AGA onset, duration of AGA and comorbidities. The mean value of DHT in serum of the men with vertex baldness was higher than those in the men with frontal baldness with statistical significance (P < 0.05). The groups did not show significant differences in mean value of serum T and PSA levels, and DHT/T ratio. No correlation was found between the serum PSA level and serum androgen levels as well as DHT/T ratio. CONCLUSIONS: Vertex baldness may signal higher exposures to circulating DHT. Serum PSA level cannot serve as surrogate diagnostic marker of increased androgenic activity in men with AGA. PMID- 29237096 TI - Four cases of anti-Mi-2 antibody-positive dermatomyositis: relationship between anti-Mi-2 antibody titre and disease severity and activity. PMID- 29237095 TI - Pharmacist-physician collaborative care model and time to goal blood pressure in the uninsured population. AB - Pharmacist-physician collaborative practice models (PPCPMs) improve blood pressure (BP) control, but their effect on time to goal BP is unknown. This retrospective cohort study evaluated the impact of a PPCPM on time to goal BP compared with usual care using data from existing medical records in uninsured patients with hypertension. The primary outcome was time from the initial visit to the first follow-up visit with a BP <140/90 mm Hg. The study included 377 patients (259 = PPCPM; 118 = usual care). Median time to BP goal was 36 days vs 259 days in the PPCPM and usual care cohorts, respectively (P < .001). At 12 months, BP control was 81% and 44% in the PPCPM and usual care cohorts, respectively (P < .001) and therapeutic inertia was lower in the PPCPM cohort (27.6%) compared with usual care (43.7%) (P < .0001). Collaborative models involving pharmacists should be considered to improve BP control in high-risk populations. PMID- 29237097 TI - Sacubitril/valsartan instead of renin-angiotensin system inhibition alone: A step forward in resistant hypertension. PMID- 29237098 TI - Flow Alignment of Extracellular Vesicles: Structure and Orientation of Membrane Associated Bio-macromolecules Studied with Polarized Light. AB - Extracellular vesicles (EVs) are currently in scientific focus, as they have great potential to revolutionize the diagnosis and therapy of various diseases. However, numerous aspects of these species are still poorly understood, and thus, additional insight into their molecular-level properties, membrane-protein interactions, and membrane rigidity is still needed. We here demonstrate the use of red-blood-cell-derived EVs (REVs) that polarized light spectroscopy techniques, linear and circular dichroism, can provide molecular-level structural information on these systems. Flow-linear dichroism (flow-LD) measurements show that EVs can be oriented by shear force and indicate that hemoglobin molecules are associated to the lipid bilayer in freshly released REVs. During storage, this interaction ceases; this is coupled to major protein conformational changes relative to the initial state. Further on, the degree of orientation gives insight into vesicle rigidity, which decreases in time parallel to changes in protein conformation. Overall, we propose that both linear dichroism and circular dichroism spectroscopy can provide simple, rapid, yet efficient ways to track changes in the membrane-protein interactions of EV components at the molecular level, which may also give insight into processes occurring during vesiculation. PMID- 29237099 TI - Calcium channel blockers for primary and secondary Raynaud's phenomenon. AB - BACKGROUND: Raynaud's phenomenon is a vasospastic disease characterized by digital pallor, cyanosis, and extremity pain. Primary Raynaud's phenomenon is not associated with underlying disease, but secondary Raynaud's phenomenon is associated with connective tissue disorders such as systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. Calcium channel blockers promote vasodilation and are commonly used when drug treatment for Raynaud's phenomenon is required. OBJECTIVES: To assess the benefits and harms of calcium channel blockers (CCBs) versus placebo for treatment of individuals with Raynaud's phenomenon with respect to Raynaud's type (primary vs secondary) and type and dose of CCBs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (May 19, 2017), MEDLINE (1946 to May 19, 2017), Embase (1947 to May 19, 2017), clinicaltrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Portal. We applied no language restrictions. We also searched bibliographies of retrieved articles and contacted key experts for additional and unpublished data. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing calcium channel blockers versus placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed search results and risk of bias and extracted trial data. We used the GRADE approach to assess the quality of evidence. MAIN RESULTS: This review contains 38 RCTs (33 cross-over RCTs) with an average duration of 7.4 weeks and 982 participants; however, not all trials reported all outcomes of interest. Nine of the identified trials studied patients with primary Raynaud's phenomenon (N = 365), five studied patients with secondary Raynaud's phenomenon (N = 63), and the rest examined a mixture of patients with primary and secondary Raynaud's phenomenon (N = 554). The most frequently encountered risk of bias types were incomplete outcome data and poor reporting of randomization and allocation methods.When researchers considered both primary and secondary Raynaud's phenomenon, evidence of moderate quality (downgraded for inconsistency) from 23 trials with 528 participants indicates that calcium channel blockers (CCBs) were superior to placebo in reducing the frequency of attacks. CCBs reduced the average number of attacks per week by six ( weighted mean difference (WMD) -6.13, 95% confidence interval (CI) -6.60 to - 5.67; I2 = 98%) compared with 13.7 attacks per week with placebo. When review authors excluded Kahan 1985C, a trial showing a very large reduction in the frequency of attacks, data showed that CCBs reduced attack frequency by 2.93 per week (95% CI -3.44 to -2.43; I2 = 77%).Low quality evidence (downgraded for imprecision and inconsistency) from six trials with 69 participants suggests that the average duration of attacks did not differ in a statistically significant or clinically meaningful way between CCBs and placebo (WMD -1.67 minutes, 95% CI -3.29 to 0); this is equivalent to a -9% difference (95% CI -18% to 0%).Moderate-quality evidence (downgraded for inconsistency) based on 16 trials and 415 participants showed that CCBs reduced attack severity by 0.62 cm (95% CI -0.72 to - 0.51) on a 10-cm visual analogue scale (lower scores indicate less severity); this was equivalent to absolute and relative percent reductions of 6% (95% CI -11% to -8%) and 9% (95% CI -11% to 8%), respectively, which may not be clinically meaningful.Improvement in Raynaud's pain (low-quality evidence; downgraded for imprecision and inconsistency) and in disability as measured by a patient global assessment (moderate-quality evidence; downgraded for imprecision) favored CCBs (pain: WMD 1.47 cm, 95% CI -2.21 to -0.74; patient global: WMD -0.37 cm, 95% CI -0.73 to 0, when assessed on a 0 to 10 cm visual analogue scale, with lower scores indicating less pain and less disability). However, these effect estimates were likely underpowered, as they were based on limited numbers of participants, respectively, 62 and 92. For pain assessment, absolute and relative percent improvements were 15% (95% -22% to -7%) and 47% (95% CI -71% to -24%), respectively. For patient global assessment, absolute and relative percent improvements were 4% (95% CI -7% to 0%) and 9% (95% CI -19% to 0%), respectively.Subgroup analyses by Raynaud's type, CCB class, and CCB dose suggest that dihydropyridine CCBs in higher doses may be more effective for primary Raynaud's than for secondary Raynaud's, and CCBs likely have a greater effect in primary than in secondary Raynaud's. However, differences were small and were not found for all outcomes. Dihydropyridine CCBs were studied as they are the subgroup of CCBs that are not cardioselective and are traditionally used in RP treatment whereas other CCBs such as verapamil are not routinely used and diltiazem is not used as first line subtype of CCBs. Most trial data pertained to nifedipine.Withdrawals from studies due to adverse effects were inconclusive owing to a wide CI (risk ratio [RR] 1.30, 95% CI 0.51 to 3.33) from two parallel studies with 63 participants (low-quality evidence downgraded owing to imprecision and a high attrition rate); absolute and relative percent differences in withdrawals were 6% (95% CI -14% to 26%) and 30% (95% CI -49% to 233%), respectively. In cross-over trials, although a meta-analysis was not performed, withdrawals were more common with CCBs than with placebo. The most common side effects were headache, dizziness, nausea, palpitations, and ankle edema. However, in all trials, no serious adverse events (death or hospitalization) were reported. AUTHORS' CONCLUSIONS: Randomized controlled trials with evidence of low to moderate quality showed that CCBs (especially the dihydropyridine class) may be useful in reducing the frequency, duration, severity of attacks, pain and disability associated with Raynaud's phenomenon. Higher doses may be more effective than lower doses and these CCBs may be more effective in primary RP. Although there were more withdrawals due to adverse events in the treatment groups, no serious adverse events were reported. PMID- 29237100 TI - Perianal tuberculosis in an immunocompetent patient. PMID- 29237101 TI - Collaborative care model for hypertension. PMID- 29237103 TI - 2017 - A Time of Change. PMID- 29237102 TI - Patient Safety - Doing Your Part. PMID- 29237104 TI - Osteoporosis in Patients with CKD: A Diagnostic Dilemma. AB - Osteoporosis in patients with chronic kidney disease (CKD) is a complex problem, with diagnostic criteria and treatment plans often debated. The debate creates a practice dilemma for clinicians faced with an aging population and an increasing incidence of fragility fractures. This article discusses the dilemma as seen from the perspective of the nephrology clinician on differentiating osteoporosis from other bone mineral disorders in patients with progressive CKD in order to provide the most efficacious and safe care. PMID- 29237105 TI - Nephrology Nursing Scope and Standards of Practice: Integration into Clinical Practice. AB - The eighth edition of the Nephrology Nursing Scope and Standards of Practice, published by the American Nephrology Nurses Association (Gomez, 2017), defines the scope of nephrology nursing practice, and provides standards of practice and professional performance in an approach similar to the American Nurses Association (ANA) 2016 standards. ANNA's eighth edition of the Nephrology Nursing Scope and Standards of Practice incorporates competencies for graduate level prepared nurses in addition to the registered nurse (RN) and advanced practice registered nurse (APRN). The section on how to use the standards in practice has been updated with user-friendly forms. This article provides an overview of the scope of practice, standards, competencies, and situations that require intervention by the nephrology nurse. PMID- 29237106 TI - Home Therapy to Reduce Office Visits for Patients with Chronic Kidney Disease and Anemia. AB - Anemia is a common complication of chronic kidney disease (CKD) and a predictor of increased mortality. This project integrated erythropoietin-stimulating agent (ESA) with CKD care under one practice setting, co-managing anemia with CKD while reducing frequency of office visits in a rural setting. Patients self administered their weekly dosage of erythropoietin with monthly follow-ups. As a result, office visits decreased by 56% for patients with CKD Stage 4 and by 54% for patients with CKD Stage 5. PMID- 29237107 TI - You Live as Much as You Have Time To: The Experience of Patients Living with Hemodialysis. AB - Changes in their daily lives that patients endure because of hemodialysis are major and also essential so they can stay alive. The aim of this study was to describe changes in life for patients with renal failure undergoing hemodialysis. The study has a qualitative descriptive approach with a qualitative content analysis based on in-depth interviews with patients undergoing hemodialysis. Results show that life in hemodialysis is experienced as a transition from liberty to captivity, adjusting to the new life, and the new life moving towards reconciliation. This study shows that support towards reconciliation is crucial for patient health. PMID- 29237108 TI - The Relationship Between Bloodstream Infections and Hemodialysis Catheters in Hospital-Based Hemodialysis Units. AB - As the number of patients requiring hemodialysis increases, so does the number of patients who require complex care and whose care requires a hospital hemodialysis unit setting rather than a freestanding unit. As a result, hospital units may have a higher ratio of complex patients, and some quality incentive program (QIP) measures may need modification to be meaningful in these settings. PMID- 29237109 TI - Enhancing Self-Care Management of Interdialytic Fluid Weight Gain in Patients on Hemodialysis: A Pilot Study Using Motivational Interviewing. AB - Patients receiving hemodialysis are challenged with restricting their fluid intake to ensure appropriate interdialytic weight gains. While nurses endeavor to promote selfcare, the ability to manage fluid gain rests on the patient's understanding and decision to limit fluid intake. A mixed-methods pilot study was undertaken to determine if motivational interviewing, a patient-centered, conversational, and collaborative approach to stimulating behavior change and resolving ambivalence, enhances self-care fluid management. Participants felt that motivational interviewing was very helpful, although findings suggest self care fluid management requires a toolkit of interventions. Key motivational interviewing actions for nurses are presented. PMID- 29237110 TI - A Blood Pressure You Can Believe In. PMID- 29237111 TI - Home Hemo on the Range. PMID- 29237112 TI - Bladder Capacity. PMID- 29237113 TI - The Replication Protein Cdc6 Suppresses Centrosome Over-Duplication in a Manner Independent of Its ATPase Activity. AB - The Cdc6 protein is essential for the initiation of chromosomal replication and functions as a licensing factor to maintain chromosome integrity. During the S and G2 phases of the cell cycle, Cdc6 has been found to inhibit the recruitment of pericentriolar material (PCM) proteins to the centrosome and to suppress centrosome over-duplication. In this report, we analyzed the correlation between these two functions of Cdc6 at the centrosome. Cdc6 depletion increased the population of cells showing centrosome over-duplication and premature centrosome separation; Cdc6 expression reversed these changes. Deletion and fusion experiments revealed that the 18 amino acid residues (197-214) of Cdc6, which were fused to the Cdc6-centrosomal localization signal, suppressed centrosome over-duplication and premature centrosome separation. Cdc6 mutant proteins that showed defective ATP binding or hydrolysis did not exhibit a significant difference in suppressing centrosome over-duplication, compared to the wild type protein. In contrast to the Cdc6-mediated inhibition of PCM protein recruitment to the centrosome, the independence of Cdc6 on its ATPase activity for suppressing centrosome over-duplication, along with the difference between the Cdc6 protein regions participating in the two functions, suggested that Cdc6 controls centrosome duplication in a manner independent of its recruitment of PCM proteins to the centrosome. PMID- 29237116 TI - HOPE FOR PKU. FUTURE. AB - I have been living with Phenylketonuria (PKU) for 45 years. My journey has been challenging for many reasons but mostly related to how the disease is viewed and the lack of awareness. PMID- 29237114 TI - Emerging Paradigm of Crosstalk between Autophagy and the Ubiquitin-Proteasome System. AB - Cellular protein homeostasis is maintained by two major degradation pathways, namely the ubiquitin-proteasome system (UPS) and autophagy. Until recently, the UPS and autophagy were considered to be largely independent systems targeting proteins for degradation in the proteasome and lysosome, respectively. However, the identification of crucial roles of molecular players such as ubiquitin and p62 in both of these pathways as well as the observation that blocking the UPS affects autophagy flux and vice versa has generated interest in studying crosstalk between these pathways. Here, we critically review the current understanding of how the UPS and autophagy execute coordinated protein degradation at the molecular level, and shed light on our recent findings indicating an important role of an autophagy-associated transmembrane protein EI24 as a bridging molecule between the UPS and autophagy that functions by regulating the degradation of several E3 ligases with Really Interesting New Gene (RING)-domains. PMID- 29237115 TI - Isolation and Functional Examination of the Long Non-Coding RNA Redrum. AB - Here, we report isolation of multiple long non-coding RNAs (lncRNAs) expressed tissue-specifically during murine embryogenesis. One of these, subsequently came to be known as Redrum, is expressed in erythropoietic cells in fetal liver and adult bone marrow. Redrum transcription is also detected during pregnancy in the spleen where extramedullary hematopoiesis takes place. In order to examine the function of Redrum in vivo, we generated a gene-targeted murine model and analyzed its embryonic and adult erythropoiesis. The homozygous mutant embryo showed no apparent deficiency or defect in erythropoiesis. Adult erythropoiesis in bone marrow and in the spleen during pregnancy likewise showed no detectable phenotype as red blood cells matured in normal fashion. The phenotype is in contrast to the reported function of Redrum in vitro, and our observation implies that Redrum plays in vivo an accessory or supplementary role whose loss is compatible with normal erythropoiesis. PMID- 29237117 TI - AN EXPLORATION OF THE AUSTRALIAN BREAST CARE NURSE ROLE IN SUPPORTING WOMEN WITH BREAST CANCER. AB - The lack of literature surrounding the role of the Australian Breast Care Nurse (BCN) and the well documented disparity between cancer survival in urban versus rural and remote areas has inspired an RN working in rural Australia to undertake doctoral research to further explore these issues. PMID- 29237118 TI - IMPROVING COMMUNICATION AROUND ANAL INCONTINENCE FOR WOMEN OF REPRODUCTIVE AGE. AB - Anal incontinence (AI) is the accidental loss of liquid or solid stool and flatus (Milsom et al. 2009). The concept of uncontrolled faecal loss can evoke social disgust and marginalize those afflicted from the community in which they live (Williams et al. 2005). PMID- 29237119 TI - EXPANDING PRACTICE INTO AREAS. ALIGNED PHILOSOPHICALLY WITH MIDWIFERY. AB - The number of midwives practicing in Australia in 1999, were 11,985 and in 2014, 23,862 (Australian Institute of Health & Welfare, 2014 workforce report). Just over 3,000 are registered as a midwife only. PMID- 29237120 TI - Ultrafast Time-Resolved Studies on Fluorescein for Recognition Strands Architecture in Amyloid Fibrils. AB - Protein aggregation is associated with numerous devastating diseases such as Alzheimer's, Parkinson's, and prion diseases. Development of therapeutics would benefit from knowledge of the structural organization of protein molecules in these amyloid aggregates, particularly in their aqueous biological milieu. However, detailed structural studies to date have been mainly on the solid state and have required large quantities of purified aggregate. Moreover, these conventional methods require the aggregated assembly to remain structurally stable over days or weeks required to perform the experiment, whereas the pathologically relevant species of in vivo aggregates may be shorter lived. Here, we show the organization of protein chains in dissolved amyloid aggregates can be readily determined spectroscopically using minute quantities of fluorescein labeled protein segments in a matter of minutes. Specifically, we investigated the possibility of using the ultrafast dynamics of fluorescein to distinguish among three categories of beta-sheet geometry: (1) antiparallel in-register, (2) parallel in-register, or (3) antiparallel out-of-register. Fluorescein, the most commonly used staining dye in biology and medicine, was covalently attached to the N-termini of peptide sequences selected from a library of known amyloid crystal structures. We investigated the aggregates in solution using steady-state and time-resolved absorption and fluorescence spectroscopy. We found that the dynamics of fluorescein relaxation from the excited state revealed amyloid structure-specific information. Particularly, the nonfluorescent cation form of fluorescein showed remarkable sensitivity to local environments created during aggregation. We demonstrate that time-resolved absorption is capable of differentiating strand organization in beta-sheet aggregates when strong intermolecular coupling between chromophores occurs. This approach can be useful in optical recognition of specific fibril architectures of amyloid aggregates. PMID- 29237121 TI - Toward Synthetic Biology Strategies for Adipic Acid Production: An in Silico Tool for Combined Thermodynamics and Stoichiometric Analysis of Metabolic Networks. AB - Adipic acid, a nylon-6,6 precursor, has recently gained popularity in synthetic biology. Here, 16 different production routes to adipic acid were evaluated using a novel tool for network-embedded thermodynamic analysis of elementary flux modes. The tool distinguishes between thermodynamically feasible and infeasible modes under determined metabolite concentrations, allowing the thermodynamic feasibility of theoretical yields to be assessed. Further, patterns that always caused infeasible flux distributions were identified, which will aid the development of tailored strain design. A review of cellular efflux mechanisms revealed that significant accumulation of extracellular product is only possible if coupled with ATP hydrolysis. A stoichiometric analysis demonstrated that the maximum theoretical product carbon yield heavily depends on the metabolic route, ranging from 32 to 99% on glucose and/or palmitate in Escherichia coli and Saccharomyces cerevisiae metabolic models. Equally important, metabolite concentrations appeared to be thermodynamically restricted in several pathways. Consequently, the number of thermodynamically feasible flux distributions was reduced, in some cases even rendering whole pathways infeasible, highlighting the importance of pathway choice. Only routes based on the shikimate pathway were thermodynamically favorable over a large concentration and pH range. The low pH capability of S. cerevisiae shifted the thermodynamic equilibrium of some pathways toward product formation. One identified infeasible-pattern revealed that the reversibility of the mitochondrial malate dehydrogenase contradicted the current state of knowledge, which imposes a major restriction on the metabolism of S. cerevisiae. Finally, the evaluation of industrially relevant constraints revealed that two shikimate pathway-based routes in E. coli were the most robust. PMID- 29237122 TI - Photoelectron Velocity-Map Imaging and Theoretical Studies of Heterotrinuclear Metal Carbonyls V2Ni(CO)n- (n = 6-10). AB - Photoelectron velocity-map imaging spectroscopy was conducted for the heterotrinuclear metal carbonyls V2Ni(CO)n- (n = 6-10). Electronic structure calculations were performed to understand the experimental spectral features. The binding motif of a V-V-Ni chain with two side-on-bonded carbonyls and two bridging carbonyls is favored in the n = 6-9 clusters. A V2Ni triangle core structure is formed at n = 10 with the involvement of two carbonyls with the carbon atom triply coordinated to metal atoms, three bridging carbonyls, and five terminal carbonyls, in which CO bonding configurations mirror the adsorption features in the three-fold hollow, bridging, and atop sites on the closely packed surface, respectively. The present study provides a stepwise picture for molecular level understanding of CO bonding on heteronuclear metal clusters, which is directly relevant to the elementary processes of CO on the alloy surfaces/interfaces. PMID- 29237124 TI - Fragmentation of Methanol Molecules after Core Excitation and Core Ionization Studied by Negative-Ion/Positive-Ion Coincidence Experiments. AB - We have studied the fragmentation of the methanol molecule after core excitation and core ionization by observing coincidences between negative and positive ions. Five different negative ions (H-, C-, CH-, O-, and OH-) were observed at both the C 1s and O 1s edges. As negative ion formation occurs after resonant and normal Auger decay of core-hole states, it is necessarily linked with the release of positively charged fragments. Our data show that such fragmentation can happen in many different ways: We found approximately 30 negative-ion/positive-ion/positive ion coincidence (NIPIPICO) channels. All involve only singly charged positive ions. Fragmentation channels leading to atomic ions are the most probable, but positive molecular ions are also frequently found in the context of anion formation. Coincidence yields as a function of photon energy were determined for the most intense NIPIPICO channels. Adding together the data measured at different photon energies, we could also verify the occurrence of four-ion coincidences, which involved one negative ion (H- or O-) and three positive ions. PMID- 29237125 TI - Natural Dietary Products and Their Effects on Appetite Control. AB - Natural dietary products have been thoroughly studied for their effects of antiadipogenesis to prevent and treat obesity for decades. Nevertheless, in the past few years appetite control for the treatment of obesity has attracted much attention as a new target. Homeostatic control of energy intake involves a complex system that conveys peripheral signals to the central nervous system where multiple signals are integrated and then provide feedback to regulate satiation. This perspective aims at elucidating the neuronal mechanisms of food intake and energy balance as well as providing an alternative pathway of controlling weight using natural dietary products. PMID- 29237123 TI - Construction of Multivalent Homo- and Heterofunctional ABO Blood Group Glycoconjugates Using a Trifunctional Linker Strategy. AB - The design and synthesis of multivalent ligands displaying complex oligosaccharides is necessary for the development of therapeutics, diagnostics, and research tools. Here, we report an efficient conjugation strategy to prepare complex glycoconjugates with 4 copies of 1 or 2 separate glycan epitopes, providing 4-8 carbohydrate residues on a tetravalent poly(ethylene glycol) scaffold. This strategy provides complex glycoconjugates that approach the size of glycoproteins (15-18 kDa) while remaining well-defined. The synthetic strategy makes use of three orthogonal functional groups, including a reactive N hydroxysuccinimide (NHS)-ester moiety on the linker to install the first carbohydrate epitope via reaction with an amine. A masked amine functionality on the linker is revealed after the removal of a fluorenylmethyloxycarbonyl (Fmoc) protecting group, allowing the attachment to the NHS-activated poly(ethylene glycol) (PEG) scaffold. An azide group in the linker was then used to incorporate the second carbohydrate epitope via catalyzed alkyne-azide cycloaddition. Using a known tetravalent PEG scaffold (PDI, 1.025), we prepared homofunctional glycoconjugates that display four copies of lactose and the A-type II or the B type II human blood group antigens. Using our trifunctional linker, we expanded this strategy to produce heterofunctional conjugates with four copies of two separate glycan epitopes. These heterofunctional conjugates included Neu5Ac, 3' sialyllactose, or 6'-sialyllactose as a second antigen. Using an alternative strategy, we generated heterofunctional conjugates with three copies of the glycan epitope and one fluorescent group (on average) using a sequential dual amine coupling strategy. These conjugation strategies should be easily generalized for conjugation of other complex glycans. We demonstrate that the glycan epitopes of heterofunctional conjugates engage and cluster target B-cell receptors and CD22 receptors on B cells, supporting the application of these reagents for investigating cellular response to carbohydrate antigens of the ABO blood group system. PMID- 29237126 TI - Impact of Ultrasmall Platinum Nanoparticle Coating on Different Morphologies of Gold Nanostructures for Multiple One-Pot Photocatalytic Environment Protection Reactions. AB - Here, we report the preparation of various morphologies of core-satellite hybrid plasmonic nanomaterials of gold and platinum, viz., the coating of platinum nanoparticles on gold nanostars (Pt@AuNSs), nanospheres (Pt@AuNPs), and nanorods (Pt@AuNRs) for visible-NIR-sunlight illuminated highly efficient photoconversion of CO2 to HCOOH and visible light mediated degradation of various organic dyes (methylene blue, methyl orange, and methyl red) in a single step at room temperature. In comparison, Pt@AuNSs shows higher conversion efficiency for CO2 photoconversion to HCOOH with 1.52% of quantum yield and 2.58% of chemical yield in visible-light illumination. There was a 200-fold increase in the conversion efficiency after PtNP coating to AuNSs. On the other hand, Pt@AuNPs (quantum yield = 1.44%) and Pt@AuNRs (quantum yield = 0.64%) also show the significant conversion rate in visible and NIR light, respectively. All the hybrid nanoparticles were found to be stable, whereas PtNPs increase the stability of AuNSs incredibly, during the photoconversion reaction and reused for five CO2 reduction reaction cycles without losing photocatalytic activity. Moreover, Pt@AuNSs also showed higher photocatalytic activity for organic pollutant degradation and degraded methylene blue, methyl red, and methyl orange in 45, 75, and 80 min with 0.104 min-1, 0.055 min-1, and 0.044 min-1 reaction rate, respectively. The results highlighted the crucial role of PtNPs as a highly efficient cocatalyst as well as the impact of increases in surface area with the change in morphology of gold nanostructures on CO2 photoconversion and organic dye degradation. PMID- 29237127 TI - Infrared Spectroscopy of the Astrochemically Relevant Protonated Formaldehyde Dimer. AB - The protonated formaldehyde dimer (H2CO)2H+ was generated in an electrical discharge and supersonic expansion of argon saturated with formalin solution vapor. Its infrared spectrum was measured in the region from 900 to 4000 cm-1 employing infrared laser photodissociation and messenger atom tagging. Comparison of the experiment to quantum chemical computations at the CCSD(T)/cc-pVQZ//MP2/cc pVTZ level reveals that the experimentally observed structure is the head-to-tail dimer and not the more stable proton-bound dimer. This is consistent with the usually observed C-O bond formation upon formaldehyde oligomerization under acidic conditions in solution and resembles the structure of the neutral (H2CO)2 dimer in the gas phase. There is no evidence for the formation of other isomers, most notably protonated glycolaldehyde, that could result from covalent bond formation. These findings may be relevant to a proposed carbohydrate formation mechanism in the interstellar medium starting from protonated formaldehyde dimer. PMID- 29237128 TI - Host Control of Fungal Infections: Lessons from Basic Studies and Human Cohorts. AB - In the last few decades, the AIDS pandemic and the significant advances in the medical management of individuals with neoplastic and inflammatory conditions have resulted in a dramatic increase in the population of immunosuppressed patients with opportunistic, life-threatening fungal infections. The parallel development of clinically relevant mouse models of fungal disease and the discovery and characterization of several inborn errors of immune-related genes that underlie inherited human susceptibility to opportunistic mycoses have significantly expanded our understanding of the innate and adaptive immune mechanisms that protect against ubiquitous fungal exposures. This review synthesizes immunological knowledge derived from basic mouse studies and from human cohorts and provides an overview of mammalian antifungal host defenses that show promise for informing therapeutic and vaccination strategies for vulnerable patients. PMID- 29237129 TI - ZAP-70 in Signaling, Biology, and Disease. AB - T cells possess an array of functional capabilities important for host defense against pathogens and tumors. T cell effector functions require the T cell antigen receptor (TCR). The TCR has no intrinsic enzymatic activity, and thus signal transduction from the receptor relies on additional signaling molecules. One such molecule is the cytoplasmic tyrosine kinase ZAP-70, which associates with the TCR complex and is required for initiating the canonical biochemical signal pathways downstream of the TCR. In this article, we describe recent structure-based insights into the regulation and substrate specificity of ZAP-70, and then we review novel methods for determining the role of ZAP-70 catalytic activity-dependent and -independent signals in developing and mature T cells. Lastly, we discuss the disease states in mouse models and humans, which range from immunodeficiency to autoimmunity, that are caused by mutations in ZAP-70. PMID- 29237131 TI - Adverse Effects of Silver Diamine Fluoride Treatment among Preschool Children. AB - This randomized clinical trial aimed to compare the adverse effects and parental satisfaction following the different regimes of silver diamine fluoride (SDF) treatment among preschool children. A total of 888 preschool children who had active dentin caries received different SDF application regimes: group 1, 12% SDF applied annually; group 2, 12% SDF applied semiannually; group 3, 38% SDF applied annually; and group 4, 38% SDF applied semiannually. Information on adverse effects-including tooth or gum pain, gum swelling, gum bleaching, and systemic toxicity-was collected through a parent-reported questionnaire within 1 wk after every SDF or placebo application. Information of parental satisfaction on children's dental appearance was collected at baseline and 30-mo examination. At the 30 mo, 799 children (90%) remained in the study. No acute systemic illness or major adverse effect was reported. No differences of all minor adverse effects among the 4 groups were found ( P > 0.05). Overall, prevalence of tooth and gum pain as perceived by patients and reported by parents was 6.6%, while gum swelling and gum bleaching were 2.8% and 4.7%, respectively. Blackening of carious lesions was common among all groups, with 36.7%, 49.5%, 65.6% and 76.3% in groups 1 to 4, respectively (chi2 test, P < 0.001). The proportion of parents who were satisfied with their children's dental appearance in groups 1 to 4 was as follows: 67.6%, 61.5%, 70.8%, and 62.3%, respectively (chi2 test, P > 0.05). Based on parental reporting, SDF does not cause acute systemic illness. Tooth or gum pain, gum swelling, and gum bleaching were uncommon and not significantly different among the study groups. Parental satisfaction with children's dental appearance was similar among all groups. The use of SDF following the study protocol for caries arrest is safe for preschool children. Collecting information on parental satisfaction and adverse effects is beneficial for dental professionals when deciding to adopt SDF treatment for preschool children (ClinicalTrials.gov NCT02385474). PMID- 29237130 TI - Laparoscopic Appendicostomy Low-Profile Balloon Button for Antegrade Enemas in Children. AB - INTRODUCTION: The Malone appendicostomy is a continent channel used for antegrade enemas. It requires daily cannulation and is susceptible to stenosis. We use an indwelling low-profile balloon button tube inserted through the appendix into the cecum for antegrade enemas. We hypothesized that this method is effective at managing constipation or fecal incontinence and is associated with a low rate of stenosis. METHODS: Children who underwent laparoscopic appendicostomy balloon button placement at our institution from January 2011 to April 2017 were identified. The primary outcome was success in managing constipation or fecal continence as measured by the Malone continence scale. Postoperative complications were analyzed. RESULTS: Thirty-six children underwent the procedure, 35 of which met the inclusion criteria. Thirty-one patients (88.5%) underwent the operation for idiopathic constipation, 3 patients (8.6%) for anorectal malformation, and 1 patient (2.9%) for hypermobility. Rate of open conversion was 3%. A full response was obtained in 24 patients (68.6%), partial response in 9 patients (25.7%), and 2 patients failed (5.7%). One patient developed an internal hernia requiring laparotomy and later developed mucosal prolapse. One patient developed a stricture noted at button change. Seven patients (20%) underwent reversal of their appendicostomy tube: 5 due to return of normal bowel function and 2 due to discomfort with flushes. CONCLUSION: A laparoscopic appendicostomy with a balloon button tube is an effective means of addressing chronic constipation or fecal incontinence. The stenosis rate associated with tube appendicostomy may be lower than those reported for Malone antegrade continence enema procedures. PMID- 29237132 TI - Anastomotic Stricture Rates Following Roux-en-Y Gastric Bypass for Morbid Obesity: A Comparison Between Linear and Circular-Stapled Anastomosis. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is an effective procedure in the management of morbid obesity with variations in outcome, which are technique dependent. Anastomotic stricture remains an important complication. The aim of this study was to assess the long-term outcome of patients undergoing either a linear-stapled anastomosis (LSA) or circular-stapled anastomosis (CSA) with an emphasis on postoperative stricture formation and excess body weight loss (EBWL). METHODS: Medical records of all patients who underwent bariatric surgery between 2008 and 2013 at a single bariatric surgical center were reviewed. All patients who had a LRYGB were included in the study. Patients were divided in two groups based on stapling technique-LSA and CSA. Patient groups were compared with regard to perioperative complication, EBWL. RESULTS: A total of 114 patients were included in the study. There were 51 patients in the LSA group and 63 in the CSA group. No differences were found between the two groups with regard to operative time, hospital stay, or in the EBWL over a 12-month follow-up period. Anastomotic stricture developed in 4 patients, all occurring in the LSA group (7.8%). Three of these patients had undergone successful endoscopic dilatation. CONCLUSIONS: Both stapling techniques resulted in a similar EBWL during the follow-up period and an acceptable safety profile. Anastomotic stricture rate was slightly higher in the LSA, but this did not affect EBWL. PMID- 29237133 TI - Transhiatal Chest Drainage After Hybrid Ivor Lewis Esophagectomy: Proof of Concept Study. AB - BACKGROUND: Intercostal pleural drainage is standard practice after transthoracic esophagectomy but has some drawbacks. We hypothesized that a transhiatal pleural drain introduced through the subxyphoid port site incision at laparoscopy can be as effective as the intercostal drainage and may enhance patient recovery. PATIENTS AND METHODS: A proof of concept study was designed to assess a new method of pleural drainage in patients undergoing hybrid Ivor Lewis esophagectomy (laparoscopy and right thoracotomy). The main study aims were safety and efficacy of transhiatal pleural drainage with a 15 Fr Blake tube connected to a portable vacuum system. Pre- and postoperative data, mean duration, and total and daily output of drainage were recorded in an electronic database. Postoperative complications were scored according to the Dindo-Clavien classification. RESULTS: Between June 2015 and December 2016, 50 of 63 consecutive patients met the criteria for inclusion in the study. No conversions from the portable vacuum system to underwater seal and suction occurred. There was no mortality. The overall morbidity rate was 40%. Two patients (4%) required reoperation for hemothorax and chylothorax, respectively. Percutaneous catheter drainage for residual pneumothorax was necessary in 2 patients (4%) on postoperative day 2. The mean duration of drainage was 7 days (interquartile range [IQR] = 2), and the total volume of drain output was 1580 mL (IQR = 880). No pleural effusion on chest X-ray was detected at the 3-month follow-up visit. CONCLUSIONS: Transhiatal pleural drainage is safe and effective after hybrid Ivor Lewis esophagectomy and could replace the intercostal drain in selected patients. PMID- 29237134 TI - A Randomized Controlled Multicenter Trial of an Investigational Liquid Nutritional Formula in Women with Cyclic Breast Pain Associated with Fibrocystic Breast Changes. AB - OBJECTIVE: A randomized, multicenter, controlled double-blind trial was performed in women with cyclic breast pain (mastalgia) associated with fibrocystic breast changes (FBCs) to determine whether a nutritional formula reduced breast pain and/or nodularity. STUDY DESIGN: Women were randomized to receive a specifically designed liquid formulation (n = 93) (1 g gamma-linolenic acid [GLA], 750 MUg iodine, and 70 MUg selenium) or control formula (n = 95) (without GLA, iodine, and selenium) daily for three cycles. Women recorded breast pain, medications, and menstrual signs daily using interactive voice-response system. Nodularity was determined by physical breast examination. RESULTS: Breast pain scores decreased similarly in the experimental (-32.2%) and control (-33.1%) groups (p = 0.64). Nodularity was reduced in the experimental, but not the control group (p = 0.03). Among women who continued pain medication, the amount was reduced in the experimental group relative to controls (p = 0.02). CONCLUSION: Women with FBC using the formula containing GLA, iodine, and selenium experienced reduced nodularity and in those women who took over-the-counter breast pain medication, a decrease in the quantity of pain medication was observed. PMID- 29237136 TI - Biomimetic Structural Materials: Inspiration from Design and Assembly. AB - Nature assembles weak organic and inorganic constituents into sophisticated hierarchical structures, forming structural composites that demonstrate impressive combinations of strength and toughness. Two such composites are the nacre structure forming the inner layer of many mollusk shells, whose brick-and mortar architecture has been the gold standard for biomimetic composites, and the cuticle forming the arthropod exoskeleton, whose helicoidal fiber-reinforced architecture has only recently attracted interest for structural biomimetics. In this review, we detail recent biomimetic efforts for the fabrication of strong and tough composite materials possessing the brick-and-mortar and helicoidal architectures. Techniques discussed for the fabrication of nacre- and cuticle mimetic structures include freeze casting, layer-by-layer deposition, spray deposition, magnetically assisted slip casting, fiber-reinforced composite processing, additive manufacturing, and cholesteric self-assembly. Advantages and limitations to these processes are discussed, as well as the future outlook on the biomimetic landscape for structural composite materials. PMID- 29237135 TI - Spontaneous Pneumothorax in Children: National Management Strategies and Outcomes. AB - INTRODUCTION: The timing of surgical intervention in the management of spontaneous pneumothorax remains controversial. The aim of this multicenter review was to compare management strategies and outcomes in children with spontaneous pneumothorax. METHODS: We retrospectively reviewed patients 10-19 years old in the Pediatric Health Information System admitted for spontaneous pneumothorax from 2010 to 2014. Three treatment groups were identified based on initial hospital management-no intervention, initial chest tube placement, and operation; and outcomes were compared. RESULTS: A total of 1040 patients were included. The majority were male (82.1%) and White (71.1%). The mean age at first encounter was 15.7 +/- 1.7 years. Initial treatment included no intervention in 336 (32.3%), chest tube in 497 (47.8%), and video-assisted thoracoscopic surgery (VATS) in 207 (19.9%). Ultimately, 417 (40.1%) patients underwent VATS during the initial admission and 559 (53.8%) during the initial admission or a subsequent encounter. Aggregate length of stay (LOS) was highest for those treated initially with chest tube alone (P < .001). For patients managed initially with chest tube, the probability of requiring surgery increased with each day of hospitalization. Initial operation was associated with a decreased risk of readmission (OR 0.67, 95% CI 0.50-0.90). Estimated adjusted hospital costs, aggregated across all encounters, were highest for chest tube alone (P < .001). CONCLUSION: Early VATS is associated with decreased hospital LOS, charges, and readmissions. For those managed initially with chest tube alone, the likelihood of requiring operation increases with each day hospitalized, and early conversion to operative management should be considered in patients with persistent pneumothorax or air leak. PMID- 29237137 TI - Endoscopic Abscess Septotomy: A Less Invasive Approach for the Treatment of Sleeve Gastrectomy Leaks. AB - BACKGROUND: Postoperative leaks develop in a low percentage of patients undergoing laparoscopic sleeve gastrectomy (LSG), representing a rare yet devastating postoperative complication increasing morbidity and hospital stay. Leaks can become collections and may be very difficult to manage. Several therapeutic options with variable results, including surgical and nonsurgical methods have been described. Endoscopic abscess septotomy is an alternative method recently performed by a few centers reporting efficacy and safety outcomes. The purpose of this report is to present our successful experience with endoscopic abscess septotomy for the treatment of postsleeve gastrectomy leaks. METHODS: Two female patients with post-LSG leaks and abscess formation diagnosed 4 weeks postprocedure, initially managed with diagnostic laparoscopy, peritoneal washout, and drain placement with poor improvement, were chosen for endoscopic abscess septotomy with concomitant lumen dilation and sleeve axis rectification. RESULTS: Endoscopic abscess septotomy was successfully performed in both patients with no complications. Clinical and radiological resolutions were accomplished at 10 and 12 weeks, respectively, postseptotomy. CONCLUSION: This endoscopic approach is a feasible and effective method for the treatment of leaks and collections after LSG. Concomitant balloon dilation of the gastric sleeve improves gastric emptying and reduces intraluminal pressure, hence favoring tissue healing and leak resolution. PMID- 29237138 TI - Characteristics Associated with Induction of Labor and Delivery Route Among Primiparous Women with Term Deliveries in the Listening to Mothers III Study. AB - BACKGROUND: Induction of labor (IOL) is increasingly common in the United States, yet characteristics associated with IOL among primiparous women delivering at term are not well understood. MATERIALS AND METHODS: Data from the Listening to Mothers III study, a survey of women aged 18-45 with singleton deliveries in U.S. hospitals in 2011-2012, were utilized. Weighted logistic regression models examined predictors of IOL among 924 primiparous women with term deliveries. Associations of maternal characteristics with delivery route (cesarean and vaginal delivery) were examined among primiparous women induced at term. RESULTS: Four hundred twenty-three (45.8%) primiparous women with term deliveries underwent IOL; subjective reasons were reported by 53% of induced women. Women who were married (odds ratios [OR] = 1.8, 95% confidence intervals [CI] 1.2-2.9), felt pressure from a provider for IOL (OR = 3.5, 95% CI 2.0-6.2), and whose provider was concerned about the size of the baby (OR = 1.9, 95% CI 1.2-2.9) were significantly more likely to undergo IOL. Nearly 30% of primiparous women who underwent IOL at term had a cesarean delivery (CD). Among the induced women, those who were overweight/obese (OR = 4.9, 95% CI 2.5-10.0), felt pressure from a provider for CD (OR = 8.6, 95% CI 3.5-21.2), and whose provider suspected the baby might be getting large near end of pregnancy (OR = 2.7, 95% CI 1.1-7.0) were significantly more likely to have CD. CONCLUSIONS: In this study, nearly half of the primiparous women with term deliveries underwent IOL, with a sizeable proportion reporting subjective reasons for induction. A better understanding of the characteristics associated with IOL at term may help reduce unnecessary interventions and, ultimately, primary CD. PMID- 29237139 TI - Outcomes of Laparoscopic Colectomy in Younger and Older Patients: An Analysis of Nationwide Readmission Database. AB - BACKGROUND: Prior studies report safety and effectiveness of laparoscopic colectomy in older patients. The study aimed to examine the impact of laparoscopic colectomy on 30-day readmissions, discharge destination, hospital length of stay, and cost in younger (19-65 years) and older adults (>65 years). MATERIALS AND METHODS: We used the nationwide readmission database from 2013 to study adults undergoing elective colectomy. The outcomes were 30-day readmissions, discharge destination for the index hospitalization (routine, skilled nursing facility [SNF]/intermediate care facility [ICF], home healthcare), length of stay, and cost. Multivariable analyses were conducted to determine the association of laparoscopic colectomy on outcome; logistic regression for 30-day readmission, multinomial logistic regression for discharge destination, and linear regression for length of stay and cost. An interaction between age and colectomy approach was included, and all models controlled gender, income, insurance status, All Patients Refined Diagnosis Related Groups (APR-DRG), Elixhauser comorbidities, hospital bed size, ownership, and teaching status. RESULTS: Of 79,581 colectomies, 40.2% were laparoscopic. Laparoscopic colectomy was more frequent in younger patients (41.9% versus 38.5%, p < .0001). Regardless of age, patients undergoing laparoscopic colectomy were 20% less likely to be readmitted within 30 days (odds ratio [OR] 0.80, confidence interval [95% CI] 0.75-0.85). For postdischarge destination, laparoscopic colectomy offered higher benefits to younger patients (SNF/ICF: OR 0.42, 95% CI 0.36-0.49; home health: OR 0.32, 95% CI 0.30-0.35) than older patients (SNF/ICF: OR 0.50, 95% CI 0.47-0.54; home health: OR 0.59, 95% CI 0.55-0.62). Regardless of age, laparoscopic colectomy resulted in 1.46 days (p < .0001) shorter hospital stays compared to open colectomy. Laparoscopic colectomy had significantly lower cost compared to open approach, particularly in younger ($1,466) versus older ($632) patients. CONCLUSIONS: Laparoscopic colectomy is superior to an open approach, with fewer 30-day readmissions, fewer discharges to SNF/ICF or home health, shorter hospital stays, and less overall cost; younger patients benefit more than older patients. PMID- 29237140 TI - High-density SNP mapping reveals closely linked QTL for resistance to Stagonospora nodorum blotch (SNB) in flag leaf and glume of hexaploid wheat. AB - The genetic control of adult plant resistance to Stagonospora nodorum blotch (SNB) is complex, consisting of genes with minor effects interacting in an additive manner. Earlier studies detected quantitative trait loci (QTL) for flag leaf resistance in successive years on chromosomes 1B, 2A, 2D, and 5B using SSR- and DArT-based genetic maps of progeny from the crosses EGA Blanco/Millewa, 6HRWSN125/WAWHT2074, and P92201D5/P91193D1. Similarly, QTL for glume resistance detected in successive years and multiple environments were identified on chromosomes 2D and 4B from genetic maps of P92201D5/P91193D1 and 6HRWSN125/WAWHT2074, respectively. The SSR- and DArT-based genetic maps had an average distance of 6.5, 7.8, and 9.7 cM between marker loci for populations EGA/Millewa, P92201D5/P91193D1, and 6HRWSN125/WAWHT2074, respectively. This study used single nucleotide polymorphism (SNP) markers from the iSelect Infinium 90K genotyping array to fine-map genomic regions harbouring QTL for flag leaf and glume SNB resistance, reducing the average distance between markers to 2.9, 3.3, and 3.4 cM for populations P92201D5/P91193D1, EGA/Millewa, and 6HRWSN125/WAWHT2074, respectively. Increasing the marker density of the genetic maps with SNPs did not identify any new QTL for SNB resistance but discriminated previously identified co-located QTL into separate but closely linked QTL. PMID- 29237141 TI - Lessons from the Barn to the Operating Suite: A Comprehensive Review of Animal Models for Fetal Surgery. AB - The International Fetal Medicine and Surgery Society was created in 1982 and proposed guidelines for fetal interventions that required demonstrations of the safety and feasibility of intended interventions in animal models prior to application in humans. Because of their short gestation and low cost, small animal models are useful in early investigation of fetal strategies. However, owing to the anatomic and physiologic differences between small animals and humans, repeated studies in large animal models are usually needed to facilitate translation to humans. Ovine (sheep) models have been used the most extensively to study the pathophysiology of congenital abnormalities and to develop techniques for fetal interventions. However, nonhuman primates have uterine and placental structures that most closely resemble those of humans. Thus, the nonhuman primate is the ideal model to develop surgical and anesthetic techniques that minimize obstetrical complications. PMID- 29237142 TI - Transanal Endoscopic Microsurgery for Patients with Rare Rectal Tumors. AB - BACKGROUND: Transanal endoscopic microsurgery (TEM) has been accepted worldwide for the treatment of local rectal lesions. Rare rectal tumors consist of several different types of malignant or benign tumors. Surgical management is considered to be the only curative option. The aim of this study is to investigate the role of TEM in the treatment of rare rectal tumors. MATERIALS AND METHODS: A total of 147 patients with rare rectal tumors underwent TEM in our center from April 2006 to May 2017. Clinical data were collected and a retrospective accurate database was constructed. Demographic characteristics, operative details, tumor details, complications, and follow-up data were analyzed. RESULTS: Seventy-eight patients were male. Mean tumor diameter was 1.2 +/- 0.7 cm and mean distance from the anal verge was 6.6 +/- 2.3 cm. Full-thickness and complete resection with negative margins was achieved in all patients. Complications occurred in 3 patients during surgery and in 20 patients after surgery. Histopathologic results were neuroendocrine tumors in 104 patients; gastrointestinal stromal tumors in 35; melanoma, lymphoma, and leiomyoma each in 2; lipoma, and squamous carcinoma each in 1. One hundred thirty-five patients were followed up for 49.3 +/- 33.2 months. Two patients died, 1 had local recurrence and 1 had a rectovaginal fistula 1 month after surgery. No local recurrence or metastasis, or fecal incontinence was observed in the remaining patients. CONCLUSION: TEM is an optimal treatment option for selected rare rectal tumors. The complication rate is low and the therapeutic effect is satisfactory. PMID- 29237143 TI - Trends in Health Insurance Coverage of Title X Family Planning Program Clients, 2005-2015. AB - BACKGROUND: The federal Title X Family Planning Program supports the delivery of family planning services and related preventive care to 4 million individuals annually in the United States. The implementation of the 2010 Affordable Care Act's (ACA's) Medicaid expansion and provisions expanding access to health insurance, which took effect in January 2014, resulted in higher rates of health insurance coverage in the U.S. population; the ACA's impact on individuals served by the Title X program has not yet been evaluated. METHODS: Using administrative data we examined changes in health insurance coverage among Title X clinic patients during 2005-2015. RESULTS: We found that the percentage of clients without health insurance decreased from 60% in 2005 to 48% in 2015, with the greatest annual decrease occurring between 2013 and 2014 (63% to 54%). Meanwhile, between 2005 and 2015, the percentage of clients with Medicaid or other public health insurance increased from 20% to 35% and the percentage of clients with private health insurance increased from 8% to 15%. CONCLUSIONS: Although clients attending Title X clinics remained uninsured at substantially higher rates compared with the national average, the increase in clients with health insurance coverage aligns with the implementation of ACA-related provisions to expand access to affordable health insurance. PMID- 29237144 TI - Robotic-Assisted Simultaneous Repair of Paraesophageal Hernia and Morgagni Hernia: Technical Report. AB - Morgagni hernias are a rare form of congenital diaphragmatic hernia, accounting for 2%-3% of cases. The presence of a simultaneous Morgagni hernia and paraesophageal hernia (PEH) is even more rare, with only a few reported cases in the surgical literature. Both open and laparoscopic surgical approaches have been previously described. Herein we discuss a robotic-assisted surgical approach to the repair of simultaneous Morgagni hernia and PEH in a 65-year-old woman. Simultaneous repair of Morgagni hernia and PEH is indicated mainly when symptoms are generally indistinctive. The use of robotic technology allowed for both hernias to be repaired both primarily and with mesh reinforcement. PMID- 29237145 TI - Current Practices in the Management of Congenital Diaphragmatic Hernia Patients Requiring Extracorporeal Membrane Oxygenation: Results of an International Survey of Pediatric Surgeons. AB - INTRODUCTION: There is little consensus on optimal management for congenital diaphragmatic hernia extracorporeal membrane oxygenation (CDH ECMO) patients. Meaningful comparisons of the various approaches have been limited due to the low number of cases in institutions. In addition, the multidisciplinary reliance and rigid institutional framework of ECMO serve to further limit exposure to alternative practices. The goal of this study is to survey the international pediatric surgery community to describe the current practice trends. METHODS: A survey was electronically distributed to the international pediatric surgical community. The results were evaluated using statistical analysis. RESULTS: A total of 123 pediatric surgeons completed the survey, of whom 89% work at institutions offering both venoatrial (VA) and venovenous (VV) ECMO. Although 69% perform VA ECMO for CDH, only 46% felt VA was the "optimal method." Among VV proponents, 21% believe the rate of VV to VA conversion to be <5% and 16% believe it to be >30% compared with 0% and 40% in VA proponents. Distribution of timing of repair: 46% post-ECMO repair, 22% early ECMO repair, 15% whenever stabilized on ECMO, and 14% late ECMO repair. Sixty-four percent (71/111) would perform an ECMO CDH repair in the unweanable patient and 27% (30/111) report successful decannulation after repair of a patient who was unweanable on ECMO for 2 weeks. Ninety-two percent do not perform exit-to-ECMO. CONCLUSION: There are significant practice variations in the management of CDH ECMO. Majority of pediatric surgeons perform VA ECMO in CDH patients; however, a significant percentage of those believe VV to be more optimal. This discrepancy is not accounted for by the VA only institutions. Although post-ECMO CDH repair is the most common approach, the majority would perform a repair "on ECMO" if the patient was unweanable. In addition, although many pediatric surgeons believe the "last ditch repair" for the unweanable patient to be futile, 27% have reported success. Exit-to-ECMO for CDH remains a minority practice. PMID- 29237146 TI - Digital Breast Tomosynthesis with Synthesized Two-Dimensional Images versus Full Field Digital Mammography for Population Screening: Outcomes from the Verona Screening Program. AB - Purpose To examine the outcomes of a breast cancer screening program based on digital breast tomosynthesis (DBT) plus synthesized two-dimensional (2D) mammography compared with those after full-field digital mammography (FFDM). Materials and Methods This prospective study included 16 666 asymptomatic women aged 50-69 years who were recruited in April 2015 through March 2016 for DBT plus synthetic 2D screening in the Verona screening program. A comparison cohort of women screened with FFDM (n = 14 423) in the previous year was included. Screening detection measures for the two groups were compared by calculating the proportions associated with each outcome, and the relative rates (RRs) were estimated with multivariate logistic regression. Results Cancer detection rate (CDR) for DBT plus synthetic 2D imaging was 9.30 per 1000 screening examinations versus 5.41 per 1000 screening examinations with FFDM (RR, 1.72; 95% confidence interval [CI]: 1.30, 2.29). CDR was significantly higher in patients screened with DBT plus synthetic 2D imaging than in those screened with FFDM among women classified as having low breast density (RR, 1.53; 95% CI: 1.13, 2.10) or high breast density (RR, 2.86; 95% CI: 1.42, 6.25). The positive predictive value (PPV) for recall was almost doubled with DBT plus synthetic 2D imaging: 23.3% versus 12.9% of recalled patients who were screened with FFDM (RR, 1.81; 95% CI: 1.34, 2.47). The recall rate was similar between groups (RR, 0.95; 95% CI: 0.84, 1.06), whereas the recall rate with invasive assessment was higher for DBT plus synthetic 2D imaging than for FFDM (RR, 1.93; 95% CI: 1.31, 2.03). The mean number of screening studies interpreted per hour was significantly lower for screening examinations performed with DBT plus synthetic 2D imaging (38.5 screens per hour) than with FFDM (60 screens per hour) (P < .001). Conclusion DBT plus synthetic 2D imaging increases CDRs with recall rates comparable to those of FFDM. DBT plus synthetic 2D imaging increased image reading time and the time needed for invasive assessments. (c) RSNA, 2017. PMID- 29237147 TI - Treatment of Early-stage Extracranial Arteriovenous Malformations with Intralesional Interstitial Bleomycin Injection: A Pilot Study. AB - Purpose To assess the efficacy and safety of intralesional interstitial bleomycin injection in the treatment of early-stage (Schobinger stage I or II) extracranial arteriovenous malformations (AVMs). Materials and Methods This prospective study involved 34 patients with early-stage AVMs, as defined by the Schobinger staging system. The patients received intralesional interstitial bleomycin injected at a maximum dose of 15 000 IU or 1000 IU per kilogram of body weight for children who weighed less than 15 kg per procedure for a total of 6 months (once every month). Therapeutic outcome was evaluated by the degree of devascularization at angiography and the clinical outcome 3 months after the last treatment. Further follow-up was evaluated based on further clinical outcome. Adverse events were recorded according to the Society of Interventional Radiology classification. Results Of the 34 patients with early-stage AVM, 32 (mean age, 20.5 years; 24 female [75%]) completed the study. The results showed that 27 (84.4%, 95% confidence interval [CI]: 71.1, 97.7) patients were responsive to bleomycin injection, including nine (28.1%) with a complete response. Four (12.5%) patients showed no response, and one (3.1%) patient experienced worsening 3 months after the last treatment. During further follow-up (mean follow-up time, 20.7 months; range, 5-28 months), the outcome remained stable in 31 (96.9%) of the 32 patients. A major complication, anaphylactic shock, was observed in one (3.1%, 95% CI: 0, 9.5) patient. Common minor complications included hyperpigmentation, nausea, pruritus, and bullae. Conclusion Intralesional interstitial bleomycin injection is a feasible approach for early-stage AVMs and yields safe and effective outcomes. (c) RSNA, 2017. PMID- 29237148 TI - Observed Deposition of Gadolinium in Bone Using a New Noninvasive in Vivo Biomedical Device: Results of a Small Pilot Feasibility Study. AB - Purpose To perform a preliminary evaluation of a noninvasive measurement system to assess gadolinium deposition in bone and to investigate the relationship between the administration of gadolinium-based contrast agents (GBCAs) and gadolinium retention in bone. Materials and Methods In vivo measurement of gadolinium retention in tibia bones was performed in 11 exposed subjects who previously received GBCAs (six exposed subjects were from a study performed 5 years previously involving injection of GBCAs in healthy volunteers; five exposed subjects had self-reported GBCA exposure), and 11 sex- and age-matched control subjects without a history of GBCA exposure. Each subject underwent one measurement of gadolinium retention in the tibia with x-ray fluorescence in a laboratory at McMaster University. A one-tailed t test was performed to compare gadolinium concentration in the exposed group with that in the control group. The relationship between the dose of GBCA administered and the gadolinium concentration measured in bone was analyzed with linear regression. Results Gadolinium concentration in bone was significantly higher in exposed subjects (mean, 1.19 MUg Gd/g bone mineral +/- 0.73 [standard deviation]) than in control subjects (mean, -1.06 MUg Gd/g bone mineral +/- 0.71) (P = .01). There was also a positive correlation between the dose of GBCA administered and the gadolinium concentration measured in bone (R2 = 0.41); gadolinium concentration in bone increased by 0.39 MUg Gd/g bone mineral +/- 0.14 per 1 mL of GBCA administered. Gadolinium was detected in bone up to 5 years after one GBCA administration. Conclusion This x-ray fluorescence system is capable of measuring gadolinium deposition in bone noninvasively in vivo. Gadolinium can be retained in bone after one dose of GBCA in healthy subjects. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29237149 TI - Association of Antibodies to Citrullinated Protein Antigens with Blood Pressure in First-Degree Relatives of Rheumatoid Arthritis Patients: The Studies of the Etiology of Rheumatoid Arthritis. AB - BACKGROUND: Hypertension is more common in patients with rheumatoid arthritis (RA) than in the general population. It is unknown whether hypertension is due to RA-related medications or the disease itself. Therefore, we sought to investigate associations between RA-related autoantibodies, specifically antibodies to citrullinated protein antigens (ACPA) and systolic blood pressure (SBP) and diastolic blood pressure (DBP) in first-degree relatives of RA patients, who were free of RA and RA-related medications. We hypothesized that a greater number of detectable ACPA would be associated with high SBP and DBP, independent of other risk factors in these first-degree relatives. METHODS: We evaluated associations between ACPA and SBP and DBP in a cross-sectional study of 72 first-degree relatives (defined as parent, child, or sibling) of RA patients. Fifteen ACPA were measured using a Bio-Plex bead-based assay; each was dichotomized as positive/negative based on pre-specified cut-points. Analysis of covariance was used to evaluate associations between ACPA positivity and SBP and DBP, adjusting for age, sex, race, body mass index (BMI), pack-years of smoking, high sensitivity C-reactive protein (hsCRP), and current use of anti-hypertensive medications. RESULTS: Average age was 51 and 69% were women. Mean SBP was 119 +/- 18 and DBP was 74 +/- 9 mm Hg. Thirty-three (46%) first-degree relatives were positive for >=1 ACPA; and were younger, had lower BMI, more pack-years of smoking, and higher hsCRP concentrations compared to ACPA negative first-degree relatives. For each additional positive ACPA, SBP was 0.98 +/- 0.5 mm Hg (p = 0.05) higher, and DBP was 0.66 +/- 0.3 mm Hg (p = 0.04) higher. Anti-cit fibrinogen A (211-230) positive and anti-cit-filaggrin positive first-degree relatives had 11.5 and 13.9 mm Hg higher SBP (p = 0.02) respectively. Anti-cit clusterin, cit-filaggrin, and cit-vimentin positive first-degree relatives had 7 8 mm Hg higher DBP (p = 0.03, 0.05, 0.05 respectively), compared to being negative for these individual ACPA. Consistent with associations between ACPA, SBP, and DBP, anti-cyclic citrullinated peptides (anti-CCP2) positive first degree relatives had 16.4+/- (p = 0.03) higher SBP and 12.1+/- mm Hg (p = 0.01) higher DBP than anti-CCP2 negative first-degree relatives. CONCLUSION: In first degree relatives without RA, ACPA positivity is associated with higher SBP and DBP. Subclinical autoimmune processes and ACPA may play a role in the vascular changes potentially leading to hypertension prior to RA onset. PMID- 29237150 TI - Evaluation of Parenteral Iron Therapy in Ambulatory Older Adults with Iron Deficiency Anaemia. PMID- 29237151 TI - Repeated Combined Chemotherapy with Cisplatin Lowers Carnitine Levels in Gastric Cancer Patients. AB - BACKGROUND/AIMS: Carnitine plays an important role in the metabolism of fatty acids. It has also been reported that the administration of anticancer drugs may lead to reductions in serum carnitine levels due to decreased activity of organic cation transporter novel 2, which plays a role in the reabsorption of carnitine in the tubules of the kidney. We therefore studied the change in carnitine levels when chemotherapy was administered repeatedly to patients with gastric cancer. METHODS: Ten patients with upper gastrointestinal cancer were enrolled in this study between December 2014 and August 2015. All patients were administered chemotherapy consisting of TS-1 and cisplatin every 3 weeks: 3 received it as adjuvant therapy post resection, the remaining 7 received it as treatment for unresectable tumors. Before the start of each chemotherapy cycle, serum was collected. RESULTS: The mean total carnitine level was 54.5 +/- 13.7 MUmol/L prior to commencing chemotherapy; it was 46.7 +/- 13.5 and 41.4 +/- 14.8 MUmol/L at the second and third cycles respectively. The total carnitine level was decreased in a statistically significant manner (p = 0.0039). The serum level of total protein and cholinesterase was also decreased significantly (p = 0.0218 and p = 0.0418). CONCLUSION: Carnitine levels decreased during repeated chemotherapy in patients with gastric cancer, and they are associated with the nutritional status. PMID- 29237152 TI - Multiple Socioeconomic Factors and Dental Caries in Swedish Children and Adolescents. AB - The study aimed to explore associations between multiple socioeconomic factors and dental caries experience in Swedish children and adolescents (3-19 years old). Electronic dental records from 300,988, in a Swedish region (97.3% coverage) were collected using the DMFT indices (decayed, missing, filled teeth: dependent variables). Socioeconomic status (SES) data (ethnicity, wealth, parental education, and employment) for individuals, parents, and families were obtained from official registers. Principal component analysis was used to explore SES data. Scores based on the first factor were used as an independent aggregated socioeconomic variable in logistic regression analyses. Dental caries experience was low in the participants: 16% in 3- to 6-year-olds (deft index: decayed, extracted, filled teeth) and 47% in 7- to 19-year-olds (DFT index). Both separate and aggregated socioeconomic variables were consistently associated with the dental caries experience irrespective of the caries index used: the crude odds ratio (OR) for having at least 1 caries lesion in 3- to 6-year-olds (deft index) in the lowest SES quintile was 3.26 (95% confidence interval [CI] 3.09 3.43) and in >=7-year-olds (DFT index) OR 1.80 (95% CI 1.75-1.84) compared with children in the 4 higher SES quintiles. Overall, associations were stronger in the primary dentition than in the permanent dentition. Large SES models contributed more to explaining the caries experience than slim models including fewer SES indicators. In conclusion, socioeconomic factors were consistently associated with dental caries experience in the children and adolescents both as single factors and as multiple factors combined in an index. Socioeconomic inequalities had stronger associations to caries experience in young children than in older children and adolescents. PMID- 29237153 TI - Very Small Left Atrial Volume as a Marker for Mortality in Patients Undergoing Nongated Computed Tomography Pulmonary Angiography. AB - OBJECTIVES: To evaluate the association between very small left atria (VSLA) on nongated computed tomography pulmonary angiography (CTPA) and mortality in patients without pulmonary embolism (PE). METHODS: Patients who underwent nongated CTPA between 2011 and 2015 in order to rule out PE, and had an echocardiogram within 24 h of the CTPA, were retrospectively identified. The left atrial volume of nongated CTPA was calculated using automatic 4-chamber volumetric analysis software. The association between the lowest 5th percentile of the left atrial volume index, referred to as the VSLA group, and mortality was investigated after adjustment for age, gender, background diseases, and laboratory values. RESULTS: The study cohort included 241 patients. Patients with VSLA had a left atrial volume index <24 mL/m2 (n = 11). Demographics and background diseases did not differ between the study groups. The median follow-up was 22.7 months (IQR 0.03-54.3). VSLA was an independent predictor of mortality (HRadj = 3.6; 95% CI 1.46-8.87; p = 0.005), along with malignancy (HRadj = 2.28; 95% CI 1.32-3.93; p = 0.003) and lower hemoglobin (HRadj = 0.86; 95% CI 0.76 0.99; p = 0.032). CONCLUSIONS: Our findings suggest that VSLA on nongated CTPA may serve as a marker for mortality. The use of CTPA volumetric analysis can help risk stratification in patients with dyspnea and no PE. PMID- 29237154 TI - Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions. AB - Early-life adversity (ELA) is one of the major risk factors for serious mental and physical health risks later in life. ELA has been associated with dysfunctional neurodevelopment, especially in brain structures such as the hippocampus, and with dysfunction of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis. Children who have experienced ELA are also more likely to suffer from mental health disorders such as depression later in life. The exact interplay of aberrant neurodevelopment and HPA axis dysfunction as risks for psychopathology is not yet clear. We investigated volume differences in the bilateral hippocampus and in stress-sensitive hippocampal subfields, behavior problems, and diurnal cortisol activity in 24 children who had experienced documented ELA (including out-of-home placement) in a circumscribed duration of adversity only in their first 3 years of life in comparison to data on 25 control children raised by their biological parents. Hippocampal volumes and stress-sensitive hippocampal subfields (Cornu ammonis [CA]1, CA3, and the granule-cell layer of the dentate gyrus [GCL-DG]) were significantly smaller in children who had experienced ELA, taking psychiatric diagnoses and dimensional psychopathological symptoms into account. ELA moderated the relationship between left hippocampal volume and cortisol: in the control group, hippocampal volumes were not related to diurnal cortisol, while in ELA children, a positive linear relationship between left hippocampal volume and diurnal cortisol was present. Our findings show that ELA is associated with altered development of the hippocampus, and an altered relationship between hippocampal volume and HPA axis activity in youth in care, even after they have lived in stable and caring foster family environments for years. Altered hippocampal development after ELA could thus be associated with a risk phenotype for the development of psychiatric disorders later in life. PMID- 29237155 TI - Paracrine Activation of the Wnt/beta-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury. AB - BACKGROUND/AIMS: Cisplatin-induced acute kidney injury (AKI) involves damage to tubular cells via excess reactive oxygen species (ROS) generation. Stem cell based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived conditioned medium (CM) against cisplatin-induced AKI. METHODS: In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/beta catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/beta-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular beta-catenin expression in kidney biopsy from AKI patients. RESULTS: CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/beta-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of beta-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1alpha, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and beta-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1alpha expression and increased mitochondrial ROS. Clinical data showed that the tubular beta-catenin level was lower in AKI patients experiencing partial recovery than in patients experiencing complete recovery. CONCLUSION: The activation of the wnt/beta-catenin pathway by CM protects against cisplatin-induced kidney injury, resulting in reduced apoptosis and intracellular ROS levels. PMID- 29237156 TI - Potential Involvement of MiR-30e-3p in Myocardial Injury Induced by Coronary Microembolization via Autophagy Activation. AB - BACKGROUND/AIMS: Coronary microembolization (CME) can lead to no-reflow or slow reflow, which is one of the important reasons for loss of clinical benefit from myocardial reperfusion therapy. MicroRNAs and autophagy are heavily implicated in the occurrence and development of almost all cardiovascular diseases. Therefore, the present study was designed to investigate the role of miR-30e-3p and autophagy in CME-induced myocardial injury rat model. METHODS: Sixty rats were randomly divided into six groups: sham, CME 1h,3h,6h,9h, and 12h (n = 10 per group). Our CME rat model was created by injecting polyethylene microspheres (42mm) into the left ventricle of the heart; the sham group was injected with same volume of normal saline. The cardiac function and serum cardiac troponin I (cTnI) level of each group was measured. HE staining and HBFP staining were used to evaluate the myocardial micro-infarction area of myocardium tissue samples. Then RT-qPCR and western blot were used to detect the expression of miR-30e-3p and, autophagy related protein LC3-II and p62, respectively. Transmission electron microscope (TEM) was used to identify autophagic vacuoles in tissue samples. RESULTS: The cardiac function of the CME 6h,9h, and 12h groups were significantly decreased compared to the sham group (P < 0.05) and the cTnI level in each group were also significantly increased (P < 0.05). The expression of miR 30e-3p in the CME 6h, 9h and 12h group were decreased significantly compared with the sham group (P < 0.05). Meanwhile, the expression of autophagy related protein LC3-II decreased significantly and p62 increased significantly in the CME 9h and 12h group (P < 0.05). TEM images showed typical autophagic vacuoles for each of the CME groups. CONCLUSIONS: Myocardial miR-30e-3p is down regulated after CME and is accompanied by inhibited autophagy and decreased cardiac function. Therefore, miR-30e-3p may be involved in CME-induced cardiac dysfunction by regulating myocardial autophagy. PMID- 29237158 TI - Dermoscopy of Morphea and Cutaneous Lichen Sclerosus: Clinicopathological Correlation Study and Comparative Analysis. AB - BACKGROUND: Dermoscopy of morphea and cutaneous lichen sclerosus (CLS) has been described by various studies, with none of them considering variability according to clinical phases and investigating dermoscopic-histological correlations. OBJECTIVE: To evaluate dermoscopic features in general and according to clinical stage, identify possible distinctive dermoscopic clues, and assess dermoscopy accuracy in detecting subclinical alterations in morphea and CLS. METHODS: A representative dermoscopic image of target lesions was evaluated for the presence of specific features, correlating them with clinical subtype (inflammatory, inflammatory-sclerotic, sclerotic, or sclerotic-atrophic). In case of clinical dermoscopic discordance (inflammatory, sclerotic, and atrophic findings in noninflammatory, nonsclerotic, and nonatrophic lesions, respectively), dermoscopic-pathological correspondence was assessed. RESULTS: A total of 86 lesions (51 morphea/35 CLS) were analyzed, with most of them displaying an inflammatory-sclerotic or sclerotic clinical pattern. The most common dermoscopic findings of morphea were "fibrotic beams," while CLS was mainly characterized by bright white/white-yellowish patches and yellowish-white keratotic follicular plugs; all these structures displayed complete specificity for the correspondent dermatosis. Additionally, pigmentary structures were significantly more frequent in morphea and white scaling and hemorrhagic spots in CLS. Only few dermoscopic features reached a statistical significance for a specific clinical stage. Regarding the clinical-dermoscopic discordance rate, it was significantly more common in morphea than CLS; in all cases there was a correspondence between dermoscopic and pathological findings. CONCLUSION: Dermoscopy of morphea and CLS reveals distinctive dermoscopic clues which are often unrelated to clinical stage but show a constant histological correspondence, thus emphasizing its usefulness in diagnosis and therapeutic management of these conditions. PMID- 29237157 TI - Hypoxia Accelerates Aggressiveness of Hepatocellular Carcinoma Cells Involving Oxidative Stress, Epithelial-Mesenchymal Transition and Non-Canonical Hedgehog Signaling. AB - BACKGROUND/AIMS: Hypoxic microenvironment, a common feature of hepatocellular carcinoma (HCC), can induce HIF-1alpha expression and promote the epithelial mesenchymal transition (EMT) and invasion of cancer cells. However, the underlying molecular mechanisms have not fully elucidated. METHODS: HCC cells were cultured under controlled hypoxia conditions or normoxic conditions. Transwell assays were used to examine the migration and invasion capacity. HIF 1alpha siRNA, cyclopamine (a SMO antagonist) and GLI1 siRNA were used to inhibit HIF-1alpha transcription or Hh signaling activation. RESULTS: In present study, we first observed a strongly positive correlation between HIF-1alpha and GLI1 expression in HCC tissues. Then, we showed that hypoxia significantly promoted EMT process and invasion of HCC cells, associated with activating the non canonical Hh pathway without affecting SHH and PTCH1 expression. HIF-1alpha knockdown mitigated hypoxia-induced SMO and GLI1 expression, EMT invasion of HCC cells. Moreover, the SMO inhibitor or GLI1 siRNA also reversed the hypoxia-driven EMT and invasion of HCC cells under hypoxia condition. Here, we show that non canonical Hh signaling is required as an important role to switch on hypoxia induced EMT and invasion in HCC cells. In addition, we found that hypoxia increased ROS production and that ROS inhibitors (NAC) blocked GLI1-dependent EMT process and invasion under hypoxic conditions. To determine a major route of ROS production, we tested whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is involved in hypoxia-induced ROS production. NOX4 expression was found to be increased at both mRNA and protein levels in hypoxic HCC cells. Furthermore, siRNA-mediated knockdown of NOX4 expression abolished hypoxia induced ROS generation and GLI1-dependent activation and invasion of HCC cells. CONCLUSION: Our findings indicate that hypoxia triggers ROS-mediated GLI1 dependent EMT progress and invasion of HCC cells through induction of NOX4 expression. Thus, hypoxia-driven ROS mediated non-canonical Hh signaling may play an important role in the initiation of EMT and provides a potential marker for cancer prevention and treatment. PMID- 29237159 TI - Sugar-Sweetened Beverages and Weight Gain in Children and Adults: A Systematic Review from 2013 to 2015 and a Comparison with Previous Studies. AB - OBJECTIVE: Partly inconsistent findings from previous reviews have fueled discussions on the impact of sugar-sweetened beverages (SSBs) on obesity development. The aim was to systematically review the recent evidence in children and adults. METHODS: Data were retrieved from the databases MEDLINE, EMBASE, and Cochrane library for the period January 2013 to October 2015. A systematic review of prospective cohort studies and randomized controlled trials (RCTs) relating SSBs to weight measures was conducted. RESULTS: 30 publications met the inclusion criteria. Prospective cohort studies (96%; n = 26) showed a positive association between consumption of SSBs and weight/BMI in adults and children (n = 242,352), and only one cohort study in children showed no association. Findings from three RCTs in children demonstrated that SSB consumption had an effect on BMI/BMI z score. The one RCT in adults showed no significant effect of the intervention. 63% of the studies were of good, 30% of medium quality, and none was funded by industry. CONCLUSION: Recent evidence suggests that SSB consumption is positively associated with or has an effect on obesity indices in children and adults. By combining the already published evidence with the new one, we conclude that public health policies should aim to reduce the consumption of SSBs and encourage healthy alternatives such as water. PMID- 29237160 TI - Hydrogen Treatment Protects Mice Against Chronic Pancreatitis by Restoring Regulatory T Cells Loss. AB - BACKGROUND/AIMS: Chronic pancreatitis is an inflammatory disease of the pancreas characterized by progressive tissue destruction and fibrogenesis. The development of chronic pancreatitis is associated with immune cell dysregulation. Currently, the specific and effective treatment of chronic pancreatitis remains absent. METHODS: By using an L-arginine induced chronic pancreatitis mouse model, we tested the therapeutic potential of hydrogen, a strong hydroxyl radicals scavenger, in the chronic pancreatitis model. Tissue inflammation, damage and fibrosis were analyzed on HE, TUNEL, MPO, and sirius staining. Pancreas levels of MDA content, SOD activity, TNF-alpha , IL-10 cytokine expression and serum amylase and lipase activity were determined by ELISA and absorbance assay. Apoptosis, T cells subtype proportion and intracellular level of reactive oxygen species (ROS) were analyzed by flow cytometry. Tregs adoptive transfer and CD25 neutralization were used to validate the role of Tregs in chronic pancreatitis. RESULTS: We found that hydrogen treatment significantly improved multiple symptoms of chronic pancreatitis. The number of Tregs was reduced in chronic pancreatitis mice, while hydrogen treatment restored the Treg loss by L-arginine administrations. Depletion of Tregs abolished the protective effect of hydrogen treatment in chronic pancreatitis. In vitro study showed that hydrogen blocked ROS generation in Tregs and promoted Tregs survival. CONCLUSION: Hydrogen treatment showed reliable benefits in controlling the severity of chronic pancreatitis. Our study supported that hydrogen could be used as a novel treatment in chronic pancreatitis patient in the future. PMID- 29237162 TI - ST Depression, No ST Change, or ST Elevation in Inferior Derivations: Which Has the Worst Outcomes in Acute Anterior Myocardial Infarction? AB - OBJECTIVE: The combination of electrical phenomena and remote myocardial ischemia is the pathophysiological mechanism of ST segment changes in inferior leads in acute anterior myocardial infarction (MI). We investigated the prognostic value of ST segment changes in inferior derivations in patients with first acute anterior MI treated with primary percutaneous coronary intervention (PCI). METHODS: In this prospective single-center analysis, we evaluated the prognostic impact of ST segment changes in inferior derivations on 354 patients with acute anterior MI. Patients were divided into the following 3 groups according to admission ST segment changes in inferior derivations: ST depression (group 1), no ST change (group 2), and ST elevation (group 3). RESULTS: In-hospital multivariate analysis revealed notably high rates of in-hospital death for patients in group 3 compared to patients in group 2 (OR 2.5; 95% CI 1.6-7.6, p < 0.001). Group 1 and group 2 had similar in-hospital and long-term mortality rates. After adjusting for confounding baseline variables, group 3 had higher rates of 18-month mortality (HR 3.3; 95% CI 1.5-8.2, p < 0.001). CONCLUSION: In patients with a first acute anterior MI treated with primary PCI, ST elevation in inferior leads had significantly worse short-term and long-term outcomes compared to no ST change or ST segment depression. PMID- 29237163 TI - [Postoperative adjuvante Therapie mit einem Mistelextrakt (Viscum album ssp. album) bei Hundinnen mit Mammatumoren]. AB - Hintergrund: Canine Mammatumoren (CMT) sind wegen ihrer Haufigkeit und hohen Malignitatsrate eine Herausforderung fur die Veterinarmedizin. Bisher ist noch keine postoperative adjuvante Therapie als wirksamer Standard etabliert und in den nachsten Jahren wohl auch nicht zu erwarten. Zusatzlich ist die Frage nach der Vertraglichkeit einer adjuvanten Therapie mit Erhaltung oder Verbesserung der Lebensqualitat (LQ) wichtig. Die Therapie mit Mistelextrakten (Viscum album L.; VAE) ist in der Humanonkologie nach adjuvanter Tumorbasistherapie (Chemotherapie und Bestrahlung) eine sehr haufig verwendete, zusatzliche adjuvante Behandlungsmethode. Auch bei verschiedenen Tierarten werden inzwischen Mistelpraparate in der Onkologie erfolgreich angewendet. Methoden: Uberprufung von Wirkung und Nutzen einer postoperativen, adjuvanten Misteltherapie beim CMT sowie Erfassung der LQ unter der VAE-Behandlung. Ausgewertet wurden 56 Hundinnen mit Mammaadenokarzinom, 33 ausschliebetalich operierte Kontrolltiere und 23 operierte Tiere, die adjuvant VAE erhielten. Ergebnisse: Die mediane Uberlebenszeit (MST) aller Tiere (n = 56) betrug 32 Monate (Interquartilbereich 13-51 Monate). Im deskriptiven Vergleich der Uberlebenszeiten (ST) nach Kaplan Meier waren nach 12, 24, 36 bzw. 48 Monaten noch 24, 20, 15 bzw. 5 Hundinnen (entsprechend 72,7%, 60,6%, 45,1%, 12,4%) der Kontrollgruppe sowie 19, 14, 11 und 1 Hundin (82,6%, 60,9%, 47,8%, 4,3%) der VAE-Gruppe am Leben. Die VAE-Therapie fuhrte zu einem geringeren Gesamtversterberisiko, das statistisch nicht signifikant war (Hazard Ratio (HR) 0,530, 95%-Konfidenzintervall (KI) 0,222 1,262; p = 0,15). Tendenziell (p = 0,07) zeigte sich eine Verringerung des tumorbedingten Sterberisikos auf 25% (HR 0,251, 95%-KI 0,056-1,122). Schlussfolgerungen: Es kann eine Tendenz zur Senkung des tumorbedingten Sterberisikos der VAE-Gruppe bei guter Vertraglichkeit der Therapie angenommen werden. Die LQ der Tiere blieb uber die gesamte Beobachtungszeit auf hohem Niveau stabil. PMID- 29237161 TI - Effects of Intentional Weight Loss on Markers of Oxidative Stress, DNA Repair and Telomere Length - a Systematic Review. AB - BACKGROUND: Altered levels of markers of oxidative stress, DNA repair, and telomere integrity have been detected in obese individuals and may underlie the pathogenesis of obesity-related diseases. However, whether or not such effects are reversed by intentional weight loss has not been systematically reviewed. METHODS: A literature search in PubMed/Medline identified 2,388 articles of which 21 studies (randomized controlled trial (RCT) (n = 10) and non-randomized intervention studies (n = 11)) were classified as testing the effects of intentional weight loss on i) oxidative stress (n = 15), ii) DNA repair (n = 2), and iii) telomere length (n = 4). RESULTS: Across a broad range of intervention designs, diet-, exercise-, surgery-, balloon-induced weight loss regimens decreased oxidative stress measures. Studies investigating DNA repair capacity or telomere length as endpoints after weight loss were less common in number and yielded null or inconsistent results, respectively. CONCLUSION: While this systematic review supports a role for intentional weight loss in reducing obesity associated oxidative stress, it is not clear whether the effects are primary outcomes or secondary to improvement in obesity-associated insulin resistance and/or chronic inflammation. Although the lack of effect of intentional weight loss on DNA repair capacity might be anticipated given that oxidative stress is reduced, additional studies are needed. The inconsistent effects of weight loss on telomere length or DNA repair suggest the need for a re-assessment of intervention designs and assay methodology to definitively address this topic. PMID- 29237164 TI - MiR-124 Inhibits Growth and Enhances Radiation-Induced Apoptosis in Non-Small Cell Lung Cancer by Inhibiting STAT3. AB - BACKGROUND/AIMS: A growing body of evidence indicates that the abnormal expression of microRNAs (miRNAs) play an important role in sensitizing the cellular response to ionizing radiation (IR). The aim of this study was to investigate whether the expression of miR-124 correlated with radiosensitivity in the context of non-small-cell lung carcinoma (NSCLC). METHODS: Quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to quantify miR 124 expression in NSCLC tissues and cell lines. The role of miR-124 in NSCLC proliferation and radiosensitivity was analyzed using CCK-8 and flow cytometry apoptosis assays. Luciferase activity assays, RT-PCR, and Western blot assays were performed to confirm the target gene of miR-124. RESULTS: In this study, we found that miR-124 was downregulated both in clinical NSCLC samples and in cell lines. miR-124 inhibited the proliferation of NSCLC cells and enhanced the apoptosis of NSCLC cells exposed to ionizing radiation. We identified signal transducer and activator of transcription 3 (STAT3) as a direct target of miR-124 by using target prediction algorithms and luciferase assays. Overexpression of STAT3 in A549 cell lines restored the enhanced radiosensitivity induced by miR 124. CONCLUSION: Taking these observations into consideration, we illustrated that miR-124 is a potential target for enhancing the radiosensitivity of NSCLC cells by targeting STAT3. PMID- 29237165 TI - Distraction versus Intensity: The Importance of Exercise Classes for Cognitive Performance in School. AB - OBJECTIVE: The aim of this study was to compare the influence of a class of aerobic exercise and an art class on brain cortical activity and possible effects on cognitive performance. SUBJECT AND METHODS: Electroencephalography was used to record the electrocortical activity of 16 schoolchildren (8-10 years old) before and after an aerobic exercise class and an art class. Performance in a standardized test of educational attainment (VERA-3) was assessed following both classes. RESULTS: A significant decrease in cortical activity was detected in all 4 lobes after exercise but not after art classes (p < 0.05). No changes in cognitive performance were observed after exercise and art classes. CONCLUSION: In this study, cortical activity was reduced after an exercise class but no effect on cognitive performance was observed. Hence, the neurophysiological effect of exercise should be further evaluated regarding different kinds of cognitive performance: creativity, knowledge acquisition as well as the outlasting effects of exercise on academic achievement. PMID- 29237166 TI - Kallikrein Cleaves C3 and Activates Complement. AB - The human plasma contact system is an immune surveillance system activated by the negatively charged surfaces of bacteria and fungi and includes the kallikrein kinin, the coagulation, and the fibrinolytic systems. Previous work shows that the contact system also activates complement, and that plasma enzymes like kallikrein, plasmin, thrombin, and FXII are involved in the activation process. Here, we show for the first time that kallikrein cleaves the central complement component C3 directly to yield active components C3b and C3a. The cleavage site within C3 is identical to that recognized by the C3 convertase. Also, kallikrein generated C3b forms C3 convertases, which trigger the C3 amplification loop. Since kallikrein also cleaves factor B to yield Bb and Ba, kallikrein alone can trigger complement activation. Kallikrein-generated C3 convertases are inhibited by factor H; thus, the kallikrein activation pathway merges with the amplification loop of the alternative pathway. Taken together, these data suggest that activation of the contact system locally enhances complement activation on cell surfaces. The human pathogenic microbe Candida albicans activates the contact system in normal human serum. However, C. albicans immediately recruits factor H to the surface, thereby evading the alternative and likely kallikrein mediated complement pathways. PMID- 29237167 TI - Health Behavior Change for Obesity Management. AB - Health behavior change is central in obesity management. Due to its complexity, there has been a growing body of research on: i) the factors that predict the adoption and maintenance of health behaviors, ii) the development and testing of theories that conceptualize relationships among these factors and with health behaviors, and iii) how these factors can be implemented in effective behavior change interventions, considering characteristics of the content (techniques) and delivery. This short review provides an overview of advances in behavior change science theories and methods, focusing on obesity management, and includes a discussion of the main challenges imposed by this research field. PMID- 29237168 TI - Evaluation of the National Swiss Skin Cancer Screening Campaign 2013: Do We Do the Right Thing. AB - BACKGROUND: Skin cancer prevention and screening programs are performed in many countries. Their benefit is discussed controversially. OBJECTIVE: Our aim is to evaluate the Skin Cancer Screening Program 2013 in Switzerland by following up screenees upon interventions. METHODS: Quality was assessed by personal follow-up via phone/e-mail of every patient that had been screened during this campaign and histological follow-up of all participants with suspicious skin lesions. RESULTS: Of the 1,087 screenees requiring interventions, 263 agreed to participate in the follow-up. We were able to obtain 66 histology reports. During this campaign 33 malignant lesions (8 melanomas) were removed. CONCLUSION: The overall melanoma detection rate in our free Skin Cancer Screening Program is comparable to those in European public activities. The costs of free screening programs compare favorably with the prevented potential therapeutic costs of late-stage melanoma. The low response rate of screenees agreeing to be followed up limits conclusions of this study. PMID- 29237169 TI - Outer Retina and Choroidal Thickness in Intermediate Age-Related Macular Degeneration: Reticular Pseudodrusen Findings. AB - PURPOSE: To evaluate outer retina and choroidal thickness in subjects with intermediate age-related macular degeneration (iAMD) and to describe associations with the presence of reticular pseudodrusen (RPD). METHODS: This was a retrospective, cross-sectional analysis of 157 consecutive eyes (specifically: 62 eyes classified as having RPD and 95 eyes with drusen >=125 um). Only cases with digital color fundus photographs, red-free, and infrared, obtained and graded according to the Age-Related Eye Disease Study to define iAMD, were used for this study. Outer retina and choroidal thickness were manually segmented and quantified at 12 locations in the horizontal meridian. RESULTS: RPD appeared to be associated with thinning of the outer layers even after adjustment for gender and age. The presence of RPD in iAMD decreased with increase of choroidal thickness (total odds ratio [OR] 0.991, 95% confidence interval [CI] 0.985-0.996; nasal OR 0.992, 95% CI 0.986-0.997), with increased thickness of the myoid zone of the photoreceptors (total OR 0.812, 95% CI 0.688-0.958; nasal OR 0.863, 95% CI 0.755-0.987) and with increased thickness of the outer segment of the photoreceptors (total OR 0.850, 95% CI 0.731-0.989; nasal OR 0.857, 95% CI 0.736 0.989). CONCLUSIONS: The greatest differences between eyes with and without RPD are found at the level of the choroidal thickness and at the level of the photoreceptors. PMID- 29237170 TI - Functional Impact of Novel Androgen Receptor Mutations on the Clinical Manifestation of Androgen Insensitivity Syndrome. AB - Androgens are responsible for the development and maintenance of male sex characteristics. Dysfunctions in androgen action due to mutations in the androgen receptor gene (AR) can lead to androgen insensitivity syndrome (AIS) that can be classified as mild (MAIS), partial (PAIS), or complete (CAIS). We have analyzed functional effects of p.Ser760Thr, p.Leu831Phe, p.Ile899Phe, p.Leu769Val, and p.Pro905Arg mutations and the combination p.Gln799Glu + p.Cys807Phe that were identified in patients with PAIS or CAIS. The p.Leu769Val and p.Pro905Arg mutations showed complete disruption of AR action under physiological hormone concentrations; however, they differed in high DHT concentrations especially in the N/C terminal interaction assay. Mutations p.Ser760Thr, p.Leu831Phe, p.Ile899Phe presented transactivation activities higher than 20% of the wild type in physiological hormone concentrations and increased with higher DHT concentrations. However, each one showed a different profile in the N/C interaction assay. When p.Gln799Glu and p.Cys807Phe were analyzed in combination, transactivation activities <10% in physiologic hormone conditions indicated an association with a CAIS phenotype. We conclude that the functional analysis elucidated the role of mutant ARs, giving clues for the molecular mechanisms associated with different clinical AIS manifestations. Differences in hormone dependent profiles may provide a basis for the response to treatment in each particular case. PMID- 29237171 TI - Peak VO2 in Obesity: Is It Worth the Effort? PMID- 29237172 TI - The Fat Lady Sings Again. PMID- 29237173 TI - Erratum. PMID- 29237174 TI - Errata. PMID- 29237182 TI - [Steroidpsychosis in otorhinolaryngology]. PMID- 29237183 TI - [Volunteers in Refugee Help: is Health Promotion (by Public Health Services) Necessary?] AB - OBJECTIVES: To investigate health-related strains and resources of volunteers in refugee help. METHODS: Qualitative interviews with 10 volunteers in refugee help as well as 11 interviews with experts involved in coordinative tasks were conducted, transcribed and analysed using qualitative content analysis. RESULTS: Volunteers' work in refugee help is experienced as a strong resource. Volunteers receive a lot of thankfulness and appreciation and experience their work as enriching and enhancing self-worth. On the other hand, they also experience several stresses and problems. Difficulties in setting up appropriate boundaries regarding time and emotional involvement are mentioned as important reasons for the experienced stresses. CONCLUSIONS: Support for volunteers in refugee help should be optimised and expanded in order to protect the volunteers from health related strains. Public Health Services could play an important role in such improvements. PMID- 29237184 TI - Transient Pseudohypoaldosteronism Caused by Intestinal Abnormalities. PMID- 29237185 TI - [How are Effects of Patient Education Programs Influenced by Psychosocial Risk Factors in Pediatrics?] AB - BACKGROUND: Modular patient education programs are effective in children with chronic conditions and their families. Little is known about the influence of socioeconomic status (SES), migration background (MB) and children's mental health problems on the programs' effects. OBJECTIVES: Do SES, MB or mental-health problems influence the success of education programs (disease-specific knowledge, children's health-related quality of life (HRQoL) and life satisfaction and parents' condition-specific burden)? MATERIALS AND METHODS: Children with different chronic conditions and their parents participated in modular patient education programs. Before and 6 weeks after the participation SES, MB, children's mental-health problems, parents' und children's disease-specific knowledge, children's HRQoL and life satisfaction and parents' condition-specific burden were assessed by standardized questionnaires. The influence on the programs' effects of SoS, MH and mental-health problems were examined with variance and correlation analyses. RESULTS: 398 children (mean age 10.2 yrs) and their parents participated. Irrespective of SoS, MH and mental-health problems the programs were associated with improved disease-specific knowledge, children's HRQoL and life satisfaction and parents' disease-specific burden. At follow-up SoS, MH and mental-health problems were associated with reduced knowledge, reduced children's' HRQoL and life satisfaction and increased parents' disease specific burden. CONCLUSIONS: Disadvantaged families and children with mental health problems benefit from education programs, but have an increased need of education due to special challenges. PMID- 29237186 TI - [Current literature overview on the therapy of obesity in children and adolescents]. AB - BACKGROUND: Obesity is a chronic disease due to the comorbidity associated with it and the need for long-term medical care. Therapeutic intervention is possible at every stage of pathophysiology. AIM: The aim of the study is to demonstrate the effect of multimodal lifestyle interventions not only on the BMI/BMI-SDS, but also on (secondary) outcomes such as comorbidities, quality of life as well as the nutritional and movement behavior. MATERIALS AND METHODS: The literature database PubMed has been searched for internationally clinical studies on lifestyle interventions among 0 to 18-year-olds with overweight and obesity in the period from 01/01/2009 to 01/01/2016. RESULTS: 64 publications with data from 55 studies were included in this overview. Through multimodal lifestyle interventions, many improvements have been achieved in the fields of comorbidity, quality of life, diet and exercise. DISCUSSION: The use of obesity therapy goes far beyond a weight reduction, which is why other parameters should be regularly recorded as therapeutic targets. Thus the improvement of comorbidities, the quality of life as well as the movement and nutritional behavior for a long-term healthy lifestyle are at least as important and reduce the risk of regain after initial weight reduction. PMID- 29237187 TI - Effect of Population-Specific Birthweight Curves on Disparities in Perinatal Mortality in Small-for-Gestational Age Pregnancies. AB - OBJECTIVE: To determine the effect of adopting sex or race/ethnicity-specific birthweight curves on small-for-gestational age (SGA)-associated mortality rates for specific populations. MATERIALS AND METHODS: Analyzing 20,095,735 singleton pregnancies, we compared rates of perinatal death associated with SGA in distinct sex and racial/ethnic groups when SGA was defined using nonspecific, sex specific, and race/ethnicity-specific birthweight curves. RESULTS: With use of a nonspecific birthweight curve, the rate of perinatal death was higher for SGA males (20.4/1,000 [95% confidence interval (CI), 20.1, 20.7]) than SGA females [14.6/1,000 (95% CI, 14.4, 14.8)]. With a sex-specific curve, this disparity was reduced, measuring 17.7/1,000 (95% CI, 17.4, 17.9) for SGA males and 16.3/1,000 (95% CI, 16.1, 16.6) for females. Using a nonspecific birthweight curve, perinatal death rates were higher for non-Hispanic blacks (20.4/1,000 [95% CI, 20.0, 20.8]) than for all other racial/ethnic groups (15.9/1,000 [95% CI, 15.7, 16.1]). This difference increased with use of a race-specific birthweight curve: perinatal mortality was 29.7/1,000 (95% CI, 29.0, 30.3) for SGA blacks and 14.7/1,000 (95% CI, 14.6, 14.9) for all other racial/ethnic groups. CONCLUSION: Population-based differences in SGA-associated mortality are reduced with adoption of a sex-specific birthweight curve, but widen with use of a race/ethnicity-specific curve. These findings highlight the importance of outcomes analysis in the selection of diagnostic criteria for SGA. PMID- 29237188 TI - Development of a Clinical Risk Assessment Tool for 6-Week Postpartum Visit Nonadherence. AB - OBJECTIVE: The 6-week postpartum visit (6WPP) is integral in addressing postpartum medical concerns. Failure to attend this routine visit is a measure of suboptimal care. This study aims to identify patients at risk of 6WPP nonadherence by developing a novel point-based risk scoring system. METHODS: In this retrospective case-control study (n = 587), a randomly selected subgroup, that is, the "test" group (n = 303), was used to develop the model. The remaining patients were used as an independent "validation" group (n = 284) to assess the model performance. RESULTS: Five factors were found to correlate with 6WPP nonadherence. Positive correlations include: Medicaid health insurance (odds ratio [OR]: 2.40, 95% confidence interval [CI]: 1.38-4.15); prenatal care initiated at >= 14 weeks' gestation (OR: 1.82, 95% CI: 1.11-2.96); and maternal age < 24.0 years (OR: 2.02, 95% CI: 1.13-3.61). Factors negatively correlated with nonadherence include: "married" marital status (OR: 0.50, 95% CI: 0.30-0.84) and primiparity (OR: 0.51, 95% CI: 0.30-0.85). The final scoring system demonstrates significant predictive power in both the test and validation groups (respectively, area under the curve = 0.682, p < 0.001 and 0.629, p < 0.001). CONCLUSION: This risk assessment tool relies on routinely collected data, making its implementation simple. Applying it in the clinical setting allows for early, targeted intervention aimed at minimizing 6WPP nonadherence. PMID- 29237189 TI - [Management of penile cancer patients: new aspects of a rare tumour entity]. AB - Over the past few decades, some principles in the treatment of penile cancer have changed fundamentally. While 15 years ago a negative surgical margin of at least 2 cm was considered mandatory, organ-sparing surgery permitting minimal negative surgical margins has a high priority nowadays. The current treatment principle requires as much organ preservation as possible and as much radicality as necessary. The implementation of organ-sparing and reconstructive surgical techniques has improved the quality of life of surviving patients. However, oncological and functional outcomes are still unsatisfactory. Alongside with adequate local treatment of the primary tumour, a consistent management of inguinal lymph nodes is of fundamental prognostic significance. In particular, clinically inconspicuous inguinal lymph nodes staged T1b and upwards need a surgical approach. Sentinel node biopsy, minimally-invasive surgical techniques and modified inguinal lymphadenectomy have reduced morbidity compared to conventional inguinal lymph node dissection. Multimodal treatment with surgery and chemotherapy is required in all patients with lymph node-positive disease; neoadjuvant chemotherapy has been established for patients with locally advanced lymph node disease, and adjuvant treatment after radical inguinal lymphadenectomy for lymph node-positive disease. An increasing understanding of the underlying tumour biology, in particular the role of the human papilloma virus (HPV) and epidermal growth factor receptor (EGFR) status, has led to a new pathological classification and may further enhance treatment options. This review summarises current aspects in the therapeutic management of penile cancer. PMID- 29237191 TI - Rett Syndrome. PMID- 29237190 TI - Determination of Acid and Neutral Cannabinoids in Extracts of Different Strains of Cannabis sativa Using GC-FID. AB - Cannabis (Cannabis sativa L.) is an annual herbaceous plant that belongs to the family Cannabaceae. Trans-Delta9-tetrahydrocannabinol (Delta9-THC) and cannabidiol (CBD) are the two major phytocannabinoids accounting for over 40% of the cannabis plant extracts, depending on the variety. At the University of Mississippi, different strains of C. sativa, with different concentration ratios of CBD and Delta9-THC, have been tissue cultured via micropropagation and cultivated. A GC-FID method has been developed and validated for the qualitative and quantitative analysis of acid and neutral cannabinoids in C. sativa extracts. The method involves trimethyl silyl derivatization of the extracts. These cannabinoids include tetrahydrocannabivarian, CBD, cannabichromene, trans-Delta8 tetrahydrocannabinol, Delta9-THC, cannabigerol, cannabinol, cannabidiolic acid, cannabigerolic acid, and Delta9-tetrahydrocannabinolic acid-A. The concentration response relationship of the method indicated a linear relationship between the concentration and peak area ratio with R2 > 0.999 for all 10 cannabinoids. The precision and accuracy of the method were found to be <= 15% and +/- 5%, respectively. The limit of detection range was 0.11 - 0.19 ug/mL, and the limit of quantitation was 0.34 - 0.56 ug/mL for all 10 cannabinoids. The developed method is simple, sensitive, reproducible, and suitable for the detection and quantitation of acidic and neutral cannabinoids in different extracts of cannabis varieties. The method was applied to the analysis of these cannabinoids in different parts of the micropropagated cannabis plants (buds, leaves, roots, and stems). PMID- 29237192 TI - Pediatric Kluver-Bucy Syndrome: Report of Two Cases and Review of the Literature. AB - Kluver-Bucy syndrome (KBS) is a rare behavioral phenotype described in monkeys and humans that appears most often after bilateral temporal damage. The main features of KBS are compulsion to examine objects orally, increased sexual activity, placidity, hypermetamorphosis, visual agnosia, and amnesia. Cases in children are scarce, and the most frequently reported etiology is herpes encephalitis. Hyperorality (90%), hypersexuality (82%), and epilepsy (70%) were the most common features of the 51 cases reported in the literature to date. Carbamazepine, selective serotonin reuptake inhibitors (SSRIs), and neuroleptics have been used for symptomatic treatment with variable control. Corticosteroids or immunosupressive agents, such as rituximab, can be an option to use in some cases, according to etiology suspicion. Cognitive and behavioral disturbances after KBS are often severe, but improvement can occur over a long time and residual disabilities vary from major to fairly mild.We report two new encephalitis-associated pediatric patients and review all of the pediatric KBS cases in the literature to better describe the clinical features of this rare neurobehavioral condition. PMID- 29237193 TI - [Attendance for Using Internet-Based Support After Inpatient Treatment - A Cross Sectional Survey]. AB - OBJECTIVE: Examination of the attendance for using internet-based measures after inpatient treatment. METHODS: Cross-sectional-survey in former inpatients (N = 247). RESULTS: 44.9 % are willing to use measures via videoconference, 34.7 % via Chat, 50.0 % via E-Mail and 38.0 % as onlinetherapy. Attendance is lower in older age groups. Benefits regarding the introduced measures are seen mainly in the flexibility and disadvantages in the impersonal character. CONCLUSIONS: A relevant share of especially younger patients is willing to use internet-based measures. PMID- 29237194 TI - [Depression Literacy - German Translation and Testing of the Depression Literacy Scale]. AB - OBJECTIVE: Translation and psychometric testing of a German adaptation of the Australian Depression Literacy Scale. METHODS: Translation of the Depression Literacy Scale by Griffith et al. (2004) into German and testing for depression literacy in a sample of 229 people with depressive syndrome. RESULTS: The investigated sample had a mean age of 49.4 years (18 - 80 years). On average, 51 % of the 22 questions were correctly answered. The scale showed a satisfactory internal consistency with alpha = .74. The first-time application of the translated D-Lit German scale showed significant differences in subgroup analyzes of sex, age, and education. Hence, women, younger persons and persons with a higher school education reported higher values on the Depression Literacy Scale. CONCLUSION: The translation of the Depression Literacy Scale (D-Lit German) resulted in an easy-to-understand and applicable questionnaire. Items relating to therapeutic and drug-related treatments of depressen were more difficult to answer. The D-Lit scale proved to be a reliable and economic instrument for the investigation of depression literacy. Future studies should include depression literacy in investigations on the demands and help-seeking behaviour of people with depression. PMID- 29237195 TI - [Interdisciplinary Inpatient Treatment for Adolescents and Young Adults (16 - 25 Years) with Mental Illness in Adolescent Psychiatry]. AB - OBJECTIVE: The investigation of clinical characteristics of patients in adolescence psychiatry relevant for transition medicine. METHODOLOGY: Sociodemographic and clinical data (SCID I/II, SIPS/SOPS, SPI-A, GAF, CGI) were consecutively taken from the interdisciplinary inpatient treatment centre for adolescents and young adults with mental disorders (N = 229, aged 16 - 25). RESULTS: Average age was 19 years (38 % male, 23 % migration background). A high proportion of early mental illnesses and comorbidities (66 %), psychosis risk syndromes (20 %) and suicidality (54 %), treatment discontinuation (33 %) with daily-life, social and family stress factors (52 % positive family history, 34 % trauma) were observed and a persistently high level of support and treatment was needed despite a significant clinical improvement (p < 0.001). CONCLUSION: The results support the need for an interdisciplinary collaboration for the joint development of care structures in transition medicine. PMID- 29237196 TI - [Young Academics in Neuropsychological Disciplines: Factors Affecting Career Aspiration in Psychiatry, Neurology and Psychosomatic Medicine]. AB - OBJECTIVE: Students with specialization preferences in psychiatry, neurology, or psychosomatic medicine were retrospectively compared with regard to aspects of motivation to choose medicine as their field of study. METHODS: To identify early predictors of specialization preferences, a nationwide online survey was conducted with 9079 medical students. The statements of those with a preference for neurology, psychiatry, or psychosomatic medicine were evaluated using analysis of variance (ANOVA). RESULTS: Prospective neurologists were motivated by scientific interest variables and less by the aspects of life management. On the other hand, students with preferences for one of the psychological disciplines reported comparatively higher degrees of desire to actively provide help and of the importance of their own medical history. There were no significant differences between future psychiatrists and psychosomatic professionals. CONCLUSION: The reported motives point to thematic orientations that might be useful in the subject-specific acquisition of young academics. PMID- 29237197 TI - [Evaluation of Suicide Risk Levels in Hospitals: Validity and Reliability Tests]. AB - OBJECTIVE: Examination of in-hospital suicide risk levels concerning their validity and their reliability. METHOD: The internal suicide risk levels were evaluated in a cross sectional study of in 163 inpatients. A reliability check was performed via determining interrater-reliability of senior physician, therapist and the responsible nurse. Within the scope of the validity check, we conducted analyses of criterion validity and construct validity. RESULTS: For the total sample an "acceptable" to "good" interrater-reliability (Kendalls W = .77) of suicide risk levels were obtained. Schizophrenic disorders showed the lowest values, for personality disorders we found the highest level of interrater reliability. When examining the criterion validity, Item-9 of the BDI-II is substantial correlated to our suicide risk levels (rhom = .54, p < .01). Within the scope of construct validity check, affective disorders showed the highest correlation (rho = .77), compatible also with "convergent validity". They differed with schizophrenic disorders which showed the least concordance (rho = .43). CONCLUSION: In-hospital suicide risk levels may represent an important contribution to the assessment of suicidal behavior of inpatients experiencing psychiatric treatment due to their overall good validity and reliability. PMID- 29237198 TI - [Sociology as a Major Factor for the Psychiatrie-Enquete in the Federal Republic of Germany - Results from Expert Interviews and Document Analyses]. AB - OBJECTIVE: This paper examines the influence of sociology as a discipline on the Psychiatrie-Enquete by analysing interviews with expert (psychiatrist, psychologist, sociologist etc.) witnesses of the Enquete process and by analysing pertinent documents. METHODS: 24 interviews were conducted and analysed using qualitative secondary analysis. RESULTS: Sociological texts and research results influenced the professional development of psychiatrists at the time. Cross-talk between psychiatry and sociology developed through seminal sociological analyses of psychiatric institutions and the interest taken in medical institutions in a number of sociological texts. Inter-disciplinary joint studies (of sociologists and psychiatrists) affected the research interest and professional behaviour of psychiatrists involved in the process on the way to the Psychiatrie-Enquete. CONCLUSION: Tenacity of psychiatrists' systems of opinion was dissolved by impulses from the sociological thought community. The forms of contact between the psychiatric and the sociological thought collective which we could reconstruct are an example of the evolution of knowledge and practice through transdisciplinary communication. PMID- 29237199 TI - [Adult Victimization of Mental Health Service Users - A Review of Prevalences, Risk Factors, and Disclosure]. AB - BACKGROUND: Although adult victimization among psychiatric patients is frequent, the subject is neglected within the mental health service literature in Germany. METHODS: Systematic review on adult victimization prevalences, introduction of risk factors and discussion against theoretical concepts and findings on disclosure of victimization. RESULTS: International studies consistently indicate high adult victimization risks compared to general population. Risk factors include psychopathology, substance abuse, (former) experiences of violence, and a lack of social integration. Disclosure of victimization is hindered by several barriers. CONCLUSIONS: Preventive and interventive measures should be provided at individual, service, and societal level. More research is needed regarding prevalences for German user populations, disclosure within (mental) health services, and situational, interactive and sociocultural factors of victimization. PMID- 29237200 TI - [Screening Instruments for the Detection of Male-Specific Symptoms of Unipolar Depression - A Critical Overview]. AB - BACKGROUND: Epidemiological studies have repeatedly pointed out gender differences in unipolar depression, whereas women have a 1.5 to 3 times higher risk of receiving a diagnosis. This however stands in sharp contrast with the 10 times higher suicide-rate of men, although depression is among the main risk factors for suicide. Current literature therefore suspects an under-diagnosis of depression in men which is yet to be explained. While there is a vast body of literature covering the influence of gender norms, different symptomatology and use of health care services of men and women, systematic examinations of the role of diagnostic inventories or screening-instruments are currently not available. METHOD: A systematic literature search was conducted in order to provide an overview of current male-specific instruments for the detection of depression and to point out research gaps in the field of depression in men. RESULTS: Gender specific inventories were used in 8 out of 122 relevant titles. Differences in the prevalence of unipolar depression tend to diminish or even disappear when gender-specific inventories are being used. DISCUSSION: Existing male-specific screening-instruments have only partly been validated and gender-specific instruments specifically designed for the detection of depression in primary care are currently lacking. PMID- 29237201 TI - Implementation of a checklist before colonoscopy: a quality improvement initiative. AB - BACKGROUND AND STUDY AIMS: Checklists can prevent errors and have a positive impact on patient morbidity and mortality in different surgical settings, and possibly also in gastrointestinal endoscopy. The aims of this study were to reinforce commitment in safety culture and better communication among team members in endoscopy, and to prove the feasibility of successful checklist adoption before colonoscopy. PATIENTS AND METHODS: The study involved a pre - post quality improvement intervention involving all consecutive patients undergoing a colonoscopy at a single academic endoscopy unit. The first part of the study was a retrospective audit, carried out over a 3-month period (July to September 2016). A checklist developed through a formal validation process was implemented during the intervention period (October to December 2016). Primary outcomes were changes in patient and team satisfaction after the quality improvement intervention, using validated 5-point scale questionnaires. Secondary outcomes included successful procedure completion rates and safety outcomes. RESULTS: During the baseline and comparative intervention period, 1317 and 1141 colonoscopies, respectively, were performed. Overall, checklists were fully completed by nurses and physicians for 791 patients (69.3 %). Mean overall patient satisfaction was high at baseline and did not differ following the quality improvement intervention (4.66 vs. 4.63; P = 0.5). Perception of team communication and teamwork was improved after checklist implementation. Comparative analyses of per-procedure and safety outcomes did not differ between the pre- and post-checklist implementation. CONCLUSION: Adoption of an endoscopy checklist before colonoscopy is feasible, and significantly increases perception of team communication and teamwork. Additional studies are needed to assess the generalizability of these results to complex endoscopic procedures and to characterize any improvement in patient safety outcomes. PMID- 29237202 TI - A double-reprocessing high-level disinfection protocol does not eliminate positive cultures from the elevators of duodenoscopes. AB - BACKGROUND AND STUDY AIM: Duodenoscopes have been the source of serious infection, despite correct performance of high-level disinfection (HLD). This study aimed to observe the impact of performing HLD twice on the rate of positive cultures from duodenoscope elevators. METHODS: We performed double HLD (DHLD; i. e. complete manual cleaning followed by automated reprocessing, with the entire process repeated) and then randomly cultured the elevators of our duodenoscopes on about 30 % of occasions. RESULTS: DHLD was associated with positive elevator cultures for any microorganism in 9.4 % of cases, with a 0.8 % rate of known pathogens (627 cultures) between May 2015 and February 2016. After February 2016, and in association with changing the precleaning fluid, as well as use of a new FDA-recommended cleaning brush, the rate of positive cultures for any microorganism after DHLD was 4.8 % and 0.2 % for known pathogens (420 cultures). In a third phase, characterized by a change in personnel performing DHLD and retirement of a duodenoscope with a high rate of positive cultures, the rate of positive cultures for any microorganism was 4.9 % (783 cultures) and the rate of positive culture for known pathogens was 0.3 %. To our knowledge, no duodenoscope transmission of infection occurred during the study interval. CONCLUSIONS: DHLD resulted in a low rate of positive cultures for known pathogens and for organisms of low pathogenic potential, but did not eliminate these, from duodenoscope elevators. Additional improvements in HLD protocols and/or duodenoscope design are needed. PMID- 29237203 TI - Short-term outcomes following endoscopic submucosal dissection of large protruding colorectal neoplasms. AB - BACKGROUND: Although submucosal dissection is useful for treating laterally spreading colorectal tumors, there is little information regarding the endoscopic treatment of large protruding colorectal neoplasms. Here, we aimed to evaluate the clinical outcomes of endoscopic submucosal dissection for protruding colorectal neoplasms >= 20 mm in diameter. METHODS: In total, 112 consecutive patients undergoing treatment between January 2005 and June 2017 were enrolled retrospectively. The study period was divided into six periods to evaluate any changes in outcomes over time. We reviewed all short-term clinical outcomes, including lesion characteristics, procedure time, and percentages of en bloc resection, curative resection, adverse events, and treatment discontinuation. RESULTS: The percentages of en bloc, en bloc R0, and en bloc curative resections were 88 %, 82 %, and 59 %, respectively. Perforation occurred in 11 patients (10 %), and the endoscopic procedure was discontinued in five patients (4 %) because of technical difficulty. For lesions >= 40 mm in diameter, the procedure time showed a statistically significant decreasing trend in the latter half of the study period. However, the rate of cure did not improve along with enhancements to the procedure's technological aspects. CONCLUSIONS: Although endoscopic submucosal dissection for large protruding lesions has advanced in terms of its technical aspects, its ability to cure large protruding neoplasms has not shown gratifying results. PMID- 29237204 TI - Aggressive intravenous hydration with lactated Ringer's solution for prevention of post-ERCP pancreatitis: a prospective randomized multicenter clinical trial. AB - : BACKGROUND AND STUDY AIMS : The present study aimed to determine the type of intravenous hydration that is best suited to reducing the incidence of post endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis. PATIENTS AND METHODS: In a prospective randomized multicenter trial, average-to-high risk patients who underwent first-time ERCP were randomly assigned to three groups (1:1:1) who received: aggressive intravenous hydration (3 mL/kg/h during ERCP, a 20-mL/kg bolus and 3 mL/kg/h for 8 hours after ERCP) with either lactated Ringer's solution (LRS) or normal saline solution (NSS), or standard intravenous hydration with LRS (1.5 mL/kg/h during and for 8 hours after ERCP). The primary end point was post-ERCP pancreatitis (PEP). RESULTS: 395 patients were enrolled, and 385 completed the protocols. The three groups showed no significant differences in demographic characteristics. There was a significant difference in the intention-to-treat (ITT) PEP rate between the aggressive LRS group (3.0 %, 95 % confidence interval [CI] 0.1 % - 5.9 %; 4 /132), the aggressive NSS group (6.7 %, 95 %CI 2.5 % - 10.9 %; 9 /134) and the standard LRS group (11.6 %, 95 %CI 6.1 % - 17.2 %; 15 /129; P = 0.03). In the two-group comparisons, the ITT PEP rate was significantly lower for the aggressive LRS group than for the standard LRS group (relative risk [RR] 0.26, 95 %CI 0.08 - 0.76; P = 0.008). There was no significant difference in the ITT PEP rate between the aggressive NSS group and the standard LRS group (RR 0.57, 95 %CI 0.26 - 1.27; P = 0.17). CONCLUSION: Aggressive hydration with LRS is the best approach to intravenous hydration for the prevention of PEP in average-to-high risk patients. PMID- 29237205 TI - [How does Diabetes Mellitus Influence Early Postoperative Results and Survival in Rectal Cancer?] AB - INTRODUCTION: Aim of this study was to investigate the influence of diabetes mellitus (DM) onto the early postoperative and long-term oncosurgical outcome after surgery for rectal cancer using data prospectively obtained in a representative number of patients. METHODS: Data (using a registration form of 68 items) from the ongoing multicenter observational study "rectal cancer (primary tumor) - elective surgery" on Quality Assurance was used including years 2008 to 2011. A voluntary and frequent follow-up was done to gain long-term data. Patients were grouped as non-diabetic and not-/insulin-dependent DM (NIDDM/IDDM). RESULTS: In total, 10 442 patients were enrolled; 11.0 % had NIDDM and 7.2 % IDDM. Average age of patients without DM was 67.3 [95 %-CI: 67,07; 67,55] years (yr) and was lower than in IDDM- (71.7 [95 %-CI: 71,01; 72,35] yr) and NIDDM patients (70.9 [95 %-CI: 70.41; 71.45] yr) (p < 0.001). Tumor stages according to classification by UICC were comparable (p = 0.547). Patients with DM were more likely to be obese and to have cardiovascular and renal risk factors as well as a more critical ASA-classification (p < 0.001 each). Postoperative morbidity (in the group 65 - 74 yr; p = 0.006) and in-hospital mortality (< 65 yr; p = 0.011) was higher in patients with DM. The 5-year overall survival (OS) was 60.6 % in patients without DM. IDDM (46.4 %) and NIDDM (53.3 %) decreased the OS (p < 0.001 each). The 5-year disease-free survival (DFS) was also worsened by IDDM (p < 0.001) and NIDDM (p = 0.004). No difference was observed concerning 5-year local recurrence rate, neither for IDDM (p = 0.524) nor NIDDM (P = 0.058). DISCUSSION: The metabolic disorder DM has a significant impact onto the outcome after surgery for rectal cancer most likely due to its own risk potential and associated comorbidities. Postoperative morbidity and mortality were increased and the oncological survival was worsened. PMID- 29237207 TI - [Test Diagnostics in PPmP]. PMID- 29237206 TI - [Piperacillin/Tazobactam Shortage: Central Restriction and Alternative Recommendations as Effective Antibiotic-Stewardship Intervention at a Maximal Care Hospital]. AB - BACKGROUND: Drug supply bottleneck is a worldwide challenge, e. g. the antibiotics Piperacillin/Tazobactam shortage in 2016/2017. The efficacy of an appropriate replacement management was evaluated at the University Hospital Frankfurt (UHF). METHODS: The Antibiotic-Stewardship (ABS)-Team at UHF decreed a restriction of PIP/TAZ and provided alternative antibiotic therapy recommendations during the shortage period. Consequences of this intervention on antibiotic consumption and overall costs were investigated. RESULTS: Over 12 weeks, PIP/TAZ-mean application rate was reduced by 71 % and was predominantly used to treat hospital acquired pneumonia (62 %), febrile neutropenian children (12 %), followed by other indications (< 10 %, each). Alternative substances' use increased (Ceftazidim + 229 %, Imipenem/Cilastatin + 18 %, Meropenem + 27 %, Ceftriaxon + 26 %, Levofloxacin + 11 %, Ciprofloxacin + 14 %, Ampicillin/Sulbactam + 83 %), however the overall antibiotic consumption declined by -5.8 % (cost savings: 13 %). Simultaneously, additional personnel costs have been noted (+ 4300 ?). The evidence rate of bloodstream infections with resistant bacteria and detection of Clostridium-difficile-toxin were both not significantly elevated, compared to windows just ahead, after and one year before intervention period. CONCLUSION: Drug shortages challenge hospital antibiotic-stewardship programs by enforced use of broad spectrum-antibiotics, endanger patient safety and require rational replacement strategies, following infectious diseases- and microbiological outlines. Whilst personnel expenditures are higher, antimicrobial stewardship interventions may successfully contribute to prevent additional medication costs. PMID- 29237209 TI - ? PMID- 29237208 TI - [Acceptance and Commitment Therapy in the Treatment of Chronic Disease]. AB - Acceptance and Commitment Therapy (ACT) is an intervention representing a transdiagnostic and contextual approach that assumes that psychological suffering is caused by experiential avoidance. The primary intention of ACT is not to eliminate symptoms and to treat mental disorders. Instead, ACT aims to increase psychological flexibility, i. e. to broaden the repertoire of cognitions and behaviors when facing inner and outer aversive events or experiences. Psychological flexibility can be enhanced by working with the 6 core components of the ACT model. Experience-focused methods like metaphors and exercises for acceptance play a crucial role in the therapeutic work. In short, with ACT patients can learn: ? that rigid and inflexible attempts to fight aversive experience are problematic ? a mindful experience of inner and outer experience ? to differentiate between unchangeable and changeable events (acceptance) ? to identify values or respectively life goals and to behave in a way that is consistent with them (commitment)The therapeutic focus of ACT is to create a balance between acceptance and behavioral change consistent with chosen values. Chronic diseases are often associated with aversive inner and outer experiences. A growing number of studies support the efficacy of ACT. There is evidence that ACT can increase psychological flexibility and potentially also lead to better self-management within the context of chronic somatic diseases. PMID- 29237211 TI - ? PMID- 29237213 TI - ? PMID- 29237212 TI - ? PMID- 29237214 TI - ? PMID- 29237215 TI - ? PMID- 29237216 TI - ? PMID- 29237217 TI - ? PMID- 29237219 TI - ? PMID- 29237218 TI - [Cylindric Abdominoperineal Rectum Exstirpation with Partial Vulvar and Vaginal Resection as well as Perineal and Vaginal Defect Reconstruction by a Vertical Rectus Abdominis Myocutaneous (VRAM) Flap]. AB - Introduction Patients with low rectal cancer or anal cancer undergoing abdominoperineal excision (APE) benefit from extended surgery and the subsequent avoidance of surgical "waisting" at the level of the puborectalis muscle. The method of cylindrical APE was introduced by T. Holm and led to a reduction of intraoperative perforations and involvement of circumferential resection margins, and subsequently reduced the risk of local recurrence. The use of myocutaneous flaps reduces perineal wound complications, which occur in up to 60% of patients with primary closure of perineal defects, especially following neoadjuvant radiochemotherapy. Flaps obliterate pelvic dead space, recruit well-vascularised tissue into irradiated regions, facilitate wound closure and allow for vaginal and perineal reconstructions. This video shows the technique of extended cylindrical APE with partial vulvar and vaginal resection and subsequent reconstruction of the posterior vaginal wall and the pelvic floor defect by a vertical rectus abdominis myocutaneous (VRAM) flap. Indication Locally advanced anal cancer with infiltration and fistula to the posterior vaginal wall without metastatic spread following neoadjuvant radiochemotherapy. Procedure Extended cylindric APE with partial vulvar and vaginal resection, construction of a descending colostomy with parastomal intraperitoneal onlay mesh augmentation, pelvic reconstruction with a VRAM flap and inlay mesh augmentation of the anterior rectus sheath. Conclusion From the oncological point of view, extralevator APE is superior to standard surgery. The use of myocutaneous flaps improves postoperative wound healing and quality of life. PMID- 29237220 TI - [New Approaches for Young Surgeons - Students' Symposium on Minimally Invasive Surgery]. AB - Background Physician shortage is particularly striking in surgical specialities. Umbrella organisations are making an effort to recruit medical students. Students' symposia during congresses seem to provide a promising approach to developing motivation and promoting interest. An exemplary students' symposium took place at the three nations meeting for minimally invasive surgery (MIS). Our aim was to evaluate the students' symposium from the students' perspective, in order to give recommendations for the future. Methods Of a total of 60 participants, half (30/60) completed the survey. Using a 5-point Likert scale, students evaluated items on the agenda, increase in interests, personal benefit and likelihood of future participation. Results Sixty percent (18/30) of the participants in the student forum reported enhanced interest in MIC - the largest increase found. For surgery in general and for robotic surgery in particular, an increase was reported by 57% (17/30) of the students. Of all the items on the agenda, laparoscopic hands-on experience was rated best - with a positive rating from 90% (27/30) of the students. Students expressed the wish for improved personal exchange with experts and professionals. Two thirds (40/60) of the students stated that future participation was definite or very likely. Discussion The increase in interest in MIS and surgery in general demonstrated the success of the students' symposium. Hands-on experiences was very popular. Future events should focus on personal exchange between students and experts. This seems necessary to reduce prejudice in the debate on a well-adjusted work-life balance. With a view to physician shortage in surgical specialties, students' symposia are a valuable option that should be firmly established and consistently developed. PMID- 29237221 TI - [The Medical Examination - Between Desire and Reality - Analysis of Consensus Between the Second Part of the Medical Licensing Exam (IMPP) and the National Catalogue of Expertise-based Learning Goals in Surgery (NKLC)]. AB - Background The working party of the German Society for Surgery (DGCH) on undergraduate surgical education has developed a national expertise-based catalogue of learning goals in surgery (NKLC). This study analyses the extent to which the questions of the German second medical licensing examination compiled by the IMPP are congruent with the NKLC and which thematic focus is emphasised. Materials and Methods Firstly, a guideline and evaluation sheet were developed in order to achieve documentation of the individual examination questions of the second licensing examination with respect to the learning goals of the NKLC. In a retrospective analysis from autumn 2009 to autumn 2014, eleven licensing examinations in human medicine were screened independently by three different reviewers. In accordance with the guideline, the surgical questions were identified and subsequently matched to the learning goals of the NKLC. The analysis included the number of surgical learning goals as well as the number of surgical questions for each examination, learning goal, and different levels of expertise (LE). Results Thirteen reviewers from six surgical disciplines participated in the analysis. On average, reviewers agreed on the differentiation between surgical and non-surgical questions in 79.1% of all 3480 questions from 11 licensing examinations. For each examination (n = 320 questions), 98.8 +/- 22.6 questions (min.: 69, max.: 150) were rated as surgical. For each surgical learning goal addressed, 2.2 +/- 0.3 questions (min.: 1, max.: 16) were asked. For each examination, 23.5 +/- 6.3 questions (min.: 11; max.: 31) referred to learning goals of LE 3, 52.5 +/- 16.7 questions (min.: 34; max.: 94) addressed learning goals of LE 2 and 22.8 +/- 7.7 questions (min.: 9; max.: 34) were related to learning goals of LE 1. 64 learning goals (27.8% of all learning goals of the NKLC) were not reflected in the examinations. With a total of 70 questions, the most frequently examined surgical topic was "disorders of the rheumatic spectrum". Conclusion The number of surgical examination questions in the German second medical licensing examination seems to be sufficient. However, the questions seem to be unevenly distributed between different surgical areas of undergraduate education. In order to achieve a more homogenous representation of relevant surgical topics, improved alignment is needed between the state examination with existing catalogues of learning goals by the IMPP. PMID- 29237222 TI - [Surgery During Pregnancy - Regulations and Requirements]. AB - Due to the marked increase in the numbers of women in medicine, professional and political discussions on equality among doctors are gaining increasing attention. One such issue is "operating during pregnancy". As a result of existing legislation and federal regulations, it has been virtually impossible for pregnant surgeons to continue their surgical work. After approval by the Federal Council or Bundesrat, the revised Maternity Protection Act will come into force on 01.01.2018. It will thereafter be easier for surgeons to operate during pregnancy. The focus will now be on the transformation of workplace practices, in which individual risk assessments of the participating surgeons will be carried out in order to achieve a risk-adapted operation, and thus to prevent premature and unwanted restrictions on the employment of pregnant female surgeons. PMID- 29237223 TI - [Not Available]. PMID- 29237224 TI - ? PMID- 29237225 TI - ? PMID- 29237226 TI - ? PMID- 29237227 TI - ? PMID- 29237228 TI - Methotrexate and azathioprine for severe atopic dermatitis: a 5-year follow-up study of a randomized controlled trial. AB - BACKGROUND: Systemic treatment is indicated for moderate-to-severe atopic dermatitis (AD) refractory to topical treatment. Long-term evidence, up to 5 years, of off-label prescribed methotrexate (MTX) and azathioprine (AZA) is lacking. OBJECTIVES: To investigate long-term effectiveness, safety and drug survival of MTX and AZA. METHODS: In an open-label follow-up phase of a clinical trial, patients were seen every 3 months for 5 years. MTX and AZA doses could be increased or decreased concurrent with daily clinical practice. Primary effectiveness outcomes were mean absolute and relative reduction in SCORing Atopic Dermatitis (SCORAD) index and Investigator's Global Assessment (IGA) after 5 years compared with baseline. To assess safety, the type, frequency, severity and relatedness to treatment of adverse events were investigated. Drug survival was analysed by Kaplan-Meier curves. RESULTS: Thirty-five of 43 originally included patients participated, of whom 27 completed the follow-up. At year 5, the mean relative reduction in SCORAD index was similar in the MTX and AZA groups: 53% and 54% using descriptive analysis. Twelve serious adverse events occurred in 5 years; for three there was a possible causal relationship. Drug survival demonstrated a longer survival for MTX, but survival in both groups was low after 5 years (MTXn = 5, AZAn = 1). CONCLUSIONS: Based on this relatively small pragmatic study, MTX and AZA seem to be effective and safe as maintenance treatments in moderate-to-severe AD up to 5 years. Few patients in both groups survive on their originally allocated drug although some discontinued because of controlled AD. PMID- 29237229 TI - Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long chain acyl-CoA dehydrogenase-deficient mice. AB - The white skeletal muscle of very long-chain acyl-CoA-dehydrogenase-deficient (VLCAD-/- ) mice undergoes metabolic modification to compensate for defective beta-oxidation in a progressive and time-dependent manner by upregulating glucose oxidation. This metabolic regulation seems to be accompanied by morphologic adaptation of muscle fibers toward the glycolytic fiber type II with the concomitant upregulation of mitochondrial fatty acid biosynthesis (mFASII) and lipoic acid biosynthesis. Dietary supplementation of VLCAD-/- mice with different medium-chain triglycerides over 1 year revealed that odd-chain species has no effect on muscle fiber switch, whereas even-chain species inhibit progressive metabolic adaptation. Our study shows that muscle may undergo adaptive mechanisms that are modulated by dietary supplementation. We describe for the first time a concomitant change of mFASII in this muscular adaptation process. PMID- 29237231 TI - The effect of parental education on child health: Quasi-experimental evidence from a reduction in the length of primary schooling in Egypt. AB - This paper examines the impact of parental education on child health using a reduction in the length of primary schooling in Egypt. We use a fuzzy regression discontinuity design to compare the health outcomes of children whose parents were exposed to different schooling requirements because they were born either side of a threshold date. Using data from the Demographic and Health Survey (1992 2014), we find no effect of maternal education on child mortality or nutritional status. There is some evidence, although not entirely robust, that father's education reduces the likelihood of child stunting. We find, however, that father's education has no impact on child mortality or other measures of nutritional status. We provide suggestive evidence that, given the low levels of parental education in Egypt accompanied with the inferior quality of primary schooling, education has little effect on intermediate outcomes-literacy and utilization of antenatal care-that may improve the health of offspring. PMID- 29237230 TI - The binding interface of kindlin-2 and ILK involves Asp344/Asp352/Thr356 in kindlin-2 and Arg243/Arg334 in ILK. AB - Focal adhesion (FA) proteins, kindlin-2 and integrin-linked kinase (ILK), regulate cell adhesion and migration. ILK interacts with and promotes kindlin-2 targeting to FAs. Leu353 and Leu357 in kindlin-2 have been reported to be important for the interaction between kindlin-2 and ILK. However, the binding interface between kindlin-2 and ILK remains unclear. Using molecular modeling and molecular dynamics simulations, we show that Asp344, Asp352, and Thr356 in kindlin-2 and Arg243 and Arg334 in ILK kinase domain (KD) are important in kindlin-2/ILK complex formation. Mutations that disrupt these interactions abrogate kindlin-2 and ILK colocalization in HeLa cells. The interactions are direct based on data from pull-down assays using purified recombinant kindlin-2 F2-pleckstrin homology and ILK KDs. These data provide additional insights into the binding interface between kindlin-2 and ILK. PMID- 29237232 TI - 3D printed phantoms mimicking cortical bone for the assessment of ultrashort echo time magnetic resonance imaging. AB - PURPOSE: Human cortical bone has a rapid T2* decay, and it can be visualized using ultrashort echo time (UTE) techniques in magnetic resonance imaging (MRI). These sequences operate at the limits of gradient and transmit-receive signal performance. Development of multicompartment anthropomorphic phantoms that can mimic human cortical bone can assist with quality assurance and optimization of UTE sequences. The aims of this study were to (a) characterize the MRI signal properties of a photopolymer resin that can be 3D printed, (b) develop multicompartment phantoms based on the resin, and (c) demonstrate the feasibility of using these phantoms to mimic human anatomy in the assessment of UTE sequences. METHODS: A photopolymer resin (Prismlab China Ltd, Shanghai, China) was imaged on a 3 Tesla MRI system (Siemens Skyra) to characterize its MRI properties with emphasis on T2* signal and longevity. Two anthropomorphic phantoms, using the 3D printed resin to simulate skeletal anatomy, were developed and imaged using UTE sequences. A skull phantom was developed and used to assess the feasibility of using the resin to develop a complex model with realistic morphological human characteristics. A tibia model was also developed to assess the suitability of the resin at mimicking a simple multicompartment anatomical model and imaged using a three-dimensional UTE sequence (PETRA). Image quality measurements of signal-to-noise ratio (SNR) and contrast factor were calculated and these were compared to in vivo values. RESULTS: The T2* and T1 (mean +/- standard deviation) of the photopolymer resin was found to be 411 +/- 19 MUs and 74.39 +/- 13.88 ms, respectively, and demonstrated no statistically significant change during 4 months of monitoring. The resin had a similar T2* decay to human cortical bone; however, had lower T1 properties. The bone water concentration of the resin was 59% relative to an external water reference phantom, and this was higher than in vivo values reported for human cortical bone. The multicompartment anthropomorphic head phantom was successfully produced and able to simulate realistic air cavities, bony anatomy, and soft tissue. Image quality assessment in the tibia phantom using the PETRA sequence showed the suitability of the resin to mimic human anatomy with high SNR and contrast making it suitable for tissue segmentation. CONCLUSIONS: A solid resin material, which can be 3D printed, has been found to have similar magnetic resonance signal properties to human cortical bone. Phantoms replicating skeletal anatomy were successfully produced using this resin and demonstrated their use for image quality and segmentation assessment of ultrashort echo time sequences. PMID- 29237233 TI - Magnetic resonance imaging cognitive fusion biopsy - is near enough good enough? PMID- 29237234 TI - Mortality effects of containing moral hazard: Evidence from disability insurance reform. AB - We exploit an age discontinuity in a Dutch disability insurance reform to identify the health impact of stricter eligibility criteria and reduced generosity. Our results show substantial adverse effects on life expectancy for women subject to the more stringent criteria. A ?1,000 reduction in annual benefits leads to a 2.4 percentage points higher probability of death more than 10 years after the reform. This negative health effect is restricted to women with low pre-disability earnings. We find that the mortality rate of men subject to the stricter rules is reduced by 0.7 percentage points. The evidence for the existence of substantial health effects implies that policymakers considering a disability insurance reform should carefully balance the welfare gains from reduced moral hazard against losses not only from less coverage of income risks but also from deteriorated health. PMID- 29237235 TI - Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study. AB - In a multicenter, open-label, study, 284 living-donor liver transplant patients were randomized at 30 +/- 5 days posttransplant to start everolimus+reduced tacrolimus (EVR+rTAC) or continue standard tacrolimus (TAC Control). EVR+rTAC was non-inferior to TAC Control for the primary efficacy endpoint of treated BPAR, graft loss or death at 12 months posttransplant: difference -0.7% (90% CI -5.2%, 3.7%); P < .001 for non-inferiority. Treated BPAR occurred in 2.2% and 3.6% of patients, respectively. The key secondary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, achieved non inferiority (P < .001 for non-inferiority), but not superiority and was similar between groups overall (mean -8.0 vs. -12.1 mL/min/1.73 m2 , P = .108), and in patients continuing randomized treatment (-8.0 vs. -13.3 mL/min/1.73 m2 , P = .046). In the EVR+rTAC and TAC control groups, study drug was discontinued in 15.5% and 17.6% of patients, adverse events with suspected relation to study drug occurred in 57.0% and 40.4%, and proteinuria >=1 g/24 h in 9.3% and 0%, respectively. Everolimus did not negatively affect liver regeneration. At 12 months, hepatocellular recurrence was only seen in the standard TAC-treated patients (5/62; 8.1%). In conclusion, early introduction of EVR+rTAC was non inferior to standard tacrolimus in terms of efficacy and renal function at 12 months, with hepatocellular carcinoma recurrence only in TAC Control patients. ClinicalTrials.gov Identifier: NCT01888432. PMID- 29237236 TI - Likelihood of pulmonary hypertension in patients with idiopathic pulmonary fibrosis and emphysema. AB - BACKGROUND AND OBJECTIVE: This study evaluated whether patients with combined pulmonary fibrosis and emphysema (CPFE) have an increased likelihood of pulmonary hypertension (PHT) when compared with idiopathic pulmonary fibrosis (IPF) patients without emphysema. METHODS: Two consecutive IPF populations having undergone transthoracic echocardiography were examined (n = 223 and n = 162). Emphysema and interstitial lung disease (ILD) extent were quantified visually; ILD extent was also quantified by a software tool, CALIPER. Echocardiographic criteria categorized PHT risk. RESULTS: The prevalence of an increased PHT likelihood was 29% and 31% in each CPFE cohort. Survival at 12 months was 60% across both CPFE cohorts with no significantly worsened outcome identified when compared with IPF patients without emphysema. Using logistic regression models in both cohorts, total computed tomography (CT) disease extent (ILD and emphysema) predicted the likelihood of PHT. After adjustment for total disease extent, CPFE had no stronger association with PHT likelihood than IPF patients without emphysema. CONCLUSION: Our findings indicate that the reported association between CPFE and PHT is explained by the summed baseline CT extents of ILD and emphysema. Once baseline severity is taken into account, CPFE is not selectively associated with a malignant microvascular phenotype, when compared with IPF patients without emphysema. PMID- 29237237 TI - Clinical judgement in the era of big data and predictive analytics. AB - Clinical judgement is a central and longstanding issue in the philosophy of medicine which has generated significant interest over the past few decades. In this article, we explore different approaches to clinical judgement articulated in the literature, focusing in particular on data-driven, mathematical approaches which we contrast with narrative, virtue-based approaches to clinical reasoning. We discuss the tension between these different clinical epistemologies and further explore the implications of big data and machine learning for a philosophy of clinical judgement. We argue for a pluralistic, integrative approach, and demonstrate how narrative, virtue-based clinical reasoning will remain indispensable in an era of big data and predictive analytics. PMID- 29237238 TI - Directional probe for radio-guided surgery: A pilot study. AB - PURPOSE: The sentinel lymph node (SLN) biopsy technique has highly evolved during the last 20 yr. Consequently, the intraoperative use of Gamma Probes (GPs) for SLN mapping is increased. This preliminary study evaluates a novel directional GP prototype. This proof-of-concept prototype is designed to identify the direction of radiopharmaceuticals uptakes, by combining the information from multiple detectors. The purpose of this work is to develop a tool able to effectively guide the surgeon reducing the surgery time. METHODS: The proposed prototype consists of three CsI(Tl) scintillation crystals, each coupled with an S10931 silicon photomultiplier (Hamamatsu Photonics K.K., Hamamatsu, JP). The three detectors lie on the same plane with an angle of 30 degrees between them. The central detector is placed as in a common GP, so it can be used to pinpoint the target tissue. Meanwhile, the lateral sensors provide a broader view of the surgical field. A dedicated data acquisition system digitizes and processes the signals from the front-end electronics. Finally, an embedded system, based on ARM processor, calculates and displays the acquired count rates. In order to assess the prototype behavior, the isosensitivity curves for the three detectors were measured. Meanwhile, for the central one, the main quality criteria measurements were also performed (i.e., sensitivity, radial sensitivity, and spatial resolution). RESULTS: For the central detector, the measured sensitivity at the tip of the probe is better than 5 cps/kBq. The full width at half maximum (FWHM) of the radial sensitivity is less than 30 degrees and the FWHM of the lateral sensitivity (spatial resolution) is about 7.2 mm. The central detector measured isosensitivity distribution shows a narrow profile in agreement with the spatial resolution measured. On the contrary, the two lateral detectors exhibit widespread isosensitivity distributions that mean a larger field of view. The system had shown satisfactory performance and reliability, meeting the minimal requirements of gamma probe systems. CONCLUSIONS: The prototype presented in this paper allows a rapid localization by the use of the whole system, while the sole central detector can be used to pinpoint the target source. This device, unlike common GPs, allows localizing simultaneously different areas of radiopharmaceuticals uptake, thus precisely guiding the surgeon to the region of interest. These preliminary results encourage to develop a further prototype for intraoperative validation. PMID- 29237240 TI - Plant behaviour under combined stress: tomato responses to combined salinity and pathogen stress. AB - Crop plants are subjected to a variety of stresses during their lifecycle, including abiotic stress factors such as salinity and biotic stress factors such as pathogens. Plants have developed a multitude of defense and adaptation responses to these stress factors. In the field, different stress factors mostly occur concurrently resulting in a new state of stress, the combined stress. There is evidence that plant resistance to pathogens can be attenuated or enhanced by abiotic stress factors. With stress tolerance research being mostly focused on plant responses to individual stresses, the understanding of a plant's ability to adapt to combined stresses is limited. In the last few years, we studied powdery mildew resistance under salt stress conditions in the model crop plant tomato with the aim to understand the requirements to achieve plant resilience to a wider array of combined abiotic and biotic stress combinations. We uncovered specific responses of tomato plants to combined salinity-pathogen stress, which varied with salinity intensity and plant resistance genes. Moreover, hormones, with their complex regulation and cross-talk, were shown to play a key role in the adaptation of tomato plants to the combined stress. In this review, we attempt to understand the complexity of plant responses to abiotic and biotic stress combinations, with a focus on tomato responses (genetic control and cross talk of signaling pathways) to combined salinity and pathogen stresses. Further, we provide recommendations on how to design novel strategies for breeding crops with a sustained performance under diverse environmental conditions. PMID- 29237239 TI - Sex steroid hormones and brain function: PET imaging as a tool for research. AB - Sex steroid hormones are major regulators of sexual characteristic among species. These hormones, however, are also produced in the brain. Steroidal hormone mediated signalling via the corresponding hormone receptors can influence brain function at the cellular level and thus affect behaviour and higher brain functions. Altered steroid hormone signalling has been associated with psychiatric disorders, such as anxiety and depression. Neurosteroids are also considered to have a neuroprotective effect in neurodegenerative diseases. So far, the role of steroid hormone receptors in physiological and pathological conditions has mainly been investigated post mortem on animal or human brain tissues. To study the dynamic interplay between sex steroids, their receptors, brain function and behaviour in psychiatric and neurological disorders in a longitudinal manner, however, non-invasive techniques are needed. Positron emission tomography (PET) is a non-invasive imaging tool that is used to quantitatively investigate a variety of physiological and biochemical parameters in vivo. PET uses radiotracers aimed at a specific target (eg, receptor, enzyme, transporter) to visualise the processes of interest. In this review, we discuss the current status of the use of PET imaging for studying sex steroid hormones in the brain. So far, PET has mainly been investigated as a tool to measure (changes in) sex hormone receptor expression in the brain, to measure a key enzyme in the steroid synthesis pathway (aromatase) and to evaluate the effects of hormonal treatment by imaging specific downstream processes in the brain. Although validated radiotracers for a number of targets are still warranted, PET can already be a useful technique for steroid hormone research and facilitate the translation of interesting findings in animal studies to clinical trials in patients. PMID- 29237242 TI - Enhanced cognition and dysregulated hippocampal synaptic physiology in mice with a heterozygous deletion of PSD-95. AB - PSD-95 is one of the most abundant proteins of the postsynaptic density of excitatory synapses. It functions as the backbone of protein supercomplexes that mediate signalling between membrane glutamate receptors and intracellular pathways. Homozygous deletion of the Dlg4 gene encoding PSD-95 was previously found to cause a profound impairment in operant and Pavlovian conditioning in Dlg4-/- mice studied in touch screen chambers that precluded evaluation of PSD 95's role in shaping more subtle forms of learning and memory. In this study, using a battery of touch screen tests, we investigated cognitive behaviour of mice with a heterozygous Dlg4 mutation. We found that in contrast to learning deficits of Dlg4-/- mice, Dlg4+/- animals demonstrated enhanced performance in the Visual Discrimination, Visual Discrimination Reversal and Paired-Associates Learning touch screen tasks. The divergent directions of learning phenotypes observed in Dlg4-/- and Dlg4+/- mice also contrasted with qualitatively similar changes in the amplitude and plasticity of field excitatory postsynaptic potentials recorded in the CA1 area of hippocampal slices from both mutants. Our results have important repercussions for the studies of genetic models of human diseases, because they demonstrate that reliance on phenotypes observed solely in homozygous mice may obscure qualitatively different changes in heterozygous animals and potentially weaken the validity of translational comparisons with symptoms seen in heterozygous human carriers. PMID- 29237241 TI - The Physcomitrella patens chromosome-scale assembly reveals moss genome structure and evolution. AB - The draft genome of the moss model, Physcomitrella patens, comprised approximately 2000 unordered scaffolds. In order to enable analyses of genome structure and evolution we generated a chromosome-scale genome assembly using genetic linkage as well as (end) sequencing of long DNA fragments. We find that 57% of the genome comprises transposable elements (TEs), some of which may be actively transposing during the life cycle. Unlike in flowering plant genomes, gene- and TE-rich regions show an overall even distribution along the chromosomes. However, the chromosomes are mono-centric with peaks of a class of Copia elements potentially coinciding with centromeres. Gene body methylation is evident in 5.7% of the protein-coding genes, typically coinciding with low GC and low expression. Some giant virus insertions are transcriptionally active and might protect gametes from viral infection via siRNA mediated silencing. Structure-based detection methods show that the genome evolved via two rounds of whole genome duplications (WGDs), apparently common in mosses but not in liverworts and hornworts. Several hundred genes are present in colinear regions conserved since the last common ancestor of plants. These syntenic regions are enriched for functions related to plant-specific cell growth and tissue organization. The P. patens genome lacks the TE-rich pericentromeric and gene rich distal regions typical for most flowering plant genomes. More non-seed plant genomes are needed to unravel how plant genomes evolve, and to understand whether the P. patens genome structure is typical for mosses or bryophytes. PMID- 29237244 TI - In silico analysis of the competition between Streptococcus sanguinis and Streptococcus mutans in the dental biofilm. AB - During dental caries, the dental biofilm modifies the composition of the hundreds of involved bacterial species. Changing environmental conditions influence competition. A pertinent model to exemplify the complex interplay of the microorganisms in the human dental biofilm is the competition between Streptococcus sanguinis and Streptococcus mutans. It has been reported that children and adults harbor greater numbers of S. sanguinis in the oral cavity, associated with caries-free teeth. Conversely, S. mutans is predominant in individuals with a high number of carious lesions. Competition between both microorganisms stems from the production of H2 O2 by S. sanguinis and mutacins, a type of bacteriocins, by S. mutans. There is limited evidence on how S. sanguinis survives its own H2 O2 levels, or if it has other mechanisms that might aid in the competition against S. mutans, nonetheless. We performed a genomic and metabolic pathway comparison, coupled with a comprehensive literature review, to better understand the competition between these two species. Results indicated that S. sanguinis can outcompete S. mutans by the production of an enzyme capable of metabolizing H2 O2 . S. mutans, however, lacks the enzyme and is susceptible to the peroxide from S. sanguinis. In addition, S. sanguinis can generate energy through gluconeogenesis and seems to have evolved different communication mechanisms, indicating that novel proteins may be responsible for intra-species communication. PMID- 29237243 TI - Exercise-related severe cardiac events. AB - Physical activity has benefits on health. However, there is a small risk of effort-related adverse events. The aim of this study is to describe exercise related severe cardiovascular events and to relate them with the type of sport performed. We performed a ten-year retrospective study in eight Spanish cardiac intensive care units. Adverse cardiac events were defined as acute myocardial infarction, cardiac arrest or syncope related to physical activity. From 117 patients included, 109 were male (93.2%), and mean age was 51.6 +/- 12.3 years; 56 presented acute myocardial infarction without cardiac arrest (47.9%), 55 sudden cardiac death (47.0%) and six syncope (5.1%). The sports with higher number of events were cycling (33%-28.2%), marathon or similar running competitions (19%-16.2%), gymnastics (18%-15.3%) and soccer (17%-14.5%). Myocardial infarction was observed more frequently in cyclists compared to other sports (69.7% vs 39.3%, P = .001). The most common cause of sudden cardiac death was myocardial infarction in those >35 years (23%-63.9%) and idiopathic ventricular fibrillation in younger patients (5%-62.5%). Significant coronary artery disease was present in 85 (79.4%). Only one patient with cardiac arrest presented with a non-shockable rhythm (asystole). Eleven patients (9.4%) died during hospitalization; in all cases, they had presented cardiac arrest. All discharged patients were alive at the end of follow-up. Exercise-related severe cardiac events are mainly seen in men. Coronary heart disease is very frequent; about half present acute myocardial infarction and the other half cardiac arrest. In our cohort, prognosis was good in patients without cardiac arrest. PMID- 29237245 TI - Molecular mechanisms and physiological relevance of RGK proteins in the heart. AB - The primary route of Ca2+ entry into cardiac myocytes is via 1,4-dihydropyridine sensitive, voltage-gated L-type Ca2+ channels. Ca2+ influx through these channels influences duration of action potential and engages excitation-contraction (EC) coupling in both the atria and the myocardium. Members of the RGK (Rad, Rem, Rem2 and Gem/Kir) family of small GTP-binding proteins are potent, endogenously expressed inhibitors of cardiac L-type channels. Although much work has focused on the molecular mechanisms by which RGK proteins inhibit the CaV 1.2 and CaV 1.3 L-type channel isoforms that expressed in the heart, their impact on greater cardiac function is only beginning to come into focus. In this review, we summarize recent findings regarding the influence of RGK proteins on normal cardiac physiology and the pathological consequences of aberrant RGK activity. PMID- 29237246 TI - THE PERFECT MUM DOESN'T EXIST BUT A GOOD ENOUGH MUM DOES: BUILDING RESILIENCE FOR BETTER MATERNAL MENTAL HEALTH. AB - The issue of women experiencing mental health problems during pregnancy which can progress and exacerbate into the transition of motherhood is one that midwives need to be alerted to. PMID- 29237248 TI - WOMEN'S HEALTH NURSES: WHY WE NEED THEM. AB - With governments reducing funding in health services, the eroding of nursing positions in the community have been severely impacted on, including women's health nurses. PMID- 29237247 TI - Efficacy of an asynchronous electronic curriculum in emergency medicine education in the United States. AB - PURPOSE: The aim of this study was to measure the effect of an iPad-based asynchronous curriculum on emergency medicine resident performance on the in training exam (ITE). We hypothesized that the implementation of an asynchronous curriculum (replacing 1 hour of weekly didactic time) would result in non inferior ITE scores compared to the historical scores of residents who had participated in the traditional 5-hour weekly didactic curriculum. METHODS: The study was a retrospective, non-inferiority study. conducted at the University of California, Irvine Emergency Medicine Residency Program. We compared ITE scores from 2012 and 2013, when there were 5 weekly hours of didactic content, with scores from 2014 and 2015, when 1 hour of conference was replaced with asynchro nous content. Examination results were compared using a non-inferiority data analysis with a 10% margin of difference. RESULTS: Using a non-inferiority test with a 95% confidence interval, there was no difference between the 2 groups (before and after implementation of asynchronous learning), as the confidence interval for the change of the ITE was -3.5 to 2.3 points, whereas the 10% non inferiority margin was 7.8 points. CONCLUSION: Replacing 1 hour of didactic conference with asynchronous learning showed no negative impact on resident ITE scores. PMID- 29237249 TI - REDUCING THE POTENTIAL NEGATIVE IMPACT OF CHRONIC LIFE STRESS ON WOMEN'S HEALTH AND WELLBEING. AB - Exposure to chronic stressors can negatively impact women's health. Data amassed over several decades has linked chronic stress with a number of health problems including mental health issues (Turner and Lloyd, 2004), somatic complaints, increased chronic disease risk (for example, diabetes and cardiovascular disease) and premature mortality (Cohen et al. 2009; Juster et al. 2010). PMID- 29237250 TI - FERTILITY--AWARENESS KNOWLEDGE, ATTITUDES, AND PRACTICES OF WOMEN ATTENDING GENERAL PRACTICE. AB - Infertility (the failure to conceive after 12 months of trying) affects one in six Australian couples. Infertile couples are increasingly being referred from general practice for assisted reproductive technology (ART) treatment. However, ART treatment is costly, highly invasive and associated with increases in morbidity and mortality for mothers and babies (Kamphuis et al. 2014). PMID- 29237251 TI - EXPERT ADVICE AND PEACE OF MIND IS JUST A CALL AWAY. AB - A team of specialized RDNS nurses are providing tailored advice and peace of mind for thousands of people around Australia who have recently become or about to become mums and dads. PMID- 29237252 TI - Usefulness of valacyclovir prophylaxis for cytomegalovirus infection after anti thymocyte globulin as rejection therapy. AB - Background/Aims: Anti-thymocyte globulin (ATG) treatment for acute T-cell mediated rejection (TCMR) can increase the risk of cytomegalovirus (CMV) infection. We aimed to evaluate the effect of valacyclovir prophylaxis against CMV infection after ATG administration as anti-rejection therapy. Methods: We retrospectively analyzed 55 kidney transplant recipients (KTRs) receiving ATG for steroid resistant TCMR. In all KTRs, we used intravenous ganciclovir during ATG injection. In 34 KTRs treated before July 2013, we performed preemptive therapy for CMV infection after ATG therapy. They were regarded as the historic control group (CONT). After July 2013, we used valacyclovir maintenance for 1 month after ATG therapy in 21 patients (VAL). The primary outcome was the incidence of CMV infection, and the secondary outcomes were subsequent acute rejection, and graft and patient outcome. Results: Valacyclovir prophylaxis significantly reduced the incidence of CMV infection (VAL, 9.6% vs. CONT, 67.6%; p < 0.001), and CMV-free survival rate was higher in the VAL group compared to the CONT group (p = 0.009). In the VAL group, two cases of CMV infection were limited to CMV viremia, but CMV disease or syndrome (n = 3) was detected in the CONT group. There was no difference in graft failure (CONT, 70.5% vs. VAL, 47.6%; p = 0.152), incidence of subsequent rejection after ATG treatment (CONT, 41.1% vs. VAL, 33.3%; p = 0.776), and graft or patient survival between the two groups. There were no major adverse events associated with valacyclovir prophylaxis. Conclusions: In conclusion, valacyclovir prophylaxis is effective in the prevention of CMV infection after ATG treatment for steroid resistant TCMR. PMID- 29237253 TI - Combination of carboplatin and intermittent normobaric hyperoxia synergistically suppresses benzo[a]pyrene-induced lung cancer. AB - BACKGROUND/AIMS: We explored the effects of intermittent normobaric hyperoxia alone or combined with chemotherapy on the growth, general morphology, oxidative stress, and apoptosis of benzo[a]pyrene (B[a]P)-induced lung tumors in mice. METHODS: Female A/J mice were given a single dose of B[a]P and randomized into four groups: control, carboplatin (50 mg/kg intraperitoneally), hyperoxia (95% fraction of inspired oxygen), and carboplatin and hyperoxia. Normobaric hyperoxia (95%) was applied for 3 hours each day from weeks 21 to 28. Tumor load was determined as the average total tumor numbers and volumes. Several markers of oxidative stress and apoptosis were evaluated. RESULTS: Intermittent normobaric hyperoxia combined with chemotherapy reduced the tumor number by 59% and the load by 72% compared with the control B[a]P group. Intermittent normobaric hyperoxia, either alone or combined with chemotherapy, decreased the levels of superoxide dismutase and glutathione and increased the levels of catalase and 8 hydroxydeoxyguanosine. The Bax/Bcl-2 mRNA ratio, caspase 3 level, and number of transferase-mediated dUTP nick end-labeling positive cells increased following treatment with hyperoxia with or without chemotherapy. CONCLUSIONS: Intermittent normobaric hyperoxia was found to be tumoricidal and thus may serve as an adjuvant therapy for lung cancer. Oxidative stress and its effects on DNA are increased following exposure to hyperoxia and even more with chemotherapy, and this may lead to apoptosis of lung tumors. PMID- 29237255 TI - An empirical approach to assessing training needs for emergency department management of intentional self-harm and related behaviors in the United States. PMID- 29237254 TI - The Impact of Skin Problems on the Quality of Life in Patients Treated with Anticancer Agents: A Cross-Sectional Study. AB - PURPOSE: Patients treated with anticancer agents often experience a variety of treatment-related skin problems, which can impair their quality of life. Materials and Methods: In this cross-sectional study, Dermatology Life Quality Index (DLQI) and clinical information were evaluated in patients under active anticancer treatment using a questionnaire survey and their medical records review. RESULTS: Of 375 evaluated subjects with anticancer therapy, 136 (36.27%) and 114 (30.40%) were treated for breast cancer and colorectal cancer, respectively. We found that women, breast cancer, targeted agent use, and longer duration of anticancer therapy were associated with higher dermatology-specific quality of life distraction. In addition, itching, dry skin, easy bruising, pigmentation, papulopustules on face, periungual inflammation, nail changes, and palmoplantar lesions were associated with significantly higher DLQI scores. Periungual inflammation and palmoplantar lesions scored the highest DLQI. CONCLUSION: We believe our findings can be helpful to clinicians in counseling and managing the patients undergoing anticancer therapy. PMID- 29237256 TI - MicroRNA-206 Protects against Myocardial Ischaemia-Reperfusion Injury in Rats by Targeting Gadd45beta. AB - MicroRNAs are widely involved in the pathogenesis of cardiovascular diseases through regulating gene expression via translational inhibition or degradation of their target mRNAs. Recent studies have indicated a critical role of microRNA-206 in myocardial ischaemia-reperfusion (I/R) injury. However, the function of miR 206 in myocardial I/R injury is currently unclear. The present study was aimed to identify the specific role of miR-206 in myocardial I/R injury and explore the underlying molecular mechanism. Our results revealed that the expression level of miR-206 was significantly decreased both in rat I/R group and H9c2 cells subjected to hypoxia/reoxygenation (H/R) compared with the corresponding control. Overexpression of miR-206 observably decreased infarct size and inhibited the cardiomyocyte apoptosis induced by I/R injury. Furthermore, bioinformatics analysis, luciferase activity and western blot assay proved that Gadd45beta (growth arrest DNA damage-inducible gene 45beta) was a direct target gene of miR 206. In addition, the expression of pro-apoptotic-related genes, such as p53, Bax and cleaved caspase3, was decreased in association with the down-regulation of Gadd45beta. In summary, this study demonstrates that miR-206 could protect against myocardial I/R injury by targeting Gadd45beta. PMID- 29237257 TI - Iron Homeostasis Controls Myeloid Blood Cell Differentiation in Drosophila. AB - Iron is an essential divalent ion for aerobic life. Life has evolved to maintain iron homeostasis for normal cellular and physiological functions and therefore imbalances in iron levels exert a wide range of consequences. Responses to iron dysregulation in blood development, however, remain elusive. Here, we found that iron homeostasis is critical for differentiation of Drosophila blood cells in the larval hematopoietic organ, called the lymph gland. Supplementation of an iron chelator, bathophenanthroline disulfate (BPS) results in an excessive differentiation of the crystal cell in the lymph gland. This phenotype is recapitulated by loss of Fer1HCH in the intestine, indicating that reduced levels of systemic iron enhances crystal cell differentiation. Detailed analysis of Fer1HCH-tagged-GFP revealed that Fer1HCH is also expressed in the hematopoietic systems. Lastly, blocking Fer1HCH expression in the mature blood cells showed marked increase in the blood differentiation of both crystal cells and plasmatocytes. Thus, our work suggests a relevance of systemic and local iron homeostasis in blood differentiation, prompting further investigation of molecular mechanisms underlying iron regulation and cell fate determination in the hematopoietic system. PMID- 29237258 TI - Diagnosis and management of moderate to severe adult atopic dermatitis: a Consensus by the Italian Society of Dermatology and Venereology (SIDeMaST), the Italian Association of Hospital Dermatologists (ADOI), the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC), and the Italian Society of Allergological, Environmental and Occupational Dermatology (SIDAPA). AB - Atopic dermatitis (AD) is a chronic immune-mediated inflammatory skin disease, currently recognized as a systemic disease possibly burdened by various comorbidities, including, but not limited to, other allergic conditions. Management guidelines issued by American and European dermatology and allergy scientific societies are available. However, some discrepancies exist in these guidelines, and some aspects of the management process, including diagnosis and severity assessment, as well as therapy duration and switch criteria, are not fully clarified by existing guidelines. Moreover, biologics such as dupilumab have now entered the therapeutic scenario of moderate-to-severe AD, offering a great opportunity to treat effectively and safely in need AD patients. For all these reasons, four Italian dermatology and allergy scientific societies joined to provide practical guidance for the management of moderate-to-severe adult AD suitable for the Italian clinical practice. Through a modified Delphi procedure, consensus was reached by 63 Italian dermatologists and allergists experienced in the management of adult AD on 14 statements covering five AD areas of interest, i.e. diagnosis, severity definition, current systemic therapies, eligibility criteria to biologic treatments, and comorbidities, with the aim to define treatment goals and improve adult AD management. The potential usefulness of a multidisciplinary approach is also underlined, given the complexity of AD and its comorbidities. PMID- 29237259 TI - Immunochemical Analysis of Paxilline and Ergot Alkaloid Mycotoxins in Grass Seeds and Plants. AB - Limited availability of toxin standards for lolitrem B and ergovaline impedes routine control of grasses for endophyte toxins. This study aimed at assessing the applicability of an enzyme immunoassay (EIA) for the indole-diterpene mycotoxin paxilline, in combination with a generic EIA for ergot alkaloids, as alternative parameters for screening purposes. Analysis of grass seeds and model pastures of four different grass species showed that both EIAs yielded highly positive results for paxilline and ergot alkaloids in perennial ryegrass seeds. Furthermore, evidence for natural occurrence of paxilline in grass in Germany was obtained. High performance liquid chromatography-tandem mass spectrometry analysis qualitatively confirmed the paxilline EIA results but showed that paxilline analogues 1'-O-acetylpaxilline and 13-desoxypaxilline were the predominant compounds in seeds and grass. In the absence of easily accessible reference standards for specific analysis of some major endophyte toxins, analysis of paxilline and ergot alkaloids by EIA may be suitable substitute parameters. The major advantage of this approach is its ease of use and speed, providing an analytical tool which could enhance routine screening for endophyte toxins in pasture. PMID- 29237260 TI - Explaining the Transition from Diffusion Limited to Reaction Limited Surface Assembly of Molecular Species through Spatial Variations. AB - Surface assembly is often decomposed into two classes: diffusion and reaction limited processes. The transition between the two cases is complex because the dynamics are so different. In this article, we simulate, explain, and experimentally discuss the evolution of the spatial distribution for surface assemblies with diffusion limited and reaction limited processes. Explicitly, we demonstrate that diffusion limited and reaction limited processes show some temporal differences, but more importantly, we show that the spatial arrangements are different enough to discriminate between the two cases. Using fundamental properties, such as the diffusion constant, we calculate the evolution of the spatial profile and derive from physical, heuristic models the assembly rate for reaction and diffusion limited processes based on the individual particle's interactions with the surface. Finally, we confirm the spatial profile differences between diffusion and reaction limited cases by experimentally measuring the surface assembly between two molecules of similar size, but having different assembly routes. Unique to our description is that we have derived and simulated everything through the particle picture in place of ensemble descriptions such as the diffusion equation, and we show the equivalence between our heuristic formulas and those derived from the diffusion equation. PMID- 29237261 TI - A Numerical Study on the Effect of Particle Surface Coverage on the Quartz Crystal Microbalance Response. AB - The quartz crystal microbalance (QCM) is a surface-sensitive measurement technique to characterize adsorption processes at solid-fluid interfaces. While QCM measurements are routinely applied to study homogeneous thin films, characterizing heterogeneous films of adsorbed particles remains challenging because QCM is sensitive to not only the mass of adsorbed particles but also to that of hydrodynamically coupled fluid. To extract information about adsorbed particles, it is necessary to model these hydrodynamic effects, however, current QCM models are restricted to the limit of either a very low surface coverage or to the extrapolated limit of saturation coverage. Herein, we investigated QCM measurement responses in the intermediate surface coverage regime, by conducting lattice Boltzmann simulations of monodisperse, spherical particles that are attached to an oscillating surface. From the simulations, we relate the overtone dependent QCM frequency and bandwidth shifts to particle size, interparticle distance, and the relevant hydrodynamic length scale. The corresponding results are in qualitative agreement with experimental QCM data for sub-100 nm, gel-phase liposomes. Furthermore, the data provide a theoretical basis for extracting particle sizes from QCM data in the high surface coverage limit. PMID- 29237262 TI - Attogram "Meth" Detection Enabled by Selective Organic Crystal Disaggregation via Directed Crystal Level Interactions. AB - In this contribution, completely different from traditional probes based on molecular host-guest interaction, crystal level interaction was proposed as an ultrasensitive design strategy for molecule detection. In such a strategy, crystal-guest interaction triggered rapid crystal disaggregation to gain great signal change, far more efficient than molecule scale coupling. Highly ordered pyrene methanol (PM) crystal was self-assembled with hydrogen bond chain and pi pi stacking force. Its {011} surface can be destabilized by methamphetamine hydrochlorate (MA, heavily used illicit drug) selectively and efficiently. The detection limit was improved to an amazing attogram level (5.4 ag/mL, 29.1 fM), 9 orders of magnitude lower than the best reported host-guest result. PMID- 29237263 TI - pH/Reduction Dual-Responsive Oxidized Alginate-Doxorubicin (mPEG-OAL-DOX/Cys) Prodrug Nanohydrogels: Effect of Complexation with Cyclodextrins. AB - Novel biocompatible and biodegradable pH/reduction dual-responsive oxidized alginate-doxorubicin (mPEG-OAL-DOX/Cys) prodrug nanohydrogels were designed for tumor-specific intracellular triggered release of anticancer drug DOX by conjugating DOX via acid-labile Schiff base linkage into the PEGylated oxidized alginate (mPEG-OAL) cross-linked with bioreducible disulfide bond. The effect of the complexation with cyclodextrins (alpha-CD and beta-CD) before or after the cross-linking of the mPEG-OAL on the DOX content and controlled release performance was investigated. It was found that the cyclodextrin inclusion complex prodrug nanohydrogels mPEG(CD)-OAL-DOX/Cys, prepared by cross-linking of the mPEG-OAL after complexation with cyclodextrins, exhibited better pH/reduction dual-responsive controlled release performance than the mPEG-OAL-DOX/Cys(CD) ones prepared by cross-linking of the mPEG-OAL before complexation with cyclodextrins, owing to the supramolecular cross-linking of the adjacent pseudopolyrotaxanes. Especially for the cyclodextrin inclusion complex prodrug nanohydrogels mPEG(alpha-CD)-OAL-DOX/Cys, DOX was released rapidly under lower pH media mimicking the tumor microenvironment and completely released within 48 h, while the premature leakage under the simulated physiological condition was ~40%, without burst release in both cases. The cellular toxicity and uptake results demonstrated that the mPEG(alpha-CD)-OAL-DOX/Cys prodrug nanohydrogels possessed similar inhibition against cancer cell growth in comparison with the free DOX and enhanced drug intracellular accumulation. PMID- 29237264 TI - Dual-Ratiometric Target-Triggered Fluorescent Probe for Simultaneous Quantitative Visualization of Tumor Microenvironment Protease Activity and pH in Vivo. AB - The abnormal expression of tumor-associated proteases and lowered extracellular pH are important signatures strongly associated with cancer invasion, progression, and metastasis. However, their malignant effects were mainly identified using cell and tissue studies. To noninvasively visualize the heterogeneous distribution of these abnormal indicators in vivo and further disclose their collective behaviors, a target-triggered fluorescent nanoprobe composed of a ratiometric pH-sensitive dye, a near-infrared dye (Cy5.5), and biocompatible Fe3O4 nanoparticles was constructed. The pH-sensitive dye was linked through a peptide substrate of matrix metalloprotease-9 (MMP-9) with Fe3O4 nanoparticles to establish a Forster resonance energy transfer (FRET) system for sensing the pH of the tumor microenvironment. Cy5.5 served as an internal reference for forming a secondary ratiometric fluorescent system together with the activated pH dye to enable the visualization of protease activities in vivo. Extensive imaging studies using a mouse model of human colon cancer revealed that the overexpression of MMP-9 and abnormal microenvironmental pH quantitatively visualized by this dual-ratiometric probe are spatially heterogeneous and synergistically guide the tumor invasion in vivo. PMID- 29237265 TI - Differentiation between Flavors of Sweet Orange (Citrus sinensis) and Mandarin (Citrus reticulata). AB - Pioneering investigations referring to citrus flavor have been intensively conducted. However, the characteristic flavor difference between sweet orange and mandarin has not been defined. In this study, sensory analysis illustrated the crucial role of aroma in the differentiation between orange flavor and mandarin flavor. To study aroma, Valencia orange and LB8-9 mandarin were used. Their most aroma-active compounds were preliminarily identified by aroma extract dilution analysis (AEDA). Quantitation of key volatiles followed by calculation of odor activity values (OAVs) further detected potent components (OAV >= 1) impacting the overall aromatic profile of orange/mandarin. Follow-up aroma profile analysis revealed that ethyl butanoate, ethyl 2-methylbutanoate, octanal, decanal, and acetaldehyde were essential for orange-like aroma, whereas linalool, octanal, alpha-pinene, limonene, and (E,E)-2,4-decadienal were considered key components for mandarin-like aroma. Furthermore, an unreleased mandarin hybrid producing fruit with orange-like flavor was used to validate the identification of characteristic volatiles in orange-like aroma. PMID- 29237266 TI - MnO2 Nanosheet-Carbon Dots Sensing Platform for Sensitive Detection of Organophosphorus Pesticides. AB - Carbon dots (CDs) combined with a nanomaterial-based quencher has created an innovative way for designing promising sensors. Herein, a novel fluorescent sensing platform was designed for sensitive detection of organophosphorus pesticides (OPs). The preparation of CDs was based on one-step hydrothermal reaction of 3-aminobenzeneboronic acid. The fluorescence of CDs can be quenched by manganese dioxide (MnO2) nanosheets via the Forster resonance energy transfer (FRET). In the presence of butyrylcholinesterase (BChE) and acetylthiocholine, the enzymatic hydrolysate (thiocholine) can efficiently trigger the decomposition of MnO2 nanosheets, resulting in the recovery of CDs fluorescence. OPs as inhibitors for BChE activity can prevent the generation of thiocholine and decomposition of MnO2 nanosheets, accompanying the fluorescence "turn-off" of the system. So the BChE-ATCh-MnO2-CDs system can be utilized to detect OPs quantitatively based on the fluorescence turn "on-off". Under the optimum conditions, the present FRET-based approach can detect paraoxon ranging from 0.05 to 5 ng mL-1 with a detection limit of 0.015 ng mL-1. Meanwhile, the present strategy also showed a visual color change in a concentration-dependent manner. Thus, the proposed assay can potentially be a candidate for OPs detection. PMID- 29237267 TI - Unsaturated Squalene Content in Emulsion Vaccine Adjuvants Plays a Crucial Role in ROS-Mediated Antigen Uptake and Cellular Immunity. AB - Emulsion-based adjuvants have been demonstrated to be an effective tool in increasing vaccine efficacy. Here, we aimed to launch a mechanistic study on how emulsion adjuvants interact with immune cells and to elucidate the roles of the core oil in vaccine immunogenicity. Our results showed that treatment of dendritic cells (DCs) and splenocytes with a squalene-based emulsion (referred as SqE) induced reactive oxidative species (ROS) production and resulted in an increase in apoptotic and necrotic cells in a concentration- and time-dependent manner. Furthermore, DCs cocultured with cellular debris of SqE-pretreated splenocytes resulted in a higher level of ovalbumin (OVA) antigen uptake by DCs than those cocultured with untreated splenocytes. Interestingly, the potency was rather attenuated when splenocytes were pretreated with N-acetyl-cysteine, an antioxidant. Notably, SqE possesses a high impact on eliciting ROS-mediated antigen uptake compared with a squalane-based emulsion (SqA). Concordantly, immunogenicity studies have shown that SqE is better able than SqA to activate antigen-presenting cells, and to enhance antigen-specific T-cell immunity. Taken together, our results show that unsaturated squalene oil cored within emulsions plays a crucial role in ROS-mediated antigen uptake and cellular immunity, providing a basis for the design and development of vaccine adjuvant. PMID- 29237268 TI - Sesquiterpenoids from the Root of Panax ginseng Attenuates Lipopolysaccharide Induced Depressive-Like Behavior through the Brain-Derived Neurotrophic Factor/Tropomyosin-Related Kinase B and Sirtuin Type 1/Nuclear Factor-kappaB Signaling Pathways. AB - The previous study indicated sesquiterpenoids from the root of Panax ginseng (SPG) exhibited a significant antidepressant-like effect, which might be mediated by the modification of the dopaminergic, GABAergic, and glutamatergic systems. This study was to investigate antidepressant effects and mechanisms on the lipopolysaccharide (LPS)-induced depression-like behavior of SPG. In the tail suspension test (TST) and forced swimming test (FST), SPG (0.25 and 1 mg/kg, i.g.) and fluoxetine (20 mg/kg, i.p.) effectively reduced the immobility time. SPG treatment significantly reduced serum levels of IL-6 and TNF-alpha and increased suppressed superoxide dismutase (SOD) activity in the hippocampus. In addition, SPG effectively upregulated the brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), and sirtuin type 1 (Sirt 1) expression in the hippocampus and downregulated the inhibitor of kappaB-alpha (IkappaB-alpha) and nuclear factor-kappaB (NF-kappaB) phosphorylation. These results suggested that SPG exhibited an antidepressant-like effect through the BDNF/TrkB and Sirt 1/NF-kappaB signaling pathways. PMID- 29237269 TI - Visualizing the Regulation of Hydroxyl Radical Level by Superoxide Dismutase via a Specific Molecular Probe. AB - Hydroxyl radical (.OH), as the most deleterious reactive oxygen species, is believed to be the etiological agent for many diseases and aging. An altered .OH level has been confirmed in certain types of superoxide dismutase (SOD) mutation, but the regulation of .OH by SOD in situ is still controversial or unclear because of the lack of effective tools to detect .OH in the biological environment. Herein we report the first two-photon excitable molecular probe (P2) for .OH, which is able to track the subtle fluctuation of .OH level both in vitro and in vivo with high sensitivity and specificity. The probe was successfully applied to visualize .OH variations in a variety of SOD1-involved biological processes, confirming that the inhibited enzymatic activity and down-regulated expression of SOD1 both lead to elevated intracellular .OH level. This is the first report to visually reveal the relationship between SOD1 and .OH level with a molecular tool. PMID- 29237270 TI - Manganese(V) Porphycene Complex Responsible for Inert C-H Bond Hydroxylation in a Myoglobin Matrix. AB - A mechanistic study of H2O2-dependent C-H bond hydroxylation by myoglobin reconstituted with a manganese porphycene was carried out. The X-ray crystal structure of the reconstituted protein obtained at 1.5 A resolution reveals tight incorporation of the complex into the myoglobin matrix at pH 8.5, the optimized pH value for the highest turnover number of hydroxylation of ethylbenzene. The protein generates a spectroscopically detectable two-electron oxidative intermediate in a reaction with peracid, which has a half-life up to 38 s at 10 degrees C. Electron paramagnetic resonance spectra of the intermediate with perpendicular and parallel modes are silent, indicating formation of a low-spin MnV-oxo species. In addition, the MnV-oxo species is capable of promoting the hydroxylation of sodium 4-ethylbenzenesulfonate under single turnover conditions with an apparent second-order rate constant of 2.0 M-1 s-1 at 25 degrees C. Furthermore, the higher bond dissociation enthalpy of the substrate decreases the rate constant, in support of the proposal that the H-abstraction is one of the rate-limiting steps. The present engineered myoglobin serves as an artificial metalloenzyme for inert C-H bond activation via a high-valent metal species similar to the species employed by native monooxygenases such as cytochrome P450. PMID- 29237271 TI - Suvorexant for the treatment of insomnia in patients with Alzheimer's disease. PMID- 29237272 TI - Bioactive Lipids and Redox Signaling: Molecular Mechanism and Disease Pathogenesis. AB - The actions of bioactive lipids and reactive oxygen species (ROS) are usually coupled, and their interplay is a common and important mechanism mediating tissue injury, inflammation, and other pathologies. Understanding the interplay of ROS and lipid mediators will extend horizons for researchers to clarify the pathogenesis of different diseases and help identify therapeutic targets for treatment of these diseases. Some bioactive lipids are converted into oxidized lipids during cell or tissue oxidative stress such as isoprostanes and isoketals, which are even more bioactive than their precursors. Moreover, many enzymes that produce lipid mediators such as prostaglandin H synthases, lipoxygenases, and cytochrome P450 isoforms may catalyze the production of ROS. Bioactive lipids lysophospholipids, sphingolipids, or deposited lipids in cells-are shown to stimulate redox enzymes to produce ROS. In addition, a lipid-channel-ROS axis in different organelles may be associated with the crosstalk of ROS and bioactive lipids. This Forum focuses on the crosstalk of ROS with sphingolipids, P450 eicosanoids, lysophospholipids, and deposited plasma lipids and related novel signaling pathway in their reciprocal actions, which is expected to provide novel insights into the pathogenesis of different diseases associated with the participation of these lipid mediators. It is imperative to further understand the molecular mechanism mediating the crosstalk of ROS with specific lipid mediators and to develop more effective therapeutic strategies to target the interplay of ROS and lipid mediators for treatment specific to different organ diseases. Antioxid. Redox Signal. 00, 000-000. PMID- 29237274 TI - Peroxiredoxin Involvement in the Initiation and Progression of Human Cancer. AB - SIGNIFICANCE: It has been proposed that cancer cells are heavily dependent on their antioxidant defenses for survival and growth. Peroxiredoxins are a family of abundant thiol-dependent peroxidases that break down hydrogen peroxide, and they have a central role in the maintenance and response of cells to alterations in redox homeostasis. As such, they are potential targets for disrupting tumor growth. Recent Advances: Genetic disruption of peroxiredoxin expression in mice leads to an increased incidence of neoplastic disease, consistent with a role for peroxiredoxins in protecting genomic integrity. In contrast, many human tumors display increased levels of peroxiredoxin expression, suggesting that strengthened antioxidant defenses provide a survival advantage for tumor progression. Peroxiredoxin inhibitors are being developed and explored as therapeutic agents in different cancer models. CRITICAL ISSUES: It is important to complement peroxiredoxin knockout and expression studies with an improved understanding of the biological function of the peroxiredoxins. Although current results can be interpreted within the context that peroxiredoxins scavenge hydroperoxides, some peroxiredoxin family members appear to have more complex roles in regulating the response of cells to oxidative stress through protein interactions with constituents of other signaling pathways. FUTURE DIRECTIONS: Further mechanistic information is required for understanding the role of oxidative stress in cancer, the function of peroxiredoxins in normal versus cancer cells, and for the design and testing of specific peroxiredoxin inhibitors that display selectivity to malignant cells. Antioxid. Redox Signal. 28, 591-608. PMID- 29237275 TI - An exploratory longitudinal study of social and language outcomes in children with autism in bilingual home environments. AB - Little is known about outcomes of early intervention for children with autism spectrum disorder reared in bilingual homes. There are concerns that social communication deficits among children with autism spectrum disorder may reduce the developmental benefits of early intervention for children with autism spectrum disorder raised in bilingual environments. We conducted an exploratory analysis of cross-sectional and longitudinal data from a larger study to explore associations between home language environment and language ability and social skills in response to early autism spectrum disorder intervention. Participants, aged 12-26 months when recruited, were a subset of a larger 2-year, randomized intervention trial (ClinicalTrials.gov identifier: NCT00698997). Children from bilingual homes ( n = 13) began intervention with lower gesture use but otherwise demonstrated equal baseline language and social abilities as compared with age and nonverbal IQ-matched children from monolingual homes ( n = 24). Significant language growth was exhibited by children from both language groups and there was no moderating effect of home language environment. The bilingual home group demonstrated increased gesture use over the course of intervention as compared with the monolingual home group. Preliminary data revealed no basis for concerns regarding negative impact of a bilingual home environment on language or social development in young children with autism spectrum disorder. PMID- 29237273 TI - A Novel Mechanism for Atherosclerotic Calcification: Potential Resolution of the Oxidation Paradox. AB - AIM: In this study, we tested the hypothesis that lipid peroxide-derived dicarboxylic acids (DCAs), by virtue of their ability to bind to calcium (Ca), might be involved in atherosclerotic calcification. We determined the ability of azelaic acid (AzA) to promote calcification in human aortic smooth muscle cells (HASMCs), identified AzA in human calcified atherosclerotic lesions, and compared its levels with control and noncalcified atherosclerotic lesions. RESULTS: HASMCs efficiently converted 9-oxononanoic acid (ONA), a lipid peroxide-derived monocarboxylic aldehyde, to AzA. In vitro incubations of AzA micelles with HASMC resulted in the formation of Ca deposits, which contained AzA. Liquid chromatography-mass spectrometry analysis of human control uninvolved artery, noncalcified, and calcified lesions showed significant increase of AzA in calcified lesions compared with noncalcified and control tissues. Calcified mouse atherosclerotic lesions also showed substantial presence of AzA in Ca complexes. INNOVATION: This study identifies a DCA, AzA, as an integral part of the Ca complex. The study also demonstrates the conversion of a lipid peroxidation product, ONA, as a potential source of AzA, and establishes the presence of AzA in calcified materials isolated from human and mouse lesions. CONCLUSION: The presence of AzA as a Ca sequestering agent in atherosclerotic lesions (i) might indicate participation of oxidized low-density lipoprotein (Ox-LDL) derived products in calcification, (ii) explain the potential correlation between calcification and overall plaque burden (as Ox-LDL has been suggested to be involved in atherogenesis), (iii) could contribute to plaque stabilization via its anti-inflammatory actions, and (iv) might explain why antioxidants failed to affect atherosclerosis in clinical studies. Antioxid. Redox Signal. 29, 471-483. PMID- 29237276 TI - Differential Effects of Left and Right Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation on Resting-State Functional Magnetic Resonance Imaging in Healthy Individuals. AB - High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has gained great interest in multiple clinical and research fields and is believed to accomplish its effect by influencing neuronal networks. The dorsolateral prefrontal cortex (dlPFC) is frequently chosen as the cortical target for HF rTMS. However, very little is known about the differential effect of HF-rTMS over the left and right dlPFC on intrinsic functional connectivity networks in patients or in healthy individuals. The current study assessed the differential effects of left or right HF-rTMS (corrected for sham) on intrinsic independent component analysis (ICA)-defined functional connectivity networks in a sample of 45 healthy individuals. All subjects had a first scanning session in which baseline functional connectivity was assessed. During the second session, individuals received one session of left, right, or sham dlPFC HF-rTMS (60 5-sec trains of 10 Hz at 110% motor threshold). The sham condition was used to correct for time and placebo effects. ICAs were performed to assess baseline differences and stimulation effects on within- and between-network functional connectivity. Stimulation of the left dlPFC resulted in decreased functional connectivity in the salience network, whereas right dlPFC stimulation resulted in increased functional connectivity within this network. No differences between left or right dlPFC stimulation were found in between-network connectivity. These results suggest that left and right HF-rTMS may have differential effects, and more research is needed on the clinical consequences. PMID- 29237277 TI - High Prevalence of Depression Diagnosis Among Medical Aid Beneficiaries: A Korean Health Insurance Database Study. AB - Little is known about the prevalence of depression diagnosis in Korea. We aimed to compare the prevalence of depression diagnosis between Medical Aid and health insurance beneficiaries in an outpatient setting in Korea. The data of patients who visited a medical institution for outpatient care in 2015 were extracted from the Health Insurance Review and Assessment Service National Patient Sample claims database, and those diagnosed with major depressive disorder, single episode (F32) or recurrent (F33), were identified. The adjusted odds ratio (aOR) and 95% confidence interval (CI) were estimated through logistic regression analyses. Among the outpatients, 2.51% were diagnosed with depression at least once. Medical Aid beneficiaries (aOR = 1.97; 95% CI = 1.96-1.98) were more likely to be diagnosed with depression than health insurance beneficiaries. PMID- 29237280 TI - Socioeconomic Determinants of the Utilization of Antenatal Care and Child Vaccination in India. AB - Antenatal care and child vaccination services are adopted worldwide to reduce the risk of child mortality, maternal mortality, and burden of infectious diseases. This article examines the effect of socioeconomic factors on the utilization of antenatal care and child vaccination services in India. The generalized linear model has been used along with the Indian National Family Health Survey data for the period 2005-2006. The analysis shows that the health insurance plan has a significant effect on the use of antenatal care but not in the child vaccination. Furthermore, there is inequality in the utilization of antenatal care as well as child vaccination services and it is positively related to the wealth. The study suggests that there is a need to improve the socioeconomic status of the financially weaker section of the society for improving the use of child and maternal care services. PMID- 29237281 TI - Reactive Oxygen Species, Photosynthesis, and Environment in the Regulation of Stomata. AB - SIGNIFICANCE: Stomata sense the intercellular carbon dioxide (CO2) concentration (Ci) and water availability under changing environmental conditions and adjust their apertures to maintain optimal cellular conditions for photosynthesis. Stomatal movements are regulated by a complex network of signaling cascades where reactive oxygen species (ROS) play a key role as signaling molecules. Recent Advances: Recent research has uncovered several new signaling components involved in CO2- and abscisic acid-triggered guard cell signaling pathways. In addition, we are beginning to understand the complex interactions between different signaling pathways. CRITICAL ISSUES: Plants close their stomata in reaction to stress conditions, such as drought, and the subsequent decrease in Ci leads to ROS production through photorespiration and over-reduction of the chloroplast electron transport chain. This reduces plant growth and thus drought may cause severe yield losses for agriculture especially in arid areas. FUTURE DIRECTIONS: The focus of future research should be drawn toward understanding the interplay between various signaling pathways and how ROS, redox, and hormonal balance changes in space and time. Translating this knowledge from model species to crop plants will help in the development of new drought-resistant crop species with high yields. Antioxid. Redox Signal. 00, 000-000. PMID- 29237282 TI - Modulation of salience network intranetwork resting state functional connectivity in women with chronic migraine. AB - Objective To investigate the intranetwork resting state fMRI connectivity within the Salience Network of chronic migraine with and without medication overuse headache. Methods We compared 351 pairs of intranetwork connectivity in chronic migraine (n = 13) and chronic migraine with medication overuse headache (n = 16) compared to matched controls, and between each chronic migraine subgroup. Results Compared to controls, 17 pairs of intranetwork connections in chronic migraine and 27 pairs in chronic migraine with medication overuse headache were decreased. When comparing chronic migraine with medication overuse headache versus chronic migraine, connectivity between bilateral extended amygdala, and between paracingulate to right ventral tegmental area/substantia nigra were decreased in chronic migraine (chronic migraine < chronic migraine with medication overuse headache). Connectivity between left dorsolateral prefrontal cortex to bilateral ventral striatum/pallidum, to bilateral dorsal anterior cingulate cortex; left anterior prefrontal cortex to contralateral orbitofrontal insula; and left ventral striatum/pallidum to ipsilateral supplementary motor area (SMA)/preSMA were decreased in chronic migraine with medication overuse headache (chronic migraine with medication overuse headache < chronic migraine). Conclusion Both chronic migraine subgroups had shared intranetwork connectivity abnormality, however, each subgroup had unique pattern of disruption within the salience network. The results suggest that the aberrant assignment of salience to external and internal stimuli plays an important role in chronic migraine and chronic migraine with medication overuse headache interictally, mostly involving mesolimbic pathways (especially bilateral extended amygdala) in chronic migraine, and prefrontal-subcortical limbic pathways in chronic migraine with medication overuse headache. PMID- 29237283 TI - Ghrelin attenuated hyperalgesia induced by chronic nitroglycerin: CGRP and TRPV1 as targets for migraine management. AB - Background According to the neurovascular theory of migraine, activation of the trigeminovascular system contributes to the development of migraine. This study examined the effects of chronic intraperitoneal ghrelin (150 ug/kg) treatment on the development of chronic migraine induced by intermittent injection of nitroglycerin 10 mg/kg. Methods Baseline and post-drug (2 h following nitroglycerin injection) mechanical and thermal sensitivity were assessed by von Frey hair and tail immersion tests, respectively on days 1, 3, 5, 7, 9 and 11. Moreover, we investigated the effect of ghrelin treatment on nitroglycerin induced aversive behavior by using a two-chamber conditioned place aversion paradigm. At the end of behavioral testing, on day 11, animals were sacrificed and plasma concentration of calcitonin gene-related peptide was measured using a rat-specific enzyme-linked immunosorbent assay kit. Also, real time polymerase chain reaction was used to quantify mRNA expression of calcitonin gene-related peptide and transient receptor potential vanilloid 1 in the trigeminal ganglion. Results Our results indicated that nitroglycerin activated the trigeminovascular system, which was reflected by mechanical and thermal hypersensitivity and elevation of mRNA expression of calcitonin gene-related peptide and transient receptor potential vanilloid-1, as migraine markers, and plasma calcitonin gene related peptide levels. Moreover, chronic nitroglycerin injection induced conditioned place aversion and body weight loss. Nevertheless, ghrelin modulated nitroglycerin-triggered changes in transient receptor potential vanilloid-1 and calcitonin gene-related peptide expression, and mitigated nitroglycerin-induced hyperalgesia. Conclusion These results provide the first convincing evidence that ghrelin has a modulating effect on central sensitization induced by chronic intermittent nitroglycerin, and its antinociceptive effect may be related to a reduction of these factors in the trigeminal ganglion. PMID- 29237284 TI - Pain worsening with physical activity during migraine attacks in women with overweight/obesity: A prospective evaluation of frequency, consistency, and correlates. AB - Background Migraine is a neurological disease involving recurrent attacks of moderate-to-severe and disabling head pain. Worsening of pain with routine physical activity during attacks is a principal migraine symptom; however, the frequency, individual consistency, and correlates of this symptom are unknown. Given the potential of this symptom to undermine participation in daily physical activity, an effective migraine prevention strategy, further research is warranted. This study is the first to prospectively evaluate (a) frequency and individual consistency of physical activity-related pain worsening during migraine attacks, and (b) potential correlates, including other migraine symptoms, anthropometric characteristics, psychological symptoms, and daily physical activity. Methods Participants were women (n = 132) aged 18-50 years with neurologist-confirmed migraine and overweight/obesity seeking weight loss treatment in the Women's Health and Migraine trial. At baseline, participants used a smartphone diary to record migraine attack occurrence, severity, and symptoms for 28 days. Participants also completed questionnaires and 7 days of objective physical activity monitoring before and after diary completion, respectively. Patterning of the effect of physical activity on pain was summarized within-subject by calculating the proportion (%) of attacks in which physical activity worsened, improved, or had no effect on pain. Results Participants reported 5.5 +/- 2.8 (mean +/- standard deviation) migraine attacks over 28 days. The intraclass correlation (coefficient = 0.71) indicated high consistency in participants' reports of activity-related pain worsening or not. On average, activity worsened pain in 34.8 +/- 35.6% of attacks, had no effect on pain in 61.8 +/- 34.6% of attacks and improved pain in 3.4 +/- 12.7% of attacks. Few participants (9.8%) reported activity-related pain worsening in all attacks. A higher percentage of attacks where physical activity worsened pain demonstrated small-sized correlations with more severe nausea, photophobia, phonophobia, and allodynia (r = 0.18 - 0.22, p < 0.05). Pain worsening due to physical activity was not related to psychological symptoms or total daily physical activity. Conclusions There is large variability in the effect of physical activity on pain during migraine attacks that can be accounted for by individual differences. For a minority of participants, physical activity consistently contributed to pain worsening. More frequent physical activity-related pain worsening was related to greater severity of other migraine symptoms and pain sensitivity, which supports the validity of this diagnostic feature. Study protocol ClinicalTrials.govIdentifier: NCT01197196. PMID- 29237285 TI - Inhibition of Diverse DsbA Enzymes in Multi-DsbA Encoding Pathogens. AB - AIMS: DsbA catalyzes disulfide bond formation in secreted and outer membrane proteins in bacteria. In pathogens, DsbA is a major facilitator of virulence constituting a target for antivirulence antimicrobial development. However, many pathogens encode multiple and diverse DsbA enzymes for virulence factor folding during infection. The aim of this study was to determine whether our recently identified inhibitors of Escherichia coli K-12 DsbA can inhibit the diverse DsbA enzymes found in two important human pathogens and attenuate their virulence. RESULTS: DsbA inhibitors from two chemical classes (phenylthiophene and phenoxyphenyl derivatives) inhibited the virulence of uropathogenic E. coli and Salmonella enterica serovar Typhimurium, encoding two and three diverse DsbA homologues, respectively. Inhibitors blocked the virulence of dsbA null mutants complemented with structurally diverse DsbL and SrgA, suggesting that they were not selective for prototypical DsbA. Structural characterization of DsbA inhibitor complexes showed that compounds from each class bind in a similar region of the hydrophobic groove adjacent to the Cys30-Pro31-His32-Cys33 (CPHC) active site. Modeling of DsbL- and SrgA-inhibitor interactions showed that these accessory enzymes could accommodate the inhibitors in their different hydrophobic grooves, supporting our in vivo findings. Further, we identified highly conserved residues surrounding the active site for 20 diverse bacterial DsbA enzymes, which could be exploited in developing inhibitors with a broad spectrum of activity. Innovation and Conclusion: We have developed tools to analyze the specificity of DsbA inhibitors in bacterial pathogens encoding multiple DsbA enzymes. This work demonstrates that DsbA inhibitors can be developed to target diverse homologues found in bacteria. Antioxid. Redox Signal. 29, 653-666. PMID- 29237286 TI - Redox-Sensing Under Hypochlorite Stress and Infection Conditions by the Rrf2 Family Repressor HypR in Staphylococcus aureus. AB - AIMS: Staphylococcus aureus is a major human pathogen and has to cope with reactive oxygen and chlorine species (ROS, RCS) during infections, which requires efficient protection mechanisms to avoid destruction. Here, we have investigated the changes in the RNA-seq transcriptome by the strong oxidant sodium hypochlorite (NaOCl) in S. aureus USA300 to identify novel redox-sensing mechanisms that provide protection under infection conditions. RESULTS: NaOCl stress caused an oxidative stress response in S. aureus as indicated by the induction of the PerR, QsrR, HrcA, and SigmaB regulons in the RNA-seq transcriptome. The hypR-merA (USA300HOU_0588-87) operon was most strongly upregulated under NaOCl stress, which encodes for the Rrf2-family regulator HypR and the pyridine nucleotide disulfide reductase MerA. We have characterized HypR as a novel redox-sensitive repressor that controls MerA expression and directly senses and responds to NaOCl and diamide stress via a thiol-based mechanism in S. aureus. Mutational analysis identified Cys33 and the conserved Cys99 as essential for NaOCl sensing, while Cys99 is also important for repressor activity of HypR in vivo. The redox-sensing mechanism of HypR involves Cys33-Cys99 intersubunit disulfide formation by NaOCl stress both in vitro and in vivo. Moreover, the HypR controlled flavin disulfide reductase MerA was shown to protect S. aureus against NaOCl stress and increased survival in J774A.1 macrophage infection assays. Conclusion and Innovation: Here, we identified a new member of the widespread Rrf2 family as redox sensor of NaOCl stress in S. aureus that uses a thiol/disulfide switch to regulate defense mechanisms against the oxidative burst under infections in S. aureus. Antioxid. Redox Signal. 29, 615-636. PMID- 29237287 TI - Early Sites of Virus Replication After Oral SIVmac251 Infection of Infant Macaques: Implications for Pathogenesis. AB - Despite optimization of preventative measures for vertical HIV-1 transmission, daily, roughly 400 infants become HIV infected, most of them through breastfeeding. Viral entry has been presumed to occur in the gastrointestinal tract; however, the exact entry site(s) have not been defined. Therefore, we quantified simian immunodeficiency virus (SIV) RNA and DNA in oral, intestinal, and systemic tissues of 15 infant macaques within 48-96 h after oral SIVmac251 exposure. SIV DNA was detected as early as 48 h, whereas SIV RNA was typically detected at later time points (72-96 h). Transmitted founder viruses were identical or very similar to a single genotype in the SIVmac251 challenge stock. SIV RNA and DNA were most frequently found in lymph nodes (LNs) draining the oral cavity and in the ileum. Using in situ hybridization, SIV-infected cells in LNs were exclusively represented by CD3+ T cells. SIV RNA and DNA were also detected in the lungs of 20% of the animals, and 60% of the animals had detectable SIV DNA in the cerebrum. The early detection of viral RNA or DNA in lung and brain tissues emphasizes the need for early treatment of pediatric HIV infection to prevent damage not only to the immune system but also to the respiratory tract and central nervous system. PMID- 29237288 TI - The Effect of Continuous Glucose Monitoring in Preventing Inpatient Hypoglycemia in General Wards: The Glucose Telemetry System. AB - BACKGROUND: Few studies have examined the use of continuous glucose monitoring (CGM) devices in the general wards. The aim of this pilot study was to examine whether CGM readings can be successfully transmitted from the bedside to a central monitoring device in the nursing station, and whether a glucose telemetry system can prevent hypoglycemic events. METHODS: We present pilot data on 5 consecutive insulin treated general medicine patients with type 2 diabetes (T2DM) whose glucose values were observed with CGM (DEXCOM) and the results were transmitted to a central nursing station monitoring system using DEXCOM Follow and Share 2 software. CGM alarms were set-up at glucose <85 mg/dl. RESULTS: Duration of CGM observation was 4.0 +/- 1.6 days (mean +/- SD). During CGM, the overall time spent within blood glucose (BG) target of 70-179 mg/dl was 64.68 +/- 15% (mean +/- SD), on hypoglycemia (<70 mg/dl) was 0.30% +/- 0.39, and time spent on hyperglycemia (>=180 mg/dl) was 35.02% +/- 15.5. Two patients had 3 actions of prevention of potential hypoglycemia (CGM BG <70 mg/dl for >20 minutes) captured by alarm. No patients had CGM glucose value <54 mg/dl. CONCLUSIONS: This pilot study indicates that the use of CGM values in hospitalized patients can be successfully transmitted to a monitoring device in the nursing station, improving patient surveillance in insulin treated patients with diabetes. PMID- 29237290 TI - Inhaled Insulin: Dead Horse or Rising Phoenix? PMID- 29237289 TI - Safely Converting an Entire Academic Medical Center From Sliding Scale to Basal Bolus Insulin via Implementation of the eGlycemic Management System. AB - OBJECTIVE: Hyperglycemia is common in the inpatient setting and providers frequently rely on sliding scale insulin. This case study reviews the experience of one hospital moving from high utilization of sliding scale to basal bolus insulin therapy. METHOD: This Retrospective Quality Improvement Study describes the journey of clinicians at a 580-bed hospital to convert from high usage of SSI to BBI. Hyperglycemic adult patients prescribed insulin, with/without a diagnosis of diabetes, were included. RESULTS: Data over the first year showed that patients treated with Glucommander (GM) spent more time in the target range of 70 180 mg/dL than patients treated with non-Glucommander (non-GM), with 2,434 fewer hypoglycemic events and 40,589 fewer hyperglycemic events. Prior to implementation of GM, SSI was close to 95%, BBI at 5%. Within the first month of use, 96% usage of BBI was achieved. Reduction of hypoglycemic events (% of BG < 70 mg/dL) by 21% with 2.16% non-GM compared to GM at 1.74% and severe Hypoglycemia (% of BG < 50 mg/dL) by 50% in the ICU 3% non-GM compared to GM at 1.5%. In addition, patients treated with GM had a shorter LOS than patients treated with non-GM by 3.18 days and used 47.4% less point of care tests per patient. CONCLUSION: Glycemic management improved with use of eGMS. The conversion from SSI to BBI enhanced overall patient safety, eliminated the time and effort otherwise required when manually titrating insulin and reduced overall cost of care for patients on insulin therapy. PMID- 29237291 TI - What Would Be Really Helpful but Nobody Ever Tells You: Five Key Recommendations Derived From Lessons Learned During a Qualitative Study in Clinical Settings. AB - The complexity of qualitative research can lead to a less thorough analysis than would be ideal. Even experienced researchers can become entwined in the myriad of decisions that must be made. Descriptions of qualitative approaches in numerous textbooks and published articles often lack sufficient details to help a researcher surface from the entanglements, especially when conducting studies in clinical settings. In this paper, we share our experiences of navigating some "real-world" issues in doing qualitative research. We describe five key, practical recommendations to assist researchers in preventing, or at least alleviating, some of the challenges that researchers may face, particularly ones that limit in-depth analysis: (1) conduct a pilot study, (2) hire a research analyst, (3) engage the "right" team, (4) attend to team cohesion, and (5) conduct conceptual analysis through a process of "node expansion." PMID- 29237292 TI - The main phytotoxic metabolite produced by a strain of Fusarium oxysporum inducing grapevine plant declining in Italy. AB - A strain of Fusarium oxysporum was isolated from grapevine showing heavy decline disease in a vineyard of Veneto region in Italy. The fungus showed to produce phytotoxic metabolites when grown in liquid culture. The main metabolite was identified as fusaric acid produced for the first time as a phytotoxin by a strain of F. oxysporom isolated from diseased grapevine plants. Its quantification in the fungus cultures filtrates was accomplished by HPLC. When tested on tobacco by leaf-puncture assay fusaric acid at 0.5 mg/mL induced the formation of extensive necrosis. PMID- 29237293 TI - CDH1 promoter methylation in patients with cervical carcinoma: a systematic meta analysis with trial sequential analysis. AB - AIM: This study was performed to evaluate the correlation between CDH1 promoter methylation and cervical cancer. METHODS: Trial sequential analysis was conducted to evaluate the required information size. RESULTS: A total of 15 studies with 950 cervical cancers and 829 controls were identified. CDH1 promoter methylation was higher in cervical cancer than in cervical intraepithelial neoplasia lesions and normal cervical tissues. Subgroup analysis of ethnicity showed that CDH1 promoter methylation correlated with cervical cancer in Caucasians, but not in Asians. CDH1 promoter methylation was higher in cervical cancer cytology samples than in normal cytology samples. It was higher in squamous cell carcinoma than adenocarcinoma, but was not correlated with tumor stage, grade and overall survival. CONCLUSION: CDH1 promoter methylation may be correlated with cervical cancer carcinogenesis, especially for Caucasians. It was associated with histological subtypes. Trial sequential analysis showed that more studies are needed. PMID- 29237294 TI - Mutagenicity evaluation of Anastatica hierochuntica L. aqueous extract in vitro and in vivo. AB - Anastatica hierochuntica L. ( A. hierochuntica), a folk medicinal plant, was evaluated for mutagenic potential via in vitro and in vivo assays. The in vitro assay was conducted according to modified Ames test, while the in vivo study was performed according to Organisation for Economic Co-operation and Development guideline for mammalian erythrocyte micronucleus assay. Four groups ( n= 5 males and 5 females per group) Sprague Dawley rats were randomly chosen as the negative control, positive control (received a single intramuscular injection of cyclophosphamide 50 mg/kg), 1000 and, 2000 mg/kg A. hierochuntica aqueous extracts. All groups except the positive control were treated orally for three days. Findings of the in vitro assay showed mutagenic potential of AHAE at 0.04 and 0.2 mg/ml. However, no mutagenic effect was demonstrated in the in vivo study up to 2000 mg/kg. No significant reduction in the polychromatic and normochromatic erythrocytes ratio was noted in any of the groups. Meanwhile, high micronucleated polychromatic erythrocytes frequency was seen in cyclophosphamide treated group only. These findings could perhaps be due to insufficient dosage of A. hierochuntica aqueous extracts to cause genetic damage on the bone marrow target cells. Further acute and chronic in vivo toxicity studies may be required to draw pertinent conclusion on the safety aspect of A. hierochuntica aqueous extracts consumption. Impact statement In this paper, we report on the mutagenicity evaluation of Anastatica hierochuntica aqueous extract. This is a significant research in view of the popularity of this herb consumption by the people across the globe despite of limited scientific evidence on its toxicity potential. This study is intended to encourage more extensive related research in order to provide sufficient evidence and guidance for determining its safe dosage. PMID- 29237295 TI - MicroRNA-16 inhibits hypoxia-induced vascular endothelial growth factor expression in ARPE-19 cells. AB - PURPOSE: To investigate the effect of microRNA-16 on hypoxia-induced VEGF expression of ARPE-19 cells. METHODS: ARPE-19 cells were cultivated under normoxia and hypoxia state. At 0 h, 12 h, 24 h, and 48 h after cultivation, the supernate of the culture medium was separated to test the VEGF secretion by ELISA, and the cells were purified to measure the expression of VEGF mRNA and microRNA-16 by qRT-PCR; microRNA-16 mimic was then transfected into ARPE-19 cells by the Hiperfect transfection reagent, a liposome transfection system. Scramble group and the non-transfected group were set as the controls. VEGF secretion and the level of VEGF mRNA were measured in these three groups. RESULTS: The VEGF secretion of the hypoxia ARPE cells was significantly higher than the initial state (p < 0.01). Compared with the normoxia cells, the VEGF secretion of the hypoxia cell was significantly increased (p < 0.01), and the division of VEGF secretion between these two groups increased by time. VEGF mRNA of the hypoxia ARPE cell was significantly higher than the initial state (p < 0.01). Compared with the normoxia cells, VEGF mRNA of the hypoxia cells was significantly increased (p < 0.01), and the division of VEGF mRNA between these two groups increased by time. After cultivating under hypoxia, the expression of microRNA-16 in ARPE-19 cells decreased significantly compared with the normal group, and the division of these two groups augmented by time. MicroRNA-16 was successfully transfected into ARPE-19 cells by the Hiperfect transfection system. Twenty four hours and 48 h after the transfection, the VEGF secretion of the miR-16 transfected cell was decreased significantly (p < 0.01) compared with the scramble and the non-transfected group under hypoxia, while VEGF mRNA level had no significant difference among these three groups. CONCLUSIONS: Hypoxia can increase the expression of VEGF mRNA and the secretion of VEGF protein of ARPE-19 cells. At the same time, microRNA-16 expression can be down-regulated by hypoxia. Transfection of microRNA-16 exogenously can down-regulate the VEGF protein secretion but cannot affect the expression of VEGF mRNA. PMID- 29237296 TI - Pharmacokinetic evaluation of besifovir for the treatment of HBV infection. AB - INTRODUCTION: Besifovir (LB80380) is a relatively new oral acyclic nucleotide phosphonate. We reviewed the pharmacokinetic characteristics of LB80380 and discussed its role in the treatment of chronic hepatitis B infection. Areas covered: LB80380 is a prodrug of LB80331 and LB80317. It is rapidly absorbed when taken orally. Escalating doses of besifovir produce linear increase of the plasma concentration. Doses above 60mg are effective for inhibiting HBV in human. Using 60mg as an example, the maximal concentration of LB80331 in plasma is 397 ng/mL. The time required to reach maximal concentration in plasma and elimination half life are 2.0 and 3.0 h, respectively. Besifovir and its metabolites are mainly excreted via the kidneys. Its antiviral efficacy is non-inferior to ETV 0.5mg daily. It is generally safe in terms of renal and bone toxicity. The most common adverse event is carnitine depletion which affects almost all patients on besifovir requiring carnitine supplementation. Expert opinion: Besifovir demonstrated predictable pharmacokinetic characteristics in human subjects. Few clinical studies on besifovir have been conducted. More data are expected particularly for special populations. The adverse events upon long term exposure should be monitored. Large scale head-to-head trials comparing besifovir with existing NA, especially tenofovir alafenamide, should be conducted. PMID- 29237297 TI - The Evolutionary Psychology of War: Offense and Defense in the Adapted Mind. AB - The study of warfare from an evolutionary perspective has expanded rapidly over the last couple of decades. However, it has tended to focus on the ancestral origins, prevalence, and instruments of war rather than adaptationist analyses of its underlying psychology. I argue that our evolved coalitional psychology may contain a set of distinct evolved heuristics designed specifically for offensive and defensive coalitional aggression. Data from two survey experiments are presented, in which subjects were given scenarios depicting offensive or defensive aggression and were told to make decisions, for example, regarding their willingness to participate in the conflict, their opinions of others who did not choose to participate, and their expectations benefit. The results indicate that humans do indeed distinguish readily between these two domains and that their willingness to participate, as well as their emotional responses toward others, is highly contingent upon this informational cue in adaptively relevant ways. In addition, and consistent with parental investment theory, data reveal a range of sex differences in attitudes toward coalitional aggression in the two conflict domains. Beyond the study of warfare, this project has implications for our understanding of the relationship between individual behavior and group dynamics, as well as for our understanding of the mechanisms by which the psychological framing of political events can lead to important social outcomes. PMID- 29237299 TI - Erratum. PMID- 29237298 TI - Passion, Relational Mobility, and Proof of Commitment: A Comparative Socio Ecological Analysis of an Adaptive Emotion in a Sexual Market. AB - Although monogamy, the exclusive bonding with a specific partner, is one characteristic of modern human mating, long-term romantic relationships inherently possess the commitment problem, which is the conflict between maintaining a relationship with a certain partner and seeking attractive alternatives. Frank has argued that love and passion help solve this problem because they make individuals commit voluntarily to the relationship, leading the other party to also be committed with less concern over being cheated on or rejected. Combining this idea with the comparative socio-ecological approach, we hypothesize that passion will be more pronounced in social environments in which people have greater freedom to choose and replace their partners (i.e., high relational mobility) than in societies in which relationships tend to be more stable and hard to change (i.e., low relational mobility). To test this hypothesis, we compared Americans (living in a society with high relational mobility) and Japanese (living in a society with low relational mobility). As predicted, Americans were more passionate toward their romantic partners than Japanese, and this cultural difference was partially explained by the levels of perceived relational mobility in participants' local ecology. Moreover, more intense passion was found to lead to greater commitment behaviors in both societies. The importance of taking socioecological factors into consideration for the theory of the adaptive function of interpersonal emotions is also discussed. PMID- 29237300 TI - Introduction of Adonis aestivalis as a new source of effective cytotoxic cardiac glycoside. AB - Cardiac glycosides are used for treatment of irregular heartbeats, cardiac arrhythmia and congestive heart failures. In this research, digitoxin as a cardiac glycoside was identified and isolated for the first time in the world from Adonis aestivalis and investigated for its cytotoxic activity against cervical cancer cell (HeLa) lines and human lymphocytes by MTT test. Digitoxin extracted from the aerial parts of the plant collected from west of Iran and purified by column and thin layer chromatographic techniques. The structure of isolated cardiac glycoside was identified by IR, 1H NMR and 13C NMR methods and so the presence of digitoxin was established. The half maximal inhibitory concentration values for cervical cancer and lymphocyte cells were obtained to be 5.62 and 412.94 MUg/mL. The results of this study introduced the new resource of digitoxin which has considerable cytotoxic effects against HeLa cancer cells but did not damage normal human lymphocyte cells. PMID- 29237301 TI - Response to Letter to the Editor entitled 'Correct microarray analysis approaches in "Hsa-circRNA11783-2 in peripheral blood is correlated with coronary artery disease and type 2 diabetes mellitus"'. AB - In the paper entailed 'Hsa-circRNA11783-2 in peripheral blood is correlated with coronary artery disease and type 2 diabetes mellitus', we illustrated the correlation of circRNA with T2DM and CAD. We used the common method - Q-PCR to select differentially expressed circular RNA (differentially expressedgenes(DEGs)), with a criteria of fold change>2 and unadjusted p values < 0.05 in expression. When the candidate RNAs have been narrowed down by GO and Pathway analysis, Q-PCR is a good verification method, although the idea that using Q-PCR to verify all the DEGs is still unrealistic. There is no denying that using an optimal statistical approach makes the survey much easier. PMID- 29237302 TI - The hypoglycemic and antioxidant activities of garden cress (Lepidium sativum L.) seed on alloxan-induced diabetic male rats. AB - The hypoglycemic and antioxidants activities of the methanol extract of Lepidium sativum seeds was tested in alloxan-induced diabetic male rats. Thirty male albino rats weighing 190-200 g were divided into five groups as follows: negative control, positive control and three diabetic groups treated with three concentrations of L. sativum methanol extract for four weeks. Induction of hyperglycemia in the positive control group increased blood glucose, glycated hemoglobin A1c, immunoglobulins, liver enzyme, lipid peroxide and kidney function, total cholesterol, low-density lipoproteins, very low-density lipoproteins and decreased antioxidants and high-density lipoproteins compared with the negative control. Furthermore, pancreas tissues showed pathological changes compared with the negative control. Treating the diabetic rats with L. sativum methanol extract decreased blood sugar and restored all biochemical and histological changes to the normal. It could be concluded that L. sativum methanol extract succeeded in controlling diabetes, increasing antioxidants and ameliorating lipid profile. PMID- 29237303 TI - Indigenous (Maori) sexual health psychologies in New Zealand: Delivering culturally congruent sexuality education. AB - Indigenous (Maori) psychologies of sexual health occur at the cultural nexus of Indigenous and Western knowledge, colonising influence and intervention. Formal school-based sexuality education holds potential to intervene in this psychological space by decolonising notions of Maori sexuality, relationships and reproduction. This research utilises an Indigenous feminist (Mana Wahine) methodology and interviews with 43 Maori participants (26 women and 17 men). We explore how Maori knowledges (matauranga Maori), responsive to the surrounding colonising context, were interwoven through four themes: relationships, reproductive responsibility, open conversations about sexuality and contraceptive education. Indigenous knowledges can contribute to good sexual health psychologies for all. PMID- 29237304 TI - The role of mitochondrial dysfunction in cardiovascular disease: a brief review. AB - Cardiovascular disease (CVD) is a leading cause of mortality worldwide. Proper mitochondrial function is necessary in tissues and organs that are of high energy demand, including the heart. Mitochondria are very sensitive to nutrient and oxygen supply and undergo metabolic adaptation to the changing environment. In CVD, such an adaptation is impaired, which, in turn, leads to a progressive decline of the mitochondrial function associated with abnormalities in the respiratory chain and ATP synthesis, increased oxidative stress, and loss of the structural integrity of mitochondria. Uncoupling of the electron transport chain in dysfunctional mitochondria results in enhanced production of reactive oxygen species, depletion of cell ATP pool, extensive cell damage, and apoptosis of cardiomyocytes. Mitophagy is a process, during which cells clear themselves from dysfunctional and damaged mitochondria using autophagic mechanism. Deregulation of this process in the failing heart, accumulation of dysfunctional mitochondria makes the situation even more adverse. In cardiac pathology, aberrations of the activity of the respiratory chain and ATP production may be considered as a core of mitochondrial dysfunction. Indeed, therapeutic restoration of these key functional properties can be considered as a primary goal for improvement of mitochondrial dysfunction in CVD. Key messages Mitochondrial dysfunction plays a crucial role in cardiovascular disease pathogenesis. Cardiovascular disease is associated with altered mithochondrial biogenesis and clearance. In cardiovascular disease, impaired mitochondrial function results in decreased ATP production and enhanced ROS formation. PMID- 29237305 TI - E/a' ratio a simple detector of left ventricular dysfunction in patients with decreased ejection fraction. AB - OBJECTIVES: Could a diastolic dysfunction and an increased LV-filling pressure according to ASE/EACVI guidelines be detected or ruled out by the E/a'ratio in patients with decreased ejection fraction. DESIGN: We retrospectively evaluated the diastolic function of 113 unselected in-hospital patients, aged 40-84 years, in sinus rhythm and with no or mild valve disease, having a decreased systolic function (EF <=50%) using the new ASE/EACVI guidelines and compared these results with the E/a'ratio derived from the E wave in the mitral flow and the a'velocity in the tissue Doppler. RESULTS: The average E/a' ratio is a strong predictor of a grade II-III diastolic dysfunction and an elevated left atrial pressure according to ASE/EACVI guidelines with an AUC of 0.92. An average E/a' ratio with a cut-off >10 had a sensitivity of 97.6% and a negative predictive value of 98.2% in detecting or ruling out a grade II-III diastolic dysfunction and an elevated left atrial pressure according to the current guidelines. CONCLUSION: The average E/a' ratio might be useful as a fast screening tool of a left ventricular dysfunction and an increased left ventricular filling pressure in patients with a decreased ejection fraction. PMID- 29237306 TI - Spiritual Criminology: The Case of Jewish Criminology. AB - Throughout the ages and in most cultures, spiritual and religious thinking have dealt extensively with offending (person against person and person against the Divine), the response to offending, and rehabilitation of offenders. Although modern criminology has generally overlooked that body of knowledge and experience, the study of spirituality and its relation to criminology is currently growing. Frequently, though, it is conducted from the secular scientific perspective, thus reducing spiritual knowledge into what is already known. Our aim here is to present a complementary perspective; that is, spiritual criminology that emerges from the spiritual perspective. Following a description of the state-of-the-art in criminological research concerning spirituality and its impact upon individuals, we focus on Jewish criminology as an illustrative case study, and present a spiritual Jewish view on good and evil, including factors that lead to criminality, the issue of free choice, the aim of punishment and societal response, crime desistance, rehabilitation, and prevention. The proposed establishment of spiritual criminology can be further developed by including parallel schools of spirituality, to create an integrated field in criminology. PMID- 29237307 TI - Oligohydramnios is an independent risk factor for perinatal morbidity among women with pre-eclampsia who delivered preterm. AB - PURPOSE: The purpose of this study is to determine the relationship between oligohydramnios and adverse maternal and neonatal outcomes in a unique cohort of preterm pre-eclamptic patients. MATERIALS AND METHODS: A retrospective matched case-control study comparing 81 preterm parturients (28 0/7 and 36 6/7 weeks) with pre-eclampsia and oligohydramnios to 81 preterm pre-eclamptic patients with a normal amniotic fluid index (AFI). RESULTS: About 4.8 percent of all our preterm pre-eclamptic patients had oligohydramnios. Patients in the study group showed a trend toward being older than 35 years (18.5%% versus 27.2%) and were more likely more likely to be primi-parous, and have previously delivered a small for gestational age (SGA) or a dead fetus (p = .012, .039, and .032). Severity of pre-eclampsia, including HELLP and eclampsia as well as gestational age at delivery did not differ statistically between the study groups (p = .47, .516). Growth restricted fetuses were more common in the study group (p < .001) but oliguria was more prevalent in patients without oligohydramnios (p = .046). Post partum complications, pre-eclampsia during the puerperium, admission to intensive care units, and MgSO4 treatment were more common in the control group (p = .028, .012, .008). But study group patients had more cesarean sections (p = .011). Neonates of study group parturients had lower fetal weight, were more likely to be SGA, and experience fetal distress during labor (p = .001, .001, and .03). Following delivery, they were more likely to have anemia and stay longer in neonatal intensive care unit (NICU) (p = .017, .017). A multivariate logistic regression analysis showed that oligohydramnios, but not the severity of pre eclampsia, significantly affected Composite Neonatal Outcome {Apgar scores at 1 & 5 min (<5 and <7, respectively), neonatal death, umbilical cord pH <7.1, fetal distress (category III fetal heart rate tracing), fetal anemia, fetal hypoglycemia}. CONCLUSIONS: Oligohydramnios is an independent risk factor for early neonatal morbidity in preterm pre-eclamptic patients. AFI <5 cm can be used as one component in the educated decision for delivery of these patients. Brief rationale The significance of oligohydramnios in pregnancies complicated by preterm delivery, preeclampsia or both is controversial. By comparing two relatively large, almost similar, cohorts of preterm preeclamptic parturient with and without oligohydramnios we demonstrated that Amniotic Fluid Index <5 cm is associated with a significant neonatal morbidity. This question was not previously addressed in proper manner aside one, much smaller, study that was under powered to address this topic. We innovate by illustrating the significance of oligohydramnios and its association with subsequent neonatal morbidity. Thus, we conclude that the presence of oligohydramnios in women with preterm preeclampsia can be a factor in the decision for or against conservative management of these patients. PMID- 29237308 TI - How Can Governmental Positive Power Decrease Violence in Crime-Oriented Arenas? The Case of English Football. AB - This article will survey the dramatic change English football had undergone since the end of the last century. The authors will closely explore the implementation of the Taylor Report recommendations, to convince that which power and management techniques were used to decrease violence in public areas that were previously considered dangerous and crime-oriented. It will be argued that disciplinarian techniques were practiced, much like those described in Foucault's Discipline and Punish, while this very power has proven to be positive and revitalizing. It will be therefore concluded that power is at its most effective when operated via techniques of discipline and social inclusion. These arguments correspond with the positive criminology theory whose popularity within the discipline is gradually increasing. PMID- 29237309 TI - Is the Nature of Communication Relevant to the Supportiveness of Women's Relationships With Probation and Parole Agents? AB - This article reports on a study of the connection of probation and parole agents' communication with relationship supportiveness as perceived by both women offenders and agents. For a sample of offenders and their agents, multilevel modeling was used to control for nonindependence of data for women assigned to the same agent. Consistent with communication theory, a conversational approach was positively related to measures of a supportive relationship, and an authoritarian/ conformity pattern of communication was negatively related to a supportive relationship. For low-risk offenders, attention to client-identified problems was positively related to more supportive relationships. For women with high risk for reoffending, the agents viewed themselves as less supportive if they addressed a high proportion of offender-identified needs. Findings suggest the efficacy of training to promote agents' conversational communication and attention to offender-identified problems. Findings also suggest the need to more fully explore agents' experience in working with very high-risk offenders. PMID- 29237310 TI - A pilot study to assess the effect of acute exercise on brain glutathione. AB - The brain is highly susceptible to oxidative stress due to its high metabolic demand. Increased oxidative stress and depletion of glutathione (GSH) are observed with aging and many neurological diseases. Exercise training has the potential to reduce oxidative stress in the brain. In this study, nine healthy sedentary males (aged 25 +/- 4 years) undertook a bout of continuous moderate intensity exercise and a high-intensity interval (HII) exercise bout on separate days. GSH concentration in the anterior cingulate was assessed by magnetic resonance spectroscopy (MRS) in four participants, before and after exercise. This was a pilot study to evaluate the ability of the MRS method to detect exercise-induced changes in brain GSH in humans for the first time. MRS is a non invasive method based on nuclear magnetic resonance, which enables the quantification of metabolites, such as GSH, in the human brain in vivo. To add context to brain GSH data, other markers of oxidative stress were also assessed in the periphery (in blood) at three time points [pre-, immediately post-, and post (~1 hour)-exercise]. Moderate exercise caused a significant decrease in brain GSH from 2.12 +/- 0.64 mM/kg to 1.26 +/- 0.36 mM/kg (p = .04). Blood GSH levels increased immediately post-HII exercise, 580 +/- 101 uM to 692 +/- 102 uM (n = 9, p = .006). The findings from this study show that brain GSH is altered in response to acute moderate exercise, suggesting that exercise may stimulate an adaptive response in the brain. Due to the challenges in MRS methodology, this pilot study should be followed up with a larger exercise intervention trial. PMID- 29237311 TI - Interventions That Target Criminogenic Needs for Justice-Involved Persons With Serious Mental Illnesses: A Targeted Service Delivery Approach. AB - This research describes the development of a targeted service delivery approach that tailors the delivery of interventions that target criminogenic needs to the specific learning and treatment needs of justice-involved people with serious mental illnesses (SMIs). This targeted service delivery approach includes five service delivery strategies: repetition and summarizing, amplification, active coaching, low-demand practice, and maximizing participation. Examples of how to apply each strategy in session are provided, as well as recommendations on when to use each strategy during the delivery of interventions that target criminogenic needs. This targeted service delivery approach makes an important contribution to the development of interventions for justice-involved people with SMI by increasing the chances that people with SMI can participate fully in and benefit from these interventions that target criminogenic needs. These developments come at a critical time in the field as the next generation of services for justice-involved people with SMI are being developed. PMID- 29237312 TI - Environmental exposure and parental collection does not affect detection or semi quantitative load assessment of bacteria in nasal swab specimens from children. PMID- 29237313 TI - The "Watchful Eye of God": The Role of Religion in the Rehabilitation and Reentry of Repentant Jewish Prisoners. AB - Can participation in a religious rehabilitation program benefit a released prisoner's reentry into the community, and if so, how? Which elements of the religious worldview can be translated into tools for promoting desistance? Using a qualitative approach, we conducted 30 interviews with released prisoners from 3 months to 5 years beyond release who participated in a Jewish faith-based rehabilitation program administered by Israel's Prisoner Rehabilitation Authority. We interviewed participants in the Torah Rehabilitation Program about the role of religion in their lives and in their desistance from crime. We map out the spiritual, behavioral, and psychological tools they feel aided them in facing the challenges of reentry. PMID- 29237314 TI - "We Now Have a Patient and Not a Criminal": An Exploratory Study of Judges and Lawyers' Views on Suicide Attempters and the Law in Ghana. AB - This study explored the views of judges and lawyers of the superior courts of Ghana on the law criminalizing attempted suicide. Qualitative data were collected from 12 experienced legal practitioners of the superior courts (five judges and seven lawyers) using a semi-structured interview schedule. Thematic analysis of the data yielded three main perspectives: In defence of the Law, Advocating a Repeal, and Pro-Health Orientation. Although exploratory, the findings of this study offer cues for stepping up suicide literacy and advocacy programmes toward either a repeal of the law or a reform. PMID- 29237315 TI - Examining the Academic Achievement-Delinquency Relationship Among Southeast Asian Americans. AB - The extent to which poor academic achievement is strongly related to delinquency among Southeast Asian Americans (SEAA) remains unclear; reasons are methodological limitations and aggregated findings for Asian Americans, which mask evidence that SEAA have a higher prevalence of criminality and poor academic performance than other Asian American groups. The present study examines the academic achievement-delinquency relationship in a diverse group of 1,214 SEAA using data from the Children of Immigrants Longitudinal Study (CILS). Propensity score matching (PSM) was used to make causal inferences and assess whether poor academic achieving SEAA, after being matched with higher academic achieving SEAA, displayed a higher prevalence of delinquency. Findings showed that, even after matching, poor academic achieving SEAA were still more likely to exhibit delinquent behavior than those who performed academically better. Interventions targeting SEAA communities will need to focus more on improving academic achievement to directly prevent and decrease delinquent behavior. PMID- 29237316 TI - Do Demographic Factors Moderate How Well Criminal Thinking Predicts Recidivism? AB - Is the relationship between criminal thinking and recidivism the same for criminal justice-involved individuals from varying demographic backgrounds? Relying on two independent samples of offenders and two measures of criminal thinking, the current studies examined whether four demographic factors-gender, race, age, and education-moderated the relationship between criminal thinking and recidivism. Study 1 consisted of 226 drug-involved probationers enrolled in a randomized clinical trial. Study 2 consisted of 346 jail inmates from a longitudinal study. Logistic regression models suggested that the strength of the relationship between criminal thinking and subsequent recidivism did not vary based on participant demographics, regardless of justice system setting or measure of criminal thinking. Criminal thinking predicts recidivism similarly for people who are male, female, Black, White, older, younger, and more or less educated. PMID- 29237317 TI - A new embolic liquid agent comprised of amino acid. AB - Transcatheter arterial or venous embolization has been widely used to address solid tumors by occluding the tumor-feeding vessels. It is also performed to treat portosystemic shunts and to stop bleeding by repair of the site of trauma. Commonly used embolic materials are gelatin sponges, coils, beads, and liquid agents such as absolute ethanol, histoacyryl, and onyx. In the field of interventional radiology, embolotherapy is performed routinely. Liquid embolization agents have different characteristics. Their coagulation time, the inflammatory reaction of the vascular wall or surrounding tissue, and their adhesion to the vascular wall vary. PuraMatrix, a liquid embolic agent not yet available for clinical use, is comprised of amino acid. We introduce and discuss preliminary experimental studies to examine its potential for use in humans. PMID- 29237318 TI - Sexual Aggressors Against Women's Sexual Lives: A Latent Class Analysis. AB - This study investigated the day-to-day deviant and nondeviant sexuality of a sample of Canadian sexual aggressors against women ( N = 160). Using latent class analysis, three latent classes were identified: internalized deviant (ID), low sexual problem (LSP), and hypersexual deviant (HD). Following the latent class analysis, the developmental, physiological, cognitive, and criminological correlates of these lifestyles were analyzed. ID ( n = 31) aggressors were characterized by sexual dissatisfaction, sexual deviance, and a bland sexual life. LSP ( n = 116) aggressors were characterized by the absence of sexual deviance or hypersexuality. HD ( n = 13) aggressors were characterized by hypersexuality and sexual deviance. Our exploratory study suggests that the day to-day nondeviant and deviant sexual life of sexual aggressors against women appear to affect their modus operandi. Furthermore, the adult sexual lifestyles of sexual aggressors against women appear to be extensions of their adolescent sexual lifestyles. The results of this study thus suggest avenues for research notably, the specific influence of sexual behaviours and internalized psychosexual problems on modus operandi-that could improve the clinical management of sexual aggressors against women. PMID- 29237319 TI - Fibrous nanocellulose, crystalline nanocellulose, carbon nanotubes, and crocidolite asbestos elicit disparate immune responses upon pharyngeal aspiration in mice. AB - With the rapid development of synthetic alternatives to mineral fibers, their possible effects on the environment and human health have become recognized as important issues worldwide. This study investigated effects of four fibrous materials, i.e. nanofibrillar/nanocrystalline celluloses (NCF and CNC), single walled carbon nanotubes (CNTs), and crocidolite asbestos (ASB), on pulmonary inflammation and immune responses found in the lungs, as well as the effects on spleen and peripheral blood immune cell subsets. BALB/c mice were given NCF, CNC, CNT, and ASB on Day 1 by oropharyngeal aspiration. At 14 days post-exposure, the animals were evaluated. Total cell number, mononuclear phagocytes, polymorphonuclear leukocytes, lymphocytes, and LDH levels were significantly increased in ASB and CNT-exposed mice. Expression of cytokines and chemokines in bronchoalveolar lavage (BAL) was quite different in mice exposed to four particle types, as well as expression of antigen presentation-related surface proteins on BAL cells. The results revealed that pulmonary exposure to fibrous materials led to discrete local immune cell polarization patterns with a TH2-like response caused by ASB and TH1-like immune reaction to NCF, while CNT and CNC caused non classical or non-uniform responses. These alterations in immune response following pulmonary exposure should be taken into account when testing the applicability of new nanosized materials with fibrous morphology. PMID- 29237320 TI - Clinical management of women with listeriosis risk during pregnancy: a review of national guidelines. AB - INTRODUCTION: Listeriosis is an uncommon foodborne infection that may cause moderate maternal illness, but can be extremely serious for the fetus and the newborn. Several guidelines have been elaborated in order to help clinicians on the care of pregnant women with known or suspected exposure to Listeria monocytogenes. The aim of this review is to collect, assess and summarize them, in order to provide a comprehensive overlook and to highlight the grey areas in the guidance that could result in failure to detect some infected but asymptomatic women. Areas covered: A literature review was performed to provide an update on listeriosis infections, with a greater focus on diagnosis and management of pregnancy-related cases. Expert commentary: Since pregnancy associated listeriosis causes potentially fatal consequences, it is important that healthcare providers recognize earlier symptoms, diagnosis methods and treatment of the infection. Listeriosis could be asymptomatic and/or a pregnant woman could not be aware of being exposed to Listeria, therefore a serological test is suggested to detect the presence of anti-listeriolysin O antibodies in blood. Finally, a final flowchart is proposed that could improve the early diagnosis of the infection in pregnant women. PMID- 29237321 TI - Impact of onset-to-groin puncture time within three hours on functional outcomes in mechanical thrombectomy for acute large-vessel occlusion. AB - Introduction Endovascular treatment for acute ischemic stroke with acute large vessel occlusion (ALVO) has established benefits, and rapid treatment is vital for mechanical thrombectomy in ALVO. Time from onset of stroke to groin puncture (OTP) is a practical and useful clinical marker, and OTP should be shortened to obtain the maximum benefit of thrombectomy. Objective The aim of the present study was to assess the impact of early treatment of anterior circulation stroke within three hours after symptom onset and to evaluate the role of OTP in determining outcomes after endovascular therapy. Methods Consecutive patients with acute stroke due to major artery (internal carotid or middle cerebral arteries) occlusion who underwent endovascular recanalization between March 2014 and January 2017 were retrospectively evaluated. Patients were stratified by OTP into three categories: 0-<=3 h, >3-<=6 h, and >6 h. The primary outcome measure was a 90-day modified Rankin scale score of 0-2 (good outcome). Results Data were analyzed from 100 patients (mean age, 76.6 years; mean National Institutes of Health Stroke Scale score, 17). Groin puncture occurred within 0-<=3 h in 51 patients, >3-<=6 h in 28, and >6 h in 21. Median OTP in each group was 126 min (range, 57-168 min), 238 min (range, 186-360 min) and 728 min (range, 365-1492 min), respectively. On multivariable logistic regression analysis, category of OTP represented an independent predictor of patient outcome (adjusted odds ratio, 0.48; 95% confidence interval, 0.25-0.93; p = 0.029). Conclusions OTP is a prehospital and in-hospital workflow-based indicator. In this single-center study, OTP was found to independently affect functional outcomes after endovascular stroke treatment. PMID- 29237322 TI - Global variation in diurnal cortisol rhythms: evidence from Garisakang forager horticulturalists of lowland Papua New Guinea. AB - The hypothalamic-pituitary-adrenal (HPA) axis represents an important and evolutionarily ancient biological pathway linking physical and psychological stressors with human health. Despite considerable research exploring the physiological stress response among developed populations, few studies have examined HPA activity in non-industrialized contexts, restricting understanding of variation in human stress reactivity across global socio-ecological diversity. The present study addresses this shortcoming by investigating diurnal cortisol rhythms among Garisakang forager-horticulturalists of remote, lowland Papua New Guinea. Using a large sample of repeated salivary cortisol measurements from 169 participants (age 4-70 years), multilevel growth curve models were constructed to assess Garisakang waking cortisol concentrations and diurnal cortisol slopes. As predicted, results demonstrate identifiable but substantially diminished diurnal cortisol rhythms relative to those of industrialized populations. Sample-wide, Garisakang cortisol concentrations are highest upon waking (mean = 4.86 nmol/L) and decrease throughout the day at a mean rate of only -0.18 nmol/L/h or 6.20%/h. Age and sex significantly predict evaluated cortisol parameters in ways not consistently reported among industrialized populations, suggesting that Garisakang diurnal cortisol rhythms are defined by distinct ontogenetic trajectories across the lifespan. These findings highlight cross-cultural diversity in HPA activity and have important implications for understanding basic mechanisms of the physiological stress response in contexts of chronic physical stressors such as limited nutrition, heavy burden of infectious disease, and high levels of physical activity. PMID- 29237323 TI - [Does methylphenidate cause liver damage? An analysis of ad hoc reports to the "Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM)"]. AB - Does methylphenidate cause liver damage? An analysis of ad hoc reports to the "Bundesinstitut fur Arzneimittel und Medizinprodukte (BfArM)" Abstract. Ad hoc reports to the "Bundesinstitut fur Arzneimittel und Medizinprodukte" (BfArM, the German Federal Institute for Drugs and Medical Devices) were analyzed concerning liver injuring stemming from therapy with methylphenidate (MPH). Clinical criteria were used to assess suspected cases of causal association. The BfArM database on adverse drug reactions (ADRs) recorded suspected cases from Germany over the period from 1 January 2006 to 23 May 2016. Using the Standardized MedDRA Queries (SMQ) search strategy, we searched the database for "MPH" and its potential ADRs "Hepatic Disorder." The ad hoc reports were checked for completeness and assessed clinically according to the Uppsala Monitoring Centre criteria. 60 suspected cases of liver damages by MPH were recorded in the database. In 15 thereof, an assessment was not possible because of insufficient documentation; in 25 cases, a link between the intake of MPH and the occurrence of liver injury was considered "unlikely." A "possible" causality was assessed in 11 cases, a "probable/likely" causality in 9 cases: 1 patient with fulminant hepatitis, 1 with increased size of benign liver tumor, and 18 cases of (reversible) hepatic enzyme elevation. According to our evaluation, MPH is well tolerated with regard to liver and gall bladder diseases. For patients with hepatic impairment or other risk factors, regular monitoring of liver values is recommended. PMID- 29237324 TI - Systemic lupus erythematosus arthropathy: the sonographic perspective. AB - Background Despite being promising, the use of ultrasound (US) in the assessment of musculoskeletal manifestations of systemic lupus erythematosus (SLE) is still limited. Literature on this topic is scarce and the spectrum and clinical relevance of US abnormalities has not yet been outlined. With this paper, we aim to explore the panel of joint and tendon US findings in a group of SLE patients. Methods Twenty-five consecutive SLE patients, with current or medical history of musculoskeletal symptoms, were studied. All patients underwent routine clinical examination and US evaluation. The US examination targeted sites clinically involved in the physical examination and/or indicated as painful in the patient's medical history. Results One or more US changes were found in all the patients. US abnormalities were detected in 85 out of the 243 scanned joints (35%), in 70 out of the 215 scanned tendons (32.6%) and in 10 out of the 41 scanned entheses (24.4%). Synovial effusion, synovial hypertrophy, "mixed" synovitis (coexistence of synovial effusion and synovial hypertrophy), joint dislocation, bone erosion, and cartilage damage were found in 9.5%, 11.5%, 14%, 3.7%, 2.1%, and 4.5% of the scanned joints, respectively. Tenosynovitis, tendon dislocation, tendon tear, tendon thinning, and tendinitis/peritendinitis were detected in 17.7%, 8.4%, 0.9%, 4.2%, and 4.7% of the scanned tendons, respectively. Power Doppler signal, hypoechogenicity, thickening, enthesophytes, calcifications, and bone erosions were detected at the entheseal level in 12.2%, 9.8%, 12.2%, 7.3%, 7.3%, and in 0% of the scanned entheses, respectively. Conclusions This study revealed an unexpectedly wide heterogeneity of US pathologic findings in the joints and tendons of patients with SLE. A broad spectrum of US changes also involving anatomic structures not considered in previous investigations, including entheses and tendons with no synovial sheath, was detected. These preliminary results suggest that US is able to identify several US "patterns" whose clinical, prognostic, and pathogenetic significance is still to be defined. PMID- 29237325 TI - The myth of a naturalised male circumcision: Heuristic context and the production of scientific objects. AB - In March, 2007, the WHO and UNAIDS established a joint recommendation at the Montreux technical consultation, making male circumcision the first surgery to be used as a preventative tool against an infectious disease. This recommendation was immediately followed by the publication of numerous articles denouncing its content, leading to two distinct controversies, one between epidemiologists, and a second between epidemiologists and social scientists. Interestingly, however, none of these works took male circumcision as an issue in itself, exploring neither that both epidemiologists and social scientists had taken the object 'circumcision' as a given, nor what each party was referring to when talking about circumcision. In this paper, taking a step back, and building on the notion of heuristic context, I show how the RCTs constructed this object in a very specific way, and how this construction was often lost in translation, leading not only to an illusion of universality, but also to misunderstandings between disciplines regarding what is at stake in global health issues. PMID- 29237326 TI - A "chamber of errors" adaptation to assess pharmaceutical assistants' knowledge in chemotherapy preparation. AB - French preparation guidelines state that pharmacy staff who manipulate cytotoxic drugs have to follow specific training. In order to assess the pharmaceutical assistants' skills and knowledge, we developed a "Cytotoxic Preparation Centralized Unit (CPCU) of errors," derived from the Canadian concept of "Chamber of horrors." A table listing 20 mistakes to track down was created and each pharmaceutical assistant spent 20 min in the "CPCU of errors" with the pharmacist, who wrote down the spotted mistakes in real time. Among the 21 trained pharmaceutical assistants, 15 were evaluated. On average, 11.9 mistakes on 20 were detected. The lowest score was 7 spotted errors on 20 and the highest was 16 on 20. Those results should be qualified depending on pharmaceutical assistants' years of experience in the preparation of chemotherapy. Those results may be explained by the way the role-playing was conducted. The simulation was not conducted during an actual preparation using the usual equipment. One of the major obstacles was the difficulty to clear some time for this project because its realization required a full-time pharmacist and the referring pharmaceutical assistant in addition to the evaluated pharmaceutical assistants. Overall, the staff feedback was positive and the role-playing led to a reminder of theoretical knowledge and the good use of some devices. It would be interesting to develop this type of project through a regional oncology network to create a medium that can be used by other hospitals. PMID- 29237327 TI - Studies on conversion of waste nitramine and fuel-rich-based propellants into liquid fertilizer. AB - The current demilitarization processes employ open burning/open detonation which is not permitted by the environmental protection agency. Therefore, a systematic study has been carried out to convert waste/rejected nitramine propellant (NP) and fuel-rich-based propellant (FRP) into liquid fertilizer by digesting in dilute nitric acid followed by neutralization with potassium hydroxide and phosphoric acid. The obtained liquid fertilizers were fully characterized for nitrate, phosphate and ammonium ions along with potassium. Further, the effect of liquid fertilizers of NP and FRP on cluster bean plants was studied by taking different concentrations from 25 to 150 mL, and their effects on germination pattern, shoot growth, thickness of stem, size and number of leaves, number of pods and length over a full-grown period of plants were investigated. The results reveal that the germination index increases as the content of liquid fertilizer increases and the same trend was observed with respect to root and shoot growth. Also, broadness and the number of leaves showed an encouraging effect as concentration increases. Further, the final product, i.e. the number of pods of cluster bean and length in each pod was found to be more for liquid fertilizer of NP compared to FRP-based liquid fertilizer. PMID- 29237328 TI - Modeling the full length HIV-1 Gag polyprotein reveals the role of its p6 subunit in viral maturation and the effect of non-cleavage site mutations in protease drug resistance. AB - HIV polyprotein Gag is increasingly found to contribute to protease inhibitor resistance. Despite its role in viral maturation and in developing drug resistance, there remain gaps in the knowledge of the role of certain Gag subunits (e.g. p6), and that of non-cleavage mutations in drug resistance. As p6 is flexible, it poses a problem for structural experiments, and is hence often omitted in experimental Gag structural studies. Nonetheless, as p6 is an indispensable component for viral assembly and maturation, we have modeled the full length Gag structure based on several experimentally determined constraints and studied its structural dynamics. Our findings suggest that p6 can mechanistically modulate Gag conformations. In addition, the full length Gag model reveals that allosteric communication between the non-cleavage site mutations and the first Gag cleavage site could possibly result in protease drug resistance, particularly in the absence of mutations in Gag cleavage sites. Our study provides a mechanistic understanding to the structural dynamics of HIV-1 Gag, and also proposes p6 as a possible drug target in anti-HIV therapy. PMID- 29237329 TI - Not all AMLETs are made equal: complexes of cow and camel alpha-lactalbumin with oleic acid show different structure and stability. PMID- 29237330 TI - Influence of cationic polyacrilamide flocculant on high-solids' anaerobic digestion of sewage sludge under thermophilic conditions. AB - Treatment of sewage sludge (SS) by biodegradable polyacrylamide-based flocculants (PAM) is considered to be an effective way to increase total solids' (TS) content prior to anaerobic digestion (AD). However, data on how PAM addition influences the efficiency of AD process are quite contradictory; moreover, no data are available for thermophilic AD (TAD). This study showed that at an optimal inoculum-to-substrate ratio (ISR, 55/45), PAM addition resulted in some decrease in initial methane production during the TAD of SS due to the formation of large flocs (up to 2-3 mm in diameter), which deteriorated the mass transfer. However, at non-optimal ISR (40/60), which led to the destabilization of TAD, PAM addition (40 mg/g TS) could restore the methanogenesis despite the inhibiting accumulation of volatile fatty acids (14-15 g/l) and pH drop (5.5). The observed positive effect of PAM-forced flocculation proposes a new interesting alternative for recovery of 'soured' reactors. PMID- 29237332 TI - Traditional, complementary, and alternative medical cures for HIV: rationale and implications for HIV cure research. AB - Traditional, complementary, and alternative medicine (TCAM) has been used by some people living with HIV (PLHIV) in an attempt to cure HIV. This article reviews the main factors influencing their decision to choose TCAM to cure HIV and discusses implications for HIV cure research. Those who decide to pursue traditional, complementary, and alternative medical cures may be influenced by the health system, cultural, and social dynamics, and their own individual beliefs and preferences. These same factors may impact participation in HIV cure research. People who search for traditional, complementary, and alternative medical cures may face special challenges as they are recruited, consented, and retained within HIV cure research studies. To address these potential challenges, we have suggested solutions focusing on culturally tailored communication and education, formative social science research, and community partnerships with key stakeholders. The social conditions that have promoted traditional, complementary and alternative medical cures will likely impact how PLHIV participate and experience HIV remission trials. Despite the potential challenges, it will be crucial to involve those who have previously sought out traditional cures for HIV in HIV cure research. PMID- 29237333 TI - Predictors of Entering a Hearing Aid Evaluation Period: A Prospective Study in Older Hearing-Help Seekers. AB - This study aimed to determine the predictors of entering a hearing aid evaluation period (HAEP) using a prospective design drawing on the health belief model and the transtheoretical model. In total, 377 older persons who presented with hearing problems to an Ear, Nose, and Throat specialist ( n = 110) or a hearing aid dispenser ( n = 267) filled in a baseline questionnaire. After 4 months, it was determined via a telephone interview whether or not participants had decided to enter a HAEP. Multivariable logistic regression analyses were applied to determine which baseline variables predicted HAEP status. A priori, candidate predictors were divided into 'likely' and 'novel' predictors based on the literature. The following variables turned out to be significant predictors: more expected hearing aid benefits, greater social pressure, and greater self-reported hearing disability. In addition, greater hearing loss severity and stigma were predictors in women but not in men. Of note, the predictive effect of self reported hearing disability was modified by readiness such that with higher readiness, the positive predictive effect became stronger. None of the 'novel' predictors added significant predictive value. The results support the notion that predictors of hearing aid uptake are also predictive of entering a HAEP. This study shows that some of these predictors appear to be gender specific or are dependent on a person's readiness for change. After assuring the external validity of the predictors, an important next step would be to develop prediction rules for use in clinical practice, so that older persons' hearing help-seeking journey can be facilitated. PMID- 29237335 TI - Patient-Centered Medical Home Measurement in School-Based Health Centers. AB - School-based health centers (SBHCs) have been suggested as potential medical homes, yet minimal attention has been paid to measuring their patient-centered medical home (PCMH) implementation. The purposes of this article were to (1) develop an index to measure PCMH attributes in SBHCs, (2) use the SBHC PCMH Index to compare PCMH capacity between PCMH certified and non-PCMH SBHCs, and (3) examine differences in index scores between SBHCs based in schools with and without adolescents. A total of six PCMH dimensions in the SBHC PCMH Index were identified through factor analysis. These dimensions were collapsed into two domains: care quality and comprehensive care. SBHCs recognized as PCMHs had higher scores on the index, both domains, and four dimensions. SBHCs based in schools with just young children and those with adolescents scored similarly on the overall index, but analysis of individual index items shows their strengths and weaknesses in PCMH implementation. PMID- 29237334 TI - The Association Between Cognitive Performance and Speech-in-Noise Perception for Adult Listeners: A Systematic Literature Review and Meta-Analysis. AB - Published studies assessing the association between cognitive performance and speech-in-noise (SiN) perception examine different aspects of each, test different listeners, and often report quite variable associations. By examining the published evidence base using a systematic approach, we aim to identify robust patterns across studies and highlight any remaining gaps in knowledge. We limit our assessment to adult unaided listeners with audiometric profiles ranging from normal hearing to moderate hearing loss. A total of 253 articles were independently assessed by two researchers, with 25 meeting the criteria for inclusion. Included articles assessed cognitive measures of attention, memory, executive function, IQ, and processing speed. SiN measures varied by target (phonemes or syllables, words, and sentences) and masker type (unmodulated noise, modulated noise, >2-talker babble, and <=2-talker babble. The overall association between cognitive performance and SiN perception was r = .31. For component cognitive domains, the association with (pooled) SiN perception was as follows: processing speed ( r = .39), inhibitory control ( r = .34), working memory ( r = .28), episodic memory ( r = .26), and crystallized IQ ( r = .18). Similar associations were shown for the different speech target and masker types. This review suggests a general association of r~.3 between cognitive performance and speech perception, although some variability in association appeared to exist depending on cognitive domain and SiN target or masker assessed. Where assessed, degree of unaided hearing loss did not play a major moderating role. We identify a number of cognitive performance and SiN perception combinations that have not been tested and whose future investigation would enable further fine-grained analyses of these relationships. PMID- 29237331 TI - Autism spectrum disorder: Consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. AB - An expert review of the aetiology, assessment, and treatment of autism spectrum disorder, and recommendations for diagnosis, management and service provision was coordinated by the British Association for Psychopharmacology, and evidence graded. The aetiology of autism spectrum disorder involves genetic and environmental contributions, and implicates a number of brain systems, in particular the gamma-aminobutyric acid, serotonergic and glutamatergic systems. The presentation of autism spectrum disorder varies widely and co-occurring health problems (in particular epilepsy, sleep disorders, anxiety, depression, attention deficit/hyperactivity disorder and irritability) are common. We did not recommend the routine use of any pharmacological treatment for the core symptoms of autism spectrum disorder. In children, melatonin may be useful to treat sleep problems, dopamine blockers for irritability, and methylphenidate, atomoxetine and guanfacine for attention deficit/hyperactivity disorder. The evidence for use of medication in adults is limited and recommendations are largely based on extrapolations from studies in children and patients without autism spectrum disorder. We discuss the conditions for considering and evaluating a trial of medication treatment, when non-pharmacological interventions should be considered, and make recommendations on service delivery. Finally, we identify key gaps and limitations in the current evidence base and make recommendations for future research and the design of clinical trials. PMID- 29237336 TI - A Call for Action to Combat the Growing Synthetic Opioid Epidemic: The Need for the Creation and Expansion of Addiction and Psychiatric Nursing Programs. PMID- 29237337 TI - Key interventions and quality indicators for quality improvement of STEMI care: a RAND Delphi survey. AB - OBJECTIVE: Identification, selection and validation of key interventions and quality indicators for improvement of in hospital quality of care for ST-elevated myocardial infarction (STEMI) patients. METHODS AND RESULTS: A structured literature review was followed by a RAND Delphi Survey. A purposively selected multidisciplinary expert panel of cardiologists, nurse managers and quality managers selected and validated key interventions and quality indicators prior for quality improvement for STEMI. First, 34 experts (76% response rate) individually assessed the appropriateness of items to quality improvement on a nine point Likert scale. Twenty-seven key interventions, 16 quality indicators at patient level and 27 quality indicators at STEMI care programme level were selected. Eighteen additional items were suggested. Experts received personal feedback, benchmarking their score with group results (response rate, mean, median and content validity index). Consequently, 32 experts (71% response rate) openly discussed items with an item-content validity index above 75%. By consensus, the expert panel validated a final set of 25 key interventions, 13 quality indicators at patient level and 20 quality indicators at care programme level prior for improvement of in hospital care for STEMI. CONCLUSIONS: A structured literature review and multidisciplinary expertise was combined to validate a set of key interventions and quality indicators prior for improvement of care for STEMI. The results allow researchers and hospital staff to evaluate and support quality improvement interventions in a large cohort within the context of a health care system. PMID- 29237338 TI - Client perfectionism and psychological symptoms throughout psychotherapy. AB - OBJECTIVE: Given the psychological issues experienced by individuals high in perfectionistic concerns (maladaptive perfectionism), or a feeling as if one is never good enough, and discrepancies in the literature as to whether these individuals experience benefits from therapy, it is imperative that research examine whether perfectionism actually improves throughout therapy. The current study improves upon past research by examining changes in perfectionism (both perfectionistic concerns and strivings) throughout therapy, rather than simply measuring perfectionism at pre- and post-therapy. This study also investigates how these changes in perfectionism, if they exist, impact changes in psychological symptoms. METHODS: In total, 153 clients at a psychology training clinic in which a general treatment paradigm was implemented completed the Short Almost Perfect Scale (SAPS; Rice et al., 2014) and Outcome Questionnaire (OQ 45.2; Lambert et al., 1996) prior to intake and sessions 1, 3, and 5. RESULTS AND CONCLUSIONS: Multilevel modeling results revealed that there were significant improvements in perfectionistic concerns and symptoms although, as expected, no significant changes in perfectionistic strivings were observed. Additionally, there was a trend effect for changes in perfectionistic concerns being associated with changes in symptoms. Further, results of latent difference score analyses revealed that changes in symptoms throughout therapy preceded changes in perfectionistic concerns. Clinical and methodological significance of this article: This study uses multilevel modeling (MLM) and latent difference score analyses to assess changes in perfectionism throughout therapy, whether they are associated with changes in symptoms, and whether changes in perfectionism precede changes in symptoms, or vice versa. To date, there have been discrepancies in the literature as to whether perfectionism improves throughout therapy, and most of these have only measured perfectionism at pre- and post-therapy. This study is an improvement over past studies as it measures perfectionism throughout therapy which has implications for therapy work with perfectionistic clients. PMID- 29237340 TI - United We Stand, As One Community. PMID- 29237339 TI - Multimodal rehabilitation in the late phase after stroke enhances the life situation of informal caregivers. AB - Purpose The burden of caregiving for stroke survivors is well known, but the effect of late stroke rehabilitation on the life situation of informal caregivers is unknown. Here, we assessed changes in the life situation of informal caregivers of stroke survivors enrolled in a multimodal intervention trial. Methods This controlled study was a questionnaire-based survey accompanying a three-armed randomized controlled trial of 123 stroke survivors. The care recipients of 106 caregivers who chose to participate were assigned to rhythm-and music-based therapy (R-MT; n = 37), horse-riding therapy (H-RT; n = 37), or delayed intervention (control group, n = 32). Perceived changes in the life situation of the caregivers were evaluated with the Life Situation among Spouses after the Stroke Event (LISS) questionnaire before randomization, after the 12 week intervention, and 3 and 6 months later. Results After the intervention, the change in the median LISS score was significantly higher among intervention caregivers (1.5 [interquartile range (IQR) 8.8]) than controls (1.5 [IQR 8.8] vs. 0.0 [IQR 12.0], p = 0.036). The improvement was maintained at 3 months (1.5 [IQR 9.0] vs. 0.0 [IQR 10.5], p = 0.039) but not at 6 months (p = 0.284). Conclusion Engaging stroke survivors in multimodal interventions late after stroke appears to have potential to produce gains also in the general life situation of informal caregivers. PMID- 29237343 TI - Advocacy, Leadership, and Transformation. PMID- 29237345 TI - Correction to: Asif et al., Genderwise clinical response of antipsychotics among schizophrenic patients: a prospective observational study from Lahore, Pakistan. PMID- 29237344 TI - Epithelial Myoepithelial Carcinoma of the Nasal Cavity: Clinical, Histopathological, and Immunohistochemical Distinction of a Case Report. AB - BACKGROUND: Epithelial myoepithelial carcinomas (EMCs) are rare low-grade salivary gland tumors. Here, we report the case of a 75-year-old man presenting with an oncocytic variant of EMC of the nasal cavity, initially diagnosed as an oncocytoma. METHODS: Our patient underwent functional sinus surgery in 2012. On pathology, an oncocytic neoplasm was found in the right nasal cavity, characterized by fragments of uniform bland oncocytic cells with bilayered arrangement of nuclei. Immunohistochemical stains demonstrated biphasic cells: luminal epithelial and basal cell-type myoepithelial cells. The tumor was best diagnosed as an oncocytoma. In 2015, the patient presented with a recurrent right inferior turbinate lesion, compatible with oncocytic EMC. RESULTS: The patient underwent oncological surgery and received adjuvant radiotherapy. He had no disease recurrence. CONCLUSION: Different variants of EMCs exist, such as oncocytic EMC. EMCs should be treated aggressively because they can be locally invasive, recur, and give rise to distant metastases. PMID- 29237342 TI - Racial-Ethnic Disparities in Late-Stage Colorectal Cancer Among Hispanics and Non Hispanic Whites of New Mexico. AB - INTRODUCTION: Hispanics in New Mexico are diagnosed with more later-stage colorectal cancer (CRC) than non-Hispanic Whites (NHW). Our study evaluated the interaction of race/ethnicity and risk factors for later-stage III and IV CRC among patients in New Mexico. METHOD: CRC patients ages 30 to 75 years ( n = 163, 46% Hispanic) completed a survey on key explanatory clinical, lifestyle, preventive health, and demographic variables for CRC risk. Adjusted logistic regression models examined whether these variables differentially contributed to later-stage CRC among NHW versus Hispanics. RESULTS: Compared with NHW, Hispanics had a higher prevalence of later-stage CRC ( p = .007), diabetes ( p = .006), high alcohol consumption ( p = .002), low education ( p = .003), and CRC diagnosis due to symptoms ( p = .06). Compared with NHW, Hispanics reporting high alcohol consumption (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.31 43.92), lower education (OR = 3.5; 95% CI = 1.28-9.65), being nondiabetic (OR = 3.23; 95% CI = 1.46-7.15), or ever smokers (OR = 2.4; 95% CI = 1.03-5.89) were at higher risk for late-stage CRC. Adjusting for CRC screening did not change the direction or intensity of the odds ratios. CONCLUSION: The ethnicity-risk factor interactions, identified for late-stage CRC, highlight significant factors for targeted intervention strategies aimed at reducing the burden of later-stage CRC among Hispanics in New Mexico with broad applicability to other Hispanic populations. PMID- 29237346 TI - Arachidonic Acid Reverses Xanthohumol-Induced Insufficiency in a Human First Trimester Extravillous Trophoblast Cell Line (HTR-8/SVneo Cells). AB - We previously described a negative effect of xanthohumol (XN) upon placentation related processes. We aimed to better characterize this effect by investigating the effect of XN upon the uptake of arachidonic acid (ARA), a crucial nutrient during pregnancy, by the HTR-8/SVneo human first-trimester extravillous trophoblast cell line and its relationship with the negative effect of XN upon placentation-related processes. Uptake of 14C-ARA (100 nM) was time dependent and inhibited by short-term (26 minutes) or long-term (24 hours) exposure to XN. Xanthohumol (24 hours; 5 uM) behaved as an uncompetitive inhibitor of 14C-ARA uptake; the mammalian target of rapamycin, tyrosine kinases, and c-Jun N-terminal kinases intracellular pathways were involved in this effect; and it markedly reduced long-chain acyl-CoA synthetase 1 messenger RNA levels. Moreover, the effects of XN (24 hours; 5 uM) upon cell proliferation, culture growth, migration, viability, and apoptosis index were prevented by high extracellular ARA but not by the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist rosiglitazone. We thus conclude that ARA is an essential nutrient regulating cell viability, proliferation, culture growth, migration, and apoptosis of HTR-8/SVneo cells and that the deleterious effects of XN involve inhibition of ARA cellular uptake but appears to be independent of PPAR-gamma activation. PMID- 29237347 TI - Pregnancy History Influences the Level of Autophagy in Peripheral Blood Mononuclear Cells From Pregnant Women. AB - OBJECTIVE: Maternal immune responses are altered during pregnancy and differ between nulliparous and multiparous women. The influence of a prior gestation on autophagy in peripheral blood mononuclear cells (PBMCs) from pregnant women has not been determined and is the subject of this investigation. METHODS: Peripheral blood mononuclear cells were isolated from 212 pregnant women and immediately lysed in the presence of protease inhibitors, and the extent of autophagy was determined by quantitation of the concentration of p62 (sequestosome-1) in the lysates by enzyme-linked immunosorbent assay (ELISA). In PBMCs, the p62 level is inversely related to the extent of autophagy. The level of the stress-inducible 70-kDa heat shock protein (hsp70), an inhibitor of autophagy, was also measured in the lysates by ELISA. Data were analyzed by the Spearman rank correlation, Mann-Whitney U test, or Kruskal-Wallis test, as appropriate. RESULTS: The p62 concentration in PBMCs increased (autophagy decreased) with the number of previous live ( P = .0322), preterm ( P = .0143), or term ( P = .0418) deliveries. The p62 level was lower (autophagy higher) in women with a prior spontaneous pregnancy loss but no deliveries as compared to women with their first conception ( P = .0087). The intracellular hsp70 concentration correlated with the p62 level ( P < .0001). CONCLUSION: Multiparity is associated with a reduced level of autophagy in PBMCs. Dysregulated autophagy might be one mechanism leading to spontaneous abortion in nulliparous women. PMID- 29237348 TI - Developmental Programming: Impact of Prenatal Testosterone Excess on Steroidal Machinery and Cell Differentiation Markers in Visceral Adipocytes of Female Sheep. AB - Prenatal testosterone (T)-treated female sheep manifest reduced adipocyte size and peripheral insulin resistance. The small adipocyte phenotype may reflect defects in adipogenesis and its steroidal machinery. To test whether prenatal T treatment from gestational days 30 to 90 alters the visceral adipose tissue (VAT) steroidal machinery and reduces adipocyte differentiation, we examined expression of the steroidogenic enzymes, steroid receptors, and adipocyte differentiation markers at fetal day 90 and postnatal ages 10 and 21 months. Because gestational T treatment increases fetal T and maternal insulin, the contributions of these were assessed by androgen receptor antagonist or insulin sensitizer cotreatment, either separately (at fetal day 90 and 21 months of age time points) or together (10 months of age). The effects on adipogenesis were assessed in the VAT-derived mesenchymal stem cells (AT-MSCs) from pre- and postpubertal time points to evaluate the effects of pubertal steroidal changes on adipogenesis. Our results show that VAT manifests potentially a predominant estrogenic intracrine milieu (increased aromatase and estrogen receptor alpha) and reduced differentiation markers at fetal day 90 and postnatal 21 months of age. These changes appear to involve both androgenic and metabolic pathways. Preliminary findings suggest that prenatal T treatment reduces adipogenesis, decreases expression of differentiation, and increases expression of commitment markers at both pre- and postpubertal time points. Together, these findings suggest that (1) increased commitment of AT-MSCs to adipocyte lineage and decreased differentiation to adipocytes may underlie the small adipocyte phenotype of prenatal T-treated females and (2) excess T-induced changes in steroidal machinery in the VAT likely participate in the programming/maintenance of this defect. PMID- 29237350 TI - Abstracts from the Society for Pediatric Pathology Spring 2017 Meeting, March 3rd 5th, San Antonio, Texas. PMID- 29237349 TI - Administration of Oral Contraceptives Could Alleviate Age-Related Fertility Decline Possibly by Preventing Ovarian Damage in a Mouse Model. AB - Age-related fertility decline is hypothesized to occur mainly by the spontaneous exhaustion and deterioration of the ovarian follicle, and the accumulation of ovarian tissue damage resulting from the ovulation cycle may play roles in the process. In this study, we hypothesized that suppressing ovulation would exert protective effects against age-related fertility decline. To test this hypothesis, we established a mouse model in which oral contraceptives (OCs) were administered daily. Female C57BL/6N mice were administered OCs daily from the age of 2 months to 12 months as an ovulation suppression mouse model. Mouse fecundity was investigated by counting oocyte number after ovarian stimulation and by examining live fetuses after mating. We found that compared with control mice administered vehicle alone, 12-month-old mice administered 2-fold dose OCs used for treating humans exhibited a significantly greater average oocyte number after ovarian stimulation (8.5 +/- 0.6 vs 5.9 +/- 0.6, P < .01). In addition, spontaneous conception with living fetuses after mating was strikingly increased in 12-month-old mice administered OCs relative to controls (6.0 +/- 1.2 vs 0.4 +/ 0.3, P < .01). In the histological examination of mouse ovarian tissues, we did not detect a significant difference in ovarian follicle number, but reduced amount of brownish foamy fibrous tissues, which might reflect ovarian tissue damage, was detected in aged mice administered OCs. These results suggest the possibility that long-term OC administration might alleviate age-related fertility decline, and the improvement mechanism could be attributed to the prevention of ovarian tissue damage by suppressing ovulation. PMID- 29237351 TI - Fabrication and characterization of a novel collagen-catechol hydrogel. AB - 3,4-Dihydroxybenzaldehyde, a derivative of catechol and an agent with an extensive pharmacological and biological activities, was used to modify collagen and prepared hydrogels. The aldehyde group of 3,4-dihydroxybenzaldehyde interacted with the E-amino group of collagen, and then the catechol group of 3,4 dihydroxybenzaldehyde was oxidized and self-polymerized. The chemical network formed due to the cross-linking bridges of polymerized catechol groups among collagen molecules, resulting in the transformation from solution to hydrogel. The results of the Fourier-transform infrared measurement indicated that the triple helix structure of collagen was integrated after cross-linking. The appearance of hydrogels changed from golden to dark brown with the increasing 3,4 dihydroxybenzaldehyde dose. When the weight ratio of 3,4-dihydroxybenzaldehyde and collagen increased from 0 to 2:1, the thermal denaturation temperature of collagen increased from 40.2 to 77.6C while the elastic modulus of collagen increased from 13.6 to 1061.4 Pa. The addition of 3,4-dihydroxybenzaldehyde also caused more compact morphologies and a dramatic enhancement in the enzymatic resistance of hydrogels. Moreover, the results of cell proliferation assay demonstrated the favorable biocompatibility of collagen hydrogels with 3,4 dihydroxybenzaldehyde. These promising data indicate that the novel hydrogels had significant potential for applications. PMID- 29237352 TI - Influence of patterned titanium coatings on polarization of macrophage and osteogenic differentiation of bone marrow stem cells. AB - Biomaterial surface topography plays a vital role in the osteointegration of implants by regulating the early cell responses and tissue growth-in. However, most of the previous researches focused on the effects of osteogenic cells, only a little is known about the immune cells which dominate osteogenesis after implanting. In this paper, patterned titanium coatings were fabricated and the effects of surface topography on the macrophage behaviors were investigated. On patterned titanium surface, macrophages preferred to polarize to M2, while macrophages on traditional titanium coatings presented higher M1 polarization. Nearly 70% higher expression of anti-inflammatory genes, including interleukin-4, interleukin-10, interleukin-1ra, and arginase, were detected on the patterned titanium coatings. While the pro-inflammatory genes, such as interleukin-1beta, interleukin-6, tumor necrosis factor-alpha, interferon-gamma, and inducible nitric oxide synthase were notably depressed. Up-regulation of the osteoinductive cytokines were also detected on the patterned coatings, which indicated advantageous osteogenic microenvironment provided by macrophages. Immunomodulation effect on osteogenesis was also investigated in this study. Stimulated with RAW cells/patterned coatings conditioned medium, bone marrow stem cells presented nearly 1.5 fold higher expression of osteogenic genes and more mineralization nodules than the traditional sprayed Ti coatings. All these results suggested that modulating materials with a patterned surface might be a valuable strategy to endow the implants with favorable osteoimmunomodulatory properties. PMID- 29237353 TI - Role of geometrical cues in bone marrow-derived mesenchymal stem cell survival, growth and osteogenic differentiation. AB - Mesenchymal stem cells play a vital role in bone formation process by differentiating into osteoblasts, in a tissue that offers not a flat but a discontinuous three-dimensional (3D) topography in vivo. In order to understand how geometry may be affecting mesenchymal stem cells, this study explored the influence of 3D geometry on mesenchymal stem cell-fate by comparing cell growth, viability and osteogenic potential using monolayer (two-dimensional, 2D) with microsphere (3D) culture systems normalised to surface area. The results suggested lower cell viability and reduced cell growth in 3D. Alkaline phosphatase activity was higher in 3D; however, both collagen and mineral deposition appeared significantly lower in 3D, even after osteogenic supplementation. Also, there were signs of patchy mineralisation in 3D with or without osteogenic supplementation as early as day 7. These results suggest that the convex surfaces on microspheres and inter-particulate porosity may have led to variable cell morphology and fate within the 3D culture. This study provides deeper insights into geometrical regulation of mesenchymal stem cell responses applicable for bone tissue engineering. PMID- 29237354 TI - The Views of the Public on Youth Offenders and the New Zealand Criminal Justice System. AB - Public perceptions of crime and punishment have taken on increasing importance as countries grapple with how to address youth violence. The current study aimed to compare the views of those who have had personal experience of victimisation from youth offenders and those who have not, on what could be improved in managing youth offending in New Zealand. A qualitative methodology was used with data from open-ended survey responses from a nationally representative sample. Public sentiments favoured addressing systemic issues and providing rehabilitation as main emphases followed by more punitive measures, prevention, and restorative justice. Victims were over-represented on sentiments of prevention whereas non victims were over-represented in support for more punitive measures and restorative justice. There was also considerable support for a multi-facetted approach that utilised a number of the approaches above, suggesting that the solution is as complex as the offender's circumstances. These findings are very much in line with the current goals of the youth justice system with its emphasis on diversion and rehabilitation. PMID- 29237355 TI - Cross-cultural Adaptation of the Victorian Institute of Sport Assessment-Achilles (VISA-A) Questionnaire for Spanish Athletes With Achilles Tendinopathy. AB - Study Design Clinical measurement study. Background Achilles tendinopathy is a prevalent sport-related injury. The Victorian Institute of Sport Assessment Achilles (VISA-A) questionnaire is a widely used patient-reported outcome to assess the severity of symptoms for this injury. Objective To adapt the VISA-A questionnaire into Spanish and to assess its psychometric properties. Methods Cross-cultural adaptation was conducted according to recommended guidelines. The Spanish VISA-A (VISA-A-Sp) questionnaire was administered to 210 subjects: 70 healthy students, 70 active at-risk subjects (participating in running and jumping), and 70 patients diagnosed with Achilles tendinopathy. Participants were assessed at baseline and after 3 to 5 days. The injured subjects were also evaluated with a quality-of-life questionnaire (Medical Outcomes Study 36-Item Short-Form Health Survey [SF-36]) and at discharge. The final VISA-A-Sp was evaluated for reliability, validity, and responsiveness. Results Cronbach alpha for the VISA-A-Sp was greater than .8. The intraclass correlation coefficient (model 2,1) was 0.993 (95% confidence interval: 0.991, 0.995; P<.05). In the confirmatory factor analysis, a 1-factor solution obtained a relatively good fit. Subjects with Achilles tendinopathy scored significantly lower than the other 2 groups (P<.001). The VISA-A-Sp score within the Achilles tendinopathy group showed significant correlations with SF-36 physical components (Spearman rho>0.5, P<.001). The standard error of the measurement was 2.53, and the minimal detectable change at the 95% confidence level was 7 points. The responsiveness indicators included an effect size of 2.16 and a standardized response mean of 1.92. Conclusion The VISA-A-Sp showed satisfactory psychometric properties that were comparable to the original English-language version. Therefore, it can be recommended for use in clinical practice and research for assessing the severity of symptoms in Spanish-speaking athletes who suffer from Achilles tendinopathy. J Orthop Sports Phys Ther 2018;48(2):111-120. Epub 13 Dec 2017. doi:10.2519/jospt.2018.7402. PMID- 29237356 TI - The Influence of Injury Definition on Injury Burden in Preprofessional Ballet and Contemporary Dancers. AB - Study Design Cohort study. Background Multiple operational definitions of injury exist in dance research. The influence that these different injury definitions have on epidemiological estimations of injury burden among dancers warrants investigation. Objective To describe the influence of injury definition on injury prevalence, incidence, and severity in preprofessional ballet and contemporary dancers. Methods Dancers registered in full-time preprofessional ballet (n = 85; 77 female; median age, 15 years; range, 11-19 years) and contemporary (n = 60; 58 female; median age, 19 years; range, 17-30 years) training completed weekly online questionnaires (modified Oslo Sports Trauma Research Centre questionnaire on health problems) using 3 injury definitions: (1) time loss (unable to complete 1 or more classes/rehearsals/performances for 1 or more days beyond onset), (2) medical attention, and (3) any complaint. Physical therapists completed injury report forms to capture dance-related medical attention and time-loss injuries. Percent agreement between injury registration methods was estimated. Injury prevalence (seasonal proportion of dancers injured), incidence rates (count of new injuries per 1000 dance-exposure hours), and severity (total days lost) were examined across each definition, registration method, and dance style. Results Questionnaire response rate was 99%. Agreement between registration methods ranged between 59% (time loss) and 74% (injury location). Depending on definition, registration, and dance style, injury prevalence ranged between 9.4% (95% confidence interval [CI]: 4.1%, 17.7%; time loss) and 82.4% (95% CI: 72.5%, 89.8%; any complaint), incidence rates between 0.1 (95% CI: 0.03, 0.2; time loss) and 4.9 (95% CI: 4.1, 5.8; any complaint) injuries per 1000 dance-hours, and days lost between 111 and 588 days. Conclusion Time-loss and medical-attention injury definitions underestimate the injury burden in preprofessional dancers. Accordingly, injury surveillance methodologies should consider more inclusive injury definitions. J Orthop Sports Phys Ther 2018;48(3):185-193. Epub 13 Dec 2017. doi:10.2519/jospt.2018.7542 Level of Evidence Symptom prevalence study, level 1b. PMID- 29237357 TI - Understanding of the significance and health implications of asplenia in a cohort of patients with haemaglobinopathy: possible benefits of a spleen registry. AB - OBJECTIVES: Asplenia and hyposplenism carry a significant risk of ongoing morbidity and mortality which can be reduced by education, vaccination and antibiotic use. We aimed to assess education and other methods of prevention in a cohort of patients with haemoglobinopathy in a tertiary referral centre, which also had access to a post-splenectomy registry created to reduce post-splenectomy infection risk. METHODS: A standardized questionnaire was used on patients who attended the service for regular therapy. Patients were also asked about standard post-splenectomy preventive therapies including antibiotics and vaccinations. RESULTS: There were 49 patients who had either had a splenectomy or knew their spleen to be non-functional. Of these, nearly half knew themselves to be on the Victorian Spleen Registry (51.0%). The median knowledge score was 12 (range 4-17) out of a possible 18. Most significantly the benefits of the registry were not seen in terms of knowledge but in delivery of recommended vaccines and the use of a medical alert card. CONCLUSION: This study examined knowledge and attitudes about splenectomy in a cohort of haemoglobinopathy patients in an Australian tertiary referral centre. The majority had good or fair knowledge with a strong association of some elements of post-splenectomy care with being placed on a spleen registry and having received targeted education. Implementation of systematic approaches by medical staff is likely to be the main benefit of a clinical registry approach in this setting. PMID- 29237358 TI - On the relationship of anthranilic derivatives structure and the FXR (Farnesoid X receptor) agonist activity. AB - Farnesoid X receptor (FXR) is a nuclear receptor related to lipid and glucose homeostasis and is considered an important molecular target to treatment of metabolic diseases as diabetes, dyslipidemia, and liver cancer. Nowadays, there are several FXR agonists reported in the literature and some of it in clinical trials for liver disorders. Herein, a compound series was employed to generate QSAR models to better understand the structural basis for FXR activation by anthranilic acid derivatives (AADs). Furthermore, here we evaluate the inclusion of the standard deviation (SD) of EC50 values in QSAR models quality. Comparison between the use of experimental variance plus average values in model construction with the standard method of model generation that considers only the average values was performed. 2D and 3D QSAR models based on the AAD data set including SD values showed similar molecular interpretation maps and quality (Q2LOO, Q2(F2), and Q2(F3)), when compared to models based only on average values. SD-based models revealed more accurate predictions for the set of test compounds, with lower mean absolute error indices as well as more residuals near zero. Additionally, the visual interpretation of different QSAR approaches agrees with experimental data, highlighting key elements for understanding the biological activity of AADs. The approach using standard deviation values may offer new possibilities for generating more accurate QSAR models based on available experimental data. PMID- 29237359 TI - Safety and Outcomes of Ipsilateral Antegrade Angioplasty for Femoropopliteal Disease. AB - PURPOSE: Previous reports have suggested higher periprocedural complications after ipsilateral antegrade femoral arterial access (AA). We looked at a contemporary series comparing complication rates between AA and contralateral retrograde femoral arterial access (RA) for femoropopliteal angioplasty. METHOD: A prospective review of all cases between 2010 and 2015 in a United Kingdom tertiary vascular center. Demographical and procedural data were obtained for those undergoing percutaneous femoropopliteal angioplasty. The primary outcome looked at periprocedural complications including retroperitoneal hematoma, pseudoaneurysm, hematoma requiring transfusion, arteriovenous fistulation, and surgical intervention. Secondary outcomes included contrast and radiation doses in addition to procedural failure leading to major amputation. RESULTS: A total of 556 (66% male) patients underwent femoropopliteal angioplasty, 461 (82%) via AA. Groups were of comparable age, sex, comorbidity, and symptomatology. AA patients had a lower body mass index, 26 versus 29 ( P = .005). No significant difference was seen in periprocedural (15.8% AA vs 11.6% RA; P = 0.292) or access site complications (3.7% AA vs 1.1% RA; P = 0.186). There was less need for a closure device, 40.3% AA vs 73% RA ( P < .01), less contrast, 94 mL AA: 114 mL RA ( P < .001), and less radiation, 3487 cGy cm2 AA: 9697 cGy cm2 RA ( P < .001). Arterial access was also associated with greater technical success of 83.8%: 73.3% RA ( P = .002). CONCLUSIONS: Arterial access is associated with higher technical success and reduced contrast/radiation doses with no significant difference in complications compared to RA contrary to previous reports. PMID- 29237360 TI - Endovascular Treatment of Thromboangiitis Obliterans (Buerger's Disease). AB - PURPOSE: When critical limb ischemia (CLI) occurs in patients with thromboangiitis obliterans (TAO) or Buerger's disease, smoking cessation alone may be insufficient to relieve rest pain and promote wound healing. Accordingly, adjunctive measures are warranted to restore adequate blood flow required for limb salvage. This study aimed to evaluate the feasibility and efficacy of percutaneous transluminal angioplasty (PTA) for the treatment of patients with TAO and CLI. In addition, a review of the literature on endovascular management of TAO is included. METHODS: Between April 2012 and June 2017, all patients with TAO and CLI who underwent PTA were studied retrospectively. Patient demographics, presentation, procedural details, and clinical response were recorded. Patients were monitored at 1 week, 1, 2, 3, and 6 months after revascularization and at least every 6 months thereafter. RESULTS: Thirteen patients with TAO and CLI, who presented with rest pain only (n = 1), ischemic ulcer (n = 4), or gangrene (n = 8) underwent endovascular interventions with primary and assisted primary technical success of 85% and 92%, respectively. A below-knee amputation was eventually done in the only patient with technical failure (limb salvage rate: 92%). Following the procedures, 11 patients had clinical response, one of whom also received intra-arterial vasodilator to achieve complete symptom relief. The other patient who failed PTA underwent a successful lumbar sympathectomy. In addition, all ulcers healed and eight minor amputations were performed due to already established gangrene. During follow-up (mean: 19.4 months), four patients needed reintervention. Patients who continued to smoke experienced more severe ischemia ( P = .017) and were more likely to require reintervention ( P = .009). CONCLUSION: Percutaneous transluminal angioplasty can be considered as a technically feasible and potentially effective treatment for patients with TAO and CLI, as well as a last resort for limb salvage when other options have failed. However, reintervention may be required, especially in patients who continue smoking. PMID- 29237361 TI - Hybrid Endovascular Aortic Arch Reconstruction for Acute Aortic Dissection: An Endovascular Bridge Technique for Complex Anatomy. AB - Acute type A aortic dissections starting at the arch pose a challenge for cardiac surgeons. Open surgical repair requires deep hypothermic circulatory arrest for arch reconstruction and is associated with significant morbidity and mortality. Hybrid aortic repair techniques, with open arch debranching and thoracic endovascular aortic repair, have been employed in high-risk cases and challenging aortic pathology. Herein, we present a case of a 33-year-old African American male with a history of open thoracoabdominal aortic reconstruction and femoral femoral artery bypass for a type B dissection who subsequently presented with new onset chest pain and was found to have a retrograde type A dissection of a bovine arch with multiple dissection flaps and possible contrast extravasation on chest computed tomography. Endovascular reconstruction of the aortic arch using a hybrid technique was utilized and proved to be feasible and further should be considered when complex anatomy limits traditional surgical options. PMID- 29237362 TI - De Novo Malignancies After Liver Transplantation: A Single Institution Experience. AB - OBJECTIVES: Our objective was to analyze characteristics, risk factors, and incidence of de novo malignancies after liver transplant. MATERIALS AND METHODS: The hospital records of 557 patients who underwent liver transplant were analyzed from the point of de novo malignancy development. We evaluated the demographic features and survival of these patients retrospectively. RESULTS: The research covered 429 patients, 9 (2%) of whom developed de novo malignancy. All of these patients were male (100%), and their mean (SD) age was 51.33 (4.69) years (range, 45-65 y). Indications for transplant included alcohol related in 4 cases, chronic hepatitis B in 2 cases, chronic hepatitis B and C in 1 case, chronic hepatitis B and D in 1 case, and chronic hepatitis C and alcohol-related cirrhosis in 1 case. The mean (SD) time from transplant to cancer diagnosis was 63.41 (37.10) months (range, 17-122 mo). The types of tumors were lung cancer, lymphoma, neuroendocrine tumor of lung, nasopharyngeal cancer, and squamous cell carcinoma of the skin. Seven cases received chemotherapy with or without radiotherapy. Two cases received surgery and radiotherapy. One patient underwent surgical treatment. One patient died before treatment was started. CONCLUSIONS: In recent years, improvements in surgical techniques and immunosuppressive therapies have helped prolong survival of patients who undergo liver transplant. However, this also has led to a rise in the incidence of long-term complications such as de novo malignancy. These patients are more likely to develop de novo malignancy than the general population, for which chronic immunosuppression is identified as a major risk factor. Early diagnosis and treatment of de novo malignancies can help obtain better prognosis and higher survival rates in these patients. PMID- 29237363 TI - Incorporation of an N-methyl Amino Acid into a Template Peptide Alters Anisotropy in the Crystal Growth of Gold Nanoparticles Synthesized by the Peptide Template Method. AB - BACKGROUND: Gold nanocrystals have unique physicochemical and biocompatible properties, and hold promise for use as catalysts and in the fields of electronics, photonic and/or plasmonic devices, sensing and/or imaging systems, targeted drug delivery, and photothermal therapies. A variety of organic templates have been used to control the size, shape, and structure of gold nanocrystals, and to modify their surfaces. For the control of the shape of gold nanocrystals, we previously designed and synthesized a beta-sheet-forming nonapeptide (RU006: Ac- AIAKAXKIA-NH2, X = L-2-naphthylalanine, Nal). A mixture of RU006 and HAuCl4 in water produced ultrathin gold nanoribbons with 50-100 nm wide, several nanometers high, and microns long. OBJECTIVES: The main objective of this study is the control of the nanoribbon crystal growth by designing and synthesizing RU006 analogs containing an N-methyl-L-alanine residue. METHODS: We report (i) the design and synthesis of four RU006 analogs in which an L-alanine (Ala) at four positions in the RU006 sequence (N-methylated RU006 analogs) is replaced with an N-methyl alanine, (ii) conformational and morphological analyses of the self-assembled Nmethylated RU006 analogs, (iii) gold nanocrystal synthesis by the peptide templating method with N-methylated RU006 analogs, and (iv) the roles of peptide self-assembly in anisotropic gold crystal growth. RESULTS: RU006 with an N-methyl moiety at the center position resulted in flattened/platelet gold nanocrystals. It was also found that decreasing the mole fraction of RU006 in mixtures with Nmethylated RU006 analogs afforded significantly different absorption spectra compared to that obtained using RU006 alone under gold nanocrystal synthesis conditions. CONCLUSION: We found that morphology of gdd nanocrystals is significantly affected by electron transfer from the naphthalene rings to HAuCl4, accompanied by cross-linking reactions between spatially adjacent naphthalene rings within the hydrophobic cavity of a template assembly. PMID- 29237364 TI - alpha-Helical Peptide-Gold Nanoparticle Hybrids: Synthesis, Characterization, and Catalytic Activity. AB - BACKGROUND: Gold nanoparticles are promising nanomaterials for catalytic reactions, sensing/imaging systems, photonic/plasmonic devices, and electronics because of their unique physical and chemical properties. To date, significant catalytic activities of gold nanoparticles have been reported for reactions such as carbon monooxide oxidation and 4-nitrophenol reduction, and diverse gold nanoparticle morphologies such as nanospheres, wires, rods, and cubes have been achieved using a variety of capping/stabilizing organic molecules. However, there are few reports on the simultaneous assembly of peptides forming secondary structures and metallic nanoparticles into peptide-metallic particle hybrids under mild aqueous conditions and demonstration of their use as catalysts. Furthermore, the gold nanoribbon surfaces are covered with beta-sheet structures, disrupting the access of substrates to the active sites, thereby possibly inhibiting their catalytic activity. OBJECTIVES: The main objective of this study is design, synthesis, and characterization of peptidegold nanoparticle hybrids that are prepared by an alpha-helical conformation of a template and examination of the catalytic activities of the hybrids. METHODS: We here report (i) the design, synthesis, and characterization of a new template peptide, RU025, that tends to form an alpha-helical conformation and self-assembles into network nanoarchitectures in aqueous solution through possibly hydrophobic and electrostatic interactions, (ii) the characterization of gold seed crystals synthesized by mixing RU025 and HAuCl4, (iii) the characterization of peptide gold nanoparticle hybrids directed by crystal growth with NaBH4 and the dependence on the conditions used for nucleation, and (iv) the catalytic activities of the hybrids towards the reduction of 4-nitrophenol to 4-aminophenol in the presence of excess NaBH4. RESULTS: We demonstrated the design, synthesis, and characterization of a new template peptide, RU025, that tends to form an alpha-helical conformation and self-assembles into network nanoarchitectures in aqueous solution. Gold seed crystals were synthesized by mixing RU025 and HAuCl4 in a 1:2 molar ratio, followed by further reduction of the gold seed crystals with NaBH4. This reaction afforded worm-like gold nanoparticles embedded in the peptide self-assemblies. The peptide-gold nanoparticle hybrids exhibited catalytic activities for the Langmuir-Hinshelwood type reduction of 4-nitrophenol to 4-aminophenol in the presence of excess NaBH4, with an activation energy of 33 kJ mol-1. CONCLUSION: The size and morphology of gold nanoparticles can be tuned in the nanometer range by altering the peptide concentration relative to HAuCl4 and by changing the nucleation time. This method for constructing peptide metallic nanoparticle hybrids, in which metallic nanoparticles are dispersed in the peptide self-assemblies, provides highly reactive catalysts. PMID- 29237365 TI - Synergic Strategies for the Enhanced Self-Assembly of Biomineralization Peptides for the Synthesis of Functional Nanomaterials. AB - INTRODUCTION: Peptide-mediated biomineralization is a promising bioinspired technique of nanostructure formation. The biomineralization peptide is responsible for the regulation of the growth and morphology of the inorganic nanostructure. The 3D properties of the biomineralization peptide is a crucial factor in which the success of creating functional nanomaterials depends on. However, given the relatively short sequence of most biomineralization peptides, controlling the multivalency and spatial orientation of the peptide can be a challenging endeavor. OBJECTIVE: This mini-review details recent advances in enhancing the self-assembly and 3D properties of the biomineralization peptide. The design and creation of fusion peptides is highlighted, which involves the conjugation of the biomineralization peptide with a control element. The control element is responsible for directing the self-assembly of the biomineralization peptide. CONCLUSION: A variety of control elements that can direct the self assembly of biomineralization peptides are available. The control element can be a small organic molecule such as a biphenyl, or a peptide segment such as the p53 tetramerization domain or the amyloid peptide. The high diversity of existing control elements further increases the ability of peptide-mediated biomineralization to create functional nanomaterials. PMID- 29237366 TI - Antigen-Antibody Interaction-Based Self-Healing Capability of Hybrid Hydrogels Composed of Genetically Engineered Filamentous Viruses and Gold Nanoparticles. AB - BACKGROUND: Filamentous M13 phages have recently been utilized as components for developing novel functional soft materials in various fields such as sensor, device, and biomedical applications. Recently, we have developed liquid crystalline hydrogels composed of M13 phages and gold nanoparticles (GNPs) based on specific interactions between the components. OBJECTIVES: The main objective of this study was to clarify the self-healing capability of the hydrogels composed of M13 phages and GNPs. METHODS: M13 phages displaying tag peptides with a sequence of YPYDVPDYA (HA phages) were genetically constructed through general molecular biology. The mechanical strength of hydrogels composed of the HA phages and anti-HA peptide antibodies-immobilized GNPs (HA-GNPs) was measured by indentation tests. The rupture point of the hydrogels was visually observed. An aliquot of buffer solution was added into the rupture point of the hydrogels after the indentation test. After incubation for 2 days, self-healing of the rupture point was checked visually. The indentation test was also performed after self-healing. To clarify the assembled structures of the components in the hydrogels, transmission electron microscopy (TEM) observation was performed by transferring the hydrogel onto a TEM grid before and after healing. RESULTS: The strength of the original hydrogel (before self-healing) required for rupture was approximately 55 mN. Self-healing of the rupture point was confirmed visually, and the hydrogels behaved as uniform hydrogels again during the vial inversion tests. As a result of the indentation test for the self-healed points of the hydrogels, the rupture force of approximately 45 mN was detected, indicating the self-healing capability of the hydrogels. TEM observation of the before and after self-healing exhibited the regularly assembled structures composed of the HA GNPs, suggesting that the ruptured networks were recovered into regularly assembled network structures. Importantly, control of the concentration of the HA GNPs resulted in suppression of decreasing the rupture forces during the repetitive self-healing processes. CONCLUSION: Our results demonstrated the self healing capability of structurally regular hybrid hydrogels composed of genetically engineered filamentous viruses displaying antigen peptides and antibody-immobilized GNPs. The results indicated that supramolecular hydrogels containing filamentous viruses would expand the applicability of virus-based soft materials. PMID- 29237367 TI - Peptides for Silica Precipitation: Amino Acid Sequences for Directing Mineralization. AB - BACKGROUND: Peptides are promising compounds for use in inorganic or organic inorganic hybrid syntheses (mineralization) and offer several advantages over proteins. Meanwhile, silica-based nanomaterials have been extensively investigated for many years because of their potential application in a diverse range of technologies, including catalysis, sensing, separation, enzyme immobilization, and gene and drug delivery. Considerable progress has been made over the past decade in understanding the molecular mechanisms underpinning biosilicification and the biomimetic synthesis of patterned nanosilica using peptides. OBJECTIVES: This mini-review focuses on various peptide sequences, especially short peptide sequences (30 residues or less), for silica mineralization. METHODS: We first briefly review early studies on silica mineralization using proteins to provide background information. This is followed by a discussion of promising peptide sequences and attempts to discern the relationship between amino acid sequence, their potential for mineralization, and the properties of the mineral product. RESULTS: The synthetic control of silica mineralization using engineered proteins, such as recombinant silicateins and silaffins, was inspired by silica biomineralization by natural proteins from organisms (sponges, diatoms, and plants). Concurrently, several papers described the utility of well-structured protein assemblies as templates for silica mineralization. These template-directed syntheses of well-structured silica deposits were first conducted using natural proteins or protein assemblies such as collagen fibers and virus hollow protein tubes. Then we reviewed a selection of short peptides (30 residues or less) that had been successfully used for silica mineralization. Almost all peptides developed to date can be sorted by classification like proteins (synthetic control of silica mineralization or utility of templates for silica mineralization): the first class of peptides is used for peptide-directed synthesis, and the second is used for template-directed synthesis after the peptides have assembled and formed nanostructure such as fibers and tubes. The presented peptides were classified and arranged according to the classification. Additionally, we briefly introduced silica mineralization triggered by the combination of short silica-precipitating peptides and template molecules. CONCLUSION: In this mini-review we focused on various peptide sequences, especially short peptide sequences of 30 residues or less, designed for silica mineralization. The peptides have been used both for peptide-directed silica mineralization and for template-directed silica mineralization. The recent advances in peptide-driven mineralization reviewed here suggest that it will soon be possible to completely control the silica mineralization process using peptides. Mineralization systems using peptides will provide researchers with new tools for controlling various inorganic syntheses and the production of organic inorganic materials for nanobiochemistry and materials chemistry research. PMID- 29237368 TI - Smartphone Assisted Naked Eye Detection of Mercury (II) Ion using Horseradish Peroxidase Inhibitive Assays. AB - BACKGROUND: Mercury (II) ion, Hg2+ is among the most common pollutants with the ability to affect the environment. The implications of their elevation in the environment are mainly due to the industrialization and urbanization process. Current methods of Hg2+ detection primarily depend on sophisticated and expensive instruments. Hence, an alternative and practical way of detecting Hg2+ ions is needed to go beyond these limitations. Here, we report a detection method that was developed using an inhibitive enzymatic reaction that can be monitored through a smartphone. Horseradish peroxidase (HRP) converted 4-aminoantipyrene (4 AAP) into a red colored product which visible with naked eye. A colorless product, on the other hand, was produced indicating the presence of Hg2+ that inhibit the reaction. OBJECTIVES: The aim of this study is to develop a colorimetric sensor to detect Hg2+ in water sources using HRP inhibitive assay. The system can be incorporated with a mobile app to make it practical for a prompt in-situ analysis. METHODS: HRP enzyme was pre-incubated with different concentration of Hg2+ at 37 degrees C for 1 hour prior to the addition of chromogen. The mix of PBS buffer, 4-AAP and phenol which act as a chromogen was then added to the HRP enzyme and was incubated for 20 minutes. Alcohol was added to stop the enzymatic reaction, and the change of colour were observed and analyse using UV-Vis spectrophotometer at 520 nm wavelength. The results were then analysed using GraphPad PRISM 4 for a non-linear regression analysis, and using Mathematica (Wolfram) 10.0 software for a hierarchical cluster analysis. The samples from spectroscopy measurement were directly used for dynamic light scattering (DLS) evaluation to evaluate the changes in HRP size due to Hg2+ malfunctionation. Finally, molecular dynamic simulations comparing normal and malfunctioned HRP were carried out to investigate structural changes of the HRP using YASARA software. RESULTS: Naked eye detection and data from UV-Vis spectroscopy showed good selectivity of Hg2+ over other metal ions as a distinctive color of Hg2+ is observed at 0.5 ppm with the IC50 of 0.290 ppm. The mechanism of Hg2+ inhibition towards HRP was further validated using a dynamic light scattering (DLS) and molecular dynamics (MD) simulation to ensure that there is a conformational change in HRP size due to the presence of Hg2+ ions. The naked eye detection can be quantitatively determined using a smartphone app namely ColorAssist, suggesting that the detection signal does not require expensive instruments to be quantified. CONCLUSION: A naked-eye colorimetric sensor for mercury ions detection was developed. The colour change due to the presence of Hg2+ can be easily distinguished using an app via a smartphone. Thus, without resorting to any expensive instruments that are mostly laboratory bound, Hg2+ can be easily detected at IC50 value of 0.29 ppm. This is a promising alternative and practical method to detect Hg2+ in the environment. PMID- 29237369 TI - Signal Enhancement Strategies for Refractive Index-Sensitive Nanobiosensor. AB - BACKGROUND: Direct bio-monitoring essentially involves optical means since photon has insignificant effects over biomolecules. Over the years, laser induced surface Plasmon resonance method with various modifications as well as versatile localized Plasmon excited by incoherent light have facilitated in recording many nanobiological activities. Yet, monitoring interactions of small molecules including drugs requires signal amplification and improvement on signal-to-noise ratio. OBJECTIVES: This paper focused on how the refractive index based nanobio sensoring gold platform can produce more efficient, adaptable and more practical detection techniques to observe molecular interactions at high degree of sensitivity. It discusses surface chemistry approach, optimisation of the refractive index of gold platform and manipulation of gold geometry augmenting signal quality. METHODS: In a normal-incidence reflectivity, r0 can be calculated using the Fresnel equation. Particularly at lambda = 470 nm the ratio of r / r0 showed significant amplitude reduction mainly stemmed from the imaginary part of the Au refractive index. Hence, the fraction of reduction, Deltar = 1 - r / r0. Experimentally, in a common reference frame reflectivity of a bare gold surface, R0 is compared with the reflectivity of gold surface in the presence of biolayer, R. The reduction rate (%) of reflectivity, DeltaR = 1 - R / R0 is denoted as the AR signal. The method therefore enables quantitative measurement of the surface bound protein by converting DeltaR to the thickness, d, and subsequently the protein mass. We discussed four strategies to improve the AR signal by changing the effective refractive index of the biosensing platform. They are; a) Thickness optimisation of Au thin layer, b) Au / Ag bimetallic layer, c) composing alloy or Au composite, and d) Au thinlayer with nano or micro holes. RESULTS: As the result we successfully 'move' the refractive index, epsilon of the AR platform (gold only) to epsilon = -0.948 + 3.455i, a higher sensitivity platform. This was done by composing Au-Ag2O composite with ratio = 1:1. The results were compared to the potential sensitivity improvement of the AR substrate using other that could be done by further tailoring the epsilon advanced method. CONCLUSION: We suggested four strategies in order to realize this purpose. It is apparent that sensitivity has been improved through Au/Ag bimetallic layer or Au-Ag2O composite thin layer, This study is an important step towards fabrication of sensitive surface for detection of biomolecular interactions. PMID- 29237370 TI - Editorial: Advances and Future Developments in Forensic Toxicology: From Standard Practices to New Psychoactive Substances. PMID- 29237371 TI - Genetic Variability of SRC Family Kinases and Its Association with Platelet Hyperreactivity and Clinical Outcomes: A Systematic Review. AB - BACKGROUND: Platelet hyperactivity has been implicated in many cardiovascular (CV) events such as ischemic stroke, myocardial infarction and CV death. Genetic variability of platelet receptors has been shown to impact Src family kinases (SFKs) activation and in turn influence platelet activation. SFKs are important signal transmitters in platelets, interacting with several receptors as GPIIB/IIIa, GPIb, PEAR 1, GPIa, GPVI, PECAM and CD148. METHODS: In this review, we focused on genetic variants of platelet receptors whose signals are transmitted mainly by SFKs and may be associated with clinical manifestations of platelet hyperactivation like MI or IS. RESULTS: The genetic variants of platelet receptors, the signals of which are transmitted by SFKs, and the associated clinical manifestations in platelet hyperactivation, have been examined. The most extensively studied receptors were glycoprotein polymorphisms. The greatest numbers of genetic variants were analyzed in GPIb. GPIIb/IIIa receptor polymorphisms were also well analyzed and many studies highlighted their associations with ischemic stroke (IS) and myocardial infarction (MI). However, there are a number of conflicting studies finding that GPIIb/IIIa receptor polymorphisms may not influence platelet hyperactivity. Moreover, variability within some other receptors like GPVI, PECAM, PEAR1, and CD148 was analyzed only in single studies. CONCLUSIONS: Src family kinases are one of the most important signal transmitters in platelets. Some receptors have well documented interactions with SFKs, while other have not been examined in humans or data about its association originated from single studies. Further studies are necessary to confirm the findings and reduce falsepositive associations. PMID- 29237372 TI - Editorial: New Trends in Enzymatic Synthesis of Nucleic Acid Derivatives. PMID- 29237373 TI - Editorial: Applications of Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC): State of the Art. PMID- 29237374 TI - mazE Antitoxin of Toxin Antitoxin System and fbpA as Reliable Targets to Eradication of Neisseria meningitidis. AB - BACKGROUND: Neisseria meningitidis is considered as a dangerous pathogen threatening human health. Nowadays, the new drug target is focused. Toxin antitoxin (TA) system is recently identified as an antimicrobial drug target. Also, in N. meningitidis, iron-uptake system could be an interesting target for drug discovery. METHODS: In this study, fbpA and mazE genes were chosen as new antimicrobial targets and treated with antisense peptide nucleic acid (PNA). Firstly, they were evaluated by bioinformatics and then analyzed by experimental procedures. Secondly, the functionality was evaluated by stress conditions. RESULTS: Our results interestingly demonstrated that when fbpA and mazE loci of N. meningitidis were targeted by antisense PNA, 8 uM concentration of fbpA-PNA as well as 30 uM concentration of mazE-PNA inhibited the growth of N. meningitides and were found to be bacteriostatic, whereas 10 MUM concentration of fbpA-PNA showed bacteriocidal activity. CONCLUSION: Our findings demonstrated the bactriocidal activity of fbpA-PNA and bacteriostatic activity of mazEPNA. Therefore, mazE and fbpA genes should be potent antimicrobial targets but further analysis including in vivo analysis should be performed. PMID- 29237375 TI - Adhesive Drug Delivery Systems Based on Polyelectrolyte Complex Nanoparticles (PEC NP) for Bone Healing. AB - BACKGROUND: In this contribution an overview is given on own work concerning drug loaded Polyelectrolyte Complex (PEC) Nanoparticles (NP) used to functionalize Bone Substitute Materials (BSM) for the therapy of bone defects associated with systemic bone diseases. In this context, drug loaded PEC NP have certain advantages, which are exemplarily summarized herein. METHODS: Concerning preparative methods PEC NP were fabricated by controlled mixing of polycation and polyanion solutions and integration of charged drugs during and after mixing. Control was taken on the stoichiometric ratio related to cationic and anionic repeating units, which was chosen close to zero for the final applied PEC NP. Concerning analytical methods a couple of physical-chemical methods were applied like colloid titration, Dynamic Light Scattering (DLS), Scanning Force Microscopy (SFM), Fourier Transform infrared (FTIR) spectroscopy, Ultraviolet-Visible (UV VIS) and Circular Dichroism (CD) spectroscopy to characterize colloid stability, adhesiveness, drug loading and release of PEC NP. Moreover, standard biochemical and microbiological assays were applied. CONCLUSION: Drug loaded PEC NP consist of oppositely charged biorelated Polyelectrolytes (PEL) like ionic polysaccharides or ionic polypeptides and also synthetic PEL, which are mixed and processed in aqueous media. At first, freshly prepared drug/PEC NP exhibit time dependent colloidal stability in the range of weeks and months, which enables and simplifies storage, transport and application in the medical field. Secondly, after deposition and drying of drug/PEC NP a local wet adhesive PEC matrix at the BSM remains in contact to relevant aqueous media (e.g. buffer, cell culture medium), which minimizes asepsis, systemic toxicity, immune or inflammatory reaction. Thirdly, cell compatible PEC NP coatings were identified, which showed only minimal effects on various relevant bone related cells due to biorelateness, complexation, local confinement and low surface area. Fourthly, PEC NP elute drugs for bone healing like bisphosphonates, antibiotics and growth factors (e.g. bone morphogenetic proteins) in delayed and sustained manner. Moreover, the onset of elution could be triggered by thermoresponsive PEL via temperature increase giving clinicians a tool into hand allowing spatiotemporal drug release on demand. Finally, drug/PEC NP could be integrated into commercial or still developed allotropic stabilizing or defect filling BSM systems. PMID- 29237376 TI - The Role of PET in Monitoring Therapy in Fungal Infections. AB - Positron emission tomography (PET) is a powerful diagnostic nuclear medicine imaging technique. PET allows in vivo detection of a wide variety of physiologic and pathologic phenomena and it offers a noninvasive tool for the monitoring of therapy in various diseases. Invasive fungal infections (IFIs) are a global concern because of the increasing population of patients at risk of IFIs and the high morbidity and mortality. Therapy with antifungal agents is long-standing and expensive. The emerging resistant fungal strains make the management of IFIs challenging. There is an absolute need for a sensitive noninvasive biomarker capable of monitoring the disease activity of IFIs and determining the efficacy of treatment at an early time point. PET imaging with 18F-fluorodeoxyglucose (FDG) was used to detect and assess disease activity in IFI foci already over 20 years ago. At that time, it was suggested it could be a useful biomarker for monitoring antifungal therapy. However, this knowledge has still not been fully exploited for the management of IFIs. The literature reveals an increasing realization of the usefulness of PET in monitoring therapy of IFIs. In this review, we highlight the advantages of nuclear medicine techniques in the management of IFIs with emphasis of the role of PET in monitoring therapy efficacy. PMID- 29237377 TI - Diet and Brain Health: Which Role for Polyphenols? AB - BACKGROUND: The aging of western societies is leading to a dramatic increase in the prevalence of chronic conditions, threatening the health status and then the sustainability of our healthcare systems. In particular, dementia is being increasingly recognized as a public health priority, given its enormous socioeconomic burdens further amplified by the absence of treatments really effective in improving the clinical course of the disease. METHODS: The question of whether some degree of cognitive deterioration is an inevitable part of aging or should be considered as a pathological pre-stage of dementia is currently debated. This is a field in need of research because accelerated brain aging as well as further decline in cognition might be preventable in the early stages of cognitive impairment. Herein, we discuss evidence from clinical and experimental studies on the role of polyphenols in preserving cognitive performance across life. RESULTS: In recent years, the possibility of favorably influencing the cognitive trajectory through promotion of lifestyle modifications has been increasingly investigated. In particular, the relationship between nutritional habits and brain health has attracted special attention. Dietary polyphenols exhibit a strong potential to promote brain due to their efficacy in protecting neurons against oxidative stress-induced injury, suppressing neuroinflammation and in ameliorating cardiovascular risk factor control and cardiovascular function thus counteracting neurotoxicity and neurodegeneration. CONCLUSION: Emerging evidence suggest that dietary polyphenols, in particular flavonoids, may exert beneficial effects on the central nervous system thus representing a potential tool to preserve cognitive performance throught senescence. PMID- 29237378 TI - Substrates for Paraoxonase. AB - BACKGROUND: Paraoxonase (PON) is a family of calcium-dependent hydrolases, which is related to many diseases. Elucidation of PON physiological roles, active center and all applications in medical fields are dependent on its substrates. OBJECTIVE: The reports about PON substrates scattered in a long span of period are collected to afford clue for drug design, diagnosis of PON status and other academic purposes. METHOD: PON substrates from 133 references are classified and compared. Structurally, PON substrates are generally classified as organic phosphorous esters, lactones and arylesters. Some phosphoramidates, organophosphorous obidoximes, aryl carboxylic acid amides and special fatty alcohol esters as PON substrates are also included. RESULTS: The electron nature, steric hindrance and hydrophilicity of substrate substituents affecting the PON catalytic ability, binding ability and specificities are discussed. Drugs, prodrugs and naturally endogenous molecules in life processes activated or inactivate by PON are reviewed. Interestingly, some organophosphate and lactone substrates are preferably hydrolyzed by one of the PON1R192Q allozymes, and such a substrate is generally essential for differentiating the three PON1192R phenotypes by using a dual-substrate method. Intricately, some chiral substrates are hydrolyzed by PON stereoselectively. CONCLUSION: As more substrates are synthesized and characterized, more facts about PON structure and catalytic properties (including PON active center and catalytic mechanism) will be revealed, and therefore the use of PON as a drug target or as an accurate disease marker will be achieved. PMID- 29237379 TI - Male Urogenital Disorders and Metabolic Syndrome: Possible Links, Characteristics and Potential Treatment Strategies. AB - BACKGROUND: Metabolic syndrome (MetS), as a cluster of metabolic derangements which are major risk factors for vascular disease is one of the most important threats to public health. Although the epidemiological and limited amount of basic science and clinical evidence link MetS to several male urogenital disorders, a holistic approach aiming to define common mechanistic pathways and new possible therapeutic targets are lacking. OBJECTIVE: The current review has focused on providing scientific evidence on the role of MetS and its components on male urogenital disorders and the definition of new therapeutic targets. METHOD: In this review, current clinical and basic science literature were assessed examining the role of MetS in etiology and pathogenesis of male urogenital disorders and performed through PubMed from 2000 to May 2017. RESULTS AND CONCLUSION: MetS shows an important association with common male urogenital disorders such as benign prostatic enlargement, lower urinary tract symptoms, erectile dysfunction, infertility and renal disease. MetS affects male urogenital system mainly through endocrine and vascular mechanisms. Obesity, hypogonadism, obesity-induced androgen deficiency, hyperinsulinemia and inflammation are the mechanisms commonly involved and may act as potential targets for MetS-male urogenital system interrelations. Future studies are needed to evaluate the therapeutic approaches for intervention in MetS-male urogenital disease relations. PMID- 29237381 TI - Targeting FGFR with BGJ398 in breast cancer: Effect on tumor growth and metastasis. AB - BACKGROUND: Endocrine resistance and metastatic dissemination comprise major clinical challenges for breast cancer treatment. The fibroblast growth factor receptor family (FGFR) consists of four tyrosine kinase transmembrane receptors, involved in key biological processes. Genomic alterations in FGFR have been identified in advanced breast cancer and thus, FGFR are an attractive therapeutic target. However, the efficacy of FGFR inhibitors on in vivo tumor growth is still controversial. OBJECTIVE: The purpose of this study was to evaluate the role of FGFR in tumor growth and breast cancer progression. METHOD: Cell proliferation was assessed by 3H-thymidine uptake and cell counting in primary cultures of endocrine resistant mammary carcinomas and a human cell line, respectively. Tumor transplants and cell injections were used to determine in vivo growth and spontaneous metastasis. FGFR1-3 and alphaSMA expression were evaluated on primary tumors by immunohistochemistry. RESULTS: Antiprogestin resistant murine transplants and a human xenograft express high levels of total FGFR1-3. In vitro treatment with the FGFR inhibitor, BGJ398, impaired cell proliferation of resistant variants versus vehicle. In vivo, versus control, BGJ398 treatment decreased one out of four resistant tumors, however all tumors showed a decreased epithelial/stromal ratio. Finally, in a model of hormone resistant mammary cancer that spontaneously metastasizes to the lung, BGJ398 decreased the number of mice with lung metastasis. CONCLUSION: FGFR inhibitors are promising tools that require further investigation to identify sensitive tumors. These studies suggest that targeting FGFR combined with other targeted therapies will be useful to impair breast cancer progression. PMID- 29237382 TI - Renin Activity and Aldosterone Assay Among Nigerians with Hypertension and Normotension: An Insight into Normative Values and Clinical Correlates. AB - OBJECTIVES: Plasma renin activity (PRA) and aldosterone tend to differ between Blacks and Caucasians and studies are very scarce among Africans. We therefore aimed to determine the normative value of plasma renin activity and serum aldosterone among school teachers in Nigeria with normal blood pressure compared with their hypertensive counterparts and relevant clinical/ demographic associations. METHODS: Plasma renin activity and serum aldosterone were measured using the kits provided by Diagnostic Biochem, Canada among randomly selected school teachers recruited as part of a study to assess their total cardiovascular risks. Mean serum values were compared between normotensive and hypertensive participants and were correlated with clinical and demographic parameters. Statistical analysis was done using SPSS 17.0, Chicago, Ill, USA. P <0.05 was taken as statistically significant. RESULT: The mean PRA level of all study participants was 0.80 +/- 0.85 ng/mL.h (mean +/- SD) while the mean serum level of aldosterone was 93.9 +/- 60.9 pg/ml. The mean aldosterone: renin ratio was 446.5 +/- 958.2. The frequency of occurrence of hypertension was 29%. Only plasma renin activity was significantly correlated with systolic and diastolic blood pressure, age and the rate pressure product (a measure of cardiovascular risk). The finding of a higher mean PRA among hypertensive subjects is definitely related to the antihypertensive medications being taken including beta blockers and angiotensin converting enzyme inhibitors among others. The prevalence of high aldosterone/ renin ratio which could reflect the proportion of primary aldosteronism was 10.8%. CONCLUSION: Nigerians have a low renin activity compared to their Caucasian counterpart. PRA may be an important determinant of blood pressure among Nigerians. Appropriate drugs that target phenotypic status of PRA and aldosterone may be useful in the management of hypertension and the choice of pharmacotherapy among Nigerians. PMID- 29237380 TI - Viscosity Control of Protein Solution by Small Solutes: A Review. AB - Viscosity of protein solution is one of the most troublesome issues for the high concentration formulation of protein drugs. In this review, we summarize the practical methods that suppress the viscosity of protein solution using small molecular additives. The small amount of salts decreases the viscosity that results from electrostatic repulsion and attraction. The chaotrope suppresses the hydrophobic attraction and cluster formation, which can lower the solution viscosity. Arginine hydrochloride (ArgHCl) also suppresses the solution viscosity due to the hydrophobic and aromatic interactions between protein molecules. The small molecular additives are the simplest resolution of the high viscosity of protein solution as well as understanding of the primary cause in complex phenomena of protein interactions. PMID- 29237383 TI - The Effect of Flubendazole on Adhesion and Migration in SW480 and SW620 Colon Cancer Cells. AB - BACKGROUND: Colon cancer is the most common type of gastrointestinal cancer. Despite advances during the last two decades, the efficacy of colorectal cancer treatment is still insufficient and new anticancer agents are necessary. METHODS: In our study, colon cancer cells derived from a primary tumor (SW480) and lymph node metastasis (SW620) from the same patient were used and compared. The effect of flubendazole (FLU) on cell adhesion and migration was monitored using the x CELLigence Real-Time Cell Analysis system. Expressions of molecules involved in adhesion and migration were analyzed using RT-PCR and western blot. Furthermore, RNA silencing of nuclear factor-kappaB in SW620 cells was used to determine the involvement of the NF-kappaB p65 regulation pathway in FLU action. RESULTS: FLU significantly suppressed the adhesion of SW480 cells and reduced the expression of adhesion markers (ICAM-1, alphaE-catenin; beta-catenin; integrin alpha5 and beta1). Moreover, a significant anti-migratory potential of FLU was manifested in the SW620 cells. In addition, FLU suppressed the phosphorylation of NF-kappaB p65 and potentiated the suppression of several metastatic markers (ICAM-1, EpCAM, integrin alpha5, beta1, alpha-tubulin) caused by NF-kappaB p65 silencing. CONCLUSION: FLU has a significant anti-migratory effect in intestinal cancer cell SW480 and its lymph node metastatic cells SW620. FLU decreases the expression of some proteins involved in metastatic processes and inhibits activation of NF kappaB p65. PMID- 29237384 TI - ROS-scavenging and anti-tyrosinase properties of crocetin on B16F10 murine melanoma cells. AB - BACKGROUND: Crocus sativus (Iridaceae) has been traditionally used in the Iranian folk medicine and as a culinary additive. Major components of the plant that are responsible for biological properties are saffranal, crocin, picrocrocin and crocetin. Although the level of crocetin is not high, some of the important activities of saffron such as antioxidant activity have been attributed to crocetin. OBJECTIVE: In the present study, we investigated the effects of crocetin on melanogenesis in B16 melanoma cells. METHODS: The effect of crocetin on intracellular and mushroom tyrosinase activity and the content of melanin was evaluated spectrophotometrically. Tyrosinase and microphthalmia-associated transcription factor (MITF) protein levels were compared between Crocetin-treated and control cells after western blot analysis. The anti-oxidative activity of crocetin was also investigated. RESULTS: Crocetin could inhibit mushroom tyrosinase activity and lower the amount of melanin in B16 melanoma cells. Protein levels of tyrosinase and MITF were also decreased by crocetin. Crocetin also showed antioxidant activity and depleted cellular reactive oxygen species (ROS) content but had no cytotoxicity in alamarBlue(r) assay. CONCLUSION: Taken together, decreased tyrosinase activity, melanin content, tyrosinase and MITF proteins levels, and ROS production showed the inhibition of melanogenesis in B16F10 cells by crocetin. Hence, crocetin could be suggested as a potential dermatological whitening agent in skin care products. PMID- 29237385 TI - Systemic Administration of Antipsychotic Asenapine Pre or Postnatal does not Induce Anxiety-like Behaviors in Mice. AB - BACKGROUND AND OBJECTIVE: Asenapine is an atypical antipsychotic approved by US Food and Drug Administration in 2009 and by European Medicines Agency in 2010 for Schizophrenia and Bipolar Disorder treatment. Currently, many studies have been developed in an attempt to clarify and minimize the risks related to the use of psychotropic during pre/postnatal period on patients with a history of mental disorders. CONCLUSION: The aim of this study was to test the impact of pre and/or postnatal exposition to asenapine on mice offspring behavior. Four groups of animals, previously treated with a dosage equivalent to 50% of the bioavailability obtained with a 20 mg daily use for human treatment, were exposed to the Open Field and Elevated plus Maze test. Only the group exposed to asenapine during both pre and postnatal periods showed response difference in the Elevated Plus Maze test, which was restricted to urination. However, our data suggest that the administration of asenapine does not induce significant anxiety like behaviors in mice. PMID- 29237386 TI - The Combined Effects of omega -3 Fatty Acids and Nano-Curcumin Supplementation on Intercellular Adhesion Molecule-1 (ICAM-1) Gene Expression and Serum Levels in Migraine Patients. AB - BACKGROUND: Migraine is an episodic headache, which is an endothelial disorder with neurological inflammation. Intercellular Adhesion Molecule-1 (ICAM-1), as an endothelial factor, leads to the adhesion of leukocytes to the walls of the cerebral blood vessels, which is an important step in the inflammation process. Curcumin and omega-3 fatty acids, by affecting transcription factors, can regulate the gene expression and serum levels of ICAM-1. Thus, this study aimed to evaluate the synergistic effects of omega-3 fatty acids and nano-curcumin on ICAM-1 gene expression and serum levels in migraine patients. METHOD: This clinical trial study was conducted on 72 episodic migraine patients in 4 groups for 2 months, with patients receiving omega-3 fatty acids, nano-curcumin, a combination of them, or a placebo during the study. At the beginning and end of the study, the gene expression and serum level of ICAM-1 were measured by real time PCR and ELISA. RESULT: The results showed no significant change in ICAM-1 gene expression in any of the 4 groups. The ICAM-1 serum concentration in the combination group, and omega-3 alone, showed a significant reduction at the end of the study compared to the beginning. In addition, a significant reduction in attack frequency was observed in the combination group. CONCLUSION: Considering the results of supplementation with omega-3 fatty acids plus curcumin led to reductions of both attack frequency and ICAM-1 serum level in patients, it seems that supplementation with these two nutrients not only can lead to improvements in the function of metabolic pathways, but can also be used effectively as a treatment or prevention of migraine complications. PMID- 29237387 TI - Italian Association of Clinical Endocrinologists (AME) and Italian AACE Chapter Position Statement for Clinical Practice: Assessment of Response to Treatment and Follow-Up in Gastroenteropancreatic Neuroendocrine Neoplasms. AB - Well-established criteria for evaluating the response to treatment and the appropriate followup of individual patients are critical in clinical oncology. The current evidence-based data on these issues in terms of the management of gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are unfortunately limited. This document by the Italian Association of Clinical Endocrinologists (AME) on the criteria for the follow-up of GEP-NEN patients is aimed at providing comprehensive recommendations for everyday clinical practice based on both the best available evidence and the combined opinion of an interdisciplinary panel of experts. The initial risk stratification of patients with NENs should be performed according to the grading, staging and functional status of the neoplasm and the presence of an inherited syndrome. The evaluation of response to the initial treatment, and to the subsequent therapies for disease progression or recurrence, should be based on a cost-effective, risk-effective and timely use of the appropriate diagnostic resources. A multidisciplinary evaluation of the response to the treatment is strongly recommended and, at every step in the follow-up, it is mandatory to assess the disease state and the patient performance status, comorbidities, and recent clinical evolution. Local expertise, available technical resources and the patient preferences should always be evaluated while planning the individual clinical management of GEP NENs. PMID- 29237388 TI - Crigler-Najjar Syndrome: Current Perspectives and the Application of Clinical Genetics. AB - BACKGROUND: Crigler-Najjar syndrome (CNS, OMIM: 218800) is the paradigm of an inborn error of metabolism and a rare genetic disease with an estimated incidence of 0.6-1.0 per million live births. Discrimination between CNS subtypes is usually done on the basis of the clinical criteria, such as response to phenobarbital treatment and other molecular and functional characteristics. METHODS: The identification of four novel pathogenic mutations and the analysis of residual activity of missense in UGT1A1 gene are useful for clinical diagnosis, and may reveal a new insight in enzyme activity, whereas the identification of pathogenic mutations will accelerate genetic counseling for newly identified CNS patients. RESULTS: Phototherapy, orthotropic liver transplantation, liver cell transplantation and gene therapy are treatment choices and candidates to fight back this syndrome. Due to the promising reports of gene therapy in small animal models, gene therapy approaches are expected to continue in preclinical research for developing safe and effective treatment of CNS. Gene transfer vectors using recombinant viruses, such as Adenovirus have been applied successfully in transferring UGT1A1 gene to the liver of Gunn rat model of CNS. CONCLUSION: In spite of remaining safety and efficiency issues, gene therapy promises to be a realistic treatment modality for CNS during the future decade. PMID- 29237389 TI - Venlafaxine Attenuates the Development of Morphine Tolerance and Dependence: Role of L-Arginine/Nitric Oxide/cGMP Pathway. AB - BACKGROUND: Severe pain reduces quality of life of patients with various diseases, often because chronic morphine therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing adverse effects. Nitric oxide (NO) plays a role in morphine tolerance and dependence. OBJECTIVE: Venlafaxine, an antidepressant, is known to modulate nitric oxide (NO) pathway in nervous tissues. In the present study, the effect of systemic venlafaxine (VLF) on the development of morphine tolerance and dependence, acute morphine-induced antinociception, and the probable involvement of the L arginine/NO/cGMP pathway in these effects were investigated in mice. METHODS: Animals developed tolerance to the antinociceptive effect of morphine (50 mg/kg, s.c. daily) for 3 consecutive days. NO modulators like L-NAME (NO synthase inhibitor) and L-Arginine (L-Arg, substrate for NO synthase), sildenafil (cGMP PDE inhibitor) alone or in combination with venlafaxine were used. RESULTS: The results showed that i.p. administration of VLF (5-40 mg/kg) produced antinociceptive effect in a dose-dependent way. Pretreatment with L-Arg (200 mg/kg, i.p.) reversed the antinociception and L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.) potentiated the antinociceptive effect. Moreover, co administration of VLF in non-effective dose (5 mg/kg) with morphine, potentiated acute morphine-induced analgesia (5 mg/kg, s.c.). This effect was antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.). On the other hand, VLF was prevented the development of morphine antinociceptive tolerance and dependence. These effects were antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.). CONCLUSION: Our data suggest that the combination of VLF with morphine may be a relevant therapeutic implication to manage pain even when tolerance to morphine exists. Moreover, our data demonstrates the involvement of L-Arg/NO/cGMP pathway in the prevention of morphine tolerance and dependence by venlafaxine. PMID- 29237390 TI - Chronopharmacokinetic Evaluation of Budesonide Multiparticulate Systems. AB - BACKGROUND: Poor oral absorption of budesonide limits the design of its solid oral dosage form. With this context, multiparticulate pulsatile system of budesonide for chronotherapy of nocturnal asthma was aimed in this study. METHODS: Initially, solid dispersions of budesonide (BD) using sodium starch glycolate (SSG) and guar gum (GG) were developed and characterized. Uniform sized non-pareil seeds (~400 um) were coated with solid dispersions to obtain immediate (BMP) and controlled release pellets by solution layering technique. Rationale of selection of BD in this research was based on recent patents such as diltiazem HCl (US5914134) and multipar-ticulate systems (US5017381). Pulsatile drug release pellets (BMPP) of BD were obtained by coating the controlled release pellets with Eudragit L100 and RS 100. Pellets were assessed by saturation sol-ubility, FTIR, DSC, micromeritic, SEM, drug content, drug release, pharmacokinetic and stability studies. RESULTS: Solubility of BD was increased by 22 folds due to inter particle distribution of BD and polymers in solid dispersions. No changes in characteristic functional groups of BD had indicated the compatibility of drug with polymers as noticed in FTIR and DSC. Fluidized bed processor enabled the production of spherical and uniformly distributed pellets with optimum angle of repose (12-19 degrees ) and friability (<1%). Solution layering technique employed in preparation of pellets had facilitated with moderately high BD content (91.5-99.6%) and 100% drug release at the end of 12hr. The pulsatile release pellets (BMPP) produced 6hr lag phase followed by 12hr controlled release. Promised pharmacokinetics was resulted as Cmax of 380ng/ml for BMP-2 and 162ng/ml for BMPP-5 and Tmax of 5 hr for BMP-2 and 12hr for BMPP-5. Increased pharmacokinetics was the direct results of increased solubility of BD due to application of solid dispersion and solution layering on pellets. CONCLUSIONS: Chronopharmacokinetics of BD were achieved with the help of Eudragit coatings on pellets. The BMP and BMPP formulations were found to be reasonably stable over a period of time. Thus, optimal chronopharmacokinetics of BD was achieved successfully by multiparticulate pulsatile technology. PMID- 29237391 TI - Utility of Pooled Cryopreserved Human Enterocytes as an In vitro Model for Assessing Intestinal Clearance and Drug-Drug Interactions. AB - BACKGROUND: A recent advancement in isolation and cryopreservation has resulted in commercially available primary human enterocytes that express various drug metabolizing enzymes (DMEs) and transporters. The main objective of this study was to further evaluate the utility of pooled cryopreserved enterocytes, specifically MetMaxTM cryopreserved human enterocytes (In vitro ADMET Laboratories), as an in vitro model for assessing intestinal clearance in comparison to hepatocytes. METHODS: It was found that, for CYP3A4/5 substrates such as midazolam, amprenavir and loperamide, in vitro metabolic clearance is generally lower in enterocytes compared to that of hepatocytes, which is consistent with the relative abundance of the enzyme between the intestine and liver. In contrast, raloxifene, a surrogate UGT activity substrate, showed 3-fold greater turnover in enterocytes than hepatocytes, which is likely attributed to the differential expression of individual UGTs in human liver and intestine. For procaine, a known CES2 substrate, the measured apparent clearance was higher in hepatocytes, but formation of 4-aminobenzoic acid, a CE2-specific metabolite, was more pronounced in enterocytes, suggesting that CE2 is more active in enterocytes. Salbutamol, a SULT1A3 substrate, showed little turnover in both enterocytes and hepatocytes, and more abundant sulfate conjugate was detected in enterocytes, indicating higher SULT activity in enterocytes than hepatocytes. As expected, ketoconazole inhibited CYP3A4/5-mediated metabolite formation in enterocytes for midazolam, amprenavir and loperamide, suggesting that cryopreserved enterocytes may be useful in determining intestinal CYP3A inhibition parameters. Interestingly, elacridar, a P-gp inhibitor, suppressed metabolite formation in enterocytes for loperamide, a substrate of CYP3A4 and P gp, suggesting that enterocytes in suspension do not have active P-gp efflux functions, and the suppression of metabolism in enterocytes is probably caused by inhibition of CYP3A4/5 by elacridar. RESULTS: Our results suggest that pooled cryopreserved human enterocytes, specifically the MetMaxTM cryopreserved human enterocytes, represent a valuable in vitro model for assessing first-pass clearance and potential drug interactions in human intestine. PMID- 29237393 TI - microRNAs Downregulation in Cancer is Associated with Guanine Enrichment in the Terminal Loop Sequences of their Precursors. AB - BACKGROUND: microRNAs (miRNAs) are small noncoding segments of RNA that negatively regulate gene expression at the post-transcriptional level and fine tune gene functions. A global repression in miRNA expression is a phenomenon observed in different types of cancer. In this study we aimed to reveal a possible association of miRNAs downregulation in cancer, with the guanine (G) content in the terminal loop (TL) sequences of their precursors. METHODS: Lists of most significantly downregulated miRNAs in different tumor types, obtained from previously published microarray experiments, were selected for bioinformatics analysis. The complete precursor, TL, and mature miRNA sequences, were analyzed for evaluation of nucleotide composition and motif enrichment. RESULTS: Herein, we show an association of miRNAs downregulation in cancer, with G enrichment in the TL sequences of their precursors. High G (and GG) content was mostly found in repressed miRNAs of breast, lung and ovary cancers, predominantly in poorly differentiated tumors. The mature sequences of repressed miRNAs had significantly low G content and were enriched with an ACA motif. CONCLUSION: This study suggests a new link between G enrichment of precursor miRNAs TLs and carcinogenesis, and the possible association of specific sequence motifs with the regulation of their expression. PMID- 29237392 TI - Chronic Exposure to Cigarette Smoke and Chewing Tobacco Alters Expression of microRNAs in Esophageal Epithelial Cells. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers with high mortality rate. Cigarette smoke and chewing tobacco are well known risk factors associated with ESCC. However, molecular mechanisms associated with development of ESCC among smokers and chewers are poorly understood. MicroRNAs play an important role in regulating physiological and disease processes including esophageal cancer. OBJECTIVE AND METHODS: In this study, we developed an in vitro model by treating non-neoplastic Het- 1A esophageal cell line with cigarette smoke and chewing tobacco. We carried out miRNA sequencing on Illumina HiSeq 2500 platform and compared miRNA expression pattern across cigarette smoke and chewing tobacco treated Het-1A cells with untreated cells. RESULTS: We identified and quantified 433 miRNAs in both smoke exposed and chewing tobacco treated cells, of which 13 miRNAs showed significantly altered expression in cigarette smoke exposed cells while 25 miRNAs showed significantly altered expression in chewing tobacco treated cells. In addition, we predicted novel miRNAs from these data-sets. We evaluated miRNAs that showed selective or context dependent expression pattern in cigarette smoke exposed or chewing tobacco treated cells. CONCLUSION: In this study, we have comprehensively mapped miRNA expression pattern in response to cigarette smoke and chewing tobacco in Het-1A cells. We identified miRNAs that show altered expression in these cell models. PMID- 29237394 TI - Prediction of miRNA and Identification of their Relationship Network Related to Late Blight Disease of Potato. AB - BACKGROUND: Late blight is a serious disease in potato caused by Phytophthora infestans. To date only few miRNA have been discovered which are related to late blight disease of potato during host pathogen interaction. Recent studies showed that miRNA, an important gene expression regulator, plays a very important role in host-pathogen interaction by silencing genes either by destructing or blocking of translation of mRNA. METHOD: Homology search was performed between non redundant mature miRNA sequences from miRBase database and Solanum tuberosum EST sequences from NCBI database. Screening of the potential miRNA was done after secondary structure prediction. The target related to late blight disease of respective miRNA was functionally annotated. To identify the relationship between the predicted and mature miRNAs, multiple sequence alignment and evolutionary relationships were established. RESULTS AND CONCLUSION: 34 Candidate miRNA related to late blight disease of potato were identified which were associated to five target genes. These miRNAs were linked with Avr3a, INF1, INF2b genes which are elicitin like protein and triggers a hypersensitive response to host cell. Mapping of target sequences showed similarity with Solanum lycopersicum NRC1 gene of chr.1, which are reported as a casual protein required for Pto-mediated cell death and resistance in N. benthamiana. NRC1 are considered as a RX-CC_like domain-containing protein which shows similarity with coiledcoil domain of the potato virus X resistance protein (RX) in Solanum tuberosum. RX recognizes pathogen effector proteins and triggers a response that may be as severe as localized cell death thereby providing resistance against potato virus X. PMID- 29237395 TI - Insights into the evolution, biogeography and natural history of the acorn ants, genus Temnothorax Mayr (hymenoptera: Formicidae). AB - BACKGROUND: Temnothorax (Formicidae: Myrmicinae) is a diverse genus of ants found in a broad spectrum of ecosystems across the northern hemisphere. These diminutive ants have long served as models for social insect behavior, leading to discoveries about social learning and inspiring hypotheses about the process of speciation and the evolution of social parasitism. This genus is highly morphologically and behaviorally diverse, and this has caused a great deal of taxonomic confusion in recent years. Past efforts to estimate the phylogeny of this genus have been limited in taxonomic scope, leaving the broader evolutionary patterns in Temnothorax unclear. To establish the monophyly of Temnothorax, resolve the evolutionary relationships, reconstruct the historical biogeography and investigate trends in the evolution of key traits, I generated, assembled, and analyzed two molecular datasets: a traditional multi-locus Sanger sequencing dataset, and an ultra-conserved element (UCE) dataset. Using maximum likelihood, Bayesian, and summary-coalescent based approaches, I analyzed 22 data subsets consisting of 103 ingroup taxa and a maximum of 1.8 million base pairs in 2485 loci. RESULTS: The results of this study suggest an origin of Temnothorax at the Eocene-Oligocene transition, concerted transitions to arboreal nesting habits in several clades during the Oligocene, coinciding with ancient global cooling, and several convergent origins of social parasitism in the Miocene and Pliocene. As with other Holarctic taxa, Temnothorax has a history of migration across Beringia during the Miocene. CONCLUSIONS: Temnothorax is corroborated as a natural group, and the notion that many of the historical subgeneric and species group concepts are artificial is reinforced. The strict form of Emery's Rule, in which a socially parasitic species is sister to its host species, is not well supported in Temnothorax. PMID- 29237396 TI - Musculoskeletal networks reveal topological disparity in mammalian neck evolution. AB - BACKGROUND: The increase in locomotor and metabolic performance during mammalian evolution was accompanied by the limitation of the number of cervical vertebrae to only seven. In turn, nuchal muscles underwent a reorganization while forelimb muscles expanded into the neck region. As variation in the cervical spine is low, the variation in the arrangement of the neck muscles and their attachment sites (i.e., the variability of the neck's musculoskeletal organization) is thus proposed to be an important source of neck disparity across mammals. Anatomical network analysis provides a novel framework to study the organization of the anatomical arrangement, or connectivity pattern, of the bones and muscles that constitute the mammalian neck in an evolutionary context. RESULTS: Neck organization in mammals is characterized by a combination of conserved and highly variable network properties. We uncovered a conserved regionalization of the musculoskeletal organization of the neck into upper, mid and lower cervical modules. In contrast, there is a varying degree of complexity or specialization and of the integration of the pectoral elements. The musculoskeletal organization of the monotreme neck is distinctively different from that of therian mammals. CONCLUSIONS: Our findings reveal that the limited number of vertebrae in the mammalian neck does not result in a low musculoskeletal disparity when examined in an evolutionary context. However, this disparity evolved late in mammalian history in parallel with the radiation of certain lineages (e.g., cetartiodactyls, xenarthrans). Disparity is further facilitated by the enhanced incorporation of forelimb muscles into the neck and their variability in attachment sites. PMID- 29237397 TI - Parental occupations, educational levels, and income and prevalence of dental caries in 3-year-old Japanese children. AB - BACKGROUND: Most studies have investigated the association between parental socioeconomic factors and dental caries in children based on educational and income levels; studies focusing on parental occupation, however, have been relatively limited. This cross-sectional study examined the associations between parental occupations and levels of education and household income and the prevalence of dental caries in Japanese children aged 3 years. METHODS: Study subjects were 6315 children. Oral examination results were obtained from the parents or guardians, who transcribed the information recorded by medical staff at a public health center from their maternal and child health handbooks to our self-administered questionnaire. Children were classified as having dental caries if one or more primary teeth had decayed or had been filled. Adjustment was made for sex, age, region of residence, breastfeeding duration, between-meal snack frequency, toothbrushing frequency, use of fluoride, regular dental check-ups, maternal smoking during pregnancy, and living with at least one household smoker. RESULTS: The prevalence of dental caries was 14.7%. Compared with having an unemployed father, having a father employed in professional and engineering, clerical, sales, security, or manufacturing process was significantly associated with a lower prevalence of dental caries. Compared with having an unemployed mother, having a mother employed in professional and engineering or service was significantly inversely associated with the prevalence of dental caries. Significant inverse associations were observed between parental levels of education and household income and the prevalence of dental caries. CONCLUSIONS: The findings of our study suggest that parental occupation affects the prevalence of dental caries in children. We confirm that higher levels of parental education and household income decreased the prevalence of dental caries. PMID- 29237398 TI - pyAmpli: an amplicon-based variant filter pipeline for targeted resequencing data. AB - BACKGROUND: Haloplex targeted resequencing is a popular method to analyze both germline and somatic variants in gene panels. However, involved wet-lab procedures may introduce false positives that need to be considered in subsequent data-analysis. No variant filtering rationale addressing amplicon enrichment related systematic errors, in the form of an all-in-one package, exists to our knowledge. RESULTS: We present pyAmpli, a platform independent parallelized Python package that implements an amplicon-based germline and somatic variant filtering strategy for Haloplex data. pyAmpli can filter variants for systematic errors by user pre-defined criteria. We show that pyAmpli significantly increases specificity, without reducing sensitivity, essential for reporting true positive clinical relevant mutations in gene panel data. CONCLUSIONS: pyAmpli is an easy to-use software tool which increases the true positive variant call rate in targeted resequencing data. It specifically reduces errors related to PCR-based enrichment of targeted regions. PMID- 29237399 TI - Redundancy analysis allows improved detection of methylation changes in large genomic regions. AB - BACKGROUND: DNA methylation is an epigenetic process that regulates gene expression. Methylation can be modified by environmental exposures and changes in the methylation patterns have been associated with diseases. Methylation microarrays measure methylation levels at more than 450,000 CpGs in a single experiment, and the most common analysis strategy is to perform a single probe analysis to find methylation probes associated with the outcome of interest. However, methylation changes usually occur at the regional level: for example, genomic structural variants can affect methylation patterns in regions up to several megabases in length. Existing DMR methods provide lists of Differentially Methylated Regions (DMRs) of up to only few kilobases in length, and cannot check if a target region is differentially methylated. Therefore, these methods are not suitable to evaluate methylation changes in large regions. To address these limitations, we developed a new DMR approach based on redundancy analysis (RDA) that assesses whether a target region is differentially methylated. RESULTS: Using simulated and real datasets, we compared our approach to three common DMR detection methods (Bumphunter, blockFinder, and DMRcate). We found that Bumphunter underestimated methylation changes and blockFinder showed poor performance. DMRcate showed poor power in the simulated datasets and low specificity in the real data analysis. Our method showed very high performance in all simulation settings, even with small sample sizes and subtle methylation changes, while controlling type I error. Other advantages of our method are: 1) it estimates the degree of association between the DMR and the outcome; 2) it can analyze a targeted or region of interest; and 3) it can evaluate the simultaneous effects of different variables. The proposed methodology is implemented in MEAL, a Bioconductor package designed to facilitate the analysis of methylation data. CONCLUSIONS: We propose a multivariate approach to decipher whether an outcome of interest alters the methylation pattern of a region of interest. The method is designed to analyze large target genomic regions and outperforms the three most popular methods for detecting DMRs. Our method can evaluate factors with more than two levels or the simultaneous effect of more than one continuous variable, which is not possible with the state-of-the-art methods. PMID- 29237400 TI - Accuracy of acute burns diagnosis made using smartphones and tablets: a questionnaire-based study among medical experts. AB - BACKGROUND: Remote assistance for burns by medical experts can support nurses and general physicians in emergency care with diagnostic and management advice. Previous studies indicate a high diagnostic accuracy based on images viewed on a computer screen, but whether image-based analysis by experts using handheld devices is accurate remains to be determined. METHOD: A review of patient data from eight emergency centres in the Western Cape, South Africa, revealed 10 typical cases of burns commonly seen in children and adults. A web-based questionnaire was created with 51 images of burns representing those cases. Burns specialists from two countries (South Africa and Sweden (n = 8 and 7 respectively)) and emergency medicine specialists from South Africa (n = 11) were contacted by email and asked to assess each burn's total body surface area (TBSA) and depth using a smartphone or tablet. The accuracy and inter-rater reliability of the assessments were measured using intraclass correlation coefficients (ICC), both for all cases aggregated and for paediatric and adult burn cases separately. Eight participants repeated the questionnaire on a computer and intra-rater reliability was calculated. RESULTS: The assessments of TBSA are of high accuracy all specialists aggregated (ICC = 0.82 overall and 0.81 for both child and adult cases separately) and remain high for all three participant groups separately. The burn depth assessments have low accuracy all specialists aggregated, with ICCs of 0.53 overall, 0.61 for child and 0.46 for adult cases. The most accurate assessments of depth are among South African burns specialists (reaching acceptable for child cases); the other two groups' ICCs are low in all instances. Computer-based assessments were similar to those made on handheld devices. CONCLUSION: As was the case for computer-based studies, burns images viewed on handheld devices may be a suitable means of seeking expert advice even with limited additional information when it comes to burn size but less so in the case of burn depth. Familiarity with the type of cases presented could facilitate image-based diagnosis of depth. PMID- 29237401 TI - Six-monthly appointment spacing for clinical visits as a model for retention in HIV Care in Conakry-Guinea: a cohort study. AB - BACKGROUND: The outbreak of the Ebola virus disease (EVD) in 2014 led to massive dropouts in HIV care in Guinea. Meanwhile, Medecins Sans Frontieres (MSF) was implementing a six-monthly appointment spacing approach adapted locally as Rendez vous de Six Mois (R6M) with an objective to improve retention in care. We sought to evaluate this innovative model of ART delivery in circumstances where access to healthcare is restricted. METHODS: A retrospective cohort study in 2014 of the outcome of a group of stable patients (viral load <=1000 copies/MUl) enrolled voluntarily in R6M compared with a group of stable patients continuing standard one to three monthly visits in Conakry. Log-rank test and Cox proportional hazards model were used to compare rates of attrition (deaths and defaulters) from care between the two groups. A linear regression analysis was used to describe the trend or pattern in the number of clinical visits over time. RESULTS: Included were 1957 adults of 15 years old and above of whom 1166 (59.6%) were enrolled in the R6M group and 791 (40.4%) in the standard care group. The proportion remaining in care at 18 months and beyond was 90% in the R6M group; significantly higher than the 75% observed in the control group (p < 0.0001). After adjusting for duration on ART and tuberculosis co-infection as covariates, the R6M strategy was associated with a 60% reduction in the rate of attrition from care compared with standard care (adjusted Hazard Ratio = 0.40, 95%CI: 0.27 0.59, p < 0.001). There was a negative secular trend in the number of monthly clinical visits for 24 months as the predicted caseload reduced on average by just below 50 visits per month (beta = -48.6, R2 = 0.82, p < 0.0001). CONCLUSION: R6M was likely to reduce staff workload and to mitigate attrition from ART care for stable patients in Conakry despite restricted access to healthcare caused by the devastating EVD on the health system in Guinea. R6M could be rolled out as the model of care for stable patients where and when feasible as a strategy likely to improve retention in HIV care. PMID- 29237402 TI - Prevalence and serotype distribution of nasopharyngeal carriage of Streptococcus pneumoniae in China: a meta-analysis. AB - BACKGROUND: To explore the overall prevalence and serotype distribution of nasopharyngeal carriage of Streptococcus pneumoniae(S. pneumoniae) among healthy children. METHODS: A search for pneumococcal nasopharyngeal carriage studies including children published up to July 31th, 2016 was conducted to describe carriage in China. The review also describes antibiotic resistance in and serotypes of S. pneumoniae and assesses the impact of vaccination on carriage in this region. Summary measures for overall prevalence, antibiotic resistance, and serotype distributions extracted from the analyzed data were determined with 95% confidence intervals (CIs) using random-effects models. Heterogeneity was assessed using I 2 test statistics. RESULTS: Thirty-seven studies were included in this review, and the majority of studies (64.9%) were located in the pre introduction period of 7-valent pneumococcal conjugate vaccine (PCV7) in China. The pooled prevalence of S. pneumoniae nasopharyngeal carriage was 21.4% (95% CI: 18.3-24.4%). Carriage was highest in children attending kindergartens [24.5%, (19.7-29.3%)] and decreased with increasing age. Before the introduction of PCV7 into China, the prevalence of S. pneumoniae nasopharyngeal carriage was 25.8% (20.7-30.9%), the pooled carriage of S. pneumoniae sharply dropped into the 14.1% (11.3-16.9%) by PCV7 vaccination period (P < 0.001). Before the pneumococcal conjugate vaccine (PCV) was introduced in China, the penicillin resistance rate in S. pneumoniae isolated from healthy children was 31.9% (21.2-42.6%); however, this rate sharply decreased after the introduction of PCV7 in China [21.6%, (7.4 35.9%)], and the difference between the rates during these two time periods was statistically significant (P value <0.05). Serotypes 19F, 6A and 23F were the most commonly isolated. Meta-analysis of data from young children showed a pooled rate estimate of 46.6% (38.8-54.4%) for PCV7 vaccine coverage and 66.2% (58.6 73.8%) for PCV13 vaccine coverage. CONCLUSIONS: The prevalence of nasopharyngeal carriage among children was high in China. PCV7 immunization was found to be associated with reduction of nasopharyngeal colonization of S. pneumoniae. Conjugate vaccination coverage was slightly affected by the introduction of PCV7 into China because of low vaccination rate. The government should implement timely adjusted conjugate vaccination strategies based on our findings. PMID- 29237403 TI - Isolated and repeated stroke-like episodes in a middle-aged man with a mitochondrial ND3 T10158C mutation: a case report. AB - BACKGROUND: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS) syndrome, is the most common phenotype of mitochondrial disease. It often develops in childhood or adolescence, usually before the age of 40, in a maternally-inherited manner. Mutations in mitochondrial DNA (mtDNA) are frequently responsible for MELAS. CASE PRESENTATION: A 55-year-old man, who had no family or past history of mitochondrial disorders, suddenly developed bilateral visual field constriction and repeated stroke-like episodes. He ultimately presented with cortical blindness, recurrent epilepsy and severe cognitive impairment approximately 6 months after the first episode. Genetic analysis of biopsied biceps brachii muscle, but not of peripheral white blood cells, revealed a T10158C mutation in the mtDNA-encoded gene of NADH dehydrogenase subunit 3 (ND3), which has previously been thought to be associated with severe or fatal mitochondrial disorders that develop during the neonatal period or in infancy. CONCLUSION: A T10158C mutation in the ND3 gene can cause atypical adult-onset stroke-like episodes in a sporadic manner. PMID- 29237404 TI - Computed tomography scan based prediction of the vulnerable carotid plaque. AB - BACKGROUND: Primary to validate a commercial semi-automated computed tomography angiography (CTA) -software for vulnerable plaque detection compared to histology of carotid endarterectomy (CEA) specimens and secondary validating calcifications scores by in vivo CTA with ex vivo non-contrast enhanced computed tomography (NCCT). METHODS: From January 2014 to October 2016 53 patients were included retrospectively, using a cross-sectional design. All patients underwent both CTA and CEA. Sixteen patients had their CEA specimen NCCT scanned. The semi-automated CTA software analyzed carotid stenosis using different HU values defining plaque components. The predictive values of CTA based detection of vulnerable plaques were calculated. Quantification of calcifications on CTA using region of interest (ROI)-function and mathematical equations was done manually, and validated by NCCT of the CEA specimen. RESULTS: The semi-automated CTA software had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 89.1% (95% CI, 73.6% - 96.4%), 31.3% (95% CI, 12.1% - 58.5%), 75% (95% CI, 59.3% - 86.2%) and 55.6% (95% CI, 22.6% - 84.6%). Strong correlation between in vivo CTA and ex vivo NCCT in quantification of calcification was observed, but CTA systematically underestimated calcificationsscore (CALS) with increasing calcification. CONCLUSION: The CTA-software cannot be used in risk assessment of patients, due to poor specificity and NPV. The correlation between in vivo CTA and ex vivo NCCT was strong, proposing it to be used in both scientifically and clinical settings, but studies with larger sample sizes are needed. PMID- 29237406 TI - Factors associated with postnatal care for newborns in Zambia: analysis of the 2013-14 Zambia demographic and health survey. AB - BACKGROUND: The importance of postnatal care cannot be overemphasised. Various studies undertaken worldwide have found that PNC is critical for the survival of newborns. However, in Zambia, despite much emphasis by the government and various international Organisations on the need for PNC, coverage continues to be low. This study attempted to assess the demographic and socio-economic factors associated with newborns' receipt of PNC and the timing of first PNC in Zambia. METHODS: Based on data from the 2013-14 Zambia Demographic and Health Survey (ZDHS), this study used bivariate, stepwise binary and multinomial logistic regression analyses to examine PNC for births at home and at health facilities. RESULTS: The results indicate that different factors influence the utilisation of PNC among home births, these include: place of delivery, mothers' exposure or access to media and having 4+ ANC visits. On the other hand, place of residence and mothers' access or exposure to media were found to be the determinants of PNC among facility deliveries. The results further indicate that among the home births, mothers' media exposure or access to media, having secondary or higher education, and having 4+ ANC visits during pregnancy increased the odds of having PNC within 48 hours. Furthermore, attending the first PNC 48 hours after delivery was determined by place of residence, media exposure and 4+ ANC visits. On the other hand, among the facility births, the timing of PNC within 48 hours, was influenced by the perceived size at birth of the newborn. CONCLUSION: The study makes the following recommendations: more attention to be given to rural based women and newborns; encourage delivery at health facilities; more emphasis on the importance of ANC visits; and need to disseminate information through various media on the importance of PNC even in rural communities. PMID- 29237405 TI - Prevalence and characteristics of hereditary non-polyposis colorectal cancer (HNPCC) syndrome in immigrant Asian colorectal cancer patients. AB - BACKGROUND: The prevalence of Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is 2 to 5% in the Caucasian population. HNPCC is caused by genomic mutations in DNA mismatch repair genes (MMR), namely MLH1, MSH2, MSH6, PMS2, and EPCAM. A non hereditary, acquired process of hypermethylation of the MLH1 promoter can also lead to silencing of MLH1 protein expression. Diagnosis of HNPCC in patients with colorectal and other related cancers is important in the clinical treatment and surveillance of related cancers. The prevalence and clinical characteristics of HNPCC in Asian colorectal cancer patients has been reported in small studies and unique features have been suggested. METHODS: We retrospectively reviewed the clinical characteristics of Asian patients who were diagnosed of colon cancer between 1/2002 and 6/2015, and performed IHC for four MMR protein expressions on tumor specimens as a screening test for HNPCC, followed by confirmatory tests of genomic sequencing and hypermethylation analysis. RESULTS: One hundred forty three patients were identified. Thirty-one patients were diagnosed younger than 50 years old, while 112 patients were diagnosed older than 50 years old. Six cases of HNPCC were found with a prevalence of 4.19%. The prevalence in the group of patients diagnosed younger than 50 years old is 16.1%, and that in patients diagnosed older than 50 years old is 0.89%. All patients with HNPCC had family histories of colon or gastric cancer. Tumor locations in the HNPCC patients were predominantly in the descending or sigmoid colon (67%). Half of the HNPCC patients had MSH6 mutations. Hypermethylation of the MLH1 gene was only present in 2.80% of the patients. CONCLUSION: The prevalence of HNPCC is high in patients younger than 50 years old and extremely low in those older than 50 years old. These results may be useful in the future development of guidelines for HNPCC laboratory screening among Asian patients. The pathological and clinical features of HNPCC in this group of Asian immigrant patients are more similar to those reported on Asian patients in their home countries than to Caucasian patients in Western countries, and will warrant further large-scale evaluation. PMID- 29237407 TI - Identification and in silico characterization of a novel p.P208PfsX1 mutation in V-ATPase a3 subunit associated with autosomal recessive osteopetrosis in a Pakistani family. AB - BACKGROUND: Osteopetrosis is a rare inherited bone disorder mainly described as an increased bone density caused by defective osteoclastic bone resorption. To date, genetic variants of eleven genes have been reported so far to be associated with different types of osteopetrosis. However, malignant infantile osteopetrosis, a lethal form of the disease, is mostly (50%) caused by mutation(s) in TCIRG1 gene. In this study, we investigated a consanguineous Pakistani family clinically and genetically to elucidate underlying molecular basis of the infantile osteopetrosis. METHODS: DNA samples from five family members were subjected to SNP-array based whole genome homozygosity mapping. Data was analyzed and potentially pathogenic mutation was identified by Sanger sequencing of two affected as well as three phenotypically healthy individuals in the family. The significance of identified pathogenic variation and its impact on protein structure and function was studied using various bioinformatics tools. RESULTS: DNA samples from five family members were subjected to genome-wide SNP array genotyping and homozygosity mapping which identified ~4 Mb region on chr11 harboring the TCIRG1 gene. Sanger sequencing unveiled a novel homozygous deletion c. 624delC in exon 6 of the TCIRG1 gene encodes a3 subunit of V-ATPase complex. The identified deletion resulted in a frame shift producing a truncated protein of 208 aa. In silico analysis of premature termination of the a3 subunit of V ATPase complex revealed deleterious effects on the protein structure, predicting impaired or complete loss of V-ATPase function causing infantile osteopetrosis. CONCLUSIONS: Since a3 subunit of V-ATPase complex plays a crucial role in bone resorption process, structurally abnormal a3 subunit might have adversely affected bone resorption process, leading to infantile osteopetrosis in Pakistani family. Therefore, the present study not only expands the genotypic spectrum of osteopetrosis but also improve understandings of the role of V-ATPase a3 subunit in bone resorption process. Moreover, our findings should help in genetic counseling and provide further insight into the disease pathogenesis and potential targeted therapy. PMID- 29237408 TI - Predictors of post-stroke body temperature elevation. AB - BACKGROUND: Growing evidence indicates that elevated body temperature after stroke is associated with unfavorable outcome. The aim of the current study was to investigate which factors predict temperature elevation within 48 h of stroke onset. Specifically, we hypothesized that temperature elevation would be associated with stroke symptom severity and that hemorrhagic stroke would cause a more pronounced temperature increase compared to ischemic stroke. METHODS: The medical records of 400 stroke patients were retrospectively reviewed. Multiple linear regression analysis was used to determine which factors were associated with elevated body temperature. RESULTS: Several factors were significantly associated with peak body temperature (the highest recorded body temperature) within 48 h of stroke onset: stroke severity measured by the National Institutes of Health Stroke Scale (NIHSS) (regression coefficient; (RC) 0.022), female gender (RC 0.157), tympanic/non-rectal temperature reading (RC -0.265), swallowing difficulties (RC 0.335), intubation (RC 0.470), antipyretic treatment (RC 0.563), and C-reactive protein > 50 or signs of infection at admission (RC 0.298). Contrary to our expectations, patients with intracerebral hemorrhage did not have higher peak body temperatures than patients with ischemic stroke. CONCLUSIONS: In conclusion, temperature elevation within the first 48 h of stroke onset is common, can be partially predicted using information at admission and is strongly associated with stroke severity. The strong association with stroke severity may, at least partly, explain the previously described association between post-stroke temperature elevation and unfavorable outcome. PMID- 29237410 TI - Trend of caesarean deliveries in Egypt and its associated factors: evidence from national surveys, 2005-2014. AB - BACKGROUND: The continued rise in caesarean section (c-section) deliveries raises a major public health concern worldwide. This study assessed the trend of c section deliveries and examined factors associated with a rise in c-section deliveries among the Egyptian mothers, from 2005 to 2014, by place of delivery. METHODS: This study utilized the 2005, 2008, and 2014 Egypt Demographic and Health Surveys (EDHS). The EDHS reported on the mode of delivery for the last birth occurred within five years preceding each survey including place of delivery and sociodemographic information for a total sample of over 29,000 mothers in the three surveys. To document trend of c-section, the EDHS-2005 was set as a reference in two binary logistic regression models; among all mothers together and for mothers stratified by place of delivery (public or private). P value for the trend was assessed by entering the year of the survey as a continuous variable. The study followed STROBE statement in reporting observational studies. RESULTS: Institutional-based c-sections increased by 40.7 points from EDHS-2005 to EDHS-2014 (aOR, 3.46, 95%CI: 3.15-3.80, P trend < 0.001). Compared to mothers with low socioeconomic status (SES), mothers with high SES had higher odds (aOR, 1.78, 95%CI: 1.25-2.54, P = 0.001) for c-section, but only in EDHS-2005. The adjusted trend of c-sections was found to be 4.19-time (95%CI: 3.73-4.70, P < 0.001) higher in private sector while that in public sector it was 2.67-time (95%CI: 2.27-3.13, P = 0.001) higher, in EDHS-2014 relative to EDHS-2005. This increase in the private sector is explained by significant increases among mothers who are potentially at low risk for c sections; mothers aged 19-24 years vs. >=35 years (aOR: 0.31, 95%CI: 0.21-0.45, in EDHS-2005 vs. 0.43, 95%CI: 0.33-0.56, in EDHS-2014, P < 0.001); primigravida mothers vs. mothers with >=4 children (aOR: 1.62, 95%CI: 1.12-2.34, in EDHS-2005 vs. 3.76, 95%CI: 2.94-4.80 in EDHS-2014); and among normal compared to high risk birth weight babies (aOR: 0.79, 95%CI: 0.62-0.99 in EDHS-2005 P < 0.05 vs. 0.83, 95%CI: 0.65-1.04 in EDHS-2014, P > 0.05). CONCLUSIONS: Results showed a steady rise in c-sections in Egypt that has reached an alarming level in recent years. This increase appears to be associated with a shift towards delivery in private health care facilities. More vigilance of c-section deliveries, particularly in the private sector, is warranted. PMID- 29237409 TI - IgA nephropathy featuring massive wire loop-like deposits in two patients with alcoholic cirrhosis. AB - BACKGROUND: Various renal manifestations are known to develop in patients with liver disease, including chronic hepatitis and cirrhosis. CASE PRESENTATION: We evaluated renal disease in two 47-year-old Japanese men with liver cirrhosis and chronic alcoholism for 34 years and 27 years, respectively. Renal biopsy demonstrated massive wire loop-like deposits in the subendothelial space of the glomerular basement membrane and in the mesangium. However, immunofluorescence was only positive for IgA and C3, and electron microscopy did not reveal any organized structures in the electron-dense deposits. IgA nephropathy was diagnosed, although the features were different from primary IgA nephropathy. Both patients had portosystemic shunts associated with liver cirrhosis. Their renal deposits and proteinuria resolved completely after 1 year of steroid therapy. CONCLUSION: Alcohol abuse may have contributed to development of secondary IgA nephropathy in these two patients, probably via their portosystemic shunts. PMID- 29237411 TI - Periprocedural heparin bridging in patients receiving oral anticoagulation: a systematic review and meta-analysis. AB - BACKGROUND: Periprocedural heparin bridging therapy aims to reduce the risk of thromboembolic events in patients requiring an interruption in their anticoagulation therapy for the purpose of an elective procedure. The efficacy and safety of heparin bridging therapy has not been well established. OBJECTIVES: To compare through meta-analysis the effects of heparin bridging therapy on the risk of major bleeding and thromboembolic events of clinical significance among patients taking oral anticoagulants. METHODS: We searched PubMed, EMBASE and the Cochrane library from January 2005 to July 2016. Studies were included if they reported clinical outcomes of patients receiving heparin bridging therapy during interruption of oral anticoagulant for operations. Data were pooled using random effects modeling. RESULTS: A total of 25 studies, including 6 randomized controlled trials and 19 observational studies, were finally included in this analysis. Among all the 35,944 patients, 10,313 patients were assigned as heparin bridging group, and the other 25,631 patients were non-heparin bridging group. Overall, compared with patients without bridging therapy, heparin bridging therapy increased the risk of major bleeding (OR = 3.23, 95%CI: 2.06-5.05), minor bleeding (OR = 1.52, 95%CI: 1.06-2.18) and overall bleeding (OR = 2.83, 95%CI: 1.86-4.30).While there was no significant difference in thromboembolic events (OR = 0.99,95%CI: 0.49-2.00), stroke or transient ischemic attack(OR = 1.45, 95%CI: 0.93-2.26,) or all-cause mortality (OR = 0.71, 95%CI: 0.31-1.65). CONCLUSIONS: Heparin-bridging therapy increased the risk of major and minor bleeding without decreasing the risk of thromboembolic events and all cause death compared to non heparin bridging. PMID- 29237412 TI - Evaluation of epidermal growth factor receptor signaling effects in gastric cancer cell lines by detailed motility-focused phenotypic characterization linked with molecular analysis. AB - BACKGROUND: Gastric cancers frequently overexpress the epidermal growth factor receptor (EGFR), which has been implicated in pathological processes including tumor cell motility, invasion and metastasis. Targeting EGFR with the inhibitory antibody cetuximab may affect the motile and invasive behavior of tumor cells. Here, we evaluated the effects of EGFR signaling in gastric cancer cell lines to link the phenotypic behavior of the cells with their molecular characteristics. METHODS: Phenotypic effects were analyzed in four gastric cancer cell lines (AGS, Hs746T, LMSU and MKN1) by time-lapse microscopy and transwell invasion assay. Effects on EGFR signaling were detected using Western blot and proteome profiler analyses. A network was constructed linking EGFR signaling to the regulation of cellular motility. RESULTS: The analysis of the effects of treatment with epidermal growth factor (EGF) and cetuximab revealed that only one cell line (MKN1) was sensitive to cetuximab treatment in all phenotypic assays, whereas the other cell lines were either not responsive (Hs746T, LMSU) or sensitive only in certain tests (AGS). Cetuximab inhibited EGFR, MAPK and AKT activity and associated components of the EGFR signaling pathway to different degrees in cetuximab-sensitive MKN1 cells. In contrast, no such changes were observed in Hs746T cells. Thus, the different phenotypic behaviors of the cells were linked to their molecular response to treatment. Genetic alterations had different associations with response to treatment: while PIK3CA mutations and KRAS mutation or amplification were not obstructive, the MET mutation was associated with non response. CONCLUSION: These results identify components of the EGFR signaling network as important regulators of the phenotypic and molecular response to cetuximab treatment. PMID- 29237414 TI - Isogenic mice exhibit sexually-dimorphic DNA methylation patterns across multiple tissues. AB - BACKGROUND: Cytosine methylation is a stable epigenetic modification of DNA that plays an important role in both normal physiology and disease. Most diseases exhibit some degree of sexual dimorphism, but the extent to which epigenetic states are influenced by sex is understudied and poorly understood. To address this deficit we studied DNA methylation patterns across multiple reduced representation bisulphite sequencing datasets (from liver, heart, brain, muscle and spleen) derived from isogenic male and female mice. RESULTS: DNA methylation patterns varied significantly from tissue to tissue, as expected, but they also varied between the sexes, with thousands of sexually dimorphic loci identified. The loci affected were largely autonomous to each tissue, even within tissues derived from the same germ layer. At most loci, differences between genders were driven by females exhibiting hypermethylation relative to males; a proportion of these differences were independent of the presence of testosterone in males. Loci harbouring gender differences were clustered in ontologies related to tissue function. CONCLUSIONS: Our findings suggest that gender is underwritten in the epigenome in a tissue-specific and potentially sex hormone-independent manner. Gender-specific epigenetic states are likely to have important implications for understanding sexually dimorphic phenotypes in health and disease. PMID- 29237413 TI - Clinical features of pulmonary cryptococcosis among patients with different levels of peripheral blood CD4+ T lymphocyte counts. AB - BACKGROUND: The clinical manifestation of pulmonary cryptococcosis varies notably between immunocompromised and immunocompetent patients. To better understand pulmonary cryptococcosis, we compared the clinical features of pulmonary cryptococcosis patients with or without decreased peripheral blood CD4+ T cell counts. METHODS: We retrospectively reviewed the medical records of 80 patients with cryptococcosis who had been treated in Jingling Hospital from January 2011 to January 2016. According to the normal range of peripheral blood CD4 + T lymphocyte counts in our population, we chose CD4 = 378/MUL as a cut-off value. RESULTS: The proportion of fever in the patients with decreased CD4+ T cells was higher than that of the patients with a normal amount of CD4+ T cells (86.7% vs 28.6%, P < 0.001). The incidence of clinical symptoms, such as cough (60.6% vs 64.7%, P = 0.729), chest pain (9.1% vs 26.5%, P = 0.064), and dyspnea (27.3% vs 23.5%, P = 0.725) showed no difference between patients with low CD4+ T cell counts and those with normal CD4+ T cell counts. The number of asymptomatic patients in the CD4+ T cell normal group was higher than that in the decreased CD4+ T cell group (17.1% vs 0%, P = 0.005). Nodules, masses, and halo signs were more common in the CD4+ T cell normal patients than in the low-CD4+ T cell patients (79.4% vs 54.5%, P = 0.03). The opposite trend was observed for cavitations (14.7% vs 51.5%, P = 0.001). The other CT findings, including pulmonary consolidation (P = 0.205), and pleural effusion (P = 0.641), did not differ significantly between the two groups. CONCLUSIONS: CD4+ T lymphocytes have a significant impact on the clinical and radiological characteristics of pulmonary cryptococcosis. The patients with normal CD4+ T cell counts were found to have less fever and more nodule-like radiographic findings. TRIAL REGISTRATION: 2011NJKY-023-01. Registered on January 10, 2011. PMID- 29237415 TI - Family history of prostate and colorectal cancer and risk of colorectal cancer in the Women's health initiative. AB - BACKGROUND: Evidence suggests that risk of colorectal and prostate cancer is increased among those with a family history of the same disease, particularly among first-degree relatives. However, the aggregation of colorectal and prostate cancer within families has not been well investigated. METHODS: Analyses were conducted among participants of the Women's Health Initiative (WHI) observational cohort, free of cancer at the baseline examination. Subjects were followed for colorectal cancer through August 31st, 2009. A Cox-proportional hazards regression modeling approach was used to estimate risk of colorectal cancer associated with a family history of prostate cancer, colorectal cancer and both cancers among first-degree relatives of all participants and stratified by race (African American vs. White). RESULTS: Of 75,999 eligible participants, there were 1122 colorectal cancer cases diagnosed over the study period. A family history of prostate cancer alone was not associated with an increase in colorectal cancer risk after adjustment for confounders (aHR =0.94; 95% CI =0.76, 1.15). Separate analysis examining the joint impact, a family history of both colorectal and prostate cancer was associated with an almost 50% increase in colorectal cancer risk (aHR = 1.48; 95% CI = 1.04, 2.10), but similar to those with a family history of colorectal cancer only (95% CI = 1.31; 95% CI = 1.11, 1.54). CONCLUSIONS: Our findings suggest risk of colorectal cancer is increased similarly among women with colorectal cancer only and among those with both colorectal and prostate cancer diagnosed among first-degree family members. Future studies are needed to determine the relative contribution of genes and shared environment to the risk of both cancers. PMID- 29237416 TI - A network-based predictive gene-expression signature for adjuvant chemotherapy benefit in stage II colorectal cancer. AB - BACKGROUND: The clinical benefit of adjuvant chemotherapy for stage II colorectal cancer (CRC) is controversial. This study aimed to explore novel gene signature to predict outcome benefit of postoperative 5-Fu-based therapy in stage II CRC. METHODS: Gene-expression profiles of stage II CRCs from two datasets with 5-Fu based adjuvant chemotherapy (training dataset, n = 212; validation dataset, n = 85) were analyzed to identify the indicator. A systemic approach by integrating gene-expression and protein-protein interaction (PPI) network was implemented to develop the predictive signature. Kaplan-Meier curves and Cox proportional hazards model were used to determine the survival benefit of adjuvant chemotherapy. Experiments with shRNA knock-down were carried out to confirm the signature identified in this study. RESULTS: In the training dataset, we identified 44 PPI sub-modules, by which we separate patients into two clusters (1 and 2) having different chemotherapeutic benefit. A predictor of 11 PPI sub modules (11-PPI-Mod) was established to discriminate the two sub-groups, with an overall accuracy of 90.1%. This signature was independently validated in an external validation dataset. Kaplan-Meier curves showed an improved outcome for patients who received adjuvant chemotherapy in Cluster 1 sub-group, but even worse survival for those in Cluster 2 sub-group. Similar results were found in both the training and the validation dataset. Multivariate Cox regression revealed an interaction effect between 11-PPI-Mod signature and adjuvant therapy treatment in the training dataset (RFS, p = 0.007; OS, p = 0.006) and the validation dataset (RFS, p = 0.002). From the signature, we found that PTGES gene was up-regulated in CRC cells which were more resistant to 5-Fu. Knock-down of PTGES indicated a growth inhibition and up-regulation of apoptotic markers induced by 5-Fu in CRC cells. CONCLUSIONS: Only a small proportion of stage II CRC patients could benefit from adjuvant therapy. The 11-PPI-Mod as a potential predictor could be helpful to distinguish this sub-group with favorable outcome. PMID- 29237417 TI - Red cell distribution width associated with adverse cardiovascular outcomes in patients with chronic kidney disease. AB - BACKGROUND: Recent studies have demonstrated that red cell distribution width (RDW) is associated with cardiovascular (CV) events and mortality. Patients with chronic kidney disease (CKD) are often anemic and have high RDW levels. In this study, we investigated the effect of RDW on major composite CV outcomes among patients with CKD. METHODS: We retrospectively analyzed patients with CKD who were admitted to the department of cardiology of a tertiary hospital in 2011. The patients were divided into 2 groups: normal RDW (RDW < 14.5%) and elevated RDW (RDW >= 14.5%). Demographic characteristics, comorbidities, blood investigation results, prescriptions, and outcomes were analyzed after a 3-year follow-up period. Six adjustment levels were performed to evaluate the effect of RDW on outcomes. RESULTS: This study involved 282 patients with CKD: 213 in the elevated RDW group and 69 in the normal RDW group. The elevated RDW group had older patients, a lower proportion of male patients, lower left ventricular ejection fraction (LVEF) values, lower hemoglobin levels, lower serum albumin levels, and higher creatinine levels, compared with the normal RDW group. A linear trend was observed toward higher RDW in patients with deteriorating renal function. In the final adjusted model, RDW >= 14.5%, older age, and lower LVEF were associated with an increased risk of major composite CV outcomes. CONCLUSION: RDW is a potentially useful cost-effective indicator of major composite CV outcomes in patients with CKD. PMID- 29237418 TI - A donor splice site mutation in CISD2 generates multiple truncated, non functional isoforms in Wolfram syndrome type 2 patients. AB - BACKGROUND: Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2) are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive neurodegenerative disorder mainly characterized by diabetes mellitus, optic atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations in the CISD2 gene have been reported. Among these mutations, the homozygous c.103 + 1G > A substitution was identified in the donor splice site of intron 1 in two Italian sisters and was predicted to cause a exon 1 to be skipped. METHODS: Here, we employed molecular assays to characterize the c.103 + 1G > A mutation using the patient's peripheral blood mononuclear cells (PBMCs). 5'-RACE coupled with RT PCR were used to analyse the effect of the c.103 + 1G > A mutation on mRNA splicing. Western blot analysis was used to analyse the consequences of the CISD2 mutation on the encoded protein. RESULTS: We demonstrated that the c.103 + 1G > A mutation functionally impaired mRNA splicing, producing multiple splice variants characterized by the whole or partial absence of exon 1, which introduced amino acid changes and a premature stop. The affected mRNAs resulted in either predicted targets for nonsense mRNA decay (NMD) or non-functional isoforms. CONCLUSIONS: We concluded that the c.103 + 1G > A mutation resulted in the loss of functional CISD2 protein in the two Italian WFS2 patients. PMID- 29237419 TI - Performance of the Alere i RSV assay for point-of-care detection of respiratory syncytial virus in children. AB - BACKGROUND: Respiratory syncytial virus (RSV) is the most important cause of severe acute respiratory tract infection in young children. Alere i RSV is a novel molecular rapid test which identifies respiratory syncytial virus in less than 13 min. METHODS: We evaluated the clinical performance of the Alere i RSV assay in a pediatric point-of-care setting during winter season 2016 / 2017. Test results from 518 nasopharyngeal swab samples were compared to a real-time reverse transcription PCR reference standard. RESULTS: The overall sensitivity and specificity of the Alere i RSV test assay was 93% (CI95 89% - 96%) and 96% (CI95 93% - 98%), respectively. Alere i RSV performed well in children of all age groups. An optimal sensitivity of 98% (CI95 94% - 100%) and specificity of 96% (CI95 90% - 99%) was obtained in children < 6 months. In children >= 2 years, sensitivity and specificity remained at 87% (CI95 73% - 96%) and 98% (CI95 92% - 100%), respectively. False negative Alere i RSV test results mostly occurred in samples with low viral load (mean CT value 31.1; CI95 29.6 - 32.6). The Alere i RSV assay is easy to use and can be operated after minimal initial training. Test results are available within 13 min, with most RSV positive samples being identified after approximately 5 min. CONCLUSION: The Alere i RSV assay has the potential to facilitate the detection of RSV in pediatric point-of-care settings. PMID- 29237420 TI - Development of mobile technologies for the prevention of cervical cancer in Santiago, Chile study protocol: a randomized controlled trial. AB - BACKGROUND: In Chile, more than 500 women die every year from cervical cancer, and a majority of Chilean women are not up-to-date with their Papanicolau (Pap) test. Mobile health has great potential in many health areas, particularly in health promotion and prevention. There are no randomized controlled trials in Latin America assessing its use in cervical cancer screening. The 'Development of Mobile Technologies for the Prevention of Cervical Cancer in Santiago, Chile' study aims to determine the efficacy of a text-message intervention on Pap test adherence among Chilean women in the metropolitan region of Santiago. METHODS/DESIGN: This study is a parallel randomized-controlled trial of 400 Chilean women aged 25-64 who are non-adherent with current recommendations for Pap test screening. Participants will be randomly assigned to (1) a control arm (usual care) or (2) an intervention arm, where text and voice messages containing information and encouragement to undergo screening will be sent to the women. The primary endpoint is completion of a Pap test within 6 months of baseline assessment, as determined by medical record review at community-based clinics. Medical record reviewers will be blinded to randomization arms. The secondary endpoint is an evaluation of the implementation and usability of the text message intervention as a strategy to improve screening adherence. DISCUSSION: This intervention using mobile technology intends to raise cervical cancer screening adherence and compliance among a Chilean population of low and middle-low socioeconomic status. If successful, this strategy may reduce the incidence of cervical cancer. TRIAL REGISTRATION: Clinicaltrials.gov NCT02376023 Registered 2/17/2015. First participant enrolled Feb 22nd 2016. PMID- 29237421 TI - First-decade patient with colorectal cancer carrying both germline and somatic mutations in APC gene. AB - BACKGROUND: Colorectal carcinoma (CRC) is one of the most common causes of cancer related deaths. The mean age of patients with CRC ranges from 49 to 60 years. Pediatric CRC is unusual, which often escapes early diagnosis because of a lack of awareness of its occurrence in children. The association between the mutation of APC and the occurrence of CRC in the first decade of life remains unknown. CASE PRESENTATION: We report a 10-year-old child with CRC; he was diagnosed with stage IIIB advanced transverse colon cancer without distal metastases. We detected a heterozygous germline mutation at c.5465 T > A in both blood and tissue samples and a heterozygous somatic mutation at c.7397C > T in the tissue sample. Both of these mutations can cause CRC tumorigenesis in the first decade of life. CONCLUSIONS: The rare genetic features of this 10-year-old patient might be the predisposing cause of pediatric CRC. Therefore, screening patients with early-onset CRC through clinical and genetic characterizations is suggested. PMID- 29237422 TI - MDRD vs. CKD-EPI in comparison to 51Chromium EDTA: a cross sectional study of Malaysian CKD cohort. AB - BACKGROUND: Accurate measurement of renal function is important: however, radiolabelled gold standard measurement of GFR is highly expensive and can only be used on a very limited scale. We aim to compare the performance of Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in the multi-ethnic population attending University Malaya Medical Centre (UMMC). METHODS: This is a cross sectional study recruiting patients, who attend UMMC Nephrology clinics on voluntary basis. 51-Chromium EDTA (51Cr-EDTA) plasma level was used to measure the reference GFR. The serum creatinine was determined by IDMS reference modified Jaffe kinetic assay (CrJaffe). The predictive capabilities of MDRD and CKD-EPI based equations were calculated. Data was analysed using SPSS version 20 and correlation, bias, precision and accuracy were determined. RESULTS: A total of 113 subjects with mean age of 58.12 +/- 14.76 years and BMI of 25.99 +/- 4.29 kg/m2 were recruited. The mean reference GFR was 66.98 +/- 40.65 ml/min/1.73m2, while the estimated GFR based on MDRD and CKD-EPI formula were 62.17 +/- 40.40, and 60.44 +/- 34.59, respectively. Both MDRD and CKD-EPI were well-correlated with reference GFR (0.806 and 0.867 respectively) and statistically significant with p < 0.001. In the overall cohort, although MDRD had smaller bias than CKD EPI (4.81 vs. 6.54), CKD-EPI was more precise (25.22 vs. 20.29) with higher accuracy within 30% of measured GFR (79.65 vs. 86.73%). CONCLUSION: The CKD-EPI equation appeared to be more precise and accurate than the MDRD equation in estimating GFR in our cohort of multi-ethnic populations in Malaysia. PMID- 29237423 TI - Deciphering the genetic regulation of peripheral blood transcriptome in pigs through expression genome-wide association study and allele-specific expression analysis. AB - BACKGROUND: Efforts to improve sustainability in livestock production systems have focused on two objectives: investigating the genetic control of immune function as it pertains to robustness and disease resistance, and finding predictive markers for use in breeding programs. In this context, the peripheral blood transcriptome represents an important source of biological information about an individual's health and immunological status, and has been proposed for use as an intermediate phenotype to measure immune capacity. The objective of this work was to study the genetic architecture of variation in gene expression in the blood of healthy young pigs using two approaches: an expression genome wide association study (eGWAS) and allele-specific expression (ASE) analysis. RESULTS: The blood transcriptomes of 60-day-old Large White pigs were analyzed by expression microarrays for eGWAS (242 animals) and by RNA-Seq for ASE analysis (38 animals). Using eGWAS, the expression levels of 1901 genes were found to be associated with expression quantitative trait loci (eQTLs). We recovered 2839 local and 1752 distant associations (Single Nucleotide Polymorphism or SNP located less or more than 1 Mb from expression probe, respectively). ASE analyses confirmed the extensive cis-regulation of gene transcription in blood, and revealed allelic imbalance in 2286 SNPs, which affected 763 genes. eQTLs and ASE genes were widely distributed on all chromosomes. By analyzing mutually overlapping eGWAS results, we were able to describe putative regulatory networks, which were further refined using ASE data. At the functional level, genes with genetically controlled expression that were detected by eGWAS and/or ASE analyses were significantly enriched in biological processes related to RNA processing and immune function. Indeed, numerous distant and local regulatory relationships were detected within the major histocompatibility complex region on chromosome 7, revealing ASE for most class I and II genes. CONCLUSIONS: This study represents, to the best of our knowledge, the first genome-wide map of the genetic control of gene expression in porcine peripheral blood. These results represent an interesting resource for the identification of genetic markers and blood biomarkers associated with variations in immunity traits in pigs, as well as any other complex traits for which blood is an appropriate surrogate tissue. PMID- 29237424 TI - p53R2 as a novel prognostic biomarker in nasopharyngeal carcinoma. AB - BACKGROUND: p53R2 is a target of p53 gene, which is essential for DNA repair, mitochondrial DNA synthesis, protection against oxidative stress, chromosomal instability, chronic inflammation and tumorigenesis. This study is aimed to investigate the expression of ribonucleotide reductase (RR) subunit p53R2 in nasopharyngeal carcinoma and its significance in the prognosis. METHODS: The expression levels of p53R2 in 201 patients with NPC were examined by immunohistochemical assay. The correlations of p53R2 expression and clinicopathological features of nasopharyngeal carcinoma patient were analysed by chi-square test. The Kaplan-Meier survival analysis and Cox multivariate regression model were used to analyze the prognostic significance of the patients with NPC. RESULTS: Immunohistochemical results showed that p53R2 was positively expressed in 92.5% (186/201) of nasopharyngeal carcinoma and the high expression rate was 38.3% (77/201). Further analysis observed that the negative correlation between expression of p53R2 and pT status had statistical significance (P < 0.05). Kaplan-Meier survival analysis found that the mean survival time of patients with high expression of p53R2 was 143.32 months, while the patients with low expression level of p53R2 was 121.63 months (P < 0.05). Cox regression analysis suggested that p53R2 protein expression could be used as an independent prognostic factor for nasopharyngeal carcinoma (P < 0.05). CONCLUSIONS: This study drew a conclusion that p53R2 could be used as a prognostic biomarker indicative of the favorable outcome for patients with nasopharyngeal carcinoma. PMID- 29237425 TI - German general practitioners' self-reported management of patients with chronic depression. AB - BACKGROUND: Patients with chronic depression (persisting symptoms for >=2 years) are a clinically relevant group with extensive (co)morbidity, high functional impairment and associated costs in primary care. The General Practitioner (GP) is the main health professional attending to these patients. The aim of this study was to examine the GPs' perception on managing patients with chronic depression. METHODS: We performed an explorative cross-sectional study with a systematic sample of GPs in central Germany. Source of data was a written questionnaire (46 items). Descriptive analysis was carried out. RESULTS: Two hundred twenty (out of 1000; 22%) GPs participated. 93% of the GPs distinguish between care for patients with chronic depression and acute depressive episode. 92% would recommend psychotherapeutic co-treatment to the chronically depressed patient. 52% of GPs would favour a general restraint on antidepressants (ADs) in older chronically depressed patients (>= 75 years) whereas 40% suggest long-term pharmacotherapy. If severe physical comorbidity is present GPs would be restrictive in prescribing ADs (65%) or would urgently refer to specialist psychiatric services (40%). In case of a comorbid anxiety disorder 66% of the GPs would suggest a combined psycho- und pharmacotherapy. If a substance use disorder coexists 84% would prefer urgent referrals to specialist services. CONCLUSIONS: Participating GPs report awareness towards chronic depression in their patients. Physical and mental comorbidity seem to play an important role in GPs' treatment decisions. PMID- 29237426 TI - Long non-coding RNA MALAT1 protects preterm infants with bronchopulmonary dysplasia by inhibiting cell apoptosis. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is a neonatal chronic lung disease characterized by impaired pulmonary alveolar development in preterm infants. Until now, little is known about the molecular and cellular basis of BPD. There is increasing evidence that lncRNAs regulate cell proliferation and apoptosis during lung organogenesis. The potential role of lncRNAs in the pathogenesis of BPD is unclear. This study aims to clarify the role of MALAT1 during the process of BPD in preterm infants and illustrate the protective effect of MALAT1 involved in preterm infants. METHODS: We assessed the expression of MALAT1 in BPD mice lung tissues by reanalyzing dataset GSE25286 (Mouse GEO Genome 4302 Array) from gene expression database gene expression omnibus (GEO), and verified MALAT1 expression in BPD patients by realtime q-PCR. Then the role of MALAT1 in regulating cell biology was examined by profiling dataset GSE43830. The expression of CDC6, a known antiapoptopic gene was verified in BPD patients and the alveolar epithelial cell line A549 cells in which MALAT1 was knocked down. Cell apoptosis was determined by FACS using PI/Annexin-V staining. RESULTS: The expression of MALAT1 was significantly evaluated in lung tissues of BPD mice at day 14 and day 29 compared to WT (P < 0.05). In consistent with mRNA array profiling analysis, MALAT1 expression level in blood samples from preterm infants with BPD was significantly increased. Bioinformative data analysis of MALAT1 knockdown in WI-38 cells showed various differentially expressed genes were found enriched in apoptosis related pathway. Down-regulation of antiapoptopic gene, CDC6 expression was further verified by q-PCR result. PI/Annexin-V apoptisis assay results showed that MALAT1 knocked down in the alveolar epithelial cell line (A549) promotes cell apoptosis. CONCLUSIONS: In our study, we found that up regulation of lncRNA MALAT1 could protect preterm infants with BPD by inhibiting cell apoptosis. These data provide novel insights into MALAT1 regulation which may be relevant to cell fate and shed light on BPD prevention and treatment. PMID- 29237427 TI - Clinical applications and effectiveness of guided implant surgery: a critical review based on randomized controlled trials. AB - BACKGROUND: Nowadays implant placement protocols are widespread among clinicians all over the world. However, available literature, only partially analyses what can be potential benefits for the clinicians and patients, often focusing just on specific aspects, such as accuracy. The purpose of this review is to compare computer guided implant placement with conventional treatment protocols. METHODS: A search strategy according to the P-I-C-O format was developed and executed using an electronic MEDLINE plus manual search from 2000 up to December 2016. This review included only randomized controlled trials (RCTs) focusing on subjects treated with digital workflow for oral implant placement compared to conventional procedures. Data were extracted from eligible papers and analysed. All kinds of outcomes were considered, even patient-related and economical outcomes. RESULTS: The search strategy revealed 16 articles; additional manual searches selected further 21 publications. Afterwards the evaluation of articles, only two studies could be selected for subsequent data extraction. The two identified RCTs analysed primary outcomes as prosthesis failure, implant failure, biological or prosthetic complications, and secondary outcomes as periimplant marginal bone loss. One RCT evaluated also the duration of treatment, post surgical progress, additional treatment costs and patient satisfaction. The other RCT focused instead on evaluating eventual improvement of patient's quality of life. In both selected studies, were not observed by the authors statistically significant differences between clinical cases treated with digital protocols and those treated with conventional ones. In one RCT, however post-surgical progress evaluation showed more patients' self-reported pain and swelling in conventional group. CONCLUSIONS: Within the limitation of this review, based on only two RCTs, the only evidence was that implant survival rate and effectiveness are similar for conventional and digital implant placement procedures. This is also confirmed by many other studies with however minor scientific evidence levels. Reduction of post-operative pain, surgical time and overall costs are discussed. Authors believe that scientific research should focus more in identifying which clinical situations can get greatest benefits from implant guided surgery. This should be done with research protocols such as RCT that assess comprehensively the advantages and disadvantages of fully digital surgical protocols. PMID- 29237428 TI - NKX2-1 expression as a prognostic marker in early-stage non-small-cell lung cancer. AB - BACKGROUND: NKX2-1, a key molecule in lung development, is highly expressed in non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (ADK), where it is a diagnostic marker. Studies of the prognostic role of NKX2-1 in NSCLC have reported contradictory findings. Two microRNAs (miRNAs) have been associated with NKX2-1: miR-365, which targets NKX2-1; and miR-33a, which is downstream of NKX2-1. We have examined the effect of NKX2-1, miR-365 and miR-33a on survival in a cohort of early-stage NSCLC patients and in sub-groups of patients classified according to the mutational status of TP53, KRAS, and EGFR. METHODS: mRNA and miRNA expression was determined using TaqMan assays in 110 early-stage NSCLC patients. TP53, KRAS, and EGFR mutations were assessed by Sanger sequencing. RESULTS: NKX2-1 expression was upregulated in never-smokers (P = 0.017), ADK (P < 0.0001) and patients with wild-type TP53 (P = 0.001). A negative correlation between NKX2-1 and miR-365 expression was found (rho = 0.287; P = 0.003) but there was no correlation between NKX2-1 and miR-33a expression. Overall survival (OS) was longer in patients with high expression of NKX2-1 than in those with low expression (80.8 vs 61.2 months (P = 0.035), while a trend towards longer OS was observed in patients with low miR-365 levels (P = 0.07). The impact of NKX2-1 on OS and DFS was higher in patients with neither TP53 nor KRAS mutations. Higher expression of NKX2-1 was related to higher OS (77.6 vs 54 months; P = 0.017) and DFS (74.6 vs 57.7 months; P = 0.006) compared to low expression. The association between NKX2-1 and OS and DFS was strengthened when the analysis was limited to patients with stage I disease (P = 0.005 and P=0.003 respectively). CONCLUSIONS: NKX2-1 expression impacts prognosis in early stage NSCLC patients, particularly in those with neither TP53 nor KRAS mutations. PMID- 29237429 TI - Using theory-based messages to motivate U.S. pregnant women to prevent cytomegalovirus infection: results from formative research. AB - BACKGROUND: An estimated 1 in 150 infants is born each year with congenital cytomegalovirus (CMV); nearly 1 in 750 suffers permanent disabilities. Congenital CMV is the result of a pregnant woman becoming infected with CMV. Educating pregnant women about CMV is currently the best approach to prevention. Limited research is available on how to effectively communicate with women about CMV. We conducted formative research on fear appeals theory-based messages about CMV and prevention with U.S. women. Fear appeal theories suggest that message recipients will take action if they feel fear. METHODS: First, we conducted in-depth interviews (N = 32) with women who had young children who tested positive for CMV. Second, we conducted eight focus groups (N = 70) in two phases and two cities (Phase 2: Atlanta, GA; Phase 3: San Diego, CA) with pregnant women and non pregnant women who had young children. Few participants knew about CMV before the focus groups. Participants reviewed and gave feedback on messages created around fear appeals theory-based communication concepts. The following concepts were tested in one or more of the three phases of research: CMV is severe, CMV is common, CMV is preventable, CMV preventive strategies are similar to other behavior changes women make during pregnancy, CMV preventive strategies can be incorporated in moderation to reduce exposure, and CMV is severe but preventable. RESULTS: Participants recommended communicating that CMV is common by using prevalence ratios (e.g., 1 in 150) or comparing CMV to other well-known disabilities. To convey the severity of CMV, participants preferred stories about CMV along with prevention strategies. Participants also welcomed prevention strategies when it included a message about risk reduction. In general, participants said messages were motivating, even if they felt that it could be difficult to make certain behavior changes. CONCLUSIONS: Findings from this research can contribute to future efforts to educate pregnant women about CMV, especially regarding use of fear appeals-based messages. Pregnant women may face certain challenges to practicing prevention strategies but, overall, are motivated make changes to increase their chances of having a healthy baby. PMID- 29237430 TI - Antitumor effect of Quercetin on Y79 retinoblastoma cells via activation of JNK and p38 MAPK pathways. AB - BACKGROUND: Quercetin (QCT) is a flavonol present in many vegetables, it is proved to show chemo preventive effect against lung, cervical, prostate, breast and colon cancer due to its anti-inflammatory, anti-tumor and anti-oxidant property. Looking into the reported chemo-preventive effect we speculated antitumor activity in retinoblastoma (RB) Y79 cells, we also studied the molecular mechanism for antitumor activity. METHODS: The effect of QCT on Y79 cell viability count was done by cell counting kit, cell cycle distribution, apoptosis studies and mitochondrial membrane potential was evaluated by flow cytometry. Protein expression was done by western blot analysis. RESULTS: The outcomes of study showed that QCT reduced Y79 cell viability and caused arrest of G1 phase in cell cycle via decreasing the expression levels of cyclin-dependent kinase (CDK)2/6 and cyclin D3 and by increasing the levels of both CDK inhibitor proteins p21 and p27. Apoptosis of Y79 cells mediated by QCT occurred via activation of both caspases-3/-9. Flow cytometry studies showed that QCT caused collapse in mitochondrial membrane potential (DeltaPsim) in Y79 cells. Western blot studies confirmed that QCT brought about phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). We also established that inhibitors of JNK and p38 MAPK suppressed QCT mediated activation of both caspases-3/-9 and subdued the apoptosis of cancerous Y79 cells. CONCLUSION: All the results of the study suggest that QCT induced the apoptosis of Y79 cells via activation of JNK and p38 MAPK pathways, providing a novel treatment approach for human RB. PMID- 29237431 TI - A case of herbicide-induced acute fibrinous and organizing pneumonia? AB - BACKGROUND: To improve the understanding of acute fibrinous and organizing pneumonia (AFOP), we present one case of AFOP proven by percutaneous lung biopsy along with clinical features, chest imaging and pathology. CASE PRESENTATION: A 50-year-old man was admitted to our department after he was given empiric therapy for community-acquired pneumonia (CAP). The clinical symptoms of the patient were dry cough, chills, night sweats and high fevers. Chest computed tomography (CT) scan showed a high-density shadow in the right lung lobe, similar to lobular pneumonia. The patient was preliminarily diagnosed with community-acquired pneumonia; however, antibacterial treatment was ineffective. To confirm the diagnosis, we performed bronchoscopy and percutaneous lung biopsy; pathology was consistent with AFOP. After he was treated with glucocorticoids, the patient's symptoms were relieved, and the shadow seen on imaging dissipated during the follow-up period. CONCLUSIONS: AFOP is a rare histopathological diagnosis that can be easily misdiagnosed. Clinicians need to consider the possibility of AFOP in the case of invalid antibacterial therapy. PMID- 29237432 TI - Multiple drill-hole osteotomy in hand surgery - description of a novel application and proof of feasibility. AB - BACKGROUND: Malunion of phalangeal and metacarpal bones are often associated with impairment of hand function and pose a challenging task for treating surgeons in most cases. When applicable, corrective osteotomy is the treatment of choice, where the affected bone is cut to correct malalignment using chisels or saws. The use of these instruments is associated with several drawbacks especially in hand surgery. We aimed to determine whether a multiple drill-hole (MDH) osteotomy technique was suitable for performing corrective osteotomies of metacarpal and phalangeal bones. METHODS: This case series included 11 patients with malalignments or malunions of phalangeal or metacarpal bones. Corrective osteotomy was performed with the MDH technique. Follow-up examinations included clinical evaluations and radiography at frequent intervals, between 2 and 22 months postoperatively. RESULTS: In all cases, planned osteotomies were technically feasible with the MDH technique. Apart from one case of a broken drillbit, no intraoperative or postoperative complication was recorded. All performed osteotomies healed within a mean of 6 weeks to radiological consolidation. In all cases, satisfactory results were achieved. CONCLUSION: The present study was the first to test MDH osteotomy for hand surgery. We demonstrated that MDH was feasible for corrective osteotomies of metacarpal and phalangeal deformities. Advantages included excellent feasibility for osteotomies performed at varying angles, precise execution, reduced risk of collateral damage, and flexibility for performing intra-articular osteotomies. PMID- 29237433 TI - Influence of screw density on thoracic kyphosis restoration in hypokyphotic adolescent idiopathic scoliosis. AB - BACKGROUND: Previous studies have reported that rod composition and diameter, as well as the correction technique are key factors associated with thoracic kyphosis (TK) restoration. However, few study has analyzed the correlation between screw density and TK restoration in hypokyphotic adolescent idiopathic scoliosis (AIS). METHODS: Fifty-seven thoracic AIS patients with preoperative TK < 10 degrees treated with all pedicle screw fixation with a minimum 2-year follow-up were recruited. Preoperative and postoperative radiographic measurements, and information of posterior instrumentation were reviewed. Pearson and Spearman correlation coefficient analysis were used to assess relationships between change in TK and number of variables. Then, the included patients were classified into two groups (Group 1: postoperative TK >= 20 degrees ; Group 2: postoperative TK < 20 degrees ) to evaluate the influence factors of TK restoration. RESULTS: The average preoperative TK was 4.75 degrees , which was significantly restored to 17.30 degrees (P < 0.001). Significant correlations were found between change in TK and flexibility of major thoracic curve (r = 0.357, P = 0.006), preoperative TK (r = -0.408, P = 0.002), and screw density of concave side (r = 0.306, P = 0.021), respectively. In the subgroup comparison, 17 patients (29.8%) maintain the postoperative TK >= 20 degrees , increased flexibility of major thoracic curve (P < 0.001), screw number of concave side (P = 0. 029), and cobalt chromium rods (P = 0.041) were found in the group of postoperative TK >= 20 degrees . CONCLUSIONS: TK restoration remains a challenge for AIS patients with hypokyphosis, especially for the poor flexibility ones. Except for thicker and cobalt chromium rods, screw density of concave side might be another positive predictor of restoring normal kyphosis, which provides a stronger corrective force on the sagittal plane with more pedicle screws. PMID- 29237434 TI - Bidirectional associations between psychosocial well-being and adherence to healthy dietary guidelines in European children: prospective findings from the IDEFICS study. AB - BACKGROUND: In children the relationship between a healthy diet and psychosocial well-being has not been fully explored and the existing evidence is inconsistent. This study investigates the chronology of the association between children's adherence to healthy dietary guidelines and their well-being, with special attention to the influence of weight status on the association. METHODS: Seven thousand six hundred seventy five children 2 to 9 years old from the eight country cohort study IDEFICS were investigated. They were first examined between September 2007 and June 2008 and re-examined again 2 years later. Psychosocial well-being was measured using self-esteem and parent relations questions from the KINDL(r) and emotional and peer problems from the Strengths and Difficulties Questionnaire. A Healthy Dietary Adherence Score (HDAS) was calculated from a 43 item food frequency questionnaire as a measure of the degree to which children's dietary intake follows nutrition guidelines. The analysis employed multilevel logistic regression (country as random effect) with bidirectional modeling of dichotomous dietary and well-being variables as both exposures and outcomes while controlling for respective baseline values. RESULTS: A higher HDAS at baseline was associated with better self-esteem (OR 1.2, 95% CI 1.0;1.4) and fewer emotional and peer problems (OR 1.2, 95% CI 1.1;1.3 and OR 1.3, 95% CI 1.2;1.4) 2 years later. For the reversed direction, better self-esteem was associated with higher HDAS 2 years later (OR 1.1 95% CI 1.0;1.29). The analysis stratified by weight status revealed that the associations between higher HDAS at baseline and better well-being at follow-up were similar in both normal weight and overweight children. CONCLUSION: Present findings suggest a bidirectional relation between diet quality and self-esteem. Additionally, higher adherence to healthy dietary guidelines at baseline was associated with fewer emotional and peer problems at follow-up, independent of children's weight status. PMID- 29237435 TI - Clinical safety of combined therapy of immune checkpoint inhibitors and Viscum album L. therapy in patients with advanced or metastatic cancer. AB - BACKGROUND: Despite improvement of tumour response rates in patients with progressive and metastatic cancer, immune checkpoint inhibitors (ICM) induce toxicities in cancer patients. Viscum album L. (VA, mistletoe) extracts are applied as add-on cancer therapy especially in German speaking countries and within integrative and anthroposophical concepts with the goal to improve quality of life. The primary objective of this pilot observational cohort study was to determine the rate of adverse events (AE) related to ICM therapy with and without VA in patients with advanced or metastatic cancer in a certified Cancer Center. METHODS: ICM or combined ICM/VA therapies were applied in patients with progressive or metastatic cancer. AE rates of both therapy groups were compared. RESULTS: A total of sixteen cancer patients were treated with ICM: nivolumab (75%), ipilimumab (19%) or pembrolizumab (6%). The median age of the study population was 64 years (IQR 57.8; 69.3); 44% were male. Of the sixteen patients receiving ICM, nine patients received additional VA (56%; ICM/VA group) and seven did not (44%; ICM group). No statistically significant differences were seen between groups with respect to AE-rates (67% ICM/VA versus 71% ICM). Adjusted multivariate regression analysis revealed that concomitant application of VA did not alter the AE rate in ICM treated patients. 85% of AEs were expected ICM reactions. No AEs of grade 3 or greater were documented for the total study cohort. CONCLUSIONS: This is the first study evaluating the clinical safety profile of ICM in combination with VA in patients with advanced or metastatic cancer. The overall AE rate of the study cohort is comparable to AE rates of ICM treatment in the literature. Our data indicate a first impression that concomitant VA application may not alter ICM-induced AE rates. However, the nature of this study does not allow excluding possible immunological interactions between ICM and VA. Further prospective trials in larger study cohorts should focus on the assessment of safety aspects, clinical efficacy and health related quality of life in patients with combined ICM/VA therapy. TRIAL REGISTRATION: DRKS00013335 , retrospectively registered (November 27th, 2017) at the German Clinical Trials Register ( www.drks.de ). PMID- 29237436 TI - High-flow nasal cannula oxygen therapy versus conventional oxygen therapy in patients with acute respiratory failure: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Acute respiratory failure (ARF) is a common and life-threatening medical emergency in patients admitted to the hospital. Currently, there is a lack of large-scale evidence on the use of high-flow nasal cannulas (HFNC) in patients with ARF. In this systematic review and meta-analysis, we evaluated whether there were differences between HFNC therapy and conventional oxygen therapy (COT) for treating patients with ARF. METHODS: The EMBASE, Medline, and Wanfang databases and the Cochrane Library were searched. Two investigators independently collected the data and assessed the quality of each study. Randomized controlled trials that compared HFNC therapy with COT in patients with ARF were included. RevMan 5.3 was used to conduct the meta-analysis. RESULTS: Four studies that involved 703 patients with ARF were included, with 371 patients in the HFNC group and 332 patients in the COT group. In the overall estimates, there were no significant differences between the HFNC and COT groups in the rates of escalation of respiratory support (RR, 0.68; 95% CI, 0.37, 1.27; z = 1.20, P = 0.23), intubation (RR, 0.74; 95% CI, 0.55, 1.00; z = 1.95, P = 0.05), mortality (RR, 0.82; 95% CI, 0.36, 1.88; z = 0.47, P = 0.64), or ICU transfer (RR, 1.09; 95% CI, 0.57, 2.09; z = 0.26, P = 0.79) during ARF treatment. However, the subgroup analysis showed that HFNC therapy may decrease the rate of escalation of respiratory support (RR, 0.71; 95% CI, 0.53, 0.97; z = 2.15, P = 0.03) and the intubation rate (RR, 0.71; 95% CI, 0.53, 0.97; z = 2.15, P = 0.03) when ARF patients were treated with HFNC therapy for >=24 h compared with COT. CONCLUSIONS: HFNC therapy was similar to COT in ARF patients. The subgroup analysis showed that HFNC therapy may decrease the rate of escalation of respiratory support and the intubation rate when ARF patients were treated with HFNC for >=24 h compared with COT. Further high-quality, large-scale studies are needed to confirm our results. PMID- 29237437 TI - The impact of a community-led program promoting weight loss and healthy living in Aboriginal communities: the New South Wales Knockout Health Challenge. AB - BACKGROUND: Aboriginal people in Australia experience significant health burden from chronic disease. There has been limited research to identify effective healthy lifestyle programs to address risk factors for chronic disease among Aboriginal people. METHODS: The Knockout Health Challenge is a community-led healthy lifestyle program for Aboriginal communities across New South Wales, Australia. An evaluation of the 2013 Knockout Health Challenge was undertaken. Participants' self-reported physical activity and diet were measured at four time points - at the start and end of the Challenge (via paper form), and 5 and 9 months after the Challenge (via telephone survey). Participants' weight was measured objectively at the start and end of the Challenge, and self-reported (via telephone survey) 5 and 9 months after the Challenge. Changes in body composition, physical activity and diet between time points were analysed using linear mixed models. As part of the telephone survey participants were also asked to identify other impacts of the Challenge; these were analysed descriptively (quantitative items) and thematically (qualitative items). RESULTS: A total of 586 people registered in 22 teams to participate in the Challenge. The mean weight at the start was 98.54kg (SD 22.4), and 94% of participants were overweight or obese. Among participants who provided data at all four time points (n=122), the mean weight loss from the start to the end of the Challenge was 2.3kg (95%CI -3.0 to -1.9, p<0.001), and from the start to 9 months after the Challenge was 2.3kg (95%CI -3.3 to -1.3, p<0.001). Body mass index decreased by an average of 0.9kg/m2 (95%CI -1.0 to -0.7, p<0.001) from the start to the end of the Challenge, and 0.8kg/m2 (95%CI -1.2 to -0.4, p<0.001) 9 months after. At the end of the Challenge, participants reported they were more physically active and had increased fruit and vegetable consumption compared with the start of the Challenge, and identified a range of other positive impacts. CONCLUSIONS: The Challenge was effective in reducing weight and promoting healthy lifestyles among Aboriginal people across New South Wales, and has potential to contribute to closing the health gap between Aboriginal and non-Aboriginal people. PMID- 29237438 TI - Effects of sesamin on primary human synovial fibroblasts and SW982 cell line induced by tumor necrosis factor-alpha as a synovitis-like model. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic synovitis, cartilage degradation and bone deformities. Synovitis is the term for inflammation of the synovial membrane, an early stage of RA. The pathogenesis of the disease occurs through cytokine induction. The major cytokine that increases the severity of RA is TNF-alpha. Thus, inhibition of the TNF-alpha cascade is an effective way to diminish the progression of the disease. We are interested in investigating the difference between primary human synovial fibroblast (hSF) cells and SW982 as synovitis models induced by TNF-alpha and in monitoring their responses to sesamin as an anti-inflammatory phytochemical. METHOD: The designed experiments were performed in hSF cells or the SW982 cell line treated with 10 ng/ml TNF-alpha with or without 0.25, 0.5 or 1 MUM sesamin. Subsequently, pro-inflammatory cytokine genes and proteins were measured in parallel with a study of associated signalling transduction involved in inflammatory processes, including NF-kappaB and MAPK pathways. RESULTS: The results demonstrated that although hSF and SW982 cells responded to TNF-alpha induction in the same fashion, they reacted at different levels. TNF-alpha could induce IL-6, IL-8 and IL-1beta in both cell types, but the levels in SW982 cells were much higher than in hSF cells. This characteristic was due to the different induction of MAPKs in each cell type. Both cell types reacted to sesamin in almost the same fashion. However, hSF cells were more sensitive to sesamin than SW982 cells in terms of the anti-RA effect. CONCLUSIONS: The responses of TNF alpha-induced hSF and SW982 were different at the signal transduction level. However, the two cell types showed almost the same reaction to sesamin treatment in terms of the end point of the response. PMID- 29237439 TI - Supporting men through their transition to fatherhood with messages delivered to their smartphones: a feasibility study of SMS4dads. AB - BACKGROUND: The transition to parenthood can be a challenging time, in which both mothers and fathers experience increased risk of distress and depression. Mothers are more likely than fathers to engage with services and have their mental health monitored and attended to during the perinatal period. The present study aimed to explore whether smartphone technology could be used to address fathers' needs across their transition to fatherhood. METHODS: A corpus of messages, including linked information and mood tracking software, was designed to support and enhance paternal relationships with their babies, their partners and themselves across the perinatal period. Messages were sent to project participants (N = 520) from 12-weeks' gestation to 24-weeks after birth. RESULTS: Of those fathers enrolled (N = 520), 21.5% scored >13 on K6 and completion rate (85%) was similar between these and other fathers. Most fathers (63.1%) clicked at least one link and responses were received for 20.5% of mood tracker questions. The probability of reporting worse mood scores decreased over time. Fathers completing post study surveys (N = 101) reported that messages helped them in their experience of becoming a new dad (92.8%), as well as helping them develop a strong relationship with their new child (54.9%), and in their relationship with their partner (79%). CONCLUSIONS: The present study has demonstrated that it is both feasible and acceptable to support new fathers with SMS4dads, a relationship-focused messaging system designed to be delivered to smartphones across fathers' transition to parenthood. PMID- 29237440 TI - Experiences of community members and researchers on community engagement in an Ecohealth project in South Africa and Zimbabwe. AB - BACKGROUND: Community engagement (CE) models have provided much needed guidance for researchers to conceptualise and design engagement strategies for research projects. Most of the published strategies, however, still show very limited contribution of the community to the engagement process. One way of achieving this is to document experiences of community members in the CE processes during project implementation. The aim of our study was to explore the experiences of two research naive communities, regarding a CE strategy collaboratively developed by researchers and study communities in a multicountry study. METHODS: The study was carried out in two research naive communities; Gwanda, Zimbabwe and uMkhanyakude, South Africa. The multicentre study was a community based participatory ecohealth multicentre study. A qualitative case study approach was used to explore the CE strategy. Data was collected through Focus Group Discussions, Key Informant Interviews and Direct Observations. Data presented in this paper was collected at three stages of the community engagement process; soon after community entry, soon after sensitisation and during study implementation. Data was analysed through thematic analysis. RESULTS: The communities generally had positive experiences of the CE process. They felt that the continuous solicitation of their advice and preferences enabled them to significantly contribute to shaping the engagement process. Communities also perceived the CE process as having been flexible, and that the researchers had presented an open forum for sharing responsibilities in all decision making processes of the engagement process. CONCLUSIONS: This study has demonstrated that research naive communities can significantly contribute to research processes if they are adequately engaged. The study also showed that if researchers put in maximum effort to demystify the research process, communities become empowered and participate as partners in research. PMID- 29237441 TI - Potential benefit of bosentan therapy in borderline or less severe pulmonary hypertension secondary to idiopathic pulmonary fibrosis-an interim analysis of results from a prospective, single-center, randomized, parallel-group study. AB - BACKGROUND: No drugs have been approved for the treatment of patients with pulmonary hypertension (PH) secondary to idiopathic pulmonary fibrosis (IPF), particularly those with idiopathic honeycomb lung. This study was conducted to investigate the long-term efficacy and safety of bosentan for PH based on changes in prognosis and respiratory failure. METHODS: IPF patients with borderline or less severe PH and completely organized honeycomb lung were randomized (1:1) to bosentan or no treatment for PH for 2 years and assessed at baseline and every 6 months for respiratory failure, activities of daily living (ADL), lung and heart functions by right cardiac catheterization, and other parameters. An interim analysis was performed, however, following detection of a significant survival benefit favoring bosentan therapy. RESULTS: Significant differences were noted for the bosentan-treated (n = 12) vs. untreated (n = 12) groups in hospital-free survival (603.44 +/- 50.074 days vs. 358.87 +/- 68.65 days; hazard ratio [HR], 0.19; P = 0.017) and overall survival (671 days vs. 433.78 +/- 66.98 days; HR, 0.10; P = 0.0082). Again, significant improvements were noted for the bosentan treated group from baseline to month 6 or 12 in several indices in ADL, pulmonary circulation, and %DLCO. Without requiring O2 inhalation, bosentan was associated with no increase but a trend toward a decrease in adverse events and an improvement in respiratory status. CONCLUSIONS: Bosentan tended to improve prognosis and ADL without worsening respiratory failure in IPF patients with borderline or less severe PH and completely organized honeycomb lung alone. TRIAL REGISTRATION: This study was registered on December 18, 2010 with UMIN-CTR Clinical Trial as UMIN000004749 to investigate the long-term influence of bosentan on cardiac function, as well as its cardioprotective efficacy and safety, in patients with pulmonary hypertension secondary to concurrent COPD and IPF, respectively. PMID- 29237443 TI - Nursing faculty academic incivility: perceptions of nursing students and faculty. AB - BACKGROUND: Incivility in nursing education can adversely affect the academic environment, the learning outcomes, and safety. Nursing faculty (NF) and nursing students (NS) contribute to the academic incivility. Little is known about the extent of NF academic incivility in the Middle East region. This study aimed at exploring the perceptions and extent of NF academic incivility in an undergraduate nursing program of a public university in Oman. METHODS: A cross sectional survey was used to collect data from 155 undergraduate NS and 40 NF about faculty academic incivility. Data was collected using the Incivility in Nursing Education Survey. RESULTS: The majority of NS and NF had similar perceptions about disruptive faculty behaviors. The incidence of faculty incivility was low (Mean = 1.5). The disruptive behaviors with the highest incidence were arriving late for scheduled activities, leaving schedule activities early, cancelling scheduled activities without warning, ineffective teaching styles and methods, and subjective grading. The most common uncivil faculty behaviors reported by participants were general taunts or disrespect to other NF, challenges to other faculty knowledge or credibility, and general taunts or disrespect to NS. CONCLUSION: The relatively low level of NF academic incivility could still affect the performance of some students, faculty, and program outcomes. Academic institutions need to ensure a policy of zero tolerance to all academic incivility, and regular monitoring and evaluation as part of the prevention strategies. PMID- 29237442 TI - Factors impacting the illness trajectory of post-infectious fatigue syndrome: a qualitative study of adults' experiences. AB - BACKGROUND: Post-infectious fatigue syndrome (PIFS), also known as post-viral fatigue syndrome, is a complex condition resulting in physical, cognitive, emotional, neurological, vocational and/or role performance disabilities in varying degrees that changes over time. The needs for health care resources are high, and costly, as is the economic burden on the affected individuals. Many factors may impact the trajectory, and frequently PIFS develops into a chronic condition. Health professionals lack understanding and knowledge, which results in delayed diagnosis, lack of recognition, appropriate treatment, support and practical help. The aim of our study was to explore, from the perspective of persons who had lived with PIFS for four years following an outbreak of Giardia l. induced enteritis, factors that may have impacted their illness trajectory and how these factors had played a role during different phases. METHODS: In this retrospective exploratory qualitative study a group of 26 affected adults between 26 and 59 years old were selected for in-depth interviews. A maximum variation sample was recruited from a physician-diagnosed cohort of persons with PIFS enrolled at a tertiary outpatient fatigue clinic. The interviews were audio recorded, transcribed verbatim and subjected to qualitative content analysis. RESULTS: Unhelpful and helpful factors were associated with the healthcare system, health professionals and the affected persons were experienced as having an impact on the trajectory. External impacting factors which are related to the health care system, providers and the social security system are misdiagnosis, trivialization of symptoms, unhelpful advice, delayed diagnosis and lack of appropriate help. Internal impacting factors related to the affected individuals were lack of knowledge, overestimating functional capacity, assuming the condition will pass, ignoring body signals and denial. A model of impacting factors in each phase of the trajectory is presented. CONCLUSION: Unmet needs may result in unnecessary disability and high societal and personal costs. Enhanced knowledge of impacting factors in each phase of the trajectory may contribute to more timely and tailored health care services and less use of health services. Increased functional capacity, improved health and ability to work or study may reduce the societal costs and the economic burden for the affected individuals. PMID- 29237444 TI - Development and assessment of an active strategy for the implementation of a collaborative care approach for depression in primary care (the INDI.i project). AB - BACKGROUND: Primary care is the principal clinical setting for the management of depression. However, significant shortcomings have been detected in its diagnosis and clinical management, as well as in patient outcomes. We developed the INDI collaborative care model to improve the management of depression in primary care. This intervention has been favorably evaluated in terms of clinical efficacy and cost-effectiveness in a clinical trial. Our aim is to bring this intervention from the scientific context into clinical practice. METHODS: Objective: To test for the feasibility and impact of a strategy for implementing the INDI model for depression in primary care. DESIGN: A quasi-experiment conducted in primary care. Several areas will be established to implement the new program and other, comparable areas will serve as control group. The study constitutes the preliminary phase preceding generalization of the model in the Catalan public healthcare system. PARTICIPANTS: The target population of the intervention are patients with major depression. The implementation strategy will also involve healthcare professionals, primary care centers, as well as management departments and the healthcare organization itself in the geographical areas where the study will be conducted: Camp de Tarragona and Valles Occidental (Catalonia). INTERVENTION: The INDI model is a program for improving the management of depression involving clinical, instructional, and organizational interventions including the participation of nurses as care managers, the efficacy and efficiency of which has been proven in a clinical trial. We will design an active implementation strategy for this model based on the PARIHS (Promoting Action on Research Implementation in Health Services) framework. MEASURES: Qualitative and quantitative measures will be used to evaluate variables related to the successful implementation of the model: acceptability, utility, penetration, sustainability, and clinical impact. DISCUSSION: This project tests the transferability of a healthcare intervention supported by scientific research to clinical practice. If implementation is successful in this experimental phase, we will use the information and experience obtained to propose and plan the generalization of the INDI model for depression in the Catalan healthcare system. We expect the program to benefit patients, the healthcare system, and society. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03285659 ; Registered 12th September, 2017. PMID- 29237445 TI - Cost of resistance to trematodes in freshwater snail populations with low clonal diversity. AB - BACKGROUND: The persistence of high genetic variability in natural populations garners considerable interest among ecologists and evolutionary biologists. One proposed hypothesis for the maintenance of high levels of genetic diversity relies on frequency-dependent selection imposed by parasites on host populations (Red Queen hypothesis). A complementary hypothesis suggests that a trade-off between fitness costs associated with tolerance to stress factors and fitness costs associated with resistance to parasites is responsible for the maintenance of host genetic diversity. RESULTS: The present study investigated whether host resistance to parasites is traded off with tolerance to environmental stress factors (high/low temperatures, high salinity), by comparing populations of the freshwater snail Melanoides tuberculata with low vs. high clonal diversity. Since polyclonal populations were found to be more parasitized than populations with low clonal diversity, we expected them to be tolerant to environmental stress factors. We found that clonal diversity explained most of the variation in snail survival under high temperature, thereby suggesting that tolerance to high temperatures of clonally diverse populations is higher than that of populations with low clonal diversity. CONCLUSIONS: Our results suggest that resistance to parasites may come at a cost of reduced tolerance to certain environmental stress factors. PMID- 29237446 TI - Trichomoniasis and associated co-infections of the genital tract among pregnant women presenting at two hospitals in Ghana. AB - BACKGROUND: Trichomonas vaginalis (TV) infection is the most prevalent non-viral sexually transmitted pathogen worldwide. Among pregnant women, the infection may cause adverse birth outcomes such as premature rupture of membranes and premature labour. In view of the paucity of information relating to TV among Ghanaian pregnant women, this study investigated its prevalence and associated co infections among pregnant women. METHODS: High vaginal swabs were obtained from 99 pregnant women using sterile cotton swab sticks. Wet preparation, Grams staining, culturing, coagulase and sensitivity testing were carried out to determine the presence of TV and associated microorganisms. RESULTS: The prevalence of TV among the pregnant women was found to be 20.2% (n = 20). Concurring with Trichomoniasis, 75% (n = 15) of participants had other infections such as Candida with prevalence of 53% (n = 8), Proteus infection - 20% (n = 3), Streptococcus infection - 13% (n = 2) and other GNRs and Gonococci having 7% each (n = 1). Moreover, there was 86.9% (n = 86) prevalence of Staphylococcus spp. among study participants. There was statistically significant correlation between TV and Gonococci infection at a correlation co-efficient of 0.107 (P < 0.05) as well as significant correlation between TV and Proteus spp. at a correlation co efficient of 0.189 (P < 0.05). TV infection was high (60%) among the most sexually active age group (19 to 29 yrs). CONCLUSION: There was 20.2% prevalence of TV among the pregnant women presenting at the hospitals, with Gonococci and Proteus infections being statistically significant associated infections. PMID- 29237447 TI - Attitudes to suicide following the suicide of a friend or relative: a qualitative study of the views of 429 young bereaved adults in the UK. AB - BACKGROUND: People bereaved by suicide are at increased risk of suicide attempt and suicide, but explanations for these associations remain theoretical. It is possible that the experience of suicide bereavement modifies personal attitudes towards suicide, but the nature of these changes remains unexplored. There is a need to understand personal attitudes to suicide following suicide bereavement, as this may inform the development of suicide prevention interventions. Our aim was to explore the attitudes of young adults bereaved by suicide towards their own likelihood of dying by suicide. METHODS: We conducted a cross-sectional study of staff and students aged 18-40 at 37 United Kingdom (UK) higher educational institutions in 2010. Ethical approval was granted by the UCL Research Ethics Committee. Qualitative responses to a question probing attitudes to own suicide were provided by 429 respondents who had experienced bereavement by the suicide of a close contact. We identified key themes in this dataset using thematic analysis. RESULTS: Analysis identified four main themes: suicide as a more tangible option (whether feared or not); identification with the deceased and awareness of shared vulnerabilities to suicide; personal determination to avoid suicide; and beliefs regarding safeguards against suicide. These themes reflected a broad split in participants' views regarding own likelihood of dying by suicide, influenced by the degree to which own suicide was feared and the extent to which they felt in control of determining a suicide death. Whilst the majority described an aversion to the idea of attempting suicide themselves, largely through an awareness of the impact on others, a minority described their experiences as having normalised suicide as a personal option. CONCLUSIONS: The views of a sample of UK-based adults bereaved by suicide suggest that exposure to the suicide of a close friend or relative can influence attitudes to suicide in ways that could influence own risk of suicide attempt. The normalising attitudes to suicide observed in a minority of respondents could contribute to the observed association between suicide bereavement and suicide attempt. PMID- 29237448 TI - Surgical outcome of atypical subtrochanteric and femoral fracture related to bisphosphonates use in osteoporotic patients with or without teriparatide treatment. AB - BACKGROUND: Atypical subtrochanteric fracture and femoral fracture have been considered to be rare complications related to long-term bisphosphonates use. A reduced bone turnover rate may lead to delayed bone healing. Limited data have revealed that teriparatide treatment may reverse the effect of bisphosphonates and be effective in bone healing. METHODS: We reviewed patients with atypical subtrochanteric and femoral fracture related to bisphosphonates use between January 2008 and December 2014. Thirteen female patients were enrolled. Radiographic findings were compatible with the characteristics of atypical fracture. Surgical intervention was performed for all, and teriparatide use was advised postoperatively. Outcome measures included perioperative results, and clinical and radiographic outcome. RESULTS: Of the 13 female patients enrolled, 10 had subtrochanteric and 6 had proximal femoral fracture; 3 had bilateral fractures. The mean age of the patients at surgery was 70.15+/-6.36 years. Most fractures (68.8%) presented prodromal thigh pain. All patients were treated with an intramedullary fixation system without severe complications. The patients were divided into 2 groups based on whether they had received treatment with teriparatide or not. The mean time to bone union was 4.4 months in the teriparatide-treated group, and 6.2 months in the non-teriparatide-treated group (p=0.116). Six patients (75%) in the teriparatide-treated group and 4 (50%) in the non-teriparatide-treated group (p= 0.3) achieved bone union within 6 months. The means of the modified Harris Hip Score and Numerical Rating Scale were significantly better in the teriparatide-treated group at postoperative 6 months. Seven patients had the same ability to walk at the 1-year follow-up as they did before the atypical fracture. CONCLUSIONS: Teriparatide treatment in patients with atypical fracture may help in fracture healing, hip function recovery, and pain relief in this reduced bone turnover patient group. PMID- 29237449 TI - High altitude population of Arabidopsis thaliana is more plastic and adaptive under common garden than controlled condition. AB - BACKGROUND: Population differentiation and their adaptation to a particular environment depend on their ability to respond to a new environment. This, in turn is governed to an extent, by the degree of phenotypic plasticity exhibited by the populations. The populations of same species inhabiting different climatic conditions may differ in their phenotypic plasticity. Himalayan populations of Arabidopsis thaliana originating from a steep altitude are exposed to different climatic conditions ranging from sub-tropical to temperate. Thus they might have experienced different selection pressures during evolution and may respond differently under common environmental condition. RESULTS: Phenotypic plasticity and differentiation of natural populations of A. thaliana grown under common garden and controlled conditions were determined. A total of seventeen morphological traits, their plasticity, association between traits and environment were performed using 45 accessions from three populations. Plants from different altitudes differed in phenotypes, their selection and fitness under two conditions. Under both the conditions lower altitude population was characterized by higher leaf count and larger silique than higher and middle altitude population. Flowering time of high altitude population increased while that of low and medium altitude decreased under controlled condition compared to open field. An increase in seed weight and germination was observed for all the population under open field than controlled. Rosette area was under divergent selection in both the condition. The heritability of lower altitude population was the highest under both the conditions, where as it was the least for higher altitude population further indicating that the high altitude populations are more responsive towards phenotypic changes under new environmental conditions. Ninety-nine percent of variability in traits and their plasticity co-varied with the altitude of their origin. The population of high altitude was more plastic and differentiated as compared to the lower altitude one. CONCLUSIONS: Arabidopsis thaliana population native to different altitudes of the west Himalaya responds differently when grown under common environments. The success of high altitude population is more in common garden than the controlled conditions. The significant variability in phenotype and its association with altitude of origin predicts for non-random genetic differentiation among the populations. PMID- 29237450 TI - Adding Chinese herbal medicine to conventional therapy brings cognitive benefits to patients with Alzheimer's disease: a retrospective analysis. AB - BACKGROUND: Conventional therapy (CT) such as donepezil and memantine are well known short-term treatments for the symptoms of Alzheimer's disease (AD). The efficacy of them, however, drops below baseline level after 9 months. In China, herbal therapy as a complementary therapy is very popular. Should conventional therapy combined with herbal therapy (CT + H) make add-on benefit? METHODS: In this retrospective cohort study, 344 outpatients diagnosed as probable dementia due to AD were collected, with the treatment of either CT + H or CT alone in clinical settings. All the patients were examined with coronary MRI scan. Cognitive functions were obtained by mini-mental state examination (MMSE) every 3 months with the longest follow-up of 24 months. RESULTS: Most of the patients were initially diagnosed with mild (MMSE = 21-26, n = 177) and moderate (MMSE = 10-20, n = 137) dementia. At 18 months, CT+ H patients scored on average 1.76 (P = 0.002) better than CT patients, and at 24 months, patients scored on average 2.52 (P < 0.001) better. At 24 months, the patients with improved cognitive function (?MMSE >= 0) in CT + H was more than CT alone (33.33% vs 7.69%, P = 0.020). Interestingly, patients with mild AD received the most robust benefit from CT + H therapy. The deterioration of the cognitive function was largely prevented at 24 months (DeltaMMSE = -0.06), a significant improvement from CT alone (DeltaMMSE = -2.66, P = 0.005). CONCLUSIONS: Compared to CT alone, CT + H significantly benefited AD patients. A symptomatic effect of CT + H was more pronounced with time. Cognitive decline was substantially decelerated in patients with moderate severity, while the cognitive function was largely stabilized in patients with mild severity over two years. These results imply that Chinese herbal medicines may provide an alternative and additive treatment for AD. PMID- 29237451 TI - Delay in diagnosis of pulmonary tuberculosis in low-and middle-income settings: systematic review and meta-analysis. AB - BACKGROUND: Assessment of delays in seeking care and diagnosis of tuberculosis is essential to evaluate effectiveness of tuberculosis control programs, and identify programmatic impediments. Thus, this review of studies aimed to examine the extent of patient, health system, and total delays in diagnosis of pulmonary tuberculosis in low- and middle- income countries. METHODS: It was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Electronic databases were searched to retrieve studies published from 2007 to 2015 including Pubmed central, Springer link, Hinari and Google scholar. Searching terms were pulmonary tuberculosis, health care seeking, health care seeking behavior, patient delay, diagnostic delay, health system delay, provider delay, and doctor delay. Retrieved studies were systematically reviewed and summarized using Comprehensive Meta-analysis software. RESULTS: Forty studies involving 18,975 patients qualified for systematic review, and 14 of them qualified for meta-analysis. The median diagnostic delay ranged from 30 to 366.5 days [IQR = 44-77.8], with a 4-199 days [IQR = 15-50] and 2-128.5 days [IQR = 12 34] due to patient and health system delays, respectively. The meta-analysis showed 42% of pulmonary tuberculosis patients delayed seeking care by a month or more; uneducated patients [pooled OR = 1.5, 95%CI = 1.1-1.9] and those who sought initial care from informal providers [pooled OR = 3, 95%CI = 2.3-3.9] had higher odds of patient delay. CONCLUSION: Delay in diagnosis is still a major challenge of tuberculosis control and prevention programs in low- and middle- income settings. Efforts to develop new strategies for better case-finding using the existing systems and improving patients' care seeking behavior need to be intensified. PMID- 29237452 TI - Molecular cloning and characterization of the family of feline leucine-rich glioma-inactivated (LGI) genes, and mutational analysis in familial spontaneous epileptic cats. AB - BACKGROUND: Leucine-rich glioma-inactivated (LGI) proteins play a critical role in synaptic transmission. Dysfunction of these genes and encoded proteins is associated with neurological disorders such as genetic epilepsy or autoimmune limbic encephalitis in animals and human. Familial spontaneous epileptic cats (FSECs) are the only feline strain and animal model of familial temporal lobe epilepsy. The seizure semiology of FSECs comprises recurrent limbic seizures with or without evolution into generalized epileptic seizures, while cats with antibodies against voltage-gated potassium channel complexed/LGI1 show limbic encephalitis and recurrent limbic seizures. However, it remains unclear whether the genetics underlying FSECs are associated with LGI family genes. In the present study, we cloned and characterized the feline LGI1-4 genes and examined their association with FSECs. Conventional PCR techniques were performed for cloning and mutational analysis. Characterization was predicted using bioinformatics software. RESULTS: The cDNAs of feline LGI1-4 contained 1674-bp, 1650-bp, 1647-bp, and 1617-bp open reading frames, respectively, and encoded proteins comprising 557, 549, 548, and 538 amino acid residues, respectively. The feline LGI1-4 putative protein sequences showed high homology with Homo sapiens, Canis familiaris, Bos taurus, Sus scrofa, and Equus caballus (92%-100%). Mutational analysis in 8 FSECs and 8 controls for LGI family genes revealed 3 non synonymous and 14 synonymous single nucleotide polymorphisms in the coding region. Only one non-synonymous single nucleotide polymorphism in LGI4 was found in 3 out of 8 FSECs. Using three separate computational tools, this mutation was not predicted to be disease causing. No co-segregation of the disease was found with any variant. CONCLUSIONS: We cloned the cDNAs of the four feline LGI genes, analyzed the amino acid sequences, and revealed that epilepsy in FSEC is not a monogenic disorder associated with LGI genes. PMID- 29237453 TI - Human microglia and astrocytes constitutively express the neurokinin-1 receptor and functionally respond to substance P. AB - BACKGROUND: The tachykinin substance P (SP) is recognized to exacerbate inflammation at peripheral sites via its target receptor, neurokinin 1 receptor (NK-1R), expressed by leukocytes. More recently, SP/NK-1R interactions have been associated with severe neuroinflammation and neuronal damage. We have previously demonstrated that NK-1R antagonists can limit neuroinflammatory damage in a mouse model of bacterial meningitis. Furthermore, we have since shown that these agents can attenuate bacteria-induced neuronal and glial inflammatory mediator production in nonhuman primate (NHP) brain explants and isolated neuronal cells, and following in vivo infection. METHODS: In the present study, we have assessed the ability of NHP brain explants, primary human microglia and astrocytes, and immortalized human glial cell lines to express NK-1R isoforms. We have utilized RT-PCR, immunoblot analysis, immunofluorescent microscopy, and/or flow cytometric analysis, to quantify NK-1R expression in each, at rest, or following bacterial challenge. Furthermore, we have assessed the ability of human microglia to respond to SP by immunoblot analysis of NF-kB nuclear translocation and determined the ability of this neuropeptide to augment inflammatory cytokine release and neurotoxic mediator production by human astrocytes using an ELISA and a neuronal cell toxicity assay, respectively. RESULTS: We demonstrate that human microglial and astrocytic cells as well as NHP brain tissue constitutively express robust levels of the full-length NK-1R isoform. In addition, we demonstrate that the expression of NK-1R by human astrocytes can be further elevated following exposure to disparate bacterial pathogens or their components. Importantly, we have demonstrated that NK-1R is functional in both human microglia and astrocytes and show that SP can augment the inflammatory and/or neurotoxic immune responses of glial cells to disparate and clinically relevant bacterial pathogens. CONCLUSIONS: The robust constitutive and functional expression of the full-length NK-1R isoform by human microglia and astrocytes, and the ability of SP to augment inflammatory signaling pathways and mediator production by these cells, support the contention that SP/NK-1R interactions play a significant role in the damaging neuroinflammation associated with conditions such as bacterial meningitis. PMID- 29237454 TI - Dietary patterns are associated with type 2 diabetes mellitus among middle-aged adults in Zhejiang Province, China. AB - BACKGROUND: Although some studies have shown the associations between dietary patterns and the risk T2DM in a general population, the associations in middle aged Chinese have been rarely studied to date. In this study, we aimed to characterize dietary patterns in Chinese adults aged 45-59y (n = 1918) and to evaluate the relationship between dietary patterns and the risk of T2DM. METHODS: The study population was a part of the population-based the Nutrition and Health Study conducted in the city of Hangzhou, Zhejiang Province, China. Dietary intake was assessed by using a validated food frequency questionnaire (FFQ). Multivariate logistic regression analyses were used to estimate the associations between dietary patterns and the risk of T2DM, adjusting for potential confounders. RESULTS: Three major dietary patterns were identified using factor analysis, including the traditional southern Chinese, the Western, and the grains vegetables patterns. After adjusting for the potential confounders, subjects in the highest quartile of the Western dietary pattern scores had greater odds ratio(OR) for T2DM(OR = 1.28; 95% confidence interval (CI): 1.103-1.697; P = 0.02) than did those in the lowest quartile. Compared with those in the lowest quartile, subjects in the highest quartile of the grains-vegetables dietary pattern scores had a lower OR for T2DM (OR = 0.72; 95% CI:0.596-0.952; P = 0.04). Moreover, no significant association was found between the traditional southern Chinese dietary pattern and risk of developing T2DM. CONCLUSIONS: Our findings indicated that the Western dietary pattern was associated with an elevated risk, whereas the grains-vegetables dietary pattern was associated with a reduced risk of T2DM. Further researches are needed to confirm these findings. PMID- 29237456 TI - Identification of potential transcriptomic markers in developing pediatric sepsis: a weighted gene co-expression network analysis and a case-control validation study. AB - BACKGROUND: Sepsis represents a complex disease with the dysregulated inflammatory response and high mortality rate. The goal of this study was to identify potential transcriptomic markers in developing pediatric sepsis by a co expression module analysis of the transcriptomic dataset. METHODS: Using the R software and Bioconductor packages, we performed a weighted gene co-expression network analysis to identify co-expression modules significantly associated with pediatric sepsis. Functional interpretation (gene ontology and pathway analysis) and enrichment analysis with known transcription factors and microRNAs of the identified candidate modules were then performed. In modules significantly associated with sepsis, the intramodular analysis was further performed and "hub genes" were identified and validated by quantitative real-time PCR (qPCR) in this study. RESULTS: 15 co-expression modules in total were detected, and four modules ("midnight blue", "cyan", "brown", and "tan") were most significantly associated with pediatric sepsis and suggested as potential sepsis-associated modules. Gene ontology analysis and pathway analysis revealed that these four modules strongly associated with immune response. Three of the four sepsis-associated modules were also enriched with known transcription factors (false discovery rate-adjusted P < 0.05). Hub genes were identified in each of the four modules. Four of the identified hub genes (MYB proto-oncogene like 1, killer cell lectin like receptor G1, stomatin, and membrane spanning 4-domains A4A) were further validated to be differentially expressed between septic children and controls by qPCR. CONCLUSIONS: Four pediatric sepsis-associated co-expression modules were identified in this study. qPCR results suggest that hub genes in these modules are potential transcriptomic markers for pediatric sepsis diagnosis. These results provide novel insights into the pathogenesis of pediatric sepsis and promote the generation of diagnostic gene sets. PMID- 29237455 TI - Molecular and histological effects of MR-guided pulsed focused ultrasound to the rat heart. AB - BACKGROUND: Image-guided high intensity focused ultrasound has been used as an extracorporeal cardiac pacing tool and to enhance homing of stem cells to targeted tissues. However, molecular changes in the myocardium after sonication have not been widely investigated. Magnetic-resonance (MR)-guided pulsed focused ultrasound (pFUS) was targeted to the rat myocardium over a range of pressures and the microenvironmental and histological effects were evaluated over time. METHODS: Eight-to-ten-week-old Sprague-Dawley rats received T2-weighted MR images to target pFUS to the left ventricular and septum without cardiac or respiratory gating. Rats were sonicated through the thoracic wall at peak negative pressures (PNP) from 1 to 8 MPa at a center frequency of 1 MHz, 10 ms pulse duration and 1 Hz pulse repetition frequency for 100 pulses per focal target. Following pFUS, myocardium was harvested over 24 h and subjected to imaging, proteomic, and histological measurements. RESULTS: pFUS to the myocardium increased expression of cytokines, chemokines, and trophic factors characterized by an initial increase in tumor necrosis factor (TNF)-alpha followed by increases in pro- and anti-inflammatory factors that returned to baseline by 24 h. Immediately after pFUS, there was a transient (< 1 h) increase in N-terminal pro b-type natriuretic peptide (NT-proBNP) without elevation of other cardiac injury markers. A relationship between PNP and expression of TNF-alpha and NT-proBNP was observed with significant changes (p < 0.05 ANOVA) >= 4 MPa compared to untreated controls. Contrast-enhanced ex vivo T1-weighted MRI revealed vascular leakage in sonicated myocardium that was accompanied by the presence of albumin upon immunohistochemistry. Histology revealed infiltration of neutrophils and macrophages without morphological myofibril changes in sonicated tissue accompanied by pulmonary hemorrhage at PNP > 4 MPa. CONCLUSIONS: MR-guided pFUS to myocardium induced transient proteomic and histological changes. The temporal proteomic changes in the myocardium indicate a short-lived sterile inflammatory response consistent with ischemia or contusion. Further study of myocardial function and strain is needed to determine if pFUS could be developed as an experimental model of cardiac injury and chest trauma. PMID- 29237457 TI - The role of Src & ERK1/2 kinases in inspiratory resistive breathing induced acute lung injury and inflammation. AB - BACKGROUND: Inspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with large negative intrathoracic pressures, due to strenuous contractions of the inspiratory muscles. IRB is shown to induce lung injury in previously healthy animals. Src is a multifunctional kinase that is activated in the lung by mechanical stress. ERK1/2 kinase is a downstream target of Src. We hypothesized that Src is activated in the lung during IRB, mediates ERK1/2 activation and IRB-induced lung injury. METHODS: Anaesthetized, tracheostomized adult rats breathed spontaneously through a 2-way non-rebreathing valve. Resistance was added to the inspiratory port to provide a peak tidal inspiratory pressure of 50% of maximum (inspiratory resistive breathing). Activation of Src and ERK1/2 in the lung was estimated during IRB. Following 6 h of IRB, respiratory system mechanics were measured by the forced oscillation technique and bronchoalveolar lavage (BAL) was performed to measure total and differential cell count and total protein levels. IL-1b and MIP-2a protein levels were measured in lung tissue samples. Wet lung weight to total body weight was measured and Evans blue dye extravasation was estimated to measure lung permeability. Lung injury was evaluated by histology. The Src inhibitor, PP-2 or the inhibitor of ERK1/2 activation, PD98059 was administrated 30 min prior to IRB. RESULTS: Src kinase was activated 30 min after the initiation of IRB. Src inhibition ameliorated the increase in BAL cellularity after 6 h IRB, but not the increase of IL-1beta and MIP-2a in the lung. The increase in BAL total protein and lung injury score were not affected. The increase in tissue elasticity was partly inhibited. Src inhibition blocked ERK1/2 activation at 3 but not at 6 h of IRB. ERK1/2 inhibition ameliorated the increase in BAL cellularity after 6 h of IRB, blocked the increase of IL-1beta and returned Evans blue extravasation and wet lung weight to control values. BAL total protein and the increase in elasticity were partially affected. ERK1/2 inhibition did not significantly change total lung injury score compared to 6 h IRB. CONCLUSIONS: Src and ERK1/2 are activated in the lung following IRB and participate in IRB-induced lung injury. PMID- 29237458 TI - Cellular effects of a turmeric root and rosemary leaf extract on canine neoplastic cell lines. AB - BACKGROUND: The use of nutraceuticals is gaining in popularity in human and canine oncology with a relatively limited understanding of the effects in the vastly different tumor types seen in canine oncology. We have previously shown that turmeric root (TE) and rosemary leaf (RE) extracts can work synergistically to reduce neoplastic cell growth, but the mechanisms are poorly understood and require further elucidation. RESULTS: Three different canine cell lines (C2 mastocytoma, and CMT-12 mammary carcinoma, D17 osteosarcoma) were treated with 6.3 MUg mL-1 extract individually, or 3.1 MUg mL-1 of each extract in combination based on studies showing synergy of these two extracts. Apoptosis, antioxidant effects, cellular accumulation of curcumin, and perturbation of signaling pathways were assessed. The TE + RE combination treatment resulted in Caspase 3/7 activation and apoptosis in all cell lines, beyond the effects of TE alone with the CMT-12 cell line being most susceptible. Both extracts had antioxidant effects with RE reducing reactive oxygen species (ROS) by 40-50% and TE reducing ROS by 80-90%. In addition RE treatment enhanced the c-jun N-terminal kinase (JNK) activity in the C2 cell line and TE + RE exposure increased activated JNK by 4-5 times in the CMT-12 cell line. Upon further examination, it was found that RE treatment caused a significant increase in the cellular accumulation of curcumin by approximately 30% in the C2 and D17 cell lines, and by 4.8-fold in the CMT-12 cell line. This increase in intracellular curcumin levels may play a role in the synergy exhibited when using TE and RE in combination. CONCLUSIONS: The use of RE in combination with TE induces a synergistic response to induce apoptosis which is better than either extract alone. This appears to be related to a variable increased TE uptake in cells and activation of pathways involved in the apoptotic response. PMID- 29237459 TI - Quantification of sterol-specific response in human macrophages using automated imaged-based analysis. AB - BACKGROUND: The transformation of normal macrophage cells into lipid-laden foam cells is an important step in the progression of atherosclerosis. One major contributor to foam cell formation in vivo is the intracellular accumulation of cholesterol. METHODS: Here, we report the effects of various combinations of low density lipoprotein, sterols, lipids and other factors on human macrophages, using an automated image analysis program to quantitatively compare single cell properties, such as cell size and lipid content, in different conditions. RESULTS: We observed that the addition of cholesterol caused an increase in average cell lipid content across a range of conditions. All of the sterol-lipid mixtures examined were capable of inducing increases in average cell lipid content, with variations in the distribution of the response, in cytotoxicity and in how the sterol-lipid combination interacted with other activating factors. For example, cholesterol and lipopolysaccharide acted synergistically to increase cell lipid content while also increasing cell survival compared with the addition of lipopolysaccharide alone. Additionally, ergosterol and cholesteryl hemisuccinate caused similar increases in lipid content but also exhibited considerably greater cytotoxicity than cholesterol. CONCLUSIONS: The use of automated image analysis enables us to assess not only changes in average cell size and content, but also to rapidly and automatically compare population distributions based on simple fluorescence images. Our observations add to increasing understanding of the complex and multifactorial nature of foam-cell formation and provide a novel approach to assessing the heterogeneity of macrophage response to a variety of factors. PMID- 29237460 TI - Validity and reliability of the Mexican resilience measurement scale in families of children with chronic conditions. AB - BACKGROUND: The resilience to face disease is a process of positive adaptation despite the loss of health. It involves developing vitality and skills to overcome the negative effects of adversity, risks, and vulnerability caused by disease. In Mexico, the Mexican Resilience Measurement Scale (RESI-M) has been validated with a general population and has a five-factor structure. However, this scale does not allow evaluation of resilience in specific subpopulations, such as caregivers. METHOD: This study investigated the psychometric properties of RESI-M in 446 family caregivers of children with chronic diseases. A confirmatory factor analysis (CFA) was performed, internal consistency values were calculated using Cronbach's alpha coefficient, and mean comparisons were determined using t-tests. RESULTS: The expected five-factor model showed an adequate fit with the data based on a maximum likelihood test. The internal consistency for each factor ranged from .76 to .93, and the global internal consistency was .95. No average difference in RESI-M and its factors was found between women and men. CONCLUSION: The RESI-M showed internal consistency and its model of five correlated factors was valid among family caregivers of children with chronic diseases. PMID- 29237462 TI - Effects of pathogen dependency in a multi-pathogen infectious disease system including population level heterogeneity - a simulation study. AB - BACKGROUND: Increased computational resources have made individual based models popular for modelling epidemics. They have the advantage of incorporating heterogeneous features, including realistic population structures (like e.g. households). Existing stochastic simulation studies of epidemics, however, have been developed mainly for incorporating single pathogen scenarios although the effect of different pathogens might directly or indirectly (e.g. via contact reductions) effect the spread of each pathogen. The goal of this work was to simulate a stochastic agent based system incorporating the effect of multiple pathogens, accounting for the household based transmission process and the dependency among pathogens. METHODS: With the help of simulations from such a system, we observed the behaviour of the epidemics in different scenarios. The scenarios included different household size distributions, dependency versus independency of pathogens, and also the degree of dependency expressed through household isolation during symptomatic phase of individuals. Generalized additive models were used to model the association between the epidemiological parameters of interest on the variation in the parameter values from the simulation data. All the simulations and statistical analyses were performed using R 3.4.0. RESULTS: We demonstrated the importance of considering pathogen dependency using two pathogens, and showing the difference when considered independent versus dependent. Additionally for the general scenario with more pathogens, the assumption of dependency among pathogens and the household size distribution in the population cohort was found to be effective in containing the epidemic process. Additionally, populations with larger household sizes reached the epidemic peak faster than societies with smaller household sizes but dependencies among pathogens did not affect this outcome significantly. Larger households had more infections in all population cohort examples considered in our simulations. Increase in household isolation coefficient for pathogen dependency also could control the epidemic process. CONCLUSION: Presence of multiple pathogens and their interaction can impact the behaviour of an epidemic across cohorts with different household size distributions. Future household cohort studies identifying multiple pathogens will provide useful data to verify the interaction processes in such an infectious disease system. PMID- 29237461 TI - Systematic literature review and meta-analysis of the efficacy of artemisinin based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: methodological challenges. AB - BACKGROUND: There is no agreed standard method to assess the efficacy of anti malarials for uncomplicated falciparum in pregnancy despite an increased risk of adverse outcomes for the mother and the fetus. The aim of this review is to present the currently available evidence from both observational and interventional cohort studies on anti-malarial efficacy in pregnancy and summarize the variability of assessment and reporting found in the review process. METHODS: Efficacy methodology and assessment of artemisinin-based treatments (ABT) and quinine-based treatments (QBT) were reviewed systematically using seven databases and two clinical trial registries (protocol registration PROSPERO: CRD42017054808). Pregnant women in all trimesters with parasitologically confirmed uncomplicated falciparum malaria were included irrespective of symptoms. This review attempted to re-calculate proportions of treatment success applying the same definition as the standard WHO methodology for non-pregnant populations. Aggregated data meta-analyses using data from randomized control trials (RCTs) comparing different treatments were performed by random effects model. RESULTS: A total of 48 eligible efficacy studies were identified including 7279 treated Plasmodium falciparum episodes. While polymerase chain reaction (PCR) was used in 24 studies for differentiating recurrence, the assessment and reporting of treatment efficacy was heterogeneous. When the same definition could be applied, PCR-corrected treatment failure of >= 10% at any time points was observed in 3/30 ABT and 3/7 QBT arms. Ten RCTs compared different combinations of ABT but there was a maximum of two published RCTs with PCR-corrected outcomes for each comparison. Five RCTs compared ABT and QBT. Overall, the risk of treatment failure was significantly lower in ABT than in QBT (risk ratio 0.22, 95% confidence interval 0.07-0.63), although the actual drug combinations and outcome endpoints were different. First trimester women were included in 12 studies none of which were RCTs of ABT. CONCLUSIONS: Efficacy studies in pregnancy are not only limited in number but use varied methodological assessments. In five RCTs with comparable methodology, ABT resulted in higher efficacy than QBT in the second and third trimester of pregnancy. Individual patient data meta-analysis can include data from observational cohort studies and could overcome some of the limitations of the current assessment given the paucity of data in this vulnerable group. PMID- 29237463 TI - The researchers' role in knowledge translation: a realist evaluation of the development and implementation of diagnostic pathways for cancer in two United Kingdom localities. AB - BACKGROUND: In examining an initiative to develop and implement new cancer diagnostic pathways in two English localities, this paper evaluates 'what works' and examines the role of researchers in facilitating knowledge translation amongst teams of local clinicians and policy-makers. METHODS: Using realist evaluation with a mixed methods case study approach, we conducted documentary analysis of meeting minutes and pathway iterations to map pathway development. We interviewed 14 participants to identify the contexts, mechanisms and outcomes (CMOs) that led to successful pathway development and implementation. Interviews were analysed thematically and four CMO configurations were developed. RESULTS: One site produced three fully implemented pathways, while the other produced two that were partly implemented. In explaining the differences, we found that a respected, independent, well-connected leader modelling partnership working and who facilitates a local, stable group that agree about the legitimacy of the data and project (context) can empower local teams to become sufficiently autonomous (mechanism) to develop and implement research-based pathways (outcome). Although both teams designed relevant, research-based cancer pathways, in the site where the pathways were successfully implemented the research team merely assisted, while, in the other, the research team drove the initiative. CONCLUSION: Based on our study findings, local stakeholders can apply local and research knowledge to develop and implement research-based pathways. However, success will depend on how academics empower local teams to create autonomy. Crucially, after re packaging and translating research for local circumstances, identifying fertile environments with the right elements for implementation and developing collaborative relationships with local leaders, academics must step back. PMID- 29237464 TI - TLR3 promotes MMP-9 production in primary human airway epithelial cells through Wnt/beta-catenin signaling. AB - BACKGROUND: Airway epithelial cells (AEC) act as the first line of defence in case of lung infections. They constitute a physical barrier against pathogens and they participate in the initiation of the immune response. Yet, the modalities of pathogen recognition by AEC and the consequences on the epithelial barrier remain poorly documented. METHOD: We investigated the response of primary human AEC to viral (polyinosinic-polycytidylic acid, poly(I:C)) and bacterial (lipopolysaccharide, LPS) stimulations in combination with the lung remodeling factor Transforming Growth Factor-beta (TGF-beta). RESULTS: We showed a strong production of pro-inflammatory cytokines (Interleukin (IL)-6, Tumor Necrosis Factor alpha, TNFalpha) or chemokines (CCL2, CCL3, CCL4, CXCL10, CXCL11) by AEC stimulated with poly(I:C). Cytokine and chemokine production, except CXCL10, was Toll Like Receptor (TLR)-3 dependent and although they express TLR4, we found no cytokine production after LPS stimulation. Poly(I:C), but not LPS, synergised with TGF-beta for the production of matrix metalloproteinase-9 (MMP-9) and fibronectin. Mechanistic analyses suggest the secretion of Wnt ligands by AEC along with a degradation of the cellular junctions after poly(I:C) exposure, leading to the release of beta-catenin from the cell membrane and stimulation of the Wnt/beta-catenin pathway. CONCLUSION: Our results highlight the cross talk between TGF-beta and TLR signaling in bronchial epithelium and its impact on the remodeling process. PMID- 29237465 TI - Mid-term results of mitral valve repair using flexible bands versus complete rings in patients with degenerative mitral valve disease: a prospective, randomized study. AB - BACKGROUND: We aimed to compare the outcomes of mitral valve repair with flexible band (FB) versus complete semirigid ring (SR) in degenerative mitral valve disease patients. METHODS: From September 2011 to 2014, 171 patients were randomized and underwent successful mitral valve repair using a SR (n = 85) or FB (n = 86). There were no significant between-group differences at baseline. RESULTS: There were no early mortalities. The mean follow up was 24.7 months. The 2-year survival was 96.0 +/- 2.3% (95% confidence interval [CI], 88.6-98.7%) and 94.3 +/- 2.8% (95% CI, 85.5-97.9%) in the SR and FB groups, respectively (p = 0.899). The left ventricle remodeling was similar between the groups. Higher transmitral peak (8.5 [3.9-17] vs. 6 [2.1-18] mmHg, p < 0.001), mean pressure gradients (3.7 [1.3-8] vs. 2.8 [0.6-6.8] mmHg, p = 0.001), and systolic pulmonary artery pressure (34.5 [20-68] vs. 29.5 [8-48] mmHg, p < 0.001) was observed in the SR group. The 2-year freedom from recurrence of significant mitral regurgitation was significantly higher in the FB group than the SR group (p = 0.002). Residual mitral regurgitation was an independent prognostic factor of recurrence of mitral regurgitation. The 3-year freedom from reoperation was significantly higher in the FB group than the SR group (p = 0.044). CONCLUSION: Patients with degenerative mitral valve disease may benefit from valve repair with FBs. Residual mitral regurgitation before discharge is an independent risk factor of late insufficiency recurrence. TRIAL REGISTRATION: ClinicalTrials.gov NCT03278574 , retrospectively registered on 06.09.2017. PMID- 29237466 TI - Rapid detection of infectious bovine Rhinotracheitis virus using recombinase polymerase amplification assays. AB - BACKGROUND: Infectious bovine rhinotracheitis virus (IBRV) is a major pathogen in cattle and has led to significant economic losses to the dairy industry worldwide, and therefore a more optimal method for the rapid diagnosis of IBRV infection is highly needed. In this study, we described the development of a lateral flow dipstrip (LFD) of isothermal recombinase polymerase amplification (RPA) method for rapid detection of IBRV. METHODS: Distinct regions were selected as a candidate target for designing the LFD-RPA primers and probes. The analytical sensitivity of the RPA assay was determined using ten-fold serially diluted IBRV DNA. The specificity of the assay was assessed with other viral pathogens of cattle with similar clinic and other herpesviruses. The clinical performance was evaluated by testing 106 acute-phase high fever clinical specimens. RESULTS: RPA primers and probe were designed to target the specific conserved UL52 region fragment of IBRV. The detection could be completed at a constant temperature of 38 degrees C for 25 min, and the amplification products were easily visualized on a simple LFD. The detection limit of this assay was 5 copies per reaction of IBRV DNA and there was no cross-reactivity with other viruses causing bovine gastrointestinal and respiratory infections or other herpesviruses. The assay performance on acute-phase high fever clinical samples collected from cattle with no vaccine against IBRV, which were suspected to be infected with IBRV, was validated by detecting 24 fecal, 36 blood, 38 nasal swab and 8 tissue specimens, and compared with SYBR Green I based real-time PCR. The coincidence between IBRV LFD-RPA and real-time PCR was 100%. CONCLUSION: IBRV LFD RPA was fast and much easier to serve as an alternative to the common measures used for IBRV diagnosis, as there is reduction in the use of instruments for identification of the infected animals. In addition, this assay may be the potential candidate to be used as point-of-care diagnostics in the field. PMID- 29237467 TI - Estimating drivers of cell state transitions using gene regulatory network models. AB - BACKGROUND: Specific cellular states are often associated with distinct gene expression patterns. These states are plastic, changing during development, or in the transition from health to disease. One relatively simple extension of this concept is to recognize that we can classify different cell-types by their active gene regulatory networks and that, consequently, transitions between cellular states can be modeled by changes in these underlying regulatory networks. RESULTS: Here we describe MONSTER, MOdeling Network State Transitions from Expression and Regulatory data, a regression-based method for inferring transcription factor drivers of cell state conditions at the gene regulatory network level. As a demonstration, we apply MONSTER to four different studies of chronic obstructive pulmonary disease to identify transcription factors that alter the network structure as the cell state progresses toward the disease state. CONCLUSIONS: We demonstrate that MONSTER can find strong regulatory signals that persist across studies and tissues of the same disease and that are not detectable using conventional analysis methods based on differential expression. An R package implementing MONSTER is available at github.com/QuackenbushLab/MONSTER. PMID- 29237469 TI - Bat rabies surveillance in France: first report of unusual mortality among serotine bats. AB - BACKGROUND: Rabies is a fatal viral encephalitic disease that is caused by lyssaviruses which can affect all mammals, including human and bats. In Europe, bat rabies cases are attributed to five different lyssavirus species, the majority of rabid bats being attributed to European bat 1 lyssavirus (EBLV-1), circulating mainly in serotine bats (Eptesicus serotinus). In France, rabies in bats is under surveillance since 1989, with 77 positive cases reported between 1989 and 2016. CASE PRESENTATION: In the frame of the bat rabies surveillance, an unusual mortality of serotine bats was reported in 2009 in a village in North East France. Six juvenile bats from an E. serotinus maternity colony counting ~200 individuals were found to be infected with EBLV-1. The active surveillance of the colony by capture sessions of bats from July to September 2009 showed a high detection rate of neutralising EBLV-1 antibodies (~ 50%) in the colony. Moreover, one out of 111 animals tested was found to shed viable virus in saliva, while lyssavirus RNA was detected by RT-PCR for five individuals. CONCLUSION: This study demonstrated that the lyssavirus infection in the serotine maternity colony was followed by a high rate of bat rabies immunity after circulation of the virus in the colony. The ratio of seropositive bats is probably indicative of an efficient virus transmission coupled to a rapid circulation of EBLV-1 in the colony. PMID- 29237468 TI - Left ventricular synchrony, torsion, and recoil mechanics in Ebstein's anomaly: insights from cardiovascular magnetic resonance. AB - BACKGROUND: Disease progression and heart failure development in Ebstein's Anomaly (EA) of the tricuspid valve is characterized by both right and left ventricular (LV) deterioration. The mechanisms underlying LV dysfunction and their role in heart failure development are incompletely understood. We hypothesized that LV dyssynchrony and impaired torsion and recoil mechanics induced by paradoxical movement of the basal septum may play a role in heart failure development. METHODS: 31 EA patients and 31 matched controls underwent prospective cardiovascular magnetic resonance (CMR). CMR feature tracking (CMR FT) was performed on apical, midventricular and basal short-axis and 4D-volume analysis was performed using three long-axis views and a short axis cine stack employing dedicated software. Circumferential uniformity ratio estimates (CURE) time-to-peak-based circumferential systolic dyssynchrony index (C-SDI), 4D volume analysis derived SDI (4D-SDI), torsion (Tor) and systolic (sysTR) and diastolic torsion rate (diasTR) were calculated for the LV. QRS duration, brain natriuretic peptide, NYHA and Total R/L-Volume Index (R/L Index) were obtained. RESULTS: EA patients (31.5 years; controls 31.4 years) had significantly longer QRS duration (123.35 ms +/- 26.36 vs. 97.33 ms +/- 11.89 p < 0.01) and showed more LV dyssynchrony (4D-SDI 7.60% +/- 4.58 vs. 2.54% +/- 0.62, p < 0.001; CURE 0.77 +/- 0.05 vs. 0.86 +/- 0.03, p < 0.001; C-SDI 7.70 +/- 3.38 vs. 3.80 +/- 0.91, p = 0.001). There were significant associations of LV dyssynchrony with heart failure parameters and QRS duration. Although torsion and recoil mechanics did not differ significantly (p > 0.05) there was an association of torsion and recoil mechanics with dyssynchrony parameters CURE (sysTR r = -0.426; p = 0.017, diasTR r = 0.419; p = 0.019), 4D-SDI (sysTR r = 0.383; p = 0.044) and C-SDI (diasTR r = -0.364; p = 0.044). CONCLUSIONS: EA is characterized by LV intra-ventricular dyssynchrony, which is associated with heart failure and disease severity parameters. Markers of dyssynchrony can easily be quantified from CMR-FT, and may have a role in the assessment of altered cardiac function, carrying potential management implications for EA patients. PMID- 29237470 TI - Gimatecan exerts potent antitumor activity against gastric cancer in vitro and in vivo via AKT and MAPK signaling pathways. AB - BACKGROUND: We investigated antitumor activity and underlying mechanisms of DNA topoisomerase I (TopI) inhibitor gimatecan and irinotecan in gastric cancer (GC) in vitro cell lines and in vivo patient-derived xenograft (PDX) models. METHODS: GC cell lines SNU-1, HGC27, MGC803 and NCI-N87 were used to evaluate cell viability and apoptosis after gimatecan or irinotecan treatment, using a cell proliferation assay and flow cytometry, respectively. DNA TopI expression and critical molecules of PI3K/AKT, MAPK and apoptosis signaling pathways were analyzed with western blot. For in vivo studies, five PDXs models were treated with gimatecan or irinotecan to assess its antitumor activity. Immunohistochemistry staining of Ki-67 was performed after mice were sacrificed. RESULTS: Gimatecan inhibited the proliferation of GC cells in vitro in a dose- and time-dependent manner by inducing apoptosis, and gimatecan had greater inhibitory effects than irinotecan. In addition, both gimatecan and irinotecan demonstrated significant tumor growth inhibition in in vivo PDX models. Gimatecan treatment significantly inhibited the expression of DNA TopI, phosphorylated AKT (pAKT), phosphorylated MEK (pMEK) and phosphorylated ERK (pERK). Meanwhile, gimatecan could also activate the JNK2 and p38 MAPK pathway as indicated by upregulation of phosphorylated p38 MAPK (p-p38) and phosphorylated JNK2 (pJNK2). CONCLUSIONS: For the first time, we have shown that the antitumor activity of gimatecan in GC via suppressing AKT and ERK pathway and activating JNK2 and p38 MAPK pathway, which indicated that gimatecan might be an alternative to irinotecan in the treatment of GC. PMID- 29237471 TI - Correlates of occupational, leisure and total sitting time in working adults: results from the Singapore multi-ethnic cohort. AB - BACKGROUND: Evidence on the health risks of sitting is accumulating. However, research identifying factors influencing sitting time in adults is limited, especially in Asian populations. This study aimed to identify socio-demographic and lifestyle correlates of occupational, leisure and total sitting time in a sample of Singapore working adults. METHODS: Data were collected between 2004 and 2010 from participants of the Singapore Multi Ethnic Cohort (MEC). Medical exclusion criteria for cohort participation were cancer, heart disease, stroke, renal failure and serious mental illness. Participants who were not working over the past 12 months and without data on sitting time were excluded from the analyses. Multivariable regression analyses were used to examine cross-sectional associations of self-reported age, gender, ethnicity, marital status, education, smoking, caloric intake and moderate-to-vigorous leisure time physical activity (LTPA) with self-reported occupational, leisure and total sitting time. Correlates were also studied separately for Chinese, Malays and Indians. RESULTS: The final sample comprised 9384 participants (54.8% male): 50.5% were Chinese, 24.0% Malay, and 25.5% Indian. For the total sample, mean occupational sitting time was 2.71 h/day, mean leisure sitting time was 2.77 h/day and mean total sitting time was 5.48 h/day. Sitting time in all domains was highest among Chinese. Age, gender, education, and caloric intake were associated with higher occupational sitting time, while ethnicity, marital status and smoking were associated with lower occupational sitting time. Marital status, smoking, caloric intake and LTPA were associated with higher leisure sitting time, while age, gender and ethnicity were associated with lower leisure sitting time. Gender, marital status, education, caloric intake and LTPA were associated with higher total sitting time, while ethnicity was associated with lower total sitting time. Stratified analyses revealed different associations within sitting domains for Indians compared to Chinese and Malays. CONCLUSION: Our findings highlight the need to focus on separate domains of sitting (occupational, leisure or total) when identifying which factors determine this behavior, and that the content of intervention programs should be tailored to domain-specific sitting rather than to sitting in general. Finally, our study showed ethnic differences and therefore we recommend to culturally target interventions. PMID- 29237472 TI - Supply kits for antenatal and childbirth care: a systematic review. AB - INTRODUCTION: It is critical to increase the uptake of interventions proven to be effective to improve maternal and perinatal outcomes. Supply kits have been suggested to be a feasible strategy designed to ensure timely availability and effective follow-up of care. OBJECTIVE: We conducted a systematic review to summarize the evidence on the uptake, effectiveness and safety of supply kits for maternal care. SEARCH STRATEGY: MEDLINE, the Cochrane Pregnancy and Childbirth Group's Trials Register, Campbell Collaboration, Lilacs, Embase and unpublished studies were searched. SELECTION CRITERIA: Studies that reported the efficacy, safety and use of supply kits for maternal healthcare were eligible. Participants were pregnant women or in childbirth. Supply kits were defined as a collection of medicines, supplies or instruments packaged together with the aim of conducting a healthcare task. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed the screening, data extraction, and methodological and quality assessment. MAIN RESULTS: 24 studies were included: 4 of them were systematic reviews and 20 primary studies. Eighteen studies evaluated a so-called "clean delivery kit". In all but two studies, the kits were used by more than half of the participants. A meta-analysis was deemed inappropriate due to the heterogeneity in study design, in the components of the interventions implemented, in the content of the kits, and in outcomes. Nine studies assessed neonatal outcomes and found statistically significant reductions in cord infection, sepsis and tetanus-related mortality in the intervention group. Three studies showed evidence of reduced neonatal mortality (OR 0.52, 0.60 and 0.71) with statistically significant confidence intervals in all cases. Four studies reported odd ratios for maternal mortality, but only one showed evidence of a statistically significant decrease in this outcome but it was ascribed to hand washing prior to childbirth and not with the use of kits. CONCLUSION: This review suggests potential benefits in the use of supply kits to improve maternal and neonatal health. However, the observational nature of the studies, the heterogeneity and the use of kits incorporated within complex interventions limit the interpretation of the findings. PMID- 29237473 TI - Sexual dimorphism in the hepatic protein response to a moderate trans fat diet in senescence-accelerated mice. AB - BACKGROUND: Aging is characterized by increases in inflammation and oxidative stress, conditions that are exacerbated by environmental factors such as diet. In this study, we investigated the effects of a trans-fatty acid (TFA) diet on the liver in adult (25 wk) and old (60 wk) senescence-accelerated mice (SAMP8 strain) of both sexes. Our goal was to assess the effects of the diet on protein markers of inflammation and oxidative stress in the liver. METHODS: Male and female mice were placed on life-long diets containing similar amounts of total fat (17%), with differing amounts of TFA: 2% (moderate TFA group) or 0.2% of total energy from TFA (control diet group). At the indicated ages, livers were harvested and evaluated for markers of inflammation and oxidative stress, as well as for enzymes of fat metabolism via immunoblotting. Relative densities of protein bands were determined and compared via a three-factor ANOVA. RESULTS: Compared to males, females demonstrated significantly lower inflammatory protein expression (ICAM-1, MCP-1, COX-2), along with lower expression of the DNA damage marker, Gadd153, and the oxidative stress marker, HO-1. Female mice demonstrated higher expression of antioxidant enzymes (SOD-1, SOD-2, and Ref-1) and lipogenic enzymes (FASN, ACLY) compared to male mice. While HO-1 was elevated in the female mice fed the TFA diet compared to controls, the diet did not affect other markers of oxidative stress or inflammation. However, the diet was associated with significant increases in FASN and ACLY in adult (25 wk) male mice. CONCLUSIONS: Our results suggest sexually dimorphic protein expression in the liver, with female mice demonstrating lower inflammation and increased oxidative stress defenses. Additionally, considering that FASN and ACLY contribute to hepatic lipogenesis, our results suggest a potential mechanism for the dyslipidemia in adult male mice that is associated with TFA diets. PMID- 29237474 TI - Dimethylarginines in patients with intracerebral hemorrhage: association with outcome, hematoma enlargement, and edema. AB - BACKGROUND: Asymmetric dimethylarginine (ADMA)--the most potent endogenous NO synthase inhibitor, has been regarded as mediator of endothelial dysfunction and oxidative stress. Considering experimental data, levels of ADMA and its structural isomer symmetric dimethylarginine (SDMA) might be elevated after intracerebral hemorrhage (ICH) and associated with clinical outcome and secondary brain injury. METHODS: Blood samples from 20 patients with acute ICH were taken at <= 24 h and 3 and 7 days after the event. Nine patients had favorable (modified Rankin Scale (mRS) at 90 days 0-2) outcome, and 11 patients unfavorable outcome (mRS 3-6). Patients' serum ADMA, SDMA, and L-arginine levels were determined by high-performance liquid chromatography-tandem mass spectrometry. Levels were compared to those of 30 control subjects without ICH. For further analysis, patients were grouped according to outcome, hematoma and perihematomal edema volumes, occurrence of hematoma enlargement, and cytotoxic edema as measured by computed tomography and serial magnetic resonance imaging. RESULTS: Levels of ADMA--but not SDMA and L-arginine--were elevated in ICH patients compared to controls (binary logistic regression analysis: ADMA <= 24 h, p = 0.003; 3 days p = 0.005; 7 days p = 0.004). If patients were grouped according to outcome, dimethylarginines were increased in patients with unfavorable outcome. The binary logistic regression analysis confirmed an association of SDMA levels <= 24 h (p = 0.048) and at 3 days (p = 0.028) with unfavorable outcome. ADMA <= 24 h was increased in patients with hematoma enlargement (p = 0.003), while SDMA <= 24 h was increased in patients with large hematoma (p = 0.029) and perihematomal edema volume (p = 0.023). CONCLUSIONS: Our data demonstrate an association between dimethylarginines and outcome of ICH. However, further studies are needed to confirm this relationship and elucidate the mechanisms behind. PMID- 29237475 TI - Recombinant human ACE2: acing out angiotensin II in ARDS therapy. PMID- 29237476 TI - Giant gastrointestinal stromal tumor with predominantly cystic changes: a case report and literature review. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) rarely present with predominantly cystic changes. Here, we report a case of giant GIST of the stomach with predominantly cystic changes in a 74-year-old female patient. CASE PRESENTATION: The tumor was 10 cm * 15 cm in size and positive for CD117, H caldesmon, and DOG-1. Complete surgical resection was performed without regional lymphadenectomy. The patient recovered uneventfully and no recurrence occurred. CONCLUSIONS: The case illustrates that GIST with cystic changes should be considered in the diagnoses of hepatic and pancreatic lesions. Furthermore, immunohistochemistry with CD117, DOG1, and other molecular markers is critical for diagnosis of GIST of the stomach and facilitates optimization of treatments for GIST. PMID- 29237477 TI - The impact of glaucoma on quality of life in Ethiopia: a case-control study. AB - BACKGROUND: Glaucoma is a chronic disease characterized by irreversible optic nerve damage and visual field loss that leads to visual impairment and blindness; ultimately limiting personal independence and compromising overall quality of life of affected individuals. There is paucity of information on how glaucoma affects the quality of life of patients in low and middle-income countries where resources for both diagnosis and treatment of such conditions are limited. In this study we investigate the impact of glaucoma on quality of life in Ethiopian patients. METHODS: The quality of life of 307 glaucoma patients and 76 normal controls that were frequency matched to the age and sex profiles of the cases was assessed using Amharic version of Glaucoma Quality of Life -15 questionnaire. Linear regression models and the t-test were employed to compare significant differences in GQL-15 scores and to generate mean and mean differences between cases and controls respectively. RESULTS: The mean GQL-15 score in the glaucoma cases was substantially higher (indicating poorer quality of life) than the controls [cases 46.3 (95% CI, 28.8-63.8) and controls 18.6 (95% CI, 15.2-22.0), p < 0.0001]. Cases with normal visual acuity and mild glaucoma had significantly higher scores than the controls. Poorer quality of life was associated with age >= 71 years old 51.1 (95%CI, 26.2-75.9), rural residence 55.7 (95%CI, 49.9-61.5), monthly income of <400 Birr (53.1; 95%CI, 50.5-55.6), diagnosis time 1-5 years (49.6; 95%CI, 41.2-57.9), severe visual impairment (70.5; 95%CI, 58.1-82.8), and advanced glaucoma (50.9; 95%CI, 43.6-58.3). CONCLUSION: These glaucoma patients, including those with normal visual acuity and early disease, had poorer quality of life compared to normal controls. Older age, rural residence, low income and more advanced disease were significantly associated with poorer quality of life. There is a need to increase awareness of the impact of glaucoma among clinicians, patients and their families, for a better understanding of the impact this disease has on a person's life. PMID- 29237478 TI - AM404, paracetamol metabolite, prevents prostaglandin synthesis in activated microglia by inhibiting COX activity. AB - BACKGROUND: N-arachidonoylphenolamine (AM404), a paracetamol metabolite, is a potent agonist of the transient receptor potential vanilloid type 1 (TRPV1) and low-affinity ligand of the cannabinoid receptor type 1 (CB1). There is evidence that AM404 exerts its pharmacological effects in immune cells. However, the effect of AM404 on the production of inflammatory mediators of the arachidonic acid pathway in activated microglia is still not fully elucidated. METHOD: In the present study, we investigated the effects of AM404 on the eicosanoid production induced by lipopolysaccharide (LPS) in organotypic hippocampal slices culture (OHSC) and primary microglia cultures using Western blot, immunohistochemistry, and ELISA. RESULTS: Our results show that AM404 inhibited LPS-mediated prostaglandin E2 (PGE2) production in OHSC, and LPS-stimulated PGE2 release was totally abolished in OHSC if microglial cells were removed. In primary microglia cultures, AM404 led to a significant dose-dependent decrease in the release of PGE2, independent of TRPV1 or CB1 receptors. Moreover, AM404 also inhibited the production of PGD2 and the formation of reactive oxygen species (8-iso-PGF2 alpha) with a reversible reduction of COX-1- and COX-2 activity. Also, it slightly decreased the levels of LPS-induced COX-2 protein, although no effect was observed on LPS-induced mPGES-1 protein synthesis. CONCLUSIONS: This study provides new significant insights about the potential anti-inflammatory role of AM404 and new mechanisms of action of paracetamol on the modulation of prostaglandin production by activated microglia. PMID- 29237479 TI - Birth delivery method affects expression of immune genes in lung and jejunum tissue of neonatal beef calves. AB - BACKGROUND: Caesarean section is a routine veterinary obstetrical procedure employed to alleviate dystocia in cattle. However, CS, particularly before the onset of labour, is known to negatively affect neonatal respiration and metabolic adaptation in humans, though there is little published information for cattle. The aim of this study was to investigate the effect of elective caesarean section (ECS) or normal trans-vaginal (TV) delivery, on lung and jejunal gene expression profiles of neonatal calves. RESULTS: Paternal half-sib Angus calves (gestation length 278 + 1.8 d) were delivered either transvaginally (TV; n = 8) or by elective caesarean section (ECS; n = 9) and immediately euthanized. Lung and jejunum epithelial tissue was isolated and snap frozen. Total RNA was extracted using Trizol reagent and reverse transcribed to generate cDNA. For lung tissue, primers were designed to target genes involved in immunity, surfactant production, cellular detoxification, membrane transport and mucin production. Primers for jejunum tissue were chosen to target mucin production, immunoglobulin uptake, cortisol reaction and membrane trafficking. Quantitative real-time PCR reactions were performed and data were statistically analysed using mixed models ANOVA. In lung tissue the expression of five genes were affected (p < 0.05) by delivery method. Four of these genes were present at lower (LAP, CYP1A1, SCN11alpha and SCN11beta) and one (MUC5AC) at higher abundance in ECS compared with TV calves. In jejunal tissue, expression of TNFalpha, Il-1beta and 1 l-6 was higher in ECS compared with TV calves. CONCLUSIONS: This novel study shows that ECS delivery affects the expression of key genes involved in the efficiency of the pulmonary liquid to air transition at birth, and may lead to an increased inflammatory response in jejunal tissue, which could compromise colostral immunoglobulin absorption. These findings are important to our understanding of the viability and management of neonatal calves born through ECS. PMID- 29237480 TI - Achilles tenodesis for calcaneal insufficiency avulsion fractures associated with diabetes mellitus. AB - BACKGROUND: Calcaneal insufficiency avulsion (CIA) fractures often present with neuropathic etiology, such as Charcot neuroarthropathy (CN). Under the same surgical procedures, the outcomes of CIA fractures are less desirable, compared to the outcomes of the traumatic calcaneal avulsion fractures. Here, the study suggests Achilles tenodesis technique using suture anchor after resection of the CIA fracture fragments could provide satisfactory clinical results in the cases of surgically indicated CIA fractures. MATERIALS AND METHODS: This retrospective study included seven patients of calcaneal avulsion fracture who had underlying diabetes mellitus (DM) and no specific traumatic event. The patients were treated with Achilles tenodesis techniques for their CIA fractures. Achilles tenodesis was performed using suture anchor with removal of the fracture fragments. The patients were evaluated with the Foot and Ankle Outcome Score (FAOS), visual analogue scale (VAS), single-heel rise test, and X-ray images on their final follow-ups. RESULTS: Initially, three of the CIA fracture cases treated with traditional open reduction and internal fixation reported pullout failure. Consequently, all patients received Achilles tenodesis using suture anchor after bone fragment resection and had good clinical outcomes. Only one subject with low compliance reported poor outcome. The FAOS of each patient were obtained at a mean of 16.3 months after surgery. The results are as follows: pain 80.6 (SD = 6.2), symptom 83.8 (SD = 4.9), activities of daily living 80.5 (SD = 8.0), sport and recreation function 75.6 (SD = 11.93), and foot- and ankle-related quality of life 77.9 (SD = 6.7). On their final follow-ups, the average VAS was 2.6 (range, 1 to 4). CONCLUSION: Achilles tenodesis using suture anchor after bone fragment resection achieved competent clinical results in the patients with CIA fractures. The study proposes that this surgical procedure could be an appropriate treatment option for patients with CIA fractures. TRIAL REGISTRATION: The study was approved by the institutional review board (IRB) of our medical center (IRB File No. 2016-07-043), retrospectively registered. PMID- 29237481 TI - Retraction Note: Transgenic mice overexpressing the ALS-linked protein Matrin 3 develop a profound muscle phenotype. AB - The authors are retracting this article. The article describes mice expressing wild-type human MATR3. However, since publication the authors have become aware that all of the lines of mice described express human MATR3 containing the F115C mutation. Transgenic mice expressing wild-type and mutant Matrin were created simultaneously in their laboratory and, at a crucial stage of generating the DNA for embryo injection, as confirmed by an investigation by the University of Florida, the DNA preparations were accidentally mislabelled. All of the founders created were mosaic, requiring extensive breeding to isolate stable lines. Mice mislabelled as expressing wild-type MATR3 were the first to produce lines that stably transmitted the transgene and thus were the first to be characterized. However, as lines of mice that were mislabelled as expressing the mutant (F115C) MATR3 were ultimately established, the data began to suggest that an error had been made. Sequence analysis of amplified tail DNA from mice descended from the lines reported in the article have revealed that they express the F115C variant. The data described are therefore an accurate description of the pathology of mice that express the F115C variant of MATR3, but not of mice expressing wild-type MATR3. The authors are preparing a new manuscript reporting data from both mice expressing the F115C variant of MATR3 and mice expressing wild-type MATR3. PMID- 29237482 TI - Extraction of amplifiable DNA from embalmed human cadaver tissue. AB - OBJECTIVE: The expansion of molecular techniques in medical diagnosis, forensics, and education requires the development of improved techniques of DNA extraction from fixed tissues. Cadaver tissues are not commonly used for genetic analysis due to DNA degradation resulting from the embalming fixation. Modification of existing techniques of tissue disruption combined with phenol-chloroform treatment was done to produce an efficient method of extracting amplifiable DNA of high quality and quantity from non-paraffin embedded embalmed cadaver tissue. RESULTS: Tissues (cerebellum, cerebral cortex, heart, and bone) from four cadavers were used to develop a procedure for DNA isolation, which includes a high heat treatment. The location and age of the tissue had a significant effect on the quantity of DNA recovered. Targeted PCR amplification of the Apolipoprotein gene was used to assess the efficacy of genotypic analysis from the recovered DNA. We report the development of a simple, reliable, and low-cost method of DNA isolation utilizing brain tissue from embalmed tissues that could be used for PCR amplification and genetic analysis. PMID- 29237483 TI - Adipocytes promote cholangiocarcinoma metastasis through fatty acid binding protein 4. AB - BACKGROUND: The early occurrence regional nodal and distant metastases cholangiocarcinoma (CCA) is one of the major reasons for its poor prognosis. However, the related mechanisms are largely elusive. Recently, increasing evidences indicate that adipocytes might be involved in the proliferation, homing, migration and invasion of several malignancies. In the present study, we attempt to determine the effects and possible mechanisms of adipocytes on regulating progression of CCA. METHODS: Adipocyte-CCA cell co-culture system and CCA metastasis mice model were used to determine the effects of adipocytes on CCA metastasis. We identified the biological functions and possible mechanisms of adipocyte-derived fatty acid binding protein 4 (FABP4) in regulating the adipocyte-induced CCA metastasis and epithelial-mesenchymal transition (EMT) phenotypes, both in vitro and in vivo. RESULTS: Adipocyte-CCA cell co-culture promotes the in vitro and in vivo tumor metastasis, leading to increased adipocyte-derived fatty acid absorbance and intracellular lipids of CCA cells, which indicates adipocytes might function as the energy source for CCA progression by providing free fatty acids. Further, highly expressed FABP4 protein was identified in adipose tissues and fully differentiated adipocytes, and upregulated FABP4 was also detected by qRT-PCR assay in CCA cells co cultivated with adipose extracts as compared to parental CCA cells. The specific FABP4 inhibitor BMS309403 significantly impaired adipocyte-induced CCA metastasis and EMT phenotypes both in vitro and in vivo. CONCLUSIONS: Together, the results demonstrate that the adipocyte-CCA interaction and the energy extraction of CCA cells from adipocytes are crucial for the invasion, migration and EMT of CCA cells. FABP4 from adipocytes mediates these adipocyte-induced variations in CCA cells, which could serve as a potential target for the treatment of CCA. PMID- 29237485 TI - Resuscitative endovascular balloon occlusion of the aorta may increase the bleeding of minor thoracic injury in severe multiple trauma patients: a case report. AB - BACKGROUND: The resuscitative endovascular balloon occlusion of the aorta, because of its efficacy and feasibility, has been widely used in treating patients with severe torso trauma. However, complications developing around the site proximal to the occlusion by resuscitative endovascular balloon occlusion of the aorta have almost never been studied. CASE PRESENTATION: A 50-year-old Japanese woman fell from a height of approximately 10 m. At initial arrival, her respiratory rate was 24 breaths/minute, her blood oxygen saturation was 95% under 10 L/minute oxygenation, her pulse rate was 90 beats per minute, and her blood pressure was 180/120 mmHg. Mild lung contusion, hemopneumothorax, unstable pelvic fracture, and retroperitoneal bleeding with extravasation of contrast media were observed in initial computed tomography. As her vital signs had deteriorated during computed tomography, a 7-French aortic occlusion catheter (RESCUE BALLOON(r), Tokai Medical Products, Aichi, Japan) was inserted and inflated for aortic occlusion at the first lumbar vertebra level and transcatheter arterial embolization was performed for the pelvic fracture. Her bilateral internal iliac arteries were embolized with a gelatin sponge; however, the embolized sites presented recanalization as coagulopathy appeared. Her bilateral internal iliac arteries were re-embolized by n-butyl-2-cyanoacrylate. The balloon was deflated 18 minutes later. After embolization, repeat computed tomography was performed and a massive hemothorax, which had not been captured on arrival, had appeared in her left pleural cavity. Thoracotomy hemostasis was performed and a hemothorax of approximately 2500 ml was aspirated to search for the source of bleeding. However, clear active bleeding was not captured; resuscitative endovascular balloon occlusion of the aorta may have been the cause of the increased bleeding of the thoracic injury at the proximal site of the aorta occlusion. CONCLUSIONS: It is necessary to note that the use of resuscitative endovascular balloon occlusion of the aorta may increase bleeding in sites proximal to occlusions, even in the case of minor injuries without active bleeding at the initial diagnosis. PMID- 29237484 TI - The clinical efficacy of Afatinib 30 mg daily as starting dose may not be inferior to Afatinib 40 mg daily in patients with stage IV lung Adenocarcinoma harboring exon 19 or exon 21 mutations. AB - BACKGROUND: Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Compared to cytotoxic chemotherapy, afatinib has been shown to have better efficacy in the treatment of non-small cell lung cancer harboring EGFR mutations. However, 40 mg daily as the initial dose is often accompanied by serious adverse drug reactions (ADRs) and 28 to 53.3% of patients required a dose reduction. No previous study has compared the clinical efficacy and ADRs of different initial doses (40 mg vs. 30 mg daily) of afatinib in lung cancer treatment. METHODS: Patients with stage IV lung adenocarcinoma diagnosed and treated in two Kaohsiung Medical University affiliated hospitals in Taiwan between May 2014 and August 2016 were identified and followed until December 2016. Demographic characteristics, responses, progression-free survival (PFS), overall survival (OS), and ADRs were recorded. RESULT: A total of 48 patients with stage IV lung adenocarcinoma harboring susceptible EGFR mutations who received afatinib as their first-line therapy were enrolled. Patients using 30 mg daily as the initial dose tended to be older and female and have a smaller body size. The patients using 30 mg of afatinib daily as their initial dose had a similar response rate to those receiving 40 mg daily (76% vs. 95%, p = 0.0862) and the same disease control rate (100% vs. 100%, p = 0.1486). The PFS was similar between the patients receiving 30 mg or 40 mg of afatinib daily (median PFS: 469 vs. 443 days, log-rank p = 0.8418). Patients receiving 30 mg daily had a significantly lower incidence of diarrhea than those using 40 mg daily (41% vs. 100%, p < 0.0001). CONCLUSION: An initial afatinib dose of 30 mg daily had similar response and progression-free survival rates as an initial dose of 40 mg daily, but resulted in fewer serious ADRs in this study. PMID- 29237486 TI - Transplantation of dental pulp stem cells improves long-term diabetic polyneuropathy together with improvement of nerve morphometrical evaluation. AB - BACKGROUND: Although previous reports have revealed the therapeutic potential of stem cell transplantation in diabetic polyneuropathy, the effects of cell transplantation on long-term diabetic polyneuropathy have not been investigated. In this study, we investigated whether the transplantation of dental pulp stem cells (DPSCs) ameliorated long-term diabetic polyneuropathy in streptozotocin (STZ)-induced diabetic rats. METHODS: Forty-eight weeks after STZ injection, we transplanted DPSCs into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation (i.e., 52 weeks after STZ injection) the effects of DPSC transplantation on diabetic polyneuropathy were assessed. RESULTS: STZ induced diabetic rats showed significant reductions in the sciatic motor/sensory nerve conduction velocity, increases in the current perception threshold, and decreases in capillary density in skeletal muscles and intra-epidermal nerve fiber density compared with normal rats, all of which were ameliorated by DPSC transplantation. Furthermore, sural nerve morphometrical analysis revealed that the transplantation of DPSCs significantly increased the myelin thickness and area. DPSC-conditioned media promoted the neurite outgrowth of dorsal root ganglion neurons and increased the viability and myelin-related protein expression of Schwann cells. CONCLUSIONS: These results indicated that the transplantation of DPSCs contributed to the neurophysiological and neuropathological recovery from a long duration of diabetic polyneuropathy. PMID- 29237487 TI - Adolescent Coordinated Transition (ACT) to improve health outcomes among young people living with HIV in Nigeria: study protocol for a randomized controlled trial. AB - BACKGROUND: Adolescents living with HIV (ALHIV) have worse health outcomes than other populations of people living with HIV. Contributing factors include lack of standard and comprehensive procedures for ALHIV transitioning from pediatric to adult care. This has contributed to poor retention at, and following transition, which is problematic especially in high ALHIV-burden, resource-limited settings like Nigeria. METHODS: Using a two-arm cluster randomized control design, the Adolescent Coordinated Transition (ACT) trial will measure the comparative effectiveness of a graduated transition and organized support group intervention against the usual practice of abrupt transfer of Nigerian ALHIV from pediatric to adult care. This study will be conducted at 12 secondary and tertiary healthcare facilities (six intervention, six control) across all six of Nigeria's geopolitical zones. The study population is 13- to 17-year-old ALHIV (N = 216, n = 108 per study arm) on antiretroviral therapy. Study participants will be followed through a 12-month pre-transfer/transition period and for an additional 24 months post transfer/transition. The primary outcome measure is the proportion of ALHIV retained in care at 12 and 24 months post transfer. Secondary outcome measures are proportions of ALHIV achieving viral suppression and demonstrating increased psychosocial wellbeing and self-efficacy measured by psychometric tests including health locus of control, functional social support, perceived mental health, and sexual risk and behavior. DISCUSSION: We hypothesize that the ACT intervention will significantly increase psychosocial wellbeing, retention in care and ultimately viral suppression among ALHIV. ACT's findings have the potential to facilitate the development of standard guidelines for transitioning ALHIV and improving health outcomes in this population. The engagement of a consortium of local implementing partners under the Nigeria Implementation Science Alliance allows for nationwide study implementation and expedient results dissemination to program managers and policy-makers. Ultimately, ACT may also provide evidence to inform transitioning guidelines not only for ALHIV but for adolescents living with other chronic diseases in resource-limited settings. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03152006 . Registered on May 12, 2017. PMID- 29237488 TI - Clinical reminder alert fatigue in healthcare: a systematic literature review protocol using qualitative evidence. AB - BACKGROUND: Integrated reminders within clinical systems have become more prevalent due to the use of electronic health records and evidence demonstrating an increase in compliance within practice. Clinical reminders are assessed for effectiveness on an individual basis, rather than in combination with existing prompts for other conditions. The growing number of prompts may be counter productive as healthcare professionals are increasingly suffering from "reminder fatigue" meaning many reminders are ignored. This work will review the qualitative evidence to identify barriers and enablers of existing prompts found within computerised decision support systems. Our focus will be on primary care where clinicians have to negotiate a plethora of reminders as they deal with increasingly complex patients and sophisticated treatment regimes. The review will provide a greater understanding of existing systems and the way clinicians interact with them to inform the development of more effective and targeted clinical reminders. METHODS: A comprehensive search using piloted terms will be used to identify relevant literature from 1960 (or commencement of database) to 2017. MEDLINE, MEDLINE In Process, EMBASE, HMIC, PsycINFO, CDSR DARE, HTA, CINAHL and CPCI, will be searched, as well as grey literature and references and citations of included papers. Manuscripts will be assessed for eligibility, bias and quality using the CASP tool with narrative data being included and questionnaire based studies excluded. Inductive thematic analysis will be performed in order to produce a conceptual framework defining the key barriers around integrated clinical reminders. DISCUSSION: Indications of alert and reminder fatigue are found throughout the current literature. However, this has not been fully investigated using a robust qualitative approach, particularly in a rapidly growing body of evidence. This review will aid people forming new clinical systems so that alerts can be incorporated appropriately. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42016029418. PMID- 29237489 TI - Self-expanding nitinol stents of high versus low chronic outward force in de novo femoropopliteal occlusive arterial lesions (BIOFLEX-COF trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Self-expanding nitinol stents must be oversized at least by a minimal amount to ensure contact with the vessel wall and prevent migration. Once the stent is deployed it exerts a continuous force upon the vascular wall, termed chronic outward force (COF). Animal studies have found an increased neointimal hyperplasia in stents with high oversizing and thus high COF. Data about correlation between COF and neointimal hyperplasia in humans are currently lacking. The objective of the BIOFLEX-COF trial is to prospectively investigate differences in formation of intimal hyperplasia at 1 and 2 years after implantation of nitinol stents with high versus low COF in de novo femoropopliteal occlusive arterial lesions. METHODS: The BIOFLEX-COF trial is a prospective, quantitative, randomized study. Eighty subjects with symptomatic peripheral arterial lesions eligible for endovascular stent implantation will be enrolled and randomly assigned to either a high COF group (LifeStent Flexstar, Bard Peripheral Vascular Inc., Tempe, AZ, USA) or low COF group (Pulsar, Biotronik AG, Bulach, Switzerland) using an online randomization program to generate a random 1:1 group allocation (block randomization). After implantation and dilatation, COF at every 2 mm along the stent axis will be calculated from the actual stent diameter versus its nominal diameter. There will be two follow up evaluations at 12 and 24 months. Primary endpoint is the amount of in-stent neointima at 1 year, assessed by contrast-enhanced CT angiography (CTA). In the control examinations, stent diameter and true lumen diameter will be measured on DICOM images every 2 mm along the stent axis to quantify the relative amount of in-stent restenosis. Secondary objectives are the amount of in-stent neointima at 2 years, device- and procedure-related adverse events and target lesion revascularization (TLR) rate. The scheduled time for recruitment is 2 years. Recruitment is expected to be complete in October 2017. DISCUSSION: This trial is the first to prospectively investigate the influence of COF on stent patency. If successful, the results will aid in a more precise selection of stent type and size in a given target vessel. The present study is challenging in that it compares two different self-expanding nitinol stents head-to-head against each other. To optimize the power of this study, traditional binary outcome parameters such as TLR and restenosis at Doppler ultrasound were dropped as primary endpoints. Instead, the amount of neointima inside the stent accessed by CTA was selected as (continuous) outcome parameter. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03097679 . Date of registration: 14 March 2017 (retrospectively registered). PMID- 29237490 TI - Linc-ROR promotes esophageal squamous cell carcinoma progression through the derepression of SOX9. AB - BACKGROUND: Novel therapies tailored to the molecular composition of esophageal squamous cell carcinoma (ESCC) are needed to improve patient survival. We investigated the regulatory network of long intergenic non-protein coding RNA, regulator of reprogramming (linc-ROR) and sex-determining region Y-box 9 (SOX9), and their therapeutic relevance in ESCC. METHODS: Linc-ROR and SOX9 expression were examined in ESCC specimens, cell lines, and cultured tumorspheres. We investigated the effects of linc-ROR on SOX9 expression and malignant phenotypes by CCK8, colony formation, Transwell, and sphere-forming assay. The linc-ROR/SOX9 interaction mediated by multiple microRNAs (miRNAs) was confirmed by bioinformatic analysis, luciferase assay, and RNA-binding protein immunoprecipitation, transient overexpression or antagonizing endogenous candidate miRNAs. The effect of linc-ROR depletion on tumor growth was assessed by xenograft assay. RESULTS: A positive correlation between linc-ROR and SOX9 expression was found in clinical ESCC specimens (r = 0.562, P = 0.036), cell lines, and tumorspheres. Silencing of linc-ROR significantly inhibited cell proliferation, motility, chemoresistance, and self-renewal capacity. Mechanistically, linc-ROR modulating the derepression of SOX9 by directly sponging multiple miRNAs including miR-15b, miR-33a, miR-129, miR-145, and miR 206. Antagonizing these miRNAs counteracted with linc-ROR silencing, whereas the repression of SOX9 abrogated malignant phenotypes induced by the cocktail of miRNA inhibitors. Moreover, linc-ROR disruption was sufficient to attenuate tumor growth and cancer stem cell marker expression in vivo. CONCLUSIONS: Our results demonstrate that the linc-ROR-miRNA-SOX9 regulatory network may represent a novel therapeutic target for ESCC. PMID- 29237491 TI - Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in adult patients with Pompe disease. AB - BACKGROUND: Pompe disease is a rare, progressive, metabolic disease, and the first treatable inheritable muscle disorder. Enzyme replacement therapy (ERT) with alglucosidase alfa is disease specific and the only medicinal product authorized for the treatment of Pompe disease. Costs of ERT are very high as for most orphan drugs. This study investigates the cost-effectiveness of ERT compared to supportive treatment in adult patients with Pompe disease. METHODS: Survival probabilities were estimated from an international observational dataset (n = 283) using a time-dependent Cox model. Quality of life was estimated on a Dutch observational dataset using a previously developed conceptual model which links clinical factors to quality of life. Costs included costs of ERT, costs of drug administration and other healthcare costs. Cost-effectiveness was estimated using a patient-level simulation model (n = 90), synthesising the information from underlying models for survival, quality of life and costs. The cost-effectiveness model estimated the (difference in) lifetime effects and costs for both treatments. Two scenarios were modelled: (1) a worse case scenario with no extrapolation of the survival gain due to ERT beyond the observed period (i.e. from 10 years onwards); and (2) a best case scenario with lifetime extrapolation of the survival gain due to ERT. Effects were expressed in (quality adjusted) life years (QALYs). Costs were discounted at 4.0% and effects at 1.5%. RESULTS: Substantial increases in survival were estimated - discounted incremental life years of ERT ranged from 1.9 years to 5.4 years in the scenarios without and with extrapolation of survival gains beyond the observed period. Quality of life was also significantly better for patients receiving ERT. Incremental costs were considerable and primarily consisted of the costs of ERT. Incremental costs per QALY were ?3.2 million for scenario 1 and ?1.8 million for scenario 2. CONCLUSIONS: The availability of extended, prospectively collected, longitudinal observational data on the most important input parameters required to construct a cost-effectiveness model is quite exceptional for orphan diseases. The cost effectiveness model showed substantial survival gains from ERT. Despite these substantial gains, ERT was not cost-effective in the treatment of adult Pompe disease because of the high cost of treatment. PMID- 29237492 TI - Pentosan polysulfate binds to STRO-1+ mesenchymal progenitor cells, is internalized, and modifies gene expression: a novel approach of pre-programing stem cells for therapeutic application requiring their chondrogenesis. AB - BACKGROUND: The pharmaceutical agent pentosan polysulfate (PPS) is known to induce proliferation and chondrogenesis of mesenchymal progenitor cells (MPCs) in vitro and in vivo. However, the mechanism(s) of action of PPS in mediating these effects remains unresolved. In the present report we address this issue by investigating the binding and uptake of PPS by MPCs and monitoring gene expression and proteoglycan biosynthesis before and after the cells had been exposed to limited concentrations of PPS and then re-established in culture in the absence of the drug (MPC priming). METHODS: Immuno-selected STRO-1+ mesenchymal progenitor stem cells (MPCs) were prepared from human bone marrow aspirates and established in culture. The kinetics of uptake, shedding, and internalization of PPS by MPCs was determined by monitoring the concentration dependent loss of PPS media concentrations using an enzyme-linked immunosorbent assay (ELISA) and the uptake of fluorescein isothiocyanate (FITC)-labelled PPS by MPCs. The proliferation of MPCs, following pre-incubation and removal of PPS (priming), was assessed using the Wst-8 assay method, and proteoglycan synthesis was determined by the incorporation of 35SO4 into their sulphated glycosaminoglycans. The changes in expression of MPC-related cell surface antigens of non-primed and PPS-primed MPCs from three donors was determined using flow cytometry. RNA sequencing of RNA isolated from non-primed and PPS-primed MPCs from the same donors was undertaken to identify the genes altered by the PPS priming protocol. RESULTS: The kinetic studies indicated that, in culture, PPS rapidly binds to MPC surface receptors, followed by internalisation and localization within the nucleus of the cells. Following PPS-priming of MPCs and a further 48 h of culture, both cell proliferation and proteoglycan synthesis were enhanced. Reduced expression of MPC-related cell surface antigen expression was promoted by the PPS priming, and RNA sequencing analysis revealed changes in the expression of 42 genes. CONCLUSION: This study has shown that priming of MPCs with low concentrations of PPS enhanced chondrogenesis and MPC proliferation by modifying their characteristic basal gene and protein expression. These findings offer a novel approach to re-programming mesenchymal stem cells for clinical indications which require the repair or regeneration of cartilaginous tissues such as in osteoarthritis and degenerative disc disease. PMID- 29237493 TI - The association between health insurance status and utilization of health services in rural Northern Ghana: evidence from the introduction of the National Health Insurance Scheme. AB - BACKGROUND: Many households in low- and middle-income countries face financial hardships due to payments for health care, while others are pushed into poverty. Risk pooling and prepayment mechanisms help to lessen the impact of the costs of care as well as assisting to achieve universal health coverage (UHC). Ghana implemented the National Health Insurance Scheme (NHIS) for the promotion of access to health services for all Ghanaians. In this paper, we examined the association between health insurance status and utilization of outpatient and inpatient health services in rural poor communities. METHODS: The study was a cross-sectional household survey conducted in the Kassena-Nankana districts of Northern Ghana. We conducted interviews in 11,175 households and collected data on 55,992 household members. Multiple logistic regression models were used to identify factors associated with the utilization of outpatient and inpatient health services. The dependent variables were the utilization of outpatient and inpatient health services. We adjusted for several potential socio-demographic factors associated with utilization and health insurance status. RESULTS: Significantly, the insured had 2.51 (95% CI 2.3-2.8) and 2.78 (95% CI 2.2-3.6) increased odds of utilizing outpatient and inpatient health services respectively. Respondents with a history of recent illness or injury [32.4 (95% CI 29.4-35.8) and 5.72 (95% CI 4.6-7.1)] and poor or very poor self-reported health status [2.08 (95% CI 1.7-2.5) and 2.52 (95% CI 1.9-3.4)] and those on chronic medication [2.79 (95% CI 2.2-3.5) and 3.48 (95% CI 2.5-4.8)] also had increased odds of utilizing both outpatient and inpatient health services respectively. Among the insured, the poorest use the Community-based Health Planning and Services (CHPS) compounds, while the least poor use private clinics and public hospitals for outpatient health services. The uninsured predominately use pharmacies or licensed chemical shops (LCSs). For inpatient health services, the insured largely use public hospitals, with the uninsured using private clinics or public health centres. CONCLUSION: The findings suggest that being insured with the NHIS is associated with increased utilization of outpatient and inpatient health services in the study area. Overall, the NHIS can be an effective tool for achieving UHC and hence pragmatic efforts should be made to sustain it. PMID- 29237494 TI - Adherence to the integrated management of childhood illness guidelines in Namibia, Kenya, Tanzania and Uganda: evidence from the national service provision assessment surveys. AB - BACKGROUND: Integrated Management of Childhood Illness (IMCI) is regarded as a standard public health approach to lowering child mortality in developing countries. However, little is known about how health workers adhere to the guidelines at the national level in sub-Saharan African countries. METHODS: Data from the Service Provision Assessment surveys of Namibia (NA) (survey year: 2009), Kenya (KE) (2010), Tanzania (TZ) (2006) and Uganda (UG) (2007) were analysed for adherence to the IMCI guidelines by health workers. Potential influencing factors included the survey country, patient's age, the different levels of the national health system, the training level of the health care provider (physician, non-physician clinician, nurse-midwife, auxiliary staff), and the status of re-training in IMCI. RESULTS: In total, 6856 children (NA: 1495; KE: 1890; TZ: 2469; UG: 1002 / male 51.2-53.5%) aged 2-73 months (2-24 months, 65.3%; median NA: 19 months; KE: 18 months; TZ: 16 months; UG: 15 months) were clinically assessed by 2006 health workers during the surveys. Less than 33% of the workers carried out assessment of all three IMCI danger signs, namely inability to eat/drink, vomiting everything, and febrile convulsions (NA: 11%; KE: 11%; TZ: 14%; UG: 31%) while the rate for assessing all three of the IMCI main symptoms of cough/difficult breathing, diarrhoea, and fever was < 60% (NA: 48%; KE: 34%; TZ: 50%; UG: 57%). Physical examination rates for fever (temperature) (NA: 97%; KE: 87%; TZ: 73%; UG: 90%), pneumonia (respiration rate/auscultation) (NA: 43%; KE: 24%; TZ: 25%; UG: 20%) and diarrhoea (dehydration status) (NA: 29%; KE: 19%; TZ: 20%; UG: 39%) varied widely and were highest when assessing children with the actual diagnosis of pneumonia and diarrhoea. Adherence rates tended to be higher in children <= 24 months, at hospitals, among higher-qualified staff (physician/non-physician clinician) and among those with recent IMCI re-training. CONCLUSION: Despite nationwide training in IMCI the adherence rates for assessment and physical examination remained low in all four countries. IMCI training should continue to be provided to all health staff, particularly nurses, midwives, and auxiliary staff, with periodic re training and an emphasis to equally target children of all age groups. PMID- 29237496 TI - Government policy interventions to reduce human antimicrobial use: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Antimicrobial resistance (AMR) is a recognized threat to global public health. Increasing AMR and a dry pipeline of novel antimicrobial drugs have put AMR in the international spotlight. One strategy to combat AMR is to reduce antimicrobial drug consumption. Governments around the world have been experimenting with different policy interventions, such as regulating where antimicrobials can be sold, restricting the use of last-resort antimicrobials, funding AMR stewardship programs, and launching public awareness campaigns. To inform future action, governments should have access to synthesized data on the effectiveness of large-scale AMR interventions. This planned systematic review will (1) identify and describe previously evaluated government policy interventions to reduce human antimicrobial use and (2) estimate the effectiveness of these different strategies. METHODS: An electronic search strategy has been developed in consultation with two research librarians. Seven databases (MEDLINE, CINAHL, EMBASE, CENTRAL, PAIS Index, Web of Science, and PubMed excluding MEDLINE) will be searched, and additional studies will be identified using several gray literature search strategies. To be included, a study must (1) clearly describe the government policy and (2) use a rigorous design to quantitatively measure the impact of the policy on human antibiotic use. The intervention of interest is any policy intervention enacted by a government or government agency in any country to change human antimicrobial use. Two independent reviewers will screen for eligibility using criteria defined a priori. Data will be extracted with Covidence software using a customized extraction form. If sufficient data exists, a meta-analysis by intervention type will be conducted as part of the effectiveness review. However, if there are too few studies or if the interventions are too heterogeneous, data will be tabulated and a narrative synthesis strategy will be used. DISCUSSION: This evidence synthesis is intended for use by policymakers, public health practitioners, and researchers to inform future government policies aiming to address antimicrobial resistance. This review will also identify gaps in the evidence about the effectiveness of different policy interventions to inform future research priorities. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017067514 . PMID- 29237495 TI - Bone marrow CD34+ cell subset under induction of moderate stiffness of extracellular matrix after myocardial infarction facilitated endothelial lineage commitment in vitro. AB - BACKGROUND: The stiffness of the myocardial extracellular matrix (ECM) and the transplanted cell type are vitally important in promoting angiogenesis. However, the combined effect of the two factors remains uncertain. The purpose of this study is to investigate in vitro the combined effect of myocardial ECM stiffness postinfarction with a bone marrow-derived cell subset expressing or not expressing CD34 on endothelial lineage commitment. METHODS: Myocardial stiffness of the infarct zone was determined in mice at 1 h, 24 h, 7 days, 14 days, and 28 days after coronary artery ligation. Polyacrylamide (PA) gel substrates of different stiffnesses were prepared to mechanically mimic the myocardial ECM after infarction. Mouse bone marrow-derived CD34+ and CD34- cells were seeded on the flexible PA gels. The double-positive expression for DiI-acetylated low density lipoprotein (acLDL) uptake and fluorescein isothiocyanate-Ulex europaeus agglutinin-1 (FITC-UEA-1) binding, the endothelial lineage antigens CD31, von Willebrand factor (vWF), Flk-1, and VE-cadherin, as well as cytoskeleton were measured by immunofluorescent staining on day 7. Cell apoptosis was evaluated by both immunofluorescent staining and flow cytometry at 24 h after culture. RESULTS: We found that the numbers of the CD34+ cell subset adherent to the flexible substrates (4-72 kPa) was much larger than that of the CD34- subset. More double-positive cells for DiI-acLDL uptake/FITC-UEA-1 binding were seen on the 42-kPa (moderately stiff) substrate, corresponding to the stiffness of myocardial ECM at 7-14 days postinfarction, compared with those on substrates of other stiffnesses. Similarly, the moderately stiff substrate showed benefits in promoting the positive expressions of the endothelial lineage markers CD31, vWF, Flk-1, and VE-cadherin. In addition, the cytoskeleton F-actin network within CD34+ cells was organized more significantly at the leading edge of the adherent cells on the moderately stiff (42 kPa) or stiff (72 kPa) substrates as compared with those on the soft (4 kPa and 15 kPa) substrates. Moreover, the moderately stiff or stiff substrates showed a lower percentage of cell apoptosis than the soft substrates. CONCLUSIONS: Infarcted myocardium-like ECM of moderate stiffness (42 kPa) more beneficially regulated the endothelial lineage commitment of a bone marrow-derived CD34+ subset. Thus, the combination of a CD34+ subset with a "suitable" ECM stiffness might be an optimized strategy for cell-based cardiac repair. PMID- 29237497 TI - Hyaluronic acid is associated with organ dysfunction in acute respiratory distress syndrome. AB - BACKGROUND: Hyaluronic acid (HA), an extracellular matrix component, is degraded in response to local tissue injury or stress. In various animal models of lung injury, HA has been shown to play a mechanistic role in modulating inflammation and injury. While HA is present in the lungs of patients with acute respiratory distress syndrome (ARDS), its relationship to patient outcomes is unknown. METHODS: We studied 86 patients with ARDS previously enrolled in the Phase II Randomized Trial of Fish Oil in Patients with Acute Lung Injury (NCT00351533) at five North American medical centers. We examined paired serum and bronchoalveolar lavage fluid (BALF) samples obtained within 48 hours of diagnosis of ARDS. We evaluated the association of HA levels in serum and BALF with local (lung injury score (LIS)) and systemic (sequential organ failure assessment score (SOFA)) measures of organ dysfunction with regression analysis adjusting for age, sex, race, treatment group, and risk factor for ARDS. RESULTS: We found that both day 0 circulating and alveolar levels of HA were associated with worsening LIS (p = 0.04 and p = 0.003, respectively), particularly via associations with degree of hypoxemia (p = 0.02 and p < 0.001, respectively) and set positive end-expiratory pressure (p = 0.01 and p = 0.02, respectively). Circulating HA was associated with SOFA score (p < 0.001), driven by associations with the respiratory (p = 0.02), coagulation (p < 0.001), liver (p = 0.006), and renal (p = 0.01) components. Notably, the alveolar HA levels were associated with the respiratory component of the SOFA score (p = 0.003) but not the composite SOFA score (p = 0.27). CONCLUSIONS: Elevated alveolar levels of HA are associated with LIS while circulating levels are associated with both lung injury and SOFA scores. These findings suggest that HA has a potential role in both local and systemic organ dysfunction in patients with ARDS. PMID- 29237498 TI - Vitreous hemorrhage and Rhegmatogenous retinal detachment that developed after botulinum toxin injection to the extraocular muscle: case report. AB - BACKGROUND: The authors report a case of a rare complication that occurred after botulinum toxin injection to the extraocular muscle, which was easily overlooked and successfully corrected by surgery. CASE PRESENTATION: A 34-year-old female patient visited our clinic for diplopia and ocular motility disorder after removal of an epidermoid tumor of the brain. At her initial visit, her best corrected visual acuity (BCVA) was 20/20 for both eyes. An alternate cover test showed 45 prism-diopter esotropia and 3 prism-diopter hypertropia in the right eye. Following 6 months of observation, the deviation of the strabismus did not improve, and botulinum toxin was injected into the right medial rectus (RMR). After 6 days, she visited our clinic with decreased visual acuity of her right eye. The BCVA was found to be 20/50 for her right eye. Funduscopic examination presented a retinal tear inferonasal to the optic disc with preretinal hemorrhage. Subretinal fluid nasal to the fovea was seen on optical coherence tomography (OCT). Barrier laser photocoagulation was done around the retinal tear; however, her visual acuity continued to decrease, and vitreous hemorrhage and subretinal fluid at the lesion did not improve. In addition, a newly developed epiretinal membrane was seen on OCT. An alternate cover test presented 30 prism-diopter right esotropia. 19 weeks after RMR botulinum toxin injection, she received pars plana vitrectomy, membranectomy, endolaser barrier photocoagulation, and intravitreal bevacizumab (Avastin(r)) injection. After 4 months, her visual acuity improved to 20/20, and only 4 prism-diopter of right hypertropia and 3 prism-diopter of exotropia were noted. Vitreous opacity and the epiretinal membrane were completely removed, as confirmed by funduscopic and examination. CONCLUSIONS: Sudden loss of vision after injection of botulinum toxin into the extraocular muscle may suggest a serious complication, and a prompt, thorough ophthalmic examination should be performed. If improvements are not observed, rapid surgical intervention is recommended to prevent additional complications. PMID- 29237499 TI - Risk factors for first hospitalization due to meniscal lesions - a population based cohort study with 30 years of follow-up. AB - BACKGROUND: Meniscal lesions are among the most common injuries of the knee, yet limited epidemiologic data is available on their risk factors. We investigated the association of lifestyle factors and physical strenuousness of work on knee injuries with a focus on meniscal lesions. METHODS: We examined a nationally representative sample of persons aged 30 to 59 years, who participated in a comprehensive health examination (the Mini-Finland Health Survey). Subjects without any injury or osteoarthritis in the knee joint at baseline (n = 4713) were subsequently followed via the National Hospital Discharge Register up to 30 years. RESULTS: During the follow-up, 338 knee injuries were identified of which 224 were meniscal lesions. Obesity and regular leisure time physical exercise were associated with an increased risk of first hospitalization due to meniscal lesions (hazard ratio (HR) 1.62 and 95% confidence interval (CI) 1.06-2.48 and 1.53, 95% CI 1.05-2.23, respectively). The types of sports predicting the highest risk of meniscal lesions were ballgames, gymnastics and jogging. Physical strenuousness of work did not predict meniscal lesion. The hazard of other knee injury was increased among those reporting irregular or regular physical exercise at baseline (HR 1.64, 95% CI 1.03-2.64 and 1.88 CI 1.05-2.36, respectively). Smoking or alcohol intake were not associated with knee injuries. CONCLUSIONS: Better safety measures in high-risk sports and weight control would likely improve the prevention of meniscal lesions in populations. PMID- 29237501 TI - Emergency transapical mitral valve-in-valve implantation for bioprosthesis failure: transapical implantation of an Edwards Sapien-XT in a dysfunctional mitral bioprosthesis in a critical patient. PMID- 29237500 TI - Impact of chronic Pseudomonas aeruginosa infection on health-related quality of life in Mycobacterium avium complex lung disease. AB - BACKGROUND: In bronchiectasis patients, chronic Pseudomonas aeruginosa (PA) infection has been associated with worse health-related quality of life (HRQL), but little is known about Mycobacterium avium complex lung disease (MACLD) patients in this context. This study aimed to evaluate HRQL and investigate the impact of chronic PA infection in MACLD patients. METHODS: This cross-sectional study was conducted using the Registry of Prospective Cohort Study including MACLD patients. The 36-item Short-Form health survey (SF-36) and St. George's Respiratory Questionnaire (SGRQ) were administered to assess clinical outcomes. Clinical variables included treatment and sputum culture status, pulmonary function tests, cavitary lesions, and modified Reiff scores on high-resolution computed tomography. RESULTS: The study included 244 MACLD patients (median age, 68 years; 196 women), 19 of whom had chronic PA infection. Modified Reiff score was higher in patients with chronic infection than in those without (P = 0.028). Regarding SF-36 scores, physical functioning subscale scores were significantly lower in patients with chronic infection (P = 0.029). Additionally, SGRQ symptoms, impact, and total scores were significantly higher in patients with chronic infection. During analysis of covariance comparisons, SGRQ symptoms and impact scores were significantly higher for patients with chronic infection (P = 0.043 and 0.021, respectively). CONCLUSIONS: MACLD patients with chronic PA infection exhibited significantly higher SGRQ scores, indicating impaired HRQL. Chronic PA infection was significantly associated with the severity of bronchiectasis. PMID- 29237502 TI - Initial clinical presentation of single soft tissue metastasis of medullary thyroid carcinoma without primary tumor in the thyroid gland. AB - BACKGROUND: Single soft tissue metastasis of medullary thyroid carcinoma is extremely rare. In addition, several occult medullary thyroid carcinomas with distant metastasis were reported, but undetectable primary lesion at diagnosis was also extremely rare. CASE PRESENTATION: A 74-year-old man was admitted to our hospital because of a painful nodule in his left buttock for over 1 year. Needle biopsy was performed, and the histological findings revealed adenocarcinoma positive for thyroid transcription factor-1. No evidence of a primary tumor, including the lung and thyroid gland, could be found elsewhere despite detailed examinations, including thyroid echography, chest computed tomography, and fluorodeoxyglucose-positron emission tomography. The soft tissue tumor was resected with a wide margin. Immunohistochemical analysis showed the tumor cells to be positive for cytokeratin-AE1/3, cytokeratin 7, synaptophysin, chromogranin A, calcitonin, and carcinoembryonic antigen, but negative for cytokeratin 20, Napsin A, Pax8, and p40, resulting in a diagnosis of metastasis of medullary thyroid carcinoma. CONCLUSION: Initial presentation with a single metastasis to soft tissue and undetectable primary tumor in the thyroid gland is an extremely rare clinical manifestation in patients with medullary thyroid carcinoma. PMID- 29237503 TI - Integration of eye health into primary care services in Tanzania: a qualitative investigation of experiences in two districts. AB - BACKGROUND: Visual impairment is a public health problem in sub-Saharan Africa, affecting nearly 5% of the population. Efforts to combat avoidable causes have been hampered by weak health systems and little evidence exists to suggest what interventions may be effective to improve the situation. Despite this, there are calls to promote some specific interventions, one of which being the closer integration of eye health services into health systems, often focusing on training primary health workers to deliver basic eye health services. This study seeks to understand how eye health services are delivered by primary health workers who have received training and what constraints remain to effective service provision. METHODS: This was a qualitative investigation into the experiences of 20 primary health workers trained in primary eye care and eight key informants working within specialist eye health services or regional and district health management positions in two districts in Tanzania. RESULTS: Despite feeling confident in their own eye care skills, most primary health workers felt constrained in the services they could provide to their communities by insufficient resources needed for diagnosis and treatment, and by lack of systematic supportive supervision to their work. Specialist ophthalmic staff were aware of this issue, although for the most part they felt it was not within their capacity to remedy and that it fell within the remit of general health managers. Many participants discussed the low support to eye health from the national government, evidenced through the lack of dedicated funding to the area and traditional reliance on outside funds including international charities. CONCLUSIONS: Although training of primary health workers is useful, it is recognised that is not sufficient to address the burden of eye health disease present in rural communities in Tanzania. It is likely that broader engagement with the general health system, and most likely with the private sector, will be necessary to improve the coverage of eye health care to remote and poor communities such as those in Morogoro. Further investment is needed to develop innovative approaches to delivering eye health services, including preventative, curative and rehabilitative services. PMID- 29237504 TI - A multivariate analysis of CalEnviroScreen: comparing environmental and socioeconomic stressors versus chronic disease. AB - BACKGROUND: The health-risk assessment paradigm is shifting from single stressor evaluation towards cumulative assessments of multiple stressors. Recent efforts to develop broad-scale public health hazard datasets provide an opportunity to develop and evaluate multiple exposure hazards in combination. METHODS: We performed a multivariate study of the spatial relationship between 12 indicators of environmental hazard, 5 indicators of socioeconomic hardship, and 3 health outcomes. Indicators were obtained from CalEnviroScreen (version 3.0), a publicly available environmental justice screening tool developed by the State of California Environmental Protection Agency. The indicators were compared to the total rate of hospitalization for 14 ICD-9 disease categories (a measure of disease burden) at the zip code tabulation area population level. We performed principal component analysis to visualize and reduce the CalEnviroScreen data and spatial autoregression to evaluate associations with disease burden. RESULTS: CalEnviroScreen was strongly associated with the first principal component (PC) from a principal component analysis (PCA) of all 20 variables (Spearman rho = 0.95). In a PCA of the 12 environmental variables, two PC axes explained 43% of variance, with the first axis indicating industrial activity and air pollution, and the second associated with ground-level ozone, drinking water contamination and PM2.5. Mass of pesticides used in agriculture was poorly or negatively correlated with all other environmental indicators, and with the CalEnviroScreen calculation method, suggesting a limited ability of the method to capture agricultural exposures. In a PCA of the 5 socioeconomic variables, the first PC explained 66% of variance, representing overall socioeconomic hardship. In simultaneous autoregressive models, the first environmental and socioeconomic PCs were both significantly associated with the disease burden measure, but more model variation was explained by the socioeconomic PCs. CONCLUSIONS: This study supports the use of CalEnviroScreen for its intended purpose of screening California regions for areas with high environmental exposure and population vulnerability. Study results further suggest a hypothesis that, compared to environmental pollutant exposure, socioeconomic status has greater impact on overall burden of disease. PMID- 29237505 TI - 1,25-Dihydroxyvitamin D3 modulates the phenotype and function of Monocyte derived dendritic cells in cattle. AB - BACKGROUND: The active form of the vitamin D3, 1,25-Dihydroxyvitamin D3 (1,25 (OH)2D3) has been shown to have major effects not only on physiological processes but also on the regulation of the immune system of vertebrates. Dendritic cells are specialised antigen presenting cells which are in charge of the initiation of T-cell dependant immune responses and as such are key regulators of responses towards pathogens. In this study we set out to evaluate the effects of 1,25 (OH)2D3 on the phenotype of cattle monocyte-derived dendritic cells (MoDCs) and how the conditioning with this vitamin affects the function of these myeloid cells. RESULTS: MoDCs were generated from CD14+ monocytes with bovine IL-4 and GM CSF with or without 1,25-(OH)2D3 supplementation for 10 days. Vitamin D conditioned MoDCs showed a reduced expression of co-stimulatory and antigen presenting molecules, as well as a reduced capability of endocytose ovalbumin. Furthermore, the capacity of MoDCs to induce proliferation in an allogeneic mixed leukocyte reaction was abolished when MoDCs were generated in presence of 1,25 (OH)2D3. LPS induced maturation of 1,25-(OH)2D3conditioned MoDCs resulted in lower secretion of IL-12 and higher IL-10 than that observed in MoDCs. CONCLUSIONS: The typical immunotolerant phenotype observed in cattle DCs after exposure to 1,25-(OH)2D3 has a significant effect on the functionality of these immune cells, inhibiting the T-cell stimulatory capacity of MoDCs. This could have profound implications on how the bovine immune system deals with pathogens, particularly in diseases such as tuberculosis or paratuberculosis. PMID- 29237506 TI - TGF-beta1-induced chondrogenesis of bone marrow mesenchymal stem cells is promoted by low-intensity pulsed ultrasound through the integrin-mTOR signaling pathway. AB - BACKGROUND: Low-intensity pulsed ultrasound (LIPUS) is a mechanical stimulus that plays a key role in regulating the differentiation of bone marrow mesenchymal stem cells (BMSCs). However, the way in which it affects the chondrogenic differentiation of BMSCs remains unknown. In this study, we aimed to investigate whether LIPUS is able to influence TGF-beta1-induced chondrogenesis of BMSCs through the integrin-mechanistic target of the Rapamycin (mTOR) signaling pathway. METHODS: BMSCs were isolated from rat bone marrow and cultured in either standard or TGF-beta1-treated culture medium. BMSCs were then subjected to LIPUS at a frequency of 3 MHz and a duty cycle of 20%, and integrin and mTOR inhibitors added in order to analyze their influence on cell differentiation. BMSCs were phenotypically analyzed by flow cytometry and the degree of chondrogenesis evaluated through toluidine blue staining, immunofluorescence, and immunocytochemistry. Furthermore, expression of COL2, aggrecan, SOX9, and COL1 was assessed by qRT-PCR and western blot analysis. RESULTS: We found that LIPUS promoted TGF-beta1-induced chondrogenesis of BMSCs, represented by increased expression of COL2, aggrecan and SOX9 genes, and decreased expression of COL1. Notably, these effects were prevented following addition of integrin and mTOR inhibitors. CONCLUSIONS: Taken together, these results indicate that mechanical stimulation combined with LIPUS promotes TGF-beta1-induced chondrogenesis of BMSCs through the integrin-mTOR signaling pathway. PMID- 29237508 TI - Making healthy homes? A pilot study of the return on investment from an external wall insulation intervention. AB - OBJECTIVES: External Wall Insulation (EWI) insulates and protect homes against damp. The Energy Company Obligation (ECO) scheme incentivised large energy providers in the UK delivering energy efficiency measures such as EWI to fuel impoverished households. Return on Investment (ROI) analysis is utilised to determine if EWI is a cost-effective procedure in terms of improving health related quality of life (HRQOL) measured using the EQ-5D-3LTM, reducing health care expenditure, and fuel costs. Data comes from Stockton-On-Tees council, health care costs data, and information collected from households in the most socially deprived areas in Stockton-on-Tees. RESULTS: The total cost of installation across all 2252 that received EWI was L10,222,954 in 2016 GBP. Annual total benefits were extrapolated across all 3265 households that received EWI. Total benefits were differences between the control and treatment groups in fuel costs, health care costs, and HRQOL multiplied by the National Institute for Health and Care Excellence Quality Adjusted Life Year threshold (L20,000). Total benefits for all households that received EWI were L1,519,045. The ROI of EWI is 41%. 7.9 years are needed to recoup the costs of the initial investment. PMID- 29237509 TI - The term "supplemental parenteral nutrition" should be restricted to studies meeting specific technical criteria. PMID- 29237507 TI - Epidemiologic analysis of families with isolated anorectal malformations suggests high prevalence of autosomal dominant inheritance. AB - BACKGROUND: Anorectal malformations (ARM) are rare abnormalities that occur in approximately 1 in 3000 live births with around 40% of patients presenting with isolated forms. Multiple familial cases reported, suggest underlying genetic factors that remain largely unknown. The recurrence in relatives is considered rare, however transmission rates of ARM by affected parents have never been determined before. The inheritance pattern of ARM was investigated in our database of patients with isolated ARM. RESULTS: Within our cohort of 327 patients with isolated ARM we identified eight adult patients from eight families who had in total 16 children with their healthy spouse. Of these ten had ARM, resulting in a recurrence risk of approximately one in two live births (10 of 16; 62%). From 226 families with 459 siblings we found two affected siblings in five families. Hence, the recurrence risk of ARM among siblings is approximately one in 92 live births (5 of 459; 1.0%). CONCLUSIONS: Comparing the observed recurrence risk in our cohort with the prevalence in the general population, we see a 1500-fold increase in recurrence risk for offspring and a 32-fold increase if a sibling is affected. The recurrence risk of approximately 62% indicates an autosomal dominant mode of inheritance. Reliable figures on recurrence of ARM are becoming increasingly important since improved surgical techniques are able to maintain sexual function resulting in more offspring of patients with ARM. These data allow more precise counseling of families with ARM and support the need for genetic studies. PMID- 29237511 TI - Toxic effects of two essential oils and their constituents on the mealworm beetle, Tenebrio molitor. AB - The study identified insecticidal effects from the cinnamon and clove essential oils in Tenebrio molitor L. (Coleoptera: Tenebrionidae). The lethal concentrations (LC50 and LC90), lethal time, and repellent effect on larvae, pupae, and adults of T. molitor after exposure to six concentrations of each essential oil and toxic compounds were evaluated. The chemical composition of the cinnamon oil was also determined and primary compounds were eugenol (10.19%), trans-3-caren-2-ol (9.92%), benzyl benzoate (9.68%), caryophyllene (9.05%), eugenyl acetate (7.47%), alpha-phellandrene (7.18%), and alpha-pinene (6.92%). In clove essential oil, the primary compounds were eugenol (26.64%), caryophyllene (23.73%), caryophyllene oxide (17.74%), 2-propenoic acid (11.84%), alpha-humulene (10.48%), gamma-cadinene (4.85%), and humulene oxide (4.69%). Cinnamon and clove essential oils were toxic to T. molitor. In toxic chemical compounds, eugenol have stronger contact toxicity in larvae, pupae, and adult than caryophyllene oxide, followed by alpha-pinene, alpha-phellandrene, and alpha-humulene. In general, the two essential oils were toxic and repellent to adult T. molitor. Cinnamon and clove essential oils and their compounds caused higher mortality and repellency on T. molitor and, therefore, have the potential for integrated management programs of this insect. PMID- 29237510 TI - Posterior Left pericardiotomy for the prevention of postoperative Atrial fibrillation after Cardiac Surgery (PALACS): study protocol for a randomized controlled trial. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery. POAF is associated with increased morbidity and hospital costs. We herein describe the protocol for a randomized controlled trial to determine if performing a posterior left pericardiotomy prevents POAF after cardiac surgery. METHODS/DESIGN: All patients submitted to cardiac surgery at our institution will be screened for inclusion into the study. The study will consist of two parallel arms with random allocation between groups to either receive a posterior left pericardiotomy or serve as a control. Masking will be done in a single-blinded fashion to the patient. Patients will be continuously monitored postoperatively for the occurrence of atrial fibrillation until discharge. At the follow-up clinic visit (15-30 days after surgery), the primary endpoint (atrial fibrillation) and other secondary endpoints, such as pleural or pericardial effusion, will be assessed. A total sample size of 350 subjects will be recruited. DISCUSSION: POAF is associated with increased morbidity, prolonged hospital stay, and increased costs after cardiac surgery. Several strategies aimed at reducing the incidence of POAF have been investigated, including beta blockers, amiodarone, and statins, all with suboptimal results. Posterior left pericardiotomy has been associated with a reduction of POAF in previous series. However, these studies had limited sample sizes and suboptimal methodology, so that the efficacy of posterior pericardiotomy in preventing POAF remains to be definitively proven. Our randomized trial aims to determine the effect of a posterior left pericardiotomy on the incidence of POAF. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02875405 , protocol record 1502015867. Registered on July 2016. PMID- 29237512 TI - Vancomycin-Resistant Enterococci (VRE) in The Intensive Care Unit in a Nonoutbreak Setting: Identification of Potential Reservoirs and Epidemiological Associations Between Patient and Environmental VRE. AB - OBJECTIVE Among nosocomial bloodstream infections caused by enterococcal species, Ireland has the highest proportion caused by vancomycin-resistant enterococci (VRE) in Europe at 45.8%. The contribution of the near-patient environment to VRE transmission outside of outbreaks was investigated. DESIGN A prospective observational study was conducted during 7 sampling periods. METHODS Recovery of VRE isolates by swabbing the near-patient environment and patients in the intensive care unit (ICU) was conducted to identify reservoirs, clinical and molecular epidemiological associations, and the success of active surveillance cultures (ASCs). RESULTS Of 289 sampling occasions involving 157 patients and their bed spaces, VRE isolates were recovered from patient bed spaces, clinical samples, or both on 114 of 289 sampling occasions (39.4%). The patient and their bed space were positive for VRE on 34 of 114 VRE-associated sampling occasions (29.8%). Of 1,647 environment samples, 107 sites (6.5%) were VRE positive, with significantly greater VRE recovery from isolation rooms than from the open-plan area (9.1% vs 4.1%; P < .0001). The most frequently VRE-contaminated sites were the drip stand, bed control panel, and chart holders, which together accounted for 61% of contaminated sites. The use of ASCs resulted in a 172% increase in identification of VRE-colonized patients. Molecular typing revealed 2 environmental clusters, 1 cluster involving 3 patients and generally greater heterogeneity of patient isolates compared to environmental isolates. CONCLUSION Even outside of outbreaks, near-patient ICU environmental contamination with VRE is common. Better infection control policies that limit environmental transmission of VRE in the ICU and that are supported by molecular epidemiological studies, in real time, are needed. Infect Control Hosp Epidemiol 2018;39:40-45. PMID- 29237514 TI - The Effects of Intraoperative Sedation on Surgical Outcomes of Deep Brain Stimulation Surgery. AB - BACKGROUND: Intraoperative sedation is often used to facilitate deep brain stimulation (DBS) surgery; however, these sedative agents also suppress microelectrode recordings (MER). To date, there have been no studies that have examined the effects of differing sedatives on surgical outcomes and the success of DBS surgery. METHODS: We performed a retrospective study to evaluate the effect of differing sedative agents on postoperative surgical outcomes at 6 months in parkinsonian adult patients who underwent DBS surgery, from January 2004 through December 2014, at one academic center. Surgical outcomes of DBS were evaluated using a simplified Unified Parkinson Diseases Rating Score-III and levodopa dose equivalent reduction at baseline and 6 months postoperatively. RESULTS: We analyzed data from 121 of 124 consecutive parkinsonian patients. Propofol, dexmedetomidine, remifentanil, and midazolam were used individually or in combination. All sedatives were routinely discontinued 20 to 30 minutes before MER, in accordance with our institutional protocol. We found no statistically significant association between the use of individual agent or combination of sedative agents and surgical outcomes at 6 months, the success of DBS, duration of MER, duration of stage 1 procedure, and perioperative complications. CONCLUSIONS: Our study showed that the choice of sedative agent was not associated with poor surgical outcomes after DBS surgery using MER and macrostimulation techniques in parkinsonian patients. PMID- 29237513 TI - Features of illnesses caused by five species of Campylobacter, Foodborne Diseases Active Surveillance Network (FoodNet) - 2010-2015. AB - The Foodborne Diseases Active Surveillance Network (FoodNet) conducts population based surveillance for Campylobacter infection. For 2010 through 2015, we compared patients with Campylobacter jejuni with patients with infections caused by other Campylobacter species. Campylobacter coli patients were more often >40 years of age (OR = 1.4), Asian (OR = 2.3), or Black (OR = 1.7), and more likely to live in an urban area (OR = 1.2), report international travel (OR = 1.5), and have infection in autumn or winter (OR = 1.2). Campylobacter upsaliensis patients were more likely female (OR = 1.6), Hispanic (OR = 1.6), have a blood isolate (OR = 2.8), and have an infection in autumn or winter (OR = 1.7). Campylobacter lari patients were more likely to be >40 years of age (OR = 2.9) and have an infection in autumn or winter (OR = 1.7). Campylobacter fetus patients were more likely male (OR = 3.1), hospitalized (OR = 3.5), and have a blood isolate (OR = 44.1). International travel was associated with antimicrobial-resistant C. jejuni (OR = 12.5) and C. coli (OR = 12) infections. Species-level data are useful in understanding epidemiology, sources, and resistance of infections. PMID- 29237515 TI - Pulsus alternans in a child with dilated cardiomyopathy. AB - A previously healthy 21-month-old presented with new-onset dilated cardiomyopathy. Evaluation noted pulsus alternans, with beat-to-beat alternations in aortic pulse wave amplitude, both clinically and on diagnostic studies. Pulsus alternans is an infrequent, complex pathophysiologic sign often associated with severe heart failure. The mechanisms are incompletely understood, but theorised aetiologies include beat-to-beat changes in left ventricular loading conditions, variations in myocardial oxygen supply/demand, and alternations in myocardial contractility. Recognition of pulsus alternans is important as it provides significant clinical information, may suggest suboptimal medical management, and may be the first warning sign of severe cardiac dysfunction. PMID- 29237516 TI - Utility of cardiac MRI in paediatric myocarditis. AB - BACKGROUND: The diagnostic role of cardiac MRI in myocarditis is evolving, however with extremely limited data in paediatrics. The goal of this study was to assess the utility of cardiac MRI in paediatric myocarditis and present a new prognostic score for risk stratification. METHOD: The present study is a retrospective investigation of children with a clinical diagnosis of myocarditis, including analysis of demographics, clinical presentation, diagnostic studies, including cardiac MRI, and outcomes. RESULTS: A total of 44 patients met the inclusion criteria, of whom 20 had undergone cardiac MRI. Patients who underwent cardiac MRI were older (median 15.6 versus 11.1 years, p=0.004), had a shorter length of hospital stay (median 4.0 versus 12.5 days, p=0.004), had overall less severe illness at presentation as evidenced by a higher left-ventricular ejection fraction on echocardiography, had lower peak brain-type natriuretic peptide, were less likely to require advanced mechanical support, and were less likely to experience cardiac death or transplant. In patients who had undergone cardiac MRI, the most common findings were increased early gadolinium enhancement (n=9) or late gadolinium enhancement (n=9). Cardiac MRI findings did not predict a worse outcome. Independent predictors of the need for heart-failure medications at 1-year follow-up included inotrope requirement, extracorporeal membrane oxygenator requirement, and antiarrhythmic requirement at presentation (p<0.05). CONCLUSION: In paediatric myocarditis, cardiac MRI is not used uniformly, has a low yield, and does not predict worse outcomes. Future research should evaluate clinical decision-making and the cost-benefit analysis of cardiac MRI in the diagnosis of paediatric myocarditis. PMID- 29237517 TI - Hypopharyngeal cancer associated with synchronous oesophageal cancer: risk factors and benefits of image-enhanced endoscopic screening. AB - OBJECTIVES: To explore the risk factors associated with the occurrence of synchronous oesophageal cancer in patients with hypopharyngeal cancer, and to investigate the roles of image-enhanced endoscopic screening in the prediction and diagnosis of early oesophageal cancer. METHODS: The clinical characteristics of patients with hypopharyngeal cancer (n = 160) were analysed. All patients underwent laryngoscopic and gastroscopic examination using image-enhanced endoscopic techniques before treatment. RESULTS: Of 160 hypopharyngeal cancer patients, 43 (27 per cent) had synchronous oesophageal cancer. Heavy drinking (odds ratio = 4.787, p = 0.029) and local invasion of three or more anatomical sites (odds ratio = 14.391, p = 0.000) were independent risk factors for synchronous oesophageal cancer. Narrow-band imaging laryngoscopy could detect more invaded anatomical sites than ordinary white light endoscopy (t = 8.532, p = 0.000). More early oesophageal cancer cases were detected with Lugol chromoendoscopy than with non-Lugol iodine staining examination (chi2 = 4.925, p = 0.026). CONCLUSION: Synchronous oesophageal cancer is common in patients with hypopharyngeal cancer. The heavy drinking patients with hypopharyngeal cancer should undergo intensive monitoring. Image-enhanced endoscopic screening is helpful in the prediction and early detection of second primary oesophageal cancer. PMID- 29237518 TI - Can endurance training improve physical capacity and quality of life in young Fontan patients? AB - OBJECTIVE: Children after Fontan palliation have reduced exercise capacity and quality of life. Our aim was to study whether endurance training could improve physical capacity and quality of life in Fontan patients. METHODS: Fontan patients (n=30) and healthy age- and gender-matched control subjects (n=25) performed a 6-minute walk test at submaximal capacity and a maximal cycle ergometer test. Quality of life was assessed with Pediatric Quality of Life Inventory Version 4.0 questionnaires for children and parents. All tests were repeated after a 12-week endurance training programme and after 1 year. RESULTS: Patients had decreased submaximal and maximal exercise capacity (maximal oxygen uptake 35.0+/-5.1 ml/minute per.kg versus 43.7+/-8.4 ml/minute.per.kg, p<0.001) and reported a lower quality of life score (70.9+/-9.9 versus 85.7+/-8.0, p<0.001) than controls. After training, patients improved their submaximal exercise capacity in a 6-minute walk test (from 590.7+/-65.5 m to 611.8+/-70.9 m, p<0.05) and reported a higher quality of life (p<0.01), but did not improve maximal exercise capacity. At follow-up, submaximal exercise capacity had increased further and improved quality of life was sustained. The controls improved their maximal exercise capacity (p<0.05), but not submaximal exercise capacity or quality of life after training. At follow-up, improvement of maximal exercise capacity was sustained. CONCLUSIONS: We believe that an individualised endurance training programme for Fontan patients improves submaximal exercise capacity and quality of life in Fontan patients and the effect on quality of life appears to be long-lasting. PMID- 29237519 TI - The Peritoneal Macrophages in Inflammatory Diseases and Abdominal Cancers. AB - Peritoneal macrophages (PMs) are the major cell type of peritoneal cells that participate in multiple aspects of innate and acquired immunity in the peritoneal cavity. PMs have an ability to release a large amount of proinflammatory and anti inflammatory cytokines and therefore play a critical role in regulating the differentiation of innate immune cells and inflammatory T cells. Accumulating studies demonstrate that the immunological reactions and inflammatory responses of PMs are strongly related to the pathogenic processes of various inflammatory diseases and abdominal cancers. Consequently, the regulation of PM activation has gradually emerged as a promising target for immunotherapy, and better understanding of the distinctly biological function of PMs in individual diseases is crucial for designing specific and effective therapeutic agents. This review covers the characterization and immunological function of PMs in hosts with inflammatory diseases and abdominal cancers. PMID- 29237520 TI - [Patterns of brain injury in neonatal hypoxic-ischemic encephalopathy on magnetic resonance imaging: recommendations on classification]. AB - Although there are unified criteria for the clinical diagnosis and grading of neonatal hypoxic-ischemic encephalopathy (HIE), clinical features and neuropathological patterns vary considerably among the neonates with HIE due to birth asphyxia in the same classification. The patterns and progression of brain injury in HIE, which is closely associated with long-term neurodevelopment outcomes, can be well shown on magnetic resonance imaging (MRI), but different sequences may lead to different MRI findings at the same time. It is suggested that diffusion-weighted imaging sequence be selected at 2-4 days after birth, and the conventional MRI sequence at 4-8 days. The major patterns of brain injury in HIE on MRI are as follows: injury of the thalamus and basal ganglia and posterior limbs of the internal capsules; watershed injury involving the cortical and subcortical white matter; focal or multifocal minimal white matter injury; extensive whole brain injury. Severe acute birth asphyxia often leads to deep grey matter injury (thalamus and basal ganglia), and the brain stem may also be involved; the pyramidal tract is the most susceptible white matter fiber tract; repetitive or intermittent hypoxic-ischemic insults, with inflammation or hypoglycemia, usually cause injuries in the watershed area and deep white matter. It is worth noting that sometimes the pattern of brain injury among those described above cannot be determined exactly, but rather a predominant one is identified; not all cases of HIE have characteristic MRI findings. PMID- 29237521 TI - [Clinical features of children with acute lymphoblastic leukemia complicated by pulmonary infection after chemotherapy]. AB - OBJECTIVE: To examine the clinical features of children with acute lymphoblastic leukemia (ALL) complicated by pulmonary infection after chemotherapy. METHODS: The clinical data of 108 ALL children (115 case-times) with post-chemotherapy pulmonary infection were retrospectively reviewed. The risk factors for pulmonary infection and the relationship between pathogens and chest CT findings were evaluated. RESULTS: The highest incidence (77.4% ) of pulmonary infection occurred during remission induction, peaking at 31-60 days after chemotherapy. Patients with neutropenia had the highest incidence rate of pulmonary infection (67.0%). Bacteria (36%) and fungi (41%) were the two most common pathogens in the 41 patients who were etiologically suspected of or diagnosed with pulmonary infection. There was no significant difference in chest CT findings between patients with bacterial and fungal infections. CONCLUSIONS: The children with ALL are most susceptible to pulmonary infection during remission induction, especially when they are neutropenic. Bacteria and fungi are the main pathogens of pulmonary infections in these patients. However, the changes in chest CT images are poor indicators of the nature of pulmonary infection. PMID- 29237522 TI - [An analysis of cardiac autonomic nerve function in girls with idiopathic central precocious puberty]. AB - OBJECTIVE: To investigate the cardiac autonomic nerve function in girls with idiopathic central precocious puberty (ICPP). METHODS: A total of 66 girls with ICPP were enrolled, among whom 36 were obese and 30 were not obese. A total of 68 age-matched healthy girls (normal controls) and 51 girls with simple obesity were enrolled as controls. All the subjects underwent 24-hour ambulatory electrocardiography, and deceleration capacity of heart rate (DC), acceleration capacity of heart rate (AC), and heart rate variability (HRV), and body mass index (BMI) were compared between groups. RESULTS: Compared with the normal control group, the ICPP group had significantly lower DC, standard deviation of normal-to-normal R-R intervals (SDNN), standard deviation of the average normal to-normal intervals (SDANN), root mean square of successive differences (RMSSD), and high-frequency power (HF) and significantly higher AC and BMI. The ICPP group had significantly lower RMSSD and BMI than the simple obesity group (P<0.05). Compared with the ICPP girls without obesity, those with obesity had significantly lower DC, RMSSD, and HF and significantly higher AC and BMI (P<0.05). CONCLUSIONS: Cardiac autonomic dysfunction is seen in girls with ICPP, especially those with obesity, mainly presenting with reduced vagal tone. PMID- 29237523 TI - [Clinical analysis of 15 851 children at risk of inherited metabolic diseases]. AB - OBJECTIVE: To explore the value of urine gas chromatography-mass spectrometry (GC MS) in the screening of children at risk of inherited metabolic diseases (IMD), and to identify the disease spectrum of IMD and the clinical characteristics of children with IMD. METHODS: The clinical data of 15 851 children at risk of IMD who underwent urine GC-MS in the Tianjin Children's Hospital between February 2012 and December 2016 were retrospectively analyzed. RESULTS: In the 15 851 children, 5 793 (36.55%) were detected to have metabolic disorders. A total of 117 (0.74%) children were confirmed to have IMD, including 77 cases of methylmalonic acidemia (65.8%). The clinical manifestations of confirmed cases in the neonatal period mainly included jaundice, metabolic acidosis, abnormal muscular tension, feeding difficulty, poor response, and lethargy or coma. The clinical manifestations of confirmed cases in the non-neonatal period mainly included delayed mental and motor development, metabolic acidosis, convulsion, recurrent vomiting, and anemia. CONCLUSIONS: GC-MS is an effective method for the screening for IMD in children at risk. Methylmalonic acidemia is the most common IMD. The clinical manifestations of IMD are different between the confirmed cases in the neonatal and non-neonatal periods. PMID- 29237524 TI - [Characteristics of tidal breathing pulmonary function in children with tracheobronchomalacia]. AB - OBJECTIVE: To investigate the characteristics of tidal breathing pulmonary function in children with tracheobronchomalacia (TBM). METHODS: In this study, 30 children who were diagnosed with TBM using electronic bronchoscopy were enrolled in the observation group; 30 healthy children were recruited in the normal control group. For individuals in each group, the assessment of tidal breath pulmonary function was performed at diagnosis and 3, 6, 9, and 12 months after diagnosis. RESULTS: There were no significant differences in tidal volume, inspiratory time, expiratory time, and inspiratory to expiratory ratio between the two groups (P>0.05). Compared with the control group, the observation group had a significantly higher respiratory rate and significantly lower ratio of time to peak tidal expiratory flow to total expiratory time (TPTEF/TE) and ratio of volume to peak tidal expiratory flow to total expiratory volume (VPTEF/VE). There was a time-dependent increase in TPTEF/TE and VPTEF/VE for TBM children from the time of initial diagnosis to 12 months after diagnosis. CONCLUSIONS: Tidal breathing pulmonary function has characteristic changes in children with TBM. Tidal breathing pulmonary function tends to be recovered with increased age in children with TBM. PMID- 29237525 TI - [Analysis of the Test of Infant Motor Performance data from 642 infants with a postconceptual age of 38-58 weeks]. AB - OBJECTIVE: To investigate the differences between the Test of Infant Motor Performance (TIMP) data from the infants at 38-58 weeks of postconceptual age in three hospitals in Chongqing, China and the America norms, and to provide a reference for the introduction and application of TIMP in China. METHODS: TIMP was used to assess 642 infants with 38-58 weeks of postconceptual age who visited the departments of preterm infants or child healthcare in the Second Affiliated Hospital of Army Medical University, Shapingba Maternal and Child Health Hospital in Chongqing, and Chongqing Maternal and Child Health Hospital between January and December, 2016. The assessment scores were analyzed and compared with the America norms. RESULTS: The TIMP scores increased with the increasing postconceptual age, with 37+/-5 points in the 38-39+6 week group and 83+/-12 points in the 56-57+6 week group. All age groups had a significantly lower mean score than the America norms (P<0.001). CONCLUSIONS: TIMP scores can reflect the motor performance in infants with various postconceptual ages. The TIMP scores from the infants with a postconceptual age of 38-58 weeks in three hospitals in Chongqing are significantly different from the America norms, suggesting that it is very necessary in China to establish the Chinese norms for assessing motor performance in infants using TIMP. PMID- 29237526 TI - [Establishment of reference ranges of sex hormones for healthy children in Shenzhen, China based on chemiluminescence]. AB - OBJECTIVE: To study the reference ranges of six sex hormones, i.e., luteinizing hormone, follicle-stimulating hormone, progesterone, prolactin, estradiol, and testosterone, for healthy children aged 0-18 years in Shenzhen, China. METHODS: Stratified cluster sampling was performed to select 2 178 healthy children aged 0 18 years in the districts of Futian, Luohu, Nanshan, Bao'an, and Longgang in Shenzhen between September 2015 and September 2016. There were 1 219 boys and 959 girls, including 81 neonates, 335 infants, 346 young children, 469 preschool children, 419 school-aged children, and 528 adolescents. The American Beckman DXI800 chemiluminescence meter was used to measure the levels of luteinizing hormone, follicle-stimulating hormone, progesterone, prolactin, estradiol, and testosterone. RESULTS: There were significant differences in the levels of luteinizing hormone, follicle-stimulating hormone, progesterone, prolactin, estradiol, and testosterone between different age groups (P<0.05). There were also significant differences in the levels of these sex hormones between boys and girls in the same age group (P<0.05). The reference ranges of six sex hormones were established for healthy children aged 0-18 years in Shenzhen based on the levels of these hormones in different age groups. CONCLUSIONS: There are significant differences in sex hormones between different age groups or sex groups. The reference ranges of six sex hormones established for different sexes or ages have great significance in the diagnosis and treatment of endocrine diseases in children. PMID- 29237527 TI - [A rhabdomyosarcoma patient from a Li-Fraumeni syndrome family: a case report and literature review]. AB - Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome, with the characteristics of early onset of cancer and high cancer incidence. TP53 is widely accepted as a pathogenic gene of LFS. A 2 years and 6 months old boy is reported in this article, who was diagnosed with embryonal rhabdomyosarcoma (RMS) in the left submandibular region. His brother died of RMS, and his grandmother was diagnosed with breast cancer. TP53 gene mutation detection was performed in this patient and some family members, indicating a missense mutation in exon 8 of the patient: c.844C>T (p.Arg282Trp, heterozygous). TP53 mutation was also found in his mother and sister. The boy met the diagnostic criteria for LFS. Among pediatric patients, the most common LFS diseases include osteosarcoma, adrenocortical cancer, central nervous system tumor, and soft tissue tumor. Additionally, leukemia and lymphoma are also involved. LFS patients have a high risk to suffer secondary or even multiple cancers. Therefore, it is necessary to perform genetic detection for pediatric cancer patients, especially those with hereditary predisposition cancers. TP53 mutation often indicates poor prognosis, so it is important to take active treatment and systematic monitoring for LFS family. PMID- 29237528 TI - [Effect of leptin on long-term spatial memory of rats with white matter damage in developing brain]. AB - OBJECTIVE: To investigate the neuroprotective effect of leptin by observing its effect on spatial memory of rats with white matter damage in developing brain. METHODS: A total of 80 neonatal rats were randomly divided into 3 groups: sham operation (n=27), model (n=27) and leptin intervention (n=27). The rats in the model and leptin intervention groups were used to prepare a model of white matter damage in developing brain, and the rats in the leptin intervention group were given leptin (100 MUg/kg) diluted with normal saline immediately after modelling for 4 consecutive days. The survival rate of the rats was observed and the change in body weight was monitored. When the rats reached the age of 21 days, the Morris water maze test was used to evaluate spatial memory. RESULTS: There was no significant difference in the survival rate of rats between the three groups (P>0.05). Within 10 days after birth, the leptin intervention group had similar body weight as the sham-operation group and significantly lower body weight than the model group (P<0.05); more than 10 days after birth, the leptin intervention group had rapid growth with higher body weight than the model and sham-operation groups (P>0.05). The results of place navigation showed that from the second day of experiment, there was a significant difference in the latency period between the three groups (P<0.05); from the fourth day of experiment, the leptin intervention group had a similar latency period as the sham-operation and a significantly shorter latency period than the model group (P<0.05). The results of space search experiment showed that compared with the sham-operation group, the model group had a significant reduction in the number of platform crossings and a significantly longer latency period (P<0.05); compared with the model group, the leptin intervention group had a significantly increased number of platform crossings and a significantly shortened latency period (P<0.05), while there was no significant difference between the leptin intervention and sham operation groups. CONCLUSIONS: Leptin can alleviate spatial memory impairment of rats with white matter damage in developing brain. It thus exerts a neuroprotective effect, and is worthy of further research. PMID- 29237529 TI - [Changes in the expression of EphA5/ephrinA5 in the CA3 region of the hippocampus in rats with epilepsy and their role in the pathogenesis of temporal lobe epilepsy]. AB - OBJECTIVE: To investigate the changes in the expression of EphA5 and its ligand ephrinA5 in the hippocampus of rats with epilepsy and their role in the pathogenesis of temporal lobe epilepsy (TLE). METHODS: A total of 240 Sprague Dawley rats were randomly divided into control group and TLE group, with 120 rats in each group. A rat model of lithium-pilocarpine TLE was established, and then the rats were divided into subgroups at 12 and 24 hours and 7, 15, 30, and 60 days after epilepsy was induced. In-situ hybridization was used to measure the mRNA expression of ephrinA5 in the CA3 region and the dentate gyrus of the hippocampus in 9 rats; immunohistochemistry was used to measure the protein expression of EphA5 in the CA3 region and the dentate gyrus of the hippocampus in 9 rats; Neo-Timm silver staining was used to observe mossy fiber sprouting in the CA3 region of the hippocampus in 2 rats. RESULTS: In-situ hybridization showed mRNA expression of ephrinA5 in the CA3 region of the hippocampus, but this was not found in the dentate gyrus. Compared with the control group at the same time point, the TLE group had a significant reduction in the mRNA expression of ephrinA5 in the CA3 region of the hippocampus at 7 and 15 days after epilepsy was induced (P<0.05); at 30 and 60 days after epilepsy was induced, the TLE group had a gradual increase in the mRNA expression of ephrinA5 in the CA3 region of the hippocampus, and there was no significant difference between the TLE and control groups (P>0.05). Immunohistochemistry showed that EphA5 protein was expressed in the CA3 region and the dentate gyrus of the hippocampus and had a similar trend of change as ephrinA5 mRNA. Neo-Timm silver staining showed that the TLE group developed marked mossy fiber sprouting in the CA3 region of the hippocampus at 7 and 15 days after epilepsy was induced. CONCLUSIONS: Downregulation of ephrinA5 and EphA5 in the CA3 region of the hippocampus may participate in the mechanism of mossy fiber sprouting and is closely associated with the development and progression of epilepsy. PMID- 29237530 TI - [Mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice]. AB - OBJECTIVE: To investigate the molecular mechanism of action of BET bromodomain inhibitor JQ1 in treating airway remodeling in asthmatic mice. METHODS: A total of 24 mice were randomly divided into control group, ovalbumin (OVA)-induced asthma group (OVA group), and JQ1 intervention group (JQ1+OVA group), with 8 mice in each group. OVA sensitization/challenge was performed to establish a mouse model of asthma. At 1 hour before challenge, the mice in the JQ1+OVA group were given intraperitoneal injection of JQ1 solution (50 MUg/g). Bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected at 24 hours after the last challenge, and the total number of cells and percentage of eosinophils in BALF were calculated. Pathological staining was performed to observe histopathological changes in lung tissue. RT-PCR and Western blot were used to measure the mRNA and protein expression of E-cadherin and vimentin during epithelial-mesenchymal transition (EMT). RESULTS: Compared with the control group, the OVA group had marked infiltration of inflammatory cells in the airway, thickening of the airway wall, increased secretion of mucus, and increases in the total number of cells and percentage of eosinophils in BALF (P<0.01). Compared with the OVA group, the JQ1+OVA group had significantly alleviated airway inflammatory response and significant reductions in the total number of cells and percentage of eosinophils in BALF (P<0.01). Compared with the control group, the OVA group had significant reductions in the mRNA and protein expression of E cadherin and significant increases in the mRNA and protein expression of vimentin (P<0.01); compared with the OVA group, the JQ1+OVA group had significant increases in the mRNA and protein expression of E-cadherin and significant reductions in the mRNA and protein expression of vimentin (P<0.01); there were no significant differences in these indices between the JQ1+OVA group and the control group (P>0.05). CONCLUSIONS: Mice with OVA-induced asthma have airway remodeling during EMT. BET bromodomain inhibitor JQ1 can reduce airway inflammation, inhibit EMT, and alleviate airway remodeling, which provides a new direction for the treatment of asthma. PMID- 29237531 TI - [Research advances in mesenchymal stem cell-derived exosomes in treatment of brain injury]. AB - Mesenchymal stem cell (MSC) transplantation is considered one of the most promising therapeutic strategies for the repair of brain injuries and plays an important role in various links of nerve repair. Recent studies have shown that MSC-derived exosomes may dominate the repair of brain injuries and help to promote angiogenesis, regulate immunity, inhibit apoptosis, and repair the nerves, and therefore, they have a great potential in the treatment of brain injuries in neonates. With reference to these studies, this article reviews the mechanism of action of exosomes in the repair of brain injuries and related prospects and challenges, in order to provide new directions for the treatment of brain injuries in neonates with stem cells. PMID- 29237532 TI - [Research progresses in the pathogenesis, diagnosis and treatment of infantile hemangioma with PHACE syndrome]. AB - Infant hemangioma, the most common benign tumor in children, is characterized by rapid proliferation, followed by slower spontaneous involution. However, some patients with facial segmental hemangioma are associated with PHACE syndrome. PHACE syndrome is characterized by vascular nerve and vascular cutaneous lesions of multiple systemic systems, often resulting in structural and functional impairments. Recent studies have demonstrated that the possible pathogeneses of PHACE syndrome mainly include hypoxia, abnormality of mesodermal vascular endothelial cells, genetic abnormality, and abnormality of interstitial mesenchymal stem cells. The current medications for hemangioma with PHACE syndrome include beta blockers, glucocorticoids, and mTOR inhibitors. This review article mainly describes the pathogenesis, diagnoses and treatments of PHACE syndrome, in order to provide directions for diagnosis and treatment of this disorder. PMID- 29237533 TI - [Research advances in the mechanism of congenital heart disease induced by pregestational diabetes mellitus]. AB - Congenital heart disease (CHD) is the most common birth defect at present and has a complex etiology which involves the combined effect of genetic and environmental factors. Pregestational diabetes mellitus is significantly associated with the development of CHD, but the detailed mechanism remains unknown. This article reviews the research advances in the molecular mechanism of CHD caused by pregestational diabetes mellitus. PMID- 29237534 TI - [Research advances in neonatal nasal intermittent positive pressure ventilation]. AB - Nasal intermittent positive pressure ventilation (NIPPV) can augment nasal continuous positive airway pressure (nCPAP) by delivering intermittent positive pressure ventilation in a noninvasive way and can provide a new option for neonatal noninvasive respiratory support. NIPPV has an advantage over nCPAP in primary and post-extubation respiratory support. Moreover, it can reduce severe apnea of prematurity. Synchronized NIPPV has promising application prospects. This review article summarizes the advances in the application of NIPPV in neonatal respiratory support to promote the understanding and standardization of this technique. PMID- 29237535 TI - [Application of movement recognition technology in assessing spontaneous general movements in preterm infants]. AB - Preterm birth is a major factor which induces neurological and motor impairments, particularly cerebral palsy, in high-risk infants. Early identification of potential neurodevelopmental impairments provides the opportunity to improve neurodevelopmental outcomes in preterm infants through early rehabilitation interventions. Clinically, the general movement assessment is a pivotal tool to predict neurodevelopmental outcomes, especially motor developmental outcomes, in high-risk infants. Movement recognition can continuously capture relevant limb movements and perform objective and quantitative assessment using computerized approaches. Various methods of recording and analyzing spontaneous general movements for infants at a risk of cerebral palsy have been extensively explored. This article summarizes the general movement assessment method and reviews the translational research on using movement recognition technology for the assessment of spontaneous general movements of preterm infants. PMID- 29237536 TI - Multivariate curve resolution using a combination of mid-infrared and near infrared spectra for the analysis of isothermal epoxy curing reaction. AB - Multivariate curve resolution (MCR) was applied to a hetero-spectrally combined dataset consisting of mid-infrared (MIR) and near-infrared (NIR) spectra collected during the isothermal curing reaction of an epoxy resin. An epoxy monomer, bisphenol A diglycidyl ether (BADGE), and a hardening agent, 4,4' diaminodiphenyl methane (DDM), were used for the reaction. The fundamental modes of the NH and OH stretches were highly overlapped in the MIR region, while their first overtones could be independently identified in the NIR region. The concentration profiles obtained by MCR using the hetero-spectral combination showed good agreement with the results of calculations based on the Beer-Lambert law and the mass balance. The band assignments and absorption sites estimated by the analysis also showed good agreement with the results using two-dimensional (2D) hetero-correlation spectroscopy. PMID- 29237537 TI - Metastatic cutaneous apocrine adenocarcinoma responsive to the programmed cell death protein 1 inhibitor pembrolizumab. PMID- 29237538 TI - Periconception Exposure to Air Pollution and Risk of Congenital Malformations. AB - OBJECTIVE: To evaluate the association between increased exposure to airborne fine particulate matter (PM2.5) during the periconception period with risk of congenital anomalies. STUDY DESIGN: Using birth certificate data from the Ohio Department of Health (2006-2010) and PM2.5 data from the US Environmental Protection Agency's 57 monitoring stations located throughout Ohio, the geographic coordinates of the mother's residence for each birth were linked to the nearest PM2.5 monitoring station and monthly exposure averages were calculated. The association between congenital anomalies and increased PM2.5 levels was estimated, with adjustment for coexistent risk factors. RESULTS: After adjustment for coexisting risk factors, exposure to increased levels of PM2.5 in the air during the periconception period was modestly associated with risk of congenital anomalies. Compared with other periconception exposure windows, increased exposure during the 1 month before conception was associated with the highest risk increase at lesser distances from monitoring stations. The strongest influences of PM2.5 on individual malformations were found with abdominal wall defects and hypospadias, especially during the 1-month preconception. CONCLUSIONS: Increased exposure to PM2.5 in the periconception period is associated with some modest risk increases for congenital malformations. The most susceptible time of exposure appears to be the 1 month before and after conception. Although the increased risk with PM2.5 exposure is modest, the potential impact on a population basis is noteworthy because all pregnant women have some degree of exposure. PMID- 29237539 TI - Cdkn2a deficiency promotes adipose tissue browning. AB - OBJECTIVES: Genome-wide association studies have reported that DNA polymorphisms at the CDKN2A locus modulate fasting glucose in human and contribute to type 2 diabetes (T2D) risk. Yet the causal relationship between this gene and defective energy homeostasis remains elusive. Here we sought to understand the contribution of Cdkn2a to metabolic homeostasis. METHODS: We first analyzed glucose and energy homeostasis from Cdkn2a-deficient mice subjected to normal or high fat diets. Subsequently Cdkn2a-deficient primary adipose cells and human-induced pluripotent stem differentiated into adipocytes were further characterized for their capacity to promote browning of adipose tissue. Finally CDKN2A levels were studied in adipocytes from lean and obese patients. RESULTS: We report that Cdkn2a deficiency protects mice against high fat diet-induced obesity, increases energy expenditure and modulates adaptive thermogenesis, in addition to improving insulin sensitivity. Disruption of Cdkn2a associates with increased expression of brown-like/beige fat markers in inguinal adipose tissue and enhances respiration in primary adipose cells. Kinase activity profiling and RNA-sequencing analysis of primary adipose cells further demonstrate that Cdkn2a modulates gene networks involved in energy production and lipid metabolism, through the activation of the Protein Kinase A (PKA), PKG, PPARGC1A and PRDM16 signaling pathways, key regulators of adipocyte beiging. Importantly, CDKN2A expression is increased in adipocytes from obese compared to lean subjects. Moreover silencing CDKN2A expression during human-induced pluripotent stem cells adipogenic differentiation promoted UCP1 expression. CONCLUSION: Our results offer novel insight into brown/beige adipocyte functions, which has recently emerged as an attractive therapeutic strategy for obesity and T2D. Modulating Cdkn2a-regulated signaling cascades may be of interest for the treatment of metabolic disorders. PMID- 29237540 TI - Prokinetic effects of neurokinin-2 receptor agonists on the bladder and rectum of rats with acute spinal cord transection. AB - The suitability of various neurokinin-2 (NK2) receptor agonists and routes of administration to elicit on-demand voiding of the bladder and bowel, as future therapy for individuals with spinal cord injury, was examined using a rat model. The current study examined the feasibility of alternative routes of administration, which are more practical for clinical use than intravenous (IV) administration. Voiding and isovolumetric cystometry were recorded in anesthetized, acutely spinalized, female rats after IV, subcutaneous (SC), intramuscular (IM), intranasal (IN), or sublingual (SL) administration of [Lys5,MeLeu9,Nle10]-NKA(4-10) (LMN-NKA). Administration of LMN-NKA (1-10MUg/kg IV; 10-300MUg/kg SC or IM; 15-1000MUg/kg IN or 300-1500MUg/kg SL) elicited rapid onset, short-duration, dose-related increases in bladder pressure and voiding with the rank order for time of both onset and duration being IV < IN < SC = IM < SL. The incidence of voiding was dependent on the dose and route, with all routes resulting in a high voiding efficiency (~ 70%). Like LMN-NKA, neurokinin A (NKA 1 100MUg/kg IV) and GR 64349 (0.1-30MUg/kg IV or 1-300MUg/kg SC) produced rapid onset, short-duration increases in bladder pressure, as well as colorectal pressure. Administration of vehicle never produced bladder or rectal contractions or voiding. Transient hypotension was observed after IV injection of LMN-NKA, which was less pronounced after SC injection. Hypotension was not apparent with GR 64349. In conclusion, selective NK2 receptor agonists, administered through various non-IV routes of administration, may provide a safe, convenient, and efficacious method for inducing voiding. PMID- 29237542 TI - Emergency department naloxone rescue kit dispensing and patient follow-up. PMID- 29237541 TI - Life-threatening hemorrhage from the corona mortis treated with balloon-assisted coiling technique. AB - Isolated pubic ramus fractures are common and generally uncomplicated injuries in the elderly. However, pubic ramus fractures are closely related to important vascular structures. The corona mortis, located in the retropubis, has an important anastomotic value, as it serves as a communication between the internal and external iliac vessels. The following case report describes an 88-year-old male who was diagnosed with a right superior pubic ramus fracture, which led to a severe picture of hemodynamic instability. Emergent angiography demonstrated injury of the corona mortis. After super-selective embolization of the corona mortis artery with a balloon-assisted coiling technique, the patient progressed satisfactorily and was discharged after 7days. PMID- 29237543 TI - Diagnosis and management of McFarland fractures. AB - BACKGROUND: McFarland fracture is the eponym for a rare Salter Harris III or IV fracture involving the medial distal tibia. These fractures can be difficult to diagnose without a high index suspicion and appropriate radiographic imaging. These fractures may result in significant growth disturbances to the pediatric patient. When diagnosed and treated acutely, these fractures can be managed with cast immobilization and close follow up. If diagnoses in a delayed fashion they can result in significant morbidity including prolonged casting and possible surgical treatment. CASE REPORT: In this case report we discuss a pediatric patient with a delayed presentation McFarland fracture which was initially diagnosed and treated as an ankle sprain. He required a prolonged course of treatment and we describe his clinical progression. We review the literature regarding this fracture pattern including history, acute management and outcomes. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: McFarland fractures are rare Salter Harris III fractures of the medial malleolus. These ankle fractures affect patients nearing skeletal maturity and may be difficult to diagnose without the appropriate orthogonal X-ray imaging. Also, a missed diagnosis can lead to unnecessary morbidity to the patient. If diagnosed acutely, these fractures can be easily treated with immobilization but if allowed to become chronic they require prolonged periods of casting and possibly even surgical intervention. A patient with a specific constellation of symptoms and history should raise suspicion for these injuries and prompt a thorough workup. PMID- 29237544 TI - Cardiac tamponade due to internal mammary artery injury after cardiopulmonary resuscitation: A case report. AB - Vascular injuries caused by cardiopulmonary resuscitation (CPR) can be associated with major complications. If patients who have received CPR have sudden abnormal hemodynamic findings, it is necessary to consider the possibility of these injuries. We report a 73-year-old man who had cardiac tamponade due to an injury to the internal mammary artery following manual chest compression. This very rare injury was detected by computed tomography and was treated by thoracotomy and hematoma evacuation. PMID- 29237545 TI - Corrigendum to "Personalized medicine: Genetic risk prediction of drug response" [Pharmacol. Ther. 175 (2017) 75-90.]. PMID- 29237547 TI - Non-alcoholic fatty liver disease: A risk factor for myocardial dysfunction? PMID- 29237546 TI - Impact of disease progression on health-related quality of life in patients with metastatic breast cancer in the PRAEGNANT breast cancer registry. AB - OBJECTIVES: Improved progression-free survival is considered as treatment goal for patients with metastatic breast cancer (MBC) since it is assumed to delay or prevent deterioration of quality of life. Aim of our analysis was to examine the influence of disease progression on health-related quality of life (HRQoL). MATERIALS AND METHODS: The PRAEGNANT study comprises a real-life registry for patients with MBC. HRQoL was assessed with the EORTC-QLQ-C30 Version 3.0 questionnaire at study entry and every 3 months thereafter. The primary endpoint was minimally important deterioration (MID) in global HRQoL score by >= five points between baseline and any follow-up assessment. A logistic regression model was built with MID (yes/no) at a follow-up timepoint as outcome variable and several covariates as predictors. RESULTS: In total, 329 patients were included in this analysis, with disease progression in 63 patients. Concerning the primary study aim, progression status predicted MID of global HRQoL status in addition to the other covariates. The adjusted odds ratio for the effect of progression status on MID was 2.22 (95% CI: 1.04 - 4.73). Comparisons of mean differences of QoL domains/scales yielded no differences. CONCLUSIONS: We provide evidence that disease progression in patients with metastatic breast cancer in a real-world registry has a significant negative impact on HRQoL as measured by MID of HRQoL. This study emphasizes the relevance of avoiding progression and prolonging PFS to maintain QoL. PMID- 29237548 TI - Dietary patterns and the risk of coronary heart disease among Jordanians: A case control study. AB - BACKGROUND AND AIMS: Dietary pattern and lifestyle have been reported to be significant risk factors in the development of coronary heart diseases (CHD). The contribution degree of these dietary risk factors in CHD development in non westernized countries is unclear. This study aimed to evaluate several dietary choices and their potential association with CHD. METHODS AND RESULTS: A case control study was conducted at Prince Hamza Hospital, a referral center for coronary angiography in Amman, Jordan. Four-hundred patients referring for elective coronary angiography with clinical suspicion of coronary artery disease were enrolled. Data was collected using interview-based questionnaires. Dietary patterns were derived using Principal Component Analysis. Multivariate logistic regression was used to estimate the relationship between dietary choices and CHD. Three dietary patterns were identified. The "Healthy Dietary Pattern", which presented a diet rich in olive oil, fruits, vegetables, legumes, whole grains, fish, and low meat intake, was associated with a significant decrease in the odds of CHD (OR = 0.53, 95% CI = 0.28-0.98). The "High-Fiber Pattern", which is mainly composed of legumes and bulgur, significantly reduced the odd of CHD (OR = 0.55, 95% CI = 0.27-0.92) for the fourth quartile compared to the first one. No significant association was found between CHD and the "Western Dietary Pattern", which is loaded with refined grains, sweets and deserts, sugary drinks, and deep fried foods. CONCLUSIONS: The "Healthy Dietary Pattern" and the "High-Fiber Pattern" were associated with a decrease in odds of CHD among Jordanians. PMID- 29237549 TI - Modeling Parkinson's disease and treatment complications in rodents: Potentials and pitfalls of the current options. AB - Animal models of neurological deficits are essential to assess new therapeutic options and reduce treatment complications. Over the last decades, several rodent models of Parkinson's disease have been developed, and have now become the first line experimental tool for therapeutic screening purposes. Which model is the most predictive for identifying the efficacy of symptomatic or disease-modifying interventions is still a matter of debate. None of the models so far available is able to recapitulate all the features of the human disease, but several well characterized models with complementary features currently provide a valuable repertoire of tools to address specific scientific hypotheses. This article reviews the rodent models of Parkinson's disease currently available, with a particular focus on symptomatic models used to mimic parkinsonian motor deficits and treatment-related complications. Advantages and disadvantages of each model are presented and discussed to assist the decision of investigators who wonder which model may be the most suitable for their particular research project. PMID- 29237550 TI - The effects of DNA methylation on human psychology. AB - DNA methylation is a fundamental epigenetic modification in the human genome; pivotal in development, genomic imprinting, X inactivation, chromosome stability, gene expression and methylation aberrations are involved in an array of human diseases. Methylation at promoters is associated with transcriptional repression, whereas gene body methylation is generally associated with gene expression. Extrinsic factors such as age, diets and lifestyle affect DNA methylation which consequently alters gene expression. Stress, anxiety, depression, life satisfaction, emotion among numerous other psychological factors also modify DNA methylation patterns. This correlation is frequently investigated in four candidate genes; NR3C1, SLC6A4, BDNF and OXTR, since regulation of these genes directly impact responses to social situations, stress, threats, behaviour and neural functions. Such studies underpin the hypothesis that DNA methylation is involved in deviant human behaviour, psychological and psychiatric conditions. These candidate genes may be targeted in future to assess the correlation between methylation, social experiences and long-term behavioural phenotypes in humans; and may potentially serve as biomarkers for therapeutic intervention. PMID- 29237551 TI - Dose-dependent and opposite effects of orexin A on prepulse inhibition response in sleep-deprived and non-sleep-deprived rats. AB - Orexin is a novel neurotransmitter released from lateral hypothalamus, that is a crucial modulator in sleep/wakefulness system. Recent studies also suggest its possible role in the neurodevelopmental disorders, such as schizophrenia. Our study consists of two experiments, where we investigate the effect of orexin A (OXA), one of two isoforms of orexin that can pass blood brain barrier, on the prepulse inhibition of acoustic startle reflex. The first experiment tested the effect of OXA on PPI response of non-sleep-deprived rats via intraperitoneal injection 30min before testing. Our results show that 40MUg/kg OXA attenuates PPI% at 78dB and 86dB prepulse intensities. The second experiment utilized 72-h REM sleep deprivation, as a model for sleep-deprivation-induced impairment of PPI response. Here, we tested the effect of OXA on PPI% of sleep-deprived rats via intraperitoneal injection at the last 30min of sleep deprivation, testing for PPI immediately afterwards. Our results showed that (1) sleep deprivation attenuates the PPI% at 74dB, 78dB and 86dB prepulse intensities and (2) 10MUg/kg OXA completely restores the impaired PPI% at 78dB only, where the highest PPI% impairment was observed. These results suggest that orexin A modulates PPI response in rats in a dose-dependent manner, oppositely for non-sleep-deprived and sleep-deprived rats, and a more detailed investigation for the etiology of this effect should follow. PMID- 29237552 TI - Female Songbirds: The unsung drivers of courtship behavior and its neural substrates. AB - Songbirds hold a prominent role in the fields of neurobiology, evolution, and social behavior. Many of these fields have assumed that females lacked the ability to produce song and have therefore treated song as a male-specific behavior. Consequently, much of our understanding regarding the evolution and neural control of song behavior has been driven by these assumptions. Here we review literature from diverse fields to provide a broader perspective of the role of females in vocal communication and courtship. Recent evidence indicates that song evolved in both males and females and instances of female song are still common. The specialized neural circuit known as the "song system," which is necessary for singing in males, is also present in females, including those that do not sing, implying broader functions that include evaluating male song and controlling courtship behavior. In addition to having flexible, individualized preferences, females actively shape their social network through their interactions with males, females, and juveniles. We suggest that by developing more accurate hypotheses concerning the role of females we may better understand the evolution and neural mechanisms of song production and courtship behavior. PMID- 29237553 TI - The SNP rs4252548 (R112H) which is associated with reduced human height compromises the stability of IL-11. AB - Height is a complex human phenotype that is influenced by variations in a high number of genes. Recently, a single nucleotide polymorphism (SNP) within IL11 (rs4252548) has been described to be associated with height in adults of European ancestry. This coding SNP leads to the exchange of Arg-112 to His-112 within the cytokine Interleukin-11 (IL-11), which has a well-established role in osteoclast development and bone turnover. The functional consequences of the R112H mutation are unknown so far. In this study, we show by molecular replacement that Arg-112 does not participate in binding of IL-11 to its receptors IL-11R and glycoprotein 130 (gp130). Recombinant IL-11 R112H expressed in E. coli displays a correct four helix-bundle folding topology, and binds with similar affinity to IL-11R and the IL-11/IL-11R/gp130 complex. IL-11 R112H induces cell proliferation and phosphorylation of the downstream transcription factor STAT3 indistinguishable from IL-11. However, IL-11 R112H fails to support the survival of osteoclast progenitor cells and is less thermally stable, which is caused by the loss of the positive charge on the protein surface since protonation of the histidine side chain recovers stability. PMID- 29237555 TI - Real-world navigation in amnestic mild cognitive impairment: The relation to visuospatial memory and volume of hippocampal subregions. AB - Spatial disorientation is a frequent symptom in Alzheimer's disease and in mild cognitive impairment (MCI). In the clinical routine, spatial orientation is less often tested with real-world navigation but rather with 2D visuoconstructive tasks. However, reports about the association between the two types of tasks are sparse. Additionally, spatial disorientation has been linked to volume of the right hippocampus but it remains unclear whether right hippocampal subregions have differential involvement in real-world navigation. Yet, this would help uncover different functional roles of the subregions, which would have important implications for understanding the neuronal underpinnings of navigation skills. We compared patients with amnestic MCI (aMCI; n = 25) and healthy elderly controls (HC; n = 25) in a real-world navigation task that engaged different spatial processes. The association between real-world navigation and different visuoconstructive tasks was tested (i.e., figures from the Consortium to Establish a Registry for Alzheimer's Disease; CERAD, the Rey-Osterrieth Complex Figure task; and clock drawing). Furthermore, the relation between spatial navigation and volume of right hippocampal subregions was examined. Linear regression and relative weight analysis were applied for statistical analyses. Patients with aMCI were significantly less able to correctly navigate through a route compared to HC but had comparable map drawing and landmark recognition skills. The association between visuoconstructive tasks and real-world navigation was only significant when using the visuospatial memory component of the Rey figure. In aMCI, more volume of the right hippocampal tail was significantly associated with better navigation skills, while volume of the right CA2/3 region was a significant predictor in HC. Standard visuoconstructive tasks (e.g., the CERAD figures or clock drawing) are not sufficient to detect real-world spatial disabilities in aMCI. Consequently, more complex visuoconstructive tasks (i.e., the Rey figure) should be routinely included in the assessment of cognitive functions in the context of AD. Moreover, in those elderly individuals with impaired complex visuospatial memory, route finding behaviour should be evaluated in detail. Regarding the contribution of hippocampal subregions to spatial navigation, the right hippocampal tail seems to be particularly important for patients with aMCI, while the CA2/3 region appears to be more relevant in HC. PMID- 29237554 TI - Feature-based attention potentiates recovery of fine direction discrimination in cortically blind patients. AB - Training chronic, cortically-blind (CB) patients on a coarse [left-right] direction discrimination and integration (CDDI) task recovers performance on this task at trained, blind field locations. However, fine direction difference (FDD) thresholds remain elevated at these locations, limiting the usefulness of recovered vision in daily life. Here, we asked if this FDD impairment can be overcome by training CB subjects with endogenous, feature-based attention (FBA) cues. Ten CB subjects were recruited and trained on CDDI and FDD with an FBA cue or FDD with a neutral cue. After completion of each training protocol, FDD thresholds were re-measured with both neutral and FBA cues at trained, blind field locations and at corresponding, intact-field locations. In intact portions of the visual field, FDD thresholds were lower when tested with FBA than neutral cues. Training subjects in the blind field on the CDDI task improved FDD performance to the point that a threshold could be measured, but these locations remained impaired relative to the intact field. FDD training with neutral cues resulted in better blind field FDD thresholds than CDDI training, but thresholds remained impaired relative to intact field levels, regardless of testing cue condition. Importantly, training FDD in the blind field with FBA lowered FDD thresholds relative to CDDI training, and allowed the blind field to reach thresholds similar to the intact field, even when FBA trained subjects were tested with a neutral rather than FBA cue. Finally, FDD training appeared to also recover normal integration thresholds at trained, blind-field locations, providing an interesting double dissociation with respect to CDDI training. In summary, mechanisms governing FBA appear to function normally in both intact and impaired regions of the visual field following V1 damage. Our results mark the first time that FDD thresholds in CB fields have been seen to reach intact field levels of performance. Moreover, FBA can be leveraged during visual training to recover normal, fine direction discrimination and integration performance at trained, blind-field locations, potentiating visual recovery of more complex and precise aspects of motion perception in cortically-blinded fields. PMID- 29237556 TI - Ubiquitination Regulates the Proteasomal Degradation and Nuclear Translocation of the Fat Mass and Obesity-Associated (FTO) Protein. AB - Genetic polymorphisms in the fat mass and obesity-associated (FTO) gene have been strongly associated with obesity in humans. The cellular level of FTO is tightly regulated, with alterations in its expression influencing energy metabolism, food intake and body weight. Although the proteasome system is involved, the cellular mechanism underlying FTO protein turnover remains unknown. Here, we report that FTO undergoes post-translational ubiquitination on Lys-216. Knock-in HeLa cells harboring the ubiquitin-deficient K216R mutation displayed a slower rate of FTO turnover, resulting in an increase in the level of FTO as well as enhanced phosphorylation of the ribosomal S6 kinase. Surprisingly, we also found that K216R mutation reduced the level of nuclear FTO and completely abolished the nuclear translocation of FTO in response to amino acid starvation. Collectively, our results reveal the functional importance of ubiquitination in controlling FTO expression and localization, which may be crucial for determining body mass and composition. PMID- 29237557 TI - eRepo-ORP: Exploring the Opportunity Space to Combat Orphan Diseases with Existing Drugs. AB - About 7000 rare, or orphan, diseases affect more than 350 million people worldwide. Although these conditions collectively pose significant health care problems, drug companies seldom develop drugs for orphan diseases due to extremely limited individual markets. Consequently, developing new treatments for often life-threatening orphan diseases is primarily contingent on financial incentives from governments, special research grants, and private philanthropy. Computer-aided drug repositioning is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Here, we present eRepo-ORP, a comprehensive resource constructed by a large-scale repositioning of existing drugs to orphan diseases with a collection of structural bioinformatics tools, including eThread, eFindSite, and eMatchSite. Specifically, a systematic exploration of 320,856 possible links between known drugs in DrugBank and orphan proteins obtained from Orphanet reveals as many as 18,145 candidates for repurposing. In order to illustrate how potential therapeutics for rare diseases can be identified with eRepo-ORP, we discuss the repositioning of a kinase inhibitor for Ras-associated autoimmune leukoproliferative disease. The eRepo-ORP data set is available through the Open Science Framework at https://osf.io/qdjup/. PMID- 29237558 TI - Atg7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi Step Recognition. AB - Atg8 is a unique ubiquitin-like protein that is covalently conjugated with a phosphatidylethanolamine through reactions similar to ubiquitination and plays essential roles in autophagy. Atg7 is the E1 enzyme for Atg8, and it activates the C-terminal Gly116 of Atg8 using ATP. Here, we report the crystal structure of Atg8 bound to the C-terminal domain of Atg7 in an unprecedented mode. Atg8 neither contacts with the central beta-sheet nor binds to the catalytic site of Atg7, both of which were observed in previously reported Atg7-Atg8 structures. Instead, Atg8 binds to the C-terminal alpha-helix and crossover loop, thereby changing the autoinhibited conformation of the crossover loop observed in the free Atg7 structure into a short helix and a disordered loop. Mutational analyses suggested that this interaction mode is important for the activation reaction. We propose that Atg7 recognizes Atg8 through multiple steps, which would be necessary to induce a conformational change in Atg7 that is optimal for the activation reaction. PMID- 29237559 TI - Editorial. PMID- 29237560 TI - Beyond the trigger: The mental health consequences of in-home firearm access among children of gun owners. AB - RATIONALE: The high prevalence of household firearms in the U.S. has ignited a growing body of research seeking to understand its health consequences. While a large number of studies examine the impact of firearm availability on health risks of gun owners in the household, relatively little attention is given to whether and how in-home firearm access may shape psychological outcomes among children of gun owners. OBJECTIVE: This study examined whether and how in-home firearm access is associated with adolescents' depressive symptoms. Given a strong social/cultural association between masculinity and gun possession as well as stark gender differences in perceptions of safety and attitudes toward firearms, this study also investigated whether this association differs for male and female adolescents. METHODS: Participants were drawn from the National Longitudinal Study of Adolescent to Adult Health (Add Health) (n = 14,013). This study used random- and fixed-effects regression analyses as well as propensity score matching models in order to reduce the chances of bias due to individual level heterogeneity. RESULTS: The present study showed that gaining access to guns at home was significantly related to increased depressive symptoms among children of gun owners, even after accounting for both observed and unobserved individual characteristics. Both fixed-effects and propensity-score matching models yielded consistent results. In addition, the observed association between in-home firearm access and depression was more pronounced for female adolescents. Finally, this study found suggestive evidence that the perceptions of safety, especially about school (but not neighborhood), are an important mechanism linking in-home firearm access to adolescent depression. CONCLUSION: As a substantial proportion of U.S. adolescents reported in-home firearm access, the findings of this study suggest that scholars and policymakers must seriously consider mental as well as physical health consequences related to household access to firearms among children of gun owners. PMID- 29237561 TI - Complete genome sequence of Planococcus faecalis AJ003T, the type species of the genus Planococcus and a microbial C30 carotenoid producer. AB - A novel type strain, Planococcus faecalis AJ003T, isolated from the feces of Antarctic penguins, synthesizes a rare C30 carotenoid, glycosyl-4,4' diaponeurosporen-4'-ol-4-oic acid. The complete genome of P. faecalis AJ003T comprises a single circular chromosome (3,495,892 bp; 40.9% G + C content). Annotation analysis has revealed 3511 coding DNA sequences and 99 RNAs; seven genes associated with the MEP pathway and five genes involved in the carotenoid pathway have been identified. The functionality and complementation of 4,4' diapophytoene synthase (CrtM) and two copies of heterologous 4,4'-diapophytoene desaturase (CrtN) involved in carotenoid biosynthesis were analyzed in Escherichia coli. PMID- 29237562 TI - Individual differences as a window into the structure and function of the visual system. PMID- 29237563 TI - Navigating the Future: Cross-sector Marine Genomics. PMID- 29237564 TI - Application of genomics in salmon aquaculture breeding programs by Ashie Norris: Who knows where the genomic revolution will lead us? PMID- 29237565 TI - Support Marine Biotech! PMID- 29237567 TI - Integrated Metabolomics and Proteomics Analysis of Hippocampus in a Rat Model of Depression. AB - Major depressive disorder (MDD) is a prevalent and serious mental disorder with high rates of suicide and disability. However, the underlying pathogenesis of MDD is complicated and remains largely unclear. An integrated analysis of multiple types of omics data may improve comprehensive understanding of the entire molecular mechanism of MDD. In this study, we applied an integrated analysis of gas chromatography/mass spectrometry (GC-MS)-based metabolomics and isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomics to investigate changes in the hippocampus in the chronic unpredictable mild stress (CUMS) rat model of depression. Only the stress-susceptible rats in the CUMS group were selected for profiling against controls. Differential analysis identified 30 metabolites and 170 proteins between the two groups. The integrated analyses revealed four major changes in the hippocampus of CUMS rats: (1) impairment in amino acid metabolism and protein synthesis/degradation; (2) dysregulation of glutamate and glycine metabolism and their transport/catabolism related proteins; (3) disturbances in fatty acid and glycerophospholipid metabolism accompanied by alterations in the corresponding metabolic enzymes; (4) abnormal expression of synapse-associated proteins. These results provide further important insights into the pathophysiology of depression and may help identify potential targets for antidepressant drugs. PMID- 29237568 TI - Radiomicrobiomics: Advancing Along the Gut-brain Axis Through Big Data Analysis. AB - The gut-brain axis communicates the brain with the gut microbiota, a bidirectional conduit that has received increasing attention in recent years thanks to its emerging role in brain development and function. Alterations in microbiota composition have been associated to neurological and psychiatric disorders, and several studies suggest that the immune system plays a fundamental role in the gut-brain interaction. Recent advances in brain imaging and in microbiome sequencing have generated a large amount of information, yet the data from both these sources need to be combined efficiently to extract biological meaning, and any diagnostic and/or prognostic benefit from these tools. In addition, the causal nature of the gut-brain interaction remains to be fully established, and preclinical findings translated to humans. In this "Perspective" article, we discuss recent efforts to combine data on the gut microbiota with the features that can be obtained from the conversion of brain images into mineable data. The subsequent analysis of these data for diagnostic and prognostic purposes is an approach we call radiomicrobiomics and it holds tremendous potential to enhance our understanding of this fascinating connection. PMID- 29237566 TI - Chronic Intermittent Ethanol Exposure Modulation of Glutamatergic Neurotransmission in Rat Lateral/Basolateral Amygdala is Duration-, Input-, and Sex-Dependent. AB - The basolateral amygdala (BLA) controls numerous behaviors, like anxiety and reward seeking, via the activity of glutamatergic principal neurons. These BLA neurons receive excitatory inputs primarily via two major anatomical pathways - the external capsule (EC), which contains afferents from lateral cortical structures, and the stria terminalis (ST), containing synapses from more midline brain structures. Chronic intermittent ethanol (CIE) exposure/withdrawal produces distinct alterations in these pathways. Specifically, 10 days of CIE (via vapor inhalation) increases presynaptic function at ST synapses and postsynaptic function at EC synapses. Given that 10-day CIE/withdrawal also increases anxiety like behavior, we sought to examine the development of these alterations at these inputs using an exposure time-course in both male and female rats. Specifically, using 3, 7, and 10 days CIE exposure, we found that all three durations increase anxiety-like behavior in the elevated plus maze. At BLA synapses, increased presynaptic function at ST inputs required shorter exposure durations relative to post-synaptic alterations at EC inputs in both sexes. But, synaptic alterations in females required longer ethanol exposures compared to males. These data suggest that presynaptic alteration at ST-BLA afferents is an early neuroadaptation during repeated ethanol exposures. And, the similar patterns of presynaptic-then-postsynaptic facilitation across the sexes suggest the former may be required for the latter. These cooperative interactions may contribute to the increased anxiety-like behavior that is observed following CIE-induced withdrawal and may provide novel therapeutic targets to reverse withdrawal induced anxiety. PMID- 29237569 TI - Identification of an industrial microalgal strain for starch production in biorefinery context: The effect of nitrogen and carbon concentration on starch accumulation. AB - The recent trends in microalgal cultures are focused on the biorefinery of the biomass components. Some of them are not completely valorised, for example starch. Since there is a wide market for starch products in food and non-food industries, the exploitation of microalgal starch fractions could improve the economic sustainability of microalgae production. In this perspective, the optimization of nitrogen and carbon source uptake for starch accumulation is a critical point for reducing the nitrogen requirement footprint and to increase CO2 capture. In this study, four robust microalgal strains, already known as starch-accumulating strain, were investigated: Chlorella sorokiniana, Scenedesmus vacuolatus, Dunaliella tertiolecta, and Tetraselmis chuii. C. sorokiniana was selected as the best starch producer in the biorefinery context, and the role nitrogen and CO2 concentration had on the starch production was investigated. For light irradiance of 300MUmolm-2s-1 the optimal nitrogen concentration for growth and starch accumulation resulted 32mgL-1. The CO2 concentration clearly does not influence the starch accumulation, but concentrations distant from 2% negatively influence microalgal growth, affecting the final starch productivity. The biomass composition during the batch growth of C. sorokiniana was also analysed in order to explicitly characterise the dynamic of starch accumulation during the different growth phases. Protein content decreased during N-depletion, carbohydrates were mainly produced during the early N-depletion, followed by the accumulation of lipids in the late depletion. PMID- 29237570 TI - Synergistic enhancement of anticancer therapeutic efficacy of HPMA copolymer doxorubicin conjugates via combination of ligand modification and stimuli response srategies. AB - N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymer has been extensively studied as drug carrier for tumor therapy. Due to the Enhanced Permeability and Retention (EPR) effect, HPMA copolymer drug conjugates are able to be passively accumulated in the tumor site. Currently, efficient uptake of this polymeric system by the cancer cells remains a big challenge, as HPMA polymer is highly hydrophilic, neutrally charged, and has low affinity towards cell membrane. In this study, selective and enhanced intracellular internalization of the copolymer-drug conjugates was achieved by utilizing a hybrid strategy including ligand modification and stimuli response. This hybrid approach was rationally designed to comprise cationic HPMA copolymer backbone as drug carrier, doxorubicin (Dox) as model drug, hydrazone bond as drug spacer, FQSIYPpIK (FQS) peptide as alphavbeta3 targeting ligand and 2, 3-Dimethylmaleic Anhydride (DMA) as a shielded/deshielded cationic group. We demonstrated our system exhibited the "seek-and-destroy" tumor tropic behavior by sequentially undergoing the following steps: (i) tumor passive targeting mediated by EPR effect; (ii) charge reversal at tumor extracellular pH of 6.5; (iii) synergistically enhanced cell uptake via electrostatic interaction with cell membrane and FQS ligand-mediated bio recognition; (iv) drug released in the lysosome; and v) anticancer effect exerted by the targeted delivery of the Dox. PMID- 29237571 TI - Identification of genes related to proliferative diabetic retinopathy through RWR algorithm based on protein-protein interaction network. AB - Proliferative diabetic retinopathy (PDR) is one of the most common complications of diabetes and can lead to blindness. Proteomic studies have provided insight into the pathogenesis of PDR and a series of PDR-related genes has been identified but are far from fully characterized because the experimental methods are expensive and time consuming. In our previous study, we successfully identified 35 candidate PDR-related genes through the shortest-path algorithm. In the current study, we developed a computational method using the random walk with restart (RWR) algorithm and the protein-protein interaction (PPI) network to identify potential PDR-related genes. After some possible genes were obtained by the RWR algorithm, a three-stage filtration strategy, which includes the permutation test, interaction test and enrichment test, was applied to exclude potential false positives caused by the structure of PPI network, the poor interaction strength, and the limited similarity on gene ontology (GO) terms and biological pathways. As a result, 36 candidate genes were discovered by the method which was different from the 35 genes reported in our previous study. A literature review showed that 21 of these 36 genes are supported by previous experiments. These findings suggest the robustness and complementary effects of both our efforts using different computational methods, thus providing an alternative method to study PDR pathogenesis. PMID- 29237572 TI - The role of AdipoR1 and AdipoR2 in liver fibrosis. AB - Activation of the adiponectin (APN) signaling axis retards liver fibrosis. However, understanding of the role of AdipoR1 and AdipoR2 in mediating this response is still rudimentary. Here, we sought to elucidate the APN receptor responsible for limiting liver fibrosis by employing AdipoR1 and AdipoR2 knock out mice in the carbon tetrachloride (CCl4) model of liver fibrosis. In addition, we knocked down receptor function in primary hepatic stellate cells (HSCs) in vitro. Following the development of fibrosis, AdipoR1 and AdipoR2 KO mice had no quantitative difference in fibrosis by Sirius red staining. However, AdipoR2 KO mice had an enhanced fibrotic signature with increased Col1-alpha1, TGFbeta-1, TIMP-1, IL-10, MMP-2 and MMP-9. Knockdown of AdipoR1 or AdipoR2 in HSCs followed by APN treatment demonstrated that AdipoR1 and AdipoR2 did not affect proliferation or TIMP-1 gene expression, while AdipoR2 modulated Col1-alpha1 and alpha-SMA gene expression, HSC migration, and AMPK activity. These finding suggest that AdipoR2 is the major APN receptor on HSCs responsible for mediating its anti-fibrotic effects. PMID- 29237573 TI - Identification of cytochrome b5 CYTB-5.1 and CYTB-5.2 in C. elegans; evidence for differential regulation of SCD. AB - Unsaturated fatty acids (UFAs) play crucial roles in living organisms regarding development, energy metabolism, stress resistance, etc. The biosynthesis of UFAs starts from the introduction of the first double bond by stearoyl-CoA desaturase (SCD), converting saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs). This desaturation is considered to be an aerobic process that requires cytochrome b5 reductase, cytochrome b5 and SCD. However, this enzyme system remains elusive in Caenorhabditis elegans. Here, we show that inactivation by RNAi knockdown or mutation (gk442189) of putative cytochrome b5 genes cytb-5.1 led to reduced conversion of C18:0 to C18:1(n-9) by SCD desaturases FAT-6/7 in C. elegans. On the contrary, cytb-5.2RNAi and cytb-5.2(gk113588) mutant worms showed decreased conversion of C16:0 to C16:1(n-7) by FAT-5 desaturase. Dietary supplementation with C18:1(n-9) and C18:2(n-6) also showed that CYTB-5.1 is likely required for the activity of FAT-6/7 desaturases, but not for FAT-1 to FAT 4 desaturases. Interestingly, co-immunoprecipitation (Co-IP) demonstrated that either FAT-7 or FAT-5 has ability to interact with both CYTB-5.1 and CYTB-5.2. Moreover, RNAi knockdown of cytb-5.1 upregulates the transcriptional and translational expression of fat-5 to fat-7, which may be due to the feedback induction by reduced C18:1(n-9) and downstream fatty acids. Furthermore, both CYTB-5.1 and CYTB-5.2 are involved in fat accumulation, fertility and lifespan in worms, which may be independent of changes in fatty acid compositions. Collectively, these findings for the first time reveal the differential regulation of various SCDs by distinct cytochrome b5 CYTB-5.1 and CYTB-5.2 in the biosynthesis of UFAs in C. elegans. PMID- 29237574 TI - Late rise in hemolymph osmolality in Macrobrachium acanthurus (diadromous freshwater shrimp) exposed to brackish water: Early reduction in branchial Na+/K+ pump activity but stable muscle HSP70 expression. AB - Some Macrobrachium shrimps (Caridea, Palaemonidae) are diadromous; freshwater adults are truly euryhaline, while larvae need saline water for development. Branchial Na+/K+-ATPase (NKA) and carbonic anhydrase (CA) are involved in NaCl absorption in freshwater. This study aimed at verifying the time course of the osmoregulatory response of adult Macrobrachium acanthurus to high salinity brackish water (200/00), from the first 30min to 5days. The goal was to detect possible transition from hyper- to hyporegulation, the putative involvement of branchial NKA and CA, or the induction of muscular HSP70 expression. Hemolymph osmotic and ionic concentrations remained relatively stable and close to control levels until ~9h of exposure, but later increased consistently (~50%). A fast reduction in NKA activity (3-6h) was observed; these shrimps seem to shut off salt absorption already in the first hours. Later on, especially after 24h, hemolymph concentrations rise but HSP70 expression is not induced, possibly because constitutive levels are already sufficient to prevent protein damage. Time-dependent response mechanisms effective in high salinity brackish water, resulting in salt loading avoidance and suggestive of hyporegulation should be further investigated in decapods that evolutionary invaded freshwater. PMID- 29237575 TI - Acclimation capacity of the cardiac HSP70 and HSP90 response to thermal stress in lake trout (Salvelinus namaycush), a stenothermal ice-age relict. AB - The ability of cold-adapted species to persist in the face of climate change will depend on the capacity of individuals for thermal acclimation, adaptation, and the degree of physiological variation that exists among populations. We tested the acclimation capacity of cardiac HSP70 and HSP90 in four populations of lake trout (Salvelinus namaycush), a cold-adapted salmonid. We acclimated fish to four temperatures (8 degrees C, 11 degrees C, 15 degrees C, and 19 degrees C) and measured cardiac HSP70 and HSP90 levels by western blot prior to and following an acute (1h) heat shock at 23 degrees C. Basal and induced cardiac HSP70 and HSP90 expression was similar among lake trout populations. Induced cardiac HSP70 was significantly lower in heat-shocked lake trout acclimated to 19 degrees C compared to all other temperatures. Acclimation temperature had no significant effect on cardiac HSP90 prior to heat shock (control HSP90) and a significant effect on HSP90 in heat-shocked fish, although most significant treatment comparisons were marginal. However, for warm-acclimated fish (15 degrees C and 19 degrees C), cardiac HSP90 levels were lower in heat-shocked versus control fish. Together, this suggests that the induction temperature of cardiac HSP synthesis may increase with warm acclimation in lake trout. This plasticity in the cardiac HSR could assist lake trout populations in coping with longer periods of thermal stress as predicted by climate change models. The cardiac HSR supports previous research suggesting lake trout thermal physiology may be conserved across a wide geographic range. PMID- 29237576 TI - The association between C-reactive protein, Interleukin-6 and depression among older adults in the community: A systematic review and meta-analysis. AB - Previous research indicates there may be an association between inflammation and depression in older adults but results are inconsistent. Therefore, the aim of this review was to determine the cross-sectional and longitudinal associations of two inflammatory markers C-reactive protein (CRP) and Interleukin-6 (IL-6) with depression in older adults. We searched five databases for cross-sectional and longitudinal studies reporting an association between CRP or IL-6 with depression among adults sampled from the community aged 50 or older. We found 32 studies (23 cross-sectional, 7 longitudinal, and 2 assessing both cross-sectional and longitudinal associations) that met eligibility criteria. These studies were entered into a random-effects meta-analysis to determine the cross-sectional association and longitudinal direction of association between both IL-6 and CRP with depression. Results indicated a cross-sectional and longitudinal association between both CRP and IL-6 with depression in older adults, with inflammation leading to depression in longitudinal studies rather than depression to inflammation. However, there was notable heterogeneity between studies as results differed based on adjusting for confounders and on how inflammation and depression were measured. These sources of heterogeneity could explain differences in study results. PMID- 29237577 TI - Randomized Controlled Trials of Technology-Based HIV/STI and Drug Abuse Preventive Interventions for African American and Hispanic Youth: Systematic Review. AB - BACKGROUND: HIV/sexually transmitted infections (STIs) and drug abuse remain significant public health concerns in the United States, and African American and Hispanic youth are disproportionately affected. Although technology-based interventions are efficacious in preventing and reducing HIV/STI and licit/illicit drug use behaviors, relatively little is known regarding the state of the science of these interventions among African American and Hispanic youth. OBJECTIVE: The aim of this review is to identify and examine randomized controlled trials (RCTs) of technology-based HIV/STI and/or drug abuse preventive interventions for African American and Hispanic youth. METHODS: We searched electronic databases (ie, PubMed, Proquest, PsycINFO, Ebscohost, Google Scholar) to identify studies between January 2006 and October 2016. RCTs of technology based interventions targeting African American and Hispanic youth HIV/STI risk behaviors, including sexual risk, licit and illicit drug use, and HIV/STI testing were included. RESULTS: Our search revealed a total of three studies that used an RCT design and included samples comprised of >50% African American and/or Hispanic youth. The follow-up assessments ranged from two weeks to six months and the number of participants in each trial ranged from 72 to 141. The three interventions were theory-driven, interactive, and tailored. The long-term effects of the interventions were mixed, and outcomes included reductions in sex partners, licit drug use, and condomless anal sex acts. CONCLUSIONS: Although technology-based interventions seem promising in the prevention of HIV/STI and drug abuse among African American and Hispanic youth, more research is needed. PMID- 29237578 TI - The Effectiveness of Exercise Therapy on Scapular Position and Motion in Individuals With Scapular Dyskinesis: Systematic Review Protocol. AB - BACKGROUND: Scapular dyskinesis is an alteration in normal scapular position and motion. Some researchers believe that altered kinematics of the scapula subsequent to dysfunction or weakness of scapular stabilizing muscles contributes to impingement syndrome. Scapular muscle exercises are included in the rehabilitation of patients with subacromial impingement syndrome and scapular dyskinesis because the muscular system is one of the major contributors of scapular positioning both at rest and during shoulder movement, but there is considerable uncertainty relating to the relative effectiveness of such approaches on changing scapular position and motion. OBJECTIVE: The aim of this systematic review protocol is to evaluate the effectiveness of exercise therapy on scapular position and motion in individuals with scapular dyskinesis. METHODS: A systematic review will be conducted using PubMed, Scopus, Web of Science, Elsevier, Ovid, ProQuest, Physiotherapy Evidence Database, and Cochrane Library. The reference lists of articles, other reviews, gray literature, and key journals will be searched for relevant articles. Clinical trials reporting the effect of therapeutic exercises (scapular strengthening exercise, scapular stabilization exercise, scapular muscle stretching) with the aims of changing scapular position and motion in individuals with scapular dyskinesis will be included. Two independent reviewers will select studies, extract data, and assess the quality of primary studies. Any disagreement during the selection of studies will be discussed and decided by the whole team. RESULTS: This systematic review began in December 2016 and is currently in progress. The findings will be synthesized to determine the effectiveness of recommended therapeutic exercise on scapular position and motion in individuals with scapular dyskinesis. CONCLUSIONS: This is the first systematic review protocol aiming to assess the effectiveness of exercise therapy in individuals with scapular dyskinesis. The systematic review doesn't require ethics approval because all data used will be provided from published documents. The results of this study will be published in a peer reviewed journal. TRIAL REGISTRATION: PROSPERO CRD42017053923; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=53923 (Archived by WebCite at http://www.webcitation.org/6uzq32T02). PMID- 29237580 TI - Detecting Smoking Events Using Accelerometer Data Collected Via Smartwatch Technology: Validation Study. AB - BACKGROUND: Smoking is the leading cause of preventable death in the world today. Ecological research on smoking in context currently relies on self-reported smoking behavior. Emerging smartwatch technology may more objectively measure smoking behavior by automatically detecting smoking sessions using robust machine learning models. OBJECTIVE: This study aimed to examine the feasibility of detecting smoking behavior using smartwatches. The second aim of this study was to compare the success of observing smoking behavior with smartwatches to that of conventional self-reporting. METHODS: A convenience sample of smokers was recruited for this study. Participants (N=10) recorded 12 hours of accelerometer data using a mobile phone and smartwatch. During these 12 hours, they engaged in various daily activities, including smoking, for which they logged the beginning and end of each smoking session. Raw data were classified as either smoking or nonsmoking using a machine learning model for pattern recognition. The accuracy of the model was evaluated by comparing the output with a detailed description of a modeled smoking session. RESULTS: In total, 120 hours of data were collected from participants and analyzed. The accuracy of self-reported smoking was approximately 78% (96/123). Our model was successful in detecting 100 of 123 (81%) smoking sessions recorded by participants. After eliminating sessions from the participants that did not adhere to study protocols, the true positive detection rate of the smartwatch based-detection increased to more than 90%. During the 120 hours of combined observation time, only 22 false positive smoking sessions were detected resulting in a 2.8% false positive rate. CONCLUSIONS: Smartwatch technology can provide an accurate, nonintrusive means of monitoring smoking behavior in natural contexts. The use of machine learning algorithms for passively detecting smoking sessions may enrich ecological momentary assessment protocols and cessation intervention studies that often rely on self-reported behaviors and may not allow for targeted data collection and communications around smoking events. PMID- 29237579 TI - Usage Pattern Differences and Similarities of Mobile Electronic Medical Records Among Health Care Providers. AB - BACKGROUND: Recently, many hospitals have introduced mobile electronic medical records (mEMRs). Although numerous studies have been published on the usability or usage patterns of mEMRs through user surveys, investigations based on the real data usage are lacking. OBJECTIVE: Asan Medical Center, a tertiary hospital in Seoul, Korea, implemented an mEMR program in 2010. On the basis of the mEMR usage log data collected over a period of 4.5 years, we aimed to identify a usage pattern and trends in accordance with user occupation and to disseminate the factors that make the mEMR more effective and efficient. METHODS: The mEMR log data were collected from March 2012 to August 2016. Descriptive analyses were completed according to user occupation, access time, services, and wireless network type. Specifically, analyses targeted were as follows: (1) the status of the mEMR usage and distribution of users, (2) trends in the number of users and usage amount, (3) 24-hour usage patterns, and (4) trends in service usage based on user occupations. Linear regressions were performed to model the relationship between the time, access frequency, and the number of users. The differences between the user occupations were examined using Student t tests for categorical variables. RESULTS: Approximately two-thirds of the doctors and nurses used the mEMR. The number of logs studied was 7,144,459. Among 3859 users, 2333 (60.46%) users were nurses and 1102 (28.56%) users were doctors. On average, the mEMR was used 1044 times by 438 users per day. The number of users and amount of access logs have significantly increased since 2012 (P<.001). Nurses used the mEMR 3 times more often than doctors. The use of mEMR by nurses increased by an annual average of 51.5%, but use by doctors decreased by an annual average of 7.7%. For doctors, the peak usage periods were observed during 08:00 to 09:00 and 17:00 to 18:00, which were coincident with the beginning of ward rounds. Conversely, the peak usage periods for the nurses were observed during 05:00 to 06:00, 12:00 to 13:00, and 20:00 to 21:00, which effectively occurred 1 or 2 hours before handover. In more than 80% of all cases, the mEMR was accessed via a nonhospital wireless network. CONCLUSIONS: The usage patterns of the mEMR differed between doctors and nurses according to their different workflows. In both occupations, mEMR was highly used when personal computer access was limited and the need for patient information was high, such as during ward rounds or handover periods. PMID- 29237581 TI - A Web-Based Training Resource for Therapists to Deliver an Evidence-Based Exercise Program for Rheumatoid Arthritis of the Hand (iSARAH): Design, Development, and Usability Testing. AB - BACKGROUND: The Strengthening and Stretching for Rheumatoid Arthritis of the Hand (SARAH) is a tailored, progressive exercise program for people having difficulties with wrist and hand function due to rheumatoid arthritis (RA). The program was evaluated in a large-scale clinical trial and was found to improve hand function, was safe to deliver, and was cost-effective. These findings led to the SARAH program being recommended in the UK National Institute for Health and Care Excellence guidelines for the management of adults with RA. To facilitate the uptake of this evidence-based program by clinicians, we proposed a Web-based training program for SARAH (iSARAH) to educate and train physiotherapists and occupational therapists on delivering the SARAH program in their practice. The overall iSARAH implementation project was guided by the 5 phases of the analysis, design, development, implementation, and evaluation (ADDIE) system design model. OBJECTIVE: The objective of our study was to conduct the first 3 phases of the model in the development of the iSARAH project. METHODS: Following publication of the trial, the SARAH program materials were made available to therapists to download from the trial website for use in clinical practice. A total of 35 therapists who downloaded these materials completed an online survey to provide feedback on practice trends in prescribing hand exercises for people with RA, perceived barriers and facilitators to using the SARAH program in clinical practice, and their preferences for the content and Web features of iSARAH. The development and design of iSARAH were further guided by a team of multidisciplinary health professionals (n=17) who took part in a half-day development meeting. We developed the preliminary version of iSARAH and tested it among therapists (n=10) to identify and rectify usability issues and to produce the final version. RESULTS: The major recommendations made by therapists and the multidisciplinary team were having a simple Web design and layout, clear exercise pictures and videos, and compatibility of iSARAH on various browsers and devices. We rectified all usability issues in the preliminary version to develop the final version of iSARAH, which included 4 short modules and additional sections on self assessment, frequently asked questions, and a resource library. CONCLUSIONS: The use of the ADDIE design model and engagement of end users in the development and evaluation phases have rendered iSARAH a convenient, easy-to-use, and effective Web-based learning resource for therapists on how to deliver the SARAH program. There is also huge potential for adapting iSARAH across different cultures and languages, thus opening more opportunities for wider uptake and application of the SARAH program into practice. PMID- 29237582 TI - The Seasonal Periodicity of Healthy Contemplations About Exercise and Weight Loss: Ecological Correlational Study. AB - BACKGROUND: Lack of physical activity and weight gain are two of the biggest drivers of health care costs in the United States. Healthy contemplations are required before any changes in behavior, and a recent study has shown that they have underlying periodicities. OBJECTIVE: The aim of this study was to examine seasonal variations in state-by-state interest in both weight loss and increasing physical activity, and how these variations were associated with geographic latitude using Google Trends search data for the United States. METHODS: Internet search query data were obtained from Google Trends (2004-2016). Time series analysis (every 2 weeks) was performed to determine search volume (normalized to overall search intensity). Seasonality was determined both by the difference in search volumes between winter (December, January, and February) and summer (June, July, and August) months and by the amplitude of cosinor analysis. RESULTS: Exercise-related searches were highest during the winter months, whereas weight loss contemplations showed a biphasic pattern (peaking in the summer and winter months). The magnitude of the seasonal difference increased with increasing latitude for both exercise (R2=.45, F1,49=40.09, beta=-.671, standard deviation [SD]=0.106, P<.001) and weight loss (R2=.24, F1,49=15.79, beta=-.494, SD=0.124, P<.001) searches. CONCLUSIONS: Healthy contemplations follow specific seasonal patterns, with the highest contemplations surrounding exercise during the winter months, and weight loss contemplations peaking during both winter and summer seasons. Knowledge of seasonal variations in passive contemplations may potentially allow for more efficient use of public health campaign resources. PMID- 29237583 TI - High-Yield HIV Testing, Facilitated Linkage to Care, and Prevention for Female Youth in Kenya (GIRLS Study): Implementation Science Protocol for a Priority Population. AB - BACKGROUND: Sub-Saharan Africa is the region with the highest HIV burden. Adolescent girls and young women (AGYW) in the age range of 15 to 24 years are twice as likely as their male peers to be infected, making females in sub-Saharan Africa the most at-risk group for HIV infection. It is therefore critical to prioritize access to HIV testing, prevention, and treatment for this vulnerable population. OBJECTIVE: Using an implementation science framework, the purpose of this research protocol was to describe the approaches we propose to optimize engagement of AGYW in both the HIV prevention and care continuum and to determine the recruitment and testing strategies that identify the highest proportion of previously undiagnosed HIV infections. METHODS: We will compare two seek recruitment strategies, three test strategies, and pilot adaptive linkage to care interventions (sequential multiple assignment randomized trial [SMART] design) among AGYW in the age range of 15 to 24 years in Homa Bay County, western Kenya. AGYW will be recruited in the home or community-based setting and offered three testing options: oral fluid HIV self-testing, staff-aided rapid HIV testing, or referral to a health care facility for standard HIV testing services. Newly diagnosed AGYW with HIV will be enrolled in the SMART trial pilot to determine the most effective way to support initial linkage to care after a positive diagnosis. They will be randomized to standard referral (counseling and a referral note) or standard referral plus SMS text message (short message service, SMS); those not linked to care within 2 weeks will be rerandomized to receive an additional SMS text message or a one-time financial incentive (approximately US $4). We will also evaluate a primary prevention messaging intervention to support identified high-risk HIV-negative AGYW to reduce their HIV risk and adhere to HIV retesting recommendations. We will also conduct analyses to determine the incremental cost-effectiveness of the seek, testing and linkage interventions. RESULTS: We expect to enroll 1200 participants overall, with a random selection of 100 high-risk HIV-negative AGYW for the SMS prevention intervention (HIV negative cohort) and approximately 108 AGYW who are living with HIV for the SMART design pilot of adaptive linkage to care interventions (HIV-positive cohort). We anticipate that the linkage to care interventions will be feasible and acceptable to implement. Lastly, the use of SMS text messages to engage participants will provide pilot data to the Kenyan government currently exploring a national platform to track and support linkage, adherence to treatment, retention, and prevention interventions for improved outcomes. CONCLUSIONS: Lessons learned will inform best approaches to identify new HIV diagnoses to increase AGYW's uptake of HIV prevention, testing, and linkage to care services in a high HIV-burden African setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT02735642; https://clinicaltrials.gov/ct2/show/NCT02735642 (Archived by WebCite at http://www.webcitation.org/6vgLLHLC9). PMID- 29237584 TI - A Mobile Text Message Intervention to Reduce Repeat Suicidal Episodes: Design and Development of Reconnecting After a Suicide Attempt (RAFT). AB - BACKGROUND: Suicide is a leading cause of death, particularly among young people. Continuity of care following discharge from hospital is critical, yet this is a time when individuals often lose contact with health care services. Offline brief contact interventions following a suicide attempt can reduce the number of repeat attempts, and text message (short message service, SMS) interventions are currently being evaluated. OBJECTIVE: The aim of this study was to extend postattempt caring contacts by designing a brief Web-based intervention targeting proximal risk factors and the needs of this population during the postattempt period. This paper details the development process and describes the realized system. METHODS: To inform the design of the intervention, a lived experience design group was established. Participants were asked about their experiences of support following their suicide attempt, their needs during this time, and how these could be addressed in a brief contact eHealth intervention. The intervention design was also informed by consultation with lived experience panels external to the project and a clinical design group. RESULTS: Prompt outreach following discharge, initial distraction activities with low cognitive demands, and ongoing support over an extended period were identified as structural requirements of the intervention. Key content areas identified included coping with distressing feelings, safety planning, emotional regulation and acceptance, coping with suicidal thoughts, connecting with others and interpersonal relationships, and managing alcohol consumption. CONCLUSIONS: The RAFT (Reconnecting AFTer a suicide attempt) text message brief contact intervention combines SMS contacts with additional Web-based brief therapeutic content targeting key risk factors. It has the potential to reduce the number of repeat suicidal episodes and to provide accessible, acceptable, and cost effective support for individuals who may not otherwise seek face-to-face treatment. A pilot study to test the feasibility and acceptability of the RAFT intervention is underway. PMID- 29237587 TI - Drone delivery of medications: Review of the landscape and legal considerations. PMID- 29237585 TI - Evaluating the Dental Caries-Related Information on Brazilian Websites: Qualitative Study. AB - BACKGROUND: Dental caries is the most common chronic oral disease, affecting 2.4 billion people worldwide who on average have 2.11 decayed, missing, or filled teeth. It impacts the quality of life of patients, socially and economically. However, the comprehension of dental caries may be difficult for most people, as it involves a multifactorial etiology with the interplay between the tooth surface, the dental biofilm, dietary fermentable carbohydrates, and genetic and behavioral factors. Therefore, the production of effective materials addressed to the education and counseling of patients for the prevention of dental caries requires a high level of specialization. In this regard, the dental caries related contents produced by laypersons and their availability on the Internet may be low-quality information. OBJECTIVE: The aim of this study was to assess the readability and the quality of dental caries-related information on Brazilian websites. METHODS: A total of 75 websites were selected through Google, Bing, Yahoo!, and Baidu. The websites were organized in rankings according to their order of appearance in each one of the 4 search engines. Furthermore, 2 independent examiners evaluated the quality of websites using the DISCERN questionnaire and the Journal of American Medical Association (JAMA) benchmark criteria. The readability of the websites was assessed by the Flesch Reading Ease adapted to Brazilian Portuguese (FRE-BP). In addition, the information presented on the websites was categorized as etiology, prevention, and treatment of dental caries. The statistical analysis was performed using Spearman rank correlation coefficient, Mann-Whitney U test, hierarchical clustering analysis by Ward minimum variance method, Kruskal-Wallis test, and post hoc Dunn test. P<.05 was considered significant. RESULTS: The Web contents were considered to be of poor quality by DISCERN (mean 33.48, standard deviation, SD 9.06) and JAMA (mean 1.12, SD 0.97) scores, presenting easy reading levels (FRE-BP: mean 62.93, SD 10.15). The rankings of the websites presented by Google (rho=-.22, P=.08), Baidu (rho= .19, P=.53), Yahoo! (rho=.22, P=.39), and Bing (rho=-.36, P=.23) were not correlated with DISCERN scores. Moreover, the quality of websites with health- and nonhealth-related authors was similar (P=.27 for DISCERN and P=.47 for JAMA); however, the pages with a greater variety of dental caries information showed significantly higher quality scores than those with limited contents (P=.009). CONCLUSIONS: On the basis of this sample, dental caries-related contents available on Brazilian websites were considered simple, accessible, and of poor quality, independent of their authorship. These findings indicate the need for the development of specific policies focused on the stimulus for the production and publication of Web health information, encouraging dentists to guide their patients in searching for recommended oral health websites. PMID- 29237586 TI - Using Social Media Data to Understand the Impact of Promotional Information on Laypeople's Discussions: A Case Study of Lynch Syndrome. AB - BACKGROUND: Social media is being used by various stakeholders among pharmaceutical companies, government agencies, health care organizations, professionals, and news media as a way of engaging audiences to raise disease awareness and ultimately to improve public health. Nevertheless, it is unclear what effects this health information has on laypeople. OBJECTIVE: This study aimed to provide a detailed examination of how promotional health information related to Lynch syndrome impacts laypeople's discussions on a social media platform (Twitter) in terms of topic awareness and attitudes. METHODS: We used topic modeling and sentiment analysis techniques on Lynch syndrome-related tweets to answer the following research questions (RQs): (1) what are the most discussed topics in Lynch syndrome-related tweets?; (2) how promotional Lynch syndrome related information on Twitter affects laypeople's discussions?; and (3) what impact do the Lynch syndrome awareness activities in the Colon Cancer Awareness Month and Lynch Syndrome Awareness Day have on laypeople's discussions and their attitudes? In particular, we used a set of keywords to collect Lynch syndrome related tweets from October 26, 2016 to August 11, 2017 (289 days) through the Twitter public search application programming interface (API). We experimented with two different classification methods to categorize tweets into the following three classes: (1) irrelevant, (2) promotional health information, and (3) laypeople's discussions. We applied a topic modeling method to discover the themes in these Lynch syndrome-related tweets and conducted sentiment analysis on each layperson's tweet to gauge the writer's attitude (ie, positive, negative, and neutral) toward Lynch syndrome. The topic modeling and sentiment analysis results were elaborated to answer the three RQs. RESULTS: Of all tweets (N=16,667), 87.38% (14,564/16,667) were related to Lynch syndrome. Of the Lynch syndrome-related tweets, 81.43% (11,860/14,564) were classified as promotional and 18.57% (2704/14,564) were classified as laypeople's discussions. The most discussed themes were treatment (n=4080) and genetic testing (n=3073). We found that the topic distributions in laypeople's discussions were similar to the distributions in promotional Lynch syndrome-related information. Furthermore, most people had a positive attitude when discussing Lynch syndrome. The proportion of negative tweets was 3.51%. Within each topic, treatment (16.67%) and genetic testing (5.60%) had more negative tweets compared with other topics. When comparing monthly trends, laypeople's discussions had a strong correlation with promotional Lynch syndrome-related information on awareness (r=.98, P<.001), while there were moderate correlations on screening (r=.602, P=.05), genetic testing (r=.624, P=.04), treatment (r=.69, P=.02), and risk (r=.66, P=.03). We also discovered that the Colon Cancer Awareness Month (March 2017) and the Lynch Syndrome Awareness Day (March 22, 2017) had significant positive impacts on laypeople's discussions and their attitudes. CONCLUSIONS: There is evidence that participative social media platforms, namely Twitter, offer unique opportunities to inform cancer communication surveillance and to explore the mechanisms by which these new communication media affect individual health behavior and population health. PMID- 29237588 TI - Wine glass size in England from 1700 to 2017: a measure of our time. PMID- 29237589 TI - Impact of Demographic Features, Lifestyle, and Comorbidities on the Clinical Expression of Hypertrophic Cardiomyopathy. PMID- 29237591 TI - Feel the heat: a short history of body temperature. PMID- 29237590 TI - Nativity Status and Cardiovascular Disease Mortality Among Hispanic Adults. AB - BACKGROUND: Hispanic persons represent a heterogeneous and growing population of any race with origins in Mexico, the Caribbean, Central America, South America, or other Spanish-speaking countries. Previous studies have documented variation in cardiovascular risk and outcomes among Hispanic subgroups. Few studies have investigated whether these patterns vary by nativity status among Hispanic subgroups. METHODS AND RESULTS: We used the National Center for Health Statistics mortality file to compare deaths of Hispanic (n=1 258 229) and non-Hispanic white (n=18 149 774) adults (aged >=25 years) from 2003 to 2012. We identified all deaths related to cardiovascular disease (CVD) and categorized them by subtype (all CVD, ischemic, or cerebrovascular) using the underlying cause of death (International Classification of Diseases, 10th Revision codes I00-I78, I20-I25, and I60-I69, respectively). Population estimates were calculated using linear interpolation from the 2000 and 2010 US censuses. CVD accounted for 31% of all deaths among Hispanic adults. Race/ethnicity and nativity status were recorded on death certificates by the funeral director using state guidelines. Nativity status was defined as foreign versus US born; 58% of Hispanic decedents were foreign born. Overall, Hispanic adults had lower age-adjusted CVD mortality rates than non-Hispanic white adults (296 versus 385 per 100 000). Foreign-born Cubans, Mexicans, and Puerto Ricans had higher CVD mortality than their US-born counterparts (rate ratio: 2.64 [95% confidence interval, 2.46-2.81], 1.17 [95% confidence interval, 1.15-1.21], and 1.91 [95% confidence interval, 1.83-1.99], respectively). CONCLUSIONS: Mortality rates for total cardiovascular, ischemic, and cerebrovascular disease are higher among foreign- than US-born Hispanic adults. These findings suggest the importance of disaggregating CVD mortality by disease subtype, Hispanic subgroup, and nativity status. PMID- 29237592 TI - Hepatic Smad7 overexpression causes severe iron overload in mice. PMID- 29237593 TI - Identification of novel recurrent STAT3-RARA fusions in acute promyelocytic leukemia lacking t(15;17)(q22;q12)/PML-RARA. PMID- 29237595 TI - Hope is a therapeutic tool. PMID- 29237594 TI - Structure-function analysis of ferroportin defines the binding site and an alternative mechanism of action of hepcidin. AB - Nonclassical ferroportin disease (FD) is a form of hereditary hemochromatosis caused by mutations in the iron transporter ferroportin (Fpn), resulting in parenchymal iron overload. Fpn is regulated by the hormone hepcidin, which induces Fpn endocytosis and cellular iron retention. We characterized 11 clinically relevant and 5 nonclinical Fpn mutations using stably transfected, inducible isogenic cell lines. All clinical mutants were functionally resistant to hepcidin as a consequence of either impaired hepcidin binding or impaired hepcidin-dependent ubiquitination despite intact hepcidin binding. Mapping the residues onto 2 computational models of the human Fpn structure indicated that (1) mutations that caused ubiquitination-resistance were positioned at helix helix interfaces, likely preventing the hepcidin-induced conformational change, (2) hepcidin binding occurred within the central cavity of Fpn, (3) hepcidin interacted with up to 4 helices, and (4) hepcidin binding should occlude Fpn and interfere with iron export independently of endocytosis. We experimentally confirmed hepcidin-mediated occlusion of Fpn in the absence of endocytosis in multiple cellular systems: HEK293 cells expressing an endocytosis-defective Fpn mutant (K8R), Xenopus oocytes expressing wild-type or K8R Fpn, and mature human red blood cells. We conclude that nonclassical FD is caused by Fpn mutations that decrease hepcidin binding or hinder conformational changes required for ubiquitination and endocytosis of Fpn. The newly documented ability of hepcidin and its agonists to occlude iron transport may facilitate the development of broadly effective treatments for hereditary iron overload disorders. PMID- 29237596 TI - EU governments step up efforts against alcohol misuse. PMID- 29237597 TI - Know-do-itis and no-do encephalopathy. PMID- 29237598 TI - Extra cash for child mental health is being diverted, report warns. PMID- 29237599 TI - Rules on reporting trials must be better enforced, say health integrity groups. PMID- 29237600 TI - Santa's little helpers: a novel approach to developing patient information leaflets. PMID- 29237602 TI - Non-existent authors. PMID- 29237603 TI - In bed with Siri and Google Assistant: a comparison of sexual health advice. PMID- 29237604 TI - Stormy weather: a retrospective analysis of demand for emergency medical services during epidemic thunderstorm asthma. AB - OBJECTIVES: To describe the demand for emergency medical assistance during the largest outbreak of thunderstorm asthma reported globally, which occurred on 21 November 2016. DESIGN: A time series analysis was conducted of emergency medical service caseload between 1 January 2015 and 31 December 2016. Demand during the thunderstorm asthma event was compared to historical trends for the overall population and across specific subgroups. SETTING: Victoria, Australia. MAIN OUTCOME MEASURES: Number of overall cases attended by emergency medical services, and within patient subgroups. RESULTS: On 21 November 2016, the emergency medical service received calls for 2954 cases, which was 1014 more cases than the average over the historical period. Between 6 pm and midnight, calls for 1326 cases were received, which was 2.5 times higher than expected. A total of 332 patients were assessed by paramedics as having acute respiratory distress on 21 November, compared with a daily average of 52 during the historical period. After adjustment for temporal trends, thunderstorm asthma was associated with a 42% (95% confidence interval 40% to 44%) increase in overall caseload for the emergency medical service and a 432% increase in emergency medical attendances for acute respiratory distress symptoms. Emergency transports to hospital increased by 17% (16% to 19%) and time critical referrals from general practitioners increased by 47% (21% to 80%). Large increases in demand were seen among patients with a history of asthma and bronchodilator use. The incidence of out-of-hospital cardiac arrest increased by 82% (67% to 99%) and pre-hospital deaths by 41% (29% to 55%). CONCLUSIONS: An unprecedented outbreak of thunderstorm asthma was associated with substantial increase in demand for emergency medical services and pre-hospital cardiac arrest. The health impact of future events may be minimised through use of preventive measures by patients and predictive early warning systems. PMID- 29237606 TI - 10 Minute consultation: Mastering management language syndrome. PMID- 29237605 TI - Association between rainfall and diagnoses of joint or back pain: retrospective claims analysis. AB - OBJECTIVE: To study the relation between rainfall and outpatient visits for joint or back pain in a large patient population. DESIGN: Observational study. SETTING: US Medicare insurance claims data linked to rainfall data from US weather stations. PARTICIPANTS: 1 552 842 adults aged >=65 years attending a total of 11 673 392 outpatient visits with a general internist during 2008-12. MAIN OUTCOME MEASURES: The proportion of outpatient visits for joint or back pain related conditions (rheumatoid arthritis, osteoarthritis, spondylosis, intervertebral disc disorders, and other non-traumatic joint disorders) was compared between rainy days and non-rainy days, adjusting for patient characteristics, chronic conditions, and geographic fixed effects (thereby comparing rates of joint or back pain related outpatient visits on rainy days versus non-rainy days within the same area). RESULTS: Of the 11 673 392 outpatient visits by Medicare beneficiaries, 2 095 761 (18.0%) occurred on rainy days. In unadjusted and adjusted analyses, the difference in the proportion of patients with joint or back pain between rainy days and non-rainy days was significant (unadjusted, 6.23% v 6.42% of visits, P<0.001; adjusted, 6.35% v 6.39%, P=0.05), but the difference was in the opposite anticipated direction and was so small that it is unlikely to be clinically meaningful. No statistically significant relation was found between the proportion of claims for joint or back pain and the number of rainy days in the week of the outpatient visit. No relation was found among a subgroup of patients with rheumatoid arthritis. CONCLUSION: In a large analysis of older Americans insured by Medicare, no relation was found between rainfall and outpatient visits for joint or back pain. A relation may still exist, and therefore larger, more detailed data on disease severity and pain would be useful to support the validity of this commonly held belief. PMID- 29237608 TI - Significance of Inducible Nonsustained Ventricular Tachycardias After Catheter Ablation for Ventricular Tachycardia in Ischemic Cardiomyopathy. AB - BACKGROUND: Noninducibility of sustained monomorphic ventricular tachycardia (SMVT) postablation does not insure absence of later recurrence in patients with ischemic cardiomyopathy. This study aims to determine the relation between inducible nonsustained VT postablation and VT recurrences. METHODS AND RESULTS: One hundred sixty-five consecutive patients (156 male; age 68+/-9 years) underwent ablation for SMVT because of ischemic cardiomyopathy; 44 patients who did not have induction testing or in whom only ventricular fibrillation was induced after ablation were excluded. In 38 patients (23%), SMVT was inducible (group C). Of the 83 patients without inducible SMVT after ablation, nonsustained VT defined as >=5 beats lasting for <30 s, was induced in 34 patients (group B, 21%), whereas the remaining 49 patients had no VT induced by the induction test (group A, 30%). Over a median follow-up of 18.7 months, freedom from recurrent VT at 24 months was 60% in group A, 45% in group B (P=0.017 versus group A), and 38% in group C (P=0.005 versus group A). In patients without inducible SMVT, inducible nonsustained VT and left ventricular ejection fraction was independently associated with VT recurrence (hazard ratio, 3.66 and 1.07; 95% CI, 1.3-11.1 and 1.01-1.14). CONCLUSIONS: Inducible nonsustained VT postablation suggests the continued presence of functional arrhythmia substrate. Further trials are needed to assess whether additional ablation would improve outcome in this group. PMID- 29237610 TI - Cardiac Magnetic Resonance in Sudden Cardiac Arrest Survivors. PMID- 29237609 TI - Diagnosis and Prognosis in Sudden Cardiac Arrest Survivors Without Coronary Artery Disease: Utility of a Clinical Approach Using Cardiac Magnetic Resonance Imaging. AB - BACKGROUND: Determining the pathogenesis of sudden cardiac arrest or periarrest without significant coronary artery disease is crucial for management and prognosis. Cardiovascular magnetic resonance (CMR) can detect morphological, functional, or tissue abnormalities, and we sought to evaluate the role of CMR in determining sudden cardiac arrest pathogenesis and prognosis in survivors. METHODS AND RESULTS: We retrospectively reviewed cardiac investigations and clinical outcomes in consecutive survivors of potentially fatal arrhythmias without coronary artery disease admitted to our institutions from 2008 to 2014. After coronary angiography and echocardiography, all underwent CMR and, when indicated, electrophysiology studies. Major adverse cardiac events (MACE), comprising significant nonfatal ventricular arrhythmia or death, was the primary outcome. Of 164 included subjects (65% men; mean age 48 [18-80] years), CMR contributed to the diagnosis in 80 (49%) and was decisive in 50 cases (30%). Dilated cardiomyopathy (n=27), myocarditis or sarcoidosis (n=22), occult myocardial infarction (n=13), and hypertrophic cardiomyopathy (n=9) were most frequent. Arrhythmic causes were found in 14% while no cause was identified in 36%. MACE occurred in 31% of subjects during a median follow-up of 32 months. MACE associated with presence of a CMR diagnosis, extent of late gadolinium enhancement, and left and right ventricular ejection fractions. Right ventricular ejection fraction was an independent predictor of MACE. CONCLUSIONS: CMR identified a likely pathogenesis for sudden cardiac arrest in nearly half of survivors in whom coronary artery disease had been excluded. One in 3 subjects had MACE; risk doubled in those with a CMR diagnosis and some CMR parameters-late gadolinium enhancement, left ventricular ejection fraction, and especially right ventricular ejection fraction-associated with prognosis. PMID- 29237607 TI - Associations of pet ownership with biomarkers of ageing: population based cohort study. AB - OBJECTIVE: To examine the prospective relation between animal companionship and biomarkers of ageing in older people. DESIGN: Analyses of data from the English Longitudinal Study of Ageing, an ongoing, open, prospective cohort study initiated in 2002-03. SETTING: Nationally representative study from England. PARTICIPANTS: 8785 adults (55% women) with a mean age of 67 years (SD 9) at pet ownership assessment in 2010-11 (wave 5). MAIN OUTCOME MEASURE: Established biomarkers of ageing in the domains of physical, immunological, and psychological function, as assessed in 2012-13 (wave 6). RESULTS: One third of study members reported pet ownership: 1619 (18%) owned a dog, 1077 (12%) a cat, and 274 (3%) another animal. After adjustment for a range of covariates, there was no evidence of a clear association of any type of pet ownership with walking speed, lung function, chair rise time, grip strength, leg raises, balance, three markers of systemic inflammation, memory, or depressive symptoms. CONCLUSION: In this population of older adults, the companionship of creatures great and small seems to essentially confer no relation with standard ageing phenotypes. PMID- 29237611 TI - Anti-PD-1 Therapy OK for Most with HIV. AB - The PD-1 inhibitor pembrolizumab poses no significant risks for patients with HIV and cancer, according to data presented at a recent meeting of the Society for Immunotherapy of Cancer. The findings suggest that patients with HIV should no longer be excluded from clinical trials testing checkpoint inhibitors and other novel therapies for cancer. PMID- 29237612 TI - CTCs May Predict Breast Cancer Recurrence. AB - Findings from a prospective study indicate that for patients diagnosed with ER positive, HER2-negative breast cancer, the presence of circulating tumor cells several years afterward considerably ups the risk-by nearly 22-fold-of their disease making a late reappearance. PMID- 29237613 TI - Doctors, dentists and children's teeth. PMID- 29237614 TI - Toxicity of long-term use of proton pump inhibitors in children. AB - Proton pump inhibitor (PPI) use is becoming increasingly common. Although the toxicity profiles of PPIs are not well understood particularly in children, PPIs have been associated with increased risks of gastrointestinal and respiratory tract infection, vitamin B12 deficiency, hypomagnesaemia, bone fractures, and rebound hyperacidity after discontinuation. Prescribers should take into account that PPI uses pose toxicity risks, which remain to be fully characterised in infants and children. PMID- 29237615 TI - Towards evidence-based medicine for paediatricians. PMID- 29237617 TI - Bisphosphonates: a therapeutic option for knee osteoarthritis? PMID- 29237616 TI - Individual differences in normal body temperature: longitudinal big data analysis of patient records. AB - OBJECTIVE: To estimate individual level body temperature and to correlate it with other measures of physiology and health. DESIGN: Observational cohort study. SETTING: Outpatient clinics of a large academic hospital, 2009-14. PARTICIPANTS: 35 488 patients who neither received a diagnosis for infections nor were prescribed antibiotics, in whom temperature was expected to be within normal limits. MAIN OUTCOME MEASURES: Baseline temperatures at individual level, estimated using random effects regression and controlling for ambient conditions at the time of measurement, body site, and time factors. Baseline temperatures were correlated with demographics, medical comorbidities, vital signs, and subsequent one year mortality. RESULTS: In a diverse cohort of 35 488 patients (mean age 52.9 years, 64% women, 41% non-white race) with 243 506 temperature measurements, mean temperature was 36.6 degrees C (95% range 35.7-37.3 degrees C, 99% range 35.3-37.7 degrees C). Several demographic factors were linked to individual level temperature, with older people the coolest (-0.021 degrees C for every decade, P<0.001) and African-American women the hottest (versus white men: 0.052 degrees C, P<0.001). Several comorbidities were linked to lower temperature (eg, hypothyroidism: -0.013 degrees C, P=0.01) or higher temperature (eg, cancer: 0.020, P<0.001), as were physiological measurements (eg, body mass index: 0.002 per m/kg2, P<0.001). Overall, measured factors collectively explained only 8.2% of individual temperature variation. Despite this, unexplained temperature variation was a significant predictor of subsequent mortality: controlling for all measured factors, an increase of 0.149 degrees C (1 SD of individual temperature in the data) was linked to 8.4% higher one year mortality (P=0.014). CONCLUSIONS: Individuals' baseline temperatures showed meaningful variation that was not due solely to measurement error or environmental factors. Baseline temperatures correlated with demographics, comorbid conditions, and physiology, but these factors explained only a small part of individual temperature variation. Unexplained variation in baseline temperature, however, strongly predicted mortality. PMID- 29237618 TI - Efficacy and safety of adrenocorticotropic hormone gel in refractory dermatomyositis and polymyositis. AB - AIM: To evaluate the efficacy, safety, tolerability and steroid-sparing effect of repository corticotropin injection (RCI), in an open-label clinical trial, in refractory adult polymyositis (PM) and dermatomyositis (DM). METHODS: Adults with refractory PM and DM were enrolled by two centres. Inclusion criteria included refractory disease defined as failing glucocorticoid and/or >=1 immunosuppressive agent, as well as active disease defined as significant muscle weakness and >2 additional abnormal core set measures (CSMs) or a cutaneous 10 cm Visual Analogue Scale score of >=3 cm and at least three other abnormal CSMs. All patients received RCI of 80 units subcutaneously twice weekly for 24 weeks. The primary end point for the trial was the International Myositis Assessment and Clinical Studies definition of improvement. Secondary end points included safety, tolerability, steroid-sparing as well as the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism myositis response criteria (EULAR) RESULTS: Ten of the 11 enrolled subjects (6 DM, 4 PM) completed the study. Seven of 10 met the primary end point of efficacy at a median of 8 weeks. There was a significant decrease in prednisone dose from baseline to conclusion (18.5 (15.7) vs 2.3 (3.2); P<0.01). Most individual CSMs improved at week 24 compared with the baseline, with the muscle strength improving by >10% and the physician global by >40%. RCI was considered safe and tolerable. No patient developed significant weight gain or an increase of haemoglobin A1c or cushingoid features. CONCLUSION: Treatment with RCI was effective in 70% of patients, safe and tolerable, and led to a steroid dose reduction in patients with adult myositis refractory to glucocorticoid and traditional immunosuppressive drugs. TRIAL REGISTRATION NUMBER: NCT01906372; Results. PMID- 29237619 TI - Performance of the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies in clinical practice. PMID- 29237620 TI - Is the PET/CT first choice for differential diagnosis of fever of FUO/IUO? PMID- 29237621 TI - Patient characteristics influence the choice of biological drug in RA, and will make non-TNFi biologics appear more harmful than TNFi biologics. AB - OBJECTIVES: With the wide range of biological disease-modifying anti-rheumatic drugs (bDMARDs) available for treating rheumatoid arthritis (RA), and limited evidence to guide the choice for individual patients, we wished to evaluate whether patient characteristics influence the choice of bDMARD in clinical practice, and to quantify the extent to which this would bias direct comparisons of treatment outcome. METHODS: Register-based study of all Swedish patients with RA initiating necrosis factor inhibitor (TNFi), rituximab, abatacept or tocilizumab in 2011-2015 as their first bDMARD (n=6481), or after switch from TNFi as first bDMARD (n=2829). Group differences in demographics, clinical characteristics and medical history were assessed in multivariable regression models. Predicted differences in safety and treatment outcomes were calculated as a function of patient characteristics, through regression modelling based on observed outcomes among patients with RA starting bDMARDs 2006-2010. RESULTS: Patients starting non-TNFi were older than those starting TNFi, had lower socioeconomic status, higher disease activity and higher burden of diseases including malignancy, serious infections and diabetes. Differences were most pronounced at first bDMARD initiation. These factors were linked to treatment outcome independent of therapy, yielding worse apparent safety and effectiveness for non-TNFi biologics, most extreme for rituximab. Standardising to the age/sex distribution of the TNFi group reduced differences considerably. CONCLUSIONS: There was significant channelling of older and less healthy patients with RA to non-TNFi bDMARDs, in particular as first bDMARD. Whether this channelling represents a maximised benefit/risk ratio is unclear. Unless differences in age, medical history and disease activity are accounted for, they will substantially confound non-randomised comparative studies of available bDMARDs' safety and effectiveness. PMID- 29237623 TI - ? PMID- 29237622 TI - In winter. PMID- 29237624 TI - Acknowledging stigma: Its presence in patient care and medical education. PMID- 29237625 TI - Will people have personal physicians anymore? Dr Ian McWhinney Lecture, 2017. PMID- 29237626 TI - ? PMID- 29237627 TI - Recommending plant-based diets. PMID- 29237628 TI - Evidence for benefit of low-dose alcohol. PMID- 29237629 TI - Cyclical hypervirulent S aureus clones and community-acquired MRSA infection. PMID- 29237630 TI - Diagnosis and treatment of pruritus. AB - OBJECTIVE: To describe an approach that allows for a streamlined assessment and accurate differentiation of most patients with itch in primary care and to provide an update on the available nonpharmacologic, topical, and systemic therapies. SOURCES OF INFORMATION: MEDLINE (Ovid) and PubMed were searched for the key words itch or pruritus. Searches were refined for each cause and treatment by adding appropriate key words, and subsequent hand searches of the references of retrieved literature were performed. MAIN MESSAGE: A good body of evidence from high-quality trials does not exist for treatment of pruritus, and the treatments that do exist are inconsistent in their success. The dominant causes of generalized itch are xerosis and eczema. Most patients will improve with nonpharmacologic therapy including frequent moisturization. If this avenue fails, further investigations are warranted to help guide subsequent treatment with any of the many cause-specific topical and systemic approaches available. CONCLUSION: Chronic itch can be debilitating for patients. The approach described allows for a streamlined assessment and accurate differentiation of most patients with itch in primary care. PMID- 29237632 TI - Virtual reality for pain and anxiety management in children. AB - Question Pain and anxiety are common in children who need procedures such as administering vaccines or drawing blood. Recent reports have described the use of virtual reality (VR) as a method of distraction during such procedures. How does VR work in reducing pain and anxiety in pediatric patients and what are the potential uses for it? Answer Recent studies explored using VR with pediatric patients undergoing procedures ranging from vaccinations and intravenous injections to laceration repair and dressing changes for burn wounds. Interacting with immersive VR might divert attention, leading to a slower response to incoming pain signals. Preliminary results have shown that VR is effective, either alone or in combination with standard care, in reducing the pain and anxiety patients experience compared with standard care or other distraction methods. PMID- 29237631 TI - ? PMID- 29237633 TI - ? PMID- 29237634 TI - Phytophotodermatitis: Rash with many faces. PMID- 29237635 TI - New-onset Bell palsy and Lyme disease. PMID- 29237636 TI - What's in your stocking? Evidence around Santa Claus. PMID- 29237637 TI - Underuse of anticoagulation therapy for atrial fibrillation: Are we failing our patients? PMID- 29237639 TI - A complete recovery. PMID- 29237638 TI - ? PMID- 29237641 TI - The CFPC welcomes its 2017-2018 President, Dr Guillaume Charbonneau. PMID- 29237640 TI - Stories I learned from: What I didn't know about family practice in Canada (and what I suspect many Canadians don't know either). PMID- 29237642 TI - ? PMID- 29237643 TI - ? PMID- 29237644 TI - Being a good colleague. PMID- 29237645 TI - ? PMID- 29237646 TI - ? PMID- 29237647 TI - Family physician perceptions of a medication assessment clinic located within a pharmacy school. AB - OBJECTIVE: To determine if the clinical services provided at a patient care clinic run by pharmacy faculty and students are valuable to family physicians. DESIGN: Paper-based postal survey. SETTING: The Medication Assessment Centre located within the College of Pharmacy and Nutrition at the University of Saskatchewan in Saskatoon. PARTICIPANTS: Family physicians who had more than 1 patient who underwent a complete assessment at the Medication Assessment Centre between April 1 and October 26, 2015, were included in the study. MAIN OUTCOME MEASURES: Family physician experience and satisfaction based on quantitative analysis of 6 Likert scale survey questions and thematic analysis of 2 open-ended survey questions. RESULTS: A total of 81 questionnaires were mailed to family physicians, with a response rate of 43.2% (n = 35). Respondents reported a very high level of support and satisfaction with the clinical pharmacist program; most (88.6%) stated that it helped them to improve the health of their patients. CONCLUSION: The family physicians who responded to the questionnaire perceived the services provided at the patient care clinic located within the pharmacy school at the University of Saskatchewan to be valuable to their practices. PMID- 29237648 TI - Parasitic stool testing in newly arrived refugees in Calgary, Alta. AB - OBJECTIVE: To determine the prevalence of intestinal parasites and rates of stool testing compliance, as well as associated patient characteristics, among newly arrived refugees at the Mosaic Refugee Health Clinic in Calgary, Alta. DESIGN: Retrospective chart review. SETTING: Primary care clinic for refugee patients. PARTICIPANTS: A total of 1390 new refugee patients at the clinic from May 1, 2011, to June 30, 2013. MAIN OUTCOME MEASURES: Stool ova and parasite test completion and proportion of positive test results. RESULTS: Of 1390 patients, 74.1% (95% CI 71.7% to 76.4%) completed at least 1 stool ova and parasite test. Among those completing tests, 29.7% (95% CI 26.9% to 32.6%) had at least 1 positive result. Patients aged 6 to 18 years were more likely to have positive test results (38.5%, 95% CI 32.2% to 45.0%) than patients aged 19 to 39 were, as were those last residing in Asia (36.4%, 95% CI 30.4% to 42.8%) or sub-Saharan Africa (30.9%, 95% CI 26.8% to 35.1%), compared with those arriving from the Middle East. Giardia lamblia, Blastocystis hominis, Dientamoeba fragilis, and Entamoeba histolytica or Entamoeba dispar were the most prevalent parasites. If B hominis and D fragilis are excluded because of their lower potential to cause harm, the overall prevalence was 16.3%. CONCLUSION: Given the high compliance of patients submitting stool ova and parasite tests and a high prevalence of positive test results in some refugee groups, targeted screening should be considered in newly arrived refugees at greater risk of intestinal parasites. PMID- 29237649 TI - Canadian physicians' knowledge and counseling practices related to antibiotic use and antimicrobial resistance: Two-cycle national survey. AB - OBJECTIVE: To establish a baseline for physicians' knowledge of and counseling practices on the use of antibiotics and antimicrobial resistance (AMR), and to determine potential changes in these measures after the implementation of a national AMR awareness campaign. DESIGN: Cross-sectional design. SETTING: Canada. PARTICIPANTS: A total of 1600 physicians. MAIN OUTCOME MEASURES: Physicians' knowledge of and counseling practices on antibiotic use and AMR at baseline and after implementation of the AMR awareness campaign. RESULTS: A total of 336 physicians responded to the first-cycle survey (before the campaign), and 351 physicians responded to the second-cycle survey (after the campaign). Overall, physicians' knowledge of appropriate antibiotic use and AMR was high and their counseling practices in relation to antibiotics were appropriate in both surveys. Counseling levels about topics related to infection prevention and control (eg, food handling, household hygiene) were slightly lower. Counseling levels were also lower for certain antibiotic-use practices (eg, proper disposal of antibiotics). In addition, physicians with less than 10 years of practice experience had significantly lower odds of counseling their patients on topics related to preventing antibiotic resistance and infection prevention than those with 15 or more years of practice experience (adjusted odds ratio = 0.27, 95% CI 0.10 to 0.74). Significantly more physicians from the second-cycle survey counseled patients on the appropriate disposal of antibiotics (P = .03), as well as on some of the infection prevention topics (eg, using antibacterial hand soap [P = .02] and cleaning supplies [P = .01]). Most respondents in both surveys reported feeling confident with respect to counseling their patients on the appropriate use of antibiotics and AMR. CONCLUSION: Physicians' knowledge of and levels of counseling on the use of antibiotics and AMR were high and fairly stable in both survey results. This shows that Canadian physicians are demonstrating behaviour patterns of AMR stewardship. Existing gaps in counseling practices might be a result of physicians believing that pharmacists or nurses are addressing these issues with patients. Future national surveys conducted among pharmacists and nurses would contribute to the evidence base for AMR stewardship activities. PMID- 29237651 TI - ? PMID- 29237650 TI - Needs of cancer patients in palliative care during medical visits: Qualitative study. AB - OBJECTIVE: To explore the needs of cancer patients in palliative care and to determine how care providers, including family physicians, could meet these needs more fully. DESIGN: Qualitative study performed using semistructured interviews. SETTING: Palliative care departments (ambulatory and intrahospital). PARTICIPANTS: Twelve patients with a diagnosis of cancer deemed to be in the palliative phase, who had already received either chemotherapy or radiation treatment. METHODS: The interviews were recorded and transcribed. They were then coded and categorized to identify and define themes describing the participants' experience. Data were collected until new interviews no longer yielded new categories of results. MAIN FINDINGS: Study participants primarily needed the expertise of their physicians, but they also needed reassurance by means of clear information about their disease, its treatment, and the prognosis delivered over the course of patient-physician visits, and by means of various measures that could act as safety nets. Participants needed to be heard without being judged. In terms of follow-up care, the oncology nurse navigator was just as important as the physician and could stand in for him or her to meet most relational needs and share and explain information on the disease. CONCLUSION: Non-family physician specialists cannot meet all of the patients' complex needs; throughout the palliative phase, non-family physician specialists need the support of a family physician and an oncology nurse navigator. Each care provider must be made aware of the patient's needs and ensure that they are met, to the best of his or her ability. Failing to do so might exacerbate the loneliness and anxiety experienced by terminally ill patients. PMID- 29237652 TI - Evidence-based recommendations on care for breast cancer survivors for primary care providers: a review of evidence-based breast cancer guidelines. AB - OBJECTIVE: To review evidence-based (EB) recommendations on survivorship care for primary care providers (PCPs) in EB breast cancer guidelines. DESIGN AND SETTING: Guidelines were collected via experts and via literature database, guideline database and cancer agency websites searches. METHOD: EB guidelines in any language published between 2012 and 2017 were collected. EB recommendations on survivorship care relevant for PCPs were extracted and grouped into three categories (recurrence detection, long-term effects and recurrence prevention). The content of the recommendations was analysed and summarised in the number and type of clinical topics addressed. The Appraisal of Guidelines for Research and Evaluation II instrument was used to evaluate the methodological quality of the guidelines. RESULTS: Six guidelines, of which two were of acceptable methodological quality, were included. One was specifically made for general practitioners. Fifteen clinical topics were identified. Guidelines differed in the clinical topics addressed and for some identical topics in the content of the recommendations. Many recommendations were based on low-quality evidence. Recurrence detection received most attention, physical examination and mammography were often highlighted. Potential complications largely varied in number and type. Intimacy concerns, vaginal dryness, dyspareunia, fatigue, menopausal symptoms, peripheral neuropathy and lymphedema were reported in more than one guideline. Recurrence prevention was mentioned in four guidelines; all recommended physical activity. CONCLUSION: The number of EB recommendations in guidelines is limited. Moreover, recommendations differ between guidelines and most are based on low-quality evidence. More high-quality research is needed to develop and adapt guidelines to support PCPs in providing optimal breast cancer survivorship care. PMID- 29237653 TI - Do psychological harms result from being labelled with an unexpected diagnosis of abdominal aortic aneurysm or prostate cancer through screening? A systematic review. AB - OBJECTIVE: A potential psychological harm of screening is unexpected diagnosis labelling. We need to know the frequency and severity of this harm to make informed decisions about screening. We asked whether current evidence allows an estimate of any psychological harm of labelling. As case studies, we used two conditions for which screening is common: prostate cancer (PCa) and abdominal aortic aneurysm (AAA). DESIGN: Systematic review with narrative synthesis. DATA SOURCES AND ELIGIBILITY CRITERIA: We searched the English language literature in PubMed, PsychINFO and Cumulative Index of Nursing and Allied Health Literature (CINAHL) for research of any design published between 1 January 2002 and 23 January 2017 that provided valid data about the psychological state of people recently diagnosed with early stage PCa or AAA. Two authors independently used explicit criteria to review and critically appraise all studies for bias, applicability and the extent to which it provided evidence about the frequency and severity of harm from labelling. RESULTS: 35 quantitative studies (30 of PCa and 5 of AAA) met our criteria, 17 (48.6%) of which showed possible or definite psychological harm from labelling. None of these studies, however, had either appropriate measures or relevant comparisons to estimate the frequency and severity of psychological harm. Four PCa and three AAA qualitative studies all showed clear evidence of at least moderate psychological harm from labelling. Seven population-based studies found increased suicide in patients recently diagnosed with PCa. CONCLUSIONS: Although qualitative and population-based studies show that at least moderate psychological harm due to screening for PCa and AAA does occur, the current quantitative evidence is insufficient to allow a more precise estimation of frequency and severity. More sensitive measures and improved research designs are needed to fully characterise this harm. In the meantime, clinicians and recommendation panels should be aware of the occurrence of this harm. PMID- 29237654 TI - Investigating the effect of sociodemographic factors on 30-day hospital readmission among medical patients in Toronto, Canada: a prospective cohort study. AB - OBJECTIVE: To examine the influence of patient-level sociodemographic factors on the incidence of hospital readmission within 30 days among medical patients in a large Canadian metropolitan city. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: Patients admitted to the General Internal Medicine service of an urban teaching hospital in Toronto, Canada participated in a survey of sociodemographic information. Patients were not surveyed if deemed medically unstable, receiving care in medical/surgical step-down beds or were isolated for infection control. Included in the final analysis was a diverse cohort of 1427 adult, non-palliative, patients who were discharged home. MEASURES: Thirteen patient-level sociodemographic variables were examined in relation to time to unplanned all-cause readmission within 30 days. Illness level was accounted for by the following covariates: self-perceived health status, previous hospital utilisation, primary diagnosis case mix group, Charlson Comorbidity Index score and inpatient length of stay. RESULTS: Approximately, 14.4% (n=205) of patients experienced readmission within 30 days. Sociodemographic factors were not significantly associated with time to readmission in unadjusted and adjusted analyses. Indicators of illness level, namely, previous hospitalisations, were the strongest risk factors for readmission within this cohort. One previous admission (adjusted HR 1.78; 95% CI 1.22 to 2.59, P<0.01) and at least four previous emergency department visits (adjusted HR 2.33; 95% CI 1.46 to 4.43, P<0.01) were associated with increased hazard of readmission within 30 days. CONCLUSIONS: Patient-level sociodemographic factors did not influence the incidence of unplanned all-cause readmission within 30 days. Further research is needed to understand the generalisability of our findings and investigate whether contextual factors, such as access to universal health insurance coverage, attenuate the effects of sociodemographic factors. PMID- 29237656 TI - Foot-strike haemolysis in an ultramarathon runner. AB - This case report describes mild anaemia and intravascular haemolysis in an otherwise healthy 41-year-old ultramarathon runner. In long-distance endurance athletes, trace gastrointestinal bleeding and plasma volume expansion are recognised sources of mild anaemia, often found incidentally. However, repetitive forceful foot striking can lead to blood cell lysis in the feet, resulting in a mild macrocytic anaemia and intravascular haemolysis, as was demonstrated in the patient described herein. Mild anaemia in runners, often called 'runner's pseudoanaemia', is typically clinically insignificant and does not require intervention. However, an unexplained anaemia can cause undue worry for otherwise healthy patients and lead to costly further testing, providing an argument against routine testing with complete blood counts in healthy, asymptomatic patients. PMID- 29237655 TI - EvaLuation Using Cardiac Insertable Devices And TelephonE in Hypertrophic Cardiomyopathy (ELUCIDATE HCM)-rationale and design: a prospective observational study on incidence of arrhythmias in Sweden. AB - INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease associated with sudden cardiac death (SCD) mainly due to ventricular tachycardia (VT) or fibrillation even though life-threatening bradycardia occurs. Risk stratification takes several variables into consideration including non-sustained VT (NSVT). An implantable cardioverter defibrillator effectively prevents SCD.Atrial fibrillation (AF) is common among patients with HCM and warrants anticoagulation even without conventional risk factors according to European guidelines. Routinely, the evaluation of arrhythmias using a 48-hour ambulatory external monitor takes place every 6-24 months if patients do not report palpitations. The remaining time the potential burden arrhythmia is unknown. Therefore, the aim of the present study is to assess NSVT and AF incidence during 18 months by an insertable cardiac monitor (ICM). METHODS: Adult patients, aged 18-65 years, with a validated diagnosis of HCM are eligible for the study. The study sample is planned to include 30 patients. A Confirm Rx is implanted at the level of the fourth rib on the left side subcutaneously after local anaesthesia. The application for monitoring is installed in the patients' smartphone and symptoms registered by the patient activation and VT detection programmed as 160 bpm during >=8 intervals. An AF episode is recorded based on >=2 min duration. Bradycardia is recorded at <=40 bpm or pause >=3.0 s. The patients are followed during 18 months before explant. ETHICS AND DISSEMINATION: The study was approved by The Regional Ethical Committee in Umea (protocol number 2017/13-31). The study protocol, including variables and prespecified research questions, the study was registered at Clinical Trial Registration NCT03259113. Each patient is informed about the study in both oral and written form by a physician and included after written consent. PMID- 29237657 TI - Rare side effect of adjuvant ipilimumab after surgical resection of melanoma: Guillain-Barre syndrome. AB - Guillain-Barre syndrome is a life-threatening neurological disorder that presents with rapid ascending paralysis and areflexia. Guillain-Barre syndrome is traditionally associated with infections from a gastrointestinal or respiratory tract source. We report the case of a 71-year-old man with melanoma who was treated with ipilimumab as adjuvant immunotherapy and subsequently developed Guillain-Barre syndrome. The diagnosis was made clinically through physical exam findings. He was successfully treated with a combination of intravenous immunoglobulin therapy and corticosteroids. PMID- 29237658 TI - Emergency salpingectomy for ruptured ectopic pregnancy in patient with Melnick Needles syndrome: a rare otopalatodigital syndrome. AB - Melnick-Needles syndrome (M-NS) is a rare genetic disorder which primarily affects skeletal developments. M-NS may also affect the cardiorespiratory and renal systems. A 35 kg patient presented complaining of abdominal pain. Following a positive pregnancy test and ultrasound examination, she was diagnosed with a ruptured ectopic pregnancy. She had a significant background history of M-NS, obstructive sleep apnoea (with narrow gauge tracheostomy in situ), obstructive lung disease and scoliosis. She received fluid resuscitation, and the case was managed using an open salpingectomy and clot evacuation under combined spinal/epidural anaesthesia. Anticipated difficulty in securing a definitive airway was pivotal to choosing a regional anaesthetic technique. The operation was successful and the patient recovered well. This was a unique surgical and anaesthetic challenge due to abnormal facial, spinal and abdominal morphology compounded by the time-critical emergency nature of the case. Individually tailored perioperative management is frequently required for patients with rare syndromes. PMID- 29237659 TI - Long-term follow-up of hepatitis-associated aplastic anaemia. AB - Prognosis of hepatitis-associated aplastic anaemia (HAAA) was improved with haematopoietic stem cell transplantation (HSCT) and immunosuppression, but the long-term outcome remains undefined. Case 1: a girl aged 3 years with acute liver failure (ALF) submitted to orthotopic liver transplantation (OLT) subsequently developed aplastic anaemia and HSCT from a compatible sibling was performed. Post HSCT, the patient developed post-transplant lymphoproliferative disorder and rituximab was administered with good response. Fifteen years later, both grafts show good outcome. Case 2: a girl aged 10 years submitted to OLT due to ALF, developed pancytopenia 2 months later. Due to the absence of a human leucocyte antigen compatible donor, she was treated with ciclosporin and antithymocyte globulin with very good long-term outcome. These clinical cases suggest that, for patients with HAAA that underwent OLT, aggressive therapy with HSCT or immunosuppression may provide a benign long-term outcome. PMID- 29237660 TI - Disseminated coccidioidomycosis-related cervical intramedullary lesion causing quadriplegia in an immunocompetent host. PMID- 29237661 TI - Exophytic cystic liver lesion: an unusual presentation of a hepatocellular carcinoma in a young female. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant primary liver tumours. However, primary hepatic carcinomas are rare in young adults, accounting for approximately 1% of tumours in people below the age of 20. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are the two most important aetiological agents of HCC. The average age at onset of HBV-related HCC (~50 years old) is 10 years younger than that of HCV-related HCC (61-64 years). Evidence for an association between the oral contraceptive pill (OCP) and development of HCC remains inconclusive. Here, we describe a case of a 28-year old woman with normal background liver, who presented with a large palpable abdominal mass due to a bilobar, exophytic, cystic lesion arising from the right lobe of the liver, later diagnosed as HCC on histological analysis. We highlight the need for considering HCC even in the unusual setting of a cystic, exophytic lesion. PMID- 29237662 TI - Advanced abdominal pregnancy in a spontaneous heterotopic pregnancy. AB - Spontaneous heterotopic pregnancy is a potentially life-threatening condition rarely considered when a patient with an intrauterine pregnancy is asymptomatic or presents with complaints such as abdominal pain. An advanced abdominal pregnancy as the form of the ectopic component, outside the context of assisted reproduction, is an even more unusual and perilous diagnosis with very few cases reported in the literature. We report such a case in a 34-year-old multipara, with no known risk factors for ectopic pregnancy. The pregnancy was initially misdiagnosed and managed as a dichorionic gestation, complicated with fetal demise of one of the twins. The correct diagnosis was only made after term delivery of the intrauterine pregnancy. The abdominal pregnancy was subsequently managed via laparotomy with no complications. PMID- 29237663 TI - Progressive myoclonic epilepsy and horizontal gaze palsy: a rare aetiology. AB - Gaucher's disease is a rare autosomal recessive, potentially fatal disorder but most common type among lysosomal storage disorders. The disease's incidence is around 1/40 000 to 1/60 000 births in the general population. A 32-year-old man, born out of non-consanguineous union, presented with generalised tonic-clonic seizures and myoclonus since 17 years of age. Seizures were noted to be resistant to multiple epileptic drugs. He developed gait imbalance, intentional tremor and dysarthria. Detailed examination revealed hepatosplenomegaly, bilateral pancerebellar signs with normal power, reflexes and sensory system. He had major cognitive impairment with impaired frontal and temporal lobar functions. Bone marrow evaluation revealed Gaucher cells, confirming the diagnosis. PMID- 29237664 TI - Giant retrocardiac foregut duplication cyst presenting with left atrial compression and palpitations. AB - A 35-year-old man presented with a 3-month history of palpitations and shortness of breath. An ECG showed premature atrial contractions and episodes of supraventricular tachycardia. A subsequent echocardiogram showed a retrocardiac cystic mass that was compressing the left atrium. A CT scan confirmed these findings by showing a large left-sided posterior mediastinal cyst compressing the left atrium and pulmonary veins. The cyst was successfully excised from the retrocardiac position via left thoracotomy after which there was complete resolution of the palpitations. Histopathology showed it to be a mediastinal cyst, most likely a foregut duplication of the enterogenic variant. This is an extremely unusual case of foregut duplication cyst presenting with compression of the left atrium and pulmonary veins leading to atrial arrhythmias. PMID- 29237665 TI - Intermittent catatonia and complex automatisms caused by frontal lobe epilepsy in dementia. AB - An 82-year-old man was admitted to the emergency department following bizarre behaviour. Police had noticed him driving erratically through his village. He did not stop when instructed, drove slowly home and appeared 'vacant' on questioning. While in hospital, he had approximately 15 episodes of catatonia, involving rigidity, negativism, mutism except echolalia and perseveration, automatic obedience and utilisation phenomena, lasting 2-20 min each. Between episodes, he was amnestic but otherwise well. Electroencephalography demonstrated bifrontal slowing with left-sided emphasis, and captured two focal onset partial seizures with the clinical correlate of the syndrome described above. He improved rapidly on levetiracetam and lorazepam, was discharged and received a diagnosis of dementia by his community mental health team shortly afterwards, based on chronic short-term memory loss, functional decline and MRI changes. This case has implications for our understanding of the neural correlate of catatonia, specifically frontal lobe pathway dysfunction. PMID- 29237666 TI - Spigelian hernia and pitfalls of postoperative anticoagulation. AB - Spigelian hernias are a rare lateral ventral abdominal hernia that carry a high risk of strangulation due to their smaller sizes, and require surgical intervention. In more complex cases involving an anticoagulated patient, perioperative management of anticoagulation must be monitored and reviewed to avoid potential pitfalls. We present an 81-year-old woman who presented with right groin pain, and was requiring warfarin anticoagulation due to her cardiac history. The spigelian hernia was diagnosed and reduced laparoscopically, and the defect was repaired and reinforced by mesh. However, the patient suffered from catastrophic complications postoperatively related to her anticoagulation management. Spigelian hernias require surgical interventions. However, in an anticoagulated patient with significant comorbidities, perioperative anticoagulation needs to be closely monitored to balance the risk of thromboembolic disease with acceptable postoperative bleeding risks. PMID- 29237667 TI - Posterior capsular rupture and spontaneous posterior dislocation of lens following electrical injury. AB - Lenticular changes are often seen following electrical injury. We report an unusual case of electrical injury with late spontaneous posterior dislocation of lens nucleus with intact anterior capsule with ruptured posterior capsule in the right eye and anterior subcapsular cataract in the left eye. The right eye was managed with pars plana vitrectomy with cortical matter removal with multipiece intraocular lens insertion in ciliary sulcus. This report adds posterior capsular rupture and posterior dislocation of lens to the usual ocular complications of electrical injury. PMID- 29237668 TI - Left-sided sinistroposition of the gall bladder: incidental presentation during elective cholecystectomy. AB - A 59-year-old male patient presented with mild gallstone pancreatitis. He underwent laparoscopic cholecystectomy during the same admission, where we encountered a left-sided gall bladder (GB). This was managed during laparoscopic surgery by modifying the laparoscopic port positions, and we did not encounter any other variations in the biliary anatomy. Thorough knowledge regarding anatomical variations of the GB will help in managing rare cases and avoid injuries to vital structures. PMID- 29237669 TI - A play that went wrong: Unique presentation of bowel perforation from an unusually large per-rectal foreign body. AB - Colorectal foreign bodies (FBs) are not unheard of in the province of surgery. They are commonly seen in men ranging from 20 to 90 years of age with a bimodal age distribution. A variety of objects have been described and reported in literature. Management involves a complete history and examination followed by the necessary investigations. Most of the time they can be removed at bedside with some manipulation techniques employing the use of some ingenious devices and/or endoscopy for adamant objects. But persistent FBs or those that are high in the rectum or those that present with complications will require operative management. We present a case of a 77 cm long FB inserted rectally for sexual gratification in a male patient, which caused a large bowel perforation, ending high intra-abdominally at the level of the spleen and diaphragm after traversing the entire abdominal cavity and requiring a laparotomy for removal. PMID- 29237670 TI - Spontaneous retrobulbar haemorrhage in idiopathic thrombocytopenic purpura. PMID- 29237671 TI - Painless aortic dissection presenting with multisystem organ failure and owl's eyes sign of the spinal cord. PMID- 29237672 TI - Dysphagia caused by an inverted papilloma. PMID- 29237673 TI - Mycotic pulmonary artery aneurysm secondary to septic emboli. PMID- 29237674 TI - Tension pneumothorax and diffuse subcutaneous emphysema as a complication of cardiopulmonary resuscitation. PMID- 29237675 TI - Gene-Based Risk Stratification for Cardiac Disorders in LMNA Mutation Carriers. AB - BACKGROUND: Mutations in LMNA (lamin A/C), which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance, atrial fibrillation, and malignant ventricular arrhythmias. Although the type of LMNA mutations have been reported to be associated with susceptibility to malignant ventricular arrhythmias, the gene based risk stratification for cardiac complications remains unexplored. METHODS AND RESULTS: The multicenter cohort included 77 LMNA mutation carriers from 45 families; cardiac disorders were retrospectively analyzed. The mean age of patients when they underwent genetic testing was 45+/-17, and they were followed for a median 49 months. Of the 77 carriers, 71 (92%) were phenotypically affected and showed cardiac conduction disturbance (81%), low left ventricular ejection fraction (<50%; 45%), atrial arrhythmias (58%), and malignant ventricular arrhythmias (26%). During the follow-up period, 9 (12%) died, either from end stage heart failure (n=7) or suddenly (n=2). Genetic analysis showed truncation mutations in 58 patients from 31 families and missense mutations in 19 patients from 14 families. The onset of cardiac disorders indicated that subjects with truncation mutations had an earlier occurrence of cardiac conduction disturbance and low left ventricular ejection fraction, than those with missense mutations. In addition, the truncation mutation was found to be a risk factor for the early onset of cardiac conduction disturbance and the occurrence of atrial arrhythmias and low left ventricular ejection fraction, as estimated using multivariable analyses. CONCLUSIONS: The truncation mutations were associated with manifestation of cardiac phenotypes in LMNA-related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification. PMID- 29237676 TI - Familial Ebstein Anomaly: Whole Exome Sequencing Identifies Novel Phenotype Associated With FLNA. AB - BACKGROUND: Familial Ebstein anomaly is a rare form of congenital heart disease. We report 7 individuals among 2 generations of 1 family with Ebstein anomaly. This family was first reported in 1991 by Balaji et al in which family members were also reported to have a mild skeletal phenotype. The most likely mechanism of inheritance was concluded to be autosomal dominant. We sought to identify the genetic pathogenesis in this family using a next generation sequencing approach. METHODS AND RESULTS: Whole exome sequencing was performed in 2 cousins in this family using the Agilent SureSelect Human all Exon 51 Mb version 5 capture kit. Data were processed through an analytic in-house pipeline. Whole exome sequencing identified a missense mutation in FLNA (Filamin A), an actin-binding protein located at Xq28, mutations in which are associated with the skeletal phenotypes Frontometaphyseal dysplasia, Otopalatodigital, and Melnick-Needles syndrome, with X-linked periventricular nodular heterotopia and FG syndrome (Omim, 305450). Review of the phenotypes of those with the mutation in this family shows increased severity of the cardiac phenotype and associated skeletal features in affected males, consistent with X-linked inheritance. CONCLUSIONS: Although congenital heart disease is reported in families with mutations in FLNA, this is the first report of individuals being affected by Ebstein anomaly because of a mutation in this gene and details the concurrent skeletal phenotype observed in this family. PMID- 29237678 TI - MYH7 Rare Variant in a Family With Double-Chambered Left Ventricle. PMID- 29237677 TI - Genome-Wide Association Study Implicates Atrial Natriuretic Peptide Rather Than B Type Natriuretic Peptide in the Regulation of Blood Pressure in the General Population. AB - BACKGROUND: Cardiomyocytes secrete atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in response to mechanical stretching, making them useful clinical biomarkers of cardiac stress. Both human and animal studies indicate a role for ANP as a regulator of blood pressure with conflicting results for BNP. METHODS AND RESULTS: We used genome-wide association analysis (n=6296) to study the effects of genetic variants on circulating natriuretic peptide concentrations and compared the impact of natriuretic peptide-associated genetic variants on blood pressure (n=27 059). Eight independent genetic variants in 2 known (NPPA-NPPB and POC1B-GALNT4) and 1 novel locus (PPP3CC) associated with midregional proANP (MR-proANP), BNP, aminoterminal proBNP (NT-proBNP), or BNP:NT proBNP ratio. The NPPA-NPPB locus containing the adjacent genes encoding ANP and BNP harbored 4 independent cis variants with effects specific to either midregional proANP or BNP and a rare missense single nucleotide polymorphism in NT-proBNP seriously altering its measurement. Variants near the calcineurin catalytic subunit gamma gene PPP3CC and the polypeptide N acetylgalactosaminyltransferase 4 gene GALNT4 associated with BNP:NT-proBNP ratio but not with BNP or midregional proANP, suggesting effects on the post translational regulation of proBNP. Out of the 8 individual variants, only those correlated with midregional proANP had a statistically significant albeit weak impact on blood pressure. The combined effect of these 3 single nucleotide polymorphisms also associated with hypertension risk (P=8.2*10-4). CONCLUSIONS: Common genetic differences affecting the circulating concentration of ANP associated with blood pressure, whereas those affecting BNP did not, highlighting the blood pressure-lowering effect of ANP in the general population. PMID- 29237679 TI - Statin Effects on Metabolic Profiles: Data From the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial). AB - BACKGROUND: Statins lower cholesterol by inhibiting HMG-CoA reductase, the rate limiting enzyme of the metabolic pathway that produces cholesterol and other isoprenoids. Little is known about their effects on metabolite and lipoprotein subclass profiles. We, therefore, investigated the molecular changes associated with pravastatin treatment compared with placebo administration using a nuclear magnetic resonance-based metabolomics platform. METHODS AND RESULTS: We performed metabolic profiling of 231 lipoprotein and metabolite measures in the PREVEND IT (Prevention of Renal and Vascular End-stage Disease Intervention Trial) study, a placebo-controlled randomized clinical trial designed to test the effects of pravastatin (40 mg once daily) on cardiovascular risk. Metabolic profiles were assessed at baseline and after 3 months of treatment. Pravastatin lowered low density lipoprotein cholesterol (change in SD units [95% confidence interval]: 1.01 [-1.14, -0.88]), remnant cholesterol (change in SD units [95% confidence interval]: -1.03 [-1.17, -0.89]), and apolipoprotein B (change in SD units [95% confidence interval]: -0.98 [-1.11, -0.86]) with similar effect magnitudes. In addition, pravastatin globally lowered levels of lipoprotein subclasses, with the exception of high-density lipoprotein subclasses, which displayed a more heterogeneous response pattern. The lipid-lowering effect of pravastatin was accompanied by selective changes in lipid composition, particularly in the cholesterol content of very-low-density lipoproteinparticles. In addition, pravastatin reduced levels of several fatty acids but had limited effects on fatty acid ratios. CONCLUSIONS: These randomized clinical trial data demonstrate the widespread effects of pravastatin treatment on lipoprotein subclass profiles and fatty acids. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03073018. PMID- 29237680 TI - Personalized Anticoagulation: Optimizing Warfarin Management Using Genetics and Simulated Clinical Trials. AB - BACKGROUND: Clinical trials testing pharmacogenomic-guided warfarin dosing for patients with atrial fibrillation have demonstrated conflicting results. Non vitamin K antagonist oral anticoagulants are expensive and contraindicated for several conditions. A strategy optimizing anticoagulant selection remains an unmet clinical need. METHODS AND RESULTS: Characteristics from 14 206 patients with atrial fibrillation were integrated into a validated warfarin clinical trial simulation framework using iterative Bayesian network modeling and a pharmacokinetic-pharmacodynamic model. Individual dose-response for patients was simulated for 5 warfarin protocols-a fixed-dose protocol, a clinically guided protocol, and 3 increasingly complex pharmacogenomic-guided protocols. For each protocol, a complexity score was calculated using the variables predicting warfarin dose and the number of predefined international normalized ratio (INR) thresholds for each adjusted dose. Study outcomes included optimal time in therapeutic range >=65% and clinical events. A combination of age and genotype identified different optimal protocols for various subpopulations. A fixed-dose protocol provided well-controlled INR only in normal responders >=65, whereas for normal responders <65 years old, a clinically guided protocol was necessary to achieve well-controlled INR. Sensitive responders >=65 and <65 and highly sensitive responders >=65 years old required pharmacogenomic-guided protocols to achieve well-controlled INR. However, highly sensitive responders <65 years old did not achieve well-controlled INR and had higher associated clinical events rates than other subpopulations. CONCLUSIONS: Under the assumptions of this simulation, patients with atrial fibrillation can be triaged to an optimal warfarin therapy protocol by age and genotype. Clinicians should consider alternative anticoagulation therapy for patients with suboptimal outcomes under any warfarin protocol. PMID- 29237681 TI - Plasma Proteomics for Epidemiology: Increasing Throughput With Standard-Flow Rates. AB - BACKGROUND: Mass spectrometry is selective and sensitive, permitting routine quantification of multiple plasma proteins. However, commonly used nanoflow liquid chromatography (LC) approaches hamper sample throughput, reproducibility, and robustness. For this reason, most publications using plasma proteomics to date are small in study size. METHODS AND RESULTS: Here, we tested a standard flow LC mass spectrometry (MS) method using multiple reaction monitoring for the application to large epidemiological cohorts. We have reduced the LC-MS run time to almost a third of the nanoflow LC-MS approach. On the basis of a comparison of the quantification of 100 plasma proteins in >1500 LC-MS runs, the SD range of the retention time during continuous operation was substantially lower with the standard-flow LC-MS (<0.05 minutes) compared with the nanoflow LC-MS method (0.26 0.44 minutes). In addition, the standard-flow LC method also offered less variation in protein measurements. However, 5* more sample volume was required to achieve similar sensitivity. Two different commercial multiple reaction monitoring kits and an antibody-based multiplexing kit were used to compare the apolipoprotein measurements in a subset of samples. In general, good agreement was observed between the 2 multiple reaction monitoring kits, but some of the multiple reaction monitoring-based measurements differed from antibody-based assays. CONCLUSIONS: The multiplexing capability of LC-MS combined with a standard-flow method increases throughput and reduces the costs of large-scale protein measurements in epidemiological cohorts, but protein rather than peptide standards will be required for defined absolute proteoform quantification. PMID- 29237682 TI - News From the Heart Natriuretic System. PMID- 29237683 TI - Pathogenicity of De Novo Rare Variants: Challenges and Opportunities. PMID- 29237684 TI - Harnessing the Power of Pharmacometabolomics: The Metabolic Footprint of Statins. PMID- 29237685 TI - Identity-by-Descent Mapping Identifies Major Locus for Serum Triglycerides in Amerindians Largely Explained by an APOC3 Founder Mutation. AB - BACKGROUND: Identity-by-descent mapping using empirical estimates of identity-by descent allele sharing may be useful for studies of complex traits in founder populations, where hidden relationships may augment the inherent genetic information that can be used for localization. METHODS AND RESULTS: Through identity-by-descent mapping, using ~400 000 single-nucleotide polymorphisms (SNPs), of serum lipid profiles, we identified a major linkage signal for triglycerides in 1007 Pima Indians (LOD=9.23; P=3.5*10-11 on chromosome 11q). In subsequent fine-mapping and replication association studies in ~7500 Amerindians, we determined that this signal reflects effects of a loss-of-function Ala43Thr substitution in APOC3 (rs147210663) and 3 established functional SNPs in APOA5. The association with rs147210663 was particularly strong; each copy of the Thr allele conferred 42% lower triglycerides (beta=-0.92+/-0.059 SD unit; P=9.6*10-55 in 4668 Pimas and 2793 Southwest Amerindians combined). The Thr allele is extremely rare in most global populations but has a frequency of 2.5% in Pimas. We further demonstrated that 3 APOA5 SNPs with established functional impact could explain the association with the most well-replicated SNP (rs964184) for triglycerides identified by genome-wide association studies. Collectively, these 4 SNPs account for 6.9% of variation in triglycerides in Pimas (and 4.1% in Southwest Amerindians), and their inclusion in the original linkage model reduced the linkage signal to virtually null. CONCLUSIONS: APOC3/APOA5 constitutes a major locus for serum triglycerides in Amerindians, especially the Pimas, and these results provide an empirical example for the concept that population-based linkage analysis is a useful strategy to identify complex trait variants. PMID- 29237686 TI - Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study. AB - BACKGROUND: The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality. METHODS: On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity-ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives. CONCLUSIONS: We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03037632. PMID- 29237689 TI - Technical Advances for the Clinical Genomic Evaluation of Sudden Cardiac Death: Verification of Next-Generation Sequencing Panels for Hereditary Cardiovascular Conditions Using Formalin-Fixed Paraffin-Embedded Tissues and Dried Blood Spots. AB - BACKGROUND: Postmortem genetic testing for heritable cardiovascular (CV) disorders is often lacking because ideal specimens (ie, whole blood) are not retained routinely at autopsy. Formalin-fixed paraffin-embedded tissue (FFPET) is ubiquitously collected at autopsy, but DNA quality hampers its use with traditional sequencing methods. Targeted next-generation sequencing may offer the ability to circumvent such limitations, but a method has not been previously described. The primary aim of this study was to develop and evaluate the use of FFPET for heritable CV disorders via next-generation sequencing. METHODS AND RESULTS: Nineteen FFPET (heart) and blood (whole blood or dried blood spot) specimens underwent targeted next-generation sequencing using a custom panel of 101 CV-associated genes. Nucleic acid yield and quality metrics were evaluated in relation to FFPET specimen age (6 months to 15 years; n=14) and specimen type (FFPET versus whole blood and dried blood spot; n=12). Four FFPET cases with a clinical phenotype of heritable CV disorder were analyzed. Accuracy and precision were 100% concordant between all sample types, with read depths >100* for most regions tested. Lower read depth, as low as 40*, was occasionally observed with FFPET and dried blood spot. High-quality DNA was obtained from FFPET samples as old as 15 years. Genomic analysis of FFPET from the 4 phenotype-positive/genotype unknown cases all revealed putative disease-causing variants. CONCLUSIONS: Similar performance characteristics were observed for next-generation sequencing of FFPET, whole blood, and dried blood spot in the evaluation of inherited CV disorders. Although blood is preferable for genetic analyses, this study offers an alternative when only FFPET is available. PMID- 29237688 TI - Heritability of Atrial Fibrillation. AB - BACKGROUND: Previous reports have implicated multiple genetic loci associated with AF, but the contributions of genome-wide variation to AF susceptibility have not been quantified. METHODS AND RESULTS: We assessed the contribution of genome wide single-nucleotide polymorphism variation to AF risk (single-nucleotide polymorphism heritability, h2g ) using data from 120 286 unrelated individuals of European ancestry (2987 with AF) in the population-based UK Biobank. We ascertained AF based on self-report, medical record billing codes, procedure codes, and death records. We estimated h2g using a variance components method with variants having a minor allele frequency >=1%. We evaluated h2g in age, sex, and genomic strata of interest. The h2g for AF was 22.1% (95% confidence interval, 15.6%-28.5%) and was similar for early- versus older-onset AF (<=65 versus >65 years of age), as well as for men and women. The proportion of AF variance explained by genetic variation was mainly accounted for by common (minor allele frequency, >=5%) variants (20.4%; 95% confidence interval, 15.1%-25.6%). Only 6.4% (95% confidence interval, 5.1%-7.7%) of AF variance was attributed to variation within known AF susceptibility, cardiac arrhythmia, and cardiomyopathy gene regions. CONCLUSIONS: Genetic variation contributes substantially to AF risk. The risk for AF conferred by genomic variation is similar to that observed for several other cardiovascular diseases. Established AF loci only explain a moderate proportion of disease risk, suggesting that further genetic discovery, with an emphasis on common variation, is warranted to understand the causal genetic basis of AF. PMID- 29237687 TI - Metabolic Profiling of Adiponectin Levels in Adults: Mendelian Randomization Analysis. AB - BACKGROUND: Adiponectin, a circulating adipocyte-derived protein, has insulin sensitizing, anti-inflammatory, antiatherogenic, and cardiomyocyte-protective properties in animal models. However, the systemic effects of adiponectin in humans are unknown. Our aims were to define the metabolic profile associated with higher blood adiponectin concentration and investigate whether variation in adiponectin concentration affects the systemic metabolic profile. METHODS AND RESULTS: We applied multivariable regression in <=5909 adults and Mendelian randomization (using cis-acting genetic variants in the vicinity of the adiponectin gene as instrumental variables) for analyzing the causal effect of adiponectin in the metabolic profile of <=37 545 adults. Participants were largely European from 6 longitudinal studies and 1 genome-wide association consortium. In the multivariable regression analyses, higher circulating adiponectin was associated with higher high-density lipoprotein lipids and lower very-low-density lipoprotein lipids, glucose levels, branched-chain amino acids, and inflammatory markers. However, these findings were not supported by Mendelian randomization analyses for most metabolites. Findings were consistent between sexes and after excluding high-risk groups (defined by age and occurrence of previous cardiovascular event) and 1 study with admixed population. CONCLUSIONS: Our findings indicate that blood adiponectin concentration is more likely to be an epiphenomenon in the context of metabolic disease than a key determinant. PMID- 29237690 TI - Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease. AB - BACKGROUND: De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database. METHODS AND RESULTS: We performed a literature search for previous publications on de novo variants associated with severe arrhythmias and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706). We identified monogenic variants in single case reports and smaller studies (<=200 subjects) and variants considered to increase susceptibility of disease in 3 larger trio studies (>1000 subjects). Of the monogenic variants, 11% (23/211) were present in ExAC, whereas 26% (802/3050) variants believed to increase susceptibility of disease were identified in ExAC. Monogenic de novo variants in ExAC had a total allele count of 109 and with ~844 expected cases in ExAC, these variants would account for 13% of all cases in the studied diseases if truly monogenetic. CONCLUSIONS: We observed numerous de novo variants associated with cardiac disease as standing variation in ExAC, thus these variants are less likely monogenetic causes or major risk contributors for cardiac disease. This highlights the importance of investigating the pathogenicity of de novo variants because they are not as exclusive and pathogenically evident as presumed previously. PMID- 29237691 TI - Four-Generation Family With Ebstein Anomaly Highlights Future Challenges in Congenital Heart Disease Genetics. PMID- 29237692 TI - Does Computer Simulation Help Facilitate Personalized Precision Medicine for the Use of Warfarin? PMID- 29237693 TI - Lamin A/C Cardiomyopathy: Cutting Edge to Personalized Medicine. PMID- 29237694 TI - Genome-Wide Association Studies Revealing the Heritability of Common Atrial Fibrillation: Is Bigger Always Better? PMID- 29237695 TI - Genes in the Basement, Postmortem Genetic Testing...and 3 (New) Realities. PMID- 29237696 TI - Searching for the Causal Variants of the Association Between Hypertriglyceridemia and the Genome-Wide Association Studies-Derived Signals? Take a Look in the Native American Populations. PMID- 29237697 TI - Triple-A syndrome: a wide spectrum of adrenal dysfunction. AB - OBJECTIVE: Triple-A or Allgrove syndrome is an autosomal recessive disorder due to mutations in the AAAS gene, which encodes a nucleoporin named ALADIN. It is characterized by a classical clinical triad: alacrima, achalasia and adrenal insufficiency, the canonic symptoms that are associated with progressive peripheral neuropathy. Only a few cohorts have been reported. The objective of the present study was to characterize the various spectra of adrenal function in Triple-A patients. METHODS: A retrospective clinical and biological monitoring of 14 patients (10 families) was done in a single multidisciplinary French center. All had AAAS gene sequenced and adrenal function evaluation. RESULTS: Nine different AAAS mutations were found, including one new mutation: c.755G>C, p.(Trp252Ser). Regarding adrenal function, defects of the zona fasciculata and reticularis were demonstrated by increased basal ACTH levels and low DHEAS levels in all cases regardless of the degree of glucocorticoid deficiency. In contrast, mineralocorticoid function was always conserved: i.e., normal plasma renin level associated with normal aldosterone level. The main prognostic feature was exacerbation of neuropathy and cognitive disorders. CONCLUSIONS: These data suggest that, in Triple-A patients, adrenal function can be deficient, insufficient or compensated. In our cohort after the first decade of life, there does not appear to be any degradation of adrenal function over time. However, patients with compensated adrenal function should be informed and educated to manage a glucocorticoid replacement therapy in case of stressful conditions, with no need for systematic long-term treatment. PMID- 29237699 TI - Single inhaler triple therapy for COPD. AB - The European Medicines Agency (EMA) has granted marketing authorisation for a pressurised metered dose inhaler (pMDI) containing beclometasone dipropionate, formoterol fumarate dihydrate and glycopyrronium bromide (Trimbow - Chiesi Pharmaceuticals) for the treatment of chronic obstructive pulmonary disease (COPD) in patients not adequately treated with a combination of an inhaled corticosteroid (ICS) and a long-acting beta2 agonist (LABA).1-3 The manufacturer claims that this is a significant treatment advance for COPD patients, and that the use of one inhaler should simplify therapy and, therefore, may improve adherence.1 Here, we consider the evidence for this product for the management of patients with moderate to severe COPD, and how it fits with current management strategies. PMID- 29237698 TI - OxyS small RNA induces cell cycle arrest to allow DNA damage repair. AB - To maintain genome integrity, organisms employ DNA damage response, the underlying principles of which are conserved from bacteria to humans. The bacterial small RNA OxyS of Escherichia coli is induced upon oxidative stress and has been implicated in protecting cells from DNA damage; however, the mechanism by which OxyS confers genome stability remained unknown. Here, we revealed an OxyS-induced molecular checkpoint relay, leading to temporary cell cycle arrest to allow damage repair. By repressing the expression of the essential transcription termination factor nusG, OxyS enables read-through transcription into a cryptic prophage encoding kilR The KilR protein interferes with the function of the major cell division protein FtsZ, thus imposing growth arrest. This transient growth inhibition facilitates DNA damage repair, enabling cellular recovery, thereby increasing viability following stress. The OxyS-mediated growth arrest represents a novel tier of defense, introducing a new regulatory concept into bacterial stress response. PMID- 29237701 TI - Thank you to contributors. PMID- 29237700 TI - Dimethyl fumarate for psoriasis. AB - Dimethyl fumarate (Skilarence - Almirall) was licensed by the European Medicines Agency in June 2017 for the treatment of moderate to severe plaque psoriasis in adults in need of systemic therapy.1 An unlicensed formulation of dimethyl fumarate has been used in the UK for the management of psoriasis for several years. Here, we consider the evidence for the new product and how it fits with current strategies for the management of adults with psoriasis. PMID- 29237702 TI - Use of a Sibling Subtraction Method for Identifying Causal Mutations in Caenorhabditis elegans by Whole-Genome Sequencing. AB - Whole-genome sequencing (WGS) is an indispensable tool for identifying causal mutations obtained from genetic screens. To reduce the number of causal mutation candidates typically uncovered by WGS, Caenorhabditis elegans researchers have developed several strategies. One involves crossing N2-background mutants to the polymorphic Hawaiian (HA) strain, which can be used to simultaneously identify mutant strain variants and obtain high-density mapping information. This approach, however, is not well suited for uncovering mutations in complex genetic backgrounds, and HA polymorphisms can alter phenotypes. Other approaches make use of DNA variants present in the initial background or introduced by mutagenesis. This information is used to implicate genomic regions with high densities of DNA lesions that persist after backcrossing, but these methods can provide lower resolution than HA mapping. To identify suppressor mutations using WGS, we developed an approach termed the sibling subtraction method (SSM). This method works by eliminating variants present in both mutants and their nonmutant siblings, thus greatly reducing the number of candidates. We used this method with two members of the C. elegans NimA-related kinase family, nekl-2 and nekl-3 Combining weak aphenotypic alleles of nekl-2 and nekl-3 leads to penetrant molting defects and larval arrest. We isolated ~50 suppressors of nekl-2; nekl-3 synthetic lethality using F1 clonal screening methods and a peel-1-based counterselection strategy. When applied to five of the suppressors, SSM led to only one to four suppressor candidates per strain. Thus SSM is a powerful approach for identifying causal mutations in any genetic background and provides an alternative to current methods. PMID- 29237704 TI - TESTING Corticosteroids in IgA Nephropathy: A Continuing Challenge. PMID- 29237703 TI - Genome Assembly and Annotation of the Medicinal Plant Calotropis gigantea, a Producer of Anticancer and Antimalarial Cardenolides. AB - Calotropis gigantea produces specialized secondary metabolites known as cardenolides, which have anticancer and antimalarial properties. Although transcriptomic studies have been conducted in other cardenolide-producing species, no nuclear genome assembly for an Asterid cardenolide-producing species has been reported to date. A high-quality de novo assembly was generated for C. gigantea, representing 157,284,427 bp with an N50 scaffold size of 805,959 bp, for which quality assessments indicated a near complete representation of the genic space. Transcriptome data in the form of RNA-sequencing libraries from a developmental tissue series was generated to aid the annotation and construction of a gene expression atlas. Using an ab initio and evidence-driven gene annotation pipeline, 18,197 high-confidence genes were annotated. Homologous and syntenic relationships between C. gigantea and other species within the Apocynaceae family confirmed previously identified evolutionary relationships, and suggest the emergence or loss of the specialized cardenolide metabolites after the divergence of the Apocynaceae subfamilies. The C. gigantea genome assembly, annotation, and RNA-sequencing data provide a novel resource to study the cardenolide biosynthesis pathway, especially for understanding the evolutionary origin of cardenolides and the engineering of cardenolide production in heterologous organisms for existing and novel pharmaceutical applications. PMID- 29237705 TI - Cilia loss sensitizes cells to transformation by activating the mevalonate pathway. AB - Although cilia loss and cell transformation are frequently observed in the early stage of tumorigenesis, the roles of cilia in cell transformation are unknown. In this study, disrupted ciliogenesis was observed in cancer cells and pancreatic cancer tissues, which facilitated oncogene-induced transformation of normal pancreatic cells (HPDE6C7) and NIH3T3 cells through activating the mevalonate (MVA) pathway. Disruption of ciliogenesis up-regulated MVA enzymes through beta catenin-T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by beta-catenin-TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting Tg737 dramatically promoted tumorigenesis in the PDAC mouse model, driven by KrasG12D , which was inhibited by statin, an inhibitor of the MVA pathway. Collectively, this study emphasizes the crucial roles of cilia in governing the early steps of the transformation by activating the MVA pathway, suggesting that statin has therapeutic potential for pancreatic cancer treatment. PMID- 29237706 TI - Patient characteristics, resource use and outcomes associated with general internal medicine hospital care: the General Medicine Inpatient Initiative (GEMINI) retrospective cohort study. AB - BACKGROUND: The precise scope of hospital care delivered under general internal medicine services remains poorly quantified. The purpose of this study was to describe the demographic characteristics, medical conditions, health outcomes and resource use of patients admitted to general internal medicine at 7 hospital sites in the Greater Toronto Area. METHODS: This was a retrospective cohort study involving all patients who were admitted to or discharged from general internal medicine at the study sites between Apr. 1, 2010, and Mar. 31, 2015. Clinical data from hospital electronic information systems were linked to administrative data from each hospital. We examined trends in resource use and patient characteristics over the study period. RESULTS: There were 136 208 admissions to general internal medicine involving 88 121 unique patients over the study period. General internal medicine admissions accounted for 38.8% of all admissions from the emergency department and 23.7% of all hospital bed-days. Over the study period, the number of admissions to general internal medicine increased by 32.4%; there was no meaningful change in the median length of stay or cost per hospital stay. The median patient age was 73 (interquartile range [IQR] 57-84) years, and the median number of coexisting conditions was 6 (IQR 3-9). The median acute length of stay was 4.6 (IQR 2.5-8.6) days, and the median total cost per hospital stay was $5850 (IQR $3915-$10 061). Patients received at least 1 computed tomography scan in 52.2% of admissions. The most common primary discharge diagnoses were pneumonia (5.0% of admissions), heart failure (4.7%), chronic obstructive pulmonary disease (4.1%), urinary tract infection (4.0%) and stroke (3.6%). INTERPRETATION: Patients admitted to general internal medicine services represent a large, heterogeneous, resource-intensive and growing population. Understanding and improving general internal medicine care is essential to promote a high-quality, sustainable health care system. PMID- 29237709 TI - Peer Review of a Manuscript Submission: A How-To Guide for Effective and Efficient Commentary. PMID- 29237710 TI - Short-Term Outcomes and Factors Associated With Adverse Events Among Adults Discharged From the Emergency Department After Treatment for Acute Heart Failure. AB - BACKGROUND: Although 80% of patients with heart failure seen in the emergency department (ED) are admitted, less is known about short-term outcomes and demand for services among discharged patients. METHODS AND RESULTS: We examined adult members of a large integrated delivery system who visited an ED for acute heart failure and were discharged from January 1, 2013, through September 30, 2014. The primary outcome was a composite of repeat ED visit, hospital admission, or death within 7 days of discharge. We identified multivariable baseline patient-, provider-, and facility-level factors associated with adverse outcomes within 7 days of ED discharge using logistic regression. Among 7614 patients, mean age was 77.2 years, 51.9% were women, and 28.4% were people of color. Within 7 days of discharge, 75% had outpatient follow-up (clinic, telephone, or e-mail), 7.1% had an ED revisit, 4.7% were hospitalized, and 1.2% died. Patients who met the primary outcome were more likely to be older, smokers, have a history of hemorrhagic stroke, hypothyroidism, and dementia, and less likely to be treated in a facility with an observation unit. In multivariable analysis, higher comorbidity scores and history of smoking were associated with a higher odds of the primary outcome, whereas treatment in a facility with an observation unit and presence of outpatient follow-up within 7 days were associated with a lower odds. CONCLUSIONS: We identified selected hospital and patient characteristics associated with short-term adverse outcomes. Further understanding of these factors may optimize safe outpatient management in ED-treated patients with heart failure. PMID- 29237711 TI - Breaking the Law of Small Numbers. PMID- 29237708 TI - Vaccine and Therapeutic Options To Control Chikungunya Virus. AB - Beginning in 2004, chikungunya virus (CHIKV) went from an endemic pathogen limited to Africa and Asia that caused periodic outbreaks to a global pathogen. Given that outbreaks caused by CHIKV have continued and expanded, serious consideration must be given to identifying potential options for vaccines and therapeutics. Currently, there are no licensed products in this realm, and control relies completely on the use of personal protective measures and integrated vector control, which are only minimally effective. Therefore, it is prudent to urgently examine further possibilities for control. Vaccines have been shown to be highly effective against vector-borne diseases. However, as CHIKV is known to rapidly spread and generate high attack rates, therapeutics would also be highly valuable. Several candidates are currently being developed; this review describes the multiple options under consideration for future development and assesses their relative advantages and disadvantages. PMID- 29237712 TI - Receptor activities of persistent pollutant serum mixtures and breast cancer risk. AB - Studies on associations between persistent organic pollutants (POPs) and breast cancer risk are inconclusive. The majority of studies have evaluated the effect of single compounds, without considering multiple exposures to and interactions between different POPs. The present study aimed at evaluating breast cancer risk related to combined effects of serum POP mixtures on cellular receptor functions. Data on breast cancer cases (n = 77) and controls (n = 84) were collected among Greenlandic Inuit women. Serum mixtures of lipophilic POPs (lipPOPs), perfluoroalkyl acids (PFAAs) and dioxin-like POPs were extracted. The effect of the mixture extracts on the estrogen receptor (ER), androgen receptor (AR) and aryl hydrocarbon receptor (AhR) was determined using cell culture reporter gene assays. The serum mixtures were analyzed alone and upon co-exposure with natural receptor ligands to determine agonistic and antagonistic/competitive activity. We found that the frequency of lipPOP mixtures eliciting no, decreasing, or agonizing xenoandrogenic effect differed by breast cancer status. Using lipPOP mixtures with no effect on AR as reference, the mixtures with decreasing effects reduced breast cancer risk (OR: 0.30 (0.12; 0.76)). The AhR-toxic equivalent of serum mixtures was significantly lower in cases than in controls, and a reduced breast cancer risk was found when comparing the third tertile to the first (OR: 0.34 (0.14; 0.83)). We found no association between the xenoestrogenic activities of lipPOPs or PFAAs and breast cancer risk. Serum lipPOP mixtures are hormone disruptive and may influence breast cancer risk, whereas PFAAs seem to influence breast cancer risk through other pathways. PMID- 29237713 TI - Unusual Prenatal Genomic Results Provide Proof-of-Principle of the Liquid Biopsy for Cancer Screening. PMID- 29237714 TI - Digital PCR: A Sensitive and Precise Method for KIT D816V Quantification in Mastocytosis. AB - BACKGROUND: The analytically sensitive detection of KIT D816V in blood and bone marrow is important for diagnosing systemic mastocytosis (SM). Additionally, precise quantification of the KIT D816V variant allele fraction (VAF) is relevant clinically because it helps to predict multilineage involvement and prognosis in cases of advanced SM. Digital PCR (dPCR) is a promising new method for sensitive detection and accurate quantification of somatic mutations. METHODS: We performed a validation study of dPCR for KIT D816V on 302 peripheral blood and bone marrow samples from 156 patients with mastocytosis for comparison with melting curve analysis after peptide nucleic acid-mediated PCR clamping (clamp-PCR) and allele specific quantitative real-time PCR (qPCR). RESULTS: dPCR showed a limit of detection of 0.01% VAF with a mean CV of 8.5% and identified the mutation in 90% of patients compared with 70% for clamp-PCR (P < 0.001). Moreover, dPCR for KIT D816V was highly concordant with qPCR without systematic deviation of results, and confirmed the clinical value of KIT D816V VAF measurements. Thus, patients with advanced SM showed a significantly higher KIT D816V VAF (median, 2.43%) compared with patients with indolent SM (median, 0.14%; P < 0.001). Moreover, dPCR confirmed the prognostic significance of a high KIT D816V VAF regarding survival (P < 0.001). CONCLUSIONS: dPCR for KIT D816V provides a high degree of precision and sensitivity combined with the potential for interlaboratory standardization, which is crucial for the implementation of KIT D816V allele burden measurement. Thus, dPCR is suitable as a new method for KIT D816V testing in patients with mastocytosis. PMID- 29237715 TI - Vaccines to combat the opioid crisis: Vaccines that prevent opioids and other substances of abuse from entering the brain could effectively treat addiction and abuse. PMID- 29237707 TI - Buruli Ulcer, a Prototype for Ecosystem-Related Infection, Caused by Mycobacterium ulcerans. AB - Buruli ulcer is a noncontagious disabling cutaneous and subcutaneous mycobacteriosis reported by 33 countries in Africa, Asia, Oceania, and South America. The causative agent, Mycobacterium ulcerans, derives from Mycobacterium marinum by genomic reduction and acquisition of a plasmid-borne, nonribosomal cytotoxin mycolactone, the major virulence factor. M. ulcerans-specific sequences have been readily detected in aquatic environments in food chains involving small mammals. Skin contamination combined with any type of puncture, including insect bites, is the most plausible route of transmission, and skin temperature of <30 degrees C significantly correlates with the topography of lesions. After 30 years of emergence and increasing prevalence between 1970 and 2010, mainly in Africa, factors related to ongoing decreasing prevalence in the same countries remain unexplained. Rapid diagnosis, including laboratory confirmation at the point of care, is mandatory in order to reduce delays in effective treatment. Parenteral and potentially toxic streptomycin-rifampin is to be replaced by oral clarithromycin or fluoroquinolone combined with rifampin. In the absence of proven effective primary prevention, avoiding skin contamination by means of clothing can be implemented in areas of endemicity. Buruli ulcer is a prototype of ecosystem pathology, illustrating the impact of human activities on the environment as a source for emerging tropical infectious diseases. PMID- 29237716 TI - Shared and distinct lipid-lipid interactions in plasma and affected tissues in a diabetic mouse model. AB - Lipids are ubiquitous metabolites with diverse functions; abnormalities in lipid metabolism appear to be related to complications from multiple diseases, including type 2 diabetes. Through technological advances, the entire lipidome has been characterized and researchers now need computational approaches to better understand lipid network perturbations in different diseases. Using a mouse model of type 2 diabetes with microvascular complications, we examined lipid levels in plasma and in renal, neural, and retinal tissues to identify shared and distinct lipid abnormalities. We used correlation analysis to construct interaction networks in each tissue, to associate changes in lipids with changes in enzymes of lipid metabolism, and to identify overlap of coregulated lipid subclasses between plasma and each tissue to define subclasses of plasma lipids to use as surrogates of tissue lipid metabolism. Lipid metabolism alterations were mostly tissue specific in the kidney, nerve, and retina; no lipid changes correlated between the plasma and all three tissue types. However, alterations in diacylglycerol and in lipids containing arachidonic acid, an inflammatory mediator, were shared among the tissue types, and the highly saturated cholesterol esters were similarly coregulated between plasma and each tissue type in the diabetic mouse. Our results identified several patterns of altered lipid metabolism that may help to identify pathogenic alterations in different tissues and could be used as biomarkers in future research into diabetic microvascular tissue damage. PMID- 29237717 TI - Particulate Matter Air Pollution Exposure and Heart Disease Mortality Risks by Race and Ethnicity in the United States: 1997 to 2009 National Health Interview Survey With Mortality Follow-Up Through 2011. AB - BACKGROUND: Most US studies of mortality and air pollution have been conducted on largely non-Hispanic white study populations. However, many health and mortality outcomes differ by race and ethnicity, and non-Hispanic white persons experience lower air pollution exposure than those who are non-Hispanic black or Hispanic. This study examines whether associations between air pollution and heart disease mortality differ by race/ethnicity. METHODS: We used data from the 1997 to 2009 National Health Interview Survey linked to mortality records through December 2011 and annual estimates of fine particulate matter (PM2.5) by census tract. Proportional hazards models were used to estimate hazard ratios and 95% confidence intervals between PM2.5 (per 10 ug/m3) and heart disease mortality using the full sample and the sample adults, which have information on additional health variables. Interaction terms were used to examine differences in the PM2.5 mortality association by race/ethnicity. RESULTS: Overall, 65 936 of the full sample died during follow-up, and 22 152 died from heart disease. After adjustment for several factors, we found a significant positive association between PM2.5 and heart disease mortality (hazard ratio, 1.16; 95% confidence interval, 1.08-1.25). This association was similar in sample adults with adjustment for smoking and body mass index (hazard ratio, 1.18; 95% confidence interval, 1.06-1.31). Interaction terms for non-Hispanic black and Hispanic groups compared with the non-Hispanic white group were not statistically significant. CONCLUSIONS: Using a nationally representative sample, the association between PM2.5 and heart disease mortality was elevated and similar to previous estimates. Associations for non-Hispanic black and Hispanic adults were not statistically significantly different from those for non-Hispanic white adults. PMID- 29237718 TI - Use of PRO Measures to Inform Tolerability in Oncology Trials: Implications for Clinical Review, IND Safety Reporting, and Clinical Site Inspections. AB - Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780-4. (c)2017 AACRSee related commentary by Nipp and Temel, p. 1777. PMID- 29237719 TI - IFT20 modulates ciliary PDGFRalpha signaling by regulating the stability of Cbl E3 ubiquitin ligases. AB - Primary cilia have pivotal roles as organizers of many different signaling pathways, including platelet-derived growth factor receptor alpha (PDGFRalpha) signaling, which, when aberrantly regulated, is associated with developmental disorders, tumorigenesis, and cancer. PDGFRalpha is up-regulated during ciliogenesis, and ciliary localization of the receptor is required for its appropriate ligand-mediated activation by PDGF-AA. However, the mechanisms regulating sorting of PDGFRalpha and feedback inhibition of PDGFRalpha signaling at the cilium are unknown. Here, we provide evidence that intraflagellar transport protein 20 (IFT20) interacts with E3 ubiquitin ligases c-Cbl and Cbl-b and is required for Cbl-mediated ubiquitination and internalization of PDGFRalpha for feedback inhibition of receptor signaling. In wild-type cells treated with PDGF-AA, c-Cbl becomes enriched in the cilium, and the receptor is subsequently ubiquitinated and internalized. In contrast, in IFT20-depleted cells, PDGFRalpha localizes aberrantly to the plasma membrane and is overactivated after ligand stimulation because of destabilization and degradation of c-Cbl and Cbl-b. PMID- 29237721 TI - REV-ERBalpha Regulates CYP7A1 Through Repression of Liver Receptor Homolog-1. AB - Nuclear heme receptor reverse erythroblastosis virus (REV-ERB) alpha (a transcriptional repressor) is known to regulate cholesterol 7alpha-hydroxylase (CYP7A1) and bile acid synthesis. However, the mechanism for REV-ERBalpha regulation of CYP7A1 remains elusive. Here, we investigate the role of LRH-1 in REV-ERBalpha regulation of CYP7A1 and cholesterol metabolism. We first characterized the tertiary amine N-(4-chloro-2-methylbenzyl)-N-(4-chlorobenzyl)-1 (5-nitrothiophen-2-yl)methanamine (GSK2945) as a highly specific Rev-erbalpha/REV ERBalpha antagonist using cell-based assays and confirmed expression of Rev erbalpha in mouse liver. GSK2945 treatment increased hepatic mouse cholesterol 7alpha-hydroxylase (Cyp7a1) level and lowered plasma cholesterol in wild-type mice. Likewise, the compound increased the expression and microsomal activity of Cyp7a1 in hypercholesterolemic mice. This coincided with reduced plasma and liver cholesterol and enhanced production of bile acids. Increased levels of Cyp7a1/CYP7A1 were also found in mouse and human primary hepatocytes after GSK2945 treatment. In these experiments, we observed parallel increases in Lrh 1/LRH-1 (a known hepatic activator of Cyp7a1/CYP7A1) mRNA and protein. Luciferase reporter, mobility shift, and chromatin immunoprecipitation assays revealed that Lrh-1/LRH-1 was a direct Rev-erbalpha/REV-ERBalpha target gene. Furthermore, conditional deletion of Lrh-1 in the liver abrogated the regulatory effects of Rev-erbalpha on Cyp7a1 and cholesterol metabolism in mice. In conclusion, Rev erbalpha regulates Cyp7a1 and cholesterol metabolism through its repression of the Lrh-1 receptor. Targeting the REV-ERBalpha/LRH-1 axis may represent a novel approach for management of cholesterol-related diseases. PMID- 29237720 TI - Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins. AB - The identification of conserved autophagy-related proteins (ATGs) that mediate bulk degradation of cytosolic material laid the foundation for breakthroughs linking autophagy to a litany of physiological processes and disease conditions. Recent discoveries are revealing that these same ATGs orchestrate processes that are related to, and yet clearly distinct from, classic autophagy. Autophagy related functions include secretion, trafficking of phagocytosed material, replication and egress of viral particles, and regulation of inflammatory and immune signaling cascades. Here, we define common processes dependent on ATGs, and discuss the challenges in mechanistically separating autophagy from these related pathways. Elucidating the molecular events that distinguish how individual ATGs function promises to improve our understanding of the origin of diseases ranging from autoimmunity to cancer. PMID- 29237722 TI - Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone. AB - RATIONALE: Resistant hypertension is a major health concern with unknown cause. Spironolactone is an effective antihypertensive drug, especially for patients with resistant hypertension, and is considered by the World Health Organization as an essential medication. Although spironolactone can act at the mineralocorticoid receptor (MR; NR3C2), there is increasing evidence of MR independent effects of spironolactone. OBJECTIVE: Here, we detail the unexpected discovery that Panx1 (pannexin 1) channels could be a relevant in vivo target of spironolactone. METHODS AND RESULTS: First, we identified spironolactone as a potent inhibitor of Panx1 in an unbiased small molecule screen, which was confirmed by electrophysiological analysis. Next, spironolactone inhibited alpha adrenergic vasoconstriction in arterioles from mice and hypertensive humans, an effect dependent on smooth muscle Panx1, but independent of the MR NR3C2. Last, spironolactone acutely lowered blood pressure, which was dependent on smooth muscle cell expression of Panx1 and independent of NR3C2. This effect, however, was restricted to steroidal MR antagonists as a nonsteroidal MR antagonist failed to reduced blood pressure. CONCLUSIONS: These data suggest new therapeutic modalities for resistant hypertension based on Panx1 inhibition. PMID- 29237724 TI - Dual alphavbeta3 and alphavbeta5 blockade attenuates fibrotic and vascular alterations in a murine model of systemic sclerosis. AB - Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibroblast activation and fibrosis of the skin and internal organs. Alterations in cell-integrin interaction are sufficient to initiate profibrotic processes. SSc fibroblasts express both alphavbeta3 and alphavbeta5 integrins and their activation induces myofibroblasts differentiation. The aim of the present study was to evaluate the effect of the anb3 and anb5 inhibitor, cilengitide, on the development of vascular and fibrotic changes in the chronic oxidant stress murine model of systemic sclerosis. SSc was induced in BALB/c mice by daily s.c. injections of HOCl for 6 weeks. Mice were randomized in three arms: HOCl alone (n=8), HOCl + Cilengitide (n=8), or Vehicle alone (n=8). Treatment with cilengitide 20 (mg/kg/i.p./day) was started 4 weeks after the first administration of HOCl and maintained throughout the remaining experimental period (2 weeks). Lung, skin, and heart fibrosis were evaluated by histology while kidney morphology by PAS staining. Collagen type I, focal adhesion kinase (FAK), and a-SMA were evaluated by immunostaining and p-FAK and TGF-beta1 by Western blot and gene expression. Both cutaneous and pulmonary fibrosis induced by HOCl were attenuated by cilengitide treatment. Cilengitide administration reduced a-SMA, TGF-beta1, and p-FAK expression and the increased deposition of fibrillar collagen in the heart and prevented glomeruli collapse in the kidneys. The inhibition of anubeta3 and anubeta5 integrin signaling prevented systemic fibrosis and renal vascular abnormalities in the reactive oxygen species model of SSc. Integrins anubeta3 and anubeta5 could prove useful as a therapeutic target in SSc. PMID- 29237723 TI - The E3 Ligase DROUGHT HYPERSENSITIVE Negatively Regulates Cuticular Wax Biosynthesis by Promoting the Degradation of Transcription Factor ROC4 in Rice. AB - Cuticular wax plays crucial roles in protecting plants from environmental stresses, particularly drought stress. Many enzyme-encoding genes and transcription factors involved in wax biosynthesis have been identified, but the underlying posttranslational regulatory mechanisms are poorly understood. Here, we demonstrate that DROUGHT HYPERSENSITIVE (DHS), encoding a Really Interesting New Gene (RING)-type protein, is a critical regulator of wax biosynthesis in rice (Oryza sativa). The cuticular wax contents were significantly reduced in DHS overexpression plants but increased in dhs mutants compared with the wild type, which resulted in a response opposite that of drought stress. DHS exhibited E3 ubiquitin ligase activity and interacted with the homeodomain-leucine zipper IV protein ROC4. Analysis of ROC4 overexpression plants and roc4 mutants indicated that ROC4 positively regulates cuticular wax biosynthesis and the drought stress response. ROC4 is ubiquitinated in vivo and subjected to ubiquitin/26S proteasome mediated degradation. ROC4 degradation was promoted by DHS but delayed in dhs mutants. ROC4 acts downstream of DHS, and Os-BDG is a direct downstream target of the DHS-ROC4 cascade. These results suggest a mechanism whereby DHS negatively regulates wax biosynthesis by promoting the degradation of ROC4, and they suggest that DHS and ROC4 are valuable targets for the engineering of drought-tolerant rice cultivars. PMID- 29237725 TI - ABIN-1 Negatively Regulates MU-Opioid Receptor Function. AB - The MU-opioid receptor (MOR) is a Gi/o protein-coupled receptor that mediates analgesic, euphoric, and reward effects. Using a bacterial two-hybrid screen, we reported that the carboxyl tail of the rat MOR associates with A20-binding inhibitor of nuclear factor kappaB (ABIN-1). This interaction was confirmed by direct protein-protein binding and coimmunoprecipitation of MOR and ABIN-1 proteins in cell lysates. Saturation binding studies showed that ABIN-1 had no effect on MOR binding. However, the interaction of ABIN-1 and MOR inhibited the activation of G proteins induced by DAMGO ([d-Ala2,N-Me-Phe4,Gly5-ol] Enkephalin). MOR phosphorylation, ubiquitination, and internalization induced by DAMGO were decreased in Chinese hamster ovary cells that coexpressed MOR and ABIN 1. The suppression of forskolin-stimulated adenylyl cyclase by DAMGO was also inhibited by the interaction of ABIN-1 with MOR. In addition, extracellular signal-regulated kinase activation was also negatively regulated by overexpression of ABIN-1. These data suggest that ABIN-1 is a negative coregulator of MOR activation, phosphorylation, and internalization in vitro. ABIN-1 also inhibited morphine-induced hyperlocomotion in zebrafish larvae (AB strain). By utilization of an antisense morpholino oligonucleotide (MO) gene knockdown technology, the ABIN-1 MO-injected zebrafish larvae showed a significant increase (approximately 60%) in distance moved compared with control MO-injected larvae after acute morphine treatment (P < 0.01). Taken together, ABIN-1 negatively regulates MOR function in vitro and in vivo. PMID- 29237727 TI - N-linked Glycan Micro-heterogeneity in Glycoproteins of Arabidopsis. AB - N-glycosylation is one of the most common protein post-translational modifications in eukaryotes and has a relatively conserved core structure between fungi, animals and plants. In plants, the biosynthesis of N-glycans has been extensively studied with all the major biosynthetic enzymes characterized. However, few studies have applied advanced mass spectrometry to profile intact plant N-glycopeptides. In this study, we use hydrophilic enrichment, high resolution tandem mass spectrometry with complementary and triggered fragmentation to profile Arabidopsis N-glycopeptides from microsomal membranes of aerial tissues. A total of 492 N-glycosites were identified from 324 Arabidopsis proteins with extensive N-glycan structural heterogeneity revealed through 1110 N glycopeptides. To demonstrate the precision of the approach, we also profiled N glycopeptides from the mutant (xylt) of beta-1,2-xylosyltransferase, an enzyme in the N-glycan biosynthetic pathway. This analysis represents the most comprehensive and unbiased collection of Arabidopsis N-glycopeptides revealing an unsurpassed level of detail on the micro-heterogeneity present in N-glycoproteins of Arabidopsis. Data are available via ProteomeXchange with identifier PXD006270. PMID- 29237728 TI - Slightly deleterious genomic variants and transcriptome perturbations in Down syndrome embryonic selection. AB - The majority of aneuploid fetuses are spontaneously miscarried. Nevertheless, some aneuploid individuals survive despite the strong genetic insult. Here, we investigate if the survival probability of aneuploid fetuses is affected by the genome-wide burden of slightly deleterious variants. We analyzed two cohorts of live-born Down syndrome individuals (388 genotyped samples and 16 fibroblast transcriptomes) and observed a deficit of slightly deleterious variants on Chromosome 21 and decreased transcriptome-wide variation in the expression level of highly constrained genes. We interpret these results as signatures of embryonic selection, and propose a genetic handicap model whereby an individual bearing an extremely severe deleterious variant (such as aneuploidy) could escape embryonic lethality if the genome-wide burden of slightly deleterious variants is sufficiently low. This approach can be used to study the composition and effect of the numerous slightly deleterious variants in humans and model organisms. PMID- 29237730 TI - An allosteric binding site of the alpha7 nicotinic acetylcholine receptor revealed in a humanized acetylcholine-binding protein. AB - Nicotinic acetylcholine receptors (nAChRs) belong to the family of pentameric ligand-gated ion channels and mediate fast excitatory transmission in the central and peripheral nervous systems. Among the different existing receptor subtypes, the homomeric alpha7 nAChR has attracted considerable attention because of its possible implication in several neurological and psychiatric disorders, including cognitive decline associated with Alzheimer's disease or schizophrenia. Allosteric modulators of ligand-gated ion channels are of particular interest as therapeutic agents, as they modulate receptor activity without affecting normal fluctuations of synaptic neurotransmitter release. Here, we used X-ray crystallography and surface plasmon resonance spectroscopy of alpha7 acetylcholine-binding protein (AChBP), a humanized chimera of a snail AChBP, which has 71% sequence similarity with the extracellular ligand-binding domain of the human alpha7 nAChR, to investigate the structural determinants of allosteric modulation. We extended previous observations that an allosteric site located in the vestibule of the receptor offers an attractive target for receptor modulation. We introduced seven additional humanizing mutations in the vestibule located binding site of AChBP to improve its suitability as a model for studying allosteric binding. Using a fragment-based screening approach, we uncovered an allosteric binding site located near the beta8-beta9 loop, which critically contributes to coupling ligand binding to channel opening in human alpha7 nAChR. This work expands our understanding of the topology of allosteric binding sites in AChBP and, by extrapolation, in the human alpha7 nAChR as determined by electrophysiology measurements. Our insights pave the way for drug design strategies targeting nAChRs involved in ion channel-mediated disorders. PMID- 29237729 TI - The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis. AB - Copper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2 Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo. PMID- 29237731 TI - Naked mole-rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers. AB - Acid-sensing ion channels (ASICs) form both homotrimeric and heterotrimeric ion channels that are activated by extracellular protons and are involved in a wide range of physiological and pathophysiological processes, including pain and anxiety. ASIC proteins can form both homotrimeric and heterotrimeric ion channels. The ASIC3 subunit has been shown to be of particular importance in the peripheral nervous system with pharmacological and genetic manipulations demonstrating a role in pain. Naked mole-rats, despite having functional ASICs, are insensitive to acid as a noxious stimulus and show diminished avoidance of acidic fumes, ammonia, and carbon dioxide. Here we cloned naked mole-rat ASIC3 (nmrASIC3) and used a cell-surface biotinylation assay to demonstrate that it traffics to the plasma membrane, but using whole-cell patch clamp electrophysiology we observed that nmrASIC3 is insensitive to both protons and the non-proton ASIC3 agonist 2-guanidine-4-methylquinazoline. However, in line with previous reports of ASIC3 mRNA expression in dorsal root ganglia neurons, we found that the ASIC3 antagonist APETx2 reversibly inhibits ASIC-like currents in naked mole-rat dorsal root ganglia neurons. We further show that like the proton insensitive ASIC2b and ASIC4, nmrASIC3 forms functional, proton-sensitive heteromers with other ASIC subunits. An amino acid alignment of ASIC3s between 9 relevant rodent species and human identified unique sequence differences that might underlie the proton insensitivity of nmrASIC3. However, introducing nmrASIC3 differences into rat ASIC3 (rASIC3) produced only minor differences in channel function, and replacing the nmrASIC3 sequence with that of rASIC3 did not produce a proton-sensitive ion channel. Our observation that nmrASIC3 forms nonfunctional homomers may reflect a further adaptation of the naked mole-rat to living in an environment with high-carbon dioxide levels. PMID- 29237726 TI - Transmission, Evolution, and Endogenization: Lessons Learned from Recent Retroviral Invasions. AB - Viruses of the subfamily Orthoretrovirinae are defined by the ability to reverse transcribe an RNA genome into DNA that integrates into the host cell genome during the intracellular virus life cycle. Exogenous retroviruses (XRVs) are horizontally transmitted between host individuals, with disease outcome depending on interactions between the retrovirus and the host organism. When retroviruses infect germ line cells of the host, they may become endogenous retroviruses (ERVs), which are permanent elements in the host germ line that are subject to vertical transmission. These ERVs sometimes remain infectious and can themselves give rise to XRVs. This review integrates recent developments in the phylogenetic classification of retroviruses and the identification of retroviral receptors to elucidate the origins and evolution of XRVs and ERVs. We consider whether ERVs may recurrently pressure XRVs to shift receptor usage to sidestep ERV interference. We discuss how related retroviruses undergo alternative fates in different host lineages after endogenization, with koala retrovirus (KoRV) receiving notable interest as a recent invader of its host germ line. KoRV is heritable but also infectious, which provides insights into the early stages of germ line invasions as well as XRV generation from ERVs. The relationship of KoRV to primate and other retroviruses is placed in the context of host biogeography and the potential role of bats and rodents as vectors for interspecies viral transmission. Combining studies of extant XRVs and "fossil" endogenous retroviruses in koalas and other Australasian species has broadened our understanding of the evolution of retroviruses and host-retrovirus interactions. PMID- 29237732 TI - Diverse NADase effector families mediate interbacterial antagonism via the type VI secretion system. AB - The bacterial type VI secretion system (T6SS) mediates antagonistic cell-cell interactions between competing Gram-negative bacteria. In plant-beneficial bacteria, this pathway has been shown to suppress the growth of bacterial pathogens; however, the identification and mode of action of T6SS effector proteins that mediate this protective effect remain poorly defined. Here, we identify two previously uncharacterized effectors required for interbacterial antagonism by the plant commensal bacterium Pseudomonas protegens Consistent with the established effector-immunity paradigm for antibacterial T6SS substrates, the toxic activities of these effectors are neutralized by adjacently encoded cognate immunity determinants. Although one of these effectors, RhsA, belongs to the family of DNase enzymes, the activity of the other was not apparent from its sequence. To determine the mechanism of toxicity of this latter effector, we determined its 1.3 A crystal structure in complex with its immunity protein and found that it resembles NAD(P)+-degrading enzymes. In line with this structural similarity, biochemical characterization of this effector, termed Tne2 (Type VI secretion NADase effector family 2), demonstrates that it possesses potent NAD(P)+ hydrolase activity. Tne2 is the founding member of a widespread family of interbacterial NADases predicted to transit not only the Gram-negative T6SS but also the Gram-positive type VII secretion system, a pathway recently implicated in interbacterial competition among Firmicutes. Together, this work identifies new T6SS effectors employed by a plant commensal bacterium to antagonize its competitors and broadly implicates NAD(P)+-hydrolyzing enzymes as substrates of interbacterial conflict pathways found in diverse bacterial phyla. PMID- 29237733 TI - Communication between N terminus and loop2 tunes Orai activation. AB - Ca2+ release-activated Ca2+ (CRAC) channels constitute the major Ca2+ entry pathway into the cell. They are fully reconstituted via intermembrane coupling of the Ca2+-selective Orai channel and the Ca2+-sensing protein STIM1. In addition to the Orai C terminus, the main coupling site for STIM1, the Orai N terminus is indispensable for Orai channel gating. Although the extended transmembrane Orai N terminal region (Orai1 amino acids 73-91; Orai3 amino acids 48-65) is fully conserved in the Orai1 and Orai3 isoforms, Orai3 tolerates larger N-terminal truncations than Orai1 in retaining store-operated activation. In an attempt to uncover the reason for these isoform-specific structural requirements, we analyzed a series of Orai mutants and chimeras. We discovered that it was not the N termini, but the loop2 regions connecting TM2 and TM3 of Orai1 and Orai3 that featured distinct properties, which explained the different, isoform-specific behavior of Orai N-truncation mutants. Atomic force microscopy studies and MD simulations suggested that the remaining N-terminal portion in the non-functional Orai1 N-truncation mutants formed new, inhibitory interactions with the Orai1 loop2 regions, but not with Orai3-loop2. Such a loop2 swap restored activation of the N-truncation Orai1 mutants. To mimic interactions between the N terminus and loop2 in full-length Orai1 channels, we induced close proximity of the N terminus and loop2 via cysteine cross-linking, which actually caused significant inhibition of STIM1-mediated Orai currents. In aggregate, maintenance of Orai activation required not only the conserved N-terminal region but also permissive communication of the Orai N terminus and loop2 in an isoform-specific manner. PMID- 29237736 TI - Delayed Treatment with Histone Deacetylase Inhibitors Promotes Stroke Recovery. PMID- 29237734 TI - Authentic CRAC channel activity requires STIM1 and the conserved portion of the Orai N terminus. AB - Calcium (Ca2+) is an essential second messenger required for diverse signaling processes in immune cells. Ca2+ release-activated Ca2+ (CRAC) channels represent one main Ca2+ entry pathway into the cell. They are fully reconstituted via two proteins, the stromal interaction molecule 1 (STIM1), a Ca2+ sensor in the endoplasmic reticulum, and the Ca2+ ion channel Orai in the plasma membrane. After Ca2+ store depletion, STIM1 and Orai couple to each other, allowing Ca2+ influx. CRAC-/STIM1-mediated Orai channel currents display characteristic hallmarks such as high Ca2+ selectivity, an increase in current density when switching from a Ca2+-containing solution to a divalent-free Na+ one, and fast Ca2+-dependent inactivation. Here, we discovered several constitutively active Orai1 and Orai3 mutants, containing substitutions in the TM3 and/or TM4 regions, all of which displayed a loss of the typical CRAC channel hallmarks. Restoring authentic CRAC channel activity required both the presence of STIM1 and the conserved Orai N-terminal portion. Similarly, these structural requisites were found in store-operated Orai channels. Key molecular determinants within the Orai N terminus that together with STIM1 maintained the typical CRAC channel hallmarks were distinct from those that controlled store-dependent Orai activation. In conclusion, the conserved portion of the Orai N terminus is essential for STIM1, as it fine-tunes the open Orai channel gating, thereby establishing authentic CRAC channel activity. PMID- 29237737 TI - What Can Recordings in the Striatum Tell Us about Associative Learning? PMID- 29237735 TI - The Expanding Toolkit of Translating Ribosome Affinity Purification. AB - Translating ribosome affinity purification is a method initially developed for profiling mRNA from genetically defined cell types in complex tissues. It has been applied both to identify target molecules in cell types that are important for controlling a variety of behaviors in the brain, and to understand the molecular consequences on those cells due to experimental manipulations, ranging from drugs of abuse to disease-causing mutations. Since its inception, a variety of methodological advances are opening new avenues of investigation. These advances include a variety of new methods for targeting cells for translating ribosome affinity purification by features such as their projections or activity, additional tags and mouse reagents increasing the flexibility of the system, and new modifications of the method specifically focused on studying the regulation of translation. The latter includes methods to assess cell type-specific regulation of translation in specific subcellular compartments. Here, I provide a summary of these recent advances and resources, highlighting both new experimental opportunities and areas for future technical development. PMID- 29237739 TI - Salt-Losing Tubulopathies in Children: What's New, What's Controversial? AB - Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle's loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders. PMID- 29237738 TI - Ascending Vasa Recta Are Angiopoietin/Tie2-Dependent Lymphatic-Like Vessels. AB - Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism. Medullary hyperosmolarity is protected from washout by countercurrent exchange and efficient removal of interstitial fluid resorbed from the loop of Henle and collecting ducts. In most tissues, lymphatic vessels drain excess interstitial fluid back to the venous circulation. However, the renal medulla is devoid of classic lymphatics. Studies have suggested that the fenestrated ascending vasa recta (AVRs) drain the interstitial fluid in this location, but this function has not been conclusively shown. We report that late gestational deletion of the angiopoietin receptor endothelial tyrosine kinase 2 (Tie2) or both angiopoietin-1 and angiopoietin-2 prevents AVR formation in mice. The absence of AVR associated with rapid accumulation of fluid and cysts in the medullary interstitium, loss of medullary vascular bundles, and decreased urine concentrating ability. In transgenic reporter mice with normal angiopoietin-Tie2 signaling, medullary AVR exhibited an unusual hybrid endothelial phenotype, expressing lymphatic markers (prospero homeobox protein 1 and vascular endothelial growth factor receptor 3) as well as blood endothelial markers (CD34, endomucin, platelet endothelial cell adhesion molecule 1, and plasmalemmal vesicle-associated protein). Taken together, our data redefine the AVRs as Tie2 signaling-dependent specialized hybrid vessels and provide genetic evidence of the critical role of AVR in the countercurrent exchange mechanism and the structural integrity of the renal medulla. PMID- 29237741 TI - Liberating cohesin from cohesion. AB - Cohesin was identified through its major role in holding sister chromatids together. We are learning through analysis of cohesin and other members of the protein family (SMC [structural maintenance of chromosomes]) and their regulators that these ring complexes contribute to chromosome organization and dynamics throughout the cell cycle. We need to consider not only how ring complexes are regulated but how they interact with their fluctuating chromatin substrate. PMID- 29237740 TI - GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation. AB - Collecting ducts make up the distal-most tubular segments of the kidney, extending from the cortex, where they connect to the nephron proper, into the medulla, where they release urine into the renal pelvis. During water deprivation, body water preservation is ensured by the selective transepithelial reabsorption of water into the hypertonic medullary interstitium mediated by collecting ducts. The collecting duct epithelium forms tight junctions composed of barrier-enforcing claudins and exhibits a higher transepithelial resistance than other segments of the renal tubule exhibit. However, the functional relevance of this strong collecting duct epithelial barrier is unresolved. Here, we report that collecting duct-specific deletion of an epithelial transcription factor, grainyhead-like 2 (GRHL2), in mice led to reduced expression of tight junction-associated barrier components, reduced collecting duct transepithelial resistance, and defective renal medullary accumulation of sodium and other osmolytes. In vitro, Grhl2-deficient collecting duct cells displayed increased paracellular flux of sodium, chloride, and urea. Consistent with these effects, Grhl2-deficient mice had diabetes insipidus, produced dilute urine, and failed to adequately concentrate their urine after water restriction, resulting in susceptibility to prerenal azotemia. These data indicate a direct functional link between collecting duct epithelial barrier characteristics, which appear to prevent leakage of interstitial osmolytes into urine, and body water homeostasis. PMID- 29237742 TI - Corrigendum: Coupled enhancer and coding sequence evolution of a homeobox gene shaped leaf diversity. PMID- 29237744 TI - Change in Cognitive Function in the Month After Hospitalization for Acute Coronary Syndromes: Findings From TRACE-CORE (Transition, Risks, and Actions in Coronary Events-Center for Outcomes Research and Education). AB - BACKGROUND: Cognitive function is often impaired during hospitalization, but whether this impairment resolves or persists after discharge is unknown. METHODS AND RESULTS: We enrolled (April 2011-May 2013) and interviewed during hospitalization and 1-month post-discharge 1521 nondemented acute coronary syndrome survivors enrolled in TRACE (Transitions, Risks and Actions in Coronary Events). Cognitive function was assessed using the Telephone Interview of Cognitive Status (range: 0-41) at both time points. Patients reported demographic and psychosocial characteristics and medical records were abstracted. Using the Telephone Interview of Cognitive Status cut point of <=28, we defined 4 groups of cognitive change based on cognitive status during hospitalization and 1 month later: consistently impaired, transiently impaired, newly impaired, and consistently nonimpaired. Characteristics associated with cognitive change categories were examined using multinomial logistic regression. Participants were 67% male, 84% non-Hispanic white, with mean age+/-SD 62+/-11 years; 16% (n=237) were cognitively impaired during hospitalization, and 11% (n=174) were impaired 1 month after discharge. Overall, 80% were consistently nonimpaired, 9% transiently impaired, 7% consistently impaired, and 4% newly impaired. Lower education level, minority status, low health literacy and numeracy, and higher severity of disease were independently associated with cognitive impairment during and after hospitalization. Male sex was associated with increased risk of cognitive impairment after hospital discharge. CONCLUSIONS: Cognitive function changes during the transition from hospital to home after acute coronary syndrome are less favorable for men and those with psychosocial vulnerability. Assessing cognitive status both in hospital and post-discharge is important for detecting patients who could benefit from tailored transitional care including early follow up and booster discharge instructions. PMID- 29237745 TI - Dyspnea Among Patients With Chronic Total Occlusions Undergoing Percutaneous Coronary Intervention: Prevalence and Predictors of Improvement. AB - BACKGROUND: Dyspnea is a common angina equivalent that adversely affects quality of life, but its prevalence in patients with chronic total occlusions (CTOs) and predictors of its improvement after CTO percutaneous coronary intervention (PCI) are unknown. We examined the prevalence of dyspnea and predictors of its improvement among patients selected for CTO PCI. METHODS AND RESULTS: In the OPEN CTO registry (Outcomes, Patient health status, and Efficiency iN Chronic Total Occlusion) of 12 US experienced centers, 987 patients undergoing CTO PCI (procedure success 82%) were assessed for dyspnea with the Rose Dyspnea Scale at baseline and 1 month after CTO PCI. Rose Dyspnea Scale scores range from 0 to 4 with higher scores indicating more dyspnea with common activities. A total of 800 (81%) reported some dyspnea at baseline with a mean (+/-SD) Rose Dyspnea Scale of 2.8+/-1.2. Dyspnea improvement was defined as a >=1 point decrease in Rose Dyspnea Scale from baseline to 1 month. Predictors of dyspnea improvement were examined with a modified Poisson regression model. Patients with dyspnea were more likely to be female, obese, smokers, and to have more comorbidities and angina. Among patients with baseline dyspnea, 70% reported less dyspnea at 1 month after CTO PCI. Successful CTO PCI was associated with more frequent dyspnea improvement than failure, even after adjustment for other clinical variables. Anemia, depression, and lung disease were associated with less dyspnea improvement after PCI. CONCLUSIONS: Dyspnea is a common symptom among patients undergoing CTO PCI and improves significantly with successful PCI. Patients with other potentially noncardiac causes of dyspnea reported less dyspnea improvement after CTO PCI. PMID- 29237747 TI - Coronary Chronic Total Occlusions: Time to Abandon a Culture of Therapeutic Nihilism? PMID- 29237748 TI - Peer Review of a Manuscript Submission: A How-To Guide for Effective and Efficient Commentary. PMID- 29237746 TI - Impact of Telemonitoring on Health Status. AB - BACKGROUND: Although noninvasive telemonitoring in patients with heart failure does not reduce mortality or hospitalizations, less is known about its effect on health status. This study reports the results of a randomized clinical trial of telemonitoring on health status in patients with heart failure. METHODS AND RESULTS: Among 1521 patients with recent heart failure hospitalization randomized in the Tele-HF trial (Telemonitoring to Improve Heart Failure Outcomes), 756 received telephonic monitoring and 765 usual care. Disease-specific health status was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) within 2 weeks of discharge and at 3 and 6 months. Repeated measures linear regression models were used to assess differences in KCCQ scores between patients assigned to telemonitoring and usual care over 6 months. The baseline characteristics of the 2 treatment arms were similar (mean age, 61 years; 43% female and 39% black). Over the 6-month follow-up period, there was a statistically significant, but clinically small, difference between the 2 groups in their KCCQ overall summary and subscale scores. The average KCCQ overall summary score for those receiving telemonitoring was 2.5 points (95% confidence interval, 0.38-4.67; P=0.02) higher than usual care, driven primarily by improvements in symptoms (3.5 points; 95% confidence interval, 1.18-5.82; P=0.003) and social function (3.1 points; 95% confidence interval, 0.30-6.00; P=0.03). CONCLUSIONS: Telemonitoring results in statistically significant, but clinically small, improvements in health status when compared with usual care. Given that the KCCQ was a secondary outcome, the benefits should be confirmed in future studies. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00303212. PMID- 29237749 TI - NO and COX2: Dual targeting for aggressive cancers. PMID- 29237751 TI - The hydraulic lift of early states societies. PMID- 29237750 TI - Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice. AB - A single-nucleotide polymorphism in the human arylamine N-acetyltransferase 2 (Nat2) gene has recently been identified as associated with insulin resistance in humans. To understand the cellular and molecular mechanisms by which alterations in Nat2 activity might cause insulin resistance, we examined murine ortholog Nat1 knockout (KO) mice. Nat1 KO mice manifested whole-body insulin resistance, which could be attributed to reduced muscle, liver, and adipose tissue insulin sensitivity. Hepatic and muscle insulin resistance were associated with marked increases in both liver and muscle triglyceride (TAG) and diacylglycerol (DAG) content, which was associated with increased PKCepsilon activation in liver and increased PKCtheta activation in skeletal muscle. Nat1 KO mice also displayed reduced whole-body energy expenditure and reduced mitochondrial oxygen consumption in white adipose tissue, brown adipose tissue, and hepatocytes. Taken together, these studies demonstrate that Nat1 deletion promotes reduced mitochondrial activity and is associated with ectopic lipid-induced insulin resistance. These results provide a potential genetic link among mitochondrial dysfunction with increased ectopic lipid deposition, insulin resistance, and type 2 diabetes. PMID- 29237752 TI - Ser7 of RNAPII-CTD facilitates heterochromatin formation by linking ncRNA to RNAi. AB - Some long noncoding RNAs (ncRNAs) transcribed by RNA polymerase II (RNAPII) are retained on chromatin, where they regulate RNAi and chromatin structure. The molecular basis of this retention remains unknown. We show that in fission yeast serine 7 (Ser7) of the C-terminal domain (CTD) of RNAPII is required for efficient siRNA generation for RNAi-dependent heterochromatin formation. Surprisingly, Ser7 facilitates chromatin retention of nascent heterochromatic RNAs (hRNAs). Chromatin retention of hRNAs and siRNA generation requires both Ser7 and an RNA-binding activity of the chromodomain of Chp1, a subunit of the RNA-induced transcriptional silencing (RITS) complex. Furthermore, RITS associates with RNAPII in a Ser7-dependent manner. We propose that Ser7 promotes cotranscriptional chromatin retention of hRNA by recruiting the RNA-chromatin connector protein Chp1, which facilitates RNAi-dependent heterochromatin formation. Our findings reveal a function of the CTD code: linking ncRNA transcription to RNAi for heterochromatin formation. PMID- 29237754 TI - The ins and outs of acid-base transport in skeletal muscle. PMID- 29237753 TI - Troy/TNFRSF19 marks epithelial progenitor cells during mouse kidney development that continue to contribute to turnover in adult kidney. AB - During kidney development, progressively committed progenitor cells give rise to the distinct segments of the nephron, the functional unit of the kidney. Similar segment-committed progenitor cells are thought to be involved in the homeostasis of adult kidney. However, markers for most segment-committed progenitor cells remain to be identified. Here, we evaluate Troy/TNFRSF19 as a segment-committed nephron progenitor cell marker. Troy is expressed in the ureteric bud during embryonic development. During postnatal nephrogenesis, Troy+ cells are present in the cortex and papilla and display an immature tubular phenotype. Tracing of Troy+ cells during nephrogenesis demonstrates that Troy+ cells clonally give rise to tubular structures that persist for up to 2 y after induction. Troy+ cells have a 40-fold higher capacity than Troy- cells to form organoids, which is considered a stem cell property in vitro. In the adult kidney, Troy+ cells are present in the papilla and these cells continue to contribute to collecting duct formation during homeostasis. The number of Troy-derived cells increases after folic acid-induced injury. Our data show that Troy marks a renal stem/progenitor cell population in the developing kidney that in adult kidney contributes to homeostasis, predominantly of the collecting duct, and regeneration. PMID- 29237756 TI - The prokaryotic Na+/Ca2+ exchanger NCX_Mj transports Na+ and Ca2+ in a 3:1 stoichiometry. AB - Intracellular Ca2+ signals control a wide array of cellular processes. These signals require spatial and temporal regulation of the intracellular Ca2+ concentration, which is achieved in part by a class of ubiquitous membrane proteins known as sodium-calcium exchangers (NCXs). NCXs are secondary-active antiporters that power the translocation of Ca2+ across the cell membrane by coupling it to the flux of Na+ in the opposite direction, down an electrochemical gradient. Na+ and Ca2+ are translocated in separate steps of the antiport cycle, each of which is thought to entail a mechanism whereby ion-binding sites within the protein become alternately exposed to either side of the membrane. The prokaryotic exchanger NCX_Mj, the only member of this family with known structure, has been proposed to be a good functional and structural model of mammalian NCXs; yet our understanding of the functional properties of this protein remains incomplete. Here, we study purified NCX_Mj reconstituted into liposomes under well-controlled experimental conditions and demonstrate that this homologue indeed shares key functional features of the NCX family. Transport assays and reversal-potential measurements enable us to delineate the essential characteristics of this antiporter and establish that its ion-exchange stoichiometry is 3Na+:1Ca2+ Together with previous studies, this work confirms that NCX_Mj is a valid model system to investigate the mechanism of ion recognition and membrane transport in sodium-calcium exchangers. PMID- 29237755 TI - Differential contribution of Ca2+ sources to day and night BK current activation in the circadian clock. AB - Large conductance K+ (BK) channels are expressed widely in neurons, where their activation is regulated by membrane depolarization and intracellular Ca2+ (Ca2+i). To enable this regulation, BK channels functionally couple to both voltage-gated Ca2+ channels (VGCCs) and channels mediating Ca2+ release from intracellular stores. However, the relationship between BK channels and their specific Ca2+ source for particular patterns of excitability is not well understood. In neurons within the suprachiasmatic nucleus (SCN)-the brain's circadian clock-BK current, VGCC current, and Ca2+i are diurnally regulated, but paradoxically, BK current is greatest at night when VGCC current and Ca2+i are reduced. Here, to determine whether diurnal regulation of Ca2+ is relevant for BK channel activation, we combine pharmacology with day and night patch-clamp recordings in acute slices of SCN. We find that activation of BK current depends primarily on three types of channels but that the relative contribution changes between day and night. BK current can be abrogated with nimodipine during the day but not at night, establishing that L-type Ca2+ channels (LTCCs) are the primary daytime Ca2+ source for BK activation. In contrast, dantrolene causes a significant decrease in BK current at night, suggesting that nighttime BK activation is driven by ryanodine receptor (RyR)-mediated Ca2+i release. The N- and P/Q-type Ca2+ channel blocker omega-conotoxin MVIIC causes a smaller reduction of BK current that does not differ between day and night. Finally, inhibition of LTCCs, but not RyRs, eliminates BK inactivation, but the BK beta2 subunit was not required for activation of BK current by LTCCs. These data reveal a dynamic coupling strategy between BK channels and their Ca2+ sources in the SCN, contributing to diurnal regulation of SCN excitability. PMID- 29237757 TI - Urine lipoarabinomannan glycan in HIV-negative patients with pulmonary tuberculosis correlates with disease severity. AB - An accurate urine test for pulmonary tuberculosis (TB), affecting 9.6 million patients worldwide, is critically needed for surveillance and treatment management. Past attempts failed to reliably detect the mycobacterial glycan antigen lipoarabinomannan (LAM), a marker of active TB, in HIV-negative, pulmonary TB-infected patients' urine (85% of 9.6 million patients). We apply a copper complex dye within a hydrogel nanocage that captures LAM with very high affinity, displacing interfering urine proteins. The technology was applied to study pretreatment urine from 48 Peruvian patients, all negative for HIV, with microbiologically confirmed active pulmonary TB. LAM was quantitatively measured in the urine with a sensitivity of >95% and a specificity of >80% (n = 101) in a concentration range of 14 to 2000 picograms per milliliter, as compared to non TB, healthy and diseased, age-matched controls (evaluated by receiver operating characteristic analysis; area under the curve, 0.95; 95% confidence interval, 0.9005 to 0.9957). Urinary LAM was elevated in patients with a higher mycobacterial burden (n = 42), a higher proportion of weight loss (n = 37), or cough (n = 50). The technology can be configured in a variety of formats to detect a panel of previously undetectable very-low-abundance TB urinary analytes. Eight of nine patients who were smear-negative and culture-positive for TB tested positive for urinary LAM. This technology has broad implications for pulmonary TB screening, transmission control, and treatment management for HIV-negative patients. PMID- 29237758 TI - Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis. AB - Persistent myofibroblast activation distinguishes pathological fibrosis from physiological wound healing, suggesting that therapies selectively inducing myofibroblast apoptosis could prevent progression and potentially reverse established fibrosis in diseases such as scleroderma, a heterogeneous autoimmune disease characterized by multiorgan fibrosis. We demonstrate that fibroblast-to myofibroblast differentiation driven by matrix stiffness increases the mitochondrial priming (proximity to the apoptotic threshold) of these activated cells. Mitochondria in activated myofibroblasts, but not quiescent fibroblasts, are primed by death signals such as the proapoptotic BH3-only protein BIM, which creates a requirement for tonic expression of the antiapoptotic protein BCL-XL to sequester BIM and ensure myofibroblast survival. Myofibroblasts become particularly susceptible to apoptosis induced by "BH3 mimetic" drugs inhibiting BCL-XL such as ABT-263. ABT-263 displaces BCL-XL binding to BIM, allowing BIM to activate apoptosis on stiffness-primed myofibroblasts. Therapeutic blockade of BCL-XL with ABT-263 (navitoclax) effectively treats established fibrosis in a mouse model of scleroderma dermal fibrosis by inducing myofibroblast apoptosis. Using a BH3 profiling assay to assess mitochondrial priming in dermal fibroblasts derived from patients with scleroderma, we demonstrate that the extent of apoptosis induced by BH3 mimetic drugs correlates with the extent of their mitochondrial priming, indicating that BH3 profiling could predict apoptotic responses of fibroblasts to BH3 mimetic drugs in patients with scleroderma. Together, our findings elucidate the potential efficacy of targeting myofibroblast antiapoptotic proteins with BH3 mimetic drugs in scleroderma and other fibrotic diseases. PMID- 29237759 TI - Durability and correlates of vaccine protection against Zika virus in rhesus monkeys. AB - An effective Zika virus (ZIKV) vaccine will require long-term durable protection. Several ZIKV vaccine candidates have demonstrated protective efficacy in nonhuman primates, but these studies have typically involved ZIKV challenge shortly after vaccination at peak immunity. We show that a single immunization with an adenovirus vector-based vaccine, as well as two immunizations with a purified inactivated virus vaccine, afforded robust protection against ZIKV challenge in rhesus monkeys at 1 year after vaccination. In contrast, two immunizations with an optimized DNA vaccine, which provided complete protection at peak immunity, resulted in reduced protective efficacy at 1 year that was associated with declining neutralizing antibody titers to subprotective levels. These data define a microneutralization log titer of 2.0 to 2.1 as the threshold required for durable protection against ZIKV challenge in this model. Moreover, our findings demonstrate that protection against ZIKV challenge in rhesus monkeys is possible for at least 1 year with a single-shot vaccine. PMID- 29237761 TI - Erratum for the Research Article: "An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target" by S. K. Mahil, M. Catapano, P. Di Meglio, N. Dand, H. Ahlfors, I. M. Carr, C. H. Smith, R. C. Trembath, M. Peakman, J. Wright, F. D. Ciccarelli, J. N. Barker, F. Capon. PMID- 29237760 TI - Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel. AB - The AAA+ adenosine triphosphatase (ATPase) Thorase plays a critical role in controlling synaptic plasticity by regulating the expression of surface alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Bidirectional sequencing of exons of ATAD1, the gene encoding Thorase, in a cohort of patients with schizophrenia and healthy controls revealed rare Thorase variants. These variants caused defects in glutamatergic signaling by impairing AMPAR internalization and recycling in mouse primary cortical neurons. This contributed to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Heterozygous Thorase-deficient mice engineered to express these Thorase variants showed altered synaptic transmission and several behavioral deficits compared to heterozygous Thorase-deficient mice expressing wild-type Thorase. These behavioral impairments were rescued by the competitive AMPAR antagonist Perampanel, a U.S. Food and Drug Administration-approved drug. These findings suggest that Perampanel may be useful for treating disorders involving compromised AMPAR-mediated glutamatergic neurotransmission. PMID- 29237764 TI - Safety in numbers. PMID- 29237762 TI - Effect of population viral load on prospective HIV incidence in a hyperendemic rural African community. AB - Monitoring HIV population viral load (PVL) has been advocated as an important means of inferring HIV transmission potential and predicting the future rate of new HIV infections (HIV incidence) in a particular community. However, the relationship between PVL measures and directly measured HIV incidence has not been quantified in any setting and, most importantly, in a hyperendemic sub Saharan African setting. We assessed this relationship using one of Africa's largest population-based prospective population cohorts in rural KwaZulu-Natal, South Africa in which we followed 8732 HIV-uninfected participants between 2011 and 2015. Despite clear evidence of spatial clustering of high viral loads in some communities, our results demonstrate that PVL metrics derived from aggregation of viral load data only from the HIV-positive members of a particular community did not predict HIV incidence in this typical hyperendemic, rural African population. Only once we used modified PVL measures, which combined viral load information with the underlying spatial variation in the proportion of the population infected (HIV prevalence), did we find a consistently strong relationship with future risk of HIV acquisition. For example, every 1% increase in the overall proportion of a population having detectable virus (PDV P ) was independently associated with a 6.3% increase in an individual's risk of HIV acquisition (P = 0.001). In hyperendemic African populations, these modified PVL indices could play a key role in targeting and monitoring interventions in the most vulnerable communities where the future rate of new HIV infections is likely to be highest. PMID- 29237763 TI - Bisphenol A, phthalate metabolites and glucose homeostasis in healthy normal weight children. AB - INTRODUCTION: Bisphenol A and several of the most commonly used phthalates have been associated with adverse metabolic health effects such as obesity and diabetes. Therefore, we analyzed these man-made chemicals in first morning urine samples from 107 healthy normal-weight Danish children and adolescents. METHOD: This was a cross-sectional study. Participants were recruited as part of the Copenhagen Puberty Study. The subjects were evaluated by an oral glucose tolerance test (OGTT), a dual-energy X-ray absorptiometry (DXA) scan, direct oxygen uptake measurement during cycle ergometry and fasting blood samples. First morning urine was collected and phthalate metabolites and BPA were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with prior enzymatic deconjugation. Individual chemical concentrations were divided into tertiles and analyzed in relation to biological outcome. RESULTS: Children in the lowest tertile of urinary BPA had significantly higher peak insulin levels during OGTT (P = 0.01), lower insulin sensitivity index (P < 0.01), higher leptin (P = 0.03), triglyceride (P < 0.01) and total cholesterol levels (P = 0.04), lower aerobic fitness (P = 0.02) and a tendency toward higher fat mass index (P = 0.1) compared with children in the highest tertile for uBPA. No significant differences in anthropometrics, body composition or glucose metabolism were associated with any of the phthalate metabolites measured. CONCLUSION: This pilot study on healthy normal-weight children suggests an inverse association between BPA and insulin resistance. Our findings contrast other cross-sectional studies showing a positive association for BPA, which may be due to confounding or reverse causation because diet is an important source of both BPA exposure and obesity. PMID- 29237765 TI - Sensing in a noisy world: lessons from auditory specialists, echolocating bats. AB - All animals face the essential task of extracting biologically meaningful sensory information from the 'noisy' backdrop of their environments. Here, we examine mechanisms used by echolocating bats to localize objects, track small prey and communicate in complex and noisy acoustic environments. Bats actively control and coordinate both the emission and reception of sound stimuli through integrated sensory and motor mechanisms that have evolved together over tens of millions of years. We discuss how bats behave in different ecological scenarios, including detecting and discriminating target echoes from background objects, minimizing acoustic interference from competing conspecifics and overcoming insect noise. Bats tackle these problems by deploying a remarkable array of auditory behaviors, sometimes in combination with the use of other senses. Behavioral strategies such as ceasing sonar call production and active jamming of the signals of competitors provide further insight into the capabilities and limitations of echolocation. We relate these findings to the broader topic of how animals extract relevant sensory information in noisy environments. While bats have highly refined abilities for operating under noisy conditions, they face the same challenges encountered by many other species. We propose that the specialized sensory mechanisms identified in bats are likely to occur in analogous systems across the animal kingdom. PMID- 29237766 TI - The opercular mouth-opening mechanism of largemouth bass functions as a 3D four bar linkage with three degrees of freedom. AB - The planar, one degree of freedom (1-DoF) four-bar linkage is an important model for understanding the function, performance and evolution of numerous biomechanical systems. One such system is the opercular mechanism in fishes, which is thought to function like a four-bar linkage to depress the lower jaw. While anatomical and behavioral observations suggest some form of mechanical coupling, previous attempts to model the opercular mechanism as a planar four-bar have consistently produced poor model fits relative to observed kinematics. Using newly developed, open source mechanism fitting software, we fitted multiple three dimensional (3D) four-bar models with varying DoF to in vivo kinematics in largemouth bass to test whether the opercular mechanism functions instead as a 3D four-bar with one or more DoF. We examined link position error, link rotation error and the ratio of output to input link rotation to identify a best-fit model at two different levels of variation: for each feeding strike and across all strikes from the same individual. A 3D, 3-DoF four-bar linkage was the best-fit model for the opercular mechanism, achieving link rotational errors of less than 5%. We also found that the opercular mechanism moves with multiple degrees of freedom at the level of each strike and across multiple strikes. These results suggest that active motor control may be needed to direct the force input to the mechanism by the axial muscles and achieve a particular mouth-opening trajectory. Our results also expand the versatility of four-bar models in simulating biomechanical systems and extend their utility beyond planar or single-DoF systems. PMID- 29237767 TI - A new method to characterize function of the Drosophila heart by means of optical flow. AB - The minuteness of Drosophila poses a challenge to quantify performance of its tubular heart and computer-aided analysis of its beating heart has evolved as a resilient compromise between instrumental costs and data robustness. Here, we introduce an optical flow algorithm (OFA) that continuously registers coherent movement within videos of the beating Drosophila heart and uses this information to subscribe the time course of observation with characteristic phases of cardiac contraction or relaxation. We report that the OFA combines high discriminatory power with robustness to characterize the performance of the Drosophila tubular heart using indicators from human cardiology. We provide proof of this concept using the test bed of established cardiac conditions that include the effects of ageing, knockdown of the slow repolarizing potassium channel subunit KCNQ and ras mediated hypertrophy of the heart tube. Together, this establishes the analysis of coherent movement as a suitable indicator of qualitative changes of the heart's beating characteristics, which improves the usefulness of Drosophila as a model of cardiac diseases. PMID- 29237768 TI - Correction: The energetic cost of filtration by demosponges and their behavioural response to ambient currents. PMID- 29237769 TI - Correction: Long-axis twisting during locomotion of elongate fishes. PMID- 29237770 TI - Correction: Honeybees in a virtual reality environment learn unique combinations of colour and shape. PMID- 29237771 TI - Correction: Audiograms of three subterranean rodent species (genus Fukomys) determined by auditory brainstem responses reveal extremely poor high-frequency cut-offs. PMID- 29237772 TI - 2017 ASCB Annual Meeting Abstracts. PMID- 29237773 TI - A Subset of Human Autoreactive CD1c-Restricted T Cells Preferentially Expresses TRBV4-1+ TCRs. AB - In humans, a substantial portion of T cells recognize lipids presented by the monomorphic CD1 proteins. Recent studies have revealed the molecular basis of mycobacterial lipid recognition by CD1c-restricted T cells. Subsets of CD1c restricted T cells recognize self-lipids in addition to foreign lipids, which may have implications in human diseases involving autoimmunity and malignancy. However, the molecular identity of these self-reactive T cells remains largely elusive. In this study, using a novel CD1c+ artificial APC (aAPC)-based system, we isolated human CD1c-restricted autoreactive T cells and characterized them at the molecular level. By using the human cell line K562, which is deficient in MHC class I/II and CD1 expression, we generated an aAPC expressing CD1c as the sole Ag-presenting molecule. When stimulated with this CD1c+ aAPC presenting endogenous lipids, a subpopulation of primary CD4+ T cells from multiple donors was consistently activated, as measured by CD154 upregulation and cytokine production in a CD1c-specific manner. These activated CD4+ T cells preferentially expressed TRBV4-1+ TCRs. Clonotypic analyses of the reconstituted TRBV4-1+ TCR genes confirmed CD1c-restricted autoreactivity of this repertoire, and the strength of CD1c reactivity was influenced by the diversity of CDR3beta sequences. Finally, alanine scanning of CDR1 and CDR2 sequences of TRBV4-1 revealed two unique residues, Arg30 and Tyr51, as critical in conferring CD1c restricted autoreactivity, thus elucidating the molecular basis of the observed V gene bias. These data provide new insights into the molecular identity of human autoreactive CD1c-restricted T cells. PMID- 29237774 TI - Quantitative Multiplexed Imaging Analysis Reveals a Strong Association between Immunogen-Specific B Cell Responses and Tonsillar Germinal Center Immune Dynamics in Children after Influenza Vaccination. AB - Generation of Ag-specific humoral responses requires the orchestrated development and function of highly specialized immune cells in secondary lymphoid organs. We used a multiparametric approach combining flow cytometry, confocal microscopy, and histocytometry to analyze, for the first time to our knowledge in children, tonsils from seasonal influenza-vaccinated children. We used these novel imaging assays to address the mucosal immune dynamics in tonsils investigating the spatial positioning, frequency, and phenotype of immune cells after vaccination. Vaccination was associated with a significantly higher frequency of follicular helper CD4 T cells compared with the unvaccinated control group. The imaging analysis revealed that potential suppressor (FOXP3hi) CD4 T cells are mainly located in extrafollicular areas. Furthermore, a significantly reduced frequency of both follicular and extrafollicular FOXP3hi CD4 T cells was found in the vaccine group compared with the control group. Levels of circulating CXCL13 were higher in those vaccinated compared with controls, mirroring an increased germinal center reactivity in the tonsils. Notably, a strong correlation was found between the frequency of tonsillar T follicular helper cells and tonsillar Ag-specific Ab-secreting cells. These data demonstrate that influenza vaccination promotes the prevalence of relevant immune cells in tonsillar follicles and support the use of tonsils as lymphoid sites for the study of germinal center reactions after vaccination in children. PMID- 29237775 TI - Induction of Immunosuppressive CD8+CD25+FOXP3+ Regulatory T Cells by Suboptimal Stimulation with Staphylococcal Enterotoxin C1. AB - Superantigens (SAgs) produced by Staphylococcus aureus at high concentrations induce proliferation of T cells bearing specific TCR Vbeta sequences and massive cytokinemia that cause toxic shock syndrome. However, the biological relevance of SAgs produced at very low concentrations during asymptomatic colonization or chronic infections is not understood. In this study, we demonstrate that suboptimal stimulation of human PBMCs with a low concentration (1 ng/ml) of staphylococcal enterotoxin C1, at which half-maximal T cell proliferation was observed, induced CD8+CD25+ T cells expressing markers related to regulatory T cells (Tregs), such as IFN-gamma, IL-10, TGF-beta, FOXP3, CD28, CTLA4, TNFR2, CD45RO, and HLA-DR. Importantly, these CD8+CD25+ T cells suppressed responder cell proliferation mediated in contact-dependent and soluble factor-dependent manners, involving galectin-1 and granzymes, respectively. In contrast, optimal stimulation of human PBMCs with a high concentration (1 MUg/ml) of staphylococcal enterotoxin C1, at which maximal T cell proliferation was observed, also induced similar expression of markers related to Tregs, including FOXP3 in CD8+CD25+ cells, but these T cells were not functionally immunosuppressive. We further demonstrated that SAg-induced TCR Vbeta-restricted and MHC class II-restricted expansion of immunosuppressive CD8+CD25+ T cells is independent of CD4+ T cells. Our results suggest that the concentration of SAg strongly affects the functional characteristics of activated T cells, and low concentrations of SAg produced during asymptomatic colonization or chronic S. aureus infection induce immunosuppressive CD8+ Tregs, potentially promoting colonization, propagation, and invasion of S. aureus in the host. PMID- 29237776 TI - Human Naive and Memory T Cells Display Opposite Migratory Responses to Sphingosine-1 Phosphate. AB - The role of sphingosine-1 phosphate (S1P) in leukocyte trafficking has been well deciphered in mice but remains largely unaddressed in humans. In this study, we assessed the ex vivo response to S1P of primary human T cell subsets. We found that tonsil but not blood leukocytes were responsive to S1P gradients, suggesting that T cell responsiveness is regulated during their recirculation in vivo. Tonsil naive T cells were readily chemoattracted by S1P in an FTY720-sensitive, S1PR1-dependent manner. Surprisingly, S1P had the opposite effect on effector memory T cells, resident memory T cells, and recently activated T cells, inhibiting their spontaneous or chemokine-induced migration. This inhibition was also more pronounced for CD4 T cells than for CD8 T cell subsets, and was dependent on S1PR2, as shown using the S1PR2 antagonist JTE-013. S1PR1 was progressively downregulated during T cell differentiation whereas S1PR2 expression remained stable. Our results suggest that the ratio between S1PR1 and S1PR2 governs the migratory behavior of T cell subsets. They also challenge previous models of the role of S1P in lymphocyte recirculation and suggest that S1P promotes retention of memory T cell subsets in secondary lymphoid organs, via S1PR2. PMID- 29237777 TI - CCL28-Deficient Mice Have Reduced IgA Antibody-Secreting Cells and an Altered Microbiota in the Colon. AB - CCL28 induces the migration of IgA Ab-secreting cells (ASCs) via CCR10 and also displays a potent antimicrobial activity in vitro. To explore the role of CCL28 in vivo, we generated CCL28-deficient mice. The mice exhibited a significant reduction and abnormal distribution of IgA ASCs in the lamina propria of the colon. The concentrations of total and Ag-specific IgA in the fecal extracts of CCL28-deficient mice were also drastically reduced. The average amount of IgA secreted by a single IgA ASC derived from the colon was also substantially reduced in CCL28-deficient mice. Furthermore, CCL28 was found to significantly increase the average amount of IgA secreted by a single IgA ASC derived from the colon in vitro. In contrast, the generation of IgA ASCs in Peyer's and cecal patches was not significantly impaired in CCL28-deficient mice. We also found a relative increase in the Class Bacilli in the fecal extracts of CCL28-deficient mice and demonstrated a potent antimicrobial activity of CCL28 against Bacillus cereus and Enterococcus faecalis, both of which belong to Class Bacilli. Thus, CCL28 may also suppress the outgrowth of some bacterial species by its direct antimicrobial activity. Finally, CCL28-deficient mice exhibited a highly aggravated dextran sodium sulfate-induced colitis that was ameliorated by pretreatment with antibiotics. Collectively, CCL28 plays a pivotal role in the homing, distribution, and function of IgA ASCs in the colon and may also affect the intestinal microbiota through its direct antimicrobial activity. PMID- 29237778 TI - mPGES1-Dependent Prostaglandin E2 (PGE2) Controls Antigen-Specific Th17 and Th1 Responses by Regulating T Autocrine and Paracrine PGE2 Production. AB - The integration of inflammatory signals is paramount in controlling the intensity and duration of immune responses. Eicosanoids, particularly PGE2, are critical molecules in the initiation and resolution of inflammation and in the transition from innate to acquired immune responses. Microsomal PGE synthase 1 (mPGES1) is an integral membrane enzyme whose regulated expression controls PGE2 levels and is highly expressed at sites of inflammation. PGE2 is also associated with modulation of autoimmunity through altering the IL-23/IL-17 axis and regulatory T cell (Treg) development. During a type II collagen-CFA immunization response, lack of mPGES1 impaired the numbers of CD4+ regulatory (Treg) and Th17 cells in the draining lymph nodes. Ag-experienced mPGES1-/- CD4+ cells showed impaired IL 17A, IFN-gamma, and IL-6 production when rechallenged ex vivo with their cognate Ag compared with their wild-type counterparts. Additionally, production of PGE2 by cocultured APCs synergized with that of Ag-experienced CD4+ T cells, with mPGES1 competence in the APC compartment enhancing CD4+ IL-17A and IFN-gamma responses. However, in contrast with CD4+ cells that were Ag primed in vivo, exogenous PGE2 inhibited proliferation and skewed IL-17A to IFN-gamma production under Th17 polarization of naive T cells in vitro. We conclude that mPGES1 is necessary in vivo to mount optimal Treg and Th17 responses during an Ag-driven primary immune response. Furthermore, we uncover a coordination of autocrine and paracrine mPGES1-driven PGE2 production that impacts effector T cell IL-17A and IFN-gamma responses. PMID- 29237779 TI - Estrogen Receptor alpha Signaling Exacerbates Immune-Mediated Nephropathies through Alteration of Metabolic Activity. AB - Glomerulonephritis is one of the most serious manifestations of systemic lupus erythematous (SLE). Because SLE is >=10 times more common in women, a role for estrogens in disease pathogenesis has long been suspected. Estrogen receptor alpha (ERalpha) is highly expressed in renal tissue. We asked whether ERalpha expression contributes to the development of immune-mediated nephropathies like in lupus nephritis. We tested the overall effects of estrogen receptors on the immune response by immunization with OVA and induction of chronic graft-versus host disease in female ERalpha-knockout mice. We used nephrotoxic serum nephritis as a model of immune-mediated nephropathy. We investigated the influence of ERalpha on molecular pathways during nephritis by microarray analysis of glomerular extract gene expression. We performed RNA sequencing of lupus patient whole blood to determine common pathways in murine and human nephritis. Absence of ERalpha protects female mice from developing nephritis, despite the presence of immune complexes and the production of proinflammatory cytokines in the kidneys and normal humoral responses to immunization. Time-course microarray analysis of glomeruli during nephrotoxic serum nephritis revealed significant upregulation of genes related to PPAR-mediated lipid metabolism and downregulation of genes in the retinol metabolism in wild-type females compared with ERalpha-knockout females. Similarly, RNA sequencing of lupus patient blood revealed similar expression patterns of these same pathways. During nephritis, the altered activity of metabolic pathways, such as retinol metabolism, occurs downstream of ERalpha activation and is essential for the progression to end stage renal failure. PMID- 29237781 TI - Pathogen Identification by Multiplex LightMix Real-Time PCR Assay in Patients with Meningitis and Culture-Negative Cerebrospinal Fluid Specimens. AB - Acute bacterial meningitis is a medical emergency, and delays in initiating effective antimicrobial therapy result in increased morbidity and mortality. Culture-based methods, thus far considered the "gold standard" for identifying bacterial microorganisms, require 24 to 48 h to provide a diagnosis. In addition, antimicrobial therapy is often started prior to clinical sample collection, thereby decreasing the probability of confirming the bacterial pathogen by culture-based methods. To enable a fast and accurate detection of the most important bacterial pathogens causing meningitis, namely, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Streptococcus agalactiae, and Listeria monocytogenes, we evaluated a commercially available multiplex LightMix real-time PCR (RT-PCR) in 220 cerebrospinal fluid (CSF) specimens. The majority of CSF samples were collected by lumbar puncture, but we also included some CSF samples from patients with symptoms of meningitis from the neurology department that were recovered from shunts. CSF samples were analyzed by multiplex RT-PCR enabling a first diagnosis within a few hours after sample arrival at our institute. In contrast, bacterial identification took between 24 and 48 h by culture. Overall, a high agreement of bacterial identification between culture and multiplex RT-PCR was observed (99%). Moreover, multiplex RT PCR enabled the detection of pathogens, S. pneumoniae (n = 2), S. agalactiae (n = 1), and N. meningitidis (n = 1), in four culture-negative samples. As a complement to classical bacteriological CSF culture, the LightMix RT-PCR assay proved to be valuable by improving the rapidity and accuracy of the diagnosis of bacterial meningitis. PMID- 29237782 TI - Elizabethkingia anophelis Is the Dominant Elizabethkingia Species Found in Blood Cultures in Singapore. PMID- 29237780 TI - Early Inhibition of Fatty Acid Synthesis Reduces Generation of Memory Precursor Effector T Cells in Chronic Infection. AB - Understanding the mechanisms of CD4 memory T cell (Tmem) differentiation in malaria is critical for vaccine development. However, the metabolic regulation of CD4 Tmem differentiation is not clear, particularly in persistent infections. In this study, we investigated the role of fatty acid synthesis (FAS) in Tmem development in Plasmodium chabaudi chronic mouse malaria infection. We show that T cell-specific deletion and early pharmaceutical inhibition of acetyl CoA carboxylase 1, the rate limiting step of FAS, inhibit generation of early memory precursor effector T cells (MPEC). To compare the role of FAS during early differentiation or survival of Tmem in chronic infection, a specific inhibitor of acetyl CoA carboxylase 1, 5-(tetradecyloxy)-2-furoic acid, was administered at different times postinfection. Strikingly, the number of Tmem was only reduced when FAS was inhibited during T cell priming and not during the Tmem survival phase. FAS inhibition during priming increased effector T cell (Teff) proliferation and strongly decreased peak parasitemia, which is consistent with improved Teff function. Conversely, MPEC were decreased, in a T cell-intrinsic manner, upon early FAS inhibition in chronic, but not acute, infection. Early cure of infection also increased mitochondrial volume in Tmem compared with Teff, supporting previous reports in acute infection. We demonstrate that the MPEC specific effect was due to the higher fatty acid content and synthesis in MPEC compared with terminally differentiated Teff. In conclusion, FAS in CD4 T cells regulates the early divergence of Tmem from Teff in chronic infection. PMID- 29237783 TI - Biographical Feature: Richard B. (Tom) Thomson, Jr., Ph.D., D(ABMM), F(AAM). PMID- 29237784 TI - Low Yield of FilmArray GI Panel in Hospitalized Patients with Diarrhea: an Opportunity for Diagnostic Stewardship Intervention. AB - The FilmArray GI panel (BioFire Diagnostics, Salt Lake City, UT) is a multiplex, on-demand, sample-to-answer, real-time PCR assay for the syndromic diagnosis of infectious gastroenteritis that has become widely adopted and, in some instances, has replaced conventional stool culture and parasite exams. Conventional testing has historically been restricted among hospitalized patients due to low diagnostic yield, but it is not known whether use of the FilmArray GI panel should be circumscribed. Cary-Blair stool samples submitted for FilmArray GI panel in adult patients admitted to an academic hospital from August 2015 to January 2017 were included in this study. Of 481 tests performed >72 h after admission, 29 (6.0%) were positive, all for a single target, excluding Clostridium difficile When follow-up tests beyond the first positive per hospitalization were excluded, 20 (4.8%) of 414 tests were positive. There was no difference in yield by immune status. Most targets detected were viral (79% of all positives [n = 23] and 70% in unique patients [n = 14]). All four cases positive for a bacterial target could not be confirmed and presentation was atypical, suggesting possible false positives. After removing potential false positives and chronic viral shedders, the yield was 3.0% (12/406). Repeat testing performed >72 h after admission and following a negative result within the first 72 h was done in 19 patients and 100% (22/22) remained negative. The FilmArray GI panel has low yield in adult patients hospitalized for >72 h, similar to conventional stool microbiology tests, and it is reasonable to restrict its use in this population. PMID- 29237785 TI - mcr-3 and mcr-4 Variants in Carbapenemase-Producing Clinical Enterobacteriaceae Do Not Confer Phenotypic Polymyxin Resistance. PMID- 29237786 TI - Waltzing around Sacred Cows on the Way to the Future. AB - Our mostly manual, agar-based clinical microbiology laboratory is slowly but steadily being redefined by automation and innovation. Ironically, the oldest test, the Gram stain test, is still manually read and interpreted by trained personnel. In a proof-of-concept study, Smith et al. (J. Clin. Microbiol. 56:e01521-17, 2018, https://doi.org/10.1128/JCM.01521-17) used computer imaging with a deep convolutional neural network to examine and interpret Gram-stained slides from positive blood culture bottles. In light of the shortage of medical technologists/microbiologists and the need for results from positive blood culture bottles 24/7, this paper paves the way for the next innovations for the clinical microbiology laboratory of the future. PMID- 29237787 TI - Point-Counterpoint: Piperacillin-Tazobactam Should Be Used To Treat Infections with Extended-Spectrum-Beta-Lactamase-Positive Organisms. AB - INTRODUCTIONBeta-lactam/beta-lactamase inhibitor combination antimicrobials (BLBLIs) are among the most controversial classes of antibiotic agents available for the treatment of infections caused by extended-spectrum-beta-lactamase (ESBL) producing Gram-negative bacteria (ESBL-GNR). Piperacillin-tazobactam (PTZ) is one of the most frequently utilized antibiotic agents for empirical Gram-negative bacterial coverage and remains active against a large proportion of ESBL-GNR strains. Furthermore, good antimicrobial stewardship practices encourage the use of carbapenem-sparing treatment regimens for infections due to ESBL-GNR. As rapid diagnostics are increasingly used in the clinical microbiology laboratory and have the capability of detecting CTX-M type or other ESBL resistance mechanisms, this issue continues to be pertinent. Some data imply reduced efficacy of PTZ against ESBLs. Several factors may affect a clinician's choice to use BLBLIs, including the isolate's MIC, the site and severity of infection, and the type of resistance mechanism. These factors are explored in this review of the pros and cons of BLBLI treatment of invasive infections due to ESBL-producing bacteria, as well as how laboratories should report results for BLBLIs for these organisms as they relate to antimicrobial stewardship. In this Point-Counterpoint, Audrey Schuetz provides the pro point of view and Sergio Reyes and Pranita Tamma provide the con, counterpoint view. PMID- 29237788 TI - Nucleic Acid Amplification Test Quantitation as Predictor of Toxin Presence in Clostridium difficile Infection. AB - Multistep algorithmic testing in which a sensitive nucleic acid amplification test (NAAT) is followed by a specific toxin A and toxin B enzyme immunoassay (EIA) is among the most accurate methods for Clostridium difficile infection (CDI) diagnosis. The obvious shortcoming of this approach is that multiple tests must be performed to establish a CDI diagnosis, which may delay treatment. Therefore, we sought to determine whether a preliminary diagnosis could be made on the basis of the quantitative results of the first test in algorithmic testing, which provide a measure of organism burden. To do so, we retrospectively analyzed two large collections of samples (n = 2,669 and n = 1,718) that were submitted to the laboratories of two Dutch hospitals for CDI testing. Both hospitals apply a two-step testing algorithm in which a NAAT is followed by a toxin A/B EIA. Of all samples, 208 and 113 samples, respectively, tested positive by NAAT. Among these NAAT-positive samples, significantly lower mean quantification cycle (Cq ) values were found for patients whose stool eventually tested positive for toxin, compared with patients who tested negative for toxin (mean Cq values of 24.4 versus 30.4 and 26.8 versus 32.2; P < 0.001 for both cohorts). Receiver operating characteristic curve analysis was performed to investigate the ability of Cq values to predict toxin status and yielded areas under the curve of 0.826 and 0.854. Using the optimal Cq cutoff values, prediction of the eventual toxin A/B EIA results was accurate for 78.9% and 80.5% of samples, respectively. In conclusion, Cq values can serve as predictors of toxin status but, due to the suboptimal correlation between the two tests, additional toxin testing is still needed. PMID- 29237789 TI - Community-Acquired Pneumonia in Children: the Challenges of Microbiological Diagnosis. AB - Community-acquired pneumonia (CAP) is the leading cause of mortality in children under 5 years of age globally. To improve the management of CAP, we must distinguish CAP from other common pediatric conditions and develop better diagnostic methods to detect the causative organism, so as to best direct appropriate resources in both industrialized and developing countries. Here, we review the diagnostic modalities available for identifying viruses and bacteria in the upper and lower respiratory tract of children, with a discussion of their utility and limitations in diagnosing CAP in children. PMID- 29237790 TI - Evaluation of a Novel Single-Tube Method for Extended Genotyping of Human Papillomavirus. AB - The use of high-risk human papillomavirus (HPV) testing for surveillance and clinical applications is increasing globally, and it is important that tests are evaluated to ensure they are fit for this purpose. In this study, the performance of a new HPV genotyping test, the Papilloplex high-risk HPV (HR-HPV) test, was compared to two well-established genotyping tests. Preliminary clinical performance was also ascertained for the detection of CIN2+ in a disease-enriched retrospective cohort. A panel of 500 cervical liquid-based cytology samples with known clinical outcomes were tested by the Papilloplex HR-HPV test. Analytical concordance was compared to two assays: a Linear Array (LA) HPV genotyping test and an Optiplex HPV genotyping test. The initial clinical performance for the detection for CIN2+ samples was performed and compared to that of two clinically validated HPV tests: a RealTime High-Risk HPV test (RealTime) and a Hybrid Capture 2 HPV test (HC2). High agreement for HR-HPV was observed between the Papilloplex and LA and Optiplex HPV tests (97 and 95%, respectively), with kappa values for HPV16 and HPV18 being 0.90 and 0.81 compared to the LA and 0.70 and 0.82 compared to the Optiplex test. The sensitivity, specificity, positive predictive value, and negative predictive value of the Papilloplex test for the detection of CIN2+ were 92, 54, 33, and 96%, respectively, and very similar to the values observed with RealTime and HC2. The Papilloplex HR-HPV test demonstrated a analytical performance similar to those of the two HPV genotyping tests at the HR-HPV level and the type-specific level. The preliminary data on clinical performance look encouraging, although further longitudinal studies within screening populations are required to confirm these findings. PMID- 29237791 TI - Multiplexed Tandem PCR (MT-PCR) Assay Using the Major Piroplasm Surface Protein Gene for the Diagnosis of Theileria orientalis Infection in Cattle. PMID- 29237793 TI - The pain of terror. PMID- 29237792 TI - Zoonotic Transfer of Clostridium difficile Harboring Antimicrobial Resistance between Farm Animals and Humans. AB - The emergence of Clostridium difficile as a significant human diarrheal pathogen is associated with the production of highly transmissible spores and the acquisition of antimicrobial resistance genes (ARGs) and virulence factors. Unlike the hospital-associated C. difficile RT027 lineage, the community associated C. difficile RT078 lineage is isolated from both humans and farm animals; however, the geographical population structure and transmission networks remain unknown. Here, we applied whole-genome phylogenetic analysis of 248 C. difficile RT078 strains from 22 countries. Our results demonstrate limited geographical clustering for C. difficile RT078 and extensive coclustering of human and animal strains, thereby revealing a highly linked intercontinental transmission network between humans and animals. Comparative whole-genome analysis reveals indistinguishable accessory genomes between human and animal strains and a variety of antimicrobial resistance genes in the pangenome of C. difficile RT078. Thus, bidirectional spread of C. difficile RT078 between farm animals and humans may represent an unappreciated route disseminating antimicrobial resistance genes between humans and animals. These results highlight the importance of the "One Health" concept to monitor infectious disease emergence and the dissemination of antimicrobial resistance genes. PMID- 29237795 TI - The headache of terror: A matched cohort study of adolescents from the Utoya and the HUNT Study. AB - OBJECTIVE: To elaborate the risk of headache among adolescent survivors exposed to terror. METHODS: On July 22, 2011, a lone man opened gunfire, killing 69 people at a summer camp for adolescents on the Utoya islet in Norway. All 358 adolescent survivors 13 to 20 years of age were invited to participate in the Utoya interview study. Among the 213 (59%) respondents, half (49%) were male, the mean age was 17.7 years, and 13 (6%) were severely injured. For each survivor, 8 matched controls were drawn from the population-based Young-HUNT3 Study, conducted between 2006 and 2008, with a participation rate of 73%. Recurrent migraine and tension-type headache (TTH) over the past 3 months served as main outcomes and were measured 4 to 5 months after the mass shooting with a validated headache interview, in accordance with the International Classification of Headache Disorders. RESULTS: After exposure to terror, the odds ratio for migraine was 4.27 (95% confidence interval 2.54-7.17) and for TTH was 3.39 (95% confidence interval 2.22-5.18), as estimated in multivariable logistic regression models adjusted for injury, sex, age, family structure and economy, prior exposure to physical or sexual violence, and psychological distress. The observed increased risk of headache in survivors was related largely to an increase in weekly and daily headaches. CONCLUSIONS: Exposure to terror increases risk of persistent weekly and daily migraine and TTH in adolescent survivors, above expected levels. The terrors of other violence may similarly increase the risk of frequent headaches. After severe psychological traumas, interventions may need to address survivors' pain to hinder chronification. PMID- 29237796 TI - CSF neurofilament light concentration is increased in presymptomatic CHMP2B mutation carriers. AB - OBJECTIVE: A rare cause of familial frontotemporal dementia (FTD) is a mutation in the CHMP2B gene on chromosome 3 (FTD-3), described in a Danish family. Here we examine whether CSF biomarkers change in the preclinical phase of the disease. METHODS: In this cross-sectional explorative study, we analyzed CSF samples from 16 mutation carriers and 14 noncarriers from the Danish FTD-3 family. CSF biomarkers included total tau (t-tau) and neurofilament light chain (NfL) as a marker for neurodegeneration, phosphorylated tau (p-tau) as a marker for tau pathology, beta-amyloid (Abeta) 38, 40, and 42 (Abeta38, Abeta40, and Abeta42) to monitor Abeta metabolism, and YKL-40 as a marker of neuroinflammation. Abeta isoform concentrations were measured using a multiplexed immunoassay; t-tau, p tau, NfL, and YKL-40 concentrations were measured using sandwich ELISAs. RESULTS: CSF NfL concentration was significantly increased in mutation carriers vs noncarriers. Further, CSF NfL concentration was significantly higher in symptomatic mutation carriers compared to presymptomatic carriers, and also significantly higher in presymptomatic carriers compared to noncarriers. No differences in t-tau and p-tau and YKL-40 concentrations between controls and mutation carriers were observed. CSF concentrations of the Abeta peptides Abeta38 and Abeta40 but not Abeta42 were significantly lower in mutation carriers compared to noncarriers. CONCLUSIONS: Increased NfL levels in presymptomatic individuals and in symptomatic patients with FTD-3 indicate a continuous process of neurodegeneration from the presymptomatic to symptomatic state. Although not specific for FTD-3 pathology, our data suggest that CSF NfL could serve as a valuable biomarker to detect onset of neurodegeneration in FTD-3 mutation carriers. PMID- 29237797 TI - Endothelial progenitor cells enhance blood-brain barrier permeability in subacute stroke. AB - OBJECTIVE: To study the association among endothelial progenitor cells (EPCs), subacute blood-brain barrier (BBB) permeability, and clinical outcome after ischemic stroke, determining the micro RNAs of EPCs responsible for good clinical outcome. METHODS: We included consecutive patients with nonlacunar acute ischemic strokes in the territory of a middle cerebral artery and ages between 18 and 80 years. Clinical outcome was defined as modified Rankin Scale score at 3 months. Neuroimaging was performed at day 0 and 7 by MRI, including assessment of BBB permeability by dynamic contrast enhancement. EPCs were isolated from peripheral venous blood, quantified, and submitted to in vitro functional tests, including migratory and angiogenic assays. Stroke hemodynamics were evaluated serially by ultrasound. Statistical significance was set at p < 0.05. RESULTS: We included 45 patients; mean age was 70.0 +/- 10.0 years. The in vitro functional properties of EPCs were associated with BBB permeability, particularly at day 7. The number of each EPC subset at both timepoints was not associated with BBB permeability. Permeability of BBB at day 7 was independently associated with improved clinical outcome (odds ratio 0.897; 95% confidence interval 0.816-0.986; p = 0.025). The EPCs (CD34+ cell subset) of patients with good clinical outcome showed 24 differentially expressed miRNAs, with a common effect on adherens junction pathway. CONCLUSIONS: The functional properties of EPCs are associated with enhanced subacute permeability of BBB and improved clinical outcome after acute ischemic stroke. PMID- 29237794 TI - Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting. AB - Multiple system atrophy (MSA) is a rare neurodegenerative disorder with substantial knowledge gaps despite recent gains in basic and clinical research. In order to make further advances, concerted international collaboration is vital. In 2014, an international meeting involving leaders in the field and MSA advocacy groups was convened in Las Vegas, Nevada, to identify critical research areas where consensus and progress was needed to improve understanding, diagnosis, and treatment of the disease. Eight topic areas were defined: pathogenesis, preclinical modeling, target identification, endophenotyping, clinical measures, imaging biomarkers, nonimaging biomarkers, treatments/trial designs, and patient advocacy. For each topic area, an expert served as a working group chair and each working group developed priority-ranked research recommendations with associated timelines and pathways to reach the intended goals. In this report, each groups' recommendations are provided. PMID- 29237798 TI - Differential effects of cognitive reserve and brain reserve on cognition in Alzheimer disease. AB - OBJECTIVE: To examine cross-sectional effects of cognitive reserve (CR) and brain reserve (BR) on cognition across the spectrum of Alzheimer disease (AD). METHODS: We included 663 AD biomarker-positive participants with dementia (probable AD, n = 462) or in the predementia stages (preclinical/prodromal AD, n = 201). Education was used as a proxy of CR and intracranial volume as a proxy of BR. Cognition was assessed across 5 domains (memory, attention, language, visuospatial, and executive functions). We performed multiple linear regression models to examine effects of CR and BR on cognitive domain Z scores, adjusted for cerebral atrophy. Furthermore, we assessed differences in effects according to disease stage and across degrees of total reserve using a 4-level variable (high CR/high BR, high CR/low BR, low CR/high BR, and low CR/low BR). RESULTS: We found positive, independent effects of both CR and BR across multiple cognitive domains. Stratification for disease stage showed that effects of CR on attention and executive functioning were greater in predementia than in dementia (beta = 0.39 vs beta = 0.21 [Welch t = 2.40, p < 0.01] and beta = 0.46 vs beta = 0.26 [t = 2.83, p < 0.01]). Furthermore, we found a linear trend for better cognitive performance in all domains in the high CR/high BR group, followed by high CR/low BR, low CR/high BR, and then low CR/low BR (p for trend <0.05). CONCLUSIONS: CR and BR both independently mitigate cognitive symptoms in AD. The positive effect of CR is most strongly expressed in the predementia stages and the additive effects of high CR and BR are most beneficial. PMID- 29237800 TI - An Integrated Clinic-Community Partnership for Child Obesity Treatment: A Randomized Pilot Trial. AB - BACKGROUND AND OBJECTIVES: Effective treatment of childhood obesity remains elusive. Integration of clinical and community systems may achieve effective and sustainable treatment. However, the feasibility and effectiveness of this integrated model are unknown. METHODS: We conducted a randomized clinical trial among children aged 5 to 11 presenting for obesity treatment. We randomized participants to clinical care or clinical care plus community-based programming at a local parks and recreation facility. Primary outcomes were the change in child BMI at 6 months and the intensity of the program in treatment hours. Secondary outcomes included health behaviors, fitness, attrition, and quality of life. RESULTS: We enrolled 97 children with obesity, and retention at 6 months was 70%. Participants had a mean age of 9.1 years and a mean baseline BMI z score of 2.28, and 70% were living in poverty. Intervention participants achieved more treatment hours than controls (11.4 vs 4.4, SD: 15.3 and 1.6, respectively). We did not observe differences in child BMI z score or percent of the 95th percentile at 6 months. Intervention participants had significantly greater improvements in physical activity (P = .010) and quality of life (P = .008). CONCLUSIONS: An integrated clinic-community model of child obesity treatment is feasible to deliver in a low-income and racially diverse population. As compared with multidisciplinary treatment, the integrated model provides more treatment hours, improves physical activity, and increases quality of life. Parks and recreation departments hold significant promise as a partner agency to deliver child obesity treatment. PMID- 29237799 TI - Differential associations between retinal signs and CMBs by location: The AGES Reykjavik Study. AB - OBJECTIVE: To test the hypothesis that age-related macular degeneration (AMD) and retinal microvascular signs are differentially associated with lobar and deep cerebral microbleeds (CMBs). METHODS: CMBs in lobar regions indicate cerebral amyloid angiopathy (CAA). beta-Amyloid deposits are implicated in both CAA and AMD. Deep CMBs are associated with hypertension, a major risk factor for retinal microvascular damage. This population-based cohort study included 2,502 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who undertook binocular digital retinal photographs at baseline (2002-2006) to assess retinal microvascular signs and AMD and brain MRI scan at both baseline and follow-up (2007-2011) to assess CMBs. We assessed retinal microvascular lesion burden by counting the 3 retinal microvascular signs (focal arteriolar narrowing, arteriovenous nicking, and retinopathy) concurrently present in the participant. We used multiple logistic models to examine the association of baseline retinal pathology to incident CMBs detected at follow-up. RESULTS: During an average 5.2 years of follow-up, 461 people (18.3%) developed new CMBs, including 293 in exclusively lobar regions and 168 in deep regions. Pure geographic atrophy was significantly associated with strictly lobar CMBs (multivariable-adjusted odds ratio 2.59, 95% confidence interval [CI] 1.01-6.65) but not with deep CMBs. Concurrently having >=2 retinal microvascular signs was associated with a 3-fold (95% CI 1.73-5.20) increased likelihood for deep CMBs but not exclusively lobar CMBs. CONCLUSIONS: Retinal microvascular signs and pure geographic atrophy may be associated with deep and exclusively lobar CMBs, respectively, in older people. These results have implications for further research to define the role of small vessel disease in cognitive impairment. PMID- 29237801 TI - Adolescent Loss-of-Control Eating and Weight Loss Maintenance After Bariatric Surgery. AB - BACKGROUND: Loss-of-control (LOC) eating is common in adults undergoing bariatric surgery and is associated with poorer weight outcomes. Its long-term course in adolescent bariatric surgery patients and associations with weight outcomes are unclear. METHODS: Adolescents (n = 234; age range = 13-19 years) undergoing bariatric surgery across 5 US sites were assessed for postsurgery follow-up at 6 months and 1, 2, 3, and 4 years. Descriptive statistics and generalized linear mixed models were used to describe the prevalence of LOC eating episodes involving objectively large amounts of food and continuous eating, respectively. Generalized linear mixed models investigated the association of any LOC eating with short- and long-term BMI changes. RESULTS: At baseline, objectively large LOC eating was reported by 15.4% of adolescents, and continuous LOC eating by 27.8% of adolescents. Both forms of LOC eating were significantly lower at all postsurgical time points relative to presurgery (range = 0.5%-14.5%; Ps < .05). However, both behaviors gradually increased from 6-month to 4-year follow-up (Ps < .05). Presurgical LOC eating was not related to percent BMI change over follow up (P = .79). However, LOC eating at 1-, 2-, and 3-year follow-up was associated with lower percent BMI change from baseline at the next consecutive assessment (Ps < .05). CONCLUSIONS: Although presurgical LOC eating was not related to relative weight loss after surgery, postoperative LOC eating may adversely affect long-term weight outcomes. Rates of LOC eating decreased from presurgery to 6 months postsurgery but increased thereafter. Therefore, this behavior may warrant additional empirical and clinical attention. PMID- 29237802 TI - Phase I Dose-Escalation Study of Anti-CTLA-4 Antibody Ipilimumab and Lenalidomide in Patients with Advanced Cancers. AB - Preclinical data suggest that combining a checkpoint inhibition with immunomodulatory derivative can increase anticancer response. We designed a dose escalation study using a 3 + 3 design to determine the safety, maximum tolerated dose (MTD) or recommended phase II dose (R2PD) and dose-limiting toxicities (DLT) of the anti-CTLA-4 antibody ipilimumab (1.5-3 mg/kg intravenously every 28 days * 4) and lenalidomide (10-25 mg orally daily for 21 of 28 days until disease progression or unacceptable toxicity) in advanced cancers. Total of 36 patients (Hodgkin lymphoma, 7; melanoma, 5; leiomyosarcoma, 4; renal cancer, 3; thyroid cancer, 3; other cancers, 14; median of 3 prior therapies) were enrolled. The MTD has not been reached and ipilimumab 3 mg/kg and lenalidomide 25 mg have been declared as R2PD. DLT were grade (G) 3 rash (3 patients) and G3 pancreatitis (1 patient). G3/4 drug-related toxicities other than DLT were G3 anemia (5 patients), G3 thromboembolism (2 patients), G3 thrombocytopenia, G3 rash, G3 hypopituitarism, G3 pneumonitis, G3 transaminitis, and G4 hypopituitarism (all in 1 patient). Eight patients had tumor shrinkage per immune-related response criteria (-79% to -2%) including a PR (-79% for 7.2+ months) in a refractory Hodgkin lymphoma. Using comprehensive genomic profiling, a total mutation burden (mutations/Mb) was evaluated in 17 patients, with one of the patients achieving a PR demonstrated intermediate mutation burden. In conclusion, combination of ipilimumab and lenalidomide is well tolerated and demonstrated preliminary signals of activity in patients with refractory Hodgkin lymphoma and other advanced cancers. Mol Cancer Ther; 17(3); 671-6. (c)2017 AACR. PMID- 29237803 TI - Antitumor Activity of Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor, in ETV6 NTRK3-Positive Acute Myeloid Leukemia. AB - Activation of tropomyosin receptor kinase (TRK) family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent, and selective kinase inhibitor against TRKA/B/C, ROS1, and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion-driven hematologic malignancies. In acute myelogenous leukemia (AML) cell lines with endogenous expression of the ETV6 NTRK3 fusion gene, entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with subnanomolar IC50 values. Phosphorylation of the ETV6-TRKC fusion protein and its downstream signaling effectors was inhibited by entrectinib treatment in a dose-dependent manner. In animal models, entrectinib treatment at clinically relevant doses resulted in tumor regression that was accompanied by elimination of residual cancer cells from the bone marrow. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with TRK fusion-driven AML and other hematologic malignancies. Mol Cancer Ther; 17(2); 455-63. (c)2017 AACR. PMID- 29237805 TI - Preclinical Evaluation of SCC244 (Glumetinib), a Novel, Potent, and Highly Selective Inhibitor of c-Met in MET-dependent Cancer Models. AB - Because the receptor tyrosine kinase c-Met plays a critical role in tumor growth, metastasis, tumor angiogenesis, and drug resistance, the c-Met axis represents an attractive therapeutic target. Herein, we report the first preclinical characterization of SCC244, a novel, potent, and highly selective inhibitor of c Met kinase. SCC244 showed subnanomolar potency against c-Met kinase activity and high selectivity versus 312 other tested protein kinases, making it one of the most selective c-Met inhibitors described to date. Moreover, this inhibitor profoundly and specifically inhibits c-Met signal transduction and thereby suppresses the c-Met-dependent neoplastic phenotype of tumor and endothelial cells. In xenografts of human tumor cell lines or non-small cell lung cancer and hepatocellular carcinoma patient-derived tumor tissue driven by MET aberration, SCC244 administration exhibits robust antitumor activity at the well-tolerated doses. In addition, the in vivo antitumor activity of SCC244 involves the inhibition of c-Met downstream signaling via a mechanism of combined antiproliferation and antiangiogenic effects. The results of the current study provide a strong foundation for the clinical investigation of SCC244 in patients with tumors harboring c-Met pathway alterations. Mol Cancer Ther; 17(4); 751-62. (c)2017 AACR. PMID- 29237806 TI - Afatinib Is a New Therapeutic Approach in Chordoma with a Unique Ability to Target EGFR and Brachyury. AB - Chordomas are rare bone tumors with no approved therapy. These tumors express several activated tyrosine kinase receptors, which prompted attempts to treat patients with tyrosine kinase inhibitors. Although clinical benefit was observed in phase II clinical trials with imatinib and sorafenib, and sporadically also with EGFR inhibitors, therapies evaluated to date have shown modest activity. With the goal of identifying new drugs with immediate therapeutic potential for chordoma patients, we collected clinically approved drugs and other advanced inhibitors of MET, PDGFRbeta, and EGFR tyrosine kinases, and assessed their antiproliferative activity against a panel of chordoma cell lines. Chordoma cell lines were not responsive to MET and PDGFRbeta inhibitors. U-CH1 and UM-Chor1 were sensitive to all EGFR inhibitors, whereas the remaining cell lines were generally insensitive to these drugs. Afatinib was the only EGFR inhibitor with activity across the chordoma panel. We then investigated the molecular mechanisms behind the responses observed and found that the antiproliferative IC50s correlate with the unique ability of afatinib to promote degradation of EGFR and brachyury, an embryonic transcription factor considered a key driver of chordoma. Afatinib displayed potent antitumor efficacy in U-CH1, SF8894, CF322, and CF365 chordoma tumor models in vivo In the panel analyzed, high EGFR phosphorylation and low AXL and STK33 expression correlated with higher sensitivity to afatinib and deserve further investigation as potential biomarkers of response. These data support the use of afatinib in clinical trials and provide the rationale for the upcoming European phase II study on afatinib in advanced chordoma. Mol Cancer Ther; 17(3); 603-13. (c)2017 AACR. PMID- 29237804 TI - Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer. AB - Although progesterone receptor (PR)-targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464-73. (c)2017 AACR. PMID- 29237807 TI - Molecularly Targeted Cancer Combination Therapy with Near-Infrared Photoimmunotherapy and Near-Infrared Photorelease with Duocarmycin-Antibody Conjugate. AB - Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that uses an antibody-photoabsorber conjugate (APC). However, the effect of NIR PIT can be enhanced when combined with other therapies. NIR photocaging groups, based on the heptamethine cyanine scaffold, have been developed to release bioactive molecules near targets after exposure to light. Here, we investigated the combination of NIR-PIT using panitumumab-IR700 (pan-IR700) and the NIR releasing compound, CyEt-panitumumab-duocarmycin (CyEt-Pan-Duo). Both pan-IR700 and CyEt-Pan-Duo showed specific binding to the EGFR-expressing MDAMB468 cell line in vitro In in vivo studies, additional injection of CyEt-Pan-Duo immediately after NIR light exposure resulted in high tumor accumulation and high tumor-background ratio. To evaluate the effects of combination therapy in vivo, tumor-bearing mice were separated into 4 groups: (i) control, (ii NIR-PIT, (iii) NIR-release, (iv) combination of NIR-PIT and NIR-release. Tumor growth was significantly inhibited in all treatment groups compared with the control group (P < 0.05), and significantly prolonged survival was achieved (P < 0.05 vs. control). The greatest therapeutic effect was shown with NIR-PIT and NIR-release combination therapy. In conclusion, combination therapy of NIR-PIT and NIR release enhanced the therapeutic effects compared with either NIR-PIT or NIR release therapy alone. Mol Cancer Ther; 17(3); 661-70. (c)2017 AACR. PMID- 29237808 TI - Human fetal liver cultures support multiple cell lineages that can engraft immunodeficient mice. AB - During prenatal development the liver is composed of multiple cell types with unique properties compared to their adult counterparts. We aimed to establish multilineage cultures of human fetal liver cells that could maintain stem cell and progenitor populations found in the developing liver. An aim of this study was to test if maturation of fetal hepatocytes in short-term cultures supported by epidermal growth factor and oncostatin M can improve their ability to engraft immunodeficient mice. Fetal liver cultures supported a mixture of albumin+ cytokertin-19+ hepatoblasts, hepatocytes, cholangiocytes, CD14++CD32+ liver sinusoidal endothelial cells (LSECs) and CD34+CD133+ haematopoietic stem cells. Transplantation of cultured cells into uPA-NOG or TK-NOG mice yielded long-term engraftment of hepatocytes, abundant LSEC engraftment and multilineage haematopoiesis. Haematopoietic engraftment included reconstitution of B-, T- and NK-lymphocytes. Colonies of polarized human hepatocytes were observed surrounded by human LSECs in contact with human CD45+ blood cells in the liver sinusoids. Thus, fetal liver cultures support multiple cell lineages including LSECs and haematopoietic stem cells while also promoting the ability of fetal hepatocytes to engraft adult mouse livers. Fetal liver cultures and liver-humanized mice created from these cultures can provide useful model systems to study liver development, function and disease. PMID- 29237810 TI - Behavioural tuning in a tropical amphibian along an altitudinal gradient. AB - Males of the coqui treefrog, Eleutherodactylus coqui, produce a distinct two-note 'co-qui' advertisement call from sunset to midnight throughout most of the year. Previous work established that both the spectrotemporal aspects of the call and the frequency of highest inner-ear sensitivity change with altitude above sea level. These variations are such that the frequency of the emitted co-note closely matches the frequency to which the inner ear is most sensitive. Given this parallel variation, we expected that the call-evoked behavioural response of male coqui treefrogs would also show an altitude dependence, and hypothesized that males would produce their most robust acoustical territorial response to advertisement calls that match calls from their own altitude. We tested this hypothesis in the field by studying the vocal response behaviour of coquis to playbacks of synthetic, altitude-dependent conspecific calls, and indeed found that the most robust vocal responses were obtained using stimuli closely matching the calls from the same altitude. PMID- 29237811 TI - Long-term UVB exposure promotes predator-inspection behaviour in a fish. AB - Ultraviolet-B radiation (UVB) reaching the earth's surface has increased due to human-caused stratospheric ozone depletion. Whereas the harmful effects of UVB on aquatic organisms are well studied at the molecular and cellular level, recent studies have also begun to address behavioural changes caused by sublethal amounts of UVB. However, the behavioural consequences of long-term exposure to ecologically relevant UVB levels over several life stages are virtually unknown, particularly with regard to predator-prey behaviour. We found increased predator inspection behaviour together with a smaller body length in three-spined sticklebacks (Gasterosteus aculeatus) after fish were exposed for about seven months to natural sunlight conditions with enhanced UVB, compared with full siblings exposed to natural sunlight only. The observed change in antipredator behaviour may reflect a direct behavioural response mediated through UVB-induced oxidative stress during development. Alternatively, the smaller body size in UVB exposed fish may result in an increased inspection effort allowing them to spend more time foraging. Our findings suggest that, within the scope of environmental change, UVB radiation constitutes an important stress factor by eliciting behavioural responses that influence crucial ecological processes, such as predator-prey interactions. PMID- 29237812 TI - Species richness alters spatial nutrient heterogeneity effects on above-ground plant biomass. AB - Previous studies have suggested that spatial nutrient heterogeneity promotes plant nutrient capture and growth. However, little is known about how spatial nutrient heterogeneity interacts with key community attributes to affect plant community production. We conducted a meta-analysis to investigate how nitrogen heterogeneity effects vary with species richness and plant density. Effect size was calculated using the natural log of the ratio in plant biomass between heterogeneous and homogeneous conditions. Effect sizes were significantly above zero, reflecting positive effects of spatial nutrient heterogeneity on community production. However, species richness decreased the magnitude of heterogeneity effects on above-ground biomass. The magnitude of heterogeneity effects on below ground biomass did not vary with species richness. Moreover, we detected no modification in heterogeneity effects with plant density. Our results highlight the importance of species richness for ecosystem function. Asynchrony between above- and below-ground responses to spatial nutrient heterogeneity and species richness could have significant implications for biotic interactions and biogeochemical cycling in the long term. PMID- 29237809 TI - The role of astrocytes in amyloid production and Alzheimer's disease. AB - Alzheimer's disease (AD) is marked by the presence of extracellular amyloid beta (Abeta) plaques, intracellular neurofibrillary tangles (NFTs) and gliosis, activated glial cells, in the brain. It is thought that Abeta plaques trigger NFT formation, neuronal cell death, neuroinflammation and gliosis and, ultimately, cognitive impairment. There are increased numbers of reactive astrocytes in AD, which surround amyloid plaques and secrete proinflammatory factors and can phagocytize and break down Abeta. It was thought that neuronal cells were the major source of Abeta. However, mounting evidence suggests that astrocytes may play an additional role in AD by secreting significant quantities of Abeta and contributing to overall amyloid burden in the brain. Astrocytes are the most numerous cell type in the brain, and therefore even minor quantities of amyloid secretion from individual astrocytes could prove to be substantial when taken across the whole brain. Reactive astrocytes have increased levels of the three necessary components for Abeta production: amyloid precursor protein, beta secretase (BACE1) and gamma-secretase. The identification of environmental factors, such as neuroinflammation, that promote astrocytic Abeta production, could redefine how we think about developing therapeutics for AD. PMID- 29237813 TI - Specificity of oral immune priming in the red flour beetle Tribolium castaneum. AB - Immune specificity is the degree to which a host's immune system discriminates among various pathogens or antigenic variants. Vertebrate immune memory is highly specific due to antibody responses. On the other hand, some invertebrates show immune priming, i.e. improved survival after secondary exposure to a previously encountered pathogen. Until now, specificity of priming has only been demonstrated via the septic infection route or when live pathogens were used for priming. Therefore, we tested for specificity in the oral priming route in the red flour beetle, Tribolium castaneum For priming, we used pathogen-free supernatants derived from three different strains of the entomopathogen, Bacillus thuringiensis, which express different Cry toxin variants known for their toxicity against this beetle. Subsequent exposure to the infective spores showed that oral priming was specific for two naturally occurring strains, while a third engineered strain did not induce any priming effect. Our data demonstrate that oral immune priming with a non-infectious bacterial agent can be specific, but the priming effect is not universal across all bacterial strains. PMID- 29237814 TI - Effects of mutations in phage restriction sites during escape from restriction modification. AB - Restriction-modification systems are widespread genetic elements that protect bacteria from bacteriophage infections by recognizing and cleaving heterologous DNA at short, well-defined sequences called restriction sites. Bioinformatic evidence shows that restriction sites are significantly underrepresented in bacteriophage genomes, presumably because bacteriophages with fewer restriction sites are more likely to escape cleavage by restriction-modification systems. However, how mutations in restriction sites affect the likelihood of bacteriophage escape is unknown. Using the bacteriophage lambda and the restriction-modification system EcoRI, we show that while mutation effects at different restriction sites are unequal, they are independent. As a result, the probability of bacteriophage escape increases with each mutated restriction site. Our results experimentally support the role of restriction site avoidance as a response to selection imposed by restriction-modification systems and offer an insight into the events underlying the process of bacteriophage escape. PMID- 29237816 TI - Glycogen synthase kinase 3beta inhibition enhances Notch1 recycling. AB - The Notch signaling pathway is essential throughout development and remains active into adulthood, where it performs a critical role in tissue homeostasis. The fact that defects in signaling can lead to malignancy illustrates the need to control Notch activity tightly. GSK3beta is an established regulator of the Notch signaling pathway, although its mechanism of action remains unclear. Given the emerging role for GSK3beta in receptor trafficking, we tested the idea that GSK3beta controls signaling by regulating Notch transport. Consistent with published reports, we find that GSK3beta inhibition enhances Notch1 signaling activity. Immunolocalization analysis reveals that Notch1 localization within a tubulovesicular compartment is altered when GSK3beta activity is disrupted. We also find that receptor cell surface levels increase following acute GSK3beta inhibition. This is followed by elevated Notch intra-cellular domain (NICD) production and a corresponding increase in signaling activity. Moreover, Notch transport assays reveal that receptor recycling rates increase when GSK3beta activity is inhibited. Collectively, results presented here support a model where GSK3beta regulates signaling by controlling postendocytic transport of Notch1. Given that GSK3beta activity is suppressed following stimulation by multiple signal transduction pathways, our findings also suggest that cells can modulate Notch1 activity in response to extracellular signals by mobilizing Notch1 from endosomal stores. PMID- 29237817 TI - An Arf6- and caveolae-dependent pathway links hemidesmosome remodeling and mechanoresponse. AB - Hemidesmosomes (HDs) are epithelial-specific cell-matrix adhesions that stably anchor the intracellular keratin network to the extracellular matrix. Although their main role is to protect the epithelial sheet from external mechanical strain, how HDs respond to mechanical stress remains poorly understood. Here we identify a pathway essential for HD remodeling and outline its role with respect to alpha6beta4 integrin recycling. We find that alpha6beta4 integrin chains localize to the plasma membrane, caveolae, and ADP-ribosylation factor-6+ (Arf6+) endocytic compartments. Based on fluorescence recovery after photobleaching and endocytosis assays, integrin recycling between both sites requires the small GTPase Arf6 but neither caveolin1 (Cav1) nor Cavin1. Strikingly, when keratinocytes are stretched or hypo-osmotically shocked, alpha6beta4 integrin accumulates at cell edges, whereas Cav1 disappears from it. This process, which is isotropic relative to the orientation of stretch, depends on Arf6, Cav1, and Cavin1. We propose that mechanically induced HD growth involves the isotropic flattening of caveolae (known for their mechanical buffering role) associated with integrin diffusion and turnover. PMID- 29237818 TI - Mps1 promotes chromosome meiotic chromosome biorientation through Dam1. AB - In budding yeast meiosis, homologous chromosomes become linked by chiasmata and then move back and forth on the spindle until they are bioriented, with the kinetochores of the partners attached to microtubules from opposite spindle poles. Certain mutations in the conserved kinase, Mps1, result in catastrophic meiotic segregation errors but mild mitotic defects. We tested whether Dam1, a known substrate of Mps1, was necessary for its critical meiotic role. We found that kinetochore-microtubule attachments are established even when Dam1 is not phosphorylated by Mps1, but that Mps1 phosphorylation of Dam1 sustains those connections. But the meiotic defects when Dam1 is not phosphorylated are not nearly as catastrophic as when Mps1 is inactivated. The results demonstrate that one meiotic role of Mps1 is to stabilize connections that have been established between kinetochores and microtubles by phosphorylating Dam1. PMID- 29237819 TI - Condensins promote chromosome individualization and segregation during mitosis, meiosis, and amitosis in Tetrahymena thermophila. AB - Condensin is a protein complex with diverse functions in chromatin packaging and chromosome condensation and segregation. We studied condensin in the evolutionarily distant protist model Tetrahymena, which features noncanonical nuclear organization and divisions. In Tetrahymena, the germline and soma are partitioned into two different nuclei within a single cell. Consistent with their functional specializations in sexual reproduction and gene expression, condensins of the germline nucleus and the polyploid somatic nucleus are composed of different subunits. Mitosis and meiosis of the germline nucleus and amitotic division of the somatic nucleus are all dependent on condensins. In condensin depleted cells, a chromosome condensation defect was most striking at meiotic metaphase, when Tetrahymena chromosomes are normally most densely packaged. Live imaging of meiotic divisions in condensin-depleted cells showed repeated nuclear stretching and contraction as the chromosomes failed to separate. Condensin depletion also fundamentally altered chromosome arrangement in the polyploid somatic nucleus: multiple copies of homologous chromosomes tended to cluster, consistent with a previous model of condensin suppressing default somatic pairing. We propose that failure to form discrete chromosome territories is the common cause of the defects observed in the absence of condensins. PMID- 29237820 TI - Vacuole-mediated selective regulation of TORC1-Sch9 signaling following oxidative stress. AB - Target of rapamycin complex 1 (TORC1) is a central cellular signaling coordinator that allows eukaryotic cells to adapt to the environment. In the budding yeast, Saccharomyces cerevisiae, TORC1 senses nitrogen and various stressors and modulates proteosynthesis, nitrogen uptake and metabolism, stress responses, and autophagy. There is some indication that TORC1 may regulate these downstream pathways individually. However, the potential mechanisms for such differential regulation are unknown. Here we show that the serine/threonine protein kinase Sch9 branch of TORC1 signaling depends specifically on the integrity of the vacuolar membrane, and this dependency originates in changes in Sch9 localization reflected by phosphatidylinositol 3,5-bisphosphate. Moreover, oxidative stress induces the delocalization of Sch9 from vacuoles, contributing to the persistent inhibition of the Sch9 branch after stress. Thus, our results establish that regulation of the vacuolar localization of Sch9 serves as a selective switch for the Sch9 branch in divergent TORC1 signaling. We propose that the Sch9 branch integrates the intrinsic activity of TORC1 kinase and vacuolar status, which is monitored by the phospholipids of the vacuolar membrane, into the regulation of macromolecular synthesis. PMID- 29237821 TI - Sequential actions of phosphatidylinositol phosphates regulate phagosome-lysosome fusion. AB - Phagosomes mature into phagolysosomes by sequential fusion with early endosomes, late endosomes, and lysosomes. Phagosome-with-lysosome fusion (PLF) results in the delivery of lysosomal hydrolases into phagosomes and in digestion of the cargo. The machinery that drives PLF has been little investigated. Using a cell free system, we recently identified the phosphoinositide lipids (PIPs) phosphatidylinositol 3-phosphate (PI(3)P) and phosphatidylinositol 4-phosphate (PI(4)P) as regulators of PLF. We now report the identification and the PIP requirements of four distinct subreactions of PLF. Our data show that (i) PI(3)P and PI(4)P are dispensable for the disassembly and activation of (phago)lysosomal soluble N-ethylmaleimide-sensitive factor attachment protein receptors, that (ii) PI(3)P is required only after the tethering step, and that (iii) PI(4)P is required during and after tethering. Moreover, our data indicate that PI(4)P is needed to anchor Arl8 (Arf-like GTPase 8) and its effector homotypic fusion/vacuole protein sorting complex (HOPS) to (phago)lysosome membranes, whereas PI(3)P is required for membrane association of HOPS only. Our study provides a first link between PIPs and established regulators of membrane fusion in late endocytic trafficking. PMID- 29237822 TI - Potassium-regulated distal tubule WNK bodies are kidney-specific WNK1 dependent. AB - With-no-lysine (WNK) kinases coordinate volume and potassium homeostasis by regulating renal tubular electrolyte transport. In the distal convoluted tubule (DCT), potassium imbalance causes WNK signaling complexes to concentrate into large discrete foci, which we call "WNK bodies." Although these structures have been reported previously, the mechanisms that drive their assembly remain obscure. Here, we show that kidney-specific WNK1 (KS-WNK1), a truncated kinase defective WNK1 isoform that is highly expressed in the DCT, is critical for WNK body formation. While morphologically distinct WNK bodies were evident in the distal tubules of mice subjected to dietary potassium loading and restriction, KS WNK1 knockout mice were deficient in these structures under identical conditions. Combining in vivo observations in kidney with reconstitution studies in cell culture, we found that WNK bodies are dynamic membraneless foci that are distinct from conventional organelles, colocalize with the ribosomal protein L22, and cluster the WNK signaling pathway. The formation of WNK bodies requires an evolutionarily conserved cysteine-rich hydrophobic motif harbored within a unique N-terminal exon of KS-WNK1. We propose that WNK bodies are not pathological aggregates, but rather are KS-WNK1-dependent microdomains of the DCT cytosol that modulate WNK signaling during physiological shifts in potassium balance. PMID- 29237823 TI - Examining the correlates and drivers of human population distributions across low and middle-income countries. AB - Geographical factors have influenced the distributions and densities of global human population distributions for centuries. Climatic regimes have made some regions more habitable than others, harsh topography has discouraged human settlement, and transport links have encouraged population growth. A better understanding of these types of relationships enables both improved mapping of population distributions today and modelling of future scenarios. However, few comprehensive studies of the relationships between population spatial distributions and the range of drivers and correlates that exist have been undertaken at all, much less at high spatial resolutions, and particularly across the low- and middle-income countries. Here, we quantify the relative importance of multiple types of drivers and covariates in explaining observed population densities across 32 low- and middle-income countries over four continents using machine-learning approaches. We find that, while relationships between population densities and geographical factors show some variation between regions, they are generally remarkably consistent, pointing to universal drivers of human population distribution. Here, we find that a set of geographical features relating to the built environment, ecology and topography consistently explain the majority of variability in population distributions at fine spatial scales across the low- and middle-income regions of the world. PMID- 29237824 TI - Spontaneous mirror symmetry breaking and origin of biological homochirality. AB - Recent reports on both theoretical simulations and on the physical chemistry basis of spontaneous mirror symmetry breaking (SMSB), that is, asymmetric synthesis in the absence of any chiral polarizations other than those arising from the chiral recognition between enantiomers, strongly suggest that the same nonlinear dynamics acting during the crucial stages of abiotic chemical evolution leading to the formation and selection of instructed polymers and replicators, would have led to the homochirality of instructed polymers. We review, in the first instance, which reaction networks lead to the nonlinear kinetics necessary for SMSB, and the thermodynamic features of the systems where this potentiality may be realized. This could aid not only in the understanding of SMSB, but also the design of reliable scenarios in abiotic evolution where biological homochirality could have taken place. Furthermore, when the emergence of biological chirality is assumed to occur during the stages of chemical evolution leading to the selection of polymeric species, one may hypothesize on a tandem track of the decrease of symmetry order towards biological homochirality, and the transition from the simple chemistry of astrophysical scenarios to the complexity of systems chemistry yielding Darwinian evolution. PMID- 29237826 TI - Flaccid skin protects hagfishes from shark bites. AB - Hagfishes defend themselves from fish predators by releasing large volumes of gill-clogging slime when they are attacked. Slime release is not anticipatory, but is only released after an attack has been initiated, raising the question of how hagfishes survive the initial attack, especially from biting predators such as sharks. We tested two hypotheses that could explain how hagfishes avoid damage from shark bites: puncture-resistant skin, and a loose and flaccid body design that makes it difficult for teeth to penetrate body musculature and viscera. Based on data from skin puncture tests from 22 fish species, we found that hagfish skin is not remarkably puncture resistant. Simulated shark bites on hagfish and their closest living relatives, lamprey, as well as whole animal inflation tests, revealed that the loose attachment of hagfish skin to the rest of the body and the substantial 'slack volume' in the subcutaneous sinus protect hagfish musculature and viscera from penetrating teeth. While recent work has found evidence that the capacious subcutaneous sinus in hagfishes is important for behaviours such as knot-tying and burrowing, our work demonstrates that it also plays a role in predator defence. PMID- 29237827 TI - Biomimetic wall-shaped adhesive microstructure for shear-induced attachment: the effects of pulling angle and preliminary displacement. AB - To date, a handful of different gecko-like adhesives inspired by spatula-shaped attachment hairs have been suggested based on wedge and flap geometry of contact elements. However, while these surface designs have been shown to have directionality in adhesion, high friction, long lifetime and the ability to work in vacuum, an experimental verification of the very basic concept of the pulling angle effect has not yet been reported. To close this gap, here we use wall shaped adhesive microstructures of three different flap heights to systematically study the effect of pulling angle on the normal and tangential components of the pull-off force tested at different preliminary tangential displacements. In accord with the prediction of the Kendall model for the normal component of peeling force, there is an optimal normal force that is required to detach the wall-shaped adhesive microstructure. The optimum is obtained at about half the distance needed to initiate sliding and at pulling angles that range within 60-90 degrees , which suggests that the wall-shaped microstructure can tolerate relatively large inaccuracies in the loading direction. The increase of the attachment force with increasing flap height is found to correlate with the flap thickness, which decreased with increasing flap height. PMID- 29237825 TI - Mitochondrial Ca2+ transport in the endothelium: regulation by ions, redox signalling and mechanical forces. AB - Calcium (Ca2+) transport by mitochondria is an important component of the cell Ca2+ homeostasis machinery in metazoans. Ca2+ uptake by mitochondria is a major determinant of bioenergetics and cell fate. Mitochondrial Ca2+ uptake occurs via the mitochondrial Ca2+ uniporter (MCU) complex, an inner mitochondrial membrane protein assembly consisting of the MCU Ca2+ channel, as its core component, and the MCU complex regulatory/auxiliary proteins. In this review, we summarize the current knowledge on the molecular nature of the MCU complex and its regulation by intra- and extramitochondrial levels of divalent ions and reactive oxygen species (ROS). Intracellular Ca2+ concentration ([Ca2+]i), mitochondrial Ca2+ concentration ([Ca2+]m) and mitochondrial ROS (mROS) are intricately coupled in regulating MCU activity. Here, we highlight the contribution of MCU activity to vascular endothelial cell (EC) function. Besides the ionic and oxidant regulation, ECs are continuously exposed to haemodynamic forces (either pulsatile or oscillatory fluid mechanical shear stresses, depending on the precise EC location within the arteries). Thus, we also propose an EC mechanotransduction mediated regulation of MCU activity in the context of vascular physiology and atherosclerotic vascular disease. PMID- 29237828 TI - Identification of Novel Structural Determinants in MW965 Env That Regulate the Neutralization Phenotype and Conformational Masking Potential of Primary HIV-1 Isolates. AB - The subtype C HIV-1 isolate MW965.26 is a highly neutralization-sensitive tier 1a primary isolate that is widely used in vaccine studies, but the basis for the sensitive neutralization phenotype of this isolate is not known. Substituting the MW965.26 V1/V2 domain into a neutralization-sensitive SF162 Env clone resulted in high resistance to standard anti-V3 monoclonal antibodies, demonstrating that this region possesses strong masking activity in a standard Env backbone and indicating that determinants elsewhere in MW965.26 Env are responsible for its unusual neutralization sensitivity. Key determinants for this phenotype were mapped by generating chimeric Envs between MW965.26 Env and a typical resistant Env clone, the consensus C (ConC) clone, and localized to two residues, Cys384 in the C3 domain and Asn502 in the C5 domain. Substituting the sensitizing mutations Y384C and K502N at these positions into several resistant primary Envs resulted in conversion to neutralization-sensitive phenotypes, demonstrating the generalizability of this effect. In contrast to the sensitizing effects of these substitutions on normally masked epitopes, these mutations reduced the sensitivity of VRC01-like epitopes overlapping the CD4-binding domain, while they had no effect on several other classes of broadly neutralizing epitopes, including members of several lineages of V2-dependent quaternary epitopes and representatives of N332 glycan-dependent epitopes (PGT121) and quaternary, cleavage-dependent epitopes centered at the gp41-gp120 interface on intact HIV-1 Env trimers (PGT151). These results identify novel substitutions in gp120 that regulate the expression of alternative conformations of Env and differentially affect the exposure of different classes of epitopes, thereby influencing the neutralization phenotype of primary HIV-1 isolates.IMPORTANCE A better understanding of the mechanisms that determine the wide range of neutralization sensitivity of circulating primary HIV-1 isolates would provide important information about the natural structural and conformational diversity of HIV-1 Env and how this affects the neutralization phenotype. A useful way of studying this is to determine the molecular basis for the unusually high neutralization sensitivities of the limited number of available tier 1a viruses. This study localized the neutralization sensitivity of MW965.26, an extremely sensitive subtype C-derived primary isolate, to two rare substitutions in the C3 and C5 domains and demonstrated that the sequences at these positions differentially affect the presentation of epitopes recognized by different classes of standard and conformation-dependent broadly neutralizing antibodies. These results provide novel insight into how these regions regulate the neutralization phenotype and provide tools for controlling the Env conformation that could have applications both for structural studies and in vaccine design. PMID- 29237829 TI - Unexpected Functional Divergence of Bat Influenza Virus NS1 Proteins. AB - Recently, two influenza A virus (FLUAV) genomes were identified in Central and South American bats. These sequences exhibit notable divergence from classical FLUAV counterparts, and functionally, bat FLUAV glycoproteins lack canonical receptor binding and destroying activity. Nevertheless, other features that distinguish these viruses from classical FLUAVs have yet to be explored. Here, we studied the viral nonstructural protein NS1, a virulence factor that modulates host signaling to promote efficient propagation. Like all FLUAV NS1 proteins, bat FLUAV NS1s bind double-stranded RNA and act as interferon antagonists. Unexpectedly, we found that bat FLUAV NS1s are unique in being unable to bind host p85beta, a regulatory subunit of the cellular metabolism-regulating enzyme, phosphoinositide 3-kinase (PI3K). Furthermore, neither bat FLUAV NS1 alone nor infection with a chimeric bat FLUAV efficiently activates Akt, a PI3K effector. Structure-guided mutagenesis revealed that the bat FLUAV NS1-p85beta interaction can be reengineered (in a strain-specific manner) by changing two to four NS1 residues (96L, 99M, 100I, and 145T), thereby creating a hydrophobic patch. Notably, ameliorated p85beta-binding is insufficient for bat FLUAV NS1 to activate PI3K, and a chimeric bat FLUAV expressing NS1 with engineered hydrophobic patch mutations exhibits cell-type-dependent, but species independent, propagation phenotypes. We hypothesize that bat FLUAV hijacking of PI3K in the natural bat host has been selected against, perhaps because genes in this metabolic pathway were differentially shaped by evolution to suit the unique energy use strategies of this flying mammal. These data expand our understanding of the enigmatic functional divergence between bat FLUAVs and classical mammalian and avian FLUAVs.IMPORTANCE The potential for novel influenza A viruses to establish infections in humans from animals is a source of continuous concern due to possible severe outbreaks or pandemics. The recent discovery of influenza A like viruses in bats has raised questions over whether these entities could be a threat to humans. Understanding unique properties of the newly described bat influenza A-like viruses, such as their mechanisms to infect cells or how they manipulate host functions, is critical to assess their likelihood of causing disease. Here, we characterized the bat influenza A-like virus NS1 protein, a key virulence factor, and found unexpected functional divergence of this protein from counterparts in other influenza A viruses. Our study dissects the molecular changes required by bat influenza A-like virus NS1 to adopt classical influenza A virus properties and suggests consequences of bat influenza A-like virus infection, potential future evolutionary trajectories, and intriguing virus-host biology in bat species. PMID- 29237830 TI - Axl Can Serve as Entry Factor for Lassa Virus Depending on the Functional Glycosylation of Dystroglycan. AB - Fatal infection with the highly pathogenic Lassa virus (LASV) is characterized by extensive viral dissemination, indicating broad tissue tropism. The major cellular receptor for LASV is the highly conserved extracellular matrix receptor dystroglycan (DG). Binding of LASV depends on DG's tissue-specific posttranslational modification with the unusual O-linked polysaccharide matriglycan. Interestingly, functional glycosylation of DG does not always correlate with viral tropism observed in vivo The broadly expressed phosphatidylserine (PS) receptors Axl and Tyro3 were recently identified as alternative LASV receptor candidates. However, their role in LASV entry is not entirely understood. Here, we examine LASV receptor candidates in primary human cells and found coexpression of Axl with differentially glycosylated DG. To study LASV receptor use in the context of productive arenavirus infection, we employed recombinant lymphocytic choriomeningitis virus expressing LASV glycoprotein (rLCMV-LASV GP) as a validated biosafety level 2 (BSL2) model. We confirm and extend previous work showing that Axl can contribute to LASV entry in the absence of functional DG using "apoptotic mimicry" in a way similar to that of other enveloped viruses. We further show that Axl-dependent LASV entry requires receptor activation and involves a pathway resembling macropinocytosis. Axl mediated LASV entry is facilitated by heparan sulfate and critically depends on the late endosomal protein LAMP-1 as an intracellular entry factor. In endothelial cells expressing low levels of functional DG, both receptors are engaged by the virus and can contribute to productive entry. In sum, we characterize the role of Axl in LASV entry and provide a rationale for targeting Axl in antiviral therapy.IMPORTANCE The highly pathogenic arenavirus Lassa virus (LASV) represents a serious public health problem in Africa. Although the principal LASV receptor, dystroglycan (DG), is ubiquitously expressed, virus binding critically depends on DG's posttranslational modification, which does not always correlate with tissue tropism. The broadly expressed phosphatidylserine receptor Axl was recently identified as an alternative LASV receptor candidate, but its role in LASV entry is unclear. Here, we investigate the exact role of Axl in LASV entry as a function of DG's posttranslational modification. We found that in the absence of functional DG, Axl can mediate LASV entry via apoptotic mimicry. Productive entry requires virus-induced receptor activation, involves macropinocytosis, and critically depends on LAMP-1. In endothelial cells that express low levels of glycosylated DG, both receptors can promote LASV entry. In sum, our study defines the roles of Axl in LASV entry and provides a rationale for targeting Axl in antiviral therapy. PMID- 29237831 TI - Maintenance of AP-2-Dependent Functional Activities of Nef Restricts Pathways of Immune Escape from CD8 T Lymphocyte Responses. AB - Nef-specific CD8+ T lymphocytes (CD8TL) are linked to extraordinary control of primate lentiviral replication, but the mechanisms underlying their efficacy remain largely unknown. The immunodominant, Mamu-B*017:01+-restricted Nef195 203MW9 epitope in SIVmac239 partially overlaps a sorting motif important for interactions with host AP-2 proteins and, hence, downmodulation of several host proteins, including Tetherin (CD317/BST-2), CD28, CD4, SERINC3, and SERINC5. We reasoned that CD8TL-driven evolution in this epitope might compromise Nef's ability to modulate these important molecules. Here, we used deep sequencing of SIV from nine B*017:01+ macaques throughout infection with SIVmac239 to characterize the patterns of viral escape in this epitope and then assayed the impacts of these variants on Nef-mediated modulation of multiple host molecules. Acute variation in multiple Nef195-203MW9 residues significantly compromised Nef's ability to downregulate surface Tetherin, CD4, and CD28 and reduced its ability to prevent SERINC5-mediated reduction in viral infectivity but did not impact downregulation of CD3 or major histocompatibility complex class I, suggesting the selective disruption of immunomodulatory pathways involving Nef AP 2 interactions. Together, our data illuminate a pattern of viral escape dictated by a selective balance to maintain AP-2-mediated downregulation while evading epitope-specific CD8TL responses. These data could shed light on mechanisms of both CD8TL-driven viral control generally and on Mamu-B*017:01-mediated viral control specifically.IMPORTANCE A rare subset of humans infected with HIV-1 and macaques infected with SIV can control the virus without aid of antiviral medications. A common feature of these individuals is the ability to mount unusually effective CD8 T lymphocyte responses against the virus. One of the most formidable aspects of HIV is its ability to evolve to evade immune responses, particularly CD8 T lymphocytes. We show that macaques that target a specific peptide in the SIV Nef protein are capable of better control of the virus and that, as the virus evolves to escape this response, it does so at a cost to specific functions performed by the Nef protein. Our results help show how the virus can be controlled by an immune response, which could help in designing effective vaccines. PMID- 29237832 TI - Heterobasidion Partitivirus 13 Mediates Severe Growth Debilitation and Major Alterations in the Gene Expression of a Fungal Forest Pathogen. AB - The fungal genus Heterobasidion includes some of the most devastating conifer pathogens in the boreal forest region. In this study, we showed that the alphapartitivirus Heterobasidion partitivirus 13 from Heterobasidion annosum (HetPV13-an1) is the main causal agent of severe phenotypic debilitation in the host fungus. Based on RNA sequencing using isogenic virus-infected and cured fungal strains, HetPV13-an1 affected the transcription of 683 genes, of which 60% were downregulated and 40% upregulated. Alterations observed in carbohydrate and amino acid metabolism suggest that the virus causes a state of starvation, which is compensated for by alternative synthesis routes. We used dual cultures to transmit HetPV13-an1 into new strains of H. annosum and Heterobasidion parviporum The three strains of H. parviporum that acquired the virus showed noticeable growth reduction on rich culturing medium, while only two of six H. annosum isolates tested showed significant debilitation. Based on reverse transcription quantitative PCR (RT-qPCR) analysis, the response toward HetPV13-an1 infection was somewhat different in H. annosum and H. parviporum We assessed the effects of HetPV13-an1 on the wood colonization efficacy of H. parviporum in a field experiment where 46 Norway spruce trees were inoculated with isogenic strains with or without the virus. The virus-infected H. parviporum strain showed considerably less growth within living trees than the isolate without HetPV13 an1, indicating that the virus also causes growth debilitation in natural substrates.IMPORTANCE A biocontrol method restricting the spread of Heterobasidion species would be highly beneficial to forestry, as these fungi are difficult to eradicate from diseased forest stands and cause approximate annual losses of ?800 million in Europe. We used virus curing and reintroduction experiments and RNA sequencing to show that the alphapartitivirus HetPV13-an1 affects many basic cellular functions of the white rot wood decay fungus Heterobasidion annosum, which results in aberrant hyphal morphology and a low growth rate. Dual fungal cultures were used to introduce HetPV13-an1 into a new host species, Heterobasidion parviporum, and field experiments confirmed the capability of the virus to reduce the growth of H. parviporum in living spruce wood. Taken together, our results suggest that HetPV13-an1 shows potential for the development of a future biocontrol agent against Heterobasidion fungi. PMID- 29237833 TI - Neutralizing Activity of Broadly Neutralizing Anti-HIV-1 Antibodies against Clade B Clinical Isolates Produced in Peripheral Blood Mononuclear Cells. AB - Recently discovered broadly neutralizing antibodies (bNAbs) against HIV-1 demonstrate extensive breadth and potency against diverse HIV-1 strains and represent a promising approach for the treatment and prevention of HIV-1 infection. The breadth and potency of these antibodies have primarily been evaluated by using panels of HIV-1 Env-pseudotyped viruses produced in 293T cells expressing molecularly cloned Env proteins. Here we report on the ability of five bNAbs currently in clinical development to neutralize circulating primary HIV-1 isolates derived from peripheral blood mononuclear cells (PBMCs) and compare the results to those obtained with the pseudovirus panels used to characterize the bNAbs. The five bNAbs demonstrated significantly less breadth and potency against clinical isolates produced in PBMCs than against Env-pseudotyped viruses. The magnitude of this difference in neutralizing activity varied, depending on the antibody epitope. Glycan-targeting antibodies showed differences of only 3- to 4 fold, while antibody 10E8, which targets the membrane-proximal external region, showed a nearly 100-fold decrease in activity between published Env-pseudotyped virus panels and PBMC-derived primary isolates. Utilizing clonal PBMC-derived primary isolates and molecular clones, we determined that the observed discrepancy in bNAb performance is due to the increased sensitivity to neutralization exhibited by 293T-produced Env-pseudotyped viruses. We also found that while full-length molecularly cloned viruses produced in 293T cells exhibit greater sensitivity to neutralization than PBMC-derived viruses do, Env pseudotyped viruses produced in 293T cells generally exhibit even greater sensitivity to neutralization. As the clinical development of bNAbs progresses, it will be critical to determine the relevance of each of these in vitro neutralization assays to in vivo antibody performance.IMPORTANCE Novel therapeutic and preventive strategies are needed to contain the HIV-1 epidemic. Antibodies with exceptional neutralizing activity against HIV-1 may provide several advantages to traditional HIV drugs, including an improved side-effect profile, a reduced dosing frequency, and immune enhancement. The activity of these antibodies has been established in vitro by utilizing HIV-1 Env-pseudotyped viruses derived from circulating viruses but produced in 293T cells by pairing Env proteins with a backbone vector. We tested PBMC-produced circulating viruses against five anti-HIV-1 antibodies currently in clinical development. We found that the activity of these antibodies against PBMC isolates is significantly less than that against 293T Env-pseudotyped viruses. This decline varied among the antibodies tested, with some demonstrating moderate reductions in activity and others showing an almost 100-fold reduction. As the development of these antibodies progresses, it will be critical to determine how the results of different in vitro tests correspond to performance in the clinic. PMID- 29237834 TI - Structural Basis for the Inhibition of Host Gene Expression by Porcine Epidemic Diarrhea Virus nsp1. AB - Porcine epidemic diarrhea virus (PEDV), an enteropathogenic Alphacoronavirus, has caused enormous economic losses in the pork industry. Nonstructural protein 1 (nsp1) is a characteristic feature of alpha- and betacoronaviruses, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses. However, the detailed structure and molecular mechanisms underlying the Alphacoronavirus nsp1 inhibition of host gene expression remain unclear. Here, we report the first full-length crystal structure of Alphacoronavirus nsp1 from PEDV. The structure displays a six stranded beta-barrel fold in the middle of two alpha-helices. The core structure of PEDV nsp1 shows high similarity to those of severe acute respiratory syndrome coronavirus (SARS-CoV) nsp1 and transmissible gastroenteritis virus (TGEV) nsp1, despite its low degree of sequence homology. Using ribopuromycylation and Renilla luciferase reporter assays, we showed that PEDV nsp1 can dramatically inhibit general host gene expression. Furthermore, three motifs (amino acids [aa] 67 to 71, 78 to 85, and 103 to 110) of PEDV nsp1 create a stable functional region for inhibiting protein synthesis, differing considerably from Betacoronavirus nsp1. These results elucidate the detailed structural basis through which PEDV nsp1 inhibits host gene expression, providing insight into the development of a new attenuated vaccine with nsp1 modifications.IMPORTANCE Porcine epidemic diarrhea virus (PEDV) has led to tremendous economic losses in the global swine industry. PEDV nsp1 plays a crucial role in inhibiting host gene expression, but its functional mechanism remains unclear. Here, we report the full-length structure of PEDV nsp1, the first among coronaviruses to be reported. The 1.25-A resolution crystal structure of PEDV nsp1 shows high similarity to severe acute respiratory syndrome coronavirus (SARS-CoV) nsp113-128 and transmissible gastroenteritis virus (TGEV) nsp11-104, despite a lack of sequence homology. Structural and biochemical characterization demonstrated that PEDV nsp1 possesses a stable functional region for inhibition of host protein synthesis, which is formed by loops at residues 67 to 71, 78 to 85, and 103 to 110. The different functional regions in PEDV nsp1 and SARS-CoV nsp1 may explain their distinct mechanisms. Importantly, our structural data are conducive to understanding the mechanism of PEDV nsp1 inhibition of the expression of host genes and may aid in the development of a new attenuated vaccine. PMID- 29237835 TI - HLA Class I-Mediated HIV-1 Control in Vietnamese Infected with HIV-1 Subtype A/E. AB - HIV-1-specific cytotoxic T cells (CTLs) play an important role in the control of HIV-1 subtype B or C infection. However, the role of CTLs in HIV-1 subtype A/E infection still remains unclear. Here we investigated the association of HLA class I alleles with clinical outcomes in treatment-naive Vietnamese infected with subtype A/E virus. We found that HLA-C*12:02 was significantly associated with lower plasma viral loads (pVL) and higher CD4 counts and that the HLA A*29:01-B*07:05-C*15:05 haplotype was significantly associated with higher pVL and lower CD4 counts than those for individuals without these respective genotypes. Nine Pol and three Nef mutations were associated with at least one HLA allele in the HLA-A*29:01-B*07:05-C*15:05 haplotype, with a strong negative correlation between the number of HLA-associated Pol mutations and CD4 count as well as a positive correlation with pVL for individuals with these HLA alleles. The results suggest that the accumulation of mutations selected by CTLs restricted by these HLA alleles affects HIV control.IMPORTANCE Most previous studies on HLA association with disease progression after HIV-1 infection have been performed on cohorts infected with HIV-1 subtypes B and C, whereas few such population-based studies have been reported for cohorts infected with the Asian subtype A/E virus. In this study, we analyzed the association of HLA class I alleles with clinical outcomes for 536 HIV-1 subtype A/E-infected Vietnamese individuals. We found that HLA-C*12:02 is protective, while the HLA haplotype HLA A*29:01-B*07:05-C*15:05 is deleterious. The individuals with HIV-1 mutations associated with at least one of the HLA alleles in the deleterious HLA haplotype had higher plasma viral loads and lower CD4 counts than those of individuals without the mutations, suggesting that viral adaptation and escape from HLA mediated immune control occurred. The present study identifies a protective allele and a deleterious haplotype for HIV-1 subtype A/E infection which are different from those identified for cohorts infected with HIV-1 subtypes B and C. PMID- 29237836 TI - Structure of the Paramyxovirus Parainfluenza Virus 5 Nucleoprotein in Complex with an Amino-Terminal Peptide of the Phosphoprotein. AB - Parainfluenza virus 5 (PIV5) belongs to the family Paramyxoviridae, which consists of enveloped viruses with a nonsegmented negative-strand RNA genome encapsidated by the nucleoprotein (N). Paramyxovirus replication is regulated by the phosphoprotein (P) through protein-protein interactions with N and the RNA polymerase (L). The chaperone activity of P is essential to maintain the unassembled RNA-free form of N in order to prevent nonspecific RNA binding and premature N oligomerization. Here, we determined the crystal structure of unassembled PIV5 N in complex with a P peptide (N0P) derived from the N terminus of P (P50) at 2.65 A. The PIV5 N0P consists of two domains: an N-terminal domain (NTD) and a C-terminal domain (CTD) separated by a hinge region. The cleft at the hinge region of RNA-bound PIV5 N was previously shown to be an RNA binding site. The N0P structure shows that the P peptide binds to the CTD of N and extends toward the RNA binding site to inhibit N oligomerization and, hence, RNA binding. Binding of P peptide also keeps the PIV5 N in the open form. A molecular dynamics (MD) analysis of both the open and closed forms of N shows the flexibility of the CTD and the preference of the N protein to be in an open conformation. The gradual opening of the hinge region, to release the RNA, was also observed. Together, these results advance our knowledge of the conformational swapping of N required for the highly regulated paramyxovirus replication.IMPORTANCE Paramyxovirus replication is regulated by the interaction of P with N and L proteins. Here, we report the crystal structure of unassembled parainfluenza virus 5 (PIV5) N chaperoned with P peptide. Our results provide a detailed understanding of the binding of P to N. The conformational switching of N between closed and open forms during its initial interaction with P, as well as during RNA release, was analyzed. Our data also show the plasticity of the CTD and the importance of domain movement for conformational switching. The results improve our understanding of the mechanism of interchanging N conformations for RNA replication and release. PMID- 29237837 TI - Molecular dynamics and mode of transmission of Koala Retrovirus (KoRV) as it invades and spreads through a wild Queensland koala population. AB - The recent acquisition of a novel retrovirus (KoRV) by koalas (Phascolarctos cinereus) has created new opportunities for retroviral research and new challenges for koala conservation. There are currently two major subtypes of KoRV; KoRV-A, which is believed to be endogenous only in koalas from the northern part of Australia, and KoRV-B, which appears to be exogenous. Understanding and management of these subtypes requires population-level studies of their prevalence and diversity, especially when co-infected in the same population, and investigations of their modes of transmission in the wild. Towards this end, we studied a wild Queensland koala population of 290 animals over a five year period and investigated the prevalence, diversity and mode of transmission of KoRV-A and KoRV-B. We found KoRV-A to have an infection level of 100% in the population, with all animals sharing the same dominant envelope gene protein sequence. By comparison, the KoRV-B infection prevalence was only 24%, with 21 different envelope protein sequence variants found in the 83 KoRV-B positive animals. Linked to severe disease outcomes, a significant association between KoRV-B positivity and both chlamydial disease and neoplasia was found in the population. Transmission of KoRV-B was found at a rate of 3% via adult-to-adult contact per year, while there was a 100% rate of KoRV-B positive mothers transmitting the virus to their joeys. Collectively, these findings demonstrate KoRV-B as the pathogenic subtype in this wild koala population and inform future intervention strategies with subtype variation and transmission data.IMPORTANCE KoRV represents a unique opportunity to study a relatively young retrovirus as it goes through its molecular evolution in both an endogenous form, and a more recently evolved exogenous form. The endogenous form, KoRV-A, now appears to have stably and completely established itself in Northern Australian koala populations and is progressing south. Conversely, the exogenous form, KoRV-B, is undergoing continuous mutation and spread in the north and, as yet, has not reached all southern koala populations. We can now link KoRV-B to neoplasia and chlamydial disease in both wild and captive koalas, making it an imminent threat to this already vulnerable species. This work represents the largest study of koalas in a wild population with respect to KoRV-A/KoRV-B infected/co-infected animals and its linkage to chlamydial disease, neoplasia, viral evolution and spread. PMID- 29237838 TI - A Single Amino Acid Substitution within the Paramyxovirus Sendai Virus Nucleoprotein Is a Critical Determinant for Production of Interferon-Beta Inducing Copyback-Type Defective Interfering Genomes. AB - One of the first defenses against infecting pathogens is the innate immune system activated by cellular recognition of pathogen-associated molecular patterns (PAMPs). Although virus-derived RNA species, especially copyback (cb)-type defective interfering (DI) genomes, have been shown to serve as real PAMPs, which strongly induce interferon-beta (IFN-beta) during mononegavirus infection, the mechanisms underlying DI generation remain unclear. Here, for the first time, we identified a single amino acid substitution causing production of cbDI genomes by successful isolation of two distinct types of viral clones with cbDI-producing and cbDI-nonproducing phenotypes from the stock Sendai virus (SeV) strain Cantell, which has been widely used in a number of studies on antiviral innate immunity as a representative IFN-beta-inducing virus. IFN-beta induction was totally dependent on the presence of a significant amount of cbDI genome containing viral particles (DI particles) in the viral stock, but not on deficiency of the IFN-antagonistic viral accessory proteins C and V. Comparison of the isolates indicated that a single amino acid substitution found within the N protein of the cbDI-producing clone was enough to cause the emergence of DI genomes. The mutated N protein of the cbDI-producing clone resulted in a lower density of nucleocapsids than that of the DI-nonproducing clone, probably causing both production of the DI genomes and their formation of a stem-loop structure, which serves as an ideal ligand for RIG-I. These results suggested that the integrity of mononegaviral nucleocapsids might be a critical factor in avoiding the undesirable recognition of infection by host cells.IMPORTANCE The type I interferon (IFN) system is a pivotal defense against infecting RNA viruses that is activated by sensing viral RNA species. RIG-I is a major sensor for infection with most mononegaviruses, and copyback (cb)-type defective interfering (DI) genomes have been shown to serve as strong RIG-I ligands in real infections. However, the mechanism underlying production of cbDI genomes remains unclear, although DI genomes emerge as the result of an error during viral replication with high doses of viruses. Sendai virus has been extensively studied and is unique in that its interaction with innate immunity reveals opposing characteristics, such as high-level IFN-beta induction and strong inhibition of type I IFN pathways. Our findings provide novel insights into the mechanism of production of mononegaviral cbDI genomes, as well as virus-host interactions during innate immunity. PMID- 29237839 TI - Upon Infection the Cellular WD Repeat-containing Protein 5 (WDR5) Localizes to Cytoplasmic Inclusion Bodies and Enhances Measles Virus Replication. AB - Replication of negative-strand RNA viruses occurs in association with discrete cytoplasmic foci called inclusion bodies. Whereas inclusion bodies represent a prominent subcellular structure induced by viral infection, our knowledge of the cellular protein components involved in inclusion body formation and function is limited. Using measles virus-infected HeLa cells, we found that the WD repeat containing protein 5 (WDR5), a subunit of histone H3 lysine 4 methyltransferases, was selectively recruited to virus-induced inclusion bodies. Furthermore, WDR5 was found in complexes containing viral proteins associated with RNA replication. WDR5 was not detected with mitochondria, stress granules, or other known secretory or endocytic compartments of infected cells. WDR5 deficiency decreased both viral protein production and infectious virus yields. Interferon production was modestly increased in WDR5 deficient cells. Thus, our study identifies WDR5 as a novel viral inclusion body-associated cellular protein and suggests a role for WDR5 in promoting viral replication.IMPORTANCE Measles virus is a human pathogen that remains a global concern with more than 100,000 measles-related deaths annually despite the availability of an effective vaccine. As measles continues to cause significant morbidity and mortality, understanding the virus host interactions at the molecular level that affect virus replication efficiency is important for development and optimization of treatment procedures. Measles virus is an RNA virus that encodes six genes and replicates in the cytoplasm of infected cells in discrete cytoplasmic replication bodies, though little is known of the biochemical nature of these structures. Here we show that the cellular protein WDR5 is enriched in the cytoplasmic viral replication factories and enhances virus growth. WDR5-containing protein complex includes viral proteins responsible for viral RNA replication. Thus, we have identified WDR5 as a host factor that enhances the replication of measles virus. PMID- 29237840 TI - Human Cytomegalovirus UL111A and US27 Gene Products Enhance the CXCL12/CXCR4 Signaling Axis via Distinct Mechanisms. AB - Human cytomegalovirus (HCMV) is a prevalent pathogen that establishes lifelong infection in the host. Virus persistence is aided by extensive manipulation of the host immune system, particularly cytokine and chemokine signaling pathways. The HCMV UL111A gene encodes cmvIL-10, an ortholog of human interleukin-10 that has many immunomodulatory effects. We found that cmvIL-10 increased signaling outcomes from human CXCR4, a chemokine receptor with essential roles in hematopoiesis and immune cell trafficking, in response to its natural ligand CXCL12. Calcium flux and chemotaxis to CXCL12 were significantly greater in the presence of cmvIL-10 in monocytes, epithelial cells, and fibroblasts that express CXCR4. cmvIL-10 effects on CXCL12/CXCR4 signaling required the IL-10 receptor and Stat3 activation. Heightened signaling occurred both in HCMV-infected cells and in uninfected bystander cells, suggesting that cmvIL-10 may broadly influence chemokine networks by paracrine signaling during infection. Moreover, CXCL12/CXCR4 signaling was amplified in HCMV-infected cells compared to mock infected cells even in the absence of cmvIL-10. Enhanced CXCL12/CXCR4 outcomes were associated with expression of the virally encoded chemokine receptor US27, and CXCL12/CXCR4 activation was reduced in cells infected with a deletion mutant lacking US27 (TB40/E-mCherry-US27Delta). US27 effects were Stat3 independent but required close proximity to CXCR4 in cell membranes of either HCMV-infected or US27-transfected cells. Thus, HCMV encodes two proteins, cmvIL-10 and US27, that exhibit distinct mechanisms for enhancing CXCR4 signaling. Either individually or in combination, cmvIL-10 and US27 may enable HCMV to exquisitely manipulate CXCR4 signaling to alter host immune responses and modify cell trafficking patterns during infection.IMPORTANCE The human chemokine system plays a central role in host defense, as evidenced by the many strategies devised by viruses for manipulating it. Human cytomegalovirus (HCMV) is widespread in the human population, but infection rarely causes disease except in immunocompromised hosts. We found that two different HCMV proteins, cmvIL-10 and US27, act through distinct mechanisms to upregulate the signaling activity of a cellular chemokine receptor, CXCR4. cmvIL-10 is a secreted viral cytokine that affects CXCR4 signaling in both infected and uninfected cells, while US27 is a component of the virus particle and impacts CXCR4 activity only in infected cells. Both cmvIL-10 and US27 promote increased intracellular calcium signaling and cell migration in response to chemokine CXCL12 binding to CXCR4. Our results demonstrate that HCMV exerts fine control over the CXCL12/CXCR4 pathway, which could lead to enhanced virus dissemination, altered immune cell trafficking, and serious health implications for HCMV patients. PMID- 29237841 TI - Mammalian Adaptation of an Avian Influenza A Virus Involves Stepwise Changes in NS1. AB - Influenza A viruses (IAVs) are common pathogens of birds that occasionally establish endemic infections in mammals. The processes and mechanisms that result in IAV mammalian adaptation are poorly understood. The viral nonstructural 1 (NS1) protein counteracts the interferon (IFN) response, a central component of the host species barrier. We characterized the NS1 proteins of equine influenza virus (EIV), a mammalian IAV lineage of avian origin. We showed that evolutionarily distinct NS1 proteins counteract the IFN response using different and mutually exclusive mechanisms: while the NS1 proteins of early EIVs block general gene expression by binding to cellular polyadenylation-specific factor 30 (CPSF30), NS1 proteins from more evolved EIVs specifically block the induction of IFN-stimulated genes by interfering with the JAK/STAT pathway. These contrasting anti-IFN strategies are associated with two mutations that appeared sequentially and were rapidly selected for during EIV evolution, highlighting the importance of evolutionary processes in immune evasion mechanisms during IAV adaptation.IMPORTANCE Influenza A viruses (IAVs) infect certain avian reservoir species and occasionally transfer to and cause epidemics of infections in some mammalian hosts. However, the processes by which IAVs gain the ability to efficiently infect and transmit in mammals remain unclear. H3N8 equine influenza virus (EIV) is an avian-origin virus that successfully established a new lineage in horses in the early 1960s and is currently circulating worldwide in the equine population. Here, we analyzed the molecular evolution of the virulence factor nonstructural protein 1 (NS1) and show that NS1 proteins from different time periods after EIV emergence counteract the host innate immune response using contrasting strategies, which are associated with two mutations that appeared sequentially during EIV evolution. The results shown here indicate that the interplay between virus evolution and immune evasion plays a key role in IAV mammalian adaptation. PMID- 29237843 TI - Human Parvovirus B19 Utilizes Cellular DNA Replication Machinery for Viral DNA Replication. AB - Human parvovirus B19 (B19V) infection of human erythroid progenitor cells (EPCs) induces a DNA damage response and cell cycle arrest at late S phase, which facilitates viral DNA replication. However, it is not clear exactly which cellular factors are employed by this single-stranded DNA virus. Here, we used microarrays to systematically analyze the dynamic transcriptome of EPCs infected with B19V. We found that DNA metabolism, DNA replication, DNA repair, DNA damage response, cell cycle, and cell cycle arrest pathways were significantly regulated after B19V infection. Confocal microscopy analyses revealed that most cellular DNA replication proteins were recruited to the centers of viral DNA replication, but not the DNA repair DNA polymerases. Our results suggest that DNA replication polymerase delta and polymerase alpha are responsible for B19V DNA replication by knocking down its expression in EPCs. We further showed that although RPA32 is essential for B19V DNA replication and the phosphorylated forms of RPA32 colocalized with the replicating viral genomes, RPA32 phosphorylation was not necessary for B19V DNA replication. Thus, this report provides evidence that B19V uses the cellular DNA replication machinery for viral DNA replication.IMPORTANCE Human parvovirus B19 (B19V) infection can cause transient aplastic crisis, persistent viremia, and pure red cell aplasia. In fetuses, B19V infection can result in nonimmune hydrops fetalis and fetal death. These clinical manifestations of B19V infection are a direct outcome of the death of human erythroid progenitors that host B19V replication. B19V infection induces a DNA damage response that is important for cell cycle arrest at late S phase. Here, we analyzed dynamic changes in cellular gene expression and found that DNA metabolic processes are tightly regulated during B19V infection. Although genes involved in cellular DNA replication were downregulated overall, the cellular DNA replication machinery was tightly associated with the replicating single-stranded DNA viral genome and played a critical role in viral DNA replication. In contrast, the DNA damage response-induced phosphorylated forms of RPA32 were dispensable for viral DNA replication. PMID- 29237842 TI - Human Norovirus NS3 Has RNA Helicase and Chaperoning Activities. AB - RNA-remodeling proteins, including RNA helicases and chaperones, act to remodel RNA structures and/or protein-RNA interactions and are required for all processes involving RNAs. Although many viruses encode RNA helicases and chaperones, their in vitro activities and their roles in infected cells largely remain elusive. Noroviruses are a diverse group of positive-strand RNA viruses in the family Caliciviridae and constitute a significant and potentially fatal threat to human health. Here, we report that the protein NS3 encoded by human norovirus has both ATP-dependent RNA helicase activity that unwinds RNA helices and ATP-independent RNA-chaperoning activity that can remodel structured RNAs and facilitate strand annealing. Moreover, NS3 can facilitate viral RNA synthesis in vitro by norovirus polymerase. NS3 may therefore play an important role in norovirus RNA replication. Lastly, we demonstrate that the RNA-remodeling activity of NS3 is inhibited by guanidine hydrochloride, an FDA-approved compound, and, more importantly, that it reduces the replication of the norovirus replicon in cultured human cells. Altogether, these findings are the first to demonstrate the presence of RNA-remodeling activities encoded by Caliciviridae and highlight the functional significance of NS3 in the noroviral life cycle.IMPORTANCE Noroviruses are a diverse group of positive-strand RNA viruses, which annually cause hundreds of millions of human infections and over 200,000 deaths worldwide. For RNA viruses, cellular or virus-encoded RNA helicases and/or chaperones have long been considered to play pivotal roles in viral life cycles. However, neither RNA helicase nor chaperoning activity has been demonstrated to be associated with any norovirus-encoded proteins, and it is also unknown whether norovirus replication requires the participation of any viral or cellular RNA helicases/chaperones. We found that a norovirus protein, NS3, not only has ATP-dependent helicase activity, but also acts as an ATP-independent RNA chaperone. Also, NS3 can facilitate in vitro viral RNA synthesis, suggesting the important role of NS3 in norovirus replication. Moreover, NS3 activities can be inhibited by an FDA approved compound, which also suppresses norovirus replicon replication in human cells, raising the possibility that NS3 could be a target for antinoroviral drug development. PMID- 29237844 TI - Herpes Simplex Virus 1 DNA Polymerase RNase H Activity Acts in a 3'-to-5' Direction and Is Dependent on the 3'-to-5' Exonuclease Active Site. AB - The catalytic subunit (Pol) of herpes simplex virus 1 (HSV-1) DNA polymerase has been extensively studied both as a model for other family B DNA polymerases and for its differences from these enzymes as an antiviral target. Among the activities of HSV-1 Pol is an intrinsic RNase H activity that cleaves RNA from RNA-DNA hybrids. There has long been a controversy regarding whether this activity is due to the 3'-to-5' exonuclease of Pol or whether it is a separate activity, possibly acting on 5' RNA termini. To investigate this issue, we compared wild-type HSV-1 Pol and a 3'-to-5' exonuclease-deficient mutant, D368A Pol, for DNA polymerase activity, 3'-to-5' exonuclease activity, and RNase H activity in vitro Additionally, we assessed the RNase H activity using differentially end-labeled templates with 5' or 3' RNA termini. The mutant enzyme was at most modestly impaired for DNA polymerase activity but was drastically impaired for 3'-to-5' exonuclease activity, with no activity detected even at high enzyme-to-DNA substrate ratios. Importantly, the mutant showed no detectable ability to excise RNA with either a 3' or 5' terminus, while the wild-type HSV-1 Pol was able to cleave RNA from the annealed RNA-DNA hairpin template, but only detectably with a 3' RNA terminus in a 3'-to-5' direction and at a rate lower than that of the exonuclease activity. These results suggest that HSV-1 Pol does not have an RNase H separable from its 3'-to-5' exonuclease activity and that this activity prefers DNA degradation over degradation of RNA from RNA-DNA hybrids.IMPORTANCE Herpes simplex virus 1 (HSV-1) is a member of the Herpesviridae family of DNA viruses, several of which cause morbidity and mortality in humans. Although the HSV-1 DNA polymerase has been studied for decades and is a crucial target for antivirals against HSV-1 infection, several of its functions remain to be elucidated. A hypothesis suggesting the existence of a 5'-to-3' RNase H activity intrinsic to this enzyme that could remove RNA primers from Okazaki fragments has been particularly controversial. In this study, we were unable to identify RNase H activity of HSV-1 DNA polymerase on RNA DNA hybrids with 5' RNA termini. We detected RNase H activity on hybrids with 3' termini, but this was due to the 3'-to-5' exonuclease. Thus, HSV-1 is unlikely to use this method to remove RNA primers during DNA replication but may use pathways similar to those used in eukaryotic Okazaki fragment maturation. PMID- 29237845 TI - Human Cytomegalovirus Replication Is Inhibited by the Autophagy-Inducing Compounds Trehalose and SMER28 through Distinctively Different Mechanisms. AB - Human cytomegalovirus (HCMV) is the top viral cause of birth defects worldwide, and current therapies have high toxicity. We previously reported that the mTOR independent autophagy-inducing disaccharide trehalose inhibits HCMV replication in multiple cell types. Here, we examine the mechanism of inhibition and introduce the autophagy inducer SMER28 as an additional inhibitor of HCMV acting through a different mechanism. We find that trehalose induces vacuolation and acidification of vacuoles and that debris, including debris with an appearance consistent with that of abnormal virions, is present in multivesicular bodies. Trehalose treatment increased the levels of Rab7, a protein required for lysosomal biogenesis and fusion, and slightly decreased the levels of Rab11, which is associated with recycling endosomes. We also present evidence that trehalose can promote autophagy without altering cellular glucose uptake. We show that SMER28 inhibits HCMV at the level of early protein production and interferes with viral genome replication in a cell type-dependent fashion. Finally, we show that SMER28 treatment does not cause the vacuolation, acidification, or redistribution of Rab7 associated with trehalose treatment and shows only a modest and cell type-dependent effect on autophagy. We propose a model in which the reciprocal effects on Rab7 and Rab11 induced by trehalose contribute to the redirection of enveloped virions from the plasma membrane to acidified compartments and subsequent degradation, and SMER28 treatment results in decreased expression levels of early and late proteins, reducing the number of virions produced without the widespread vacuolation characteristic of trehalose treatment.IMPORTANCE There is a need for less toxic HCMV antiviral drugs, and modulation of autophagy to control viral infection is a new strategy that takes advantage of virus dependence on autophagy inhibition. The present study extends our previous work on trehalose by showing a possible mechanism of action and introduces another autophagy-inducing compound, SMER28, that is effective against HCMV in several cell types. The mechanism by which trehalose induces autophagy is currently unknown, although our data show that trehalose does not inhibit cellular glucose uptake in cells relevant for HCMV replication but instead alters virion degradation by promoting acidic vacuolization. The comparison of our cell types and those used by others highlights the cell type-dependent nature of studying autophagy. PMID- 29237846 TI - The Three-Fold Axis of the HIV-1 Capsid Lattice Is the Species-Specific Binding Interface for TRIM5alpha. AB - Rhesus TRIM5alpha (rhTRIM5alpha) potently restricts replication of human immunodeficiency virus type 1 (HIV-1). Restriction is mediated through direct binding of the C-terminal B30.2 domain of TRIM5alpha to the assembled HIV-1 capsid core. This host-pathogen interaction involves multiple capsid molecules within the hexagonal HIV-1 capsid lattice. However, the molecular details of this interaction and the precise site at which the B30.2 domain binds remain largely unknown. The human orthologue of TRIM5alpha (hsTRIM5alpha) fails to block infection by HIV-1 both in vivo and in vitro This is thought to be due to differences in binding to the capsid lattice. To map the species-specific binding surface on the HIV-1 capsid lattice, we used microscale thermophoresis and dual focus fluorescence correlation spectroscopy to measure binding affinity of rhesus and human TRIM5alpha B30.2 domains to a series of HIV-1 capsid variants that mimic distinct capsid arrangements at each of the symmetry axes of the HIV-1 capsid lattice. These surrogates include previously characterized capsid oligomers, as well as a novel chemically cross-linked capsid trimer that contains cysteine substitutions near the 3-fold axis of symmetry. The results demonstrate that TRIM5alpha binding involves multiple capsid molecules along the 2-fold and 3 fold interfaces between hexamers and indicate that the binding interface at the 3 fold axis contributes to the well-established differences in restriction potency between TRIM5alpha orthologues.IMPORTANCE TRIM5alpha is a cellular protein that fends off infection by retroviruses through binding to the viruses' protein shell surrounding its genetic material. This shell is composed of several hundred capsid proteins arranged in a honeycomb-like hexagonal pattern that is conserved across retroviruses. By binding to the complex lattice formed by multiple capsid proteins, rather than to a single capsid monomer, TRIM5alpha restriction activity persists despite the high mutation rate in retroviruses such as HIV-1. In rhesus monkeys, but not in humans, TRIM5alpha confers resistance to HIV-1. By measuring the binding of human and rhesus TRIM5alpha to a series of engineered HIV-1 capsid mimics of distinct capsid lattice interfaces, we reveal the HIV-1 capsid surface critical for species-specific binding by TRIM5alpha. PMID- 29237847 TI - A Trimeric HIV-1 Envelope gp120 Immunogen Induces Potent and Broad Anti-V1V2 Loop Antibodies against HIV-1 in Rabbits and Rhesus Macaques. AB - Trimeric HIV-1 envelope (Env) immunogens are attractive due to their ability to display quaternary epitopes targeted by broadly neutralizing antibodies (bNAbs) while obscuring unfavorable epitopes. Results from the RV144 trial highlighted the importance of vaccine-induced HIV-1 Env V1V2-directed antibodies, with key regions of the V2 loop as targets for vaccine-mediated protection. We recently reported that a trimeric JRFL-gp120 immunogen, generated by inserting an N terminal trimerization domain in the V1 loop region of a cyclically permuted gp120 (cycP-gp120), induces neutralizing activity against multiple tier-2 HIV-1 isolates in guinea pigs in a DNA prime/protein boost approach. Here, we tested the immunogenicity of cycP-gp120 in a protein prime/boost approach in rabbits and as a booster immunization to DNA/modified vaccinia Ankara (MVA)-vaccinated rabbits and rhesus macaques. In rabbits, two cycP-gp120 protein immunizations induced 100-fold higher titers of high-avidity gp120-specific IgG than two gp120 immunizations, with four total gp120 immunizations being required to induce comparable titers. cycP-gp120 also induced markedly enhanced neutralizing activity against tier-1A and -1B HIV-1 isolates, substantially higher binding and breadth to gp70-V1V2 scaffolds derived from a multiclade panel of global HIV-1 isolates, and antibodies targeting key regions of the V2-loop region associated with reduced risk of infection in RV144. Similarly, boosting MVA- or DNA/MVA primed rabbits or rhesus macaques with cycP-gp120 showed a robust expansion of gp70-V1V2-specific IgG, neutralization breadth to tier-1B HIV-1 isolates, and antibody-dependent cellular cytotoxicity activity. These results demonstrate that cycP-gp120 serves as a robust HIV Env immunogen that induces broad anti-V1V2 antibodies and promotes neutralization breadth against HIV-1.IMPORTANCE Recent focus in HIV-1 vaccine development has been the design of trimeric HIV-1 Env immunogens that closely resemble native HIV-1 Env, with a major goal being the induction of bNAbs. While the generation of bNAbs is considered a gold standard in vaccine-induced antibody responses, results from the RV144 trial showed that nonneutralizing antibodies directed toward the V1V2 loop of HIV-1 gp120, specifically the V2 loop region, were associated with decreased risk of infection, demonstrating the need for the development of Env immunogens that induce a broad anti-V1V2 antibody response. In this study, we show that a novel trimeric gp120 protein, cycP-gp120, generates high titers of high-avidity and broadly cross-reactive anti-V1V2 antibodies, a result not found in animals immunized with monomeric gp120. These results reveal the potential of cycP-gp120 as a vaccine candidate to induce antibodies associated with reduced risk of HIV-1 infection in humans. PMID- 29237848 TI - Looking for unity in diversity: human cooperative childcare in comparative perspective. AB - Humans engage in cooperative childcare, which includes some elements not found in other animals, such as the presence of post-reproductive helpers, extensive food sharing among adults and a pervasive sexual division of labour. In animals, cooperative offspring care has typically been studied in two different contexts. The first mainly involves helpers contributing care in cooperatively breeding family groups; the second context is allomaternal care in species usually not categorized as cooperative breeders (e.g. plural and communal breeders, often without male care). Comparative analyses suggest that cooperative breeding and allomaternal care in plural and communal breeders have distinct evolutionary origins, with humans fitting neither pathway entirely. Nevertheless, some critical proximate mechanisms of helping, including hormonal regulators, are likely to be shared across species. Other mechanisms may vary among species, such as social tolerance, proactive prosociality or conditional mother-infant bonding. These are presumably associated with specific details of the care system, such as whether all group members contribute, or whether mothers can potentially raise offspring alone. Thus, cooperative offspring care is seen in different contexts across animal lineages, but may nonetheless share several important psychological characteristics. We end by discussing how work on humans may play a unifying role in studying cooperative offspring care. PMID- 29237849 TI - Experimental evolution of insect immune memory versus pathogen resistance. AB - Under strong pathogen pressure, insects often evolve resistance to infection. Many insects are also protected via immune memory (immune priming), whereby sublethal exposure to a pathogen enhances survival after secondary infection. Theory predicts that immune memory should evolve when the pathogen is highly virulent, or when pathogen exposure is relatively rare. However, there are no empirical tests of these hypotheses, and the adaptive benefits of immune memory relative to direct resistance against a pathogen are poorly understood. To determine the selective pressures and ecological conditions that shape immune evolution, we imposed strong pathogen selection on flour beetle (Tribolium castaneum) populations, infecting them with Bacillus thuringiensis (Bt) for 11 generations. Populations injected first with heat-killed and then live Bt evolved high basal resistance against multiple Bt strains. By contrast, populations injected only with a high dose of live Bt evolved a less effective but strain specific priming response. Control populations injected with heat-killed Bt did not evolve priming; and in the ancestor, priming was effective only against a low Bt dose. Intriguingly, one replicate population first evolved priming and subsequently evolved basal resistance, suggesting the potential for dynamic evolution of different immune strategies. Our work is the first report showing that pathogens can select for rapid modulation of insect priming ability, allowing hosts to evolve divergent immune strategies (generalized resistance versus specific immune memory) with potentially distinct mechanisms. PMID- 29237850 TI - Stabilizing selection on microsatellite allele length at arginine vasopressin 1a receptor and oxytocin receptor loci. AB - The loci arginine vasopressin receptor 1a (avpr1a) and oxytocin receptor (oxtr) have evolutionarily conserved roles in vertebrate social and sexual behaviour. Allelic variation at a microsatellite locus in the 5' regulatory region of these genes is associated with fitness in the bank vole Myodes glareolus Given the low frequency of long and short alleles at these microsatellite loci in wild bank voles, we used breeding trials to determine whether selection acts against long and short alleles. Female bank voles with intermediate length avpr1a alleles had the highest probability of breeding, while male voles whose avpr1a alleles were very different in length had reduced probability of breeding. Moreover, there was a significant interaction between male and female oxtr genotypes, where potential breeding pairs with dissimilar length alleles had reduced probability of breeding. These data show how genetic variation at microsatellite loci associated with avpr1a and oxtr is associated with fitness, and highlight complex patterns of selection at these loci. More widely, these data show how stabilizing selection might act on allele length frequency distributions at gene-associated microsatellite loci. PMID- 29237852 TI - Cues of upper body strength account for most of the variance in men's bodily attractiveness. AB - Evolution equips sexually reproducing species with mate choice mechanisms that function to evaluate the reproductive consequences of mating with different individuals. Indeed, evolutionary psychologists have shown that women's mate choice mechanisms track many cues of men's genetic quality and ability to invest resources in the woman and her offspring. One variable that predicted both a man's genetic quality and his ability to invest is the man's formidability (i.e. fighting ability or resource holding power/potential). Modern women, therefore, should have mate choice mechanisms that respond to ancestral cues of a man's fighting ability. One crucial component of a man's ability to fight is his upper body strength. Here, we test how important physical strength is to men's bodily attractiveness. Three sets of photographs of men's bodies were shown to raters who estimated either their physical strength or their attractiveness. Estimates of physical strength determined over 70% of men's bodily attractiveness. Additional analyses showed that tallness and leanness were also favoured, and, along with estimates of physical strength, accounted for 80% of men's bodily attractiveness. Contrary to popular theories of men's physical attractiveness, there was no evidence of a nonlinear effect; the strongest men were the most attractive in all samples. PMID- 29237851 TI - MicroRNAs regulate the sesquiterpenoid hormonal pathway in Drosophila and other arthropods. AB - Arthropods comprise the majority of all described animal species, and understanding their evolution is a central question in biology. Their developmental processes are under the precise control of distinct hormonal regulators, including the sesquiterpenoids juvenile hormone (JH) and methyl farnesoate. The control of the synthesis and mode of action of these hormones played important roles in the evolution of arthropods and their adaptation to diverse habitats. However, the precise roles of non-coding RNAs, such as microRNAs (miRNAs), controlling arthropod hormonal pathways are unknown. Here, we investigated the miRNA regulation of the expression of the juvenile hormone acid methyltransferase gene (JHAMT), which encodes a rate-determining sesquiterpenoid biosynthetic enzyme. Loss of function of the miRNA bantam in the fly Drosophila melanogaster increased JHAMT expression, while overexpression of the bantam repressed JHAMT expression and resulted in pupal lethality. The male genital organs of the pupae were malformed, and exogenous sesquiterpenoid application partially rescued the genital deformities. The role of the bantam in the regulation of sesquiterpenoid biosynthesis was validated by transcriptomic, qPCR and hormone titre (JHB3 and JH III) analyses. In addition, we found a conserved set of miRNAs that interacted with JHAMT, and the sesquiterpenoid receptor methoprene-tolerant (Met) in different arthropod lineages, including insects (fly, mosquito and beetle), crustaceans (water flea and shrimp), myriapod (centipede) and chelicerate (horseshoe crab). This suggests that these miRNAs might have conserved roles in the post-transcriptional regulation of genes in sesquiterpenoid pathways across the Panarthropoda. Some of the identified lineage specific miRNAs are potential targets for the development of new strategies in aquaculture and agricultural pest control. PMID- 29237853 TI - The behavioural response of migrating humpback whales to a full seismic airgun array. AB - Despite concerns on the effects of noise from seismic survey airguns on marine organisms, there remains uncertainty as to the biological significance of any response. This study quantifies and interprets the response of migrating humpback whales (Megaptera novaeangliae) to a 3130 in3 (51.3l) commercial airgun array. We compare the behavioural responses to active trials (array operational; n = 34 whale groups), with responses to control trials (source vessel towing the array while silent; n = 33) and baseline studies of normal behaviour in the absence of the vessel (n = 85). No abnormal behaviours were recorded during the trials. However, in response to the active seismic array and the controls, the whales displayed changes in behaviour. Changes in respiration rate were of a similar magnitude to changes in baseline groups being joined by other animals suggesting any change group energetics was within their behavioural repertoire. However, the reduced progression southwards in response to the active treatments, for some cohorts, was below typical migratory speeds. This response was more likely to occur within 4 km from the array at received levels over 135 dB re 1 uPa2s. PMID- 29237854 TI - Oceanic swarms of Antarctic krill perform satiation sinking. AB - Antarctic krill form some of the highest concentrations of animal biomass observed in the world's oceans potentially due to their prolific ability to swarm. Determining the movement of Antarctic krill within swarms is important to identify drivers of their behaviour and their biogeochemical impact on their environment. We examined vertical velocity within approximately 2000 krill swarms through the combined use of a shipborne echosounder and an acoustic Doppler current profiler. We revealed a pronounced downward anomaly in vertical velocity within swarms of -0.6 cm s-1 compared with vertical motion outside the swarm. The anomaly changed over the diel cycle, with smaller downward anomalies occurring at night. Swarms in regions of high phytoplankton concentrations (a proxy for food availability) also exhibited significantly smaller downward anomalies. We propose that the anomaly is the result of downward velocities generated by the action of krill beating their swimming appendages. During the night and in high phytoplankton availability, when krill are more likely to feed to the point of satiation, swimming activity is lowered and the anomaly is reduced. Our findings are consistent with laboratory work where krill ceased swimming and adopted a parachute posture when sated. Satiation sinking behaviour can substantially increase the efficiency of carbon transport to depth through depositing faecal pellets at the bottom of swarms, avoiding the reingestion and break-up of pellets by other swarm members. PMID- 29237856 TI - Humans as model organisms. AB - Like every other species, our species is the result of descent with modification under the influence of natural selection; a tip in an increasingly large and deep series of nested clades, as we trace its ancestry back to increasingly remote antecedents. As a consequence of shared history, our species has much in common with many others; as a consequence of its production by the general mechanisms of evolution, our species carries information about the mechanisms that shaped other species as well. For reasons unconnected to biological theory, we have far more information about humans than we do about other species. So in principle and in practice, humans should be usable as model organisms, and no one denies the truth of this for mundane physical traits, though harnessing human data for more general questions proves to be quite challenging. However, it is also true that human cognitive and behavioural characteristics, and human social groups, are apparently radically unlike those of other animals. Humans are exceptional products of evolution and perhaps that makes them an unsuitable model system for those interested in the evolution of cooperation, complex cognition, group formation, family structure, communication, cultural learning and the like. In all these respects, we are complex and extreme cases, perhaps shaped by mechanisms (like cultural evolution or group selection) that play little role in other lineages. Most of the papers in this special issue respond by rejecting or downplaying exceptionalism. I argue that it can be an advantage: understanding the human exception reveals constraints that have restricted evolutionary options in many lineages. PMID- 29237855 TI - Sex-specific adaptation and genomic responses to Y chromosome presence in female reproductive and neural tissues. AB - Y chromosomes typically harbour a small number of genes and an abundance of repetitive sequences. In Drosophila, the Y chromosome comprises multimegabase long segments of repetitive DNA and a handful of protein-coding genes. In mammals, the Y chromosome also harbours a disproportionally high abundance of repeats. Here, we built on a Drosophila melanogaster model in which the Y chromosome is decoupled from sexual determination. Genotypes were genetically identical for the autosomes, X chromosome, and mitochondria, but differ by the presence or dose of the Y chromosome. Addition of an extra Y chromosome had limited impact in males. However, the presence of a Y chromosome in females induced a disproportionate response in genes expressed in the ovaries as well as genes encoded by the mitochondrial genome. Furthermore, the data revealed significant consequences of Y chromosome presence in larvae neuronal tissue. This included the repression of genes implicated in reproductive behaviour, courtship, mating and synaptic function. Our findings exhibit the Y chromosome as a hotspot for sex-specific adaptation. They suggest roles for natural selection on Y-linked genetic elements exerting impact on sex-specific tissues as well as somatic tissues shared by males and females. PMID- 29237858 TI - Humans as a model for understanding biological fundamentals. AB - How special are humans? This question drives scholarly output across both the sciences and the humanities. Whereas some disciplines, and the humanities in particular, aim at gaining a better understanding of humans per se, most biologists ultimately aim to understand life in general. This raises the question of whether and when humans are acceptable, or even desirable, models of biological fundamentals. Especially for basic biological processes, non-human species are generally accepted as a relevant model to study topics for which studying humans is impractical, impossible, or ethically inadvisable, but the reverse is controversial: are humans 'too unique' to be informative with respect to biological fundamentals relevant to other species? Or are there areas where we share key components, or for which our very uniqueness serves to allow novel explorations? In this special feature, authors from disciplines including biology, psychology, anthropology, neuroscience and philosophy tackle this question. Their overall conclusion is a qualified yes: humans do tell us about biological fundamentals, in some contexts. We hope this special feature will spur a discussion that will lead to a more careful delineation of the similarities and the differences between humans and other species, and how these impact the study of biological fundamentals. PMID- 29237857 TI - Using knowledge from human research to improve understanding of contest theory and contest dynamics. AB - Our understanding of animal contests and the factors that affect contest dynamics and decisions stems from a long and prosperous collaboration between empiricists and theoreticians. Over the last two decades, however, theoretical predictions regarding the factors that affect individual decisions before, during and after a contest are becoming increasingly difficult to test empirically. Extremely large sample sizes are necessary to experimentally test the nuanced theoretical assumptions surrounding how information is used by animals during a contest, how context changes the information used, and how individuals change behaviour as a result of both the information available and the context in which the information is acquired. In this review, we discuss how the investigation of contests in humans through the collaboration of biologists and psychologists may advance contest theory and dynamics in general. We argue that a long and productive history exploring human behaviour and psychology combined with technological advancements provide a unique opportunity to manipulate human perception during contests and collect unbiased data, allowing more targeted examinations of particular aspects of contest theory (e.g. winner/loser effects, information use as a function of age). We hope that our perspective provides the impetus for many future collaborations between biologists and psychologists. PMID- 29237859 TI - Differences between hard and soft phylogenetic data. AB - When building the tree of life, variability of phylogenetic signal is often accounted for by partitioning gene sequences and testing for differences. The same considerations, however, are rarely applied to morphological data, potentially undermining its use in evolutionary contexts. Here, we apply partition heterogeneity tests to 59 animal datasets to demonstrate that significant differences exist between the phylogenetic signal conveyed by 'hard' and 'soft' characters (bones, teeth and shells versus myology, integument etc). Furthermore, the morphological partitions differ significantly in their consistency relative to independent molecular trees. The observed morphological differences correspond with missing data biases, and as such their existence presents a problem not only for phylogeny reconstruction, but also for interpretations of fossil data. Evolutionary inferences drawn from clades in which hard, readily fossilizable characters are relatively less consistent and different from other morphology (mammals, bivalves) may be less secure. More secure inferences might be drawn from the fossil record of clades that exhibit fewer differences, or exhibit more consistent hard characters (fishes, birds). In all cases, it will be necessary to consider the impact of missing data on empirical data, and the differences that exist between morphological modules. PMID- 29237860 TI - Human infancy and parenting in global perspective: specificity. AB - We address three long-standing fundamental questions about early human development and parental caregiving within a specificity framework using data from 796 infant-mother dyads from 11 societies worldwide. Adopting a cross society view opens a vista on universal biological origins of, and contextual influences on, infant behaviours and parenting practices. We asked: how do infant behaviours and parenting practices vary across societies? How do infant behaviours relate to other infant behaviours, and how do parent practices relate to other parent practices? Are infant behaviours and parent practices related to one another? Behaviours of firstborn five-month infants and parenting practices of their mothers were microanalysed from videorecords of extensive naturally occurring interactions in the home. In accord with behavioural specificity, biological expectations and cultural influences, we find that infants and mothers from diverse societies exhibit mean-level society differences in their behaviours and practices; domains of infant behaviours generally do not cohere, nor do domains of maternal practices; and only specific infant behaviours and mother practices correspond. Few relations were moderated by society. PMID- 29237861 TI - The early Cambrian fossil embryo Pseudooides is a direct-developing cnidarian, not an early ecdysozoan. AB - Early Cambrian Pseudooides prima has been described from embryonic and post embryonic stages of development, exhibiting long germ-band development. There has been some debate about the pattern of segmentation, but this interpretation, as among the earliest records of ecdysozoans, has been generally accepted. Here, we show that the 'germ band' of P. prima embryos separates along its mid axis during development, with the transverse furrows between the 'somites' unfolding into the polar aperture of the ten-sided theca of Hexaconularia sichuanensis, conventionally interpreted as a scyphozoan cnidarian; co-occurring post-embryonic remains of ecdysozoans are unrelated. We recognize H. sichuanensis as a junior synonym of P. prima as a consequence of identifying these two form-taxa as distinct developmental stages of the same organism. Direct development in P. prima parallels the co-occuring olivooids Olivooides, and Quadrapyrgites and Bayesian phylogenetic analysis of a novel phenotype dataset indicates that, despite differences in their tetra-, penta- and pseudo-hexa-radial symmetry, these hexangulaconulariids comprise a clade of scyphozoan medusozoans, with Arthrochites and conulariids, that all exhibit direct development from embryo to thecate polyp. The affinity of hexangulaconulariids and olivooids to extant scyphozoan medusozoans indicates that the prevalence of tetraradial symmetry and indirect development are a vestige of a broader spectrum of body-plan symmetries and developmental modes that was manifest in their early Phanerozoic counterparts. PMID- 29237863 TI - Correction to 'A phosphorus threshold for mycoheterotrophic plants in tropical forests'. PMID- 29237862 TI - Abiotic niche partitioning and negative density dependence drive tree seedling survival in a tropical forest. AB - In tropical tree communities, processes occurring during early life stages play a critical role in shaping forest composition and diversity through differences in species' performance. Predicting the future of tropical forests depends on a solid understanding of the drivers of seedling survival. At the same time, factors determining spatial and temporal patterns of seedling survival can play a large role in permitting species coexistence in diverse communities. Using long term data on the survival of more than 45 000 seedlings of 238 species in a Neotropical forest, we assessed the relative importance of key abiotic and biotic neighbourhood variables thought to influence individual seedling survival and tested whether species vary significantly in their responses to these variables, consistent with niche differences. At the community level, seedling survival was significantly correlated with plant size, topographic habitat, neighbourhood densities of conspecific seedlings, conspecific and heterospecific trees and annual variation in water availability, in descending order of effect size. Additionally, we found significant variation among species in their sensitivity to light and water availability, as well as in their survival within different topographic habitats, indicating the potential for niche differentiation among species that could allow for species coexistence. PMID- 29237864 TI - Correction to 'Can't live with them, can't live without them? Balancing mating and competition in two-sex populations'. PMID- 29237866 TI - Leadership by Example: The Editorial Tenure of Dean Hess. PMID- 29237867 TI - Ecological Validity in the Critical Care Environment: Closing the Loop on Evidence Based Medicine. PMID- 29237868 TI - COPD and Physical Activity: A Call to Action for Respiratory Therapists and Patients. PMID- 29237869 TI - Noninvasive Ventilation in Obese Patients After Acute Respiratory Failure: Big Questions Remain. PMID- 29237870 TI - Why All the Shots at Airway Pressure Release Ventilation When Conventional Ventilation Doesn't Have Consensus? PMID- 29237871 TI - Airway Pressure Release Ventilation Letter-Reply. PMID- 29237876 TI - In the dark hours. PMID- 29237875 TI - An autobiography in brief. PMID- 29237877 TI - J. B. S. Haldane, as I knew him. PMID- 29237879 TI - J. B. S. Haldane: an isolated souvenir. PMID- 29237878 TI - J. B. S. Haldane: an uncommon scientist. PMID- 29237880 TI - J. B. S. Haldane and the origin of life. AB - In 1929 the British biologist John Burdon Sanderson Haldane published a hypothesis on the origin of life on earth, which was one of the most emblematic of the interwar period. It was a scenario describing the progressive evolution of matter on the primitive earth and the emergence of life. Firstly, this paper presents the main ideas put forward by Haldane in this famous text. The second part makes comparisons between Haldane and Alexander Ivanovitch Oparin's ideas regarding the origins of life (1924). These two theories, apparently very similar, presented distinct conclusions. The third part focusses on Haldane's reflections on the emergence of life during the 1950s and 1960s, and shows how they were linked to the recent developments of prebiotic chemistry and molecular biology. PMID- 29237881 TI - Haldane, Fisher and Wright. PMID- 29237882 TI - A Haldane perspective from a Fisher student. PMID- 29237883 TI - Haldane and Fisher - scientific interactions. PMID- 29237884 TI - Haldane's The causes of evolution and the Modern Synthesis in evolutionary biology. AB - This paper argues that Haldane's The causes of evolution was the most important founding document in the emergence of the received view of evolutionary theory which is typically referred to as the Modern Synthesis. Whether or not this historical development is characterized as a synthesis (which remains controversial), this paper argues the most important component of the emergence of the received view consisted of showing how the formal rules of Mendelian inheritance are based on (or emerge from) the material basis of heredity established by classical genetics primarily through the experimental work on Drosophila genetics of the Morgan school in the 1910s and 1920s. This is one of the most important achievements of Haldane's book. Thus this paper rejects both (i) the view that the synthesis was a unification of biometry and Mendelism and (ii) the claim that it arose from work primarily done in the late 1930s and 1940s by naturalists rather than theoretical population and classical experimental geneticists. PMID- 29237885 TI - Haldane's view of natural selection. AB - Among many things, J. B. S. Haldane is known for demonstrating how the principle of natural selection can be used to build a mathematical, and in particular quantitative, theory of evolution. However, to the end, he remained open to the idea of other evolutionary mechanisms. In his late writings, he repeatedly drew attention to situations in which natural selection did not operate, was hemmed in by constraints, or worked in a surprising manner. In this respect Haldane stands out among the architects of the Modern Synthesis. PMID- 29237886 TI - Haldane and modern evolutionary genetics. PMID- 29237887 TI - Haldane and the analysis of linkage. PMID- 29237888 TI - Haldane, Waddington and recombinant inbred lines: extension of their work to any number of genes. AB - In the early 1930s, J. B. S. Haldane and C. H. Waddington collaborated on the consequences of genetic linkage and inbreeding. One elegant mathematical genetics problem solved by them concerns recombinant inbred lines (RILs) produced via repeated self or brother-sister mating. In this classic contribution, Haldane and Waddington derived an analytical formula for the probabilities of 2-locus and 3 locus RIL genotypes. Specifically, the Haldane-Waddington formula gives the recombination rate R in such lines as a simple function of the per generation recombination rate r. Interestingly, for more than 80 years, an extension of this result to four or more loci remained elusive. In 2015, we generalized the Haldane Waddington self-mating result to any number of loci. Our solution used self consistent equations of the multi-locus probabilities 'for an infinite number of generations' and solved these by simple algebraic operations. In practice, our approach provides a quantum leap in the systems that can be handled: the cases of up to six loci can be solved by hand while a computer program implementing our mathematical formalism tackles up to 20 loci on standard desktop computers. PMID- 29237889 TI - The cleverest man I never met. PMID- 29237890 TI - Becoming an Indian. PMID- 29237891 TI - J. B. S. Haldane: the John Innes years. PMID- 29237892 TI - Janaki Ammal, C. D. Darlington and J. B. S. Haldane: scientific encounters at the end of empire. AB - Right from the beginning, genetics has been an international venture, with international networks involving the collaboration of scientists across continents. Janaki Ammal's career illustrates this. This paper traces her scientific path by situating it in the context of her relationships with J. B. S. Haldane and C. D. Darlington. PMID- 29237893 TI - J. B. S. Haldane and Lisenkovshchina (Lysenkovschina). PMID- 29237894 TI - J. B. S. Haldane's passage to India: reconfiguring science. AB - In 1957, John Burdon Sanderson (JBS) Haldane (1892-1964), the world's leading population geneticist, committed political radical and one of the three 'founders' of neo-Darwinian 'Modern Synthesis' of twentieth century biology (Sarkar 1995; Haldane 1932; Cain 2009; Smocovitis 1996), ostentatiously renounced both his British citizenship and his prestigious chair at University College London. In a decisively and very public anti-imperial gesture, ostensibly played out as a reaction to the Suez crisis (although his discontent was simmering for quite some time), Haldane, and his partner, geneticistHelen Spurway (1917-1977), turned their backs on Britain and set off to India to offer their considerable scientific prestige, their inexhaustible organisational abilities, along with their leading Journal of Genetics, behind the efforts to build a 'modern', democratic India emerging out of the ashes of colonial rule. Haldane's support of independent India was a major triumph for the new state, itself in the midst of negotiating a fine balance between rapid modernization through science and technology and an postcolonial respect for traditional 'non-Western' values. Although his time in India was short, Haldane's few years in India were marked by a frenzied engagement with the new India, its science, its government and its culture (Rao 2013). PMID- 29237895 TI - J. B. S. Haldane and Journal of Genetics. AB - This is a brief sketch of the history of Journal of Genetics from its beginning in 1909 to the taking over of its publication by the Indian Academy of Sciences in 1985. The account is centred on J. B. S. Haldane's involvement with it over many years, especially as Editor, initially in the UK and later in India. PMID- 29237896 TI - Microwave ablation: Results with three different diameters of antennas in ex vivo bovine and in vivo porcine liver. AB - PURPOSE: To evaluate the ablation ranges and temperature rising rates of three microwave antenna with different diameters in vitro bovine and in vivo porcine livers. MATERIALS AND METHODS: In vitro and in vivo study, microwave ablations (MWA) were induced at a power output of 70 W for 5, 8, and 10 min; a total of 54 and 36 ablations were performed, respectively. Temperature measurements were performed in the 70 W/10 min group with 3 different microwave antennas. RESULTS: In vitro study, the long axis diameter for the 16G microwave antenna was longer than the 15G (P < 0.05) and 14G microwave antennae (P < 0.05). The sphericity index for the 14G and 15G microwave antennae was higher than the 16G microwave antenna (P < 0.05 for both). In the in vivo study, the short- and long-axis diameters, and sphericity index were not statistically different between the 14G, 15G, and 16G groups. The temperature data were not statistically different in both studies. CONCLUSIONS: Although the thin microwave antenna had a longer long axis diameter and a lower sphericity index in vitro study, the thin microwave antenna achieved the same ablation effect in vivo application. MWA has several advantages, and the thin microwave antenna decreases the puncture risk and complication rate. Thus, a thin microwave antenna (15G and 16G) is beneficial in clinical applications and will have a significant influence in the development of MWA. PMID- 29237897 TI - Brachytherapy with iodine 125 seeds for bone metastases. AB - OBJECTIVE: To evaluate the treatment safety and efficacy of iodine 125 (I125) seeds implantation in patients with bone metastases and assess the availability of quality of life (QOL) as an index for efficacy evaluation. PATIENTS AND METHODS: The study enrolled 98 patients with 133 bone metastases from July 2010 to January 2016, who had undergone computed tomography-guided brachytherapy with I125 seeds. Brief pain inventory was administered to assess the degree of pain at the preoperative (W0) and postoperative 2 weeks, 4 weeks, 8 weeks, 12 weeks, and 24 weeks (W2, W4, W8, W12, and W24). Drug use, QOL score, and complications were also assessed. RESULTS: Postoperative pain scores were significantly decreased and maintained for a long term. Numerical rating scale score at W0 was 7.3 +/- 1.6, which was decreased to 4.5 +/- 1.7 (P < 0.01), 3.7 +/- 1.3 (P < 0.01), 2.5 +/- 1.1 (P < 0.01), 1.9 +/- 0.9 (P < 0.01), and 1.3 +/- 0.5 (P < 0.01) at W2, W4, W8, W12, and W24, respectively. After standardized transformation, the dose of morphine for patients at W0 was 175.2 +/- 24.5 mg, which was decreased to 91.2 +/ 21.7 mg (P < 0.01), 89.4 +/- 24.6 mg (P < 0.01), 89.4 +/- 24.6 mg (P < 0.01), 72.8 +/- 14.8 mg (P < 0.01), and 56.7 +/- 11.3 mg (P < 0.01) at W2, W4, W8, W12, and W24, respectively. The efficiency reached 65.3%, 85.1%, 91.2%, 95.2%, and 92.7% at postoperative W2, W4, W8, W12, and W24, respectively. QOL score at W0 was 17.4 +/- 3.3, which increased to 23.2 +/- 4.5 (P < 0.01), 28.6 +/- 7.6 (P < 0.01), 43.2 +/- 9.1 (P < 0.01), 45.6 +/- 10.3 (P < 0.01), and 47.6 +/- 9.8 (P < 0.01) at W2, W4, W8, W12, and W24, respectively. CONCLUSION: Brachytherapy with I125 seeds was safe and effective for treating bone metastases, offering a potential alternative to external-beam radiotherapy. QOL could be applied to evaluate the efficacy of I125 seeds implantation for treating bone metastases. PMID- 29237898 TI - Optimization of b-values in diffusion-weighted imaging for esophageal cancer: Measuring the longitudinal length of gross tumor volume and evaluating chemoradiotherapeutic efficacy. AB - PURPOSE: To study the optimization of b-values of magnetic resonance-diffusion weighted (MR-DWI) in evaluating the chemoradiotherapeutic efficacy for esophageal squamous cell carcinoma (ESCC) and measuring the longitudinal length of gross tumor volume (GTV) of ESCC. MATERIALS AND METHODS: Eighteen patients with biopsy proven ESCC were undergoing concurrent chemoradiotherapy (CCRT). Conventional magnetic resonance imaging (MRI) combined with DWI using b-values of 600 s/mm2, 800 s/mm2, and 1000 s/mm2 was performed before CCRT and after the 1st, 3rd, 5th, and 10th weeks. The apparent diffusion coefficient (ADC) values of ESCC were derived from DWI using multiple b-values. The correlations between ADC values and apoptosis positive rates of ESCC cells obtained from the endoscope biopsy were statistically analyzed. Thirty-eight patients with confirmed ESCC who underwent radical surgery were analyzed. Longitudinal length of GTV of ESCC was measured using endoscopy, esophageal barium fluoroscopy, computed tomography (CT), and T2 weighted MRI and DWI using different b-values (b = 400, 600, and 800 s/mm2) before surgery and were compared with pathologic lesion length. RESULTS: The ADC values of DWI images with different b-values are positively correlated with ESCC cell apoptosis positive ratios, the relation is significant, especially in the group of b = 1000 s/mm2 (P < 0.01). The measured length of esophageal lesions from short to long was MR-DWI b = 800 s/mm2, endoscopy, real tumor, MR-DWI b = 600 s/mm2, esophageal barium fluoroscopy, CT, and MR-DWI b = 400 s/mm2. CONCLUSION: MR-DWI b = 800 s/mm2 and b = 1000 s/mm2 are in favor of observing the chemoradiotherapeutic efficacy with time variation and evaluating the chemoradiotherapeutic efficacy, respectively. MR-DWI b = 600 s/mm2 could be used as a supplementary means in measuring the length of ESCC. PMID- 29237899 TI - Role of surgical treatment for hepatolithiasis-associated intrahepatic cholangiocarcinoma: A retrospective study in a single institution. AB - CONTEXT: The extent of hepatectomy and lymph node dissection (LND) in the treatment of hepatolithiasis-associated intrahepatic cholangiocarcinoma (HL-iCCA) is still controversial. AIMS: The aim of this retrospective study was to evaluate the role of surgical treatment for HL-iCCA. METHODS: The clinical data of 63 patients with HL-iCCA who undergoing surgery between January 2005 and December 2015 were analyzed retrospectively. STATISTICAL ANALYSIS USED: All data were analyzed by the SPSS 17.0 software program (IMB Inc., Chicago, IL, USA). Survival curves were analyzed by the Kaplan-Meier method and compared by the Log-rank test. A P < 0.05 was considered statistically significant. RESULTS: Forty-nine patients (77.8%) underwent surgical resection including 35 with LND and 14 without LND. The overall 1-, 3-, and 5-year survival rates were 58.1%, 28.2%, and 10.6%, respectively, and the median survival time was 19 months. The 1-, 3-, and 5-year survival rates of resection group were 78.9%, 36.3%, and 13.5%, respectively, while the 1-year survival rate of exploratory laparotomy group was 0 (P < 0.0001). The 1-, 3-, and 5-year survival rates of patients with LND were significantly superior to those of without LND (75.9%, 39.4%, and 20.2% vs. 71.4%, 17.9%, and 0, P = 0.043). According to the N status, the 1-, 3-, and 5 year survival rates of pN0 subgroup were 81.8%, 49.2%, and 28.1%; pN1 subgroup were 65.3%, 18.6%, and 0%; and pNx subgroup were 71.4%, 17.9%, and 0%, respectively (pN0 vs. pN1, P = 0.005; pN0 vs. pNx, P = 0.004; pN1 vs. pNx, P = 0.653). The 1-, 3-, and 5-year survival rates of R0 resection (n = 42) were 80.2%, 36.7%, and 14.9%, respectively, and those of R1 resection (n = 7) were 71.4%, 0%, and 0%, respectively (P = 0.028). CONCLUSIONS: Radical resection is the most effective therapy for HL-iCCA. Regional lymphadenectomy is strongly recommended in resectable HL-iCCA, which is helpful in tumor staging and long term survival. PMID- 29237900 TI - Laparoscopic surgery for endometrial cancer in aged patients: Experience from a tertiary referral center in Eastern China. AB - OBJECTIVE: The aim of the present study was to evaluate the feasibility and safety of laparoscopic surgery for endometrial cancer in aged patients and show the experiences of laparoscopic surgery for elderly endometrial cancer patients in Eastern China. MATERIALS AND METHODS: A total of 211 patients (>=60 years) with endometrial carcinoma treated with surgery were retrospectively analyzed, including 104 patients who underwent laparoscopic surgery, and 107 who underwent laparotomy. RESULTS: The operation time was similar in both groups (192.9 vs. 185.5 min, P = 0.722). For all cases, the estimated blood loss was less in the laparoscopic group relative to that of in the open group (227.5 vs. 382.6 ml, P = 0.000). There was no difference in the complication rate between the two groups (21.2% vs. 29.0%, P = 0.191). Overall, right pelvic and periaortic lymph node dissections were similar for the laparoscopic and laparotomy groups, but the former procedure dissected more left pelvic lymph nodes than that of in laparotomy (13.3 vs. 7.2 nodes, P = 0.038). The hospital stay was shorter after laparoscopic surgery than that of after laparotomy (7 vs. 10.5 days, P = 0.000). The recurrence rate was similar in the two groups (7.7% vs. 10.3%, P = 0.511). CONCLUSIONS: Laparoscopy could be a safe alternative to laparotomy for endometrial cancer in aged patients. PMID- 29237901 TI - Transarterial chemoembolization with gelatin sponge microparticles for barcelona clinic liver cancer Stage C and large hepatocellular carcinoma: Initial clinical experience. AB - OBJECTIVE: The purpose of this investigation is to present a preliminary clinical experience in transarterial chemoembolization (TACE) with gelatin sponge microparticles (GSMs) for barcelona clinic liver cancer (BCLC) Stage C and large hepatocellular carcinoma (HCC) patients in China. MATERIALS AND METHODS: Between August 2009 and August 2012, 20 BCLC Stage C HCC patients with tumor size >=5 cm undergoing GSMs-TACE were retrospectively analyzed. Tumor response was evaluated using modified response evaluation criteria in solid tumors (mRECIST) with enhanced magnetic resonance/computed tomography imaging performed 4-6 weeks after each GSMs-TACE procedure. Kaplan-Meier curves were used to assess overall survival (OS). Complications postprocedure was also analyzed. RESULTS: In this cohort of 20 HCC patients, vascular invasion was present in 8 patients (40%), extrahepatic metastases in 6 patients (30%), and both in 6 individuals (30%). Median tumor size was 9.9 +/- 3.2 cm. All procedures were successfully performed with minimal complications. The mean number of TACE per patient was 2.6 sessions (range 1-5). Median OS (mOS) was 14 months for the entire study population. Survival rates at 6 and 12 months were 85% and 73.7%, respectively. According to mRECIST criteria, follow-up images were obtained 6 months after initial GSMs TACE. Five patients (25.0%) achieved complete response, 8 patients (40.0%) had partial response, 4 (20.0%) had stable disease, and 3 (15.0%) had progressive disease. The objective response rate for TACE was 65%. CONCLUSIONS: From our preliminary clinical experience, GSMs-TACE in the treatment of BCLC Stage C and large HCC appears to offer favorable survival and tumor response with low morbidity. However, further prospective studies are required to assess its safety and efficacy. PMID- 29237902 TI - The significance of prophylactic transarterial chemoembolization after radical resection of small hepatocellular carcinoma: A retrospective analysis. AB - PURPOSE: To clarify the necessity of prophylactic transarterial chemoembolization (pTACE) after radical resection for small hepatocellular carcinoma (sHCC) (<3.0 cm) and identify prognostic determinants. MATERIALS AND METHODS: Consecutive 161 patients with sHCC in Zhejiang Cancer Hospital from May 2009 to May 2014 were retrospectively studied. In these patients, 87 patients only received radical resection alone (control group), while other 74 patients received pTACE after radical resection (pTACE group). The overall survival (OS) and recurrence-free survival (RFS) were evaluated by Kaplan-Meier method and the related factors on OS and RFS were analyzed by Cox regression analysis. RESULTS: The median OS for all patients was 33.6 months. The median OS in the pTACE and control group was 34.1 and 33.4 months, respectively (P = 0.508). The 1-, 3-, and 5-year survival rates were 91.9%, 73.4%, and 42.7% in the pTACE group and 93.1%, 77.9%, and 51.4% in the control group, respectively. The median RFS in pTACE and control group was 21.6 and 31.3 months (P = 0.002), respectively. The 1-, 3-, and 5-year RFS rate in pTACE group and control group was 81.0%, 47.4%, and 27.6% and 86.9%, 71.7%, and 49.9%, respectively. Preoperative gamma-glutamyl transferase (GGT) serum level >=60 U/L (hazard ratio [HR] = 2.603, 95% confidence interval [CI] =1.506 4.501, P = 0.001) and recurrence (HR = 6.034, 95% CI = 2.931-12.421, P = 0.003) were independent prognostic determinants associated with poor prognosis in multivariate analysis. Resection followed by pTACE (HR = 2.046, 95% CI = 1.262 3.319, P = 0.004) and preoperative GGT serum level >=60 U/L (HR = 1.864, 95% CI = 1.152-3.017, P = 0.011) were independent prognostic factors associated with higher rate of recurrence. CONCLUSIONS: Instead of improving the survival time, postoperative pTACE increased the rate of recurrence in sHCC patients. Preoperative GGT serum level >=60 U/L and recurrence were independent prognostic determinants associated with poor prognosis. PMID- 29237903 TI - Clinicopathological features and prognostic evaluation of bone metastasis in triple-negative breast cancer. AB - BACKGROUND: Bone metastases (BMs) are common for breast cancer patients. However, triple-negative breast cancer (TNBC) with BM is relatively rare and few data on it are available. In this study, we aim to investigate the incidence and clinicopathological features and to evaluate the prognosis of TNBC patients with BM. MATERIALS AND METHODS: A total of 616 patients with TNBC (120 out of them had BM) between 2007 and 2011 were involved in the study. Clinicopathological characteristics were statistically analyzed. RESULTS: A total of 120 (19.5%) patients developed BM with a median age of 53.1 years. The median overall survival (OS) was 40 months, and the 5-year OS rate was 37.3% in TNBC patients with BM. Patients without BM had longer survival time than those with BM (P < 0.001). In the univariate analysis, lymph nodes metastasis, tumor Stage III-IV, multiple BMs, and coexistence of visceral metastasis were correlated to a poor prognosis (P = 0.020; P < 0.001; P < 0.001; P < 0.001). Moreover, multivariate analysis demonstrated that tumor stage, number of BM, and visceral metastasis were significantly independent factors for OS (P < 0.001; P < 0.001; P < 0.001). CONCLUSIONS: Tumor Stage III-IV, multiple BMs, or coexistence of visceral metastasis were associated with poor prognosis for OS in TNBC patients with BM. These associations may contribute to prevention, early detection, and goal directed treatment of bone metastatic TNBC. PMID- 29237904 TI - Efficacy and safety of temozolomide plus whole-brain radiotherapy in the treatment of intracranial metastases. AB - OBJECTIVE: This study aimed to explore the clinical efficacy and safety of temozolomide (TMZ) plus whole-brain radiotherapy (WBRT) in the treatment of intracranial metastases. SUBJECTS AND METHODS: A total of 72 patients with intracranial metastases were randomly divided into observation group and control group (each n = 36). The patients of observation group received WBRT plus TMZ, while the patients of control group received WBRT. The observation index of both groups included the short- and long-term clinical efficacies, improvement of symptoms and signs, quality of life (QOL), and adverse responses. RESULTS: After treatment, the objective remission rate in observation group (77.78%, 28/36) was evidently higher than that of in control group (47.22%, 17/36), with significant difference (P = 0.0074). However, the disease control rate in observation group (94.44%, 34/36) was only slightly higher than that of in control group (86.11%, 31/36) (P = 0.4263). Moreover, after treatment, compared to control group, observation group showed markedly better improvement in symptoms and signs, as well as QOL (P < 0.001), with significantly longer overall survival and progression-free survival (P < 0.001). CONCLUSION: TMZ concomitant with WBRT can increase the local control, prolong the survival time and improve the QOL of patients with intracranial metastases. PMID- 29237905 TI - A clinical study of polyethylene glycol recombinant human granulocyte colony stimulating factor prevention neutropenia syndrome in patients with esophageal carcinoma and lung cancer after concurrent chemoradiotherapy. AB - OBJECTIVE: To compare the efficacy and safety of PEG-rhG-CSF and recombinant human G-CSF (rhG-CSF) for the prevention and delayed application in febrile neutropenia, hospitalization rate in concurrent chemoradiotherapy of tumors. METHODS: A total of 163 patients, who received concurrent chemoradiotherapy for solid tumors. There were 75 patients in the PEG-rhG-CSF group (PEG group), who received 146 cycles of concurrent chemoradiotherapy, of which 132 cycles (90.42%) were prophylactic therapy, while 9 cycles (6.16%) were delayed therapy. There were 88 patients in the rhG-CSF group (rhG group), who received 164 cycles of concurrent chemoradiotherapy, of which 48 cycles (29.3%) were prophylactic, while 116 cycles (70.7%) were delayed therapy. G-CSF was used for prophylaxis in 180 cycles of chemotherapy, with delayed use in 130 cycles. RESULTS: Comparison between the prevention group and the delayed group showed that the incidence of neutropenia-related hospitalization was 4.44% and 14.62%, respectively (OR = 0.272, 95% CI, 0.115-0.642) (P = 0.002). Intravenous antibiotics usage was 2.78% vs. 11.54%, (OR = 0.004, 95% CI, 0.077-0.619) (P = 0.004). Dose reduction of chemotherapy or delay was 5% vs. 17.69% (OR = 0.245, 95% CI, 0.109-0.549) (P = 0.001). The prevention group had protective effects from all factors as compared to the delayed group (all P < 0.05, and all OR < 1). Moreover, the protective role of intravenous antibiotics was the strongest in the prevention group. CONCLUSION: Prophylactic use of GSF reduced hospitalization rate and the rate of intravenous application of antibiotics. PMID- 29237906 TI - Clinical efficacy of preoperative vaginal intracavitary irradiation for Stage Ib2 and IIa cervical cancer. AB - OBJECTIVE: The purpose of this study was to evaluate the clinical efficacy of preoperative vaginal intracavitary irradiation for Stage Ib2 and IIa cervical cancer. MATERIALS AND METHODS: From June 2008 to June 2014, data from 78 Stage Ib2 and IIa cervical cancer patients (age <=75 years) with a diameter of local lesions >4 cm were collected in our hospital. Before treatment, all cases were confirmed by biopsy. The patients' general state was good, Karnofsky Performance Score >=90, heart and lung functioning was normal, and patients were able to tolerate the surgery. The 78 patients were randomly divided into two groups: neoadjuvant radiotherapy group (NRG) (n = 38) and radical surgery group (n = 40). Patients in NRG received 2000~3000 cGy192 Ir irradiation of preoperatively intracavitary brachytherapy (radioactive source at 1 cm distance). After a rest of 10-14 days, radical hysterectomy with pelvic lymphadenectomy was performed. Surgery alone group (SAG) (n = 40) underwent radical surgery directly. The treatment outcomes between these two groups were compared, and the effect of preoperative intracavitary brachytherapy and presence of postoperative complications were evaluated. RESULTS: The total clinical efficacy for intracavitary brachytherapy was 94.7% (36/38) with complete response 13 (34.2%), partial response 23 (60.5%), and stable disease 2 (5.3%). Moreover, no patients developed progression disease; for SAG patients, 32 cases successfully finished the extensive hysterectomy and pelvic lymphadenectomy. Operation time <240 min was found in 19 patients. Moreover, the positive complication for lymphatic cyst and urinary retention was 20.0% and 15.0%, respectively. For NAG group, 36 patients successfully finished the extensive hysterectomy and pelvic lymphadenectomy. Operation time <240 min was found in 22 patients. Moreover, the positive complication for lymphatic cyst and urinary retention was 15.8% and 13.2%, respectively. The median follow-up time for NRG and SAG was 28 and 30 months, respectively. Three cases lost to follow-up in the SAG with the follow-up rate of 92.5% (37/40). In the NRG group, 3 cases lost to follow-up with the follow-up rate of 92.1% (35/38). The locoregional control rate for 1, 3, and 5 years was 80.0%, 61.3%, and 52.6%, respectively, for SAG group and 89.5%, 82.9%, and 76.9%, respectively, for NRG group with significant statistical difference for 3 and 5 years. CONCLUSION: Preoperative intracavitary brachytherapy is an effective procedure for the treatment for Stage Ib2 and IIa cervical cancer and can significantly improve the locoregional control rate. PMID- 29237907 TI - Long noncoding RNA activated by transforming growth factor-beta promotes cancer development and is a prognostic marker in cervical cancer. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) have been highlighted as crucial elements in cancer biology. LncRNA activated by transforming growth factor-beta (ATB) was identified to promote the development of multiple cancers and may serve as a potential therapeutic target in human cancers. However, to the best of our knowledge, the functional role of ATB in cervical cancer has not been verified yet. MATERIALS AND METHODS: The expression of lncRNA ATB was evaluated by quantitative reverse transcriptase-polymerase chain reaction assay in cervical cancer cell lines and clinical specimens. The clinical significance of ATB was statistically evaluated by analyzing the relationship between ATB overexpression and the clinicopathological characteristics of cervical cancer patients. Moreover, Kaplan-Meier analysis and log-rank test were conducted to investigate the role of ATB in the overall survival (OS) and progression-free survival (PFS) of cervical cancer patients or subgroup patients. Furthermore, univariate and multivariate analyses were adopted to identify the risk factors of OS and PFS of cervical cancer patients. RESULTS: LncRNA ATB was upregulated in cervical cancer cell lines and tissues (P < 0.05). Statistical analysis revealed that ATB overexpression was correlated with higher squamous cell carcinoma antigen level, larger tumor size, lymph node metastasis, and more advanced International Federation of Gynecology and Obstetrics (FIGO) stage of cervical cancer patients (P < 0.05). In addition, survival analysis showed that ATB upregulation was associated with poorer OS in cervical cancer patients and in subgroup patients without/with lymph node metastasis and with FIGO Stage I/II (P < 0.05). Furthermore, high ATB expression was defined as an independent risk factor of poorer OS and early recurrence of cervical cancer patients (P < 0.05). CONCLUSION: LncRNA ATB correlates with the malignant phenotypes and poor prognosis of cervical cancer. ATB may serve as a promising prognostic marker and therapeutic target of cervical cancer patients. PMID- 29237908 TI - Lymphoepithelioma is a nonkeratinizing squamous cell carcinoma with Epstein-Barr virus infection in China. AB - OBJECTIVE: The objective of this study is to investigate the histogenesis of lymphoepithelial carcinoma (LEC) and its relationship with Epstein-Barr virus (EBV). MATERIALS AND METHODS: The expression of EBV was detected using in situ hybridization, and the CK5/6, p63, and p40 expression levels were detected using immunohistochemistry in 45 paraffin-embedded tissues from LEC. RESULTS: In 45 paraffin-embedded LEC tissues from 10 different samples, the positive CK5/6 signals were located in the cell membrane. The positive signals for p63 and p40 were located in the cell nucleus. In all LEC cases, the positive rates of CK5/6, p63, and p40 were 93.3% (42/45), 95.6% (43/45), and 93.3% (42/45), respectively. The positive EBV-encoded RNA (EBER) signals were located in the cell nucleus. In the 45 LEC cases, the expression of EBER was strongly positive with a positive rate of 100% (45/45). CONCLUSIONS: LEC is closely related to EBV, and EBV plays an important role in the development of LEC. LEC showed positive squamous cell markers, indicating that the samples contain squamous cell carcinoma (SQCC). LEC is EBV (+) with nonkeratinizing SQCC, and this name better reflects the nature of this disease. PMID- 29237909 TI - Change of circulating antibodies against CD25-derived peptide antigen in hepatocellular carcinoma. AB - AIMS: Several studies have shown altered levels of plasma anti-CD25 antibodies in patients with malignancy in lung, esophagus and breast. The present study was thus designed to test whether circulating anti-CD25 antibody levels were changed in hepatocellular carcinoma (HCC). METHODS: An enzyme-linked immunosorbent assay (ELISA) was developed in-house to detect plasma IgG antibodies to CD25-derived linear peptide antigens in 122 patients with HCC and 121 control subjects. RESULTS: Student's t-test showed that plasma anti-CD25 IgG levels were significantly higher in HCC patients than control subjects (t = 4.96, P < 0.001), in which male patients mainly contributed to the increased IgG levels (t = 5.11, P < 0.001). Further analysis showed that plasma anti-CD25 IgG levels were dependent on the stages of HCC although there was no significant correlation between plasma anti-CD25 IgG levels and BCLC stages (r = 0.145, P = 0.110, N = 122); a significant increase in anti-CD25 IgG levels was observed in HCC patients with stages B (t = 4.43, P < 0.001) and C+D (t = 4.89, P < 0.001) as compared with control subjects. Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curve (AUC) was 0.66 (SE = 0.035, 95% CI 0.60 0.73). The sensitivity of anti-CD25 IgG assay was 12.3% against a specificity of 99.2%. CONCLUSIONS: The present study suggests that circulating anti-CD25 IgG antibodies may have prognostic rather than early diagnostic values for HCC. PMID- 29237910 TI - Clinical significance of Twist, E-cadherin, and N-cadherin protein expression in endometrioid adenocarcinoma. AB - OBJECTIVE: The aim of the study was to investigate the expression of Twist, E cadherin, and N-cadherin both in normal endometrium and in endometrioid adenocarcinoma tissues (NET and EAT), and further discuss the relationship between the proteins expression and the clinical parameters. METHODS: Seventy-six EAT and 50 NET were collected from endometrioid adenocarcinoma patients and patients who received hysterectomy. We used immunohistochemistry (two steps methods) to detect the expression of Twist, E-cadherin, and N-cadherin proteins in EAT and NET. The Twist, E-cadherin, and N-cadherin protein positive expression rate in EAT and NET were compared by Chi-square test. Moreover, the correlation between patients' clincial characteristics and Twist, E-cadherin, and N-cadherin protein expression was evaluated. RESULTS: The positive expression of Twist and N cadherin proteins in EAT was significantly higher than those in NET (u = 14.8, 9.04, P < 0.05), the positive expression of E-cadherin protein in ENT was significantly lower than those in NET (u = 4.14, P < 0.05). The Twist, E cadherin, and N-cadherin expressions were related with endometrioid adenocarcinoma under different International Federation of Gynecology and Obstetrics (FIGO) clinical stages (P < 0.05), depths of tumor invasion (P < 0.05), and tumor differentiation degrees (P < 0.05). However, these proteins exerted no influence on vessel and lymph metastases (P > 0.05). The Spearman rank correlation analysis showed that the expression of the Twist protein and that of the E-cadherin (r = -0.584, P < 0.05), N-cadherin protein (r = 0.460, P < 0.05) in endometrioid adenocarcinoma was significant correlated with statistical difference. CONCLUSION: Twist, E-cadherin, and N-cadherin protein were different expressed in EAT and NET which indicating their potential function for endometrioid adenocarcinoma development. Twist may participate in the occurrence of epithelial-mesenchymal transition, affect the expression of E-cadherin and N cadherin and may be related to metastasis and progression of endometrioid adenocarcinoma. PMID- 29237911 TI - Functional analysis of RET with multiple endocrine neoplasia type 2. AB - BACKGROUND: Multiple endocrine neoplastic type 2 (MEN2) is an endocrine carcinoma syndrome which is caused by a germline activation mutation that occurs during transfection (RET) proto-oncogene transmission. MEN2A patients are affected by RET (C634Y, C634R) mutation; MEN2B patients are affected by RET (M918T) mutation. AIMS: We aim to identify RET mutations' (C634R and M918T) expression, location, and signaling activation during the disease's progression, which providing a theoretical basis for the study on etiology of multiple endocrine neoplasia. SETTINGS AND DESIGN: This study was conducted to determine whether RET dysfunction involves an induced mutation into SK-N-MC cells. MATERIALS AND METHODS: Wildtype RET and mutant RET plasmids (M918T and C634R) were constructed and transfected into SK-N-MC cells, the protein level was detected by Western blot, the efficiency of the transfected cells was detected by real time PCR, and the location of RET protein in cells as-determined by immunofluorescence. SK-N-MC cells with different RET plasmids treated/untreated by GDNF, AKT and ERK1/2 phosphorylation detected by specific antibodies. RESULTS: We found that C634R mutation could enhance RET protein expression and change the location of the mutated protein and forced it into the nucleus, GDNF treatment alone can only enhance M918T RET phosphorylation level and not impact WT or C614R mutation, and AKT/ERK1/2 pathway can be affected by GDNF treatment. CONCLUSION: RET dysfunction involves an induced mutation into SK-N-MC cells. PMID- 29237912 TI - Effects of exogenous hydrogen sulfide on the proliferation and invasion of human Bladder cancer cells. AB - OBJECTIVE: The objective of this study is to evaluate the effects of exogenous hydrogen sulfide (H2S) on the proliferation and invasion of human bladder cancer cells. METHODS: Human bladder cancer EJ cells were cultured and then treated with sodium bisulfide (NaHS) (100 MUmol/L for low dosage, 200 MUmol/L for moderate dosage, 400 MUmol/L for high dosage). The differences on proliferation and invasion of EJ cells were detected among different groups with MTT and transwell invasion assays. The differences in the expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 among the groups were detected with Western blot. RESULTS: Cell proliferation activity was elevated by exogenous NaHS, with significantly statistical difference compared to the blank control group (P < 0.05). With the increased NaHS concentration, the EJ cell proliferation activity presented a statistically significant trend of increase, showing comparative differences among different groups (P < 0.05). Exogenous NaHS could also improve the invasion ability of bladder cancer EJ cells, which was significantly enhanced with increased NaHS dose (P < 0.001). The levels of MMP2 and MMP9 in EJ cells were significantly upregulated with the increased NaHS dose (P < 0.001). CONCLUSION: Exogenous H2S may promote cell proliferation and invasion by upregulating the expression level of MMP2 and MMP9 in human bladder cancer EJ cells. PMID- 29237913 TI - The clinical significance of secreted protein acidic and rich in cysteine expression in breast cancer tissue and its association with prognosis. AB - OBJECTIVE: The aim of this study was to evaluate the secreted protein acidic and rich in cysteine (SPARC) expression in breast cancer tissue and its association with patients' clinical pathology characteristics and prognosis. MATERIALS AND METHODS: Eight-eight cases with confirmed diagnosis of breast cancer who received operation from January 2010 to February 2016 were included in this study. The SPARC expression in cancer tissue was examined by immunohistochemical method. The SPARC expression status, clinical pathology characteristics, and prognosis of included patients were recorded and evaluated. RESULTS: SPARC protein was mainly expressed in cytoplasm and stroma of tumor tissue with dark brown and purple stain. The SPARC protein-positive expression rate was 69.3% (61/88) in cancer tissue. The positive expression of SPARC in breast tissues was not significantly correlated with age, menstruation status, tumor, node, and metastasis stage, tumor size, progesterone level, and HER-2 status (P > 0.05). However, SPARC protein-positive expression was correlated with tumor differentiation (P < 0.05), estrogen receptor expression (P < 0.05), and lymph node metastasis (P < 0.05). The 3-year disease-free survival (DFS) was 60.8% and 71.2% for SPARC-positive and -negative groups with no statistical difference (P > 0.05); there was no statistical difference of disease progression risk between the SPARC-positive and -negative groups (hazard ratio = 1.78, 95% confidence interval: 0.80-3.57, P > 0.05). However, SPARC-positive and -negative patients have shown a trend of DFS difference. CONCLUSION: SPARC is closely related to the development of breast cancer and can be used as a tumor marker for breast cancer recurrence. PMID- 29237914 TI - The prognostic value of preoperative serum albumin-globulin ratio for high-grade bladder urothelial carcinoma treated with radical cystectomy: A propensity score matched analysis. AB - OBJECTIVES: Albumin-globulin ratio (AGR) has been reported as an independent risk factor for survival outcomes of a variety of malignancies. We aimed to further examine the prognostic value of AGR for urothelial carcinoma of bladder (UCB) using a propensity score-matched (PSM) analysis. MATERIALS AND METHODS: The medical data of 189 high-grade UCB patients undergoing radical cystectomy were retrospectively reviewed. AGR was defined as the ratio of serum albumin to nonalbumins (serum total protein-albumin). The association of preoperative AGR with clinicopathologic characteristics and prognosis were assessed. Multivariate analyses using Cox regression models were applied to evaluate the independent prognostic factors. RESULTS: The receiver operating curve analysis indicated 1.55 as the optimal cutoff value to define low or high AGR. In prematched cohorts, Kaplan-Meier analysis indicated that AGR lower than 1.55 was associated with poorer overall survival (OS), progression-free survival (PFS), and tumor-specific survival (TSS) (P < 0.001 for all). Multivariable cox analyses also showed that AGR lower than 1.55 were an independent risk factor for survival outcomes, including OS, PFS, and TSS (P < 0.01 for all). In particular, AGR lower than 1.55 remained its prognostic value after PSM analysis. CONCLUSION: Low AGR was a significant unfavorable factor for UCB patients treated with radical cystectomy. This viable parameter should be enrolled in the pretreatment risk stratification for UCB. PMID- 29237915 TI - Effect of auricular points treatment combined with acupoints application in patients with constipation after lung cancer surgery. AB - OBJECT: To assess the effect of auricular points treatment combined with acupoints application on patient with constipation after lung cancer surgery. METHODS: Design and participants: This is a single-center randomized controlled trial. Totally 341 after lung cancer surgery patients were randomly assigned into the experimental group (n = 174) and the control group (n = 167). The control group received routine nursing care, which was included psychological support, diet instruction, and post-operative activities guidance. The experimental group received auricular points treatment combined with acupoints application therapy in addition to the routine nursing care. All the patients had defecation within 3 days after operation. The characteristics of the stool were recorded, and the progress and performance of the incidence of constipation was recorded in two groups. RESULTS: The incidence of constipation in the control group was higher than that in the experimental group (P < 0.001). Moreover, the stool characteristics of experimental group were better than it in the control group by rank-sum test (P = 0.047). CONCLUSION: On the basis of routine measures to prevent constipation after lung cancer surgery, auricular point sticking combined with acupoint application therapy can effectively decrease the incidence of postoperative constipation. PMID- 29237916 TI - Meta-analysis of efficacy of laparoscopic hepatectomy versus open hepatectomy for hepatocarcinoma. AB - OBJECTIVE: The aim of this study was to summarize the current evidence to evaluate the effects of laparoscopic hepatectomy (LH) and open hepatectomy (OH) in the treatment of hepatocarcinoma. METHODS: A comprehensive literature search was performed using PubMed, Embase, and Google Scholar to identify all relevant studies. After we screened further, 22 published studies were included in this meta-analysis. We pooled the odds ratios (ORs), standardized mean difference (SMD) and conducted heterogeneity, quality assessment. RESULTS: The outcomes of treatment effects included surgical blood loss, surgical time, postoperative complications, perioperative mortality, 3-year survival rate, and 5-year survival rate. Comparing OH for liver cancer patients, the pooled SMD of surgical blood loss was -0.65 (95% confidential index [confidence interval (CI)] = [-0.80, 0.50]), the pooled SMD of surgical time was -0.12 (95% CI = [-0.25, -0.00]), the pooled OR of postoperative complications was 0.48 (95% CI = [0.38, 0.62]), the pooled OR of perioperative mortality was 0.34 (95% CI = [0.14, 0.84]), the pooled OR of 3-year survival rate was 1.03 (95% CI = [0.76, 1.39]), and the pooled OR of 5-year survival rate was 0.99 (95% CI = [0.75, 1.30]). CONCLUSION: LH was found to significantly decrease patients' blood loss. LH slightly decreases surgical time. In addition, LH appears not to affect 3- and 5-year survival rate, but it offers less postoperative complications and perioperative mortality. PMID- 29237917 TI - Influence of risk factors on stomal recurrence after total laryngectomy for laryngeal carcinomas: A meta-analysis. AB - BACKGROUND: Total laryngectomy is preserved for those the most advanced larynx cancer and nonsurgical cases. However, stomal recurrence is frequently occurred and leads to high mortality. Herein, we aimed to determine the risk factors for the stomal recurrence after total laryngectomy (SRAL). METHODS: Databases such as PubMed and EMBASE were comprehensively searched using the keywords "stomal recurrence" and "total laryngectomy." Based on the inclusion and exclusion criteria, qualified studies would be incorporated in this meta-analysis, followed by quality evaluation and data extraction. Risk ratios (RRs) were used. RESULTS: A total of six studies were included in the meta-analysis, and the pooled RRs showed that subglottic location increased the incidence of stomal recurrence most among the four primary locations. Expectedly, advanced tumor stage before the laryngectomy was the risk factor for stomal recurrence, while lymph node metastases showed no difference in this meta-analysis. Further, preoperative tracheostomy increased two times more risk in the stomal recurrence compared with nonpreoperative surgery. CONCLUSIONS: In this study, we proved that subglottic location, advanced tumor stage, especially T4 stage, and preoperative tracheostomy were risk factors for SRAL for larynx cancer. However, many other potential risk factors, such as surgical margins, could not be determined for inadequate records. Hence, more prospective trials should be designed to determine the risk factors for SRAL for larynx cancer. PMID- 29237918 TI - Meta-analysis of diagnostic accuracy of magnetic resonance imaging and mammography for breast cancer. AB - OBJECTIVE: The aim of this study was to compare the performance of mammography (MG) and magnetic resonance imaging (MRI) in the diagnosis of breast cancer. METHODS: Searching in the databases including PubMed, Embase, and Google Scholar about comparative study of MG and MRI in the diagnosis of breast cancer during 2000-2017. After we screened further, the extracted effective data were calculated by Meta-Disc 1.4 software. RESULTS: we obtained 11 articles. The pooled estimates for sensitivity of MG and MRI were 0.75 (95% confidence interval [CI], [0.72, 0.78]) and 0.92 (95% CI, [0.89, 0.94]) respectively, and for specificity were 0.71 (95% CI, [0.67, 0.74]) and 0.70 (95% CI, [0.66, 0.73]), respectively. Their weighted area under the summary receiver operating characteristic curve was 0.79 and 0.93, respectively. CONCLUSION: MRI remains to be a satisfactory method for the diagnosis of breast cancer and should first be considered for patients. PMID- 29237919 TI - Efficacy and safety of bevacizumab in elderly patients with advanced colorectal cancer: A meta-analysis. AB - AIMS: Bevacizumab plus chemotherapy (CT) has been the standard treatment for advanced colorectal cancer (ACRC) in the last decade. However, whether geriatric patients treated with this combination achieved more benefits or suffered severer toxicities than CT alone remained controversial. This meta-analysis was aimed to provide more convincing evidence. SUBJECTS AND METHODS: Randomized control trials (RCTs) and retrospective comparative studies on the comparison between bevacizumab plus CT and CT for geriatric ACRC patients were retrieved in PubMed, Web of Science, EMBASE, and Ovid until June 2016. One RCT, five subgroup analyses of RCTs, and two retrospective studies with efficacy and safety data were identified, involving a total of 2813 cases. The included primary outcomes were overall survival (OS), progression-free survival (PFS), and adverse events (AEs). RESULTS: For geriatric ACRC, both OS (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.74-0.94, P = 0.003) and PFS (HR 0.55, 95% CI 0.48-0.63, P < 0.001) have been improved after the addition of bevacizumab to CT. The odds ratios (ORs) for total grade and grade 3-5 AEs were 1.85 (95% CI 1.12-3.04, P = 0.02) and 2.09 (95% CI 1.69-2.58, P < 0.001), respectively. For overall grade toxicities, proteinuria (OR 10.89, 95% CI 1.37-86.28, P = 0.02), hypertension (OR 4.44, 95% CI 1.85-10.62, P < 0.05), and fistulae/abscess (OR 12.07, 95% CI 1.54 94.88, P < 0.05) were significantly higher in the bevacizumab arm. For grades 3 5, increased risk of hypertension (OR 3.91, 95% CI 2.48-6.16, P < 0.001), arterial thromboembolism (OR 3.25, 95% CI 1.70-6.19, P < 0.001), and venous thromboembolism (OR 2.17, 95% CI 1.11-4.25, P = 0.02) was observed in the bevacizumab group. CONCLUSIONS: After the addition of bevacizumab to CT in geriatric ACRC, both PFS and OS could be significantly improved, while it would also lead to some high-grade AEs, hypertension, and arterial and venous thromboembolism. PMID- 29237920 TI - Adenocarcinoma located at a Meckel's Diverticulum: A case report and literature review. AB - Tumors arising from Meckel's diverticulum (MD) reported in the literature are mainly carcinoid and gastrointestinal stromal tumors. We herein report a rare case of adenocarcinoma arising from intestinal mucosa in an MD with multiple liver metastases at the onset of symptoms. A 57-year-old female complaining of bloody stool for 2 weeks was admitted to our hospital. Colonoscopy revealed massive bloody fluids but did not find any neoplasm. Computed tomography (CT) found a heterogeneous mass at the distal ileum and multiple liver metastases. A segmental ileal resection with local mesentery excision was performed to control the bleeding. During surgery, a tumor arising from a diverticulum in the antimesenteric border of ileum was observed. Histologic examination revealed moderate to poorly differentiated adenocarcinoma. Majority of the MD remain asymptomatic and are diagnosed incidentally during small bowel contrast study, laparoscopy or laparotomy done for unrelated conditions, or until complications arise from the diverticulum. Malignancies are reported to account for only 0.5% 3.2% of the complications. The occurrence of adenocarcinoma in an MD is exceedingly rare. In the few cases described so far, the prognosis of adenocarcinoma within an MD has been poor due to the advanced stage as seen at the time of surgery. Despite the availability of many publications, there is a little consensus concerning the management of an incidental finding of MD. Adenocarcinoma in an MD is extremely sporadic and prognosis has been reported as very poor. However, early diagnosis is challenging. When found incidentally during laparotomy, MD should be carefully examined and best treated with prophylactic resection. PMID- 29237921 TI - Impact of Proton-pump Inhibitors on the Pharmacodynamic Effect and Clinical Outcomes in Patients Receiving Dual Antiplatelet Therapy after Percutaneous Coronary Intervention: A Propensity Score Analysis. AB - BACKGROUND: Prior studies have reported controversial conclusions regarding the risk of adverse cardiovascular events in patients using proton-pump inhibitors (PPIs) combined with clopidogrel therapy, causing much uncertainty in clinical practice. We sought to evaluate the safety of PPIs use among high-risk cardiovascular patients who underwent percutaneous coronary intervention (PCI) in a long-term follow-up study. METHODS: A total of 7868 consecutive patients who had undergone PCI and received dual antiplatelet therapy (DAPT) at a single center from January 2013 to December 2013 were enrolled. Adenosine diphosphate (ADP)-induced platelet aggregation inhibition was measured by modified thromboelastography (mTEG) in 5042 patients. Propensity score matching (PSM) was applied to control differing baseline factors. Cox proportional hazards regression was used to evaluate the 2-year major adverse cardiovascular and cerebrovascular events (MACCEs), as well as individual events, including all cause death, myocardial infarction, unplanned target vessel revascularization, stent thrombosis, and stroke. RESULTS: Among the whole cohort, 27.2% were prescribed PPIs. The ADP-induced platelet aggregation inhibition by mTEG was significantly lower in PPI users than that in non-PPI users (42.0 +/- 30.9% vs. 46.4 +/- 31.4%, t = 4.435, P < 0.001). Concomitant PPI use was not associated with increased MACCE through 2-year follow-up (12.7% vs. 12.5%, chi2 = 0.086, P = 0.769). Other endpoints showed no significant differences after multivariate adjustment, regardless of PSM. CONCLUSION: In this large cohort of real-world patients, the combination of PPIs with DAPT was not associated with increased risk of MACCE in patients who underwent PCI at up to 2 years of follow-up. PMID- 29237922 TI - Outcomes of Coronary Artery Bypass Graft Surgery Versus Percutaneous Coronary Intervention in Patients Aged 18-45 Years with Diabetes Mellitus. AB - BACKGROUND: Debate on treatment for young patients with coronary artery disease still exists. This study aimed to investigate the intermediate- and long-term outcomes between coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) in patients aged 18-45 years with diabetes mellitus (DM). METHODS: Between January 2006 and March 2016, a total of 2018 DM patients aged 18 45 years including 517 cases of CABG and 1501 cases of PCI were enrolled in the study. Using propensity score matching (PSM), 406 patients were matched from each group. The intermediate- and long-term data were collected. The primary end point of this study was long-term death. The secondary end points included long-term major adverse cardiovascular and cerebrovascular events (MACCEs), stroke, angina, myocardial infarction (MI), and repeat revascularization. RESULTS: Before PSM, the in-hospital mortality was 1.2% in the CABG group and 0.1% in the PCI group, with statistically significant difference (P < 0.0001). The 10-year follow-up outcomes including long-term survival rate and freedom from MACCEs were better in the CABG group than those in the PCI group (97.3% vs. 94.5%, P = 0.0072; 93.2% vs. 86.3%, P < 0.0001), but CABG group was associated with lower freedom from stoke compared to PCI group (94.2% vs. 97.5%, P = 0.0059). After propensity score matched analysis, these findings at 10-year follow-up were also confirmed. Freedom from MACCEs was higher in CABG group compared to PCI group, but no significant difference was observed (93.1% vs. 89.2%, P = 0.0720). The freedom from recurrent MI was significantly higher in CABG patients compared with PCI patients (95.6% vs. 92.5%, P = 0.0260). Furthermore, CABG was associated with a higher rate of long-term survival rate than PCI (97.5% vs. 94.6%, P = 0.0403). There was no significant difference in the freedom from stroke between CABG and PCI groups (95.3% vs. 97.3%, P = 0.9385). The hospital cost was greater for CABG (13,936 +/- 4480 US dollars vs. 10,926 +/- 7376 US dollars, P < 0.0001). CONCLUSIONS: In DM patients aged 18-45 years, the cumulative survival rate, and freedom from MI and repeat revascularization for CABG were superior to those of PCI. However, a better trend to avoid stroke was observed with PCI. PMID- 29237923 TI - Systemic Therapy after Radiotherapy Significantly Reduces the Risk of Mortality of Patients with 1-3 Brain Metastases: A Retrospective Study of 250 Patients. AB - BACKGROUND: For patients with a brain metastasis (BM), systemic therapy is usually administered after the completion of radiotherapy, especially in cases of multiple BMs. However, the role of systemic therapy in patients with a limited number of BMs is not clear. Therefore, we conducted a retrospective study to explore this question. METHODS: Consecutive patients with a pathologically confirmed malignancy and 1-3 intracranial lesions that had been documented within the last decade were selected from the databases of three hospitals in China. RESULTS: A total of 250 patients were enrolled; of them, 135 received radiotherapy alone and 115 received radiotherapy plus systemic therapy. In patients receiving whole-brain radiation therapy (WBRT) as radiotherapy, 28 received WBRT alone and 35 patients received WBRT plus systemic therapy. Of the patients treated with stereotactic radiosurgery (SRS), 107 received SRS alone and 80 received SRS plus systemic therapy. Multivariate analysis revealed that systemic therapy significantly reduced the risk of mortality compared with radiotherapy alone (hazard ratio [HR] = 0.294, 95% confidence interval [CI] = 0.158-0.548). Further, when the analysis was conducted in subgroups of WBRT (HR = 0.230, 95% CI = 0.081-0.653) or SRS (HR = 0.305, 95% CI = 0.127-0.731), systemic therapy still showed the ability to reduce the risk of mortality in patients with BMs. CONCLUSION: Systemic therapy after either SRS or WBRT radiotherapy may significantly reduce the risk of mortality of patients with 1-3 BMs. PMID- 29237924 TI - Glaucoma in Patients with Eyes Close to Areas Affected by Port-wine Stain has Lateral and Gender Predilection. AB - BACKGROUND: The location of facial port-wine stain (PWS) may be helpful for predicting some associated anomalies; high glaucoma incidence is found in patients with eyes close to PWS-affected areas (V1, ophthalmic branch area of the trigeminal nerve). This study aimed to investigate the characteristics of glaucoma in V1-affected PWS. METHODS: A total of 569 patients with V1 area affected PWS were reviewed in the study. The large series was based on the referral system between the Department of Plastic and Reconstructive Surgery and the Department of Ophthalmology. All patients were screened for glaucoma with assessments of intraocular pressure, cup-to-disc ratio, corneal diameter (only for infants), and axial length. RESULTS: Of the 569 patients, 110 (19.3%) patients had glaucoma. Among the patients, 18.1% (76/420) had early-onset glaucoma (under 4-year-old group). In the 4 to 18-year-old age group, 29.3% (29/99) of the patients had glaucoma. Compared with right lateral and bilateral PWS, left-sided PWS had a lower risk of glaucoma in this study (odds ratio = 0.432 [95% confidence interval, 0.264-0.706], P = 0.01). The under 4-year-old group showed a slight predominance of males (61.8%) in glaucoma. CONCLUSIONS: High glaucoma incidence was observed in patients with eyes close to PWS. More attention should be paid to glaucoma screening for right lateral and bilateral PWS patients. The predominance of males in Sturge-Weber syndrome (SWS) early onset glaucoma patients might be due to the limitation of the case number; however, it might also provide us a new clue of potential relationship between SWS and PCG. PMID- 29237925 TI - Corneal Endothelial Cell Loss in Femtosecond Laser-assisted Descemet's Stripping Automated Endothelial Keratoplasty: A 12-month Follow-up Study. AB - BACKGROUND: Descemet's stripping automated endothelial keratoplasty (DSAEK) surgery offers a more standardized approach and reliable method to create corneal grafts with an instrument such as a microkeratome. With the development of Descemet's membrane endothelial keratoplasty, an excellent clinical outcome is seen in the treatment of corneal endothelial dysfunctions, which indicates that thinner corneal graft results in better clinical outcome. With the recent development of the femtosecond laser, ultrathin corneal graft preparation has become possible. This study aimed to report corneal graft endothelial cell loss (ECL) in a large series of cases undergoing DSAEK with femtosecond laser-assisted corneal graft preparation within a 12-month period. METHODS: This study was designed as a prospective, noncomparative, interventional case series. Totally 126 consecutive eyes with endothelial failure of 120 patients, who had corneal endothelial decompensation and underwent femtosecond-assisted DSAEK using the VisuMax femtosecond laser system, were included in the study. Central endothelial cell density (ECD) was recorded postoperatively at 2 weeks (n = 126), 1 month (n = 126), 3 months (n = 110), 6 months (n = 101), and 12 months (n = 71) and then compared with the preoperative eye bank measurements. Pre- and postoperative central ECDs were evaluated using Heidelberg retina tomography-III confocal microscopy. ECL was calculated for each postoperative time point. Graft thickness was examined using anterior segment-optical coherence tomography. RESULTS: Mean preoperative cell count was 3383 +/- 350 cells/mm2. Mean postoperative cell counts were 2382 +/- 707 cells/mm2, 2179 +/- 685 cells/mm2, 2074 +/- 688 cells/mm2, 1884 +/- 662 cells/mm2, and 1723 +/- 624 cells/mm2 at 2 weeks, 1, 3, 6, and 12 months, respectively; these represented the ECL of 29.7 +/- 19.7%, 35.4 +/- 19.5%, 38.6 +/- 19.8%, 44.3 +/- 18.9%, and 48.9 +/- 18.4% at the each corresponding time point. The mean corneal graft thickness after surgery was 142 +/- 48 MUm, 118 +/- 41 MUm, 108 +/- 37 MUm, 100 +/- 32 MUm, and 99 +/- 32 MUm at each corresponding study visit, respectively. There was no correlation between corneal graft thickness and corneal ECL (R = 0.039). CONCLUSIONS: Corneal ECL remained relatively stable up to 12 months after femtosecond laser-assisted ultrathin DSAEK in a large case series. No correlation between cell loss and corneal graft thickness was found, which indicated that corneal graft preparation by the femtosecond laser was safe. ECL was faster within the first 6 months and relatively stable thereafter. PMID- 29237926 TI - Endoscopic Approach to Remove Intra-extracranial Tumors in Various Skull Base Regions: 10-year Experience of a Single Center. AB - BACKGROUND: Some problems have been found in the usually adopted combined approach for the removal of intra-extracranial tumors in skull base. Herein, we described a pure endoscopic transnasal or transoral approach (ETA) for the removal of intra-extracranial tumors in various skull base regions. METHODS: Retrospectively, clinical data, major surgical complications, pre- and postoperative images, and follow-up information of a series of 85 patients with intra-extracranial tumors in various skull base regions who were treated by surgery via ETA in our skull base center during the past 10 years were reviewed and analyzed. RESULTS: Gross total tumor removal was achieved in 80/85 cases (94.1%) in this study. All 37 cases with tumors in anterior skull base and all 14 cases with tumors in jugular foramen received total tumor removal. Thirteen and three cases with tumors in clivus received total and subtotal tumor removal, respectively. Total and subtotal tumor removal was performed for 16 cases and 2 cases in lateral skull base, respectively. The complications in this study included: cerebrospinal fluid leakage (n = 3), meningitis (n = 3), and new cranial nerve deficits (n = 3; recovered in 3 months after surgery). In the follow-up period of 40-151 months (median: 77 months), seven patients (8.8%) out of the 80 cases of total tumor removal experienced recurrence. CONCLUSIONS: Complete resection of intra-extracranial growing tumors in various skull base regions can be achieved via the pure ETA in one stage in selected cases. Surgical procedure for radical removal of tumors is feasible and safe. PMID- 29237927 TI - Distinct Rab7-related Endosomal-Autophagic-Lysosomal Dysregulation Observed in Cortex and Hippocampus in APPswe/PSEN1dE9 Mouse Model of Alzheimer's Disease. AB - BACKGROUND: Amyloid-beta deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer's disease (AD). Dysregulation of the endosomal autophagic-lysosomal (EAL) pathway, which impairs amyloid precursor protein processing, is one of the earliest changes in AD. However, the precise role of EAL pathway in neurodegeneration remains unclear. This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction. METHODS: We used 3-, 7-, and 12-month-old APPswe/PSEN1dE9 (APP/PS1) mice to model different stages of AD with age- and gender-matched wild-type littermates as controls (4-7 mice per group) and detected the changes of EAL markers, endosomal organizers Rab5 and Rab7, autophagosome marker LC3B, and lysosomal proteins Lamp1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis. To further explore the mechanism of EAL dysregulation in AD, components of the class III phosphatidylinositol 3-kinase (PI3KC3) complex, activators of Rab7 (Beclin1 and UVRAG), and the negative regulator of Rab7 (Rubicon) were also measured in this two brain regions. RESULTS: In 7-month-old APP/PS1 brain that amyloid beta initiated to accumulate intracellularly, EAL pathway, and related PI3KC3 members, UVRAG and Beclin1 were upregulated both in cortex and hippocampus (all P < 0.05). By the age of 12 months old, when abundant amyloid plaques formed, EAL markers, UVRAG, and Beclin1 were also upregulated in the cortex (all P < 0.05). However, Rab7 was decreased significantly (P = 0.0447), accompanied by a reduction of its activating PI3KC complex component Beclin1 (P = 0.0215) and enhancement of its inhibiting component Rubicon (P = 0.0055) in the hippocampus. CONCLUSIONS: Our study implies that EAL pathway, represented as Rab7 and its PI3KC3 regulators' expressions, showed temporal and spatial variation in brains at different stages of AD. It provides new insights into the role of EAL pathway in pathogenesis and indicates potential therapeutic targets in neurodegenerative diseases. PMID- 29237929 TI - Contralateral C7 Nerve Root Transfer for Function Recovery in Adults: A Meta analysis. AB - BACKGROUND: Root avulsion to all 5 roots of the brachial plexus is a common presentation and keeps a major reconstructive challenge. The contralateral C7 (CC7) nerve transfer has been used in treating brachial plexus avulsion injury (BPAI) since 1986. However, the effectiveness of the procedure remains a subject of controversy. The aim of this meta-analysis was to study surgical outcomes regarding motor and sensory recovery after CC7 nerve transfer. METHODS: Chinese or English (i.e., "contralateral c-7", "contralateral c7", "c7 nerve root", and "seventh cervical nerve root") keywords were used for a literature search for articles related to CC7 nerve transfer in several databases (i.e., PubMed, Cochrane, Embase, CNKI, CQVIP, and Wanfang Data). Clinical research articles were screened, and animal studies as well as duplicate publications were excluded. Muscle strength and sensory recovery were considered to be effective only when the scores on the United Kingdom Medical Research Council scale were equal to or higher than M3 and S3, respectively. RESULTS: The overall ipsilateral recipient nerve recovery rates were as follows: the efficiency rate for muscle strength recovery after CC7 nerve transfer was 0.57 (95% confidence interval [CI]: 0.48 0.66) and for sensory recovery was 0.52 (95% CI: 0.46-0.58). When the recipient nerve was the median nerve, the efficiency rate for muscle strength recovery was 0.50 (95% CI: 0.39-0.61) and for sensory was 0.56 (95% CI: 0.50-0.63). When the recipient nerve was the musculocutaneous nerve and the radial nerve, the efficiency rate for muscle strength recovery was 0.74 (95% CI: 0.65-0.82) and 0.50 (95% CI: 0.31-0.70), respectively. CONCLUSIONS: Transfer of CC7 nerves to musculocutaneous nerves leads to the best results. CC7 is a reliable donor nerve, which can be safely used for upper limb function reconstruction, especially for entirely BPAI. When modifying procedures, musculocutaneous nerves and median nerve can be combined as recipient nerves. PMID- 29237928 TI - Correlations between Mitofusin 2 Expression in Fibroblasts and Pelvic Organ Prolapse: An In vitro Study. AB - BACKGROUND: Both Mitofusin 2 (Mfn2) and pelvic organ prolapse (POP) are related to aging. The aim of the present study was to investigate the variations of Mfn2 expression in the uterosacral ligaments of patients with and/or without POP and their correlations with the expression of procollagen. METHODS: Fibroblasts were cultured using tissue specimens that were harvested from the uterosacral ligaments of POP and non-POP (NPOP) patients (n = 10 for each group) from September 2016 to December 2016. The Cell Counting Kit-8 (CCK-8) assay was used to compare the differences in cell proliferation between the two groups. Relative quantitative reverse transcription-polymerase chain reaction and Western blotting assays were employed to assess the differences in the mRNA and protein expression levels of Mfn2 and procollagen 1A1/1A2/3A1 between the two groups. The changes in procollagen expression were assessed following the downregulation of Mfn2 in the POP group using RNAi. The data were assessed with independent sample t- test or general linear model univariate analysis using the SPSS 13.0 software. RESULTS: The results from CCK-8 assay indicated that cell viability in the POP group was significantly lower compared with that of the NPOP group (td5, 7, 9, 11= -5.925, 6.851, -9.129, and -9.661, respectively, all P < 0.001, from D5 to D11). The mRNA and protein expression levels of Mfn2 in the cultured fibroblasts of the POP group were significantly higher compared with those of the NPOP group (mRNA: t = 2.425, P = 0.032; protein: t = 2.392, P = 0.037, respectively), whereas only the expression levels of procollagen 1A1/1A2/3A1 were significantly higher in the NPOP group (mRNA: t = -2.165, P1A1 = 0.041; t = -2.741, P1A2 = 0.026; t = -2.147, P3A1 = 0.045, respectively; protein: t = -2.418, P1A1 = 0.029; t = -2.405, P1A2 = 0.033; t = -2.470, P3A1 = 0.012, respectively). The expression levels of procollagen in the POP group increased following the downregulation of Mfn2. CONCLUSIONS: The proliferation rate and cell viability of the fibroblasts in the POP group were significantly lower compared with those in the NPOP group. In the POP fibroblasts, Mfn2 expression was increased, while procollagen expression was decreased. PMID- 29237930 TI - Effects of Prior Antiplatelet Therapy on the Prognosis of Primary Intracerebral Hemorrhage: A Meta-analysis. AB - BACKGROUND: Antiplatelet therapy (APT) was prevalently being used in the prevention of vascular disease, but the influence of prior APT on the prognosis of patients with intracerebral hemorrhage (ICH) remains controversial. This meta analysis was to explore the effects of prior APT on the prognosis of patients with primary ICH. METHODS: PubMed and Embase were searched to identify the eligible studies. The studies comparing the mortality of ICH patients with or without prior APT were included. The quality of these studies was evaluated by the Newcastle-Ottawa quality assessment scale. The adjusted or unadjusted odds ratio (OR) for mortality between ICH patients with and without prior APT were pooled with 95% confidence interval (95% CI) as the effect of this meta-analysis. RESULTS: Twenty-two studies fulfilled the inclusion criteria and exhibited high qualities. The pooled OR was 1.37 (95% CI: 1.13-1.66, P = 0.001) for univariate analysis and 1.41 (95% CI: 1.05-1.90, P = 0.024) for multivariate analysis. The meta-regression indicated that for each 1-day increase in the time of assessment, the adjusted OR for the mortality of APT patients decreased by 0.0049 (95% CI: 0.0006-0.0091, P = 0.026) as compared to non-APT patients. CONCLUSION: Prior APT was associated with high mortality in patients with ICH that might be attributed primarily to its strong effect on early time. PMID- 29237932 TI - Current Progress and Controversies in Prostate Cancer Management. AB - OBJECTIVE: The optimal management strategy for prostate cancer (PCa) remains controversial. We performed a systemic review of current progress and controversies regarding the diagnosis and treatment of PCa. DATA SOURCES: We searched PubMed for recently published articles up to July 2017 using the following key words: "prostate cancer," "progress," "controversy," "immunotherapy," and "prevention." STUDY SELECTION: Articles were obtained and reviewed to provide a systematic review of the current progress and controversies regarding PCa management. RESULTS: The value of serum prostate-specific antigen (PSA) screening remains controversial, but PSA screening is recommended to facilitate the early diagnosis of PCa in high-risk groups. Prostate biopsy via the transrectal or perineal approach has both advantages and disadvantages. There was a significant correlation between testosterone levels and PCa prognosis. The current research is focused on the mechanisms responsible for PCa. Active surveillance has been proposed as a management strategy for low-risk, localized PCa, but there is an urgent need for further clinical studies to establish the criteria for recommending this approach. The main complications of radical resection for PCa are urinary incontinence and erectile dysfunction, though three dimensional laparoscopic and robot-assisted laparoscopic techniques have obvious advantages over radical surgery. Radiotherapy is also a therapeutic option for PCa, while immunotherapies may alter the prostate tumor microenvironment. Ongoing studies aim to provide guidance on effective sequential and combination strategies. Prevention remains an important strategy for reducing PCa morbidity and mortality. CONCLUSIONS: The diagnosis, treatment, and prevention of PCa are complex issues, worthy of intensive study. Further studies are needed to improve the management of PCa. PMID- 29237933 TI - Advance of Peripheral Nerve Injury Repair and Reconstruction. PMID- 29237934 TI - Root Canal Morphology of Maxillary Premolars among the Elderly. PMID- 29237931 TI - Tau-mediated Neurodegeneration and Potential Implications in Diagnosis and Treatment of Alzheimer's Disease. AB - OBJECTIVE: To review recent research advances on tau, a major player in Alzheimer's disease (AD) pathogenesis, a biomarker for AD onset, and potential target for AD therapy. DATA SOURCES: This review was based on a comprehensive search using online literature databases, including PubMed, Web of Science, and Google Scholar. STUDY SELECTION: Literature search was based on the following keywords: Alzheimer's disease, tau protein, biomarker, cerebrospinal fluid (CSF), therapeutics, plasma, imaging, propagation, spreading, seeding, prion, conformational templating, and posttranslational modification. Relevant articles were carefully reviewed, with no exclusions applied to study design and publication type. RESULTS: Amyloid plaques enriched with extracellular amyloid beta (Abeta) and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau proteins are the two main pathological hallmarks of AD. Although the Abeta hypothesis has dominated AD research for many years, clinical Abeta-targeting strategies have consistently failed to effectively treat AD or prevent AD onset. The research focus in AD has recently shifted to the role of tau in AD. In addition to phosphorylation, tau is acetylated and proteolytically cleaved, which also contribute to its physiological and pathological functions. Emerging evidence characterizing pathological tau propagation and spreading provides new avenues for research into the molecular and cellular mechanisms underlying AD pathogenesis. Techniques to detect tau at minute levels in CSF and blood have been developed, and improved tracers have facilitated tau imaging in the brain. These advances have potential to accurately determine tau levels at early diagnostic stages in AD. Given that tau is a potential therapeutic target, anti-tau immunotherapy may potentially be a viable treatment strategy in AD intervention. CONCLUSION: Detecting changes in tau and targeting tau pathology represent a promising lead in the diagnosis and treatment of AD. PMID- 29237935 TI - Isolated Thyrotropin Elevation is Associated with Insufficient Night-sleep in Night-sleep Restricted Subjects. PMID- 29237936 TI - Characteristics of Mercury Intoxication Induced by Skin-lightening Products. PMID- 29237937 TI - Drug-induced Liver Injury Due to Lepidium meyenii (Maca) Medicinal Liquor. PMID- 29237938 TI - Molecular and Cytogenetic Characterization of a Fetus with Mosaic Ring Chromosome 13: A Very Rare Case. PMID- 29237939 TI - A Novel Mutation of PRKAR1A Caused Carney Complex in a Chinese Patient. PMID- 29237941 TI - Successful Management of a Live 14-week Primary Hepatic Ectopic Pregnancy Combined with a Residual Horn of the Uterus Using Laparoscopy. PMID- 29237940 TI - A Huge Congenital Left Atrial Appendage Aneurysm. PMID- 29237942 TI - Side Effects of Pyrethroid and Supporting Role of Onion in the Male Rat's Spermatogenesis. PMID- 29237943 TI - Pulmonary Lymphangiomyomatosis Associated with Renal and Hepatic Angiomyolipoma Mass in a Patient with Tuberous Sclerosis Complex. PMID- 29237944 TI - Cutaneous Metastases Arising from Synovial Sarcoma: A Case Report. PMID- 29237945 TI - Erratum: Shanghai Score: A Prognostic and Adjuvant Treatment-evaluating System Constructed for Chinese Patients with Hepatocellular Carcinoma after Curative Resection. AB - [This corrects the article DOI: 10.4103/0366-6999.218019.]. PMID- 29237946 TI - Leukodystrophy without Ovarian Failure Caused by Compound Heterozygous Alanyl tRNA Synthetase 2 Mutations. PMID- 29237947 TI - A Case of Pagetoid Bowen's Disease. PMID- 29237948 TI - Optical coherence tomography in oral cancer: A transpiring domain. AB - Identification of oral cancer at an early curable stage not only aids in controlling the mortality and morbidity rate but also improves the quality of life of the patient. Indeed, regular monitoring of such life-threatening disease has held an imperative role in cancer diagnostics. Various light-based diagnostics are currently available to the clinician for early diagnosis of oral cancer. Optical coherence tomography (OCT) is one such emerging light-based diagnostic modality that provides noninvasive, real-time images at a depth of 1.5 2 mm and can also be compared to corresponding histopathological sections, hence this procedure can also be referred as optical biopsy. This technique can also be used as an adjunct to histopathology in circumstances where large areas are needed to be examined, screening apprehensive patients, larger populations, and for regular monitoring of patients. The current article is a brief review that highlights basic principle, various versions, and applications of OCT in the diagnosis of oral cancer. PMID- 29237949 TI - Diagnosis and management of gastrointestinal stromal tumors: An up-to-date literature review. AB - Gastrointestinal stromal tumors (GISTs) are rare life-threatening forms of cancer that may arise anywhere in the GI tract. Herein, we aimed to review the literature to describe the incidence, management, and outcomes of GISTs. We conducted a traditional narrative review using PubMed and EMBASE, searching for English-language publications for GISTs between January 2001 and January 2016 using keywords ""gastrointestinal" "stromal tumors." Among 4582 retrieved articles, 50 articles were relevant over the last 15 years. Several risk stratification systems exist to predict the outcomes of GISTs based on certain criteria such as the primary site of occurrence, size of the tumor, mitotic activity, staining for proliferating cells, and tumor necrosis. Risk stratification is crucial in the management and outcomes of the disease. Surgical resection remains the gold standard option of GISTs treatment. Complete resection of the tumor is the main predictor of the postoperative patient's survival. Laparoscopic resections are associated with less intraoperative blood loss, early return of bowel function, early resumption of diet, and short hospital stay. However, laparoscopy is difficult to perform in large and unfavorably placed GISTs and may result in disease progression, recurrence, and poor survival. Robot assisted laparoscopic resections provide instruments for surgeons to perform technically demanding operations. Moreover, extensive research work including large clinical trials is ongoing to establish promising role of the adjuvant and neo-adjuvant therapy for better disease- free survival in GIST patients. PMID- 29237950 TI - Occupational doses of cardiologists in cath labs and simulation method. AB - In recent years, using the ionizing radiation in the interventional cardiology has been increased; this is because of the rapid growth of the number of interventional procedures and the high levels of radiation dose in these examinations. Therefore, it is necessary to develop procedures for managing the use of fluoroscopy radiation to ensure that patients and personnel are not exposed to excessive levels of radiation. It seems that by the new generation devices of fluoroscopy that are equipped with a real dosimeters or dose area product (DAP)-meter which are able to record the produced dose rate in the area of patient's body in each procedure, it is possible to calculate the cardiologist dose with simulation. In addition, a relationship can be made between the patient DAP and cardiologist dose that is defined as an appropriate conversion factor. Hence, in each procedure, besides the record of patient's DAP, the cardiologist dose is recorded as well. PMID- 29237951 TI - Optical diagnostics in oral cancer: An update on Raman spectroscopic applications. AB - Raman spectroscopy (RS) is a sensitive vibrational spectroscopic method that can detect even subtle biochemical changes during the onset of disease. Consequently, RS has been extensively investigated for disease diagnosis, including cancers. Oral cancers are known to suffer from dismal survival rates, which have not improved for several decades. As delayed diagnosis contributes to the low disease free survival rate observed in oral cancers, RS has also been explored for the early diagnosis of oral cancers. This review summarizes the major developments in the field, including diagnosis, surgical margin assessment and prediction of treatment response, and in the overall management of oral cancers. The article comprises an overview of epidemiology, diagnosis, treatment, and recently introduced diagnostic adjuncts for oral cancers, the basic principle, instrumentation of RS, multivariate analysis that impart objectivity to the approach, and finally a discussion on the recent applications in oral cancers. PubMed and Google Scholar database have been used to compile information available online till December 2015. PMID- 29237952 TI - Cancer-related fatigue treatment: An overview. AB - Cancer-related fatigue is a symptom of cancer where most patients or the general practitioners tend to misinterpret due to the insufficient understanding or knowledge of cancer-related fatigue (CRF). This paper will provide a better perspective for the patients and the health professionals on how to manage and handle CRF for both mild and severe fatigue patients. Articles were selected from the searches of PubMed database that had the terms "randomized controlled trials," "cancer," "fatigue," "pharmacologic treatment," and "nonpharmacologic treatment" using both Mesh terms and keywords. The authors have reviewed the current hypothesis and evidence of the detailed etiology of the CRF present in the literature for healthier management, directives, and strategies to improve the treatment of cancer-related fatigue. An algorithm has been blueprinted on screening, and management, of the CRF, and various kinds of effective treatments and assessment tools have been briefly studied and explained. Although many strategies seemed promising, the quality of randomized controlled trials is generally quite low in studies, making it difficult to draw conclusions about the effectiveness of each self-care strategies. Therefore, future studies require better design and reporting of methodological issues to ensure evidence-based self-care recommendations for people receiving cancer treatment. PMID- 29237953 TI - Quantitative determination of tumor platinum concentration of patients with advanced Breast, lung, prostate, or colorectal cancers undergone platinum-based chemotherapy. AB - CONTEXT: Previous studies have reported direct relationship between tumor reduction and its platinum concentration following platinum-based (Pt-based) chemotherapy. However, quantitative data of tumor platinum concentration have not yet been reported for the most common cancers. AIMS: Determination of tumor platinum concentration of breast, lung, prostate, and colorectal cancers after Pt based chemotherapy; and evaluation of the influence of chemo drug type, chemotherapy regimen, and time lapse from last chemotherapy on tumor platinum concentration. MATERIALS AND METHODS: Tumor samples of patients with advanced breast, lung, prostate, and colorectal cancers undergone Pt-based chemotherapy were collected from pathology collection of various hospitals. The platinum concentration of each sample was measured by inductively coupled plasma optical emission spectrometry. The data were categorized by drug type, time lapse from last chemotherapy, and regimen type to evaluate their effects on platinum concentration. STATISTICAL ANALYSIS: ANOVA, Mann-Whitney U and Kruskal-Wallis tests were used. RESULTS: Tumor platinum concentrations of breast, lung, prostate, and colorectal cancers were all obtained in the range of 1-10 MUg/g tumor tissue. Large values of P (>0.05) indicate no significant differences between various chemo drug, regimen, and time groups. CONCLUSIONS: In general, the platinum concentration was higher in prostate and lower in lung tumors. The type of Pt-based chemo drug, time lapse from the last chemotherapy, and concurrency of other antineoplastic agents administered with Pt-based chemo drugs had no significant effect on tumor platinum concentration. PMID- 29237954 TI - Assessment of the scatter correction procedures in single photon emission computed tomography imaging using simulation and clinical study. AB - BACKGROUND: Compton-scattered photons transfer incorrect spatial information. These photons are detected in used photo-peak energy window. In this study, three scatter correction procedures including dual-energy window (DEW), three energy window (TEW), and new approach were evaluated, and then the best procedure based on simulation and clinical conditions introduced. MATERIALS AND METHODS: In this study, simulation projections and three-dimensional nonuniform rational B-spline based Cardiac-Torso phantoms were produced by GEANT4 application for emission tomography simulation code. For clinical study, 2-day stress/rest myocardial perfusion imaging (MPI) protocol was performed with 99m Tc-sestamibi for 46 patients. Image quality parameters including contrast, signal-to-noise ratio (SNR), and relative noise of the background (RNB) were evaluated. RESULTS: The simulation results showed that contrast values for DEW, TEW, and new approach were (0.45 +/- 0.07, 0.5 +/- 0.08, and 0.63 +/- 0.09), SNR values (4.74 +/- 0.94, 5.58 +/- 1.08, and 6.56 +/- 1.24), and RNB values (0.33 +/- 0.06, 0.33 +/- 0.07, and 0.33 +/- 0.05), respectively. In clinical study, the contrast values for DEW, TEW, and new approach were 0.53 +/- 0.03, 0.57 +/- 0.07, and 0.62 +/- 0.04 in rest MPI and were 0.52 +/- 0.04, 0.57 +/- 0.06, and 0.6 +/- 0.05 in stress MPI, respectively. Moreover, for the rest images, the SNR values were 7.65 +/- 1.9, 9.08 +/- 2.2, and 10.2 +/- 1.75 and for stress images were 7.76 +/- 1.99, 9.12 +/ 2.25, and 10.17 +/- 2.04, respectively. Finally, RNB values for rest and stress images were 0.12 +/- 0.03, 0.13 +/- 0.03, and 0.13 +/- 0.03, respectively. CONCLUSION: The simulation and the clinical studies showed that the new approach could be better performance than DEW, TEW methods, according to values of the contrast, and the SNR for scatter correction. PMID- 29237955 TI - Accelerated hypofractionation (OCTA SHOT): Palliative radiation schedule in advanced head and neck carcinoma. AB - BACKGROUND: Head and neck cancers are attributed to be the most common type of malignancy in the developing countries with most cases presenting in advanced stage. This pilot study was performed to evaluate the effect of an accelerated hypofractionated 4 days schedule (octa shot) in providing palliation to such advanced cases of head and neck cancer. MATERIALS AND METHODS: Twenty-two patients with advanced (Stage VIB-IVB) squamous cell carcinoma of head and neck region were enrolled in the study. All these patients were planned for radiotherapy at Cobalt Unit with a fractionation schedule of 3.5 Gy/fraction, 2 fractions/day with 6 h interval between two fractions, for four days (28 Gy/8Fr/4 days). Patients were reviewed at 2 and 4 weeks to assess change in tumor size, any symptomatic relief, or toxicity. The tumor response, dermal, and mucosal toxicities were assessed using WHO criteria. RESULTS: Median age of these 22 patients (17M male + 5F female) in the study was 59.8 years. After completion of radiotherapy, first response evaluation done at 15th day showed >=50% objective response in 14 patients. At 1 month, this response increased to >=75% in 16 patients and 50%-75% in three patients. None of the patients had disease progression. Improvement in symptoms was reported with respect to pain and dysphagia by patients subjectively. Only two patients reported Grade III mucositis; remaining patients had mucositis and dermatitis up to Grade II. CONCLUSION: The study concludes that this "octa shot" is an effective palliative radiotherapy schedule. With a decreased duration of hospital stay, it is also favorable for outpatients. PMID- 29237956 TI - Utility of the laminin immunohistochemical stain in distinguishing invasive from noninvasive urothelial carcinoma. AB - BACKGROUND: To study the utility of the laminin immunostain in distinguishing invasive from noninvasive urothelial carcinoma (UC). The distinction is difficult but clinically significant as it can affect the decision to administer intravesical Bacillus Calmette-Guerin or can even lead to cystectomy. MATERIALS AND METHODS: Representative sections of the transurethral resection of bladder tumor specimens from 25 cases of formalin-fixed paraffin-embedded invasive UCs and 25 cases of noninvasive UCs were selected for immunohistochemical (IHC) staining with laminin (Ventana, Oro Valley, AZ, USA). These cases were selected using a computer-assisted search of our laboratory information system (Cerner CoPath). Tissue from five paraffin-embedded tissue blocks containing unremarkable urothelial-lined bladder parenchyma was chosen as controls. RESULTS: All five control cases demonstrated crisp linear staining of the basement membrane underlying the unremarkable urothelium. Similar findings were also noted in the 25 cases of noninvasive UC. All 25 cases of the invasive UC demonstrated a complete absence of the staining around invasive and malignant urothelial cells. Laminin staining was also noted in both the muscularis mucosae and the detrusor muscle, although the pattern of staining in these areas was granular and was distinguishable from the crisp linear staining of the basement membrane. CONCLUSION: Laminin IHC staining can be useful in differentiating invasive from noninvasive UC. PMID- 29237957 TI - Efficacy of centrifuged liquid-based cytology over conventional cytology: A comparative study. AB - BACKGROUND: Exfoliative cytology is the microscopic examination of a shed or desquamated cells from the epithelial surface. Centrifuged liquid-based cytology (CLBC) is a modified technique that is used in the current study. AIMS: To compare the efficacy of CLBC with conventional cytology in apparently normal mucosa and histologically proven cases of oral squamous cell carcinoma after staining with Papanicolaou stain. MATERIALS AND METHODS: The study sample was collected from fifty individuals with no habits and apparently normal oral mucosa (Group 1) and forty cases of histologically proven cases of oral squamous cell carcinoma (Group 2). One smear was taken and spread on the slide by a conventional technique. The second sample was flushed out in a suspending solution, centrifuged, and the cell pellet obtained was used to make the smear. The stained smears were compared for nine parameters such as adequate cellularity, clear background, uniform distribution, cellular overlapping, cellular elongation, mucus, inflammatory blood, and microbial colonies. Chi square test was used for statistical analysis and P <= 0.05 was considered statistically significant. RESULTS: There was a statistically significant result with parameters such as adequate cellularity, clear background, uniform distribution, cellular overlapping, and cellular elongation in CLBC technique, in comparison with the conventional technique. The presence of mucus, microbial colonies, and inflammatory cells were also less in CLBC technique in comparison with the conventional technique. CONCLUSION: CLBC has better efficacy over conventional method in all the parameters analyzed. PMID- 29237958 TI - The effect of ciprofloxacin on the growth of B16F10 melanoma cells. AB - OBJECTIVE: The antitumor effect of ciprofloxacin has been widely assessed in vitro, and positive results have been reported. The aim of this study was to investigate the influence of ciprofloxacin treatment on the growth of B16F10 melanoma cells both in-vitro and in-vivo. MATERIALS AND METHODS: Groups of C57BL/6 female mice challenged with B16F10 melanoma cells were kept untreated or were treated with sterile water, intraperitoneal ciprofloxacin, or ciprofloxacin through drinking water for 10 days. The serum levels of vascular endothelial growth factor (VEGF) were measured by ELISA 1 and 3 h after the last dose of ciprofloxacin. Mice were monitored for an additional 10 days for survival assessment. Moreover, B16F10 melanoma cells were cultured in 24-well plates and exposed to different concentrations of ciprofloxacin (10-1000 MUg/ml). Viability was determined, after 24 and 48 h, using trypan blue. RESULTS: The serum levels of VEGF significantly decreased in ciprofloxacin-treated mice when compared to the controls. None of the control mice survived beyond day 8, whereas 16.67% of those treated with ciprofloxacin survived up to 18 days. In addition, the viability of B16F10 melanoma cells, in-vitro, significantly decreased with increasing concentrations of ciprofloxacin after 24 and 48 h. CONCLUSION: Ciprofloxacin seems to exhibit antitumor activity both in-vivo and in-vitro. This effect might be explained by several mechanisms such as directly inducing cancer cell death or altering the immune response through the modification of the normal microbiota. PMID- 29237959 TI - Cardiotoxicity associated with bortezomib: A single-center experience. AB - BACKGROUND: Studies evaluating the prevalence of cardiotoxicity associated with bortezomib are limited. We proposed this study to evaluate the prevalence of cardiotoxicity associated with bortezomib and its relation to multiple myeloma and other malignancies. MATERIALS AND METHODS: This is a retrospective, chart review study. Subjects who received bortezomib at the HealthEast care system for various oncologic conditions were evaluated after obtaining IRB approval. RESULTS: A total of 64 patients received bortezomib for various malignancies. Nine out of 64 (14%) patients developed cardiotoxicity during treatment with bortezomib, and the majority of these patients had a prior cardiac history and other cardiac risk factors. On further review, we did not find any significant causal relationship between these cardiac events and bortezomib. CONCLUSION: Cardiotoxicity is probably not related to bortezomib, even though there are some case reports suggestive of cardiac events related to bortezomib. Our findings need to be confirmed in multicenter, prospective studies. PMID- 29237960 TI - Spritzer: For diagnostic cytopathology. AB - BACKGROUND: Exfoliative cytology is an easy, economical, noninvasive, and feasible method for early detection and screening program of any premalignant or malignant lesion. In case of routine cytological procedure, classical Papanicolaou (PAP) stain is widely used while Romanowsky stains are sparingly used. Leishman-Giemsa (LG) cocktail, being a easier, cost effective staining technique, has not been used in exfoliative cytology. Therefore, this pilot study was carried out to compare and contrast the role of LG stain in routine cytological procedure which is very cost-effective, less time-consuming and requires less infrastructural support. AIM AND OBJECTIVES: To study the diagnostic efficiency of LG cocktail in comparison with PAP stain and Feulgen stain in mucosal cells for evaluating cellular changes of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Three cytological smears were prepared from 10 healthy controls and 10 patients clinically diagnosed with OSCC, and they were stained with LG cocktail stain, PAP stain, and Feulgen stain. The stained smears were evaluated for cytologic diagnosis and the staining characteristics such as nuclear and cytoplasmic details were recorded as per criteria by Sujathan et al. STATISTICAL ANALYSIS: The data were statistically evaluated with analysis of variance test using SPSS 15 software for windows. RESULTS: The results from the cases diagnosed as OSCC by PAP and LG cocktail were almost identical and superior to Feulgen stain both in diagnostic ability and in staining characteristics. CONCLUSION: The one-step LG cocktail is easy, very cost effective, less time-consuming with less infrastructural support as compared to PAP stain; however, it warrants further evaluation for screening of oral cancer as a potential aid. PMID- 29237961 TI - Assessment the accuracy of dose calculation in build-up region for two radiotherapy treatment planning systems. AB - AIM: Our objective is to quantify dose calculation accuracy in the build-up region using TiGRT and Prowess Panther treatment planning systems (TPSs). MATERIALS AND METHODS: Thermoluminescent dosimeter-100 chips were used in a phantom for dose measurement. TiGRT Version 1.2 (LinaTech, Sunnyvale, CA, USA) and Prowess Panther version 5.1 (Prowess Inc., Concord, CA, USA) TPSs were also used for dose calculations. Finally, the confidence limit values obtained to quantify dose calculation accuracy of the TPSs at build-up region for different field sizes and various gantry angles. RESULTS: For 8 cm * 10 cm, 10 cm * 10 cm, and 15 cm * 10 cm field sizes, the confidence limit values for TiGRT TPS were 16.64, 16.56, and 25.85; for Prowess TPS with fast photon effective (FPE) algorithm were 15.17, 14.22, and 9.73; and for Prowess TPS with collapsed cone convolution superposition (CCCS) algorithm were 10.53, 9.97, and 9.76, respectively. For wedged field with gantry angles of 15 degrees , 30 degrees , and 60 degrees , the confidence limit values for TiGRT TPS were 12.11, 12.96, and 22.69 and for Prowess TPS with FPE algorithm were 24.50, 22.07, and 7.82, respectively. CONCLUSIONS: It is concluded that for open field sizes without gantry angulation, dose calculation accuracy in Prowess TPS with CCCS algorithm is better than TiGRT and Prowess TPSs with FPE algorithm. Furthermore, it is concluded that for wedged field with large gantry angle, dose calculation accuracy of Prowess TPS with FPE algorithm is better than TiGRT TPS while, for medium and small gantry angles, dose calculation accuracy of TiGRT TPS is better than Prowess TPS with FPE algorithm. PMID- 29237962 TI - Evaluation of the effect of soft tissue composition on the characteristics of spread-out Bragg peak in proton therapy. AB - AIM: The aim of this study is to evaluate the effect of soft tissue composition on dose distribution and spread-out Bragg peak (SOBP) characteristics in proton therapy. SUBJECTS AND METHODS: Proton beams with nominal energies of 70, 120 and 210 MeV were considered. The soft tissues and tissue equivalent materials implemented in this study are: 9-component soft tissue, 4-component soft tissue, adipose tissue, muscle (skeletal), lung tissue, breast tissue, A-150 tissue equivalent plastic, perspex and water. Each material was separately defined inside a 20 cm * 20 cm * 40 cm phantom. A multilayer phantom was evaluated as well. The effect of tissue composition on the relative dose in SOBP region (relative to the dose in SOBP region in water), range of SOBP, length of SOBP, and uniformity index of SOBP was evaluated. RESULTS: Various soft tissues and tissue equivalent materials have shown different dose level in SOBPs, ranges of SOBPs, lengths of SOBPs and uniformity indices. CONCLUSIONS: Based on the obtained results, various soft tissues and tissue equivalent materials have quite different SOBP characteristics. Since in clinical practice with proton therapy, only the range of SOBP is corrected for various tissues, omission of the above effects may result in major discrepancies in proton beam radiotherapy. To improve treatment accuracy, it is necessary to introduce such effects in treatment planning in proton therapy. PMID- 29237963 TI - Analysis of factors affecting initial cyclosporine level and its impact on post transplant outcomes in acute leukemia. AB - BACKGROUND: Trough cyclosporine (CsA) blood level can influence incidence of graft-versus-host disease (GVHD) and relapse in patients with acute leukemia undergoing allogeneic hematopoietic stem cell transplant (HSCT). We sought to determine factors affecting initial trough CsA level (CsA-1) and its impact on transplant outcome in acute leukemia. MATERIALS AND METHODS: Seventy-seven patients underwent HSCT for acute leukemia between January 2008 and March 2013 and were included. GVHD prophylaxis included CsA + methotrexate. (MTX) in 53 patients and CsA + mycophenolate mofetil (MMF) in 24 patients CsA-1 was measured on day 3-5 of starting CsA and subsequent dose was modified to achieve therapeutic level of 150-200. ng/mL. According to CsA-1, patients were divided into three groups - 27 in Group A (dose escalated), 13 in Group B (dose de escalated), and 37 in Group C (same dose continued). RESULTS: On univariate analysis, cyclophosphamide with total-body irradiation (TBI) based conditioning regimen and lower body mass index (BMI) were associated with lower CsA-1, while use of fludarabine and higher BMI were associated with higher CsA-1. On multivariate analysis, only fludarabine use and BMI affected CsA-1. Incidence of acute and chronic GVHD (aGVHD and cGVHD), transplant-related mortality, relapse incidence, and relapse-free and overall survival (OS) were similar in the three groups. CONCLUSION: While fludarabine use in conditioning regimen and higher BMI leads to higher CsA-1, transplant outcomes are not affected by CsA-1. PMID- 29237964 TI - Myeloid sarcoma: A clinicopathological study with emphasis on diagnostic difficulties. AB - BACKGROUND: Myeloid sarcoma (MS) is a rare tumor composed of proliferation of myeloid precursors at extramedullary sites. They can arise de-novo or in association with hematological malignancies, most commonly acute myeloid leukemia. Clinically, it can masquerade as an abscess, cutaneous ulcer, or mass lesion. Morphologically, MS can mimic a variety of small round cell tumors including lymphomas and rhabdomyosarcoma. AIMS: (1) To study the clinical presentations and laboratory findings in patients with MS; (2) to revisit the histomorphological findings and the differential diagnosis of MS; (3) to evaluate the diagnostic role of immunohistochemistry (IHC) and determine the useful markers for accurate diagnosis of MS. MATERIALS AND METHODS: We reviewed cases of MS reported in our institution over a 10-year period from January 2004 to December 2013. The clinical presentations, laboratory data, and histopathological and immunohistochemical findings were studied. RESULTS: There were nine cases in our database, none of which were clinically suspected to be MS. Age ranged from 3 to 55 years, with a slight female preponderance. Cervical lymph nodes were the most common site involved. Histologically, the common finding was the presence of medium- to large-sized cells with fine granular chromatin, small nucleolus, and scant cytoplasm along with scattered eosinophil precursors. Myeloperoxidase was the most useful IHC marker. All cases were also positive for leukocyte common antigen contributing to the diagnostic confusion with lymphoma. CONCLUSION: The possibility of MS should be considered when dealing with unusual lymphoma-like neoplasms that cannot be categorized as any of the Non-Hodgkin lymphoma subtypes. PMID- 29237965 TI - Investigating different computed tomography techniques for internal target volume definition. AB - PURPOSE: The aim of this work was to evaluate the various computed tomography (CT) techniques such as fast CT, slow CT, breath-hold (BH) CT, full-fan cone beam CT (FF-CBCT), half-fan CBCT (HF-CBCT), and average CT for delineation of internal target volume (ITV). In addition, these ITVs were compared against four dimensional CT (4DCT) ITVs. MATERIALS AND METHODS: Three-dimensional target motion was simulated using dynamic thorax phantom with target insert of diameter 3 cm for ten respiration data. CT images were acquired using a commercially available multislice CT scanner, and the CBCT images were acquired using On-Board Imager. Average CT was generated by averaging 10 phases of 4DCT. ITVs were delineated for each CT by contouring the volume of the target ball; 4DCT ITVs were generated by merging all 10 phases target volumes. Incase of BH-CT, ITV was derived by boolean of CT phases 0%, 50%, and fast CT target volumes. RESULTS: ITVs determined by all CT and CBCT scans were significantly smaller (P < 0.05) than the 4DCT ITV, whereas there was no significant difference between average CT and 4DCT ITVs (P = 0.17). Fast CT had the maximum deviation (-46.1% +/- 20.9%) followed by slow CT (-34.3% +/- 11.0%) and FF-CBCT scans (-26.3% +/- 8.7%). However, HF-CBCT scans (-12.9% +/- 4.4%) and BH-CT scans (-11.1% +/- 8.5%) resulted in almost similar deviation. On the contrary, average CT had the least deviation (-4.7% +/- 9.8%). CONCLUSIONS: When comparing with 4DCT, all the CT techniques underestimated ITV. In the absence of 4DCT, the HF-CBCT target volumes with appropriate margin may be a reasonable approach for defining the ITV. PMID- 29237966 TI - A study of the pathological outcome of positron emission tomography-computed tomography 2-(18F)-fluro-2-deoxy-D-glucose avid lesion: A 5 years retrospective study. AB - INTRODUCTION: Positron emission tomography-computed tomography (PET-CT) has been commonly used for staging and follow-up in cancer patients. The present study compares radiological and pathological outcomes at all the sites. The benign nonphysiological uptake reduces the specificity of the modality due to high false positive (FP) rate although sensitivity for malignant lesions may be high. AIMS AND OBJECTIVES: To study the sensitivity, specificity, positive and negative predictive value (PPV and NPV) of PET-CT in the detection of malignant lesions for all sites using pathological and final clinical outcome. MATERIALS AND METHODS: A retrospective study of 195 cases of PET-CT detected lesions subjected to pathological diagnosis in the form of fine-needle aspiration cytology (FNAC) and/or Tru-cut biopsies were performed on patients with proven or suspected malignancy over a period of 1-year (2009) with a 5 years follow-up. During the same period, 2900 PET-CT imaging studies were performed, of which 195 were suspected to be malignant or benign. Of these, 193 patients were subjected for tissue diagnosis for confirmation. FNAC smears and Tru-cut biopsy were prepared and examined as per standard protocols. RESULTS: Of 195 aspirates in 183 aspirates, a conclusive tissue diagnosis was rendered. The follow-up was available in 79 cases of suspicious PET avid lesions for a period of 1-5 years. The PET-CT correlation with the tissue diagnosis and clinical outcome showed the sensitivity of 97.7% and an overall accuracy of 83% for malignant lesions. However, due to a large number of FP (n = 28) the specificity was only 43% and FP rates were 57%. PPV and NPV for malignant lesions was 82.4% and 87.5%, respectively. CONCLUSION: PET-CT is a sensitive investigation for detection of malignant lesions in treated and newly diagnosed cases of malignancy. PMID- 29237967 TI - Evaluation of dose calculation accuracy of various algorithms in lung equivalent inhomogeneity: Comparison of calculated data with Gafchromic film measured results. AB - AIM: To evaluate dose calculation accuracy of various algorithms in lung equivalent inhomogeneity comprising tumor within it and comparison with Gafchromic film data. MATERIALS AND METHODS: Gafchromic film measured central axis absorbed dose in lung insert (-700 Hounsfield unit [HU]), in racemosa wood cylindrical inhomogeneity (-725 HU) and at three surfaces of tumor (-20 HU) created in cylindrical inhomogeneity, put in the cavity of computerized imaging reference systems (CIRS) thorax phantom were compared with convolution (CON), superposition (SP), fast SP (FSP), and X-ray voxel Monte Carlo (XVMC) algorithms calculated dose using 6 MV beams of field size 2 cm * 2 cm, 3 cm * 3 cm, 4 cm * 4 cm, 5 cm * 5 cm, and 8 cm * 8 cm. RESULTS: XVMC was in good agreement with film measured results for all selected field sizes except 3 cm * 3 cm. SP under estimated by 5.7% at the center of the lung insert while deviation up to 6% was found at the cent of wood inhomogeneity in 2 cm * 2 cm. Except CON, increase in dose from proximal to the central surface of the tumor and then dose falloff from central to the distal surface for field size 2 cm * 2 cm to 4 cm * 4 cm was recorded. The change in film measured percentage depth dose from 2 cm * 2 cm to 3 cm * 3 cm field sizes was found -8% however for consecutive field size(s) larger than 3 cm * 3 cm this difference was less. CON and FSP produced overestimated results. CONCLUSION: Out of four algorithms, XVMC found consistent with measured data. The electronic disequilibrium within and at the interface of inhomogeneity make the accurate dose predictions difficult. These limitations results in deviations from the expected results of the treatments. PMID- 29237968 TI - Atypical teratoid rhabdoid tumor of the central nervous system: Case series from a regional Tertiary Care Cancer Centre in South India. AB - BACKGROUND: Atypical teratoid rhabdoid tumors (AT/RT) constitute a rare group of pediatric brain tumors. AIM: To study the clinical, histopathological, and immunohistochemical (IHC) profile, management and outcome of children with AT/RT of the central nervous system who presented between the years 2007 and 2015 in a regional tertiary care center in South India. MATERIALS AND METHODS: This was a retrospective study. Demographic and clinical data were obtained from the clinical case files. Archived slides and tissue blocks were retrieved. All cases had hematoxylin and eosin stained sections. IHC was available in all the cases. RESULTS: There were eight cases with the mean age of presentation being 4 years (range: 4 months to 15 years) and with slight male predominance (male:female = 1.66:1). Most of the presenting complaints were due to raised intra-cranial tension. The median duration of symptoms was 0.75 months. About 62.5% of the tumors were infratentorial in location. The tumors were heterogeneous showing variable expression of cytokeratin, epithelial membrane antigen, glial fibrillary acid protein, and synaptophysin. Loss of integrase interactor-1 expression was demonstrated in seven cases in which it was done. Multimodal treatment comprising surgical resection, radiotherapy and chemotherapy was tailored based on location of tumor, resectability and patient's age. The median overall survival was 2.5 months (range: 1.5-30 months). CONCLUSION: Awareness of this tumor is important as it portends a poor outcome in most patients, in spite of multi-modal treatment. Several new molecules which aim to prolong survival and improve quality of life are being developed to combat this enigmatic tumor. PMID- 29237969 TI - Agreement analysis between three different short geriatric screening scales in patients undergoing chemotherapy for solid tumors. AB - BACKGROUND: Comprehensive geriatric assessment (CGA) in routine practice is not logistically feasible. Short geriatric screening tools are available for selecting patients for CGA. However none of them is validated in India. In this analysis we aim to compare the level of agreement between three commonly used short screening tools (Flemish version of TRST (fTRST), G8 and VES-13. METHODS: Patients >=65 years with a solid tumor malignancy undergoing cancer directed treatment were interviewed between March 2013 to July 2014. Geriatric screening with G8, fTRST and VES-13 tools was performed in these patients. G8 score <=14, fTRST score >=1 and VES-13 score >=3 were taken as indicators for the presence of a high risk geriatric profile respectively. R version 3.1.2 was used for analysis. Cohen kappa agreement statistics was used to compare the agreement between the 3 tools. p value of 0.05 was taken as significant. RESULTS: The kappa statistics value for agreement between G8 score and fTRST, between VES-13 and fTRST and between VES-13 and G8 were 0.12 (P = 0.04), 0.16 (P = 0.07) and 0.05 (P = 0.45) respectively. It was found that maximum agreement was observed for VES-13 and fTRST. The agreement value of VES-13 and fTRST observed was 59.44 %(39.63% for high risk profile and 19.81% for low risk profile). The agreement value of G 8 and fTRST was 39.62% (2.83% only for high risk profile and 36.79% for low risk profile). The lowest agreement was between G8 and VES-13, 35.84% (7.54% for high risk detection and 28.30% for low risk detection). CONCLUSION: There was poor agreement (in view of kappa value been below 0.2) between the 3 short geriatric screening tools. Research needs to be directed to compare the agreement level between these 3 scales and CGA, so that the appropriate short screening tool can be selected for routine use. PMID- 29237970 TI - A dosimetric comparison between three-dimensional conformal radiation therapy and intensity-modulated radiation therapy in the treatment of posterior fossa boost in medulloblastoma. AB - AIMS: To compare three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) in posterior fossa (PF) boost in children with medulloblastoma (MB); dosimetrically evaluating and comparing both techniques with regard to target coverage and doses to organs at risk. SETTINGS AND DESIGN: Structured. SUBJECTS AND METHODS: Seven previously irradiated patients of MB were retrieved and re-planned with both 3DCRT and IMRT techniques. Dosimetric comparison was done by performing two plans for the PF boost for the same patient. Prescription dose and normal tissue constraints were identical for both plans. STATISTICAL ANALYSIS USED: SPSS, version 19, statistical software package was used. For quantitative data, paired t-test was applied to calculate the difference between two means. RESULTS: Mean values of planning target volume (PTV); PTV95% and PTV5% in IMRT were 97.19% and 106.07% and for 3DCRT were 96.57% and 106.33%, respectively. The dose homogeneity was better in IMRT (1.091) as compared to 3DCRT (1.100), but was not statistically significant (P = 0.341). Conformity index was comparable in both the plans, i.e., 3DCRT (0.979) and IMRT (0.976) with P = 0.819. IMRT plan provided reduced mean dose to cochlea relative to the 3DCRT plans with P = 0.032 for the right cochlea and 0.020 for the left cochlea. IMRT showed no advantage over 3DCRT in sparing the anterior cranial structures where mean doses to the right and left lens were 0.61 Gy and 0.56 Gy for IMRT and 0.16 Gy and 0.09 Gy for 3DCRT, respectively. CONCLUSIONS: IMRT technique was able to improve homogeneity index, spare the cochleae, but 3DCRT plans were superior in sparing anterior cranial structures without compromising the dose to PF. PMID- 29237971 TI - Expression of WW domain-containing protein 2 is correlated with pathological grade and recurrence of glioma. AB - OBJECTIVE: WW domain-containing protein 2 (WWP2) is an E3 ubiquitin ligase, which belongs to the NEDD4-like protein family. Recently, it is reported to play a key role in tumorigenesis and development of tumors such as prostate and lung cancer. However, there has been not related report on glioma until now. The aim of this study is to detect the expression of WWP2 and analyze its correlation to the pathological grade and tumor recurrence in patients with glioma. MATERIALS AND METHODS: Western blot and immunohistochemistry were separately used to detect the expression of WWP2 protein in 31 brain glioma tissue samples and 80 brain glioma paraffin specimens. The method of Kaplan-Meier was used to analyze the correlation between the WWP2 expression and glioma recurrence. RESULTS: The protein expression level of WWP2 in glioma tissue was significantly higher than that in nontumorous brain tissue (P < 0.05), and the protein expression level of WWP2 in high-grade glioma (Grade III-IV) was significantly higher than that in low-grade glioma (Grade I-II) (P < 0.05). Kaplan-Meier analysis indicated that the patients with high WWP2 expression had significantly shorter tumor recurrence time than the patients with low WWP2 expression (P < 0.05). CONCLUSION: Our study suggests that WWP2 may play a role in the genesis and development of glioma; it may be a potential biomarker to predict pathological grade and tumor recurrence in patients with glioma. PMID- 29237972 TI - Multinodular fibroepithelioma of Pinkus with an isolated focus of evolving basal cell carcinoma in chronic lymphedematous lower limb. AB - Fibroepithelioma of Pinkus (FEP) is a rare, indolent variant of basal cell carcinoma (BCC) with a unique anastomosing type of epidermal hyperplasia. Certain benign and neoplastic conditions including BCC are known to develop in a setting of chronic lymphedema. We report for the 1st time the histological spectrum of evolution of a large exophytic multinodular FEP, bearing a single initiating focus of BCC, in preexisting chronic lymphedema of the lower limb. The lesion possibly evolved from long-standing local immune suppression, and clinically resembled a high-grade carcinoma. Oozing lymphatic fluid may interfere with the success of skin grafting following wide local excision in a lymphedematous limb, thus offering a challenging scenario from the management point of view. PMID- 29237974 TI - Multiple pelvic cysts in a patient with familial Mediterranean fever: Benign cystic mesothelioma. AB - Benign cystic mesothelioma (BCM) is a rare tumor arising from endothelial cells of the pelvic visceral or parietal peritoneum. It is a clinically and histopathologically benign disease. Etiology and pathogenesis of BCM remain unclear. Familial Mediterranean fever (FMF) is an inherited disorder characterized by episodes of fever, and abdominal, chest and/or joint inflammation. Association between malignant mesothelioma and FMF has been reported previously; however, co-existence of FMF and BCM is rare. Here, we report a case of BCM in a 43-year-old male patient with FMF. PMID- 29237973 TI - Detection of balanced translocations in acute lymphoblastic leukemia by a novel multiplex reverse transcriptase reverse transcription-polymerase chain reaction. AB - Fusion transcripts detection is essential for subtyping and diagnosis of acute lymphoblastic leukemia (ALL). This enables institution of appropriate therapy and provides a parameter to monitor disease progression and response to therapy. This study endeared to detect and analyze various balanced translocations known in ALL by using a novel polymerase chain reaction (PCR) method. A pilot study was done in which 16 consecutive cases of ALL were analyzed and followed-up for a period of 1 year. Diagnosis of ALL was established after subjecting blood/bone marrow aspirate samples to morphological examination, immunophenotyping, and detection of fusion transcripts by multiplex reverse transcription (RT)-PCR using HemaVision kit. Results were analyzed by correlating with morphology, immunophenotype, and response to therapy. Epi-Info statistical software was used. 43% (seven cases) showed balanced translocations, with all seven cases being B ALL and t(9;22) being the most common. There was a consistent association of CD25 cases with t(9;22). Analyses of relation to other parameters were as expected by their respective WHO 2008 subtype. No significant correlation in terms of survival benefit was seen between cases with and without balanced translocations (P = 0.7472). The study demonstrated the utility of multiplex RT-PCR in the initial evaluation, subtyping, and monitoring minimal residual disease in ALL cases with balanced translocations, thereby guiding both therapy and prognosis. The consistent association of CD25 in cases of t(9;22) ALL indicated that CD25 could be used as a surrogate marker. PMID- 29237975 TI - Intrarectal fixative for positioning of the prostate for intensity modulated radiotherapy. AB - Dose escalation improves local control in carcinoma prostate, but rectal toxicity remains a concern. Various techniques have been there to reduce the dose to the rectum. Mobility of the prostate results in a necessary expansion of the target volume. We describe a new intrarectal fixative, developed in-house with transrectal ultrasonography through the fixative itself for localization of the organ by reporting a case with early carcinoma prostate. Concerns of rectal toxicity limit dose escalation in the treatment of prostate cancer. Intra- and interfraction prostate motion is a concern in dose conformity techniques. The intrarectal fixative system developed in-house physically separates the prostate and rectum during radiation treatment. Thus, both intra- and inter-fractional movement of the organ are addressed, therefore planning target volume expansion can be kept minimal. PMID- 29237976 TI - Two cases of non-Hodgkin lymphoma of urinary bladder: Primary and secondary. AB - Lymphoma of urinary bladder is rare and can be primary (0.2% of all bladder neoplasms) or secondary (1.8% of secondary tumors of the bladder), the latter being more common. Here, we report a case each of primary and secondary lymphoma of the bladder who had undergone treatment at our hospital. Both patients underwent cystoscopy and resection of the bladder growth followed by immunohistochemical staining which revealed them to be lymphomas. PMID- 29237977 TI - Blastic plasmacytoid dendritic cell neoplasm presenting as leukemia without cutaneous lesion. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy, recognized as a distinct entity in the WHO 2008 classification of hematolymphoid neoplasm. Described for the first time in 1994 as CD4+ cutaneous lymphoma with high expression of CD56, BPDCN has been known previously with various names such as blastic natural killer (NK) leukemia/lymphoma, agranular CD4+ CD56+ hematodermic neoplasm, and agranular CD4+ NK cell leukemia. This disease usually presents with cutaneous involvement as the first manifestation, with subsequent or simultaneous spread to bone marrow and peripheral blood. Leukemia as the first presenting symptom without any cutaneous involvement is a rare finding and can masquerade as acute undifferentiated leukemia. We present here such a case of a 59-year-old male who presented as leukemia without any cutaneous lesion but subsequently developed a scalp nodule. PMID- 29237978 TI - Triple malignancy involving breast, ovary, and uterine vault: A case report and literature review. AB - The occurrence of two or more primary malignant neoplasms in the same person is rare. We report a case report of a 45-year-old woman with triple malignancy involving breast, ovary, and uterine vault managed at our center for 5 years. Our patient presented as a postoperated case of two primary malignant neoplasms of carcinoma, breast and ovary. For carcinoma ovary, she underwent adjuvant chemotherapy and interval cytoreductive surgery. For carcinoma breast, she received adjuvant locoregional radiotherapy and chemotherapy. After 42 months, the patient was diagnosed with squamous cell carcinoma vault, for which she received pelvic radiotherapy. She is on regular follow-up. Our patient had two synchronous and one metachronous malignancy. She was diagnosed with carcinoma uterine vault when she was in regular follow-up, and the two previous primaries were controlled. This emphasizes the importance of a regular follow-up and the need of a meticulous workup for early diagnosis and prompt management of any metachronous malignancy. PMID- 29237979 TI - Choroidal metastases as the presenting feature of adenocarcinoma of the lung: A case report and an overview of the role of radiotherapy in its management. AB - Although metastasis to the eye is the most common ophthalmic malignancy, it is usually asymptomatic and rarely a presenting symptom that leads to the diagnosis of a primary. Here, we report a patient who was evaluated for visual symptoms and was eventually diagnosed to have disseminated adenocarcinoma of the lung. He was treated with external radiotherapy to the choroidal metastasis, attaining an excellent response that was sustained until his death. A brief review on the role of radiotherapy in the management of uveal metastases is also presented. PMID- 29237980 TI - To B(iopsy) or not to B(iopsy). AB - Often in metastatic disease, biopsy confirmation of suspicious central nervous system (CNS) lesions is not mandated according to the American College of Radiology, International Radiosurgery Association, and the National Comprehensive Cancer Network. We present a case of an individual who was thought to have metastatic nonsmall cell lung cancer (NSCLC) T2aN0M1b with motor deficits and CNS metastasis to the left postcentral gyrus. The patient underwent biopsy of the primary lung mass confirming NSCLC. He subsequently underwent treatment with stereotactic radiosurgery (SRS) for presumed CNS oligometastatic disease and palliative chemotherapy. Two months after SRS, the patient had progression of CNS disease with new motor deficits. A magnetic resonance imaging revealed and enlarging mass in the previously radiated area. The patient underwent craniotomy with tumor resection and a second primary CNS tumor was discovered. That patient was downstaged from a Stage IV to a Stage IIB lung cancer with concomitant CNS primary. PMID- 29237981 TI - Incision site metastasis: Adding insult to injury. AB - Incision site metastasis is a rare yet well-recognized complication of oncologic operations. We describe the case of a 60-year-old man with a large mass at the site of abdominal incision for a nephrectomy. The operation was performed for infection in an obstructed kidney, which in retrospect harbored malignancy. Percutaneous core biopsy of the mass revealed metastatic conventional renal cell carcinoma (RCC). Surgical resection was obviated by the presence of nodal disease on imaging. Palliative targeted therapy with tyrosine kinase inhibitor was initiated. RCC can not only mimic an inflammatory renal mass radiologically but also coexist with infective renal conditions. Diligent histopathological examination as a routine following nephrectomy for complicated diagnoses is imperative. PMID- 29237982 TI - Small bowel and cecal Involvement: Unusual metastasis sites from adenoid cystic carcinoma of the minor salivary gland. AB - Adenoid cystic carcinoma (ACC) is a rare neoplasm and the most frequent pathology occurring in the minor salivary glands. Lung, bone, liver, and brain are the most frequent metastasis sites in ACC cases. To our knowledge, cecal and ileum metastasis from ACC has not been previously reported in literature. Herein, we reported a case of cecal and small bowel metastasis (ileum) in a patient with ACC. A 41-year-old male patient with ACC developed iron and Vitamin B12 deficiency anemia during further controls. Lower gastrointestinal (GI) endoscopy detected an ulcerated polypoid lesion with raised margins in cecum. Pathological evaluation of polyp biopsy was consistent with metastasis from ACC. The patient underwent surgery of right hemicolectomy. Pathological examinations revealed an ACC of cecum and small bowel (ileum) showing positive staining with CD117, CK7, and panCK. We aimed to emphasize that performing GI stromal screening in ACC patients presenting with iron deficiency is important for early diagnosis of metastasis. PMID- 29237983 TI - Neurofibromatosis type-1 in a patient with ataxia-telangiectasia. PMID- 29237984 TI - Middle East respiratory syndrome virus: Is there any carcinogenicity property? PMID- 29237985 TI - The feasibility of smoker's surcharge policy in tobacco control. PMID- 29237986 TI - Isolated myeloid sarcoma of cervix: Aleukemic presentation. PMID- 29237987 TI - Extramedullary sarcomatoid variant of plasmablastic plasmacytoma. PMID- 29237988 TI - Erratum: Occupational doses of cardiologists in cath labs and simulation method. AB - [This corrects the article DOI: 10.4103/0973-1482.192767.]. PMID- 29237989 TI - The characteristics of non-respondents and respondents of a mental health survey among evacuees in a disaster: The Fukushima Health Management Survey. AB - The Fukushima Medical University conducted a mental health care program for evacuees after the Fukushima Daiichi nuclear power plant accident. However, the mental health status of non-respondents has not been considered for surveys using questionnaires. Therefore, the aim of this study was to clarify the characteristics of non-respondents and respondents. The target population of the survey (FY2011-2013) is people living in the nationally designated evacuation zone of Fukushima prefecture. Among these, the participants were 967 people (20 years or older). We examined factors that affected the difference between the groups of participants (i.e., non-respondents and respondents) using multivariate logistic regression analysis. Employment was higher in non-respondents (p=0.022) and they were also more socially isolated (p=0.047) when compared to respondents; non-respondents had a higher proportional risk of psychological distress compared to respondents (p<0.033). The results of the multivariate logistic regression analysis showed that, within the participants there was a significant association between employment status (OR=1.99, 95% confidence interval [CI]:1.12-3.51) and psychological distress (OR=2.17, 95% CI:1.01-4.66). We found that non-respondents had a significantly higher proportion of psychological distress compared to the respondents. Although the non-respondents were the high-risk group, it is not possible to grasp the complexity of the situation by simply using questionnaire surveys. Therefore, in the future it is necessary to direct our efforts towards the mental health of non-respondents and respondents alike. PMID- 29237990 TI - Predictive Validity of CRUSADE, ACTION and ACUITY-HORIZONS Bleeding Risk Scores in Chinese Patients With ST-Segment Elevation Myocardial Infarction. AB - BACKGROUND: The CRUSADE, ACTION and ACUITY-HORIZONS bleeding scores have been derived using Caucasian patients, and little is known about which has the better predictive ability in Chinese patients, especially for patients with STEMI.Methods and Results:We retrospectively analyzed 2,208 consecutive STEMI patients undergoing primary PCI (PPCI). Major bleeding events were defined according to Bleeding Academic Research Consortium criteria (type 3 or 5). Predictive ability of the 3 scores was assessed using logistic regression and AUC. Unadjusted HR for 1-year death were determined on Cox proportional hazard modeling. The major bleeding rate was 2.4%. The AUC of the CRUSADE, ACTION and ACUTIY-HORIZONS models was 0.88 (95% CI: 0.84-0.92), 0.90 (95% CI: 0.87-0.94), and 0.78 (95% CI: 0.87-0.94). The calibration of the ACUTIY-HORIZONS model was not acceptable overall, or in the subgroup of access site (P<0.05). In the high risk category, 1-year mortality was approximately 4-7-fold greater than in the low-risk category (CRUSADE: HR, 7.27; 95% CI: 3.30-16.02, P<0.001; ACTION: HR, 7.13; 95% CI: 2.19-15.41, P<0.001; ACUITY-HORIZONS: HR, 4.06; 95% CI: 1.62-10.16; P=0.003). CONCLUSIONS: The CRUSADE and ACTION scores have greater predictive ability for in-hospital major bleeding than the ACUITY-HORIZONS risk score in Chinese STEMI patients undergoing PPCI. Mortality would increase with the transition from low- to high-risk category in 1 year. PMID- 29237991 TI - Survival of HeartMate II Patients Despite Cessation of Anticoagulation - Outcomes and Hemostatic Analysis. AB - BACKGROUND: In long-term left ventricular assist device (LVAD) therapy, recurrent bleeding events may justify cessation of anticoagulation therapy (AT). However, data about THE safety and risks of AT cessation in LVAD patients are scarce.Methods and Results:Between 2010 and 2015, 128 patients received a HeartMate II (HMII). Following recurrent bleeding events, we ceased vitamin K antagonist (VKA) therapy in 13 patients (10%) (no-VKA group). To characterize the hemostatic profile, we performed von Willebrand factor (vWF), platelet function (PF), and other hemostatic tests in all HMII patients. The incidence of pump thrombosis (PT), ischemic stroke (IS) and bleeding events in this HMII population was 4.7 %, 6.2% and 36.7%, respectively. Median survival without VKA was 435 days. No cases of PT and only 1 of IS occurred after AT discontinuation. All patients had impaired PF and acquired von Willebrand syndrome (AvWS). However, the vWF collagen-binding activity to antigen ratio before and after VKA cessation was significantly lower in the no-VKA group compared with the HMII population (0.60+/-0.12 vs. 0.73+/-0.14, P=0.006). The thrombin-antithrombin III complex (TAT) value was significantly higher in the no-VKA group (P=0.0005). CONCLUSIONS: We experienced good results with AT cessation in specific HMII patients. The simultaneous onset of AvWS and high TAT values could explain at least in part the low thromboembolic rate in HMII patients without VKA. PMID- 29237992 TI - Message From the Editor-in-Chief. PMID- 29237993 TI - Eukaryotic Microbiomes of Membrane-Attached Biofilms in Membrane Bioreactors Analyzed by High-Throughput Sequencing and Microscopic Observations. AB - Limited information is currently available on the contribution of eukaryotes to the reactor performance of membrane bioreactors (MBRs). Using high-throughput Illumina sequencing of 18S rRNA genes and microscopic observations, we investigated eukaryotic microbiomes in membrane-attached biofilms in MBRs treating piggery wastewater. Protozoa preying on bacteria were frequently detected under stable conditions when membrane clogging was suppressed. However, the eukaryotes preying upon protozoa became predominant in biofilms when membrane fouling rapidly progressed. We herein demonstrated that a comprehensive investigation of eukaryotic microbiomes using high-throughput sequencing contributes to a better understanding of the microbial ecology involved in wastewater treatment. PMID- 29237994 TI - Evaluation of operational parameters role on the emission of fumes. AB - Electric arc welding is a routine operation in the construction of metallic structures, but the fumes generated during the welding process can threaten the health of welders. Fumes are undesirable products of the majority of welding operations and may have various detrimental effects on health. The purpose of this study was to investigate the effect of operational parameters of the shielded metal arc welding (SMAW) process on the emission of fumes. A dust monitor was used to measure the number and mass concentration of fumes generated by SMAW. Measurements were made at the distances of 23 cm (hood inlet) and 41 cm (welder's breathing zone) from the weld point, with different values assigned to three operational parameters, namely current intensity, travel speed, and heat input (HI). Number concentration (NC) decreased with the increase in particle size. The highest mass concentrations (MC) were observed for MC1 (0.35-0.5 MUm) and MC8 (Larger than 6.5 MUm). For reducing exposures to fumes, welders are recommended to use the lowest voltage and amperage and the highest travel speed to the extent that does not compromise in the quality of welds. For assessment of exposure to airborne particles in industrial workplaces and specially in welding operations, it is thought that taking, solely, mass concentration in to consideration and lack of attention to number concentration would not be able to reflect accurate assessment of the adverse effects of particles on the body organs. PMID- 29237995 TI - Recovery of Bordetella bronchiseptica sequence type 82 and B. pseudohinzii from urban rats in Terengganu, Malaysia. AB - Rodents have historically been associated with zoonotic pandemics that claimed the lives of large human populations. Appropriate pathogen surveillance initiatives could contribute to early detection of zoonotic infections to prevent future outbreaks. Bordetella species are bacteria known to cause mild to severe respiratory disease in mammals and, some have been described to infect, colonize and spread in rodents. There is a lack of information on the population diversity of bordetellae among Malaysian wild rodents. Here, bordetellae recovered from lung tissues of wild rats were genotypically characterized using 16S rDNA sequencing, MLST and nrdA typing. A novel B. bronchiseptica ST82, closely related to other human-derived isolates, was discovered in three wild rats (n=3) from Terengganu (5.3333 degrees N, 103.1500 degrees E). B. pseudohinzii, a recently identified laboratory mice inhabitant, was also recovered from one rat (n=1). Both bordetellae displayed identical antimicrobial resistance profiles, indicating the close phylogenetic association between them. Genotyping using the 765-bp nrdA locus was shown to be compatible with the MLST-based phylogeny, with the added advantage of being able to genotype non-classical bordetellae. The recovery of B. pseudohinzii from wild rat implied that this bordetellae has a wider host range than previously thought. The findings from this study suggest that bordetellae surveillance among wild rats in Malaysia has to be continued and expanded to other states to ensure early identification of species capable of causing public health disorder. PMID- 29237996 TI - A clinical case of neosporosis in a 4-week-old holstein friesian calf which developed hindlimb paresis postnatally. AB - A 4-week-old female Holstein Friesian calf presented with hindlimb paresis. Neurologic examination of spinal reflexes revealed depressed or absent reflexes of the hindlimbs. Menace responses on both sides disappeared on examination of cranial nerves. The calf was finally diagnosed with Neospora caninum infection by pathological findings including nonsuppurative inflammation associated with cysts in the cerebrum and spinal cord. High levels of antibody against recombinant surface antigen 1 of N. caninum (NcSAG1) were detected by ELISA from both serum and cerebrospinal fluid (CSF) samples. This result suggests that detection of antibodies against N. caninum by NcSAG1-ELISA in serum and CSF could be useful for the clinical diagnosis of neosporosis in calves with acquired neurological signs. PMID- 29237997 TI - Radiographic and ultrasonographic characteristics of ventral abdominal hernia in pigeons (Columba livia). AB - Five female egg-laying pigeons presented with painless, reducible, ventral abdominal swellings located between the keel and the pubis, or close to the cloaca. Based on clinical, radiographic, and ultrasonographic examination, these pigeons were diagnosed with ventral abdominal hernia requiring surgical interference. Reduction was successfully performed under general anesthesia. Radiographic and ultrasonographic examinations were beneficial for confirming the diagnosis and visualizing the hernial content for surgical planning. Lateral radiographs were more helpful than ventrodorsal radiographs for identification of the hernial content and its continuation with the abdominal muscles. Ultrasonographic examination offered a non-invasive diagnostic tool that allowed for the differentiation of hernia from other abdominal swellings. In addition, it played a beneficial role in identification of the hernial content and follow up after surgical interference. In conclusion, radiographic and ultrasonographic examinations were beneficial in the diagnosis, surgical planning, and follow up after surgical interference of ventral abdominal hernia in pigeons. PMID- 29237998 TI - Neutralization antibody response to booster/priming immunization with new equine influenza vaccine in Japan. AB - Equine influenza (EI) vaccine has been widely used. However, the causative EI virus (H3N8) undergoes continuous antigenic drift, and the vaccine strains must be periodically reviewed and if necessary, updated to maintain vaccine efficacy against circulating viruses. In 2016, the Japanese vaccine was updated by replacing the old viruses with the Florida sub-lineage Clade (Fc) 2 virus, A/equine/Yokohama/aq13/2010 (Y10). We investigated the virus neutralization (VN) antibody response to Fc2 viruses currently circulating in Europe, after booster or primary immunization with the new vaccine. These European viruses have the amino acid substitution A144V or I179V of the hemagglutinin. In horses that had previously received a primary course and bi-annual boosters with the old vaccine booster, immunization with the updated vaccine increased the VN antibody levels against the European Fc2 viruses as well as Y10. There were no significant differences in the VN titers against Y10 and the Fc2 viruses with A144V or I179V substitution in horses that had received a primary course of the updated vaccine. However, a mixed primary course where the first dose was the old vaccine and the second dose was the updated vaccine, reduced VN titers against the European viruses compared to that against Y10. In summary, the new vaccine affords horses protective level of VN titers against the Fc2 viruses carrying A144V or I179V substitution, but our results suggest that the combination of the old and new vaccines for primary immunization would not be optimum. PMID- 29237999 TI - The relationships among hyperuricemia, body mass index and impaired renal function in type 2 diabetic patients. AB - Chronic kidney disease (CKD) is a common chronic microvascular complication and the major cause of death in diabetic patients. This study was conceived to explore the possible mechanisms of how hyperuricemia and obesity contribute to renal function impairment in type 2 diabetic (T2DM) patients. A cross-sectional study in 609 participants recruited from a T2DM population in North China was conducted. The multiplicative interaction between body mass index (BMI) and uric acid (UA) level was assessed using an interaction term in a logistic regression analysis. Our results indicate that male T2DM patients having higher BMI (OR 1.711, p = 0.038), blood urine nitrogen (BUN) (OR 1.100, p = 0.034), and 24-hour urinary micro-albumin levels (OR 1.004, p = 0.021) were much more likely to have high UA. Whereas, for female T2DM patients, the OR of BMI, BUN, and triglyceride were 1.169 (p = 0.001), 1.337 (p = 0.000), and 1.359 (p = 0.006), respectively. In this study population, obesity and elevated UA work together to increase the risk of renal injury. In vitro experiments indicate that reactive oxygen species (ROS) production increased with UA treatment in human renal glomerular endothelial cells (HRGECs), while endothelial nitric oxide synthase (eNOS) production level dropped. UA also increased monocyte chemotactic protein-1 (MCP 1) expression and nuclear factor kappa B (NF-kappaB) activation. Taken together, our results indicate that high concentrations of UA lead to endothelial dysfunction through the activation of the inflammatory response and induction of oxidative stress, even in non-obese T2DM patients. PMID- 29238000 TI - Elevation of Serum Acid Sphingomyelinase Activity in Children with Acute Respiratory Syncytial Virus Bronchiolitis. AB - Acid sphingomyelinase (ASM) is a lysosomal enzyme that hydrolyzes sphingomyelin into ceramide, a bioactive lipid to regulate cellular physiological functions. Thus, ASM activation has been reported as a key event in pathophysiological reactions including inflammation, cytokine release, oxidative stress, and endothelial damage in human diseases. Since ASM activation is associated with extracellular ASM secretion through unknown mechanisms, it can be detected by recognizing the elevation of secretory ASM (S-ASM) activity. Serum S-ASM activity has been reported to increase in chronic diseases, acute cardiac diseases, and systemic inflammatory diseases. However, the serum S-ASM has not been investigated in common acute illness. This study was designed to evaluate serum S ASM activity in children with common acute illness. Fifty children with common acute illness and five healthy children were included in this study. The patients were categorized into five groups based on clinical diagnoses: acute respiratory syncytial virus (RSV) bronchiolitis, adenovirus infection, streptococcal infection, asthma, and other infections due to unknown origin. The serum S-ASM activity was significantly elevated at 6.9 +/- 1.6 nmol/0.1 mL/6 h in the group of acute RSV bronchiolitis patients compared with healthy children who had a mean level of 1.8 +/- 0.8 nmol/0.1 mL/6 h (p < 0.05). In the other illness groups, the serum S-ASM activity was not significantly elevated. The results suggest an association of ASM activation with RSV infection, a cause for common acute illness. This is the first report to describe the elevation of serum S-ASM activity in respiratory tract infection. PMID- 29238001 TI - The Inverse Relationship between Cardiorespiratory Fitness and Intima-Media Thickness with Prehypertensive Middle-Aged Women. AB - Individuals with prehypertension have a greater risk of developing hypertension and cardiovascular disease than those with normal blood pressure. Good cardiorespiratory fitness has been associated with a reduced risk for cardiovascular diseases, but whether it is related to slower progression of early atherosclerosis is unclear. We evaluated 442 women, aged 40-60 years, with resting systolic blood pressure 120-139 mmHg and diastolic blood pressure 80-89 mmHg, defined as prehypertension in cross-sectional study. Blood glucose, blood lipids and carotid intima-media thickness (CIMT) were measured at rest. Cardiorespiratory fitness (VO2peak) was measured by respiratory gas exchange during a treadmill exercise test. Participants were divided into three cardiorespiratory fitness levels: low, moderate, and high. The prevalence of subclinical carotid atherosclerosis was defined as a mean carotid intima-media thickness greater than the 75th percentile. After adjustment for various confounders, a high cardiorespiratory fitness level was associated with significantly lower SBP, DBP and CIMT compared with low and moderate fitness (p < 0.05). After adjustment for established risk factors, high and moderate fitness were each associated with significantly lower odds ratios for carotid atherosclerosis 0.74 (95% CI 0.45-0.92) and 0.70 (95% CI 0.46-0.95), respectively, compared with low fitness. Our results indicate that good cardiorespiratory fitness is associated with a slower progression of early atherosclerosis in middle-aged women. These findings are important, because they emphasize that middle-aged women can be evaluated for cardiorespiratory fitness to estimate their future risk for atherosclerotic vascular diseases. PMID- 29238002 TI - Yin-yang regulating effects of cancer-associated genes, proteins, and cells: An ancient Chinese concept in vogue in modern cancer research. AB - Great achievements have been made in human cancer research, but most of this research is focused on conditions at the microscopic rather than the systemic level. Recent studies have increasingly cited the ancient Chinese theory of yin yang in an effort to expand beyond the microscopic level. Various cancer associated genes and proteins such as mitogen-activated protein kinase (MAPK), p38, p53, c-Myc, tumor necrosis factor (TNF)-alpha, NF-kappaB, Cyclin D1, and cyclin-dependent kinase (CDK) and cells such as T cells, B cells, macrophages, neutrophils, and fibroblasts have been reported to regulate various types of cancers in a yin-yang manner. These studies have brought the theory of yin-yang into vogue in cancer research worldwide. PMID- 29238003 TI - Direct-acting agents for hepatitis C virus before and after liver transplantation. AB - Chronic hepatitis C virus (HCV) infection remains a widespread public health concern and many people are infected with HCV. HCV is one of the leading indications for liver transplantation. Direct-acting antiviral agents (DAAs) against HCV have changed the course of chronic HCV infection, however, making it a curable disease. DAA treatment may be initiated before or after liver transplantation. In the present review, we present the available data on DAA treatment of HCV in liver transplant recipients. PMID- 29238004 TI - Frailty in elderly diabetes patients. AB - Frailty is a state of vulnerability and a consequence of cumulative decline in multiple physiological systems over a lifespan. The occurrence of frailty depends on deterioration in muscle and nerve function, declining cardiopulmonary reserve and loss of executive function. Diabetes mellitus (DM) often causes functional impairment in each of the above systems, thus leading to a loss of whole body homeostasis and deterioration in physical function. Inability of self-management in DM patients may also have considerable impact on the development of sarcopenia/frailty. Thus, there may be positive feedback between the progression of diabetic complications and frailty/sarcopenia. While various factors are involved in this process, insulin resistance or insulin depletion may be an important factor in the progression of frailty in diabetes patients since insulin is well known to be an anabolic hormone in muscle. Interestingly, in our study targeting elderly DM patients, low HbA1c was a significant and independent risk factor for frailty, as assessed using a broad sense frailty scale, the Clinical Frailty Scale (CSF), suggesting that reverse metabolism due to malnutrition in elderly type 2 DM patients might be involved. Therefore, an intervention that includes proper nutrition and exercise training may be essential for the prevention of frailty. The pathogenesis of frailty in DM patients is extensively discussed in this review. PMID- 29238005 TI - The Advantage of Synthetic MRI for the Visualization of Anterior Temporal Pole Lesions on Double Inversion Recovery (DIR), Phase-sensitive Inversion Recovery (PSIR), and Myelin Images in a Patient with CADASIL. PMID- 29238006 TI - Detection of Cerebral Venous Sinus Thrombosis on a R2* Map. PMID- 29238007 TI - Diagnostic Performance of Arterial Spin Labeling for Grading Nonenhancing Astrocytic Tumors. AB - PURPOSE: We evaluated the utility of arterial spin labeling (ASL) imaging of tumor blood flow (TBF) for grading non-enhancing astrocytic tumors. MATERIALS AND METHODS: Thirteen non-enhancing astrocytomas were divided into high-grade (n = 7) and low-grade (n = 6) groups. Both ASL and conventional sequences were acquired using the same magnetic resonance machine. Intratumoral absolute maximum TBF (TBFmax), absolute mean TBF (TBFmean), and corresponding values normalized to cerebral blood flow (TBFmax and TBFmean ratios) were measured. The Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis were used to assess the accuracy of TBF variables for tumor grading. RESULTS: Compared with low-grade astrocytoma, high-grade astrocytoma exhibited significantly greater absolute TBFmax (90.93 +/- 24.96 vs 46.94 +/- 20.97 ml/100 g/min, P < 0.001), TBFmean (58.75 +/- 19.89 vs 31.16 +/- 17.63 ml/100 g/min, P < 0.001), TBFmax ratio (3.34 +/- 1.22 vs 1.35 +/- 0.5, P < 0.001), and TBFmean ratio (2.15 +/- 0.94 vs 0.88 +/- 0.41, P < 0.001). The TBFmax ratio yielded the highest diagnostic accuracy (sensitivity 100%, specificity 86.3%), while absolute TBFmean yielded the lowest accuracy (sensitivity 85.7%, specificity 70.1%) by ROC analysis. CONCLUSION: Parameters from ASL perfusion imaging, particularly TBFmax ratio, may be useful for distinguishing high-grade from low-grade astrocytoma in cases with equivocal conventional MRI findings. PMID- 29238008 TI - Association Between Platelet Count and Postoperative Blood Loss in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass and Fresh Frozen Plasma Administration Guided by Thromboelastometry. AB - BACKGROUND: Coagulopathy after cardiopulmonary bypass (CPB) is caused by multiple factors, including reduced coagulation factors and a low platelet count.Methods and Results:In this study, we undertook a post hoc analysis to identify factors associated with increased postoperative blood loss in 97 patients undergoing cardiac surgery with CPB, with fresh frozen plasma administered according to a ROTEM-guided algorithm. We identified 24 patients for the top quartile of postoperative blood loss, >528 mL and defined as having excessive blood loss. Using Spearman's rank correlation test and multivariable linear regression, we reanalyzed the participants' demographic, surgical and anesthetic variables, laboratory test results, blood loss, and transfusion data. Univariate analysis indicated that patients who experienced higher postoperative blood loss received a significantly higher heparin dose, had a higher requirement for fresh frozen plasma transfusion during surgery, and had a significantly lower hematocrit and platelet count at the end of surgery compared with patients without excessive blood loss. Multivariate analysis showed that platelet count at the end of surgery (odds ratio 0.780, 95% confidence interval 0.629-0.967; P=0.024) was an independent factor for excessive blood loss. CONCLUSIONS: Low platelet count at the end of surgery was associated with excessive postoperative bleeding during cardiac surgery with CPB. PMID- 29238009 TI - Segmental Difference in Vasoreactivity of the Human Right Gastroepiploic Artery. AB - BACKGROUND: The gastroepiploic artery (GEA) plays an important role in the era of multiple arterial revascularization, but spasm is a major matter of concern. The internal thoracic artery has been shown to have a strong tendency to spasm in its distal bifurcating part, whereas the segmental difference in vasoreactivity of the GEA has never been performed.Methods and Results:The full length of the GEA obtained from 21 patients undergoing a total gastrectomy was divided into 3 sections: proximal (5 cm from the origin), middle, and distal (5 cm from the end). Concentration-response curves for vasoconstrictors (phenylephrine, prostaglandin F2alpha, and endothelin-1) and vasodilators (carperitide, nitroglycerin, and nifedipine) were then established using organ baths. All the vasoconstrictors and vasodilators produced concentration-dependent responses in each section. As the concentration of the vasoconstrictors increased, segments at the distal section showed a significantly greater contraction than those at the middle and proximal sections regardless of the type of vasoconstrictor. The effective concentration of drugs that caused 50% of the maximal response for endothelin-1 was significantly greater in the distal section than that in the proximal sections. No significant difference was found in vasodilators-induced relaxation. CONCLUSIONS: The contractility increases toward to the end of the GEA. Clinically, the distal portion of the GEA should be trimmed off and not be used as an anastomotic site wherever possible. PMID- 29238010 TI - Rationale and Descriptive Analysis of Specific Health Guidance: the Nationwide Lifestyle Intervention Program Targeting Metabolic Syndrome in Japan. AB - AIM: All health insurers in Japan are mandated to provide Specific Health Checkups and Specific Health Guidance (SHG) focusing on metabolic syndrome (MetS) in middle-aged adults, beginning in 2008; intensive HG for individuals who have abdominal obesity and two or more additional MetS risk factors, and motivational HG for individuals with one risk factor. The aim of this study is to describe medium-term changes in health indexes for intensive and motivational HG groups using the National Database. METHODS: We compared changes of risk factors and initiation of pharmacological therapy over 3 yr between participants (n=31,790) and nonparticipants (n=189,726) who were eligible for SHG in 2008. RESULTS: Body weight reduction in intensive HG was 1.98 kg (participants) vs 0.42 kg (nonparticipants) in men (p<0.01) and 2.25 vs 0.68 kg in women (p<0.01) after 1 yr. In motivational HG, the respective reduction was 1.40 vs 0.30 kg in men (p<0.01) and 1.53 vs 0.42 kg in women (p<0.01). Waist circumference reduction was also greatest among participants in intensive HG (2.34 cm in men and 2.98 cm in women). These reductions were fairly unchanged over 3 yr and accompanied greater improvements in MetS risk factors in participants. We also detected significantly smaller percentages of SHG participants who initiated pharmacological therapy compared with nonparticipants. CONCLUSION: Participants in SHG showed greater improvements in MetS profiles with proportionally smaller pharmacological treatment initiations than did nonparticipants for 3 yr. Although selection bias may be present, this study suggests SHG would be a feasible strategy to prevent MetS and its sequelae. PMID- 29238012 TI - Announcement: UEDA Heart Award for 2017. AB - We are pleased to announce that the following 4 articles have been selected for the the UEDA Heart Awards for the Year 2017.First PlaceGeneration of Induced Pluripotent Stem Cells From Patients With Duchenne Muscular Dystrophy and Their Induction to CardiomyocytesAkihito Hashimoto, Atsuhiko T. Naito, Jong-Kook Lee, Rika Kitazume-Taneike, Masamichi Ito, Toshihiro Yamaguchi, Ryo Nakata, Tomokazu Sumida, Katsuki Okada, Akito Nakagawa, Tomoaki Higo, Yuki Kuramoto, Taku Sakai, Koji Tominaga, Takeshi Okinaga, Shigetoyo Kogaki, Keiichi Ozono, Shigeru Miyagawa, Yoshiki Sawa, Yasushi Sakata, Hiroyuki Morita, Akihiro Umezawa, Issei KomuroInt Heart J 2016 ; 57 (1) : 112-117Second PlaceEffect of Allopurinol on Myocardial Energy Metabolism in Chronic Heart Failure Rats After Myocardial InfarctZhenzhen Wang, Juan Ding, Xiang Luo, Siliang Zhang, Gang Yang, Que Zhu, Dichuan LiuInt Heart J 2016 ; 57 (6) : 753-759Third PlacePlasma Levels of Receptor for Advanced Glycation End-Products and High-Mobility Group Box 1 in Patients With Pulmonary HypertensionSatoshi Suzuki, Kazuhiko Nakazato, Koichi Sugimoto, Akiomi Yoshihisa, Takayoshi Yamaki, Hiroyuki Kunii, Hitoshi Suzuki, Shu ichi Saitoh, Yasuchika TakeishiInt Heart J 2016 ; 57 (2) : 234-240Tolvaptan Reduces Long-Term Total Medical Expenses and Length of Stay in Aquaporin-Defined RespondersTeruhiko Imamura, Koichiro Kinugawa, Daisuke Nitta, Issei KomuroInt Heart J 2016 ; 57 (5) : 593-599November 2017International Heart Journal Association. PMID- 29238011 TI - Plaque Calcification During Atherosclerosis Progression and Regression. AB - Plaque calcification develops by the inflammation-dependent mechanisms involved in progression and regression of atherosclerosis. Macrophages can undergo two distinct polarization states, that is, pro-inflammatory M1 phenotype in progression and anti-inflammatory M2 phenotype in regression. In plaque progression, predominant M1 macrophages promote the initial calcium deposition within the necrotic core of the lesions, called as microcalcification, through not only vesicle-mediated mineralization as the result of apoptosis of macrophages and vascular smooth muscle cells (VSMCs), but also VSMC differentiation into early phase osteoblasts. On the other hand, in plaque regression M2 macrophages are engaged in the healing response to plaque inflammation. In association with the resolution of chronic inflammation, M2 macrophages may facilitate macroscopic calcium deposition, called as macrocalcification, through induction of osteoblastic differentiation and maturation of VSMCs. Oncostatin M, which has been shown to promote osteoblast differentiation in bone, may play a pivotal role in the development of plaque calcification. Clinically, two types of plaque calcification have distinct implications. Macrocalcification leads to plaque stability, while microcalcification is more likely to be associated with plaque rupture. Statin therapy, which reduces cardiovascular mortality, has been shown to exert its dual actions on plaque morphology, that is, regression of atheroma and increment of macroscopic calcium deposits. Statins may facilitate the healing process against plaque inflammation by enhancing M2 polarization of macrophages. Vascular calcification has pleiotropic properties as pro-inflammatory "microcalcification" and anti-inflammatory "macrocalcification". The molecular mechanisms of this process in relation with plaque progression as well as plaque regression should be intensively elucidated. PMID- 29238013 TI - Definitive Determinant of Late Significant Tricuspid Regurgitation After Aortic Valve Replacement. AB - BACKGROUND: Uncertainties remain regarding the course of existing tricuspid regurgitation (TR) after aortic valve replacement (AVR), and its long-term impact on outcome. We investigated changes in existing TR after isolated AVR for severe aortic stenosis (AS), the impact of preoperative TR on long-term outcome, and predictors of late significant TR.Methods and Results:After excluding mild mitral regurgitation and severe TR, 226 consecutive patients undergoing isolated AVR for severe AS between 2002 and 2015 were reviewed. Patients were classified into a non-TR (none/trivial preoperative TR, n=159) and a TR group (mild/moderate preoperative TR, n=67). During follow-up (median, 4.3 years), late significant TR was more prevalent in the TR group (n=20; 35.0%) than in the non-TR group (n=13; 9.6%; HR, 10.0; 95% CI: 4.44-24.7; P<0.001). The TR group developed more right heart failure (n=3; 5% vs. no patients in the non-TR group, P=0.007), and had a decreased estimated glomerular filtration rate (relative to baseline) until 5 years postoperatively. The tricuspid annulus diameter index was an independent predictor of late significant TR development. CONCLUSIONS: Preoperative mild or moderate TR is aggravated after isolated AVR, resulting in a high incidence of renal dysfunction and right heart failure. Concomitant tricuspid valve intervention should be considered in patients undergoing AVR for severe AS with mild or moderate TR accompanied by dilated tricuspid annulus. PMID- 29238014 TI - [From property of IL-1beta to imaging of inflammation]. AB - Interleukin-1beta is widely known as an inflammatory cytokine, and is an important and indispensable factor to understand inflammation. Therefore many researchers have investigated function and property of interleukin-1beta. However some questions still remain to be fully elucidated. To approach these questions, bioimaging technology has been exploited recently. As interleukin-1beta is regulated by unique mechanism via transcriptional activation and protein processing, several imaging tools have been developed for analyzing interleukin 1beta by applying the regulatory mechanism. In this review I introduce representative interleukin-1beta-related imaging technologies including basic principle of them and findings obtained with them. Additionally I referred briefly to other imaging technologies for monitoring inflammation in the last section. PMID- 29238015 TI - [In vivo imaging of cutaneous inflammation: novel insights into cutaneous immune responses revealed by multi-photon microscopic analysis]. AB - Skin is an outermost organ that serves as an interface between the host and the environment. The skin provides not only mechanical barrier functions, but also an active immunological barrier that provides the first line of defense against infections. For the effective clearance of pathogens or antigens in the skin, immune cells, especially effector T cells, must quickly exert their effector functions while avoiding the host damage by their excess activation. Therefore, the quality, magnitude, and the duration of the effector T cell activity must be carefully regulated. Here, we will review our recent findings on the effector T cell dynamics, dendritic cell dynamics, and the regulatory mechanisms for effector T cells activation in the skin, as revealed by the live imaging techniques using multi-photon microscopy. PMID- 29238016 TI - [Imaging of bone and joint destruction]. AB - Osteoclasts are bone-resorbing giant polykaryons that differentiate from mononuclear macrophage/monocyte-lineage hematopoietic precursors. We have originally established an advanced imaging system for visualizing in vivo behavior of osteoclasts and their precursors with intravital two-photon microscopy. By means of the system, we found that sphingosine-1-phosphate, a lipid mediator enriched in blood, controlled the migratory behavior of osteoclast precursors. We also developed pH-sensing chemical fluorescent probes to detect localized acidification by bone-resorbing osteoclasts on the bone surface in vivo, and identified two distinct functional states of differentiated osteoclasts, 'bone-resorptive' and 'non-resorptive'. In this review, we summarize our recent studies on the dynamics and functions of osteoclasts. Our intravital imaging techniques would be beneficial for studying the cellular dynamics in arthritic inflammation and bone destruction in vivo and would thus be useful for evaluating novel therapies targeting aspects of osteoclast dynamics in patients with bone-destructive diseases. PMID- 29238017 TI - [The interface between the immune system and autonomic nervous system]. AB - The nervous system and the immune system are two major systems in human body. Although it was revealed these two systems correlated, the control of immune cell dynamics by the nervous system has come to draw a lot of attention at the present time. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in several animal models. One well-characterized cytokine-inhibiting mechanism, termed the "inflammatory reflex", is dependent upon vagus nerve stimulation that inhibits cytokine production and attenuates the inflammation. And the mechanism for controlling lymphocyte trafficking becomes clear, and molecular basis of immune regulation by the nervous system was reported. On the other hand, the nervous system is protected from the invasion of harmful agents by the barrier. However, there are neuroimmunological disorders, which is associated with autoimmunity, tumor immunity, and infection immunity. Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to widespread autonomic manifestations, in which autoantibodies to ganglionic nicotinic acetylcholine receptors play a central role. Previously, we elucidated the prevalence of extra autonomic manifestations in patients with AAG. It is necessary to establish the new systems for the detection of autoantibodies to other subunits of acetylcholine receptor. PMID- 29238018 TI - [Regulation of bone by IL-17-producing T cells]. AB - Bone is a component of the skeletal-locomotor system but also functions as an immunological organ that harbors hematopoietic stem and progenitor cells. Since the immune and skeletal systems are closely related through a number of shared regulatory molecules including cytokines and receptors, bone can be affected in various immune disorders. Rheumatoid arthritis is a typical disease in which the immune system affects the bone metabolism. The enhanced activity of osteoclasts by the activation of Th17 cells causes the joint destruction in rheumatoid arthritis. Studies on bone destruction associated rheumatoid arthritis have highlighted the importance of the interplay between the immune and bone systems, and promoted the new interdisciplinary field of "osteoimmunology". Furthermore, recent studies have suggested that regulation of bone tissues by IL-17 is more complicated than we had expected. IL-17-prodcuing cells contribute to new bone formation at the enthesis in ankylosing spondylitis, and IL-17-producing gammadelta T cells promote bone regeneration by acting on the mesenchymal stem cells in bone fracture healing. It would be necessary to comprehensively understand the interplay between the immune and bone systems for elucidation of the molecular mechanisms underlying the pathogenesis of various diseases that involves the two systems. PMID- 29238019 TI - [Inflammation and osteoclasts]. AB - Osteoclasts are differentiated from precursors of the monocyte/macrophage lineage originated from bone marrow hematopoietic stem cells and are the sole bone-resorbing cells in the body. Osteoclast differentiation is thought to require M-CSF (macrophage colony-stimulating factor) and RANKL (receptor activator of nuclear factor kappa-B ligand) signaling. However, it has recently been proposed that under chronic inflammatory conditions, such as systemic autoimmune diseases (e.g., rheumatoid arthritis), an increase in inflammatory cytokine levels within joints induces pathological osteoclast differentiation, causing excessive bone resorption. In addition, the authors have reported that stimulating mouse bone marrow monocytes and human CD14+ monocytes with combination of TNFalpha and IL-6 can induce differentiation of osteoclast-like cells, which are cells with bone resorption activity. In the present article, we discuss the mechanism of osteoclast differentiation of RANKL-independent bone resorbing cells, using both data from the aforementioned report as well as the latest findings. Understanding the mechanisms underlying RANKL-independent, cytokine-mediated osteoclast differentiation could facilitate the development of novel therapies for inflammatory joint diseases. PMID- 29238020 TI - [Prolonged optic disc swelling in Kawasaki disease - A case report and literature review]. AB - Kawasaki disease (KD), an acute childhood panvasculitis, presents a variety of ocular complications as well as conjunctival injection among the principal symptoms. However, most pediatricians are unfamiliar with the ophthalmological complications of KD. A 2-year-old girl was referred to us from the ophthalmology department due to injected bulbar conjunctivae and optic disc swelling. She had familial exudative vitreoretinopathy as an underlying disease and the ocular findings had been made by chance while the patient was receiving an eye examination. Although she was afebrile at the time of her first medical interview, KD was diagnosed based on the presence of four of the principal symptoms including fever and dilatation of the coronary arteries. Intravenous immunoglobulin (IVIG) therapy was administered on Day 15 from the onset of fever. After IVIG administration, her laboratory test results showed rapid improvement but her optic disc swelling continued for six months. Eye complications in KD generally occur in the anterior segment, and recovery occurs within two months. Past reports have shown that in three of seven KD cases with optic disc involvement, optic disc swelling lasted over two months. This is the second case in which the condition lasted six months. PMID- 29238021 TI - [Granulomatosis with Polyangiitis Complicated with Gastrointestinal Perforation: A Case Report and Review of Literature]. AB - A 51-year-old man was detected nasal bleeding, multiple pulmonary nodule and mass, urinalysis abnormality, renal involvement and high titer of proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA), and was suspected of granulomatosis with polyangiitis and initiated with steroid pulse therapy. On the day after the start of steroid pulse therapy, generalized peritonitis due to ileal perforation occurred, and emergency ileectomy and peritonitis surgery were performed. Induction therapy with steroid pulse therapy, plasma exchange and intravenous cyclophosphamide therapy (IVCY) and maintenance therapy with glucocorticoid and azathioprine led to good therapeutic outcomes. Gastrointestinal perforation in GPA is a rare complication, and we examined the clinical features, treatment contents, and prognosis of GPA with gastrointestinal perforation from this case and previous reports. Lung involvements were complicated in all reported cases. Gastrointestinal perforations in GPA were frequent in the small intestine, occurred just before and immediately after the start of treatment, and were severe involvement with poor prognosis because of the high mortality rate (46.7%). The frequency of ear, nose and upper respiratory tract lesions in the surviving group was significantly higher than in the dead group (survival 87.5%, death 28.3%, P = 0.041). IVCY were more frequently used in the surviving group (62.5%) than the death group (16.7%), but it was not significantly. GPA complicated with gastrointestinal perforation is a severe condition with poor prognosis, but there is a possibility to improve prognosis by early diagnosis and early initiation of strong treatment. PMID- 29238022 TI - [Coexistence of Takayasu's arteritis and inflammatory colitis detected by fluorodeoxyglucose positron emission tomography]. AB - A woman in her thirties was diagnosed as Takayasu's arteritis (TAK) by dilatation, wall thickness of her abdominal aorta in contrast-enhanced computed tomography. Although she didn't have any subjective bowel symptoms, fluorodeoxyglucose (FDG)-positron emission tomography (PET) also revealed uptake of FDG in descending colon, and colonoscopy revealed aphthous colitis. After the start of steroid therapy, both arteritis and colitis were improved. FDG-PET can detect TAK and inflammatory bowel diseases at an early stage. FDG-PET is a less invasive module with a high sensitivity for detecting colitis, therefore should be considered for TAK even without physical colon symptoms. PMID- 29238023 TI - Study of Cationic and Nonionic Mixed Micelles with NaBr and 3,5-Cl2C6H3CO2Na by Use of Probe Nucleophilic Reaction of Piperidine with Ionized Phenyl Salicylate. AB - Behaviors of cationic and nonionic mixed micelles in the form of hexadecyltrimethylammonium bromide (HDABr) and hexadecyltrimethylammonium bromide Polyethylene glycol hexadecyl ether (C16E20), in the presence of inert salts (NaBr and 3,5-dichlorosodium benzoate), by the use of reaction probe between Pp and ionized PhSH (Pp = piperidine and PhSH = phenyl salicylate), has been reported in this work. The values of RXBr (RXBr denotes ion exchange constants obtained in the presence of micelles of different structural features) or KXBr (KXBr denotes ion exchange constants obtained in the presence of micelles of the same structural features) for 3,5-Cl2C6H3CO2- were almost the same at three different [HDABr]T (0.006, 0.010 and 0.015 M). The average value of RXBr or KXBr determined, in the presence of pure HDABr micelles, using semi empirical kinetic (SEK) method appeared to be almost 21/2-fold larger (RXBr or KXBr = 198) than that in the presence of mixed HDABr-C16E20 micelles (RXBr or KXBr = 78). Rheological measurements indicated the existence of wormlike/twisted micelles and vesicle at 0.015 M pure HDABr, various [3,5-Cl2C6H3CO2Na], and 25 and 35C whereas there were evidence of only spherical micelles in the presence of mixed HDABr C16E20 ([HDABr]T = 0.015 M and [C16E20]T = 0.006 M) at both temperatures. PMID- 29238024 TI - Preparation of Margarine Stock Rich in Naturally Bioactive Components by Enzymatic Interesterification. AB - Fully hydrogenated expanded press soybean oil (FHEPSO) rich in naturally bioactive components was prepared using Palladium on Carbon (Pd/C) catalyst. Interesterified fat was prepared from binary blends of FHEPSO and cold press corn oil (CPCO) with FHEPSO/CPCO mass ratios of 50:50, 40:60 and 30:70. Lipozyme RM IM (6 wt% of total substrate) was used in a supercritical CO2 system to catalyze the transesterification. The fatty acid compositions had no significant changes in the fats before and after interesterification, and trans-fatty acid (TFA) was not detected. The fatty acid compositions within triacylglycerol (TAG) were rearranged, and the amounts of trisaturated and triunsaturated TAG decreased, whereas that of mixed TAG increased as a result of interesterification. The enzymatic interesterified fats (EIEF) had a lower solid fat content (SFC), broader melting and plasticity ranges compared to the noninteresterified blend (NIB). According to X-ray diffraction (XRD), the predominant crystal form had changed from beta to beta'. EIEF contained 0.33-0.51 g/100 g phospholipids, 88.6 105.6 mg/100 g total tocopherols, and 916-1053 mg/100 g total phytosterols, which could confer health benefits. The results indicated that EIEF may have a potential use in trans-free margarine stock preparation. PMID- 29238025 TI - Analytical Methods to Evaluate the Quality of Edible Fats and Oils: The JOCS Standard Methods for Analysis of Fats, Oils and Related Materials (2013) and Advanced Methods. AB - Edible fats and oils are among the basic components of the human diet, along with carbohydrates and proteins, and they are the source of high energy and essential fatty acids such as linoleic and linolenic acids. Edible fats and oils are used in for pan- and deep-frying, and in salad dressing, mayonnaise and processed foods such as chocolates and cream. The physical and chemical properties of edible fats and oils can affect the quality of oil foods and hence must be evaluated in detail. The physical characteristics of edible fats and oils include color, specific gravity, refractive index, melting point, congeal point, smoke point, flash point, fire point, and viscosity, while the chemical characteristics include acid value, saponification value, iodine value, fatty acid composition, trans isomers, triacylglycerol composition, unsaponifiable matters (sterols, tocopherols) and minor components (phospholipids, chlorophyll pigments, glycidyl fatty acid esters). Peroxide value, p-anisidine value, carbonyl value, polar compounds and polymerized triacylglycerols are indexes of the deterioration of edible fats and oils. This review describes the analytical methods to evaluate the quality of edible fats and oils, especially the Standard Methods for Analysis of Fats, Oils and Related Materials edited by Japan Oil Chemists' Society (the JOCS standard methods) and advanced methods. PMID- 29238026 TI - Multi-objective Optimization of Molecular Distillation Conditions for Oleic Acid from a Rich-in-Fatty Acid Model Mixture. AB - Oleic acid is a commercially valuable compound and has many positive health effects. Determining optimum conditions in a physical separation process is an industrially significant point due to environmental and health related concerns. Molecular distillation avoids the use of chemicals and adverse effects of high temperature application. The objective of this study was to determine the molecular distillation conditions for oleic acid to increase its purity and distillation yield in a model fatty acid mixture. For this purpose, a short-path evaporator column was used. Evaporation temperature ranged from 110 to 190C, while absolute pressure was from 0.05 to 5 mmHg. Results showed that elevating temperature generally increased distillation yield until a maximum evaporation temperature. Vacuum application also affected the yield at a given temperature, and amount of distillate increased at higher vacuums except the case applied at 190C. A multi-objective optimization procedure was then used for maximizing both yield and oleic acid amounts in distillate simultaneously, and an optimum point of 177.36C and 0.051 mmHg was determined for this purpose. Results also demonstrated that evaporation of oleic acid was also suppressed by a secondary dominant fatty acid of olive oil - palmitic acid, which tended to evaporate easier than oleic acid at lower evaporation temperatures, and increasing temperature achieved to transfer more oleic acid to distillate. At 110C and 0.05 mmHg, oleic and palmitic acid concentrations in distillate were 63.67% and 24.32%, respectively. Outcomes of this study are expected to be useful for industrial process conditions. PMID- 29238027 TI - Viscous Flow Behaviour of Karanja Oil Based Bio-lubricant Base Oil. AB - Karanja oil (KO) is widely used for synthesis of bio-fuel karanja oil methyl ester (KOME) due to its competitive price, good energy values and environmentally friendly combustion properties. Bio-lubricant is another value added product that can be synthesized from KO via chemical modification. In this work karanja oil trimethylolpropane ester (KOTMPE) bio-lubricant was synthesized and evaluated for its viscous flow behaviour. A comparison of viscous flow behaviours of natural KO and synthesized bio-fuel KOME and bio-lubricant KOTMPE was also made. The aim of this comparison was to validate the superiority of KOTMPE bio-lubricant over its precursors KO and KOME in terms of stable viscous flow at high temperature and high shear rate conditions usually encountered in engine operations and industrial processes. The free fatty acid (FFA) content of KO was 5.76%. KOME was synthesized from KO in a two-step, acid catalyzed esterification followed by base catalyzed transesterification, process at 65 degrees C for 5 hours with oil methanol ratio 1:6, catalysts H2SO4 and KOH (1 and 1.25% w/w KO, respectively). In the final step, KOTMPE was prepared from KOME via transesterification with trimethylolpropane (TMP) at 150 degrees C for 3 hours with KOME-TMP ratio 4:1 and H2SO4 (2% w/w KOME) as catalyst. The viscosity versus temperature studies were made at 0-80 degrees C temperatures in shear rate ranges of 10-1000 s-1 using a Discovery Hybrid Rheometer, model HR-3 (TA instruments, USA). The study found that viscosities of all three samples decreased with increase in temperature, though KOTMPE was able to maintain a good enough viscosity at elevated temperatures due to chemical modifications in its molecular structure. The viscosity index (VI) value for KOTMPE was 206.72. The study confirmed that the synthesized bio-lubricant KOTMPE can be used at high temperatures as a good lubricant, though some additives may be required to improve properties other than viscosity. PMID- 29238028 TI - Konjac Ceramide (kCer) Regulates NGF-Induced Neurite Outgrowth via the Sema3A Signaling Pathway. AB - The tuber of the konjac plant is a source enriched with GlcCer (kGlcCer), and has been used as a dietary supplement to improve the dry skin and itching that are caused by a deficiency of epidermal ceramide. Previously, we showed chemoenzymatically prepared konjac ceramide has a neurite-outgrowth inhibitory effect that is very similar to that of Sema3A and is not seen with animal-type ceramides. While, it has been unclear whether kCer may act on Sema3A or TrkA signaling pathway. In the present study, we showed kCer induces phosphorylation of CRMP2 and microtubules depolymerization via Sema3A signaling pathway not TrkA. It is concluded that kCer may be a potential Sema3A-like agonist that activates Sema3A signaling pathway directly. PMID- 29238029 TI - Characterization of Konjac Ceramide (kCer) Binding to Sema3A Receptor Nrp1. AB - Konjac ceramide (kCer) can be prepared by a chemoenzymatic method as previously published (Usuki, S.; Tamura, N.; Sakai, S.; Tamura, T.; Mukai, K.; Igarashi, Y. Biochem. Biophys. Rep. 5, 160-167 (2016)). Thus prepared kCer showed an activation effect on Sema3A signaling pathway to induce phosphorylation of CRMP2 and microtubule depolymerizaion, resulting in opposing NGF-induced neurite outgrowth. In the present study, we have shown that kCer is a potential Sema3A like ligand that has a competitive effect on Sema3A binding to a cell surface receptor Nrp1, but animal-type ceramides have no effect on Sema3A binding to Nrp1. In addition, kCer showed a direct molecular interaction with Nrp1, but animal-type ceramides, C16Cer, C18Cer, and C24Cer show no specific bindings to Nrp1. Further, kCer showed an additive effect to activate the Sema3A signaling pathway together with low-dose Sema3A but a reversed effect to inhibit this pathway when combined with high-dose Sema3A. PMID- 29238030 TI - A New Synthetic Tool: The Pseudo-Intramolecular Process. AB - An efficient synthetic protocol based on a new concept named "the pseudo intramolecular process" is developed. Substrates are brought closed to each other by forming a salt, and this spatial proximity facilitates an efficient reaction like an intramolecular process, despite actually proceeding via an intermolecular pathway. This concept can be widely applied in organic synthesis. For instance, alpha-aryl-beta-keto esters undergo a transacylation with amines accompanied by high efficiency, regioselectivity, and chemoselectivity. On the other hand, alpha nitro-beta-keto nitriles react via a tandem cyclization to afford polyfunctionalized azaheterocyclic compounds, which cannot be easily prepared by alternative methods. These synthetic protocols are practically useful because each reaction can be conducted without using any special reagent under mild reaction conditions through only simple experimental manipulations. PMID- 29238031 TI - Preparation of Artificial Skin that Mimics Human Skin Surface and Mechanical Properties. AB - We have developed an artificial skin that mimics the morphological and mechanical properties of human skin. The artificial skin comprises a polyurethane block possessing a microscopically rough surface. We evaluated the tactile sensations when skin-care cream was applied to the artificial skin. Many subjects perceived smooth, moist, and soft feels during the application process. Cluster analysis showed that these characteristic tactile feels are similar to those when skin care cream is applied to real human skin. Contact angle analysis showed that an oil droplet spread smoothly on the artificial skin surface, which occurred because there were many grooves several hundred micrometers in width on the skin surface. In addition, when the skin-care cream was applied, the change in frictional force during the dynamic friction process increased. These wetting and frictional properties are important factors controlling the similarity of artificial skin to real human skin. PMID- 29238032 TI - Influence of Fruit Ripening on Color, Organic Acid Contents, Capsaicinoids, Aroma Compounds, and Antioxidant Capacity of Shimatogarashi (Capsicum frutescens). AB - Shimatogarashi (Capsicum frutescens) is a typical chili pepper domesticated in southern Japan. Important traits of Shimatogarashi peppers, such as color; proportion of organic acids, capsaicinoids, and aromatic compounds; and antioxidant activity in three stages of maturity (green (immature), orange (turning), and red (mature) stages) were characterized. The results indicated that the concentration of organic acids, including ascorbic, citric, and malic acid, increased during ripening. In addition, the amount of capsaicinoids, which are responsible for the pungent taste of chili peppers, increased as the fruit matured to the orange and red stages. The volatile compound profile of Shimatogarashi was dominated by the presence of esters, which mainly contributed to fruity notes. The total amount of volatile compounds analyzed by gas chromatography-headspace solid-phase microextraction (GC-HS-SPME), especially esters, decreased as the fruit changed in color from green to red. This was in contrast to the amount of terpenoids, especially limonene, which increased at the red stage, denoting a change in flavor from fruity to a more citrus-like aroma. Based on the total phenolic content (TPC), the oxygen radical absorbance capacity (ORAC) and the diphenylpicrylhydrazyl (DPPH) free radical method, the antioxidant capacity of Shimatogarashi showed an increase at the mature red stage. However, while the red stage showed higher pungency and antioxidant capacity as well as an attractive color, the results of aromatic compound analysis revealed that the immature green stage had the advantages of having pleasant fruity smell, making it suitable for use in condiments. PMID- 29238033 TI - Dermatopathic Lymphadenitis Mimicking Breast Cancer with Lymphatic Metastasis: A Case Report and Discussion. AB - BACKGROUND Dermatopathic lymphadenitis is a rare benign lymphatic hyperplasia commonly associated with exfoliative or eczematoid dermatitis. Of interest, this condition can be confused with lymphatic metastasis in adults. CASE REPORT In this report, we describe the case of a 56-year-old woman diagnosed with left breast invasive ductal carcinoma in remission, who presented with dermatopathic lymphadenitis mimicking breast cancer recurrence. CONCLUSIONS Dermatopathic lymphadenitis is a benign entity that needs to be considered in the differential diagnosis of lymphadenopathy. Pursuing extensive workup in asymptomatic patients with a similar presentation and initial negative tests for malignancy recurrence is not recommended. PMID- 29238034 TI - Inverse Relationship Between Serum Bilirubin Levels and Diabetic Foot in Chinese Patients with Type 2 Diabetes Mellitus. AB - BACKGROUND Several studies demonstrated that bilirubin, a potent endogenous antioxidant, is a strong protective factor for many diabetic complications such as nephropathy, retinopathy, neuropathy, and vasculopathy. The purpose of this study was to assess the association between serum bilirubin levels and diabetic foot (DF) in Chinese patients with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS The present cross-sectional study of bilirubin levels in relation to DF was conducted in 1,269 T2DM patients with (n=578) and without (n=691) DF. Blood test results were obtained on hospital admission, including total bilirubin (T BIL), direct bilirubin (D-BIL), and indirect bilirubin (I-BIL). Data on Wagner classification and amputation procedure in patients with DF were collected by reviewing electronic medical records. Univariate or multivariate analysis were performed to explore the association between bilirubin and DF. RESULTS Serum I BIL levels were shown to play a protective role regarding the presence and severity of DF (OR=0.75, p=0.029 and OR=0.90, p=0.021, respectively). In addition, in a comparison of the lowest and highest tertiles of serum bilirubin concentration, the highest tertile of serum T-BIL (OR=0.51, p=0.011) and I-BIL (OR=0.28, p<0.001) was significantly related with a lower Wagner grade of DF. Patients with DF in the highest tertiles of T-BIL carried a significantly lower risk of amputation events than those in the lowest tertiles (OR=0.47, p=0.025). CONCLUSIONS The present study provided evidence that decreased serum bilirubin levels were independently associated with the presence and severity of DF and amputation events in patients with DF. PMID- 29238035 TI - Long non-coding RNA MEG3 functions as a competing endogenous RNA to regulate ischemic neuronal death by targeting miR-21/PDCD4 signaling pathway. AB - Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been demonstrated as an important regulator in diverse human cancers. However, its function and regulatory mechanism in ischemic stroke remains largely unknown. Here, we report that MEG3 is physically associated with microRNA-21 (miR-21), while miR-21 is downregulated following ischemia in the ischemic core in vitro and in vivo, which is opposite to MEG3. Besides, overexpression of miR-21 protects oxygen-glucose deprivation and reoxygenation (OGD/R)-induced apoptotic cell death. Furthermore, MEG3 functions as a competing endogenous RNAs (ceRNAs) and competes with programmed cell death 4 (PDCD4) mRNA for directly binding to miR-21, which mediates ischemic neuronal death. Knockdown of MEG3 protects against ischemic damage and improves overall neurological functions in vivo. Thus, our data uncovers a novel mechanism of lncRNA MEG3 as a ceRNA by targeting miR-21/PDCD4 signaling pathway in regulating ischemic neuronal death, which may help develop new strategies for the therapeutic interventions in cerebral ischemic stroke. PMID- 29238036 TI - Identification of additional EHMT2 variant associated with the risk of chronic hepatitis B by GWAS follow-up study. AB - Chronic hepatitis B (CHB) is a precursor to liver cirrhosis and hepatocellular carcinoma, caused by a Hepatitis B viral infection. Genome-wide association studies (GWASs) have been conducted to find genes associated with CHB risk. In previous GWAS, EHMT2 was identified as one of the susceptibility genes for CHB. To further characterize this association and discover possible causal variants, we conducted an additional association study. A total of 11 EHMT2 single nucleotide polymorphisms (SNP) were selected and genotyped in 3902 subjects (1046 CHB patients and 2856 controls). An additional eight imputed SNPs were also included in further analysis. As a result, rs35875104 showed a strong association with the CHB, along with the previously reported genetic marker for CHB risk, rs652888 (odds ratio (OR) = 0.53, P = 2.20 * 10-8 at rs35875104 and OR = 1.58, P = 9.90 * 10-12 at rs652888). In addition, linkage disequilibrium and conditional analysis identified one SNP (rs35875104) as a novel genetic marker for CHB susceptibility. The GRSs (genetic risk scores) were calculated to visualize the combined genetic effects of all known CHB-associated loci, including EHMT2 rs35875104, which was additionally identified in this study. The findings from the present study may be useful for further understanding of the genetic etiology of CHB. PMID- 29238037 TI - The association of sarcopenia, telomere length, and mortality: data from the NHANES 1999-2002. AB - BACKGROUND/OBJECTIVES: Sarcopenia is defined as the loss of muscle mass or function with aging and is associated with adverse outcomes. Telomere shortening is associated with mortality, yet its relationship with sarcopenia is unknown. SUBJECTS/METHODS: Adults >=60 years from the 1999-2002 NHANES with body composition measures were identified. Sarcopenia was defined using the two Foundation for the National Institute of Health definitions: appendicular lean mass (ALM) (men <19.75; women <15.02 kg); or ALM divided by body mass index (BMI) (ALM:BMI, men <0.789; women <0.512). Telomere length was assessed using quantitative PCR. Regression models predicted telomere length with sarcopenia (referent = no sarcopenia). RESULTS: We identified 2672 subjects. Mean age was 70.9 years (55.5% female). Prevalence of ALM and ALM:BMI sarcopenia was 29.2 and 22.1%. Deaths were higher in persons with sarcopenia as compared to those without sarcopenia (ALM: 46.4 vs. 33.4%, p < 0.001; ALM:BMI: 46.7 vs. 33.2%, p < 0.001). No adjusted differences were observed in telomere length in those with/without sarcopenia (ALM: 0.90 vs. 0.92, p = 0.74, ALM:BMI 0.89 vs. 0.92, p = 0.24). In men with ALM:BMI-defined sarcopenia, adjusted telomere length was significantly lower compared to men without sarcopenia (0.85 vs. 0.91, p = 0.013). With sarcopenia, we did not observe a significant association between telomere length and mortality (ALM: HR 1.11 [0.64,1.82], p = 0.68; ALM:BMI: HR 0.97 [0.53,1.77], p = 0.91), but noted significance in those without sarcopenia with mortality (ALM: HR 0.59 [0.40,0.86], p = 0.007; ALM:BMI: HR 0.62 [0.42,0.91]; p = 0.01). CONCLUSIONS: We observed a potentially inverse relationship between telomere length and mortality in those without sarcopenia but did not observe a significant relationship between telomere length and mortality in the presence of sarcopenia. PMID- 29238038 TI - Fluid consumption pattern and hydration among 8-14 years-old children. AB - BACKGROUND/OBJECTIVES: Children consume various fluids to meet dietary water intake needs. However, the contribution of different fluid types on hydration is unclear. The purpose of this study was to develop fluid intake patterns and examine their association with hydration, as indicated by 24-h urine osmolality. SUBJECTS/METHODS: Two hundred ten (105 girls) healthy children (height: 1.49 +/- 0.13 m, weight: 43.4 +/- 12.6 kg, body fat: 25.2 +/- 7.8%) recorded their fluid intake for two consecutive days, and collected their urine for 24-h during the 2nd day, while conducting their normal daily activities. Urine samples were analyzed for specific gravity and osmolality. Factor analysis with principal components method was applied to extract dietary patterns from six fluid groups. Linear regression analysis evaluated the associations between the extracted dietary patterns and hydration based on 24-h urine osmolality. RESULTS: The analysis revealed the following six components: 1, characterized by consumption of milk and fresh juice, but not packaged juice; 2, by regular soda and other drinks, but not water; 3, by fresh juice and other drinks; 4, by packaged juice, but not regular soda; 5, by water and milk; and 6, by fresh juice. Component 5 was negatively correlated with urine osmolality (P = 0.001) indicating better hydration, whereas component 2 was positively correlated with urine osmolality (P = 0.001). CONCLUSIONS: A drinking pattern based on water and milk was associated with better hydration, as indicated by lower urine osmolality, whereas drinking regular soda and other drinks but not water was associated with inferior hydration. PMID- 29238039 TI - Helicobacter pylori VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway. AB - The Helicobacter pylori vacuolating cytotoxin (VacA) can promote progressive vacuolation and gastric injury and may be associated with human gastric cancer. Increasing evidence indicates that autophagy is involved in the cell death induced by VacA, but the specific mechanisms need to be further elucidated. We show here that VacA could induce autophagy and increase cell death in human gastric cancer cell lines. Further investigations revealed that inhibition of autophagy could decrease the VacA-induced cell death in AGS cells. Furthermore, numerous dilated endoplasmic reticula (ER) were observed, and the phosphorylation of a subunit of eukaryotic translation initiation factor 2 subunit 1 also increased in the VacA-treated AGS cells, while repression of ER stress could reduce autophagy and cell death through knockdown of activating transcription factor 4 and DNA-damage-inducible transcript 3. In addition, the expression of pseudokinase tribbles homolog 3 (TRIB3) upon ER stress was triggered by VacA, and knockdown of TRIB3 could also decrease VacA-induced cell death. Finally, inhibition of autophagy could decrease VacA s1m1 -induced cell death and apoptosis, and apoptosis inhibitor Z-VAD had no significant effect on autophagy induced by VacA s1m1 . Thus, these results suggested that VacA causes autophagic cell death via ER stress in gastric epithelial cells. PMID- 29238040 TI - IL-3R-alpha blockade inhibits tumor endothelial cell-derived extracellular vesicle (EV)-mediated vessel formation by targeting the beta-catenin pathway. AB - The proangiogenic cytokine Interleukin-3 (IL-3) is released by inflammatory cells in breast and ovarian cancer tissue microenvironments and also acts as an autocrine factor for human breast and kidney tumor-derived endothelial cells (TECs). We have previously shown that IL-3-treated endothelial cells (ECs) release extracellular vesicles (EVs), which serve as a paracrine mechanism for neighboring ECs, by transferring active molecules. The impact of an anti-IL-3R alpha blocking antibody on the proangiogenic effect of EVs released from TECs (anti-IL-3R-EVs) has therefore been investigated in this study. We have found that anti-IL-3R-EV treatment prevented neovessel formation and, more importantly, also induced the regression of in vivo TEC-derived neovessels. Two miRs that target the canonical wingless (Wnt)/beta-catenin pathway, at different levels, were found to be differentially regulated when comparing the miR-cargo of naive TEC-derived EVs (EVs) and anti-IL-3R-EVs. miR-214-3p, which directly targets beta catenin, was found to be upregulated, whereas miR-24-3p, which targets adenomatous polyposis coli (APC) and glycogen synthase kinase-3beta (GSK3beta), was found to be downregulated. In fact, upon their transfer into the cell, low beta-catenin content and high levels of the two members of the "beta-catenin destruction complex" were detected. Moreover, c-myc downregulation was found in TECs treated with anti-IL-3R-EVs, pre-miR-214-3p-EVs and antago-miR-24-3p-EVs, which is consistent with network analyses of miR-214-3p and miR-24-3p gene targeting. Finally, in vivo studies have demonstrated the impaired growth of vessels in pre-miR-214-3p-EV- and antago-miR-24-3p-EV-treated animals. These effects became much more evident when combo treatment was applied. The results of the present study identify the canonical Wnt/beta-catenin pathway as a relevant mechanism of TEC-derived EV proangiogenic action. Furthermore, we herein provide evidence that IL-3R blockade may yield some significant advantages, than miR targeting, in inhibiting the proangiogenic effects of naive TEC-derived EVs by changing TEC-EV-miR cargo. PMID- 29238041 TI - FoxO1 is a regulator of MHC-II expression and anti-tumor effect of tumor associated macrophages. AB - Macrophages are a critical component in host immune responses against tumor. In this work we investigated the role of forkhead box O1 (FoxO1) in the transcriptional regulation in macrophages, which affects the anti-tumor functions of tumor-associated macrophages (TAMs). First, we showed that TAMs expressed reduced levels of FoxO1, which was associated with their protumoral M2 polarization state. The suppression of FoxO1 expression in TAM was induced by the hypoxic condition in the tumor microenviroment. Next, we confirmed that FoxO1 positively regulates MHC-II genes by binding to the promoter region of Ciita gene, the master activator of multiple MHC-II genes. Loss of FoxO1 in TAMs resulted in reduced MHC-II expression. Furthermore, we used FoxO1 conditional knockout mice to show that FoxO1 deficiency in myeloid cells exacerbates tumor growth. These results demonstrate that the protumoral property of TAMs is induced by the hypoxia-triggered FoxO1 deficiency, which could be a potential target of novel anti-tumor therapies. PMID- 29238042 TI - Author Correction: Full-gap superconductivity in spin-polarised surface states of topological semimetal beta-PdBi2. AB - The original version of this article contained an error in Fig. 3. The calculated patterns of quasiparticle interference in the figure were incorrect due to the wrong Wannier transformation in the calculation. This correction does not affect the discussion or the conclusion of the article. PMID- 29238044 TI - Validation of a post-hypomethylating agent failure prognostic model in myelodysplastic syndromes patients treated in a randomized controlled phase III trial of rigosertib vs. best supportive care. PMID- 29238043 TI - BCL-XL overexpression promotes tumor progression-associated properties. AB - By using human melanoma and glioblastoma cell lines and their derivative BCL-XL overexpressing clones, we investigated the role of BCL-XL in aggressive features of these two tumor histotypes. We found that in both models, BCL-XL overexpression increased in vitro cell migration and invasion and facilitated tumor cells to form de novo vasculogenic structures. Furthermore, BCL-XL overexpressing cells exhibited higher tumors sphere formation capacity and expressed higher levels of some stem cell markers, supporting the concept that BCL-XL plays essential roles in the maintenance of cancer stem cell phenotype. BCL-XL expression reduction by siRNA, the exposure to a BCL-XL-specific inhibitor and the use of a panel of human melanoma cell lines corroborated the evidence that BCL-XL regulates tumor progression-associated properties. Finally, the vascular markers and the vasculogenic mimicry were up-regulated in the BCL-XL overexpressing xenografts derived from both tumor histotypes. In conclusion, our work brings further support to the understanding of the malignant actions of BCL XL and, in particular, to the concept that BCL-XL promotes stemness and contributes to the aggressiveness of both melanoma and glioblastoma. PMID- 29238046 TI - Clinically meaningful benefit: real world use compared against the American and European guidelines. PMID- 29238045 TI - RIPK3 promotes adenovirus type 5 activity. AB - Oncolytic adenoviral mutants infect human malignant cells and replicate selectively within them. This induces direct cytotoxicity that can also trigger profound innate and adaptive immune responses. However, the mechanism by which adenoviruses produce cell death remains uncertain. We previously suggested that type 5 adenoviruses, including the E1A CR2 deletion mutant dl922-947, might induce a novel form of programmed death resembling necroptosis. Here we have investigated the roles of core necrosis proteins RIPK1, RIPK3 and MLKL in the cytotoxicity of dl922-947 and other adenovirus serotypes. By electron microscopy, we show that dl922-947 induces similar necrotic morphology as TSZ treatment (TNF alpha, Smac mimetic, zVAD.fmk). However, dl922-947-mediated death is independent of TNF-alpha signalling, does not require RIPK1 and does not rely upon the presence of MLKL. However, inhibition of caspases, specifically caspase-8, induces necroptosis that is RIPK3 dependent and significantly enhances dl922-947 cytotoxicity. Moreover, using CRISPR/Cas9 gene editing, we demonstrate that the increase in cytotoxicity seen upon caspase inhibition is also MLKL dependent. Even in the absence of caspase inhibition, RIPK3 expression promotes dl922-947 and wild-type adenovirus type 5 efficacy both in vitro and in vivo. Together, these results suggest that adenovirus induces a form of programmed necrosis that differs from classical TSZ necroptosis. PMID- 29238048 TI - Cardiac regeneration: A hydrogel-miRNA complex stimulates heart recovery. PMID- 29238049 TI - Milestone 7: A breakthrough for out-of-hospital treatment of thrombosis. PMID- 29238050 TI - Milestone 12: In search of better therapies to prevent device-induced thrombosis. PMID- 29238047 TI - Negative control of the HGF/c-MET pathway by TGF-beta: a new look at the regulation of stemness in glioblastoma. AB - Multiple target inhibition has gained considerable interest in combating drug resistance in glioblastoma, however, understanding the molecular mechanisms of crosstalk between signaling pathways and predicting responses of cancer cells to targeted interventions has remained challenging. Despite the significant role attributed to transforming growth factor (TGF)-beta family and hepatocyte growth factor (HGF)/c-MET signaling in glioblastoma pathogenesis, their functional interactions have not been well characterized. Using genetic and pharmacological approaches to stimulate or antagonize the TGF-beta pathway in human glioma initiating cells (GIC), we observed that TGF-beta exerts an inhibitory effect on c-MET phosphorylation. Inhibition of either mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) or phosphatidylinositol 3 kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway attenuated this effect. A comparison of c-MET-driven and c-MET independent GIC models revealed that TGF-beta inhibits stemness in GIC at least in part via its negative regulation of c-MET activity, suggesting that stem cell (SC) maintenance may be controlled by the balance between these two oncogenic pathways. Importantly, immunohistochemical analyses of human glioblastoma and ex vivo single-cell gene expression profiling of TGF-beta and HGF confirm the negative interaction between both pathways. These novel insights into the crosstalk of two major pathogenic pathways in glioblastoma may explain some of the disappointing results when targeting either pathway alone in human glioblastoma patients and inform on potential future designs on targeted pharmacological or genetic intervention. PMID- 29238051 TI - Milestone 9: Ximelagatran sets the stage for NOACs. PMID- 29238052 TI - Milestone 1: Discovery and purification of heparin. PMID- 29238054 TI - Milestone 5: High-dose heparin for secondary prevention. PMID- 29238053 TI - Trends in rate of acute myocardial infarction among patients aged <30 years. PMID- 29238055 TI - Milestone 14: COMPASS-guided secondary prevention. PMID- 29238056 TI - Milestone 10: Era of the NOACs. PMID- 29238057 TI - Milestone 11: Quest to find the optimal duration. PMID- 29238059 TI - Milestone 6: Birth of the INR. PMID- 29238058 TI - Milestone 4: Low-dose heparin for VTE - prevention is better than cure. PMID- 29238060 TI - Revascularization in 2017: Technical and diagnostic improvements in PCI: more pieces in the puzzle. PMID- 29238061 TI - Milestone 8: Targeting the Xa factor. PMID- 29238062 TI - Milestone 3: Heparin and a VKA - a winning combination. PMID- 29238063 TI - Milestone 13: Putting on the brakes: NOAC antidotes. PMID- 29238065 TI - Milestone 2: Warfarin: from rat poison to clinical use. PMID- 29238064 TI - Role of titin in cardiomyopathy: from DNA variants to patient stratification. AB - Dilated cardiomyopathy (DCM) affects approximately 1 in 250 individuals and is the leading indication for heart transplantation. DCM is often familial, and the most common genetic predisposition is a truncating variation in the giant sarcomeric protein, titin, which occurs in up to 15% of ambulant patients with DCM and 25% of end-stage or familial cases. In this article, we review the evidence for the role of titin truncation in the pathogenesis of DCM and our understanding of the molecular mechanisms and pathophysiological consequences of variation in the gene encoding titin (TTN). Such variation is common in the general population (up to 1% of individuals), and we consider key features that discriminate variants with disease-causing potential from those that are benign. We summarize strategies for clinical interpretation of genetic variants for use in the diagnosis of patients and the evaluation of their relatives. Finally, we consider the contemporary and potential future role for genetic stratification in cardiomyopathy and in the general population, evaluating titin variation as a predictor of outcome and treatment response for precision medicine. PMID- 29238066 TI - Correlation between markers of bone metabolism and vitamin D levels in patients with monoclonal gammopathy of undetermined significance (MGUS). PMID- 29238067 TI - Alternative NHEJ pathway proteins as components of MYCN oncogenic activity in human neural crest stem cell differentiation: implications for neuroblastoma initiation. AB - Neuroblastoma is a cancer of neural crest stem cell (NCSC) lineage. Signaling pathways that regulate NCSC differentiation have been implicated in neuroblastoma tumorigenesis. This is exemplified by MYCN oncogene targets that balance proliferation, differentiation, and cell death similarly in normal NCSC and in high-risk neuroblastoma. Our previous work discovered a survival mechanism by which MYCN-amplified neuroblastoma circumvents cell death by upregulating components of the error-prone non-canonical alternative nonhomologous end-joining (alt-NHEJ) DNA repair pathway. Similar to proliferating stem cells, high-risk neuroblastoma cells have enhanced DNA repair capacity, overcoming DNA damage with higher repair efficiency than somatic cells. Adequate DNA maintenance is required for lineage protection as stem cells proliferate and during tumor progression to overcome oncogene-induced replication stress. On this basis, we hypothesized that alt-NHEJ overexpression in neuroblastoma is a cancer cell survival mechanism that originates from DNA repair systems of NCSC, the presumed progenitor cell of origin. A human NCSC model was generated in which inducible MYCN triggered an immortalized phenotype capable of forming metastatic neuroectodermal tumors in mice, resembling human neuroblastoma. Critical alt-NHEJ components (DNA Ligase III, DNA Ligase I, and Poly [ADP-ribose polymerase 1]) were highly expressed in normal early NCSC, and decreased as cells became terminally differentiated. Constitutive MYCN expression maintained high alt-NHEJ protein expression, preserving the expression pattern of the immature neural phenotype. siRNA knockdown of alt-NHEJ components reversed MYCN effects on NCSC proliferation, invasion, and migration. DNA Ligase III, Ligase I, and PARP1 silencing significantly decreased neuroblastoma markers expression (TH, Phox2b, and TRKB). These results utilized the first human NCSC model of neuroblastoma to uncover an important link between MYCN and alt-NHEJ expression in developmental tumor initiation, setting precedence to investigate alt-NHEJ repair mechanics in neuroblastoma DNA maintenance. PMID- 29238068 TI - MicroRNA-105 is involved in TNF-alpha-related tumor microenvironment enhanced colorectal cancer progression. AB - TNF-alpha is a central proinflammatory cytokine contributing to malignant tumor progression in tumor microenvironment. In this study, we found the upregulation of miR-105 in colorectal cancer was associated with aggressive phenotype, and the enhanced expression of miR-105 was required for TNF-alpha-induced epithelial mesenchymal transition (EMT). The expression of miR-105 was remarkably stimulated by TNF-alpha in a time-dependent manner using real-time qPCR analysis. Inhibition of miR-105 remarkably weakened the aggressive effects of TNF-alpha through preventing the activation of NF-kappaB signaling and the initiation of EMT. Furthermore, miR-105 was demonstrated directly targeted on the 3'-UTRs of RAP2C, a Rap2 subfamily of small GTP-binding protein. Consistently, suppression of RAP2C stimulated the role of miR-105, which dramatically promoted the invasion and metastasis of CRC cells. Thalidomide, a TNF-alpha and NF-kappaB inhibitor, significantly weakened the metastasis and homing capacity of miR-105 overexpressed CRC cells in nude mice. Our investigation initiatively illustrated the modulatory role of miR-105 in TNF-alpha-induced EMT and further CRC metastasis. We also offer a better understanding of TNFalpha-induced metastasis and suggest an effective therapeutic strategy against CRC metastasis. PMID- 29238069 TI - Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have been demonstrated to be anti-inflammatory against various immune disorders through several factors, including indoleamine 2,3-dioxygenase (IDO) and TNF-stimulated gene 6 (TSG-6). However, little is known about the necessity for both of these key immunosuppressive factors. Here we employed the mouse lipopolysaccharide (LPS)-induced acute lung injury (ALI) model, and found that IDO is necessary to achieve the effect of human umbilical cord-derived MSC (hUC-MSC)-based treatment on ALI. Notably, when IDO was deleted or inhibited, the expression of TSG-6 was decreased. This specific IDO-mediated regulation of TSG-6 expression was found to be exerted through its metabolite, kynurenic acid (KYNA), as inhibition of KYNA production led to decreased TSG-6 expression. Importantly, KYNA pretreatment of human MSCs enhanced their therapeutic effect on ALI. Mechanistically, KYNA activates aryl hydrocarbon receptor (AhR), which directly binds to the TSG-6 promoter to enhance TSG-6 expression. Therefore, our study has uncovered a novel link between IDO and TSG 6, and demonstrates that a metabolite of IDO controls the TSG-6-mediated anti inflammatory therapeutic effects of human MSCs. PMID- 29238070 TI - The interplay between mutant p53 and the mevalonate pathway. AB - Missense mutations in the TP53 gene lead to accumulation of dysfunctional TP53 proteins in tumors, showing oncogenic gain-of-function (GOF) activities. Stabilization of mutant TP53 (mutp53) is required for the GOF; however, the mechanisms by which mutp53 promotes cancer progression and how mutp53 stability is regulated are not completely understood. Recent work from our laboratory has identified statins, inhibitors of the mevalonate pathway, as degraders of conformational mutp53. Specific reduction of mevalonate-5-phosphate (MVP), a metabolic intermediate in the mevalonate pathway, by statins or mevalonate kinase (MVK) knockdown triggers CHIP ubiquitin ligase-mediated degradation of conformational mutp53 by inhibiting interaction between mutp53 and DNAJA1, a Hsp40 family member. Thus, the mevalonate pathway contributes to mutp53 stabilization. Given that mutp53 is shown to promote cancer progression by upregulating mRNA expression of mevalonate pathway enzymes by binding to the sterol regulatory element-binding protein 2 (SREBP2) and subsequently increasing activities of mevalonate pathway-associated oncogenic proteins (e.g., Ras, Rho, YAP/TAZ), there is a positive-feedback loop between mutp53 and the mevalonate pathway. Here, we summarize recent evidence linking the mevalonate pathway-mutp53 axis with cancer progression and further discuss the clinical relevance of this axis. PMID- 29238071 TI - APP upregulation contributes to retinal ganglion cell degeneration via JNK3. AB - Axonal injury is a common feature of central nervous system insults. Upregulation of amyloid precursor protein (APP) is observed following central nervous system neurotrauma and is regarded as a marker of central nervous system axonal injury. However, the underlying mechanism by which APP mediates neuronal death remains to be elucidated. Here, we used mouse optic nerve axotomy (ONA) to model central nervous system axonal injury replicating aspects of retinal ganglion cell (RGC) death in optic neuropathies. APP and APP intracellular domain (AICD) were upregulated in retina after ONA and APP knockout reduced Tuj1+ RGC loss. Pathway analysis of microarray data combined with chromatin immunoprecipitation and a luciferase reporter assay demonstrated that AICD interacts with the JNK3 gene locus and regulates JNK3 expression. Moreover, JNK3 was found to be upregulated after ONA and to contribute to Tuj1+ RGC death. APP knockout reduced the ONA induced enhanced expression of JNK3 and phosphorylated JNK (pJNK). Gamma secretase inhibitors prevented production of AICD, reduced JNK3 and pJNK expression similarly, and protected Tuj1+ RGCs from ONA-induced cell death. Together these data indicate that ONA induces APP expression and that gamma secretase cleavage of APP releases AICD, which upregulates JNK3 leading to RGC death. This pathway may be a novel target for neuronal protection in optic neuropathies and other forms of neurotrauma. PMID- 29238072 TI - Tissue transglutaminase in the pathogenesis of heart failure. PMID- 29238073 TI - Stage-dependent therapeutic efficacy in PI3K/mTOR-driven squamous cell carcinoma of the skin. AB - Cutaneous squamous cell carcinoma (SCC) is a recurrent cancer that is prevalent in predisposed subjects such as immunosuppressed patients and patients being treated for other malignancies. Model systems to trial therapies at different stages of SCC development are lacking, therefore precluding efficient therapeutic interventions. Here, we have disrupted the expression of the tumor suppressor GRHL3 to induce loss of PTEN and activation of the PI3K/mTOR signaling pathway in mice and human skin, promoting aggressive SCC development. We then examined the potential for targeting PI3K/mTOR and an oncogenic driver miR-21, alone and in combination, for the prevention and treatment of SCC during the initiation, promotion/progression and establishment stages. Treatment with PI3K/mTOR inhibitors completely prevented tumor initiation, and these inhibitors significantly delayed the course of papilloma progression to malignancy. However, established SCC did not undergo any growth regression, indicating that this therapy is ineffective in established cancers. Mechanistically, the resistant SCCs displayed increased miR-21 expression in mice and humans where antagonists of miR-21 rescued expression levels of GRHL3/PTEN, but the combination of miR-21 antagonism with PI3K/mTOR inhibition resulted in acquired SCC resistance in part via c-MYC and OCT-4 upregulation. In conclusion, our data provide molecular evidence for the efficacy of targeting oncogenic drivers of SCC during the initiation and promotion stages and indicate that combination therapy may induce an aggressive phenotype when applied in the establishment stage. PMID- 29238074 TI - Thank you and goodbye! PMID- 29238076 TI - Climatic suitability, isolation by distance and river resistance explain genetic variation in a Brazilian whiptail lizard. AB - Spatial patterns of genetic variation can help understand how environmental factors either permit or restrict gene flow and create opportunities for regional adaptations. Organisms from harsh environments such as the Brazilian semiarid Caatinga biome may reveal how severe climate conditions may affect patterns of genetic variation. Herein we combine information from mitochondrial DNA with physical and environmental features to study the association between different aspects of the Caatinga landscape and spatial genetic variation in the whiptail lizard Ameivula ocellifera. We investigated which of the climatic, environmental, geographical and/or historical components best predict: (1) the spatial distribution of genetic diversity, and (2) the genetic differentiation among populations. We found that genetic variation in A. ocellifera has been influenced mainly by temperature variability, which modulates connectivity among populations. Past climate conditions were important for shaping current genetic diversity, suggesting a time lag in genetic responses. Population structure in A. ocellifera was best explained by both isolation by distance and isolation by resistance (main rivers). Our findings indicate that both physical and climatic features are important for explaining the observed patterns of genetic variation across the xeric Caatinga biome. PMID- 29238077 TI - A novel linkage-disequilibrium corrected genomic relationship matrix for SNP heritability estimation and genomic prediction. AB - Single nucleotide polymorphism (SNP)-heritability estimation is an important topic in several research fields, including animal, plant and human genetics, as well as in ecology. Linear mixed model estimation of SNP-heritability uses the structures of genomic relationships between individuals, which is constructed from genome-wide sets of SNP-markers that are generally weighted equally in their contributions. Proposed methods to handle dependence between SNPs include, "thinning" the marker set by linkage disequilibrium (LD)-pruning, the use of haplotype-tagging of SNPs, and LD-weighting of the SNP-contributions. For improved estimation, we propose a new conceptual framework for genomic relationship matrix, in which Mahalanobis distance-based LD-correction is used in a linear mixed model estimation of SNP-heritability. The superiority of the presented method is illustrated and compared to mixed-model analyses using a VanRaden genomic relationship matrix, a matrix used by GCTA and a matrix employing LD-weighting (as implemented in the LDAK software) in simulated (using real human, rice and cattle genotypes) and real (maize, rice and mice) datasets. Despite of the computational difficulties, our results suggest that by using the proposed method one can improve the accuracy of SNP-heritability estimates in datasets with high LD. PMID- 29238078 TI - The genetic architecture of ecological adaptation: intraspecific variation in host plant use by the lepidopteran crop pest Chloridea virescens. AB - Intraspecific variation in ecologically important traits is a cornerstone of Darwin's theory of evolution by natural selection. The evolution and maintenance of this variation depends on genetic architecture, which in turn determines responses to natural selection. Some models suggest that traits with complex architectures are less likely to respond to selection than those with simple architectures, yet rapid divergence has been observed in such traits. The simultaneous evolutionary lability and genetic complexity of host plant use in the Lepidopteran subfamily Heliothinae suggest that architecture may not constrain ecological adaptation in this group. Here we investigate the response of Chloridea virescens, a generalist that feeds on diverse plant species, to selection for performance on a novel host, Physalis angulata (Solanaceae). P. angulata is the preferred host of Chloridea subflexa, a narrow specialist on the genus Physalis. In previous experiments, we found that the performance of C. subflexa on P. angulata depends on many loci of small effect distributed throughout the genome, but whether the same architecture would be involved in the generalist's adoption of P. angulata was unknown. Here we report a rapid response to selection in C. virescens for performance on P. angulata, and establish that the genetic architecture of intraspecific variation is quite similar to that of the interspecific differences in terms of the number, distribution, and effect sizes of the QTL involved. We discuss the impact of genetic architecture on the ability of Heliothine moths to respond to varying ecological selection pressures. PMID- 29238082 TI - Neurodegenerative disease: Tackling tauopathy. PMID- 29238083 TI - Motor systems: Cortical instructions. PMID- 29238080 TI - Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun. AB - Mitogen-activated protein kinases (MAPKs) are conserved protein kinases that regulate a variety of important cellular signaling pathways. Among them, c-Jun N terminal kinases (JNK) are known to be activated by various environmental stresses including virus infections. Previously, activation of the JNK pathway has been detected in cells infected with several coronaviruses. However, detailed characterization of the pathway as well as its implication in host-virus interactions has not been fully investigated. Here we report that the JNK pathway was activated in cells infected with the avian coronavirus infectious bronchitis virus (IBV). Of the two known upstream MAPK kinases (MKK), MKK7, but not MKK4, was shown to be responsible for IBV-induced JNK activation. Moreover, knockdown and overexpression experiments demonstrated that JNK served as a pro-apoptotic protein during IBV infection. Interestingly, pro-apoptotic activity of JNK was not mediated via c-Jun, but involved modulation of the anti-apoptotic protein B cell lymphoma 2 (Bcl2). Taken together, JNK constitutes an important aspect of coronavirus-host interaction, along with other MAPKs. PMID- 29238079 TI - Dorsal root ganglion neurons regulate the transcriptional and translational programs of osteoblast differentiation in a microfluidic platform. AB - Innervation by the sensory nervous system plays a key role in skeletal development and in orchestration of bone remodeling and regeneration. However, it is unclear how and in which bone cells can sensory nerves act to control these processes. Here, we show a microfluidic coculture system comprising dorsal root ganglion (DRG) neurons and mesenchymal stem cells (MSCs) that more faithfully represents the in vivo scenario of bone sensory innervation. We report that DRG neurons promote the osteogenic differentiation capacity of MSCs, by mediating the increase of alkaline phosphatase activity and the upregulation of osteoblast specific genes. Furthermore, we show that DRG neurons have a positive impact on Cx43 levels in MSCs during osteoblastogenesis, especially at an early stage of this process. Conversely, we described a negative impact of DRG neurons on MSCs N cadherin expression at a later stage. Finally, we demonstrate a cytoplasmic accumulation of beta-catenin translocation into the nucleus, and subsequently Lymphoid Enhancer Binding Factor 1-responsive transcriptional activation of downstream genes in cocultured MSCs. Together, our study provides a robust body of evidence that the direct interaction of DRG neurons with MSCs in a bone-like microenvironment leads to an enhancement of osteoblast differentiation potential of MSCs. The osteogenic effect of DRG neurons on MSCs is mediated through the regulation of Cx43 and N-cadherin expression and activation of the canonical/beta catenin Wnt signaling pathway. PMID- 29238084 TI - Neuronal circuits: A risky connection. PMID- 29238081 TI - Pyridoxine 5'-phosphate oxidase is a novel therapeutic target and regulated by the TGF-beta signalling pathway in epithelial ovarian cancer. AB - Pyridoxine 5'-phosphate oxidase (PNPO) is an enzyme that converts pyridoxine 5' phosphate into pyridoxal 5'-phosphate (PLP), an active form of vitamin B6 implicated in several types of cancer. However, the role of PNPO and its regulatory mechanism in epithelial ovarian cancer (EOC) are unknown. In the present study, PNPO expression in human ovarian tumour tissue and its association with the clinicopathological features of patients with EOC were examined. Further, the biological function of PNPO in EOC cells and in xenograft was evaluated. We demonstrated for the first time that PNPO was overexpressed in human EOC. Knockdown of PNPO induced EOC cell apoptosis, arrested cell cycle at G2/M phase, decreased cell proliferation, migration and invasion. Xenografts of PNPO-shRNA-expressing cells into the nude mouse attenuated tumour growth. PNPO at mRNA and protein levels in EOC cells was decreased after transforming growth factor-beta1 (TGF-beta1) treatment. The inhibitory effect of TGF-beta1 on PNPO expression was abolished in the presence of SB-431542, a TGF-beta type I receptor kinase inhibitor. Moreover, we found that TGF-beta1-mediated PNPO expression was at least in part through the upregulation of miR-143-3p. These data indicate a mechanism underlying PNPO regulation by the TGF-beta signalling pathway. Furthermore, PLP administration reduced PNPO expression and decreased EOC cell proliferation, suggesting a feedback loop between PLP and PNPO. Thus, our findings reveal that PNPO can serve as a novel tissue biomarker of EOC and may be a potential target for therapeutic intervention. PMID- 29238086 TI - Axo-myelinic neurotransmission: a novel mode of cell signalling in the central nervous system. AB - This corrects the article DOI: 10.1038/nrn.2017.128. PMID- 29238087 TI - Synaptic transmission: Closer encounters. AB - This corrects the article DOI: 10.1038/nrn.2017.150. PMID- 29238088 TI - Neurotransmission: A discrete form of secretion. PMID- 29238089 TI - Gene expression: Evolving expression patterns. PMID- 29238090 TI - Neuroimmunology: A painful release. PMID- 29238085 TI - Communication dynamics in complex brain networks. AB - Neuronal signalling and communication underpin virtually all aspects of brain activity and function. Network science approaches to modelling and analysing the dynamics of communication on networks have proved useful for simulating functional brain connectivity and predicting emergent network states. This Review surveys important aspects of communication dynamics in brain networks. We begin by sketching a conceptual framework that views communication dynamics as a necessary link between the empirical domains of structural and functional connectivity. We then consider how different local and global topological attributes of structural networks support potential patterns of network communication, and how the interactions between network topology and dynamic models can provide additional insights and constraints. We end by proposing that communication dynamics may act as potential generative models of effective connectivity and can offer insight into the mechanisms by which brain networks transform and process information. PMID- 29238091 TI - Behavioural neuroscience: Regulating roaming. PMID- 29238092 TI - Sleep: Let sleeping flies lie. PMID- 29238093 TI - circHIPK2-mediated sigma-1R promotes endoplasmic reticulum stress in human pulmonary fibroblasts exposed to silica. AB - Silicosis is characterized by fibroblast accumulation and excessive deposition of extracellular matrix. Although the roles of SiO2-induced chemokines and cytokines released from alveolar macrophages have received significant attention, the direct effects of SiO2 on protein production and functional changes in pulmonary fibroblasts have been less extensively studied. Sigma-1 receptor, which has been associated with cell proliferation and migration in the central nervous system, is expressed in the lung, but its role in silicosis remains unknown. To elucidate the role of sigma-1 receptor in fibrosis induced by silica, both the upstream molecular mechanisms and the functional effects on cell proliferation and migration were investigated. Both molecular biological assays and pharmacological techniques, combined with functional experiments, such as migration and proliferation, were applied in human pulmonary fibroblasts from adults to analyze the molecular and functional changes induced by SiO2. SiO2 induced endoplasmic reticulum stress in association with enhanced expression of sigma-1 receptor. Endoplasmic reticulum stress promoted migration and proliferation of human pulmonary fibroblasts-adult exposed to SiO2, inducing the development of silicosis. Inhibition of sigma-1 receptor ameliorated endoplasmic reticulum stress and fibroblast functional changes induced by SiO2. circHIPK2 is involved in the regulation of sigma-1 receptor in human pulmonary fibroblasts-adult exposed to SiO2. Our study elucidated a link between SiO2-induced fibrosis and sigma-1 receptor signaling, thereby providing novel insight into the potential use of sigma-1 receptor/endoplasmic reticulum stress in the development of novel therapeutic strategies for silicosis treatment. PMID- 29238094 TI - Energy expenditure after spinal cord injury in people with motor-complete tetraplegia or motor-complete paraplegia. AB - STUDY DESIGN: Cross-sectional. OBJECTIVES: This study aimed to describe and compare VO2 and energy expenditure at rest (REE) and during standardized sedentary, non-exercise physical activity, and exercise activities, in people with motor-complete tetraplegia (C5-C8). Further, REE and energy expenditure (EE) for the different activities were compared to data from a reference group of people with motor-complete paraplegia (T7-T12). SETTING: Sweden. METHODS: The sample of people with motor-complete tetraplegia consisted of 26 adults (seven women) with SCI, C5-C8 AIS A-B. REE and EE for the different activities were measured with indirect calorimetry. The results were further compared to people with motor-complete paraplegia. RESULTS: Resting VO2 was 2.57 ml O2 kg-1 min-1, 2.54 for men and 2.60 for women. The VO2 or activity energy expenditure related to body weight increased three to four times during non-exercise physical activity compared to sedentary activities for the people with motor-complete tetraplegia, and up to six times during exercise activity. No significant differences were seen in resting or sedentary activity VO2 between the people with motor-complete tetraplegia and those with motor-complete paraplegia. Activities of daily life revealed no or small differences in VO2, except for setting a table, while the people with tetraplegia had ~50% lower VO2 during exercise activities. CONCLUSIONS: Non-exercise physical activities of daily life may be significant for increasing total daily EE in people with motor-complete tetraplegia. This might act to motivate the individual, and might be clinically important when designing adapted lifestyle intervention programs for the target group. PMID- 29238095 TI - Increased psychological distress among individuals with spinal cord injury is associated with central neuropathic pain rather than the injury characteristics. AB - STUDY DESIGN: Cross-sectional study. OBJECTIVES: Central neuropathic pain (CNP) is common after spinal cord injury (SCI). The psychological impact of CNP is not clear. Previous studies reported depression and pain catastrophizing among patients with SCI and CNP; however, the lack of control groups prevented discerning whether these were attributed to CNP or to the SCI itself. The aim was to examine the psychological distress among individuals with SCI with and without CNP and controls to evaluate its impact and possible source. SETTING: Outpatient clinic of a large rehabilitation center. METHODS: Individuals with SCI and CNP (n = 27) and without CNP (n = 23), and able-bodied controls (n = 20) participated. Data collection included sociodemographics, SCI characteristics, and level of post-traumatic stress disorder (PTSD), anxiety, stress, depression, and pain catastrophizing. The sensory, affective, and cognitive dimensions of CNP were analyzed. RESULTS: Individuals with SCI and CNP exhibited elevated levels of PTSD, anxiety, stress, depression, and pain catastrophizing compared to the two control groups, which presented similar levels. The psychological variables among the CNP group correlated positively only with the affective dimension of CNP. Neither CNP nor the psychological variables correlated with SCI characteristics. CONCLUSIONS: Irrespective of CNP intensity, the affective dimension (suffering) is associated with increased psychological distress. Perhaps individual differences in the response to SCI and/or individual traits rather than the mere exposure to SCI may have a role in the emergence of CNP and psychological distress/mood dysfunction. Rehabilitation programs should prioritize stress management and prevention among individuals with SCI and CNP. PMID- 29238096 TI - Assembly of a mononuclear ferrous site using a bulky aldehyde-imidazole ligand. AB - A new iron(II) complex has been prepared and characterized. [Fe(TrImA)2(OTf)2] (1, TrImA = 1-Tritylimidazole-4-carboxaldehyde). The solid state structure of 1 has been determined by X-ray crystallography. Compound 1 crystallizes in monoclinic space group P21/c, with a = 10.8323(18) A, b = 8.1606(13) A and c = 24.818(4) A. The iron center is coordinated to two imidazole groups, two pendant aldehyde-derived carbonyl oxygens and two triflate oxygens. The complex is high spin between 300 and 20 K as indicated by variable field variable temperature magnetic measurements. A fit of the magnetic data yielded g = 2.17 and D = 4.05 cm-1. A large HOMO-LUMO gap energy (4.49 eV) exists for 1 indicating high stability. PMID- 29238097 TI - A synthesis of European seahorse taxonomy, population structure, and habitat use as a basis for assessment, monitoring and conservation. AB - Accurate taxonomy, population demography, and habitat descriptors inform species threat assessments and the design of effective conservation measures. Here we combine published studies with new genetic, morphological and habitat data that were collected from seahorse populations located along the European and North African coastlines to help inform management decisions for European seahorses. This study confirms the presence of only two native seahorse species (Hippocampus guttulatus and H. hippocampus) across Europe, with sporadic occurrence of non native seahorse species in European waters. For the two native species, our findings demonstrate that highly variable morphological characteristics, such as size and presence or number of cirri, are unreliable for distinguishing species. Both species exhibit sex dimorphism with females being significantly larger. Across its range, H. guttulatus were larger and found at higher densities in cooler waters, and individuals in the Black Sea were significantly smaller than in other populations. H. hippocampus were significantly larger in Senegal. Hippocampus guttulatus tends to have higher density populations than H. hippocampus when they occur sympatrically. Although these species are often associated with seagrass beds, data show both species inhabit a wide variety of shallow habitats and use a mixture of holdfasts. We suggest an international mosaic of protected areas focused on multiple habitat types as the first step to successful assessment, monitoring and conservation management of these Data Deficient species. PMID- 29238098 TI - Mesh hiatal reinforcement in laparoscopic Nissen fundoplication for neurologically impaired children is safe and feasible. AB - Fundoplication is a standard treatment for gastroesophageal reflux disease (GERD) in neurologically impaired children. However, it has a high recurrence rate due to wrap herniation and disruption resulting from the failure or enlargement of the esophageal hiatus suture site. In adult patients with GERD, reinforcement of the sutured esophageal hiatus with a mesh significantly reduces the recurrence rate after surgery for esophageal hiatus hernia. In children, there are no big series of fundoplication with mesh reinforcement. Therefore, we confirmed the safety and feasibility of an expanded polytetrafluoroethylene mesh hiatal reinforcement with fundoplication as an additional procedure for neurologically impaired children. Neurologically impaired children (age, >=5 years) who underwent laparoscopic fundoplication and gastrostomy at our institution between 2011 and 2013 were included in this study. The operative time, bleeding amount, complications, and recurrence were retrospectively evaluated. Thirteen patients were included in this study. The mean age at operation was 147.2 +/- 37.8 months, and mean body weight was 18.5 +/- 7.9 kg. The complication rate of epilepsy and scoliosis was 100% and 84.6%, respectively. The operative time was 265.1 +/- 38.1 minutes, and mean blood loss was 26.5 +/- 34.7 mL. There were no peri- or postoperative complications. None of the patients showed recurrent symptoms such as repeated vomiting and aspiration pneumonia during the mean follow-up period of 2.5 +/- 0.6 years. The mesh hiatal reinforcement with fundoplication for neurologically impaired children is safe and feasible. PMID- 29238099 TI - 8-F balloon guide catheter for embolization of anterior circulation aneurysms: an institutional experience in 152 patients. AB - The use of 8-F balloon guide catheter (BGC) for proximal flow control was previously shown to prevent distal embolic complications during mechanical clot retrieval in patients with acute ischemic stroke. In this retrospective study, the utility of 8-F BGCs for proximal flow control during endovascular coiling of anterior circulation aneurysms was investigated. Patients who underwent endovascular coiling for anterior circulation aneurysms between August 2013 and December 2016 were retrospectively analyzed. Among a total of 152 patients included in this series, 64 patients presented with aneurysmal rupture, whereas the aneurysms were detected incidentally or due to mass effects in the remaining patients. 8-F BGCs were successfully navigated in all patients. The balloon was inflated during navigation in 19 patients. Inflation of the catheter balloon during coil embolization was required in 34 patients; this was performed as an emergency maneuver in six of these patients. Thromboembolic complications occurred in one patient. 8-F BGC can be effectively used for proximal flow control during endovascular treatment of anterior circulation aneurysms. The other advantages included improved navigation of tortuous arterial anatomy, coil stabilization during aneurysmal coiling, and freedom to utilize aneurysmal neck remodeling balloons for additional adjunctive techniques or to deploy rescue stents. This novel approach might be safely and effectively used in patients undergoing endovascular treatment for anterior circulation aneurysms. PMID- 29238100 TI - Clinical outcomes and quality of life after surgery for dilated ascending aorta at the time of aortic valve replacement; wrapping versus graft replacement. AB - Wrapping and graft replacement are two optional procedures for the treatment of dilated ascending aorta at the time of aortic valve replacement (AVR). Wrapping is considered less invasive. The aim of this study was to compare the short- and long-term clinical outcomes as well as the long-term quality of life in patients undergoing these two procedures.This study enrolled 40 consecutive patients with dilated ascending aorta who had undergone either wrapping (WAA group, n=20) or replacement (RAA group, n=20) of the ascending aorta at the time of AVR. Short term outcomes, long-term deaths, and aortic events were evaluated, as was quality of life using the SF-36 Short Form. Long-term maximal proximal aortic diameter was also obtained.There were no early deaths in either group. Pump time was shorter, and transfusion (55% vs. 95%, p=0.035) and postoperative atrial fibrillation (5% vs. 30%, p=0.036) rates were lower, in the WAA than in the RAA group. At a mean follow-up of 4.9 years, the overall 5 year survival rates in the WAA and RAA groups were 78.1% and 87.5%, respectively. There were no significant between group differences in SF-36 scores in any subcategory of this survey. Long term maximal aortic diameter remained stable in both groups. Both surgical interventions for dilated ascending aorta at the time of AVR yield favorable and comparable results in patients with suitable anatomy. Furthermore, we found no differences in quality of life between these procedures. PMID- 29238101 TI - Feasibility of the unilateral-flange stent for the treatment of benign pancreatic duct stricture: a pilot study. AB - Endoscopic placement of the plastic stent has been adopted as an initial treatment for chronic pancreatitis with pancreatic duct stricture. Stent fracture while attempting removal is one of the complications of stent exchange. The use of the unilateral-flange stent in these patients has never been reported. We investigated the outcomes associated with the use of this stent with regard to stent exchange and stent-related adverse events. From 2011 to 2015, 9 patients with chronic pancreatitis and main pancreatic duct (MPD) stricture treated with the unilateral-flange stent were included. Eleven endoscopic treatment sessions, 53 endoscopic stent deployments or exchange procedures were analyzed. Technical success rate was 100%. Forty-eight stents were exchanged on a regular basis in 1 to 6-month intervals. Another 5 stent exchange procedures were urgently performed due to stent obstruction and caused pancreatitis (n=2), symptomatic external stent migration (n=2), and concurrent cholangitis (n=1). The rate of symptomatic migration was 3.7%. The mean duration for stent exchange was 29 minutes and no stent fracture occurred during the procedure. Of 11 endoscopic treatment sessions, 7 were successful, 3 were changed to the metallic stents, and 1 was lost to follow-up. According to this study, unilateral-flange stent placement for benign MPD stricture is technically feasible and effective. Stent removal during the exchange period is unchallenging and without stent fracture. PMID- 29238102 TI - Prevention and prediction of postoperative bowel bladder disorder using an anal plug electrode with Tc-MsEP monitoring during spine surgery. AB - A retrospective study was performed to examine the efficacy of intraoperative monitoring of the external anal sphincter (EAS) muscle-evoked potential after a transcranial muscle-action potential (Tc-MsEP) in spinal cord surgery, and to evaluate alarm points for EAS waveform deterioration related to postoperative bowel bladder disorder (BBD). BBD is caused by damage to the hypogastric, pelvic, and pudendal nerves and leads to a significant reduction in quality of life. Intraoperative Tc-MsEP monitoring using the EAS is common to prevent neurological deficit, but the relationship of BBD with intraoperative monitoring of the EAS has not been examined. Waveform derivation from the EAS using a plug-type surface electrode was investigated in 123 spine surgeries in which Tc-MsEP was recorded intraoperatively outside the anal sphincter. An acceptable baseline waveform from the EAS was detected in 105 of the 123 cases (85.3%). Preoperative BBD was present in 16 cases, postoperative BBD occurred in 8 cases, and intraoperative waveform deterioration from the EAS was detected in 25 cases. The derivation rate was significantly lower in cases with preoperative BBD compared to those without BBD (62.5% vs. 88.9%, p<0.01). Waveform deterioration from the EAS had a sensitivity of 100%, specificity of 93.0%, positive predictive value of 50%, and negative predictive value of 100% for detection of postoperative BBD. All postoperative BBD was detected with an EAS amplitude decrease to <30% of baseline. Therefore, in spine surgery, a Tc-MsEP intraoperative EAS amplitude decrease to <30% of the control waveform may be useful for prediction of postoperative BBD. PMID- 29238103 TI - Clinical features of patients with infective endocarditis presenting to the emergency department: a retrospective case series. AB - Infective endocarditis (IE) is an uncommon clinical problem with diverse, nonspecific presentations. Therefore, information on the clinical features of IE patients presenting to emergency departments (EDs) is scarce. To descriptively analyze the pertinent data, we performed a retrospective chart review. We reviewed 15 consecutive IE patients admitted directly from ED in a university hospital in Japan between 2013 and 2015. We compared their clinical features with those of 14 IE patients admitted during the same period without ED presentations. Patients admitted directly from ED were older than those without ED presentations (median, 78 vs. 52 years; adjusted p = 0.036) and were more likely to have come without referrals (referral rate, 21% vs. 86%; adjusted p = 0.012). These patients were less likely to have been treated with antibiotics before admission (antibiotic-exposure rate, 7% vs. 64%; adjusted p = 0.013) and had earlier blood culture positivity (median, 2 vs. 5 days; adjusted p = 0.012), resulting in earlier diagnosis (median duration of symptoms before diagnosis, 5 vs. 30 days; adjusted p = 0.012). Other clinical features, including causative pathogens and IE-related comorbidities, were similar between the groups, consistent with previous a nationwide Japanese study. In conclusion, most IE patients admitted to the hospital from ED were elderly, were antibiotic-naive, and had presented without a referral. Relatively few patients had classical presentations of IE. Given the limited data, more research is needed to confirm that IE patients presenting to EDs constitute a unique group of elderly patients with specific clinical features. PMID- 29238104 TI - Indole-3-propionic acid suppresses indoxyl sulfate-induced expression of fibrotic and inflammatory genes in proximal tubular cells. AB - Indoxyl sulfate (IS) induces fibrosis and inflammation in kidneys via oxidative stress through the induction of transforming growth factor-beta1 (TGF-beta1) and monocyte chemotactic protein-1 (MCP-1). Furthermore, IS is a potent endogenous agonist for aryl hydrocarbon receptor (AHR), which regulates the transcription of genes such as cytochrome P450 (CYP) 1A1. Indole-3-propionic acid (IPA) is an antioxidant and has been reported to be neuroprotective. We determined whether IPA suppresses IS-induced expression of AHR, CYP1A1, TGF-beta1, and MCP-1 in proximal tubular cells. The effects of IS on the expression of AHR, CYP1A1, TGF beta1, and MCP-1 were studied using normotensive rats and hypertensive rats. The effects of IPA on IS-induced expression of AHR, CYP1A1, TGF-beta1, and MCP-1 were studied using proximal tubular cells (HK-2). Furthermore, the effects of IPA on IS-induced expression and phosphorylation of signal transducer and activator of transcription 3 (Stat3) were studied in HK-2 cells. Administration of IS induced the expression of AHR, CYP1A1, TGF-beta1, and MCP-1 in the tubular cells of rat kidneys. IPA significantly suppressed IS-induced mRNA and protein expression of AHR, CYP1A1, TGF-beta1, and MCP-1 in HK-2 cells. IPA suppressed the IS-induced expression and phosphorylation of Stat3 in HK-2 cells. Furthermore, knockdown of Stat3 inhibited the IS-induced mRNA and protein expression of AHR, CYP1A1, TGF beta1, and MCP-1 in HK-2 cells. In conclusion, IPA suppressed the IS-induced expression of AHR, CYP1A1, TGF-beta1, and MCP-1 through suppression of Stat3 in proximal tubular cells. Thus, IPA suppresses IS-induced expression of fibrotic and inflammatory genes in proximal tubular cells. PMID- 29238105 TI - Relationship between patellar mobility and patellofemoral joint cartilage degeneration after anterior cruciate ligament reconstruction. AB - Patellofemoral cartilage degeneration is a potential complication of anterior cruciate ligament reconstruction (ACLR) surgery. Hypomobility of the patella in the coronal plane is often observed after ACLR. Few studies, however, have examined the relationship between cartilage degeneration in the patellofemoral joint and mobility after ACLR. The present study investigated 1) the coronal mobility of the patella after ACLR, 2) the relationship between patellar mobility and cartilage degeneration of the patellofemoral joint, and 3) the relationship between patellar mobility and knee joint function after ACLR. Forty patients who underwent medial hamstring-based ACLR participated in the study. Lateral and medial patellar displacements were assessed with a modified patellofemoral arthrometer, and the absolute values of the displacements were normalized to patient height. The International Cartilage Repair Society (ICRS) cartilage injury classification of the patellar and femoral (trochlear) surfaces, and the Lysholm Knee Scoring Scale were used to evaluate knee function. Lateral and medial patellar displacements were reduced compared with the non-operated knee at the second-look arthroscopy and bone staple extraction operation (second operation; 24.4 +/- 7.9 months after ACLR, P<0.01). The ICRS grades of the patellofemoral joint (patella and trochlea) were significantly worse than those pre-ACLR. Neither lateral nor medial patellar mobility, however, were significantly correlated with the ICRS grade or the Lysholm score. Although patellar mobility at approximately 2 years after ACLR was decreased compared to the non-operated knee, small displacement of the patella was not related to cartilage degeneration or knee joint function at the time of the second operation. PMID- 29238106 TI - Measures and effects on prevention of fall: the role of a fall working group at a university hospital. AB - Fall in hospitalized patients can cause trauma and fractures, which can reduce ADL and QOL, whereas prevention of fall decreases medical expenses. The purpose of this study is to examine prevention of fall due to intervention from a fall working group established in our hospital. The working group focused on three main points. First, colored wrist bands for patients classified as grade 3 risk for fall are used to alert medical staff. Second, information on fall prevention was distributed to patients. Third, standardization of two bed fences and reduced use of slippers for inpatients have been introduced. We investigated falls during hospitalization for 5 years from April 2012 to March 2017. The risk of fall was evaluated as grade 1 (mild) to grade 3 (severe) using an assessment sheet developed by the working group. The incidence of fall decreased over time, with a significant decrease from 2.1% in 2012 to 1.3% in 2016 (p<0.01). Slipper use in fall cases showed a significant decrease from 45.8% in 2012 to 11.0% in 2016 (p<0.01). Among all falls, the percentage of cases with fall risks grade 1 and 2 decreased, while that for grade 3 risk increased from 32.0% in 2012 to 40.3% in 2016 (p<0.05). These results support the efforts of the fall working group have reduced the overall incidence of fall. However, fall in patients with grade 3 risk has not decreased, which suggests that better sharing of information is needed for patients at high risk for fall. PMID- 29238107 TI - Hemispheric divided coiling technique for coil embolization of middle- and large sized intracranial aneurysms. AB - Despite major developments in treating intracranial aneurysms by endovascular coil embolization, complete occlusion of the entire aneurysmal neck remains a problem. We present a novel endovascular strategy for middle- and large sized aneurysms called the "hemispheric divided coiling technique" and compare the short-term follow-up results of this technique with those of conventional coil embolization. Ten patients (mean age, 69.7 +/- 9.7 years) with middle- or large sized ruptured or unruptured intracranial aneurysms (mean maximum aneurysmal diameter, 12.09 +/- 3.6 mm) were treated by the hemispheric divided coiling technique, in combination with various adjunctive techniques. We compared the initial occlusion grade, volume embolization ratio, and recurrence rate in this group of patients (hemispheric group) with the results from 20 previous cases (conventional group: mean age, 62.8 +/- 9.8 years; mean maximum aneurysmal diameter, 11.43 +/- 3.5 mm). The mean volume embolization ratio of the hemispheric group was significantly higher than that of the conventional group (42.3% vs. 31.1%). The hemispheric divided coiling technique achieved a high volume embolization ratio for middle- and large sized intracranial aneurysms, with a low recurrence rate. PMID- 29238108 TI - Medical facility statistics in Japan. AB - Medical facility statistics provide essential information to policymakers, administrators, academics, and practitioners in the field of health services. In Japan, the Health Statistics Office of the Director-General for Statistics and Information Policy at the Ministry of Health, Labour and Welfare is generating these statistics. Although the statistics are widely available in both Japanese and English, the methodology described in the technical reports are primarily in Japanese, and are not fully described in English. This article aimed to describe these processes for readers in the English-speaking world. The Health Statistics Office routinely conduct two surveys called the Hospital Report and the Survey of Medical Institutions. The subjects of the former are all the hospitals and clinics with long-term care beds in Japan. It comprises a Patient Questionnaire focusing on the numbers of inpatients, admissions, discharges, and outpatients in one month, and an Employee Questionnaire, which asks about the number of employees as of October 1. The Survey of Medical Institutions consists of the Dynamic Survey, which focuses on the opening and closing of facilities every month, and the Static Survey, which focuses on staff, facilities, and services as of October 1, as well as the number of inpatients as of September 30 and the total number of outpatients during September. All hospitals, clinics, and dental clinics are requested to submit the Static Survey questionnaire every three years. These surveys are useful tools for collecting essential information, as well as providing occasions to implicitly inform facilities of the movements of government policy. PMID- 29238109 TI - Present and future roles of FDG-PET/CT imaging in the management of gastrointestinal cancer: an update. AB - Positron emission tomography/computed tomography (PET/CT) integrated with 2 [18F]fluoro-2-deoxy-D-glucose (FDG) is a useful tool for acquisition of both glucose metabolism and anatomic imaging data, as only a single device and one diagnostic session is required, thus opening a new field in clinical oncologic imaging. FDG-PET/CT has been successfully used for initial staging, restaging, assessment of early treatment response, evaluation of metastatic disease response, and prognostication of intestinal cancer as well as various malignant tumors. We reviewed the current status and role of FDG-PET/CT for management of patients with esophageal cancer, gastric cancer, and colorectal cancer, with focus on both its usefulness and limitations. PMID- 29238110 TI - Intrawound Vancomycin powder as the prophylaxis of surgical site infection after invasive spine surgery with a high risk of infection. AB - Surgical site infections (SSIs) are one of the most serious complications in spine surgery. We investigated the efficacy of locally administered vancomycin (VCM) powder for prophylaxis on SSI after invasive spine surgery. We retrospectively studied 174 consecutive patients who underwent spine surgery. In patients of the VCM group (n = 81), VCM powder was administered in the wound before closing wound. Patients who did not receive VCM treatment were set as a control group (n = 93). We compared the patients' background, operation time, intraoperative blood loss, usage of implants, presence of deep SSI, and side effects between the two groups. There were no significant differences between the groups in age, gender, and BMI. The operation time and the intraoperative blood loss were longer and greater in the VCM group than in the control group (P < 0.005, P < 0.001, respectively). Implants were used in 85% of the VCM group, and in 31% of the control group (P < 0.001). Deep SSI was not observed in the VCM group, whereas it was observed in 4 patients in the control group. No side effects were observed in any of the cases. In conclusion, surgeons applied VCM for cases which were invasive or had a high risk of infection. However, deep SSI was not observed in anyone in the VCM group. The intrawound administration of VCM might be effective to prevent SSI in cases with high risks of infection. PMID- 29238111 TI - Distal radius nonunion after volar locking plate fixation of a distal radius fracture: a case report. AB - We describe a 59-year-old man who had nonunion of a right distal radius fracture after volar locking plate fixation. He underwent open reduction and internal fixation with a volar locking plate system for a dorsally displaced, unstable distal radius fracture at a previous hospital 5 months ago. Radiographs of the injured wrist showed nonunion of the distal radius with 1.5-mm ulnar minus variance. Radiographs of the unaffected wrist showed 3.5-mm ulnar plus variance. Intraoperative findings of surgical revision showed an unstable nonunion; thus, debridement of the nonunion, autogenous inlay bone grafting, and internal fixation using another type of volar locking plate system were performed. Healing of the re-operative site was confirmed radiographically 3 months postoperatively. We considered that volar locking plate fixation with excessive distraction of the fracture may lead to nonunion. PMID- 29238112 TI - Crevice sign as an indicator of plaque laceration associated with postoperative severe thromboembolism after carotid artery stenting: a case report. AB - Carotid artery stenting (CAS) is increasingly utilized in patients with carotid artery stenosis. Various intraprocedural and postprocedural complications have been reported in the literature. We present a case of symptomatic major thromboembolism after CAS. The intraprocedural angiogram showed extraordinary slow filling of the contrast medium into the plaque, which we named as "crevice sign." An 83-year-old man presented repeat right amaurosis fugax for 6 months. The radiological examinations revealed 85% stenosis of the origin of the right internal carotid artery. The patient underwent right CAS. The procedure was performed without any problems; however, the angiogram showed slow filling of contrast medium into the carotid plaque through the stent (crevice sign). Sixty minutes later in the ward, the patient presented sudden onset of left hemiparesis and aphasia. Emergency catheter angiography did not show in-stent thrombus, major artery occlusion, or the crevice sign. Magnetic resonance imaging on the next day revealed wide acute infarction of the right cerebral hemisphere. Physicians should be aware of the intraprocedural crevice sign so that a subsequent catastrophic ischemic event can be prevented. PMID- 29238113 TI - Religious Change over the Generations in an Extremely Secular Society: The Case of Sweden. AB - The main argument of this paper is that religious change caused by modifying supply in the religious market takes time due to intergenerational value change. Unlike previous research, this study suggests that not only do religious agents on the supply side need time to adjust, but that the time lag is probably even greater among individuals on the demand side of the religious market. Using time series data, the study demonstrates that, despite shrinking church attendance, interest in religious concepts such as "salvation" has increased in the generations born after 1970 in Sweden. Describing the transformation of the Swedish religious market from a regulated religious monopoly before 1970 to an increasingly deregulated and competitive religious supply since 1970, the study explains this revival in religious interest on the part of generations whose formative years were after 1970. As these generations replace previous generation with less religious interest, religious interest is rising in the Swedish population. The conclusion holds even when controlling for period and lifecycle effects, as well as alternative explanations of religious change such as increased migration and the existential security thesis. PMID- 29238114 TI - Quantitative evaluation of performance of 3D printed lenses. AB - We present an analysis of the shape, surface quality, and imaging capabilities of custom 3D printed lenses. 3D printing technology enables lens prototypes to be fabricated without restrictions on surface geometry. Thus, spherical, aspherical and rotationally non-symmetric lenses can be manufactured in an integrated production process. This technique serves as a noteworthy alternative to multistage, labor-intensive, abrasive processes such as grinding, polishing and diamond turning. Here, we evaluate the quality of lenses fabricated by Luxexcel using patented Printoptical(c) technology that is based on an inkjet printing technique by comparing them to lenses made with traditional glass processing technologies (grinding, polishing etc.). The surface geometry and roughness of the lenses were evaluated using white-light and Fizeau interferometers. We have compared peak-to-valley wavefront deviation, root-mean-squared wavefront error, radii of curvature and the arithmetic average of the roughness profile (Ra) of plastic and glass lenses. Additionally, the imaging performance of selected pairs of lenses was tested using 1951 USAF resolution target. The results indicate performance of 3D printed optics that could be manufactured with surface roughness comparable to that of injection molded lenses (Ra < 20 nm). The RMS wavefront error of 3D printed prototypes was at a minimum 18.8 times larger than equivalent glass prototypes for a lens with a 12.7 mm clear aperture, but when measured within 63% of its clear aperture, 3D printed components' RMS wavefront error was comparable to glass lenses. PMID- 29238115 TI - High spatial sampling light-guide snapshot spectrometer. AB - A prototype fiber-based imaging spectrometer was developed to provide snapshot hyperspectral imaging tuned for biomedical applications. The system is designed for imaging in the visible spectral range from 400 to 700 nm for compatibility with molecular imaging applications as well as satellite and remote sensing. An 81 * 96 pixel spatial sampling density is achieved by using a custom-made fiber optic bundle. The design considerations and fabrication aspects of the fiber bundle and imaging spectrometer are described in detail. Through the custom fiber bundle, the image of a scene of interest is collected and divided into discrete spatial groups, with spaces generated in between groups for spectral dispersion. This reorganized image is scaled down by an image taper for compatibility with following optical elements, dispersed by a prism, and is finally acquired by a CCD camera. To obtain an (x, y, lambda) datacube from the snapshot measurement, a spectral calibration algorithm is executed for reconstruction of the spatial spectral signatures of the observed scene. System characterization of throughput, resolution, and crosstalk was performed. Preliminary results illustrating changes in oxygen-saturation in an occluded human finger are presented to demonstrate the system's capabilities. PMID- 29238116 TI - A Schutzian Analysis of Prayer with Perspectives from Linguistic Philosophy. AB - In this paper, we propose to analyze the phenomenon of Christian prayer by way of combining two different analytical frameworks. We start by applying Schutz's theories of "intersubjectivity," "inner time," "politheticality," and "multiple realities," and then proceed by drawing on the ideas and insights of linguistic philosophers, notably, Wittgenstein's "language-game," Austin's "speech act," and Evans's "logic of self-involvement". In conjoining these accounts, we wish to demonstrate how their combination sheds new light on understanding the phenomenon of prayer. Prayer is a complex phenomenon that involves two major dimensions: the private and the social, as Matthew (6: 6) and Acts (1: 14), respectively, demonstrate. Schutz's study of the phenomenon of "inner time" and the "polithetical" structure of consciousness, at both the subjective and intersubjective level, provides a useful lens to analyze these two dimensions. In addition, prayer, in following a specific set of rules, can also be considered as a specific, i.e., religious "language-game". In the last analysis, however, we propose to analyze prayer (and, finally, religion) within the Schutzian framework of "multiple realities," "enclaves," and "symbolic appresentation," which permits accessing the "religious finite province of meaning" in the very midst of the paramount reality of everyday life. In a nutshell, we claim that Christian prayer is a practice of constructing and living within a "religious province of meaning" in the everyday world; it is a practice that revolves around self-involving language-activities such as praising, confessing, thanksgiving, or requesting to God, which enable the praying subject to transfigure the language of everydayness and "see through" (Schutz) the world of everyday life in order to let it appear in a different light, e.g., the light of grace, gift, and salvation. PMID- 29238118 TI - Mechanisms and Model Diversity of Trade-Wind Shallow Cumulus Cloud Feedbacks: A Review. AB - Shallow cumulus clouds in the trade-wind regions are at the heart of the long standing uncertainty in climate sensitivity estimates. In current climate models, cloud feedbacks are strongly influenced by cloud-base cloud amount in the trades. Therefore, understanding the key factors controlling cloudiness near cloud-base in shallow convective regimes has emerged as an important topic of investigation. We review physical understanding of these key controlling factors and discuss the value of the different approaches that have been developed so far, based on global and high-resolution model experimentations and process-oriented analyses across a range of models and for observations. The trade-wind cloud feedbacks appear to depend on two important aspects: (1) how cloudiness near cloud-base is controlled by the local interplay between turbulent, convective and radiative processes; (2) how these processes interact with their surrounding environment and are influenced by mesoscale organization. Our synthesis of studies that have explored these aspects suggests that the large diversity of model responses is related to fundamental differences in how the processes controlling trade cumulus operate in models, notably, whether they are parameterized or resolved. In models with parameterized convection, cloudiness near cloud-base is very sensitive to the vigor of convective mixing in response to changes in environmental conditions. This is in contrast with results from high-resolution models, which suggest that cloudiness near cloud-base is nearly invariant with warming and independent of large-scale environmental changes. Uncertainties are difficult to narrow using current observations, as the trade cumulus variability and its relation to large-scale environmental factors strongly depend on the time and/or spatial scales at which the mechanisms are evaluated. New opportunities for testing physical understanding of the factors controlling shallow cumulus cloud responses using observations and high-resolution modeling on large domains are discussed. PMID- 29238117 TI - Life satisfaction and sexual minorities: Evidence from Australia and the United Kingdom. AB - Very little is known about how the differential treatment of sexual minorities could influence subjective reports of overall well-being. This paper seeks to fill this gap. Data from two large surveys that provide nationally representative samples for two different countries -Australia and the UK - are used to estimate a simultaneous equations model of life satisfaction. The model allows for self reported sexual identity to influence a measure of life satisfaction both directly and indirectly through seven different channels: (i) income; (ii) employment; (iii) health (iv) marriage and de facto relationships; (v) children; (vi) friendship networks; and (vii) education. Lesbian, gay and bisexual persons are found to be significantly less satisfied with their lives than otherwise comparable heterosexual persons. In both countries this is the result of a combination of direct and indirect effects. PMID- 29238119 TI - Automatic segmentation and statistical shape modeling of the paranasal sinuses to estimate natural variations. AB - We present an automatic segmentation and statistical shape modeling system for the paranasal sinuses which allows us to locate structures in and around the sinuses, as well as to observe the natural variations that occur in these structures. This system involves deformably registering a given patient image to a manually segmented template image, and using the resulting deformation field to transfer labels from template to patient. We use 3D snake splines to correct errors in the deformable registration. Once we have several accurately segmented images, we build statistical shape models for each structure in the sinus allowing us to observe the mean shape of the population, as well as the variations observed in the population. These shape models are useful in several ways. First, regular video-CT registration methods are insufficient to accurately register pre-operative computed tomography (CT) images with intra-operative endoscopy video because of deformations that occur in structures containing high amounts of erectile tissue. Our aim is to estimate these deformations using our shape models in order to improve video-CT registration, as well as to distinguish normal variations in anatomy from abnormal variations, and automatically detect and stage pathology. We can also compare the mean shape and variances of different populations, such as different genders or ethnicities, and observe the differences and similarities, as well as of different age groups, and observe the developmental changes that occur in the sinuses. PMID- 29238120 TI - Biomarkers of Cardiovascular Disease. PMID- 29238121 TI - Epidemic preparedness and management: A guide on Lassa fever outbreak preparedness plan. AB - Epidemic prone diseases threaten public health security. These include diseases such as cholera, meningitis, and hemorrhagic fevers, especially Lassa fever for which Nigeria reports considerable morbidity and mortality annually. Interestingly, where emergency epidemic preparedness plans are in place, timely detection of outbreaks is followed by a prompt and appropriate response. Furthermore, due to the nature of spread of Lassa fever in an outbreak setting, there is the need for health-care workers to be familiar with the emerging epidemic management framework that has worked in other settings for effective preparedness and response. This paper, therefore, discussed the principles of epidemic management using an emergency operating center model, review the epidemiology of Lassa fever in Nigeria, and provide guidance on what is expected to be done in preparing for epidemic of the disease at the health facilities, local and state government levels in line with the Integrated Disease Surveillance and Response strategy. PMID- 29238122 TI - Right ventricular function in patients with heart failure in a cardiac clinic in Southwest Nigeria. AB - Background: Right ventricular (RV) function is an important entity in heart failure. Patients with RV dysfunction (RVD) have poorer prognosis and exercise tolerance than those with preserved RV systolic function. Tricuspid annular plane systolic excursion (TAPSE) has been proposed as a simple and reproducible parameter for the qualitative assessment of RV systolic function/ejection fraction (EF). This study aims at describing RV function/RVD among heart failure patients in a specialized cardiac facility in Southwestern Nigeria. Materials and Methods: One hundred and thirty-two patients with clinical diagnosis of heart failure were recruited into the study between June 2011 and December 2014. Baseline data, laboratory investigations, electrocardiography, and echocardiography were taken for the participants. RV function was assessed with TAPSE. Statistical analysis was done using Statistical Package for Social Sciences 16.0 (Chicago Ill. USA). P < 0.05 was considered statistically significant. Results: The mean age of study participants was 62.1 +/- 14.2 years. RV systolic dysfunction (TAPSE <20 mm) was found in 86 (65.2%) of all patients while moderate-to-severe RVD (TAPSE <15 mm) was found in 26 (19.7%) patients. Those with RVD are more likely to be older and had a larger left ventricular internal diastolic dimension than those without RVD. Systolic blood pressure, diastolic blood pressure, and EF were significantly lower among patients with RVD than those with normal RV function. Conclusion: RVD is common and is associated with more advanced heart failure and possibly worse prognosis among Nigerians with heart failure. Screening for RVD is encouraged to identify and aggressively treat to reduce the associated increased mortality. PMID- 29238123 TI - Epidemiology, triggers, and severity of childhood asthma in Ilesa, Nigeria: Implications for management and control. AB - Background: Knowledge about childhood asthma in a locality will assist clinicians to adequately manage the condition. This study set out to report the epidemiology, triggers of exacerbation, comorbid conditions, and severity of childhood asthma at a tertiary health facility in Nigeria and the implication of these, in management and symptoms control. Methods: Over a 15-month study period, children (aged <15 years) with physician-diagnosed asthma were consecutively recruited at the pediatric chest clinic of the hospital. Sociodemographic history, triggers, and comorbidities in the children were recorded. The severity and level of symptoms control were determined using Global Initiative for Asthma criteria. The children were examined and had lung function test. Appropriate descriptive and inferential statistics were used to analyze the data obtained. Results: A total of 110 children were recruited for the study with an overall male preponderance 1.6:1, however, more adolescent females than males were observed. The ages of the children ranged from 10 months to 14 years with mean (standard deviation) of 6.4 (3.9) years. The median (interquartile range) age at diagnosis was 2.5 (1.5-6.0) years. The comorbidities were allergic rhinoconjunctivitis (45.5%), atopic dermatitis (10.9%), and overweight/obesity (7.3%). The recognizable triggers of exacerbations were respiratory tract infections (RTIs) seen more in preschool than school age children (chi2 = 6.225; P = 0.031), exercise, dust, and fumes. Mild intermittent asthma (82.7%) was the most common forms, 13 (25.0%) of the children who had Spirometry had obstructive ventilatory pattern and 17.3% had suboptimal asthma control. Conclusion: The majority of children with asthma at the Wesley Guild Hospital, Ilesa were school age children, however, 10% were <2 years and most asthmatics (72.7%) were diagnosed before age five. RTI is a major trigger of exacerbation and more than one-half had other allergic conditions which should be looked for and managed to ensure successful asthma management. PMID- 29238124 TI - Rare craniofacial cleft in a dark-skinned African population. AB - Background: Craniofacial clefts are congenital anomalies which pose a management challenge to cleft surgeons, especially in developing countries. The aim of this study is to share our experience regarding the management of these atypical facial clefts. Patients and Methods: This prospective study was carried out from May 2009 to May 2014 at Federal Medical Centre, Nguru, Nigeria. Diagnosis was based on clinical examination and Tessier classification was used to describe these clefts. Results: A total of seven patients with rare facial clefts were seen. There were four cases of midline clefts, two cases of bilateral clefts, and one case of multiple facial clefts. All cases were surgically treated, except one case of premaxillary agenesis type holoprosencephaly. Conclusion: To achieve an optimal management of patients with rare facial cleft, a well-equipped craniofacial center must be established which is still lacking in low-resource centers. PMID- 29238125 TI - Determinants of contraceptive use by women in the central senatorial zone of Bayelsa State, Nigeria: A cross-sectional survey. AB - Background: Contraceptives are known to contribute to maternal health and well being as well as improve child survival. Due to the multiethnic nature of Nigeria, it is known that the factors that influence contraceptive use may vary from one location to another and as such a blanket policy by the federal government on improving contraceptive use may not take into account the subtle differences in sociocultural practices that may influence contraceptive use. The aim of the study was to determine the contraceptive prevalence and explore factors that determine the use of contraceptives among women of Bayelsa Central Senatorial Zone. Materials and Methods: A cross-sectional survey of 210 women aged between 18 and 49 years who completed a close-ended questionnaire was carried out. Descriptive analysis was done for sociodemographic data, and tests of significance were done using SPSS version 20. Results: The prevalence of modern contraceptives in the Central Senatorial Zone of Bayelsa State was 36.8%. Condoms were the most common type of contraceptives used. Education, religious beliefs, and knowledge of fertile days were factors that significantly predicted contraceptive use. Age and number of children influenced the type of contraception a woman used. Conclusion: The contraceptive prevalence in this study is high. The factors that determine contraceptive use such as education and religion have been identified and can be leveraged upon to increase its use. PMID- 29238126 TI - Should venous doppler ultrasonography be routinely applied before lower extremity major orthopedic surgery? AB - Background: Hip-knee arthroplasty and knee arthroscopy (KA) is frequently applied in the orthopaedic surgery. The approach does not exist related with the preoperative asymptomatic deep venous thrombosis (DVT). In this study, the patients who would undergo surgery lower extremity were screened for asymptomatic DVT, using the venous Doppler ultrasonography (USG). Patients and Methods: DVT was screened by venous Doppler USG in the patients who would undergo hip-knee arthroplasty and KA between the dates of November 2013 and September 2015. The patients were investigated regarding the age, gender, and the planned operation. The cases were separated to the following three groups: group I (<49 years), Group II (49-69 years), and Group III (>=70 years). Results: The study included 222 patients; of these, 174 were female and 48 were male. Group I, Group II, and Group III included 45, 115, and 62 patients, respectively. Of the six patients determined to exist with DVT, 2 (1.73%) were in Group II, and 4 (6.45%) were in Group III. Conclusion: Although the differences were not found to be statistically significant, it may be useful to screen asymptomatic DVT by Doppler USG in the preoperative period in the 70-year-old male patients, and in those over 70. PMID- 29238127 TI - Comparison between brain natriuretic peptide and calcitonin gene-related peptide in children with dilated cardiomyopathy and controls. AB - Background: Dilated cardiomyopathy (DCM) is revealed with the left ventricular dilatation and systolic dysfunction. Objective: This study was performed to determine the level of calcitonin gene-related peptide (CGRP) and brain natriuretic peptide (BNP) in children with DCM and controls and comparison of these two biomarkers in patients. Materials and Methods: This study was performed from April 2014 to March 2015 on patients with DCM. The levels of BNP and CGRP were measured by ELISA, and final amounts of biomarkers were compared with the echocardiographic finding. Results: In this study, the mean age was 10.567 +/- 5.50 and 12.135 +/- 4.626 years for controls and cases, respectively (P = 0.321). The majority of echocardiographic indices in the left and right heart had different means in cases and controls (P < 0.05). Means of BNP were 213.814 +/- 309.601 and 2.76 +/- 1.013 for case and control, respectively (P < 0.001). Means of CGRP were 2.278 +/- 1.586 and 1.488 +/- 0.501 for cases and controls, respectively, (P = 0.001). In the patients group, however, no significant relationship was observed between CGRP level and Ross classification but observed a direct relationship of Ross classification with BNP (chi2 = 15.845, P < 0.05). Conclusions: The present research was performed on DCM patients and showed that most echocardiographic parameters, mean of CGRP and mean of BNP increased in patients compared to healthy children. The severity of illness based on the Ross classification showed significant and positive correlation with BNP level but not with CGRP. Probably, it could be concluded that BNP would be a better biomarker in DCM patients. PMID- 29238130 TI - Closure to "Component-Based Model for Single-Plate Shear Connections with Pretension and Pinched Hysteresis". PMID- 29238128 TI - Evaluation of outcomes of tuberculosis management in private for profit and private-not-for profit directly observed treatment short course facilities in Lagos State, Nigeria. AB - Background: The engagement of private practitioners in the public-private mix of tuberculosis (TB) management started in 2007 in Lagos State Nigeria. This study compared the treatment outcomes of patients managed at private for profit (PFP) and private not for profit (PNFP) directly observed treatment short course (DOTS) facilities. Methods: A retrospective review of treatment cards of TB patients managed between January 1, 2012, and June 30, 2012, in seven PFP and four PNFP DOTS facilities that served as treatment and microscopy center under the Lagos State TB and Leprosy Control Programme (LSTBLCP) at least 2 years before data collection was conducted. Results: A total of 372 treatment cards of TB patients were reviewed, of which 132 (35.5%) and 240 (64.5%) were from PFP and PNFP DOTS facilities, respectively. Treatment success rate was higher among patients managed at PFP (89.4%) DOTS facilities than PNFP (81.3%) DOTS facilities (P = 0.04). The proportion of patients lost to follow-up (12.5% vs. 8.3%), dead (3.3% vs. 1.5%) and treatment failure (2.5% vs. 0.8%) was higher among patients managed at PNFP DOTS facilities (P > 0.05). The odds that patients treated at PFP DOTS facilities had treatment success were about four times higher than PNFP DOTS facilities when other variables have been controlled for (P < 0.05). Conclusion: There is need by the LSTBLCP to engage more private practitioners to increase case detection and improve treatment outcomes of TB patients. PMID- 29238129 TI - Persistent hypocalcemia and hungry bone syndrome after parathyroidectomy and renal transplantation in a patient with end-stage renal disease. AB - Hungry bone syndrome (HBS) defines as persistent and severe hypocalcemia after parathyroidectomy surgery. It is treated by oral or venous discrimination of calcium carbonate. The present treatment is mostly effective. Hereby, we describe a 60-year-old man who had developed hyperparathyroidism secondary to end-stage renal disease and then parathyroidectomy was performed for him twice before renal transplantation. Up to 500 vials of calcium gluconate (100 mg/ml calcium gluconate 10%) were administered for him to control serum calcium level after parathyroidectomy and renal transplantation. Furthermore, high-dose calcium carbonate was administered for his outpatient care. Therefore, HBS, which was resistant to standard treatment, was detected for him. PMID- 29238131 TI - Manganese redox buffering limits arsenic release from contaminated sediments, Union Lake, New Jersey. AB - The sediments of Union Lake in Southern New Jersey are contaminated with arsenic released from the Vineland Chemical Company Superfund site 11 km upstream. Seasonal anoxia has been shown to release arsenic from sediments to similar lakes; this process was hypothesized as a major arsenic source to Union Lake. Data indicate, however, that releases of arsenic to bottom waters from the sediments or from pore waters within the sediments are relatively minor: bottom water arsenic concentrations reached ~30 ppb (~12 MUM) at most, representing <13% of the dissolved arsenic content of the lake. Manganese concentrations increase more quickly and to higher levels than arsenic and iron concentrations; maximum [Mn]= ~13 ppm (~250 MUM), maximum [Fe] = ~6 ppm (~120 MUM). Incubation experiments support the hypothesis that manganese acts as a redox buffer and prevents large arsenic releases. Under the observed conditions, little of the arsenic in the water column is from contaminated sediment. This study also suggests that arsenic release from sediment to lake water may be more important in lakes that remain anoxic more continuously. PMID- 29238132 TI - Implementing Evidence-Based Nutrition Practice Guidelines for Type 2 Diabetes Mellitus in Lebanon. AB - Lebanon is a Middle Eastern country experiencing a surge in the prevalence of type 2 diabetes mellitus among adults. This pilot study evaluated the feasibility and outcomes of implementing the Academy of Nutrition and Dietetics Evidence Based Nutrition Practice Guidelines (EBNPGs) as part of medical care for patients newly diagnosed with type 2 diabetes mellitus. Seventy-five patients were recruited from 3 Lebanese hospitals, received nutrition care according to EBNPGs, and were followed up for 12 months. Patients achieved significant improvement in clinical outcomes between baseline and 3, 6, and 12 months. Further research is recommended to confirm the benefits of using EBNPGs. PMID- 29238133 TI - Antibodies to beta1 integrins inhibit dendritic growth in rat sympathetic neurons. AB - We have examined the role of integrins in the development of dendrites in embryonic rat sympathetic neurons in vitro. Previous studies have established that exposure to a basement membrane extract (BME) causes these neurons to form dendrites (Lein and Higgins, 1989). The current experiments demonstrate that the dendrite-promoting activity of BME can be markedly inhibited by antibodies directed against the beta1 integrin subunit. Although the specific ? integrin sub unit(s) that mediate the effect of BME on dendritic growth were not identified, it was found that neither the ?1, or ?4 sub-units, nor RGD-binding integrins were involved to any significant extent. These data suggest that, in addition to their well established role in regulating axonal growth, beta1 integrins also participate in dendritic growth. PMID- 29238134 TI - Greetings. PMID- 29238135 TI - Working in unison to achieve excellence. PMID- 29238136 TI - Tetracycline as local drug delivery in treatment of chronic periodontitis: A systematic review and meta-analysis. AB - Background: The aim of the present meta-analysis is to determine the efficacy of tetracycline group of antibiotics as local drug delivery agents in the treatment of chronic periodontitis. Materials and Methods: MEDLINE, EBSCO, Cochrane database, and Google Scholar were used to identify studies in English published up to January 31, 2017. An additional hand search of relevant journals and of the bibliographies of the paper identified was also performed. Articles retrieved were screened using specific inclusion criteria by two independent reviewers. Randomized control trials investigating the effect of tetracycline group of antibiotics as local drug delivery agents in chronic periodontitis were included in the study. Results: Ten relevant articles were selected for the meta-analysis, of which five articles were retrieved after electronic search, three articles were included after hand search, and two unpublished articles were included. The number of patients in studies ranged from 13 to 140 sites with mean age ranging from 20 to 75. A total of 588 sites were treated using tetracycline group of antibiotics as local drug delivery agents in the treatment of chronic periodontitis. The meta-analysis showed standard difference in mean -1.02 mm (95% confidence interval [CI] 0.28, 1.75) for clinical gain in attachment in favor of tetracycline group. Standard difference in mean for probing depth (PD) was 1.20 mm (95% CI 0.57, 1.87) in tetracycline group. Conclusion: The results of this meta-analysis showed a significant improvement in periodontal parameters such as CAL, PD, and sulcular bleeding index in favor of tetracycline as local drug delivery compared to placebo. PMID- 29238137 TI - Genotoxic assessment of chlorhexidine mouthwash on exfoliated buccal epithelial cells in chronic gingivitis patients. AB - Background: Chlorhexidine (CHX) is the gold standard of all chemical plaque control agents and the most commonly prescribed mouthwash. However, several studies have shown cytotoxic and genotoxic effects of CHX on various eukaryotic cells. In this study, we have used micronuclei as a biomarker of DNA damage in buccal epithelial cells of chronic gingivitis patients who were given adjunct 0.2% CHX for plaque control. Materials and Methods: Chronic gingivitis patients who were exclusively on mechanical plaque control methods were taken as control (Group A) (n = 101), and chronic gingivitis patients who along with mechanical plaque control measures were taking 0.2% chlorhexidine mouthwash as adjunct were taken as cases (Group B) (n = 255). The Group B was further divided into 5 subgroups (B1, B2, B3, B4, B5) (n = 51) on increasing duration of usage of CHX from <=1 week to 24 weeks. Buccal epithelial cells were gently scrapped from the buccal mucosa using soft toothbrush. The epithelial cells were collected in buffer solution and centrifuged at 8000 rpm for 5 min. The buccal epithelial cells were air dried, fixed, and stained with 5% Giemsa stain on preheated glass microscopic slides and observed under microscope to screen 2000 nucleated cells per individual for number of micronucleated cells and micronuclei as genotoxic measure. Results: The mean number of micronucleated cells was found to be 0.41 +/ 0.71 for Group A as compared values ranging from 1.65 +/- 2.09 (Group B1) to 11.7 +/- 1.87 (Group B5) in different subgroups of Group B, and similarly, the mean number of micronuclei was found to be 0.48 +/- 0.80 for Group A as compared to values ranging from 2.57 +/- 1.64 (Group B1) to 14.5 +/- 2.49 (Group B5) in different subgroups of Group B using analysis of variance (P < 0.001). Conclusion: We conclude that CHX mouthwash is genotoxic to buccal epithelial cells and there is incremental trend in genotoxicity as the duration of usage is increased. PMID- 29238138 TI - Influence of interventional nonsurgical periodontal treatment on levels of salivary and serum nitric oxide in smokers and nonsmokers with chronic periodontitis. AB - Background and Objective: Nitric oxide (NO) is a widespread signaling molecule which is known to influence varied biological processes. However, an uncontrolled high level of NO accelerates tissue destruction. The pathogenesis of periodontal disease is also affected by smoking which alters the inflammatory response. The present study was thus performed to assess the effect of nonsurgical periodontal treatment on salivary and serum NO levels in smokers and nonsmokers with chronic periodontitis. Materials and Methods: Forty patients with chronic periodontitis, including 20 nonsmokers and equal number of smokers participated in the present study. Probing depth, clinical attachment level, plaque index, gingival index were assessed, serum and saliva samples were obtained from the patients at baseline and after Phase I therapy at 6 weeks to estimate NO by Griess colorimetric reaction. Results: Smokers showed higher serum and saliva NO levels 30.3 +/- 3.28 and 50.4 +/- 4.07 MUM as compared to nonsmokers 20.05 +/- 2.42 MUM and 37.5 +/- 2.95 MUM, respectively, at baseline. After Phase I therapy, both the groups exhibited significant improvement in clinical parameters and reduction in serum and saliva NO levels; however, reduction was higher in nonsmokers. Conclusion: More destructive expression of periodontal disease in smokers causes an increase in the concentrations of NO and less reduction after Phase I therapy as compared to nonsmokers with chronic periodontitis. Hence, NO levels in saliva and serum could be used as indicators of periodontal inflammatory condition. PMID- 29238139 TI - Comparative evaluation of two subgingival irrigating solutions in the management of periodontal disease: A clinicomicrobial study. AB - Context: Local administration of antimicrobial agents offer a "site-specific" approach to the periodontal therapy and it has several benefits. Aim: The present study was aimed to assess the clinical and microbial changes by subgingival irrigation using different subgingival irrigants in periodontitis patients and also to assess the mechanical effect of different local irrigation devices; if any. Settings and Design: Split-mouth design was employed on ten individuals. Materials and Methods: The study sample consisted of 10 individuals in whom full mouth scaling and root planing was performed and subgingival irrigation therapy was instituted for an experimental period of 30 days. The clinical as well as microbiological parameters were evaluated. Statistical Analysis Used: To calculate baseline data with day thirty data, paired t-test was used. Intergroup comparison was carried out using one-way ANOVA. Multiple comparisons among groups were carried out using post hoc Tamhane's T2 test. Results: Among the different subgingival irrigants used, 0.2% chlorhexidine gluconate is most effective followed by ozonated water, whereas saline was found to be ineffective when compared to the other two subgingival irrigants. Subgingival irrigation using pulsated device may not have any additive effect in alteration of the subgingival microflora. Conclusion: Within the limits and scope of the study, it can be safely concluded that 0.2% chlorhexidine may be used as an adjunct to mechanical therapy for achieving a significant reduction in inflammatory periodontal changes and also reduction in periodontopathogenic microflora. PMID- 29238140 TI - Traditionally used herbal medicines with antibacterial effect on Aggegatibacter actinomycetemcomitans: Boswellia serrata and Nigella sativa. AB - Background: Since bacterial strains developed resistance against commonly used antibiotics and side effects became more serious, other alternatives have been postulated. There is an answer for this issue in ancient medicine. Many plants have been proved to provide antibacterial effect. In this study, Boswellia serrata (BS) and Nigella sativa (NS) were assessed to evaluate the antibacterial effect on Aggregatibacter actinomycetemcomitans (A.a) known as main pathogen of aggressive periodontitis. Materials and Methods: Broth microdilution method was used to obtain minimum inhibitory concentration (MIC) of crude extract of BS and NS. Furthermore, the logarithm of colony forming units grown in fresh brain heart infusion bacterial culture was assessed. Three groups including BS+ (containing only BS), NS+ (containing only NS), and BS-NS- (control group) were defined. For each group, the experiment was repeated 12 times. Results: MIC of BS and NS were 512 MUg/mL and 128 MUg/mL, respectively. No growth was observed in our negative control group. The mean +/- standard deviation of logarithm of CFU/mL for BS, NS, and control group was 4.32 +/- 0.36, 3.61 +/- 0.3, and 5.57 +/- 0.19, respectively. ANOVA test revealed significant difference (P values < 0.0001) of these groups which was later confirmed using the post hoc test of Tukey's honest significant difference (all P < 0.0001). Conclusions: Both BS and NS are effective against A.a which should be taken into account as appropriate ingredient for oral hygiene products. PMID- 29238141 TI - Comparative evaluation of efficacy of three treatment modalities - tetracycline fibers, scaling and root planing, and combination therapy: A clinical study. AB - Background: Tetracycline is one of the primary antibiotics prescribed for antimicrobial therapy in periodontics. It has a broad spectrum of activity being effective against most bacteria as well as spirochetes. Due to limitations of systemic drug therapy, recent formulations of the drug for local administration in the subgingival area have been introduced, including collagen fibers impregnated with tetracycline. Aims and Objective: To compare the effectiveness of tetracycline fibers alone or in combination with scaling and root planing (SRP) on clinical parameters in chronic periodontitis patients. Materials and Methods: A total of twenty patients comprising of both sexes in the age group of 35-60 years with chronic periodontitis were selected. Split-mouth design was used, and three teeth from each patient with periodontal pocket measuring > 5 mm were selected which were treated with different treatment modality. They were randomly divided into site A (SRP), site B (tetracycline fibers only), and site C (combination therapy). Clinical parameters of plaque index (PI), gingival index (GI), pocket probing depth, and clinical attachment level (CAL) were recorded at 0, 30, and 45 days. The data obtained was compiled and put to statistical analysis. Results: All the three groups showed improvement in PI, GI, probing pocket depth, and CAL. Results of the study showed greater improvements in clinical parameters in Group C compared to Group A and Group B. Conclusion: The results indicate that the adjunctive use of tetracycline fibers with SRP is a clinically effective and simple nonsurgical treatment method to improve periodontal health. PMID- 29238142 TI - Comparing the outcomes of incisions made by colorado microdissection needle, electrosurgery tip, and surgical blade during periodontal surgery: A randomized controlled trial. AB - Context: Electrosurgery offers many unique advantages such as hemostasis and precise tissue cutting; however, there are a number of disadvantages including thermal injury and delayed wound healing. Aims: The aim of the present study was to compare the outcomes of incisions made by Colorado(r) microdissection needle, electrosurgery tip, and surgical blade during periodontal surgery. Settings and Design: Twenty-two individuals participated in this study. Three quadrants in each individual were randomly assigned into each of the following experimental groups: Colorado(r) microdissection needle (CMD), electrosurgery tip (EC) and surgical blade (BP), in which, incisions were given with Colorado(r) microdissection needle, straight electrocautery tip, and a scalpel blade, respectively. Materials and Methods: Blood loss (BL) was measured immediately after surgery, and changes in interdental papilla dimensions were recorded at baseline, 7, 30, 120, and 180 days after surgery. Measures of periodontal disease were recorded at baseline, 120, and 180 days after surgery. Postoperative pain and wound healing were recorded at 1, 7, and 15 days after surgery. Results: The use of CMD for periodontal surgery showed better results over EC in all parameters. CMD resulted in lesser bleeding and less postoperative pain and attained similar results to that of BP in clinical parameters of periodontal disease. Conclusions: Colorado(r) microdissection needle may be a better choice for incisions as it seems to show less tissue damage than cautery and offers tissue healing comparable to scalpel blade. PMID- 29238143 TI - Impact of well-controlled type 2 diabetes mellitus on quality of life of chronic periodontitis patients. AB - Background: The purpose of the study is to examine the quality of life (QoL) in chronic periodontitis (CP) patients associated with or not with well-controlled type 2 diabetes mellitus (DM2). Materials and Methods: Five hundred CP patients, 250 with DM2 (GDM2 group) and 250 age- and gender-matched controls without DM2 (GND), were enrolled in this cross-sectional case-controlled study from January to September 2015. They were interviewed by a QoL questionnaire (Functional Assessment of Chronic Illness Therapy-Fatigue) validated to Portuguese. Periodontal examinations were also performed to confirm CP: probing pocket depth and clinical attachment level must be >3 mm. Results: An association between the presence of DM2 and a high negative impact on QoL was observed. All domains in GDM2 patients presented mean values above 19. On the other hand, three functional domains in GND (physical, social/family, and emotional) showed values below 19 (medium negative impact). Comparisons between GND and GDM2 revealed the statistical difference between them for all domains (P < 0.05). Conclusions: This study shows that DM2 associated with CP negatively affect QoL, even considering well-controlled diabetic patients. PMID- 29238144 TI - Oral manifestation of sarcoidosis: A case report and review of the literature. AB - Sarcoidosis is a common multisystemic granulomatous disease characterized by the formation of nonnecrotizing epithelioid granulomas in various body organs. The most commonly affected organs in the head-and-neck region include salivary glands and cervical lymph nodes. Involvement of the oral mucosa is very rare. The purpose of this report is to present an atypical oral manifestation of sarcoidosis with ulcerations of the buccal mucosa in a 59-year-old female. PMID- 29238145 TI - Oral mucous membrane pemphigoid - Two case reports with varied clinical presentation. AB - Mucous membrane pemphigoid (MMP) is a heterogeneous group of autoimmune chronic inflammatory, subepithelial blistering disorder, predominantly involving the mucous membranes. It has a female predilection and commonly occurring after the fifth decade of life. The oral mucosa is affected in more than 90% of cases. Dentists could be the first health personnel to identify and diagnose this rare mucocutaneous lesion. Two unique cases of oral MMP with varied clinical presentation, the diagnostic modality, treatment and follow-up are presented. PMID- 29238146 TI - Gingival fibroma versus verrucous leukoplakia - A clinical dilemma!!! AB - Gingival overgrowths found in the oral cavity are mostly due to reactive hyperplasia and rarely depict neoplastic nature. It is a challenge for the clinician to give final diagnoses of gingival overgrowth. Gingiva is a common site for various benign and malignant lesions. Oral cavity is an ideal niche for the manifestation of various precancerous and cancerous lesions. Fibrous growths present in the oral cavity include a varying group of reactive, precancerous, and cancerous conditions. This report describes a case of a 55-year-old male who clinically presented with a localized fibromatous gingival overgrowth in relation to lower left mandibular canine-premolar region that was diagnosed as a gingival fibroma associated with leukoplakia. On histopathological examination, it was diagnosed as a case of proliferative verrucous leukoplakia. Many a times, clinicians face dilemma while diagnosing an overgrowth as it is difficult to differentiate clinically. Hence, a thorough clinical knowledge and a pathologist's opinion become mandatory to give final diagnosis to such gingival overgrowths. PMID- 29238147 TI - Periodontal regenerative management of residual tunnel osseous defect results from the enucleation of lateral periodontal cyst in anterior maxilla: A rare case report. AB - The lateral periodontal cyst (LPC) is a nonkeratinized, noninflammatory developmental cyst occurring adjacent or lateral to tooth root. It is a relatively uncommon lesion found in the maxillary incisors and found mostly in adults during 5th to 7th decades. In this case, 45-year-old male patient reported with occasional mild discomfort between left maxillary central and lateral incisor region since 1 year. Interproximally, a well-defined round radiolucent area with corticated borders was determined radiographically between vital tooth #21 and #22. Preliminary diagnosis of LPC was established based on clinical and radiographical findings. Following enucleation of the lesion, an anticipated residual tunnel osseous defect was observed, which was managed successfully utilizing bone graft and guided tissue regeneration-assisted technique. Cystic tissue removed was examined histologically; hematoxylin- and eosin-stained sections showed features suggestive of LPC. Complete healing of tunnel defect was achieved at 1 year follow-up. PMID- 29238148 TI - Innovative use of laterally positioned periosteal pedicle graft for coverage of gingivitis artefacta. AB - There are many etiological factors for nonplaque-induced gingival diseases, out of which physical trauma due to psychiatric reasons leading to self-infliction is less studied upon. This case report presents one such case which has been successfully treated stepwise where psychological counseling was done to restrain from habit followed by using an innovative laterally positioned periosteal pedicle graft for dehiscence coverage. PMID- 29238149 TI - A novel single-step surgical technique for vestibular deepening using laser in conjunction with periodontal flap surgery. AB - Moderate-to-severe chronic periodontitis results in clinical loss of attachment, reduced width of attached gingiva (AG), periodontal pockets beyond mucogingival junction (MGJ), gingival recession, loss of alveolar bone, and decreased vestibular depth (VD). The encroachment of frenal and muscle attachments on marginal gingiva increases the rate of progression of periodontal pockets, prevents healing, and causes their recurrence after therapy. Loss of VD and AG associated with continuous progression of pocket formation and bone loss requires two-stage surgical procedures. In this article, one-stage surgical procedure is being described for the first time, to treat the periodontal pockets extending beyond the MGJ by periodontal flap surgery along with vestibular deepening with diode laser to increase the AG. One-step surgical technique is illustrated whereby pocket therapy with reconstruction of lost periodontal tissues can be done along with gingival augmentation by vestibular deepening. PMID- 29238150 TI - Replacement of a molar with two narrow-diameter dental implants. AB - Dental implants have demonstrated a high degree of success in the restorations of teeth in partially or completely edentulous patients. However, when the buccolingual width of the edentulous crest is insufficient for the placement of standard sized implants, the use of two or more smaller diameter implants should be considered to avoid the need for invasive reconstruction techniques such as grafting procedures. The present case report describes the replacement of a single mandibular first molar with two narrow-diameter implants, in a 41-year- old male patient. No postoperative complications were reported in the 3-year follow-up period. The placement of two narrow-diameter implants replacing a missing mandibular molar could eliminate the mesiodistal bending, double the support capacity in the buccolingual direction, and minimize stress on the implants. PMID- 29238151 TI - Adsorption and Reaction of CO on (Pd-)Al2O3 and (Pd-)ZrO2: Vibrational Spectroscopy of Carbonate Formation. AB - gamma-Alumina is widely used as an oxide support in catalysis, and palladium nanoparticles supported by alumina represent one of the most frequently used dispersed metals. The surface sites of the catalysts are often probed via FTIR spectroscopy upon CO adsorption, which may result in the formation of surface carbonate species. We have examined this process in detail utilizing FTIR to monitor carbonate formation on gamma-alumina and zirconia upon exposure to isotopically labelled and unlabelled CO and CO2. The same was carried out for well-defined Pd nanoparticles supported on Al2O3 or ZrO2. A water gas shift reaction of CO with surface hydroxyls was detected, which requires surface defect sites and adjacent OH groups. Furthermore, we have studied the effect of Cl synthesis residues, leading to strongly reduced carbonate formation and changes in the OH region (isolated OH groups were partly replaced or were even absent). To corroborate this finding, samples were deliberately poisoned with Cl to an extent comparable to that of synthesis residues, as confirmed by Auger electron spectroscopy. For catalysts prepared from Cl-containing precursors a new CO band at 2164 cm-1 was observed in the carbonyl region, which was ascribed to Pd interacting with Cl. Finally, the FTIR measurements were complemented by quantification of the amount of carbonates formed via chemisorption, which provides a tool to determine the concentration of reactive defect sites on the alumina surface. PMID- 29238152 TI - A novel sequence space related to [Formula: see text] defined by Orlicz function with application in pattern recognition. AB - In the field of pattern recognition, clustering groups the data into different clusters on the basis of similarity among them. Many a time, the similarity level between data points is derived through a distance measure; so, a number of clustering techniques reliant on such a measure are developed. Clustering algorithms are modified by employing an appropriate distance measure due to the high versatility of a data set. The distance measure becomes appropriate in clustering algorithm if weights assigned at the components of the distance measure are in concurrence to the problem. In this paper, we propose a new sequence space [Formula: see text] related to [Formula: see text] using an Orlicz function. Many interesting properties of the sequence space [Formula: see text] are established by the help of a distance measure, which is also used to modify the k-means clustering algorithm. To show the efficacy of the modified k-means clustering algorithm over the standard k-means clustering algorithm, we have implemented them for two real-world data set, viz. a two-moon data set and a path based data set (borrowed from the UCI repository). The clustering accuracy obtained by our proposed clustering algoritm outperformes the standard k-means clustering algorithm. PMID- 29238154 TI - Internet Dilettantes' Crowd-Based Peer Review: An Exercise in Mediocrity. PMID- 29238153 TI - Risk Factors for Open Conversion in Minimally Invasive Cholecystectomy. AB - Background and Objectives: Open conversion (OC) occurs in 5 to 10% of laparoscopic cholecystectomies (LCs) and results in suboptimal outcomes. Herein, we report our experience with OC in cholecystectomy performed with the minimally invasive (MIS) approach. Methods: Data from 960 minimally invasive cholecystectomies performed in the University of Illinois at Chicago (UIC) Division of General, Minimally Invasive, and Robotic Surgery were retrospectively compiled. Patient demographics and outcomes were analyzed for the major indicators that may predispose to OC. Results: Male gender and intraoperative diagnosis of acute or gangrenous cholecystitis were identified as statistically significant individual predictors for OC. Conversion incidence was significantly lower in every paired demographic combination when compared with the laparoscopic data. Conclusions: Our retrospective study identified some specific factors associated with significantly higher risk of OC in both laparoscopic and robotic cholecystectomy. The impact of these risk factors seems to be lesser in the robotic than in the laparoscopic approach. Further investigation is necessary to validate these findings. PMID- 29238156 TI - Do Individuals Perceive Income Tax Rates Correctly? AB - This article uses data from survey questions fielded on the 2011 wave of the Cognitive Economics Study to uncover systematic errors in perceptions of income tax rates. First, when asked about the marginal tax rates (MTRs) for households in the top tax bracket, respondents underestimate the top MTR on wages and salary income, overestimate the MTR on dividend income, and therefore significantly underestimate the currently tax-advantaged status of dividend income. Second, when analyzing the relationship between respondents' self-reported average tax rates (ATRs) and MTRs, many people do not understand the progressive nature of the federal income tax system. Third, when comparing self-reported tax rates with those computed from self-reported income, respondents systematically overestimate their ATR while reported MTR are accurate at the mean, the responses are consistent with underestimation of tax schedule progressivity. PMID- 29238155 TI - Postoperative Pain After Single-Site Versus Multiport Hysterectomy. AB - Background and Objectives: With advances in laparoscopic surgery, the goal of surgeons and patients is to minimize pain to allow for faster recovery and return to normal daily activities. One of these advances is single-site surgery. In this study, we compared postoperative pain in laparoendoscopic single-site surgery (LESS) to that in traditional multiple-incision hysterectomy. Methods: Seventy patients were selected for this prospective cohort study, with 35 undergoing multiple-incision and 35 undergoing LESS hysterectomy. All patients were included who were undergoing hysterectomy with the primary surgeon. All multiport hysterectomies were performed laparoscopically. Six patients underwent LESS hysterectomy and 29 underwent robotic single-site surgery (rLESS). Patients recorded pain levels for 3 weeks after surgery on a variety of measures, including overall and incisional pain. Linear mixed effects models for repeated measures were used for all multivariate analyses, with an unstructured covariance matrix accounting for correlation between time points. Results: Overall, across all time points, there was an average reduction in pain by 1.26 (SD 0.69) points in the single-site group (P = .06). Days 3 and 14 had a marginally significant reduction in pain (P = .06 and 0.058, respectively). On days 4 and 7 there was a significant reduction in overall pain (P = .04 and .04, respectively). Conclusion: Based on the results, it is likely that single-site hysterectomy leads to less postoperative pain and achieves a lower pain score faster than multiport surgery. A randomized control trial is necessary to confirm these results before accepting them in clinical practice. PMID- 29238157 TI - Access to Scientific Research: The Return on the Taxpayer's Investment. PMID- 29238158 TI - Full Step Cycle Kinematic and Kinetic Comparison of Barefoot Walking and a Traditional Shoe Walking in Healthy Youth: Insights for Barefoot Technology. AB - Objective: Barefoot technology shoes are becoming increasingly popular, yet modifications are still needed. The present study aims to gain valuable insights by comparing barefoot walking to neutral shoe walking in a healthy youth population. Methods: 28 healthy university students (22 females and 6 males) were recruited to walk on a 10-meter walkway both barefoot and in neutral running shoes at their comfortable walking speed. Full step cycle kinematic and kinetic data were collected using an 8-camera motion capture system. Results: In the early stance phase, the knee extension moment (MK1), the first peak absorbed joint power at the knee joint (PK1), and the flexion angle of knee/dorsiflexion angle of the ankle were significantly reduced when walking in neutral running shoes. However, in the late stance, barefoot walking resulted in decreased hip joint flexion moment (MH2), second peak extension knee moment (MK3), hip flexors absorbed power (PH2), hip flexors generated power (PH3), second peak absorbed power by knee flexors (PK2), and second peak anterior-posterior component of joint force at the hip (APFH2), knee (APFK2), and ankle (APFA2). Conclusions: These results indicate that it should be cautious to discard conventional elements from future running shoe designs and rush to embrace the barefoot technology fashion. PMID- 29238159 TI - Comparison of surgically induced astigmatism following different glaucoma operations. AB - Aim: To compare surgically induced astigmatism (SIA) among glaucomatous eyes treated with trabeculectomy (LEC), EX-PRESS(r) shunt (EXP), ab externo trabeculotomy (exLOT), or microhook ab interno trabeculotomy (MULOT). Subjects and methods: Eighty right eyes of 80 subjects who underwent LEC (n=20), EXP (n=20), exLOT (n=20), or MULOT (n=20) were included. The dataset including the best-corrected visual acuity (BCVA), intraocular pressure (IOP), and keratometry recordings preoperatively and 3 months postoperatively was collected by chart review. The means of the vector magnitude, vector meridian, and arithmetic magnitude of the preoperative and postoperative astigmatism and SIA were calculated. The correlations among the SIA magnitude, postoperative BCVA, and IOP were assessed. Results: The mean astigmatic arithmetic magnitudes did not differ significantly (P=0.0732) preoperatively among the four groups, but the magnitude was significantly (P=0.0002) greater in the LEC group than the other groups postoperatively. The mean SIA vectors were calculated to be 1.01 D at 56 degrees , 0.62 D at 74 degrees , 0.23 D at 112 degrees , and 0.12 D at 97 degrees for the LEC, EXP, exLOT, and MULOT groups, respectively. The mean SIA arithmetic magnitudes were significantly (P<0.0001) greater in the LEC group than the other groups. Three months postoperatively, the SIA magnitude was correlated positively with the logarithm of the minimum angle of resolution (logMAR) BCVA (r=0.3538) and negatively with the IOP (r=-0.3265); the logMAR BCVA was correlated negatively with the IOP (r=-0.3105). Conclusion: EXP, exLOT, and MULOT induce less corneal astigmatism than LEC in the early postoperative period. PMID- 29238160 TI - Agreement of swept-source and spectral-domain optical coherence-tomography retinal thickness measurements in neovascular age-related macular degeneration. PMID- 29238161 TI - Prevalence and causes of blindness, visual impairment, and cataract surgery in Timor-Leste. AB - Purpose: To estimate the prevalence and causes of blindness and visual impairment, cataract surgical coverage (CSC), visual outcome of cataract surgery, and barriers to uptake cataract surgery in Timor-Leste. Method: In a nationwide rapid assessment of avoidable blindness (RAAB), the latest population (1,066,409) and household data were used to create a sampling frame which consists of 2,227 population units (study clusters) from all 13 districts, with populations of 450 900 per unit. The sample size of 3,350 was calculated with the assumed prevalence of blindness at 4.5% among people aged >=50 years with a 20% tolerable error, 95% CI, and a 90% response rate. The team was trained in the survey methodology, and inter-observer variation was measured. Door-to-door visits, led by an ophthalmologist, were made in preselected study clusters, and data were collected in line with the RAAB5 survey protocol. An Android smart phone installed with mRAAB software was used for data collection. Result: The age-gender standardized prevalence of blindness, severe visual impairment, and visual impairment were 2.8%, (1.8-3.8), 1.7% (1.7-2.3), and 8.1% (6.6-9.6), respectively. Cataract was the leading cause of blindness (79.4%). Blindness was more prevalent in the older age group and in women. CSC was 41.5% in cataract blind eyes and 48.6% in cataract blind people. Good visual outcome in the cataract-operated eyes was 62% (presenting) and 75.2% (best corrected). Two important barriers to not using available cataract surgical services were accessibility (45.5%) and lack of attendants to accompany (24.8%). Conclusion: The prevalence of blindness and visual impairment in Timor-Leste remains high. CSC is unacceptably low; gender inequity in blindness and CSC exists. Lack of access is the prominent barrier to cataract surgery. PMID- 29238162 TI - Rapid resolution of toxoplasma chorioretinitis treatment using quadruple therapy. AB - Purpose: To compare the effectiveness of quadruple-drug therapy consisting of cotrimoxazole (trimethopin and sulfamethoxazole), clindamycin antibiotics, and oral corticosteroid versus triple therapy consisting of pyrimetamine, sulphadiazine, and oral corticosteroid in the resolution of toxoplasmic chorioretinitis. Methods: This was a double-blind randomized controlled trial with repeated measures using parallel design to compare the effectiveness of quadruple-drug therapy and triple-drug therapy in patients with toxoplasmic chorioretinitis. The measurement of lesion was done using automated computer software, calculating the average of lesion size from three fundus photographs taken from the baseline and at each follow-up visit. The analytical statistics were obtained using Mann-Whitney test, comparing percentage of lesion remission test in each examination. Results: The percentage of lesion remission in quadruple-drug therapy was higher than in triple-drug therapy from the first visit until the first follow-up visit, with a p-value of 0.001. In addition, the mean percentage of lesion remission from first visit to last visit was 57.5% and the median was 70.9% in the quadruple therapy group, while in the triple-drug therapy group the mean was 52.5% and the median was 54.0% (p=0.720). Conclusion: We conclude that the quadruple-drug therapy has a more rapid resolution effect on chorioretinitis lesion compared to triple therapy. PMID- 29238163 TI - The coexpression of multi-immune inhibitory receptors on T lymphocytes in primary non-small-cell lung cancer. AB - Non-small-cell lung cancer (NSCLC) is a common disease threatening the health of humankind. It has a low survival rate and a poor prognosis. Under normal circumstances, tumor infiltrating lymphocytes (TILs) play the main role in the antitumor process, but studies in recent years have found that NSCLC is capable of releasing various immunosuppressive factors, inducing the TILs to exhibit high expression of immune inhibitory receptors and relevant immunosuppressive factors. They can not only activate their own signal pathways but also block those of TILs, which causes inefficiency of tumor destruction. Researchers have now developed targeted drugs that specifically bind to immunosuppression receptors. By blocking signal transmission of immune inhibitory receptors, restraint on T lymphocytes can be released to recover antitumor role. Further research and understanding of the immunosuppression signal pathways of NSCLC are of significant importance to promote the development of immune-targeted drugs and the formulation of new treatment plans. This paper summarizes the immunosuppressive mechanisms of multiple important and newly discovered immune inhibitory receptors on T lymphocytes and immunosuppressive factors released by NSCLC cells, and their influence on patients' survival rate and prognosis. Further laboratory and clinical studies on immune-targeted drugs for primary NSCLC are needed to provide more evidence. PMID- 29238164 TI - A novel transdermal nanoethosomal gel of betahistine dihydrochloride for weight gain control: in-vitro and in-vivo characterization. AB - Background: Betahistine dihydrochloride (BDH) is a histamine analog used to control weight gain, with short elimination half-life and gastric irritation as side effects. Objective: The aim of the current investigation is to formulate and optimize a topical BDH ethosomal gel for weight gain control. Materials and methods: Box-Behnken design was applied to study the effect of independent variables: phosphatidylcholine (PC), propylene glycol (PG), and ethanol on vesicle size; entrapment efficiency; % drug release; and flux. The morphology and zeta potential of the optimized formulation were evaluated. The % drug release, flux, and pharmacodynamics of the optimized formulation gel were studied. Results: The size and entrapment efficiency percent had a direct positive relationship with the concentration of PC and negative relationship with ethanol and PG. The % drug release and flux decreased with increasing PC and PG, while ethanol enhanced both responses. Regression modeling indicated a good correlation between dependent and independent variables, where F16 was chosen as the optimized formulation. F16 showed well-defined spherical vesicles and zeta potential of -24 mV, and % release from the gel exceeded 99.5% over 16 h with the flux of 0.28 mg/cm2/h. Food intake and weight gain of rats were significantly decreased after transdermal application of the BDH ethosomal gel when compared with control, placebo, and BDH gel. The histopathological findings proved the absence of inflammation and decrease in adipose tissue. Conclusion: Results obtained showed a significant, sustained transdermal absorption of BDH ethosomal gel and, consequently, a decrease in food intake and weight gain. PMID- 29238165 TI - Synthesis, characterization, and antimicrobial evaluation of novel 5-benzoyl-N substituted amino- and 5-benzoyl-N-sulfonylamino-4-alkylsulfanyl-2-pyridones. AB - The present research describes the synthesis of novel 5-benzoyl-N-substituted amino- and 5-benzoyl-N-sulfonylamino-4-alkylsulfanyl-2-pyridones 5a-c and 6a-c via the reaction of 2-benzoyl-3,3-bis(alkylthio)acrylonitriles 2a-c with N cyanoacetohydrazide 3 and cyanoaceto-N-phenylsulfonylhydrazide 4, respectively. Also, the reactivity of the compounds 5a-c toward hydrazine hydrate to give product 1H-pyrazolo[4,3-c]pyridine derivative 7 was studied. In addition, the reactivity of the 2a-c toward 1-cyanoacetyl-4 arylidenesemicarbazides 8a-c afforded 3,5-dihydro[1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile derivatives (12 14)a-c, which reacted with hydrazine hydrate to give 3H-pyrazolo[4,3 c][1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile derivatives 15a-c. The structures of the new products were characterized based on 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, infrared, mass-spectroscopy, and elemental analyses. The products were screened in vitro for their antibacterial and antifungal activity properties. PMID- 29238166 TI - Cardiovascular, liver, and renal toxicity associated with an intravenous ferric carboxymaltose similar versus the originator compound. AB - Background: Ferric carboxymaltose (FCM) is a stable, non-dextran-based intravenous iron complex used to treat iron deficiency of various etiologies. As FCM is a nonbiological complex drug and cannot be fully characterized by physicochemical analyses, it is important to demonstrate in nonclinical models that FCM similars (FCMS) have similar biodistribution. Materials and methods: A total of 30 nonanemic rats were treated weekly with 40 mg iron/kg body weight intravenous FCM, FCMS, or isotonic saline (controls) for 4 weeks. Blood pressure, liver enzymes, and renal function were evaluated. In liver, heart, and kidney tissue, markers for oxidative stress (malondialdehyde to assess lipid peroxidation and antioxidant enzymes) and inflammation (TNFalpha and IL6) were measured. Iron deposits were localized. Results: The FCMS-treated group had significantly lower blood pressure, higher liver enzymes, increased proteinuria, and reduced creatinine clearance versus the FCM and control groups by day 29. Serum iron and transferrin saturation were significantly higher with FCMS versus FCM or controls. Iron deposition was altered in FCMS-treated animals, with decreased ferritin deposits and iron deposition outside the physiological storage compartments. Markers for lipid peroxidation and antioxidant-enzyme activity were significantly increased after FCMS administration versus FCM and controls, as were inflammatory markers. Conclusion: Results from this blinded nonclinical study demonstrated significant differences between the originator FCM and this FCMS. PMID- 29238168 TI - The role of maintenance therapy in the treatment of elderly non-small-cell lung cancer patients: a meta-analysis of randomized controlled trials. AB - Purpose: Maintenance therapy is an effective treatment strategy for advanced non small-cell lung cancer (NSCLC). We aim to investigate whether age would affect the efficacy of maintenance therapy in the treatment of advanced NSCLC. Materials and methods: Relevant trials were identified by searching electronic databases and conference meetings. Prospective randomized controlled trials assessing maintenance therapy in elderly patients with advanced NSCLC were included. Outcomes of interest included overall survival (OS) and progression-free survival (PFS) in elderly patients with advanced NSCLC. Results: A total of 2,724 patients from 5 randomized controlled trials were included for analysis, with 897 patients aged >=65 years and 1,577 patients aged <65 years. Single-agent maintenance therapy in elderly patients significantly improved PFS (hazard ratio [HR] 0.65, 95% CI: 0.43-0.98, p=0.04) and OS (HR 0.81, 95% CI: 0.68-0.97, p=0.024) when compared with placebo. In addition, doublet maintenance therapy significantly improved PFS (HR 0.81, 95% CI: 0.68-0.97, p=0.024) in comparison with single agent maintenance therapy. However, doublet maintenance did not improve OS in comparison with single-agent maintenance therapy (HR 1.05, 95% CI: 0.60-1.83, p=0.86). Conclusions: The findings of this study suggest that single-agent maintenance therapy in elderly patients with advanced NSCLC offers an improved PFS and OS when compared with placebo. Further trials are recommended to clearly investigate the efficacy of combination maintenance therapy for advanced NSCLC in this setting. PMID- 29238167 TI - Comparison of dexmedetomidine and fentanyl as local anesthetic adjuvants in spinal anesthesia: a systematic review and meta-analysis of randomized controlled trials. AB - Purpose: To compare the effects of dexmedetomidine (Dex) and fentanyl as adjuvants to local anesthetics in spinal anesthesia. Methods: Two researchers independently searched the PUBMED, EMBASE, Cochrane library, and CBM for randomized controlled trials comparing the effects of Dex and fentanyl as adjuvants to local anesthetics for intrathecal injection. Results: A total of 639 patients from nine studies were included in this meta-analysis. The results showed that Dex resulted in statistically significant longer duration of stable sensory block (mean difference [MD] =27.12; 95% confidence interval [CI] [9.89, 44.34], P<0.01, I2=97%), sensory block (standardized mean difference [SMD] =3.81; 95% CI [2.35, 5.27], P<0.01, I2=97%), motor block (SMD =3.64; 95% CI [2.19, 5.08], P<0.01, I2=97%), and pain free period (SMD =2.98; 95% CI [1.69, 4.27], P<0.01, I2=96%); reducing the incidence of pruritus (relative risk [RR] =0.15; 95% CI [0.06, 0.39], P<0.01, I2=0%) compared with fentanyl. However, the onset of sensory and motor block, the time to peak sensory level, and the incidence of hypotension and bradycardia, and the side effects (nausea, vomiting, shivering and respiratory depression) were not significantly different between Dex and fentanyl. Conclusion: Compared to fentanyl, Dex as local anesthetics adjuvant in spinal anesthesia prolonged the duration of spinal anesthesia, improved postoperative analgesia, reduced the incidence of pruritus, and did not increase the incidence of hypotension and bradycardia. PMID- 29238169 TI - Bioequivalence study of two formulations of flupirtine maleate capsules in healthy male Chinese volunteers under fasting and fed conditions. AB - Aim: This study developed a high-performance liquid chromatography-tandem mass spectrometry method to simultaneously determine the concentrations of flupirtine and its major active metabolite D-13223 in human plasma in order to assess the bioequivalence (BE) of two flupirtine maleate capsules among healthy male Chinese volunteers under fasting and fed conditions. Materials and methods: There were two single-center, randomized, single-dose, open-label, laboratory-blinded, two period, cross-over studies which included 24 healthy male Chinese volunteers under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 48 h after dosing. The concentrations of flupirtine and its major active metabolite D-13223 in plasma samples were determined by a validated method, that is, high-performance liquid chromatography coupled with a tandem mass spectrometry detector. Pharmacokinetic metrics of area from time zero to the last measurable concentration (AUC0-t), area under the plasma concentration-time curve from administration to infinite time (AUC0-infinity), and Cmax were used for BE assessment. Results: Forty-eight healthy volunteers who met the criteria were enrolled and completed the study. According to the observation of vital signs and laboratory measurement, no volunteers had any adverse reactions. Under fasting condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 103.0% (98.1%-108.2%) for AUC0-t, 102.9% (98.2%-107.9%) for AUC0-infinity, and 97.0% (85.9%-109.5%) for Cmax. Under fed condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 101.7% (98.4%-105.1%) for AUC0-t, 101.6% (98.5%-104.8%) for AUC0-infinity, and 103.5% (94.7%-113.0%) for Cmax. The difference between test and reference formulations, Tmax, was not statistically significant. The 90% CIs of the test/reference AUC ratio and Cmax ratio of D-13223 were also within the acceptance range for BE both under fasting and fed conditions. Conclusion: The two formulations of flupirtine maleate capsule were bioequivalent (the test and the reference products) under fasting and fed conditions, and thus both can be used interchangeably in the clinical setting. PMID- 29238170 TI - Adherence to treatment and evaluation of disease and therapy knowledge in Lebanese hypertensive patients. AB - Background: Adherence to treatment, healthy lifestyle, physical activities, smoking, diet, and salt intake are important factors to control for an effective decrease in blood pressure (BP) values for patients diagnosed with essential hypertension (HT). The aim of this work was to study the adherence to antihypertensive treatment and factors predicting this behavior in Lebanese patients. In addition, we evaluated the extent of patient's knowledge and perceptions about HT, risk factors, and medication side effects. Methods: The cross-sectional study was conducted between May and September 2015 among 249 participants randomly recruited from community and hospital pharmacies (56.6%), private cardiology clinics (37%), and outpatient clinics located in hospitals (6.4%) in Baabda region of Lebanon. The questionnaire was prepared after reviewing published literature. Data were collected by trained and certified interviewers and analyzed by Statistical Package for the Social Sciences program. p-value less than 0.05 was considered to determine the statistical significance. Results: Among the 249 patients interviewed, 48% were females with a mean age of 62+/-17.2 years. Overweight and obesity was declared in 42.2% and 35.3%, respectively. Only 52.6% of participants reported visiting their physicians for regular checkups, and 72% claimed checking their BP routinely at home. Awareness of complications related to HT was very high (97%). However, our results showed that 89.2% of the participants were found to be adherent to treatment, and forgetfulness was cited as the main reason for non-adherence to therapy. Only health coverage showed statistical significance (p=0.01) between adherent and non adherent participants. Conclusion: A better communication between patients and their physicians, the use of a special container for medication packaging, and reminder to refill prescriptions are important parameters to enhance adherence to treatment. HT can be better managed if an educational system is implemented to increase awareness. PMID- 29238171 TI - A 5-year follow-up study of neonates with Hirschsprung's disease undergoing transanal Soave or Swenson surgery. AB - Objective: To investigate different outcomes and long-term efficacy of transanal Soave or Swenson surgery in treatment for neonates with Hirschsprung's disease (HD). Methods: In the present study, a total of 29 neonatal patients were included, with 20 patients undergoing the Soave procedure and nine patients undergoing the Swenson procedure. Data collected from the patients included basic demographics, age and weight at the time of operation, pathological typing, type of operation, operative time, blood loss, length of hospital stay, bowel function, and complications. The follow-up lasted for 5 years for all patients via the outpatient clinics or by telephone. Results were statistically analyzed using SPSS version 18.0. Results: The age, weight, and pathological type of patients with different surgical approaches showed no significant difference. The operation time and blood loss of patients who underwent Swenson procedure were significantly lower than those who underwent Soave procedure; P<0.05. However, intraoperative complications showed no significant difference between the two groups; P>0.05. Bowel function (Rintala score) and postoperative complications in the two groups also showed no significant difference when evaluated 3 months after the surgery; P>0.05. Patients were followed-up for a 5-year period at 3 months, 6 months, 2 years, and 5 years after surgery, respectively. Results showed that complications and bowel function recovery during the 5-year follow-up showed no significant difference between the two methods. Conclusion: The operation time and blood loss of the transanal Swenson pull-through procedure was lower than transanal Soave method; however the long-term outcomes of the two methods showed no significant difference. These results may give more clinical evidence in this field. PMID- 29238172 TI - Closing the loop in person-centered care: patient experiences of a chronic kidney disease self-management intervention. AB - Purpose: The provision of self-management support (SMS) for people with earlier stages (1-4) of chronic kidney disease (CKD) can improve patient outcomes and extend time to dialysis. However, attempts to deliver such support have often not taken patient preferences into account. After the development, implementation, and quantitative evaluation of the person-centered CKD-SMS intervention, the aim of this study was to investigate participant experiences and perceptions of the program, as well as to seek suggestions to improve future SMS attempts. Patients and methods: Semi-structured, face-to-face interviews were conducted with almost all (63/66) participants in the CKD-SMS. Deductive categories were derived from previous research into self-management from the CKD patient's perspective, and this was supplemented by categories that emerged inductively during multiple readings of interview transcripts. Content analysis was used to analyze interview data. Results: Participants recognized self-management of CKD as complex and multifaceted. They felt that the CKD-SMS helped them develop skills to engage in necessary self-management tasks, as well as their knowledge about their condition and confidence to take an active role in their healthcare. These participants experience a healthcare environment that is characterized by complexity and inconsistency, and participation in the intervention helped them to navigate it. The benefit of participating in this research to contribute to the scientific literature was also recognized by participants. Overall, participants found the CKD-SMS useful in its current format, and made some suggestions for future interventions. Conclusion: People with CKD must engage in self-management behavior within a complex health environment. Individualized SMS such as the CKD SMS provides an opportunity to support patients to manage their health effectively. PMID- 29238173 TI - A light-assisted in situ embedment of silver nanoparticles to prepare functionalized fabrics. AB - This article presents a simple, one-step, in situ generation of silver nanoparticle-functionalized fabrics with antibacterial properties, circumventing the conventional, multistep, time-consuming methods. Silver nanoparticle formation was studied with a library of capping agents (branched polyethylenimine [BPEI] of molecular weight [Mw] 10,000 and 25,000, polyvinylpyrrolidone, polyethylene glycol, polyvinylalcohol and citrate) mixed with silver nitrate. The mixture was then exposed to an assortment of light wavelengths (ultraviolet, infrared and simulated solar light) for studying the light-assisted synthesis of nanoparticles. The formation of nanoparticles corresponded with the reducing capabilities of the polymers wherein BPEI gave the best response. Notably, the irradiation wavelengths had little effect on the formation of the nanoparticle when the total irradiation energy was kept constant. The feasibility of utilizing this method for in situ nanoparticle synthesis on textile fabrics (towel [100% cotton], gauze [100% cotton], rayon, felt [100% polyester] and microfiber [15% nylon, 85% polyester]) was verified by exposing the fabrics soaked in an aqueous solution of 1% (w/v) AgNO3 and 1% (w/v) BPEI (Mw 25,000) to light. The formation of nanoparticles on fabrics and their retention after washing was verified using scanning electron microscopy and quantified by inductively coupled plasma optical emission spectrometry. The functional property of the fabric as an antibacterial surface was successfully demonstrated using model bacteria such as Staphylococcus aureus, Enterococcus faecalis and Escherichia coli. The successful generation of silver nanoparticle-functionalized textile fabrics without the use of caustic chemicals, solvents and excessive heating presents a major step towards realizing a scalable green chemistry for industrial generation of functionalized fabrics for a wide range of applications. PMID- 29238175 TI - Timed Up and Go Test can predict recurrent falls: a longitudinal study of the community-dwelling elderly in China. AB - Purpose: Falling is a major health problem in community-dwelling elderly individuals. The aim of the present study was to conduct a prospective investigation to evaluate the accuracy of the Timed Up and Go Test (TUGT), 4 meter walking test, and grip strength test to screen for the risk of falls and to determine a cutoff point to be used clinically. Patients and methods: This was a prospective study that included 541 participants. The fall data were obtained via face-to-face interview, and the date, site, and circumstances of any falls were recorded. TUGTs were recorded as part of a comprehensive geriatric assessment. We collected the same data at baseline and after follow-up via comprehensive geriatric assessment. Results: The incidence of falls of our study subjects was 20.8%. The recurrent-fall group had a fall rate of 6.8% during the follow-up year. The standard area under the curve (AUC) of our screening tool was >0.70, and hence our tool can be used for clinical purposes. After adjusting for age and gender, the AUC of TUGT became 0.642, so it cannot be used as a predictive tool for measuring any types of falls. However, when recurrent falls were adjusted for age and gender, the TUGT's AUC improved to 0.733 and a score of 15.96 seconds is used as a cut-point to screen recurrent falls in community-dwelling elderly Chinese individuals. Conclusion: Future falls were best predicted by TUGT in recurrent fallers at baseline. A score of 15.96 seconds is used as a cut-point to screen recurrent falls in community-dwelling elderly Chinese individuals. PMID- 29238176 TI - Emotion experience and frailty in a sample of Italian community-dwelling older adults. AB - Frailty increases individual vulnerability to external stressors and involves high risk for adverse geriatric outcomes. To date, few studies have addressed the role of emotion perception and its association with frailty in aged populations. This cross-sectional study aimed to explore whether a significant association between frailty and emotional experience exists in a sample of Italian community dwelling older adults. Our sample consisted of 104 older adults (age 76+/-8 years; 59.6% women) living in Piedmont, Italy. Frailty was measured using the Italian version of the Tilburg Frailty Indicator (TFI), and emotion perception was measured with the Positive and Negative Affect Schedule (PANAS). The Mini Mental State Examination was used as a screening tool for cognitive functions (people with a score <=20 points were excluded). One-way analysis of covariance (ANCOVA), adjusted for interesting variables, and post hoc tests were performed where appropriate. According to the TFI, 57.7% of participants resulted as frail. Analysis showed a significant greater severity of frailty in the low positive affect (PA) group compared to the high PA group. Similarly, those with high negative affect (NA) showed significantly higher levels of frailty than the low NA group. As expected, significant differences for frailty were also found among the groups composed of 1) people with high PA and low NA, 2) people with low PA or high NA, and 3) people with low PA and high NA. Post hoc tests showed a greater severity of frailty in the second and in the third groups compared to the first one. Lastly, robust participants aged >75 years showed higher levels of PA than the group aged between 60 and 75 years. These findings demonstrate that both PA and NA may influence frailty, giving new insights for the evaluation and prevention of frailty in older adults. PMID- 29238174 TI - Human Polyomaviruses: The Battle of Large and Small Tumor Antigens. AB - About 40 years ago, the large and small tumor antigens (LT-Ag and sT-Ag) of the polyomavirus (PyVs) simian vacuolating virus 40 have been identified and characterized. To date, it is well known that all the discovered human PyVs (HPyVs) encode these 2 multifunctional and tumorigenic proteins, expressed at viral replication early stage. The 2 T-Ags are able to transform cells both in vitro and in vivo and seem to play a distinct role in the pathogenesis of some tumors in humans. In addition, they are involved in viral DNA replication, transcription, and virion assembly. This short review focuses on the structural and functional features of the HPyVs' LT-Ag and sT-Ag, with special attention to their transforming properties. PMID- 29238177 TI - The mediating role of psychological symptoms on falls risk among older adults with osteoarthritis. AB - The purpose of this study was to investigate the role of fear of falling (FoF) and psychological symptoms in explaining the relationship between osteoarthritis (OA) symptom severity and falls. Individuals aged >=65 years with >=2 falls or >=1 injurious fall over the past 12 months were included in the falls group, while volunteers aged >=65 years with no history of falls over 12 months were recruited as controls. The presence of lower extremity OA was determined radiologically and clinically. Severity of symptoms was assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. FoF and psychological status were measured with the shortened version of the Falls Efficacy Scale-International and the 21-item Depression, Anxiety and Stress Scale (DASS-21), respectively. Of 389 (229 fallers, 160 non-fallers) potential participants, mean (SD) age: 73.74 (6.60) years, 141 had clinical OA and 171 had radiological OA. Fallers with both radiological OA and clinical OA had significantly higher FoF and DASS-21 scores than non-fallers. FoF was significantly positively correlated with symptom severity in fallers and non fallers with radiological and clinical OA. Depression, anxiety, and stress scores were only significantly correlated with symptom severity among fallers but not non-fallers in both clinical and radiological OA. The relationship between mild symptoms and reduced risk of falls compared to no symptoms in those with radiological OA was attenuated by increased anxiety. The increased falls risk associated with severe symptoms compared to mild symptoms in clinical OA was attenuated by FoF. FoF may, therefore, be a potentially modifiable risk factor for OA-associated falls which could be considered in future intervention studies. PMID- 29238178 TI - Clinical application of arthroscopy-assisted minimally invasive therapy in Chinese elderly with type III Pilon fracture. AB - Objective: Pilon fracture is so complex that its therapy poses a great challenge to surgeons. Few studies have compared arthroscopy-assisted minimally invasive therapy and external fixation combined with limited internal fixation (EFLIF), and an optimal choice of surgical therapy remains unclear in patients with type III Pilon fracture. Moreover, to our knowledge, very few studies have specifically evaluated arthroscopy-assisted minimally invasive therapy in Chinese elderly with type III Pilon fracture. The current study was performed to observe the clinical application of arthroscopy-assisted minimally invasive therapy, compared with EFLIF, in Chinese elderly with type III Pilon fracture. Methods: There were 230 Chinese elderly with type III Pilon fracture assigned to undergo EFLIF (group A, n=115) or arthroscopy-assisted minimally invasive therapy (group B, n=115), and followed up for 1 year after surgery. Results: Age, sex, causes, sides and types of Pilon fractures were not different between the two groups (P>0.05 for all). Compared with EFLIF, arthroscopy-assisted minimally invasive therapy achieved a better reduction result, bone union and Mazur system (P<0.05 for all). Patient satisfaction, screw loosening and infection prevalence were not different between the two groups (P>0.05 for all). There was no skin necrosis in the two groups. Traumatic arthritis had a significantly lower prevalence in participants with arthroscopy-assisted minimally invasive therapy than EFLIF (P<0.05 for all). Conclusion: Compared with EFLIF, arthroscopy-assisted minimally invasive therapy for type III Pilon fracture significantly improved reduction result, bone union and functional status, and decreased traumatic arthritis, demonstrating that arthroscopy-assisted minimally invasive therapy is an optimal choice for type III Pilon fracture in Chinese elderly. PMID- 29238179 TI - Role of poly (ADP-ribose) polymerase-1 and cytokines in acute renal injury in elderly Chinese patients with diabetes mellitus. AB - Objective: The primary objective of this study was to evaluate whether the polymorphism of poly (ADP-ribose) polymerase-1 (PARP-1) is involved as a potential risk factor in the development of acute renal injury in elderly Chinese patients with diabetes mellitus. Subjects and methods: In this pilot study, diabetic patients of either gender (aged >=65 years) with a confirmed diagnosis of acute renal injury and individuals with no clinical symptoms of acute renal injury were enrolled at Nanxishan Hospital of Guangxi Zhuang Autonomous Region, China. Genetic polymorphism of PARP-1 was assessed using polymerase chain reaction-restriction fragment length polymorphism assay. Cytokine levels (interleukin [IL]-6, IL-1beta and tumor necrosis factor-alpha) were measured in the serum samples by sandwich enzyme-linked immunosorbent assay technique. Results: A total of 130 Chinese patients with acute renal injury and 130 Chinese individuals with no clinical symptoms of acute renal injury were included. We found that the patients with GG genotype and carriers of the G and C alleles of PARP-1 were at high risk of developing acute renal injury. Moreover, del/ins polymorphism of the NF-kappaB1 gene was also found to be associated with acute renal injury. In addition, the levels of IL-6, IL-1beta and tumor necrosis factor alpha were significantly increased in patients with acute renal injury (p<0.05). Conclusion: Our findings showed the involvement of PARP-1 polymorphisms in the development of acute renal injury in Chinese individuals. This study identified the involvement of two SNPs of PARP-1 (C410T and G1672A) in development of acute renal injury among Chinese diabetic patients. Also, increased expression of C and G alleles of PARP-1 can be considered as one of the potential risk factors for developing acute renal injury. Increased serum cytokine levels can be considered as one of the potential risk factors for developing acute renal injury. PMID- 29238180 TI - Efficacy comparison of intramedullary nails, locking plates and conservative treatment for displaced proximal humeral fractures in the elderly. AB - Purpose: The incidence of proximal humeral fractures is high in the elderly, and the superior management of these fractures remains a controversy. The study aims to compare clinical outcomes of intramedullary nails, locking plates and conservative treatment for the management of displaced proximal humeral fractures in the elderly. Patients and methods: In this prospective study, a total of 198 patients with 2- or 3-part proximal humeral fractures who received fixation of locking plates or intramedullary nails or conservative treatment were included. The primary outcome was the 24-month Constant-Murley score. The secondary outcomes included the American Shoulder and Elbow Surgeons (ASES) scores, the visual analog scale (VAS) pain scores, shoulder range of motion and complication rate. Results: There were no statistically significant differences in the Constant-Murley scores and ASES scores among the plate group, the nail group and the conservative group for 2-part fractures. For 3-part fractures, Constant Murley scores and ASES scores were lower in the conservative group compared with those in the plate group and the nail group. Besides, the conservative group showed a significantly lower external rotation during follow-ups. The complication rate was comparable among the plate group, the nail group and the conservative group for both 2-part and 3-part fractures. Conclusion: Similar satisfactory functional outcomes can be achieved with the locking plates, intramedullary nails or conservative treatment for 2-part proximal humeral fractures in the elderly. The advantages in functional outcomes favor locking plates and intramedullary nails in the management of 3-part proximal humeral fractures. PMID- 29238181 TI - The link between weight shift asymmetry and gait disturbances in chronic hemiparetic stroke patients. AB - Introduction: While the asymmetry of body posture and the asymmetrical nature of hemiparetic gait in poststroke (PS) patients are well documented, the role of weight shift asymmetry in gait disorders after stroke remains unclear. Objective: We examined the association of weight-bearing asymmetry (WBA) between paretic and nonparetic lower limbs during quiet standing with the degree of deviation of hemiplegic gait from normal gait evaluated by the Gillette Gait Index (GGI) incorporating 16 distinct clinically important kinematic and temporal parameters in chronic PS patients. Participants and methods: Twenty-two ambulatory patients with chronic stroke aged between 50 and 75 years were included in this study. Fourteen patients had hemiparesis on the nondominant side and 8 on the dominant side. The mean time PS was 2 years and 6 months. The reference group consisted of 22 students from the University of the Third Age presenting no neurological disorders. The examination consisted of posturographic weight-bearing (WB) distribution and 3-dimensional gait analyses. Results: A significant positive relationship between WBA and GGI was revealed. Moreover, we observed a significant negative association between WBA and paretic step length and walking speed. With regard to kinematic data, the range of motion of knee flexion and peak dorsiflexion in the swing phase of the paretic leg were significantly negatively associated with WBA. Conclusion: Although further research is needed to determine a causal link between postural control asymmetry and gait disturbance in hemiplegics, our findings support the inclusion of WB measurements between paretic and nonparetic body sides in early assessment after stroke. PMID- 29238182 TI - Adherence to a COPD treatment guideline among patients in Hong Kong. AB - Background: This study aimed to assess the adherence rate of pharmacological treatment to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline published in 2011 and the prevalence of comorbidities among patients with COPD in Hong Kong (HK). Methods: Patients were recruited from five tertiary respiratory centers and followed up for 12 months. Data on baseline physiological, spirometric parameters, use of COPD medications and coexisting comorbidities were collected. The relationship between guideline adherence rate and subsequent COPD exacerbations was assessed. Results: Altogether, 450 patients were recruited. The mean age was 73.7+/-8.5 years, and 92.2% of them were males. Approximately 95% of them were ever-smokers, and the mean post-bronchodilator (BD) forced expiratory volume in 1 second was 50.8%+/-21.7% predicted. The mean COPD Assessment Test and modified Medical Research Council Dyspnea Scale were 13.2+/-8.1 and 2.1+/-1.0, respectively. In all, five (1.1%), 164 (36.4%), eight (1.8%) and 273 (60.7%) patients belonged to COPD groups A, B, C and D, respectively. The guideline adherence rate for pharmacological treatment ranged from 47.7% to 58.1% in the three clinic visits over 12 months, with overprescription of inhaled corticosteroids (ICS) and underutilization of long acting BDs in group B COPD patients. Guideline nonadherence was not associated with increased risk of exacerbation after adjustment of confounding variables. However, this study was not powered to assess a difference in exacerbations. In all, 80.9% of patients had at least one comorbidity. Conclusion: A suboptimal adherence to GOLD guideline 2011, with overprescription of ICS, was identified. The commonly found comorbidities also aligned with the trend observed in other observational cohorts. PMID- 29238183 TI - Gene and miRNA expression profiles in PBMCs from patients with severe and mild emphysema and PiZZ alpha1-antitrypsin deficiency. AB - Introduction: COPD has complex etiologies involving both genetic and environmental determinants. Among genetic determinants, the most recognized is a severe PiZZ (Glu342Lys) inherited alpha1-antitrypsin deficiency (AATD). Nonetheless, AATD patients present a heterogeneous clinical evolution, which has not been completely explained by sociodemographic or clinical factors. Here we performed the gene expression profiling of blood cells collected from mild and severe COPD patients with PiZZ AATD. Our aim was to identify differences in messenger RNA (mRNA) and microRNA (miRNA) expressions that may be associated with disease severity. Materials and methods: Peripheral blood mononuclear cells from 12 COPD patients with PiZZ AATD (6 with severe disease and 6 with mild disease) were used in this pilot, high-throughput microarray study. We compared the cellular expression levels of RNA and miRNA of the 2 groups, and performed functional and enrichment analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene-ontology (GO) terms. We also integrated the miRNA and the differentially expressed putative target mRNA. For data analyses, we used the R statistical language R Studio (version 3.2.5). Results: The severe and mild COPD AATD groups were similar in terms of age, gender, exacerbations, comorbidities, and use of augmentation therapy. In severe COPD-AATD patients, we found 205 differentially expressed genes (DEGs) (114 upregulated and 91 downregulated) and 28 miRNA (20 upregulated and 8 downregulated) compared to patients with mild COPD AATD disease. Of these, hsa-miR-335-5p was downregulated and 12 target genes were involved in cytokine signaling, MAPK/mk2, JNK signaling cascades, and angiogenesis were much more highly expressed in severe compared with mild patients. Conclusions: Despite the small sample size, we identified downregulated miRNA (hsa-miR-335) and the activation of pathways related to inflammation and angiogenesis on comparing patients with severe vs mild COPD-AATD. Nonetheless, our findings warrant further validation in large studies. PMID- 29238184 TI - Determinants of exacerbation risk in patients with COPD in the TIOSPIR study. AB - Background: Exacerbation history is used to grade the risk of COPD exacerbation, but its reliability and relationship to other risk factors and prior therapy is unclear. To examine these interrelationships, we conducted a post hoc analysis of patients in the TIOSPIR trial with >=2 years' follow-up or who died on treatment. Patients and methods: Patients were grouped by their annual exacerbation rate on treatment into nonexacerbators, infrequent, and frequent exacerbators (annual exacerbation rates 0, <=1, and >1, respectively), and baseline characteristics discriminating among the groups were determined. We used univariate and multivariate analyses to explore the effect of baseline characteristics on risk of exacerbation, hospitalization (severe exacerbation), and death (all causes). Results: Of 13,591 patients, 6,559 (48.3%) were nonexacerbators, 4,568 (33.6%) were infrequent exacerbators, and 2,464 (18.1%) were frequent exacerbators; 45% of patients without exacerbations in the previous year exacerbated on treatment. Multivariate analysis identified baseline pulmonary maintenance medication as a predictive factor of increased exacerbation risk, with inhaled corticosteroid treatment associated with increased exacerbation risk irrespective of exacerbation history. Conclusion: Our data confirm established risk factors for exacerbation, but highlight the limitations of exacerbation history when categorizing patients and the importance of prior treatment when identifying exacerbation risk. PMID- 29238185 TI - Occupational exposure to vapor, gas, dust, or fumes and chronic airflow limitation, COPD, and emphysema: the Swedish CArdioPulmonary BioImage Study (SCAPIS pilot). AB - Background: The aim of this study was to estimate the occupational burden of airflow limitation, chronic airflow limitation, COPD, and emphysema. Materials and methods: Subjects aged 50-64 years (n=1,050) were investigated with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Airflow limitation was defined as FEV1/FVC <0.7 before bronchodilation. Chronic airflow limitation was defined after bronchodilation either according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as FEV1/FVC <0.7 or according to the lower limit of normal (LLN) approach as FEV1/FVC < LLN. COPD was defined as chronic airflow limitation (GOLD) in combination with dyspnea, wheezing, or chronic bronchitis. Emphysema was classified according to findings from computed tomography of the lungs. Occupational exposure was defined as self reported occupational exposure to vapor, gas, dust, or fumes (VGDF). Odds ratios (OR) were calculated in models adjusted for age, gender, and smoking; population attributable fractions and 95% CI were also calculated. Results: There were significant associations between occupational exposure to VGDF and COPD (OR 2.7, 95% CI 1.4-51), airflow limitation (OR 1.8, 95% CI 1.3-2.5), and emphysema (OR 1.8, 95% CI 1.1-3.1). The associations between occupational exposure to VGDF and chronic airflow limitation were weaker, and for the OR, the CIs included unity. The population-attributable fraction for occupational exposure to VGDF was 0.37 (95% CI 0.23-0.47) for COPD and 0.23 (95% CI 0.05-0.35) for emphysema. Conclusion: The occupational burden of COPD and computed tomography-verified emphysema is substantial. PMID- 29238186 TI - Severe COPD cases from Korea, Poland, and USA have substantial differences in respiratory symptoms and other respiratory illnesses. AB - Purpose: Chronic obstructive pulmonary disease (COPD), characterized by irreversible airflow obstruction, is a major cause of morbidity and mortality worldwide. However, geographic differences in the clinical characteristics of severe COPD patients have not been widely studied. Methods: We recruited a total of 828 severe COPD cases from three continents. Subjects in Poland were enrolled by the Institute of Tuberculosis and Lung Diseases in Warsaw; subjects in Korea participated at several university hospitals in Korea; and subjects in USA were enrolled at two clinics affiliated with academic medical centers. All subjects were over the age of 30 with at least 10 pack-years of cigarette smoking history. Cases manifested severe to very severe airflow obstruction with post bronchodilator forced expiratory volume in 1 second (FEV1) <50% predicted and FEV1/forced vital capacity <0.7. All subjects completed a detailed questionnaire and underwent standardized pre-bronchodilator and post-bronchodilator spirometry. Subjects with known tuberculosis (TB)-associated lung parenchymal destruction were excluded. Univariate and multivariate assessments of the impact of the country of origin on respiratory symptoms and respiratory illness were performed. Results: In both univariate and multivariate analyses, a history of TB (38.7%) and physician-diagnosed asthma (43.9%) were significantly more common in subjects with severe COPD from Korea than USA or Poland, while attacks of bronchitis (64.2%) were more common in subjects with severe COPD from Poland. COPD subjects from Poland had more severe dyspnea (modified Medical Research Council 3.3+/-1.0) and more frequently reported symptoms of chronic bronchitis (52.2%). A history of TB was also more common in Poland (10.8%) than in USA (0.3%) severe COPD patients. Conclusion: Respiratory symptoms and other respiratory illnesses associated with severe COPD differed widely among three continents. PMID- 29238187 TI - Hand grip endurance test relates to clinical state and prognosis in COPD patients better than 6-minute walk test distance. AB - Purpose: Patients with COPD present peripheral muscle dysfunction and atrophy, expressed as muscle strength and endurance reduction. The goal of this study was direct dynamometric assessment of hand grip endurance and strength in relation to the stage of disease, multidimensional predictors of mortality, and 6-minute walk test (6MWT). To the best of our knowledge, there has been no previous study determining these parameters. Patients and methods: In this observational study, 58 consecutive outpatients with stable COPD and 25 volunteers without respiratory problems were compared. All COPD subjects underwent a comprehensive examination to determine COPD severity, prognostic scales, and 6MWT. Body composition, basic spirometric parameters, and hand grip strength and endurance were determined in all study participants. Results: Patients in the COPD group had a 15% decrease in maximum strength (P=0.012) and a 28% decrease in area under the force/time curve (AUC) of the endurance test (P<0.001) compared to the control group. Dynamometric parameters were significantly negatively associated with the stage of disease and values of multivariable prediction indexes, and positively associated with the results of 6MWT. In most cases, closer associations were found with AUC than with 6MWT and in the gender-specific groups. Conclusion: Both hand grip strength and endurance are impaired in COPD patients in comparison with the control group. In particular, AUC could be considered as an attractive option not only to assess exercise capacity but also as a predictive marker with a better prognostic value than 6MWT in COPD patients. This is the first study to observe the dependence of hand grip endurance on combined COPD assessment. PMID- 29238189 TI - Diethyl citrate and sodium citrate reduce the cytotoxic effects of nanosized hydroxyapatite crystals on mouse vascular smooth muscle cells. AB - Objective: This study aimed to investigate the damage mechanism of nanosized hydroxyapatite (nano-HAp) on mouse aortic smooth muscle cells (MOVASs) and the injury-inhibiting effects of diethyl citrate (Et2Cit) and sodium citrate (Na3Cit) to develop new drugs that can simultaneously induce anticoagulation and inhibit vascular calcification. Methods: The change in cell viability was evaluated using a cell proliferation assay kit, and the amount of lactate dehydrogenase (LDH) released was measured using an LDH kit. Intracellular reactive oxygen species (ROS) and mitochondrial damage were detected by DCFH-DA staining and JC-1 staining. Cell apoptosis and necrosis were detected by Annexin V staining. Intracellular calcium concentration and lysosomal integrity were measured using Fluo-4/AM and acridine orange, respectively. Results: Nano-HAp decreased cell viability and damaged the cell membrane, resulting in the release of a large amount of LDH. Nano-HAp entered the cells and damaged the mitochondria, and then induced cell apoptosis by producing a large amount of ROS. In addition, nano-HAp increased the intracellular Ca2+ concentration, leading to lysosomal rupture and cell necrosis. On addition of the anticoagulant Et2Cit or Na3Cit, cell viability and mitochondrial membrane potential increased, whereas the amount of LDH released, ROS, and apoptosis rate decreased. Et2 Cit and Na3Cit could also chelate with Ca+ to inhibit the intracellular Ca2+ elevations induced by nano HAp, prevent lysosomal rupture, and reduce cell necrosis. High concentrations of Et2Cit and Na3Cit exhibited strong inhibitory effects. The inhibitory capacity of Na3Cit was stronger than that of Et2Cit at similar concentrations. Conclusion: Both Et2Cit and Na3Cit significantly reduced the cytotoxicity of nano-HAp on MOVASs and inhibited the apoptosis and necrosis induced by nano-HAp crystals. The chelating function of citrate resulted in both anticoagulation and binding to HAp. Et2Cit and Na3Cit may play a role as anticoagulants in reducing injury to the vascular wall caused by nano-HAp. PMID- 29238188 TI - Effects of major parameters of nanoparticles on their physical and chemical properties and recent application of nanodrug delivery system in targeted chemotherapy. AB - Chemotherapy is still one of the main cancer therapy treatments, but the curative effect of chemotherapy is relatively low, as such the development of a new cancer treatment is highly desirable. The gradual maturation of nanotechnology provides an innovative perspective not only for cancer therapy but also for many other applications. There are a diverse variety of nanoparticles available, and choosing the appropriate carriers according to the demand is the key issue. The performance of nanoparticles is affected by many parameters, mainly size, shape, surface charge, and toxicity. Using nanoparticles as the carriers to realize passive targeting and active targeting can improve the efficacy of chemotherapy drugs significantly, reduce the mortality rate of cancer patients, and improve the quality of life of patients. In recent years, there has been extensive research on nanocarriers. In this review, the effects of several major parameters of nanoparticles on their physical and chemical properties are reviewed, and then the recent progress in the application of several commonly used nanoparticles is presented. PMID- 29238190 TI - Development of coated liposomes loaded with ghrelin for nose-to-brain delivery for the treatment of cachexia. AB - The aim of the present study was to develop a ghrelin-containing formulation based on liposomes coated with chitosan intended for nose-brain delivery for the treatment of cachexia. Among the three types of liposomes developed, anionic liposomes provided the best results in terms of encapsulation efficiency (56%) and enzymatic protection against trypsin (20.6% vs 0% for ghrelin alone) and carboxylesterase (81.6% vs 17.2% for ghrelin alone). Ghrelin presented both electrostatic and hydrophobic interactions with the anionic lipid bilayer, as demonstrated by isothermal titration calorimetry. Then, anionic liposomes were coated with N-(2-hydroxy) propyl-3-trimethyl ammonium chitosan chloride. The coating involved a size increment from 146.9+/-2.7 to 194+/-6.1 nm, for uncoated and coated liposomes, respectively. The zeta-potential was similarly increased from -0.3+/-1.2 mV to 6+/-0.4 mV before and after coating, respectively. Chitosan provided mucoadhesion, with an increase in mucin adsorption of 22.9%. Enhancement of permeation through the Calu3 epithelial monolayer was also observed with 10.8% of ghrelin recovered in the basal compartment in comparison to 0% for ghrelin alone. Finally, aerosols generated from two nasal devices (VP3 and SP270) intended for aqueous dispersion were characterized with either coated or uncoated liposomes. Contrarily to the SP270 device, VP3 device showed minor changes between coated and uncoated liposome aerosols, as shown by their median volume diameters of 38.4+/-5.76 and 37.6+/-5.74 um, respectively. Overall, the results obtained in this study show that the developed formulation delivered by the VP3 device can be considered as a potential candidate for nose-brain delivery of ghrelin. PMID- 29238191 TI - Induction of apoptosis in HeLa cancer cells by an ultrasonic-mediated synthesis of curcumin-loaded chitosan-alginate-STPP nanoparticles. AB - Natural herbal compounds have been widely introduced as an alternative therapeutic approach in cancer therapy. Despite potent anticancer activity of curcumin, its clinical application has been limited because of low water solubility and resulting poor bioavailability. In this study, we designed a novel ultrasonic-assisted method for the synthesis of curcumin-loaded chitosan-alginate sodium tripolyphosphate nanoparticles (CS-ALG-STPP NPs). Furthermore, antitumor effect of curcumin-loaded NPs was evaluated in vitro. Field emission scanning electron microscopy (FE-SEM) and atomic force microscopy (AFM) were used to characterize the properties of NPs. Antitumor activity of curcumin-loaded NPs was assessed by using MTT and quantitative real-time polymerase chain reaction (qRT PCR). FE-SEM and AFM data revealed the spherical morphology, and the average size of NPs was <50 nm. In vitro cytotoxicity assay suggested that curcumin-loaded CS ALG-STPP NPs displayed significant antitumor activity compared with the free curcumin. Gene expression level analyses showed that curcumin NPs significantly increased the apoptotic gene expression. Collectively, our results suggest that curcumin-loaded NPs significantly suppressed proliferation and promoted the induction of apoptosis in human cervical epithelioid carcinoma cancer cells, which might be regarded as an effective alternative strategy for cancer therapy. PMID- 29238192 TI - Transcriptome-wide elucidation of liposomal formulations for anticancer drug delivery. AB - Although widely used in chemotherapy, free doxorubicin (Dox) might enhance cell malignancy undesirably. Liposomal Dox (Doxlipo) has been clinically approved for the treatment of breast cancer due to reduced systematical toxicity and increased tumor targeting, yet the transcriptome-wide elucidation of the Doxlipo formulations remains elusive. To this end, we explored the impact of two Dox liposomal formulations, Doxlipo mainly containing hydrogenated soy phosphatidylcholine or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, on the transcriptional pattern of MCF-7 cells. The two types of Dox liposomal formulations with different drug release kinetics were investigated to reveal the relationship between the formulation and tumor malignancy. Interestingly, we found that liposomal formulation significantly altered the transcriptional pattern of a wide range of genes. Under equivalent dosage of Dox, free Dox substantially changed the expression of ANK1, ACTA2, GPR87, GDF15, FZD6, and WNT4 in MCF-7 cells. Notably, free Dox induced much higher expression of ABCB1 and significantly enhanced the cell migration behavior in comparison with HSPC Doxlipo under a similar level of cytotoxicity. Finally, siRNA targeting GPR87 was codelivered with cationic Doxlipo to reduce the expression of malignancy-related genes. Our study, for the first time, provides an overview of the influence of formulation on the malignancy at transcriptional level and reveals the relationship between cytotoxicity and cell malignancy from the formulation aspect, offering valuable reference for the future formulation design for anticancer drug delivery. PMID- 29238193 TI - In vivo evaluation of a novel nanocomposite porous 3D scaffold in a rabbit model: histological analysis. AB - The healing of load-bearing segmental defects in long bones is a challenge due to the complex nature of the weight that affects the bone part and due to bending, shearing, axial, and torsional forces. An innovative porous 3D scaffolds implant of CaCO3 aragonite nanocomposite derived from cockle shell was advanced for substitute bone solely for load-bearing cases. The biomechanical characteristics of such materials were designed to withstand cortical bone strength. In promoting bone growth to the implant material, an ideal surface permeability was formed by means of freeze drying and by adding copolymers to the materials. The properties of coating and copolymers supplement were also assessed for bone-implant connection resolutions. To examine the properties of the material in advanced biological system, an experimental trial in an animal model was carried out. Critical sized defect of bone was created in rabbit's radial bone to assess the material for a load-bearing application with a short and extended period assessment with histological evaluation of the incorporated implanted material to the bone of the host. Trials in animal models proved that the material has the capability of enduring load-bearing conditions for long-term use devoid of breaking or generating stress that affects the host bone. Histological examination further confirmed the improved integration of the implanted materials to the host bone with profound bone development into and also above the implanted scaffold, which was attained with negligible reaction of the tissues to a foreign implanted material. PMID- 29238194 TI - Polyethyleneimine-capped silver nanoclusters for microRNA oligonucleotide delivery and bacterial inhibition. AB - Efficient and safe nonviral gene delivery systems are a prerequisite for the clinical application of therapeutic genes. In this paper, polyethyleneimine capped silver nanoclusters (PEI-AgNCs) were prepared for the purpose of microRNA (miRNA) delivery. The resultant PEI-AgNCs were characterized by a photoluminescence assay and transmission electron microscopy. A cytotoxicity assay showed that PEI-AgNCs exhibit relatively low cytotoxicity. Interestingly, PEI-AgNCs were confirmed to transfect miRNA mimics more effectively than PEI in HepG2 and 293A cells. In this regard, hsa-miR-21 or hsa-miR-221 mimics (miR 21/221m) were transported into HepG2 cells by using PEI-AgNCs. The miR-21/221 expression was determined post-transfection by quantitative real-time polymerase chain reaction. Compared with the negative control, PEI-AgNCs/miR-21/221m groups exhibited higher miR-21/221 levels. In addition, AgNCs endow PEI with stronger antibacterial activity, and this advantage provided PEI-AgNCs the potential to prevent bacterial contamination during the transfection process. Furthermore, we showed that PEI-AgNCs are viable nanomaterials for plain imaging of the cells by laser scanning confocal microscopy, indicating great potential as an ideal fluorescent probe to track the transfection behavior. These results demonstrated that PEI-AgNCs are promising and novel nonviral vectors for gene delivery. PMID- 29238195 TI - Cytokines and depression in cancer patients and caregivers. AB - Objective: A better understanding of the biobehavioral mechanisms underlying depression in cancer is required to translate biomarker findings into clinical interventions. We tested for associations between cytokines and the somatic and psychological symptoms of depression in cancer patients and their healthy caregivers. Patients and methods: The GRID Hamilton Rating Scale for Depression (Ham-D) was administered to 61 cancer patients of mixed type and stage, 26 primary caregivers and 38 healthy controls. Concurrently, blood was drawn for multiplexed plasma assays of 15 cytokines. Multiple linear regression, adjusted for biobehavioral variables, identified cytokine associations with the psychological (Ham-Dep) and somatic (Ham-Som) subfactors of the Ham-D. Results: The Ham-Dep scores of cancer patients were similar to their caregivers, but their Ham-Som scores were significantly higher (twofold, p=0.016). Ham-Som was positively associated with IL-1ra (coefficient: 1.27, p<=0.001) in cancer patients, and negatively associated with IL-2 (coefficient: -0.68, p=0.018) in caregivers. Ham-Dep was negatively associated with IL-4 (coefficient: -0.67, p=0.004) in cancer patients and negatively associated with IL-17 (coefficient: 1.81, p=0.002) in caregivers. Conclusion: The differential severity of somatic symptoms of depression in cancer patients and caregivers and the unique cytokine associations identified with each group suggests the potential for targeted interventions based on phenomenology and biology. The clinical implication is that depressive symptoms in cancer patients can arise from biological stressors, which is an important message to help destigmatize the development of depression in cancer patients. PMID- 29238196 TI - The role of new antidepressants in clinical practice in Canada: a brief review of vortioxetine, levomilnacipran ER, and vilazodone. AB - Although many branded and generic antidepressants are approved for the treatment of major depressive disorder (MDD) in Canada, efficacy and tolerability differ among patients, and new treatment options are needed. Symptom types (eg, fatigue, energy/motivation, cognition, and functioning), medication type, treatment duration, and the need for maintenance therapy are factors that may influence treatment effectiveness. Three antidepressants, vortioxetine, levomilnacipran extended-release (ER), and vilazodone have recently become available in Canada. The aim of this review is to contextualize differences in their mechanistic and clinical profiles, thereby providing practitioners with knowledge to support treatment decisions. In trials versus placebo, each drug improved depressive symptoms in adult patients with MDD. The antidepressant effect of vortioxetine may be related to enhanced serotonergic activity via reuptake inhibition and agonism and/or antagonism of various serotonin receptors. Vortioxetine may also improve cognitive functioning in MDD, and has proven efficacious in relapse prevention. Nausea was the most commonly reported adverse event (AE); rates of sexual dysfunction were low and abrupt discontinuation was well tolerated. Levomilnacipran ER, a serotonin norepinephrine reuptake inhibitor, demonstrated greater improvement versus placebo in functional impairment as well as depressive symptoms; in post hoc analyses, improvement in symptoms of motivation and energy were observed. Nausea was the most commonly reported AE; gradual discontinuation is recommended to avoid discontinuation syndrome. Vilazodone is a serotonin reuptake inhibitor and partial serotonergic 5-HT1A receptor agonist. In addition to improvement in depressive symptoms, evidence suggests that vilazodone may be particularly well suited for depressed patients with high anxiety levels. Diarrhea, nausea, and headache were the most common AEs; low rates of sexual dysfunction were reported. The 2016 Canadian Network for Mood and Anxiety Treatments guidelines for MDD includes vortioxetine as a first-line treatment; levomilnacipran ER and vilazodone are considered as second-line treatments due to lack of relapse prevention data at the time of approval. PMID- 29238197 TI - Effect of handedness on auditory attentional performance in ADHD students. AB - The relationship between handedness and attentional performance is poorly understood. Continuous performance tests (CPTs) using visual stimuli are commonly used to assess subjects suffering from attention deficit hyperactivity disorder (ADHD). However, auditory CPTs are considered more useful than visual ones to evaluate classroom attentional problems. A previous study reported that there was a significant effect of handedness on students' performance on a visual CPT. Here, we examined whether handedness would also affect CPT performance using only auditory stimuli. From an initial sample of 337 students, 11 matched pairs were selected. Repeated ANOVAs showed a significant effect of handedness on attentional performance that was exhibited even in the control group. Left handers made more commission errors than right-handers. The results were interpreted considering that the association between ADHD and handedness reflects that consistent left-handers are less lateralized and have decreased interhemispheric connections. Auditory attentional data suggest that left-handers have problems in the impulsive/hyperactivity domain. In ADHD, clinical therapeutics and rehabilitation must take handedness into account because consistent sinistrals are more impulsive than dextrals. PMID- 29238199 TI - Outcome and safety of tailored surgical treatments of nonmalignant esophagotracheobronchial fistula: report of fourteen patients. AB - Introduction: Acquired benign esophageal tracheobronchial fistulae are clinically rare. In this paper, we summarize our experiences in surgical treatment of 14 consecutive patients with acquired benign esophageal tracheobronchial fistula. Methods: This series included patients who underwent surgery between January 2002 and June 2015 at our institution. We retrieved and analyzed data on demographics, operative characteristics, and surgical outcome of the patients. Results: Bronchofiberscopy revealed the membranous trachea openings of fistulae and gastroendoscopy further showed lesions in the anterolateral wall of the esophagus. Thoracotomy, division of the fistulous tract, and closure of the esophagus and trachea and other procedures were performed. All operations were uneventful, and there was no perioperative and postoperative complication or death. Symptoms disappeared after surgery in patients. The median length of hospital stay was 53 (range 31-270) days. The patients were followed up for a median of 33.5 (range 15-168) months. No recurrence was reported. Conclusion: Our results suggest that acquired benign esophageal tracheobronchial fistulae have a broad spectrum of anatomic pathologies and exhibit markedly varied clinical manifestations, and a surgical approach tailored to the condition of individual patients is recommended. PMID- 29238200 TI - MicroRNA-211 promotes non-small-cell lung cancer proliferation and invasion by targeting MxA. AB - Recent studies have shown that microRNAs play a pivotal role in the pathogenesis of cancer. In our current study, the expression levels of microRNA-211 (miR-211) were measured in human non-small-cell lung cancer (NSCLC) tissues and cell lines. We found that miR-211 expression levels were increased in NSCLC tissues and cell lines and that the overexpression of miR-211 promotes cell proliferation and invasion. Using bioinformatics, we demonstrated that miR-211 binds to the 3' untranslated region of MxA and overexpression of miR-211 suppresses the expression of MxA at both the transcriptional and translational levels in NSCLC cell lines. Furthermore, knockdown of MxA increased the proliferation and invasion of NSCLC cell lines in vitro. High levels of miR-211 expression were associated with a shorter survival time in patients with NSCLC. Taken together, these results suggest that miR-211 promotes tumor proliferation and invasion by regulating MxA expression in NSCLC. This study provides insights into molecular mechanisms of miR-211-mediated tumorigenesis and oncogenesis. PMID- 29238198 TI - Oral microbiome and peri-implant diseases: where are we now? AB - Peri-implant infective diseases (PIIDs) in oral implantology are commonly known as peri-implant mucositis (PIM) and periimplantitis (PI). While PIM is restricted to the peri-implant mucosa and is reversible, PI also affects implant-supporting bone and, therefore, is very difficult to eradicate. PIIDs in clinical outcome may resemble gingivitis and periodontitis, as they share similar risk factors. However, recent study in the field of proteomics and other molecular studies indicate that PIIDs exhibit significant differences when compared to periodontal diseases. This review aims to elucidate the current knowledge of PIIDs, their etiopathology and diversified microbiology as well as the role of molecular studies, which may be a key to personalized diagnostic and treatment protocols of peri-implant infections in the near future. PMID- 29238201 TI - Diagnostic significance of circulating long noncoding RNA PCAT6 in patients with non-small cell lung cancer. AB - Aim: We have previously shown that the long noncoding RNA prostate cancer associated transcript 6 (PCAT6) promoted the proliferation and invasion of lung adenocarcinoma (LUAD) cells. In this study, the diagnostic significance of tissue and serum PCAT6 was evaluated in non-small cell lung cancer (NSCLC). Materials and methods: Tissue expression of PCAT6 was systematically evaluated in five Gene Expression Omnibus datasets (GSE19804, GSE18842, GSE30219, GSE19188, and GSE27262). Circulating and tissue expressions of PCAT6 were detected by quantitative reverse-transcriptase polymerase chain reaction in NSCLC patients from Union Hospital. Results: PCAT6 was significantly increased in lung cancer tissues and could be used to distinguish LUAD from adjacent normal tissues with an area under the receiver operating characteristic curve (AUC) of 0.9210 (p<0.0001; sensitivity, 98.82%; specificity, 78.57%) in GSE30219, 0.9333 (p<0.0001; sensitivity, 86.67%; specificity, 90.77%) in GSE19188, 0.9584 (p<0.0001; sensitivity, 92.00%; specificity, 96.00%) in GSE27262, and 0.9574 (p<0.0001; sensitivity, 95.89%; specificity, 87.67%) in patients from Union Hospital. As for lung squamous cell carcinoma (LUSC), the AUC of PCAT6 was 0.9567 (p<0.0001; sensitivity, 100%; specificity, 85.71%) in GSE30219, 0.9795 (p<0.0001; sensitivity, 96.30%; specificity, 92.31%) in GSE19188, and 0.9942 (p<0.0001; sensitivity, 100%; specificity, 98.04%) in patients from Union Hospital. We further noticed that the plasma levels of PCAT6 were significantly increased in 73 LUAD and 51 LUSC patients compared with 39 healthy controls (p<0.0001). The AUC of circulating PCAT6 was 0.9213 (p<0.0001; sensitivity, 87.67%; specificity, 97.44%) in LUAD and 0.9583 (p<0.0001; sensitivity, 94.12%; specificity, 100%) in LUSC. Conclusion: Together with our previous findings, our results suggest that PCAT6 could be used as a potential diagnostic and prognostic biomarker in NSCLC. PMID- 29238202 TI - Antitumor effects of pristimerin on human osteosarcoma cells in vitro and in vivo. AB - There are very few treatments for musculoskeletal tumors, compared to other cancers; thus, novel therapeutic drugs are needed. Pristimerin (PM) is a triterpene compound isolated from plant extracts that reportedly has antitumor effects on various cancers, such as of the breast and prostate. The purpose of this study was to evaluate the antitumor effects of PM on human osteosarcoma cells. Treatment of the human osteosarcoma cell lines, MNNG and 143B, with PM led to a dose-dependent decrease in cell viability. The effects of PM on apoptosis were evaluated with the Annexin V/propidium iodide assay and analysis of caspases 3, 8, and 9 activities. Western blot analysis showed that PM caused a decrease in the expression of Akt, mTOR, and NF-kappaB. The volumes and weights of human osteosarcoma xenografts decreased significantly with PM treatment. The results of this study revealed that PM can inhibit human osteosarcoma growth in vitro and in vivo, and may be a novel therapeutic agent for the disease. PMID- 29238203 TI - Expression patterns of microRNA-329 and its clinical performance in diagnosis and prognosis of breast cancer. AB - This study was aimed to assess the expression and clinical performance of microRNA-329 (miR-329) in breast cancer. We recruited 134 breast cancer patients and 70 healthy volunteers for this study. MiR-329 expression was estimated by quantitative real-time polymerase chain reaction. A receiver operating characteristic assay was performed to evaluate the diagnostic value of serum miR 329. In addition, the prognostic significance of miR-329 was evaluated through Kaplan-Meier survival and Cox regression analyses. According to quantitative real time polymerase chain reaction, miR-329 expression was downregulated in cancerous samples compared with healthy and normal controls (P<0.01), and its expression in serum specimens positively correlated with its expression in tissue samples (R=0.493, P<0.001). The decreased expression of miR-329 correlated with lymph node metastasis (P=0.015) and TNM stage (P=0.003). A receiver operating characteristic curve with an area under the curve of 0.932 was constructed, indicating the high diagnostic accuracy of miR-329. From the survival and multivariate Cox assays, we found that downregulated miR-329 expression was associated with poor overall survival (log-rank P<0.001) and served as an independent prognostic factor (hazard ratio =2.987, 95% CI =1.681-5.308, and P<0.001). In silico analysis using The Cancer Genome Atlas confirmed that miR-329 expression was lower in breast cancer cases compared with normal controls (P<0.001) and could be an efficient biomarker for cancer patients. Down-regulated miR-329 expression was an effective diagnostic and prognostic biomarker, which could be used for targeted therapy in patients with breast cancer. PMID- 29238204 TI - Low expression of DAB2IP predicts an unfavorable prognosis in human bladder carcinoma. AB - The DOC-2/DAB2 interactive protein (DAB2IP) is a novel member of the Ras GTPase activating protein family, and its downregulation is an unfavorable prognostic factor in several human malignancies. In this study, we retrospectively analyzed clinicopathological features, outcomes, and DAB2IP expression in 77 patients with urothelial carcinoma of the bladder (UCB). Expression of DAB2IP and p-STAT3 was examined in tumors and in matched adjacent non-cancerous tissues, using immunohistochemistry. We found a marked reduction in the expression of DAB2IP in UCB specimens, which was significantly associated with advanced pathological stage (P=0.037), high pathological grade (P=0.016), and muscle invasion (P=0.004). Moreover, multivariate analysis identified DAB2IP as an independent prognostic factor of cancer-specific survival (hazard ratio [HR] =0.23, 95% confidence interval [CI] =0.07-0.78, P=0.018). Most importantly, DAB2IP was negatively correlated with p-STAT3 expression (P=0.009), which predicted a shorter overall survival in patients with UCB (HR =2.68, 95% CI =1.63-6.99, P=0.044). In conclusion, downregulation of DAB2IP is associated with features of biologically aggressive UCB and may be a promising biomarker in patients after radical cystectomy. PMID- 29238205 TI - Predictive value of interim PET/CT visual interpretation in the prognosis of patients with aggressive non-Hodgkin's lymphoma. AB - Objective: The objective of the study was to evaluate the prognostic value of positron emission tomography (PET)/computed tomography (CT) visual interpretation in patients with aggressive non-Hodgkin's lymphoma (NHL) using a meta-analysis and systematic review. Methods: Using the PubMed, Embase, and Web of Science databases, we performed a systematic review of the use of visual evaluation mid chemotherapy to evaluate the prognosis of aggressive NHL in studies published up to May 2017. Prospective and retrospective studies assessing progression-free survival (PFS) and overall survival (OS) were included. We used hazard ratio (HR) to determine the value of Deauville criteria and International Harmonization Project (IHP) criteria for measuring survival. Subgroup analysis was performed based on the number of chemotherapy cycles before the mid-term evaluation as well as the visual evaluation method. Results: A total of 11 studies were included. PFS (HR =2.93, 95% confidence interval [CI]: 2.93-3.90, p<0.0001) and OS (HR =2.55, 95% CI: 1.76-3.68, p<0.0001) of PET/CT-positive patients were significantly lower when determined by the visual method. In subgroup analysis, IHP, Deauville criteria, and having no standard interpretation groups were factors able to predict PFS; IHP and having no standard interpretation group were able to predict OS. With PET/CT, IHP, and Deauville 5-point criteria, the PFS of patients receiving 2-4 cycles of chemotherapy before PET/CT was significantly lower than that of PET/CT-negative patients. No significant difference in OS was observed when patients received 3 or fewer cycles of chemotherapy before PET/CT, though OS was significantly lower in patients receiving more than 3 chemotherapy cycles. Conclusion: IHP and Deauville criteria are commonly used for PET/CT visual evaluation at present. Interim PET/CT analysis after 3-4 chemotherapy cycles is capable of predicting disease prognosis. Large-scale prospective clinical trials are needed to confirm whether PET/CT analysis can be used as an indication for changing a treatment strategy. PMID- 29238206 TI - Cisplatin versus carboplatin in combination with paclitaxel as neoadjuvant regimen for triple negative breast cancer. AB - Background: Platinum salts have demonstrated sufficient efficacy and safety for consideration of their use in a neoadjuvant setting for triple negative breast cancer (TNBC). Patients and methods: We retrospectively analyzed 145 TNBC cases to compare the activity and tolerability of cisplatin and carboplatin. Two groups received weekly paclitaxel and platinum salts. Results: In total, 87% of patients in the cisplatin group and 82% of patients in the carboplatin group experienced a clinical objective response after four cycles (complete response or partial response; P=0.570). Pathological complete response (pCR) occurred similarly in the cisplatin group and the carboplatin group (44% versus 42%, P=0.789). In survival analysis, there was no difference between the two regimens. The most common grade 3/4 adverse events were neutropenia and leukopenia. Conclusion: There was no significant difference between the groups in terms of adverse events. Both types of platinum salts and weekly paclitaxel are feasible therapies that achieved high pCR rates and tolerability in TNBC patients. PMID- 29238207 TI - Advances in T-cell checkpoint immunotherapy for head and neck squamous cell carcinoma. AB - Head and neck squamous cell carcinoma (HNSCC) has been found to be a complex group of malignancies characterized by their profound immunosuppression and high aggressiveness. In most cases of advanced HNSCC, treatment fails to obtain total cancer cure. Efforts are needed to develop new therapeutic approaches to improve HNSCC outcomes. In this light, T-cells "immune checkpoint" has attracted much attention in cancer immunotherapy. It has been broadly accepted that inhibitory T cell immune checkpoints contribute to tumor immune escape through negative immune regulatory signals (cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], programmed cell death 1 [PD-1], B7-H3, and B7-H4, etc). Current data suggest that PD-1 and CTLA-4 receptors can inhibit T-cell receptors and T-cell proliferation. Blockade of PD-1/PD-L1 and/or CTLA-4/CD28 pathways has shown promising tumor outcomes in clinical trials for advanced solid tumors like melanoma, renal cell cancer, and non-small cell lung cancer. The present review attempts to explore what is known about PD-1/PD-L1 and CTLA-4/CD28 pathways with a focus on HNSCC. We further discuss how these pathways can be manipulated with therapeutic intent. PMID- 29238208 TI - Is it severe asthma or asthma with severe comorbidities? AB - Severe asthma is defined as asthma that requires treatment with high-dose inhaled corticosteroids (ICSs) plus a second controller and/or systemic corticosteroids to prevent it from becoming uncontrolled or that remains uncontrolled despite this therapy. This definition has limitations: 1) it does not define any biological characteristic that distinguishes severe asthma from asthma in general and 2) it relies on the clinical interpretation of asthma symptoms that are not specific. Actually, wheezing, dyspnea, cough and chest tightness may be caused by the comorbidities (such as rhinosinusitis, obesity and vocal cord dysfunction [VCD]) which are associated with asthma. In clinical practice, clinicians are often prone to diagnose uncontrolled asthma and increase doses of ICSs without considering the comorbidities, resulting in poor control of symptoms. This commentary wishes the clinicians to focus on the comorbidities of asthma, particularly in patients with severe asthma, because the correct diagnosis of these comorbidities implies specific treatments that lead to a better asthma control. PMID- 29238209 TI - Transplant-acquired food allergy: current perspectives. AB - Mechanisms that regulate the tolerance to dietary proteins or the loss of this and subsequent development of disease are poorly understood. In food allergy, there is growing awareness of the urgency in understanding these events to aid in the development of next-generation therapies and interventions. This review focuses on the accumulating evidence related to food allergy that develops after transplantation. This intriguing immunological phenomenon has been described in several different types of transplant settings and to variety of different foods. We outline these studies and the evidence from them that support transplant acquired food allergy being a process regulated by both the donor allergic status and the recipient genetics and treatments. A number of key risk factors seem prevalent throughout transplant-acquired food allergy and include type of transplant, age and general health of the recipient, modality of immunosuppression and potentially the genetics of both donor and recipient. Importantly, these studies provide a window into better general understanding of food allergy, and facilitate clearer understanding of the critical immunological and epidemiological factors needed to allow the adoptive transfer of a food specific allergic disease from one individual to another. PMID- 29238210 TI - Biological therapy utilization, switching, and cost among patients with psoriasis: retrospective analysis of administrative databases in Southern Italy. AB - Purpose: The aim was to describe the current use of biological therapies among patients affected by psoriasis and to analyze a drug utilization profile in naive patients in terms of switching and treatment costs in a Local Health Unit (LHU) of Southern Italy. Methods: We conducted an observational retrospective cohort analysis using the health-related administrative databases of a LHU in Southern Italy covering a population of about one million inhabitants. All subjects with a main or secondary diagnosis of psoriasis who received at least one prescription of biological therapies between January 1, 2010 and December 31, 2014 were analyzed. Switching rate was evaluated in naive patients within the first year of treatment. Drug cost was calculated for all drugs prescribed and comprised both costs for psoriasis drugs and costs for other treatments. Results: About 20% of patients identified with a diagnosis of psoriasis were under treatment with biological drugs. Among 385 subjects treated with biological therapy, 51.2% were in treatment with etanercept and 33% with adalimumab. Among naive patients, switching rate to a different biological drug, within the first year of treatment, was 7.3%. The per patient yearly drug cost was ?10,536: 96.8% for psoriasis-related drugs and 3.2% for other pharmaceutical treatments. The annual average cost per patient switching from the initial treatment was ?13,021, while for those who did not switch from the initial treatment, the annual average cost was ?10,342, with a significant difference of about ?2,680 per patient per year (p=0.002). Conclusion: Our data may be useful in exploring the dynamics that characterize the use of biological therapy within a specific context and to optimize the use of resources for a better management of the disease. PMID- 29238212 TI - Effects of an antimicrobial restriction system on appropriate carbapenem use in a hospital without infectious diseases consultation. AB - Background: Gram-negative bacteria are becoming increasingly resistant to carbapenems and are related to the use of carbapenems. Thus, the main objective of this study was to compare the appropriateness of prescribing carbapenem before and after using an antimicrobial restriction system without infectious diseases consultation. Materials and methods: A retrospective cross-sectional before and after study was conducted in Lamphun Hospital to limit the prescription of carbapenems. Data were obtained by a review of the medical records and electronic databases from the period September 2014 to January 2015 (before) and from September 2015 to January 2016 (after). Results: A total of 360 antibacterial prescriptions were analyzed. The appropriateness of prescribing was higher after using the antimicrobial restriction (55.0%) than before using the antimicrobial restriction system (38.3%; p=0.001). The amount of carbapenem in the defined daily dose per 1,000 bed days increased by 3.48% after using the antimicrobial restriction system when compared with before using the antimicrobial restriction system, which was not statistically significant (p=0.611). The incidence rates of nosocomial infections caused by resistance of Enterobacteriaceae to ertapenem before and after the intervention to limit antimicrobial therapy was found to have decreased from 4.80 to 0.95 infections per 1,000 patient days, respectively (p=1.00). The expenditure for carbapenems in the average value of baht per patient was found to have decreased by 36.33% after using the antimicrobial restriction system when compared with before using the antimicrobial restriction system (p=0.001). Conclusion: These results suggest that antimicrobial restriction systems can increase the appropriateness of prescribing antibiotics. The expenditure for carbapenem was found to decrease after using the antimicrobial restriction system when compared with before using the antimicrobial restriction system, even without infectious diseases consultation. However, the amount of carbapenem in the defined daily dose per 1,000 bed days was not found to reduce after using the antimicrobial restriction system. PMID- 29238211 TI - Interdependency between mechanical parameters and afferent nerve discharge in remodeled diabetic Goto-Kakizaki rat intestine. AB - Background: Gastrointestinal disorders are very common in diabetic patients, but the pathogenesis is still not well understood. Peripheral afferent nerves may be involved due to the complex regulation of gastrointestinal function by the enteric nervous system. Objective: We aimed to characterize the stimulus-response function of afferent fibers innervating the jejunum in the Goto-Kakizaki (GK) type 2 diabetic rat model. A key question is whether changes in afferent firing arise from remodeled tissue or from adaptive afferent processes. Design: Seven 32 week-old male GK rats and seven age-matched normal Wistar rats were studied. Firing from mesenteric afferent nerves was recorded in excised jejunal segments of seven GK rats and seven normal Wistar rats during ramp test, stress relaxation test, and creep test. The circumferential stress-strain, spike rate increase ratio (SRIR), and single unit firing rates were calculated for evaluation of interdependency of the mechanical stimulations and the afferent nerve discharge. Results: Elevated sensitivity to mechanical stimuli was found for diabetic nerve bundles and single unit activity (P<0.05). The stress relaxed less in the diabetic intestinal segment (P<0.05). Linear association between SRIR and the thickness of circumferential muscle layer was found at high stress levels as well as for SRIR and the glucose level. Conclusion: Altered viscoelastic properties and elevated mechanosensitivity were found in the GK rat intestine. The altered nerve signaling is related to muscle layer remodeling and glucose levels and may contribute to gastrointestinal symptoms experienced by diabetic patients. PMID- 29238213 TI - First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid. AB - Paracetamol is arguably the most commonly used analgesic and antipyretic drug worldwide, however its mechanism of action is still not fully established. It has been shown to exert effects through multiple pathways, some actions suggested to be mediated via N-arachidonoylphenolamine (AM404). AM404, formed through conjugation of paracetamol-derived p-aminophenol with arachidonic acid in the brain, is an activator of the capsaicin receptor, TRPV1, and inhibits the reuptake of the endocannabinoid, anandamide, into postsynaptic neurons, as well as inhibiting synthesis of PGE2 by COX-2. However, the presence of AM404 in the central nervous system following administration of paracetamol has not yet been demonstrated in humans. Cerebrospinal fluid (CSF) and blood were collected from 26 adult male patients between 10 and 211 minutes following intravenous administration of 1 g of paracetamol. Paracetamol was measured by high performance liquid chromatography with UV detection. AM404 was measured by liquid chromatography-tandem mass spectrometry. AM404 was detected in 17 of the 26 evaluable CSF samples at 5-40 nmol?L-1. Paracetamol was measurable in CSF within 10 minutes, with a maximum measured concentration of 60 MUmol?L-1 at 206 minutes. This study is the first to report on the presence of AM404 in human CSF following paracetamol administration. This may represent an important finding in our understanding of paracetamol's mechanism of action, although measured concentrations were far below the previously documented IC50 for this metabolite. PMID- 29238214 TI - Pain sensitivity and torque used during measurement predicts change in range of motion at the knee. AB - Objective: To determine the extent to which changes in knee range of motion (ROM) after a stretching program are related to sensory factors at the time of testing and the amount of force used during the measurement of ROM, rather than changes in soft-tissue properties. Design: Randomized, single-blind design. Participants were randomly assigned to a control or stretching group. Setting: Research laboratory. Participants: Forty-four healthy volunteers (22.8+/-2.8 years of age; 23 men). Interventions: The stretching group undertook static stretching twice a day for 8 weeks. The control group continued with routine activity, but was discouraged from starting a flexibility program. Main outcome measures: ROM and tissue extensibility was assessed using a Biodex3 dynamometer, and ratings of thermal pain were collected at baseline and at 4 and 8 weeks by an examiner blinded to group assignment. Multilevel modeling was used to examine predictors of ROM across time. Results: The stretching group showed a 6% increase, and the control group had a 2% increase, in ROM over the 8-week program. However, when fixed and random effects were tested in a complete model, the group assignment was not significant. End-point torque during ROM testing (p=0.021) and the ratings in response to thermal testing (p<0.001) were significant, however. Conclusion: ROM measured in a testing session was not predicted by assignment to a stretching program. Rather, ROM was predicted by the ratings of thermal stimuli and the peak torque used to apply the stretch. PMID- 29238215 TI - Electrical stimulation of the posterior tibial nerve reduces neuropathic pain in patients with polyneuropathy. AB - Peripheral neuropathic pain (PNP) is caused by neuronal damage to the peripheral nervous system and usually affects the distal extremities. This open-label study examined the effect of short-term peripheral nerve stimulation (PNS) on individuals with PNP due to polyneuropathy. A total of 12 patients (mean age, 63.0 +/- 10.0 years, 41.7% male) with daily bilateral PNP for at least 6 months (mean duration, 7.4 +/- 7.8 years) received a total of six direct electrical stimulation therapies to the posterior tibial nerve at 3-4-day intervals. Eight patients completed the study and were included in the efficacy analysis. The average pain at baseline was 36.6 +/- 3.80 estimated by the Short-Form McGill Pain Questionnaire. After the last stimulation, pain was significantly reduced by 85.5% to 4.88 +/- 3.1 (p = 0.008). Six patients (75%) had over 50% decrease in pain after the first stimulation therapy and 99.2% after the final stimulation therapy. The patients also reported statistically significant decreases in pain level (measured by visual analog scale), ranging from 54.85% to 87.50% after each of the stimulations as compared to the pain experienced prior to the stimulations. The procedure was safe without any serious adverse events. PNS has demonstrated excellent efficacy and improvement of PNP symptoms. Further studies in larger patient populations are warranted. PMID- 29238216 TI - Improved health-related quality of life, participation, and autonomy in patients with treatment-resistant chronic pain after an intensive social cognitive intervention with the participation of support partners. AB - Despite the availability of various specific treatments, most patients with chronic pain (CP) consider their pain problem as undertreated. Recently, multiple sclerosis (MS) patients who were given an intensive 3-day social cognitive treatment with the participation of support partners experienced lasting improvements in health-related quality of life (HRQoL) and self-efficacy. In this study, a similar intervention was given to treatment-resistant CP patients with stressors, relational problems with support partner, and distress, anxiety or depression. Before and 1, 3, and 6 months after the intervention, patients completed the Euro-Qol 5 Dimensions 5 Levels (EQ-5D-5L) and Impact on Participation and Autonomy (IPA) questionnaires (primary outcomes), and the Survey Of Pain Attitudes (SOPA), the Four-Dimensional Symptom Questionnaire (4DSQ) (distress, depression, anxiety, and somatization), and Visual Analog Scale for pain intensity, whereas the support partners completed the Caregiver Strain Index (CSI) questionnaire. Differences between baseline and post-treatment were tested via paired t-tests (significance level 0.05). Of the 39 patients who were included, 34 (87.2%) completed the 3-day treatment. At 1, 3, and 6 months, improvements were seen in EQ-5D-5L-Index (+40.6%; +22.4%; +31.7%), Health Today (+61.8%; +36.3%; +46.8%), Control attitude (+45.8%; not significant [NS]; +55.0%) and decreases in IPA-Problems (-14.8%; NS; -20.4%), Harm attitude (-18.9%; 15.0%; -17.7%), Distress (-17.7%; -31.8%; -37.1%), and Depression (-37.4%; 31.4%; -35.7%) scores. The CSI score had decreased by -29.0%, -21.4%, and -25.9%, respectively. In conclusion, after an intensive 3-day social cognitive intervention, treatment-resistant CP patients experienced substantial and lasting improvements in HRQoL and in problematic limitations to participation and autonomy, in association with improvements in pain attitudes, depression, and distress. To assess whether this innovative approach may be an effective treatment for this subgroup of CP patients, future randomized controlled studies are needed. PMID- 29238218 TI - Breaking the Cycle, Cholesterol Cycling, and Synapse Damage in Response to Amyloid-beta. AB - Soluble amyloid-beta (Abeta) oligomers, a key driver of pathogenesis in Alzheimer disease, bind to cellular prion proteins (PrPC) expressed on synaptosomes resulting in increased cholesterol concentrations, movement of cytoplasmic phospholipase A2 (cPLA2) to lipid rafts and activation of cPLA2. The formation of Abeta-PrPC-cPLA2 complexes was controlled by the cholesterol ester cycle. Thus, Abeta activated cholesterol ester hydrolases which released cholesterol from stores of cholesterol esters; the increased cholesterol concentrations stabilised Abeta-PrPC-cPLA2 complexes. Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Abeta-PrPC-cPLA2. In cultured neurons, the cholesterol ester cycle regulated Abeta-induced synapse damage; inhibition of cholesterol ester hydrolases protected neurons, whereas inhibition of cholesterol esterification increased the Abeta-induced synapse damage. Here, I speculate that a failure to deactivate signalling pathways can lead to pathology. Consequently, the esterification of cholesterol is a key factor in the dispersal of Abeta-induced signalling platforms and synapse degeneration. PMID- 29238217 TI - Effects of voluntary exercise on blood pressure, angiotensin II, aldosterone, and renal function in two-kidney, one-clip hypertensive rats. AB - Spontaneous dynamic exercise promotes sympathoinhibition and decreases arterial pressure in two-kidney, one-clip (2K-1C) hypertensive rats. Renal sympathetic nerves stimulate renin secretion and increase renal tubular sodium reabsorption. We hypothesized that daily voluntary wheel running exercise by 2K-1C rats will decrease mean arterial pressure (MAP), plasma angiotensin II (Ang II), and aldosterone as well as normalize urinary sodium and potassium excretion independent of changes in glomerular filtration rate (GFR). Five-week-old male Sprague Dawley rats underwent sham clipping (Sham) or right renal artery clipping (2K-1C). Rats were randomized to standard caging (SED) or cages with running wheels (EX). After 12 weeks, rats were assigned to either collection of aortic blood for measurement of Ang II and aldosterone or assessment of inulin clearances and excretory function. Running distances were comparable in both EX groups. MAP was lower in 2K-1C EX vs 2K-1C SED rats (P<0.05). Plasma Ang II and aldosterone were significantly higher in 2K-1C SED rats and decreased in 2K-1C EX rats to levels similar to Sham SED or Sham EX rats. Clipped kidney weights were significantly lower in both 2K-1C groups, but GFR and urine flow rates were no different from right and left kidneys among the four groups. Total and fractional sodium excretion rates from the unclipped kidney of 2K-1C SED rats were higher vs either Sham group (P<0.05). Values in 2K-1C EX rats were similar to the Sham groups. Potassium excretion paralleled sodium excretion. These studies show that voluntary dynamic exercise in 2K-1C rats decreases plasma Ang II and aldosterone, which contribute to the lower arterial pressure without deleterious effects on GFR. The effects on sodium excretion underscore the impact of pressure natriuresis despite elevated plasma Ang II and aldosterone in sedentary 2K-1C rats. In contrast, potassium excretion is primarily regulated by circulating aldosterone and distal sodium delivery. PMID- 29238220 TI - Effect of statins on breast cancer recurrence and mortality: a review. AB - Statins, or 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are medications that have been used for decades to lower cholesterol and to prevent or treat cardiovascular diseases. Since their approval by the US Food and Drug Administration in the 1980s, other potential uses for statins have been speculated on and explored. Basic science and clinical research suggest that statins are also effective in the management of breast cancer. Specifically, in various breast cancer cell lines, statins increase apoptosis and radiosensitivity, inhibit proliferation and invasion, and decrease the metastatic dissemination of tumors. Clinical trials in breast cancer patients support these laboratory findings by demonstrating improved local control and a mortality benefit for statin users. A role for statins in the management of aggressive breast cancers with poor outcomes - namely, inflammatory breast cancer and triple negative breast cancer - is particularly implicated. However, data exist showing that statins may actually promote invasive breast disease after long-term use and thus should be prescribed cautiously. Furthermore, a general consensus on the type of statin that should be administered, for how long, and when in relation to time of diagnosis is lacking. Given their low toxicity profile, affordability, and ease of use, consideration of statins as a therapy for breast cancer patients is imminent. In this review, we summarize current evidence regarding statins and clinical breast cancer outcomes, as well as discuss potential future studies that could shed light on this increasingly relevant topic. PMID- 29238221 TI - Selective serotonin reuptake inhibitors and the risk of hepatocellular carcinoma in hepatitis B virus-infected patients. AB - Background: This study aimed to investigate the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Methods: We conducted a population-based cohort study by using claims data from the Taiwan National Health Insurance Research Database (NHIRD). The study cohort comprised 1380 newly diagnosed HBV-infected patients with SSRI use who were frequency matched by age, sex, liver cirrhosis, and index year with HBV-infected patients without SSRI use in the comparison cohort. Each patient case was followed from 2000 to 2012 to identify incident HCC cases. Cox proportional hazards regression was performed to evaluate the association between SSRI use and HCC risk. The further sensitivity analysis used case-control study design. A total of 9070 HCC subjects retrieved from NHIRD, and equal non-HCC subjects were analyzed after matching for age and sex. Results: We identified 9 and 24 HCC cases in the study and comparison cohorts during the follow-up period of 7056 and 6845 person-years, respectively. The incidence rate of HCC was 1.28 and 3.51 per 1000 person-years for SSRI and non-SSRI users, respectively. After adjusting for potential confounders, the adjusted hazard ratio (HR) for SSRI use was 0.28 (95% confidence interval [CI], 0.12-0.64; p = 0.0027). For SSRI users with a cumulative defined daily dose (cDDD) of 28-89, 90-364, and >=365, the adjusted HRs were 0.51, 0.22, and 0.12, respectively, (95% CI, 0.21-1.25, 0.05-0.94, and 0.02-0.90, respectively) compared with non-SSRI users (<28 cDDD). The sensitivity analysis showed that the SSRI presented with a dose-response protective effect for HCC in the multivariate analysis. Conclusion: SSRIs use may possibly reduce the risk of HCC in HBV-infected patients in a dose-responsive manner. PMID- 29238219 TI - Hypoxia Stress Modifies Na+/K+-ATPase, H+/K+-ATPase, [Formula: see text], and nkaalpha1 Isoform Expression in the Brain of Immune-Challenged Air-Breathing Fish. AB - Fishes are equipped to sense stressful stimuli and are able to respond to environmental stressor such as hypoxia with varying pattern of stress response. The functional attributes of brain to hypoxia stress in relation to ion transport and its interaction during immune challenge have not yet delineated in fish. We, therefore, explored the pattern of ion transporter functions and messenger RNA (mRNA) expression of alpha1-subunit isoforms of Na+/K+-ATPase (NKA) in the brain segments, namely, prosencephalon (PC), mesencephalon (MC), and metencephalon (MeC) in an obligate air-breathing fish exposed either to hypoxia stress (30 minutes forced immersion in water) or challenged with zymosan treatment (25-200 ng g-1 for 24 hours) or both. Zymosan that produced nonspecific immune responses evoked differential regulation of NKA, H+/K+-ATPase (HKA), and [Formula: see text] (NNA) in the varied brain segments. On the contrary, hypoxia stress that demanded activation of NKA in PC and MeC showed a reversed NKA activity pattern in MeC of immune-challenged fish. A compromised HKA and NNA regulation during hypoxia stress was found in immune-challenged fish, indicating the role of these brain ion transporters to hypoxia stress and immune challenges. The differential mRNA expression of alpha1-subunit isoforms of NKA, nkaalpha1a, nkaalpha1b, and nkaalpha1c, in hypoxia-stressed brain showed a shift in its expression pattern during hypoxia stress-immune interaction in PC and MC. Evidence is thus presented for the first time that ion transporters such as HKA and NNA along with NKA act as functional brain markers which respond differentially to both hypoxia stress and immune challenges. Taken together, the data further provide evidence for a differential Na+, K+, H+, and [Formula: see text] ion signaling that exists in brain neuronal clusters during hypoxia stress-immune interaction as a result of modified regulations of NKA, HKA, and NNA transporter functions and nkaalpha1 isoform regulation. PMID- 29238222 TI - The burden of selected cancers in the US: health behaviors and health care resource utilization. AB - Objective: To characterize the disease burden among survivors of those cancers having the highest incidence in the US. Methods: Adult (>=18 years) survivors of the 11 most frequently diagnosed cancers were identified from publically available data sources, including the Surveillance Epidemiology and End Results 9 1973-2012, National Health Interview Survey 2013, and the Medical Expenditure Panel Survey 2011. Chi-square tests and one-way analyses of variance were utilized to assess differences between cancer survivors and non-cancer controls in behavioral characteristics, symptoms and functions, preventative screenings, and health care costs. Results: Hematologic malignancies, melanoma, and breast, prostate, lung, colon/rectal, bladder, kidney/renal, uterine, thyroid, and pancreatic cancers had the highest incidence rates. Breast cancer had the highest incidence among women (156.4 per 100,000) and prostate cancer among men (167.2 per 100,000). The presence of pain (P=0.0003), fatigue (P=0.0005), and sadness (P=0.0012) was consistently higher in cancer survivors 40-64 years old vs. non cancer controls. Cancer survivors >=65 years old had higher rates of any functional limitations (P=0.0039) and reported a lack of exercise (P<0.0001) compared with the non-cancer controls. However, obesity rates were similar between cancer survivors and non-cancer controls. Among cancer survivors, an estimated 13.5 million spent $169.4 billion a year on treatment, with the highest direct expenditures for breast cancer ($39 billion), prostate cancer ($37 billion), and hematologic malignancies ($25 billion). Prescription medications and office-based visits contributed equally as the cost drivers of direct medical spending for breast cancer, while inpatient hospitalization was the driver for prostate (52.8%) and lung (38.6%) cancers. Conclusion: Understanding the resource utilization implications, health, and well-being of cancer survivors can inform approaches to interventions for improving long-term care. PMID- 29238223 TI - The effect of medication nonadherence on progression-free survival among patients with renal cell carcinoma. AB - Objective: To examine how observed medication nonadherence to 2 second-line, oral anticancer medications (axitinib and everolimus) affects progression-free survival (PFS) among patients with renal cell carcinoma. Methods: We used an adherence-exposure-outcome model to simulate the impact of adherence on PFS. Using a pharmacokinetic/pharmacodynamic (PK/PD) population model, we simulated drug exposure measured by area under the plasma concentration-time curve (AUC) and minimum blood or trough concentration (Cmin) under 2 scenarios: 1) optimal adherence and 2) real-world adherence. Real-world adherence was measured using the medication possession ratios as calculated from health insurance claims data. A population PK/PD model was simulated on individuals drawn from the Medical Expenditure Panel Survey (MEPS), a large survey broadly representative of the US population. Finally, we used previously published PK/PD models to estimate the effect of drug exposure (i.e., Cmin and AUC) on PFS outcomes under optimal and real-world adherence scenarios. Results: Average adherence measured using medication possession ratios was 76%. After applying our simulation model to 2164 individuals in MEPS, drug exposure was significantly higher among adherent patients compared with nonadherent patients for axitinib (AUC: 249.5 vs. 159.8 ng*h/mL, P<0.001) and everolimus (AUC: 185.4 vs. 118.0 ug*h/L, P<0.001). Patient nonadherence in the real world decreased the expected PFS from an optimally adherent population by 29% for axitinib (8.4 months with optimal adherence vs. 6.0 months using real-world adherence, P<0.001) and by 5% (5.5 vs. 5.2 months, P<0.001) for everolimus. Conclusion: Nonadherence by renal cell carcinoma patients to second-line oral therapies significantly decreased the expected PFS. PMID- 29238224 TI - Prognostic value of Cox-2 and PD-L1 expression and its relationship with tumor infiltrating lymphocytes in resected lung adenocarcinoma. AB - Programmed cell death-1 ligand 1 (PD-L1), tumor-infiltrating CD8-positive T lymphocytes (CD8-positive TILs), and cyclooxygenase-2 (Cox-2) have been used as prognostic tools in patients with lung adenocarcinoma. We conducted a retrospective review of data from 170 patients who had undergone pulmonary resection as an initial treatment for clinical T1-2 N0 lung adenocarcinoma. We then investigated the expressions of three biomarkers using immunohistochemical analyses and compared the expression levels with the clinicopathological characteristics and outcomes of the patients. Next, we classified the tumors into four groups based on the PD-L1 and CD8-positive TILs statuses and evaluated the prognostic significance of Cox-2 expression according to the tumor immune microenvironment classification. Tumors with positive PD-L1 expression levels had a significantly larger number of CD8-positive TILs than tumors with negative PD L1 expression levels, whereas tumors with high Cox-2 expressions had significantly fewer CD8-positive TILs than tumors with low Cox-2 expressions. A multivariate analysis showed that histological subtype, nodal metastasis, CD8 positive TILs count, and PD-L1 expression were independent predictors of patient outcome. Using a classification based on the PD-L1 and CD8-positive TILs statuses, the outcomes of patients with a negative PD-L1 expression and a high CD8-positive TIL count were significantly better than those with other classifications. In patients with negative PD-L1 and low CD8-positive TILs, the rate of EGFR mutation was significantly higher than that in other classifications, and Cox-2 expression was a powerful predictor of outcome. Clinical and pathological features in conjunction with the tumor immune microenvironment classification indicate that lung adenocarcinoma should be divided into different subgroups for prognosis and treatment. Classification according to the PD-L1 and CD8-positive TILs statuses might enable the effects of Cox-2 inhibitor to be predicted. PMID- 29238225 TI - Validity and completeness of rheumatoid arthritis diagnoses in the nationwide DANBIO clinical register and the Danish National Patient Registry. AB - Objectives: In Denmark, patients with rheumatoid arthritis (RA) are registered in the nationwide clinical DANBIO quality register and the Danish National Patient Registry (DNPR). The aim was to study the validity of the RA diagnosis and to estimate the completeness of relevant RA cases in each registry. Study design and setting: Patients registered for the first time in 2011 with a diagnosis of RA were identified in DANBIO and DNPR in January 2013. For DNPR, filters were applied to reduce false-positive cases. The diagnosis was verified by a review of patient records. We calculated the positive predictive values (PPVs) of the RA diagnosis registrations in DANBIO and DNPR, and estimated the registry completeness of relevant RA cases for both DANBIO and DNPR. Updated data from 2011 to 2015 from DANBIO were retrieved to identify patients with delayed registration, and the registry completeness and PPV was recalculated. Results: We identified 1,678 unique patients in DANBIO or in DNPR. The PPV (2013 dataset) was 92% in DANBIO and 79% in DNPR. PPV for DANBIO on the 2015 update was 96%. The registry completeness of relevant RA cases was 43% in DANBIO, increasing to 91% in the 2015 update and 90% in DNPR. Conclusion: DANBIO held a high proportion of true RA cases (96%) and was found to be superior to the DNPR (79%) with regard to the validity of the diagnosis. Both registries were estimated to have a high completeness of RA cases treated in hospital care (~90%). PMID- 29238226 TI - Maternal diabetes and incidence of childhood cancer - a nationwide cohort study and exploratory genetic analysis. AB - Background: The etiology of childhood cancer is not well understood, but may be linked to prenatal and perinatal factors, such as maternal diabetes. However, this association has not been examined in depth. We aimed to determine if maternal diabetes is associated with risk of childhood brain tumor (CBT), leukemia (all types combined and acute lymphoblastic leukemia [ALL] separately), and lymphoma. Methods: All children born in Sweden between 1973 and 2014 (n=4,239,965) were followed from birth until first cancer diagnosis, age 15 years, or December 31, 2015. Data on maternal diabetes, childhood cancer, and covariates were obtained from nationwide health registers. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using Cox regression adjusted for potential confounders/mediators. Additionally, we performed an exploratory analysis using results from published genome-wide association studies and functional annotation. Results: Maternal diabetes was associated with lower risk of CBT (adjusted IRR [95% CI]: 0.56 [0.35-0.91]) and higher risk of leukemia (adjusted IRR: 1.47 [1.13-1.92] for all leukemia combined and 1.64 [1.23-2.18] for ALL). These associations were similar for both maternal type 1 diabetes and gestational diabetes. Associations of five previously identified genetic loci were compatible with a causal effect of diabetes traits on neuroblastoma and common Hodgkin's lymphoma. Conclusion: Children whose mother had diabetes had lower risk of CBT and higher risk of leukemia, compared with children whose mother did not have diabetes. Our results are compatible with a role of prenatal and perinatal glycemic environment in childhood cancer etiology. PMID- 29238227 TI - Validation of asthma recording in electronic health records: a systematic review. AB - Objective: To describe the methods used to validate asthma diagnoses in electronic health records and summarize the results of the validation studies. Background: Electronic health records are increasingly being used for research on asthma to inform health services and health policy. Validation of the recording of asthma diagnoses in electronic health records is essential to use these databases for credible epidemiological asthma research. Methods: We searched EMBASE and MEDLINE databases for studies that validated asthma diagnoses detected in electronic health records up to October 2016. Two reviewers independently assessed the full text against the predetermined inclusion criteria. Key data including author, year, data source, case definitions, reference standard, and validation statistics (including sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) were summarized in two tables. Results: Thirteen studies met the inclusion criteria. Most studies demonstrated a high validity using at least one case definition (PPV >80%). Ten studies used a manual validation as the reference standard; each had at least one case definition with a PPV of at least 63%, up to 100%. We also found two studies using a second independent database to validate asthma diagnoses. The PPVs of the best performing case definitions ranged from 46% to 58%. We found one study which used a questionnaire as the reference standard to validate a database case definition; the PPV of the case definition algorithm in this study was 89%. Conclusion: Attaining high PPVs (>80%) is possible using each of the discussed validation methods. Identifying asthma cases in electronic health records is possible with high sensitivity, specificity or PPV, by combining multiple data sources, or by focusing on specific test measures. Studies testing a range of case definitions show wide variation in the validity of each definition, suggesting this may be important for obtaining asthma definitions with optimal validity. PMID- 29238228 TI - Prenatal exposure to antipsychotic medication and use of primary health care system in childhood: a population-based cohort study in Denmark. AB - Background: Antipsychotic (AP) medication is increasingly used for many health conditions. Prenatal exposure to AP medication has been associated with several adverse outcomes, but the findings remain inconsistent. Purpose: We aimed to investigate prenatal exposure to AP medication and the use of primary health care system in childhood. Subjects and methods: All live-born singletons in Denmark during 1997-2012 were identified in the nationwide Danish National Patient Register and followed until December 31, 2013 (n = 963,010). Information on prenatal exposure to AP medication was obtained from the Danish Register of Medicinal Product Statistics. Contacts to the general practitioner (GP) were used as a proxy for the overall health of the children. Negative binomial regression was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between prenatal exposure to AP medication and number and type of GP contacts, excluding routine well-child visits and vaccinations. The models were adjusted for sex and birth date of the child, maternal age, parity, cohabitation status, income, education, smoking status, diagnosis of substance abuse, severe psychiatric disorder, depression and epilepsy as well as the use of antiepileptic drugs, antidepressants, benzodiazepines and insulin. Results: The prenatally AP-exposed children had 7% more GP contacts than unexposed children, IRR: 1.07 (95% CI: 1.03, 1.11). The association was slightly stronger among children of mothers with no diagnosis of severe psychiatric disorder (IRR: 1.08, 95% CI: 1.04-1.13) than among children of mothers with severe psychiatric disorder (IRR: 1.03, 95% CI: 0.96-1.11), but the difference was not statistically significant. We found no difference between prenatally AP exposed children and their unexposed siblings, IRR: 1.00 (95% CI: 0.97-1.04) for total contacts. Conclusion: Children of women using AP medication in pregnancy had more GP contacts in childhood than children of mothers not using AP medication. However, this might be explained by confounding from maternal behavior and mental illness. PMID- 29238229 TI - Coinfections with hepatitis B and C virus and syphilis among HIV-infected clients in Southern Ethiopia: a cross-sectional study. AB - Introduction: Hepatitis B virus (HBV) and hepatitis C virus (HCV) are hepatotropic viruses of public health significance worldwide. Despite their severe clinical impact in HIV-infected patients, there is inadequate information regarding the epidemiology of hepatitis/HIV coinfections in Ethiopia. Thus, this study aimed to determine the prevalence of HBV and HCV infections among HIV infected patients at a tertiary hospital in Southern Ethiopia. Methods: Stored sera, which were originally collected for the investigation of syphilis among HIV infected clients, were analyzed in this study. Samples were tested for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen using rapid diagnostic tests. Those samples that tested positive for HBsAg were further analyzed for hepatitis B e antigen. All sera were tested for antibody to HCV infection using rapid diagnostic test. Results: HBsAg was positive for 6.3% of the participants; of whom, 10% were positive for hepatitis B e antigen. The exposure rates to HBV (antibody to hepatitis B core antigen) and HCV (anti-HCV) infections were 22.4 and 3.1%, respectively. The rates of coinfections with HBV syphilis, HCV-syphilis, and HBV-HCV were found to be 3.1, 0.6, and 1.3%, respectively. HBV exposure rate was significantly higher among participants in the age range 40-49 years (adjusted odds ratio [AOR], 1.98; 95% CI, 1.01-3.88) and those who had a CD4+ T cell count <200 cells/MUL (AOR, 2.40; 95% CI, 1.13 5.10) and 200-349 cells/MUL (AOR, 2.36; 95% CI, 1.28-4.35). Conclusion: The rates of HBV and HCV infections were found to be similar to other subpopulations in Ethiopia. Age and CD4+ T cell level influenced the rate of HBV exposure. As human immunodeficiency virus-hepatitis coinfections are clinically consequential in people living with human immunodeficiency virus/acquired immunodeficiency syndrome, the need to screen this population for HBV and HCV infections is critically important. PMID- 29238230 TI - Community narratives about women and HIV risk in 21 high-burden communities in Zambia and South Africa. AB - Public health researchers repeatedly represent women as a group vulnerable to ill health. This has been particularly true in the field of HIV research, where women are disproportionately affected by HIV in terms of disease burden and the social effects of the epidemic. Although women have been the focus of many prevention and treatment programs, structural barriers to implementation of these targeted programs persist. In this article we explore how high HIV-burden communities in South Africa and Zambia engage with the concepts of "woman" and "HIV risk". The data are drawn from participatory storytelling activities completed with 604 participants across 78 group discussions between December 2012 and May 2013. During discussions we found that participants made use of the core archetypal caricatures of "goodness," "badness," and "vulnerability" when describing women's HIV risk. Community members shifted between these categories in their characterizations of women, as they acknowledged the multiple roles women play, internalized different stories about women, and sometimes shifted register in the same stories. Findings suggest that health implementers, in consultation with community members, should consider the multiple positions women occupy and how this impacts the wider community's understandings of women and "risk". This approach of taking on board community understandings of the complexity of HIV risk can inform the design and implementation of HIV prevention and care programs by rendering programs more focused and in-line with community needs. PMID- 29238231 TI - Adverse maternal outcomes and birth weight discordance in twin gestation: British Columbia, Canadian data. AB - Objective: The aim of this study was to determine whether twin pregnancies with birth weight discordance were associated with higher rates of maternal morbidities. Study design: A large retrospective population-based cohort study of twins born in British Columbia, Canada, from 2000 to 2010 was performed. Maternal morbidities and growth discordant were evaluated. Results: There were 6,328 twin deliveries during the study period. Pregnancies carrying growth-discordant twins had higher frequencies of hypertension disorders, preterm labor, and cesarean delivery compared with growth-concordant twins. They also stayed longer than 3 days in hospital. Multivariate generalized estimating equation modeling found higher odds of preeclampsia, pregnancy-induced hypertension, preterm delivery, and cesarean delivery in mothers carrying growth-discordant twins compared with those carrying growth-concordant category. The modeling also resulted in higher odds in the length of stay longer than 3 days in mothers carrying growth discordant twins compared with those carrying growth-concordant twins after adjustment for chorionicity. Conclusion: Maternal complications are associated with growth discordance. Screening for birth weight discordance during pregnancy may alert clinicians to predict subclinical maternal conditions. PMID- 29238232 TI - Efficacy of thermoablation in treating cervical precancerous lesions in a low resource setting. AB - Introduction: Treating cervical intraepithelial neoplasia (CIN) grades 2 and 3 is the recommended strategy for preventing invasive carcinoma in low- and middle income countries (LMICs). Our objective was to assess the efficacy of thermoablation in the treatment of CIN2 and CIN3 in a screen-and-treat approach. Methods: Women aged 30-49 years in Dschang, Cameroon, were invited to undergo vaginal sampling for human papillomavirus (HPV), samples being assessed by an Xpert HPV Assay. HPV-positive women underwent visual inspection with acetic acid (VIA) and visual inspection with Lugol's iodine (VILI), cervical biopsy, and endocervical curettage. Women positive for HPV-16/18/45 or other HPV types with abnormal VIA/VILI were treated by thermoablation on the same day. The primary outcome was persistence of high-grade disease on cytologic examination at 12 months. Results: Of a total of 1,012 recruited women, 188 were HPV-positive, 121 patients required thermoablation, and 99 had a CIN of grade <2, making the overtreatment rate 9.9%. The cure rate for CIN2 and CIN3 at 12 months was 70.6%. Failure (higher risk of persistent disease) was associated with the presence of occult endocervical lesions at baseline diagnosis (adjusted odds ratio [aOR] =128.97 [95% confidence interval [CI], 8.80-1,890.95]; p<0.0001). First sexual intercourse before the age of 15 was also a risk factor (aOR =0.003 [95% CI, 0.001-0.61]; p=0.023). Conclusion: In LMICs, use of thermoablation in a screen and-treat approach is a valuable treatment option for CIN2 and CIN3. Studies comparing thermoablation with cryotherapy are needed to determine the most appropriate treatment for cervical precancer in such countries. PMID- 29238233 TI - An in vivo comparison of the efficacy of hemostatic powders, using two porcine bleeding models. AB - Background: Usage of topical hemostatic agents in surgery is increasing, including use during minimally invasive procedures, and even for surgeries that have a low risk of bleeding complications. A novel product, Surgicel(r) Powder - Absorbable Hemostatic Powder (SP), made from oxidized regenerated cellulose (ORC) fabric, has been developed for adjunctive use in surgical procedures to assist in control of oozing bleeding over broad areas and where access could be difficult with a fabric ORC product. This study compares the new SP to other commercially available hemostatic powder products in two in vivo models. Methods: Hemostatic efficacy of SP was compared to two polysaccharide-based hemostats in a porcine liver punch biopsy model and to three polysaccharide-based hemostats and one non regenerated oxidized cellulose hemostat in a porcine liver abrasion model. Primary outcomes measured were hemostatic efficacy, defined as hemostasis within 10 minutes of application, and time-to-hemostasis (TTH). Results: In the punch biopsy model, SP displayed significantly higher effective hemostasis rates than one of the polysaccharide hemostats (p=0.047) and faster TTH than both (p<0.001). In the liver abrasion model, SP had significantly higher effective hemostasis rates (p<=0.002) and faster TTH (p<0.001) than the other four hemostatic agents. The amount of powder applied within the ranges used did not appear to affect hemostatic efficacy. Conclusion: In both the liver punch biopsy model of mild to moderate bleeding and the liver abrasion model of mild but diffuse oozing, SP provided more effective hemostasis and faster TTH than other marketed hemostatic powders. The results from this in vivo study suggest that Surgicel Powder may be useful in clinical applications where control of oozing capillary, mild venous, and small arterial hemorrhage is required including bleeding in difficult-to access locations. PMID- 29238234 TI - Development of a psychological test to measure ability-based emotional intelligence in the Indonesian workplace using an item response theory. AB - This study aimed to develop an emotional intelligence (EI) test that is suitable to the Indonesian workplace context. Airlangga Emotional Intelligence Test (Tes Kecerdasan Emosi Airlangga [TKEA]) was designed to measure three EI domains: 1) emotional appraisal, 2) emotional recognition, and 3) emotional regulation. TKEA consisted of 120 items with 40 items for each subset. TKEA was developed based on the Situational Judgment Test (SJT) approach. To ensure its psychometric qualities, categorical confirmatory factor analysis (CCFA) and item response theory (IRT) were applied to test its validity and reliability. The study was conducted on 752 participants, and the results showed that test information function (TIF) was 3.414 (ability level = 0) for subset 1, 12.183 for subset 2 (ability level = -2), and 2.398 for subset 3 (level of ability = -2). It is concluded that TKEA performs very well to measure individuals with a low level of EI ability. It is worth to note that TKEA is currently at the development stage; therefore, in this study, we investigated TKEA's item analysis and dimensionality test of each TKEA subset. PMID- 29238236 TI - Pro-gastrin-releasing peptide (ProGRP) as a biomarker in small-cell lung cancer diagnosis, monitoring and evaluation of treatment response. AB - Lung cancer belongs to malignant tumors that possess the highest rates of morbidity and mortality in the world. A number of morphological, biological and clinical features justify the distinction of small-cell carcinoma with respect to the other histological types of lung cancer. The predominant neuroendocrine phenotype is critical for the selection of biomarkers used in diagnostics, monitoring and evaluation of treatment response; early onset relapses in patients with small-cell lung cancer (SCLC) and the evaluation of their prognosis. Although for a long time the neuron-specific enolase (NSE) was considered to be the marker of choice for this tumor, it is now increasingly important to pay attention to concentrations of pro-gastrin-releasing peptide (ProGRP). The results of this marker have been implicated in the differential diagnosis of non small lung cancer and SCLC, chemotherapy and radiotherapy monitoring as well as evaluation of treatment response. The subject of this series of studies is to determine the usefulness of ProGRP in the evaluation of patients' prognosis and its predictive value. The current aim for the optimization of the effectiveness of biochemical diagnostics of SCLC is recommended by complementary ProGRP and NSE studies. The present work is a summary of the latest reports regarding diagnostic utility of these markers in SCLC. PMID- 29238235 TI - Oppositional defiant disorder: current insight. AB - Oppositional defiant disorder (ODD) is diagnosed broadly on the basis of frequent and persistent angry or irritable mood, argumentativeness/defiance, and vindictiveness. Since its inception in the third Diagnostic and Statistical Manual of Mental Disorders, epidemiological and longitudinal studies have strongly suggested a distinct existence of ODD that is different from other closely related externalizing disorders, with different course and outcome and possibly discrete subtypes. However, several issues, such as symptom threshold, dimensional versus categorical conceptualization, and sex-specific symptoms, are yet to be addressed. Although ODD was found to be highly heritable, no genetic polymorphism has been identified with confidence. There has been a definite genetic overlap with other externalizing disorders. Studies have begun to explore its epigenetics and gene-environment interaction. Neuroimaging findings converge to implicate various parts of the prefrontal cortex, amygdala, and insula. Alteration in cortisol levels has also been demonstrated consistently. Although a range of environmental factors, both familial and extrafamilial, have been studied in the past, current research has combined these with other biological parameters. Psychosocial treatment continues to be time-tested and effective. These include parental management training, school-based training, functional family therapy/brief strategic family therapy, and cognitive behavior therapy. Management of severe aggression and treatment of co-morbid disorders are indications for pharmacotherapy. In line with previous conceptualization of chronic irritability as a bipolar spectrum abnormality, most studies have explored antipsychotics and mood stabilizers in the management of aggression, with limited effects. PMID- 29238237 TI - Adolescent pre-exposure prophylaxis for HIV prevention: current perspectives. AB - Adolescents are a critical population that is disproportionately impacted by the HIV epidemic. More than 2 million adolescents between the age group of 10 and 19 years are living with HIV, and millions are at risk of infection. HIV risks are considerably higher among girls, especially in high-prevalence settings such as eastern and southern Africa. In addition to girls, there are other vulnerable adolescent subgroups, such as teenagers, who use intravenous (IV) drugs, gay and bisexual boys, transgender youth, male sex workers, and people who fall into more than one of these categories. Pre-exposure prophylaxis (PrEP) is a new intervention for people at high risk for acquiring HIV, with an estimated HIV incidence of >3%. Recent data from trials show evidence of the efficacy of PrEP as a powerful HIV prevention tool in high-risk populations, including men who have sex with men, HIV-1-serodiscordant heterosexual couples, and IV drug users. The reported efficacy in those trials of the daily use of oral tenofovir, alone or in combination with emtricitabine, to prevent HIV infection ranged from 44% to 75% and was heavily dependent on adherence. Despite the proven efficacy of PrEP in adult trials, concerns remain about its feasibility in real-life scenarios due to stigma, cost, and limited clinician experience with PrEP delivery. Recent studies are attempting to expand the inquiry into the efficacy of such HIV prophylaxis approaches in adolescent populations, but there are still many gaps in knowledge, and no country has yet approved it for use with adolescents. The aim of this review was to identify and summarize the evidence from studies on PrEP for adolescents. We have compiled and reviewed published studies focusing on safety, feasibility, adherence to therapeutics, self-perception, and legal issues related to PrEP in people aged between 10 and 24 years. PMID- 29238238 TI - Diversity in Cycas (Cycadales: Cycadaceae) Species Offered as Larval Food Influences Fecundity of Chilades pandava (Lepidoptera: Lycaenidae) Adults. AB - Chilades pandava (Lepidoptera: Lycaenidae) larval food quality was studied to determine its influence on adult life history traits. A wild population from Cycas nongnoochiae (Cycadales: Cycadaceae) endemic habitat behaved similarly to the population collected from a garden setting. Cycas micronesica, Cycas revoluta, and Cycas seemannii leaves were used as high-quality food, whereas C nongnoochiae, Cycas taitungensis, and Cycas condaoensis leaves were used as low quality food. The daily oviposition rate was not influenced by food quality, but longevity and lifetime fecundity of females were increased by high-quality larval food. These results indicate that in situ Cycas species impose a physiological constraint on the genetic capacity to produce offspring by C pandava. The removal of that constraint by high-quality novel Cycas species may be one reason this butterfly can increase in population rapidly after an invasion event and express greater herbivory of Cycas species within invaded regions. PMID- 29238239 TI - SAFE QI - a framework to overcome the challenges of implementing a quality improvement curriculum into a residency program. AB - Quality improvement (QI) is an essential component of medical practice. Medical students and residents must learn the skills to conduct clinical QI during their educational programs. Medical educators must create and implement a curriculum in QI to empower their students to develop this skill and knowledge. However, developing and implementing a QI curriculum may be challenging for some residency programs. Residency programs with a relatively short duration of training - for example, only 2 years - may be unable to implement an extensive QI curriculum without siphoning away time for other learning objectives. Small residency programs may lack faculty with expertise to teach this topic. Residency programs with only a few residents may find it difficult to evaluate the success of a QI curriculum using robust statistical analysis. These residency programs need a QI curriculum with several features. The curriculum must be deliverable in a short period of time. There must be tools to assess the residents' attainment of the curricular objectives. The curriculum must give the residents practical skills to develop their own QI initiatives. Finally, there must be simple methods to evaluate the curriculum's effectiveness. To address these goals, we developed the SAFE QI (QI curriculum which is short, assessed, functional, and effective) framework for the 2-year subspecialty respirology residency program at the University of Alberta. There are 2-3 entrants per year for a total of 4-6 residents. This framework helps medical educators overcome the challenges of implementing a QI curriculum into their educational programs. This article illustrates how this framework was used to develop and deliver an institution's own QI curriculum. PMID- 29238240 TI - The effect of DPP-4 inhibitors on asthma control: an administrative database study to evaluate a potential pathophysiological relationship. AB - Rationale: DPP-4 may regulate immunological pathways implicated in asthma. Assessing whether DPP-4 inhibitor (DPP-4i) use might affect asthma control is clinically important because DPP-4i use in type 2 diabetes mellitus management (T2DM) is increasing. This study evaluated associations between DPP-4i use and asthma control. Methods: This was a retrospective, observational, matched cohort study using administrative claims in the MarketScan(r) Commercial Claims and Encounters (Commercial) and Medicare Supplemental and Coordination of Benefits (Medicare Supplemental) databases. Adult asthma patients initiating an oral DPP 4i or a non-DPP-4i between November 1, 2006 and March 31, 2014 were included. Patients were followed for asthma-related outcomes for 12 months after initiation of the antidiabetes medication. Outcomes included risk-domain asthma control (RDAC), defined as no asthma hospitalizations, no lower respiratory tract infections, and no oral corticosteroid (OCS) prescriptions; overall asthma control (RDAC criteria plus limited short-acting beta agonist use); treatment stability (RDAC criteria plus no increase of >=50% in inhaled corticosteroid dose or addition of other asthma therapy); and severe asthma exacerbation rates (asthma-related hospitalizations, emergency room visits, or acute treatments with OCS). Comparisons were made between two matched cohorts (DPP-4i vs. non-DPP-4i initiators) using multivariable logistic regression and generalized linear modeling. Covariates included baseline demographic and clinical characteristics related to asthma and T2DM. Results: The adjusted odds of achieving RDAC (odds ratio [OR]: 1.05; 95% CI: 0.964 to 1.147), overall asthma control (OR: 1.04; 95% CI: 0.956 to 1.135), and treatment stability (OR: 1.04; 95% CI: 0.949 to 1.115) did not differ between the DPP-4i and non-DPP-4i cohorts. A difference was not found between cohorts in severe asthma exacerbation rates during the 12 months following initiation of antidiabetes treatment (mean = 0.32 vs. 0.34 exacerbations per subject-year, respectively; p=0.064). Conclusion: Asthma control was similar between patients initiating DPP-4i and non-DPP-4i antidiabetes medications, suggesting no association between DPP-4i use and asthma control. PMID- 29238241 TI - Predictors of Mortality within Prison and after Release among Persons Living with HIV in Indonesia. AB - Objectives: HIV-related mortality is increasing in Indonesia, where prisons house many people living with HIV and addiction. We examined all-cause mortality in HIV infected Indonesian prisoners within prison and up to 24 months post-release. Materials and Methods: Randomly selected HIV-infected male prisoners (n=102) from two prisons in Jakarta, Indonesia completed surveys in prison and were followed up for 2 years (until study completion) or until they died or were lost to follow up. Death dates were determined from medical records and interviews with immediate family members. Kaplan-Meier and Cox proportional hazards regression models were analyzed to identify mortality predictors. Results: During 103 person years (PYs) of follow-up, 15 deaths occurred, including ten in prison. The crude mortality rate within prison (125.2 deaths per 1,000 PYs) was surpassed by the crude mortality rate in released prisoners (215.7 deaths per 1,000 PYs). HIV associated opportunistic infections were the most common probable cause of death. Predictors of within-prison and overall mortality were similar. Shorter survival overall was associated with being incarcerated within a specialized "narcotic" prison for drug offenders (hazard ratio [HR] 9.2, 95% confidence interval [CI] 1.1-76.5; P=0.03), longer incarceration (HR 1.06, 95% CI 1.01-1.1; P=0.01), and advanced HIV infection (CD4+ T-cell count<200cells/MUL; HR 4.8, 95% CI 1.2-18.2; P=0.02). Addiction treatment was associated with longer survival (HR 0.1, 95% CI 0.01-0.9; P=0.03), although treatment with antiretroviral therapy (ART) or methadone was not. Conclusions: Mortality in HIV-infected prisoners is extremely high in Indonesia, despite limited provision of ART in prisons. Interventions to restore immune function with ART and provide prophylaxis for opportunistic infections during incarceration and after release would likely reduce mortality. Narcotics prisons may be especially high-risk environments for mortality, emphasizing the need for universal access to evidence-based HIV treatments. PMID- 29238242 TI - Heart Rate Variability is a Moderating Factor in the Workload-Injury Relationship of Competitive CrossFitTM Athletes. AB - Heart rate variability (HRV) is a popular tool for monitoring training adaptation and readiness in athletes, but it also has the potential to indicate early signs of somatic tissue overload prior to the onset of pain or fully developed injury. Therefore, the aim of this study was to investigate the interaction between HRV, workloads, and risk of overuse problems in competitive CrossFitTM athletes. Daily resting HRV and workloads (duration * session-RPE) were recorded in six competitive CrossFitTM athletes across a 16 week period. The Oslo Sports Trauma Research Center Overuse Injury Questionnaire was distributed weekly by e-mail. Acute-to-chronic workload ratios (ACWR) and the rolling 7-day average of the natural logarithm of the square root of the mean sum of the squared differences between R-R intervals (Ln rMSSDweek) were parsed into tertiles (low, moderate/normal, and high) based on within-individual z-scores. The interaction between Ln rMSSDweek and ACWR on overuse injury risk in the subsequent week was assessed using a generalized linear mixed-effects model and magnitude-based inferences. The risk of overuse problems was substantially increased when a 'low' Ln rMSSDweek was seen in combination with a 'high' ACWR (relative risk [RR]: 2.61, 90% CI: 1.38 - 4.93). In contrast, high ACWRs were well-tolerated when Ln rMSSDweek remained 'normal' or was 'high'. Monitoring HRV trends alongside workloads may provide useful information on an athlete's emerging global pattern to loading. HRV monitoring may therefore be used by practitioners to adjust and individualise training load prescriptions, in order to minimise overuse injury risk. PMID- 29238243 TI - Analysis of Time-Motion and Heart Rate in Elite Male and Female Beach Handball. AB - Beach handball is a spectacular new team sport; however, scientific knowledge about the demands in beach handball is very low. Consequently, the aim of this study was to analyze the physical demands of elite beach handball players by means of time-motion analysis with GPS technology and physiological response with Heart Rate (HR). Both male (n = 12) and female (n = 12) players from the Spanish Beach Handball National Team were recruited for this study. The sample consisted in four matches of two 10-min periods each. Time-motion analysis was performed through GPS devices (SPI Pro X, 15 Hz, GPSports) with synchronized HR monitoring (Polar Electro, Finland). All parameters were recorded for matches and halves to express overall and time-dependent physical and physiological responses. Total match distance covered by male and female players were 1234.7 +/- 192 m and 1118.2 +/- 221.8 m, respectively. Female players covered more total distance (p = 0.049, ES = 0.79) and distance walking (p < 0.001, ES = 2.04) in the first half, whereas they covered more distance standing (p = 0.008, ES = 1.05) in the second half at a higher average speed (p < 0.001, ES = 2.28). The number of accelerations distributed over low-, moderate- and high-intensity categories were 43.2 +/- 11.6, 9.4 +/- 4.9; 0.8 +/- 0.9 m/s2 for male players, and 40.3 +/- 12.7, 4.3 +/- 3.0; 0.1 +/- 0.3 m/s2 for female players; equivalent to one body acceleration every 23 s and 27 s, respectively. Finally, male and female players obtained a maximum/mean HR of 173 +/- 13 / 137 +/- 12 bpm, and 177 +/- 13 / 138 +/- 18 bpm, with 20.3% and 29.2% of the total time in the anaerobic zone (81 - 90% HRmax), respectively. These results demonstrated that beach handball is a demanding sport, with numerous moderate-to-high intensity displacements, distributed intermittently throughout the game: long periods of low intensity activity interspersed by short bursts of high intensity. PMID- 29238244 TI - Influence of A Thermogenic Dietary Supplement on Safety Markers, Body Composition, Energy Expenditure, Muscular Performance and Hormone Concentrations: A Randomized, Placebo-Controlled, Double-Blind Trial. AB - Dietary supplementation is commonly employed by individuals seeking to improve body composition and exercise performance. The purpose of the present study was to examine the safety and effectiveness of a commercially available dietary supplement designed to promote thermogenesis and fat loss. In a randomized double blind trial, participants were assigned to consume placebo or a multi-ingredient supplement containing caffeine, green tea extract, l-carnitine, evodiamine and other ingredients that purportedly enhance thermogenesis. The study included acute baseline testing, a 6-week progressive resistance training and supplementation intervention, and post-intervention testing. Laboratory assessments included resting energy expenditure responses to acute supplement ingestion, evaluation of body composition and muscular performance, and analysis of blood variables (metabolic panel, testosterone, estrogen and cortisol). Dependent variables were analyzed using ANOVA with repeated measures. No unfavorable effects of supplementation were reported, and the supplement did not adversely affect safety markers. However, the supplement did not reduce fat mass or increase lean mass relative to placebo. In the supplement group, lower body maximal strength was increased relative to placebo (+18%, d=1.1 vs. +10%, d=0.5), and cortisol concentrations were decreased relative to placebo (-16%; d=-0.4 vs. +15%, d=.75). However, no differences were observed for upper body maximal strength or muscular endurance. REE increased in response to both supplement and placebo ingestion (placebo: +5%; supplement: +11.5%), but the difference between conditions was not statistically significant. Overall, some select parameters may have been beneficially modified by supplementation, but this did not result in superior weight or fat loss over 6 weeks of supplementation and resistance training. PMID- 29238245 TI - Explaining Match Outcome During The Men's Basketball Tournament at The Olympic Games. AB - In preparation for the Olympics, there is a limited opportunity for coaches and athletes to interact regularly with team performance indicators providing important guidance to coaches for enhanced match success at the elite level. This study examined the relationship between match outcome and team performance indicators during men's basketball tournaments at the Olympic Games. Twelve team performance indicators were collated from all men's teams and matches during the basketball tournament of the 2004-2016 Olympic Games (n = 156). Linear and non linear analyses examined the relationship between match outcome and team performance indicator characteristics; namely, binary logistic regression and a conditional interference (CI) classification tree. The most parsimonious logistic regression model retained 'assists', 'defensive rebounds', 'field-goal percentage', 'fouls', 'fouls against', 'steals' and 'turnovers' (delta AIC <0.01; Akaike weight = 0.28) with a classification accuracy of 85.5%. Conversely, four performance indicators were retained with the CI classification tree with an average classification accuracy of 81.4%. However, it was the combination of 'field-goal percentage' and 'defensive rebounds' that provided the greatest probability of winning (93.2%). Match outcome during the men's basketball tournaments at the Olympic Games was identified by a unique combination of performance indicators. Despite the average model accuracy being marginally higher for the logistic regression analysis, the CI classification tree offered a greater practical utility for coaches through its resolution of non-linear phenomena to guide team success. PMID- 29238246 TI - Preventive and Regenerative Foam Rolling are Equally Effective in Reducing Fatigue-Related Impairments of Muscle Function following Exercise. AB - Objectives of the study were to compare the effects of a single bout of preventive or regenerative foam rolling (FR) on exercise-induced neuromuscular exhaustion. Single-centre randomised-controlled study was designed. Forty-five healthy adults (22 female; 25+/-2 yrs) were allocated to three groups: 1) FR of the lower limb muscles prior to induction of fatigue, 2) FR after induction of fatigue, 3) no-treatment control. Neuromuscular exhaustion was provoked using a standardized and validated functional agility short-term fatigue protocol. Main outcome measure was the maximal isometric voluntary force of the knee extensors (MIVF). Secondary outcomes included pain and reactive strength (RSI). Preventive (-16%) and regenerative FR (-12%) resulted in a decreased loss in MIVF compared to control (-21%; p < 0.001) five minutes after exhaustion. Post-hoc tests indicated a large-magnitude, non-significant trend towards regenerative foam rolling to best restore strength (Cohen's d > 0.8, p < 0.1). Differences over time (p < 0.001) between groups regarding pain and RSI did not turn out to be clinically meaningful. A single bout of foam rolling reduces neuromuscular exhaustion with reference to maximal force production. Regenerative rather than preventive foam rolling seems sufficient to prevent further fatigue. PMID- 29238247 TI - Effects of Hypoxic Training versus Normoxic Training on Exercise Performance in Competitive Swimmers. AB - In swimming competition, optimal swimming performance is characterized by a variety of interchangeable components, such as aerobic exercise capacity, anaerobic power and muscular function. Various hypoxic training methods would potentiate greater performance improvements compared to similar training at sea level. Therefore, this study aimed to evaluate the effects of six-weeks of hypoxic training on exercise performance in moderately trained competitive swimmers. Twenty swimmers were equally divided into a normoxic training group (n = 10) for residing and training at sea-level (PIO2 = 149.7 mmHg), and a hypoxic training group (n = 10) for residing at sea-level but training at 526 mmHg hypobaric hypoxic condition (PIO2 = 100.6 mmHg). Aerobic exercise capacity, anaerobic power, muscular function, hormonal response and 50 and 400 m swimming performance were measured before and after training, which was composed of warm up, continuous training, interval training, elastic resistance training, and cool down. The training frequency was 120 min, 3 days per week for 6 weeks. Muscular function and hormonal response parameters showed significant interaction effects (all p < 0.032, eta2 > 0.288) in muscular strength and endurance, growth hormone; GH, insulin like growth factor-1; IGF-1, and vascular endothelial growth factor; VEGF. The other variables demonstrated no significant interaction effects. However, a hypoxic training group also showed significantly increased maximal oxygen consumption; VO2max (p = 0.001), peak anaerobic power (p = 0.001), and swimming performances for 50 m (p = 0.000) and 400 m (p = 0.000). These results indicated that the hypoxic training method proposed in our study is effective for improvement of muscular strength and endurance in moderately trained competitive swimmers compared to control group. However, our hypoxic training method resulted in unclear changes in aerobic exercise capacity (VO2max), anaerobic power, and swimming performance of 50 m and 400 m compared to normoxic training. PMID- 29238248 TI - Comparing Matchplay Characteristics and Physical Demands of Junior and Professional Tennis Athletes in the Era of Big Data. AB - Differences in the competitive performance characteristics of junior and professional tennis players are not well understood. The present study provides a comprehensive comparative analysis of junior and professional matchplay. The study utilized multiple large-scale datasets covering match, point, and shot outcomes over multiple years of competition. Regression analysis was used to identify differences between junior and professional matchplay. Top professional men and women were found to play significantly more matches, sets, and games compared to junior players of an equivalent ranking. Professional players had a greater serve advantage, men winning 4 and women winning 2 additional percentage points on serve compared to juniors. Clutch ability in break point conversion was 6 to 8 percentage points greater for junior players. In general, shots were more powerful and more accurate at the professional level with the largest differences observed for male players on serve. Serving to the center of the court was more than two times more common for junior players on first serve. While male professionals performed 50% more total work in a Grand Slam match than juniors, junior girls performed 50% more work than professional women. Understanding how competitiveness, play demands, and the physical characteristics of shots differ between junior and professional tennis players can help set realistic expectations and developmentally appropriate training for transitioning players. PMID- 29238249 TI - Influence of Competitive-Anxiety on Heart Rate Variability in Swimmers. AB - The aim of this study was to analyze the relationship between competitive anxiety and heart rate variability (HRV) in swimming athletes. A total of 66 volunteers (41 male and 27 female) who swam the 400-m freestyle in the Brazilian Swimming Championships participated. Thirty minutes before the 400-m freestyle event, the athletes answered the Competitive Anxiety Inventory (CSAI-2R) questionnaire, then underwent anthropometric (body weight, height, and skinfold thickness) and HRV measurements. Then, at a second meeting, held 3 h after the 400-m freestyle event, the athletes returned to the evaluation room for HRV measurement (Polar(r) RS800cx, Kempele, Finland). Multiple linear regression was used to evaluate the relationship between competitive anxiety and HRV. The multiple linear regression was performed in three blocks (block 1: cognitive anxiety, block 2: somatic anxiety, and block 3: self-confidence), adopting the forward model. The results indicated a significant association between cognitive anxiety (p = 0.001) and HRV. An increased magnitude of the association was observed when somatic anxiety was inserted in the model (p = 0.001). In contrast, self-confidence showed, which was inserted in block 3, no relationship with HRV (p = 0.27). It was concluded that cognitive and somatic anxieties were associated with the HRV of swimmers. Athletes with a high magnitude of cognitive and/or somatic anxiety demonstrated more significant autonomic nervous system disturbance. Practically, psychological interventions are needed to improve anxiety states that are specific to perform well, and to improve HRV. PMID- 29238250 TI - Influence of Tennis Racquet Kinematics on Ball Topspin Angular Velocity and Accuracy during the Forehand Groundstroke. AB - Forehand groundstroke effectiveness is important for tennis success. Ball topspin angular velocity (TAV) and accuracy are important for forehand groundstroke effectiveness, and have been extensively studied, previously; despite previous, quality studies, it was unclear whether certain racquet kinematics relate to ball TAV and shot accuracy during the forehand groundstroke. This study evaluated potential relationships between (1) ball TAV and (2) forehand accuracy, and five measures of racquet kinematics: racquet head impact angle (i.e., closed or open face), horizontal and vertical racquet head velocity before impact, racquet head trajectory (resultant velocity direction, relative to horizontal) before impact, and hitting zone length (quasi-linear displacement, immediately before and after impact). Thirteen collegiate-level tennis players hit forehand groundstrokes in a biomechanics laboratory, where racquet kinematics and ball TAV were measured, and on a tennis court, to assess accuracy. Correlational statistics were used to evaluate potential relationships between racquet kinematics, and ball TAV (mixed model) and forehand accuracy (between-subjects model; alpha = 0.05). We observed an average (1) racquet head impact angle, (2) racquet head trajectory before impact, relative to horizontal, (3) racquet head horizontal velocity before impact, (4) racquet head vertical velocity before impact, and (5) hitting zone length of 80.4 +/- 3.6, 18.6 +/- 4.3, 15.4 +/- 1.4 m.s-1, 6.6 +/- 2.2 m.s-1, and 79.8 +/- 8.6 mm, respectively; and an average ball TAV of 969 +/- 375 revolutions per minute. Only racquet head impact angle and racquet head vertical velocity, before impact, significantly correlated with ball TAV (p < 0.01). None of the observed racquet kinematics significantly correlated to the measures of forehand accuracy. These results confirmed mechanical logic and indicate that increased ball TAV is associated with a more closed racquet head impact angle (ranging from 70 to 85, relative to the ground) and increased racquet head vertical velocity before impact. PMID- 29238251 TI - The Acute Effects of Static and Cyclic Stretching on Muscle Stiffness and Hardness of Medial Gastrocnemius Muscle. AB - This study aimed to clarify the acute effects of static stretching (SS) and cyclic stretching (CS) on muscle stiffness and hardness of the medial gastrocnemius muscle (MG) by using ultrasonography, range of motion (ROM) of the ankle joint and ankle plantar flexor. Twenty healthy men participated in this study. Participants were randomly assigned to SS, CS and control conditions. Each session consisted of a standard 5-minute cycle warm-up, accompanied by one of the subsequent conditions in another day: (a) 2 minutes static stretching, (b) 2 minutes cyclic stretching, (c) control. Maximum ankle dorsiflexion range of motion (ROM max) and normalized peak torque (NPT) of ankle plantar flexor were measured in the pre- and post-stretching. To assess muscle stiffness, muscle tendon junction (MTJ) displacement (the length changes in tendon and muscle) and MTJ angle (the angle made by the tendon of insertion and muscle fascicle) of MG were measured using ultrasonography at an ankle dorsiflexion angle of -10 degrees , 0 degrees , 10 degrees and 20 degrees before and after SS and CS for 2 minutes in the pre- and post-stretching. MG hardness was measured using ultrasound real-time tissue elastography (RTE). The results of this study indicate a significant effect of SS for ROM maximum, MTJ angle (0 degrees , 10 degrees , 20 degrees ) and RTE (10 degrees , 20 degrees ) compared with CS (p < 0.05). There were no significant differences in MTJ displacement between SS and CS. CS was associated with significantly higher NPT values than SS. This study suggests that SS of 2 minutes' hold duration significantly affected muscle stiffness and hardness compared with CS. In addition, CS may contribute to the elongation of muscle tissue and increased muscle strength. PMID- 29238252 TI - The Effect of Respiratory Muscle Training on Fin-Swimmers' Performance. AB - Although respiratory muscle functions can influence swimming performance, respiratory muscle training (RMT) is not routinely used for improving fin swimmers' performance. The aim of our study was to verify the benefit of a one month of RMT in young fin-swimmers. We assessed the effect of this training on respiratory muscles and on maximal underwater swimming distance. 28 fin-swimmers were randomly divided into an experimental group (EG) and a control group (CG). The study finished with 20 fin-swimmers (EG: n = 12; average age 12.0; weight 47.4 kg; height 1.58 m; CG: n = 8; age 11.5; weight 49.6 kg; height 1.53 m). Both group performed regular swimming training, during which the EG used Threshold PEP (positive expiratory pressure) and IMT (inspiratory muscle trainer) for RMT for one month. After one-month washout period, the CG also performed RMT. RMT showed significant improvement of inspiratory muscles in both groups (Z = <1.96; 2.59>; p < 0.05). Significant improvement was observed also in apnoea (AP) max (ZCG = 2.03; p < 0.05; ZEG=2.93; p < 0.01). A long-term effect was observed in the respiratory muscle strength and AP max in the EG (ZEG = 2.52; p < 0.05). RMT in fin-swimmers improves both respiratory muscle strength and the performance in AP max. PMID- 29238254 TI - Assessment of Three-Dimensional Trunk Kinematics and Muscle Activation during Cycling with Independent Cranks. AB - Independent cranks (IC) are recently introduced bicycle cranks that are decoupled; therefore allowing each leg to pedal independent of the other. Despite this introduction, limited research has been conducted assessing biomechanical changes when cycling with IC. Therefore, the purpose of this study was to evaluate and compare trunk kinematics and surface electromyography (sEMG) during IC and normal crank (NC) cycling during a graded exercise test to volitional fatigue. Ten healthy, physically active men performed two tests (IC and NC) on a cycling ergometer on separate days. 3D motion capture data of the trunk and pelvis and sEMG of the latissimus dorsi, tibialis anterior, gastrocnemius lateral head, rectus femoris, vastus lateralis and the biceps femoris were collected bilaterally. The first 30 seconds (beginning) and the last 30 seconds (end) of each trial were analyzed with respect to external load (beginning vs end), crank type (IC vs NC) side (left vs right), and phase of the pedal cycle (push vs recovery). Mean load at volitional fatigue in NC (351 W) was significantly greater than IC (318 W; p < 0.001). As external load increased, there was a similar increase in spine flexion angle in the sagittal plane for both NC (8.2 degrees ) and IC (4.6 degrees ). The NC condition demonstrated significantly greater increase in muscle activation from the beginning to the end than the IC condition in the tibialis anterior, rectus femoris and biceps femoris in the push phase, and the rectus femoris and biceps femoris in the recovery phase. As IC demonstrated less increase in activation, they cause less variation in muscular contraction from beginning to end throughout the full pedal range of motion, yet do not alter gross trunk kinematics. Due to altered muscle activation patterns when cycling with IC, they are proposed as a potentially beneficial training tool to increase training diversity. PMID- 29238253 TI - Plyometric Training Improves Sprinting, Jumping and Throwing Capacities of High Level Female Volleyball Players Better Than Skill-Based Conditioning. AB - There is an evident lack of studies on the effectiveness of plyometric- and skill based-conditioning in volleyball. This study aimed to evaluate effects of 12-week plyometric- and volleyball-skill-based training on specific conditioning abilities in female volleyball players. The sample included 41 high-level female volleyball players (21.8 +/- 2.1 years of age; 1.76 +/- 0.06 cm; 60.8 +/- 7.0 kg), who participated in plyometric- (n = 21), or skill-based-conditioning program (n = 20). Both programs were performed twice per week. Participants were tested on body-height, body-mass (BM), countermovement jump (CMJ), standing broad jump (SBJ), medicine ball throw, (MBT) and 20-m sprint (S20M). All tests were assessed at the study baseline (pre-) and at the end of the 12-week programs (post-testing). Two-way ANOVA for repeated measurements showed significant (p<0.05) "Group x Time" effects for all variables but body-height. Plyometric group significantly reduced body-mass (trivial effect size [ES] differences; 1% average pre- to post-measurement changes), and improved their performance in S20M (moderate ES; 8%), MBT (very large ES; 25%), CMJ (large ES; 27%), and SBJ (moderate ES; 8%). Players involved in skill-based-conditioning significantly improved CMJ (large ES; 18%), SBJ (small ES; 3%), and MBT (large ES; 9%). The changes which occurred between pre- and post-testing were more inter-correlated in plyometric-group. Although both training-modalities induced positive changes in jumping- and throwing-capacities, plyometric-training is found to be more effective than skill-based conditioning in improvement of conditioning capacities of female senior volleyball players. Future studies should evaluate differential program effects in less experienced and younger players. PMID- 29238255 TI - Does Shoe Collar Height Influence Ankle Joint Kinematics and Kinetics in Sagittal Plane Maneuvers? AB - The Objective of the study is to investigate the effects of basketball shoes with different collar heights on ankle kinematics and kinetics and athletic performance in different sagittal plane maneuvers. Twelve participants who wore high-top and low-top basketball shoes (hereafter, HS and LS, respectively) performed a weight-bearing dorsiflexion (WB-DF) maneuver, drop jumps (DJs), and lay-up jumps (LJs). Their sagittal plane kinematics and ground reaction forces were recorded using the Vicon motion capture system and Kistler force plates simultaneously. Moreover, ankle dorsiflexion and plantarflexion angles, moment, power, stiffness, and jump height were calculated. In the WB-DF test, the peak ankle dorsiflexion angle (p = 0.041) was significantly smaller in HS than in LS. Additionally, the peak ankle plantarflexion moment (p = 0.028) and power (p = 0.022) were significantly lower in HS than in LS during LJs but not during DJs. In both jumping maneuvers, no significant differences were found in the jump height or ankle kinematics between the two shoe types. According to the WB-DF test, increasing shoe collar height can effectively reduce the ankle range of motion in the sagittal plane. Although the HS did not restrict the flexion extension performance of the ankle joint during two jumping maneuvers, an increased shoe collar height can reduce peak ankle plantarflexion moment and peak power during the push-off phase in LJs. Therefore, a higher shoe collar height should be used to circumvent effects on the partial kinetics of the ankle joint in the sagittal plane. PMID- 29238256 TI - The Influence of a Pacesetter on Psychological Responses and Pacing Behavior during a 1600 m Run. AB - This study compared the effects of following a pacer versus following a self paced plan on psychological responses and pacing behavior in well-trained distance runners. Pacing in the present study was individually tailored where each participant developed a personal strategy to ensure their goal time was achieved. We expected that following a pacer would associate with goal achievement, higher pre-run confidence, positive emotions and lower perceived exertion during performance. In a mixed-design repeated-measures study, nineteen well-trained runners completed two 1600m running time trials. Ten runners had a pacer (paced group) who supported their individual pacing strategy, and nine participants self-paced running alone (control group). Both groups could check pace using their wrist watch. In contrast to our expectation, results indicated that the paced group reported higher pre-run anxiety with no significant differences in finish time, goal confidence, goal difficulty, perceived exertion, and self-rated performance between groups. We suggest that following a pacer is a skill that requires learning. Following a personalised pacer might associate with higher anxiety due to uncertainty in being able to keep up with the pacer and public visibility of dropping behind, something that is not so observable in a self-paced run completed alone. Future research should investigate mechanisms associated with effective pacing. PMID- 29238257 TI - Validation of an Arm Crank Ergometer Test for Use in Sedentary Adults. AB - The maximal oxygen uptake (VO2peak) test is an approved pre-operative examination tool, in a clinical setting: Both VO2peak and anaerobic threshold indicate a patient's physiological tolerance for major surgery and post-operative mortality, with cycle ergometry being routinely used for VO2peak tests in clinical settings, in many European countries. Nevertheless, the opportunities to assess populations with restricted mobility of the lower limbs are limited, as alternative methods (such as an arm-crank test protocol) to assess VO2peak are yet to be established. Twelve sedentary middle-aged adults (55.1 +/- 5.0 years) performed two incremental protocols on an arm crank and cycle ergometer on separate occasions. During exercise, gas exchange was collected and analysed by an online breath-by breath analysis system. Regression analysis showed that the model with dependent variable cycle ergometer VO2peak (CEVO2peak) in ml.kg-1.min-1 and independent variables arm crank VO2peak (ACEVO2peak) in ml.kg-1.min-1, lean body mass lower limbs (LBMLL) and total lean body mass (TLBM) fitted the population the best, with r2 = 0.87, adj. r2 = 0.82 and SEE = 3.14. The equation estimated with this model is: CE VO2peak = 11.776 + 1.418 X ACE VO2peak(ml.kg-1.min-) - 1.454 x TLBM + 3.967 X LLLBM. Our study suggests that arm cranking could be an alternative mode of exercise for sedentary middle-aged adults (and potentially in clinical settings) to assess the cardiorespiratory fitness of people with restricted lower limb mobility. PMID- 29238258 TI - Do Red and Blue Uniforms Matter in Football and Handball Penalties? AB - Past research has revealed ambiguous results on the impact of red uniforms in sports competition. The current study was aimed at analyzing the role of red and blue uniforms in football and handball penalties. Two experiments were conducted using a within subjects design, where participants rated uniform color manipulated video clips. In the first study, participants (n = 39) watched footage of football players kicking a penalty, whereas in the second study (n = 118) videos of handball penalty takers, handball goalkeepers and football goalkeepers preparing themselves to score/save a penalty were shown. Participants rated player's/goalkeeper's level of confidence and the expected position of the ball crossing the goal line in the first experiment and additionally the probability of scoring the penalty against the goalkeepers in the second experiment. The videos stopped at the point where the ball was leaving the foot and hand respectively. Results did not show any beneficial impact of red uniforms. Rather, football players wearing blue were rated to kick the ball higher. The study contradicts any positive effect of red versus blue uniforms in the context of football and handball penalties, which emphasizes the need of searching for potential moderators of color's impact on human behavior. PMID- 29238259 TI - Front Crawl Swimming Performance and Bi-Lateral Force Asymmetry during Land-Based and Tethered Swimming Tests. AB - The aims of this study were to investigate whether land-based and tethered swimming strength tests can explain swimming performance in 200-meter front crawl and, whether these tests were able to identify bilateral symmetry in force production. In the first session, eighteen swimmers completed a maximum effort 200 m front crawl swim (swimming performance) and 15 seconds maximal effort tethered front crawl swim. In the second session, participants performed the upper extremity isometric strength test. Peak force production of tethered swimming and isometric strength tests were significantly correlated for the strongest and weakest sides (r = 0.58 and r = 0.63, respectively; p < 0.05), but only peak force production during tethered swimming correlated with 200 m swimming performance time (r = -0.55, p < 0.05). Bilateral asymmetries in peak force and rate of force development were similar between the tethered swimming and isometric strength tests (peak force: 13%, p = 0.24; rate of force development: 15%, p = 0.88) However, both tests detected significant difference of peak force and rate of force development between body sides. The tethered swimming test can partially explain the 200 m front crawl swimming performance. In addition, the land-based and tethered swimming tests may be used to identify bilateral asymmetry of swimming. PMID- 29238260 TI - The Effect of 400 ug Inhaled Salbutamol on 3 km Time Trial Performance in a Low Humidity Environment. AB - The Objectives of the study were to investigate whether 400 ug inhaled salbutamol influences 3 km running time-trial performance and lung function in eucapnic voluntary hyperpnoea positive (EVH+ve) and negative (EVH-ve) individuals. Fourteen male participants (22.4 +/- 1.6yrs; 76.4 +/- 8.7kg; 1.80 +/- 0.07 m); (7 EVH+ve; 7 EVH-ve) were recruited following written informed consent. All participants undertook an EVH challenge to identify either EVH+ve (?FEV1>10%) or EVH-ve (?FEV1<10%). Participants performed three separate 3 km running time trials in a low-humidity (20-25%) environment on a non-motorized treadmill, 15 minutes following inhalation of salbutamol (400 ug), placebo (non-active inhalant) or control (no inhalant), in a randomized, single-blind, repeated measures design. Forced vital capacity maneuvers were performed at baseline, 10 minutes post inhalation and post time-trial. Time to complete 3 km and lung function data were analyzed using mixed model repeated measures ANOVA. Significance was assumed at p < 0.05. All EVH+ve participants had FEV1 falls from baseline between 10-25% post-challenge. There was no difference in performance time between trial conditions in EVH+ve (1012.7 +/- 129.6s; 1002.4 +/- 123.1s; 1015.9 +/- 113.0s) (p = 0.774) and EVH-ve (962.1 +/- 99.2s; 962.0 +/- 76.2s; 950.8 +/- 84.9s) (p = 0.401) groups for salbutamol, placebo and control trials, respectively. Exercising heart rate was significantly higher (p = 0.05) in the salbutamol trial (183 +/- 8 beats?min-1) compared to control (180 +/- 9 beats?min 1) with a trend towards significance (p=0.06) in the placebo trial (179 +/- 9 beats?min-1) for the pooled groups, no differences were seen between trials in groups individually. There was an increase in FEV1 in both EVH+ve (4.01 +/- 0.8L; 4.26 +/- 0.7L; 4.25 +/- 0.5L) and EVH-ve (4.81 +/- 0.4L; 5.1 +/- 0.4L; 5.1 +/- 0.5L) groups which was significant post-inhalation (p = 0.01; p = 0.02), but not post-time-trial (p = 0.27; p = 0.06), respectively, following salbutamol. EVH+ve participants did not demonstrate significant falls (>10% from baseline) in FEV1 following any time-trial. Administration of 400ug inhaled salbutamol does not improve 3 km time-trial performance in either mild EVH+ve or EVH-ve individuals despite significantly increased HR and FEV1. PMID- 29238261 TI - Physical, Physiological and Perceptual Match Demands of Amateur Mixed Gender Touch Players. AB - The purpose of this study was to provide a position specific (middle, link [male], link [female], wing) analysis of mixed gender touch on the physical physiological and perceptual demands of amateur players during match-play across a season. Distance and speed measures were obtained through the use of 10-Hz global positioning system devices, whilst telemetric heart rate devices were used determine a range of physiological measures. Players also provided a rating of perceived exertion following each match. The greatest physical demand was associated with the middle playing position by comparison to all others (Distance travelled >=5.00 m.s-1 effect size [ES]: 0.01-0.13; average distance >=5.00 m.s-1 ES: 0.11-0.38). Those playing as a middle also displayed a greater physiological (Mean heart rate ES: 0.05-0.13) and perceptual demand (rating of perceived exertion ES: 0.01-0.04). However, most measures reported only a trivial effect between each playing position. The findings provide an insight into the differing demands associated with the different playing positions within mixed gender touch which practitioners can use to provide more position-specific conditioning programs. PMID- 29238262 TI - Effect of Upper-Extremity Strengthening Exercises on the Lumbar Strength, Disability and Pain of Patients with Chronic Low Back Pain: A Randomized Controlled Study. AB - The present study aimed to analyze the impacts of a low back rehabilitation program accompanied with neck, shoulder and upper back exercises on pain, disability, and physical characteristics of patients with chronic low back pain. Twenty sedentary male patients with chronic low back pain participated in the study on a voluntary basis. The patients were randomly allocated into two groups: a conventional low back exercise group (CE) and a supported exercise group (SE; CE plus upper back, neck, and shoulder exercises). The Modified Oswestry Disability Questionnaire (MODQ) was used to evaluate the disability status and the Visual Analog Scale (VAS) was used to identify the pain states of the patients. In addition, neck, lumbar and shoulder isokinetic and isometric strengths of the patients were evaluated. The CE group performed lumbar stretching, mobilization and stabilization exercises in addition to low-back and abdominal isometric and concentric strengthening exercises. The SE group performed static stretching and isotonic exercises for the neck, upper-back, and shoulder muscles, in addition to the exercises performed in CE group. The exercises were implemented 3 days a week for 6 weeks in both groups. Following the 6-week exercise periods in both groups, statistically significant (p < 0.01) improvements were observed in the patients' levels of pain and the scores of MODQ reflecting an easing of disability. With respect to the levels of pain and disability, the improvements observed in the SE group was significantly (p < 0.01) greater than the improvement observed in the CE group. Based on the findings of this study, we can conclude that a low back exercise program used in combination with neck, shoulder and upper back exercises reduces the level of pain and disability in patients with chronic low back pain more prominently than conventional low back exercises. PMID- 29238263 TI - Sleep/Wake Behaviours in Elite Athletes from Three Different Football Codes. PMID- 29238265 TI - The UK's 100,000 Genomes Project: manifesting policymakers' expectations. AB - The UK's 100,000 Genomes Project has the aim of sequencing 100,000 genomes from UK National Health Service (NHS) patients while concomitantly transforming clinical care such that whole genome sequencing becomes routine clinical practice in the UK. Policymakers claim that the project will revolutionize NHS care. We wished to explore the 100,000 Genomes Project, and in particular, the extent to which policymaker claims have helped or hindered the work of those associated with Genomics England - the company established by the Department of Health to deliver the project. We interviewed 20 individuals linked to, or working for Genomics England. Interviewees had double-edged views about the context within which they were working. On the one hand, policymakers' expectations attached to the venture were considered vacuous "genohype"; on the other hand, they were considered the impetus needed for those trying to advance genomic research into clinical practice. Findings should be considered for future genomes projects. PMID- 29238264 TI - Auditory verbal hallucinations: Social, but how? AB - Auditory verbal hallucinations (AVH) are experiences of hearing voices in the absence of an external speaker. Standard explanatory models propose that AVH arise from misattributed verbal cognitions (i.e. inner speech), but provide little account of how heard voices often have a distinct persona and agency. Here we review the argument that AVH have important social and agent-like properties and consider how different neurocognitive approaches to AVH can account for these elements, focusing on inner speech, memory, and predictive processing. We then evaluate the possible role of separate social-cognitive processes in the development of AVH, before outlining three ways in which speech and language processes already involve socially important information, such as cues to interact with others. We propose that when these are taken into account, the social characteristics of AVH can be explained without an appeal to separate social-cognitive systems. PMID- 29238266 TI - Erythropoietin promoted the proliferation of hepatocellular carcinoma through hypoxia induced translocation of its specific receptor. AB - Background: Erythropoietin (EPO) is a hypoxia-inducible stimulator of erythropoiesis. Besides its traditional application in anemia therapy, it offers an effective treatment in the cancer patients, especially those who receive chemotherapy. Several reports indicated that it could promote the tumor cell proliferation through its specific receptor (EPOR). Unfortunately, the role of EPO/EPOR in hepatocellular carcinoma (HCC) progressing is still uncertain. Methods: Protein in tumor tissue from HCC patients or H22 tumor-bearing mice was detected with immunohistochemistry. Cells were cultured under 1% oxygen to establish hypoxia. RT-PCR and western blotting were used to measure mRNA and protein of EPO/EPOR, respectively. MTT, flow cytometry and PCNA staining were used to detect cell proliferation. Immunofluorescence staining was applied to study the expression and location of cellular EPOR. The EPOR binding studies were performed with 125I-EPO radiolabeling assay. Results: EPO and EPOR protein were up-regulated in HCC tissue of patients and H22-bearing mice. These were positively correlated with hypoxia-inducible factor -1 alpha and ki-67. Hypoxia up-regulated the expression of EPO and EPOR in HepG2 cells. It also induced the proliferation and increased the percentage of divided cells after 24, 48 and 72 h treatment. These were inhibited in cells pre-treated with 0.5 MUg/mL soluble EPOR. Immunofluorescence staining presented that EPOR was obviously translocated from nucleus to cytoplasm and membrane under hypoxia. EPOR binding activity was also increased after exposure to hypoxia. Recombinant human erythropoietin obviously elevated cell proliferation rate and the percentage of divided under hypoxia but not normoxia, which were also inhibited by soluble-EPOR. Conclusions: Our result indicated for the first time that EPO promoted the proliferation of HCC cells through hypoxia induced translocation of it specific receptor. Trial registration TJC20141113, retrospectively registered. PMID- 29238267 TI - Augmented expression of cardiac ankyrin repeat protein is induced by pemetrexed and a possible marker for the pemetrexed resistance in mesothelioma cells. AB - Background: Pemetrexed (PEM) is an anti-cancer agent targeting DNA and RNA synthesis, and clinically in use for mesothelioma and non-small cell lung carcinoma. A mechanism of resistance to PEM is associated with elevated activities of several enzymes involved in nucleic acid metabolism. Methods: We established two kinds of PEM-resistant mesothelioma cells which did not show any increase of the relevant enzyme activities. We screened genes enhanced in the PEM resistant cells with a microarray analysis and confirmed the expression levels with Western blot analysis. A possible involvement of the candidates in the PEM resistance was examined with a WST assay after knocking down the expression with si-RNA. We also analyzed a mechanism of the up-regulated expression with agents influencing AMP-activated protein kinase (AMPK) and p53. Results: We found that expression of cardiac ankyrin repeat protein (CARP) was elevated in the PEM resistant cells with a microarray and Western blot analysis. Down-regulation of CARP expression with si-RNA did not however influence the PEM resistance. Parent and PEM-resistant cells treated with PEM increased expression of CARP, AMPK, p53 and histone H2AX. The CARP up-regulation was however irrelevant to the p53 genotypes and not induced by an AMPK activator. Augmented p53 levels with nutlin 3a, an inhibitor for p53 degradation, and DNA damages were not always associated with the enhanced CARP expression. Conclusions: These data collectively suggest that up-regulated CARP expression is a potential marker for development of PEM resistance in mesothelioma and that the PEM-mediated enhanced expression is not directly linked with immediate cellular responses to PEM. PMID- 29238268 TI - The mental health and substance misuse needs of male ex-armed forces personnel in prison. AB - Ex-armed forces personnel constitute the largest known occupational group in prison but there is little evidence regarding their mental health, or substance misuse, needs. A total of 105 participants were interviewed and measures assessing symptoms of common mental health (CMH) problems and substance misuse were completed along with a review of their health care records. Forty (38%) participants screened for current CMH problems (CCMH) and high levels of dual symptomology and alcohol misuse were assessed. Thirty-nine (37%) had a mental health diagnosis recorded, most commonly for post-traumatic stress disorder (PTSD), depression and personality disorder. Those who screened for a CCMH problem were more likely to have pre-service vulnerability to negative health outcomes and those with dual symptomology were more likely to have experienced deployment during their service. Findings suggest the mental health needs of this group are similar to the general prison population. Potentially higher prevalences of PTSD and alcohol misuse may direct service provision. PMID- 29238269 TI - Promoting Excellence in Symptom Management Case Series: Case Study: A New Intervention for Rapid End-of-Life Symptom Control in the Home Setting. AB - The oral route is compromised for nearly all patients at the end of life (EOL). This article reviews the benefits and burdens of the usual alternative routes of medication delivery when the oral route fails and presents a case study on the use of a new innovation for the rectal delivery of medication to control EOL symptoms. A 62-year-old male hospice patient with end-stage metastatic prostate cancer presented with severe symptoms (Face, Legs, Activity, Cry and Consolability scale score, 9/10) that were uncontrollable with medications given via oral or sublingual routes. The patient goals were to remain at home with optimal symptom management. Rapid relief of symptoms was accomplished by the administration of medications already present in the home delivered with a new rectal catheter that provides discreet access for ongoing medication administration. Significant relief was noted within 20 minutes of dosing. The patient died peacefully 18 hours later, meeting his EOL goals, and the family was empowered to provide effective care for the patient at home. The family found the intervention easy to use. This case demonstrates how this new innovation can be used to ensure rapid symptom management and decreased burden of care by facilitating immediate and easy use of medications already present in the home. PMID- 29238270 TI - Treatment of Latent Tuberculosis Infection. AB - The treatment of latent tuberculosis infection (LTBI) is an essential component of tuberculosis (TB) elimination in regions that have a low incidence of TB. However, the decision to treat individuals with LTBI must consider the limitations of current diagnostic tests for LTBI, the risk of developing active TB disease, the potential adverse effects from chemoprophylactic therapy, and the importance of treatment adherence. When an individual has been diagnosed with LTBI and active TB has been ruled out, this is followed by an evaluation of the risks and benefits of LTBI treatment within the context of the regional epidemiology of TB and public health priorities. Once the decision to treat LTBI has been reached, and the infection is not suspected to be due to drug-resistant TB, the recommended regimens include isoniazid and/or rifamycin-derivatives, and the choice of regimen will depend upon the clinical considerations for that individual, such as patient preference, concomitant medications, hepatic disease, pregnancy, or immunodeficiency. As the duration of treatment of LTBI therapy is many months, therapy must be offered within a plan that monitors for adverse drug reactions and emphasizes adherence. For latent multidrug-resistant TB (MDR-TB) or extensively drug-resistant TB (XDR-TB) infection, the management is more complicated as there are few options for chemoprophylactic therapy and little evidence regarding the efficacy or risks of these regimens. PMID- 29238271 TI - Dual Depression: A Sex Perspective. AB - Mood and substance use disorders (SUDs) are mental conditions that are highly prevalent in the general population. Cooccurrence of major depression and SUD, also known as dual depression, is very common in the field of substance addiction. Sex differences are found in both major depression and SUD. This review, after presenting the state of the art of dual depression as regards prevalence, ethiopathologic mechanisms, and clinical aspects, is focused on dual depression in women. An overview of some potential factors associated with the sex gap in dual depression such as injecting, sexual risk behavior, intimate partner violence, and the reproductive cycle is presented. PMID- 29238272 TI - The dyadic effects of HIV stigma on the mental health of children and their parents in South Africa. AB - HIV stigma - both 'self-stigma' towards positive individuals and 'stigma by association' towards their families - is linked with adverse mental health. This study examined how stigma was associated with the mental health of parents and children in South Africa. Parent-child dyads (n=2477 dyads) in South Africa participated in a cross-sectional survey. For both parents and children, greater stigma was associated with their own reports of greater anxious and depressive symptoms. Parents reports of stigma was associated with children's greater anxious and depressive symptoms. Children's reports of stigma was related to parents greater anxious and depressive symptoms. There was a significant interaction, such that the association between parent stigma and depression was stronger when children also reported high levels of stigma. Findings provide support the effect of HIV stigma on the mental health of families and illustrate the importance of taking a family-based approach to stigma-reduction interventions to alleviate mental health problems. PMID- 29238273 TI - Dual Effects of N,N-dimethylformamide on Cell Proliferation and Apoptosis in Breast Cancer. AB - N,N-dimethylformamide (DMF) has been widely used as an organic solvent in industries. DMF is a potential medication. However, the antitumorigenic role of DMF in breast cancer remains unclear. Here, we examined dose-dependent effects of DMF on proliferation and apoptosis in breast cancer MCF-7 and nontumorous MCF-12A cells. We found that DMF had a growth inhibitory effect in MCF-12A cells in a dose-dependent manner. By contrast, however, DMF had dual effects on cell proliferation and apoptosis in MCF-7 cells. DMF at a high dose (100 mM) significantly inhibited MCF-7 cell growth while at a low dose (1 mM) significantly stimulated MCF-7 cell growth (both P < .05). The inhibitory effect of DMF on cell proliferation was accompanied by the decrease of cyclin D1 and cyclin E1 protein expression, leading to the cell cycle arrest at the G0/G1 phase. Furthermore, a high-dose DMF significantly increased the number of early apoptotic cells by increasing cleaved caspase-9 and proapoptotic protein Bax expression and decreased the ratio of Bcl-xL/Bax (P < .01). Thus, our data demonstrated for the first time that DMF has dual effects on breast cancer cell behaviors depending upon its dose. Caution must be warranted in determining its effective dose for targeting breast cancer. PMID- 29238274 TI - Hormetic Response by Silver Nanoparticles on In Vitro Multiplication of Sugarcane (Saccharum spp. Cv. Mex 69-290) Using a Temporary Immersion System. AB - Background: Hormesis is considered a dose-response phenomenon characterized by growth stimulation at low doses and inhibition at high doses. The hormetic response by silver nanoparticles (AgNPs) on in vitro multiplication of sugarcane was evaluated using a temporary immersion system. Methods: Sugarcane shoots were used as explants cultured in Murashige and Skoog medium with AgNPs at concentrations of 0, 25, 50, 100, and 200 mg/L. Shoot multiplication rate and length were used to determine hormetic response. Total content of phenolic compounds of sugarcane, mineral nutrition, and reactive oxygen species (ROS) was determined. Results: Results were presented as a dose-response curve. Stimulation phase growth was observed at 50 mg/L AgNPs, whereas inhibition phase was detected at 200 mg/L AgNPs. Mineral nutrient analysis showed changes in macronutrient and micronutrient contents due to the effect of AgNPs. Moreover, AgNPs induced ROS production and increased total phenolic content, with a dose-dependent effect. Conclusion: Results suggested that the production of ROS and mineral nutrition are key mechanisms of AgNP-induced hormesis and that phenolic accumulation was obtained as a response of the plant to stress produced by high doses of AgNPs. Therefore, small doses of AgNPs in the culture medium could be an efficient strategy for commercial micropropagation. PMID- 29238275 TI - 13C-assisted metabolic flux analysis to investigate heterotrophic and mixotrophic metabolism in Cupriavidus necator H16. AB - Introduction: Cupriavidus necator H16 is a gram-negative bacterium, capable of lithoautotrophic growth by utilizing hydrogen as an energy source and fixing carbon dioxide (CO2) through Calvin-Benson-Bassham (CBB) cycle. The potential to utilize synthesis gas (Syngas) and the prospects of rerouting carbon from polyhydroxybutyrate synthesis to value-added compounds makes C. necator an excellent chassis for industrial application. Objectives: In the context of lack of sufficient quantitative information of the metabolic pathways and to advance in rational metabolic engineering for optimized product synthesis in C. necator H16, we carried out a metabolic flux analysis based on steady-state 13C labelling. Methods: In this study, steady-state carbon labelling experiments, using either d-[1-13C]fructose or [1,2-13C]glycerol, were undertaken to investigate the carbon flux through the central carbon metabolism in C. necator H16 under heterotrophic and mixotrophic growth conditions, respectively. Results: We found that the CBB cycle is active even under heterotrophic condition, and growth is indeed mixotrophic. While Entner-Doudoroff (ED) pathway is shown to be the major route for sugar degradation, tricarboxylic acid (TCA) cycle is highly active in mixotrophic condition. Enhanced flux is observed in reductive pentose phosphate pathway (redPPP) under the mixotrophic condition to supplement the precursor requirement for CBB cycle. The flux distribution was compared to the mRNA abundance of genes encoding enzymes involved in key enzymatic reactions of the central carbon metabolism. Conclusion: This study leads the way to establishing 13C-based quantitative fluxomics for rational pathway engineering in C. necator H16. PMID- 29238276 TI - Computer-Aided Drug Discovery in Plant Pathology. AB - Control of plant diseases is largely dependent on use of agrochemicals. However, there are widening gaps between our knowledge on plant diseases gained from genetic/mechanistic studies and rapid translation of the knowledge into target oriented development of effective agrochemicals. Here we propose that the time is ripe for computer-aided drug discovery/design (CADD) in molecular plant pathology. CADD has played a pivotal role in development of medically important molecules over the last three decades. Now, explosive increase in information on genome sequences and three dimensional structures of biological molecules, in combination with advances in computational and informational technologies, opens up exciting possibilities for application of CADD in discovery and development of agrochemicals. In this review, we outline two categories of the drug discovery strategies: structure- and ligand-based CADD, and relevant computational approaches that are being employed in modern drug discovery. In order to help readers to dive into CADD, we explain concepts of homology modelling, molecular docking, virtual screening, and de novo ligand design in structure-based CADD, and pharmacophore modelling, ligand-based virtual screening, quantitative structure activity relationship modelling and de novo ligand design for ligand based CADD. We also provide the important resources available to carry out CADD. Finally, we present a case study showing how CADD approach can be implemented in reality for identification of potent chemical compounds against the important plant pathogens, Pseudomonas syringae and Colletotrichum gloeosporioides. PMID- 29238277 TI - The Incidence of Alternaria Species Associated with Infected Sesamum indicum L. Seeds from Fields of the Punjab, Pakistan. AB - Sesame (Sesamum indicum) is an important oil seed crop of Asia. Yields can be negatively impacted by various factors, including disease, particularly those caused by fungi which create problems in both production and storage. Foliar diseases of sesame such as Alternaria leaf blight may cause significant yield losses, with reductions in plant health and seed quality. The work reported here determined the incidence of Alternaria species infecting sesame seeds grown in the Punjab, Pakistan. A total of 428 Alternaria isolates were obtained from 105 seed samples and grouped into 36 distinct taxonomic groups based on growth pattern and morphological characters. Isolation frequency and relative density of surface sterilized and non-surface sterilized seeds showed that three isolates (A13, A47 and A215) were the most common morphological groups present. These isolates were further identified using sequencing of the Internal Transcribed Spacer (ITS) region of ribosomal DNA (rDNA) and the Alternaria major allergen gene (Alt a 1). Whilst ITS of rDNA did not resolve the isolates into Alternaria species, the Alt a 1 sequences exhibited > 99% homology with Alternaria alternata (KP123850.1) in GenBank accessions. The pathogenicity and virulence of these isolates of Alternaria alternata was confirmed in inoculations of sesame plants resulting in typical symptoms of leaf blight disease. This work confirms the identity of a major source of sesame leaf blight in Pakistan which will aid in formulating effective disease management strategies. PMID- 29238278 TI - Role of Metcalfa pruinosa as a Vector for Pseudomonas syringae pv. actinidiae. AB - After 20 years of steady increase, kiwifruit industry faced a severe arrest due to the pandemic spread of the bacterial canker, caused by Pseudomonas syringae pv. actinidiae (Psa). The bacterium penetrates the host plant primarily via natural openings or wounds, and its spread is mainly mediated by atmospheric events and cultural activities. Since the role of sucking insects as vectors of bacterial pathogens is widely documented, we investigated the ability of Metcalfa pruinosa Say (1830), one of the most common kiwifruit pests, to transmit Psa to healthy plants in laboratory conditions. Psa could be isolated both from insects feeding over experimentally inoculated plants, and from insects captured in Psa infected orchards. Furthermore, insects were able to transmit Psa from experimentally inoculated plants to healthy ones. In conclusion, the control of M. pruinosa is recommended in the framework of protection strategies against Psa. PMID- 29238279 TI - Elimination of Grapevine leafroll associated virus-3, Grapevine rupestris stem pitting associated virus and Grapevine virus A from a Tunisian Cultivar by Somatic Embryogenesis and Characterization of the Somaclones Using Ampelographic Descriptors. AB - Prospecting of local grapevine (Vitis vinifera L.) germplasm revealed that Tunisia possesses a rich patrimony which presents diversified organoleptic characteristics. However, viral diseases seriously affect all local grapevine cultivars which risk a complete extinction. Sanitation programs need to be established to preserve and exploit, as a gene pool, the Tunisian vineyards areas. The presence of the Grapevine leafroll associated virus-3 (GLRaV-3), Grapevine stem pitting associated virus (GRSPaV) and Grapevine virus A (GVA), were confirmed in a Tunisian grapevine cultivar using serological and molecular analyses. The association between GRSPaV and GVA viruses induces more rugose wood symptoms and damages. For this reason the cleansing of the infected cultivar is highly advisable. Direct and recurrent somatic embryos of cv. 'Hencha' were successfully induced from filament, when cultured on Chee and Pool (1987). based medium, enriched with 2 mg 1-1 of 2,4-dichlorophenoxyacetic acid and 2.5 mg 1-1 of Thidiazuron, after 36 weeks of culture. After six months of acclimatization, RT-PCR carried on 50 somaplants confirmed the absence of GVA, GRSPa-V as well as GLRaV-3 viruses in all somaplants. Ampelographic analysis, based on eight OIV descriptors, was carried out on two years acclimated somaplants, compared to the mother plant. Results demonstrated that the shape and contours of 46 somaclones leaves are identical to mother plant leaves and four phenotypically off-type plants were observed. The healthy state of 100% 'Hencha' somaclones and the high percentage of phenotypically true-to-type plants demonstrate that somatic embryogenesis is a promising technique to adopt for grapevine viruses elimination. PMID- 29238280 TI - Effect of the Combination Hot Water - Calcium Chloride on the In Vitro Growth of Colletotrichum gloeosporioides and the Postharvest Quality of Infected Papaya. AB - Anthracnose of papaya fruit caused by the fungus Colletotrichum gloeosporioides is one of the most economically important postharvest diseases. Hot water immersion (HW) and calcium chloride (Ca) treatments have been used to control papaya postharvest diseases; however, the effect of the combination HW-Ca on the pathogen growth and the development of the disease in infected papaya fruit has been scarcely studied. The aim of this study was to evaluate the effect of the HW Ca treatment on the in vitro growth of C. gloesporioides conidia and the quality of infected papaya. In vitro, the HW-Ca treated conidia showed reduced mycelial growth and germination. In vivo, the HW-Ca treatment of infected papaya delayed for 5 days the onset of the anthracnose symptoms and improved the papaya postharvest quality. The combined treatment HW-Ca was better than any of the individual treatments to inhibit the in vitro development of C. gloeosporioides and to reduce the negative effects of papaya anthracnose. PMID- 29238281 TI - Differential Inhibitory Activities of Four Plant Essential Oils on In Vitro Growth of Fusarium oxysporum f. sp. fragariae Causing Fusarium Wilt in Strawberry Plants. AB - The objective of this study was to determine inhibitory activities of four volatile plant essential oils (cinnamon oil, fennel oil, origanum oil and thyme oil) on in vitro growth of Fusarium oxysporum f. sp. fragariae causing Fusarium wilt of strawberry plants. Results showed that these essential oils inhibited in vitro conidial germination and mycelial growth of F. oxysporum f. sp. fragariae in a dose-dependent manner. Cinnamon oil was found to be most effective one in suppressing conidial germination while fennel oil, origanum oil and thyme oil showed moderate inhibition of conidial germination at similar levels. Cinnamon oil, origanum oil and thyme oil showed moderate antifungal activities against mycelial growth at similar levels while fennel oil had relatively lower antifungal activity against mycelial growth. Antifungal effects of these four plant essential oils in different combinations on in vitro fungal growth were also evaluated. These essential oils demonstrated synergistic antifungal activities against conidial germination and mycelial growth of F. oxysporum f. sp. fragariae in vitro. Simultaneous application of origanum oil and thyme oil enhanced their antimicrobial activities against conidial germination and fungal mycelial growth. These results underpin that volatile plant essential oils could be used in eco-friendly integrated disease management of Fusarium wilt in strawberry fields. PMID- 29238282 TI - Triazole Fungicides Sensitivity of Sclerotinia homoeocarpa in Korean Golf Courses. AB - Chemical management of dollar spot in turf may lead to the development of Sclerotinia homoeocarpa populations with reduced fungicide sensitivity. The objective of this study was to investigate resistance of S. homoeocarpa isolates to triazole fungicides and to test cross-resistance among three triazole fungicides. A total of 66 isolates of S. homoeocarpa were collected from 15 golf courses across Korea, and tested via in vitro sensitivity assay against hexaconazole, propiconazole and tebuconazole. EC50 values of the isolates to these fungicides were distributed in the range of 0.001-1.1 a. i. MUg ml-1. Based on the EC50 values, twelve representative strains were selected as sensitive isolates including control and insensitive isolates with respect to each fungicide. At a concentration of 0.1 a. i. MUg ml-1 for all fungicides, the selected strains were distinguished as sensitive or resistant isolates with the mycelial growth inhibition rate of 50% as the criterion. The EC50 values of resistant strains exposed to hexaconazole, propiconazole and tebuconazole were 20 50 times, 50-70 times, and 77 times greater, respectively, than that of the control strains. Two isolates of S. homoeocarpa S0-41 and Sh14-2-1 showed sensitivity toward all the fungicides used, while two other isolates Sh7-5-1 and Sh2-1-1 showed resistance to all fungicides. Each isolate showed similar resistance to the three types of triazole fungicides, whereby cross-resistance of isolates was confirmed in the present study; all three triazole fungicide combinations displayed significant correlation coefficients equivalent to or greater than 0.8. PMID- 29238283 TI - Involvement of a Polyketide Synthetase ClPKS18 in the Regulation of Vegetative Growth, Melanin and Toxin Synthesis, and Virulence in Curvularia lunata. AB - The clpks18 gene was first cloned and identified in Curvularia lunata. It contains 6571 base pairs (bp) and an 6276 bp open reading frame encoding 2091 amino acids. The ClPKS18 deletion mutant displayed an albino phenotype, and almost lost the ability to product 5-(hydroxymethyl) furan-2-carboxylate (M5HF2C) toxin, implying that clpks18 gene in C. lunata is not only involved in 1,8 dihydroxynaphthalene melanin synthesis, but also relatively associated with M5HF2C toxin biosynthesis of the pathogen. The pathogenicity assays revealed that DeltaClPKS18 was impaired in colonizing the maize leaves, which corresponds to the finding that ClPKS18 controls the production of melanin and M5HF2C in C. lunata. Results indicate that ClPKS18 plays a vital role in regulating pathogenicity of in C. lunata. PMID- 29238284 TI - Functional and Proteomic Analyses Reveal That ScpBXv Is Involved in Bacterial Growth, Virulence, and Biofilm Formation in Xanthomonas campestris pv. vesicatoria. AB - Segregation and condensation protein B (ScpB) is essential for replication and segregation in living organisms. Here, we reported the functions of ScpBXv (ScpB like protein in Xanthomonas campestris pv. vesicatoria) using phenotypic and proteomic analyses. Growth of XcvDeltascpBXv (ScpBXv knockout mutant) was reduced under both slow and fast growth conditions in rich medium, but comparable to this of the wild-type in plant-mimic conditions. Interestingly, the mutant was significantly less virulent than the wild-type in tomato, indicating that ScpBXv is involved in virulence. To investigate ScpBXv-associated mechanisms, comparative proteomic analyses were carried out and the abundance of 187 proteins was altered. Among them, diverse transcriptional regulators involved in biofilm formation and virulence were abundant in the wild-type. We further showed that biofilm formation of XcvDeltascpBXv was reduced. This study provides new insights into the functions of ScpBXv in bacterial replication and biofilm formation, which may contribute to the virulence of Xcv. PMID- 29238285 TI - Generation of an Infectious Clone of a New Korean Isolate of Apple chlorotic leaf spot virus Driven by Dual 35S and T7 Promoters in a Versatile Binary Vector. AB - The full-length sequence of a new isolate of Apple chlorotic leaf spot virus (ACLSV) from Korea was divergent, but most closely related to the Japanese isolate A4, at 84% nucleotide identity. The full-length cDNA of the Korean isolate of ACLSV was cloned into a binary vector downstream of the bacteriophage T7 RNA promoter and the Cauliflower mosaic virus 35S promoter. Chenopodium quinoa was successfully infected using in vitro transcripts synthesized using the T7 promoter, detected at 20 days post inoculation (dpi), but did not produce obvious symptoms. Nicotiana occidentalis and C. quinoa were inoculated through agroinfiltration. At 32 dpi the infection rate was evaluated; no C. quinoa plants were infected by agroinfiltration, but infection of N. occidentalis was obtained. PMID- 29238286 TI - Cell Wall Localization of Two DUF642 Proteins, BIIDXI and TEEBE, during Meloidogyne incognita Early Inoculation. AB - The root-knot nematode Meloidogyne incognita infects a variety of plants, including Arabidopsis thaliana. During migration, root-knot nematodes secrete different proteins to modify cell walls, which include pectolytic enzymes. However, the contribution of host cell wall proteins has not been described during this process. The function of two DUF642 cell wall proteins, BIIDXI (BDX, At4g32460) and TEEBE (TEB, At2g41800), in plant development could be related to the regulation of pectin methyl esterification status in the cell walls of different tissues. Accordingly, the expression of these two genes is up-regulated by auxin. BDX and TEB were highly induced during early M. incognita inoculation. Moreover, cell wall localization of the proteins was also induced. The cell wall localization of BDX and TEB DUF642 proteins during M. incognita early inoculation suggested that these two proteins could be involved in the regulation of the degree of pectin methylation during cell separation. PMID- 29238287 TI - Survey among ESGE members on leiomyosarcoma morcellation incidence. AB - Background: Increased awareness of leiomyosarcoma (LMS) risk during myomectomy or hysterectomy is essential. Objective and correct reasoning should prevail on any decision regarding the extent and type of surgery to employ. The anticipated risk of a sarcoma after myoma or uterus morcellation is low, and the frequency of leiomyosarcoma especially in women below the age of 40 is very rare. The prevalence data has a wide range and is therefore not reliable. The European Society of Gynaecological Endoscopy (ESGE) initiated a survey among its members looking into the frequency of morcellated leiomyosarcoma after endoscopic surgery.The ESGE Central office sent 3422 members a structured electronic questionnaire with multiple answer choices for each question. After 3 months, the answers were classified with a unique number in the EXCEL spread sheet. Statistical analysis was done using the SPSS v.18. Results: Out of 3422 members, 294 (8.6%) gynaecologists replied to the questionnaire; however, only 240 perform myomectomies by laparoscopy and hysteroscopy and hysterectomies by laparoscopy. The reported experience in performing laparoscopic myomectomy, hysteroscopic myomectomy, laparoscopic hysterectomy (LH), and laparoscopic subtotal hysterectomy (LSH) on an average was 10.8 (1-32) years. The vast majority of 67.1% had over 5 years of practice in laparoscopic surgery. The total number of 221 leiomyosarcoma was reported among 429,777 minimally invasive surgeries (laparoscopic and hysteroscopic myomectomies and LH and LSH), performed by all doctors in their lifetime. The overall reported sarcoma risk of all types of endoscopic myoma surgeries has been estimated to be 1.5% of operations which is very rare. Categorizing by type, 57 (0.06%) LMS were operated by laparoscopic myomectomy and 54 (0.07%) by hysteroscopic myomectomy, while 38 (0.13%) leiomyosarcoma operated by laparoscopic subtotal hysterectomy and 72 (0.31%) by laparoscopic hysterectomy. The probability of a sarcoma after morcellation to be falsely diagnosed by histopathology as a benign tumour and later identified as a sarcoma in a later examination has been reported and calculated to be 0.2%. The low risk of a sarcoma is also reflected by the small number of surgeries, where only 32 doctors reported that they operated once, 29 twice, and 18 operated on 3 10 sarcomas by laparoscopy during their lifetime. Conclusion: The survey demonstrated that myomectomy by hysteroscopy or laparoscopy has similar risks of sarcoma with an estimated incidence of 0.07%, much lower than that by laparoscopic hysterectomy and subtotal hysterectomy. Hence, for young patients with myoma infertility problem and low risk for LMS, myomectomy by MIS can be the first option of treatment. The fact that only 12.5% (216/1728) of uterine sarcoma cases are operated laparoscopically demonstrates the surgeons' awareness and alertness about LMS and the potential of spreading sarcomatous cells after myoma/uterus power morcellation. PMID- 29238289 TI - Extracellular Tau and Its Potential Role in the Propagation of Tau Pathology. AB - The pathological aggregation of tau protein is a hallmark of a set of neurodegenerative diseases collectively referred to as tauopathies. Tau aggregates independently in each neuron, but this aggregation can also occur in a non-cell autonomous manner in which aggregated tau is transmitted from one cell to another. Such trans-cellular propagation is initiated by the uptake of extracellular tau, which then seeds soluble tau in the recipient cells to spread the tau pathology. Accumulating evidence has demonstrated that tau is not only present in the cytoplasm of neurons but also actively released into the extracellular space. This finding has led to the idea that extracellular tau could be a novel therapeutic target to halt the propagation of tau pathology. From this perspective, the present review article focuses on recent advances in understanding the mechanisms regulating the levels of extracellular tau and discusses the role of such mechanisms in the propagation of tau pathology. PMID- 29238288 TI - A High-Capacitance Salt-Free Dielectric for Self-Healable, Printable, and Flexible Organic Field Effect Transistors and Chemical Sensor. AB - Printable and flexible electronics attract sustained attention for their low cost, easy scale up, and potential application in wearable and implantable sensors. However, they are susceptible to scratching, rupture, or other damage from bending or stretching due to their "soft" nature compared to their rigid counterparts (Si-based electronics), leading to loss of functionality. Self healing capability is highly desirable for these "soft" electronic devices. Here, a versatile self-healing polymer blend dielectric is developed with no added salts and it is integrated into organic field transistors (OFETs) as a gate insulator material. This polymer blend exhibits an unusually high thin film capacitance (1400 nF cm -2 at 120 nm thickness and 20-100 Hz). Furthermore, it shows pronounced electrical and mechanical self-healing behavior, can serve as the gate dielectric for organic semiconductors, and can even induce healing of the conductivity of a layer coated above it together with the process of healing itself. Based on these attractive properties, we developed a self-healable, low voltage operable, printed, and flexible OFET for the first time, showing promise for vapor sensing as well as conventional OFET applications. PMID- 29238290 TI - Intermittent Fasting Protects against Alzheimer's Disease Possible through Restoring Aquaporin-4 Polarity. AB - The impairment of amyloid-beta (Abeta) clearance in the brain plays a causative role in Alzheimer's disease (AD). Polarity distribution of aquaporin-4 (AQP4) is important to remove Abeta from brain. AQP4 polarity can be influenced by the ratio of two AQP4 isoforms M1 and M23 (AQP4-M1/M23), however, it is unknown whether the ratio of AQP4-M1/M23 changes in AD. Histone deacetylase 3 has been reported to be significantly increased in AD brain. Moreover, evidence indicated that microRNA-130a (miR-130a) possibly mediates the regulation of histone deacetylase 3 on AQP4-M1/M23 ratio by repressing the transcriptional activity of AQP4-M1 in AD. This study aimed to investigate whether intermittent fasting (IF), increasing the level of an endogenous histone deacetylases inhibitor beta hydroxybutyrate, restores AQP4 polarity via miR-130a mediated reduction of AQP4 M1/M23 ratio in protection against AD. The results showed that IF ameliorated cognitive dysfunction, prevented brain from Abeta deposition, and restored the AQP4 polarity in a mouse model of AD (APP/PS1 double-transgenic mice). Additionally, IF down-regulated the expression of AQP4-M1 and histone deacetylase 3, reduced AQP4-M1/M23 ratio, and increased miR-130a expression in the cerebral cortex of APP/PS1 mice. In vitro, beta-hydroxybutyrate was found to down-regulate the expression of AQP4-M1 and histone deacetylase 3, reduce AQP4-M1/M23 ratio, and increase AQP4-M23 and miR-130a expression in 2 MUM Abeta-treated U251 cells. Interestingly, on the contrary to the result observed in 2 MUM Abeta-treated cells, AQP4 expression was obviously decreased in cells exposed to 10 MUM Abeta. miR-130a mimic decreased the expression of AQP4-M1 and the ratio of AQP4-M1/M23, as well as silencing histone deacetylase 3 caused the up-regulation of AQP4 and miR-130a, and the reduction of AQP4-M1/M23 ratio in U251 cells. In conclusion, IF exhibits beneficial effects against AD. The mechanism may be associated with recovery of AQP4 polarity, resulting from the reduction of AQP4-M1/M23 ratio. Furthermore, beta-hydroxybutyrate may partly mediate the effect of IF on the reduction of AQP4-M1/M23 ratio in AD, in which miR-130a and histone deacetylase 3 may be implicated. PMID- 29238292 TI - Effect of VEGF on Inflammatory Regulation, Neural Survival, and Functional Improvement in Rats following a Complete Spinal Cord Transection. AB - After complete transection of the thoracic spinal segment, neonatal rats exhibit spontaneous locomotor recovery of hindlimbs, but this recovery is not found in adult rats after similar injury. The potential mechanism related to the difference in recovery of neonatal and adult rats remains unknown. In this study, 342 animals were analyzed. The vascular endothelial growth factor (VEGF) level in spinal segments below injury sites was significantly higher in postnatal day 1 rats (P1) compared with 28-day-old adult rats (P28) following a complete T9 transection. VEGF administration in P28 rats with T9 transection significantly improved the functional recovery; by contrast, treatment with VEGF receptor inhibitors in P1 rats with T9 transection slowed down the spontaneous functional recovery. Results showed more neurons reduced in the lumbar spinal cord and worse local neural network reorganization below injury sites in P28 rats than those in P1 rats. Transynaptic tracing with pseudorabies virus and double immunofluorescence analysis indicated that VEGF treatment in P28 rats alleviated the reduced number of neurons and improved their network reorganization. VEGF inhibition in neonates resulted in high neuronal death rate and deteriorated network reorganization. In in vivo studies, T9 transection induced less increase in the number of microglia in the spinal cord in P1 animals than P28 animals. VEGF treatment reduced the increase in microglial cells in P28 animals. VEGF administration in cultured spinal motoneurons prevented lipopolysaccharide (LPS) induced neuronal death and facilitated neurite growth. Western blots of the samples of lumbar spinal cord after spinal transection and cultured spinal motoneurons showed a lower level of Erk1/2 phosphorylation after the injury or LPS induction compared with that in the control. The phosphorylation level increased after VEGF treatment. In conclusion, VEGF is a critical mediator involved in functional recovery after spinal transection and can be considered a potential target for clinical therapy. PMID- 29238293 TI - The Impact of Anesthetic State on Spike-Sorting Success in the Cortex: A Comparison of Ketamine and Urethane Anesthesia. AB - Spike sorting is an essential first step in most analyses of extracellular in vivo electrophysiological recordings. Here we show that spike-sorting success depends critically on characteristics of coordinated population activity that can differ between anesthetic states. In tetrode recordings from mouse auditory cortex, spike sorting was significantly less successful under ketamine/medetomidine (ket/med) than urethane anesthesia. Surprisingly, this difficulty with sorting under ket/med anesthesia did not appear to result from either greater millisecond-scale burstiness of neural activity or increased coordination of activity among neighboring neurons. Rather, the key factor affecting sorting success appeared to be the amount of coordinated population activity at long time intervals and across large cortical distances. We propose that spike-sorting success is directly dependent on overall coordination of activity, and is most disrupted by large-scale fluctuations in cortical population activity. Reliability of single-unit recording may therefore differ not only between urethane-anesthetized and ket/med-anesthetized states as demonstrated here, but also between synchronized and desynchronized states, asleep and awake states, or inattentive and attentive states in unanesthetized animals. PMID- 29238294 TI - Unique Temporal Expression of Triplicated Long-Wavelength Opsins in Developing Butterfly Eyes. AB - Following gene duplication events, the expression patterns of the resulting gene copies can often diverge both spatially and temporally. Here we report on gene duplicates that are expressed in distinct but overlapping patterns, and which exhibit temporally divergent expression. Butterflies have sophisticated color vision and spectrally complex eyes, typically with three types of heterogeneous ommatidia. The eyes of the butterfly Papilio xuthus express two green- and one red-absorbing visual pigment, which came about via gene duplication events, in addition to one ultraviolet (UV)- and one blue-absorbing visual pigment. We localized mRNAs encoding opsins of these visual pigments in developing eye disks throughout the pupal stage. The mRNAs of the UV and blue opsin are expressed early in pupal development (pd), specifying the type of the ommatidium in which they appear. Red sensitive photoreceptors first express a green opsin mRNA, which is replaced later by the red opsin mRNA. Broadband photoreceptors (that coexpress the green and red opsins) first express the green opsin mRNA, later change to red opsin mRNA and finally re-express the green opsin mRNA in addition to the red mRNA. Such a unique temporal and spatial expression pattern of opsin mRNAs may reflect the evolution of visual pigments and provide clues toward understanding how the spectrally complex eyes of butterflies evolved. PMID- 29238295 TI - Audio-Visual Integration in a Redundant Target Paradigm: A Comparison between Rhesus Macaque and Man. AB - The mechanisms underlying multi-sensory interactions are still poorly understood despite considerable progress made since the first neurophysiological recordings of multi-sensory neurons. While the majority of single-cell neurophysiology has been performed in anesthetized or passive-awake laboratory animals, the vast majority of behavioral data stems from studies with human subjects. Interpretation of neurophysiological data implicitly assumes that laboratory animals exhibit perceptual phenomena comparable or identical to those observed in human subjects. To explicitly test this underlying assumption, we here characterized how two rhesus macaques and four humans detect changes in intensity of auditory, visual, and audio-visual stimuli. These intensity changes consisted of a gradual envelope modulation for the sound, and a luminance step for the LED. Subjects had to detect any perceived intensity change as fast as possible. By comparing the monkeys' results with those obtained from the human subjects we found that (1) unimodal reaction times differed across modality, acoustic modulation frequency, and species, (2) the largest facilitation of reaction times with the audio-visual stimuli was observed when stimulus onset asynchronies were such that the unimodal reactions would occur at the same time (response, rather than physical synchrony), and (3) the largest audio-visual reaction-time facilitation was observed when unimodal auditory stimuli were difficult to detect, i.e., at slow unimodal reaction times. We conclude that despite marked unimodal heterogeneity, similar multisensory rules applied to both species. Single-cell neurophysiology in the rhesus macaque may therefore yield valuable insights into the mechanisms governing audio-visual integration that may be informative of the processes taking place in the human brain. PMID- 29238291 TI - Modulation of Neocortical Development by Early Neuronal Activity: Physiology and Pathophysiology. AB - Animal and human studies revealed that patterned neuronal activity is an inherent feature of developing nervous systems. This review summarizes our current knowledge about the mechanisms generating early electrical activity patterns and their impact on structural and functional development of the cerebral cortex. All neocortical areas display distinct spontaneous and sensory-driven neuronal activity patterns already at early phases of development. At embryonic stages, intermittent spontaneous activity is synchronized within small neuronal networks, becoming more complex with further development. This transition is accompanied by a gradual shift from electrical to chemical synaptic transmission, with a particular role of non-synaptic tonic currents before the onset of phasic synaptic activity. In this review article we first describe functional impacts of classical neurotransmitters (GABA, glutamate) and modulatory systems (e.g., acetylcholine, ACh) on early neuronal activities in the neocortex with special emphasis on electrical synapses, nonsynaptic and synaptic currents. Early neuronal activity influences probably all developmental processes and is crucial for the proper formation of neuronal circuits. In the second part of our review, we illustrate how specific activity patterns might interfere with distinct neurodevelopmental processes like proliferation, migration, axonal and dendritic sprouting, synapse formation and neurotransmitter specification. Finally, we present evidence that transient alterations in neuronal activity during restricted perinatal periods can lead to persistent changes in functional connectivity and therefore might underlie the manifestation of neurological and neuropsychiatric diseases. PMID- 29238296 TI - The Effects of rTMS Combined with Motor Training on Functional Connectivity in Alpha Frequency Band. AB - It has recently been reported that repetitive transcranial magnetic stimulation combined with motor training (rTMS-MT) could improve motor function in post stroke patients. However, the effects of rTMS-MT on cortical function using functional connectivity and graph theoretical analysis remain unclear. Ten healthy subjects were recruited to receive rTMS immediately before application of MT. Low frequency rTMS was delivered to the dominant hemisphere and non-dominant hand performed MT over 14 days. The reaction time of Nine-Hole Peg Test and electroencephalography (EEG) in resting condition with eyes closed were recorded before and after rTMS-MT. Functional connectivity was assessed by phase synchronization index (PSI), and subsequently thresholded to construct undirected graphs in alpha frequency band (8-13 Hz). We found a significant decrease in reaction time after rTMS-MT. The functional connectivity between the parietal and frontal cortex, and the graph theory statistics of node degree and efficiency in the parietal cortex increased. Besides the functional connectivity between premotor and frontal cortex, the degree and efficiency of premotor cortex showed opposite results. In addition, the number of connections significantly increased within inter-hemispheres and inter-regions. In conclusion, this study could be helpful in our understanding of how rTMS-MT modulates brain activity. The methods and results in this study could be taken as reference in future studies of the effects of rTMS-MT in stroke patients. PMID- 29238297 TI - Short-Term Total Sleep-Deprivation Impairs Contextual Fear Memory, and Contextual Fear-Conditioning Reduces REM Sleep in Moderately Anxious Swiss Mice. AB - The conditioning tasks have been widely used to model fear and anxiety and to study their association with sleep. Many reports suggest that sleep plays a vital role in the consolidation of fear memory. Studies have also demonstrated that fear-conditioning influences sleep differently in mice strains having a low or high anxiety level. It is, therefore, necessary to know, how sleep influences fear-conditioning and how fear-conditioning induces changes in sleep architecture in moderate anxious strains. We have used Swiss mice, a moderate anxious strain, to study the effects of: (i) sleep deprivation on contextual fear conditioned memory, and also (ii) contextual fear conditioning on sleep architecture. Animals were divided into three groups: (a) non-sleep deprived (NSD); (b) stress control (SC); and (c) sleep-deprived (SD) groups. The SD animals were SD for 5 h soon after training. We found that the NSD and SC animals showed 60.57% and 58.12% freezing on the testing day, while SD animals showed significantly less freezing (17.13% only; p < 0.001) on the testing day. Further, we observed that contextual fear-conditioning did not alter the total amount of wakefulness and non-rapid eye movement (NREM) sleep. REM sleep, however, significantly decreased in NSD and SC animals on the training and testing days. Interestingly, REM sleep did not decrease in the SD animals on the testing day. Our results suggest that short term sleep deprivation impairs fear memory in moderate anxious mice. It also suggests that NREM sleep, but not REM sleep, may have an obligatory role in memory consolidation. PMID- 29238298 TI - Enhancement of Pleasure during Spontaneous Dance. AB - Dancing emphasizes the motor expression of emotional experiences. The bodily expression of emotions can modulate the subjective experience of emotions, as when adopting emotion-specific postures and faces. Thus, dancing potentially offers a ground for emotional coping through emotional enhancement and regulation. Here we investigated the emotional responses to music in individuals without any prior dance training while they either freely danced or refrained from movement. Participants were also tested while imitating their own dance movements but in the absence of music as a control condition. Emotional ratings and cardio-respiratory measures were collected following each condition. Dance movements were recorded using motion capture. We found that emotional valence was increased specifically during spontaneous dance of groovy excerpts, compared to both still listening and motor imitation. Furthermore, parasympathetic-related heart rate variability (HRV) increased during dance compared to motor imitation. Nevertheless, subjective and physiological arousal increased during movement production, regardless of whether participants were dancing or imitating. Significant correlations were found between inter-individual differences in the emotions experienced during dance and whole-body acceleration profiles. The combination of movement and music during dance results in a distinct state characterized by acutely heightened pleasure, which is of potential interest for the use of dance in therapeutic settings. PMID- 29238299 TI - The HTM Spatial Pooler-A Neocortical Algorithm for Online Sparse Distributed Coding. AB - Hierarchical temporal memory (HTM) provides a theoretical framework that models several key computational principles of the neocortex. In this paper, we analyze an important component of HTM, the HTM spatial pooler (SP). The SP models how neurons learn feedforward connections and form efficient representations of the input. It converts arbitrary binary input patterns into sparse distributed representations (SDRs) using a combination of competitive Hebbian learning rules and homeostatic excitability control. We describe a number of key properties of the SP, including fast adaptation to changing input statistics, improved noise robustness through learning, efficient use of cells, and robustness to cell death. In order to quantify these properties we develop a set of metrics that can be directly computed from the SP outputs. We show how the properties are met using these metrics and targeted artificial simulations. We then demonstrate the value of the SP in a complete end-to-end real-world HTM system. We discuss the relationship with neuroscience and previous studies of sparse coding. The HTM spatial pooler represents a neurally inspired algorithm for learning sparse representations from noisy data streams in an online fashion. PMID- 29238300 TI - Supervised Estimation of Granger-Based Causality between Time Series. AB - Brain effective connectivity aims to detect causal interactions between distinct brain units and it is typically studied through the analysis of direct measurements of the neural activity, e.g., magneto/electroencephalography (M/EEG) signals. The literature on methods for causal inference is vast. It includes model-based methods in which a generative model of the data is assumed and model free methods that directly infer causality from the probability distribution of the underlying stochastic process. Here, we firstly focus on the model-based methods developed from the Granger criterion of causality, which assumes the autoregressive model of the data. Secondly, we introduce a new perspective, that looks at the problem in a way that is typical of the machine learning literature. Then, we formulate the problem of causality detection as a supervised learning task, by proposing a classification-based approach. A classifier is trained to identify causal interactions between time series for the chosen model and by means of a proposed feature space. In this paper, we are interested in comparing this classification-based approach with the standard Geweke measure of causality in the time domain, through simulation study. Thus, we customized our approach to the case of a MAR model and designed a feature space which contains causality measures based on the idea of precedence and predictability in time. Two variations of the supervised method are proposed and compared to a standard Granger causal analysis method. The results of the simulations show that the supervised method outperforms the standard approach, in particular it is more robust to noise. As evidence of the efficacy of the proposed method, we report the details of our submission to the causality detection competition of Biomag2014, where the proposed method reached the 2nd place. Moreover, as empirical application, we applied the supervised approach on a dataset of neural recordings of rats obtaining an important reduction in the false positive rate. PMID- 29238301 TI - Association of HLA-A and HLA-B Alleles with Lamotrigine-Induced Cutaneous Adverse Drug Reactions in the Thai Population. AB - Background: Lamotrigine (LTG) is commonly used for treatment of epilepsy and bipolar disorder. It is one of the common cause of cutaneous adverse drug reactions (CADR). Clinical symptoms of LTG-induced CADR range from maculopapular exanthema (MPE) to severe cutaneous adverse reactions (SCAR). This study aimed to determine the association of the LTG-induced CADR with human leukocyte antigen (HLA) alleles in Thai patients. Methods: Fifteen patients with LTG-induced CADR [10 MPE; 4 Stevens-Johnson syndrome; and 1 drug reaction with eosinophilia and systemic symptoms] and 50 LTG-tolerant controls were included in the study. HLA-A and HLA-B genotyping was performed using polymerase chain reaction-sequence specific oligonucleotides probes. Results: The proportion of HLA-A*02:07 and HLA B*15:02 allele carriers were significantly higher in the LTG-induced CADR group than in the tolerant controls [odds ratio (OR): 7.83; 95% confidence interval (CI): 1.60-38.25; P = 0.013, and OR: 4.89; 95% CI: 1.28-18.67; P = 0.014]. In addition, subjects with HLA-A*33:03, HLA-B*15:02, and HLA-B*44:03 were significantly higher in the LTG-induced MPE group than in the tolerant controls (OR: 8.27; 95% CI: 1.83-37.41; P = 0.005, OR: 7.33; 95% CI: 1.63-33.02; P = 0.005; and OR: 10.29; 95% CI: 1.45-72.81; P = 0.029). In contrast to the LTG induced MPE group, there were no significant differences between HLA alleles and LTG-induced SCAR group. Conclusion:HLA-A*02:07 and HLA-B*15:02 were associated with LTG-induced CADR in Thai patients. We also identified an association between HLA-A*33:03, HLA-B*15:02, and HLA-B*44:03 and LTG-induced MPE in this population. These results suggest that these alleles could be useful screening markers for preventing CADR before LTG treatment in Thai patients, but further replication studies with larger sample sizes are needed. PMID- 29238302 TI - Sevoflurane Induces Exaggerated and Persistent Cognitive Decline in a Type II Diabetic Rat Model by Aggregating Hippocampal Inflammation. AB - Recent studies show that a moderate duration of sevoflurane, one of the most commonly used volatile anesthetics in clinical practice, does not induce cognitive impairment in animals under physiological conditions. However, the influence of sevoflurane on cognitive function under diabetic conditions remains unclear. The aim of this study was to determine whether sevoflurane causes cognitive decline in a rat model of type 2 diabetes mellitus (DM) and if so, to explore a possible underlying mechanism. Diabetic Goto-Kakizaki (GK) rats and non diabetic Wistar rats underwent 2.6% sevoflurane for 4 h or sham (control) exposure. Cognitive function and hippocampal inflammation were assessed 1 week and 5 months after sevoflurane or sham exposure. Compared with Wistar control rats, GK control rats exhibited shorter freezing times in Trace fear conditioning task 1 week after exposure, took longer to locate the submerged platform and had shorter dwell-time in the target quadrant in Morris Water Maze task 5 months after exposure. GK rats that received sevoflurane not only exhibited less freezing times 1 week after exposure, but also spent more time to locate the submerged platform and had less dwell-time in the target quadrant, compared with GK control rats. Molecular studies revealed that the levels of pro-inflammatory cytokines and activated microglia in the hippocampus were higher in GK control rats than those in Wistar control rats at both time points and were further increased in GK rats receiving sevoflurane. Wistar rats that received sevoflurane and Wistar control rats did not differ in any cognitive performance and molecular assessment. The results suggest that diabetic GK rats exhibit cognitive dysfunction probably due to increased hippocampal inflammation, and that sevoflurane induces exaggerated and persistent cognitive decline in GK rat by aggregating hippocampal inflammation. PMID- 29238303 TI - Near-Wall Migration Dynamics of Erythrocytes in Vivo: Effects of Cell Deformability and Arteriolar Bifurcation. AB - Red blood cell (RBC) deformability has a significant impact on microcirculation by affecting cell dynamics. Despite previous studies that have demonstrated the margination of rigid cells and particles in vitro, little information is available on the in vivo margination of deformability-impaired RBCs under physiological flow and hematocrit conditions. Thus, in this study, we examined how the deformability-dependent, RBC migration alters the cell distribution under physiological conditions, particularly in arteriolar network flows. The hardened RBCs (hRBCs) were found to preferentially flow near the vessel walls of small arterioles (diameter = 47.1-93.3 MUm). The majority of the hRBCs (63%) were marginated within the range of 0.7R-0.9R (R: radial position normalized by vessel radius), indicating that the hRBCs preferentially accumulated near the vessel walls. The laterally marginated hRBCs maintained their lateral positions near the walls while traversing downstream with attenuated radial dispersion. In addition, the immediate displacement of RBCs while traversing a bifurcation also contributes to the near-wall accumulation of hRBCs. The notable difference in the inward migration between the marginated nRBCs and hRBCs after bifurcations further supports the potential role of bifurcations in the accumulation of hRBCs near the walls. PMID- 29238304 TI - Neck Circumference, a Novel Indicator for Hyperuricemia. AB - Background: Waist circumference has been correlated with the risk of hyperuricemia. Whether neck circumference is also associated with hyperuricemia has not been assessed. This study aimed to investigate whether neck circumference is associated with hyperuricemia. Methods: This study population from Beijing is part of the larger China-wide Risk Evaluation of Cancers in Chinese Diabetic Individuals: a lONgitudinal (REACTION) study. For this Beijing sub-center cross sectional study, a total of 8971 subjects were recruited. Gender-specific multivariable-adjusted regression analyses were conducted to analyze the association of neck circumference and waist circumference with hyperuricemia and the association of neck circumference with serum uric acid levels in the non hyperuricemia population. Results: After adjusting for confounding variables, regression analyses showed that neck circumference was positively associated with hyperuricemia [OR, 2.61 (1.86-3.67) for males and 3.27 (2.53-4.22) for females] in both genders; further, neck circumference was also positively associated with serum uric acid levels in non-hyperuricemia subjects [b, 2.58 (1.76-3.39) for males and 4.27 (3.70-4.84) for females] in both genders. Additionally, we demonstrated that neck circumference was similar to waist circumference in terms of the strength of association (OR, 3.03 for waist circumference vs. 2.61 for neck circumference in males, and 3.50 vs. 3.27 for females) with hyperuricemia and the ability to predict hyperuricemia (AUC, 0.63 for waist circumference vs. 0.61 for neck circumference in males, and 0.66 vs. 0.66 in females). Conclusion: Neck circumference is positively and independently associated with hyperuricemia in both genders and is also associated with serum uric acid levels in the non hyperuricemia population. PMID- 29238305 TI - MiR-29a Suppresses Spermatogenic Cell Apoptosis in Testicular Ischemia Reperfusion Injury by Targeting TRPV4 Channels. AB - Background: MicroRNAs (miRNAs) have emerged as gene expression regulators in the progression of ischemia-reperfusion injury (IRI). Accumulating evidences have indicated miR-29a play roles in myocardial and cerebral IRI. However, the role of miR-29a in testicular IRI has not been elucidated. Methods: Changes in expression of miR-29a and Transient Receptor Potential Vanilloid 4 (TRPV4) in animal samples and GC-1 spermatogenic cells were examined. The effects of miR-29a on spermatogenic cell apoptosis in testicular IRI were analyzed both in vitro and in vivo. Results: The expression of MiR-29a was negatively correlated with the expression of TRPV4 and significantly downregulated in animal samples and GC-1 cells as testicular IRI progressed. Further studies revealed TRPV4 as a downstream target of miR-29a. Inhibition of miR-29a expression increased the expression of TRPV4 and promoted spermatogenic cell apoptosis, whereas overexpression of miR-29a downregulated TRPV4 expression and suppressed spermatogenic cell apoptosis caused by testicular IRI in vitro and in vivo. Conclusion: Our results suggest that miR-29a suppresses apoptosis induced by testicular IRI by directly targeting TRPV4. PMID- 29238306 TI - Calcium Imaging of Nerve-Mast Cell Signaling in the Human Intestine. AB - Introduction: It is suggested that an altered microenvironment in the gut wall alters communication along a mast cell nerve axis. We aimed to record for the first time signaling between mast cells and neurons in intact human submucous preparations. Methods: We used the Ca2+ sensitive dye Fluo-4 AM to simultaneously image changes in intracellular calcium [Ca+2]i (%DeltaF/F) in neurons and mast cells. Data are presented as median with interquartile ranges (25/75%). Results: We recorded nerve responses in 29 samples upon selective activation of 223 mast cells by IgE receptor cross linking with the antibody mAb22E7. Mast cells responded to mAb22E7 with a median [Ca+2]i increase of 20% (11/39) peaking 90 s (64/144) after the application. Only very few neurons responded and the median percentage of responding neuronal area was 0% (0/5.9). Mast cell activation remained in the presence of the fast sodium channel blocker tetrodotoxin. Specific neuronal activation by transmural electrical field stimulation (EFS) in 34 samples evoked instantaneously [Ca+2]i signals in submucous neurons. This was followed by a [Ca+2]i peak response of 8%DeltaF/F (4/15) in 33% of 168 mast cells in the field of view. The mast cell response was abolished by the nerve blocker tetrododoxin, reduced by the Calcitonin Gene-Related Peptide receptor 1 antagonist BIBN-4096 and the Vasoactive Intestinal Peptide receptor antagonist PG97-269, but not by blockade of the neurokinin receptors 1-3. Conclusion: The findings revealed bidirectional signaling between mast cells and submucous neurons in human gut. In our macroscopically normal preparations a nerve to mast cell signaling was very prominent whereas a mast cell to nerve signaling was rather rare. PMID- 29238307 TI - In Vivo Evaluation of Biocompatibility and Chondrogenic Potential of a Cell-Free Collagen-Based Scaffold. AB - Injured articular cartilage has a limited innate regenerative capacity, due to the avascular nature and low cellularity of the tissue itself. Although several approaches have been proposed to repair the joint cartilage, none of them has proven to be effective. The absence of suitable therapeutic options has encouraged tissue-engineering approaches combining specific cell types and biomaterials. In the present work, we have evaluated the potential of a cell-free Collagen I-based scaffold to promote the augmentation of cartilage-like phenotype after subcutaneous implantation in the mouse. Forty female mice were grafted subcutaneously with scaffolds, while four additional mice without scaffold were used as negative controls. The effects of scaffold were evaluated at 1, 2, 4, 8, or 16 weeks after implantation. Immunohistochemical analysis shows the expression of typical cartilage markers, including type-II Collagen, Aggrecan, Matrilin-1 and Sox 9. These data are also confirmed by qRT-PCR that further show that both COL2A1 and COL1A1 increase over time, but the first one increases more rapidly, thus suggesting a typical cartilage-like address. Histological analysis shows the presence of some pericellular lacunae, after 8 and 16 weeks. Results suggest that this scaffold (i) is biocompatible in vivo, (ii) is able to recruit host cells (iii) induce chondrogenic differentiation of host cells. Such evidences suggest that this cell-free scaffold is promising and represents a potential approach for cartilage regeneration. PMID- 29238308 TI - Duration of Absence from Work Is Related to Psychopathology, Personality, and Sociodemographic Variables in a Longitudinal Cohort. AB - Objective: To examine, in a non-clinical sample, the association of psychopathology, personality, sociodemographic information, and psychosocial indicators of non-occupational functioning with the duration of absence from work in the past 12 months. Method: A longitudinal community cohort of 591 adults from Switzerland was analyzed using multilevel ordered logistic regression, with several alternative models as robustness checks. Psychopathology was assessed using the total score (Global Severity Index) of the Symptom Check List-90 Revised. Results: The highest psychopathology levels were associated with absences of 3 or more week duration, largely independently of age. Extraversion and being divorced, widowed or separated also corresponded with longer absences from work in some analyses. No effect of sex was found. Most effects tested were not statistically significant and estimates showed large uncertainty. Conclusion: Although tentative, our results suggest a possible influence of psychopathology on work participation. It may thus be desirable in insurance-medical appraisals of work ability to include instruments for measuring psychopathology. PMID- 29238309 TI - Who Seeks Treatment When Medicine Opens the Door to Pathological Gambling Patients-Psychiatric Comorbidity and Heavy Predominance of Online Gambling. AB - Background: Few studies have assessed treatment-seeking behavior and patient characteristics in pathological gambling focusing on psychiatric comorbidity, particularly in a setting of heavy exposure to online gambling. This study aimed to address patient characteristics in a novel health care-based treatment modality for pathological gambling, including potential associations between gambling types, psychiatric comorbidity, and gender. Methods: All patients undergoing structured assessment between January 2016 and April 2017 were included (N = 106), and patient records were reviewed for cooccurring psychiatric disorders and types of problem games. Results: Eighty percent were men, and 58% received a psychiatric disorder apart from pathological gambling. Problematic gambling on online casino and online sports betting represented 84% of patients. Non-substance-related psychiatric comorbidity was significantly associated with female gender. Conclusion: Online gambling is more clearly predominating in this setting than in studies from other countries. High rates of comorbidity call for structured psychiatric assessment in problem gambling, with a particular focus on female patients with pathological gambling. PMID- 29238311 TI - Assessing Risk of Bias in Randomized Controlled Trials for Autism Spectrum Disorder. AB - Aim: To determine construct validity and reliability indicators of the Cochrane risk of bias (RoB) tool in the context of randomized clinical trials (RCTs) for autism spectrum disorder (ASD). Methods: Confirmatory factor analysis was used to evaluate a unidimensional model consisting of 9 RoB categorical indicators evaluated across 94 RCTs addressing interventions for ASD. Results: Only five of the nine original RoB items returned good fit indices and so were retained in the analysis. Only one of this five had very high factor loadings. The remaining four indicators had more measurement error than common variance with the RoB latent factor. Together, the five indicators showed poor reliability (omega = 0.687; 95% CI: 0.613-0.761). Conclusion: Although the Cochrane model of RoB for ASD exhibited good fit indices, the majorities of the items have more residual variance than common variance and, therefore, did not adequately capture the RoB in ASD intervention trials. PMID- 29238310 TI - Parameter-Based Evaluation of Attentional Impairments in Schizophrenia and Their Modulation by Prefrontal Transcranial Direct Current Stimulation. AB - Background: Attentional dysfunctions constitute core cognitive symptoms in schizophrenia, but the precise underlying neurocognitive mechanisms remain to be elucidated. Methods: In this randomized, double-blind, sham-controlled study, we applied, for the first time, a theoretically grounded modeling approach based on Bundesen's Theory of Visual Attention (TVA) to (i) identify specific visual attentional parameters affected in schizophrenia and (ii) assess, as a proof of concept, the potential of single-dose anodal transcranial direct current stimulation (tDCS; 20 min, 2 mA) to the left dorsolateral prefrontal cortex to modulate these attentional parameters. To that end, attentional parameters were measured before (baseline), immediately after, and 24 h after the tDCS intervention in 20 schizophrenia patients and 20 healthy controls. Results: At baseline, analyses revealed significantly reduced visual processing speed and visual short-term memory storage capacity in schizophrenia. A significant stimulation condition * time point interaction in the schizophrenia patient group indicated improved processing speed at the follow-up session only in the sham condition (a practice effect), whereas performance remained stable across the three time points in patients receiving verum stimulation. In healthy controls, anodal tDCS did not result in a significant change in attentional performance. Conclusion: With regard to question (i) above, these findings are indicative of a processing speed and short-term memory deficit as primary sources of attentional deficits in schizophrenia. With regard to question (ii), the efficacy of single dose anodal tDCS for improving (speed aspects of visual) cognition, it appears that prefrontal tDCS (at the settings used in the present study), rather than ameliorating the processing speed deficit in schizophrenia, actually may interfere with practice-dependent improvements in the rate of visual information uptake. Such potentially unexpected effects of tDCS ought to be taken into consideration when discussing its applicability in psychiatric populations. The study was registered at http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00011665. PMID- 29238312 TI - Impact of Relationship Status and Quality (Family Type) on the Mental Health of Mothers and Their Children: A 10-Year Longitudinal Study. AB - Mothers and children of single or unstable relationships have higher rates of mental health problems than those in stable two-parent families. Despite results that mothers and children of conflictual two-parent families also show impairments, most studies do not consider relationship quality. Therefore, the present study combines relationship status and relationship quality to a "family type." The present study compares German mothers and children of two-parent families with high relationship quality to those from two-parent families with a low quality, single mothers, and unstable families. Data of n = 249 families from a 10-year follow-up longitudinal study show that mothers with a high relationship quality show the highest levels of mental health whereas all other groups show at least a 3.2 times higher probability of mental health symptoms. Children of mothers in unstable relationships show a 8.2 times higher probability to emotional or behavioral problems than children of mothers with high relationship quality. Therefore, not only relationship status but also relationship quality should be combined and this "family type" should be considered in future research. PMID- 29238313 TI - Differential Neural Processing of Social Exclusion and Inclusion in Adolescents with Non-Suicidal Self-Injury and Young Adults with Borderline Personality Disorder. AB - Introduction: Non-suicidal self-injury (NSSI) is a symptom of borderline personality disorder (BPD). However, NSSI often occurs independently of BPD. Altered neural processing of social exclusion has been shown in adolescents with NSSI and adults with BPD with additional alterations during social inclusion in BPD patients. Aims of this study were to investigate differences in neural processing of social inclusion and exclusion situations between adolescents with NSSI and young adults with BPD and NSSI. Methods: Using fMRI, neural processing of positive and negative social situations (paradigm: "Cyberball") was explored. Participants were 14 adolescents with NSSI, but without BPD (Mage = 15.4; SD = 1.9), 15 adults with BPD and NSSI (Mage = 23.3; SD = 4.1), as well as 15 healthy adolescents (Mage = 14.5; SD = 1.7), and 16 healthy adults (Mage = 23.2; SD = 4.4). Results: Behavioral results showed enhanced feelings of social exclusion in both patient groups as compared to healthy controls but only the NSSI group showed enhanced activation during social exclusion versus inclusion compared to the other groups. While both NSSI and BPD groups showed enhanced activation in the ventral anterior cingulate cortex during social exclusion as compared to their age-matched controls, enhanced activation during social inclusion as compared to a passive watching condition was mainly observed in the BPD group in the dorsolateral and dorsomedial prefrontal cortex, and the anterior insula. Discussion: While neural processing of social exclusion was pronounced in adolescents with NSSI, BPD patients also showed increased activity in a per se positive social situation. These results might point toward a higher responsiveness to social exclusion in adolescents with NSSI, which might then develop into a generalized increased sensitivity to all kinds of social situations in adults with BPD. PMID- 29238314 TI - Computational Psychometrics for the Measurement of Collaborative Problem Solving Skills. AB - This paper describes a psychometrically-based approach to the measurement of collaborative problem solving skills, by mining and classifying behavioral data both in real-time and in post-game analyses. The data were collected from a sample of middle school children who interacted with a game-like, online simulation of collaborative problem solving tasks. In this simulation, a user is required to collaborate with a virtual agent to solve a series of tasks within a first-person maze environment. The tasks were developed following the psychometric principles of Evidence Centered Design (ECD) and are aligned with the Holistic Framework developed by ACT. The analyses presented in this paper are an application of an emerging discipline called computational psychometrics which is growing out of traditional psychometrics and incorporates techniques from educational data mining, machine learning and other computer/cognitive science fields. In the real-time analysis, our aim was to start with limited knowledge of skill mastery, and then demonstrate a form of continuous Bayesian evidence tracing that updates sub-skill level probabilities as new conversation flow event evidence is presented. This is performed using Bayes' rule and conversation item conditional probability tables. The items are polytomous and each response option has been tagged with a skill at a performance level. In our post-game analysis, our goal was to discover unique gameplay profiles by performing a cluster analysis of user's sub-skill performance scores based on their patterns of selected dialog responses. PMID- 29238315 TI - Approaches to Cognitive Modeling in Dynamic Systems Control. AB - Much of human decision making occurs in dynamic situations where decision makers have to control a number of interrelated elements (dynamic systems control). Although in recent years progress has been made toward assessing individual differences in control performance, the cognitive processes underlying exploration and control of dynamic systems are not yet well understood. In this perspectives article we examine the contribution of different approaches to modeling cognition in dynamic systems control, including instance-based learning, heuristic models, complex knowledge-based models and models of causal learning. We conclude that each approach has particular strengths in modeling certain aspects of cognition in dynamic systems control. In particular, Bayesian models of causal learning and hybrid models combining heuristic strategies with reinforcement learning appear to be promising avenues for further work in this field. PMID- 29238316 TI - Spelling and Meaning of Compounds in the Early School Years through Classroom Games: An Intervention Study. AB - The study aimed to evaluate the intervention effects on spelling and meaning of compounds by Greek students via group board games in classroom settings. The sample consisted of 60 pupils, who were attending the first and second grade of two primary schools in Greece. Each grade-class was divided into an intervention (N = 29 children) and a control group (N = 31 children). Before intervention, groups were evaluated by standardized tests of reading words/pseudowords, spelling words, and vocabulary. Students were also assessed on compound knowledge by a word analogy task, a meaning task and a spelling task. The experimental design of the intervention included a pre-test, a training program, and a post test. The pre- and post-assessments consisted of the spelling and the meaning tasks entailing equally morphologically transparent and opaque compounds. The training program was based on word families (N = 10 word families, 56 trained items, 5 sessions) and aimed to offer instruction of morphological decomposition and meaning of words. The findings showed that training was effective in enhancing the spelling and most notably the meaning of compounds. A closer inspection of intervention data in terms of morphological transparency, revealed that training group of first graders improved significantly both on transparent and opaque compounds, while the degree of gains was larger on opaque items for the second graders. These findings are consistent with the experimental literature and particularly optimistic for the literacy enhancement of typically developing children in regular classrooms. PMID- 29238317 TI - Therapeutic Self-Disclosure within DBT, Schema Therapy, and CBASP: Opportunities and Challenges. AB - In recent years, various therapeutic interventions have been established that extended behavior and cognitive behavior therapy (CBT) by so-called "third-wave" strategies. In order to address specific therapeutic challenges in certain subgroups of patients who do not sufficiently respond to "classical CBT," some of these third-wave strategies put particular emphasis on therapist self-disclosure. This article highlights therapeutic self-disclosure as a means to address interpersonal problems by comparing three third-wave strategies: (a) acceptance and change strategies as used in Dialectical Behavioral Therapy (DBT), (b) the concept of "limited reparenting" as used in Schema Therapy (ST), and (c) disciplined personal involvement as used in the Cognitive Behavioral Analysis System of Psychotherapy (CBASP). On the basis of a critical discussion on opportunities and challenges within these three concepts, self-disclosure is proposed to be a promising therapeutic tool that is worth to be investigated in more depth in future studies. PMID- 29238318 TI - Auditory Perceptual Abilities Are Associated with Specific Auditory Experience. AB - The extent to which auditory experience can shape general auditory perceptual abilities is still under constant debate. Some studies show that specific auditory expertise may have a general effect on auditory perceptual abilities, while others show a more limited influence, exhibited only in a relatively narrow range associated with the area of expertise. The current study addresses this issue by examining experience-dependent enhancement in perceptual abilities in the auditory domain. Three experiments were performed. In the first experiment, 12 pop and rock musicians and 15 non-musicians were tested in frequency discrimination (DLF), intensity discrimination, spectrum discrimination (DLS), and time discrimination (DLT). Results showed significant superiority of the musician group only for the DLF and DLT tasks, illuminating enhanced perceptual skills in the key features of pop music, in which miniscule changes in amplitude and spectrum are not critical to performance. The next two experiments attempted to differentiate between generalization and specificity in the influence of auditory experience, by comparing subgroups of specialists. First, seven guitar players and eight percussionists were tested in the DLF and DLT tasks that were found superior for musicians. Results showed superior abilities on the DLF task for guitar players, though no difference between the groups in DLT, demonstrating some dependency of auditory learning on the specific area of expertise. Subsequently, a third experiment was conducted, testing a possible influence of vowel density in native language on auditory perceptual abilities. Ten native speakers of German (a language characterized by a dense vowel system of 14 vowels), and 10 native speakers of Hebrew (characterized by a sparse vowel system of five vowels), were tested in a formant discrimination task. This is the linguistic equivalent of a DLS task. Results showed that German speakers had superior formant discrimination, demonstrating highly specific effects for auditory linguistic experience as well. Overall, results suggest that auditory superiority is associated with the specific auditory exposure. PMID- 29238319 TI - Evaluating Distal and Proximal Explanations for Withdrawal: A Rejoinder to Varnum and Kwon's "The Ecology of Withdrawal". AB - In their 2016 commentary on our theorizing about how youth withdrawal from economic and social participation in Japanese society (i.e., NEET and Hikikomori phenomena) stems from generational inequality of economic opportunities, Varnum and Kwon correctly point out that our explanation for withdrawal is yet untested. They then offered an alternative, evolutionary psychological explanation for withdrawal in which they claim that in resource-rich ecologies like Japan, the option to withdraw from participating in society is a possible life strategy, a strategy that would be much more costly in resource-poor ecologies. While we agree with this premise, we argue that this distal explanatory framework, at least in its current form, has limits in reconciling some of the more recent cross-cultural observations, as well as well-established sociological claims about the causes of withdrawal. Thus we argue that much work remains in refining and expanding the explanatory power of more distal explanations on the issue of withdrawal. Until then, the more proximal and culture-specific explanations are probably the useful and meaningful explanations for the withdrawal phenomenon. PMID- 29238320 TI - Understanding Appearance-Enhancing Drug Use in Sport Using an Enactive Approach to Body Image. AB - From an enactive approach to human activity, we suggest that the use of appearance-enhancing drugs is better explained by the sense-making related to body image rather than the cognitive evaluation of social norms about appearance and consequent psychopathology-oriented approach. After reviewing the main psychological disorders thought to link body image issues to the use of appearance-enhancing substances, we sketch a flexible, dynamic and embedded account of body image defined as the individual's propensity to act and experience in specific situations. We show how this enacted body image is a complex process of sense-making that people engage in when they are trying to adapt to specific situations. These adaptations of the enacted body image require effort, perseverance and time, and therefore any substance that accelerates this process appears to be an easy and attractive solution. In this enactive account of body image, we underline that the link between the enacted body image and substance use is also anchored in the history of the body's previous interactions with the world. This emerges during periods of upheaval and hardship, especially in a context where athletes experience weak participatory sense-making in a sport community. We conclude by suggesting prevention and intervention designs that would promote a safe instrumental use of the body in sports and psychological helping procedures for athletes experiencing difficulties with substances use and body image. PMID- 29238321 TI - The Development of Motor Self-Regulation in Ravens. AB - Inhibitory control refers to the ability to stop impulses in favor of more appropriate behavior, and it constitutes one of the underlying cognitive functions associated with cognitive flexibility. Much attention has been given to cross-species comparisons of inhibitory control; however, less is known about how and when these abilities develop. Mapping the ontogeny of inhibitory control in different species may therefore reveal foundational elements behind cognitive processes and their evolution. In this study, we tested the development of motor self-regulation in raven chicks (Corvus corax), using two detour tasks that required inhibition of motor impulses to directly reach for a visible reward behind a barrier. One task included a mesh barrier, which partly occluded the reward, and the other task used a completely transparent barrier, the cylinder task. The results suggest that the more visible a reward is, the more difficult it is to inhibit motor impulses toward it, and further, that this inhibitory challenge gradually decreases during development. The mesh barrier is reliably detoured before the animals pass the task with the wholly transparent cylinder. As the majority of the birds begun testing as nestlings, and as we provided them with experiences they normally would not receive in a nest, it is likely that they showed the earliest possible onset of these skills. A control subject, tested at a later age, showed that the mesh detours required no particular training, but that tasks including complete transparency likely require more specific experiences. Adult ravens without explicit training are highly proficient in inhibitory detour tasks, and, together with chimpanzees, they are the best performers of all tested species in the cylinder task. Our results suggest that their skills develop early in life, around their third month. Their developmental pattern of inhibitory skills for detours resembles that of children and rhesus macaques, albeit the pace of development is markedly faster in ravens. Investigating the development of cognition is crucial to understanding its foundations within and across species. PMID- 29238322 TI - Acute Ischemic Pediatric Stroke Management: An Extended Window for Mechanical Thrombectomy? AB - Ischemic stroke is a rare condition to afflict the pediatric population. Congenital cardiomyopathy represents one of several possible etiologies in children. We report a 9-year-old boy who developed right middle cerebral artery stroke secondary to primary restrictive cardiomyopathy. In the absence of pediatric guidelines, the child met adult criteria for mechanical thrombectomy given the small core infarct and large penumbra. The literature suggests children may benefit from mechanical thrombectomy in carefully selected cases. Our patient exemplifies specific circumstances in which acute stroke therapy with thrombolysis and thrombectomy may be safe. PMID- 29238323 TI - Relationship between Hypothyroidism and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. AB - Background: Previous studies propose that hypothyroidism might play a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), but findings from published studies on the relationship between hypothyroidism and NAFLD are still controversial. Our study aimed to make a comprehensive evaluation of the relationship between hypothyroidism and NAFLD through a meta-analysis. Methods: PubMed, China Dissertation Database, and EMBASE databases were searched to find observational studies assessing the relationship between hypothyroidism and NAFLD. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to evaluate the strength of the relationship between hypothyroidism and NAFLD through meta-analysis. Results: Thirteen articles were ultimately included in our meta-analysis. Meta-analysis of the 13 studies found a high correlation between hypothyroidism and NAFLD (OR = 1.52, 95% CI 1.24-1.87, P < 0.001). Meta-analysis of 9 studies providing adjusted ORs found that hypothyroidism was independently correlated with NAFLD (OR = 1.72, 95% CI 1.32 2.23, P < 0.001). Subgroup analysis found that both overt hypothyroidism and subclinical hypothyroidism were significantly correlated with NAFLD, and the pooled ORs were 1.70 (95% CI 1.23-2.36, P = 0.002) and 1.40 (95% CI 1.10-1.77, P = 0.006), respectively. Besides, meta-analysis of studies providing adjusted ORs also found that both overt hypothyroidism and subclinical hypothyroidism were independently correlated with NAFLD, and the pooled ORs were 1.81 (95% CI 1.30 2.52, P < 0.001) and 1.63 (95% CI 1.19-2.24, P = 0.002), respectively. Conclusion: The meta-analysis provides strong epidemiological evidence for the relationship between hypothyroidism and NAFLD. Both individuals with subclinical and overt hypothyroidism are at higher risk for NAFLD than euthyroid subjects. PMID- 29238325 TI - Probiotic Bacteria Alter Pattern-Recognition Receptor Expression and Cytokine Profile in a Human Macrophage Model Challenged with Candida albicans and Lipopolysaccharide. AB - Probiotics are live microorganisms that confer benefits to the host health. The infection rate of potentially pathogenic organisms such as Candida albicans, the most common agent associated with mucosal candidiasis, can be reduced by probiotics. However, the mechanisms by which the probiotics interfere with the immune system are largely unknown. We evaluated the effect of probiotic bacteria on C. albicans challenged human macrophages. Macrophages were pretreated with lactobacilli alone (Lactobacillus rhamnosus LR32, Lactobacillus casei L324m, or Lactobacillus acidophilus NCFM) or associated with Escherichia coli lipopolysaccharide (LPS), followed by the challenge with C. albicans or LPS in a co-culture assay. The expression of pattern-recognition receptors genes (CLE7A, TLR2, and TLR4) was determined by RT-qPCR, and dectin-1 reduced levels were confirmed by flow cytometry. The cytokine profile was determined by ELISA using the macrophage cell supernatant. Overall probiotic lactobacilli down-regulated the transcription of CLEC7A (p < 0.05), resulting in the decreased expression of dectin-1 on probiotic pretreated macrophages. The tested Lactobacillus species down-regulated TLR4, and increased TLR2 mRNA levels in macrophages challenged with C. albicans. The cytokines profile of macrophages challenged with C. albicans or LPS were altered by the probiotics, which generally led to increased levels of IL-10 and IL-1beta, and reduction of IL-12 production by macrophages (p < 0.05). Our data suggest that probiotic lactobacilli impair the recognition of PAMPs by macrophages, and alter the production of pro/anti-inflammatory cytokines, thus modulating inflammation. PMID- 29238326 TI - A Probabilistic Decision-Making Scoring System for Quality and Safety Management in Alorena de Malaga Table Olive Processing. AB - Table olives are one of the most representatives and consumed fermented vegetables in Mediterranean countries. However, there is an evident lack of standardization of production processes and HACCP systems thus implying the need of establishing decision-making tools allowing their commercialization and shelf life extension. The present work aims at developing a decision-making scoring system by means of a probabilistic assessment to standardize production process of Alorena de Malaga table olives based on the identification of potential hazards or deficiencies in hygienic processes for the subsequent implementation of corrective measures. A total of 658 microbiological and physico-chemical data were collected over three consecutive olive campaigns (2014-2016) to measure the variability and relative importance of each elaboration step on total hygienic quality and product safety. Three representative companies were visited to collect samples from food-contact surfaces, olive fruits, brines, air environment, olive dressings, water tanks, and finished/packaged products. A probabilistic assessment was done based on the establishment of Performance Hygiene and Safety Scores (PHSS 0-100%) through a standardized system for evaluating product acceptability. The mean value of the global PHSS for the Alorena de Malaga table olives processing (PHHSFTOT) was 64.82% (90th CI: 52.78 76.39%) indicating the high variability among facilities in the evaluated processing steps on final product quality and safety. Washing and cracking, and selection and addition of olive dressings were detected as the most deficient ones in relation to PHSSFi values (p < 0.05) (mean = 53.02 and 56.62%, respectively). The relative contribution of each processing step was quantified by different experts (n = 25) from the Alorena de Malaga table olive sector through a weighted PHSS (PHSSw). The mean value of PHSSw was 65.53% (90th CI: 53.12-77.52%). The final processing steps obtained higher values for PHSSw being the finished product the most relevant one (mean = 18.44%; 90% CI: 10.34-25.33%). Sensitivity analysis concluded that intervention measures focused on reducing the contamination of washing brines could lead to an improvement of PHSSFTOT value to 67.03%. The present work can be potentially applied in the Alorena de Malaga table olive food sector for improving food quality and safety assurance. PMID- 29238324 TI - Immunopathogenesis and Virus-Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease. AB - Enterovirus 71 (EV71) is a global infectious disease that affects millions of people. The virus is the main etiological agent for hand, foot, and mouth disease with outbreaks and epidemics being reported globally. Infection can cause severe neurological, cardiac, and respiratory problems in children under the age of 5. Despite on-going efforts, little is known about the pathogenesis of EV71, how the host immune system responds to the virus and the molecular mechanisms behind these responses. Moreover, current animal models remain limited, because they do not recapitulate similar disease patterns and symptoms observed in humans. In this review the role of the host-viral interactions of EV71 are discussed together with the various models available to examine: how EV71 utilizes its proteins to cleave host factors and proteins, aiding virus replication; how EV71 uses its own viral proteins to disrupt host immune responses and aid in its immune evasion. These discoveries along with others, such as the EV71 crystal structure, have provided possible targets for treatment and drug interventions. PMID- 29238328 TI - Impact of Aerosol Dust on xMAP Multiplex Detection of Different Class Pathogens. AB - Environmental or city-scale bioaerosol surveillance can provide additional value for biodefense and public health. Efficient bioaerosol monitoring should rely on multiplex systems capable of detecting a wide range of biologically hazardous components potentially present in air (bacteria, viruses, toxins and allergens). xMAP technology from LuminexTM allows multiplex bead-based detection of antigens or nucleic acids, but its use for simultaneous detection of different classes of pathogens (bacteria, virus, toxin) is questionable. Another problem is the detection of pathogens in complex matrices, e.g., in the presence of dust. In the this research, we developed the model xMAP multiplex test-system aiRDeTeX 1.0, which enables detection of influenza A virus, Adenovirus type 6 Salmonella typhimurium, and cholera toxin B subunit representing RNA virus, DNA virus, gram negative bacteria and toxin respectively as model organisms of biologically hazardous components potentially present in or spreadable through the air. We have extensively studied the effect of matrix solution (PBS, distilled water), environmental dust and ultrasound treatment for monoplex and multiplex detection efficiency of individual targets. All targets were efficiently detectable in PBS and in the presence of dust. Ultrasound does not improve the detection except for bacterial LPS. PMID- 29238327 TI - Transmission of Airborne Bacteria across Built Environments and Its Measurement Standards: A Review. AB - Human health is influenced by various factors including microorganisms present in built environments where people spend most of their lives (approximately 90%). It is therefore necessary to monitor and control indoor airborne microbes for occupational safety and public health. Most studies concerning airborne microorganisms have focused on fungi, with scant data available concerning bacteria. The present review considers papers published from 2010 to 2017 approximately and factors affecting properties of indoor airborne bacteria (communities and concentration) with respect to temporal perspective and to multiscale interaction viewpoint. From a temporal perspective, bacterial concentrations in built environments change depending on numbers of human occupancy, while properties of bacterial communities tend to remain stable. Similarly, the bacteria found in social and community spaces such as offices, classrooms and hospitals are mainly associated with human occupancy. Other major sources of indoor airborne bacteria are (i) outdoor environments, and (ii) the building materials themselves. Indoor bacterial communities and concentrations are varied with varying interferences by outdoor environment. Airborne bacteria from the outdoor environment enter an indoor space through open doors and windows, while indoor bacteria are simultaneously released to the outer environment. Outdoor bacterial communities and their concentrations are also affected by geographical factors such as types of land use and their spatial distribution. The bacteria found in built environments therefore originate from any of the natural and man-made surroundings around humans. Therefore, to better understand the factors influencing bacterial concentrations and communities in built environments, we should study all the environments that humans contact as a single ecosystem. In this review, we propose the establishment of a standard procedure for assessing properties of indoor airborne bacteria using four factors: temperature, relative humidity (RH), air exchange rate, and occupant density, as a minimum requirement. We also summarize the relevant legislation by country. Choice of factors to measure remain controversial are discussed. PMID- 29238329 TI - Relative Quantitative Proteomic Analysis of Brucella abortus Reveals Metabolic Adaptation to Multiple Environmental Stresses. AB - Brucella spp. are facultative intracellular pathogens that cause chronic brucellosis in humans and animals. The virulence of Brucella primarily depends on its successful survival and replication in host cells. During invasion of the host tissue, Brucella is simultaneously subjected to a variety of harsh conditions, including nutrient limitation, low pH, antimicrobial defenses, and extreme levels of reactive oxygen species (ROS) via the host immune response. This suggests that Brucella may be able to regulate its metabolic adaptation in response to the distinct stresses encountered during its intracellular infection of the host. An investigation into the differential proteome expression patterns of Brucella grown under the relevant stress conditions may contribute toward a better understanding of its pathogenesis and adaptive response. Here, we utilized a mass spectrometry-based label-free relative quantitative proteomics approach to investigate and compare global proteomic changes in B. abortus in response to eight different stress treatments. The 3 h short-term in vitro single-stress and multi-stress conditions mimicked the in vivo conditions of B. abortus under intracellular infection, with survival rates ranging from 3.17 to 73.17%. The proteomic analysis identified and quantified a total of 2,272 proteins and 74% of the theoretical proteome, thereby providing wide coverage of the B. abortus proteome. By including eight distinct growth conditions and comparing these with a control condition, we identified a total of 1,221 differentially expressed proteins (DEPs) that were significantly changed under the stress treatments. Pathway analysis revealed that most of the proteins were involved in oxidative phosphorylation, ABC transporters, two-component systems, biosynthesis of secondary metabolites, the citrate cycle, thiamine metabolism, and nitrogen metabolism; constituting major response mechanisms toward the reconstruction of cellular homeostasis and metabolic balance under stress. In conclusion, our results provide a better understanding of the global metabolic adaptations of B. abortus associated with distinct environmental stresses. The identification of proteins necessary for stress resistance is crucial toward elucidating the infectious process in order to control brucellosis, and may facilitate the discovery of novel therapeutic targets and effective vaccines. PMID- 29238330 TI - An Assessment of Different Genomic Approaches for Inferring Phylogeny of Listeria monocytogenes. AB - Background/objectives: Whole genome sequencing (WGS) has proven to be a powerful subtyping tool for foodborne pathogenic bacteria like L. monocytogenes. The interests of genome-scale analysis for national surveillance, outbreak detection or source tracking has been largely documented. The genomic data however can be exploited with many different bioinformatics methods like single nucleotide polymorphism (SNP), core-genome multi locus sequence typing (cgMLST), whole genome multi locus sequence typing (wgMLST) or multi locus predicted protein sequence typing (MLPPST) on either core-genome (cgMLPPST) or pan-genome (wgMLPPST). Currently, there are little comparisons studies of these different analytical approaches. Our objective was to assess and compare different genomic methods that can be implemented in order to cluster isolates of L. monocytogenes. Methods: The clustering methods were evaluated on a collection of 207 L. monocytogenes genomes of food origin representative of the genetic diversity of the Anses collection. The trees were then compared using robust statistical analyses. Results: The backward comparability between conventional typing methods and genomic methods revealed a near-perfect concordance. The importance of selecting a proper reference when calling SNPs was highlighted, although distances between strains remained identical. The analysis also revealed that the topology of the phylogenetic trees between wgMLST and cgMLST were remarkably similar. The comparison between SNP and cgMLST or SNP and wgMLST approaches showed that the topologies of phylogenic trees were statistically similar with an almost equivalent clustering. Conclusion: Our study revealed high concordance between wgMLST, cgMLST, and SNP approaches which are all suitable for typing of L. monocytogenes. The comparable clustering is an important observation considering that the two approaches have been variously implemented among reference laboratories. PMID- 29238331 TI - Sensitive and Rapid Detection of the Plasmid-Encoded Colistin-Resistance Gene mcr 1 in Enterobacteriaceae Isolates by Loop-Mediated Isothermal Amplification. AB - The emergence of the plasmid-encoded colistin-resistance gene mcr-1 in Enterobacteriaceae represents a new threat to the treatment of infection in the clinical setting. A sensitive and rapid molecular method for detection of the mcr 1 gene in clinical isolates is needed to control the spread of this gene. In this study, we established a loop-mediated isothermal amplification (LAMP) assay for rapid detection of the mcr-1 gene. This assay was applied to cultured bacteria and spiked human stools. Real-time monitoring of turbidity and chromogenic visualization were used to assess the reaction results. The specificity and sensitivity of the primers in the LAMP reactions for detection of the mcr-1 gene were determined. All 20 clinically resistant isolates without the mcr-1 gene tested negative, indicating the high specificity of the LAMP primers. The sensitivity of LAMP, with a detection limit of 0.2 pg/MUL DNA, was 10-fold greater than that of polymerase chain reaction (PCR). The assay was also conclusive when applied to human stools spiked with mcr-1-positive Escherichia coli. During clinical screening in a major hospital in Beijing, China, seven isolates were identified as positive from the 556 Enterobacteriaceae isolates. In conclusion, the LAMP assay we developed was useful for detection of the mcr-1 gene in the clinical setting. PMID- 29238332 TI - Application of FLP-FRT System to Construct Unmarked Deletion in Helicobacter pylori and Functional Study of Gene hp0788 in Pathogenesis. AB - Helicobacter pylori is a Gram-negative, microaerophilic bacterium associated with human gastric diseases. Further investigations on virulence genes are still required to clarify the pathogenic mechanism of H. pylori and the heterogeneous problem of infection. In order to develop an efficient and accurate method to study gene functions in H. pylori pathogenesis, an unmarked deletion method for both a single gene and a large fragment was established based on the FLP-FRT recombination system. Using this method, the gene hp0788, encoding an outer membrane protein (HofF), was deleted. Deletion of hp0788 did not affect growth or motility of H. pylori, but reduced the adherence of the bacteria to gastric epithelial cells. The apoptosis of GES-1 cells caused by H. pylori infection was also reduced by the defection of hp0788. These suggest that hp0788 takes part in the bacterium-host interaction and plays an important role in H. pylori infection. Furthermore, a large genomic fragment deletion from hp0541 to hp0547 in cag pathogenicity island was also successfully achieved using FLP-FRT method. The innovative application of the FLP-FRT recombination system in H. pylori to construct unmarked deletion would provide a helpful tool for further function research of putative pathogenic genes and contribute to the understanding of H. pylori pathogenesis. PMID- 29238333 TI - Environmental Factors Shape Water Microbial Community Structure and Function in Shrimp Cultural Enclosure Ecosystems. AB - The effects of environmental factors on water microbial communities have been extensively studied, but little is known about the effects in shrimp cultural enclosure ecosystems. We analyzed 16S rRNA gene amplicons to determine the principal environmental factors that shape the structure and function of microbial communities in shrimp cultural enclosure ecosystems from Guangdong and Hainan provinces, in China. High quality sequences were clustered into operational taxonomic units (OTUs) at the 97% similarity level, generating 659 1,835 OTUs per sample. The 10 most abundant phyla were Proteobacteria, Bacteroidetes, Cyanobacteria, Planctomycetes, Actinobacteria, Verrucomicrobia, Firmicutes, Chlorobi, Chloroflexi, and Chlamydiae. The results of canonical correspondence analyses (CCA) indicated that salinity, total phosphate (TP), total nitrogen (TN), temperature, and pH were the most important factors shaping microbial community structure. Differences in microbial community structure between high and low salinity samples were explained by changes in the relative abundances of some OTUs (e.g., OTU5, OTU19, OTU21, OTU39, and OTU71). Moreover, the contribution of spatial distribution to the microbial community assembly was investigated via aggregated boosted tree (ABT) analyses, and the results indicated spatial isolation was not a major factor affecting the phylogenetic diversity and phylotypes of water microbial communities. Furthermore, we predicted water microbial community functional profiling using the PICRUSt program and principal component analyses (PCA) suggested that salinity was a major contributor to the structure and function of the microbial communities. Collectively, these results showed that environmental factors influenced the structure and function of water microbial communities, while salinity was the principal environmental factor instead of temperature, TP, TN, and pH in shrimp cultural enclosure ecosystems. PMID- 29238334 TI - Evaluation of Bronchoalveolar Lavage Fluid Cytokines as Biomarkers for Invasive Pulmonary Aspergillosis in At-Risk Patients. AB - Background: Invasive pulmonary aspergillosis (IPA) is an infection that primarily affects immunocompromised hosts, including hematological patients and stem-cell transplant recipients. The diagnosis of IPA remains challenging, making desirable the availability of new specific biomarkers. High-throughput methods now allow us to interrogate the immune system for multiple markers of inflammation with enhanced resolution. Methods: To determine whether a signature of alveolar cytokines could be associated with the development of IPA and used as a diagnostic biomarker, we performed a nested case-control study involving 113 patients at-risk. Results: Among the 32 analytes tested, IL-1beta, IL-6, IL-8, IL 17A, IL-23, and TNFalpha were significantly increased among patients with IPA, defining two clusters able to accurately differentiate cases of infection from controls. Genetic variants previously reported to confer increased risk of IPA compromised the production of specific cytokines and impaired their discriminatory potential toward infection. Collectively, our data indicated that IL-8 was the best performing cytokine, with alveolar levels >=904 pg/mL predicting IPA with elevated sensitivity (90%), specificity (73%), and negative predictive value (88%). Conclusions: These findings highlight the existence of a specific profile of alveolar cytokines, with IL-8 being the dominant discriminator, which might be useful in supporting current diagnostic approaches for IPA. PMID- 29238335 TI - Treatment with Cefotaxime Affects Expression of Conjugation Associated Proteins and Conjugation Transfer Frequency of an IncI1 Plasmid in Escherichia coli. AB - Horizontal gene transfer (HGT) is the major mechanism responsible for spread of antibiotic resistance. Antibiotic treatment has been suggested to promote HGT, either by directly affecting the conjugation process itself or by selecting for conjugations subsequent to DNA transfer. However, recent research suggests that the effect of antibiotic treatment on plasmid conjugation frequencies, and hence the spread of resistance plasmids, may have been overestimated. We addressed the question by quantifying transfer proteins and conjugation frequencies of a blaCTX M-1 encoding IncI1 resistance plasmid in Escherichia coli MG1655 in the presence and absence of therapeutically relevant concentrations of cefotaxime (CTX). Analysis of the proteome by iTRAQ labeling and liquid chromatography tandem mass spectrometry revealed that Tra proteins were significantly up-regulated in the presence of CTX. The up-regulation of the transfer machinery was confirmed at the transcriptional level for five selected genes. The CTX treatment did not cause induction of the SOS-response as revealed by absence of significantly regulated SOS associated proteins in the proteome and no significant up-regulation of recA and sfiA genes. The frequency of plasmid conjugation, measured in an antibiotic free environment, increased significantly when the donor was pre-grown in broth containing CTX compared to growth without this drug, regardless of whether blaCTX M-1 was located on the plasmid or in trans on the chromosome. The results shows that antibiotic treatment can affect expression of a plasmid conjugation machinery and subsequent DNA transfer. PMID- 29238336 TI - Combination of Classifiers Identifies Fungal-Specific Activation of Lysosome Genes in Human Monocytes. AB - Blood stream infections can be caused by several pathogens such as viruses, fungi and bacteria and can cause severe clinical complications including sepsis. Delivery of appropriate and quick treatment is mandatory. However, it requires a rapid identification of the invading pathogen. The current gold standard for pathogen identification relies on blood cultures and these methods require a long time to gain the needed diagnosis. The use of in situ experiments attempts to identify pathogen specific immune responses but these often lead to heterogeneous biomarkers due to the high variability in methods and materials used. Using gene expression profiles for machine learning is a developing approach to discriminate between types of infection, but also shows a high degree of inconsistency. To produce consistent gene signatures, capable of discriminating fungal from bacterial infection, we have employed Support Vector Machines (SVMs) based on Mixed Integer Linear Programming (MILP). Combining classifiers by joint optimization constraining them to the same set of discriminating features increased the consistency of our biomarker list independently of leukocyte-type or experimental setup. Our gene signature showed an enrichment of genes of the lysosome pathway which was not uncovered by the use of independent classifiers. Moreover, our results suggest that the lysosome genes are specifically induced in monocytes. Real time qPCR of the identified lysosome-related genes confirmed the distinct gene expression increase in monocytes during fungal infections. Concluding, our combined classifier approach presented increased consistency and was able to "unmask" signaling pathways of less-present immune cells in the used datasets. PMID- 29238338 TI - A Novel TetR Family Transcriptional Regulator, CalR3, Negatively Controls Calcimycin Biosynthesis in Streptomyces chartreusis NRRL 3882. AB - Calcimycin is a unique ionophoric antibiotic that is widely used in biochemical and pharmaceutical applications, but the genetic basis underlying the regulatory mechanisms of calcimycin biosynthesis are unclear. Here, we identified the calR3 gene, which encodes a novel TetR family transcriptional regulator and exerts a negative effect on calcimycin biosynthesis. Disruption of calR3 in Streptomyces chartreusis NRRL 3882 led to significantly increased calcimycin and its intermediate cezomycin. Gene expression analysis showed that the transcription of calR3 and its adjacent calT gene were dramatically enhanced (30- and 171-fold, respectively) in GLX26 (DeltacalR3) mutants compared with the wild-type strains. Two CalR3-binding sites within the bidirectional calR3-calT promoter region were identified using a DNase I footprinting assay, indicating that CalR3 directly repressed the transcription of its own gene and the calT gene. In vitro electrophoretic mobility shift assays suggested that both calcimycin and cezomycin can act as CalR3 ligands to induce CalR3 to dissociate from its binding sites. These findings indicate negative feedback for the regulation of CalR3 in calcimycin biosynthesis and suggest that calcimycin production can be improved by manipulating its biosynthetic machinery. PMID- 29238337 TI - The Role of Type 2 Diabetes for the Development of Pathogen-Associated Cancers in the Face of the HIV/AIDS Epidemic. AB - The contribution of HIV to the development of pathogen-associated cancers has long been recognized, as has the contribution of type 2 diabetes for the development of several types of cancer. While HIV/AIDS-associated immunosuppression reduces immunosurveillance and indirectly contributes favorably to cancerogenesis, diabetes directly increases cancer development due to chronic low-grade inflammation, dysregulated glucose metabolism, hyperactivation of insulin-responsive pathways, and anti-apoptotic signaling. Pathogen-associated cancers contribute significantly to the cancer burden particularly in low- and middle-income countries. In those countries, the incidence of type 2 diabetes has increased alarmingly over the last decades, in part due to rapid changes in diet, lifestyle, and urbanization. It is likely that the HIV/AIDS epidemic and the steadily increasing rate of type 2 diabetes display synergistic effects on oncogenesis. Although this possible link has not been extensively investigated, it might become more important in the years to come not least due to the stimulating effects of antiretroviral therapy on the development of type 2 diabetes. This review provides an overview of the current understanding of pathogen- and diabetes- associated cancers with focus on geographical regions additionally burdened by the HIV/AIDS epidemic. As both HIV and carcinogenic infections as well as the onset of type 2 diabetes involve environmental factors that can be avoided to a certain extent, this review will support the hypothesis that certain malignancies are potentially preventable. Deploying effective infection control strategies together with educational policies on diet and lifestyle may in the long term reduce the burden of preventable cancers which is of particular relevance in low-resource settings. PMID- 29238339 TI - Comparing the Healthy Nose and Nasopharynx Microbiota Reveals Continuity As Well As Niche-Specificity. AB - To improve our understanding of upper respiratory tract (URT) diseases and the underlying microbial pathogenesis, a better characterization of the healthy URT microbiome is crucial. In this first large-scale study, we obtained more insight in the URT microbiome of healthy adults. Hereto, we collected paired nasal and nasopharyngeal swabs from 100 healthy participants in a citizen-science project. High-throughput 16S rRNA gene V4 amplicon sequencing was performed and samples were processed using the Divisive Amplicon Denoising Algorithm 2 (DADA2) algorithm. This allowed us to identify the bacterial richness and diversity of the samples in terms of amplicon sequence variants (ASVs), with special attention to intragenus variation. We found both niches to have a low overall species richness and uneven distribution. Moreover, based on hierarchical clustering, nasopharyngeal samples could be grouped into some bacterial community types at genus level, of which four were supported to some extent by prediction strength evaluation: one intermixed type with a higher bacterial diversity where Staphylococcus, Corynebacterium, and Dolosigranulum appeared main bacterial members in different relative abundances, and three types dominated by either Moraxella, Streptococcus, or Fusobacterium. Some of these bacterial community types such as Streptococcus and Fusobacterium were nasopharynx-specific and never occurred in the nose. No clear association between the nasopharyngeal bacterial profiles at genus level and the variables age, gender, blood type, season of sampling, or common respiratory allergies was found in this study population, except for smoking showing a positive association with Corynebacterium and Staphylococcus. Based on the fine-scale resolution of the ASVs, both known commensal and potential pathogenic bacteria were found within several genera - particularly in Streptococcus and Moraxella - in our healthy study population. Of interest, the nasopharynx hosted more potential pathogenic species than the nose. To our knowledge, this is the first large-scale study using the DADA2 algorithm to investigate the microbiota in the "healthy" adult nose and nasopharynx. These results contribute to a better understanding of the composition and diversity of the healthy microbiome in the URT and the differences between these important URT niches. Trial Registration: Ethical Committee of Antwerp University Hospital, B300201524257, registered 23 March 2015, ClinicalTrials.gov Identifier: NCT02 933983. PMID- 29238340 TI - Commentary: Proteomics Analysis Revealed that Crosstalk between Helicobacter pylori and Streptococcus mitis May Enhance Bacterial Survival and Reduces Carcinogenesis. PMID- 29238341 TI - DM9 Domain Containing Protein Functions As a Pattern Recognition Receptor with Broad Microbial Recognition Spectrum. AB - DM9 domain was first identified in Drosophila melanogaster, and it was subsequently found to integrate with or without other protein domains across a wide range of invertebrates and vertebrates. In the present study, a member of DM9 domain containing protein (DM9CP) family from marine invertebrate Crassostrea gigas (designated CgDM9CP-1), which was only composed of two DM9 domains, was taken as a protein model to study the biological functions of DM9 domain and its molecular determinants. CgDM9CP-1 was found to exhibit high binding specificity and avidity toward d-mannose residue. It served as a pattern recognition receptor (PRR) with a broad range of recognition spectrum to various pathogen-associated molecular patterns, including lipopolysaccharide, peptidylglycan, mannan, and beta-1, 3-glucan in a d-mannose-dependent manner, as well as bacteria and fungi. In order to reveal the molecular mechanism underlying its pattern recognition activity, the crystal structures of wild-type and loss-of-function mutants were solved, and Asp22 and Lys43 were found to be the critical residues for ligand recognition. Moreover, CgDM9CP-1 protein was found to mainly distribute on the surface of C. gigas hemocytes, and it could be translocated into cytoplasm and colocalized with the engulfed microbes during hemocyte phagocytosis. The present result clearly indicated that CgDM9CP-1 was a PRR, and it provided an important clue for the better understanding of DM9CP function. PMID- 29238343 TI - Thrombospondin-1 Partly Mediates the Cartilage Protective Effect of Adipose Derived Mesenchymal Stem Cells in Osteoarthritis. AB - Objective: Assuming that mesenchymal stem cells (MSCs) respond to the osteoarthritic joint environment to exert a chondroprotective effect, we aimed at investigating the molecular response setup by MSCs after priming by osteoarthritic chondrocytes in cocultures. Methods: We used primary human osteoarthritic chondrocytes and adipose stem cells (ASCs) in mono- and cocultures and performed a high-throughput secretome analysis. Among secreted proteins differentially induced in cocultures, we identified thrombospondin-1 (THBS1) as a potential candidate that could be involved in the chondroprotective effect of ASCs. Results: Secretome analysis revealed significant induction of THBS1 in ASCs/chondrocytes cocultures at mRNA and protein levels. We showed that THBS1 was upregulated at late stages of MSC differentiation toward chondrocytes and that recombinant THBS1 (rTHBS1) exerted a prochondrogenic effect on MSC indicating a role of THBS1 during chondrogenesis. However, compared to control ASCs, siTHBS1 transfected ASCs did not decrease the expression of hypertrophic and inflammatory markers in osteoarthritic chondrocytes, suggesting that THBS1 was not involved in the reversion of osteoarthritic phenotype. Nevertheless, downregulation of THBS1 in ASCs reduced their immunosuppressive activity, which was consistent with the anti-inflammatory role of rTHBS1 on T lymphocytes. THBS1 function was then evaluated in the collagenase-induced OA model by comparing siTHBS1-transfected and control ASCs. The protective effect of ASCs evaluated by histological and histomorphological analysis of cartilage and bone was not seen with siTHBS1 transfected ASCs. Conclusion: Our data suggest that THBS1 did not exert a direct protective effect on chondrocytes but might reduce inflammation, subsequently explaining the therapeutic effect of ASCs in OA. PMID- 29238342 TI - Breastfeeding Behaviors and the Innate Immune System of Human Milk: Working Together to Protect Infants against Inflammation, HIV-1, and Other Infections. AB - The majority of infants' breastfeeding from their HIV-infected mothers do not acquire HIV-1 infection despite exposure to cell-free virus and cell-associated virus in HIV-infected breast milk. Paradoxically, exclusive breastfeeding regardless of the HIV status of the mother has led to a significant decrease in mother-to-child transmission (MTCT) compared with non-exclusive breastfeeding. Although it remains unclear how these HIV-exposed infants remain uninfected despite repeated and prolonged exposure to HIV-1, the low rate of transmission is suggestive of a multitude of protective, short-lived bioactive innate immune factors in breast milk. Indeed, recent studies of soluble factors in breast milk shed new light on mechanisms of neonatal HIV-1 protection. This review highlights the role and significance of innate immune factors in HIV-1 susceptibility and infection. Prevention of MTCT of HIV-1 is likely due to multiple factors, including innate immune factors such as lactoferrin and elafin among many others. In pursuing this field, our lab was the first to show that soluble toll-like receptor 2 (sTLR2) directly inhibits HIV infection, integration, and inflammation. More recently, we demonstrated that sTLR2 directly binds to selective HIV-1 proteins, including p17, gp41, and p24, leading to significantly reduced NFkappaB activation, interleukin-8 production, CCR5 expression, and HIV infection in a dose-dependent manner. Thus, a clearer understanding of soluble milk-derived innate factors with known antiviral functions may provide new therapeutic insights to reduce vertical HIV-1 transmission and will have important implications for protection against HIV-1 infection at other mucosal sites. Furthermore, innate bioactive factors identified in human milk may serve not only in protecting infants against infections and inflammation but also the elderly; thus, opening the door for novel innate immune therapeutics to protect newborns, infants, adults, and the elderly. PMID- 29238344 TI - Scrambled Eggs: Apoptotic Cell Clearance by Non-Professional Phagocytes in the Drosophila Ovary. AB - For half of a century, it has been known that non-professional phagocytes, such as fibroblasts, endothelial, and epithelial cells, are capable of efferocytosis (engulfment of apoptotic cells). Non-professional phagocytes differ from professional phagocytes in the range and efficiency of engulfment. Much of the recognition and underlying signaling machinery between non-professional and professional phagocytes is the same, but it is not known how the engulfment capacity of non-professional phagocytes is controlled. Moreover, the signaling networks involved in cell corpse recognition, engulfment, and phagosome maturation are only partially understood. The Drosophila ovary provides an excellent system to investigate the regulation of phagocytic activity by epithelial cells, a major class of non-professional phagocytes. During Drosophila oogenesis, mid-stage egg chambers undergo apoptosis of the germline in response to nutrient deprivation. Epithelial follicle cells then undergo major cell shape changes and concomitantly engulf the germline material. Our previous work has established that Draper and the integrin alpha-PS3/beta-PS heterodimer are required in follicle cells for germline cell clearance. In addition, we have characterized phagosome maturation pathways, and found that the JNK pathway amplifies the engulfment response. In this review, we discuss recent advances on the interplay between engulfment pathways in the follicular epithelium for cell clearance in the Drosophila ovary. We also provide a comparison to apoptotic cell clearance mechanisms in C. elegans and mammals, illustrating strong conservation of efferocytosis mechanisms by non-professional phagocytes. PMID- 29238345 TI - F-Type Lectins: A Highly Diversified Family of Fucose-Binding Proteins with a Unique Sequence Motif and Structural Fold, Involved in Self/Non-Self-Recognition. AB - The F-type lectin (FTL) family is one of the most recent to be identified and structurally characterized. Members of the FTL family are characterized by a fucose recognition domain [F-type lectin domain (FTLD)] that displays a novel jellyroll fold ("F-type" fold) and unique carbohydrate- and calcium-binding sequence motifs. This novel lectin family comprises widely distributed proteins exhibiting single, double, or greater multiples of the FTLD, either tandemly arrayed or combined with other structurally and functionally distinct domains, yielding lectin subunits of pleiotropic properties even within a single species. Furthermore, the extraordinary variability of FTL sequences (isoforms) that are expressed in a single individual has revealed genetic mechanisms of diversification in ligand recognition that are unique to FTLs. Functions of FTLs in self/non-self-recognition include innate immunity, fertilization, microbial adhesion, and pathogenesis, among others. In addition, although the F-type fold is distinctive for FTLs, a structure-based search revealed apparently unrelated proteins with minor sequence similarity to FTLs that displayed the FTLD fold. In general, the phylogenetic analysis of FTLD sequences from viruses to mammals reveals clades that are consistent with the currently accepted taxonomy of extant species. However, the surprisingly discontinuous distribution of FTLDs within each taxonomic category suggests not only an extensive structural/functional diversification of the FTLs along evolutionary lineages but also that this intriguing lectin family has been subject to frequent gene duplication, secondary loss, lateral transfer, and functional co-option. PMID- 29238346 TI - Generating a Tolerogenic Cell Therapy Knowledge Graph from Literature. AB - Tolerogenic cell therapies provide an alternative to conventional immunosuppressive treatments of autoimmune disease and address, among other goals, the rejection of organ or stem cell transplants. Since various methodologies can be followed to develop tolerogenic therapies, it is important to be aware and up to date on all available studies that may be relevant to their improvement. Recently, knowledge graphs have been proposed to link various sources of information, using text mining techniques. Knowledge graphs facilitate the automatic retrieval of information about the topics represented in the graph. The objective of this work was to automatically generate a knowledge graph for tolerogenic cell therapy from biomedical literature. We developed a system, ICRel, based on machine learning to extract relations between cells and cytokines from abstracts. Our system retrieves related documents from PubMed, annotates each abstract with cell and cytokine named entities, generates the possible combinations of cell-cytokine pairs cooccurring in the same sentence, and identifies meaningful relations between cells and cytokines. The extracted relations were used to generate a knowledge graph, where each edge was supported by one or more documents. We obtained a graph containing 647 cell-cytokine relations, based on 3,264 abstracts. The modules of ICRel were evaluated with cross-validation and manual evaluation of the relations extracted. The relation extraction module obtained an F-measure of 0.789 in a reference database, while the manual evaluation obtained an accuracy of 0.615. Even though the knowledge graph is based on information that was already published in other articles about immunology, the system we present is more efficient than the laborious task of manually reading all the literature to find indirect or implicit relations. The ICRel graph will help experts identify implicit relations that may not be evident in published studies. PMID- 29238347 TI - Langerhans Cells-Programmed by the Epidermis. AB - Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels. These cells determine the appropriate adaptive immune response (inflammation or tolerance) by interpreting the microenvironmental context in which they encounter foreign substances. In a normal physiological, "non dangerous" situation, LCs coordinate a continuous state of immune tolerance, preventing unnecessary and harmful immune activation. Conversely, when they sense a danger signal, for example during infection or when the physical integrity of skin has been compromised as a result of a trauma, they instruct T lymphocytes of the adaptive immune system to mount efficient effector responses. Recent advances investigating the molecular mechanisms underpinning the cross talk between LCs and the epidermal microenvironment reveal its importance for programming LC biology. This review summarizes the novel findings describing LC origin and function through the analysis of the transcriptomic programs and gene regulatory networks (GRNs). Review and meta-analysis of publicly available datasets clearly delineates LCs as distinct from both conventional dendritic cells (DCs) and macrophages, suggesting a primary role for the epidermal microenvironment in programming LC biology. This concept is further supported by the analysis of the effect of epidermal pro-inflammatory signals, regulating key GRNs in human and murine LCs. Applying whole transcriptome analyses and in silico analysis has advanced our understanding of how LCs receive, integrate, and process signals from the steady-state and diseased epidermis. Interestingly, in homeostasis and under immunological stress, the molecular network in LCs remains relatively stable, reflecting a key evolutionary need related to tissue localization. Importantly, to fulfill their key role in orchestrating antiviral adaptive immune responses, LC share specific transcriptomic modules with other DC types able to cross-present antigens to cytotoxic CD8+ T cells, pointing to a possible evolutionary convergence mechanism. With the development of more advanced technologies allowing delineation of the molecular networks at the level of chromatin organization, histone modifications, protein translation, and phosphorylation, future "omics" investigations will bring in-depth understanding of the complex molecular mechanisms underpinning human LC biology. PMID- 29238348 TI - The Mannose Receptor in Regulation of Helminth-Mediated Host Immunity. AB - Infection with parasitic helminths affects humanity and animal welfare. Parasitic helminths have the capacity to modulate host immune responses to promote their survival in infected hosts, often for a long time leading to chronic infections. In contrast to many infectious microbes, however, the helminths are able to induce immune responses that show positive bystander effects such as the protection to several immune disorders, including multiple sclerosis, inflammatory bowel disease, and allergies. They generally promote the generation of a tolerogenic immune microenvironment including the induction of type 2 (Th2) responses and a sub-population of alternatively activated macrophages. It is proposed that this anti-inflammatory response enables helminths to survive in their hosts and protects the host from excessive pathology arising from infection with these large pathogens. In any case, there is an urgent need to enhance understanding of how helminths beneficially modulate inflammatory reactions, to identify the molecules involved and to promote approaches to exploit this knowledge for future therapeutic interventions. Evidence is increasing that C type lectins play an important role in driving helminth-mediated immune responses. C-type lectins belong to a large family of calcium-dependent receptors with broad glycan specificity. They are abundantly present on immune cells, such as dendritic cells and macrophages, which are essential in shaping host immune responses. Here, we will focus on the role of the C-type lectin macrophage mannose receptor (MR) in helminth-host interactions, which is a critically understudied area in the field of helminth immunobiology. We give an overview of the structural aspects of the MR including its glycan specificity, and the functional implications of the MR in helminth-host interactions focusing on a few selected helminth species. PMID- 29238349 TI - The Roles of Glycodelin in Cancer Development and Progression. AB - Glycodelin is a kind of glycoprotein expressed in secretory endometrium, pregnancy deciduas, and amniotic fluid originally, which is vital for the maintenance of normal human reproductive activities. Recent researches have reported that glycodelin is specifically expressed in various malignancies, including female-specific cancers such as endometrial cancer, ovarian cancer and breast cancer, and non-gender specific cancers including lung cancer, and colon cancer, and glycodelin expression correlates with the diagnosis and prognosis of cancer patients. This review focuses on the expression of glycodelin in different cancers and its role in cancer development and progression. Glycodelin possesses the abilities to regulate cancer cell proliferation, differentiation, and invasion, promote cancer angiogenesis, and modulate the differentiation and function of immune cells including T cells, dendritic cells, monocyte macrophages, natural killer cells and B cells participating in cancer development. The expression of glycodelin can be regulated by stromal cells, lysophosphatidic acid, histone deacetylase inhibitors, and relaxin. In summary, glycodelin is a promising biomarker for the diagnosis and prognosis of cancer patients, and depending on its distinct immunoregulatory effects, glycodelin can be a prospective target for cancer immunotherapy. PMID- 29238350 TI - Differentiation and Transmigration of CD4 T Cells in Neuroinflammation and Autoimmunity. AB - CD4+ T cells play a central role in orchestrating protective immunity and autoimmunity. The activation and differentiation of myelin-reactive CD4+ T cells into effector (Th1 and Th17) and regulatory (Tregs) subsets at the peripheral tissues, and their subsequent transmigration across the blood-brain barrier (BBB) into the central nervous system (CNS) parenchyma are decisive events in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. How the Th1, Th17, and regulatory Tregs transmigrate across the BBB into the CNS and cause CNS inflammation is not clearly understood. Studies with transgenic and gene knockout mice have unraveled that Th1, Th17, and Tregs play a critical role in the induction and resolution of neuroinflammation. However, the plasticity of these lineages and functional dichotomy of their cytokine products makes it difficult to understand what role CD4+ T cells in the peripheral lymphoid organs, endothelial BBB, and the CNS parenchyma play in the CNS autoimmune response. In this review, we describe some of the recent findings that shed light on the mechanisms behind the differentiation and transmigration of CD4+ T cells across the BBB into the CNS parenchyma and also highlight how these two processes are interconnected, which is crucial for the outcome of CNS inflammation and autoimmunity. PMID- 29238351 TI - Natural Killer Cell Activity and Interleukin-12 in Metabolically Healthy versus Metabolically Unhealthy Overweight Individuals. AB - The purpose of this study was to determine whether the immune system is involved in the different metabolic circumstances in healthy and unhealthy overweight individuals. We examined the metabolic and immune characteristics of 117 overweight individuals. Subjects were classified as metabolically healthy overweight (MHO, n = 72) or metabolically unhealthy overweight (MUO, n = 45). The immune response was measured by circulating levels of natural killer (NK) cell activity and cytokines. Both groups were comparable with regards to age, sex distribution, smoking and drinking status, and body mass index. When compared to the MHO group, the MUO group showed higher systolic and diastolic blood pressure, serum levels of triglyceride, glucose, glucose-related markers, and lower levels of HDL cholesterol. Compared to the MHO group, the MUO group showed 39% lower interferon-gamma levels (not significant) and 41% lower interleukin (IL)-12 levels (significant). The MUO group also showed lower NK cell activity at E:T ratios of 10:1, 5:1, 2.5:1, and 1.25:1 (all Ps < 0.05) than the MHO group. This study indicates that individuals displaying the MUO phenotype present an unfavorable immune system with lower NK cell activities under all assay conditions and lower serum levels of IL-12 than the activities and levels in similarly overweight MHO individuals. This result suggests that the immune system may be altered in overweight individuals who are at risk for overweight/obesity related comorbidities. PMID- 29238352 TI - Overexpression of ERF1-V from Haynaldia villosa Can Enhance the Resistance of Wheat to Powdery Mildew and Increase the Tolerance to Salt and Drought Stresses. AB - The APETALA 2/Ethylene-responsive element binding factor (AP2/ERF) transcription factor gene family is widely involved in the biotic and abiotic stress regulation. Haynaldia villosa (VV, 2n = 14), a wild species of wheat, is a potential gene pool for wheat improvement. H. villosa confers high resistance to several wheat diseases and high tolerance to some abiotic stress. In this study, ERF1-V, an ethylene-responsive element-binding factor gene of the AP2/ERF transcription factor gene family from wild H. villosa, was cloned and characterized. Sequence and phylogenetic analysis showed that ERF1-V is a deduced B2 type ERF gene. ERF1-V was first identified as a Blumeria graminis f. sp. tritici (Bgt) up-regulated gene, and later found to be induced by drought, salt and cold stresses. In responses to hormones, ERF1-V was up-regulated by ethylene and abscisic acid, but down-regulated by salicylic acid and jasmonic acid. Over expression of ERF1-V in wheat could improve resistance to powdery mildew, salt and drought stress. Chlorophyll content, malondialdehyde content, superoxide dismutase and peroxidase activity were significantly differences between the recipient Yangmai158 and the transgenic plants following salt treatment. Furthermore, the expression levels of some stress responsive genes were differences after drought or salt treatments. Although ERF1-V was activated by the constitutive promoter, the agronomic traits, including flowering time, plant height, effective tiller number, spikelet number per spike and grain size, did not changed significantly. ERF1-V is a valuable gene for wheat improvement by genetic engineering. PMID- 29238353 TI - Rhizosphere Microbiome Recruited from a Suppressive Compost Improves Plant Fitness and Increases Protection against Vascular Wilt Pathogens of Tomato. AB - Suppressive composts represent a sustainable approach to combat soilborne plant pathogens and an alternative to the ineffective chemical fungicides used against those. Nevertheless, suppressiveness to plant pathogens and reliability of composts are often inconsistent with unpredictable effects. While suppressiveness is usually attributed to the compost's microorganisms, the mechanisms governing microbial recruitment by the roots and the composition of selected microbial communities are not fully elucidated. Herein, the purpose of the study was to evaluate the impact of a compost on tomato plant growth and its suppressiveness against Fusarium oxysporum f. sp. lycopersici (Foxl) and Verticillium dahliae (Vd). First, growth parameters of tomato plants grown in sterile peat-based substrates including 20 and 30% sterile compost (80P/20C-ST and 70P/30C-ST) or non-sterile compost (80P/20C and 70P/30C) were evaluated in a growth room experiment. Plant height, total leaf surface, and fresh and dry weight of plants grown in the non-sterile compost mixes were increased compared to the plants grown in the sterile compost substrates, indicating the plant growth promoting activity of the compost's microorganisms. Subsequently, compost's suppressiveness against Foxl and Vd was evaluated with pathogenicity experiments on tomato plants grown in 70P/30C-ST and 70P/30C substrates. Disease intensity was significantly less in plants grown in the non-sterile compost than in those grown in the sterile compost substrate; AUDPC was 2.3- and 1.4-fold less for Foxl and Vd, respectively. Moreover, fungal quantification in planta demonstrated reduced colonization in plants grown in the non-sterile mixture. To further investigate these findings, we characterized the culturable microbiome attracted by the roots compared to the unplanted compost. Bacteria and fungi isolated from unplanted compost and the rhizosphere of plants were sequence-identified. Community-level analysis revealed differential microbial communities between the compost and the rhizosphere, suggesting a clear effect of the plant in the microbiome assembly. Proteobacteria and Actinobacteria were highly enriched in the rhizosphere whereas Firmicutes were strongly represented in both compartments with Bacillus being the most abundant species. Our results shed light on the composition of a microbial consortium that could protect plants against the wilt pathogens of tomato and improve plant overall health. PMID- 29238354 TI - Unravelling Protein-Protein Interaction Networks Linked to Aliphatic and Indole Glucosinolate Biosynthetic Pathways in Arabidopsis. AB - Within the cell, biosynthetic pathways are embedded in protein-protein interaction networks. In Arabidopsis, the biosynthetic pathways of aliphatic and indole glucosinolate defense compounds are well-characterized. However, little is known about the spatial orchestration of these enzymes and their interplay with the cellular environment. To address these aspects, we applied two complementary, untargeted approaches-split-ubiquitin yeast 2-hybrid and co-immunoprecipitation screens-to identify proteins interacting with CYP83A1 and CYP83B1, two homologous enzymes specific for aliphatic and indole glucosinolate biosynthesis, respectively. Our analyses reveal distinct functional networks with substantial interconnection among the identified interactors for both pathway-specific markers, and add to our knowledge about how biochemical pathways are connected to cellular processes. Specifically, a group of protein interactors involved in cell death and the hypersensitive response provides a potential link between the glucosinolate defense compounds and defense against biotrophic pathogens, mediated by protein-protein interactions. PMID- 29238355 TI - Effect of the Winter Wheat Cheyenne 5A Substituted Chromosome on Dynamics of Abscisic Acid and Cytokinins in Freezing-Sensitive Chinese Spring Genetic Background. AB - The effect of short- and long-term cold treatment on the abscisic acid (ABA) and cytokinin (CK) metabolism, and their main biosynthesis- and signaling-related genes were investigated in freezing-sensitive and freezing-tolerant wheat genotypes. Varieties Cheyenne and Chinese Spring substituted with the 5A Cheyenne chromosome, which represented freezing-tolerant genotypes, were compared with the freezing-sensitive Chinese Spring. Hormone levels and gene expression data indicated that the short- and long-term cold treatments are associated with specific regulation of the accumulation of cold-protective proteins and phytohormone levels, as well as the expression profiles of the hormone-related genes. The significant differences were observed between the genotypes, and between their leaf and crown tissues, too. The level of dehydrins, including WCS120 protein, and expression of WCS120 gene were considerably higher in the freezing-tolerant genotypes after 21 days of cold treatment. Expression of Cor14b and CBF14, cold-responsive regulator genes, was increased by cold treatment in all genotypes, to higher extent in freezing-tolerant genotypes. Cluster analysis revealed that the tolerant genotypes had a similar response to cold treatment, regarding expression of the ABA and CK metabolic genes, as well as hormone levels in leaves. As far as hormone levels in crowns are concerned, however, the strongly freezing-tolerant Cheyenne variety clustered separately from the Chinese Spring and the substitution line, which were more similar to each other after both 1 and 21 days of cold treatment than to Cheyenne. Based on these results we concluded that the 5A chromosome of wheat might have both a direct and an indirect impact on the phytohormone-dependent cold-induced freezing tolerance. Based on the gene expression data, novel genetic markers could be developed, which may be used to determine the freezing tolerance level in a wide range of wheat varieties. PMID- 29238356 TI - Arbuscular Mycorrhizal Fungus Enhances Lateral Root Formation in Poncirus trifoliata (L.) as Revealed by RNA-Seq Analysis. AB - Arbuscular mycorrhizal fungi (AMF) establish symbiosis with most terrestrial plants, and greatly regulate lateral root (LR) formation. Phosphorus (P), sugar, and plant hormones are proposed being involved in this regulation, however, no global evidence regarding these factors is available so far, especially in woody plants. In this study, we inoculated trifoliate orange seedlings (Poncirus trifoliata L. Raf) with an AMF isolate, Rhizophagus irregularis BGC JX04B. After 4 months of growth, LR formation was characterized, and sugar contents in roots were determined. RNA-Seq analysis was performed to obtain the transcriptomes of LR root tips from non-mycorrhizal and mycorrhizal seedlings. Quantitative real time PCR (qRT-PCR) of selected genes was also conducted for validation. The results showed that AMF significantly increased LR number, as well as plant biomass and shoot P concentration. The contents of glucose and fructose in primary root, and sucrose content in LR were also increased. A total of 909 differentially expressed genes (DEGs) were identified in response to AMF inoculation, and qRT-PCR validated the transcriptomic data. The numbers of DEGs related to P, sugar, and plant hormones were 31, 32, and 25, respectively. For P metabolism, the most up-regulated DEGs mainly encoded phosphate transporter, and the most down-regulated DEGs encoded acid phosphatase. For sugar metabolism, the most up-regulated DEGs encoded polygalacturonase and chitinase. For plant hormones, the most up-regulated DEGs were related to auxin signaling, and the most down-regulated DEGs were related to ethylene signaling. PLS-SEM analysis indicates that P metabolism was the most important pathway by which AMF regulates LR formation in this study. These data reveal the changes of genome-wide gene expression in responses to AMF inoculation in trifoliate orange and provide a solid basis for the future identification and characterization of key genes involved in LR formation induced by AMF. PMID- 29238359 TI - Mapping X-Disease Phytoplasma Resistance in Prunus virginiana. AB - Phytoplasmas such as "Candidatus Phytoplasma pruni," the causal agent of X disease of stone fruits, lack detailed biological analysis. This has limited the understanding of plant resistance mechanisms. Chokecherry (Prunus virginiana L.) is a promising model to be used for the plant-phytoplasma interaction due to its documented ability to resist X-disease infection. A consensus chokecherry genetic map "Cho" was developed with JoinMap 4.0 by joining two parental maps. The new map contains a complete set of 16 linkage groups, spanning a genetic distance of 2,172 cM with an average marker density of 3.97 cM. Three significant quantitative trait loci (QTL) associated with X-disease resistance were identified contributing to a total of 45.9% of the phenotypic variation. This updated genetic linkage map and the identified QTL will provide the framework needed to facilitate molecular genetics, genomics, breeding, and biotechnology research concerning X-disease in chokecherry and other Prunus species. PMID- 29238357 TI - Structural and Functional Diversity of Plant Virus 3'-Cap-Independent Translation Enhancers (3'-CITEs). AB - Most of the positive-strand RNA plant viruses lack the 5'-cap and/or the poly(A) tail that act synergistically to stimulate canonical translation of cellular mRNAs. However, they have RNA elements in the 5'- or 3'-untranslated regions of their RNAs that are required for their cap-independent translation. Cap independent translation enhancers (CITEs) have been identified in the genomic 3' end of viruses belonging to the family Tombusviridae and the genus Luteovirus. Seven classes of 3'-CITEs have been described to date based on their different RNA structures. They generally control the efficient formation of the translation initiation complex by varying mechanisms. Some 3'-CITEs bind eukaryotic translation initiation factors, others ribosomal subunits, bridging these to the 5'-end by different mechanisms, often long-distance RNA-RNA interactions. As previously proposed and recently found in one case in nature, 3'-CITEs are functionally independent elements that are transferable through recombination between viral genomes, leading to potential advantages for virus multiplication. In this review, the knowledge on 3'-CITEs and their functioning is updated. We also suggest that there is local structural conservation in the regions interacting with eIF4E of 3'-CITEs belonging to different classes. PMID- 29238358 TI - Characterization of the Wheat Leaf Metabolome during Grain Filling and under Varied N-Supply. AB - Progress in improving crop growth is an absolute goal despite the influence multifactorial components have on crop yield and quality. An Avalon * Cadenza doubled-haploid wheat mapping population was used to study the leaf metabolome of field grown wheat at weekly intervals during the time in which the canopy contributes to grain filling, i.e., from anthesis to 5 weeks post-anthesis. Wheat was grown under four different nitrogen supplies reaching from residual soil N to a luxury over-fertilization (0, 100, 200, and 350 kg N ha-1). Four lines from a segregating doubled haploid population derived of a cross of the wheat elite cvs. Avalon and Cadenza were chosen as they showed pairwise differences in either N utilization efficiency (NUtE) or senescence timing. 108 annotated metabolites of primary metabolism and ions were determined. The analysis did not provide genotype specific markers because of a remarkable stability of the metabolome between lines. We speculate that the reason for failing to identify genotypic markers might be due to insufficient genetic diversity of the wheat parents and/or the known tendency of plants to keep metabolome homeostasis even under adverse conditions through multiple adaptations and rescue mechanism. The data, however, provided a consistent catalogue of metabolites and their respective responses to environmental and developmental factors and may bode well for future systems biology approaches, and support plant breeding and crop improvement. PMID- 29238360 TI - Impact of chronic kidney disease on mortality in older adults treated with pacemaker implantation. AB - Objective: To investigate whether chronic kidney disease could negatively impact survival in older adults needing pacemaker implantation after admission for bradyarrhythmias. Methods: This retrospective observational study considered 538 older adults consecutively admitted, who had been followed-up for 31 +/- 20 months. Subjects with poor short-term prognosis were excluded. Charlson comorbidity index (CCI) and estimated glomerular filtration rate (eGFR) was calculated, along with the independent relationship between all-cause mortality and clinical data. Hazard Ratio (HR) was calculated by Cox regression analysis. Results: Mean age of the population was 85 +/- 3.7 years, and causes for implantation were atrioventricular block in 51.9% and other bradyarrhythmias in 48.1% of cases. Mean eGFR was 58.3 +/- 24 mL/min per 1.73 m2, and mean CCI was 3.65 +/- 2.28. Death for all-causes was recorded in 213 subjects. Deceased patients were older, had lower eGFR, higher comorbidity, higher prevalence of myocardial infarction, congestive heart failure, cerebrovascular disease, dementia and chronic pulmonary disease. Age (HR: 1.081, 95% CI: 1.044-1.119; P < 001), CCI (HR: 1.651, 95% CI: 1.286-2.121, P < 001) and eGFR <= 45 mL/min per 1.73 m2 (HR: 1.360, 95% CI: 1.024-1.806; P = 0.033) were predictors of death. Conclusions: Renal dysfunction, as well as comorbidity, impacts negatively survival of older adults treated with pacemaker implantation because of bradyarrhythmias. PMID- 29238361 TI - Effect of Chinese national holidays and weekends versus weekday admission on clinical outcomes in patients with STEMI undergoing primary PCI. AB - Background: Data regarding the influence of weekends and Chinese national holiday's admission on the outcomes of patients with ST-elevated myocardial infarction (STEMI) is lacking. This study sought to investigate the effect of Chinese national holidays and weekend admission on outcomes in patients with STEMI undergoing primary percutaneous coronary intervention (PPCI). Methods: Patients presenting with STEMI within 12 h of symptom onset who underwent PPCI were retrospectively enrolled. The primary outcome of in-hospital mortality and major adverse cardiovascular events in patients presenting Chinese national holidays and weekends versus weekdays was evaluated. Results: A total of 441 STEMI patients were enrolled in this study. Of these, 129 (29.3%) patients were admitted during Chinese national holidays and weekends and 312 (70.7%) during weekdays. Patients admitted during holidays and weekends were more likely to present with Killip class III-IV. Patients admitted during holidays and weekends experienced a significantly longer door-to-balloon time, symptom onset-to-door time as well as symptom onset-to-balloon time. The in-hospital mortality between patients presenting holidays and weekends versus weekdays was comparable. However, patients admitted during holidays and weekends have a significantly higher rate of in-hospital major adverse cardiovascular events. Multivariate analysis demonstrated that holidays and weekends admission was independently associated with adverse outcomes. Conclusions: In China, STEMI patients undergoing PPCI during national holidays and weekends have worse in-hospital outcomes compared to those admitted during weekdays. These findings suggest that continuous efforts should be undertaken to enhance the Chinese healthcare system and to ensure that comparable outcomes are achieved for all STEMI patients regardless of time of presentation. PMID- 29238362 TI - Combined thrombectomy and intracoronary administration of glycoprotein IIb/IIIa inhibitors improves myocardial reperfusion in patients undergoing primary percutaneous coronary intervention: a meta-analysis. AB - Background: Suboptimal myocardial reperfusion is common in patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Furthermore, it results in increased infarct size and mortality rates. We performed a meta-analysis to evaluate the role of aspiration thrombectomy (AT) combined with intracoronary administration of glycoprotein IIb/IIIa inhibitors (GPI) in the improvement of myocardial reperfusion and clinical outcomes. Methods: PubMed, Embase, Web of Science, and CENTRAL databases were searched for randomized controlled trials (RCTs) investigating combined AT and intracoronary GPI treatment versus AT alone. Outcomes of interest were thrombolysis in myocardial infarction myocardial perfusion grade (TMPG), infarct size (IS) assessed by cardiac magnetic resonance imaging, left ventricular ejection fraction (LVEF), major adverse cardiac events (MACE) at short-term (<= 1 month) and long-term (6-12 months) follow-up, and bleeding complications during the hospital stay. Results: Eight trials involving 923 patients were included. Compared with AT alone, combined AT and intracoronary GPI significantly increased TMPG 3 flow (RR: 1.15, 95% CI: 1.04 to 1.26), reduced IS [mean difference (MD): -3.46, 95% CI: -5.18 to -1.73], and improved LVEF (MD: 1.44, 95% CI: 0.54 to 2.33). Furthermore, GPI use decreased the risk of MACE at long-term follow-up (RR: 0.60, 95% CI: 0.37 to 0.98). There was no significant difference between the two groups in the incidence of minor and major bleeding complications. Conclusions: Our findings showed that compared with AT alone, combined AT and intracoronary GPI treatment resulted in improved myocardial reperfusion, better cardiac function, and MACE-free survival benefits at the long term follow-up for patients with STEMI undergoing PPCI. PMID- 29238363 TI - Bleeding outcomes after non-emergency percutaneous coronary intervention in the very elderly. AB - Background: Octogenarians constitute an increasing proportion of patients presenting for non-emergency percutaneous coronary intervention (PCI). Methods: This study evaluated the in-hospital procedural characteristics and outcomes, including the bleeding events of 293 octogenarians presenting between January 2010 and December 2012 for non-emergency PCI to a single large volume tertiary care Australian center. Comparisons were made with 293 consecutive patients aged less than or equal to 60 years, whose lesions were matched with the octogenarians. Results: Non-ST elevation myocardial infarction was the most frequent indication for non-emergency PCI in octogenarians. Compared to the younger cohort, they had a higher prevalence of co-morbidities and more complex coronary disease, comprising more type C and calcified lesions. Peri-procedural use of low molecular weight heparin (LMWH; 1.0% vs. 5.8%; P < 0.001) and glycoprotein IIb/IIIa inhibitors (2.1% vs. 9.6%; P < 0.001) was lower, while femoral arterial access was used more commonly than in younger patients (80.9% vs. 67.6%; P < 0.001). Overall, there was a non-significant trend towards higher incidence of all bleeding events in the elderly (9.2% vs. 5.8%; P = 0.12). There was no significant difference in access site or non-access site bleeding and major or minor bleeding between the two cohorts. Sub-analysis did not reveal any significant influence on bleeding rates by the use of LMWH, glycoprotein IIb/IIIa inhibitors or femoral arterial access. In addition, there were no significant differences in the rates of in-hospital mortality, stroke or acute stent thrombosis between the two groups. Conclusions: In this single center study, we did not observe significant increases in adverse in-hospital outcomes including the incidence of bleeding in octogenarians undergoing non-emergency PCI. PMID- 29238364 TI - Age related differences and outcome of patients with Takotsubo syndrome. AB - Background: Takotsubo syndrome (TS) is an important cardiac disease that affects predominantly postmenopausal women. This study was conducted to determine the impact of age on the short- and long-term outcome of TS patients. Methods & Results: The data from a collective of 114 TS patients with a mean follow-up of 1591 +/- 1079 days was retrospectively analysed. The study population was divided into two groups (<= 65 and > 65 years) so as to evaluate the impact of age on the short- and long-term mortality of TS patients. In-hospital events like life threatening arrhythmias (14.58% vs. 9.09%; P = 0.036), need for mechanical respiratory support (41.66% vs. 28.78%; P = 0.15) as well as inotropic agent use (22.91% vs. 15.15%; P = 0.29), although not reaching the statistical cut-of, tended to occur more often in the younger group. Heart failure was more common in the elderly age group (P = 0.03). The use of multivariate analysis ruled out age as a significant marker of long term mortality (HR: 1.0; 95% CI: 0.9-1.0; P = 0.60). Conclusions: Age does not influence the clinical course of TS in terms of the short- as well as long-term outcome. The study revealed a higher incidence of life threatening arrhythmias in the younger patient age-group and a higher incidence of heart failure among the older group of patients. PMID- 29238365 TI - Spontaneous type 1 pattern, ventricular arrhythmias and sudden cardiac death in Brugada Syndrome: an updated systematic review and meta-analysis. PMID- 29238366 TI - Topical anaesthesia before transradial approach for supraoartic vessels angiography and stenting in the elderly: a feasible alternative. PMID- 29238367 TI - Cardiac resynchronization therapy improved the clinical outcomes in pacemaker patients upgraded to biventricular device. PMID- 29238368 TI - Transient severe mitral regurgitation after paroxysmal supraventricular tachycardia in patient with WPW syndrome. PMID- 29238369 TI - Reversal of Wolff-Parkinson-White Syndrome induced dilated cardiomyopathy via resynchronization and subsequent accessory pathway ablation. PMID- 29238370 TI - Comments to "Neutrophil-to-lymphocyte ratio compared to N-terminal pro-brain natriuretic peptide as a prognostic marker of adverse events in elderly patients with chronic heart failure". PMID- 29238371 TI - Application of the AMLprofiler Diagnostic Microarray in the South African Setting. AB - Acute myeloid leukemia (AML) is characterized by proliferation of the myeloid lineage and accumulation of immature hematopoietic cells in the bone marrow and is typified by marked heterogeneity both in response to treatment and survival. AMLprofiler is a qualitative in vitro diagnostic microarray incorporating seven molecular biomarkers used to diagnose and predict posttherapy survival rates. In this study, we compared AMLprofiler to routine AML diagnostic methodologies employed in South Africa, focusing on consistency of the results, cost, and time to result. RNA was isolated from bone marrow and peripheral blood samples from patients with de novo AML and was processed using Affymetrix Gene Profiling Reagent kits. The results from AMLprofiler and standard methodologies were highly comparable. In addition, many samples were determined to be positive for biomarkers not routinely investigated in South Africa, namely, CEBPA double mutants, NPM1 variants, and altered expression levels of BAALC and EVI1. 38% of samples presented with no positive biomarker; AMLprofiler nonetheless enabled 26% of AML patients to be classified into either favorable or poor prognostic categories. This study highlights the comprehensive nature of the microarray. Decreased time to result and refinement of risk stratification are notable benefits. PMID- 29238372 TI - Transplantation of Rat Mesenchymal Stem Cells Overexpressing Hypoxia-Inducible Factor 2alpha Improves Blood Perfusion and Arteriogenesis in a Rat Hindlimb Ischemia Model. AB - Mesenchymal stem cells (MSCs) have been increasingly tested in cell-based therapy to treat numerous diseases. Genetic modification to improve MSC behavior may enhance posttransplantation outcome. This study aims to test the potential therapeutic benefits of rat bone marrow MSCs overexpressing hypoxia-inducible factor 2alpha (rMSCsHIF-2alpha ) in a rat hindlimb ischemia model. PBS, rMSCs, or rMSCsHIF-2alpha were injected into rat ischemic hindlimb. Compared with the injection of PBS or rMSCs, transplantation of rMSCsHIF-2alpha significantly improved blood perfusion, increased the number of vessel branches in the muscle of the ischemic hindlimb, and improved the foot mobility of the ischemic hindlimb (all P < 0.05). rMSCHIF-2alpha transplantation also markedly increased the expression of proangiogenic factors VEGF, bFGF, and SDF1 and Notch signaling proteins including DII4, NICD, Hey1, and Hes1, whereas it reduced the expression of proapoptotic factor Bax in the muscle of the ischemic hindlimb. Overexpression of HIF-2alpha did not affect rMSC stemness and proliferation under normoxia but significantly increased rMSC migration and tube formation in matrigel under hypoxia (all P < 0.05). RMSCsHIF-2alpha stimulated endothelial cell invasion under hypoxia significantly (P < 0.05). Genetic modification of rMSCs via overexpression of HIF-2alpha improves posttransplantation outcomes in a rat hindlimb ischemia model possibly by stimulating proangiogenic growth factors and cytokines. PMID- 29238373 TI - Guided tissue regeneration and platelet rich growth factor for the treatment of Grade II furcation defects: A randomized double-blinded clinical trial - A pilot study. AB - Background: The treatment of furcation area defects remained as a challenging issue in periodontal treatments. Regeneration treatment of furcation defects is the most discussed periodontal treatment. Although not completely hopeless in prognosis, the presence of the furcation involvement significantly increases the chance of tooth loss. The current research was conductedeto compare theeadditive effect of combined guided tissue regeneration (GTR) and platelet-rich growth factor (PRGF) on the treatment of furcation bony defects. Materials and Methods: A randomized, triple-blinded, split-mouth study was designed. It included patients with a moderate to severe chronic periodontitis with bilateral Grade II furcation involvement of first or second mandibular molars. Each side of mouth was randomly allocated for the treatment with either Bio-Gide American Society of Anesthesiologists GTR or a PRGF or PRGF by itself. Plaque index, gingival index, vertical clinical attachment level, vertical probing depth, recession depth (REC), horizontal probing depth, fornix to alveolar crest (FAC), fornix to base of defect (FBD), furcation vertical component and furcation horizontal component (FHC) were recorded. The current research was conducted to compare the additive effect of combined GTR and PRGF on treatment of furcation bony defects. Altman's nomogram, Kolmogorov-Smirnov test, Friedman test, general linear model, repeated measures, and paired t-test were used as statistical analysis in this research. P < 0.05 was considered statistically significant. Results: Eight patients were finally enrolled for this study. Overly, general and specific clinical and furcation parameters were improved except REC that was deteriorated insignificantly and FAC improved not significantly. Intergroup comparison revealed better improvement of FHC in GTR/PRGF group (P = 0.02). Conclusion: A significant improvement in the Grade II furcation defects treated with either GTR or PRGF/GTR was noticed. Further large-scale trials are needed to reveal differences of mentioned treatment in more details. PMID- 29238374 TI - Zygoma implants in oral rehabilitation: A review of 28 cases. AB - Background: The functional and esthetic rehabilitation of patients with atrophic maxilla or posterior maxillary defect is often challenging. The aim of this study was to determine patient demographics, indications, success rate, and complications following the use of zygoma implants. Materials and Methods: All patients who had zygoma implant placement in our clinic between 1998 and 2013 were retrospectively assessed for implant outcome. Data were analyzed using Statistical Package for the Social Sciences (SPSS) version 16 and Microsoft Excel 2007 test for significance (rho) using Pearson's Chi-square (chi2) set at 0.05. Results: A total of 28 patients consisting of 22 females (78.6%) and 6 males (21.4%) were treated, and their age ranged from 41 years to 83 years with a mean age of 60.3 +/- 10.6 years. The main indication for zygoma implant placement was atrophic maxilla 12 (42.9%). In the prosthetic rehabilitation of the patients, 2 had epithetic prostheses, and 2 had obturators while 18 patients had conventional removable dental prostheses. Four patients (14.3%) had perimplantitis and one implant was accidentally placed into the maxillary sinus. A cumulative success rate of 88.1% was obtained from this retrospective analysis. Conclusion: A cumulative success rate of 88.1% reported in this study is lower than the reports from other studies. The difference in success rates may be related to different criteria for assessment of zygoma implant success and to the difference in inclusion criteria and follow-up period. PMID- 29238375 TI - Allergic rhinitis and dental caries in preschool children. AB - Background: Allergic rhinitis (AR) may be overdocumented in cases of dental caries because of controversies in the literature This study was conducted to investigate the potential relationship between AR and dental caries in children. Materials and Methods: A total of 296 children were included in this cross sectional study. Participants were evaluated using the decay-missing-filled (DMF) index, and their AR status was evaluated by physical examination and through a standard questionnaire. Baseline demographics and clinical characteristics were compared among groups using Student's t-test or the Mann-Whitney U-test, the Chi square test, and/or Fisher's exact test as appropriate. A level of P < 0.05 was regarded as statistically significant. Results: Evidence of AR was found in 77 (35.1%) participants. There was no significant difference in the rate of tooth decay or DMF between participants with or without AR (P = 0.07), but a significant difference was observed in the number of missing and filled teeth between those with and without AR (P < 0.05). There were no significant differences in educational level, family income, milk intake, use of pacifier, use of a toothbrush, saliva secretion, or body mass index (P > 0.05 in all cases) between AR-positive and AR-negative patients. Fluoride therapy and oral breathing were identified as confounding factors and controlled using log-linear analysis. The mean rate of DMF in patients who also had AR was 20% greater than in the AR negative group (odds ratio [OR] = 1.21, confidence interval [CI]: 1.05-1.35) and 15% greater in among children who breathed orally than those who did not (OR = 1.15 CI: 1.02-1.31). Conclusion: AR and oral breathing may have an effect on oral health and dental condition, leading to an increased rate of tooth loss, oral fillings, and development of dental caries. PMID- 29238376 TI - The effect of different root canal sealers on the fracture resistance of endodontically treated teeth-in vitro study. AB - Background: The aim of this study was to compare the in vitro effects of four different root canal sealers on the fracture resistance of endodontically treated teeth. Materials and Methods: Seventy-five freshly extracted human mandibular premolars were used for the study. Teeth were divided into five groups based on type of root canal sealers used. Gutta-percha was used for all the samples: Group I: AH Plus root canal sealer, Group II: MTA Fillapex root canal sealer, Group III: Apexit root canal sealer, Group IV: Conventional zinc oxide-eugenol (ZOE) sealer, Group V: Control (unobturated teeth). The teeth were embedded in acrylic resin blocks and fracture force was measured using a universal testing machine (Asian Test Equipments). Data obtained were statistically evaluated using one-way ANOVA and post hoc test (Tukey's test). All groups showed statistically significant result (P < 0.05). Results: Group I and Group II showed higher resistance to fracture than other three groups. There was comparable difference in fracture force between Group I and Group II. Moreover, there was no statistically significant difference between Group III and Group IV and between Group IV and Group V. Conclusion: Based on this in vitro study, resin-based sealer was more effective as compared to other sealers and the control group. However, no significant differences were observed between ZOE and control group. PMID- 29238377 TI - Masking ability of a zirconia ceramic on composite resin substrate shades. AB - Background: Masking ability of a restorative material plays an important role to cover discolored tooth structure; however, this ability has not yet been well understood in zirconia-based restorations. This study assessed the masking ability of a zirconia ceramic on composite resin substrates with different shades. Materials and Methods: Ten zirconia disc specimens, with 0.5 mm thickness and 10 mm diameter, were fabricated by a computer-aided design/computer-aided manufacturing system. A white substrate (control) and six composite resin substrates with different shades including A1, A2, A3, B2, C2, and D3 were prepared. The substrates had a cylindrical shape with 10 mm diameter and height. The specimens were placed onto the substrates for spectrophotometric evaluation. A spectrophotometer measured the L*, a*, and b* values for the specimens. DeltaE values were calculated to determine the color differences between the groups and the control and then were compared with a perceptional threshold (DeltaE = 2.6). Repeated measures ANOVA and Bonferroni tests were used for data analysis (P < 0.05). Results: The mean and standard deviation of DeltaE values for A1, A2, A3, B2, C2, and D3 groups were 6.78 +/- 1.59, 8.13 +/- 1.66, 9.81 +/- 2.64, 9.61 +/- 1.38, 9.59 +/- 2.63, and 8.13 +/- 1.89, respectively. A significant difference was found among the groups in the DeltaE values (P = 0.006). The DeltaE values were more than the perceptional threshold in all the groups (P < 0.0001). Conclusion: Within the limitations of this study, it can be concluded that the tested zirconia ceramic could not thoroughly mask different shades of the composite resin substrates. Moreover, color masking of zirconia depends on the shade of substrate. PMID- 29238378 TI - Association of macrophage migration inhibitory factor gene polymorphisms with chronic periodontitis in a South Eastern Iranian population. AB - Background: Macrophage migration inhibitory factor (MIF) is a key proinflammatory mediator. It plays a vital role in immune response against the oral disease. MIF is a regulator of innate immunity, and bacterial antigens can stimulate serum level of this protein. In experimental gingivitis, the expression level of MIF increases and this increment positively correlates with oral plaque index. The single nucleotide polymorphisms in the gene encoding the MIF protein can control the function of MIF. The aim of the present study was a clarification of the associations between MIF-173 G/C, MIF 95 bp, and 189 bp insertion/deletion (I/D) polymorphisms and chronic periodontitis (CP) compared with healthy controls. Materials and Methods: This case-control study was carried out on 210 CP patients and 100 normal subjects. MIF-173 G/C and MIF 95 bp and 189 bp I/D polymorphisms were genotyped, using polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) and PCR, respectively. Allele and genotype frequencies of the variants were compared between patients and controls using Chi-square. test. The value of P < 0.05 was considered statistically significant. Results: The study findings showed that MIF-173 G/C polymorphism, especially the C allele increased the risk of CP. The 95-bp I/D polymorphism was not associated with CP and the 185-bp I/D variant was not polymorphic in our population. Conclusion: Therefore, MIF-137 G/C variant increased the risk of CP in the South East of the Iranian population. In other words, polymorphisms in MIF gene influence clinical outcome of CP infection and influence the susceptibility to disease. Further studies with larger sample sizes and different ethnicities are required to validate our findings. PMID- 29238379 TI - Correlation of Vitamin D status and orthodontic-induced external apical root resorption. AB - Background: Adequate Vitamin D is essential for dental and skeletal health in children and adult. The purpose of this study was to assess the correlation of serum Vitamin D level with external-induced apical root resorption (EARR) following fixed orthodontic treatment. Materials and Methods: In this cross sectional study, the prevalence of Vitamin D deficiency (defined by25 hydroxyvitamin-D) was determined in 34 patients (23.5% male; age range 12-23 years; mean age 16.63 +/- 2.84) treated with fixed orthodontic treatment. Root resorption of four maxillary incisors was measured using before and after periapical radiographs (136 measured teeth) by means of a design-to-purpose software to optimize data collection. Teeth with a maximum percentage of root resorption (%EARR) were indicated as representative root resorption for each patient. A multiple linear regression model and Pearson correlation coefficient were used to assess the association of Vitamin D status and observed EARR. P < 0.05 was considered statistically significant. Results: The Pearson coefficient between these two variables was determined about 0.15 (P = 0.38). Regression analysis revealed that Vitamin D status of the patients demonstrated no significant statistical correlation with EARR, after adjustment of confounding variables using linear regression model (P > 0.05). Conclusion: This study suggests that Vitamin D level is not among the clinical variables that are potential contributors for EARR. The prevalence of Vitamin D deficiency does not differ in patients with higher EARR. These data suggest the possibility that Vitamin D insufficiency may not contribute to the development of more apical root resorption although this remains to be confirmed by further longitudinal cohort studies. PMID- 29238381 TI - Assessment of the anterior loop of mental nerve in an Iranian population using cone beam computed tomography scan. AB - Background: The anterior loop is an important structure in the interforaminal area of the mandible. The aim of the present study was to assess the prevalence and length of the anterior loop of mental nerve using cone beam computed tomography (CBCT) scan and to compare the differences between age, gender, and side. Materials and Methods: A total of 180 projections were analyzed in different sectional planes. The inferior alveolar nerve was determined. To measure the length of anterior loop in tangential plane, two parallel lines from the anterior point of mental foramen and anterior point of anterior loop were drawn. The distance between these two lines was measured by drawing a perpendicular line on them. The data were analyzed by SPSS (version 22). McNemar's test, Chi-square test, and t-test were performed to compare the significance of findings regarding side, age, and gender. P < 0.05 was considered statistically significant. Results: The results showed that 32.8% of images had anterior loop. The mean lengths of anterior loop in the right and left sides were 2.69 mm (standard deviation [SD] = 1.56) and 2.36 mm (SD = 1.16), respectively. There were no statistically significant differences between the mean lengths of the anterior loop in both sides (P = 0.18). Conclusion: Great care is required when placing implants in proximity to mental foramen to avoid anterior loop injury. Because of the variations of anterior loop length in each patient, a fixed distance anterior to the mental foramen is not safe, and the anterior loop length should be determined for each individual. The use of CBCT provides accurate measurements of the length of anterior loop. PMID- 29238380 TI - Static and kinetic frictional forces of silica-insert ceramic brackets with coated archwires in artificial saliva. AB - Background: During sliding mechanics, the frictional force (FF) is an important counterforce to orthodontic tooth movement. The purpose of this in vitro study was to investigate the static and kinetic FFs of S silica-insert ceramic (SIC) brackets with Teflon-coated (TC) and conventional S stainless steel (SS) archwires. Materials and Methods: The target group of this study included 80 maxillary canine 0.022 inch slot SIC brackets. Forty SS brackets were used as the control. TC and conventional uncoated SS archwires of different dimensions (0.016, 0.018, 0.016 * 0.022, and 0.018 * 0.025 inch) were examined. All tests were carried out under artificial saliva injected condition. Scanning Electron Micrographs were prepared for two samples of coated and uncoated archwires. Analysis of variance and Tukey post hoc tests were used for statistical purposes (level of significance P < 0.05). Results: SIC brackets showed significantly lower levels of FFs than SS brackets. TC archwires had greater frictional values than conventional uncoated ones. They also exhibited an unusual behavior of increasing kinetic FFs with time. Indentation and delamination of coating were obvious under scanning electron microscopy observations. Conclusion: From the standpoint of friction, SIC brackets may serve well, even better than SS brackets, in sliding mechanics. The coating layer of the archwires may delaminate and lost, causing an impediment to tooth movement. PMID- 29238382 TI - A case of central mucoepidermoid carcinoma associated with dentigerous cyst. AB - Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland neoplasm. Central MEC (CMEC) is a rare primary intraosseous bony lesion with an incidence of 2%-4.3% of all MECs reported. In this article, we present a rare case of a CMEC in the anterior region of maxilla at a 43-year-old female patient that was arising from a dentigerous cyst. CMECs are extremely rare tumor. They are usually low-grade lesions with favorable prognosis. Odontogenic cysts are one of the origins of this lesion. Treatment of impacted tooth is necessary in the early stage for prevention of this neoplasm. PMID- 29238383 TI - Plasma rich in growth factors in dogs: Two sides of the same coin. PMID- 29238384 TI - Antiarthritic Activity of Qi-Wu Rheumatism Granule (a Chinese Herbal Compound) on Complete Freund's Adjuvant-Induced Arthritis in Rats. AB - Objective: The aim was to study the therapeutic effects and mechanisms of QWRG on adjuvant-induced RA in rats. Methods: The RA rat models were manipulated and subsequently divided into five experimental groups: AIA, DEX, and QWRG groups. The paw volume, body weight, arthritic score, and mechanical nociceptive threshold were assessed. The serum levels of the RF, MDA, ALP, AST, ALT, IL 1beta, IL-2, IL-16, and TNF-alpha were measured. The proliferative capacity of lymphocytes was evaluated, and the synovial tissue was histopathologically examined. Results: The paw swelling and arthritic scores were relieved, and the variation of relative body weight and mechanical nociceptive threshold had improved in the AIA rats. The serum levels of RF, MDA, ALP, AST, and ALT were alleviated, and the inflammation and cartilage damage were effectively attenuated in the AIA rats. Simultaneously, the inflammation of the synovial cavity was alleviated, and the grading of synovitis reduced by inhibiting the expressions of IL-1beta, TNF-alpha, and IL-16 in the serum and synovium tissue. Conclusion: Our results suggested that the antiarthritic properties of QWRG may be due to immunodepression and downregulation of inflammatory cytokines, which may be a potential candidate for the treatment of RA. PMID- 29238385 TI - Experiences Providing Medical Assistance during the Sewol Ferry Disaster Using Traditional Korean Medicine. AB - Background: This study aimed to investigate medical records using traditional Korean medicine (TKM) in Sewol Ferry disaster in 2014 and further explore the possible role of traditional medicine in disaster situation. Methods: After Sewol Ferry accident, 3 on-site tents for TKM assistance by the Association of Korean Medicine (AKOM) in Jindo area were installed. The AKOM mobilized volunteer TKM doctors and assistants and dispatched each on-site tent in three shifts within 24 hours. Anyone could use on-site tent without restriction and TKM treatments including herb medicine were administered individually. Results: The total of 1,860 patients were treated during the periods except for medical assistance on the barge. Most patients were diagnosed in musculoskeletal diseases (66.4%) and respiratory diseases (7.4%) and circulatory diseases (8.4%) followed. The most frequently used herbal medicines were Shuanghe decoction (80 days), Su He Xiang Wan (288 pills), and Wuji powder (73 days). Conclusions: TKM in medical assistance can be helpful to rescue worker or group life people in open shelter when national disasters occur. Therefore, it is important to construct a rapid respond system using TKM resources based on experience. PMID- 29238386 TI - Optimized-SopungSunkiwon, a Herbal Formula, Attenuates Abeta Oligomer-Induced Neurotoxicity in Alzheimer's Disease Models. AB - Alzheimer's disease (AD), the most common form of dementia, is an age-related neurodegenerative disease that is characterized by memory dysfunction, neuronal cell damage, and neuroinflammation. It is believed that AD-related pathology is mostly due to the overproduction of Abeta, especially the oligomeric form (AbetaO), in the brain. Evidence of the effects of multifunctional medicinal herbs in the treatment of AD has been steadily increasing. Optimized SopungSunkiwon (OSS), a multiherbal formulation that is composed of six medicinal herbs derived from SopungSunkiwon, is a traditional medicine that is prescribed for neurodegenerative disorders in elderly patients. We previously reported that OSS showed an antiamnesic and memory enhancing effect in mice, but it is unknown whether OSS has a protective effect against AbetaO neurotoxicity. In this study, we investigated the effects of OSS in AD models induced by AbetaO in vitro and in vivo. We found that OSS protected neuronal cells and inhibited the generation of nitric oxide and reactive oxygen species against AbetaO toxicity in vitro. These results were confirmed by in vivo data that oral administration of OSS for 14 days attenuated memory impairments and neuronal cell death by modulating gliosis, glutathione depletion, and synaptic damage in the mouse hippocampus induced by AbetaO. PMID- 29238387 TI - The Tight-interlocked Rhythm Section: Production and Perception of Synchronisation in Jazz Trio Performance. AB - This study investigates the production and perception of timing, synchronisation and dynamics in jazz trio performances. In a production experiment, six trio combinations of one saxophonist, two bassists, and three drummers were recorded while they performed three popular jazz songs. Onset timing and dynamics of each performer were extracted and analysed. Results showed that the tempo was significantly influenced by the timing of the drummers and all performers showed higher temporal precision on the backbeats. The drummers demonstrated individual swing-ratios, accentuations of beats and intrapersonal asynchronies between simultaneous hi-hat and ride cymbal onsets, which resulted in a hi-hat played 2 26 ms ahead of the pulse of the music. In a subsequent perception test, participants ([Formula: see text]) rated 12 excerpts of the jazz recordings. They selected their preferred version from a pool of stimuli containing the original version, but also manipulations with artificially increased or reduced asynchronies. Stimuli with reduced asynchronies smaller than 19 ms were preferred by the listeners over the original or the fully quantised timing. This suggests that listeners endorse a 'tight-interlocked' jazz rhythm section, with asynchronies smaller than the perceptual threshold (temporal masking), but with natural timing variabilities that makes it distinguishable from a computer generated playback. PMID- 29238388 TI - What Do Transgender Patients Teach Us About Idiopathic Intracranial Hypertension? AB - Idiopathic intracranial hypertension (IIH), a condition of raised intracranial pressure, is characterised by headaches and visual disturbances. Its pathogenesis is currently unknown; however, dysregulation of androgens may be implicated. Here, the authors present a case of a 22-year-old patient undergoing female-to male (FTM) gender reassignment who developed IIH shortly after commencing testosterone therapy. This interesting case presents the possibility of androgens having a pathogenic role in IIH. PMID- 29238389 TI - The Role of Physical Activity on Mood State and Functional Skills of Elderly Women. AB - Introduction: Ageing is associated with several physical, psychological and behavioral changes. These changes are closely related with global health and functional capacity in the elderly. Mood disturbances are common among the elderly and may significantly increase apathy, resulting in decreased habitual physical activity levels. Materials and Methods: The purpose of this cross sectional study was to evaluate the mood state and functional motor capacities of elderly women engaged in a public physical activity program in Brazil and compare them with physically inactive elderly. Thirty elderly women were included in the study and categorized into two groups: physically active group, composed of participants enrolled on a public physical activity program (n = 16, 69+/-5 years) and physically inactive group (n = 14, 68+/-4 years). Total mood disturbance was assessed using the Profile of Mood States, whereas functional motor capacity was evaluated with the Sitting and Rising test. Independent t test and Mann-Whitney U] were used to compare groups. Results: The physically active group had lower total mood disturbance (p=0.02), confusion (p<0.01), tension (p<0.01), hostility (p=0.05) and fatigue (p=0.01) compared to the physically inactive group. There were no group differences regarding vigor, depression and sitting and rising performance (p>0.05). Conclusion: Lack of difference in functional motor capacity between the physically active and inactive elderly may be explained by the absence of exercise systematization in these programs. PMID- 29238390 TI - Modulatory Effect of Association of Brain Stimulation by Light and Binaural Beats in Specific Brain Waves. AB - Introduction: One of the positive effects of brain stimulation is interhemispheric modulation as shown in some scientific studies. This study examined if a type of noninvasive stimulation using binaural beats with led lights and sound would show different modulatory effects upon Alfa and SMR brain waves of elderlies and children with some disease types. Subjects: The sample included 75 individuals of both genders, being, randomly, divided in 6 groups. Groups were named elderly without dementia diagnosis (EWD), n=15, 76+/-8 years, elderly diagnosed with Parkinson's disease (EDP), n=15, 72+/-7 years, elderly diagnosed with Alzheimer's disease (EDA), n=15, 81+/-6 years. The other groups were named children with Autism (CA), n=10, 11+/-4 years, children with Intellectual Impairment (CII), n=10, 12 +/-5 years and children with normal cognitive development (CND), n=10, 11+/-4 years. Instruments and procedure: Instruments were the Mini Mental State Examination Test (MMSE), EEG-Neurocomputer instrument for brain waves registration, brain stimulator, Digit Span Test and a Protocol for working memory training. Data collection followed a pre and post conjugated stimulation version. Results: The results of the inferential statistics showed that the stimulation protocol had different effects on Alpha and SMR brain waves of the patients. Also, indicated gains in memory functions, for both, children and elderlies as related to gains in brain waves modulation. Conclusion: The results may receive and provide support to a range of studies examining brain modulation and synaptic plasticity. Also, it was emphasized in the results discussion that there was the possibility of the technique serving as an accessory instrument to alternative brain therapies. PMID- 29238391 TI - Functional Impairment and Painful Physical Symptoms in Patients with Major Depressive Disorder Treated with Antidepressants: Real-World Evidence from the Middle East. AB - Background: The Global Burden of Disease 2010 study reported the relative size of major depressive disorder (MDD) burden to be greater in the Middle East and North Africa than anywhere else. However, little research has been carried out to examine the comparative effectiveness of antidepressants in this region. Objective: To assess and compare functioning levels in Middle Eastern patients with MDD treated with either duloxetine or a selective serotonin reuptake inhibitor (SSRI), and to examine the impacts of depression-related pain on functioning by the type of treatment. Method: This post-hoc analysis, which focused on Middle Eastern patients, used data from a 6-month prospective observational study that included 1,549 MDD patients without sexual dysfunction. Levels of functional impairment and depression-related pain were assessed using the Sheehan Disability Scale (SDS) and the modified Somatic Symptom Inventory, respectively. A mixed model with repeated measures (MMRM) was employed. Results: The mean age of the patients was 37.3 (SD=8.4) years, and 34.6% were female. Patient functioning was, on average, moderately impaired at baseline, but improved substantially during follow-up in both the duloxetine (n=152) and the SSRI (n=123) cohorts. The MMRM results showed a lower level of functional impairment at 24 weeks in the duloxetine cohort than in the SSRI cohort (p<0.001). Pain severity at baseline was positively associated with functional impairment during follow-up only in the SSRI cohort (p=0.003). Conclusion: Duloxetine-treated MDD patients achieved better functioning than SSRI-treated patients. This treatment difference was partly driven by depression-related pain. PMID- 29238392 TI - Risk for Depression, Burnout and Low Quality of Life Among Personnel of a University Hospital in Italy is a Consequence of the Impact One Economic Crisis in the Welfare System? AB - Background: Research literature suggests that burnout, depression, and a low mental quality of life (QOL) are common among health care workers. Economic crisis might have increased the burden of burnout, depression and low QOL in health care workers. Objectives: To identify depression risk, burnout levels, and quality of life in a sample of workers of an Italian university hospital. Method: Cross sectional study with comparison with two community surveys database results (n = 2000 and 1500, respectively). Overall, 522 workers accepted to take part in the study, representing a 78% response rate (out of 669 individuals). Results: The frequency of positivity at the screener for Major Depressive Disorder among health care workers was more than double than that in the standardized community sample (33.3% vs 14.1%, p<0.0001). All professionals, except the administrative staff and technicians (i.e. those who do not have contact with patients), showed a statistically higher frequency of positivity for depressive episodes compared to the controls. Among the medical staff, the highest risk was found in the surgeon units, while the lowest one was in the laboratories. Surgeons also were those most exposed to high risk of burnout, as measured by the Maslach Burnout Inventory. Conclusion: Since burnout is linked to patient safety and quality of patient care, and contribute to medical errors, dedicated interventions aimed at reducing poor mental health and low quality of life in medical staff are indicated. PMID- 29238393 TI - Influence of Severe Carotid Stenosis on Cognition, Depressive Symptoms and Quality of Life. AB - Background: Carotid artery disease is not just a causal risk factor of ischemic stroke, but may predispose patients to depressive symptoms and low health related quality of life (HRQoL). Objectives: The objectives of the present study were to assess the association between severe carotid artery stenosis (CAS) and cognitive impairment, frequency of depressive symptoms and status of HRQoL. Methods: Cross sectional study involved 55 patients with severe CAS and 54 patients with lower extremity peripheral artery disease (PAD). Cognitive impairment was assessed using Montreal Cognitive Assessment Scale (MoCA), depressive symptoms - PHQ-9 scale. HRQoL was measured using Medical Outcome Survey Short Form version 2 (SF 36v2). Results: Median MoCA score 24 [23;26] was significantly lower in patients with severe CAS than in patients with PAD - 26 [25-28],(p=0.005; effect size r=0.3). There was no statistically significant difference of median PHQ-9 scores the in CAS group (median PHQ-9 score 4.0 [5]) and in the PAD group (median PHQ-9 score 5.5 [7]), (p=0.08, effect size r=0.18). Mean SF-36v2 scores were similar in CAS and PAD groups except for bodily pain (p=0.001, Cohen's d value = 0.77) and vitality (p=0.02, Cohen's d value = 0.49). Conclusion: In summary, our findings indicate that severe CAS could play a role in cognitive decline. Further studies should be conducted using larger patient cohorts without ischemic brain lesions and with balanced vascular risk profiles to investigate impact of CAS on cognition. There was no association between severe CAS and depressive symptoms in the present study. As patients with severe CAS did not exhibit physical symptoms, HRQoL was better for those patients than for patients with lower extremity PAD. PMID- 29238394 TI - Physical Exercise As Stabilizer For Alzheimer'S Disease Cognitive Decline: Current Status. AB - Introduction: Mental health decline is one of the main responsible factors for augments in health care costs, and diagnosis of Alzheimer's disease (AD). Some studies stated physical exercise is useful for reduction in cognitive decline and AD. Moreover, a recent review argued that evidence are scarce due to few studies published and lack of configuration information of exercise protocol, such as intensity and duration of exercise, number of sessions and other relevant data, to allow appropriate assessment. Materials and Methods: Here, we discussed the possible confounders or factors responsible for these differences and possible neurophysiological mechanisms. Results: Most studies revealed a possible positive association between physical exercise and cognitive assessments. There are inconsistencies in studies design responsible for varying use of cognitive assessments and different assessments of fitness. However, these studies do not fail to provide evidence about the benefits of exercise, but fail to make it possible because of the lack of dose-response information in AD patients. Physical exercise of moderate intensity should be considered as standard recommendation to reduce cognitive decline, probably due to the improvement in neurodegenerative mechanisms, and the increase in neuroplastic and neuroprotective neurotrophic factors. Conclusion: Therefore, it is suggested that physical exercise is an important neuroprotective modulator, bringing significant control of the disease and amplifying brain functions. PMID- 29238395 TI - Cognitive Dysfunction in Asian Patients with Depression (CogDAD): A Cross Sectional Study. AB - Background: Cognitive dysfunction is a predominant symptom of Major Depressive Disorder (MDD), contributing to functional impairment. Objective: The primary objective of this study was to assess and describe perceived cognitive dysfunction amongst Asian patients diagnosed with MDD. The secondary objective was to explore the associations between depression severity, perceived cognitive dysfunction and functional disability. Methods: This was a multi-country, multi centre, cross-sectional study. Adults with a current episode of MDD were recruited from 9 university/general hospital clinics in Asia. During a single study visit, psychiatrists assessed depression severity (Clinical Global Impression-Severity, CGI-S); patients completed questionnaires assessing depression severity (Patient Health Questionnaire-9 items, PHQ-9), perceived cognitive dysfunction (Perceived Deficit Questionnaire-Depression, PDQ-D) and functional disability (Sheehan Disability Scale, SDS). Results: Patients (n=664), predominantly women (66.3%), were aged 46.5+/-12.5 years, lived in urban areas (81.3%) and were employed (84.6%). 51.5% of patients were having their first depressive episode; 86.7% were receiving treatment; 82.2% had a current episode duration >8 weeks. Patients had mild-to-moderate depression (CGI-S=3.3+/-1.0; PHQ 9=11.3+/-6.9). Patients reported perceived cognitive dysfunction (PDQ-D=22.6+/ 16.2) and functional disability (SDS=11.3+/-7.9). PHQ-9, PDQ-D and SDS were moderately-to-highly correlated (PHQ-9 and SDS: r=0.72; PHQ-9 and PDQ-D: r=0.69; PDQ-D and SDS, r=0.63). ANCOVA showed that after controlling for patient-reported depression severity (PHQ-9), perceived cognitive dysfunction (PDQ-D) was significantly associated with functional disability (SDS) (p<0.001). Conclusions: Asian patients with MDD reported perceived cognitive dysfunction. There is a need for physicians to evaluate cognitive dysfunction in the clinical setting in order to reach treatment goals, including functional recovery beyond remission of mood symptoms. PMID- 29238396 TI - "VelaMente?!" - Sailin in a Crew to Improve Self-Efficacy in People with Psychosocial Disabilities: A Randomized Controlled Trial. AB - Introduction: It has been proposed that sailing can improve quality of life, personal and social skills of people with severe psychosocial disabilities. This study aimed to assess the efficacy of a psychosocial rehabilitative intervention focused on sailing on quality of life, self-efficacy and sense of coherence in people with severe psychosocial disabilities. Methods: The study was a randomized, with parallel groups, waiting-list controlled trial. Participants were 51 people with severe psychosocial disabilities. The intervention was a structured course to learn sailing in a crew lasting three months. A randomized group began the sailing course immediately after a pre-treatment assessment; the waitlist group began the sailing course after a three months period of treatments as usual. Participants were assessed before and after the sailing course, or the waiting list period, on the General Self-Efficacy scale (GSES), Sense Of Coherence scale (SOC) and Health Survey-short form (SF-12). Results: Self efficacy significantly increased after the sailing course and decreased after treatment as usual (p=0.015). Sense of coherence and the levels of quality of life tended to improve after the sailing course, albeit below levels of statistical significance. Conclusion: When compared to more traditional psychosocial rehabilitative activities, an intervention focused on sailing in a crew positively impacts the sense of coherence and the levels of quality of life and significantly improves self-efficacy of people with severe psychosocial disabilities. Further longitudinal research is required. PMID- 29238397 TI - A method to generate the surface cell layer of the 3D virtual shoot apex from apical initials. AB - Background: The development of cell pattern in the surface cell layer of the shoot apex can be investigated in vivo by use of a time-lapse confocal images, showing naked meristem in 3D in successive times. However, how this layer is originated from apical initials and develops as a result of growth and divisions of their descendants, remains unknown. This is an open area for computer modelling. A method to generate the surface cell layer is presented on the example of the 3D paraboloidal shoot apical dome. In the used model the layer originates from three apical initials that meet at the dome summit and develops through growth and cell divisions under the isotropic surface growth, defined by the growth tensor. The cells, which are described by polyhedrons, divide anticlinally with the smallest division plane that passes depending on the used mode through the cell center, or the point found randomly near this center. The formation of the surface cell pattern is described with the attention being paid to activity of the apical initials and fates of their descendants. Results: The computer generated surface layer that included about 350 cells required about 1200 divisions of the apical initials and their derivatives. The derivatives were arranged into three more or less equal clonal sectors composed of cellular clones at different age. Each apical initial renewed itself 7-8 times to produce the sector. In the shape and location and the cellular clones the following divisions of the initial were manifested. The application of the random factor resulted in more realistic cell pattern in comparison to the pure mode. The cell divisions were analyzed statistically on the top view. When all of the division walls were considered, their angular distribution was uniform, whereas in the distribution that was limited to apical initials only, some preferences related to their arrangement at the dome summit were observed. Conclusions: The realistic surface cell pattern was obtained. The present method is a useful tool to generate surface cell layer, study activity of initial cells and their derivatives, and how cell expansion and division are coordinated during growth. We expect its further application to clarify the question of a number and permanence or impermanence of initial cells, and possible relationship between their shape and oriented divisions, both on the ground of the growth tensor approach. PMID- 29238398 TI - Description of olive morphological parameters by using open access software. AB - Background: The morphological analysis of olive leaves, fruits and endocarps may represent an efficient tool for the characterization and discrimination of cultivars and the establishment of relationships among them. In recent years, much attention has been focused on the application of molecular markers, due to their high diagnostic efficiency and independence from environmental and phenological variables. Results: In this study, we present a semi-automatic methodology of detecting various morphological parameters. With the aid of computing and image analysis tools, we created semi-automatic algorithms applying intuitive mathematical descriptors that quantify many fruit, leaf and endocarp morphological features. In particular, we examined quantitative and qualitative characters such as size, shape, symmetry, contour roughness and presence of additional structures such as nipple, petiole, endocarp surface roughness, etc.. Conclusion: We illustrate the performance and the applicability of our approach on Greek olive cultivars; on sets of images from fruits, leaves and endocarps. In addition, the proposed methodology was also applied for the description of other crop species morphologies such as tomato, grapevine and pear. This allows us to describe crop morphologies efficiently and robustly in a semi-automated way. PMID- 29238399 TI - Phylogeny reconstruction based on the length distribution of k-mismatch common substrings. AB - Background: Various approaches to alignment-free sequence comparison are based on the length of exact or inexact word matches between pairs of input sequences. Haubold et al. (J Comput Biol 16:1487-1500, 2009) showed how the average number of substitutions per position between two DNA sequences can be estimated based on the average length of exact common substrings. Results: In this paper, we study the length distribution of k-mismatch common substrings between two sequences. We show that the number of substitutions per position can be accurately estimated from the position of a local maximum in the length distribution of their k mismatch common substrings. PMID- 29238400 TI - Relationship between Alexithymia and latent trigger points in the upper Trapezius. AB - Background: Latent trigger points (LTrPs) can be activated by future events, leading to pain. Few studies have reported LTrP risk factors. It has been suggested that alexithymia is associated with myofascial pain and diminished awareness of physical sensation. This study was designed to evaluate the relation between alexithymia and LTrPs found the upper trapezius of healthy individuals. Methods: The correlation between LTrPs and alexithymia, and between LTrPs and depression was analyzed in 160 healthy participants (80 male, mean age: 40.5 years [20 to 66 years]). Each participant was evaluated for potential LTrPs by careful manual examination and completed the Toronto Alexithymia Scale-20 (TAS 20) and the Beck Depression Inventory (BDI) to assess potential alexithymia and depressive symptoms, respectively. Results: LTrPs were observed in the upper trapezius of 76 participants (47.5%). TAS-20 scores were significantly higher in subjects with LTrPs than without LTrPs (p < 0.001); in contrast, there was no significant BDI score difference between these groups (p = 0.451). The LTrP risk for alexithymia was 2.74 (95% confidence interval [95% CI]: 2.10-3.58). There was no correlation between the TAS-20 and BDI scores (correlation coefficient: 0.04). Significant risk factors associated with LTrPs included the TAS-20 score (odds ratio [OR]: 1.11, 95% CI: 1.07-1.15) and age (OR: 1.05, 95% CI: 1.01-1.09). Conclusions: Alexithymia was associated with LTrPs in the upper trapezius of healthy individuals, suggesting that it may serve as a useful predictive factor. Trial registration: UMIN000027468. Registered 23 May 2017(retrospectively registered). PMID- 29238401 TI - Health needs of older populations affected by humanitarian crises in low- and middle-income countries: a systematic review. AB - Background: The combination of global demographic changes and a growing number of humanitarian crises in middle-income countries that have a higher life expectancy has led to an increase in the number of older populations affected by humanitarian crises. The aim of this review was to systematically examine evidence on the health needs of older populations in humanitarian crises, including both armed conflicts and natural disasters, in low- and middle-income countries (LMICs). Methods: A systematic review methodology was used. The search strategy used terms related to older populations and humanitarian crises in LMICs. Five bibliographic databases were used, along with relevant grey literature sources. Descriptive analysis was used, and a quality assessment conducted using the Newcastle-Ottawa Scale and CASP instruments. Results: A total of 36 studies were eligible for review. The majority of the studies were cross sectional, three were cohort studies, and four used qualitative methodologies. The main health outcomes were mental health, physical health, functioning, and nutrition. Vulnerability factors included older age, female gender, being widowed, increased exposure to traumatic events, prior mental health problems, low income and education, and rural residency. Ten studies addressed the responsiveness of health systems and access to such services. The quality of the included studies was generally low. Conclusions: There is an urgent need to strengthen the evidence base on the health needs of older populations in humanitarian crises. PMID- 29238402 TI - Expressing accessory proteins in cellulolytic Yarrowia lipolytica to improve the conversion yield of recalcitrant cellulose. AB - Background: A recently constructed cellulolytic Yarrowia lipolytica is able to grow efficiently on an industrial organosolv cellulose pulp, but shows limited ability to degrade crystalline cellulose. In this work, we have further engineered this strain, adding accessory proteins xylanase II (XYNII), lytic polysaccharide monooxygenase (LPMO), and swollenin (SWO) from Trichoderma reesei in order to enhance the degradation of recalcitrant substrate. Results: The production of EG I was enhanced using a promoter engineering strategy. This provided a new cellulolytic Y. lipolytica strain, which compared to the parent strain, exhibited higher hydrolytic activity on different cellulosic substrates. Furthermore, three accessory proteins, TrXYNII, TrLPMOA and TrSWO, were individually expressed in cellulolytic and non-cellulolytic Y. lipolytica. The amount of rhTrXYNII and rhTrLPMOA secreted by non-cellulolytic Y. lipolytica in YTD medium during batch cultivation in flasks was approximately 62 and 52 mg/L, respectively. The purified rhTrXYNII showed a specific activity of 532 U/mg protein on beechwood xylan, while rhTrLPMOA exhibited a specific activity of 14.4 U/g-protein when using the Amplex Red/horseradish peroxidase assay. Characterization of rhTrLPMOA revealed that this protein displays broad specificity against beta-(1,4)-linked glucans, but is inactive on xylan. Further studies showed that the presence of TrLPMOA synergistically enhanced enzymatic hydrolysis of cellulose by cellulases, while TrSWO1 boosted cellulose hydrolysis only when it was applied before the action of cellulases. The presence of rTrXYNII enhanced enzymatic hydrolysis of an industrial cellulose pulp and of wheat straw. Co-expressing TrXYNII and TrLPMOA in cellulolytic Y. lipolytica with enhanced EG I production procured a novel engineered Y. lipolytica strain that displayed enhanced ability to degrade both amorphous (CIMV-cellulose) and recalcitrant crystalline cellulose in complex biomass (wheat straw) by 16 and 90%, respectively. Conclusions: This study has provided a potent cellulose degrading Y. lipolytica strain that co-expresses a core set of cellulolytic enzymes and some accessory proteins. Results reveal that the tuning of cellulase production and the production of accessory proteins leads to optimized performance. Accordingly, the beneficial effect of accessory proteins for cellulase-mediated degradation of cellulose is underlined, especially when crystalline cellulose and complex biomass are used as substrates. Findings specifically underline the benefits and specific properties of swollenin. Although in our study swollenin clearly promoted cellulase action, its use requires process redesign to accommodate its specific mode of action. PMID- 29238403 TI - Mosaicism for structural non-centromeric autosomal rearrangement in prenatal diagnoses: evidence for sex-specific selection against chromosomal abnormalities. AB - Background: Mosaicism for chromosome rearrangements is common in preimplantation diagnoses, yet is rare in prenatal diagnoses as well as in other groups of patients referred to cytogenetic testing. Consequently, there is a lack of detailed studies on this kind of mosaicism in all groups of patients. Previous reports have identified a deficit of males among asymptomatic carriers of N/unbalanced Rea. Three mechanisms were proposed for explaining this phenomenon, including a high instability in the early female embryonic development, a male specific selection against abnormal cells in the early embryo development, or a high intrauterine lethality of male carriers. To address these possibilities, we have performed a meta-analysis of male-to-female ratio (sex ratio, SR) in prenatally diagnosed and in spontaneously aborted carriers of mosaic Rea. Results: One hundred and twenty one prenatally detected cases of normal cell line/autosome rearrangement mosaicism (N/Rea) with known carriers' sex were identified from the literature. Carriers of N/unbalanced Rea presented with 38 abnormal and 28 normal/apparently normal outcomes while carriers of N/balanced Rea presented with 24 normal and 3 abnormal outcomes. 58% of carriers of N/unbalanced Rea with an abnormal outcome displayed a high proportion (> 50%) of amniocytes with the abnormality compared to 25% of carriers with normal/apparently normal outcome. More female carriers of N/unbalanced Rea were identified with an abnormal outcome (15 M/23F) in contrast to a notable male predominance (18 M/10F) among those with normal outcome. Additionally, among spontaneously aborted carriers of N/unbalanced Rea, there was a strong female predominance (7 M/23F). Conclusion: Previous reports have identified a deficit of male among asymptomatic carriers of N/unbalanced Rea. The current data suggests a male-specific selection against chromosomal abnormalities. PMID- 29238404 TI - PMLB: a large benchmark suite for machine learning evaluation and comparison. AB - Background: The selection, development, or comparison of machine learning methods in data mining can be a difficult task based on the target problem and goals of a particular study. Numerous publicly available real-world and simulated benchmark datasets have emerged from different sources, but their organization and adoption as standards have been inconsistent. As such, selecting and curating specific benchmarks remains an unnecessary burden on machine learning practitioners and data scientists. Results: The present study introduces an accessible, curated, and developing public benchmark resource to facilitate identification of the strengths and weaknesses of different machine learning methodologies. We compare meta-features among the current set of benchmark datasets in this resource to characterize the diversity of available data. Finally, we apply a number of established machine learning methods to the entire benchmark suite and analyze how datasets and algorithms cluster in terms of performance. From this study, we find that existing benchmarks lack the diversity to properly benchmark machine learning algorithms, and there are several gaps in benchmarking problems that still need to be considered. Conclusions: This work represents another important step towards understanding the limitations of popular benchmarking suites and developing a resource that connects existing benchmarking standards to more diverse and efficient standards in the future. PMID- 29238406 TI - Real-time field sports scene classification using colour and frequency space decompositions. AB - This paper presents a novel approach to recognize a scene presented in an image with specific application to scene classification in field sports video. We propose different variants of the algorithm ranging from bags of visual words to the simplified real-time implementation, that takes only the most important areas of similar colour into account. All the variants feature similar accuracy which is comparable to very well-known image indexing techniques like SIFT or HoGs. For the comparison purposes, we also developed a specific database which is now available online. The algorithm is suitable in scene recognition task thanks to changes in speed and robustness to the image resolution, thus, making it a good candidate in real-time video indexing systems. The procedure features high simplicity thanks to the fact that it is based on the very well-known Fourier transform. PMID- 29238405 TI - The effect of a running task on muscle shear elastic modulus of posterior lower leg. AB - Background: Medial tibial stress syndrome (MTSS) is one of the most common causes of exercise-related leg pain in runners. Because stopping training due to pain from MTSS could decrease the athlete's competitiveness, it is necessary to construct MTSS prevention and treatment programs. However, the effect of running, which is believed to cause MTSS, on shear elastic modulus of the posterior lower leg is unclear. Therefore, the purpose of this study was to investigate the effect of 30 min of running on shear elastic modulus of the posterior lower leg in healthy subjects. Methods: Twenty healthy males volunteered to participate in this study (age, 20.9 +/- 0.6 y; height, 169.6 +/- 4.5 cm; weight, 62.6 +/- 5.2 kg). The shear elastic modulus of the posterior lower leg was measured using ultrasonic shear wave elastography before and immediately after a 30-min running task. Results: Shear elastic moduli of the flexor digitorum longus and tibialis posterior were significantly increased after 30 min running task. However, there were no significant changes in shear elastic moduli of the lateral gastrocnemius, medial gastrocnemius, peroneus longus and peroneus brevis. Conclusion: The results suggested that the increases in shear elastic moduli of flexor digitorum longus and tibialis posterior after running could be a risk factor for running related MTSS development. PMID- 29238407 TI - Scientists' Understandings of Risk of Nanomaterials: Disciplinary Culture Through the Ethnographic Lens. AB - There is a growing literature on how scientific experts understand risk of technology related to their disciplinary field. Previous research shows that experts have different understandings and perspectives depending on disciplinary culture, organizational affiliation, and how they more broadly look upon their role in society. From a practice-based perspective on risk management as a bottom up activity embedded in work place routines and everyday interactions, we look, through an ethnographic lens, at the laboratory life of nanoscientists. In the USA and Sweden, two categories of nanoscientists have been studied: upstream scientists who are mainly electrical and physical engineers and downstream scientists who are toxicologists, often with a more multidisciplinary background, including physics, chemistry, biology, and engineering. The results show that although the two groups of scientists share the same norms of appropriate laboratory conduct to promote safety and good science practice, they have very different perspectives on risk with nanomaterials. Upstream scientists downplay risk; they emphasize the innovative potential of the new materials to which they express an affectionate and personalized stance. The downstream scientists, instead, focus on the uncertainties and unpredictability of nanomaterials and they see some materials as potentially highly dangerous. The results highlight the ambiguous and complex role of scientific experts in policy processes about the risk and regulation of nanotechnology. PMID- 29238408 TI - Nanoparticle Risks and Identification in a World Where Small Things Do Not Survive. AB - The risks of materials containing nanoscale components are in the public debate discussed as if a manufactured nanomaterial will remain invariant with time and environmental exposure, and as if we can identify its risks by the risks of its nanoscale components. Additionally, the debate on mitigation of specific nanorisks by new legislation implicitly assumes that we can have full and accurate knowledge of the distribution and composition of nanomaterials in a product or the environment. In this discussion note, I argue that physical laws intrinsic to the behavior of nanoparticles both lead to limits on the risks to which we are likely exposed and on our technological ability to verify compliance with new regulations. My conclusion is that governmental actors should be careful not to overreact in their response to a technological revolution that only in few areas is likely to lead to increased public exposure, and in doing so using legal measures for which compliance cannot be monitored. PMID- 29238409 TI - Safe-by-Design: from Safety to Responsibility. AB - Safe-by-design (SbD) aims at addressing safety issues already during the R&D and design phases of new technologies. SbD has increasingly become popular in the last few years for addressing the risks of emerging technologies like nanotechnology and synthetic biology. We ask to what extent SbD approaches can deal with uncertainty, in particular with indeterminacy, i.e., the fact that the actual safety of a technology depends on the behavior of actors in the value chain like users and operators. We argue that while indeterminacy may be approached by designing out users as much as possible in attaining safety, this is often not a good strategy. It will not only make it more difficult to deal with unexpected risks; it also misses out on the resources that users (and others) can bring for achieving safety, and it is undemocratic. We argue that rather than directly designing for safety, it is better to design for the responsibility for safety, i.e., designers should think where the responsibility for safety is best situated and design technologies accordingly. We propose some heuristics that can be used in deciding how to share and distribute responsibility for safety through design. PMID- 29238410 TI - Saved by Design? The Case of Legal Protection by Design. AB - This discussion note does three things: (1) it explains the notion of 'legal protection by design' in relation to data-driven infrastructures that form the backbone of our new 'onlife world', (2) it explains how the notion of 'by design' relates to the relational nature of what an environment affords its inhabitants, referring to the work of James Gibson, and (3) it explains how this affects our understanding of human capabilities in relation to the affordances of changing environments. Finally, this brief note argues that 'safer by design' in the case of nanotechnology will require legal protection by design to make sure that human capabilities are reinvented and sustained in nano-technical environments. PMID- 29238411 TI - Ex-vivo Smear Layer Removal Efficacy of Two Activated Irrigation Techniques After Reciprocating Instrumentation in Curved Canals. AB - Introduction: This study aimed to compare the effectiveness of two activated irrigation techniques in removing the smear layer after single-file reciprocating instrumentation in curved canals. Materials and Methods: Sixty distobuccal roots of maxillary molars were standardized to create a closed system, and then instrumented using WaveOne Primary (Dentsply Maillefer, Ballaigues, Switzerland) instruments. Fifty-four specimens were randomly distributed into 3 groups for final irrigation: Non-activated irrigation, passive ultrasonic irrigation (PUI), and EndoActivator (EA;Dentsply Maillefer, Tulsa, USA) irrigation. All specimens received 3 mL of 17% EDTA for 1 minute, followed by irrigation with 6 mL of 2.5% NaOCl. The apical, middle and cervical thirds of the specimens were analyzed using scanning electronic microscopy (SEM), and the amount of remaining smear layer on the canal walls was rated by three examiners using a five-category scoring system. Kendall's concordance coefficient was used to assess inter-rater agreement. Kruskal-Wallis and Mann-Whitney (Bonferroni) tests were used to compare the scores. Results: Kendall's concordance coefficient was >= 0.7, indicating an excellent level of agreement between the raters. No statistically significant difference in irrigation techniques efficacy for removal of the smear layer (p=0.061) was found for the apical third. The scores attributed to the specimens irrigated with the EA system were significantly lower than those of the other groups in the cervical and middle thirds (p< 0.05). Conclusions: The efficacy of the EA system in removing the smear layer in the cervical and middle thirds of root canals instrumented with reciprocating motion was significantly higher than that of either PUI or non-activated irrigation. Both EA and PUI performed similarly in apical third. PMID- 29238412 TI - Oral Leiomyoma in an Adult Male: A Case Report. AB - Introduction: Oral leiomyomas are rare, benign neoplasms of smooth muscle origin, presenting as a solitary, asymptomatic, nodular mass. Case Presentation: Here we present the case of a 54-year-old male with a lesion in the midline of his hard palate, which was diagnosed as a localized benign leiomyoma, along with a review of the recent literature. Discussion: Diagnosis of a leiomyoma must be based on the histopathological assessment of tissue as the clinical appearance is non specific. The peak prevalence of head and neck leiomyoma is observed in the 4th and 5th decade of life with uncertain gender predilection. Histological features include interlacing fascicles of smooth muscle small cells with eosinophilic cytoplasm. Complete excision is usually curative and recurrence is rare. Conclusion: Due to their rare nature, it is important that cases of oral leiomyoma can be reported in the literature to improve our understanding of this entity. PMID- 29238413 TI - Remineralization Strategies in Oral Hygiene: A Position Paper of Italian Society of Oral Hygiene Sciences-S.I.S.I.O. Working Group. AB - Background/Objective: The clinical conditions that lead to an alteration of the enamel structure are numerous. The diet high in sugars and acidifying substances, psychological stress that triggers parafunctional behaviors, the reduced intake of fiber-rich foods or alkalizing substances, together with other factors, contribute to demineralization of the tooth enamel. Dental mineralizing products on the current market are distinguished according to the dosage form, the active ingredient, the release technology, clinical indications and patient choice. Currently, it is necessary to propose to oral health professionals a guide to orient themselves in this chaotic choice, in order to prefer the most effective product for their own clinical target. Methods: Italian Society of Oral Hygiene Sciences-S.I.S.I.O. is one of the leading scientific Italian societies representing those dental hygienists working with high-quality standards and in agreement with scientific evidence: in the last year, the SISIO working group has carried out a study focused on remineralizing agents in dentistry, in order to give an authoritative point of view to indicate a guideline in the decision process of the choice of a remineralizing agent. We will report the results pointed out from the last consensus meeting in 2017. Results: We have reported the good the bad and the ugly have been discussed in a critical discussion of such topic. Conclusion: The SISIO experience has been reported in this position paper with the aim to serve as a useful aid in the daily choice of the clinical steps to perform, when dental professionals need to treat demineralized teeth. PMID- 29238415 TI - Facial and Orbital Fractures: A Fifteen Years Retrospective Evaluation of North East Sicily Treated Patients. AB - Background: Orbital fractures are classified as diseases usually related to common midface trauma. It represents the most challenging treatment due to the complex anatomy, physiology, and aesthetic role. A midface trauma involves also the zygomatic complex and the nose, however the orbit fracture seems to be a more frequent disease due to its anatomical features. Objective: The purpose of this work is to retrospectively evaluate and record the frequency of the midfacial traumas and orbital fractures observed in the North Eastern Sicily. The results of the present data may be useful for the clinicians in order to recognize the kind of fracture just from the first general visit having a quick diagnosis and management. Methods: In the years between 2001 and 2016, about 1200 patients with midfacial trauma and about 100 patients involving the orbital floor have been evaluated. All those patients underwent the surgical fracture reduction and a CT scan follow up control at one month, three months, six months and one year. Results: Data showed high percentage of orbital floor, nose and mandibular body and ramus fractures; moreover the most frequent causes of fractures seem to be related to motor vehicle accident, followed by assaults, work and fall. Conclusion: The results have highlighted the changing trends in the causes of facial injuries, particularly the increasing incidence of assaults and the falling incidence of motor vehicle accidents in developed countries. The quick diagnosis and management proved fundamental for the successful treatment. Clinicians should be able to recognize the first symptoms in order to avoid possible complications. PMID- 29238416 TI - Oral Health-Related Quality of Life Appraised by OHIP-14 Between Urban and Rural Areas in Kutai Kartanegara Regency, Indonesia: Pilot Pathfinder Survey. AB - Background: Health-Related Quality of Life (HRQoL) periphrastically has a significant impact on oral health. A recent study has shown the significant facts of the oral health-related quality of life based on many factors such as individual, social status, household management, daily habits, and local factors. The differences in the oral health status possibly occur in between countries, different regions, and topographical areas frequently and indirectly contributing to oral health status. Objective: The objective is to evaluate the difference of Oral Health-Related Quality of Life (OHRQoL) and to assess the main affected dimension between rural and urban areas in Kutai Kartanegara Regency. Methods: This study uses pilot pathfinder design. The respondents comprised of 214 adults who were elder than 18 years and were randomly selected from urban and rural areas in Kutai Kartanegara Regency, Indonesia. The data were collected by 103 samples from the rural area and 111 respondents from the urban area. Oral Health Impacts Profile (OHIP-14) has been translated to Bahasa (Indonesia version). OHIP 14 was used to assess the subjects' oral health-related impact. Shapiro-Wilk and Mann Whitney tests were used to analyze the data, and p-value was set at P < 0.05. Results: The mean OHIP scores in the urban and the rural areas were 25.4 and 28.8, respectively. The overall OHIP-14 score showed a significant statistical difference P= 0,009 (P < 0.05) between rural and urban area. Conclusion: This study illustrates that oral health-related quality of life in the urban area is better than in the rural area. Physical pain components of the OHRQoL are the major oral problems associated with both the areas. PMID- 29238414 TI - Oral Manifestations in Pediatric Patients with Coeliac Disease - A Review Article. AB - Background: Coeliac disease is a chronic enteropathy that remains a challenge for the clinician, due to its atypical manifestations and etiopathogenic complexity. Objective: This article intends to describe the oral characteristics of Coeliac Disease in children in order to facilitate their management in the dental office. Methods: A review of the literature was performed electronically in PubMed (PubMed Central, and MEDLINE) for articles published in English from 2000 to April of 2017. The article is also based on the authors' clinical experience with children with coeliac disease. The searched keywords were "coeliac disease ","oral manifestations ", "dental enamel defects", "recurrent aphthous stomatitis" and "oral aphthous ulcers". Results: There are some oral manifestations which are strictly related to coeliac disease: dental enamel defects, recurrent aphthous stomatitis, delayed tooth eruption, multiple caries, angular cheilitis, atrophic glossitis, dry mouth and burning tongue. Conclusion: The complete knowledge of the oral manifestations of coeliac disease can trigger an effective change in the quality of life of the patients with this disease. PMID- 29238417 TI - The Effect of Music Intervention on Dental Anxiety During Dental Extraction Procedure. AB - Background: In order to minimize the possibility of unsuccessful dental extraction procedure due to dental anxiety, there are several approaches that can be used, including music intervention. Objective: The objective of this research was to investigate the effectiveness of classical and religious Islamic music on reducing dental anxiety. Materials and methods: Two hundred and twenty-five muslim participants (105 males, 120 females) were recruited for this study and randomly assigned to three groups: classical music group, religious Islamic music group, and the group with no music intervention, equally in numbers. Participant's blood pressure (BP) and blood sample were taken prior to and after dental extraction to evaluate systolic and diastolic BP as well as nor-adrenaline plasma (NAP) level. All data were then analyzed by using t-test, ANOVA test, Mann Whitney and Kruskawallis test. Results: There was a decrease in NAP level in the religious music group (0.110 ng/mL) and the control group (0.013 ng/mL) when initial NAP level was compared to post extraction NAP level, whilst the classical music group showed an increase of 0.053 ng/mL. There were significant differences found between the religious Islamic music group and the classical music group (p = 0.041) as well as the control group (p = 0.028) for the difference between pre and post NAP level, of which the NAP level of the religious Islamic group participants were lower. Conclusion: Religious Islamic music was proven to be effective in reducing dental anxiety in Muslim participants compared to classical music. Despite, further evaluation in a more heterogenous population with various religious and cultural background is needed. PMID- 29238419 TI - Correlation Between Stress and Quality of Life Experienced by Caregivers: Perception of a Group of Healthcare Professionals. AB - Aim: This study aims to evaluate the relationship between perceived level of stress and quality of life of professionals working in Prompt Service Units in the city of Palmas, Tocantins. Methods: A cross-sectional study was performed among 164 professionals from Prompt Service Units. Stress levels were evaluated using the Perceived Stress Scale. The WHOQOL-bref was used to evaluate the perception of quality of life. Quantitative variables distribution was evaluated using Shapiro-Wilk's test. For the analyses of correlations among perceived level of stress, total quality of life score, and the physical health domain of the WHOQOL-bref, Pearson's correlation test was applied. The significance level adopted for this trial was 95%. The study was approved by the Committee of Ethics in Research with Human Beings. Results: When assessing the perceived level of stress with the total quality of life score, there was no significant correlation between those variables. However, there was an association between the perceived level of stress and the physical health domain of quality of life. Conclusion: Perceived quality of life was correlated with the physical health domain, and this result reinforces the importance of the facets that make up this area. PMID- 29238418 TI - The Effect of Scaling and Root Planning on Salivary TNF-alpha and IL-1alpha Concentrations in Patients with Chronic Periodontitis. AB - Objective: Periodontitis is one of the main diseases in the oral cavity that causes tooth loss. The host immune response and inflammatory factors have important role in periodontal tissue. The current study was done with the objective to determine the effect of scaling and root planning on the salivary concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-alpha (IL-1alpha). Methods: In this quasi-experimental clinical trial, 29 patients with chronic periodontitis and 29 healthy subjects without periodontitis were studied. Clinical examination findings and salivary TNF-alpha and IL-1alpha (using ELISA method) were compared before and after scaling, root planning. Results: Before starting treatment, salivary TNF-alpha and IL-1alpha concentrations were higher in healthy control group than in periodontitis group (P< 0.05). Non-surgical treatment increased the concentration of these two biomarkers in the saliva. However, increase in IL-1alpha concentration was not statistically significant (P= 0.056). There was a negative relationship between TNF-alpha and IL-1alpha levels with pocket depth and attachment loss (P< 0.05). Conclusion: Scaling and root planning improved periodontal disease indices and salivary TNF-alpha and IL 1alpha levels. PMID- 29238420 TI - Editorial: Methodological Approaches for Quantitative Nursing Research. PMID- 29238421 TI - Anchoring Vignettes in EQ-5D-5L Questionnaire: Validation of a New Instrument. AB - Background: Health Related Quality of Life (HRQoL) is an indicator of patient's physical, psychological and social life. HRQoL is influenced by experience, beliefs, perceptions and expectations, and measures subjective perspective of the patient himself. EQ-5D-5L and SF-12 questionnaires are validated instruments useful to measure HRQoL, increasingly administered in electronic formats. Objective: The main purpose is to evaluate the feasibility of anchoring vignettes for the EQ-5D-5L questionnaire, with the aim to improve intergroup comparability of responses among different subjects. A comparison with SF-12 questionnaire is carried out. Method: This is a cross-sectional study conducted at the ambulatories of cardiology of the University Hospital of Padova, in Italy. Thirty eight subjects with a diagnosis of cardiovascular disease or at risk of cardiovascular disease were enrolled. A factorial analysis has been performed to assess the convergent validity of EQ-5D-5L questionnaire compared to Sf-12. Moreover, a compound Hierarchical Ordered Probit (Chopit) model has been estimated to evaluate if the questionnaire form affects the subjective evaluation process in order to compare EQ-5D-5L with and without vignettes. Results: Correlation and factor analysis demonstrate that EQ_5D questionnaire is coherent with SF-12 in paper format. Chopit model estimation shows that questionnaire format does not affect the subjective question interpretation. Moreover, in a parametric model including vignettes, education attainment, disease severity, and gender are predictors of HRQoL status. Conclusion: The EQ-5D including vignettes in electronic format seems to be a valid tool to measure HRQoL as compared to EQ 5D without vignettes in paper format and to SF-12 questionnaire. PMID- 29238422 TI - Electronic Questionnaires Design and Implementation. AB - Background: Nursing and health care research are increasingly using e questionnaires and e-forms for data collection and survey conduction. The main reason lies in costs, time and data-entry errors containment, increased flexibility, functionality and usability. In spite of this growing usage, no specifc and comprehensive guidelines for designing and submitting e questionnaires have been produced so far. Objective: The aim of this review is to collect information on the current best practices, taking them from various fields of application. An evaluation of the efficacy of the single indication is provided. Method: A literature review of guidelines currently available on WebSM (Web Survey Methodology) about electronic questionnaire has been performed. Four search strings were used: "Electronic Questionnaire Design", "Electronic Questionnaire", "Online Questionnaire" and "Online survey". Articles' inclusion criteria were English language, relevant topic in relation to the aim of the research and the publication date from January 1998 to July 2014. Results: The review process led to identify 48 studies. The greater part of guidelines is reported for Web, and e-mail questionnaire, while a lack of indications emerges especially for app and e-questionnaires. Conclusion: Lack of guidelines on e questionnaires has been found, especially in health care research, increasing the risk of use of ineffective and expensive instruments; more research in this field is needed. PMID- 29238423 TI - An Epistemological View on Risk Exposure Assessment: A Case Study. AB - Background: Research in Health Risk Assessment is increasingly covering a preeminent role in health care studies. However, risk assessment faces the issue of properly measuring risk exposure. Objective: The aim of the study has been to tackle some methodological issues regarding the risk assessment analysis in the health field, giving more emphasis to a philosophical and epistemological approach in order to show the difficulties in adopting suitable exposure assessment techniques. Method: Here, we present a methodological review and a critical discussion of foreign body injuries articles in child population as a case study. A Medline, Econlite and CIS bibliographic search was conducted considering the term "foreign bodies" only in "children" and "risk". Only English papers are considered. Further research on CDC, CPSC, DGSANCO databases has been performed. Different approaches in risk assessment are reviewed using four case study papers with the purpose of pointing out their limitations. Result: Ten papers are retrieved though literature review reporting risk estimate of foreign bodies injuries in children. Conclusion: Considering that different variables affecting the risk of choking injuries, like intrinsic characteristic of a product or the intensity levels at which children are exposed, and then it seems very difficult to correctly evaluate risk of injuries. For this reason, we have argued for an epistemological and holistic approach toward risk assessment. PMID- 29238424 TI - High Agreement and High Prevalence: The Paradox of Cohen's Kappa. AB - Background: Cohen's Kappa is the most used agreement statistic in literature. However, under certain conditions, it is affected by a paradox which returns biased estimates of the statistic itself. Objective: The aim of the study is to provide sufficient information which allows the reader to make an informed choice of the correct agreement measure, by underlining some optimal properties of Gwet's AC1 in comparison to Cohen's Kappa, using a real data example. Method: During the process of literature review, we have asked a panel of three evaluators to come up with a judgment on the quality of 57 randomized controlled trials assigning a score to each trial using the Jadad scale. The quality was evaluated according to the following dimensions: adopted design, randomization unit, type of primary endpoint. With respect to each of the above described features, the agreement between the three evaluators has been calculated using Cohen's Kappa statistic and Gwet's AC1 statistic and, finally, the values have been compared with the observed agreement. Results: The values of the Cohen's Kappa statistic would lead to believe that the agreement levels for the variables Unit, Design and Primary Endpoints are totally unsatisfactory. The AC1 statistic, on the contrary, shows plausible values which are in line with the respective values of the observed concordance. Conclusion: We conclude that it would always be appropriate to adopt the AC1 statistic, thus bypassing any risk of incurring the paradox and drawing wrong conclusions about the results of agreement analysis. PMID- 29238425 TI - A Social Network Approach to the Estimation of Perceived Quality of Health Care. AB - Background: Measuring service quality aids health care providers to recognize specific and unmet needs of patients. Nevertheless, perceived quality of health care services (PQC) is often investigated with inadequate techniques which may lead to biased results. Objective: The aim of the present study is to develop a proof-of-concept for estimating the PQC using the scale-up estimator, with reference to a concrete assessment in patients of a major Oncology Hospital in Veneto (IOV). Results have then been compared with those collected by the Customer Relations Office (CRO) after the annual survey conducted with traditional questionnaire based techniques. Material and Methods: Seven hundred and eighty-three sets consisting of two questionnaires were handed out to IOV patients between 26 and 28 November 2012. The first questionnaire was the CRO annual one composed by 15 direct questions about the perception of quality satisfaction rate using a Likert scale. The second questionnaire was the scale-up (NSUM) one, composed by 20 indirect questions, 5 of which were reproducing the main target of CRO for estimating PQC. Results: The comparisons made over 299 sets of questionnaires showed differences between the two techniques. Network Scale-Up Method (NSUM) questionnaire seems to be able to produce lower estimates of PQC with respect to the CRO annual questionnaire. In some cases, the NSUM showed dissatisfaction rates which are 20-fold higher respect to CRO. Conclusion: NSUM could be a promising method for assessing the perceived quality of care. PMID- 29238426 TI - Wearable Devices for Caloric Intake Assessment: State of Art and Future Developments. AB - Background: The self-monitoring of caloric intake is becoming necessary as the number of pathologies related to eating increases. New wearable devices may help people to automatically record energy assumed in their meals. Objective: The present review collects the released articles about wearable devices or method for automatic caloric assessments. Method: A literature research has been performed with PubMed, Google Scholar, Scopus and ClinicalTrials.gov search engines, considering released articles regarding applications of wearable devices in eating environment, from 2005 onwards. Results: Several tools allow caloric assessment and food registration: wearable devices counting the number of bites ingested by the user, instruments detecting swallows and chewings, methods that analyse food with digital photography. All of them still require more validation and improvement. Conclusion: Automatic recording of caloric intake through wearable devices is a promising method to monitor body weight and eating habits in clinical and non-clinical settings, and the research is still going on. PMID- 29238428 TI - Does Red Cell Distribution Width Predict Outcome in Traumatic Brain Injury: Comparison to Corticosteroid Randomization After Significant Head Injury. AB - Background: Traumatic brain injury (TBI) is a leading cause of death and disability. The role of red cell distribution width (RDW) as a prognostic biomarker for outcome in TBI patients is unknown. Based on the corticosteroid randomization after significant head injury (CRASH) trial database, a prognosis calculator (CRASH) has been developed for outcome prediction in TBI. The objectives of this study are to investigate the association between RDW on day 1 of TBI and outcome, and to compare outcome prediction from RDW to that from CRASH. Methods: We performed a retrospective review of patients with TBI and a Glasgow coma scale (GCS) score of 14 or less. Day 1 RDW and CRASH data were extracted. CRASH was calculated for each patient. Outcome was defined as mortality at 14 days and GOS at 6 months, with poor outcome defined as GOS of 1 - 3. Patients were stratified according to RDW values into six groups, and according to CRASH values into six groups. Results: A total of 416 patients with TBI were included, with 339 survivors (S) and 77 non-survivors (NS). Compared to survivors, non-survivors were of similar age in years (58 +/- 23 vs. 58 +/- 23, P = 1.0), had lower GCS scores (5 +/- 3 vs. 12 +/- 3, P = 0.0001), similar RDW (14.0 +/- 1.2 vs. 13.9 +/- 1.5, P = 0.6), and higher CRASH values (68 +/- 26 vs. 24 +/- 22, P = 0.0001). Estimating the receiver-operating characteristic (ROC) area under the curve (AUC) showed that CRASH was a significantly better predictor of mortality compared to RDW (AUC = 0.91 +/- 0.01 for CRASH compared to 0.66 +/- 0.03 for RDW; P < 0.0001). In addition, CRASH was a better predictor of neurologic outcome compared to RDW (AUC = 0.85 +/- 0.02 for CRASH compared to 0.76 +/- 0.03 for RDW; P = 0.005). Conclusions: CRASH calculator was a strong predictor of mortality in patients with TBI. RDW on day 1 did not differ between survivors and non-survivors, and was a poor predictor of mortality. Both RDW on day 1 and CRASH calculator are good predictors of 6-month outcome in TBI patients, although CRASH calculator remains a better predictor. PMID- 29238429 TI - The Effect of Ongoing Vitamin D and Low-Fat Milk Intake on Bone Metabolism in Female High-School Endurance Runners. AB - Background: Vitamin D and calcium are essential nutrients for bone health. In addition, vitamin D suppresses inflammatory cytokines and increases bone resorption. Therefore, improvements in bone health by calcium and vitamin D supplementation have the potential to not only improve calcium metabolism but also suppress inflammation associated with exercise training. The purpose of this study was to determine whether ongoing vitamin D supplementation and low-fat milk intake by female high-school endurance runners would improve bone metabolism by suppressing inflammatory cytokines and the parathyroid hormone (PTH). Methods: Twenty female high-school runners were assigned to a vitamin D supplement and low fat milk intake group (MKD) or a control group (CON). Participants in the MKD group consumed a vitamin D supplement (1,000 IU/day) and low-fat milk (Ca 315 mg/day) for 6 months. Bone mineral density measurements, blood samples, and questionnaires (regarding menses and diet) were carried out. The UMIN Clinical Trials Registry number is UMIN000027854. Results: The 25-hydroxyvitamin D (25(OH)D) concentration in MKD was sustained and PTH concentration was decreased regardless of the state of menses. The correlation coefficients of 25(OH)D or PTH concentrations and bone metabolism markers were analyzed by partial correlation coefficient via adjusting the model for frequency of menses. CTX and 25(OH)D concentration were significantly and inversely correlated at baseline (r = -0.61, P < 0.01), 3 months (r = -0.54, P = 0.02), and 6 months (r = -0.53, P = 0.02). CTX and PTH were significantly and positively correlated at 3 months (r = 0.63, P < 0.01) and 6 months (r = 0.52, P = 0.02). The bone alkaline phosphatase (BAP)/CTX ratio and 25(OH)D concentration were significantly and positively correlated at 3 months (r = 0.59, P = 0.01) and 6 months (r = 0.56, P = 0.01). The BAP/CTX ratio and PTH were significantly and inversely correlated at 3 months (r = -0.59, P = 0.01) and 6 months (r = -0.58, P < 0.01). Conclusions: This study suggested that vitamin D and low-fat milk supplementation improves bone metabolism by sustaining the 25(OH)D concentration and decreasing the PTH concentration in female high-school endurance runners regardless of the state of menses. PMID- 29238427 TI - HIV-Associated Nephropathy in Africa: Pathology, Clinical Presentation and Strategy for Prevention. AB - The human immunodeficiency virus (HIV) infection can lead to progressive decline in renal function known as HIV-associated nephropathy (HIVAN). Importantly, individuals of African ancestry are more at risk of developing HIVAN than their European descent counterparts. An in-depth search on Google Scholar, Medline and PubMed was conducted using the terms "HIVAN" and "pathology and clinical presentation", in addition to "prevalence and risk factors for HIVAN", with special emphasis on African countries for any articles published between 1990 and 2017. HIVAN is characterized by progressive acute renal failure, proteinuria and enlarged kidneys. A renal biopsy is necessary to establish definitive diagnosis. Risk factors are male gender, low CD4 counts, high viral load and long use of combined antiretroviral medication (cART). There is a wide geographical variation in the prevalence of HIVAN as it ranges from 4.7% to 38% worldwide and little published literature is available about its prevalence in African nations. Microalbuminuria is a common finding in African populations and is significantly associated with severity of HIV disease progression and CD4 count less than 350 cells/uL. Other clinical presentations in African populations include acute kidney injury (AKI), nephrotic syndrome and chronic kidney disease. The main HIV associated renal pathological lesions were focal segmental glomerulosclerosis, mainly the collapsing form, acute interstitial nephritis (AIN), and immune complex-mediated glomerulonephritis (ICGN). HIV infection-induced transcriptional program in renal tubular epithelial cells as well as genetic factors is incriminated in the pathogenesis of HIVAN. This narrative review discusses the prevalence, presentation, pathogenesis and the management of HIVAN in Africa. In low resource setting countries in Africa, dealing with HIV complications like HIVAN may add more of a burden on the health system (particularly renal units) than HIV medication itself. Therefore, the obvious recommendation is early use of cART in order to decrease risk factors that lead to HIVAN. PMID- 29238430 TI - Safety of Landiolol Hydrochloride as a Premedication for Producing an Appropriate Heart Rate for Multidetector-Row Computed Tomography Coronary Angiography. AB - Background: We evaluated the safety of a bolus injection of landiolol hydrochloride, an ultrashort-acting beta1-selective antagonist, as a premedication prior to multidetector-row computed tomography coronary angiography (CTA). Methods: The subjects consisted of 176 patients (M/F = 64:112, 67 +/- 11 years) who had heart rate (HR) at rest >= 70 beats/min (bpm) and underwent CTA. Systolic/diastolic blood pressure (SBP/DBP) and HR were measured before and after the administration of landiolol. Results: SBP/DBP and HR upon entry to the CT room were 136 +/- 17/80 +/- 11 mm Hg and 83 +/- 10 bpm, respectively. HR was significantly reduced at the time of CTA scan (62 +/- 7 bpm). Next, we divided the patients into three groups according to HR upon entry to the CT room: 70 - 79 bpm (n = 76), 80 - 89 bpm (n = 60) and >= 90 bpm (n = 40). HR at the time of CTA scan was significantly lower than that upon entry to the CT room in all three groups: 70 - 79 bpm (74 +/- 3 bpm upon entry to the CT room to 61 +/- 6 bpm at the time of CAT scan), 80 - 89 bpm (84 +/- 3 to 63 +/- 7 bpm) and >= 90 bpm (98 +/- 6 to 65 +/- 7 bpm). Although SBP/DBP was significantly decreased after the CTA scan (123 +/- 18/72 +/- 12 mm Hg), landiolol had no severe adverse events throughout CTA. Conclusion: In conclusion, a bolus injection of landiolol reduced HR by about 20 bpm without any severe adverse effects. Thus, a bolus injection of landiolol hydrochloride may be a suitable pretreatment for controlling HR in CTA. PMID- 29238431 TI - Toxoplasma gondii Infection and Headache: A Matched Case-Control Study in a Public Hospital in Durango City, Mexico. AB - Background: Toxoplasma gondii (T. gondii) can disseminate to brain in infected hosts. Little is known about the magnitude of the association between this infection and headache. Therefore, we sought to determine the association of T. gondii seropositivity and headache in patients attending neurological consultations in a public hospital in Durango City, Mexico. Methods: Through an age- and gender-matched case-control study, 105 patients suffering from headache and 105 subjects without headache were examined for anti-T. gondii IgG and IgM antibodies using commercially available enzyme-linked immunoassays. Seropositive cases were analyzed for detection of T. gondii DNA by polymerase chain reaction. Results: Anti-T. gondii IgG antibodies were found in five (4.8%) of the 105 cases and in seven (6.7%) of the 105 controls (odds ratio (OR) = 0.70; 95% confidence interval (CI): 0.21 - 2.28; P = 0.76). The frequency of high (> 150 IU/mL) levels of anti-T. gondii IgG antibodies among anti-T. gondii IgG positive individuals was significantly (P = 0.01) higher in cases (5/5) than in controls (1/7). Anti T. gondii IgM antibodies were found in one (20.0%) of the five IgG seropositive cases, and in three (42.9%) of the seven IgG seropositive controls (P = 0.60). T. gondii DNA was not detected in any of the five anti-T. gondii IgG positive cases. No association between T. gondii infection and specific headache types was found. Conclusions: This is the first matched case-control study on the association between T. gondii infection and headache. Results suggest that high anti-T. gondii IgG antibody levels, but not T. gondii seropositivity, were associated with headache in the population studied. PMID- 29238432 TI - Renal Function During an Open-Label Prospective Observational Trial of Sitagliptin in Patients With Diabetes: A Sub-Analysis of the JAMP Study. AB - Background: The aim of the study was to determine the effects of sitagliptin on renal function in a diabetic population including patients with normal renal function. Methods: We analyzed the association between 12-month, 50 mg/day sitagliptin and renal function in outpatients with type 2 diabetes mellitus and poor blood glucose control in a subset of patients in the larger Januvia Multicenter Prospective Trial in Type 2 Diabetes observational study. Stratified analyses of changes in estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) were performed. Factors associated with changes in eGFR at 3 months were examined by multivariate regression analysis. Results: Of the 779 patients enrolled, 585 were followed up for 12 months. eGFR decreased significantly from baseline at 3 and 12 months in patients with a baseline eGFR of >= 90 mL/min/1.73 m2 and in those with a baseline eGFR of >= 60 to < 90 mL/min/1.73 m2. Conversely, eGFR tended to increase at 3 and 12 months in patients with a baseline eGFR of >= 45 to < 60 mL/min/1.73 m2 and in those with a baseline eGFR of >= 30 to < 45 mL/min/1.73 m2. UACR decreased significantly ( 21.6 (-46.8, 7.8)) at 3 months in patients with a baseline UACR of >= 30 mg/g Cre. Multivariate regression analysis of factors associated with changes in eGFR at 3 months revealed that higher baseline eGFR and greater decline in UACR were associated with more conspicuous decreases in eGFR. Conclusions: In this group of diabetic patients receiving sitagliptin, eGFR declined in patients with high baseline eGFR, but not in those with a low baseline eGFR. PMID- 29238433 TI - Improvement of Diurnal Blood Pressure Variation by Azilsartan. AB - Background: Azilsartan is an angiotensin II receptor blocker with a potent antihypertensive effect. Methods: In a multicenter, prospective, open-label study, 265 patients with poor blood pressure control despite treatment with other angiotensin II receptor blockers were switched to 20 mg/day of azilsartan (patients on standard dosages) or 40 mg/day of azilsartan (patients on high dosages). Results: Blood pressure was 149/83 mm Hg before switching and was significantly reduced from 1 month after switching until final assessment (132/76 mm Hg, P < 0.001). The pulse rate was 72/min before switching and increased significantly from 3 months after switching until final assessment (74/min, P < 0.005). A significant decrease of home morning systolic and diastolic pressure was observed from 1 and 3 months, respectively. Home morning blood pressure was 143/82 mm Hg before switching and 130/76 mm Hg at final assessment (P < 0.01). The morning-evening difference of systolic blood pressure decreased from 14.6 to 6.6 mm Hg after switching (P = 0.09). The estimated glomerular filtration rate was significantly decreased at 3, 6, and 12 months after switching, and serum uric acid was significantly increased at 12 months. No serious adverse events occurred. Conclusion: Azilsartan significantly reduced the blood pressure and decreased diurnal variation in patients responding poorly to other angiotensin II receptor blockers. PMID- 29238434 TI - Predictors of Achieving Recommended Daily Physical Activity Among Anesthesiologists at a Large Tertiary Care Academic Center. AB - Background: The goal of the current study was to determine if the daily work patterns of anesthesiologists meet the recommended daily levels of activity. Methods: Attending and resident anesthesiologists at a tertiary academic center were invited to participate. The subjects wore a pedometer during five regular clinical days at work and recorded the number of steps walked. The participants also completed the International Physical Activity Questionnaire (IPAQ) during one regular week. The results were analyzed using analysis of variance, Chi square test and multivariate linear regression using STATA 12.1. Results: During work, attending, compared with senior and junior resident, anesthesiologists had the most steps (5,953 +/- 1,213, 5,153 +/- 905, and 5,710 +/- 1,513 steps, respectively, P = 0.2). Outside work, senior residents had the highest level of activity (3,592 +/- 1,626 metabolic equivalent of task (MET)-minutes/week) compared to junior residents (1,788 +/- 1,089 MET-minutes/week) and attending (2,104 +/- 1,594 MET-minutes/week, P = 0.005); the percentage of recommended daily level of activity represented by this outside activity was senior residents (78.5%), junior residents (27%) and attending (21%) anesthesiologists (P = 0.002). When activity at and outside work was combined, most anesthesiologists met the recommended 10,000 steps daily, P < 0.009. Conclusions: The daily physical activity of faculty and trainee anesthesiologists at work in a busy tertiary care is low active. However, when additional physical activity is pursued outside of work, most anesthesiologists met recommended daily levels of activity. These results highlight the inadequacy of daily activity at work, and the need to pursue additional physical activity outside of work; such awareness can assist in promoting a healthy lifestyle. PMID- 29238436 TI - Idiopathic Isolated Colonic Varices: An Extremely Rare Condition. AB - Colonic varices are an incredibly rare phenomenon to begin with; however, they are even more unusual when isolated and occurring in the absence of common comorbidities, like portal hypertension or portal vein thrombosis. We present a case of a 71-year-old female, who was asymptomatic and referred to gastroenterology for a routine colorectal cancer screening. The patient was ultimately found to have this anomalous condition when colonic varices were first identified on colonoscopy. Since these varices did not result from any obvious etiology, they were determined to be idiopathic colonic varices, an especially unusual presentation. PMID- 29238435 TI - Primary Aldosteronism With Type 2 Diabetes Mellitus Requires More Antihypertensive Drugs for Blood Pressure Control: A Retrospective Observational Study. AB - Background: Diabetes mellitus (DM) and primary aldosteronism (PA) have been reported to induce drug-resistant hypertension and atherosclerosis. It is likely that blood pressure (BP) control becomes far more difficult in PA patients with DM. However, precise clinical characteristics of PA with type 2 DM especially in the aspect of BP control are not clear. Methods: The study included 18 patients who were diagnosed as PA with DM and 52 PA patients without DM who matched age and sex and chosen as a control group. We have compared differences in BP control, use of antihypertensive agents and clinical characteristics between PA patients with and without DM. Results: There was no difference with regard to the duration of hypertension and BP control between either group. Interestingly, the PA with DM group was found to require more antihypertensive agents than the PA without DM group (number of antihypertensive agents used, 2.0 +/- 1.5 vs. 1.3 +/- 1.1; P < 0.05, respectively). In the 28 patients who underwent measurement of central BP (CBP) values, plasma aldosterone concentration (PAC) was high in the PA with DM group. Furthermore, a positive correlation was shown between PAC and CBP (r = 0.58; P < 0.01); the higher the PAC, the higher the CBP of patient. Conclusions: These results might suggest that hypertension becomes more difficult to control in PA patients with DM in the future. PMID- 29238437 TI - Persistent Primary Aldosteronism Despite Iatrogenic Adrenal Hemorrhage After Adrenal Vein Sampling. AB - Before surgery for primary aldosteronism (PA), localization is evaluated with adrenal vein sampling (AVS). A 56-year-old Japanese woman had a right adrenal mass, hypokalemia, and a high aldosterone/renin ratio. Stress tests confirmed the diagnosis of PA. Subsequently, preoperative AVS was performed and right adrenal hemorrhage (AH) occurred unexpectedly. Because hypertension persisted, laparoscopic right adrenalectomy was performed. Postoperatively, the blood pressure was normalized. Pathological examination revealed an adrenal cortical adenoma largely unaffected by necrosis and hemorrhage. Previous reports have also indicated that AH may not ameliorate PA. We discussed the clinical progress of AH and the measures to prevent causing AH. PMID- 29238439 TI - In Situ SEM Nanomanipulation and Nanomechanical/Electrical Characterization. PMID- 29238440 TI - Osteochondrolipoma of the Mandible. AB - Objective: Lipomas are very common benign tumors located in any part of the body in which fat is normally present, but lipomas containing both osseous and cartilaginous elements are rare. Methods: A case of osteochondrolipoma in a 72 year-old man is reported. The tumor in the mental region was 2*1.5*1.5 cm. Results: After resection of the tumor, there has been no recurrence during the 6 month postoperative follow-up. Histological examination confirmed the definitive diagnosis. Conclusions: Osteochondrolipoma is an extremely unusual lesion that should be kept in mind in the differential diagnosis of soft-tissue tumors. PMID- 29238438 TI - Aqueous, Heterogeneous Parahydrogen-Induced 15N Polarization. AB - The successful transfer of parahydrogen-induced polarization to 15N spins using heterogeneous catalysts in aqueous solutions was demonstrated. Hydrogenation of a synthesized unsaturated 15N-labeled precursor (neurine) with parahydrogen (p-H2) over Rh/TiO2 heterogeneous catalysts yielded a hyperpolarized structural analog of choline. As a result, 15N polarization enhancements of over two orders of magnitude were achieved for the 15N-ethyl trimethyl ammonium ion product in deuterated water at elevated temperatures. Enhanced 15N NMR spectra were successfully acquired at 9.4 T and 0.05 T. Importantly, long hyperpolarization lifetimes were observed at 9.4 T, with a 15N T1 of ~6 min for the product molecules, and the T1 of the deuterated form exceeded 8 min. Taken together, these results show that this approach for generating hyperpolarized species with extended lifetimes in aqueous, biologically compatible solutions is promising for various biomedical applications. PMID- 29238441 TI - Reconstruction of an Irradiated Perineal Wound With a Superior Gluteal Artery Perforator Flap. PMID- 29238442 TI - Reducing greenhouse gas emissions and improving air quality: Two global challenges. AB - There are many good reasons to promote sustainable development and reduce greenhouse gas emissions and other combustion emissions. The air quality in many urban environments is causing many premature deaths because of asthma, cardiovascular disease, chronic obstructive pulmonary disease, lung cancer, and dementia associated with combustion emissions. The global social cost of air pollution is at least $3 trillion/year; particulates, nitrogen oxides and ozone associated with combustion emissions are very costly pollutants. Better air quality in urban environments is one of the reasons for countries to work together to reduce greenhouse gas emissions through the Paris Agreement on Climate Change. There are many potential benefits associated with limiting climate change. In the recent past, the concentrations of greenhouse gases in the atmosphere have been increasing and the number of weather and climate disasters with costs over $1 billion has been increasing. The average global temperature set new record highs in 2014, 2015, and 2016. To reduce greenhouse gas emissions, the transition to electric vehicles and electricity generation using renewable energy must take place in accord with the goals of the Paris Agreement on Climate Change. This work reviews progress and identifies some of the health benefits associated with reducing combustion emissions. PMID- 29238443 TI - Editors' Note. PMID- 29238444 TI - User Authentication in Smartphones for Telehealth. AB - Many functions previously conducted on desktop computers are now performed on smartphones. Smartphones provide convenience, portability, and connectivity. When smartphones are used in the conduct of telehealth, sensitive data is invariably accessed, rendering the devices in need of user authentication to ensure data protection. User authentication of smartphones can help mitigate potential Health Insurance Portability and Accountability Act (HIPAA) breaches and keep sensitive patient information protected, while also facilitating the convenience of smartphones within everyday life and healthcare. This paper presents and examines several types of authentication methods available to smartphone users to help ensure security of sensitive data from attackers. The applications of these authentication methods in telehealth are discussed. PMID- 29238445 TI - The Social Validity of Telepractice among Spanish-Speaking Caregivers of English Learners: An Examination of Moderators. AB - The purpose of the present paper was to examine the social validity of telepractice as a service delivery model for Spanish-speaking families of English learners. Quantitative survey methodology was employed to examine 79 caregivers' opinions regarding telepractice and to obtain background information about participants' home environments. Findings revealed that approximately 46% of the participant sample reported being interested in their children receiving services via telepractice. Caregivers reported limited familiarity with telepractice as an option, but were likely to express interest if their child had an identified speech or language disorder or if they were interested in increased access to Spanish language support for their children. In conclusion, although telepractice is not universally accepted among Spanish-speaking families, it appears to be a promising service delivery model. It is recommended that service providers offer thorough information and address common myths when considering telepractice as a service delivery model for families. PMID- 29238446 TI - Results of a Survey Offering Clinical Insights into Speech-Language Pathology Telepractice Methods. AB - A telepractice survey was administered to the American Speech-Language-Hearing Association Special Interest Group 18 Telepractice affiliates and attendees of the Waldo County General Hospital Speech-Language Pathology Telepractice Training program in Maine, USA over the summer of 2016. Sixty-seven respondents completed the survey. The survey explored demographics of clients and clinicians, costs and equipment, learning opportunities, use of the client's environment and caregivers/e-helpers, and method adaptations in telepractice. The results of the survey provide information on the current state of telepractice methods in speech language pathology from experienced practitioners. This information may be used to develop telepractice models and to prepare speech-language pathology graduate students in the delivery of telepractice methods. PMID- 29238447 TI - Telerehabilitation Feasibility in Total Joint Replacement. AB - Despite documented benefits, many Total Joint Replacement (TJR) patients find it difficult to access rehabilitation following discharge from hospital. One solution to improve access for TJR patients is telerehabilitation. This study aimed to assess the feasibility of introducing a telerehabilitation program for TJR patients. TJR patients at QEII Jubilee Hospital were invited to complete a questionnaire regarding their access, feelings towards and preferences in using technology. Seventy-five patients were recruited. Most patients had computer access (72%) and internet (69%) at home. Sixty-five percent of participants were willing to participate in telerehabilitation. A significant difference was found between older and younger patients. Watching videos on an electronic device was the preferred method for a technology-based home exercise program and phone call the preferred method of communication. Results indicate telerehabilitation in the TJR population is feasible from the perspective of access to, feelings toward, and preferences for technology. PMID- 29238448 TI - A Systematic Review of Research Studies Examining Telehealth Privacy and Security Practices used by Healthcare Providers. AB - The objective of this systematic review was to systematically review papers in the United States that examine current practices in privacy and security when telehealth technologies are used by healthcare providers. A literature search was conducted using the Preferred Reporting Items for Systematic Reviews and Meta Analyses Protocols (PRISMA-P). PubMed, CINAHL and INSPEC from 2003 - 2016 were searched and returned 25,404 papers (after duplications were removed). Inclusion and exclusion criteria were strictly followed to examine title, abstract, and full text for 21 published papers which reported on privacy and security practices used by healthcare providers using telehealth. Data on confidentiality, integrity, privacy, informed consent, access control, availability, retention, encryption, and authentication were all searched and retrieved from the papers examined. Papers were selected by two independent reviewers, first per inclusion/exclusion criteria and, where there was disagreement, a third reviewer was consulted. The percentage of agreement and Cohen's kappa was 99.04% and 0.7331 respectively. The papers reviewed ranged from 2004 to 2016 and included several types of telehealth specialties. Sixty-seven percent were policy type studies, and 14 percent were survey/interview studies. There were no randomized controlled trials. Based upon the results, we conclude that it is necessary to have more studies with specific information about the use of privacy and security practices when using telehealth technologies as well as studies that examine patient and provider preferences on how data is kept private and secure during and after telehealth sessions. PMID- 29238449 TI - The Physical Therapy Compact: From Development to Implementation. AB - The Federation of State Boards of Physical Therapy (FSBPT) began the process of implementing the Physical Therapy Compact (PTC) in 2010 with a delegate assembly motion. An interstate compact is an agreement between states to enact legislation and enter into a contract for a specific, limited purpose or to address a particular policy issue. An interstate compact benefits patients, consumers, and licensees by addressing workforce concerns improving licensure portability from state-to-state; facilitating short-term mobility and telehealth consultation for physical therapists. FSBPT formed strategic partnerships with the American Physical Therapy Association (APTA) and Council for State Governments' (CSG) to develop and implement the PTC. From April 2014-present, FSBPT followed the CSG recommended stages of compact development: Advisory, Drafting, Education, Enactment, and Transition. The enactment phase began once the threshold number of ten states required in legislation passed the compact bill in 2017. FSBPT anticipates the compact will be fully operational and licensees will be able to take advantage of the compact by mid-2018. PMID- 29238451 TI - A Survey of Telepractice in Speech-Language Pathology and Audiology in India. AB - Telepractice has emerged as a form of service delivery to assess and treat individuals with communication disorders. The present study surveyed speech language pathologists and audiologists in India about the use of telepractice. Two hundred and five (N=205) speech-language pathologists and audiologists responded to a questionnaire, with 12.19% reporting their use of telepractice to deliver clinical services. Respondents also indicated an urgent shortage of professionals in India to deliver clinical services in speech-language pathology and audiology, and opined that these needs can be met via the use of telepractice. India is well known throughout the world for the advanced application of Information and Communication Technology (ICT), with 931.95 million telephone subscribers, over 900 million mobile phone users, and the second-largest mobile phone usage in the world. India has also experienced a tremendous rise in the number of internet users. Therefore, India is well poised to fully develop telepractice to overcome the barriers of distance and amplify the availability of speech-language pathology, audiology and other healthcare services. But first, the widespread use of telepractice throughout the nation will require an improved infrastructure (e.g., to uphold privacy and security); training for professionals; and telepractice policies. While very promising, the deployment of telepractice throughout India will require the attention of policy makers and government organizations. PMID- 29238450 TI - American Telemedicine Association's Principles for Delivering Telerehabilitation Services. AB - Telehealth is a broad term used to describe the use of electronic or digital information and communications technologies to support clinical healthcare, patient and professional health related education, and public health and health administration. Telerehabilitation refers to the delivery of rehabilitation and habilitation services via information and communication technologies (ICT), also commonly referred to as" telehealth" technologies. Telerehabilitation services can include evaluation, assessment, monitoring, prevention, intervention, supervision, education, consultation, and coaching. Telerehabilitation services can be deployed across all patient populations and multiple healthcare settings including clinics, homes, schools, or community-based worksites. This document was adapted from the American Telemedicine Association's (ATA) "A Blueprint for Telerehabilitation Guidelines" (2010) and reflects the current utilization of telerehabilitation services. It was developed collaboratively by members of the ATA Telerehabilitation Special Interest Group, with input and guidance from other practitioners in the field, strategic stakeholders, and ATA staff. Its purpose is to inform and assist practitioners in providing effective and secure services that are based on client needs, current empirical evidence, and available technologies. Rehabilitation professionals, in conjunction with professional associations and other organizations are encouraged to use this document as a resource for developing discipline-specific standards, guidelines, and practice requirements. PMID- 29238452 TI - Letter to the Editor: Licensure Portability for Occupational Audiologists is Essential. AB - Occupational audiologists have a crisis in their profession and need advocates. These audiologists are primarily responsible for industrial hearing conservation programs and their compliance with multiple regulations, such as Occupational Safety and Health Administration (OSHA), Mine Safety and Health Administration (MSHA) and the Federal Railroad Administration. Occupational hearing programs, for the most part, are multi-state programs as companies and corporations are national organizations. Also, companies may contract services across state lines as local services may not be desired or available. Individual state telepractice regulations require audiologists who are professionally supervising these programs via the internet and phone, to secure licensure in each state. For this licensure redundancy, the cost in time and tracking are enormous. It is imperative that the American Speech-Language-Hearing Association (ASHA), secure multistate licensure for speech-language pathologists and audiologists. For the profession of occupational audiology, it is essential. PMID- 29238453 TI - Day-to-day affect is surprisingly stable: A two-year longitudinal study of well being. AB - Previous research suggests global assessments of cognitive well-being-life satisfaction-are relatively stable over time. Far fewer studies have examined the extent to which experiential measures of affective well-being-the moods/emotions people regularly experience-are stable, especially over extended periods of time. The present study used longitudinal data from a representative sample of Germans to investigate the long-term stability of different components of well-being. Participants provided global ratings of life satisfaction and affect, along with experiential measures of well-being up to three times over two years. Results indicated between one third and one half of the variance in people's daily affect was attributable to trait-like latent variables. Replicating meta-analytic findings, 50% of the variance in global measures of well-being was attributable to trait-like latent variables. PMID- 29238454 TI - Phenotypic and genotypic features of first biofilm forming nasopharyngeal colonized Streptococcus pneumoniae isolates. AB - Background and Objectives: Designing control and therapeutic policies for antibiotic resistant Streptococcus pneumoniae, which is an important causative agent of several invasive and noninvasive infectious diseases and its carriage rates, has been described as the main target in World Health Organization (WHO). The present study was conducted to determine antibiotic resistance pattern, evaluate biofilm forming ability in S. pneumoniae isolates, and find the genetic relationship between cultured strains. Materials and Methods: Following the isolation and identification of S. pneumoniae strains from nasopharyngeal swabs, the ability of biofilm formation and susceptibility pattern of the isolates were screened using semi-quantitative microplate and disk diffusion procedures. Subsequently, Pulse field gel electrophoresis (PFGE) method was used to determine the clonal diversity of isolates. Results: The pneumococcal colonization rate in this study was found to be 24%. A large number of our isolates had strong biofilm forming ability. However, there was variation in antibiotic resistance patterns of isolates in children who lived in nursery houses. The genetic similarity among the isolates in PFGE varied from 26.5% to 100% in our isolates. This was the first report of biofilm formation of nasopharyngeal colonized S. pneumoniae in Iran. Genetic variations were also noticeable, when the isolates were fingerprinted by PFGE. Conclusion: The findings of this study revealed the need for thoughtful use of antimicrobial agents, continued monitoring of pneumococcal resistance patterns, and prevention of the spread of multi-drug resistant clones. PMID- 29238455 TI - In vitro activity of recombinant lysostaphin in combination with linezolid, vancomycin and oxacillin against methicillin-resistant Staphylococcus aureus. AB - Background and Objectives: The antimicrobial combination with synergistic mechanism is recommended to provide broad-spectrum coverage, and prevent the emergence of resistant mutants. In the present study, the synergistic activity of lysostaphin with linezolid, oxacillin and vancomycin, against methicillin resistant Staphylococcus aureus (MRSA) clinical isolates was determined. Materials and Methods: Seventy-three MRSA isolates collected from clinical specimens were tested, for in vitro synergistic activity of lysostaphin with linezolid, vancomycin and oxacillin, by checkerboard assay. Results: Lysostaphin showed synergistic activity with linezolid and oxacillin, against all MRSA isolates, tested in the present study. Whereas, only 19.1% of the isolates showed synergistic activity with vancomycin and remaining 80.9% of the MRSA isolates showed additive activity. Conclusion: Lysostaphin causes rapid lysis of S. aureus. Combination therapies that include linezolid and lysostaphin could be used in life-threatening infections, such as endocarditis to increase the early in vivo activity of the antibiotics, and to prevent the emergence of linezolid resistant mutants. Further, in vivo studies are warranted to confirm our results. PMID- 29238456 TI - Seroepidemiological study of Q fever in Lorestan province, western Iran, 2014. AB - Background and Objectives: Q fever is a zoonotic disease and farm animals serve as the main reservoir of the disease. The aim of this study was to evaluate the seroprevalence of Q fever in sheep, in Lorestan province in western Iran. Materials and Methods: In this cross-sectional study, 330 blood samples were collected from sheep, from each county in Lorestan province. The samples were tested by ELISA for the presence of immunoglobulin (IgG) against Coxiella burnetii. Results: Among the samples tested, 45 samples (13.64%) were seropositive. Of 35 studied herds, 21 (60%) had a history of infection. In terms of number of positive samples, there was no significant difference between the three geographical regions (central, west and east) (p=0.687). There was no statistically significant difference between age groups (p =0.604). Gender also had no effect on infection rates, in female and male sheep (p =0.814). No significant difference was observed between the number of lactation and positive serology (p =0.376). The rate of infection with Q fever and abortion also had no statistically significant difference (p =0.152). Conclusion: The findings of this study showed that sheep in Lorestan were infected by Q fever and the cycle of disease transmission had been established between animals and ticks. PMID- 29238457 TI - Molecular detection of Bordetella holmesii in two infants with pertussis-like syndrome: the first report from Iran. AB - Background and Objectives: Bordetella holmesii is associated with a pertussis like respiratory syndrome in healthy individuals and also a rare cause of septicaemia, endocarditis, pneumonia, and septic arthritis, mostly in immunocompromised patients. Culture technique and real-time PCR are 2 methods used to detect Bordetella spp. Materials and Methods: In this study, 435 nasopharyngeal specimens of patients with suspected whooping cough were checked for the presence of B. holmesii using 2 methods of culture technique and real time PCR. Results: In this study, we detected hIS1001 and IS481 of B. holmesii in 2 infants suspected of having pertussis-like syndrome. Conclusion: Our observations demonstrate that accurate diagnosis is needed to discriminate between B. holmesii and B. pertussis infections among pertussis cases; otherwise, it could lead to misestimating pertussis rate and vaccine efficacy. PMID- 29238458 TI - Bacteriocinogenic potential and virulence traits of Enterococcus faecium and E. faecalis isolated from human milk. AB - Background and Objectives: Human milk is a continuous supply of Lactic Acid bacteria (LAB), including enterococci with probiotic potentials. The aim of this study was to analyze two Enterococcus species, isolated from human milk for their probiotic potential, bacteriocin producing ability and virulence traits. Materials and Methods: Enterococcus faecium TA0033 and E. faecalis TA102 were tested for acid and bile tolerance, survival in simulated gastric and intestinal conditions. The antibacterial spectrum of the isolates was tested by agar well diffusion assay. The antagonistic agent was characterized by physico-chemical methods. The enterocin structural genes, virulence determinants, vancomycin resistance and biogenic amine genes, such as hdc1, hdc2, tdc, ldc and odc were also determined. Results: The tested isolates survived acidic conditions, high bile salt (1%), simulated gastric and intestinal conditions. The culture supernatant fluids of the two isolates inhibited the growth of Escherichia coli, Listeria monocytogenes, Salmonella typhi, Staphylococcus aureus, Shigella dysenteriae and Streptococcus agalactiae. The antagonistic activity was lost in the presence of proteolytic enzymes but tolerated the action of catalase, lysozyme and lipase. In contrast to enterocin TA102, enterocin TA0033 possessed bactericidal mode of action. Bacteriocin structural genes, entA and entB were present in the genome of the two isolates, while E. faecalis TA102 additionally harboured entP and bac31 genes. The phenotypic and genotypic virulence assessment studies indicated hyaluronidase (hyl) production and vancomycin resistance in E. faecalis TA102 while, none of the isolates harboured the biogenic amine genes. Conclusion: The presence of virulence genes in E. faecalis TA102 calls for careful monitoring of Enterococcus isolates for their safety parameters. PMID- 29238459 TI - Isolation and characterization of probiotics from dairies. AB - Background and Objectives: Probiotics are live microorganisms, which show beneficial health effects on hosts once consumed in sufficient amounts. LAB group can be isolated and characterized from traditional dairy sources. This study aimed at isolating, identifying, and in vitro characterizing (low pH/high bile salt tolerance, antibacterial activity, and antibiotic susceptibility) LAB strains from traditional Iranian dairy products. Materials and Methods: Isolated strains were identified by Gram staining, catalase assay, and 3 molecular identification methods; namely, (GTG) 5-PCR fingerprinting, ARDRA, and 16S rDNA gene sequencing. Results: A total of 19 LAB strains belonging to 4 genera (Lactococcus, Leuconostoc, Lactobacillus and Enterococcus) were identified. Conclusion: The experiments revealed that L. plantarum 15HN, L. lactis subsp. cremoris 44L and E. mundtii 50H strains, which were isolated from shiraz, cheese and shiraz, respectively, displayed a desirable tolerance to low pH and high bile salts, favorable anti-pathogen activity, and acceptable antibiotic susceptibility; hence, they could be considered as novel probiotic candidates and applied in the food industry. PMID- 29238460 TI - Synthetic peptides mimicking lipopolysaccharide as a potential vaccine candidates against Vibrio cholerae serogroup O1. AB - Background and Objectives: Cholera is a life-threatening diarrhea caused mainly by Gram-negative marine habitant Vibrio cholerae serogroup O1. Cholera vaccination is limited mainly to developed countries, due to the cumbersome and expensive task of vaccine production. In the present work, the aim was to study the immunogenicity of the synthetic mimotopes through two different routes of injection and oral administration. Lipopolysaccharide (LPS) is one of the immunogenic components in Gram-negative bacteria, which cannot be used as a vaccine candidate, due to its high toxic effect. Materials and Methods: Three phage-displayed selected peptides, with high affinity to anti-LPS VHH tested in our previous study, were chemically synthesized and used as a potential vaccine candidate. In order to enhance the antigenic properties and safe delivery, these peptides were conjugated to BSA as a carrier and encapsulated with PLGA. Peptides were injected intra-peritoneally or administered orally, alone or in combined form. Mice sera and feces were collected for assessment of humoral and mucosal antibody titers, respectively. ELISA plates were coated with mimotope conjugates and V. cholerae, Shigella sonnei and ETEC were used as target antigens. Antibody titer was measured by adding IgG and IgA as primary antibodies. Results: Mice receiving three selected synthetic peptide conjugates (individually or in combination) showed higher antibody titer compared to control groups. The mice immunized with synthetic peptides were protected against more than 15 LD50 of V. cholerae. Conclusion: These peptides are mimicking LPS and can potentially act as vaccine candidates against V. cholerae. PMID- 29238461 TI - Cloning, expression and purification of a polytopic antigen comprising of surface antigens of Toxoplasma gondii. AB - Background and Objectives: Polytopic antigens are recently applied for replacing crude antigens, for control of infectious agents. The surface of the Toxoplasma is covered with immunogenic antigens namely surface antigens (SAGs). These antigens possess several immunogenic epitopes, inducing immune responses. Materials and Methods: In this study, a DNA construct comprising of sequences encoding epitopes from SAG1, 2 and 3 was designed and cloned into pET28a expression vector and subsequently expressed and purified, using Ni-NTA column. Results: The SDS-PAGE and Western blotting analysis showed that polytopic genes were successfully expressed and purified. Conclusion: The surface antigenic protein of T. gondii can be applied in the future epitope-based applications. PMID- 29238462 TI - Mechanisms of spinal cord injury regeneration in zebrafish: a systematic review. AB - Objectives: To determine the molecular and cellular mechanisms of spinal cord regeneration in zebrafish. Materials and Methods: Medical databases of PubMed and Scopus were searched with following key words: Zebrafish; spinal cord injuries; regeneration; recovery of function. The map of mechanisms was performed using Xmind software. Results: Wnt/beta-catenin signaling, L1.1, L1.2, Major vault protein (MVP), contactin-2 and High mobility group box1 (HMGB1) had positive promoting effects on axonal re-growth while Ptena had an inhibitory effect. Neurogenesis is stimulated by Wnt/beta-catenin signaling as well as HMGB1, but inhibited by Notch signaling. Glial cells proliferate in response to fibroblast growth factor (FGF) signaling and Lysophosphatidic acid (LPA). Furthermore, fgf signaling pathway causes glia bridge formation in favor of axonal regeneration. LPA and HMGB1 in acute phase stimulate inflammatory responses around injury and suppress regeneration. LPA also induces microglia activation and neuronal death in addition to glia cell proliferation, but prevents neurite sprouting. Conclusion: This study provides a comprehensive review of the known molecules and mechanisms in the current literature involved in the spinal cord injury (SCI) regeneration in zebrafish, in a time course manner. A better understanding of the whole determining mechanisms for the SCI regeneration should be considered as a main goal for future studies. PMID- 29238463 TI - Protective effect of metformin on toxicity of butyric acid and arsenic in isolated liver mitochondria and langerhans islets in male mice: an in vitro study. AB - Objectives: Arsenic, a toxic metal in drinking water and butyric acid (BA) is a free fatty acid found in many foods. These two can induce oxidative stress in some tissues. The present study investigated the protective effect of metformin against toxicity induced by Arsenic (As) and BA in isolated mice liver mitochondria and pancreatic islets. Materials and Methods: In this study, liver mitochondria were isolated by adopting different centrifugation methods and pancreatic islets isolated by a collagenase method. Mitochondria were incubated by BA (75 MUM), As (100 MUM) and metformin (0, 0.5, 1, 3, 10 mM) and the islets also incubated by BA (1000 MUM), As (100 MUM) and metformin (0, 1, 3, 10 mM) for 1 hr. At the end of study, mitochondrial viability (MTT), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), malondial- dehyde (MDA), glutathione (GSH) and islets insulin secretion were measured employing specific relevant methods. Results: As and BA significantly increased ROS, MDA and DeltaPsim levels and decreased GSH level, succinate dehydrogenase activity and insulin secretion. On the other hand, pretreatment with metformin, returned mitochondrial complex II activity, reduced ROS, MDA and DeltaPsim levels and increased GSH level and insulin secretion of pancreatic islets. Conclusion: As and BA in combination or in isolation induce oxidative stress in liver mitochondria and decrease insulin secretion of pancreatic islets. Metformin has a protective effect probably caused by its antioxidant feature. The findings suggest the potential role of metformin in mitochondria therapy and insulin secretion in many diseases. PMID- 29238464 TI - Curcumin enhances liver SIRT3 expression in the rat model of cirrhosis. AB - Objectives: Bill duct ligation (BDL) is a representative model of biliary cholestasis in animals. Curcumin has a protective effect on the liver; however, its underlying mechanisms are not completely known. This study explored the hepatoprotective activity of curcumin on hepatic damage via measuring the expression of sirtuin3 (SIRT3), AMP-activated protein kinase (AMPK), carnitine palmitoyltransferase 1A (CPT-1A), isocitrate dehydrogenase2 (IDH2) and manganese superoxide dismutase (MnSOD) as well as the level of serum lipid profile in the BDL fibrotic rat model. Materials and Methods: The study consisted of four groups (n=8 for each of Wistar rats): sham group, sham+curcumin (sham+Cur) group (received curcumin 100 mg/kg/day), BDL+Cur group, and BDL group. Transcription levels of SIRT3, AMPK, CPT-1A, IDH2, MnSOD and protein expression level of SIRT3 were measured by real-time PCR and Western blotting, respectively. Results: It was identified that SIRT3, AMPK, CPT-1A, IDH2 and MnSOD expression significantly decreased in BDL rats compared to sham rats; however, in the curcumin treatment of BDL rats, the expression of these factors increased significantly compared to BDL (P<0.05). It was, moreover, observed that treatment of BDL rats with curcumin reduced liver injury as verified by a reduction in the levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) and increase in high-density lipoprotein (HDL) (P <0.05). Conclusion: Curcumin reduced liver damage and oxidative stress in the liver tissue of BDL rats through up-regulation of SIRT3, AMPK, CPT-1A, IDH2 and MnSOD as well as changing the level of serum lipid profile. PMID- 29238465 TI - Genistein preserves the lungs of ovariectomized diabetic rats: addition to apoptotic and inflammatory markers in the lung. AB - Objectives: The role of isoflavones in pulmonary structure and function during menopause is not well studied. Moreover, the important role of estrogen in the physiological function of respiratory system has been revealed. Genistein, as an isoflavone, mimics estrogenic in diabetic and ovariectomized rats. Here, we hypothesized that genistein would reverse changes in the protein expression levels related to estrogen deficiency in the lung of ovariectomized diabetic rats. Materials and Methods: Wistar female rats were assigned to four experimental groups (n=10 in each group): sham, rats underwent laparotomy without removing the ovaries; OVX, rats that underwent ovariectomy; OVX.D, rats underwent bilateral ovariectomy and were fed a high-fat diet (HFD); OVX.D.G, ovariectomized diabetic rats with genistein administration (1 mg/kg /day). After ovariectomy, rats continued to feed HFD for a 4-week period. After 4 weeks of HFD feeding, a single dose of 30 mg/kg of streptozotocin was administered in the diabetic group. Genistein was administered for eight weeks. At the end of the experiment, lung tissue was removed and Western blotting technique and hematoxylin-eosin staining were used for evaluation of the lung. Results: Treatment with genistein significantly decreased inflammatory and apoptotic biomarkers in the ovariectomized diabetic rats compared to non-treated animals (P<0.05). Also, genistein exerted a protective effect in the lung architecture. Conclusion: Genistein partly reversed ovariectomy-induced changes in apoptotic and inflammatory biomarkers in the lung. Our data suggest that genistein treatment as a natural replacement therapy may prevent the estrogen deficiency effects in the lung of diabetic menopausal women. PMID- 29238466 TI - Antimalarial and cytotoxic activities of roots and fruits fractions of Astrodaucus persicus extract. AB - Objectives: Astrodaucus persicus (Apiaceae) is one of the two species of this genus which grows in different parts of Iran. Roots of this plant were rich in benzodioxoles and used as food additive or salad in Iran and near countries. The aim of present study was evaluation of antimalarial and cytotoxic effects of different fractions of A. persicus fruits and roots extracts. Materials and Methods: Ripe fruits and roots of A. persicus were extracted and fractionated by hexane, chloroform, ethyl acetate and methanol, separately. Antimalarial activities of fractions were performed based on Plasmodium berghei suppressive test in mice model and percentage of parasitemia and suppression were determined for each sample. Cytotoxicity of fruits and roots fractions were investigated against human breast adenocarcinoma (MCF-7), colorectal carcinoma (SW480) and normal (L929) cell lines by MTT assay and IC50 of them were measured. Results: Hexane fraction of roots extract (RHE) and ethyl acetate fraction of fruits extract (FEA) of A. persicus demonstrated highest parasite inhibition (73.3 and 72.3%, respectively at 500 mg/kg/day) which were significantly different from negative control group (P<0.05). In addition, RHE showed potent anticancer activities against MCF-7 (IC50 of 0.01 ug/ml), SW480 (IC50 of 0.36 ug/ml) and L929 (IC50 of 0.70 ug/ml) cell lines. Conclusion: According to the results, RHE and FEA fractions of A. persicus could be introduced as excellent choice for antimalarial drug discovery. In addition, cytotoxic activity of RHE was noticeable. PMID- 29238467 TI - Neuroprotection of a sesamin derivative, 1, 2-bis [(3-methoxyphenyl) methyl] ethane-1, 2-dicaroxylic acid (MMEDA) against ischemic and hypoxic neuronal injury. AB - Objectives: Stroke may cause severe neuronal damage. The sesamin have been demonstrated to possess neuroprotection by its antioxidant and anti-inflammatory properties. One sesamin derivative was artificially composited, 1, 2-bis [(3 methoxyphenyl) methyl] ethane-1, 2-dicaroxylic acid (MMEDA) had been developed to study its antioxidative activity and neuroprotection. Materials and Methods: The infaction of Sprague Dawley (SD) rats and hypoxia models of BV-2 microglia or PC12 cells were investigated for in vivo and in vitro test respectively. Lipid peroxidation and reactive oxygen species (ROS), prostaglandin E2 (PGE2) and related signaling pathways from hypoxic cells were analyzed by ELISA or Western blot assay, respectively. Results: MMEDA showed a protective effect when given 90 min after the focal cerebral ischemia. The neuroprotection of MMEDA was further confirmed by attenuating ROS and PGE2 release from hypoxic BV-2 or PC12 cells. MMEDA significantly reduced hypoxia-induced JNK and caspase-3 (survival and apoptotic pathways) in PC12 cells. Conclusion: The neuroprotective effect of MMEDA on ischemia/hypoxia models was involved with its antioxidative activity and anti-inflammatory effects. These results suggest that MMEDA exert effective neuroprotection against ischemia/hypoxia injury. PMID- 29238468 TI - Effect of fetal and adult bovine serum on pyocyanin production in Pseudomonas aeruginosa isolated from clinical and soil samples. AB - Objectives: Pyocyanin is a blue-greenish redox-active pigment, produced by Pseudomonas aeruginosa, with a wide range of biological and biotechnological applications. Pyocyanin biosynthesis is regulated by the quorum-sensing (QS) system in which the expression of QS genes and QS-controlled virulence genes may be affected by serum as a complex medium. In the current study, effects of adult bovine serum (ABS) and fetal bovine serum (FBS) on the production of pyocyanin were examined in order to develop it. Materials and Methods: The presence of pyocyanin-producing specific genes and proteins in clinical and soil isolates of P. aeruginosa was confirmed using PCR and SDS-PAGE. Isolates were inoculated to media containing different concentrations of complement-active/-inactivated ABS or FBS and pyocyanin concentration was measured by spectrophotometry. Extracted pigment was characterized by using UV-Visible spectrophotometry. Titration of ABS antibodies against studied isolates was performed by the tube agglutination test. Results: Adding ABS to P. aeruginosa culture medium decreased pyocyanin production compared to the control, while its production increased in FBS containing media (113.21+/-2.581 vs. 55.26+/-0.827 MUg.ml-1 and 126.80+/-2.036 vs. 30.56+/-0.382 MUg.ml-1 of C11 and E8 pyocyanin concentration in the presence of 10% FBS vs. control, respectively). Conclusion: In this study, due to the presence of inhibitors such as complement proteins and antibodies in ABS samples, the use of FBS devoid of antibodies was effective to increase pyocyanin production in studied isolates. PMID- 29238469 TI - The role of sirolimus in proteinuria in diabetic nephropathy rats. AB - Objectives: The aim of this study was to observe the impact of sirolimus on proteinuria in streptozotocin (STZ) induced diabetic rats. Materials and Methods: Rats were given a single injection of STZ to induce diabetic rat model. Rats' 24 hr urine was collected to test, urinary and the kidney tissues were harvested at the 8th and 20th weeks, respectively. Podocyte morphological changes were examined by electron microscopy and the ZO-1, podocin expressions in kidneys were detected by immunohistochemistry; the protein levels of Raptor and pS6 were measured by Western blot assay. Results: In the early stage of diabetic nephropathy (DN), sirolimus reduced the proteinuria significantly (P<0.05); but in the advanced stage of DN, sirolimus worsened proteinuria (P<0.05). Electron microscopy test suggested that sirolimus could reduce the injury of podocyte at the early DN, but increased the injury at the late DN podocyte. Immunohistochemistry results indicated that sirolimus increased the expressions of podocin and ZO-1 at the early DN (P<0.05), but reduced the expressions of ZO-1 and podocin (P<0.05) at the advanced DN. In the different periods of DN, the expression levels of Raptor and pS6 in sirolimus-treated groups were significantly lower than in the DN control groups (P<0.05). Conclusion: Sirolimus can reduce proteinuria and alleviate the early DN podocyte injury in diabetic rat model by inhibiting the activity of mTORC1; but in the advanced stage of DN, sirolimus can increase podocyte injury and urine protein level. PMID- 29238470 TI - The effects of activated omental extract on nuclear and cytoplasmic in vitro maturation of rat oocytes. AB - Objective: The role of growth factors, including vascular endothelial growth factor of activated omentum on mitosis is clearly known, though not on all the aspects of in vitro oocyte maturation. This study was designed to assess the effect of activated-omental extract (AOE) on in vitro maturation (IVM) of rat cumulus-oocyte complexes (COCs). Materials and Methods: In this experimental study, the COCs were incubated in Ham's F-10 supplemented with either 20% AOE, 20% fetal bovine serum (FBS) or serum-free media. Post-culture COCs were studied according to the cumulus cells (CCs) expansion, nuclear maturation and cytoplasmic maturation. Cumuli expansion was evaluated by inverted microscope without staining; nuclear maturation was assessed by aceto-orcein staining (light microscope) and cytoplasmic maturation was also observed by TEM. Results: Expansion of CCs and nuclear maturation of the oocytes in in vitro for 24 hr was significantly higher in AOE- and FBS-supplemented groups (P=0.000 and 0.013) and (P=0.004 and 0.014), respectively, compared to serum-free group. At ultra structural level, after 24 hr, both FBS and AOE-supplemented media showed uniformly wide perivitelline space (PVS). After 12 hr, the cortical granules were found in the oocytes cultured in FBS and AOE-supplemented media. Within 24 hr, both granules and mitochondria were large without any detectable topographic tendency across the ooplasm. In AOE and FBS-supplemented oocytes, the number and size of microvilli were more than those in serum-free one. Conclusion: Although AOE supplementation induced a higher rate of the CCs expansion, and resuming meiosis, it was not as potent as FBS to provide cytoplasmic maturation of rat oocytes. PMID- 29238471 TI - The effects of specific expression of apoptin under the control of PSES and PSA promoter on cell death and apoptosis of LNCaP cells. AB - Objectives: Apoptotic effect of apoptin has been demonstrated in numerous studies. However, its tumor specificity has been questioned by some reports. The aim of this study was to confine the expression of apoptin in the prostate tumor cells by inducing its gene expression under the control of a chimeric enhancer composing of prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) regulatory elements (PSES). Furthermore, we investigated the effects of apoptin expression on LNCaP prostate carcinoma cell survival and apoptosis using MTT assay and annexin V/7-AAD flow cytometry assay. Materials and Methods: Recombinant plasmids containing apoptin gene under the control of PSES/PSA promoter or Cytomegalovirus (CMV) promoter were constructed. Tumor cell lines including LNCaP cells and HeLa cells, and LX-2 cells (as a normal control) were transfected with the plasmids and the expression of apoptin was evaluated by real time-PCR and western blot analyses. The effects of apoptin expression on cell survival and apoptosis were then investigated using MTT and annexinV/7-AAD flow cytometry assay, respectively. Results: Western blot and real time PCR analyses confirmed the specific expression of apoptin under the control of PSES/PSA regulatory element in the LNCaP cells, while CMV promoter caused apoptin expression in both tumor and normal cell lines. Apoptin expression significantly increased cell death and apoptosis in tumor cells when compared with the normal cells (P<0.001). Conclusion: These results suggest that PSES/PSA regulatory element may be considered as an efficient approach for specific expression of apoptin gene in prostate tumor cells and treatment of prostate cancer. PMID- 29238472 TI - Vitamin E improved bone strength and bone minerals in male rats given alcohol. AB - Objectives: Alcohol consumption induces oxidative stress on bone, which in turn increases the risk of osteoporosis. This study determined the effects of vitamin E on bone strength and bone mineral content in alcohol-induced osteoporotic rats. Materials and Methods: Three months old Sprague Dawley male rats were randomly divided into 5 groups: (I) control group; (II) alcohol (3g/kg) + normal saline; (III) alcohol (3g/kg) + olive oil; (IV) alcohol (3g/kg) + alpha-tocopherol (60mg/kg) and (V) alcohol (3g/kg) + palm vitamin E (60mg/kg). The treatment lasted for three months. Following sacrifice, the right tibia was subjected to bone biomechanical test while the lumbar (fourth and fifth lumbar) and left tibia bones were harvested for bone mineral measurement. Results: Alcohol caused reduction in bone biomechanical parameters (maximum force, ultimate stress, yield stress and Young's modulus) and bone minerals (bone calcium and magnesium) compared to control group (P<0.05). Palm vitamin E was able to improve bone biomechanical parameters by increasing the maximum force, ultimate stress and Young's modulus (P<0.05) while alpha-tocopherol was not able to. Both alpha tocopherol and palm vitamin E were able to significantly increase tibia calcium and magnesium content while only alpha-tocopherol caused significant increase in lumbar calcium content (P<0.05). Conclusion: Both palm vitamin E and alpha tocopherol improved bone mineral content which was reduced by alcohol. However, only palm vitamin E was able to improve bone strength in alcohol treated rats. PMID- 29238473 TI - The effects of CCK-8S on spatial memory and long-term potentiation at CA1 during induction of stress in rats. AB - Objectives: Cholecystokinin (CCK) has been proposed as a mediator in stress. However, it is still not fully documented what are its effects. We aimed to evaluate the effects of systemic administration of CCK exactly before induction of stress on spatial memory and synaptic plasticity at CA1 in rats. Materials and Methods: Male Wistar rats were divided into 4 groups: the control, the control CCK, the stress and the stress-CCK. Restraint stress was induced 6 hr per day, for 24 days. Cholecystokinin sulfated octapeptide (CCK-8S) was injected (1.6 ug/kg, IP) before each session of stress induction. Spatial memory was evaluated by Morris water maze test. Long-term potentiation (LTP) in Schaffer collateral CA1 synapses was assessed (by 100 Hz tetanization) in order to investigate synaptic plasticity. Results: Stress impaired spatial memory significantly (P<0.01). CCK in the control rats improved memory (P<0.05), and prevented the impairments in the stress group. With respect to the control group, both fEPSP amplitude and slope were significantly (P<0.05) decreased in the stress group. However, there were no differences between responses of the control-CCK and Stress-CCK groups compared to the control group. Conclusion: The present results suggest that high levels of CCK-8S during induction of stress can modulate the destructive effects of stress on hippocampal synaptic plasticity and memory. Therefore, the mediatory effects of CCK in stress are likely as compensatory responses. PMID- 29238474 TI - Cytotoxic and apoptotic effects of root extract and tanshinones isolated from Perovskiaabrotanoides Kar. AB - Objectives: Perovskiaabrotanoides Kar., from family Lamiaceae, is a little known medicinal plant growing in various regions of Iran. In the present study, cryptotanshinone (CT), tanshinone 2A (Tan2A), and hydroxycryptotanshinone (HCT) were isolated and purified from the roots of P. abrotanoides. In addition, cytotoxic and apoptotic effects of total root extract (TE) and three purified tanshinones were investigated in human cervical carcinoma (HeLa) and human breast cancer (MCF-7) cell lines. Materials and Methods: Alamar Blue(r) assay was used to determine cell viability. Cell apoptotic rate was detected using propidium iodide staining of DNA fragmentation by flowcytometry (sub-G1 peak). The PARP cleavage, as the sign of apoptosis, was investigated by Western blotting. Results: The results revealed that CT, Tan2A, HCT, and TE exhibited significant cytotoxicity in cancer cell lines. All of these compounds caused apoptosis in treated cells and induced sub-G1 peak in the related flowcytometry histograms. HCT was found to have the highest anti-proliferative activity on cancer cells. Western blotting analysis showed cleavage of PARP protein in MCF-7 cells treated with purified tanshinones and TE after 48 hr contact with cells. Conclusion: The findings suggest that root extract of P. abrotanoides and purified tanshinones especially Tan2A and HCT have cytotoxic and apoptotic effects against cancer cell lines. So, they may serve as potential cytotoxic agents for future investigations. PMID- 29238475 TI - Sodium hydrosulfide upregulates mRNA and protein expression of TGF-alpha in gastric mucosa in experimental model of stimulated gastric acid secretion in rats. AB - Objectives: Transforming growth factor alpha (TGF-alpha) has been shown to modulate the gastric acid secretion. Therefore, the aim of the present study was to investigate the effect of sodium hydrosulfide (NaHS) on TGF-alpha expression in gastric mucosa in rats. Materials and Methods: Eighteen rats were randomly divided into 3 groups (6 per group). To determine the effect of NaHS on gene and protein expression of TGF-alpha in gastric mucosa in response to gastric acid, the acid output induced by gastric distension. At the end of experiment, rats were euthanized by anesthetics, and gastric effluents, in addition to mucosa were collected to measure the pH of gastric effluents and to quantify protein and gene expression of TGF-alpha. Results: The stimulated gastric acid upregulated expression levels of TGF-alpha in gastric mucosa. These levels were higher in animals pretreated with NaHS. Conclusion: TGF-alpha upregulatory effect of sodium hydrosulfate implied that TGF-alpha is involved in the acid inhibitory effect of NaHS. PMID- 29238476 TI - Anti-hyperglycemic and antioxidant potential of Croton bonplandianus. Bail fractions in correlation with polyphenol content. AB - Objectives: Diabetes mellitus, a carbohydrate metabolic disorder, occurs due to absolute or relative deficiency of insulin. Current treatment strategies involve either preventing or delaying the intestinal absorption of glucose to lower the levels of postprandial hyperglycemia (PPHG). Herbal remedies have been since ancient times for treating diabetes mellitus. Therefore, identifying novel phytocompounds with alpha-amylase and alpha-glucosidase inhibitory activity that would reduce the glucose absorption as well as the rise in postprandial blood glucose level is vital. Consequently, the present study was aimed to investigate the anti-hyperglycemic activity of Croton bonplandianus against these pancreatic enzymes. Materials and Methods: The methanol extract of C. bonplandianus leaf was prepared and further fractionation was performed with n-hexane, ethyl acetate and chloroform. The antioxidant activity and anti-hyperglycemic activity of the extracts and its fractions were determined. Further, GC-MS analysis was performed for the leaf extract. Results: The chloroform fraction (ChF) was found to contain highest quantity of polyphenols (114.28 ug/ml of GAE), flavonoids (95.68 ug/ml of quercetin) and tannins (63.80 ug/ml of GAE) and also possessed effective inhibitory activity against alpha amylase (IC5095.78 ug/ml) and alpha glucosidase (IC50 126.81ug/ml). The antioxidant activity of ChFwas also higher when compared to other fractions. Further, GC-MS analysis of ChF showed the presence of various components that may be responsible for the above mentioned activities. Conclusion: The study findings suggest that the components present in the leaves of C. bonplandianus, may provide a potential therapeutic source in developing treatment forhyperglycemia. Further bioassay guided fractionation procedure is required to identify the active constituents. PMID- 29238478 TI - Exploring the challenges of the Iranian parliament about passing laws for resource allocation in healthcare: a qualitative study. AB - Background: Awareness about the process of law making and the factors that affect the legislative process have an important role in improving legislations that are approved by parliaments. Objective: This study aimed to explore and analyze the process of development and enactment of law in Iran's parliament, and factors that might affect the enactment of laws that are related to the allocation and distribution of health sector resources in Iran. Methods: In this case study, data were collected through review of literature and national documents, and experts' interviews. Interviews were performed with selected members of parliament (MPs), ex members of parliament and professionals from the Ministry of Health and Medical Education (MOHME) (15 persons). MAX QDA 10 was used for coding and constructing themes. Data were analyzed in five steps (familiarization, developing a conceptual framework, coding, indexing, and interpretation) using a content analysis with inductive and deductive approaches. Results: The main factors that could affect the approval and enactment of legislations related to allocation of healthcare resources in the Iranian parliament were categorized in seven themes including: Importance of issue, resource availability, legislator's awareness about the topic, lobbying and unofficial relations with influential officials, mentioning strong reasons by MOHME, weakness of previous laws, and positive feedback related to the same laws. Conclusion: Although the process of law making in parliament, and implementation of them in health organizations have legal stages, the study showed that several key factors affect this trend. In fact, it is suggested the health policy makers and MPs consider extending a range of factors to improve the process of law making and the efficiency of legislation related to allocation of healthcare resources. PMID- 29238477 TI - Prevalence of metabolic syndrome in Iran: A meta-analysis. AB - Background: Metabolic syndrome) MetS( is a complex risk factor which increases the risk of cardiovascular diseases and type 2 diabetes. There are many studies with various populations and results about the prevalence of MetS in Iran; in order to authenticate these studies and have an overall estimation of its prevalence in Iran, performing a meta-analysis seems to be necessary. Objective: This study aimed to investigate the prevalence of MetS and its components in Iran via meta-analysis method. Methods: All associated published papers in national and international journals of PubMed, Scopus, Web of Science, Magiran, Iranmedex, Science Direct, Medlib, and SID databases were searched from January, 2000 to October, 2016. All types of studies, including local and national surveys that reported the prevalence of MetS among healthy populations in Iran were reviewed. The effects of age, sample size and publication date as possible sources of heterogeneity among the study findings was examined by meta-regression. P-values less than 0.05 were considered as significant in heterogeneity tests. All analysis was done by R Ver. 3.2.1 and STATA (version 10). Results: Seventy eligible studies were selected for meta-analysis. The overall estimation of MetS prevalence was 25% (95% CI: 22-29%) based on the Adult Treatment Panel III (ATP III) criteria, 30% (95% CI: 25-36%) according to the International Diabetes Federation (IDF), and 39% (95% CI: 26-52%) based on the Joint Interim Societies (JIS) criteria. The prevalence of MetS was lower in men than in women (26.9% versus 35.7%). The prevalence of various MetS components including High TG (triglyceride), Low HDL-C, High BP and High FBS (fasting blood sugar) was 43%, 54%, 38% and 22% among the adult population. Conclusion: Findings from the present meta-analyses study displayed a high prevalence of metabolic syndrome in Iran, especially in women, which increases with age in both sexes. It alerts health care providers and policy makers to find solutions in order to take action to reduce MetS risk in society. PMID- 29238479 TI - Vitamin D receptor gene polymorphisms as a risk factor for obesity in Saudi men. AB - Background: The prevalence of obesity and vitamin D deficiency in Saudi Arabia has increased recently. Decreased physical activity might play a role in obesity. Previous studies showed an association between low vitamin D level and its receptor polymorphism with obesity development. Objective: To determine association of low vitamin D level and its receptor polymorphism with obesity in Saudi men. Methods: This case control study was carried out from March 2016 through March 2017. Three hundred Saudi male students (from applied medical sciences in Taif University, Taif, Saudi Arabia) were classified according to BMI into lean, overweight and obese groups. For each individual, blood glucose, cholesterol, HDL-C, LDL-C, insulin and 25-(OH) vitamin D were measured. In addition, Apal, BsmI and TaqI genotypes were performed for each individual from March 2016 through March 2017, through computer-based search of the following databases: PubMed, Web of Science (Thomson ReutersTM). The references of the original literature and the related articles were also searched, for potential complementary studies. Data were analyzed by SPSS version 16, using Spearman's rho and ANOVA tests. Results: There was significant negative association between 25-(OH) vitamin D level and obesity (p<0.01). Genotyping study showed that both bb of BsmI and tt of TaqI genotypes were higher in the obese group compared with lean group (p<0.05). Moreover, bb genotype has higher BMI and HOMA-IR than both BB and Bb; and tt genotype also has higher BMI and HOMA-IR than TT and Tt genotypes (p<0.05). Conclusion: Low vitamin D level and VDR BsmI and Taq1 genotypes may be a risk factor of obesity. PMID- 29238480 TI - Maternal recto vaginal colonization in term and preterm deliveries. AB - Background and aim: Maternal recto-vaginal organisms are the main cause of early onset sepsis in neonates. The aim of this study was to determine the most common organisms and compare maternal recto-vaginal colonization in term and preterm delivery. Methods: This cross-sectional study was done from October 2014 through October 2016 among participants referred to Ayatollah Rouhani Hospital in Babol, Northern Iran. All pregnant women within gestational age (GA) >= 26 weeks and labor pain were included in this study. By a cotton applicator, culture from the lower third of the vagina and another one from the rectum were taken and transported by Stuart media to the laboratory, and were cultured on main Medias within 24 hours. Then microorganisms in preterm and term delivery were compared together. Data were analyzed using SPSS 16. The variables were compared between two groups by chi-squared test, Fisher's exact test and logistic regression. P<0.05 was statistically considered significant. Results: Among 511 mothers with successful culturing, 417 delivered at term and 94 fewer than 37 weeks. Staphylococcus epidermidis and Escherichia coli (E. coli) were the most abundant organisms. The frequency of E. coli in term and preterm delivery was 52.5% and 68.1% respectively (p=0.006). Group B strep was more frequent in term delivery (13.7% vs. 3.2%, p=0.004). Conclusion: Based on our findings, the frequency E. coli and other gram-negative bacteria were higher in preterm delivery groups which indicates the need to assess the efficacy of chemoprophylaxis in situations such as prolonged rupture of membrane, and preterm delivery. PMID- 29238481 TI - Effect of electronic report writing on the quality of nursing report recording. AB - Background and Aim: Recording performed nursery actions is one of the main chores of nurses. The findings have shown that recorded reports are not qualitatively valid. Since electronic reports can be regarded as a base to write reports, this study aims at determining the effect of utilizing electronic nursing reports on the quality of the records. Methods: This quasi-experimental study was conducted with the aim of applying an electronic system of nursing recording in the heart department of Shahid Rahimi Medical Center, Lorestan University of Medical Science. The samples were nursing reports on the hospitalized patients in the heart department, the basis of complete enumeration (census) during the fall of 2014. The subjects were sixteen employed nurses. To do the study, the software of nursing records was set based on the Clinical Care Classification system (CCC). The research's tool was the checklist of the Standards of Nursing Documentation. Results: The findings indicated that before and after the intervention, the amount of reports' adaption with the written standards, respectively, was (21.8%) and (71.3%), and the most complete recording was medicine status (58%) and (100%). The worst complete recording before the intervention, acute changes was (99.1%) and nursing processes was (78%) and after, the medicine status, intake and output status and patient's education (100%); while the nursing report structure was regarded in all cases (100%). The results showed that there is a significant difference in the quality of reporting before and after using CCC (p<0.001). Conclusions: Since the necessary parameters for recording a standard report do exist in electronic reporting (CCC), from one point, nurses are reminded to record the necessary parts and from the other point, the system does not allow the user to shut it down unless the necessary parameters are recorded. For this reason, the quality of recorded reports with electronic reporting improves. PMID- 29238482 TI - A historical review of the concept of labor support in technocratic, humanistic and holistic paradigms of childbirth. AB - Background: In the past century, maternal support during childbirth has been changed according to the different approaches suggested by various health care paradigms. Objective: The aim of this review was to argue the maternity supportive care paradigms of the past century and to closely analyze each paradigm. Methods: This is a historical review, in which published articles were retrieved from databases including Scopus, Science Direct, PubMed and Google Scholar. Sage Journals and Springer's publications were also searched due to the high citation rate of their articles. The keywords entered were "Labor support", "Normal delivery", "Birth attendance", "Supportive approaches", "Health care paradigms", and "Midwifery models of care". They were entered alone or in combinations using "AND". Also, Persian articles were searched in local databases including Irandoc, SID, IranMedex, and Magiran using the above-mentioned keywords in Persian. Sixty articles met inclusion criteria. Results: The review revealed four main themes including the definitions of continuous labor support, the technocratic paradigm, the humanistic paradigm and the naturalistic paradigm as models of labor support. According to the evidence, labor support has changed from technocratic to humanistic and holistic approaches, which in turn, caused some changes in midwifery models of care used by midwives in the practice. Conclusion: Labor support based on the holistic approaches and the naturalistic paradigms could bring about remarkable outcomes, the most important being satisfied with the birth experience, increased mother's self-confidence, enhanced mother's ability in childbirth and better completion of the childbirth process. PMID- 29238483 TI - The influence of polishing techniques on pre-polymerized CAD?CAM acrylic resin denture bases. AB - Background: Lately, computer-aided design and computer-aided manufacturing (CAD/CAM) has broadly been successfully employed in dentistry. The CAD/CAM systems have recently become commercially available for fabrication of complete dentures, and are considered as an alternative technique to conventionally processed acrylic resin bases. However, they have not yet been fully investigated. Objective: The purpose of this study was to inspect the effects of mechanical polishing and chemical polishing on the surface roughness (Ra) and contact angle (wettability) of heat-cured, auto-cured and CAD/CAM denture base acrylic resins. Methods: This study was conducted at the Advanced Dental Research Laboratory Center of King Abdulaziz University from March to June 2017. Three denture base materials were selected: heat cure poly-methylmethacrylate resin, thermoplastic (polyamide resin) and (CAD?CAM) denture base resin. Sixty specimens were prepared and divided into three groups, twenty in each. Each group was divided according to the polishing techniques into (Mech P) and (Chem P), ten specimens in each; surface roughness and wettability were investigated. Data were analyzed by SPSS version 22, using one-way ANOVA and Pearson coefficient. Results: One-way analysis of variance (ANOVA) and post hoc tests were used for comparing the surface roughness values between three groups which revealed a statistical significant difference between them (p1<0.001). Heat-cured denture base material of (Group I) in both methods, showed the highest mean surface roughness value (2.44+/-0.07, 2.72+/-0.09, Mech P and Chem P respectively); while CAD?CAM denture base material (group III) showed the least mean values (1.08+/ 0.23, 1.39+/-0.31, Mech P and Chem P respectively). CAD/CAM showed the least contact angle in both polishing methods, which were statistically significant at 5% level (p=0.034 and p<0.001). Conclusion: Mechanical polishing produced lower surface roughness of CAD?CAM denture base resin with superior smooth surface compared to chemical polishing. Mechanical polishing is considered the best effective polishing technique. CAD/CAM denture base material should be considered as the material of choice for complete denture construction in the near future, especially for older dental patients with changed salivary functions, because of its wettability. PMID- 29238484 TI - Pattern and factors associated with cardiovascular diseases among patients attending the cardiac center in Arar City, Northern Saudi Arabia. AB - Background: Cardiovascular diseases (CVD) are among the main causes of premature death and hospital admission worldwide, constituting a great economic burden on health care systems. Additionally, thyroid diseases may exert a deleterious effect on the outcomes of CVD patients. Aim: This study was conducted to identify the pattern and factors associated with CVD distribution and the relation with thyroid dysfunction in the study population. Methods: This cross sectional study was conducted on 181 participants in the cardiac center in Arar, Kingdom of Saudi Arabia (KSA), from September 2016 to March 2017. A questionnaire was designed for collecting data about socio-demographic variables, smoking, types of CVD, and thyroid dysfunction among participants. Results: Findings showed that 42.5% of the participants were hypertensive, 11.6% had myocardial infarction, 8.9% were ischemic and 7.2 % had arrhythmia. The majority of participants (80.6%) were euthyroid. In contrast, 13.3% of the participants had hypothyroidism and 6.1% were hyperthyroid. Most of the studied factors had no significant effect on CVD distribution while smoking showed a remarkable variation among patients with different CVD types (p=0.013). Data were analyzed by SPSS version 15, using descriptive statistics and Chi-square test. Conclusion: Our findings indicated the urgent need for stressing on tobacco use control measures and increasing public awareness about hazards of tobacco especially among CVD patients. PMID- 29238485 TI - Prevention of osteoporosis in female students based on the Orem self-care model. AB - Background: The World Health Organization has introduced osteoporosis as the fourth main enemy of mankind. Self care has served as a new trend in health care. Objective: Educational intervention for osteoporosis related preventive self care in female university students using the Orem model. Methods: This study is a controlled filed trial, carried out with female students of Islamic Azad University, Shahrekord Branch, Iran, from October 28, 2014 to November 15, 2016. Two-stage random stratified sampling was performed and the data were collected through a validated questionnaire developed by the researcher for osteoporosis preventive self-care based on the Orem model. The intervention group received education about osteoporosis preventive self-care through two months training, as per the dimensions in the Orem model. For statistical analysis, independent samples t-test and paired t-test were used in SPSS version 23. Results: As revealed, mean scores for self-care agency, self-care demand, self-care operation structures and total self-care in the intervention group were significantly different before and after the intervention (p=0.014, p<0.001, p=0.002, and p<0.001, respectively). Accordingly, educational intervention seems to be effective in promoting self-care for the prevention of osteoporosis. While the control group, showed no significant difference in any of the above-mentioned aspects before and after intervention (p=0.90, p=0.53, p=0.51, and p= 0.97, respectively). Conclusion: The results are in favor of the effects of educational intervention on osteoporosis preventive self-care among female students. It can be suggested that education during a woman's young age, can be very beneficial for the prevention of osteoporosis in the future. Trial registration: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: IRCT201510028742N8. Funding: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 29238486 TI - Deep Venous Thrombosis among hypertensive patients in King Abdulaziz University (KAU) Hospital, Jeddah, Kingdom of Saudi Arabia. AB - Background: Deep venous thrombosis (DVT) is a frequent cardiovascular disorder. It is among the main causes of morbidity and mortality among hospitalized patients and, at the same time, can be easily avoided. Studies clarified that there are a variety of factors which can be significantly associated with the development of DVT in hospitalized patients. Objective: to identify frequency and factors associated with occurrence of DVT among hypertensive patients referred to KAU hospital, Jeddah, Kingdom of Saudi Arabia. Methods: A cross-sectional hospital-based study was conducted from October 2016 to March, 2017. All hypertensive patients referred to or admitted to the hospital departments and who were suspected to have DVT and subjected to Doppler examination were included in the study. A questionnaire was designed to obtain data about DVT frequency among participants and factors associated with the development of DVT among them. Data was collected through face to face interviews of patients included in the study. Results: DVT was detected in 13.5 % of the studied hypertensive patients. Increased age and gender had no significant association with the development of DVT among the studied patients. In addition, other studied factors and comorbidities had no significant role in DVT development among the study participants. Conclusion: Knowing the most common risk factors and their significance in developing DVT is essential for early detection of DVT to prevent it, especially for hypertensive patients. Awareness campaigns should be held more often in different neighborhoods of the city. PMID- 29238487 TI - Morphology of the corpus callosum and schizophrenia: A case-control study in Kashan, Iran. AB - Background: Corpus Callosum (CC) plays a significant role in hemispheric communication and in lateralized brain function and behaviors. Structural abnormalities in the corpus callosum of schizophrenic patients were reported. However, previous studies regarding the relationship between morphology of CC in patients with schizophrenia and healthy people are controversial. Objective: To evaluate the morphological differences of the CC between patients with chronic schizophrenia and healthy people and to examine the relationship between the characteristics of the CC and schizophrenia severity. Methods: This cross sectional study was conducted on 63 patients with chronic schizophrenia (the case group) referred to Kargarnezhad Psychiatric Hospital in Kashan, Iran, and 63 healthy people (the control group) between January 2013 and December 2014. All participants underwent brain magnetic resonance imaging. Shape, anteroposterior length, and area of the CC were measured and compared in both groups. The severity of the symptoms occurring in patients with schizophrenia was evaluated using the positive and negative syndrome scale. In this study, we employed Chi square test, t-test, Pearson product-moment correlation coefficient test, bivariate analysis of variance and logistic regression were used to test the association between different variables using SPSS software version 20. Results: Results showed that the most common shape of the CC in each group was splenial bulbosity. The length and area of the CC in patients with schizophrenia were less than those of the control group and were greater in men compared with women in both groups. Although there was a significant difference in the surface area of the CC between the schizophrenic and control groups (p<0.001), no significant difference was seen regarding the anteroposterior length of CC (p=0.75). Moreover, a significant correlation was found between the surface area and anteroposterior length of the CC (p<0.001 and p<0.014, respectively). Conclusions: Morphologic characteristics of the CC can be helpful to anticipate schizophrenia especially in patients' family, and it can be used for suitable and faster treatment to prevent progressive cognitive dysfunction. PMID- 29238488 TI - Effect of hydrofluoric acid surface treatments on micro-shear bond strength of CAD/CAM ceramics. AB - Introduction: Dental ceramics are appreciated as highly esthetic restorative materials that can simulate the appearance of natural dentition better than other materials. The aim of this study was to evaluate the effect of hydrofluoric acid concentration and etching time on micro-shear bond strength (MUSBS) to IPS e.max CAD and Vita Mark II of a dual cured resin cement (Panavia F2.0). Methods: This study was an experimental in vitro study, performed in the dental material research center of Babol University of Medical Sciences in 2016. Two hydrofluoric acid concentrations (5% and 10%) and three different etching times (20, 60 and 120 seconds) were used to etch the specimens respectively. A silane coupling agent (Clearfil porcelain activator) and priming and bonding agent (Clearfil SE bond) were used on the etched surfaces in accordance to the manufacturer's instructions of use. Then resin cement was applied on the prepared ceramic surfaces and light cured. MUSBS between resin cement and the porcelains were measured with a universal testing machine. Mode of failure was observed with 40* magnification by means of a Stereo microscope. Data were analyzed with ANOVA and independent-samples t-test and Chi-square tests. Results: In both e.max and Vita Mark II groups, MUSBS were not significantly different when different etching times (one-way ANOVA) and HF acid concentrations (Independent-samples t-test) were used (p>0.05), but the highest MUSBS was shown in e.max specimens etched 60 s with 5% HF and Vita Mark II specimens etched 20 s with 10% HF. MUSBS of e.max was significantly higher than Vita Mark II (p=0.00). Conclusion: Best surface treatment for e.max and Vita Mark II ceramics is 20 s etch using 5 % hydrofluoric acid. PMID- 29238489 TI - Comparison of mammography and ultrasonography findings with pathology results in patients with breast cancer in Birjand, Iran. AB - Background: Early diagnosis of breast cancer, the incidence of which among Iranian women is about a decade earlier than in developed countries, is important. Objective: To compare mammography and ultrasonography findings with those of pathology in patients with breast cancer. Methods: This descriptive cross-sectional study was performed using medical records of 79 patients with breast malignancies, who were referred to Imam Reza Hospital and private laboratories of Birjand, Iran, from December 2012 to December 2014. The patients' information was recorded using a checklist, which included name, code, age, ultrasonography, and mammography results and pathology reports. The results of ultrasonography and mammography were compared with pathology findings as the gold standard. SPSS Version 21 was used for data analysis. Results: The mean age of the patients was 46.94 +/- 11.76 years. The results showed that 74.7%, 16.5%, and 7.6% of the patients had ductal carcinoma, lobular carcinoma, and mixed carcinoma, respectively. About 72.5%, 24.6%, and 2.9% of the patients had stage 2, 3, and 1 breast cancer, respectively. In addition, both breasts were involved in 1.3% of the patients. The ultrasound findings were positive and false negative in 97.5% and 2.5% of the cases. Moreover, the mammography results were positive and false negative in 98.7% and 1.3% of the patients. Conclusion: This study showed that mammography is the preferred modality in screening breast cancer patients; the use of complementary tests such as ultrasonography is recommended, especially in high-risk women. PMID- 29238490 TI - Gastroesophageal reflux disease among population of Arar City, Northern Saudi Arabia. AB - Background: During the recent decade, several studies about prevalence of symptom based GERD have revealed increase of its prevalence. In addition to the highly disturbing typical symptoms, it has a series of known consequences and may affect the quality of life. Objective: To determine the prevalence of gastroesophageal reflux disease (GERD) as well as their main characteristics and risk factors among the population of Arar City, Northern Saudi Arabia. Methods: A cross sectional study was carried out on a sample of 302 individuals from population of Arar city from October 01, 2016 to May 30, 2017, using a researcher made questionnaire and checklist. The questionnaire was administrated in online method. Data were analyzed by SPSS version 22, using descriptive statistics and Chi-Square test. Results: total prevalence of GERD among the studied respondents was 61.8%. In 11.8% there was severe pain. Further, 61.8% reported loss of appetite as an associated condition, 57% reported nausea and vomiting, 55.9% indigestion, 55.4% food regurgitation, 41.4% chest pain and 35.5% headache. The main found risk factors were fatty meals in 84.9% followed by coffee drinking in 77.4%, stress in 71%, spicy food in 58.1% NSAD in 24.7% and smoking in 17.2%. There were no significant effect of sex, age, educational level, marital status or occupational status in the occurrence of GERD (p>0.05). Conclusion: This is the first population-based study in Arar, Northern Saudi Arabia, reporting prevalence of GERD. The rate of 61.8% was substantially high. Coffee drinking, stress, spicy food, prolonged use of NSAID, fatty meals and smoking were the reported risk factors. Population-based endoscopic studies are recommended. PMID- 29238491 TI - The effect of training interventions on the psychological factors of oral health in pregnant women. AB - Background and aim: Oral health is crucial for high-risk pregnant women in order to preserve their health and the health of their infants. Therefore, this study aimed to determine the impact of training programs on the behavior of pregnant mothers concerning oral health in Khorramabad, Iran. Methods: This is an educational experimental study carried out in 2015 on 164 pregnant women referring to health centers in the city of Khorramabad who were randomly divided into two groups (each n=82). The instruments for data collection included a questionnaire based on the Health Belief Model regarding oral health and two checklists of oral health indexes (OHIS and DMFT). Data were analyzed using SPSS 20 via paired-samples t-test, independent-samples t-test and Chi-square. Results: The mean score of knowledge and performance, and the variables of the components of the Health Belief Model including the perceived susceptibility, severity, benefits, barriers and self-efficacy regarding the oral health care, significantly increased in the intervention group following the training intervention (p<0.001). However, the DMFT index did not show any changes after the intervention in the intervention and control groups (p=0.381). On the other hand, the OHIS index significantly decreased in the intervention group as compared with the pre-intervention scores (p=0.002). Conclusion: The results of this study showed that training based on the Health Belief Model leads to the enhancement of performance regarding oral health in pregnant women and thus prevents any increase in OHIS and DMFT levels during pregnancy. PMID- 29238492 TI - The prevalence of visual disorders in Iranian students: A meta-analysis study and systematic review. AB - Background: Visual defects have dramatic effects on health, self-esteem, and educational function of students, and delayed diagnosis will cause complications, like academic failure and psychologic disorders. Objective: The present study aimed to investigate the prevalence of ocular disorders in Iranian students in a systematic review. Methods: We searched databases, including PubMed, SID, Magiran, Google Scholar, and Iranmedex using the following keywords in Persian and English: disorders, vision, amblyopia, refractive errors, astigmatism, student, and Iran with all the possible combinations, important, chief, and sensitive words. Search resulted in 28 articles, conducted during a period from 1996 to 2014 in Iran and their data was analyzed using meta-analysis and random effects model. Heterogeneity of studies was assessed using I2 index, and data was finally analyzed with R Software and STATA (Version 11.2). Results: Total number of subjects in the study was 1,117,274, aged 2 to 18 years. The prevalence of disorders related to amblyopia, refractive error, and strabismus was 8%, 7% and 1%, respectively. The greatest amount of refractive error was related to astigmatism (19%) followed by myopia (17%). Conclusion: According to the study results, the prevalence of visual disorders among Iranian students indicated the critical necessity of screening programs for prevention of visual disorders in this age group. PMID- 29238493 TI - Correlation of Gerkin, Queen's College, George, and Jackson methods in estimating maximal oxygen consumption. AB - Background and aim: Test of maximal oxygen consumption is the gold standard for measuring cardio-pulmonary fitness. This study aimed to determine correlation of Gerkin, Queen's College, George, and Jackson methods in estimating maximal oxygen consumption, and demographic factors affecting maximal oxygen consumption. Methods: This descriptive cross-sectional study was conducted in a census of medical emergency students (n=57) in Qazvin University of Medical Sciences in 2016. The subjects firstly completed the General Health Questionnaire (PAR-Q) and demographic characteristics. Then eligible subjects were assessed using exercise tests of Gerkin treadmill, Queen's College steps and non-exercise George, and Jackson. Data analysis was carried out using independent t-test, one way analysis of variance and Pearson correlation in the SPSS software. Results: The mean age of participants was 21.69+/-4.99 years. The mean of maximal oxygen consumption using Gerkin, Queen's College, George, and Jackson tests was 4.17, 3.36, 3.64, 3.63 liters per minute, respectively. Pearson statistical test showed a significant correlation among fours tests. George and Jackson tests had the greatest correlation (r=0.85, p>0.001). Results of tests of one-way analysis of variance and t-test showed a significant relationship between independent variable of weight and height in four tests, and dependent variable of maximal oxygen consumption. Also, there was a significant relationship between variable of body mass index in two tests of Gerkin and Queen's College and variable of exercise hours per week with the George and Jackson tests (p>0.001). Conclusion: Given the obtained correlation, these tests have the potential to replace each other as necessary, so that the non-exercise Jackson test can be used instead of the Gerkin test. PMID- 29238494 TI - Prevalence of diabetes mellitus and its relation with obesity in Turaif (Saudi Arabia) in 2017. AB - Background: The significant increase in the prevalence of obesity over past decades caused the concomitant rise in the incidence of glucose intolerance and diabetes. Objective: To determine the prevalence of diabetes among Saudi nationals in Turaif, Kingdom of Saudi Arabia and to examine the association between diabetes and obesity in the studied population. Methods: This study was conducted during the period from May 01 to May 31, 2017. Data was collected from 402 individuals aged between 6-63 years via a predesigned questionnaire covering medical history of diabetes, age and sex. Body weight and height was measured to calculate BMI. Data were analyzed by SPSS version 15, using descriptive statistics and Chi-Square test. Results: Mean age (+/- SD) was 23.27 (+/-13.509) years, male to female ratio was 38.1% to 61.9%. The total prevalence of DM among the studied population was 4.5%, pre-diabetic cases were 7.5%. There is significant effect of age, sex and BMI on the occurrence of diabetes among the studied population (p<0.05). Conclusions: Awareness campaigns and prevention programs about diabetes should be instituted and control strategies should be implemented. There is a need for a diabetes screening and management programs, focusing on access to health care in the city. PMID- 29238495 TI - Assessment of life skills of medical students in Mashhad, Iran, in 2015. AB - Background: Developing social skills and mental health is a crucial part of the psychosocial health status of medical students. Objective: The aim of this study was to assess the life skills of medical students in Mashhad University of Medical Sciences (MUMS). Methods: This cross-sectional study was performed in Mashhad University of Medical Sciences, Iran in 2015. By census method, 146 interns were entered into the study. The life skill questionnaire, consisting of 144 questions, was used as the measurement tool. Over 3 months, all the medical students in internship period were asked to complete the questionnaire. Data were analyzed by independent-samples t-test, one-way ANOVA, and Mann-Whitney with SPSS version 11.5 software. Results: Women were shown to have higher decision-making ability than men (p=0.046). It was also shown in the study that social behavior (p=0.018), participation in activities that improve benefits (p=0.006), critical thinking (p=0.007), observing and using safety points (p=0.005), and mental health status (p=0.034) were significantly lower in men than in women. The data also suggests that men (13.97+/-4.7249) are more likely to become global citizens than women (12.15+/-3.6298) (p=0.010). Furthermore, there was a significant difference when comparing smoking and non-smoking in freedom and justice (p=0.003) and becoming a global citizen (p=0.012). Conclusion: Our study provides helpful information about medical students' life skills for policy makers and university authorities. We suggest that gender differences should be considered during life skill training. PMID- 29238497 TI - The role of anxiety and depression on acceptance and action, considering emotional schemas in diabetics of Birjand (Iran). AB - Background: Diabetes is one of the most common noncommunicable diseases around the world that accompanies assorted psychiatric disorders including anxiety and depression due to being chronic. Objective: The aim of this study was to evaluate the effect of anxiety and depression on acceptance and action, considering emotional schemas of diabetics referring to diabetes clinics of health centers in Birjand, Iran. Methods: This study was conducted in 2016 and was a correlational study with a structural equation modeling approach. The statistical population of this study were all men and women with type 2 diabetes in Birjand, with an active health record in health centers of this county. To collect data, Depression, Anxiety, and Stress Scale (DASS-21), Acceptance and Action Questionnaire-II (AAQ II) and Leahy Emotional Schema Scale (LESS) were employed. Using SPSS19 and LISREL, data were analyzed via multiple regression and modeling at p<=0.05. Results: In general, 350 subjects entered the study, most of whom were between 50 and 60 years of age and of whom, (47.7%) were women. Results show that depression has had a negative contribution in predicting quality of life (p=0.0001). In addition, results demonstrated the negative relation of anxiety and depression in predicting no emotional avoidance (flexibility) (p=0.0001). Anxiety and rumination had a positive effect and emotional unawareness had a negative effect on predicting no emotional avoidance (p=0.0001). Conclusion: Results of this study showed that by reducing adaptive emotional schemas, emotions reduce psychological flexibility and increase emotional avoidance. In addition, by increasing non-adaptive emotional schemas, it increases no flexibility and emotional avoidance that finally reduces quality of life as well as acceptance and action. PMID- 29238496 TI - Lifelong learning strategies in nursing: A systematic review. AB - Background: Lifelong learning is an expectation in the professional performance of nurses, which is directly related to the success of students in nursing schools. In spite of the considerable attention paid to this issue, lifelong learning strategies are not fully understood. Objective: The aim of this study was to clarify lifelong learning strategies of nursing students with respect to international experience. Methods: In this systematic review, an extensive investigation was carried out using Persian and English studies in Pub Med, ProQuest, Cochrane, Ovid, Scopus, Web of Science, SID, and Iran Doc using the following keywords: lifelong learning, self-directed learning, lifelong learning model, continuing education, nursing education, and lifelong program. Finally, 22 articles published from 1994 to 2016 were selected for the final analysis. Data extracted from the selected articles was summarized and classified based on the research questions. Results: In this study, 8 main themes, namely intellectual and practical independence, collaborative (cooperative) learning, researcher thinking, persistence in learning, need-based learning, learning management, suitable learning environment, and inclusive growth, were extracted from the article data. Conclusion: Having identified and clarified lifelong learning strategies in nursing, it is recommended to use the research findings in the programs and teaching systems of nursing schools. Use of strategies of lifelong learning will led to increased quality of education, development of nursing competency and finally, increased quality of patient care. PMID- 29238498 TI - Explaining family physicians' beliefs about antibiotic prescription. AB - Background: Antibiotics are among those drugs prescribed abundantly in hospitals due to their high efficiency. However, excessive, non-logical and unnecessary use of antibiotics regardless of physicians' recommendations is considered as a challenge. Objectives: The aim of this study was to explain family physicians' beliefs about antibiotic prescription in Ahvaz. Methods: This study is part of a content-analysis qualitative research conducted in Ahvaz in 2016. Study subjects were selected according to purposive sampling and data collection continued to data saturation. Required data were collected using semi-structured in-depth interviews with participation of eight subjects. Data analysis was conducted along with conducting interviews using constant comparison analysis, and it continued to the last interview. Strength and accuracy of data were investigated by experts and participants. Results: From data analysis, four major categories were extracted that were composed of 20 subcategories. They were 1) expected outcomes of antibiotics (perceived pros and cons); 2) perceived pressure to follow others' opinions; 3) the level of access to antibiotics; and 4) individual's perception for prescription. Conclusion: Findings of this study showed that various factors affect physicians' decisions to prescribe antibiotics and it is emphasized to consider these factors. PMID- 29238499 TI - Exploring perceptions of policymakers about main strategies to enhance fertility rate: A qualitative study in Iran. AB - Background: Total fertility rate in Iran has declined unprecedentedly over the past thirty years. However, debating on proper strategies to increase fertility is still a matter of discussion among experts. Objective: To explain the main strategies to increase fertility from the viewpoints of the policy makers. Methods: This is a qualitative study using content analysis. Purposeful sampling approach was used to gather data. The data were collected via semi-structured interviews. Eight experts participated in the study and the main criteria were executive experience related to public health, scientific publication in these areas and availability as well as their own interest. Content analysis was used to extract the codes. Results: The main theme extracted was improving the infrastructures. Almost all participants agreed on interventions around removing marriage obstacles, improving working conditions for women, improving the quality of the educational system, training and consultation, research, and improving services to increase fertility rate. Conclusions: The government should formulate long-term instead of short-term policies, and note that improving the economic conditions along with the promotion of social welfare, and enabling women in balancing work and family, are highly influential in childbearing decision making, as they ensure a better future for the next generation. In addition, people should touch on the potential risk of future fertility reduction, so it is suggested to inform the public through free discussions. PMID- 29238500 TI - Effects of dexmedetomidine on heart arrhythmia prevention in off-pump coronary artery bypass surgery: A randomized clinical trial. AB - Background: Arrhythmia occurring during and after surgery is one of the major complications in open-heart surgery. Dexmedetomidine is an intravenous alpha-2 agonist and very specific short-acting drug to protect the various organs against ischemic injuries and blood reflow. However, the effect of dexmedetomidine for preventing intraoperative heart arrhythmias has not been recognized. Objective: This study aimed to determine the effect of dexmedetomidine on the incidence rate of heart arrhythmias and anesthetic required in off-pump coronary artery bypass surgery. Methods: This randomized clinical trial was conducted on patients who were candidates for off-pump coronary artery bypass referring to Imam Reza Hospital of Mashhad, Iran, from July 2016 through January 2017. The patients were randomly assigned to two groups of intervention (infusion of 0.5 mcg/kg/h dexmedetomidine together with induction followed by infusion of 0.5 mcg/kg/h by the end of the surgery) or control (saline infusion). Mean arterial pressure (MAP) and heart rate (HR) were measured before induction, during surgery operation and ICU admission. Data were analyzed by SPSS version 18 using Chi Square and independent-samples t-test. Results: A total of 76 patients with a mean age of 59.8 +/- 8.2 years (in two groups of 38) were studied. The two groups had no statistically significant difference in terms of background variables. The MAP and HR values before induction, during surgery and ICU admission were significantly higher in the control group than in the intervention group (p=0.001). Out of the studied arrhythmias, the values of PAC (55.2% vs. 15.7%), PVC (81.5% vs. 21.0%), AF (26.3% vs. 7.8%), VTAC (21.0% vs. 2.6%) were significantly lower in dexmedetomidine group (p=0.001). Conclusion: It seems that dexmedetomidine administration during induction and surgery can cause significant reduction in most of the common arrhythmias in off-pump coronary bypass surgery. The use of dexmedetomidine maintains MAP and HR at significantly lower values, and changes compared to the control group as well as reduces the need for anesthetic compounds. Trial Registration: The present study has been registered at the Iranian Registry of Clinical Trials (www.IRCT.IR) with a code of IRCT2016072413159N9 before starting the study. Founding: This study was fully sponsored by the Research Deputy at Mashhad University of Medical Sciences, Iran (grant number 941413). PMID- 29238501 TI - The effect of perineal massage during the second stage of birth on nulliparous women perineal: A randomization clinical trial. AB - Background: Childbirth and puerperium are of the most important periods in women's lives and can affect different aspects of their lives. Objective: To determine the effect of perineal massage in the second stage of labor on perineal lacerations, episiotomy, and perineal pain in nulliparous women. Methods: This randomization clinical trial was conducted at Be'sat Hospital in Sanandaj, Iran, from 2013 to 2014. A total of 195 nulliparous women were included in the study. The participants were selected through convenience sampling, and randomly assigned to two groups: intervention and control groups. The intervention group received 30-minute perineal massage during second stage of labor. Subsequently, we analyzed perineal laceration, episiotomy, and perineal pain among the two groups. All of them were taught about postpartum perineal pain and its severity, and the researcher followed them up 3 days, 10 days, and 3 months after childbirth by telephone. The data were analyzed using SPSS version 18. We used descriptive statistics and analytical statistics, including t test, Chi-square test, and Fisher's test. Results: Frequency of episiotomy was 69.47% in the intervention group and 92.31% in the control group, and the difference was statistically significant (p<0.05). The results revealed 23.16% of first-degree perineal laceration and 2.11% of second-degree perineal laceration in the intervention group, and no vestibular laceration or third- and fourth-degree lacerations in the intervention group. However, there were 5.13% of vestibular laceration, 7.69% of first-degree laceration, 2.56% of second-degree laceration, and 1.05% of third-degree laceration (one woman) in the control group. Based on the results, the postpartum perineal pain was significantly different in both groups. Conclusion: Regarding the results of this study and those of other studies, perineal massage during the second stage of labor can reduce the need to episiotomy, perineal injuries, and perineal pain. Trial registration: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct.ID: IRCT2013090314556N1. Funding: This study received by financial support of Kurdistan University of Medical Sciences, Sanandaj, Iran. PMID- 29238502 TI - Profile of facial palsy in Arar, northern Saudi Arabia. AB - Background: The term facial palsy generally refers to weakness of the facial muscles, mainly resulting from temporary or permanent damage to the facial nerve. Common causes of facial paralysis include infection or inflammation of the facial nerve, head trauma, head or neck tumor, stroke. Objective: To outline the incidence of several etiologies and the profile of patients with peripheral facial paralysis attending the outpatient clinic of the neurology department in Hospitals of Arar City, Saudi Arabia. Methods: This cross-sectional study was carried out in Arar city from October 2016 to May 2017. The study was conducted in the outpatient clinic of the neurology department in hospitals of Arar City. Any ages of both sexes of all newly diagnosed unilateral facial palsy were included in the study. Data were analyzed by SPSS version 15, using descriptive statistics and Chi-square test. P-value was considered significant if <0.05. Results: The mean age of the facial palsy cases was 33.65 (+/-11.71) years. Among the studied participants, the total prevalence of facial palsy was 26.3% (61% females and 39% males). The right side of the face was affected in 51.2% and the etiology was exposure to cold air current in 92.7% of cases. The treatment was physiotherapy in 80.5% of the cases, medical in 17.1% and surgical in 2.4%. There was significant relationship between smoking and the occurrence of facial palsy (p<0.05). Conclusion: The study revealed that facial palsy was common in Arar city. The rate is higher among males than females. We also concluded that exposure to cold air current was the main etiology. We recommend health education sittings to bring awareness to the public about the nature, causes, risk factors, prevention and treatment of the disease. PMID- 29238503 TI - Designing and validation: a questionnaire of hope for family members of patients hospitalized in intensive care unit. AB - Background: Families of patients are faced with stressors in the intensive care unit (ICU) that cannot be controlled sometimes. Having hope is one of the strategies for obtaining self-control in patients' families, which deals with such situations. Objective: The purpose of this study was to design and validate a questionnaire of hope for family members of patients hospitalized in intensive care units. Methods: This study was conducted for family members of patients hospitalized in the intensive care units of Kurdistan and Tehran provinces, in Iran, between the years 2015-2016. In this study, 126 family members were selected using convenience sampling. The study was conducted using a questionnaire of hope scale for family members of patients hospitalized in intensive care units and demographic characteristics. During the study, construct and criterion validity of the tool was determined. The Reliability was determined using internal consistency and test-retest coefficient. Data were analyzed through factor analysis, correlation coefficient and Cronbach's alpha. Construct validity of the scale was analyzed using exploratory factor analysis (EFA). Results: Participants in this study included 12 family members of patients hospitalized in the intensive care units. Cronbach's alpha coefficients obtained from analysis of questionnaires completed by family members of patients was 0.916. Cronbach's alpha under the first scale (compatibility) was 0.898, Cronbach's alpha of the second subscale (self-confidence) was 87%, Cronbach's alpha under the third subscale (Sense of responsibility) was 0.770. The fourth subscale (Looking to the future) was 0.571. Pearson correlation coefficients between the scores obtained from two family members responses to the hope scale were 0.939 which showed that scale stability was average. As a result, exploratory factor analysis, four factors were found that were named according to the statements of each group. Conclusion: Consistency coefficients between the two tests was 0.939 that the stability over time the questionnaire was confirmed. A questionnaire of hope in the intensive care unit can measure different dimensions of hope to the families of these patients and help to improve the care of these patients. Validity and reliability of "scale for hope of families of these patients" was appropriate and it could be used to measure hope in families of these patients. PMID- 29238504 TI - Iron overload assessment in beta Thalassemia Major - is T2* Magnetic Resonance Imaging the answer? PMID- 29238505 TI - Surveying the factor structure and reliability of the Persian version of the Jefferson Scale of Physician Lifelong Learning (JeffSPLL) in staff of medical sciences. AB - Background: In medical sciences, commitment to lifelong learning has been expressed as an important element. Today, due to the rapid development of medical information and technology, lifelong learning is critical for safe medical care and development in medical research. JeffSPLL is one of the scales for measuring lifelong learning among the staff of medical sciences that has never been used in Iran. Objectives: The aim of the present study was to determine the factor structure and reliability of the Persian version of JeffSPLL among Persian speaking staff of universities of medical sciences in Iran. Methods: This study was a cross-sectional study, methodologically, that was conducted in 2012-2013. In this study, 210 staff members of Birjand University of Medical Sciences were selected. Data collection tool was the Persian version of JeffSPLL. To investigate the factor structure of this tool, confirmatory factor analysis was used and to evaluate the model fit, goodness-of-fit indices, root mean square error of approximation (RMSEA), the ratio of chi-square to the degree of freedom associated with it, comparative fit index (CFI), and root mean square residual (RMR) were used. To investigate the reliability of tool, Cronbach's alpha was employed. Data analysis was conducted using LISREL8.8 and SPSS 20 software. Results: Confirmatory factor analysis showed that RMSEA was close to 0.1, and CFI and GFI were close to one. Therefore, four-factor model was appropriate. Cronbach's alpha was 0.92 for the whole tool and it was between 0.82 and 0.89 for subscales. Conclusion: The present study verified the four-factor structure of the 19-item Persian version of JeffSPLL that included professional learning beliefs and motivation, scholarly activities, attention to learning opportunities, and technical skills in information seeking among the staff. In addition, this tool has acceptable reliability. Therefore, it was appropriate to assess lifelong learning in the Persian-speaking staff population. PMID- 29238506 TI - Comparison of the effect of topiramate versus gabapentin on neuropathic pain in patients with polyneuropathy: A randomized clinical trial. AB - Background: Neuropathic pain is one of the most common complaints of neurologic clinics. Neuropathic pain is common and important and has inappropriate complications, and despite their importance, there is no effective treatment for them. Objective: Because of the importance of neuropathic pain and safe and effective treatment, in this study, we determined the effect of topiramate versus gabapentin in patients with neuropathic pain. Methods: In this randomized clinical trial, 30 patients with pain attributed to neuropathy who had at least one month of neuropathic pain in one area, were randomized to receive either gabapentin, titrated from 300 mg/day to a maximum of 900 mg/day or topiramate, titrated from 50 mg/day to a maximum of 100 mg/day after a 4-week period in the neurology clinic of Imam Khomeini Hospital of Urmia city, Iran in 2015. Complication, drug tolerance rate and pain were investigated. The pain was measured on visual analog scale (VAS). The data were analyzed by SPSS version 18, and using descriptive statistics, t-test, and ANOVA. Results: In patients treated by gabapentin, the primary pain score was 74.33+/-10.29, this score decreased to 49.46+/-11.41 and 29.93+/-11.92 in the second and fourth week after intervention with gabapentin. In topiramate treated patients, the primary score was 76.00+/ 9.69. It decreased to 54.33+/-10.31 and 34.20+/-6.09 at the same time. There were no significant differences between both groups in terms of average reduction of pain intensity [gabapentin group (59.73%) compared with topiramate (55%) (p=0.48)]. In the present study, the only complication reported in patients treated by gabapentin was drowsiness, but other uncommon side effects were nausea and dizziness. Conclusion: This study showed that both gabapentin and topiramate reduce pain. Topiramate can also be a good alternative choice, if gabapentin has side effects for patients and it cannot be tolerated, topiramate can be a good replacement. Trial registration: The trial was registered at the Thai Registry of Clinical Trials (http://www.clinicaltrials.in.th) with the TCTR ID: TCTR20170615001. Funding: This research has been financially supported by Research Council of Urmia University of Medical Sciences. PMID- 29238507 TI - Kinetic parameters and nitrate, nitrite changes in bioremediation of Toxic Pentaerythritol Tetranitrate (PETN) contaminated soil. AB - Background: Cleanup of areas contaminated by explosives is a public health concern. Some explosives can be carcinogenic in humans. Pentaerythritol Tetranitrate (PETN), a powerful explosive with very low water solubility, can be easily transported to ground waters. Objective: This study was conducted to determine the removal efficiencies of PETN from soil by bioremediation, and obtain kinetic parameters of biological process. Methods: This experimental study was conducted at the Environmental Health Engineering Lab (Isfahan University of Medical Sciences, Isfahan, Iran) in 2015-2016. In the present work, bioremediation of the explosive-polluted soils by PETN in anaerobic-aerobic landfarming method was performed. The influence of seeding and biosurfactant addition on bioremediation was also evaluated. The data were analyzed using Microsoft Excel software. Results: The results show that, as the initial concentration of PETN increased, the lag phase was increased and the specific growth rate was increased up to 0.1/day in concentration of 50 mg/kg, and then it was decreased to 0.04/day. Subsequent decreases in specific growth rate can cause substrate inhibition. Seeding causes decrease in lag phase significantly. Biosurfactant addition had little to no impact on the length of lag phase, but biosurfactant plus seeding can increase the growth rate to 0.2/day, however, inhibitory effect of the initial concentration was started in very high concentration of PETN (150 mg/kg). Conclusion: Biosurfactant addition and seeding together have an impressive effect on biodegradation of PETN, furthermore seeding can enhance active microbial consortium and biosurfactant can improve the poor aqueous solubility of PETN, therefore making the substrate more accessible. PMID- 29238508 TI - Effectiveness of teaching cognitive-behavioral techniques on locus of control in hemodialysis patients. AB - Background: Many of the cognitive behavioral models and therapeutic protocols developed so far for psychological disorders and chronic diseases have proved effective through clinical research. Objective: This study aimed to determine the effectiveness of teaching cognitive-behavioral techniques on locus of control in hemodialysis patients. Methods: This controlled clinical trial study was conducted in 2015 with 76 patients selected by census and treated with a hemodialysis machine in the dialysis department of Vali-Asr Hospital in the city of Meshkinshahr. A total of four patients were excluded because of their critical conditions while the rest, who were recruited, were randomly divided into two equal groups of 36 patients as the intervention and control groups. First, the locus of control was measured in both groups through a pretest, and cognitive behavioral techniques were then taught to the intervention group during eight 45 to 90-minute sessions. The locus of control in patients of both groups was finally re-measured through a posttest. Data were collected using Rotter's Locus of Control Inventory. The Wilcoxon test and Mann-Whitney U test were respectively used in SPSS18 for data analysis. Results: In the pretest and posttest stages respectively, 4.8% and 14.3% of samples in the control group as well as 14.3% and 33.3% of samples in the intervention group enjoyed internal locus of control. The difference between the pretest and posttest scores of internal locus of control in the intervention group was significant (p=0.004), which indicates the positive effect of cognitive-behavioral psychotherapeutic intervention on internalization of locus of control in this group. Conclusions: Given the external locus of control in most of the study patients and also the positive significant effect of cognitive-behavioral psychotherapy on internalization of locus of control in this group of patients, it appears necessary to have a psychology resident present in the hemodialysis department to teach the necessary cognitive-behavioral techniques to internalize the locus of control. Trial registration: The trial was registered at the Thai Clinical Trial Registry (http://www.clinicaltrials.in.th) with the TCTID: TCTR20170707003. Funding: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 29238509 TI - Areal location of hazardous atmospheres simulation on toxic chemical release: A scenario-based case study from Ray, Iran. AB - Background and aim: Chemical accidents cause significant danger for residents living close to chemical facilities. For this reason, this study assessed the impacts of a simulated chemical accident on surrounding residents in the city of Ray, Iran. Methods: In this scenario-based case study in 2015, the Areal Location of Hazardous Atmospheres (ALOHA) model was applied to simulate a toxic chemical release from a chlorine warehouse in Shourabad, Ray, Iran. The population of the area was calculated based on the latest census in Iran, 2011. The atmospheric variables included were wind speed, air temperature, and relative humidity. We also included data on pollution source such as diameter, length and volume, and condition of chemicals. The simulation was repeated for each seasonal period. The simulated threat zones were mapped using Geographical Information System. The percentage of residents sustaining injuries and death was calculated using probit. Results: The maximum and minimum simulated threat zones by chlorine release are during summer and winter at 8.8 and 6.4 kilometers respectively. The total affected population was estimated at approximately 30,000 people. The greater percent of injuries and death was estimated to occur in the winter and autumn, compared to summer and spring, because of greater climatic instability. The number of individuals affected by chlorine release in the spring, summer, autumn and winter at 8.3, 8.8, 7.6 and 6.4 kilometers, are estimated at 22,500, 25,000, 28,100 and 27,500, respectively. Populations located in hot and warm zones of toxic chemical releases should have access to medical resources. Conclusions: The results showed that relevant factors impact human vulnerability, and these should be examined to mitigate the harmful consequences of chemical accidents. Establishing a multi-level Emergency Response Program is also recommended in the area under study. PMID- 29238511 TI - Health information technology and health care activists: Where is the place of Iranians? AB - Background: The level of knowledge and using health information technology by clinicians, students and staff has always been one of the essential issues in the field of health. Objective: The objective of the present study was to evaluate HIT knowledge, attitude, and practice habits among health care professionals and students in educational hospitals in Iran. Methods: This case study was carried out in 2016 on 539 personnel of 65 educational hospitals in Iran entailing three subgroups of physicians (n=128), medical students (n=97), and health record staff (n=314). A pretested self-administered questionnaire was designed to evaluate the knowledge, attitude and practice of health information technology. It was comprised of three parts of "baseline general characteristics", "knowledge categories", and "attitude and practice". Results: In total, 28.8% of participants had a good level of knowledge about computer science, whereas 37.7% had a poor level of knowledge. A total of 40% showed good attitude and practice, while 25.6% had poor attitude and practice. Furthermore, 16.4% of physicians, 32% of students and 33.1% of health record staff had good knowledge, while poor knowledge was reported in 45.3% of physicians, 25.8% of students, and 37.6% of staff (p=0.304). The trend of good attitude and practice habits were respectively 28.9%, 50.5%, and 40.8% in physicians, students, and staff, whereas these trends were respectively 30.5%, 4.1%, and 29.9% for poor attitude and practice (p=0.163). Generally, the knowledge level of participants was positively related to the rate of attitude and practice (r=0.847, p<0.001), so the higher knowledge level brought about the higher score in attitude and practice. Conclusion: The level of knowledge and practice of HIT was low among the physicians, students, and staff. Our university can provide a plenary program to promote the level of knowledge and information on practice of HIT. PMID- 29238510 TI - Epidemiology, transmission, diagnosis, and outcome of Hepatitis C virus infection. AB - Hepatitis C infection is one of the main causes of chronic liver disorders worldwide. Nearly three percent (3%) of the world population has an HCV infection. Prevalence of HCV infection was higher in some groups such as injected drug users (IDUs) and HIV positive populations. Acute hepatitis has proven asymptomatic in most cases, and delay of diagnosis might lead to late onset of hepatocellular carcinoma and cirrhosis. Some host characteristics such as age, gender, body mass index, and viral properties are associated with HCV outcome hepatitis. Although disease progression is typically slow, some risk factors such as alcohol abuse and coinfection of patients with HBV and HIV can worsen the disease. On the other hand, viral overload is one of the main causes of prediction of HCV infection outcome. Prevalence of HCV infection will increase if we do not consider means of transmission, virus behaviors, and immunologic responses. Rapid diagnostic tests can help us to create preventive strategies among undeveloped villages and prisoners. Screening and training of the high-risk population such as IV drug users, dialysis patients, and hemophiliacs must be one of main HCV preventive programs. The present review is intended to help health policymakers to design suitable preventive and management programs. PMID- 29238512 TI - An Approach to Developing Customized Total Knee Replacement Implants. AB - Total knee replacement (TKR) has been performed for patients with end-stage knee joint arthritis to relieve pain and gain functions. Most knee replacement patients can gain satisfactory knee functions; however, the range of motion of the implanted knee is variable. There are many designs of TKR implants; it has been suggested by some researchers that customized implants could offer a better option for patients. Currently, the 3-dimensional knee model of a patient can be created from magnetic resonance imaging (MRI) or computed tomography (CT) data using image processing techniques. The knee models can be used for patient specific implant design, biomechanical analysis, and creating bone cutting guide blocks. Researchers have developed patient-specific musculoskeletal lower limb model with total knee replacement, and the models can be used to predict muscle forces, joint forces on knee condyles, and wear of tibial polyethylene insert. These available techniques make it feasible to create customized implants for individual patients. Methods and a workflow of creating a customized total knee replacement implant for improving TKR kinematics and functions are discussed and presented in this paper. PMID- 29238514 TI - Diagnostic value of glycemic markers HbA1c, 1,5-anhydroglucitol and glycated albumin in evaluating gestational diabetes mellitus. AB - Background: The oral glucose tolerance test (OGTT) is the current established method performed worldwide to diagnose gestational diabetes mellitus (GDM). The purpose of this study was to assess the utility of the use of long- and short term markers of glycemic status. Methods: The study group was composed of 80 pregnant women, 40 with GDM and 40 with normal glucose tolerance. GDM was diagnosed with the American Diabetes Association criteria. Glycemic markers were measured in the OGTT blood samples of women at 24-28 weeks of gestation. Results: HbA1c was significantly higher in the GDM group when compared with the controls, whereas 1,5-anhydroglucitol (1,5-AG) levels were significantly lower. There was not a significant difference between the groups for glycated albumin. Whereas HbA1c levels were correlated with fasting and 1 h glucose and negatively correlated with mean corpuscular volume, 1,5-AG was only negatively correlated with the first hour glucose. No difference was found for the diagnostic performances of HbA1c and 1,5-AG (receiver operating characteristic of the area under the concentration curve values were 0.756 and 0.722, respectively). Conclusion: HbA1c and 1,5-AG alone does not have sufficient diagnostic accuracy to diagnose GDM. 1,5-AG values were correlated with post-load glucose values in pregnant women so will improve the GDM management and be useful to predict complications. PMID- 29238513 TI - Color Constancy in Two-Dimensional and Three-Dimensional Scenes: Effects of Viewing Methods and Surface Texture. AB - There has been debate about how and why color constancy may be better in three dimensional (3-D) scenes than in two-dimensional (2-D) scenes. Although some studies have shown better color constancy for 3-D conditions, the role of specific cues remains unclear. In this study, we compared color constancy for a 3 D miniature room (a real scene consisting of actual objects) and 2-D still images of that room presented on a monitor using three viewing methods: binocular viewing, monocular viewing, and head movement. We found that color constancy was better for the 3-D room; however, color constancy for the 2-D image improved when the viewing method caused the scene to be perceived more like a 3-D scene. Separate measurements of the perceptual 3-D effect of each viewing method also supported these results. An additional experiment comparing a miniature room and its image with and without texture suggested that surface texture of scene objects contributes to color constancy. PMID- 29238515 TI - Role of therapeutic plasma exchange in the treatment of severe hypertriglyceridemia: an experience. AB - Hypertriglyceridemia of obesity, the metabolic syndrome, and type II diabetes mellitus are highly prevalent in Saudi Arabia. Severe hypertriglyceridemia is a rare but well known cause of acute pancreatitis. In treatment pancreatic rest, lifestyle changes, and lipid-lowering medications are essential, but the response is slow. Recently the role of therapeutic plasma exchange (TPE) has been stressed for fast and effective management in addition to insulin and heparin infusion. TPE for hypertriglyceridemic pancreatitis resulted in drastic improvements in clinical and laboratory findings and patient outcomes as suggested in our cases. However, this procedure is limited due to its high cost and availability only in specialized hospitals. PMID- 29238516 TI - Antidiabetic medications and mortality reduction: a shift from surrogate to clinical endpoints. PMID- 29238517 TI - Exogenous H2S restores ischemic post-conditioning-induced cardioprotection through inhibiting endoplasmic reticulum stress in the aged cardiomyocytes. AB - Background: A gasotransmitter hydrogen sulfide (H2S) plays an important physiological and pathological role in cardiovascular system. Ischemic post conditioning (PC) provides cardioprotection in the young hearts but not in the aged hearts. Exogenous H2S restores PC-induced cardioprotection by inhibition of mitochondrial permeability transition pore opening and oxidative stress and increase of autophagy in the aged hearts. However, whether H2S contributes to the recovery of PC-induced cardioprotection via down-regulation of endoplasmic reticulum stress (ERS) in the aged hearts is unclear. Methods: The aged H9C2 cells (the cardiomyocytes line) were induced using H2O2 and were exposed to H/R and PC protocols. Cell viability was observed by CCK-8 kit. Apoptosis was detected by Hoechst 33342 staining and flow cytometry. Related protein expressions were detected through Western blot. Results: In the present study, we found that 30 MUM H2O2 induced H9C2 cells senescence but not apoptosis. Supplementation of NaHS protected against H/R-induced apoptosis, the expression of cleaved caspase-3 and cleaved caspase-9 and the release of cytochrome c. The addition of NaHS also counteracted the reduction of cell viability caused by H/R and decreased the expression of GRP 78, CHOP, cleaved caspase-12, ATF 4, ATF 6 and XBP-1 and the phosphorylation of PERK, eIF 2alpha and IRE 1alpha. Additionally, NaHS increased Bcl-2 expression. PC alone did not provide cardioprotection in H/R-treated aged cardiomyocytes, which was significantly restored by the supplementation of NaHS. The beneficial role of NaHS was similar to the supply of 4-PBA (an inhibitor of ERS), GSK2656157 (an inhibitor of PERK), STF083010 (an inhibitor of IRE 1alpha), respectively, during PC. Conclusion: Our results suggest that the recovery of myocardial protection from PC by exogenous H2S is associated with the inhibition of ERS via down-regulating PERK-eIF 2alpha ATF 4, IRE 1alpha-XBP-1 and ATF 6 pathways in the aged cardiomyocytes. PMID- 29238518 TI - miR-124 promotes proliferation and differentiation of neuronal stem cells through inactivating Notch pathway. AB - Background: Neural stem cells (NSCs) are able to differentiate into neurons and astroglia. miRNAs have been demonstrated to be involved in NSC self-renewal, proliferation and differentiation. However, the exact role of miR-124 in the development of NSCs and its underlying mechanism remain to be explored. Methods: Primary NSCs were isolated from embryos of Wistar rats. Immunocytochemistry was used to stain purified NSCs. miR-124, Delta-like 4 (DLL4), ki-67, Nestin, beta tubulin III, glial fibrillary acidic protein (GFAP), HES1, HEY2, and cyclin D1 (CCND1) expressions were detected by qRT-PCR and western blot. The interaction between miR-124 and DLL4 was confirmed by luciferase reporter assay. Cell proliferation was assessed by MTT assay. Results: NSCs could self-proliferate and differentiate into neurons and astrocyte. miR-124 was up-regulated and DLL4 was down-regulated during NSC differentiation. DLL4 was identified as a target of miR 124 in NSCs. Ectopic expression of miR-124 or knockdown of DLL4 promoted the proliferation and the formation of NSCs to neurospheres. Moreover, miR-124 overexpression or DLL4 down-regulation improved beta-tubulin III expression but decreased GFAP expression in NSCs. Furthermore, enforced expression of DLL4 partially reversed the effects of miR-124 on NSCs proliferation and differentiation. Elevated expression of miR-124 suppressed the expressions of HES1, HEY2, and CCND1 in NSCs, while these effects were attenuated following the enhancement of DLL4 expression. Conclusion: miR-124 promoted proliferation and differentiation of NSCs through inactivating Notch pathway. PMID- 29238520 TI - Detecting latitudinal and altitudinal expansion of invasive bamboo Phyllostachys edulis and Phyllostachys bambusoides (Poaceae) in Japan to project potential habitats under 1.5 degrees C-4.0 degrees C global warming. AB - Rapid expansion of exotic bamboos has lowered species diversity in Japan's ecosystems by hampering native plant growth. The invasive potential of bamboo, facilitated by global warming, may also affect other countries with developing bamboo industries. We examined past (1975-1980) and recent (2012) distributions of major exotic bamboos (Phyllostachys edulis and P. bambusoides) in areas adjacent to 145 weather stations in central and northern Japan. Bamboo stands have been established at 17 sites along the latitudinal and altitudinal distributional limit during the last three decades. Ecological niche modeling indicated that temperature had a strong influence on bamboo distribution. Using mean annual temperature and sun radiation data, we reproduced bamboo distribution (accuracy = 0.93 and AUC (area under the receiver operating characteristic curve) = 0.92). These results infer that exotic bamboo distribution has shifted northward and upslope, in association with recent climate warming. Then, we simulated future climate data and projected the climate change impact on the potential habitat distribution of invasive bamboos under different temperature increases (i.e., 1.5 degrees C, 2.0 degrees C, 3.0 degrees C, and 4.0 degrees C) relative to the preindustrial period. Potential habitats in central and northern Japan were estimated to increase from 35% under the current climate (1980-2000) to 46%-48%, 51%-54%, 61%-67%, and 77%-83% under 1.5 degrees C, 2.0 degrees C, 3.0 degrees C, and 4.0 degrees C warming levels, respectively. These infer that the risk areas can increase by 1.3 times even under a 1.5 degrees C scenario and expand by 2.3 times under a 4.0 degrees C scenario. For sustainable ecosystem management, both mitigation and adaptation are necessary: bamboo planting must be carefully monitored in predicted potential habitats, which covers most of Japan. PMID- 29238519 TI - How to manage anaphylaxis in primary care. AB - Anaphylaxis is defined as a severe life-threatening generalized or systemic hypersensitivity reaction characterized by rapidly developing airway and/or circulation problems. It presents with very different combinations of symptoms and apparently mild signs and can progress to fatal anaphylactic shock unpredictably. The difficulty in recognizing anaphylaxis is due, in part, to the variability of diagnostic criteria, which in turn leads to a delay in administration of appropriate treatment, thus increasing the risk of death. The use of validated clinical criteria can facilitate the diagnosis of anaphylaxis. Intramuscular epinephrine (adrenaline) is the medication of choice for the emergency treatment of anaphylaxis. Administration of corticosteroids and H1 antihistamines should not delay the administration of epinephrine, and the management of a patient with anaphylaxis should not end with the acute episode. Long-term management of anaphylaxis should include avoidance of triggers, following confirmation by an allergology study. Etiologic factors suspected in the emergency department often differ from the real causes of anaphylaxis. Evaluation of patients with a history of anaphylaxis should also include an assessment of personal data, such as age and comorbidities, which may increase the risk of severe reactions. Special attention should also be paid to co factors, as these may easily confound the cause of the anaphylaxis. Patients experiencing anaphylaxis should administer epinephrine as soon as possible. Education (including the use of Internet and social media), written personalized emergency action plans, and self-injectable epinephrine have proven useful for the treatment of further anaphylaxis episodes. PMID- 29238521 TI - Limited polymorphism of the functional MHC class II B gene in the black-spotted frog (Pelophylax nigromaculatus) identified by locus-specific genotyping. AB - Amphibians can be more vulnerable to environmental changes and diseases than other species because of their complex life cycle and physiological requirements. Therefore, understanding the adaptation of amphibians to environmental changes is crucial for their conservation. Major histocompatibility complex (MHC) presents an excellent tool for the investigation of adaptive variations and the assessment of adaptive potential because it can be under strong diversifying selection. Here, we isolated the MHC class II B (MHCIIB) gene from cDNA sequences of the black-spotted frog (Pelophylax nigromaculatus), a widespread amphibian species in China, and designed locus-specific primers to characterize adaptive variability of this amphibian. Ten alleles were identified from 67 individual frogs of three populations and no more than two alleles were present in each individual animal. Furthermore, none of the sequences had indels or/and stop codons, which is in good agreement with locus-specific amplification of a functional gene. However, we found low polymorphism at both nucleotide and amino acid levels, even in the antigen-binding region. Purifying selection acting at this locus was supported by the findings that the dN/dS ratio across all alleles was below 1 and that negatively selected sites were detected by different methods. Allele frequency distributions were significantly different among geographic populations, indicating that physiographic factors may have strong effect on the genetic structure of the black-spotted frog. This study revealed limited polymorphism of three adjacent black-spotted frog populations at the functional MHCIIB locus, which may be attributed to region-specific differences. The locus-specific genotyping technique developed in this study would provide a foundation for future studies on adaptive divergence among different frog populations. PMID- 29238522 TI - Multilocus genetic analyses and spatial modeling reveal complex population structure and history in a widespread resident North American passerine (Perisoreus canadensis). AB - An increasing body of studies of widely distributed, high latitude species shows a variety of refugial locations and population genetic patterns. We examined the effects of glaciations and dispersal barriers on the population genetic patterns of a widely distributed, high latitude, resident corvid, the gray jay (Perisoreus canadensis), using the highly variable mitochondrial DNA (mtDNA) control region and microsatellite markers combined with species distribution modeling. We sequenced 914 bp of mtDNA control region for 375 individuals from 37 populations and screened seven loci for 402 individuals from 27 populations across the gray jay range. We used species distribution modeling and a range of phylogeographic analyses (haplotype diversity, PhiST, SAMOVA, FST, Bayesian clustering analyses) to examine evolutionary history and population genetic structure. MtDNA and microsatellite markers revealed significant genetic differentiation among populations with high concordance between markers. Paleodistribution models supported at least five potential areas of suitable gray jay habitat during the last glacial maximum and revealed distributions similar to the gray jay's contemporary during the last interglacial. Colonization from and prolonged isolation in multiple refugia is evident. Historical climatic fluctuations, the presence of multiple dispersal barriers, and highly restricted gene flow appear to be responsible for strong genetic diversification and differentiation in gray jays. PMID- 29238523 TI - Ad hoc instrumentation methods in ecological studies produce highly biased temperature measurements. AB - In light of global climate change, ecological studies increasingly address effects of temperature on organisms and ecosystems. To measure air temperature at biologically relevant scales in the field, ecologists often use small, portable temperature sensors. Sensors must be shielded from solar radiation to provide accurate temperature measurements, but our review of 18 years of ecological literature indicates that shielding practices vary across studies (when reported at all), and that ecologists often invent and construct ad hoc radiation shields without testing their efficacy. We performed two field experiments to examine the accuracy of temperature observations from three commonly used portable data loggers (HOBO Pro, HOBO Pendant, and iButton hygrochron) housed in manufactured Gill shields or ad hoc, custom-fabricated shields constructed from everyday materials such as plastic cups. We installed this sensor array (five replicates of 11 sensor-shield combinations) at weather stations located in open and forested sites. HOBO Pro sensors with Gill shields were the most accurate devices, with a mean absolute error of 0.2 degrees C relative to weather stations at each site. Error in ad hoc shield treatments ranged from 0.8 to 3.0 degrees C, with the largest errors at the open site. We then deployed one replicate of each sensor-shield combination at five sites that varied in the amount of urban impervious surface cover, which presents a further shielding challenge. Bias in sensors paired with ad hoc shields increased by up to 0.7 degrees C for every 10% increase in impervious surface. Our results indicate that, due to variable shielding practices, the ecological literature likely includes highly biased temperature data that cannot be compared directly across studies. If left unaddressed, these errors will hinder efforts to predict biological responses to climate change. We call for greater standardization in how temperature data are recorded in the field, handled in analyses, and reported in publications. PMID- 29238524 TI - Functional redundancy modifies species-area relationship for freshwater phytoplankton. AB - Although species-area relationship (SAR) is among the most extensively studied patterns in ecology, studies on aquatic and/or microbial systems are seriously underrepresented in the literature. We tested the algal SAR in lakes, pools and ponds of various sizes (10-2-108 m2) and similar hydromorphological and trophic characteristics using species-specific data and functional groups. Besides the expectation that species richness increases monotonously with area, we found a right-skewed hump-shaped relationship between the area and phytoplankton species richness. Functional richness however did not show such distortion. Differences between the area dependence of species and functional richness indicate that functional redundancy is responsible for the unusual hump-backed SAR. We demonstrated that the Small Island Effect, which is a characteristic for macroscopic SARs can also be observed for the phytoplankton. Our results imply a so-called large lake effect, which means that in case of large lakes, wind induced mixing acts strongly against the habitat diversity and development of phytoplankton patchiness and finally results in lower phytoplankton species richness in the pelagial. High functional redundancy of the groups that prefer small-scale heterogeneity of the habitats is responsible for the unusual humpback relationship. The results lead us to conclude that although the mechanisms that regulate the richness of both microbial communities and communities of macroscopic organisms are similar, their importance can be different in micro- and macroscales. PMID- 29238525 TI - Have bird distributions shifted along an elevational gradient on a tropical mountain? AB - An upward shift in elevation is one of the most conspicuous species responses to climate change. Nevertheless, downward shifts and, apparently, the absences of response have also been recently reported. Given the growing evidence of multiple responses of species distributions due to climate change and the paucity of studies in the tropics, we evaluated the response of a montane bird community to climate change, without the confounding effects of land-use change. To test for elevational shifts, we compared the distribution of 21 avian species in 1998 and 2015 using occupancy models. The historical data set was based on point counts, whereas the contemporary data set was based on acoustic monitoring. We detected a similar number of species in historical (36) and contemporary data sets (33). We show an overall pattern of no significant change in range limits for most species, although there was a significant shift in the range limit of eight species (38%). Elevation limits shifted mostly upward, and this pattern was more common for upper than lower limits. Our results highlight the variability of species responses to climate change and illustrate how acoustic monitoring provides an easy and powerful way to monitor animal populations along elevational gradients. PMID- 29238526 TI - Genetic implications of bottleneck effects of differing severities on genetic diversity in naturally recovering populations: An example from Hawaiian coot and Hawaiian gallinule. AB - The evolutionary trajectory of populations through time is influenced by the interplay of forces (biological, evolutionary, and anthropogenic) acting on the standing genetic variation. We used microsatellite and mitochondrial loci to examine the influence of population declines, of varying severity, on genetic diversity within two Hawaiian endemic waterbirds, the Hawaiian coot and Hawaiian gallinule, by comparing historical (samples collected in the late 1800s and early 1900s) and modern (collected in 2012-2013) populations. Population declines simultaneously experienced by Hawaiian coots and Hawaiian gallinules differentially shaped the evolutionary trajectory of these two populations. Within Hawaiian coot, large reductions (between -38.4% and -51.4%) in mitochondrial diversity were observed, although minimal differences were observed in the distribution of allelic and haplotypic frequencies between sampled time periods. Conversely, for Hawaiian gallinule, allelic frequencies were strongly differentiated between time periods, signatures of a genetic bottleneck were detected, and biases in means of the effective population size were observed at microsatellite loci. The strength of the decline appears to have had a greater influence on genetic diversity within Hawaiian gallinule than Hawaiian coot, coincident with the reduction in census size. These species exhibit similar life history characteristics and generation times; therefore, we hypothesize that differences in behavior and colonization history are likely playing a large role in how allelic and haplotypic frequencies are being shaped through time. Furthermore, differences in patterns of genetic diversity within Hawaiian coot and Hawaiian gallinule highlight the influence of demographic and evolutionary processes in shaping how species respond genetically to ecological stressors. PMID- 29238527 TI - Ancestrality and evolution of trait syndromes in finches (Fringillidae). AB - Species traits have been hypothesized by one of us (Ponge, 2013) to evolve in a correlated manner as species colonize stable, undisturbed habitats, shifting from "ancestral" to "derived" strategies. We predicted that generalism, r-selection, sexual monomorphism, and migration/gregariousness are the ancestral states (collectively called strategy A) and evolved correlatively toward specialism, K selection, sexual dimorphism, and residence/territoriality as habitat stabilized (collectively called B strategy). We analyzed the correlated evolution of four syndromes, summarizing the covariation between 53 traits, respectively, involved in ecological specialization, r-K gradient, sexual selection, and dispersal/social behaviors in 81 species representative of Fringillidae, a bird family with available natural history information and that shows variability for all these traits. The ancestrality of strategy A was supported for three of the four syndromes, the ancestrality of generalism having a weaker support, except for the core group Carduelinae (69 species). It appeared that two different B strategies evolved from the ancestral state A, both associated with highly predictable environments: one in poorly seasonal environments, called B1, with species living permanently in lowland tropics, with "slow pace of life" and weak sexual dimorphism, and one in highly seasonal environments, called B2, with species breeding out-of-the-tropics, migratory, with a "fast pace of life" and high sexual dimorphism. PMID- 29238528 TI - Trends and uncertainties in budburst projections of Norway spruce in Northern Europe. AB - Budburst is regulated by temperature conditions, and a warming climate is associated with earlier budburst. A range of phenology models has been developed to assess climate change effects, and they tend to produce different results. This is mainly caused by different model representations of tree physiology processes, selection of observational data for model parameterization, and selection of climate model data to generate future projections. In this study, we applied (i) Bayesian inference to estimate model parameter values to address uncertainties associated with selection of observational data, (ii) selection of climate model data representative of a larger dataset, and (iii) ensembles modeling over multiple initial conditions, model classes, model parameterizations, and boundary conditions to generate future projections and uncertainty estimates. The ensemble projection indicated that the budburst of Norway spruce in northern Europe will on average take place 10.2 +/- 3.7 days earlier in 2051-2080 than in 1971-2000, given climate conditions corresponding to RCP 8.5. Three provenances were assessed separately (one early and two late), and the projections indicated that the relationship among provenance will remain also in a warmer climate. Structurally complex models were more likely to fail predicting budburst for some combinations of site and year than simple models. However, they contributed to the overall picture of current understanding of climate impacts on tree phenology by capturing additional aspects of temperature response, for example, chilling. Model parameterizations based on single sites were more likely to result in model failure than parameterizations based on multiple sites, highlighting that the model parameterization is sensitive to initial conditions and may not perform well under other climate conditions, whether the change is due to a shift in space or over time. By addressing a range of uncertainties, this study showed that ensemble modeling provides a more robust impact assessment than would a single phenology model run. PMID- 29238529 TI - Elevational diversity gradients of Tibetan loaches: The relative roles of ecological and evolutionary processes. AB - It is widely believed that species richness patterns (SRPs) are shaped by both ecological and evolutionary processes. However, the relative roles of these processes remain unclear, especially for aquatic organisms. In this study, we integrated ecological and evolutionary measures to tease apart the relative influences of these factors on the SRP of Tibetan loaches along an extensive elevational gradient. We found that the Tibetan loaches displayed a richness pattern that peaked at midelevations. The mean annual temperature (MAT), mid domain effect (MDE), and summed age of colonization (SAC, complex of colonization age and colonization frequency) were the main drivers, accounting for 85%, 51%, and 88% of the variations in the SRP, respectively. The three predictors had very high combined effects (MAT-MDE-SAC, MAT-SAC, and MDE-SAC were 44%, 38%, and 6%, respectively). Our analyses suggested that energy input, time-for-speciation, and species dispersal may directly guide the SRP or mediate it by geometric constraints. Conclusively, the SRP of the Tibetan loaches with elevation is the outcome of interactions between biogeographical processes and regional ecological conditions. PMID- 29238530 TI - Body size variation in aquatic consumers causes pervasive community effects, independent of mean body size. AB - Intraspecific phenotypic variation is a significant component of biodiversity. Body size, for example, is variable and critical for structuring communities. We need to understand how homogenous and variably sized populations differ in their ecological responses or effects if we are to have a robust understanding of communities. We manipulated body size variation in consumer (tadpole) populations in mesocosms (both with and without predators), keeping mean size and density of these consumers constant. Size-variable consumer populations exhibited stronger antipredator responses (reduced activity), which had a cascading effect of increasing the biomass of the consumer's resources. Predators foraged less when consumers were variable in size, and this may have mediated the differential effects of predators on the community composition of alternative prey (zooplankton). All trophic levels responded to differences in consumer size variation, demonstrating that intrapopulation phenotypic variability can significantly alter interspecific ecological interactions. Furthermore, we identify a key mechanism (size thresholds for predation risk) that may mediate impacts of size variation in natural communities. Together, our results suggest that phenotypic variability plays a significant role in structuring ecological communities. PMID- 29238531 TI - The Saturniidae of Barro Colorado Island, Panama: A model taxon for studying the long-term effects of climate change? AB - We have little knowledge of the response of invertebrate assemblages to climate change in tropical ecosystems, and few studies have compiled long-term data on invertebrates from tropical rainforests. We provide an updated list of the 72 species of Saturniidae moths collected on Barro Colorado Island (BCI), Panama, during the period 1958-2016. This list will serve as baseline data for assessing long-term changes of saturniids on BCI in the future, as 81% of the species can be identified by their unique DNA Barcode Index Number, including four cryptic species not yet formally described. A local species pool of 60 + species breeding on BCI appears plausible, but more cryptic species may be discovered in the future. We use monitoring data obtained by light trapping to analyze recent population trends on BCI for saturniid species that were relatively common during 2009-2016, a period representing >30 saturniid generations. The abundances of 11 species, of 14 tested, could be fitted to significant time-series models. While the direction of change in abundance was uncertain for most species, two species showed a significant increase over time, and forecast models also suggested continuing increases for most species during 2017-2018, as compared to the 2009 base year. Peaks in saturniid abundance were most conspicuous during El Nino and La Nina years. In addition to a species-specific approach, we propose a reproducible functional classification based on five functional traits to analyze the responses of species sharing similar functional attributes in a fluctuating climate. Our results suggest that the abundances of larger body-size species with good dispersal abilities may increase concomitantly with rising air temperature in the future, because short-lived adults may allocate less time to increasing body temperature for flight, leaving more time available for searching for mating partners or suitable oviposition sites. PMID- 29238532 TI - Seasonal genetic variation associated with population dynamics of a poecilogonous polychaete worm. AB - Poecilogonous species show variation in developmental mode, with larvae that differ both morphologically and ecologically. The spionid polychaete Pygospio elegans shows variation in developmental mode not only between populations, but also seasonally within populations. We investigated the consequences of this developmental polymorphism on the spatial and seasonal genetic structure of P. elegans at four sites in the Danish Isefjord-Roskilde-Fjord estuary at six time points, from March 2014 until February 2015. We found genetic differentiation between our sampling sites as well as seasonal differentiation at two of the sites. The seasonal genetic shift correlated with the appearance of new size cohorts in the populations. Additionally, we found that the genetic composition of reproductive individuals did not always reflect the genetic composition of the entire sample, indicating that variance in reproductive success among individuals is a likely explanation for the patterns of chaotic genetic patchiness observed during this and previous studies. The heterogeneous, unpredictable character of the estuary might maintain poecilogony in P. elegans as a bet-hedging strategy in the Isefjord-Roskilde-Fjord complex in comparison with other sites where P. elegans are expected to be fixed to a certain mode of development. PMID- 29238533 TI - Genetic variation in Tertiary relics: The case of eastern-Mediterranean Abies (Pinaceae). AB - The eastern-Mediterranean Abies taxa, which include both widely distributed species and taxa with minuscule ranges, represent a good model to study the impacts of range size and fragmentation on the levels of genetic diversity and differentiation. To assess the patterns of genetic diversity and phylogenetic relationships among eastern-Mediterranean Abies taxa, genetic variation was assessed by eight nuclear microsatellite loci in 52 populations of Abies taxa with a focus on those distributed in Turkey and the Caucasus. Both at the population and the taxon level, the subspecies or regional populations of Abies nordmanniana s.l. exhibited generally higher allelic richness, private allelic richness, and expected heterozygosity compared with Abies cilicica s.l. Results of both the structure analysis and distance-based approaches showed a strong differentiation of the two A. cilicica subspecies from the rest as well as from each other, whereas the subspecies of A. nordmanniana were distinct but less differentiated. ABC simulations were run for a set of scenarios of phylogeny and past demographic changes. For A. *olcayana, the simulation gave a poor support for the hypothesis of being a taxon resulting from a past hybridization, the same is true for Abies equi-trojani: both they represent evolutionary branches of Abies bornmuelleriana. PMID- 29238534 TI - Conservation of social effects (Psi) between two species of Drosophila despite reversal of sexual dimorphism. AB - Indirect genetic effects (IGEs) describe the effect of the genes of social partners on the phenotype of a focal individual. Here, we measure indirect genetic effects using the "coefficient of interaction" (Psi) to test whether Psi evolved between Drosophila melanogaster and D. simulans. We compare Psi for locomotion between ethanol and nonethanol environments in both species, but only D. melanogaster utilizes ethanol ecologically. We find that while sexual dimorphism for locomotion has been reversed in D. simulans, there has been no evolution of social effects between these two species. What did evolve was the interaction between genotype-specific Psi and the environment, as D. melanogaster varies unpredictably between environments and D. simulans does not. In this system, this suggests evolutionary lability of sexual dimorphism but a conservation of social effects, which brings forth interesting questions about the role of the social environment in sexual selection. PMID- 29238536 TI - Body macronutrient composition is predicted by lipid and not protein content of the diet. AB - Diet is an important determinant of fitness-related traits including growth, reproduction, and survival. Recent work has suggested that variation in protein:lipid ratio and particularly the amount of protein in the diet is a key nutritional parameter. However, the traits that mediate the link between dietary macronutrient ratio and fitness-related traits are less well understood. An obvious candidate is body composition, given its well-known link to health. Here, we investigate the relationship between dietary and body macronutrient composition using a first-generation laboratory population of a freshwater fish, the three-spine stickleback (Gasterosteus aculeatus). Carbohydrate is relatively unimportant in the diet of predatory fish, facilitating the exploration of how dietary protein-to-lipid ratio affects their relative deposition in the body. We find a significant effect of lipid intake, rather than protein, on body protein:lipid ratio. Importantly, this was not a result of absorbing macronutrients in relation to their relative abundance in the diet, as the carcass protein:lipid ratios differed from those of the diets, with ratios usually lower in the body than in the diet. This indicates that individuals can moderate their utilization, or uptake, of ingested macronutrients to reach a target balance within the body. We found no effect of diet on swimming endurance, activity, or testes size. However, there was an effect of weight on testes size, with larger males having larger testes. Our results provide evidence for the adjustment of body protein:lipid ratio away from that of the diet. As dietary lipid intake was the key determinant of body composition, we suggest this occurs via metabolism of excess protein, which conflicts with the predictions of the protein leverage hypothesis. These results could imply that the conversion and excretion of protein is one of the causes of the survival costs associated with high-protein diets. PMID- 29238535 TI - A workflow of massive identification and application of intron markers using snakes as a model. AB - Relative to the commonly used mitochondrial and nuclear protein-coding genes, the noncoding intron sequences are a promising source of informative markers that have the potential to resolve difficult phylogenetic nodes such as rapid radiations and recent divergences. Yet many issues exist in the use of intron markers, which prevent their extensive application as conventional markers. We used the diverse group of snakes as an example to try paving the way for massive identification and application of intron markers. We performed a series of bioinformatics screenings which identified appropriate introns between single copy and conserved exons from two snake genomes, adding particular constraints on sequence length variability and sequence variability. A total of 1,273 candidate intron loci were retrieved. Primers for nested polymerase chain reaction (PCR) were designed for over a hundred candidates and tested in 16 snake representatives. 96 intron markers were developed that could be amplified across a broad range of snake taxa with high PCR successful rates. The markers were then applied to 49 snake samples. The large number of amplicons was subjected to next generation sequencing (NGS). An analytic strategy was developed to accurately recover the amplicon sequences, and approximately, 76% of the marker sequences were recovered. The average p-distances of the intron markers at interfamily, intergenus, interspecies, and intraspecies levels were .168, .052, .015, and .004, respectively, suggesting that they were useful to study snake relationships of different evolutionary depths. A snake phylogeny was constructed with the intron markers, which produced concordant results with robust support at both interfamily and intragenus levels. The intron markers provide a convenient way to explore the signals in the noncoding regions to address the controversies on the snake tree. Our improved strategy of genome screening is effective and can be applied to other animal groups. NGS coupled with appropriate sequence processing can greatly facilitate the extensive application of molecular markers. PMID- 29238537 TI - Rarefaction and extrapolation of species richness using an area-based Fisher's logseries. AB - Fisher's logseries is widely used to characterize species abundance pattern, and some previous studies used it to predict species richness. However, this model, derived from the negative binomial model, degenerates at the zero-abundance point (i.e., its probability mass fully concentrates at zero abundance, leading to an odd situation that no species can occur in the studied sample). Moreover, it is not directly related to the sampling area size. In this sense, the original Fisher's alpha (correspondingly, species richness) is incomparable among ecological communities with varying area sizes. To overcome these limitations, we developed a novel area-based logseries model that can account for the compounding effect of the sampling area. The new model can be used to conduct area-based rarefaction and extrapolation of species richness, with the advantage of accurately predicting species richness in a large region that has an area size being hundreds or thousands of times larger than that of a locally observed sample, provided that data follow the proposed model. The power of our proposed model has been validated by extensive numerical simulations and empirically tested through tree species richness extrapolation and interpolation in Brazilian Atlantic forests. Our parametric model is data parsimonious as it is still applicable when only the information on species number, community size, or the numbers of singleton and doubleton species in the local sample is available. Notably, in comparison with the original Fisher's method, our area-based model can provide asymptotically unbiased variance estimation (therefore correct 95% confidence interval) for species richness. In conclusion, the proposed area-based Fisher's logseries model can be of broad applications with clear and proper statistical background. Particularly, it is very suitable for being applied to hyperdiverse ecological assemblages in which nonparametric richness estimators were found to greatly underestimate species richness. PMID- 29238538 TI - Strong positive effects of termites on savanna bird abundance and diversity are amplified by large herbivore exclusion. AB - Vast areas of the African savanna landscapes are characterized by tree-covered Macrotermes termite mounds embedded within a relatively open savanna matrix. In concert with termites, large herbivores are important determinants of savanna woody vegetation cover. The relative cover of woody species has considerable effects on savanna function. Despite the potentially important ecological relationships between termite mounds, woody plants, large herbivores, and birds, these associations have previously received surprisingly little attention. We experimentally studied the effects of termites and large herbivores on the avian community in Lake Mburo National Park, Uganda, where woody vegetation is essentially limited to termite mounds. Our experiment comprised of four treatments in nine replicates; unfenced termite mounds, fenced mounds (excluding large mammals), unfenced adjacent savanna, and fenced savanna. We recorded species identity, abundance, and behavior of all birds observed on these plots over a two-month period, from late dry until wet season. Birds used termite mounds almost exclusively, with only 3.5% of observations occurring in the treeless intermound savanna matrix. Mean abundance and species richness of birds doubled on fenced (large herbivores excluded) compared to unfenced mounds. Feeding behavior increased when large mammals were excluded from mounds, both in absolute number of observed individuals, and relative to other behaviors. This study documents the fundamental positive impact of Macrotermes termites on bird abundance and diversity in an African savanna. Birds play crucial functional roles in savanna ecosystems, for example, by dispersing fruits or regulating herbivorous insect populations. Thus, the role of birds in savanna dynamics depends on the distribution and abundance of termite mounds. PMID- 29238539 TI - Dispersal influences genetic and acoustic spatial structure for both males and females in a tropical songbird. AB - Animals exhibit diverse dispersal strategies, including sex-biased dispersal, a phenomenon common in vertebrates. Dispersal influences the genetic structure of populations as well as geographic variation in phenotypic traits. Patterns of spatial genetic structure and geographic variation may vary between the sexes whenever males and females exhibit different dispersal behaviors. Here, we examine dispersal, spatial genetic structure, and spatial acoustic structure in Rufous-and-white Wrens, a year-round resident tropical bird. Both sexes sing in this species, allowing us to compare acoustic variation between males and females and examine the relationship between dispersal and song sharing for both sexes. Using a long-term dataset collected over an 11-year period, we used banding data and molecular genetic analyses to quantify natal and breeding dispersal distance in Rufous-and-white Wrens. We quantified song sharing and examined whether sharing varied with dispersal distance, for both males and females. Observational data and molecular genetic analyses indicate that dispersal is female-biased. Females dispersed farther from natal territories than males, and more often between breeding territories than males. Furthermore, females showed no significant spatial genetic structure, consistent with expectations, whereas males showed significant spatial genetic structure. Overall, natal dispersal appears to have more influence than breeding dispersal on spatial genetic structure and spatial acoustic structure, given that the majority of breeding dispersal events resulted in individuals moving only short distances. Song sharing between pairs of same-sex animals decreases with the distance between their territories for both males and females, although males exhibited significantly greater song sharing than females. Lastly, we measured the relationship between natal dispersal distance and song sharing. We found that sons shared fewer songs with their fathers the farther they dispersed from their natal territories, but that song sharing between daughters and mothers was not significantly correlated with natal dispersal distance. Our results reveal cultural differences between the sexes, suggesting a relationship between culture and sex-biased dispersal. PMID- 29238540 TI - Variation in the benefits of multiple mating on female fertility in wild stalk eyed flies. AB - Polyandry, female mating with multiple males, is widespread across many taxa and almost ubiquitous in insects. This conflicts with the traditional idea that females are constrained by their comparatively large investment in each offspring, and so should only need to mate once or a few times. Females may need to mate multiply to gain sufficient sperm supplies to maintain their fertility, especially in species in which male promiscuity results in division of their ejaculate among many females. Here, we take a novel approach, utilizing wild caught individuals to explore how natural variation among females and males influences fertility gains for females. We studied this in the Malaysian stalk eyed fly species Teleopsis dalmanni. After an additional mating, females benefit from greatly increased fertility (proportion fertile eggs). Gains from multiple mating are not uniform across females; they are greatest when females have high fecundity or low fertility. Fertility gains also vary spatially, as we find an additional strong effect of the stream from which females were collected. Responses were unaffected by male mating history (males kept with females or in male-only groups). Recent male mating may be of lesser importance because males in many species, including T. dalmanni, partition their ejaculate to maintain their fertility over many matings. This study highlights the importance of complementing laboratory studies with data on wild-caught populations, where there is considerable heterogeneity between individuals. Future research should focus on environmental, demographic and genetic factors that are likely to significantly influence variation in individual female fecundity and fertility. PMID- 29238541 TI - How beta diversity and the underlying causes vary with sampling scales in the Changbai mountain forests. AB - This study aims to establish a relationship between the sampling scale and tree species beta diversity temperate forests and to identify the underlying causes of beta diversity at different sampling scales. The data were obtained from three large observational study areas in the Changbai mountain region in northeastern China. All trees with a dbh >=1 cm were stem-mapped and measured. The beta diversity was calculated for four different grain sizes, and the associated variances were partitioned into components explained by environmental and spatial variables to determine the contributions of environmental filtering and dispersal limitation to beta diversity. The results showed that both beta diversity and the causes of beta diversity were dependent on the sampling scale. Beta diversity decreased with increasing scales. The best-explained beta diversity variation was up to about 60% which was discovered in the secondary conifer and broad-leaved mixed forest (CBF) study area at the 40 * 40 m scale. The variation partitioning result indicated that environmental filtering showed greater effects at bigger grain sizes, while dispersal limitation was found to be more important at smaller grain sizes. What is more, the result showed an increasing explanatory ability of environmental effects with increasing sampling grains but no clearly trend of spatial effects. The study emphasized that the underlying causes of beta diversity variation may be quite different within the same region depending on varying sampling scales. Therefore, scale effects should be taken into account in future studies on beta diversity, which is critical in identifying different relative importance of spatial and environmental drivers on species composition variation. PMID- 29238542 TI - Broadening the voice of science: Promoting scientific communication in the undergraduate classroom. AB - Effective and accurate communication of scientific findings is essential. Unfortunately, scientists are not always well trained in how to best communicate their results with other scientists nor do all appreciate the importance of speaking with the public. Here, we provide an example of how the development of oral communication skills can be integrated with research experiences at the undergraduate level. We describe our experiences developing, running, and evaluating a course for undergraduates that complemented their existing undergraduate research experiences with instruction on the nature of science and intensive training on the development of science communication skills. Students delivered science talks, research monologues, and poster presentations about the ecological and evolutionary research in which they were involved. We evaluated the effectiveness of our approach using the CURE survey and a focus group. As expected, undergraduates reported strong benefits to communication skills and confidence. We provide guidance for college researchers, instructors, and administrators interested in motivating and equipping the next generation of scientists to be excellent science communicators. PMID- 29238543 TI - Nitrogen loss from karst area in China in recent 50 years: An in-situ simulated rainfall experiment's assessment. AB - Karst topography covers more than 1/3 of the People's Republic of China in area. The porous, fissured, and soluble nature of the underlying karst bedrock (primarily dolomite and limestone) leads to the formation of underground drainage systems. Karst conduit networks dominate this system, and rainfall takes a crucial role on water cycle at China karst area. Nitrogen loss from the karst system is of particular concern, with regard to nutrient use efficiency as well as water quality, as much of the karst system, including steeply sloping terrain, is used for intensive agriculture. We use simulated rainfall experiments to determine the relationship between rainfall and nitrogen loss at typical karst slope land and then estimate nitrogen loss from the karst soil. The results show that both surface runoff and subsurface runoff have a significant linear correlation with rainfall at all studied sites. Subsurface runoff is larger than surface runoff at two karst sites, while the opposite is true at the non-karst site. Exponential function satisfactorily described the correlation between rainfall and nitrogen concentrations in runoff. Nitrates accounted for 60%-95% of the dissolved nitrogen loss (DN, an index of N-loss in this research). The estimated annual N-loss load varies between 1.05 and 1.67 Tg N/year in the whole karst regions of China from 1961 to 2014. Approximately, 90% of the N-loss load occurred during the wet season, and 90% of that passed through the subsurface. Understanding the processes and estimating N-loss is highly valuable in determining long-term soil security and sustainability in karst regions. PMID- 29238544 TI - Population genomics of the Asian tiger mosquito, Aedes albopictus: insights into the recent worldwide invasion. AB - Aedes albopictus, the "Asian tiger mosquito," is an aggressive biting mosquito native to Asia that has colonized all continents except Antarctica during the last ~30-40 years. The species is of great public health concern as it can transmit at least 26 arboviruses, including dengue, chikungunya, and Zika viruses. In this study, using double-digest Restriction site-Associated DNA (ddRAD) sequencing, we developed a panel of ~58,000 single nucleotide polymorphisms (SNPs) based on 20 worldwide Ae. albopictus populations representing both the invasive and the native range. We used this genomic-based approach to study the genetic structure and the differentiation of Ae. albopictus populations and to understand origin(s) and dynamics of the recent invasions. Our analyses indicated the existence of two major genetically differentiated population clusters, each one including both native and invasive populations. The detection of additional genetic structure within each major cluster supports that these SNPs can detect differentiation at a global and local scale, while the similar levels of genomic diversity between native and invasive range populations support the scenario of multiple invasions or colonization by a large number of propagules. Finally, our results revealed the possible source(s) of the recent invasion in Americas, Europe, and Africa, a finding with important implications for vector-control strategies. PMID- 29238545 TI - Historical Biogeography of endemic seed plant genera in the Caribbean: Did GAARlandia play a role? AB - The Caribbean archipelago is a region with an extremely complex geological history and an outstanding plant diversity with high levels of endemism. The aim of this study was to better understand the historical assembly and evolution of endemic seed plant genera in the Caribbean, by first determining divergence times of endemic genera to test whether the hypothesized Greater Antilles and Aves Ridge (GAARlandia) land bridge played a role in the archipelago colonization and second by testing South America as the main colonization source as expected by the position of landmasses and recent evidence of an asymmetrical biotic interchange. We reconstructed a dated molecular phylogenetic tree for 625 seed plants including 32 Caribbean endemic genera using Bayesian inference and ten calibrations. To estimate the geographic range of the ancestors of endemic genera, we performed a model selection between a null and two complex biogeographic models that included timeframes based on geological information, dispersal probabilities, and directionality among regions. Crown ages for endemic genera ranged from Early Eocene (53.1 Ma) to Late Pliocene (3.4 Ma). Confidence intervals for divergence times (crown and/or stem ages) of 22 endemic genera occurred within the GAARlandia time frame. Contrary to expectations, the Antilles appears as the main ancestral area for endemic seed plant genera and only five genera had a South American origin. In contrast to patterns shown for vertebrates and other organisms and based on our sampling, we conclude that GAARlandia did not act as a colonization route for plants between South America and the Antilles. Further studies on Caribbean plant dispersal at the species and population levels will be required to reveal finer-scale biogeographic patterns and mechanisms. PMID- 29238547 TI - Temporal constraints on the potential role of fry odors as cues of past reproductive success for spawning lake trout. AB - Deciding where to reproduce is a major challenge for most animals. Many select habitats based upon cues of successful reproduction by conspecifics, such as the presence of offspring from past reproductive events. For example, some fishes select spawning habitat following odors released by juveniles whose rearing habitat overlaps with spawning habitat. However, juveniles may emigrate before adults begin to search for spawning habitat; hence, the efficacy of juvenile cues could be constrained by degradation or dissipation rates. In lake trout (Salvelinus namaycush), odors deposited by the previous year's offspring have been hypothesized to guide adults to spawning reefs. However, in most extant populations, lake trout fry emigrate from spawning reefs during the spring and adults spawn during the fall. Therefore, we postulated that the role of fry odors in guiding habitat selection might be constrained by the time between fry emigration and adult spawning. Time course chemical, physiological, and behavioral assays indicated that the odors deposited by fry likely degrade or dissipate before adults select spawning habitats. Furthermore, fry feces did not attract wild lake trout to constructed spawning reefs in Lake Huron. Taken together, our results indicate fry odors are unlikely to act as cues for lake trout searching for spawning reefs in populations whose juveniles emigrate before the spawning season, and underscore the importance of environmental constraints on social cues. PMID- 29238548 TI - Energy and speleogenesis: Key determinants of terrestrial species richness in caves. AB - The aim of this study was to unravel the relative role played by speleogenesis (i.e., the process in which a cave is formed), landscape-scale variables, and geophysical factors in the determination of species richness in caves. Biological inventories from 21 caves located in the southeastern Iberian Peninsula along with partial least square (PLS) regression analysis were used to assess the relative importance of the different explanatory variables. The caves were grouped according to the similarity in their species composition; the effect that spatial distance could have on similarity was also studied using correlation between matrices. The energy and speleogenesis of caves accounted for 44.3% of the variation in species richness. The trophic level of each cave was the most significant factor in PLS regression analysis, and epigenic caves (i.e., those formed by the action of percolating water) had significantly more species than hypogenic ones (i.e., those formed by the action of upward flows in confined aquifers). Dissimilarity among the caves was very high (multiple-site betasim = 0.92). Two main groups of caves were revealed through the cluster analysis, one formed by the western caves and the other by the eastern ones. The significant but low-correlation found between faunistic dissimilarity and geographical distance (r = .16) disappeared once the caves were split into the two groups. The extreme beta-diversity suggests a very low connection among the caves and/or a very low dispersal capacity of the species. In the region under study, two main factors are intimately related to the richness of terrestrial subterranean species in caves: the amount of organic material (trophic level) and the formation process (genesis). This is the first time that the history of a cave genesis has been quantitatively considered to assess its importance in explaining richness patterns in comparison with other factors more widely recognized. PMID- 29238546 TI - Receptor uptake arrays for vitamin B12, siderophores, and glycans shape bacterial communities. AB - Molecular variants of vitamin B12, siderophores, and glycans occur. To take up variant forms, bacteria may express an array of receptors. The gut microbe Bacteroides thetaiotaomicron has three different receptors to take up variants of vitamin B12 and 88 receptors to take up various glycans. The design of receptor arrays reflects key processes that shape cellular evolution. Competition may focus each species on a subset of the available nutrient diversity. Some gut bacteria can take up only a narrow range of carbohydrates, whereas species such as B. thetaiotaomicron can digest many different complex glycans. Comparison of different nutrients, habitats, and genomes provides opportunity to test hypotheses about the breadth of receptor arrays. Another important process concerns fluctuations in nutrient availability. Such fluctuations enhance the value of cellular sensors, which gain information about environmental availability and adjust receptor deployment. Bacteria often adjust receptor expression in response to fluctuations of particular carbohydrate food sources. Some species may adjust expression of uptake receptors for specific siderophores. How do cells use sensor information to control the response to fluctuations? This question about regulatory wiring relates to problems that arise in control theory and artificial intelligence. Control theory clarifies how to analyze environmental fluctuations in relation to the design of sensors and response systems. Recent advances in deep learning studies of artificial intelligence focus on the architecture of regulatory wiring and the ways in which complex control networks represent and classify environmental states. I emphasize the similar design problems that arise in cellular evolution, control theory, and artificial intelligence. I connect those broad conceptual aspects to many testable hypotheses for bacterial uptake of vitamin B12, siderophores, and glycans. PMID- 29238549 TI - Rapid extirpation of a North American frog coincides with an increase in fungal pathogen prevalence: Historical analysis and implications for reintroduction. AB - As extinctions continue across the globe, conservation biologists are turning to species reintroduction programs as one optimistic tool for addressing the biodiversity crisis. For repatriation to become a viable strategy, fundamental prerequisites include determining the causes of declines and assessing whether the causes persist in the environment. Invasive species-especially pathogens-are an increasingly significant factor contributing to biodiversity loss. We hypothesized that Batrachochytrium dendrobatidis (Bd), the causative agent of the deadly amphibian disease chytridiomycosis, was important in the rapid (<10 years) localized extirpation of a North American frog (Rana boylii) and that Bd remains widespread among extant amphibians in the region of extirpation. We used an interdisciplinary approach, combining interviews with herpetological experts, analysis of archived field notes and museum specimen collections, and field sampling of the extant amphibian assemblage to examine (1) historical relative abundance of R. boylii; (2) potential causes of R. boylii declines; and (3) historical and contemporary prevalence of Bd. We found that R. boylii were relatively abundant prior to their rapid extirpation, and an increase in Bd prevalence coincided with R. boylii declines during a time of rapid change in the region, wherein backcountry recreation, urban development, and the amphibian pet trade were all on the rise. In addition, extreme flooding during the winter of 1969 coincided with localized extirpations in R. boylii populations observed by interview respondents. We conclude that Bd likely played an important role in the rapid extirpation of R. boylii from southern California and that multiple natural and anthropogenic factors may have worked in concert to make this possible in a relatively short period of time. This study emphasizes the importance of recognizing historical ecological contexts in making future management and reintroduction decisions. PMID- 29238550 TI - Plant community composition and species richness in the High Arctic tundra: From the present to the future. AB - Arctic plant communities are altered by climate changes. The magnitude of these alterations depends on whether species distributions are determined by macroclimatic conditions, by factors related to local topography, or by biotic interactions. Our current understanding of the relative importance of these conditions is limited due to the scarcity of studies, especially in the High Arctic. We investigated variations in vascular plant community composition and species richness based on 288 plots distributed on three sites along a coast inland gradient in Northeast Greenland using a stratified random design. We used an information theoretic approach to determine whether variations in species richness were best explained by macroclimate, by factors related to local topography (including soil water) or by plant-plant interactions. Latent variable models were used to explain patterns in plant community composition. Species richness was mainly determined by variations in soil water content, which explained 35% of the variation, and to a minor degree by other variables related to topography. Species richness was not directly related to macroclimate. Latent variable models showed that 23.0% of the variation in community composition was explained by variables related to topography, while distance to the inland ice explained an additional 6.4 %. This indicates that some species are associated with environmental conditions found in only some parts of the coast-inland gradient. Inclusion of macroclimatic variation increased the model's explanatory power by 4.2%. Our results suggest that the main impact of climate changes in the High Arctic will be mediated by their influence on local soil water conditions. Increasing temperatures are likely to cause higher evaporation rates and alter the distribution of late-melting snow patches. This will have little impact on landscape-scale diversity if plants are able to redistribute locally to remain in areas with sufficient soil water. PMID- 29238551 TI - Genetic differentiation and spatiotemporal history of diploidy and tetraploidy of Clintonia udensis. AB - Polyploidy is an important factor shaping the geographic range of a species. Clintonia udensis (Clintonia) is a primary perennial herb widely distributed in China with two karyotypic characteristics-diploid and tetraploid and thereby used to understand the ploidy and distribution. This study unraveled the patterns of genetic variation and spatiotemporal history among the cytotypes of C. udensis using simple sequence repeat or microsatellites. The results showed that the diploids and tetraploids showed the medium level of genetic differentiation; tetraploid was slightly lower than diploid in genetic diversity; recurrent polyploidization seems to have opened new possibilities for the local genotype; the spatiotemporal history of C. udensis allows tracing the interplay of polyploidy evolution; isolated and different ecological surroundings could act as evolutionary capacitors, preserve distinct karyological, and genetic diversity. The approaches of integrating genetic differentiation and spatiotemporal history of diploidy and tetraploidy of Clintonia udens would possibly provide a powerful way to understand the ploidy and plant distribution and undertaken in similar studies in other plant species simultaneously contained the diploid and tetraploid. PMID- 29238552 TI - Taking movement data to new depths: Inferring prey availability and patch profitability from seabird foraging behavior. AB - Detailed information acquired using tracking technology has the potential to provide accurate pictures of the types of movements and behaviors performed by animals. To date, such data have not been widely exploited to provide inferred information about the foraging habitat. We collected data using multiple sensors (GPS, time depth recorders, and accelerometers) from two species of diving seabirds, razorbills (Alca torda, N = 5, from Fair Isle, UK) and common guillemots (Uria aalge, N = 2 from Fair Isle and N = 2 from Colonsay, UK). We used a clustering algorithm to identify pursuit and catching events and the time spent pursuing and catching underwater, which we then used as indicators for inferring prey encounters throughout the water column and responses to changes in prey availability of the areas visited at two levels: individual dives and groups of dives. For each individual dive (N = 661 for guillemots, 6214 for razorbills), we modeled the number of pursuit and catching events, in relation to dive depth, duration, and type of dive performed (benthic vs. pelagic). For groups of dives (N = 58 for guillemots, 156 for razorbills), we modeled the total time spent pursuing and catching in relation to time spent underwater. Razorbills performed only pelagic dives, most likely exploiting prey available at shallow depths as indicated by the vertical distribution of pursuit and catching events. In contrast, guillemots were more flexible in their behavior, switching between benthic and pelagic dives. Capture attempt rates indicated that they were exploiting deep prey aggregations. The study highlights how novel analysis of movement data can give new insights into how animals exploit food patches, offering a unique opportunity to comprehend the behavioral ecology behind different movement patterns and understand how animals might respond to changes in prey distributions. PMID- 29238553 TI - Understanding predation risk and individual variation in risk avoidance for threatened boreal caribou. AB - Predation risk is a driver of species' distributions. Animals can increase risk avoidance in response to fluctuations in predation risk, but questions remain regarding individual variability and the capacity to respond to changes in spatial risk across human-altered landscapes. In northeast British Columbia, Canada, boreal caribou populations declined as roads and seismic lines have increased, which are theorized to increase gray wolf predation. Our goal was to model risk and to evaluate individual variability and the development of risk perception by examining individual risk avoidance in response to reproductive status and age. We used locations from collared caribou and wolves to identify landscape features associated with the risk of a potential wolf-caribou encounter and risk of being killed given an encounter. We built resource selection functions to estimate individual responses to risk. We used general linear regressions to evaluate individual risk and linear feature avoidance as a function of age and reproductive status (calf or no calf). Linear features increased the risk of encounter. Older caribou and caribou with calves demonstrated stronger avoidance of the risk of encounter and roads, but weaker avoidance in late summer to the risk of being killed relative to younger and calf less individuals. Mechanisms explaining the inverse relationships between the risk of encounter and risk of being killed are uncertain, but it is conceivable that caribou learn to avoid the risk of encounter and roads. Responses by females with vulnerable calves to the risk of encounter and risk of being killed might be explained by a trade-off between these two risk types and a prioritization on the risk of encounter. Despite the capacity to alter their responses to risk, the global decline in Rangifer populations (caribou and wild reindeer) suggests these behaviors are insufficient to mitigate the impacts of anthropogenic disturbances. PMID- 29238554 TI - Geographic isolation facilitates the evolution of reproductive isolation and morphological divergence. AB - Geographic isolation is known to contribute to divergent evolution, resulting in unique phenotypes. Oftentimes morphologically distinct populations are found to be interfertile while reproductive isolation is found to exist within nominal morphological species revealing the existence of cryptic species. These disparities can be difficult to predict or explain especially when they do not reflect an inferred history of common ancestry which suggests that environmental factors affect the nature of ecological divergence. A series of laboratory experiments and observational studies were used to address what role biogeographic factors may play in the ecological divergence of Hyalella amphipods. It was found that geographic isolation plays a key role in the evolution of reproductive isolation and divergent morphology and that divergence cannot be explained by molecular genetic variation. PMID- 29238555 TI - Residence time, native range size, and genome size predict naturalization among angiosperms introduced to Australia. AB - Although critical to progress in understanding (i) if, and (ii) at what rate, introduced plants will naturalize and potentially become invasive, establishing causal links between traits and invasion success is complicated by data gaps, phylogenetic nonindependence of species, the inability to control for differences between species in residence time and propagule pressure, and covariance among traits. Here, we focus on statistical relationships between genomic factors, life history traits, native range size, and naturalization status of angiosperms introduced to Australia. In a series of analyses, we alternately investigate the role of phylogeny, incorporate introduction history, and use graphical models to explore the network of conditional probabilities linking traits and introduction history to naturalization status. Applying this ensemble of methods to the largest publicly available data set on plant introductions and their fates, we found that, overall, residence time and native range size best predicted probability of naturalization. Yet, importantly, probability of naturalization consistently increased as genome size decreased, even when the effects of shared ancestry and residence time in Australia were accounted for, and that this pattern was stronger in species without a history of cultivation, but present across annual-biennials, and herbaceous and woody perennials. Thus, despite introduction biases and indirect effects of traits via introduction history, across analyses, reduced genome size was nevertheless consistently associated with a tendency to naturalize. PMID- 29238556 TI - Reliable effective number of breeders/adult census size ratios in seasonal breeding species: Opportunity for integrative demographic inferences based on capture-mark-recapture data and multilocus genotypes. AB - The ratio of the effective number of breeders (Nb) to the adult census size (Na), Nb/Na, approximates the departure from the standard capacity of a population to maintain genetic diversity in one reproductive season. This information is relevant for assessing population status, understanding evolutionary processes operating at local scales, and unraveling how life-history traits affect these processes. However, our knowledge on Nb/Na ratios in nature is limited because estimation of both parameters is challenging. The sibship frequency (SF) method is adequate for reliable Nb estimation because it is based on sibship and parentage reconstruction from genetic marker data, thereby providing demographic inferences that can be compared with field-based information. In addition, capture-mark-recapture (CMR) robust design methods are well suited for Na estimation in seasonal-breeding species. We used tadpole genotypes of three pond breeding amphibian species (Epidalea calamita, Hyla molleri, and Pelophylax perezi, n = 73-96 single-cohort tadpoles/species genotyped at 15-17 microsatellite loci) and candidate parental genotypes (n = 94-300 adults/species) to estimate Nb by the SF method. To assess the reliability of Nb estimates, we compared sibship and parentage inferences with field-based information and checked for the convergence of results in replicated subsampled analyses. Finally, we used CMR data from a 6-year monitoring program to estimate annual Na in the three species and calculate the Nb/Na ratio. Reliable ratios were obtained for E. calamita (Nb/Na = 0.18-0.28) and P. perezi (0.5), but in H. molleri, Na could not be estimated and genetic information proved insufficient for reliable Nb estimation. Integrative demographic studies taking full advantage of SF and CMR methods can provide accurate estimates of the Nb/Na ratio in seasonal breeding species. Importantly, the SF method provides results that can be readily evaluated for reliability. This represents a good opportunity for obtaining robust demographic inferences with wide applications for evolutionary and conservation research. PMID- 29238557 TI - Keystone nonconsumptive effects within a diverse predator community. AB - The number of prey killed by diverse predator communities is determined by complementarity and interference among predators, and by traits of particular predator species. However, it is less clear how predators' nonconsumptive effects (NCEs) scale with increasing predator biodiversity. We examined NCEs exerted on Culex mosquitoes by a diverse community of aquatic predators. In the field, mosquito larvae co-occurred with differing densities and species compositions of mesopredator insects; top predator dragonfly naiads were present in roughly half of surveyed water bodies. We reproduced these predator community features in artificial ponds, exposing mosquito larvae to predator cues and measuring resulting effects on mosquito traits throughout development. Nonconsumptive effects of various combinations of mesopredator species reduced the survival of mosquito larvae to pupation, and reduced the size and longevity of adult mosquitoes that later emerged from the water. Intriguingly, adding single dragonfly naiads to ponds restored survivorship of larval mosquitoes to levels seen in the absence of predators, and further decreased adult mosquito longevity compared with mosquitoes emerging from mesopredator treatments. Behavioral observations revealed that mosquito larvae regularly deployed "diving" escape behavior in the presence of the mesopredators, but not when a dragonfly naiad was also present. This suggests that dragonflies may have relaxed NCEs of the mesopredators by causing mosquitoes to abandon energetically costly diving. Our study demonstrates that adding one individual of a functionally unique species can substantially alter community-wide NCEs of predators on prey. For pathogen vectors like mosquitoes, this could in turn influence disease dynamics. PMID- 29238558 TI - Environmental change, shifting distributions, and habitat conservation plans: A case study of the California gnatcatcher. AB - Many species have already experienced distributional shifts due to changing environmental conditions, and analyzing past shifts can help us to understand the influence of environmental stressors on a species as well as to analyze the effectiveness of conservation strategies. We aimed to (1) quantify regional habitat associations of the California gnatcatcher (Polioptila californica); (2) describe changes in environmental variables and gnatcatcher distributions through time; (3) identify environmental drivers associated with habitat suitability changes; and (4) relate habitat suitability changes through time to habitat conservation plans. Southern California's Western Riverside County (WRC), an approximately 4,675 km2 conservation planning area. We assessed environmental correlates of distributional shifts of the federally threatened California gnatcatcher (hereafter, gnatcatcher) using partitioned Mahalanobis D2 niche modeling for three time periods: 1980-1997, 1998-2003, and 2004-2012, corresponding to distinct periods in habitat conservation planning. Highly suitable gnatcatcher habitat was consistently warmer and drier and occurred at a lower elevation than less suitable habitat and consistently had more CSS, less agriculture, and less chaparral. However, its relationship to development changed among periods, mainly due to the rapid change in this variable. Likewise, other aspects of highly suitable habitat changed among time periods, which became cooler and higher in elevation. The gnatcatcher lost 11.7% and 40.6% of highly suitable habitat within WRC between 1980-1997 to 1998-2003, and 1998-2003 to 2004 2012, respectively. Unprotected landscapes lost relatively more suitable habitat (-64.3%) than protected landscapes (30.5%). Over the past four decades, suitable habitat loss within WRC, especially between the second and third time periods, was associated with temperature-related factors coupled with landscape development across coastal sage scrub habitat; however, development appears to be driving change more rapidly than climate change. Our study demonstrates the importance of providing protected lands for potential suitable habitat in future scenarios. PMID- 29238559 TI - Evolution to environmental contamination ablates the circadian clock of an aquatic sentinel species. AB - Environmental contamination is a common cause of rapid evolution. Recent work has shown that Daphnia pulex, an important freshwater species, can rapidly evolve increased tolerance to a common contaminant, sodium chloride (NaCl) road salt. While such rapid evolution can benefit organisms, allowing them to adapt to new environmental conditions, it can also be associated with unforeseen tradeoffs. Given that exposure to environmental contaminants can cause circadian disruption, we investigated whether the circadian clock was affected by evolving a tolerance to high levels of road salt. By tracking the oscillations of a putative clock gene, period, we demonstrated that D. pulex express per mRNA with approximately 20-hr oscillations under control conditions. This putative circadian rhythm was ablated in response to high levels of salinity; populations adapted to high NaCl concentrations exhibited an ablation of period oscillation. Moreover, we showed that while gene expression is increased in several other genes, including clock, actin, and Na+/K+-ATPase, upon the adaptation to high levels of salinity, per expression is unique among the genes we tracked in that it is the only gene repressed in response to salt adaptation. These results suggest that rapid evolution of salt tolerance occurs with the tradeoff of suppressed circadian function. The resultant circadian disruption may have profound consequences to individuals, populations, and aquatic food webs by affecting species interactions. In addition, our research suggests that circadian clocks may also be disrupted by the adaptation to other environmental contaminants. PMID- 29238560 TI - Patterns of genomic variation in Coho salmon following reintroduction to the interior Columbia River. AB - Coho salmon were extirpated in the mid-20th century from the interior reaches of the Columbia River but were reintroduced with relatively abundant source stocks from the lower Columbia River near the Pacific coast. Reintroduction of Coho salmon to the interior Columbia River (Wenatchee River) using lower river stocks placed selective pressures on the new colonizers due to substantial differences with their original habitat such as migration distance and navigation of six additional hydropower dams. We used restriction site-associated DNA sequencing (RAD-seq) to genotype 5,392 SNPs in reintroduced Coho salmon in the Wenatchee River over four generations to test for signals of temporal structure and adaptive variation. Temporal genetic structure among the three broodlines of reintroduced fish was evident among the initial return years (2000, 2001, and 2002) and their descendants, which indicated levels of reproductive isolation among broodlines. Signals of adaptive variation were detected from multiple outlier tests and identified candidate genes for further study. This study illustrated that genetic variation and structure of reintroduced populations are likely to reflect source stocks for multiple generations but may shift over time once established in nature. PMID- 29238561 TI - Precopulatory but not postcopulatory male reproductive traits diverge in response to mating system manipulation in Drosophila melanogaster. AB - Competition between males creates potential for pre- and postcopulatory sexual selection and conflict. Theory predicts that males facing risk of sperm competition should evolve traits to secure their reproductive success. If those traits are costly to females, the evolution of such traits may also increase conflict between the sexes. Conversely, under the absence of sperm competition, one expectation is for selection on male competitive traits to relax thereby also relaxing sexual conflict. Experimental evolution studies are a powerful tool to test this expectation. Studies in multiple insect species have yielded mixed and partially conflicting results. In this study, we evaluated male competitive traits and male effects on female costs of mating in Drosophila melanogaster after replicate lines evolved for more than 50 generations either under enforced monogamy or sustained polygamy, thus manipulating the extent of intrasexual competition between males. We found that in a setting where males competed directly with a rival male for access to a female and fertilization of her ova polygamous males had superior reproductive success compared to monogamous males. When comparing reproductive success solely in double mating standard sperm competition assays, however, we found no difference in male sperm defense competitiveness between the different selection regimes. Instead, we found monogamous males to be inferior in precopulatory competition, which indicates that in our system, enforced monogamy relaxed selection on traits important in precopulatory rather than postcopulatory competition. We discuss our findings in the context of findings from previous experimental evolution studies in Drosophila ssp. and other invertebrate species. PMID- 29238563 TI - A biogeographical study on tropical flora of southern China. AB - The tropical climate in China exists in southeastern Xizang (Tibet), southwestern to southeastern Yunnan, southwestern Guangxi, southern Guangdon, southern Taiwan, and Hainan, and these southern Chinese areas contain tropical floras. I checked and synonymized native seed plants from these tropical areas in China and recognized 12,844 species of seed plants included in 2,181 genera and 227 families. In the tropical flora of southern China, the families are mainly distributed in tropical areas and extend into temperate zones and contribute to the majority of the taxa present. The genera with tropical distributions also make up the most of the total flora. In terms of geographical elements, the genera with tropical Asian distribution constitute the highest proportion, which implies tropical Asian or Indo-Malaysia affinity. Floristic composition and geographical elements are conspicuous from region to region due to different geological history and ecological environments, although floristic similarities from these regions are more than 90% and 64% at the family and generic levels, respectively, but lower than 50% at specific level. These differences in the regional floras could be influenced by historical events associated with the uplift of the Himalayas, such as the southeastward extrusion of the Indochina geoblock, clockwise rotation and southeastward movement of Lanping-Simao geoblock, and southeastward movement of Hainan Island. The similarity coefficients between the flora of southern China and those of Indochina countries are more than 96% and 80% at family and generic levels, indicating their close floristic affinity and inclusion in the same biogeographically floristic unit. PMID- 29238562 TI - Colorful seashells: Identification of haem pathway genes associated with the synthesis of porphyrin shell color in marine snails. AB - Very little is known about the evolution of molluskan shell pigments, although Mollusca is a highly diverse, species rich, and ecologically important group of animals comprised of many brightly colored taxa. The marine snail genus Clanculus was chosen as an exceptional model for studying the evolution of shell color, first, because in Clanculus margaritarius and Clanculus pharaonius both shell and foot share similar colors and patterns; and second, because recent studies have identified the pigments, trochopuniceus (pink-red), and trochoxouthos (yellow brown), both comprised of uroporphyrin I and uroporphyrin III, in both shell and colored foot tissue of these species. These unusual characteristics provide a rare opportunity to identify the genes involved in color production because, as the same pigments occur in the shell and colored foot tissue, the same color related genes may be simultaneously expressed in both mantle (which produces the shell) and foot tissue. In this study, the transcriptomes of these two Clanculus species along with a third species, Calliostoma zizyphinum, were sequenced to identify genes associated with the synthesis of porphyrins. Calliostoma zizyphinum was selected as a negative control as trochopuniceus and trochoxouthos were not found to occur in this species. As expected, genes necessary for the production of uroporphyrin I and III were found in all three species, but gene expression levels were consistent with synthesis of uroporphyrins in mantle and colored foot tissue only in Clanculus. These results are relevant not only to understanding the evolution of shell pigmentation in Clanculus but also to understanding the evolution of color in other species with uroporphyrin pigmentation, including (mainly marine) mollusks soft tissues and shells, annelid and platyhelminth worms, and some bird feathers. PMID- 29238564 TI - Evidence of exceptional oyster-reef resilience to fluctuations in sea level. AB - Ecosystems at the land-sea interface are vulnerable to rising sea level. Intertidal habitats must maintain their surface elevations with respect to sea level to persist via vertical growth or landward retreat, but projected rates of sea-level rise may exceed the accretion rates of many biogenic habitats. While considerable attention is focused on climate change over centennial timescales, relative sea level also fluctuates dramatically (10-30 cm) over month-to-year timescales due to interacting oceanic and atmospheric processes. To assess the response of oyster-reef (Crassostrea virginica) growth to interannual variations in mean sea level (MSL) and improve long-term forecasts of reef response to rising seas, we monitored the morphology of constructed and natural intertidal reefs over 5 years using terrestrial lidar. Timing of reef scans created distinct periods of high and low relative water level for decade-old reefs (n = 3) constructed in 1997 and 2000, young reefs (n = 11) constructed in 2011 and one natural reef (approximately 100 years old). Changes in surface elevation were related to MSL trends. Decade-old reefs achieved 2 cm/year growth, which occurred along higher elevations when MSL increased. Young reefs experienced peak growth (6.7 cm/year) at a lower elevation that coincided with a drop in MSL. The natural reef exhibited considerable loss during the low MSL of the first time step but grew substantially during higher MSL through the second time step, with growth peaking (4.3 cm/year) at MSL, reoccupying the elevations previously lost. Oyster reefs appear to be in dynamic equilibrium with short-term (month-to-year) fluctuations in sea level, evidencing notable resilience to future changes to sea level that surpasses other coastal biogenic habitat types. These growth patterns support the presence of a previously defined optimal growth zone that shifts correspondingly with changes in MSL, which can help guide oyster-reef conservation and restoration. PMID- 29238565 TI - New specific primers for amplification of the Internal Transcribed Spacer region in Clitellata (Annelida). AB - Nuclear molecular evidence, for example, the rapidly evolving Internal Transcribed Spacer region (ITS), integrated with maternally inherited (mitochondrial) COI barcodes, has provided new insights into the diversity of clitellate annelids. PCR amplification and sequencing of ITS, however, are often hampered by poor specificity of primers used. Therefore, new clitellate-specific primers for amplifying the whole ITS region (ITS: 29F/1084R) and a part of it (ITS2: 606F/1082R) were developed on the basis of a collection of previously published ITS sequences with flanking rDNA coding regions. The specificity of these and other ITS primers used for clitellates were then tested in silico by evaluating their mismatches with all assembled and annotated sequences (STD, version r127) from EMBL, and the new primers were also tested in vitro for a taxonomically broad sample of clitellate species (71 specimens representing 11 families). The in silico analyses showed that the newly designed primers have a better performance than the universal ones when amplifying clitellate ITS sequences. In vitro PCR and sequencing using the new primers were successful, in particular, for the 606F/1082R pair, which worked well for 65 of the 71 specimens. Thus, using this pair for amplifying the ITS2 will facilitate further molecular systematic investigation of various clitellates. The other pair (29F/1084R), will be a useful complement to existing ITS primers, when amplifying ITS as a whole. PMID- 29238566 TI - Water level affects availability of optimal feeding habitats for threatened migratory waterbirds. AB - Extensive ephemeral wetlands at Poyang Lake, created by dramatic seasonal changes in water level, constitute the main wintering site for migratory Anatidae in China. Reductions in wetland area during the last 15 years have led to proposals to build a Poyang Dam to retain high winter water levels within the lake. Changing the natural hydrological system will affect waterbirds dependent on water level changes for food availability and accessibility. We tracked two goose species with different feeding behaviors (greater white-fronted geese Anser albifrons [grazing species] and swan geese Anser cygnoides [tuber-feeding species]) during two winters with contrasting water levels (continuous recession in 2015; sustained high water in 2016, similar to those predicted post-Poyang Dam), investigating the effects of water level change on their habitat selection based on vegetation and elevation. In 2015, white-fronted geese extensively exploited sequentially created mudflats, feeding on short nutritious graminoid swards, while swan geese excavated substrates along the water edge for tubers. This critical dynamic ecotone successively exposes subaquatic food and supports early-stage graminoid growth during water level recession. During sustained high water levels in 2016, both species selected mudflats, but also to a greater degree of habitats with longer established seasonal graminoid swards because access to tubers and new graminoid growth was restricted under high-water conditions. Longer established graminoid swards offer less energetically profitable forage for both species. Substantial reduction in suitable habitat and confinement to less profitable forage by higher water levels is likely to reduce the ability of geese to accumulate sufficient fat stores for migration, with potential carryover effects on subsequent survival and reproduction. Our results suggest that high water levels in Poyang Lake should be retained during summer, but permitted to gradually recede, exposing new areas throughout winter to provide access for waterbirds from all feeding guilds. PMID- 29238567 TI - Mind the gap! Integrating taxonomic approaches to assess ant diversity at the southern extreme of the Atlantic Forest. AB - Understanding patterns of species diversity relies on accurate taxonomy which can only be achieved by long-term natural history research and the use of complementary information to establish species boundaries among cryptic taxa. We used DNA barcoding to characterize the ant diversity of Iguazu National Park (INP), a protected area of the Upper Parana Atlantic Forest ecoregion, located at the southernmost extent of this forest. We assessed ant diversity using both cytochrome c oxidase subunit 1 (COI) sequences and traditional morphological approaches, and compared the results of these two methods. We successfully obtained COI sequences for 312 specimens belonging to 124 species, providing a DNA barcode reference library for nearly 50% of the currently known ant fauna of INP. Our results support a clear barcode gap for all but two species, with a mean intraspecific divergence of 0.72%, and an average congeneric distance of 17.25%. Congruently, the library assembled here was useful for the discrimination of the ants of INP and allowed us to link unidentified males and queens to their worker castes. To detect overlooked diversity, we classified the DNA barcodes into Molecular Operational Taxonomic Units (MOTUs) using three different clustering algorithms, and compared their number and composition to that of reference species identified based on morphology. The MOTU count was always higher than that of reference species regardless of the method, suggesting that the diversity of ants at INP could be between 6% and 10% higher than currently recognized. Lastly, our survey contributed with 78 new barcode clusters to the global DNA barcode reference library, and added 36 new records of ant species for the INP, being 23 of them new citations for Argentina. PMID- 29238569 TI - Transient cardiac dysfunction but elevated cardiac and kidney biomarkers 24 h following an ultra-distance running event in Mexican Tarahumara. AB - Background: The Mexican Tarahumara are accustomed to running ultra-distance races. No data exist on the acute physiological changes following ultra-distance running and physiological-biomarker associations in this population. Thus, we aimed to investigate the acute impact (<= 24 h) on functional and biochemical changes of the cardiac muscle and biochemical changes associated with kidney function following a 63-km ultra-distance race with an altitude difference of 1800 m in Mexican Tarahumara athletes. Methods: Ten Tarahumara male athletes (mean +/- SD age = 29.9 +/- 6.6 years) volunteered to participate in the study. VO2max was assessed by a sub-maximal step test individually calibrated combining heart rate and accelerometry. Standard transthoracic echocardiography methodology and venipuncture blood tests were carried out at four time points: pre-race, immediately post-race, 6 h, and 24 h post-race. Results: Estimated mean VO2max was 54.5 (+/- 8.8) mL O2 min-1 kg-1 and average physiological activity intensity was 746 (+/- 143) J min-1 kg -1 (~ 11.5 METs). When compared to pre-race values, significant changes in left ventricular ejection fraction (LVEF) and LV end diastolic volume (- 15%, p < 0.001 for both parameters), cardiac output (39%, p < 0.001), and maximal longitudinal velocity (- 13%, p < 0.009) were seen post-race with LVEF also being decreased at < 6 h post-race (- 8%, p < 0.014). Plasma biomarkers mid-regional pro-atrial natriuretic peptide, copeptin-ultra sensitive, and high-sensitivity cardiac troponin T remained significantly elevated at 24 h post-race, and the two latter were inversely associated with LVEF (p < 0.04). Kidney dysfunction was indicated by increased post-race copeptin-ultra sensitive. Conclusions: The athletes participating in this study had acute transient cardiac dysfunction as assessed by echocardiography but elevated cardiac and kidney biomarkers at 24 h following a 63-km race with extreme altitude variation. PMID- 29238570 TI - Impact of ASA score misclassification on NSQIP predicted mortality: a retrospective analysis. AB - Background: The ASA physical classification score has a major impact on the observed/expected (O/E) mortality ratio in the NSQIP General Vascular Mortality Model. The difference in predicted mortality is greatest between ASAs 3 and 4. We hypothesized under-classified ASA scores significantly affect the O/E mortality. Methods: We conducted a retrospective review of NSQIP essential surgery cases from January 2014 to December 2014 (n = 1264) with mortality sub-analysis (n = 33) at our institution. We recorded transfer and emergency status and independently calculated the ASA score for mortalities using published definitions. A random sample of 50 survivors and 10 emergency survivors were reviewed and ASA recalculated. We performed statistical modeling to simulate the effects of ASA misclassifications. Statistical analysis was performed using JMP 10 and SAS 9.4. Results: ASA was under-classified in 18.2% of mortalities, most commonly ASAs 3 and 4. Sixteen percent of ASA 3 survivors were misclassified, including 60% in the emergency subgroup (p < 0.05 vs. elective cases). Patients transferred from other institutions were more likely to be emergency cases than non-transferred patients (43.5 vs. 7.84%, p < 0.05). Transferred patients had a higher proportion of ASAs 3-5 vs. ASAs 1-2 compared with non-transfers (84.38 vs. 49.76%, p < 0.05) Simulation data showed ASA misclassification underestimated predicted mortality by 2.5 deaths on average. Conclusion: ASA misclassification significantly impacts O/E mortality. With accurate ASA classification, observed mortality would not have exceeded expected mortality in our institution. Education regarding the impact of ASA scoring is critical to ensure accurate O/E mortality data at hospitals using NSQIP to assess surgical quality. PMID- 29238568 TI - Predictions of response to temperature are contingent on model choice and data quality. AB - The equations used to account for the temperature dependence of biological processes, including growth and metabolic rates, are the foundations of our predictions of how global biogeochemistry and biogeography change in response to global climate change. We review and test the use of 12 equations used to model the temperature dependence of biological processes across the full range of their temperature response, including supra- and suboptimal temperatures. We focus on fitting these equations to thermal response curves for phytoplankton growth but also tested the equations on a variety of traits across a wide diversity of organisms. We found that many of the surveyed equations have comparable abilities to fit data and equally high requirements for data quality (number of test temperatures and range of response captured) but lead to different estimates of cardinal temperatures and of the biological rates at these temperatures. When these rate estimates are used for biogeographic predictions, differences between the estimates of even the best-fitting models can exceed the global biological change predicted for a decade of global warming. As a result, studies of the biological response to global changes in temperature must make careful consideration of model selection and of the quality of the data used for parametrizing these models. PMID- 29238571 TI - Immunonutrition within enhanced recovery after surgery (ERAS): an unresolved matter. AB - Preoperative malnutrition because of poor oral intake significantly increases the risk of adverse events after surgery and leads to increased length of stay. While immunonutrition has been utilized in the non-ERAS setting, its utility in both minimally invasive surgery and ERAS pathway procedures remain poorly defined. There are at least ten meta-analyses regarding the assessment of immunonutrition, but virtually, all of these were performed in an era prior to minimally invasive surgery, adoption of enhanced recovery protocols, and an understanding of the assessment and physiology of sarcopenia. In terms of immunonutrition within an ERAS pathway, the few studies that have been published have severe flaws in design and sample, bringing their overall conclusion into question. Furthermore, the optimal components of immunonutrition have yet to be adequately determined and may vary for patients based on comorbidities as well as the proposed procedures. Risk stratification based on markers of nutritionally deficient states such as image assessed sarcopenia, Glasgow Prognostic Score, prognostic nutrition index, or assessment of methylarginines are needed prior to the initiation of any such immunotherapy. Lastly, there is a need for properly designed randomized control trials that stratify patients appropriately and determine the optimal timing, composition, and duration of immunotherapy. PMID- 29238572 TI - Management and investigation of a Serratia marcescens outbreak in a neonatal unit in Switzerland - the role of hand hygiene and whole genome sequencing - R1, ARIC D-17-00143. AB - Background: Many outbreaks due to Serratia marcescens among neonates have been described in the literature but little is known about the role of whole genome sequencing in outbreak analysis and management. Methods: Between February and March 2013, 2 neonates and 2 infants previously hospitalised in the neonatal unit of a tertiary care centre in Switzerland, were found to be colonised with S. marcescens. An investigation was launched with extensive environmental sampling and neonatal screening in four consecutive point prevalence surveys between April and May 2013. All identified isolates were first investigated by fingerprinting and later by whole genome sequencing. Audits of best practices were performed and a hand hygiene promotion programme was implemented. Results: Twenty neonates were colonised with S. marcescens. No invasive infection due to S. marcescens occurred. All 231 environmental samples were negative. Hand hygiene compliance improved from 51% in April 2013 to 79% in May 2013 and remained high thereafter. No S. marcescens was identified in point prevalence surveys in June and October 2013. All strains were identical in the fingerprinting analysis and closely related according to whole genome sequencing. Conclusions: Improving best practices and particularly hand hygiene proved effective in terminating the outbreak. Whole genome sequencing is a helpful tool for genotyping because it allows both sufficient discrimination of strains and comparison to other outbreaks through the use of an emerging international database. PMID- 29238573 TI - Estimate of undergraduate university student alcohol use in China: a systematic review and meta-analysis. AB - Objective: To develop an estimate of self-reported last 30 day alcohol use by university students in China. Methods: A search of papers published in English and Chinese between 2006 and 2015, following pre-established selection criteria, identified 30 papers that were included in this meta-analysis. Nine moderator variables were preselected for this analysis. Results: A total of 749 papers were identified in the keyword search, and 30 studies (28 in Chinese, 2 in English) met all selection criteria and were included in the meta-analysis. The self reported last-30-day alcohol use for undergraduate university students was 66.8% for males and 31.7% for females. Meta-regression identified three moderators associated with the different drinking rates reported: the definition of drinking, the origin of the questionnaire used in the survey, and the geographic region where the survey was conducted. These three moderators explained 56% of the heterogeneity of reported drinking rates for the male students and 47% of the heterogeneity of reported drinking rates for the female students. Conclusions: The results of this meta-analysis provide an estimate of last 30 day alcohol use by university students (age 18-23) and increase our understanding of drinking by young people in China. The meta-analysis suggested three variables that could have affected the results and which are worthy of further study. The discussion places these results in the context of Chinese drinking culture and university life. PMID- 29238574 TI - Role of guaifenesin in the management of chronic bronchitis and upper respiratory tract infections. AB - Guaifenesin, a mucoactive drug, acts by loosening mucus in the airways and making coughs more productive. It is used for relief of wet cough and chest congestion due to the common cold, and remains the only legally marketed expectorant in the US (per OTC Monograph). An ingredient in numerous over-the-counter (OTC) cough/cold medications, guaifenesin has a secondary indication for use in stable chronic bronchitis (professional indication). Clinical pharmacology and patient studies support the clinical utility of guaifenesin in respiratory conditions where mucus hypersecretion is prevalent: acute upper respiratory tract infections (URTIs), stable chronic bronchitis, and possibly rhinosinusitis. Guaifenesin has a well-established and favorable safety and tolerability profile in adult and pediatric populations. Its dosing range (200-400 mg 4-hourly, up to 6* daily) allows flexible dose titration to allow an increase of plasma concentrations. Multiple daily doses are needed to maintain 24-h therapeutic effect with immediate-release formulations. Extended-release guaifenesin tablet formulations are available, providing convenience with 12-hourly dosing and portability compared to liquids. Guaifenesin is considered as a safe and effective expectorant for the treatment of mucus-related symptoms in acute URTIs and stable chronic bronchitis. Its clinical efficacy has been demonstrated most widely in chronic respiratory conditions, where excess mucus production and cough are more stable symptoms. Progress is being made to establish clinical models and measures that are more appropriate for studying symptomatic relief with guaifenesin in acute respiratory infections. This will help generate the up-to-date and high quality data needed to optimize guaifenesin's effectiveness in established uses, and in new respiratory indications associated with mucus hypersecretion. PMID- 29238575 TI - Non-traumatic isolated medial cuneiform fracture: A unique mechanism of a rare injury. AB - We report a case of a 23-year-old woman who sustained a stress fracture to the medial cuneiform. Isolated medial cuneiform fractures are extremely rare with less than 10 cases reported in the literature. The patient initially presented to an urgent care facility complaining of right midfoot pain that occurred while running. Radiographs obtained at the time showed no acute abnormality and the patient was told to resume normal activities. Several weeks later, she presented to urgent care again after exercising, this time unable to bear weight and with swelling and ecchymoses of the right foot. Plain radiographs were again normal, but a high suspicion for injury remained, so a magnetic resonance imaging of the foot was obtained. The advanced imaging showed an acute, non-displaced fracture of the medial cuneiform. Because the fracture was discovered soon after the injury and was non-displaced, she was treated conservatively and at 6-month follow up had returned to all pre-injury activities with no complaints. These rare fractures are often missed at initial presentation because they are usually not evident on plain radiographs. Unless more advanced imaging is obtained to rule out a fracture, a delay of diagnosis can occur resulting in additional morbidity for the patient. Level of clinical evidence: Level 5. PMID- 29238576 TI - A case of legionella pneumonia caused by home use of continuous positive airway pressure. AB - A 67-year-old woman with morbid obesity and severe obstructive sleep apnea presented to the emergency department with 2 days of productive cough, fever, shortness of breath and loose stools. A chest x-ray showed extensive bilateral infiltrates, and she was quickly intubated for acute hypoxic respiratory failure. A urine legionella antigen test was positive, and she was admitted to the intensive care unit with a diagnosis of severe legionella pneumonia. She improved over the next week with a course of levofloxacin. Once improved, the state health department visited her home and interviewed her husband and determined that she had not been cleaning her continuous positive pressure mask, tubing and humidifier appropriately. They concluded that the legionella likely came from her continuous positive airway pressure equipment. Cases of legionella pneumonia have frequently been reported through infected water supplies and even respiratory equipment. It is crucial that the mask and tubing used with these devices are cleaned appropriately to minimize the risk of infection. PMID- 29238577 TI - Lower gastrointestinal bleeding due to rectal Dieulafoy's lesion. AB - Dieulafoy's lesion is a relatively rare but serious cause of gastrointestinal bleeding. It usually involves the upper gastrointestinal tract. However, it has recently been reported in different regions of the gastrointestinal tract, including the rectum. Here, we report the case of a female patient who presented with fresh bleeding per rectum for 1 day with low hemoglobin level. Colonoscopy revealed an actively bleeding rectal Dieulafoy's lesion which was successfully treated with a clip. To our knowledge, there have been few reported cases of lower gastrointestinal bleeding caused by Dieulafoy's lesion in the rectum. PMID- 29238578 TI - Bone-eating kidney disease. AB - In the current era of early detection of chronic kidney disease and efficient therapeutic options for management of its complications, skeletal manifestations of renal hyperparathyroidism are increasingly rare. A 31-year-old female patient presented for evaluation of severe pain in the left forearm, right hand, right knee, right hip, and lower back following a fall sustained 3 days prior to presentation. She had a history of end-stage renal disease and received maintenance hemodialysis. Review of the medical records revealed that she had poor compliance with her diet, medications, and dialysis treatments. Laboratory values were significant for marked elevation in serum parathyroid hormone level (1735 pg/mL), as well as hyperphosphatemia and normal serum calcium levels. Interestingly, X-ray images showed generalized severe demineralization of the extremities with the pelvic computed tomography scan revealing presence of diffuse brown tumors. In addition, she had insufficiency fractures of the extremities that left her incapacitated and had to be managed conservatively due to her poor functional status and ongoing severe hyperparathyroidism. Unfortunately, the patient refused surgical removal of the parathyroid glands and was hence treated with a high-dose phosphate binder and a calcimimetic agent together with reinforcement of compliance. This case highlights the importance of metabolic assessment of patients presenting with unexpected bone complications and can be used to raise awareness of the physicians on the extreme cases of mineral bone complications secondary to renal disease that are observed rarely. PMID- 29238579 TI - Acute abdomen with a misleading clinical entity. AB - Massive ovarian edema is a rare, non-neoplastic solid tumor-like lesion. It results from compromised venous and lymphatic drainage due to partial or intermittent torsion of ovarian pedicle. Pain, distension or abdominal mass, menstrual irregularities, infertility and hormone-related symptoms can be the clinical presentation. We report a case of massive ovarian edema in a 28-year-old female who presented with acute pain abdomen. She was diagnosed clinico radiologically with solid ovarian tumor and massive ovarian edema on histology. Massive ovarian edema should be suspected in female of reproductive age group presenting with abdominal pain, solid enlargement of ovary on radiology and normal serum tumor markers. PMID- 29238580 TI - Endometrioid adenocarcinoma arising from colon endometriosis. AB - Endometriosis-associated intestinal tumors represent the malignant transformation of gastrointestinal endometriosis. Approximately 50 cases have been reported in the literature. They are most commonly found among women aged 30-60 years, whereas exogenous hormone therapy and obesity are primary risk factors for the malignant transformation of endometriotic lesions. Clinical features simulate a primary colonic carcinoma. A high index of suspicion in conjunction with careful histological and immunohistochemical examination (CK7, CK20, CDX2, CD10, ER, and PR) is important for establishing a correct diagnosis. In this article, a rare case of a postmenopausal woman with no risk factors and conflicting clinical presentation, diagnosed with endometriosis-associated intestinal tumor, is described. PMID- 29238581 TI - A spicy status: Synthetic cannabinoid (spice) use and new-onset refractory status epilepticus-A case report and review of the literature. AB - Synthetic cannabinoids refer to a wide variety of chemicals engineered to bind cannabinoid receptors (CB1 and CB2) and mimic the effects of delta-9 tetrahydrocanabinol. The potential for severe toxicity and limited in vivo data make synthetic cannabinoid intake an important public health and safety concern. Neurologic toxidromes associated with their use include mental status changes, panic attacks, memory distortions, acute psychosis (e.g. paranoia, delusional thoughts), disorganized behavior, and suicidal and homicidal thoughts. Systemic complications include vomiting, sinus tachycardia, myocardial infarction, and acute kidney injury. Seizures are common; however, status epilepticus is not widely reported. In this case report, we describe a patient who developed acute psychosis and new-onset refractory status epilepticus necessitating emergent neurological life-support and prolonged admission to an intensive care unit following abuse of synthetic cannabinoids. We include a brief review of the literature to prepare the treating clinician for the broad clinical spectrum of this increasingly common intoxication. PMID- 29238582 TI - Inferior colliculus syndrome: Clinical magnetic resonance microscopy anatomic analysis on a 7 T system. AB - We performed detailed structural analysis of a case of a unilateral lesion of the inferior colliculus using magnetic resonance microscopy on a 7 T system. A 36 year-old right-handed man had an intracerebral hemorrhage circumscribed to the right inferior colliculus. Following recovery from the acute phase, he had only residual left ear tinnitus and left trochlear palsy and no hearing loss. Microscopic imaging analysis on a 7 T magnetic resonance imaging system demonstrated a chronic lesion confined primarily to the right central nucleus of the inferior colliculus. Sound localization was significantly impaired in the contralateral hemispace. The case confirms prior clinical reports of unilateral inferior colliculus dysfunction, the specific anatomic characterization of which was demonstrated in this case by magnetic resonance microscopy. It furthermore supports the notion that central nucleus of the inferior colliculus dysfunction can produce tinnitus and sound localization deficits, without hearing loss. PMID- 29238583 TI - A modified wire-loop snare technique for the retrieval of inferior vena cava filter with embedded hook. AB - Common obstacles to successful retrieval of retrievable inferior vena cave filter include embedded filter hook and severe tilt of the filter. We described a modified wire-loop snare technique using self-made fishhook-like pigtail catheter and 11-F-long sheath to retrieve a severe tilted filter with embedded hook successfully. The modified wire-loop snare technique is simple and effective requiring only standard equipment and single venous access. This technique may be suitable for some types of retrievable filter with embedded hook. PMID- 29238584 TI - Systematic review and meta-analysis of the performance of nurses in small bowel capsule endoscopy reading. AB - Introduction: Increasing demands on healthcare systems mean that nurses are taking on more roles as physician extenders. Capsule endoscopy (CE) is a laborious procedure where specialist nurses could reduce physician workload and rationalise resource utilisation. The aim of this review and meta-analysis is to consolidate data on nurses' performance in small bowel CE (SBCE). Materials and methods: A comprehensive literature search was conducted for randomised controlled trials and comparative studies on nurses in SBCE reading compared to physicians. We examined the performance of nurses compared to SBCE-trained physicians. Results: Sixteen relevant studies were identified, with 820 SBCE examinations involving 20 nurses. 11/16 studies reported the numbers of SBCE findings detected. Overall, the pooled proportion of all findings reported by physicians and nurses was 86%. Studies involving nurses with endoscopic experience showed a summative detection rate of 89%. 7/16 studies reported the number of videos where there was agreement between the nurse and physicians for overall findings/diagnosis. The overall proportion of videos with agreement was 68%. In studies where nurses had endoscopy experience, the proportion of videos with agreement was 71%. Conclusion: Our meta-analysis supports a more active role for nurses in SBCE reading. We suggest nurses can function as independent CE readers in general, given adequate training and formal credentialing. PMID- 29238585 TI - Human intestinal epithelium in a dish: Current models for research into gastrointestinal pathophysiology. AB - Determining the exact pathogenesis of chronic gastrointestinal diseases remains difficult due to the complex in vivo environment. In this review we give an overview of the available epithelial cell culture systems developed to investigate pathophysiology of gastrointestinal diseases. Traditionally used two dimensional (2D) immortalised (tumour) cell lines survive long-term, but are not genetically stable nor represent any human in particular. In contrast, primary cultures are patient unique, but short-lived. Three-dimensional (3D) organoid cultures resemble the crypt-villus domain and contain all cell lineages, are long lived and genetically stable. Unfortunately, manipulation of the 3D organoid system is more challenging. Combining the 3D and 2D technologies may overcome limitations and offer the formation of monolayers on permeable membranes or flow chambers. Determining the right model to use will depend on the pathology of interest and the focus of the research, defining which cell types need to be included in the model. PMID- 29238587 TI - Bacterial infections in acute variceal hemorrhage despite antibiotics-a multicenter study of predictors and clinical impact. AB - Background and aims: Current guidelines recommend antibiotic prophylaxis in all patients presenting with cirrhosis and acute variceal hemorrhage (AVH). We aimed to evaluate the characteristics and clinical impact of "early" infections (developing within 14 days) of AVH in a real-world setting. Methods: We analyzed retrospective data from a cohort of 371 adult patients with cirrhosis and AVH all of whom had received antibiotic prophylaxis (74% men; mean age 56 years), admitted to tertiary care hospitals in Edmonton, Alberta, Canada, and Barcelona, Spain. Sensitivity analyses were presented for culture-positive (confirmed) infections. Results: The mean MELD was 16. Fifty-two percent of patients received quinolones, 45% third-generation cephalosporins and 3% other antibiotics. Fourteen percent (51/371) developed an infection within 14 days of AVH. Seventy five percent of infections were culture positive and occurred at a mean of six days from AVH. When all infections were considered, respiratory infections were the most common (53%) followed by urinary tract infections (17%) and bacteremia (16%). Resistance patterns differed between countries. Outpatient antibiotic prophylaxis (OR 5.4) and intubation (OR 2.6) were independent predictors of bacterial infection. Bacterial infection (OR 2.6) and the MELD (OR 1.2) were independent predictors of six-week mortality. Conclusions: Early bacterial infections develop in 14% of cirrhotic patients with AVH despite antibiotic prophylaxis, and have a negative impact on six-week mortality. Intubation and outpatient antibiotic prophylaxis are associated with increased risk of early bacterial infections. Patients at risk should be followed closely with prompt infection workup and local antibiogram-based expansion of antibiotic therapy in case of clinical decline. PMID- 29238586 TI - International prospective observational study of upper gastrointestinal haemorrhage: Does weekend admission affect outcome? AB - Introduction: Out of hours admissions have higher mortality for many conditions but upper gastrointestinal haemorrhage studies have produced variable outcomes. Methods: Prospective study of 12 months consecutive admissions of upper gastrointestinal haemorrhage from four international high volume centres. Admission period (weekdays, weeknights or weekends), demographics, haemodynamic parameters, laboratory results, endoscopy findings, further procedures and 30-day mortality were recorded. Five upper gastrointestinal haemorrhage risk scores were calculated. Results: 2118 patients, 60% male, median age 66 years were studied. Compared with patients presenting on weekdays, patients presenting at weekends had no significant differences in comorbidity, pulse, systolic BP, risk scores, frequency of peptic ulcers or varices. Those presenting on weekdays had lower haemoglobin (p = 0.007) and were more likely to have a normal endoscopy (p < 0.01). Time to endoscopy was less for weeknight presentation (p = 0.001). Sixty seven per cent of those presenting on weekdays, 75% on weeknights and 60% at weekends had endoscopy within 24 h. Transfusion requirements, need for endoscopic therapy or surgery/embolization, rebleeding rates (6.1%) and mortality (7.2%) did not differ with presentation time. Conclusion: This multi-centre international study in large centres found no difference in demographics, comorbidity or haemodynamic stability and no increase in mortality for patients presenting with upper gastrointestinal haemorrhage out of hours. PMID- 29238588 TI - The role of TIPS in the management of liver transplant candidates. AB - Background: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is used for treatment of several complications in patients with liver cirrhosis. Recent studies have identified a survival benefit for patients on the waiting list after TIPS implantation, but the optimal time point for TIPS implantation prior to orthotopic liver transplantation (OLT) has not been established. Study: This study retrospectively assessed patients undergoing TIPS implantation before or after listing for OLT at the Medical University of Vienna. n = 98 patients with TIPS on the waiting list between January 1993 and December 2013 were identified (n = 73 (74.5%) pre-listing TIPS, n = 25 (25.5%) post-listing TIPS). A matched control group at the time of OLT without TIPS (n = 60) was included. Results: More patients with post-listing TIPS (28.0%, 7/25) showed clinical improvement and went off-list than patients with pre-listing TIPS (8.2%, 6/73, p = .0119). A similar proportion of patients with pre-listing TIPS (19.2%, 14/73) and post-listing TIPS (20.0%, 5/25) died on the OLT waiting list. Transplant surgery time was similar in patients with and without TIPS: 348(+/-13) vs. 337(+/ 10) minutes (p = .5139). Estimated 1-year post-transplant survival was similar across all groups (pre-listing TIPS: 76.2%, post-listing TIPS: 86.0%, no TIPS: 91.2%, log-rank p = .1506). Conclusion: TIPS should be considered in all liver transplant candidates, since it can obviate the need for OLT and optimize bridging to OLT. PMID- 29238589 TI - Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells. AB - Background: Clostridium difficile toxin A is responsible for colonic damage observed in infected patients. Drugs able to restore Clostridium difficile toxin A-induced toxicity have the potential to improve the recovery of infected patients. Cannabidiol is a non-psychotropic component of Cannabis sativa, which has been demonstrated to protect enterocytes against chemical and/or inflammatory damage and to restore intestinal mucosa integrity. Objective: The purpose of this study was to evaluate (a) the anti-apoptotic effect and (b) the mechanisms by which cannabidiol protects mucosal integrity in Caco-2 cells exposed to Clostridium difficile toxin A. Methods: Caco-2 cells were exposed to Clostridium difficile toxin A (30 ng/ml), with or without cannabidiol (10-7-10-9 M), in the presence of the specific antagonist AM251 (10-7 M). Cytotoxicity assay, transepithelial electrical resistence measurements, immunofluorescence analysis and immunoblot analysis were performed in the different experimental conditions. Results: Clostridium difficile toxin A significantly decreased Caco-2 cells' viability and reduced transepithelial electrical resistence values and RhoA guanosine triphosphate (GTP), bax, zonula occludens-1 and occludin protein expression, respectively. All these effects were significantly and concentration dependently inhibited by cannabidiol, whose effects were completely abolished in the presence of the cannabinoid receptor type 1 (CB1) antagonist, AM251. Conclusions: Cannabidiol improved Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor. PMID- 29238590 TI - The learning curve for needle knife precut sphincterotomy revisited. AB - Background: There is no consensus on what constitutes adequate training for needle knife precut sphincterotomy. Objective: The purpose of this study was to determine the number of procedures required before effective and safe precut sphincterotomy can be achieved. Methods: This retrospective study examined the cumulative experience of a single endoscopist from January 2006-December 2015. Precut sphincterotomy success and complication rates were analyzed as a function of number of procedures performed. Acceptable success and complication rates were defined as 85% and 10% respectively. A one-sided binomial test was used to test success and complication rates of every 25 precut sphincterotomies performed. Results: The index endoscopic retrograde cholangiopancreatography was successful in 141/158 (89.2%) patients who underwent precut sphincterotomy. This increased to 148/158 (93.7%) when endoscopic retrograde cholangiopancreatography was repeated on another day. Six precut sphincterotomies were required to achieve an 85% success probability. This was maintained consistently above 85% after 13 precuts, and was significantly higher (91.2%; p = 0.029) than 85% at the 125th precut. Bleeding and pancreatitis developed in 2/158 (1.3%) and 5/158 (3.2%). Probability of either complications remained below 5% after 50 precuts. No perforation occurred. Conclusion: At least 13 precut sphincterotomies were required to achieve a sustained success rate greater than 85%. The probability of bleeding or pancreatitis was less than 5% after 50 precut sphincterotomies. PMID- 29238591 TI - Menopausal hormone therapy and pancreatic cancer risk in women: a population based matched cohort study. AB - Background: The role of menopausal hormone therapy (MHT) in the development of pancreatic cancer is inconclusive owing to small studies and lack of proper study design. Methods: This population-based matched cohort study included all Swedish women who used systemic MHT between 1 July 2005 and 31 December 2012. For each user of MHT, three never-users of MHT were randomly selected, matched for childbirth, history of thromboembolic events, and previous hysterectomy, as well as for year of birth, diabetes, obesity, and smoking- or alcohol-related disorders. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between MHT use and pancreatic cancer. The effect of MHT duration on pancreatic cancer development was calculated using multivariable Poisson regression. Results: There were 290,186 ever-users of MHT and 870,165 matched never-users. During the follow up, 311 (0.0011%) ever-users of MHT and 1220 (0.0014) never-users developed pancreatic cancer. In a multivariable adjusted model, ever-users had a 23% reduced risk (OR 0.77; 95% CI: 0.68-0.87) of pancreatic cancer. This risk decreased by 35% (incidence rate ratio (IRR) 0.65; 95% CI: 0.33-1.27) in women who used MHT 1-2 years and by 60% (IRR 0.40; 95% CI: 0.18-0.88) in women who used MHT >= 3 years compared to women with <1 year of MHT use. The type of MHT did not change the results. Conclusion: Systemic MHT use might reduce the risk of pancreatic cancer. PMID- 29238593 TI - Severity assessment of acute pancreatitis using four prognostic factors - a nationwide multicenter study of 3682 cases in Japan. PMID- 29238592 TI - Predictors and characteristics of angioectasias in patients with obscure gastrointestinal bleeding identified by video capsule endoscopy. AB - Background: In obscure gastrointestinal bleeding, angioectasias are common findings in video capsule endoscopy (VCE). Objective: The objective of this study was to identify predictors and characteristics of small bowel angioectasias. Methods: Video capsule examinations between 1 July 2001 and 31 July 2011 were retrospectively reviewed. Patients with obscure gastrointestinal bleeding were identified, and those with small bowel angioectasia were compared with patients without a definite bleeding source. Univariate and multivariable statistical analyses for possible predictors of small bowel angioectasia were performed. Results: From a total of 717 video capsule examinations, 512 patients with obscure gastrointestinal bleeding were identified. Positive findings were reported in 350 patients (68.4%) and angioectasias were documented in 153 of these patients (43.7%). These angioectasias were mostly located in the proximal small intestine (n = 86, 56.6%). Patients' age >65 years (odds ratio (OR) 2.15, 95% confidence interval (CI) 1.36-3.38, p = .001) and overt bleeding type (OR 1.89, 95% CI 1.22-2.94, p = .004) were identified as significant independent predictors of small bowel angioectasia. Conclusion: Angioectasias are the most common finding in VCE in patients with obscure gastrointestinal bleeding. They are mostly located in the proximal small bowel and are associated with higher age and an overt bleeding type. PMID- 29238594 TI - Young GI angle: The role of bibliometrics in scientist's career development. PMID- 29238596 TI - Limb symmetry during double-leg squats and single-leg squats on land and in water in adults with long-standing unilateral anterior knee pain; a cross sectional study. AB - Background: The presence of pain during movement typically results in changes in technique. However, the physical properties of water, such as flotation, means that water-based exercise may not only reduce compensatory movement patterns but also allow pain sufferers to complete exercises that they are unable to perform on land. The purpose of this study was to assess bilateral kinematics during double-leg squats and single-leg squats on land and in water in individuals with unilateral anterior knee pain. A secondary aim was to quantify bilateral asymmetry in both environments in affected and unaffected individuals using a symmetry index. Methods: Twenty individuals with unilateral knee pain and twenty healthy, matched controls performed body weight double- and single-leg squats in both environments while inertial sensors (100 Hz) recorded trunk and lower body kinematics. Repeated-measures statistics tested for environmental effects on movement depths and peak angles within the anterior knee pain group. Differences in their inter-limb symmetry in each environments was compared to the control group using analysis of variance tests. Results: Water immersion allowed for greater movement depths during both exercises (double-leg squat: +7 cm, p = 0.032, single-leg squat: +9 cm, p = 0.002) for the knee pain group. The double leg squat was symmetrical on land but water immersion revealed asymmetries in the lower body frontal plane movements. The single-leg squat revealed decreased hip flexion and frontal plane shank motions on the affected limb in both environments. Water immersion also affected the degree of lower limb asymmetry in both groups, with differences also showing between groups. Conclusions: Individuals with anterior knee pain achieved increased squat depth during both exercises whilst in water. Kinematic differences between the affected and unaffected limbs were often increased in water. Individuals with unilateral anterior knee pain appear to utilise different kinematics in the affected and unaffected limb in both environments. PMID- 29238595 TI - Electrochemical processes and mechanistic aspects of field-effect sensors for biomolecules. AB - Electronic biosensing is a leading technology for determining concentrations of biomolecules. In some cases, the presence of an analyte molecule induces a measured change in current flow, while in other cases, a new potential difference is established. In the particular case of a field effect biosensor, the potential difference is monitored as a change in conductance elsewhere in the device, such as across a film of an underlying semiconductor. Often, the mechanisms that lead to these responses are not specifically determined. Because improved understanding of these mechanisms will lead to improved performance, it is important to highlight those studies where various mechanistic possibilities are investigated. This review explores a range of possible mechanistic contributions to field-effect biosensor signals. First, we define the field-effect biosensor and the chemical interactions that lead to the field effect, followed by a section on theoretical and mechanistic background. We then discuss materials used in field-effect biosensors and approaches to improving signals from field-effect biosensors. We specifically cover the biomolecule interactions that produce local electric fields, structures and processes at interfaces between bioanalyte solutions and electronic materials, semiconductors used in biochemical sensors, dielectric layers used in top-gated sensors, and mechanisms for converting the surface voltage change to higher signal/noise outputs in circuits. PMID- 29238597 TI - Effects of nine weeks isokinetic training on power, golf kinematics, and driver performance in pre-elite golfers. AB - Background: It has previously been shown that isotonic strength training can improve driver performance among golfers, though few studies have investigated effects of strength training on swing kinematics together with driver performance. In this study we investigated whether isokinetic rotational training could improve driver performance and swing kinematic variables amongst elite golfers. Methods: Twenty competitive pre-elite golfers (handicap better than 3.0), 13 men and 7 women, were split into two groups, one group received the isokinetic power training (IK) alongside their normal isotonic pre-season strength-training and the other group continued with their normal isotonic pre season strength-training regime (IT). The IK group completed 12 sessions of isokinetic power training on a standing rotation exercise (10% body weight at 1 m/s) and barbell squat (25 kg plus 10% body weight at 0.5 m/s). The IT group continued with their normal isotonic pre-season strength-training regime. Participants were tested for rotational power, lower body power, golf swing kinematics, and driver performance before and after a nine-week training period. Results: After the nine-week training period both the IK and the IT groups increased their dominant side rotational force and power (effect sizes between 0.50-0.96) and magnitude based inference indicated that IK had a likely (> 80%) more beneficial increase in dominant side rotational force and power. For swing kinematics, IK had a likely (> 80%) more beneficial improvement in lead arm speed and acceleration compared to the IT group. For driver performance, IK had a possible (65%) beneficial effect on ball speed and likely (78%) beneficial effect on carry distance when compared to IT, whereas neither of the groups improved club head speed. Conclusion: In the present study on pre-elite golfers we found that 9 weeks of isokinetic training increased seated rotational force and power, peak arm speed and arm acceleration, ball speed, and carry distance more compared to isotonic training. Even though isokinetic training did not increase CHS, it did result in greater carry distance. PMID- 29238598 TI - Breeding next generation tree fruits: technical and legal challenges. AB - The new plant breeding technologies (NPBTs) have recently emerged as powerful tools in the context of 'green' biotechnologies. They have wide potential compared to classical genetic engineering and they are attracting the interest of politicians, stakeholders and citizens due to the revolutionary impact they may have on agriculture. Cisgenesis and genome editing potentially allow to obtain pathogen-resistant plants or plants with enhanced qualitative traits by introducing or disrupting specific genes in shorter times compared to traditional breeding programs and by means of minimal modifications in the plant genome. Grapevine, the most important fruit crop in the world from an economical point of view, is a peculiar case for NPBTs because of the load of cultural aspects, varietal traditions and consumer demands, which hinder the use of classical breeding techniques and, furthermore, the application of genetic engineering to wine grape cultivars. Here we explore the technical challenges which may hamper the application of cisgenesis and genome editing to this perennial plant, in particular focusing on the bottlenecks of the Agrobacterium-mediated gene transfer. In addition, strategies to eliminate undesired sequences from the genome and to choose proper target sites are discussed in light of peculiar features of this species. Furthermore is reported an update of the international legislative frameworks regulating NPBT products which shows conflicting positions and, in the case of the European Union, a prolonged lack of regulation. PMID- 29238599 TI - Characterization of physiological and molecular processes associated with potato response to Zebra chip disease. AB - Transcriptional analyses identified molecular mechanisms associated with the response of leaf and root potato tissues to 'Candidatus. Liberibacter solanacearum' (Lso) infection, presumptive causal agent of zebra chip disease (ZC). Putative Lso infection affected several host processes including defense response-, regulation-, starch metabolism- and energy production-related processes. Interestingly, while proteinase inhibitors were strongly upregulated in leaf tissues, a concomitant downregulation was observed in root tissues. Quantitative polymerase chain reaction (qPCR) analysis suggests that alternative splicing might play a role. Furthermore, the transcriptional expression of redox homeostasis-related genes, including superoxide dismutase, showed the most inconsistent response to Lso in leaf and root tissues, highlighting potential targets of Lso susceptibility. Additionally, a net increase in gene expression in ZC-affected tissues despite the concomitant downregulation of photosynthesis related processes, suggests a putative Lso-mediated low resource-use-efficiency. Subsequent nutritional analyses revealed a hypothesized Lso-mediated increase in nutrient accumulation, particularly a 210 and 108% increases in the potassium concentration of ZC-affected leaf and root tissues, respectively, suggesting an important role for potassium in ZC pathophysiology. This study highlights insights of above and below ground tissues in molecular and physiological aspects associated with potato response to ZC. PMID- 29238600 TI - Morbidity and health-related quality of life of patients accessing laparoscopic sleeve gastrectomy: a single-centre cross-sectional study in one province of Canada. AB - Background: In Canada, severe obesity (BMI >= 35 kg/m2) affects 5% or 1.2 million adults. Bariatric surgery is the only effective treatment for severe obesity, but the demand for publicly funded procedures is high and capacity limited. Little is known in Canada about the types of patients undergoing these procedures, especially laparoscopic sleeve gastrectomy (LSG). The study objective is to examine the socio-demographic profile, morbidity and HRQoL of patients accessing LSG in one Canadian province. Methods: Health status and HRQoL were examined in patients (n = 195) undergoing LSG. HRQoL was assessed using the EQ-5D-3L, SF-12v2 and the Impact of Weight on Quality of Life-lite questionnaire. Results: Mean age and BMI were 44 and 49 kg/m2 and most were women (82%). Pre-surgery, comorbidities were sleep apnea (65%), dyslipidemia (48%), hypertension (47%) and osteoarthritis (44%). Patients reported impaired HRQoL with 44-67% reporting problems in mobility, usual activities, pain and anxiety/depression. Physical health was impaired more than mental health. There were few socio-demographic differences between women and men, but significant differences in comorbid conditions such as sleep apnea, dyslipidemia, hypertension and gout exist (p < .05). Women reported fewer problems with self-care (9.5% vs. 25.0%, p < .05), and better overall health (VAS 61.5 vs. 52.0, p < .05) and General Health (39.3 vs. 32.9, p < .05), but greater impairment in self-esteem (27.3 vs. 44.1, p < .01) and sexual life (49.2 vs. 63.6, p < .05). Conclusions: Before LSG, patients reported significant morbidity and impaired HRQoL. Although baseline characteristics were similar between men and women, gender specific differences were observed in comorbid profile and HRQoL. PMID- 29238601 TI - Clinicians approaches to management of background treatment in patients with SLE in clinical remission: results of an international observational survey. AB - Background: The definition of remission in systemic lupus erythematosus (SLE) remains unclear, especially how background treatment should be interpreted. Objective: To determine preferences of clinicians in treatment of patients in clinical remission from SLE and to assess how previous severity, duration of remission and serology influence changes in treatment. Methods: We undertook an internet-based survey of clinicians managing patients with SLE. Case scenarios were constructed to reflect different remission states, previous organ involvement, serological abnormalities, duration of remission and current treatment (hydroxychloroquine (HCQ), steroids and/or immunosuppressive (ISS) agents). Results: 130 clinicians from 30 countries were surveyed. The median (range) duration of practice and number of patients with SLE seen each month was 13 (2-42) years and 30 (2-200), respectively. Management decisions in all scenarios varied with greater caution in treatment reduction with shorter duration of remission, extent of serological abnormalities and previous disease severity. Even with mild disease, normal serology and a 5-year clinical remission, 113 (86.9%) clinicians continue to prescribe HCQ. Persistent abnormal serology in any scenario led to a reluctance to reduce or discontinue medications. Prescribing in remission, particularly of steroids and HCQ, varied significantly according to geographical location. Conclusions: Clinicians preferences in withdrawing or reducing treatment in patients with SLE in clinical remission vary considerably. Serological abnormalities, previous disease severity and duration of remission all influence the decision to reduce treatment. It is unusual for clinicians to stop HCQ even after prolonged periods of clinical remission. Any definition(s) of remission needs to take into consideration such evidence on how maintenance treatments are managed. PMID- 29238602 TI - Single-cell gene expression patterns in lupus monocytes independently indicate disease activity, interferon and therapy. AB - Objectives: Important findings can be masked in gene expression studies of mixed cell populations. We examined single-cell gene expression in SLE patient monocytes in the context of clinical and immunological features. Methods: Monocytes were purified from patients with SLE and controls, and individually isolated for single-cell gene expression measurement. A panel of monocyte-related transcripts were measured in individual classical (CL) and non-classical (NCL) monocytes. Results: Analyses of both CL and NCL monocytes demonstrated that many genes had a lower expression rate in SLE monocytes than in controls. Unsupervised hierarchical clustering of the CL and NCL data sets demonstrated independent clusters of cells from the patients with SLE that were related to disease activity, type I interferon (IFN) and medication use. Thus, each of these factors exerted a different impact on monocyte gene expression that could be identified separately, and a number of genes correlated uniquely with disease activity. We found within-cell correlations between genes directly induced by type I IFN induced and other non-IFN-induced genes, suggesting the downstream biological effects of type I IFN in individual human SLE monocytes which differed between CLs and NCLs. Conclusions: In summary, single-cell gene expression in monocytes was associated with a wide range of clinical and biological features in SLE, providing much greater detail and insight into the cellular biology underlying the disease than previous mixed-cell population studies. PMID- 29238603 TI - Early proteinuria response: a valid real-life situation predictor of long-term lupus renal outcome in an ethnically diverse group with severe biopsy-proven nephritis? AB - Objective: Two recent important lupus nephritis trials reported that proteinuria was a good predictor of renal outcome in Caucasians, but data on real-life situation, other races and severe nephritis are lacking to substantiate this finding as a simple test to guide clinical practice. The aim of this study was to validate proteinuria as a predictor of long-term renal outcome in real-life situation in a racially diverse group of patients with severe nephritis. Methods: Proteinuria, serum creatinine (SCr) and urine red blood cells were assessed at baseline and after 3, 6 and 12 months, as early predictors of long-term renal outcome (SCr <1.5 mg/dL at 7 years), in 94 patients with biopsy-proven lupus nephritis. The parameter performance and cut-off values were computed by receiver operating characteristic curves. Kaplan-Meier curves were used to validate the parameter. Results: A proteinuria <0.8 g/24 hours at 12 months was the best single predictor of long-term renal outcome (sensitivity 90%, specificity 78%, positive predictive value 67%, negative predictive value (NPV) 94% and area under the curve 0.86; p<0.001). Addition of other variables to proteinuria such as SCr and haematuria at 12 months did not improve its performance. The proteinuria cut off value of 0.8 g/24 hours at 12 months was a good predictor of 7-year renal survival (years free of dialysis) for patients with pure membranous (p=0.005) and proliferative nephritis (p=0.043), as well as black (p=0.002) and white race (p=0.001), anti-dsDNA positive (p=0.001) and anti-dsDNA negative (p=0.04) and male (p=0.028) and female (p=0.003) patients. Conclusion: We provided novel evidence that, in a real-life situation, proteinuria at 12 months of follow-up was the single best predictor of renal outcome at 7 years for an ethnically diverse group of patients with severe nephritis and a valid parameter for distinct histological classes, races, genders and anti-dsDNA profiles. The remarkably high NPV obtained reinforces its recommendation as the ideal predictor for clinical practice, since it is of low cost, easy to interpret, non-invasive and widely available. PMID- 29238604 TI - Novel PAX6 mutation reported in an aniridia patient. AB - An aniridia patient was found to have a novel PAX6 mutation. A genetic duplication within PAX6, which caused a frameshift mutation, ultimately created a nonsense stop codon and premature truncation of the protein. Consequently, the patient presented with a clouded cornea as a result of partial limbal stem cell deficiency, foveal hypoplasia, nystagmus and a pale, cupped optic disc caused by glaucoma. PMID- 29238605 TI - Docosahexaenoic acid and the preterm infant. AB - Docosahexaenoic acid (DHA) is a long chain poly-unsaturated fatty acid (LCPUFA) that has a role in the cognitive and visual development, as well as in the immune function of newborns. Premature infants are typically deficient in DHA for several reasons, to include fetal accretion of DHA that typically occurs during the third trimester. These premature infants are reliant on enteral sources of DHA, most commonly through breast milk. The DHA content in breast milk varies in direct correlation with maternal DHA intake and mothers consuming a Western diet typically have lower levels of DHA in their breast milk. Maternal DHA supplementation and direct supplementation of DHA to the infant has been tried successfully but there are still conflicting results on the optimal dosage and method of delivery of DHA to the infant. This has led to inconsistent results in trials evaluating the effects of DHA supplementation to the preterm infant in terms of cognitive and immunological outcomes. While short-term benefits have been seen in several studies, long-term benefits are not consistent. Future studies continue to be needed to optimize DHA intake in our premature infants. PMID- 29238606 TI - Effects of amino acid composition in pig diet on odorous compounds and microbial characteristics of swine excreta. AB - Background: Major amino acids in pig diets are Lys, Met, Thr, and Trp, but little is known about the requirements for the other essential amino acids, especially on odorous compounds and microbial characteristics in feces of growing-finishing pigs. To this end, different levels of amino acid composition added to diets to investigate the effects of amino acid composition on microbial characteristics and odorous compounds concentration. Methods: A total eight (n = 8) barrows (Landrace * Yorkshire * Duroc) with an average bodyweight of 89.38 +/- 3.3 kg were individually fed diets formulated by Korean Feeding Standards 2007 (old version) or 2012 (updated with ideal protein concept) in metabolism crates with two replication. After 15-day adaptation period, fresh faecal samples were collected directly from pigs every week for 4 weeks and analysed for total volatile fatty acids (VFA), phenols and indoles by using gas chromatography. The nitrogen was determined by Kjeldahl method. Bacterial communities were detected by using a 454 FLX titanium pyrosequencing system. Results: Level of VFA tended to be greater in 2012 than 2007 group. Among VFAs, 2012 group had greater (p < 0.05) level of short chain fatty acids (SCFA) than control.Concentration of odorous compounds in feces was also affected by amino acid composition in pig diet. Levels of ammonium and indoles tended to be higher in 2012 group when compared with 2007 group.Concentration of phenols, p-cresol, biochemical oxygen demand, and total Kjeldahl nitrogen, however, were lower (P < 0.05) in 2012 treatment group compare to 2007. The proportion of Firmicute phylum were decreased, while the Bacteriodetes phylum proportion increased and bacterial genera includingCoprococcus, Bacillus, and Bacteroides increased (p < 0.05) in 2012 compare to 2007 group. Conclusion: Results from our current study indicates that well balanced amino acid composition reduces odor by modulating the gut microbial community. Administration of pig diet formulated with the ideal protein concept may help improve gut fermentation as well as reduce the odor causing compounds in pig manure. PMID- 29238607 TI - Protocol for a feasibility randomised controlled trial of the use of Physical ACtivity monitors in an Exercise Referral Setting: the PACERS study. AB - Background: Exercise referral schemes are recommended by the National Institute for Clinical Excellence (NICE) for physical activity promotion among inactive patients with health conditions or risk factors. Whilst there is evidence for the initial effectiveness and cost-effectiveness of such schemes for increasing physical activity, evidence of long-term effects is limited. Techniques such as goal setting, self-monitoring and personalised feedback may support motivation for physical activity. Technologies such as activity monitoring devices provide an opportunity to enhance delivery of motivational techniques. This paper describes the PACERS study protocol, which aims to assess the feasibility and acceptability of implementing an activity monitor within the existing Welsh National Exercise Referral Scheme (NERS) and proposed evaluation methodology for a full-scale randomised controlled trial. Methods/design: The PACERS study consists of a pilot randomised controlled trial, process evaluation and exploratory economic analyses. Participants will be recruited from the generic pathway of the Welsh NERS and will be randomly assigned to receive the intervention or usual practice. Usual practice is a 16-week structured exercise programme; the intervention consists of an accelerometry-based activity monitor (MyWellnessKey) and an associated web platform (MyWellnessCloud). The primary outcomes are predefined progression criteria assessing the acceptability and feasibility of the intervention and feasibility of the proposed evaluation methodology. Postal questionnaires will be completed at baseline (time 0: T0), 16 weeks after T0 (T1) and 12 months after T0 (T2). Routinely collected data will also be accessed at the same time points. A sub-sample of intervention participants and exercise referral staff will be interviewed following initiation of intervention delivery and at the end of the study. Discussion: The PACERS study seeks to assess the feasibility of adding a novel motivational component to an existing effective intervention in order to enhance effects on physical activity and support longer-term maintenance. The study will provide insight into the acceptability of activity-monitoring technologies to an exercise referral population and delivery staff. Data from this study will be used to determine whether and how to proceed to a full-scale trial of effectiveness of the intervention, including any necessary refinements to intervention implementation or the proposed evaluation methodology. Trial registration: ISRCTN85785652. PMID- 29238608 TI - Study protocol for Enhancing Parenting In Cancer (EPIC): development and evaluation of a brief psycho-educational intervention to support parents with cancer who have young children. AB - Background: Parents with cancer have high rates of psychological morbidity, and their children are at risk of poor psychosocial outcomes, particularly in the context of parental distress and poor family communication. Parents express concerns about the impact of cancer on their children and report a lack of professional guidance in meeting their children's needs. Few parenting interventions exist and current interventions have extensive infrastructure demands making them unsuitable for routine use in most health settings. The aims of this study are to develop and establish the feasibility and acceptability of a novel and accessible psycho-educational intervention to improve parenting efficacy and decrease parental stress among adults with cancer who have children aged 3-12 years. The intervention will be suitable for parents with cancer who are receiving treatment with a view to longer term survival, irrespective of cancer diagnosis, and their respective co-parents. Methods/design: This study comprises two phases using the UK Medical Research Council framework for developing complex interventions. In the development phase, intervention content will be iteratively developed and evaluated in consultation with consumers, and in the piloting phase, feasibility will be tested in a clinical sample of 20 parents with cancer and their co-parents using a single arm, pre-test post-test design. The intervention will comprise an audiovisual resource (DVD), a question prompt list, and a telephone call with a clinical psychologist. Questionnaires administered pre- and 1 month post-intervention will assess parental stress, psychological morbidity, quality of life, self-efficacy and perceptions of child adjustment, and family functioning. Intervention feasibility will be determined by mixed-method participant evaluation of perceived usefulness, benefits, and acceptability. Discussion: This new initiative will translate existing descriptive evidence into an accessible intervention that supports parenting during cancer treatment and meets the information needs of parents with cancer and their families. This is an important advance: despite increasing recognition of the impact of parental cancer on the family, intervention research lags behind the descriptive literature. This low-intensity, accessible, and targeted intervention places minimal burden on infrastructure and promotes patient autonomy and self-management. If feasible, this style of intervention may be a template for future interventions with similar populations. PMID- 29238609 TI - Blunted heart rate recovery is associated with coronary artery spasm in patients with suspected vasospastic angina. AB - Background: Autonomic nervous system activity has been shown to be altered in patients with vasospastic angina (VA). Heart rate recovery (HRR) is a simple, non invasive measurement of autonomic nervous system dysfunction. We aimed to investigate whether HRR is related to VA, as established by an ergonovine test. Methods: A total of 976 consecutive patients (47.5% male, mean age 55 years) without significant coronary artery disease who underwent both an ergonovine provocation test and a treadmill exercise test were enrolled. The relationship between VA and HRR was evaluated. Results: A total of 30.7% (300/976) of patients were diagnosed with VA, as documented by the ergonovine provocation test. HRR was significantly reduced in patients with VA compared to patients without VA (24.6 +/- 18.0 vs. 30.5 +/- 22.2, p < 0.001), and HRR was lowest in patients with multi vessel spasm (21.9 +/- 17.3). The proportion of blunted HRR, which was defined as HRR less than 12 beats, was significantly higher in patients with VA than in those without coronary artery spasm (26.6% vs. 39.3%, p < 0.001). In multivariable regression analyses, age (odds ratio (OR) = 1.03; 95% confidence interval (CI): 1.01-1.04; p = 0.001), blunted HRR (OR = 1.71; 95% CI: 1.26-2.31; p < 0.001), current smoking status (OR = 2.11; 95% CI: 1.50-2.98; p < 0.001), and male gender (OR = 2.00; 95% CI: 1.43-2.78; p < 0.001) were significant independent predictors of VA presence. Conclusion: Blunted HRR was an independent predictor of VA presence, which suggests a link between coronary artery spasm and autonomic dysregulation. PMID- 29238610 TI - A role for ErbB signaling in the induction of reactive astrogliosis. AB - Reactive astrogliosis is a hallmark of many neurological disorders, yet its functions and molecular mechanisms remain elusive. Particularly, the upstream signaling that regulates pathological responses of astrocytes is largely undetermined. We used a mouse traumatic brain injury model to induce astrogliosis and revealed activation of ErbB receptors in reactive astrocytes. Moreover, cell autonomous inhibition of ErbB receptor activity in reactive astrocytes by a genetic approach suppressed hypertrophic remodeling possibly through the regulation of actin dynamics. However, inhibiting ErbB signaling in reactive astrocytes did not affect astrocyte proliferation after brain injury, although it aggravated local inflammation. In contrast, active ErbB signaling in mature astrocytes of various brain regions in mice was sufficient to initiate reactive responses, reproducing characterized molecular and cellular features of astrogliosis observed in injured or diseased brains. Further, prevalent astrogliosis in the brain induced by astrocytic ErbB activation caused anorexia in animals. Therefore, our findings defined an unrecognized role of ErbB signaling in inducing reactive astrogliosis. Mechanistically, inhibiting ErbB signaling in reactive astrocytes prominently reduced Src and focal adhesion kinase (FAK) activity that is important for actin remodeling, although ErbB signaling activated multiple downstream signaling proteins. The discrepancies between the results from loss- and gain-of-function studies indicated that ErbB signaling regulated hypertrophy and proliferation of reactive astrocytes by different downstream signaling pathways. Our work demonstrated an essential mechanism in the pathological regulation of astrocytes and provided novel insights into potential therapeutic targets for astrogliosis-implicated diseases. PMID- 29238611 TI - Structural basis for nucleotide-modulated p97 association with the ER membrane. AB - Association of the cytosolic AAA (ATPases associated with various cellular activities) protein p97 to membranes is essential for various cellular processes including endoplasmic reticulum (ER)-associated degradation. The p97 consists of two ATPase domains and an N domain that interacts with numerous cofactors. The N domain of p97 is known to undergo a large nucleotide-dependent conformation switch, but its physiological relevance is unclear. Here we show p97 is recruited to canine ER membranes predominantly by interacting with VCP-interacting membrane protein (VIMP), an ER-resident protein. We found that the recruitment is modulated through a nucleotide-dependent conformation switch of the N domain in wild-type p97, but this modulation is absent in pathogenic mutants. We demonstrate the molecular mechanism of the modulation by a series of structures of p97, VIMP and their complexes and suggest a physiological role of the nucleotide-dependent N domain conformation switch. The lack of modulation in pathogenic mutants is caused by changes in interactions between the N and D1 domain, as demonstrated by multiple intermediate positions adopted by N domains of mutant p97. Our findings suggest the nucleotide-modulated membrane association may also have a role in other p97-dependent processes. PMID- 29238613 TI - Public involvement could usefully inform ethical review, but rarely does: what are the implications? AB - Plain English summary: Researchers carrying out research in the NHS in England have to obtain approval for their study from an NHS Research Ethics Committee (REC). Involving the public in research helps to ensure studies are ethically acceptable to the people taking part, and therefore supports the REC review. The form used by RECs asks researchers to describe any involvement that has taken place before the review or any planned for the future. We analysed researchers' reports of involvement in 2748 applications to RECs in 2014, to assess how well their approaches to involvement are informing the review process. We found that researchers rarely describe involvement in enough detail to help REC members. It is difficult to judge whether previous involvement has shaped the research design in any way, and whether plans for future involvement are meaningful. It also seems that some researchers remain unclear about involvement and its purpose at different stages. This may be severely limiting its impact.So that public involvement can usefully inform REC reviews in future, the Health Research Authority, which oversees RECs, will carry out further work to find out what information RECS need about involvement. This information will be used to change the application form and to develop guidance and training for REC members and the wider research community. Researchers may also benefit from clearer guidance on the value and purpose of involvement at key research stages: early design, data collection and the dissemination of results. Abstract: Background Researchers conducting research in the NHS in England are required to submit their study for approval by an NHS Research Ethics Committee (REC). Public involvement in research prior to REC review helps to ensure studies are ethically acceptable to participants, thus informing the review process. The Integrated Research Application System (IRAS) used by RECs, asks researchers to describe any involvement in the development of their project, and in its delivery and dissemination. We analysed researchers' reports of involvement to assess how well current approaches to involvement are supporting REC review. Methods We used a mixed methods approach. The anonymised free-text data from all 2748 non educational applications submitted to RECs in 2014 were analysed using NVivo. Themes were developed from the data and used to summarise and categorise the different types of reports of involvement. The frequency of common types of report was analysed using simple statistics. Results In general, researchers rarely describe any prior involvement in sufficient detail to know what was done and what difference this made. This makes it difficult to judge whether the involvement shaped the research design in any way to make it more ethically acceptable. Similarly, researchers' plans for future involvement are not clear enough to enable RECs to make a proper assessment of whether this involvement will be meaningful, or whether potential ethical concerns raised by involvement have been addressed. This analysis also shows there is still considerable misunderstanding amongst researchers around what involvement means, and its purpose at different stages of a project. This may be severely limiting the potential for impact. Conclusions So that public involvement can usefully inform REC review in future, the HRA is undertaking a collaborative exercise to understand what information RECS need about involvement, and what changes need to be made to the IRAS form. At the same time it will develop guidance and training for REC members and the wider research community about how public involvement can support ethical review. Researchers may also benefit from guidance on the value and purpose of involvement at the research stages: design, data collection and dissemination of results. PMID- 29238614 TI - Recurrence rate and need for reoperation after surgery with or without internal limiting membrane removal for the treatment of the epiretinal membrane. AB - Purpose: To compare the recurrence rate and need for reoperation after epiretinal membrane surgery with and without removal of the internal limiting membrane. Methods: In this retrospective study, 125 patients operated for epiretinal membrane removal were evaluated, with a minimum 6-month follow-up. Removal of the epiretinal membrane (ERM) was performed in 78 patients, while 47 had removal of the epiretinal membrane associated with internal limiting membrane peeling (ERM + ILM). Results: The mean age in the ERM group was 65.8 years old, ranging from 41 to 80 years old. In the ERM + ILM group, the mean age was 67.2 years old, ranging from 52 to 82 years old. The mean preoperative visual acuity in the ERM group was 20/80p, and in the ERM + ILM group, it was 20/80. The mean postoperative visual acuity in both groups was 20/30. The mean preoperative macular thickness in the ERM group was 467 um ranging from 281 to 663 um; in the ERM + ILM group, the preoperative macular thickness was 497 um, ranging from 172 to 798 um. After surgery, a reduction in macular thickness was observed in both groups. In the ERM group, the mean macular thickness reduction was 361 +/- 101. um, whereas in the ERM + ILM group, it was 367 +/- 75.2 um. Twenty-two patients presented with a recurrence of epiretinal membrane, of which 16 (20.5%) were from the ERM group and 6 (12.8%) were from the ERM + ILM group (p = 0.39); one patient (2%) was retreated in the ERM + ILM group, whereas 5 patients (6%) where retreated in the ERM group. Conclusion: We postulate that ILM peeling for the treatment of epiretinal membrane is not a relevant factor either for visual recovery or macular thickness reduction, but it may reduce the recurrence and reoperation rate. PMID- 29238612 TI - Co-creation of a digital tool for the empowerment of parents of children with physical disabilities. AB - Plain English summary: Parents of children with physical disabilities do a lot to support their child in daily life. In doing this they are faced with many challenges. These parents have a wide range of unmet needs, especially for information, on different topics. It is sometimes hard for them to get the right information at the right moment, and to ask the right questions to physicians and other healthcare professionals. In order to develop a digital tool to help parents formulate questions and find information, we thought it would be crucial to work together in a process of co-creation with parents, researchers, IT specialists and healthcare professionals. In close collaboration with them we developed a tool that aims to help parents ask questions, find information and take a more leading role in consultations with healthcare professionals, called the WWW-roadmap (WWW-wijzer in Dutch).In two groups of parents (one group with and one group without experience of using the tool), we will study the effects of using this tool, on consultations with physicians. We expect that using the tool will result in better empowerment, satisfaction and family-centred care. Abstract: Background: Parents of children with physical disabilities do much to support their child in daily life. In doing so, they are faced with many challenges. These parents have a wide range of unmet needs, especially for information, on various topics. Getting timely and reliable information is very difficult for parents, whereas being informed is a major requirement for the process of empowerment and shared decision-making. This paper describes the development of a digital tool to support parents in this process. During its development, working together with parents was crucial to address relevant topics and design a user-centred intervention. Methods: In co-creation with parents, healthcare professionals, IT-professionals and researchers, a digital tool was developed, the 'WWW-roadmap' ['WWW-wijzer' in Dutch]. This digital tool aims to enable parents to explore their questions (What do I want to know?), help in their search for information (Where can I find the information I need), and refer to appropriate professionals (Who can assist me further?).During the process, we got extensive feedback from a parent panel consisting of parents of children with physical disabilities, enabling us to create the tool 'with' rather than 'for' them. This led to a user-friendly and problem-driven tool. Discussion: The WWW roadmap can function as a tool to help parents formulate their questions, search for information and thus prepare for consultations with healthcare professionals, and to facilitate parental empowerment and shared-decision making by parent and professional. Effects of using the WWW-roadmap on consultations with professionals will be studied in the future. PMID- 29238615 TI - Profile of Geohelminth Eggs, Cysts, and Oocysts of Protozoans Contaminating the Soils of Ten Primary Schools in Dschang, West Cameroon. AB - Helminthiasis and protozoans infections have been recognized as an important public health problem. The aim of the present study was to screen soil samples collected from 10 primary schools in the city of Dschang for the presence of soil transmitted helminth eggs, cysts, and oocysts of protozoans. A total of 400 soil samples were collected around latrines, at playgrounds, and behind classrooms in each school. These samples were examined using the sucrose flotation method. From the result obtained, an overall contamination rate of 7.75% was observed. Five genera of nematodes (Ascaris, Trichuris, Capillaria, Cooperia, and hookworms) were identified, while neither cysts nor oocysts of protozoans were detected. The contamination rate and the number of species found were significantly different in wet season as compared to the dry season. During the rainy season, this rate was 12.5% with all the parasitic stages identified, while, in the dry season, the soil contamination rate was 3% with the presence of only two genera (Ascaris and Trichuris). This suggests that parasite infection may occur mainly in rainy season rather than in the dry season. The most common eggs were those of Ascaris with 2% and 5% contamination rates in the dry and rainy seasons, respectively. Also, the soils around latrines were more contaminated (11.9%) as compared to those collected behind classrooms (7.5%) and those at playground (2.5%). It was concluded that the pupils of these schools may have played a major role in the contamination of their environment. Thus, sanitary education, enforcement of basic rules of hygiene, and deworming remain a necessity in the entire population of the study area in general and in the schools in particular in order to prevent helminth infections and to ensure effective environmental health. PMID- 29238616 TI - Applying a New Automated Perimetry Pattern Based on the Stimulus Distribution of the Multifocal ERG to Improve Structure-Function Investigation in Glaucoma. AB - Purpose: To validate a new automated perimetry pattern (mf103 pattern) for the investigation of retinal structure-function relationships in glaucoma in comparison to the standard G2 pattern and to relate either field's performance to optical coherence tomography (OCT). Methods: Automated perimetry data from the mfERG103 pattern were compared with the standard G2 pattern in glaucoma patients (18) and controls (15). The results of both (mean defect (MD) and mean sensitivity (MS)) were compared with optical coherence tomography (OCT): retinal nerve fiber layer (RNFL) thickness, macular thickness (mT), and ganglion cell analysis (GCIPL). Nine patients were followed up after one year. Results: G2 pattern and mf103 pattern did not differ significantly in MD or MS. The mf103 pattern associated significantly with more RNFL sectors in both MD and MS (p < 0.01 and p < 0.05, resp.). GCIPL thickness was not significantly associated with either SAP protocols. Both protocols remained comparable after one-year follow up. Conclusions: G2 and mf103 pattern can both differentiate patients from controls with no significant difference in performance. RNFL thickness defects correlated better with mf103 than G2 with POAG. The mfERG-103 perimetry pattern can be used to establish structure-function correlations in glaucoma and may enable a more direct comparison with objective electrophysiological data. PMID- 29238617 TI - Conditions Affecting the Performance of Peripheral Vein Cannulation during Hospital Placement: A Case Study. AB - Learning practical nursing skills is an important part of the baccalaureate in nursing. However, many newly qualified nurses lack practical skill proficiency required to ensure safe patient care. The invasive skill peripheral vein cannulation (PVC) is particularly challenging to learn and perform. This study explored conditions influencing nursing students' learning and performance of the technical implementation of a PVC during their clinical placement period. A qualitative and descriptive case study design with two students in Norway practicing PVC during their clinical placement was conducted. One student who mastered the vein cannulation was compared with one student who did not. Data were collected in late 2012 using multiple data sources: semistructured interviews, ad hoc conversations, and video recordings. Video recordings of the two students' cannula implementations were used to help clarify and validate the descriptions and to identify gaps between what students said and what they did. Thematic analysis of the transcribed text data enabled identifying themes that influenced skill performance. There were two overall themes: individual and contextual conditions influencing the technical implementation of a peripheral vein cannula. These findings were evaluated in terms of Benner's work on scientific and practical knowledge, defined as "knowing that" and "knowing how." PMID- 29238618 TI - The Prevalence of and Factors Associated with Neck, Shoulder, and Low-Back Pains among Medical Students at University Hospitals in Central Saudi Arabia. AB - Aim: The study aim was to determine the prevalence of neck, shoulder, and low back pains and to explore the factors associated with musculoskeletal pain (MSP) among medical students at university hospitals in central Saudi Arabia. Method: This cross-sectional study was conducted at a government institution using an online self-administered, modified version of the Standardised Nordic Questionnaire in the English language. Results: A total of 469 students responded to our survey. The prevalence of MSP in at least one body site at any time, in the past week, and in the past year was 85.3%, 54.4%, and 81.9%, respectively. Factors significantly associated with MSP in at least one body site at any time were being in the clinical year (P = 0.032), history of trauma (P = 0.036), history of depressive symptoms (P < 0.001), and history of psychosomatic symptoms (P < 0.001). On multivariable regression analysis, factors associated with MSP were history of trauma (P = 0.016) and depressive (P = 0.002) or psychosomatic symptoms (P = 0.004). Conclusion: MSP among Saudi medical students is high, particularly among those in the clinical years and those with history of trauma and with depressive or psychosomatic symptoms. Medical institutions should be aware of this serious health issue and preventive measures are warranted. PMID- 29238620 TI - AngioVac System Used for Vegetation Debulking in a Patient with Tricuspid Valve Endocarditis: A Case Report and Review of the Literature. AB - AngioVac is a vacuum-based device approved in 2014 for percutaneous removal of undesirable materials from the intravascular system. Although numerous reports exist with regard to the use of the AngioVac device in aspiration of iliocaval, pulmonary, upper extremity, and right-sided heart chamber thrombi, very few data are present demonstrating its use in treatment of right-sided endocarditis. In this case report, we describe the novel device used in debulking a large right sided tricuspid valve vegetation reducing the occurrence of septic embolisation and enhancing the efficacy of antibiotics in clearance of bloodstream infection. Further research is needed in larger RSIE patient populations to confirm the benefits and the potential of improved outcomes associated with the AngioVac device as well as identify its potential complications. PMID- 29238621 TI - Burkholderia Aortic Aneurysm: A Case Report and Review of the Literature. AB - Melioidosis is a frequently fatal infection caused by the Gram-negative bacillus Burkholderia pseudomallei endemic to Southeast Asia and Northern Australia. It is a rare imported pathogen in the United States and is a potential bioterror agent. We report the case of an 82-year-old previously healthy man who presented with 2 weeks of fever and epigastric pain after he returned from the Philippines. A diagnosis of nondissecting mycotic aneurysm in the descending thoracic aorta was made with the help of CT angiogram and positive blood cultures. The patient completely recovered with a 6-month antibiotic therapy followed by surgical repair of the aneurysm. Given the slight increase in the number of melioidosis cases reported by CDC since 2008, melioidosis might be considered an emerging infectious disease in the United States. The purpose of this report is to raise awareness of the disease among clinicians as well as travelers. PMID- 29238619 TI - Hippocampal Regulation of Postsynaptic Density Homer1 by Associative Learning. AB - Genes involved in synaptic plasticity, particularly genes encoding postsynaptic density proteins, have been recurrently linked to psychiatric disorders including schizophrenia and autism. Postsynaptic density Homer1 proteins contribute to synaptic plasticity through the competing actions of short and long isoforms. The activity-induced expression of short Homer1 isoforms, Homer1a and Ania-3, is thought to be related to processes of learning and memory. However, the precise regulation of Homer1a and Ania-3 with different components of learning has not been investigated. Here, we used in situ hybridization to quantify short and long Homer1 expression in the hippocampus following consolidation, retrieval, and extinction of associative fear memory, using contextual fear conditioning in rats. Homer1a and Ania-3, but not long Homer1, were regulated by contextual fear learning or novelty detection, although their precise patterns of expression in hippocampal subregions were dependent on the isoform. We also show for the first time that the two short Homer1 isoforms are regulated after the retrieval and extinction of contextual fear memory, albeit with distinct temporal and spatial profiles. These findings support a role of activity-induced Homer1 isoforms in learning and memory processes in discrete hippocampal subregions and suggest that Homer1a and Ania-3 may play separable roles in synaptic plasticity. PMID- 29238622 TI - Recurrent Occipital Seizures with Transient MRI Changes. AB - Peri-ictal magnetic resonance imaging (MRI) findings following seizure activity are a recognized phenomenon that is not well understood (Cole, 2004). Transient changes are not usually expected to be present in postictal MRI studies because of their rarity. Here, we present a unique case of peri-ictal MRI findings located in the occipital lobe, present in a 34-year-old female with recurrent occipital seizures occurring twice in four years. MRI changes completely resolved after both episodes with no residual focal damage. The peri-ictal occipital changes on MRI in this patient are unique because they have been captured on more than one occasion. Peri-ictal MRI findings are a known phenomenon with unknown pathophysiology, although attempts have been made to understand these findings. Though the MRI findings and presentation appear to be stroke-like or PRES-like, seizures should be kept in the differential for better treatment outcomes. PMID- 29238623 TI - CART Peptides and Drugs of Abuse: A Review of Recent Progress. AB - Earlier studies suggesting an involvement of cocaine and amphetamine regulated transcript peptide (CARTp) in the actions of drugs of abuse are confirmed in the most recent publications. This seems especially true for the psychostimulants where CARTp in the nucleus accumbens inhibits or regulates the actions of these drugs; the regulation is lost after repeated drug use which may be an important mechanism in addiction. The other drugs, including nicotine, alcohol, opiates, and perhaps caffeine can affect CARTp or CART mRNA levels. While the exact mechanism is not always clear, the hope is that these findings may provide some insight for the development of medications. While binding studies indicate the existence of specific G-protein coupled receptors (GPCR) receptors for CARTp, major work to be done is the cloning of these receptors. PMID- 29238624 TI - High-Sensitivity Determination of K, Ca, Na, and Mg in Salt Mines Samples by Atomic Emission Spectrometry with a Miniaturized Liquid Cathode Glow Discharge. AB - An atomic emission spectrometer (AES) based on a novel atmospheric pressure liquid cathode glow discharge (LCGD) as one of the most promising miniaturized excitation sources has been developed, in which the glow discharge is produced between a needle-like Pt anode and the electrolyte (as cathode) overflowing from a quartz capillary. Lower energy consumption (<50 W) and higher excitation efficiency can be realized by point discharge of the needle-like Pt. The miniaturized LCGD seems particularly well suited to rapid and high-sensitivity determination of K, Ca, Na, and Mg in salt mines samples. The optimized analytical conditions of LCGD-AES were pH = 1 with HNO3 as electrolyte, 650 V discharge voltage, and 3 mL min-1 solution flow rate. The limits of detections (LODs) of K, Ca, Na, and Mg were 0.390, 0.054, 0.048, and 0.032 mg L-1, respectively. Measurement results of the LCGD-AES are in good agreement with the comparison value obtained by inductively coupled plasma (ICP) and ion chromatography (IC). All results suggested that the developed portable analytical instrument can be used for on-site and real-time monitoring of metal elements in field with further improvement. PMID- 29238625 TI - Should we be concerned about preserving agency and personal identity in patients with Adaptive Deep Brain Stimulation systems? PMID- 29238626 TI - c-kit Positive Cardiac Outgrowth Cells Demonstrate Better Ability for Cardiac Recovery Against Ischemic Myopathy. AB - Objective: Resident cardiac stem cells are expected to be a therapeutic option for patients who suffer from severe heart failure. However, uncertainty remains over whether sorting cells for c-kit, a stem cell marker, improves therapeutic outcomes. Materials and methods: Cardiac outgrowth cells cultured from explants of rat heart atrium were sorted according to their positivity (+) or negativity ( ) for c-kit. These cells were exposed to hypoxia for 3 d, and subsequently harvested for mRNA expression measurement. The cell medium was also collected to assess cytokine secretion. To test for a functional benefit in animals, myocardial infarction (MI) was induced in rats, and c-kit+ or c-kit- cells were injected. The left ventricular ejection fraction (LVEF) was measured for up to 4 weeks, after which the heart was harvested for biological and histological analyses. Results and conclusion: Expression of the angiogenesis-related genes, VEGF and ANGPTL2, was significantly higher in c-kit+ cells after 3 d of hypoxic culture, although we found no such difference prior to hypoxia. Secretion of VEGF and ANGPTL2 was greater in the c-kit+ group than in the c-kit- group, while hypoxia tended to increase cytokine expression in both groups. In addition, IGF-1 was significantly increased in the c-kit+ group, consistent with the relatively low expression of cleaved-caspase 3 revealed by western blot assay, and the relatively low count of apoptotic cells revealed by histochemical analysis. Administration of c-kit+cells into the MI heart improved the LVEF and increased neovascularization. These results indicate that c-kit+cells may be useful in cardiac stem cell therapy. PMID- 29238628 TI - Intraprostatic Fiducials Compared with Bony Anatomy and Skin Marks for Image Guided Radiation Therapy of Prostate Cancer. AB - Purpose Prostate motion occurs during radiotherapy for localized prostate cancer. We evaluated the input of intraprostatic fiducials for image-guided radiation therapy and compared it with bony anatomy and skin marks. Methods Eleven patients were implanted with three fiducial markers in the prostate. Daily sets of orthogonal kV-kV images were compared with digitally reconstructed radiography. Data were recorded for skin marks, bony anatomy, and fiducial markers. The variations were analyzed along three principal axes (left-right: LR, superoinferior: SI, and anteroposterior: AP). Results A total of 2,417 measures were recorded over 38 fractions of radiotherapy (76 Gy). Fiducial marker movements from bony anatomy were <= 5 mm for 84.2% (confidence interval: CI 95%+/ 1.5), 91.3% (CI 95%+/-1.1), and 99.5% (CI 95%+/-0.4) of the measures along the AP, SI, and LR axes, respectively. Ninety-five percent of the shifts between a fiducial marker and the bony anatomy were < 8 mm in the AP and SI axes, and < 3 mm in the LR axis. Fiducial marker movements from skin marks were <= 5 mm for 64.8% (CI 95%+/-1.9), 79.2% (CI 95%+/-1.6), and 87.2% (CI 95%+/-1.3) of the measures along the AP, SI, and LR axes, respectively. Bony anatomy movements from skin marks were <= 5 mm for 84% (CI 95%+/-1.4), 92% (CI 95%+/-1.1), and 87% (CI 95%+/-1.3) of the measurements along the AP, SI, and LR axes, respectively. Conclusion Using fiducial markers provides better accuracy of repositioning of the prostate than using bony anatomy and skin marks for image-guided radiotherapy of prostate cancer. PMID- 29238629 TI - Assessing Health Implications of the Potential Radiation Exposure in the Community During Pregnancy: A Case Study. AB - The unintentional radiation exposure can have significant implications. We present a case of a 30-year-old pregnant female who was exposed to a potentially radioactive rock for over a one week period during her 13th week of pregnancy. After an arduous process of obtaining activity measurements, the most conservative estimate of dose, the female was exposed to, was found to fall within the permissible limits. We briefly describe the literature on fetal radiation toxicity levels and discuss logistical issues faced in managing such cases. PMID- 29238627 TI - Non-neuronal cell outgrowth in C. elegans. AB - Cell outgrowth is a hallmark of some non-migratory developing cells during morphogenesis. Understanding the mechanisms that control cell outgrowth not only increases our knowledge of tissue and organ development, but can also shed light on disease pathologies that exhibit outgrowth-like behavior. C. elegans is a highly useful model for the analysis of genes and the function of their respective proteins. In addition, C. elegans also has several cells and tissues that undergo outgrowth during development. Here we discuss the outgrowth mechanisms of nine different C. elegans cells and tissues. We specifically focus on how these cells and tissues grow outward and the interactions they make with their environment. Through our own identification, and a meta-analysis, we also identify gene families involved in multiple cell outgrowth processes, which defined potential C. elegans core components of cell outgrowth, as well as identify a potential stepwise cell behavioral cascade used by cells undergoing outgrowth. PMID- 29238630 TI - Hematoma in the Bucco-Mandibular Space: First Case Report. AB - Our previous studies based on intraoral dissection of fresh cadavers revealed that the fissure and loose connective tissues deep to the mucosa between the incisivus labii inferioris muscle and buccinator muscle form the entrance of the newly discovered bucco-mandibular space. To support the clinical significance of this space, we report the finding of a hematoma within this space in an adult fresh cadaver. Such a finding lends credence to studying the bucco-mandibular space and might help better understand the spread of some infections in the oral region. PMID- 29238631 TI - Ethnic and Age Disparities in Patients Taking Long-acting Injectable Atypical Antipsychotics. AB - Introduction This study will determine whether different ethnicities and different age groups receive equal amounts of long-acting atypical antipsychotics in comparison to their oral equivalents. Methods Secondary analyses of data from the Los Angeles County Department of Health Services Electronic Health Record (total N=63,134 inpatient visits) were performed. Chi-squared statistics were used to compare ethnicity and age with the use of either risperidone injectable or paliperidone palmitate (r-LAIs) versus risperidone oral. Results Among the 63,134 total inpatient visits, there were 3,011 patient visits that included the use of an atypical antipsychotic. Of these 3,011 visits, 452 (15.0%) were on r LAIs and 2,559 (85.0%) were on risperidone oral. No statistically significant disparities were identified with the use of r-LAIs as compared to oral risperidone amongst ethnic groups (chi-square = 0.88, df = 3, p = 0.831). However, there was a statistically significant difference with the use of r-LAIs as compared to oral Risperidone amongst age groups, favoring younger patients (chi-square = 13.46, df = 3, p < 0.004). Conclusion Our data indicate a lack of ethnic disparities in prescribing long-acting atypical antipsychotics and an increased percentage of younger patients being treated with atypical depot antipsychotics over their oral equivalents. PMID- 29238632 TI - A patient with white blood cell counts more than a million: A diagnostic and therapeutic challenge. AB - Prolymphocytic leukemias (PLLs) are rare mature lymphoid disorders of B- and T cell subtypes with distinct features and an aggressive clinical course. PLL represents only 2% of all mature lymphocytic leukemias in adults. T-PLL represents 20% of all PLLs cases. T-cell prolymphocytic leukemia (T-PLL) is more rare and more rapidly progressive and aggressive than B-PLL; it is generally resistant to conventional chemotherapy, and historically the median survival has been about 7 months. Clinicians will often only see a case of T-PLL once every 5 to 10 years, which makes recognition of the disorder difficult. The prognosis is poor and there is no curative therapy. We report a 77-year-old male patient with de novo T-PLL presenting with WBC count of 1,115,000. We will discuss the clinical, morphologic, immunophenotypic and cytogenetic features of this rare entity. A distinctive hematologic aspect of T-PLL is a rapidly rising white blood cell count with a doubling time of weeks to months. The key morphologic feature in the diagnosis of T-PLL is a population of more than 55% prolymphocytes in the peripheral blood. The diagnosis can be made on peripheral blood by flow cytometry where a monoclonal lymphocyte population will show positivity for T-cell markers. T-PLL is characterized by complex chromosomal abnormalities, which suggests that chromosomal aberrations might occur progressively during the course of the disease, thus explaining the aggressive nature of this condition. The main challenge as a clinician treating T-PLL is to deliver long-term disease-free survival. The most important predictor of outcome is response to alemtuzumab therapy (Campath). Knowledge of the disrupted pathways and mechanisms underlying activation and proliferation in T-PLL has raised the possibility of developing future and promising treatment approach that targets these pathways and signals by the use of future molecule inhibitors. T-PLL is a rare disease and careful attention should be given to correctly diagnose this T-cell leukemia. Physicians should be aware of this unusual entity. With the advent of alemtuzumab, although much progress has been made in the treatment of this disease, autologous or allogeneic hematologic stem cell transplant (HSCT) still remains the only hope for cure. PMID- 29238633 TI - Editorial. PMID- 29238634 TI - ASA Classification as a Risk Stratification Tool in Adult Spinal Deformity Surgery: A Study of 5805 Patients. AB - Study Design: Retrospective analysis of prospectively collected data. Objectives: Adult spinal deformity (ASD) surgery is a highly complex procedure that has high complication rates. Risk stratification tools can improve patient management and may lower complication rates and associated costs. The goal of this study was to identify the independent association between American Society of Anesthesiologists (ASA) class and postoperative outcomes following ASD surgery. Methods: The 2010-2014 American College of Surgeons National Surgical Quality Improvement Program database was queried using Current Procedural Terminology and International Classification of Diseases, Ninth Revision, codes relevant to ASD surgery. Patients were divided based on their ASA classification. Bivariate and multivariate logistic regression analyses were employed to quantify the increased risk of 30-day postoperative complications for patients with increased ASA scores. Results: A total of 5805 patients met the inclusion criteria, 2718 (46.8%) of which were ASA class I-II and 3087 (53.2%) were ASA class III-IV. Multivariate logistic regression revealed ASA class to be a significant risk factor for mortality (odds ratio [OR] = 21.0), reoperation within 30 days (OR = 1.6), length of stay >=5 days (OR = 1.7), overall morbidity (OR = 1.4), wound complications (OR = 1.8), pulmonary complications (OR = 2.3), cardiac complications (OR = 3.7), intra-/postoperative red blood cell transfusion (OR = 1.3), postoperative sepsis (OR = 2.7), and urinary tract infection (OR = 1.6). Conclusions: This is the first study evaluating the role of ASA class in ASD surgery with a large patient database. Use of ASA class as a metric for preoperative health was verified and the association of ASA class with postoperative morbidity and mortality in ASD surgery suggests its utility in refining the risk stratification profile and improving preoperative patient counseling for those individuals undergoing ASD surgery. PMID- 29238635 TI - Anesthesia Duration as an Independent Risk Factor for Early Postoperative Complications in Adults Undergoing Elective ACDF. AB - Study Design: Retrospective study. Objective: To determine the presence of any potential associations between anesthesia time with postoperative outcome and complications following elective anterior cervical discectomy and fusion (ACDF). Methods: Patients who underwent elective ACDF were identified in the American College of Surgeons National Quality Improvement Program database. Patient demographics, medical comorbidities, and perioperative and postoperative complications up to 30 days were analyzed by univariate and multivariate analysis. Results: A total of 3801 patients undergoing elective ACDF were identified. Patients were subdivided into quintiles of anesthesia time: Group 1, 48 to 129 minutes (n = 761, 20%); Group 2, 129 to 156 minutes (n = 760, 20%); Group 3, 156 to 190 minutes (n = 760, 20%); Group 4, 190 to 245 minutes (n = 760, 20%); and Group 5, 245 to 1025 minutes (n = 760, 20%). Univariate analysis showed significantly higher rates of any complication (P < .0001), pulmonary complication (P < .0001), intra-/postoperative blood transfusions (P < .0001), sepsis (P = .017), wound complications (P = .002), total length of stay >5 days (P < .0001), and return to operating room (P = .006) in the highest quintile compared to those of other groups. Multivariate regression analysis revealed that prolonged anesthesia was an independent factor for increased odds of overall complications (odds ratio [OR] = 2.71, P = .012), venous thromboembolism (OR = 2.69, P = .011), and return to the operating room (OR = 2.92, P = .004). The 2 groups with the longest anesthesia durations (quintiles 4 and 5) had increased total length of stay more than 5 days (for quintile 4, OR = 3.10, P = .0004; for quintile 5, OR = 3.61, P < .0001). Conclusion: Prolonged anesthesia duration is associated with increased odds of complication, venous thromboembolism, increased length of stay, and return to the operating room. PMID- 29238636 TI - Functional Outcome of Neurologic-Controlled HAL-Exoskeletal Neurorehabilitation in Chronic Spinal Cord Injury: A Pilot With One Year Treatment and Variable Treatment Frequency. AB - Study Design: Longitudinal prospective study. Objectives: Whether 1-year HAL BWSTT of chronic spinal cord injured patients can improve independent ambulated mobility further as a function of training frequency, after an initial 3-month training period. Methods: Eight patients with chronic SCI were enrolled. They initially received full standard physical therapy and neurorehabilitation in the acute/subacute posttrauma phase. During this trial, all patients first underwent a daily (5 per week) HAL-BWSTT for 12 weeks. Subsequently, these patients performed a 40-week HAL-BWSTT with a training session frequency of either 1 or 3 to 5 sessions per week. The patients' functional status including HAL-associated treadmill-walking time, -distance, and -speed with additional analysis of gait pattern, and their independent (without wearing the robot suit) functional mobility improvements, were assessed using the 10-Meter-Walk Test (10MWT), Timed Up-and-Go Test (TUG) and 6-Minute-Walk Test (6MinWT) on admission, at 6 weeks, 12 weeks, and 1 year after enrollment. The data were analyzed separately for the 2 training frequency subgroups after the initial 12-week training period, which was identical in both groups. Results: During the 1-year follow-up, HAL-associated walking parameters and independent functional improvements were maintained in all the patients. This result held irrespective of the training frequency. Conclusions: Long-term 1-year maintenance of HAL-associated treadmill walking parameters and of improved independent walking abilities after initial 12 weeks of daily HAL-BWSTT is possible and depends mainly on the patients' ambulatory status accomplished after initial training period. Subsequent regular weekly training, but not higher frequency training, seems to be sufficient to preserve the improvements accomplished. PMID- 29238637 TI - Spinal Instability Neoplastic Score (SINS): Reliability Among Spine Fellows and Resident Physicians in Orthopedic Surgery and Neurosurgery. AB - Study Design: Reliability analysis. Objectives: The Spinal Instability Neoplastic Score (SINS) was developed for assessing patients with spinal neoplasia. It identifies patients who may benefit from surgical consultation or intervention. It also acts as a prognostic tool for surgical decision making. Reliability of SINS has been established for spine surgeons, radiologists, and radiation oncologists, but not yet among spine surgery trainees. The purpose of our study is to determine the reliability of SINS among spine residents and fellows, and its role as an educational tool. Methods: Twenty-three residents and 2 spine fellows independently scored 30 de-identified spine tumor cases on 2 occasions, at least 6 weeks apart. Intraclass correlation coefficient (ICC) measured interobserver and intraobserver agreement for total SINS scores. Fleiss's kappa and Cohen's kappa analysis evaluated interobserver and intraobserver agreement of 6 component subscores (location, pain, bone lesion quality, spinal alignment, vertebral body collapse, and posterolateral involvement of spinal elements). Results: Total SINS scores showed near perfect interobserver (0.990) and intraobserver (0.907) agreement. Fleiss's kappa statistics revealed near perfect agreement for location; substantial for pain; moderate for alignment, vertebral body collapse, and posterolateral involvement; and fair for bone quality (0.948, 0.739, 0.427, 0.550, 0.435, and 0.382). Cohen's kappa statistics revealed near perfect agreement for location and pain, substantial for alignment and vertebral body collapse, and moderate for bone quality and posterolateral involvement (0.954, 0.814, 0.610, 0.671, 0.576, and 0.561, respectively). Conclusions: The SINS is a reliable and valuable educational tool for spine fellows and residents learning to judge spinal instability. PMID- 29238638 TI - Efficacy of Early Fusion With Local Bone Graft and Platelet-Rich Plasma in Lumbar Spinal Fusion Surgery Followed Over 10 Years. AB - Study Design: Prospective clinical study. Objective: Many oral surgeons use platelet-rich plasma (PRP) for bone defects, but the efficacy of PRP for spinal arthrodesis remains uncertain. The objective was to compare the efficacy of autologous local bone graft and PRP with local bone graft alone for promotion of bony union in posterolateral lumbar fusion (PLF) surgery, with investigation of the safety of PRP over 10 years. Methods: A prospective study was conducted in 29 consecutive patients who underwent one-level PLF at L4/5 for degenerative lumbar disease. Local bone on the left (control) side and local bone with PRP on the right side were grafted. The fusion area and absorption of grafted bone at 58 regions were determined using computed tomography at 2 weeks and 3, 6, and 12 months after surgery. Results: Average bone fusion areas on the PRP side were significantly wider at 3 and 6 months after surgery (P < .05). Average absorption values were significantly lower on the PRP side than on the control side at 3 and 6 months after surgery (P < .05). The PRP/control ratio was significantly different at 3 and 6 months compared to that at 2 weeks (P < .005). No adverse events related to PRP occurred with good clinical outcome over 10 years follow up. Conclusions: Local application of PRP combined with autologous local bone graft has a positive impact on early fusion for lumbar arthrodesis with no adverse events over 10 years, and thus is a safe and low cost autologous option in spinal fusion. PMID- 29238639 TI - The Use of Vacuum Dressings for Dead Space Management in Deep Surgical Site Infections Allows Implant and Bone Graft Retention. AB - Study Design: Retrospective, descriptive study. Objectives: Managing early surgical site infection following elective lumbar spine surgery remains a challenge with controversy regarding retention of instrumentation and bone graft. Wound closure may also pose considerable challenges. We aim to report on our method of managing deep surgical site infections complicating elective spine surgery with surgeon assembled deep vacuum dressings. Identification of causative organisms with their sensitivities was a secondary objective. Methods: Patients were identified from a prospectively maintained, single-surgeon database from 2003-2015. Patients who had an infective or trauma related diagnosis, cervical procedures, and were younger than 18 years were excluded. Records were reviewed to identify bacteriology, laboratory tests performed, antibiotics administered, and type and frequency of surgical management. One thousand two hundred twenty patients qualified for inclusion, with 19 identified as having developed acute wound sepsis. Results: All patients had surgical debridement on the day of presentation and the majority of wounds were managed with a vacuum dressing. In all but 1 patient was instrumentation retained. Specimens for culture were taken at each debridement and antibiotics changed accordingly. Patients received a minimum 6 weeks of antibiotics. Conclusions: The management of deep surgical site infection is labor intensive and frustrating for both surgeon and patient due to the unexpected prolonged admission. Management goals are identification and eradication of the causative organism with subsequent healing of the surgical wound. This process is enhanced with the use of negative-suction dressings made from theatre stock replaced at regular intervals and allows retention of bone graft and instrumentation in the majority of cases. PMID- 29238640 TI - High-Risk Subgroup Membership Is a Predictor of 30-Day Morbidity Following Anterior Lumbar Fusion. AB - Study Design: Retrospective cohort study. Objective: To determine if membership in a high-risk subgroup is predictive of morbidity and mortality following anterior lumbar fusion (ALF). Methods: The American College of Surgeons National Surgical Quality Improvement Program database was utilized to identify patients undergoing ALF between 2010 and 2014. Multivariate analysis was utilized to identify high-risk subgroup membership as an independent predictor of postoperative complications. Results: Members of the elderly (>=65 years) (OR = 1.3, P = .02) and non-Caucasian (black, Hispanic, other) (OR = 1.7, P < .0001) subgroups were at greater risk for a LOS >=5 days. Obese patients (>=30 kg/m2 ) were at greater risk for an operative time >=4 hours (OR = 1.3, P = .005), and wound complications (OR = 1.8, P = .024) compared with nonobese patients. Emergent procedures had a significantly increased risk for LOS >=5 days (OR = 4.9, P = .021), sepsis (OR = 14.8, P = .018), and reoperation (OR = 13.4, P < .0001) compared with nonemergent procedures. Disseminated cancer was an independent risk factor for operative time >=4 hours (OR = 8.4, P < .0001), LOS >=5 days (OR = 15.2, P < .0001), pulmonary complications (OR = 7.4, P = .019), and postoperative blood transfusion (OR = 3.1, P = .040). Conclusions: High-risk subgroup membership is an independent risk factor for morbidity following ALF. These groups should be targets for aggressive preoperative optimization, and quality improvement initiatives. PMID- 29238641 TI - Complication Rates in Posterior Lumbar Interbody Fusion (PLIF) Surgery With Human Bone Morphogenetic Protein 2: Medicare Population. AB - Study Design: Retrospective cohort study among Medicare beneficiaries who underwent posterior lumbar interbody fusion (PLIF) surgery. Objective: To identify the complication rates associated with the use of bone morphogenetic protein 2 (BMP2) in PLIF. Human BMP2 is commonly used in the "off-label" manner for various types of spine fusion procedures, including PLIF. However, recent studies have reported potential complications associated with the recombinant human BMP2 (rhBMP2) use in the posterior approach. Methods: Medicare records within the PearlDiver database were queried for patients undergoing PLIF procedure with and without rhBMP2 between 2005 and 2010. We evaluated complications within 1 year postoperatively. Chi-square was used to compare the complication rates between the 2 groups. Results: A total of 8609 patients underwent PLIF procedure with or without rhBMP2. Individual complication rates in the rhBMP2 group ranged from 0.45% to 7.68% compared with 0.65% to 10.99 in the non-rhBMP2 group. Complication rates for cardiac, pulmonary, lumbosacral neuritis, infection, wound, and urinary tract (include acute kidney failure and post-operative complications) were significantly lower in the rhBMP2 group (P < .05). There was no difference in the rates of central nervous system complications or radiculitis between the 2 groups. Conclusion: Our data showed that the patients who received rhBMP2 had lower complication rates compared to the non-rhBMP2 group. However, use of rhBMP2 was associated with a higher rate of pseudarthrosis. We did not observe any difference in radiculitis and central nervous system complications between the groups. PMID- 29238642 TI - Effect of Social Support and Marital Status on Perceived Surgical Effectiveness and 30-Day Hospital Readmission. AB - Study Design: Retrospective cohort review. Objective: To determine whether higher levels of social support are associated with improved surgical outcomes after elective spine surgery. Methods: The medical records of 430 patients (married, n = 313; divorced/separated/widowed, n = 71; single, n = 46) undergoing elective spine surgery at a major academic medical center were reviewed. Patients were categorized by their marital status at the time of surgery. Patient demographics, comorbidities, and postoperative complication rates were collected. All patients had prospectively collected outcomes measures and a minimum of 1-year follow-up. Patient reported outcomes instruments (Oswestry Disability Index, Short Form-36, and visual analog scale-back pain/leg pain) were completed before surgery, then at 1 year after surgery. Results: Baseline characteristics were similar in all cohorts. There was no statistically significant difference in the length of hospital stay across all 3 cohorts, although "single patients" had longer duration of in-hospital stays that trended toward significance (single 6.24 days vs married 4.53 days vs divorced/separated/widowed 4.55 days, P = .05). Thirty day readmission rates were similar across all cohorts (married 7.03% vs divorced/separated/widowed 7.04% vs single 6.52%, P = .99). Additionally, there were no significant differences in baseline and 1-year patient reported outcomes measures between all groups. Conclusions: Increased social support did not appear to be associated with superior short and long-term clinical outcomes after spine surgery; however, it was associated with a shorter duration of in-hospital stay with no increase in 30-day readmission rates. PMID- 29238643 TI - Factors Associated With Clinical Outcomes After Lumbar Interbody Fusion With a Porous Nitinol Implant. AB - Study Design: A retrospective cohort study. Objective: The aim of this study is to assess the association of demographic and perioperative factors with clinical outcomes of lumbar interbody fusion with a porous nitinol (TiNi) implant for degenerative disc disease. Methods: Forty-one patients with degenerative lumbar disease were prospectively followed for a mean of 4.8 years. All patients were instrumented with porous TiNi interbody fusion devices. The Oswestry Disability Index (ODI) and return to work were used to assess clinical outcomes. Factors including age, body mass index, smoking status, insurance status, number of comorbidities, duration of surgery, estimated blood loss, number of levels fused, time since surgery, and preoperative ODI score were assessed. A multiple linear regression analysis was performed to look for demographic and perioperative factors associated with clinical outcome. Results: All patients except one (98%) showed complete fusion on radiography at 1 year. Estimated blood loss and duration of surgery were significantly associated with higher postoperative ODI scores (P = .002 and P = .019, respectively). Smoking status, salary insurance status, age, body mass index, number of comorbidities, number of levels fused, time since surgery, and preoperative ODI score were not significantly associated with outcome. Conclusions: Porous nitinol permitted fusion rates similar to those reported in the literature for alternative fusion cages. Poor functional outcome of patients was strongly associated with intraoperative blood loss and duration of surgery. We believe that estimated blood loss should be carefully evaluated in studies of postoperative outcome, as it may affect midterm outcomes. Level of Evidence: Level 3. PMID- 29238644 TI - Impact of Preoperative Anemia on Outcomes in Adults Undergoing Elective Posterior Cervical Fusion. AB - Study Design: Retrospective analysis of prospectively collected data. Objectives: Few studies have investigated the role of preoperative anemia on postoperative outcomes of posterior cervical fusion. This study looked to investigate the potential relationship between preoperative anemia and postoperative outcomes following posterior cervical spine fusion. Methods: Data from patients undergoing elective posterior cervical fusions between 2005 and 2012 was collected from the American College of Surgeons National Surgical Quality Improvement Program database using inclusion/exclusion criteria. Multivariate analyses were used to identify the predictive power of anemia for postoperative outcomes. Results: A total of 473 adult patients undergoing elective posterior cervical fusions were identified with 106 (22.4%) diagnosed with anemia preoperatively. Anemic patients had higher rates of diabetes (P = .0001), American Society of Anesthesiologists scores >=3 (P < .0001), and higher dependent functional status prior to surgery (P < .0001). Intraoperatively, anemic patients also had higher rates of neuromuscular injuries (P = .0303), stroke (P = .013), bleeding disorders (P = .0056), lower albumin (P < .0001), lower hematocrit (P < .0001), and higher international normalized ratio (P = .002). Postoperatively, anemic patients had higher rates of complications (P < .0001), death (P = .008), blood transfusion (P = .001), reoperation (P = .012), unplanned readmission (P = .022), and extended length of stay (>5 days; P < .0001). Conclusions: Preoperative anemia is linked to a number of postoperative complications, which can increase length of hospital stay and increase the likelihood of reoperation. Identifying preoperative anemia may play a role in optimizing and minimizing the complication rates and severity of comorbidities following posterior cervical fusion. PMID- 29238645 TI - The Effectiveness of Bioskills Training for Simulated Open Lumbar Laminectomy. AB - Study Design: Randomized, prospective study within an orthopedic surgery resident program at a large urban academic medical center. Objectives: To develop an inexpensive, user-friendly, and reproducible lumbar laminectomy bioskills training module and evaluation protocol that can be readily implemented into residency training programs to augment the clinical education of orthopedic and neurosurgical physicians-in-training. Methods: Twenty participants comprising senior medical students and orthopedic surgical residents. Participants were randomized to control (n = 9) or intervention (n = 11) groups controlling for level of experience (medical students, junior resident, or senior resident). The intervention group underwent a 40-minute bioskills training module, while the control group spent the same time with self-directed study. Pre- and posttest performance was self-reported by each participant (Physician Performance Diagnostic Inventory Scale [PPDIS]). Objective outcome scores were obtained from a blinded fellowship-trained attending orthopedic spine surgeon using Objective Structured Assessment of Technical Skills (OSATS) and Objective Decompression Score metrics. Results: When compared with the control group, the intervention group yielded a significant mean improvement in OSATS (P = .022) and PPDIS (P = .0001) scores. The Objective Decompression Scores improved in the intervention group with a trend toward significance (P = .058). Conclusions: We conclude that a concise lumbar laminectomy bioskills training session can be a useful educational tool for to augment clinical education. Although no direct clinical correlation can be concluded from this study, the improvement in trainee's technical and procedural skills suggests that Sawbones training modules can be an efficient and effective tool for teaching fundamental spine surgical skills outside of the operating room. PMID- 29238649 TI - Editorial Perspective. PMID- 29238646 TI - Stem Cells in Spinal Fusion. AB - Study Design: Review of literature. Objectives: This review of literature investigates the application of mesenchymal stem cells (MSCs) in spinal fusion, highlights potential uses in the development of bone grafts, and discusses limitations based on both preclinical and clinical models. Methods: A review of literature was conducted looking at current studies using stem cells for augmentation of spinal fusion in both animal and human models. Results: Eleven preclinical studies were found that used various animal models. Average fusion rates across studies were 59.8% for autograft and 73.7% for stem cell-based grafts. Outcomes included manual palpation and stressing of the fusion, radiography, micro-computed tomography (MUCT), and histological analysis. Fifteen clinical studies, 7 prospective and 8 retrospective, were found. Fusion rates ranged from 60% to 100%, averaging 87.1% in experimental groups and 87.2% in autograft control groups. Conclusions: It appears that there is minimal clinical difference between commercially available stem cells and bone marrow aspirates indicating that MSCs may be a good choice in a patient with poor marrow quality. Overcoming morbidity and limitations of autograft for spinal fusion, remains a significant problem for spinal surgeons and further studies are needed to determine the efficacy of stem cells in augmenting spinal fusion. PMID- 29238647 TI - RSA in Spine: A Review. AB - Study Design: Systematic review of literature. Objectives: This systematic review was conducted to investigate the accuracy of radiostereometric analysis (RSA), its assessment of spinal motion and disorders, and to investigate the limitations of this technique in spine assessment. Methods: Systematic review in all current literature to invesigate the role of RSA in spine. Results: The results of this review concluded that RSA is a very powerful tool to detect small changes between 2 rigid bodies such as a vertebral segment. The technique is described for animal and human studies for cervical and lumbar spine and can be used to analyze range of motion, inducible displacement, and fusion of segments. However, there are a few disadvantages with the technique; RSA percutaneous procedure needs to be performed to implant the markers (and cannot be used preoperatively), one needs a specific knowledge to handle data and interpret the results, and is relatively time consuming and expensive. Conclusions: RSA should be looked at as a very powerful research instrument and there are many questions suitable for RSA studies. PMID- 29238648 TI - Trends in Spinal Surgery for Pott's Disease (2000-2016): An Overview and Bibliometric Study. AB - Study Design: Systematic review. Objectives: (1) What are the surgical indications? Have they changed over time since the year 2000? (2) What is the current surgical approaches of choice? Have they changed over time since the year 2000? Do they vary by geographical region? (3) What are the most common outcome measures following surgery? Methods: Electronic databases and reference lists of key articles were searched from database inception from January 1, 2000 to December 31, 2016 to identify studies specifically evaluating surgical indications, current surgical approaches, and outcome measures for spinal tuberculosis. Results: Six randomized controlled trials were identified from our search (1 excluded: no surgical arm identified after review) Neurological deficit, instability and deformity were common indications identified. Surgical approach included predominantly anterior for cervical spine and posterior for thoracic and lumbar spine. Combined approach was preferred in pediatric cases. Degree of deformity correction, neurological outcomes, and fusion formed the main bases of assessing surgical outcomes. Conclusions: Majority of the current literature is from South Asia. The presence of neurological compromise, deformity, and instability were the primary criteria for surgical intervention. The preferred approach varied with the anatomical region of the spine in adults. Outcome measures predominantly involved deformity correction, neurological deficit, and fusion. PMID- 29238650 TI - Identification of the joint effect of a dynamic treatment intervention and a stochastic monitoring intervention under the no direct effect assumption. AB - The management of chronic conditions is characterized by frequent re-assessment of therapy decisions in response to the patient's changing condition over the course of the illness. Evidence most suitable to inform care thus often concerns the contrast of adaptive treatment strategies that repeatedly personalize treatment decisions over time using the latest accumulated data available from the patient's previous clinic visits such as laboratory exams (e.g., hemoglobin A1c measurements in diabetes care). The frequency at which such information is monitored implicitly defines the causal estimand that is typically evaluated in an observational or randomized study of such adaptive treatment strategies. Analytic control of monitoring with standard estimation approaches for time varying interventions can therefore not only improve study generalizibility but also inform the optimal timing of clinical surveillance. Valid inference with these estimators requires the upholding of a positivity assumption that can hinder their applicability. To potentially weaken this requirement for monitoring control, we introduce identifiability results that will facilitate the derivation of alternate estimators of effects defined by general joint treatment and monitoring interventions in the context of time-to-event outcomes. These results are developed based on the nonparametric structural equation modeling framework using a no direct effect assumption originally introduced in a prior paper that inspired this work. The relevance and scope of the results presented here are illustrated with examples in diabetes comparative effectiveness research. PMID- 29238652 TI - Handling of laundry in nursing homes in Frankfurt am Main, Germany, 2016 - laundry and professional clothing as potential pathways of bacterial transfer. AB - Background: In accordance with the German Infection Protection Act, the treatment and handling of laundry was checked by the Public Health Department in 2016 in all Frankfurt nursing homes with special focus on the staff's clothing. Methods: On-site visits and surveys were conducted in all 44 nursing homes in Frankfurt/Main, Germany, and random microbiological examinations of 58 reprocessed and 58 already worn protective gowns were performed to determine the numbers of the colony forming units (cfu) and microbiological differentiation of the pathogen species. Results: 41 (93%) of the 44 homes tested had contracted a certified laundry service. 23 (52%) of the homes also ran a laundry of their own; in 21 of these, laundry was reprocessed and disinfected in an industrial washing machine. Regular technical or microbiological tests were carried out in 16 or 12 of the home-owned laundries, respectively. Only 31 homes (70%) provided uniforms for their employees. The staff's clothing was processed in 25 homes by the external laundry, in 9 homes by the internal laundry, and in 12 homes, the nursing staff had to do this privately at their own home. Used coats exhibited significantly higher contamination than freshly prepared ones (median: 80 vs. 2 cfu/25 cm2; P 95 percentile: 256 cfu vs. 81 cfu/25 cm2). Clothing prepared in private homes showed significantly higher contamination rates than those washed in the certified external laundry or in the nursing homes themselves (Median: 16 cfu/25 cm2 vs. 0.5-1 cfu/25 cm2). Conclusion: Considering various publications on pathogen transfers and outbreaks due to contaminated laundry in medical facilities, the treatment of laundry, in particular the uniforms, must be given more attention, also in nursing homes for the elderly. The private reprocessing of occupational clothing by the employees at home must be rejected on hygienic principles, and is furthermore prohibited by law in Germany. PMID- 29238651 TI - Management of Treatment-Resistant Panic Disorder. AB - Purpose of Review: Purpose of Review Management of treatment-resistant (TR) panic disorder (PD) is an unresolved issue. In this paper, we provide a brief summary of previous findings, an updated (2015-2017) systematic review of pharmacological/non-pharmacological studies, and our personal perspective on this topic. Recent Findings: Recent Findings We found a very limited number of recent findings. Quetiapine extended-release augmentation has not been found to be beneficial, in comparison to placebo, in non-responders to previously recommended pharmacotherapy. In non-responders to cognitive behavioral therapy (CBT), switching to paroxetine/citalopram has been found to be more effective than continuing CBT. Acceptance and commitment therapy (ACT) has shown some improvement in patients' resistance to previous psychological/pharmacological interventions compared with a waiting-list condition. Summary: Summary Previous and recent findings regarding the treatment of TR PD suffer from several methodological limitations. Available studies provide insufficient evidence to support the use of medications alternative to the recommended medications; the efficacy of ACT needs confirmation with more rigorous methodology. Prolonged pharmacotherapy may produce significant improvement in patients with unsatisfactory response to short-term pharmacotherapy, while switching to pharmacotherapy may help non-responders to CBT. We discuss our personal perspective on the definition of "treatment resistance" as it relates to PD and provide personalized intervention strategies to increase favorable clinical outcomes based on our clinical expertise and review of experimental studies on the pathophysiology of PD. PMID- 29238653 TI - Formation of yttria-stabilized zirconia nanotubes by atomic layer deposition toward efficient solid electrolytes. AB - We describe a fabrication strategy for preparing yttria-stabilized zirconia nanotube (YSZ-NT) arrays embedded in porous alumina membranes by means of template-directed atomic layer deposition (ALD) technique. The individual YSZ-NTs have a high aspect-ratio of well over 120, about ~ 110 nm in diameter, and ~ 14 um in length. Interfacing the tube arrays with porous Pt was also introduced on the basis of partial etching technique in order to construct Pt/YSZ-NTs/Pt membrane electrode assembly (MEA) structures. The resulting YSZ-NTs MEAs show a 7 mm in diameter with a roughness factor of ~ 2. Area specific resistance was measured up to 1.84 Omega cm2 at 400 degrees C using H2 as fuel. PMID- 29238654 TI - Primary Endocrine Therapy in Older Women with Breast Cancer. AB - Purpose of Review: Breast cancer incidence increases with age. In recent years, primary endocrine therapy has been increasingly used as a treatment option for frail elderly women with breast cancer, although surgery is still the guideline recommended treatment. In this review, we discuss the evidence for primary endocrine therapy versus surgical treatment in older women with early breast cancer. Recent Findings: Both randomised controlled trials and recent observational studies showed a favourable progression-free survival but not overall survival for surgery plus adjuvant endocrine therapy versus primary endocrine therapy. Information about quality of life with either treatment strategy is so far lacking. Deciding who is fit for surgery and has sufficiently long life expectation to be at risk of disease progression can be supported by performing an individual geriatric assessment. Summary: This review suggests that primary endocrine therapy is a reasonable alternative to primary surgery in frail older women with breast cancer. Future studies should focus on the long-term effects on quality of life and physical functioning. PMID- 29238656 TI - Basic concepts and recent advancements in penile prosthetic urology. PMID- 29238655 TI - Duodenal-Jejunal Bypass Surgery Reverses Diabetic Phenotype and Reduces Obesity in db/db Mice. AB - Type 2 diabetes mellitus (T2DM), a complex metabolic disorder typically accompanying weight gain, is associated with progressive beta-cell failure and insulin resistance. Bariatric surgery ameliorates glucose tolerance and provides a near-perfect treatment. Duodenal-jejunal bypass (DJB) is an experimental procedure and has been studied in several rat models, but its influence in db/db mice, a transgenic model of T2DM, remains unclear. To investigate the effectiveness of DJB in db/db mice, we performed the surgery and evaluated metabolism improvement. Results showed that mice in DJB group weighed remarkably less than sham group two weeks after surgery. Compared to the preoperative level, postoperative fasting blood glucose (FBG) was dramatically reduced. Statistical analysis revealed that changes in body weight and FBG were significantly correlated. Besides, DJB surgery altered plasma insulin level with approximate 40% reduction. Thus, for the first time we proved that DJB can achieve rapid therapeutic effect in transgenic db/db mice with severe T2DM as well as obesity. In addition, decreased insulin level reflected better insulin sensitivity induced by DJB. In conclusion, our study demonstrates that DJB surgery may be a potentially effective way to treat obesity-associated T2DM. PMID- 29238657 TI - 30-day adverse event rates following penile prosthesis surgery: an American College of Surgeons National Surgical Quality Improvement Program based evaluation. AB - Background: Commonly utilized as a third-line therapy for erectile dysfunction (ED) management, the penile prostheses have become a staple treatment for ED refractory to pharmacological interventions. There is however a paucity of data in the literature pertaining to short-term adverse outcomes following penile prosthesis surgery. We thus sought to leverage the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) to evaluate such outcomes within 30 days of surgery in these patients. We hypothesized that such data will lead to a more informed patient-physician consultation. Methods: Relying on the ACS-NSQIP database [2005-2013], patients undergoing penile prosthesis placement were identified utilizing the Current Procedural Terminology (CPT) codes: 54400, 54401, 54405, 54406, 54407, 54408, 54410, 54411, 54416 and 54417. Outcomes assessed included system-wise categorized complications, length of-stay (LOS), and re-intervention, readmission and 30-day mortality rates. Descriptive statistics were used to analyze available data. Multivariate analysis could not be performed due to small sample size. Results: Overall, 98 cases of patients who underwent surgery for penile prosthesis placements between the years 2005 and 2013 were reported by the ACS-NSQIP affiliated hospitals. The median age was 65 years (interquartile range, 58-70 years). The overall 30-day complication rate was 11.3% (n=11); 5 of the 11 complications were infectious in etiology, and three were a postoperative blood transfusion event. The median LOS was 1 day. One (1.0%) patient needed to return to the operating room, two patients (2.6%) were readmitted and there was one (1.0%) death within 30 days of the original surgery. Conclusions: Surgery for penile prosthesis appears to be a safe operation despite the routinely advanced age of the patients requiring it. Complications in the immediate postoperative setting are usually infectious. This data can be used in the clinical setting for a more informed patient-physician discussion and patient expectation management. PMID- 29238659 TI - The use of penile prostheses in the management of priapism. AB - Priapism is a relatively uncommon condition that can result in erectile dysfunction (ED) and corporal fibrosis. Cases of prolonged priapism are particularly prone to ED, which arises when priapism is treatment refractory or had a delayed presentation. Due to the emergent nature of priapism, it behooves urologists to be familiar with all potential treatment modalities to minimize adverse outcomes. In this review paper, we aim to summarize the literature regarding the use of penile prosthesis (PP) implantation in the setting of ischemic priapism (IP). In some patients who present later or have prolonged initial treatment, early insertion of PP may be indicated. PMID- 29238658 TI - Non-pharmacological and non-surgical strategies to promote sexual recovery for men with erectile dysfunction. AB - Erectile dysfunction (ED), the most commonly reported sexual problem for men, reduces the quality of life for both patients and their partners. Even when physiologically effective, long-term adherence to ED treatments is poor. We review here the implication of having patients' partners involved in ED treatment, starting with treatment selection. We suggest that having partners engaged from the outset may promote an erotic association of the treatment with the partner, i.e., conceptually linking the aid to the sexual pleasure that the partner provides. We hypothesize that this erotic association should enhance the sexual aid's effectiveness and might potentially help improve long-term adherence. The primary focus of this review, though, is non-pharmacological and non-surgical options for maintaining sexual activity for men with ED. Though not ED treatments per se, anecdotal data suggest that these options may be effective for some patients and their partners in regaining a satisfying sex life. The aids discussed include external penile prostheses, penile sleeves, and penile support devices. These devices can allow men to participate in penetrative sexual intercourse despite moderate to severe ED. External penile prostheses can be personalized so they match in size and shape a man's normal full erection. Penile sleeves can similarly be customized with a lumen that fits best a patient's penis for optimal tactile stimulation. We review how multi-sensory integration can enhance sexual arousal for men who use such devices, allowing them to achieve orgasm despite intractable ED. Patients are not always advised within ED clinics about these options nor why and how they can facilitate non-erection dependent sexual recovery. Clinicians need to be aware of these devices and their positive attributes, so they can objectively counsel and encourage couples to explore their use as an alternative to more invasive treatments. The most commonly promoted non-medical ED aid offered to patients is the vacuum erection device. We discuss how erections achieved with the vacuum erection device have a "hinge effect", that is an underappreciated barrier to the effectiveness of the erection. With a hinged erection, the penis points downward rather than upward. We show how the normal kinematics of the penis during coitus is not strictly linear (i.e., not uniaxial; not just in-and-out), and is impeded by hinging. Positional adjustment, such as the receptive partner being on top, may help overcome this problem for some couples. Lastly, we suggest that, in the case where ED can be anticipated from a pending medical treatment, such as a prostatectomy, pre-habilitative approaches may potentially improve adherence to sexual aid use in the long-term. In conclusion, non-pharmacological and non surgical options for sexual recovery are available. Scientific studies on the effectiveness of these interventions in restoring satisfying sex are warranted. PMID- 29238660 TI - Salvage penile prosthetic surgery utilizing temporary malleable implants. AB - The inflatable penile prosthesis (IPP) is an effective erectile dysfunction (ED) treatment modality when oral and injectable therapies fail to achieve satisfactory results. Unfortunately, infection of the prosthetic remains a dreaded complication occurring in a small fraction of patients despite advances in device design and surgical techniques. With a prosthetic infection or erosion, classic management has included removal of all hardware with thorough irrigation of the infected spaces. To prevent corporal fibrosis and scarring that can make a subsequent implant challenging, an immediate salvage procedure with a three-piece prosthesis has been advocated when possible. However, there has been recent interest in using malleable devices during salvage procedures to serve as a temporary implant and further improve outcomes. Based on a literature review of immediate salvage procedures for infected penile prostheses, management with typical Mulcahy washout and IPP reimplant may be quite successful in appropriately selected patients. Based on one case series and a second multicenter trial of malleable salvage procedures, utilizing a malleable as a temporary implant is similarly, if not more, successful at eradicating prosthetic infection. The malleable implant not only serves as a temporary space-filling corporal implant to prevent fibrosis, but may also prove an adequate destination therapy for some given the lower than expected rate of delayed conversion to inflatable prosthesis. Future studies are needed to better characterize the role of malleable devices for penile prosthetic salvage and query patient satisfaction with the malleable device and repeated surgeries. PMID- 29238661 TI - Penile prosthetic surgery for the management of Peyronie's disease. AB - With the increased prevalence of Peyronie's disease (PD) among men, there is also an up-rise of associated erectile dysfunction (ED) which can be devastating psychologically and sexually to most men. A wide range of therapies including medical and surgical procedures are available to satisfactorily address this condition. However when ED coexists, the gold standard treatment is penile prosthetic prosthesis (PP) with or without additional straightening procedures. We herein systematically review the contemporary literature addressing the role of the PP in the management of PD with concomitant ED with particular emphasis on patient's satisfaction, outcomes and safety. PMID- 29238662 TI - Medical pre-operative considerations for patients undergoing penile implantation. AB - Penile prosthesis surgery has become the standard treatment for patients with erectile dysfunction refractory to medical management. Refinements in the both the surgical technique and device manufacturing have made this a safe and reliable treatment with excellent patient satisfaction. In this review, we will overview the basic medical and pre-operative considerations for patients undergoing penile prosthesis implantation. We intend to provide a simple and practical checklist for the implanter to reference when considering implantation of a penile prosthesis. PMID- 29238663 TI - Prevention, identification, and management of post-operative penile implant complications of infection, hematoma, and device malfunction. AB - Penile prosthesis implant surgery is an effective management approach for a number of urological conditions, including medication refractory erectile dysfunction (ED). Complications encountered post-operatively include infection, bleeding/hematoma, and device malfunction. Since the 1970s, modifications to these devices have reduced complication rates through improvement in antisepsis and design using antibiotic coatings, kink-resistant tubing, lock-out valves to prevent autoinflation, and modified reservoir shapes. Device survival and complication rates have been investigated predominately by retrospective database derived studies. This review article focuses on the identification and management of post-operative complications following penile prosthetic and implant surgery. Etiology for ED, surgical technique, and prosthesis type are variable among studies. The most common post-operative complications of infection, bleeding, and device malfunction may be minimized by adherence to consistent technique and standard protocol. Novel antibiotic coatings and standard antibiotic regimen may reduce infection rates. Meticulous hemostasis and intraoperative testing of devices may further reduce need for revision surgery. Additional prospective studies with consistent reporting of outcomes and comparison of surgical approach and prosthesis type in patients with variable ED etiology would be beneficial. PMID- 29238664 TI - A history of penile implants. AB - Erectile dysfunction (ED) has long been described by physicians and patients, with treatments for ED proposed starting in the 8th century BC. In the last 50 years, however, there have been many advances in medical and surgical management of ED, notably the introduction of the inflatable penile prosthesis (IPP) in 1973 and phosphodiesterase type 5 inhibitors (PDE5Is) in 1998. Here we review the evolution of the IPP from 1973 through the current day. The 3-piece device was first described in 1973 by Dr. F. Brantley Scott, who helped found American Medical Systems (AMS) to market and sell the device. In 1983, Mentor (now Coloplast) started marketing a competing device. AMS and Mentor have made multiple modifications to the device over the years, which have increased rigidity, durability and patient satisfaction, and have decreased surgical variability, post-operative infection and spontaneous inflation. Today, the IPP is a safe and effective option for many men who have failed medical therapies, with high satisfaction from both patients and partners. PMID- 29238665 TI - Penile implants: a look into the future. AB - Inflatable penile prosthesis (IPP) has been around since the 1970's as a durable and one-time cure for erectile dysfunction (ED). For the past 40 years, many changes have been made to make the device better and currently IPP boasts a high percentage of long-term patient satisfaction. The next paradigm shift in IPP treatment for ED is upon us. Funding for ED related medications and devices has been a hot topic in health policy over the last 10 years. This suggests that the device must improve and patient advocacy and education must increase for IPP to remain as a viable solution for ED. In this paper, we conduct a literature search for innovations in IPP and argue that IPP must constantly improve to compete with oral, injectable, shockwave, and potentially gene therapies. PMID- 29238667 TI - Penile prosthesis in the management of erectile dysfunction following cancer therapy. AB - Erectile dysfunction (ED) is a common problem in older men and occurs with even greater frequency following the treatment of pelvic malignancies. Inflatable penile prosthesis (IPP) implantation is a safe and effective form of definitive ED treatment for those men who fail more conservative measures, and it can be used with similar outcomes in men following cancer therapy. Although many of these men remain dissatisfied with other therapeutic options for ED, IPPs are underutilized in this population. This review will discuss the current practice patterns, outcomes and nuances to surgical technique regarding the use of IPPs in patients with ED following cancer therapy. PMID- 29238666 TI - Preoperative counseling and expectation management for inflatable penile prosthesis implantation. AB - The inflatable penile prosthesis (IPP) is the gold standard surgical treatment for medical refractory erectile dysfunction (ED). While the modern IPP has enjoyed high satisfaction rates as a product of its continued innovation, reliability, and performance, patient dissatisfaction can still occur. IPP implantation restores physiologic function with cosmetic and psychological consequences, both of which place inherent emphasis on preoperative counseling and expectation management. This review aims to highlight the complex nature of such counseling and provide practitioners with a roadmap to navigate the landscape. Preoperative counseling begins with appropriate patient selection and identification of those patients who are at risk for dissatisfaction as a result of personality characteristics. The informed consent provides a natural framework to discuss the host of complications and risks that are associated with surgery, including infection, device malfunction, damage to nearby structures, and device erosion. Device selection is a nuanced process that merges patient preference with clinical factors and consideration. We address device selection through a description of cylinder construction, pump design, and reservoir placement in the context of preoperative counseling. Lastly, we draw attention to expectation management with a specific focus on possible post-operative changes to penile length and sensation as well as partner involvement. The modern IPP provides excellent results with high patient and partner satisfaction. Ultimately, satisfaction is dependent on multiple factors, but providing accurate, realistic counseling and expectation management prepares patients for the best possible outcomes. PMID- 29238668 TI - Troubleshooting intraoperative complications of penile prosthesis placement. AB - Placement of a penile prosthesis is an excellent option for well-selected patients, offering high patient satisfaction and a low rate of complications. Most urologists who perform the procedure are not high volume implanters and may have limited experience with troubleshooting intraoperative issues. In this review, the authors use current literature to provide recommendations for the management of various intraoperative issues such as difficultly with dilation, incongruent measurement, perforation, urethral injury, crossover, complications of reservoir placement, penile curvature, glans mobility, and hemostasis are all discussed. Preparedness for the management of intraoperative issues can help improve patient outcomes and limit morbidity. PMID- 29238669 TI - Use of amnion chorion and umbilical cord grafts in conjunction with penile implant procedures. AB - Biologics have increased in popularity lately as a novel and exciting new therapy for men with a spectrum of sexual dysfunction ailments-ranging from erectile dysfunction, Peyronie's disease, and ejaculatory disorders. In this series, sequential patients were analyzed who received biologic materials at the time of their penile implant surgery, with various metrics assessed. The information gathered includes recovery time, need for postoperative analgesics, and satisfaction with the final outcome. In this study, early metrics appear to point to improved outcomes in select criteria. Further study will need to address whether treatment with biologics has broader appeal, but in the penile implant patient, the surgery seems to be augmented with the placement of biologic material into the surgical wound. PMID- 29238670 TI - Specific Organ Targeted Vestibular Physiotherapy: The Pivot in the Contemporary Management of Vertigo and Imbalance. AB - Introduction: Advancements in our understanding of vestibular physiology and how it is changes in different diseases have established that of the three therapeutic approaches to treat disorders of the vestibular system viz. pharmacotherapy, surgery and physical therapy, it is the later i.e., physical therapy which is the most efficacious modality in the management of balance disorders. The futility of vestibular sedatives in the correction of vestibular disorders and in the restoration of balance and the very limited role of surgery has now been recognised. Advancements in vestibulometry now enable us to localise any lesion in the vestibular system with utmost precision and also determine the exact cause of the balance disorder. The site of lesion and the specific organ that is defective can now be very precisely identified. Treatment modalities especially that for physical therapy hence have to be organ specific, and if possible, also disease specific. Aims and Objectives: The study aims at evaluating the efficacy of physiotherapy in the management of balance disorders and also assesses the efficacy of organ targeted physical therapy, a new concept in restoring balance after vestibulometry has identified the offending organ. Materials and Methods: The study was conducted in the specialised physical therapy unit for balance and gait disorder patients which is a part of Vertigo and Deafness Clinic in Kolkata, India. Special instruments for physical therapy devised by the first author were used for stimulation of specific sense organs in the vestibular labyrinth that were found to be defective in vestibulometry. Specially made Virtual reality programs were used in patients suffering from psychogenic balance disorders. The pre and post therapy status was evaluated by different standard scales to assess balance and dizziness. Results: Very promising results were obtained. Organ targeted physiotherapy where defective sense organs were specifically stimulated showed remarkable improvement in different measures. Virtual reality exercises too showed very promising results in patients of psychogenic vertigo. PMID- 29238671 TI - Dizziness in a Tertiary Care Centre in Sikkim: Our Experience and Limitations. AB - Dizziness is a common symptom and though most of the causes are benign yet some may be potentially life threatening. Diagnosis can be a challenge sometimes due to lack of dedicated vestibular lab and injudicious use of vestibular suppressant medications. A 2 year retrospective study of the hospital records from September 2014 to August 2016 was done to study the causes of dizziness and the limitations and challenges in the diagnosis. 75 complete records of patients presenting with dizziness were accessed and analysed. 54.7% of the patients were males and most patients were young adults. Most of the cases were benign and Benign paroxysmal positional vertigo was the commonest diagnosed case (20%). Potentially life threatening cases diagnosed were cerebellar infarct and posterior fossa space occupying lesion (5.3%). Complete evaluation of a dizzy patient must be done to arrive at a causal diagnosis. Injudicious use of vestibular sedatives should be discouraged. Proper training and education to the primary care physician should be imparted so that they can adopt a practical approach for evaluation and management of a dizzy person. PMID- 29238672 TI - Rigid Bronchoscopy in Pediatric Patients. AB - Aspiration of foreign-bodies remains a major life-threatening situation in children and have always been a source of interest and confusion to otolaryngologists due to their varied presentations. These conditions if not promptly diagnosed and managed can prove to be fatal, but the current mortality is only one percent compared to pre bronchoscopy era (Rothman and Boeckman in Ann Otol Rhinol Laryngol 89:434-436, 1980). Peak incidence of this condition is in early childhood due to child's habit of putting small objects in mouth to determine their taste and texture and chew while teething. This is a study conducted retrospectively from 2012 to 2017 in a teritiary care center. It includes a total of 70 cases of foreign body in airway who underwent rigid bronchoscopy under general anaesthesia. The patients were all in paediatric age group but mostly between 6 months to 3 years. The youngest patient was 3 months old and the oldest 12 years old. Male children (70%, n = 49) were more common than female children (30%, n = 21) with a male to female ratio of 2.33:1. A definite history of foreign body aspiration was given in only 70% cases, but the most common symptom were cough (100%) and breathlessness (80%). Organic foreign bodies (76.36%, n = 42) were more common when compared to inorganic foreign bodies. Foreign body most commonly impacted in Right main bronchus (49.09%, n = 27) followed by Left main bronchus (31.42%) and lastly the trachea (19.49%). Even though the mortality in patients of foreign body aspiration is low, it is essential to have proper cooperation between the otolaryngologists, paediatrician and the radiologist for rapid diagnosis and prompt management. It is advised to have a second look to check all the bronchopulmonary segments. Life saving steps are Prompt referral, early diagnosis and vigilant management. PMID- 29238673 TI - Sialendoscopic Approach in Management of Juvenile Recurrent Parotitis. AB - : To assess the role of sialendoscopy as a diagnostic and therapeutic modality in juvenile recurrent parotitis. Juvenile recurrent parotitis (JRP) is the second most frequent salivary gland disease in childhood and is characterized by recurrent non suppurative and non obstructive parotid inflammation. These attacks influence the quality of life and can even lead to gland destruction, and there are no definitive treatment to avoid them. Sialendoscopic dilatation is emerging as the new treatment modality in this aspect. STUDY DESIGN: retrospective study. STUDY SETTING: Department of Otorhinolaryngology in tertiary care hospital. 17 cases of juvenile recurrent parotitis (i.e. children of age group 3-11 years presenting with complaints of recurrent parotid region swelling and pain, sometimes associated with fever) were included in the study during October 2012 September 2015. All cases underwent sialendoscopy under general anaesthesia. Diagnostic (classifying the ductal lesion) and interventional sialendoscopic procedure (dilatation with instillation of steroid) were carried out in single sitting. Follow up was done for a minimum of 6 months (range 6-36 months). 17 patients with mean age of 5.6 years and gender distribution of 47:53 (boys:girls) underwent sialendoscopy for JRP. 8 patients presented with unilateral parotitis and 9 with bilateral. The mean number of attacks in previous 1 year were 9.2. Average time for procedure was 20 min. All cases had ductal stenosis and ductal mucosa was pale in 15 cases on endoscopy. 1 patient underwent repeat endoscopy after 2 years. 50% had complete resolution of symptoms and 6 patients had one mild (swelling not associated with fever which subsided on its own) attack after treatment. Follow up period ranged from 6 months to 3 years. No complications were observed. Sialendoscopy has emerged as a viable option for assessment and treatment of JRP. Dilatation of the parotid duct and steroid instillation has significantly reduced the morbidity of this condition. PMID- 29238674 TI - Incidence and Preoperative Predictive Indicators of Incudal Necrosis in CSOM: A Prospective Study in a Tertiary Care Centre. AB - Both type of CSOM, tubotympanic which is considered safe as well as atticoantral which is considered unsafe may lead to erosion of the ossicular chain. Discontinuity of the ossicular chain is typically confirmed only during an operation. Knowing before surgery whether the patient has an ossicular discontinuity is important because it allows the surgeon to know the possibility of performing an ossiculoplasty and obtaining patient consent. The aims is to (1) study the incidence of incus necrosis in safe and unsafe CSOM. (2) Determine the preoperative predictive factors for incus necrosis. (3) Use angled otoscopes to determine the incidence of residual disease peroperative after conventional microscopic surgery. This is a prospective study carried out in the department of otorhinolaryngology, Govt Doon medical college, Dehradun from July 2014 to July 2016. A total of 100 patients who presented with CSOM and have not undergone any surgical procedure for the same were included in this study. Patients group was divided into cholesteatoma and non cholesteatoma group. Both groups were subdivided into intact and eroded incus group and were analysed in 11 parameters which were compared statistically. Incudal necrosis is more common in cholesteatoma group. In non cholesteatoma ears subtotal perforation with exposure of IS joint is reliable indicators of incudal necrosis. In non cholesteatoma group extension of cholesteatoma to tympanic sinus and mastoid and presence of persistent discharge are reliable indicators of necrosed incus. Moderate to moderately severe hearing loss indicate incudal necrosis in both groups therefore we conclude that these parameters can be reliably considered as predictors for incudal necrosis preoperatively. PMID- 29238675 TI - Is Pterygopalatine Fossa Injection with Adrenaline an Effective Technique for Better Surgical Field in Fess? AB - Functional endoscopic sinus surgery (FESS) is one of most common surgeries in otorhinolaryngology practice. It is done in the narrow confines of the nasal cavity. Bleeding into the surgical field is a major problem faced by endoscopic surgeons. To assess the effectiveness of pterygopalatine fossa infiltration with lignocaine and adrenaline in controlling surgical field bleeding during endoscopic sinus surgery. A randomized blinded study was done among 68 patients who underwent FESS. Infiltration with 2% lignocaine with 1:80,000 adrenaline was given only on one side and the surgeon was blinded as to which side was infiltrated and he was asked to assess the surgical field using a standard scale. There was statistical significant improvement in surgical field on the infiltrated side (p = 0.001) with almost 25-30% improvement in surgical field on the infiltrated side. The surgical field bleeding also varied with the blood pressure with a positive correlation. There were no complications associated with the procedure. Pterygopalatine fossa infiltration with lignocaine and adrenaline is an effective technique in reducing surgical field bleeding during FESS. It can be combined with nasal decongestion or hypotensive anaesthesia for an optimum surgical field. PMID- 29238676 TI - Double Posterior Based Flap Technique in Primary Endoscopic Dacryocystorhinostomy With and Without Using Powered Instrument. AB - To demonstrate the surgical technique and outcomes of double posterior based flap technique in primary endoscopic dacryocystorhinostomy (DCR) with and without use of powered instrument. 28 patients of nasolacrimal duct obstruction were included in the study from September 2012 to February 2015. All underwent endoscopic dacryocystorhinostomy with double posterior based nasal and lacrimal flap technique. In patients of group A (14 patients), bone removal was done with the help of Smith-Kerrison punch forceps and in patients of group B (14 patients), powered drill has been used for the same. Patients were visited the endoscopic clinic at 1, 3, 6 months and 1 year after the surgery for post operative evaluation. Of 28 patients, 26(92.85%) were found free of symptoms at the end of 1, 3 and at 6 months. One from each group had recurrence of symptoms. At the end of 12 months of 25 patients, 3(12%) patients were found to have recurrence of symptoms of which 1(8.33%) patients was from group A and 2(15.38%) were from group B and failures were because of granulation tissue and stomal stenosis. Patients assisted with powered drill had more postoperative complications compared to cold instrument. Double posterior based flap technique in primary endoscopic DCR without the assistance of powered drill could be an effective surgical option for the patients of chronic nasolacrimal duct obstruction enabling early epithelisation by preventing peristomal granulation tissue resulting in encouraging surgical outcome with least postoperative complication. PMID- 29238677 TI - Concept, Importance and Practice of Lateral Tucking in Tympanoplasty. AB - The current study aims at observing the technique and results of doing lateral tucking during tympanoplasty surgery. It is intended to provide additional support to the graft and prevent displacement as well. 98 cases included in the study and the graft uptake rate of 97.96% noted. Average pre operative air bone gap (ABG) was 31.12 db and average post operative ABG observed to be 14.01 db. Gain of 17.11 +/- 7 db achieved by the procedure. Lateral tucking is a concept that requires to be inculcated in routine tympanoplasty surgeries, especially where canal skin incisions are used. It is easy to practice and the results are good and complications are minimal. PMID- 29238678 TI - A Study of Effect of Consanguinity on Cochlear Morphology in Patients with Congenital Bilateral Profound Sensorineural Hearing Loss. AB - Consanguinity has been considered as one of the risk factors predisposing to the development of congenital hearing loss. Effect of consanguinity on cochlear morphology has been subject of speculation, though many studies have provided insight into functional aspect of cochlea. This study was conducted to know the effect of consanguinity on cochlear morphology, if any. A prospective, observational study, including prelingually deaf children with bilateral profound sensorineural hearing loss who are registered as candidates for cochlear implantation at a tertiary care centre, was conducted. Seven children born out of consanguineous marriages and having bilateral congenital sensorineural hearing loss were imaged for their inner ears by MRI and various cochlear measurements were compared with that of seven control children born out of non-consanguineous marriages and who had congenital bilateral sensorineural hearing deafness. No statistically significant differences were noticed in the measurements of mean cochlear length, cross sectional diameter of cochlea at apex, middle turn and at basal turns; between children born of consanguineous and non-consanguineous marriages. Study revealed normal cochlear morphology in all the children born out of consanguineous marriages. Consanguinity, as a risk factor for development of sensorineural hearing loss, may not result in gross structural anomaly of cochlea. The genetic testing of these patients need not be extensive and can be limited to selective screening of genes responsible for functioning of cochlea rather than its anatomical development. PMID- 29238679 TI - Novel Program of Using Village Health Workers in Early Detection and Awareness of Head and Neck Cancers: Audit of a Community Screening Program. AB - Head and neck cancers together (oral cavity, pharynx and larynx) are sixth commonest worldwide and are the commonest cancers in developing countries. The Cancer Project was started in Kheda/Anand, Gujarat, a harvest land of tobacco. The objective of this programme was to indoctrinate the most vulnerable and the least tended upon; the basics of head and neck cancers via the medium of their own kins. Voluntary village health workers were educated and trained to pick up the early signs of head and neck cancers. Oral self examination was taught to them and they went to peripheral villages to screen the population. They would refer suspicious cases to tertiary healthcare centre. The population was enlightened upon the basics of preventable measures, treatment options and rehabilitation facilities for head and neck cancer patients. Knowledge, attitude and practice analysis was done in the population which showed widespread disbelief and false practices. A population of 26,10,432 was surveyed in 1862 villages of which 10,522 (1.1%) individuals successfully quit the habit. The minimally educated workers referred 3309 suspicious individuals to higher centre of which 1890 (57.11%) tested positive for cancer. A lot of resource is put in research and development of rapid diagnosis and complete cure; however such a minimally costing program may help the most in primordial, primary and secondary level of prevention. Such programs should be advocated on the global platform on lines of Breast Self Examination. PMID- 29238680 TI - Diagnostic Accuracy of Nasal Endoscopy as Compared to Computed Tomography in Chronic Rhinosinusitis. AB - The study was done with the aims to evaluate the accuracy of nasal endoscopy as compared to computed tomography (CT) in diagnosing chronic rhinosinusitis (CRS) and to evaluate the correlation between Endoscopy Score and CT Score. It was a cross sectional study. Every consecutive, symptomatic patient of CRS who fulfilled the criteria of American Academy of Otolaryngology-Head and Neck Surgery Task Force were included in the study. Rigid diagnostic nasal endoscopy (DNE) was done and Lund-Kennedy scoring system was used. Plain CT of paranasal sinuses was done on the same day and severity was assessed using Lund-Mackay scoring system. Results were analysed considering CT as a gold standard. Out of 54 study patients, 45 (83.33%) had abnormal endoscopic examination while 50 (92.59%) were showing positive CT scan. Sensitivity and specificity of DNE against CT scan were 94% (95% CI 81.43-98.33%) and 75% (95% CI 42-99.24%), respectively. The positive predictive value was 98% and negative predictive value was 67%. Correlation between Lund-Mackay overall CT and Lund-Kennedy Endoscopy Score was high [Pearson's correlation coefficient (r) = 0.881, p value < 0.0001]. The conclusion was drawn that, endoscopy is valuable in individuals with symptoms consistent with CRS and can be used to confirm the diagnosis and to know the severity of the disease. CT scan can be advised in those with high clinical suspicion of CRS but negative endoscopy and in those having persistent symptoms after optimum medical management requiring Functional Endoscopic Sinus Surgery. PMID- 29238681 TI - Comparative Study of Outcome of Type I Tympanoplasty in Chronic Otitis Media Active Mucosal Disease (Wet Ear) Versus Chronic Otitis Media Inactive Mucosal Disease (Dry Ear). AB - To compare the outcome of type I tympanoplasty with cortical mastoidectomy in chronic otitis media active mucosal disease (wet ear) versus chronic otitis media inactive mucosal disease (dry ear). An observational analytic study was conducted and data collection was done from August 2014 to August 2016. All patients of chronic otitis media with mucosal disease were divided into two groups, one with active disease (group A) and another with inactive disease (group B). The outcome was studied in the form of graft take up rate. Total 103 patients were studied, group A (wet ear) had 67 and group B (dry ear) had 36 patients. Graft take up rate was 94% in wet ear and 100% in dry ear and p value was 0.2. There was no statistically significant difference found between the two groups. PMID- 29238682 TI - Cochlear Implantation in Children with Anomalous Cochleovestibular Anatomy: Our Experience. AB - To report operative findings, postoperative course, and postimplantation performance in patients with cochlear malformations who underwent cochlear implantation. Seventeen patients with malformations which included enlarged vestibular aqueduct (n = 6), Mondini's dysplasia (n = 5) common cavity deformity (n = 3) and incomplete partition type 2 (n = 3) underwent cochlear implantation with Nucleus 22 straight array device at our center. Operative findings described facial nerve anatomy and cerebrospinal fluid leak. Standard tests of speech perception were used to evaluate the postoperative performance for each subject. Operative findings included cerebrospinal fluid leak (thirteen patients) all of which were repaired successfully with graft. None had abnormal facial nerve anatomy. No surgical complications occurred. All the patients except two with common cavity had complete insertion. Electrode thresholds and discomfort levels were variable for several months after implantation. All patients demonstrated improved performance after implantation. Patients with enlarged vestibular aqueduct fared better than patients with other inner ear malformations. Cochlear implantation can be a successful method of rehabilitation in patients with congenital deafness who have cochlear malformations. PMID- 29238683 TI - Flexible Laryngoscopy in Management of Congenital Stridor. AB - The incidence of congenital stridor is on rise due to improved neonate and infant survival rate. The gold standard investigation for evaluation of stridor is rigid laryngotracheobronchoscopy, but this is invasive and requires general anesthesia. Flexible fibreoptic laryngoscopy, a relatively simple and less invasive procedure can be done under topical anaesthesia for evaluation of stridor. In this study, we have presented our experience of flexible laryngoscopy in children with congenital stridor, their results and management. Laryngomalacia was the commonest cause of stridor accounting for 80% of cases. 15% (6) patients required tracheostomy for relieving airway obstruction and 22.5% (9) patients required a definitive surgical procedure for correcting the cause. Flexible laryngoscopy is safe and gives a comprehensive analysis of airway including its dynamic functions. We also recommend flexible laryngoscopy as a frontline investigation for evaluation of stridor. PMID- 29238684 TI - A Study of Clinical Significance of the Depth of Olfactory Fossa in Patients Undergoing Endoscopic Sinus Surgery. AB - The endoscope has revolutionized the diagnosis and treatment of diseases of the nose and paranasal sinuses. Endoscopic sinus surgery (ESS), like all minimally invasive surgery, is designed to combine an excellent outcome with minimal patient discomfort. Successful outcome with minimal complications can only be achieved with good knowledge of the endoscopic anatomy, appropriate training in the procedure and the understanding of the anatomical variations. The intraoperative complications of ESS are bleeding and injury to surrounding structures commonly the orbital structures and fovea ethmoidalis. This is a hospital based prospective observational study with an objective to define the distribution of Keros classification of the depth of olfactory fossa and its asymmetrical distribution rates based on Keros type. Prospective study in a tertiary rural based hospital. 100 patients above the age of 10 years from October 2013 to March 2015 for a period of one year six months undergoing endoscopic sinus surgery in the Department of ENT, P.E.S. Institute of Medical Sciences and Research, Kuppam were chosen randomly. The data was collected from these patients who will met the inclusion criteria of the study and before undergoing endoscopic sinus surgery by subjecting them to CT scan of paranasal sinuses. It is observed that a total of 100 patients had been studied in which the mean age of the population is 36.65 + 13.36 years. Youngest patient was 12 years old and eldest patient was 70 years old. Among the patients 50(50%) were males and remaining 50(50%) were females with a female to male ratio is 1:1. In the present study, the depth of olfactory fossa ranged from 2.1 to 8.3 mm inclusive of both sides in 200 CT images with a mean height of 5.21 mm. Of the 200 sides measured, the distribution of Keros classification is as the following Keros type I 39(19.5%), Keros type II 143(71.5%) and Keros type III 18(9%) sides. Based on these observations, type II is the most common Keros type prevalent followed by type 1 Keros type and the least prevalent is the type III Keros type in the studied population. In the present study, on considering sides separately, the right side olfactory fossa depth ranged from 2.1 to 8.3 mm with a mean height of 5.43 mm and the left side olfactory fossa depth ranged from 2.1 to 8.1 mm with a mean height of 4.98 mm. On the right side, of 100 sides measured, the distribution of Keros classification is as the following-Keros type I 19(19%), Keros type II 68(68%) and Keros type III 13(13%) sides. On the left side, of 100 sides measured, the distribution of Keros classification is as the following Keros type I 25(25%), Keros type II 70(70%) and Keros type III 5(5%) sides. Based on these observations, type II is the most common Keros type prevalent followed by type 1 Keros type and the least prevalent is the type III Keros type in the studied population on both sides. In the present study, out of 100 patients 23 patients were having asymmetric olfactory fossa between right and left sides based on Keros type, where as remaining 77% had symmetric Keros type on right and left sides. Out of 23 patients, 16 patients were having lower or deep olfactory fossa on right side, where as remaining 7 patients were having lower or deep olfactory fossa on left side. Based on these observations, a lower or deep ethmoid roof occurred more frequently on the right side than on the left side. Wilcoxon matched pair signed rank test is applied to see the significant difference between depth of right and left olfactory fossae. Since P value is < 0.001 the depth of olfactory fossa is significantly different from each other. The present study presents a precise, quantitative analysis of the olfactory fossa and ethmoid roof position as well as individual asymmetry. This information may be useful during pre-operative evaluation of CT images, as well as intraoperatively. The surgeon's understanding of the anatomy of a patient's ethmoid roof and its possible variations is crucial for countering possible complication risks during endoscopic sinus surgery. PMID- 29238685 TI - Prevalence of Goitre in Raichur District (Karnataka): A Descriptive Study. AB - This prevalence study was exclusively for the goitre detection in individuals who has no prior awareness of thyroid disorder and also those patients giving history of signs and symptoms of such conditions. Subjects underwent investigations for (T3, T4, TSH and FNAC) to analyze status and type of Goitre. Of the first 30 cases, only 8 cases were investigated and later on personal interest for confirmation of goitre disorder prevalence additional 70 cases were assessed of which 51 cases were investigated. On basis of investigation and epidemiology, we concluded that probably soil and water sources contain less iodine. Sample shown are comparatively less, but in our area number of goitre cases are more and it needs further extensive survey. PMID- 29238686 TI - Mutilating Lesions of Face. AB - The destructive lesions affect midline facial areas causing extensive destruction. These lesions are challenging till date due to peculiarity in presentation and non availability of any single objective test. An attempt has been done to evaluate these different clinical presentations of lesions presenting at a single centre and the challenges faced by us at a tertiary government setup. Prospective study done on 15 patients presenting in department during period of 2006-2016. After a detailed history, hematological and biochemical markers, ESR, radiographical tests, pus culture, C ANCA, CECT PNS and histopathogical evaluation were done. 12 out of 15 patients were male; Most common age group was above 45 years of age. All cases had ulceration of nose, 9 had cartilaginous destruction and 3 had osseocartilaginous destruction. 5 cases of mucormycosis had hyperglycemia with 2 having ketonuria and 4 had nerve palsies. All patients needed multiple biopsies. 3 cases of wegners and 4 cases were suspected of IMDD and immunohistochemistry was advised. C ANCA was negative in wegners cases as they were in limited form. Mutilating diseases of face usually present at an advanced stage with diverse etiology, are slowly progressive and require detailed evaluation. Due to lack of availability of IHC markers and C-ANCA at every centre it is difficult to diagnose them. The treatment is challenging due to incomplete response and frequent relapses. These cases require proper work up plan and perseverance leads to a final diagnosis. PMID- 29238687 TI - Status of Otorhinolaryngology as Specialty of Choice Among Female Medical Graduates. AB - Specialty choices among medical graduates have undergone changes over time. We aimed to analyze status of otorhinolaryngology as specialty of choice among female medical graduates and factors affecting it. A total of 123 female medical graduates were surveyed during their internship over a period of 1 year in a tertiary-care hospital. Each intern was assessed using a questionnaire at the end of otorhinolaryngology rotation. The survey included nine questions about future career choices with special focus on ENT as a choice for specialization. Questions on choice of specialty, reason for choice, quality of undergraduate teaching and clinical postings were included. The post graduation specialty choices in descending order are Medicine, Pediatrics, Surgery, Obstetrics and Gynecology, Dermatology, Ophthalmology, Radiology, ENT, Anesthesia, Psychiatry followed by Physiology, Anatomy and Biochemistry. Among surgical branches most popular choice was General Surgery followed by Obstetrics and Gynecology, Ophthalmology, ENT and Orthopedics in descending order. Reason for the choice included advice from family and friends. Forty two interns (34.2%) followed advice of senior colleagues, 42 (34.2%) followed advice of relatives in the medical field, 25 (20.3%) took advice of non-medico parents while 14 (11.3%) followed their peer group. Regarding the opinion on the quality of undergraduate teaching and clinical postings, both were rated good by the majority. Otorhinolaryngology is less preferred than other general surgery, Obstetrics and Gynecology and ophthalmology by female medical graduates among surgical disciplines. Possible reasons and ways to improve status of Otorhinolaryngology are discussed. PMID- 29238688 TI - Second Branchial Anomalies: A Study of 94 Cases. AB - Ninety-four patients with second branchial anomalies were retrospectively analysed at a tertiary care centre from January 2006 to September 2016 to determine the demographical data and management. Branchial sinus and fistula presented earlier as compared to branchial cyst. The mean age at presentation in case of branchial sinuses, fistulae and cysts was 5.07, 5.79 and 7.31 years respectively. There was preponderance in males as compared to females, more so in bilateral cases. Male to female sex ratio was 2.91:1. The branchial fistulae were the most common type of lesions, followed by the branchial sinuses. The branchial anomalies were more on the right side (65.96%) probably due to right handedness of the population. Only eight patients (8.51%) had bilateral anomalies. Four patients had familial association, it was seen in bilateral cases and they presented earlier than unilateral cases. Early and complete surgical excision is the treatment of choice. Preoperative sinogram/fistulogram and intraoperative methylene blue dye injection is not mandatory for excision of a branchial sinus/fistula. Post-operative wound infection was the most common complication (4.25%). PMID- 29238689 TI - Baha Attract: Our Experience. AB - In this study, we have highlighted our experience with a new transcutaneous bone conduction hearing device, the Baha Attract System along with finer details on its surgical technique, some challenges faced intraoperatively and the surgical outcome. This study was carried out in our tertiary care hospital over the last 1 year. Our study included the first 4 patients, all of which were males; with a mean age of 13.25 years in whom the new Baha Attract System was used. The mean air-bone gap was 48 dB. Bone smoothening around the implant was needed in 2 patients. We did the switch-on after 6-12 weeks for all the patients where the programmed processor was applied with the help of a magnet at the implanted site. Our study results suggest that the Baha Attract System is promising for the patients with microtia-anotia having conductive or mixed hearing loss. These patients cannot be offered conventional air conduction hearing aids. Their hearing outcomes were comparable to percutaneous Baha systems. PMID- 29238690 TI - Tonsillectomy-Comparative Study of Various Techniques and Changing Trend. AB - Tonsillectomy is a major surgical procedure in terms of volume in the general otolaryngological practice. It is a 3000-year-old surgical operation, referred in Hindu medicine. There has been a conceptual change in the indications and surgical technique in the last 40 years. A comparative study between the various methods of tonsillectomy was done. The study was carried out in the single institutional set up by the same surgeon but using different techniques. The study aimed at comparing the intra-operative factors (blood loss, time taken for surgery), postoperative results (pain, bleeding, dehydration, time taken for complete healing), and other complications like vomiting and hospitalization time between different groups of surgical methods. This study was done in 2500 patients undergoing tonsillectomy with or without adenoid removal in a period of 35 years (1979-2013). The majority of the patients (approximately 41%) in the first half of this period underwent cold steel tonsillectomy whereas 39% underwent microdebrider assisted tonsillectomy. Microdebrider assisted tonsil surgery was done as day care procedure in 90%. In 21% of the patients, other methods viz coblation, radio frequency and laser were used. Microdebrider intracapsular tonsillectomy is associated with lower mortality and morbidity as compared to cold steel, coblation, electrodissection, laser and radio frequency. PMID- 29238691 TI - A Rare Presentation of Rhinosporidiosis. AB - Rhinosporidiosis is a common condition seen in India specially in endemic areas and in low socio economic areas. Here we present with a rare presentation of cheek swelling caused by obstruction of stenson's duct with a short history of 5 months. Sialolith of parotid duct is uncommon presentation but not unheard of, the subsequent treatment and further histopathology of the ductoceol reveled the causative factor for the obstruction of parotid duct was Rhinosporidiosis which a very rare presentation with very few cases reported in literature. On further investigations it was found to be primary Rhinosporidiosis. Hence it is eminent that Rhinosporidiosis should also be kept in mind while looking for a cause for salivary duct obstruction specially in endemic areas. PMID- 29238692 TI - Migraine Related Vertigo. AB - Migraine related vertigo (MRV) is largely accepted in the vestibular community and probably represents the second most common cause of vertigo after benign positional vertigo by far exceeding Meniere's disease. The data on vestibular migraine management is still relatively poor, despite its enormous importance in daily practice. A 55-year old male presented with history of giddiness, imbalance, sweating and sensation of nausea with severe pulsating headache of one day duration. Ear, Nose and Throat examination was normal. Neurological tests were negative. Audiogram and Electronystagmography were within normal limits. Nystagmus was positive on turning his head to left side. By reviewing the available literature on MRV, the report aims to outline a protocol for future management. The patient and caretakers were thoroughly counseled and educated, started on Flunarizine 10 mg and Dimenhydrinate 50 mg; advice healthy life style, necessary precautions, compliance to treatment. Patient was reportedly followed up and was symptom free over a period of 9 years. There is a call for proper diagnosis to address the complaint and manage of symptoms in acute attack and prophylaxis. In addition, this case highlight the ongoing need for proper systematic evaluation, therapeutic management, follow up by ensuring compliance to medication, necessary precautions and life style modification. PMID- 29238693 TI - Isolated Congenital Midline Upper Lip Sinus in A 5-year Old Child: A Rarity. PMID- 29238694 TI - Kimura Disease: A Rare Case Report From Himalayan Region. AB - Kimura's disease is a rare disorder of uncertain aetiology seen in Asian population, and presents as painless lymphadenopathy or subcutaneous masses in head-neck region. Peripheral eosinophilia, elevated levels of serum IgE, lymphoid proliferation and eosinophilic infiltration are its characteristic pathological features. We report a case of 40 year old male patient who presented with swelling behind right ear after successful ear surgery. The diagnosis was confirmed by histopathology and was treated by oral steroids. PMID- 29238695 TI - High Frequency Jet Ventilation during Transoral Laser Microsurgery for Tis-T2 Laryngeal Cancer. AB - Background: Transoral laser microsurgery (TLM) for early to intermediate laryngeal squamous cell cancer (SCC) can be technically challenging when adequate exposure of the posterior laryngeal compartment is required due to the presence of the orotracheal tube. The goal of our study was to analyze the efficacy of high frequency jet ventilation (HFJV) in achieving appropriate laryngeal exposure and safe oncologic resection of lesions located in such a position. Methods: We reviewed the clinical records of 62 patients affected by Tis-T2 SCC of the posterior laryngeal compartment treated by TLM between 02/2012 and 12/2016. The cohort was divided into two groups according to the anesthesiologic technique used: Group A included patients treated using intraoperative infraglottic HFJV, while Group B encompassed patients treated by standard orotracheal intubation. The main outcome was postoperative surgical margin status. Group comparison analysis was performed. Results: Significant difference in deep margin status was observed between the two groups: in Group A, the rate of negative deep margins was 86% compared to 56% in Group B (p = 0.04). A trend of better overall and superficial margin control was observed for patients treated using HFJV (Group A), although no statistical significance was achieved. Conclusion: Use of HFJV during TLM allows easier and safer management of patients affected by Tis-T2 SCC of the posterior laryngeal compartment, reducing the rates of positive superficial and deep surgical margins. PMID- 29238696 TI - Identification of Clinically Approved Drugs Indacaterol and Canagliflozin for Repurposing to Treat Epidermal Growth Factor Tyrosine Kinase Inhibitor-Resistant Lung Cancer. AB - In advanced lung cancer, epidermal growth factor tyrosine kinase inhibitors (EGFR TKIs) have extraordinary clinical efficacy. However, their usefulness is severely compromised by drug resistance mediated by various mechanisms, the most important of which is the secondary EGFR T790M mutation. The mutation blocks the binding of EGFR TKIs to the receptor kinase, thereby abolishing the therapeutic efficacy. In this study, we used our free and open-source protein-ligand docking software idock to screen worldwide approved small-molecule drugs against EGFR T790M. The computationally selected drug candidates were evaluated in vitro in resistant non small cell lung cancer (NSCLC) cell lines. The specificity of the drugs toward the mutant EGFR was demonstrated by cell-free kinase inhibition assay. The inhibition of EGFR kinase activity and its downstream signaling pathways in NSCLC cells was shown by immunoblot analysis. The positive hints were revealed to be indacaterol, canagliflozin, and cis-flupenthixol, all of which were shown to induce apoptosis in NSCLC cells harboring the EGFR T790M mutation. Moreover, the combination of indacaterol with gefitinib was also found to produce synergistic anticancer effect in NSCLC cells bearing EGFR T790M. The observed synergistic effect was likely contributed by the enhanced inhibition of EGFR and its downstream signaling molecules. PMID- 29238697 TI - Ataxia-Telangiectasia Mutated Modulation of Carbon Metabolism in Cancer. AB - The ataxia-telangiectasia mutated (ATM) protein kinase has been extensively studied for its role in the DNA damage response and its association with the disease ataxia telangiectasia. There is increasing evidence that ATM also plays an important role in other cellular processes, including carbon metabolism. Carbon metabolism is highly dysregulated in cancer due to the increased need for cellular biomass. A number of recent studies report a non-canonical role for ATM in the regulation of carbon metabolism. This review highlights what is currently known about ATM's regulation of carbon metabolism, the implication of these pathways in cancer, and the development of ATM inhibitors as therapeutic strategies for cancer. PMID- 29238698 TI - Detection of Merkel Cell Polyomavirus DNA in Serum Samples of Healthy Blood Donors. AB - Merkel cell polyomavirus (MCPyV) has been detected in 80% of Merkel cell carcinomas (MCC). In the host, the MCPyV reservoir remains elusive. MCPyV DNA sequences were revealed in blood donor buffy coats. In this study, MCPyV DNA sequences were investigated in the sera (n = 190) of healthy blood donors. Two MCPyV DNA sequences, coding for the viral oncoprotein large T antigen (LT), were investigated using polymerase chain reaction (PCR) methods and DNA sequencing. Circulating MCPyV sequences were detected in sera with a prevalence of 2.6% (5/190), at low-DNA viral load, which is in the range of 1-4 and 1-5 copies/MUl by real-time PCR and droplet digital PCR, respectively. DNA sequencing carried out in the five MCPyV-positive samples indicated that the two MCPyV LT sequences which were analyzed belong to the MKL-1 strain. Circulating MCPyV LT sequences are present in blood donor sera. MCPyV-positive samples from blood donors could represent a potential vehicle for MCPyV infection in receivers, whereas an increase in viral load may occur with multiple blood transfusions. In certain patient conditions, such as immune-depression/suppression, additional disease or old age, transfusion of MCPyV-positive samples could be an additional risk factor for MCC onset. PMID- 29238700 TI - Requirement for Ergosterol in Berberine Tolerance Underlies Synergism of Fluconazole and Berberine against Fluconazole-Resistant Candida albicans Isolates. AB - Candida albicans is one of the most common fungal pathogens. Our previous study demonstrated that concomitant use of berberine (BBR) and fluconazole (FLC) showed a synergistic action against FLC-resistant C. albicans in vitro and BBR had a major antifungal effect in the synergism, while FLC played a role of increasing the intracellular BBR concentration. Since the antifungal activity of BBR alone is very weak (MIC > 128 MUg/mL), it was assumed that FLC-resistant C. albicans was naturally tolerant to BBR, and this tolerance could be reversed by FLC. The present study aimed to elucidate the mechanism underlying BBR tolerance in FLC resistant C. albicans and its disruption by FLC. The ergosterol quantitative analysis showed that the BBR monotreatment could increase the content of cellular ergosterol. Real-time RT-PCR revealed a global upregulation of ergosterol synthesis genes in response to BBR exposure. In addition, exogenous ergosterol could decrease intracellular BBR concentration and increase the expression of drug efflux pump genes, further reducing the susceptibility of C. albicans to BBR. Similar to FLC, other antifungal agents acting on ergosterol were able to synergize with BBR against FLC-resistant C. albicans. However, the antifungal agents not acting on ergosterol were not synergistic with BBR. These results suggested that ergosterol was required for BBR tolerance, and FLC could enhance the susceptibility of FLC-resistant C. albicans to BBR by inhibiting ergosterol synthesis. PMID- 29238702 TI - Clinical usefulness of urine cytology in the detection of bladder tumors in patients with neurogenic lower urinary tract dysfunction. AB - Introduction: Screening for bladder cancer in patients with neurogenic lower urinary tract dysfunction is a challenge. Cystoscopy alone is not sufficient to detect bladder tumors in this patient group. We investigated the usefulness of combined cystoscopy and urine cytology. Materials and methods: By a systematic chart review, we identified all patients with neurogenic lower urinary tract dysfunction who underwent combined cystoscopy and urine cytology testing. In patients with suspicious findings either in cytology or cystoscopy, transurethral resection was performed. Results: Seventy-nine patients (age 54.8+/-14.3 years, 38 female, 41 male) were identified; 44 of these used indwelling catheters. Cystoscopy was suspicious in 25 patients and cytology was suspicious in 17 patients. Histologically, no tumor was found in 15 patients and bladder cancer was found in 6 patients. Sensitivity for both cytology and cystoscopy was 83.3%; specificity was 43.7% for cytology and 31.2% for cystoscopy. One bladder tumor was missed by cytology and three tumors were missed by cystoscopy. If a biopsy was taken only if both findings were suspicious, four patients would have been spared the procedure, and one tumor would not have been diagnosed. Conclusion: A combination of cystoscopy and urine cytology can improve bladder tumor detection rates and lower the number of unnecessary biopsies. PMID- 29238699 TI - Ticks and Tick-Borne Pathogens of the Caribbean: Current Understanding and Future Directions for More Comprehensive Surveillance. AB - Ticks are obligate hematophagous arthropods of significant importance to human and veterinary medicine. They transmit a vast array of pathogens, including bacteria, viruses, protozoa, and helminths. Most epidemiological data on ticks and tick-borne pathogens (TBPs) in the West Indies are limited to common livestock pathogens such as Ehrlichia ruminantium, Babesia spp. (i.e., B. bovis and B. bigemina), and Anaplasma marginale, and less information is available on companion animal pathogens. Of note, human tick-borne diseases (TBDs) remain almost completely uncharacterized in the West Indies. Information on TBP presence in wildlife is also missing. Herein, we provide a comprehensive review of the ticks and TBPs affecting human and animal health in the Caribbean, and introduce the challenges associated with understanding TBD epidemiology and implementing successful TBD management in this region. In particular, we stress the need for innovative and versatile surveillance tools using high-throughput pathogen detection (e.g., high-throughput real-time microfluidic PCR). The use of such tools in large epidemiological surveys will likely improve TBD prevention and control programs in the Caribbean. PMID- 29238701 TI - A Novel Heat Shock Element (HSE) in Entamoeba histolytica that Regulates the Transcriptional Activation of the EhPgp5 Gene in the Presence of Emetine Drug. AB - Transcriptional regulation of the multidrug resistance EhPgp5 gene in Entamoeba histolytica is induced by emetine stress. EhPgp5 overexpression alters the chloride-dependent currents that cause trophozoite swelling, diminishing induced programmed cell death (PCD) susceptibility. In contrast, antisense inhibition of P-glycoprotein (PGP) expression produces synchronous death of trophozoites and the enhancement of the biochemical and morphological characteristics of PCD induced by G418. Transcriptional gene regulation analysis identified a 59 bp region at position -170 to -111 bp promoter as putative emetine response elements (EREs). However, insights into transcription factors controlling EhPgp5 gene transcription are missing; to fill this knowledge gap, we used deletion studies and transient CAT activity assays. Our findings suggested an activating motif ( 151 to -136 bp) that corresponds to a heat shock element (HSE). Gel-shift assays, UV-crosslinking, binding protein purification, and western blotting assays revealed proteins of 94, 66, 62, and 51 kDa binding to the EhPgp5 HSE that could be heat shock-like transcription factors that regulate the transcriptional activation of the EhPgp5 gene in the presence of emetine drug. PMID- 29238703 TI - Characterization of alpha-fetoprotein effects on dendritic cell and its function as effector immune response activator. AB - Tumor antigen alpha-fetoprotein (AFP) can promote immune tolerance toward tumor cells by inducing regulatory functions of the immune system. The purpose of this study was to characterize the effects of AFP on dendritic cells (DC) in their antitumor immune response stimulation and subsequent immune tolerance toward tumor cells. Monocytes were cultured in medium with GM-CSF and IL-4 and incubated for 6 days to generate immature DC (imDC). AFP was added into the treatment group at the beginning of the monocyte-derived DC culture. Mature DC (mDC) were generated by an addition of lipopolysaccharide (LPS) into the culture and incubation for another 48 hours. We observed that the addition of AFP in early DC culture was able to decrease the binding of LPS onto imDC surface, which lowered the strength of stimulation and consequently the maturity of DC. As expected, the expression of mDC surface markers, which are known to be crucial in effector cell proliferation and activation such as HLA-DR, CD40, CD80, CD83, and CD86, were confirmed to be reduced on AFP-exposed DC. DC potential in stimulating proliferation of CD4+ T cells was decreased, in line with the reduction of surface markers' expression. Additionally, an increased secretion of cytokine TGF beta by DC was observed. In summary, AFP inhibited the effector immune responses while increasing the regulatory immune responses in DC. This might lead to tolerance toward antigens and tumor cell survival, such as in cases of hepatocellular carcinoma patients with high levels of AFP. PMID- 29238705 TI - Can Zika Account for the Missing Babies? AB - The Zika virus (ZIKV) spread rapidly in Brazil in 2015 and 2016. Rio de Janeiro was among the Brazilian cities which were hit the hardest, with more that a hundred thousand confirmed cases up to the end of 2016. Given the severity of the neurological damage caused by ZIKV on fetuses, we wondered whether it would also cause an increase in the number of miscarriages, especially very early ones. As early miscarriages are unlikely to be recorded as a health event, this effect-if it occurred-would only show up as a reduction in the number of live births. In this article, we show that there was a 15% drop in live births between September and December 2016 compared with the previous year, and that this sharp drop from epidemiological week 33 onward is strongly correlated with the number of recorded cases of Zika about 40 weeks earlier. We postulate that ZIKV is directly responsible for this drop in the birth rate. Further work is required to ascertain whether other factors such as the fear of having a microcephaly baby or the economic crisis are having a significant effect. PMID- 29238704 TI - Laparoscopy-Assisted versus Open Hepatectomy for Live Liver Donor: Systematic Review and Meta-Analysis. AB - Objective: To assess the feasibility, safety, and potential benefits of laparoscopy-assisted living donor hepatectomy (LADH) in comparison with open living donor hepatectomy (ODH) for liver transplantation. Background: LADH is becoming increasingly common for living donor liver transplant around the world. We aim to determine the efficacy of LADH and compare it with ODH. Methods: A systematic search on PubMed, Embase, Cochrane Library, and Web of Science was conducted in May 2017. Results: Nine studies were suitable for this analysis, involving 979 patients. LADH seemed to be associated with increased operation time (WMD = 24.85 min; 95% CI: -3.01~52.78, P = 0.08), less intraoperative blood loss (WMD = -59.92 ml; 95% CI: -94.58~-25.27, P = 0.0007), similar hospital stays (WMD = -0.47 d; 95% CI: -1.78~0.83, P = 0.47), less postoperative complications (RR = 0.70, 95% CI: 0.51~0.94, P = 0.02), less analgesic use (SMD = -0.22; 95% CI: -0.44~-0.11, P = 0.04), similar transfusion rates (RR = 0.82; 95% CI: 0.24~3.12, P = 0.82), and similar graft weights (WMD = 7.31 g; 95% CI: 23.45~38.07, P = 0.64). Conclusion: Our results indicate that LADH is a safe and effective technique and, when compared to ODH. PMID- 29238706 TI - Angular Phenozaxine Ethers as Potent Multi-microbial Targets Inhibitors: Design, Synthesis, and Molecular Docking Studies. AB - The reaction of diaza-5H-benzo[a]phenoxazin-5-one and 5H-benzo[a]phenoxazin-5-one with various phenols catalyzed by Pd/t-BuXPhos/K3PO4 system gave previously unknown ether derivatives (7a-f and 8a-f) in good yields. UV-visible, FTIR, and 1H NMR data were used to confirm structures of the synthesized compounds. The parent compounds and the derivatives were screened in-silico for their drug likeness and binding affinities to the microbial targets through molecular docking. Molinspiration software and AutoDock were used for the drug-likeness and docking studies, respectively. All the synthesized compounds showed strong drug likeness. They also showed excellent binding affinities with glucosamine-6 phosphate synthase (2VF5), AmpC beta-lactamase (1KE4), and Lanosterol-14alpha demethylase (3JUV), with compound 7e having the highest binding energies -9.5, 9.3, and -9.3 kcal/mol, respectively. These were found to be higher than the binding energies of the standard drugs. The binding energies of ciprofloxacin with 2VF5 and 1KE4 were -7.8 and -7.5 kcal/mol, respectively, while that of ketoconazole with 3JUV was -8.6 kcal/mol. The study showed that the synthesized compounds have multi-target inhibitory effects and can be very useful in multi drug resistance cases. A 2D quantitative structural activity relationship (QSAR) model against target Glucosamine-6-phosphate synthase (2VF5) was developed using partial least squares regression (PLS) with good internal prediction (R2 = 0.7400) and external prediction (R2_ predicted = 0.5475) via Molecular Operating Environment (2014). PMID- 29238707 TI - Drug Repurposing for the Treatment of Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accumulation of immature myeloid progenitor cells in the bone marrow, compromising of normal blood cell production and ultimately resulting in bone marrow failure. With a 20% overall survival rate at 5 years and 50% in the 18- to 65-year-old age group, new medicines are needed. It is proposed that development of repurposed drugs may be a part of the new therapy needed. AML is subdivided into recurrent molecular entities based on molecular genetics increasingly accessible for precision medicine. Novel therapy developments form a basis for novel multimodality therapy and include liposomal daunorubicin/cytarabine, broad or FLT3-specific tyrosine kinase inhibitors, Bcl-2 family inhibitors, selective inhibitors of nuclear export, metabolic inhibitors, and demethylating agents. The use of non-transplant immunotherapy is in early development in AML with the exceptional re-approval of a toxin-conjugated anti-CD33. However, the full potential of small molecule inhibitors and modalities like immunological checkpoint inhibitors, immunostimulatory small molecules, and CAR-T cell therapy is unknown. Some novel therapeutics will certainly benefit AML patient subgroups; however, due to high cost, more affordable alternatives are needed globally. Also the heterogeneity of AML will likely demand a broader repertoire of therapeutic molecules. Drug repurposing or repositioning represent a source for potential therapeutics with well-known toxicity profiles and reasonable prices. This implies that biomarkers of response need to accompany the development of antileukemic therapies for sharply defined patient subgroups. We will illustrate repurposing in AML with selected examples and discuss some experimental and regulatory limitations that may obstruct this development. PMID- 29238708 TI - Longitudinal "Real-World" Outcomes of Pirfenidone in Idiopathic Pulmonary Fibrosis in Greece. AB - Background: Pirfenidone is an antifibrotic compound able to slow down disease progression in patients with idiopathic pulmonary fibrosis (IPF). Objective: To investigate the safety and efficacy of pirfenidone in patients with IPF in a real life setting. Methods: This was a multicenter, retrospective, real-life, observational study for patients with IPF receiving pirfenidone. Results: We identified 92 patients with IPF receiving pirfenidone. Eighty patients (70 males and 10 females, mean age +/- SD: 68.1 + 7.5, mean %FVC +/- SD = 74.9 +/- 17.2, mean %DLCO +/- SD = 48.1 +/- 16.9) were included in the analysis. Skin-related (25%) and gastrointestinal (17.5%) adverse events were the most common and led to drug discontinuation in 22.5% of cases. The majority (87%) of patients experienced side effects during the first 6 months of treatment. At 36 months, changes in %FVC and %DLCO were -9.25 +/- 16.34 and -9.26 +/- 15.26, respectively. At 6, 12, and 24 months after treatment initiation (n = 80, 60, and 26), 18, 15, and 5 patients (22.5, 25, and 19.2%) experienced significant (>10%) and 11, 3, and 3 patients (13.8, 5, and 11.5%) experienced marginal (5-10%) %FVC improvement; and 13, 6, and 1 patient (16.2, 10, and 3.9%) experienced marginal ( 5 to -10%) and 20, 21, and 8 patients (25, 35, and 30.8%) experienced significant decline (<-10%) in %FVCpred. Median survival was 851 days, and 41 patients died during the study period. Conclusion: Pirfenidone demonstrated an acceptable safety and therapeutic profile in patients with IPF on a longitudinal basis. Prospective observational registries are urgently needed to provide a real-world view of outcomes of pirfenidone in clinical practice. PMID- 29238709 TI - Is Life Extension Today a Faustian Bargain? PMID- 29238710 TI - The Use of Keystone Flaps in Periarticular Wound Closure: A Case Series. AB - The Keystone perforator island flap (Keystone flap), is a Type A fasciocutaneous advancement flap, consisting of two V to Y advancement flaps. Skin cancer excision around joints presents a number of reconstructive challenges. Owing to the mobile nature of joints, the optimal periarticular reconstructive option should possess the ability to provide adequate tissue coverage and withstand regional changes in tensile pressures. We report a single-surgeon series of five cases of periarticular keystone flap between 2014 and 2017. Data were collected from operation notes, clinical photography, histopathology, and outpatient clinic records. The indication for keystone flap was skin cancer in all cases (n = 5). The largest defect size post-excision in was 75 mm * 40 mm * 15 mm. All keystone flaps demonstrate a color and cosmetic appearance comparable to adjacent tissue. There were no major postoperative complications including flap failure or impaired range of joint movement in the follow up period. Superficial wound infection occurred postoperatively in one case. This is the first case series to discuss the use of keystone flaps in periarticular wound closure. Locoregional fasciocutaneous wound coverage offered by keystone flaps may alleviate the risks of graft failure, contour defects, and donor site morbidity associated with alternative reconstructive options, with good functional and cosmetic outcomes. We advocate their use as a robust reconstructive option in periarticular areas. PMID- 29238711 TI - Long-term Dose Stability of OnabotulinumtoxinA Injection for Adductor Spasmodic Dysphonia: A 19-Year Single Institution Experience. AB - Objectives: Adductor spasmodic dysphonia (AdSD) is a focal dystonia predominantly involving the laryngeal adductor muscles. AdSD is reported to be a largely non progressive neurological disorder, though fluctuations in symptom severity do occur. Repeated laryngeal onabotulinumtoxinA (BTX-A) injections are the primary management for AdSD. A number of studies have demonstrated long-term dose stability as evidence of this long-term disease stability. Methods: A retrospective review was performed on all patients undergoing BTX-A injections for AdSD from April 1994 to September 2013 by a single laryngologist at a tertiary referral laryngology center. Patient demographics, injection doses, use of diazepam and/or lidocaine, and self-reported vocal function were recorded. Multiple linear regression analyses were performed. Results: 83 patients underwent a total of 1,168 injections over 19 years. The mean starting dose was 2.35 MU (0.79 SD). The mean long-term dose was 2.36 MU (0.79 SD). After adjusting for confounders, the change in the relative dose of BTX-A, with every year elapsed since initial dose was 0.13% (95% confidence interval -0.31 to 0.57%), p = 0.568. Conclusion: BTX-A dose is stable over time in our large cohort of patients treated with bilateral thyroarytenoid injections for AdSD. PMID- 29238712 TI - Cytotoxic Effect on Human Myeloma Cells and Leukemic Cells by the Agaricus blazei Murill Based Mushroom Extract, AndosanTM. AB - Agaricus blazei Murill is an edible mushroom of the Basidiomycetes family, which has been found to contain a number of compounds with antitumor properties, such as proteoglycans and ergosterol. In the present investigation, we show that the commercial mushroom product Andosan, which contains 82.4% Agaricus blazei Murill, together with medicinal mushrooms Hericium erinaceus (14.7%) and Grifola frondosa (2.9%), has a cytotoxic effect on primary myeloma cells, other myeloma cell lines, and leukemia cell lines in vitro. Although the exact content and hence the mechanisms of action of the Andosan extract are unknown, we have found in this investigation indications of cell cycle arrest when myeloma cell lines are cultivated with Andosan. This may be one of the possible explanations for the cytotoxic effects of Andosan. PMID- 29238713 TI - Sodium Mercaptoethane Sulfonate Reduces Collagenolytic Degradation and Synergistically Enhances Antimicrobial Durability in an Antibiotic-Loaded Biopolymer Film for Prevention of Surgical-Site Infections. AB - Implant-associated surgical-site infections can have significant clinical consequences. Previously we reported a method for prophylactically disinfecting implant surfaces in surgical pockets, where an antibiotic solution containing minocycline (M) and rifampin (R) was applied as a solid film in a crosslinked biopolymer matrix that partially liquefied in situ to provide extended prophylaxis. Here we studied the effect of adding sodium 2-mercaptoethane sulfonate (MeSNA) on durability of prophylaxis in an in vitro model of implant associated surgical-site infection. Adding MeSNA to the M/R biopolymer, antimicrobial film extended the duration for which biofilm formation by multidrug resistant Pseudomonas aeruginosa (MDR-PA) was prevented on silicone surfaces in the model. M/R films with and without MeSNA were effective in preventing colonization by methicillin-resistant Staphylococcus aureus. Independent experiments revealed that MeSNA directly inhibited proteolytic digestion of the biopolymer film and synergistically enhanced antimicrobial potency of M/R against MDR-PA. Incubation of the MeSNA containing films with L929 fibroblasts revealed no impairment of cellular metabolic activity or viability. PMID- 29238715 TI - Chemopreventive Potential of 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucoside on the Formation of Aberrant Crypt Foci in Azoxymethane-Induced Colorectal Cancer in Rats. AB - 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucoside (THSG) has been shown to have antioxidative and anti-inflammatory effects. Oxidative and inflammatory reactions are related to the development of colorectal carcinoma (CRC). In the present study, we characterized the preventive activities of THSG on colon carcinogenesis using the azoxymethane- (AOM-) mediated rat colon carcinogenesis model. F344 male rats were randomly divided into 5 groups (untreated and AOM model rats treated with or without THSG at 30, 150, or 250 mg/kg) after which the numbers of aberrant crypt foci (ACF) were assessed in the colon tissues of all rats. The expressions of nuclear factor-kappaB (NF-kappaB), cyclooxygenase-2 (COX-2), matrix metalloproteinase proteins (MMPs), and carcinoembryonic antigen (CEA) were measured as effective early predictors of CRC using western blot analysis. Treatment with THSG (150 or 250 mg/kg) induced a 50% reduction in total colonic ACF formation (P < 0.05). Furthermore, our results revealed a downregulation of CEA and NF-kappaB protein levels in the reduced number of ACF elicited by treatment with THSG, whereas levels of COX-2 and MMPs proteins were not changed. Collectively, THSG may be a promising natural lead compound or drug candidate for treating early phases of CRC. PMID- 29238716 TI - Pediatric Multiple Sclerosis in Tunisia: A Retrospective Study over 11 Years. AB - Introduction: Pediatric multiple sclerosis (pMS) is a rare demyelinating disorder with an onset before the age of 18 years. In this study, we aimed to investigate the characteristics of pMS in Tunisian children. Patients and Methods: We conducted a retrospective study over 11 years (2005-2016) including all patients diagnosed with pMS according to the International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria of 2012 and followed up in a tertiary care research center. Epidemiological, clinical, neuroimaging, laboratory, and therapeutic data were collected and analyzed. Results: There were 21 patients. The male-female ratio was 1 : 3. Mean age at onset was 11 years (range: 3-17 years). Three patients had type 1 diabetes. Polyfocal presentation was preponderant (81%) with motor dysfunction in 57% of patients. Paroxysmal dystonia was noticed in 24%. All patients were diagnosed with relapsing-remitting form. Interferon beta was prescribed in 80% with a reduction of annual relapse rate. Conclusion: The annual incidence of pMS in Tunisian children aged below 18 years could be estimated as 0.05 per 100,000. Singular features in our cohort were the frequent association with type 1 diabetes and the increased occurrence of dystonia. Greater awareness of pMS may be helpful to improve management strategies of children and their families. PMID- 29238717 TI - Corrigendum to "Start-Up Characteristics of a Granule-Based Anammox UASB Reactor Seeded with Anaerobic Granular Sludge". AB - [This corrects the article DOI: 10.1155/2013/396487.]. PMID- 29238714 TI - Corneal Nerve Fiber Structure, Its Role in Corneal Function, and Its Changes in Corneal Diseases. AB - Recently, in vivo confocal microscopy is used to examine the human corneal nerve fibers morphology. Corneal nerve fiber architecture and its role are studied in healthy and pathological conditions. Corneal nerves of rats were studied by nonspecific acetylcholinesterase (NsAchE) staining. NsAchE-positive subepithelial (stromal) nerve fiber has been found to be insensitive to capsaicin. Besides, NsAchE-negative but capsaicin-sensitive subbasal nerve (leash) fibers formed thick mesh-like structure showing close interconnections and exhibit both isolectin B4- and transient receptor potential vanilloid channel 1- (TRPV1-) positive. TRPV1, TRPV3, TRPA (ankyrin) 1, and TRPM (melastatin) 8 are expressed in corneal nerve fibers. Besides the corneal nerve fibers, the expressions of TRPV (1, 3, and 4), TRPC (canonical) 4, and TRPM8 are demonstrated in the corneal epithelial cell membrane. The realization of the importance of TRP channels acting as polymodal sensors of environmental stresses has identified potential drug targets for corneal disease. The pathophysiological conditions of corneal diseases are associated with disruption of normal tissue innervation, especially capsaicin-sensitive small sensory nerve fibers. The relationships between subbasal corneal nerve fiber morphology and neurotrophic keratopathy in corneal diseases are well studied. The recommended treatment for neurotrophic keratopathy is administration of preservative free eye drops. PMID- 29238718 TI - Effects of Structured Physical Activity Program on Chinese Young Children's Executive Functions and Perceived Physical Competence in a Day Care Center. AB - Purpose: To examine the effects of a structured physical activity program on executive functions and perceived physical competence as compared to a traditional recess among preschool children. Methods: Participants were 40 preschool children aged 4-5 from an urban child care center in a southern Chinese metropolitan area. Prior to the intervention, baseline assessments of children's executive functions and perceived physical competence were conducted. Children were then assigned to (1) intervention condition: a structured physical activity intervention group; (2) control condition: free-activity recess. The structured physical activity or recess programs were provided to the intervention and control groups 30 minutes daily for 3 months, respectively, followed by the identical postintervention measures. Results: Thirty-nine children (19 girls; mean age = 4.67 years old, BMI = 15.54 +/- 1.21) were included in the analysis. In general, children's executive functions and perceived physical competence increased over time. Repeated measures analysis of variance revealed the intervention group had significant greater increases in executive functions compared to the control children (F(1, 37) = 4.20, p = 0.04, eta2 = .10), yet there were no greater increases in perceived physical competence (F(1, 37) = 2.35, p = 0.13, eta2 = .06). Conclusion: The intervention exerted significant greater increases in executive functions in preschool children. It is meaningful to offer structured physical activity programs in day care centers. PMID- 29238719 TI - Can Replacing CA125 with HE4 in Risk of Malignancy Indices 1-4 Improve Diagnostic Performance in the Presurgical Assessment of Adnexal Tumors? AB - Aims: To assess whether replacing CA125 with HE4 in the classical formulas of risk of malignancy indices (RMIs) can improve diagnostic performance. Methods: For each of 312 patients with an adnexal mass, classical RMIs 1-4 were computed based on ultrasound score, menopausal status, and serum CA125 levels. Additionally, modified RMIs (mRMIs) 1-4 were recalculated by replacing CA125 with HE4. Results: Malignant pathology was diagnosed in 52 patients (16.67%). There was no significant difference in diagnostic performance (area under the receiver operating characteristic curve [AUC]) between each classical RMI and its corresponding mRMI. In the entire sample, the AUC was 0.899, 0.900, 0.895, and 0.908 for classical RMIs 1-4 compared to 0.903, 0.929, 0.930, and 0.931 for mRMIs 1-4. In premenopausal patients, the AUC was 0.818, 0.798, 0.795, and 0.802 for classical RMIs 1-4 compared to 0.839, 0.875, 0.876, and 0.856 for mRMIs 1-4. In postmenopausal patients, the AUC was 0.906, 0.895, 0.896, and 0.906 for classical RMIs 1-4 compared to 0.907, 0.923, 0.924, and 0.930 for mRMI 1-4. Conclusions: Use of HE4 instead of CA125 did not significantly improve diagnostic performance of RMIs 1-4 in patients with an adnexal mass. PMID- 29238720 TI - Calcifying Matrix Vesicles and Atherosclerosis. AB - Artery calcification is a well-recognized predictor of late atherosclerotic complications. In the intima media, calcification starts with apoptosis of vascular smooth muscle cells (VSMCs) and the release of calcifying matrix vesicles with diameter of 0.5-15 MUm that can be observed microscopically. In complicated plaques, calcification is generally less frequent. Calcifying vesicles are released by proatherosclerotic VSMCs into the collagen-rich matrix. The vesicles can penetrate into the intima media and protrude into the arterial lumen and thereby may represent a potential cause of atherothrombosis. In calcified fibrolipid plaques, the rate of calcification is increased but is followed with healing of a lesion rupture and exhibited by further erosion and/or intimal thickening. Generally, calcification directly correlates with the apoptosis of VSMCs and macrophages accompanied by the release of osteogenic matrix vesicles. This is a hallmark of atherosclerosis-related apoptosis of VSMCs that is commonly released in plaque stabilization. PMID- 29238721 TI - Macrovascular Complications in Patients with Diabetes and Prediabetes. AB - Diabetes is a significant health problem worldwide, and its association with cardiovascular disease (CVD) was reported in several studies. Hyperglycemia and insulin resistance seen in diabetes and prediabetes lead to an increase in reactive oxygen species, which triggers intracellular molecular signaling. The resulting prothrombotic state and increase in inflammatory mediators expedite atherosclerotic changes and the development of macrovascular complications. Individuals with diabetes or prediabetes have a higher risk of developing myocardial infarction, stroke, and peripheral artery disease. However, no significant difference in cardiovascular morbidity has been observed with tight glycemic control despite a reduction in some CVD outcomes, and the risk of adverse outcomes such as hypoglycemia was increased. Recently, some GLP-1 receptor agonists and SGLT-2 inhibitors have been shown to reduce cardiovascular events and mortality. In this review we give an overview of the risk and pathogenesis of cardiovascular disease among diabetic and prediabetic patients, as well as the implication of recent changes in diabetes management. PMID- 29238722 TI - Clinical, Epidemiological, and Histopathological Features of Respiratory Involvement in Rheumatoid Arthritis. AB - Although by definition rheumatoid arthritis (RA) is an articular disorder, it is a systemic disease, and 18-40% of patients experience extra-articular manifestations (EAMs). The involvement of the respiratory system occurs in about 30-40% of RA patients, and in about 10-20% of them it represents the first manifestation of RA. A wide range of pulmonary manifestations are detectable in RA patients, including pulmonary parenchymal disease, pleural involvement, and airway and pulmonary inflammation. The clinical, radiological, and histological spectra of respiratory manifestations in RA reflect chronic immune activation, increased susceptibility to infection (often related to immunosuppressive medications), or direct drug. The type and severity of pulmonary involvement influence the prognosis, ranging from mild self-limiting conditions to severe life-threatening complications. Herein, we reviewed the various manifestations of respiratory involvement in RA, providing an overview on epidemiological, histological, clinical, and radiological data. PMID- 29238723 TI - Relationship between Malaria and ABO Blood Types in East China. AB - Objectives: This study aims at investigating the relationship between malaria and blood group types in east China. Methods: Between 1 January 2011 and 31 March 2017, 99 malaria patients were enrolled for the study. Laboratory tests were conducted on their infection status and blood types. Clinical data of the participants were retrieved for analysis. Results: There was no mortality during the period of study. Overall, 90 (90.91%) of the patients were positive for Plasmodium falciparum, 8 (8.08%) were infected with Plasmodium vivax, and only 1 (1.01%) was infected with Plasmodium malariae. The most common blood group among the participants was group O (38.38%) followed by blood groups A, B, and AB, with 32.32%, 22.22%, and 7.07% cases, respectively. There was no significant relationship between the prevalence of malaria and ABO blood types (P > 0.05). In the blood group O, the prevalence of haemolytic-uremic syndrome and cerebral malaria was 13.16% and 5.25%, respectively, which was lower than that of the other three blood types (P > 0.05). Conclusion: There was no mortality among the malaria patients in this study. The blood group O was the most common blood type. Due to small sample size of data, there was no significant association between ABO blood types and malaria infection. PMID- 29238724 TI - DNA Damage as a Driver for Growth Delay: Chromosome Instability Syndromes with Intrauterine Growth Retardation. AB - DNA is constantly exposed to endogenous and exogenous mutagenic stimuli that are capable of producing diverse lesions. In order to protect the integrity of the genetic material, a wide array of DNA repair systems that can target each specific lesion has evolved. Despite the availability of several repair pathways, a common general program known as the DNA damage response (DDR) is stimulated to promote lesion detection, signaling, and repair in order to maintain genetic integrity. The genes that participate in these pathways are subject to mutation; a loss in their function would result in impaired DNA repair and genomic instability. When the DDR is constitutionally altered, every cell of the organism, starting from development, will show DNA damage and subsequent genomic instability. The cellular response to this is either uncontrolled proliferation and cell cycle deregulation that ensues overgrowth, or apoptosis and senescence that result in tissue hypoplasia. These diverging growth abnormalities can clinically translate as cancer or growth retardation; both features can be found in chromosome instability syndromes (CIS). The analysis of the clinical, cellular, and molecular phenotypes of CIS with intrauterine growth retardation allows inferring that replication alteration is their unifying feature. PMID- 29238725 TI - The Accuracy of New and Aged Mechanical Torque Devices Employed in Five Dental Implant Systems. AB - Purpose: Friction-style and spring-style torque wrenches are used to tighten implant abutments and prosthetic screws. The mechanical stability of these torque wrenches is crucial for the implant-abutment connection. The purposes of this study were to assess the performance of five brands (Straumann, Zimmer, Implant KA, Bredent, and Biohorizons) of wrench and to evaluate possible changes in applied torque values of aged wrenches. Materials and Methods: Five new and aged wrenches that had been used approximately 250 times in a 1-year period were tested. The torque applied by friction- and spring-style wrenches was measured with a specially designed strain gauge indicator. Descriptive statistics, the one sample t-test, and the independent-samples t-test were used to analyze values obtained from all torque wrenches. Results: The accuracy of new and aged torque devices of all brands except Bredent differed significantly from the target values, but the mean values for aged and new wrenches did not differ significantly from each other (p > 0.05). Values for the spring- and friction type torque wrenches deviated from the target values by 11.6% and 10.2%, respectively. Conclusion: The accuracy of aged torque wrenches is adequate for prosthetic screw tightening, but that of new torque wrenches is unsatisfactory and must be examined carefully before delivery. PMID- 29238726 TI - Downregulation of Profilin-1 Expression Attenuates Cardiomyocytes Hypertrophy and Apoptosis Induced by Advanced Glycation End Products in H9c2 Cells. AB - Cardiomyocytes hypertrophy and apoptosis induced by advanced glycation end products (AGEs) is the crucial pathological foundation contributing to the onset and development of diabetic cardiomyopathy (DCM). However, the mechanism remains poorly understood. Here, we report that profilin-1 (PFN-1), a well-known actin binding protein, serves as a potent regulator in AGEs-induced cardiomyocytes hypertrophy and apoptosis. PFN-1 was upregulated in AGEs-treated H9c2 cells, which was associated with increased cardiomyocytes hypertrophy and apoptosis. Silencing PFN-1 expression remarkably attenuated AGEs-induced H9c2 cell hypertrophy and apoptosis. Mechanistically, AGEs increased PFN-1 expression through elevating ROS production and RhoA and ROCK2 expression. Consequently, elevated PFN-1 promoted actin cytoskeleton disorganization. When either ROS production/ROCK activation was blocked or cells were treated with Cytochalasin D (actin depolymerizer), H9c2 cells were protected against AGEs-induced cardiac myocyte abnormalities, concomitantly with downregulated expression of PFN-1 and improved actin cytoskeleton alteration. Collectively, these data suggest that PFN 1 may play an important role in AGEs-induced hypertrophy and apoptosis in H9c2 cells. PMID- 29238727 TI - Glycyrrhizic Acid Prevents Diabetic Nephropathy by Activating AMPK/SIRT1/PGC 1alpha Signaling in db/db Mice. AB - Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD). Glycyrrhizic acid (GA) is an effective inhibitor of reactive oxygen species (ROS) production. We investigated the role of GA in the progression of renal injury in DN. Albumin (Alb)/creatinine (crea) levels were significantly lower, and renal histopathology was attenuated in the diabetic db/db mice that were treated with GA (15 mg/kg via intraperitoneal injection) once per day for eight weeks. These changes were associated with significantly lower levels of alpha-smooth muscle actin (alpha-SMA) and transforming growth factor beta1 (TGF-beta1) expression. Additionally, diabetic db/db mice displayed more terminal deoxynucleotidyl transferase-mediated nick-end labeling- (TUNEL-) positive nuclei and diabetes induced ROS production in the kidneys, and these effects were attenuated by the treatment with GA, which activated adenosine monophosphate-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1)/peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha) signaling in the kidneys. In summary, in diabetic db/db mice, the effect of GA on DN involved, in part, the inhibition of ROS and the activation of AMPK/SIRT1/PGC-1alpha signaling in the kidneys. GA, therefore, shows therapeutic potential for preventing and treating DN. PMID- 29238728 TI - Retinal Photoreceptors and Microvascular Changes in Prediabetes Measured with Adaptive Optics (rtx1TM): A Case-Control Study. AB - Background: Patients with prediabetes are at risk for diabetes, cardiovascular events, and microvascular complications. The rtx1 (Imagine Eyes, France) permits early detection of changes in the retinal photoreceptors and vessels. Objective: Cone parameters and retinal microvasculature were analyzed with the rtx1 in 12 prediabetic patients and 22 healthy subjects. The analysis was based on cone density (DM), interphotoreceptor distance (SM), cone packing regularity, and retinal vessel parameters: wall thickness, lumen diameter (LD), wall-to-lumen ratio (WLR), and cross-sectional area of the vascular wall. Results: DM in the prediabetic group was not significantly lower than that in the control group (18,935 +/- 1713 cells/mm2 and 19,900 +/- 2375 cells/mm2, respectively; p = 0.0928). The LD and WLR means differed significantly between the prediabetic and the control groups (LD 94.3 +/- 10.9 versus 101.2 +/- 15, p = 0.022; WLR 0.29 +/- 0.05 versus 0.22 +/- 0.03, p < 0.05). A multivariate regression analysis showed that the WLR was significantly correlated with BMI and total cholesterol. Conclusions: Abnormalities found in rtx1 examinations indicated early signs of arteriolar dysfunction, prior to impaired glucose tolerance progressing to diabetes. The rtx1 retinal image analysis offers noninvasive measurement of early changes in the vasculature that routine clinical examination cannot detect. PMID- 29238729 TI - The Underlying Mechanisms of Diabetic Myopathy. PMID- 29238730 TI - Interaction of Pubertal Development and Metabolic Control in Adolescents with Type 1 Diabetes Mellitus. AB - Background: In T1DM, delayed pubertal development and reduced final height are associated with inadequate metabolic control. Objective: To assess whether T1DM affects pubertal growth spurt and whether metabolic control during puberty is gender-related. Methods: Using a large multicentre database, longitudinal data from 1294 patients were analysed. Inclusion criteria: complete records of height and HbA1c from the age of seven to 16 years. Exclusion criteria: other significant chronic diseases and medications, T1DM duration less than three months, and initial BMI < 3rd or >97th percentile. Results: Growth velocity (GV) was impaired with a significant reduction of peak GV by 1.2 cm in boys. HbA1c increase during male puberty was lower except for a period of 1.5 years. The highest HbA1c increase in boys coincided with maximum growth spurt. In girls, the highest HbA1c increase was observed during late puberty. Even though there is impaired GV, both sexes reach a height at 16 years of age which corresponds to the background population height. Conclusion: Worsening of metabolic control is sex-discordant and associated with gender-specific alterations of GV. However, the vast majority of boys and girls with T1DM seems to reach normal height at the age of 16 years. PMID- 29238732 TI - Neutrophils: Their Role in Innate and Adaptive Immunity 2017. PMID- 29238733 TI - The Impact of Body Checking on Youth Ice Hockey Injuries. AB - Background: Body checking is a common cause of youth ice hockey injuries. Consequently, USA Hockey raised the minimum age at which body checking is permitted from the Pee Wee level (11-12 years old) to the Bantam level (13-14 years old) in 2011. Purpose/Hypothesis: The purpose of this investigation was to determine the impact of body checking on the distribution of injuries reported in youth ice hockey players. We hypothesized that the elimination of body checking at the Pee Wee level would lower the frequency of serious injuries, particularly concussions. Study Design: Descriptive epidemiology study. Methods: Injury data from the National Electronic Injury Surveillance System (NEISS), a United States Consumer Product Safety Commission database, were analyzed for Pee Wee and Bantam players between January 1, 2008 and December 31, 2010 and again between January 1, 2013 and December 31, 2015. Data on the location of injury, diagnosis, and mechanism of injury were collected. The location of injury was categorized into 4 groups: head and neck, upper extremity, lower extremity, and core. Diagnoses investigated included concussions, fractures, lacerations, strains or sprains, internal organ injuries, and other. The mechanism of injury was broken down into 2 categories: checking and other. Results: Between the 2008-2010 and 2013-2015 seasons, overall injuries decreased by 16.6% among Pee Wee players, with injuries caused by body checking decreasing by 38.2% (P = .012). There was a significant change in the distribution of diagnoses in the Pee Wee age group during this time frame (P = .007): strains or sprains, internal organ injuries, and fractures decreased in frequency, while the number of concussions increased by 50.0%. In the Bantam age group, recorded injuries decreased by 6.8%, and there was no change in the distribution of the location of injury, diagnosis, or mechanism of injury (P > .05). Conclusion: There was an observed reduction in the total number, mechanism, and type of injuries when body checking was eliminated from the Pee Wee level. There was, however, an unexpected increase in the number of concussions. PMID- 29238731 TI - Porcine to Human Heart Transplantation: Is Clinical Application Now Appropriate? AB - Cardiac xenotransplantation (CXTx) is a promising solution to the chronic shortage of donor hearts. Recent advancements in immune suppression have greatly improved the survival of heterotopic CXTx, now extended beyond 2 years, and life supporting kidney XTx. Advances in donor genetic modification (B4GALNT2 and CMAH mutations) with proven Gal-deficient donors expressing human complement regulatory protein(s) have also accelerated, reducing donor pig organ antigenicity. These advances can now be combined and tested in life-supporting orthotopic preclinical studies in nonhuman primates and immunologically appropriate models confirming their efficacy and safety for a clinical CXTx program. Preclinical studies should also allow for organ rejection to develop xenospecific assays and therapies to reverse rejection. The complexity of future clinical CXTx presents a substantial and unique set of regulatory challenges which must be addressed to avoid delay; however, dependent on these prospective life-supporting preclinical studies in NHPs, it appears that the scientific path forward is well defined and the era of clinical CXTx is approaching. PMID- 29238734 TI - Platelet-Rich Plasma Injection With Percutaneous Needling for Recalcitrant Lateral Epicondylitis: Comparison of Tenotomy and Fenestration Techniques. AB - Background: Recalcitrant lateral epicondylitis (LE) is a common debilitating condition, with numerous treatment options of varying success. An injection of platelet-rich plasma (PRP) has been shown to improve LE, although it is unclear whether the method of needling used in conjunction with a PRP injection is of clinical importance. Purpose: To determine whether percutaneous needle tenotomy is superior to percutaneous needle fenestration when each is combined with a PRP injection for the treatment of recalcitrant LE. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 93 patients with recalcitrant LE were treated with a PRP injection and percutaneous needle fenestration (n = 45) or percutaneous needle tenotomy (n = 48) over a 5-year study interval. Preoperative patient data, including visual analog scale for pain (VAS-P), Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH), and Patient-Rated Tennis Elbow Evaluation (PRTEE) scores and grip strength, were obtained from a chart review and compared with postoperative values obtained prospectively. Secondary outcomes included the incidence of complications, need for additional interventions, return to work, and patient satisfaction. Results: At a mean follow-up of 40 months, significant improvements in VAS-P (mean, -6.1; 95% CI, -6.8 to -5.5; P < .0001), QuickDASH (mean, -46; 95% CI, -52 to -40; P < .0001), and PRTEE (mean, 57; 95% CI, -64 to -50; P < .0001) scores and grip strength (mean, +6.1 kg; 95% CI, 4.9 to 7.3; P < .0001) were observed across the entire study cohort, with no significant differences noted between the fenestration and tenotomy groups. Nine of 45 patients (22%) underwent additional procedures to treat recurrent symptoms in the fenestration group compared with 5 of 48 patients (10%) in the tenotomy group (P = .05). No complications occurred in any patients, and no patients expressed dissatisfaction with their treatment course. Conclusion: A PRP injection with concomitant percutaneous needling is an effective treatment for recalcitrant LE, with sustained improvements in pain, strength, and function demonstrated at a mean follow-up of longer than 3 years. Although the method of concomitant needling does not appear to have a significant effect on treatment outcomes, more aggressive needle tenotomy is less likely to require conversion to open tenotomy than needle fenestration in the short term to midterm. PMID- 29238736 TI - Combination of Fluorescent in situ Hybridization (FISH) and Immunofluorescence Imaging for Detection of Cytokine Expression in Microglia/Macrophage Cells. AB - Microglia and macrophage cells are the primary producers of cytokines in response to neuroinflammatory processes. But these cytokines are also produced by other glial cells, endothelial cells, and neurons. It is essential to identify the cells that produce these cytokines to target their different levels of activation. We used dual RNAscope(r) fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) techniques to visualize the mRNA expression pattern of pro- and anti-inflammatory cytokines in microglia/macrophages cells. Using these methods, we can associate one mRNA to specific cell types when combining with different cellular markers by immunofluorescence. Results from RNAscope(r) probes IL-1beta, TNFalpha, TGFbeta, IL-10 or Arg1, showed colocalization with antibodies for microglia/macrophage cells. These target probes showed adequate sensitivity and specificity to detect mRNA expression. New FISH detection techniques combined with immunohistochemical techniques will help to jointly determine the protein and mRNA localization, as well as provide reliable quantification of the mRNA expression levels. PMID- 29238735 TI - Post-keratoplasty astigmatism management by relaxing incisions: a systematic review. AB - Postoperative visual acuity can be limited by post-keratoplasty astigmatism, even with a clear corneal graft. Astigmatism management can be performed by selective suture removal, adjustment of sutures, optical correction, photorefractive procedures, wedge resection, intra-ocular lens implantation, intracorneal ring segments, relaxing incisions with or without compression sutures and repeated keratoplasty. Relaxing incisions can be made in the graft, graft-host interface or host cornea. Despite the unpredictability of the method because the flat and steep meridians are usually not orthogonal after penetrating keratoplasty, with asymmetric power distribution, all the studies showed an overall reduction of refractive, keratometric or topographic astigmatism, ranging from 30% to 72% with manual or femtosecond-assisted techniques. Most patients with astigmatism higher than 6 diopters had residual cylinder less than or equal to 3 diopters, which can be treated by laser excimer ablation or secondary intraocular lens implantation. PMID- 29238737 TI - Transitions From Pediatric to Adult Care. PMID- 29238738 TI - Sociodemographic Characteristics, Health Literacy, and Care Compliance in Families With Spina Bifida. AB - Children with spina bifida experience varying rates of disease complications and health system overutilization. Data on sociodemographics, urinary tract infection, clean intermittent catheterization, and health system utilization were collected from caregiver-patient dyads. Newest Vital Sign (NVS) and Brief Health Literacy Screen (BRIEF) were administered to evaluate health literacy (HL). In total, 105 dyads completed enrolment with 24.8% versus 12.4% of caregivers scoring poor/marginal on the NVS and BRIEF, respectively. Nearly half on clean intermittent catheterization missed a catheterization over the previous week. Medicaid insurance, parental education, and household income predicted HL (P < .01). Over the preceding 5 years, 68.5% visited our hospital's emergency department. Eighteen (25%) visited the emergency department >6 times and 12 incurred charges over $50 000. Caregivers of children who missed >=4 catheterizations per week had lower NVS scores (P = .03). Children with spina bifida represent high utilizers, and consideration of sociodemographic and HL differences is necessary when tailoring care plans. PMID- 29238739 TI - Mild Chest Pain After Gymnastic Backflip in a 14-Year-Old Boy. PMID- 29238740 TI - Differential effects of negative emotion on memory for items and associations, and their relationship to intrusive imagery. AB - A crucial aspect of episodic memory formation is the way in which our experiences are stored within a coherent spatio-temporal context. We review research that highlights how the experience of a negative event can alter memory encoding in a complex manner, strengthening negative items but weakening associations with other items and the surrounding context. Recent evidence suggests that these opposing effects can occur through amygdala up-modulation to facilitate item encoding, while the hippocampal provision of contextual binding is down modulated. We consider how these characteristics of memory for negative events might contribute to the development and maintenance of distressing intrusive imagery in posttraumatic stress disorder, and how they should influence therapeutic interventions. PMID- 29238741 TI - Chemistry, properties, and applications of fluorographene. AB - Fluorographene, formally a two-dimensional stoichiometric graphene derivative, attracted remarkable attention of the scientific community due to its extraordinary physical and chemical properties. We overview the strategies for the preparation of fluorinated graphene derivatives, based on top-down and bottom up approaches. The physical and chemical properties of fluorographene, which is considered as one of the thinnest insulators with a wide electronic band gap, are presented. Special attention is paid to the rapidly developing chemistry of fluorographene, which was advanced in the last few years. The unusually high reactivity of fluorographene, which can be chemically considered perfluorinated hydrocarbon, enables facile and scalable access to a wide portfolio of graphene derivatives, such as graphene acid, cyanographene and allyl-graphene. Finally, we summarize the so far reported applications of fluorographene and fluorinated graphenes, spanning from sensing and bioimaging to separation, electronics and energy technologies. PMID- 29238742 TI - Class C G protein-coupled receptors: reviving old couples with new partners. AB - G protein-coupled receptors (GPCRs) are key players in cell communication and are encoded by the largest family in our genome. As such, GPCRs represent the main targets in drug development programs. Sequence analysis revealed several classes of GPCRs: the class A rhodopsin-like receptors represent the majority, the class B includes the secretin-like and adhesion GPCRs, the class F includes the frizzled receptors, and the class C includes receptors for the main neurotransmitters, glutamate and GABA, and those for sweet and umami taste and calcium receptors. Class C receptors are far more complex than other GPCRs, being mandatory dimers, with each subunit being composed of several domains. In this review, we summarize our actual knowledge regarding the activation mechanism and subunit organization of class C GPCRs, and how this brings information for many other GPCRs. PMID- 29238744 TI - Energy coupling mechanisms of AcrB-like RND transporters. AB - Prokaryotic AcrB-like proteins belong to a family of transporters of the RND superfamily, and as main contributing factor to multidrug resistance pose a tremendous threat to future human health. A unique feature of AcrB transporters is the presence of two separate domains responsible for carrying substrate and generating energy. Significant progress has been made in elucidating the three dimensional structures of the homo-trimer complexes of AcrB-like transporters, and a three-step functional rotation was identified for this class of transporters. However, the detailed mechanisms for the transduction of the substrate binding signal, as well as the energy coupling processes between the functionally distinct domains remain to be established. Here, we propose a model for the interdomain communication in AcrB that explains how the substrate binding signal from the substrate-carrier domain triggers protonation in the transmembrane domain. Our model further provides a plausible mechanism that explains how protonation induces conformational changes in the substrate-carrier domain. We summarize the thermodynamic principles that govern the functional cycle of the AcrB trimer complex. PMID- 29238743 TI - Choosing proper fluorescent dyes, proteins, and imaging techniques to study mitochondrial dynamics in mammalian cells. AB - Mitochondrial dynamics refers to the processes maintaining mitochondrial homeostasis, including mitochondrial fission, fusion, transport, biogenesis, and mitophagy. Mitochondrial dynamics is essential for maintaining the metabolic function of mitochondria as well as their regulatory roles in cell signaling. In this review, we summarize the recently developed imaging techniques for studying mitochondrial dynamics including: mitochondrial-targeted fluorescent proteins and dyes, live-cell imaging using photoactivation, photoswitching and cell fusion, mitochondrial transcription and replication imaging by in situ hybridization, and imaging mitochondrial dynamics by super-resolution microscopy. Moreover, we discuss examples of how to choose and combine proper fluorescent dyes and/or proteins. PMID- 29238745 TI - Dye-based mito-thermometry and its application in thermogenesis of brown adipocytes. AB - : Mitochondrion is the main intracellular site for thermogenesis and attractive energy expenditure targeting for obesity therapy. Here, we develop a method of mitochondrial thermometry based on Rhodamine B methyl ester, which equilibrates as a thermosensitive mixture of nonfluorescent and fluorescent resonance forms. Using this approach, we are able to demonstrate that the efficacy of norepinephrine-induced thermogenesis is low, and measure the maximum transient rate of temperature increase in brown adipocytes. Electronic Supplementary Material: The online version of this article (doi:10.1007/s41048-017-0039-6) contains supplementary material, which is available to authorized users. PMID- 29238746 TI - Determining the target protein localization in 3D using the combination of FIB SEM and APEX2. AB - Determining the cellular localization of proteins of interest at nanometer resolution is necessary for elucidating their functions. Besides super-resolution fluorescence microscopy, conventional electron microscopy (EM) combined with immunolabeling or clonable EM tags provides a unique approach to correlate protein localization information and cellular ultrastructural information. However, there are still rare cases of such correlation in three-dimensional (3D) spaces. Here, we developed an approach by combining the focus ion beam scanning electron microscopy (FIB-SEM) and a promising clonable EM tag APEX2 (an enhanced ascorbate peroxidase 2) to determine the target protein localization within 3D cellular ultrastructural context. We further utilized this approach to study the 3D localization of mitochondrial dynamics-related proteins (MiD49/51, Mff, Fis1, and Mfn2) in the cells where the target proteins were overexpressed. We found that all the target proteins were located at the surface of the mitochondrial outer membrane accompanying with mitochondrial clusters. Mid49/51, Mff, and hFis1 spread widely around the mitochondrial surface while Mfn2 only exists at the contact sites. PMID- 29238747 TI - Protocol for analyzing protein ensemble structures from chemical cross-links using DynaXL. AB - Chemical cross-linking coupled with mass spectroscopy (CXMS) is a powerful technique for investigating protein structures. CXMS has been mostly used to characterize the predominant structure for a protein, whereas cross-links incompatible with a unique structure of a protein or a protein complex are often discarded. We have recently shown that the so-called over-length cross-links actually contain protein dynamics information. We have thus established a method called DynaXL, which allow us to extract the information from the over-length cross-links and to visualize protein ensemble structures. In this protocol, we present the detailed procedure for using DynaXL, which comprises five steps. They are identification of highly confident cross-links, delineation of protein domains/subunits, ensemble rigid-body refinement, and final validation/assessment. The DynaXL method is generally applicable for analyzing the ensemble structures of multi-domain proteins and protein-protein complexes, and is freely available at www.tanglab.org/resources. PMID- 29238748 TI - Non motor symptoms in progressive supranuclear palsy: prevalence and severity. AB - NMSs have been extensively studied in PD patients but not in other forms of parkinsonism such as Progressive Supranuclear Palsy (PSP). The primary objective of this study was to analyze the frequency, severity and the type of non-motor symptoms (NMS) in PSP patients using the non-motor symptoms scale (NMSS). The secondary objective was to differentiate NMS between PSP and Parkinson's disease (PD). We enrolled in this cross-sectional study 50 consecutive PSP and 100 matched Parkinson's disease (PD) patients, in the proportion PSP/PD = 1/2, matched in age, sex, and disease duration. Motor and Non Motor symptoms (different scales for each disease) were evaluated at baseline using PSP scale, SCOPA Motor, Montreal Cognitive Assessment (MOCA), HADS, Hamilton, and Non Motor Symptom scale (NMSS). Comparative analysis was done using chi-squared test, Mann Whitney test and Fisher's exact test. Fifty PSP (56% female) and 100 PD (59% female) patients completed the study protocol and were included for statistical analysis. The NMSS total domains score in the PSP group was 77.58 +/- 42.95 (range 14-163) with NMS burden grade: 4, very severe, and the in the PD group was 41.97 +/- 35.45 (range: 0-215) with NMS burden grade: 3, severe. The comparative analysis showed that NMS total score (p < 0.0001), Sleep/Fatigue (p = 0.0007), Mood/Apathy (p = 0.0001), Gastrointestinal (p < 0.0001), and Urinary dysfunction (p = 0.0001) domains were significantly more severe in PSP patients than in PD. This observational study reports that NMSs are very frequent in PSP patients hence the higher burden of NMS in PSP specifically related to mood/apathy, attention/memory, gastrointestinal, urinary disturbances compared to PD. PMID- 29238749 TI - A feasibility study of neoadjuvant talazoparib for operable breast cancer patients with a germline BRCA mutation demonstrates marked activity. AB - This study was undertaken to determine the feasibility of enrolling breast cancer patients on a single-agent-targeted therapy trial before neoadjuvant chemotherapy. Specifically, we evaluated talazoparib in patients harboring a deleterious BRCA mutation (BRCA+). Patients with a germline BRCA mutation and >=1 cm, HER2-negative primary tumors were eligible. Study participants underwent a pretreatment biopsy, 2 months of talazoparib, off-study core biopsy, anthracycline, and taxane-based chemotherapy +/- carboplatin, followed by surgery. Volumetric changes in tumor size were determined by ultrasound at 1 and 2 months of therapy. Success was defined as 20 patients accrued within 2 years and <33% experienced a grade 4 toxicity. The study was stopped early after 13 patients (BRCA1 + n = 10; BRCA2 + n = 3) were accrued within 8 months with no grade 4 toxicities and only one patient requiring dose reduction due to grade 3 neutropenia. The median age was 40 years (range 25-55) and clinical stage included I (n = 2), II (n = 9), and III (n = 2). Most tumors (n = 9) were hormone receptor-negative, and one of these was metaplastic. Decreases in tumor volume occurred in all patients following 2 months of talazoparib; the median was 88% (range 30-98%). Common toxicities were neutropenia, anemia, thrombocytopenia, nausea, dizziness, and fatigue. Single-agent-targeted therapy trials are feasible in BRCA+ patients. Given the rapid rate of accrual, profound response and favorable toxicity profile, the feasibility study was modified into a phase II study to determine pathologic complete response rates after 4-6 months of single agent talazoparib. PMID- 29238750 TI - Biomarkers of aging associated with past treatments in breast cancer survivors. AB - Radiation and chemotherapy are effective treatments for cancer, but are also toxic to healthy cells. Little is known about whether prior exposure to these treatments is related to markers of cellular aging years later in breast cancer survivors. We examined whether past exposure to chemotherapy and/or radiation treatment was associated with DNA damage, telomerase activity, and telomere length 3-6 years after completion of primary treatments in breast cancer survivors (stage 0-IIIA breast cancer at diagnosis). We also examined the relationship of these cellular aging markers with plasma levels of Interleukin (IL)-6, soluble TNF-receptor-II (sTNF-RII), and C-reactive protein (CRP). Ninety four women (36.4-69.5 years; 80% white) were evaluated. Analyses adjusting for age, race, BMI, and years from last treatment found that women who had prior exposure to chemotherapy and/or radiation compared to women who had previously received surgery alone were more likely to have higher levels of DNA damage (P = .02) and lower telomerase activity (P = .02), but did not have differences in telomere length. More DNA damage and lower telomerase were each associated with higher levels of sTNF-RII (P's < .05). We found that exposure to chemotherapy and/or radiation 3-6 years prior was associated with markers of cellular aging, including higher DNA damage and lower telomerase activity, in post-treatment breast cancer survivors. Furthermore, these measures were associated with elevated inflammatory activation, as indexed by sTNF-RII. Given that these differences were observed many years after the treatment, the findings suggest a long lasting effect of chemotherapy and/or radiation exposure. PMID- 29238751 TI - Tree Leaf Bacterial Community Structure and Diversity Differ along a Gradient of Urban Intensity. AB - Tree leaf-associated microbiota have been studied in natural ecosystems but less so in urban settings, where anthropogenic pressures on trees could impact microbial communities and modify their interaction with their hosts. Additionally, trees act as vectors spreading bacterial cells in the air in urban environments due to the density of microbial cells on aerial plant surfaces. Characterizing tree leaf bacterial communities along an urban gradient is thus key to understand the impact of anthropogenic pressures on urban tree-bacterium interactions and on the overall urban microbiome. In this study, we aimed (i) to characterize phyllosphere bacterial communities of seven tree species in urban environments and (ii) to describe the changes in tree phyllosphere bacterial community structure and diversity along a gradient of increasing urban intensity and at two degrees of tree isolation. Our results indicate that, as anthropogenic pressures increase, urban leaf bacterial communities show a reduction in the abundance of the dominant class in the natural plant microbiome, the Alphaproteobacteria. Our work in the urban environment here reveals that the structures of leaf bacterial communities differ along the gradient of urban intensity. The diversity of phyllosphere microbial communities increases at higher urban intensity, also displaying a greater number and variety of associated indicator taxa than the low and medium urban gradient sites. In conclusion, we find that urban environments influence tree bacterial community composition, and our results suggest that feedback between human activity and plant microbiomes could shape urban microbiomes. IMPORTANCE In natural forests, tree leaf surfaces host diverse bacterial communities whose structure and composition are primarily driven by host species identity. Tree leaf bacterial diversity has also been shown to influence tree community productivity, a key function of terrestrial ecosystems. However, most urban microbiome studies have focused on the built environment, improving our understanding of indoor microbial communities but leaving much to be understood, especially in the nonbuilt microbiome. Here, we provide the first multiple-species comparison of tree phyllosphere bacterial structures and diversity along a gradient of urban intensity. We demonstrate that urban trees possess characteristic bacterial communities that differ from those seen with trees in nonurban environments, with microbial community structure on trees influenced by host species identity but also by the gradient of urban intensity and by the degree of isolation from other trees. Our results suggest that feedback between human activity and plant microbiomes could shape urban microbiomes. PMID- 29238752 TI - Colonic Butyrate-Producing Communities in Humans: an Overview Using Omics Data. AB - Given the key role of butyrate for host health, understanding the ecology of intestinal butyrate-producing communities is a top priority for gut microbiota research. To this end, we performed a pooled analysis on 2,387 metagenomic/transcriptomic samples from 15 publicly available data sets that originated from three continents and encompassed eight diseases as well as specific interventions. For analyses, a gene catalogue was constructed from gene targeted assemblies of all genes from butyrate synthesis pathways of all samples and from an updated reference database derived from genome screenings. We demonstrate that butyrate producers establish themselves within the first year of life and display high abundances (>20% of total bacterial community) in adults regardless of origin. Various bacteria form this functional group, exhibiting a biochemical diversity including different pathways and terminal enzymes, where one carbohydrate-fueled pathway was dominant with butyryl coenzyme A (CoA):acetate CoA transferase as the main terminal enzyme. Subjects displayed a high richness of butyrate producers, and 17 taxa, primarily members of the Lachnospiraceae and Ruminococcaceae along with some Bacteroidetes, were detected in >70% of individuals, encompassing ~85% of the total butyrate-producing potential. Most of these key taxa were also found to express genes for butyrate formation, indicating that butyrate producers occupy various niches in the gut ecosystem, concurrently synthesizing that compound. Furthermore, results from longitudinal analyses propose that diversity supports functional stability during ordinary life disturbances and during interventions such as antibiotic treatment. A reduction of the butyrate-producing potential along with community alterations was detected in various diseases, where patients suffering from cardiometabolic disorders were particularly affected. IMPORTANCE Studies focusing on taxonomic compositions of the gut microbiota are plentiful, whereas its functional capabilities are still poorly understood. Specific key functions deserve detailed investigations, as they regulate microbiota-host interactions and promote host health and disease. The production of butyrate is among the top targets since depletion of this microbe-derived metabolite is linked to several emerging noncommunicable diseases and was shown to facilitate establishment of enteric pathogens by disrupting colonization resistance. In this study, we established a workflow to investigate in detail the composition of the polyphyletic butyrate producing community from omics data extracting its biochemical and taxonomic diversity. By combining information from various publicly available data sets, we identified universal ecological key features of this functional group and shed light on its role in health and disease. Our results will assist the development of precision medicine to combat functional dysbiosis. PMID- 29238753 TI - On the Power of Uncertainties in Microbial System Modeling: No Need To Hide Them Anymore. AB - For decades, microbiologists have considered uncertainties as an undesired side effect of experimental protocols. As a consequence, standard microbial system modeling strives to hide uncertainties for the sake of deterministic understanding. However, recent studies have highlighted greater experimental variability than expected and emphasized uncertainties not as a weakness but as a necessary feature of complex microbial systems. We therefore advocate that biological uncertainties need to be considered foundational facets that must be incorporated in models. Not only will understanding these uncertainties improve our understanding and identification of microbial traits, it will also provide fundamental insights on microbial systems as a whole. Taking into account uncertainties within microbial models calls for new validation techniques. Formal verification already overcomes this shortcoming by proposing modeling frameworks and validation techniques dedicated to probabilistic models. However, further work remains to extract the full potential of such techniques in the context of microbial models. Herein, we demonstrate how statistical model checking can enhance the development of microbial models by building confidence in the estimation of critical parameters and through improved sensitivity analyses. PMID- 29238754 TI - Do the SRS-22 self-image and mental health domain scores reflect the degree of asymmetry of the back in adolescent idiopathic scoliosis? AB - Background: Patient-reported outcomes are becoming increasingly recognised in the management of patients with adolescent idiopathic scoliosis (AIS). Integrated Shape Imaging System 2 (ISIS2) surface topography is a validated tool to assess AIS. Previous studies have failed to demonstrate strong correlations between AIS and patient-reported outcomes highlighting the need for additional objective surface parameters to define the deformities associated with AIS. The aim of this study was to examine whether the Scoliosis Research Society-22 (SRS-22) outcome questionnaire reflects the degree of measurable external asymmetry of the back in AIS and thus is a measure of patient outcome for external appearance. Methods: A total of 102 pre-operative AIS patients were identified retrospectively. Objective parameters were measured using ISIS2 surface topography. The associations between these parameters and the self-image and mental health domains of the SRS-22 questionnaire were investigated using correlation coefficients. Results: All correlations between the parameters of asymmetry and SRS-22 self-image score were of weak strength. Similarly, all correlations between the parameters of asymmetry and SRS-22 mental health score were of weak strength. Conclusion: The SRS-22 mental health and self-image domains correlate poorly with external measures of deformity. This demonstrates that the assessment of mental health and self-image by the SRS-22 has little to do with external torso shape. Whilst the SRS-22 assesses the patient as a whole, it provides little information about objective measures of deformity over which a surgeon has control. PMID- 29238755 TI - Spatiotemporal Progression of Early Human Ventricular Fibrillation. AB - Objectives: The objective of this study was to evaluate the spatio-temporal organization and progression of human ventricular fibrillation (VF) in the left (LV) and right (RV) ventricles. Background: Studies suggest that localized sources contribute to VF maintenance, but the evolution of VF episodes has not been quantified. Methods: Synchrony between electrograms recorded from 25 patients with induced VF is computed and used to define the Asynchronous Index (ASI), indicating regions which are out-of-step with surrounding tissue. Computer simulations show that ASI can identify the location of VF-maintaining sources, where larger values of ASImax correlate with more stable sources. Results: Automated synchrony analysis shows elevated values of ASI in a majority of self terminating episodes (LV: 8/9, RV: 7/8) and sustained episodes (LV: 11/11, RV: 12/12). The locations of ASImax in sustained episodes co-localize with rotor cores when rotational activity is simultaneously present in phase maps (LV: 8/8, RV: 5/7, p<.05). The distribution of ASImax differentiates self-terminating from sustained episodes (mean ASImax = 0.60+/-0.14 and 0.70+/-0.16, respectively; p=0.01). Across sustained episodes the LV exhibits an increase in ASImax with time. Conclusions: Quantitative analysis identifies localized asynchronous regions that correlate with sources in VF, with sustained episodes evolving to exhibit more stable activation in the LV. This successive increase in stability indicates a stabilizing agent may be responsible for perpetuating fibrillation in a "migrate-and-capture" mechanism in the LV. PMID- 29238756 TI - Outcomes of internal hemipelvectomy for pelvic tumors: a developing country's prospective. AB - Introduction: Previously, external hemipelvectomy was the mainstay of treatment for pelvic tumors. However, with technological advancements, limb salvage procedures such as internal hemipelvectomy have emerged as a viable alternative. However, there is limited literature available on long-term outcomes and complications of internal hemipelvectomy, especially from developing countries. Therefore, the objective of this study was to share our experience of internal hemipelvectomy at a tertiary care center in a developing country. Materials and methods: A retrospective review was conducted in which all 24 patients undergoing internal hemipelvectomy from January 1, 2005 to December 31, 2015 at our institution were included. Medical record files were reviewed for intraoperative and early and late postoperative complications, and functional outcomes were assessed by contacting each patient on telephone. Results: Ewing sarcoma was found to be the most common diagnosis, followed by osteosarcoma as the second most common. The mean follow-up period was 18.7+/-13.9 months. Intraoperatively there were 4 cases of iatrogenic neurovascular injury and 2 cases each of urinary tract injury and dural tear. Four patients developed early wound infections, 7 developed late wound infections, and 2 developed flap necrosis. Three patients developed recurrence, whereas 7 patients developed metastasis postoperatively. The mean survival was calculated to be 28 months and the mean Musculoskeletal Tumor Society score was 19.3+/-5.2. Conclusions: Outcomes and prevalence of complications shown in this study are comparable to those in the international literature, which suggests that hemipelvectomy is a viable option in developing countries also. However, more such studies are warranted to validate the findings and to identify the challenges and morbidities associated with hemipelvectomy in Asian and developing countries. PMID- 29238757 TI - How to apply to a summer undergraduate research program. AB - Want to get more experience in research, but find it difficult as an undergraduate? A summer research project may be the answer and there are many ways to organize this. Various universities around the world offer summer undergraduate research programs. These tend to be very competitive; hundreds, even thousands of students can apply for only a handful of positions. However, with some proactivity and strong planning, diligent undergraduate students can get accepted onto these prestigious programs. In this article, we outline the steps involved in selecting and successfully applying to a summer undergraduate research program. PMID- 29238758 TI - Self Super-resolution for Magnetic Resonance Images. AB - It is faster and therefore cheaper to acquire magnetic resonance images (MRI) with higher in-plane resolution than through-plane resolution. The low resolution of such acquisitions can be increased using post-processing techniques referred to as super-resolution (SR) algorithms. SR is known to be an ill-posed problem. Most state-of-the-art SR algorithms rely on the presence of external/training data to learn a transform that converts low resolution input to a higher resolution output. In this paper an SR approach is presented that is not dependent on any external training data and is only reliant on the acquired image. Patches extracted from the acquired image are used to estimate a set of new images, where each image has increased resolution along a particular direction. The final SR image is estimated by combining images in this set via the technique of Fourier Burst Accumulation. Our approach was validated on simulated low resolution MRI images, and showed significant improvement in image quality and segmentation accuracy when compared to competing SR methods. SR of FLuid Attenuated Inversion Recovery (FLAIR) images with lesions is also demonstrated. PMID- 29238761 TI - Dupilumab: human monoclonal antibody against IL-4Ralpha for moderate to severe atopic dermatitis. AB - Atopic dermatitis (AD) is one of the most common skin disorders with a prevalence of about 20% in children and affecting adults in significant numbers. Moderate to severe AD significantly impairs a patient's quality of life with severe pruritus as a major issue that impairs sleep and contributes to major psychological disturbances. Detailed studies of its pathogenesis have revealed that immune mechanisms are involved including activation of T helper type 2 cells (Th2). Dupilumab is a fully human Ig4 monoclonal antibody directed against the interleukin-4 receptor subunit alpha (IL-4Ralpha) of IL-4 and IL-13 receptors. In clinical studies it has been demonstrated to significantly reduce the molecular signature in the skin of patients with AD and to significantly reduce the clinical manifestations of moderate to severe AD. It also very importantly significantly reduces the pruritus of moderate to severe AD thus improving the patients' quality of life. Dupilumab is administered by subcutaneous injection every other week. It was approved by the FDA in March 2017 for the treatment of moderate to severe AD. PMID- 29238764 TI - Effect of topography-dependent light coupling through a near-field aperture on the local photocurrent of a solar cell. AB - An aperture-type scanning near-field optical microscope (a-SNOM) is readily used for the optical and optoelectronic characterizations of a wide variety of chemical, biological and optoelectronic samples with sub-wavelength optical resolution. These samples mostly exhibit nanoscale topographic variations, which are related to local material inhomogeneity probed either by an optical contrast or by secondary effects such as photoconductivity or photoluminescence. To date, in the interpretation and evaluation of the measurement results from a-SNOM or derived methods, often only the local material inhomogeneity is taken into account. A possible influence of the optical interaction between the scanning probe and the surface topography is rarely discussed. In this paper, we present experimental and theoretical investigation of the effects of nanoscale topographic features on a-SNOM measurement results. We conduct local photocurrent measurements on a thin-film solar cell with an a-SNOM as the illumination source. A clear correlation between the photocurrent response and local topography is observed in all measurements with a signal contrast of up to ~30%, although the sample features homogeneous permittivity and electrical properties. With the help of finite-difference time-domain (FDTD) simulations, this correlation is reproduced and local light coupling is identified as the mechanism which determines the local photocurrent response. Our results suggest that a-SNOM-based measurements of any sample with material inhomogeneity will be superimposed by the local light-coupling effect if surface topography variation exists. This effect should always be taken into consideration for an accurate interpretation of the measurement results. PMID- 29238762 TI - Etelcalcetide: injectable calcimimetic for the treatment of secondary hyperparathyroidism in hemodialysis-dependent patients. AB - Chronic kidney disease is associated with mineral and bone disorders that are now considered as a syndrome. One of the major complications of this syndrome is secondary hyperparathyroidism (SHPT). SHPT increases bone turnover and the risk of fracture. SHPT is also associated with cardiovascular calcification and high mortality risk. The classical medical therapies of SHPT lack long-term efficacy and have undesirable effects on serum calcium and phosphate levels. Surgical parathyroidectomy is a radical therapeutic solution potentially exposing patients to a permanent state of hypoparathyroidism among other complications. Oral cinacalcet revolutionized the treatment of SHPT because of its great efficacy; however, more than one-third of patients do not respond appropriately to cinacalcet, mostly because of intolerance and lack of compliance. Intravenous etelcalcetide improves medical adherence and reduces pill burden. It is 10-15% superior than cinacalcet in controlling parathyroid hormone, but also leads to more frequent episodes of hypocalcemia. PMID- 29238760 TI - Dinutuximab for the treatment of pediatric patients with neuroblastoma. AB - Dinutuximab is a monoclonal antibody targeted at disialoganglioside (GD2), a tumor-associated antigen widely expressed in human neuroblastoma cells. The incorporation of dinutuximab into standard treatment regimens for patients with high-risk neuroblastoma has changed the landscape of neuroblastoma therapy. Dinutuximab has shown to be effective in prolonging survival for patients receiving standard multimodal treatment regimens and has now become standard of care during the final phase of treatment. More recently, it has also shown promising efficacy and tolerability in patients with relapsed or progressive neuroblastoma. The most effective way of incorporating dinutuximab into treatment protocols is still being explored, and is the focus of numerous ongoing clinical trials. PMID- 29238765 TI - Bacteriorhodopsin based non-magnetic spin filters for biomolecular spintronics. AB - We discuss spin injection and spin valves, which are based on organic and biomolecules, that offer the possibility to overcome some of the limitations of solid-state devices, which are based on ferromagnetic metal electrodes. In particular, we discuss spin filtering through bacteriorhodopsin in a solid state biomolecular spin valve that is based on the chirality induced spin selectivity (CISS) effect and shows a magnetoresistance of ~2% at room temperature. The device is fabricated using a layer of bacteriorhodopsin (treated with n-octyl thioglucoside detergent: OTG-bR) that is adsorbed on a cysteamine functionalized gold electrode and capped with a magnesium oxide layer as a tunneling barrier, upon which a Ni top electrode film is placed and used as a spin analyzer. The bR based spin valves show an antisymmetric magnetoresistance response when a magnetic field is applied along the direction of the current flow, whereas they display a positive symmetric magnetoresistance curve when a magnetic field is applied perpendicular to the current direction. PMID- 29238759 TI - Neuropsychological evidence for the temporal dynamics of category-specific naming. AB - Multiple accounts have been proposed to explain category-specific recognition impairments. Some suggest that category-specific deficits may be caused by a deficit in recurrent processing between the levels of a hierarchically organized visual object recognition system. Here, we tested predictions of interactive processing theories on the emergence of category-selective naming deficits in neurologically intact observers and in patient GA, a single case showing a category-specific impairment for natural objects after a herpes simplex encephalitis infection. Fragmented object outlines were repeatedly presented until correct naming occurred (maximum 10 times), and the fragments increased in length with every repetition. We studied how shape complexity, object category, and fragment curvature influence the timing of correct object identification. The results of a survival analysis are consistent with the idea that deficits in recurrent processing between low- and high-level visual object representations can cause category-selective impairments. PMID- 29238767 TI - Real-time monitoring for reforming processes of liquid hydrocarbon fuel-air pre mixtures by non-thermal plasmas using ion attachment mass spectrometry. AB - Plasma induced reforming processes of fuel-air mixtures were investigated to understand the mechanism of the plasma-assisted combustion technique, which can improve the thermal efficiency and stability of internal combustion engines. In this study, a mixture of air with isooctane or n-heptane fuels was reformed by non-thermal plasma in a flow reactor, generated by a dielectric barrier discharge, and then directly analyzed using ion attachment mass spectrometry. Plasma irradiation of an air/hydrocarbon mixture produced an oxygen atom which then reacted with a hydrocarbon, leading to hydroxyl and alkyl radicals. The alkyl radical was immediately converted to alkyl hydroperoxide, which is suggested to be a long-living intermediate for the fuel reforming process. Finally, ketone and aldehyde were formed through the alkyloxy radical intermediate. The details of each reaction process were investigated by ab initio calculations. The proposed plasma induced fuel reforming processes are strongly supported by the computational results. PMID- 29238763 TI - Modalities to enumerate circulating tumor cells in the bloodstream for cancer prognosis and to monitor the response to the therapy. AB - Certain malignant cells may detach from the primary tumor and enter the vascular system, forming so-called circulating tumor cells (CTCs). Clusters of malignant cells associated with other cell types can also be observed in the peripheral blood of oncological patients. Such cell clusters are termed circulating tumor microemboli (CTM). The isolation and quantification of CTCs and/or CTM from blood samples allow for an accurate prognosis of the clinical course of the disease and to monitor the response to therapy. Current protocols rely on epithelial markers for the isolation of CTCs and/or CTM from hematopoietic cells. However, epithelial markers may be silenced during the progression of the epithelial mesenchymal transition, which regulates the detachment and migration of malignant cells from the primary tumor. This review summarizes the achievements and challenges of various modalities for the isolation, enrichment, analysis and enumeration of CTCs and/or CTM, in order to assess the advancement of the disease and the response to therapy. PMID- 29238768 TI - Atomic adsorption on graphene with a single vacancy: systematic DFT study through the periodic table of elements. AB - Vacancies in graphene present sites of altered chemical reactivity and open possibilities to tune graphene properties by defect engineering. The understanding of chemical reactivity of such defects is essential for successful implementation of carbon materials in advanced technologies. We report the results of a systematic DFT study of atomic adsorption on graphene with a single vacancy for the elements of rows 1-6 of the periodic table of elements (PTE), excluding lanthanides. The calculations have been performed using the PBE, long range dispersion interaction-corrected PBE (PBE+D2 and PBE+D3) and non-local vdW DF2 functionals. We find that most elements strongly bind to the vacancy, except for the elements of groups 11 and 12, and noble gases, for which the contribution of dispersion interaction to bonding is most significant. The strength of the interaction with the vacancy correlates with the cohesive energy of the elements in their stable phases: the higher the cohesive energy is, the stronger bonding to the vacancy can be expected. As most atoms can be trapped at the SV site we have calculated the potentials of dissolution and found that in most cases the metals adsorbed at the vacancy are more "noble" than they are in their corresponding stable phases. PMID- 29238769 TI - Discrimination between hydrogen bonding and protonation in the spectra of a surface-enhanced Raman sensor. AB - We investigate the surface-enhanced Raman spectra of 4-mercaptopyridine on gold in a variety of acids. 4-Mercaptopyridine is a known pH sensor which exhibits characteristic spectral changes when the pH is changed. Here we show with the help of experiment and density functional calculations that the ring breathing mode is also highly sensitive to hydrogen bonding. Its spectral signature is a broad band with up to three contributions from free, protonated and hydrogen bonded 4-mercaptopyridine. Unlike pyridine in solution, where protonation leads to a higher ring breathing frequency than hydrogen-bonding, we find that protonated adsorbed 4-mercaptopyridine possesses a frequency which is lower than the corresponding hydrogen-bonded species. The Raman spectra indicate an orientation change of the aromatic ring in acidic solutions, which could be caused by a cation/pi interaction between protonated and deprotonated 4 mercaptopyridine. As the frequencies of the three species are well separated, adsorbed 4-mercaptopyridine can probe more complex changes in the solution environment than just pH. PMID- 29238770 TI - Molecular cocrystals: design, charge-transfer and optoelectronic functionality. AB - Organic cocrystals, formed by a combination of electron-rich donors and electron poor acceptors, play an important role in tailoring the optoelectronic properties of molecular materials. Charge transfer interactions in cocrystals not only endow them with an ordered three-dimensional (3D) supramolecular network in different constituent units, but also render them ideal scaffolds to control the intermolecular interactions in multicomponent solids. In this perspective, we firstly introduce preparation methods, molecular packing modes and charge transfer in organic cocrystals. Then, we focus on the novel and promising optoelectronic properties of organic cocrystals based on charge transfer interactions. Finally, we briefly discuss the outlook for the future development of these multicomponent crystalline materials. PMID- 29238771 TI - Understanding the reaction mechanism of the oxidative addition of ammonia by (PXP)Ir(i) complexes: the role of the X group. AB - An analysis of the electronic rearrangements for the oxidative addition of ammonia to a set of five representative (PXP)Ir pincer complexes (X = B, CH, O, N, SiH) is performed. We aim to understand the factors controlling the activation and reaction energies of this process by combining different theoretical strategies based on DFT calculations. Interestingly, complexes featuring higher activation barriers yield more exothermic reactions. The analysis of the reaction path using the bonding evolution theory shows that the main chemical events, N-H bond cleavage and Ir-H bond formation, take place before the transition structure is reached. Metal oxidation implies an electron density transfer from non-shared Ir pairs to the Ir-N bond. This decrement in the atomic charge of the metal provokes different effects in the ionic contribution of the Ir-X bonding depending on the nature of the X atom as shown by the interacting quantum atoms methodology. PMID- 29238781 TI - Structure and dynamics of the radical cation of ethane arising from the Jahn Teller and pseudo-Jahn-Teller effects. AB - The pulsed-field-ionization zero-kinetic-energy photoelectron spectrum of C2H6 has been recorded in the region of the adiabatic ionization threshold. The partially rotationally resolved spectrum indicates the existence of several vibronic states of C2H6+ with less than 600 cm-1 of internal excitation. The analysis of the rotational structures assisted by ab initio calculations enabled the determination of the adiabatic ionization energy of C2H6 and the investigation of the structure and dynamics of C2H6+ at low energies. The ground state of C2H6+ is found to be a 2Ag state of diborane-like structure with strongly mixed (a1g)-1 and (eg)-1 configurations. The vibrational structure reveals the importance of large-amplitude nuclear motions involving the diborane distortion modes, the C-C stretching motion, and the internal rotation at elongated C-C distances. The spectrum is analyzed in the light of the information obtained in earlier studies of C2H6+ by ab initio quantum chemistry, EPR spectroscopy and photoelectron spectroscopy. PMID- 29238782 TI - A new heptadentate picolinate-based ligand and its corresponding Gd(iii) complex: the effect of pendant picolinate versus acetate on complex properties. AB - To attain high relaxivity as well as stability, a new water-soluble, water coordinated Gd(iii) complex, which was synthesised by reacting equimolar amounts of picolinate-based ligand H4peada and GdCl3.xH2O at pH ~ 6.5, was examined. The number of inner sphere water molecules (q) in the complex was found to be 1.7 +/- 0.1 from luminescence lifetime measurements of its Tb(iii) congener, complex 2. At 1.41 T, 25 degrees C, and pH = 7.4, the longitudinal relaxivity (r1) value of the complex was found to be 6.08 mM-1 s-1, which remained almost constant in the pH range 4-10. The r1 relaxivity value has not been affected in the presence of a 100 fold excess of bicarbonate and phosphate anions, whereas in the case of fluoride ions, the value dropped to 4.6 mM-1 s-1 due to a binding interaction of fluoride ions by replacing inner sphere water molecules of the complex. From the potentiometric titration method, the stability constant of the complex was found to be log KGdL = 17.0 +/- 0.08 (in 0.15 M KCl and 25 degrees C). At pH = 7.4, the pGd value of ligand H4peada was found to be 14.01 which was comparable to the commercially available MRI contrast agent Omniscan(r). Phantom MR images of the complex under a clinical MR scanner at 1.5 T also demonstrated the usefulness of complex 1 as a potential MRI contrast agent. PMID- 29238785 TI - Synthesis of thieno[2,3-b]quinoline and selenopheno[2,3-b]quinoline derivatives via iodocyclization reaction and a DFT mechanistic study. AB - In this letter, we report the regioselective iodocyclization reaction of 3 alkynyl-2-(methylthio)quinolines and 3-alkynyl-2-(methylseleno)quinolines for the synthesis of thieno[2,3-b]quinoline and selenopheno[2,3-b]quinoline derivatives. Furthermore, by employing various palladium-catalyzed Sonogashira, Suzuki, and Heck reactions, the structural diversification of the resulting halide derivatives, which can act as the important intermediates for building other valuable compounds, was achieved. All compounds were fully characterized by the FT-IR, mass, 1H NMR, and 13C NMR spectral data. Finally, the structure of the thieno[2,3-b]quinoline derivative was confirmed by X-ray crystallography. This methodology provided a novel pathway to access quinoline fused heterocycles via iodocyclization reaction. Furthermore, the reaction process was well elucidated by density functional theory calculations. PMID- 29238789 TI - All-inorganic perovskite nanocrystal assisted extraction of hot electrons and biexcitons from photoexcited CdTe quantum dots. AB - Excitation of semiconductor quantum dots (QDs) by photons possessing energy higher than the band-gap creates a hot electron-hole pair, which releases its excess energy as waste heat or under certain conditions (when hnu > 2Eg) produces multiple excitons. Extraction of these hot carriers and multiple excitons is one of the key strategies for enhancing the efficiency of QD-based photovoltaic devices. However, this is a difficult task as competing carrier cooling and relaxation of multiple excitons (through Auger recombination) are ultrafast processes. Herein, we study the potential of all-inorganic perovskite nanocrystals (NCs) of CsPbX3 (X = Cl, Br) as harvesters of these short-lived species from photo-excited CdTe QDs. The femtosecond transient absorption measurements show CsPbX3 mediated extraction of both hot and thermalized electrons of the QDs (under a low pump power) and (under a high pump fluence) extraction of multiple excitons prior to their Auger assisted recombination. A faster timescale of thermalized electron transfer (~2 ps) and a higher extraction efficiency of hot electrons (~60%) are observed in the presence of CsPbBr3. These observations demonstrate the potential of all-inorganic perovskite NCs in the extraction of these short-lived energy rich species implying that complexes of the QDs and perovskite NCs are better suited for improving the efficiency of QD sensitized solar cells. PMID- 29238784 TI - ROS-mediated carbon monoxide and drug release from drug-conjugated carboxyboranes. AB - Elevated levels of reactive oxygen species (ROS) are associated with several detrimental diseases. Therefore, using this condition for selective treatments could be a great advantage in fighting these disorders. Here, we present amine carboxyboranes as a class of molecules for therapeutic CO gas generation and for delivering drug molecules in the presence of ROS. Our findings indicate amine carboxyboranes to be very slow CO releasers at physiological pH and temperature without any inducers but generate CO faster when reacted with a non-radical ROS (H2O2). Furthermore, a radical ROS (OH) dramatically expedites the production of CO from amine carboxyboranes. A decomposition profile shows the release of the amine group during the decarbonylation process from drug-conjugated carboxyboranes. This suggests that the carboxyborane moiety can be a useful tool for the delivery of amine-containing drugs to disease sites which display abundant ROS levels. PMID- 29238786 TI - Unravelling cationic cellulose nanofibril hydrogel structure: NMR spectroscopy and small angle neutron scattering analyses. AB - Stiff, elastic, viscous shear thinning aqueous gels are formed upon dispersion of low weight percent concentrations of cationically modified cellulose nanofibrils (CCNF) in water. CCNF hydrogels produced from cellulose modified with glycidyltrimethylammonium chloride, with degree of substitution (DS) in the range 10.6(3)-23.0(9)%, were characterised using NMR spectroscopy, rheology and small angle neutron scattering (SANS) to probe the fundamental form and dimensions of the CCNF and to reveal interfibrillar interactions leading to gelation. As DS increased CCNF became more rigid as evidenced by longer Kuhn lengths, 18-30 nm, derived from fitting of SANS data to an elliptical cross-section, cylinder model. Furthermore, apparent changes in CCNF cross-section dimensions suggested an "unravelling" of initially twisted fibrils into more flattened ribbon-like forms. Increases in elastic modulus (7.9-62.5 Pa) were detected with increased DS and 1H solution-state NMR T1 relaxation times of the introduced surface -N+(CH3)3 groups were found to be longer in hydrogels with lower DS, reflecting the greater flexibility of the low DS CCNF. This is the first time that such correlation between DS and fibrillar form and stiffness has been reported for these potentially useful rheology modifiers derived from renewable cellulose. PMID- 29238790 TI - Synthesis of polyheterocycles via multicomponent reactions. AB - Polyheterocycles are one of the most desired synthetic targets due to their numerous and valuable applications in various fields. Multicomponent reactions (MCRs) are highly convergent one-pot processes, in which three or more reagents are combined sequentially to construct complex products, with almost all the atoms coming from the starting reagents. In this context, the syntheses of 'heterocycles' via MCR-based processes have been reviewed a number of times. However, there is not a single review (recent or otherwise) covering the synthesis of 'polyheterocycles' via a direct MCR or via a one-pot process involving MCRs coupled to further cyclizations (via ionic, metal-catalyzed, pericyclic, or free-radical-mediated cyclizations). This issue is consequently the main topic of the present review, which considers work from the last decade. The work is categorized according to the key processes involved in the syntheses of polyheterocycles, aiming to give readers an easy understanding of this MCR based chemistry and to provide insights for further investigations. The reaction mechanisms providing novel elements to these MCR-based methods for the synthesis of polyheterocycles are also discussed. PMID- 29238793 TI - Cost Sharing Does Not Lead to an Overall Increase of Involuntary Commitments in the Netherlands-Reply. PMID- 29238792 TI - Cost Sharing Does Not Lead to an Overall Increase of Involuntary Commitments in the Netherlands. PMID- 29238794 TI - The Veterans Affairs Medical Center's Contribution to Plastic Surgery Education. PMID- 29238796 TI - Sources of Parent-Offspring Resemblance for Major Depression in a National Swedish Extended Adoption Study. AB - Importance: Twin studies have assessed sibling resemblance for major depression (MD) but cannot address sources of resemblance across generations. Objective: To clarify the relative importance of genetic and rearing effects on the parent offspring resemblance for MD. Design: This Swedish population register-based study examined parents and children from the following 5 family types: intact (2 041 816 offspring), adoptive (14 104 offspring), not-lived-with (NLW) father (116 601 offspring), stepfather (67 826 offspring), and triparental (29 205 offspring). The 5 family types permitted quantification of parent-offspring resemblance for genes plus rearing, genes-only, and rearing-only associations. Treated MD was assessed from national primary care, specialist care, and inpatient registries. Data were collected from January 1, 1960, through December 31, 2016. Exposure: Diagnosis of MD vs no diagnosis in parents. Main Outcomes and Measures: Registration for MD. Results: The study population included 2 269 552 offspring (51.5% male and 48.5% female; median age, 42; range, 26-56 years). The weighted tetrachoric correlations for MD across family types and across mothers and fathers were r = 0.17 (95% CI, 0.16-0.17) for genes plus rearing, r = 0.08 (95% CI, 0.06-0.09) for genes-only, and r = 0.08 (95% CI, 0.07-0.09) for rearing only parent-child associations. Only the genes plus rearing association differed significantly between mothers (weighted tetrachoric correlation, r = 0.18; 95% CI, 0.18-0.18) and fathers (weighted tetrachoric correlation, r = 0.15; 95% CI, 0.15-0.16). In triparental families, the parent-offspring correlations for MD were estimated at r = 0.19 (95% CI, 0.17-0.22) for mothers in the genes plus rearing association, r = 0.10 (95% CI, 0.07-0.13) for NLW fathers in the genes only association, and r = 0.08 (95% CI, 0.05-0.11) for stepfathers in the rearing only association. In adoptive families, the effect of affected biological and affected adoptive parents on adoptee risk for MD was additive. In intact families, parental MD diagnosed by specialists in hospital or outpatient settings and primary care physicians affected equally the risk for MD in offspring. Conclusions and Relevance: The parent-offspring resemblance for treated MD arises from genetic factors and rearing experiences to an approximately equal extent. Both forms of cross-generational transmission act additively on the risk for MD in the offspring. PMID- 29238797 TI - Opioid Stewardship and the Surgeon. PMID- 29238798 TI - Association Between Hypercoagulable Conditions and Calciphylaxis in Patients With Renal Disease: A Case-Control Study. AB - Importance: Calciphylaxis is a rare skin disease with high morbidity and mortality that frequently affects patients with renal disease. Hypercoagulable conditions are frequently observed in both patients with calciphylaxis and those with chronic kidney disease (CKD), complicating our understanding of which hypercoagulable conditions are specific to calciphylaxis. Objective: To identify hypercoagulable conditions that are risk factors for developing calciphylaxis while controlling for CKD. Design, Setting, and Participants: This was a case control study, comparing the hypercoagulability status of patients with calciphylaxis and with renal disease with that of a matched control population at 2 large urban academic hospitals in Boston, Massachusetts. Retrospective medical record review of laboratory values was performed to identify patients with hypercoagulable conditions. Case and control patients were further stratified based on both severity of CKD and warfarin. Patients with a dermatologic diagnosis of calciphylaxis between 2006 and 2014 and concomitant CKD were included as cases (n = 38). Three controls (n = 114) per case patient with CKD were included, and were matched by age, sex, and race. Main Outcomes and Measures: The rate of various hypercoagulable states (ie, antithrombin III [ATIII] deficiency, protein C and S deficiency, factor V Leiden mutation, prothrombin gene mutation [G20210A], elevated factor VIII level, lupus anticoagulant, anti-IgG or IgM cardiolipin antibodies, heparin-induced thrombocytopenia antibodies, and elevation of homocysteine) in patients with calciphylaxis compared with their matched controls. Results: Of the calciphylaxis cohort, 28 (58%) were female and 18 (55%) were non-Hispanic white. Among all patients, lupus anticoagulant (13 [48%] positive in cases vs 1 [5%] in controls; P = .001), protein C deficiency (9 [50%] vs 1 [8%]; P = .02), and combined thrombophilias (18 [62%] vs 10 [31%]; P = .02) were found to be significantly associated with calciphylaxis. In a subanalysis of patients with stage 5 CKD, only lupus anticoagulant (12 [53%] vs 9 [0%]; P = .01) and combined thrombophilia (15 [63%] vs 1 [8%]; P = .004) remained significantly associated with calciphylaxis. In a separate subanalysis of warfarin-unexposed patients, only lupus anticoagulant (7 [50%] vs 1 [6%]; P = .01) and protein C deficiency (5 [46%] vs 10 [0%]; P = .04) remained significantly associated with calciphylaxis. Conclusions and Relevance: Presence of lupus anticoagulant and combined thrombophilias are risk factors for the development of calciphylaxis in patients with late-stage renal disease. Clinicians should be aware of these associations in patients with impaired kidney function and may consider increased screening and appropriate anticoagulation treatment to reduce the risk of calciphylaxis development. PMID- 29238795 TI - Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations: A Cohort Study From the International Pregnancy Safety Study Consortium. AB - Importance: Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety. Objective: To examine the risk of congenital malformations associated with intrauterine exposure to stimulants. Design, Setting, and Participants: Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017. Exposures: Methylphenidate and amphetamines dispensed during the first trimester. Main Outcomes and Measures: Major congenital malformations and subgroup of cardiac malformations. Results: In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64). Conclusions and Relevance: These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy. PMID- 29238799 TI - Association of Clinical, Dermoscopic, and Histopathologic Findings With Gene Expression in Patients With Balloon Cell Melanoma. AB - Importance: Balloon cell melanoma is a rare subtype of melanoma that is underrecognized clinically and is challenging to diagnose on histologic studies. Objective: To further characterize the clinical, dermoscopic, and histopathologic features of balloon cell melanomas and their correlation to gene expression. Design, Setting, and Participants: Case series of 2 patients with balloon cell melanoma whose medical records were retrieved from the database of Thomas Jefferson University Dermatopathology Center in Philadelphia, Pennsylvania. Both cases had been referred to the institution's dermatopathology laboratory and provided complete data on clinical, dermoscopic, and histopathologic findings and gene-expression profiles. Main Outcomes and Measures: Dermoscopic findings, histopathologic findings, and results of gene expression tests. Results: In the 2 patients included, translucent hypopigmented areas on gross examination and a translucent white-gray veil and dull yellow globules on dermoscopic examination correlated with the balloon cell melanocytic region demonstrated on histologic studies with hematoxylin-eosin stain. Specifically, dull yellow globules corresponded to the balloon cell melanocytic nests. Both lesions presented with a second, morphologically distinct population of melanocytes, common in balloon cell melanocytic neoplasms. In both cases, a prominent junctional component that consisted of cells demonstrating ample clear-to-granular cytoplasm and a central nucleus were present. Cytologic atypia was minimal to lacking in both cases, and architectural disorder served as a better clue to the diagnosis. Findings of a gene expression profiling test corroborated the diagnosis in both cases. Conclusions and Relevance: Balloon cell melanomas may present with characteristic clinical and dermoscopic findings, and a gene expression profiling test may provide additional useful diagnostic information in cases that are difficult to interpret. PMID- 29238800 TI - Tender Nodules on the Lower Legs. PMID- 29238801 TI - Shedding Light on the Risks of Methylphenidate and Amphetamine in Pregnancy. PMID- 29238803 TI - Noninvasive Gene Expression Testing in Amelanotic Melanoma. PMID- 29238802 TI - Dyspnea in a Young Man. PMID- 29238805 TI - A Solution-Focused Research Approach to Achieve an Implementable Revolution in Digital Mental Health. PMID- 29238804 TI - Efficacy of High-Sensitivity Troponin T in Identifying Very-Low-Risk Patients With Possible Acute Coronary Syndrome. AB - Importance: Physicians need information on how to use the first available high sensitivity troponin (hsTnT) assay in the United States to identify patients at very low risk for 30-day adverse cardiac events (ACE). Objective: To determine whether a negative hsTnT assay at 0 and 3 hours following emergency department presentation could identify patients at less than 1% risk of a 30-day ACE. Design, Setting, and Participants: A prospective, observational study at 15 emergency departments in the United States between 2011 and 2015 that included individuals 21 years and older, presenting to the emergency department with suspected acute coronary syndrome. Of 1690 eligible individuals, 15 (no cardiac troponin T measurement) and 320 (missing a 0-hour or 3-hour sample) were excluded from the analyses. Exposures: Serial hsTnT measurements (fifth-generation Roche Elecsys hsTnT assay). Main Outcomes and Measures: Serial blood samples from each patient were collected after emergency department presentation (once identified as a potential patient with acute coronary syndrome) and 3 hours, 6 to 9 hours, and 12 to 24 hours later. Adverse cardiac events were defined as myocardial infarction, urgent revascularization, or death. The upper reference level for the hsTnT assay, defined as the 99th percentile, was established as 19 ng/L in a separate healthy US cohort. Patients were considered ruled out for acute myocardial infarction if their hsTnT level at 0 hours and 3 hours was less than the upper reference level. Gold standard diagnoses were determined by a clinical end point committee. Evaluation of assay clinical performance for acute myocardial infarction rule-out was prespecified; the hypothesis regarding 30-day ACE was formulated after data collection. Results: In 1301 healthy volunteers (50.4% women; median age, 48 years), the upper reference level was 19 ng/L. In 1600 patients with suspected acute coronary syndrome (48.4% women; median age, 55 years), a single hsTnTlevel less than 6 ng/L at baseline had a negative predictive value for AMI of 99.4%. In 974 patients (77.1%) with both 0-hour and 3 hour hsTnT levels of 19 ng/L or less, the negative predictive value for 30-day ACE was 99.3% (95% CI, 99.1-99.6). Using sex-specific cutpoints, C statistics for women (0.952) and men (0.962) were similar for acute myocardial infarction. Conclusions and Relevance: A single hsTnT level less than 6 ng/L was associated with a markedly decreased risk of AMI, while serial levels at 19 ng/L or less identified patients at less than 1% risk of 30-day ACE. PMID- 29238806 TI - Vertical Jump Height Estimation Algorithm Based on Takeoff and Landing Identification Via Foot-Worn Inertial Sensing. AB - Vertical jump height is widely used for assessing motor development, functional ability, and motor capacity. Traditional methods for estimating vertical jump height rely on force plates or optical marker-based motion capture systems limiting assessment to people with access to specialized laboratories. Current wearable designs need to be attached to the skin or strapped to an appendage which can potentially be uncomfortable and inconvenient to use. This paper presents a novel algorithm for estimating vertical jump height based on foot-worn inertial sensors. Twenty healthy subjects performed countermovement jumping trials and maximum jump height was determined via inertial sensors located above the toe and under the heel and was compared with the gold standard maximum jump height estimation via optical marker-based motion capture. Average vertical jump height estimation errors from inertial sensing at the toe and heel were -2.2+/ 2.1 cm and -0.4+/-3.8 cm, respectively. Vertical jump height estimation with the presented algorithm via inertial sensing showed excellent reliability at the toe (ICC(2,1)=0.98) and heel (ICC(2,1)=0.97). There was no significant bias in the inertial sensing at the toe, but proportional bias (b=1.22) and fixed bias (a= 10.23cm) were detected in inertial sensing at the heel. These results indicate that the presented algorithm could be applied to foot-worn inertial sensors to estimate maximum jump height enabling assessment outside of traditional laboratory settings, and to avoid bias errors, the toe may be a more suitable location for inertial sensor placement than the heel. PMID- 29238808 TI - New Inroads Against Multiple Sclerosis. PMID- 29238809 TI - Accreditation Readiness in US Multidisciplinary Rectal Cancer Care: A Survey of OSTRICH Member Institutions. PMID- 29238807 TI - Bringing Surgical Care to the Home Through Video Visits. PMID- 29238810 TI - Correlation Between 24-Hour Predischarge Opioid Use and Amount of Opioids Prescribed at Hospital Discharge. AB - Importance: The United States is experiencing an opioid abuse epidemic. Opioid overprescription by physicians may contribute to this epidemic. Objectives: To determine if there was a correlation between a postoperative patient's 24-hour predischarge opioid use and the amount of opioids prescribed at hospital discharge and to determine the number of patients who used no opioids prior to discharge but were still prescribed opioids after hospital discharge. Design, Setting, and Participants: This cross-sectional study performed a retrospective record review of 18 343 postoperative patients at Boston Medical Center and Lahey Hospital and Medical Center-Burlington Campus who were discharged home after a postoperative inpatient admission of at least 24 hours. Data collection spanned from May 22, 2014, to June 30, 2016, in the Boston Medical Center data set and from March 23, 2015, to September 7, 2016, in the Lahey Hospital and Medical Center-Burlington Campus data set. Exposures: Surgery requiring a postoperative inpatient hospital stay longer than 24 hours. Main Outcomes and Measures: The main outcome measures were the patient's 24-hour predischarge opioid use and the total quantity of opioids prescribed at hospital discharge. Potential overprescription was defined as the number of patients who used no opioids in the 24 hours prior to hospital discharge but were still prescribed opioids after hospital discharge. Results: Among the 18 343 patients (10 069 women and 8274 men; mean age, 52.2 years) who underwent 21 452 surgical procedures, there was wide variation in the amount of opioids prescribed at hospital discharge given a postoperative patient's 24-hour predischarge opioid use. A total of 6548 patients (35.7%) used no opioids in the 24 hours prior to hospital discharge; however, 2988 of these patients (45.6%) were prescribed opioids at hospital discharge, suggesting potential overprescription. Services that had the highest rates of potential overprescription (obstetrics [adjusted odds ratio (AOR), 3.146; 95% CI, 2.094-4.765] and gynecology [AOR, 2.355; 95% CI, 1.663-3.390], orthopedics [AOR, 0.943; 95% CI, 0.719-1.242], and plastic surgery [AOR, 0.733; 95% CI, 0.334 1.682]) generally had the highest rates of patients still using opioids at hospital discharge. Pediatric surgery was the only service that did not have any cases of potential overprescription (AOR, 2.09 * 10-7; 95% CI, 0.000-0.016). Conclusions and Relevance: Opioids are not regularly prescribed in a patient specific manner to postoperative patients. Potential opioid overprescription occurs regularly after surgery among almost all surgical specialties. PMID- 29238811 TI - Displacement Propagation in Fibrous Networks Due to Local Contraction. AB - The extracellular matrix provides macroscale structure to tissues and microscale guidance for cell contraction, adhesion, and migration. The matrix is composed of a network of fibers, which each deform by stretching, bending, and buckling. Whereas the mechanics has been well characterized in uniform shear and extension, the response to more general loading conditions remains less clear, because the associated displacement fields cannot be predicted a priori. Studies simulating contraction, such as due to a cell, have observed displacements that propagate over a long range, suggesting mechanisms such as reorientation of fibers toward directions of tensile force and nonlinearity due to buckling of fibers under compression. It remains unclear which of these two mechanisms produces the long range displacements and how properties like fiber bending stiffness and fiber length affect the displacement field. Here, we simulate contraction of an inclusion within a fibrous network and fit the resulting radial displacements to ur ~ r-n where the power n quantifies the decay of displacements over distance, and a value of n less than that predicted by classical linear elasticity indicates displacements that propagate over a long range. We observed displacements to propagate over a longer range for greater contraction of the inclusion, for networks having longer fibers, and for networks with lower fiber bending stiffness. Contraction of the inclusion also caused fibers to reorient into the radial direction, but, surprisingly, the reorientation was minimally affected by bending stiffness. We conclude that both reorientation and nonlinearity are responsible for the long-range displacements. PMID- 29238812 TI - ANNUAL SPECIAL ISSUE "Biomechanical Engineering-Year in Review". PMID- 29238814 TI - Error in Table 2. PMID- 29238815 TI - The Wait for High-Sensitivity Troponin Is Over-Proceed Cautiously. PMID- 29238813 TI - Erratum: "Evaluation of Meniscal Mechanics and Proteoglycan Content in a Modified Anterior Cruciate Ligament Transection Model" [ASME J. Biomech. Eng. 2014, 136(7), p. 071001; DOI: 10.1115/1.4027468]. PMID- 29238816 TI - Design and Evaluation of an Instrumented Wobble Board for Assessing and Training Dynamic Seated Balance. AB - Methods that effectively assess and train dynamic seated balance are critical for enhancing functional independence and reducing risk of secondary health complications in the elderly and individuals with neuromuscular impairments. The objective of this research was to devise and validate a portable tool for assessing and training dynamic seated balance. An instrumented wobble board was designed and constructed that (1) elicits multidirectional perturbations in seated individuals, (2) quantifies seated balance proficiency, and (3) provides real-time, kinematics-based vibrotactile feedback. After performing a technical validation study to compare kinematic wobble board measurements against a gold standard motion capture system, 15 nondisabled participants performed a dynamic sitting task using the wobble board. Our results demonstrate that the tilt angle measurements were highly accurate throughout the range of wobble board dynamics. Furthermore, the posturographic analyses for the dynamic sitting task revealed that the wobble board can effectively discriminate between the different conditions of perturbed balance, demonstrating its potential to serve as a clinical tool for the assessment and training of seated balance. Vibrotactile feedback decreased the variance of wobble board tilt, demonstrating its potential for use as a balance training tool. Unlike similar instrumented tools, the wobble board is portable, requires no laboratory equipment, and can be adjusted to meet the user's balance abilities. While future work is warranted, obtained findings will aid in effective translation of assessment and training techniques to a clinical setting, which has the potential to enhance the diagnosis and prognosis for individuals with seated balance impairments. PMID- 29238817 TI - Finite Element Framework for Computational Fluid Dynamics in FEBio. AB - The mechanics of biological fluids is an important topic in biomechanics, often requiring the use of computational tools to analyze problems with realistic geometries and material properties. This study describes the formulation and implementation of a finite element framework for computational fluid dynamics (CFD) in FEBio, a free software designed to meet the computational needs of the biomechanics and biophysics communities. This formulation models nearly incompressible flow with a compressible isothermal formulation that uses a physically realistic value for the fluid bulk modulus. It employs fluid velocity and dilatation as essential variables: The virtual work integral enforces the balance of linear momentum and the kinematic constraint between fluid velocity and dilatation, while fluid density varies with dilatation as prescribed by the axiom of mass balance. Using this approach, equal-order interpolations may be used for both essential variables over each element, contrary to traditional mixed formulations that must explicitly satisfy the inf-sup condition. The formulation accommodates Newtonian and non-Newtonian viscous responses as well as inviscid fluids. The efficiency of numerical solutions is enhanced using Broyden's quasi-Newton method. The results of finite element simulations were verified using well-documented benchmark problems as well as comparisons with other free and commercial codes. These analyses demonstrated that the novel formulation introduced in FEBio could successfully reproduce the results of other codes. The analogy between this CFD formulation and standard finite element formulations for solid mechanics makes it suitable for future extension to fluid structure interactions (FSIs). PMID- 29238818 TI - Multiscale Poroviscoelastic Compressive Properties of Mouse Supraspinatus Tendons Are Altered in Young and Aged Mice. AB - Rotator cuff disorders are one of the most common causes of shoulder pain and disability in the aging population but, unfortunately, the etiology is still unknown. One factor thought to contribute to the progression of disease is the external compression of the rotator cuff tendons, which can be significantly increased by age-related changes such as muscle weakness and poor posture. The objective of this study was to investigate the baseline compressive response of tendon and determine how this response is altered during maturation and aging. We did this by characterizing the compressive mechanical, viscoelastic, and poroelastic properties of young, mature, and aged mouse supraspinatus tendons using macroscale indentation testing and nanoscale high-frequency AFM-based rheology testing. Using these multiscale techniques, we found that aged tendons were stiffer than their mature counterparts and that both young and aged tendons exhibited increased hydraulic permeability and energy dissipation. We hypothesize that regional and age-related variations in collagen morphology and organization are likely responsible for changes in the multiscale compressive response as these structural parameters may affect fluid flow. Importantly, these results suggest a role for age-related changes in the progression of tendon degeneration, and we hypothesize that decreased ability to resist compressive loading via fluid pressurization may result in damage to the extracellular matrix (ECM) and ultimately tendon degeneration. These studies provide insight into the regional multiscale compressive response of tendons and indicate that altered compressive properties in aging tendons may be a major contributor to overall tendon degeneration. PMID- 29238820 TI - On Shipboard. PMID- 29238819 TI - Biased Estimates in Mendelian Randomization Studies Conducted in Unrepresentative Samples. PMID- 29238821 TI - Multibody Kinematics Optimization for the Estimation of Upper and Lower Limb Human Joint Kinematics: A Systematized Methodological Review. AB - Multibody kinematics optimization (MKO) aims to reduce soft tissue artefact (STA) and is a key step in musculoskeletal modeling. The objective of this review was to identify the numerical methods, their validation and performance for the estimation of the human joint kinematics using MKO. Seventy-four papers were extracted from a systematized search in five databases and cross-referencing. Model-derived kinematics were obtained using either constrained optimization or Kalman filtering to minimize the difference between measured (i.e., by skin markers, electromagnetic or inertial sensors) and model-derived positions and/or orientations. While hinge, universal, and spherical joints prevail, advanced models (e.g., parallel and four-bar mechanisms, elastic joint) have been introduced, mainly for the knee and shoulder joints. Models and methods were evaluated using: (i) simulated data based, however, on oversimplified STA and joint models; (ii) reconstruction residual errors, ranging from 4 mm to 40 mm; (iii) sensitivity analyses which highlighted the effect (up to 36 deg and 12 mm) of model geometrical parameters, joint models, and computational methods; (iv) comparison with other approaches (i.e., single body kinematics optimization and nonoptimized kinematics); (v) repeatability studies that showed low intra- and inter-observer variability; and (vi) validation against ground-truth bone kinematics (with errors between 1 deg and 22 deg for tibiofemoral rotations and between 3 deg and 10 deg for glenohumeral rotations). Moreover, MKO was applied to various movements (e.g., walking, running, arm elevation). Additional validations, especially for the upper limb, should be undertaken and we recommend a more systematic approach for the evaluation of MKO. In addition, further model development, scaling, and personalization methods are required to better estimate the secondary degrees-of-freedom (DoF). PMID- 29238822 TI - Orchard in Bloom, Louveciennes. PMID- 29238823 TI - 2017 Editors' Choice Papers. PMID- 29238824 TI - Effect of Perioperative Gabapentin on Postoperative Pain Resolution and Opioid Cessation in a Mixed Surgical Cohort: A Randomized Clinical Trial. AB - Importance: Guidelines recommend using gabapentin to decrease postoperative pain and opioid use, but significant variation exists in clinical practice. Objective: To determine the effect of perioperative gabapentin on remote postoperative time to pain resolution and opioid cessation. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled trial of perioperative gabapentin was conducted at a single-center, tertiary referral teaching hospital. A total of 1805 patients aged 18 to 75 years scheduled for surgery (thoracotomy, video assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy) were screened. Participants were enrolled from May 25, 2010, to July 25, 2014, and followed up for 2 years postoperatively. Intention-to-treat analysis was used in evaluation of the findings. Interventions: Gabapentin, 1200 mg, preoperatively and 600 mg, 3 times a day postoperatively or active placebo (lorazepam, 0.5 mg) preoperatively followed by inactive placebo postoperatively for 72 hours. Main Outcomes and Measures: Primary outcome was time to pain resolution (5 consecutive reports of 0 of 10 possible levels of average pain at the surgical site on the numeric rating scale of pain). Secondary outcomes were time to opioid cessation (5 consecutive reports of no opioid use) and the proportion of participants with continued pain or opioid use at 6 months and 1 year. Results: Of 1805 patients screened for enrollment, 1383 were excluded, including 926 who did not meet inclusion criteria and 273 who declined to participate. Overall, 8% of patients randomized were lost to follow-up. A total of 202 patients were randomized to active placebo and 208 patients were randomized to gabapentin in the intention-to-treat analysis (mean [SD] age, 56.7 [11.7] years; 256 (62.4%) women and 154 (37.6%) men). Baseline characteristics of the groups were similar. Perioperative gabapentin did not affect time to pain cessation (hazard ratio [HR], 1.04; 95% CI, 0.82-1.33; P = .73) in the intention-to-treat analysis. However, participants receiving gabapentin had a 24% increase in the rate of opioid cessation after surgery (HR, 1.24; 95% CI, 1.00-1.54; P = .05). No significant differences were noted in the number of adverse events as well as the rate of medication discontinuation due to sedation or dizziness (placebo, 42 of 202 [20.8%]; gabapentin, 52 of 208 [25.0%]). Conclusions and Relevance: Perioperative administration of gabapentin had no effect on postoperative pain resolution, but it had a modest effect on promoting opioid cessation after surgery. The routine use of perioperative gabapentin may be warranted to promote opioid cessation and prevent chronic opioid use. Optimal dosing and timing of perioperative gabapentin in the context of specific operations to decrease opioid use should be addressed in further research. Trial Registration: clinicaltrials.gov Identifier: NCT01067144. PMID- 29238825 TI - Association of Cumulative Childhood Adversity and Adolescent Violent Offending With Suicide in Early Adulthood. AB - Importance: Childhood adversity (CA) is associated with an increased risk of suicide in young adulthood that might be explained by maladaptive trajectories during adolescence. Although adolescent violent offending is linked with suicide, little is known about its role in the association between CA and suicide. Objective: To examine whether adolescent violent offending mediates the association between CA and suicide in early adulthood. Design, Setting, and Participants: This population-based, longitudinal cohort study with a follow-up time spanning 5 to 9 years included 476 103 individuals born in Sweden between 1984 and 1988. The study population was prospectively followed up from 20 years of age until December 31, 2013, with respect to suicide. Data analysis was performed from January 1, 1984, to December 31, 2013. Exposures: Register-based CAs included parental death, parental substance abuse and psychiatric disorder, parental criminal offending, parental separation, public assistance recipiency, child welfare intervention, and residential instability. Adolescent violent offending was defined as being convicted of a violent crime between the ages of 15 and 19 years. Main Outcomes and Measures: Estimates of risk of suicide after 20 years of age (from 2004 if born in 1984 and from 2008 if born in 1988) until the end of 2013 were calculated as incidence rate ratios (IRRs) with 95% CIs using Poisson regression analysis. Adjustments were made for demographics and psychiatric disorder. In addition, binary mediation analysis with logistic regression was used. Results: A total of 476 103 individuals (231 699 [48.7%] female) were included in the study. Those with a conviction for violent offending had been exposed to all CAs to a greater extent than those with no violent offending. Cumulative CA was associated with risk of suicide in nonconvicted (adjusted IRR, 2.4; 95% CI, 1.5-3.9) and convicted youths, who had a higher risk of suicide (adjusted IRR, 8.5; 95% CI, 4.6-15.7). Adolescent violent offending partly mediated the association between CA and suicide. Conclusions and Relevance: Individuals with a history of CA who also engage in violent offending in adolescence have a high risk of suicide. Interventions to prevent externalizing behavior during childhood and increased support to youths with delinquent behavior may have the potential to prevent suicide related to CA. PMID- 29238827 TI - Saint John Dictating to the Venerable Bede. PMID- 29238826 TI - A Re-Engineered Software Interface and Workflow for the Open-Source SimVascular Cardiovascular Modeling Package. AB - Patient-specific simulation plays an important role in cardiovascular disease research, diagnosis, surgical planning and medical device design, as well as education in cardiovascular biomechanics. simvascular is an open-source software package encompassing an entire cardiovascular modeling and simulation pipeline from image segmentation, three-dimensional (3D) solid modeling, and mesh generation, to patient-specific simulation and analysis. SimVascular is widely used for cardiovascular basic science and clinical research as well as education, following increased adoption by users and development of a GATEWAY web portal to facilitate educational access. Initial efforts of the project focused on replacing commercial packages with open-source alternatives and adding increased functionality for multiscale modeling, fluid-structure interaction (FSI), and solid modeling operations. In this paper, we introduce a major SimVascular (SV) release that includes a new graphical user interface (GUI) designed to improve user experience. Additional improvements include enhanced data/project management, interactive tools to facilitate user interaction, new boundary condition (BC) functionality, plug-in mechanism to increase modularity, a new 3D segmentation tool, and new computer-aided design (CAD)-based solid modeling capabilities. Here, we focus on major changes to the software platform and outline features added in this new release. We also briefly describe our recent experiences using SimVascular in the classroom for bioengineering education. PMID- 29238828 TI - Validation of the Strain Assessment of a Phantom of Abdominal Aortic Aneurysm: Comparison of Results Obtained From Magnetic Resonance Imaging and Stereovision Measurements. AB - Predicting aortic aneurysm ruptures is a complex problem that has been investigated by many research teams over several decades. Work on this issue is notably complex and involves both the mechanical behavior of the artery and the blood flow. Magnetic resonance imaging (MRI) can provide measurements concerning the shape of an organ and the blood that flows through it. Measuring local distortion of the artery wall is the first essential factor to evaluate in a ruptured artery. This paper aims to demonstrate the feasibility of this measure using MRI on a phantom of an abdominal aortic aneurysm (AAA) with realistic shape. The aortic geometry is obtained from a series of cine-MR images and reconstructed using Mimics software. From 4D flow and MRI measurements, the field of velocity is determined and introduced into a computational fluid dynamic (CFD) model to determine the mechanical boundaries applied on the wall artery (pressure and ultimately wall shear stress (WSS)). These factors are then converted into a solid model that enables wall deformations to be calculated. This approach was applied to a silicone phantom model of an AAA reconstructed from a patient's computed tomography-scan examination. The calculated deformations were then compared to those obtained in identical conditions by stereovision. The results of both methods were found to be close. Deformations of the studied AAA phantom with complex shape were obtained within a gap of 12% by modeling from MR data. PMID- 29238829 TI - The Role of Gabapentin in Multimodal Postoperative Pain Management. PMID- 29238831 TI - Numerical Study of Transport of Anticancer Drugs in Heterogeneous Vasculature of Human Brain Tumors Using Dynamic Contrast Enhanced-Magnetic Resonance Imaging. PMID- 29238830 TI - Firefighter Skin Cancer and Sun Protection Practices: Evidence From the Florida Firefighter Cancer Initiative. PMID- 29238832 TI - Dynamic Simulation of Human Gait Model With Predictive Capability. AB - In this paper, it is proposed that the central nervous system (CNS) controls human gait using a predictive control approach in conjunction with classical feedback control instead of exclusive classical feedback control theory that controls based on past error. To validate this proposition, a dynamic model of human gait is developed using a novel predictive approach to investigate the principles of the CNS. The model developed includes two parts: a plant model that represents the dynamics of human gait and a controller that represents the CNS. The plant model is a seven-segment, six-joint model that has nine degrees-of freedom (DOF). The plant model is validated using data collected from able-bodied human subjects. The proposed controller utilizes model predictive control (MPC). MPC uses an internal model to predict the output in advance, compare the predicted output to the reference, and optimize the control input so that the predicted error is minimal. To decrease the complexity of the model, two joints are controlled using a proportional-derivative (PD) controller. The developed predictive human gait model is validated by simulating able-bodied human gait. The simulation results show that the developed model is able to simulate the kinematic output close to experimental data. PMID- 29238835 TI - What's in a Name-Dermoscopy vs Dermatoscopy. PMID- 29238833 TI - A Potential Tool for the Study of Venous Ulcers: Blood Flow Responses to Load. AB - Venous ulcers are deep wounds that are located predominantly on the lower leg. They are prone to infection and once healed have a high probability of recurrence. Currently, there are no effective measures to predict and prevent venous ulcers from formation. Hence, the goal of this work was to develop a Windkessel-based model that can be used to identify hemodynamic parameters that change between healthy individuals and those with wounds. Once identified, these parameters have the potential to be used as indicators of when internal conditions change, putting the patient at higher risk for wound formation. In order to achieve this goal, blood flow responses in lower legs were measured experimentally by a laser Doppler perfusion monitor (LDPM) and simulated with a modeling approach. A circuit model was developed on the basis of the Windkessel theory. The hemodynamic parameters were extracted for three groups: legs with ulcers ("wounded"), legs without ulcers but from ulcer patients ("nonwounded"), and legs without vascular disease ("healthy"). The model was executed by two independent operators, and both operators reported significant differences between wounded and healthy legs in localized vascular resistance and compliance. The model successfully replicated the experimental blood flow profile. The global and local vascular resistances and compliance parameters rendered quantifiable differences between a population with venous ulcers and healthy individuals. This work supports that the Windkessel modeling approach has the potential to determine patient specific parameters that can be used to identify when conditions change making venous ulcer formation more likely. PMID- 29238836 TI - Solitude and Sunshine in Daniel Defoe's Robinson Crusoe. PMID- 29238837 TI - Joseph Goldberger-Public Health Champion and Investigator of Pellagra. PMID- 29238838 TI - Jay Frank Schamberg, MD-Beyond the Eponymous Disease. PMID- 29238839 TI - Rona McLeod MacKie, MD, FRCP, FRCPath-A Trendsetter in the Field of Melanoma. PMID- 29238840 TI - Dermatology in Epic Poetry-From Beowulf to The Odyssey. PMID- 29238841 TI - Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. PMID- 29238843 TI - Management Practices Used in Agricultural Drainage Ditches to Reduce Gulf of Mexico Hypoxia. AB - Agricultural non-point sources of nutrients and sediments have caused eutrophication and other water quality issues in aquatic and marine ecosystems, such as the annual occurrence of hypoxia in the Gulf of Mexico. Management practices have been implemented adjacent to and in agricultural drainage ditches to promote their wetland characteristics and functions, including reduction of nitrogen, phosphorus, and sediment losses downstream. This review: (1) summarized studies examining changes in nutrient and total suspended solid concentrations and loads associated with management practices in drainage ditches (i.e., riser and slotted pipes, two-stage ditches, vegetated ditches, low-grade weirs, and organic carbon amendments) with emphasis on the Lower Mississippi Alluvial Valley, (2) quantified management system effects on nutrient and total suspended solid concentrations and loads and, (3) identified information gaps regarding water quality associated with these management practices and research needs in this area. In general, management practices used in drainage ditches at times reduced losses of total suspended solids, N, and P. However, management practices were often ineffective during storm events that were uncommon and intense in duration and volume, although these types of events could increase in frequency and intensity with climate change. Studies on combined effects of management practices on drainage ditch water quality, along with research towards improved nutrient and sediment reduction efficiency during intense storm events are urgently needed. PMID- 29238846 TI - Positive end-expiratory pressure selection based on best respiratory system compliance or collapse/hyperdistension curves in patients with acute respiratory distress syndrome: lack of correlation with alveolar recruitment. PMID- 29238844 TI - Cardiomyokines from the heart. AB - The heart is regarded as an endocrine organ as well as a pump for circulation, since atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were discovered in cardiomyocytes to be secreted as hormones. Both ANP and BNP bind to their receptors expressed on remote organs, such as kidneys and blood vessels; therefore, the heart controls the circulation by pumping blood and by secreting endocrine peptides. Cardiomyocytes secrete other peptides besides natriuretic peptides. Although most of such cardiomyocyte-derived peptides act on the heart in autocrine/paracrine fashions, several peptides target remote organs. In this review, to overview current knowledge of endocrine properties of the heart, we focus on cardiomyocyte-derived peptides (cardiomyokines) that act on the remote organs as well as the heart. Cardiomyokines act on remote organs to regulate cardiovascular homeostasis, systemic metabolism, and inflammation. Therefore, through its endocrine function, the heart can maintain physiological conditions and prevent organ damage under pathological conditions. PMID- 29238847 TI - Which pre-hospital triage parameters indicate a need for immediate evaluation and treatment of severely injured patients in the resuscitation area? AB - PURPOSE: To find ways to reduce the rate of over-triage without drastically increasing the rate of under-triage, we applied a current guideline and identified relevant pre-hospital triage predictors that indicate the need for immediate evaluation and treatment of severely injured patients in the resuscitation area. METHODS: Data for adult trauma patients admitted to our level 1 trauma centre in a one year period were collected. Outpatients were excluded. Correct triage for trauma team activation was identified for patients with an ISS or NISS >= 16 or the need for ICU treatment due to trauma sequelae. In this retrospective analysis, patients were assigned to trauma team activation according to the S3 guideline of the German Trauma Society. This assignment was compared to the actual need for activation as defined above. 13 potential predictors were retained. The relevance of the predictors was assessed and 14 models of interest were considered. The performance of these potential triage models to predict the need for trauma team activation was evaluated with leave one-out cross-validated Brier and logarithmic scores. RESULTS: A total of 1934 inpatients >= 16 years were admitted to our trauma department (mean age 48 +/- 22 years, 38% female). Sixty-nine per cent (n = 1341) were allocated to the emergency department and 31% (n = 593) were treated in the resuscitation room. The median ISS was 4 (IQR 7) points and the median NISS 4 (IQR 6) points. The mortality rate was 3.5% (n = 67) corresponding to a standardized mortality ratio of 0.73. Under-triage occurred in 1.3% (26/1934) and over-triage in 18% (349/1934). A model with eight predictors was finally selected with under-triage rate of 3.3% (63/1934) and over-triage rate of 10.8% (204/1934). CONCLUSION: The trauma team activation criteria could be reduced to eight predictors without losing its predictive performance. Non-relevant parameters such as EMS provider judgement, endotracheal intubation, suspected paralysis, the presence of burned body surface of > 20% and suspected fractures of two proximal long bones could be excluded for full trauma team activation. The fact that the emergency physicians did a better job in reducing under-triage compared to our final triage model suggests that other variables not present in the S3 guideline may be relevant for prediction. PMID- 29238845 TI - Junctional adhesion molecule-A: functional diversity through molecular promiscuity. AB - Cell adhesion molecules (CAMs) of the immunoglobulin superfamily (IgSF) regulate important processes such as cell proliferation, differentiation and morphogenesis. This activity is primarily due to their ability to initiate intracellular signaling cascades at cell-cell contact sites. Junctional adhesion molecule-A (JAM-A) is an IgSF-CAM with a short cytoplasmic tail that has no catalytic activity. Nevertheless, JAM-A is involved in a variety of biological processes. The functional diversity of JAM-A resides to a large part in a C terminal PDZ domain binding motif which directly interacts with nine different PDZ domain-containing proteins. The molecular promiscuity of its PDZ domain motif allows JAM-A to recruit protein scaffolds to specific sites of cell-cell adhesion and to assemble signaling complexes at those sites. Here, we review the molecular characteristics of JAM-A, including its dimerization, its interaction with scaffolding proteins, and the phosphorylation of its cytoplasmic domain, and we describe how these characteristics translate into diverse biological activities. PMID- 29238849 TI - Video-Assisted Thyroidectomy for Papillary Thyroid Carcinoma: Oncologic Outcome in Patients with Follow-Up >= 10 Years. AB - BACKGROUND: Video-assisted thyroidectomy (VAT) arisen as a valid treatment for selected patients with papillary thyroid carcinoma (PTC), but no data concerning long-term oncologic outcome are available. The primary aim of the study was to evaluate the oncologic outcome of patients who underwent VAT for PTC with a follow-up >= 10 years. METHODS: The medical charts of all the patients who successfully underwent VAT for PTC were reviewed. The patients with a minimum follow-up period of 120-months were included. Patients with unifocal PTC <= 1 cm, in the absence of lymph node metastases, without gross extracapsular invasion and age < 45 years were considered "low-risk" patients and followed with ultrasound and serum thyroglobulin (sTg) on levothyroxine (LT4); the remaining patients underwent nuclear medicine evaluation. RESULTS: Two hundred and fifty-seven patients, operated on between May 2000 and October 2006, were included. Postoperative complications included four transient recurrent palsies, 76 transient and 1 permanent hypocalcemia. One hundred and four low-risk patients were followed with ultrasound and sTg on LT4. At a mean follow-up of 136.6 months, mean sTg on LT4 was 0.1 +/- 0.1 ng/ml. None of them showed recurrence. The remaining 153 patients underwent nuclear medicine evaluation. Among these 153, 62 did not undergo radioiodine ablation (RAI). At a mean follow-up of 150.8 months, mean sTg on LT4 was 0.1 +/- 0.1 ng/ml. None of them showed recurrence. The remaining 91 patients underwent RAI. Mean pre-RAI sTg off-LT4 was 8.3 +/- 5.8 ng/ml, mean radioiodine uptake was 2.8 +/- 4.4%. Among these 91, three pN1a patients developed a lateral neck node recurrence. No other recurrence was registered. At the latest follow-up mean sTg on LT4 in this subgroup of patients was 0.1 +/- 0.2 ng/ml. CONCLUSIONS: The long-term (>= 10 years) oncologic outcome further demonstrates that VAT is a valid option for selected PTC patients. PMID- 29238848 TI - Biology of Bone Sarcomas and New Therapeutic Developments. AB - Bone sarcomas are tumours belonging to the family of mesenchymal tumours and constitute a highly heterogeneous tumour group. The three main bone sarcomas are osteosarcoma, Ewing sarcoma and chondrosarcoma each subdivided in diverse histological entities. They are clinically characterised by a relatively high morbidity and mortality, especially in children and adolescents. Although these tumours are histologically, molecularly and genetically heterogeneous, they share a common involvement of the local microenvironment in their pathogenesis. This review gives a brief overview of their specificities and summarises the main therapeutic advances in the field of bone sarcoma. PMID- 29238850 TI - Risk Factors for Central Neck Lymph Node Metastases in Micro- Versus Macro- Clinically Node Negative Papillary Thyroid Carcinoma. AB - BACKGROUND: Tumor size has been advocated as possible risk factors for occult central lymph node metastases (CNM) in papillary thyroid carcinoma (PTC) patients. This prospective study evaluated factors that could identify patients at higher risk of occult CNM, especially comparing micro-PTC and macro-PTC. METHODS: One hundred and eighty-six patients were recruited. All the patients had cN0 clinically unifocal PTC and underwent total thyroidectomy and bilateral prophylactic central neck dissection. Risk factors for occult CNM in micro- and macro-PTC patients were evaluated. RESULTS: Eighty-two patients showed CNM. The rate of CNM did not differ among different sizes cut off (<=20 mm, <=10 mm, <=5 mm P = NS). Significantly more pN1a than pN0 patients had pT3 tumors (35/82 vs. 26/104) (P < 0.05), extracapsular invasion (35/82 vs. 22/104) (P < 0.01) and microscopic multifocal disease (50/82 vs. 47/104) (P < 0.05). Independent risk factors for CNM were extracapsular invasion and multifocality at multivariate analysis. Risk factors for CNM in 77 micro-PTC were extracapsular invasion (16/31 pN1 vs. 10/46 pN0, P < 0.05) and multifocality (21/31 pN1 vs. 16/46 pN0, P < 0.01). Among 109 macro-PTC, risk factors for CNM were angioinvasion (15/51 pN1 vs. 7/58 pN0, P < 0.05) and classic PTC at the final histology (PTC vs. tall cell variant vs. follicular variant PTC) (P < 0.05). CONCLUSIONS: Risk factors for CNM can differ between micro- and macro-PTC, but no preoperatively known clinical parameter is predictor of CNM in cN0 clinically unifocal PTC. PMID- 29238851 TI - Phase I/II study of mocetinostat in combination with gemcitabine for patients with advanced pancreatic cancer and other advanced solid tumors. AB - PURPOSE: To evaluate the safety and efficacy of mocetinostat (a Class I/IV HDAC inhibitor) in combination with gemcitabine in patients with solid tumors, including pancreatic cancer. METHODS: In this open-label, non-randomized Phase I/II study (NCT00372437) sequential cohorts of patients with solid tumors received gemcitabine (1000 mg/m2, day 1 of three consecutive weeks, 4-week cycles) and oral mocetinostat [50-110 mg, three times per week (TIW)]. The maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) was determined based on dose-limiting toxicities in Cycle 1 (Phase I study). The MTD/RP2D was further evaluated in patients with advanced pancreatic cancer (Phase II study) using a two-stage design. The Phase II primary endpoint was overall response rate (ORR). RESULTS: Forty-eight patients were enrolled into the Phase I (n = 25) and Phase II (n = 23) studies. In the Phase I study, the MTD/RP2D was mocetinostat 90 mg TIW + gemcitabine 1000 mg/m2. Grade >= 3 treatment-related adverse events (AEs) were reported by 81% of all patients, the most frequent being fatigue (38%) and thrombocytopenia (19%). The ORR was 11% in the Phase I study (n = 2 patients with pancreatic cancer, responses lasting for 16.8 and 4.0 months, respectively). As no responses were seen in the Phase II cohort, the study was terminated. CONCLUSIONS: Mocetinostat TIW in combination with gemcitabine was associated with significant toxicities in patients with advanced pancreatic cancer. The level of clinical activity of this treatment combination was not considered high enough to merit further testing in this setting. PMID- 29238852 TI - Combined in-depth, 3D, en face imaging of the optic disc, optic disc pits and optic disc pit maculopathy using swept-source megahertz OCT at 1050 nm. AB - PURPOSE: To demonstrate papillary imaging of eyes with optic disc pits (ODP) or optic disc pit associated maculopathy (ODP-M) with ultrahigh-speed swept-source optical coherence tomography (SS-OCT) at 1.68 million A-scans/s. To generate 3D renderings of the papillary area with 3D volume-reconstructions of the ODP and highly resolved en face images from a single densely-sampled megahertz-OCT (MHz OCT) dataset for investigation of ODP-characteristics. METHODS: A 1.68 MHz prototype SS-MHz-OCT system at 1050 nm based on a Fourier-domain mode-locked laser was employed to acquire high-definition, 3D datasets with a dense sampling of 1600 * 1600 A-scans over a 45 degrees field of view. Six eyes with ODPs, and two further eyes with glaucomatous alteration or without ocular pathology are presented. 3D-rendering of the deep papillary structures, virtual 3D reconstructions of the ODPs and depth resolved isotropic en face images were generated using semiautomatic segmentation. RESULTS: 3D-rendering and en face imaging of the optic disc, ODPs and ODP associated pathologies showed a broad spectrum regarding ODP characteristics. Between individuals the shape of the ODP and the appending pathologies varied considerably. MHz-OCT en face imaging generates distinct top-view images of ODPs and ODP-M. MHz-OCT generates high resolution images of retinal pathologies associated with ODP-M and allows visualizing ODPs with depths of up to 2.7 mm. CONCLUSIONS: Different patterns of ODPs can be visualized in patients for the first time using 3D-reconstructions and co-registered high-definition en face images extracted from a single densely sampled 1050 nm megahertz-OCT (MHz-OCT) dataset. As the immediate vicinity to the SAS and the site of intrapapillary proliferation is located at the bottom of the ODP it is crucial to image the complete structure and the whole depth of ODPs. Especially in very deep pits, where non-swept-source OCT fails to reach the bottom, conventional swept-source devices and the MHz-OCT alike are feasible and beneficial methods to examine deep details of optic disc pathologies, while the MHz-OCT bears the advantage of an essentially swifter imaging process. PMID- 29238853 TI - Detection and genotyping of HPV in urine samples from Chilean women attending primary health care centers. AB - Cervical cancer is the second most common malignant neoplasm in women worldwide representing approximately 10% of all types of cancers. Triage of women through cervical cytology has been an important strategy for the surveillance and control of new cases of cervical cancer. However, in many regions around the world cervical cytology has a low coverage compared to developed countries. The molecular detection of HPV is the most effective method to increase the screening sensitivity of women at risk of developing cervical cancer. There are very few studies about the efficacy of urine testing for detection of HPV in women followed up in primary health care centers. Consequently, the efficacy of using urine HPV screening in these populations has not been addressed yet. Here, we compared the detection of HPV in simultaneous urine and cervical samples of women followed up in primary health care centers. Urine and cervical samples were analyzed in 543 women attending at primary health care centers. HPV was detected by real time PCR, and HPV typing performed by PCR-RLB. A general HPV concordance of 86.2% (kappa = 0.72) was determined between urine and cervical samples. The concordance for HPV-16 and 18 was almost perfect (kappa = 0.82) and strong (kappa = 0.77), respectively. The sensitivity and specificity for all HPV genotypes in urine using cervical samples as reference were 82.1 and 93.7%, respectively. The results showed that urine is a good alternative as clinical sample for HPV screening in women attending primary health care centers. Therefore, urine should be used as an alternative sample for increasing triage coverage either in refractory women participating in Pap surveillance programs or when cervical samples are not available. PMID- 29238855 TI - Epigenesis by experience: Romantic empiricism and non-Kantian biology. AB - Reconstructions of Romantic-era life science in general, and epigenesis in particular, frequently take the Kantian logic of autotelic "self-organization" as their primary reference point. I argue in this essay that the Kantian conceptual rubric hinders our historical and theoretical understanding of epigenesis, Romantic and otherwise. Neither a neutral gloss on epigenesis, nor separable from the epistemological deflation of biological knowledge that has received intensive scrutiny in the history and philosophy of science, Kant's heuristics of autonomous "self-organization" in the third Critique amount to the strategic capture of epigenesis from nature, for thought, in thought's critical transcendence of nature. This essay looks to Jean-Baptiste Lamarck and his English contemporary Erasmus Darwin to begin to reconstruct the rigorously materialist, naturalist, and empiricist theories of epigenesis (still) marginalized by Kantian argumentation. As theorists of environmental and social collaboration in the ontogeny of viable forms, Lamarck and Darwin illuminate features of our own epigenetic turn obscured by the rhetoric of "self organization," allowing us to glimpse an alternative Romantic genealogy of the biological present. PMID- 29238854 TI - Effect of Weight Extremes on Ventricular Volumes and Myocardial Strain in Repaired Tetralogy of Fallot as Measured by CMR. AB - Pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot (rTOF-TAP) is often based on cardiac MRI (CMR) right ventricular (RV) volumes indexed to body surface area (BSA). Weight extremes result in increased patient morbidity and affect indexed measurements. We hypothesized that patients with rTOF-TAP at extremes of weight have (1) over- or underestimated indexed volumes and (2) altered parameters of cardiac function. CMRs in patients with rTOF-TAP were retrospectively reviewed; analysis included right and left ventricular (LV) volumes and ejection fractions (EF) and peak global LV circumferential strain (epsilon cc) from myocardial tagged images. Indexed volumes were recalculated using ideal BSA. Weight categories were assigned: underweight, appropriate weight, overweight, and obese. Linear regression models with weight category, spline of age, and gender were created to assess the association of weight and parameters of volume and function. When RV volumes were corrected for ideal BSA, 11 (31%) additional overweight and obese patients met published criteria for PVR and 3 (38%) underweight patients no longer met criteria. Obese and overweight patients had larger absolute LV and RV diastolic volumes, but no difference in volumes indexed to ideal BSA. Modeling demonstrated no difference in LVEF or RVEF by weight categories but significant differences in global LV epsilon cc. Extremes of body weight may result in inappropriate timing of PVR. Extremes of weight lead to abnormalities in global LV epsilon cc. Although clinical implications of abnormal epsilon cc are unclear, these patients may be at higher risk for early ventricular dysfunction. PMID- 29238856 TI - Anti-endotoxin mechanism of the KW4 peptide in inflammation in RAW 264.7 cells induced by LTA and drug-resistant Staphylococcus aureus 1630. AB - Drug-resistant microorganism infections cause serious disease and can lead to mortality and morbidity. In particular, Staphylococcus aureus induces pyrogenic and toxigenic infections, and drug-resistance occurs rapidly. Multidrug-resistant S. aureus, such as methicillin-resistant S. aureus and methicillin-sensitive S. aureus, can also cause immunodeficiency and immune deficiency syndrome from lipoteichoic acid. However, antimicrobial peptides, such as KW4, have strong antimicrobial activity, low cytotoxicity, and high neutralization activity against endotoxin substances from Gram-negative bacteria. The objective of this study was to use a synthetic KW4 antimicrobial peptide to evaluate the inhibition of drug-resistance development, antimicrobial activity, and neutralizing activity in S. aureus Gram-positive bacteria. The KW4 peptide showed strong antimicrobial activity against drug-resistant S. aureus strains and significantly increased the anti-neutralizing activity of lipoteichoic acid in S. aureus 1630 drug-resistant bacteria. In addition, S. aureus ATCC 29213 did not develop resistance to KW4 as with other antibiotic drugs. These results suggest that the KW4 peptide is an effective antibiotic and anti-neutralizing agent against multidrug-resistant S. aureus strains. PMID- 29238857 TI - FTO rs9939609 A allele influences anthropometric outcome in response to dietary intervention, but not in response to physical exercise program. AB - PURPOSE: The fat mass and obesity-associated (FTO) gene is involved in energy homeostasis. The A allele of the rs9939609 (SNP; T>A) is associated with obesity and higher food intake, while its effect in energy expenditure remains unclear. The aim of this study is to examine whether FTO rs9939609 is associated with the anthropometric outcomes of a physical exercise program and a dietary intervention. METHODS: We studied two independent samples. The first was composed by children and adolescents in which overweight and obese individuals were submitted to a physical exercise program (n = 136) and normal weight participants served as a control group (n = 172). The second sample was composed by obese women submitted to a hypocaloric dietary intervention (n = 126). RESULTS: Physical exercise and dietary intervention were effective, independently of genotype. We found no association of FTO rs9939609 with obesity in children and adolescents (p = 0.67). The rs9939609 affected the response to dietary intervention in obese women: A allele carriers reduced 2.7 cm less of abdominal circumference (AC) than homozygous TT (p = 0.04), while no effect was observed in response to physical exercise in overweight and obese children and adolescents. CONCLUSIONS: The A allele is associated with a worse outcome in response to the hypocaloric dietary intervention regarding abdominal circumference reduction; the same allele did not show interaction with any anthropometric outcomes in response to the exercise program applied. PMID- 29238858 TI - Spatial organization of chromosome territories in the interphase nucleus of trisomy 21 cells. AB - In the interphase cell nucleus, chromosomes adopt a conserved and non-random arrangement in subnuclear domains called chromosome territories (CTs). Whereas chromosome translocation can affect CT organization in tumor cell nuclei, little is known about how aneuploidies can impact CT organization. Here, we performed 3D FISH on control and trisomic 21 nuclei to track the patterning of chromosome territories, focusing on the radial distribution of trisomic HSA21 as well as 11 disomic chromosomes. We have established an experimental design based on cultured chorionic villus cells which keep their original mesenchymal features including a characteristic ellipsoid nuclear morphology and a radial CT distribution that correlates with chromosome size. Our study suggests that in trisomy 21 nuclei, the extra HSA21 induces a shift of HSA1 and HSA3 CTs out toward a more peripheral position in nuclear space and a higher compaction of HSA1 and HSA17 CTs. We posit that the presence of a supernumerary chromosome 21 alters chromosome compaction and results in displacement of other chromosome territories from their usual nuclear position. PMID- 29238859 TI - [Influence of thermodisinfection on impaction of cancellous bone : An in vitro model of femoral impaction bone grafting]. AB - BACKGROUND: The reconstruction of bony defects during endoprosthesis revision surgery using "impaction bone grafting" leads to the possibility of a longstanding osseous integration to achieve good clinical results. Native allogeneic cancellous bone is often used for the procedure. This study examines the influence of thermodisinfection on the impaction behaviour of cancellous bone of different geometries and on the cement distribution. METHODS: The cancellous bone was obtained from the femoral heads of 7-month old pigs. One half of the head was thermodisinfected while the other remained native. Bone chips with sizes of 3-5, 5-8 and 8-10 mm were produced. The impaction was performed in a cylinder model with an internal diameter of 30 mm and with standardized impaction force using an impactor with a weight of 1450 g. The best particle combination was used for the subsequent computer tomography examination of the cement distribution and the contact surface to the bone in different parts of the shaft in seven investigations. For statistic measurements two-dimensional variance analysis including repetitions of measurement and Bonferroni correction, the LSD post-hoc zest and the Mann Whitney U Test were used. The error probability was set at alpha = 5%. The SPSS(r) for Windows software was used for the statistical analysis. RESULTS: The distribution of the cancellous and compacted bone also along the shaft revealed no significant difference between thermodisinfected and native cancellous bone at different levels (p > 0.05). Impacted native cancellous bone showed less inclusion of air, which resulted in a better distribution of density compared with thermodisinfected bone overall (p < 0.001). In the distal shaft area the cement volume was significantly larger in conjunction with the native bone. The overall area of cement penetration appeared to be significantly larger for native cancellous bone (p < 0.001). CONCLUSIONS: The impaction of thermodisinfected and native cancellous bone showed greater deformation of the processed bone without any significant difference in the maximum density reached at different levels. Cement volume and cement penetration were pronounced proximally in native and processed cancellous bone. The cement distribution was significantly more distal for the native bone. Distally, the stabilization of the shaft appears to be increasingly dependent on the density of the impacted spongiosa, while proximally, the penetration of the cement into cancellous bone seems to correlate with porosity. PMID- 29238860 TI - Antioxidant responses in the earthworm Aporrectodea caliginosa of eastern Slovakia: application of principal component analysis as a tool to identify metal contaminated areas. AB - The soil of Slovak Republic is severely contaminated with heavy metals, creating hazards to soil health. In order to assess the current status with the prospect of selecting the appropriate treatment methods and land use, this investigation aimed to determine a panel of complementary and ecologically relevant biomarkers that reflect adverse biological responses towards terrestrial pollutants. To attain this objective, the concentration of reduced glutathione and enzymes of glutathione antioxidant system were assessed in clitellate earthworm, Aporrectodea caliginosa sampled from selected sites of eastern Slovakia along with the pH and total metal concentration (As, Cd, Pb, Cr, Hg, Mn, Fe, Co, Ni, Cu, Zn) of soils. Positive, significant (p < 0.05) induction of glutathione peroxidase, glutathione reductase, and glutathione-S-transferase activities and depletion of reduced glutathione level (negative correlation) were associated with the increased soil metal concentrations. Metal interference was found in the detoxification process and antioxidant defense mechanism does not efficiently counteract the oxidative stress induced by chronic metal exposure. The tested biomarkers confirmed sensitive and affective response to the pollution of soil contaminants, in this case metals. This has a potential use in ecotoxicological field monitoring. The proposed principal component analysis is a multivariate model of data analysis that represents a cost-effective approach to differentiate metalliferous soils of eastern Slovakia with different health status. PMID- 29238861 TI - Metals and limnological variables in an urban reservoir: compartmentalization and identification of potential impacted areas. AB - Reservoirs in urban areas are used for different purposes and are liable to different types of pressures that can cause the loss of chemical and biological quality, hence diminishing their ecological, economic, and cultural benefits. Here, a study of surface water heterogeneity was undertaken at the Guarapiranga urban reservoir (Sao Paulo, Brazil) in order to improve understanding of the structure and functioning of these ecosystems. Sampling was performed during the dry and rainy seasons at 33 sites. Limnological variables and total contents of the metals cadmium, nickel, lead, and zinc were analyzed. The risks associated with the metals were evaluated based on the toxicity unit approach. A principal component analysis enabled differentiation of the reservoir into six different areas. Some of the most powerful discriminatory variables (nutrients and metals) showed the existence of anthropogenic impacts on the system. The most strongly affected compartments were located in the following: (1) upstream area, under the influence of the Parelheiros stream, with the highest total phosphorus levels (318 mg L-1) and (2) dam area, with high values for total nitrogen, suspended organic matter, total solids, and pH. The results for the dam compartment were a consequence of substantial urbanization and a longer residence time. Despite high levels of cadmium during the rainy season, no significant potential risk for zooplankton was observed. The data indicated the need to control unauthorized land occupation and to implement adequate sanitation in the Guarapiranga watershed. This research provides information that should assist water resource agencies in the sustainable management of urban reservoirs. PMID- 29238862 TI - Pursuing extreme sensitivity for determination of endogenous brassinosteroids through direct fishing from plant matrices and eliminating most interferences with boronate affinity magnetic nanoparticles. AB - Brassinosteroids (BRs) are important plant hormones regulating plant growth and development. High-performance analytical methods for quantifying endogenous BRs are important for studying the molecular mechanisms of BR action. Herein we developed a high-performance sample pretreatment method based on boronate affinity magnetic nanoparticles (BAMNPs). The high specificity of boronate affinity enables direct fishing of BRs from plant matrices. The strong binding energy makes it possible to remove most contaminants in plant matrices with a small loss of target BRs. Besides these advantages, the novel two-step oxidation hydrolysis elution system raised BR recoveries to 70.5%-98.2%, which was much higher than other boronate affinity applications. The high cleanliness of the final eluents lowered the matrix effects to 85.2%-92.4%. As a result, this method enables simultaneously good recoveries of endogenous BRs and thorough removal of matrix interferences, which greatly improves the sensitivity of BR analysis and reduces the use of plant materials for routine analysis to <10 mg. In addition, the sample handling time can be shortened to <3 h due to the operating convenience of BAMNPs and their easy separation from plant powders. Based on these advantages of BAMNP solid phase extraction, the organ-specific BR distribution analysis in Arabidopsis and rice tissues demonstrates excellent sensitivity, good reproducibility and high throughput of the method. Graphical abstract A high-sensitivity and time-saving UPLC-MS/MS-based quantification method for brassinosteroids (BRs) was developed through directly fishing BRs from plant matrices and eliminating most matrix interferences with as-prepared boronate affinity magnetic nanoparticles (BAMNPs). PMID- 29238863 TI - Normal-phase liquid chromatography retention behavior of polycyclic aromatic sulfur heterocycles and alkyl-substituted polycyclic aromatic sulfur heterocycle isomers on an aminopropyl stationary phase. AB - Retention indices for 67 polycyclic aromatic sulfur heterocycles (PASHs) and 80 alkyl-substituted PASHs were determined using normal-phase liquid chromatography (NPLC) on an aminopropyl (NH2) stationary phase. The retention behavior of PASH on the NH2 phase is correlated with the number of aromatic carbon atoms and two structural characteristics have a significant influence on their retention: non planarity (thickness, T) and the position of the sulfur atom in the bay-region of the structure. Correlations between solute retention on the NH2 phase and T of PASHs were investigated for three cata-condensed (cata-) PASH isomer groups: (a) 13 four-ring molecular mass (MM) 234 Da cata-PASHs, (b) 20 five-ring MM 284 Da cata-PASHs, and (c) 12 six-ring MM 334 Da cata-PASHs. Correlation coefficients ranged from r = -0.49 (MM 234 Da) to r = -0.65 (MM 334 Da), which were significantly lower than structurally similar PAH isomer groups (r = -0.70 to r = -0.99). The NPLC retention behavior of the PASHs are compared to similar results for PAHs. PMID- 29238864 TI - Species' traits do not converge on optimum values in preferred habitats. AB - Plant trait expression is shaped by filters, which can alter trait means and variances, theoretically driving species toward an "optimum" trait value for a set of environmental conditions. Recent research has highlighted the ubiquity of intraspecific variation in functional traits, which can cause plants to diverge from a hypothesized "optimum". We examined whether species occurring in "core" habitats (where they occur frequently, abundantly, and consistently) express traits that are nearer to "optimum", as captured by the community-weighted mean (CWM). We also asked whether trait variance showed signs of environmental filtering. We used cluster analysis to group plots based on environmental factors along a wet-to-dry ecotone. We used indicator species analysis to identify species with strong associations within each cluster. Trait means and variances were compared, and evidence of variance filtering was tested using a null-model approach. Trait means and trait variances respond to local-scale environmental filtering and species in core habitats were not necessarily nearer to the CWM than in other habitats. Intraspecific trait variability shows a strong signal of filtering, as variability was reduced for nearly all species and all traits compared to estimates of variability generated in the absence of environmental filtering. Our results provide strong evidence that species traits are not necessarily near "optimum" trait values in core habitats, and that trait distributions within species are strongly shaped by the environment. Future analyses should account for this divergence when calculating metrics of functional diversity, and extrapolating to ecosystem function. PMID- 29238865 TI - Construct validity and sensitivity to change of Belgrade Ultrasound Enthesitis Score in patients with spondyloarthritis: a pilot study. AB - The objective of this study was to determine the construct validity and sensitivity to change of Belgrade Ultrasound Enthesitis Score (BUSES) in spondyloarthritis patients. Seventy-six spondyloarthritis patients with enthesitis were included in this pilot, prospective, double-blinded ultrasound study. Thirty-four patients received biological and forty-two patients received non-biological therapy. BUSES was determined at the beginning, after 1, 3, and 6 months. Spearman's correlation coefficient was calculated between BUSES and baseline characteristics. Brunner-Langer mixed non-parametric ANOVA was used to examine sensitivity to change of BUSES and effect of biological therapy on BUSES. Effect of time on the presence of each of the ultrasound enthesitis signs (increased thickness, hypoehogenicity, Power Doppler, enthesophytes, and erosions) was assessed using Cochran Q test. There was a weak, positive correlation between BUSES and disease duration, clinical enthesitis score, BASFI, BASDAI, and ASDAS-ESR/CRP. BUSES was higher at the beginning than after 1 month (p = 0.004), after 3 months (p < 0.001) and after 6 months (p < 0.001), as well as BUSES was higher after 1 month than after 3 months (p < 0.001) and after 6 months (p = 0.002). There is no difference in efficiency between non-biological and biological therapies on BUSES. Increased thickness, hypoechogenicity, and Power Doppler have decreased on Achilles tendon's and plantar fascia's enthesis over time. BUSES has a certain degree of construct validity because of the weak, positive correlation with parameters referring to severity of spondyloarthritis. BUSES demonstrated sensitivity to change over time due to decreasing of ultrasound acute enthesitis signs in treated spondyloarthritis patients. BUSES could be useful for monitoring the progression of enthesitis and effectiveness of the treatment. PMID- 29238866 TI - Validation of goose liver fat measurement by QCT and CSE-MRI with biochemical extraction and pathology as reference. AB - OBJECTIVES: This study aimed to validate the accuracy and reliability of quantitative computed tomography (QCT) and chemical shift encoded magnetic resonance imaging (CSE-MRI) to assess hepatic steatosis. METHODS: Twenty-two geese with a wide range of hepatic steatosis were collected. After QCT and CSE MRI examinations, the liver of each goose was removed and samples were taken from the left lobe, upper and lower half of the right lobe for biochemical measurement and histology. Fat percentages by QCT and proton density fat fraction by MRI (MRI PDFF) were measured within the sample regions of biochemical measurement and histology. The accuracy of QCT and MR measurements were assessed through Spearman correlation coefficients (r) and Passing and Bablok regression equations using biochemical measurement as the "gold standard". RESULTS: Both QCT and MRI correlated highly with chemical extraction [r = 0.922 (p < 0.001) and r = 0.949 (p < 0.001) respectively]. Chemically extracted triglyceride was accurately predicted by both QCT liver fat percentages (Y = 0.6 + 0.866 * X) and by MRI-PDFF (Y = -1.8 + 0.773 * X). CONCLUSIONS: QCT and CSE-MRI measurements of goose liver fat were accurate and reliable compared with biochemical measurement. KEY POINTS: * QCT and CSE-MRI can measure liver fat content accurately and reliably * Histological grading of hepatic steatosis has larger sampling variability * QCT and CSE-MRI have potential in the clinical setting. PMID- 29238867 TI - A direct comparison of contrast-enhanced ultrasound and dynamic contrast-enhanced magnetic resonance imaging for prostate cancer detection and prediction of aggressiveness. AB - INTRODUCTION: Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) analyse tissue vascularization. We evaluated if CEUS can provide comparable information as DCE-MRI for the detection of prostate cancer (PCa) and prediction of its aggressiveness. MATERIAL AND METHODS: A post-hoc evaluation of 92 patients was performed. In each patient CEUS and DCE-MRI parameters of the most suspicious lesion identified on MRI were analysed. The predictive values for discrimination between benign lesions, low /intermediate- and high-grade PCa were evaluated. Results of targeted biopsy served as reference standard (benign lesions, n=51; low- and intermediate-grade PCa [Gleason grade group 1 and 2], n=22; high-grade PCa [>= Gleason grade group 3], n=19). RESULTS: In peripheral zone lesions of all tested CEUS parameters only time to peak (TTPCEUS) showed significant differences between benign lesions and PCa (AUC 0.65). Of all tested DCE-MRI parameters, rate constant (Kep) was the best discriminator of high-grade PCa in the whole prostate (AUC 0.83) and in peripheral zone lesions (AUC 0.89). CONCLUSION: DCE-MRI showed a superior performance for detection of PCa and prediction of its aggressiveness. CEUS and DCE-MRI performed better in peripheral zone lesions than in transition zone lesions. KEY POINTS: * DCE-MRI gathers information about vascularization and capillary permeability characteristics of tissues. * DCE-MRI can detect PCa and predict its aggressiveness. * CEUS also gathers information about vascularization of tissues. * For detection of PCa and prediction of aggressiveness DCE-MRI performed superiorly. * Both imaging techniques performed better in peripheral zone lesions. PMID- 29238868 TI - Early Experience and Lessons Learnt with Customized Fenestrated Thoracic Endovascular Aortic Reconstruction for Aortic Arch Pathology in an Asian Population. AB - PURPOSE: Thoracic endovascular aortic repair (TEVAR) is the preferred treatment of descending thoracic aorta pathology. However, TEVAR in the aortic arch remains challenging. Customized fenestrated TEVAR (fTEVAR) allows extension of the proximal seal zone, while preserving the involved supra-aortic vessels. There is a paucity of information on fTEVAR; hence, we aim to evaluate our early experience and lessons learnt with fTEVAR in the aortic arch. METHODS: This is a retrospective single-centre review of fTEVAR endografts for aortic arch pathology over 24 months. Seven patients with mean age of 72.8 years (range 63-84 years) were included. A total of 15 supra-aortic branches were treated [left subclavian artery (n = 7), left carotid artery (n = 5), innominate artery (n = 1), bovine origins (n = 2)], involving a total of nine fenestrations and six scallops. No supra-aortic debranching was required. RESULTS: Median follow-up was 15 months. Technical success was 86%, and one patient had malalignment of the fTEVAR endograft requiring salvage with double chimney technique. There were no early endoleaks with one type 2 endoleak detected in the follow-up period. Two access site pseudoaneurysms required intervention. There was a learning curve involved reflected by higher than average mean operative time of 224 min with average radiation dose of 3029.86 mGy and mean contrast volume of 283 mls. CONCLUSION: fTEVAR in the aortic arch is feasible in Asian patients, although there was a learning curve involved, and careful patient selection is advised. Longer term data in a larger population are required to assess its durability. PMID- 29238869 TI - Lymphangiography and Lymphatic Embolization for the Treatment of Refractory Chylous Ascites. AB - PURPOSE: Assess the effectiveness of conventional lymphangiography, MR lymphangiography, and lymphatic embolization for the diagnosis and treatment of refractory chylous ascites. MATERIALS AND METHODS: A retrospective review of 31 patients (M/F:16/15, average age 52) who presented for the management of refractory chylous ascites was conducted to assess the diagnostic value of conventional and MR lymphangiography and outcome of lymphatic embolization. RESULTS: Of the total 31 patients, 25 presented with chylous ascites secondary to iatrogenic trauma and six patients with a non-traumatic etiology. All patients underwent conventional lymphangiography and nine underwent MR lymphangiogram. The lymphatic leak was visualized in 17/31 (55%) of the patients (15 of which were traumatic) and in 7/9 MR lymphangiograms (six traumatic and one non-traumatic). Embolization with n-BCA glue and/or coils of the leak was performed in 11 of the 17 patients whose leak was identified (65%) with resolution of chylous ascites in 9/11 (82%) patients. Lymphangiogram alone was curative in 7/20 (35%) patients. Overall, 16/31 patients (52%) had clinical resolution of ascites. Ascites resolved in 13/17 (76%) patients in whom the site of leak could be identified compared to 3/14 (21%) of patients in whom the site of leak could not be identified (p = 0.0038). CONCLUSIONS: Lymphangiography and embolization can be used to treat chylous ascites. Identification of the site of leak is associated with significantly greater rate of clinical success compared to those whose site could not be identified. PMID- 29238870 TI - Chest Radiograph Measurement Technique Facilitates Accurate Bedside Peripherally Inserted Central Catheter Placement in Children. AB - PURPOSE: To report the chest radiograph measurement technique for placing bedside peripherally inserted central catheters (PICCs). MATERIALS AND METHODS: Two hundred and thirty-two consecutive pediatric patients, mean age of 56.3 months (range: 0-203 months), underwent PICC placement from January 2015 to May 2017 (28 months) with a total of 232 PICCs placed. Measurements were taken from the cavoatrial junction to clavicle, clavicle to medial margin of mid-humeral head, and medial margin of mid-humeral head to mid-humerus. The difference between total radiographic measured length and actual PICC length was then calculated, and the percent difference (from actual cut length) was recorded. An equivalence test was performed using the two, one-sided test method. RESULTS: Mean +/- standard deviation cavoatrial junction to clavicle length was 5.29 +/- 2.20 cm (range: 2.1-12.6 cm). Mean clavicle to shoulder length was 8.20 +/- 3.59 cm (range: 3.23-19.06 cm). Mean shoulder to mid-humerus length was 7.88 +/- 3.87 cm (range: 2.01-16.8 cm). Mean total radiographic measured length was 21.37 +/- 9.19 cm (range: 7.42-43.6 cm). Mean actual cut PICC length was 20.64 +/- 8.72 cm (range: 8.5-44 cm). The mean difference between predicted, or total radiographic measured length, and actual cut PICC length was 0.73 +/- 2.51 (range: - 5.42-8.60 cm). The mean percent difference was 4.07 +/- 12.65% (range: - 23.84-47.80%). An equivalence test rejected the null hypothesis of the true percent difference greater/less than +/- 6.67% with a p value of 0.002. CONCLUSION: The chest radiograph measurement technique is an accurate method to determine catheter length for PICC placement at bedside in the pediatric population. PMID- 29238871 TI - Minimally invasive stabilisation of posterior pelvic ring instabilities with pedicle screws connected to a transverse rod. AB - PURPOSE: The goal was to evaluate the clinical outcomes, quality of reduction and complications of pelvic fractures treated by minimally invasive stabilisation of posterior pelvic ring instabilities with pedicle screws connected to a transverse rod. METHODS: Retrospective analysis of prospectively collected data in a consecutive patient series with pelvic fractures treated by minimally invasive stabilisation of posterior pelvic ring instabilities with pedicle screws between January 2010 and January 2016. The functional outcomes evaluated by Majeed scores, and fracture reduction results were evaluated using the Tornetta and Matta standard. As well as recording the duration of the surgical procedure, intraoperative blood loss, the times of intra-operative fluoroscopy and complications. RESULTS: A total of 29 patients (15 men and 14 women; age range, 21-72 years; mean, 40.8 years) could be followed-up after an average of 38.2 +/- 21.3 months (range, 12-84 months). According to the AO/OTA classification, there were 24 patients with B2 injury and five patients with C1 injury of the pelvic ring. For the sacral fractures, according to Denis classification, four cases were zone I fractures and 25 cases were zone II fractures. The duration of the surgical procedure, intra-operative blood loss and the times of intra-operative fluoroscopic of the posterior-ring surgical procedure was 28.2 +/- 4.6 minutes (range, 20-38 minutes), 46.7 +/- 4.9 ml (range, 39-56 ml), and 13.1 +/- 1.6 seconds (range, 10-17 seconds) respectively. Posterior-ring fracture reduction was excellent in 11 patients and 15 were good, three cases were fair; the excellent and good rate was 89.7% (26/29). At the final follow-up, the function result was rated as excellent in ten cases, good in 16, fair in three, and poor in zero cases; the excellent and good rate was 89.7% (26/29). There was no incision infection, intra-operative neurovascular injury, pedicle screw loose or breakage, and non-union of the posterior arch did not occur. Two patients requested removal of the fixator: one patient with breakage of the anterior pelvic ring internal fixator, and the pedicle screw was also taken out in the same operative session; another one with moderate pain on the posterior pelvic ring. CONCLUSIONS: Minimally invasive stabilisation of posterior-pelvic-ring instabilities with pedicle screw connected to a transverse rod may be a good alternative to sacroiliac screw fixation because it is quick, safe and associated with a good functional outcome; thus being a useful option in patients who do not qualify for sacroiliac screw fixation. PMID- 29238873 TI - Insights into the generation of monoclonal antibody acidic charge variants during Chinese hamster ovary cell cultures. AB - Charge variation is one of the most important heterogeneities during monoclonal antibody (mAb) manufacturing and this study presents insights into the generation of acidic charge variants during cell culture processes. Since acidic variants generate both intracellularly and extracellularly, main charge fraction collected by weak cation exchange chromatography (WCX) was incubated in harvested cell supernatant (HCS) to simulate and investigate the extracellular process firstly. It is found that the main fraction was degraded rapidly into acidic variants rather than basic variants extracellularly, and the degradation sites were located in both Fab and Fc fragments indicated by papain digestion. Besides, certain process parameters were investigated as their potential roles in the extracellular process. As a result, media composition showed significant influence on degradation while culture time point did not, suggesting that the extracellular process was a spontaneous process without enzyme catalysis. Additionally, kinetics study reveals that the extracellular process was a pseudo first-order reaction. The E app value (21.59 kcal/mol) estimated from the Arrhenius equation suggests that the extracellular degradation might be mainly attributed to asparagine deamidation. Furthermore, we established an acidic variants generation model, indicating that the extracellular process plays a dominant role in modulating the final acidic variant level. This study provides better understanding for controlling product heterogeneity in mAb manufacturing. PMID- 29238872 TI - Characterization of two carbonyl reductases from Ogataea polymorpha NBRC 0799. AB - The enzyme responsible for the enantioselective production of (S)-1,1,1-trifluoro 2-propanol ((S)-TFP) from 1,1,1-trifluoroacetone (TFA) has been identified in Ogataea polymorpha NBRC 0799. We purified two carbonyl reductases, OpCRD-A and OpCRD-B from this strain, and revealed their characteristics. Both enzymes were specific to NADH, but the following characteristics were different: The molecular mass of subunit OpCRD-A was 40 kDa and that of OpCRD-B was 43 kDa. Amino acid sequences of both enzymes were only 21% identical. OpCRD-B contained 4 mol of zinc per mole of enzyme, but OpCRD-A did not. The optimal pH, temperature, pH stability, thermostability, and inhibitor specificity were also remarkably different. With regard to substrate specificity, both enzymes exhibited high reductase activity toward a wide variety of ketones, aldehydes and fluoroketones, and dehydrogenase activity toward 2-propanol and 2-butanol. The reductase activity was much higher than the dehydrogenase activity at acidic pH. OpCRD-A enantioselectively produced (S)-TFP from TFA, but OpCRD-B preferentially produced (R)-TFP. Thus, we concluded that OpCRD-A plays the main role in the production of (S)-TFP by a reaction of O. polymorpha NBRC 0799 cells and that OpCRD-A has great potential for efficient production of (S)-TFP, as it is an S-specific enzyme and does not catalyze the dehydrogenation of (S)-TFP. PMID- 29238874 TI - Bacteria-mediated phthalic acid esters degradation and related molecular mechanisms. AB - Phthalic acid esters (PAEs) have long been known as the most widely used plasticizer with a broad range of industrial application. PAEs are ubiquitous in different environments and our daily life due to their large and widespread application. Recent PAEs research mainly focused on their environmental fate (including leaching, migration, transformation) and toxicology and risk assessment. With the comprehensive recognition of their potential hazard, the elimination of PAEs has attracted worldwide concerns. Although many factors may contribute to the degradation of PAEs, the dominant role of biodegradation was widely reported. Many PAEs-degrading bacteria were isolated, metabolites and metabolic pathways were proposed, and enzymes involved in the degradation were identified. The current paper presents an overview of available reports about PAEs-degrading bacteria and related molecular mechanisms. The metabolic pathways deduced from the identified intermediates were presented. The upstream and downstream pathways of PAEs metabolism were summarized, including the aerobic and anaerobic pathways of phthalic acid (PA) degradation. Known enzymes involved in the hydrolysis of ester bonds were characterized according to their properties. Based on phylogenetic analysis, all these enzymes were distributed in four families of esterases and one unknown family. For these five families, conserved sequence motifs were identified and the biological properties of these motifs were characterized. Challenges and emerging opportunities are also discussed. PMID- 29238875 TI - Pepsin in saliva as a diagnostic biomarker in laryngopharyngeal reflux: a meta analysis. AB - OBJECTIVE: Pepsin in saliva has been proposed as a biomarker for the diagnosis of laryngopharyngeal reflux (LPR), but the results remain controversial. We assessed the diagnostic value of pepsin in saliva for LPR. METHODS: PubMed, Embase, and Web of Science were searched for studies in English that evaluated the utility of pepsin in saliva in the diagnosis of LPR, published up to 15 March 2017. We used Stata 12.0 to summarize the diagnostic indexes for the meta-analysis. RESULTS: Eleven eligible studies met the inclusion criteria. After the meta-analysis of included studies, the pooled sensitivity and specificity were 64% [95% confidence interval (CI) 43-80%] and 68% (95% CI 55-78%), respectively; the positive (PLR) and negative (NLR) likelihood ratios were 2.0 (95% CI 1.4-2.9) and 0.54 (95% CI 0.33-0.87), respectively; the diagnostic odds ratio (DOR) was 4 (95% CI 2-8); and the area under the curve (AUC) was 0.71 (95% CI 0.67-0.75). CONCLUSION: Pepsin in saliva has moderate value in the diagnosis of LPR. The cutoff value used could affect the diagnostic value. Therefore, further investigations are required to find the optimal method to detect salivary pepsin in diagnosing LPR. PMID- 29238876 TI - Independent association between prediabetes and future pancreatic fat accumulation: a 5-year Japanese cohort study. AB - BACKGROUND: The association between pancreatic fat and glucose dysmetabolism has been reported in several cross-sectional studies; however, a recent longitudinal study showed that baseline pancreatic fat did not cause subsequent diabetes mellitus. We hypothesized that pancreatic fat is not a cause but a manifestation of glucose dysmetabolism and aimed to investigate the association between baseline prediabetes and future pancreatic fat accumulation. METHODS: Between 2008 and 2015, 198 nondiabetic participants, who underwent a health check-up via unenhanced computed tomography (CT) twice with CT intervals >= 5 years, were enrolled as prediabetes (n = 48) and non-prediabetes participants (n = 150). Prediabetes was defined as fasting plasma glucose of 100-125 mg/dl or hemoglobin A1c of 5.7-6.4%. Pancreatic fat was evaluated using a histologically validated method to measure the difference between pancreas and spleen attenuations (P-S) on CT. Pancreatic fat accumulation during follow-up was measured as P-S change from baseline. Multiple linear regression was used to evaluate the association between baseline prediabetes and future pancreatic fat accumulation with adjustment for age, sex, body mass index, physical activity, and liver fat at baseline. RESULTS: Mean pancreatic fat accumulation was 0.30 (SD, 5.8) Hounsfield units during follow-up. On univariate analysis, baseline prediabetes was associated with future pancreatic fat accumulation (beta = 3.73; 95% CI 1.91 5.55; P < 0.001). This association remained statistically significant on multivariate analysis (beta = 3.14; 95% CI 1.25-5.03; P = 0.001). CONCLUSIONS: Prediabetes is a risk factor for future pancreatic fat accumulation. Pancreatic fat may be a manifestation of glucose dysmetabolism. PMID- 29238878 TI - Offal dumping sites influence the relative abundance and roosting site selection of Black Kites (Milvus migrans govinda) in urban landscape: a study from Kolkata metropolis, India. AB - Although Black Kites (Milvus migrans govinda) serve as major scavenging raptor in most of the urban areas, scientific studies on this important ecosystem service provider are almost non-existent in Indian context. The present study was carried out in a metropolis in eastern India to find out the factors influencing relative abundance and roosting site selection of Black Kites. Separate generalized linear models (GLMs) were performed considering encounter rate and roosting Black Kite abundance as response variables. The study conclusively indicated that encounter rates of Black Kites were significantly influenced by the presence of garbage dumps in its vicinity. Numbers of Black Kites were also higher in the roosting sites situated closer to garbage dumps and open spaces. In addition, expected counts of Black Kites significantly increased in roosting sites situated away from buildings and water bodies. However, built-up area and tree cover around the roosting sites had no influence on the abundance of Black Kites therein. With rapid urbanization and changing offal disposal patterns, our findings would be useful to ensure continued availability of food and roosting sites of Black Kites in urban areas. PMID- 29238877 TI - Cryptogenic cholestasis in young and adults: ATP8B1, ABCB11, ABCB4, and TJP2 gene variants analysis by high-throughput sequencing. AB - BACKGROUND: Mutations in ATP-transporters ATPB81, ABCB11, and ABCB4 are responsible for progressive familial intrahepatic cholestasis (PFIC) 1, 2 and 3, and recently the gene for tight junction protein-2 (TJP2) has been linked to PFIC4. AIM: As these four genes have been poorly studied in young people and adults, we investigated them in this context here. METHODS: In patients with cryptogenic cholestasis, we analyzed the presence of mutations by high-throughput sequencing. Bioinformatics analyses were performed for mechanistic and functional predictions of their consequences on biomolecular interaction interfaces. RESULTS: Of 108 patients, 48 whose cause of cholestasis was not established were submitted to molecular analysis. Pathogenic/likely pathogenic mutations were found in ten (21%) probands for 13 mutations: two in ATP8B 1, six in ABCB11, two in ABCB4, three in TJP2. We also identified seven variants of uncertain significance: two in ATP8B1, one in ABCB11, two in ABCB4 and two in TJP2. Finally, we identified 11 benign/likely benign variants. Patients with pathogenic/likely pathogenic mutations had higher levels of liver stiffness (measured by FibroScan(r)) and bile acids, as well as higher rates of cholestatic histological features, compared to the patients without at least likely pathogenic mutations. The multivariate analysis showed that itching was the only independent factor associated with disease-causing mutations (OR 5.801, 95% CI 1.244-27.060, p = 0.025). CONCLUSIONS: Mutations in the genes responsible for PFIC may be involved in both young and adults with cryptogenic cholestasis in a considerable number of cases, including in heterozygous status. Diagnosis should always be suspected, particularly in the presence of itching. PMID- 29238880 TI - In vitro performance of prefilled CO2 absorbers with the Zeus(r). AB - Low fresh gas flows (FGFs) decrease the use of anesthetic gases, but increase CO2 absorbent usage. CO2 absorbent usage remains poorly quantified. The goal of this study is to determine canister life of 8 commercially available CO2 absorbent prepacks with the Zeus(r). Pre-packed CO2 canisters of 8 different brands were tested in vitro: Amsorb Plus, Spherasorb, LoFloSorb, LithoLyme, SpiraLith, SpheraSorb, Dragersorb 800+, Dragersorb Free, and CO2ntrol. CO2 (160 mL min- 1) flowed into the tip of a 2 L breathing bag that was ventilated with a tidal volume of 500 mL, a respiratory rate of 10/min, and an I:E ratio of 1:1 using the controlled mechanical ventilation mode of the Zeus(r) (Drager, Lubeck, Germany). In part I, canister life of 5 canisters each of 2 different lots of each brand was determined with a 350 mL min- 1 FGF. Canister life is the time it takes for the inspired CO2 concentration (FICO2) to rise to 0.5%. In part II, canister life was measured accross a FGF range of 0.25 to 4 L min- 1 for Dragersorb 800+ (2 lots) and SpiraLith (1 lot). In part III, the calculated canister life per 100 g fresh granule content of the different brands was compared between the Zeus and (previously published data for) the Aisys. In vitro canister life of prefilled CO2 absorber canisters differed between brands, and depended on the amount of CO2 absorbent and chemical composition. Canister life expressed as FCU0.5 (the fraction of the canister used per hour) was proportional to FGF over 0.2-2 L min 1 range only, but was non-linear with higher FGF: FCU0.5 was larger than expected with FGF > 2 L min-1, and even with FGF > minute ventilation FCU0.5 did not become zero, indicating some CO2 was being absorbed. Canister life on a per weight basis of the same brand is higher with the Zeus than the Aisys. Canister life of prefilled CO2 absorber canisters differs between brands. The FCU0.5-FGF relationship is not linear across the entire FGF range. Canister life of prepacks of the same brand for the Zeus and Aisys differs, the exact etiology of which is probably multifactorial, and may include differences in the absolute amount of absorbent and different rebreathing characteristics of the machines. PMID- 29238879 TI - The small vesicular culprits: the investigation of extracellular vesicles as new targets for cancer treatment. AB - Extracellular vesicles (EVs) are membranous vesicles released from almost all type of cells including cancer cells. EVs transfer their components, such as microRNAs (miRNAs), messenger RNAs, lipids and proteins, from one cell to another, affecting the target cells. Emerging evidence suggests that reciprocal interactions between cancer cells and the cells in their microenvironment via EVs drive disease progression and therapy resistance. Therefore, understanding the roles of EVs in cancer biology will provide us with new opportunities to treat patients. EVs are also useful for monitoring disease processes. EVs have been found in many kinds of biological fluids such as blood, urine, saliva and semen. Because of their accessibility, EVs offer ease of collection with minimal discomfort to patients and are preferred for serial collection. In addition, they reflect and carry dynamic changes in disease, allowing us to access crucial molecular information about the disease status. Therefore, EVs hold great possibility as clinically useful biomarkers to provide multiple non-invasive snapshots of primary and metastatic tumors. In this review, we summarize current knowledge of miRNAs in EVs in cancer biology and as biomarkers. Furthermore, we discuss the potential of miRNAs in EVs for clinical application. PMID- 29238881 TI - Peritoneal Carcinomatosis of Urachus Origin Treated by Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An International Registry of 36 Patients. AB - PURPOSE: Peritoneal carcinomatosis or pseudomyxoma peritonei from urachus is a rare form of presentation, often diagnosed at an advanced state of tumor burden. Because of its rarity, little is known about its natural history, prognosis, or optimal treatment. We searched a large international multicenter database of peritoneal surface disease to identify cases of peritoneal carcinomatosis of urachus that were treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) at expert centers. The aim is to improve knowledge and understanding of the disease and standardize its treatment. METHODS: A prospective multicenter international database was retrospectively searched to identify all patients with urachus tumor and peritoneal metastases who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI). Postoperative complications, long-term results, and principal prognostic factors were analyzed. RESULTS: The analysis included 36 patients. After median follow-up of 48 months, median overall survival (OS) was 58.5 months. Three- and 5-year OS was 55.4 and 46.2%, respectively. Patients who underwent complete macroscopic CRS had significantly better survival than those treated with incomplete CRS, with median OS not achieved and of 20.1 months, respectively [95% confidence interval (CI) 4.4-30.5, p < 0.001]. There were no postoperative deaths, and 37.9% of patients had major complications. CONCLUSION: CRS and HIPEC may increase long-term survival in selected patients with peritoneal metastases of urachus origin, especially when complete CRS is achieved. PMID- 29238882 TI - The presentation and management of hypertension in a large cohort of Takayasu arteritis. AB - The objective of this study was to explore the presentation and management of hypertension secondary to Takayasu arteritis (TA) in a large cohort, single center in China. We retrospectively analyzed 381 TA patients with hypertension hospitalized in Fuwai hospital between Jan. 2004 and Feb. 2014. Diagnosis of hypertension was according to clinic blood pressure or the central blood pressure measured during angiography. Renal artery stenosis was the most common cause (264, 69.3%), followed by the thoracic descending aorta stenosis (98, 25.7%), abdominal aorta stenosis (78, 20.5%), and severe aortic regurgitation (45, 11.8%). More than two kinds of pathologies were found in 98 (25.7%) patients. The mean age of hypertension onset was 25.0 +/- 14.3 years. The mean blood pressure of upper extremity in patients without bilateral subclavian artery stenosis (321, 84.3%) was 176.0 +/- 29.4 mmHg/97.2 +/- 23.0 mmHg, while in 60 (15.7%) patients with bilateral subclavian artery stenosis, the mean central blood pressure was 192.7 +/- 30.8 mmHg/102.4 +/- 121.1 mmHg. A total of 305 were followed for 38.4 +/- 36.7 months, and the rate of blood pressure control, improvement, and failure was 50.8, 41.0, and 8.2%, respectively. Immunosuppressive therapy (OR 2.402, 95% confidence interval 1.253-4.603, P = 0.008) and the pathogenesis of hypertension (P = 0.010) were associated with prognosis of hypertension. The pathogenesis of hypertension due to TA is very complex and multifactorial. Renal artery stenosis is most frequently observed, followed by stenosis of the thoracic descending aorta, abdominal aorta, and severe aortic regurgitation. Immunosuppressive therapy and identifying the pathogenesis of hypertension is of great importance in patients with TA. PMID- 29238883 TI - Increasing Parents' Awareness of Social Host Laws: A Pilot Study of Coalition Efforts. AB - States and municipalities across the U.S. are adopting social host ordinances (SHOs) to reduce alcohol use by underage youth in private settings. SHOs are most likely to be effective if parents and other adults are aware of them and they are enforced. We examined the association between a multi-media SHO awareness campaign in northern California municipalities and parents' awareness of SHOs and SHO enforcement. We collected survey data from 1798 parents in a northern California county in fall 2014; all municipalities within the county had SHOs. We conducted descriptive and logistic regression analyses to determine whether parents living in municipalities with a SHO awareness campaign were more likely to be aware of SHOs and SHO enforcement than parents in municipalities without such a campaign. Findings showed that 55.6% of parents in municipalities with a SHO awareness campaign were aware of SHOs compared to 35.7% in municipalities without a campaign. Parents in municipalities with a SHO awareness campaign were also more likely to be aware of SHO enforcement activities (16.3 vs. 8.7%). Regression analyses indicated significant positive associations between the SHO awareness campaign and parental awareness of SHOs and SHO enforcement when controlling for parents' attitudes related to youth drinking, parenting characteristics, normative beliefs regarding other parents' awareness and youth drinking, and demographic characteristics. These findings suggest that a multi media awareness campaign implemented by coalitions was positively associated with parental awareness of SHOs and perceived SHO enforcement, which may help to prevent or reduce underage drinking. PMID- 29238884 TI - Research of differential expression of sIL1RAP in low-grade gliomas between children and adults. AB - Glioma is the most common intracranial malignant tumor. Low-grade gliomas (LGG) occupy almost 80% in all of the gliomas. The prognosis of LGG in children is much better than in adult, however, the molecular mechanism is still unclear. In our investigation, it was first found that the level of soluble IL1RAP (sIL1RAP) was significantly higher in the LGG from children than that from adult. We also revealed that sIL1RAP could induce the apoptosis of U251. In cells with overexpression of sIL-1RAP, the cell proliferation promoted by IL-1 was significantly inhibited. These decreased tumor growth ability and better prognosis of low-grade gliomas in children patients than that in adult patients. The expression level of sIL1RAP may become one of the potential indexes for determining the prognosis of low-grade gliomas. PMID- 29238885 TI - Peanut cake can replace soybean meal in supplements for lactating cows without affecting production. AB - This study evaluated the total replacement of soybean meal with peanut cake in the concentrate supplement of lactating cows grazing. Eight crossbred 5/8 Holstein * 3/8 Zebu cows between the 45th and 60th day of lactation and 507 +/- 35 kg BW were distributed in a 4 * 4 double Latin square design with four levels of peanut cake (0, 110, 220, and 330 g/kg of the dry matter-DM) as a replacement of soybean meal in the concentrate supplement. The intake of pasture, total (pasture + concentrate), crude protein (CP), neutral detergent fiber (NDF), total digestible nutrients, and digestibility of the DM, CP, ether extract (EE), and NDF was not affected by the replacement of soybean meal with peanut cake. However, the EE (P = 0.83) intake and non-fiber carbohydrate digestibility (P = 0.09) exhibited an increasing linear trend by the peanut cake inclusion. The NDF exhibited a decreasing linear trend (P = 0.07) as the level of peanut cake increased. Production, corrected production, and protein, fat, lactose, total solid, and non-fat solid composition concentrations in the cows' milk were not affected (P > 0.05) by the peanut cake inclusion. The protein/fat ratio exhibited an increasing linear trend (P = 0.082) by the peanut cake inclusion. Peanut cake can completely replace soybean meal in the concentrate mixture because it does not alter dry matter intake, production, and composition of milk, and in addition it can reduce the cost of feeding. PMID- 29238886 TI - Poultry production and constraints in Eastern Province of Rwanda: case study of Rukomo sector, Nyagatare district. AB - A study was conducted in Rukomo sector, Nyagatare district, to determine the status of poultry production. A structured questionnaire was used to collect data from 100 poultry farmers randomly as 20 farmers from each of the five cells. Data were analyzed using SPSS version 16 and presented in chart and tables. The majority of the farmers (84%) reared their poultry in free range system while 10% practiced semi-intensive and only 6% did intensive production. Only 12% of the respondents kept exotic poultry breeds. The breeding stock were mostly obtained from local markets (63%) and the average flock size was about 1-10 birds per homestead (70%). The confinement of poultry at night was either in the main domestic house (33%), in kitchen (32%), or in separate poultry house (35%). Flock records were rare and kept by only 9% of respondents. Poultry products were reportedly at high demand by 87% of respondents and 89% farmers reported profit from their enterprises. Lack of veterinary and financial assistance was reported by 72% of respondents. Newcastle disease (57%) was the main health constraint followed by ectoparasites and internal worms. Many farmers (50%) were in dire need of veterinary assistance and financial support to improve their poultry enterprises. Poor management practices were reported to be one of the crucial factors leading to poor production. Lack of quality feeds (38%) and feeding of poultry, credit (20%), and poor market accessibility (19%) were the main challenges reported. PMID- 29238887 TI - Cyber Victimization and Internalizing Difficulties: The Mediating Roles of Coping Self-Efficacy and Emotion Dysregulation. AB - Cyber victimization has consistently been associated with internalizing difficulties in adolescents. However, the underlying psychological mechanisms linking this relationship have not been adequately examined. The present study aimed to investigate the mediational roles of coping self-efficacy and emotion dysregulation in the relationships between cyber victimization with depression and social anxiety. Participants were 459 students (199 girls) from independent middle-class schools in grades 8 (M age = 13 years 9 months) and 10 (M age = 15 years 7 months). They completed a self-report questionnaire about cyberbullying participation, internalizing symptoms, coping self-efficacy, and emotion dysregulation. Structural equation modeling revealed that most domains of coping self-efficacy and emotion dysregulation partially mediated the relationship between cyber victimization and depression, and fully mediated the relationship between cyber victimization and social anxiety. The results highlight the importance of targeting these mediating factors in intervention programs to reduce the negative impact of cyber victimization on adolescents. PMID- 29238889 TI - Immunomodulatory effects of Rhodomyrtus tomentosa leaf extract and its derivative compound, rhodomyrtone, on head kidney macrophages of rainbow trout (Oncorhynchus mykiss). AB - Rhodomyrtus tomentosa is a medicinal plant that shows biological effects including immunomodulatory activity on human and other mammals but not in fish. In this study, we evaluated the in vitro immunomodulatory effects of R. tomentosa leaf extract and its active compound, rhodomyrtone, on the immune responses, using rainbow trout (Oncorhynchus mykiss) head kidney (HK) macrophages as a model. The tested immune functions included the expression of genes involved in innate immune and inflammatory responses and the production of reactive oxygen species (ROS). Gene expression was evaluated after exposure to 10 MUg mL-1 of R. tomentosa and 1 MUg mL-1 of rhodomyrtone for 4 and 24 h. R. tomentosa and rhodomyrtone induced changes in the expression of pro-inflammatory cytokines (il1beta, il8, and tnfalpha), anti-inflammatory cytokines (il10 and tgfbeta), inducible enzymes (inos, cox2, and arginase), and an antioxidant enzyme (gpx1). Co-exposure of R. tomentosa with LPS resulted in a prominent reduction in the expression of genes related to an inflammatory process (il1beta, il8, tnfalpha, inos, saa, hepcidin, and gpx1), suggesting anti-inflammatory effects. Similarly, co-exposure of rhodomyrtone with LPS led to a downregulation of inflammation related genes (il1beta, inos, saa, and hepcidin). In addition, exposure to both natural plant products caused a reduction in cellular ROS levels by HK macrophages. The present results indicate that R. tomentosa and rhodomyrtone exerted immunostimulatory and anti-inflammatory effects on fish macrophages, thus opening up the possibility of using these natural products to further develop immunostimulants for health management in aquaculture. PMID- 29238888 TI - Synthesis and evaluation of bile acid amides of [Formula: see text] cyanostilbenes as anticancer agents. AB - A series of amino-substituted [Formula: see text]-cyanostilbene derivatives and their bile acid (cholic and deoxycholic acid) amides were designed and synthesized. A comparative study on the anticancer and antibacterial activity evaluation on the synthesized analogs was carried against the human osteosarcoma (HOS) cancer cell line, and two gram -ve (E. coli and S. typhi) and two gram [Formula: see text]ve (B. subtilis and S. aureus) bacterial strains. All the cholic acid [Formula: see text]-cyanostilbene amides showed an [Formula: see text] in the range 2-13 [Formula: see text] against human osteosarcoma cells (HOS) with the most active analog (6g) possessing an [Formula: see text] of [Formula: see text]. One of the amino-substituted [Formula: see text] cyanostilbene, 4e, was found to possess an [Formula: see text] of [Formula: see text]. An increase in the number of cells at the sub-[Formula: see text] phase of the cell was observed in the in vitro cell cycle analysis of two most active compounds in the series (4e, 6g) suggesting a clear indication toward induction of apoptotic cascade. With respect to antibacterial screening, amino-substituted [Formula: see text]-cyanostilbenes were found to be more active than their corresponding bile acid amides. The synthesized compounds were also subjected to in silico study to predict their physiochemical properties and drug-likeness score. PMID- 29238890 TI - Real-time detection of BRAF V600E mutation from archival hairy cell leukemia FFPE tissue by nanopore sequencing. AB - The MinION is a miniaturized high-throughput next generation sequencing platform of novel conception. The use of nucleic acids derived from formalin-fixed paraffin-embedded samples is highly desirable, but their adoption for molecular assays is hurdled by the high degree of fragmentation and by the chemical-induced mutations stemming from the fixation protocols. In order to investigate the suitability of MinION sequencing on formalin-fixed paraffin-embedded samples, the presence and frequency of BRAF c.1799T > A mutation was investigated in two archival tissue specimens of Hairy cell leukemia and Hairy cell leukemia Variant. Despite the poor quality of the starting DNA, BRAF mutation was successfully detected in the Hairy cell leukemia sample with around 50% of the reads obtained within 2 h of the sequencing start. Notably, the mutational burden of the Hairy cell leukemia sample as derived from nanopore sequencing proved to be comparable to a sensitive method for the detection of point mutations, namely the Digital PCR, using a validated assay. Nanopore sequencing can be adopted for targeted sequencing of genetic lesions on critical DNA samples such as those extracted from archival routine formalin-fixed paraffin-embedded samples. This result let speculating about the possibility that the nanopore sequencing could be trustably adopted for the real-time targeted sequencing of genetic lesions. Our report opens the window for the adoption of nanopore sequencing in molecular pathology for research and diagnostics. PMID- 29238891 TI - Can human experts predict solubility better than computers? AB - In this study, we design and carry out a survey, asking human experts to predict the aqueous solubility of druglike organic compounds. We investigate whether these experts, drawn largely from the pharmaceutical industry and academia, can match or exceed the predictive power of algorithms. Alongside this, we implement 10 typical machine learning algorithms on the same dataset. The best algorithm, a variety of neural network known as a multi-layer perceptron, gave an RMSE of 0.985 log S units and an R2 of 0.706. We would not have predicted the relative success of this particular algorithm in advance. We found that the best individual human predictor generated an almost identical prediction quality with an RMSE of 0.942 log S units and an R2 of 0.723. The collection of algorithms contained a higher proportion of reasonably good predictors, nine out of ten compared with around half of the humans. We found that, for either humans or algorithms, combining individual predictions into a consensus predictor by taking their median generated excellent predictivity. While our consensus human predictor achieved very slightly better headline figures on various statistical measures, the difference between it and the consensus machine learning predictor was both small and statistically insignificant. We conclude that human experts can predict the aqueous solubility of druglike molecules essentially equally well as machine learning algorithms. We find that, for either humans or algorithms, combining individual predictions into a consensus predictor by taking their median is a powerful way of benefitting from the wisdom of crowds. PMID- 29238893 TI - Postprandial cardiogenic syncope caused by gastric polyp-induced pyloric obstruction in an elderly woman with a giant hiatal hernia: a case report. AB - BACKGROUND: Hiatal hernias are common. In some reports, hiatal hernias have been implicated in causing dyspnea, syncope, and heart failure. CASE PRESENTATION: An 82-year-old woman with a hiatal hernia was admitted to our hospital because she had experienced postprandial syncope during the last few years. Esophagogastroduodenoscopy revealed a large hiatal hernia and a pedunculated polyp of the stomach antrum that fit into the pylorus. An upper gastrointestinal contrast study showed that the entire stomach had relocated to the thoracic cavity and that the body of the stomach was located above the fundus, resulting in a so-called upside-down stomach. Contrast-enhanced computed tomography revealed that a large portion of the stomach, transverse colon, and part of the pancreas were present in the mediastinum. We then performed transthoracic echocardiography followed by a water pouring test using a nasogastric tube. After instillation of 2000 ml of saline, the left atrium was markedly compressed and the area of the mitral annulus was reduced. We determined that stomach dilation by the hiatal hernia and gastric polyp had caused the syncope. The patient underwent laparoscopic hiatal hernia repair and endoscopic gastric polypectomy, and she experienced no syncopal episodes for 5 months postoperatively. CONCLUSIONS: Clinicians should recognize that a large hiatal hernia may be a risk factor for syncope. PMID- 29238892 TI - Recombinant Human Erythropoietin Protects Against Hippocampal Damage in Developing Rats with Seizures by Modulating Autophagy via the S6 Protein in a Time-Dependent Manner. AB - Epilepsy is among the most common neurological disorders. Recurrent seizures result in neuronal death, cognitive deficits and intellectual disabilities in children. Currently, recombinant human erythropoietin (rhEPO) is considered to play a neuroprotective role in nervous system disorders. However, the precise mechanisms through which rhEPO modulates epilepsy remain unknown. Based on results from numerous studies, we hypothesized that rhEPO protects against hippocampal damage in developing rats with seizures probably by modulating autophagy via the ribosomal protein S6 (S6) in a time-dependent manner. First, we observed that rats with recurrent seizures displayed neuronal loss in the hippocampal CA1 region. Second, rhEPO injection reduced neuronal loss and decreased the number of apoptotic cells in the hippocampal CA1 region. Moreover, rhEPO increased the Bcl-2 protein expression levels and decreased the ratio of cleaved caspase-3/caspase-3 in the hippocampus. Finally, rhEPO modulated autophagy in the hippocampus in a time-dependent manner, probably via the S6 protein. In summary, rhEPO protects against hippocampal damage in developing rats with seizures by modulating autophagy in a time-dependent manner, probably via the S6 protein. Consequently, rhEPO is a likely drug candidate that is capable of attenuating brain injury. PMID- 29238894 TI - A nonparametric maximum likelihood approach for survival data with observed cured subjects, left truncation and right-censoring. AB - We consider observational studies in pregnancy where the outcome of interest is spontaneous abortion (SAB). This at first sight is a binary 'yes' or 'no' variable, albeit there is left truncation as well as right-censoring in the data. Women who do not experience SAB by gestational week 20 are 'cured' from SAB by definition, that is, they are no longer at risk. Our data is different from the common cure data in the literature, where the cured subjects are always right censored and not actually observed to be cured. We consider a commonly used cure rate model, with the likelihood function tailored specifically to our data. We develop a conditional nonparametric maximum likelihood approach. To tackle the computational challenge we adopt an EM algorithm making use of "ghost copies" of the data, and a closed form variance estimator is derived. Under suitable assumptions, we prove the consistency of the resulting estimator which involves an unbounded cumulative baseline hazard function, as well as the asymptotic normality. Simulation results are carried out to evaluate the finite sample performance. We present the analysis of the motivating SAB study to illustrate the advantages of our model addressing both occurrence and timing of SAB, as compared to existing approaches in practice. PMID- 29238895 TI - An overview of combined D-2- and L-2-hydroxyglutaric aciduria: functional analysis of CIC variants. AB - Combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA) is a devastating neurometabolic disorder, usually lethal in the first years of life. Autosomal recessive mutations in the SLC25A1 gene, which encodes the mitochondrial citrate carrier (CIC), were previously detected in patients affected with combined D/L-2 HGA. We showed that transfection of deficient fibroblasts with wild-type SLC25A1 restored citrate efflux and decreased intracellular 2-hydroxyglutarate levels, confirming that deficient CIC is the cause of D/L-2-HGA. We developed and implemented a functional assay and applied it to all 17 missense variants detected in a total of 26 CIC-deficient patients, including eight novel cases, showing reduced activities of varying degrees. In addition, we analyzed the importance of residues affected by these missense variants using our existing scoring system. This allowed not only a clinical and biochemical overview of the D/L-2-HGA patients but also phenotype-genotype correlation studies. PMID- 29238896 TI - Outcomes of Salvage Liver Transplantation and Re-resection/Radiofrequency Ablation for Intrahepatic Recurrent Hepatocellular Carcinoma: A New Surgical Strategy Based on Recurrence Pattern. AB - BACKGROUND: The treatment of intrahepatic recurrent hepatocellular carcinoma (HCC) has been poorly investigated, and the optimal treatment strategy remains unclear. AIMS: The aim of this study was to compare outcomes between salvage liver transplantation (SLT) and re-resection (RR)/radiofrequency ablation (RFA) for intrahepatic recurrent HCC according to recurrence pattern. METHODS: Based on postoperative histopathological examination, 122 patients with intrahepatic recurrent HCC were divided into an intrahepatic metastasis (IM, n = 75) group and a multicentric occurrence (MO, n = 47) group. The demographic, clinical, and primary and recurrent tumor characteristics of the IM group and the MO group were collected and compared. Overall survival (OS) and disease-free survival (DFS) were analyzed, and subgroup analysis according to retreatment type (SLT vs. RR/RFA) was conducted. Twenty-nine clinicopathological variables potentially related to prognostic factors affecting survival were analyzed using a Cox proportional hazard model. RESULTS: The patients that received SLT treatment exhibited favorable DFS compared to patients that received RR/RFA (P = 0.002). OS (P < 0.001) and DFS (P = 0.008) rates were significantly increased in the MO group compared with in the IM group. Subgroup analysis revealed that DFS was significantly improved for patients in the MO group treated with SLT compared to patients treated with RR/RFA (P = 0.017). Recurrence pattern was an independent prognostic factor for both OS [hazard ratio (HR) = 0.093, 95% confidence interval (CI): 0.026-0.337, P < 0.001] and DFS (HR = 0.318, 95% CI: 0.125-0.810, P = 0.016; HR = 3.334, 95% CI: 1.546-7.18, P = 0.002). CONCLUSIONS: For patients with intrahepatic recurrent HCC, an MO recurrence pattern is associated with better long-term outcomes than the IM pattern. SLT is the preferred option for intrahepatic recurrent HCC, especially for MO cases. PMID- 29238897 TI - Carbamazepine-Associated Hypersensitivity Colitis. PMID- 29238898 TI - Comprehensive bioinformation analysis of the miRNA of PLCE1 knockdown in esophageal squamous cell carcinoma. AB - Phospholipase C epsilon 1 (PLCE1) has been recognized as a novel susceptibility marker for esophageal squamous cell carcinoma (ESCC). The purpose of our study is to investigate its effect on the regulation of miRNA expression so as to translating the data into a novel strategy in control of ESCC. In this study, PLCE1 siRNA and vector-only plasmid were stably transfected into Eca109 and EC9706 cells and then subjected to miRNA array analysis, and quantitative real time PCR was applied to validate miRNA array data. Then bioinformatic analyses, such as GO and pathway software, were conducted to obtain data on these differentially expressed miRNAs-targeted genes (DEGs) and clarify their function and pathway. The results showed that 36 miRNAs were found to be differentially expressed in PLCE1 siRNA-transfected cells compared with the control cells. In particular, 28 miRNAs were upregulated while 8 miRNAs were downregulated. Gene Ontology analysis showed that the function of the DEGs included cell cycle arrest, cell-matrix adhesion, apoptosis, etc. After this, the major pathways associated with the DEGs were regulation of actin cytoskeleton, TGF-beta signaling pathway, Notch signaling pathway and so on. Taken together, these results showed that the knockdown of PLCE1 may play a vital role in the control of ESCC. Further investigation will reveal and verify the function and pathway of the DEGs for the development of novel treatment strategy for the better control of ESCC. PMID- 29238899 TI - Induction of apoptosis in human glioma cell lines of various grades through the ROS-mediated mitochondrial pathway and caspase activation by Rhaponticum carthamoides transformed root extract. AB - The present study is the first investigation of the inhibitory effect of Rhaponticum carthamoides transformed roots (TR) extract on the proliferation of grade II and III human glioma cells. TR extract showed the cytotoxic effect and inhibited the colony formation of both glioma cell lines in dose-dependent manner. The root extract induced apoptosis by increasing of the reactive oxygen species (about threefold compared to the control cells) leading to a disruption of mitochondrial membrane potential. Additionally, the mRNA levels of the apoptotic factors such as Bax, Tp53, caspase-3, and caspase-9 were observed to increase. These results indicate that the TR extract possesses anticancer activity by inhibiting glioma cell proliferation and inducing apoptotic cell death, and may be used as a promising anticancer agent. PMID- 29238900 TI - Forecasting the 2001 Foot-and-Mouth Disease Epidemic in the UK. AB - Near real-time epidemic forecasting approaches are needed to respond to the increasing number of infectious disease outbreaks. In this paper, we retrospectively assess the performance of simple phenomenological models that incorporate early sub-exponential growth dynamics to generate short-term forecasts of the 2001 foot-and-mouth disease epidemic in the UK. For this purpose, we employed the generalized-growth model (GGM) for pre-peak predictions and the generalized-Richards model (GRM) for post-peak predictions. The epidemic exhibits a growth-decelerating pattern as the relative growth rate declines inversely with time. The uncertainty of the parameter estimates [Formula: see text] narrows down and becomes more precise using an increasing amount of data of the epidemic growth phase. Indeed, using only the first 10-15 days of the epidemic, the scaling of growth parameter (p) displays wide uncertainty with the confidence interval for p ranging from values ~ 0.5 to 1.0, indicating that less than 15 epidemic days of data are not sufficient to discriminate between sub exponential (i.e., p < 1) and exponential growth dynamics (i.e., p = 1). By contrast, using 20, 25, or 30 days of epidemic data, it is possible to recover estimates of p around 0.6 and the confidence interval is substantially below the exponential growth regime. Local and national bans on the movement of livestock and a nationwide cull of infected and contiguous premises likely contributed to the decelerating trajectory of the epidemic. The GGM and GRM provided useful 10 day forecasts of the epidemic before and after the peak of the epidemic, respectively. Short-term forecasts improved as the model was calibrated with an increasing length of the epidemic growth phase. Phenomenological models incorporating generalized-growth dynamics are useful tools to generate short-term forecasts of epidemic growth in near real time, particularly in the context of limited epidemiological data as well as information about transmission mechanisms and the effects of control interventions. PMID- 29238901 TI - Tower of Babel Problem in Telehealth: Addressing the Health Information Exchange Needs of the North Carolina Statewide Telepsychiatry Program (NC-STeP). AB - Telepsychiatry is a viable option for providing psychiatric care to those who are currently underserved or who lack access to services. While the current technology is adequate for most uses, and continues to advance, there remain barriers to its widespread utilization. One such barrier when working with different healthcare systems is that they utilize different electronic medical record systems (EMRs). This paper describes the experience of the North Carolina Statewide Telepsychiatry Program (NC-STeP) with this problem and how the program successfully resolved it by establishing a web portal that connects participating hospital emergency departments and remote psychiatric providers to share secure electronic health information regarding patient encounters across different EMRs. The Portal also facilitates scheduling, status tracking, and reporting on each patient encounter, as well as delivers the necessary data for the billing to process charges for each consult and to administrators for the operation of the program. The portal effectively bridges the needs of the multiple actors in the telepsychiatry virtual encounter. It provides an efficient experience for the patient and the point-of-care provider, a reliable document exchange for the psychiatric provider, and effective record keeping for the billing and government entities. PMID- 29238903 TI - A time local subset feature selection for prediction of sudden cardiac death from ECG signal. AB - Prediction of sudden cardiac death continues to gain universal attention as a promising approach to saving millions of lives threatened by sudden cardiac death (SCD). This study attempts to promote the literature from mere feature extraction analysis to developing strategies for manipulating the extracted features to target improvement of classification accuracy. To this end, a novel approach to local feature subset selection is applied using meticulous methodologies developed in previous studies of this team for extracting features from non linear, time-frequency, and classical processes. We are therefore enabled to select features that differ from one another in each 1-min interval before the incident. Using the proposed algorithm, SCD can be predicted 12 min before the onset; thus, more propitious results are achieved. Additionally, through defining a utility function and employing statistical analysis, the alarm threshold has effectively been determined as 83%. Having selected the best combination of features, the two classes are classified using the multilayer perceptron (MLP) classifier. The most effective features would subsequently be discussed considering their prevalence in the rank-based selection. The results indicate the significant capacity of the proposed method for predicting SCD as well as selecting the appropriate processing method at any time before the incident. Graphical abstract ?. PMID- 29238902 TI - Dietary Therapy for Eosinophilic Esophagitis: Elimination and Reintroduction. AB - Eosinophilic esophagitis (EoE) is a food antigen-mediated disorder of the esophagus characterized by eosinophil predominant inflammation and symptoms of esophageal dysfunction. Dietary antigen elimination induces clinical and histological remission in patients with EoE. The most restrictive of elimination diets (the elemental diet) removes all possible food antigens while empiric elimination diets remove all (or a subset) of food antigens most commonly reported to cause esophageal eosinophilia and food allergies (milk, egg, wheat, soy, peanuts, tree nuts, fish, or legumes). Elimination diets are effective treatments for EoE but pose psychosocial and financial challenges to patients and consequently may impair quality of life. Foods that are commonly eliminated, especially milk, are also nutrient-dense and therefore their elimination may result in inadequate nutrient intake or deficiencies without careful diet planning to include nutritionally comparable and safe food substitutes. After remission is achieved with elimination diets, foods can be reintroduced sequentially to identify specific food triggers, but this reintroduction is not standardized. Food elimination and food reintroductions should consider the patient's lifestyle, nutrition needs, and skills and ideally be managed by a team with knowledge of eosinophilic gastrointestinal disorders and nutrition. PMID- 29238904 TI - Anti-inflammatory activity of anti-hyperlipidemic drug, fenofibrate, and its phase-I metabolite fenofibric acid: in silico, in vitro, and in vivo studies. AB - Fenofibrate, an anti-hyperlipidemic drug and its phase-I biotransformed metabolite fenofibric acid, was studied for COX-1 (PDB ID: 3N8Y) and COX-2 (PDB ID: 1PXX) inhibition potentials in silico and in vitro for their effects on human recombinant COX-2 enzyme isolated from a Baculovirus expression system in sf21 cells (EC 1.14.99.1) using a conventional spectrophotometric assay. Furthermore, the compounds were also screened for their anti-inflammatory potentials in vivo using carrageenan-induced paw oedema method in Wistar rats. The test compounds fenofibric acid, fenofibrate, and the standard drug diclofenac exhibited binding energies of - 9.0, - 7.2, and - 8.0 kcal mol-1, respectively, against COX-2 and - 7.2, - 7.0, and - 6.5 kcal mol-1, respectively, against COX-1. In in vitro studies, both the test compounds inhibited COX-2 enzyme activity. Fenofibric acid showed an IC50 value of 48 nM followed by fenofibrate (82 nM), while diclofenac showed an IC50 value of 58 nM. Furthermore, under in vivo conditions in carrageenan-induced paw oedema rodent model, fenofibric acid exhibited relatively potent anti-inflammatory activity compared with fenofibrate. Hence, we conclude that fenofibric acid and fenofibrate are not only anti-hyperlipidemic but also shows potent anti-inflammatory activity, which may have an additional impact in the treatment of diabetic complications, viz., hyperlipidemia and inflammation leading to atherosclerosis. PMID- 29238907 TI - Race/Ethnicity, and Behavioral Health Status: First Arrest and Outcomes in a Large Sample of Juvenile Offenders. AB - The objective of this study was to assess the simultaneous effects of gender, race/ethnicity, and pre-arrest behavioral health (BH) service-use on age at first arrest, and first arrest outcomes. Between January 2004 and December 2011, arrest and medical records were collected on a retrospective longitudinal cohort of 12,476 first-time offenders, ages 8-18 years. Black youth were arrested at younger ages than white or Hispanic youth. Youth with psychiatric problems were arrested at younger ages than youth with substance-use, dual-diagnoses, or no BH problems. Compared to white males, black males had lower odds of detention and BH referrals. Compared to white females, black females had higher odds of release and lower odds of probation, detention, and BH referrals. A significant gender-by BH problem interaction revealed males and females with previous psychiatric problems were arrested at younger ages than youth with substance, dual-diagnosis, or no prior problems. Implications are discussed. PMID- 29238905 TI - Biologic agents for severe asthma patients: clinical perspectives and implications. AB - Asthma is a chronic inflammatory multifactorial disorder of the airways characterized by the involvement of immune cells and mediators in its onset and maintenance. Traditional therapeutic strategies have been unsatisfactory in controlling the underlying pathology, especially in the more severe states. Hence in the last couple of decades, new biological approaches targeting molecular mediators have been developed. In this narrative review we examine biological agents currently available for the management of severe asthma, focusing our attention on their clinical application, pros and cons, and in particular on gaps regarding the use of these agents. The most well-known and used biologic agent in clinical practice is omalizumab, though there is emerging evidence for mepolizumab too. The future of these biological therapies is to broaden our knowledge of their practical use and ascertain predictive biomarkers, or define an algorithm, useful in the optimal application of these 'biological weapons'. PMID- 29238906 TI - Thyroid dysfunctions secondary to cancer immunotherapy. AB - BACKGROUND: Immunotherapy is a firmly established pillar in the treatment of cancer, alongside the traditional approaches of surgery, radiotherapy, and chemotherapy. Like every treatment, also cancer immunotherapy causes a diverse spectrum of side effects, collectively referred to as immune-related adverse events. OBJECTIVE: This review will examine the main forms of immunotherapy, the proposed mechanism(s) of action, and the incidence of thyroid dysfunctions. METHODS: A comprehensive MEDLINE search was performed for articles published up to March 30, 2017. RESULTS: Following the pioneering efforts with administration of cytokines such as IL-2 and IFN-g, which caused a broad spectrum of thyroid dysfunctions (ranging in incidence from 1 to 50%), current cancer immunotherapy strategies comprise immune checkpoint inhibitors, oncolytic viruses, adoptive T cell transfer, and cancer vaccines. Oncolytic viruses, adoptive T-cell transfer, and cancer vaccines cause thyroid dysfunctions only rarely. In contrast, immune checkpoint blockers (such as anti-CTLA-4, anti-PD-1, anti-PD-L1) are associated with a high risk of thyroid autoimmunity. This risk is highest for anti-PD-1 and increases further when a combination of checkpoint inhibitors is used. CONCLUSIONS: Cancer patients treated with monoclonal antibodies that block immune checkpoint inhibitors are at risk of developing thyroid dysfunctions. Their thyroid status should be assessed at baseline and periodically after initiation of the immunotherapy. PMID- 29238908 TI - Thalassemia: a prevalent disease yet unknown term among college students in Saudi Arabia. AB - Thalassemia is a life-threatening blood disorder that has a high prevalence in Saudi Arabia despite the implementation of mandatory premarital testing and the availability of genetic counseling. This study aimed to assess college students' knowledge of thalassemia. A cross-sectional survey of a random sample of 920 senior students enrolled at King Abdulaziz University was conducted. A self administered questionnaire was used to collect information about thalassemia and socio-demographic characteristics. Of the 920 students, 445 (48%) had ever heard of thalassemia. Despite the mandatory premarital testing for thalassemia, only 50% of married students stated having heard of the disease. The mean thalassemia knowledge score was 4.4 +/- 2.2 out of a maximum of 12. Knowledge was significantly influenced by university faculty, gender, and education outside of Saudi Arabia. Those who had heard of thalassemia had misconceptions about the disease characteristics and pattern of inheritance such as associating thalassemia with low iron levels. A substantial proportion of the participants had a low knowledge of thalassemia. This lack of awareness requires a reassessment of the goals and success of the premarital testing program, including the genetic counseling services, and also indicates the importance of emphasizing thalassemia in school curricula and promoting and scaling up existing thalassemia campaigns in the region. PMID- 29238909 TI - Tree-Based Unrooted Phylogenetic Networks. AB - Phylogenetic networks are a generalization of phylogenetic trees that are used to represent non-tree-like evolutionary histories that arise in organisms such as plants and bacteria, or uncertainty in evolutionary histories. An unrooted phylogenetic network on a non-empty, finite set X of taxa, or network, is a connected, simple graph in which every vertex has degree 1 or 3 and whose leaf set is X. It is called a phylogenetic tree if the underlying graph is a tree. In this paper we consider properties of tree-based networks, that is, networks that can be constructed by adding edges into a phylogenetic tree. We show that although they have some properties in common with their rooted analogues which have recently drawn much attention in the literature, they have some striking differences in terms of both their structural and computational properties. We expect that our results could eventually have applications to, for example, detecting horizontal gene transfer or hybridization which are important factors in the evolution of many organisms. PMID- 29238910 TI - Jaw clonus in motor neuron disease: an interesting case and review of literature. PMID- 29238911 TI - Correction to: Cognitive control in media multitaskers: Two replication studies and a meta-Analysis. AB - In the original article, the number of HMMs and LMMs who took part in the first study was reported to have been 13and 10, respectively (p. 2624). PMID- 29238912 TI - Hue distinctiveness overrides category in determining performance in multiple object tracking. AB - The visual distinctiveness between targets and distractors can significantly facilitate performance in multiple object tracking (MOT), in which color is a feature that has been commonly used. However, the processing of color can be more than "visual." Color is continuous in chromaticity, while it is commonly grouped into discrete categories (e.g., red, green). Evidence from color perception suggested that color categories may have a unique role in visual tasks independent of its chromatic appearance. Previous MOT studies have not examined the effect of chromatic and categorical distinctiveness on tracking separately. The current study aimed to reveal how chromatic (hue) and categorical distinctiveness of color between the targets and distractors affects tracking performance. With four experiments, we showed that tracking performance was largely facilitated by the increasing hue distance between the target set and the distractor set, suggesting that perceptual grouping was formed based on hue distinctiveness to aid tracking. However, we found no color categorical effect, because tracking performance was not significantly different when the targets and distractors were from the same or different categories. It was concluded that the chromatic distinctiveness of color overrides category in determining tracking performance, suggesting a dominant role of perceptual feature in MOT. PMID- 29238913 TI - Phthalazinone Pyrazole Enhances the Hepatic Functions of Human Embryonic Stem Cell-Derived Hepatocyte-Like Cells via Suppression of the Epithelial-Mesenchymal Transition. AB - During liver development, nonpolarized hepatic progenitor cells differentiate into mature hepatocytes with distinct polarity. This polarity is essential for maintaining the intrinsic properties of hepatocytes. The balance between the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) plays a decisive role in differentiation of polarized hepatocytes. In this study, we found that phthalazinone pyrazole (PP), a selective inhibitor of Aurora A kinase (Aurora-A), suppressed the EMT during the differentiation of hepatocyte like cells (HLCs) from human embryonic stem cells. The differentiated HLCs treated with PP at the hepatoblast stage showed enhanced hepatic morphology and functions, particularly with regard to the expression of drug metabolizing enzymes. Moreover, we found that these effects were mediated though suppression of the AKT pathway, which is involved in induction of the EMT, and upregulation of hepatocyte nuclear factor 4alpha expression rather than Aurora-A inhibition. In conclusion, these findings provided insights into the regulatory role of the EMT on in vitro hepatic maturation, suggesting that inhibition of the EMT may drive transformation of hepatoblast cells into mature and polarized HLCs. PMID- 29238914 TI - Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Biliary Tract Cancers Associated with Lynch Syndrome. AB - PURPOSE: Patients with Lynch syndrome (LS) have a significantly elevated lifetime risk of developing biliary tract cancers (BTCs) compared to the general population. However, few studies have characterized the clinical characteristics, genetic features, or long-term outcomes of mismatch-repair deficient (dMMR) cholangiocarcinomas associated with LS. METHODS: A retrospective review of a prospectively maintained Familial High-Risk GI Cancer Clinic database identified all patients with BTCs evaluated from 2006 to 2016 who carried germline mutations in MLH1, MSH2, MSH6, or PMS2. RESULTS: Eleven patients with BTCs were identified: four perihilar, four intrahepatic, one extrahepatic, one gallbladder, and one ampulla of Vater. All patients had underlying germline mutations and a personal history of a LS-associated malignancy, most commonly (63.3%) colorectal cancer. Ten (90.9%) patients were surgically explored, and margin negative resection was possible in seven (63.3%). Chemotherapy (90.9%) and/or chemoradiation (45.5%) was administered to most patients. Among the seven patients presenting with non metastatic disease who underwent surgical resection with curative intent, the 5 year overall survival rate was 53.3%. The median overall survival for the four patients not treated with curative intent was 17.2 months. CONCLUSIONS: dMMR biliary tract cancers associated with LS are rare but long-term outcomes may be more favorable than contemporaneous cohorts of non-Lynch-associated cholangiocarcinomas. Given the emerging promise of immunotherapy for patients with dMMR malignancies, tumor testing for dMMR followed by confirmatory germline testing should be considered in patients with BTC and a personal history of other LS cancers. PMID- 29238915 TI - SEOM clinical guidelines for endometrial cancer (2017). AB - Endometrial cancer (EC) is the most common gynecological cancer in developed countries. Most patients are diagnosed at an early stage with a low risk of relapse. However, there is a group of patients with a high risk of relapse and poor prognosis. Despite the recent publication of randomized trials, the adjuvant treatment of high-risk EC is still to be defined and there are many open questions about the best approach and the right timing. Unfortunately, the survival of metastatic or recurrent EC is short, due to the poor results of chemotherapy and the lack of a second line of treatment. Advances in the knowledge of the molecular abnormalities in EC have permitted the development of promising targeted therapies. PMID- 29238916 TI - Impact of Bariatric Surgical Intervention on Peripheral Blood Neutrophil (PBN) Function in Obesity. AB - AIM: The aim of this study was to investigate the impact of weight loss following gastric band surgery on multiple measures of peripheral blood neutrophil (PBN) function. MATERIAL AND METHODS: Twenty-three obese patients undergoing gastric band surgery were recruited to a longitudinal intervention study, alongside non obese, healthy gender- and age-matched controls. Eighteen pairs of patients and controls completed all stages of the study. PBNs were isolated by density centrifugation and a comprehensive analysis of PBN function was undertaken at various stages of the patients' bariatric surgical care pathway. RESULTS: Obese patients exhibited exaggerated PBN activity in response to various stimuli, characterised by higher reactive oxygen species (ROS) generation (n = 18, p < 0.001) and release of pro-inflammatory cytokines (n = 10, p < 0.05) and lower PBN extracellular trap (NET) formation (n = 18, p < 0.01). PBN chemotactic accuracy was also impaired prior to surgery (n = 18, p < 0.01). Weight loss was associated with normalised NET production and lower ROS production and cytokine release relative to healthy controls. However, chemotactic accuracy remained impaired in patients. CONCLUSIONS: Weight loss following gastric band surgery was associated with a decrease in the pro-inflammatory activities of peripheral blood neutrophils (PBNs). A hyper-inflammatory PBN phenotype, involving excess ROS and cytokine release, reduced NET formation and chemotaxis, may lead to a reduced ability to eliminate infection, alongside inflammation-mediated tissue damage in obese individuals. PMID- 29238917 TI - Cadmium Testicular Toxicity in Male Wistar Rats: Protective Roles of Zinc and Magnesium. AB - Cadmium (Cd) is a highly toxic element, which may cause toxicity to most organs in the body. Zinc (Zn) and magnesium (Mg) are essential minerals with probable benefits on Cd harmful effects. Finding an efficient and non-pathological treatment against Cd toxicity seems promising. Fifty adult rats were divided into ten experimental groups of five rats each. The Cd group was treated with 1 mg Cd/kg and the control group received 0.5 cm3 normal saline. The other eight groups received Zn (0.5 and 1.5 mg/kg) and Mg (0.5 and 1.5 mg/kg) either alone or in combination with 1 mg Cd/kg through IP injection for 3 weeks. Testis malondialdehyde (MDA), sperm parameters, and testis histopathology were investigated. Cd reduced sperm parameters and increased testis MDA. Moreover, Cd exposure caused a significant histological damage in testis of male rats. However, Zn or Mg treatment prevented and reversed Cd toxic alterations in testis. These findings suggest that co-administration of Zn or Mg could improve cadmium testicular toxicity in male Wistar rats. PMID- 29238918 TI - Treatment of acute hepatitis C: recommendations from an expert panel of the Italian Society of Infectious and Tropical Diseases. AB - AIM: This paper is aimed at providing practical recommendations for the management of acute hepatitis C (AHC). METHODS: This is an expert position paper based on the literature revision. Final recommendations were graded by level of evidence and strength of the recommendations. RESULTS: Treatment of AHC with direct-acting antivirals (DAA) is safe and effective; it overcomes the limitations of INF-based treatments. CONCLUSIONS: Early treatment with DAA should be offered when available. PMID- 29238919 TI - A novel fully automatic multilevel thresholding technique based on optimized intuitionistic fuzzy sets and tsallis entropy for MR brain tumor image segmentation. AB - In the present paper, a hybrid multilevel thresholding technique that combines intuitionistic fuzzy sets and tsallis entropy has been proposed for the automatic delineation of the tumor from magnetic resonance images having vague boundaries and poor contrast. This novel technique takes into account both the image histogram and the uncertainty information for the computation of multiple thresholds. The benefit of the methodology is that it provides fast and improved segmentation for the complex tumorous images with imprecise gray levels. To further boost the computational speed, the mutation based particle swarm optimization is used that selects the most optimal threshold combination. The accuracy of the proposed segmentation approach has been validated on simulated, real low-grade glioma tumor volumes taken from MICCAI brain tumor segmentation (BRATS) challenge 2012 dataset and the clinical tumor images, so as to corroborate its generality and novelty. The designed technique achieves an average Dice overlap equal to 0.82010, 0.78610 and 0.94170 for three datasets. Further, a comparative analysis has also been made between the eight existing multilevel thresholding implementations so as to show the superiority of the designed technique. In comparison, the results indicate a mean improvement in Dice by an amount equal to 4.00% (p < 0.005), 9.60% (p < 0.005) and 3.58% (p < 0.005), respectively in contrast to the fuzzy tsallis approach. PMID- 29238920 TI - QTL analysis of falling number and seed longevity in wheat (Triticum aestivum L.). AB - Pre-harvest sprouting (PHS) and seed longevity (SL) are complex biological processes of major importance for agricultural production. In the present study, a recombinant inbred line (RIL) population derived from a cross between the German winter wheat (Triticum aestivum L.) cultivars History and Rubens was used to identify genetic factors controlling these two physiological seed traits. A falling number (FN) test was employed to evaluate PHS, while SL was measured using a germination test (and the speed of germination) after controlled deterioration. FN of the population was assessed in four environments; SL traits were measured in one environment. Four major quantitative trait loci (QTL) for FN were detected on chromosomes 4D, 5A, 5D, and 7B, whereas for SL traits, a major QTL was found on chromosome 1A. The FN QTL on chromosome 4D that coincided with the position of the dwarfing gene Rht-D1b only had effects in environments that were free of PHS. The remaining three QTL for FN were mostly pronounced under conditions conducive to PHS. The QTL on the long arm of chromosome 7B corresponded to the major gene locus controlling late maturity alpha-amylase (LMA) in wheat. The severity of the LMA phenotype became truly apparent under sprouting conditions. The position on the long arm of chromosome 1A of the QTL for SL points to a new QTL for this important regenerative seed trait. PMID- 29238922 TI - Rational evaluation of the therapeutic effect and dosimetry of auger electrons for radionuclide therapy in a cell culture model. AB - OBJECTIVE: Radionuclide therapy with low-energy auger electron emitters may provide high antitumor efficacy while keeping the toxicity to normal organs low. Here we evaluated the usefulness of an auger electron emitter and compared it with that of a beta emitter for tumor treatment in in vitro models and conducted a dosimetry simulation using radioiodine-labeled metaiodobenzylguanidine (MIBG) as a model compound. METHODS: We evaluated the cellular uptake of 125I-MIBG and the therapeutic effects of 125I- and 131I-MIBG in 2D and 3D PC-12 cell culture models. We used a Monte Carlo simulation code (PHITS) to calculate the absorbed radiation dose of 125I or 131I in computer simulation models for 2D and 3D cell cultures. In the dosimetry calculation for the 3D model, several distribution patterns of radionuclide were applied. RESULTS: A higher cumulative dose was observed in the 3D model due to the prolonged retention of MIBG compared to the 2D model. However, 125I-MIBG showed a greater therapeutic effect in the 2D model compared to the 3D model (respective EC50 values in the 2D and 3D models: 86.9 and 303.9 MBq/cell), whereas 131I-MIBG showed the opposite result (respective EC50 values in the 2D and 3D models: 49.4 and 30.2 MBq/cell). The therapeutic effect of 125I-MIBG was lower than that of 131I-MIBG in both models, but the radionuclide-derived difference was smaller in the 2D model. The dosimetry simulation with PHITS revealed the influence of the radiation quality, the crossfire effect, radionuclide distribution, and tumor shape on the absorbed dose. Application of the heterogeneous distribution series dramatically changed the radiation dose distribution of 125I-MIBG, and mitigated the difference between the estimated and measured therapeutic effects of 125I-MIBG. CONCLUSIONS: The therapeutic effect of 125I-MIBG was comparable to that of 131I-MIBG in the 2D model, but the efficacy was inferior to that of 131I-MIBG in the 3D model, since the crossfire effect is negligible and the homogeneous distribution of radionuclides was insufficient. Thus, auger electrons would be suitable for treating small-sized tumors. The design of radiopharmaceuticals with auger electron emitters requires particularly careful consideration of achieving a homogeneous distribution of the compound in the tumor. PMID- 29238921 TI - Bacillus Probiotic Supplementations Improve Laying Performance, Egg Quality, Hatching of Laying Hens, and Sperm Quality of Roosters. AB - The study aims at elucidating the effect of bacilli probiotic preparations on the physiology of laying hens and roosters. Probiotic formulations were prepared as soybean products fermented by Bacillus subtilis KATMIRA1933 and Bacillus amyloliquefaciens B-1895. In this study, groups of male and female chickens were used. These groups received a probiotic preparation based on either B. subtilis KATMIRA1933 or B. amyloliquefaciens B-1895, or of a mixture of strains, from the first day to the age of 39 weeks. These preparations positively affected egg production, quality of sperm production, and quality and hatchery of eggs. Considering the simplicity and cost effectiveness of the soy-based probiotic preparation, these formulations should be considered as advantageous in modern livestock production. PMID- 29238923 TI - Endoscopic therapy and curative effect in pituitary adenoma patients complicated by acromegalic cardiomyopathy. AB - The study aimed to retrospectively analyze the clinical characteristics of patients with pituitary adenomas complicated by acromegalic cardiomyopathy and to evaluate the effect of endoscopic surgery. Eighty-six pituitary adenoma patients complicated by acromegalic cardiomyopathy who were treated with endoscopic surgery in the First Affiliated Hospital of Soochow University from January 2010 to December 2016 were enrolled. We noted patient clinical characteristics and explored the relationships with surgical treatment. Before and after surgery, all patients underwent an examination of pituitary endocrinology, brain magnetic resonance (MR), and echocardiography. The serum levels of growth hormone (GH), left ventricular end-diastolic diameter (LVIDd), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular ejection fraction (EF), and mitral valve (E/A ratio) were examined with non-invasive methods, and the results were compared. Of the 86 patients, there were 23 with microadenomas, 27 with large adenomas, and 36 with giant adenomas. There were 28 patients with invasive adenomas and 58 with non-invasive adenomas. The pre-operative mean GH level was 71.23 +/- 3.29 MUg/L, which was positively correlated with tumor volume (r = 0.751, P < 0.01). Via trans sphenoidal endoscopic pituitary adenoma resection, 51 patients underwent total tumor resections, 25 underwent subtotal resections, 8 underwent major part resections, and 2 underwent partial resections. After surgery, the GH mean level was 3.81 +/- 1.03 MUg/L, which was significantly different (t = 3.72, P < 0.01) from the pre-operative level. Cardiac function indices, including LVIDd, IVST, LVPWT, E/A, and EF, were significantly improved. The long-term curative rate was 39.17% and the remission rate was 77.29%. For pituitary adenoma patients complicated by acromegalic cardiomyopathy, endoscopic surgery resulted in a good curative effect and the growth hormone levels were maintained, which can significantly improve cardiac structure and function. PMID- 29238924 TI - Effects of government regulations on Manufacturer's behaviors under carbon emission reduction. AB - This paper shifts the discussion of low-carbon technology from science to the economy, especially the reactions of a manufacturer to government regulations. One major concern in this paper is uncertainty about the effects of government regulation on the manufacturing industry. On the trust side, will manufacturers trust the government's commitment to strictly supervise carbon emission reduction? Will a manufacturer that is involved in traditional industry consciously follow a low-carbon policy? On the profit side, does equilibrium between a manufacturer and a government exist on deciding which strategy to undertake to meet a profit maximization objective under carbon emission reduction? To identify the best solutions to these problems, this paper estimates the economic benefits of manufacturers associated with policy regulations in a low-carbon technology market. The problem of an interest conflict between the government and the manufacturer is formalized as a game theoretic model, and a mixed strategy Nash equilibrium is derived and analyzed. The experiment results indicate that when the punishment levied on the manufacturer or the loss to the government is sizable, the manufacturer will be prone to developing innovative technology and the government will be unlikely to supervise the manufacturer. PMID- 29238925 TI - Combination of UVC-LEDs and ultrasound for peroxymonosulfate activation to degrade synthetic dye: influence of promotional and inhibitory agents and application for real wastewater. AB - Several efforts have been carried out to present an efficient method for PMS activation. This work presented the use of UVC-LEDs (light emitting diodes) and US (ultrasound) to activate PMS for decolorization of Direct Orange 26 (DO26). The performance of UVC-LEDs/US/PMS process was effective in a broad range of pH (3.0-9.0). Complete decolorization was obtained in only 12 min in pH = 7.0 and 1.5 mM PMS. Bicarbonate and nitrite ions showed inhibitory effect on decolorization while sulfate, chloride, and nitrate had no significant effect on the performance of the process. Transition metals in homogenous (Fe2+ and Co2+) and heterogeneous forms (Fe3O4 and Co3O4) accelerated decolorization in UVC LEDs/US/PMS system. The presence of turbidity declined the performance of UVC LEDs/US/PMS through the prevention of PMS activation by UV and US. Compared to other oxidants (S2O82-, H2O2 and 2Na2CO3.3H2O2), PMS proved the higher function in decolorization of DO26 in UVC-LEDs/US/oxidant system. Scavenging experiments showed that 1O2, HO*, and SO4*- contributed in the degradation of DO26. Moreover, the UVC-LEDs/US/PMS system could markedly increase the biodegradability of real textile wastewater. These results promised an effective process for degradation of organic pollutants from aquatic environment. PMID- 29238926 TI - Legal regulations of restrictions of air pollution made by non-road mobile machinery-the case study for Europe: a review. AB - The high awareness of intensification and frequency of smog phenomenon all over the world in XXI age makes for detailed analyses of the reasons of its formation and prevention. The governments of the developed countries and conscious of real hazards, including many European countries, aim to restrict the emission of harmful gases. In literature, we can find the discussions on the influence of this phenomenon on the health and life of inhabitants of contaminated areas. Some elaborations of prognostic models, descriptions of pollution sources, the manner of their restriction, and the analysis of causal-consecutive correlation are also popular. The influence of pollutions resulting from the operation of vehicles, planes, and the industry are well described. However, every machine and device which is driven with a combustion engine has the effect on the general level of anthropogenic pollutions. These drives are subject of different regulations limiting their emission for service conditions and applications. One of the groups of such machines described in European and American regulations is non road mobile machinery. The aim of this paper is the presentation of the problem of weak analysis and application of engineering and technological tools for machinery drive emission, despite of many publications on hazards and problems of emission. These machines have the influence on both the increase of global contamination and the machine users. The regulations of the European Union take into consideration the generated hazards and restrict the emission of machine exhaust gases by approval tests-these regulations are continually improved, and the effects of these works are new emission limits in 2019. However, these activities seem to be liberal as opposed to limits of the emission for passenger and goods vehicles where the technological development of the construction is greater and the regulations are the most rigorous. During the analysis of the development of non-road mobile machinery in the correlation with automotive vehicles, we can indicate engineering and technological solutions which are limiting the emission of non-road mobile machinery, but which are not applied. Due to liberal regulations for this group of machinery, the producers do not apply innovative solutions which can be found in road vehicles. The paper presents the synthetic review of existing EU regulations concerning limits of the emission of harmful exhaust gases which are generated by spark-ignition combustion engines of non-road mobile machinery. The authors show the divergences between the limits of the emission of harmful exhaust gases generated by road vehicles and non-road mobile machinery (boats and railway engines are not taken into account). The authors present the directions of the development of the combustion process control and systems limiting the emission of harmful exhaust gases. High innovative automotive industry was indicated as the direction of the development for limiting the influence of the emission on the environment by non road mobile machinery. PMID- 29238929 TI - Evaluation of zinc oxide nanoparticles on lettuce (Lactuca sativa L.) growth and soil bacterial community. AB - The wide spread of nanoparticles (NPs) has caused tremendous concerns on agricultural ecosystem. Some metallic NPs, such as zinc oxide (ZnO), can be utilized as a nano-fertilizer when used at optimal doses. However, little is known about the responses of plant development and concomitant soil bacteria community to ZnO NPs. The present pot experiment studied the impacts of different doses of ZnO NPs and bulk ZnO (0, 1, 10, 100 mg ZnO/kg), on the growth of lettuce (Lactuca sativa L.) and the associated rhizospheric soil bacterial community. Results showed that at a dose of 10 mg/kg, ZnO NPs and bulk ZnO, enhanced the lettuce biomass and the net photosynthetic rate; whereas, the Zn content in plant tissue was higher in NPs treatment than in their bulk counterpart at 10 mg/kg dose or higher. For the underground observations, 10 mg/kg treatment doses (NPs or bulk) significantly changed the soil bacterial community structure, despite the non-significant variations in alpha diversity. Taxonomic distribution revealed that some lineages within Cyanobacteria and other phyla individually demonstrated similar or different responses to ZnO NPs and bulk ZnO. Moreover, some lineages associated with plant growth promotion were also influenced to different extents by ZnO NPs and bulk ZnO, suggesting the distinct microbial processes occurring in soil. Collectively, this study expanded our understanding of the influence of ZnO NPs on plant performance and the associated soil microorganisms. PMID- 29238928 TI - Green electrochemical modification of RVC foam electrode and improved H2O2 electrogeneration by applying pulsed current for pollutant removal. AB - The performance of cathode on H2O2 electrogeneration is a critical factor that limits the practical application of electro-Fenton (EF) process. Herein, we report a simple but effective electrochemical modification of reticulated vitreous carbon foam (RVC foam) electrode for enhanced H2O2 electrogeneration. Cyclic voltammetry, chronoamperometry, and X-ray photoelectron spectrum were used to characterize the modified electrode. Oxygen-containing groups (72.5-184.0 MUmol/g) were introduced to RVC foam surface, thus resulting in a 59.8-258.2% higher H2O2 yield. The modified electrodes showed much higher electrocatalytic activity toward O2 reduction and good stability. Moreover, aimed at weakening the extent of electroreduction of H2O2 in porous RVC foam, the strategy of pulsed current was proposed. H2O2 concentration was 582.3 and 114.0% higher than the unmodified and modified electrodes, respectively. To test the feasibility of modification, as well as pulsed current, EF process was operated for removal of Reactive Blue 19 (RB19). The fluorescence intensity of hydroxybenzoic acid in EF with modified electrode is 3.2 times higher than EF with unmodified electrode, illustrating more hydroxyl radicals were generated. The removal efficiency of RB 19 in EF with unmodified electrode, modified electrode, and unmodified electrode assisted by pulsed current was 53.9, 68.9, and 81.1%, respectively, demonstrating that the green modification approach, as well as pulsed current, is applicable in EF system for pollutant removal. Graphical abstract ?. PMID- 29238930 TI - Modeling the impacts of ambient temperatures on cardiovascular mortality in Yinchuan: evidence from a northwestern city of China. AB - No evidence is available on whether cardiovascular mortality is affected by the ambient temperatures in Yinchuan, which is located in the northwestern region of China, with a typical continental semi-humid semi-arid climate. Daily data on cardiovascular mortality and meteorological factors was collected from Yinchuan city for the period of 2010-2015. A distributed lag non-linear model with quasi Poisson link was used to assess the association between daily temperatures and cardiovascular deaths, after controlling for seasonality, day of the week, atmospheric pressure, humidity, sunshine duration, and wind speed. The relationship between ambient temperature and cardiovascular mortality was non linear, with a U-shaped exposure-response curve. For all cardiovascular mortality, the effects of high temperatures appeared at lag 2-5 days, with the largest hot effect at lag 3 day (RR 1.082, 95% CI 1.021-1.146), while the effects of cold temperatures were insignificant. Both cold and high temperatures have more serious influence on the elderly (age >= 65) and males than the youth and females, respectively. The study has shown that both cold and high temperatures affect cardiovascular mortality. The findings may be helpful to identify the susceptible subgroups of cardiovascular mortality induced by temperatures, and to provide useful information for establishing public health programs that would better protect local population health from ambient temperatures. PMID- 29238931 TI - Time-varying causality between energy consumption, CO2 emissions, and economic growth: evidence from US states. AB - This study is the first attempt to investigate the relationship between CO2 emissions, energy consumption, and economic growth at a state level, for the 50 US states, through a time-varying causality approach using annual data over the periods 1960-2010. The time-varying causality test facilitates the better understanding of the causal relationship between the covariates owing to the fact that it might identify causalities when the time-constant hypothesis is rejected. Our findings indicate the existence of a time-varying causality at the state level. Specifically, the results probe eight bidirectional time-varying causalities between energy consumption and CO2 emission, six cases of two-way time-varying causalities between economic growth and energy consumption, and five bidirectional time-varying causalities between economic growth and CO2 emission. Moreover, we examine the traditional environmental Kuznets curve hypothesis for the states. Notably, our results do not endorse the validity of the EKC, albeit the majority of states support an inverted N-shaped relationship. Lastly, we can identify multiple policy implications based on the empirical results. PMID- 29238927 TI - Metal-tolerant thermophiles: metals as electron donors and acceptors, toxicity, tolerance and industrial applications. AB - Metal-tolerant thermophiles are inhabitants of a wide range of extreme habitats like solfatara fields, hot springs, mud holes, hydrothermal vents oozing out from metal-rich ores, hypersaline pools and soil crusts enriched with metals and other elements. The ability to withstand adverse environmental conditions, like high temperature, high metal concentration and sometimes high pH in their niche, makes them an interesting subject for understanding mechanisms behind their ability to deal with multiple duress simultaneously. Metals are essential for biological systems, as they participate in biochemistries that cannot be achieved only by organic molecules. However, the excess concentration of metals can disrupt natural biogeochemical processes and can impose toxicity. Thermophiles counteract metal toxicity via their unique cell wall, metabolic factors and enzymes that carry out metal-based redox transformations, metal sequestration by metallothioneins and metallochaperones as well as metal efflux. Thermophilic metal resistance is heterogeneous at both genetic and physiology levels and may be chromosomally, plasmid or transposon encoded with one or more genes being involved. These effective response mechanisms either individually or synergistically make proliferation of thermophiles in metal-rich habitats possibly. This article presents the state of the art and future perspectives of responses of thermophiles to metals at genetic as well as physiological levels. PMID- 29238932 TI - Risk factors and clinical outcomes of hypervirulent Klebsiella pneumoniae induced bloodstream infections. AB - The prevalence of hypervirulent Klebsiella pneumoniae (hvKP) is high in China, but clinical characteristics and outcomes of hvKP induced bloodstream infections (BSIs) are not clear. The purpose of the present study was to determine the risk factors and clinical outcomes of hvKP-BSIs in populations admitted in a teaching hospital of Nanjing, China. The genetic characteristics and antibiotic resistance patterns of the hvKP strains were further analyzed. A retrospective study was conducted in 143 patients with K. pneumoniae BSIs at Jinling Hospital in China from September 2015 to December 2016. A positive polymerase chain reaction (PCR) amplification of the plasmid-borne rmpA (p-rmpA) and aerobactin (iucA) was identified as hvKP. Overall, 24.5% (35/143) of K. pneumoniae isolates were hvKP. Multivariate analysis implicated diabetes mellitus (OR = 3.356) and community acquired BSIs (OR = 4.898) as independent risk factors for hvKP-BSIs. The 30-day mortality rate of the hvKP-BSIs group was 37.1% (13/35) compared with 40.7% (44/108) in the cKP-BSIs control group (P = 0.706). The KPC-producing isolates (OR = 2.851), underlying disease with gastrointestinal fistula (OR = 3.054), APACHE II score >= 15 (OR = 6.694) and Pitt bacteremia score >= 2 (OR = 6.232) at infection onset were independent predictors for 30-day mortality of K. pneumoniae bacteremia patients. A high percentage (57.1%, 20/35) of KPC-producing isolates was observed among hvKP strains and ST11 was dominant in hvKP strains (17/35, 48.6%). KPC-producing hvKP is emerging, indicating the importance of epidemiologic surveillance and clinical awareness of this pathogen. PMID- 29238933 TI - Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) from Pakistan: molecular characterisation by microarray technology. AB - The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in Pakistan is known to be high, but very few studies have described the molecular epidemiology of the different MRSA clones circulating in the country. Forty-four MRSA isolates were collected from two tertiary care hospitals of the Rawalpindi district of Pakistan. All strains were identified by a conventional phenotypic method and then subjected to genotyping by microarray hybridisation. Six clonal complexes (CCs) and 19 strains were identified. The most commonly identified strains were: (i) Panton-Valentine leucocidin (PVL)-positive CC772-MRSA-V, "Bengal Bay Clone" (ten isolates; 22.3%), (ii) ST239-MRSA [III + ccrC] (five isolates) and (iii) a CC8-MRSA-IV strain, as well as CC6-MRSA-IV (both with four isolates; 9.1% each). Several of the strains detected indicated epidemiological links to the Middle Eastern/Arabian Gulf region. Further studies are needed to type MRSA from countries with less known epidemiology and to monitor the distribution and spread of strains, as well as possible links to global travel, migration and commerce. PMID- 29238935 TI - Best practices for storing and shipping cryopreserved cells. AB - Successfully recovering stored cryopreserved cells requires attention to two major factors, i.e., storage temperature and proper handling of the frozen samples. These key considerations are in turn impacted by how the inventory system is constructed, the frequency and process for retrieving specimens, as well as how the material is secured. In addition, shipping biological materials requires attention to the type of material transported, adherence to regulatory requirements, packaging materials and proper assembly, labeling, and engaging reputable carriers. This paper provides an overview discussion of the current best practices for storing, handling, and shipping of cryopreserved cells and provides references to more detailed information on specific topics. PMID- 29238936 TI - Perceived Social Support Mediates the Longitudinal Relations between Ambivalence over Emotional Expression and Quality of Life among Chinese American Breast Cancer Survivors. AB - PURPOSE: The present study examined perceived social support as a mediator of the longitudinal link between ambivalence over emotional expression (AEE) and quality of life among a sample of Chinese breast cancer survivors. METHODS: Ninety-six Chinese breast cancer survivors recruited from Southern California completed four surveys in total: (1) a baseline survey (T1), 1-month follow-up (T2), 3-month follow-up (T3), and 6-month follow-up (T4). Participants filled out a paper-pen questionnaire containing the Ambivalence over Emotional Expression Questionnaire (AEQ), the Functional Assessment of Cancer Therapy-General (FACT-G), and the Medical Outcomes Study Social Support Scale (MOS-SSS). RESULTS: Higher T1 AEE was associated with lower T1 social support (B = -0.01, SE = 0.004, p < 0.01) which in turn was associated with lower quality of life at T2 (B = 2.98, SE = 0.64, p < 0.01), T3 (B = 2.14, SE = 0.54, p < 0.01), and T4 (B = 2.08, SE = 0.68, p < 0.01). CONCLUSIONS: These results suggest that the harmful effect of AEE on quality of life is explained by reduced social support. Given the detrimental effects of AEE on social support and quality of life, future research on interventions that facilitate emotional disclosure is needed. Implications for the effects of Chinese culture on AEE are discussed. PMID- 29238934 TI - Treatment outcome of non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae infections: a multicenter study in Taiwan. AB - Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are associated with high mortality, and experiences with its treatment are usually based on carbapenemase-producing strains. Non-carbapenemase-producing CRKP is of clinical significance, but relevant studies are lacking. This nationwide study aimed to evaluate the outcome of antimicrobial therapy in patients with non-carbapenemase producing CRKP infections. Patients with non-carbapenemase-producing CRKP infections were enrolled from 16 hospitals during January 2013 to December 2014 in Taiwan. Carbapenem resistance was defined as reduced susceptibility with a minimum inhibitory concentration of >=2 mg/L for imipenem or meropenem. The resistance mechanisms of CRKP isolates were analyzed, and the clinical data of these patients were collected retrospectively. Independent risk factors of 14-day morality were determined by Cox regression analysis. A total of 99 patients with non-carbapenemase-producing CRKP infections were enrolled, and 14-day mortality was 27.3%. Among 67 patients treated with appropriate antimicrobial therapy, most (n = 61) patients received monotherapy. The 14-day mortality was lower in patients treated with appropriate monotherapy (21.3%) than in those with inappropriate therapy (37.5%). The multivariate regression model identified monotherapy (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.13-0.71; P = 0.005) as protective factor, and APACHE II scores (HR, 1.09; 95% CI, 1.01-1.18; P = 0.022) as risk factor associated with 14-day mortality. Tigecycline, colistin, and carbapenem were the most commonly used drugs in monotherapy. This study provides evidence supporting the efficacy of monotherapy in the treatment of non-carbapenemase-producing CRKP infections, and provides a future target for antibiotics stewardship for CRKP infection. PMID- 29238937 TI - Demographic Challenges of Pediatric NHL: A Report on 280 Patients. PMID- 29238938 TI - Genetic Polymorphism and Preterm Birth. PMID- 29238939 TI - Harlequin Syndrome. PMID- 29238940 TI - Seasonality in Pediatric Cancer. AB - Although seasonal trends in incidence and diagnosis of pediatric cancers have been widely investigated, the results have been inconclusive. A consistent seasonal trend may possibly provide etiological insights into pediatric cancers. This study aims to determine if there is a seasonal variation in cancer diagnoses in the pediatric population at the IWK Health Centre, a tertiary care center serving three Canadian provinces: Nova Scotia, New Brunswick, and Prince Edward Island. All pediatric cancer patients aged 0-20 y diagnosed from 1995 to 2015 at the center were included in this study. The annual data was divided into four seasonal periods (December to February, March to May, June to August, and September to November). The cancer diagnoses were categorized as leukemia, lymphoma, sarcoma, brain tumors, and miscellaneous. Seasonal variation was assessed by a harmonic function in a Poisson regression model. The amplitude of multiplicative change in the incidence rate caused by the seasonal variation is expressed as the incidence rate ratio (IRR). For all cancer diagnoses for the entire cohort of 1200 patients, the IRR was 1.03 [95% confidence interval (CI) 0.96-1.13]. None of the IRRs for the cancer groups indicated a statistically significant seasonality of cancer diagnosis: Leukemia 1.11 (95% CI 0.96-1.28); Lymphoma 1.17 (95% CI 0.93-1.47); Sarcoma 1.29 (95% CI 0.99-1.69); Brain tumors 1.16 (95% CI 0.97-1.38); Miscellaneous 1.09 (95% CI 0.93-1.27). The present study did not show a seasonal variation in the various cancer types in the pediatric population at the IWK. PMID- 29238941 TI - Lane Hamilton Syndrome. PMID- 29238942 TI - Salmonella typhimurium Meningitis in an Infant Presenting with Recurrent Meningitis. AB - Salmonella typhimurium meningitis in infancy is very uncommon and does not respond to usual duration of empirical antibiotic therapy. A 5-mo-old infant presented with clinical picture of acute pyogenic meningitis and was treated with empirical antibiotic therapy for 14 d. But, 2 wk after the discharge, the child presented again with similar complaints. CSF culture had grown Salmonella typhimurium following which dual antibiotic therapy was given for 6 wk. PMID- 29238943 TI - Effect of Personal and School Factors on Juvenile Delinquency. PMID- 29238944 TI - Recurrent Kawasaki Disease. PMID- 29238945 TI - Combined Poly(Lactide-Co-Glycolide) Microspheres Containing Diphtheria Toxoid for a Single-shot Immunization. AB - To develop a single-shot vaccine containing diphtheria toxoid (DT) with a sufficient immune response, poly(lactide-co-glycolide) (PLGA) microspheres were prepared by water-in-oil-in-water double emulsification and solvent extraction techniques using low or high-molecular-weight PLGA (LMW-MS or HMW-MS). Stearic acid (SA) was introduced to HMW-MS (HMW/SA-MS) as a release modulator. Mean particle sizes (dvs, MUm) varied between the prepared microspheres, with LMW-MS, HMW-MS, and HMW/SA-MS having the sizes of 29.83, 110.59, and 69.5 MUm, respectively; however, the protein entrapment and loading efficiency did not vary, with values of 15.2-16.8 MUg/mg and 61-75%, respectively. LMW-MS showed slower initial release (~ 2 weeks) but faster and higher release of antigen during weeks 3~7 than did HMW-MS. HMW/SA-MS showed rapid initial release followed by a continuous release over an extended period of time (~ 12 weeks). Mixed PLGA microspheres (MIX-MS), a combination of HMW/SA-MS and LMW-MS (1:1), demonstrated a sufficient initial antigen release and a subsequent boost release in a pulsatile manner. Serum antibody levels were measured by ELISA after DT immunization of Balb/c mice, and showed a greater response to MIX-MS than to alum adsorbed DT (control). A lethal toxin challenge test with MIX-MS (a DT dose of 18 Lf) using Balb/c mice revealed complete protection, indicating a good candidate delivery system for a single-shot immunization. PMID- 29238946 TI - PAPP-A2 a new key regulator of growth. AB - Short stature is the main problem that paediatric endocrinologists have to grapple with. Endocrine disorders account for only 5% of patients with short stature, but this is still one of the most common causes of reports to the endocrine clinic and hospitalisation in the endocrine department. A properly functioning growth hormone/insulin-like growth factor (GH/IGF) axis is one of the most important factors in proper growth. A lot of genetic defects in this axis lead to syndromes marked by impaired growth, like Laron syndrome, muta-tions in the STAT5B, insulin-like growth factor 1 (IGF1), and insulin-like growth factor 1 receptor (IGF1R) and mutations in the acid labile subunit (ALS). Two proteases important for the proper functioning of the GH/IGF axis: pregnancy-associated plasma protein-A (PAPP-A) and pregnancy-associated plasma protein-A2 (PAPP-A2), have been described. The first description of the new syndrome of growth failure associated with mutation in the PAPP-A2 gene was given by Andrew Dauber et al. This review evaluates the current data concerning PAPP-A2 function, and particularly the effect of PAPP-A2 mutation on growth. PMID- 29238947 TI - Thyroid ectopy - diagnostic and therapeutic challenges before and in the era of TSH neonatal screening. AB - Despite TSH screening in newborns is currently conducted in most developed countries, patients with thyroid ectopy born before the procedure was introduced or those in whom the screening failed to establish diagnosis, might still appear. In the paper we revise the current state of knowledge regarding the clinical presentation, diagnosis and treatment of patients with thyroid ectopy. As an example, we report diagnostic and therapeutic difficulties in our three patients with thyroid ectopy remaining undiagnosed and untreated during early childhood. Introduction of neonatal screening for congenital hypothyroidism does not guarantee that all patients with thyroid ectopy will be correctly diagnosed and properly treated due to the possibility of falsely negative result of TSH screening or lack of compliance from parents. Visualization of an ectopic thyroid on ultrasound examination may be challenging for unexperienced sonographists; muscles in the thyroid bed may be misdiagnosed as heterogeneous and hypoechogenic thyroid gland with features suggesting autoimmune thyroid disease. Thyroid scintiscan is crucial for confirmation of the diagnosis of thyroid ectopy. In conclusion, hypothyroidism due to thyroid developmental anomaly should be taken into consideration in case of hypothyroidism and normal thyroid autoantibodies in a patient at any age. PMID- 29238948 TI - Antioxidants for preventing and reducing muscle soreness after exercise. AB - BACKGROUND: Muscle soreness typically occurs after intense exercise, unaccustomed exercise or actions that involve eccentric contractions where the muscle lengthens while under tension. It peaks between 24 and 72 hours after the initial bout of exercise. Many people take antioxidant supplements or antioxidant enriched foods before and after exercise in the belief that these will prevent or reduce muscle soreness after exercise. OBJECTIVES: To assess the effects (benefits and harms) of antioxidant supplements and antioxidant-enriched foods for preventing and reducing the severity and duration of delayed onset muscle soreness following exercise. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, SPORTDiscus, trial registers, reference lists of articles and conference proceedings up to February 2017. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials investigating the effects of all forms of antioxidant supplementation including specific antioxidant supplements (e.g. tablets, powders, concentrates) and antioxidant enriched foods or diets on preventing or reducing delayed onset muscle soreness (DOMS). We excluded studies where antioxidant supplementation was combined with another supplement. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, assessed risk of bias and extracted data from included trials using a pre-piloted form. Where appropriate, we pooled results of comparable trials, generally using the random-effects model. The outcomes selected for presentation in the 'Summary of findings' table were muscle soreness, collected at times up to 6 hours, 24, 48, 72 and 96 hours post exercise, subjective recovery and adverse effects. We assessed the quality of the evidence using GRADE. MAIN RESULTS: Fifty randomised, placebo-controlled trials were included, 12 of which used a cross-over design. Of the 1089 participants, 961 (88.2%) were male and 128 (11.8%) were female. The age range for participants was between 16 and 55 years and training status varied from sedentary to moderately trained. The trials were heterogeneous, including the timing (pre exercise or post-exercise), frequency, dose, duration and type of antioxidant supplementation, and the type of preceding exercise. All studies used an antioxidant dosage higher than the recommended daily amount. The majority of trials (47) had design features that carried a high risk of bias due to selective reporting and poorly described allocation concealment, potentially limiting the reliability of their findings.We tested only one comparison: antioxidant supplements versus control (placebo). No studies compared high-dose versus low dose, where the low-dose supplementation was within normal or recommended levels for the antioxidant involved.Pooled results for muscle soreness indicated a small difference in favour of antioxidant supplementation after DOMS-inducing exercise at all main follow-ups: up to 6 hours (standardised mean difference (SMD) -0.30, 95% confidence interval (CI) -0.56 to -0.04; 525 participants, 21 studies; low quality evidence); at 24 hours (SMD -0.13, 95% CI -0.27 to 0.00; 936 participants, 41 studies; moderate-quality evidence); at 48 hours (SMD -0.24, 95% CI -0.42 to -0.07; 1047 participants, 45 studies; low-quality evidence); at 72 hours (SMD -0.19, 95% CI -0.38 to -0.00; 657 participants, 28 studies; moderate quality evidence), and little difference at 96 hours (SMD -0.05, 95% CI -0.29 to 0.19; 436 participants, 17 studies; low-quality evidence). When we rescaled to a 0 to 10 cm scale in order to quantify the actual difference between groups, we found that the 95% CIs for all five follow-up times were all well below the minimal important difference of 1.4 cm: up to 6 hours (MD -0.52, 95% CI -0.95 to 0.08); at 24 hours (MD -0.17, 95% CI -0.42 to 0.07); at 48 hours (MD -0.41, 95% CI -0.69 to -0.12); at 72 hours (MD -0.29, 95% CI -0.59 to 0.02); and at 96 hours (MD -0.03, 95% CI -0.43 to 0.37). Thus, the effect sizes suggesting less muscle soreness with antioxidant supplementation were very unlikely to equate to meaningful or important differences in practice. Neither of our subgroup analyses to examine for differences in effect according to type of DOMS-inducing exercise (mechanical versus whole body aerobic) or according to funding source confirmed subgroup differences. Sensitivity analyses excluding cross-over trials showed that their inclusion had no important impact on results.None of the 50 included trials measured subjective recovery (return to previous activities without signs or symptoms).There is very little evidence regarding the potential adverse effects of taking antioxidant supplements as this outcome was reported in only nine trials (216 participants). From the studies that did report adverse effects, two of the nine trials found adverse effects. All six participants in the antioxidant group of one trial had diarrhoea and four of these also had mild indigestion; these are well-known side effects of the particular antioxidant used in this trial. One of 26 participants in a second trial had mild gastrointestinal distress. AUTHORS' CONCLUSIONS: There is moderate to low-quality evidence that high dose antioxidant supplementation does not result in a clinically relevant reduction of muscle soreness after exercise at up to 6 hours or at 24, 48, 72 and 96 hours after exercise. There is no evidence available on subjective recovery and only limited evidence on the adverse effects of taking antioxidant supplements. The findings of, and messages from, this review provide an opportunity for researchers and other stakeholders to come together and consider what are the priorities, and underlying justifications, for future research in this area. PMID- 29238949 TI - A Pilot of a Brief Positive Parenting Program on Children Newly Diagnosed with Autism Spectrum Disorder. AB - Disruptive behaviors can be of comparable or greater concern to parents than the core symptoms of Autism Spectrum Disorder (ASD). Provision of effective interventions to address these behaviors within the first year of initial diagnosis holds great potential for improving the child's, parents', and family's functioning. We piloted a four-session, manualized, positive parenting program on 21 parents of newly diagnosed children ages 2 through 12 years using a mixed methods design. Seventy-five percent of parents completed four sessions, with 100% reporting high levels of service satisfaction. Preliminary results indicated clinically and statistically significant reductions in child maladaptive behaviors, as well as improvements in parental and family functioning. Practitioners and parents identified several potential implementation adaptations, including additional sessions to focus on ASD education and real time parent-child interactions. Taken as a whole, these data suggest that a brief positive parenting intervention may be a feasible way to improve child, parent, and family functioning during the first year of ASD diagnosis. Findings point to the need for additional research to determine treatment efficacy and to assist with the identification of moderators and mediators of effects. PMID- 29238950 TI - Age estimation in older adults: Use of pulp/tooth ratios calculated from tooth sections. AB - OBJECTIVES: Accurate age estimates are foundational for bioarchaeological research, yet the ability to accurately age older adult skeletons remains elusive. This study uses a new version of pulp/tooth area calculations to investigate chronological age of older archaeological individuals. MATERIALS AND METHODS: Pulp/tooth area ratios were calculated on modern control teeth (n = 10) that were first radiographed and then sectioned for comparative analysis. Pulp/tooth area ratios were determined on sectioned teeth using ImageJ software for: (a) modern individuals of known age (n = 26); (b) individuals from Belleville, Ontario, Canada (1821-1874) with documented age (n = 50); and (c) Belleville individuals with skeletally estimated age (n = 122). RESULTS: Calculations from tooth sections on modern teeth (n = 10) resulted in a mean absolute error (MAE) of +/-3.9 years, whereas the radiographic method for the same teeth had an MAE of +/-14.45 years. Results indicate that sectioned pulp/tooth area ratios are a significant predictor of chronological age (p < .005), with MAEs of +/-4.53 years for Belleville and +/-3.77 years for modern individuals. There were no statistically significant differences in age estimations between modern and archaeological individuals, or with respect to tooth type, sex, or intra/inter-observer estimations. DISCUSSION: This study provides a new more accurate method for estimating age-at-death, particularly for individuals in the 50+ age category. Sectioning the teeth and directly measuring exposed pulp chambers results in age estimations that were within +/-4.15 years for both modern and archaeological individuals, thus presenting a method that will enhance the ability to age older individuals. PMID- 29238951 TI - Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation. AB - Disruption of microvascular blood flow is a common cause of tissue hypoxia in disease, yet no therapies are available that directly target the microvasculature to improve tissue oxygenation. Red blood cells (RBCs) autoregulate blood flow through S-nitroso-hemoglobin (SNO-Hb)-mediated export of nitric oxide (NO) bioactivity. We therefore tested the idea that pharmacological enhancement of RBCs using the S-nitrosylating agent ethyl nitrite (ENO) may provide a novel approach to improve tissue oxygenation. Serial ENO dosing was carried out in sheep (1-400 ppm) and humans (1-100 ppm) at normoxia and at reduced fraction of inspired oxygen (FiO2 ). ENO increased RBC SNO-Hb levels, corrected hypoxia induced deficits in tissue oxygenation, and improved measures of oxygen utilization in both species. No adverse effects or safety concerns were identified. Inasmuch as impaired oxygenation is a major cause of morbidity and mortality, ENO may have widespread therapeutic utility, providing a first-in class agent targeting the microvasculature. PMID- 29238952 TI - Executive functions in children with developmental coordination disorder: a 2 year follow-up study. AB - AIM: Executive function impairments have been identified in children with poor motor skills, with and without a diagnosis of developmental coordination disorder (DCD). However, most studies are cross-sectional. This study investigates the development of executive function in children with poor motor skills over 2 years. METHOD: Children aged 7 to 11 years (n=51) were assessed twice, 2 years apart, on verbal and nonverbal measures of executive functions: executive-loaded working memory (ELWM); fluency; response inhibition; planning; and cognitive flexibility. Typically developing children (n=17) were compared with those with a clinical diagnosis of DCD (n=17) and those with identified motor difficulties (n=17) but no formal diagnosis of DCD. RESULTS: Developmental gains in executive function were similar between groups, although a gap between children with poor motor skills and typically developing children on nonverbal executive functions persisted. Specifically, children with DCD performed significantly more poorly than typically developing children on all nonverbal executive function tasks and verbal fluency tasks at both time points; and children with motor difficulties but no diagnosis of DCD showed persistent executive function problems in nonverbal tasks of ELWM and fluency. INTERPRETATION: Children with DCD and motor difficulties demonstrated executive function difficulties over 2 years, which may affect activities of daily living and academic achievement, in addition to their motor deficit. WHAT THIS PAPER ADDS: Executive function difficulties in children with poor motor skills persist throughout middle childhood. Children with motor difficulties, without a developmental coordination disorder (DCD) diagnosis, demonstrate less pervasive executive function difficulties than those with DCD. Executive function problems in the groups with motor difficulties and DCD affect mostly nonverbal domains. All groups showed similar developmental gains in executive function. PMID- 29238953 TI - Proceedings of the Eighty-Sixth Business Meeting of the American Association of Physical Anthropologists New Orleans, Louisiana April 21, 2017. PMID- 29238954 TI - Interleukin-25 is involved in cutaneous T-cell lymphoma progression by establishing a T helper 2-dominant microenvironment. AB - BACKGROUND: Interleukin (IL)-25 is a member of the IL-17 family, which can promote and augment T-helper (Th) type 2 responses. The expression of IL-25 and its cognate receptor, IL-25 receptor (IL-25R), is upregulated and correlated with disease activity in Th2-associated diseases. OBJECTIVES: To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL). METHODS: Expression and location of IL-25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL-25 production from normal human epidermal keratinocytes was assessed by quantitative reverse transcription real-time polymerase chain reaction. Serum IL-25 levels were measured by enzyme-linked immunosorbent assay. The direct effect of IL-25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sezary syndrome. RESULTS: IL-25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL 4 and IL-13, and periostin induced IL-25 expression by normal human epidermal keratinocytes. Serum IL-25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL 25R and its expression was augmented by stimulation with IL-25. IL-25 enhanced IL 13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sezary syndrome expressed IL-25R and showed increase of IL-13 production by IL-25. CONCLUSIONS: Th2 cytokines highly expressed in CTCL lesional skin induce IL-25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2-dominant microenvironment through the direct induction of IL 13 by tumour cells. PMID- 29238955 TI - Single Batch Bioequivalence Paradigm for Orally Inhaled Products: Time for Change. PMID- 29238956 TI - A test of the preauricular sulcus as an indicator of sex. AB - OBJECTIVES: Although the presence of a preauricular sulcus is often cited as an indicator of female sex, very little research has been conducted to substantiate this claim. This article examines both the relationship between the incidence and morphology of the preauricular sulcus and sex. MATERIALS AND METHODS: A total of 500 left ossa coxae from the Hamann-Todd Human Osteological Collection belonging to 261 males and 239 females were examined to investigate the relationship between the preauricular sulcus and sex. The sample includes both American Blacks and Whites. Each individual was scored based on groove presence and morphology. Differences between the sexes in terms of overall prevalence and morphology were investigated using chi-squared tests. Additionally, possible relationships between ancestry and the manifestation of the preauricular sulcus were investigated using multiple regression analysis. RESULTS: Overall, the presence or absence of the preauricular sulcus resulted in correct sex assessment in 75.8% of ossa coxae. However, the accuracy differed between the sexes, with 62.84% of males and 89.96% of females being assessed correctly. Males were significantly more likely to display a short, narrow sulcus (score 4) than females, whereas females were observed to be significantly more likely to have a wide, long sulcus. Ancestry was not related to sulcus manifestation. DISCUSSION: The results presented here suggest that the presence of a preauricular sulcus should not be considered positive proof of female sex. However, the complete lack of a sulcus could be considered suggestive of male sex. PMID- 29238957 TI - Sleep, oxygen saturation, and seizures in Dravet syndrome. PMID- 29238958 TI - Parasites driving host diversity: Incidence of disease correlated with Daphnia clonal turnover. AB - According to the Red Queen hypothesis, clonal diversity in asexual populations could be maintained by negative frequency-dependant selection by coevolving parasites. If common clones are selected against and rare clones gain a concomitant advantage, we expect that clonal turnover should be faster during parasite epidemics than between them. We tested this hypothesis exploring field data of the Daphnia-Caullerya host-parasite system. The clonal make-up and turnover of the Daphnia host population was tracked with high temporal resolution from 1998 until 2013, using first allozyme and later microsatellite markers. Significant differences in the clonal composition between random and infected subsamples of Daphnia populations were detected on six of seven tested occasions, confirming genetic specificity of the host-parasite interaction in this system. We used time series analysis to compare the rates of host clonal turnover to the incidence of parasitism, and found that Caullerya prevalence was significantly associated with microsatellite-based clonal turnover. As alternate hypotheses, we further tested whether turnover was related to a variety of biotic, abiotic, and host demographic parameters. Other significant correlates of turnover were cyanobacterial biomass and (weakly) temperature. Overall, parasitism seems to be a strong driver of host clonal turnover, in support of the Red Queen hypothesis. PMID- 29238959 TI - Cognition in childhood dystonia: a systematic review. AB - AIM: Cognitive impairments have been established as part of the non-motor phenomenology of adult dystonia. In childhood dystonia, the extent of cognitive impairments is less clear. This systematic review aims to present an overview of the existing literature to elucidate the cognitive profile of primary and secondary childhood dystonia. METHOD: Studies focusing on cognition in childhood dystonia were searched in MEDLINE and PsychInfo up to October 2017. We included studies on idiopathic and genetic forms of dystonia as well as dystonia secondary to cerebral palsy and inborn errors of metabolism. RESULTS: Thirty-four studies of the initial 527 were included. Studies for primary dystonia showed intact cognition and IQ, but mild working memory and processing speed deficits. Studies on secondary dystonia showed more pronounced cognitive deficits and lower IQ scores with frequent intellectual disability. Data are missing for attention, language, and executive functioning. INTERPRETATION: This systematic review shows possible cognitive impairments in childhood dystonia. The severity of cognitive impairment seems to intensify with increasing neurological abnormalities. However, the available data on cognition in childhood dystonia are very limited and not all domains have been investigated yet. This underlines the need for future research using standardized neuropsychological procedures in this group. WHAT THIS PAPER ADDS: There is limited data on cognition in childhood dystonia. Primary dystonia showed intact cognition and IQ, but mild working memory and processing speed deficits. Secondary dystonia showed more pronounced deficits and lower IQ, with frequent intellectual disability. There is a strong need for case control studies assessing cognition using standardized neuropsychological tests. PMID- 29238960 TI - Is inpatient ictal video-electroencephalographic monitoring mandatory in mesial temporal lobe epilepsy with unilateral hippocampal sclerosis? A prospective study. AB - OBJECTIVE: To compare surgical outcome in mesial temporal lobe epilepsy (MTLE) patients with unilateral hippocampal sclerosis (MTLE-HS) who had or did not have preoperative video-electroencephalographic monitoring (VEEG). METHODS: A prospective study was undertaken with 166 consecutive pharmacoresistant unilateral MTLE-HS patients. All patients were investigated with detailed seizure semiology, serial routine outpatient EEG, magnetic resonance imaging, neuropsychological evaluation, and if necessary, other examinations. Postoperative follow-up ranged between 2 and 16 years. Patients were divided into: (1) patients operated on based on routine outpatient EEG information, with >80% of EEGs with unilateral interictal epileptiform discharges (IEDs) ipsilateral to HS or ictal events (n = 71); and (2) patients submitted to preoperative VEEG (n = 95). To avoid the bias generated by ictal recordings, we performed a subanalysis of: (1) patients without preoperatively ictal recordings (n = 80) and (2) patients with ictal recordings in VEEG or routine outpatient EEG (n = 86). RESULTS: Groups were similar regarding gender, age at surgery, seizure onset, preoperative seizure frequency, and duration of follow-up. Overall, 136/166 (81.92%) were classified as Engel I seizure outcome, with no difference between groups; 76.84% and 88.73% of patients with and without VEEG, respectively, had Engel I postoperative seizure outcome (P = .77). The time lag until surgery was shorter in the group without VEEG (80 vs 38 months; P = .01). Considering ictal recordings, 76.74% of patients with seizures recorded and 87.50% without ictal recordings had Engel I outcome (P = .11). SIGNIFICANCE: We performed the first prospective study in a tertiary epilepsy center comparing surgical outcomes in unilateral MTLE-HS patients investigated preoperatively with and without VEEG. Based on the surgical outcome, VEEG is not imperative in patients with unilateral MTLE-HS who have compatible semiology and clearly ipsilateralized IEDs evaluated by a multidisciplinary and experienced epilepsy group. PMID- 29238961 TI - Couple Relationship Standards and Migration: Comparing Hong Kong Chinese with Australian Chinese. AB - Rates of international migration are increasing, which raises the question of how migration might influence couple relationship standards and impact on the standards of migrants forming intercultural relationships. We compared relationship standards in n = 286 Chinese living in Hong Kong, China, with standards in n = 401 Chinese migrants to a Western country (Australia) by administering the Chinese-Western Intercultural Couple Standards Scale (CWICSS). We also compared these two groups to n = 312 Westerners living in Australia. We first tested the structural invariance of the CWICSS across the three samples with a multigroup confirmatory factor analysis. There was marginal but acceptable fit of a model of two positively correlated latent factors: Couple Bond (with four indicators, such as demonstration of love and caring) and Family Responsibility (also with four indicators, such as extended family relations and preserving face). Within the limitations of the study, results suggest migration is associated predominantly with differences in women's, but not men's, relationship standards. Migrant Chinese women show alignment of Couple Bond standards with Western standards, and divergence of Family Responsibility standards from Western standards. Discussion focused on how migration and intercultural relationship experiences might differentially influence various domains of relationship standards, gender differences in migration effects on standards, and the implications for working with culturally diverse couples. PMID- 29238962 TI - Population Pharmacokinetics of Polymyxin B. AB - Polymyxin B is used as a last treatment resort for multidrug-resistant Gram negative bacterial infections. The objectives of this study were to examine the population pharmacokinetics of polymyxin B and investigate factor(s) influencing pharmacokinetic variability. Four serial blood samples each were collected from 35 adult patients at steady state. The concentrations of individual polymyxin B components were analyzed using a validated liquid chromatography / tandem mass spectrometry assay and combined to derive total concentrations. A maximum likelihood expectation maximization approach was used to fit the data. Various demographic variables were investigated as potential covariates for clearance and volume of distribution (Vd ) using linear regression analysis. A one-compartment model fit to the data satisfactorily (r2 = 0.96). The best-fit mean +/- SD for clearance and Vd were 2.5 +/- 1.1 L/h and 34.3 +/- 16.4 L, respectively. Creatinine clearance was found to be a statistically significant covariate of clearance, but the magnitude was deemed clinically insignificant. PMID- 29238963 TI - Life expectancy after the first suicide attempt. AB - OBJECTIVE: To assess excess mortality among suicide attempters compared to the general population. METHOD: Remaining life expectancy was calculated for a nationwide cohort of all 187 894 persons 18 years or older hospitalised for the first time attempted suicide in Sweden in 1971-2010. RESULTS: Life expectancy was shortened throughout the lifespan for both men and women debuting with suicide attempt. The reduction in life expectancy for men debuting with a suicide attempt at 20 years of age was 18 years while the reduction for men debuting at 50 years of age was 10 years. For women attempting suicide, the life expectancy was shortened by 11 and 8 years respectively. The gender difference in life expectancy attenuated in patients making their first suicide attempt at age 70 years or older. Suicide deaths explained about 20% of the total mortality within 10 years of the suicide attempt and 5% in those with duration of four decades since the first suicide attempt. CONCLUSION: The life expectancy is dramatically reduced in patients attempting suicide. With most excess deaths being due to physical health conditions, public efforts should be directed both towards improving physical health and to prevent suicide. PMID- 29238964 TI - Reading comprehension difficulties in children with rolandic epilepsy. AB - AIM: Difficulties in reading comprehension can arise from either word reading or listening comprehension difficulties, or a combination of the two. We sought to determine whether children with rolandic epilepsy had poor reading comprehension relative to typically developing comparison children, and whether such difficulties were associated with word reading and/or general language comprehension difficulties. METHOD: In this cross-sectional study, children with rolandic epilepsy (n=25; 16 males, 9 females; mean age 9y 1mo, SD 1y 7mo) and a comparison group (n=39; 25 males, 14 females; mean age 9y 1mo, SD 1y 3mo) completed assessments of reading comprehension, listening comprehension, word/non word reading, speech articulation, and Non-verbal IQ. RESULTS: Reading comprehension and word reading were worse in children with rolandic epilepsy (F1,61 =6.89, p=0.011, etap2=0.10 and F1,61 =6.84, p=0.011, etap2=0.10 respectively), with listening comprehension being marginal (F1,61 =3.81, p=0.055, etap2=0.06). Word reading and listening comprehension made large and independent contributions to reading comprehension, explaining 70% of the variance. INTERPRETATION: Children with rolandic epilepsy may be at risk of reading comprehension difficulties. Thorough assessment of individual children is required to ascertain whether the difficulties lie with decoding text, or with general comprehension skills, or both. WHAT THIS PAPER ADDS: Children with rolandic epilepsy may be at risk of poor reading comprehension. This was related to poor word reading, poor listening comprehension, or both. Reading comprehension interventions should be tailored to the profile of difficulties. PMID- 29238965 TI - Sieve analysis using the number of infecting pathogens. AB - Assessment of vaccine efficacy as a function of the similarity of the infecting pathogen to the vaccine is an important scientific goal. Characterization of pathogen strains for which vaccine efficacy is low can increase understanding of the vaccine's mechanism of action and offer targets for vaccine improvement. Traditional sieve analysis estimates differential vaccine efficacy using a single identifiable pathogen for each subject. The similarity between this single entity and the vaccine immunogen is quantified, for example, by exact match or number of mismatched amino acids. With new technology, we can now obtain the actual count of genetically distinct pathogens that infect an individual. Let F be the number of distinct features of a species of pathogen. We assume a log-linear model for the expected number of infecting pathogens with feature "f," f = 1 , ... , F . The model can be used directly in studies with passive surveillance of infections where the count of each type of pathogen is recorded at the end of some interval, or active surveillance where the time of infection is known. For active surveillance, we additionally assume that a proportional intensity model applies to the time of potentially infectious exposures and derive product and weighted estimating equation (WEE) estimators for the regression parameters in the log-linear model. The WEE estimator explicitly allows for waning vaccine efficacy and time-varying distributions of pathogens. We give conditions where sieve parameters have a per-exposure interpretation under passive surveillance. We evaluate the methods by simulation and analyze a phase III trial of a malaria vaccine. PMID- 29238966 TI - Aberrant proliferation and differentiation of glycogen storage disease type Ib mesenchymal stem cells. AB - Glycogen storage disease type Ib (GSD-Ib) is caused by mutations of the glucose-6 phosphate transporter (G6PT) and characterized by disrupted glucose homeostasis, neutropenia, and neutrophil dysfunction. To investigate the role of G6PT in human adipose-derived mesenchymal stem cells (hMSCs), the G6PT gene was mutated by CRISPR/Cas9 technology and single cell-derived G6PT-/- hMSCs were established. G6PT-/- hMSCs have significantly increased cell proliferation but impaired adipogenesis and osteogenesis. These phenotypes are associated with two mechanisms: i) metabolic reprogramming in G6PT-/- hMSCs causing a metabolic shift toward glycolysis rather than oxidative phosphorylation and ii) increased cyclooxygenase-2-derived prostaglandin E2 secretion in G6PT-/- hMSCs. This study demonstrates that G6PT is essential for proliferation and differentiation of MSCs, providing important insights into the GSD-Ib phenotypes. PMID- 29238968 TI - Immigrants Coping with Transnational Deaths and Bereavement: The Influence of Migratory Loss and Anticipatory Grief. AB - This study examines immigrants' experiences of bereavement and coping with the deaths of family members in a transnational context. Data were collected through in-depth personal interviews with middle-aged and older immigrants from different countries of origin, who have been living in the United States for a majority of their adult lives. Thematic analysis of participants' narratives showed that immigrants' geographic distance from family complicated caregiving circumstances and rituals surrounding burial, and impacted the grieving process. At the same time, this distance also served as an emotional barrier and provided protection from prolonged grief. Immigrants' U.S.-based family and work responsibilities served as buffers from prolonged grief. Over time, immigrants became Americanized in their attitudes toward coping with death and favored a fast return to productive activities. Finally, immigrants' experience of migratory loss and anticipatory grief early in immigration, along with their personal growth and resilience developed over time, impacted their bereavement experiences later in life. Considering the limitations and the exploratory nature of the present study, further research is needed to investigate the specifics of coping with loss and bereavement among immigrants. PMID- 29238967 TI - Potent Anti-Inflammatory and Pro-Resolving Effects of Anabasum in a Human Model of Self-Resolving Acute Inflammation. AB - Anabasum is a synthetic analog of Delta8 -tetrahydrocannabinol (THC)-11-oic acid that in preclinical models of experimental inflammation exerts potent anti inflammatory actions with minimal central nervous system (CNS) cannabimimetic activity. Here we used a novel model of acute inflammation driven by i.d. UV killed E. coli in healthy humans and found that anabasum (5 mg) exerted a potent anti-inflammatory effect equivalent to that of prednisolone in terms of inhibiting neutrophil infiltration, the hallmark of acute inflammation. These effects arose from the inhibition of the neutrophil chemoattractant LTB4 , while the inhibition of antiphagocytic prostanoids (PGE2 , TxB2 , and PGF2 alpha) resulted in enhanced clearance of inflammatory stimulus from the injected site. Anabasum at the higher dose of 20 mg possessed the additional properties of triggering the biosynthesis of specialized pro-resolving lipid mediators including LXA4 , LXB4 , RvD1, and RvD3. Collectively, we demonstrate for the first time a striking anti-inflammatory and pro-resolution effects of a synthetic analog of THC in healthy humans. PMID- 29238969 TI - Axially-confined in vivo single-cell labeling by primed conversion using blue and red lasers with conventional confocal microscopes. AB - Green-to-red photoconvertible fluorescent proteins have been found to undergo efficient photoconversion by a new method termed primed conversion that uses dual wave-length illumination with blue and red/near-infrared light. By modifying a confocal laser-scanning microscope (CLSM) such that two laser beams only meet at the focal plane, confined photoconversion at the axial dimension has been achieved. The necessity of this custom modification to the CLSM, however, has precluded the wide-spread use of this method. Here, we investigated whether spatially-restricted primed conversion could be achieved with CLSM without any hardware modification. We found that the primed conversion of Dendra2 using a conventional CLSM with two visible lasers (473 nm and 635 nm) and a high NA objective lens (NA, 1.30) resulted in dramatic restriction of photoconversion volume: half-width half-maximum for the axial dimension was below 5 MUm, which is comparable to the outcome of the original method that used the microscope modification. As a proof of this method's effectiveness, we used this technique in living zebrafish embryos and succeeded in revealing the complex anatomy of individual neurons packed between neighboring cells. Because unmodified CLSMs are widely available, this method can be widely applicable for labeling cells with single-cell resolution. PMID- 29238970 TI - The consequences of sexual selection in well-adapted and maladapted populations of bean beetles?. AB - Whether sexual selection generally promotes or impedes population persistence remains an open question. Intralocus sexual conflict (IaSC) can render sexual selection in males detrimental to the population by increasing the frequency of alleles with positive effects on male reproductive success but negative effects on female fecundity. Recent modeling based on fitness landscape theory, however, indicates that the relative impact of IaSC may be reduced in maladapted populations and that sexual selection therefore might promote adaptation when it is most needed. Here, we test this prediction using bean beetles that had undergone 80 generations of experimental evolution on two alternative host plants. We isolated and assessed the effect of maladaptation on sex-specific strengths of selection and IaSC by cross-rearing the two experimental evolution regimes on the alternative hosts and estimating within-population genetic (co)variance for fitness in males and females. Two key predictions were upheld: males generally experienced stronger selection compared to females and maladaptation increased selection in females. However, maladaptation consistently decreased male-bias in the strength of selection and IaSC was not reduced in maladapted populations. These findings imply that sexual selection can be disrupted in stressful environmental conditions, thus reducing one of the potential benefits of sexual reproduction in maladapted populations. PMID- 29238971 TI - Postauthorization safety study of Clottafact(r) , a triply secured fibrinogen concentrate in acquired fibrinogen deficiency: a prospective observational study. AB - BACKGROUND AND OBJECTIVES: A postauthorization safety study was performed between 2009 and 2012 to describe the use of Clottafact(r) in acquired fibrinogen deficiency in real-life medical practice in France. MATERIALS AND METHODS: One hundred and fifty patients were planned for 28 days of prospective follow-up after infusion. The analysis of this observational study was descriptive and performed according to the type of treatment (curative or preventive) and the origin of the bleed. RESULTS: One hundred and fifty-six patients (16-87 years) were included in 13 centres and treated in five different medical bleeding situations: postpartum (59), other gynaecological/obstetrical (6), trauma (34), liver (13), cardiovascular (23) and other various bleeding situations (21). The mean follow-up time was 18.9 +/- 12.3 days. Two patients presented adverse drug reactions: one a pulmonary embolism and the other a four-site venous thromboembolic episode. All were serious with a dubious causal relationship with the study treatment. Efficacy data were collected as a secondary objective. In 150 patients receiving curative treatment, 117 of 159 infusions (73.6%) were considered as successful by the investigators, 35 as moderate (22%) and seven as no response (4.4%). CONCLUSION: The Clottafact(r) safety profile observed during the study matched the known profile of fibrinogen during use. PMID- 29238972 TI - The functional anatomy of the cerebrocerebellar circuit: A review and new concepts. AB - The cerebrocerebellar circuit is a feedback circuit that bidirectionally connects the neocortex and the cerebellum. According to the classic view, the cerebrocerebellar circuit is specifically involved in the functional regulation of the motor areas of the neocortex. In recent years, studies carried out in experimental animals by morphological and physiological methods, and in humans by magnetic resonance imaging, have indicated that the cerebrocerebellar circuit is also involved in the functional regulation of the nonmotor areas of the neocortex, including the prefrontal, associative, sensory and limbic areas. Moreover, a second type of cerebrocerebellar circuit, bidirectionally connecting the hypothalamus and the cerebellum, has been detected, being specifically involved in the regulation of the hypothalamic functions. This review analyzes the morphological features of the centers and pathways of the cerebrocerebellar circuits, paying particular attention to their organization in different channels, which separately connect the cerebellum with the motor areas and nonmotor areas of the neocortex, and with the hypothalamus. Actually, a considerable amount of new data have led, and are leading, to profound changes on the views on the anatomy, physiology, and pathophysiology of the cerebrocerebellar circuits, so much they may be now considered to be essential for the functional regulation of many neocortex areas, perhaps all, as well as of the hypothalamus and of the limbic system. Accordingly, clinical studies have pointed out an involvement of the cerebrocerebellar circuits in the pathophysiology of an increasing number of neuropsychiatric disorders. PMID- 29238973 TI - Demethylzeylasteral (ZST93) inhibits cell growth and enhances cell chemosensitivity to gemcitabine in human pancreatic cancer cells via apoptotic and autophagic pathways. AB - The overall 5-year survival rate of patients with human pancreatic cancer remains less than 8% because of its aggressive growth, early metastasis and resistance to conventional chemoradiotherapy. It is essential to develop innovative and effective therapeutic agents to improve its prognosis. Demethylzeylasteral (ZST93) is a novel triterpenoid monomer extracted from the xylem of Tripterygium roots. Our study aimed to assess the effects of ZST93 on cell proliferation and its role in the chemosensitivity to gemcitabine in human pancreatic cancer cells. The effects of ZST93 on cancer cell proliferation, cell cycle distribution, apoptosis and autophagy were evaluated in various human pancreatic cancer cell lines, and the antitumor effects of ZST93 alone and in combination with gemcitabine were identified in a xenograft mouse model. The results showed that ZST93 could inhibit the proliferation of pancreatic cancer cells and arrest cell cycle at G0/G1 phase by regulating the expression of Cyclin D1 and Cyclin A2. Moreover, ZST93 killed pancreatic cancer cells through two different mechanisms: inducing autophagic cell death at low concentrations and apoptotic cell death at high concentrations. Furthermore, ZST93 could enhance the chemosensitivity of pancreatic cancer cells to gemcitabine both in vitro and in vivo through modulation of the cross talk between autophagy and apoptosis. ZST93 is a potential therapeutic agent for developing novel therapeutic strategies in human pancreatic cancer. PMID- 29238974 TI - A randomized Phase III trial of neoadjuvant recombinant human endostatin, docetaxel and epirubicin as first-line therapy for patients with breast cancer (CBCRT01). AB - To further assess the efficacy and safety of recombinant human endostatin (rh endostatin), a Phase III, multicenter, prospective, randomized, controlled clinical trial was conducted. Patients to be treated with neoadjuvant docetaxel and epirubicin (DE) or DE plus rh-endostatin (DEE) were eligible for this trial. The primary endpoint was clinical/pathological response. Secondary endpoints included adverse events and quality of life (QOL). Finally, 803 patients were enrolled and randomly assigned to receive DE (n = 402) or DEE (n = 401) regimen. After three cycles of neoadjuvant therapy, "complete response" achieved in 14.2% of patients in DEE group versus 6.7% in DE group, "partial response" achieved in 76.8% versus 71.1%, while "stable disease" in 6.0% versus 18.9%, "progressive disease" in 3.0% versus 3.2% of patients. The rate of objective response in DEE and DE group was 91.0% and 77.9%, respectively (p < 0.001). In spite of a relatively higher pathological complete response achieved following the combination therapy, no significant difference was found between two arms. Adverse events were mostly of Grades 1-2. No significant difference in adverse event and QOL was found between the two arms. In conclusion, the combination of chemotherapy and rh-endostatin achieved better outcomes than chemotherapy alone, and thus can be considered as a promising therapeutic strategy for breast cancer. PMID- 29238975 TI - Effect of rural and urban geography on larynx cancer incidence and survival. AB - OBJECTIVES/HYPOTHESIS: Investigate the impact of rural geography on larynx cancer incidence and survival. STUDY DESIGN: Surveillance, Epidemiology, and End Results (SEER) database study. METHODS: Incidence and survival rates by Rural-Urban Continuum codes for larynx squamous cell carcinoma patients diagnosed from 2004 to 2012 were evaluated using SEER statistical software and Cox proportional hazards survival analysis. RESULTS: The lowest age-adjusted incidence rates for larynx cancer were seen in densely populated urban regions, with mean rates of 2.8 per 100,000 person years (95% confidence interval [CI]: 2.7-2.8); the highest were in the most rural areas, with mean rates of 5.3 per 100,000 person years (95% CI: 4.7-5.9). Nevertheless, of 23,659 larynx cancer patients diagnosed over this period, 19,556 (82.7%) arose in urban residents, compared with 1,428 or 6% from rural areas. Urban larynx cancer patients more likely lived in counties with an American College of Surgeons-approved cancer center and/or a fourfold greater otolaryngology physician supply. Nevertheless, frequency of advanced stage at initial presentation was similar. Cause-specific and overall survival were no different, both on univariable and multivariable analyses. CONCLUSIONS: Compared with urban populations, Rural populations are at greater risk of developing larynx cancer, but initial stage and survival after diagnosis are comparable. Priority should be given to prevention strategies to decrease incidence rates. LEVEL OF EVIDENCE: 4 Laryngoscope, 1874-1880, 2018. PMID- 29238977 TI - Microinvasive parathyroidectomy: Incremental improvement in minimally invasive parathyroid surgery. PMID- 29238976 TI - A spontaneously immortalized Schwann cell line from aldose reductase-deficient mice as a useful tool for studying polyol pathway and aldehyde metabolism. AB - The increased glucose flux into the polyol pathway via aldose reductase (AR) is recognized as a major contributing factor for the pathogenesis of diabetic neuropathy, whereas little is known about the functional significance of AR in the peripheral nervous system. Spontaneously immortalized Schwann cell lines established from long-term cultures of AR-deficient and normal C57BL/6 mouse dorsal root ganglia and peripheral nerves can be useful tools for studying the physiological and pathological roles of AR. These cell lines, designated as immortalized knockout AR Schwann cells 1 (IKARS1) and 1970C3, respectively, demonstrated distinctive Schwann cell phenotypes, such as spindle-shaped morphology and immunoreactivity to S100, p75 neurotrophin receptor, and vimentin, and extracellular release of neurotrophic factors. Conditioned media obtained from these cells promoted neuronal survival and neurite outgrowth of cultured adult mouse dorsal root ganglia neurons. Microarray and real-time RT-PCR analyses revealed significantly down-regulated mRNA expression of polyol pathway-related enzymes, sorbitol dehydrogenase and ketohexokinase, in IKARS1 cells compared with those in 1970C3 cells. In contrast, significantly up-regulated mRNA expression of aldo-keto reductases (AKR1B7 and AKR1B8) and aldehyde dehydrogenases (ALDH1L2, ALDH5A1, and ALDH7A1) was detected in IKARS1 cells compared with 1970C3 cells. Exposure to reactive aldehydes (3-deoxyglucosone, methylglyoxal, and 4 hydroxynonenal) significantly up-regulated the mRNA expression of AKR1B7 and AKR1B8 in IKARS1 cells, but not in 1970C3 cells. Because no significant differences in viability between these two cell lines after exposure to these aldehydes were observed, it can be assumed that the aldehyde detoxification is taken over by AKR1B7 and AKR1B8 in the absence of AR. PMID- 29238978 TI - Use of autologous adipose-derived mesenchymal stem cells for creation of laryngeal cartilage. AB - OBJECTIVES/HYPOTHESIS: Adipose-derived mesenchymal stem cells (ASCs) are an exciting potential cell source for tissue engineering because cells can be derived from the simple excision of autologous fat. This study introduces a novel approach for tissue-engineering cartilage from ASCs and a customized collagen oligomer solution, and demonstrates that the resultant cartilage can be used for laryngeal cartilage reconstruction in an animal model. STUDY DESIGN: Basic science experimental design. METHODS: ASCs were isolated from F344 rats, seeded in a customized collagen matrix, and cultured in chondrogenic differentiation medium for 1, 2, and 4 weeks until demonstrating cartilage-like characteristics in vitro. Large laryngeal cartilage defects were created in the F344 rat model, with the engineered cartilage used to replace the cartilage defects, and the rats followed for 1 to 3 months. Staining examined cellular morphology and cartilage specific features. RESULTS: In vitro histological staining revealed rounded chondrocyte-appearing cells evenly residing throughout the customized collagen scaffold, with positive staining for cartilage-specific markers. The cartilage was used to successfully repair large cartilaginous defects in the rat model, with excellent functional results. CONCLUSIONS: This study is the first study to demonstrate, in an animal model, that ASCs cultured in a unique form of collagen oligomer can create functional cartilage-like grafts that can be successfully used for partial laryngeal cartilage replacement. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E123-E129, 2018. PMID- 29238979 TI - Evaluating the Performance Diagnostic Checklist-Human Services to assess incorrect error-correction procedures by preschool paraprofessionals. AB - The Performance Diagnostic Checklist-Human Services (PDC-HS) has been used to assess variables contributing to undesirable staff performance. In this study, three preschool teachers completed the PDC-HS to identify the factors contributing to four paraprofessionals' inaccurate implementation of error correction procedures during discrete trial training sessions. The PDC-HS indicated insufficient training as a contributing factor. We then implemented a nonindicated intervention (posting reminders), followed by an indicated intervention (behavioral skills training). The nonindicated intervention failed to produce desired performance improvements; however, the PDC-HS indicated intervention resulted in improvements for all paraprofessionals. PMID- 29238980 TI - Influence of paeoniflorin and menthol on puerarin transport across MDCK and MDCK MDR1 cells as blood-brain barrier in vitro model. AB - OBJECTIVE: Our objective of this research was (1) to investigate the transport characteristics of puerarin through MDCK-MDR1 and MDCK cells and (2) to evaluate the effects of paeoniflorin and menthol on puerarin transport so as to (3) explore the enhancement mechanism. METHODS: The cytotoxicity of drugs on MDCK and MDCK-MDR1 was evaluated by the MTT assay, and the transport studies were performed in both directions. The membrane fluidity was evaluated by fluorescence recovery after photobleaching, and the membrane potential was estimated by the accumulation of DiBAC4(3) in the cells. KEY FINDINGS: Puerarin showed relatively poor absorption and purely passive diffusion. However, the efflux ratio of puerarin was <2 in MDCK-MDR1 models, which suggested puerarin was not P-gp substrates so as to the P-glycoprotein activity determination of puerarin. With the existence of menthol, the transcellular transport of puerarin increased and puerarin transport significantly increased when co-administrated with paeoniflorin and menthol. CONCLUSIONS: The enhancing effect of paeoniflorin and menthol may be attributed to the significant enhancement on cell membrane fluidity, the decrease in membrane potential. Immunostaining results indicated that menthol behaved as transport enhancer by disassembly effect on tight junction integrity. PMID- 29238981 TI - Incidence, risk factors, and outcome of transfusion-associated circulatory overload in a mixed intensive care unit population: a nested case-control study. AB - BACKGROUND: The objective of this study was to determine the incidence, risk factors, and outcome of transfusion-associated circulatory overload (TACO) in a cohort of mixed intensive care unit patients and to compare risk factors with those for cardiac overload in the absence of transfusion. STUDY DESIGN AND METHODS: In a retrospective cohort study, patients who developed TACO were compared using multivariate analysis of two control groups: patients without pulmonary deterioration who received transfusion and patients who developed circulatory overload in the absence of transfusion. RESULTS: TACO was diagnosed in 66 of 1140 patients who received transfusions (5.8%). A total of 585 control transfusion recipients and 76 control patients who developed circulatory overload also were identified. Risk factors were the referring specialties cardiology (odds ratio [OR], 13.6; 95% confidence interval [CI], 5.1-35.7; p <= 0.001) and cardiothoracic surgery (OR, 8.8; 95% CI, 3.7-20.7; p <= 0.001), history of cardiac failure (OR, 2.4; 95% CI, 1.2-4.6; p = 0.01), continuous veno-venous hemofiltration (OR, 3.2; 95% CI, 1.2-8.9; p = 0.03), and degree of positive fluid balance (OR, 1.15; 95% CI, 1.07-1.24; p <= 0.001), which was associated less with the onset of TACO compared with circulatory overload (OR, 0.89; 95% CI, 0.82 0.97; p = 0.005). Patients in the TACO group had a longer length of stay in the intensive care unit compared with the transfusion and circulatory overload controls groups (median, 7.2 vs. 4.3 vs. 4.4 days; p = 0.001 vs. p = 0.008). CONCLUSIONS: The incidence of TACO is high in a mixed intensive care unit population. The risk factors identified for TACO are cardiac failure, renal failure, and degree of positive fluid balance. A positive fluid balance may be less essential in the onset of TACO than in the onset of circulatory overload in the absence of transfusion. PMID- 29238982 TI - Niche partitioning of intertidal seagrasses: evidence of the influence of substrate temperature. AB - The influence of soil temperature on rhizome depths of four intertidal seagrass species was investigated in central Queensland, Australia. We postulated that certain intertidal seagrass species are soil temperature-sensitive and vertically stratify rhizome depths. Below-ground vertical stratification of intertidal seagrass rhizome depths was analysed based upon microclimate (soil temperature) and microhabitat (soil type). Soil temperature profiles exhibited heat transfer from surface layers to depth that varied by microhabitat, with vertical stratification of rhizome depths between species. Halodule uninervis rhizomes maintain a narrow median soil temperature envelope; compensating for high surface temperatures by occupying deeper, cooler soil substrates. Halophila decipiens, Halophila ovalis and Zostera muelleri rhizomes are shallow-rooted and exposed to fluctuating temperatures, with broader median temperature envelopes. Halodule uninervis appears to be a niche specialist, with the two Halophila species considered as generalist niche usage species. The implications of niche use based upon soil temperature profiles and rhizome rooting depths are discussed in the context of species' thermal tolerances and below-ground biomass O2 demand associated with respiration and maintenance of oxic microshields. This preliminary evidence suggests that soil temperature interaction with rhizome rooting depths may be a factor that influences the distribution of intertidal seagrasses. PMID- 29238983 TI - Brain volume changes in hyposmic patients before and after olfactory training. AB - OBJECTIVES/HYPOTHESIS: Olfactory dysfunction is thought to be associated with reduced gray matter (GM) volume in olfactory-related brain areas. The aim of this study was to determine GM structural changes within olfactory-related regions of the brain in patients with smell loss due to upper respiratory tract infection (URTI) before and after olfactory rehabilitation. STUDY DESIGN: Prospective intervention case-control study. METHODS: Magnetic resonance imaging structural brain images were collected from 30 patients with smell loss due to URTI and 31 controls. Patients exposed themselves to odors (olfactory training [OT]) over 12 weeks and then were rescanned. Olfactory testing was performed using the validated Sniffin' Sticks test. GM was investigated with voxel-based morphometry. RESULTS: GM volumes were found to be reduced in the limbic system and thalamus among pretraining patients compared to controls; in patients, OT was associated with a significant increase of GM volume in these two regions. The GM volume within other olfactory-related regions was not different between patients and controls. In addition, no relevant difference between the GM volume pre- and post OT was observed in primary olfactory-related regions. CONCLUSIONS: OT was associated with an increase in GM volume of the hippocampus and the thalamus, possibly pointing toward a strategy for more effective exploitation of olfactory signals based on a higher degree of attention toward odors and association of memories with olfactory input. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:1531 1536, 2018. PMID- 29238984 TI - Differing disintegration and dissolution rates, pharmacokinetic profiles and gastrointestinal tolerability of over the counter ibuprofen formulations. AB - OBJECTIVES: Formulations of over the counter (OTC) NSAIDs differ substantially, but information is lacking on whether this alters their gastrointestinal profiles. To assess disintegration and dissolution rates and pharmacokinetics of four preparations of OTC ibuprofen and relate these with spontaneously reported gastrointestinal adverse events. METHODS: Disintegration and dissolution rates of ibuprofen tablets as (a) acid, (b) sodium salt, (c) lysine salt, and (d) as a liquid gelatine capsule were assessed. Pharmacokinetic data gastrointestinal and spontaneously reported adverse events arising from global sales were obtained from files from Reckitt Benckiser. KEY FINDINGS: Disintegration at low pH was progressively shorter for the preparations from a-to-d with formation of correspondingly smaller ibuprofen crystals, while dissolution was consistently poor. Dissolution at a neutral pH was least rapid for the liquid gelatine capsule. Pharmacokinetic data showed a shorter tmax and a higher Cmax for preparations b-d as compared with ibuprofen acid. Spontaneously reported abdominal symptoms were rare with the liquid gelatine preparation. CONCLUSIONS: The formulations of OTC ibuprofen differ in their disintegration and dissolution properties, pharmacokinetic profiles and apparent gastrointestinal tolerability. Spontaneously reported abdominal symptoms were five times lower with the liquid gelatine capsule as compared with ibuprofen acid despite a 30% increase in Cmax . PMID- 29238986 TI - Clinical implications of magnetic resonance imaging in temporomandibular disorders patients presenting ear fullness. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to investigate whether findings detected by temporomandibular joint magnetic resonance imaging (TMJ-MRI) can provide pathognomonic evidence of temporomandibular disorders (TMD) in patients with nonspecific ear fullness (EF). The association of nonspecific EF with clinical characteristics of TMD based on TMJ-MRI findings was examined. STUDY DESIGN: Retrospective analysis. METHODS: Thirty-four subjects (42 ears) who had no detectable otologic problems as a cause of EF were enrolled in this study. Each subject underwent TMJ-MRI to identify pathology of the TMJ as a possible cause of nonspecific EF. All subjects participated in the re-evaluation process following TMD treatment. RESULTS: Anatomical abnormalities in TMJ-MRI, irrespective of TMD signs, were observed in 34 of the 42 ears (80.9%), such as degenerative change of the TMJ (16 ears), articular disc displacement (11 ears), and joint effusion (seven ears). Specific abnormalities of the TMJ were associated with nonspecific EF, and this symptom showed improvement following individualized TMD treatment in those with internal derangement and/or effusion of the TMJ. However, abnormal TMJ-MRI findings were also observed in seven of nine ears with no TMD signs, and there was no significant association between the presence of TMD signs and abnormal TMJ-MRI findings (chi2 = 0.075, P = .784). CONCLUSIONS: Patients presenting with nonspecific EF may have TMD, which can be effectively diagnosed using TMJ-MRI. The present study revealed the causal relationship between nonspecific EF and abnormal TMJ findings based on MRI. Individualized TMD treatments based on TMJ-MRI led to improved treatment outcomes with special regard to nonspecific EF LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1692-1698, 2018. PMID- 29238987 TI - Modeling the effect of platelet concentrate supernatants on endothelial cells: focus on endocan/ESM-1. AB - BACKGROUND: Platelets (PLTs) are prone to activation and the release of biologic response modifiers (BRMs) under storage conditions. The transfusion inflammatory reaction in the vascular compartment involves endothelial cell activation due to cell-cell interactions and BRMs infused with the blood products. Endocan/ESM-1 is a proteoglycan secreted by endothelial cells under the control of proinflammatory cytokines. We aimed to measure endocan activity in supernatants of PLT components (PCs), implicated in serious adverse reactions (SARs) or not (no.AR), sampled at different stages during storage. STUDY DESIGN AND METHODS: PLT function, by quantification of soluble CD62P, and their ability to produce endocan were assessed. Functional testing of PC supernatants was performed on EA.hy926 endothelial cells in vitro by exposing them to PC supernatants from each group (no.AR or SARs); EA.hy926 activation was evaluated by their production of interleukin (IL)-6 and endocan. RESULTS: PLT endocan secretion was not induced in response to PLT surface molecule agonists, and no significant correlation was observed between sCD62P and endocan concentration after PLT activation. However, we observed a significant increase in the secretion of IL-6 and endocan after EA.hy926 activation by all PC supernatants. IL-6 and endocan secretion were significantly higher for cells stimulated with SAR than those stimulated with no.AR PC supernatants, as well as cell apoptosis. CONCLUSION: The correlation between the secretion of endocan and that of IL-6 by endothelial cells suggests that endocan can be used as a predictive marker of inflammation for the quality assessment of transfusion grade PLTs. PMID- 29238985 TI - Impaired functional vitamin B6 status is associated with increased risk of lung cancer. AB - Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3 hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4thvs.1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status. PMID- 29238988 TI - Plerixafor and granulocyte-colony-stimulating factor for mobilization of hematopoietic stem cells for autologous transplantation in Chinese patients with non-Hodgkin's lymphoma: a randomized Phase 3 study. AB - BACKGROUND: This Phase 3 randomized, double-blind study evaluated the efficacy and safety of plerixafor plus granulocyte-colony-stimulating factor for the mobilization of hematopoietic stem cells in Chinese patients with non-Hodgkin's lymphoma. STUDY DESIGN AND METHODS: Adults (ages 18-75 years) with non-Hodgkin's lymphoma in first or second complete or partial remission, without previous hematopoietic stem cell mobilization or autologous transplant, were included. Patients received granulocyte-colony-stimulating factor 10 ug/kg/day from Days 1 through 4 before they were randomized (1:1) to receive either plerixafor 0.24 mg/kg/day or placebo subcutaneously on Days 4 through 7 plus continued granulocyte-colony-stimulating factor on Days 5 through 8. Apheresis began on Day 5 and continued for no more than 4 days. The primary endpoint was collection of 5 * 106 CD34+ cells/kg or greater over no more than 4 days of apheresis. Other endpoints included the collection of 2 * 106 CD34+ cells/kg or greater and safety. RESULTS: Overall, 101 patients were enrolled, and 50 were randomized to each group. More patients in the plerixafor group achieved 5 * 106 CD34+ cells/kg or greater (62 vs. 20%; p < 0.0001) or 2 * 106 CD34+ cells/kg or greater (88 vs. 66%) and underwent transplantation (88 vs. 68%) compared with those in the placebo group. The most common plerixafor-related adverse events were nausea (7.8%) and diarrhea (3.9%). CONCLUSION: Plerixafor plus granulocyte-colony stimulating factor is superior to placebo plus granulocyte-colony-stimulating factor for the mobilization of CD34+ cells for autologous transplantation and is generally well tolerated in Chinese patients with non-Hodgkin's lymphoma. PMID- 29238990 TI - Associations between developmental changes in error-related brain activity and executive functions in early childhood. AB - Behavioral evidence indicates that skills associated with children's cognitive control (e.g., response inhibition and attentional control) undergo rapid development during early childhood. A particularly important time is the transition to elementary school. Yet, at present, relatively little is known about developmental changes in the brain processes linked to cognitive control during this period, including those associated with error monitoring, including the error-related negativity (ERN) and the error positivity (Pe). Moreover, understanding how ERP correlates of cognitive control relate to behavioral measures of these skills over time is also limited. In the present study, repeated assessments of 4- to 6-year-old children's (N = 49, mean age = 5 years 10 months) performance on a go/no-go task were collected to examine developmental changes in error processing and response inhibition across 6 months. Data revealed the presence of both the ERN and Pe at each time point, but also showed individual differences in the test-retest associations for each component. Behavioral changes in response inhibition on the go/no-go task and a standardized measure of attentional control were associated with changes in electrophysiological measures of error processing. Additional analyses comparing children of the same age who had completed the go/no-go task once to those who participated longitudinally revealed that, with repeated assessments, children exhibited behavioral changes in performance that could be attributed to both development and to the effects of practice, such as strategic accommodation. PMID- 29238989 TI - Nanoparticle delivery of RNA-based therapeutics to alter the vocal fold tissue response to injury. AB - OBJECTIVES/HYPOTHESIS: Our laboratory and others hypothesized that Smad3 is a principle mediator of the fibrotic phenotype in the vocal folds (VFs), and we further posited that alteration of Smad3 expression through short interfering (si)RNA holds therapeutic promise, yet delivery remains challenging. To address this issue, we employed a novel synthetic oligomer, lipitoid, complexed with siRNA to improve stability and cellular uptake with the goal of increased efficiency of RNA-based therapeutics. STUDY DESIGN: In vitro study and in vivo animal model. METHODS: In vitro, lipitoid cytotoxicity was quantified via colorimetric and LIVE/DEAD assays in immortalized human VF fibroblasts and primary rabbit VF fibroblasts. In addition, optimal incubation interval and solution for binding siRNA to lipitoid for intracellular delivery were determined. In vivo, a rabbit model of VF injury was employed to evaluate Smad3 knockdown following locally injected lipitoid-complexed siRNA. RESULTS: In vitro, lipitoid did not confer additional toxicity compared to commercially available reagents. In addition, 20-minute incubation in 1* phosphate-buffered saline resulted in maximal Smad3 knockdown. In vivo, Smad3 expression increased following VF injury. This response was significantly reduced in injured VFs at 4 and 24 hours following injection (P = .035 and .034, respectively). CONCLUSIONS: The current study is the first to demonstrate targeted gene manipulation in the VFs as well as the potential utility of lipitoid for localized delivery of genetic material in vivo. Ideally, these data will serve as a platform for future investigation regarding the functional implications of therapeutic gene manipulation in the VFs. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E178-E183, 2018. PMID- 29238992 TI - An innovative solution for T-tube obstruction: The tracheostomy-customized stent combination. AB - The Montgomery T-tube (MTT) is a useful tool for post-tracheostomy tracheal stenosis. However, MTTs can get blocked. We present a case series of life threatening MTT blockage, wherein a split-function option was implemented, which was a customized silicone Dumon stent above the tracheostomy to maintain both airway and phonation. This tracheostomy-customized stent combination serves the same function as an MTT, with a greater margin of safety due to the easy suctioning capacity of the tracheostomy. With a fenestrated tracheostomy and stent above, speech is effectively preserved. We recommend this strategy in severe MTT blockage as a superior option to regular tracheostomy. Laryngoscope, 1795-1797, 2018. PMID- 29238993 TI - Donor deferral policies for men who have sex with men: past, present and future. AB - We review the history and evolution of blood donor criteria for men who have sex with men (MSM). Deferral policies in many jurisdictions, including Australia, New Zealand, Canada, the United States, Brazil and many western European countries are based on a period of abstinence from MSM, often of 12 months duration. Several countries (Italy, Spain and Portugal) defer donors based on sexual behaviours considered to be at high risk, regardless of whether the partner is same sex or opposite sex. Compliance is a key determinant in the efficacy of any deferral policy. We summarize research themes and strategies discussed at a January 2017 meeting held in Toronto, Canada, to provide an evidence basis for future policy changes. PMID- 29238991 TI - Distribution and diversity of intrinsically photosensitive retinal ganglion cells in tree shrew. AB - Intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate the pupillary light reflex, circadian entrainment, and may contribute to luminance and color perception. The diversity of ipRGCs varies from rodents to primates, suggesting differences in their contributions to retinal output. To further understand the variability in their organization and diversity across species, we used immunohistochemical methods to examine ipRGCs in tree shrew (Tupaia belangeri). Tree shrews share membership in the same clade, or evolutionary branch, as rodents and primates. They are highly visual, diurnal animals with a cone-dominated retina and a geniculo-cortical organization resembling that of primates. We identified cells with morphological similarities to M1 and M2 cells described previously in rodents and primates. M1-like cells typically had somas in the ganglion cell layer, with 23% displaced to the inner nuclear layer (INL). However, unlike M1 cells, they had bistratified dendritic fields ramifying in S1 and S5 that collectively tiled space. M2-like cells had dendritic fields restricted to S5 that were smaller and more densely branching. A novel third type of melanopsin immunopositive cell was identified. These cells had somata exclusively in the INL and monostratified dendritic fields restricted to S1 that tiled space. Surprisingly, these cells immunolabeled for tyrosine hydroxylase, a key component in dopamine synthesis. These cells immunolabeled for an RGC marker, not amacrine cell markers, suggesting that they are dopaminergic ipRGCs. We found no evidence for M4 or M5 ipRGCs, described previously in rodents. These results identify some organizational features of the ipRGC system that are canonical versus species-specific. PMID- 29238994 TI - Intestinal P-glycoprotein inhibitors, benzoxanthone analogues. AB - OBJECTIVES: The inhibitors of P-glycoprotein (P-gp) which limits an access of exogenous compounds in the luminal membrane of the intestine have been studied to enhance the intestinal P-gp-mediated absorption of anticancer drugs. METHODS: Inhibition of the efflux pump by synthesized benzoxanthone derivatives was investigated in vitro and in vivo. MCF-7/ADR cell line was used for cytotoxicity assay and [3 H]-daunomycin (DNM) accumulation/efflux study. Eight benzoxanthone analogues were tested for their effects on DNM cytotoxicity. Among them, three analogues were selected for the accumulation/efflux and P-gp ATPase studies. Paclitaxel (PTX), a P-gp substrate anticancer drug, was orally administered to rats with/without compound 1 (8,10-bis(thiiran-2-ylmethoxy)-7H-benzo[c]xanthen-7 one). The pharmacokinetic parameters of PTX in the presence/absence of compound 1 were evaluated from the plasma concentration-time profiles. KEY-FINDINGS: Compound 1 increased the DNA accumulation to 6.5-fold and decreased the DNM efflux to approximately 1/2 in the overexpressing P-gp cell line. Relative bioavailability (RB) of PTX in rats was significantly increased up to 3.2-fold by compound 1 (0.5 or 2 mg/kg). CONCLUSIONS: Benzoxanthone analogue, compound 1 is strongly suggested to be a promising inhibitor of P-gp to improve an oral absorption of compounds for cancer therapy. PMID- 29238995 TI - Test Dose Pharmacokinetics in Pediatric Patients Receiving Once-Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach? AB - Intravenous (IV) busulfan test dose pharmacokinetics (PK) has been shown to accurately predict once-daily dose requirements and improve outcomes in adult transplant patients, but there are limited data to support this approach in children. Test doses of busulfan ~0.8 mg/kg were infused over 2 to 3 hours, followed by serial sampling to 4-6 hours postinfusion in pediatric hematopoietic stem cell transplant recipients (n = 5). Once-daily busulfan doses were calculated based on a myelosuppressive area under the concentration-time curve (AUC) target of ~3700 to 4000 MUmol.min/L and assumed dose-proportionality to the test dose. PK analysis was then repeated at full daily doses within 6-8 days of test dose administration. Plasma PK samples collected under test and full-dose conditions were analyzed using validated commercial assays and noncompartmental methods. In 4 out of 5 patients, PK estimates after once-daily IV busulfan administration differed in comparison to test dose estimates (AUC range -38.2% to +49.7%, clearance range -34.3% to +61.8%). Patients 1, 2, and 3 required increases in remaining daily busulfan doses to achieve AUC targets, and no adjustment was required in patient 4. Patient 5's AUC was 49.7% higher than expected, and he subsequently developed fatal sinusoidal obstruction syndrome. In our experience with pediatric patients, test dose PK failed to reliably predict daily dosing requirements with large discrepancies from predicted AUC targets. This article highlights the necessity for therapeutic drug monitoring of IV busulfan and inadvisability of relying solely on test-dose busulfan PK in pediatric patients. Furthermore, clinicians should consider strategies to expedite dose adjustments in real time. PMID- 29238996 TI - Quality management of a massive transfusion protocol. AB - BACKGROUND: Massive transfusion is a response to massive uncontrolled hemorrhage. To be effective, it must be timely and address the patient's needs for blood volume, oxygen transport, and hemostasis. STUDY DESIGN AND METHODS: A review was performed on all activations of the massive transfusion protocol (MTP) in a hospital with large emergency medicine, trauma, and vascular surgery programs. Indications, transfused amounts, and outcomes were determined for each MTP event to determine appropriateness of MTP use. Results are presented as descriptive statistics, categorical associations, and simple linear trend relationships. RESULTS: The MTP was activated 309 times in 2016. Of these episodes, 237 were for trauma, 29 for gastrointestinal bleeding, 16 for ruptured abdominal aortic aneurisms, and 25 for a variety of other causes. Trauma-related MTP activations had a mean injury severity score of 32. Blood use averaged 6.6 units of red blood cells (RBCs), 6.5 units of plasma, and 1.2 units of apheresis platelets. Fourteen activations ended without the administration of any blood products, and 45 (14%) did not meet the critical administration threshold of three components. Only 60 (19%) activations met the historic definition of massive with at least 10 units of RBCs administered. Mortality was 15% for the trauma-related activations. CONCLUSIONS: Massive transfusion protocol activations were frequent and conducted with high fidelity to the 1:1:1 unit ratio standard. Making blood components available quickly was associated with low rates of total component usage and low mortality for trauma patients and was not associated with overuse. PMID- 29238997 TI - When should a level IIB neck dissection be performed in treatment of head and neck squamous cell carcinoma? PMID- 29238998 TI - Postmenopausal craniofacial hyperhidrosis. AB - Hyperhidrosis is a condition marked by excessive sweating, which can either be localized or generalized. Primary focal hyperhidrosis (PFH) can arise from the palms, plantar feet, axillae and also from the face and scalp. PFH primarily affects a younger population of children and young adults, with the majority presenting before the age of 25 years. We report a distinct subtype of craniofacial hyperhidrosis in 20 postmenopausal women; this subtype is often under-recognized. PMID- 29238999 TI - Physiological gas exchange mapping of hyperpolarized 129 Xe using spiral-IDEAL and MOXE in a model of regional radiation-induced lung injury. AB - PURPOSE: To map physiological gas exchange parameters using dissolved hyperpolarized (HP) 129 Xe in a rat model of regional radiation-induced lung injury (RILI) with spiral-IDEAL and the model of xenon exchange (MOXE). Results are compared to quantitative histology of pulmonary tissue and red blood cell (RBC) distribution. METHODS: Two cohorts (n = 6 each) of age-matched rats were used. One was irradiated in the right-medial lung, producing regional injury. Gas exchange was mapped 4 weeks postirradiation by imaging dissolved-phase HP 129 Xe using spiral-IDEAL at five gas exchange timepoints using a clinical 1.5 T scanner. Physiological lung parameters were extracted regionally on a voxel-wise basis using MOXE. Mean gas exchange parameters, specifically air-capillary barrier thickness (delta) and hematocrit (HCT) in the right-medial lung were compared to the contralateral lung as well as nonirradiated control animals. Whole-lung spectroscopic analysis of gas exchange was also performed. RESULTS: delta was significantly increased (1.43 +/- 0.12 MUm from 1.07 +/- 0.09 MUm) and HCT was significantly decreased (17.2 +/- 1.2% from 23.6 +/- 1.9%) in the right medial lung (i.e., irradiated region) compared to the contralateral lung of the irradiated rats. These changes were not observed in healthy controls. delta and HCT correlated with histologically measured increases in pulmonary tissue heterogeneity (r = 0.77) and decreases in RBC distribution (r = 0.91), respectively. No changes were observed using whole-lung analysis. CONCLUSION: This work demonstrates the feasibility of mapping gas exchange using HP 129 Xe in an animal model of RILI 4 weeks postirradiation. Spatially resolved gas exchange mapping is sensitive to regional injury between cohorts that was undetected with whole-lung gas exchange analysis, in agreement with histology. Gas exchange mapping holds promise for assessing regional lung function in RILI and other pulmonary diseases. PMID- 29239000 TI - Minimal Physiologically Based Pharmacokinetic and Drug-Drug-Disease Interaction Model of Rivaroxaban and Verapamil in Healthy and Renally Impaired Subjects. AB - Current dosing recommendations for rivaroxaban advocate dosage reduction in patients with moderate to severe renal impairment and avoidance of concomitant strong inhibitors of CYP3A or P-glycoprotein. However, rivaroxaban dosing in patients with mild renal impairment taking concomitant moderate inhibitors of CYP3A and P-glycoprotein is not addressed. To quantify the impacts of concomitant verapamil administration and renal impairment on rivaroxaban pharmacokinetics, a minimal physiologically based pharmacokinetic model system was developed and used to evaluate potential increases in rivaroxaban exposure and the consequent increase in risk of major bleeding. Data from a phase 1, drug-drug interaction study were used to qualify the minimal physiologically based pharmacokinetic model system. Model-based simulations indicate that coadministration of rivaroxaban with verapamil substantially increases rivaroxaban exposure across all renal function categories, resulting in an exponential increase in bleeding risk. Reduction of the daily rivaroxaban dose to 10 to 15 mg reduces the major bleeding risk below the designated 4.5% threshold in the majority of patients with normal or mildly impaired renal function. A reduction to 10 mg daily in patients with moderate to severe renal impairment provides additional risk reduction so that 90% of those patients fall below the 4.5% threshold. A risk threshold of 4.5% was selected because it is the median predicted risk in patients treated concomitantly with ketoconazole, which is contraindicated for use with rivaroxaban. Patients taking both rivaroxaban and verapamil should take a reduced daily dose of rivaroxaban to minimize bleeding risk. PMID- 29239001 TI - Comparison of infliximab with adalimumab in 827 biologic-naive patients with Crohn's disease: a population-based Danish cohort study. AB - BACKGROUND: There are conflicting data on comparative effectiveness of adalimumab and infliximab in patients with Crohn's disease (CD). AIMS: To compare the effectiveness and safety of adalimumab and infliximab in biologic-naive patients with CD, in a nationwide register-based propensity score-matched cohort study in Denmark. METHODS: A total of 2908 Danish adults with CD had been treated with adalimumab or infliximab as their first biologic agent between 2005-2014. By Cox regression, we compared rates of all-cause hospitalisation, CD-related hospitalisation, major abdominal surgery and serious infections after variable 2:1 propensity score matching, accounting for baseline disease characteristics, healthcare utilisation and use of CD-related medications. RESULTS: After propensity-score matching, we included 315 adalimumab- (34.9 +/- 12.9 years, 41.9% males) and 512 infliximab-treated (33.6 +/- 12.6 years, 40.8% males) patients, with median disease duration 4.0 years; 36.9% had prior abdominal surgery. Over a median follow-up 2.3 years after starting biological therapy, there were no significant differences in rate of CD-related hospitalisation (hazard ratio [HR], 0.81 [95% CI, 0.55-1.20]) or major abdominal surgery (HR, 1.24 [0.66-2.33]) between adalimumab- and infliximab-treated patients, though rate of all-cause hospitalisation was lower in adalimumab-treated patients (HR, 0.74 [0.56-0.97]). There was no significant difference in incidence of serious infections requiring hospitalisation (HR, 1.06 [0.26-4.21]). These results were stable in patients treated with biological monotherapy (all-cause hospitalisation: HR, 0.75 [0.53-1.05]; CD-related hospitalisation: HR, 0.82 [0.51 1.32], abdominal surgery: HR, 1.47 [0.63-3.47]) or in combination with immunomodulators (all-cause hospitalisation: HR, 0.70 [0.44-1.11]; CD-related hospitalisation: HR, 0.80 [0.42-1.52], abdominal surgery: HR, 1.02 [0.39-2.64]). CONCLUSIONS: In this population-based, propensity score matched, real-life cohort study using administrative claims, there was no significant difference in effectiveness and safety of adalimumab and infliximab in biologic-naive patients with CD. PMID- 29239002 TI - Pharmacokinetics of Osimertinib in Chinese Patients With Advanced NSCLC: A Phase 1 Study. AB - Osimertinib is an oral, irreversible, central nervous system active epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) selective for both EGFR-TKI sensitizing and T790M resistance mutations. The study's (NCT02529995) primary objective was to characterize the pharmacokinetics (PK) of osimertinib and its metabolites in Chinese patients enrolled in China. PK was assessed following single and multiple doses of 40 or 80 mg osimertinib once daily. Patients were aged >= 18 years with locally advanced or metastatic EGFR-TKI sensitizing (EGFRm) non-small cell lung cancer and World Health Organization performance status of 0/1, who had progressed following prior EGFR-TKI. Thirty one patients were assigned to treatment (40 mg, n = 15; 80 mg, n = 16), and 25 were included in the PK analyses set (40 mg, n = 12; 80 mg, n = 13). Six were excluded from analyses because of prior treatment with an osimertinib-like substance. At steady state a flat PK profile with a low maximum-minimum plasma concentration ratio was observed. Investigator-assessed objective response rate was 47% (7 of 15; 95%CI, 21.3-73.4) in the 40-mg cohort and 75% (12 of 16; 95%CI, 47.6-92.7) in the 80-mg cohort. Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 2 patients (6%) and 3 patients (10%), respectively. Serious AEs were reported in 8 patients (26%) and AEs leading to death in 1 patient (3%). Interstitial lung disease/pneumonitis-like event was reported in 1 patient (3%). Osimertinib PK in a Chinese patient population is well characterized and consistent with the global population, supporting the use of a once-daily 80-mg dose. PMID- 29239003 TI - Assessing natural infection with Zika virus in the southern house mosquito, Culex quinquefasciatus, during 2016 in Puerto Rico. AB - The epidemic of Zika in the Western hemisphere has led to intense investigations of all species important in the transmission of Zika virus (ZikV), including putative mosquito vectors. Although evidence points to Stegomyia (= Aedes) (Diptera: Culicidae) mosquitoes as the primary vectors in nature among humans, there remains the possibility that other common mosquito species may be implicated in the rapid spread of the virus. Herein, field-caught Culex quinquefasciatus (Diptera: Culicidae) collected during June 2016 in different neighbourhoods in San Juan, Puerto Rico were examined for the presence of natural infection with ZikV. Stegomyia aegypti (= Aedes aegypti) from the same locations were also analysed. None of the Cx. quinquefasciatus tested showed natural infection for ZikV, whereas S. aegypti tested positive at seven sites. The present results suggest that Cx. quinquefasciatus was not involved in the transmission of ZikV in San Juan, Puerto Rico in 2016. PMID- 29239004 TI - Providing Comprehensive Medication Management in Telehealth. AB - The goal of this white paper is to provide direction for clinical pharmacists providing telehealth. Telehealth care is rapidly emerging to improve patient access to health care and optimize patient health outcomes. With the increasing ability to access electronic health record portals, as many as 75 million telehealth encounters are expected in North America annually. Although electronic "point of access" undoubtedly increases the use of medical and pharmacy services, the real value of telehealth lies in improved access to patients in remote areas lacking adequate medical and pharmacy services and to high-risk patients requiring frequent monitoring. This document is intended to serve as a guide for those interested in or already using telehealth to provide direct patient care. Specifically, it focuses on general concepts of telehealth and demonstrates how the delivery of comprehensive medication management (CMM) by telehealth aligns with the Standards of Practice for Clinical Pharmacists set forth by the American College of Clinical Pharmacy. Although clinical pharmacists must be appropriately credentialed and privileged to provide CMM, their process of care must also be adapted to suit the remote patient. Patient assessment, evaluation of medication therapy, development and implementation of a plan of care, follow-up, monitoring, and documentation of all processes of care are influenced by the technology available, the collaborations established, and the applicable regulations and requirements for telehealth practice. PMID- 29239005 TI - Automated image quality assessment for chest CT scans. AB - PURPOSE: Medical image quality needs to be maintained at standards sufficient for effective clinical reading. Automated computer analytic methods may be applied to medical images for quality assessment. METHODS: For chest CT scans in a lung cancer screening context, an automated quality assessment method is presented that characterizes image noise and image intensity calibration. This is achieved by image measurements in three automatically segmented homogeneous regions of the scan: external air, trachea lumen air, and descending aorta blood. Profiles of CT scanner behavior are also computed. RESULTS: The method has been evaluated on both phantom and real low-dose chest CT scans and results show that repeatable noise and calibration measures may be realized by automated computer algorithms. Noise and calibration profiles show relevant differences between different scanners and protocols. CONCLUSIONS: Automated image quality assessment may be useful for quality control for lung cancer screening and may enable performance improvements to automated computer analysis methods. PMID- 29239007 TI - Pemetrexed-induced painful erythematous nodules in both legs in a patient with recurrent mesothelioma. PMID- 29239006 TI - Does the mosquito Culex pipiens represent a potential vector of hepatitis C virus? AB - Infection with hepatitis C virus (HCV) is a public health burden in several countries. Although transmission through blood is the most likely potential route of HCV infection, other sources warrant exploration. This study was designed to examine the possibility that the mosquito Culex pipiens (Diptera: Culicidae) might serve as a vector of HCV. A series of laboratory experiments were conducted in female Cx. pipiens that were fed on blood taken from HCV patients and tested for the presence of HCV RNAs using a reverse transcription polymerase chain reaction technique. In addition, the ability of the female mosquito to transmit HCV to human blood through membrane feeding or to its offspring (larvae) was tested. Although positive strand RNA was detected on days 1,7 and 14, negative strand HCV RNA was detected in mosquito body homogenate on days 7 and 14. Positive strands were also detected in the head, alimentary canal and salivary glands of mosquito adults at 1 week post-feeding, as well as in their offspring (larvae). An ex vivo assay demonstrated that HCV-infected mosquitoes were able to transmit the virus RNA into naive human blood samples via a membrane feeder. The present data indicate that the mosquito Cx. pipiens may be a potential vector of HCV. PMID- 29239008 TI - Dermocystidium sp. infection in farmed hybrid fish Colossoma macropomum * Piaractus brachypomus in Brazil. PMID- 29239010 TI - Silicon-containing analogs of camptothecin as anticancer agents. AB - The plant pentacyclic alkaloid camptothecin and its structural analogs were extensively studied. These compounds are interesting due to the antitumor activity associated with their ability to inhibit topoisomerase I in tumor cells. During the last decades of the 20th century, a large number of the silicon containing camptothecins (silatecans) were synthesized. 7-tert-Butyldimethylsilyl 10-hydroxy-camptothecin (DB-67 or AR-67) has enhanced lipophilicity and demonstrates a antitumor activity superior to its carbon analog. To date, certain silatecans are under clinical trials and their ultimate role in cancer therapy appears promising. In this review, we present chemical methodologies for the synthesis of silicon-containing camptothecins, their chemical properties, biological activity, and results of clinical trials. PMID- 29239009 TI - Falls in older adults with multiple myeloma. AB - OBJECTIVE: To examine the prevalence of falls, factors associated with falls and the relationship between falls and survival in older adults with multiple myeloma. METHODS: In an analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare Health Outcomes Survey (MHOS)-linked database, we examined 405 older adults with multiple myeloma (MM) and 513 matched non-cancer controls. The primary outcome was self-reported within the past 12 months. Age, race, gender, symptoms, and comorbidities were self-reported in the MHOS. Survival was calculated from SEER data. RESULTS: Of the patients with MM, 171 were within 1 year of diagnosis (cohort 1) and 234 were >=1 year postdiagnosis (cohort 2). Patients in cohorts 1 and 2 were more likely to have fallen than controls (26% and 33% vs 23%, P = .012). On multivariate analysis, among patients with myeloma (combined cohorts 1 and 2), factors associated with falls included self-report of fatigue (aOR 2.52 [95% CI 1.34-4.93]), depression (aOR 1.90 [95% CI 1.14-3.18]), or poorer general health (aOR 1.86 [95% CI 1.05-3.36]). Falls were not associated with survival. CONCLUSIONS: Older adults with MM have a greater prevalence of falls than matched controls. Self-reported fatigue, depression, and poorer general health are associated with greater odds of falls. PMID- 29239011 TI - Relationship between serum anti-varicella zoster virus antibody titer and time from onset of herpes zoster. AB - Herpes zoster is an internal reactivation of varicella zoster virus, and its onset depends on immunity against this virus. We have previously reported that antiviral antibody titers are inversely correlated with patient numbers. In this study, we hypothesized that patients with higher titers may be late visitors to the clinic, whose antibodies were already boosted at presentation because of the time lapse between onset of zoster and measurement of antibodies. We analyzed antibody titers of patients with acute herpes zoster who visited Fukuoka University Hospital from January 2009 to May 2016 (n = 141, 62 males and 79 females). Varicella zoster virus-specific immunoglobulin G, M and complement fixation tests were positive in 93.9%, 12.0% and 64.2% of the patients, respectively. Immunoglobulin G and complement fixation titers were strongly correlated (Spearman's r = 0.8634, P < 0.0001). Patients with high immunoglobulin G and complement fixation titers were immunoglobulin M-negative. Unexpectedly, immunoglobulin G and complement fixation titers showed large inter-subject variation, and were only weakly correlated with onset-measurement time lapse. Patients with consecutive tests tended to show increasing immunoglobulin G and complement fixation titers. Our data suggest that herpes zoster preferentially occurs in patients with low immunoglobulin G and complement fixation titers, and subsequently causes antibody elevation. However, the timing of elevation varies and can be as late as 10 days after zoster. The large variation in antibody titer over the time from onset to testing suggests that some mechanism exists that resists the local breakthrough of virus in the skin, and so delays the onset of blisters. PMID- 29239012 TI - Maintenance of equine anaesthesia over the last 50 years: Controlled inhalation of volatile anaesthetics and pulmonary ventilation. AB - In the first edition of this journal, Barbara Weaver wrote a review titled 'Equine Anaesthesia', stating that, at that time, it was quickly becoming accepted practice that many horses were being anaesthetised 'by essentially similar procedures, i.e. premedication, induction and then maintenance by controlled inhalation'. To celebrate the 50th anniversary of the first edition of this journal, this review covers the development of understanding and practice of inhalational anaesthesia and controlled ventilation in horses over the last 50 years. We review how the perceived benefits of halothane led to its widespread use, but subsequently better understanding of halothane's effects led to changes in equine anaesthetic practice and the utilisation of different inhalation agents (e.g. isoflurane and sevoflurane). We discuss how more recently, better understanding of the effects of the 'newer' inhalation agents' effects has led to yet more changes in equine anaesthetic practice, and while, further new inhalation agents are unlikely to appear in the near future, further enhancements to anaesthetic practice may still lead to improved outcomes. We review advances in our understanding of the anatomy and pathophysiology of the equine lung as well of the effects of anaesthesia on lung function and how these predispose to some of the common problems of gas exchange and ventilation during anaesthesia. We identify the aims of optimal mechanical ventilation for anaesthetic management and whether the various methods of ventilatory support during equine anaesthesia achieve them. We also highlight that further developments in equipment and optimal ventilator modes are likely in the near future. PMID- 29239013 TI - Failed Attempt With Paired Associative Stimulation to Separate Functional and Organic Dystonia. PMID- 29239014 TI - Cortical electrical stimulation in female rats with a cervical spinal cord injury to promote axonal outgrowth. AB - Electrical stimulation (ES) to promote corticospinal tract (CST) repair after spinal cord injury (SCI) is underinvestigated. This study is the first to detail intracortical ES of the injured CST. We hypothesize that cortical ES will promote CST collateralization and regeneration, prevent dieback, and improve recovery in an SCI rat model. The CST was transected at the the fourth cervical level in adult female Lewis rats trained in a stairwell grasping task. Animal groups included (a) ES333 (n = 14; 333 Hz, biphasic pulse for 0.2-ms duration every 500 ms, 30 pulses per train); (b) ES20 (n = 14; 20 Hz, biphasic pulse for 0.2-ms duration every 1 s, 60 pulses per train); (c) SCI only (n = 10); and (d) sham (n = 10). ES of the injured forelimb's motor cortex was performed for 30 min immediately prior to SCI. Comparisons between histological data were performed with a 1-way ANOVA or Kruskal-Wallis test, and grasping scores were compared using repeated-measures 2-way ANOVA. Significantly more axonal collateralization was found in ES333 animals compared with controls (p < .01). Axonal dieback analysis revealed ES20 rats to have consistently more dieback than the other groups at all points measured (p < .05). No difference in axonal regeneration was found between groups, nor was there any difference in functional recovery. Cortical ES of the injured CST results in increased collateral sprouting and influences neuroplasticity depending on the ES parameters used. Further investigation regarding optimal parameters and its functional effects is required. PMID- 29239015 TI - Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study. AB - Hepatic encephalopathy (HE) influences short-term and long-term prognoses. Recently, glycerol phenylbutyrate (PB), that lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion, has shown that it was effective in preventing the occurrence of HE in RCT. The aim was to assess the benefits of sodium PB in cirrhotic patients admitted to ICU for overt HE, in terms of ammonia levels decrease, neurological improvement, and survival. Cirrhotic patients who presented with overt HE, ammonia levels >100 MUmol/L, and did not display any contra-indication were included. Sodium PB was administered at 200 mg/kg/day. Control group included historical controls treated by standard therapy, matched for age, sex, MELD score, and severity of HE. Eighteen patients were included and treated with sodium PB (age: 59 [45-68], male gender: 15 [83%], Child-Pugh B: 8 [44%], Child-Pugh C: 10 [56%], and MELD score: 16 [13-23]). Ammonia levels significantly decreased in the PB as compared to the control group from inclusion to 12 h and from inclusion to 48 h (P = 0.0201 and P = 0.0230, respectively). The proportion of patients displaying neurological improvement was only higher in the PB-treated group as compared to controls at ICU discharge (15 [83%] vs. 9 [50%], P = 0.0339). ICU discharge survival was significantly higher in patients treated with PB (17 [94%] vs. 9 [50%], P = 0.0017). In cirrhotic patients with overt HE, sodium PB could be effective in reducing ammonia levels and might be effective in improving neurological status and ICU discharge survival. More extensive data, especially a RCT, are mandatory. PMID- 29239016 TI - Intestinal and hepatic contributions to the pharmacokinetic interaction between gamithromycin and rifampicin after single-dose and multiple-dose administration in healthy foals. AB - BACKGROUND: Standard treatment of foals with severe abscessing lung infection caused by Rhodococcus equi using rifampicin and a macrolide antibiotic can be compromised by extensive inhibition and/or induction of drug metabolising enzymes (e.g. CYP3A4) and transport proteins (e.g. P-glycoprotein), as has been shown for rifampicin and clarithromycin. The combination of rifampicin with the new, poorly metabolised gamithromycin, a long-acting analogue of azithromycin and tulathromycin with lower pharmacokinetic interaction potential, might be a suitable alternative. OBJECTIVES: To evaluate the pharmacokinetic interactions and pulmonary distribution of rifampicin and gamithromycin in healthy foals, and to investigate the cellular uptake of gamithromycin in vitro. STUDY DESIGN: Controlled, four-period, consecutive, single-dose and multiple-dose study. METHODS: Pharmacokinetics and lung distribution of rifampicin (10 mg/kg) and gamithromycin (6 mg/kg) were measured in nine healthy foals using LC-MS/MS. Enzyme induction was confirmed using the 4beta-OH-cholesterol/cholesterol ratio. Affinity of gamithromycin to drug transport proteins was evaluated in vitro using equine hepatocytes and MDCKII-cells stably transfected with human OATP1B1, OATP1B3 and OATP2B1. RESULTS: Rifampicin significantly (P<0.05) increased the plasma exposure of gamithromycin (16.2 +/- 4.77 vs. 8.57 +/- 3.10 MUg * h/mL) by decreasing the total body clearance. Otherwise, gamithromycin significantly lowered plasma exposure of single- and multiple-dose rifampicin (83.8 +/- 35.3 and 112 +/- 43.1 vs. 164 +/- 96.7 MUg * h/mL) without a change in metabolic ratio and half-life. Gamithromycin was identified as an inhibitor of human OATP1B1, OATP1B3 and OATP2B1 and as a substrate of OATP2B1. In addition, it was extracted by equine hepatocytes via a mechanism which could be inhibited by rifampicin. MAIN LIMITATIONS: Influence of gamithromycin on pulmonary distribution of rifampicin was not evaluated. CONCLUSION: The plasma exposure of gamithromycin is significantly increased by co-administration of rifampicin which is most likely caused by inhibition of hepatic elimination. PMID- 29239017 TI - Five key lncRNAs considered as prognostic targets for predicting pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and the 5-year survival rate was only 7.7%. To improve prognosis, a screening biomarker for early diagnosis of pancreatic cancer is in urgent need. Long non-coding RNA (lncRNA) expression profiles as potential cancer prognostic biomarkers play critical roles in development of tumorigenesis and metastasis of cancer. However, lncRNA signatures in predicting the survival of a patient with PDAC remain unknown. In the current study, we try to identify potential lncRNA biomarkers and their prognostic values in PDAC. LncRNAs expression profiles and corresponding clinical information for 182 cases with PDAC were acquired from The Cancer Genome Atlas (TCGA). A total of 14 470 lncRNA were identified in the cohort, and 175 PDAC patients had clinical variables. We obtained 108 differential expressed lncRNA via R packages. Univariate and multivariate Cox proportional hazards regression, lasso regression was performed to screen the potential prognostic lncRNA. Five lncRNAs have been recognized to significantly correlate with OS. We established a linear prognostic model of five lncRNA (C9orf139, MIR600HG, RP5 965G21.4, RP11-436K8.1, and CTC-327F10.4) and divided patients into high- and low risk group according to the prognostic index. The five lncRNAs played independent prognostic biomarkers of OS of PDAC patients and the AUC of the ROC curve for the five lncRNAs signatures prediction 5-year survival was 0.742. In addition, targeted genes of MIR600HG, C9orf139, and CTC-327F10.4 were explored and functional enrichment was also conducted. These results suggested that this five lncRNAs signature could act as potential prognostic biomarkers in the prediction of PDAC patient's survival. PMID- 29239019 TI - Trial of hyperthermic treatment for Bowen's disease with disposable chemical pocket warmers: A report of two cases. PMID- 29239018 TI - Design, synthesis, and biological evaluation of 1-ethyl-3-(thiazol-2-yl)urea derivatives as Escherichia coli DNA gyrase inhibitors. AB - Discovery of novel DNA gyrase B inhibitors remains an attractive field in the search for new antibacterial drugs to overcome the known bacterial resistance mechanisms. In the present study, we designed and synthesized novel ethylurea derivatives of 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-2,6-diamine, 2-(2 aminothiazol-4-yl)acetic acid, and benzo[1,2-d]thiazole-2,6-diamine and evaluated their Escherichia coli DNA gyrase inhibition. The most potent DNA gyrase inhibitors in the prepared library of compounds were benzo[1,2-d]thiazoles 32-34, 36, and 37 with IC50 values in the low micromolar range. The most promising inhibitors identified were evaluated against selected Gram-positive and Gram negative bacterial strains. Compound 33 showed a MIC of 50 MUM against an E. coli efflux pump-defective strain, which suggests that efflux decreases the on-target concentrations of these compounds. PMID- 29239020 TI - Successful treatment of task-specific lower extremity dystonia by ventro-oral thalamotomy. PMID- 29239021 TI - A systematic review of instruments for assessing parent satisfaction with family centred care in neonatal intensive care units. AB - : This systematic review synthesised and described instruments measuring parent satisfaction with the increasing standard practice of family-centred care (FCC) in neonatal intensive care units. We evaluated 11 studies published from January 2006 to March 2016: two studies validated a parent satisfaction questionnaire, and nine developed or modified previous questionnaires to use as outcome measures in their local settings. Most instruments were not tested on reliability and validity. CONCLUSION: Only two validated instruments included all six of the FCC principles and could assess parent satisfaction with FCC in neonatal intensive care units and be considered as outcome indicators for further research. PMID- 29239022 TI - Fndc5 knockdown induced suppression of mitochondrial integrity and significantly decreased cardiac differentiation of mouse embryonic stem cells. AB - Fibronectin type III domain-containing 5 protein (Fndc5) is a glycosylated protein with elevated expression in high energy demanded tissues as heart, brain, and muscle. It has been shown that upregulation of Fndc5 is regulated by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC 1alpha), which is known as a master regulator of mitochondrial function and biogenesis. Also, our group indicated that Fndc5 expression increases gradually during cardiac differentiation of mouse embryonic stem cells (mESCs). In this paper, to clarify the importance of Fndc5 in cardiac differentiation, we south to knock down Fndc5 expression by generation a stably transduced mESC line that derives the expression of a short hairpin RNA (shRNA) against Fndc5 gene following doxycycline (Dox) induction. Knock-down of Fndc5 demonstrated a considerable decrease in expression of cardiac progenitor and cardiomyocyte markers. Considering the fact that mitochondria play a crucial role in cardiac differentiation of ESCs, we investigated the role of Fndc5, as a downstream target of PGC1-alpha, on mitochondrial indices. Results showed that expression of nuclear encoded mitochondrial genes including PGC1-alpha, Atp5b, Ndufb5, and SOD2 significantly decreased. Moreover, mitochondrial membrane potential (DeltaPsim) and relative ATP content of cardiomyocytes decreased markedly with relative ROS level increase. Together, our results suggest that Fndc5 attenuates process of cardiac differentiation of mESCs which is associated with modulation of mitochondrial function and gene expression. PMID- 29239023 TI - Sclerosing lipogranuloma presenting as movable masses induced by large doses of progesterone injection. PMID- 29239025 TI - Fine structure of conformational ensembles in adenylate kinase. AB - Adenylate kinase (ADK) catalyzes the reversible Mg2+ -dependent phosphoryl transfer reaction Mg2+ +2ADP <->Mg2+ +ATP + AMP in essential cellular systems. This reaction is a major player in cellular energy homeostasis and the isoform network of ADK plays an important role in AMP metabolic signaling circuits. ADK has 3 domains, the LID, NMP, and CORE domains, that undergo large conformational rearrangements during ADK's catalytic cycle. In spite of extensive experimental and computational studies, details of the conformational pathway from open to closed forms remain uncertain. In this paper we explore this pathway using coarse grained molecular dynamics (MD) trajectories of ADK calculated by GROMACS using a SMOG model and classify the conformations within the resultant trajectories by K means clustering. ADK conformations segregate naturally into open; intermediate; and closed forms with long-term residence in the intermediate state. Structural clustering divides the intermediate conformation into 3 sub-states that are distinguished from one another on the basis of differences in both structure and dynamics. These distinctions are defined on the basis of a number of different metrics including radius of gyration, dihedral angle fluctuation, and fluctuations of interatomic pair distances. Furthermore, differences in the sub states appear to correspond to the distinct ways each sub-state contributes to the molecular mechanism of catalysis: One sub-state acts as a gate-way to the open conformation; one sub-state a gate-way to the closed conformation. A third intermediate sub-state appears to represent a metastable off-pathway structure that is nevertheless frequently visited during the passage from open to closed state. PMID- 29239024 TI - Concordance between administrative data and clinical review for mortality in the randomized on/off bypass follow-up study (ROOBY-FS). AB - BACKGROUND: The optimal methodology to identify cardiac versus non-cardiac cause of death following cardiac surgery has not been determined. METHODS: The Randomized On/Off Bypass Trial was a multicenter, randomized, controlled clinical trial of 2203 patients (February 2002-May 2008) comparing 1-year cardiac outcomes between off-pump and on-pump bypass surgery. In 2013, the Veterans Affairs (VA) Cooperative Studies Program funded a follow-up study to assess 5-year outcomes including mortality. Deaths were identified and confirmed using the National Death Index (NDI), VA Vital Status file, and medical records. An Endpoints Committee (EC) reviewed patient medical records and classified each cause of death as cardiac, non-cardiac, or unknown. Using pre-determined ICD-10 codes, NDI death certificates were independently used to classify deaths as cardiac or non cardiac. Cause of death was compared between the NDI and EC classifications and concordance measured, using Kappa statistics. RESULTS: Of the 297 5-year deaths identified by the NDI and/or VA vital status file and confirmed by the EC, 219 had adequate patient records for EC cause of death determination. The EC adjudicated 141 of these deaths as non-cardiac and 78 as cardiac, while the NDI classified 150 as non-cardiac and 69 as cardiac; agreement was 77.6% (kappa 0.500; P < 0.001). CONCLUSIONS: Since concordance between EC and NDI cause of death classifications was only moderate, caution should be exercised in relying exclusively on NDI data to determine cause of death. A hybrid approach, integrating multiple information sources, may provide the most accurate approach to classifying cause of death. PMID- 29239026 TI - Early cutaneous eruptions after oral hydroxychloroquine in a lupus erythematosus patient: A case report and review of the published work. AB - Hydroxychloroquine (HCQ) is an effective treatment of lupus erythematosus. Although adverse effects, mainly gastrointestinal and cutaneous manifestations, are rare, they may result in the cessation of medication in some patients with severe reactions. Therefore, the evaluation of a patient's condition is important for a dermatologist to decide whether to cease or continue HCQ. We herein report a case of a 36-year-old Japanese woman with systemic lupus erythematosus and cutaneous eruptions caused by the p.o. administration of HCQ. Because she wanted to continue the medication and had only mild cutaneous eruptions without any adverse effects in other organs, we continued HCQ with careful monitoring. All cutaneous eruptions disappeared within 1 week. We also reviewed published case reports on skin lesions that developed after HCQ treatments, and propose strategies for early cutaneous eruptions after HCQ treatments. When the cutaneous reactions are mild without any reactions in other organs, withdrawal of the drug is not required. However, when cutaneous eruptions are accompanied by some common reactions, HCQ needs to be stopped for a period of time and may subsequently be carefully re-administrated. PMID- 29239027 TI - Reply: The iron-deficient rat as a model of restless legs syndrome: Was anything lost in translation? PMID- 29239028 TI - Recovery of myocardial mechanics in Kawasaki disease demonstrated by speckle tracking and tissue Doppler methods. AB - AIM: To investigate myocardial deformation and function during treatment for Kawasaki disease (KD) in children. METHODS: We performed speckle tracking echocardiography (STE) and tissue Doppler imaging (TDI) in 15 children with KD and 15 healthy children during treatment for KD. STE was performed for longitudinal and circumferential strain (S) and strain rate (SR) at the left ventricle (LV) and for longitudinal S and SR at the right ventricle (RV). TDI was performed at the base of interventricular septum (IVS), LV, and RV. RESULTS: Among TDI parameters, Em and ejection time (ET) at IVS, ET at LV and ET at RV obtained obtained before treatment were significantly lower in patients with KD compared to controls. After treatment, in spite of improvements, ET at IVS and ET at RV remained significantly lower in patients with KD compared to controls. Left ventricular global longitudinal and circumferential S and SR values obtained before treatment were significantly lower in patients with KD compared to controls. Left ventricular S and SR values were found to be increased after treatment. However, left ventricular global circumferential S value remained significantly lower in patients with KD compared to controls. There were no significant differences in right ventricular global longitudinal S and SR values between patients and controls before treatment. CONCLUSION: During acute phase, patients with KD have reduced global left ventricular S and SR which may be more sensitive indicators of myocardial inflammation. This study showed gradual improvements in left ventricular myocardial function during treatment for KD. PMID- 29239029 TI - The meaning and experience of stress among supported employment clients with mental health problems. AB - Many clinicians are concerned that competitive work may cause excessive stress for people with severe mental health problems. Individual Placement and Support (IPS) is acknowledged as the most effective model of supported employment for this population. The manner in which IPS clients define and experience employment related stress is poorly understood. This qualitative study aims to explore how people with mental health problems receiving IPS services define and experience employment-related stress. We purposively sampled and interviewed 16 clients of an IPS programme, who had been competitively employed for more than 1 month. Data were collected between September 2014 and July 2015 in Montreal, Canada. Transcripts of semi-structured interviews were analysed using grounded theory methodology. IPS clients often defined stress similar to its common understanding: the result of experiencing prolonged or/and cumulative strains, or of an incongruence between efforts and rewards, hopes and reality. Stress experienced in this way could exacerbate psychiatric symptoms, especially depression or psychotic symptoms. However, when maintained at a more manageable level, stress stimulated learning and improved planning of tasks. Participants described different coping mechanisms, such as sharing their experiences and difficulties with others, focusing on problem resolution and avoidance. The first two of these helped IPS clients remain at work and bolstered their confidence. Work-related stress has potentially positive as well as negative consequences for IPS clients. In order to maximise the potential beneficial effects of stress, employment specialists can help clients anticipate potential stressors and plan how they might cope with them. Further research on the most effective ways of helping clients cope with stress is needed. PMID- 29239030 TI - Neuromuscular training reduces lower limb injuries in elite female basketball players. A cluster randomized controlled trial. AB - The study was a two-armed, parallel group, cluster randomized controlled trial in which 15 teams (160 players) were assigned to either an experimental group (EG, 8 teams n = 86), which warmed-up with bodyweight neuromuscular exercises, or a control group (CG, 7 teams, n = 74) that performed standard tactical-technical exercises before training. All injuries during the 2015-2016 regular season were counted. Epidemiologic incidence proportion and incidence rate were also calculated. Countermovement jump (CMJ) and composite Y-Excursion Balance test (YBT) were used to assess lower limb strength and postural control. A total of 111 injuries were recorded. Chi-square test detected statistically significant differences between EG and CG (32 vs 79, P = .006). Significant differences in the injuries sustained in the EG (21 vs 11, P = .024) and CG (52 vs 27, P = .0001) during training and matches, respectively, were observed. Significant differences in post-intervention injuries were observed between in EG and CG during training (21 vs 52, P < .0001) and matches (11 vs 27, P = .006). Significant differences in epidemiologic incidence (0.37 vs 1.07, P = .023) and incidence rate (1.66 vs 4.69, P = .012) between the EG and the CG were found. Significant improvement in CMJ (+9.4%, P < .0001; d = 1.2) and composite YBT (right: +4.4%, P = .001, d = 1.0; left: +3.0%, P = .003; d = 0.8) for the EG was noted. Significant differences in post-intervention CMJ (+5.9%, P = .004) and composite YBT scores (right, +3.7%, P = .012; left, +2.3%, P = .007) between the EG and the CG were observed. Including bodyweight neuromuscular training into warm-up routines reduced the incidence of serious lower limb injuries in elite female basketball players. PMID- 29239031 TI - Molecular alterations of neuroendocrine tumours of the lung. AB - Neuroendocrine tumours of the lung comprise low [typical carcinoid (TC)], intermediate [atypical carcinoid (AC)] and high-grade [small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC)] malignancies, while a pre invasive lesion [diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)] may generate a subset of peripheral carcinoid tumours. These neoplasms are differentiated conventionally based on mitotic rate, presence of necrosis and cytological details, according to the 2015 World Health Organisation (WHO) classification. Clinical data and molecular alterations distinguish carcinoids and high-grade carcinomas into two separate categories. Previous studies have demonstrated a significantly higher rate of chromosomal aberrations in carcinomas (e.g. 3p and 17p deletions), but restriction of multiple endocrine neoplasia type 1 (MEN1) mutations to carcinoids. High-grade carcinomas are also characterised by TP53 and RB1 gene inactivation. In this review, a critical analysis of the diagnostic and prognostic role of Ki67 labelling index and a concise discussion of the most relevant findings regarding molecular characterisation of lung neuroendocrine neoplasms are reported. In addition, we illustrate how the development of promising therapeutic strategies based on the identification of molecular targets (mTOR inhibitors in carcinoids and targeting of the Notch ligand DLL3 in SCLC) may require the assessment of predictive biomarkers, even in the group of neuroendocrine tumours of the lung. PMID- 29239032 TI - Challenges in surgical pathology of adrenocortical tumours. AB - Adrenocortical carcinomas are rare tumours that can be diagnostically challenging. Numerous multiparametric scoring systems and diagnostic algorithms have been proposed to differentiate adrenocortical adenoma from adrenocortical carcinoma. Adrenocortical neoplasms must also be differentiated from other primary adrenal tumours, such as phaeochromocytoma and unusual primary adrenal tumours, as well as metastases to the adrenal gland. Myxoid, oncocytic and sarcomatoid variants of adrenocortical tumours must be recognized so that they are not confused with other tumours. The diagnostic criteria for oncocytic adrenocortical carcinoma are different from those for conventional adrenocortical carcinomas. Adrenocortical neoplasms in children are particularly challenging to diagnose, as histological features of malignancy in adrenocortical neoplasms in adults may not be associated with aggressive disease in the tumours of children. Recent histological and immunohistochemical studies and more comprehensive and integrated genomic characterizations continue to advance our understanding of the tumorigenesis of these aggressive neoplasms, and may provide additional diagnostic and prognostic utility and guide the development of therapeutic targets. PMID- 29239033 TI - What's new in pituitary pathology? AB - The increasing recognition of pituitary disorders and their impact on quality of life and longevity has made understanding of this small gland a subject of paramount importance. Pituitary pathology has seen many significant studies that indicate progress in identification and classification of pituitary lesions, as well as improved management strategies for patients. In this review, we outline six major areas of advances: (i) changes in terminology from 'adenoma' to 'pituitary neuroendocrine tumour'; (ii) reclassification of hormone-negative tumours based on transcription factor expression that defines lineage; (iii) updates in new pathogenetic mechanisms, including those that underlie rare lesions such as X-LAG and pituitary blastoma; (iv) clarification of hypophysitis due to immunotherapy, xanthomatous hypophysitis due to rupture of a Rathke's cleft cyst and IgG4 disease as the cause of inflammatory pseudotumour; (v) the consolidation of pituicytoma variants, including spindle cell oncocytoma and granular cell tumour based on thyroid transcription factor-1 (TTF-1) reactivity; and (vi) the pathogenetic mechanisms that distinguish papillary from adamantinomatous craniopharyngioma. The remaining challenge is clarification of the pathogenetic mechanisms underlying the development of many of these disorders. PMID- 29239034 TI - Succinate dehydrogenase (SDH)-deficient neoplasia. AB - The succinate dehydrogenase (SDH) complex is a key respiratory enzyme composed of four subunits: SDHA, SDHB, SDHC and SDHD. Remarkably, immunohistochemistry for SDHB becomes negative whenever there is bi-alleic inactivation of any component of SDH, which is very rare in the absence of syndromic disease. Therefore, loss of SDHB immunohistochemistry serves as a marker of syndromic disease, usually germline mutation of one of the SDH subunits. Tumours which show loss of SDHB expression are termed succinate dehydrogenase-deficient. In addition to loss of SDHB, tumours associated with SDHA mutation also show loss of SDHA expression. Fifteen per cent of pheochromocytoma and paraganglioma (PHEO/PGL) are associated with germline SDH mutation, and therefore SDH-deficient. We recommend screening SDHB immunohistochemistry for all PHEO/PGL. SDH-deficient gastrointestinal stromal tumours (GISTs) show distinctive features, including absent KIT proto oncogene receptor tyrosine kinase/platelet-derived growth factor receptor A (KIT/PDGFRA) mutations [but positive staining for cKIT and DOG1], virtually exclusive gastric location, lobulated growth, multi-focality, a prognosis not predicted by size and mitotic rate, frequent metastasis to lymph nodes and primary resistance to imatinib therapy. Thirty per cent are associated with SDHA germline mutation and 50% are associated with SDHC epimutation (post-zygotic promoter hypermethylation) - the hallmark of the syndromic but non-hereditary Carney triad (SDH- deficient GIST, SDH-deficient paraganglioma and pulmonary chondroma). SDH-deficient renal carcinoma is newly recognized under the World Health Organization (WHO) 2016 classification and shows vacuolated eosinophilic cytoplasmic and cytoplasmic inclusions. It is particularly associated with SDHB mutation, although SDHC and SDHA mutation occur. SDH-deficient pituitary adenomas are recognized, but appear to be the least common SDH-deficient neoplasm. PMID- 29239035 TI - Heritable forms of primary hyperparathyroidism: a current perspective. AB - Primary hyperparathyroidism (PHPT) is one of the most common of all endocrine disorders encountered by the practising histopathologist. The vast majority of lesions are sporadic in nature, approximately 85% of which are parathyroid adenomas, while hyperplasia and carcinoma account for 10-15% and fewer than 1%, of cases, respectively. Heritable forms of PHPT are much less common and present challenges both to clinicians and pathologists, particularly when they are the presenting feature of an endocrine syndrome. In such instances, pathologists play a key role in alerting physicians to the possibility of an underlying heritable endocrine syndrome and the potential for extra-endocrine manifestations. Therefore, a working knowledge of these disorders is essential for providing guidance to treating physicians. The aim of this update is to review the clinicopathological features, genetic bases and current management for patients with PHPT associated with multiple endocrine neoplasia (MEN) types 1, 2A and 4 and hyperparathyroidism-jaw tumour (HPT-JT) syndrome in the context of the 2017 World Health Organization (WHO) Classification of Tumours of the Endocrine Organs. Additionally, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism are discussed. PMID- 29239036 TI - A user's guide to non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). AB - The term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently introduced to replace a subset of follicular variant of papillary thyroid carcinoma (FVPTC). The goal of this change was to promote more conservative management of these tumours and spare patients the psychological burden of a cancer diagnosis. The histological diagnosis of NIFTP is stringent: the tumour needs to demonstrate encapsulation or circumscription, a purely follicular architecture and the presence of nuclear features of papillary thyroid carcinoma, while lacking capsular and vascular invasion, a significant component of solid growth and high-grade features (increased mitotic activity and necrosis). In order to ensure that these inclusion and exclusion criteria are met, the tumour must be sampled extensively, with the entire capsule/periphery submitted in all cases. When sampled by fine-needle aspiration, NIFTP is usually classified within the indeterminate categories of the Bethesda System for Reporting Thyroid Cytopathology. NIFTP is characterized genetically by frequent RAS mutations, although rarely other alterations, such as the BRAF K601E mutation and gene rearrangements in PPARG or THADA, may occur. In this review, we will examine the history of FVPTC and the findings and factors that culminated in the introduction of the NIFTP terminology. A discussion will follow with the histological, cytological and molecular characteristics of NIFTP. We will conclude by considering the potential impact of the introduction of the NIFTP terminology. PMID- 29239037 TI - Well-differentiated pancreatic neuroendocrine tumours (PanNETs) and poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs): concepts, issues and a practical diagnostic approach to high-grade (G3) cases. AB - With increasing accessibility and advancements in abdominal imaging modalities, the incidence of pancreatic neuroendocrine neoplasms has increased steadily during the past few decades. By definition, neuroendocrine neoplasms of the pancreas show neuroendocrine differentiation, but they represent a broad and heterogeneous group of neoplasms with diverse clinical and pathological characteristics. The majority of pancreatic neuroendocrine neoplasms can be classified as well-differentiated pancreatic neuroendocrine tumours (PanNETs) or poorly differentiated pancreatic neuroendocrine carcinomas (PanNECs). While PanNETs and PanNECs are distinct entities with respect to clinical presentation, outcome and therapeutic approach, they may exhibit overlapping histopathological features. Moreover, the frequent modifications in nomenclature and prognostic grading systems over the years of not only pancreatic neuroendocrine neoplasms, but neuroendocrine neoplasms from other organ sites, has created confusion for both pathologists and clinicians as to the appropriate use of terminology and grading when evaluating these neoplasms. This review examines the current concepts and issues of nomenclature and grading of PanNETs and PanNECs. In addition, considering the morphological overlap between high-grade (G3) PanNETs and PanNECs, we discuss an integrative and practical diagnostic approach to aid in discriminating challenging cases. PMID- 29239038 TI - Gastroenteropancreatic neuroendocrine neoplasms: selected pathology review and molecular updates. AB - Gastroenteropancreatic (GEP) neuroendocrine neoplasms can be broadly separated into well- and poorly differentiated categories. Tumours within each category have similarities in morphology and immunophenotype, but vary in grade, behaviour, molecular signature and responses to therapy. The aetiology of these differences is multifactorial. Site of origin, mucosal milieu and hereditary influences are some of the currently known factors. Given these differences, staging and grading systems continue to evolve, and the most recent World Health Organization classification of pancreatic neuroendocrine neoplasms reflects this by introducing a grade 3 neuroendocrine tumour category for morphologically well differentiated tumours with an elevated Ki-67 proliferation index and/or mitotic count. This review aims to highlight current classification guidelines with discussion of unique site-specific features of selected GEP neuroendocrine neoplasms and an emphasis on practical issues related to daily reporting. PMID- 29239039 TI - Annual review issue: Endocrine pathology: a pathological, clinical and molecular integration. PMID- 29239040 TI - Molecular pathology of thyroid tumours of follicular cells: a review of genetic alterations and their clinicopathological relevance. AB - Thyroid cancer is the most common endocrine malignancy. Knowledge of the molecular pathology of thyroid tumours originating from follicular cells has greatly advanced in the past several years. Common molecular alterations, such as BRAF p.V600E, RAS point mutations, and fusion oncogenes (RET-PTC being the prototypical example), have been, respectively, associated with conventional papillary carcinoma, follicular-patterned tumours (follicular adenoma, follicular carcinoma, and the follicular variant of papillary carcinoma/non-invasive follicular thyroid neoplasm with papillary-like nuclear features), and with papillary carcinomas from young patients and arising after exposure to ionising radiation, respectively. The remarkable correlation between genotype and phenotype shows how specific, mutually exclusive molecular changes can promote tumour development and initiate a multistep tumorigenic process that is characterised by aberrant activation of mitogen-activated protein kinase and phosphoinositide 3-kinase-PTEN-AKT signalling. Molecular alterations are becoming useful biomarkers for diagnosis and risk stratification, and as potential treatment targets for aggressive forms of thyroid carcinoma. What follows is a review of the principal genetic alterations of thyroid tumours originating from follicular cells and of their clinicopathological relevance. PMID- 29239041 TI - Hereditary and familial thyroid tumours. AB - The worldwide incidence of thyroid malignancies has been increasing rapidly. Sensitive imaging modalities and early detection of thyroid lesions have made thyroid cancers the most rapidly increasing cancers in the USA in 2017 (SEER Cancer Facts, 2017). Clinical awareness of potential risk factors, such as inherited thyroid cancers, has allowed earlier recognition of more vulnerable population clusters. Hereditary thyroid neoplasms arising from calcitonin producing C cells are known as familial medullary thyroid carcinomas (FMTCs), and include well-documented syndromes such as multiple endocrine neoplasia IIA or IIB, and pure familial medullary thyroid carcinoma syndrome. Familial thyroid cancers arising from follicular cells are referred to as familial non-medullary thyroid carcinoma (FNMTC), or familial follicular cell-derived carcinoma. Clinicopathological correlations have resulted in the further subclassification of FNMTCs into two groups. Among the first group are found syndromes characterised by a predominance of non-thyroidal tumours, including familial adenomatous polyposis, Cowden syndrome, Werner syndrome, Carney complex, and Pendred syndrome. The second group encompasses a spectrum of familial syndromes characterised by a predominance of non-medullary thyroid tumours, such as pure familial papillary thyroid carcinoma with or without oxyphilia, familial papillary thyroid carcinoma with papillary renal cell carcinoma, and familial papillary carcinoma with multinodular goitre. Most familial thyroid cancers have been described as being more aggressive than sporadic thyroid cancers, with a predisposition for lymph node metastasis, extrathyroidal invasion, and a younger age of onset. The distinct thyroid pathology in some of these syndromes should alert the pathologist to a possible familial cancer syndrome. PMID- 29239042 TI - Special types of thyroid carcinoma. AB - This article reviews the small percentage of thyroid tumours that are not classified as classic papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma. It includes subtypes of papillary thyroid carcinoma, including, tall-cell, hobnail/micropapillary, columnar cell, diffuse sclerosing and solid variants. Poorly differentiated carcinoma, high-grade carcinoma and anaplastic thyroid carcinoma are reviewed. Also discussed are entities that are unusual but need to be recognized as primary thyroid neoplasms, i.e. mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia, and mammary analogue secretory carcinoma/secretory carcinoma. The pathological features and prognostic factors are described; a brief review of molecular correlates of these neoplasms is included. PMID- 29239043 TI - Annual review issue: An overview of 50 years of progress in endocrine pathology. PMID- 29239044 TI - Pathology and genetics of phaeochromocytoma and paraganglioma. AB - Phaeochromocytoma and paraganglioma (PHEO/PGL) are rare tumours with an estimated annual incidence of 3 per million. Advances in molecular understanding have led to the recognition that at least 30-40% arise in the setting of hereditary disease. Germline mutations in the succinate dehydrogenase genes SDHA, SDHB, SDHC, SDHD and SDHAF2 are the most prevalent of the more than 19 hereditary genetic abnormalities which have been reported. It is therefore recommended that, depending on local resources and availability, at least some degree of genetic testing should be offered to all PHEO/PGL patients, including those with clinically sporadic disease. It is now accepted that that all PHEO/PGL have some metastatic potential; therefore, concepts of benign and malignant PHEO/PGL have no meaning and have been replaced by a risk stratification approach. Although there is broad acceptance that certain features, including high proliferative activity, invasive growth, increased cellularity, large tumour nests and comedonecrosis, are associated with an increased risk of metastasis, it remains difficult to predict the clinical behaviour of individual tumours and no single risk stratification scheme is endorsed or in widespread use. In this review, we provide an update on advances in the pathology and genetics of PHEO/PGL with an emphasis on the changes introduced in the WHO 2017 classification of endocrine neoplasia relevant to practising surgical pathologists. PMID- 29239045 TI - Flourishing: positive emotion regulation strategies of pharmacy students. AB - OBJECTIVES: The aim of this study was to investigate whether flourishing students use different emotion regulation strategies from moderately mentally healthy and languishing students. METHODS: Registered pharmacy students (779) at the North West University in South Africa completed the emotion regulation profile and Mental Health Continuum - Short Form. The data were analysed using a latent class analysis in Mplus 7.31. KEY FINDINGS: Three latent classes were revealed comprising languishing (14.2%), moderately mentally healthy (47.5%) and flourishing students (38.3%). Students who flourished were more likely to use adaptive positive emotion regulation strategies (savouring the moment, behavioural display, capitalising). Students who languished were inclined to use maladaptive emotion regulation strategies (inattention, fault finding, external attribution). CONCLUSION: Flourishing students increase or maintain their positive emotions and refrain from decreasing their positive emotions. PMID- 29239046 TI - Sperm preparation through SephadexTM filtration improves in vitro fertilization rate of buffalo oocytes. AB - Routinely, swim-up method is used to separate high-quality sperm; however, long processing time and close cell-to-cell contact during the centrifugation step are inevitable elements of oxidative stress to sperm. The objective was to evaluate SephadexTM and glass wool filtration to separate motile, intact and viable sperm for in vitro fertilization in buffalo. The cumulus-oocyte complexes (COCs) were collected from ovaries of slaughtered buffaloes by aspiration and matured for 24 hr in CO2 incubator at 38.5 degrees C and 5% CO2 . Matured COCs were rinsed twice in fertilization TALP and placed in the pre-warmed fertilization medium without sperm. Cryopreserved buffalo semen was thawed at 37 degrees C for 30 s and processed through SephadexTM , glass wool filtration and swim-up (control). Total and motile sperm recovery rates were assessed, resuspended in fertilization TALP and incubated for 15-20 min in CO2 incubator. Samples prepared by each method were divided into two aliquots: one aliquot was studied for sperm quality (progressive motility, membrane integrity, viability, liveability), while the other was subjected to co-incubation with sets of 10-15 in vitro matured oocytes. Data on sperm quality were analysed by ANOVA, while in vitro fertilizing rates were compared by chi-squared test using SPSS-20. Least significant difference (LSD) test was used to compare treatment means. Glass wool filtration yielded higher total and motile sperm recovery rate, while SephadexTM filtration improved (p < .05) sperm quality (progressive motility, membrane integrity, viability, liveability). Sperm preparation through Sephadex filtration yielded higher in vitro fertilization rate in terms of cleavage rate compared to glass wool filtration and swim-up (control). In conclusion, cryopreserved Nili-Ravi buffalo sperm selected through Sephadex filtration showed improved quality and yielded better fertilization rates (cleavage rate) of in vitro matured/fertilized oocytes. Sephadex filtration could be a promising technique for use in in vitro fertilization in buffalo. PMID- 29239047 TI - Does the amount of lower extremity movement variability differ between injured and uninjured populations? A systematic review. AB - Movement variability during repetitive performance of a dynamic activity (eg, running, jumping, kicking) is considered an integral characteristic of optimal movement execution; however, its relationship with musculo-skeletal injury is not known. The primary aim of this study was to review published comparison trials to determine whether movement variability differs between uninjured controls and subjects with a lower limb musculo-skeletal injury. A systematic search of online databases; MEDLINE, Sports Discus, Scopus, and Web of Science was conducted from July to November 2016. Studies were selected if they (a) included participants with a lower limb injury, (b) compared injured participants to uninjured controls, (c) examined movement variability for at least one dependent variable, and (d) provided a statistical between-group comparison when comparing measures of movement variability. Studies were excluded if they (a) investigated neurological disorders, (b) examined musculo-skeletal injury in the upper extremity or spine, and (c) used nonlinear measures to examine variability (ie, complexity). A significant difference between injured and uninjured populations was reported in 73% of the included studies, and of these, 64% reported greater movement variability in the injured group. This is the first systematic review with a best-evidence synthesis investigating the association between movement variability and musculo-skeletal injury. Findings suggest that movement variability in those with a musculo-skeletal injury differs from uninjured individuals. Interestingly, there was an overall trend toward greater movement variability being associated with the injured groups, although it should be noted that this trend was not consistent across all subcategories (eg, injury type). For a clearer insight into the clinical application of variability, greater methodological homogeneity is required and prospective research is recommended. PMID- 29239048 TI - Drug and alcohol treatment providers' views about the disease model of addiction and its impact on clinical practice: A systematic review. AB - ISSUES: Addiction treatment providers' views about the disease model of addiction (DMA), and their contemporary views about the brain disease model of addiction (BDMA), remain an understudied area. We systematically reviewed treatment providers' attitudes about the DMA/BDMA, examined factors associated with positive or negative attitudes and assessed their views on the potential clinical impact of both models. APPROACH: Pubmed, EMBASE, PsycINFO, CINAHL Plus and Sociological Abstracts were systematically searched. Original papers on treatment providers' views about the DMA/BDMA and its clinical impact were included. Studies focussing on tobacco, behavioural addictions or non-Western populations were excluded. KEY FINDINGS: The 34 included studies were predominantly quantitative and conducted in the USA. Among mixed findings of treatment providers' support for the DMA, strong validity studies indicated treatment providers supported the disease concept and moral, free-will or social models simultaneously. Support for the DMA was positively associated with treatment providers' age, year of qualification, certification status, religious beliefs, being in recovery and Alcoholics Anonymous attendance. Greater education was negatively associated with DMA support. Treatment providers identified potential positive (e.g. reduced stigma) and negative (e.g. increased sense of helplessness) impacts of the DMA on client behaviour. IMPLICATIONS/CONCLUSION: The review suggests treatment providers may endorse disease and other models while strategically deploying the DMA for presumed therapeutic benefits. Varying DMA support across workforces indicated service users may experience multiple and potentially contradictory explanations of addiction. Future policy development will benefit by considering how treatment providers adopt disease concepts in practice. PMID- 29239049 TI - A New 3D Printing Strategy by Harnessing Deformation, Instability, and Fracture of Viscoelastic Inks. AB - Direct ink writing (DIW) has demonstrated great potential as a multimaterial multifunctional fabrication method in areas as diverse as electronics, structural materials, tissue engineering, and soft robotics. During DIW, viscoelastic inks are extruded out of a 3D printer's nozzle as printed fibers, which are deposited into patterns when the nozzle moves. Hence, the resolution of printed fibers is commonly limited by the nozzle's diameter, and the printed pattern is limited by the motion paths. These limits have severely hampered innovations and applications of DIW 3D printing. Here, a new strategy to exceed the limits of DIW 3D printing by harnessing deformation, instability, and fracture of viscoelastic inks is reported. It is shown that a single nozzle can print fibers with resolution much finer than the nozzle diameter by stretching the extruded ink, and print various thickened or curved patterns with straight nozzle motions by accumulating the ink. A quantitative phase diagram is constructed to rationally select parameters for the new strategy. Further, applications including structures with tunable stiffening, 3D structures with gradient and programmable swelling properties, all printed with a single nozzle are demonstrated. The current work demonstrates that the mechanics of inks plays a critical role in developing 3D printing technology. PMID- 29239050 TI - Therapeutic potential of amniotic fluid stem cells to treat bilateral ovarian dystrophy in dairy cows in a subtropical region. AB - Amniotic fluid is a rich source of multipotent mesenchymal stem cells (MSCs). Amniotic fluid stem cells (AFSCs) have become a new source of stem cells; they have low immunogenicity and are easily harvested. For this reason, they may be useful in clinical tissue engineering. Moreover, AFSCs have anti-inflammatory properties and can repair tissues. This study evaluated the utility of AFSC injection to treat bilateral ovarian dystrophy in Holstein-Friesian cows. Bovine AFSCs (BAFSCs) were collected at slaughter from Holstein-Friesian cows during the third or fourth month of pregnancy and cultured in vitro. The BAFSCs began to show a fibroblast-like morphology. They were positive for beta-integrin, CD44, CD73, CD106 and Oct4 and negative for CD34 and CD45. After induction, the cells differentiated into mesodermal lineages. Bilateral ovarian dystrophy was confirmed by ultrasonography in 16 lactating cows. The subsequent experiment lasted 15 weeks. Serum was collected weekly to analyse progesterone concentrations, and weekly ultrasonography recorded ovarian changes. Each cow was equipped with an automatic heat detection system to facilitate oestrus observation and breeding records. The progesterone concentration of two cows in the treatment group (25%) significantly increased during weeks 10-15. On ultrasonography, the treatment group demonstrated mature follicles after BAFSCs injection, and foetuses were visualized approximately 40 days after artificial insemination (AI). Oestrus rates in the control and treatment groups were 0% (0/8) and 50% (4/8), respectively; pregnancy rates were 0% (0/8) and 25% (2/8), respectively. Calves were successfully delivered in both cases of pregnancy. These results show that BAFSCs can alleviate bovine ovarian dystrophy and restore fertility. PMID- 29239051 TI - Coronary and carotid atherosclerosis in asymptomatic male marathon runners. AB - The aim of the study was to evaluate the diagnostic accuracy of carotid ultrasound (CU) to predict coronary atherosclerosis in asymptomatic male marathon runners. A total of 49 male marathon runners older than 45 years (mean age 53.3 +/- 7.2 years, range 45-74 years) received CU and cardiac CT angiography (CTA) including calcium scoring (CS). Results of CU and CTA were classified binary: 1. Absence of atherosclerosis and 2. Presence of atherosclerosis. The extent of atherosclerosis was not primary end point of the study. Mean PROCAM score was 2.3% (SD 2.2, range 0.44%-12.34%). One person had to be excluded from analysis (one missing CT-scan). From the remaining 48 marathon runners, 17 (35.4%) had carotid atherosclerosis and 22 (45.8%) coronary atherosclerosis. Atherosclerosis in either exam was diagnosed in 27/48 (56.3%) marathon runners. Diagnostic accuracy of CU to predict coronary atherosclerosis was: sensitivity 54.55% (95% CI 32.2-75.6), specificity 80.8% (CI 60.6-93.4), positive predictive value 70.6 (CI 44.1-89.9), negative predictive value 67.7 (CI 48.6-83.3) with a positive likelihood ratio of 2.84 (CI 1.18-6.82) and a negative likelihood ratio of 0.56 (CI 0.34-0.92). Coronary and/or carotid atherosclerosis can be detected in more than 50% of male marathon runners aged older than 45 years. The diagnostic value of carotid ultrasound to predict coronary atherosclerosis is low but higher than the accuracy of rest- or stress-ECG. As outcome studies in sportsmen are still missing, the routine evaluation of the carotid arteries by ultrasound or even cardiac CT cannot be recommended at present. Furthermore, the incidence of atherosclerosis by our method in normal population is not known. PMID- 29239052 TI - Impact of Anxiety on the Satisfaction of Dental Implant Patients. AB - PURPOSE: To study the influence of anxiety on dental implant patient satisfaction, and to explore if hemoglobin levels and the amount of body fat affected patient satisfaction. MATERIALS AND METHODS: One hundred three partially edentulous patients (mean age 42.06 years) who had received dental implant therapy were enrolled in the study. Self-administered questionnaires were given to those patients to evaluate their level of satisfaction with implant treatment. The State-Trait Anxiety Inventory (STAI) self-reported questionnaire was used to determine anxiety levels. Hemoglobin levels (HB) were measured using an electronic hemoglobin meter, and body fat (BF) was measured using a special diagnostic scale. Statistical analysis was conducted using T-test to assess any significant differences between the groups. Pearson Correlation was used to measure the correlation between variables. RESULTS: Overall satisfaction for all patients was high (86.7%) for both STAI-trait and STAI -state anxiety groups. Highly significant differences in patient satisfaction were found between high and low STAI-state anxiety groups (p < 0.01). Patients with low STAI-state anxiety levels demonstrated significant negative correlations of many parts of patient satisfaction with HB levels and STAI-state scores. While for patients in the low STAI-trait anxiety group, the negative correlation was just with HB levels. For the patients with high STAI-state anxiety levels, a highly significant positive correlation was observed between many elements of patient satisfaction and BF and patient age. CONCLUSION: The results of this study indicated that patient satisfaction with dental implant treatment was high in all patients. STAI-state anxiety had a greater impact on patient satisfaction than did trait anxiety. HB levels negatively affected patient satisfaction in patients with low STAI-trait and STAI-state anxiety levels. BF positively affected patient satisfaction in patients with high STAI-state anxiety levels. PMID- 29239053 TI - Effect of Implant Connection Type and Depth on the Seating Accuracy of Hand Tightened Abutments. AB - PURPOSE: Improper seating of abutment on the implant is a common problem. This study investigated the effect of the type of implant/abutment interface on the complete seating of the abutments on the head of implants placed at different gingival depths. MATERIALS AND METHODS: Three implant systems with three different connections including straight external hexagon, butt-joint internal tri-lobed, and conical internal hexagon were used. Two gingival thicknesses (2 and 7 mm) were created using pink baseplate wax around the straight abutments seated on the implants. After placing the implants in acrylic blocks, the wax was replaced with the gingival mask material to simulate the gingival drape around the implant heads. Afterwards, 15 prosthodontists were asked to hand-tighten the straight abutments in the corresponding implant bodies relying only on their tactile sense. At the final stage, the gingival mask was removed, and the seating quality of the abutments on implant bodies was assessed visually. The effect of implant connection and depth on abutment seating accuracy was analyzed using Kruskal-Wallis and multiple-comparison tests. RESULTS: No significant difference was found regarding the effect of either depth or connection design on the accuracy of the abutment seating (p > 0.05); however, pairwise comparison of the combined effect of the depth and connection design was significant (p = 0.009). Accuracy of abutment seating on the Nobel Active implants at both 2 and 7 mm depths were significantly better than Replace system with 7 mm depth (p = 0.027). The same results were obtained in comparison between Nobel Active system at both 2 and 7 mm depths with Branemark system with 7 mm depth (p = 0.006). CONCLUSION: An increase in implant placement depth meant a decrease in accuracy of the abutment seating. The internal conical connection design showed the best result in abutment positioning in deep implants as compared with external and internal butt-joint connection designs. PMID- 29239054 TI - Reinforcement of Single Implant-Retained Mandibular Overdenture with a Cobalt Chromium Framework before Implant Surgery. AB - Previous clinical research has shown promising results in oral rehabilitation of elderly adults by a single implant-retained mandibular overdenture; however, the high incidence of fracture in the anterior region of these overdentures is a concern for clinicians. To minimize catastrophic overdenture fracture, we propose a technique to insert an individualized metal framework in single implant retained overdentures prior to implant surgery. PMID- 29239055 TI - Brain structural alterations associated with dysfunctional cognitive control of pain in patients with low back pain. AB - BACKGROUND: Recent evidence has shown that chronic back pain (CBP) can lead to functional alterations in the circuitry underlying the cognitive control of pain. Thought suppression (TS) is a common type of cognitive control of pain. Previous research has shown that TS has paradoxical effects that may increase the awareness of pain. Pain-related TS may also increase individuals' attention to pain, which may also increase pain sensation, but thus far, the relationship between pain-related TS and structural brain alterations is unknown. METHODS: In this study, we investigated a group of 30 patients 6 months after lumbar disc surgery by applying voxel-based morphometry (VBM) to identify brain regions correlated with TS scores. RESULTS: Since pain-related TS has been positively correlated with depression, all calculations were controlled for depression and age. VBM revealed a negative correlation between the TS score and regional grey matter volume (GMV) in the left superior temporal gyrus (LSTG) and the left middle temporal gyrus (L MTG), which is part of the left temporoparietal junction (L TPJ). In addition, a mediation analysis revealed a significant mediation effect of the pain-related TS on the association between GMV of the left TPJ and reported pain intensity in the last 7 days. CONCLUSIONS: These findings are consistent with previous research on the dysfunctional cognitive control of pain and may therefore provide potential insights into the neural substrates of obstructive cognitive control in chronic low back pain, with a special emphasis on pain-related TS. SIGNIFICANCE: The link between pain-related thought suppression and brain morphology may provide a new perspective on the understanding of cognitive control of pain in chronic low back pain, which may help improve cognitive behavioural therapy. PMID- 29239056 TI - Association of body mass index and weight gain patterns with albumin excretion in pregnancy. AB - AIM: We examined body mass index (BMI) and gestational weight gain (GWG) patterns of pregnant women and investigated the impact of these factors on the urinary albumin-creatinine ratio (ACR) during pregnancy. METHODS: The data of 163 women whose basal BMI and ACR were measured during the first trimester were used in this study. Body weight alone between 12-16 weeks and body weight together with ACR after 37 weeks of gestation were measured. RESULTS: Overall, 46% of women were overweight or obese, 60.7% had excessive weight gain and 16.6% had inadequate weight gain. Only 22.7% of women gained weight within the recommended range. There was no difference in weight gain patterns with respect to BMI. ACR during the third trimester was significantly higher than during the first trimester (7.08 [0.00-1180.90] mg/g vs 4.73 [0.00-275.00] mg/g, respectively; P = 0.001). The ACR of obese women was higher than in normal weight subjects during the third trimester (16.79 mg/g [0.01-1180.90] vs 8.07 mg/g [0.10-402.14] respectively; adjusted P = 0.015). Both ACR change and third trimester ACR were weakly but significantly correlated with basal BMI (r: 0.228 P: 0.003 and r: 0.301 P < 0.001, respectively) but not with GWG or GWG rate. Basal BMI was not associated with first-trimester ACR. CONCLUSION: Obesity is associated with an increase in urinary albumin excretion during the course of pregnancy. Distinction of this relationship during pregnancy offers an opportunity for further research on pathophysiological mechanisms. The alarmingly high rate of non-compliance with IOM guidelines in pregnant women is a concern. Prompt measures for counseling of women before and during pregnancy in order to maintain healthy weight are needed. PMID- 29239058 TI - Maternal alcohol consumption during pregnancy and its association with offspring renal function at 30 years: observation from a birth cohort study. AB - AIM: Prenatal exposure to alcohol has adverse ramifications on foetal development resulting in developmental abnormalities and major congenital anomalies. Experimental studies have documented effects on kidney structure and function among offspring exposed to alcohol during foetal life; however, human evidence is scarce. Thus, the present study aimed to determine the development of CKD among a cohort of 30-year-old Australian offspring whose mothers reported consumption of alcohol during pregnancy. METHODS: The study sample comprised 1626 offspring of the birth the Australia cohort study (MUSP) who serum creatinine was assessed at 30 years old and CKD was categorised from stage 1 to stage 5 based on their level of eGFR following the CKD-EPI definition. RESULTS: Seven percent (n = 111) of offspring had mild to moderate (stage 2 and 3) CKD at 30 years. The overall adjusted odds of CKD were 2.01 (95% CI 0.97 to 4.13) for offspring of moderate to heavy drinking mothers in late pregnancy, 1.60 (0.70 to 3.37) for early pregnancy and 1.18 (0.72 to 1.94) for pre-pregnancy. The association was higher for female offspring-2.69 (1.02 to 7.14) for late pregnancy and 2.95 (1.12 to 7.80) for early pregnancy. Higher but insignificant odds were found for male offspring at late pregnancy 1.44 (0.46 to 4.47) only. CONCLUSION: Maternal alcohol exposure during early and late pregnancy is associated with development of mild to moderate CKD in their offspring at 30 years. This association is stronger for female than male offspring. PMID- 29239057 TI - In which preterm labor-patients is intravenous maintenance tocolysis effective? AB - AIM: We evaluated whether maintenance tocolysis (intravenous ritodrine hydrochloride and/or magnesium sulfate) was effective in cases of spontaneous preterm labor with intact membranes. METHODS: One hundred and thirty preterm labor patients who reached 36 weeks of gestation by maintenance tocolysis were selected. Immediate delivery (ID) after ceasing maintenance tocolysis was defined as an 'effective case'. The correlated factors between ID and no immediate delivery (NID) were statistically analyzed. RESULTS: Thirty-six patients delivered < two days after ceasing maintenance tocolysis (27.7%) and were defined as effective cases. Multiple logistic regression analysis revealed that amniotic fluid interleukin-8 at admission (>= 2.3 ng/mL; odds ratio [OR] 5.6, 95% confidence interval [CI] 2.1-17.6; P < 0.001), pre-pregnancy body mass index (<= 21.4; OR 5.3, 95% CI 2.0-16.2; P < 0.001) and cerclage (OR 3.6, 95% CI 1.1-11.8; P = 0.028) were independent factors correlated with ID (< 2 days). CONCLUSION: Maintenance tocolysis may be effective in limited cases with mild intra-amniotic inflammation, in lean women and in cerclage cases. Maintenance tocolysis should be ceased in cases without these clinical factors when clinical symptoms disappear. PMID- 29239059 TI - Comparison of robotic-assisted versus laparoscopy for transperitoneal infrarenal para-aortic lymphadenectomy in patients with endometrial cancer. AB - AIM: This study was conducted to evaluate the clinical feasibility of robotic assisted transperitoneal infrarenal para-aortic lymphadenectomy (TIPAL) in patients with endometrial cancer. METHODS: From June 2006 to October 2016, we retrospectively analyzed 42 patients who underwent laparoscopic (n = 16) or robotic-assisted (n = 26) staging operations, including TIPAL for endometrial cancer. Perioperative data including age; body mass index; operation duration; the number of lymph nodes retrieved and the ratio of time to lymph node retrieval during pelvic, infrarenal para-aortic and total lymphadenectomy; estimated blood loss and postoperative complications were compared. RESULTS: The operative duration of pelvic (21.7 +/- 5.31 vs 30.7 +/- 10.8 min; P = 0.002), and total (62.6 +/- 14.0 vs 87.0 +/- 30.4 min; P = 0.010) lymphadenectomy was significantly shorter in the robotic-assisted than the laparoscopic group, whereas there was no statistical difference in the duration of infrarenal para-aortic lymphadenectomy. By contrast, the number of infrarenal para-aortic lymph nodes retreived was significantly higher (29.4 +/- 10.7 vs 23.3 +/- 9.16; P = 0.016) in the robotic assisted group. Consequently, the ratio of time to number of lymph nodes retrieved during infrarenal (1.51 +/- 0.49 vs 2.62 +/- 1.34; P = 0.002) and total (1.43 +/- 0.48 vs 2.15 +/- 0.93; P = 0.014) lymphadenectomy was lower in the robotic-assisted compared to the laparoscopic group. CONCLUSIONS: The robotic assisted approach took less time per infrarenal para-aortic and total lymph nodes retrieved compared to the conventional laparoscopic approach. Robotic-assisted TIPAL could be feasible and effective for the staging and treatment of patients with endometrial cancer. PMID- 29239060 TI - Prevalence and predictors of depression, pain, and fatigue in older- versus younger-adult cancer survivors. AB - BACKGROUND: As the number of older adults in the United States continues to grow, there will be increasing demands on health care providers to address the needs of this population. Cancer is of particular importance, with over half of all cancer survivors older than 65 years. In addition, depression, pain, and fatigue are concerns for older adults with cancer and have been linked to poorer physical outcomes. METHODS: For this retrospective chart review, 1012 eligible participants were identified via a query of the Electronic Medical Record for all patients referred to 1 of 4 Survivorship Clinics at Memorial Sloan Kettering Cancer Center. All patients were between the ages of 30 to 55 (younger adults) and >65 (older adults). Depression was measured using the Patient Health Questionnaire-9 (PHQ-9). RESULTS: The overall rate of depression in this sample of adult cancer survivors was 9.3%. There were no differences in the rates of clinically significant depression (defined as PHQ-9 score >=10) between younger and older adult cohorts. However, there was a small trend toward higher mean PHQ 9 scores in the younger adult cohort (3.42 vs 2.95; t = 1.763, P = .10). Women reported greater rates of depression and higher pain and fatigue scores. Hispanic/Latino patients also reported significantly greater rates of depression. CONCLUSION: There were no observed differences in depression between older and younger adult cancer survivors. Gender and ethnic discrepancies in depression were observed. Future research should focus on understanding the nature of these differences and targeting interventions for the groups most vulnerable to depression after cancer treatment. PMID- 29239061 TI - Progesterone inhibited endoplasmic reticulum stress associated apoptosis induced by interleukin-1beta via the GRP78/PERK/CHOP pathway in BeWo cells. AB - AIM: Pre-eclampsia (PE) is a pregnancy complication characterized by new onset maternal hypertension and proteinuria. Its underlying mechanisms are unclear. This study investigated the relationship between progesterone and endoplasmic reticulum stress (ERS) associated apoptosis induced by interleukin (IL)-1beta via the glucose regulated protein 78 (GRP78)/protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP-homologous protein (CHOP) pathway in BeWo cells. METHODS: Venous blood and placental tissues were collected from PE patients, normal pregnancy and preterm delivery cases, respectively. Progesterone serum levels were detected by enzyme-linked immunosorbent assay and ERS-related protein expression in placentas was examined by immunohistochemistry, reverse transcriptase-polymerase chain reaction and Western blot. BeWo cells were stimulated by IL-1beta to induce ERS associated apoptosis in vitro. The apoptotic rate was measured by flow cytometry. The mechanism of progesterone acting on IL 1beta induced ERS associated apoptosis was investigated by reverse transcriptase polymerase chain reaction, Western blot and PERK small interfering RNA, with RU486 used as a receptor inhibitor. RESULTS: PE patients exhibited decreased serum levels of progesterone and activated ERS and increased ERS-related protein expression. IL-1beta could induce ERS and associated cell apoptosis by activating the GRP78/PERK/CHOP signal pathway, which could be inhibited by progesterone. PERK could be upregulated and phosphorylation activated in ERS. The protective effects of progesterone could be attenuated by RU486. CONCLUSION: IL-1beta could induce ERS associated cell apoptosis by activating the GRP78/PERK/CHOP signal pathway in BeWo cells and may play an important role in PE occurrence. Progesterone levels were decreased in patients with PE and seemed to have a protective effect by inhibiting ERS associated cell apoptosis. PMID- 29239062 TI - Graft-Versus-Host Disease Amelioration by Human Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Is Associated with Peripheral Preservation of Naive T Cell Populations. AB - A substantial proportion of patients with acute graft-versus-host disease (aGVHD) respond to cell therapy with culture-expanded human bone marrow mesenchymal stromal/stem cells (BM-MSCs). However, the mechanisms by which these cells can ameliorate aGVHD-associated complications remain to be clarified. We show here that BM-MSC-derived extracellular vesicles (EVs) recapitulated the therapeutic effects of BM-MSCs against aGVHD. Systemic infusion of human BM-MSC-derived EVs prolonged the survival of mice with aGVHD and reduced the pathologic damage in multiple GVHD-targeted organs. In EV-treated GVHD mice, CD4+ and CD8+ T cells were suppressed. Importantly, the ratio of CD62L-CD44+ to CD62L + CD44- T cells was decreased, suggesting that BM-MSC-derived EVs suppressed the functional differentiation of T cells from a naive to an effector phenotype. BM-MSC-derived EVs also preserved CD4 + CD25 + Foxp3+ regulatory T cell populations. In a culture of CD3/CD28-stimulated human peripheral blood mononuclear cells with BM MSC-derived EVs, CD3+ T cell activation was suppressed. However, these cells were not suppressed in cultures with EVs derived from normal human dermal fibroblasts (NHDFs). NHDF-derived EVs did not ameliorate the clinical or pathological characteristics of aGVHD in mice, suggesting an immunoregulatory function unique to BM-MSC-derived EVs. Microarray analysis of microRNAs in BM-MSC-derived EVs versus NHDF-derived EVs showed upregulation of miR-125a-3p and downregulation of cell proliferative processes, as identified by Gene Ontology enrichment analysis. Collectively, our findings provide the first evidence that amelioration of aGVHD by therapeutic infusion of BM-MSC-derived EVs is associated with the preservation of circulating naive T cells, possibly due to the unique microRNA profiles of BM MSC-derived EVs. Stem Cells 2018;36:434-445. PMID- 29239064 TI - Case of rapidly progressing condylomatous squamous cell carcinoma of the uterine cervix associated with low-risk human papillomavirus type 6. AB - Condylomatous, or warty squamous cell carcinoma (SCC) of the uterine cervix, is a rare variant of invasive SCC. Here, we describe a case of aggressive condylomatous SCC of the uterine cervix. A 43-year-old woman was monitored for 3 years for suspected low-grade squamous intraepithelial lesion. A whitish papillary mass occupied the cervix, and the colposcopic diagnosis was condyloma acuminatum. A cervical biopsy revealed papillary proliferating thick squamous epithelium, which consisted of koilocytes and atypical cells with enlarged nuclei. Hysterectomy specimens showed a thick layer of atypical squamous epithelium with koilocytosis invading the stroma. Immunohistochemistry revealed negative p16 expression. Hysterectomy specimens tested positive for low-risk human papillomavirus type 6, but negative for other high-risk human papillomavirus types. The bilateral pelvic and para-aortic lymph nodes were positive for metastases. In spite of adjuvant chemotherapy, the case relapsed with multiple lymph nodes and lung metastases shortly after the operation. PMID- 29239063 TI - Stimulating neural plasticity with real-time fMRI neurofeedback in Huntington's disease: A proof of concept study. AB - Novel methods that stimulate neuroplasticity are increasingly being studied to treat neurological and psychiatric conditions. We sought to determine whether real-time fMRI neurofeedback training is feasible in Huntington's disease (HD), and assess any factors that contribute to its effectiveness. In this proof-of concept study, we used this technique to train 10 patients with HD to volitionally regulate the activity of their supplementary motor area (SMA). We collected detailed behavioral and neuroimaging data before and after training to examine changes of brain function and structure, and cognitive and motor performance. We found that patients overall learned to increase activity of the target region during training with variable effects on cognitive and motor behavior. Improved cognitive and motor performance after training predicted increases in pre-SMA grey matter volume, fMRI activity in the left putamen, and increased SMA-left putamen functional connectivity. Although we did not directly target the putamen and corticostriatal connectivity during neurofeedback training, our results suggest that training the SMA can lead to regulation of associated networks with beneficial effects in behavior. We conclude that neurofeedback training can induce plasticity in patients with Huntington's disease despite the presence of neurodegeneration, and the effects of training a single region may engage other regions and circuits implicated in disease pathology. PMID- 29239065 TI - Vitamin D receptor rs2228570 polymorphism and susceptibility to ovarian cancer: An updated meta-analysis. AB - AIM: The FokI polymorphism (C>T, rs2228570) of the vitamin D receptor gene is a coding nonsynonymous single nucleotide polymorphism in the translational initiation codon reported to have functional significance. Although the role of rs2228570 in the risk of ovarian cancer has been widely researched, the association is still unclear. We performed an updated meta-analysis to clarify this issue. METHODS: Eligible studies were retrieved from electronic databases for the period 2007-2016. The association was measured by unadjusted odds ratio combined with 95% confidence intervals (CIs). Random-effect or fixed-effect models were used according to the heterogeneity of the studies. We further appreciated the strength of evidence according to Venice guidance. RESULTS: Fourteen studies (4448 cases and 7242 controls) were included in the meta analysis. Studies were predominantly conducted in Caucasian populations (4152 cases and 6693 controls). A dominant genetic model was determined to be the most appropriate genetic model. Overall meta-analysis showed a fixed-effect odds ratio of 1.14 (95% CI 1.05-1.23) under a dominant model. The fixed-effect odds ratios were 1.12 (95% CI 1.03-1.21) and 1.49 (95% CI 1.06-2.09) in Caucasian and Asian populations, respectively. The strength of the evidence was moderate. CONCLUSION: The rs2228570 polymorphism increased the risk of ovarian cancer in Caucasian populations in a dominant genetic model. The role of this polymorphism in the risk of ovarian cancer in Asian populations should be further studied. PMID- 29239066 TI - The obesity supine death syndrome (OSDS). AB - The obesity supine death syndrome refers to a catastrophic cascade of cardiorespiratory complications resulting from the supine positioning of a morbidly obese subject which can ultimately lead to death. It was first described in 1977 in two massively obese patients who were forced to lie down for medical procedures. But surprisingly, despite the current worldwide epidemic of obesity, very few cases have been reported yet. It can be assumed that the syndrome is poorly recognized in clinical practice and may participate in the high rate of unexplained death in morbidly obese patients. Based on the previously published cases and on those we met, this review aims at helping clinicians to early detect at-risk patients, to correctly diagnose this dramatic syndrome and to understand the underlying pathophysiology. More importantly, the main objective is to convince the attending clinicians that they have to do everything in their power to prevent obesity supine death syndrome occurrence by maintaining morbidly obese patients in the sitting or upright position whenever possible. When the syndrome unfortunately occurs, the best therapeutic approach is based on the immediate return to sitting position. PMID- 29239067 TI - Optical and Mechanical Properties of Newly Developed Monolithic Multilayer Zirconia. AB - PURPOSE: To evaluate the optical and mechanical properties of newly introduced monolithic multilayer zirconia with two types of monolithic zirconia. MATERIALS AND METHODS: Three brands of monolithic zirconia were used in this study: Ceramill Zolid FX Multilayer (CZF), Prettau Anterior (PA), and Zenostar T (ZT). Translucency parameter (TP), contrast ratio (CR), flexural strength, fracture toughness, hardness, brittleness index, and microstructures were assessed. Data were analyzed using one-way ANOVA and Tukey's test. The statistical significance was set at p < 0.05. A Weibull analysis was conducted on the flexural strength data. RESULTS: CZF revealed significantly higher TP and lower CR compared with PA and ZT monolithic zirconia (p < 0.05). ZT showed higher flexural strength and fracture toughness compared with CZF and PA (p < 0.001). On the other hand, CZF revealed significantly higher hardness values compared with PA and ZT (p < 0.001). CZF and PA revealed higher brittleness index than ZT monolithic zirconia (p < 0.001). ZT showed small grain microstructure while CZF and PA showed larger grains. ZT had a higher characteristic strength (sigma0 ), Weibull modulus (m), and a lower probability of failure compared with CZF and PA. CONCLUSIONS: The optical and mechanical properties of the tested monolithic zirconia are material dependent. Fully stabilized monolithic zirconia materials (CZF and PA) are relatively more translucent than partially stabilized zirconia (ZT). PMID- 29239069 TI - The antiviral role of zinc and metallothioneins in hepatitis C infection. AB - Metallothioneins (MTs) are small, cysteine-rich proteins characterized by a high affinity for monovalent and divalent cations, such as copper and zinc. Of the four known MT isoforms, only, members of the MT 1 and 2 subfamilies are widely expressed, acting as metal chaperones whose primary role is to mediate intracellular zinc homoeostasis. Metallothioneins are potently induced by heavy metals and other sources of oxidative stress where they facilitate metal binding and detoxification as well as free radical scavenging. Metallothionein expression is well documented in the context of viral infection; however, it remains uncertain whether MTs possess specific antiviral roles or whether induction is merely a consequence of cellular stress. To better understand the role of MTs following hepatitis C virus (HCV) infection, we examined MT expression and localization in vitro and in vivo and used a siRNA knockdown approach to ascertain their antiviral efficacy. We confirmed HCV-driven MT induction in vitro and demonstrated MT accumulation in the nucleus of HCV-infected hepatocytes by immunofluorescence. Using a pan-MT siRNA to knock down all members of the MT1 and MT2 subfamilies, we demonstrate that they are mildly antiviral against the JFH1 strain of HCV in vitro (~1.4 fold increase in viral RNA, P < .05). Furthermore, the antiviral effect of zinc treatment against HCV in vitro was mediated through MT induction (P < .05). Our data suggest a potential benefit of using zinc as a low-cost adjunct to current HCV antiviral therapies and suggest that zinc may facilitate the antiviral role of MTs against other viruses. PMID- 29239068 TI - Estimating chronic hepatitis C prognosis using transient elastography-based liver stiffness: A systematic review and meta-analysis. AB - Chronic hepatitis C (CHC) is a leading cause of hepatic fibrosis and cirrhosis. The level of fibrosis is traditionally established by histology, and prognosis is estimated using fibrosis progression rates (FPRs; annual probability of progressing across histological stages). However, newer noninvasive alternatives are quickly replacing biopsy. One alternative, transient elastography (TE), quantifies fibrosis by measuring liver stiffness (LSM). Given these developments, the purpose of this study was (i) to estimate prognosis in treatment-naive CHC patients using TE-based liver stiffness progression rates (LSPR) as an alternative to FPRs and (ii) to compare consistency between LSPRs and FPRs. A systematic literature search was performed using multiple databases (January 1990 to February 2016). LSPRs were calculated using either a direct method (given the difference in serial LSMs and time elapsed) or an indirect method given a single LSM and the estimated duration of infection and pooled using random-effects meta analyses. For validation purposes, FPRs were also estimated. Heterogeneity was explored by random-effects meta-regression. Twenty-seven studies reporting on 39 groups of patients (N = 5874) were identified with 35 groups allowing for indirect and 8 for direct estimation of LSPR. The majority (~58%) of patients were HIV/HCV-coinfected. The estimated time-to-cirrhosis based on TE vs biopsy was 39 and 38 years, respectively. In univariate meta-regressions, male sex and HIV were positively and age at assessment, negatively associated with LSPRs. Noninvasive prognosis of HCV is consistent with FPRs in predicting time-to cirrhosis, but more longitudinal studies of liver stiffness are needed to obtain refined estimates. PMID- 29239070 TI - Clinical features of new-onset systemic lupus erythematosus in pregnant patients. AB - AIM: This study was conducted to examine the clinical characteristics of new onset systemic lupus erythematosus (SLE) during pregnancy. METHODS: We performed a retrospective study of all pregnancies in patients with SLE managed at The People's Hospital of Peking University from 2008 to 2015. In total, 97 pregnancies were identified and studied, 22 of which were first diagnosed with SLE during pregnancy or puerperium. RESULTS: New-onset SLE mainly occurred during the first and second pregnancy trimesters. Blood and multi-organ involvement were detected in 95.45% and 45.45% of new-onset patients, respectively, and both had a higher incidence than in active patients. Thrombocytopenia was the most common blood involvement in new-onset patients. All three maternal deaths occurred in new-onset patients. There were nine (40.91%) fetal losses, three (13.64%) low birth weight infants, one (4.54%) fetal malformation and two (9.09%) cases of neonatal lupus in new-onset patients. CONCLUSION: New-onset pregnant SLE patients were characterized with blood system involvement and generally experienced more adverse maternal outcomes than active patients with SLE history. However, adverse fetal outcomes in new-onset patients were the same as those of active patients with an SLE history. PMID- 29239071 TI - Comorbidity of chronic kidney disease, diabetes and lower glycated hemoglobin predicts support/care-need certification in community-dwelling older adults. AB - AIM: Chronic kidney disease (CKD), diabetes and lower glycated hemoglobin (HbA1c ) range in diabetes patients are associated with higher mortality. We investigated whether these conditions were associated with the risk of loss of independence in community-dwelling older adults. METHODS: We analyzed 1078 older adults with no history of support/care-need certification in Long-Term Care Insurance aged 65-94 years. Associations of baseline CKD, diabetes, and lower HbA1c range of <6.0% in the diabetes patients, at baseline health checkup with risk of later certification and/or death for 5 years were estimated using the Cox proportional hazards regression model. RESULTS: The prevalence of both CKD and diabetes in the total population increased with age, due to a net increase in the coexistence of CKD and diabetes. The prevalence of the lower HbA1c range also increased with age in participants with the coexistence. During 5 years, 135 certifications and 53 deaths occurred. After adjustment, patients with comorbidity of the triad of CKD, diabetes and the lower HbA1c range had significantly higher hazard ratios (HR) for certification (HR 3.52, 95% confidence interval [CI] 1.91-6.48, P < 0.001) and for death (HR 3.79, 95% CI 1.46-9.85, P = 0.006) compared with those without CKD and diabetes. The harmful impact of the lower HbA1c range on later certification compared with higher HbA1c range of >=6.0% was maintained in diabetes patients with use of antidiabetic agents and CKD (HR 2.40, 95% CI 1.06-6.45, P = 0.036). CONCLUSIONS: Excessive HbA1c reduction might cause discontinuance of disability-free survival in community-dwelling older diabetes patients with CKD. Geriatr Gerontol Int 2018; 18: 521-529. PMID- 29239072 TI - Redox imbalance correlates with high Nugent score in bacterial vaginosis. AB - AIM: The main goal of this work was to highlight the significance of redox imbalance in the pathophysiology of bacterial vaginosis (BV). We studied the pro oxidant (malondialdehyde) and antioxidants (glutathione, total antioxidant capacity) in the vaginal fluids of women and compared them on the basis of their Nugent score (NS). METHODS: Women were clinically screened using Amsel criteria (>=2 were regarded as positive) and were further screened for NS on the basis of microscopic examination. Subjects were classified into one of three groups - healthy controls, intermediate, and BV - on the basis of NS (0-3, 4-6, and 7-10, respectively). High vaginal swabs were collected from the study participants in order to estimate the levels of pro and antioxidants in the vaginal fluids. RESULTS: Our results indicated that levels of both pro- and antioxidants were elevated in high vaginal swabs of women in the intermediate (NS: 4-6) and BV (NS: 7-10) groups as compared to those of healthy control women. The difference in mean values for total antioxidant capacity and glutathione was found to be statistically significant. Furthermore, in the BV group (NS: >=7) both antioxidants (glutathione and total antioxidant capacity) and the pro-oxidant, malondialdehyde, were found to be negatively correlated to NS. Interestingly, the correlation between NS and malondialdehyde was statistically significant. CONCLUSION: Our results suggest a significant correlation between redox imbalance and NS, which signifies changes in vaginal ecology from normal flora (Lactobacillus spp.) towards a more mixed bacterial population representing BV. PMID- 29239073 TI - Knowledge, perception, access and utilisation of HIV counselling and testing among pregnant women in rural communities of Osogbo town, Nigeria. AB - OBJECTIVE: To assess knowledge, perception, access and utilisation of HIV counselling and testing among pregnant women from rural communities in Nigeria. DESIGN: Descriptive cross-sectional survey. SETTING: Primary health care facilities in rural communities of Osogbo, Osun State, Nigeria. PARTICIPANTS: Three-hundred pregnant women attending antenatal clinics in primary health care facilities. MAIN OUTCOME MEASURES: Knowledge of HIV counselling and testing, perception of HIV counselling and testing, utilisation of HIV counselling and testing and barriers associated with HIV counselling and testing utilisation. RESULTS: Findings showed that 59.0% had good knowledge, while 56.7% had good perception. Majority (88.4%) of the 77.7% of respondents who reported the availability of HIV counselling and testing services said it was free and 61.3% of the respondents had HIV counselling and testing done before. Majority (78.3%) had one-on-one counselling, while a little above half (55.4%) gave consent for testing. However, less than half (36.3%) of the respondents were willing to have HIV counselling and testing done in the present pregnancy. There is significant association between the level of perception and utilisation of HIV counselling and testing. A significant association is also found between knowledge of HIV counselling and testing and utilisation. Key barriers found to be associated with utilisation of HIV counselling and testing include 'fear of how to cope with being positive' and 'absence of HIV counselling and testing centre'. CONCLUSION: Many women selected from rural communities demonstrated good knowledge and perception of HIV counselling and testing. The majority of them also had access to HIV counselling and testing and used it. However, some still have misconception about mother-to-child transmission of HIV. PMID- 29239074 TI - Barriers to the use of emergency medical services for ST-elevation myocardial infarction: Determining why many patients opt for self-transport. AB - RATIONALE, AIMS, AND OBJECTIVES: Access to timely ST-elevation myocardial infarction (STEMI) care is facilitated by paramedics and emergency medical services (EMS). However, a large proportion of STEMI patients do not access care through EMS. This study sought to identify patient-reported factors for their decision to use (or not use) EMS. METHODS: Semi-structured interviews were conducted with a sample of STEMI patients admitted to a large tertiary care centre between November 2011 and January 2012. Participants were grouped according to mode of transportation to hospital at time of index event (EMS vs self-transport). Participant responses were classified using a published framework (modified for a STEMI population) as barriers or facilitators to EMS use, and compared between groups. RESULTS: Data were collected on 61 patients (32 EMS, 29 self-transport). Mean age was 60.3 (SD 11.5), and 23% were female. EMS users were more likely to have a Killip Class >1 (25% vs 4%; P = 0.03). Self transport patients were more likely to perceive EMS as slower (48% vs 0%) and express concerns over resources misuse (34% vs 3%; P = 0.002), when compared to EMS patients. Patients who accessed EMS were more likely to acknowledge the benefits of EMS (44% vs 7%; P = 0.001) and were more likely to have been encouraged by a family member to call EMS (34% vs 4%; P = 0.003). CONCLUSIONS: STEMI patient perceptions are a key factor in determining EMS use. Health care stakeholders should target the identified barriers to improve utilization of EMS, and develop strategies to optimize care for patients who do not access EMS. PMID- 29239075 TI - Risk of recurrence after a single manic or mixed episode - a systematic review and meta-analysis. AB - OBJECTIVES: For the first time to estimate the risk of recurrence among patients with a single manic/mixed episode by systematically reviewing prior studies on cohorts of adults, and cohorts of children and adolescents, respectively. METHODS: A systematic literature search up to August 2017 was carried out including studies in which < 25% of the participants were estimated to have had a mood episode that required pharmacological treatment prior to the index manic or mixed episode at inclusion. RESULTS: Three studies including a total of 293 adult patients with a single manic or mixed episode and three studies of children and adolescents including 126 patients were identified. In the adult studies, 31%, 40% and 42% experienced recurrence after recovery within 1 year, 59% after 2 years, and 58% after 4 years, respectively. In the studies on children and adolescents, 40% and 52% experienced recurrence after recovery within 1 year, 30% and 60% after 2 years and 64% and 67% after 4 to 5 years, respectively. Results from meta-analyses showed a 1-year rate of recurrence of 35% (95% confidence interval [CI]: 30-41%) in adults, and in adolescents/children, a 1-year rate of recurrence of 48% (95% CI: 38-58%), a 2-year rate of 46% (95% CI: 33-60%) and a 4 5-year rate of recurrence of 65% (95% CI: 52-77%; as data from different studies were included at 1, 2 and 5 years, rates of recurrence did not increase steadily with time). CONCLUSIONS: The rate of recurrence is high among adults as well as children and adolescents. It is important that clinicians and patients as well as relatives are well informed about these high risks when deciding to start maintenance treatment or not following onset of a single manic or mixed episode. PMID- 29239076 TI - Allogeneic hematopoietic stem cell transplantation is associated with cure and durable remission of late-onset primary isolated central nervous system hemophagocytic lymphohistiocytosis. AB - Primary isolated CNS presentation of HLH is exceedingly rare and typically associated with significant morbidity and mortality. We describe an adolescent patient with late-onset, primary isolated CNS HLH and a compound heterozygous PRF1 mutation (c50delT (p.L17 fs); c.1229G>C (p.R410P)), not previously reported with this phenotype. He was successfully treated with allogeneic HSCT following a reduced-intensity conditioning regimen, despite a high pre-HSCT comorbidity index. Two years after transplant, he is alive and in disease remission. While patients with systemic HLH and active CNS disease have relatively poorer outcomes, a high index of suspicion may aid with early diagnosis of primary isolated CNS HLH; prompt treatment with HSCT may be associated with improved cure and durable remission of this rare disease. PMID- 29239077 TI - High incidence of biliary stricture after associating liver partition and portal vein ligation for staged hepatectomy. AB - BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a two-stage procedure most frequently applied in the setting of an extended right-sided hemi-hepatectomy. Initial reports of high mortality have sparked debate regarding the safety and efficacy of the procedure. We describe a higher incidence of early post-operative bile duct strictures after ALPPS, a complication rarely seen after conventional liver resection. METHODS: An institutional review was conducted to assess the incidence of post-operative biliary strictures following conventional right-sided or extended right-sided hemi-hepatectomy and ALPPS. Patient demographics and operative data were obtained from the patient database of Karolinska University Hospital. RESULTS: Between 2010 and 2015, 528 hemi-hepatectomies or extended hemi-hepatectomies were performed, of which 500 were conventional liver resections and 28 were ALPPS. The incidence of post-operative biliary stricture was 10.7% (n = 3) following ALPPS, 1.4% (n = 2) following extended right-sided hepatectomy (P = 0.023; OR = 8.46; 95% CI 1.35-53.2) and 1.1% following formal right-sided hepatectomy (P = 0.004; OR = 11.0; 95% CI 2.11-57.6). All biliary strictures were at the level of the hilum affecting the left hepatic duct. Pre-operative comorbidity was less in the ALPPS group and post-operative complications were more severe following ALPPS. CONCLUSION: Iatrogenic biliary strictures following conventional liver resection is an uncommon complication. It does, however, occur more frequently following ALPPS and is associated with an increased morbidity. Caution should therefore be exercised when dividing the right hilar pedicle at stage 2 of ALPPS. PMID- 29239078 TI - Driving Chemistry and Europe. AB - "... Mobility that favors individual exchanges between researchers is extremely important for the scientific community. The merging of scientific publications within a consortium of European journals and the creation of the European Chemistry Congresses have been major successes ..." Read more in the Guest Editorial by Gilberte Chambaud. PMID- 29239079 TI - A Flexible Solid Electrolyte Interphase Layer for Long-Life Lithium Metal Anodes. AB - Lithium (Li) metal is a promising anode material for high-energy density batteries. However, the unstable and static solid electrolyte interphase (SEI) can be destroyed by the dynamic Li plating/stripping behavior on the Li anode surface, leading to side reactions and Li dendrites growth. Herein, we design a smart Li polyacrylic acid (LiPAA) SEI layer high elasticity to address the dynamic Li plating/stripping processes by self-adapting interface regulation, which is demonstrated by in situ AFM. With the high binding ability and excellent stability of the LiPAA polymer, the smart SEI can significantly reduce the side reactions and improve battery safety markedly. Stable cycling of 700 h is achieved in the LiPAA-Li/LiPAA-Li symmetrical cell. The innovative strategy of self-adapting SEI design is broadly applicable, providing opportunities for use in Li metal anodes. PMID- 29239080 TI - HCV-positive lymphoma after sustained virological response with direct-acting antiviral agents: The game is not over after HCV eradication. PMID- 29239081 TI - Development and Validation of 2D Difference Intensity Analysis for Chemical Library Screening by Protein-Detected NMR Spectroscopy. AB - An academic chemical screening approach was developed by using 2D protein detected NMR, and a 352-chemical fragment library was screened against three different protein targets. The approach was optimized against two protein targets with known ligands: CXCL12 and BRD4. Principal component analysis reliably identified compounds that induced nonspecific NMR crosspeak broadening but did not unambiguously identify ligands with specific affinity (hits). For improved hit detection, a novel scoring metric-difference intensity analysis (DIA)-was devised that sums all positive and negative intensities from 2D difference spectra. Applying DIA quickly discriminated potential ligands from compounds inducing nonspecific NMR crosspeak broadening and other nonspecific effects. Subsequent NMR titrations validated chemotypes important for binding to CXCL12 and BRD4. A novel target, mitochondrial fission protein Fis1, was screened, and six hits were identified by using DIA. Screening these diverse protein targets identified quinones and catechols that induced nonspecific NMR crosspeak broadening, hampering NMR analyses, but are currently not computationally identified as pan-assay interference compounds. The results established a streamlined screening workflow that can easily be scaled and adapted as part of a larger screening pipeline to identify fragment hits and assess relative binding affinities in the range of 0.3-1.6 mm. DIA could prove useful in library screening and other applications in which NMR chemical shift perturbations are measured. PMID- 29239082 TI - Utility of early transperineal template-guided prostate biopsy for risk stratification in men undergoing active surveillance for prostate cancer. AB - OBJECTIVE: To assess the accuracy and utility of routine multiparametric magnetic resonance imaging (mpMRI) and transperineal template-guided prostate biopsy (TPB) after enrolment in active surveillance (AS). PATIENTS AND METHODS: From April 2012 to December 2016 consecutive men from our single institution, diagnosed with low- or intermediate-risk prostate cancer on transrectal ultrasonography-guided biopsy, were offered further staging with early mpMRI and TPB within 12 months of diagnosis. Data were collected prospectively. Eligibility criteria comprised: age <=77 years; Gleason score <=3 + 4; clinical stage T1-T2; PSA <=15 ng/mL; and <50% positive biopsy cores. RESULTS: A total of 208 men were enrolled, including 196 with Gleason score 3 + 3 and 12 with Gleason score 3 + 4 disease. The median (range) number of TPB cores was 50 (17-161), with a mean TPB core density of 1.2 cores/cm3 prostate volume. A total of 83 men (39.9%) underwent histopathological upgrading after TPB, including 76 men (38.8%) with Gleason score 3 + 3 disease and seven men (58.3%) with Gleason score 3 + 4 disease. Of these, 26 (31.3%) were found to harbour primary pattern Gleason grade >=4 disease. In all, 24 (28.9%) upgraded cases had Prostate Imaging Reporting and Data System (PI-RADS) score 1 or 2 lesions on mpMRI, including five men with Gleason score >=4 + 3 disease. Of these, 14 (58.3%) had a prostate-specific antigen (PSA) density of >=0.15, including four out of the five men with Gleason >=4 + 3 disease. Overall there was a change in prostate cancer management in 77 men (37.0%) after TPB. CONCLUSIONS: Early TPB during AS is associated with significant upgrading and a change in treatment plan in over a third of men. If TPB was omitted in men with a PI-RADS score <3 and a PSA density <0.15, 12% of those harbouring more significant disease would have been misclassified. PMID- 29239083 TI - Physical growth and diets of school children: Trends from 2001 to 2015 in rural West Java, Indonesia. AB - OBJECTIVES: This study aimed to assess changes in physical growth and diets of school children in rural West Java, Indonesia, between 2001 and 2015, a period of rapid socioeconomic change. METHODS: In 2001 and 2015, anthropometric measurements (height, weight, mid-upper arm circumference, skin-fold thickness), food consumption surveys, and questionnaires on socioeconomic status were completed by fourth-grade school children in a rural village in West Java. RESULTS: Height increments of 5.9 cm for boys and 4.7 cm for girls during this 14 year period were calculated as 4.21 cm per decade for boys and 3.36 cm per decade for girls, which is equivalent to height increments observed during rapid economic development periods in other countries. Weights also increased by 3.8 kg for boys and 2.0 kg for girls during this period. Variations in weight status significantly increased in 2015; while 98% of the children were within the 'normal' range in 2001, the prevalence of overweight increased from 2.4% in 2001 to 13.7% in 2015 and that of thinness was 4.3% in 2015. Energy, protein, and fat intakes significantly increased in 2015. In 2015, a significant correlation between nutritional intake and weight status was observed, especially among boys. CONCLUSIONS: Socioeconomic changes between 2001 and 2015 caused increased heights and weights and greater variation in weight status, especially among boys. PMID- 29239084 TI - Identification of influence factors for the implementation of communication curricula in dental education. AB - INTRODUCTION: The aim of the study was to reveal possible obstacles or advantages for the implementation of a dental communication curriculum. It was questioned whether (i) universities with a communication curriculum in medicine realise the same development in dentistry, (ii) the existence and usage of a learning objectives catalogue is a main factor to facilitate the implementation, and (iii) it is more easy to establish with a lower number of students. MATERIAL AND METHODS: Data of two recently published surveys were taken as the basis for further analysis. The quality of the curricula was evaluated by a scoring system. Correlations were calculated between the scores and possible influence factors. A t test for paired samples was accomplished to reveal differences between medical and dental curricula, and a Mann-Whitney U test to identify differences in schools with and without the usage of a learning objectives catalogue. RESULTS: No significant correlation was found between the quality scores of medical and dental schools; t tests revealed significant differences between them (P = .004). Correlation between cohort size and quality of the curriculum was marginal. Mann Whitney U test revealed significantly higher quality scores for dental schools using a learning objectives catalogue (P = .001). CONCLUSIONS: The existence of a learning objectives catalogue might facilitate the implementation of communication curricula at dental schools. A missing notable curriculum in the corresponding medical school should not detain from a respective campaign in the dental curriculum. Large student numbers should also not discourage from developing a communication curriculum. PMID- 29239085 TI - Developing educators of European undergraduate dental students: Towards an agreed curriculum. AB - INTRODUCTION: Recent developments in European dental education are student focused, concerned with competency-based and problem-based learning. The development of dental educators has so far received little consideration. This study aimed to agree curriculum content for developing dental educators so that they are better able to support changing undergraduate dental education. METHODS: Adopting consensus methodology, a 2-round Delphi was conducted in 2012. Fifty three dental educators and 39 dental students across Europe volunteered to take part. The Delphi questionnaire was developed based on literature, piloted and sent to participants to gather opinions and seek consensus on educational content using rating scales and open-ended questions. Numeric data were analysed using descriptive statistics, and qualitative data were analysed thematically. RESULTS AND DISCUSSION: This study revealed 7 domains of curriculum content for dental educators. Four of these domains were considered essential: educational principles; educational practice in dentistry; curriculum, quality and improvement; and educational professionalism. Three domains were viewed as optional and could be tailored to local needs: educational principles in relation to specific contexts, educational research, and educational and healthcare management. When developing training for dental educators, factors which need consideration were identified as the academic position and teaching experience of educators, and the nature of clinical dental education. CONCLUSION: The results are beneficial for individual educators to inform professional development plans; institutions to devise faculty developments; ADEE to inform policies on developing European dental educators; and other disciplines to inform training for their educators. PMID- 29239086 TI - Treatment of pathologic peri-implant pockets. AB - Peri-implant and periodontal pockets share a number of anatomical features but also have distinct differences. These differences make peri-implant pockets more susceptible to trauma and infection than periodontal pockets. Inadequate maintenance can lead to infections (defined as peri-implant mucositis and peri implantitis) within peri-implant pockets. These infections are recognized as inflammatory diseases, which ultimately lead to the loss of supporting bone. Diagnostic and treatment methods conventionally used in periodontics have been adopted to assess and treat these diseases. Controlling infection includes elimination of the biofilm from the implant surface and efficient mechanical debridement. However, the prosthetic supra-structure and implant surface characteristics can complicate treatment. Evidence shows that when appropriately managed, peri-implant mucositis is reversible. Nonsurgical therapy, with or without the use of antimicrobials, will occasionally resolve peri-implantitis, but for the majority of advanced lesions this approach is insufficient and surgery is indicated. The major objective of the surgical approach is to provide access and visualize the clinical situation. Hence, a more informed decision can be made regarding whether to use a resective or a regenerative surgical technique. Evidence shows that following successful decontamination, surgical treatment to regenerate the bone can be performed, and a number of regenerative techniques have been proposed. After treatment, regular maintenance and good oral hygiene are essential for a predictable outcome and long-term stability. PMID- 29239088 TI - Quantitative evaluation of cue-induced reinstatement model for evidence-based experimental optimization. AB - Cue-induced reinstatement is a widely used model for investigating relapse of reward-seeking behavior with high face validity in relation to clinical observations. Yet, face validity is not sufficient to evaluate an animal model, and quantitative, evidence-based analysis is required to estimate the ultimate applicability of this paradigm. Furthermore, such analysis would allow an accurate and reproducible design of future experiments. Here, we conducted meta analysis and cluster analysis to characterize the impact of cue type (visual, auditory, olfactory or combinations thereof), intensity (e.g. light frequency, sound volume and odor concentration), reward type (e.g. different drugs of abuse, sucrose and food pellets) and model parameters (e.g. housing condition, age, gender and strain of animals) on reinstatement levels. We selected 184 publications for meta-analysis based on inclusion criteria with a total number of 3889 rats. Our analysis suggested that the exact level of reinstatement depends on neither cue type, nor intensity nor on the type of reward. While all cues induced reinstatement to reward-seeking behavior, it is the model parameters, in particular, the housing conditions, age and strain, that defined the final reinstatement levels. In particular, single-housed, adolescent, Wistar or Lister Hooded rats showed significantly higher reinstatement than adult, Sparague-Dawley rats housed in groups. Our findings suggest that model parameters (for example, single housing) evoke stress-induced behaviors that affect reinstatement more than cue/reward factors. PMID- 29239087 TI - Danaparoid reduces transplant-related mortality in stem cell transplantation for children. AB - In SCT, death from transplant-related complications is the major obstacle hindering improvement of transplant outcomes, and proper supportive care is essential to reduce TRM. The transplant outcomes of 210 pediatric patients with malignant and non-malignant disorders who consecutively underwent SCT in our institution from 2000 to 2013 were analyzed. The transplant years were divided into three periods: A (2000-2004), B (2005-2008), and C (2009-2013), and an improvement in 5-year OS and a decrease in 5-year TRM were observed over these time periods; that is, OS was 61.5%, 60.3%, and 79.5% (P = .062), and TRM was 19.9%, 7.9%, and 0.0% (P < .001) in periods A, B, and C, respectively. On multivariate analysis, the prognostic factor for TRM for all patients was administration of danaparoid (HR = 0.109, 95% CI = 0.033-0.363, P < .001), and for patients with hematological malignancies in allogeneic SCT, the prognostic factors were danaparoid (HR = 0.046, 95% CI = 0.006-0.326, P = .002) and advanced disease at SCT (HR = 4.802, 95% CI = 1.734-13.30, P = .003). A reduction in TRM after SCT was observed over the time periods, and supportive care with danaparoid was found to be significantly effective in reducing TRM in SCT for children. PMID- 29239089 TI - Response to "actual body weight or perceived body, comments on 'childhood obesity and school absenteeism: a systematic review and meta-analysis' ". PMID- 29239090 TI - Dynamic Covalent Chemistry within Biphenyl Scaffolds: Reversible Covalent Bonding, Control of Selectivity, and Chirality Sensing with a Single System. AB - Axial chirality is a prevalent and important phenomenon in chemistry. Herein we report a combination of dynamic covalent chemistry and axial chirality for the development of a versatile platform for the binding and chirality sensing of multiple classes of mononucleophiles. An equilibrium between an open aldehyde and its cyclic hemiaminal within biphenyl derivatives enabled the dynamic incorporation of a broad range of alcohols, thiols, primary amines, and secondary amines with high efficiency. Selectivity toward different classes of nucleophiles was also achieved by regulating the distinct reactivity of the system with external stimuli. Through induced helicity as a result of central-to-axial chirality transfer, the handedness and ee values of chiral monoalcohol and monoamine analytes were reported by circular dichroism. The strategies introduced herein should find application in many contexts, including assembly, sensing, and labeling. PMID- 29239091 TI - Extra-corporeal normothermic machine perfusion of the porcine kidney: working towards future utilization in Australasia. AB - BACKGROUND: The ongoing supply-demand gap with respect to donor kidneys for transplantation necessitates the increased use of higher kidney donor profile index and/or donation after circulatory death (DCD) kidneys. Machine perfusion (MP) preservation has become increasingly popular as a means to preserve such organs. Human data regarding normothermic kidney MP (NMP) is in its infancy, and such a system has not been established in the Australasian clinical setting. METHODS: Modified cardio-pulmonary bypass technology was utilized to develop a viable NMP kidney perfusion system using a porcine DCD model. System development and optimization occurred in two stages, with system components added in each experiment to identify optimal perfusion conditions. RESULTS: Device functionality was demonstrated by the successful perfusion of and urine production by, eight porcine kidneys. Urine production diminished in the presence of colloid in the perfusate. Pressure-controlled (compared with flow-controlled) perfusion is preferable as a safe perfusion pressure range can be maintained. More physiologic perfusion conditions are achieved if oxygenation is provided by an oxygen/carbon dioxide mixture compared to 100% oxygen. CONCLUSION: A viable and reproducible NMP system was established and tested in porcine kidneys, which was able to simulate graft function extra-corporeally. Further work is required to identify the most optimal perfusion conditions. Prior to its utilization in clinical transplantation, the system should be tested in non-transplanted human kidneys. PMID- 29239092 TI - Long-term evaluation of quality of life and satisfaction between implant bar overdentures and conventional complete dentures: A 23 years retrospective study. AB - BACKGROUND: Dental implants have been used in edentulous jaws to improve the retention and stability of complete dentures. Attachment to the implants improves stability and function of the prostheses and increases patient satisfaction. PURPOSE: The aim of this study was to evaluate quality of life and satisfaction between patients with implant overdentures and complete dentures for more than 20 years. METHODS: Forty patients with overdentures and 40 patients with conventional complete dentures were included in this study. Both groups are carriers of their prosthesis more than 20 years. All patients completed an OHIP 14 and perception and satisfaction questionnaire related their implant prothesis. RESULTS: Follow-up mean in patients with overdentures were 23.27 +/- 1.87 years and 23.20 +/- 3.91 years for conventional prosthesis group. A worse quality of life was shown in the group of patients with conventional dentures in the 7 dimensions and in the total value, with statistically significant differences in 6 dimensions and in the total value (P <= .05). Patients with implants overdenture were more satisfied than patients with conventional dentures, with statistically significant differences (P < .001). CONCLUSIONS: Implant overdentures on cobalt chrome and gold bars offer an excellent long-term solution for edentulism compared with conventional denture. PMID- 29239093 TI - Bimetallic Ag-Pt Sub-nanometer Supported Clusters as Highly Efficient and Robust Oxidation Catalysts. AB - A combined experimental and theoretical investigation of Ag-Pt sub-nanometer clusters as heterogeneous catalysts in the CO->CO2 reaction (COox) is presented. Ag9 Pt2 and Ag9 Pt3 clusters are size-selected in the gas phase, deposited on an ultrathin amorphous alumina support, and tested as catalysts experimentally under realistic conditions and by first-principles simulations at realistic coverage. In situ GISAXS/TPRx demonstrates that the clusters do not sinter or deactivate even after prolonged exposure to reactants at high temperature, and present comparable, extremely high COox catalytic efficiency. Such high activity and stability are ascribed to a synergic role of Ag and Pt in ultranano-aggregates, in which Pt anchors the clusters to the support and binds and activates two CO molecules, while Ag binds and activates O2 , and Ag/Pt surface proximity disfavors poisoning by CO or oxidized species. PMID- 29239094 TI - Controlling the Polymer Microstructure in Anionic Polymerization by Compartmentalization. AB - An ideal random anionic copolymerization is forced to produce gradient structures by physical separation of two monomers in emulsion compartments. One monomer (M) is preferably soluble in the droplets, while the other one (D) prefers the continuous phase of a DMSO-in-cyclohexane emulsion. The living anionic copolymerization of two activated aziridines is thus confined to the DMSO compartments as polymerization occurs selectively in the droplets. Dilution of the continuous phase adjusts the local concentration of monomer D in the droplets and thus the gradient of the resulting copolymer. The copolymerizations in emulsion are monitored by real-time 1 H NMR kinetics, proving a change of the reactivity ratios of the two monomers upon dilution of the continuous phase from ideal random to adjustable gradients by simple dilution. PMID- 29239095 TI - Structural and Conformational Chemistry from Electrochemical Molecular Machines. Replicating Biological Functions. A Review. AB - Each constitutive chain of a conducting polymer electrode acts as a reversible multi-step electrochemical molecular motor: reversible reactions drive reversible conformational movements of the chain. The reaction-driven cooperative actuation of those molecular machines generates, or destroys, inside the film the free volume required to lodge/expel balancing counterions and solvent: reactions drive reversible film volume variations, which basic structural components are here identified and quantified from electrochemical responses. The content of the reactive dense gel (chemical molecular machines, ions and water) mimics that of the intracellular matrix in living functional cells. Reaction-driven properties (composition-dependent properties) and devices replicate biological functions and organs. An emerging technological world of soft, wet, reaction-driven, multifunctional and biomimetic devices and the concomitant zoomorphic or anthropomorphic robots is presented. PMID- 29239096 TI - Well-Defined Cobalt Catalyst with N-Doped Carbon Layers Enwrapping: The Correlation between Surface Atomic Structure and Electrocatalytic Property. AB - Admittedly, the surface atomic structure of heterogenous catalysts toward the electrochemical oxygen reduction reaction (ORR) are accepted as the important features that can tune catalytic activity and even catalytic pathway. Herein, a surface engineering strategy to controllably synthesize a carbon-layer-wrapped cobalt-catalyst from 2D cobalt-based metal-organic frameworks is elaborately demonstrated. Combined with synchrotron radiation X-ray photoelectron spectroscopy, the soft X-ray absorption near-edge structure results confirmed that rich covalent interfacial Co?N?C bonds are efficiently formed between cobalt nanoparticles and wrapped carbon-layers during the polydopamine-assisted pyrolysis process. The X-ray absorption fine structure and corresponding extended X-ray absorption fine structure spectra further reveal that the wrapped cobalt with Co-N coordinations shows distinct surface distortion and atomic environmental change of Co-based active sites. In contrast to the control sample without coating layers, the 800 degrees C-annealed cobalt catalyst with N-doped carbon layers enwrapping achieves significantly enhanced ORR activity with onset and half-wave potentials of 0.923 and 0.816 V (vs reversible hydrogen electrode), highlighting the important correlation between surface atomic structure and catalytic property. PMID- 29239097 TI - Spatially Probed Plasmonic Photothermic Nanoheater Enhanced Hybrid Polymeric Metallic PVDF-Ag Nanogenerator. AB - Surface plasmon-based photonics offers exciting opportunities to enable fine control of the site, span, and extent of mechanical harvesting. However, the interaction between plasmonic photothermic and piezoresponse still remains underexplored. Here, spatially localized and controllable piezoresponse of a hybrid self-polarized polymeric-metallic system that correlates to plasmonic light-to-heat modulation of the local strain is demonstrated. The piezoresponse is associated to the localized plasmons that serve as efficient nanoheaters leading to self-regulated strain via thermal expansion of the electroactive polymer. Moreover, the finite-difference time-domain simulation and linear thermal model also deduce the local strain to the surface plasmon heat absorption. The distinct plasmonic photothermic-piezoelectric phenomenon mediates not only localized external stimulus light response but also enhances dynamic piezoelectric energy harvesting. The present work highlights a promising surface plasmon coordinated piezoelectric response which underpins energy localization and transfer for diversified design of unique photothermic-piezotronic technology. PMID- 29239098 TI - Direct Experimental Observation of Facet-Dependent SERS of Cu2 O Polyhedra. AB - Semiconductor-based surface enhanced Raman scattering (SERS) has attracted great attention due to its excellent spectral reproducibility, high uniformity, and good anti-interference ability. However, its relatively low SERS sensitivity still hinders its further developments in both performance and applications. Since the SERS is a peculiar surface effect, investigating the facet-dependent SERS activity of semiconductor nanostructures is crucial to boost their SERS signals. Although the semiconductor facet-dependent SERS effect is predicted via numerical calculations, convincing experimental evidence is scarce due to complicated and undefined surface conditions. In this work, three facet-defined ({100}, {110}, and {111} facets) Cu2 O microcrystals (MCs) with clear surface atomic configuration are utilized to investigate the facet-dependent SERS effect. The results from the Kelvin probe force microscopy measurements on single Cu2 O polyhedron, demonstrate that the facet-dependent work function plays a crucial role in the interfacial charge transfer process. Comparing with the {110} and {111} facets, the {100} facet possesses the lowest electronic work function, which enables more efficient interfacial charge transfer. The simulation results further confirm that the {100}-facets can transfer the most electrons from Cu2 O MCs to molecules due to its lowest facet work function, resulting in the largest increment of the molecular polarization. PMID- 29239099 TI - Double layered stents for carotid angioplasty: A meta-analysis of available clinical data. AB - OBJECTIVES: The objective of this meta-analysis is to evaluate clinical efficacy of double layered mesh covered carotid stent systems in the clinical practice. BACKGROUND: The need for an increase plaque coverage to decrease the risk of debris dislodgement through the stent struts, following carotid artery stenting (CAS), has brought to the design of a new generation of double layered carotid stents. Several small sized clinical studies evaluating two different devices have been recently published, unfortunately these are not sufficiently powered to test for device related and clinical endpoints and no comparison, between the two available devices, has been reported yet. METHODS: Ten studies, enrolling 635 patients, were included in the present meta-analysis. Our study analyzed a composite endpoint of 30-day stroke and death and the occurrence of procedural unsuccess after CAS with the use of two different double layered carotid stent systems. RESULTS: Thirty-day stroke and death rate was quite low (patients 635, event rate 0.02, 95% CI: 0.01-0.04, P < 0.0001). The incidence of procedural unsuccess with these devices was relatively low (patients 635, event rate 0.03, 95% CI: 0.01-0.08, P < 0.0001). When a subgroup analysis was performed, according to the specific subtype of carotid stent, no differences in the occurrence of 30 day death and stroke rate and procedural unsuccess were observed (P = 0.979). CONCLUSIONS: This meta-analysis suggests that dual layered carotid stents could be safely used for the treatment of extracranial carotid artery stenosis, with a relatively low rate of procedural unsuccess, and allow achieving a quite low rate of postprocedural adverse events. PMID- 29239100 TI - Insulin-like growth factor 2 expression in prostate cancer is regulated by promoter-specific methylation. AB - Deregulation of the insulin-like growth factor (IGF) axis and dysbalance of components of the IGF system as potential therapeutic targets have been described in different tumor types. IGF2 is a major embryonic growth factor and an important activator of IGF signaling. It is regulated by imprinting in a development- and tissue-dependent manner and has been implicated in a broad range of malignancies including prostate cancer (PCa). Loss of imprinting (LOI) usually results in bi-allelic gene expression and increased levels of IGF2. However, the regulatory mechanisms and the pathophysiological impact of altered IGF2 expression in PCa remain elusive. Here, we show that in contrast to many other tumors, IGF2 mRNA and protein levels were decreased in 80% of PCa in comparison with non-neoplastic adjacent prostate and were independent of LOI status. Instead, IGF2 expression in both tumors and adjacent prostate depended on preferential usage of the IGF2 promoters P3 and P4. Decreased IGF2 expression in tumors was strongly related to hypermethylation of these two promoters. Methylation of the A region in promoter P4 correlated specifically with IGF2 expression in the 20% of PCa where IGF2 was higher in tumors than in adjacent prostate. We conclude that IGF2 is downregulated in most PCa and may be particularly relevant during early stages of tumor development or during chemotherapy and androgen deprivation. PCa differs from other tumors in that IGF2 expression is mainly regulated through methylation of promoter-specific and not by imprinting. Targeting of promoter-specific regions may have relevance for the adjuvant treatment of PCa. PMID- 29239101 TI - Acquired Von Willebrand syndrome and response to desmopressin. PMID- 29239102 TI - SERPINH1 overexpression in clear cell renal cell carcinoma: association with poor clinical outcome and its potential as a novel prognostic marker. AB - Precision therapy for clear cell renal cell carcinoma (ccRCC) requires molecular biomarkers ascertaining disease prognosis. In this study, we performed integrated proteomic and transcriptomic screening in all four tumour-node-metastasis stages of ccRCC and adjacent normal tissues (n = 18) to investigate differentially expressed genes. Most identified differentially expressed genes revealed a strong association with transforming growth factor-beta level and the epithelial-to mesenchymal transition process. Of them, Serpin peptidase inhibitor clade H member 1 (SERPINH1) revealed the strongest association with poor prognosis and regulation on the expression levels of epithelial-to-mesenchymal transition markers. Subsequently, two independent sets (n = 532 and 105) verified the high level of SERPINH1 in ccRCC tissues and its association with reduced overall survival and disease-free survival in all tumour-node-metastasis stages and patients with von Hippel-Lindau wild-type (VHL-WT). SERPINH1 was an independent predictor of poor overall survival (hazard ratio 0.696 for all patients) and disease-free survival (hazard ratio 0.433 for all patients and 0.362 for patients with VHL-WT) in ccRCC. We have thus shown for the first time that SERPINH1 is an independent precision predictor for unfavourable prognosis in ccRCC. This could assist in identifying patients who need early aggressive management and deepen our understanding of the pathogenesis of VHL-WT ccRCC. PMID- 29239103 TI - Out-of-Plane 3D-Printed Microfibers Improve the Shear Properties of Hydrogel Composites. AB - One challenge in biofabrication is to fabricate a matrix that is soft enough to elicit optimal cell behavior while possessing the strength required to withstand the mechanical load that the matrix is subjected to once implanted in the body. Here, melt electrowriting (MEW) is used to direct-write poly(epsilon caprolactone) fibers "out-of-plane" by design. These out-of-plane fibers are specifically intended to stabilize an existing structure and subsequently improve the shear modulus of hydrogel-fiber composites. The stabilizing fibers (diameter = 13.3 +/- 0.3 um) are sinusoidally direct-written over an existing MEW wall-like structure (330 um height). The printed constructs are embedded in different hydrogels (5, 10, and 15 wt% polyacrylamide; 65% poly(2-hydroxyethyl methacrylate) (pHEMA)) and a frequency sweep test (0.05-500 rad s-1 , 0.01% strain, n = 5) is performed to measure the complex shear modulus. For the rheological measurements, stabilizing fibers are deposited with a radial architecture prior to embedding to correspond to the direction of the stabilizing fibers with the loading of the rheometer. Stabilizing fibers increase the complex shear modulus irrespective of the percentage of gel or crosslinking density. The capacity of MEW to produce well-defined out-of-plane fibers and the ability to increase the shear properties of fiber-reinforced hydrogel composites are highlighted. PMID- 29239104 TI - The Development of Nonanatomic Denture Occlusion - Part I. AB - Part I of this two-part article concentrates on the early 20th century origin of the nonanatomic concept of complete denture occlusion. It focuses on Dr. Victor Sears, who in 1922 made a courageous departure from convention when he introduced the design for his "Chewing Members." Development of these teeth marked the birth of the School of Nonanatomic Denture Occlusion. Dr. Sears' 35-year journey of research and development is traced here through his mid-1950s association with Dr. Simon Myerson. Their Myerson-Sears design set the standard for flat-planed, nonanatomic denture teeth for the next half century. PMID- 29239105 TI - Iron-Catalyzed Aminative Cyclization/Intermolecular Homolytic Aromatic Substitution Using Oxime Esters and Simple Arenes. AB - Intermolecular C-H alkylation of simple arenes in the presence of an iron catalyst has been achieved in a cascade manner with an aminative cyclization triggered by N-O bond cleavage of an alkene-tethered oxime ester. Various arenes, including electron-rich and electron-poor arenes, and heteroarenes can be employed in the reaction system. Regioselectivity and radical trapping experiments support the involvement of alkyl radical species, which undergo a homolytic aromatic substitution (HAS) to afford the arylation products. PMID- 29239107 TI - Regulation of tumor-stroma interactions by the unfolded protein response. AB - The unfolded protein response (UPR) is a conserved adaptive pathway that helps cells cope with the protein misfolding burden within the endoplasmic reticulum (ER). Imbalance between protein folding demand and capacity in the ER leads to a situation called ER stress that is often observed in highly proliferative and secretory tumor cells. As such, activation of the UPR signaling has emerged as a key adaptive mechanism promoting cancer progression. It is becoming widely acknowledged that, in addition to its intrinsic effect on tumor biology, the UPR can also regulate tumor microenvironment. In this review, we discuss how the UPR coordinates the crosstalk between tumor and stromal cells, such as endothelial cells, normal parenchymal cells, and immune cells. In addition, we further describe the involvement of ER stress signaling in the response to current treatments as well as its impact on antitumor immunity mainly driven by immunogenic cell death. Finally, in this context, we discuss the relevance of targeting ER stress/UPR signaling as a potential anticancer approach. PMID- 29239108 TI - Ultrasensitive determination of highly polar trimethyl phosphate in environmental water by molecularly imprinted polymeric fiber headspace solid-phase microextraction. AB - A sensitive, accurate, and cost effective method for the quantification of trimethyl phosphate, which is highly polar and volatile, in environmental water is presented. Trimethyl phosphate was headspace solid-phase microextracted on a molecularly imprinted polymeric fiber, and then the fiber was thermally desorbed in the gas chromatograph injector, and the compound was determined. The trimethyl phosphate imprinted polymeric fiber was prepared by copolymerization in a fused silica capillary tube and obtained by removal of the wall of fused silica capillary tube. The monolithic fiber displayed good selectivity toward trimethyl phosphate among its structural analogues. It was thermally stable up to 320 degrees C so that it can withstand the high temperature of the gas chromatograph injector for desorption. The factors influencing the performance of its headspace solid-phase microextraction were studied. Under the optimal conditions, the method for quantification of trimethyl phosphate in environmental water was well developed. It exhibited significant linearity, the lowest limit of quantification to date, and good recoveries. Using this method, trimethyl phosphate was detected in five out of seven environmental water samples at concentration levels from 0.28 to 1.22 MUg/L, illustrating the heavy pollution of trimethyl phosphate in environmental water. PMID- 29239109 TI - Shape-Controlled 3D Periodic Metal Nanostructures Fabricated via Nanowelding. AB - A novel method for fabricating 3D metallic nanostructures to be used in polarized color filters based on nanoimprint lithography, electron-beam evaporation, and nanowelding is proposed. The shape of the nanostructures can be controlled by adjusting the temperature for the nanowelding process. Ag nanowires deposited on polymer patterns are accumulated by the nanowelding process to build up diverse 3D nanostructures. The morphologies of the fabricated 3D nanostructures are analyzed using scanning electron microscopy, atomic force microscopy, and focused ion beam; the heating temperature is varied from 90 to 130 degrees C in steps of 10 degrees C. In order to analyze the recrystallization phenomenon after welding, transmission electron microscopy is utilized. The 3D metallic nanostructure has different morphologies and optical properties corresponding to welding temperature conditions and accumulated layer thicknesses. Based on preliminary experimental results, the process parameters are optimized and a polarized color filter is fabricated. Optical characteristics of the filter are evaluated using polarizer and spectrometer. Through this work, it is shown that the proposed method is an effective way to realize various 3D metallic nanostructures for special optical properties, therefore the method based on nanowelding can be utilized in fabrication of functional metamaterials, optical filters, biosensors, and others. PMID- 29239110 TI - Association of prognostic features and treatment on survival time of dogs with systemic mastocytosis: A retrospective analysis of 40 dogs. AB - Systemic mastocytosis is a rare phenomenon, with limited information regarding prognostic features and effective treatment of canine patients with this disease. The objective of this study is to determine the impact of certain features and treatments on dogs with systemic mastocytosis. The medical records of 40 dogs from 4 northeastern US veterinary hospitals, with evidence of systemic mast cell disease, were evaluated retrospectively. Variables analysed with relation to overall survival and prognostic significance included treatment protocol used, substage, presence of a cutaneous or visceral tumour, presence of multiple cutaneous Mast cell tumours, grade of the primary tumour and metastatic site(s). Dogs with metastatic disease confined to distant lymph nodes lived longer than those with circulating mast cells in the blood (P = .001), and those with metastatic disease evident in more than 2 sites had a worse prognosis than those with disease in a single location (P = .005). Additionally, administration of chemotherapeutic agents led to increased survival over prednisone therapy alone (P = .008), with the combination of lomustine, vinblastine and prednisone prolonging survival over the tyrosine kinase inhibitor, toceranib phosphate (P = .002). Presence of mast cells in the blood and/or evidence of disease in more than 2 sites indicate widespread dissemination suggesting their use as negative prognostic features. Furthermore, a chemotherapy protocol including combination lomustine and vinblastine therapy may be more effective than toceranib phosphate for the treatment of dogs with disseminated mast cell disease. Overall, patients with systemic mastocytosis have a grave prognosis and more effective treatment options are needed. PMID- 29239106 TI - ER stress in skeletal muscle remodeling and myopathies. AB - Skeletal muscle is a highly plastic tissue in the human body that undergoes extensive adaptation in response to environmental cues, such as physical activity, metabolic perturbation, and disease conditions. The endoplasmic reticulum (ER) plays a pivotal role in protein folding and calcium homeostasis in many mammalian cell types, including skeletal muscle. However, overload of misfolded or unfolded proteins in the ER lumen cause stress, which results in the activation of a signaling network called the unfolded protein response (UPR). The UPR is initiated by three ER transmembrane sensors: protein kinase R-like endoplasmic reticulum kinase, inositol-requiring protein 1alpha, and activating transcription factor 6. The UPR restores ER homeostasis through modulating the rate of protein synthesis and augmenting the gene expression of many ER chaperones and regulatory proteins. However, chronic heightened ER stress can also lead to many pathological consequences including cell death. Accumulating evidence suggests that ER stress-induced UPR pathways play pivotal roles in the regulation of skeletal muscle mass and metabolic function in multiple conditions. They have also been found to be activated in skeletal muscle under catabolic states, degenerative muscle disorders, and various types of myopathies. In this article, we have discussed the recent advancements toward understanding the role and mechanisms through which ER stress and individual arms of the UPR regulate skeletal muscle physiology and pathology. PMID- 29239111 TI - Effect of 670 nm laser photobiomodulation on vascular density and fibroplasia in late stages of tissue repair. AB - This study aimed to investigate the effects of gallium-aluminum-arsenium (GaAlAs) (670 nm) laser therapy on neoangiogenesis and fibroplasia during tissue remodelling. Forty male Wistar rats underwent cutaneous surgery and were divided into 2 experimental groups: the Control and Laser group (9 mW, 670 nm, 0.031 W/cm2 , 4 J/cm2 ). After 14, 21, 28, and 35 days, the animals were euthanised. Descriptive and quantitative analyses were performed in sections stained with haematoxylin-eosin and Sirius Red, respectively. The amounts of VEGF+ and CD31+ cells were evaluated by immunohistochemistry and histomorphometric analysis, respectively. Statistical analysis was performed using the Mann-Whitney, Friedman, and Spearman correlation test, P < 0.05. The collagen expression was significantly higher in the laser group compared with the control group on days 14 and 21 after the creation of the skin wound (P = 0.008; P = 0.016) and in the control group between 14 and 28 and 14 and 35 days (P = 0.001; P = 0.007). There were more blood vessels in three periods of the study only in the (Laser) treated group, with statistical significance at day 14 (P = 0.016). There was no statistically significant difference in VEGF+ cell count in the different experimental groups throughout the study, although a positive correlation was shown with the area of collagen on days 14 and 28 (P = 0.037). Laser treatment had a positive effect in the late course of healing, particularly with regards to collagen expression and the number of newly formed vessels. VEGF+ cells were present in both experimental groups, and VEGF appeared to influence fibroplasia in the treated group. PMID- 29239112 TI - Male reproductive tract and spermatozoa ultrastructure in the grasshopper Orphulella punctata (De Geer, 1773) (Insecta, Orthoptera, Caelifera). AB - Identification Orphulellini grasshoppers (Acrididae: Gomphocerinae) species has been difficult due to high polymorphism rate. Orphulella Giglio-Tos, 1894 is a genus with widespread geographical distribution and poor descriptions. Orphulella punctata (De Geer, 1773) has an extensive record of occurrence and available information about the phallic complex, however, there is poor data describing other parts of the male reproductive tract. The objective of this study was characterizes the internal organs of the male reproductive system and spermatozoa of O. punctata. Orphulella punctata testes are of Fountain type, each having only four follicles. Spermatozoa into the seminal vesicle are arranged in bundles with c.a. 2320 um length, with a nucleus 110 um long. The spermatozoa are covered by a glycocalyx, the nucleus is cylindrical with condensed chromatin and connected to the flagellum by a dense and lamellar centriole adjunct. The axoneme have 9 + 9 + 2 pattern and present two symmetrical mitochondrial derivatives. A fibrous net and two flat membranous cisternae fill the space between the axoneme and mitochondrial derivatives. This is the first description of the reproductive system of a Gomphocerinae representative. PMID- 29239113 TI - Detection of novel syntrophic acetate-oxidizing bacteria from biogas processes by continuous acetate enrichment approaches. AB - To enrich syntrophic acetate-oxidizing bacteria (SAOB), duplicate chemostats were inoculated with sludge from syntrophic acetate oxidation (SAO)-dominated systems and continuously supplied with acetate (0.4 or 7.5 g l-1 ) at high-ammonia levels. The chemostats were operated under mesophilic (37 degrees C) or thermophilic (52 degrees C) temperature for about six hydraulic retention times (HRT 28 days) and were sampled over time. Irrespective of temperature, a methane content of 64-69% and effluent acetate level of 0.4-1.0 g l-1 were recorded in chemostats fed high acetate. Low methane production in the low-acetate chemostats indicated that the substrate supply was below the threshold for methanization of acetate via SAO. Novel representatives within the family Clostridiales and genus Syntrophaceticus (class Clostridia) were identified to represent putative SAOB candidates in mesophilic and thermophilic conditions respectively. Known SAOB persisted at low relative abundance in all chemostats. The hydrogenotrophic methanogens Methanoculleus bourgensis (mesophilic) and Methanothermobacter thermautotrophicus (thermophilic) dominated archaeal communities in the high acetate chemostats. In line with the restricted methane production in the low acetate chemostats, methanogens persisted at considerably lower abundance in these chemostats. These findings strongly indicate involvement in SAO and tolerance to high ammonia levels of the species identified here, and have implications for understanding community function in stressed anaerobic processes. PMID- 29239114 TI - Engineering thermal stability and solvent tolerance of the soluble quinoprotein PedE from Pseudomonas putida KT2440 with a heterologous whole-cell screening approach. AB - Due to their ability for direct electron transfer to electrodes, the utilization of rare earth metals as cofactor, and their periplasmic localization, pyrroloquinoline quinone-dependent alcohol dehydrogenases (PQQ-ADHs) represent an interesting class of biocatalysts for various biotechnological applications. For most biocatalysts protein stability is crucial, either to increase the performance of the protein under a given process condition or to maximize robustness of the protein towards mutational manipulations, which are often needed to enhance or introduce a functionality of interest. In this study, we describe a whole-cell screening assay, suitable for probing PQQ-ADH activities in Escherichia coli BL21(DE3) cells, and use this assay to screen smart mutant libraries for increased thermal stability of the PQQ-ADH PedE (PP_2674) from Pseudomonas putida KT2440. Upon three consecutive rounds of screening, we identified three different amino acid positions, which significantly improve enzyme stability. The subsequent combination of the beneficial mutations finally results in the triple mutant R91D/E408P/N410K, which not only exhibits a 7 degrees C increase in thermal stability but also a twofold increase in residual activity upon incubation with up to 50% dimethyl sulfoxide (DMSO), while showing no significant difference in enzymatic efficiency (kcat /KM ). PMID- 29239115 TI - Case management in early psychosis intervention programme: Perspectives of clients and caregivers. AB - AIM: This qualitative study explored the perspectives of clients and caregivers on case management provided by the Singapore Early Psychosis Intervention Programme (EPIP), with the intent to understand the salient aspects of case management from their perspective. METHODS: Clients and their caregivers were recruited from the EPIP outpatient clinics. Focus group discussions (FGDs) were conducted at a community centre outside the hospital with 47 clients and 19 caregivers. Facilitators were experienced researchers who were not involved in the care of the clients and trained in qualitative research methodologies. All FGDs were audio recorded and transcribed verbatim with all participants' identifiers omitted to protect confidentiality. Qualitative data analysis was conducted using thematic analysis. RESULTS: There were 11 themes that emerged from the FGDs: therapeutic alliance, holistic monitoring, collaborative role with other care providers, counselling and guidance, crisis management, bridging role, client-centred care, client empowerment and strength building, psychoeducation/education on illness, support and problem solving. "Problem solving" surfaced only from the client FGDs; the remaining themes were common to both groups. CONCLUSIONS: The voices of clients and caregivers are important to EPIP case management service. This study has provided insights into their perspectives, understandings and lived experiences of case management and its impact on clients and caregivers. PMID- 29239116 TI - Raman detection and identification of normal and leukemic hematopoietic cells. AB - The analysis of leukocytes of peripheral blood is a crucial step in hematologic exams commonly used for disease diagnosis and, typically, requires molecular labelling. In addition, only a detailed, laborious phenotypic analysis allows identifying the presence and stage of specific pathologies such as leukemia. Most of the biochemical information is lost in the routine blood tests. In the present study, we tackle 2 important issues of label-free biochemical identification and classification of leukocytes using Raman spectroscopy (RS). First, we demonstrate that leukocyte subpopulations of lymphocytes (B, T and NK cells), monocytes and granulocytes can be identified by the unsupervised statistical approach of principal component analysis and classified by linear discriminant analysis with approximately 99% of accuracy. Second, we apply the same procedure to identify and discriminate normal B cells and transformed MN60 lymphocyte leukemic cell lines. In addition, we demonstrate that RS can be efficiently used for monitoring the cell response to low-dose chemotherapy treatment, experimentally eliciting the sensitivity to a dose-dependent cell response, which is of fundamental importance to determine the efficacy of any treatment. These results largely expand established Raman-based research protocols for label-free analysis of white blood cells, leukemic cells and chemotherapy treatment follow-up. PMID- 29239117 TI - Deep Omics. AB - Deep learning has revolutionized research in image processing, speech recognition, natural language processing, game playing, and will soon revolutionize research in proteomics and genomics. Through three examples in genomics, protein structure prediction, and proteomics, we demonstrate that deep learning is changing bioinformatics research, shifting from algorithm-centric to data-centric approaches. PMID- 29239119 TI - A retrospective review of acute myeloid leukaemia in 35 dogs diagnosed by a combination of morphologic findings, flow cytometric immunophenotyping and cytochemical staining results (2007-2015). AB - Acute myeloid leukaemia (AML) is an uncommon, rapidly progressive neoplasm in dogs. The aim of this retrospective study was to characterize the clinical presentation, haematologic findings, diagnostic imaging results, treatment and survival time of a contemporary cohort of dogs with AML. Diagnosis was based on >20% blasts in bone marrow or blood identified as myeloid based on morphologic findings, flow cytometric immunophenotyping and cytochemical staining. Medical records of 35 dogs diagnosed with AML from 2007 to 2015 were included. Most dogs presented with inappetence (66%) and lethargy (57%) and physical examination findings of peripheral lymphadenopathy (74%) and tachypnea (62%). Common haematologic findings were quantifiable circulating blasts (85%; median blast count 35 700/MUL; range: 300-276 500/MUL), anaemia (median haematocrit 34%; range: 11%-52%) and thrombocytopenia (median 57 000/MUL; range: 9000-252 000/MUL). Bicytopenia and pancytopenia were each found in 44% of dogs. Follow-up information was available for 34 dogs. The overall median survival time from diagnosis was 19 days (range: 1-121 days). Clinical progression in some dogs was not as rapid as previously reported. Haematologic responses to various chemotherapeutics were documented in 3 dogs, with associated survival times of 62, 103 and 121 days. Dogs treated with prednisone or a combination of chemotherapy and prednisone had improved survival compared to dogs that received symptomatic care only (P < .0001). Our results show canine AML has an overlapping clinical presentation with lymphoma. The prognosis for canine AML remains extremely guarded. Further studies are needed to optimize therapeutic regimens for dogs with AML. PMID- 29239120 TI - A call for prevention and early intervention in obsessive-compulsive disorder. AB - BACKGROUND: Evidence suggests that many people with obsessive-compulsive disorder (OCD) have subclinical symptoms years before the development of their disorder and that early treatment may reduce its severity. AIM: To explore prevention and early intervention strategies for OCD. METHODS: A narrative literature review was conducted. RESULTS: The literature in relation to the prevention of OCD is sparse. Genetic and environmental factors appear to be relevant to the aetiology of OCD, for example, the observation that hoarding symptoms and contamination/cleaning symptoms are more likely to also be present in first degree relatives. Psychoeducation and the reduction of family accommodation, that is the act of parents, siblings or partners accommodating to the high-risk individual's requests to comply with their compulsions, are promising areas for prevention and early intervention in high-risk groups. Tertiary prevention has also been limited by an inadequate number of trained clinicians to deliver evidence-based treatments. CONCLUSIONS: Much more research is needed in relation to the prevention of OCD. There is limited scope for primary prevention with respect to biological aetiological factors, but there is potential for strategies addressing environmental factors (eg, family factors). The effectiveness of psychoeducation for parents with OCD as a primary prevention strategy for OCD in their children requires scientific evaluation. Improving access to effective treatments for OCD would also improve tertiary prevention. PMID- 29239118 TI - Zoonotic origin and transmission of Middle East respiratory syndrome coronavirus in the UAE. AB - Since the emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, there have been a number of clusters of human-to-human transmission. These cases of human-to-human transmission involve close contact and have occurred primarily in healthcare settings, and they are suspected to result from repeated zoonotic introductions. In this study, we sequenced whole MERS-CoV genomes directly from respiratory samples collected from 23 confirmed MERS cases in the United Arab Emirates (UAE). These samples included cases from three nosocomial and three household clusters. The sequences were analysed for changes and relatedness with regard to the collected epidemiological data and other available MERS-CoV genomic data. Sequence analysis supports the epidemiological data within the clusters, and further, suggests that these clusters emerged independently. To understand how and when these clusters emerged, respiratory samples were taken from dromedary camels, a known host of MERS-CoV, in the same geographic regions as the human clusters. Middle East respiratory syndrome coronavirus genomes from six virus-positive animals were sequenced, and these genomes were nearly identical to those found in human patients from corresponding regions. These data demonstrate a genetic link for each of these clusters to a camel and support the hypothesis that human MERS-CoV diversity results from multiple zoonotic introductions. PMID- 29239121 TI - Effect of Rivaroxaban on thrombin generation in vivo. A study in obese patients. PMID- 29239122 TI - Crystal structure of native beta-N-acetylhexosaminidase isolated from Aspergillus oryzae sheds light onto its substrate specificity, high stability, and regulation by propeptide. AB - : beta-N-acetylhexosaminidase from the fungus Aspergillus oryzae is a secreted extracellular enzyme that cleaves chitobiose into constituent monosaccharides. It belongs to the GH 20 glycoside hydrolase family and consists of two N glycosylated catalytic cores noncovalently associated with two 10-kDa O glycosylated propeptides. We used X-ray diffraction and mass spectrometry to determine the structure of A. oryzae beta-N-acetylhexosaminidase isolated from its natural source. The three-dimensional structure determined and refined to a resolution of 2.3 A revealed that this enzyme is active as a uniquely tight dimeric assembly further stabilized by N- and O-glycosylation. The propeptide from one subunit forms extensive noncovalent interactions with the catalytic core of the second subunit in the dimer, and this chain swap suggests the distinctive structural mechanism of the enzyme's activation. Unique structural features of beta-N-acetylhexosaminidase from A. oryzae define a very stable and robust framework suitable for biotechnological applications. The crystal structure reported here provides structural insights into the enzyme architecture as well as the detailed configuration of the active site. These insights can be applied to rational enzyme engineering. DATABASE: Structural data are available in the PDB database under the accession number 5OAR. ENZYME: beta-N-acetylhexosaminidase (EC 3.2.1.52). PMID- 29239123 TI - Seeing the light to change colour: An evolutionary perspective on the role of melanopsin in neuroendocrine circuits regulating light-mediated skin pigmentation. AB - Melanopsin photopigments, Opn4x and Opn4m, were evolutionary selected to "see the light" in systems that regulate skin colour change. In this review, we analyse the roles of melanopsins, and how critical evolutionary developments, including the requirement for thermoregulation and ultraviolet protection, the emergence of a background adaptation mechanism in land-dwelling amphibian ancestors and the loss of a photosensitive pineal gland in mammals, may have helped sculpt the mechanisms that regulate light-controlled skin pigmentation. These mechanisms include melanopsin in skin pigment cells directly inducing skin darkening for thermoregulation/ultraviolet protection; melanopsin-expressing eye cells controlling neuroendocrine circuits to mediate background adaptation in amphibians in response to surface-reflected light; and pineal gland secretion of melatonin phased to environmental illuminance to regulate circadian and seasonal variation in skin colour, a process initiated by melanopsin-expressing eye cells in mammals, and by as yet unknown non-visual opsins in the pineal gland of non mammals. PMID- 29239124 TI - The Molecular Structure of gauche-1,3-Butadiene: Experimental Establishment of Non-planarity. AB - The planarity of the second stable conformer of 1,3-butadiene, the archetypal diene for the Diels-Alder reaction in which a planar conjugated diene and a dienophile combine to form a ring, is not established. The most recent high level calculations predicted the species to adopt a twisted, gauche structure owing to steric interactions between the inner terminal hydrogens rather than a planar, cis structure favored by the conjugation of the double bonds. The structure cis 1,3-butadiene is unambiguously confirmed experimentally to indeed be gauche with a substantial dihedral angle of 34 degrees , in excellent agreement with theory. Observation of two tunneling components indicates that the molecule undergoes facile interconversion between two equivalent enantiomeric forms. Comparison of experimentally determined structures for gauche- and trans-butadiene provides an opportunity to examine the effects of conjugation and steric interactions. PMID- 29239125 TI - Autofluorescence and white light imaging-guided endoscopic Raman and diffuse reflectance spectroscopy for in vivo nasopharyngeal cancer detection. AB - Nasopharyngeal cancer (NPC) is an endemic with high incidence in Southern China and Southeast Asia countries. Screening for NPC under conventional white light imaging (WLI) nasopharyngoscope examination remains a great clinical challenge due to its poor sensitivity. Here, we developed an integrated 4-modality endoscopy system combining WLI, autofluorescence imaging (AFI), diffuse reflectance spectroscopy and Raman spectroscopy technologies for in vivo endoscopic cancer detection for the first time. A pilot clinical test of the system for NPC detection was conducted, in which 283 in vivo Raman and diffuse reflectance spectral data sets from 30 NPC patients and 30 healthy subjects were acquired under the guidance of AFI and WLI. Both high diagnostic sensitivity (98.6%) and high specificity (95.1%) for differentiating cancer from normal tissue sites were achieved using this system combined with principal component analysis-linear discriminant analysis diagnostic algorithm, demonstrating great potential for improving real-time, in vivo diagnosis of NPC at endoscopy. PMID- 29239126 TI - Sexual dimorphism of microglia and synapses during mouse postnatal development. AB - Microglia participate in synapse remodeling in the cortex and hippocampus during mouse postnatal development. Although sex differences in microglia activity during embryonic development have been reported in these regions, it remains unexplored whether microglia show sexually dimorphic features during the early postnatal period, a critical window for synapse formation and maturation. Here, we investigated morphological and functional features of microglia across early postnatal development as well as morphological features of both pre- and postsynaptic neuronal compartments in the mouse hippocampus. We found a sex dependent shift in microglia volume and phagocytic capacity across the first four postnatal weeks. Measurements of synaptic features revealed sex differences in the density of synaptic spines and boutons during the second postnatal week. These data are consistent with a precocious development of both microglia and synapses in the female brain. We further hypothesize that this bias may contribute to sex-specific brain wiring. (c) 2017 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 618-626, 2018. PMID- 29239127 TI - Prognostic predictability of the new American Joint Committee on Cancer 8th staging system for distal bile duct cancer: limited usefulness compared with the 7th staging system. AB - BACKGROUND: The new 8th American Joint Committee on Cancer (AJCC) staging has recently been released and there are major changes in distal bile duct (DBD) cancer staging. However, clinical validation is needed before the changes can be widely implemented. METHODS: This study was performed to evaluate the prognostic predictability of the 8th AJCC staging compared with that of the 7th using C statistics. RESULTS: A total of 293 consecutive patients who had curative intended surgery were enrolled. There was no significant difference of the 5-year survival rate between 7th T1 and T2 (P = 0.123), but significant difference between T2 and T3 (P = 0.039). There were significant differences in pairwise comparisons between the 8th T stage (T1 vs. T2, P = 0.001; T2 vs. T3, P = 0.014). The number of regional lymph node metastases also showed prognostic predictability. The 8th T and N stage both showed comparable prognostic predictability with the 7th (95% confidential intervals for C; T, -0.043 -0.097, N, -0.001 - 0.008). CONCLUSIONS: The 8th AJCC staging for DBD cancer does not have better prognostic predictability than the 7th stage does. The previous pathologic results would become useless unless they were reviewed entirely. Therefore, introduction of the AJCC 8th staging has to be reconsidered, especially for new T staging. PMID- 29239128 TI - Efficacy of anakinra in a patient with systemic amyloidosis presenting as amyloidoma. AB - Amyloidosis is a heterogeneous group of disorders characterized by extracellular deposition of unique protein fibrils. The least common presentation of an amyloid deposition is as a discrete mass called amyloidoma or amyloid tumor. We report a case of a soft tissue amyloidoma in the abdomen of a 16-year-old girl who was diagnosed as having systemic amyloidosis. A girl aged 16 years was referred to our hospital with a pre-diagnosis of a retroperitoneal mass documented with abdominal ultrasonography and tomography. A laboratory examination revealed nephrotic syndrome. She underwent surgery for a complete resection of the lesion. A histopathologic examination with Congo red and crystal violet dyes verified the diagnosis of amyloidoma. An immunohistochemical study for amyloid A protein was positive. A renal biopsy was also compatible with AA amyloidosis. A detailed search for the etiology of systemic amyloidosis revealed heterozygous mutation in the Mediterranean fever gene. Treatment with colchicine and anakinra were started with the diagnosis of familial Mediterranean fever because the other causes of secondary amyloidosis were ruled out. After 3 months of anakinra treatment, the laboratory findings returned to normal and excessive proteinuria disappeared. In countries where FMF and other autoinflammatory diseases are prevelant, systemic amyloidosis should be kept in mind in the differential diagnosis of children who present with nephrotic syndrome and abdominal mass. Taking previously reported cases and our case together, it appears that anti-interleukin-1 treatment represents a promising new approach in a subset of patients with systemic amyloidosis secondary to autoinflammatory diseases. PMID- 29239129 TI - Association of prenatal exposure to gestational diabetes with offspring body composition and regional body fat distribution. AB - The aim of this cohort study was to compare body composition and regional body fat distribution between children exposed (GDM+) or unexposed (GDM-) in utero to gestational diabetes mellitus (GDM) and to investigate the association with the glycaemic and the insulin profile. Data from 56 GDM+ and 30 GDM- were analysed. Height, weight and waist circumference were measured. Total and regional body composition was measured by dual-energy X-ray absorptiometry. Insulin, glucose and HbA1c were obtained from a fasting plasma sample, and the HOMA-IR index was calculated. anova was performed to compare adiposity measures between GDM+ and GDM-. Associations between the glycaemic and insulin profile and adiposity measures were studied using partial Pearson correlations. Mean age was 6.6 +/- 2.3 years. Waist circumference, fat mass percentage, android fat mass, android fat mass percentage and android-to-gynoid fat mass ratio were higher among GDM+, and lean mass percentage was lower (P < 0.05). Among GDM+ children, body mass index (BMI) z score, waist circumference, fat mass percentage, android fat mass percentage and android-to-gynoid fat mass ratio were all positively correlated with HbA1C (r = 0.32-0.43, P < 0.05). Prenatal exposure to GDM is associated with increased total and abdominal adiposity. This increased adiposity observed among GDM+ children is associated with an altered glycaemic profile. This study is registered in the Clinical Trials.gov registry (NCT01340924). PMID- 29239130 TI - Establishing the cascade of care for hepatitis C in England-benchmarking to monitor impact of direct acting antivirals. AB - Little is known about engagement and retention in care of people diagnosed with chronic hepatitis C (HCV) in England. Establishing a cascade of care informs targeted interventions for improving case finding, referral, treatment uptake and retention in care. Using data from the sentinel surveillance of blood-borne virus (SSBBV) testing between 2005 and 2014, we investigate the continuum of care of those tested for HCV in England. Persons >=1 year old with an anti-HCV test and subsequent RNA tests between 2005 and 2014 reported to SSBBV were collated. We describe the cascade of care, as the patient pathway from a diagnostic test, referral into care, treatment and patient outcomes. Between 2005 and 2014, 2 390 507 samples were tested for anti-HCV, corresponding to 1 766 515 persons. A total of 53 038 persons (35 190 men and 17 165 women) with anti-HCV positive were newly reported to SSBBV. An RNA test was conducted on 77.0% persons who were anti-HCV positive, 72.3% of whom were viraemic (RNA positive) during this time period, 21.4% had evidence of treatment and 3130 49.5% had evidence of a sustained virological response (SVR). In multivariable models, confirmation of viraemia by RNA test varied by age and region/test setting; evidence of treatment varied by age, year of test and region/test setting; and SVR varied by age, year of test and region/setting of test. In conclusion, our findings provide HCV cascade of care estimates prior to the introduction of direct acting antivirals. These findings provide important baseline cascade estimates to benchmark progress towards elimination of HCV as a major public health threat. PMID- 29239131 TI - Finasteride treatment and male breast cancer: a register-based cohort study in four Nordic countries. AB - A potential link has been suggested between dispensed finasteride and increased risk of male breast cancer (MBC). Due to the rare occurrence of MBC, it remains to be established if such a relationship exists. The purpose of this study was to combine nationwide registers in four countries to assess the potential association between dispensed finasteride and MBC. A cohort of all males with dispensed finasteride in Denmark, Finland, Norway, and Sweden (1,365,088 person years) was followed up for up to 15 years for breast cancer, and compared to a cohort of males unexposed to finasteride. Individual-level register data included country, dates of dispensed finasteride, MBC diagnosis, and death. Incidence rate ratios (IRRs) were estimated using a generalized linear model with a Poisson distribution. An increased risk of MBC was found among finasteride users (IRR = 1.44, 95% confidence interval [95% CI] = 1.11-1.88) compared to nonusers. The IRR increased to 1.60 (95% CI = 1.20-2.13) when users in Norway and Sweden with short follow-up time were excluded. The highest IRR was seen among men with medium duration of dispensed finasteride, medium accumulated consumption of finasteride, and among men with first dispensed finasteride prescription 1-3 years prior to diagnosis. The analyses suggested possible ascertainment bias and did not support a clear relationship between dispensed finasteride and MBC. In conclusion, a significant association between dispensed finasteride and MBC was identified. However, due to limited data for adjustment of potential confounding and surveillance bias in the present study, further research is needed to confirm these results. PMID- 29239132 TI - Translational Systems Pharmacology Studies in Pregnant Women. AB - Pregnancy involves rapid physiological adaptation and complex interplay between mother and fetus. New analytic technologies provide large amounts of genomic, proteomic, and metabolomics data. The integration of these data through bioinformatics, statistical, and systems pharmacology techniques can improve our understanding of the mechanisms of normal maternal physiologic changes and fetal development. New insights into the mechanisms of pregnancy-related disorders, such as preterm birth (PTB), may lead to the development of new therapeutic interventions and novel biomarkers. PMID- 29239133 TI - Simplicity at the cost of predictive accuracy in diffuse large B-cell lymphoma: a critical assessment of the R-IPI, IPI, and NCCN-IPI. AB - The international prognostic index (IPI) and similar models form the cornerstone of clinical assessment in newly diagnosed diffuse large B-cell lymphoma (DLBCL). While being simple and convenient to use, their inadequate use of the available clinical data is a major weakness. In this study, we compared performance of the International Prognostic Index (IPI) and its variations (R-IPI and NCCN-IPI) to a Cox proportional hazards (CPH) model using the same covariates in nondichotomized form. All models were tested in 4863 newly diagnosed DLBCL patients from population-based Nordic registers. The CPH model led to a substantial increase in predictive accuracy as compared to conventional prognostic scores when evaluated by the area under the curve and other relevant tests. Furthermore, the generation of patient-specific survival curves rather than assigning patients to one of few predefined risk groups is a relevant step toward personalized management and treatment. A test-version is available on lymphomapredictor.org. PMID- 29239134 TI - Recent Advances in Managing Atherosclerosis via Nanomedicine. AB - Atherosclerosis, driven by chronic inflammation of the arteries and lipid accumulation on the blood vessel wall, underpins many cardiovascular diseases with high mortality rates globally, such as stroke and ischemic heart disease. Engineered bio-nanomaterials are now under active investigation as carriers of therapeutic and/or imaging agents to atherosclerotic plaques. This Review summarizes the latest bio-nanomaterial-based strategies for managing atherosclerosis published over the past five years, a period marked by a rapid surge in preclinical applications of bio-nanomaterials for imaging and/or treating atherosclerosis. To start, the biomarkers exploited by emerging bio nanomaterials for targeting various components of atherosclerotic plaques are outlined. In addition, recent efforts to rationally design and screen for bio nanomaterials with the optimal physicochemical properties for targeting plaques are presented. Moreover, the latest preclinical applications of bio-nanomaterials as carriers of imaging, therapeutic, or theranostic agents to atherosclerotic plaques are discussed. Finally, a mechanistic understanding of the interactions between bio-nanomaterials and the plaque ("athero-nano" interactions) is suggested, the opportunities and challenges in the clinical translation of bio nanomaterials for managing atherosclerosis are discussed, and recent clinical trials for atherosclerotic nanomedicines are introduced. PMID- 29239135 TI - Oxymatrine inhibits non-small cell lung cancer via suppression of EGFR signaling pathway. AB - Epidermal growth factor receptor (EGFR) plays a crucial role in human non-small cell lung cancer (NSCLC) tumorigenesis. In this study, oxymatrine was identified as an EGFR signaling pathway inhibitor in NSCLC. Oxymatrine inhibited anchorage dependent and independent growth of NSCLC cell lines but had no cytotoxicity in normal lung cells. We found that exposure to oxymatrine not only suppressed the activity of wild-type EGFR but also inhibited the activation of exon 19 deletion and L858R/T790M mutated EGFR. Flow cytometry analysis suggested that oxymatrine induced cell cycle G0/G1 arrest was dependent on EGFR-Akt signaling. Exogenous overexpression of Myr-Akt rescued cyclin D1 expression in HCC827 cells. Moreover, oxymatrine prominently suppressed tumor growth in a xenograft mouse model. Thus, oxymatrine appears to be a novel therapeutic agent for NSCLC treatment. PMID- 29239136 TI - Composite Polymer Colloids for SERS-Based Applications. AB - Polymers and nanoparticles can be combined into different materials with applications in various fields like catalysis, biotechnology, or drug delivery, to cite just a few. Colloidal composites may vary significantly, ranging from a single nanoparticle stabilized by a polymer shell through a polymeric carrier decorated with hundreds of particles. We review here composite colloids comprising gold nanoparticles, with an emphasis in systems with potential application in surface enhanced Raman scattering (SERS). The focus is on selected strategies for synthesis and functionalization, such as: encapsulation of gold nanoparticles by amphiphilic polymers, polymeric matrices as nanoparticle carriers and smart polymer based composites. We stress the benefits derived from the combination of polymers and metal particles toward SERS, such as chemical and colloidal stabilization in complex environments, and collective optical effects through hot spot generation for optimized SERS enhancement or improved imaging tags. PMID- 29239137 TI - Medical management of gastric cancer: a 2017 update. AB - Gastric cancer remains a considerable health burden throughout the world. The Cancer Genome Atlas (TCGA) analysis has recently unveiled 4 genotypes of gastric cancer with data not ready to change treatment strategy yet. A multimodality approach to therapy is the cornerstone of screening, diagnosing, staging, treating and supporting patients with gastric cancer. The evidence-based approach to localized gastric cancer (>cT1b) is to use an either preoperative or postoperative strategy to maximize the benefit of surgery. The focus of future research is to optimize chemotherapy regimens, determine the role of radiation therapy and investigate the effect of treatment timing. In metastatic gastric cancer, biologic therapies have been introduced targeting markers shown to be prognostic. The results of ongoing randomized controlled phase 3 trials using targeted and immunotherapy agents, either in combination or alone, have the potential to alter the current treatment landscape of advanced gastric cancer. PMID- 29239138 TI - Greater Reward-Related Neuronal Response to Hedonic Foods in Women Compared with Men. AB - OBJECTIVE: The current study aimed to identify how sex influences neurobiological responses to food cues, particularly those related to hedonic eating, and how this relates to obesity propensity, using functional magnetic resonance imaging (fMRI). METHODS: Adult men and women who were either obesity resistant (OR) or obesity prone (OP) underwent fMRI while viewing visual food cues (hedonic foods, neutral foods, and nonfood objects) in both fasted and fed states. RESULTS: When fasted, a significant sex effect on the response to hedonic vs. neutral foods was observed, with greater responses in women than men in the nucleus accumbens (P = 0.0002) and insula (P = 0.010). Sex-based differences were not observed in the fed state. No significant group effects (OP vs. OR) or group-by-sex interactions were observed in fasted or fed states. CONCLUSIONS: Greater fasted responses to hedonic food cues in reward-related brain regions were observed in women compared with men, suggesting that women may be more sensitive to the reward value of hedonic foods than men when fasted. This may indicate sex-dependent neurophysiology underlying eating behaviors. PMID- 29239139 TI - BTG2 is a tumor suppressor gene upregulated by p53 and PTEN in human bladder carcinoma cells. AB - Although widely deemed as a tumor suppressor gene, the role of B-cell translocation gene 2 (BTG2) in bladder cancer is still inconclusive. We investigated the role and regulatory mechanism of BTG2 in bladder cancer. BTG2 expression in human bladder tissues was determined by RT-qPCR and immunoblotting assays. Expressions of BTG2 and PTEN in bladder carcinoma cells were determined by immunoblotting, RT-qPCR, or reporter assays. The 3 H-thymidine incorporation assay, flow cytometry, and the xenograft animal model were used to determine the cell growth. BTG2 expression was lower in human bladder cancer tissues than normal bladder tissues. Highly differentiated bladder cancer cells, RT4, expressed higher BTG2 than the less-differentiated bladder cancer cells, HT1376 and T24. Overexpression of BTG2 in T24 cells inhibited cell growth in vitro and in vivo. Camptothecin and doxorubicin treatments in RT-4 cells or transient overexpression of p53 into p53-mutant HT1376 cells induced p53 and BTG2 expression. Further reporter assays with site-mutation of p53 response element from GGGAAAGTCC to GGAGTCC within BTG2 promoter area showed that p53-induced BTG2 gene expression was dependent on the p53 response element. Ectopic PTEN overexpression in T24 cells blocked the Akt signal pathway which attenuated cell growth via upregualtion of BTG2 gene expression, while reverse effect was found in PTEN-knockdown RT-4 cells. PTEN activity inhibitor (VO-OHpic) treatment decreased BTG2 expression in RT-4 and PTEN-overexpressed T24 cells. Our results suggested that BTG2 functioned as a bladder cancer tumor suppressor gene, and was induced by p53 and PTEN. Modulation of BTG2 expression seems a promising way to treat human bladder cancer. PMID- 29239140 TI - Acquired myospherulosis secondary to gluteal augmentation on fine needle aspiration cytology: A diagnostic challenge. AB - A 30-year-old female presented with a three-month history of a multilocular cystic lesion over the lumbosacral spine. Fine-needle aspiration biopsy (FNA) of the lesion was performed at an outside institution, and a cytologic diagnosis, suspicious for chordoma, was rendered. The patient presented for surgical consultation at our institution. Repeat FNA demonstrated an unusual fat-like material. Upon further inquiry, the patient provided a recent history of gluteal contour improvement with fibroadipose tissue implants. A diagnosis of myospherulosis was made with a concurrent surgical pathology correlation. No evidence of chordoma was identified. To date, this is the first reported case of acquired myospherulosis in the context of gluteal contour enhancement and represents an important diagnostic pitfall to consider on cytology preparations. PMID- 29239141 TI - Characterizing the Pattern of Weight Loss and Regain in Adults Enrolled in a 12 Week Internet-Based Weight Management Program. AB - OBJECTIVE: Although the trajectory of weight change during and/or after behavioral weight management interventions is believed to include a period of weight loss followed by maintenance and later regain, the sparse data produced by existing study designs (conducting assessments at 3- to 6-month intervals) have limited investigation into the precise pattern. METHODS: Seventy-five adults were asked to self-weigh daily via "smart" scales during a 12-week, Internet-based weight loss program and for an additional 9 months with no further intervention. Longitudinal change-point mixed-effect models were used to characterize overall weight change patterns and identify when individuals moved from weight loss to maintenance/regain. RESULTS: Analyses suggested a three-phase model. During the first phase, participants lost weight at a (mean +/- SE) rate of -0.46 +/- 0.04 kg/wk; after 77.66 +/- 3.96 days, they transitioned to regain (0.07 +/- 0.02 kg/wk). The next transition occurred at 222.55 +/- 7.23 days, after which the rate of regain decreased slightly (0.06 +/- 0.02 kg/wk). Exploratory analyses identified baseline/demographic factors predicting the timing of transition points and slope of weight change within phases. CONCLUSIONS: In contrast to the hypothesized trajectory, results demonstrated that participants transitioned immediately from weight loss to regain (with no "maintenance" period) and later to a slower rate of regain. Future studies should investigate whether extended care programs change or merely delay this pattern. PMID- 29239142 TI - Insufficiency of a Damus-Kaye-Stansel anastomosis in a Fontan patient: Transfemoral implantation of an Edwards Sapien 3 valve. AB - We present a 22-year-old patient with a univentricular heart who had already undergone five open heart surgeries including a Damus-Kaye-Stansel procedure, Fontan completion and tricuspid valve replacement. In addition, epimyocardial pacemaker implantation and repeated revisions had been necessary. He developed symptomatic free regurgitation of the pulmonary portion of his DKS anastomosis. To avoid additional high-risk open-heart surgery, we successfully implanted an Edwards Sapien 3 valve transfemorally in the pulmonary portion of the DKS anastomosis relieving insufficiency. PMID- 29239143 TI - Role of Plasmapheresis in the Management of Acute Kidney Injury in Patients With Multiple Myeloma: Should We Abandon It? AB - The aim of the current study was to determine whether plasmapheresis in combination with chemotherapy could significantly remove free light chains (FLC) in multiple myeloma (MM) patients with acute kidney injury (AKI) and therefore improve renal recovery and patient survival. During the study period, 29 patients with MM and AKI presented to our unit and were treated with two different therapy modalities (plasmapheresis with chemotherapy or bortezomib). At the end of treatment, a significant decrease of FLCs was present in the group treated with plasmapheresis compared to the bortezomib group. Patients treated with plasmapheresis had similar survival compared to patients treated with bortezomib. There was a significantly higher decrease of FLCs and longer survival in patients treated with three or more plasmapheresis sessions than in patients treated with two plasmapheresis sessions. Plasmapheresis therapy still remains a useful and effective method in the treatment of AKI in MM patients. Plasmapheresis significantly reduces FLCs compared to bortezomib especially with higher number of plasma exchange sessions but it must be combined with other chemotherapy agents in order to prolong renal recovery and therefore patient survival. PMID- 29239144 TI - SMG-1 inhibition by miR-192/-215 causes epithelial-mesenchymal transition in gastric carcinogenesis via activation of Wnt signaling. AB - SMG-1,a member of the phosphoinositide kinase-like kinase family, functioned as a tumor suppressor gene. However, the role of SMG-1 in GC remain uncharacterized. In this study, regulation of SMG-1 by miR-192 and-215, along with the biological effects of this modulation, were studied in GC. We used gene microarrays to screening and luciferase reporter assays were to verify the potential targets of miR-192 and-215. Tissue microarrays analyses were applied to measure the levels of SMG-1 in GC tissues. Western blot assays were used to assess the signaling pathway of SMG-1 regulated by miR-192 and-215 in GC. SMG-1 was significantly downregulated in GC tissues.The proliferative and invasive properties of GC cells were decreased by inhibition of miR-192 and-215, whereas an SMG-1siRNA rescued the inhibitory effects. Finally, SMG-1 inhibition by miR-192 and-215 primed Wnt signaling and induced EMT. Wnt signaling pathway proteins were decreased markedly by inhibitors of miR-192 and-215, while SMG-1 siRNA reversed the inhibition apparently. Meanwhile, miR-192 and-215 inhitibtors increased E-cadherin expression and decreased N-cadherin and cotransfection of SMG-1 siRNA reversed these effects. In summary, these findings illustrate that SMG-1 is suppressed by miR-192 and-215 and functions as a tumor suppressor in GC by inactivating Wnt signaling and suppressing EMT. PMID- 29239146 TI - Vorinostat enhances the anticancer effect of oxaliplatin on hepatocellular carcinoma cells. AB - Oxaliplatin-based systemic chemotherapy has been proposed to have efficacy in hepatocellular carcinoma (HCC). We investigated the combination of vorinostat and oxaliplatin for possible synergism in HCC cells. SMMC7721, BEL7402, and HepG2 cells were treated with vorinostat and oxaliplatin. Cytotoxicity assay, tumorigenicity assay in vitro, cell cycle analysis, apoptosis analysis, western blot analysis, animal model study, immunohistochemistry, and quantitative PCR were performed. We found that vorinostat and oxaliplatin inhibited the proliferation of SMMC7721, BEL7402, and HepG2 cells. The combination index (CI) values were all <1, and the dose-reduction index values were all greater than 1 in the three cell lines, indicating a synergistic effect of combination of the two agents. Coadministration of vorinostat and oxaliplatin induced G2/M phase arrest, triggered caspase-dependent apoptosis, and decreased tumorigenicity both in vitro and in vivo. Vorinostat suppressed the expression of BRCA1 induced by oxaliplatin. In conclusion, cotreatment with vorinostat and oxaliplatin exhibited synergism in HCC cells. The combination inhibited cell proliferation and tumorigenicity both in vitro and in vivo through induction of cell cycle arrest and apoptosis. Our results predict that a combination of vorinostat and oxaliplatin may be useful in the treatment of advanced HCC. PMID- 29239147 TI - Crowdsourced Asparagus Urinary Odor Population Kinetics. AB - The consumption of asparagus is associated with the production of malodorous urine with considerable interindividual variability (IIV). To characterize the urinary odor kinetics after consumption of asparagus spears, we conducted a study with consenting attendees from two American Society for Clinical Pharmacology and Therapeutics (ASCPT) meetings. Subjects were randomized to eat a specific number of asparagus spears, and then asked to report their urinary odor perception. Eighty-seven subjects were included in the final analysis. A mixed effect proportional odds model was developed that adequately characterized the dose response relationship. We estimated the half-life of the asparagus effect on malodorous urine to be 4.7 hours (relative standard error (RSE) = 13.2%), and identified a dose-response slope term with good precision (24.3%). Age was found as the predictor of IIV in slope estimates. This study design and tools can be used as a demonstration "crowdsourcing" project for studying population kinetics in organizational and educational settings. PMID- 29239148 TI - Effects of closed-loop intravenous anesthesia guided by Bispectral Index in adult patients on emergence delirium: a randomized controlled study. AB - BACKGROUND: Emergence delirium (ED) is an acute change in cognition after general anesthesia (GA) occurring in operative room, recovery room or in postanesthesia care. The automated propofol-remifentanil titration by Bispectral Index (BIS) (AutoTIVA) avoids period of deep (BIS<40) anesthesia and could potentially decrease the ED. The aim of this study was to evaluate ED in surgical patients under AutoTIVA, manual titration of propofol-remifentanil (ManualTIVA) or volatile BIS-guided GA. Moreover, we aimed to evaluate age-related postoperative Mini-Mental State Examination (MMSE) changes. METHODS: One hundred and thirty-two adult patients scheduled for elective urologic surgery were randomized in: AutoTIVA, desflurane (DES), sevoflurane (SEVO), ManualTIVA anesthesia. The MMSE was performed before GA and 15 minutes after tracheal extubation. RESULTS: The percentage of BIS 40-60 was significantly higher in the AutoTIVA compared to DES, SEVO and ManualTIVA (87% vs. 78 %, 58%, 39%, respectively; P<=0.001). The percentage of BIS<40 was significantly lower in AutoTIVA than in the other groups (P<0.001). No difference in hemodynamics was found among groups. Postoperative MMSE scores were similar to baseline in the AutoTIVA (26 [24-28] vs. 26 [23-28]) while they markedly decreased in all other groups (P<0.001). Postoperative MMSE decreased at any age. None experienced awareness was recorded. CONCLUSIONS: Our results suggest that patients treated with AutoTIVA performed better in the cognitive test compared to the other groups receiving manual target-controlled GA due to a higher adequate level of anesthesia measured by BIS. Cognitive tests should be performed to test ED in all patients undergoing GA. PMID- 29239149 TI - Agreement between ccNexfin CO-trek cardiac output and intermittent cold-bolus pulmonary thermodilution in a prospective multicenter study. AB - BACKGROUND: The ccNexfin System uses the CO-trek algorithm to analyze a non invasively obtained arterial pressure waveform and calculate cardiac output (NEXCO). It remains matter of debate whether NEXCO can replace invasive, pulmonary artery catheter-derived, cold-bolus pulmonary thermodilution cardiac output measurement (PACCO). This study aimed at testing NEXCO-PACCO agreement in a large sample size, multicenter study. We hypothesized that agreement between NEXCO and PACCO would be demonstrated by a mean accuracy (bias) <0.6 L/min with a percentage error <30%. METHODS: Patients undergoing cardiac surgery in three academic hospitals clinically requiring pulmonary artery catheterization were included. Exclusion criteria were aortic, pulmonary and tricuspid (valve) abnormalities, non-sinus rhythm and insufficient perfusion of the digits such as in Raynaud's disease. After induction of anesthesia, cardiac output was measured with four cold bolus thermodilution measurements and four averaged 30-second ccNexfin measurements randomized through the respiratory cycle to obtain one measurement pair. Mean accuracy and precision of ccNexfin were expressed as bias (mean of all NEXCO-PACCO differences) and limits of agreement (LOA) (1.96.SD of bias). Percentage error was calculated as [LOA / (NEXCO-PACCO average)]. RESULTS: Fifty-five patients were enrolled in the study, 51 completed the protocol. Median PACCO was 3.7 (IQR: 3.2 to 4.6) L/min and median NEXCO was 3.8 (IQR: 3.1 to 4.7) L/min. NEXCO-PACCO bias was 0.1 (LOA: -1.4 to +1.6) L/min with a 37% percentage error. CONCLUSIONS: In this study, cardiac output measurement with ccNexfin failed to meet the predefined criteria for agreement with cold-bolus pulmonary artery thermodilution. PMID- 29239150 TI - Gender differences in septic intensive care unit patients. AB - INTRODUCTION: The world population is mostly male at birth, although there is a shift in predominance over 55 years of age with more females than males. Male gender was recently hypothesized to be a risk factor for sepsis and septic shock; the reasons and the consequences of this odd discrepancy are yet a matter of debate. We investigated the percentage of males and females in a large number of trials performed on septic adult patients admitted to Intensive Care Units. EVIDENCE ACQUISITION: We analyzed all the multicenter randomized controlled trials ever published in peer-reviewed Journals reporting a significant effect on mortality in intensive care unit septic adult patients; furthermore, we retrieved all the manuscripts dealing with sepsis or septic shock patients published in the last 3 years in the three medical Journals with the highest impact factor. EVIDENCE SYNTHESIS: We analyzed data from 12 multicenter randomized controlled trials (for a total of 5080 patients, 61% males) and from further 22 trials published in the New England Journal of Medicine, the Lancet, and the Journal of the American Medical Association (for a total of 493,066 patients, 54% males). Data on gender ratio in survivors were not available. CONCLUSIONS: Data from 34 large studies on 498,146 septic adult patients clearly showed a prevalence of males despite the expected female predominance. Further studies are required to explain the reasons, to evaluate if a difference is present in survival rate, and to identify gender-tailored preventive measures and treatments. PMID- 29239145 TI - LINE-1 retrotransposons in healthy and diseased human brain. AB - Long interspersed element-1 (LINE-1 or L1) is a transposable element with the ability to self-mobilize throughout the human genome. The L1 elements found in the human brain is hypothesized to date back 56 million years ago and has survived evolution, currently accounting for 17% of the human genome. L1 retrotransposition has been theorized to contribute to somatic mosaicism. This review focuses on the presence of L1 in the healthy and diseased human brain, such as in autism spectrum disorders. Throughout this exploration, we will discuss the impact L1 has on neurological disorders that can occur throughout the human lifetime. With this, we hope to better understand the complex role of L1 in the human brain development and its implications to human cognition. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 434-455, 2018. PMID- 29239151 TI - An Observational Veneto Research on Ventilator-Associated Pneumonia (OVeRVAP): attributable mortality and cumulative incidence of ventilator-associated pneumonia. AB - BACKGROUND: The relationship between ventilator-associated pneumonia (VAP) and mortality varies from study to study, and its entity is uncertain due a considerable variation in the attributable mortality. The aim of this study was to evaluate the relationship between VAP frequency and mortality in a cohort of mechanically ventilated patients. METHODS: A multicenter prospective observational study was conducted in 21 Intensive Care Units (ICUs). The patients were recruited from 2008 to 2010 within randomly selected periods. 842 patients of 2595 admitted, met the eligibility criteria and were enrolled in the study. The study's primary outcome was death by any cause in one of the ICUs. We modelled VAP occurrence as a time-dependent covariate and fitted a competing risk analysis model. We estimated the attributable mortality of VAP as the population attributable fraction of ICU mortality. RESULTS: A total of 121 patients developed VAP (14.4%), for an incidence rate of 15.7 cases per 1000 ventilator days; of the 175 patients (20.8%) who died during the study period, 31 (25.6%) had VAP. The ICU mortality rate in the patients who developed VAP was 22.6 per 1000 ventilator days (95% CI: 15.9-32.1). We estimated an attributable mortality of 8.4%. CONCLUSIONS: In 8.4% of cases, VAP was the leading cause of death in our study. This indicates that the patients died more frequently with VAP rather than because of it. PMID- 29239152 TI - The safety and efficiency of a fast-track protocol for sleeve gastrectomy: a team approach. AB - BACKGROUND: Increasing numbers of morbid obese patients has led to increased numbers of bariatric procedures. Fast-track protocols are being developed to enhance the available resources, while maintaining a safe procedure. Reported results on safety merely apply to a mixed bariatric population. The objective was to evaluate safety and efficiency of the fast-track principles in patients undergoing sleeve gastrectomy. METHODS: Retrospective observational study including patients undergoing primary sleeve gastrectomy at the Obesity Centre of the Catharina Hospital Eindhoven, the Netherlands. Conventional perioperative care (CC) (2008-2011) versus a fast-track protocol (FT) (2011-2013), using short acting anesthetic agents, a multi-modal pain protocol to reduce opioids, and early mobilization. The main parameters for safety were intraoperative, early and late postoperative complications. Procedure time and hospital stay were used to evaluate efficiency. RESULTS: This study included 805 patients, 494 patients were subjected to the conventional care and 318 patients to fast-track protocol. A reduction of median operation time from 60 (CC) to 40 minutes (FT) (P<0.001) and a reduction in median length of hospital stay from three to two days (P=0.001), with a significant reduction in early postoperative complications (9.9% [CC] vs. 5% [FT], P=0.016) was achieved. The amount of late complications was comparable for both groups (5.1% [CC] vs. 4.4% [FT] [P=0.738]). CONCLUSIONS: Implementation of a fast-track protocol for sleeve gastrectomy is safe and efficient. It effectively reduces operation time and length of hospital stay, while improving postoperative outcome. This pleads for standard implementation of the fast-track protocol in sleeve gastrectomy. PMID- 29239153 TI - Time to change the classical vision of coagulation in liver disease: from the balance disequilibrium to systems biology network modeling. AB - The longstanding dogma that patients with liver disease have a hemostasis related bleeding tendency is neglected from the last 10 years however, despite this tremendous change of paradigm no longer progress had been made in this field. A mathematical model is a description of a system using mathematical concepts and language. Mathematical models are able to analyze large amount of data and they can make predictions about behavior. Mathematical models are used in the social sciences, engineering as well as in medicine. Blood coagulation in patients with liver disease is difficult to predict due to its network complexity and moreover, due to all factors that potentially can impact hemostasis in this patient population outside of the coagulation itself, as portal hypertension, endothelial dysfunction and renal injury, between others. Although ambitious and extremely complex, the aforementioned approach requires a substantial investment of multidisciplinary human and technologic resources, this holistic overview is the closest to the real situation. The ability of the mathematical modeling to predict bleeding and thrombotic complications in patients with liver disease deserves to be investigated. PMID- 29239154 TI - Neuromuscular block in laparoscopic surgery. AB - There is an increased interest in the current literature to evaluate the potential clinical benefit of a sustained deep neuromuscular blockade (i.e. a post-tetanic count <=3) during various laparoscopic surgical procedures. This deep block concept represents a new area of clinical research, which concerns both, anesthesiologists and surgeons. We reviewed a selection of recent publications about the indications and the potential benefits of a maintained deep neuromuscular blockade during different laparoscopic procedures. Moreover, the contribution of the diaphragmatic relaxation to the overall surgical conditions is also highlighted. There is convincing evidence that deep neuromuscular blockade compared to moderate neuromuscular block improves surgical conditions, at least for the following surgical procedures: laparoscopic cholecystectomy, prostatectomy, nephrectomy and laparoscopic bariatric surgery. Moreover, first evidence suggests that deep block may reduce perioperative surgical complications and improve patient's outcome. There are situations during laparoscopic surgery where a better communication between surgeon and anesthesiologist may improve patient's outcome. Moreover, clinical research has now to identify which additional procedures and type of patients may benefit most from this new deep block concept and ultimately, whether the implementation of a routine deep neuromuscular block may affect patient's outcome. PMID- 29239155 TI - Is ultrasound-guided cervical periradicular injection useful for cervical facet joint syndrome? PMID- 29239156 TI - Do patients require "escorts" or "carers" for discharge following day surgery and office-based anesthesia? Both sides of the debate explored. AB - Over the past few years, there has been a rapid rise in office-based procedures, out of hospital and day surgery procedures, particularly as an effort to combat the escalating costs of hospital-based services. Coincident with this burgeoning demand for office-based anesthesia, is the accompanying increased risk of anesthesia and sedation-related complications. In the 1990's and 2000's, the risk of mortality was higher for anesthetics and sedations performed outside of the operating theater setting. Although guidelines exist for ambulatory and office based anesthesia, they are being continuously reviewed and reconsidered. A challenge for office-based settings, is the expectation of having an "escort" available to assume responsibility for the patient at time of discharge from the post anesthesia care setting. Challenges in securing an escort can lead to delays, cancellations and same day patient "no shows." This expert review, the first one to ever be published on this topic, will explore the medicolegal, regulatory, pharmacologic and pharmacokinetic issues involved on both sides of this debate need to be carefully considered and understood, considering the pros and cons of requiring an escort for same day post anesthesia discharge. PMID- 29239157 TI - From balanced to precision anesthesia: a complex road map. PMID- 29239158 TI - Tailored anesthetic dosing: we need to straighten a few things out. PMID- 29239159 TI - Perioperative ultrasound: time to move forward! PMID- 29239160 TI - Facing up to limits: a lesson from the Charlie Gard case. PMID- 29239161 TI - Critical care ultrasound: beyond black and white imaging. PMID- 29239162 TI - Transorbital intracranial penetrating trauma with carotid artery injury: a multidisciplinary approach to management. PMID- 29239163 TI - False lateralization of pre-surgical work-up in a child with a cortical cavernous malformation and intractable epilepsy. PMID- 29239164 TI - Incidental schwannomas in patients with symptomatic lumbar stenosis. PMID- 29239165 TI - Peri-electrode edema after bilateral subthalamic deep brain stimulation for Parkinson's disease. PMID- 29239166 TI - Reply to Comment on "Identification of Major Sources of Atmospheric NH3 In An Urban Environment In Northern China During Wintertime". PMID- 29239167 TI - Molecular Layer Deposition-Modified 5A Zeolite for Highly Efficient CO2 Capture. AB - Effective pore mouth size of 5A zeolite was engineered by depositing an ultrathin layer of microporous TiO2 on its external surface and appropriate pore misalignment at the interface. As a result, a slightly bigger N2 molecule (kinetic diameter: 0.364 nm) was effectively excluded, whereas CO2 (kinetic diameter: 0.33 nm) adsorption was only influenced slightly. The prepared composite zeolite sorbents showed an ideal CO2/N2 adsorption selectivity as high as ~70, a 4-fold increase over uncoated zeolite sorbents, while maintaining a high CO2 adsorption capacity (1.62 mmol/g at 0.5 bar and 25 degrees C) and a fast CO2 adsorption rate. PMID- 29239169 TI - One-Step in Situ Detection of miRNA-21 Expression in Single Cancer Cells Based on Biofunctionalized MoS2 Nanosheets. AB - Here, we report the one-step in situ detection of targeted miRNAs expression in single living cancer cells via MoS2 nanosheet-based fluorescence on/off probes. The strategy is based on the folic acid (FA)-poly(ethylene glycol)-functionalized MoS2 nanosheets with adsorbed dye-labeled single-stranded DNA (ssDNA). Once the nanoprobes are internalized into cancer cells, the hybridization between the probes and target miRNA results in the detachment of dye-labeled ssDNA from MoS2 nanosheets surface, leading to the green fluorescence recovery. In this nanoprobe, MoS2 nanosheets offer advantages of high fluorescence quenching efficiency and extremely low toxicity. The FA conjugation could protect the probes and improve cancer cell transfection efficiency. The ability of this nanoprobe for endogenous miRNA detection in single living cancer cells is demonstrated for two types of cancer cells with different miRNA-21 expressions (MCF-7 and Hela cells). This functionalized MoS2 nanosheet-based nanoprobes could provide a sensitive and real-time detection of intracellular miRNA detection platform. PMID- 29239170 TI - Best-Matched Internal Standard Normalization in Liquid Chromatography-Mass Spectrometry Metabolomics Applied to Environmental Samples. AB - The goal of metabolomics is to measure the entire range of small organic molecules in biological samples. In liquid chromatography-mass spectrometry-based metabolomics, formidable analytical challenges remain in removing the nonbiological factors that affect chromatographic peak areas. These factors include sample matrix-induced ion suppression, chromatographic quality, and analytical drift. The combination of these factors is referred to as obscuring variation. Some metabolomics samples can exhibit intense obscuring variation due to matrix-induced ion suppression, rendering large amounts of data unreliable and difficult to interpret. Existing normalization techniques have limited applicability to these sample types. Here we present a data normalization method to minimize the effects of obscuring variation. We normalize peak areas using a batch-specific normalization process, which matches measured metabolites with isotope-labeled internal standards that behave similarly during the analysis. This method, called best-matched internal standard (B-MIS) normalization, can be applied to targeted or untargeted metabolomics data sets and yields relative concentrations. We evaluate and demonstrate the utility of B-MIS normalization using marine environmental samples and laboratory grown cultures of phytoplankton. In untargeted analyses, B-MIS normalization allowed for inclusion of mass features in downstream analyses that would have been considered unreliable without normalization due to obscuring variation. B-MIS normalization for targeted or untargeted metabolomics is freely available at https://github.com/IngallsLabUW/B-MIS-normalization . PMID- 29239168 TI - Variation in LOV Photoreceptor Activation Dynamics Probed by Time-Resolved Infrared Spectroscopy. AB - The light, oxygen, voltage (LOV) domain proteins are blue light photoreceptors that utilize a noncovalently bound flavin mononucleotide (FMN) cofactor as the chromophore. The modular nature of these proteins has led to their wide adoption in the emerging fields of optogenetics and optobiology, where the LOV domain has been fused to a variety of output domains leading to novel light-controlled applications. In this work, we extend our studies of the subpicosecond to several hundred microsecond transient infrared spectroscopy of the isolated LOV domain AsLOV2 to three full-length photoreceptors in which the LOV domain is fused to an output domain: the LOV-STAS protein, YtvA, the LOV-HTH transcription factor, EL222, and the LOV-histidine kinase, LovK. Despite differences in tertiary structure, the overall pathway leading to cysteine adduct formation from the FMN triplet state is highly conserved, although there are slight variations in rate. However, significant differences are observed in the vibrational spectra and kinetics after adduct formation, which are directly linked to the specific output function of the LOV domain. While the rate of adduct formation varies by only 3.6 fold among the proteins, the subsequent large-scale structural changes in the full-length LOV photoreceptors occur over the micro- to submillisecond time scales and vary by orders of magnitude depending on the different output function of each LOV domain. PMID- 29239171 TI - Thermoresponsive Arrays Patterned via Photoclick Chemistry: Smart MALDI Plate for Protein Digest Enrichment, Desalting, and Direct MS Analysis. AB - Sample desalting and concentration are crucial steps before matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) analysis. Current sample pretreatment approaches require tedious fabrication and operation procedures, which are unamenable to high-throughput analysis and also result in sample loss. Here, we report the development of a smart MALDI substrate for on-plate desalting, enrichment, and direct MS analysis of protein digests based on thermoresponsive, hydrophilic/hydrophobic transition of surface-grafted poly(N isopropylacrylamide) (PNIPAM) microarrays. Superhydrophilic 1-thioglycerol microwells are first constructed on alkyne-silane-functionalized rough indium tin oxide substrates based on two sequential thiol-yne photoclick reactions, whereas the surrounding regions are modified with hydrophobic 1H,1H,2H,2H perfluorodecanethiol. Surface-initiated atom-transfer radical polymerization is then triggered in microwells to form PNIPAM arrays, which facilitate sample loading and enrichment of protein digests by concentrating large-volume samples into small dots and achieving on-plate desalting through PNIPAM configuration change at elevated temperature. The smart MALDI plate shows high performance for mass spectrometric analysis of cytochrome c and neurotensin in the presence of 1 M urea and 100 mM NaHCO3, as well as improved detection sensitivity and high sequence coverage for alpha-casein and cytochrome c digests in femtomole range. The work presents a versatile sample pretreatment platform with great potential for proteomic research. PMID- 29239172 TI - Electrical Control of Shape in Voxelated Liquid Crystalline Polymer Nanocomposites. AB - Liquid crystal elastomers (LCEs) exhibit anisotropic mechanical, thermal, and optical properties. The director orientation within an LCE can be spatially localized into voxels [three-dimensional (3-D) volume elements] via photoalignment surfaces. Here, we prepare nanocomposites in which both the orientation of the LCE and single-walled carbon nanotube (SWNT) are locally and arbitrarily oriented in discrete voxels. The addition of SWNTs increases the stiffness of the LCE in the orientation direction, yielding a material with a 5:1 directional modulus contrast. The inclusion of SWNT modifies the thermomechanical response and, most notably, is shown to enable distinctive electromechanical deformation of the nanocomposite. Specifically, the incorporation of SWNTs sensitizes the LCE to a dc field, enabling uniaxial electrostriction along the orientation direction. We demonstrate that localized orientation of the LCE and SWNT allows complex 3-D shape transformations to be electrically triggered. Initial experiments indicate that the SWNT-polymer interfaces play a crucial role in enabling the electrostriction reported herein. PMID- 29239173 TI - Corrections to Methyl Mercury Formation in Hillslope Soils of Boreal Forests: The Role of Forest Harvest and Anaerobic Microbes. PMID- 29239174 TI - Comment on "Identification of Major Sources of Atmospheric NH3 in an Urban Environment in Northern China During Wintertime". PMID- 29239175 TI - Chemically Designed Metallic/Insulating Hybrid Nanostructures with Silver Nanocrystals for Highly Sensitive Wearable Pressure Sensors. AB - With the increase in interest in wearable tactile pressure sensors for e-skin, researches to make nanostructures to achieve high sensitivity have been actively conducted. However, limitations such as complex fabrication processes using expensive equipment still exist. Herein, simple lithography-free techniques to develop pyramid-like metal/insulator hybrid nanostructures utilizing nanocrystals (NCs) are demonstrated. Ligand-exchanged and unexchanged silver NC thin films are used as metallic and insulating components, respectively. The interfaces of each NC layer are chemically engineered to create discontinuous insulating layers, i.e., spacers for improved sensitivity, and eventually to realize fully solution processed pressure sensors. Device performance analysis with structural, chemical, and electronic characterization and conductive atomic force microscopy study reveals that hybrid nanostructure based pressure sensor shows an enhanced sensitivity of higher than 500 kPa-1, reliability, and low power consumption with a wide range of pressure sensing. Nano-/micro-hierarchical structures are also designed by combining hybrid nanostructures with conventional microstructures, exhibiting further enhanced sensing range and achieving a record sensitivity of 2.72 * 104 kPa-1. Finally, all-solution-processed pressure sensor arrays with high pixel density, capable of detecting delicate signals with high spatial selectivity much better than the human tactile threshold, are introduced. PMID- 29239176 TI - Development of Betalain Producing Callus Lines from Colored Quinoa Varieties (Chenopodium quinoa Willd). AB - Betalains are water-soluble plant pigments of hydrophilic nature with promising bioactive potential. Among the scarce edible sources of betalains is the grain crop quinoa (Chenopodium quinoa Willd), with violet, red, and yellow grains being colored by these pigments. In this work, callus cultures have been developed from differently colored plant varieties. Stable callus lines exhibited color and pigment production when maintained on Murashige and Skoog medium supplemented with the plant growth regulators 6-benzylaminopurine (8.88 MUM) and 2,4 dichlorophenoxyacetic acid (6.79 MUM) with a reduction of the nitrogen source to 5.91 mM. Pigment analysis by HPLC-DAD and ESI-MS/MS fully describes the content of individual pigments in the cell lines and allows the first report on the pigments present in quinoa seedlings. Phyllocactin and vulgaxanthin I are described as novel pigments in the species and show the potential of C. quinoa culture lines in the production of compounds of nutritional value. PMID- 29239177 TI - Observation of Exciton-Exciton Interaction Mediated Valley Depolarization in Monolayer MoSe2. AB - The valley pseudospin in monolayer transition metal dichalcogenides (TMDs) has been proposed as a new way to manipulate information in various optoelectronic devices. This relies on a large valley polarization that remains stable over long time scales (hundreds of nanoseconds). However, time-resolved measurements report valley lifetimes of only a few picoseconds. This has been attributed to mechanisms such as phonon-mediated intervalley scattering and a precession of the valley pseudospin through electron-hole exchange. Here we use transient spin grating to directly measure the valley depolarization lifetime in monolayer MoSe2. We find a fast valley decay rate that scales linearly with the excitation density at different temperatures. This establishes the presence of strong exciton-exciton Coulomb exchange interactions enhancing the valley depolarization. Our work highlights the microscopic processes inhibiting the efficient use of the exciton valley pseudospin in monolayer TMDs. PMID- 29239178 TI - Capillary Structured Suspensions from In Situ Hydrophobized Calcium Carbonate Particles Suspended in a Polar Liquid Media. AB - We demonstrate that capillary suspensions can be formed from hydrophilic calcium carbonate particles suspended in a polar continuous media and connected by capillary bridges formed of minute amounts of an immiscible secondary liquid phase. This was achieved in two different polar continuous phases, water and glycerol, and three different oils, oleic acid, isopropyl myristate, and peppermint oil as a secondary liquid phase. The capillary structuring of the suspension was made possible through local in situ hydrophobization of the calcium carbonate particles dispersed in the polar media by adding very small amounts of oleic acid to the secondary liquid phase. We observed a strong increase in the viscosity of the calcium carbonate suspension by several orders of magnitude upon addition of the secondary oil phase compared with the same suspension without secondary liquid phase or without oleic acid. The stability and the rheological properties of the obtained capillary structured materials were studied in relation to the physical properties of the system such as the particle size, interfacial tension between the primary and secondary liquid phases, as well as the particle contact angle at this liquid-liquid interface. We also determined the minimal concentrations of the secondary liquid phase at fixed particle concentration as well as the minimal particle concentration at fixed secondary phase concentration needed to form a capillary suspension. Capillary suspensions formed by this method can find application in structuring pharmaceutical and food formulations as well as a variety of home and personal care products. PMID- 29239180 TI - Correction to Effective Removal of Selenite and Selenate Ions from Aqueous Solution by Barite. PMID- 29239179 TI - Solid State Auto-Inversion of C-Centrochirality: Enantioselective Total Synthesis of Furocarbazolones (-)-epi-Claulansine D and (-)-Claulansine D and Pyranocarbazolone (+)-epi-Claulansine C. AB - Starting from dimethyl (E)-2-{[(1-tert-butoxycarbonyl)-1H-indol-3 yl]methylene}succinate and (R)-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde, facile synthesis of (-)-epi-claulansine D was accomplished via condensation and two intramolecular cyclizations. The (-)-epi-claulansine D in the solid state exists in a metastable form, and after an induction period of 30-90 days, it underwent complete epimerization to exclusively deliver the desired natural product (-)-claulansine D in quantitative yield. The witnessed inversion of C centrochirality in the solid state is conceptually novel and takes place for relatively higher crystal stability reasons. Base-catalyzed ring expansion of both (+/-)/(-)-epi-claulansine D and (+/-)/(-)-claulansine D resulted in (+/ )/(+)-epi-claulansine C in very good yields. PMID- 29239181 TI - Photolysis of Tertiary Amines in the Presence of CO2: The Paths to Formic Acid, alpha-Amino Acids, and 1,2-Diamines. AB - The photolysis of triethylamine (1a) in the presence of carbon dioxide leads to the hydrogenation of CO2, the alpha-C-C coupling of 1a, and the CO2 insertion into the alpha-C-H sigma-bond of amine 1a. This reaction is proposed to proceed through the radical ion pair [R3N*+.CO2*-] generated by the photoionization of amine 1a and the electron capture by CO2. The presence of lithium tetrafluoroborate in the reaction medium promotes the efficient and stereoselective alpha-C-C coupling of 1a by enhancing the production of alpha dialkylamino radicals and the isomerization of N,N,N',N'-tetraethylbutane-2,3 diamine (4a). PMID- 29239182 TI - Copper-Catalyzed Redox-Neutral Cyanoalkylarylation of Activated Alkenes with Cyclobutanone Oxime Esters. AB - The copper-catalyzed cyclization of activated alkenes with cyclobutanone O-acyl oximes under redox-neutral conditions has been reported. This facile protocol provided an efficient approach to a variety of cyanoalkylated oxindoles and dihydroquinolin-2(1H)-ones with a broad substrate scope and excellent functional group tolerance. In this reaction, sequential C-C bond cleavage, radical addition, and cyclization processes were involved, wherein multiple bonds were constructed in a one-pot reaction. Mechanistic studies suggest that the reaction probably proceeded via a radical pathway. PMID- 29239183 TI - Transition-Metal Free Oxidative Alkynylation of 2-Oxindoles with Ethynylbenziodoxolone (EBX) Reagents. AB - We report an efficient direct alkynylations of 3-alkyl/aryl 2-oxindoles employing ethynyl-1,2-benziodoxol-3(1H)-one (EBX) to afford a wide variety of 3-alkynyl-3 alkyl/aryl 2-oxindole under transition-metal free condition. In addition to activated carbonyl compounds viz. 2-oxindole-3-alkylcarboxylates, this direct alkynylations protocol works efficiently on 3-alkyl/aryl 2-oxindols as well thereby widening the scope even further. Eventually, a Pd(0)-catalyzed asymmetric decarboxylative allylation of few products is shown to furnish synthetically viable enantioenriched 2-oxindoles with C-3 quaternary stereocenters. PMID- 29239184 TI - Organocatalytic C(sp3)-H Functionalization via Carbocation-Initiated Cascade [1,5]-Hydride Transfer/Cyclization: Synthesis of Dihydrodibenzo[b,e]azepines. AB - Carbocation-initiated cascade [1,5]-hydride transfer/cyclization and dimerization reactions were developed to synthesize dihydrodibenzo[b,e]azepine and octahydrodipyrroloquinoline derivatives in high yields. These redox-neutral C(sp3)-H functionalization-involving cascade reactions feature transition-metal free, high atom- and step-economy, and environmental friendliness with water as the sole byproduct. PMID- 29239185 TI - Chemoselective Reduction of Sterically Demanding N,N-Diisopropylamides to Aldehydes. AB - A sequential one-pot process for chemoselectively reducing sterically demanding N,N-diisopropylamides to aldehydes has been developed. In this reaction, amides are activated with EtOTf to form imidates, which are reduced with LiAlH(OR)3 [R = t-Bu, Et] to give aldehydes by hydrolysis of the resulting hemiaminals. The non nucleophilic base 2,6-DTBMP remarkably improves reaction efficiency. The combination of EtOTf/2,6-DTBMP and LiAlH(O-t-Bu)3 was found to be optimal for reducing alkyl, alkenyl, alkynyl, and 2-monosubstituted aryl N,N diisopropylamides. In contrast, EtOTf and LiAlH(OEt)3 in the absence of base were found to be optimal for reducing extremely sterically demanding 2,6-disubstituted N,N-diisopropylbenzamides. The reaction tolerates various reducible functional groups, including aldehyde and ketone. 1H NMR studies confirmed the formation of imidates stable in water. The synthetic usefulness of this methodology was demonstrated with N,N-diisopropylamide-directed ortho-metalation and C-H bond activation. PMID- 29239186 TI - High-Yield Fabrication of Entangled Photon Emitters for Hybrid Quantum Networking Using High-Temperature Droplet Epitaxy. AB - Several semiconductor quantum dot techniques have been investigated for the generation of entangled photon pairs. Among the other techniques, droplet epitaxy enables the control of the shape, size, density, and emission wavelength of the quantum emitters. However, the fraction of the entanglement-ready quantum dots that can be fabricated with this method is still limited to around 5%, and matching the energy of the entangled photons to atomic transitions (a promising route toward quantum networking) remains an outstanding challenge. Here, we overcome these obstacles by introducing a modified approach to droplet epitaxy on a high symmetry (111)A substrate, where the fundamental crystallization step is performed at a significantly higher temperature as compared with previous reports. Our method drastically improves the yield of entanglement-ready photon sources near the emission wavelength of interest, which can be as high as 95% due to the low values of fine structure splitting and radiative lifetime, together with the reduced exciton dephasing offered by the choice of GaAs/AlGaAs materials. The quantum dots are designed to emit in the operating spectral region of Rb-based slow-light media, providing a viable technology for quantum repeater stations. PMID- 29239187 TI - [Immunotherapy for Bladder Cancer]. AB - Urothelial carcinoma is the most common urological malignancy. Nonspecific immunotherapy using the Bacillus Calmette-Guerin vaccine has long been the mainstay for the treatment of high-risk superficial bladder carcinoma in an adjuvant setting after transurethral endoscopic resection. In metastatic disease, cisplatin-based chemotherapy remains the main therapeutic modality. In Europe, the standard second-line chemotherapy for patients with cisplatin-refractory tumours is vinflunine. Other systemic treatments with a lower level of evidence include paclitaxel and docetaxel. Studies of tumour microenvironment indicate a significant role for the immune system in the pathogenesis of urothelial tumours and the presence of a CD8 lymphocyte infiltrate is associated with better survival. In urothelial tumours, the correlation between PD-L1 expression in the tumour and the response to PD-1/PD-L1 inhibitors has been repeatedly demonstrated in clinical studies. Several inhibitors of PD-1/PD-L1 pathway are undergoing advanced-phase clinical trials and atezolizumab, nivolumab, pembrolizumab, durvalumab, and avelumab have already have received permanent or temporary registration status in the United States, mostly as second-line treatments for patients progressing on cisplatin-based chemotherapy. Three of these agents are currently registered in Europe: nivolumab for second line treatment and atezolizumab and pembrolizumab for first line treatment in patients not eligible for cisplatin as well as and for second line treatment. These novel immunotherapeutic agents for bladder cancer are relatively well tolerated and therefore potentially useful for patients with contraindications or intolerance to platinum regimens. The main toxicities include asthenia/fatigue, lymphopenia, anaemia, musculoskeletal pain, decreased appetite, and nausea.Key words: bladder cancer - imunotherapy - PD-1 receptor - antibodies - monoclonal This work was supported by the Czech Ministry of Health CR - RVO Thomayer Hospital - TN 0064190. The author declare he has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 29. 8. 2017Accepted: 3. 10. 2017. PMID- 29239188 TI - [Evaluation of Inflammatory Cells (Tumor Infiltrating Lymphocytes) in Solid Tumors]. AB - BACKGROUND: The tumor microenvironment plays an important role in tumorigenesis and the tumor-host relationship. An important part of the tumor microenvironment is inflammatory infiltration. Its evaluation in solid tumors has prognostic meaning and appears also to be predictive of outcome, which is particularly important for predicting responses to immune checkpoint inhibitors. However, the methodology used to assess inflammatory infiltration is problematic, because it has been standardized only for certain types of tumors. OBJECTIVE: The present study provides an overview of current issues related to the evaluation of inflammatory cells (tumor infiltrating lymphocytes) in solid tumors, specifically in tumors of the breast, lung, head and neck, gastrointestinal tract, female genital tract, urogenital tract, brain, malignant mesothelioma, and malignant melanoma. Various methodologies for evaluation are mentioned, including the efforts that are being made to standardize these methodologies and the importance of immunophenotyping inflammatory infiltrates. With regard to clinical meaning, prognostic and predictive significance are also discussed. CONCLUSION: The evaluation of TILs in solid tumors often has predictive value; however, the results have been equivocal. There is also ambiguity about the predictive use of this marker. Despite all the methodological developments, which have resulted in the implementation of complicated technologies (image analysis, multiplex fluorescence immunohistochemistry, and mass spectrometry) for the evaluation of the various aspects of inflammatory infiltrates present in tumors, including their functional characteristics, there is still a need for standardization and development of inexpensive and universally available methodologies to enable the wide use of TIL evaluations in clinical settings. The recently proposed unified methodology may be used in all solid tumors and could help resolve one of the main limitations of the routine use of TIL, i.e., the inconsistent approach to assessment.Key words: solid tumors - tumor-infiltratig lymphocytes - inflammatory cells This work was supported by program of the Czech Ministry of Health No. RVO VFN 64165 and AZV project No. 16-30954A, Charles University and OPPK (CZ.2.16/3.1.00/24509). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 24. 9. 2017Accepted: 3. 10. 2017. PMID- 29239189 TI - [Immunotherapy in the Treatment of Lung Cancer]. AB - BACKGROUND: Lung cancer occupies the leading position of cancer incidence and mortality worldwide, including in the Czech Republic. Despite significant advances in systemic oncology treatments, lung cancer still has the worst prognosis, which is driving the need for innovative therapies and methods to treat this disease. Immunotherapy is a developing area of systemic oncology treatment, which has recently begun to be significantly applied to patients with lung carcinoma. The most useful type of immunotherapy currently employs checkpoint inhibitors, including CTLA-4 inhibitors (ipilimumab and tremelimumab) and PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, durvalumab, and avelumab). Except for monotherapy, different combinations of these inhibitors or combinations between one more of these inhibitors and chemotherapy or targeted treatment are being actively studied. Despite intensive investigations, anti tumor vaccines and cytokines have not had an important impact on the treatment of lung cancer. Checkpoint inhibitors have yielded favorable results, especially for the treatment of advanced (i.e., stage IIIB and IV) non-small cell lung cancer (NSCLC) and are being extensively investigated for the treatment of SCLC. AIM: The aim of this review was to summarize the most important achievements, possibilities, and perspectives of modern immunotherapy for the treatment of patients with lung cancer. CONCLUSION: Immunotherapy is an important tool in todays arsenal of oncology treatments, and for patients with lung cancer it offers the hope of prolonging life and img iprovints quality.Key words: immunotherapy - lung cancer - NSCLC - SCLC - checkpoint inhibitors This work was supported by National Sustainability Programme I No. LO1503 provided by Ministry of education, youth and sports and program No. 17-30748A devided by The Ministry of Health of the Czech Republic. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 31. 8. 2017Accepted: 7. 9. 2017. PMID- 29239190 TI - [Comparison of RECIST 1.1 and iRECIST for Response Evaluation in Solid Tumours]. AB - BACKGROUND: Immunotherapy is a relatively new and developing modality in oncological treatment, which may significantly improve treatment results for some patients with malignant tumors. With the increasing number of clinical trials, the demand for a suitable tool to assess and compare treatment responses is growing. Currently, the most common response assessment system for solid tumors is RECIST (response Evaluation Criteria in Solid Tumors) version 1.1. However, in immuno-oncology, a small percentage of patients manifest a new response pattern termed pseudoprogression, in which, after the initial increase in tumor burden or after the discovery of new lesions, a response or at least a prolonged stabilization of the disease can occur. This patient group would be included in the progression category when using RECIST 1.1 and effective treatment would be discontinued. Therefore, iRECIST criteria were established to capture the phenomenon of pseudoprogression, the need for PD confirmation (according to RECIST 1.1) was introduced, and changes were made in the evaluation of new lesions. AIM: The present work introduces criteria for the evaluation of oncological responses in solid tumors using RECIST version 1.1 and iRECIST immunotherapy variant (including a brief overview of previous immune criteria). These criteria are compared in an immuno-oncological context and their potential pitfalls are discussed. CONCLUSION: iRECIST criteria were established by expert consensus; however, sufficient data for final validation has not yet been collected. As a result, RECIST 1.1 should be the primary assessment system in immuno-oncology. The use of iRECIST should be reserved for research purposes (testing and validation). Distinguishing pseudoprogression from true PD in patients treated with immunotherapy remains a major challenge in oncological imaging.Key words: RECIST - response criteria - immunotherapy - measurement - tumor burden The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 24. 9. 2017Accepted: 3. 10. 2017. PMID- 29239191 TI - [Advances in Immunotherapy of Malignant Melanoma]. AB - Development of immunotherapy has dramatically changed poor prognosis of metastatic malignant melanoma (MM). Inhibition of immune checkpoints represents a new effective treatment. Monoclonal antibodies against CTLA-4 ipilimumab and against PD-1 (programme death 1) nivolumab and pembrolizumab prolong progression free survival and overall survival (OS) in patients with advanced metastatic MM. Both achieved significant improvement in relapse-free survival and OS also in adjuvant setting. It looks like the efficacy of the combined immunotherapy of ipilimumab with anti-PD-1 antibodies is superior to the monotherapy, but combined therapy is accompanied by higher toxicity. Management of adverse events of ipilimumab plus nivolumab combination were solved in several clinical trials. New combinations such as immunotherapy with intralesional oncolytic vaccination are explored. In this review, some results of clinical trials presented at ASCO (American Society of Clinical Oncology) 2017 are mentioned. Interesting data were obtained from the evaluation of long-term efficacy of immunotherapy in patients who had to stop the treatment for adverse events. Other trial (CheckMate 172) evaluated the safety and efficiency of nivolumab in MM patients who failed on or after therapy with ipilimumab. Considerable attention has been paid to the efficacy of immunotherapy in the treatment of brain metastases.Key words: malignant melanoma - immunotherapy - ipilimumab - nivolumab - pembrolizumab - talimogene laherparepvec - brain metastases The author declares she no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 31. 8. 2017Accepted: 24. 10. 2017. PMID- 29239192 TI - [Combined Regimens in Immunotherapy]. AB - The advent of immunotherapy has changed our concept of how to manage metastatic disease. With the exception of relatively rare tumors, the treatment of metastatic cancer is still considered as palliative, and in systemic treatment immunotherapy is often selected, considering better tolerance. Immunotherapy opens the perspective of a long-term, possibly durable, response, and, in contrast to other approaches to targeted therapy, is active across a spectrum of tumors. Combined regimens that increase the efficacy, given the context, are thus of importance. The most promising results are currently obtained using a combination of ipilimumab and nivolumab for the treatment of metastatic malignant melanoma and metastatic renal cell carcinoma. Toxicity of the treatment can be managed by supportive care, and combination immunotherapy is gradually becoming established as a standard option in the management of these two neoplastic disorders. Moreover, additional trials using a combination of ipilimumab and nivolumab to treat other tumors are underway as well as studies of other combinations, including those that employ antibodies acting on immune checkpoints in combination with other targeted agents or cytotoxic chemotherapy. Other options include combinations with surgical therapy, i.e., adjuvant or neoadjuvant administration of immunotherapy or with radiotherapy based on the abscopal effect of radiation. Thus, although the results of combination immunotherapy are very promising, this strategy is still in its infancy. Thus, only the next generation of clinical trials will be able to determine to what extent these combined regimens can meet the high expectations of medical oncologists and the general public.Key words: immunotherapy - ipilimumab - nivolumab - pembrolizumab The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 27. 9. 2017Accepted: 3. 10. 2017. PMID- 29239193 TI - [Checkpoint Inhibitors in the Treatment of Upper Gastrointestinal Tract Tumors]. AB - Chemotherapy prolongs overall survival (OS) in esophageal (EC) and gastric cancer (GC). Unsatisfactory results of systemic therapy initiated a search for new treatment options. In metastatic disease, a number of targeted drugs were tested; however, several phase III studies assessing receptor tyrosin kinase-related signaling pathways, such as EGFR, MET/HGF or mTOR, failed. Trastuzumab remains the only targeted drug with a known molecular predictor, which extended the OS in metastatic gastric adenocarcinoma and adenocarcinoma of esophago-gastric junction. In the past two years, The Cancer Genome Atlas group published an analysis based on the genomic characteristics of GC and EC. Therefore, a better understanding of tumor biology may be a way towards stratification of treatment based on genetic and molecular characteristics and not merely on anatomical or histological basis. The rapid development in research of anti-tumor immunity and an achievement in the field of checkpoint inhibitors use in malignant melanoma have also enabled research in other cancers, including gastrointestinal malignancies. Checkpoints are part of a comprehensive and complex process of the immune system, and at the same time, the key points in the emergence of tumor tolerance. Their activation protects the organism against autoimmune reactions, but at the same time allows induction of tumor tolerance. Discussing checkpoints include the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD 1) receptors and the ligand PD-1 receptor, programmed death ligand-1 (PD-L1). In this article, I summarize current findings on the use of anti PD1 agents in EC and GC.Key words: esophageal cancer - stomach cancer - checkpoint inhibitors This work was supported by the project of Ministry of Health of the Czech Republic No. 15 P03- 17-29389A and by projects LO1413, DRO and LM15089 BBMRI-CZ. The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 17. 9. 2017Accepted: 5. 11. 2017. PMID- 29239194 TI - [Immunotherapy of Renal Cell Carcinoma]. AB - Treatment of renal cell carcinoma is still palliative. Targeted therapy increases response rates and prolongs overall survival and progression-free survival compared with cytokines and chemotherapy. Checkpoint inhibitors constitute the up date of therapeutic approaches, and anti-PD-1 antibody, one checkpoint inhibitor, is now well established as a second and/or third palliative treatment for patients with renal cell carcinoma. In this study, we present the latest data from current studies on cytokines, cancer vaccines, ipilimumab, and nivolumab. The therapeutic efficacies of combinations such as targeted therapy with immune checkpoint inhibitors and anti-CTLA-4 with anti PD-1 (-L1) have been reported in many studies. Preliminary results are encouraging but the high toxicities and elevated cost are limiting. Treatments with combinations of bevacizumab and atezolizumab, axitinib and pembrolizumab or avelumab, lenvatinib and pembrolizumab, and nivolumab and ipilimumab (results from study phase I, II, and sometimes III) are reported to be highly effective and to result in long-lasting responses with response-rates of 70-100%. So far, valid predictors for these therapies have not been forthcoming, but considerable work is being exerted in this area. Heng and Memorial Sloan Kettering Cancer Center (MSKCC) models are still being used to select patients for immunotherapy. Immunotherapy will definitely continue to play an important role in the treatment of patients with renal cell carcinoma; however, many questions remain.Key words: renal cell carcinoma - immunotherapy - checkpoint inhibitors - target therapy Supported by MH CZ - DRO (MMCI, 00209805) This work was supported by program of the Czech Ministry of Health No. P03-15-34 678A. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 16. 8. 2017Accepted: 7. 9. 2017. PMID- 29239195 TI - [Immunotherapy of Colorectal and Anal Carcinoma]. AB - BACKGROUND: The lower part of the digestive tract includes the large intestine, rectum and anus. Treatment algorithms of cancers in these localities have significant differences in both early and advanced stages. The vast majority of metastatic cases are incurable. A few years ago, it was generally accepted that gastrointestinal tumors are poorly immunogenic and modern immunotherapy would not work in gastrointestinal cancers. The breakthrough has become the recognition of the mismatch repair system (MMR) that affects the microsatellite instability (MSI) and its role in the development of colorectal carcinoma (CRC). Metastatic colorectal carcinoma (mCRC) with defect MMR (dMMR) and MSI-H, resp. is immunogenic and can be a target of modern imunotherapy directed on the PD1/PD-L1 axis. Such a treatment can improve prognosis and life quality od patients with mCRC MSI-H. Immunotherapy effectiveness was shown also in a subgroup of patients with a BRAF mutation where the effectiveness of existing systemic treatment is low. The proven predictive factor is dMMR/MSI-H. PD-1 expression does not have this significance. Results of clinical studies with nivolumab and pembrolizumab result in the inclusion of these drugs in mCRC treatment algorithms. Phase II study shows nivolumab effectiveness also in pretreated metastatic anal cancer. PURPOSE: An overview of basic information on the possibilities of immunotherapy in CRC and anal cancers.Key words: cancer immunotherapy - checkpoint inhibitors - colorectal cancer - anal cancer - nivolumab - pembrolizumab Supported by MH CZ - DRO (MMCI, 00209805) I declare that, in connection with the abovementioned contribution, which I am an author, I have a conflict of interest with the following companies: BMS, Roche, Merck, Amgem and Bayer. The author declares he has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 7. 9. 2017Accepted: 5. 11. 2017. PMID- 29239196 TI - Clinical experience of positron-emission tomography in infective aortic disease. AB - Background Fluorine-18-fluorodeoxyglucose positron-emission tomography with computed tomography has revolutionized medical diagnosis by adding functional activity to anatomic imaging. We report our experience with this technique in patients with mycotic aortic pathology and aortic vascular graft infection. Methods We conducted a retrospective review of a prospective database of patients who underwent 18F-fluorodeoxyglucose positron-emission tomography with computed tomography for suspected infective aortic disease. From 2012 to 2016, 13 patients underwent 18F-fluorodeoxyglucose positron-emission tomography. Of these, 9 (69%) had a vascular graft infection (5 infrarenal aorta, 1 para-visceral, 2 descending, and 1 arch; 2 had previous open surgery and 7 had endovascular interventions) and 4 (31%) had a mycotic aneurysm (2 aortic arch, 1 infrarenal aorta, and 1 distal aorta and common iliac; 3 had endografts). The indications for imaging, location of pathology, 18F uptake, and clinical outcomes were analyzed. Results Eight (62%) patients had a single scan and 5 (38%) had serial scans performed. Among the 5 patients who had serial imaging, 3 showed decreased 18F uptake and 2 had increased uptake. Only one patient underwent subsequent endograft removal; the others were treated with lifelong antibiotics. There were 5 (38%) deaths on follow-up. Conclusion 18F-fluorodeoxyglucose positron-emission tomography with computed tomography could be a valuable adjunct in the diagnosis and surveillance of patients with aortic infection. Serial scans may be useful for monitoring disease activity and response to antibiotic therapy. PMID- 29239197 TI - Maintaining Quality in Lower Volume Cardiac Surgery: A Blueprint From a Military Program. AB - Although there is a clear volume-outcome relationship in the field of cardiac surgery, the existence of high-performing programs with relatively low case volumes is well established. This report describes the programmatic and institutional processes in place at a lower volume cardiac surgery center in a US military hospital, which have been executed to optimally leverage available resources in the delivery of exemplary patient care. By implementing a highly collaborative practice, rigorous outcomes review, evidence-based standardized care pathways, consistent attending surgeon oversight for care delivery, careful case selection, and a mechanism for support from highly experienced outside cardiac surgeons, the cardiac surgery program at the authors' institution delivers care on par with its higher volume counterparts. A review of these practices and available supporting evidence may provide a model for other programs seeking success in this setting. PMID- 29239198 TI - Faecal microbiota transplantation for Clostridium difficile infection using a lyophilized inoculum from non-related donors: A case series involving 19 patients. AB - Faecal microbiota transplantation (FMT) has been reported to be effective in treating relapsing of refractory Clostridium difficile infections, although some practical barriers are limiting its widespread use. In this study, our objective was to evaluate the rate of resolution of diarrhea following administration of lyophilized and resolved FMT via a nasogastric (NG) tube. We recruited 19 patients suffered from laboratory-confirmed C. difficile infection. Each of them was treated by lyophilized and resolved inoculum through a NG tube. One participant succumbed following the procedure due to unrelated diseases. Out of 18 cases, 15 patients reportedly experienced a resolution of the symptoms. One patient was treated with another course of antibiotics, and two of the non responders were successfully retreated with another course of FMT utilizing a lyophilized inoculum. Notably, no significant adverse activities were observed. In accordance to our clinical experiences, a patient will likely benefit from FMT treatment including lyophilized inoculum. PMID- 29239199 TI - Sequence analysis of Schmallenberg virus genomes detected in Hungary. AB - Since its emergence near the German-Dutch border in 2011, Schmallenberg virus (SBV) has been identified in many European countries. In this study, we determined the complete coding sequence of seven Hungarian SBV genomes to expand our knowledge about the genetic diversity of circulating field strains. The samples originated from the first case, an aborted cattle fetus without malformation collected in 2012, and from the blood samples of six adult cattle in 2014. The Hungarian SBV sequences shared >=99.3% nucleotide (nt) and >=97.8% amino acid (aa) identity with each other, and >=98.9 nt and >=96.7% aa identity with reference strains. Although phylogenetic analyses showed low resolution in general, the M sequences of cattle and sheep origin SBV strains seemed to cluster on different branches. Both common and unique mutation sites were observed in different groups of sequences that might help understanding the evolution of emerging SBV strains. PMID- 29239200 TI - Digital health and perioperative care. AB - According to the U.S. Food and Drug Administration 'the broad scope of digital health includes categories such as mobile health (mHealth), health information technology (IT), wearable devices, telehealth and telemedicine, and personalised medicine, and is used by providers and other stakeholders in their efforts to reduce inefficiencies, improve access, reduce costs, increase quality, and make medicine more personalised for patients (FDA 2016). More recently, Paul Sonier, a digital health strategist and founder of the Linkedin digital health group with more than 40,000 members, defined digital health as 'the convergence of the digital and genomic revolutions with health, healthcare, living, and society' (storyofdigitalhealth.com 2016). PMID- 29239201 TI - Cost effectiveness of preoperative screening for healthy patients undergoing robotic hysterectomy. AB - The objective of this study was to determine whether routine preoperative type and screen blood testing is cost effective and medically warranted for benign diagnosis in healthy patients undergoing robotic hysterectomy. The study was designed as a cross sectional retrospective descriptive study. Four hundred and twenty two medical records of American Society of Anesthesiologists (ASA) Classifications I and II patients undergoing robotically-assisted laparoscopic hysterectomy between 1 June 2011 and 31 May 2014 at a 211 bed regional medical center were analysed. The results from this study paralleled the findings of other published research. Preoperative type and screen testing was performed on 249 (59%) of the patients in the study. Ten patients (2.4% of the group) converted to open laparotomy. Mean estimated blood loss was 59.59ml. No perioperative transfusions were required. The results indicate that preoperative type and screen testing is not warranted for patients meeting the inclusion criteria. PMID- 29239202 TI - Validation of the TRUST tool in a Greek perioperative setting. AB - The aim of this study was to translate, culturally adapt and validate the TRUST questionnaire in a Greek perioperative setting. The TRUST questionnaire assesses the relationship between trust and performance. The study assessed the levels of trust and performance in the surgery and anaesthesiology department during a very stressful period for Greece (economic crisis) and offered a user friendly and robust assessment tool. The study concludes that the Greek version of the TRUST questionnaire is a reliable and valid instrument for measuring team performance among Greek perioperative teams. PMID- 29239203 TI - Access through altruism: A community-based free outpatient surgery program for the working poor in the United States. AB - Despite healthcare reform, a large population in the United States is without healthcare coverage. The Surgery for People in Need (SPIN) program offers free outpatient surgical procedures to working, uninsured adults. Taking nearly one year to construct, the program has been operational for three years and has performed 22 procedures. Free surgery programs can improve healthcare access by providing interventions to patients who otherwise have no outlet for surgical care. PMID- 29239206 TI - The Reliability and Validity of the Inventory of Callous Unemotional Traits: A Meta-Analytic Review. AB - In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, a Limited Prosocial Emotions specifier was added to the conduct disorder diagnostic criteria to designate a subgroup of children who exhibit callous unemotional (CU) traits. The Inventory of Callous Unemotional Traits (ICU) is the only dedicated measure of CU traits and was influential in the development of the Limited Prosocial Emotions specifier. Despite its role in the research and diagnosis of CU traits, some questions have persisted regarding the internal consistency and validity of the ICU and its three subscales: callous, uncaring, and unemotional. Results of a meta-analysis revealed acceptable internal consistency and external validity for total ICU, callous, and uncaring scores, but not unemotional scores. These results support the utility of the total ICU, callous, and uncaring scales, but indicate weaknesses in the scale or construct of unemotionality as it relates to interpersonal callousness, uncaring, and antisociality. PMID- 29239204 TI - John Hunter's operation for popliteal aneurysm. AB - An aneurysm is defined as a "sac communicating with the lumen of an artery" and the treatment of the various types of this disease has intrigued surgeons through the ages. Aneurysms of the popliteal artery today are fairly uncommon. However, in the 18th century they were quite frequently encountered, many of them in coach drivers. We can only surmise that this was the result of repetitive trauma to the artery, already the seat of arteriosclerosis, against the rim at the top of the long leather riding boot which was worn at that time. PMID- 29239207 TI - Psychometric Properties of the Impairment Rating Scale in Samples of Adults With Attention Deficit Hyperactivity Disorder. AB - Adults with attention deficit hyperactivity disorder (ADHD) are impaired in numerous domains. However, psychometrically sound measures assessing broad ranging impairment, particularly brief scales for diagnostic purposes, are scarce. The Impairment Rating Scale (IRS), originally developed to assess ADHD related impairment in children, has been adapted to a 12-item self-report measure of impairment in adults. In this study, the psychometric properties of the adult IRS were examined in three samples. In Studies 1 and 2, the adult IRS demonstrated good convergent, divergent, and incremental validity among college students and an online sample of adults, respectively. In the same studies, an appropriate clinical cutoff score was identified (IRS item score >=1) using diagnostic tests. In Study 3, the adult IRS demonstrated good interrater reliability between ratings provided by romantic partners. Overall, findings support the clinical utility of the adapted IRS for assessing the impairment diagnostic criterion for ADHD in adults. PMID- 29239208 TI - The Perceptual Maze Test Revisited: Evaluating the Difficulty of Automatically Generated Mazes. AB - The Elithorn perceptual maze test is widely used in clinical research and practice. However, there is little evidence of its psychometric properties, and its application is limited by the technical difficulty of developing more mazes. The current research aims to adopt a rigorous approach to evaluate 18 mazes that were automatically generated by a novel R software package. Various item response theory models were employed to examine the difficulty parameters. The findings suggested that the data best fitted the Rasch model. The linear logistic test model revealed meaningful contribution to the sources of maze difficulty. Additionally, the linear logistic test model plus error was considered the most parsimonious model. The Automatic Perceptual Maze Test was moderately correlated with a nonverbal intelligence test. By introducing more mazes to provide adequate information on participants' ability at all levels, the Automatic Perceptual Maze Test promises future clinical and research utility for the study of cognitive performance. PMID- 29239209 TI - Editorial Comment on: Perioperative Morbidity of Open Versus Minimally Invasive Partial Nephrectomy: A Contemporary Analysis of the National Surgical Quality Improvement Program by Pereira et al. PMID- 29239210 TI - Serum neuron-specific enolase levels at presentation and long-term neurological sequelae after acute charcoal burning-induced carbon monoxide poisoning. AB - OBJECTIVE: This study aimed to investigate whether clinical parameters and serum neuron-specific enolase (NSE) levels measured at emergency department (ED) presentation help stratify the risk of acute or delayed persistent severe neurological sequelae after acute carbon monoxide (CO) poisoning induced by charcoal burning. METHODS: This retrospective study included 236 patients who suffered from CO poisoning. Demographic information, serum NSE levels measured in the ED, treatment, clinical course, and long-term neurological outcomes were recorded. RESULTS: The median serum NSE level at presentation was 15.5 (10.9 22.7) ng/mL. No differences were observed in the duration of CO exposure; the initial Glasgow Coma Scale (GCS) score; the levels of arterial HCO3-, white blood cells (WBCs), C-reactive protein (CRP) or troponin I; or the frequency of abnormal diffusion-weighted imaging finding at presentation among the groups with different serum NSE levels at presentation. The incidences of acute and delayed persistent neurologic sequelae assessed at 22.3 months after acute charcoal CO poisoning were 5.1% and 8.5%, respectively. No difference in the NSE level was observed between patients stratified according to long-term neurological status. According to the multinomial logistic regression analysis, age, serum CRP levels and the initial GCS score were risk factors for the two types of persistent severe neurological sequelae, whereas troponin I levels were associated only with the acute persistent severe neurological sequelae. However, the adjusted NSE level was not a risk factor for any persistent neurological sequelae. CONCLUSIONS: Serum NSE levels at presentation were not correlated with the risk of acute or delayed persistent neurological sequelae. Further studies with blood sampling at optimal time points and serial measurements should be conducted. Age, initial GCS score, and CRP levels may be risk factors for persistent severe neurological sequelae. PMID- 29239211 TI - Editorial Comment on: Competency-Based Training and Simulation: Making a "Valid" Argument by Noureldin et al. PMID- 29239212 TI - Sarcoma family kinase activity is required for cortical spreading depression. AB - Objectives Sarcoma family kinase activity is associated with multiple diseases including ischemia and cancer; however, its role in the mechanism of migraine aura has been less well characterised. This study aims to investigate whether sarcoma family kinase is required for cortical spreading depression. Methods Cortical spreading depression was induced by topical application of K+ to the cerebral cortex and was monitored using electrophysiology in rats, and intrinsic optical signal in mouse brain slices. Drugs were perfused into the contralateral cerebral ventricle for pharmacological manipulations in rats. Western blot analysis was used for detecting the level of phosphorylated, and total, sarcoma family kinase in the ipsilateral cortex of rats. Key results The data demonstrate that a single cortical spreading depression in rats induced ipsilateral cortical sarcoma family kinase phosphorylation at the Y416 site. Deactivation of sarcoma family kinase by its inhibitor (3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1 H pyrazolo[3,4- dpyrimidin-4-amine) suppressed the elevated enzyme activity and cortical susceptibility to cortical spreading depression. Interestingly, the inhibitory effect of the N-methyl-D-aspartate receptor antagonist NVP-AAM077 on cortical spreading depression was reversed by the sarcoma family kinase activator pYEEI (EPQY(PO3H2)EEEIPIYL), suggesting a link between this enzyme and N-methyl-D aspartate receptors. Similarly, after deactivation of sarcoma family kinase, a reduction of sarcoma family kinase phosphorylation and cortical susceptibility to cortical spreading depression was observed with NVP-AAM077. Conclusions We conclude that activation of sarcoma family kinase is required for cortical spreading depression, and this process is regulated by recruiting N-methyl-D aspartate receptors. This study provides novel insight for sarcoma family kinase function in the mechanism of migraine aura. PMID- 29239213 TI - Features of aura in paediatric migraine diagnosed using the ICHD 3 beta criteria. AB - Background In children and adolescents, the prevalence rate of migraine with aura is 1.6%. Few studies concerning migraine with aura features in paediatric population have been reported. Aim The aim of our study was to investigate clinical features of aura in a retrospective cohort of children with migraine with aura. Furthermore, we studied whether the International Classification of Headache Disorder (ICHD) 3 beta version criteria could efficiently detect migraine with aura in a paediatric population. Results We included 164 patients who experienced aura associated with headache (mean age 9.92 +/- 2.64 years). When the ICHD-II criteria were used, a final diagnosis of migraine with typical aura was obtained in 15.3% of patients, probable migraine with typical aura in 13.4%, and typical aura with headache in 61.8%, while in in 9.5% of patients the diagnosis was undetermined. According to ICHD-3 beta, we diagnosed migraine with typical aura in 77.7% of patients, probable migraine with typical aura in 13.4%, and an undetermined diagnosis in 9.5% (less than two attacks). Conclusion Aura features did not depend on age and were similar to those of adults. However, the headache could be difficult to classify if headache duration was considered. In this view, the ICHD-3 beta offers the advantage of not considering headache features, including pain duration, for the diagnosis of migraine with typical aura, thus making this diagnosis easier in children and adolescents. PMID- 29239214 TI - Brainstem metastases treated with Gamma Knife stereotactic radiosurgery: the Indiana University Health experience. AB - Brainstem metastases offer a unique challenge in cancer treatment, yet stereotactic radiosurgery (SRS) has proven to be an effective modality in treating these tumors. This report discusses the clinical outcomes of patients with brainstem metastases treated at Indiana University with Gamma Knife (GK) radiosurgery from 2008 to 2016. 19 brainstem metastases from 14 patients who had follow-up brain imaging were identified. Median tumor volume was 0.04 cc (range: 0.01-2.0 cc). Median prescribed dose was 17.5 Gy to the 50% isodose line (range: 14-22 Gy). Median survival after GK SRS treatment to brainstem lesion was 17.2 months (range: 2.8-45.6 months). The experience at Indiana University confirms the safety and efficacy of range of GK SRS prescription doses (14-22 Gy) to brainstem metastases. PMID- 29239215 TI - Editorial Comment on: Predictive Factors for Achieving Superorior Pentafecta Outcomes Following Robot-Assisted Partial Nephrectomy in Patients with Localized Renal Cell Carcinoma by Kang et al. (From: Kang M, Gong I-H, Park HJ, et al. J Endourol 2017;31:1231-1236). PMID- 29239217 TI - Effects of occupational exposure to aluminium on some oxidative stress and DNA damage parameters. AB - AIM: The aim of this work was to investigate the relationships between aluminium levels, oxidative status and DNA damage in workers occupationally exposed to aluminium. SUBJECTS AND METHODS: This study was conducted in a secondary aluminium smelter. It included 96 male workers occupationally exposed to aluminium fume and dust compared to 96 male nonexposed individuals. Full history and clinical examination were done for all participants. Laboratory investigations in the form of serum aluminium, total antioxidant capacity (TAC), urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and comet assay test were performed. RESULTS: Serum aluminium level ranged from 4 to 30 ug/L of median: 10 ug/L; urinary 8-OHdG ranged from 2.7 to 17.2 ng/mg creatinine of median: 7.6 ng/mg creatinine; comet tail length (CTL) ranged from 19.7 to 50.5 um of median: 45 um, were statistically significantly increased in the exposed group compared to nonexposed group. In exposed workers, a statistically significant positive correlations were found between serum aluminium level and urinary 8-OHdG ( r = 0.75, p < 0.001); aluminium level and CTL ( r = 0.71, p < 0.001); and urinary 8 OHdG and CTL ( r = 0.71, p < 0.001). There was a statistically significant negative correlation between serum aluminium and TAC ( r = -0.76, p < 0.001). CONCLUSION: Occupational exposure to aluminium in secondary aluminium smelters was related to the induction of oxidative stress and DNA damage. This may promote the development of adverse health hazards in the exposed workers. PMID- 29239218 TI - The influence of aripiprazole and venlafaxine on the antidepressant-like effect observed in prenatally stressed rats (animal model of depression). AB - Depression is a nosological entity which may appear alone or concomitantly (e.g. in schizophrenia). Analysis of data from both clinical and experimental studies allows a conclusion that atypical antipsychotics, such as aripiprazole (ARI), may also be effective in treating depression in addition to antidepressants. The aim of the studies was to determine antidepressant efficacy of ARI, venlafaxine (VEN) and combined therapy using both drugs, in prenatally stressed rats (animal depression model) and control group. In addition, this article was aimed at determining the effect of these drugs on locomotor activity of these animals. The effect of chronic stress used in pregnant rats and the use of drugs such as ARI (1.5 mg/kg) and VEN (20 mg/kg) were studied in forced swimming test (FST; antidepressant effect) and locomotor activity test. Performed tests confirmed the antidepressant effect of ARI, VEN and efficacy of combined drugs in FST in both prenatally stressed rats (effect present upon single administration and after 7, 14 and 21 days of testing) and control group rats (effect present upon single administration and 7 days of testing). Moreover, upon single administration of the used drugs to prenatally stressed rats, it was found sedative effect - reduced animals' locomotor activity. Study results have proven antidepressant and sedative efficacy of ARI, VEN and combined administration of these drugs. Due to the small amount of data on the above preparations, in particular in the context of animal depression models, further studies in this respect are recommended. PMID- 29239216 TI - Protein depalmitoylases. AB - Protein depalmitoylation describes the removal of thioester-linked long chain fatty acids from cysteine residues in proteins. For many S-palmitoylated proteins, this process is promoted by acyl protein thioesterase enzymes, which catalyze thioester hydrolysis to solubilize and displace substrate proteins from membranes. The closely related enzymes acyl protein thioesterase 1 (APT1; LYPLA1) and acyl protein thioesterase 2 (APT2; LYPLA2) were initially identified from biochemical assays as G protein depalmitoylases, yet later were shown to accept a number of S-palmitoylated protein and phospholipid substrates. Leveraging the development of isoform-selective APT inhibitors, several studies report distinct roles for APT enzymes in growth factor and hormonal signaling. Recent crystal structures of APT1 and APT2 reveal convergent acyl binding channels, suggesting additional factors beyond acyl chain recognition mediate substrate selection. In addition to APT enzymes, the ABHD17 family of hydrolases contributes to the depalmitoylation of Ras-family GTPases and synaptic proteins. Overall, enzymatic depalmitoylation ensures efficient membrane targeting by balancing the palmitoylation cycle, and may play additional roles in signaling, growth, and cell organization. In this review, we provide a perspective on the biochemical, structural, and cellular analysis of protein depalmitoylases, and outline opportunities for future studies of systems-wide analysis of protein depalmitoylation. PMID- 29239219 TI - Multifunctional redox-responsive and CD44 receptor targeting polymer-drug nanomedicine based curcumin and alendronate: synthesis, characterization and in vitro evaluation. AB - The traditional therapy of cancer has systemic side effects, and many cancers, such as human breast cancer and lung cancer easily metastasize to bones, leading to the formation of secondary tumours. This study was aimed at enhancing the anti tumour effect of curcumin (CUR) and preventing tumour spread to the bone. A novel multifunctional redox-responsive and CD44 receptor targeting polymer-drug, poly alendronate-hyaluronan-S-S-curcumin copolymer (ALN-oHA-S-S-CUR) based CUR and alendronate (ALN) were synthesized successfully with the disulphide bond linker. The structure of ALN-oHA-S-S-CUR was characterized by 1H-NMR. The nanomedicine had natural anti-tumour drugs (CUR) as the hydrophobic kernel, and targeting CD44 receptor oligosaccharides of hyaluronan (oHA) and other anti-tumour drugs (ALN) as hydrophilic shell, named ALN-oHA-S-S-CUR conjugates, which could self-assemble into micelle-like nano-spheres in water via a dialysis method with hydrodynamic diameters of 179 +/- 23 nm. Interestingly, the cur-loaded ALN-oHA-S-S-CUR micelles were stable in PBS but were capable of releasing the drug under the reducing environment. The rate of drug release was proportional to the GSH concentration. The uptake and cytotoxicity of micelles were higher in MDA-MB-231 cells than in MCF-7 cells because of a higher expression of the CD44 receptor in the former cell line. And compared to the cur-loaded oHA-CUR micelles, the cur loaded ALN-oHA-S-S-CUR micelles had a good cellular uptake in 2D cancer cell and penetrability in 3D cancer cell spheroids. These results indicated the active targeting redox-sensitive micelles were promising as intracellular drug delivery systems for cancer treatment. PMID- 29239220 TI - Is It Time to Rethink the Notion of Carbapenem-Sparing Therapy Against Extended Spectrum beta-Lactamase-Producing Enterobacteriaceae Bloodstream Infections? A Critical Review. AB - OBJECTIVE: To present systematic recommendations for carbapenem-sparing therapy against extended-spectrum beta-lactamases (ESBLs) Enterobacteriaceae bloodstream infections (BSIs) derived from a critical review of clinical data. DATA SOURCES: A systematic literature search using PubMed and MEDLINE databases (January 1, 2012, to June 30, 2017) was performed using key MESH terms: ESBL or extended spectrum beta-lactamases and bacteremia or bloodstream infection with piperacillin/tazobactam, ciprofloxacin, levofloxacin, cefepime, cephamycins, carbapenem, doripenem, meropenem, and ertapenem. References within articles of interest were also evaluated. STUDY SELECTION AND DATA EXTRACTION: All English language trials were considered, and results were limited to clinical efficacy trials. Articles were screened by title and abstract for inclusion. DATA SYNTHESIS: Studies comparing noncarbapenem versus carbapenem therapy for ESBL BSIs were critically analyzed to identify heterogeneity among studies. Data abstracted included empirical or definitive therapy, patient population, dosing, source of infection and severity, infectious etiology, and outcome. CONCLUSIONS: Completely sparing carbapenem therapy cannot be justified among patients with ESBL BSIs. Determining the source of infection is critical to identify patients for whom carbapenem-sparing therapy is appropriate. PMID- 29239221 TI - High-density lipoprotein and cardiac glucose metabolism: Implications for management of acute coronary syndromes. PMID- 29239222 TI - Minimal Incision/Minimally Invasive Medializing Displacement Calcaneal Osteotomy. AB - : Minimally invasive techniques are readily applicable to calcaneal osteotomies and have the potential to accomplish hindfoot correction equivalent to open procedures with less morbidity and pain. Use of a guidance jig makes the procedure more predictable. While most anatomic features of the procedure are the same as those with open techniques, special care must be taken to avoid neurovascular injury because there is no open exposure. Anatomic guidelines have been established for appropriately localizing the osteotomy. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 29239223 TI - Raman, Infrared, and Laser-Induced Breakdown Spectroscopy Identification of Particles in Raw Materials. AB - Raw materials need to be of a certain quality with respect to physical and chemical composition. They also need to have no contaminants, including particles, because these could indicate raw material impurities or contaminate the product. Particle identification allows determination of process conditions that caused them and whether the quality of the final product is acceptable. Particles may appear to the eye to be very different things than they actually are. They may be coated with the raw material and may consist of several components; therefore, chemical and elemental analyses are required for accuracy in proper identification and definitive information about their source. Thus, microscope versions of Raman spectroscopy, laser-induced breakdown spectroscopy (LIBS), and infrared (IR) spectroscopy are excellent tools for identifying particles in materials. Those tools are fast and accurate, and can provide chemical and elemental composition as well as images that can aid identification. The micro-analysis capabilities allow for easy analysis of different portions of samples so that multiple components can be identified and sample preparation can be reduced or eliminated. The differences in sensitivities of Raman and IR spectroscopies to different functional groups as well as the elemental analysis provided by LIBS and the image analysis provided by the microscopy makes these complementary techniques and provides the advantage of identifying various chemical components. Proper spectral searching techniques and interpretation of the results are important for interpretation and identification of trace contaminants. PMID- 29239224 TI - Editorial Comment on: Age, Body Mass Index, and Gender Predict 24-Hour Urine Parameters in Recurrent Idiopathic Calcium Oxalate Stone Formers by Otto et al. (From: Otto BJ, Bozorgmehri S, Kuo J, et al. J Endourol 2017;31:1335-1341). PMID- 29239225 TI - Ureteroscopic High-Frequency Dusting Utilizing a 120-W Holmium Laser. AB - INTRODUCTION AND OBJECTIVE: Recently there has been interest in a dusting technique for lithotripsy during ureteroscopy (URS) utilizing high-frequency and low-pulse energy (HiFr-LoPE) settings. We assessed a 120-W holmium laser that permits high-frequency (>50 Hz) dusting. MATERIALS AND METHODS: Consecutive URS cases performed by a single surgeon using the P120H (Lumenis, San Jose, CA) were reviewed. Lithotripsy was performed using HiFr-LoPE settings (50-80 Hz/0.2-0.5 J [10-40 W]). Residual fragments (RFs) were determined on postoperative radiography, ultrasonography, or CT. Complications were classified using the Clavien-Dindo grade. RESULTS: URS was performed on 82 renal units (71 patients). Renal stones constituted the majority (73%), including four partial staghorn stones. Mean stone size and density (HU) were 12.5 mm (SD 8.7; range 5.0-50.0) and 993 (SD 353; range 230-1580), respectively. Ureteral access sheath was used in 15 (21%) patients. Mean total laser energy per case was 5.2 kJ (range 0.1 42.1). Dusting was exclusively performed in 84% of cases. Postoperative stents were placed in 91% (41% string). Zero-fragment and <=2 mm RF rates were 62.1% and 74.2%, respectively. There were 11 complications (13%) (grade 1 = 5, grade 2 = 6). The emergency department visit rate was 5.6%. There were no hospitalizations or reinterventions. CONCLUSIONS: Refinements in laser technology have expanded methods to ablate urinary stones. Outcomes utilizing a dusting technique demonstrated acceptable RF and complication rates. However, not all stones are amenable to dusting, and further study is needed to define the optimal role of this technique during laser lithotripsy. PMID- 29239226 TI - The Efficacy of Ureteroscopy Without Fluoroscopy for Ureteral and Renal Stones in Pediatric Patients. AB - OBJECTIVES: In the pediatric population, there have been significant improvements in the treatment of stones in recent years. Conventionally, ureteroscopy (URS) and/or retrograde intrarenal surgery are techniques performed with fluoroscopy. When using fluoroscopy, problems, including malignancy, may arise because of radiation exposure in the patient, physician, and operation room staff. The aim of this study is to evaluate the possibility of ureteroscopic treatment without fluoroscopy in children with ureteral and renal stones. MATERIALS AND METHODS: Between December 2010 and April 2017, pediatric patients were enrolled in this study. Data were retrospectively evaluated. URS was performed by the experienced surgeons in our center. Fluoroscopy was not routinely used during the operations. Demographic data, perioperative parameters, and success and complication rates were evaluated. RESULTS: Sixty-seven renal units from 61 patients were operated on. URS without fluoroscopy was achieved in 95.0% of 61 patients (95.5% of 67 renal units). Three patients needed fluoroscopy during the operation. The mean stone size was 12.4 +/- 5.3 mm, and the mean operation time was 41.9 +/- 15.1 minutes. The success rates in the postoperative first and third mounts were 82.1% (55 renal units) and 88.0% (59 renal units), respectively. For 10 patients, second-session URS without fluoroscopy was needed. Clinically insignificant residual fragments were detected in three patients. There were no major complications. CONCLUSION: URS without fluoroscopy for ureteral and renal stones in pediatric patients can be safely and effectively performed in experienced centers. PMID- 29239227 TI - Micro-Costing Analysis Demonstrates Comparable Costs for LithoVue Compared to Reusable Flexible Fiberoptic Ureteroscopes. AB - INTRODUCTION: Reusable ureteroscope durability and need for repair are significant sources of expense and inefficiency for patients and urologists. Utilization of LithoVueTM, a disposable flexible digital ureteroscope, may address some of these concerns. To identify its economic impact on clinical care, we performed a micro-cost comparison between flexible reusable fiberoptic ureteroscopes (URF-P6TM) and LithoVue. PATIENTS AND METHODS: For this prospective, single-center micro-costing study, all consecutive ureteroscopies performed during 1 week each in July and August 2016 utilized either URF-P6 or LithoVue ureteroscopes respectively. Workflow data were collected, including intraoperative events, postoperative reprocessing cycle timing, consumables usage, and ureteroscope cost data. RESULTS: Intraoperative data analysis showed mean total operating room time for URF-P6 and LithoVue cases were 93.4 +/- 32.3 and 73.6 +/- 17.4 minutes, respectively (p = 0.093). Mean cost of operating room usage per case was calculated at $1618.72 +/- 441.39 for URF-P6 and $1348.64 +/- 237.40 for LithoVue based on institutional cost rates exclusive of disposables. Postoperative data analysis revealed costs of $107.27 for labor and consumables during reprocessing for URF-P6 cases. The costs of ureteroscope repair and capital acquisition for each URF-P6 case were $957.71 and $116.02, respectively. The total ureteroscope cost per case for URF-P6 and LithoVue were $2799.72 and $2852.29, respectively. CONCLUSIONS: Micro-cost analysis revealed that the cost of LithoVue acquisition is higher per case compared to reusable fiberoptic ureteroscopes, but savings are realized in labor, consumables, and repair. When accounting for these factors, the total cost per case utilizing these two ureteroscopes were comparable. PMID- 29239228 TI - Comparison of Holmium Laser Enucleation and Plasmakinetic Resection of Prostate: A Randomized Trial with 72-Month Follow-Up. AB - PURPOSE: To evaluate the long-term and flexible cystourethroscopy results of holmium laser enucleation of the prostate (HoLEP) and to compare them with those of plasmakinetic resection of the prostate (PKRP). METHODS: In the long-term follow-up, variables, including the international prostatic symptomatic score, quality of life scores, maximum flow rate (Qmax), and international index of erectile function (IIEF), and the adverse events, including the need for retreatment, were specifically assessed. One hundred twenty-two HoLEP and 119 PKRP of the initial 280 patients included in this study were available, with 10 deceased and 29 lost to follow-up. RESULTS: We found that none of the assessable patients required reoperation for recurrent benign prostatic enlargement (BPE) in the HoLEP group, whereas two required reoperation in the PKRP group. There were no significant differences in most variables between the two groups in the long term results. But in terms of Qmax, transrectal ultrasound prostate volume, prostate specific antigen (PSA) level, IIEF-5 score, and long-term posttrial follow-up of flexible cystourethroscopy, the HoLEP group showed better results. CONCLUSION: The long-term follow-up data of this randomized trial confirm that HoLEP and PKRP are both effective and durable surgical interventions for the treatment of lower urinary tract symptoms due to BPE. Given the clinically relevant advantages associated with HoLEP, the alternation of PSA level, sexual function, and urination can be improved. PMID- 29239229 TI - In Vitro Evaluation of Single-Use Digital Flexible Ureteroscopes: A Practical Comparison for a Patient-Centered Approach. AB - OBJECTIVE: To compare the manufacturing and in vitro performance characteristics of two single-use flexible ureteroscopes with a permanent optical flexible ureteroscope. MATERIALS AND METHODS: Two single-use flexible ureteroscopes, LithoVue (Boston Scientific) and Pusen (1rs. generation; Zhuhai Pusen Medical Technology Company Limited, China), were tested and compared with a permanent Flex-X2 ureteroscope (Karl Storz, Germany) in terms of technical characteristics, optics, deflection mechanism, and additional parameters which could potentially affect surgical technique. RESULTS: Pusen was the lightest ureteroscope while the LithoVue had the longest working length. LithoVue had a higher resolution power than the other two ureteroscopes at all distances tested (p < 0.001). Pusen showed higher resolution than Flex-X2 (p < 0.01). Field of view was wider for LithoVue (87 degrees ), followed by Flex-X2 (85 degrees ) and Pusen (75 degrees ). Color representation was superior for Flex-X2 than LithoVue and then Pusen. LithoVue outperformed Pusen and Flex-X2 for all settings with instruments in terms of deflection loss (p < 0.01). Pusen had the highest irrigation flow (52 mL/min) with an empty working channel (p < 0.01). LithoVue and Pusen showed similar flow rates with a 200 MUm (21 mL/min) and 365 MUm laser fiber (7 mL/min) and 1.3F basket (18 mL/min), being superior to Flex-X2 (p < 0.01). With the 1.9F basket, LithoVue had superior flow rate (7 mL/min) than Pusen (3.5 mL/min) and Flex-X2 (4 mL/min; p = 0.01). CONCLUSION: LithoVue outperformed the other ureteroscopes in terms of optical resolution, field of view, deflection capacity, and irrigation flow with larger instruments. Pusen is the lighter scope and showed better results in terms of irrigation when no instruments are in place. Flex-X2 was superior in terms of color representation. PMID- 29239231 TI - Intratumoral cavernous-like malformation in subependymomas. PMID- 29239230 TI - Impact of a scribe program on patient throughput, physician productivity, and patient satisfaction in a community-based emergency department. AB - Previous literature on the impact of scribe programs varies and has mostly been reported from academic institutions or other clinics. We report the implementation of the scribe program in the emergency room of a community hospital and its impact on patient throughput, physician productivity, and patient satisfaction. We performed a quasi-experimental, before-and-after study measuring patient throughput metrics, physician productivity, and patient satisfaction. The intervention measuring the scribe implementation was divided into pre- and post-implementation periods. Patient throughput metrics were (1) door-to-room time, (2) room-to-doc time, (3) door-to-doc time, (4) doc-to disposition time, and (5) length of stay for discharged/admitted patients. Our secondary outcome was physician productivity, which was calculated by measuring total patients seen per hour and work relative value units per hour. Additionally, we calculated the time-motion analysis in minutes to measure the emergency department physician's efficiency by recording the following: (1) chart preparation, (2) chart review, (3) doctor-patient interaction, (4) physical examination, and (5) post-visit documentation. Finally, we measured patient satisfaction as provided by Press Ganey surveys. Data analysis was conducted in 12,721 patient encounters in the pre-scribe cohort, and 13,598 patient encounters in the post-scribe cohort. All the patient throughput metrics were statistically significant (p < 0.0001). The patients per hour increased from 2.3 +/- 0.3 pre scribe to 3.2 +/- 0.6 post-scribe cohorts (p < 0.001). Total work relative value units per hour increased from 241(3.1 +/- 1.5 per hour) pre-scribe cohort to 336 (5.2 +/- 1.4 per hour) post-scribe cohort (p < 0.001). The pre-scribe patient satisfaction was high and remained high in the post-scribe cohort. There was a significant increase in the clinician providing satisfactory feedback from the pre-scribe (3.9 +/- 0.3) to the post-scribe (4.7 +/- 0.1) cohorts (p < 0.01). We describe a prospective trial of medical scribe use in the emergency department setting to improve patient throughput, physician productivity, and patient satisfaction. We illustrate that scribe use in community emergency department is feasible and results in improvement in all three metrics. PMID- 29239232 TI - Effectiveness of Single- and Multiple-Tablet Antiretroviral Regimens in Correctional Setting for Treatment-Experienced HIV Patients. AB - Minimal information is available regarding antiretroviral prescribing patterns and outcomes for HIV patients in correctional systems. This study analyzes single (STR) and multiple- (MTR) tablet regimen effectiveness in patients receiving HIV telemedicine care through the Illinois Department of Corrections (IDOC). This study involves a retrospective review of HIV-positive adult patients in IDOC on either an STR (efavirenz, rilpivirine, elvitegravir based) or an MTR (emtricitabine/tenofovir with atazanavir/ritonavir, darunavir/ritonavir, or raltegravir). No significant differences in virologic suppression were seen between groups at baseline, weeks 24, 48, 96, and last clinic visit. Similar proportions of patient-reported adverse effects, self-reported adherence, and discontinuation rates were found in both groups. With similar rates of viral suppression, tolerability, adherence, and discontinuation, administering MTR in the incarcerated population is a viable alternative to STR. PMID- 29239233 TI - In vitro metabolism study of a novel P38 kinase inhibitor: in silico predictions, structure elucidation using MS/MS-I. AB - AIM: Metabolism study of PH-797804, a promising newly developed drug for treatment of chronic inflammation which inhibits P38 mitogen-activated protein kinase. MATERIALS & METHODS: Susceptibility of PH-797804 to metabolism was first investigated using SMARTCyp and Xenosite web servers. Molecular docking of the drug into CYP3A4 crystal structures evaluated binding interactions with active site. The predicted results were confirmed by in vitro incubation with rat S9 fraction. Metabolites of PH-797804 were identified by MS/MS. RESULTS: A hydroxy metabolite and a cysteine/glutathione conjugate were detected. Computational prediction of reactive site of PH-797804 was conducted. CONCLUSION: The probable cysteine/glutathione adduct is indicative of potential drug chemical reactivity with potential to damage DNA and may provide guidance to the design of analogs with minimum toxicity. PMID- 29239234 TI - Adoption of in vitro systems and zebrafish embryos as alternative models for reducing rodent use in assessments of immunological and oxidative stress responses to nanomaterials. AB - Assessing the safety of engineered nanomaterials (NMs) is paramount to the responsible and sustainable development of nanotechnology, which provides huge societal benefits. Currently, there is no evidence that engineered NMs cause detrimental health effects in humans. However, investigation of NM toxicity using in vivo, in vitro, in chemico, and in silico models has demonstrated that some NMs stimulate oxidative stress and inflammation, which may lead to adverse health effects. Accordingly, investigation of these responses currently dominates NM safety assessments. There is a need to reduce reliance on rodent testing in nanotoxicology for ethical, financial and legislative reasons, and due to evidence that rodent models do not always predict the human response. We advocate that in vitro models and zebrafish embryos should have greater prominence in screening for NM safety, to better align nanotoxicology with the 3Rs principles. Zebrafish are accepted for use by regulatory agencies in chemical safety assessments (e.g. developmental biology) and there is growing acceptance of their use in biomedical research, providing strong foundations for their use in nanotoxicology. We suggest that investigation of the response of phagocytic cells (e.g. neutrophils, macrophages) in vitro should also form a key part of NM safety assessments, due to their prominent role in the first line of defense. The development of a tiered testing strategy for NM hazard assessment that promotes the more widespread adoption of non-rodent, alternative models and focuses on investigation of inflammation and oxidative stress could make nanotoxicology testing more ethical, relevant, and cost and time efficient. PMID- 29239235 TI - Assessing self-reported disability in a low-literate population with chronic low back pain: cross-cultural adaptation and psychometric testing of Igbo Roland Morris disability questionnaire. AB - PURPOSE: Cross-culturally adapt and validate the Igbo Roland Morris Disability Questionnaire. METHOD: Cross-cultural adaptation, test-retest, and cross sectional psychometric testing. Roland Morris Disability Questionnaire was forward and back translated by clinical/non-clinical translators. An expert committee appraised the translations. Twelve participants with chronic low back pain pre-tested the measure in a rural Nigerian community. Internal consistency using Cronbach's alpha; test-retest reliability using intra-class correlation coefficient and Bland-Altman plot; and minimal detectable change were investigated in a convenient sample of 50 people with chronic low back pain in rural and urban Nigeria. Pearson's correlation analyses using the eleven-point box scale and back performance scale, and exploratory factor analysis were used to examine construct validity in a random sample of 200 adults with chronic low back pain in rural Nigeria. Ceiling and floor effects were investigated in the two samples. RESULTS: Modifications gave the option of interviewer-administration and reflected Nigerian social context. The measure had excellent internal consistency (alpha = 0.91) and intraclass correlation coefficient (ICC =0.84), moderately high correlations (r > 0.6) with performance-based disability and pain intensity, and a predominant uni-dimensional structure, with no ceiling or floor effects. CONCLUSIONS: Igbo Roland Morris Disability Questionnaire is a valid and reliable measure of pain-related disability. Implications for rehabilitation Low back pain is the leading cause of years lived with disability worldwide, and is particularly prevalent in rural Nigeria, but there are no self-report measures to assess its impact due to low literacy rates. This study describes the cross cultural adaptation and validation of a core self-report back pain specific disability measure in a low-literate Nigerian population. The Igbo Roland Morris Disability Questionnaire is a reliable and valid measure of self-reported disability in Igbo populations as indicated by excellent internal consistency (alpha = 0.91) and intra-class correlation coefficient (ICC =0.84), moderately high correlations (r > 0.6) with performance-based disability and pain intensity that supports a pain-related disability construct, a predominant one factor structure with no ceiling or floor effects. The measure will be useful for researchers and clinicians examining the factors associated with low back pain disability or the effects of interventions on low back pain disability in this culture. This measure will support global health initiatives concurrently involving people from several cultures or countries, and may inform cross cultural disability research in other populations. PMID- 29239236 TI - Home. PMID- 29239237 TI - Dave and the person in the room. PMID- 29239238 TI - Interpersonal Contact and Attitudes Toward Adolescents Who Abuse Substances. AB - Only 7.6% of adolescents in need of substance abuse treatment actually receive it. Many adolescents are hesitant to seek treatment due to public stigma (i.e., negative attitudes and beliefs of the general public toward individuals who abuse substances). However, decades of research indicate that interpersonal contact with stigmatized groups helps reduce stigma. This study used structural equations and data from 638 undergraduate students to test the relationships between students' total interpersonal contact with individuals who abuse substances and their attitudes toward those individuals. We found that total contact did not have significant effects on stigma and was associated with better helping attitudes toward adolescents who abuse alcohol but not marijuana. In addition, African Americans and females endorsed greater stigmatization of adolescents who abuse alcohol but better helping attitudes toward those who had received treatment. Increasing contact with individuals who abuse substances, irrespective of type and valence, may not be widely useful as a way of improving attitudes toward such people. PMID- 29239240 TI - Applications of mid-infrared spectroscopy in the clinical laboratory setting. AB - Fourier transform mid-infrared (MIR-FTIR) spectroscopy is a nondestructive, label free, highly sensitive and specific technique that provides complete information on the chemical composition of biological samples. The technique both can offer fundamental structural information and serve as a quantitative analysis tool. Therefore, it has many potential applications in different fields of clinical laboratory science. Although considerable technological progress has been made to promote biomedical applications of this powerful analytical technique, most clinical laboratory analyses are based on spectroscopic measurements in the visible or ultraviolet (UV) spectrum and the potential role of FTIR spectroscopy still remains unexplored. In this review, we present some general principles of FTIR spectroscopy as a useful method to study molecules in specimens by MIR radiation together with a short overview of methods to interpret spectral data. We aim at illustrating the wide range of potential applications of the proposed technique in the clinical laboratory setting with a focus on its advantages and limitations and discussing the future directions. The reviewed applications of MIR spectroscopy include (1) quantification of clinical parameters in body fluids, (2) diagnosis and monitoring of cancer and other diseases by analysis of body fluids, cells, and tissues, (3) classification of clinically relevant microorganisms, and (4) analysis of kidney stones, nails, and faecal fat. PMID- 29239239 TI - Depressive disorders in patients with pharmaco-resistant mesial temporal lobe epilepsy. AB - Objectives To assess depressive disorders in patients with mesial temporal lobe epilepsy (MTLE) refractory to medical treatment. Methods Adult patients with refractory MTLE completed two questionnaires (Mini International Neuropsychiatric Interview (MINI) and the Beck Depression Inventory (BDI) had a semi-structured psychiatric interview and a high resolution MRI scan. For complete neuropsychiatric diagnosis, as per International Classification of Diseases (ICD 10), the results were combined with clinical history and additional information from the patients' family. Results Of the 40 patients identified for this case series study which took place from 2008-2012, 31 (77.5%) had a depressive disorder: 14 had dysthymia, 11 had recurrent depressive disorder and 6 had bipolar disorder. Of the nine patients without a firm diagnosis of mood disorder, seven had isolated symptoms of depression or anxiety and two presented with mixed depression/anxiety symptoms. Only 8/31 (25.8%) patients were receiving antidepressant treatment. There was no association between BDI scores and seizure frequency. No significant difference was found between patients with and without depression and the presence or laterality of HA. Conclusions Depressive disorders are common, underdiagnosed and undertreated in patients with refractory MTLE. PMID- 29239241 TI - Tuberculous spondylitis after vertebral augmentation: A case report with a literature review. AB - Tuberculous spondylitis of vertebral augmentation following percutaneous vertebroplasty or kyphoplasty is rare. We report an unusual case of tuberculous spondylitis diagnosed after percutaneous kyphoplasty (PKP). A 54-year-old woman presented to hospital complaining of back pain following a fall 20 days prior. Radiology showed an acute osteoporotic compression (L3 fracture). The patient denied a history of pulmonary tuberculosis and there were no signs of infection. The patient was discharged from hospital 2 days after undergoing L3 PKP with a dramatic improvement in her back pain. The patient was readmitted 10 months later with a history of recurrent back pain and low-grade fever for 3 months. Imaging examinations showed severe spondylitis at the L2-L3 level, with paravertebral abscess formation and bony destruction of L2 and L3. A positive result of the T SPOT test preliminarily confirmed the diagnosis of tuberculous spondylitis. The tuberculosis test was positive, and serum C-reactive protein levels and erythrocyte sedimentation were relatively high. Treatment for tuberculous spondylitis was started. She underwent posterior fusion and instrumentation from T12-L5 after markers for infection returned to normal. After surgery, the patient continued antituberculous and anti-osteoporosis treatments. Her low back pain was relieved and low-grade fever and sweating disappeared. PMID- 29239243 TI - Lifestyle changes in cancer patients undergoing curative or palliative chemotherapy: is it feasible? AB - INTRODUCTION: This study aimed to explore the feasibility of an individualized comprehensive lifestyle intervention in cancer patients undergoing curative or palliative chemotherapy. MATERIAL AND METHODS: At one cancer center, serving a population of 180,000, 100 consecutive of 161 eligible newly diagnosed cancer patients starting curative or palliative chemotherapy entered a 12-month comprehensive, individualized lifestyle intervention. Participants received a grouped startup course and monthly counseling, based on self-reported and electronically evaluated lifestyle behaviors. Patients with completed baseline and end of study measurements are included in the final analyses. Patients who did not complete end of study measurements are defined as dropouts. RESULTS: More completers (n = 61) vs. dropouts (n = 39) were married or living together (87 vs. 69%, p = .031), and significantly higher baseline physical activity levels (960 vs. 489 min.wk-1, p = .010), more healthy dietary choices (14 vs 11 points, p = .038) and fewer smokers (8 vs. 23%, p = .036) were observed among completers vs. dropouts. Logistic regression revealed younger (odds ratios (OR): 0.95, 95% confidence interval (CI): 0.91, 0.99) and more patients diagnosed with breast cancer vs. more severe cancer types (OR: 0.16, 95% CI: 0.04, 0.56) among completers vs. dropouts. Improvements were observed in completers healthy (37%, p < 0.001) and unhealthy dietary habits (23%, p = .002), and distress (94%, p < .001). No significant reductions were observed in physical activity levels. Patients treated with palliative intent did not reduce their physical activity levels while healthy dietary habits (38%, p = 0.021) and distress (104%, p = 0.012) was improved. DISCUSSION: Favorable and possibly clinical relevant lifestyle changes were observed in cancer patients undergoing curative or palliative chemotherapy after a 12-month comprehensive and individualized lifestyle intervention. Palliative patients were able to participate and to improve their lifestyle behaviors. PMID- 29239242 TI - Fluconazole-loaded solid lipid nanoparticles topical gel for treatment of pityriasis versicolor: formulation and clinical study. AB - Solid lipid nanoparticles (SLNs) are very potential formulations for topical delivery of antifungal drugs. Hence, the purpose of this research was to formulate the well-known antifungal agent Fluconazole (FLZ)-loaded SLNs topical gel to improve its efficiency for treatment of Pityriasis Versicolor (PV). FLZ SLNs were prepared by modified high shear homogenization and ultrasonication method using different concentration of solid lipid (Compritol 888 ATO, Precirol ATO5) and surfactant (Cremophor RH40, Poloxamer 407). The physicochemical properties and the in vitro release study for all FLZ-SLNs were investigated. Furthermore, the optimized FLZ-SLN formula was incorporated into gel using Carpobol 934. A randomized controlled clinical trial (RCT) of potential batches was carried out on 30 well diagnosed PV patients comparing to market product Candistan(r) 1% cream. Follow up was done for 4 weeks by clinical and KOH examinations. The results showed that FlZ-SLNs were almost spherical shape having colloidal sizes with no aggregation. The drug entrapment efficiency ranged from 55.49% to 83.04%. The zeta potential values lie between -21 and -33 mV presenting good stability. FLZ showed prolonged in vitro release from SLNs dispersion and its Carbapol gel following Higuchi order equation. Clinical studies registered significant improvement (p < .05) in therapeutic response (1.4-fold; healing%, 4 fold; complete eradication) in terms of clinical cure and mycological cure rate from PV against marketed cream. Findings of the study suggest that the developed FLZ loaded SLNs topical gels have superior significant fast therapeutic index in treatment of PV over commercially available Candistan(r) cream. PMID- 29239245 TI - Serum and plasma amino acids as markers of prediabetes, insulin resistance, and incident diabetes. AB - Presently, routine screening misses many cases of prediabetes and early type 2 diabetes (T2D). Therefore, better biomarkers are needed for a simple and early detection of abnormalities of glucose metabolism and prediction of future T2D. Possible candidates for this include plasma or serum amino acids because glucose and amino acid metabolism are closely connected. This review presents the available evidence of this connectivity and discusses its clinical implications. First, we examine the underlying physiological, pre-analytical, and analytical issues. Then, we summarize results of human studies that evaluate amino acid levels as markers for insulin resistance, prediabetes, and future incident T2D. Finally, we illustrate the interconnection of amino acid levels and metabolic syndrome with our own data from a deeply phenotyped human cohort. We also discuss how amino acids may contribute to the pathophysiology of T2D. We conclude that elevated branched-chain amino acids and reduced glycine are currently the most robust and consistent amino acid markers for prediabetes, insulin resistance, and future T2D. Yet, we are cautious regarding the clinical potential even of these parameters because their discriminatory power is insufficient and their levels depend not only on glycemia, but also on other components of the metabolic syndrome. The identification of more precise intermediates of amino acid metabolism or combinations with other biomarkers will, therefore, be necessary to obtain in order to develop laboratory tests that can improve T2D screening. PMID- 29239244 TI - Roles of macrophage migration inhibitory factor in polymyositis: Inflammation and regeneration. AB - Objective To elucidate the clinical significance of macrophage migration inhibitory factor (MIF) serum concentration in patients with polymyositis. Methods Thirty-six patients with polymyositis were enrolled. Serum samples were obtained and stored to detect MIF and interleukin (IL)-6 using commercially available enzyme-linked immunosorbent assay kits. The relationships between these cytokines and clinical data were analyzed. Results The serum MIF concentration was significantly lower in patients in remission (34.74 +/- 17.75) and in healthy controls (38.87 +/- 9.30 ng/ml) than that in patients with active polymyositis (50.04 +/- 23.84 ng/ml). There were no significant differences between healthy controls and patients in remission. The serum IL-6 concentration in patients with active polymyositis (19.67 +/- 7.16 pg/ml) was significantly higher than that in patients in remission (15.81 +/- 4.00 pg/ml) and controls (8.14 +/- 3.71 pg/ml). The serum IL-6 concentration was negatively correlated with the serum MIF concentration (r = -0.283). No relationship was found between the serum MIF concentration and glucocorticoid dose. The MIF concentration peaked twice during treatment when the creatine kinase concentration was decreasing. Conclusion MIF and IL-6 play important roles in the inflammation associated with polymyositis. MIF might also be involved in the early stage of regeneration in polymyositis. MIF may thus serve as a biomarker of disease activity and outcome. PMID- 29239246 TI - Association between sonographically measured mesenteric fat thickness and brachial artery flow-mediated dilation in Chinese young male adults. AB - Objective To investigate the potential correlation between sonographically measured mesenteric fat thickness (MFT) and brachial artery flow-mediated dilation (FMD) in a sample of healthy Chinese male young adults. Methods Healthy male participants were recruited from Hong Kong Polytechnic University for this prospective observational study. The physical activity readiness questionnaire and ultrasound measurements of carotid intima media thickness were used to screen for clinically healthy subjects. MFT and brachial artery FMD were measured by ultrasound, and body mass index (BMI) was recorded. Results A total of 34 healthy male subjects, aged 19-26 years (mean +/- SD BMI, 21.7 +/- 3.2 kg/m2) were included. Pearson's correlation coefficient test showed that brachial artery FMD had a statistically significant inverse relationship with BMI and with Log (MFT). Further stepwise multiple linear regression analysis showed that Log (MFT), and not BMI, was an independent predictor of impaired brachial artery FMD. Conclusions Sonographic measurements of MFT were an independent predictor of brachial artery FMD in Chinese male young adults. PMID- 29239248 TI - Use of and microbial resistance to antibiotics in China: a path to reducing antimicrobial resistance. AB - We analyzed China's current use of and microbial resistance to antibiotics, and possible means of reducing antimicrobial resistance. Interventions like executive orders within clinical settings and educational approach with vertical approaches rather than an integrated strategy to curb the use of antimicrobials remain limited. An underlying problem is the system of incentives that has resulted in the intensification of inappropriate use by health professionals and patients. There is an urgent need to explore the relationship between financial and non financial incentives for providers and patients, to eliminate inappropriate incentives. China's national health reforms have created an opportunity to contain inappropriate use of antibiotics through more comprehensive and integrated strategies. Containment of microbial resistance may be achieved by strengthening surveillance at national, regional and hospital levels; eliminating detrimental incentives within the health system; and changing prescribing behaviors to a wider health systems approach, to achieve long-term, equitable and sustainable results and coordinate stakeholders' actions through transparent sharing of information. PMID- 29239247 TI - Correlations between polymorphisms in the uridine diphosphate glucuronosyltransferase 1A and C-C motif chemokine receptor 5 genes and infection with the hepatitis B virus in three ethnic groups in China. AB - Objective To determine whether genetic polymorphisms in the uridine diphosphate glucuronosyltransferase 1A ( UGT1A) and the C-C motif chemokine receptor 5 ( CCR5) genes are associated with hepatitis B virus (HBV) infection in Yi, Yao and Han ethnic groups in the Guizhou Province of China. Methods The study enrolled subjects with and without HBV infection. Whole blood was used for DNA genotyping using standard techniques. The study determined the frequencies of several polymorphic alleles ( UGT1A6 [rs2070959], UGT1A1 [rs8175347], CCR5-59029 [rs1799987] and CCR5Delta32 [rs333]) and then characterized their relationship with HBV infection. Results A total of 404 subjects were enrolled in the study: 138 from the Yao group, 101 from the Yi group and 165 from the Han group. There was a significant difference in the frequency of UGT1A1 rs8175347 polymorphisms among the three groups. The rates of 7TA carriers of UGT1A1 rs8175347 in all three groups were significantly higher than the other genotypes. Individuals with genotype AA of UGT1A6 rs2070959 in the Yi group had a higher risk for HBV infection than in the Yao and Han groups. The frequency of genotype GG in CCR5 59029 in the Yao group was significantly higher than in the Yi group. The genotypes of CCR5Delta32 were not associated with HBV infection. Conclusion These findings provide genetic and epidemiological evidence for an association of UGT1A and CCR5-59029 polymorphisms with HBV infection in Chinese Yi and Yao populations. PMID- 29239249 TI - The Association of Perioperative Glycemic Control With Postoperative Surgical Site Infection Following Open Carpal Tunnel Release in Patients With Diabetes. AB - BACKGROUND: The primary goal of the study was to evaluate the association of hemoglobin A1c (HbA1c) levels in diabetic patients with the incidence of surgical site infection (SSI) following open carpal tunnel release (CTR). Our secondary objective was to calculate an HbA1c level in diabetic patients that predicted SSI after open CTR. METHODS: A national private-payer insurance database was queried for patients who underwent open CTR using Current Procedural Terminology (CPT) code 64721. Patients who underwent concomitant procedures were excluded. Diabetic patients who had their HbA1c level checked within 3 months of surgery were stratified into 6 mutually exclusive groups based on HbA1c levels in 1.0 mg/dL increments from <6.0 to >10 mg/dL. The incidence of SSI was determined for each group by either a diagnosis or procedure for SSI within 1 year using CPT and International Classification of Diseases, 9th Revision (ICD-9) codes. A receiver operating characteristic (ROC) analysis was performed to determine an HbA1c level above which the risk of postoperative SSI was significantly increased. RESULTS: 7958 diabetic patients who underwent open CTR and had an HbA1c recorded within 3 months of surgery were assessed. The incidence of SSI within 1 year was associated with HbA1c levels. The inflection point of the ROC curve corresponded to an HbA1c level between 7 and 8 mg/dL. CONCLUSIONS: Increased HbA1c levels are associated with increased SSI rates in diabetic patients undergoing open CTR. A perioperative HbA1c between 7 and 8 mg/dL could serve as a threshold for an increased risk of SSI following open CTR. PMID- 29239250 TI - History Off-Hand: Bunnell's No-Man's Land. AB - BACKGROUND: To date, it remains unclear what inspired Dr Sterling Bunnell to start using the typical World War I military term no-man's land in hand surgical context, only in 1948. To commemorate that Bunnell passed away 60 years ago on August 20, I report on my quest to clarify this. METHODS: An extensive bibliography of Bunnell was made up by use of the McDowell Series of Plastic Surgery Indexes and cross-checked by use of a PubMed search. Bunnell's round robin letters were searched for in the Sterling Bunnell Hand Surgery Archives of the California Pacific Medical Center Health Services Library in San Francisco, California. In addition, some of the second-generation hand surgeons were personally approached to try and trace the round-robin letters. Finally, the publications of the chiefs of the 9 hand surgical centers and 6 coworkers of Bunnell were checked for referrals to the term no-man's land. RESULTS: Prior to 1948, no-man's land was not used in print in hand surgical context. Bunnell's nearness to the trenches during World War I appears not to have inspired him immediately to start using the term. The reconnaissance tunnels dug through the soil of the no man's land between the Allied and German trenches likely inspired him to replace a cut tendon through incisions proximal and distal to no-man's land. CONCLUSIONS: Bunnell must have associated his tendon grafting techniques to that of the World War I trenches and tunnels at some time between 1947 and 1948. PMID- 29239251 TI - Treatment of Distal Interphalangeal Ganglion Cysts by Volar Corticosteroid Injection. AB - BACKGROUND: Various options exist for operative and nonoperative treatment of symptomatic distal interphalangeal (DIP) ganglion cysts. We describe the technique and efficacy of a novel treatment of DIP ganglion cysts using a volar, transtendon, intra-articular injection of corticosteroid. METHODS: This was a single center, retrospective study (2010-2015) of 21 patients who received a volar, intra-articular corticosteroid injection for treatment of DIP ganglion cysts. The patients were contacted via mailing with a short survey. For those potential study participants who did not respond to the mailing or were not seen in follow-up, contact was made via telephone. The primary study outcome was resolution of the cyst; secondary outcomes included pain and postinjection complications. RESULTS: A total of 21 patients (14 female; 7 male) with 23 DIP ganglion cysts were treated in this study. The dominant hand was involved in 56.5% cases. Twelve (52.2%) resolved or had near complete resolution following injection at an average follow-up of 20 months. CONCLUSIONS: For patients with DIP ganglion cysts, this newly described technique of volar, transtendon, intra articular injection of corticosteroid provides a safe and effective treatment. This technique allows for ease and consistency of needle placement for intra articular corticosteroid delivery while minimizing the potential soft tissue and infection concerns described with other techniques. PMID- 29239252 TI - Single-Bundle vs Double-Bundle (Anatomical) Reconstruction of the Thumb Ulnar Collateral Ligament: Biomechanical Study. AB - BACKGROUND: The goal of this study is to compare the biomechanical properties of anatomic (double-bundle) versus single-bundle reconstruction of the thumb metacarpophalangeal (MCP) joint ulnar collateral ligament (UCL) in a cadaveric model. METHODS: Twelve fresh frozen cadaver hands were randomly assigned to single- or double-bundle reconstruction groups using a palmaris longus autograft and tenodesis screws. Two blinded examiners performed mechanical testing and measurements using fluoroscopic imaging. We evaluated MCP joint congruence and angle in the coronal plane at 0 degrees , 30 degrees , and 60 degrees of flexion with valgus loads of 1.36 and 2.72 kg. Maximum MCP flexion and extension with a 0.45 kg load was also measured. RESULTS: There was no significant difference between single- versus double-bundle reconstruction in ulnar congruence or MCP angle. With varying amounts of flexion, there was no significant difference in MCP valgus angle between the 2 techniques, suggesting comparable joint congruity and coronal MCP angle along the arc of thumb MCP motion. CONCLUSIONS: Single- and double-bundle UCL reconstructions of the thumb MCP joint have comparable biomechanical properties in regard to joint congruity under valgus load. PMID- 29239254 TI - The relationship between cell apoptosis dysfunction and FEN1 E160D mutation in lupus nephritis patients. AB - OBJECTIVE: This study aims to evaluate the role of FEN1 E160D mutation in lupus nephritis (LN) patients with cell apoptosis dysfunction. METHODS: (1) Cell apoptosis was detected from 50 paraffin samples obtained from renal biopsies of patients with Class IV LN by TUNEL method and the relationship of the systemic lupus erythematosus disease activity index 2000 (SLEDAI 2000) and renal tissue cell apoptotic index (AI) was discussed. (2) FEN1 gene 61563142-61563342 containing E160D were analysed by extracting genomic DNA from peripheral blood collected from the above 50 LN patients and 25 patients with nephrectomy caused by renal trauma. The difference between these two groups was statistically significant. RESULTS: Cell apoptosis was detected in all patients with LN, and correlation analysis results revealed a positive relationship between SLEDAI 2000 and AI (r = 0.39, p = .032). The FEN1 gene 61563142-61563342 fragment had site mutations at C/- (+61563189), A/T (+61563198), A/- (+61563204), G/T (+61563303), and T/C (+61563304). However, no statistical significance was found between LN patients detected with cell apoptosis and healthy individuals. CONCLUSIONS: This study revealed that cell apoptosis dysfunction plays a key role in the pathogenesis of LN, even though the difference in FEN1 gene 61563142-61563342 between LN patients and healthy individuals was not statistically significant. Larger sample size studies or genome-wide association studies are needed. PMID- 29239253 TI - Fifty top-cited spine articles from mainland China: A citation analysis. AB - Objective To identify the 50 top-cited spine articles from mainland China and to analyze their main characteristics. Methods Web of Science was used to identify the 50 top-cited spine articles from mainland China in 27 spine-related journals. The title, year of publication, number of citations, journal, anatomic focus, subspecialty, evidence level, city, institution and author were recorded. Results The top 50 articles had 29-122 citations and were published in 11 English language journals; most (32) were published in the 2000s. The journal Spine had the largest number of articles and The Lancet had the highest impact factor. The lumber spine was the most discussed anatomic area (18). Degenerative spine disease was the most common subspecialty topic (22). Most articles were clinical studies (29); the others were basic research (21). Level IV was the most common evidence level (17). Conclusions This list indicates the most influential articles from mainland China in the global spine research community. Identification of these articles provides insights into the trends in spine care in mainland China and the historical contributions of researchers from mainland China to the international spine research field. PMID- 29239255 TI - Nonfunctional pancreatic endocrine tumor in the peripancreatic region in a Chinese patient with multiple endocrine neoplasia type 1. AB - Nonfunctional pancreatic neuroendocrine tumors (NF-pNETs) in patients with multiple endocrine neoplasia type 1 (MEN1), which results from a mutation in the MEN1 gene, are commonly small, multiple tumors located in the pancreatic head and inside the pancreatic parenchyma. We herein describe a 35-year-old woman with bone pain and a 7-year history of a prolactinoma. She was clinically diagnosed with MEN1 based on the presence of the prolactinoma and parathyroid hyperplasia. Abdominal computed tomography revealed a 5-cm mass close to the splenic hilum. This soft tissue tumor, which was located outside the pancreatic parenchyma and the tissue origin of which could not be identified preoperatively, was found to be connected to the pancreatic tail. After resection, histological examination revealed a well-differentiated neuroendocrine tumor of pancreatic origin. Genetic testing revealed a heterozygous transition mutation of guanine to adenine at the coding nucleotide 133 in exon 2 (c.133G>A), resulting in an amino acid substitution of glutamic acid with lysine (E45K) in the MEN1 gene. This patient with MEN1 presented with a clinical condition involving a single non-metastatic NF-pNET located outside the pancreatic parenchyma with a missense mutation in the MEN1 gene, which could easily have been misdiagnosed as an accessory spleen. PMID- 29239256 TI - Use of three-dimensional finite element models of the lateral ankle ligaments to evaluate three surgical techniques. AB - Objective To compare three surgical techniques for lateral ankle ligament reconstruction using finite element (FE) models. Methods A three-dimensional FE model of the left foot of a healthy volunteer and lateral collateral ligament injury models were developed. Three tendons [one-half of the autologous peroneus longus tendon (PLT), one-half of the peroneus brevis tendon (PBT), and an allogeneic tendon] were used for lateral collateral ligament reconstruction. The ankle varus stress and anterior drawer tests were performed to compare the three surgical techniques. Results The ankle varus stress test showed that the equivalent stresses of the anterior talofibular ligament (ATFL) (84.00 MPa) and calcaneofibular ligament (CFL) (27.01 MPa) were lower in allogeneic tendon reconstruction than in the other two techniques but similar to those of normal individuals (138.48 and 25.90 MPa, respectively). The anterior drawer test showed that the equivalent stresses of the ATFL and CFL in autologous PLT reconstruction (31.31 and 28.60 MPa, respectively) and PBT reconstruction (31.47 and 29.07 MPa, respectively) were lower than those in allogeneic tendon reconstruction (57.32 and 52.20 MPa, respectively). Conclusions The allogeneic tendon reconstruction outcome was similar to normal individuals. Allogeneic tendon reconstruction may be superior for lateral ankle ligament reconstruction without considering its complications. PMID- 29239257 TI - Cardiac magnetic resonance assessment of diastolic dysfunction in acute coronary syndrome. AB - Chest pain is an important presenting symptom. However, few cases of chest pain are diagnosed as acute coronary syndrome (ACS) in the acute setting. This results in frequent inappropriate discharge and major delay in treatment for patients with underlying ACS. The conventional methods of assessing ACS, which include electrocardiography and serological markers of infarct, can take time to manifest. Recent studies have investigated more sensitive and specific imaging modalities that can be used. Diastolic dysfunction occurs early following coronary artery occlusion and its detection is useful in confirming the diagnosis, risk stratification, and prognosis post-ACS. Cardiac magnetic resonance provides a single imaging modality for comprehensive evaluation of chest pain in the acute setting. In particular, cardiac magnetic resonance has many imaging techniques that assess diastolic dysfunction post-coronary artery occlusion. Techniques such as measurement of left atrial size, mitral inflow, and mitral annular and pulmonary vein flow velocities with phase-contrast imaging enable general assessment of ventricular diastolic function. More novel imaging techniques, such as T2-weighted imaging for oedema, T1 mapping, and myocardial tagging, allow early determination of regional diastolic dysfunction and oedema. These findings may correspond to specific infarcted arteries that may be used to tailor eventual percutaneous coronary artery intervention. PMID- 29239258 TI - Is the Preoperative Level of Procalcitonin a Valid Indicator for Predicting Postoperative Fever After Percutaneous Nephrolithotomy? AB - OBJECTIVE: To evaluate the risk factors for postoperative fever and to identify the value of preoperative procalcitonin (PCT) in predicting postoperative fever after percutaneous nephrolithotomy (PNL). PATIENTS AND METHODS: Patients who underwent PNL between January 2014 and March 2017 were studied. In total, 363 medical records with complete data were determined to be eligible for analysis. Patients were classified into a control or febrile group according to the presence of a body temperature over 38 degrees C. Demographic and perioperative data were compared between the groups. Variables found to be statistically significant were included in a binary logistic regression analysis. RESULTS: Ninety-one (25.1%) patients experienced postoperative fever. Univariate analysis revealed a statistically significant difference between postoperative fever and factors, such as sex (p = 0.009), preoperative fever (p < 0.001), stone burden (p < 0.001), pyuria (p = 0.013), urine culture (p < 0.001), and serum levels of C reactive protein (CRP) (p = 0.003), PCT (p < 0.001), and interleukin-6 (IL-6) (p = 0.003). Binary logistic regression analysis indicated the presence of preoperative fever (p = 0.037), stone burden >353 mm2 (p = 0.002), PCT >0.05 ng/mL (p < 0.001), or positive urine culture (p = 0.004) as independent risk factors for postoperative fever following PNL. CONCLUSIONS: We concluded that patients with preoperative fever, stone burden >353 mm2, PCT >0.05 ng/mL, or positive urine culture were more likely to develop postoperative fever and that routinely detecting PCT levels before PNL would be helpful in predicting postoperative fever. PMID- 29239259 TI - Oral paracetamol versus oral ibuprofen for treatment of patent ductus arteriosus. AB - Objective This study was performed to investigate the safety and efficacy of oral paracetamol versus oral ibuprofen in the treatment of patent ductus arteriosus (PDA) in premature infants. Methods Premature infants with PDA with a gestational age of <=32 weeks or birth weight of <=1500 g were included in this randomized study. Results A total of 120 premature infants fulfilled the inclusion criteria. Of these 120 infants, 34 fulfilled the treatment criteria and 22 were finally randomized. We found no significant difference in the mortality or primary closure rates between the two groups. We also found no significant difference in the short-term neonatal outcomes. Conclusions Either oral paracetamol or oral ibuprofen can be used safely and effectively to treat PDA in premature infants. PMID- 29239260 TI - A 1-year follow-up of a randomized clinical trial with focus on manual and electric toothbrushes' effect on dental hygiene in nursing homes. AB - OBJECTIVE: A 2-month randomized clinical trial (RCT) study comparing electric and manual toothbrushes used by residents in nursing homes showed significant reduction in plaque score for both groups. The aim of this follow up study was to study if the effect sustained in a longer perspective when toothbrushes were used according to resident's own preference. MATERIALS AND METHODS: One year after baseline of the RCT-study, 100 participants were re-examined. The simplified oral hygiene index (OHI-S) was used as outcome measure on dental plaque. RESULTS: The mean age was 86.6, 78.1% had three or more medical diagnoses and 52.2% had moderate to severe cognitive impairment. The mean number of natural teeth was 18.8. After 1 year, mean plaque scores was significantly reduced within the population, from 1.2 to 0.7 (p < .001). A total of 46 participants preferred to use an electric toothbrush and 54 preferred manual. No significant difference in plaque score was found between electric and manual toothbrushes. CONCLUSION: After 1 year, the improvement in dental hygiene from the RCT study sustained for users of both electric and manual toothbrush. Focus upon tooth brushing seems to be efficient and both manual and electric toothbrushes should be available in nursing homes. PMID- 29239261 TI - White Matter Tract Integrity: An Indicator of Axonal Pathology after Mild Traumatic Brain Injury. AB - We seek to elucidate the underlying pathophysiology of injury sustained after mild traumatic brain injury (mTBI) using multi-shell diffusion magnetic resonance imaging, deriving compartment-specific white matter tract integrity (WMTI) metrics. WMTI allows a more biophysical interpretation of white matter (WM) changes by describing microstructural characteristics in both intra- and extra axonal environments. Thirty-two patients with mTBI within 30 days of injury and 21 age- and sex-matched controls were imaged on a 3 Tesla magnetic resonance scanner. Multi-shell diffusion acquisition was performed with five b-values (250 2500 sec/mm2) along 6-60 diffusion encoding directions. Tract-based spatial statistics (TBSS) was used with family-wise error (FWE) correction for multiple comparisons. TBSS results demonstrated focally lower intra-axonal diffusivity (Daxon) in mTBI patients in the splenium of the corpus callosum (sCC; p < 0.05, FWE-corrected). The area under the curve value for Daxon was 0.76 with a low sensitivity of 46.9% but 100% specificity. These results indicate that Daxon may be a useful imaging biomarker highly specific for mTBI-related WM injury. The observed decrease in Daxon suggests restriction of the diffusion along the axons occurring shortly after injury. PMID- 29239262 TI - Outcomes following proton therapy for pediatric ependymoma. AB - BACKGROUND: Proton therapy can reduce the low and intermediate radiation dose to uninvolved brain tissue in children with intracranial ependymomas, which may improve functional outcomes and reduce second malignancies in survivors. Accordingly, ependymoma has become the most common pediatric tumor treated with proton therapy, yet data on efficacy and toxicity are limited. MATERIAL AND METHODS: Between June 2007 and February 2017, 179 children (<=21 years old) with nonmetastatic grade II/III intracranial ependymoma received proton therapy at our institution. Median age, 3.5 years (range, 0.7-21); 58% were male. Most (66%) tumors were in the posterior fossa and classified as WHO grade III (67%). 27% underwent multiple operations to maximize the extent of resection; ultimately 85% had a gross total or near total tumor resection before radiotherapy. 33% received preradiation chemotherapy. Median radiation dose in children <=3 years old, 54 Gy(RBE). Most (>90%) children over 3 years old received 59.4 Gy(RBE). Patient and treatment variables were assessed for correlation with disease control. RESULTS: Median follow-up, 3.2 years. 3-year local control, progression-free survival, and overall survival rates were 85%, 76%, and 90%, respectively. First site of progression was local, metastatic, or simultaneous in 14, 17 and 6 patients, respectively. On multivariate analysis, subtotal resection was associated with inferior local control (67% vs. 88%; p <= .01) and progression-free survival (59% vs. 79%; p < .05). Male sex was associated with inferior progression-free (67% vs. 87%; p< .05) and overall survival (84% vs. 99%; p < .01). The 3-year CTCAE grade 2 + brainstem toxicity rate was 5.5% (95% CI: 2.9-10.2), including 1 grade 5 toxicity. CONCLUSIONS: This series of proton therapy for pediatric intracranial ependymoma demonstrates disease control comparable to photon series without unexpected toxicity. Subtotal resection and male sex were associated with inferior disease control. Additional follow-up to quantify the expected reductions in late toxicity with proton therapy is ongoing. PMID- 29239264 TI - Clinical significance of plasma presepsin levels in patients with systemic lupus erythematosus. AB - OBJECTIVES: Presepsin (PSEP: soluble CD14 subtype) is produced from bacteria stimulated monocytes or neutrophils, thus recognized as a biomarker of sepsis. Aberrant functions in monocyte or neutrophils are increasingly recognized in systemic lupus erythematosus (SLE). We investigated whether plasma PSEP reflects disease activity in patients with SLE. METHODS: This retrospective study comprised 35 patients with SLE and 72 with non-SLE autoimmune diseases who visited our facility during the period from August 2012 to September 2015. Plasma PSEP levels and laboratory data were compared between SLE and non-SLE. Clinical markers of SLE disease activity, including SLE disease activity index 2000 (SLEDAI-2K), serum complement concentrations and serum anti-ds-DNA antibodies were assessed in correlation with plasma PSEP levels. RESULTS: Plasma PSEP levels in SLE were higher than those in non-SLE. This phenomenon holds true when comparing SLE and non-SLE patients in the absence of infection (p = .0008). Plasma PSEP levels in SLE patients negatively correlated with C3 (r = -0.4454, p = .0430), CH50 (r = -0.4502, p = .0406) and positively with SLEDAI-2K (r = 0.4801, p = .0237). CONCLUSION: Elevated plasma PSEP levels were correlated with disease activity of SLE, suggesting inappropriate monocyte or neutrophil activation in the pathophysiology of SLE exacerbation. PMID- 29239265 TI - Decreased Number of Self-Paced Saccades in Post-Concussion Syndrome Associated with Higher Symptom Burden and Reduced White Matter Integrity. AB - The aim of this study was to examine the potential utility of a self-paced saccadic eye movement as a marker of post-concussion syndrome (PCS) and monitoring the recovery from PCS. Fifty-nine persistently symptomatic participants with at least two concussions performed the self-paced saccade (SPS) task. We evaluated the relationships between the number of SPSs and 1) number of self-reported concussion symptoms, and 2) integrity of major white matter (WM) tracts (as measured by fractional anisotropy [FA] and mean diffusivity) that are directly or indirectly involved in saccadic eye movements and often affected by concussion. These tracts included the uncinate fasciculus (UF), cingulum (Cg) and its three subcomponents (subgenual, retrosplenial, and parahippocampal), superior longitudinal fasciculus, and corpus callosum. Mediation analyses were carried out to examine whether specific WM tracts (left UF and left subgenual Cg) mediated the relationship between the number of SPSs and 1) interval from last concussion or 2) total number of self-reported symptoms. The number of SPSs was negatively correlated with the total number of self-reported symptoms (r = -0.419, p = 0.026). The number of SPSs were positively correlated with FA of left UF and left Cg (r = 0.421, p = 0.013 and r = 0.452, p = 0.008; respectively). FA of the subgenual subcomponent of the left Cg partially mediated the relationship between the total number of symptoms and the number of SPSs, while FA of the left UF mediated the relationship between interval from last concussion and the number of SPSs. In conclusion, SPS testing as a fast and objective assessment may reflect symptom burden in patients with PCS. In addition, since the number of SPSs is associated with the integrity of some WM tracts, it may be useful as a diagnostic biomarker in patients with PCS. PMID- 29239263 TI - Percutaneous mechanical thrombectomy combined with catheter-directed thrombolysis in the treatment of acute pulmonary embolism and lower extremity deep venous thrombosis: A novel one-stop endovascular strategy. AB - Objective This study was performed to evaluate the efficacy and feasibility of percutaneous mechanical thrombectomy (PMT) combined with catheter-directed thrombolysis (CDT) in patients with acute pulmonary embolism (APE) and lower extremity deep venous thrombosis (LEDVT). Methods In total, 20 consecutive patients with APE and LEDVT were prospectively selected for PMT combined with CDT. Mechanical thrombus fragmentation and aspiration using a pigtail rotation catheter followed by CDT was performed in each patient. Details regarding the patients' clinical presentation and outcome, pulmonary status parameters (pulmonary arterial pressure, partial pressure of oxygen in arterial blood, Miller score, thigh and calf circumference, and shock index), and lower extremity parameters (thrombus-lysis grade and Villalta scale score) were recorded. Results All 20 patients' clinical manifestations significantly improved. Both the clinical success rate and technical success rate were 100%. No major adverse events occurred during hospitalization. Four patients developed iliac vein compression syndrome and underwent stent implantation in the iliac vein. No pulmonary embolism recurred within 16.5+/-6.8 months of follow-up. Conclusions The combination of PMT and CDT is a safe and effective treatment for APE and LEDVT with good short- and intermediate-term clinical outcomes. PMID- 29239266 TI - Epidemiology of invasive pulmonary aspergillosis in patients with liver failure: Clinical presentation, risk factors, and outcomes. AB - Objective Invasive pulmonary aspergillosis (IPA) is a severe and often lethal infection. The possible risk factors, clinical presentation, and treatment of patients with simultaneous liver failure and IPA have received little attention in previous studies. The aim of this study was to investigate the epidemiology of IPA in patients with liver failure in an effort to reduce patient mortality. Methods The patients with liver failure (including acute liver failure , sub acute liver failure , acute-on-chronic liver failure and chronic liver failure) were recruited from 2011 to 2016. The clinical data of these patients were retrieved for the study. Results In total, 1077 patients with liver failure were included in this study. Of the 1077 patients, 53 (4.9%) had IPA. Forty-four (83%) patients with IPA died. Independent risk factors for IPA were male sex (hazard ratio [HR] = 2.542), hepatorenal syndrome (HR = 2.463), antibiotic use (HR = 4.631), and steroid exposure (HR = 18.615). Conclusions IPA is a fatal complication in patients with liver failure. Male sex, hepatorenal syndrome, antibiotic use, and steroid exposure were independent risk factors for IPA. When patients with liver failure have these risk factors and symptoms of pneumonia such as cough or hemoptysis, clinicians should be cautious about the possibility of IPA. PMID- 29239267 TI - A Retrospective Study of Predictors of Return to Duty versus Medical Retirement in an Active Duty Military Population with Blast-Related Mild Traumatic Brain Injury. AB - Traumatic Brain Injury (TBI) has been described as the "signature injury" of the Global War on Terror. Explosive blast TBI has become a leading cause of injury as a result of the widespread use of improvised explosive devices in Iraq and Afghanistan. We present a retrospective cross-sectional study of patients with blast-related mild TBI (mTBI, N = 303) seen at the Intrepid Spirit Concussion Recovery Center at Naval Medical Center Camp Lejeune. The objective was to predict outcomes of return to duty (RTD) vs. medical retirement via medical evaluation board (MEB), based on brain imaging, neuropsychological data, and history of mTBI. The motivation is to inform prognosis and target resources to improve outcomes for service members who are less likely to RTD through the standard treatment program. The RTD was defined operationally as individuals who completed treatment and were not recommended for medical retirement or separation for TBI or related sequelae. Higher scores on the Repeatable Battery for Neuropsychological Status (RBANS) test were associated positively with RTD (p = 0.001). A history of three or more lifetime concussions was associated negatively with RTD, when compared with one concussion (p = 0.04). Elevated apparent diffusion coefficient (ADC) in the anterior corona radiata was associated negatively with RTD (p = 0.04). A logistic regression model was used to classify individuals with RBANS and imaging data (n = 81) as RTD or MEB according to RBANS, ADC, and a history of multiple (>=3) concussions. The RBANS (p = 0.003) and multiple concussions (p = 0.03) were significant terms in the logistic model, but ADC was not (p = 0.27). The area under the receiver operating characteristic curve was 0.77 (95% confidence interval 0.66-0.86). These results suggest cognitive testing and TBI history might be used to identify service members who are more likely to be retired medically from active duty. PMID- 29239269 TI - Pharmacogenetic landscape of DPYD variants in south Asian populations by integration of genome-scale data. AB - AIM: Adverse drug reactions to 5-Fluorouracil(5-FU) is frequent and largely attributable to genetic variations in the DPYD gene, a rate limiting enzyme that clears 5-FU. The study aims at understanding the pharmacogenetic landscape of DPYD variants in south Asian populations. MATERIALS & METHODS: Systematic analysis of population scale genome wide datasets of over 3000 south Asians was performed. Independent evaluation was performed in a small cohort of patients. RESULTS: Our analysis revealed significant differences in the the allelic distribution of variants in different ethnicities. CONCLUSIONS: This is the first and largest genetic map the DPYD variants associated with adverse drug reaction to 5-FU in south Asian population. Our study highlights ethnic differences in allelic frequencies. PMID- 29239268 TI - A Community Perspective on Bowel Management and Quality of Life after Spinal Cord Injury: The Influence of Autonomic Dysreflexia. AB - Autonomic dysfunction is common in individuals with spinal cord injury (SCI) and leads to numerous abnormalities, including profound cardiovascular and bowel dysfunction. In those with high-level lesions, bowel management is a common trigger for autonomic dysreflexia (AD; hypertension provoked by sensory stimuli below the injury level). Improving bowel care is integral for enhancing quality of life (QoL). We aimed to describe the relationships between bowel care, AD, and QoL in individuals with SCI. We performed an online community survey of individuals with SCI. Those with injury at or above T7 were considered at risk for AD. Responses were received from 287 individuals with SCI (injury levels C1 sacral and average duration of injury 17.1 +/- 12.9 [standard deviation] years). Survey completion rate was 73% (n = 210). Bowel management was a problem for 78%: it interfered with personal relationships (60%) and prevented staying (62%) and working (41%) away from home. The normal bowel care duration was >60 min in 24% and most used digital rectal stimulation (59%); 33% reported bowel incontinence at least monthly. Of those at risk for AD (n = 163), 74% had AD symptoms during bowel care; 32% described palpitations. AD interfered with activities of daily living in 51%. Longer durations of bowel care (p < 0.001) and more severe AD (p = 0.04) were associated with lower QoL. Bowel management is a key concern for individuals with SCI and is commonly associated with symptoms of AD. Further studies should explore ways to manage bowel dysfunction, increase self-efficacy, and ameliorate the impact of AD to improve QoL. PMID- 29239270 TI - [Pharmacotherapy for children and adolescents with sleep disorders: an overview]. AB - Pharmacotherapy for children and adolescents with sleep disorders: an overview Abstract. Sleep difficulties are a relevant symptom in childhood and adolescence with a prevalence of approximately 20 %. Because of the reduced psychosocial functioning and the burden of suffering associated with insomnia, effective treatment strategies are needed. If interventions such as the implementation of an adequate sleep hygiene and other non-drug treatment approaches are not sufficient, pharmacotherapeutic treatment is often considered. The present work provides a literature overview on the use of different substance classes in hypnotic indications. The use of melatonin in children and adolescents with autism spectrum disorder has been well studied and is associated with a positive effect on sleep in this patient group. To date, there is little evidence regarding the efficacy and tolerability of other medication in primary insomnia or sleep disorders in the context of other psychiatric disorders in minors. For this reason, non-drug treatment strategies are preferred and pharmacotherapy is only to be considered secondarily after critical examination. PMID- 29239271 TI - How Can We Keep Immigrant Travelers Healthy? Health Challenges Experienced by Canadian South Asian Travelers Visiting Friends and Relatives. AB - Immigrant travelers who visit friends and relatives (VFR travelers) experience substantially higher rates of travel-related infections than other travelers, in part due to low uptake of pretravel health advice. While barriers to accessing advice have been identified, better characterization is needed to inform targeted interventions. We sought to understand how South Asian VFR travelers perceived and responded to travel-related health risks by conducting group interviews with 32 adult travelers from an ethnoculturally diverse Canadian region. Travelers positioned themselves as knowledgeable of key health risks, despite not seeking pretravel health advice. Their responses to risks were pragmatic and rooted in experience, but often constrained by competing concerns, including rushed travel, familial obligations, cost, and a desire to preserve authentic experiences. Moving beyond risk awareness to reinforcing the value of medical advice and intervention, in a manner that is sensitive to these unique concerns, is needed when delivering tailored health promotion messages to VFR travelers. PMID- 29239272 TI - Mental Models of Cause and Inheritance for Type 2 Diabetes Among Unaffected Individuals Who Have a Positive Family History. AB - Using the familial risk perception (FRP) model as a framework, we elicited causal and inheritance explanations for type 2 diabetes (T2D) from people who do not have T2D but have a family history for it. We identified four composite mental models for cause of T2D: (a) purely genetic; (b) purely behavioral/environmental; (c) direct multifactorial, in which risk factors interact and over time directly lead to T2D; and (d) indirect multifactorial, in which risk factors interact and over time cause a precursor health condition (such as obesity or metabolic syndrome) that leads to T2D. Interestingly, participants described specific risk factors such as genetics, food habits, lifestyle, weight, and culture as "running in the family." Our findings provide insight into lay beliefs about T2D that can be used by clinicians to anticipate or make sense of responses to questions they pose to patients about mental models for T2D. PMID- 29239273 TI - Bioluminescent High-Throughput Succinate Detection Method for Monitoring the Activity of JMJC Histone Demethylases and Fe(II)/2-Oxoglutarate-Dependent Dioxygenases. AB - The modification of a diverse array of substrates by Fe(II)/2-oxoglutarate dependent dioxygenases is central to the modulation of distinct biological processes such as epigenetics, hypoxic signaling, and DNA/RNA repair. Of these, JumonjiC domain-containing histone lysine demethylases (JMJCs) and prolyl hydroxylases are potential drug targets due to their relevance to human diseases. Thus, assays to interrogate this enzyme superfamily are needed to identify selective and potent inhibitors as leads for drug development and that could also be useful research tools. Since succinate is a common product to all Fe(II)/2 oxoglutarate-dependent dioxygenase reactions, a method that detects succinate would be suitable to all members of this enzyme superfamily. We therefore developed a bioluminescent and homogenous succinate detection assay and validated its use with diverse sets of enzyme classes. We evaluated the substrate specificities of these enzymes, their apparent kinetic constants, and inhibition profiles and mode of action of reported and novel inhibitors. Our results indicate that succinate detection is a useful readout for the monitoring of enzymatic activities with distinct substrate entities, as well as for the discovery of novel inhibitors. By investigating a large number of Fe(II)/2 oxoglutarate-dependent enzymes, this method could have a significant impact on the field of dioxygenase research. PMID- 29239274 TI - Magnetic resonance feature of "paintbrush borders" sign as a novel way to predict recurrence of giant cell tumor of bone after curettage: a pilot study. AB - Objective To identify the prognostic factors for local recurrence of giant cell tumor of bone (GCTB) through assessment of the preoperative imaging features of the tumor border. Methods Patients with GCTBs treated with intralesional procedures in the proximal tibia and distal femur were prospectively enrolled and then followed up for at least 2 years. The GCTBs were grouped according to their preoperative imaging features. GCTBs treated with en bloc resection were enrolled for investigation of the pathologic basis of specific imaging features. Differences between rates were evaluated by the chi-square test or Fisher's exact test; independent factors were identified by multivariate logistic regression analysis. Results Fifty-three patients were enrolled and successfully followed up. Relapse occurred in 22 patients. Patients with a "paintbrush borders" sign (n = 21) had a significantly higher rate of local recurrence (71.43%) than patients without this sign (21.88%). The "paintbrush borders" sign was identified as an independent prognostic factor for local recurrence. Other imaging features were not significantly associated with recurrence. The "paintbrush borders" sign showed a correlation with local invasion of bone. Conclusion The "paintbrush borders" sign on preoperative magnetic resonance imaging is an independent prognostic factor for local recurrence of GCTB. PMID- 29239275 TI - Activation of Lysophosphatidic Acid Receptor 3 Inhibits Megakaryopoiesis in Human Hematopoietic Stem Cells and Zebrafish. AB - Lysophosphatidic acid (LPA) is a membrane-derived lysophospholipid that exists in the plasma and platelets. It exerts its functions through activation of various LPA receptors (LPARs), which belong to the family of G protein-coupled receptors. Activation of LPARs has important roles in stem cell differentiation. However, how LPA affects human hematopoietic stem cell (HSC) differentiation remains elusive. In our previous studies, we have suggested that LPA receptor 2 (LPA2) and LPA receptor 3 (LPA3) play opposing roles and may act as a molecular switch during megakaryocytic differentiation in K562 cells. In this study, human CD34+ HSCs and zebrafish are adopted to investigate the roles of LPA3 during megakaryopoiesis/thrombopoiesis in vitro and in vivo. Our results show that LPAR3 mRNA expression level is decreased upon induction by thrombopoietin and stem cell factor in human HSCs. Using pharmacological activators and shRNA knockdown experiments, we demonstrate that activation of LPA3 inhibits megakaryopoiesis in human HSCs. In addition, pharmacological activation of LPA3 suppressed thrombopoiesis in zebrafish. Furthermore, blockage of LPA3 translation by morpholino increased the number of CD41-GFP+ cells in Tg(CD41:eGFP) zebrafish. Moreover, the mRNA expression level of zCD41 increased significantly in LPA3 knockout zebrafish. These results clarify the negative role of LPA3 during megakaryopoiesis and provide important information for potential treatments of related diseases, such as megakaryopenia. PMID- 29239276 TI - Radiolabeled Anti-Adenosine Triphosphate Synthase Monoclonal Antibody as a Theragnostic Agent Targeting Angiogenesis. AB - INTRODUCTION: The potential of a radioiodine-labeled, anti-adenosine triphosphate synthase monoclonal antibody (ATPS mAb) as a theragnostic agent for simultaneous cancer imaging and treatment was evaluated. METHODS: Adenosine triphosphate synthase monoclonal antibody was labeled with radioiodine, then radiotracer uptake was measured in 6 different cancer cell lines. In vivo biodistribution was evaluated 24 and 48 hours after intravenous injection of 125I-ATPS mAb into MKN 45 tumor-bearing mice (n = 3). For radioimmunotherapy, 18.5 MBq 131I-ATPS mAb (n = 7), isotype immunoglobulin G (IgG) (n = 6), and vehicle (n = 6) were injected into MKN-45 tumor-bearing mice for 4 weeks, and tumor volume and percentage of tumor growth inhibition (TGI) were compared each week. RESULTS: MKN-45 cells showed the highest in vitro cellular binding after 4 hours (0.00324 +/- 0.00013%/MUg), which was significantly inhibited by unlabeled ATPS mAb at concentrations of greater than 0.4 MUM. The in vitro retention rate of 125I-ATPS mAb in MKN-45 cells was 64.1% +/- 1.0% at 60 minutes. The highest tumor uptake of 125I-ATPS mAb in MKN-45 tumor-bearing mice was achieved 24 hours after injection (6.26% +/- 0.47% injected dose [ID]/g), whereas tumor to muscle and tumor to blood ratios peaked at 48 hours. The 24-hour tumor uptake decreased to 3.43% +/- 0.85% ID/g by blocking with unlabeled ATPS mAb. After 4 weeks of treatment, mice receiving 131I-ATPS mAb had significantly smaller tumors (679.4 +/- 232.3 mm3) compared with control (1687.6 +/- 420.4 mm3, P = .0431) and IgG-treated mice (2870.2 +/- 484.1 mm3, P = .0010). The percentage of TGI of 131I-ATPS mAb was greater than 50% during the entire study period (range: 53.7%-75.9%). CONCLUSION: The specific binding and antitumor effects of radioiodinated ATPS mAb were confirmed in in vitro and in vivo models of stomach cancer. PMID- 29239278 TI - Welcome to the 19th volume of Pharmacogenomics. PMID- 29239277 TI - Nuclear G protein-coupled oestrogen receptor (GPR30) predicts poor survival in patients with ovarian cancer. AB - Objective To demonstrate the correlation between nuclear and cytoplasmic G protein-coupled oestrogen receptor (GPR30) expression and clinicopathological features and outcome in patients with ovarian cancer. Methods Nuclear and cytoplasmic GPR30 expressions were determined using immunohistochemistry to identify the intracellular location in tissues from patients with ovarian cancer. Data were correlated with clinicopathological characteristics and outcomes. Results Tissue samples were obtained from 110 patients with epithelial ovarian cancer between 2005 and 2010. Nuclear GPR30 was significantly more frequent in the group of patients with recurrence. The presence of nuclear GPR30 predicted lower overall survival) and 5-year progression-free survival in all patients with ovarian cancer and overall survival in patients with high grade ovarian cancer. Cytoplasmic GPR30 was observed significantly more often in advanced ovarian cancer and did not predict survival. Conclusion This study showed that nuclear GPR30 is an independent negative prognostic indicator in patients with ovarian cancer, especially in those with a high grade malignancy. PMID- 29239280 TI - Perceived Injustice and Its Correlates after Mild Traumatic Brain Injury. AB - Perceived injustice is a belief that one has been treated unfairly and disrespectfully, and is suffering unnecessarily as a result of another person's actions. Perceived injustice predicts chronic disability after musculoskeletal injury but to our knowledge has not been empirically studied in people with mild traumatic brain injuries (mTBIs). We examined perceived injustice and its correlates in patients who were slow to recover from mTBI. Patients (n = 102) were recruited from four concussion clinics. The sample was on average 41.2 years old (standard deviation [SD] = 11.7; range = 21-64), 53.9% were women, and patients were evaluated 2-26 weeks post-injury (mean = 12.1, SD = 6.3). Patients completed measures assessing perceived injustice (Injustice Experience Questionnaire; IEQ), post-concussion symptoms, post-traumatic stress, depression, pain, disability, and neuropsychological performance validity. Patients frequently endorsed items such as "I just want to have my life back" (85.2%) and "people don't understand how severe my condition is" (89.1%), with 23.5% of the sample scoring in the clinically significant range on the IEQ (Total Score >30). Internal consistency was high (Cronbach's alpha = 0.91). Patients who failed performance validity testing (Cohen's d = 0.48) or were seeking/receiving compensation (d = 0.92) reported greater perceived injustice. Greater perceived injustice was associated with greater post-concussion symptoms (r = 0.48), traumatic stress (r = 0.69), depression (r = 0.60), bodily pain (r = 0.32), and negative expectations for recovery (r = 0.40; all p < 0.01). Given that perceived injustice is a belief system that can influence health behaviors, it might be a viable target for psychological treatment. PMID- 29239279 TI - Radiosensitization by CpG ODN7909 in an epidermoid laryngeal carcinoma Hep-2 cell line. AB - Objective To evaluate the radiosensitivity effect of CpG oligodeoxyribonucleotide (ODN) 7909 on human epidermoid cancer strain-2 (Hep-2) cells in vitro and discuss the potential for improved radiotherapy treatment in patients with laryngeal squamous cell carcinoma. Methods Toll-like receptor ( TLR) 9 expression was assessed in Hep-2 cells using Western blots and reverse transcription polymerase chain reaction. Cell Counting Kit-8 was used to detect Hep-2 cell viability at 24 and 48 h following treatment with different CpG ODN7909 concentrations. Cellular colonization was evaluated using microscopy. Cell cycle distribution and apoptosis rate was determined with flow cytometry. Interleukin (IL)-12 and tumour necrosis factor (TNF)-alpha concentrations were detected by enzyme-linked immunosorbent assay. Results Hep-2 cells were found to express TLR9, and CpG ODN7909 treatment suppressed Hep-2 cell viability in a dose- and time-dependent manner. Cell survival curve analyses revealed a sensitivity enhancement ratio of the mean death dose of 1.225 for CpG ODN7909 plus irradiation versus irradiation alone. Furthermore, the population of Gap 2/mitotic-phase cells, apoptosis rate and secreted IL-12 and TNF-alpha levels were significantly increased in Hep-2 cells treated with CpG ODN7909 plus irradiation versus IR alone. Conclusion CpG ODN7909 enhanced the radiosensitivity of Hep-2 cells in vitro. PMID- 29239281 TI - Methods for Expansion of Three-Dimensional Cultures of Human Embryonic Stem Cells Using a Thermoresponsive Polymer. AB - Human pluripotent stem cells (hPSCs) are viewed as promising candidates for applications in regenerative medicine and therapy due to their proliferative and pluripotent properties. However, obtaining clinically significant numbers of hPSCs remains a limiting factor and impedes their use in therapeutic applications. Conventionally, hPSCs are cultured on two-dimensional surfaces coated with a suitable substrate, such as MatrigelTM. This method, however, requires a large surface area to generate sufficient cell numbers to meet clinical needs and is therefore impractical as a manufacturing platform for cell expansion. In addition, the use of enzymes for cell detachment and small molecule inhibitors to increase plating efficiency may impact future cell behavior when used for routine subculturing. In this study, we describe a protocol to generate and maintain hPSC aggregates in a three-dimensional suspension culture by utilizing thermoresponsive nanobridges. The property of the polymer used in the nanobridges enables passaging and expansion through a temperature change in combination with mechanically applied shear to dissociate aggregates; thus, we eliminate the need of enzymes or small molecules for cell dissociation and viability, respectively. Utilizing this platform, maintenance of human embryonic stem cells for three continuous passages demonstrated high expression levels in key pluripotent markers. PMID- 29239282 TI - Generation of Human-Induced Pluripotent Stem Cells from Wolfram Syndrome Type 2 Patients Bearing the c.103 + 1G>A CISD2 Mutation for Disease Modeling. AB - Wolfram syndrome (WFS) is a rare autosomal premature aging syndrome that shows signs of diabetes mellitus, optic atrophy, and deafness in addition to central nervous system and endocrine complications. The frequent form of WFS type 1 (WFS1) harbors causative mutations in the WFS1 gene, whereas the rare form or WFS type 2 (WFS2) involves CISD2. Mutations in these two genes are recognized by a subset of variable clinical symptoms and a set of overlapping features. In this study, we report on the generation of stable human-induced pluripotent stem cells (hiPSCs) derived from primary fibroblasts of a previously reported Italian family with CISD2 mutation (c.103 + 1G>A), occurring in the consensus intron 1 splicing site in two sisters, deleting the first exon of the transcript. The generated hiPSCs provide a cell model system to study the mutation's role in the multisystemic clinical disorders previously described and test eventual drug effects on the specific and associated clinical phenotype. PMID- 29239283 TI - Effects of stress on emotional memory in patients with Alzheimer's disease and in healthy elderly. AB - : ABSTRACTObjective:We aimed at examining the relation between stress markers (cortisol levels and state anxiety) with memory for emotional information in AD patients and in healthy elderly. DESIGN, SETTING, AND PARTICIPANTS: Baseline and changes in stress markers during memory testing were assessed in a sample of 98 elderly (46 mild-to-moderate Alzheimer's disease patients and 52 controls) recruited from dementia day centers and adult day centers, respectively. MEASUREMENTS: Salivary cortisol, state anxiety, and measures of immediate recall and delayed recognition using the International Affective Pictures System. RESULTS: Patients' performance in memory tasks was not associated with either cortisol levels or anxiety. In controls, quadratic and linear associations were found between cortisol and immediate recall scores (total and bias, respectively). Besides, quadratic and linear associations were observed between anxiety and delayed recognition scores (total and bias, respectively). CONCLUSIONS: The emotional memory of patients with Alzheimer's disease is not related to stress markers as healthy older adults' is. Future studies that include moderating variables are needed to explain the lack of association. PMID- 29239284 TI - Maternal obesity and excessive maternal weight gain during pregnancy: effects on outcomes after neonatal cardiac surgical procedures. AB - : Introduction Maternal obesity is associated with an increased risk for adverse perinatal outcomes. Obesity is also associated with a chronic inflammatory state and metabolic derangements that affect the newborn. The additional use of cardiopulmonary bypass during the neonatal period could impact the systemic inflammatory response in the immediate postoperative period that manifests as cardiac depression and multi-organ dysfunction. This study aimed to determine the association of maternal obesity and excessive weight gain during pregnancy with the immediate postoperative morbidity of neonatal patients undergoing cardiopulmonary bypass. METHODS: A retrospective review of neonates who underwent cardiopulmonary bypass within the first 30 days of life at our institution between 2011 and 2013 was conducted. Postoperative variables investigated included the duration of length of mechanical ventilation, length of stay in the ICU, peak vasoactive inotrope scores, and peak lactate level. Maternal obesity was defined as 1st trimester body mass index ?30 kg/m2. Excessive weight gain was defined as ?12 kg gained during pregnancy. In order to determine the association between maternal obesity or excessive weight gain and postoperative variables, we used multiple linear regression, adjusting for birth weight and risk adjustment for congenital heart surgery score. RESULTS: Records from 58 mother-baby dyads were examined. After controlling for birth weight and risk adjustment for congenital heart surgery score, there were no significant associations between maternal obesity and excessive weight gain during pregnancy versus all postoperative outcomes measured. CONCLUSION: Despite the known negative impact of maternal obesity on perinatal outcomes, we were unable to find associations between maternal obesity and excessive weight gain during pregnancy versus postoperative outcomes. PMID- 29239285 TI - Predictors of coverage of the national maternal pertussis and infant rotavirus vaccination programmes in England. AB - This study assessed variation in coverage of maternal pertussis vaccination, introduced in England in October 2012 in response to a national outbreak, and a new infant rotavirus vaccination programme, implemented in July 2013. Vaccine eligible patients were included from national vaccine coverage datasets and covered April 2014 to March 2015 for pertussis and January 2014 to June 2016 for rotavirus. Vaccine coverage (%) was calculated overall and by NHS England Local Team (LT), ethnicity and Index of Multiple Deprivation (IMD) quintile, and compared using binomial regression. Compared with white-British infants, the largest differences in rotavirus coverage were in 'other', white-Irish and black Caribbean infants (-13.9%, -12.1% and -10.7%, respectively), after adjusting for IMD and LT. The largest differences in maternal pertussis coverage were in black other and black-Caribbean women (-16.3% and -15.4%, respectively). Coverage was lowest in London LT for both programmes. Coverage decreased with increasing deprivation and was 14.0% lower in the most deprived quintile compared with the least deprived for the pertussis programme and 4.4% lower for rotavirus. Patients' ethnicity and deprivation were therefore predictors of coverage which contributed to, but did not wholly account for, geographical variation in coverage in England. PMID- 29239286 TI - Reduced cortical thickness and increased gyrification in generalized anxiety disorder: a 3 T MRI study. AB - BACKGROUND: Although the study of the neuroanatomical correlates of generalized anxiety disorder (GAD) is gaining increasing interest, up to now the cortical anatomy of GAD patients has been poorly investigated and still no data on cortical gyrification are available. The aim of the present study is to quantitatively examine the cortical morphology in patients with GAD compared with healthy controls (HC) using magnetic resonance imaging (MRI). To the best of our knowledge, this is the first study analyzing the gyrification patterns in GAD. METHODS: A total of 31 GAD patients and 31 HC underwent 3 T structural MRI. For each subject, cortical surface area (CSA), cortical thickness (CT), gray matter volume (GMV), and local gyrification index (LGI) were estimated in 19 regions of interest using the Freesurfer software. These parameters were then compared between the two groups using General Linear Model designs. RESULTS: Compared with HC, GAD patients showed: (1) reduced CT in right caudal middle frontal gyrus (p < 0.05, Bonferroni corrected), (2) hyper-gyrification in right fusiform, inferior temporal, superior parietal and supramarginal gyri and in left supramarginal and superior frontal gyri (p < 0.05, Bonferroni corrected). No significant alterations in CSA and GMV were observed. CONCLUSIONS: Our findings support the hypothesis of a neuroanatomical basis for GAD, highlighting a possible key role of the right hemisphere. The alterations of CT and gyrification in GAD suggest a neurodevelopmental origin of the disorder. Further studies on GAD are needed to understand the evolution of the cerebral morphology with age and during the clinical course of the illness. PMID- 29239287 TI - School performance from primary education in the adolescent offspring of parents with schizophrenia and bipolar disorder- a national, register-based study. AB - BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BP) are causes of severe disability worldwide and parents' severe mental illness (SMI) is associated with childhood adversity, and socio-emotional and cognitive problems in children. Yet, how parental BP and SZ affect educational attainment in offspring is still unclear. METHOD: We included all children (N = 684.248) born and living in Denmark between 1986 and 1996 and their parents. Our follow-up lasted from 1986 until children's graduation in 2014. The main outcome variable was their school grades following their primary education. School outcomes were divided into four categories: not graduated, low-grade point average (GPA), medium GPA and high GPA. We then performed a multiple logistic regression with medium GPA as the reference category, with the children of parents without SZ or BP as the reference group. RESULTS: Children of parents with SZ faced higher odds than their peers of not graduating primary education (OR 2.6), along with low GPA (odds ratios (OR) 1.6) and lower odds for a high GPA (OR 0.7). Moreover, it was the children of mothers rather than fathers with BP who had higher odds of not graduating primary education (OR 1.6). Lastly, child placement was associated with lower grades and lower graduation rates, and outcomes for children of parents with SMI were favorable compared with other children placed in care. CONCLUSION: For children, parental SZ is associated with lower grades and lower chances for graduating primary education. In contrast, the children of parents with BP were indistinguishable from the reference group regarding school grades. This signifies that specificity of parental severe mental illness is important in relation to educational achievement of children. PMID- 29239288 TI - Metaxonchium toroense n. sp. (Nematoda, Dorylaimida, Belondiridae) from Costa Rica, with the first molecular study of a representative of the genus. AB - The new species Metaxonchium toroense n. sp. from natural habitats of Costa Rica is described, including light microscopy (LM), scanning electron microscopy (SEM) and molecular (D2-D3 28S rDNA) analyses. The new species is characterized by its general size, the dimensions and appearance of its lip region, the length of the odontostyle and its fusiform aspect, the length of the neck and its pharyngeal expansion, the reduction of the anterior genital branch to a very short uterine sac without any rudiment of ovary or oviduct, tripartite and non-echinophor posterior uterus, the somewhat posterior vulva position, the length and shape of the caudal region, and the absence of males. Molecular analyses, the first to be performed on a Metaxonchium species, show a close relationship of the new species with representatives of the genera Axonchoides and Syncheilaxonchium. PMID- 29239289 TI - Immune complex detection in saliva samples: an innovative proposal for the diagnosis of human strongyloidiasis. AB - Human strongyloidiasis is caused by helminth Strongyloides stercoralis. It has a worldwide distribution, often neglected and cause of severe morbidity. The parasitological diagnosis is hindered by the low and irregular amount of larvae in feces. The goal of the present study was to detect IgG and IgG immune complex using conventional serum samples and saliva as alternative samples. We collected samples from 60 individuals, namely: group I composed of 30 healthy individuals; and group II composed of 30 individuals eliminating S. stercoralis larvae in feces. We calculated the area under the curve, general index of diagnostic accuracy, Kappa index and determined the correlations between different diagnostic tests. The detection of IgG levels was performed by an immunoenzymatic assay with alkaline extract of S. venezuelensis larvae as antigen. Positivity of anti-S. stercoralis IgG in serum samples from group I was 3.3%, and from group II 93.3%. The detection of immune complex indicated that group I exhibited 3.3% and group II 56.7%. In the saliva samples, IgG detection was 26.7% for group I and 43.3% for group II. Immune complex was detected in 20% of group I, and 30% of group II. IgG immune complex in conventional serum samples and saliva as alternative samples can be considered biomarkers for the diagnosis of active strongyloidiasis. PMID- 29239290 TI - Re-evaluation of the life cycle of Eimeria maxima Tyzzer, 1929 in chickens (Gallus domesticus). AB - A time-course study was conducted to resolve discrepancies in the literature and better define aspects of the Eimeria maxima life cycle such, as sites of development and both morphology and number of asexual stages. Broiler chickens were inoculated orally with five million E. maxima oocysts (APU1), and were necropsied at regular intervals from 12 to 120 h p.i. Small intestine tissue sections and smears were examined for developmental stages. The jejunum contained the highest numbers of developmental stages. At 12 h p.i., sporozoites were observed inside a parasitophorous vacuole (PV) in the epithelial villi and the lamina propria. By 24 h, sporozoites enclosed by a PV were observed in enterocytes of the glands of Lieberkuhn. At 48 h p.i., sporozoites, elongated immature and mature schizonts, were all seen in the glands with merozoites budding off from a residual body. By 60 h, second-generation, sausage-shaped schizonts containing up to 12 merozoites were observed around a residual body in the villar tip of invaded enterocytes. At 72 and 96 h, profuse schizogony associated with third- and fourth-generation schizonts was observed throughout the villus. At 120 h, another generation (fifth) of schizonts were seen in villar tips as well as in subepithelium where gamonts and oocysts were also present; a few gamonts were in epithelium. Our finding of maximum parasitization of E. maxima in jejunum is important because this region is critical for nutrient absorption and weight gain. PMID- 29239291 TI - The impact of schizophrenia and mood disorder risk alleles on emotional problems: investigating change from childhood to middle age. AB - BACKGROUND: Previous studies find that both schizophrenia and mood disorder risk alleles contribute to adult depression and anxiety. Emotional problems (depression or anxiety) begin in childhood and show strong continuities into adult life; this suggests that symptoms are the manifestation of the same underlying liability across different ages. However, other findings suggest that there are developmental differences in the etiology of emotional problems at different ages. To our knowledge, no study has prospectively examined the impact of psychiatric risk alleles on emotional problems at different ages in the same individuals. METHODS: Data were analyzed using regression-based analyses in a prospective, population-based UK cohort (the National Child Development Study). Schizophrenia and major depressive disorder (MDD) polygenic risk scores (PRS) were derived from published Psychiatric Genomics Consortium genome-wide association studies. Emotional problems were assessed prospectively at six time points from age 7 to 42 years. RESULTS: Schizophrenia PRS were associated with emotional problems from childhood [age 7, OR 1.09 (1.03-1.15), p = 0.003] to mid life [age 42, OR 1.10 (1.05-1.17), p < 0.001], while MDD PRS were associated with emotional problems only in adulthood [age 42, OR 1.06 (1.00-1.11), p = 0.034; age 7, OR 1.03 (0.98-1.09), p = 0.228]. CONCLUSIONS: Our prospective investigation suggests that early (childhood) emotional problems in the general population share genetic risk with schizophrenia, while later (adult) emotional problems also share genetic risk with MDD. The results suggest that the genetic architecture of depression/anxiety is not static across development. PMID- 29239292 TI - Ethnic density effects for adult mental health: systematic review and meta analysis of international studies. AB - BACKGROUND: Despite increased ethnic diversity in more economically developed countries it is unclear whether residential concentration of ethnic minority people (ethnic density) is detrimental or protective for mental health. This is the first systematic review and meta-analysis covering the international literature, assessing ethnic density associations with mental health outcomes. METHODS: We systematically searched Medline, PsychINFO, Sociological Abstracts, Web of Science from inception to 31 March 2016. We obtained additional data from study authors. We conducted random-effects meta-analysis taking into account clustering of estimates within datasets. Meta-regression assessed heterogeneity in studies due to ethnicity, country, generation, and area-level deprivation. Our main exposure was ethnic density, defined as the residential concentration of own racial/ethnic minority group. Outcomes included depression, anxiety and the common mental disorders (CMD), suicide, suicidality, psychotic experiences, and psychosis. RESULTS: We included 41 studies in the review, with meta-analysis of 12 studies. In the meta-analyses, we found a large reduction in relative odds of psychotic experiences [odds ratio (OR) 0.82 (95% confidence interval (CI) 0.76 0.89)] and suicidal ideation [OR 0.88 (95% CI 0.79-0.98)] for each 10 percentage point increase in own ethnic density. For CMD, depression, and anxiety, associations were indicative of protective effects of own ethnic density; however, results were not statistically significant. Findings from narrative review were consistent with those of the meta-analysis. CONCLUSIONS: The findings support consistent protective ethnic density associations across countries and racial/ethnic minority populations as well as mental health outcomes. This may suggest the importance of the social environment in patterning detrimental mental health outcomes in marginalized and excluded population groups. PMID- 29239293 TI - The interplay between cognitive ability, alcohol consumption, and health characteristics. AB - BACKGROUND: Higher cognitive ability is associated with favourable health characteristics. The relation between ability and alcohol consumption, and their interplay with other health characteristics, is unclear. We aimed to assess the relationship between cognitive ability and alcohol consumption and to assess whether alcohol consumption relates differently to health characteristics across strata of ability. METHODS: For 63 120 Norwegian males, data on cognitive ability in early adulthood were linked to midlife data on alcohol consumption frequency (times per month, 0-30) and other health characteristics, including cardiovascular risk factors and mental distress. Relations were assessed using linear regression and reported as unstandardised beta coefficients [95% confidence interval (CI)]. RESULTS: The mean +/- s.d. frequency of total alcohol consumption in the sample was 4.0 +/- 3.8 times per month. In the low, medium, and high group of ability, the frequencies were 3.0 +/- 3.3, 3.7 +/- 3.5, and 4.7 +/- 4.1, respectively. In the full sample, alcohol consumption was associated with physical activity, heart rate, fat mass, smoking, and mental distress. Most notably, each additional day of consumption was associated with a 0.54% (0.44 0.64) and 0.14% (0.09-0.18) increase in the probability of current smoking and mental distress, respectively. In each strata of ability (low, medium, high), estimates were 0.87% (0.57-1.17), 0.48% (0.31-0.66) and 0.49% (0.36-0.62) for current smoking, and 0.44% (0.28-0.60), 0.10% (0.02-0.18), and 0.09% (0.03-0.15) for mental distress, respectively. CONCLUSIONS: Participants with low cognitive ability drink less frequently, but in this group, more frequent alcohol consumption is more strongly associated with adverse health characteristics. PMID- 29239294 TI - Demographics, Interests, and Quality of Life of Canadian Neurosurgery Residents. AB - BACKGROUND: Neurosurgical residents face a unique combination of challenges, including long duty hours, technically challenging cases, and uncertain employment prospects. We sought to assess the demographics, interests, career goals, self-rated happiness, and overall well-being of Canadian neurosurgery residents. METHODS: A cross-sectional survey was developed and sent through the Canadian Neurosurgery Research Collaborative to every resident enrolled in a Canadian neurosurgery program as of April 1, 2016. RESULTS: We analyzed 76 completed surveys of 146 eligible residents (52% response rate). The median age was 29 years, with 76% of respondents being males. The most popular subspecialties of interest for fellowship were spine, oncology, and open vascular neurosurgery. The most frequent self-reported number of worked hours per week was the 80- to 89-hour range. The majority of respondents reported a high level of happiness as well as stress. Sense of accomplishment and fatigue were reported as average to high and overall quality of life was low for 19%, average for 49%, and high for 32%. Satisfaction with work-life balance was average for 44% of respondents and was the only tested domain in which significant dissatisfaction was identified (18%). Overall, respondents were highly satisfied with their choice of specialty, choice of program, surgical exposure, and work environment; however, intimidation was reported in 36% of respondents and depression by 17%. CONCLUSIONS: Despite a challenging residency and high workload, the majority of Canadian neurosurgery residents are happy and satisfied with their choice of specialty and program. However, work-life balance, employability, resident intimidation, and depression were identified as areas of active concern. PMID- 29239295 TI - Kdm6a overexpression improves the development of cloned mouse embryos. AB - Somatic cell nuclear transfer (SCNT) is an important technique for life science research. However, most SCNT embryos fail to develop to term due to undefined reprogramming defects. Here, we show that abnormal Xi occurs in somatic cell NT blastocysts, whereas in female blastocysts derived from cumulus cell nuclear transfer, both X chromosomes were inactive. H3K27me3 removal by Kdm6a mRNA overexpression could significantly improve preimplantation development of NT embryos, and even reached a 70.2% blastocyst rate of cleaved embryos compared with the 38.5% rate of the control. H3K27me3 levels were significantly reduced in blastomeres from cloned blastocysts after overexpression of Kdm6a. qPCR indicated that rDNA transcription increased in both NT embryos and 293T cells after overexpression of Kdm6a. Our findings demonstrate that overexpression of Kdm6a improved the development of cloned mouse embryos by reducing H3K27me3 and increasing rDNA transcription. PMID- 29239296 TI - Ascites in an uncorrected tetralogy of Fallot with pulmonary valve absence in an adult patient. AB - This is a case of a 37-year-old woman with uncorrected tetralogy of Fallot with the absence of pulmonary valve and history of heart murmur in childhood who did not have a medical approach. At 29 years of age she started with dyspnoea that in the last 7 months progressed to be of small effort and also referred increase of the abdominal perimeter. PMID- 29239297 TI - Dynamic flow imaging using 320-detector row CT and motion coherence analysis in coronary aneurysms associated with Kawasaki disease. AB - : Introduction We propose a new dynamic flow imaging using 320-detector row CT, and investigate the assessment of coronary flow in aneurysms of Kawasaki disease in adulthood. METHODS: Six patients with Kawasaki disease and coronary aneurysms associated (26.7 years old) and six controls were enrolled. Dynamic coronary CT angiography with 320-row CT was continuously performed at mid-diastole throughout 15-25 cardiac cycles with prospective Electrocardiogram gating after injection of contrast media. Dynamic data sets of 15-25 cycles were computed into 90-100 data sets by motion coherence image processing. Next, time-density curves for coronary arteries were calculated for all the phases. On the basis of the maximum slope method, coronary flow index was defined as the ratio of the maximum upslope of the attenuation of coronary arteries to the upslope of the attenuation of ascending aorta on the time-density curves. Coronary flow indexes for the proximal and distal sites of coronary arteries and intra-aneurysm were measured. PMID- 29239298 TI - Optimized conditions for the in vitro excystment of Calicophoron daubneyi metacercariae. AB - Paramphistomosis, caused by Calicophoron daubneyi, is an emerging infection of ruminants throughout Western Europe. Despite its prevalence, many questions remain regarding the basic biology of this parasite and how it interacts with its host. Consequently, there is a need to develop methods to study C. daubneyi in vitro to improve our understanding of rumen fluke biology. Towards this, we aimed to identify a suitable protocol for in vitro excystment of C. daubneyi metacercariae. Six methods that have been used to excyst metacercariae from a number of trematode species were tested with C. daubneyi metacercariae. Three of these achieved an average of >50% excystment whilst one method, which included an acid-pepsin treatment, incubation in reducing conditions and an alkaline/bile salt solution to activate the larvae, consistently gave >80% excystment. The latter protocol also showed no detrimental effect on the motility of newly excysted juvenile (NEJ) parasites when observed for up to 24 h in RPMI 1640 medium post-excystment. The successful production of C. daubneyi NEJs in vitro is a significant step forward, and will enable the discovery of infective stage specific parasite antigens and facilitate drug screening trials, to aid the development of much needed diagnostic and therapeutic options for paramphistomosis. PMID- 29239300 TI - Hydrodynamic instabilities in miscible fluids. AB - Hydrodynamic instabilities in miscible fluids are ubiquitous, from natural phenomena up to geological scales, to industrial and technological applications, where they represent the only way to control and promote mixing at low Reynolds numbers, well below the transition from laminar to turbulent flow. As for immiscible fluids, the onset of hydrodynamic instabilities in miscible fluids is directly related to the physics of their interfaces. The focus of this review is therefore on the general mechanisms driving the growth of disturbances at the boundary between miscible fluids, under a variety of forcing conditions. In the absence of a regularizing mechanism, these disturbances would grow indefinitely. For immiscible fluids, interfacial tension provides such a regularizing mechanism, because of the energy cost associated to the creation of new interface by a growing disturbance. For miscible fluids, however, the very existence of interfacial stresses that mimic an effective surface tension is debated. Other mechanisms, however, may also be relevant, such as viscous dissipation. We shall review the stabilizing mechanisms that control the most common hydrodynamic instabilities, highlighting those cases for which the lack of an effective interfacial tension poses deep conceptual problems in the mathematical formulation of a linear stability analysis. Finally, we provide a short overview on the ongoing research on the effective, out of equilibrium interfacial tension between miscible fluids. PMID- 29239299 TI - How does obesity lead to insulin resistance? AB - Experiments on mice show that an enzyme called DNA methyltransferase 3a is involved in insulin resistance via an epigenetic mechanism. PMID- 29239301 TI - Intermediate valence state of the Sm and Eu in SmB6 and EuCu2Si2: neutron spectroscopy data and analysis. AB - The analysis of the magnetic neutron scattering data for Sm (SmB6, Sm(Y)S) and Eu (EuCu2Si2-xGex) intermediate valence compounds has been performed in terms of generalized model of the intermediate-radius exciton. A special attention is drawn to the correlation between average ion's valence and parameters of the low energy excitation in the neutron spectra, such as resonance mode, including its magnetic form factor. Along with specific features of the intermediate valence state formation for Sm and Eu ions, common physical mechanisms have been revealed for the systems based on these elements from the middle part of the rare-earth series. The consistent description of the existing experimental data has been obtained by using a loosely bound hole concept for Eu f-electron shell in the intermediate valence state, in analogy with previously established loosely bound electron model for Sm ion. PMID- 29239302 TI - Pressure dependence of Ce valence in CeRhIn5. AB - We have studied the Ce valence as a function of pressure in CeRhIn5 at 300 K and at 22 K using x-ray absorption spectroscopy in partial fluorescent yield mode. At room temperature, we found no detectable change in Ce valence greater than 0.01 up to a pressure of 5.5 GPa. At 22 K, the valence remains robust against pressure below 6 GPa, in contrast to the predicted valence crossover at P = 2.35 GPa. This work yields an upper limit for the change in Ce-valence and suggests that the critical valence fluctuation scenario, in its current form, is unlikely. PMID- 29239303 TI - Ultrafast dynamics of differently aligned COOH-DTE-BODIPY conjugates linked to the surface of TiO2. AB - The photoinduced dynamics of two DTE-BODIPY conjugates A, B with carboxylic acid anchoring groups coupled to the surface of TiO2 were studied by ultrafast transient absorption spectroscopy. For compound A, with an orthogonal orientation of the BODIPY chromophore and the photoswitchable DTE unit, a charge separated state could not be reliably detected. Nevertheless, besides the energy transfer from the BODIPY to the closed DTE, indications for an electron transfer reaction were found by analyzing fluorescence quenching on TiO2 in steady state fluorescence measurements. For compound B with a parallel orientation of chromophore and photoswitch, a charge separated state was conclusively identified via the observation of a positive absorption signal (at lambdapr > 610 nm) at later delay times. An electron transfer rate of 7 x 1010 s-1 can be extracted, indicating slower processes in the dyads in comparison to previously published electron transfer reactions of DTE compounds coupled to TiO2. PMID- 29239304 TI - Bound magnetic polaron in Zn-rich cobalt-doped ZnSe nanowires. AB - The micro-luminescence spectra of the diluted magnetic semiconductor (DMS) can reflect the spin-exciton interaction and related relaxation process. Here the micro-photoluminescence (micro-PL) spectra and PL lifetime measurements have been done on an individual ferromagnetic (FM)-coupled cobalt (Co) doped zinc selenide (ZnSe) nanowire. There occurs a double-peak profile in its near bandedge emission spectrum: the first peak is from free exciton (FX) and the second comes from magnetic polaron (MP). In their temperature dependent PL spectra, the MP emission peak demonstrates obviously temperature-independent behavior, in contrast to the behaviors of FX and reported exciton MP in nanobelt. It is found that in this Co(II) doped ZnSe nanowires, this MP's temperature-independent emission is related to the coupling between exciton and a FM nanocluster (???). The nanocluster is likely due to the interaction of Se vacancies of the wide bandgap semiconductors with the antiferromagnetic (AFM) arrangement transition metal (TM) ions in these Se-deficient Co doped ZnSe nanowires. These results reflect that the AFM coupling TM ions pair can give rise to FM behavior with the involvement of positive charge defect, also indicating that the micro-luminescence detection can be used to study the magnetic coupling in DMS. PMID- 29239305 TI - A mean-field approach to Kondo-attractive-Hubbard model. AB - With the purpose of investigating coexistence between magnetic order and superconductivity, we consider a model in which conduction electrons interact with each other, via an attractive Hubbard on-site coupling U, and with local moments on every site, via a Kondo-like coupling, J. The model is solved on a simple cubic lattice through a Hartree-Fock approximation, within a 'semi classical' framework which allows spiral magnetic modes to be stabilized. For a fixed electronic density, n c , the small J region of the ground state (T = 0) phase diagram displays spiral antiferromagnetic (SAFM) states for small U. Upon increasing U, a state with coexistence between superconductivity (SC) and SAFM sets in; further increase in U turns the spiral mode into a Neel antiferromagnet. The large J region is a (singlet) Kondo phase. At finite temperatures, and in the region of coexistence, thermal fluctuations suppress the different ordered phases in succession: the SAFM phase at lower temperatures and SC at higher temperatures; also, reentrant behaviour is found to be induced by temperature. Our results provide a qualitative description of the competition between local moment magnetism and superconductivity in the borocarbides family. PMID- 29239306 TI - In-plane x-ray diffraction for characterization of monolayer and few-layer transition metal dichalcogenide films. AB - There is significant interest in the growth of single crystal monolayer and few layer films of transition metal dichalcogenides (TMD) and other 2D materials for scientific exploration and potential applications in optics, electronics, sensing, catalysis and others. The characterization of these materials is crucial in determining the properties and hence the applications. The ultra-thin nature of 2D layers presents a challenge to the use of x-ray diffraction (XRD) analysis with conventional Bragg-Brentano geometry in analyzing the crystallinity and epitaxial orientation of 2D films. To circumvent this problem, we demonstrate the use of in-plane XRD employing lab scale equipment which uses a standard Cu x-ray tube for the analysis of the crystallinity of TMD monolayer and few-layer films. The applicability of this technique is demonstrated in several examples for WSe2 and WS2 films grown by chemical vapor deposition on single crystal substrates. In plane XRD was used to determine the epitaxial relation of WSe2 grown on c-plane sapphire and on SiC with an epitaxial graphene interlayer. The evolution of the crystal structure orientation of WS2 films on sapphire as a function of growth temperature was also examined. Finally, the epitaxial relation of a WS2/WSe2 vertical heterostructure deposited on sapphire substrate was determined. We observed that WSe2 grows epitaxially on both substrates employed in this work under all conditions studied while WS2 exhibits various preferred orientations on sapphire substrate which are temperature dependent. In contrast to the sapphire substrate, WS2 deposited on WSe2 exhibits only one preferred orientation which may provide a route to better control the orientation and crystal quality of WS2. In the case of epitaxial graphene on SiC, no graphene-related peaks were observed in in-plane XRD while its presence was confirmed using Raman spectroscopy. This demonstrates the limitation of the in-plane XRD technique for characterizing low electron density materials. PMID- 29239307 TI - On the role of tip curvature on flapping plates. AB - During the flapping motion of a fish's tail, the caudal fin exhibits antero posterior bending and dorso-ventral bending, the latter of which is referred to as chord-wise bending herein. The impact of chord-wise tip curvature on the hydrodynamic forces for flapping plates is investigated to explore potential mechanisms to improve the maneuverability or the performance of autonomous underwater vehicles. First, actuated chord-wise tip curvature is explored. Comparison of rigid curved geometries to a rigid flat plate as a baseline suggests that an increased curvature decreases the generated forces. An actuated plate with a dynamic tip curvature is created to illustrate a modulation of this decrease in forces. Second, the impact of curvature is isolated using curved plates with an identical planform area. Comparison of rigid curved geometries as a baseline corroborates the result that an increased curvature decreases the generated forces, with the exception that presenting a concave geometry into the flow increases the thrust and the efficiency. A passively-actuated plate is designed to capitalize on this effect by presenting a concave geometry into the flow throughout the cycle. The dynamically and passively actuated plates show potential to improve the maneuverability and the efficiency of autonomous underwater vehicles, respectively. PMID- 29239308 TI - Enhanced field emission properties of carbon nanotube bundles confined in SiO2 pits. AB - It has been widely reported that carbon nanotubes (CNTs) exhibit superior field emission (FE) properties due to their high aspect ratios and unique structural properties. Among the various types of CNTs, random growth CNTs exhibit promising FE properties due to their reduced inter-tube screening effect. However, growing random growth CNTs on individual catalyst islands often results in spread out CNT bundles, which reduces overall field enhancement. In this study, significant improvement in FE properties in CNT bundles is demonstrated by confining them in microfabricated SiO2 pits. Growing CNT bundles in narrow (0.5 MUm diameter and 2 MUm height) SiO2 pits achieves FE current density of 1-1.4 A cm-2, which is much higher than for freestanding CNT bundles (76.9 mA cm-2). From the Fowler Nordheim plots, confined CNT bundles show a higher field enhancement factor. This improvement can be attributed to the reduced bundle diameter by SiO2 pit confinement, which yields bundles with higher aspect ratios. Combining the obtained outcomes, it can be conclusively summarized that confining CNTs in SiO2 pits yields higher FE current density due to the higher field enhancement of confined CNTs. PMID- 29239309 TI - Detecting coupling of Majorana bound states with an Aharonov-Bohm interferometer. AB - We study the transport properties of an interferometer composed by a quantum dot (QD) coupled with two normal leads and two one-dimensional topological superconductor nanowires (TNWs) hosting Majorana bound states (MBS) at their ends. The geometry considered is such that one TNW has both ends connected with the QD, forming an Aharonov-Bohm (AB) interferometer threaded by an external magnetic flux, while the other TNW is placed near the interferometer TNW. This geometry can alternatively be seen as a long wire contacted across a local defect, with possible coupling between independent-MBS. We use the Green's function formalism to calculate the conductance across normal current leads on the QD. We find that the conductance exhibits a half-quantum value regardless of the AB phase and location of the dot energy level, whenever the interferometer configuration interacts with the neighboring TNW. These findings suggest that such a geometry could be used for a sensitive detection of MBS interactions across TNWs, exploiting the high sensitivity of conductance to the AB phase in the interferometer. PMID- 29239310 TI - MicroRNAs as diagnostic markers and therapeutic targets for traumatic brain injury. AB - Traumatic brain injury (TBI) is characterized by primary damage to the brain from the external mechanical force and by subsequent secondary injury due to various molecular and pathophysiological responses that eventually lead to neuronal cell death. Secondary brain injury events may occur minutes, hours, or even days after the trauma, and provide valuable therapeutic targets to prevent further neuronal degeneration. At the present time, there is no effective treatment for TBI due, in part, to the widespread impact of numerous complex secondary biochemical and pathophysiological events occurring at different time points following the initial injury. MicroRNAs control a range of physiological and pathological functions such as development, differentiation, apoptosis and metabolism, and may serve as potential targets for progress assessment and intervention against TBI to mitigate secondary damage to the brain. This has implications regarding improving the diagnostic accuracy of brain impairment and long-term outcomes as well as potential novel treatments. Recent human studies have identified specific microRNAs in serum/plasma (miR-425-p, -21, -93, -191 and -499) and cerebro-spinal fluid (CSF) (miR-328, -362-3p, -451, -486a) as possible indicators of the diagnosis, severity, and prognosis of TBI. Experimental animal studies have examined specific microRNAs as biomarkers and therapeutic targets for moderate and mild TBI (e.g., miR-21, miR-23b). MicroRNA profiling was altered by voluntary exercise. Differences in basal microRNA expression in the brain of adult and aged animals and alterations in response to TBI (e.g., miR-21) have also been reported. Further large-scale studies with TBI patients are needed to provide more information on the changes in microRNA profiles in different age groups (children, adults, and elderly). PMID- 29239311 TI - Interferon regulatory factor 2 binding protein 2: a new player of the innate immune response for stroke recovery. AB - Ischemic brain injury triggers an inflammatory response. This response is necessary to clear damaged brain tissue but can also exacerbate brain injury. Microglia are the innate immune cells of the brain that execute this critical function. In healthy brain, microglia perform a housekeeping function, pruning unused synapses between neurons. However, microglia become activated to an inflammatory phenotype upon brain injury. Interferon regulatory factors modulate microglial activation and their production of inflammatory cytokines. This review briefly discusses recent findings pertaining to these regulatory mechanisms in the context of stroke recovery. PMID- 29239312 TI - Endogenous retinal neural stem cell reprogramming for neuronal regeneration. AB - In humans, optic nerve injuries and associated neurodegenerative diseases are often followed by permanent vision loss. Consequently, an important challenge is to develop safe and effective methods to replace retinal neurons and thereby restore neuronal functions and vision. Identifying cellular and molecular mechanisms allowing to replace damaged neurons is a major goal for basic and translational research in regenerative medicine. Contrary to mammals, the zebrafish has the capacity to fully regenerate entire parts of the nervous system, including retina. This regenerative process depends on endogenous retinal neural stem cells, the Muller glial cells. Following injury, zebrafish Muller cells go back into cell cycle to proliferate and generate new neurons, while mammalian Muller cells undergo reactive gliosis. Recently, transcription factors and microRNAs have been identified to control the formation of new neurons derived from zebrafish and mammalian Muller cells, indicating that cellular reprogramming can be an efficient strategy to regenerate human retinal neurons. Here we discuss recent insights into the use of endogenous neural stem cell reprogramming for neuronal regeneration, differences between zebrafish and mammalian Muller cells, and the need to pursue the identification and characterization of new molecular factors with an instructive and potent function in order to develop theurapeutic strategies for eye diseases. PMID- 29239314 TI - Taking out the garbage: cathepsin D and calcineurin in neurodegeneration. AB - Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathepsin D to the Ca2+/calmodulin dependent phosphatase calcineurin. In a yeast model for Parkinson's disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca2+ homeostasis as well as lysosomal impairment is connected to a plethora of neurodegenerative disorders, this novel interplay might very well impact pathologies beyond Parkinson's disease. PMID- 29239313 TI - Regulation of neuronal survival by DNA methyltransferases. AB - The limited regenerative capacity of neuronal cells requires tight orchestration of cell death and survival regulation in the context of longevity, age-associated diseases as well as during the development of the nervous system. Subordinate to genetic networks epigenetic mechanisms like DNA methylation and histone modifications are involved in the regulation of neuronal development, function and aging. DNA methylation by DNA methyltransferases (DNMTs), mostly correlated with gene silencing, is a dynamic and reversible process. In addition to their canonical actions performing cytosine methylation, DNMTs influence gene expression by interactions with histone modifying enzymes or complexes increasing the complexity of epigenetic transcriptional networks. DNMTs are expressed in neuronal progenitors, post-mitotic as well as adult neurons. In this review, we discuss the role and mode of actions of DNMTs including downstream networks in the regulation of neuronal survival in the developing and aging nervous system and its relevance for associated disorders. PMID- 29239315 TI - The role of general anesthetics and the mechanisms of hippocampal and extra hippocampal dysfunctions in the genesis of postoperative cognitive dysfunction. AB - Postoperative cognitive dysfunction (POCD) is a multifactorial process with a huge number of predisposing, causal, and precipitating factors. In this scenario, the neuroinflammation and the microglial activation play a pivotal role by triggering and amplifying a complex cascade involving the immuno-hormonal activation, the micro circle alterations, the hippocampal oxidative stress activation and, finally, an increased blood-brain barrier's permeability. While the role of anesthetics in the POCD's genesis in humans is debated, a huge number of preclinical studies have been conducted on the topic and many mechanisms have been proposed to explain the potential neurodegenerative effects of general anesthetics. Probably, the problem concerns on what we are searching for and how we are searching and, surprisingly, preclinical studies showed that anesthetics may also manifest neuroprotective properties. The aim of this paper is to offer an overview on the potential impact of general anesthetics on POCD. Mechanisms of hippocampal and extra-hippocampal dysfunction due to neuroinflammation are discussed, whereas further research perspectives are also given. PMID- 29239316 TI - Design and criteria of electrospun fibrous scaffolds for the treatment of spinal cord injury. AB - The complex pathophysiology of spinal cord injury may explain the current lack of an effective therapeutic approach for the regeneration of damaged neuronal cells and the recovery of motor functions. Many efforts have been performed to design and develop suitable scaffolds for spinal cord regeneration, keeping in mind that the reconstruction of a pro-regenerative environment is the key challenge for an effective neurogenesis. The aim of this review is to outline the main features of an ideal scaffold, based on biomaterials, produced by the electrospinning technique and intended for the spinal cord regeneration. An overview of the polymers more investigated in the production of neural fibrous scaffolds is also provided. PMID- 29239317 TI - DeltaN-Bcl-xL, a therapeutic target for neuroprotection. AB - The B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produces a fragmented form, DeltaN-Bcl-xL. Accumulation of DeltaN-Bcl-xL is associated with mitochondrial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of DeltaN-Bcl-xL protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor ABT-737 exerts dose dependent effects in primary neurons. When primary hippocampal neurons were treated with 1 MUM ABT-737, glutamate-mediated mitochondrial damage and neuronal death were exacerbated, whereas 10 nM ABT-737, a 100-fold lower concentration, protected mitochondrial function and enhanced neuronal viability against glutamate toxicity. In addition, we suggested acute vs. prolonged formation of DeltaN-Bcl-xL may have different effects on mitochondrial or neuronal functions. Unlike acute production of DeltaN-Bcl-xL by glutamate, overexpression of DeltaN Bcl-xL did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for DeltaN-Bcl-xL-mediated mitochondrial dysfunction. Although the detailed mechanism of ABT-mediated neurotoxicity neuroprotection is still unclear, our study shows that the mitochondrial membrane protein DeltaN-Bcl-xL is a central target for interventions. PMID- 29239318 TI - Pathophysiology of periventricular leukomalacia: What we learned from animal models. PMID- 29239319 TI - DJ-1 as a deglycating enzyme: A unique function to explain a multifaceted protein? PMID- 29239320 TI - Outlook on the neuroprotective effect of estrogen. PMID- 29239321 TI - Should we have a guard against therapeutic nihilism for patients with severe traumatic brain injury? PMID- 29239322 TI - Targeting inflammation to reduce brain injury in growth restricted newborns: A potential treatment? PMID- 29239323 TI - Targeting mitoNEET with pioglitazone for therapeutic neuroprotection after spinal cord injury. PMID- 29239324 TI - Motor neuroprosthesis for injured spinal cord: who is an ideal candidate? PMID- 29239325 TI - Therapeutic capacities of human and mouse skeletal muscle-derived stem cells for a long gap peripheral nerve injury. PMID- 29239326 TI - Targeting transcriptional regulators to regenerate midbrain dopaminergic axons in Parkinson's disease. PMID- 29239327 TI - Influence of vascular endothelial growth factor and radiation on gap junctional intercellular communication in glioblastoma multiforme cell lines. AB - Glioblastoma multiforme (GBM) is a highly aggressive glial brain tumor with an unfavorable prognosis despite all current therapies including surgery, radiation and chemotherapy. One characteristic of this tumor is a strong synthesis of vascular endothelial growth factor (VEGF), an angiogenesis factor, followed by pronounced vascularization. VEGF became a target in the treatment of GBM, for example with bevacizumab or the tyrosine kinase inhibitor axitinib, which blocks VEGF receptors. To improve patients' prognosis, new targets in the treatment of GBM are under investigations. The role of gap junctions in GBM remains unknown, but some experimental therapies affect these intercellular channels to treat the tumor. Gap junctions are composed of connexins to allow the transport of small molecules between adjacent cells through gap junctional intercellular communication (GJIC). Based on data derived from astrocytes in former studies, which show that VEGF is able to enhance GJIC, the current study analyzed the effects of VEGF, radiation therapy and VEGF receptor blockade by axitinib on GJIC in human GBM cell lines U-87 and U-251. While VEGF is able to induce GJIC in U 251 cells but not in U-87 cells, radiation enhances GJIC in both cell lines. VEGF receptor blockade by axitinib diminishes radiation induced effects in U-251 partially, while increases GJIC in U-87 cells. Our data indicate that VEGF and radiation are both modifying components of GJIC in pathologic brain tumor tissue. PMID- 29239328 TI - Leap Motion-based virtual reality training for improving motor functional recovery of upper limbs and neural reorganization in subacute stroke patients. AB - Virtual reality is nowadays used to facilitate motor recovery in stroke patients. Most virtual reality studies have involved chronic stroke patients; however, brain plasticity remains good in acute and subacute patients. Most virtual reality systems are only applicable to the proximal upper limbs (arms) because of the limitations of their capture systems. Nevertheless, the functional recovery of an affected hand is most difficult in the case of hemiparesis rehabilitation after a stroke. The recently developed Leap Motion controller can track the fine movements of both hands and fingers. Therefore, the present study explored the effects of a Leap Motion-based virtual reality system on subacute stroke. Twenty six subacute stroke patients were assigned to an experimental group that received virtual reality training along with conventional occupational rehabilitation, and a control group that only received conventional rehabilitation. The Wolf motor function test (WMFT) was used to assess the motor function of the affected upper limb; functional magnetic resonance imaging was used to measure the cortical activation. After four weeks of treatment, the motor functions of the affected upper limbs were significantly improved in all the patients, with the improvement in the experimental group being significantly better than in the control group. The action performance time in the WMFT significantly decreased in the experimental group. Furthermore, the activation intensity and the laterality index of the contralateral primary sensorimotor cortex increased in both the experimental and control groups. These results confirmed that Leap Motion-based virtual reality training was a promising and feasible supplementary rehabilitation intervention, could facilitate the recovery of motor functions in subacute stroke patients. The study has been registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-OCH-12002238). PMID- 29239329 TI - Activation of the Akt/mTOR signaling pathway: A potential response to long-term neuronal loss in the hippocampus after sepsis. AB - Survivors of sepsis may suffer chronic cognitive impairment as a long-term sequela. However, the precise mechanisms of cognitive dysfunction after sepsis are not well understood. We employed the cecal ligation-and-puncture-induced septic mouse model. We observed elevated phosphorylation of Akt, mammalian target of rapamycin (mTOR) and p70S6K on days 14 and 60, progressive neuronal loss in the cornu ammonis 1 region, and abnormal neuronal morphology in the hippocampus in the sepsis mouse model. These findings indicate that changes in neuronal morphology and number in the hippocampus after sepsis were associated with strong activation of the Akt/mTOR signaling pathway, and may reflect a "self-rescuing" feedback response to neuronal loss after sepsis. PMID- 29239330 TI - Expression of NG2 and platelet-derived growth factor receptor alpha in the developing neonatal rat brain. AB - Platelet-derived growth factor receptor alpha (PDGFRalpha) is a marker of oligodendrocyte precursor cells in the central nervous system. NG2 is also considered a marker of oligodendrocyte precursor cells. However, whether there are differences in the distribution and morphology of oligodendrocyte precursor cells labeled by NG2 or PDGFRalpha in the developing neonatal rat brain remains unclear. In this study, by immunohistochemical staining, NG2 positive (NG2+) cells were ubiquitous in the molecular layer, external pyramidal layer, internal pyramidal layer, and polymorphic layer of the cerebral cortex, and corpus callosum, external capsule, piriform cortex, and medial septal nucleus. NG2+ cells were stellate or fusiform in shape with long processes that were progressively decreased and shortened over the course of brain development. The distribution and morphology of PDGFRalpha positive (PDGFRalpha+) cells were coincident with NG2+ cells. The colocalization of NG2 and PDGFRalpha in the cell bodies and processes of some cells was confirmed by double immunofluorescence labeling. Moreover, cells double-labeled for NG2 and PDGFRalpha were predominantly in the early postnatal stage of development. The numbers of NG2+/PDGFRalpha+ cells and PDGFRalpha+ cells decreased, but the number of NG2+ cells increased from postnatal days 3 to 14 in the developing brain. In addition, amoeboid microglial cells of the corpus callosum, newborn brain macrophages in the normal developing brain, did not express NG2 or PDGFRalpha, but NG2 expression was detected in amoeboid microglia after hypoxia. The present results suggest that NG2 and PDGFRalpha are specific markers of oligodendrocyte precursor cells at different stages during early development. Additionally, the NG2 protein is involved in inflammatory and pathological processes of amoeboid microglial cells. PMID- 29239331 TI - Ankle-brachial index and brachial-ankle pulse wave velocity are risk factors for ischemic stroke in patients with Type 2 diabetes. AB - The incidence of ischemic stroke in patients with diabetes is increasing. While brachial-ankle pulse wave velocity (BaPWV) and ankle-brachial index (ABI) are known to be associated with ischemic cardiovascular and cerebrovascular diseases, whether these measures predict the risk of ischemic cerebrovascular disease in diabetic patients remains unclear. 117 patients with type 2 diabetes were enrolled in this study. According to the results of head magnetic resonance imaging, the patients were divided into a diabetes-only group (n = 55) and a diabetes and ischemic stroke group (n = 62). We then performed ABI and BaPWV examinations for all patients. Compared with the diabetes-only group, we found decreased ABI and increased BaPWV in the diabetes and ischemic stroke group. Multivariate logistic regression analyses revealed that BaPWV and ABI were risk factors for ischemic stroke in patients with type 2 diabetes. Our findings indicate that decreased ABI and increased BaPWV are objective indicators of increased risk of ischemic stroke in patients with type 2 diabetes. PMID- 29239332 TI - Ramulus Cinnamomi extract attenuates neuroinflammatory responses via downregulating TLR4/MyD88 signaling pathway in BV2 cells. AB - Ramulus Cinnamomi (RC), a traditional Chinese herb, has been used to attenuate inflammatory responses. The purpose of this study was to investigate the effect of RC extract on lipopolysaccharide (LPS)-induced neuroinflammation in BV2 microglial cells and the underlying mechanisms involved. BV2 cells were incubated with normal medium (control group), LPS, LPS plus 30 MUg/mL RC extract, or LPS plus 100 MUg/mL RC extract. The BV2 cell morphology was observed under an optical microscope and cell viability was detected by MTT assay. Nitric oxide level in BV2 cells was detected using Griess regents, and the levels of interleukin-6, interleukin-1beta, and tumor necrosis factor alpha in BV2 cells were determined by ELISA. The expression levels of cyclooxygenase-2, Toll-like receptor 4 and myeloid differentiation factor 88 proteins were detected by western blot assay. Compared with the LPS group, both 30 and 100 MUg/mL RC extract had no significant effect on the viability of BV2 cells. The levels of nitric oxide, interleukin-6, interleukin-1beta and tumor necrosis factor alpha in BV2 cells were all significantly increased after LPS induction, and the levels were significantly reversed after treatment with 30 and 100 MUg/mL RC extract. Furthermore, RC extract significantly inhibited the protein expression levels of cyclooxygenase 2, Toll-like receptor 4 and myeloid differentiation factor 88 in LPS-induced BV2 cells. Our findings suggest that RC extract alleviates neuroinflammation by downregulating the TLR4/MyD88 signaling pathway. PMID- 29239333 TI - Nigral dopaminergic neuron replenishment in adult mice through VE-cadherin expressing neural progenitor cells. AB - The function of dopaminergic neurons in the substantia nigra is of central importance to the coordination of movement by the brain's basal ganglia circuitry. This is evidenced by the loss of these neurons, resulting in the cardinal motor deficits associated with Parkinson's disease. In order to fully understand the physiology of these key neurons and develop potential therapies for their loss, it is essential to determine if and how dopaminergic neurons are replenished in the adult brain. Recent work has presented evidence for adult neurogenesis of these neurons by Nestin+/Sox2- neural progenitor cells. We sought to further validate this finding and explore a potential atypical origin for these progenitor cells. Since neural progenitor cells have a proximal association with the vasculature of the brain and subsets of endothelial cells are Nestin+, we hypothesized that dopaminergic neural progenitors might share a common cell lineage. Therefore, we employed a VE-cadherin promoter-driven CREERT2:THlox/THlox transgenic mouse line to ablate the tyrosine hydroxylase gene from endothelial cells in adult animals. After 26 weeks, but not 13 weeks, following the genetic blockade of tyrosine hydroxylase expression in VE-cadherin+ cells, we observed a significant reduction in tyrosine hydroxylase+ neurons in the substantia nigra. The results from this genetic lineage tracing study suggest that dopaminergic neurons are replenished in adult mice by a VE-cadherin+ progenitor cell population potentially arising from an endothelial lineage. PMID- 29239334 TI - Calycosin improves cognitive function in a transgenic mouse model of Alzheimer's disease by activating the protein kinase C pathway. AB - The major pathological changes in Alzheimer's disease are beta amyloid deposits and cognitive impairment. Calycosin is a typical phytoestrogen derived from radix astragali that binds to estrogen receptors to produce estrogen-like effects. Radix astragali Calycosin has been shown to relieve cognitive impairment induced by diabetes mellitus, suggesting calycosin may improve the cognitive function of Alzheimer's disease patients. The protein kinase C pathway is upstream of the mitogen-activated protein kinase pathway and exerts a neuroprotective effect by regulating Alzheimer's disease-related beta amyloid degradation. We hypothesized that calycosin improves the cognitive function of a transgenic mouse model of Alzheimer's disease by activating the protein kinase C pathway. Various doses of calycosin (10, 20 and 40 mg/kg) were intraperitoneally injected into APP/PS1 transgenic mice that model Alzheimer's disease. Calycosin diminished hippocampal beta amyloid, Tau protein, interleukin-1beta, tumor necrosis factor-alpha, acetylcholinesterase and malondialdehyde levels in a dose-dependent manner, and increased acetylcholine and glutathione activities. The administration of a protein kinase C inhibitor, calphostin C, abolished the neuroprotective effects of calycosin including improving cognitive ability, and anti-oxidative and anti inflammatory effects. Our data demonstrated that calycosin mitigated oxidative stress and inflammatory responses in the hippocampus of Alzheimer's disease model mice by activating the protein kinase C pathway, and thereby improving cognitive function. PMID- 29239335 TI - Saponins from Panax japonicus attenuate age-related neuroinflammation via regulation of the mitogen-activated protein kinase and nuclear factor kappa B signaling pathways. AB - Neuroinflammation is recognized as an important pathogenic factor for aging and related cognitive disorders. Mitogen-activated protein kinase and nuclear factor kappa B signaling pathways may mediate neuroinflammation. Saponins from Panax japonicus are the most abundant and bioactive members in rhizomes of Panax japonicus, and show anti-inflammatory activity. However, it is not known whether saponin from Panax japonicus has an anti-inflammatory effect in the aging brain, and likewise its underlying mechanisms. Sprague-Dawley rats were divided into control groups (3-, 9-, 15-, and 24-month-old groups) and saponins from Panax japonicus-treated groups. Saponins from Panax japonicus-treated groups were orally administrated saponins from Panax japonicus at three doses of 10, 30, and 60 mg/kg once daily for 6 months until the rats were 24 months old. Immunohistochemical staining and western blot assay results demonstrated that many microglia were activated in 24-month-old rats compared with 3- and 9-month old rats. Expression of interleukin-1beta, tumor necrosis factor-alpha, cyclooxygenase-2, and inducible nitric oxide synthase increased. Each dose of saponins from Panax japonicus visibly suppressed microglial activation in the aging rat brain, and inhibited expression levels of the above factors. Each dose of saponins from Panax japonicus markedly diminished levels of nuclear factor kappa B, IkappaBalpha, extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38. These results confirm that saponins from Panax japonicus can mitigate neuroinflammation in the aging rat brain by inhibition of the mitogen activated protein kinase and nuclear factor kappa B signaling pathways. PMID- 29239336 TI - Neural progenitor cells but not astrocytes respond distally to thoracic spinal cord injury in rat models. AB - Traumatic spinal cord injury (SCI) is a detrimental condition that causes loss of sensory and motor function in an individual. Many complex secondary injury cascades occur after SCI and they offer great potential for therapeutic targeting. In this study, we investigated the response of endogenous neural progenitor cells, astrocytes, and microglia to a localized thoracic SCI throughout the neuroaxis. Twenty-five adult female Sprague-Dawley rats underwent mild-contusion thoracic SCI (n = 9), sham surgery (n = 8), or no surgery (n = 8). Spinal cord and brain tissues were fixed and cut at six regions of the neuroaxis. Immunohistochemistry showed increased reactivity of neural progenitor cell marker nestin in the central canal at all levels of the spinal cord. Increased reactivity of astrocyte-specific marker glial fibrillary acidic protein was found only at the lesion epicenter. The number of activated microglia was significantly increased at the lesion site, and activated microglia extended to the lumbar enlargement. Phagocytic microglia and macrophages were significantly increased only at the lesion site. There were no changes in nestin, glial fibrillary acidic protein, microglia and macrophage response in the third ventricle of rats subjected to mild-contusion thoracic SCI compared to the sham surgery or no surgery. These findings indicate that neural progenitor cells, astrocytes and microglia respond differently to a localized SCI, presumably due to differences in inflammatory signaling. These different cellular responses may have implications in the way that neural progenitor cells can be manipulated for neuroregeneration after SCI. This needs to be further investigated. PMID- 29239337 TI - Globose basal cells for spinal cord regeneration. AB - Spinal cord injury (SCI) is a devastating condition with loss of motor and sensory functions below the injury level. Cell based therapies are experimented in pre-clinical studies around the world. Neural stem cells are located intra cranially in subventricular zone and hippocampus which are highly invasive sources. The olfactory epithelium is a neurogenic tissue where neurogenesis takes place throughout the adult life by a population of stem/progenitor cells. Easily accessible olfactory neuroepithelial stem/progenitor cells are an attractive cell source for transplantation in SCI. Globose basal cells (GBCs) were isolated from rat olfactory epithelium, characterized by flow cytometry and immunohistochemically. These cells were further studied for neurosphere formation and neuronal induction. T10 laminectomy was done to create drop-weight SCI in rats. On the 9th day following SCI, 5 * 105 cells were transplanted into injured rat spinal cord. The outcome of transplantation was assessed by the Basso, Beattie and Bresnahan (BBB) locomotor rating scale, motor evoked potential and histological observation. GBCs expressed neural stem cell markers nestin, SOX2, NCAM and also mesenchymal stem cell markers (CD29, CD54, CD90, CD73, CD105). These cells formed neurosphere, a culture characteristics of NSCs and on induction, differentiated cells expressed neuronal markers betaIII tubulin, microtubule-associated protein 2, neuronal nuclei, and neurofilament. GBCs transplanted rats exhibited hindlimb motor recovery as confirmed by BBB score and gastrocnemius muscle electromyography amplitude was increased compared to controls. Green fluorescent protein labelled GBCs survived around the injury epicenter and differentiated into betaIII tubulin-immunoreactive neuron-like cells. GBCs could be an alternative to NSCs from an accessible source for autologous neurotransplantation after SCI without ethical issues. PMID- 29239338 TI - Effects of neuregulin-1 on autonomic nervous system remodeling post-myocardial infarction in a rat model. AB - Sympathetic nerve and vagus nerve remodeling play an important part in cardiac function post-myocardial infarction (MI). Increasing evidence indicates that neuregulin-1 (NRG-1) improves cardiac function following heart failure. Since its impact on cardiac function and neural remodeling post-MI is poorly understood, we aimed to investigate the role of NRG-1 in autonomic nervous system remodeling post-MI. Forty-five Sprague-Dawley rats were equally randomized into three groups: sham (with the left anterior descending coronary artery exposed but without ligation), MI (left anterior descending coronary artery ligation), and MI plus NRG-1 (left anterior descending coronary artery ligation followed by intraperitoneal injection of NRG-1 (10 MUg/kg, once daily for 7 days)). At 4 weeks after MI, echocardiography was used to detect the rat cardiac function by measuring the left ventricular end-systolic inner diameter, left ventricular diastolic diameter, left ventricular end-systolic volume, left ventricular end diastolic volume, left ventricular ejection fraction, and left ventricular fractional shortening. mRNA and protein expression levels of tyrosine hydroxylase, growth associated protein-43 (neuronal specific protein), nerve growth factor, choline acetyltransferase (vagus nerve marker), and vesicular acetylcholine transporter (cardiac vagal nerve fiber marker) in ischemic myocardia were detected by real-time PCR and western blot assay to assess autonomous nervous remodeling. After MI, the rat cardiac function deteriorated significantly, and it was significantly improved after NRG-1 injection. Compared with the MI group, mRNA and protein levels of tyrosine hydroxylase and growth associated protein-43, as well as choline acetyltransferase mRNA level significantly decreased in the MI plus NRG-1 group, while mRNA and protein levels of nerve growth factor and vesicular acetylcholine transporters, as well as choline acetyltransferase protein level slightly decreased. Our results indicate that NRG-1 can improve cardiac function and regulate sympathetic and vagus nerve remodeling post-MI, thus reaching a new balance of the autonomic nervous system to protect the heart from injury. PMID- 29239339 TI - Evaluation of sensory function and recovery after replantation of fingertips at Zone I in children. AB - Sensory function is the most significant criterion when evaluating the prognosis of replanted fingers. Current clinical research has focused on surgical techniques and indications for finger replantation; however, few studies have focused on recovery of finger sensory function after replantation. This study retrospectively assessed data of eight patients who had undergone nine Zone I replantations of the fingertips in the First Affiliated Hospital of Sun Yat-sen University of China from July 2014 to January 2016. Variations in the extent of damage, with the residual vessels or nerves in some fingers being too short or even missing, prevented tension-free suture repair in some patients. Thus, repair of four of the nine fingertips included arteriovenous anastomosis, the remaining five undergoing arterial anastomosis during replantation of the amputated fingers. Three patients underwent nerve repair, whereas the remaining six cases did not. Fingertip replantations were successful in all eight patients. Compared with the patients without vascular anastomosis, no obvious atrophy was visible in the fingertips of patients who did undergo vascular anastomosis during replantation and their sensory function did recover. Fingertip replantation provides good sensory function and cosmetic outcomes when good artery and vein anastomoses have been created, even when digital nerves have not been repaired. PMID- 29239341 TI - Delayed degeneration of an injured spinothalamic tract in a patient with diffuse axonal injury. PMID- 29239342 TI - Transgastric submucosal excision of small- to medium-sized gastrointestinal stromal tumours by pure minimally invasive approach. AB - AIM: The aim of this study is to evaluate the results of a single and common approach for transgastric submucosal excision of small- to medium-sized gastrointestinal stromal tumours (GIST) having different locations in upper two third of the stomach by pure minimally invasive approach. MATERIALS AND METHODS: A retrospective study from February 2012 to January 2015 on 11 patients was conducted including both male and female. Their age ranged from 40 to 65 years. All were subjected to laparoscopic transgastric submucosal excision of GIST in upper two-third of the stomach with 1 cm margin having different locations in stomach. Excised tumours were subjected to histopathological study. These patients were followed for 12 months assessing operative time, post-operative complications, conversion rates, morbidity, hospital stay and recurrence rate. RESULTS: Duration of surgery was 150.6 +/- 20.4 min. Mean hospital stay was 8 (range: 7-10) days. There were no post-operative complications. There were no conversions to open procedure. There were no recurrences. Morbidity was comparable to any other laparoscopic procedures. CONCLUSION: We conclude that a single and common approach of transgastric submucosal excision of small- to medium-sized stromal tumours with 1 cm margin having different locations in upper two-third of stomach, by pure minimally invasive approach, has a better outcome and brings a uniformity in laparoscopic management of GIST. PMID- 29239343 TI - Surgery and considerations for the repair of Petersen's space hernia after mini gastric bypass. AB - This paper reports a case of Petersen's space hernia after mini gastric bypass. This is an anecdotal post-operative complication in the mini gastric bypass technique, with an estimated rate of 1/5000 cases. Similar cases described in the literature were treated by the surgical hernia reduction and the closure of the mesenteric defect. Our patient had a unique management, performing a conversion to Roux-en-Y gastric bypass with dissection of the biliopancreatic limb at the anastomosis and creation of a variable foot-point anastomosis with excellent mid term post-operative results. This should provide better long-term results as compared to simple mesenteric closure, avoiding the complications of mini gastric bypass technique. PMID- 29239340 TI - Research on human glioma stem cells in China. AB - Research on human glioma stem cells began early in the 21st century and since then has become a rapidly growing research field with the number of publications increasing year by year. The research conducted by our diverse group of investigators focused primarily on cell culture techniques, molecular regulation, signaling pathways, cancer treatment, the stem cell microenvironment and the cellular origin and function of glioma stem cells. In particular, we put forward our view that there are inverse or forward transformations among neural stem cells, glial cells and glioma stem cells in glioma tissues under certain conditions. Based on the background of the progress of international research on human glioma stem cells, we aim to share our progress and current findings of human glioma stem cell research in China with colleagues around the world. PMID- 29239344 TI - Percutaneous ultrasonography-guided nephroscopic evacuation of hydatid cyst in posterior segment of liver. AB - Hydatid disease commonly affects liver and treatment of choice is surgery. Ultrasound examination is helpful to diagnose, classify and plan management of the cyst. Surgical treatment is done using a conventional open technique or minimal access technique. We report our experience of using ultrasound-guided percutaneous nephroscopic approach to treat liver hydatid cyst. PMID- 29239345 TI - Extramucosal pancreaticojejunostomy at laparoscopic pancreaticoduodenectomy. AB - While the 'best pancreatic anastomosis technique' debate is going during Whipple procedure, the laparoscopic pancreaticoduodenectomy lately began to appear more and more often in the medical literature. All the popular anastomosis techniques used in open pancreas surgery are being experienced in laparoscopic pancreaticoduodenectomy. However, when they were adapted to laparoscopy, their implementation was not technically easy, and assistance of robotic surgery was sometimes required at the pancreatic anastomosis stage of the procedure. Feasibility and simplicity of a new technique have a vital role in its adaptation to laparoscopic surgery. We frequently use the extra-mucosal single row handsewn anastomosis method in open and laparoscopic surgery of the stomach, small and large bowel and we found it easy and reliable. Here, we defined the adaptation of this technique to the laparoscopic pancreas anastomosis. The outcomes were not inferior to the other previously described techniques and it has the advantage of simplicity. PMID- 29239346 TI - Correction: Anxiety disorders. AB - This corrects the article DOI: 10.1038/nrdp.2017.24. PMID- 29239347 TI - Chronic constipation. AB - Chronic constipation is a prevalent condition that severely impacts the quality of life of those affected. Several types of primary chronic constipation, which show substantial overlap, have been described, including normal-transit constipation, rectal evacuation disorders and slow-transit constipation. Diagnosis of primary chronic constipation involves a multistep process initiated by the exclusion of 'alarm' features (for example, unintentional weight loss or rectal bleeding) that might indicate organic diseases (such as polyps or tumours) and a therapeutic trial with first-line treatments such as dietary changes, lifestyle modifications and over-the-counter laxatives. If symptoms do not improve, investigations to diagnose rectal evacuation disorders and slow-transit constipation are performed, such as digital rectal examination, anorectal structure and function testing (including the balloon expulsion test, anorectal manometry or defecography) or colonic transit tests (such as the radiopaque marker test, wireless motility capsule test, scintigraphy or colonic manometry). The mainstays of treatment are diet and lifestyle interventions, pharmacological therapy and, rarely, surgery. This Primer provides an introduction to the epidemiology, pathophysiological mechanisms, diagnosis, management and quality of life associated with the commonly encountered clinical problem of chronic constipation in adults unrelated to opioid abuse. PMID- 29239349 TI - Influences of Ivabradine treatment on serum levels of cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in patients with chronic heart failure. AB - Chronic heart failure (CHF) represents a major cause of hospitalization and death. Recent evidence shows that novel biomarkers such as soluble suppression of tumorigenicity (sST2), growth-differentiation factor-15 (GDF-15), soluble urokinase plasminogen activator receptor (suPAR) and heart-type fatty acid binding protein (H-FABP) are correlated with inflammatory and ischemic responses in CHF patients. In this study we examined the effects of Ivabradine that inhibited the hyperpolarization-activated cyclic nucleotide-gated channel (HCN channel, also called funny current If), thereby leading to selective heart rate reduction and improved myocardial oxygen supply on the cardiac biomarkers sST2, GDF-15, suPAR and H-FABP in 50 CHF patients at the University Hospital of Jena. Patients were divided into three groups based on the etiology of CHF: dilated cardiomyopathy (DCM, n=20), ischemic cardiomyopathy (ICM, n=20) and hypertensive cardiomyopathy (HCM, n=10). The patients were administered Ivabradine (5 mg, bid for 3 months, and 7.5 mg bid for further 3 months). Analyses of cardiovascular biomarkers were performed at baseline as well as at 3- and 6-month follow-ups. At 6-month follow-up, GDF-15 levels were significantly reduced compared to baseline levels (P=0.0215), indicating a reduction in the progress of cardiac remodeling. H-FABP concentration was significantly lower in DCM patients compared to ICM (1.89 vs 3.24 MUg/mL) and HCM patients (1.89 vs 3.80 MUg/mL), and decreased over the 6-month follow-up (P=0.0151). suPAR median levels remained elevated, implying major ongoing inflammatory processes. As shown by significant decreases in GDF-15 and H-FABP levels, a reduction in ventricular remodeling and sub-clinical ischemia could be assumed. However, markers of hemodynamic stress (sST2) and inflammation (suPAR) showed no change or progression after 6 months of Ivabradine treatment in CHF patients. Further studies are necessary to validate the clinical applicability of these novel cardiovascular biomarkers. PMID- 29239350 TI - Suppression of eEF-2K-mediated autophagy enhances the cytotoxicity of raddeanin A against human breast cancer cells in vitro. AB - Recent evidence shows that raddeanin A (RA), an oleanane-type triterpenoid saponin extracted from Anemone raddeana Regel, exerts remarkable cytotoxicity against cancer cells in vitro and in vivo. In addition, RA has also been found to activate autophagy in human gastric cancer cells. In this study, we investigated the molecular mechanisms underlying RA-induced autophagy as well as the relationship between RA-induced autophagy and its cytotoxicity in human breast cancer cells in vitro. Treatment with RA (2-8 MUmol/L) dose-dependently enhanced autophagy, as evidenced by increased LC3 levels in breast cancer cell lines T47D, MCF-7 and MDA-MB-231. Furthermore, the Akt-mTOR-eEF-2K signaling pathway was demonstrated to be involved in RA-induced activation of autophagy in the 3 breast cancer cell lines. Treatment with RA (2-10 MUmol/L) dose-dependently induced apoptosis in the 3 breast cancer cell lines. Pretreatment with the autophagy inhibitor chloroquine (CQ, 20 MUmol/L) significantly enhanced RA-caused cytotoxicity via promoting apoptosis. In conclusion, our results suggest that modulating autophagy can reinforce the cytotoxicity of RA against human breast cancer cells. PMID- 29239352 TI - A compositional tipping point governing the mobilization and eruption style of rhyolitic magma. AB - The most viscous volcanic melts and the largest explosive eruptions on our planet consist of calcalkaline rhyolites. These eruptions have the potential to influence global climate. The eruptive products are commonly very crystal-poor and highly degassed, yet the magma is mostly stored as crystal mushes containing small amounts of interstitial melt with elevated water content. It is unclear how magma mushes are mobilized to create large batches of eruptible crystal-free magma. Further, rhyolitic eruptions can switch repeatedly between effusive and explosive eruption styles and this transition is difficult to attribute to the rheological effects of water content or crystallinity. Here we measure the viscosity of a series of melts spanning the compositional range of the Yellowstone volcanic system and find that in a narrow compositional zone, melt viscosity increases by up to two orders of magnitude. These viscosity variations are not predicted by current viscosity models and result from melt structure reorganization, as confirmed by Raman spectroscopy. We identify a critical compositional tipping point, independently documented in the global geochemical record of rhyolites, at which rhyolitic melts fluidize or stiffen and that clearly separates effusive from explosive deposits worldwide. This correlation between melt structure, viscosity and eruptive behaviour holds despite the variable water content and other parameters, such as temperature, that are inherent in natural eruptions. Thermodynamic modelling demonstrates how the observed subtle compositional changes that result in fluidization or stiffening of the melt can be induced by crystal growth from the melt or variation in oxygen fugacity. However, the rheological effects of water and crystal content alone cannot explain the correlation between composition and eruptive style. We conclude that the composition of calcalkaline rhyolites is decisive in determining the mobilization and eruption dynamics of Earth's largest volcanic systems, resulting in a better understanding of how the melt structure controls volcanic processes. PMID- 29239351 TI - Association of serum uric acid levels with osteoporosis and bone turnover markers in a Chinese population. AB - Recent evidence shows that uric acid is protective against some neurological diseases, but can be detrimental in many metabolic and cardiovascular disorders. In this study, we examined the association between serum uric acid levels and bone metabolism in Chinese males and postmenopausal females. A total of 943 males and 4256 postmenopausal females were recruited in Shanghai. The levels of serum uric acid and bone turnover markers (BTMs) were detected along with other biochemical traits. In addition, the fat distribution was calculated through MRI and image analysis software, and bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry. For postmenopausal females, the prevalence of osteoporosis was significantly lower in the hyperuricemia group compared with the normouricemic group (P=4.65E-06). In females, serum uric acid level was significantly associated with osteoporosis, with odds ratio (OR) and 95% confidence interval (95% CI) of 0.844 [0.763; 0.933] (P=0.0009) after adjusting for age, body mass index, HbA1c, lean mass, visceral and subcutaneous fat areas, albumin, 25-hydroxyvitamin D3 [25(OH)D3], and parathyroid hormone (PTH). In females, serum uric acid level was positively correlated with the BMD of the femoral neck (beta+/-SE: 0.0463+/-0.0161; P=0.0042), total hip (beta+/-SE: 0.0433+/-0.0149; P=0.0038) and L1-4 (beta+/-SE: 0.0628+/-0.0165; P=0.0001) after further adjusting for age, BMI, HbA1c, lean mass, VFA, SFA, albumin, 25(OH)D3 and PTH. Regarding BTMs, serum uric acid level was negatively correlated with N terminal procollagen of type I collagen (PINP) in females (beta+/-SE: -0.1311+/ 0.0508; P=0.0100). In summary, our results suggest that uric acid has a protective effect on bone metabolism independent of body composition in Chinese postmenopausal females. PMID- 29239353 TI - Initiation and long-term instability of the East Antarctic Ice Sheet. AB - Antarctica's continental-scale ice sheets have evolved over the past 50 million years. However, the dearth of ice-proximal geological records limits our understanding of past East Antarctic Ice Sheet (EAIS) behaviour and thus our ability to evaluate its response to ongoing environmental change. The EAIS is marine-terminating and grounded below sea level within the Aurora subglacial basin, indicating that this catchment, which drains ice to the Sabrina Coast, may be sensitive to climate perturbations. Here we show, using marine geological and geophysical data from the continental shelf seaward of the Aurora subglacial basin, that marine-terminating glaciers existed at the Sabrina Coast by the early to middle Eocene epoch. This finding implies the existence of substantial ice volume in the Aurora subglacial basin before continental-scale ice sheets were established about 34 million years ago. Subsequently, ice advanced across and retreated from the Sabrina Coast continental shelf at least 11 times during the Oligocene and Miocene epochs. Tunnel valleys associated with half of these glaciations indicate that a surface-meltwater-rich sub-polar glacial system existed under climate conditions similar to those anticipated with continued anthropogenic warming. Cooling since the late Miocene resulted in an expanded polar EAIS and a limited glacial response to Pliocene warmth in the Aurora subglacial basin catchment. Geological records from the Sabrina Coast shelf indicate that, in addition to ocean temperature, atmospheric temperature and surface-derived meltwater influenced East Antarctic ice mass balance under warmer than-present climate conditions. Our results imply a dynamic EAIS response with continued anthropogenic warming and suggest that the EAIS contribution to future global sea-level projections may be under-estimated. PMID- 29239355 TI - Magnetically gated accretion in an accreting 'non-magnetic' white dwarf. AB - White dwarfs are often found in binary systems with orbital periods ranging from tens of minutes to hours in which they can accrete gas from their companion stars. In about 15 per cent of these binaries, the magnetic field of the white dwarf is strong enough (at 106 gauss or more) to channel the accreted matter along field lines onto the magnetic poles. The remaining systems are referred to as 'non-magnetic', because until now there has been no evidence that they have a magnetic field that is strong enough to affect the accretion dynamics. Here we report an analysis of archival optical observations of the 'non-magnetic' accreting white dwarf in the binary system MV Lyrae, whose light curve displays quasi-periodic bursts of about 30 minutes duration roughly every 2 hours. The timescale and amplitude of these bursts indicate the presence of an unstable, magnetically regulated accretion mode, which in turn implies the existence of magnetically gated accretion, in which disk material builds up around the magnetospheric boundary (at the co-rotation radius) and then accretes onto the white dwarf, producing bursts powered by the release of gravitational potential energy. We infer a surface magnetic field strength for the white dwarf in MV Lyrae of between 2 * 104 gauss and 1 * 105 gauss, too low to be detectable by other current methods. Our discovery provides a new way of studying the strength and evolution of magnetic fields in accreting white dwarfs and extends the connections between accretion onto white dwarfs, young stellar objects and neutron stars, for which similar magnetically gated accretion cycles have been identified. PMID- 29239354 TI - An electric-eel-inspired soft power source from stacked hydrogels. AB - Progress towards the integration of technology into living organisms requires electrical power sources that are biocompatible, mechanically flexible, and able to harness the chemical energy available inside biological systems. Conventional batteries were not designed with these criteria in mind. The electric organ of the knifefish Electrophorus electricus (commonly known as the electric eel) is, however, an example of an electrical power source that operates within biological constraints while featuring power characteristics that include peak potential differences of 600 volts and currents of 1 ampere. Here we introduce an electric eel-inspired power concept that uses gradients of ions between miniature polyacrylamide hydrogel compartments bounded by a repeating sequence of cation- and anion-selective hydrogel membranes. The system uses a scalable stacking or folding geometry that generates 110 volts at open circuit or 27 milliwatts per square metre per gel cell upon simultaneous, self-registered mechanical contact activation of thousands of gel compartments in series while circumventing power dissipation before contact. Unlike typical batteries, these systems are soft, flexible, transparent, and potentially biocompatible. These characteristics suggest that artificial electric organs could be used to power next-generation implant materials such as pacemakers, implantable sensors, or prosthetic devices in hybrids of living and non-living systems. PMID- 29239356 TI - Nine researchers sue University of Rochester over sexual-harassment allegations. PMID- 29239357 TI - Snow leopard conservation status is spot on. PMID- 29239358 TI - How to spare half a planet. PMID- 29239359 TI - Ronald Breslow (1931-2017). PMID- 29239361 TI - Acupuncture in cancer study reignites debate about controversial technique. PMID- 29239362 TI - Research funding for US universities up for first time in five years in 2016. PMID- 29239363 TI - The science that's never been cited. PMID- 29239364 TI - Brexit fears continue to plague European scientists. PMID- 29239365 TI - Bureaucratic drag dents Japan's nuclear science. PMID- 29239366 TI - Five priorities for weather and climate research. PMID- 29239369 TI - Longer life through an odd Pol enzyme. PMID- 29239370 TI - Antarctic ice dynamics in warm climates. PMID- 29239371 TI - Deploy vaccines to fight superbugs. PMID- 29239372 TI - Early embryos kept in check. PMID- 29239373 TI - Standardize future device connections for computers. PMID- 29239374 TI - Spinal-cord injury: s purring regrowth. PMID- 29239377 TI - Dodgy citations, fusion milestone and a skeleton called Little Foot. PMID- 29239376 TI - How museum work can combine research and public engagement. PMID- 29239378 TI - Pricing not enough for deep carbon cuts. PMID- 29239379 TI - Tasmanian tiger genome offers clues to its extinction. PMID- 29239380 TI - New tricks from old dogs join the fight against ageing. PMID- 29239382 TI - Argentinian geoscientist faces criminal charges over glacier survey. PMID- 29239381 TI - Loss of net neutrality could harm research. PMID- 29239383 TI - Chile's chance to embrace science for the twenty-first century. PMID- 29239384 TI - Stellar cannibalism in fits and starts. PMID- 29239385 TI - Repairing the neural highway. PMID- 29239386 TI - Viruses hijack a long non-coding RNA. PMID- 29239388 TI - DNA self-assembly scaled up. PMID- 29239387 TI - Zimbabwe's new government must commit to science. PMID- 29239389 TI - US graduate students in uproar over proposed tax hike. PMID- 29239390 TI - A dark side to omega-3 fatty acids. PMID- 29239392 TI - How to avoid glib interdisciplinarity. PMID- 29239391 TI - Medical legacy of sanctions in Iran. PMID- 29239393 TI - An increased prevalence of medical co-morbidities may underscore future growth in the numbers of men requiring penile prostheses. PMID- 29239394 TI - Quantitative MR Image Analysis for Brian Tumor. AB - This paper presents an integrated quantitative MR image analysis framework to include all necessary steps such as MRI inhomogeneity correction, feature extraction, multiclass feature selection and multimodality abnormal brain tissue segmentation respectively. We first obtain mathematical algorithm to compute a novel Generalized multifractional Brownian motion (GmBm) texture feature. We then demonstrate efficacy of multiple multiresolution texture features including regular fractal dimension (FD) texture, and stochastic texture such as multifractional Brownian motion (mBm) and GmBm features for robust tumor and other abnormal tissue segmentation in brain MRI. We evaluate these texture and associated intensity features to effectively delineate multiple abnormal tissues within and around the tumor core, and stroke lesions using large scale public and private datasets. PMID- 29239395 TI - Treatment of Peyronie's disease via preoperative intralesional collagenase clostridium histolyticum followed by placement of an inflatable penile prosthesis: the new standard of care? PMID- 29239396 TI - The importance of the malleable implant salvage technique (MIST) in modern prosthetic urology. PMID- 29239397 TI - Challenges surrounding penile prostheses insertion following acute priapism. PMID- 29239398 TI - Improved outcomes from penile prosthetic implantation surgery may be achieved via a consistent, team-based approach. PMID- 29239399 TI - Centers of excellence for penile prosthetics are a novel concept that will likely prove difficult to implement. PMID- 29239400 TI - Post-operative antibiotics following placement of a penile prosthesis. PMID- 29239401 TI - The value of medical pre-operative assessment for patients receiving penile prostheses. PMID- 29239402 TI - Informed consent for penile prosthesis surgery. PMID- 29239403 TI - Correction to: CRISPR-like sequences in Helicobacter pylori and application in genotyping. AB - [This corrects the article DOI: 10.1186/s13099-017-0215-8.]. PMID- 29239404 TI - Amnion/chorion grafts and their applications in urology. PMID- 29239405 TI - A novel proposal to address the future of penile prosthetics: are we currently focused in the wrong direction? PMID- 29239406 TI - Erectile dysfunction following cancer therapy: is there a role for penile rehabilitation? PMID- 29239407 TI - External penile prosthesis as a novel approach to the treatment of erectile dysfunction. PMID- 29239408 TI - QCM-nanomagnetic beads biosensor for lead ion detection. AB - As lead poses a serious threat to humans even in small amounts, all kinds of lead detection sensors with high sensitivity and selectivity are being constantly improved and put forward. In this report, a novel, simple and label-free quartz crystal microbalance (QCM) biosensor is proposed for detecting lead ions (Pb2+). The biosensor takes full advantage of the high specificity of GR-5 DNAzyme to Pb2+ and the high sensitivity of QCM. In particular, nanomagnetic beads (NMBs) are used as a novel and effective mean of signal amplification in the biosensor because of their mass and their ability to enhance the inductive effect, which are very beneficial for both higher sensitivity and a lower detection limit. In practice, GR-5 DNAzyme, innovatively combined with NMBs, was modified on the gold electrode of the QCM through gold-sulfur self-assembly. When the electrode was exposed to Pb2+ solution, DNAzyme was severed into two parts at the RNA site (rA), along with the release of NMBs, which caused a great increase in frequency shift of the QCM electrode. Finally, a perfect linear correlation between the logarithm of Pb2+ concentration and the change in frequency was obtained from 1 pM to 50 nM, with a detection limit as low as 0.3 pM. Moreover, the biosensor shows both an average recovery of 97 +/- 6% in a drinking water sample and an excellent specificity for Pb2+ compared with other metal ions. PMID- 29239409 TI - Polyhydric polymer-loaded pyrene composites as powerful adsorbents and fluorescent probes: highly efficient adsorption and test strips-based fluorimetric analysis of curcumin in urine and plant extracts. AB - Polyhydric poly (vinyl alcohol) was covalently loaded with a 1 pyrenecarboxyaldehyde fluorophore. The yielded PVA-Pyr composites can serve as powerful adsorbents and strong fluorescent probes for the highly efficient adsorption and sensitive fluorimetric detection with test strips of curcumin in samples of urine and plant extracts. PMID- 29239410 TI - Uptake and transcytosis of functionalized superparamagnetic iron oxide nanoparticles in an in vitro blood brain barrier model. AB - Two major hurdles in nanomedicine are the limited strategies for synthesizing stealth nanoparticles and the poor efficacy of the nanoparticles in translocating across the blood brain barrier (BBB). Here we examined the uptake and transcytosis of iron oxide nanoparticles (IONPs) grafted with biomimetic phosphorylcholine (PC) brushes in an in vitro BBB model system, and compared them with bare, PEG or PC-PEG mixture grafted IONPs. Hyperspectral imaging indicated IONP co-localization with cells. Quantitative analysis with total reflection X ray fluorescence spectrometry showed that after 24 h, 78% of PC grafted, 68-69% of PEG or PC-PEG grafted, and 30% of bare IONPs were taken up by the BBB. Transcytosis of IONPs was time-dependent and after 24 h, 16-17% of PC or PC-PEG mixture grafted IONPs had passed the BBB model, significantly more than PEG grafted or bare IONPs. These findings point out that grafting of IONPs with PC is a viable strategy for improving the uptake and transcytosis of nanoparticles. PMID- 29239411 TI - A far-red fluorescent probe based on a phospha-fluorescein scaffold for cytosolic calcium imaging. AB - The far-red emissive fluorescent probe CaPF-1 based on a phospha-fluorescein scaffold enables the detection of cytosolic calcium ions in living cells. The probe can be excited in the red region (lambdaabs = 636 nm) and exhibits a sufficiently high fluorescence turn-on response in the far-red region (lambdaem = 663 nm) upon complexation with calcium ions. The hydrophilic and anionic characteristics of this phospha-fluorescein fluorophore allowed the cytosolic localization of CaPF-1. Moreover, it was possible to visualize histamine-induced calcium oscillation in HeLa cells using CaPF-1. PMID- 29239412 TI - Screening natural libraries of human milk oligosaccharides against lectins using CaR-ESI-MS. AB - Human milk oligosaccharides (HMOs) afford many health benefits to breast-fed infants, such as protection against infection and regulation of the immune system, through the formation of non-covalent interactions with protein receptors. However, the molecular details of these interactions are poorly understood. Here, we describe the application of catch-and-release electrospray ionization mass spectrometry (CaR-ESI-MS) for screening natural libraries of HMOs against lectins. The HMOs in the libraries were first identified based on molecular weights (MWs), ion mobility separation arrival times (IMS-ATs) and collision-induced dissociation (CID) fingerprints of their deprotonated anions. The libraries were then screened against lectins and the ligands identified from the MWs, IMS-ATs and CID fingerprints of HMOs released from the lectin in the gas phase. To demonstrate the assay, four fractions, extracted from pooled human milk and containing >=35 different HMOs, were screened against a C-terminal fragment of human galectin-3 (hGal-3C), for which the HMOs specificities have been previously investigated, and a fragment of the blood group antigen-binding adhesin (BabA) from Helicobacter pylori, for which the HMO specificities have not been previously established. The structures of twenty-one ligands, corresponding to both neutral and acidic HMOs, of hGal-3C were identified; all twenty-one were previously shown to be ligands for this lectin. The presence of HMO ligands at six other MWs was also ascertained. Application of the assay to BabA revealed nineteen specific HMO structures that are recognized by the protein and HMO ligands at two other MWs. Notably, it was found that BabA exhibits broad specificity for HMOs, and recognizes both neutral HMOs, including non-fucosylated ones, and acidic HMOs. The results of competitive binding experiments indicate that HMOs can interact with BabA at previously unknown binding sites. The affinities of eight purified HMOs for BabA were measured by ESI-MS and found to be in the 103 M-1 to 104 M-1 range. PMID- 29239413 TI - Hexacyano-[3]-radialene anion-radical salts: a promising family of highly soluble p-dopants. AB - Organic and inorganic salts of the hexacyano-[3]-radialene anion-radical are readily available and thermally stable compounds (up to ~180 degrees C). The tetrabutylammonium salt exhibits an extremely high solubility in a range of solvents (>300 mg l-1 in CHCl3) and acts as an efficient p-dopant for poly(3 hexylthiophene) to provide composite films with a conductivity above 2 S cm-1. PMID- 29239414 TI - Efficient synthesis of benzocyclotrimer analogues by Negishi cross-coupling and intramolecular nucleophilic substitution. AB - We report a new and efficient synthetic strategy that allows access to flexible and functionalized benzocyclotrimers under mild conditions and in few steps. The Negishi cross-coupling reaction was used for the C-C bond formation, whereas intramolecular O-alkylations provided the oxepane rings. PMID- 29239415 TI - An A-D-A'-D-A type small molecule acceptor with a broad absorption spectrum for organic solar cells. AB - Organic molecules with wide absorption spectra exhibit great sunlight harvesting capability and are critically important for solar cell applications. In this manuscript, we develop an A-D-A'-D-A type small molecule acceptor (IID-IC) using isoindigo (IID) as the electron-deficient core unit (A'), thiophene as the electron-rich bridging units (D) and 2-(3-oxo-2,3-dihydroinden-1 ylidene)malononitrile (IC) as the electron-deficient endcapping groups (A). IID IC shows a wide absorption spectrum with the full width at half maximum (FWHM) of 190 nm, which is almost twice that of a typical A-D-A type molecule acceptor. The wide absorption spectrum of IID-IC is possibly due to the partially suppressed intramolecular charge transfer effect with the additional electron-deficient core unit. An organic solar cell (OSC) device based on IID-IC exhibits the power conversion efficiency of 2.82% with broad photoresponse from 320 nm to 780 nm. PMID- 29239416 TI - Lead encapsulation by a golden clamp through multiple electrostatic, metallophilic, hydrogen bonding and weak interactions. AB - The structure of the complex [{Pb(HBpz3)}{Au3(o-C6BrF4)3(HBpz3)}] consists of a host-guest heterometallic system built up through a plethora of interactions including electrostatic, metallophilic, H-bonding, AuBr or weak CC or PbBr contacts. Computational studies show that the dispersive interactions are responsible for the attraction of the Pb(ii) cationic moiety within the basket like trinuclear Au(i) fragment, whereas the ionic component of the interaction placed at the rings produces a molecular clamp. PMID- 29239418 TI - Divergent reactivity of nucleophilic 1-bora-7a-azaindenide anions. AB - The reactions of 1-bora-7a-azaindenide anions, prepared in moderate to excellent yields by reduction of the appropriate 1-bora-7a-azaindenyl chlorides with KC8 in THF, with alkyl halides and carbon dioxide were studied. With alkyl halides (CH2Cl2, CH3I and BrCH(D)CH(D)tBu), the anions behave as boron anions, alkylating the boron centre via a classic SN2 mechanism. This was established with DFT methods and via experiments utilizing the neo-hexyl stereoprobe BrCH(D)CH(D)tBu. These reactions were in part driven by a re-aromatization of the six membered pyridyl ring upon formation of the product. Conversely, in the reaction of the 1 bora-7a-azaindenide anions with CO2, a novel carboxylation of the C-2 carbon alpha to boron was observed. Computations indicated that while carboxylation of the boron centre was kinetically feasible, the products of B-carboxylation were not thermodynamically favored relative to the observed C-2 carboxylated species, which were formed preferably due to the generation of both C-C and B-O bonds. In these products, the pyridyl ring remains non-aromatic, in part accounting for the observed reversibility of carboxylation. PMID- 29239420 TI - Ligand substitution and conformational effects on the ultrafast luminescent decay of [Re(CO)3(phen)(L)]+ (L = imidazole, pyridine): non-adiabatic quantum dynamics. AB - The effects of ligand substitution and conformational flexibility on the ultrafast luminescent decay of [Re(CO)3(phen)(L)]+ (L = imidazole, pyridine) complexes are investigated by means of density functional theory (DFT/time dependent DFT (TD-DFT)) electronic structure calculations and non-adiabatic quantum dynamics based on the linear vibronic coupling (LVC) approach including spin-orbit coupling (SOC) applied to the Cs conformers. The optical, luminescent and structural properties are not drastically affected either by the ligand substitution, or by the ligand rotation. However, the occurrence of two conformers, as investigated in detail for the pyridine substituted complex, significantly modifies the early time dynamics below 100 fs and the associated spin-vibronic mechanism. PMID- 29239423 TI - Two-step synthesis and characterization of vertically stacked SnS-WS2 and SnS MoS2 p-n heterojunctions. AB - We demonstrate the synthesis of unique heterostructures consisting of SnS and WS2 (or SnS and MoS2) by two-step chemical vapor deposition (CVD). After the first CVD growth of triangular WS2 (MoS2) grains, the second CVD step was performed to grow square SnS grains on the same substrate. We found that these SnS grains can be grown at very low temperature with the substrate temperature of 200 degrees C. Most of the SnS grains nucleated from the side edges of WS2 (MoS2) grains, resulting in the formation of partly stacked heterostructures with a large overlapping area. The SnS grains showed doped p-type transfer character with a hole mobility of 15 cm2 V-1 s-1, while the WS2 and MoS2 grains displayed n-type character with a high on/off ratio of >106. The SnS-WS2 and SnS-MoS2 heterostructures exhibited clear rectifying behavior, signifying the formation of p-n junctions at their interfaces. This heterostructure growth combined with the low temperature SnS growth will provide a promising means to exploit two dimensional heterostructures by avoiding possible damage to the first material. PMID- 29239425 TI - Solid-state organization of n-type carbazole-based semiconductors for organic thin-film transistors. AB - The development of new organic semiconductors has been mainly led by the search for new pi-conjugated cores, but recently the use of flexible side chains is attracting more and more attention to control the molecular packing and order in the solid state to improve the charge-transporting properties. In this work, the charge transport properties of a series of tricyanovinyl-substituted carbazole based materials with different alkyl chain lengths have been investigated and correlated with the respective intermolecular interactions and molecular packings via X-ray diffraction (XRD) studies. PMID- 29239426 TI - Heat of adsorption, adsorption stress, and optimal storage of methane in slit and cylindrical carbon pores predicted by classical density functional theory. AB - Temperature, pressure and pore-size dependences of the heat of adsorption, adsorption stress, and adsorption capacity of methane in simple models of slit and cylindrical carbon pores are studied using classical density functional theory (CDFT) and grand-canonical Monte-Carlo (MC) simulation. Studied properties depend nontrivially on the bulk pressure and the size of the pores. Heat of adsorption increases with loading, but only for sufficiently narrow pores. While the increase is advantageous for gas storage applications, it is less significant for cylindrical pores than for slits. Adsorption stress and the average adsorbed fluid density show oscillatory dependence on the pore size and increase with bulk pressure. Slit pores exhibit larger amplitude of oscillations of the normal adsorption stress with pore size increase than cylindrical pores. However, the increase of the magnitude of the adsorption stress with bulk pressure increase is more significant for cylindrical than for slit pores. Adsorption stress appears to be negative for a wide range of pore sizes and external conditions. The pore size dependence of the average delivered density of the gas is analyzed and the optimal pore sizes for storage applications are estimated. The optimal width of slit pore appears to be almost independent of storage pressure at room temperature and pressures above 10 bar. Similarly to the case of slit pores, the optimal radius of cylindrical pores does not exhibit much dependence on the storage pressure above 15 bar. Both optimal width and optimal radii of slit and cylindrical pores increase as the temperature decreases. A comparison of the results of CDFT theory and MC simulations reveals subtle but important differences in the underlying fluid models employed by the approaches. The differences in the high-pressure behaviour between the hard-sphere 2-Yukawa and Lennard-Jones models of methane, employed by the CDFT and MC approaches, respectively, result in an overestimation of the heat of adsorption by the CDFT theory at higher loadings. However, both adsorption stress and adsorption capacity appear to be much less sensitive to the differences between the models and demonstrate excellent agreement between the theory and the computer experiment. PMID- 29239428 TI - Ultrafast coherent vibrational dynamics in dimethyl methylphosphonate radical cation. AB - Femtosecond pump-probe measurements of the nerve agent simulant dimethyl methylphosphonate (DMMP) demonstrate the preparation of a robust coherent vibrational state in the corresponding radical cation. The oscillations in the transient ion yields have a period of 45 fs (750 cm-1), which is at least 3 times faster than any previously observed oscillations in polyatomic radical cations. Use of 1200-1600 nm, as opposed to 800 nm, wavelengths for ionization increases the oscillation amplitude by a factor of 5 and doubles the number of visible oscillation periods from 6 to 12, indicating that an adiabatic ionization mechanism significantly enhances preparation of the coherent state. The coherent motion is assigned to a bending mode in DMMP+ with frequency in the range of 742.2-754.7 cm-1 based on the results of DFT calculations. The observation of coherent nuclear dynamics in the dissociation of DMMP+ suggests the potential utility of coherent control schemes for controlling the dissociation of DMMP and related molecules, which has important implications for developing detection and decontamination technologies for organophosphorus chemical warfare agents. PMID- 29239429 TI - Electronic structure of alpha-sexithiophene ultrathin films grown on. AB - We investigated the electronic states of alpha-sexithiophene (alpha-6T) on by means of angle-resolved photoelectron spectroscopy using synchrotron radiation. The characteristic features of pi states are observed in the valence region. The increase in the population of the S1 band, assigned to the surface state of , upon deposition of alpha-6T was measured and the change in the electron density was evaluated. The band diagram was constructed based on the measurement of the HOMO level and work function. The work function was found to change with the alpha-6T thickness in a characteristic manner. We constructed a model of the electron transfer at each growth stage based on the core levels of the substrate (Si 2p, Ag 3d) and alpha-6T molecule (C 1s, S 2p), as well as the valence state and work function change. PMID- 29239430 TI - Copper(i) complexes based on ligand systems with two different binding sites: synthesis, structures and reaction with O2. AB - The synthesis of the ligand systems L1 and L2 with two different N3-binding sites linked through a dibenzofuran spacer and their coordination properties towards a variety of CuI precursors are reported. The reaction of L1 with copper halides leads to the formation of a bimetallic species [(L1)(CuICl)2] (1), and metallodimers [((L1)(CuIX)2)2(MU-(Cu)(MU-X)2)] (2: X = Br, 3: X = I) in which two dicopper complexes are bridged by a (MU-(Cu)(MU-X)2)-moiety whereas L2 reacts with copper chloride to afford {[Cu(L2)Cl2]}n (8). Furthermore, starting from L1 in combination with copper(i) salts of weakly coordinating anions the dicopper complexes [(L1)(CuI(NCCH3))2](BF4)2 (4), [(L1)(CuI(NCCH3))(Cu(Y))](Y) (5: Y = OTf, 6: Y = ClO4) and [(L1)(Cu(dppe))](PF6)2 (7) were isolated, and employing L2, the complexes [(L2)(CuI(NCCH3))2](Z)2 (9: Z = PF6, 10: Z = OTf) and [(L2)(Cu(dppe))](PF6)2 (11) were obtained. Complexes 4-6 as well as 9 and 10 react rapidly with O2 to form metastable O2 adducts in acetone at -90 degrees C, where O2 is bound between the two copper centers within one dicopper molecule, as evidenced by UV/Vis spectroscopy, kinetic investigations, Raman spectroscopy and studies with ligands containing the isolated donor sites. The reactivity of the O2 adducts towards selected substrates was also investigated, showing their ability to act as electrophiles as well as nucleophiles. PMID- 29239431 TI - Protein staining agents from low toxic platinum(ii) complexes with bidentate ligands. AB - Three new luminescent platinum(ii) complexes with bidentate C^N and O^O ligands have been designed and synthesized in this work. Along with the changing of C^N ligands, the emission peaks of these complexes range from 489 to 629 nm and the photoluminescence quantum efficiencies are up to 55% at room temperature. DFT and TD-DFT calculations have also been employed to investigate the ground and excited states of these platinum(ii) complexes. Most importantly, these platinum(ii) complexes with bidentate ligands have almost no cytotoxicity towards HeLa cells and their applications in living cell imaging and protein staining are focused on in this work. PMID- 29239432 TI - cis- and trans-9,10-di(1H-imidazol-1-yl)-anthracene based coordination polymers of ZnII and CdII: synthesis, crystal structures and luminescence properties. AB - New functional coordination polymers based on the semi-flexible 9,10-di(1H imidazol-1-yl)-anthracene ligand (L) with ZnII and CdII, namely {[Zn(MU2 L)2](ClO4)2.m(MeOH).n(DCM)}n (1), {[Zn(MU2-L)2](BF4)2.m(MeOH).n(DCM)}n (2), {[Zn(MU2-L)2(p-Tos)2].m(DCM).n(MeOH)}n (3), {[Cd(MU2-L)2(p-Tos)2].m(DCM)}n (4) {[Cd(MU2-L)2(p-Tos)2].m(MeOH).n(Dioxane)}n (5) and {[Zn(MU2 L)2(CF3CO2)2].2(Dioxane)}n (6), were obtained. Dissolving L in polar solvent mixtures MeOH-DCM (4 : 1) or MeOH-dioxane (1 : 1) with ZnII and CdII salts resulted in the formation of complexes 1, 2, and 5 adopting a cis-conformation of the imidazole groups with respect to anthracene. In less polar mixtures of solvents such as MeOH-DCM (1 : 4) trans-L is observed, leading to the coordination polymers 3-4 with ZnII and CdII. In an intermediate solvent mixture such as MeOH-dioxane (1 : 4), the cis- and trans-conformation coexist as exemplified in complex 6 with ZnII. In the solid state, complexes 1-5 assemble as supramolecular 2-D coordination polymers with a (4,4) topology, while 6 forms a tridimensional porous network with a cds topology. All compounds reveal strong blue emission in the solid state at room temperature. PMID- 29239433 TI - Photophysical properties of acetylene-linked syn bimane oligomers: a molecular photonic wire. AB - Computational studies using correlated wave function methods and density functional theory were carried out on a series of acetylene-linked bimane oligomers with particular emphasis on their excitonic properties and implications for intra-chain excitation energy transfer (EET). The low energy barriers found for the rotation of bimane subunits about the longitudinal axis are such that the pi-conjugation is easily disrupted. Nevertheless, a distinctive feature of the oligomer lies in the parallel alignment of the S1 transition dipole along the longitudinal axis, which sustains electronic coupling between adjacent bimane subunits over a range of torsional angles and is crucial for driving intra-chain EET. Using a model that comprises hexameric donor and acceptor fragments, we evaluated electronic couplings and spectral overlaps, and applied Fermi's golden rule (in the weak electronic coupling regime) to approximate the lower limit of intra-chain EET in an acetylene-linked bimane photonic wire. PMID- 29239434 TI - Suppressing the effect of lithium dendritic growth by the addition of magnesium bis(trifluoromethanesulfonyl)amide. AB - Practical applications of Li-S and Li-air batteries require the morphology of the Li metal negative electrode during charge/discharge (i.e., Li deposition/dissolution) cycling to be precisely controlled. Herein, we used magnesium bis(trifluoromethanesulfonyl)amide [Mg(TFSA)2] as an electrolyte additive to suppress the growth of Li dendrites, utilizing the occurrence of an alloying reaction between the initially substrate-deposited Mg and the subsequently deposited Li. Notably, no metallic Mg formation and no change in Li deposition morphology were observed at an electrolyte composition of 0.1 M Mg(TFSA)2 + 0.9 M LiTFSA/triglyme, irrespective of the applied potential. In contrast, increasing the Mg salt concentration to 0.5 M resulted in the deposition of interconnected granules, reflecting a dramatic morphology improvement. X-ray diffraction analysis revealed the occurrence of the abovementioned alloying, which finally afforded a deposit composition of Li0.9Mg0.1via the formation of an intermediate Li0.14Mg0.86 phase. Importantly, the deposits obtained under various applied potentials were relatively smooth, with no needle-like morphology observed. PMID- 29239435 TI - Formation of uniform carrot-like Cu31S16-CuInS2 heteronanostructures assisted by citric acid at the oil/aqueous interface. AB - A simple two-phase strategy was developed to prepare Cu31S16-CuInS2 heterostructures (HNS) at the oil/aqueous interface, in which the In(OH)3 phase was often obtained in the products due to the reaction between indium ions and hydroxyl ions in the aqueous phase. To prevent the formation of the In(OH)3 phase, citric acid was incorporated into the aqueous phase to assist in the synthesis of uniform carrot-like Cu31S16-CuInS2 semiconductor HNS at the oil/aqueous interface for the first time. By manipulating the dosage of citric acid and Cu/In precursor ratios, the morphology of the Cu31S16-CuInS2 HNS could be tailored from mushroom to carrot-like, and the presence of citric acid played a critical role in the synthesis of high-quality Cu31S16-CuInS2 HNS, which inhibited the formation of the In(OH)3 phase due to the formation of the indium(iii)-citric acid complex. The formation mechanism was studied by monitoring the morphology and phase evolution of the Cu31S16-CuInS2 HNS with reaction time, which revealed that the Cu31S16 seeds were first formed and then the cation-exchange reaction directed the subsequent anisotropic growth of the Cu31S16-CuInS2 HNS. PMID- 29239436 TI - A mesoionic nitrogen-donor ligand: structure, iridium coordination, and catalytic effects. AB - A mesoinic pyridylideneamide ligand (PYA) was synthetized and fully characterized and coordinated to an iridium(iii) center. This ligand represents the first example of a mesoionic N-donor ligand. Structural and spectroscopic analysis revealed unique properties which were exploited in chemically driven water oxidation catalysis. PMID- 29239437 TI - Solution structure of a pentachromium(ii) single molecule magnet from DFT calculations, isotopic labelling and multinuclear NMR spectroscopy. AB - The structure of pentachromium(ii) extended metal atom chain [Cr5(tpda)4Cl2] (2), which behaves as a single molecule magnet at low temperature, was investigated by Density Functional Theory (DFT) calculations and spectroscopic studies without the constraints of a crystal lattice (H2tpda = N2,N6-bis(pyridin-2-yl)pyridine 2,6-diamine). DFT studies both in the gas phase and including CH2Cl2 solvent effects indicate that an unsymmetric structure (C4 point group), with pairs of formally quadruply-bonded metal ions and one terminal metal center, is slightly more stable (2.9 and 3.9 kcal mol-1) than a symmetric structure (D4 point group). Isotopically-labelled samples (2-d8 and 2-d16) have then been prepared to aid in molecular symmetry determination by combined 1H and 2H NMR studies in dichloromethane solution. The spectra are strongly suggestive of a symmetric (D4) framework, indicating fast shuttling between the two unsymmetric forms over the timescale of NMR experiments. Procedures for a high-yield Pd-free synthesis of H2tpda and for site-selective post-synthetic H/D exchange of aromatic H2tpda hydrogens are also reported. PMID- 29239438 TI - Ultrafast interfacial charge transfer from the LUMO+1 in ruthenium(ii) polypyridyl quinoxaline-sensitized solar cells. AB - This paper describes the implementation of robust and modular sensitizers containing aromatic-amphiphilic ligands to provide new insights into the relationship between the molecular structure and electron injection process governing the efficiency of dye-sensitized solar cells (DSSCs). The significance of this work lies in the combination of favorable experimental and theoretical results in a new class of Ru(ii) polypyridyl complexes with the molecular formula of [Ru(E101)(Dicnq)x(Y)] which is named M101-M104 when X = 1 and Y = bpy, X = 1 and Y = phen, X = 2, and X = 1 and Y = 2 NCS, respectively. E101 and Dicnq ligands are 1,10-phenanthroline-5,6 heptan ammin and 6,7-dicyanodipyrido[2,2 d:2',3'-f]quinoxaline, respectively. The good agreement between the experimental and the time-dependent density functional theory (TDDFT)-calculated absorption spectra of the M101-104 sensitizers allowed us to provide a detailed assignment of the main spectral features of the investigated dyes. M102 which contained phen as an ancillary ligand had the best photovoltaic performance which can be attributed to the higher light harvesting of M102 in the visible light region. A DSSC based on complex M102 without the E101 ligand did not show any observable power conversion efficiency (PCE), indicating the importance of the amphiphilic ligand, E101. Transient absorption studies indicated that the ratio of kreg/krec (krec = the rate constant of the recombination of the dye and kreg = the rate constant of regeneration in the presence of the electrolyte) for M101-104 is 1.1, 2.9, 1.3, and 1.2, clearly confirming a weak competition between dye regeneration and recombination. Therefore, because this ratio for M101, 103, and 104 is small, kreg ~ krec, the operation of the device has been limited by back electron transports, subsequently enhancing the recombination process. However, the rate of recombination is relatively normal for an efficient DSSC, while the rate of regeneration is very low. Subsequently, the PCE will be poor, confirming the role of aliphatic chains in reducing the recombination process. To obtain a deeper insight into the charge transfer process in the investigated devices, ab initio DFT molecular dynamics simulations and quantum dynamics of electronic relaxation were carried out, clearly showing that the interfacial electron transfer (IET) time scale particularly depends on the type of ancillary ligand. The IET results substantially proved that M102 has the fast lifetime of 2.3 ps and 90 fs for the LUMO and LUMO+1, respectively, indicating the experimentally higher PCE of M102 compared to the other three investigated sensitizers. PMID- 29239440 TI - The coordination- and photochemistry of copper(i) complexes: variation of N^N ligands from imidazole to tetrazole. AB - The prediction of coordination modes is of high importance when structure property relationships are discussed. Herein, the coordination chemistry of copper(i) with pyridine-amines with a varying number of coordinating N-atoms, namely pyridine-benzimidazole, -triazole and -tetrazole, or their deprotonated analogues, and different phosphines was systematically studied and the photoluminescence properties of all synthesized complexes examined and related to DFT data. Each complex was characterized by single-crystal X-ray analysis and elemental analysis, and a set of prediction rules derived for the coordination chemistry of copper(i) with these ligands. A mononuclear cationic coordination motif was found for PPh3 or DPEPhos with all N^N ligands, which exhibits blue to green luminescence of MLCT character d(Cu) -> pi*(pyridine-amine ligand) with quantum yields up to 46%. With the deprotonated N^N ligands, mononuclear neutral complexes were only expected with DPEPhos. The emission's nature of this complex type is strongly dependent on the electronic effects of the N^N ligand and was characterized as (ML + IL)CT transition. In contrast to the high quantum yields up to 78% for the tetrazolate complexes (as reported before), the triazolate and imidazolate based complexes show much lower emission efficiencies below 10%. Besides the mononuclear copper(i) complexes, cluster-type complexes were obtained, which show moderate luminescence in the blue to green region of the visible spectrum (469-505 nm). PMID- 29239439 TI - Diversified polyoxovanadate derivatives obtained by copper(i)-catalysed azide alkyne cycloaddition reaction: their synthesis and structural characterization. AB - In this work, we confirmed that the copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction is an effective method for the organic-functionalization of polyoxometalates (POMs). Herein, for the first time, four novel 1,2,3-triazole functionalized polyoxovanadate (POV) organic-inorganic hybrids, (Bu4N)2[V6O13{(OCH2)3C5H6N3O}2].1.5CH3CN 2, (Bu4N)2[V6O13{(OCH2)3C7H8N3O2}2].2CH3CN 3, (Bu4N)2[V6O13{(OCH2)3C11H10N3}2] 4 and (Bu4N)2[V6O13{(OCH2)3C10H7N3Cl}2] 5 were prepared through the CuAAC reaction using the azide functionalized hexavanadate, (Bu4N)2[V6O13{(OCH2)3CCH2N3}2].2.5CH3CN 1, as the precursor, where CuI was used as the catalyst and N,N-diisopropylethylamine (DIPEA) as a stabilizer for CuI. All the four compounds were structurally and compositionally characterized by single-crystal X-ray diffraction, elemental analyses, powder X-ray diffraction (XRD), Fourier transform infrared (FT-IR), 1H NMR, ESI-MS, UV-Vis and thermogravimetric analysis (TGA). PMID- 29239441 TI - Ligand dependent assembly of trinuclear titanium-oxo units into coordination tetrahedra and capsules. AB - In the presence of phosphorous acid and by selecting different bridging ligands, trinuclear Ti3(MU3-O) units have been assembled into coordination cages with topologies such as {Ti6} clusters, {Ti9Cu} tetrahedrons and {Ti18} capsules. PMID- 29239442 TI - Hydrodynamics-mediated trapping of micro-swimmers near drops. AB - In this paper, we investigate the swimming characteristics and dynamics of a model micro-swimmer in the vicinity of a clean drop, and of a surfactant covered drop. We model the swimmer as a force dipole and utilize the image-singularity system to study the dynamical behavior of the swimmer. Motivated by bacterial bio remediation of insoluble hydrocarbons (HCs) released during oil spills, we report the 'trapping characteristics' - critical trapping radius, basin of attraction and trapping time distribution - of deterministic and stochastic swimmers, as a function of viscosity ratio, and dimensionless surface viscosity. We find that addition of surfactant reduces the critical trapping radius of a drop by ~30%. The basin of attraction though, is not affected acutely for any combination in the parameter space of viscosity ratio and surface viscosity. We also carry out a dynamical system analysis of our problem, for deterministic swimmers, to clarify the aforementioned concepts. For hydrodynamics combined with diffusion based motion, we note increments ranging from ~5-25% in the interface-retention times of surfactant-laden drops, as compared to clean drops. These differences occur for low values of surface viscosity, and saturate rapidly as the surface viscosity increases. With potential applications in bioremediation, our results highlight the importance of considering dispersant-addition in oil spills involving insoluble hydrocarbons. PMID- 29239443 TI - [Ag15(N-triphos)4(Cl4)](NO3)3: a stable Ag-P superatom with eight electrons (N triphos = tris((diphenylphosphino)methyl)amine). AB - A first and stable Ag-P superatom nanocluster [Ag15(N-triphos)4(Cl4)](NO3)3 (1) has been successfully synthesized and characterized. X-ray analysis shows that this Ag15 cluster has a hexacapped body-centered cubic (bcc) framework which is consolidated by four tripodal N-triphos ligands. The identity of 1 is confirmed by high resolution ESI-MS. Cluster 1 has an electronic and geometric shell closure structure with 8 free electrons, matching the stability idea of superatom theory for a nanocluster. DFT calculation of this Ag15 cluster reveals the superatom feature with a 1S21P6 configuration. The chelation of multidentate phosphines enhances the stability of this Ag15 cluster. The AgAg distances between the centered and the vertical Ag atoms of this bcc (Ag@Ag8) are in the range of 2.57-2.71 A, and the distances between the face-capped and the vertical silver atoms are in the range of 2.84-2.92 A, showing strong AgAg interactions within this cluster core. This superatom complex exhibits a relatively high thermal and photolytic stability. PMID- 29239444 TI - Total synthesis of selaginpulvilins A and C. AB - An efficient formal total synthesis of two compounds from the selaginpulvilin family of natural products, selaginpulvilin A and C, has been successfully achieved. The tetradehydro Diels-Alder (TDDA) reaction between an enyne and alkyne has been utilized for the creation of the necessary fluorene skeleton. Attempts at the conversion of selaginpulvilin A to selaginpulvilin B, F and H were unsuccessful. PMID- 29239445 TI - Addressing the exciton fine structure in colloidal nanocrystals: the case of CdSe nanoplatelets. AB - We study the band-edge exciton fine structure and in particular its bright-dark splitting in colloidal semiconductor nanocrystals by four different optical methods based on fluorescence line narrowing and time-resolved measurements at various temperatures down to 2 K. We demonstrate that all these methods provide consistent splitting values and discuss their advances and limitations. Colloidal CdSe nanoplatelets with thicknesses of 3, 4 and 5 monolayers are chosen for experimental demonstrations. The bright-dark splitting of excitons varies from 3.2 to 6.0 meV and is inversely proportional to the nanoplatelet thickness. Good agreement between experimental and theoretically calculated size dependence of the bright-dark exciton splitting is achieved. The recombination rates of the bright and dark excitons and the bright to dark relaxation rate are measured by time-resolved techniques. PMID- 29239446 TI - Shear thickening in concentrated suspensions of smooth spheres in Newtonian suspending fluids. AB - Shear thickening is a phenomenon in which the viscosity of a suspension increases with increasing stress or shear rate, sometimes in a discontinuous fashion. While the phenomenon, when observed in suspensions of corn starch in water, or Oobleck, is popular as a science experiment for children, shear thickening is actually of considerable importance for technological applications and exhibited by far simpler systems. Concentrated suspensions of smooth hard spheres will exhibit shear thickening, and understanding this behavior has required a fundamental change in the paradigm of describing low-Reynolds-number solid-fluid flows, in which contact forces have traditionally been absent. Here, we provide an overview of our understanding of shear thickening and the methods that have been developed to describe it, as well as outstanding questions. PMID- 29239447 TI - Carbon nanotubes as nanovectors for intracellular delivery of laronidase in Mucopolysaccharidosis type I. AB - The immobilization of proteins on carbon nanotubes (CNTs) has been widely reported mainly for the preparation of sensors while the conjugation of enzymes for therapeutic purposes has scarcely been considered. Herein we report, to the best of our knowledge, the first example of intracellular delivery of a therapeutic enzyme by means of CNTs, retaining its activity. Mucopolysaccharidosis I is a rare genetic disease characterized by the deficiency or absence of the activity of the alpha-l-iduronidase (IDUA) enzyme. We evaluated the capacity of the recombinant form of the human IDUA enzyme, laronidase (Aldurazyme(r)), conjugated with CNTs to be internalized by fibroblasts from subjects affected with Mucopolysaccharidosis type I and the capacity of the enzyme to retain its activity after internalization. The enzyme was successfully delivered into the lysosomal space and the enzymatic activity of the conjugate was preserved after internalization up to 48 hours. This paves the way towards the use of such a kind of construct for therapeutic applications. PMID- 29239448 TI - Organic matter identifies the nano-mechanical properties of native soil aggregates. AB - Localized variations at the nanoscale in soil aggregates and in the spatial organisation of soil organic matter (SOM) are critical to understanding the factors involved in soil composition and turnover. However soil nanoscience has been hampered by the lack of suitable methods to determine soil biophysical properties at nanometre spatial resolution with minimal sample preparation. Here we introduce for the first time an Atomic Force Microscopy (AFM)-based Quantitative Nano-Mechanical mapping (QNM) approach that allows the characterisation of the role of SOM in controlling surface nano-mechanical properties of soil aggregates. SOM coverage resulted in an increased roughness and surface variability of soil, as well as in decreased stiffness and adhesive properties. The latter also correlates with nano- to macro-wettability features as determined by contact angle measurements and Water Drop Penetration Time (WDPT) testing. AFM thus represents an ideal quantitative tool to complement existing techniques within the emerging field of soil nanoscience. PMID- 29239449 TI - Synthesis of spirocyclic orthoesters by 'anomalous' rhodium(ii)-catalysed intramolecular C-H insertions. AB - A tetrahydropyranyl acetal bearing a proximal phenyl diazoketone substituent underwent Rh(ii)-catalysed C-H insertion via an 'anomalous' C-O bond-forming, rather than C-C bond-forming, transformation, giving spirocyclic orthoesters. Density functional theory calculations with M06 show that the formation of these anomalous products involves hydride transfer to the rhodium carbene, giving an intermediate zwitterion which undergoes C-O bond formation in preference to C-C bond formation. PMID- 29239450 TI - Synthesis of spiro-4H-pyrazole-oxindoles and fused 1H-pyrazoles via divergent, thermally induced tandem cyclization/migration of alkyne-tethered diazo compounds. AB - A thermally induced, substrate-dependent reaction of alkynyl diazo compounds has been developed. This transformation produces spiro-4H-pyrazole-oxindoles and fused 1H-pyrazoles in good to high yields from the corresponding alpha-cyano and alpha-sulfonyl diazo compounds. The salient features of this reaction include excellent chemoselectivity and atom-economy, mild reaction conditions, simple purification and potential for large scale production. PMID- 29239451 TI - Metal-polymer interface influences apparent electrical properties of nano structured polyaniline films. AB - The interface between the conductive polymer, polyaniline (PAn-Cl), and gold, platinum, or an interceding layer of electrodeposited platinum on gold or platinum, markedly influences the apparent electrical properties and the electronic to ionic transition in physiological buffers. Polyester-supported, sputter-deposited gold and platinum thin films were laser patterned to yield co planar Thin Film Electrodes (TFEs) suitable for platinization and deposition of PAn-Cl nanofibers. Electrodeposition of platinum from chloroplatinic acid (50 mC cm-2) onto gold produced larger feature sizes and larger surface roughness (23.5 nm) when compared to platinization of platinum (15.2 nm) and both similarly reduced interfacial impedance in water and physiologically relevant buffers, PBS and HEPES. UV-Vis characterization produced absorption edges (DI water 2.36 eV, PBS 2.64 eV, and HEPES 2.66 eV) reflective of the ionic strength of the medium. Thin films (23 +/- 2 MUm) of PAn-Cl nanofibers were deposited onto Au, Pt, Au|Pt, Pt|Pt TFEs and each characterized by Electrical Impedance Spectroscopy (EIS) over the range 106-10-1 Hz at RT in air, DI water, PBS, and HEPES buffers and by multiple scan rate cyclic voltammetry (MSRCV) in PBS. Platinized gold and platinized platinum decorated with PAn-Cl behaved quite differently in these test environments confirming a role for the contacting surface roughness/nano topography in influencing apparent electrical properties. Equivalent circuit modeling of EIS data revealed a modified Randles circuit (R(QR)) of low chi square values (<0.05) that rationalized the capacitance and membrane resistance and confirmed that platinization of gold served to increase the PAn-Cl apparent resistance while platinization of platinum served to decrease the PAn-Cl apparent resistance. PMID- 29239452 TI - Search for a photoinduced (site-selective) cleavage of the Ar-Cl bond in dichloroanisoles. AB - The site-selective cleavage of an Ar-X bond in polyhalogenated aromatics is an important tool in synthetic planning especially when more than one identical halogen atom is present. An alternative to the usual metal-catalyzed cleavage is represented by photochemistry although only a few examples have been reported. We then investigated the feasibility of the site-selective photodechlorination of some dichloroanisoles through a combined experimental and computational study. In the case of 2,4-dichloroanisole, selective detachment of the chlorine atom at the ortho position with respect to the OMe group was observed upon photohomolysis (in cyclohexane) or photoheterolysis (in MeOH) of the Ar-Cl bond. In the latter case, 5-chloro-2-methoxy-1,1'-biphenyl was exclusively formed upon reaction of the resulting phenyl cation with benzene. The substitution of an OH group for a OMe group was detrimental since a lower photoreactivity resulted with no improvement in the selectivity. PMID- 29239453 TI - A pH and salt dually responsive emulsion in the presence of amphiphilic macromolecules. AB - A pH and salt dually responsive emulsion has been designed on the basis of a novel amphiphilic macromolecule. It was found that the water separation of an oil in-water emulsion reached up to ~60% after standing for 10 min at low pH. 2 (Diethylamino)ethyl methacrylate (DEA) residues were found to induce the macromolecules to protonate and to be hydrophilic at pH values between 2 and 6, resulting in dewetting from oil droplet surfaces in water. Besides, the macromolecules form aggregates with different structures at the water/oil interface, depending on the pH value or salt concentration of the emulsion system, enabling the system to be demulsified in response to the pH or salt stimulus. The experimental results also showed that with the addition of aluminium chloride at 100 mg L-1, the water separation was about 70% after 20 min. A possible mechanism with respect to demulsifying was proposed on the basis of an "ion bridge" among sodium acrylate (SA) residues, inducing the macromolecules to "cross-link" and become insoluble, and leading to oil/water separation. Furthermore, at a fixed pH of 5, addition of salt to the aqueous dispersion increased the degree of oil-water interfacial activity and batch emulsions were significantly unstable to coalesce at a low salinity of 25-50 mg L 1. This finding presents a new manipulation on emulsion stability and potential applications in the fields of oil recovery, wastewater treatment, sludge removal, and so on. PMID- 29239454 TI - Organelle-targeting surface-enhanced Raman scattering (SERS) nanosensors for subcellular pH sensing. AB - The pH value of subcellular organelles in living cells is a significant parameter in the physiological activities of cells. Its abnormal fluctuations are commonly believed to be associated with cancers and other diseases. Herein, a series of surface-enhanced Raman scattering (SERS) nanosensors with high sensitivity and targeting function was prepared for the quantification and monitoring of pH values in mitochondria, nucleus, and lysosome. The nanosensors were composed of gold nanorods (AuNRs) functionalized with a pH-responsive molecule (4 mercaptopyridine, MPy) and peptides that could specifically deliver the AuNRs to the targeting subcellular organelles. The localization of our prepared nanoprobes in specific organelles was confirmed by super-high resolution fluorescence imaging and bio-transmission electron microscopy (TEM) methods. By the targeting ability, the pH values of the specific organelles can be determined by monitoring the vibrational spectral changes of MPy with different pH values. Compared to the cases of reported lysosome and cytoplasm SERS pH sensors, more accurate pH values of mitochondria and nucleus, which could be two additional intracellular tracers for subcellular microenvironments, were disclosed by this SERS approach, further improving the accuracy of discrimination of related diseases. Our sensitive SERS strategy can also be employed to explore crucial physiological and biological processes that are related to subcellular pH fluctuations. PMID- 29239455 TI - Quasi-Talbot effect of orbital angular momentum beams for generation of optical vortex arrays by multiplexing metasurface design. AB - The quasi-Talbot effect of orbital angular momentum (OAM) beams, in which the centers are placed in a rotationally symmetric position, is demonstrated both numerically and experimentally for the first time. Since its multiplication factor is much higher than the conventional fractional Talbot effect, the quasi Talbot effect can be used in the generation of vortex beam arrays. A metasurface based on this theory was designed and fabricated to test the validity of this assumption. The agreement between the numerical and measured results suggests the practicability of this method to realize vortex beam arrays with high integrated levels, which can open a new door to achieve various potential uses related to optical vortex arrays in integrated optical systems for wide-ranging applications. PMID- 29239456 TI - Pain-induced depression in the elderly: Validation of psychometric properties of the Brazilian version of the "Geriatric Emotional Assessment of Pain" - GEAP-b. AB - OBJECTIVE: In order to introduce an instrument within our midst that allows a comprehensive clinical evaluation of pain-induced depression in the elderly, we proposed the translation, cross-cultural adaptation into Brazilian Portuguese, and study of the psychometric properties of the "Geriatric Psychosocial Assessment of Pain-induced Depression" (GEAP) scale. This instrument was especially developed for the screening of depression associated with chronic pain in the elderly. METHOD: We performed translation and cross-cultural adaptation of the GEAP scale, whose psychometric properties were analyzed in a sample of 48 elderly individuals. Sociodemographic data and information related to chronic pain were ascertained, as well as those related to depression. The GEAP-b scale was applied at three different times on the same day by two different interviewers (I1 and I2), and after 15 days by one of those interviewers (I3). RESULTS: The GEAP-b proved to be an easy-to-apply instrument with a high internal consistency value, according to the Cronbach's alpha coefficient (0.835). The reproducibility of the instrument was optimal, achieving intraclass correlations of 98.5 and 92% for interobserver and intraobserver, respectively. There was "considerable" agreement (between 0.419 and 1.0) for each GEAP-b item, except for item 19, according to the kappa statistic. As for the validity of the GEAP-b criterion, positive and statistically significant correlations were obtained for pain, according to GPM-p (r=49.5%, p<0.001), and depression, according to GDS (r=59%, p<0.001), both values being considered regular (between 40-60%). CONCLUSION: The GEAP-b scale has proven to be reliable and valid in the screening of pain-related depression in the elderly. PMID- 29239457 TI - Opioids and immunosupression in oncological postoperative patients. AB - INTRODUCTION: Recent animal studies demonstrated immunosuppressive effects of opioid withdrawal resulting in a higher risk of infection. The aim of this study was to determine the impact of remifentanil discontinuation on Post-Anesthesia Care Unit (PACU)-acquired infection after a schedule of sedoanalgesia of at least 6 days. METHOD: All patients over 18 years of age with a unit admission of more than 4 days were consecutively selected. The study population was the one affected by surgical pathology of any origin where sedation was based on any hypnotic and the opioid remifentanil was used as analgesic for at least 96 hours in continuous perfusion. Patients who died during admission to the unit and those with combined analgesia (peripheral or neuroaxial blocks) were excluded. Bivariate analysis was performed to determine risk factors for infection acquired in the unit. A comparative study between periods of 6 days before and after the cessation of remifentanil was performed. Paired samples test and McNemar test was used for quantitative and categorical variables, respectively. RESULTS: There were 1,789 patients admitted to the PACU during the study and the population eligible was constituted for 102 patients. The incidence rate of PACU-acquired infection was 38 per 1,000 PACU days. Ventilator-associated pneumonia was the most frequently diagnosed PACU-acquired infection. Pseudomona aeruginosa was the most frequently isolated microorganism. Hospital mortality was 36.27%. No statistically significant differences were seen in the incidence of HAI in cancer patients in relation to discontinuation of remifentanil (p=0.068). CONCLUSION: The baseline state of immunosuppression of cancer patients does not imply a higher incidence of HAI in relation to the interruption of remifentanil. It would be of interest to carry out a multicenter PACU study that included immunological patterns. PMID- 29239458 TI - Treatment of advanced melanoma - A changing landscape. AB - Following decades of relative ostracism, advances in the treatment of melanoma have brought a new reality for patients, physicians and researchers. While antibodies targeting molecules involved in the modulation of the interaction between melanoma and immune cells changed the meaning of the term "cancer immunotherapy," a better characterization of the molecular aberrations involved in melanoma carcinogenesis prompted the development of inhibitors of the mitogen activated protein kinase pathway (MAPK) that also led to significant improvements both in response rates and survival. As a result, new drugs have been approved for clinical use in the United States and Europe, including the immune-checkpoint blockers ipilmumab, pembrolizumab and nivolumab, the oncolytic herpesvirus talimogene laherparepvec, and the targeted-agents vemurafenib, dabrafenib, cobimetinib and trametinib. In this article, we review the results of studies that brought new approaches to the bedside and discuss how these developments are being incorporated into the care of patients in Brazil. PMID- 29239460 TI - Guidelines for the treatment of lung cancer using radiotherapy. PMID- 29239459 TI - Ischemic left ventricle systolic dysfunction: An evidence-based approach in diagnostic tools and therapeutics. AB - Coronary artery disease (CAD) associated with left ventricular systolic dysfunction is a condition related to poor prognosis. There is a lack of robust evidence in many aspects related to this condition, from definition to treatment. Ischemic cardiomyopathy is a spectrum ranging from stunned myocardium associated with myocardial fibrosis to hibernating myocardium and repetitive episodes of ischemia. In clinical practice, relevance lies in identifying the myocardium that has the ability to recover its contractile reserve after revascularization. Methods to evaluate cellular integrity tend to have higher sensitivity, while the ones assessing contractile reserve have greater specificity, since a larger mass of viable myocytes is required in order to generate contractility change. Since there are many methods and different ways to detect viability, sensitivity and specificity vary widely. Dobutamine-cardiac magnetic resonance with late gadolinium enhancement has the best accuracy is this setting, giving important predictors of prognostic and revascularization benefit such as scar burden, contractile reserve and end-systolic volume index. The latter has shown differential benefit with revascularization in some recent trials. Finally, authors discuss interventional procedures in this population, focusing on coronary artery bypass grafting and evolution of evidence from CASS to post-STICH era. PMID- 29239462 TI - Isoflavones derived from Glycine max (L.) Merr. in the treatment of vaginal atrophy: A new frontier. PMID- 29239461 TI - Subclinical atherogenesis in patients with mild psoriasis: A role for IL-6? AB - INTRODUCTION: A link of psoriasis with subclinical atherosclerosis has been postulated and cytokine network might intermediate this association. Few data are available in patients with mild psoriasis. We evaluated carotid intima-media thickness (cIMT) in drug-free psoriatic individuals and controls. In parallel, we searched for associations of cIMT with disease activity indexes and serum interleukins (IL) in psoriatic patients. METHOD: An experienced radiologist performed the cIMT analyses. Cytokine concentrations were assessed by flow cytometry. Disease activity was evaluated based on psoriasis area and severity index (PASI) as well as body surface area (BSA). RESULTS: Sixty-five (65) patients and 64 controls were studied. Mean age of patients (50.9 years) did not differ from controls (p=0.362). A low PASI and BSA (< 10) prevailed (69.2% and 56.9%, respectively). Median levels of IL-12p70, TNF-alpha, IL-1beta and IL-10 were significantly lower in cases than in controls (adjusted p<0.05), while IL-6 and IL-8 medians did not differ between groups (adjusted p>0.05). Smoking habit and diabetes mellitus predominated in cases (p=0.002). An altered cIMT (>= 0.9 mm) was more frequent in cases than in controls (23.8% versus 8.5%, adjusted p=0.045). Mean cIMT was higher in cases with a borderline significance (p=0.057). cIMT scores did not correlate to PASI (rs=0.066; p=0.250) or BSA (rs=0.175; p=0.185), but did correlate significantly with serum IL-6 (rs=0.26; p=0.005). CONCLUSION: Subclinical atherosclerosis was more frequent in patients with mild psoriasis than controls. cIMT in psoriatic individuals correlated with serum IL 6, pointing to an eventual proatherogenic role of IL-6 in these patients. Newer studies should clarify the connection of atherogenesis with cytokines in psoriasis. PMID- 29239463 TI - Common mental disorders in medical students: A repeated cross-sectional study over six years. AB - INTRODUCTION: Becoming a medical doctor is a very complex process. Factors related to the student's personality, the educational process and the daily experience with death contribute to peculiar psycho-emotional experiences, not always properly investigated during medical training. OBJECTIVE: To estimate the prevalence of common mental disorders (CMD) and associated factors, over six years of medical undergraduate course among all students of a class at a public university in Brazil. METHOD: Cross-sectional study based on repeated surveys. All 40 students enrolled in 2006 in the first year of our medical school were included and evaluated annually until 2011 using the SRQ-20 and a structured questionnaire prepared by the authors on sociodemographic, personal and educational aspects. We performed Poisson regression and correspondence analysis [corrected]. RESULTS: The 40 freshmen in the first evaluation had a mean age of 20 years (SD=2.4), 57.5% were female, and 41% were approved after taking their third entrance exam. The prevalence of CMD increased over the years: from 12.5% in the first year to 43.2% in the fifth. The following variables were potentially associated with CMD: female sex (PR=1.38), originating from capital cities (PR=1.97), the program was less than they expected (PR=3.20), discomfort with program activities (PR=2.10), dissatisfaction with teaching strategies (PR=1.38), and feeling that the program is not a source of pleasure (PR=2.06), being R2=28.8% and AIC=60.04. CONCLUSION: The factors potentially associated with the high prevalence of CMD were those related to medical training, showing that it is necessary to implement preventive measures and review the educational process in order to reduce the damages caused by the development of CMD. PMID- 29239464 TI - CD20 role in pathophysiology of Hodgkin's disease. AB - Hodgkin's lymphoma (HL) is a tumor comprising non-malignant and malignant B cells. Classical HL expresses CD15+ and CD30+ antigens, and 20 to 40% of patients are CD20+. This antigen is a ligand free protein present in B lymphocyte cells and its function is not well known. Some studies suggest that expression of CD20 may play a major role in Hodgkin's disease pathophysiology and may affect the patients' treatment prognosis, as well as relapse and refractory response. In the past few years, development of monoclonal anti-CD20 antibodies changed drastically the treatment for non-Hodgkin lymphomas in which CD20 is expressed. HL treatment is essentially composed of radiotherapy and chemotherapy; however, monoclonal anti-CD20 antibodies applicability is not well delimitated due to lack of information about clinical outcomes with anti-CD20 monotherapy or combined drug therapy using a classic regimen, as well as about CD20 pathophysiology mechanisms in B-cells tumors. The objective of our review is to discuss CD20 function in Hodgkin's lymphoma development, its influence on disease evolution and outcomes, as well as its effects on therapeutics and patients' prognostic. PMID- 29239465 TI - Vitamin B12, bone mineral density and fracture risk in adults: A systematic review. AB - OBJECTIVE: To consolidate information available on the effect of vitamin B12 on bone mineral density and fracture risk, with emphasis on clinical trials, observational and longitudinal data conducted in humans. METHOD: A systematic review of the literature of the past decade on the role of vitamin B12 in bone mineral density and fracture risk in subjects of all ages and both sexes was performed by means of a PubMed, Science Direct, Medline and SciELO database search. Articles included in this review were identified using the search terms: B12 Vitamin and Bone Mineral Density and Vitamin B12 and Risk of Fractures. Evidence quality of the included articles was evaluated by GRADE system. RESULTS: A total of 25 original studies were identified. After reviewing the titles and abstracts of articles, only 17 articles met the inclusion criteria. The present review provides evidence that the role of vitamin B12 on bone mineral density or fracture risk should be further elucidated. Controversies are explained by heterogeneity of methodologies used for the diagnosis of vitamin B12 and also by differences among populations investigated on the studies. CONCLUSION: A real effect of vitamin B12 deficiency in bone health and the mechanisms associated with bone metabolism is not well established yet. It is extremely important to carry out more clarifying studies about this theme, especially with vulnerable groups such as postmenopausal and elderly women, as is well-known that they are greatly affected by deficiency of this vitamin. PMID- 29239466 TI - Rupture of the myocardium in autopsied MI hearts. AB - Although myocardial rupture occurs in only 2% to 4% of cases of acute myocardial infarction (AMI), there is a high mortality rate due to acute cardiogenic shock. We present the anatomopathological findings of three cases of myocardial rupture in autopsied hearts in the last 30 years, with a diagnosis of cardiac rupture in acute myocardial infarction. In these 30 years the percentage of AMI with myocardial rupture was 0.2%. Risk factors for post-AMI myocardial rupture include older age, atherosclerosis, diabetes mellitus and systemic arterial hypertension. PMID- 29239467 TI - The impact of anemia and body mass index (BMI) on neuromotor development of preschool children. AB - OBJECTIVE: According to data from the World Health Organization (WHO), anemia is a prevalent health problem that leads to increased morbidity and mortality, especially in preschool children. Anemia is recognized as a major health problem due to its negative effects on the mental and physical development during childhood. The aim of our study was to determine the levels of anemia of children in a kindergarten affiliated to the Directorate of National Education using a non invasive method, and to investigate the effects of anemia on the physical, mental and neuromotor development of children. METHOD: The levels of anemia was evaluated by using a non-invasive measurement device. Data collection was performed by means of a questionnaire to evaluate the children's physical development and set Denver Developmental Screening Test II scores. RESULTS: Our findings show that 21% of non-anemic and 15% of anemic children are in the suspected abnormal group according to their DDST II total score. Furthermore, it has been identified that mild anemia has a positive effect on neuromotor development, while overweight and obesity affect neuromotor development in a negative way. CONCLUSION: According to the results obtained from the study, mild anemia may have a positive effect on the children's neuromotor development, while malnutrition could have a negative impact. PMID- 29239469 TI - Bariatric surgery in the elderly: A narrative review. AB - INTRODUCTION: Due to population ageing, the elderly obese population is increasing. Bariatric surgery is the standard treatment option for morbid obesity nowadays, but there is some controversy regarding its routine indication in the elderly population. Objetive: To review the current evidence about bariatric surgery in the elderly. METHOD: On-line search in the electronic databases Medline and Lilacs and compilation of the most significant data. The most relevant studies in the area over the past 16 years have been considered for this review. RESULTS: There was significant methodological heterogeneity in the studies found in the literature. Historically, old age was associated with poorer outcomes after bariatric surgery, both in regards to early postoperative complications and less weight loss, and resolution of comorbidities. More recent studies have shown better results, with morbidity and mortality comparable to those observed in younger populations. More cautious patient selection and the evolution of the surgical technique appear to be the cause of such improvement. An extended multidisciplinary team including a geriatrician and a social worker may also help to improve the preoperative approach. CONCLUSION: Bariatric surgery is a safe and effective therapeutic option in the elderly population, but careful patient selection and specific preoperative assessment are mandatory. PMID- 29239468 TI - The importance of risk factors for the prediction of patients with invasive pulmonary aspergillosis. AB - OBJECTIVE: Invasive pulmonary aspergillosis (IPA) is a major challenge in the management of immunocompromised patients. Despite all the advances in diagnosis, it remains a problem. The purpose of our study was to investigate the risk factors associated with IPA seen in patients with hematological malignancies. METHOD: A total of 152 febrile neutropenia (FEN) patients with hematological malignancies aged over 18 years and receiving high-dose chemotherapy or stem cell transplant between January 1, 2010, and December 31, 2012 were included in the study. Sixty-five (65) cases with IPA according to the European Organization for the Research and Treatment of Cancer and Infectious Diseases Mycoses Study Group criteria were enrolled as the case group, while 87 patients without IPA development during concomitant monitoring were enrolled as the control group. Incidence of IPA was 21.4% (3/14) in patients receiving bone marrow transplant (allogeneic 2, autologous 1) and those cases were also added into the case group. The two groups were compared in terms of demographic, clinical and laboratory findings and risk factors associated with IPA investigated retrospectively. RESULTS: Presence of relapse of primary disease, neutropenia for more than 3 weeks, presence of bacterial infection, and non-administration of antifungal prophylaxis were identified as risk factors associated with IPA. CONCLUSION: It may be possible to reduce the incidence of the disease by eliminating preventable risk factors. Predicting those risks would, per se, enable early diagnosis and treatment and, thus, the mortality rate of these patients would unquestionably decline. PMID- 29239470 TI - Nutritional knowledge and body mass index: A cross-sectional study. AB - OBJECTIVE: To verify the knowledge about food and nutrition and its association with the nutritional status of obese patients with noncommunicable diseases (NCDs), and to identify the relationship between information sources and level of knowledge. METHOD: Cross-sectional study that included 263 outpatients of a cardiology referral hospital in Porto Alegre, Rio Grande do Sul, Brazil. The participants filled out a questionnaire on socioeconomic data and knowledge about food and nutrition and had their nutritional status evaluated by body mass index (BMI), waist circumference (WC) and waist-hip ratio (WHR). RESULTS: BMI showed a significant inverse association with the percentage of correct answers (p=0.002), as well as WC (p=0.000) and WHR (p<0.001). This was also true for education (p<0.001) and female gender (p=0.005) compared to males. More than 60% of patients reported using television and 23% reported using newspaper as sources of nutritional information. CONCLUSION: Our study revealed a significant association between BMI and the level of knowledge about foods, showing that there is need for more information on obesity-related NCDs for greater understanding by patients. PMID- 29239471 TI - Age-related changes in the morphology and the distribution of IgA and IgG in the palatine tonsils of yaks (Bos grunniens). AB - This study aimed to describe the age-related morphological changes and the distribution of IgA and IgG antibody-secreting cells (ASCs) in yaks. The palatine tonsils of twenty clinically healthy yaks, viz. newborn juvenile, adult and aged, were studied using histology, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). The results showed that the palatine tonsils found in two tonsillar sinus were elongated kidney-shaped structures. Some external crypts and internal crypts were present. The palatine tonsils were partially enclosed by a connective tissue capsule and had trabeculae extending into the organ. Within these encapsulated organs, mucous glands were seen very obviously. Each crypt was highly branched and lined with stratified squamous non-keratinized epithelium. Several nonepithelial cells infiltrated between the epithelial cells, forming patches of reticular epithelium or lymphoepithelium. In newborn yaks, the lymphoid follicles were not observed. In other groups, the lymphoid follicles consisted of primary lymphoid follicles and secondary lymphoid follicles. Both IgA and IgG ASCs were distributed in the interfollicular areas, lymphoid follicles, the subepithelial areas of the non-reticular crypt epithelium, and the reticular crypt epithelium, with a few positive cells aggregated around the gland. The density of the two ASCs and the expression of the two proteins gradually increased from newborn to adult and reached a peak at adult age; they then decreased with age. However, the density of the IgG ASCs and the expression of IgG protein was significantly higher than that of IgA in all groups (P<0.01). The results indicated that the palatine tonsils were not only lymphoepithelial structures but also typical secondary lymphoid organs. IgG could be a significant component of mucosal immune responses in the palatine tonsils of yaks. PMID- 29239472 TI - Definitive thermochemistry and kinetics of the interconversions among conformers of n-butane and n-pentane. AB - The focal-point analysis (FPA) technique is used for the definitive characterization of conformational interconversion parameters, including activation energy barriers, activation free energies, and kinetic rate coefficients at 298 K, of two n-alkanes, n-butane, and n-pentane, yielding the first complete analysis of their interconversion kinetics. The FPA implementation developed in this study is based on geometry optimizations and harmonic frequency computations carried out with density functional theory methods and single-point energy computations up to the CCSD(T) level of electronic structure theory using atom-centered Gaussian basis sets as large as cc-pV5Z. The anharmonic vibrational computations are carried out, at the MP2/6-31G* level of theory. Reflecting the convergence behavior of the Gibbs free-energy terms and the interconversion parameters, well-defined uncertainties, mostly neglected in previous theoretical studies, are provided. Finally, the effect of these uncertainties on the concentrations of the conformers of n-butane and n-pentane is examined via a global Monte-Carlo uncertainty analysis. (c) 2017 Wiley Periodicals, Inc. PMID- 29239473 TI - Polyamines regulating phytic acid degradation in mung bean sprouts. AB - BACKGROUND: Polyamines are essentially involved in cell division and differentiation. Transport of polyamines is adenosine triphosphate (ATP) dependent, while phytic acid is the major reserve of phosphate essential to the energy-producing machinery of cells. Thus polyamines might enhance phytic acid degradation during mung bean germination. In this study, different polyamines (putrescine (Put), spermidine (Spd) and spermine (Spm)) and dicyclohexylamine (DCHA, an inhibitor of Spd synthesis) were applied to investigate the function of polyamines on phytic acid degradation. RESULTS: Spd exhibited the best effect at the same concentration. Simultaneously, exogenous Spd improved sprout growth and enhanced the accumulation of gibberellin acid 3 (GA3 ), indole-3-acetic acid (IAA), abscisic acid (ABA) and cytokinin (CTK). This must be due to the increased endogenous polyamine contents. Apart from dramatically reducing phytic acid content, Spd resulted in the up-regulation of PA, PAP, MIPP and ALP transcript levels and the enhancement of phytase and acid phosphatase activities. However, DCHA application caused the opposite results, because it decreased endogenous polyamine contents. Furthermore, Spd alleviated the DCHA-induced inhibitory effect to some extent. CONCLUSION: Overall, polyamines, especially Spd, could accelerate phytic acid degradation in mung bean sprouts by inducing the synthesis of endogenous polyamines and phytohormones and enhancing the growth of sprouts. (c) 2017 Society of Chemical Industry. PMID- 29239474 TI - Maternal liver transplant: Another cause of discordant fetal sex determination using cell-free DNA. AB - Noninvasive prenatal testing (NIPT) can very accurately determine fetal sex during pregnancy. We present an exceptional case where NIPT contradicts the ultrasound-based sex determination. The pregnant woman was recipient of a liver transplant from a male donor. Graft-derived cell-free DNA released into the maternal circulation clouded the NIPT-based sex determination. Hence, NIPT is not advisable when the pregnant mother underwent an organ transplant. PMID- 29239475 TI - The production of hydrolysates from industrially defatted rice bran and its surface image changes during extraction. AB - BACKGROUND: This research employed a mild subcritical alkaline water (mild-SAW) extraction technique to overcome the difficulty of active compound extractability from industrially defatted rice bran (IDRB). Mild-SAW (pH 9.5, 130 degrees C, 120 min) treatment followed by enzymatic hydrolysis (Protease G6) was applied to produce rice bran hydrolysate (RBH). Response surface methodology was used to identify proteolysis conditions for maximizing protein content and ABTS radical scavenging activity (ABTS-RSA). Microstructural changes occurring in IDRB during extraction were monitored. The selected RBH was characterized for protein recovery, yield, antioxidant activities, phenolic profile and hydroxymethylfufural (HMF) content. RESULTS: Optimal proteolysis conditions were 20 mL kg-1 IDRB (enzyme/substrate ratio) for 6 h. Under these conditions, the yield, ABTS-RSA, ferric reducing antioxidant power and total phenolic content of the RBH were 46.1%, 294.22 umol trolox g-1 , 57.72 umol FeSO4 g-1 and 22.73 mg gallic acid g-1 respectively, with relatively low HMF level (0.21 mg g-1 ). The protein recovery was 4.8 times greater than that by conventional alkaline extraction. Its major phenolic compounds were p-coumaric and ferulic acids. The microstructural changes of IDRB confirmed that the mild-SAW/Protease G6 process enhanced the release of active compounds. CONCLUSION: The process of mild-SAW extraction followed by proteolysis promotes the release of active compounds from IDRB. (c) 2017 Society of Chemical Industry. PMID- 29239476 TI - Complications associated with surgical dehorning in goats: A retrospective study of 239 cases. AB - OBJECTIVE: This article describes complications following surgical dehorning of goats. STUDY DESIGN: Retrospective. Medical records of goats that underwent surgical dehorning were reviewed. ANIMALS: Two hundred thirty-nine goats. METHODS: The medical records of 239 goats, not previously dehorned by other methods, that were cosmetically dehorned between January 2006 and April 2016, were reviewed. Data retrieved from the medical records included breed, weight, the surgeon performing the procedure, intraoperative complications, and the occurrence of return visits to the teaching hospital because of complications related to the dehorning procedure. The owner of record then completed a standard questionnaire during a telephone interview. RESULTS: One or more complications following the surgical dehorning procedure were reported in 93/239 (38.91%) of goats. Complications were divided into major and minor categories. Eighty-four of 239 goats (35.14%) had minor complications, 3/239 goats (1.26%) experienced major complications, and 6/239 (2.51%) had both major and minor complications. The mean weight of goats with complications was 29.73 kg compared to 24.91 kg for goats without complications. This difference was statistically significant (P = .015). CONCLUSION: Surgical dehorning of goats results in a high rate of complications; however, the majority of these complications are minor and do not affect health and performance of the goats. Goats experiencing complications weighed significantly more than goats without complications. CLINICAL SIGNIFICANCE: Surgical dehorning of goats requires minimal aftercare and results in a low rate of serious complications. PMID- 29239477 TI - Effect of incorporation of natural chemicals in water ice-glazing on freshness and shelf-life of Pacific saury (Cololabis saira) during -18 degrees C frozen storage. AB - BACKGROUND: Microbial spoilage and lipid oxidation are two major factors causing freshness deterioration of Pacific saury (Cololabis saira) during frozen storage. To provide a remedy, the effects of several natural chemicals incorporated alone or in combination in traditional water ice-glazing on the freshness and shelf life of Pacific saury during frozen storage at -18 degrees C were investigated. Pacific sauries were subjected to individual quick freezing followed immediately by dipping into cold tap water (control) or solutions containing nisin, chitosan, phytic acid (single-factor experiment) or their combinations ((L9 (34 ) orthogonal experiment) for 10 s at 1 degrees C and then packaged in polypropylene bags before frozen storage at -18 degrees C. The storage duration tested was up to 12 months. RESULTS: All ice-glazing treatments with individual chemicals could significantly (P < 0.05) inhibit the accumulation of thiobarbituric acid-reactive substances (TBARS), total volatile basic nitrogen (TVB-N) and histamine as well as the increase in bacterial total viable count (TVC) compared with controls, while the combination treatments gave even better effects. The L9 (34 ) orthogonal experiment showed that the optimal combination was A2 B1 C2 (i.e. 0.5 g L-1 nisin, 5 g L-1 chitosan and 0.2 g L-1 phytic acid). The TBARS, TVB-N, histamine and TVC values in A2 B1 C2 -treated samples remained far below the maximum acceptable limit for good-freshness fish after 12 months of frozen storage at -18 degrees C. CONCLUSION: The incorporation of natural chemicals tested herein in ice-glazing could inhibit microbial spoilage and lipid oxidation and therefore maintain the freshness of Pacific saury during frozen storage. Under the optimal conditions, the shelf-life of Pacific saury could be extended up to 12 months at -18 degrees C. The study indicated that the combination treatment with natural chemicals could be commercially utilized to maintain the freshness and prolong the shelf-life of Pacific saury. (c) 2017 Society of Chemical Industry. PMID- 29239478 TI - The effect of emotionally valenced eye region images on visuocortical processing of surprised faces. AB - In this study, we presented pictorial representations of happy, neutral, and fearful expressions projected in the eye regions to determine whether the eye region alone is sufficient to produce a context effect. Participants were asked to judge the valence of surprised faces that had been preceded by a picture of an eye region. Behavioral results showed that affective ratings of surprised faces were context dependent. Prime-related ERPs with presentation of happy eyes elicited a larger P1 than those for neutral and fearful eyes, likely due to the recognition advantage provided by a happy expression. Target-related ERPs showed that surprised faces in the context of fearful and happy eyes elicited dramatically larger C1 than those in the neutral context, which reflected the modulation by predictions during the earliest stages of face processing. There were larger N170 with neutral and fearful eye contexts compared to the happy context, suggesting faces were being integrated with contextual threat information. The P3 component exhibited enhanced brain activity in response to faces preceded by happy and fearful eyes compared with neutral eyes, indicating motivated attention processing may be involved at this stage. Altogether, these results indicate for the first time that the influence of isolated eye regions on the perception of surprised faces involves preferential processing at the early stages and elaborate processing at the late stages. Moreover, higher cognitive processes such as predictions and attention can modulate face processing from the earliest stages in a top-down manner. PMID- 29239479 TI - Investigating canine elbow joint stabilisation through mechanical constraints of the deep fascia and other soft tissues. AB - The objective of this research was to investigate how the range of flexion and extension of the canine elbow joint is constrained by the mechanical connections and attachments of soft tissue structures. The skin, a section of deep fascia and several muscles from both forelimbs from six adult greyhounds and seven other breeds were sequentially transected or removed, over 13 steps. During each step, repeated measurements of elbow flexion and extension were recorded using a goniometer. Only marginally significant changes to the range of flexion occurred in any of the 13 steps or overall for the greyhounds. Clearly significant changes to extension occurred in several dissection steps. Removing the skin resulted in a significant increase in elbow extension of 1.7 degrees +/- 0.3 (P < 0.001) in the greyhounds and 1.6 degrees +/- 0.3 (P < 0.001) in the other breeds. Severing the deep fascia from the humerus and its connections across the elbow joint resulted in the largest significant change in elbow extension of 9.9 degrees +/- 0.3 (P < 0.001) in the greyhounds and 6.9 degrees +/- 0.7 (P < 0.001) in the other breeds. Transecting the biceps brachii m. close to the elbow resulted in an increase of 2.8 degrees +/- 0.3 (P < 0.001) in the greyhounds but a non significant change in the other breeds. Transecting the extensor carpi radialis m. from its origin resulted in an increase of 5.5 degrees +/- 0.4 (P < 0.001) in the greyhounds and 3.9 degrees +/- 0.7 (P < 0.001) in the other breeds. These results suggest that the collagenous framework and attachments of the skin, deep fascia, and extensor carpi radialis m., play a significant role in the function of the canine elbow by restricting it from overextension and hence stabilising it during periods of loading, in a variety of different canine breeds, and that these structures are functionally integrated into the way the forelimb supports the bodyweight separately from any involvement of muscle tone or muscle movements. Observations on the anatomical connections of the deep fascia between the cranial distal humerus and the antebrachial fascia highlighted its probable importance in relating movements between the shoulder and the carpus. PMID- 29239482 TI - Using agent-based modeling to study multiple risk factors and multiple health outcomes at multiple levels. AB - Most health studies focus on one health outcome and examine the influence of one or multiple risk factors. However, in reality, various pathways, interactions, and associations exist not only between risk factors and health outcomes but also among the risk factors and among health outcomes. The advance of system science methods, Big Data, and accumulated knowledge allows us to examine how multiple risk factors influence multiple health outcomes at multiple levels (termed a 3M study). Using the study of neighborhood environment and health as an example, I elaborate on the significance of 3M studies. 3M studies may lead to a significantly deeper understanding of the dynamic interactions among risk factors and outcomes and could help us design better interventions that may be of particular relevance for upstream interventions. Agent-based modeling (ABM) is a promising method in the 3M study, although its potentials are far from being fully explored. Future challenges include the gap of epidemiologic knowledge and evidence, lack of empirical data sources, and the technical challenges of ABM. PMID- 29239481 TI - The self-curing phenomenon of schistosome infection in rhesus macaques: insight from in vitro studies. AB - A reduction in the burden of schistosomiasis is potentially achievable by integrating a schistosomiasis vaccine with current control measures. Here, we determine parasite-specific in vitro responses of B, T, and NK cells from naive uninfected rhesus macaques to Schistosoma mansoni (Sm) egg (SmEA) and worm antigen (SmWA) preparations isolated from infected baboons. Pronounced B cell responses to SmEA and NK cell responses to both SmEA and SmWA were observed. High levels of IL-2 and IL-21 responses against Sm antigens were observed in T and non T cells of lymph nodes (LNs) and gut lamina propria-derived lymphocytes (LPLs). Data analysis showed multifunctionality of LN-derived CD4+ , CD8+ , and CD4+ CD8+ double positive T cells against either SmWA or SmWA+SmEA antigen preparations. Distinct SmEA-specific multifunctional responses were observed in gut LPLs, suggesting simultaneous responses against egg antigens. These data provide insight into the immune effectors involved in schistosome responses by rhesus macaques. PMID- 29239480 TI - Cobinamide is effective for treatment of hydrogen sulfide-induced neurological sequelae in a mouse model. AB - Hydrogen sulfide (H2 S) is a highly neurotoxic gas. Acute exposure can lead to neurological sequelae among survivors. A drug for treating neurological sequelae in survivors of acute H2 S intoxication is needed. Using a novel mouse model we evaluated the efficacy of cobinamide (Cob) for increasing survival of, and reducing neurological sequalae in, mice exposed to sublethal doses of H2 S. There were two objectives: (1) to determine the dose-response efficacy of Cob and (2) to determine the effective therapeutic time window of Cob. To explore objective 1, mice were injected intramuscularly with Cob at 0, 50, or 100 mg/kg at 2 min after H2 S exposure. For objective 2, mice were injected intramuscularly with 100 mg/kg Cob at 2, 15, and 30 min after H2 S exposure. For both objectives, mice were exposed to 765 ppm of H2 S gas. Cob significantly reduced H2 S-induced lethality in a dose-dependent manner (P < 0.05). Cob-treated mice exhibited significantly fewer seizures and knockdowns compared with the H2 S-exposed group. Cob also reversed H2 S-induced weight loss, behavioral deficits, neurochemical changes, cytochrome c oxidase enzyme inhibition, and neurodegeneration in a dose- and time-dependent manner (P < 0.01). Overall, these findings show that Cob increases survival and is neuroprotective in a mouse model of H2 S-induced neurological sequelae. PMID- 29239483 TI - The effects of olfactory stimulation on the behavior of captive ring-tailed lemurs (Lemur catta). AB - Ring-tailed lemurs reside in many animal collections worldwide. Lemur welfare may be a cause of concern due to some captive individuals exhibiting stereotypic behavior. Despite these concerns, there has been little exploration of methods of environmental enrichment for ring-tailed lemurs. Olfactory stimulation can enhance captive animal welfare by encouraging species-typical behaviors, enhancing behavioral diversity, and decreasing stereotypic behaviors. We aimed to investigate the effects of olfactory stimulation via lavender, peppermint, coconut, and prey odor upon the behavior of eight captive ring-tailed lemurs. We exposed the lemurs to six individual odor conditions (odor control, novel object control, lavender, peppermint, coconut, and Morio worms) and observed them for 4 hr a day for 3 days with an intervening period of 4 days between conditions. We recorded the lemurs' behavior under each condition using instantaneous scan sampling. We found significant effects of olfactory stimulation on the ring tailed lemurs' behavior in the initial analysis but these did not survive correction for multiple testing. Overall, while our findings are suggestive of a general effect of olfactory stimulation on the captive ring-tailed lemurs they did not indicate a marked influence of olfactory condition. However, further investigation with a larger sample size and more biologically relevant odors may be beneficial to fully examine potential effects of olfactory stimulation in captive lemurs. PMID- 29239484 TI - Inactivation of Middle East respiratory syndrome-coronavirus in human plasma using amotosalen and ultraviolet A light. AB - BACKGROUND: Middle East respiratory syndrome-coronavirus (MERS-CoV) is a novel zoonotic pathogen. Although the potential for MERS-CoV transmission through blood transfusion is not clear, MERS-CoV was recognized as a pathogen of concern for the safety of the blood supply especially after its detection in whole blood, serum, and plasma of infected individuals. Here we investigated the efficacy of amotosalen and ultraviolet A light (UVA) to inactivate MERS-CoV in fresh-frozen plasma (FFP). STUDY DESIGN AND METHODS: Pooled FFP units were spiked with a recent clinical MERS-CoV isolate. Infectious and genomic viral titers were determined in plasma before and after inactivation with amotosalen/UVA treatment by plaque assay and reverse transcription-quantitative polymerase chain reaction, respectively. In addition, residual replicating or live virus after inactivation was examined by passaging in the permissive Vero E6 cells. RESULTS: The mean MERS CoV infectious titer in pretreatment samples was 4.67 +/- 0.25 log plaque-forming units (pfu)/mL, which was reduced to undetectable levels after inactivation with amotosalen/UVA demonstrating a mean log reduction of more than 4.67 +/- 0.25 pfu/mL. Furthermore, inoculation of inactivated plasma on Vero E6 cells did not result in any cytopathic effect (CPE) even after 7 days of incubation and three consecutive passages, nor the detection of MERS RNA compared to pretreatment samples which showed complete CPE within 2 to 3 days postinoculation and log viral RNA titer ranging from 9.48 to 10.22 copies/mL in all three passages. CONCLUSION: Our data show that amotosalen/UVA treatment is a potent and effective way to inactivate MERS-CoV infectious particles in FFP to undetectable levels and to minimize the risk of any possible transfusion-related MERS-CoV transmission. PMID- 29239485 TI - Comparison of umbilical cord occlusion methods: Radiofrequency ablation versus laser photocoagulation. AB - OBJECTIVE: To compare outcomes between 2 umbilical cord occlusion (UCO) methods: radiofrequency ablation (RFA) versus fetoscopic-guided laser photocoagulation. METHODS: Retrospective study of all monochorionic diamniotic multiple gestations that underwent UCO with RFA (preferred after 2014) or laser (preferred before 2014). In bivariate analysis, patients treated with RFA were compared with laser. Risk factors for intrauterine fetal demise (IUFD) and 30-day survival of the co twin were identified, and multiple logistic models were fitted to examine whether the UCO method was associated with these outcomes. RESULTS: Of 60 UCO cases, 18 (30%) underwent RFA and 42 (70%) underwent laser surgery. The RFA method was associated with co-twin IUFD after surgery (6/18 [33.3%] vs 1/42 [2.4%], P = 0.0021). In logistic regression models, patients who underwent RFA were more likely than patients who underwent laser to have an IUFD of the co-twin (OR 13.2, 1.23-142.62, P = 0.0331). These patients were also less likely to have 30-day survival of the co-twin, although this was not statistically significant (OR 0.20, 0.04-1.15, P = 0.0710). CONCLUSION: Despite clear technical advantages of RFA compared with laser, we found that RFA appeared to be associated with increased risk of post-procedure fetal demise. Further studies should be conducted to confirm these findings. PMID- 29239486 TI - Commentary on significant skin tightening by closure of fractional ablative laser holes. PMID- 29239487 TI - Evolution of skull shape in the family Salamandridae (Amphibia: Caudata). AB - We carried out a comparative morphometric analysis of 56 species of salamandrid salamanders, representing 19 out of 21 extant genera, with the aim of uncovering the major patterns of skull shape diversification, and revealing possible trends and directions of evolutionary change. To do this we used micro-computed tomography scanning and three-dimensional geometric morphometrics, along with a well-resolved molecular phylogeny. We found that allometry explains a relatively small amount of shape variation across taxa. Congeneric species of salamandrid salamanders are more similar to each other and cluster together producing distinct groups in morphospace. We detected a strong phylogenetic signal and little homoplasy. The most pronounced changes in the skull shape are related to the changes of the frontosquamosal arch, a unique feature of the cranial skeleton for the family Salamandridae, which is formed by processes arising from the frontal and squamosal bones that arch over the orbits. By mapping character states over the phylogeny, we found that a reduction of the frontosquamosal arch occurs independently in three lineages of the subfamily Pleurodelinae. This reduction can probably be attributed to changes in the development and ossification rates of the frontosquamosal arch. In general, our results are similar to those obtained for caecilian amphibians, with an early expansion into the available morphospace and a complex history characterizing evolution of skull shape in both groups. To evaluate the specificity of the inferred evolutionary trajectories and Caudata-wide trends in the diversity of skull morphology, information from additional groups of tailed amphibians is needed. PMID- 29239488 TI - Translational Pathology and the Understanding of Disease. PMID- 29239489 TI - How many melanomas might be prevented if more people applied sunscreen regularly? AB - BACKGROUND: Ultraviolet radiation causes cutaneous melanoma. Sunscreen prevents sunburn and protects skin cells against mutations. High-quality epidemiological studies suggest regular sunscreen use prevents melanoma. OBJECTIVES: To calculate the potential impact fraction (PIF) for melanoma in the U.S.A. and Australia assuming a range of different intervention scenarios intended to increase sunscreen use. METHODS: We calculated the PIF, the proportional difference between the observed number of melanomas arising under prevailing levels of sunscreen use compared with the number expected under counterfactual scenarios. We used published melanoma incidence projections for Australia and the white population in the U.S.A. from 2012 through to 2031 as the baseline condition, with estimates for protective effects of 'regular sunscreen use' from the literature. Sunscreen prevalence was sourced from national or state surveys. RESULTS: Under a plausible public health intervention scenario comprising incremental increases in sunscreen prevalence over a 10-year implementation programme, we estimated that cumulatively to 2031, 231 053 fewer melanomas would arise in the U.S. white population (PIF 11%) and 28 071 fewer melanomas would arise in Australia (PIF 10%). Under the theoretical maximum model of sunscreen use, almost 797 000 (PIF 38%) and approximately 96 000 (PIF 34%) melanomas would be prevented in the U.S.A. and Australia, respectively between 2012 and 2031. A sensitivity analysis using weaker effect estimates resulted in more conservative PIF estimates. CONCLUSIONS: Overall, interventions to increase use of sunscreen would result in moderate reductions in melanoma incidence, assuming no compensatory overexposure to the sun. Countries with a high incidence of melanoma should monitor levels of sunscreen use in the community. PMID- 29239490 TI - Proteomic changes of the porcine skeletal muscle in response to chronic heat stress. AB - BACKGROUND: Heat stress (HS) has an adverse effect on meat quality; however, the underlying molecular mechanisms altering meat quality due to muscle responses to stress remain unclear. Sixteen castrated male crossbreeds between Landrace * Yorkshire sows and Duroc boars (79.00 +/- 1.50 kg body weight) were exposed to either thermal neutral (22 degrees C, n = 8) or HS (30 degrees C, n = 8) conditions for 3 weeks. Subsequently, the longissimus dorsi (LD) muscle of all pigs was assayed for meat quality parameters and proteome analysis. RESULTS: HS decreased post mortem (24 h) pH and intramuscular fat, changed ultimate L*, a* and b* values and increased drip loss and shear force. Proteome analysis of the LD was conducted by two-dimensional gel electrophoresis and mass spectrometry. A total of 23 differentially expressed proteins were identified, of which three were verified by western blotting analysis. The identified proteins were involved in six types of biological process: carbohydrate metabolism, myofibrillar and cytoskeleton structure, stress response, antioxidant and detoxification, calcium binding and cellular apoptosis. Interestingly, HS induced higher levels of heat shock protein, antioxidants and calcium binding proteins, which are involved in the mechanisms of defense and homeostasis. CONCLUSION: The results indicate that HS-induced changes in the expression of myofibrillar proteins, glucose and energy metabolism-related proteins, heat shock protein and antioxidant enzymes might, at least partly, contribute to increase in meat tenderness. These findings will provide the foundation for developing future mitigating solutions and preventative therapies to reduce the detrimental effects of chronic HS on muscle function, metabolism and meat quality. (c) 2017 Society of Chemical Industry. PMID- 29239491 TI - Regulation of microvascular function by voltage-gated potassium channels: New tricks for an "ancient" dog. AB - Arterial tone is tightly regulated by a variety of potassium (K+ ) permeable ion channels at the sarcolemma of vascular smooth muscle cells. In particular, several types of KV channels provide a significant hyperpolarizing influence and serve to oppose pressure and agonist-induced membrane depolarization to promote smooth muscle relaxation and augmentation of vascular diameter and blood flow. In recent years, a number of studies have underscored previously unknown roles for particular KV subunits, new modes of channel regulation, and distinct cellular functions for these channels during physiological and pathological conditions. In this overview, we highlight articles contained in this Special Topics Issue that focus on the latest, most exciting advancements in the field of KV channels in the microcirculation. The collection of articles aims to highlight important new discoveries and controversies in the field of vascular KV channels as well as to shed light on key questions that require additional investigation. PMID- 29239492 TI - Stereoselective Palladium-Catalyzed Approach to Vitamin D3 Derivatives in Protic Medium. AB - We describe an efficient convergent synthesis of vitamin D3 metabolites and analogues. The synthetic strategy relies on a tandem Pd-catalyzed A-ring closure and Suzuki-Miyaura coupling to the CD-side chain component to set directly the vitamin D triene system under protic conditions. This strategy enables rapid access to vitamin D3 and 3-epi-vitamin D3 metabolites and analogues modified at the side chain for biological evaluation and structural and metabolic studies. PMID- 29239494 TI - Ru-Catalyzed Completely Deoxygenative Coupling of 2-Arylethanols through Base Induced Net Decarbonylation. AB - Substituted arylethanols can be coupled by using a readily available Ru catalyst in a fully deoxygenative manner to produce hydrocarbon chains in one step. Control experiments indicate that the first deoxygenation occurs through an aldol condensation, whereas the second occurs through a base-induced net decarbonylation. This double deoxygenation enables further development in the use of alcohols as versatile and green alkylating reagents, as well as in other fields, such as deoxygenation and upgrading of overfunctionalized biomass to produce hydrocarbons. PMID- 29239493 TI - Mortality in patients with community-onset pneumonia at low risk of drug resistant pathogens: Impact of beta-lactam plus macrolide combination therapy. AB - BACKGROUND AND OBJECTIVE: Drug-resistant pathogen (DRP) risk stratification is important for choosing a treatment strategy for community-onset pneumonia. Evidence for benefits of non-antipseudomonal beta-lactam plus macrolide combination therapy (BLM) on mortality is limited in patients at low DRP risk. Risk factors for mortality remain to be clarified. METHODS: Post hoc analysis using a prospective multicentre study cohort of community-onset pneumonia was performed to assess 30-day differences in mortality between non-antipseudomonal beta-lactam monotherapy (BL) and BLM groups. Logistic regression analysis was performed to assess the therapeutic effect and risk factors for mortality in patients at low DRP risk. RESULTS: In total, 594 patients with community-onset pneumonia at low DRP risk (369 BL and 225 BLM) were analysed. The 30-day mortality in BL and BLM was 13.8% and 1.8%, respectively (P < 0.001). Multivariate analysis showed that BLM reduced the 30-day mortality (adjusted odds ratio: 0.28, 95% CI: 0.09-0.87) compared with BL. Independent prognostic factors for 30-day mortality included arterial partial pressure of carbon dioxide (PaCO2 ) > 50 mm Hg, white blood cell count < 4000/mm3 , non-ambulatory status, albumin < 3.0 g/dL, haematocrit < 30%, age >= 80 years, respiratory rate > 25/min and body temperature < 36 degrees C. CONCLUSION: In patients with community-onset pneumonia at low DRP risk, BLM treatment reduced 30-day mortality compared with BL. Independent risk factors for mortality are potential confounding factors when assessing antibiotic effects in randomized clinical trials. PMID- 29239495 TI - Comparisons between traditional medicines and pharmacotherapies for Alzheimer disease: A systematic review and meta-analysis of cognitive outcomes. AB - OBJECTIVES: To evaluate the clinical evidence for traditional medicines (TMs) used in East Asia on measures of cognition in Alzheimer disease, determine the effect sizes at different time points for the TMs and pharmacotherapies, and assess the tolerability of the TMs. METHODS: We searched 12 databases in English, Chinese, and Japanese for eligible randomised controlled trials that compared orally administered TMs with pharmacotherapy and reported cognitive outcomes. Meta-analyses were conducted for Alzheimer's Disease Assessment Scale-cognitive subscale and/or Mini-Mental State Examination (MMSE). Mean differences and 95% confidence intervals were calculated to evaluate treatment effects. RESULTS: Thirty randomised controlled trials met inclusion criteria. Twenty-nine compared TMs with donepezil. Single studies provided comparisons with galantamine, rivastigmine, or memantine. There were no significant differences between the TM and donepezil groups at 12 or 24 weeks for Alzheimer's Disease Assessment Scale cognitive subscale or MMSE. Improvements over baseline were significant for MMSE at 12 and 24 weeks within the TM and donepezil groups and remained significant at 1 year. Effect sizes were reduced in the 3 double-blind studies. At 24 weeks, donepezil 10 mg/d generally produced greater improvements in MMSE than 5 mg/d. Tolerability reporting was incomplete and inconsistent between studies. CONCLUSIONS: The results suggested that the clinical benefits of the TMs were not less than donepezil at comparable time points, with both groups showing improvements. However, lack of blinding in most studies and other design and measurement issues are likely to have resulted in overestimation of effect sizes in both groups. Further well-designed studies are needed. PMID- 29239496 TI - Two-phase designs for joint quantitative-trait-dependent and genotype-dependent sampling in post-GWAS regional sequencing. AB - We evaluate two-phase designs to follow-up findings from genome-wide association study (GWAS) when the cost of regional sequencing in the entire cohort is prohibitive. We develop novel expectation-maximization-based inference under a semiparametric maximum likelihood formulation tailored for post-GWAS inference. A GWAS-SNP (where SNP is single nucleotide polymorphism) serves as a surrogate covariate in inferring association between a sequence variant and a normally distributed quantitative trait (QT). We assess test validity and quantify efficiency and power of joint QT-SNP-dependent sampling and analysis under alternative sample allocations by simulations. Joint allocation balanced on SNP genotype and extreme-QT strata yields significant power improvements compared to marginal QT- or SNP-based allocations. We illustrate the proposed method and evaluate the sensitivity of sample allocation to sampling variation using data from a sequencing study of systolic blood pressure. PMID- 29239497 TI - Clinical outcomes of unrelated cord blood transplantation in children with malignant and non-malignant diseases: Multicenter experience in China. AB - This multicenter retrospective study included 184 children with malignant and non malignant diseases who underwent UCBT between January 1998 and August 2012. The malignant disease group included 101 children with ALL, AML, CML, JMML, and MDS, and the non-malignant disease group included 83 children with PID, beta thalassemia, IMD BMF, and HLH. The median duration to neutrophil and platelet engraftment was 16 and 35 days in the malignant disease group vs 15 and 38 days in the non-malignant disease group. The cumulative incidence of grade II-IV aGVHD and cGVHD was 25.6% and 13.5% in the malignant disease group vs 19.7% and 11.1% in the non-malignant disease group, respectively. The median duration and cumulative incidence of neutrophil and platelet engraftment, and the cumulative incidence of grade II-IV aGVHD and cGVHD were similar between the two groups. Of the 184 pediatric patients, 114 patients survived during a median follow-up period of 14 months (range 4-138). The 5-year OS and DFS were not statistically different between the two groups (56.3% and 46.1% in malignant disease group vs 68.5% and 52.8% in non-malignant disease group). The above results indicate that UCB is a viable source for HSCT for children with malignant or non-malignant diseases, especially in urgent cases. PMID- 29239498 TI - Amyloid-like aggregation of designer bolaamphiphilic peptides: Effect of hydrophobic section and hydrophilic heads. AB - Amyloid-like aggregation of natural proteins or polypeptides is an important process involved in many human diseases as well as some normal biological functions. Plenty of works have been done on this ubiquitous phenomenon, but the molecular mechanism of amyloid-like aggregation has not been fully understood yet. In this study, we showed that a series of designer bolaamphiphilic peptides could undergo amyloid-like aggregation even though they didn't possess typical beta-sheet secondary structure. Through systematic amino acid substitution, we found that for the self-assembling ability, the number and species of amino acid in hydrophobic section could be variable as long as enough hydrophobic interaction is provided, while different polar amino acids as the hydrophilic heads could change the self-assembling nanostructures with their aggregating behaviors affected by pH value change. Based on these results, novel self assembling models and aggregating mechanisms were proposed, which might provide new insight into the molecular basis of amyloid-like aggregation. PMID- 29239499 TI - Oligothienylenevinylene Polarons and Bipolarons Confined between Electron Accepting Perchlorotriphenylmethyl Radicals. AB - A detailed analysis is undertaken of positively charged species generated on a series of thienylenevinylene (nTV) wires terminally substituted with two perchlorotriphenylmethyl (. PTM) radical acceptor groups, . PTM-nTV-PTM. (n=2-7). Motivated by the counterintuitive key role played by holes in the nTV bridges on the operating mechanism of electron transfer in their radical anion mixed-valence derivatives, a wide combination of experimental and theoretical techniques is used, with the aim of gaining further insights into their structural location. Consequently, contributions of the . PTM units for the stabilization of the radical cations and hole localization, particularly in the case of the shortest molecular wire, are probed. In this sense, the formation of quinoidal ring segments, resulting from the coupling of the unpaired electron of the . PTM radical site with those generated along the nTV chains is found. Additionally, open-shell dications, described by the recovery of the central aromaticity and two terminal quinoidal segments, assisted by the . PTM units, are detected. PMID- 29239500 TI - Ethylene Epoxidation Catalyzed by Ag Nanoparticles on Ag-LSX Zeolites formed by Pressure- and Temperature-Induced Auto-Reduction. AB - Ag+ -Exchanged LSX (Ag-LSX: Ag96 Al96 Si96 O384 ?n H2 O), a large pore low silica analogue (Si/Al=1.0) of faujasite, was prepared and post-synthetically modified using pressure and temperature in the presence of various pore-penetrating fluids. Using high-resolution synchrotron X-ray powder and single crystal diffraction we derive structural models of the as-prepared and post-synthetically modified Ag-LSX materials. In the as-prepared Ag-LSX model, we located 96 silver cations and 245 H2 O molecules distributed over seven and five distinctive sites, respectively. At 1.4(1) GPa pressure and 150 degrees C in ethanol the number of silver cations within the pores of Ag-LSX is reduced by ca. 47.4 %, whereas the number of H2 O molecules is increased by ca. 40.8 %. The formation of zero-valent silver nanoparticles deposited on Ag-LSX crystallites depends on the fluid present during pressurization. Ag-nanoparticle-Ag-zeolite hybrid materials are recovered after pressure release and shown to have different chemical reactivity when used as catalysts for ethylene epoxidation. PMID- 29239501 TI - Revisiting the Ullman's Radical Chemistry for Phthalocyanine Derivatives. AB - Phthalocyanine derivatives do not cease to gain attention due to their numerous properties and applications (e.g., sensor, PDT). This makes them a unique scaffold for the design of new material. In this context, we were interested to develop the synthesis of an imino nitroxide-substituted phthalocyanine by Ullman's procedure; a challenge due to the intrinsic low solubility of most phthalocyanine derivative in much solvents. To overcome this solubility problem, we designed a phthalocyanine with bulky neopentyl substituents in peripheral positions as counterpart to the imino nitroxide moieties. The imino nitroxide substituted phthalocyanine was obtained by condensation of a monoformyl substituted phthalocyanine with 2,3-bis(hydroxylamino)-2,3-dimethylbutane in refluxing THF-MeOH (2:1) mixture in the presence of p-toluenesulfonic acid monohydrate, follow by oxidation with PbO2 . Characterization was performed by electrochemistry, UV/Vis and EPR spectroscopy in solution as well as SQUID in solid state. PMID- 29239502 TI - Insecticide susceptibility status of invasive Aedes albopictus across dengue endemic districts of Odisha, India. AB - BACKGROUND: Aedes albopictus is currently the most invasive mosquito species in the world. Keeping in view the wide emergence of insecticide resistance, it is imperative to focus on the current susceptibility status for various insecticides in Ae. albopictus. This study focused on understanding the insecticide resistance mechanism of Ae. albopictus collected from dengue-endemic districts of Odisha. RESULTS: Insecticide resistance was evaluated by using standardized bioassay kits (WHO) and biochemical analysis. Larval bioassays revealed the highest level of resistance from Jaipur (JP) population with a RR50 of 15.3 and LC50 of 1.177 ppm compared with an LC50 of 0.077 for the susceptible strain LabS. Results indicated the presence of dichlorodiphenyltrichloroethane resistance in the majority of adult populations. Elevated activity of nonspecific esterases and cytochrome P450s MFO indicated probable resistance to organophosphates and pyrethroids. Molecular screening for common insecticide target-site mutations confirmed the absence of the 'knockdown resistance' response for pyrethroid insecticide in Ae. albopictus population, suggesting its continual effectiveness as the major insecticide of significant importance in future vector-control programmes. CONCLUSION: This is the first report of a kdr mutation in Ae. albopictus in India and highlights the need for intensive research on other unexplored target-site mutations that might also contribute to pyrethroid resistance. Effective management and sustainable use of insecticides can be implemented by understanding resistance mechanisms and development of appropriate diagnostic tools. (c) 2017 Society of Chemical Industry. PMID- 29239503 TI - Re: Pre-eclampsia is primarily a placental disorder: The arteriolar injury in pre eclampsia. PMID- 29239504 TI - Re: Partner smoking influences whether mothers quit smoking during pregnancy: a prospective cohort study. PMID- 29239505 TI - Authors' reply re: Genetic variation in the progesterone receptor gene and susceptibility to recurrent pregnancy loss: a case-control study. PMID- 29239506 TI - Authors' reply re: Maternal prepregnancy obesity and the risk of shoulder dystocia: a meta-analysis. PMID- 29239507 TI - Synthesis of alpha-Chiral Ketones and Chiral Alkanes Using Radical Polar Crossover Reactions of Vinyl Boron Ate Complexes. AB - Vinyl boron ate complexes of enantioenriched secondary alkyl pinacolboronic esters undergo stereospecific radical-induced 1,2-migration in radical polar crossover reactions. In this three-component process various commercially available alkyl iodides act as radical precursors and light is used for chain initiation. Subsequent oxidation and protodeborylation leads to valuable alpha chiral ketones and chiral alkanes, respectively, with excellent enantiopurity. PMID- 29239508 TI - Author's reply re: Pre-eclampsia is primarily a placental disorder: AGAINST: Pre eclampsia: the heart matters. PMID- 29239509 TI - Understanding Bronsted-Acid Catalyzed Monomolecular Reactions of Alkanes in Zeolite Pores by Combining Insights from Experiment and Theory. AB - Acidic zeolites are effective catalysts for the cracking of large hydrocarbon molecules into lower molecular weight products required for transportation fuels. However, the ways in which the zeolite structure affects the catalytic activity at Bronsted protons are not fully understood. One way to characterize the influence of the zeolite structure on the catalysis is to study alkane cracking and dehydrogenation at very low conversion, conditions for which the kinetics are well defined. To understand the effects of zeolite structure on the measured rate coefficient (kapp ), it is necessary to identify the equilibrium constant for adsorption into the reactant state (Kads-H+ ) and the intrinsic rate coefficient of the reaction (kint ) at reaction temperatures, since kapp is proportional to the product of Kads-H+ and kint . We show that Kads-H+ cannot be calculated from experimental adsorption data collected near ambient temperature, but can, however, be estimated accurately from configurational-bias Monte Carlo (CBMC) simulations. Using monomolecular cracking and dehydrogenation of C3 -C6 alkanes as an example, we review recent efforts aimed at elucidating the influence of the acid site location and the zeolite framework structure on the observed values of kapp and its components, Kads-H+ and kint . PMID- 29239510 TI - High-Resolution Absorption and Electronic Circular Dichroism Spectra of (R)-(+)-1 Phenylethanol. Confident Interpretation Based on the Synergy between Experiments and Computations. AB - Using density functional theory and its time-dependent extension for excited states, the S0 ->S1 high-resolution vibronic absorption and electronic circular dichroism spectra of (R)-(+)-1-phenylethanol are computed and compared to experimental spectra measured in jet-cooled conditions in the region within 1000 cm-1 of the 0-0 transition. The agreement between theory and computation is satisfactory and allows a confident assignment of several experimental bands in terms of fundamentals of different modes. Cases are documented for which the analysis of optical anisotropy factors, owing to their signed nature, remarkably enhances the possibility of a robust assignment of the experimental absorption bands. Computational analysis shows that the experimental spectra are dominated by Herzberg-Teller contributions and that the electronic circular dichroism spectrum and the anisotropy factors are also strongly modulated by the effect of Duschinsky mixings. PMID- 29239511 TI - Influence of a Confined Methanol Solvent on the Reactivity of Active Sites in UiO 66. AB - UiO-66, composed of Zr-oxide bricks and terephthalate linkers, is currently one of the most studied metal-organic frameworks due to its exceptional stability. Defects can be introduced in the structure, creating undercoordinated Zr atoms which are Lewis acid sites. Here, additional Bronsted sites can be generated by coordinated protic species from the solvent. In this Article, a multilevel modeling approach was applied to unravel the effect of a confined methanol solvent on the active sites in UiO-66. First, active sites were explored with static periodic density functional theory calculations to investigate adsorption of water and methanol. Solvent was then introduced in the pores with grand canonical Monte Carlo simulations, followed by a series of molecular dynamics simulations at operating conditions. A hydrogen-bonded network of methanol molecules is formed, allowing the protons to shuttle between solvent methanol, adsorbed water, and the inorganic brick. Upon deprotonation of an active site, the methanol solvent aids the transfer of protons and stabilizes charged configurations via hydrogen bonding, which could be crucial in stabilizing reactive intermediates. The multilevel modeling approach adopted here sheds light on the important role of a confined solvent on the active sites in the UiO-66 material, introducing dynamic acidity in the system at finite temperatures by which protons may be easily shuttled from various positions at the active sites. PMID- 29239512 TI - Inheritance and fitness costs of Spodoptera frugiperda (Lepidoptera: Noctuidae) resistance to spinosad in Brazil. AB - BACKGROUND: Spodoptera frugiperda is a pest of economically important crops in South America. In Brazil, this species is considered the most destructive pest of maize. Use of spinosyn insecticides in insect resistance management (IRM) has been one strategy to control this pest. In this study, we selected a strain of S. frugiperda resistant to spinosad and evaluated the inheritance and fitness costs of the resistance. RESULTS: Estimated LC50 (concentration required to kill 50% of larvae) values were 0.011 and 9.80 ug cm-2 for the spinosad-susceptible (Sus) and -resistant (Spin-res) strains, respectively. This represents an 890-fold resistance ratio. LC50 values for reciprocal crosses were 0.18 and 0.14 ug cm-2 , indicating that resistance to spinosad is an autosomal incompletely recessive trait. Backcrosses of the F1 progeny from reciprocal crosses with the parental Spin-res strain showed a polygenic effect. The estimated minimum number of independent segregations was ~ 2.45, indicating that resistance to spinosad is associated with multiple genes. In greenhouse assays, third-instar larvae from the Spin-res strain showed >92% survival on spinosad-treated maize. By contrast Sus and reciprocal crosses exhibited 0% and <5% survival, respectively, indicating that resistance is recessive. Life history studies to investigate the fitness cost of resistance revealed a 41% reduction in the rate of survival to adulthood and a 49% lower reproductive rate in the Spin-res strain compared with the Sus strain. CONCLUSIONS: The autosomal, incompletely recessive and polygenic resistance to spinosad in S. frugiperda and the fitness costs associated with this resistance can be exploited in IRM strategies to preserve the lifetime of spinosad for control of S. frugiperda in Brazil. (c) 2017 Society of Chemical Industry. PMID- 29239513 TI - With or without pheromone habituation: possible differences between insect orders? AB - BACKGROUND: Habituation to sex pheromones is one of the key mechanisms in mating disruption, an insect control tactic. Male moths often show reduced sexual response after pre-exposure to female sex pheromone. Mating disruption is relatively rare in insect orders other than Lepidoptera. RESULTS: As a positive control we confirmed habituation in a moth (Epiphyas postvittana) using 24 h pre exposure to sex pheromone to reduce subsequent activation behaviour. We then tested the impact of pre-exposure to sex or trail pheromone on subsequent behavioural response with insects from three other orders. Similar pre-exposure for 24 h to either sex pheromone [Pseudococcus calceolariae (Homoptera) and apple leaf curling midge Dasineura mali (Diptera), or trail pheromone of Argentine ants (Linepithema humile (Hymenoptera)], followed by behavioural assay in clean air provided no evidence of habituation after pre-exposure in these latter cases. CONCLUSIONS: The moths alone were affected by pre-exposure to pheromone. For pests without habituation, sustained attraction to a point source may make lure and kill more economical. Improved knowledge of behavioural processes should lead to better success in pest management and mechanisms should be investigated further to inform studies and practical efforts generally enhancing effectiveness of pheromone-based management. (c) 2017 Society of Chemical Industry. PMID- 29239514 TI - Analyses of Monascus pigment secretion and cellular morphology in non-ionic surfactant micelle aqueous solution. AB - Monascus pigments produced by Monascus spp. are widely used as natural food colourants. Extractive fermentation technology can facilitate the secretion of intracellular Monascus pigments into extracellular non-ionic surfactant micelle aqueous solution, so as to avoid the feedback inhibition and decomposition. In this study, behaviour of the trans-membrane secretion of Monascus pigments was investigated using morphological and spectroscopic analyses. Laser scanning confocal microscopy (LSCM) traced that pigment secretion occurred through rapid trans-membrane permeation in 4 min, with a simultaneous conversion in pigment characteristics. Approximately 50% of intracellular pigments (AU470 ) extracted to extracellular broth with 40 g l-1 Triton X-100, indicating the capacity for pigment extraction was limited by the saturation concentrations of surfactant. Scanning electron microscope (SEM) and transmission electron microscope (TEM) imaging showed some damage in the cell wall but an intact cell membrane with a slightly increased mycelial diameter. However, the physiological properties of the cell membrane, including integrity, fluorescence intensity and permeability, were altered. A diagram was provided to demonstrate the behaviour of Monascus pigment secretion induced by Triton X-100. This study lays a foundation for the further investigation of Monascus pigment metabolism and secretion in extractive fermentation. PMID- 29239515 TI - Rationale and design of TRANSITION: a randomized trial of pre-discharge vs. post discharge initiation of sacubitril/valsartan. AB - AIMS: The prognosis after hospitalization for acute decompensated heart failure (ADHF) remains poor, especially <30 days post-discharge. Evidence-based medications with prognostic impact administered at discharge improve survival and hospital readmission, but robust studies comparing pre-discharge with post discharge initiation are rare. The PARADIGM-HF trial established sacubitril/valsartan as a new evidence-based therapy in patients with heart failure (HF) and reduced left ventricular ejection fraction (<40%) (rEF). In common with other landmark studies, it enrolled patients who were ambulatory at the time of inclusion. In addition, there is also still limited knowledge of initiation and up-titration of sacubitril/valsartan in ACEi/ARB- naive patients and in de novo HF with rEF patients. METHODS AND RESULTS: TRANSITION is a multicentre, open-label study in which ~1000 adults hospitalized for ADHF with rEF are randomized to start sacubitril/valsartan in a pre-discharge arm (initiated >=24 h after haemodynamic stabilization) or a post-discharge arm (initiated within Days 1-14 after discharge). The protocol allows investigators to select the appropriate starting dose and dose adjustments according to clinical circumstances. Over a 10 week treatment period, the primary and secondary objectives assess the feasibility and safety of starting sacubitril/valsartan in-hospital, early after haemodynamic stabilization. Exploratory objectives also include assessment of HF signs and symptoms, readmissions, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T levels, and health resource utilization parameters. CONCLUSIONS: TRANSITION will provide new evidence about initiating sacubitril/valsartan following hospitalization for ADHF, occurring either as de novo ADHF or as deterioration of chronic HF, and in patients with or without prior ACEI/ARB therapy. The results of TRANSITION will thus be highly relevant to the management of patients hospitalized for ADHF with rEF. PMID- 29239516 TI - Engineering Contactless Particle-Particle Interactions in Active Microswimmers. AB - Artificial self-propelled colloidal particles have recently served as effective building blocks for investigating many dynamic behaviors exhibited by nonequilibrium systems. However, most studies have relied upon excluded volume interactions between the active particles. Experimental systems in which the mobile entities interact over long distances in a well-defined and controllable manner are valuable so that new modes of multiparticle dynamics can be studied systematically in the laboratory. Here, a system of self-propelled microscale Janus particles is engineered to have contactless particle-particle interactions that lead to long-range attraction, short-range repulsion, and mutual alignment between adjacent swimmers. The unique modes of motion that arise can be tuned by modulating the system's parameters. PMID- 29239517 TI - Nanoparticulate Delivery of Cancer Cell Membrane Elicits Multiantigenic Antitumor Immunity. AB - Anticancer vaccines train the body's own immune system to recognize and eliminate malignant cells based on differential antigen expression. While conceptually attractive, clinical efficacy is lacking given several key challenges stemming from the similarities between cancerous and healthy tissue. Ideally, an effective vaccine formulation would deliver multiple tumor antigens in a fashion that potently stimulates endogenous immune responses against those antigens. Here, it is reported on the fabrication of a biomimetic, nanoparticulate anticancer vaccine that is capable of delivering autologously derived tumor antigen material together with a highly immunostimulatory adjuvant. The two major components, tumor antigens and adjuvant, are presented concurrently in a fashion that maximizes their ability to promote effective antigen presentation and activation of downstream immune processes. Ultimately, it is demonstrated that the formulation can elicit potent antitumor immune responses in vivo. When combined with additional immunotherapies such as checkpoint blockades, the nanovaccine demonstrates substantial therapeutic effect. Overall, the work represents the rational application of nanotechnology for immunoengineering and can provide a blueprint for the future development of personalized, autologous anticancer vaccines with broad applicability. PMID- 29239518 TI - Oxygen Vacancies Dominated NiS2 /CoS2 Interface Porous Nanowires for Portable Zn Air Batteries Driven Water Splitting Devices. AB - The development of highly active and stable oxygen evolution reaction (OER) electrocatalysts is crucial for improving the efficiency of water splitting and metal-air battery devices. Herein, an efficient strategy is demonstrated for making the oxygen vacancies dominated cobalt-nickel sulfide interface porous nanowires (NiS2 /CoS2 -O NWs) for boosting OER catalysis through in situ electrochemical reaction of NiS2 /CoS2 interface NWs. Because of the abundant oxygen vacancies and interface porous nanowires structure, they can catalyze the OER efficiently with a low overpotential of 235 mV at j = 10 mA cm-2 and remarkable long-term stability in 1.0 m KOH. The home-made rechargeable portable Zn-air batteries by using NiS2 /CoS2 -O NWs as the air-cathode display a very high open-circuit voltage of 1.49 V, which can maintain for more than 30 h. Most importantly, a highly efficient self-driven water splitting device is designed with NiS2 /CoS2 -O NWs as both anode and cathode, powered by two-series-connected NiS2 /CoS2 -O NWs-based portable Zn-air batteries. The present work opens a new way for designing oxygen vacancies dominated interface nanowires as highly efficient multifunctional electrocatalysts for electrochemical reactions and renewable energy devices. PMID- 29239519 TI - Long-Range Tunneling Processes across Ferritin-Based Junctions. PMID- 29239520 TI - On the Existence of Excitonic Signatures in the Optical Response of Metal-Organic Frameworks: Comment on "van der Waals Metal-Organic Framework as an Excitonic Material for Advanced Photonics". AB - In a recent experimental paper, it was claimed that pronounced excitonic signatures are observed in optical response of Zn-based metal-organic frameworks (MOFs) at room temperature. Performing ab initio modelling, it is demonstrated that an alternative interpretation based on single-electron optical transitions between narrow pi-bands in the system of aromatic rings of the ligand is far more plausible. Although these results do not rule the possibility of exciton formation in MOFs out completely, they show that extreme caution should be taken in attributing the features in photoabsorption spectra alone to excitons, and additional proof, such as data on long-distance energy transfer, is necessary. PMID- 29239521 TI - Response to Comment "On the Existence of Excitonic Signatures in the Optical Response of Metal-Organic Frameworks". AB - This is a response to a comment on the interpretation of the origin of the nonlinear changes of optical properties of van der Waals' metal-organic frameworks (MOFs). The concerns are addressed by clarifying potential pitfalls in density functional theory (DFT) simulations, careful analysis of prior literature, and additionally discussing the previous experimental results to emphasize the applicability of the excitonic concept in molecular crystals, such as MOFs. PMID- 29239522 TI - Authors' reply to the comment by Patel J, Martin JH and Lucas CJ. PMID- 29239523 TI - Iridoids of Chemotaxonomy Relevance, a New Antirrhinoside Ester and Other Constituents from Kickxia spuria subsp. integrifolia (Brot.) R.Fern. AB - In this work, the secondary metabolite content of the EtOH extract of Kickxia spuria subsp. integrifolia (Brot.) R.Fern. is reported. Fourteen compounds were isolated and identified by means of column chromatography and NMR and MS instrumental techniques, respectively. Among the identified compounds, the chemotaxonomic markers of the species were evidenced, whereas others were reported for the first time in the genus. Among these, a new antirrhinoside derivative (12) was recognized. The iridoid content showed a molecular pattern very similar to those reported for other taxa comprised in the Antirrhinae tribe of Plantaginaceae, thus providing an additional evidence that supports the current botanical classification of the Kickxia genus. Anyway, most of the recognized components are able to exert important pharmacological properties which might suggest the possible employment of also this species in traditional medicine just like it happens for some other species of the Kickxia genus. PMID- 29239524 TI - Performance measures for a dialysis setting. AB - OBJECTIVES: This study from Japan extracted performance measures for dialysis unit management and investigated their characteristics from professional views. METHODS: Two surveys were conducted using self-administered questionnaires, in which dialysis managers/staff were asked to rate the usefulness of 44 performance indicators. A total of 255 managers and 2,097 staff responded. RESULTS: Eight performance measures were elicited from dialysis manager and staff responses: these were safety, operational efficiency, quality of working life, financial effectiveness, employee development, mortality, patient/employee satisfaction and patient-centred health care. These performance measures were almost compatible with those extracted in overall healthcare settings in a previous study. Internal reliability, content and construct validity of the performance measures for the dialysis setting were ensured to some extent. As a general trend, both dialysis managers and staff perceived performance measures as highly useful, especially for safety, mortality, operational efficiency and patient/employee satisfaction, but showed relatively low concerns for patient-centred health care and employee development. However, dialysis managers' usefulness perceptions were significantly higher than staff. CONCLUSIONS: Important guidelines for designing a holistic hospital/clinic management system were yielded. Performance measures must be balanced for outcomes and performance shaping factors (PSF); a common set of performance measures could be applied to all the healthcare settings, although performance indicators of each measure should be composed based on the application field and setting; in addition, sound causal relationships between PSF and outcome measures/indicators should be explored for further improvement. PMID- 29239525 TI - Isolation of sinapic acid from broccoli using molecularly imprinted polymers. AB - A molecularly imprinted polymer was synthesized for the purpose of sinapic acid isolation from Egyptian nutraceutical Botrytis italica, L. (broccoli) due to its prominent medicinal and wide pharmacological activities. A computational study was first developed to determine the optimal template to functional monomer molar ratio. Based on the computational results, five polymers were synthesized using a bulk polymerization method with sinapic acid as the template molecule. Evaluation of the synthesized polymers binding performance was carried out using batch rebinding assay, which revealed that the molecularly imprinted polymer of molar ratio (1:4:20), template to functional monomer (4-vinyl pyridine) to crosslinker (ethylene glycol dimethacrylate) was of optimum performance, thus, this polymer was applied for sinapic acid isolation from closely related analogues. This represents a more practical approach to isolate sinapic acid from different natural extracts selectively. PMID- 29239526 TI - Polysaccharide-based chiral stationary phases as halogen bond acceptors: A novel strategy for detection of stereoselective sigma-hole bonds in solution. AB - In the last few years, halogen bonds have been exploited in a variety of research areas both in the solid state and in solution. Nevertheless, several factors make formation and detection of halogen bonds in solution challenging. Moreover, to date, few chiral molecules containing electrophilic halogens as recognition sites have been reported. Recently, we described the first series of halogen-bond driven enantioseparations performed on cellulose tris(3,5 dimethylphenylcarbamate) by high-performance liquid chromatography. Herein the performances of amylose tris(3,5-dimethylphenylcarbamate) as halogen bond acceptor were also investigated and compared with respect to cellulose tris(3,5 dimethylphenylcarbamate). With the aim to explore the effect of polysaccharide backbone on the enantioseparations, the thermodynamic parameters governing the halogen-dependent enantioseparations on both cellulose and amylose polymers were determined by a study at variable temperature and compared. Molecular dynamics were performed to model the halogen bond in polysaccharide-analyte complexes. Chiral halogenated 4,4'-bipyridines were used as test compounds (halogen bond donors). On this basis, a practical method for detection of stereoselective halogen bonds in solution was developed, which is based on the unprecedented use of high-performance liquid chromatography as technical tool with polysaccharide polymers as molecular probes (halogen bond acceptors). The analytical strategy showed higher sensitivity for the detection of weak halogen bonds. PMID- 29239527 TI - Removal of epileptically compromised tissue in the frontal cortex restores oculomotor selection in the antisaccade task. AB - The frontal cortex is heavily involved in oculomotor selection. Here, we investigated the neural correlates of eye movement selection during an antisaccade task in a young epileptic patient in whom the seizure focus included the frontal cortex and affected its function. Before resection surgery, the patient had difficulty in performing correct antisaccades towards the visual field contralateral to the seizure focus. Because the FEF is the only area in the human frontal cortex that is known to have a lateralized oculomotor function in the antisaccade task, this behavioural imbalance between the two visual fields suggests a disruption of FEF functioning by the nearby seizure focus. Electrocorticographic recordings at the seizure focus indeed showed that the seizure focus interfered with correct antisaccade performance. These results were in line with fMRI recordings revealing less task-related frontal activity for the hemisphere of the seizure focus, possibly reflecting diminished top-down engagement of the oculomotor system. Two months after removal of the compromised tissue, the seizures had disappeared, and antisaccade performance was the same for both visual hemifields. We conclude that a seizure focus in the frontal cortex can induce a dysfunction in the selection of eye movements, which is resolved after removal of interfering tissue. PMID- 29239528 TI - Quantifying the effect of air gap, depth, and range shifter thickness on TPS dosimetric accuracy in superficial PBS proton therapy. AB - This study quantifies the dosimetric accuracy of a commercial treatment planning system as functions of treatment depth, air gap, and range shifter thickness for superficial pencil beam scanning proton therapy treatments. The RayStation 6 pencil beam and Monte Carlo dose engines were each used to calculate the dose distributions for a single treatment plan with varying range shifter air gaps. Central axis dose values extracted from each of the calculated plans were compared to dose values measured with a calibrated PTW Markus chamber at various depths in RW3 solid water. Dose was measured at 12 depths, ranging from the surface to 5 cm, for each of the 18 different air gaps, which ranged from 0.5 to 28 cm. TPS dosimetric accuracy, defined as the ratio of calculated dose relative to the measured dose, was plotted as functions of depth and air gap for the pencil beam and Monte Carlo dose algorithms. The accuracy of the TPS pencil beam dose algorithm was found to be clinically unacceptable at depths shallower than 3 cm with air gaps wider than 10 cm, and increased range shifter thickness only added to the dosimetric inaccuracy of the pencil beam algorithm. Each configuration calculated with Monte Carlo was determined to be clinically acceptable. Further comparisons of the Monte Carlo dose algorithm to the measured spread-out Bragg Peaks of multiple fields used during machine commissioning verified the dosimetric accuracy of Monte Carlo in a variety of beam energies and field sizes. Discrepancies between measured and TPS calculated dose values can mainly be attributed to the ability (or lack thereof) of the TPS pencil beam dose algorithm to properly model secondary proton scatter generated in the range shifter. PMID- 29239529 TI - Authors' reply re: Ultrasound bladder wall thickness and detrusor overactivity: a multicentre test accuracy study. PMID- 29239530 TI - Author's reply re: Pre-eclampsia is primarily a placental disorder: FOR: Pre eclampsia is primarily a placental disorder. PMID- 29239531 TI - DNA Synthesis by Primer Exchange Reaction Cascades. AB - Swap and extend: The autonomous synthesis of single-stranded DNA molecules of arbitrary size and sequence composition can easily be achieved by primer exchange reaction (PER) cascades, in which the sequential polymerase-mediated extension of DNA primers is guided by catalytic hairpins. This highlight illustrates the potential of this method for applications in DNA nanotechnology. PMID- 29239532 TI - A 3D Real-Scale, Biomimetic, and Biohybrid Model of the Blood-Brain Barrier Fabricated through Two-Photon Lithography. AB - The investigation of the crossing of exogenous substances through the blood-brain barrier (BBB) is object of intensive research in biomedicine, and one of the main obstacles for reliable in vitro evaluations is represented by the difficulties at the base of developing realistic models of the barrier, which could resemble as most accurately as possible the in vivo environment. Here, for the first time, a 1:1 scale, biomimetic, and biohybrid BBB model is proposed. Microtubes inspired to the brain capillaries were fabricated through two-photon lithography and used as scaffolds for the co-culturing of endothelial-like bEnd.3 and U87 glioblastoma cells. The constructs show the maturation of tight junctions, good performances in terms of hindering dextran diffusion through the barrier, and a satisfactory trans-endothelial electrical resistance. Moreover, a mathematical model is developed, which assists in both the design of the 3D microfluidic chip and its characterization. Overall, these results show the effective formation of a bioinspired cellular barrier based on microtubes reproducing brain microcapillaries to scale. This system will be exploited as a realistic in vitro model for the investigation of BBB crossing of nanomaterials and drugs, envisaging therapeutic and diagnostic applications for several brain pathologies, including brain cancer. PMID- 29239534 TI - ? PMID- 29239533 TI - Corrigendum: Discovery of a Potent BTK Inhibitor with a Novel Binding Mode by Using Parallel Selections with a DNAEncoded Chemical Library. PMID- 29239535 TI - [Evidence based treatment of hallux valgus]. AB - Hallux valgus is a frequent disorder of the foot and decision-making about the best treatment provokes many questions among patients and specialists. These include the need for surgery, which surgical technique is the best choice, and is minimally invasive surgery going to replace open techniques? While the modern media provides patients with easy access to details concerning surgical techniques, they rarely include means for the patient to distinguish between objective information and publicity. The general practitioner is a person of trust for the patient and should help him or her consider treatment proposals. With these factors in mind, the aim of this paper is to share the evidence-based information regarding the treatment of hallux valgus with the general practitioner. PMID- 29239536 TI - [Patellar instability : diagnosis and treatment]. AB - The aim of this paper is to present recent advances in surgical management of patellar instability. Several anatomical factors were reported to promote instability. We propose to classify them in two groups. Extra articular factors are valgus and torsion deformity. Articular factors include trochlea and patella dysplasia, tibial tubercle lateralization and medial patellofemoral ligament (MPFL) insufficiency. Acute patellar dislocations are treated conservatively, with exception for osteochondral and MPFL avulsion fractures that require acute reinsertion. Surgery is considered for recurrent instability. As we aim for a correction of all contributing elements, we prefer a two stages approach. Extra articular factors are treated first by osteotomy, followed by articular factors after 4-6 months. This allows separate rehabilitation protocols. PMID- 29239537 TI - [Does total knee arthroplasty meet patient's expectations ?] AB - Total knee arthroplasty has grown considerably over the past decade, due to the aging of the population, the increase in the prevalence of obesity, and an increasing demand. The 10-year revision rate is less than 5%. Functional outcomes, assessed by range of motion measures and functional scores, were significantly improved with the advent of more reliable and less invasive surgical techniques, better management of postoperative pain, and early high intensity rehabilitation protocols. However, 20% of patients say they are dissatisfied with their knee replacement, either because of the persistence of pain, or because their function does not match their preoperative expectations. Improved preoperative communication between patient and surgeon is essential to match patients' expectations to realistic treatment outcomes. PMID- 29239538 TI - [Do degenerative meniscal tears need surgery ?] AB - Degenerative meniscal tears (DMT) are common, often asymptomatic, and are associated with early-stage knee osteoarthritis in patients over 35 years of age. Conservative treatment, including exercise, physiotherapy and pain medication, should be offered as a first management approach for patients with symptomatic DMT. The indication for partial arthroscopic meniscectomy should be considered carefully, and based on specific criteria. Recently, several randomized controlled studies comparing partial medial meniscectomy to conservative treatment or to a sham procedure have questioned the effectiveness of surgical treatment of these lesions.The purpose of this article is to provide an update on the diagnosis and treatment of DMT. PMID- 29239539 TI - [Fractures of the distal humerus in the elderly : osteosynthesis or elbow arthoplasty ?] AB - With an aging population, distal humerus fractures are becoming an emerging problem. Whereas open reduction and internal fixation has been the treatment of choice, results have not been as conclusive in elderly patients. Over two thirds of the cases in this population present with a highly comminuted articular fracture and poor bone stock, jeopardizing the quality and stability of the construct. Total elbow arthroplasty has gained popularity in the treatment of such fractures, and has shown higher results in terms of pain, function, and patient satisfaction. Nevertheless, it also has a high complication rate, such as infection, ulnar neuropathy and loosening, that should be discussed with patients before surgery. The aim of this article was thus to review the different treatment options and propose a treatment algorithm. PMID- 29239540 TI - [Clavicle fracture : what's new in 2017?] AB - Clavicle fracture is a common injury for the general practitioner, the accident and emergency department doctor and the orthopedic trauma surgeon. Historically, most clavicle fractures were treated conservatively. During the last two decades, clinical studies have shown higher rates of nonunion or symptomatic malunion than previously thought. These publications lead to an increase in surgical management of clavicle fractures. However, recent randomized controlled trials failed to confirm any strong clinical outcome improvement after surgical treatment. Based on recent literature, we present up-to-date recommendations and a treatment algorithm for clavicle fractures management. PMID- 29239541 TI - ? PMID- 29239542 TI - ? PMID- 29239543 TI - ? PMID- 29239544 TI - ? PMID- 29239545 TI - ? PMID- 29239546 TI - ? PMID- 29239547 TI - ? PMID- 29239548 TI - A concise, straightforward presentation can be worth more than a thousand words. AB - Not available. PMID- 29239549 TI - Impact of walkability with regard to physical activity in the prevention of diabetes. AB - Walkability, a component of urban design intended to facilitate pedestrian traffic, depends on parameters associated with the connectivity of routes, population density and availability of destinations in the neighbourhood. The aim is to achieve levels of physical activity related to the prevention of risk factors associated with diseases, such as diabetes and the improvement of glycaemia control. It is important to consider that the effects of walkability depend on its relation with other variables present in the neighbourhood, e.g., environmental and socioeconomic factors. Considering this, improving walkability levels could be an effective strategy to reduce disease, the prevalence of diabetes in particular, in the population and thus reduce public spending. To investigate these relationships, PUBMED and ScienceDirect databases were searched using the following key words: Diabetes, Walkability and Physical activity. PMID- 29239550 TI - Physical inactivity displays a mediator role in the association of diabetes and poverty: A spatiotemporal analysis. AB - Physical inactivity is one of the risk factors of diabetes. In addition, physical inactivity is attributed to urbanization-related factors, such as poverty, which is also one of the risk factors of diabetes. We hypothesized that physical inactivity is a mediator in the association between diabetes and poverty, and that spatial heterogeneity exists in these relationships. This study adopted a spatiotemporal modelling approach to conduct this mediator analysis. From 2004 2011, data were collected at the county level in 48 contiguous states (with a total of 3,109 counties) from the Behavioral Risk Factor Surveillance System (BRFSS) and American Community Survey. Poverty percentage significantly affected physical inactivity prevalence and diabetes prevalence in two separate models. Using a model with both physical inactivity and poverty percentages as independent variables, we verified that physical inactivity prevalence is a significant mediator. In this model, physical inactivity prevalence resulted in a significant positive association with diabetes prevalence, and the influence of poverty percentage on diabetes prevalence was significantly reduced (P=0.0009). An advanced spatiotemporal analysis revealed that 32.65% of counties having a significant positive association between diabetes prevalence and physical inactivity prevalence also had a significant positive association between physical inactivity prevalence and poverty percentage. Those counties were also likely located in the South and Southeast of USA. In summary, the findings of this study demonstrate the mediating effect of physical inactivity between diabetes and poverty. When implementing diabetes prevention in communities with higher poverty, appropriate strategies to reduce the cost burden of physical activity programmes should be considered. PMID- 29239551 TI - Spread of Ebola virus disease based on the density of roads in West Africa. AB - On March 23rd 2014 the World Health Organization announced that a new Ebola outbreak had appeared in West Africa involving three countries. The objective of this study was to show how a road density index (RDI) could be constructed and a study of its association with Ebola cases during the outbreak. The study was carried out at the district level across the affected countries. RDI was calculated by km2 of territory as a proxy for the mobility of the population. To calculate this index, the number of km of road constructed in each district was estimated and subsequently divided by the area of each district expressed in km2. The accumulated incidence of Ebola was calculated per district. A generalised linear model with a Poisson distribution was used. The RDI varied from 0.12 to 0.84 between the districts. An RDI increase of 0.01 indicates a 3% increase in Ebola infection risk (RR is 1.03; CI 1.03-1.04). The density of the road network can influence the increased incidence of Ebola cases in the affected zone. An exhaustive mapping of the area could help the relevant organisations to manage another outbreak in the future and it could help the distribution of resources in an emergency situation. PMID- 29239552 TI - The use of geographic information system as a tool for schistosomiasis surveillance in the province of Davao del Norte, the Philippines. AB - Schistosomiasis (SCH) in The Philippines is caused by Schistosoma japonicum and remains endemic in 28 provinces in 12 regions. Effective SCH control requires describing areas at risk where control efforts may be focused. This study aims at demonstrating the utility of geographical information system (GIS) as a tool for SCH surveillance in the province of Davao del Norte. Qualitative and quantitative data on SCH determinants, obtained from local government offices, partner agencies and institutions, were standardised, formatted and incorporated into a GIS map. Atrisk areas are described in terms of determinants and (variables), which included geography and climate (topography, temperature and flood-prone areas), agriculture (irrigation and land use), poverty (percentage of households with income below the poverty threshold), sanitation level (percentage of households with sanitary toilets), intermediate and reservoir hosts (presence of snail colonies and reservoir hosts) as well as prevalence and treatment coverage. Endemic villages (barangays) were generally found to be located in flood-prone areas in the lowlands near major rivers. New Corella has the highest poverty index among the SCH-endemic areas studied as well as the highest number of confirmed snail colonies. Among known endemic localities in Davao del Norte, Tagum City was found to be the only city meeting the poverty index target of <16.6%. Clustering of SCH cases were reported in six barangays ranging from 0.48% (8 out of 1,655) in Braulio Dujali to 2% (25 out of 1,405) in Asuncion. This study demonstrates the utility of GIS in predicting and assessing SCH risk, which allows prioritisation and allocation of control resources and delivery of services in areas at the highest risk for SCH. PMID- 29239553 TI - Detecting space-time disease clusters with arbitrary shapes and sizes using a co clustering approach. AB - Ability to detect potential space-time clusters in spatio-temporal data on disease occurrences is necessary for conducting surveillance and implementing disease prevention policies. Most existing techniques use geometrically shaped (circular, elliptical or square) scanning windows to discover disease clusters. In certain situations, where the disease occurrences tend to cluster in very irregularly shaped areas, these algorithms are not feasible in practise for the detection of space-time clusters. To address this problem, a new algorithm is proposed, which uses a co-clustering strategy to detect prospective and retrospective space-time disease clusters with no restriction on shape and size. The proposed method detects space-time disease clusters by tracking the changes in space-time occurrence structure instead of an in-depth search over space. This method was utilised to detect potential clusters in the annual and monthly malaria data in Khyber Pakhtunkhwa Province, Pakistan from 2012 to 2016 visualising the results on a heat map. The results of the annual data analysis showed that the most likely hotspot emerged in three sub-regions in the years 2013-2014. The most likely hotspots in monthly data appeared in the month of July to October in each year and showed a strong periodic trend. PMID- 29239554 TI - CutL: an alternative to Kulldorff's scan statistics for cluster detection with a specified cut-off level. AB - When searching for epidemiological clusters, an important tool can be to carry out one's own research with the incidence rate from the literature as the reference level. Values exceeding this level may indicate the presence of a cluster in that location. This paper presents a method of searching for clusters that have significantly higher incidence rates than those specified by the investigator. The proposed method uses the classic binomial exact test for one proportion and an algorithm that joins areas with potential clusters while reducing the number of multiple comparisons needed. The sensitivity and specificity are preserved by this new method, while avoiding the Monte Carlo approach and still delivering results comparable to the commonly used Kulldorff's scan statistics and other similar methods of localising clusters. A strong contributing factor afforded by the statistical software that makes this possible is that it allows analysis and presentation of the results cartographically. PMID- 29239555 TI - Analytical report of the 2016 dengue outbreak in Cordoba city, Argentina. AB - After elimination of the Aedes aegypti vector in South America in the 1960s, dengue outbreaks started to reoccur during the 1990s; strongly in Argentina since 1998. In 2016, Cordoba City had the largest dengue outbreak in its history. In this article we report this outbreak including spatio-temporal analysis of cases and vectors in the city. A total of 653 dengue cases were recorded by the laboratory-based dengue surveillance system and georeferenced by their residential addresses. Case maps were generated from the epidemiological week 1 (beginning of January) to week 19 (mid-May). Dengue outbreak temporal evolution was analysed globally and three specific, high-incidence zones were detected using Knox analysis to characterising its spatio-temporal attributes. Field and remotely sensed data were collected and analysed in real time and a vector presence map based on the MaxEnt approach was generated to define hotspots, towards which the pesticide- based strategy was then targeted. The recorded pattern of cases evolution within the community suggests that dengue control measures should be improved. PMID- 29239556 TI - Revealed access to haemodialysis facilities in northeastern Iran: Factors that matter in rural and urban areas. AB - Poor access to haemodialysis facilities is associated with high mortality and morbidity rates. This study investigated factors affecting revealed access to the haemodialysis facilities considering patients living in rural and urban areas without any haemodialysis facility (Group A) and those living urban areas with haemodialysis facilities (Group B). This study is based on selfreported Actual Access Time (AAT) to referred haemodialysis facilities and other information regarding travel to haemodialysis facilities from patients. All significant variables on univariate analysis were entered into a univariate general linear model in order to identify factors associated with AAT. Both spatial (driving time and distance) and non-spatial factors (sex, income level, caregivers, transportation mode, education level, ethnicity and personal vehicle ownership) influenced the revealed access identified in Group A. The non-spatial factors for Group B patients were the same as for Group A, but no spatial factor was identified in Group B. It was found that accessibility is strongly underestimated when driving time is chosen as accessibility measure to haemodialysis facilities. Analysis of revealed access determinants provides policymakers with an appropriate decision base for making appropriate decisions and finding solutions to decrease the access time for patients under haemodialysis therapy. Driving time alone is not a good proxy for measuring access to haemodialysis facilities as there are many other potential obstacles, such as women's special travel problems, poor other transportation possibilities, ethnicity disparities, low education levels, low caregiver status and low-income. PMID- 29239557 TI - Variability of nutrients intake, lipid profile and cardiovascular mortality among geographical areas in Spain: The DRECE study. AB - It has often been suggested that cardiovascular mortality and their geographical heterogeneity are associated with nutrients intake patterns and also lipid profile. The large Spanish study Dieta y Riesgo de Enfermedades Cardiovasculares en Espana (DRECE) investigated this theory from 1991 to 2010. Out of the 4,783 Spanish individuals making up the DRECE cohort, 220 subjects (148 men and 72 women) died (4.62%) during the course of the study. The mean age of patients who died from cardiovascular causes (32 in all) was 61.08 years 95% CI (57.47-64.69) and 70.91% of them were males. The consumption of nutrients and the lipid profile by geographical area, studied by geospatial models, showed that the east and southern area of the country had the highest fat intake coupled to a high rate of unhealthy lipid profile. It was concluded that the spatial geographical analysis showed a relationship between high fat intake, unhealthy lipid profile and cardiovascular mortality in the different geographical areas, with a high variability within the country. PMID- 29239558 TI - The influence of socioeconomic deprivation, access to healthcare and physical environment on old-age survival in Portugal. AB - Spatial inequalities in old-age survival exist in Portugal and might be associated with factors pertaining to three distinct domains: socioeconomic, physical environmental and healthcare. We evaluated the contribution of these factors on the old-age survival across Portuguese municipalities deriving a surrogate measure of life expectancy, a 10-year survival rate that expresses the proportion of the population aged 75-84 years old who reached 85-94. As covariates we used two internationally comparable multivariate indexes: the European deprivation index and the multiple physical environmental deprivation index. A national index was developed to evaluate the access to healthcare. Smoothed rates and odds ratios (OR) were estimated using Bayesian spatial models. Socioeconomic deprivation was found to be the most relevant factor influencing old-age survival in Portugal [women: least deprived areas OR=1.132(1.064-1.207); men OR=1.044(1.001- 1.094)] and explained a sizable amount of the spatial variance in survival, especially among women. Access to healthcare was associated with old-age survival in the univariable model only; results lost significance after adjustment for socioeconomic circumstances [women: higher access to healthcare OR=1.020(0.973- 1.072); men OR=1.021(0.989-1.060)]. Physical environmental deprivation was unrelated with old-age survival. In conclusion, socioeconomic deprivation was the most important determinant in explaining spatial disparities in old-age survival in Portugal, which indicates that policy makers should direct their efforts to tackle socioeconomic differentials between regions. PMID- 29239559 TI - Spatio-temporal outbreaks of campylobacteriosis and the role of fresh-milk vending machines in the Czech Republic: A methodological study. AB - Inspired by local outbreaks of campylobacteriosis in the Czech Republic in 2010 linked to the debate about alleged health risks of the raw milk consumption, a detailed study was carried out. Firstly, scanning was utilised to identify spatio temporal clusters of the disease from 2008 to 2012. Then a spatial method (geographical profiling originally developed for criminology) served as assessment in selecting fresh-milk vending machines that could have contributed to some of the local campylobacteriosis outbreaks. Even though an area of increased relative risk of the disease was identified in the affected city of Ceske Budejovice during January and February 2010, geoprofiling did not identify any vending machines in the area as the potential source. However, possible sources in some nearby cities were suggested. Overall, 14 high-rate clusters including the localisation of 9% of the vending machines installed in the Czech Republic were found in the period 2008-2012. Although the vending machines are subject to strict hygiene standards and regular testing, a potential link between a small number of them and the spatial distribution of campylobacteriosis has been detected in the Czech Republic. This should be taken into account in public health research of the disease. PMID- 29239560 TI - A 24-year exploratory spatial data analysis of Lyme disease incidence rate in Connecticut, USA. AB - Despite efforts to control Lyme disease in Connecticut, USA, it remains endemic in many towns, posing a heavy burden. We examined changes in the spatial distribution of significant spatial clusters of Lyme disease incidence rates at the town level from 1991 to 2014 as an approach for targeted interventions. Lyme disease data were grouped into four discrete time periods and incidence rates were smoothed with Empirical Bayes estimation in GeoDa. Local clustering was measured using a local indicator of spatial autocorrelation (LISA). Elliptic spatial scan statistics (SSS) in different shapes and directions were also performed in SaTScan. The accuracy of these two cluster detection methods was assessed and compared for sensitivity, specificity, and overall accuracy. There was significant clustering during each period and significant clusters persisted predominantly in western and eastern parts of the state. Generally, the SSS method was more sensitive, while LISA was more specific with higher overall accuracy in identifying clusters. Even though the location of clusters changed over time, some towns were persistently (across all four periods) identified as clusters in LISA and their neighbouring towns (three of four periods) in SSS suggesting these regions should be prioritized for targeted interventions. PMID- 29239561 TI - Spatial analysis of cutaneous leishmaniasis in an endemic area of Iran based on environmental factors. AB - Leishmaniasis is a parasitic disease caused by different species of protozoan parasites. Cutaneous leishmaniasis (CL) is still a great public health problem in Iran, especially in Isfahan Province. Distribution and abundance of vectors and reservoirs of this disease is affected by different factors such as climatic, socioeconomic and cultural. This study aimed to identify the hotspot areas for CL in Isfahan and assess the relations between the climatic and topographic factors with CL incidence using spatial analysis. We collected data on the total number of CL cases, population at risk, vegetation coverage, altitude and climatic data for each district of the province from 2011 to 2015. Global Moran's Index was used to map clustering of CL cases across districts and the Getis-Ord (Gi*) statistics was used to determine hotspots areas of the disease in Isfahan. We applied overlay analysis to assess the correlation between the climatic and topographic factors with CL incidence. We found the CL distribution significantly clustered (Moran's Index=0.17, P<0.001) with the Ardestan and Aran va Bidgol (P<0.01) districts along with the Naein and Natanz districts (P<0.05) to be strong hotspot areas. Overlay analysis revealed a high incidence of CL in areas with relative humidity of 27-30%, mean temperature of 15-19 degrees C, mean precipitation of 5-20 mm, maximum wind speed about 12-16 m/s and an altitude of 600-1,800 m. Our study showed that spatial analysis is a feasible approach for identifying spatial disease pattern and detecting hotspots of this infectious disease. PMID- 29239562 TI - Balancing geo-privacy and spatial patterns in epidemiological studies. AB - To balance the protection of geo-privacy and the accuracy of spatial patterns, we developed a geo-spatial tool (GeoMasker) intended to mask the residential locations of patients or cases in a geographic information system (GIS). To elucidate the effects of geo-masking parameters, we applied 2010 dengue epidemic data from Taiwan testing the tool's performance in an empirical situation. The similarity of pre- and post-spatial patterns was measured by D statistics under a 95% confidence interval. In the empirical study, different magnitudes of anonymisation (estimated Kanonymity >=10 and 100) were achieved and different degrees of agreement on the pre- and post-patterns were evaluated. The application is beneficial for public health workers and researchers when processing data with individuals' spatial information. PMID- 29239563 TI - A geographical information system for the management of the aquaculture data in the Adriatic Sea - the Strengthening of Centres for Aquaculture Production and Safety surveillance in the Adriatic countries experience: Present capabilities, tools and functions. AB - The European Commission (EC) regulation no. 854/2004 requires a systematic monitoring of chemical and microbiological contaminants in live bivalve molluscs, live echinoderms, live tunicates and live marine gastropods for human consumption through surveillance plans to be implemented in all European Union (EU) countries.A consortium of five Adriatic countries was set up in the framework of the Instrument of Pre-accession Assistance Adriatic Cross-border Cooperation Programme (IPA Adriatic CBC) 2007- 2013 with the aim of collecting data and distribute information on harvesting and production in mollusc areas. A web-based geographical information system (GIS) application was developed to support the partners to manage data and to make these data available to final users, policy makers and to risk assessors. The GIS for the Strengthening of Centres for Aquaculture Production and Safety surveillance in the Adriatic countries (CAPS2) is divided into two levels, the national and the supranational one, and it distributes spatial and epidemiological information coming from various data acquisition and management sites. The great innovation is the possibility for each country to use online drawing, modifying and change of the geographic areas according to national surveillance needs. Currently it hosts data coming from about 230 production and relay areas with more than 29,478 laboratory tests performed on collected samples since August 2014. Data collected are used by each national competent authority to classify production or relay areas according to the EC regulation mentioned and to conduct risk assessment studies to evaluate the level of consumers' exposure to contaminants in the consumption of bivalve mollusc products. PMID- 29239564 TI - Evaluating the utility of companion animal tick surveillance practices for monitoring spread and occurrence of human Lyme disease in West Virginia, 2014 2016. AB - Domestic dogs and cats are potentially effective sentinel populations for monitoring occurrence and spread of Lyme disease. Few studies have evaluated the public health utility of sentinel programmes using geo-analytic approaches. Confirmed Lyme disease cases diagnosed by physicians and ticks submitted by veterinarians to the West Virginia State Health Department were obtained for 2014 2016. Ticks were identified to species, and only Ixodes scapularis were incorporated in the analysis. Separate ordinary least squares (OLS) and spatial lag regression models were conducted to estimate the association between average numbers of Ix. scapularis collected on pets and human Lyme disease incidence. Regression residuals were visualised using Local Moran's I as a diagnostic tool to identify spatial dependence. Statistically significant associations were identified between average numbers of Ix. scapularis collected from dogs and human Lyme disease in the OLS (beta=20.7, P<0.001) and spatial lag (beta=12.0, P=0.002) regression. No significant associations were identified for cats in either regression model. Statistically significant (P<=0.05) spatial dependence was identified in all regression models. Local Moran's I maps produced for spatial lag regression residuals indicated a decrease in model over- and under estimation, but identified a higher number of statistically significant outliers than OLS regression. Results support previous conclusions that dogs are effective sentinel populations for monitoring risk of human exposure to Lyme disease. Findings reinforce the utility of spatial analysis of surveillance data, and highlight West Virginia's unique position within the eastern United States in regards to Lyme disease occurrence. PMID- 29239565 TI - Spatio-temporal analysis and visualisation of the anthrax epidemic situation in livestock in Kazakhstan over the period 1933-2016. AB - An analysis of the anthrax epidemic situation among livestock animals in the Republic of Kazakhstan over the period 1933-2016 is presented. During this time, 4,064 anthrax outbreaks (mainly in cattle, small ruminants, pigs and horses) were recorded. They fall into five historical periods of increase and decrease in the annual anthrax incidence (1933-1953; 1954-1968; 1969-1983; 1984- 2001; and 2002 2016), which has been associated with changes in economic activity and veterinary surveillance. To evaluate the temporal trends of incidence variation for each of these time periods, the following methods were applied: i) spatio-temporal analysis using a space-time cube to assess the presence of hotspots (i.e., areas of outbreak clustering) and the trends of their emergence over time; and ii) a linear regression model that was used to evaluate the annual numbers of outbreaks as a function of time. The results show increasing trends during the first two periods followed by a decreasing trend up to now. The peak years of anthrax outbreaks occurred in 1965-1968 but outbreaks still continue with an average annual number of outbreaks of 1.2 (95% confidence interval: 0.6-1.8). The space time analysis approach enabled visualisation of areas with statistically significant increasing or decreasing trends of outbreak clustering providing a practical opportunity to inform decision-makers and allowing the veterinary services to concentrate their efforts on monitoring the possible risk factors in the identified locations. PMID- 29239566 TI - Mapping displaced populations with reference to social vulnerabilities for post disaster public health management. AB - Millions of people are currently displaced from their homes because of local and international conflicts. In the last two decades, a substantial increase in the number of displaced people has been recorded. We measured the social vulnerabilities of displaced populations using a mathematical approach in combination with application of geographical information systems (GIS) tools and techniques to visualise movement and draw attention to the location of significant concentration of vulnerabilities. A retrospective study approach based on datasets collected from governmental and non-governmental organisations working with refugees and internally displaced persons in Pakistan was used. We applied simple mathematical formulas to calculate and map various types of vulnerability, such as refugee population, absorption capacity, unmet needs and overall vulnerability. This approach displays risks and vulnerabilities of displaced populations in an easily understood and straightforward manner that can be replicated in other parts of the world. PMID- 29239567 TI - Regional variation of alanine aminotransferase serum levels in the People's Republic of China. AB - The regional variation of the blood concentration of alanine aminotransferase (ALT), a sensitive predictor of liver damage, was studied in the People's Republic of China with reference to its potential association with environmental variables and geographic location. The research results presented are based on 121,977 blood samples from healthy adults in 93 cities in the country using correlation analysis, ridge regression estimation and trend surface analysis that were applied to explore if there was any tendency of spatial variation. A regression formula using a simulation equation under the condition of known local geographic factors was used. Statistical significance was set at P<0.05. A positive correlation between ALT concentration altitude and sunshine hours and a negative correlation between ALT concentration and temperature, humidity and precipitation were found. With respect to geographical location, there was a negative correlation between ALT concentration and longitude. Higher ALT values were found in western China compared to eastern regions, dividing the country into three different regions with respect to serum ALT levels. PMID- 29239568 TI - Spatiotemporal transmission and socio-climatic factors related to paediatric tuberculosis in north-western Ethiopia. AB - The burden of tuberculosis (TB) in children reflects continuing and recent transmission within a population. This study aimed to identify spatiotemporal and socio-climatic factors associated with paediatric TB in north-western Ethiopia. Multivariate Poisson regression models were computed using a Bayesian framework. Estimates of parameters were generated using Markov chain Monte Carlo simulation. A total of 2,240 children aged under 15 years diagnosed with TB during the years 2013- 2016 were included in the analysis. The annual TB incidence rates were 44 and 28 per 100,000 children, for children aged under 15 and 5 years, respectively. Spatial clustering of TB was observed in the border area of north western Ethiopia. The spatio-temporal transmission of childhood TB was found to be associated with district level socio-climatic factors such as urbanisation [relative risk (RR): 1.8; 95% credible interval (CrI): 1.2, 2.6], lower educational status (RR: 1.5; 95% CrI: 1.0, 2.1), a high percentage of internal migration (RR: 1.3; 95% CrI: 1.0, 1.6), high temperature (RR: 1.3; 95% CrI: 1.0, 1.7) and high rainfall (RR: 1.5; 95% CrI: 1.1, 2.0). We conclude that interventions targeting hotspot districts with a high proportion of childhood TB are important to reduce TB transmission in northwest Ethiopia. PMID- 29239569 TI - Climate impact on malaria in northern Burkina Faso. AB - The Paluclim project managed by the French Centre National d'Etudes Spatiales (CNES) found that total rainfall for a 3-month period is a confounding factor for the density of malaria vectors in the region of Nouna in the Sahel administrative territory of northern Burkina Faso. Following the models introduced in 1999 by Craig et al. and in 2003 by Tanser et al., a climate impact model for malaria risk (using different climate indices) was created. Several predictions of this risk at different temporal scales (i.e. seasonal, inter-annual and low-frequency) were assessed using this climate model. The main result of this investigation was the discovery of a significant link between malaria risk and low-frequency rainfall variability related to the Atlantic Multi-decadal Oscillation (AMO). This result is critical for the health information systems in this region. Knowledge of the AMO phases would help local authorities to organise preparedness and prevention of malaria, which is of particular importance in the climate change context. PMID- 29239570 TI - Spatial analysis of the prevalence of schistosomiasis in an endemic coastal area in north-eastern Brazil. AB - Due to contact and misuse of water drainage channels, schistosomiasis has spread and become a constant concern in northeastern Brazil. The aim of this study was to monitor human cases of Schistosomiasis mansoni and the breeding areas of the snail intermediate host Biomphalaria glabrata through spatial analysis in a community named Invasao do Canal do Guaxinim, located in Barra dos Coqueiros City in an endemic coastal part of the state of Sergipe, Brazil. This research was performed as a cross-sectional epidemiological study conducted with parasitological and malacological surveys. To verify the spatial analysis, a two year spatial point pattern analysis was performed by means of Kernel intensity estimation using TerraView software 4.2.2. A schistosomiasis prevalence reduction from 8.1% (2013) to 4.9% (2014) was observed but mild infection prevailed in adolescents and/or young adults during the two-year study. In malacological research, 387 specimens of snails of the genus B. glabrata were collected and all were negative with regard to schistosomiasis. Spatial analysis showed a strong, spatial trend of increased transmission risk areas north and south of the community, both in 2013 and 2014. In Invasao do Canal do Guaxinim itself, the increased risk was only seen in the northern part. When combined, the human and the malacological spatial analyses constituted an important methodological approach for monitoring and controlling this parasitic disease. PMID- 29239571 TI - Spatial-temporal analysis of prostate cancer incidence from the Pennsylvania Cancer Registry, 2000-2011. AB - Prostate cancer is the most common cancer diagnosed among males, and the incidence in Pennsylvania, USA is considerably higher than nationally. Knowledge of regional differences and time trends in prostate cancer incidence may contribute to a better understanding of aetiologic factors and racial disparities in outcomes, and to improvements in preventive intervention and screening efforts. We used Pennsylvania Cancer Registry data on reported prostate cancer diagnoses between 2000 and 2011 to study the regional distribution and temporal trends of prostate cancer incidence in both Pennsylvania White males and Philadelphia metropolitan area Black males. For White males, we generated and mapped county-specific age-adjusted incidence and standardised incidence ratios by period cohort, and identified spatial autocorrelation and local clusters. In addition, we fitted Bayesian hierarchical generalised linear Poisson models to describe the temporal and aging effects separately in Whites state-wide and metropolitan Philadelphia blacks. Incidences of prostate cancer among white males declined from 2000-2002 to 2009-2011 with an increasing trend to some extent in the period 2006-2008 and significant variation across geographic regions, but less variation exists for metropolitan Philadelphia including majority of Black patients. No significant aging effect was detected for White and Black men, and the peak age group for prostate cancer risk varied by race. Future research should seek to identify potential social and environmental risk factors associated with geographical/racial disparities in prostate cancer. As such, there is a need for more effective surveillance so as to detect, reduce and control the cancer burden associated with prostate cancer. PMID- 29239572 TI - Shrinking risk profiles after deworming of children in Port Elizabeth, South Africa, with special reference to Ascaris lumbricoides and Trichuris trichiura. AB - Risk maps facilitate discussion among different stakeholders and provide a tool for spatial targeting of health interventions. We present maps documenting shrinking risk profiles after deworming with respect to soil-transmitted helminthiasis among schoolchildren from disadvantaged neighbourhoods in Port Elizabeth, South Africa. Children were examined for soil-transmitted helminth infections using duplicate Kato-Katz thick smears in March 2015, October 2015 and May 2016, and subsequently treated with albendazole after each survey. The mean infection intensities for Ascaris lumbricoides were 9,554 eggs per gram of stool (EPG) in March 2015, 4,317 EPG in October 2015 and 1,684 EPG in March 2016. The corresponding figures for Trichuris trichiura were 664 EPG, 331 EPG and 87 EPG. Repeated deworming shrank the risk of soil-transmitted helminthiasis, but should be complemented by other public health measures. PMID- 29239573 TI - Urbanisation and its effect on risk factors associated with childhood diarrhoea in Mbour, Senegal: A visualisation. AB - Rapid urbanisation, particularly in secondary cities in Africa, brings along specific challenges for global health, including the prevention and control of infectious diseases such as diarrhoea. Our purpose was to visualise urbanisation trends and its effect on risk factors associated with childhood diarrhoea, e.g. water supply, sanitation, wastewater and solid waste management in Mbour, a secondary city in south-western Senegal. Our visualisation is facilitated by epidemiological and geographical surveys carried out in 2016. A deeper spatial and visual understanding of the urbanisation trends and the disparities of diarrhoea-associated risk factors might lead to the implementation of suitable health interventions and preventive measures. Our visualisation is aimed to serve as a basis for discussion and as a decision support tool for policymakers, municipal officials and local communities to prioritise interventions related to water, sanitation and waste management with a view to reduce the environmental and health risks in the rapidly growing city of Mbour, which is set as an example for other similar secondary cities across low- and middle-income countries in Africa. PMID- 29239574 TI - DUI offenders may have multiple health and social problems - doctors play a central role in monitoring the use of medications affecting the central nervous system. AB - While the overall number of driving under the influence (DUI) cases has reduced, the proportion of drivers under the influence of medications or illicit drugs has increased. In studies based on Finnish register data sets, the factors involved in DUI have been examined with the conclusion that drunk driving may be an indication of multiple health or social problems. According to several measures, DUI offenders who had used medications, especially benzodiazepines, were ill and disadvantaged. Doctors play a central role in reducing the number of DUI cases, e.g. by treating substance abuse problems and by monitoring the use of drugs which affect the central nervous system. It is possible that a DUI offender has accumulated a number of different problems at the same time, which is why the treatment of DUI offenders should pay attention to a comprehensive mapping of the situation and the use of multidisciplinary cooperation. PMID- 29239575 TI - What's at Stake: States' Progress on Health Coverage and Access to Care, 2013 2016. AB - Issue: Given uncertainty about the future of the Affordable Care Act, it is useful to examine the progress in coverage and access made under the law. Goal: Compare state trends in access to affordable health care between 2013 and 2016. Methods: Analysis of recent data from the U.S. Census Bureau and the Behavioral Risk Factor Surveillance System. Findings and Conclusions: Between 2013 and 2016, the uninsured rate for adults ages 19 to 64 declined in all states and the District of Columbia, and fell by at least 5 percentage points in 47 states. Among children, uninsured rates declined by at least 2 percentage points in 33 states. There were reductions of at least 2 percentage points in the share of adults age 18 and older who reported skipping care because of costs in the past year in 36 states and D.C., with greater declines, on average, in Medicaid expansion states. The share of at-risk adults without a recent routine checkup, and of nonelderly individuals who spent a high portion of income on medical care, declined in at least of half of states and D.C. These findings offer evidence that the ACA has improved access to health care for millions of Americans. However, actions at the federal level - including a shortened open enrollment period for marketplace coverage, a failure to extend CHIP funding, and a potential repeal of the individual mandate's penalties - could jeopardize the gains made to date. PMID- 29239576 TI - Living donor kidney transplantation. AB - While the majority of kidney transplantations in Finland have been traditionally performed from deceased donors, the frequency of living donors should be increased. Kidney donation is a safe procedure for a carefully examined donor, and for the recipient living donation enables elective surgery and preemptive transplantation. Potential risks for the donor must be minimized, but according to current recommendations, mild hypertension or obesity are not absolute contraindications for donation. Guidelines for donor selection and examination have been updated to simplify the process for all parties. Legislation in Finland requires changes to optimize the use of all potential living donors. PMID- 29239577 TI - Mechanical compression devices for cardiac arrest: report of three cases. AB - Mechanical compression devices enable transportation of patients with cardiac arrest to the catheterization laboratory. Coronary angiography and coronary interventions can be performed while the patients are being resuscitated with these devices. In this report, we describe three cases in whom resuscitation with mechanical compression devices and rapid transportation to the catheterization laboratory resulted in favorable cardiac and neurological outcome. PMID- 29239578 TI - National vaccination program - a success story of public health and economy. AB - The savings in treatment costs generated by disease cases prevented by the national vaccination program exceed the costs of the vaccination program by at least 60 million euros. In addition, other costs due to contracting the illness are avoided. Vaccinations serve the purpose of both increasing well-being and releasing resources for other uses. Financial support of vaccinations through the health insurance system would be costly and targetted to those with the ability to pay. Public funds should be directed to the development of a vaccination program. New vaccines coming on the market are expensive. Adding a new vaccine to the vaccination program is based on scientific evidence-based expert assessments and cost-effectiveness. In addition to preliminary assessments carried out in support of decision-making, the National Institute of Health and Welfare monitors by using population-based health registers the effectiveness and cost effectiveness of the vaccination program. From the standpoint of transparency of decision-making it would be preferred that the decision-makers define a willingness to pay threshold below which an intervention would be accepted and lead to funding. PMID- 29239580 TI - Promotion of mental health in the core of public health work. AB - Positive trends achieved in health in Finland are not equally reflected mental health, hence mental health promotion deserves a central position. Mental health promotion refers to strengthening of psychological resources, and has been linked to increased well-being and life satisfaction. Health care has an important role in supporting a solid foundation of mental health and in preventing intergenerational transmission of problems. Mental health promotion requires strong involvement of non-health sectors. There are means for strengthening mental health skills also on the individual level. The gap between existing evidence on effectiveness and cost-effectiveness of mental health promotion and the lack of large scale implementation needs to addressed by future health and social policies. PMID- 29239581 TI - Association Between Nutritional Status and Quality of Life in (Pre) Frail Community-Dwelling Older Persons. AB - BACKGROUND: For developed countries, healthy aging is one of the challenges and the number of healthy life years and especially the quality of life (QoL) are important. OBJECTIVE: This study aimed to assess the association between nutritional status and different domains of QoL in (pre)frail community-dwelling elders. DESIGN: Baseline data from persons, who participated in a 12-week nutritional and physical training intervention program, conducted from September 2013 - July 2015. Setting: (Pre)frail community-dwelling elders living in Vienna, Austria. PARTICIPANTS: A total of 83 older persons living at home, 12 men and 71 women (86%) aged 65 to 98 years. Measurements: Structured interviews were conducted at participants' homes. Mini Nutritional Assessment(r) long-form (MNA(r)-LF) was used to investigate the nutritional status. The QoL domains were assessed with the World Health Organization Quality of Life questionnaires. Simple and multiple linear regression analyses were performed to evaluate the association between nutritional status and QoL domains, adjusted for possible confounders. RESULTS: 45% of the participants were at risk of malnutrition and 3% were malnourished. Compared to normal nourished people, persons who had an impaired nutritional status, significantly differed in the QoL domain 'autonomy' with mean (SD) scores of 50.0 (14.9) vs. 57.3 (13.7); p=0.022 and in the QoL domain 'social participation' with scores of 40.1 (13.6) vs. 47.0 (11.2); p=0.014, respectively. According to linear regression analyses, the MNA(r)-LF score was significantly associated with 'overall QoL' (beta=0.26; p=0.016) and the QoL domains 'physical health' (beta=0.23; p=0.036), 'autonomy' (beta=0.27; p=0.015), and 'social participation' (beta=0.28; p=0.013).CONCLUSIONS: There was a significant association between nutritional status and QoL in elderly (pre)frail community-dwelling people, in particular for the QoL domains 'autonomy' and 'social participation'. However, it remains unclear whether malnutrition was the cause or the consequence, or it was mediated through a third possible factor e.g. the functional status. PMID- 29239582 TI - Health promotion among the population of foreign origin in Finland involves special issues. AB - The population of foreign origin in Finland is a heterogenic group, diverse for example with respect to reasons for and age at migration. While migration to Finland is a recent phenomenon, the size of the population of foreign origin has grown rapidly and will continue to increase. Changes in the population structure need to be taken into account in health promotion. For example lifestyle, health status, functional capacity, mental health, infectious diseases and reproductive health differ in foreign origin population compared with the general Finnish population. These differences may provide opportunities but also create challenges for service provision and health promotion planning. PMID- 29239583 TI - Social media in the promotion of health. AB - Social media has brought about a major change in communication. Besides ordinary people, the change applies to organizations and public authorities. In the social media, the public becomes an active player and content provider. With social media, communication will become increasingly media-centered. The change in communication scenery has challenged traditional expertise. On the other hand, social media also opens up many possibilities for the establishment of expertise and health communication. Within the social media, communities can become significant sites for the production of knowledge and expertise. They may generate useful activity as regards the combination of health information activities and everyday life, but sometimes they can also become a cradle of false information. In its various forms, social media provides a versatile forum for health communication, where people can be met interactively. PMID- 29239584 TI - Children's rights and the possibilities of health promotion in early childhood. AB - National and international research evidence of the importance of early childhood and early childhood education to human well-being, resilience and attachment to the society justifies the investment in childhood and children. From the society, this requires national intent, management by knowledge, and strengthening of fundamental rights of children. PMID- 29239585 TI - How to help patients adopt and maintain a healthy lifestyle? A review of behavioral evidence of determinants and means. AB - A significant part of the population do not follow dietary and exercise recommendations. In Current Care Guidelines, lifestyle counseling is considered as part of good medical care. Lifestyle diseases are, however, not decreasing. Does counseling fail to reach its goal, or is it being provided at all? In the narrative review article based on systematic surveys, we approach the change in lifestyle through both conscious and automatic psychosocial processes. Research evidence indicates that a change in behavior can be supported through both processes. While intervention studies have been so far conducted mainly by influencing conscious processes, evidence of benefits of using automated processes is growing stronger. We present practical measures to support the desire for change and skills and establishments of habits. The same methods may in part be utilized to change professionals in their own behavior so that provision of quick and simple lifestyle counseling becomes a matter actualized in everyday life. PMID- 29239586 TI - Factors Associated With Nutritional Risk Among Homebound Older Adults With Depressive Symptoms. AB - OBJECTIVES: This study used the Evans model of public health determinants to identify factors associated with nutritional risk in older adults. DESIGN: The Evans model domains (physical and mental well-being, social/environmental statuses, individual choice, and economic security) were measured in a sample of homebound older adults. Regularized logistic regression analysis with LASSO penalty function was used to determine the strongest domain of the Evans model. Using traditional logistic regression, individual variables across all domains were compared to identify the significant predictors. SETTING: Older adults receiving home meal services were referred to the study by community program staff. PARTICIPANTS: Participants included 164 homebound older adults (age > 60) who endorsed at least one gateway symptom of depression. MEASUREMENTS: Measurements: Nutritional risk was determined using the Mini Nutritional Assessment. Domains of the Evans model were measured using the MAI Medical Condition Checklist, items from the IADL scale, the Structured Clinical Interview for DSM-IV Axis I Disorders, the Duke Social Support Index, living arrangements, marital status, the Alcohol Use Disorders Identification Test, items from the SCID Screening Module, and a self-report of perceived financial security. RESULTS: Poor mental well-being, defined by a diagnosis of major depressive disorder, was identified as the strongest Evans model domain in the prediction of nutritional risk. When each variable was independently evaluated across domains, instrumental support (Wald's Z=-2.24, p=0.03) and a history of drug use (Wald's Z=-2.40, p=0.02) were significant predictors. CONCLUSIONS: The Evans model is a useful conceptual framework for understanding nutritional health, with the mental domain found to be the strongest domain predictor of nutritional risk. Among individual variables across domains, having someone to help with shopping and food preparation and a history of drug use were associated with lower nutritional risk. These analyses highlight potential targets of intervention for nutritional risk among older adults. PMID- 29239587 TI - Redefining "Medical Care." AB - President Donald J. Trump has said he will repeal the Affordable Care Act (ACA) and replace it with health savings accounts (HSAs). Conservatives have long preferred individual accounts to meet social welfare needs instead of more traditional entitlement programs. The types of "medical care" that can be reimbursed through an HSA are listed in section 213(d) of the Internal Revenue Code (Code) and include expenses "for the diagnosis, cure, mitigation, treatment, or prevention of disease, or for the purpose of affecting any structure or function of the body." In spite of the broad language, regulations and court interpretations have narrowed this definition substantially. It does not include the many social factors that determine health outcomes. Though the United States spends over seventeen percent of gross domestic product (GDP) on "healthcare", the country's focus on the traditional medicalized model of health results in overall population health that is far beneath the results of other countries that spend significantly less. Precision medicine is one exceptional way in which American healthcare has focused more on individuals instead of providing broad, one-size-fits-all medical care. The precision medicine movement calls for using the genetic code of individuals to both predict future illness and to target treatments for current illnesses. Yet the definition of "medical care" under the Code remains the same for all. My proposal for precision healthcare accounts involves two steps-- the first of which requires permitting physicians to write prescriptions for a broader range of goods and services. The social determinants of health are as important to health outcomes as are surgical procedures and drugs--or perhaps more so according to many population health studies. The second step requires agencies and courts to interpret what constitutes "medical care" under the Code differently depending on the taxpayer's income level. Childhood sports programs and payments for fruits and vegetables may be covered for those in the lower income brackets who could not otherwise afford these items and would not choose to spend scarce resources on them if they could. This all assumes that the government takes funds previously used to subsidize the purchase of health insurance under the ACA (or allocates new funds) and puts the funds in individual accounts so the poor or near poor have money to pay for these expenses. Section I of this Article will explore the current definition of medical care, which excludes the social determinants of health from "healthcare" spending. I then address how precision medicine has changed the types of services and treatments that it makes sense to reimburse for each individual. If efficacy can vary from person to person based on genetic code, then it also can vary depending on environment. There is an opportunity to not only vary the types of "medical care" that can be reimbursed or deducted within the traditional range of services and drugs, but also outside of that range. Section II addresses the historical shift towards health financing through individual accounts, and specifically through HSAs. If this is the only avenue for health reform in the next few years, I advocate using it to engage in the type of experiments that are typically only possible under the cover of tax expenditures. My proposal for precision healthcare accounts moves the government to experiment with individual social spending that can lead to improved overall health outcomes. Finally, in Section III, I address two dichotomies that affect any healthcare proposal: (1) entitlement programs v. grants-in-aid, and (2) pooled insurance v. consumer-driven health plans (CDHPs). In the end, I argue that an entitlement method of funding precision HSAs along with pooled insurance subsidized by the government is the most realistic resolution to these dichotomies. Only a broad-based entitlement to funding for all healthcare expenses (medical and social) allows for significant improvements in overall population health. PMID- 29239588 TI - Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. PMID- 29239589 TI - Genetic Associations with Spontaneous Preterm Birth. PMID- 29239590 TI - Measuring Activity Performance of Continuing Care Residents Using the activPAL: An Exploratory Study. AB - Few studies have measured the activity patterns of continuing care residents using objective, uniaxial, accelerometers such as the activPAL. This exploratory study described the activity performance of continuing care residents and explored the correlation of activity performance with grip strength, falls and mobility. Data were gathered from 24 continuing care residents. Participants (82.3 +/- 5.8 years of age), wore the activPAL an average of 12.60 hours per day (SD = 0.96) and were stepping for a median of 0.47 hours (25th and 75th percentiles = 0.31, 0.81) with a median step count of 1906 steps (25th and 75th percentiles = 1216, 3420). Participants were inactive (sitting/lying/standing) for a mean 11.99 hours (SD = 1.03). No statistically significant correlations were identified between activity performance (active time, inactive time or step count) and grip strength, falls or mobility. Ambulatory older adults in continuing care centres were more sedentary compared to community-dwelling older adults or older adults with cancer. PMID- 29239591 TI - Macrophages and cancer. AB - Macrophages are an important type of white blood cells in the dialogue between inflammatory response and cancer. Macrophages can maintain a chronic inflammatory state that predisposes to the development of cancer. In the tumor, macrophages phagocytose and kill cancer cells directly and promote the generation of antitumoral cytotoxic lymphocyte response. Cancer cells, however, often modulate the functions of macrophages in several ways to promote tumor progression. Such protumoral macrophages increase neovascularization, produce molecules promoting the growth and dissemination of cancer cells, and suppress antitumoral immune responses. Hence, abundant macrophage infiltration correlates with poor prognosis in most types of cancer. Many cancer treatments also affect the antitumoral properties of macrophages. New drugs are developed to reduce the accumulation of macrophages into malignant tissue and to re-educate pro-tumoral macrophages to anti-tumoral macrophages and some of these drugs have already entered clinical trials. PMID- 29239592 TI - Third Dose of MMR Vaccine for Mumps Control. PMID- 29239593 TI - Clinical significance of gene defects in B-cell lymphomas. AB - Lymphomas are a heterogenous group of malignant diseases. Identification of sub groups has created pressure for a more detailed diagnosis and individualized treatment. Although the underlying genetic and molecular pathologic factors of the most common B-cell derived lymphomas, i.e. diffuse large B-cell lymphoma and follicular lymphoma, have become more accurate, prognosis is evaluated and treatment options still selected mainly on the basis of clinical variables. In the future, new generation sequencing methods that are becoming more common in clinical practice will allow the assessment of prognosis and treatment on the basis of biologic and genetic risk factors. To achieve this both comprehensive basic research and clinical drug trials taking the pathogenesis of different diseases into consideration are required. PMID- 29239594 TI - The Emergence of Frailty May Lead to a State of Burnt Out Type 2 Diabetes. AB - Ageing is associated with hyperglycaemic tendency due to the change in body composition leading to accumulation of visceral fat and increased insulin resistance on the one hand and reduced insulin secretion due to decreased number and function of the beta-cells of the pancreas on the other. However, with the emergence of frailty there may be a tendency towards normoglycaemia or even hypoglycaemia due to malnutrition, weight loss and reduced physiologic reserve. This shift in glucose metabolism induced by frailty may change the natural history of type 2 diabetes from a progressive to a regressive course. Studies which showed increased risk of mortality with low HbA1c included frail patients in the lower HbA1c categories and healthier patients in the higher HbA1c categories suggesting that frailty is a possible confounding factor. Therefore, hypoglycemia may be a prognostic tool to identify vulnerable patients who may be at increased risk of mortality. The metabolic changes of insulin/glucose dynamics associated with frailty need further research. PMID- 29239595 TI - Explaining the absence of surgical procedure regulation. AB - Each year in the United States, surgeons perform approximately 64 million surgical procedures, ranging from tooth extraction to open heart surgery. Yet, notwithstanding the frequency of surgical procedures and their often critical importance to patient health, no state or federal agency either approves the use of new surgical procedures or directly regulates existing procedures. The absence of surgical procedure regulation differs from the regulation of new pharmaceutical products, which can be introduced into interstate commerce only after the Food and Drug Administration (FDA) has reviewed "adequate and well controlled [clinical] investigations" and concluded the data from those studies sufficiently establish the drug's safety and efficacy. Surgical procedures, by contrast, are more often conveyed from professor to student, the result being that surgical approaches may vary considerably from one geographic region to another. Whether different techniques produce different outcomes is not always clear, in part because the absence of regulation means that evidence often has not been systematically generated or may be in a form not suitable for comparison. Commentators have noted the differing treatment that persists between surgery and pharmaceuticals and have offered a number of justifications. For example, they have suggested that the surgical profession should self-regulate, that excessive regulation could deter surgeries of unproven benefit even when the surgery may be in the best interest of the patient, and that surgical trials could disrupt the doctor-patient relationship, such as by emphasizing uncertainty in a context where patient trust is important. In the context of innovative (as opposed to established) surgical procedures, controlled trials might be disfavored due to concern that desperate patients might unwisely submit themselves to risky experimental treatments undertaken by overzealous researchers. When commentators advocate for increased surgical regulation, they generally limit their calls for reform to innovative surgical procedures. The absence of direct regulation, however, has implications for the quality of evidence available to support an optimal choice from among all of the alternatives in the surgeon's armamentarium, whether innovative or standard, and whether surgical or non-surgical. This Article first examines the current framework of indirect regulation surrounding surgical procedures and then offers potential explanations as to why surgical procedures themselves are not already subject to direct federal regulation. Finally, it considers possible contributions of increased surgical regulation, including the identification of evidence gaps, the generation or collection of evidence to fill those gaps, and the impact on surgeon decision-making and patient consent. PMID- 29239596 TI - Third Dose of MMR Vaccine for Mumps Control. PMID- 29239598 TI - Effective Formaldehyde Capture by Green Cyclodextrin-Based Metal-Organic Framework. AB - A kind of metal-organic framework made from gamma-cyclodextrin (gamma-CD) and potassium ions were explored as excellent formaldehyde (HCHO) absorbents. The adsorption capacity and speed of gamma-CD-MOF-K are both about 9 times higher than those of activated carbon, which are attributed to the porous structure and synergistic effect of hydrogen bonding and host-guest interactions. PMID- 29239599 TI - Tau Derived Hexapeptide AcPHF6 Promotes Beta-Amyloid (Abeta) Fibrillogenesis. AB - We studied the interactions of a tau derived hexapeptide AcPHF6 with beta-amyloid peptides Abeta40 and Abeta42 which reveals its unusual ability to promote Abeta fibrillogenesis. The results demonstrate that the N-acetylated and C-amidated AcPHF6 hexapeptide can cause significant acceleration in Abeta40 and Abeta42 fibril growth. Aggregation kinetic studies at pH 7.4 show that at 25 MUM, AcPHF6 hexapeptide was able to cause ~2.3-fold increase in Abeta40 fibrillogenesis dramatically changing the aggregation kinetics. In addition, AcPHF6 peptide was able to reduce cellular toxicity mediated by Abeta40 and Abeta42 in hippocampal neuronal cell line (HT22). Computational studies suggest that the AcPHF6 peptide can act as an anchor and provides a hydrophobic surface for Abeta monomer to bind and undergo rapid fibrillogenesis to form less toxic fibrils and alter the aggregation kinetics. At the molecular level we propose a "dock-and-pack" mechanism where the AcPHF6 hexapeptide aggregates can stabilize the beta-hairpin and promote rapid Abeta self-assembly and growth to form less toxic oligomers or fibrils. Our results have direct implications in designing novel peptide/peptidomimetics as novel pharmacological tools to study protein aggregation and potentially prevent Abeta-mediated toxicity in Alzheimer's disease. PMID- 29239600 TI - Exonuclease III-Assisted Upconversion Resonance Energy Transfer in a Wash-Free Suspension DNA Assay. AB - Sensitivity is the key in optical detection of low-abundant analytes, such as circulating RNA or DNA. The enzyme Exonuclease III (Exo III) is a useful tool in this regard; its ability to recycle target DNA molecules results in markedly improved detection sensitivity. Lower limits of detection may be further achieved if the detection background of autofluorescence can be removed. Here we report an ultrasensitive and specific method to quantify trace amounts of DNA analytes in a wash-free suspension assay. In the presence of target DNA, the Exo III recycles the target DNA by selectively digesting the dye-tagged sequence-matched probe DNA strand only, so that the amount of free dye removed from the probe DNA is proportional to the number of target DNAs. Remaining intact probe DNAs are then bound onto upconversion nanoparticles (energy donor), which allows for upconversion luminescence resonance energy transfer (LRET) that can be used to quantify the difference between the free dye and tagged dye (energy acceptor). This scheme simply avoids both autofluorescence under infrared excitation and many tedious washing steps, as the free dye molecules are physically located away from the nanoparticle surface, and as such they remain "dark" in suspension. Compared to alternative approaches requiring enzyme-assisted amplification on the nanoparticle surface, introduction of probe DNAs onto nanoparticles only after DNA hybridization and signal amplification steps effectively avoids steric hindrance. Via this approach, we have achieved a detection limit of 15 pM in LRET assays of human immunodeficiency viral DNA. PMID- 29239597 TI - Degradation of Bioresorbable Mg-4Zn-1Sr Intramedullary Pins and Associated Biological Responses in Vitro and in Vivo. AB - This article reports the degradation and biological properties of as-drawn Mg-4Zn 1Sr (designated as ZSr41) and pure Mg (P-Mg) wires as bioresorbable intramedullary pins for bone repair. Specifically, their cytocompatibility with bone marrow derived mesenchymal stem cells (BMSCs) and degradation in vitro, and their biological effects on peri-implant tissues and in vivo degradation in rat tibiae were studied. The as-drawn ZSr41 pins showed a significantly faster degradation than P-Mg in vitro and in vivo. The in vivo average daily degradation rates of both ZSr41 and P-Mg intramedullary pins were significantly greater than their respective in vitro degradation rates, likely because the intramedullary site of implantation is highly vascularized for removal of degradation products. Importantly, the concentrations of Mg2+, Zn2+, and Sr2+ ions in the BMSC culture in vitro and their concentrations in rat blood in vivo were all lower than their respective therapeutic dosages, i.e., in a safe range. Despite of rapid degradation with a complete resorption time of 8 weeks in vivo, the ZSr41 intramedullary pins showed a significant net bone growth because of stimulatory effects of the metallic ions released. However, proportionally released OH- ions and hydrogen gas caused adverse effects on bone marrow cells and resulted in cavities in surrounding bone. Thus, properly engineering the degradation properties of Mg-based implants is critical for harvesting the bioactivities of beneficial metallic ions, while controlling adverse reactions associated with the release of OH- ions and hydrogen gas. It is necessary to further optimize the alloy processing conditions and/or modify the surfaces, for example, applying coatings onto the surface, to reduce the degradation rate of ZSr41 wires for skeletal implant applications. PMID- 29239602 TI - Improving Estimates of Nitrogen Emissions for Life Cycle Assessment of Cropping Systems at the Scale of an Agricultural Territory. AB - In life cycle assessment (LCA), simple models are currently used to estimate cropping system nitrogen (N) emissions on farms. At large spatial scales (e.g., countries), these models are valid. At a smaller spatial scale (e.g., territories), these models may be less accurate, since they completely or partially ignore local conditions such as management practices, soil or climate. The purpose of this study was to consider the variability of those factors when estimating N emissions in LCA at the watershed scale. To this end, Syst'N, decision-support software based on a simulation model of crop and soil N dynamics at field and crop-rotation scales, was applied to predict N emissions from cropping systems in a coastal watershed (Lieue de Greve, France). Syst'N predictions were compared to N emissions estimated by AGRIBALYSE, a static site dependent method at field and single-crop scales. Syst'N was more sensitive to site-specific soil properties than AGRIBALYSE. Estimates of N emissions that include spatial variability in soil and climate therefore become possible in LCA when a simulation model such as Syst'N is used in the inventory phase. PMID- 29239601 TI - Preparation and Pharmaceutical Characterizations of Lipidated Dimeric Xenopus Glucagon-Like Peptide-1 Conjugates. AB - A pair of glucagon-like peptide-1 (GLP-1) analogs (1 and 2) were synthesized by hybridizing the key sequences of GLP-1, exendin-4, lixisenatide, and xenGLP-1B (Xenopus GLP-1 analog). To achieve long-acting hypoglycemic effects and to further improve their anti-diabetic potencies, lipidization and dimerization strategies were used to afford two lipidated dimeric conjugates (9 and 11). Conjugates 9 and 11 showed stronger receptor activation potency than GLP-1 and exendin-4 in vitro. Moreover, 9 and 11 exhibited superior hypoglycemic and insulinotropic activities to liraglutide in type 2 diabetic C57BL/6J-m+/+ Leprdb (db/db) mice. Pharmacokinetic studies revealed that the circulating half-lives (t1/2) of 9 and 11 were 2.3- and 1.7-fold longer than that of liraglutide. The improved pharmacokinetic profiles led to significantly protracted in vivo anti diabetic effects as confirmed by multiple oral glucose tolerance tests and hypoglycemic duration tests. Most importantly, chronic treatment studies found that once daily administration of 9 or 11 in db/db mice achieved more beneficial effects on HbA1c reduction and glucose tolerance normalization than liraglutide. Our research demonstrated lipidization and dimerization as useful tools for the development of novel GLP-1 receptor agonists. The preclinical studies suggested the potential of 9 and 11 to be developed as novel anti-diabetic agents. PMID- 29239603 TI - Thermodynamics of Amyloid-beta Fibril Elongation: Atomistic Details of the Transition State. AB - Amyloid-beta (Abeta) fibrils and plaques are one of the hallmarks of Alzheimer's disease. While the kinetics of fibrillar growth of Abeta have been extensively studied, several vital questions remain. In particular, the atomistic origins of the Arrhenius barrier observed in experiments have not been elucidated. Employing the familiar thermodynamic integration method, we have directly simulated the dissociation of an Abeta(15-40) (D23N mutant) peptide from the surface of a filament along its most probable path (MPP) using all-atom molecular dynamics. This allows for a direct calculation of the free energy profile along the MPP, revealing a multipeak energetic barrier between the free peptide state and the aggregated state. By definition of the MPP, this simulated unbinding process represents the reverse of the physical elongation pathway, allowing us to draw biophysically relevant conclusions from the simulation data. Analyzing the detailed atomistic interactions along the MPP, we identify the atomistic origins of these peaks as resulting from the dock-lock mechanism of filament elongation. Careful analysis of the dynamics of filament elongation could prove key to the development of novel therapeutic strategies for amyloid-related diseases. PMID- 29239604 TI - Nitrosoreductase-Like Nanocatalyst for Ultrasensitive and Stable Biosensing. AB - Enzyme-like nanocatalytic reactions developed for high signal amplification in biosensors are of limited use because of their low reaction rates and/or unwanted side reactions in aqueous electrolyte solutions containing dissolved O2. Herein, we report a nitrosoreductase-like catalytic reaction, employing 4-nitroso-1 naphthol, Pd nanoparticles, and H3N-BH3, which affords a high reaction rate and minimal side reactions, enabling its use in ultrasensitive electrochemical biosensors. 4-Nitroso-1-naphthol was chosen after five hydroxy-nitro(so)arene compounds were compared in terms of high signal and low background levels. Importantly, the nanocatalytic reaction occurs without the self-hydrolysis and induction period observed in the nanocatalytic reduction of nitroarenes by NaBH4. The high signal level results from (i) fast nanocatalytic 4-nitroso-1-naphthol reduction, (ii) fast electrochemical redox cycling, and (iii) the low influence of dissolved O2. The low background level results from (i) slow direct reaction between 4-nitroso-1-naphthol and H3N-BH3, (ii) slow electrode-mediated reaction between 4-nitroso-1-naphthol and H3N-BH3, and (iii) slow electrooxidation of H3N BH3 at electrode. When applied to the detection of parathyroid hormone, the detection limit of the newly developed biosensor was ~0.3 pg/mL. The nitrosoreductase-like nanocatalytic reaction is highly promising for ultrasensitive and stable biosensing. PMID- 29239605 TI - Correction to Suppressing Isomerization of Phosphine-Protected Au9 Cluster by Bond Stiffening Induced by a Single Pd Atom Substitution. PMID- 29239606 TI - Biosurfactant-Protein Interaction: Influences of Mannosylerythritol Lipids-A on beta-Glucosidase. AB - In this work, the influences of a biosurfactant, mannosylerythritol lipids-A (MEL A) toward beta-glucosidase activity and their molecular interactions were studied by using differential scanning calorimetry (DSC), circular dichroism spectroscopy (CD), isothermal titration calorimetry (ITC), and docking simulation. The enzyme inhibition kinetics data showed that MEL-A at a low concentration (< critical micelle concentration (CMC), 20.0 +/- 5.0 MUM) enhanced beta-glucosidase activity, whereas it inhibited the enzyme activity at higher concentrations more than 20.0 MUM, followed by a decreased Vmax and Km of beta-glucosidase. The thermodynamics and structural data demonstrated that the midpoint temperature (Tm) and unfolding enthalpy (DeltaH) of beta-glucosidase was shifted to high values (76.6 degrees C, 126.3 J/g) in the presence of MEL-A, and the secondary structure changes of beta-glucosidase, including the increased alpha-helix, beta turn, or random coil contents, and a decreased beta-sheet content were caused by MEL-A at a CMC concentration. The further ITC and docking simulations suggested the bindings of MEL-A toward beta-glucosidase were driven by weak hydrophobic interactions happened between the amino acid residues of beta-glucosidase and the fatty acid residues of MEL-A, in addition to hydrogen bonds between amino acids and hydroxyl in glycosyl residues of this biosurfactant. PMID- 29239607 TI - Correction to Analysis of Heterocyclic Amines in Meat by the Quick, Easy, Cheap, Effective, Rugged, and Safe Method Coupled with LC-DAD-MS-MS. PMID- 29239608 TI - Choline-Based Amino Acid ILs-Collagen Interaction: Enunciating Its Role in Stabilization/Destabilization Phenomena. AB - Given the potential of productive interaction between choline-based amino acid ionic liquids (CAAILs) and collagen, we investigated the role of four CAAILs, viz., choline serinate, threoninate, lysinate, and phenylalaninate, and the changes mediated by them in the structure of collagen at different hierarchical orderings, that is, at molecular and fibrillar levels. The rheological, dielectric behavior and the secondary structural changes signify the alteration in the triple helical structure of collagen at higher concentrations of CAAILs. A marginal swelling and slight decrease in the thermal stability of rat tail tendon collagen fibers were observed for choline serinate and threoninate, albeit distortions in banding patterns were noticed for choline lysinate and phenylalaninate, suggesting chaotropicity of the ions at the fibrillar level. This signifies the changes in the hydrogen-bonding environment of collagen with increasing concentrations of CAAILs, which could be due to competitive hydrogen bonding between the carbonyl group of amino acid ionic liquids and the hydroxyl groups of collagen. PMID- 29239609 TI - NitroxylFluor: A Thiol-Based Fluorescent Probe for Live-Cell Imaging of Nitroxyl. AB - Detection of nitroxyl (HNO), the transient one-electron reduced form of nitric oxide, is a significant challenge owing to its high reactivity with biological thiols (with rate constants as high as 109 M-1 s-1). To address this, we report a new thiol-based HNO-responsive trigger that can compete against reactive thiols for HNO. This process forms a common N-hydroxysulfenamide intermediate that cyclizes to release a masked fluorophore leading to fluorescence enhancement. To ensure that the cyclization step is rapid, our design capitalizes on two established physical organic phenomena; the alpha-effect and the Thorpe-Ingold effect. Using this new trigger, we developed NitroxylFluor, a selective HNO responsive fluorescent probe. Treatment of NitroxylFluor with an HNO donor results in a 16-fold turn-on. This probe also exhibits excellent selectivity over various reactive nitrogen, oxygen, and sulfur species and efficacy in the presence of thiols (e.g., glutathione in mM concentrations). Lastly, we successfully performed live cell imaging of HNO using NitroxylFluor. PMID- 29239610 TI - Nanosensing of Pesticides by Zinc Oxide Quantum Dot: An Optical and Electrochemical Approach for the Detection of Pesticides in Water. AB - Present study reveals the low concentrations (~4 ppm) of pesticide sensing vis-a vis degradation of pesticides with the help of nontoxic zinc oxide quantum dots (QD). In our study, we have taken four different pesticides viz., aldrin, tetradifon, glyphosate, and atrazine, which are widely used in agriculture and have structural dissimilarities/diversity. By using optical sensing techniques such as steady state and time-resolved fluorescence, we have analyzed the detailed exciton dynamics of QD in the presence of different pesticides. It has been found that the pesticide containing good leaving groups (-Cl) can interact with QD promptly and has high binding affinity (~107 M-1). The different binding signatures of QD with different pesticides enable us to differentiate between the pesticides. Time resolved fluorescence spectroscopy provides significant variance (~150-300 ns) for different pesticides. Furthermore, a large variation (105 Omega to 7 * 104 Omega) in the resistance of QD in the presence of different pesticides was revealed by electrochemical sensing technique. Moreover, during the interaction with pesticides, QD can also act as a photocatalyst to degrade pesticides. Present investigation explored the fact that the rate of degradation is positively affected by the binding affinity, i.e., the greater the binding, the greater is the degradation. What is more, both optical and electrochemical measurements of QD, in tandem, as described in our study could be utilized as the pattern recognition sensor for detection of several pesticides. PMID- 29239611 TI - Novel Peptidase Kunitz Inhibitor from Platypodium elegans Seeds Is Active against Spodoptera frugiperda Larvae. AB - A novel Kunitz-type inhibitor from Platypodium elegans seeds (PeTI) was purified and characterized. The mass spectrometry analyses of PeTI indicated an intact mass of 19 701 Da and a partial sequence homologous to Kunitz inhibitors. PeTI was purified by ion exchange and affinity chromatographies. A complex with a 1:1 ratio was obtained only for bovine trypsin, showing a Ki = 0.16 nM. Stability studies showed that PeTI was stable over a wide range of temperature (37-80 degrees C) and pH (2-10). The inhibitory activity of PeTI was affected by dithiothreitol (DTT). Bioassays of PeTI on Spodoptera frugiperda showed negative effects on larval development and weight gain, besides extending the insect life cycle. The activities of digestive enzymes, trypsin and chymotrypsin, were reduced by feeding larvae with 0.2% PeTI in an artificial diet. In summary, we describe a novel Kunitz inhibitor with promising biotechnological potential for pest control. PMID- 29239612 TI - Central Role of Bicarbonate Anions in Charging Water/Hydrophobic Interfaces. AB - Aqueous interfaces are ubiquitous in Nature and play a fundamental role in environmental or biological processes or modern nanotechnologies. These interfaces are negatively charged, and despite several decades of research, the rationale behind this phenomenon is still under debate. Two main controversial schools of thought argue on this issue; the first relies on the adsorption of hydroxide anions on hydrophobic surfaces, whereas the second one supports a self rearrangement of water molecules at the interface bearing hydronium ions. Here, we report on two series of independent experimental studies (nanoprecipitation and interfacial tension measurements) that demonstrate that in the pH 5-10 range the negative interfacial charge of the colloids mostly stems from bicarbonate ions, whereas at lower and higher pH, protons and hydroxide ions contribute, with bicarbonate ions, to the interfacial charging. This new interpretation complies with previous studies and opens new perspectives to this striking physical chemical issue. PMID- 29239613 TI - Dewetting of Thin Liquid Films Surrounding Air Bubbles in Microchannels. AB - As an air bubble translates in a microchannel, a thin film of liquid is formed on the bounding walls. In a microchannel with a rectangular cross-section, the liquid in the film leaks toward the low-pressure corners of the geometry, which leads to the appearance of local minima in the film thickness in the cross sectional plane. In such a configuration, theory suggests that the minimum film thickness scales with Ca and Ca4/3 depending on the distance from the nose of the bubble, where Ca = MUUb/gamma is the flow capillary number based on the bubble velocity Ub, liquid viscosity MU, and surface tension gamma, and Ca ? 1. We show that the film of a partially wetting liquid dewets on the channel wall at the sites of the local minima in the film thickness as it acquires thicknesses around and below 100 nm. Our experiments show that the distance Lw between the nose of the bubble and the initial dewetting location is a function of Ca and surface wettability. For channels of different wettability, Lw always scales proportional to Caalpha, where 1.7 < alpha < 2 for the range of 10-5 < Ca < 10-2. Moreover, Lw increases up to 10 times by enhancing the wettability of the surface at a given Ca. Our present measurements of Lw provide a design constraint on the lengths of bubbles to maintain a liquid wet channel without dry patches on the wall. PMID- 29239614 TI - Nonadiabatic Dynamics via the Symmetrical Quasi-Classical Method in the Presence of Anharmonicity. AB - The symmetrical quasi-classical (SQC) method recently proposed by Miller and Cotton allows one to simulate nonadiabatic dynamics based on an algorithm with classical-like scaling with respect to system size. This is made possible by casting the electronic degrees of freedom in terms of mapping variables that can be propagated in a classical-like manner. While SQC was shown to be rather accurate when applied to benchmark models with harmonic electronic potential energy surfaces, it was also found to become inaccurate and to suffer numerical instabilities when applied to anharmonic systems. In this paper, we propose an extended SQC (E-SQC) methodology for overcoming those discrepancies by describing the anharmonic nuclear modes, which are coupled to the electronic degrees of freedom, in terms of classical-like mapping variables. The accuracy of E-SQC relative to standard SQC is demonstrated on benchmark models with quartic and Morse potential energy surfaces. PMID- 29239615 TI - Direct Activation of beta-sp3-Carbons of Saturated Carboxylic Esters as Electrophilic Carbons via Oxidative Carbene Catalysis. AB - An N-heterocyclic carbene-catalyzed oxidative LUMO activation of the beta-cabons of saturated carboxylic esters is disclosed. This approach allows for efficient asymmetric access to lactams and lactones by directly installing functional groups to the typically inert beta-sp3 carbons of saturated esters. The use of HOBt as an additive was found to significantly improve both yields and enantioselectivities of the reactions. PMID- 29239616 TI - Tertiary and Quaternary Carbon Formation via Gallium-Catalyzed Nucleophilic Addition of Organoboronates to Cyclopropanes. AB - GaCl3 and (IPr)GaCl3/AgSbF6 formed gamma-tertiary and gamma-quaternary carbons via homoconjugate addition of organoboron nucleophiles to diester- and ketone functionalized cyclopropanes. Electron donor group cyclopropane substituents were not needed, allowing electron-deficient aryl, alkenyl, alkyl, and hydrogen substituted cyclopropanes to be used. The catalytic conditions were compatible with alkenyl, alkynyl, and aryl nucleophiles, including ortho-substituted aromatics, to synthesize highly hindered quaternary carbons. Alkynyl nucleophiles formed substituted cyclopentenes. A control experiment supports an intermediate carbocation in quaternary carbon center formation. PMID- 29239617 TI - Multiheterocyclic Motifs via Three-Component Reactions of Benzynes, Cyclic Amines, and Protic Nucleophiles. AB - A broadly general, three-component reaction strategy for the construction of compounds containing multiple heterocycles is described. Thermal benzyne formation (by the hexadehydro-Diels-Alder (HDDA) reaction) in the presence of tertiary cyclic amines and a protic nucleophile (HNu) gives, via ring-opening of intermediate ammonium ion/Nu- ion pairs, heterocyclic products. Many reactions are efficient even when the stoichiometric loading of the three reactants approaches unity. Use of HOSO2CF3 as the HNu gives ammonium triflate intermediates, which can then be ring opened by an even wider variety of nucleophiles. PMID- 29239618 TI - Synthesis of Bifunctional Thiophenes via Fiesselmann Condensation of Ynone Trifluoroborate Salts. AB - Ynone trifluoroborate salts undergo a base-promoted condensation reaction with alkylthiols to generate thiophene boronates with complete regiocontrol. The products are isolated in high yield and can be further derivatized through conventional C-B bond functionalization reactions. PMID- 29239619 TI - Visible-Light-Photocatalyzed Synthesis of Phenanthridinones and Quinolinones via Direct Oxidative C-H Amidation. AB - A straightforward synthetic strategy to construct biologically relevant phenanthridinones and quinolinones was developed via visible-light-promoted direct oxidative C-H amidation. In this photocatalytic system, amidyl radicals can be generated by homolysis of the N-H bond of simple amide precursors via single-electron transfer under blue LED illumination, which leads to oxidative intramolecular C-H amidation. Moreover, an efficient synthetic strategy using a photocascade enabled facile assembly of quinolinone structures through a catalytic sequence involving triplet energy (ET) transfer-based E/Z olefin isomerization and subsequent photocatalytic generation of amidyl radical intermediates. PMID- 29239620 TI - Wax Spreading in Paper under Controlled Pressure and Temperature. AB - This work describes a novel rapid method to fabricate high-resolution paper-based microfluidic devices using wax-ink-based printing. This study demonstrates that both temperature and pressure are important knobs in controlling the device resolution. High-resolution lines and patterns were obtained by heating the paper asymmetrically from one side up to 110 degrees C while applying pressure up to 49 kPa. Starting with wax lines with an initial width of 130 MUm, we achieve a thorough penetration through a 190 MUm-thick paper with lateral spreading on the front as narrow as 90 MUm. The role of temperature and pressure are systematically studied and compared with the prediction of the Lucas-Washburn equation. We found that the temperature dependence of spreading can be explained by the viscosity change of the wax, according to the Lucas-Washburn equation. The pressure dependence deviates from Lucas-Washburn behavior because of compression of the paper. An optimal condition for achieving full depth penetration of the wax yet minimizing lateral spreading is suggested after exploring various parameters including temperature, pressure, and paper type. These findings could lead to a rapid roll-to-roll fabrication of high-resolution paper-based diagnostic devices. PMID- 29239621 TI - A qualitative analysis of gabapentin misuse and diversion among people who use drugs in Appalachian Kentucky. AB - Gabapentin, an anticonvulsant and analgesic for postherpetic neuralgia, has been thought to have no abuse potential despite numerous published reports to the contrary. Gabapentin has been linked with impaired driving and opioid use, highlighting the need to more fully understand its risk profile. Thirty-three individuals reporting recent nonmedical use of gabapentin were recruited from two ongoing longitudinal studies of drug users in Appalachian Kentucky to participate in focus groups. Four sessions were held (two in the community and two in jail settings), during which participants responded to questions regarding their personal experiences with gabapentin misuse. Focus group participants were similar to other gabapentin users in the larger cohort studies with respect to demographics and drug use behaviors. Overall, the sample reported having initiated gabapentin more than 10 years earlier after having it prescribed for a legitimate, though generally off-label, medical indication (e.g., pain, anxiety, opioid detoxification). Participants reported use of gabapentin in combination with buprenorphine, other opioids, cocaine, and caffeine to produce sought-after central nervous system effects (e.g., muscle relaxation, pain reduction, sleep induction, feeling drunk, and feeling "high"). Focus group responses highlighted the low cost of gabapentin for the purpose of getting high and noted increasing popularity in the community, particularly over the last 2 years. Gabapentin was a prominent drug of abuse in two cohorts of the primarily opioid-using individuals. Providers should be aware of gabapentin's abuse potential, and a reexamination of the need for scheduling is warranted. (PsycINFO Database Record PMID- 29239622 TI - Coactivation of cognitive control networks during task switching. AB - OBJECTIVE: The ability to flexibly switch between tasks is considered an important component of cognitive control that involves frontal and parietal cortical areas. The present study was designed to characterize network dynamics across multiple brain regions during task switching. METHOD: Functional magnetic resonance images (fMRI) were captured during a standard rule-switching task to identify switching-related brain regions. Multiregional psychophysiological interaction (PPI) analysis was used to examine effective connectivity between these regions. RESULTS: During switching trials, behavioral performance declined and activation of a generic cognitive control network increased. Concurrently, task-related connectivity increased within and between cingulo-opercular and fronto-parietal cognitive control networks. Notably, the left inferior frontal junction (IFJ) was most consistently coactivated with the 2 cognitive control networks. Furthermore, switching-dependent effective connectivity was negatively correlated with behavioral switch costs. The strength of effective connectivity between left IFJ and other regions in the networks predicted individual differences in switch costs. CONCLUSIONS: Task switching was supported by coactivated connections within cognitive control networks, with left IFJ potentially acting as a key hub between the fronto-parietal and cingulo-opercular networks. (PsycINFO Database Record PMID- 29239623 TI - Environmental scaling influences the use of local but not global geometric cues during spatial reorientation. AB - During spatial reorientation, the use of local geometric cues (e.g., corner angles) and global geometric cues (e.g., principal axis) is differentially influenced by enclosure size. Local geometric cues exert more influence in large enclosures compared to small enclosures, whereas the use of global geometric cues is not influenced by changes in enclosure size. Such effects are suggested to occur because of differences in training enclosures sizes or differences in testing enclosure sizes, but investigations of enclosure-size effects on spatial cue use have been confounded by environmental scaling between training and testing. We trained participants in a trapezoid-shaped enclosure to respond to a corner uniquely specified by both local and global geometric cues and tested participants in a rectangle (isolating the use of global geometric cues) and in a parallelogram (placing local and global geometric cues in conflict). Between groups, participants experienced different training environment sizes but identical testing environment sizes or identical training environment sizes but different testing environment sizes, and this allowed categorization with respect to the direction of environmental scaling. We found that environmental scaling between training and testing size (but not training size differences or testing size differences) influenced the relative use of local geometric cues. The use of global geometric cues was not influenced by enclosure size. Results challenge prior explanations of the influence of enclosure size on relative spatial cue use during spatial reorientation. (PsycINFO Database Record PMID- 29239624 TI - Proactive control processes in event-based prospective memory: Evidence from intraindividual variability and ex-Gaussian analyses. AB - The present study implemented an individual differences approach in conjunction with response time (RT) variability and distribution modeling techniques to better characterize the cognitive control dynamics underlying ongoing task cost (i.e., slowing) and cue detection in event-based prospective memory (PM). Three experiments assessed the relation between proactive control ability, ex-Gaussian parameter estimates (MU and tau), intraindividual variability in responding (coefficient of variation, CoV), and PM cue detection. Experiment 1 examined these relations using a standard nonfocal PM paradigm. Experiments 2 and 3 further assessed how PM importance and PM cue focality, respectively, influenced performance. Across all experiments, nonfocal PM was associated with increases in all cost measures, but only MU reliably predicted cue detection. Importance instructions and focal PM cues selectively increased and decreased MU cost, respectively, relative to the standard nonfocal condition. These findings suggest that MU cost may reflect a target-checking process that benefits cue detection and produces slowing throughout the entire ongoing task. Additionally, across all experiments proactive control was positively associated with MU cost and cue detection, and generally negatively associated with variability cost (tau and CoV). These findings suggest that natural variation in proactive control ability may affect reliance on more efficacious monitoring processes that facilitates cue detection. Furthermore, variability in responding may have little influence on successful PM. The results from the current study highlight the utility of RT variability and distribution analyses in understanding PM costs and have important implications for extant theories of PM concerning the cognitive control processes underlying cue detection. (PsycINFO Database Record PMID- 29239625 TI - Adaptive memory: Is there a reproduction-processing effect? AB - Like all biological systems, human memory is likely to have been influenced by evolutionary processes, and its abilities have been subjected to selective mechanisms. Consequently, human memory should be primed to better remember information relevant to one's evolutionary fitness. Supporting this view, participants asked to rate words based on their relevance to an imaginary survival situation better recall those words (even the words rated low in relevancy) than the same words rated with respect to non-survival situations. This mnemonic advantage is called the "survival-processing effect," and presumably it was selected for because it contributed to evolutionary fitness. The same reasoning suggests that there should be an advantage for recall of information that has been rated for relevancy to reproduction and/or mate seeking, although little evidence has existed to assess this proposition. We used an experimental design similar to that in the original survival-processing effect study (Nairne, Thompson, & Pandeirada, 2007) and across 3 experiments tested several newly designed scenarios to determine whether a reproduction-processing effect could be found in an ancestral environment, a modern mating environment, and an ancestral environment in which the emphasis was on raising offspring as opposed to finding a mate. Our results replicated the survival-processing effect but provided no evidence of a reproduction-processing effect when the scenario emphasized finding a mate. However, when rating items on their relevancy to raising one's offspring in an ancestral environment, a mnemonic advantage comparable to that of the survival-processing effect was found. (PsycINFO Database Record PMID- 29239626 TI - Maternal psychological control, maternal borderline personality disorder, and adolescent borderline features. AB - Linehan (1993) theorized that the experience of invalidating parenting interacts with emotional vulnerability in the development of borderline personality disorder (BPD). Parental psychological control is a type of invalidating parenting, defined as manipulation by parents of their offspring's psychological and emotional expression and experience (Barber, 1996). In a normative sample of adolescent females, adolescent-reported maternal psychological control was related to maternal borderline symptoms (Zalewski et al., 2014). The current study expanded on these findings to sample mothers with a diagnosis of BPD (n = 28) and normative comparisons (n = 28) with male and female adolescents aged 14 18. We assessed maternal and adolescent self-reported borderline features (affective instability, negative relationships, identity disturbance, and self harm) and coded maternal psychological control from filmed problem-solving interactions. Controlling for current major depressive disorder and family income, mothers with BPD used more total psychological control with their adolescents in comparison with normative mothers. Further, maternal psychological control was positively associated with all mothers' borderline features and with adolescent affective instability. Finally, we found a significant indirect effect for maternal affective instability between maternal total psychological control and adolescent affective instability. We discuss adolescents' risk of developing BPD themselves and prevention and treatment implications. (PsycINFO Database Record PMID- 29239627 TI - Clinical severity as a moderator of outcome in psychodynamic and dialectical behavior therapies for borderline personality disorder. AB - The aim of the present study was to assess the effect of initial level of psychiatric severity on treatment outcome in psychodynamic therapy and dialectical behavior therapy (DBT) for borderline personality disorder (BPD). It was hypothesized that DBT would lead to better outcome for patients with high psychiatric severity, whereas dynamic treatment would lead to better outcome for patients with lower psychiatric severity. Data from the 5th-year follow-up of the Stockholm City Council's and the Karolinska Institute's Psychotherapy Project were used in the present study. A total of 106 female patients diagnosed with BPD with at least 2 past suicide attempts were randomized into object-relational psychotherapy (ORP; based on transference-focused psychotherapy), DBT, and treatment as usual. Patients' baseline global severity index was used as a moderator. Global Assessment of Functioning (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [American Psychiatric Association, 1994]) was used to examine outcome. There was a significant 3-way interaction of Time * Treatment * Severity. Post hoc analyses suggested that patients with lower levels of severity had significantly better outcomes in object-relational psychotherapy. For patients with higher severity, the 3 treatments resulted in similar outcomes in terms of level of functioning. Outcome of treatment for BPD might differ significantly for patients depending on their initial levels of overall psychiatric severity. If our findings are replicated for patients with low severity and supported for a high-severity sample, psychiatric severity can be used as a low-cost and effective tool to match patients with BPD to optimal treatments. (PsycINFO Database Record PMID- 29239628 TI - Psychopathy in detained boys: The search for primary and secondary variants in a clinical setting. AB - This study investigates whether primary and secondary variants of psychopathy can be identified in an applied, forensic setting based on self-reports of psychopathy and anxiety. Data were available for two samples of detained boys (Sample A: N = 847, Sample B: N = 749). Using three psychopathy dimensions and anxiety as clustering variables, latent profile analysis arrived at 4 latent classes (LCs) that were tentatively labeled as control (LC1), high anxiety (LC2), moderate psychopathy (LC3), and high psychopathy (LC4). Boys in LC4 engaged in higher levels of alcohol/drug use, conduct problems, reactive and proactive aggression than their counterparts in LC1 and in higher levels of conduct problems, alcohol/drug use, and proactive aggression than boys in LC3. Findings further indicated that the risk for future nonviolent arrests was the highest in LC4 as compared with LC2 and LC3, though no class differences in risk for future violent arrests emerged. Overall, these findings were well replicated in Sample B. Exploratory analyses included additional measures of negative affect (depressed feeling and anger-irritability), maltreatment, and/or number of past arrests (as proxy of a 4th psychopathy dimension) as clustering variables and identified all but 1 (LC3) of the 4 aforementioned LCs. Notwithstanding that our findings challenge the expected relevance of differentiating primary and secondary variants of youth psychopathy, they do suggest that it is possible to identify detained boys with high levels of psychopathic traits who display features associated with adult psychopathy. Implications for theory, research, and practice are discussed. (PsycINFO Database Record PMID- 29239629 TI - Gender differences in the initiation of negotiations: A meta-analysis. AB - Gender differences in the initiation of negotiation have been suggested to reinforce unequal distributions of resources between men and women. Because previous research had yielded heterogeneous results, the authors conducted a meta analysis investigating gender differences in initiating negotiation. On the basis of social role theory, they hypothesized that women are less likely to initiate negotiations than men, but also that the effect varies depending on characteristics of the immediate negotiation situation and the wider societal context. The meta-analysis comprised 55 effect sizes with 17,504 individuals, including both students and employees. A random-effects model confirmed that women were indeed less likely to initiate negotiations than men (g = 0.20). Additional moderator analyses, tested with mixed-effects models and metaregressions, revealed that gender differences were smaller when situational ambiguity regarding the appropriateness of negotiating was low rather than high as well as when situational cues were more consistent with the female gender role than with the male gender role. Gender differences decreased by year of publication (from 1977 to 2016) but were unrelated to the degree of gender inequality in the countries in which the studies were conducted. The authors conclude that gender differences in the initiation of negotiation exist, but they are small and context-bound. Finally, they discuss mechanisms that alter the gender difference with a particular focus on potential starting points for practical interventions. (PsycINFO Database Record PMID- 29239630 TI - A meta-analytic review of two modes of learning and the description-experience gap. AB - People can learn about the probabilistic consequences of their actions in two ways: One is by consulting descriptions of an action's consequences and probabilities (e.g., reading up on a medication's side effects). The other is by personally experiencing the probabilistic consequences of an action (e.g., beta testing software). In principle, people taking each route can reach analogous states of knowledge and consequently make analogous decisions. In the last dozen years, however, research has demonstrated systematic discrepancies between description- and experienced-based choices. This description-experience gap has been attributed to factors including reliance on a small set of experience, the impact of recency, and different weighting of probability information in the two decision types. In this meta-analysis focusing on studies using the sampling paradigm of decisions from experience, we evaluated these and other determinants of the decision-experience gap by reference to more than 70,000 choices made by more than 6,000 participants. We found, first, a robust description-experience gap but also a key moderator, namely, problem structure. Second, the largest determinant of the gap was reliance on small samples and the associated sampling error: free to terminate search, individuals explored too little to experience all possible outcomes. Third, the gap persisted when sampling error was basically eliminated, suggesting other determinants. Fourth, the occurrence of recency was contingent on decision makers' autonomy to terminate search, consistent with the notion of optional stopping. Finally, we found indications of different probability weighting in decisions from experience versus decisions from description when the problem structure involved a risky and a safe option. (PsycINFO Database Record PMID- 29239631 TI - Video game training does not enhance cognitive ability: A comprehensive meta analytic investigation. AB - As a result of considerable potential scientific and societal implications, the possibility of enhancing cognitive ability by training has been one of the most influential topics of cognitive psychology in the last two decades. However, substantial research into the psychology of expertise and a recent series of meta analytic reviews have suggested that various types of cognitive training (e.g., working memory training) benefit performance only in the trained tasks. The lack of skill generalization from one domain to different ones-that is, far transfer has been documented in various fields of research such as working memory training, music, brain training, and chess. Video game training is another activity that has been claimed by many researchers to foster a broad range of cognitive abilities such as visual processing, attention, spatial ability, and cognitive control. We tested these claims with three random-effects meta-analytic models. The first meta-analysis (k = 310) examined the correlation between video game skill and cognitive ability. The second meta-analysis (k = 315) dealt with the differences between video game players and nonplayers in cognitive ability. The third meta-analysis (k = 359) investigated the effects of video game training on participants' cognitive ability. Small or null overall effect sizes were found in all three models. These outcomes show that overall cognitive ability and video game skill are only weakly related. Importantly, we found no evidence of a causal relationship between playing video games and enhanced cognitive ability. Video game training thus represents no exception to the general difficulty of obtaining far transfer. (PsycINFO Database Record PMID- 29239633 TI - Spatial but not temporal numerosity thresholds correlate with formal math skills in children. AB - Humans and other animals are able to make rough estimations of quantities using what has been termed the approximate number system (ANS). Much evidence suggests that sensitivity to numerosity correlates with symbolic math capacity, leading to the suggestion that the ANS may serve as a start-up tool to develop symbolic math. Many experiments have demonstrated that numerosity perception transcends the sensory modality of stimuli and their presentation format (sequential or simultaneous), but it remains an open question whether the relationship between numerosity and math generalizes over stimulus format and modality. Here we measured precision for estimating the numerosity of clouds of dots and sequences of flashes or clicks, as well as for paired comparisons of the numerosity of clouds of dots. Our results show that in children, formal math abilities correlate positively with sensitivity for estimation and paired-comparisons of the numerosity of visual arrays of dots. However, precision of numerosity estimation for sequences of flashes or sounds did not correlate with math, although sensitivities in all estimations tasks (for sequential or simultaneous stimuli) were strongly correlated with each other. In adults, we found no significant correlations between math scores and sensitivity to any of the psychophysical tasks. Taken together these results support the existence of a generalized number sense, and go on to demonstrate an intrinsic link between mathematics and perception of spatial, but not temporal numerosity. (PsycINFO Database Record PMID- 29239632 TI - A meta-analysis of work-family conflict and social support. AB - The relationship between social support and work-family conflict is well established, but the notion that different forms, sources, and types of social support as well as contextual factors can alter this relationship has been relatively neglected. To address this limitation, the current study provides the most comprehensive and in-depth examination of the relationship between social support and work-family conflict to date. We conduct a meta-analysis based on 1021 effect sizes and 46 countries to dissect the social support and work-family conflict relationship. Using social support theory as a theoretical framework, we challenge the assumption that social support measures are interchangeable by comparing work/family support relationships with work-family conflict across different support forms (behavior, perceptions), sources (e.g., supervisor, coworker, spouse), types (instrumental, emotional), and national contexts (cultural values, economic factors). National context hypotheses use a strong inferences paradigm in which utility and value congruence theoretical perspectives are pitted against one another. Significant results concerning support source are in line with social support theory, indicating that broad sources of support are more strongly related to work-family conflict than are specific sources of support. In line with utility perspective from social support theory, culture and economic national context significantly moderate some of the relationships between work/family support and work interference with family, indicating that social support is most beneficial in contexts in which it is needed or perceived as useful. The results suggest that organizational support may be the most important source of support overall. (PsycINFO Database Record PMID- 29239634 TI - Mother-child positivity and negativity: Family-wide and child-specific main effects and interactions predict child adjustment. AB - Links between positive and negative aspects of the parent-child relationship and child adjustment are undisputed. Scholars recognize the importance of parental differential treatment (PDT) of siblings, yet, less is known about PDT in the context of the shared (family-wide) parent-child relationship climate, or about the extent to which positivity may buffer children's adjustment from negativity. Controlling for behavioral stability, we examined the potential for positive and negative parent-child processes to interact across and between child-specific and family-wide levels in the prediction of children's adjustment. Specifically, in a sample of 2,039 United Kingdom families, we used multilevel models to examine child-specific and family-wide mother-child relationships (at 4 years)-including interactive processes-in the prediction of prosocial behavior and conduct problems (at 7 years). The majority of variance in children's adjustment resided within-families: siblings were strikingly different. Accounting for behavioral stability, family-wide negativity and negative PDT associated with both prosociality and conduct problems. More important, we demonstrated interactions between, (a) family-wide negativity and negative PDT for conduct problems, as well as, (b) positive and negative PDT in the prediction of both prosocial behavior and conduct problems. Results suggest negative PDT associates with increased conduct problems over time, even when the overall family climate is low in negativity. They also indicate a buffering role of positive PDT on the deleterious effects of negative PDT for children's adjustment. Implications for both research and practice are discussed, including the importance of information gained by considering more than one child in the family. (PsycINFO Database Record PMID- 29239635 TI - "Will I know more in the future than I know now?" Preschoolers' judgments about changes in general knowledge. AB - An important aspect of perspective-taking ability is the appreciation that mental states such as beliefs, desires, and knowledge change over time. The current study focused specifically on 3-, 4-, and 5-year-olds' understanding that they will have knowledge in the future that they do not currently possess-for example, that when they are grown-ups, they will know what the words on a newspaper say. We also compared this understanding to children's understanding that adults have knowledge that children do not. To address the possibility that children's correct responses stemmed from a general rule that "adults know everything," we also included questions to which adults could not know the answer. Results show that children's understanding that they will have knowledge in the future that they do not currently possess and that adults possess knowledge that children do not improves substantially during the preschool years. Moreover, only the 5-year olds in our study acknowledged that certain things are "unknowable," even by adults. Finally, children's performance did not differ as a function of whether they were asked about their own future knowledge or an adult's current knowledge. Findings are discussed in terms of their implications for theories of perspective taking and mental state reasoning, future thinking, and children's motivation to learn. (PsycINFO Database Record PMID- 29239636 TI - Time-varying associations of parent-adolescent cultural conflict and youth adjustment among Chinese American families. AB - The purpose of this study was to examine time-varying associations of parent adolescent cultural conflict with depressive symptoms and grade point average (GPA) among Chinese Americans from ages 11-22. We pooled two independently collected longitudinal data sets (N = 760 at Wave 1) and used time-varying effect modeling (TVEM) to show that the frequency of parent-adolescent conflict increased during early adolescence (12 years), peaked at mid adolescence (16 years), and gradually decreased throughout late adolescence and young adulthood. In general, parent-adolescent conflict was associated with negative adjustment (more depressive symptoms and lower GPA) more strongly during mid- to late adolescence (15 to 17 years) compared with other developmental periods. These time-varying associations differed slightly by gender, at least for GPA. Our findings provide important developmental knowledge of parent-adolescent conflict for Chinese American youth and suggest that attention to conflict and links to adjustment is especially relevant during mid to late adolescence. Our study also illustrates the usefulness of integrative data analysis and TVEM to investigate how the strength of conflict-adjustment associations might change throughout development. (PsycINFO Database Record PMID- 29239637 TI - Discrete emotion regulation strategy repertoires and parasympathetic physiology characterize psychopathology symptoms in childhood. AB - Certain psychopathologies are often linked to dysregulation of specific emotions (e.g., anxiety is associated with dysregulation of fear), but few studies have examined how regulatory repertoires for specific emotions (e.g., the strategies a person uses to regulate fear) relate to psychopathology, and fewer still have examined this in childhood. A total of 106 7- to 11-year-olds (M = 9.37 years; SD = 1.30; 44% girls) participated in a multimethod investigation of emotion regulation and psychopathology. Parents reported on family characteristics and children's symptoms. Resting parasympathetic function (respiratory sinus arrhythmia; RSA) was measured to assess physiological regulation. Children were interviewed about past experiences that made them feel anger, fear, and sadness, and reported what they had done to make themselves feel better in each emotion context. The strategies children described were summed to create an emotion regulation strategy repertoire measure for each emotion. Children's resting RSA interacted with age to predict externalizing symptoms, such that low resting RSA was associated with more externalizing symptoms for younger children only. In contrast, the link between RSA and anxiety was qualified by both strategy repertoire for fear and age, such that higher resting RSA was most strongly associated with fewer anxiety symptoms for older children with larger strategy repertoires for fear. Contrary to our expectations, neither resting RSA nor strategy repertoire for sadness related to children's depressive symptoms. Findings underscore the importance of considering children's discrete emotion regulation strategy repertoires to more fully characterize the dysregulated affective processes associated with psychopathology in childhood. (PsycINFO Database Record PMID- 29239638 TI - Empathy trumps prejudice: The longitudinal relation between empathy and anti immigrant attitudes in adolescence. AB - Although research has shown the effects of empathy manipulations on prejudice, little is known about the long-term relation between empathy and prejudice development, the direction of effects, and the relative effects of cognitive and affective aspects of empathy. Moreover, research has not examined within-person processes; hence, its practical implications are unclear. In addition, longitudinal research on development of prejudice and empathy in adolescence is still scarce. This 3-wave study of adolescents (N = 574) examined a longitudinal, within-person relation between empathy and anti-immigrant attitudes. The "standard" cross-lagged model showed bidirectional effects between empathic concern, perspective taking, and anti-immigrant attitudes. In contrast, the Random-Intercept Cross-Lagged Panel Model showed that only perspective taking directly predicted within-person changes in anti-immigrant attitudes. Empathic concern predicted within-person changes in anti-immigrant attitudes indirectly, via its effects on perspective taking. No effects of anti-immigrant attitudes on within-person changes in empathy were found. The relations between empathic concern, perspective taking, and anti-immigrant attitudes were significant at the between-person level. In addition, the results showed changes in anti-immigrant attitudes and perspective taking and a change in empathic concern in mid- but not late adolescence. The results provide strong evidence for the effects of perspective taking on development of anti-immigrant attitudes in adolescence. They also suggest that the link between empathic concern and adolescents' anti immigrant attitudes can be explained by indirect, within-person effects and by between-person differences. The findings suggest that programs aimed at reducing anti-immigrant attitudes in adolescence should work more closely with youth perspective taking and empathic concern. (PsycINFO Database Record PMID- 29239639 TI - Future planning in preschool children. AB - The capacity to plan ahead and provide the means for future ends is an important part of human practical reasoning. When this capacity develops in ontogeny is the matter of an ongoing debate. In this study, 4- and 5-year-olds performed a future planning task in which they had to create the means (a picture of a particular object, e.g., a banana) that was necessary to address a future end (of completing a game in which such a picture was missing). Children of both ages drew more targets than children in a control condition in which there was no future end to be pursued. Along with prior findings, the results suggest a major progression in children's future thinking between 3 and 5 years. Our findings expand on prior knowledge by showing that young children cannot only identify the probate means to future ends but determine such ends and create the means to achieve them, thus offering compelling evidence for future planning. (PsycINFO Database Record PMID- 29239640 TI - Bad behavior keeps you up at night: Counterproductive work behaviors and insomnia. AB - Drawing from recent research on counterproductive work behaviors (CWB) and moral self-regulation literature, we examine the intraindividual consequences of engaging in CWB. We posit that CWB represents morally discrediting work behaviors that can lead to moral deficits, create distress for perpetrators and ultimately result in insomnia. Specifically, we hypothesized that on days in which employees engage in CWB, they will tend to experience moral deficits and heightened levels of rumination that undermine their sleep that night. Moreover, we hypothesized that these effects will be stronger for those who are high in moral identity internalization. Data from 2 within-individual field studies and 1 experimental study provided consistent support for most of our hypotheses. Overall, we found that by engaging in CWB employees can create problems for their own sleep health. (PsycINFO Database Record PMID- 29239641 TI - Further understanding incivility in the workplace: The effects of gender, agency, and communion. AB - Research conducted on workplace incivility-a low intensity form of deviant behavior-has generally shown that women report higher levels of incivility at work. However, to date, it is unclear as to whether women are primarily treated uncivilly by men (i.e., members of the socially dominant group/out-group) or other women (i.e., members of in-group) in organizations. In light of different theorizing surrounding gender and incivility, we examine whether women experience increased incivility from other women or men, and whether this effect is amplified for women who exhibit higher agency and less communion at work given that these traits and behaviors violate stereotypical gender norms. Across three complementary studies, results indicate that women report experiencing more incivility from other women than from men, with this effect being amplified for women who are more agentic at work. Further, agentic women who experience increased female-instigated incivility from their coworkers report lower well being (job satisfaction, psychological vitality) and increased work withdrawal (turnover intentions). Theoretical implications tied to gender and incivility are discussed. (PsycINFO Database Record PMID- 29239642 TI - Are creative individuals bad apples? A dual pathway model of unethical behavior. AB - Research has been inconsistent in its quest to discover whether dispositional creativity is associated with more or less unethical behavior. Drawing on social cognitive theory, we propose that moral disengagement and moral imagination are 2 parallel mechanisms that encourage or inhibit unethical behavior, and that which of these mediation processes occur depends on moral identity. Study 1, a 3-wave study of a food service organization, shows that employees high on both dispositional creativity and moral identity are less likely to be morally disengaged and behave less unethically. The results of Study 2 replicate Study 1's findings in a scenario-based study of college students, and further show that individuals who are high on both dispositional creativity and moral identity are more likely to be morally imaginative and to behave less unethically. Theoretical and practical implications of our model are discussed. (PsycINFO Database Record PMID- 29239643 TI - Not all differentiation is the same: Examining the moderating effects of leader member exchange (LMX) configurations. AB - Leaders often influence whether an employee stays or quits and yet research in collective turnover, or turnover at the work-unit level, has neglected leadership as a key antecedent. In the current study we examine how the quality of leader member relationships within a group (i.e., leader-member exchange, LMX) influences building a shared mindset of collective organizational commitment and ultimately influences collective turnover. We build on a key tenet of LMX theory that leaders form differentiated relationships with followers and propose that not all LMX differentiation is the same and therefore, researchers must take into account the configuration, or mix of high and low LMX relationships, within a group. We expect LMX configurations will moderate the influence of LMX differentiation on collective turnover through the mechanism of collective organizational commitment. We find 5 configurations of LMX relationships, including a bimodal, solo-status low LMX, solo-status high LMX, and 2 fragmented configurations. As hypothesized, LMX differentiation positively relates to collective organizational commitment and negatively relates to collective turnover in a solo-status low LMX configuration and a fragmented LMX configuration, and negatively relates to collective organizational commitment and positively relates to collective turnover in a bimodal configuration. Theoretical implications and future research directions are discussed. (PsycINFO Database Record PMID- 29239644 TI - The effects of team reflexivity on psychological well-being in manufacturing teams. AB - While the impact of team reflexivity (a.k.a. after-event-reviews, team debriefs) on team performance has been widely examined, we know little about its implications on other team outcomes such as member well-being. Drawing from prior team reflexivity research, we propose that reflexivity-related team processes reduce demands, and enhance control and support. Given the centrality of these factors to work-based strain, we posit that team reflexivity, by affecting these factors, may have beneficial implications on 3 core dimensions of employee burnout, namely exhaustion, cynicism, and inefficacy (reduced personal accomplishment). Using a sample of 469 unskilled manufacturing workers employed in 73 production teams in a Southern Chinese factory, we implemented a time lagged, quasi-field experiment, with half of the teams trained in and executing an end-of-shift team debriefing, and the other half assigned to a control condition and undergoing periodic postshift team-building exercises. Our findings largely supported our hypotheses, demonstrating that relative to team members assigned to the control condition, those assigned to the reflexivity condition experienced a significant improvement in all 3 burnout dimensions over time. These effects were mediated by control and support (but not demands) and amplified as a function of team longevity. (PsycINFO Database Record PMID- 29239645 TI - Keeping (future) rivals down: Temporal social comparison predicts coworker social undermining via future status threat and envy. AB - The extant social undermining literature suggests that employees envy and, consequently, undermine coworkers when they feel that these coworkers are better off and thus pose a threat to their own current status. With the present research, we draw on the sociofunctional approach to emotions to propose that an anticipated future status threat can similarly incline employees to feel envy toward, and subsequently undermine, their coworkers. We argue that employees pay special attention to coworkers' past development in relation to their own, because faster-rising coworkers may pose a future status threat even if they are still performing worse in absolute terms in the present. With a set of two behavioral experiments (N = 90 and N = 168), we establish that participants react to faster-rising coworkers with social undermining behavior when the climate is competitive (vs. less competitive). We extended these results with a scenario experiment (N = 376) showing that, in these situations, participants extrapolate lower future status than said coworker and thus respond with envy and undermining behavior. A two-wave field study (N = 252) replicated the complete moderated serial mediation model. Our findings help to explain why employees sometimes undermine others who present no immediate threat to their status. As such, we extend theorizing on social undermining and social comparison. (PsycINFO Database Record PMID- 29239646 TI - A comparison of personality in the common and Bolivian squirrel monkey (Saimiri sciureus and Saimiri boliviensis). AB - Personality has been studied in all of the great apes, many Old World monkey species, but only a handful of New World monkey species. Because understanding the personalities of New World monkeys is crucial to understanding personality evolution in primates, we used the Hominoid Personality Questionnaire to assess personality in 55 common squirrel monkeys (Saimiri sciureus) and 40 Bolivian squirrel monkeys (Saimiri boliviensis). We found 4 personality components in each species, and labeled them Openness, Neuroticism, Assertiveness, and Agreeableness. We then, in a genus-level analysis, found 5 components, which we labeled Neuroticism, Openness, Assertiveness, Agreeableness, and Decisiveness. Comparisons of the genus- and species-level structures revealed that common squirrel monkeys had a personality structure that more closely resembled the genus-level structure than did Bolivian squirrel monkeys. We then compared the personality structures of common and Bolivian squirrel monkeys with that of brown capuchin monkeys, Sapajus apella. The personality structure of Bolivian squirrel monkeys more closely resembled that of brown capuchins. These findings suggest that the Bolivian squirrel monkey personality structure is ancestral and that Assertiveness and Openness are ancestral to both the Saimiri genus and brown capuchins; Agreeableness and Neuroticism seem to be derived in Saimiri. We discuss these findings in relation to differences in the social structures and ecologies of these species. (PsycINFO Database Record PMID- 29239647 TI - The transfer of category knowledge by macaques (Macaca mulatta) and humans (Homo sapiens). AB - Cognitive psychologists distinguish implicit, procedural category learning (stimulus-response associations learned outside declarative cognition) from explicit-declarative category learning (conscious category rules). These systems are dissociated by category learning tasks with either a multidimensional, information-integration (II) solution or a unidimensional, rule-based (RB) solution. In the present experiments, humans and two monkeys learned II and RB category tasks fostering implicit and explicit learning, respectively. Then they received occasional transfer trials-never directly reinforced-drawn from untrained regions of the stimulus space. We hypothesized that implicit-procedural category learning-allied to associative learning-would transfer weakly because it is yoked to the training stimuli. This result was confirmed for humans and monkeys. We hypothesized that explicit category learning-allied to abstract category rules-would transfer robustly. This result was confirmed only for humans. That is, humans displayed explicit category knowledge that transferred flawlessly. Monkeys did not. This result illuminates the distinctive abstractness, stimulus independence, and representational portability of humans' explicit category rules. (PsycINFO Database Record PMID- 29239648 TI - The influence of reward quality and quantity and spatial proximity on the responses to inequity and contrast in capuchin monkeys (Cebus [Sapajus] apella). AB - Recent evidence within the field of comparative psychology has demonstrated that small differences in procedure may lead to significant differences in outcome. Therefore, failing to fully explore the impact of different contexts on a behavior limits our ability to fully understand that behavior. A behavior that has exhibited substantial variation, both within and across studies, is animals' responses to violations of their expectations, either when expectations were based on another's outcome (inequity) or one's previous outcome (contrast). We explored this further in capuchin monkeys, focusing on the following 2 factors that often vary in such tests but have not yet been rigorously explored: the relative values of the food rewards and the degree of separation of the subjects. Concerning the first, we examined responses to violation of expectations when the difference between what was expected (or what the partner got) and what was received differed in either quality or quantity. Concerning the second, we compared responses when the 2 individuals were separated by a clear partition (barrier condition) versus sharing the same enclosure without the partition (no barrier condition). Our results suggest that responses to inequity are most likely to emerge when the food received is low-value food, regardless of the difference between the actual and the expected outcome. However, capuchins did not respond differently to different quantities of rewards, nor did the degree of separation between subjects significantly affect results. We consider the implications of this work for both studies of violation of expectation and other cognitive and behavioral tasks. (PsycINFO Database Record PMID- 29239649 TI - Goal-directed tail use in Colombian spider monkeys (Ateles fusciceps rufiventris) is highly lateralized. AB - Behavioral laterality refers to a bias in the use of one side of the body over the other and is commonly studied in paired organs (e.g., hands, feet, eyes, antennae). Less common are reports of laterality in unpaired organs (e.g., trunk, tongue, tail). The goal of the current study was to examine tail use biases across different tasks in the Colombian spider monkey (Ateles fusciceps rufiventris) for the first time (N = 14). We hypothesized that task context and task complexity influence tail laterality in spider monkeys, and we predicted that monkeys would exhibit strong preferences for using the tail for manipulation to solve out-of-reach feeding problems, but not for using the tail at rest. Our results show that a subset of spider monkeys solved each of the experimental problems through goal-directed tail use (N = 7). However, some tasks were more difficult than others, given the number of monkeys who solved the tasks. Our results supported our predictions regarding laterality in tail use and only partially replicated prior work on tail use preferences in Geoffroy's spider monkeys (Ateles geoffroyi). Overall, skilled tail use, but not resting tail use, was highly lateralized in Colombian spider monkeys. (PsycINFO Database Record PMID- 29239650 TI - Exploring the solitaire illusion in guppies (Poecilia reticulata). AB - The solitaire illusion is a numerosity illusion that occurs when the spatial arrangement of items influences quantity estimation. To date, this illusion has been reported in monkeys, although it seems to be weaker compared with its prevalence in humans, and no study has investigated whether nonprimate species perceive it. In the present work, we asked whether a more distantly related species, fish, perceived the solitaire illusion. To achieve this goal, adult guppies (Poecilia reticulata) were trained to select the array containing the larger quantity of black dots in the presence of 2 mixed arrays containing white and black dots. After reaching the learning criterion, guppies were presented with novel dot quantities, including test trials with 2 solitaire arrangements. The overall performance of the subjects indicated that they perceived the illusion, although analyses at the individual level indicated interindividual differences. These results align with recent evidence from nonhuman primates suggesting that distantly related species also may perceive this illusion, even though numerosity misperception arising from the solitaire arrangement appears to be less robust than in human and nonhuman primates. (PsycINFO Database Record PMID- 29239651 TI - Working memory facilitates insight instead of hindering it: Comment on DeCaro, Van Stockum, and Wieth (2016). AB - The "nothing-special" account of insight predicts positive correlations of insight problem solving and working memory capacity (WMC), whereas the "special process" account expects no, or even negative, correlations. In the latter vein, DeCaro, Van Stockum Jr., and Wieth (2016) have recently reported weak negative WMC correlations with 2 constraint relaxation matchstick problems and 3 insight problems, and thus they claim that WM hinders insight. Here, we report on 3 studies that investigated WMC and various matchstick and classical problems (including 1 study that precisely replicated DeCaro et al.'s procedure). All 3 studies yielded moderate positive correlations of WMC with both the constraint relaxation and the classical problems. WMC explained 10% variance in problem solving, no matter what problems were used or how they were applied. Thus, DeCaro et al.'s claim that WM hinders insight is unwarranted. The opposite is true: WM facilitates insight. (PsycINFO Database Record PMID- 29239652 TI - The relationship between working memory and insight depends on moderators: Reply to Chuderski and Jastrzebski (2017). AB - Chuderski and Jastrzebski (2017) found a positive relationship between working memory capacity and insight problem solving, and concluded that "people with less effective cognition" are therefore "less creative" (p. 2003). This interpretation discounts substantial evidence that devoting less executive control facilitates insight. We develop an initial framework for understanding these contradictory findings. We describe (a) how both working memory-demanding processes and less demanding associative processes impact insight and (b) how individual, situational, and task-specific factors interact to influence whether greater working memory is a help or a hindrance. We propose that insight will be supported if the level of executive control used matches the level of control optimal for different phases of insight problem solving. We use this framework to explain why Chuderski and Jastrzebski's (2017) findings may have differed from DeCaro, Van Stockum, and Wieth (2016), and offer direction for a more unified account of insight problem solving. (PsycINFO Database Record PMID- 29239653 TI - Magical thinking decreases across adulthood. AB - Magical thinking, or illogical causal reasoning such as superstitions, decreases across childhood, but almost no data speak to whether this developmental trajectory continues across the life span. In four experiments, magical thinking decreased across adulthood. This pattern replicated across two judgment domains and could not be explained by age-related differences in tolerance of ambiguity, domain-specific knowledge, or search for meaning. These data complement and extend findings that experience, accumulated over decades, guides older adults' judgments so that they match, or even exceed, young adults' performance. They also counter participants' expectations, and cultural sayings (e.g., "old wives' tales"), that suggest that older adults are especially superstitious. (PsycINFO Database Record PMID- 29239654 TI - Spousal preferences for joint retirement: Evidence from a multiactor survey among older dual-earner couples. AB - The general assumption in past research on coupled retirement is that men and women prefer joint retirement. The current study tests this assumption and hypothesizes that preferences to retire jointly are associated with (a) the work and relationship attachment of both members of the couple, and (b) the respective spouse's preferences. The results show that the majority of dual-earner couples have no preference for joint retirement. Male and female spouses with either weak work attachment or strong relationship attachment are more likely to prefer to retire jointly. Moreover, spouses strongly influence each other's preferences. (PsycINFO Database Record PMID- 29239655 TI - Music to my ears: Age-related decline in musical and facial emotion recognition. AB - We investigated young-old differences in emotion recognition using music and face stimuli and tested explanatory hypotheses regarding older adults' typically worse emotion recognition. In Experiment 1, young and older adults labeled emotions in an established set of faces, and in classical piano stimuli that we pilot-tested on other young and older adults. Older adults were worse at detecting anger, sadness, fear, and happiness in music. Performance on the music and face emotion tasks was not correlated for either age group. Because musical expressions of fear were not equated for age groups in the pilot study of Experiment 1, we conducted a second experiment in which we created a novel set of music stimuli that included more accessible musical styles, and which we again pilot-tested on young and older adults. In this pilot study, all musical emotions were identified similarly by young and older adults. In Experiment 2, participants also made age estimations in another set of faces to examine whether potential relations between the face and music emotion tasks would be shared with the age estimation task. Older adults did worse in each of the tasks, and had specific difficulty recognizing happy, sad, peaceful, angry, and fearful music clips. Older adults' difficulties in each of the 3 tasks-music emotion, face emotion, and face age were not correlated with each other. General cognitive decline did not appear to explain our results as increasing age predicted emotion performance even after fluid IQ was controlled for within the older adult group. (PsycINFO Database Record PMID- 29239656 TI - Attentional effects of hand proximity occur later in older adults: Evidence from event-related potentials. AB - Research with young adults has shown hand proximity biases attention both early (by the time stimuli are categorized as relevant for action) and later, selectively for goal-relevant-stimuli. We examined age-related changes in this multisensory integration of vision and proprioception by comparing behavior and event-related potentials (ERPs) between younger and older adults. In a visual detection task, the hand was placed near or kept far from target and nontarget stimuli matched for frequency and visual features. Although a behavioral hand proximity effect-faster response times for stimuli appearing near the hand-was found for both age groups, a proportionately larger effect was found for younger adults. ERPs revealed age-related differences in the time course of the hand's effect on visual processing. Younger adults showed selective increases in contralateral N1 and parietal P3 amplitudes for targets near the hand, but older adults only showed hand effects at the P3 which were accompanied by concurrent neural activity in bilateral frontal regions. This neural pattern suggests that compared with younger adults, older adults may produce the behavioral hand proximity effect by integrating hand position and visual inputs relying more on later, task-related, frontal attentional mechanisms and less on early, posterior, multisensory integration. (PsycINFO Database Record PMID- 29239657 TI - Age-differences in the temporal properties of proactive interference in working memory. AB - The inability to suppress irrelevant information has been suggested as a primary cause of proactive interference (PI), and this deficit may be enhanced in aging. The current study examines age differences and temporal boundaries of PI, by manipulating lure distances in a verbal 2-back working memory task. Both younger and older adults showed effects of interference for proximal 3- and 4-back lures, and this effect was greater for older adults. Whereas younger adults showed less interference during 4-back compared to 3-back lures, in both reaction times and accuracy, older adults improved only in accuracy. For distant lures, when the time between the 1st presentation of an item to its reappearance as a lure item was longer (e.g., 5- to 10-back lures), younger adults were no longer affected by PI. However, older adults were affected by PI throughout all distant lures, up to the most distant lure (9-/10-back). The results suggest that older adults were less successful in resolving interference from both proximal and distant familiar lures. Further, younger adults were able to overcome the effects of PI completely after a specific lure distance. The age differences in temporal properties of PI may therefore highlight a unique component linked to impaired interference control and aging. (PsycINFO Database Record PMID- 29239658 TI - Working memory training in older adults: Bayesian evidence supporting the absence of transfer. AB - The question of whether working memory training leads to generalized improvements in untrained cognitive abilities is a longstanding and heatedly debated one. Previous research provides mostly ambiguous evidence regarding the presence or absence of transfer effects in older adults. Thus, to draw decisive conclusions regarding the effectiveness of working memory training interventions, methodologically sound studies with larger sample sizes are needed. In this study, we investigated whether or not a computer-based working memory training intervention induced near and far transfer in a large sample of 142 healthy older adults (65 to 80 years). Therefore, we randomly assigned participants to either the experimental group, which completed 25 sessions of adaptive, process-based working memory training, or to the active, adaptive visual search control group. Bayesian linear mixed-effects models were used to estimate performance improvements on the level of abilities, using multiple indicator tasks for near (working memory) and far transfer (fluid intelligence, shifting, and inhibition). Our data provided consistent evidence supporting the absence of near transfer to untrained working memory tasks and the absence of far transfer effects to all of the assessed abilities. Our results suggest that working memory training is not an effective way to improve general cognitive functioning in old age. (PsycINFO Database Record PMID- 29239660 TI - Detection of biomarkers of acute myocardial infarction by high-throughput suspension array technology in serum sample. AB - AIM: In order to assist and support early diagnosis of acute myocardial infarction (AMI), suspension array technology was established for multiplexed, rapid and accurate measurement of AMI biomarkers in serum samples. Methodology & results: It was developed by coating AMI biomarkers on distinguishable microbeads and competing with free biomarkers for complementary antibodies. The limits of detection of three AMI biomarkers were 2.5- to 50-times lower than that of the previous methods and the working ranges were four to five orders of magnitude. Accuracy and stability also met satisfying acceptance criteria in both of the intra- and interbatch testing. The variation coefficients and relative standard deviations were all less than 10%. CONCLUSION: Suspension array technology is completely applicable for requirements of rapid clinical diagnosis in serum sample. PMID- 29239659 TI - Characteristics, Properties and Analytical Methods of Paclitaxel: A Review. AB - Paclitaxel is a diterpenoid pseudoalkaloid, isolated from Taxus brevifolia, and is largely used as an antitumoral drug. The formulation of paclitaxel known as Taxol(r) employs a mixture of Cremophor EL and dehydrated ethanol, due the low drug water solubility. However, Taxol(r) causes some unwanted side effects due to the presence of Cremophor EL and ethanol in the formulation. Based on this, there is a need for the development of drug delivery systems to enhance the solubility, permeability and stability of paclitaxel and to promote a controlled and targeted delivery for better therapeutic effect and reduced side effects. In addition, the drug has been qualitatively and quantitatively analyzed in different delivery systems. In this context, several approaches were reported focusing on the optimization of analytical methods and development of new ones, considering the need of a fast, simple, with enough sensibility and selectivity assay, which can be a problem in some analysis. This review presents a summary of methods used in quantification of paclitaxel in different matrices, such as plasma, urine, plant extract, cells and delivery systems. PMID- 29239661 TI - Enhancement of the antimycobacterial activity of macrophages by ajoene. AB - Ajoene, a garlic-derived sulfur-containing compound, has broad-spectrum antimicrobial activity. To assess the potential of ajoene for treating tuberculosis (TB), we determined whether it induces the stress response of the endoplasmic reticulum (ER), which plays an important role in TB. We showed that ajoene stimulation induced the production of ER stress sensor molecules and reactive oxygen species (ROS) levels. Ajoene-induced ROS production was dependent on c-Jun N-terminal kinase (JNK) activation. Interestingly, the inhibition of JNK activity and suppression of ROS production reduced ajoene-induced CHOP production in macrophages. Because ER stress activates autophagy, the activation of which suppresses the growth of mycobacteria, we investigated the ajoene-induced production of autophagy-related factors, including LC3-II, P62 and Beclin-1. As expected, ajoene treatment increased the levels of these factors in RAW 264.7 cells. Remarkably, the total amount of Mycobacterium tuberculosis (Mtb) H37Rv was significantly reduced in ajoene-treated RAW 264.7 cells. The treatment of macrophages with ajoene resulted in the activation of JNK, induction of ROS synthesis and accumulation of ROS, possibly leading to the activation of ER stress and autophagy. These results reveal the mechanism of the antimycobacterial effects of ajoene against Mtb H37Rv. Our findings might facilitate the development of novel therapies for patients with TB. PMID- 29239662 TI - The effect of electronic health records on patient safety: A qualitative exploratory study. AB - BACKGROUND: Electronic health records (EHRs) are increasingly used in healthcare settings and it is believed that they have brought benefits to patients and healthcare services alike. Few previous studies, however, have explored the impact of these records on patient safety. AIM: The overall purpose of this study was to explore the effect of EHRs on patient safety, as perceived by nurses. METHODS: This qualitative exploratory study was conducted using semi-structured interviews with staff nurses working in hospitals that employed the same EHR system in Jordan. Seventeen nurses were interviewed working in various units and wards of ten hospitals which had used EHRs between 1 and 5 years. Field notes were taken during interviews and analyzed thematically. RESULTS: Two major themes emerged from the data. One regarded the enhancements that EHRs have made to patient safety; and the other surrounded concerns raised by the use of these systems. Under each main theme there were four subthemes. EHRs directly or indirectly improved patient safety by minimizing medication errors, improving documentation of data, enhancing the completeness of data, and improving the sustainability of data. The interviewees expressed concern that the following may jeopardize patient safety: data entry errors, technical problems, minimal clinical alerts, and poor use of system communication channels. CONCLUSION: A range of opinions were reported by the interviewees, from being fully supportive of EHRs to being reluctant to agree with the idea that they can improve patient safety. However, the concerns raised by the interviewees might be associated with poor system design or improper human use of the system. Thus, it is necessary to design systems with specifications that support patient safety and, moreover, involving nurses in this process might facilitate this outcome. PMID- 29239663 TI - Laser desorption/ionization MS imaging of cancer kidney tissue on silver nanoparticle-enhanced target. AB - AIM: Renal cell carcinoma is a very aggressive and often fatal disease for which there are no specific biomarkers found to date. The purpose of work was to find substances that differentiate the cancerous and healthy tissue by using laser desorption/ionization MS imaging combined with silver nanoparticle-enhanced target. RESULTS: Ion images and comparative analysis of spectra revealed differences in intensities for several metabolites, for which their biochemical properties were discussed. Statistical analysis allowed to distinguish healthy and cancer tissue without the involvement of a pathologist. CONCLUSION: Laser desorption/ionization MS imaging technology combined with silver nanoparticle enhanced target enabled rapid visualization of the differences between the clear cell renal cell carcinoma and the healthy part of the kidney tissue. PMID- 29239664 TI - Efficacy and safety of twice daily sustained-release paracetamol formulation for osteoarthritis pain of the knee or hip: a randomized, double-blind, placebo controlled, twelve-week study. AB - OBJECTIVE: Evaluate efficacy and safety of an investigational, twice daily sustained-release (SR) paracetamol formulation in subjects with knee or hip osteoarthritis (OA). METHODS: In this multicenter, double-blind, parallel study (NCT02311881), subjects with hip or knee OA were randomly assigned to SR paracetamol 2 * 1000 mg BID, extended-release (ER) paracetamol 2 * 665 mg TID or placebo for 12 weeks. Primary endpoint was mean change from baseline through 12 weeks in WOMAC Osteoarthritis Index pain. Secondary efficacy endpoints included other WOMAC categories, Global Patient Assessment of Osteoarthritis (GPAOA), Patient Global Assessment of Response to Therapy (PGART) and responder rate. RESULTS: A total of 676 subjects were included in the analysis population (mITT). Mean change from baseline in WOMAC pain subscale was not significantly greater with SR paracetamol BID versus placebo (LS mean [SE]: -28.25 [1.697] vs. -25.74 [1.713]; p = .163). Reduction in WOMAC physical function and stiffness subscales with SR paracetamol BID was not significantly greater than with placebo (p = .089 and .054, respectively). Significant improvement over placebo was observed for GPAOA (p = .043), PGART (p = .012), and proportion of high-improvement responders (p = .015). Safety and tolerability were consistent with the known profile of paracetamol. CONCLUSIONS: Improvement in WOMAC pain, physical function and stiffness subscales from treatment with SR paracetamol BID versus placebo in subjects with knee or hip OA was not significant. SR paracetamol BID demonstrated significant improvements in GPAOA, PGART, and high-responder rate. High placebo response may have contributed to lack of statistical separation on some outcomes. All interventions were generally well tolerated. PMID- 29239665 TI - Health and hierarchy: soldiers, civilians and mental healthcare in Scotland, 1914 34. AB - During the First World War injured servicemen were constructed as a better class of patient than civilians, and their care was prioritized in social and political discourses. For the mentally disordered servicemen themselves, however, these distinctions were permeable and transient. This article will challenge the reality of the 'privileged' service patient in civil asylums in Scotland. By examining the impact of the war on asylum structures, economies and patient health, this study will explore exactly which patients were valued in these difficult years. In so doing, this paper will also reveal how the lives of institutionalized ex-servicemen and the civilian insane inside district asylums were not quite as distinct as political and social groups would have liked. PMID- 29239666 TI - Highly selective and sensitive measurement of active forms of FGF21 using novel immunocapture enrichment with LC-MS/MS. AB - AIM: Recombinant FGF21 analogs are under wide ranging investigations as a potential therapeutic agent for Type 2 diabetes, as well as other metabolic disorders. The endogenous FGF21 is often used as a surrogate pharmacodynamic(PD) biomarker to assess drug efficacy and safety. Results & methodology: Immunocapture was performed using a monoclonal antibody which had been generated to bind to specific domain of native FGF21 as the capture reagent. After immunocapture, enzymatic digestion was performed and a native FGF21-specific tryptic peptide was monitored using LC-MS/MS by selective reaction monitoring. CONCLUSION: We have successfully developed and validated a bioanalytical assay which provides the specificity to differentiate the endogenous FGF21 from the recombinant therapeutic agent which has nearly identical sequence to the endogenous molecule. PMID- 29239667 TI - The prevalence of radiological glenohumeral osteoarthritis in long-term type 1 diabetes: the Dialong shoulder study. AB - OBJECTIVES: This study compares the prevalence of radiological osteoarthritis (OA) in patients with type 1 diabetes mellitus (DM1) for > 45 years and controls, and explores the association with shoulder pain and glycaemic burden in patients with DM1. METHOD: The Dialong study is a cross-sectional, observational study with 30 years of historical data on long-term glycaemic control. We included 102 patients with DM1 and 73 diabetes-free controls. Demographic data, worst shoulder pain last week [numeric rating scale (NRS) 0-10], pain on abduction at examination (NRS 0-10), and current and historical glycosylated haemoglobin (HbA1c) levels were collected. Standardized shoulder X-rays were taken and interpreted for OA applying the Kellgren-Lawrence classification. RESULTS: In the diabetes group (49% women), the mean +/- sd duration of DM1 was 50.6 +/- 4.8 years, mean 30 year HbA1c 7.4%, and age 61.9 +/- 7.1 years. The mean age of controls (57% women) was 62.6 +/- 7.0 years. Radiological glenohumeral OA was found in 36 diabetes patients (35%) and 10 controls (14%) [odds ratio (OR) 3.4, 95% confidence interval (CI) 1.6 to 7.5; p = 0.002]. Few persons had moderate and severe OA [6.9% vs 1.3%, OR 5.3 (95% Cl 0.6 to 44.1); p = 0.1]. Fifteen diabetes patients had painful OA versus two controls (adjusted OR 5.4, 95% CI 0.6 to 47.9; p = 0.13). There was no association between OA and long-term glycaemic burden (mean 30 year HbA1c) in the diabetes group (p > 0.2). CONCLUSIONS: Radiological glenohumeral OA was more common in patients with DM1 than in controls for mild, but not moderate and severe OA. The radiological findings were not associated with shoulder pain or long-term glycaemic burden. PMID- 29239669 TI - In real news, we may be facing a doctor exodus. PMID- 29239672 TI - The theory of the NHS. PMID- 29239673 TI - International health partnerships and mutual learning. PMID- 29239674 TI - Cushny and Peebles, optical isomers and the birth of modern statistics. PMID- 29239676 TI - Bleaching of sugar cane juice using a food-grade adsorber resin and explained by a kinetic model describing the variation in time of the content of adsorbate. AB - This work studies the adsorption of colored compounds in cane juice using a food grade macroporous adsorber resin without functional groups. The adsorption equilibrium was studied through the adsorption isotherms at 30, 40, and 50 C. The absorbance at 420 nm was used to measure the concentration of colored compounds, which enables correlation of the residual concentration with the adsorbed concentration. Furthermore, the efficiency of the adsorption process was studied, from which it was observed that there was an improvement in efficiency with increasing resin content, while the increase in temperature was less important in the process. The kinetic study was performed using the Ibarz model and intraparticle diffusion model, which correctly account for the kinetics of the adsorption process. The adsorption kinetic constant was always greater than the desorption kinetic constant, indicating that the adsorption step predominates over the desorption step. PMID- 29239677 TI - Effects of Kinect Adventures Games Versus Conventional Physical Therapy on Postural Control in Elderly People: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the effectiveness of Kinect Adventures games versus conventional physiotherapy to improve postural control (PC), gait, cardiorespiratory fitness, and cognition of the elderly. In addition, we evaluated the safety, acceptability, and adherence to the interventions. MATERIALS AND METHODS: The study was a randomized clinical trial in which 46 elderly individuals were selected, mean age 69.3 (5.34) years. Participants were allocated to the Kinect Adventures Training Group (KATG) or the Conventional Physical Therapy Group (CPTG), 23 individuals in each group. Participants of both groups participated in 14 training sessions lasting 1 hour each, twice a week. The KATG practiced four Kinect Adventures games. The CPTG participated in conventional physiotherapy. The primary outcome was PC: Mini-Balance Evaluation Systems Test (Mini-BESTest), and secondary outcomes were gait: Functional Gait Assessment (FGA), cardiorespiratory fitness: Six-minute step test (6MST), and cognition: Montreal Cognitive Assessment (MoCA). Acceptability was assessed through a questionnaire created by the researchers themselves. Adherence was assessed by the "frequency of the number of elderly individuals who completed the interventions and safety through the presence of adverse effects." Participants were assessed immediately pre- and posttreatment and fourth week after the end of the treatment. Statistical analysis was done through repeated-measures analysis of variance and Tukey post hoc test. RESULTS: Both groups presented a significant improvement in the PC (Mini-BEST), gait (FGA), and cognition (MoCA) posttreatment that was maintained at fourth week after treatment (post hoc Tukey test; P < 0.05). Regarding cardiorespiratory fitness (6MST), the KATG presented improvement posttreatment and maintenance of the results in the fourth week after treatment. CPTG showed improvement only in fourth week after treatment (post hoc Tukey tests; P < 0.05). Regarding the acceptability, the questionnaire showed that both groups were satisfied with regard to the proposed interventions. There was 91% adherence in both training sessions. Regarding the safety, 34% and 26% of the individuals of the KATG and CPTG, respectively, presented adverse effects of delayed muscle pain in the lower limbs after the first session only. CONCLUSION: There were no significant differences between the KATG and CPTG; both interventions provided positive effects on PC, gait, cardiorespiratory fitness, and cognition of the elderly. PMID- 29239678 TI - The effect of antibiotic prophylaxis for acute pelvic inflammatory disease after hysterosalpingography: a retrospective cohort study. AB - AIMS: Concerns about acute pelvic inflammatory disease (PID) after hysterosalpingography (HSG) have been raised since 1980. However, the effectiveness of prophylactic antibiotics remains unclear. This study investigated the effect of antibiotic prophylaxis in women undergoing HSG. METHODS: Women undergoing HSG between 2000 and 2012 were screened from the Taiwan National Health Insurance Research Database for eligibility. The prophylactic cohort included patients using any antibiotics of 1st-generation cephalosporins, doxycycline, clindamycin, and metronidazole, within 7 days before HSG (n = 3257). Patients not using any antibiotics were registered as the non-prophylactic cohort (n = 4662). An unconditional logistic regression model was applied to calculate the odds ratio (OR) and 95% confidence interval (CI) of acute PID after HSG associated with prophylactic antibiotics. RESULTS: The cumulative incidences of acute PID after HSG were 0.46% and 1.42% in the prophylactic and non-prophylactic cohorts, respectively. Prophylactic patients had a significantly reduced estimated relative risk of acute PID compared with non-prophylactic patients (adjusted OR = 0.33, 95% CI = 0.19-0.58; p = .001). Doxycycline users had the lowest adjusted OR of 0.20 (95% CI = 0.04-0.81; p = .02), followed by users of 1st-generation cephalosporins (adjusted OR = 0.35, 95% CI = 0.18-0.68; p = .002). Multivariate sub-group analysis verified this protective effect for almost all sub-groups of prophylactic patients. CONCLUSIONS: Antibiotic prophylaxis is associated with a decreased estimated relative risk of acute PID in HSG patients. Doxycycline and 1st-generation cephalosporins may be effective prophylactic regimens for HSG. PMID- 29239679 TI - Primary care variability in patients at higher risk for colorectal cancer: evaluation of screening and preventive care practices. AB - OBJECTIVE: Sub-optimal colorectal cancer (CRC) evaluations have been attributed to both physician and patient factors. The primary objective of this study was to evaluate physician practice variation in patients with a higher risk of CRC. We wanted to identify the physician characteristics and the types of patients that were associated with missed screening opportunities; we also explored whether screening for CRC served as a proxy for better preventive care practices. METHODS: A total of 213 board-certified family and internal medicine physicians participated in the study, conducted between September and December 2016. We used Clinical Performance and Value (CPV(r)) vignettes, simulated patients, to collect data on CRC screening. The CPV patients presented with a typical range of signs and symptoms of potential CRC. The care provided to the simulated patients was scored against explicit evidence-based criteria. The main outcome measure was rate a diagnostic CRC workup was ordered. This data quantified the clinical practice variability for CRC screening in high risk patients and other preventive and screening practices. RESULTS: A total of 81% of participants ordered appropriate CRC workup in patients at risk for CRC, with a majority (71%) selecting diagnostic colonoscopy over FIT/FOBT. Only 6% of physicians ordering CRC workup, however, counseled patients on their higher risk for CRC. The most commonly recognized symptoms prompting testing were unexplained weight loss or inadequate screening history, while the least recognized symptoms of CRC risk were abdominal discomfort found on review of systems. CONCLUSION: This study shows that primary care physician screening of CRC varies widely. Those physicians who successfully screened for CRC were more likely to complete other prevention and screening practices. PMID- 29239680 TI - The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology. AB - PURPOSE: To present a semiquantitative ocular scoring system comprising elements and criteria that address many of the limitations associated with systems commonly used in preclinical studies, providing enhanced cross-species applicability and predictive value in modern ocular drug and device development. METHODS: Revisions to the ocular scoring systems of McDonald-Shadduck and Hackett McDonald were conducted by board-certified veterinary ophthalmologists at Ocular Services On Demand (OSOD) over the execution of hundreds of in vivo preclinical ocular drug and device development studies and general toxicological investigations. This semiquantitative preclinical ocular toxicology scoring (SPOTS) system was driven by limitations of previously published systems identified by our group's recent review of slit lamp-based scoring systems in clinical ophthalmology, toxicology, and vision science. RESULTS: The SPOTS system provides scoring criteria for the anterior segment, posterior segment, and characterization of intravitreal test articles. Key elements include: standardized slit lamp settings; expansion of criteria to enhance applicability to nonrabbit species; refinement and disambiguation of scoring criteria for corneal opacity, fluorescein staining severity, and aqueous flare; introduction of novel criteria for scoring of aqueous and anterior vitreous cell; and introduction of criteria for findings observed with drugs/devices targeting the posterior segment. A modified Standardization of Uveitis Nomenclature (SUN) system is also introduced to facilitate accurate use of SUN's criteria in laboratory species. CONCLUSIONS: The SPOTS systems provide criteria that stand to enhance the applicability of semiquantitative scoring criteria to the full range of laboratory species, in the context of modern approaches to ocular therapeutics and drug delivery and drug and device development. PMID- 29239682 TI - Safety and immunogenicity of a seasonal trivalent inactivated split influenza vaccine: a phase I randomized clinical trial in healthy Serbian adults. AB - This study was a phase I double-blind, randomized, placebo-controlled trial to evaluate the safety and immunogenicity of a Serbian-produced seasonal trivalent split, inactivated influenza vaccine in healthy adults. The vaccine was manufactured in eggs by the Torlak Institute of Virology, Vaccines and Sera, Belgrade, Serbia and contained A/H1N1, A/H3N2 and B viruses. The clinical trial took place at the Clinical Center of Serbia in Belgrade. Sixty healthy volunteers, aged 18-45 years, were enrolled in the trial. On the day of immunization, volunteers were randomly assigned to receive either a single dose of the trivalent seasonal influenza vaccine (15 MUg of hemagglutinin per strain) or placebo (phosphate-buffered saline). Subjects were monitored for adverse events through a clinical history and physical examination, and blood was taken for testing at screening and on day 8 to assess vaccine safety. Serum samples obtained before and 21 days after immunization were tested for influenza antibody titers using hemagglutination-inhibition (HAI) and microneutralization (MN) tests. No serious adverse events were reported. Pain and tenderness at the injection site were the most commonly reported symptoms in both vaccine and placebo groups. Overall, serum HAI responses of fourfold or greater magnitude were observed to H1, H3, and B antigen in 80%, 75%, and 70% of subjects, respectively. Seroprotection rates as measured by HAI were also high (100%, 100% and 86.67%, respectively, for H1, H3 and B). Thus, Torlak's seasonal trivalent influenza vaccine was not associated with adverse events, was well-tolerated and immunogenic. It should be further evaluated in clinical trials to provide sufficient safety and immunogenicity data for licensing in Serbia. PMID- 29239683 TI - Managing cancer care through service delivery networks: The role of professional collaboration in two European cancer networks. AB - Background The study examines two meso-strategic cancer networks, exploring to what extent collaboration can strengthen or hamper network effectiveness. Unlike macro-strategic networks, meso-strategic networks have no hierarchical governance structures nor are they institutionalised within healthcare services' delivery systems. This study aims to analyse the models of professional cooperation and the tools developed for managing clinical practice within two meso-strategic, European cancer networks. Methods Multiple case study design based on the comparative analysis of two cancer networks: Iridium, in Antwerp, Belgium and the Institut Catala d'Oncologia in Catalonia, Spain. The case studies applied mixed methods, with qualitative research based on semi-structured interviews ( n = 35) together with case-site observation and material collection. Results The analysis identified four levels of collaborative intensity within medical specialties as well as in multidisciplinary settings, which became both platforms for crosscutting clinical work between hubs' experts and local care teams and the levers for network-based tools development. The organisation of clinical practice relied on professional-based cooperative processes and tiers, lacking vertical integration mechanisms. Conclusions The intensity of professional linkages largely shaped the potential of meso-strategic cancer networks to influence clinical practice organisation. Conversely, the introduction of managerial techniques or network governance structures, without introducing vertical hierarchies, was found to be critical solutions. PMID- 29239684 TI - A new retrieval method for an already detached coil mass in the aneurysm sac: 'Thread and catch' technique. AB - During endovascular coiling, unexpected procedure-related complications such as coil misplacement have been reported, and these complications may induce emboli or thrombotic vessel occlusion. A malpositioned detached coil contained and immobilized within an intracranial aneurysm is difficult to remove using current methods. We report an effective retrieval technique for detached coils. The 'thread and catch technique' can be used when the malpositioned detached coil is immobilized within the aneurysm. PMID- 29239685 TI - In vitro angiographic comparison of the flow-diversion performance of five neurovascular stents. AB - Background and purpose Data differentiating flow diversion properties of commercially available low- and high-porosity stents are limited. This in vitro study applies angiographic analysis of intra-aneurysmal flow to compare the flow diversion performance of five neurovascular devices in idealized sidewall and bifurcation aneurysm models. Methods Five commercial devices (Enterprise, Neuroform, LVIS, FRED, and Pipeline) were implanted in silicone sidewall and bifurcation aneurysm models under physiological average flow of blood analog fluid. High-speed angiographic images were acquired pre- and post-device implantation and contrast concentration-time curves within the aneurysm were recorded. The curves were quantified with five parameters to assess changes in contrast transport, and thus aneurysm hemodynamics, due to each device. Results Inter-device flow-diversion performance was more easily distinguished in the sidewall model than the bifurcation model. There were no obvious overall statistical trends in the bifurcation parameters but the Pipeline performed marginally better than the other devices. In the sidewall geometry, overall evidence suggests that the LVIS performed better than the Neuroform and Enterprise. The Pipeline and FRED devices were statistically superior to the three stents and Pipeline was superior to FRED in all sidewall parameters evaluated. Conclusions Based on this specific set of experiments, lower-porosity flow diverters perform significantly better in reducing intra-aneurysmal flow activity than higher-porosity stents in sidewall-type geometries. The LVIS device is potentially a better flow diverter than the Neuroform and Enterprise devices, while the Pipeline is potentially better than the FRED. PMID- 29239686 TI - Recurrent posterior circulation infarcts secondary to vertebral artery external compression treated with endovascular deconstruction. AB - When multiple, recurrent infarcts occur in spite of maximal medical management, the level of suspicion for atypical vascular injury should be heightened. We present a case of a patient who presented with recurrent posterior circulation infarcts despite optimized medical management. On imaging, he was found to have external anatomical vertebral artery muscular and/or osseous compression leading to repetitive vascular injury and strokes. Recurrent intimal injury and vertebral artery to intracranial emboli despite anticoagulation and subsequent dual antiplatelet therapy necessitated definitive operative management. Surgical bypass, external surgical decompression, reconstructive endovascular, and deconstructive endovascular techniques were carefully considered. A deconstructive endovascular approach was chosen as the least morbid option. The use of endovascular plugs such as a microvascular plug provides a quick and effective means of achieving a therapeutic parent artery occlusion in lieu of traditional coil occlusion. Although reserved as a last resort, parent artery occlusion can be a viable option to treat recurrent strokes, particularly in a nondominant vertebral artery. PMID- 29239687 TI - Open-cell stent and use of cone-beam CT enables a safe and effective coil embolization of true ophthalmic artery and anterior choroidal artery aneurysms with preservation of parent vessel: Clinical and angiographic results. AB - Background Treatment of true ophthalmic artery (OA) or anterior choroidal artery (AChA) aneurysms with preservation of the parent vessel may be challenging. Flow diverters have limitations when dealing with branch vessels arising from the aneurysm sac. Visual loss or AChA territory infarcts have been reported both for surgical and endovascular treatment. Methods We evaluated the safety and efficacy of an open-cell design, laser-cut, self-expanding Nitinol stent, and use of cone beam computed tomography (CBCT) for stent-assisted coil embolization. Results A total of seven patients with unruptured OA or AChA aneurysms were enrolled in this prospective small case study and the data were analyzed retrospectively. A complete obliteration was achieved in all aneurysms immediately post-intervention or at six-month follow-up without any evidence for recanalization at up to three year follow-up. All patients tolerated the procedure well and there was no change in baseline modified Rankin Scale. Conclusions Our study suggests that specific features of an open-cell stent allow a safe and effective treatment of OA or AChA aneurysms with a high technical success rate and excellent mid-term angiographic and clinical outcome. CBCT is a useful intraoperative imaging tool. PMID- 29239689 TI - An enhanced mixture method for constructing gatekeeping procedures in clinical trials. AB - It is increasingly common to encounter complex multiplicity problems with several multiplicity components in confirmatory Phase III clinical trials. These components are often based on several endpoints (primary and secondary endpoints) and several dose-control comparisons. When constructing a multiplicity adjustment in these settings, it is important to control the Type I error rate over all multiplicity components. An important class of multiple testing procedures, known as gatekeeping procedures, was derived using the mixture method that enables clinical trial sponsors to set up efficient multiplicity adjustments that account for clinically relevant logical relationships among the hypotheses of interest. An enhanced version of this mixture method is introduced in this paper to construct more powerful gatekeeping procedures for a specific type of logical relationships that rely on transitive serial restrictions. Restrictions of this kind are very common in Phase III clinical trials and the proposed method is applicable to a broad class of multiplicity problems. Several examples are provided to illustrate the new method and results of simulation trials are presented to compare the performance of gatekeeping procedures derived using this method and other available methods. PMID- 29239690 TI - Antibody-drug conjugates: Design and development for therapy and imaging in and beyond cancer, LabEx MAbImprove industrial workshop, July 27-28, 2017, Tours, France. AB - The annual "Antibody Industrial Symposium", co organized by LabEx MAbImprove, MabDesign and Polepharma, was held in Tours, France on June 27-28, 2017. The focus was on antibody-drug-conjugates (ADCs), new entities which realize the hope of Paul Ehrlich's magic bullet. ADCs result from the bioconjugation of a highly cytotoxic drug to a selective monoclonal antibody, which acts as a vector. Building on knowledge gained during the development of three approved ADCs, brentuximab vedotin (Adcetris(r)), ado trastuzumab emtansine (Kadcyla(r)) and inotuzumab ozogamicin (Besponsa(r)), and the many ADCs in development, this meeting addressed strategies and the latest innovations in the field from fundamental research to manufacturing. PMID- 29239688 TI - Compromising asymmetric stem cell division in Drosophila central brain: Revisiting the connections with tumorigenesis. AB - Asymmetric cell division (ACD) is an essential process during development for generating cell diversity. In addition, a more recent connection between ACD, cancer and stem cell biology has opened novel and highly intriguing venues in the field. This connection between compromised ACD and tumorigenesis was first demonstrated using Drosophila neural stem cells (neuroblasts, NBs) more than a decade ago and, over the past years, it has also been established in vertebrate stem cells. Here, focusing on Drosophila larval brain NBs, and in light of results recently obtained in our lab, we revisit this connection emphasizing two main aspects: 1) the differences in tumor suppressor activity of different ACD regulators and 2) the potential relevance of environment and temporal window frame for compromised ACD-dependent induction of tumor-like overgrowth. PMID- 29239691 TI - Degradation of phenol in wastewater by cathodic microarc plasma electrolysis. AB - In this paper, the cathodic microarc plasma electrolysis (CMPE) was tentatively performed to degrade the phenol in aqueous solution by vapor-gaseous envelope discharge around the Ti cathode. Degradation efficiency of phenol was measured and the intermediate products were evaluated. The suspended particles in solution were analyzed and the decomposition mechanism of phenol in the process of cathodic microarc plasma degradation was discussed. The instantaneous current efficiency reached a peak value firstly and then decreased with the discharge time. In the cathodic plasma region, the Cl substituted the hydrogen on benzene ring in the initial time, which was replaced by a hydroxyl immediately, then the polyhydroxy phenol was easily decomposed. In addition, optical emission spectroscopy was carried out to characterize the plasma features during the CMPE process. The temperature of electron around the microarc discharge envelope reached about 4000 K; thus the phenol was partly carbonized to become graphite particles. CMPE is a promising approach to degrade quickly the phenol in wastewater. PMID- 29239694 TI - A novel prenyl-polybasic domain code determines lipid-binding specificity of the K-Ras membrane anchor. AB - Ras proteins must localize to the plasma membrane (PM) for biological function. The membrane anchor of the K-Ras4B isoform comprises a farnesylated and methylated C-terminal cysteine together with an adjacent hexa-lysine polybasic domain (PBD). Traditionally, polybasic sequences have been thought to interact electrostatically with negatively charged membranes showing no specificity for anionic lipid head groups. By contrast we recently showed that the K-Ras membrane anchor actually exhibits a very high degree of specificity for phosphatidylserine (PtdSer). The selectivity for PtdSer is determined by a combinatorial code comprising the PBD sequence plus the prenyl anchor. Lipid binding specificity is therefore altered by PBD point mutations that in turn modulate signaling output. For example, mutating Lys177 or Lys178 to glutamine switches K-Ras4B lipid affinity from PtdSer to phosphoinositol 4,5-bisphosphate (PIP2). Changing the lipid anchor from farnesyl to geranylgeranyl or the PBD lysines to arginines also changes lipid binding specificity. All-atom molecular dynamics simulations reveal the structural basis for these K-Ras anchor lipid-binding preferences. Here we examine the PM interactions of a series of geranylgeranylated PBD mutants and provide further evidence that the precise PBD sequence and prenyl lipid determines lipid sorting specificity of the K-Ras anchor and hence biological function. PMID- 29239695 TI - Gender differences in romantic relationship memories: who remembers? Who cares? AB - Two studies were conducted to assess patterns of gender differences in memory for romantic relationship events. Results suggested that people believe that women have better memory for romantic relationship events than men, that better relationship memory predicts higher levels of relationship well-being, and that the association between relationship memory and relationship well-being is somewhat stronger for women than for men. Women did tend to have somewhat better relationship memory than men, as assessed via subjective reports from both partners in mixed-sex relationships, and via the number of details partners provided when asked to recall a specific relationship event (i.e., their first date). Consistent with the lay theories, both own and partner's better relationship memory predicted higher levels of relationship well-being; however, the association between better relationship memory and higher levels of relationship well-being was equally strong for both genders. Implications and future research directions are discussed. PMID- 29239696 TI - Compression garments and cerebral blood flow: Influence on cognitive and exercise performance. AB - This study aimed to describe the effect of compression garments on middle cerebral artery blood flow velocity (MCAv) in relation to cognitive and exercise performance whilst cycling. In a randomised-controlled-cross-over design, 15 well trained male cyclists were recruited to participate in three identical trials wearing loose fitting shorts (control), low-grade, or medium-grade compression garments. The protocol involved four 8 min increments of cycling at 30%, 50%, 70%, and 85% maximal power output and a 4 km time-trial. Participants undertook a cognitive Stroop task at baseline and at the midpoint of each increment. MCAv was monitored with Transcranial Doppler Ultrasonography. Mean arterial pressure (MAP) and partial pressure of end-tidal CO2 (PetCO2) were measured throughout. MCAv, MAP, PetCO2, and reaction time of the complex Stroop task were influenced by exercise intensity, but not compression garments. Compression garments significantly affected cognitive accuracy in the complex Stroop task such that low-grade compression appeared to enhance cognitive accuracy in comparison to the control condition at the highest intensity (p = .010). Time-trial performance did not differ between the control (338.0 +/- 17.3 s), low-grade (338.7 +/- 18.7 s), or medium-grade (342.2 +/- 19.3 s) conditions (p = .114). Compression garments did not affect MCAv during exercise or time-trial performance, but compression may be beneficial for improved cognitive accuracy during high-intensity exercise. Further research is required to elucidate the potential impact on cognitive performance. PMID- 29239697 TI - Who is sleepier on the night shift? The influence of bio-psycho-social factors on subjective sleepiness of female nurses during the night shift. AB - Sleepiness is a common complaint during the night shift and may impair performance. The current study aims to identify bio-psycho-social factors associated with subjective sleepiness during the night shift. Ninety-two female nurses working rotating shifts completed a sociodemographic questionnaire, the Munich ChronoType Questionaire for shift workers, the Pittsburg Sleep Quality Index, and the Pre-sleep Arousal Scale. Subjective sleepiness was measured hourly during two night shifts using the Karolinska Sleepiness Scale, and activity monitors assessed sleep duration 24-h before each shift. Findings showed that increased sleepiness was associated with increased age in nurses with early chronotypes and with more children. High cognitive pre-sleep arousal, but not sleep, was associated with increased sleepiness, especially in late chronotypes. The impact of bio-psycho-social factors on night shift sleepiness is complex, and depends on mutual interactions between these factors. Nurses most prone to increased sleepiness must develop personal strategies for maintaining vigilance on the night shift. Practitioner Summary: This study aims to identify bio-psycho social factors associated with subjective sleepiness of female nurses during the night shift. Increasing sleepiness was associated with increased age in nurses with early chronotypes and with more children. Increased cognitive pre-sleep arousal, but not sleep, was associated with increased sleepiness, especially in late chronotypes. PMID- 29239698 TI - Editorial Board Page: EOV. PMID- 29239699 TI - Nucleosides 9: Design and synthesis of new 8-nitro and 8-amino xanthine nucleosides of expected biological activity. AB - The coupling reaction of 1,3-dimethylxanthine (theophylline), 3-benzylxanthine and 3-benzyl-1-methylxanthine with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D ribofuranose afforded the corresponding protected nucleosides, respectively. Nitration of each of the theophylline and 3-benzy-1-methyllxanthine protected nucleosides yielded the corresponding 8-nitronucleosides derivatives, which were reduced to give the corresponding 8-aminonucleoside derivatives. Debenzoylation of protected nucleosides formed by using methanolic sodium methoxide afforded the corresponding free N-nucleosides, respectively. The structures of products have been elucidated and reported and also some of the products were screened for their antimicrobial activity. Some of tested products showed moderate activity. PMID- 29239700 TI - Blood transfusion: devil and God: co-existing. PMID- 29239701 TI - Variations on the Migratory Theme: Immigrants or Exiles, Refugees or Asylees. AB - When a country is engulfed in war, or overrun by a dictator who begins killing, its citizens are forced to flee. In such situations, the only compassionate response is to take people in. With the ongoing mass migration to Europe, these refugees pay smugglers to take them to safety, but there is no safe place to go since nobody wants them. They leave in a rush to save their lives and their families due to political and religious fear, death threats, rape of women, or forced labor. They do not have time to mourn the losses, there is no time for "ideal migration" where destination countries can choose whom they will take in. The initial hope and dream to escape to a safe "haven" is transformed into a nightmare of humiliation and fear. These asylum seekers will be or already are suffering from PTSD due to massive psychic trauma. PMID- 29239702 TI - A Brief Introduction to Mass Migration: Then and Now. AB - To provide a context, this introduction presents a bird's-eye view of migration history, of some differences between voluntary and forced motivation for leaving home territories, and the significance of large group relocations.(mass migrations). The challenges of adjustment and acculturation as well as the interactional effects on migrants and host populations, including mental health issues and facilities, are considered. PMID- 29239703 TI - Managing Narcissistic Impulse-Reminiscence and Cultural Ideal Under the Circumstances of Mass Immigration. AB - Mass immigration is an occurrence associated with group psychology and triggers unusual reactions between newcomers and the indigenous population. This paper presents some results of psychological counseling work in an ongoing project of providing early psychological help for current traumatized refugees and asylum seekers in Europe who otherwise are unable to afford treatment, not even the usual consultations in common mental health settings. In particular, thoughts about the management of "cultural ideals" during the process of mass immigration came to light. PMID- 29239692 TI - Consequences of Rab GTPase dysfunction in genetic or acquired human diseases. AB - Rab GTPases are important regulators of intracellular membrane trafficking in eukaryotes. Both activating and inactivating mutations in Rab genes have been identified and implicated in human diseases ranging from neurological disorders to cancer. In addition, altered Rab expression is often associated with disease prognosis. As such, the study of diseases associated with Rabs or Rab-interacting proteins has shed light on the important role of intracellular membrane trafficking in disease etiology. In this review, we cover recent advances in the field with an emphasis on cellular mechanisms. PMID- 29239705 TI - Living in Germany as a Kanak: Some Thoughts About Nonbelonging. AB - Kanak is a swear word used by Germans for Turkish migrants. From the beginning of Turkish migration sixty years up to now the meaning of this swear word has changed. The word Kanak transformed from a swear word to a name that is carried now "with proud defiance" by the children and grandchildren of the first generation migrants. Kanak became a synonym for a new and different "German ness." Introducing and relating to the concepts of the "internal racial other" of Fahkry Davids, the "large group identity" of Vamik Volkan, and his own conception of hybrid identity development, the author analyzes the impact of such identity transformations on the "migrants" as well as on the "natives" and in particular on the host large group. PMID- 29239707 TI - Immigration, Psychic Dislocation, and the Re-creation of Community. AB - Communities are "psychic entities" that serve powerful psychological functions for the individuals living within them. They also serve multiple functions, including as a potential space where individuals are "held" and within which individuals "play" in ways akin to Winnicott's formulations regarding how infants "use" the me-not-me zone of experiencing, the potential space created by the gap between symbiotic engagement and the maternal object, in a zone between desire for fusion and fear of disintegrating abandonment. This paper explores the psychic destruction of community and the attempts to reconstruct "usable" community in migration, drawing from Winnicott and other psychoanalytic theorists to help us understand how communities work as psychological spaces and, specifically, to understand the near universal clustering that we see in immigrant communities. PMID- 29239708 TI - Psychoanalytic Thoughts on the European Refugee Crisis and the Other. AB - There are many aspects-political, economic, legal, medical, cultural, religious of the present refugee crisis in Europe. Difficulties at border crossings, settlement programs, life-saving issues, and security measures come to mind immediately, but the refugee crisis also needs to be examined from a psychological angle. This paper outlines psychoanalytic findings on voluntary and forced immigration and human responses to the Other. Change in the twenty-first century is occurring at an unprecedented pace and scale. Globalization, incredible advances in communication technology, fast travel, recourse limitations, terrorist activities, and now the refugee crisis in Europe make psychoanalytic investigation of the Other a necessity. PMID- 29239710 TI - Liver Fibrosis: Deep Convolutional Neural Network for Staging by Using Gadoxetic Acid-enhanced Hepatobiliary Phase MR Images. AB - Purpose To investigate the performance of a deep convolutional neural network (DCNN) model in the staging of liver fibrosis using gadoxetic acid-enhanced hepatobiliary phase magnetic resonance (MR) imaging. Materials and Methods This retrospective study included patients for whom input data (hepatobiliary phase MR images, static magnetic field of the imaging unit, and hepatitis B and C virus testing results available, either positive or negative) and reference standard data (liver fibrosis stage evaluated from biopsy or surgical specimens obtained within 6 months of the MR examinations) were available were assigned to the training (534 patients) or the test (100 patients) group. For the training group (54, 53, 81, 113, and 233 patients with fibrosis stages F0, F1, F2, F3, and F4, respectively; mean patient age, 67.4 +/- 9.7 years; 388 men and 146 women), MR images with three different section levels were augmented 90-fold (rotated, parallel-shifted, brightness-changed and contrast-changed images were generated; a total of 144 180 images). Supervised training was performed by using the DCNN model to minimize the difference between the output data (fibrosis score obtained through deep learning [FDL score]) and liver fibrosis stage. The performance of the DCNN model was evaluated in the test group (10, 10, 15, 20, and 45 patients with fibrosis stages F0, F1, F2, F3, and F4, respectively; mean patient age, 66.8 years +/- 10.7; 71 male patients and 29 female patients) with receiver operating characteristic (ROC) analyses. Results The FDL score was correlated significantly with fibrosis stage (Spearman rank correlation coefficient: 0.63; P < .001). Fibrosis stages F4, F3, and F2 were diagnosed with areas under the ROC curve of 0.84, 0.84, and 0.85, respectively. Conclusion The DCNN model exhibited a high diagnostic performance in the staging of liver fibrosis. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29239711 TI - Interval Breast Cancer Rates and Histopathologic Tumor Characteristics after False-Positive Findings at Mammography in a Population-based Screening Program. AB - Purpose To compare rates and tumor characteristics of interval breast cancers (IBCs) detected after a negative versus false-positive screening among women participating in the Norwegian Breast Cancer Screening Program. Materials and Methods The Cancer Registry Regulation approved this retrospective study. Information about 423 445 women aged 49-71 years who underwent 789 481 full-field digital mammographic screening examinations during 2004-2012 was extracted from the Cancer Registry of Norway. Rates and odds ratios of IBC among women with a negative (the reference group) versus a false-positive screening were estimated by using logistic regression models adjusted for age at diagnosis and county of residence. Results A total of 1302 IBCs were diagnosed after 789 481 screening examinations, of which 7.0% (91 of 1302) were detected among women with a false positive screening as the most recent breast imaging examination before detection. By using negative screening as the reference, adjusted odds ratios of IBCs were 3.3 (95% confidence interval [CI]: 2.6, 4.2) and 2.8 (95% CI: 1.8, 4.4) for women with a false-positive screening without and with needle biopsy, respectively. Women with a previous negative screening had a significantly lower proportion of tumors that were 10 mm or less (14.3% [150 of 1049] vs 50.0% [seven of 14], respectively; P < .01) and grade I tumors (13.2% [147 of 1114] vs 42.9% [six of 14]; P < .01), but a higher proportion of cases with lymph nodes positive for cancer (40.9% [442 of 1080] vs 13.3% [two of 15], respectively; P = .03) compared with women with a previous false-positive screening with benign biopsy. A retrospective review of the screening mammographic examinations identified 42.9% (39 of 91) of the false-positive cases to be the same lesion as the IBC. Conclusion By using a negative screening as the reference, a false-positive screening examination increased the risk of an IBC three-fold. The tumor characteristics of IBC after a negative screening were less favorable compared with those detected after a previous false-positive screening. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29239712 TI - Multiparametric MR Imaging of Age-related Changes in Healthy Thigh Muscles. AB - Purpose To use multiparametric magnetic resonance (MR) imaging to assess for and establish age-related differences in healthy thigh muscles. Materials and Methods Ninety-five subjects (47 men, 48 women; median age, 47 years) with healthy body mass index were grouped according to age: 30-39 years (n = 25), 40-49 years (n = 25), 50-59 years (n = 25), and 60-69 years (n = 20). Multiparametric MR imaging (intravoxel incoherent motion diffusion-weighted, diffusion-tensor, multiecho Dixon, and dynamic contrast material-enhanced MR imaging) was performed at 3.0 T. Two radiologists independently evaluated parametric maps of the anterior, medial, and posterior compartments. Welch-modified one-way analysis of variance and post hoc Dunnet T3 test were used to evaluate differences in apparent diffusion, true diffusion, and pseudodiffusion coefficients; perfusion fraction; fractional anisotropy (FA); fat percentage; volume transfer constant; constant efflux rate from the extravascular-extracellular space to plasma; volume fraction of the extravascular-extracellular space (Ve); incremental area under the curve; and Pearson and Spearman correlation coefficients were used to evaluate relationship strength. Multiple regression analysis was performed to identify independent predictors of age, and interrater reliability was assessed with intraclass correlation coefficients. Results There were significant differences among the age groups in apparent diffusion coefficients (P = .010), true diffusion coefficients (P = .045), FA (P < .001), Ve (P = .029) of the anterior compartment muscles, and fat percentages of all three compartments (P <= .001). Moreover, FA (Pearson r = 0.428, Spearman rho = 0.431; P < .001) and Ve (r = 0.226, P = .030 and rho = 0.309, P = .003) in the anterior compartment and fat percentages in all three compartments (r = 0.481, 0.475, and 0.573; rho = 0.515, 0.487, and 0.667; respectively; P < .001) were positively associated with age. Multiple regression analysis showed that age was predictive of fat percentage in the posterior compartment (beta = 0.500, P < .001) and of FA in the anterior compartment (beta = 0.194, P = .042). Interrater reliability was excellent (intraclass correlation coefficient, 0.745-0.992). Conclusion Multiple MR imaging parameters were significantly associated with age in thigh muscles. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29239713 TI - Leptospira venezuelensis sp. nov., a new member of the intermediate group isolated from rodents, cattle and humans. AB - Three strains, CLM-U50T, CLM-R50 and IVIC-Bov1, belonging to the genus Leptospira, were isolated in Venezuela from a patient with leptospirosis, a domestic rat (Rattus norvegicus) and a cow (Bos taurus), respectively. The initial characterisation of these strains based on the rrs gene (16S rRNA) suggested their designation as a novel species within the 'intermediates' group of the genus Leptospira. Further phylogenomic characterisation based on single copy core genes was consistent with their separation into a novel species. The average nucleotide identity between these three strains was >99 %, but below 89 % with respect to any previously described leptospiral species, also supporting their designation as a novel species. Given this evidence, these three isolates were considered to represent a novel species, for which the name Leptospiravenezuelensis sp. nov. is proposed, with CLM-U50T (=CIP 111407T=DSM 105752T) as the type strain. PMID- 29239714 TI - Fusion proteins towards fungi and bacteria in plant protection. AB - In agriculture, although fungi are considered the foremost problem, infections by bacteria also cause significant economical losses. The presence of different diseases in crops often leads to a misuse of the proper therapeutic, or the combination of different diseases forces the use of more than one pesticide. This work concerns the development of a 'super-Blad': a chimeric protein consisting of Blad polypeptide, the active ingredient of a biological fungicide already on the market, and two selected peptides, SP10-5 and Sub5, proven to possess biological potential as antibacterial agents. The resulting chimeric protein obtained from the fusion of Blad with SP10-5 not only maintained strong antibacterial activity, especially against Xanthomonas spp. and Pseudomonas syringae, but was also able to retain the ability to inhibit the growth of both yeast and filamentous fungi. However, the antibacterial activity of Sub5 was considerably diminished when fused with Blad, which seems to indicate that not all fusion proteins behave equally. These newly designed drugs can be considered promising compounds for use in plant protection. A deeper and focused development of an appropriate formulation may result in a potent biopesticide that can replace, per se, two conventional chemistries with less impact on the environment. PMID- 29239715 TI - Mitigating the risk of Zika virus contamination of raw materials and cell lines in the manufacture of biologicals. AB - Ensuring the virological safety of biologicals is challenging due to the risk of viral contamination of raw materials and cell banks, and exposure during in process handling to known and/or emerging viral pathogens. Viruses may contaminate raw materials and biologicals intended for human or veterinary use and remain undetected until appropriate testing measures are employed. The outbreak and expansive spread of the mosquito-borne flavivirus Zika virus (ZIKV) poses challenges to screening human- and animal -derived products used in the manufacture of biologicals. Here, we report the results of an in vitro study where detector cell lines were challenged with African and Asian lineages of ZIKV. We demonstrate that this pathogen is robustly detectable by in vitro assay, thereby providing assurance of detection of ZIKV, and in turn underpinning the robustness of in vitro virology assays in safety testing of biologicals. PMID- 29239716 TI - Pseudomonas fluvialis sp. nov., a novel member of the genus Pseudomonas isolated from the river Ganges, India. AB - A bacterial strain, designated ASS-1T, was isolated and identified from a sediment sample of the river Ganges, Allahabad, India. The strain was Gram-stain negative, formed straw-yellow pigmented colonies, was strictly aerobic, motile with a single polar flagellum, and positive for oxidase and catalase. The major fatty acids were C16 : 1omega7c/ 16 : 1 C16 : 1omega6c, C18 : 1omega7c and C16 : 0. Sequence analysis based on the 16S rRNA gene revealed that strain ASS-1T showed high similarity to Pseudomonas guguanensis CC-G9AT (98.2 %), Pseudomonas alcaligenes ATCC 14909T (98.2 %), Pseudomonas oleovorans DSM 1045T (98.1 %), Pseudomonas indolxydans IPL-1T (98.1 %) and Pseudomonas toyotomiensis HT-3T (98.0 %). Analysis of its rpoB and rpoD housekeeping genes confirmed its phylogenetic affiliation and showed identities lower than 93 % with respect to the closest relatives. Phylogenetic analysis based on the 16S rRNA, rpoB, rpoD genes and the whole genome assigned it to the genus Pseudomonas. The results of digital DNA-DNA hybridization based on the genome-to-genome distance calculator and average nucleotide identity revealed low genome relatedness to its close phylogenetic neighbours (below the recommended thresholds of 70 and 95 %, respectively, for species delineation). Strain ASS-1T also differed from the related strains by some phenotypic characteristics, i.e. growth at pH 5.0 and 42 degrees C, starch and casein hydrolysis, and citrate utilization. Therefore, based on data obtained from phenotypic and genotypic analysis, it is evident that strain ASS-1T should be regarded as a novel species within the genus Pseudomonas, for which the name Pseudomonasfluvialis sp. nov. is proposed. The type strain is ASS-1T (=KCTC 52437T=CCM 8778T). PMID- 29239717 TI - Niveispirillum lacus sp. nov., isolated from cyanobacterial aggregates in a eutrophic lake. AB - A bacterial strain, 1-14T, was isolated from cyanobacterial aggregates in a eutrophic lake, Taihu Lake, China. Cells were observed to be slightly curved, rod shaped, aerobic and Gram-stain-negative. Optimal growth occurred at pH 7.0 (range: 5.0-9.0), 28 degrees C (range: 20-32 degrees C) and 0 % (w/v) NaCl (range: 0-1.0 %) in R2A broth. No growth is observed at 37 degrees C. The cells were found to be positive for oxidase and catalase activities. The major respiratory quinone was ubiquinone Q-10. The major fatty acids (>10 %) were identified as C18 : 1omega6c/C18 : 1omega7c, C16 : 0 3-OH and C18 : 1 2-OH. The major polar lipids were found to consist of phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidylglycerol and phosphatidylcholine. Within the genus Niveispirillum, strain 1-14T was most closely related to Niveispirillum cyanobacteriorum TH16T (98.3 % 16S rRNA gene sequence similarity), followed by Niveispirillum irakense DSM 11586T (97.8 %) and Niveispirillum fermenti CC-LY736T (97.0 %). The genomic G+C content of strain 1-14T was 62.2 mol% based on total genome calculations. Genes coding for light-harvesting complexes LHI and LHII, and a photosynthetic reaction centre were detected in the genome. Average nucleotide identities and digital DNA-DNA hybridizations for complete genomes ranged from 76.4 to 83.5 and from 21.5 to 27.4 % between strain 1-14T and strains within the genus Niveispirillum. The phenotypic, chemotaxonomic and phylogenetic properties, and genome analysis suggested that strain 1-14T represents a novel species within the genus Niveispirillum, for which the name Niveispirillum lacus sp. nov. is proposed. The type strain is 1-14T (=CGMCC 1.12980T=LMG 28363T). PMID- 29239718 TI - New hepatitis C virus genotype 1 subtype naturally harbouring resistance associated mutations to NS5A inhibitors. AB - Hepatitis C virus (HCV) is a highly divergent virus currently classified into seven major genotypes and 86 subtypes (ICTV, June 2017), which can have differing responses to therapy. Accurate genotyping/subtyping using high-resolution HCV subtyping enables confident subtype identification, identifies mixed infections and allows detection of new subtypes. During routine genotyping/subtyping, one sample from an Equatorial Guinea patient could not be classified into any of the subtypes. The complete genomic sequence was compared to reference sequences by phylogenetic and sliding window analysis. Resistance-associated substitutions (RASs) were assessed by deep sequencing. The unclassified HCV genome did not belong to any of the existing genotype 1 (G1) subtypes. Sliding window analysis along the complete genome ruled out recombination phenomena suggesting that it belongs to a new HCV G1 subtype. Two NS5A RASs (L31V+Y93H) were found to be naturally combined in the genome which could limit treatment possibilities in patients infected with this subtype. PMID- 29239719 TI - Live-cell mapping of organelle-associated RNAs via proximity biotinylation combined with protein-RNA crosslinking. AB - The spatial organization of RNA within cells is a crucial factor influencing a wide range of biological functions throughout all kingdoms of life. However, a general understanding of RNA localization has been hindered by a lack of simple, high-throughput methods for mapping the transcriptomes of subcellular compartments. Here, we develop such a method, termed APEX-RIP, which combines peroxidase-catalyzed, spatially restricted in situ protein biotinylation with RNA protein chemical crosslinking. We demonstrate that, using a single protocol, APEX RIP can isolate RNAs from a variety of subcellular compartments, including the mitochondrial matrix, nucleus, cytosol, and endoplasmic reticulum (ER), with specificity and sensitivity that rival or exceed those of conventional approaches. We further identify candidate RNAs localized to mitochondria-ER junctions and nuclear lamina, two compartments that are recalcitrant to classical biochemical purification. Since APEX-RIP is simple, versatile, and does not require special instrumentation, we envision its broad application in a variety of biological contexts. PMID- 29239720 TI - Akt regulation of glycolysis mediates bioenergetic stability in epithelial cells. AB - Cells use multiple feedback controls to regulate metabolism in response to nutrient and signaling inputs. However, feedback creates the potential for unstable network responses. We examined how concentrations of key metabolites and signaling pathways interact to maintain homeostasis in proliferating human cells, using fluorescent reporters for AMPK activity, Akt activity, and cytosolic NADH/NAD+ redox. Across various conditions, including glycolytic or mitochondrial inhibition or cell proliferation, we observed distinct patterns of AMPK activity, including both stable adaptation and highly dynamic behaviors such as periodic oscillations and irregular fluctuations that indicate a failure to reach a steady state. Fluctuations in AMPK activity, Akt activity, and cytosolic NADH/NAD+ redox state were temporally linked in individual cells adapting to metabolic perturbations. By monitoring single-cell dynamics in each of these contexts, we identified PI3K/Akt regulation of glycolysis as a multifaceted modulator of single-cell metabolic dynamics that is required to maintain metabolic stability in proliferating cells. PMID- 29239721 TI - Natural changes in light interact with circadian regulation at promoters to control gene expression in cyanobacteria. AB - The circadian clock interacts with other regulatory pathways to tune physiology to predictable daily changes and unexpected environmental fluctuations. However, the complexity of circadian clocks in higher organisms has prevented a clear understanding of how natural environmental conditions affect circadian clocks and their physiological outputs. Here, we dissect the interaction between circadian regulation and responses to fluctuating light in the cyanobacterium Synechococcus elongatus. We demonstrate that natural changes in light intensity substantially affect the expression of hundreds of circadian-clock-controlled genes, many of which are involved in key steps of metabolism. These changes in expression arise from circadian and light-responsive control of RNA polymerase recruitment to promoters by a network of transcription factors including RpaA and RpaB. Using phenomenological modeling constrained by our data, we reveal simple principles that underlie the small number of stereotyped responses of dusk circadian genes to changes in light. PMID- 29239722 TI - Calcium-mediated shaping of naive CD4 T-cell phenotype and function. AB - Continuous contact with self-major histocompatibility complex ligands is essential for the survival of naive CD4 T cells. We have previously shown that the resulting tonic TCR signaling also influences their fate upon activation by increasing their ability to differentiate into induced/peripheral regulatory T cells. To decipher the molecular mechanisms governing this process, we here focus on the TCR signaling cascade and demonstrate that a rise in intracellular calcium levels is sufficient to modulate the phenotype of mouse naive CD4 T cells and to increase their sensitivity to regulatory T-cell polarization signals, both processes relying on calcineurin activation. Accordingly, in vivo calcineurin inhibition leads the most self-reactive naive CD4 T cells to adopt the phenotype of their less self-reactive cell-counterparts. Collectively, our findings demonstrate that calcium-mediated activation of the calcineurin pathway acts as a rheostat to shape both the phenotype and effector potential of naive CD4 T cells in the steady-state. PMID- 29239723 TI - Intermittent Ca2+ signals mediated by Orai1 regulate basal T cell motility. AB - Ca2+ influx through Orai1 channels is crucial for several T cell functions, but a role in regulating basal cellular motility has not been described. Here, we show that inhibition of Orai1 channel activity increases average cell velocities by reducing the frequency of pauses in human T cells migrating through confined spaces, even in the absence of extrinsic cell contacts or antigen recognition. Utilizing a novel ratiometric genetically encoded cytosolic Ca2+ indicator, Salsa6f, which permits real-time monitoring of cytosolic Ca2+ along with cell motility, we show that spontaneous pauses during T cell motility in vitro and in vivo coincide with episodes of cytosolic Ca2+ signaling. Furthermore, lymph node T cells exhibited two types of spontaneous Ca2+ transients: short-duration 'sparkles' and longer duration global signals. Our results demonstrate that spontaneous and self-peptide MHC-dependent activation of Orai1 ensures random walk behavior in T cells to optimize immune surveillance. PMID- 29239724 TI - SIRT2 and lysine fatty acylation regulate the transforming activity of K-Ras4a. AB - Ras proteins play vital roles in numerous biological processes and Ras mutations are found in many human tumors. Understanding how Ras proteins are regulated is important for elucidating cell signaling pathways and identifying new targets for treating human diseases. Here we report that one of the K-Ras splice variants, K Ras4a, is subject to lysine fatty acylation, a previously under-studied protein post-translational modification. Sirtuin 2 (SIRT2), one of the mammalian nicotinamide adenine dinucleotide (NAD)-dependent lysine deacylases, catalyzes the removal of fatty acylation from K-Ras4a. We further demonstrate that SIRT2 mediated lysine defatty-acylation promotes endomembrane localization of K-Ras4a, enhances its interaction with A-Raf, and thus promotes cellular transformation. Our study identifies lysine fatty acylation as a previously unknown regulatory mechanism for the Ras family of GTPases that is distinct from cysteine fatty acylation. These findings highlight the biological significance of lysine fatty acylation and sirtuin-catalyzed protein lysine defatty-acylation. PMID- 29239725 TI - T-cell calcium dynamics visualized in a ratiometric tdTomato-GCaMP6f transgenic reporter mouse. AB - Calcium is an essential cellular messenger that regulates numerous functions in living organisms. Here, we describe development and characterization of 'Salsa6f', a fusion of GCaMP6f and tdTomato optimized for cell tracking while monitoring cytosolic Ca2+, and a transgenic Ca2+ reporter mouse with Salsa6f targeted to the Rosa26 locus for Cre-dependent expression in specific cell types. The development and function of T cells was unaffected in Cd4-Salsa6f mice. We describe Ca2+ signals reported by Salsa6f during T cell receptor activation in naive T cells, helper Th17 T cells and regulatory T cells, and Ca2+ signals mediated in T cells by an activator of mechanosensitive Piezo1 channels. Transgenic expression of Salsa6f enables ratiometric imaging of Ca2+ signals in complex tissue environments found in vivo. Two-photon imaging of migrating T cells in the steady-state lymph node revealed both cell-wide and localized sub cellular Ca2+ transients ('sparkles') as cells migrate. PMID- 29239727 TI - Clinical effects of submucosal middle turbinectomy for eosinophilic chronic rhinosinusitis. AB - OBJECTIVE: The preservation or resection of the middle turbinate (MT) during endoscopic sinus surgery (ESS) currently remains a matter of debate. The present study aimed to investigate the effects of submucosal middle turbinectomy (SMT) in ESS for eosinophilic chronic rhinosinusitis (ECRS). METHODS: The study included 38 ECRS patients (63 sides) who had undergone full-house ESS with SMT and 20 ECRS patients (40 sides) without SMT as a control group. Post-operative middle turbinate lateralization (MTL), synechia formation, and the patency grade of the olfactory cleft (OC) were assessed as the primary outcomes 3 months after surgery. CT scans and the T&T test were performed on the SMT group 3 months after surgery and assessed as secondary outcomes. RESULTS: MTL and synechia formation rates were slightly higher in the control group than in the SMT group (20% vs. 7.9%, p=0.072, 17.5% vs. 9.5%, p=0.235), although neither reached statistically significance. The mean patency score of OC was significantly better in the SMT group than in the control group (0.5+/-0.6 vs. 1.3+/-0.7, <0.001). CT findings and T&T test scores showed good improvements after SMT combined with ESS. No major adverse events occurred due to SMT. CONCLUSION: We demonstrated the potential advantages of SMT for ECRS patients. This method may avoid physiological functional loss through its preservation of the mucosa and structure of the MT. PMID- 29239726 TI - cAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool. AB - It is widely accepted that cAMP regulates gene transcription principally by activating the protein kinase A (PKA)-targeted transcription factors. Here, we show that cAMP enhances the generation of 5-hydroxymethylcytosine (5hmC) in multiple cell types. 5hmC is converted from 5-methylcytosine (5mC) by Tet methylcytosine dioxygenases, for which Fe(II) is an essential cofactor. The promotion of 5hmC was mediated by a prompt increase of the intracellular labile Fe(II) pool (LIP). cAMP enhanced the acidification of endosomes for Fe(II) release to the LIP likely through RapGEF2. The effect of cAMP on Fe(II) and 5hmC was confirmed by adenylate cyclase activators, phosphodiesterase inhibitors, and most notably by stimulation of G protein-coupled receptors (GPCR). The transcriptomic changes caused by cAMP occurred in concert with 5hmC elevation in differentially transcribed genes. Collectively, these data show a previously unrecognized regulation of gene transcription by GPCR-cAMP signaling through augmentation of the intracellular labile Fe(II) pool and DNA hydroxymethylation. PMID- 29239728 TI - Wound healing of cutaneous substance losses based on infectious, inflammatory and traumatic skin disorders: The experience of a center. AB - INTRODUCTION: There is no reference available concerning the standard healing time based on dermatological diseases responsible for cutaneous substance losses. The aim of our study was to assess the healing time after surgical debridement of necrotizing fasciitis (NF), hidradenitis suppurativa (HS) and skin necrosis due to trauma (SNT) based on multiples existing co-morbidities among these patients to provide surgeons with accurate scientific data in order to inform and educate patients and nurses who are practicing care under the supervision of the surgeon. MATERIALS AND METHODS: This was a retrospective study. The primary endpoint was the time for complete wound healing, which was calculated from the time of the last surgical procedure to the complete wound healing corresponding to the time of complete reepithelialization, when daily dressings were no longer needed. RESULTS: A total of 107 patients were included. The mean time for complete wound healing was 64.94+/-31.55 days in patients with NF, 45.70+/-21.40 days in patients with SNT and 75.02+/-26.41 days in patients with HS (SNT versus NF, P=0.004** and SNT versus HS, P<0.0001**). CONCLUSION: The mean time for complete wound healing was 64.94 days in patients with NF, 45.70 days in patients with SNT, 75.02 days in patients with HS. This study can be considered as a referential based on the experience of a reference centre for these 3 pathologies (NF, HS, and SNT) whose aim is to inform plastic surgeons in order to anticipate the management or educate the patient. PMID- 29239729 TI - Corrigendum to "Anti-inflammatory effects of Perillae Herba ethanolic extract against TNF-alpha/IFN-gamma-stimulated human keratinocyte HaCaT cells" [J. Ethnopharmacol. 211 (2018) 217-223]. PMID- 29239730 TI - Directed differentiation of periocular mesenchyme from human embryonic stem cells. AB - Corneal tissue is the most transplanted of all body tissues. Currently, cadaveric donor tissues are used for transplantation. However, a global shortage of transplant grade material has prompted development of alternative, cell-based therapies for corneal diseases. Pluripotent stem cells are attractive sources of cells for regenerative medicine, because large numbers of therapeutically useful cells can be generated. However, a detailed understanding of how to differentiate clinically relevant cell types from stem cells is fundamentally required. Periocular mesenchyme (POM), a subtype of cranial neural crest, is vital for development of multiple cell types in the cornea, including clinically relevant cells such as corneal endothelium and stromal keratocytes. Herein, we describe protocols for differentiation of POM from pluripotent stem cells. Using defined media containing inhibitors of TGFbeta and WNT signalling, we generated neural crest cells that express high levels of the POM transcription factors PITX2 and FOXC1. Furthermore, we identified cells resembling POM in the adult cornea, located in a niche between the trabecular meshwork and peripheral endothelium. The generation and expansion of POM is an important step in the generation of a number of cells types that could prove to be clinically useful for a number of diseases of the cornea. PMID- 29239731 TI - Practice Patterns and Outcomes for Pemetrexed Plus Platinum Doublet as Neoadjuvant Chemotherapy in Adenocarcinomas of Lung: Looking Beyond the Usual Paradigm. AB - AIMS: Neoadjuvant chemotherapy (NACT) is the standard of care in non-small cell lung cancers (NSCLC) with locally advanced N2 disease. There is a scarcity of data for the pemetrexed-platinum regimen as NACT. Also, apart from N2 disease, the role of NACT in locally advanced NSCLCs for tumour downstaging is unclear. MATERIALS AND METHODS: Non-metastatic adenocarcinomas of lung treated with pemetrexed-platinum-based NACT were analysed. The patients with locoregionally advanced N2 disease and those who were borderline candidates for upfront definitive treatment were planned for NACT after discussion in a multidisciplinary clinic. In total, four cycles of 3-weekly pemetrexed and platinum were delivered in the combined neoadjuvant and adjuvant setting. A response assessment was carried out using RECIST criteria. Progression-free (PFS) and overall survival were calculated using the Kaplan-Meier method. RESULTS: Of 114 patients, 96 evaluable patients received NACT with pemetrexed-platinum. The most common indication for NACT was N2 disease at baseline (46.8%). The objective response rate was 36.4% (95% confidence interval 22-52%), including two complete and 32 partial responses, whereas 12.5% of patients had progressive disease on NACT. The median PFS was 14 months (95% confidence interval 10.7-17.3) and the median overall survival was 22 months (95% confidence interval 15.6-28.4) at a median follow-up of 16 months. There was a significant improvement in the overall survival of patients undergoing definitive therapy versus no definitive therapy (median overall survival 25 months [95% confidence interval 19.6-30.4] versus 12 months [95% confidence interval 3.2-20.7], respectively; P = 0.015, hazard ratio 0.56 [95% confidence interval 0.3-0.9]). Among patients who could not undergo definitive chemoradiation upfront due to dosimetric constraints (n = 34), 24 (70.6%) patients finally underwent definitive therapy after NACT. CONCLUSIONS: Pemetrexed-platinum-based NACT seems to be an effective option and many borderline cases, where upfront definitive therapy is not feasible, may become amenable to the same after incorporation of NACT. PMID- 29239732 TI - Too Big to Fail? The Current Status of Proton Therapy in the USA. PMID- 29239733 TI - Breast conserving surgery for extensive DCIS using multiple radioactive seeds. AB - BACKGROUND AND OBJECTIVES: Breast conserving surgery (BCS) can be challenging for large regions of ductal carcinoma in situ (DCIS), resulting in high rates of positive resection margins. Radioactive seed localization (RSL) using multiple radioactive iodine (125I) seeds can be used to bracket extensive DCIS (eDCIS). The goal of this study was to retrospectively compare the use of a single or multiple 125I seeds in RSL to enable BCS in patients with eDCIS. METHODS: All patients with eDCIS (area of >=3.0 cm) who underwent either single or multiple seed RSL between January 2008 and December 2016 were included. Patient, tumor and surgery characteristics were compared between both groups. Primary outcome measures were positive resection margin and re-operation rates. RESULTS: Respectively 48 and 58 patients with eDCIS underwent single- and multiple-seed RSL and subsequent BCS. The rate of positive resection margin (focal and more than focal) with single-seed RSL was 47.9%, compared to 29.3% with multiple-seed RSL (p = 0.06). The re-operation rate was 39.6% with single-seed RSL and 20.7% in the multiple-seed RSL group (p = 0.05). CONCLUSION: Multiple-seed RSL enables bracketing of large areas of DCIS, with the potential to decrease the high rate of positive resection margins in this patient group. PMID- 29239734 TI - What we know about the purpose, theoretical foundation, scope and dimensionality of existing self-management measurement tools: A scoping review. AB - OBJECTIVES: To identify self-report, self-management measures for adults with chronic conditions, and describe their purpose, theoretical foundation, dimensionality (multi versus uni), and scope (generic versus condition specific). METHODS: A search of four databases (8479 articles) resulted in a scoping review of 28 self-management measures. RESULTS: Although authors identified tools as measures of self-management, wide variation in constructs measured, purpose, and theoretical foundations existed. Subscales on 13 multidimensional tools collectively measure domains of self-management relevant to clients, however no one tool's subscales cover all domains. CONCLUSIONS: Viewing self-management as a complex, multidimensional whole, demonstrated that existing measures assess different, related aspects of self-management. Activities and social roles, though important to patients, are rarely measured. Measures with capacity to quantify and distinguish aspects of self-management may promote tailored patient care. PRACTICE IMPLICATIONS: In selecting tools for research or assessment, the reason for development, definitions, and theories underpinning the measure should be scrutinized. Our ability to measure self-management must be rigorously mapped to provide comprehensive and system-wide care for clients with chronic conditions. Viewing self-management as a complex whole will help practitioners to understand the patient perspective and their contribution in supporting each individual patient. PMID- 29239735 TI - Burns Centre and fire services: What information can be exchanged to manage the burn patient? AB - AIM: To describe the experience of using a "Burns Extrication Form" at a regional Burns Centre. Communication between the fire services and burns team previously has been regarded as poor. Significant information is collected by the fire services at the scene and this can aid the management of the patient. METHODS: The Burns Extrication Form was devised to provide a clear framework of communication between the two services. Information regarding time frames, exposure to heat & smoke, fire loading (potential severity of a fire in a given space by measuring amount of combustible material in confined space), building construction, chemicals involved is passed to the medical team through this form through a National Health Service mailbox. Also, treatment provided by the fire service was documented. All data collected by this form was collated for the purpose of this study. Data ranging from 2014 to 2017 was included in this descriptive study. RESULTS: The patient journey following contact by fire services shows that out of the 598 persons who were involved in a fire only 92 (15%) attended the Accident and Emergency (A&E) department at the Queen Elizabeth Hospital. Signs of smoke inhalation, singed nose hair and coughing were found in 190 (32%) patients; the fire service administered oxygen to 106 (18%) of these patients although this may have been initiated by Ambulance crews who were on scene prior to the Fire Crew. The remaining 506 (85%) may have not attended A&E at UHB or may have attended another A&E in the West Midlands base on the location of the incident and clinical needs. Of the 92 patients who attended the A&E at UHB 48 (52%) were admitted to the Burns Centre in the hospital. Nine (19%) of these patients had smoke inhalation and three of these patients were managed by intubation. Birmingham North and Black Country North had the highest incidence of burns incidents, 120 and 103 respectively. Whilst, the lowest numbers were found in Birmingham South and Coventry and Solihull with 65 and 61 respectively. Additional results are described in the study. CONCLUSION: Data provided by the Fire Extrication forms helps us to assess the magnitude of fire-related injury across the West Midlands. The fire services have been shown to provide important first aid as one of the first responders at the scene. Their value in assessing the environment in and patient status helps clinicians further down the patient's journey. PMID- 29239736 TI - Factors affecting the uncaging efficiency of 500 nm light-activatable BODIPY caging group. AB - Photoremovable protective groups, or caging groups, enable us to regulate the activities of bioactive molecules in living cells upon photoirradiation. Nevertheless, requirement of UV light for activating caging group is a significant limitation due to its cell toxicity and its poor tissue penetration. Our group previously reported a 500 nm light-activatable caging group based on BODIPY scaffold, however, its uncaging efficiency was lower than those of conventional caging groups. Here we show that the uncaging quantum yield (QY) of BODIPY caging group depends upon the driving force of photo-induced electron transfer (PeT). We also found that the uncaging QY increased in less polar solvents. We applied these findings to develop BODIPY-caged capsaicin, which is well localized to low-polarity intracellular compartments, as a tool to stimulate TRPV1 in live cells in response to blue-green light. PMID- 29239737 TI - Comparison of the acidogenic and methanogenic potential of agroindustrial residues. AB - The methanogenic and acidogenic potentials of six different agroindustrial residues, i.e. of fruit pulps and brewery residues, were determined. For all substrates, the methanogenic conversion yield was systematically higher than the acidogenic one in Chemical Oxygen Demand (COD) terms, ranging from 0.46 to 0.87 gCOD_CH4/gCOD_substrate_fed and from 0.24 to 0.56 gCOD_tVFA/gCOD_substrate_fed, respectively. During methanogenic conversion, brewery trub exhibited the highest methane potential (304mlCH4/gCOD_substrate). Trub also exhibited the highest total volatile fatty acids (tVFA) concentrations in the mixed liquor (ML) during acidogenic conversion (29.7 gCOD_tVFA/kgML). Acetic, butyric and caproic acids were the main carboxylates produced by the different substrates. Despite the lower conversion yields, the economic value of the acidogenic product (carboxylate streams) is higher than that of methanogenic conversion (methane) due to the higher value of carboxylates and their potential use in finer applications (e.g. bio-based products) compared to energy production form methane. PMID- 29239738 TI - On the use of substandard medicines in hematology: An emerging concern in the Middle East and North Africa region. PMID- 29239739 TI - Endophenotypes: A conceptual link between anorexia nervosa and autism spectrum disorder. AB - The paper, by translating the concept and the two models of endophenotype (EP), strengthens the hypothesis that there exists a linkage between anorexia nervosa (AN) and autism spectrum disorder (ASD). Specifically, the paper synthesizes empirical research that supported the idea that individuals with AN and individuals with ASD share similarities with respect to their neurocognitive EPs and temperament EPs. The paper then introduces an innovative structure to emphasize the subtle difference between neurocognitive EPs and temperament EPs in relation to AN and ASD. This structure constitutes the categorization of the shared neurocognitive EPs to the liability-index model of EP and the shared temperament EPs to the mediational model of EP. The paper argues that the shared neurocognitive EPs under the liability index model of EP are trait markers signaling the effects of genes on the phenotypes of AN and ASD; whereas, the shared temperament EPs under the mediational model of EP are state markers describing the symptomatic status of AN and ASD. The proposition of the paper suggests clinicians and researchers should target the atypical state markers (i.e., temperament EPs) shared between AN and ASD when tailoring environment based treatments for individuals with AN who exhibit autistic behaviors and individuals with ASD who display disordered eating behaviors or anorexic symptoms. PMID- 29239740 TI - Hyperthyroxinemia is positively associated with prevalent and incident type 2 diabetes mellitus in two population-based samples from Northeast Germany and Denmark. AB - BACKGROUND AND AIMS: A potential causal relationship between thyroid function and type 2 diabetes mellitus is currently under debate, but the current state of research is limited. Our aim was to investigate the association of thyroid hormone levels with prevalent and incident type 2 diabetes mellitus (T2DM) in two representative studies. METHODS AND RESULTS: Analyses are based on data from the Study of Health in Pomerania (SHIP), a German population based cohort with 4308 individuals at baseline and 3300 individuals at a five-year follow-up, and from INTER99, a Danish population-based randomized controlled trial with 6784 individuals at baseline and 4516 individuals at the five-year-follow-up. Serum thyroid-stimulating hormone (TSH) and free thyroxine (fT4) concentrations were measured in both studies, while free triiodothyronine was measured in SHIP only. T2DM was defined by self report or intake of anti-diabetic medication. Neither in SHIP nor in INTER99 we detected significant associations of serum TSH levels with prevalent or incident T2DM. Serum fT4 levels were significantly positively associated with prevalent T2DM in SHIP and INTER99. In longitudinal analyses baseline levels of fT4 were significantly positively associated with incident T2DM in SHIP (RR per pmol/L = 1.07; 95%-CI = 1.05-1.10), while this association barely missed statistical significance in INTER99 (RR per pmol/L = 1.03; 95%-CI = 0.99-1.06). In SHIP baseline fT3 levels were significantly associated with incident T2DM (RR per pmol/L = 1.21; 95%-CI = 1.16-1.27). CONCLUSION: We demonstrated positive associations of thyroid hormones with prevalent and incident type 2 diabetes mellitus suggesting that hyperthyroxinemia may contribute to the pathogenesis of this condition. PMID- 29239742 TI - Comment on Late-Onset Nonketotic Hyperglycinemia With a Heterozygous Novel Point Mutation of the GLDC Gene. PMID- 29239741 TI - Farewell to monomodality treatment in patients with WHO lower grade glioma? PMID- 29239743 TI - Phenotypic and Molecular Spectrum of Aicardi-Goutieres Syndrome: A Study of 24 Patients. AB - BACKGROUND: Aicardi-Goutieres syndrome is a rare genetic neurological disorder with variable clinical manifestations. Molecular detection of specific mutations is required to confirm the diagnosis. The aim of this study was to review the clinical and molecular diagnostic findings in 24 individuals with Aicardi Goutieres syndrome who presented during childhood in an Arab population. MATERIALS AND METHODS: We reviewed the records of 24 patients from six tertiary hospitals in different Arab countries. All included patients had a molecular diagnosis of Aicardi-Goutieres syndrome. RESULTS: Six individuals with Aicardi Goutieres syndrome (25%) had a neonatal presentation, whereas the remaining patients presented during the first year of life. Patients presented with developmental delay (24 cases, 100%); spasticity (24 cases, 100%); speech delay (23 cases, 95.8%); profound intellectual disability (21 cases, 87.5%); truncal hypotonia (21 cases, 87.5%); seizures (eighteen cases, 75%); and epileptic encephalopathy (15 cases, 62.5%). Neuroimaging showed white matter abnormalities (22 cases, 91.7%), cerebral atrophy (75%), and small, multifocal calcifications in the lentiform nuclei and deep cerebral white matter (54.2%). Homozygous mutations were identified in RNASEH2B (54.2%), RNASEH2A (20.8%), RNASEH2C (8.3%), SAMHD1 (8.3%), TREX1 (4.2%), and heterozygous mutations in IFIH1 (4.2%), with c.356A>G (p.Asp119Gly) in RNASEH2B being the most frequent mutation. Three novel mutations c.987delT and c.625 + 1G>A in SAMHD1 gene and c.961G>T in the IFIHI1 gene were identified. CONCLUSIONS: This is the largest molecularly confirmed Aicardi-Goutieres syndrome cohort from Arabia. By presenting these clinical and molecular findings, we hope to raise awareness of Aicardi-Goutieres syndrome and to demonstrate the importance of specialist referral and molecular diagnosis. PMID- 29239744 TI - Comment on "Lung and Liver growth and retinoic acid status in human fetuses with congenital diaphragmatic hernia". PMID- 29239745 TI - Vitamin A status in human fetuses with congenital diaphragmatic hernia: (Author reply to comment by Rocke AW and Clugston RD). PMID- 29239746 TI - Stepping reaction time and gait adaptability are significantly impaired in people with Parkinson's disease: Implications for fall risk. AB - BACKGROUND: Decline in the ability to take effective steps and to adapt gait, particularly under challenging conditions, may be important reasons why people with Parkinson's disease (PD) have an increased risk of falling. This study aimed to determine the extent of stepping and gait adaptability impairments in PD individuals as well as their associations with PD symptoms, cognitive function and previous falls. METHODS: Thirty-three older people with PD and 33 controls were assessed in choice stepping reaction time, Stroop stepping and gait adaptability tests; measurements identified as fall risk factors in older adults. RESULTS: People with PD had similar mean choice stepping reaction times to healthy controls, but had significantly greater intra-individual variability. In the Stroop stepping test, the PD participants were more likely to make an error (48 vs 18%), took 715 ms longer to react (2312 vs 1517 ms) and had significantly greater response variability (536 vs 329 ms) than the healthy controls. People with PD also had more difficulties adapting their gait in response to targets (poorer stepping accuracy) and obstacles (increased number of steps) appearing at short notice on a walkway. Within the PD group, higher disease severity, reduced cognition and previous falls were associated with poorer stepping and gait adaptability performances. CONCLUSIONS: People with PD have reduced ability to adapt gait to unexpected targets and obstacles and exhibit poorer stepping responses, particularly in a test condition involving conflict resolution. Such impaired stepping responses in Parkinson's disease are associated with disease severity, cognitive impairment and falls. PMID- 29239747 TI - Functional testing on engineered cartilage to identify the role played by shearing. AB - Compressive loading is crucial for tissue regeneration in cartilage; however, the role played by shearing induced from translational or rotational motion of the knee joint has yet to be identified. This study aims at investigating the effects of in vivo like dynamic load-compression integrated with shearing on tissue regeneration, particularly to identify the role played by shearing induced from rotational motion. Tissue samples fabricated from a calcium alginate hydrogel embedded with chondrocytes were subjected to a dynamic tissue culture. Three culturing regimes were included: a static culture control (CON), compression combined with shearing induced from translational motion (CS), and compression combined with shearing induced from both translational and rotational motion (CSR). The results indicate that the CS group has a significantly larger chondrocyte proliferation rate (p < .01), and that the CSR group has no advantages over the CS group. However, the CSR group was found to have a marked influence on the matrix synthesis compared to that of the CS group (p < .01). It can be concluded that shearing from individual joint motions offers a different contribution to the chondrocyte proliferation, matrix synthesis, and phenotype maintenance, and better insight into these individual roles will be necessary for determining the efficacy of in vivo/vitro cartilageous tissue functionalization. PMID- 29239748 TI - Validation of an alignment method using motion tracking system for in-vitro orientation of cadaveric hip joints with reduced set of anatomical landmarks. AB - Accurate in-vitro orientation of cadaveric hip joints is challenging due to limited available anatomical landmarks. Published hip joint in-vitro investigations commonly lack details on methods used to achieve reported orientations and the accuracy with which the desired orientation has been achieved. The aim of this study was to develop an accurate method for orienting hip joints with limited anatomical landmarks for in-vitro investigations, and to compare this method against orientation using guiding axes and by visual approximation. The proposed orientation method resulted in orientation angles achieved to within one degree (SD +/- 0.58 degrees ). For most specimens, orientation using physical tools resulted in errors of +/-8 degrees and +/-12 degrees in at least one of three orientation angles used to place the femur and pelvis in neutral orientation, respectively. Precision was also worse, with SDs ranging from +/-1 degrees to +/-5 degrees for orientation angles of femoral specimens and SDs ranging from +/-1 degrees to +/-8 degrees for pelvic specimens. The error in the orientation angles was worse for orientation by visual approximation and the range of SDs were greater for both the femur and pelvis. Finite element modeling was used to assess the effects of observed orientation errors, on prediction of fracture load. In most cases, the largest error in fracture load among all trials exceeded 30%, relative to a femur oriented without any error in the orientation angles. PMID- 29239749 TI - Robotic Ureteral Reconstruction Using Buccal Mucosa Grafts: A Multi-institutional Experience. AB - BACKGROUND: Minimally invasive treatment of long, multifocal ureteral strictures or failed pyeloplasty is challenging. Robot-assisted buccal mucosa graft ureteroplasty (RBU) is a technique for ureteral reconstruction that avoids the morbidity of bowel interposition or autotransplantation. OBJECTIVE: To evaluate outcomes for RBU in a multi-institutional cohort of patients treated for revision ureteropelvic junction obstruction and long or multifocal ureteral stricture at three tertiary referral centers. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study involved data for 19 patients treated with RBU at three high volume centers between October 2013 and July 2016. SURGICAL PROCEDURE: RBU was performed using either an onlay graft after incising the stricture or an augmented anastomotic repair in which the ureter was transected and re anastomosed primarily on one side, and a graft was placed on the other side. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Preoperative, intraoperative, and postoperative variables and outcomes were assessed. A descriptive statistical analysis was performed. RESULTS AND LIMITATIONS: The onlay technique was used for 79%, while repair was carried out using the augmented anastomotic technique for the remaining cases. The reconstruction was reinforced with omentum in 95% of cases. The ureteral stricture location was proximal in 74% and mid in 26% of cases. A prior failed ureteral reconstruction was present in 53% of patients. The median stricture length was 4.0cm (range 2.0-8.0), operative time was 200min (range 136-397), estimated blood loss was 95ml (range 25-420), and length of stay was 2 d (range 1-15). There were no intraoperative complications. At median follow-up of 26 mo, the overall success rate was 90%. CONCLUSIONS: RBU is a feasible and effective technique for managing complex proximal and mid ureteral strictures. PATIENT SUMMARY: We studied robotic surgery for long ureteral strictures using grafts at three referral centers. Our results demonstrate that robotic buccal mucosa graft ureteroplasty is a feasible and effective technique for ureteral reconstruction. PMID- 29239750 TI - [Post operative fistula after photovaporisation (PVP) laser green light XPS 180W: About two cases]. PMID- 29239751 TI - Feasibility of single- vs two-physician procedural sedation in a small community emergency department. AB - OBJECTIVE: Sedation is commonly required for painful procedures in the emergency department (ED). Some facilities mandate two physicians be present for deep sedation cases. Evidence is lacking, however, that a two-physician approach improves safety outcomes. We report our experience on the feasibility of replacing a two-physician ED procedural sedation policy with a single-physician policy in a small, single-coverage community ED. METHODS: This is a retrospective, before/after, single-center observational study of prospectively collected data from January 2013 through December 2016. In September 2014, our medical center implemented a single-physician policy requiring only one emergency physician, accompanied by a sedation-trained ED registered nurse. The primary outcome was a sedation-related escalation of care that resulted in one of the following adverse events or interventions: dysrhythmia (symptomatic bradycardia or ventricular arrhythmias), cardiac arrest, endotracheal intubation, or unanticipated hospitalization. Secondary outcomes included hypoxemia (peripheral oxygen saturation less than 90% for greater than 1min), the use of bag-valve mask ventilation (BVM), use of a reversal agent, laryngospasm or pulmonary aspiration. RESULTS: We performed 381 sedations during the study period: 135 patients in the two-physician group (before) and 246 patients in the single-physician group (after). The two groups were comparable in age and gender. There was no occurrence of the primary outcome. Secondary outcomes were uncommon, and were similar in the two groups. CONCLUSIONS: In this small, single-coverage community ED, replacement of a two-physician policy with a single-physician policy for deep sedation in the ED was feasible and was not associated with an increase in adverse events. PMID- 29239752 TI - Dizziness in a patient with a permanent VVI pacemaker. AB - A 83-year-old woman with a single-chamber pacemaker implanted 15 years earlier was brought to the ED due to symptomatic bradycardia. ECG continuous monitoring allowed the diagnosis of atrial fibrillation with complete atrioventricular block in the setting of a complete failure to capture. The differing timing cycles of pacing outputs can confirm that sensing is preserved in the absence of a pacemaker programmer. PMID- 29239753 TI - The use of intranasal analgesia for acute pain control in the emergency department: A literature review. AB - BACKGROUND: Traditional routes for administration of pain medications include oral (PO), intravenous (IV), or intramuscular routes (IM). When these routes are not feasible, the intranasal (IN) route may be considered. The objectives of this evidence-based review were: to review the literature which compared the safety and efficacy of IN analgesia to traditional routes and to determine if IN analgesia should be considered over traditional routes for acute pain control in the ED. METHODS: The MEDLINE and EMBASE databases from July 1970 to July 2017 were searched. Randomized controlled trials (RCT) that evaluated the use of IN analgesia for acute pain in the ED were included. Methodological quality of the trials was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. RESULTS: Eleven randomized controlled trials (RCT) met the inclusion criteria. Four trials found significant reductions in pain scores, favoring IN analgesia. However, in all of the trials, pain relief was not sustained. Three trials reported superior pain reduction with comparators and three trials reported no statistical significance. One trial described effective pain relief with IN analgesia but did not provide data on statistical analysis. CONCLUSION: Eleven randomized controlled trials with various methodological flaws revealed conflicting conclusions. There is limited evidence to support the use of the IN analgesia over traditional routes for acute pain in the ED. The IN route may be a good alternative in scenarios where IV access is not feasible, patients are refusing injectable medications, or a fast onset of pain relief is needed. PMID- 29239754 TI - Characterization of Rhodococcus sp. A5wh isolated from a high altitude Andean lake to unravel the survival strategy under lithium stress. AB - Lithium (Li) is widely distributed in nature and has several industrial applications. The largest reserves of Li (over 85%) are in the so-called "triangle of lithium" that includes the Salar de Atacama in Chile, Salar de Uyuni in Bolivia and Salar del Hombre Muerto in Argentina. Recently, the use of microorganisms in metal recovery such as copper has increased; however, there is little information about the recovery of lithium. The strain Rhodococcus sp. A5wh used in this work was previously isolated from Laguna Azul. The assays revealed that this strain was able to accumulate Li (39.52% of Li/g microbial cells in 180min) and that it was able to grow in its presence up to 1M. In order to understand the mechanisms implicated in Li tolerance, a proteomic approach was conducted. Comparative proteomic analyses of strain A5wh exposed and unexposed to Li reveal that 17 spots were differentially expressed. The identification of proteins was performed by MALDI-TOF/MS, and the obtained results showed that proteins involved in stress response, transcription, translations, and metabolism were expressed under Li stress. This knowledge constitutes the first proteomic approach to elucidate the strategy followed by Rhodococcus to adapt to Li. PMID- 29239755 TI - Target meta-awareness is a necessary condition for physiological responses to masked emotional faces: Evidence from combined skin conductance and heart rate assessment. AB - Much heated debate surrounds the extent to which we can process emotional stimuli without awareness. In particular the extent to which masked emotional faces can elicit changes in physiology measurements, such as heart rate and skin conductance responses, has produced controversial findings. In the present study, we aimed to determine whether briefly presented faces can elicit physiological changes and, specifically, whether this is due to unconscious processing. We measured and adjusted for individual differences in the detection threshold using both receiver operating characteristics and hit rates. For this we also used a strict Bayesian assessment of participant thresholds. We then measured physiological responses to threshold adjusted emotional faces and for hits, misses and post-binary subdivisions of target meta-awareness. Our findings based on receiver operating characteristics revealed that, when faces were successfully masked there were no significant physiological differences in response to stimuli with different emotional connotations. In contrast, when targets were masked based on hit rates we did find physiological responses to masked emotional faces. With further analysis we found that this effect was specific to correct detection of angry and fearful faces and that increases in experienced arousal were associated with higher confidence ratings for correct detection of these stimuli. Collectively, our results do not support the notion of unconscious processing when using markers of physiological processes. Rather they suggest that target meta-awareness is a necessary condition for - and possibly determined by - physiological changes in response to masked emotional faces. PMID- 29239756 TI - Lack of postexposure analgesic efficacy of low concentrations of eugenol in zebrafish. AB - OBJECTIVE: To test the postexposure analgesic efficacy of low doses of eugenol in zebrafish. STUDY DESIGN: Prospective experimental study. ANIMALS: A total of 76 large adult zebrafish (Danio rerio). METHODS: Fish swimming behavior (median velocity, freeze time, high-speed swimming and distance moved in the vertical direction) was recorded in a 1.6 L video arena before and after exposure to eugenol (0, 1, 2, 5, 10 and 20 mg L-1). In a second experiment, fish were anesthetized with 2-phenoxy-ethanol and treated with an injection of 5% acetic acid (noxious stimulus), and then exposed to 0, 1, 2 and 5 mg L-1 eugenol. The fish swimming behavior was also recorded. RESULTS: The higher doses (10 and 20 mg L-1) reduced the median velocity, high-speed swimming and distance moved in the vertical direction, and increased the freeze time. Zebrafish behavior was not altered by eugenol (1, 2 and 5 mg L-1) after noxious stimulation. CONCLUSIONS AND CLINICAL RELEVANCE: The change in the behavior of zebrafish associated with a noxious stimulus can be monitored and is a good model for studying analgesia in fish. Eugenol (10 and 20 mg L-1) induced zebrafish sedation. The response after a noxious stimulus was not affected by postexposure to lower doses, and thus we cannot recommend its use as an analgesic. PMID- 29239757 TI - Design of back-streaming white neutron beam line at CSNS. AB - A white neutron beam line using back-streaming neutrons from the spallation target is under construction at China Spallation Neutron Source (CSNS). Different spectrometers, to be installed in the so-called Back-n beam line for nuclear data measurements, are also being developed in phases. The physical design of the beam line is carried out with the help of a complicated collimation system and a sophisticated neutron dump, taking the overview of the neutron beam characteristics into account. This includes energy spectrum, flux and time structure, the optimizations of neutron beam spots and in-hall background. The wide neutron energy range of 1eV-100MeV is excellent for supporting different applications, especially nuclear data measurements. At Endstation#2, which is about 80m away from the target, the main properties of the beam line include neutron flux of 106n/cm2/s, time resolution of a few per mille over nearly the entire energy range, and in-hall background of about 0.01/cm2/s for both neutron and gamma. With its first commission in late 2017, Back-n will not only be the first high-performance white neutron source in China, but also one of the best white neutron sources in the world. PMID- 29239758 TI - Efficacy and safety comparison between different types of novel design enhanced open-irrigated ablation catheters in creating cavo-tricuspid isthmus block. AB - BACKGROUND: Clinical utility of irrigation-tip ablation catheters for cavo tricuspid isthmus (CTI) ablation is established. Recently, new-generation enhanced-cooling irrigation-tip catheters were introduced into clinical use. This study compared the performance of different types of novel irrigation-tip catheters in CTI ablation. METHODS: One hundred patients undergoing CTI ablation with novel irrigated-tip catheters were included. Ablation was performed with a power output of 30-35W using either 4-mm flexible tip catheters [FlexAbility (FAs) St. Jude Medical, St. Paul, MN, USA] or 3.5-mm enhanced-cooling ring-tip catheters without [ThermoCool SurroundFlow (SFs), Biosense Webster, Diamond Bar, CA, USA] and with contact force sensing [ThermoCool SmartTouch SurroundFlow (STSFs), Biosense Webster] in 32, 34, and 34 patients, respectively. RESULTS: The successful CTI block creation rate was significantly higher for FAs than SFs/STSFs [32/32 (100%), 30/34 (88.2%), and 27/34 (79.4%), p=0.006]. In all 11 failed procedures, block was created by additional 5 (2-7) applications with 8-mm tip catheters. The radiofrequency (RF) application number (p=0.001) and energy (p=0.021) were significantly lower, and total RF time (p=0.005) and procedure time (p=0.036) significantly shorter in the FA than SF/STSF groups. The FA catheter was associated with significantly higher tip temperature readings (34.9 degrees C vs. 32.0/33.0 degrees C, p<0.001) and lower initial impedances than SF/STSF catheters (both p<0.001). The tip temperature reached the maximum temperature setting in 15/295 (5.1%) FA catheter applications among 11 (34.3%) patients, 0/521 (0%) ST applications, and 0/448 (0%) STSF applications. The mean RF power achieved during RF applications was significantly lower for FA than SF/STSF catheters (28.6W vs. 30.4/30.8W, p<0.001). Audible steam pops were detected in 1/448 applications in only the STSF group. CONCLUSIONS: In human CTI ablation, flexible irrigation-tip catheters showed a significantly better performance than rigid enhanced-cooling irrigation-tip catheters. PMID- 29239759 TI - Alternative Treatment Options for Atrioventricular-Nodal-Reentry Tachycardia: An Emergency Medicine Review. AB - BACKGROUND: Atrioventricular-nodal-reentry tachycardia (AVNRT) is a form of supraventricular tachycardia (SVT) that is relatively common in the emergency department (ED). It is rarely indicative of underlying electrical or structural pathology. OBJECTIVE: This review evaluates the literature and controversies concerning treatment of AVNRT in the ED. DISCUSSION: For treatment of narrow complex tachycardia, Advanced Cardiovascular Life Support guidelines recommend the use of vagal maneuvers, followed by adenosine. Recent literature suggests that nondihydropyridine calcium channel blockers, such as verapamil and diltiazem, may be as effective as adenosine, without the negative short-term side effects. Multiple studies have demonstrated that although adenosine is rapid acting, there is no statistically significant difference in conversion rate between adenosine and calcium channel blockers. Both medications result in a conversion rate above 90%, but there are significantly more minor adverse effects, such as flushing or chest discomfort, with adenosine. Calcium channel blockers are a viable option for treatment for AVNRT, especially in refractory states. Beta-blockers have been evaluated but should not be used routinely due to lower efficacy. AVNRT is the most common tachydysrhythmia in pregnancy, and vagal maneuvers and adenosine are first line. Electrical cardioversion should be utilized for hemodynamically unstable patients. Most patients with AVNRT may be discharged with appropriate follow-up. CONCLUSION: Several studies demonstrate that nondihydropyridine calcium channels (verapamil and diltiazem) are equally as efficacious as adenosine in converting AVNRT to sinus rhythm, without the negative (albeit short-lived) side effects. If given over 20 min, the risk for hypotension is low. PMID- 29239760 TI - Male with Severe Hypertension and Dyspnea. PMID- 29239761 TI - Deflate to Extricate: A Technique for Rectal Foreign Body Removal of Inflatable Ball. AB - BACKGROUND: Rectal foreign bodies are commonly encountered in the emergency department (ED). Three techniques are well described in literature, including using a Foley catheter, "scooping" the object out, or grasping the object directly with ring forceps. We present a novel extraction method for an inflatable foreign body. CASE REPORT: A 27-year-old man presented to the ED 13 h after inserting a rubber inflatable child's ball into his rectum. After well described extraction techniques failed to remove the ball, an 18-gauge needle at the end of a syringe was inserted into the rectum to puncture the ball and partially deflate it. The ball was then able to be removed easily. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although recent published literature has pushed for early consultation of surgical specialties in lieu of emergency physician bedside extraction, this case report highlights the ability of emergency physicians to modify known extraction techniques to safely remove rectal foreign bodies in well-appearing patients at the bedside using appropriate analgesia, positioning, and readily available equipment. PMID- 29239762 TI - Bronchiolitis: What's All the Fuss About? PMID- 29239763 TI - The Tourniquet Gap: A Pilot Study of the Intuitive Placement of Three Tourniquet Types by Laypersons. AB - BACKGROUND: The "Stop the Bleed" campaign in the United States advocates for nonmedical personnel to be trained in basic hemorrhage control and that "bleeding control kits" be available in high-risk areas. However, it is not clear which tourniquets are most effective in the hands of laypersons. OBJECTIVES: The objective of this pilot study was to determine which tourniquet type was the most intuitive for a layperson to apply correctly. METHODS: This project is a randomized study derived from a "Stop the Bleed" education initiative conducted between September 2016 and March 2017. Novice tourniquet users were randomized to apply one of three commercially available tourniquets (Combat Action Tourniquet [CAT; North American Rescue, LLC, Greer, SC], Ratcheting Medical Tourniquet [RMT; m2 Inc., Winooski, VT], or Stretch Wrap and Tuck Tourniquet [SWAT-T; TEMS Solutions, LLC, Salida, CO]) in a controlled setting. Individuals with formal medical certification, prior military service, or prior training with tourniquets were excluded. The primary outcome of this study was successful tourniquet placement. RESULTS: Of 236 possible participants, 198 met the eligibility criteria. Demographics were similar across groups. The rates of successful tourniquet application for the CAT, RMT, and SWAT-T were 16.9%, 23.4%, and 10.6%, respectively (p = 0.149). The most common causes of application failure were: inadequate tightness (74.1%), improper placement technique (44.4%), and incorrect positioning (16.7%). CONCLUSION: Our pilot study on the intuitive nature of applying commercially available tourniquets found unacceptably high rates of failure. Large-scale community education efforts and manufacturer improvements of tourniquet usability by the lay public must be made before the widespread dissemination of tourniquets will have a significant public health effect. PMID- 29239765 TI - Immune Responses - Transcriptional and Post-Transcriptional Networks Pass the Baton. AB - Diverse gene regulatory mechanisms impact on immune homeostasis, and a new model now emerges as fundamental in light of recent genome-wide studies. In this picture, transcriptional networks drive functional changes during immune activation, whereas autoregulatory feedback loops of post-transcriptional programs ensure the original cell lineage identity and subsequent immune resolution. PMID- 29239764 TI - Treatment choices for the glycaemic management of patients with type 2 diabetes and chronic kidney disease: Analysis of the SAIL patient linked dataset. AB - AIMS: Chronic kidney disease (CKD) is common in type 2 diabetes and limits the treatment choices for glycaemic control. Our aim was to examine real-world prescribing for managing hyperglycaemia in the presence of CKD. METHODS: The SAIL (Secure Anonymised Information Linkage) databank was used to examine prescribing during the period from the 1st of January to 30th December 2014. CKD was defined as:- none or mild CKD, eGFR >=60mL/min/1.73m2; moderate CKD eGFR <60mL/min/1.73m2; and severe CKD eGFR <30mL/min/1.73m2 or requiring dialysis. RESULTS: We identified 9585 subjects who received any form of glucose lowering therapy (8363 had no/mild CKD; 1137 moderate CKD; 85 severe CKD). There was a linear association between insulin use and CKD severity with approximately 54% of those with severe CKD receiving insulin. Sulphonylureas use did not differ among the CKD groups and was approximately 40%. Metformin showed a linear decrease across the groups, however approximately 21% in the severe CKD group received metformin. The use of dipeptidyl peptidase 4 inhibitors (DPP-4i) was approximately 20% and did not differ among groups. The DPP-4 inhibitor choice was:- 1% vildagliptin, 9% saxagliptin, 58% sitagliptin, and 32% linaglitpin. With respect to sitagliptin and saxagliptin, 72% and 62% received an inappropriately high dose in the setting of CKD. CONCLUSIONS: We observed that a considerable proportion of patients with type 2 diabetes and CKD were receiving metformin and non dose-adjusted DPP-4 inhibitors. Careful consideration of medication use and dosaging is required in the setting of CKD and type 2 diabetes. PMID- 29239766 TI - FAM13A is a modifier gene of cystic fibrosis lung phenotype regulating rhoa activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition. AB - BACKGROUND: Cystic fibrosis (CF) lung disease severity is highly variable and dependent on several factors including genetic modifiers. Family with sequence similarity 13 member A (FAM13A) has been previously associated with lung function in the general population as well as in several chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), we examined whether FAM13A is a modifier gene of CF lung phenotype. We also studied how FAM13A may contribute to the physiopathological mechanisms associated with CF. METHODS: We investigated the association of FAM13A with lung function in CF French patients (n=1222) by SNP-wise analysis and Versatile Gene Based Association Study. We also analyzed the consequences of FAM13A knockdown in A549 cells and primary bronchial epithelial cells from CF patients. RESULTS: We found that FAM13A is associated with lung function in CF patients. Utilizing lung epithelial A549 cells and primary human bronchial epithelial cells from CF patients we observed that IL 1beta and TGFbeta reduced FAM13A expression. Knockdown of FAM13A was associated with increased RhoA activity, induction of F-actin stress fibers and regulation of epithelial-mesenchymal transition markers such as E-cadherin, alpha-smooth muscle actin and vimentin. CONCLUSION: Our data show that FAM13A is a modifier gene of CF lung phenotype regulating RhoA activity, actin cytoskeleton dynamics and epithelial-mesenchymal transition. PMID- 29239767 TI - Everyday cognitive failure and depressive symptoms predict fatigue in sarcoidosis: A prospective follow-up study. AB - BACKGROUND: Fatigue is a major and disabling problem in sarcoidosis. Knowledge concerning correlates of the development of fatigue and possible interrelationships is lacking. OBJECTIVE: A conceptual model of fatigue was developed and tested. METHODS: Sarcoidosis outpatients (n = 292) of Maastricht University Medical Center completed questionnaires regarding trait anxiety, depressive symptoms, cognitive failure, dyspnea, social support, and small fiber neuropathy (SFN) at baseline. Fatigue was assessed at 6 and 12 months. Sex, age, and time since diagnosis were taken from medical records. Pathways were estimated by means of path analyses in AMOS. RESULTS: Everyday cognitive failure, depressive symptoms, symptoms suggestive of SFN, and dyspnea were positive predictors of fatigue. Fit indices of the model were good. CONCLUSIONS: The model validly explains variation in fatigue. Everyday cognitive failure and depressive symptoms were the most important predictors of fatigue. In addition to physical functioning, cognitive and psychological aspects should be included in the management of sarcoidosis patients. PMID- 29239768 TI - Phenotypic spectrum of Tessier facial cleft number 5. AB - INTRODUCTION: Craniofacial clefts belong to the most disfiguring and rare congenital malformations of the face and among these, orbito-facial clefts constitute approximately 0.22 % of the cases with Tessier cleft number 5 being the least common. Our aim was to define the phenotypic spectrum for this subgroup to improve clinical management. METHODS: Our study group consisted of four patients which were treated at two different cleft centers. Retrospective chart review and anatomical analysis were conducted for each patient based on clinical evaluation and imaging studies. Morphological anomalies including soft tissue, bone and oral components were recorded. RESULTS: Based on our analysis and literature review, we could define two subtypes of Tessier facial cleft number 5. (1) Medial clefts are the more severe subtype, creating a significant soft tissue and bone defect that runs vertically, through the eyelid, infraorbital rim, maxillary sinus and cheek. They have the poorer esthetic and functional prognosis, due to orbital dystopia and absence of lower eyelid. (2) Lateral clefts are a less severe subtype characterized by the presence of a vertical furrow of the cheek running laterally to the maxillary sinus. CONCLUSIONS: We identified two subtypes of facial cleft number 5 which require an individualized surgical management. PMID- 29239769 TI - Modelling the Kinetic Response to Nutrient Fluctuations. AB - Understanding and predicting how microbes respond to environmental fluctuations is a central challenge in present-day microbiology. Erickson et al. have proposed a quantitative and (kinetic) parameters-free model of Escherichia coli growth that successfully anticipates changes in gene expression and biomass accumulation in response to nutrients up- and down-shifts. PMID- 29239770 TI - Lead identification and optimization of bacterial glutamate racemase inhibitors. AB - Mycobacterium tuberculosis glutamate racemase is an essential enzyme involved in peptidoglycan synthesis and conserved in most bacteria. Small molecule inhibitors were reported on other bacterial species whereas in M. tuberculosis it wasn't explored much. In this study we have screened in house compound library using fluorescence thermal shift assay and enzyme inhibition assay, form this (1-(3 (benzo[d]thiazol-2-yl)phenyl)-3-(p-tolyl)thiourea) was identified as lead compound with IC50 19.47 +/- 0.81 MUM. Further lead optimization by synthesis resulted in twenty-three compounds, of which Compound 25 has shown more efficacy compared to lead 1 showing non-competitive mode of inhibition with IC50 1.32 +/- 0.43 MUM. It also showed significant activity (represented in log reduction) in nutrient starved dormant M. tuberculosis model (2.1), M. tuberculosis biofilm assay (2.0) and in vivo M. marinum infected zebrafish model (3.5). PMID- 29239771 TI - Burnout Among Chinese Adult Reconstructive Surgeons: Incidence, Risk Factors, and Relationship With Intraoperative Irritability. AB - BACKGROUND: Burnout is a major concern in human service occupations, mainly characterizing in emotional exhaustion and depersonalization. There is very limited research dealing with burnout in orthopedic surgeons. Exploring burnout prevalence, risk factors, and intraoperative irritability-related incidences is necessary to improve the quality of life for surgeons. METHODS: The study population consisted of 202 registered adult reconstructive doctors in China. Burnout was measured using a normalized translated version of the Maslach Burnout Inventory-Human Service Survey. Demographics, professional characteristics, and intraoperative irritability-related questions were also collected by electronic questionnaires. Statistical analysis was performed using SPSS 22.0. RESULTS: The overall rate of burnout was 85.1%. Variables significantly associated with high emotional exhaustion scores included poor sleeping time per day (P = .008), more nights on call per week (P = .048), and absence of research (P = .014). For depersonalization, absence of marriage (P < .001) and more nights on call per week (P < .001) were selected as risk factors. The incidence of losing temper in operation is 58.9%, significantly higher in senior surgeons (P = .001). Three major reasons for irritation during operations included delays by companies providing operative devices, poor coordination of assistants, and slow movements of instrument nurses. Intraoperative irritability was found to be significantly correlated with burnout, especially in emotional exhaustion. Residents were the population having the least opportunities to lose temper in operation. CONCLUSION: Burnout is highly prevalent in Chinese adult reconstructive surgeons, and it had some correlations with irritability. Further research is needed to determine more risk factors and reduce intraoperative irritability-related incidences. PMID- 29239772 TI - Does a Program Based on Cognitive Behavioral Therapy Affect Kinesiophobia in Patients Following Total Knee Arthroplasty? A Randomized, Controlled Trial With a 6-Month Follow-Up. AB - BACKGROUND: To evaluate the effects of a cognitive behavioral therapy (CBT) program on kinesiophobia, knee function, pain and pain catastrophizing in patients following total knee arthroplasty (TKA). METHODS: This was a parallel group, randomized, controlled pilot study in which 100 patients who exhibited kinesiophobia after TKA were randomly assigned to participate in a CBT (experimental group) or standard care (control group) program. Each group included 50 patients. Before intervention (preintervention), 4 weeks after intervention (postintervention), and 6 months after the end of intervention (follow-up), patients were assessed via the Tampa Scale for Kinesiophobia, the Pain Catastrophizing Scale, a numerical rating scale, and the Hospital for Special Surgery knee rating scale. Repeated-measures analysis of variance was used to test the significance of each outcome measure. RESULTS: The CBT program had significant group (P < .001), time (P < .001), and group-by-time interaction (P < .001) effects on kinesiophobia, pain catastrophizing, and knee function, and these effects lasted for at least 6 months after the end of the intervention. Pain was reduced in both groups after the intervention, but there were significant time and group effects (P = .003) in favor of the experimental group. CONCLUSION: The CBT program was superior to standard care in reducing kinesiophobia, pain catastrophizing, and knee pain and in enhancing knee function in patients who have a high level of kinesiophobia following TKA. The treatment effect was clinically significant and lasted for at least 6 months after the end of the intervention. PMID- 29239773 TI - Femoral Nerve Palsy Following Total Hip Arthroplasty: Incidence and Course of Recovery. AB - BACKGROUND: Femoral nerve palsy (FNP) is a relatively uncommon complication following total hip arthroplasty (THA). There is little recent literature regarding the incidence of FNP and the natural course of recovery. METHODS: Using our institutional database, we identified postoperative FNPs from 17,350 consecutive primary THAs performed from 2011 to 2016. Hip exposures were performed using a direct lateral (modified Hardinge), direct anterior (Smith Peterson), anterolateral (Watson-Jones), or posterolateral (Southern or Moore) approach. Patients with FNP were contacted to provide a subjective assessment of convalescence and underwent objective muscle testing to determine the extent of motor recovery. RESULTS: The overall incidence of FNP was 0.21% after THA, with the incidence 14.8-fold higher in patients undergoing anterior hip surgery using either a direct anterior (0.40%) or anterolateral (0.64%) approach. Significant recovery from FNP did not commence for a majority of patients until greater than 6 months postoperatively. Motor weakness had resolved in 75% of patients at 33.3 months, with remaining patients suffering from mild residual weakness that typically did not necessitate an assistive walking device or a knee brace. Nearly all patients had improved sensory manifestations, but such symptoms had completely resolved in less than 20% of patients. CONCLUSION: FNP after hip surgery remains relatively uncommon, but may increase with a growing interest in anterior THA exposures. A near complete recovery with only mild motor deficits can be expected for a majority of patients in less than 2 years, although sensory symptoms may persist. PMID- 29239775 TI - Subjective evaluation of dreams in pregnant women in the different trimesters and in non-pregnant women. PMID- 29239774 TI - The clinical use of mechanical insufflation-exsufflation in children with neuromuscular disorders in Europe. AB - Mechanical insufflation-exsufflation (MI-E) is a strategy to treat pulmonary exacerbations in neuromuscular disorders (NMDs). Pediatric guidelines for optimal setting titration of MI-E are lacking and the settings used in studies vary. Our objective was to assess the actual MI-E settings being used in current clinical treatment of children with NMDs and a survey was sent in July 2016 to European expertise centers. Ten centers from seven countries gave information on MI-E settings for 240 children aged 4 months to 17.8 years (mean 10.5). Settings varied greatly between the centers. Auto mode was used in 71%, triggering of insufflation in 21% and manual mode in 8% of the cases. Mean (SD) time for insufflation (Ti) and exsufflation (Te) were 1.9 (0.5) and 1.8 (0.6) s respectively, both ranging from 1 to 4s. Asymmetric time settings were common (65%). Mean (SD) insufflation (Pi) and exsufflation (Pe) pressures were 32.4 (7.8) and -36.9 (7.4), ranging 10 to 50 and -10 to -60cmH2O, respectively. Asymmetric pressures were as common as symmetric. Both Ti, Te, Pi and Pe increased with age (p < 0.001). In conclusion, pediatric MI-E settings in clinical use varied greatly and altered with age, highlighting the need of more studies to improve our knowledge of optimal settings in MI-E in children with NMDs. PMID- 29239776 TI - Differential release of dopamine in the nucleus accumbens evoked by low-versus high-frequency medial prefrontal cortex stimulation. AB - : The medial prefrontal cortex (mPFC) coordinates goal-directed behaviors, which may be mediated through mPFC regulation of dopamine release in the nucleus accumbens (NAc). Furthermore, frequency-specific oscillatory activity between the frontal cortex and downstream structures may facilitate inter-region communication. Although high-frequency (e.g., 60 Hz) mPFC stimulation is known to increase basal dopamine levels in the NAc, little is known about how phasic dopamine release is affected by mPFC stimulation. Understanding the frequency specific control of phasic dopamine release by mPFC stimulation could elucidate mechanisms by which the mPFC modulates other regions. It could also inform optimization of deep brain stimulation for treatment of neurological disorders. OBJECTIVE: The goal of this work was to characterize the frequency response of NAc dopamine release resultant from mPFC stimulation. We hypothesized that the magnitude of dopamine release in the NAc would increase with increasing stimulation frequency. METHODS: Electrical stimulation of the mPFC of anesthetized rats was delivered at 4-60 Hz and at varying durations while measuring NAc dopamine release with fast-scan cyclic voltammetry. RESULTS: mPFC stimulation resulted in phasic dopamine release in the NAc. Furthermore, 20 Hz stimulation evoked the largest peak response for stimulation intervals >5 s when compared to higher or lower frequencies. CONCLUSIONS: Activation of the mPFC drives dopamine release in the NAc in a complex frequency- and duration-dependent manner. This has implications for the use of deep brain stimulation treatment of disorders marked by dopaminergic dysregulation, and suggest that mPFC may exert more specialized control over neuromodulator release than previously understood. PMID- 29239777 TI - A content review of online naloxone Continuing Education courses for pharmacists in states with standing orders. AB - BACKGROUND: Many community pharmacists are uncomfortable educating patients about naloxone, an opioid reversal agent. OBJECTIVE: To examine whether training materials prepare pharmacists to counsel patients and caregivers about naloxone, online naloxone education materials for pharmacists in the 13 states with standing orders were analyzed. METHODS: Two coders reviewed 12 naloxone training programs and extracted data for 15 topics that were clustered in four categories: background/importance, naloxone products, business/operations, and communication. Programs that included communication content were coded for whether they: 1) suggested specific verbiage for naloxone counseling; 2) recommended evidence based communication practices; and 3) included example naloxone conversations. RESULTS: Most programs covered the majority of topics, with the exception of extended treatment for individuals who overdose and naloxone storage/expiration information. Eleven programs addressed pharmacist-patient communication, although information on communication was often limited. Only one program included an example pharmacist-patient naloxone conversation, but the conversation was 10 min long and occurred in a private room, limiting its applicability to most community pharmacies. CONCLUSIONS: Online naloxone training materials for pharmacists include limited content on how to communicate with patients and caregivers. Training materials that include more in-depth content on communication may increase pharmacists' confidence to discuss the topics of overdose and naloxone. PMID- 29239778 TI - Accuracy of medication histories collected by pharmacy technicians during hospital admission. AB - BACKGROUND: Transitioning activities that do not require clinical judgment from pharmacists to pharmacy technicians has been endorsed as a strategy to increase patient access to clinical pharmacy services. One role becoming increasingly common is using pharmacy technicians to collect the medication history within medication reconciliation processes. OBJECTIVE: To assess the ability of pharmacy technicians to gather a complete and accurate medication history during the inpatient admission process at a regional medical center. METHODS: Prospective study of unscheduled inpatient admissions at Salem Hospital. Patients where the initial information source was patient or caregiver interview, had two medication histories collected - one by a pharmacy technician through usual care processes and one by a student pharmacist with pharmacist oversight. Medication histories were then compared and a percent accuracy ranging from 0 - 100% was calculated for each of the pharmacy technician-collected histories. RESULTS: A total of 101 patients were included from January 19 to March 6, 2016. Patients were on average 65 +/- 19 years of age and taking 7 +/- 6 medications at admission. The accuracy of the technician collected histories was 92.9 +/- 14.2%. Accuracy was not impacted by age, number of medications, or admitting shift (all p > 0.05). CONCLUSIONS: Pharmacy technicians can collect complete and accurate medication histories. Results add to the growing body of literature supporting an expanded role for pharmacy technicians in medication reconciliation processes. PMID- 29239779 TI - Gender differences in residual effect of prior drop jumps on oxygen uptake during heavy cycling exercise. AB - BACKGROUND AND OBJECTIVE: Unaccustomed eccentric or eccentric-concentric exercise leaves us stiff and sore the next day and can cause muscle damage. The data about the residual effect of prior eccentric-concentric exercises on oxygen uptake (VO2) during constant cycling exercise in women or the data about differences of such effect between genders are scarce. Therefore, the aim of this study was to assess differences of the residual effect of PDJ on VO2 during HCE and indirect muscle damage parameters between women and men. MATERIALS AND METHODS: The study aimed to asses differences of the residual effect of prior drop jumps (PDJ) on VO2 during heavy cycling exercise (HCE) and indirect muscle damage parameters between men (n=8) and women (n=11). On four different days participants performed one incremental cycling exercise and three HCE (control [CON], 45min [45' PDJ] and 24h [24h PDJ] after 100 drop jumps). The intensity of HCE was set to work rate corresponding to 50% of the difference between the second and the first ventilatory thresholds which were determined analyzing pulmonary gas exchange parameters during incremental cycling exercise. Capillary blood samples were collected in order to measure blood lactate concentration immediately after HCE and serum creatine kinase (CK) activity 24h after PDJ. Subjects rated perceived exertion and delayed onset muscle soreness (DOMS) using 20 and 10 point scales, respectively. RESULTS: VO2 at 3-6min of HCE performed 45' after PDJ was significantly increased as compared to CON HCE only in the male group. Both men and women felt moderate muscle pain. CK activity was significantly increased 24h after PDJ in the male group. Both during HCE 45' PDJ and 24h PDJ, the significant positive correlation was observed between relative changes of VO2 during steady state of HCE and CK activity only in the male group. CONCLUSIONS: Prior eccentric concentric exercise of thigh muscles (100 drop jumps) accelerates VO2 kinetics at the start and increases VO2 during steady state of heavy cycling only in the male group. So, prior exercise of such type has a higher negative impact on cycling economy in men than in women and this might be related to greater muscle damage and fatigue in physically active male persons after plyometric exercise. PMID- 29239780 TI - Recurrent Failure of Positive-Pressure Ventilation: Machine Malfunction or a Rare, Unexpected Cause? PMID- 29239781 TI - Erratum to "Reconstruction design before tumour resection: A new concept of through-and-through cheek defect reconstruction" [Oral Oncol. 74 (2017) 123-129]. PMID- 29239782 TI - The morphology of foot soft tissues is associated with running shoe type in healthy recreational runners. AB - OBJECTIVES: To determine the differences in the morphology of foot soft tissues between runners using different types of running shoes. DESIGN: Cross-sectional study. METHODS: Thirty-eight recreational runners were divided into four groups based on running shoe type, namely, neutral shoes, motion control shoes, minimalistic shoes and neutral shoes with custom-made insoles. An arch height index and a relative arch deformation index were calculated for each participant. An ultrasound device was used to measure the cross-sectional area and/or the thickness of selected intrinsic foot muscles (abductor hallucis, flexor hallucis brevis and flexor digitorum brevis) and extrinsic foot muscles (flexor digitorum longus, tibialis anterior and the peroneus muscles), and the thickness of the plantar fascia, Achilles tendon and heel pad. RESULTS: Recreational runners using minimalistic shoes demonstrated stiffer foot arches than those using neutral shoes. Among the selected foot muscles, only abductor hallucis showed a significant morphological difference between shoe groups. Runners using minimalistic shoes had the thickest abductor hallucis. The minimalistic shoe runners also showed a thinner proximal plantar fascia and a thicker Achilles tendon than other runners. Insole runners had a thinner heel pad than neutral shoe runners. CONCLUSIONS: This study suggests that the morphology of foot soft tissues is associated with running shoe type in recreational runners. A sudden change in running shoe type without adjusting training volume should be undertaken with caution, since it may take time for foot soft tissues to adapt to a new shoe condition. PMID- 29239783 TI - Early adulthood determinants of mid-life leisure-time physical inactivity stability and change: Findings from a prospective birth cohort. AB - OBJECTIVES: Physical inactivity is highly prevalent. Knowledge is needed of influences on inactive lifestyles. We aimed to establish whether early adult factors predict subsequent inactivity patterns in mid-adulthood. DESIGN: Leisure time inactivity (activity frequency<1/week) was assessed at 33y and 50y in the 1958 British Birth cohort (N=12,271). METHODS: We assessed associations of early adult (23-33y) physical status, mental function, social, family and neighbourhood circumstances with four 33-50y patterns (never inactive, persistently inactive, deteriorating or improving) using multinomial logistic regression with and without adjustment for childhood factors (e.g. social class). RESULTS: Inactivity prevalence was similar at 33y and 50y (~31%), but 17% deteriorated and 18% improved with age. Factors associated with persistent vs never inactive were: limiting illness (relative risk ratio (RRR):1.21(1.04,1.42) per number of ages exposed (0,1 or 2 times across ages 23y and 33y), obesity (1.33(1.16,1.54) per number of ages exposed), height (0.93(0.89,0.98) per 5cm), depression (1.32(1.19,1.47) per number of ages exposed); education (1.28(1.20,1.38) per decrease on 5-point scale) and neighbourhood (1.59(1.37,1.86) in 'industrial/local authority housing areas' and 1.33(1.12,1.58) in 'growth/metropolitan inner areas' vs 'suburbs, service, rural or seaside areas'). Associations were broadly similar for inactivity deterioration. Industrial/local authority housing areas (0.75(0.61,0.91)) and longer obesity exposure (0.78(0.64,0.95)) were associated with lower RRRs for improvement. Number of children was associated with improvement, although associations varied by age. Associations remained after adjustment for childhood factors. CONCLUSIONS: Several early adult factors are associated with inactivity persistence and deterioration; fewer with improvement. Obesity duration and neighbourhood lived in during young adulthood had long-lasting associations with inactivity patterns in mid-life. PMID- 29239784 TI - New perspectives for natural triterpene glycosides as potential adjuvants. AB - BACKGROUND: Triterpene glycosides are a vast group of secondary metabolites widely distributed in plants including a high number of biologically active compounds. The pharmacological potential is evaluated by using many bioassays particularly in the field of cancerology, immunology, and microbiology. The adjuvant concept is well known for these molecules in vaccines, but there is little preclinical evidence to support this concept in the management of cancer, infections and inflammation. PURPOSE: We aim to review some examples of triterpene glycosides from natural sources which exhibit adjuvant activity when they are co-adminitered with anticancer drugs, targeted toxins, antimicrobial, anti-inflammatory drugs and with antigens in vaccines. METHODS: The scientific literature on the adjuvant potential of triterpene glycosides covering mainly the last two decades has been identified by using relevant key words in the databases, using the online service such as Medline/PubMed, Scopus, Web of Science, Google Scholar. RESULTS: We divided these findings in four kind of examples, the combination of triterpene glycosides (1) with chemotherapeutic agents in conventional tumor therapies and with targeted toxins, (2) with antimicrobial drugs, (3) with antiinflammatory drugs, and (4) with an antigen in prophylactic and therapeutic vaccines. Pharmacological studies have revealed that some triterpene glycosides co-administered with anticancer drugs such as cisplatin, paclitaxel, cyclophosphamide, etoposide, 5-fluorouracyl, mitoxantrone exhibited increased cytotoxicity in tumor cells better than when the drugs were administered alone. However in vivo toxicological and pharmacokinetic studies are required before the combination strategy can be applied into clinical practice. Other studies showed that combined application of triterpene glycosides with targeted toxins resulted in the increased efficacy of the toxin, simultaneously reducing the dosage, and side effects. It was also shown that the co administration of the triterpenoids with corticosteroids synergistically inhibited the inflammatory response induced by carrageenan in rats. The search for new alternative adjuvants in vaccines in comparison with the aluminium salts inducing only a Th2-type immune response resulted in the discovery of the promising purified fraction QS-21 from Quillaja saponaria, which has been used in the development of a variety of prophylactic and therapeutic vaccines. Over 120 clinical trials for around 20 vaccine indications in infectious diseases, cancer, degenerative disorders have been reported involving more than 50,000 patients. CONCLUSION: This review summarized the successfull in vitro and in vivo studies showing that this combination approach of triterpene glycosides co-adminitered with anticancer, antimicrobial and anti-inflammatory drug may provide an exciting road for further developments in the treatment of some cancers, parasitic and inflammatory diseases and in the rational design of vaccines against infectious diseases and cancer. From a clinical point of view, the potential benefit of QS 21, a promising triterpene glycoside from Quillaja saponaria has been highlighted in several vaccine clinical trials with a favorable ratio efficacy/toxicity. PMID- 29239785 TI - Cytokines dysregulation in schizophrenia: A systematic review of psychoneuroimmune relationship. AB - INTRODUCTION: Schizophrenia is a multifactorial psychiatric disease with complex interactions among the brain and the immune system. A psycho-immune relationship underling schizophrenia is supported by several studies and integrates a specific area of knowledge - psychoneuroimmunology. METHODS: A systematic review was performed by 2009 Preferred Reporting Items (PRISMA) recommendations. Based on the inclusion/exclusion criteria, publications with relevant information (evaluated by the Joanna Briggs Institute Critical Appraisals tools to quality assessment) were included. RESULTS: In this review, we considered the inflammatory activity promoted by cytokine alterations in schizophrenia aetiology, which reflects the systemic comprehension of this disease in opposition to the traditional approach focused solely on the brain. We focus on the analysis of several specific outcomes, such as proinflammatory cytokines, sample sort, laboratory techniques, diagnosis scales and results of each publication. CONCLUSION: This systematic review confirms the existence of cytokines abnormalities in schizophrenia disease. Immune imbalances such as increased levels of some cytokines (either at protein level or at mRNA expression), cytokine mRNAs, as well as cytokine gene polymorphisms have been reported with a large support in schizophrenia. These findings provide a strong evidence of a concomitant process of inflammatory activity in schizophrenia illness course. PMID- 29239786 TI - [Nephrogenic fibrosing dermatosis: From clinic to microscopy]. AB - Nephrogenic systemic fibrosis is a rare entity occurred in patients with renal failure. It is related to toxicity to gadolinium, which is used as a contrast agent in magnetic resonance imaging. Clinic manifestations are variable. They begin by a thickening of the skin in the lower limbs and extending to the upper limbs. We report a new case of nephrogenic systemic fibrosis where cutaneous lesions begin in the upper right limb as indurated and ulcerated nodules. The diagnosis is histological. PMID- 29239787 TI - Deciphering psoriasis. A bioinformatic approach. AB - BACKGROUND: Psoriasis is an immune-mediated, inflammatory and hyperproliferative disease of the skin and joints. The cause of psoriasis is still unknown. The fundamental feature of the disease is the hyperproliferation of keratinocytes and the recruitment of cells from the immune system in the region of the affected skin, which leads to deregulation of many well-known gene expressions. OBJECTIVE: Based on data mining and bioinformatic scripting, here we show a new dimension of the effect of psoriasis at the genomic level. METHODS: Using our own pipeline of scripts in Perl and MySql and based on the freely available NCBI Gene Expression Omnibus (GEO) database: DataSet Record GDS4602 (Series GSE13355), we explore the extent of the effect of psoriasis on gene expression in the affected tissue. RESULTS: We give greater insight into the effects of psoriasis on the up regulation of some genes in the cell cycle (CCNB1, CCNA2, CCNE2, CDK1) or the dynamin system (GBPs, MXs, MFN1), as well as the down-regulation of typical antioxidant genes (catalase, CAT; superoxide dismutases, SOD1-3; and glutathione reductase, GSR). We also provide a complete list of the human genes and how they respond in a state of psoriasis. CONCLUSION: Our results show that psoriasis affects all chromosomes and many biological functions. If we further consider the stable and mitotically inheritable character of the psoriasis phenotype, and the influence of environmental factors, then it seems that psoriasis has an epigenetic origin. This fit well with the strong hereditary character of the disease as well as its complex genetic background. PMID- 29239788 TI - Amylolysis is predominated by cell-surface-bound hydrolase during anaerobic fermentation under mesophilic conditions. AB - While knowing the amylolysis mechanism is important to effectively decompose corn starch fed into an anaerobic digestor, the objective of this study was to detect the activities and locations of alpha-amylase in a continuous reactor and batch cultures. In the continuous reactor operated at 35 degrees C, the greatest cell bound alpha-amylase activity was found to be 4.7 CU mL-1 at hydraulic retention time (HRT) = 9 h, while the greatest volumetric hydrogen production rate (rH2) was observed at HRT = 3 h as 61 mmol L-1 day-1. In the batch tests, the cell bound alpha-amylase activities increased when the carbohydrate concentration decreased, and no significant reducing sugar accumulation was found in the serum bottles. By examining the specific hydrogen production rate (qH2) against different corn starch concentrations, the half-saturation constant (KSta) and the maximum qH2 were regressed to be 0.47 g L-1 and 6 mmol g-VSS-1 d-1, respectively. The electronic microscopic images showed that the microbes could colonize on the starch granules without the disturbance of any floc-like materials. Conclusively, by excluding the methanogens and floc matrix, the secreted alpha-amylases are predominately bound on the cell surfaces and enabled the microbial cells favorably attach on large substrates for hydrolysis under the mesophilic condition. PMID- 29239789 TI - Anterior cingulate volume predicts response to psychotherapy and functional connectivity with the inferior parietal cortex in major depressive disorder. AB - In major depressive disorder (MDD), the anterior cingulate cortex (ACC) has been associated with clinical outcome as well as with antidepressant treatment response. Nonetheless, the association between individual differences in ACC structure and function and the response to cognitive behavioral therapy (CBT) is still unexplored. For this aim, twenty-five unmedicated patients with MDD were scanned with structural and resting state functional magnetic resonance imaging before the beginning of CBT treatment. ACC morphometry was correlated with clinical changes following psychotherapy. Furthermore, whole-brain resting state functional connectivity with the ACC was correlated with clinical measures. Greater volume in the left subgenual (subACC), the right pregenual (preACC), and the bilateral supragenual (supACC) predicted depressive symptoms improvement after CBT. Greater subACC volume was related to stronger functional connectivity with the inferior parietal cortex and dorsolateral prefrontal cortex. Stronger subACC-inferior parietal cortex connectivity correlated with greater adaptive rumination. Greater preACC volume was associated with stronger functional connectivity with the inferior parietal cortex and ventrolateral prefrontal cortex. In contrast, greater right supACC volume was related to lower functional connectivity with the inferior parietal cortex. These results suggest that ACC volume and its functional connectivity with the fronto-parietal cortex are associated with CBT response in MDD, and this may be mediated by adaptive forms of rumination. Our findings support the role of the subACC as a potential predictor for CBT response. PMID- 29239790 TI - Anti-inflammatory profile of Aegle marmelos (L) Correa (Bilva) with special reference to young roots grown in different parts of India. AB - BACKGROUND: Aegle marmelos (Bilva) is being used in Ayurveda for the treatment of several inflammatory disorders. The plant is a member of a fixed dose combination of Dashamoola in Ayurveda. However, the usage of roots/root bark or stems is associated with sustainability concerns. OBJECTIVES: The present study is aimed to compare the anti-inflammatory properties of different extracts of young roots (year wise) and mature parts of Bilva plants collected from different geographical locations in India, so as to identify a sustainable source for Ayurvedic formulation. MATERIALS AND METHODS: A total of 191 extracts (petroleum ether, ethyl acetate, ethanol and aqueous) of roots, stems and leaves of A. marmelos (collected from Gujarat, Maharashtra, Odisha, Chhattisgarh, Karnataka and Andhra Pradesh region) were tested for anti-inflammatory effects in vitro on isolated target enzymes cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and 5 lipoxygenase (5-LOX), lymphocyte proliferation assay (LPA), cytokine profiling in LPS induced mouse macrophage (RAW 264.7) cell line and in vivo carrageenan induced paw edema in mice. RESULTS: Of 191 extracts, 44 extracts showed COX-2 inhibition and 38 extracts showed COX-1 inhibition, while none showed 5-LOX inhibition. Cytokine analysis of the 44 extracts showing inhibition of COX-2 suggested that only 17 extracts modulated the cytokines by increasing the anti inflammatory cytokine IL-2 and reducing the pro-inflammatory cytokines like IL 1beta, MIP1-alpha and IL-6. The young (2 and 3 years) roots of Bilva plants from Gujarat and young (1 yr) roots from Odisha showed the most potent anti inflammatory activity by suppressing the pro-inflammatory cytokines and inducing anti-inflammatory cytokines. These three extracts have also shown in vivo anti inflammatory activity comparable to that in adult stem and root barks. CONCLUSION: The present study reveals that young roots of Bilva plants from Gujarat and Odisha region could form a sustainable source for use in Ayurvedic formulations with anti-inflammatory activities. The present study also indicates that the region in which the plants are grown and the age of the plants play an important role in exhibiting the anti-inflammatory effect. PMID- 29239791 TI - In vitro flowering in Oldenlandia umbellata L. AB - BACKGROUND: Oldenlandia umbellata L. (Indian madder) is an antique Ayurvedic Indian herb and a source of various anthraquinone derivatives. The red dye from its roots has been used in diverse applications since ancient times. OBJECTIVES: To establish reliable and effective protocols for in vitro flowering of O. umbellata. MATERIALS AND METHODS: For in vitro flowering, organogenic calli were subcultured onto Murashige and Skoog (MS) medium supplemented with various concentrations of Naphthalene acetic acid (NAA) (0.15-1.0 mg/l) and Benzyladenine(BA) (0.5-1.5 mg/l) with and without 0.4% of coconut milk (CM). RESULTS: The highest number of in vitro flowers (22.8%) and best response (92.73%) was achieved on MS medium supplemented with 0.7 mg/l NAA + 1.5 mg/l BA with 0.4% CM. It was found that MS medium devoid of BA promoted best root development (47.3 per calli) as well as response (100%). It was also observed that when embryogenic calli grown in depletion of required nutrition transferred to fresh media induced more flowering. In vivo and in vitro floral comparative analysis revealed that in vitro flower induction was required for short time duration (20.67 days) than in vivo flower. CONCLUSION: To the best of our knowledge, this is the first report on in vitro flowering and this study will help to overcome problems associated with flower development and seed production. As a result, this study may be a potent conservation tool to restore innate population size in its natural habitat. PMID- 29239792 TI - Francisella tularensis and other bacteria in hares and ticks in North Rhine Westphalia (Germany). AB - Tularemia is a zoonotic disease caused by the bacterium Francisella tularensis. The disease can be transmitted to humans through contact with infected animals such as the European brown hare (Lepus europaeus) and ticks as vectors. The aim of this study was to isolate F. tularensis from ticks and hares in North Rhine Westphalia using cysteine heart agar to determine their genetic relatedness and to identify other bacteria that grow on this medium. 848 European brown hares and 1556 questing ticks (all Ixodes ricinus) from forests were tested using cultivation and MALDI-TOF mass spectrometry or partial 16S rRNA gene sequencing. The majority of F. tularensis isolates from hares (n=24; 96%) and genomic F. tularensis DNA recovered from ticks belonged to the basal genetic clade IV and subclade B.18. These isolates were sensitive to erythromycin and were assigned to biovar I. Only a single strain isolated from a hare was assigned to basal clade I (B.12/B.35). All isolates were sensitive to tetracycline, doxycycline, streptomycin, gentamicin, chloramphenicol, and ciprofloxacin. Only 4 tick pools were positive for F. tularensis and cultivation was not successful in any of the pools. Most of the other isolated bacteria belonged to the order Bacillales with 36 Staphylococcus isolates, 9 Bacillus isolates and 8 Paenibacillus isolates. Prominent members of Enterobacterales were represented by different genera like Pantoea, Erwinia, Raoultella etc. Several of the bacterial species were soil or plant-associated, but some of the bacterial species were found in I. ricinus for the first time. Our results showed that F. tularensis was detected only in few ticks of an endemic area, but ticks were also infected by several other bacteria with zoonotic potential. Therefore, a wider spectrum of pathogens should be considered if a patient was bitten by a tick. PMID- 29239793 TI - Medical societies, patient education initiatives, public debate and marketing of unproven stem cell interventions. AB - Businesses marketing unproven stem cell interventions proliferate within the U.S. and in the larger global marketplace. There have been global efforts by scientists, patient advocacy groups, bioethicists, and public policy experts to counteract the uncontrolled and premature commercialization of stem cell interventions. In this commentary, we posit that medical societies and associations of health care professionals have a particular responsibility to be an active partner in such efforts. We review the role medical societies can and should play in this area through patient advocacy and awareness initiatives. PMID- 29239794 TI - Use of hydrotherapy during labour: Assessment of pain, use of analgesia and neonatal safety. AB - AIM: To evaluate the effectiveness of the use of hydrotherapy in pain perception and requesting analgesia in women who use hydrotherapy during childbirth and to identify possible adverse effects in infants born in water. METHOD: A multicentre prospective cohort study was performed between September 2014 and April 2016. A total of 200 pregnant women were selected and assigned to the hydrotherapy group (HG) or the control group (CG) according to desire and availability of use, data collection started at 5cm dilatation. The instruments used were the numerical rating scale (NRS), use of analgesia, Apgar Test, umbilical cord pH and NICU admission. Participants were distributed into: HG (n=111; 50 water birth) and CG (n=89). RESULTS: Pain at 30 and 90min was lower in the HG than in the CG (NRS 30min 6.7 [SD 1.6] vs 7.8 [SD 1.2] [P<.001] and NRS 90min 7.7 [SD 1.2] vs. 8.9 [SD 1.1] [P<.001]). During the second stage of labour, pain was lower in pregnant women undergoing a water birth (NRS HG 8.2 [SD 1.2], n=50; NRS CG 9.5 [SD 0.5], n=89 [P<.001]). Relative to the use of analgesia, in the CG 30 (33.7%) pregnant women requested epidural analgesia vs. 24 (21.1%) pregnant women in HG (P=.09). The neonatal parameters after water birth were not modified compared to those born out of water. CONCLUSION: The use of hydrotherapy reduces pain during labour, and during second stage in women who undergo a water birth and the demand for analgesia decreases in multiparous pregnant women. No adverse effects were seen in infants born under water. PMID- 29239796 TI - The global cost of tuberculosis. PMID- 29239795 TI - Effects of very low calorie diets on liver size and weight loss in the preoperative period of bariatric surgery: a systematic review. AB - Restrictive diet implementation in bariatric surgery (BS) preoperative period is common, although its benefits are not well established. This study aimed to assess the effects of very low calorie diets (VLCD) on liver size and weight loss during BS preoperative period. Surgery-related complications were also assessed. A systematic review of the literature was performed. Terms such as "bariatric surgery" and "very low energy diet" were included in the search strategy. Inclusion criteria were adult patients (aged>18 yr); VLCD treatment in BS preoperative period (10 d to 12 wk); and assessment of 1 the following outcomes: weight loss, liver volume reduction, and surgical complications. There were 9 studies included (849 patients including 250 controls, 196 controls without VLCD). Of the studies, 3 were randomized clinical trials and 6 were observational studies. VLCD treatment led to weight loss (-2.8 to -14.8 kg) and to liver size reduction by 5% to 20% of the initial volume. VLCD treatment did not significantly reduce perioperative complications. However, 1 study (n = 273) reported a protective effect 30 days after surgery. This systematic review found VLCD treatment led to significant weight loss and liver volume reduction when applied to patients with obesity in BS preoperative period. The effect of VLCD on surgical risks is not clear. Standardization of dietary characteristics is needed, because weight loss and decrease in liver size were not connected to higher caloric restriction. This is an important matter in clinical practice as to avoid unnecessary prolonged and/or excessive dietary restriction. PMID- 29239797 TI - Autologous breast reconstruction using the immediately lipofilled extended latissimus dorsi flap. AB - BACKGROUND: The latissimus dorsi flap is a popular choice for autologous breast reconstruction. To dramatically improve volume, we report our experience of using the immediately lipofilled extended latissimus dorsi (ELD) flap and show it as a valid option for autologous breast reconstruction. METHODS: Patients undergoing the procedure between December 2013 and June 2016 were included. Demographic, clinical and operative factors were analysed, together with in-hospital morbidity and duration of postoperative hospital stay. RESULTS: A total of 71 ELD flaps with immediate lipofilling were performed. Forty-five reconstructions were immediate and the remaining 26 delayed. Median (range) volume of autologous fat injected immediately was 171 ml (40-630 ml). Contralateral reductions were performed in 25 patients with the median reduction volume 185 g (89-683 g). Median duration of admission was 6.5 (3-18) days and patients were followed up for 12 months (1-37). Three total flap failures occurred and had to be excised (4%). One haematoma occurred requiring drainage (1%). Signs of infection requiring intravenous antibiotics occurred in five patients (7%). In 5 patients wound dehiscence occurred, and only two of these required resuturing (3%). In total, 7 patients developed a seroma requiring repeated drainage (10%). Three reconstructions experienced mild mastectomy flap necrosis with no needing reoperation (4%). CONCLUSIONS: Our experience represents the largest series to date and shows that in carefully selected patients the technique is safe, can avoid the requirement for implants, and has the potential to streamline the reconstructive journey. PMID- 29239798 TI - Retrobulbar hematoma: A systematic review of factors related to outcomes. AB - INTRODUCTION: Retrobulbar hematoma (RBH), a rare but serious condition, can result in permanent vision loss. Although it is a known complication following trauma or facial fracture reduction, sinus surgery, or blepharoplasty, factors related to patient outcomes are not well-defined. A systematic review was performed to determine the relation of patient/treatment factors to outcomes. METHODS: Articles retrieved from a PubMed search (1989-2017) were reviewed. Demographic information, etiology, symptoms, and final vision outcomes were analyzed using Fisher's exact tests, single and multiple predictor logistic regression. RESULTS: Of 429 articles identified, 16 were included in the study. 93 cases of retrobulbar hematoma were included. 74% occurred after trauma, while 26% occurred postoperatively. Onset of symptoms occurred after approximately 24 hours. 28% received treatment within 1 hour, 54% within 1-24 hours, and 18% after 24 hours. 51% had complete visual recovery, while 27% had partial recovery, and 22% developed blindness. Older patients and patients who sustained trauma were less likely to have a full recovery (p = 0.029, p = 0.023). Increasing number of symptoms trended towards a prediction of blindness (p = 0.092). Surgical decompression and shorter time to treatment were each highly predictive of full recovery (p = 0.024, p = 0.003) and decreased likelihood of blindness (p = 0.037, p = 0.045); use of steroids was not found to be significant. DISCUSSION: Retrobulbar hematoma is a diagnostic and therapeutic emergency. Factors associated with improved outcomes include younger age, decreased number of total symptoms, surgical decompression, and shorter time to treatment. If recognized and treated early with surgical decompression, recovery of vision is possible. PMID- 29239799 TI - Occupational Determinants of Successful Aging in Older Physicians. AB - OBJECTIVES: Demographic, physical and psychological associations of successful aging (SA) have been evaluated, but occupational factors have not. Nor has SA been evaluated in a specific occupational group. The aims of this study were to examine the occupational associations of SA in older physicians, and to explore the concept of occupational SA. METHODS: Physicians aged 55+ years completed self ratings of occupational and personal SA on a 10-point visual analogue scale (VAS; 1 being "least successful" and 10 "most successful"). Associations between occupational and personal SA (defined as 8-10 on the VAS), respectively, and demographic and practice characteristics; health; social and financial resources; cognitive, emotional and motivational resources; work centrality; and anxiety about aging were examined. RESULTS: Rates of occupational SA (69.2%; 95% CI: 66.3 72.0) were significantly higher than personal SA (63.1%; 95% CI: 60.1-66.0) in the sample of 1,048 physicians. Occupational and personal SA were strongly positively correlated (r = 0.73, N = 1,041, p < 0.001). Personal SA was predicted by demographic (older age, female, international medical graduate, urban practice), physical (better self-rated health), psychological (less depression, better cognitive, emotional and motivational resources, and greater anxiety about aging), and occupational (higher work centrality, fewer practice adaptations and not intending to retire) factors. CONCLUSIONS: Occupational factors are central to physicians' self-conceptualization of SA. That greater work centrality, fewer work adaptations and less retirement planning were associated with personal SA suggests older physicians' sense of "success" is intertwined with continuing practice. There is a need for educating physicians to adapt to aging and retirement. PMID- 29239800 TI - Added Value of the Personalized Intervention for Depressed Patients with COPD. PMID- 29239801 TI - Psychogenic nonepileptic seizures: A disconnect between body and mind. PMID- 29239802 TI - Re. 'Retrograde intrarenal surgery using ureteral access sheaths is a safe and effective treatment for renal stones in children weighing <20 kg'. PMID- 29239803 TI - Ultrasound guided ureteroscopy in children: Safety and success. AB - INTRODUCTION: Ureteroscopy has been shown to be a highly efficacious and safe modality for the treatment of pediatric urolithiasis. However, conventional ureteroscopy relies on fluoroscopy for intraoperative guidance, exposing both patient and operating room personnel to ionizing radiation. Pediatric urolithiasis patients are at a particularly increased risk from this radiation exposure. The use of ultrasound in place of fluoroscopy for intraoperative guidance has emerged as one modification that can reduce radiation exposure during ureteroscopy. Although ultrasound-guided ureteroscopy has been shown to be a safe, and effective approach to stone management in adults, there have been no studies to date utilizing this approach in children. OBJECTIVE: The aim was to describe our initial experience with ultrasound-guided ureteroscopy in children as a safe and feasible modality to manage pediatric urolithiasis. STUDY DESIGN: A retrospective review of consecutive patients that underwent ultrasound-guided ureteroscopy by one pediatric urologist (A.K.S.) from 2014 to 2016 for symptomatic urolithiasis was performed. Patient data were extracted from our center's IRB-approved prospectively maintained database of all children with urolithiasis. MATERIALS AND METHODS: Real-time ultrasonic guidance was provided by a pediatric uroradiology attending, with fluoroscopy available on standby. With the probe positioned on the patient's flank, ultrasound was used to visualize advancement of guidewire, dual-lumen catheter, and ureteroscope through the ureteral orifice and up to the renal pelvis (Figure). Stones were identified and removed via basket retrieval. At the conclusion of each case, ultrasonography was then used to confirm stent placement of indwelling double pigtail ureteral catheters. RESULTS: Eleven patients were identified that underwent 12 ultrasound guided ureteroscopic procedures in an outpatient setting. Stones were accessed in various locations and were removed by basket retrieval. Laser calycostomy into calyceal diverticulum and balloon dilations of ureterovesical junction and calyceal infundibulum were also performed. There were Clavien grade I and II complications in four patients; all of which were related to pain control. DISCUSSION: To our knowledge, this is the first study reporting the successful use of ultrasound-guided ureteroscopy in children. The main limitation of this feasibility study is its small sample size. A larger series is needed to corroborate these findings and make them generalizable to a wider population. CONCLUSION: This feasibility study accomplished its aim of demonstrating for the first time that ultrasound-guided ureteroscopy can be safely used in children to manage urolithiasis. PMID- 29239804 TI - Sex determination and differentiation genes in a functional hermaphrodite scallop, Nodipecten subnodosus. AB - The lion-paw, Nodipecten subnodosus is one of three scallop species commercially exploited on the west coast of the Peninsula of Baja California. Because nothing is known about sex determination and sexual differentiation in hermaphrodite scallops, in the present work, a global transcriptomic analysis was performed in two early developmental stages, settling eyed-larvae and spat, as well as in three tissues (undifferentiated gonad, digestive gland, and adductor muscle). Over 27 million Illumina paired-end reads were obtained through the MiSeq platform. After processing the reads a total of 243,774 transcripts were assembled with an N50 of 980 and an average length of 775nt. A total of 43,252 proteins were inferred and 36,103 transcripts had at least one homolog in the SwissProt database according to a blastx search. After differential expression analyses and GO annotations it was possible to identify several sex-related genes in the scallop, including one known to be involved in the sex determination pathway of the hermaphrodite model organism Caenorhabditis elegans, N. subnodosus sex1 (Ns-sex1). Other interesting sex determination and differentiation genes were Ns-dmrta2, Ns-sox9, Ns-wnt4, Ns-doa, Ns-ovo, Ns-vir, among others. Most of these genes were mainly expressed in the testis region, suggesting their participation in male gonad region sex differentiation. These results represent the first available information on the genetics of sex determination and differentiation in a functional hermaphrodite scallop. PMID- 29239805 TI - Australian heterosexual women's experiences of healthcare provision following a pregnancy loss. AB - BACKGROUND: Despite increased awareness of the psychological impact of pregnancy loss, a lack of recognition continues with regards to women's experiences. Healthcare professionals have an important role to play in supporting women following a pregnancy loss, yet to date only a relatively small body of research has examined women's experiences with healthcare providers. AIM: This paper seeks to contribute to the literature on women's engagement with healthcare professionals by exploring the experiences of an Australian sample. METHOD: Fifteen heterosexual women living in South Australia were interviewed about their experiences of pregnancy loss. A thematic analysis was undertaken, focused on responses to one interview question that explored experiences with healthcare professionals. FINDINGS: Three themes were identified. The first theme involved negative experiences with healthcare providers, and included four subthemes: (1) 'confusing and inappropriate language and communication', (2) 'the hospital environment', (3) 'lack of emotional care', and (4) 'lack of follow-up care'. Under the second theme of positive experiences, the sub-themes of (1) 'emotionally-engaged and present individual staff', and (2) 'the healthcare system as a whole' were identified. Finally, a third theme was identified, which focused holistically on the importance of healthcare professionals. CONCLUSION: The paper concludes by discussing the importance of training for healthcare professionals in supporting women who experience a pregnancy loss, and the need for further research to explore the experiences of other groups of people affected by pregnancy loss. PMID- 29239806 TI - Development of postural control and maturation of sensory systems in children of different ages a cross-sectional study. AB - OBJECTIVE: To evaluate the stability, postural adjustments and contributions of sensory information for postural control in children. METHODS: 40 boys and 40 girls were equally divided into groups of 5, 7, 9 and 12 years (G5, G7, G9 and G12). All children were submitted to dynamic posturography using a modified sensory organization test, using four sensory conditions: combining stable or sway referencing platform with eyes opened, or closed. The area and displacements of the center of pressure were used to determine stability, while the adjustments were used to measure the speed of the center of pressure displacements. These measurements were compared between groups and test conditions. RESULTS: Stability tends to increase with age and to decrease with sensory manipulation with significant differences between G5 and G7 in different measures. G7 differed from G12 under the conditions of stable and sway platform with eyes open. G9 did not differ from G12. Similar behavior was observed for adjustments, especially in anterior-posterior directions. CONCLUSION: Postural stability and adjustments were associated with age and were influenced by sensory manipulation. The ability to perform anterior-posterior adjustments was more evident and sensory maturation occurred firstly on the visual system, then proprioceptive system, and finally, the vestibular system, reaching functional maturity at nine years of age. Seven year-olds seem to go through a period of differentiated singularity in postural control. PMID- 29239807 TI - An Objective Measurement of Lacunar Infarct Location from the Middle Cerebral Artery Stem. AB - BACKGROUND: There is emerging interest in the relationship between neuroimaging location of lacunar infarcts and underlying stroke risk factors. Recent methods used for localization of lacunar infarcts are affected by high inter-rater variability. We used a novel algorithm-driven method that provided quantitative assessment of the distance of the lacunar infarct from the origins of the lenticulostriate arteries. METHODS: We conducted a retrospective analysis of patients who presented with lacunar infarcts between 2007 and 2011. Diffusion weighted imaging and magnetic resonance angiography were used to manually mark the infarct lesion and the ipsilateral origins of lenticulostriate arteries. A 3 dimensional distance formula computed the distance between the infarct and the arterial region of interest. All distances were adjusted for brain volumes. Agreement testing using 2 blinded assessors was used to determine reproducibility of this method. RESULTS: One hundred and ten patients were included in our study, with a median age of 72 years (interquartile range 58-81); 67 (61%) were male and 33 (30%) had hypertension and other vascular risk factors including hypercholesterolemia 45 (41%), smoking 33 (30%), diabetes 24 (22%), ischemic heart disease 18 (16%), and atrial fibrillation 9 (8%). The agreement test for 33 patients demonstrated an intraclass correlation of .89 and Lin's correlation coefficient of .89 (95% confidence interval .816-.963). The median distance for the study cohort was 24.5 mm, with shorter median distances of 13.7 mm observed in patients with atrial fibrillation (P value < .005). CONCLUSION: Our study used a novel method to calculate a distance measurement, which has high inter-rater correlation. PMID- 29239808 TI - Drug Class, Renal Elimination, and Outcomes of Direct Oral Anticoagulants in Asian Patients: A Meta-Analysis. AB - BACKGROUND: Direct oral anticoagulants (DOACs) have a better risk benefit profile in Asian patients with atrial fibrillation (AF). Whether treatment effects could be modified by drug class and dependency on renal elimination of studied agents has not yet been explored. METHODS: We searched PubMed, CENTRAL, and CINAHL databases through November 2016 for phase III randomized controlled trials comparing DOACs with warfarin in patients with AF. Efficacy and safety outcomes were pooled according to drug class and dependency on renal elimination of DOACs and were compared with the Mantel-Haenszel fixed-effects model. Effect differences were assessed with Bucher's indirect comparisons using common estimates, once heterogeneity was low, and with the Bayesian method. RESULTS: Among 6496 Asian patients from 6 trials, both direct thrombin inhibitors and factor Xa inhibitors, compared with warfarin, were associated with lower risks of stroke or systemic embolism and major bleeding (risk ratio [95% confidence interval], 0.51 [0.33-0.78], 0.74 ([0.58-0.96], 0.60 [0.41-0.86], and 0.59 [0.47 0.76], respectively). There was no between-group difference in direct thrombin inhibitors and factor Xa inhibitors or in DOACs with renal elimination less than 50% and 50% or greater (all I2 < 25% and interaction P > .05). Indirect comparisons within strata of drug class and dependency on renal elimination showed no preferential effect of any given regimen over another. There was no difference in effects on ischemic and hemorrhagic stroke, intracranial hemorrhage, myocardial infarction, and all-cause mortality between DOACs stratified by pharmacologic characteristics. CONCLUSIONS: DOACs, as a therapeutic class, outperform warfarin in efficacy and safety in Asian patients with AF. PMID- 29239810 TI - Pin-up Glottoplasty: Feasibility Study of a Novel Approach Medializing or Lateralizing Immobile Vocal Folds. AB - Principles in medializing and lateralizing vocal folds have not changed a lot within the last decades (Isshiki et al, 1974; Bruenings, 1911). We present a feasibility study for a completely new approach to perform medialization and lateralization of immobile vocal folds. The method was tested on 20 human larynges by inserting a 21G needle into the vocal fold, medializing (or, in other cases, lateralizing) the vocal cord and fixing the needle at the cricoid cartilage posteriorly. The anterior and posterior fixation points of the needle allow for a stable positioning of the needle, which we consider necessary in both cases of medialization or lateralization. The needle position was examined visually as well as three-dimensionally via cone beam computed tomography. PMID- 29239809 TI - Influence of the thickness of the transverse carpal ligament in carpal tunnel syndrome. AB - OBJECTIVE: To determine if the thickness of the transverse carpal ligament measured by T2 axial magnetic resonance imaging actually influences the onset of carpal tunnel syndrome. MATERIAL AND METHOD: 94 patients between January 2015 and June 2016, of whom 28 had carpal tunnel syndrome, underwent magnetic resonance imaging, 37 with discomfort in different carpus regions without symptoms of carpal tunnel and 29 healthy subjects. Two observers performed 3 measurements in 3 different levels, and in the 3 groups of patients. RESULTS: No statistically significant differences in transverse carpal ligament thickness measurements between the carpal tunnel syndrome group and the group without carpal tunnel involvement became apparent, but statistical differences between the control group and the carpal tunnel syndrome group, and between the control group and the group without involvement of the carpal tunnel were observed. In both these groups, the thickness of the transverse ligament was higher than in the control group. DISCUSSION: An increase in the thickness of the transverse ligament in was found in this study in subjects with involvement of carpal tunnel syndrome as evidenced by numerous studies in the literature. There is no certain causative factor, but rather a set of facts that make onset of the syndrome possible in a specific group of patients. CONCLUSION: Carpal tunnel syndrome is multifactorial. The thickness of the transverse ligament does not directly affect the onset of symptoms. PMID- 29239811 TI - The Wnt/beta-catenin pathway is deregulated in cemento-ossifying fibromas. AB - OBJECTIVE: The molecular pathogenesis of cemento ossifying fibroma (COF) is unclear. The purpose of this study was to investigate mutations in 50 oncogenes and tumor suppressor genes, including APC and CTNNB1, in which mutations in COF have been previously reported. In addition, we assessed the transcriptional levels of the Wnt/beta-catenin pathway genes in COF. STUDY DESIGN: We used a quantitative polymerase chain reaction array to evaluate the transcriptional levels of 44 Wnt/beta-catenin pathway genes in 6 COF samples, in comparison with 6 samples of healthy jaws. By using next-generation sequencing (NGS) in 7 COF samples, we investigated approximately 2800 mutations in 50 genes. RESULTS: The expression assay revealed 12 differentially expressed Wnt/beta-catenin pathway genes in COF, including the upregulation of CTNNB1, TCF7, NKD1, and WNT5 A, and downregulation of CTNNBIP1, FRZB, FZD6, RHOU, SFRP4, WNT10 A, WNT3 A, and WNT4, suggesting activation of the Wnt/beta-catenin signaling pathway. NGS revealed 5 single nucleotide variants: TP53 (rs1042522), PIK3 CA (rs2230461), MET (rs33917957), KIT (rs3822214), and APC (rs33974176), but none of them was pathogenic. CONCLUSIONS: Although NGS detected no oncogenic mutation, deregulation of key Wnt/beta-catenin signaling pathway genes appears to be relevant to the molecular pathogenesis of COF. PMID- 29239812 TI - Dosimetric impact of inter-observer catheter reconstruction variability in ultrasound-based high-dose-rate prostate brachytherapy. AB - PURPOSE: To investigate the dosimetric impact of interobserver catheter reconstruction variability in transrectal ultrasound-guided prostate high-dose rate (HDR) brachytherapy. METHODS AND MATERIALS: Twenty consecutive patients with intermediate- or high-risk prostate cancer were treated with a single, 15-Gy HDR brachytherapy boost as part of this study. The treated plan was used as the study reference plan (PR). Three expert treatment planners (observers) manually reconstructed the catheter paths on the static three-dimensional transrectal ultrasound images, and new plans were generated from the updated positions (POBS); subsequently, the dwell time and positions from the POBS plans were superimposed on the PR catheter paths to evaluate the dosimetric effect of the interobserver variations (PEVAL). Plans from each group were stratified by observer and by number of catheters (12 or 16) and then compared using a one-way Kruskal-Wallis H test with post hoc Mann-Whitney U tests reserved for significant variations (alpha = 0.05). RESULTS: Greater than 98.9% of catheter reconstruction variations were <3 mm. When stratified by observer, there was a significant decrease (p << 0.05) in planning target volume (PTV) V100% and increases in the urethral Dmax between the POBS plans propagated to the PR catheter paths and dosimetry evaluated and PR plans only. Stratification of plans by catheter number showed nonclinically significant decreases in PTV V100%, and D90% and increases in urethral Dmax for the 12-catheter plans. CONCLUSIONS: Limiting interobserver variability, and its effects on prostate HDR brachytherapy plan quality, is critical to achieving good dosimetric outcomes; small variations in catheter reconstruction may translate to inadequate PTV coverage, excessive urethral dose, or both. PMID- 29239813 TI - Experimental assessment of the Advanced Collapsed-cone Engine for scalp brachytherapy treatments. AB - PURPOSE: To experimentally assess the performance of the Advanced Collapsed-cone Engine (ACE) for 192Ir high-dose-rate brachytherapy treatment planning of nonmelanoma skin cancers of the scalp. METHODS AND MATERIALS: A layered slab phantom was designed to model the head (skin, skull, and brain) and surface treatment mold using tissue equivalent materials. Six variations of the phantom were created by varying skin thickness, skull thickness, and size of air gap between the mold and skin. Treatment planning was initially performed using the Task Group 43 (TG-43) formalism with CT images of each phantom variation. Doses were recalculated using standard and high accuracy modes of ACE. The plans were delivered to Gafchromic EBT3 film placed between different layers of the phantom. RESULTS: Doses calculated by TG-43 and ACE and those measured by film agreed with each other at most locations within the phantoms. For a given phantom variation, average TG-43- and ACE-calculated doses were similar, with a maximum difference of (3 +/- 12)% (k = 2). Compared to the film measurements, TG-43 and ACE overestimated the film-measured dose by (13 +/- 12)% (k = 2) for one phantom variation below the skull layer. CONCLUSIONS: TG-43- and ACE-calculated and film measured doses were found to agree above the skull layer of the phantom, which is where the tumor would be located in a clinical case. ACE appears to underestimate the attenuation through bone relative to that measured by film; however, the dose to bone is below tolerance levels for this treatment. PMID- 29239814 TI - Surgical considerations and challenges in the pediatric and adolescent gynecologic patient. AB - It is important for practitioners to recognize that there are special considerations when performing gynecologic surgery in a pediatric or adolescent patient. A provider must be familiar with differences in anatomy, physiology, surgical technique, and psychosocial concerns. This can be challenging for a provider who does not routinely operate on patients in this population. A minimally invasive surgical approach is preferred in the pediatric and adolescent patient whenever possible. While a good command of laparoscopy in the adult patient is certainly a useful skill when operating on pediatric and adolescent patients, there are technical adaptations and challenges to consider. This chapter reviews the pre-operative preparation, operative technique and challenges, and post-operative care of the surgical pediatric and adolescent gynecologic patient. PMID- 29239815 TI - Provider recommendations for patient-reported muscle symptoms on statin therapy: Insights from the Understanding Statin Use in America and Gaps in Patient Education survey. AB - BACKGROUND: Statin-associated muscle symptoms are reported by 10% to 29% of patients in clinical practice and are a major determinant of statin nonadherence, discontinuation, and switching. Little is known about what advice patients receive from their providers when dealing with these symptoms. OBJECTIVE: The objective of the study was to assess patient's reports of provider advice when experiencing new or worsened muscle symptoms while taking a statin. METHODS: Data were analyzed from the Understanding Statin Use in America and Gaps in Education survey, a self-administered internet-based survey of 10,138 adults with a reported history of high cholesterol and statin use. RESULTS: Of the respondents, 60% of former statin users (n = 1220) reported ever experiencing new or worsened muscle pain on a statin, in contrast to 25% of current users (n = 8918; P < .001). Former statin users reported stopping more statins because of muscle symptoms (mean +/- standard deviation, 2.2 +/- 1.7) compared with current users (mean 1.6 +/- 1.5, P < .0001). For those with muscle-related symptoms while on a statin, participants reported that providers most often suggested switching to another statin (33.8%), stopping the statin (15.9%), continuing the statin with further monitoring of muscle symptoms (12.2%), reducing the statin dose (9.8%), or getting a blood test for signs of muscle damage (9.2%). A lower percentage were advised to add either vitamin D (7.0%) or coenzyme Q10 (5.8%), or to switch to nonstatin therapy (6.1%) or red yeast rice (2.6%). CONCLUSIONS: This study highlights patient experience with statin-associated muscle symptoms and the strategies recommended by providers in managing these symptoms. More research is needed to develop patient-centric and evidence-based approaches to managing statin-associated muscle symptoms, which is especially important in light of recent data showing increased cardiovascular risk among those who discontinue statin therapy. PMID- 29239816 TI - MiR-9-5p promotes cell growth and metastasis in non-small cell lung cancer through the repression of TGFBR2. AB - BACKGROUND: Increasing evidence indicates that the dysregulation of microRNAs (miRNAs) play critical roles tumor progression and metastasis, but very few papers had reported the function of miR-9-5p in lung cancer, especially in NSCLCs. METHODS: In this study, we investigated the role of miR-9-5p in non-small cell lung cancers (NSCLCs). MiR-9-5p level were analyzed in 62 clinical NSCLC lung tissue samples and adjacent normal lung tissues by RT-PCR. The target of miR 9-5p was predicted by TargetScan and luciferase reporter assay was used to verify the binding site of miR-9-5p on TGFBR2 mRNA. MTT assay, wound healing assay and invasion assay were performed in both miR-5p inhibitor transfected A549 and miR 5p mimic transfected SK-MES-1 cells. To further investigate whether TGFBR2 is the major target of miR-9-5p, we used TGFBR2 siRNA to transfect A549 and SK-MES-1 cells with miR-9-5p inhibitor or miR-9-5p mimic transfection. Western blot were then used to analyze TGFBR2, p-smad2 and p-smad3 protein expressions after transfection. RESULTS: Results indicated that NSCLC patients' tissues had a significantly higher expression of miR-9-5p compared to adjacent normal lung tissues. MiR-9-5p mimic transfection promoted proliferation, metastasis and invasion abilities in both A549 and SK-MES-1 cells. Conversely, miR-9-5p inhibitor transfection showed the decreased abilities of these cells. Luciferase reporter assay indicated that TGFBR2 is a direct target of miR-9-5p and the up regulation of TGFBR2 suppressed cell proliferation, metastasis and invasion. The knock down of TGFBR2 abrogated the effect of miR-9-5p in down-regulating p-smad2 and p-smad3 expressions, which indicated that TGFBR2 is the major target of miR-9 5p in NSCLC cells. CONCLUSIONS: Our finding indicated that miR-9-5p promotes the proliferation, metastasis and invasion of NSCLC cells by down-regulating TGFBR2 expression. PMID- 29239817 TI - In vitro and in vivo antitumor effects of the diterpene-enriched extract from Taxodium ascendens through the mitochondrial-dependent apoptosis pathway. AB - Extracts and components of Taxodium ascendens Brongn, an excellent afforestation tree, have exhibited several activities, including antibacterial activity and inhibitory activity on carbonic anhydrase II. However, the anti-hepatocellular carcinoma (anti-HCC) activity of extracts from the leaves of T. ascendens (TALE) remains unclear. In the present study, six diterpenoid compounds were isolated from a TALE extract. Here, the pro-apoptotic activities and the molecular mechanisms of TALE and the compounds 1-6 on HepG2 and Hep3B HCC cells were evaluated. Results show that the TALE and compounds 1-6 were able to induce apoptosis in the HepG2 and Hep3B HCC cells, particularly ferruginol (3). Mechanistically, the application of TALE and ferruginol (3) resulted in a significant decrease in mitochondria membrane potential, which was coupled with an increase in the Bax/Bcl-2 ratio and caspase-3/-9 activity. In vivo experiments showed that oral administration of TALE inhibited the proliferation of transplanted H22 cells in Kunming mice. However, TALE toxicity in KM mice was undetectable. The study provides strong evidence for the anti-HCC capacity of TALE. PMID- 29239818 TI - Inhibitory effect of compound Chuanxiong Kangxian granules on bleomycin-induced pulmonary fibrosis in rats. AB - BACKGROUND: The diverse medicinal properties of herbal compounds make them suitable candidates to treat multifactorial conditions such as pulmonary fibrosis. We investigated the effects and mechanisms of compound Chuanxiong Kangxian granules (CCKG) on a bleomycin (BLM)-induced pulmonary fibrosis model in rats. METHODS AND RESULTS: Following an intratracheal instillation of BLM, Sprague Dawley rats were intragastrically administrated with different doses of CCKG solution or hydrocortisone for 28 d, while control and BLM-treated rats were administered with saline solution. The effects of CCKG treatment on pulmonary injury were evaluated with lung wet/dry weight ratios, histopathology and levels of hydroxyproline. Oxidative stress was evaluated by detecting serum levels of glutathione and total superoxide dismutase. Inflammation was assessed by measuring levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 in bronchoalveolar lavage fluid. Immunohistochemistry and western blotting was used to analyze protein expressions of matrix metalloproteinase-2, 9, alpha smooth muscle actin and transforming growth factor-beta1 in lung tissue. The results indicate that CCKG treatment can ameliorate BLM-induced pulmonary fibrosis and attenuate BLM-induced oxidative stress and inflammation. CONCLUSIONS: We found that CCKG-mediated suppression of fibroproliferation and may contribute to the anti-fibrotic effect by inhibiting oxidative stress and inflammatory responses. Our study indicates a therapeutic potential for CCKG in the treatment of pulmonary fibrosis. PMID- 29239819 TI - LncRNA HOXD-AS1 promotes epithelial ovarian cancer cells proliferation and invasion by targeting miR-133a-3p and activating Wnt/beta-catenin signaling pathway. AB - BACKGROUND: Long non-coding RNA (lncRNA) HOXD cluster antisense RNA 1 (HOXD-AS1) functions as a crucial regulator in the progression and development of tumors. The aim of this study is to unravel the underlying mechanisms of HOXD-AS1 on epithelial ovarian cancer (EOC). METHODS: 43 paired EOC tissues and adjacent non tumor tissues were collected postoperatively from patients. QRT-PCR was used to explore HOXD-AS1 expression in both EOC tissues and cell lines. Cell proliferation and invasion were monitored by MTT assay and transwell invasion assay. RESULTS: In the current study, we found that the expression of HOXD-AS1 was upregulated in EOC tissues and cell lines. High HOXD-AS1 expression was correlated with advanced FIGO stage, lymph node metastasis, and poor overall survival in EOC patients. We also showed that HOXD-AS1 promoted cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) via activating Wnt/beta-catenin signaling in EOC cells. Furthermore, we found that miR-133a-3p was a direct downstream target of HOXD-AS1 in EOC. HOXD-AS1 promoted cell proliferation, invasion, and EMT process through sponging miR-133a-3p in EOC cells. CONCLUSION: Our study indicated that lncRNA HOXD-AS1 promoted the proliferation, invasion, and EMT process of EOC cells via targeting miR-133a-3p and activating Wnt/beta-catenin signaling pathway. PMID- 29239820 TI - All-trans retinoic acid induces mitochondria-mediated apoptosis of human adipose derived stem cells and affects the balance of the adipogenic differentiation. AB - The all-trans-retinoic acid (ATRA) is the most active form of vitamin A that helps to regulate the proliferation, differentiation and apoptosis of several types of cells, mainly the adipocytes, and causes weight loss through the reduction of adipogenesis and lipogenesis. In this present study we demonstrated that ATRA concentrations of 20.75, 50 and 100 MUM decreased the cell viability in vitro of human adipose-derived stem cells (ADSCs), and in ADSCs during adipogenic differentiation. The cells cycle assessment showed that ATRA increased the cell frequency in Sub-G1 at 4.02x and decreased it in G1 in 2.54x. Moreover, the membrane integrity loss increased by 4.66x and apoptosis increased by 33.56x in ATRA-treated cultures. The gene expression assay suggested that the treatment using ATRA leads to mitochondrial membrane permeabilization and to consequent release of proapoptotic BAK and BAX molecules (increased expression 5.5 and 5.4x respectively); in addition, it increased CASP3 expression (by 8.8x). These events may activate the Bcl-2 (4.1x increase), GADD45 (increase 3.14x) and PPAR-gamma (16x increase) expressions, as well as, to reduce the p53 (by -1.38x) expression; therefore, these events should be further mediated by increased RARalpha expression (by 3.8x). The results evidenced that ATRA may be a good proposal for mesotherapy strategies in order to control the development of subcutaneous adipose tissue; as this tissue have a higher development in some specific areas and ATRA interferes not only in the ADSCs differentiation but also in the apoptosis of ADSCs, preadipocytes and adipocytes. PMID- 29239821 TI - Long noncoding RNA FEZF1-AS1 indicates a poor prognosis of gastric cancer and promotes tumorigenesis via activation of Wnt signaling pathway. AB - Long non-coding RNAs (lncRNAs) have been demonstrated that it plays very important role in development and progression of carcinomas. LncRNA FEZF1 antisense RNA 1 (FEZF1-AS1) has been proved to be implicated in tumor initiation and progression of various cancers, recently. Nevertheless, the biological function and clinical significance of lncRNA FEZF1-AS1 in gastric cancer (GC) are not clear enough. Here, we concentrated on the association of FEZF1-AS1 expression and clinicopathological factors in GC tissues and cells. Moreover, we explored the potential regulatory mechanisms. The results showed that lncRNA FEZF1-AS1 was observably upregulated in human GC tissues and GC cell lines, compared with the adjacent non-tumor tissues and human gastric epithelial cell line (GES-1). Moreover, high expression of lncRNA FEZF1-AS1 was significantly associated with later stage and higher grade. Furthermore, Kaplan-Meier survival analysis was conducted, indicating that lncRNA FEZF1-AS1 may be an independent prognostic factor in GC. Additionally, the area under the receiver operating characteristic (ROC) curve of lncRNA FEZF1-AS1 exhibited its diagnostic value in GC. Notably, whenever the lncRNA FEZF1-AS1 was silenced, the proliferation of GC cells were significantly inhibited and the cell cycle was arrested at a G0/G1 stage in GC cells. Furthermore, downregulation of lncRNA FEZF1-AS1 could suppress the activation of the Wnt/beta-catenin signaling pathway. Conclusively, our findings indicated that lncRNA FEZF1-AS1 could be considered as a novel biomarker for the treatment of GC. PMID- 29239822 TI - The Effect of Antiretroviral Stock-Outs on Medication Adherence Among Patients Living With HIV in Ghana: A Qualitative Study. AB - Stock-outs of medications for antiretroviral therapy have been reported as a significant barrier to HIV care in sub-Saharan Africa, but patient responses to these shortages have not been fully described. The aim of our study was to employ qualitative methods to examine the role of medication stock-outs in contributing to treatment interruption among a sample of patients already engaged in care for HIV at Komfo Anokye Teaching Hospital in Kumasi, Ghana. We found that medication stock-outs presented a number of challenges to adherence for patients undergoing HIV treatment. Often, patients interrupted treatment until the stock-out ended. Those who did not interrupt treatment during stock-outs coped with shortages by stockpiling old medication or experienced clinic-initiated changes to their treatment regimens. Particularly in areas lacking the resources to monitor viral load or viral genotype, viral resistance could develop due to frequent unstructured treatment interruptions as a result of stock-outs. PMID- 29239823 TI - Getting HIV Self-Test Kits into the Home for Young African American MSM in Los Angeles: A Qualitative Report. PMID- 29239824 TI - The evolution of cerebrovascular changes in Kohlmeier-Degos disease: An 11-year follow-up case report. AB - Kohlmeier-Degos disease is rare idiopathic vasculopathy, the exact pathogenesis of which remains unclear. Here, we review pertinent literatutre and present a case of a Kohlmeier-Degos disease with central nervous system involvement followed-up over 11 years with various neuroimaging modalities. Evolution of neurovascular and neuropathological changes over an extended time period has not been previously described. PMID- 29239825 TI - Palpebral portion of the orbicularis oculi muscle to repetitive nerve stimulation testing: A potential assessment indicator in patients with generalized myasthenia gravis. AB - Repetitive nerve stimulation (RNS) is a valuable diagnostic method for myasthenia gravis (MG). However, its association with clinical severity was scarcely studied. We reviewed medical records and retrospectively enrolled 121 generalized MG patients. Sensitivity of different muscles to RNS and clinical scoring systems was evaluated. RNS testing revealed facial muscles have the highest positive rate, followed by proximal muscles and distal muscles, with the palpebral portion of the orbicularis oculi muscle most sensitive. Amplitude decrement of compound muscle action potential (CMAP) in the palpebral portion of the orbicularis oculi muscle is related to quantitative myasthenia gravis (QMG) scores, MG-specific manual muscle testing (MMT) scores and myasthenia gravis-related activities of daily living (MG-ADL) scores. We suggest that RNS testing of the palpebral portion of the orbicularis oculi muscle is a potential assessment indicator in patients with generalized MG. PMID- 29239827 TI - Factors affecting body composition in preterm infants: Assessment techniques and nutritional interventions. AB - Limited research has been conducted that elucidates the growth and body composition of preterm infants. It is known that these infants do not necessarily achieve extra-utero growth rates and body composition similar to those of their term counterparts. Preterm infants, who have difficulty in achieving these growth rates, could suffer from growth failure. These infants display an increased intra abdominal adiposity and abnormal body composition when they achieve catch-up growth. These factors affect the quality of weight gain, as these infants are not only shorter and lighter than term infants, they also have more fat mass (FM) and less fat-free mass (FFM), resulting in a higher total fat percentage. This could cause metabolic syndrome and cardiovascular problems to develop later in a preterm infant's life. The methods used to determine body composition in preterm infants should be simple, quick, non-invasive and inexpensive. Available literature was reviewed and the Dauncey anthropometric model, which includes skinfold thickness at two primary sites and nine body dimensions, is considered in this review the best method to accurately determine body composition in preterm infants, especially in resource-poor countries. It is imperative to accurately assess the quality of growth and body composition of this fragile population in order to determine whether currently prescribed nutritional interventions are beneficial to the overall nutritional status and quality of life-in the short- and long-term-of the preterm infant, and to enable timely implementation of appropriate interventions, if required. PMID- 29239826 TI - Circulating cathelicidin LL-37 level is increased in euthymic patients with bipolar disorder. AB - More and more data seems to imply that immune mechanisms are involved in the pathomechanism of bipolar disorder (BD). However, the primary role of cathelicidin LL-37 is defense against pathogens, more and more data indicated that this peptide strongly modulates immune system functioning and contributes to immune pathology of chronic and inflammatory diseases. No data is available on the level of LL-37 in bipolar patients. The aim of the study was to examine the circulating levels of cathelicidin LL-37 in euthymic patients with BD. Forty patients with BD and fifty-nine healthy volunteers were enrolled into the study. Concentration of LL-37 in serum was assessed using immunoenzymatic test ELISA. The mean LL-37 concentration in bipolar patients and in healthy subjects were 4.60 +/- 7.65 ng/mL and 1.92 +/- 2.89 ng/mL, respectively, and the difference was statistically significant (p = 0.035). Within the BD group LL-37 level was significantly higher in women than in men (p = 0.045). The evaluation of serum LL 37 concentration during stable 8 week treatment indicated that at baseline (T1) mean level of LL-37 was 5.82 +/- 10.59 ng/mL; and after treatment (T2) was 4.33 +/- 5.87 ng/mL; the difference between T1 and T2 was not significant. Elevated serum levels of LL-37 in bipolar patients may suggest the role of this peptide in the pathomechanism of BD. PMID- 29239828 TI - Evaluate the diagnosis of neonatal sepsis by measuring interleukins: A systematic review. AB - Neonatal sepsis is a dangerous and common disease among infants which is associated with high morbidity and mortality. Interleukins may be helpful for diagnosis of neonatal sepsis. Therefore, this study is conducted to investigate the role of interleukins in the diagnosis of neonatal sepsis. In this study, databases including PubMed, Cochrane Library, ISI and Google Scholar were searched up to 2016. Keywords were: Sepsis, neonatal, interleukins, prediction and diagnosis. Study inclusion criteria were: Articles about the relationship between the diagnosis of neonatal sepsis and interleukins; studies on babies; English and Persian articles and enough information from test results. Articles that had focused on adult sepsis or had used other markers except ILs or just their abstracts were available were excluded from the study. Of 100 searched studies, eventually, 16 articles were considered including 12 prospective studies, 3 cross-sectional studies and 1 retrospective study. IL6 has been studied more than other interleukins (50% of articles). ILs 6, 8 and 10 are among the initial markers of neonatal sepsis diagnosis. IL6 above 68 pg/ml had 85% sensitivity and 80% specificity, IL8 above 269.51 pg/ml had 80% sensitivity and 50% specificity, IL10 above 27 pg/ml had 60% sensitivity and 87% specificity and combined interleukins above 186.83 pg/ml had 75.63% sensitivity and 71.49% specificity in sepsis diagnosis. Interleukins can be helpful in the diagnosis of neonatal sepsis based on the results of this study. IL6 had the most sensitivity and IL10 had the most specificity for diagnosis of sepsis. PMID- 29239830 TI - The hazards of look alike packaging in anaesthesia practice. PMID- 29239829 TI - Marked elevation of circulating CD19+CD38hiCD24hi transitional B cells give protection against neonatal sepsis. AB - BACKGROUND: Adequate functions of immunoregulation, mediated by regulatory cells such as IL-10 producing CD19+CD38hiCD24hi transitional B cells (Trans), play an important role in control of excessive inflammatory response. Yet, the role of Trans in neonatal sepsis is incompletely understood. We investigated the role of Trans in late-onset sepsis (LOS). METHODS: We used multicolor flow cytometry to analyse the phenotypes of B cells drawn from a cohort of 16 neonatal late-onset sepsis (LOS) (12 survivors and 4 non-survivors) and 20 healthy neonates over time. RESULTS: Patients undergone a serious decline of lymphocytes at the beginning of sepsis and then noticeable elevation during one week of follow-up had a good prognosis. Intriguingly, peripheral blood B cells, especially Trans, were the marked increase lymphocyte subset and maintained a high level of producing IL-10 during the 7 days of follow-up. CONCLUSION: The level of IL-10 producing Trans was significantly elevated in peripheral blood of good prognosis newborns with LOS and might contribute to the successful immunoprotective state of the disease. PMID- 29239831 TI - Factors associated with in-hospital mortality among critically ill surgical patients with multidrug-resistant Gram-negative infections. AB - PURPOSE: Multidrug-resistant (MDR) Gram-negative infection increases risk of mortality, other complications, and costs. The objective of this study was to determine the prevalence of and identify factors associated with in-hospital mortality among critically ill surgical patients. MATERIALS AND METHODS: This case-control study included critically ill surgical patients from 2011 to 2014 who had a carbapenem-resistant Enterobacteriaceae (CRE), MDR P. aeruginosa, or MDR Acinetobacter spp. infection. Characteristics of patients surviving to hospital discharge were compared to those of non-survivors. RESULTS: Sixty-two patients were included. Of these, 21 (33.9%) died prior to discharge. Vasopressors and mechanical ventilation prior to index culture were more common in non-survivors vs. survivors (76.2% vs. 46.3%, p=0.03; and 100% vs. 63.4%, p=0.001). ICU and hospital LOS prior to index culture was longer in non-survivors vs. survivors (median 19 vs. 4days, p=0.001; and median 25 vs. 7days, p=0.009). In multivariate logistic regression, achievement of source control was the only variable associated with decreased in-hospital mortality [0.04 (95% CI 0.003 0.52); p=0.01]. CONCLUSIONS: MDR Gram-negative infection is associated with significant in-hospital mortality among critically ill surgical patients. Source control, along with prior ICU LOS, mechanical ventilation status, vasopressor use, and definitive antibiotic choice, are important predictors of survival in this population. PMID- 29239832 TI - Magnetic resonance elastography for examining developmental changes in the mechanical properties of the brain. AB - Magnetic resonance elastography (MRE) is a quantitative imaging technique for noninvasively characterizing tissue mechanical properties, and has recently emerged as a valuable tool for neuroimaging. The measured mechanical properties reflect the microstructural composition and organization of neural tissue, and have shown significant effects in many neurological conditions and normal, healthy aging, and evidence has emerged supporting novel relationships between mechanical structure and cognitive function. The sensitivity of MRE to brain structure, function, and health make it an ideal technique for studying the developing brain; however, brain MRE studies on children and adolescents have only just begun. In this article, we review brain MRE and its findings, discuss its potential role in developmental neuroimaging, and provide suggestions for researchers interested in adopting this technique. PMID- 29239834 TI - Do Residency Selection Factors Predict Radiology Resident Performance? AB - RATIONALE AND OBJECTIVES: The purpose of our study is to determine what information in medical student residency applications predicts radiology residency success as defined by objective clinical performance data. MATERIALS AND METHODS: We performed a retrospective cohort study of residents who entered our institution's residency program through the National Resident Matching Program as postgraduate year 2 residents and completed the program over the past 2 years. Medical school grades, selection to Alpha Omega Alpha (AOA) Honor Society, United States Medical Licensing Examination (USMLE) scores, publication in peer-reviewed journals, and whether the applicant was from a peer institution were the variables examined. Clinical performance was determined by calculating each resident's cumulative major discordance rate for on-call cases the resident read and gave a preliminary interpretation. A major discordance was defined as a difference between the preliminary resident and the final attending interpretations that could immediately impact the care of the patient. A multivariate logistic regression was performed to determine significant variables. RESULTS: Twenty-seven residents provided preliminary reports on call for 67,145 studies. The mean major discordance rate was 1.08% (range 0.34% 2.54%). Higher USMLE Step 1 scores, publication before residency, and election to AOA Honor Society were all statistically significant predictors of lower major discordance rates (P values 0.01, 0.01, and <0.001, respectively). CONCLUSIONS: Overall resident performance was excellent. There are predictors that help select the better performing residents, namely higher USMLE Step 1 scores, one to two publications during medical school, and election to AOA in the junior year of medical school. PMID- 29239833 TI - Diagnostic Utility of 3T Lung MRI in Children with Interstitial Lung Disease: A Prospective Pilot Study. AB - RATIONALE AND OBJECTIVES: The objective of this study was to assess the diagnostic utility of 3-tesla (3T) magnetic resonance imaging (MRI) of lungs in the detection of interstitial lung disease (ILD) in pediatric patients. MATERIALS AND METHODS: Twelve children (mean: 8.5 years, range: 4-12 years) with ILD were consecutively enrolled in this prospective study. HRCT and 3T lung MRI were performed in all patients within 2 days of each other. The sensitivity, the specificity, the positive predictive value, and the negative predictive value of detecting lung abnormalities related to ILD with 3T lung MRI were calculated, with high-resolution computed tomography (HRCT) as a standard of reference. Agreement between HRCT and 3T lung MRI, as well as between two reviewers, was calculated with the kappa coefficient. RESULTS: 3T lung MRI had low sensitivity (66.67%) and high specificity (97.33%) in the detection of abnormalities related to ILD when compared to HRCT in children. Although 3T lung MRI performed well in the detection of consolidation, parenchymal bands and fissural thickening with a sensitivity of 100%, the sensitivity of 3T lung MRI in the detection of septal thickening, ground-glass opacity, nodules, and cysts was relatively low (50.0%, 50.0%, 66.67%, and 25.0%, respectively). Substantial agreement was seen between HRCT and 3T lung MRI (k = 0.7), whereas perfect agreement was seen between two reviewers in detecting abnormalities related to pediatric ILD (k = 0.9-1.0). CONCLUSIONS: In comparison to HRCT, 3T lung MRI with routinely available MRI protocols and sequences can also well detect abnormalities such as consolidation, parenchymal bands, and fissural thickening in children with ILD. However, evaluation of septal thickening, ground-glass opacity, nodules, and cysts is limited with 3T lung MRI. PMID- 29239835 TI - Income Inequality and Mortality Owing to Breast Cancer: Evidence From Brazil. AB - BACKGROUND: The relationship between breast cancer and inequality income is unclear. This study analyzed the correlation between income inequality and mortality standardized by age and proportional mortality owing to breast cancer among Brazilian women. PATIENTS AND METHODS: This is an ecological study using data of the federative units and Federal District of Brazil in 2010. The age standardized mortality owing to breast cancer was estimated using data from the Department of Informatics of Brazil's Unified Health System. Income inequality indicators used included the Gini index, Theil-L index, Palma index, and the ratio of income distribution quintiles obtained from the United Nations Development Program. We used Pearson correlation and linear regression adjusted for income per capita and other variables. RESULTS: An increase of 0.1 in the Gini index was associated with increases of 9.8 deaths per 100,000 women (95% confidence interval [CI], 1.7-17.9); an increase in the Palma index was associated with increases in mortality of 0.7 deaths per 100,000 women (95% CI, 0.1-1.4), an increase in the Theil-L index was associated with increases in mortality of 4.9 deaths per 100,000 women (95% CI, 1.9-7.9), and of 0.8 (95% CI, 0.2-1.5) in the proportional mortality. CONCLUSION: Income inequality, as assessed by the Gini, Palma, and Theil-L indexes, is positively associated with an increase in breast cancer mortality in Brazil. PMID- 29239836 TI - Determinants of Weight Gain During Adjuvant Endocrine Therapy and Association of Such Weight Gain With Recurrence in Long-term Breast Cancer Survivors. AB - BACKGROUND: Weight gain is a negative prognostic factor in breast cancer (BC) patients. The risk factors for weight gain during adjuvant endocrine therapy (ET) and the extent to which such weight gain is associated with disease recurrence remain unclear. PATIENTS AND METHODS: We retrospectively identified a cohort of women with a diagnosis of stage I-III, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC from January 1997 to August 2008, who had received initial treatment at the MD Anderson Cancer Center, had completed 5 years of ET, and had remained free of locoregional or distant relapse or contralateral BC for >= 5 years after diagnosis. The weight change at the end of 5 years of ET was measured as the percentage of the change in weight from the start of ET, with a weight gain of > 5% considered clinically significant. Multivariable logistic regression and Cox proportional hazards models were used to assess the determinants of such weight gain and the risk of recurrence after 5 years. RESULTS: Of 1282 long-term BC survivors, 432 (33.7%) had a weight gain of > 5% after 5 years of ET. Women who were premenopausal at diagnosis were 1.40 times more likely than women who were postmenopausal at diagnosis to have a weight gain of > 5%. Asian women had the lowest risk of gaining weight. The recurrence risks of patients who had gained weight and those who had not were not significantly different. CONCLUSION: Premenopausal BC patients had an increased risk of weight gain after 5 years of ET; however, BC patients with a weight gain of > 5% did not have an increased risk of disease recurrence. PMID- 29239837 TI - Advancing the Role of Neuroimmunity and Genetic Susceptibility in Gulf War Illness. PMID- 29239838 TI - Mediator Kinase Phosphorylation of STAT1 S727 Promotes Growth of Neoplasms With JAK-STAT Activation. AB - Constitutive JAK-STAT signaling drives the proliferation of most myeloproliferative neoplasms (MPN) and a subset of acute myeloid leukemia (AML), but persistence emerges with chronic exposure to JAK inhibitors. MPN and post-MPN AML are dependent on tyrosine phosphorylation of STATs, but the role of serine STAT1 phosphorylation remains unclear. We previously demonstrated that Mediator kinase inhibitor cortistatin A (CA) reduced proliferation of JAK2-mutant AML in vitro and in vivo and also suppressed CDK8-dependent phosphorylation of STAT1 at serine 727. Here we report that phosphorylation of STAT1 S727 promotes the proliferation of AML cells with JAK-STAT pathway activation. Inhibition of serine phosphorylation by CA promotes growth arrest and differentiation, inhibits colony formation in MPN patient samples and reduces allele burden in MPN mouse models. These results reveal that STAT1 pS727 regulates growth and differentiation in JAK STAT activated neoplasms and suggest that Mediator kinase inhibition represents a therapeutic strategy to regulate JAK-STAT signaling. PMID- 29239840 TI - Therapeutic monoclonal antibody N-glycosylation - Structure, function and therapeutic potential. AB - Therapeutic antibodies (IgG-type) contain several post-translational modifications (PTMs) whereby introducing a large heterogeneity, both structural and functional, into this class of therapeutics. Of these modifications, glycosylation in the fragment crystallizable (Fc) region is the most heterogeneous PTM, which can affect the stability of the molecule and interactions with Fc-receptors in vivo. Hence, the glycoform distribution can affect the mode of action and have implications for bioactivity, safety and efficacy of the drug. Main topics of the manuscript include: What factors influence the (Fc) glycan pattern in therapeutic antibodies and how can these glycans be characterized? How does structure of the Fc-glycan relate to function and what methods are available to characterize those functions? Although heterogeneous in their scope, the different sections are intended to combine current knowledge on structure-function correlations of IgG glycan structures with regard to Fc (effector) functions, as well as basic aspects and methodologies for their assessment. PMID- 29239841 TI - Totally intra-corporeal Pringle maneuver during laparoscopic liver resection. AB - INTRODUCTION: Laparoscopic resection has gained a significant place in liver surgery. As in open liver resection, bleeding control during hepatic transection remains a major issue and it represents the main reason for conversion to laparotomy. Pringle maneuver (PM) remains the standard inflow occlusion technique and a specific step-by-step description of totally intracorporeal laparoscopic PM is described. METHODS: The technique includes placement of a tape around the hepatoduodenal which is then passed through a plastic drain. This creates a tourniquet that is locked with a heavy duty clip to allow intermittent use. RESULTS: This technique has been used in over 400 cases over the past 15 years and has proved safe and efficient with no specific complications encountered. It has been used in in 97 of 170 cases (57%) in the past 4 years and its feasibility has been 97%. Its intracorporeal position does not require an additional trocar and does not interfere with the surgeons' view and operating technique. Cycles of clamping and unclamping can be performed in few seconds including in the emergency setting. CONCLUSIONS: Totally laparoscopic PM is a simple, reproducible and inexpensive method of inflow occlusion during laparoscopic liver resection. PMID- 29239839 TI - The Formin, DIAPH1, is a Key Modulator of Myocardial Ischemia/Reperfusion Injury. AB - The biochemical, ionic, and signaling changes that occur within cardiomyocytes subjected to ischemia are exacerbated by reperfusion; however, the precise mechanisms mediating myocardial ischemia/reperfusion (I/R) injury have not been fully elucidated. The receptor for advanced glycation end-products (RAGE) regulates the cellular response to cardiac tissue damage in I/R, an effect potentially mediated by the binding of the RAGE cytoplasmic domain to the diaphanous-related formin, DIAPH1. The aim of this study was to investigate the role of DIAPH1 in the physiological response to experimental myocardial I/R in mice. After subjecting wild-type mice to experimental I/R, myocardial DIAPH1 expression was increased, an effect that was echoed following hypoxia/reoxygenation (H/R) in H9C2 and AC16 cells. Further, compared to wild type mice, genetic deletion of Diaph1 reduced infarct size and improved contractile function after I/R. Silencing Diaph1 in H9C2 cells subjected to H/R downregulated actin polymerization and serum response factor-regulated gene expression. Importantly, these changes led to increased expression of sarcoplasmic reticulum Ca2+ ATPase and reduced expression of the sodium calcium exchanger. This work demonstrates that DIAPH1 is required for the myocardial response to I/R, and that targeting DIAPH1 may represent an adjunctive approach for myocardial salvage after acute infarction. PMID- 29239842 TI - Relative rates not relative risks: addressing a widespread misinterpretation of hazard ratios. AB - The use of the Cox proportional hazards model is ubiquitous in modern medical research. Despite the widespread implementation of this model, the terminology and interpretation that is used to describe the estimate hazard ratio (HR) has become loose and, unfortunately, often incorrect. Although some journals offer guidelines that advise against reporting HRs as relative risks, these guidelines are frequently overlooked. Perhaps due to a lack of understanding, authors continue to interpret the resultant HR as a relative risk-such an interpretation is inappropriate and can be misleading. The HR should be described as a relative rate, not as a relative risk. This article demonstrates that although the direction of the HR can be used to explain the direction of the relative risk, the magnitude of the HR alone cannot be used to explain the magnitude of the relative risk. This article clarifies the relationship between HRs and relative risks in a way that may be better suited for the applied clinical researcher. We also provide a convenient table illustrating the magnitude of relative risk under various values of the HR; the table demonstrates that for a given constant HR, the magnitude of the relative risk can vary substantially. As a take-home message, authors should refrain from using the magnitude of the HR to describe the magnitude of the relative risk. Authors should be strongly encouraged to ascribe accurate interpretations to the statistics derived from fitted Cox proportional hazards regression models. PMID- 29239843 TI - Corrections. PMID- 29239844 TI - Selected High-Risk Patients With Upper Tract Urothelial Carcinoma Treated With Radical Nephroureterectomy for Adjuvant Chemotherapy: A Multi-Institutional Retrospective Study. AB - BACKGROUND: No definitive evidence exists regarding use of adjuvant chemotherapy (AC) for high-risk cases after radical nephroureterectomy (RNU), and the benefit of AC remains controversial. The aims of this study were to evaluate the efficacy of AC in patients with upper tract urothelial carcinoma (UTUC) and to determine those who qualified for AC. PATIENTS AND METHODS: From 1990 to 2015, 449 patients with nonmetastatic UTUC underwent RNU at 6 Kitasato University-affiliated hospitals. Eight patients who received neoadjuvant chemotherapy were excluded from this study. One hundred patients (23%) received platinum-based AC for a median of 3 courses. Disease-free survival and cancer-specific survival (CSS) were estimated using the Kaplan-Meier method. Multivariate analyses were performed with the Cox proportional hazards regression model, controlling for the effects of clinicopathological factors. RESULTS: The median age was 69 years, and the median follow-up period was 35.7 months. In multivariate analyses, factors independently predictive of poorer survival included pT stage (>=pT3), lymph node status (pN+), tumor grade (Grade 3), lymphovascular invasion, and soft tissue surgical margin. For the risk stratification model, patients were categorized into 3 groups on the basis of these 5 risk factors. In the high-risk group (at least 3 risk factors, 83 patients), 41 patients (49%) were treated with AC, and the 5-year CSS rate was higher in the AC group compared with the non-AC group (P = .02). CONCLUSION: Having more than 3 risk factors defined the high-risk group among UTUC patients after RNU. AC was associated with improved CSS in patients with high-risk UTUC. PMID- 29239845 TI - Oncologic Effect of Cumulative Smoking Exposure in Patients Treated With Salvage Radical Prostatectomy for Radiation-recurrent Prostate Cancer. AB - INTRODUCTION: The purpose of the present study was to investigate the association of smoking with biochemical recurrence (BCR) and metastasis in radiation recurrent prostate cancer (PCa) patients undergoing salvage radical prostatectomy (SRP). PATIENTS AND METHODS: A total of 214 patients treated with SRP for radiation-recurrent PCa in 5 tertiary referral centers were included from January 2007 to December 2015. Kaplan-Meier analyses were used to assess the time to BCR and metastasis. Pre- and postoperative multivariable Cox proportional hazard regression models were fitted. RESULTS: Overall, 120 (56.1%), 49 (22.9%), and 45 (21%) patients were never, former, and current smokers, respectively. Low-, medium-, and high-cumulative smoking exposure was registered in 59.8%, 16.4%, and 23.8% of cases, respectively. Patients with high cumulative smoking exposure had a significantly greater rate of a pathologic Gleason score of >= 8 (P = .01) and extracapsular extension (P = .004). Smoking status, cumulative smoking exposure, intensity, and duration were significantly associated with BCR-free survival (P < .001 for all). Smoking status, cumulative smoking exposure, and smoking intensity were significantly associated with metastasis-free survival (P = .03 for all). High cumulative smoking exposure was independently associated with BCR in both pre- (hazard ratio, 2.23; P = .001) and postoperative (hazard ratio, 1.64; P = .04) multivariable models adjusted for the effects of established clinicopathologic features. Smoking cessation did not affect either BCR- or metastasis-free survival (P = .56 and P = .40, respectively). CONCLUSION: High cumulative smoking exposure was associated with the biologic and clinical aggressiveness of PCa in patients treated with SRP for radiation-recurrent disease. Smoking is a modifiable risk factor that detrimentally affected the outcomes, even in patients with advanced PCa. PMID- 29239846 TI - Molecular Subtypes of Clear Cell Renal Cell Carcinoma Are Associated With Outcome During Pazopanib Therapy in the Metastatic Setting. AB - BACKGROUND: We previously described 4 molecular subtypes of metastatic clear cell renal cell carcinoma (mccRCC), named ccrcc1-4 (Beuselinck et al, 2015). These have both prognostic and predictive value for patients treated with first-line sunitinib, with distinctive objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The ccrcc2 and ccrcc3 tumors have the best outcomes, followed by ccrcc1 and then ccrcc4. We hypothesized that these molecular subtypes would show similar outcomes with first-line pazopanib treatment. PATIENTS AND METHODS: We classified 28 mccRCC tumors treated with pazopanib as first-line therapy, as described previously. The primary endpoints were PFS and OS from the start of pazopanib. A secondary endpoint was ORR. Because there were only 2 ccrcc3 tumors, they were pooled with the ccrcc2 tumors for outcome analysis. RESULTS: PFS was 9 months for the ccrcc2 and ccrcc3 tumors, 5 months for ccrcc1 tumors, and 3 months for the ccrcc4 tumors (P = .011). The corresponding OS duration was 69, 19, and 5 months (P = .003). The corresponding ORR was 50%, 33%, and 0%. The corresponding mean tumor size decreased by 34%, 6%, and 2% (P = .032). The ccrcc1-4 classification was a stronger predictor of outcome than the International Metastatic Renal Cell Carcinoma Database Consortium score on univariate analysis (P = .011 vs. P = .094 for PFS and P = .003 vs. .013 for OS). Both remained independent on bivariate analysis. CONCLUSION: The molecular subtypes of mccRCC are associated with outcome on pazopanib as first-line therapy. The prognostic and predictive value of the ccrcc1-4 molecular classification requires validation in prospective trials. PMID- 29239847 TI - Metastatic Primitive Neuroectodermal Tumor of the Prostate: A Case Report and Review of the Literature. PMID- 29239848 TI - Human spermatogonial markers. AB - In this review, we provide an up-to-date compilation of published human spermatogonial markers, with focus on the three nuclear subtypes Adark, Apale and B. In addition, we have extended our recently published list of putative spermatogonial markers with protein expression and RNA-sequencing data from the Human Protein Atlas and supported these by literature evidence. Most importantly, we have put substantial effort in acquiring a comprehensive list of new and potentially interesting markers by refiltering the raw data of 15 published germ cell expression datasets (four human, eleven rodent) and subsequent building of intersections to acquire a robust, cross-species set of spermatogonia-enriched or -specific transcripts. PMID- 29239849 TI - Hepatitis during pregnancy: A case of hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe and potentially fatal syndrome that can occur during pregnancy. A 36 years-old woman, at 29 weeks of gestation, presented with itchiness and jaundice since a week. On clinical examination she was apyrexial and frankly icteric. Laboratory data showed evidence of acute hepatitis. A complete work-up was made excluding viral hepatitis (HAV, HEV, HBV, HCV, HHV6, CMV, EBV) and autoimmune liver disease. Liver diseases related to pregnancy were not completely excluded. A liver biopsy was performed and firstly interpreted as showing features of acute hepatitis. The clinical situation worsened, she developed fever with signs of fetal distress and emergent delivery was done. A second look at the liver biopsy showed features compatible with HLH, which was also confirmed on bone marrow biopsy. Extensive work-up with exclusion of infectious and malignant diseases, lead us to the diagnosis of HLH secondary to pregnancy and short term steroid therapy was started. She then completely recovered and didn't present any relapse after 4 months of follow up. HLH during pregnancy is very rare and this is the first case of HLH presenting as acute hepatitis and diagnosed on a liver biopsy. PMID- 29239850 TI - Small bowel capsule endoscopy: May we delegate it to nurses? AB - AIM: Small bowel capsule endoscopy (CE) is a non-invasive and validated technique allowing the visualization of the small intestine mucosa. It generated more than 40,000 images per examination and induced a long median time of medical reading that may exceed 1 hour. In a transfer of skills' program, the CE reading might be transferred to nurses. We herein evaluate and present a feasibility study of the CE to nurses. METHODS: Nurses experienced in endoscopy were trained for small bowel CE reading, selection and interpretation of pathological images. Two strategies were experienced: a partial delegation to nurses, restricted to the selection of picture and an interpretation of the selected pictures by experts in CE (strategy A) or a total delegation including the selection of pictures, their interpretation, and the realization of a report (strategy B). Nurses were volunteers to participate to the study. Strategies were compared to the reference procedure (control) and a blinded analysis of the CE by experts was performed. Selection of pictures and their interpretation were timely evaluated in all strategies. The stomach and small intestine transit times and the reading time were recorded. The accuracy of the whole CE interpretation was compared. Experts reviewed all discordant interpretations. RESULTS: The extent of transit time in the stomach and the small intestine, and the identification of a normal endoscopic examination were not statistically different between strategy A and control (P=0.71). The accuracy of reports from strategy A and control was 95% (P=0.9). In one case, a nurse has not selected the pathological image, corresponding to a duodenal ulcer. The median medical time for reading was significantly shorter in strategy A than in control (9.2min [range: 4-20] vs 34.0min [range: 10-60]; P<0.01). The accuracy of reports performed by nurses in strategy B was 80% (P=0.11). In 4 cases, the medical interpretation in strategy B was discordant. The discrepancy was due to a lack of pathological images' selection of the selected pictures for the final report (n=1) and a lack of interpretation (n=3). The median time for analysis was not significantly different between strategy B and control (34.7 [range: 10-75] versus 34.0min [range: 15-60]; P=0.53). CONCLUSION: In small bowel CE, a pre-selection of pathological images by a trained nurse could be integrated in a transfer of skills' program and appeared feasible. The gain of time for the gastroenterologists is significant and reduced the medical time for reading from 34 to 9minutes per examination. Meantime, an overall delegation of small bowel CE to nurses suffered for a lack of efficacy. Our study paved the way for a nurse' training program in the pre-selection and identification of CE images. PMID- 29239851 TI - Association between allergic diseases, allergic sensitization and attention deficit/hyperactivity disorder in children: A large-scale, population-based study. AB - BACKGROUND: Increasing prevalence of allergic diseases has been matched by parallel trends in attention-deficit/hyperactivity disorder (ADHD). However, previous studies concerning the association between ADHD and allergic diseases have been inconsistent. Moreover, it is not clear whether this association is modified by allergic sensitization status. Therefore, we evaluated the association between allergic diseases, allergic sensitization, and ADHD in children. METHODS: We conducted a large-scale cross-sectional, population-based survey to investigate the relationship between allergic diseases, allergic sensitization, and ADHD. Children aged between 3 and 6 years were selected from kindergartens, and received skin prick tests (SPTs) for mite, cockroach, dog, milk, egg, and crab allergens. Information about allergic diseases, environmental exposures, and physician-diagnosed ADHD were collected. Multiple logistic regressions were performed to estimate the association between allergic diseases and ADHD, with adjustments made for potential confounders. RESULT: A total of 2772 children were found to be eligible for analysis; of these 411 (14.8%) had atopic dermatitis (AD), 954 (34.4%) had allergic rhinitis (AR), 451 (16.3%) had asthma, and 28 (1.01%) had ADHD. Children who had AD and asthma with allergic sensitization were found to be at increased risk for ADHD, with adjusted ORs (95% CI) of 4.50 (1.28-15.86) and 3.65 (1.07-12.49). Children who had AR, allergic conjunctivitis, or food allergies were also related to ADHD, though failed to reach statistical significance. CONCLUSION: Our results suggest that AD and asthma with allergic sensitization are associated with ADHD in children. As allergic sensitization is an increased factor of developing allergic diseases, early control of environmental and allergens exposure could help to modify the burden of ADHD. PMID- 29239852 TI - Management specificities for abdominal, pelvic and vascular penetrating trauma. AB - Management of patients with penetrating trauma of the abdomen, pelvis and their surrounding compartments as well as vascular injuries depends on the patient's hemodynamic status. Multiple associated lesions are the rule. Their severity is directly correlated with initial bleeding, the risk of secondary sepsis, and lastly to sequelae. In patients who are hemodynamically unstable, the goal of management is to rapidly obtain hemostasis. This mandates initial laparotomy for abdominal wounds, extra-peritoneal packing (EPP) and resuscitative endovascular balloon occlusion of the aorta (REBOA) in the emergency room for pelvic wounds, insertion of temporary vascular shunts (TVS) for proximal limb injuries, ligation for distal vascular injuries, and control of exteriorized extremity bleeding with a tourniquet, compressive or hemostatic dressings for bleeding at the junction or borderline between two compartments, as appropriate. Once hemodynamic stability is achieved, preoperative imaging allow more precise diagnosis, particularly for retroperitoneal or thoraco-abdominal injuries that are difficult to explore surgically. The surgical incisions need to be large, in principle, and enlarged as needed, allowing application of damage control principles. PMID- 29239853 TI - Averaged head phantoms from magnetic resonance images of Korean children and young adults. AB - Increased use of mobile phones raises concerns about the health risks of electromagnetic radiation. Phantom heads are routinely used for radiofrequency dosimetry simulations, and the purpose of this study was to construct averaged phantom heads for children and young adults. Using magnetic resonance images (MRI), sectioned cadaver images, and a hybrid approach, we initially built template phantoms representing 6-, 9-, 12-, 15-year-old children and young adults. Our subsequent approach revised the template phantoms using 29 averaged items that were identified by averaging the MRI data from 500 children and young adults. In females, the brain size and cranium thickness peaked in the early teens and then decreased. This is contrary to what was observed in males, where brain size and cranium thicknesses either plateaued or grew continuously. The overall shape of brains was spherical in children and became ellipsoidal by adulthood. In this study, we devised a method to build averaged phantom heads by constructing surface and voxel models. The surface model could be used for phantom manipulation, whereas the voxel model could be used for compliance test of specific absorption rate (SAR) for users of mobile phones or other electronic devices. PMID- 29239854 TI - Synthesis and structural characteristics of high surface area TiO2 aerogels by ultrasonic-assisted sol-gel method. AB - TiO2 aerogel is a unique three-dimensional porous nano-particle material with the characteristics of high specific surface area and good light transmittance. In this paper, a novel method involving ultrasonic-assisted sol-gel, solvent exchange, and vacuum drying was successfully developed to synthesis the TiO2 aerogel. The morphology and properties of the prepared TiO2 aerogels were characterized by the Brunauer-Emmett-Teller theory (BET), x-ray diffraction, field-emission scanning electron microscopy, energy dispersive spectroscopy, thermogravimetric analysis-differential thermal analysis, Fourier transform infrared spectroscopy, and Raman spectroscopy. The adsorption and photocatalytic activity of TiO2 aerogels was evaluated by monitoring the degradation of Rhodamine B solution. Our results indicated that: (1) with an optimum ratio of Ti:H2O = 8:1 the BET surface area, average pore diameter, and total pore volume of TiO2 aerogel are enhanced to 563.6 m2 g-1, 3.01 nm, and 0.42 cm3 g-1, respectively; (2) the TiO2 aerogels possessed controllable crystal form depending on the thermal treatments conditions. The crystal face (101) of anatase, complete anatase, mixed state of anatase and rutile, and rutile were obtained by increasing the temperature from 200 degrees C-300 degrees C, from 400 degrees C-500 degrees C, 600 degrees C, and from 700 degrees C-1000 degrees C, respectively; and (3) the excellent catalytic activity of the as-prepared TiO2 aerogels for the ultraviolet photolytic degradation of Rhodamine B had attributed to the synergistic effect of adsorption and photoactivity. PMID- 29239855 TI - Experimental verification of stopping-power prediction from single- and dual energy computed tomography in biological tissues. AB - An experimental setup for consecutive measurement of ion and x-ray absorption in tissue or other materials is introduced. With this setup using a 3D-printed sample container, the reference stopping-power ratio (SPR) of materials can be measured with an uncertainty of below 0.1%. A total of 65 porcine and bovine tissue samples were prepared for measurement, comprising five samples each of 13 tissue types representing about 80% of the total body mass (three different muscle and fatty tissues, liver, kidney, brain, heart, blood, lung and bone). Using a standard stoichiometric calibration for single-energy CT (SECT) as well as a state-of-the-art dual-energy CT (DECT) approach, SPR was predicted for all tissues and then compared to the measured reference. With the SECT approach, the SPRs of all tissues were predicted with a mean error of (-0.84 +/- 0.12)% and a mean absolute error of (1.27 +/- 0.12)%. In contrast, the DECT-based SPR predictions were overall consistent with the measured reference with a mean error of (-0.02 +/- 0.15)% and a mean absolute error of (0.10 +/- 0.15)%. Thus, in this study, the potential of DECT to decrease range uncertainty could be confirmed in biological tissue. PMID- 29239856 TI - Bioinspired nanoparticle spray-coating for superhydrophobic flexible materials with oil/water separation capabilities. AB - Much of the inspiration for the creation of superhydrophobic surfaces has come from nature, from plants such as the sacred lotus (Nelumbo nucifera), where the micro-scale papillae epidermal cells on the surfaces of the leaves are covered with nano-scale epicuticular wax crystalloids. The combination of the surface roughness and the hydrophobic wax coating produces a superhydrophobic wetting state on the leaves, allowing them to self-clean and easily shed water. Here, a simple scaled-up carbon nanoparticle spray coating is presented that mimics the surface of sacred lotus leaves and can be applied to a wide variety of materials, complex structures, and flexible substrates, rendering them superhydrophobic, with contact angles above 160 degrees . The sprayable mixture is produced by combining toluene, polydimethylsiloxane, and inherently hydrophobic rapeseed soot. The ability to spray the superhydrophobic coating allows for the hydrophobisation of complex structures such as metallic meshes, which allows for the production of flexible porous superhydrophobic materials that, when formed into U-shaped channels, can be used to direct flows. The porous meshes, whilst being superhydrophobic, are also oleophilic. Being both superhydrophobic and oleophilic allows oil to pass through the mesh, whilst water remains on the surface. The meshes were tested for their ability to separate mixtures of oil and water in flow conditions. When silicone oil/water mixtures were passed over the meshes, all meshes tested were capable of separating more than 93% of the oil from the mixture. PMID- 29239857 TI - Performance of a PTW 60019 microDiamond detector in a 1.5 T MRI-linac. AB - Accurate small-field dosimetry is critical for a magnetic resonance linac (MRI linac). The PTW 60019 microDiamond is close to an ideal detector for small field dosimetry due to its small physical size, high signal-to-noise ratio and approximate water equivalence. It is important to fully characterise the performance of the detector in a 1.5 T magnetic field prior to its use for MRI linac commissioning and quality assurance. Standard techniques of detector testing have been implemented, or adapted where necessary to suit the capabilities of the MRI-linac. Detector warmup, constancy, dose linearity, dose rate linearity, field size dependence and leakage were within tolerance. Measurements with the detector were consistent with ion chamber measurements for medium sized fields. The effective point of measurement of the detector when used within a 1.5 T magnetic field was determined to be 0.80 +/- 0.23 mm below the top surface of the device, consistent with the existing vendor recommendation and alignment mark at 1.0 mm. The angular dependence was assessed. Variations of up to 9.7% were observed, which are significantly greater than in a 0 T environment. Within the expected range of use, the maximum effect is approximately 0.6% which is within tolerance. However for large beams within a magnetic field, the divergence and consequent variation in angle of photon incidence means that the microDiamond would not be ideal for characterising the profiles and it would not be suitable for determining large-field beam parameters such as symmetry. It would also require a correction factor prior to use for patient-specific QA measurements where radiation is delivered from different gantry angles. The results of this study demonstrate that the PTW 60019 microDiamond detector is suitable for measuring small radiation fields within a 1.5 T magnetic field and thus is suitable for use in MRI-linac commissioning and quality assurance. PMID- 29239859 TI - Sensing the flow beneath the fins. AB - Flow sensing, maneuverability, energy efficiency and vigilance of surroundings are the key factors that dictate the performance of marine animals. Be it swimming at high speeds, attack or escape maneuvers, sensing and survival hydrodynamics are a constant feature of life in the ocean. Fishes are capable of performing energy efficient maneuvers, including capturing energy from vortical structures in water. These impressive capabilities are made possible by the uncanny ability of fish to sense minute pressure and flow variations on their body. This is achieved by arrays of biological neuromast sensors on their bodies that 'feel' the surroundings through 'touch at a distance' sensing. The main focus of this paper is to review the various biomimetic material approaches in developing superficial neuromast inspired ultrasensitive MEMS sensors. Principals and methods that translate biomechanical filtering properties of canal neuromasts to benefit artificial MEMS sensors have also been discussed. MEMS sensors with ultrahigh flow sensitivity and accuracy have been developed mainly through inspiration from the hair cell and cupula structures in the neuromast. Canal inspired packages have proven beneficial in hydrodynamic flow filtering in artificial sensors enabling signal amplification and noise attenuation. A special emphasis has been placed on the recent innovations that closely mimic the structural and material designs of stereocilia of neuromasts by exploring soft polymers. PMID- 29239858 TI - Prediction of breast cancer risk using a machine learning approach embedded with a locality preserving projection algorithm. AB - In order to automatically identify a set of effective mammographic image features and build an optimal breast cancer risk stratification model, this study aims to investigate advantages of applying a machine learning approach embedded with a locally preserving projection (LPP) based feature combination and regeneration algorithm to predict short-term breast cancer risk. A dataset involving negative mammograms acquired from 500 women was assembled. This dataset was divided into two age-matched classes of 250 high risk cases in which cancer was detected in the next subsequent mammography screening and 250 low risk cases, which remained negative. First, a computer-aided image processing scheme was applied to segment fibro-glandular tissue depicted on mammograms and initially compute 44 features related to the bilateral asymmetry of mammographic tissue density distribution between left and right breasts. Next, a multi-feature fusion based machine learning classifier was built to predict the risk of cancer detection in the next mammography screening. A leave-one-case-out (LOCO) cross-validation method was applied to train and test the machine learning classifier embedded with a LLP algorithm, which generated a new operational vector with 4 features using a maximal variance approach in each LOCO process. Results showed a 9.7% increase in risk prediction accuracy when using this LPP-embedded machine learning approach. An increased trend of adjusted odds ratios was also detected in which odds ratios increased from 1.0 to 11.2. This study demonstrated that applying the LPP algorithm effectively reduced feature dimensionality, and yielded higher and potentially more robust performance in predicting short-term breast cancer risk. PMID- 29239860 TI - Reference intervals for the evoked tympanic membrane displacement measurement: a non-invasive measure of intracranial pressure. AB - OBJECTIVE: Evoked tympanic membrane displacement (TMD) is a non-invasive technique for assessing intracranial pressure (ICP). The aim of this study was to define reference intervals (RIs) in the healthy population. APPROACH: Measurements were made in 154 healthy adults. Results were quantified by V m, which is the most frequently described TMD measurement. Distributions were determined for sitting and supine posture. Differences between right and left ears were explored using a Wilcoxon signed-rank test. Postural changes were used to assess pressure transfer between the cerebral spinal fluid (CSF) and the perilymph. MAIN RESULTS: The range in which 95% of scores fall is -283 to 722 nl (M = 132 nl) left sitting, -232 to 623 nl (M = 97 nl) right sitting, -543 to 717 nl (M = 37 nl) left supine and -584 to 504 nl (M = -15 nl) right supine. No significant difference was seen between the left and right ears in the sitting position; a significant difference was seen in the supine position. A significant effect of posture was seen for both the left and right ears. Postural changes indicated pressure transfer between the CSF and perilymph more often in the right ear (75.3%) than the left (61.9%). Pressure transfer could not be assumed in either ear for 13.4% of participants. SIGNIFICANCE: We present the largest dataset of evoked TMD in healthy individuals and the first set of RIs for V m. A patient cohort with both invasive ICP and evoked TMD measurements is needed to validate the technique for clinical use. PMID- 29239861 TI - Capacitance-voltage analysis of electrical properties for WSe2 field effect transistors with high-k encapsulation layer. AB - Doping effects in devices based on two-dimensional (2D) materials have been widely studied. However, detailed analysis and the mechanism of the doping effect caused by encapsulation layers has not been sufficiently explored. In this work, we present experimental studies on the n-doping effect in WSe2 field effect transistors (FETs) with a high-k encapsulation layer (Al2O3) grown by atomic layer deposition. In addition, we demonstrate the mechanism and origin of the doping effect. After encapsulation of the Al2O3 layer, the threshold voltage of the WSe2 FET negatively shifted with the increase of the on-current. The capacitance-voltage measurements of the metal insulator semiconductor (MIS) structure proved the presence of the positive fixed charges within the Al2O3 layer. The flat-band voltage of the MIS structure of Au/Al2O3/SiO2/Si was shifted toward the negative direction on account of the positive fixed charges in the Al2O3 layer. Our results clearly revealed that the fixed charges in the Al2O3 encapsulation layer modulated the Fermi energy level via the field effect. Moreover, these results possibly provide fundamental ideas and guidelines to design 2D materials FETs with high-performance and reliability. PMID- 29239862 TI - Co3O4 based non-enzymatic glucose sensor with high sensitivity and reliable stability derived from hollow hierarchical architecture. AB - Inspired by kinetics, the design of hollow hierarchical electrocatalysts through large-scale integration of building blocks is recognized as an effective approach to the achievement of superior electrocatalytic performance. In this work, a hollow, hierarchical Co3O4 architecture (Co3O4 HHA) was constructed using a coordinated etching and precipitation (CEP) method followed by calcination. The resulting Co3O4 HHA electrode exhibited excellent electrocatalytic activity in terms of high sensitivity (839.3 MUA mM-1 cm-2) and reliable stability in glucose detection. The high sensitivity could be attributed to the large specific surface area (SSA), ample unimpeded penetration diffusion paths and high electron transfer rate originating from the unique two-dimensional (2D) sheet-like character and hollow porous architecture. The hollow hierarchical structure also affords sufficient interspace for accommodation of volume change and structural strain, resulting in enhanced stability. The results indicate that Co3O4 HHA could have potential for application in the design of non-enzymatic glucose sensors, and that the construction of hollow hierarchical architecture provides an efficient way to design highly active, stable electrocatalysts. PMID- 29239863 TI - Electronic properties of topological insulator candidate CaAgAs. AB - The topological phases of matter provide the opportunity to observe many exotic properties, such as the existence of 2D topological surface states in the form of Dirac cones in topological insulators and chiral transport through the open Fermi arc in Weyl semimetals. However, these properties affect the transport characteristics and, therefore, may be useful for applications only if the topological phenomena occur near the Fermi level. CaAgAs is a promising candidate for which the ab initio calculations predict line-nodes at the Fermi energy. However, the compound transforms into a topological insulator on considering spin orbit interaction. In this study, we investigated the electronic structure of CaAgAs with angle-resolved photoemission spectroscopy (ARPES), ab initio calculations, and transport measurements. The results from ARPES show that the bulk valence band crosses the Fermi energy at the Gamma-point. The measured band dispersion matches the ab initio calculations closely when shifting the Fermi energy in the calculations by -0.5 eV. The ARPES results are in good agreement with transport measurements, which show abundant p-type carriers. PMID- 29239864 TI - Trabeculectomy Outcomes After Glaucoma Drainage Device Surgery. AB - PURPOSE: To evaluate outcomes of trabeculectomy with adjunctive mitomycin C in patients with uncontrolled intraocular pressure (IOP) after glaucoma drainage device implantation. MATERIALS AND METHODS: Consecutive patients who had undergone a trabeculectomy after GDD were reviewed. The primary outcome was surgical success with stratified IOP targets based on the following criteria: (A) IOP<18 mm Hg and IOP reduction of 20%; (B) IOP<15 mm Hg and IOP reduction of 25%; (C) IOP<12 mm Hg and IOP reduction of 30%. Secondary outcomes were number of glaucoma medications, complications, and need for additional glaucoma surgery. RESULTS: Twenty eyes (19 patients) were included for analysis. Median follow-up and age were 3.7 years (range, 1.1 to 10.2 y) and 64.2 years (range, 25.2 to 85.6 y), respectively. Mean IOP (+/-SD) has dropped from 19.3+/-4.2 mm Hg preoperatively to 9.8+/-2.2 mm Hg at 1 year, 8.8+/-3.2 mm Hg at 3 years and 8.4+/ 1.5 mm Hg at 5 years (P<0.001 for all). Hypotony maculopathy was the only serious complication (2/19 patients; 10%) that needed surgical revision. The cumulative success rate (+/-SD) for criterion A and B were 73.2% (+/-10.0%) and 68.2% (+/ 9.5%), respectively, between the first and fifth year of follow-up, for criterion C it was 49.1% (+/-10.8%) at the first year and 32.7% (+/-12%) between the second and fifth year of follow-up. CONCLUSIONS: Trabeculectomy is a viable surgical option to treat IOP that is uncontrolled after GDD implantation. PMID- 29239865 TI - Large Databases for Pediatric Research on Children with Autism Spectrum Disorder. AB - OBJECTIVE: This article reviews the data available in 3 large databases for use in conducting studies of children with autism spectrum disorder (ASD). METHODS: The article describes the data structure, data elements, and strengths and weaknesses of the 3 data sets. RESULTS: Each of the 3 data sets, the Interactive Autism Network (IAN), the Autism Treatment Network (ATN), and PEDSnet have large cohorts of children with ASD. IAN has strengths in patient-reported measures, ATN in clinical characterization, and PEDSnet in health care encounters and electronic medical record data. CONCLUSION: The data sets described here have potential for further studies that could help improve the care and well-being of children with ASD and their families. PMID- 29239866 TI - Validation of the professional device for blood pressure measurement Microlife WatchBP Office in adults and children according to the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization standard. AB - OBJECTIVE: To assess the accuracy of the professional oscillometric blood pressure (BP) monitor Microlife WatchBP Office in adults and children according to the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-2:2013 standard. METHODS: Adults and children (aged 3-12 years) were recruited to fulfil the age, sex, BP and cuff distribution criteria of the ANSI/AAMI/ISO standard using the same-arm sequential BP measurement method. Three cuffs of the test device were used for arm circumferences of 14-22, 22-32 and 32-42 cm. RESULTS: A total of 115 participants were recruited and 88 were included in the analysis (51 adults and 37 children). For criterion 1, the mean+/-SD of the differences between the test device and reference BP was -1.0+/ 7.0/-4.7+/-5.4 mmHg (systolic/diastolic). For criterion 2, the SD of the averaged BP differences between the test device and reference per participant was 5.15/4.77 mmHg (systolic/diastolic). CONCLUSION: The professional Microlife WatchBP Office BP monitor fulfilled the requirements of the ANSI/AAMI/ISO validation standard for adults and children and can be recommended for clinical use. PMID- 29239867 TI - Effects of triple combination therapy with azilsartan/amlodipine/hydrochlorothiazide on office/home blood pressure: a randomized-controlled trial in Japanese essential hypertensive patients. AB - OBJECTIVE: The efficacy and safety of triple therapy with azilsartan (AZI), amlodipine besylate (AML), and hydrochlorothiazide (HCTZ) compared with dual therapy with AZI/AML or HCTZ monotherapy were evaluated in Japanese essential hypertensive patients in a double-blinded manner. PATIENTS AND METHODS: A total of 353 patients with office blood pressure (BP) of at least 150/95 mmHg were randomized to a 10-week treatment with AZI/AML/HCTZ 20/5/12.5 mg, AZI/AML/HCTZ 20/5/6.25 mg, AZI/AML 20/5 mg, HCTZ 12.5 mg, or HCTZ 6.25 mg. RESULTS: The mean change from baseline in office diastolic/systolic BPs at week 10 was -25.9/-41.4, -24.9/-38.6, and -22.4/-34.5 mmHg in the AZI/AML/HCTZ 20/5/12.5 mg, AZI/AML/HCTZ 20/5/6.25 mg, and AZI/AML 20/5 mg groups, respectively. AZI/AML/HCTZ 20/5/12.5 mg led to a significantly greater reduction in diastolic and systolic BP than the dual therapy. In addition, the change in home diastolic BP measured with telemetry devices showed a significant difference between the two triple therapy groups. The incidences of adverse events except dizziness postural were similar among the treatment groups in the triple therapy groups. CONCLUSION: Triple therapy with AZI/AML/HCTZ 20/5/12.5 mg shows a greater antihypertensive effect than the dual therapy and has acceptable safety profiles for Japanese essential hypertensive patients. It was also observed that home BP measurement by automated telemetry could detect changes in BP that were not detected in office BP measurement, although further investigation is needed. PMID- 29239868 TI - Prolonged Preoperative Weakness Affects Recovery of Motor Function After Anterior Cervical Diskectomy and Fusion. AB - INTRODUCTION: Some patients who undergo anterior cervical diskectomy and fusion for radiculopathy or myelopathy demonstrate preoperative weakness. The purpose of this study was to determine which factors predict motor recovery in patients undergoing anterior cervical diskectomy and fusion. METHODS: A retrospective review of our institutional database identified patients undergoing anterior cervical diskectomy and fusion between 2010 and 2013 with 2 years of clinical follow-up. Patients with substantial weakness, defined as preoperative grade <=3 (on a scale from 0 to 5) in one or more upper extremity muscle groups, were identified. Regression analysis was used to determine risk factors associated with persistent postoperative weakness. RESULTS: Of the 1,001 patients who were included, 54 (5.4%) demonstrated substantial weakness. By 2 years postoperatively, 47 of 54 patients (87%) demonstrated motor recovery. The duration of preoperative weakness was an independent predictor of recovery (median, 4 months of preoperative weakness among patients with recovery versus 10 months in patients with persistent weakness; P = 0.012). DISCUSSION: Duration of preoperative motor weakness is an independent predictor of motor recovery after anterior cervical diskectomy and fusion in patients with substantial motor weakness. CONCLUSION: Patients being considered for anterior cervical diskectomy and fusion who have substantial preoperative motor deficits may benefit from earlier surgical intervention. PMID- 29239869 TI - Challenges in the Management of Anterior Cruciate Ligament Ruptures in Skeletally Immature Patients. AB - Although initially considered rare, anterior cruciate ligament (ACL) ruptures in pediatric patients recently have increased substantially as a result of greater awareness of the injury and increased participation in youth sports. Although pediatric patients with an ACL injury and a clinically stable joint may handle the injury well and return to sports activity without requiring surgical reconstruction, young, active patients with an ACL rupture and an unstable joint may be good candidates for ACL reconstruction to prevent ongoing instability and additional joint damage. ACL reconstruction techniques have been developed to prevent physeal injury in skeletally immature patients. The surgical treatment of skeletally immature patients with an ACL rupture may differ from that of adults with an ACL rupture and presents unique challenges with regard to reconstruction technique selection, graft preparation, rehabilitation, and return to sports activity. Orthopaedic surgeons should understand various physeal-sparing ACL reconstruction techniques and the general challenges associated with the surgical management of ACL ruptures in pediatric patients. PMID- 29239870 TI - Factors Motivating Medical Students in Selecting a Career Specialty: Relevance for a Robust Orthopaedic Pipeline. PMID- 29239872 TI - Blepharospasm and Hemifacial Spasm. PMID- 29239871 TI - Integrative Medicine as an Adjunct to Orthopaedic Surgery. AB - Patients often seek nontraditional forms of treatment, including alternative/complementary medical options, such as chiropractic care and acupuncture, to meet their personal needs. In the United States, interest has grown in methods to reduce pain and improve function through Ayurvedic medicine, which uses plant-based supplements, such as turmeric. Traditional allopathic medicine attempts to provide patients with evidence-based therapeutic regimens for their musculoskeletal conditions. Integrative medicine often is used to prevent and manage the sequelae associated with injuries and illnesses; however, competitive athletes and military personnel use complementary medicine for performance enhancement. Thus, physicians should be aware of the evolving field of integrative medicine, including the reported benefits as well as any potential drawbacks, to facilitate an educated discussion with their patients. PMID- 29239873 TI - The History of Blepharospasm in Medicine. PMID- 29239874 TI - Benign Essential Blepharospasm: What We Know and What We Don't. PMID- 29239875 TI - The Benign Essential Blepharospasm Research Foundation. PMID- 29239876 TI - Oral Pharmacotherapy for Benign Essential Blepharospasm. PMID- 29239877 TI - Botulinum Toxins for Treating Essential Blepharospasm and Hemifacial Spasm. PMID- 29239879 TI - Secondary Blepharospasm Associated With Ocular Surface Disease. PMID- 29239878 TI - Surgical Myectomy for Essential Blepharospasm and Hemifacial Spasm. PMID- 29239880 TI - Spasmodic Dysphonia. PMID- 29239881 TI - The Facial Nerve and Selective Neurectomy for Treatment of Benign Essential Blepharospasm. PMID- 29239882 TI - Neurological Imaging for Hemifacial Spasm. PMID- 29239883 TI - Microvascular Decompression for Hemifacial Spasm. PMID- 29239885 TI - The Present State of Neurointensivist Training in the United States: A Comparison to Other Critical Care Training Programs. AB - OBJECTIVE: This manuscript describes the state of neurocritical care fellowship training, compares its written standards to those of other critical care fellowship programs, and discusses how programmatic oversight by the United Council for Neurological Subspecialties should evolve to meet American College of Graduate Medical Education standards. This review is a work product of the Society of Critical Care Medicine Neuroscience section and was reviewed and approved by the Council of the Society of Critical Care Medicine. DATA SOURCES: We evaluated the published training criteria and requirements of American College of Graduate Medical Education Critical Care subspecialty fellowships programs of Internal Medicine, Surgery, and Anesthesia and compared them with the training criteria and required competencies for neurocritical care. STUDY SELECTION: We have reviewed the published training standards from American College of Graduate Medical Education as well as the United Council for Neurologic Subspecialties subspecialty training documents and clarified the definition and responsibilities of an intensivist with reference to the Leapfrog Group, the National Quality Forum, and the Joint Commission. DATA EXTRACTION: No data at present exist to test the concept of similarity across specialty fellowship critical care training programs. DATA SYNTHESIS: Neurocritical care training differs in its exposure to clinical entities that are directly associated to other critical care subspecialties. However, the core critical care knowledge, procedural skills, and competencies standards for neurocritical care appears to be similar with some important differences compared with American College of Graduate Medical Education critical care training programs. CONCLUSIONS: The United Council for Neurologic Subspecialties has developed a directed program development strategy to emulate American College of Graduate Medical Education standards with the goal to have standards that are similar or identical to American College of Graduate Medical Education standards. PMID- 29239886 TI - Acute Coronary Artery Dissection: A Review of the Literature and Current Evidence. AB - Acute coronary artery dissection is a rare, complex disease occurring particularly in young women without traditional cardiovascular risk factors. The pathophysiology and treatment are different from acute coronary syndrome caused by plaque rupture or erosion. Its clinical presentation may vary from unstable angina to sudden cardiac death. Hence, early detection is crucial to manage the dissection and reduce the mortality and morbidity rates. Most coronary dissections will heal spontaneously, and conservative treatment is recommended for uncomplicated cases. In the acute phase, primary percutaneous coronary intervention remains the reperfusion strategy of choice; however, in small- and medium-sized arteries with normalized blood flow, conservative treatment is beneficial. Medical therapy should be tailored to the individual depending on the underlying severity of the condition. Percutaneous coronary intervention should be performed by experienced operators, with the use of intravascular imaging, and preferably with on-site surgical back-up due to the increased risk of complications. The prognosis is favorable; however, patients have a high risk of recurrent dissections in other arteries several weeks after the first event, suggesting a general weakness of the arteries. In the recent past, optical coherence tomography has played an important role in the diagnosis of acute coronary artery dissection; however, its therapeutic potential is underestimated. We recommend that long-term clinical trials should be conducted to fully determine the long-term mortality and morbidity rates of these patients. PMID- 29239887 TI - Incidence of sexually transmitted infections before and after preexposure prophylaxis for HIV. AB - OBJECTIVE: Use of preexposure prophylaxis (PrEP) for HIV raises concerns about sexually transmitted infection (STI) incidence because of decreased condom use among MSM. This study examines whether PrEP is associated with STIs in the 12 months following PrEP prescription relative to the 12 months prior to PrEP and if STI rates are higher among PrEP users relative to individuals receiving postexposure prophylaxis (PEP). DESIGN: Retrospective cohort study including PrEP users with more than 12 months of follow-up before PrEP prescription and individuals receiving PEP from 2010 to 2015 at Clinique l'Actuel (Montreal, Canada). METHODS: Incidence of chlamydia, gonorrhoea, syphilis and hepatitis C virus over 12 months was compared before and after PrEP; and for PrEP versus PEP users using Poisson models to generate incidence rate ratios (IRRs) with 95% confidence intervals (CIs) and adjusted IRRs (aIRRs) controlling for frequency of STI-screening visits. Models comparing PrEP and PEP users were further adjusted for age and education. RESULTS: One hundred and nine PrEP and 86 PEP users were included. Increased rates of STIs were observed in the 12 months after PrEP relative to the 12 months prior (IRR: 1.72, CI: 1.22-2.41; aIRR: 1.39, CI 0.98 1.96). PrEP users were also at higher STI risk relative to PEP users (IRR: 2.18, CI: 1.46-3.24; aIRR: 1.76, CI: 1.14-2.71). CONCLUSION: Increased rates of STIs among individuals after initiation of PrEP may suggest greater risk behaviours during the first year on PrEP. Further studies are needed to measure long-term trends in STI acquisition following PrEP initiation. PMID- 29239889 TI - Are trajectories of a syndemic index in adolescence linked to HIV vulnerability in emerging and young adulthood? AB - OBJECTIVES: To examine trajectories of adolescent psychosocial risk - drug use, depressive and anxiety symptoms, and violence victimization and observation - and the longitudinal relationship between psychosocial risk trajectories during adolescence and HIV risk behaviors in adulthood. METHODS: The 18-year longitudinal study was conducted from September 1994 through May 2013, in Michigan. Eight hundred and fifty predominantly (80%) African-American adolescents completed demographics and measures of drug use, depressive and anxiety symptoms, violence victimization and observation at Times 1-4, sexual risk behaviors at Times 5 and 6, and social conditions (i.e. family, peer, and community-level factors) between 14.9 and 32.0 years of age. RESULTS: Growth mixture modeling revealed two trajectories of psychosocial risk factors which can be characterized as a syndemic index: high-frequency and low-frequency. The high frequency class was more likely to report HIV risk behaviors, including condomless sex at last sexual intercourse with their primary and secondary partner, sexual intercourse with someone they just met, at least four sexual partners, and licit and illicit drug use prior to sexual intercourse at Time 5 (mean age 23.1). At Time 6 (mean age 32.0), the high-frequency class was more likely to report sexual intercourse with someone they just met and at least four sexual partners, relative to the low-frequency class. In addition, the high frequency class was linked to peer and family-level indicators of social conditions. CONCLUSION: A syndemic index comprised of co-occurring psychosocial risk factors in adolescence seem to have lasting effects on the vulnerability to engage in HIV risk behaviors in emerging adulthood, some of which extend into young adulthood. PMID- 29239892 TI - Addressing HIV on the French Guianese-Brazilian border: no choice but collaboration! PMID- 29239891 TI - Cancer burden attributable to cigarette smoking among HIV-infected people in North America. AB - OBJECTIVE: With combination-antiretroviral therapy, HIV-infected individuals live longer with an elevated burden of cancer. Given the high prevalence of smoking among HIV-infected populations, we examined the risk of incident cancers attributable to ever smoking cigarettes. DESIGN: Observational cohort of HIV infected participants with 270 136 person-years of follow-up in the North American AIDS Cohort Collaboration on Research and Design consortium. Among 52 441 participants, 2306 were diagnosed with cancer during 2000-2015. MAIN OUTCOME MEASURES: Estimated hazard ratios and population-attributable fractions (PAF) associated with ever cigarette smoking for all cancers combined, smoking-related cancers, and cancers that were not attributed to smoking. RESULTS: People with cancer were more frequently ever smokers (79%) compared with people without cancer (73%). Adjusting for demographic and clinical factors, cigarette smoking was associated with increased risk of cancer overall [hazard ratios = 1.33 (95% confidence interval: 1.18-1.49)]; smoking-related cancers [hazard ratios = 2.31 (1.80-2.98)]; lung cancer [hazard ratios = 17.80 (5.60-56.63)]; but not nonsmoking-related cancers [hazard ratios = 1.12 (0.98-1.28)]. Adjusted PAFs associated with ever cigarette smoking were as follows: all cancers combined, PAF = 19% (95% confidence interval: 13-25%); smoking-related cancers, PAF = 50% (39 59%); lung cancer, PAF = 94% (82-98%); and nonsmoking-related cancers, PAF = 9% (1-16%). CONCLUSION: Among HIV-infected persons, approximately one-fifth of all incident cancer, including half of smoking-related cancer, and 94% of lung cancer diagnoses could potentially be prevented by eliminating cigarette smoking. Cigarette smoking could contribute to some cancers that were classified as nonsmoking-related cancers in this report. Enhanced smoking cessation efforts targeted to HIV-infected individuals are needed. PMID- 29239893 TI - Switch from tenofovir disoproxil fumarate combination to dolutegravir with rilpivirine improves parameters of bone health. AB - OBJECTIVE: Bone mineral density (BMD) loss, a risk factor for osteoporosis, has been attributed to HIV infection and antiretroviral therapy (ART), including regimens containing tenofovir disoproxil fumarate. DESIGN: Study 202094 is an open-label, parallel-group, sub-study of the phase III SWORD-1 and SWORD-2 studies (ClinicalTrials.gov identifier, NCT02478632). METHODS: HIV-1-infected adults with HIV-1 RNA less than 50 copies/ml who received ART containing tenofovir disoproxil fumarate for at least 6 months were randomized to receive dolutegravir with rilpivirine or continue current ART regimen. Total hip and lumbar spine BMD were measured by dual-energy X-ray absorptiometry (DXA) scans. The primary endpoint was percentage change from baseline in total hip BMD. RESULTS: DXA scans were evaluable for 81 participants at baseline and Week 48. Percentage increase in total hip BMD was significantly greater in participants who switched to dolutegravir with rilpivirine (1.34%) compared with participants who continued current ART (0.05%; treatment difference, +1.29%; 95% CI 0.27-2.31; P = 0.014). Lumbar spine BMD significantly increased in the dolutegravir with rilpivirine group by 1.46% (95% CI 0.65-2.28) compared with 0.15% (95% CI -0.79 to 1.09) in the current ART group (treatment difference, 1.32; 95% CI 0.07-2.57; P = 0.039). Participants in the dolutegravir with rilpivirine group experienced significantly greater reductions in bone formation and resorption biomarkers compared with the current ART group. CONCLUSION: Switch to dolutegravir with rilpivirine was associated with significant improvement in BMD and bone turnover markers compared with tenofovir-based three-drug regimens, providing a robust option for preserving bone health while continuing suppressive ART. PMID- 29239894 TI - Temporal variation in HIV-specific IgG subclass antibodies during acute infection differentiates spontaneous controllers from chronic progressors. AB - OBJECTIVE: Given the emerging appreciation for the role of antibody-dependent effector functions and IgG subclass distribution among spontaneous controllers of HIV, we sought to determine whether antibody-associated features diverged in early HIV infection between patients who ultimately became controllers versus those who became progressors. METHODS: IgG was purified from plasma from nine acutely infected patients who subsequently controlled HIV spontaneously (controllers) and 10 acutely infected individuals who did not control viremia (progressors). Antibody profiles were compared at weeks 4, 12, 24 and 48 postinfection. Levels of clade B gp120-specific, gp140-specific and gp41-specific IgG antibody subclasses were measured. In addition, gp120-specific antibody dependent cellular phagocytosis, rapid fluorescent antibody-dependent cellular cytotoxicity and antibody-dependent cellular viral inhibition were all assessed. RESULTS: Although no single antibody-related measurement was significantly associated with long-term HIV control, combinations of antibody-associated variables were able to accurately differentiate controllers and progressors. In contrast to controllers, progressors showed greater dynamic changes in gp120 specific subclass selection profiles, with increasing levels of Env-specific IgG2 antibodies and losses in Env-specific IgG3 antibodies. Moreover, progressors, but not controllers, lost antibody-dependent cellular viral inhibition function over time. Together, these results highlight changes in IgG subclass selection profiles in progressive, but not controlled, HIV infection. CONCLUSION: This study suggests that the temporal variation and maintenance of Env-specific IgG subclasses during acute HIV infection are predictive of eventual disease control. The maintenance of gp120-specific and gp140-specific IgG3 may contribute to control of disease in spontaneous controllers. Thus, strategies to induce stable IgG3 responses may preserve control of the viral reservoir. PMID- 29239895 TI - Development of broad neutralization activity in simian/human immunodeficiency virus-infected rhesus macaques after long-term infection. AB - OBJECTIVE: Nonhuman primates (NHPs) are the only animal model that can be used to evaluate protection efficacy of HIV-1 envelope vaccines. However, whether broadly neutralizing antibodies (bnAbs) can be elicited in NHPs infected with simian/human immunodeficiency virus (SHIV) has not been fully understood. The objective of this study is to investigate whether broad neutralization activities were developed in SHIV-infected macaques after long-term infection as in humans. DESIGN: Neutralization breadth and specificities in plasmas from SHIV-infected macaques were determined by analyzing a panel of tier 2 viruses and their mutants. METHODS: Forty-four Chinese macaques infected with SHIV1157ipd3N4, SHIVSF162P3 or SHIVCHN19P4 were followed for 54-321 weeks. Archived plasmas from 19 macaques were used to determine neutralization breadth and specificities against 17 tier 2 envelope-pseudoviruses. RESULTS: Longitudinal plasma from three SHIVSF162P3-infected macaques and three SHIV1157ipd3N4-infected macaques rarely neutralized viruses (<25%) within 1 year of infection. The neutralization breadth in two SHIV1157ipd3N4-infected macaques significantly increased (>=65%) by year 6. Four of six SHIV1157ipd3N4-infected macaques could neutralize 50-75% viruses, whereas none of macaques infected with SHIVSF162P3 or SHIVCHN19P4 could neutralize more than 25% of viruses after 6 years of infection (P = 0.035). Neutralization specificity analysis showed mutations resistant to bnAbs in V2, V3 or CD4bs regions could abrogate neutralization by year-6 plasma from three SHIV1157ipd3N4-infected macaques. CONCLUSION: These results demonstrate that bnAbs targeting common HIV-1 epitopes can be elicited in SHIV1157ipd3N4-infected macaques as in humans after 4-6 years of infection, and SHIV/NHP can serve as an ideal model to study bnAb maturation. PMID- 29239896 TI - Ex-vivo antiretroviral potency of newer integrase strand transfer inhibitors cabotegravir and bictegravir in HIV type 1 non-B subtypes. AB - OBJECTIVE: To determine the antiretroviral activity of the integrase strand transfer inhibitors (INSTIs), raltegravir (RAL), elvitegravir (EVG), dolutegravir (DTG), cabotegravir (CAB) and bictegravir (BIC), against different subtypes as well as primary and acquired drug resistance mutations (DRMs) in a patient-cohort infected with diverse subtypes. DESIGN: Biochemical and virological drug sensitivity analyses using patient-derived HIV type 1 (HIV-1) genes and cross sectional/longitudinal clinical study. METHODS: Assays for 50% inhibition of 3' end processing (IC50-3EP), strand transfer (IC50-ST) and drug sensitivity for five INSTIs were done using patient-derived integrase or gag-pol genes from subtypes A1, B, C, 01_AE and 02_AG. Integrase from INSTI-naive (n = 270) and experienced (n = 96) patients were sequenced. RESULTS: RAL had higher IC50-ST than the other INSTIs for all subtypes. EVG had higher IC50-ST for HIV 1 subtype C (P < 0.05) and 02_AG (P < 0.05) than HIV 1 subtype B (HIV-1B). DTG showed lower IC50-ST in HIV 1 subtype C than HIV-1B (P = 0.003). In CAB , the non-B subtypes showed lower IC50-ST (P < 0.05) than HIV-1B. In BIC, lower IC50-ST in 01_AE (P = 0.017) and 02_AG (P = 0.045) than HIV-1B. In drug sensitivity assay, inhibiting virus replication by 50% for DTG [median (IQR) 2.14 (1.3-2.56)], CAB [1.68 (1.34 2.55)] and BIC [1.07 (0.22-2.53)] were lower than RAL and EVG. One patient had a primary DRMs (0.3%, 1/270), but 17 (6.3%) had one major accessory DRM, of which 12 were E157Q. CONCLUSION: The equal or higher potency in non-B subtypes of DTG, CAB and BIC compared with RAL and EVG confirms their suitability for use in countries dominated by non-B subtypes. Any impact of the high prevalence of major accessory mutations, especially E157Q, requires long-term follow-up studies. PMID- 29239897 TI - Ex-vivo expression of chemokine receptors on cells surrounding cutaneous nerves in patients with HIV-associated sensory neuropathy. AB - OBJECTIVE: HIV-associated sensory neuropathy (HIV-SN) remains common in HIV+ individuals receiving antiretroviral therapy (ART), even though neurotoxic antiretroviral drugs (e.g. stavudine) have been phased out of use. Accumulating evidence indicates that the neuropathy is immune-mediated. We hypothesize that chemokines produced locally in the skin promote migration of macrophages and T cells into the tissue, damaging cutaneous nerves causing HIV-SN. DESIGN: We assessed chemokine receptor expression on infiltrating CD14 and CD3 cells around cutaneous nerves in standardized skin biopsies from HIV-SN+ patients (n = 5), HIV SN- patients (n = 9) and healthy controls (n = 4). METHODS: The AIDS Clinical Trials Group Brief Peripheral Neuropathy Screen was used to assess Indonesian HIV+ patients receiving ART without stavudine (case definition: bilateral presence of at least one symptom and at least one sign of neuropathy). Distal leg skin biopsies were stained to visualize chemokine receptors (CCR2, CCR5, CXCR3, CXCR4, CX3CR1), infiltrating CD3 and CD14 cells, and protein-gene-product 9.5 on nerves, using immunohistochemistry and 4-colour confocal microscopy. RESULTS: Intraepidermal nerve fibre density was variable in patients without HIV-SN and generally lower in those with HIV-SN. CX3CR1 was more evident on CD14 cells whereas CCR2, CCR5, CXCR3 and CXCR4 were more common on CD3 cells. Expression of CX3CR1, CCR2 and CCR5 was more common in HIV-SN+ patients than those without HIV SN. CXCR3 and CXCR4 were upregulated in all HIV+ patients, compared with healthy controls. CONCLUSION: Inflammatory macrophages expressing CX3CR1 and T cells expressing CCR2 and CCR5 may participate in peripheral nerve damage leading to HIV-SN in HIV+ patients treated without stavudine. Further characterization of these cells is warranted. PMID- 29239898 TI - Patient-level and program-level monitoring and evaluation of differentiated service delivery for HIV: a pragmatic and parsimonious approach is needed. PMID- 29239899 TI - Stroke severity quantification by critical care physicians in a mobile stroke unit. AB - BACKGROUND: Cerebral revascularization in acute stroke requires robust diagnostic tools close to symptom onset. The quantitative National Institute of Health Stroke Scale (NIHSS) is widely used in-hospital, whereas shorter and less specific stroke scales are used in the prehospital field. This study explored the accuracy and potential clinical benefit of using NIHSS prehospitally. PATIENTS AND METHODS: Thirteen anesthesiologists trained in prehospital critical care enrolled patients with suspected acute stroke in a mobile stroke unit. NIHSS was completed twice in the acute phase: first prehospitally and then by an on-call resident neurologist at the receiving hospital. The agreement between prehospital and in-hospital NIHSS scores was assessed by a Bland-Altman plot, and inter-rater agreement for predefined clinical categories was tested using Cohen's kappa. RESULTS: This Norwegian Acute Stroke Prehospital Project study included 40 patients for analyses. The mean numerical difference between prehospital and in hospital NIHSS scores was 0.85, with corresponding limits of agreement from -5.94 to 7.64. Inter-rater agreement (kappa) for the corresponding clinical categories was 0.38. A prehospital diagnostic workup (NIHSS and computed tomographic examination) was completed in median (quartiles) 10 min (range: 7-14 min). Time between the prehospital and in-hospital NIHSS scores was median (quartiles) 40 min (32-48 min). CONCLUSION: Critical care physicians in a mobile stroke unit may use the NIHSS as a clinical tool in the assessment of patients experiencing acute stroke. The disagreement in NIHSS scores was mainly for very low values and would not have changed the handling of the patients.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 29239900 TI - Isoniazid Preventive Therapy for People With HIV Who Are Heavy Alcohol Drinkers in High TB-/HIV-Burden Countries: A Risk-Benefit Analysis. AB - BACKGROUND: Isoniazid preventive therapy (IPT) reduces mortality among people living with HIV (PLHIV) and is recommended for those without active tuberculosis (TB) symptoms. Heavy alcohol use, however, is contraindicated for liver toxicity concerns. We evaluated the risks and benefits of IPT at antiretroviral therapy (ART) initiation to ART alone for PLHIV who are heavy drinkers in 3 high TB-/HIV burden countries. METHODS: We developed a Markov simulation model to compare ART alone to ART with either 6 or 36 months of IPT for heavy drinking PLHIV enrolling in care in Brazil, India, and Uganda. Outcomes included nonfatal toxicity, fatal toxicity, life expectancy, TB cases, and TB death. RESULTS: In this simulation, 6 months of IPT + ART (IPT6) extended life expectancy over both ART alone and 36 months of IPT + ART (IPT36) in India and Uganda, but ART alone dominated in Brazil in 51.5% of simulations. Toxicity occurred in 160/1000 persons on IPT6 and 415/1000 persons on IPT36, with fatal toxicity in 8/1000 on IPT6 and 21/1000 on IPT36. Sensitivity analyses favored IPT6 in India and Uganda with high toxicity thresholds. CONCLUSIONS: The benefits of IPT for heavy drinkers outweighed its risks in India and Uganda when given for a 6-month course. The toxicity/efficacy trade-off was less in Brazil where TB incidence is lower. IPT6 resulted in fatal toxicity in 8/1000 people, whereas even higher toxicities of IPT36 negated its benefits in all countries. Data to better characterize IPT toxicity among HIV infected drinkers are needed to improve guidance. PMID- 29239902 TI - Oath Taking at U.S. and Canadian Medical School Ceremonies: Historical Perspectives, Current Practices, and Future Considerations. AB - The widespread use of oaths at medical commencements is a recent phenomenon of the late 20th century. While many are referred to as "Hippocratic," surveys have found that most oaths are modern, and the use of unique oaths has been rising. Oaths taken upon entry to medical school are even more recent, and their content has not been reported. The authors surveyed all Association of American Medical Colleges-member schools in the United States and Canada in 2015 and analyzed oath texts. Of 111 (70.2%) responses, full texts were submitted for 80 commencement and 72 white coat oaths. Previous studies have shown that while oaths before World War II were commonly variations on the original Hippocratic text and subsequently more often variations on the Geneva or Lasagna oath, now more than half of commencement ceremonies use an oath unique to that school or written by that class. With a wider range of oath texts, content elements are less uniformly shared, so that only three elements (respecting confidentiality, avoiding harm, and upholding the profession's integrity) are present in as many as 80% of oaths. There is less uniformity in the content of oaths upon entry to medical school. Consistently all of these oaths represent the relationship between individual physicians and individual patients, and only a minority express obligations to teach, advocate, prevent disease, or advance knowledge. They do not reflect obligations to ensure that systems operate safely, for example. None of the obligations in these oaths are unique to physicians. PMID- 29239901 TI - Prevention of HIV-1 Transmission Through Breastfeeding: Efficacy and Safety of Maternal Antiretroviral Therapy Versus Infant Nevirapine Prophylaxis for Duration of Breastfeeding in HIV-1-Infected Women With High CD4 Cell Count (IMPAACT PROMISE): A Randomized, Open-Label, Clinical Trial. AB - BACKGROUND: No randomized trial has directly compared the efficacy of prolonged infant antiretroviral prophylaxis versus maternal antiretroviral therapy (mART) for prevention of mother-to-child transmission throughout the breastfeeding period. SETTING: Fourteen sites in Sub-Saharan Africa and India. METHODS: A randomized, open-label strategy trial was conducted in HIV-1-infected women with CD4 counts >=350 cells/mm (or >=country-specific ART threshold if higher) and their breastfeeding HIV-1-uninfected newborns. Randomization at 6-14 days postpartum was to mART or infant nevirapine (iNVP) prophylaxis continued until 18 months after delivery or breastfeeding cessation, infant HIV-1 infection, or toxicity, whichever occurred first. The primary efficacy outcome was confirmed infant HIV-1 infection. Efficacy analyses included all randomized mother-infant pairs except those with infant HIV-1 infection at entry. RESULTS: Between June 2011 and October 2014, 2431 mother-infant pairs were enrolled; 97% of women were World Health Organization Clinical Stage I, median screening CD4 count 686 cells/mm. Median infant gestational age/birth weight was 39 weeks/2.9 kilograms. Seven of 1219 (0.57%) and 7 of 1211 (0.58%) analyzed infants in the mART and iNVP arms, respectively, were HIV-infected (hazard ratio 1.0, 96% repeated confidence interval 0.3-3.1); infant HIV-free survival was high (97.1%, mART and 97.7%, iNVP, at 24 months). There were no significant differences between arms in median time to breastfeeding cessation (16 months) or incidence of severe, life threatening, or fatal adverse events for mothers or infants (14 and 42 per 100 person-years, respectively). CONCLUSIONS: Both mART and iNVP prophylaxis strategies were safe and associated with very low breastfeeding HIV-1 transmission and high infant HIV-1-free survival at 24 months. PMID- 29239903 TI - Proposed Performance-Based Metrics for the Future Funding of Graduate Medical Education: Starting the Conversation. AB - Graduate medical education (GME) in the United States is financed by contributions from both federal and state entities that total over $15 billion annually. Within institutions, these funds are distributed with limited transparency to achieve ill-defined outcomes. To address this, the Institute of Medicine convened a committee on the governance and financing of GME to recommend finance reform that would promote a physician training system that meets society's current and future needs. The resulting report provided several recommendations regarding the oversight and mechanisms of GME funding, including implementation of performance-based GME payments, but did not provide specific details about the content and development of metrics for these payments. To initiate a national conversation about performance-based GME funding, the authors asked: What should GME be held accountable for in exchange for public funding? In answer to this question, the authors propose 17 potential performance-based metrics for GME funding that could inform future funding decisions. Eight of the metrics are described as exemplars to add context and to help readers obtain a deeper understanding of the inherent complexities of performance-based GME funding. The authors also describe considerations and precautions for metric implementation. PMID- 29239905 TI - Specific association of the rs6500265 and rs9933632 single-nucleotide polymorphisms in Japanese patients with antipyretic analgesic-related Stevens Johnson syndrome and toxic epidermal necrolysis with severe ocular involvements. AB - A recent study using the microarray for single-nucleotide polymorphisms (SNPs) genotyping specifically designed for the Japanese population in combination with genome-wide imputation showed the association of several SNPs with cold medicine related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications. However, it remains to be determined whether these polymorphisms are associated with the onset of antipyretic analgesic (AA)-related SJS/TEN, the progression of severe ocular involvements (SOIs), or both AA-related SJS/TEN and SOI phenotypes. To gain a better understanding of the features of these genetic markers, we compared the allele and carrier frequencies of these SNPs among our original SJS/TEN patient groups: (a) AA-related SJS/TEN with SOIs, (b) AA-related SJS/TEN without SOIs, and (c) AA-unrelated SJS/TEN with SOIs. AA related SJS/TEN with SOIs were found to be associated significantly with both rs6500265 [allele frequency: odds ratio (OR): 2.18; 95% confidence interval (CI): 1.30-3.65; P=0.0052; carrier frequency: OR: 2.52; 95% CI: 1.33-4.78; P=0.058] and rs9933632 (allele frequency: OR: 2.28: 95% CI: 1.37-3.79; P=0.0032; carrier frequency: OR: 2.76; 95% CI: 1.46-5.22; P=0.0031). In contrast, allele and carrier frequencies of these SNPs in patients with AA-related SJS/TEN without SOIs or with SOIs not treated with any AAs were comparable with those in healthy Japanese controls. Collectively, our findings indicate that the rs6500265 and rs9933632 SNPs could be specific markers for AA-related SJS/TEN with SOIs, suggesting that certain genetic backgrounds contribute toward the etiology of this complex syndrome. PMID- 29239907 TI - The 2017 Cervical Spine Research Society International Traveling Fellowship. PMID- 29239906 TI - Nerve Growth Factor Changes and Corneal Nerve Repair after Keratoplasty. AB - SIGNIFICANCE: Measured tear concentration of nerve growth factor is correlated with postoperative corneal reinnervation among patients who undergo keratoplasty. This may be a future therapeutic target for post-keratoplasty corneal nerve regeneration. PURPOSE: To determine the relationship between changes in the content of nerve growth factor (NGF) in tear fluid and corneal subepithelial nerve regeneration in patients after keratoplasty. METHODS: In this retrospective study, 30 eyes of 28 patients (15 males, 13 females; mean age 42.8 [range 16-73] years) who underwent primary keratoplasty for the first time were recruited through the clinics of the Department of Ophthalmology, Jilin University affiliated First Hospital, between May and December 2015. All patients underwent a complete ophthalmic examination preoperatively. Tear fluid samples were collected to detect the content of NFG at different time points in the follow-up period (day 1 preoperatively and days 1, 7, 30, and 90 postoperatively) and analyzed correlations between NFG content and age, infective factors, and variables of the surgical procedure as well as with subepithelial nerve repair at 30 and 90 days postoperatively. RESULTS: The NFG content in tear fluid on day 1 postoperatively was lower than that on the day preceding surgery; however, it was higher than the preoperative value on postoperative days 7, 30, and 90 (F = 5.046, P < 0.05). Further, the NFG content of tear fluid at 30 days postoperatively correlated with the surgical procedure (coefficient = -2.775, P = 0.010); however, no significant correlation was found on postoperative day 1 (coefficient = -1.315, P > 0.05). At all study time points, the NFG content of tear fluid had no correlation with infective factors or age (P > 0.05). Postoperatively, at day 30, small nerve buds were observed in the periphery of the corneal graft in 13 eyes (43.3% of cases) but not in 17 eyes (56.7% of cases), which showed a significant correlation with the NFG content of tear fluid (coefficient = -3.370, P = 0.010). By postoperative day 90, small nerve buds were observed in the periphery of the corneal graft in 24 eyes (80.0% of cases) and showed a significant correlation with the NFG content of tear fluid (coefficient = -2.750, P = 0.006). CONCLUSIONS: The NFG content in tear fluid increases with the increasing ratio of small nerve buds indicating corneal nerve regeneration. NFG promotes subepithelial nerve regeneration in patients after keratoplasty. PMID- 29239908 TI - Vitamin C is not the Missing Link Between Cigarette Smoking and Spinal Pain. AB - STUDY DESIGN: A nationwide cross-sectional study. OBJECTIVES: To measure the associations between cigarette smoking (defined as serum cotinine concentration >15 ng/mL) and the 3-month prevalence of spinal pain (neck pain, low back pain, low back pain with pain below knee, and self-reported diagnosis of arthritis/rheumatism) and related limitations, and to verify whether these associations are mediated by serum concentrations of vitamin C. SUMMARY OF BACKGROUND DATA: Cigarette smoking has been consistently associated with back pain, but this association has never been explained. Because vitamin C has recently been reported to be associated with spinal pain and related functional limitations, and the metabolism of vitamin C differs between smokers and nonsmokers, we hypothesized that the prevalence of spinal pain and related limitations might be greater among smokers because they are more susceptible to be in a state of hypovitaminosis C. METHODS: We conducted secondary analyses of National Health and Nutrition Examination Survey (NHANES) 2003 to 2004 data on 4438 individuals aged >=20 years. RESULTS: Serum concentrations of vitamin C and cotinine were strongly and inversely correlated (r = -0.35, P < 0.0001). Smoking was statistically associated with the prevalence of neck pain [adjusted odds ratio: aOR: 1.25; 95% confidence interval (95% CI): 1.06-1.47], low back pain (aOR: 1.20; 95% CI: 1.04-1.39), and low back pain with pain below knee (aOR: 1.58; 95% CI: 1.13-2.22) and related limitations, with a dose-response relationship (P < 0.05). However, the associations between smoking and spinal pain were not mediated by concentrations of vitamin C. CONCLUSION: These results confirm the relationship between smoking and spinal pain, but they do not support a mediating effect of vitamin C on this relationship. LEVEL OF EVIDENCE: 2. PMID- 29239909 TI - Pediatric High-flow Pial Arteriovenous Fistula (AVF) for Glue Embolization: An Anesthetic Challenge. PMID- 29239910 TI - Open Wide and Say A-Ha: Adding Oral Health Content to the Nurse Practitioner Curriculum. AB - While aligning our nurse practitioner curriculum to the competencies of the National Organization of Nurse Practitioner Faculties, we realized that there was a lack of oral health content in our program. As we did not possess the knowledge needed to teach this content, we invited a dental school faculty member to do this for our class. This experience led to a change in the delivery of our teaching content through the use of the STAR Legacy Cycle model and the How People Learn theory. The purpose of this article is to share our journey with others. PMID- 29239911 TI - Monitoring Student Immunization, Screening, and Training Records for Clinical Compliance: An Innovative Use of the Institutional Learning Management System. AB - Clinical compliance for nursing students is a complex process mandating them to meet facility employee occupational health requirements for immunization, screening, and training prior to patient contact. Nursing programs monitor clinical compliance with in-house management of student records, either paper or electronic, or by contracting with a vendor specializing in online record tracking. Regardless of method, the nursing program remains fully accountable for student preparation and bears the consequences of errors. This article describes how the institution's own learning management system can be used as an accurate, cost-neutral, user-friendly, and Federal Educational Rights Protection Act compliant clinical compliance system. PMID- 29239912 TI - Evaluating the Effectiveness of Visual Narrative Illustrations Used to Teach Pathophysiology to Undergraduate Nursing Students. AB - Nursing students and nurses often struggle with understanding pathophysiology concepts. Seventy-five students participated in two phases of an exploratory study that evaluated knowledge of pathophysiology concepts when taught using an innovation known as "visual narrative illustrations" (VNIs). Students taught using VNIs performed significantly better on a knowledge posttest and commented that the VNI humor and visual images helped them learn complex concepts. Used in combination with other teaching strategies, VNIs enhanced knowledge and understanding of pathophysiology concepts. PMID- 29239913 TI - Transforming the Role of the Clinical Faculty Coordinator in the Dedicated Education Unit. AB - The dedicated education unit (DEU) clinical education model has been identified nationally as an innovative model for clinical nursing education. This article identifies the core values of the DEU clinical faculty coordinator role and describes the transformation of this role across three clinical models. The role has been adapted to fit the needs of acute care, post-acute care, and community nursing DEU models, meeting the needs of the clinical educational environment and clinical staff as well as student learning outcomes. PMID- 29239914 TI - Message From the Editor. PMID- 29239915 TI - Preclinical Assessment of CAR T-Cell Therapy Targeting the Tumor Antigen 5T4 in Ovarian Cancer. AB - Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome both quantitative and qualitative shortfalls of the host immune system relating to the detection and subsequent destruction of tumors. The identification of antigens expressed specifically on the surface of tumor cells is a critical first step in the ability to utilize CAR T cells for the treatment of cancer. The 5T4 is a tumor-associated antigen which is expressed on the cell surface of most solid tumors including ovarian cancer. Matched blood and tumor samples were collected from 12 patients with ovarian cancer; all tumors were positive for 5T4 expression by immunohistochemistry. Patient T cells were effectively transduced with 2 different anti-5T4 CAR constructs which differed in their affinity for the target antigen. Co-culture of CAR T cells with matched autologous tumor disaggregates resulted in antigen-specific secretion of IFN gamma. Furthermore, assessment of the efficacy of anti-5T4 CAR T cells in a mouse model resulted in therapeutic benefit against established ovarian tumors. These results demonstrate proof of principle that 5T4 is an attractive target for immune intervention in ovarian cancer and that patient T cells engineered to express a 5T4-specific CAR can recognize and respond physiologically to autologous tumor cells. PMID- 29239917 TI - Natural Compounds as Epigenetic Regulators of Human Dendritic Cell-mediated Immune Function. AB - Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs) and are poised to capture antigen, migrate to draining lymphoid organs, and postmaturation process. Recent evidences have suggested that tumor microenvironment has an effect on DCs by inactivating various components of the immune system responsible for tumor clearance, eventually leading to tumorigenesis. This inactivation is owed to the epigenetic modifications [ie, microRNA (miRNA)] at the posttranscriptional level, thus regulating the differentiation patterns and functional behavior of DCs. Thus, need of the hour is to develop protocols for ex vivo generation of DCs which may provide a foundation for designing and developing DC-based vaccination for treatment of solid tumors. To achieve this, it is crucial to modulate DCs by identifying miRNAs which may increase the efficacy of DC-based vaccines by reprogramming the immunosuppressive nature of tumor microenvironment. Furthermore, it would be an interesting aspect to check the immunomodulatory potential of natural compounds in reprogramming the immune responses through DCs. Thus, this review aims to improvise the understanding of DC immune biology and miRNAs at genetic level in cancer which can be pivotal for designing novel or improved therapeutic approaches that will allow proper functioning of DCs in patient care. Furthermore, we have highlighted the candidate target molecules and signaling mechanisms having a vital role in the immune-modulatory activities of natural compounds and its derived phytocompounds. This review also establishes a link between miRNA expressions and biological roles of natural compounds modulating the activity of DCs. PMID- 29239916 TI - Early Experience With CliniMACS Prodigy CCS (IFN-gamma) System in Selection of Virus-specific T Cells From Third-party Donors for Pediatric Patients With Severe Viral Infections After Hematopoietic Stem Cell Transplantation. AB - Viral reactivation is a frequent complication of allogeneic hematopoietic stem cell transplantation especially in children. For refractory cases, rapid virus specific T-cell therapy would be ideally implemented within a few days. Over the course of a year in our pediatric cohort of 43 allogeneic transplantation, 9 patients fulfilled criteria for virus-specific T-cell therapy. Viral infections were due to cytomegalovirus (CMV) in 3, Epstein-Barr virus (EBV) in 2, and adenovirus (AdV) in 1 case, whereas >1 virus was detected in 3 cases. Viral diseases necessitating a T-cell therapy were CMV pneumonitis and colitis, AdV enteritis and cystitis, and EBV-induced posttransplantation lymphoproliferative disease. Cells were produced by the CliniMACS Prodigy CCS (IFN-gamma) System within 24 hours after mononuclear leukapheresis. Eight patients became completely asymptomatic, whereas 7 also cleared the virus. Six patients are alive without viral illness or sequelae demonstrating viral DNA clearance in peripheral blood with a median follow-up of 535 (350-786) days. One patient with CMV pneumonitis died of respiratory insufficiency. In 2 cases the viral illness improved or cleared, however, the patients died of invasive aspergillosis. No cases of graft versus-host disease, rejection, organ toxicity, or recurrent infection were noticed. Virus-specific T-cell therapy implemented by the CliniMACS Prodigy CCS (IFN-gamma) System is an automated, fast, safe, and probably effective way to control resistant viral diseases after pediatric hematopoietic stem cell transplantation. PMID- 29239918 TI - Anti-Neutrophil Cytoplasmic Antibody-Negative Central Nervous System Granulomatosis With Polyangiitis and Its Clinical Characteristics. AB - Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis occasionally affecting central nervous system (CNS), and GPA patients with initial CNS symptoms are even rarer, whose diagnosis is further confused by an absence of positive antineutrophil cytoplasmic antibody. The authors described the characteristics of antineutrophil cytoplasmic antibody -negative GPA with CNS onset in a patient and discussed on its management, which may contribute to future diagnosis and treatment of patients with similar conditions. PMID- 29239919 TI - Accessory Auricles: Systematic Review of Definition, Associated Conditions, and Recommendations for Clinical Practice. AB - Accessory auricles are rare congenital abnormalities embryologically derived from the first branchial arch. Presentation may be variable with locations grouped into anatomical zones based on the frequency of location found in the literature. This study reviewed the papers between 1981 and 2017. Findings included an association with syndromes including Goldenhar, VACTERL, Treacher-Collins, Townes Brocks, and Wolf-Hirschhorn. Based on histological and embryological evidence, the term "accessory auricle" is best used as an umbrella term to define this difference. Finally, indications are provided for imaging and laboratory investigations to guide the physician treating patients with accessory auricles. PMID- 29239920 TI - A Rare Complication After Septoplasty: Visual Loss Due to Right Retinal Artery Spasm. AB - Septoplasty is a commonly used procedure for correcting septal cartilage deformities. Hemorrhage, abscesses, scaling, adhesions, and scar tissue are often seen after the operation of the septoplasty, but temporary or permanent visual loss due to local anesthetic use has been reported very rarely in the literature. The authors also aimed to present a female patient with retinal artery spasm in the right eye after septoplasty in this article. A 27-year-old female patient was admitted to the authors' clinic with long-standing nasal obstruction and postnasal drip. There was no feature in her history and also no sign other than nasal septal deviation on physical examination. The patient was informed about the operation and the operation was planned. Emergency eye consultation was requested after the patient said that the right eye of the patient had never seen in the postoperative wake-up hall. Examination by an ophthalmologist; mild exotropia and total loss of vision in the right eye (including loss of light reflex) was detected. The light reaction in the affected eye was negative and indirect reaction was positive. After enlargement of the pupil, fundus examination revealed that the right posterior pole region (inside of the macula and vessel arches) was pale and no central retinal artery pulsation was observed. The patient was diagnosed with central retinal artery occlusion and emergency intervention was performed. The right eye massage, paracentesis, and hyperbaric oxygen therapy returned to the patient's visual function. PMID- 29239922 TI - Critical Appraisal in Plastic Surgery: Nullius in Verba. PMID- 29239921 TI - Inferiorly Pedicled Nasolabial Flap for Reconstruction of Anterior Maxilla Defects Class I and II. AB - OBJECTIVES: The aim of this study was to present the use of inferiorly pedicled nasolabial flap (IPNF) in the reconstruction of anterior maxilla defects class I and II. METHODS: Seven patients, 4 females and 3 males, aging from 38 to 75 (mean = 55.9) years old, from 2014 to 2017 reconstructed anterior part of maxilla with or without oronasal communication were included in this study. Five patients diagnosed with squamous cell carcinoma, 1 patient presented with epithelial myoepithelial carcinoma, and 1 patient had ameloblastoma. The IPNFs were harvested in 7 patients. Follow-up data were collected for a period ranging from 9 to 26 months. Speech, mastication, and aesthetic outcomes were evaluated with a questionnaire in interview. RESULTS: All patients healed without infection, flap loss, and flap failure. Five patients without prothetic treatment had little pronunciation problem (score: 1 to 3 points), while 2 patients with removable partial denture had excellent speech clarity (score: 1 to 2 points). All patients had no problem with mastication (score: 1 to 2 points). Aesthetic outcomes were acceptable in all patients (score: 1 to 3 points). CONCLUSION: The IPNF is a good option for reconstruction of anterior maxilla defects class I and II. PMID- 29239923 TI - Primary Closure of Oroantral Communication Using Pedicled Buccal Fat Pad Following Maxillary Cyst Enucleation. AB - Odontogenic keratocyst (OKC) is a clinically aggressive developmental odontogenic cyst with a high recurrence rate as 62%. Oroantral communication (OAC) is a gateway through the maxillary sinus and the oral cavity, which, if not treated, will develop into oroantral fistula or chronical sinus diseases. Different methods for closure of OAC were described but only few of them have common usage. In recent years, the use of a pedicled buccal fat pad (BFP) in closure of large oroantral defects has been become popular. In our patient, the OAC resulted from the surgical removal of OKC was closed with BFP. PMID- 29239924 TI - A Novel Method to Calculate the Volume of Alveolar Cleft Defect Before Surgery. AB - BACKGROUND: This study aimed to evaluate a novel subtractive method for the precise calculation of alveolar cleft defect volume before surgery using the three-dimensional imaging software Mimics. METHODS: Ten patients (3 female, 7 male, age range 8-12 years) with unilateral alveolar cleft were enrolled in the study. Preoperative helical computed tomography scans were performed for all patients. A new subtractive method was introduced to precisely calculate the alveolar cleft defect volume before surgery with the aid of Mimics. The DICOM data of every patient were processed using the subtractive method. Statistical analyses were performed using Pearson's correlation test and t test. RESULTS: The mean volume of the alveolar cleft defect was 1811.97 +/- 817.90 mm. The mean time spent to calculate an alveolar cleft defect volume was 60.60 +/- 11.67 minutes. The Pearson correlation test (r = 0.38, P = 0.279) indicated a poor correlation between alveolar cleft defect volume and calculation time. CONCLUSIONS: Preoperative knowledge of defect volume is crucial in alveolar cleft repair. Accurate estimation of graft volume in alveolar cleft patients can be performed using this new subtractive method. Compared with previous methods, this new subtractive method is time-saving and suitable for both unilateral and bilateral clefts. Surgeons can use this method to design a surgical plan for each patient before surgery within a short time, and with less cost. PMID- 29239925 TI - The Validity of Training Endoscopic Sinus and Skull Base Surgery Techniques on the Experimental Head Model. AB - OBJECTIVES: The aim of this study was to better understand the usual learning curve in acquiring endonasal endoscopic sinus and skull base surgery (ESSBS) techniques during the novice training on the lamb's head model. METHODS: Ten novices were asked to perform 10 bilateral dissections on the particular lamb's head each. The dissections were uniform, consisted of 10 well-defined steps, beginning from the simple removal of the inferior turbinate, and ending with more complicated procedures like cerebrospinal fluid leak repair, Draf 3 procedure for the frontal sinus and elevation of the nasal septal flap. The dissections have been supervised by experienced surgeons. A set of standard ESSBS instruments and 0 degrees and 45 degrees endoscopes have been used under the navigational system. The time required to complete each step has been measured in minutes. RESULTS: In general and quite expectedly, time rates have been obviously lowering as the number of the dissections performed has been growing in each of the participants. CONCLUSION: Training of the endonasal ESSBS techniques on the lamb's head proved to be useful for novices in getting basic surgical skills in the field. Because of the high degree of anatomic similarity and high level of the anatomic dimensions congruency between the lamb's head and human head (sheep's head has bigger dimensions!) it proved to be an essential preparation for the human cadaveric dissection. The median values of the time rates having been needed to complete the particular of the 10 steps in the last novices' dissections could be accepted as an orientation, just suggesting that once the time needed to complete 1 of the 10 steps has been and achieved by the particular novice, this could be an approximate sign of the maturity for the exercises on human cadaver head. PMID- 29239926 TI - A Case of Clinically Amyopathic Dermatomyositis With Hoarseness Due to Vocal Cord Necrosis. PMID- 29239927 TI - An Adult Patient With a Novel Mutation in NLRP3 Gene Associated With Cryopyrin Associated Periodic Syndrome Mimicking Adult-Onset Still Disease. PMID- 29239928 TI - Aspergillus Pneumonia in a Patient With Adult-Onset Still Disease Successfully Treated With Anakinra. PMID- 29239929 TI - Successful Recanalization of a Complete Left Mainstem Bronchus Occlusion Using Fluoroscopic, Contrast-Assisted Guidewire Placement With Bronchoscopic Airway Balloon Dilation in a Patient With GPA. PMID- 29239930 TI - Primary Hypertrophic Osteoarthropathy With SLCO2A1 Mutation in a Chinese Patient Successfully Treated With Etoricoxib. PMID- 29239931 TI - A Case of Amyloidosis Caused by Sporadic Muckle-Wells Syndrome: Response to Treatment With Anakinra. PMID- 29239932 TI - Plantar Kaposi Sarcoma Revealed by Antisynthetase Syndrome. PMID- 29239933 TI - Xanthomatous Multicentric Reticulohistiocytosis: An Underrecognized Variant. PMID- 29239934 TI - Safe Use of Rituximab in an Elderly Patient With Rheumatoid Arthritis and Severe Heart Failure. PMID- 29239935 TI - The Impact of Primary Antiphospholipid Syndrome on Long-term Cardiovascular Outcomes After Percutaneous Coronary Intervention and Stenting in Patients With Myocardial Infarction. PMID- 29239936 TI - Cat-Scratch Disease, a Diagnostic Consideration for Chronic Recurrent Multifocal Osteomyelitis. PMID- 29239937 TI - Hydroxychloroquine-Induced Reversible Hypomnesis in Systemic Lupus Erythematosus. PMID- 29239938 TI - Latest Advances in Ultrasound Assessment of Salivary Glands in Sjogren Syndrome. AB - OBJECTIVE: There are different imaging techniques to assess the parotid glands (i.e., sialography, salivary gland scintigraphy) in patients with Sjogren syndrome (SS). However, their use is limited by the invasive character or high cost. Ultrasound (US) is gaining interest by rheumatologists as a complementary diagnostic tool for SS. To date, there is an increasing body of evidence supporting its sensitivity in the assessment of salivary glands in SS. The aim of our study was to analyze the potential role of US as a diagnostic and prognostic tool in SS and to discuss existing evidence to support its application use. METHODS: A systematic search was performed in the electronic database PubMed, using the following search terms: (salivary glands OR parotid glands OR submandibular glands) AND Sjogren's syndrome AND (ultrasonography OR ultrasound OR sonography). Titles, abstracts, and full reports were systematically screened. RESULTS: The results of the studies analyzed in this review show encouraging results in terms of accuracy, validity, and diagnostic value, which leads us to believe that in the future US could become the reference imaging tool to assess SS. The studies include a small cohort of patients, and there is no standardized approach in terms of US techniques for the assessment of salivary glands. CONCLUSIONS: Ultrasound of major salivary glands is a useful tool for diagnosis, prognostic evaluation, and response to treatment in SS. The use of this imaging technology is still under development, and more multicentric studies are needed to validate this tool. PMID- 29239939 TI - An Environment Is More Than a Climate. PMID- 29239941 TI - Meeting Report for the 39th Annual Meeting and Workshops of the Society of Cardiovascular Anesthesiologists. PMID- 29239940 TI - Prolonged Duration Local Anesthesia Using Liposomal Bupivacaine Combined With Liposomal Dexamethasone and Dexmedetomidine. AB - BACKGROUND: The relatively short duration of effect of local anesthetics has been addressed by encapsulation in drug delivery systems. Codelivery with a single compound that produces an adjuvant effect on nerve block but without intrinsic local anesthetic properties can further prolong the nerve block effect. Here, we investigated whether codelivery of more than 1 encapsulated adjuvant compound can further enhance nerve blockade. METHODS: Liposomes loaded with bupivacaine (Bup), dexamethasone phosphate (DexP), or dexmedetomidine (DMED) were synthesized and its in vitro drug release profiles were determined. Animals (Sprague-Dawley rats) were injected with liposomal Bup (Lipo-Bup) and adjuvants at the sciatic nerve and underwent a modified hot plate test to assess the degree of nerve block. The duration of block was monitored and the tissue reaction was assessed. RESULTS: Coinjection of Lipo-Bup with liposomal DexP (Lipo-DexP) and liposomal DMED (Lipo DMED) prolonged the duration of sciatic nerve block 2.9-fold compared to Lipo-Bup alone (95% confidence interval, 1.9- to 3.9-fold). The duration of the block using this combination was significantly increased to 16.2 +/- 3.5 hours compared to Lipo-Bup with a single liposomal adjuvant (8.7 +/- 2.4 hours with Lipo-DMED, P = .006 and 9.9 +/- 5.9 hours with Lipo-DexP, P = .008). The coinjection of Lipo Bup with liposomal adjuvants decreased tissue inflammation (P = .014) but did not have a significant effect on myotoxicity when compared to Lipo-Bup alone. Coinjection of Lipo-Bup with unencapsulated adjuvants prolonged the duration of nerve block as well (25.0 +/- 6.3 hours; P < .001) however was accompanied by systemic side effects. CONCLUSIONS: Codelivery of Lipo-DexP and Lipo-DMED enhanced the efficacy of Lipo-Bup. This benefit was also seen with codelivery of both adjuvant molecules in the unencapsulated state, but with marked systemic toxicity. PMID- 29239944 TI - Retrospective Review of Universal Preoperative Pregnancy Testing: Results and Perspectives. AB - Unrecognized pregnancy in patients presenting for elective surgery is of particular concern due to the potential for significant complications. Accurate and inexpensive urine pregnancy tests are widely available in the developed world. As a result, universal preoperative pregnancy screening is commonly implemented. However, the utility of such routine testing is controversial. We retrospectively studied 8245 immediate presurgery pregnancy tests at Mayo Clinic Hospital, Phoenix, AZ, and found 11 positive tests of which 6 were false positives. We constructed a census-based approximation for unrecognized pregnancies, which shows significantly low pretest probability in this patient population. Taken together, the utility of immediate universal presurgical pregnancy testing is questionable. PMID- 29239942 TI - Targeted Temperature Management After Cardiac Arrest: Systematic Review and Meta analyses. AB - BACKGROUND: Targeted temperature management (TTM) with therapeutic hypothermia is an integral component of postarrest care for survivors. However, recent randomized controlled trials (RCTs) have failed to demonstrate the benefit of TTM on clinical outcomes. We sought to determine if the pooled data from available RCTs support the use of prehospital and/or in-hospital TTM after cardiac arrest. METHODS: A comprehensive search of SCOPUS, Elsevier's abstract and citation database of peer-reviewed literature, from 1966 to November 2016 was performed using predefined criteria. Therapeutic hypothermia was defined as any strategy that aimed to cool post-cardiac arrest survivors to a temperature <=34 degrees C. Normothermia was temperature of >=36 degrees C. We compared mortality and neurologic outcomes in patients by categorizing the studies into 2 groups: (1) hypothermia versus normothermia and (2) prehospital hypothermia versus in hospital hypothermia using standard meta-analytic methods. A random effects modeling was utilized to estimate comparative risk ratios (RR) and 95% confidence intervals (CIs). RESULTS: The hypothermia and normothermia strategies were compared in 5 RCTs with 1389 patients, whereas prehospital hypothermia and in hospital hypothermia were compared in 6 RCTs with 3393 patients. We observed no difference in mortality (RR, 0.88; 95% CI, 0.73-1.05) or neurologic outcomes (RR, 1.26; 95% CI, 0.92-1.72) between the hypothermia and normothermia strategies. Similarly, no difference was observed in mortality (RR, 1.00; 95% CI, 0.97-1.03) or neurologic outcome (RR, 0.96; 95% CI, 0.85-1.08) between the prehospital hypothermia versus in-hospital hypothermia strategies. CONCLUSIONS: Our results suggest that TTM with therapeutic hypothermia may not improve mortality or neurologic outcomes in postarrest survivors. Using therapeutic hypothermia as a standard of care strategy of postarrest care in survivors may need to be reevaluated. PMID- 29239945 TI - Error Grid Analysis for Arterial Pressure Method Comparison Studies. AB - The measurement of arterial pressure (AP) is a key component of hemodynamic monitoring. A variety of different innovative AP monitoring technologies became recently available. The decision to use these technologies must be based on their measurement performance in validation studies. These studies are AP method comparison studies comparing a new method ("test method") with a reference method. In these studies, different comparative statistical tests are used including correlation analysis, Bland-Altman analysis, and trending analysis. These tests provide information about the statistical agreement without adequately providing information about the clinical relevance of differences between the measurement methods. To overcome this problem, we, in this study, propose an "error grid analysis" for AP method comparison studies that allows illustrating the clinical relevance of measurement differences. We constructed smoothed consensus error grids with calibrated risk zones derived from a survey among 25 specialists in anesthesiology and intensive care medicine. Differences between measurements of the test and the reference method are classified into 5 risk levels ranging from "no risk" to "dangerous risk"; the classification depends on both the differences between the measurements and on the measurements themselves. Based on worked examples and data from the Multiparameter Intelligent Monitoring in Intensive Care II database, we show that the proposed error grids give information about the clinical relevance of AP measurement differences that cannot be obtained from Bland-Altman analysis. Our approach also offers a framework on how to adapt the error grid analysis for different clinical settings and patient populations. PMID- 29239943 TI - Achieving Milestones as a Prerequisite for Proceeding With a Clinical Trial. AB - BACKGROUND: Although the National Institutes of Health (NIH) invests $30 billion in research annually, many funded studies fail to generate results that can inform practice. The National Institutes of Health introduced a phased funding mechanism as one potential solution. Study-specific milestones are established for an initial pilot phase. We assess the utility of this phased approach through the ongoing Electroencephalography (EEG) Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) pragmatic clinical trial. The hypothesis of the trial is that EEG guidance of general anesthesia, through prevention of EEG suppression, can decrease postoperative delirium and its downstream negative sequelae. METHODS: In collaboration with study stakeholders, we identified critical milestones for the ENGAGES study, with themes common to many clinical trials. These themes include: regulatory tasks; enrollment targets; feasibility and impact of study intervention; primary outcome incidence; measurement reliability of primary outcome; and follow-up. Progress in achieving the milestones was assessed at regular intervals during the pilot phase by ENGAGES investigators, a National Institute on Aging program officer, and a nonpartisan research organization (Westat). RESULTS: Regulatory tasks, including institutional review board approval, infrastructure establishment, and trial registration, were completed on schedule. A total of 117 patients were randomized, exceeding the target by 51. The EEG-guided protocol was successfully implemented, and a relevant effect on anesthetic practice was demonstrated (decrease in median age-adjusted minimum alveolar anesthetic concentration from 0.93 to 0.78 [P < .001] and increase in median proportion of zero EEG suppression time from 87% to 94% [P < .01]). Nearly all patients (115 of 117, 98.3%) were assessed for delirium using the Confusion Assessment Method, and the delirium incidence was similar (28.1%; 95% CI, 20%-37%) to the estimate (25%) used for the sample size calculation. Good interrater reliability of delirium assessment was demonstrated (kappa = 0.94 [95% CI, 0.86-1]). Finally, 1-month follow-up vital status data were obtained for 96.9% of patients, with 85.7% of patients completing at least 1 survey. CONCLUSIONS: With the ENGAGES trial, we demonstrated that key milestones can be identified and progressively assessed during a pilot phase. Success in attaining appropriate milestones hypothetically predicts meaningful completion of a study, and can provide justification for proceeding beyond a pilot phase. The impact of this phased approach on return on investment and scientific yield requires additional study. PMID- 29239946 TI - In Response. PMID- 29239947 TI - Treatment of Chronic Pain With Various Buprenorphine Formulations: A Systematic Review of Clinical Studies. AB - Clinical studies demonstrate that buprenorphine is a pharmacologic agent that can be used for the treatment of various types of painful conditions. This study investigated the efficacy of 5 different types of buprenorphine formulations in the chronic pain population. The literature was reviewed on PubMed/MEDLINE, EMBASE, Cochrane Database, clinicaltrials.gov, and PROSPERO that dated from inception until June 30, 2017. Using the population, intervention, comparator, and outcomes method, 25 randomized controlled trials were reviewed involving 5 buprenorphine formulations in patients with chronic pain: intravenous buprenorphine, sublingual buprenorphine, sublingual buprenorphine/naloxone, buccal buprenorphine, and transdermal buprenorphine, with comparators consisting of opioid analgesics or placebo. Of the 25 studies reviewed, a total of 14 studies demonstrated clinically significant benefit with buprenorphine in the management of chronic pain: 1 study out of 6 sublingual and intravenous buprenorphine, the only sublingual buprenorphine/naloxone study, 2 out of 3 studies of buccal buprenorphine, and 10 out of 15 studies for transdermal buprenorphine showed significant reduction in pain against a comparator. No serious adverse effects were reported in any of the studies. We conclude that a transdermal buprenorphine formulation is an effective analgesic in patients with chronic pain, while buccal buprenorphine is also a promising formulation based on the limited number of studies. PMID- 29239950 TI - A Retrospective Analysis of Clinical Research Misconduct Using FDA-Issued Warning Letters and Clinical Investigator Inspection List From 2010 to 2014. AB - BACKGROUND: The US Food and Drug Administration (FDA) conducts inspections of clinical investigation sites as a component of clinical trial regulation. The FDA describes the results of these inspections in the Clinical Investigator Inspection List (CLIIL). More serious violations are followed up in FDA warning letters issued to investigators. The primary objective of the current study is to qualitatively and quantitatively describe the CLIIL data and contents of FDA issued warning letters from 2010 to 2014. METHODS: We retrospectively analyzed the CLIIL and FDA warning letters. For the CLIIL, we quantified the frequency of each violation among other data points. We compared recent data (2010-2014) to the previous 5 years (2005-2009). To analyze FDA warning letters, we developed a coding system to quantify the frequency of violations found. RESULTS: We analyzed 3637 inspections in the CLIIL database and 60 warning letters. Overall, there was a decrease or no change in all violations in the CLIIL database. The largest violation code reported was "failure to follow investigational plan" in both the 2005-2009 and 2010-2014 timeframes. Coding of FDA warning letters shows that the most common violations reported were failing to maintain accurate case histories (10.82%), enrolling ineligible subjects (8.85%), and failing to perform required tests (8.52%). CONCLUSIONS: The overall decrease in violations is encouraging. But, the high proportion of violations related to failure to follow the investigational plan is concerning as the complexity of trials increases. We conclude that more detailed information is necessary to accurately evaluate these violations. The current study provides a model for creating more granular data of violations to better inform clinical investigators and improve clinical trials. PMID- 29239951 TI - The Clinical Utility of Noninvasive Pulse Co-oximetry Hemoglobin Measurements in Dark-Skinned Critically Ill Patients. AB - BACKGROUND: The primary objective of this study was to assess the clinical usefulness of a point-of-care device which measures hemoglobin noninvasively (SpHb) in a group of critically ill participants with dark skin pigmentation. METHODS: One hundred forty-six adult and pediatric participants from a multidisciplinary intensive care unit had intermittent readings of noninvasive hemoglobin measurements performed at a minimum of 4 hourly intervals. A total of 371 readings were analyzed. Concurrent blood samples were taken to assess hemoglobin levels using point-of-care blood gas analyzer, as well as sent to a central laboratory where hemoglobin was measured using the sodium lauryl sulfate method. Bland-Altman plots were constructed to assess the agreement between results from the 2 point-of-care devices with the reference standard (laboratory hemoglobin). RESULTS: SpHb exhibited significant bias when compared to laboratory hemoglobin, while blood gas hemoglobin did not. Mean bias for SpHb was +1.64 with limits of agreement of -1.03 to 4.31 compared to blood gas hemoglobin which showed a bias of 0.26 and limits of agreement of -0.84 to 1.37. The magnitude of the bias for SpHb increased with increasing mean hemoglobin levels. Of all the additional study variables assessed for effect on the bias, only Acute Physiology and Chronic Health Evaluation II score in adult patients (P < .0001) and mean arterial blood pressure (P = .001) had an effect. Skin pigmentation did not have any effect on the magnitude of bias. CONCLUSIONS: Noninvasive Hemoglobin measurement is a promising tool in dark-skinned critically ill patients with low hemoglobin levels, but requires further refinements for it to have clinical usefulness. PMID- 29239949 TI - Labor Analgesia as a Predictor for Reduced Postpartum Depression Scores: A Retrospective Observational Study. AB - BACKGROUND: Using labor, epidural analgesia has been linked to a reduced risk of postpartum depression, but the role of labor pain relief in this association remains unclear. The goal of this study was to test the hypothesis that effective epidural analgesia during labor is associated with reduced postpartum depression symptomatology. METHODS: A single, institutional, retrospective, observational cohort design was chosen. The primary outcome was Edinburgh postnatal depression scale (EPDS) score, measured at the 6-week postpartum visit. Subjects included in the final analysis had (1) received labor epidural analgesia; (2) pain assessed during labor both before and during initiation of labor epidural analgesia by 0 10 numeric rating scores; and (3) depression risk assessed by the EPDS and documented at their 6-week postpartum visit. Simple and multiple linear regression was used to identify the best model for assessing the association between pain improvement, defined as percent improvement in pain (PIP), and depression, after adjusting for a history of anxiety or depression, other psychiatric history, abuse, trauma, mode of delivery, and other maternal or fetal comorbid diseases. RESULTS: Two hundred one patients were included in the final analysis. Women with higher improvements in pain were associated with lower EPDS scores (r = 0.025; P = .002). Variables known to be associated with depression (body mass index, anxiety and/or depression, third- and fourth-degree perineal lacerations, and anemia) were significantly correlated with EPDS score and included in the final model. After we adjusted for these covariates, PIP remained a significant predictor of EPDS score (r = 0.49; P = .008), accounting for 6.6% of the variability in postpartum depression scores. The full model including pain, body mass index, anxiety and/or depression, perineal lacerations, and anemia explained 24% of the variability in postpartum depression scores. CONCLUSIONS: Although the extent of labor pain relief by epidural analgesia predicts lower postpartum depression scores, the relative contribution of PIP to risk for postpartum depression symptoms may be less than other established risk factors for depression. These data support that the clinical significance of labor analgesia in the development of postpartum depression needs to be more clearly defined. PMID- 29239952 TI - In Response. PMID- 29239953 TI - The Impact of Prehospital Tranexamic Acid on Blood Coagulation in Trauma Patients. AB - BACKGROUND: There is limited data on prehospital administration of tranexamic acid (TXA) in civilian trauma. The aim of this study was to evaluate changes in coagulation after severe trauma from on-scene to the hospital after TXA application in comparison to a previous study without TXA. METHODS: The study protocol was registered at ClinicalTrials.gov (NCT02354885). A prospective, multicenter, observational study investigating coagulation status in 70 trauma patients receiving TXA (1 g intravenously) on-scene versus a control group of 38 patients previously published without TXA. To account for potential differences in patient and trauma epidemiology, crystalloid and colloidal resuscitation fluid, 2 propensity score matched groups (n = 24 per group) were created. Measurements included ROTEM, standard coagulation tests and blood gas analyses on scene and emergency department admission. Presented values are mean and [standard deviation], and difference in means and 95% confidence intervals. RESULTS: Patient epidemiology was not different between groups. Coagulation assays on scene were comparable between the TXA and C. Prehospital hyperfibrinolysis was blunted in all 4 patients in the TXA group. Viscoelastic FIBTEM maximum clot firmness (MCF), representing functional fibrinogen levels, did not change from on scene to the emergency department in the TXA group, whereas MCF decreased -3.7 [1.8] mm in the control group. Decrease of MCF was significantly reduced in the TXA group in EXTEM by 9.2 (7.2-11.2) mm (P < .001) and INTEM by 6.8 (4.7-9.0) mm (P < .001) in favor of the TXA group. Production of fibrinogen fragments (represented by D-dimers) was significantly lower in the TXA group compared to group C. CONCLUSIONS: Early prehospital administration of TXA leads to clot stabilization and a reduction of fibrinolytic activity, causing a decrease in fibrin degradation products buildup (D-dimer). PMID- 29239954 TI - Analysis of Inpatient Falls After Total Knee Arthroplasty in Patients With Continuous Femoral Nerve Block. AB - Continuous femoral nerve block (cFNB) is thought to increase the risk of falls after total knee arthroplasty (TKA). Previous studies have failed to consider the timing of cFNB removal in relation to inpatient falls. We investigated all inpatient falls after TKA over a 3-year period using our institutional safety report database. Ninety-five falls were reported from a total of 3745 patients. The frequency of falls after TKA persisted at a similar rate despite removal of cFNB and likely regression of femoral nerve block. Other modifiable risk factors may play a more prominent role in falls risk after TKA. PMID- 29239955 TI - Response to Improving the Success Rate of Chest Compression-Only CPR by Untrained Bystanders in Adult Out-of-Hospital Cardiac Arrest: Maintaining Airway Patency May Be the Way Forward. PMID- 29239956 TI - The Anesthesia Workstation: Quo Vadis? AB - Ensuring adequate ventilation and oxygenation and delivering inhaled anesthetic agent to the patient remain core responsibilities of the anesthesia provider during general anesthesia. Because of the emphasis placed on physiology, pharmacology, clinical sciences, and administrative duties, the stellar anesthesia workstation technology may be underutilized by the anesthesia community. Target-controlled O2 and agent delivery and automated end-expired CO2 control have entered the clinical arena, with only cost, luddism, and administrative hurdles preventing their more widespread use. This narrative review will explain technological aspects of existing and recently introduced anesthesia workstations. Concepts rather than particular anesthesia machines will be addressed, but examples will mostly pertain to the more recently introduced workstations. The anesthesia workstation consists of a ventilator, a carrier gas and agent delivery system, a scavenging system, and monitors. Mainly, the circle breathing circuit configuration, ventilator, and carrier gas and agent delivery technology are discussed. Occasionally, technical details are provided to give the reader a taste of the modern technology. PMID- 29239957 TI - American College of Surgeons Children's Surgery Verification Quality Improvement Program: What Anesthesiologists Need to Know Now. AB - A task force of pediatric surgical specialists with the support of The American College of Surgeons recently launched a verification program for pediatric surgery, the Children's Surgery Verification quality improvement program, with the goal of improving pediatric surgical, procedural, and perioperative care. Included in this program are specific standards for the delivery of pediatric anesthesia care across a variety of practice settings. We review the background, available evidence, requirements for verification, and verification process and its implications for the practice of pediatric anesthesia across the country. In addition, we have included a special roundtable interview of 3 recently Children's Surgery Verification-verified program directors to provide an up-to date real-world perspective of this children's surgery quality improvement program. PMID- 29239958 TI - Nerve Blockade and Chronic Opiate Use After Orthopedic Surgery. PMID- 29239960 TI - Another Possible Reason to Use Prophylactic Phenylephrine Infusions to Reduce Spinal Anesthesia-Associated Hypotension: Do These Patients Stay Warmer? PMID- 29239959 TI - Bias in Before-After Studies: Narrative Overview for Anesthesiologists. AB - Before-after study designs are effective research tools and in some cases, have changed practice. These designs, however, are inherently susceptible to bias (ie, systematic errors) that are sometimes subtle but can invalidate their conclusions. This overview provides examples of before-after studies relevant to anesthesiologists to illustrate potential sources of bias, including selection/assignment, history, regression to the mean, test-retest, maturation, observer, retrospective, Hawthorne, instrumentation, attrition, and reporting/publication bias. Mitigating strategies include using a control group, blinding, matching before and after cohorts, minimizing the time lag between cohorts, using prospective data collection with consistent measuring/reporting criteria, time series data collection, and/or alternative study designs, when possible. Improved reporting with enforcement of the Enhancing Quality and Transparency of Health Research (EQUATOR) checklists will serve to increase transparency and aid in interpretation. By highlighting the potential types of bias and strategies to improve transparency and mitigate flaws, this overview aims to better equip anesthesiologists in designing and/or critically appraising before-after studies. PMID- 29239961 TI - Oxytocin Study Raises Concerns About Carbetocin Use. PMID- 29239962 TI - In Response. PMID- 29239963 TI - In Vitro Evaluation of a Novel Image Processing Device to Estimate Surgical Blood Loss in Suction Canisters. AB - BACKGROUND: Clinicians are tasked with monitoring surgical blood loss. Unfortunately, there is no reliable method available to assure an accurate result. Most blood lost during surgery ends up on surgical sponges and within suction canisters. A novel Food and Drug Administration-cleared device (Triton system; Gauss Surgical, Inc, Los Altos, CA) to measure the amount of blood present on sponges using computer image analysis has been previously described. This study reports on performance of a complementary Food and Drug Administration cleared device (Triton Canister System; Gauss Surgical, Inc, Los Altos, CA) that uses similar image analysis to measure the amount of blood in suction canisters. METHODS: Known quantities of expired donated whole blood, packed red blood cells, and plasma, in conjunction with various amounts of normal saline, were used to create 207 samples representing a wide range of blood dilutions commonly seen in suction canisters. Each sample was measured by the Triton device under 3 operating room lighting conditions (bright, medium, and dark) meant to represent a reasonable range, resulting in a total of 621 measurements. Using the Bland Altman method, the measured hemoglobin (Hb) mass in each sample was compared to the results obtained using a standard laboratory assay as a reference value. The analysis was performed separately for samples measured under each lighting condition. It was expected that under each separate lighting condition, the device would measure the various samples within a prespecified clinically significant Hb mass range (+/-30 g per canister). RESULTS: The limits of agreement (LOA) between the device and the reference method for dark (bias: 4.7 g [95% confidence interval {CI}, 3.8-5.6 g]; LOA: -8.1 g [95% CI, -9.7 to -6.6 g] to 17.6 g [95% CI, 16.0-19.1 g]), medium (bias: 3.4 g [95% CI, 2.6-4.1 g]; LOA: 7.4 g [95% CI, -8.7 to -6.1 g] to 14.2 g [95% CI, 12.9-15.5 g]), and bright lighting conditions (bias: 4.1 g [95% CI, 3.2-4.9 g]; LOA: -7.6 g [95% CI, -9.0 to -6.2 g] to 15.7 g [95% CI, 14.3-17.1 g]) fell well within the predetermined clinically significant limits of +/-30 g. Repeated measurements of the samples under the various lighting conditions were highly correlated with intraclass correlation coefficient of 0.995 (95% CI, 0.993-0.996; P < .001), showing that lighting conditions did not have a significant impact on measurements. Hb mass bias was significantly associated with hemolysis level (Spearman rho correlation coefficient, -0.137; P = .001) and total canister volume (Spearman rho correlation coefficient, 0.135; P = .001), but not ambient illuminance. CONCLUSIONS: The Triton Canister System was able to measure the Hb mass reliably with clinically acceptable accuracy in reconstituted blood samples representing a wide range of Hb concentrations, dilutions, hemolysis, and ambient lighting settings. PMID- 29239964 TI - Superior Efficacy of Lipid Emulsion Infusion Over Serum Alkalinization in Reversing Amitriptyline-Induced Cardiotoxicity in Guinea Pig. AB - BACKGROUND: Tricyclic antidepressants (TCAs) are a major cause of fatal drug poisoning due to their cardiotoxicity. Alkalinization by sodium bicarbonate (NaHCO3) administration, the first-line therapy for TCA-induced cardiotoxicity, can occasionally yield insufficient efficacy in severe cases. Because most TCAs are highly lipophilic, lipid emulsion may be more effective than alkalinization. However, it remains to be determined whether lipid emulsion is more beneficial than alkalinization in reversing amitriptyline-induced cardiotoxicity. METHODS: Hemodynamic variables were recorded from in vivo guinea pig models and Langendorff-perfused hearts. Whole-cell patch-clamp experiments were conducted on enzymatically isolated ventricular cardiomyocytes to record fast sodium currents (INa). Lipid solutions were prepared using 20% Intralipid. The pH of the alkaline solution was set at 7.55. We assessed the effect of lipid emulsion on reversing amitriptyline-induced cardiotoxicity, in vivo and in vitro, compared to alkalinization. The data were evaluated by Student t test, 1-way repeated measures analysis of variance, or analysis of covariance (covariate = amitriptyline concentration); we considered data statistically significant when P < .05. RESULTS: In the in vivo model, intervention with lipids significantly reversed the amitriptyline-induced depression of mean arterial pressure and prolongation of QRS duration on electrocardiogram more than alkalinization (mean arterial pressure, mean difference [95% confidence interval]: 19.0 mm Hg [8.5 29.4]; QRS duration, mean difference [95% confidence interval] -12.0 milliseconds [-16.1 to -7.8]). In the Langendorff experiments, perfusion with 1% and 2% lipid solutions demonstrated significant recovery in left ventricular developed pressure (LVdevP), maximum change rate of increase of LVdevP (dP/dtmax) and rate pressure product compared with alkaline solution (LVdevP [mm Hg], alkaline 57 +/- 35, 1% lipid 94 +/- 12, 2% lipid 110 +/- 14; dP/dtmax [mm Hg/s], alkaline 748 +/- 441, 1% lipid 1502 +/- 334, 2% lipid 1753 +/- 389; rate-pressure product [mm Hg.beats.minute], alkaline 11,214 +/- 8272, 1% lipid 19,025 +/- 8427, 2% lipid 25,261 +/- 4803 with analysis of covariance). Furthermore, lipid solutions (0.5% 4%) resulted in greater recovery of hemodynamic parameters at 3 MUM amitriptyline. Amitriptyline inhibited INa in a dose-dependent manner: the half maximal inhibitory concentration (IC50) was 0.39 MUM. The IC50 increased to 0.75 MUM in the alkaline solution, 3.2 MUM in 1% lipid solution, and 6.1 MUM in 2% lipid solution. Furthermore, the lipid solution attenuated the use-dependent block of sodium channels by amitriptyline more than alkaline solution. On 30 consecutive pulses at 1 Hz, the current decreased to 50.1 +/- 2.1, 60.3 +/- 1.9, and 90.4% +/- 1.8% in standard, alkaline, and 1% lipid solution, respectively. Even 0.5% lipid solution showed greater effects than the alkaline solution in all experiments. CONCLUSIONS: Lipid emulsion significantly suppressed amitriptyline induced INa, inhibition, which was likely related to the marked improvement in hemodynamic status observed in vivo and in isolated perfused hearts. These results suggest the superiority of lipid emulsion as the first-line therapy for TCA-induced cardiotoxicity compared to alkalinization therapy. PMID- 29239965 TI - Videolaryngoscopy for Physician-Based, Prehospital Emergency Intubation: A Prospective, Randomized, Multicenter Comparison of Different Blade Types Using A.P. Advance, C-MAC System, and KingVision. AB - BACKGROUND: Videolaryngoscopy is a valuable technique for endotracheal intubation. When used in the perioperative period, different videolaryngoscopes vary both in terms of technical use and intubation success rates. However, in the prehospital environment, the relative performance of different videolaryngoscopic systems is less well studied. METHODS: We conducted this prospective, randomized, multicenter study at 4 German prehospital emergency medicine centers. One hundred sixty-eight adult patients requiring prehospital emergency intubation were treated by an emergency physician and randomized to 1 of 3 portable videolaryngoscopes (A.P. Advance, C-MAC PM, and channeled blade KingVision) with different blade types. The primary outcome variable was overall intubation success and secondary outcomes included first-attempt intubation success, glottis visualization, and difficulty with handling the devices. P values for pairwise comparisons are corrected by the Bonferroni method for 3 tests (P[BF]). All presented P values are adjusted for center. RESULTS: Glottis visualization was comparable with all 3 devices. Overall intubation success for A.P. Advance, C MAC, and KingVision was 96%, 97%, and 61%, respectively (overall: P < .001, A.P. Advance versus C-MAC: odds ratio [OR], 0.97, 95% confidence interval [CI], 0.13 7.42, P[BF] > 0.99; A.P. Advance versus KingVision: OR, 0.043, 95% CI, 0.0088 0.21, P[BF] < 0.001; C-MAC versus KingVision: OR, 0.043, 95% CI, 0.0088-0.21, P[BF] < 0.001). Intubation success on the first attempt with A.P. Advance, C-MAC, and KingVision was 86%, 85%, and 48%, respectively (overall: P < .001, A.P. Advance versus C-MAC: OR, 0.89, 95% CI, 0.31-2.53, P[BF] > 0.99; A.P. Advance versus KingVision: OR, 0.24, 95% CI, 0.055-0.38, P[BF] = 0.0054; C-MAC versus KingVision: OR, 0.21, 95% CI, 0.043-.34, P[BF] < 0.003). Direct laryngoscopy for successful intubation with the videolaryngoscopic device was necessary with the A.P. Advance in 5 patients, and with the C-MAC in 4 patients. In the KingVision group, 21 patients were intubated with an alternative device. CONCLUSIONS: During prehospital emergency endotracheal intubation performed by emergency physicians, success rates of 3 commercially available videolaryngoscopes A.P. Advance, C-MAC PM, and KingVision varied markedly. We also found that although any of the videolaryngoscopes provided an adequate view, actual intubation was more difficult with the channeled blade KingVision. PMID- 29239966 TI - Passive Ventilation in Chest Compression-Only CPR by Untrained Bystanders: A Reply. PMID- 29239967 TI - Faith and Choice and International Meetings. PMID- 29239969 TI - Minimal Invasive Rhinoplasty: Fat Injection for Nasal Dorsum Contouring. PMID- 29239970 TI - Patient-Reported Outcomes Needed for Chest Masculinization. PMID- 29239971 TI - Optimizing Radiotherapy for Keloids: A Meta-Analysis Systematic Review Comparing Recurrence Rates Between Different Radiation Modalities. PMID- 29239972 TI - Modified Suzuki Technique With Cable-Ties for Unstable Fracture-Dislocations of the Proximal Interphalangeal Joint. PMID- 29239973 TI - Involvement of adenosine triphosphate-sensitive potassium channels in the neuroprotective activity of hydrogen sulfide in the 6-hydroxydopamine-induced animal model of Parkinson's disease. AB - Studies have shown that hydrogen sulfide (H2S) exerts a neuroprotective effect and may have a therapeutic value for treating neurodegenerative diseases including Parkinson's disease. However, little is known about the mechanisms underlying the neuroprotective activity of H2S in vivo. Here, we evaluated the effect of glibenclamide, an ATP-sensitive potassium channel blocker, on the neuroprotective activity of H2S in the 6-hydroxydopamine (6-OHDA) animal model of Parkinson's disease. 6-OHDA was administered by stereotaxic surgery into the medial forebrain bundle. Sodium hydrosulfate (NaHS, 3 and 5.6 mg/kg), as a donor of H2S, alone or in combination with glibenclamide (5 mg/kg), was daily injected for 7 days starting 1-2 h before the stereotaxic surgery. After an apomorphine induced rotational test, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta was determined by immunofluorescence. The striatal dopamine level and oxidative stress markers were also measured in brain homogenates. Pretreatment with NaHS significantly attenuated 6-OHDA-induced motor asymmetry in the rotational test. Histological and biochemical evaluations demonstrated that NaHS, especially at high dose, increased the survival of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta and reduced the decreasing effect of 6-OHDA on striatal dopamine levels. However, co administration of glibenclamide reversed the antiparkinsonian and neuroprotective effects of NaHS. However, glibenclamide did not change the reducing effect of NaHS on 6-OHDA-induced overproduction of malondialdehyde. Our data show that ATP sensitive potassium channels are involved in the antiparkinsonian and neuroprotective effects of H2S in the 6-OHDA animal model of Parkinson's disease. PMID- 29239974 TI - Additive and subadditive antiallodynic interactions between MU-opioid agonists and N-methyl D-aspartate antagonists in male rhesus monkeys. AB - MU-Opioid agonists are clinically effective analgesics, but also produce undesirable effects such as sedation and abuse potential that limit their clinical utility. Glutamatergic systems also modulate nociception and N-methyl D aspartate (NMDA) receptor antagonists have been proposed as one useful adjunct to enhance the therapeutic effects and/or attenuate the undesirable effects of MU opioid agonists. Whether NMDA antagonists enhance the antiallodynic effects of MU agonists in preclinical models of thermal hypersensitivity (i.e. capsaicin induced thermal allodynia) are unknown. The present study determined the behavioral effects of racemic ketamine, (+)-MK-801, (-)-nalbuphine, and (-) oxycodone alone and in fixed proportion mixtures in assays of capsaicin-induced thermal allodynia and schedule-controlled responding in rhesus monkeys. Ketamine, nalbuphine, and oxycodone produced dose-dependent antiallodynia. MK-801 was inactive up to doses that produced undesirable effects. Ketamine, but not MK-801, enhanced the potency of MU-agonists to decrease rates of operant responding. Ketamine and nalbuphine interactions were additive in both procedures. Ketamine and oxycodone interactions were additive or subadditive depending on the mixture. Furthermore, oxycodone and MK-801 interactions were subadditive on antiallodynia and additive on rate suppression. These results do not support the broad clinical utility of NMDA receptor antagonists as adjuncts to MU-opioid agonists for thermal allodynic pain states. PMID- 29239975 TI - Caring from a Christian Worldview: Exploring Nurses' Source of Caring, Faith Practices, and View of Nursing. AB - This study explored Christian nurses' views of their source of caring (Deity or other), adherence to biblical faith practices, and view of nursing as a job, career, profession, or calling. Participants who reported Deity (God, Christ, Holy Spirit) as their source of caring were more likely to view nursing as a calling and report a higher degree of volunteering (serving), giving (financially to a religious community), devotions and prayer (personal walk), and fellowship (meeting with a community of other believers). Results have implications for understanding the concept of caring within the context of a Christian worldview. PMID- 29239976 TI - Abnormalities of P300 before and after antidepressant treatment in depression: an ERP-sLORETA study. AB - Despite a wide range of reports on depression-induced P300 changes, it is still debatable whether P300 can return to a pattern characteristic of healthy individuals following antidepressant treatment. Thus, the present study aims to compare P300 and its underlying neural activation in depressed patients before and after antidepressant treatment to explore the brain regions related to pathogenesis and to evaluate the prognosis after treatment. P300 was evoked by the oddball auditory paradigm and collected from 14 sex-matched, age-matched, and education level-matched patients and controls. P300 was also collected in the same patients after treatment. sLORETA was used to explore the source activation of P300 components. Depressed patients before and after antidepressant treatment tended to show lower P300 amplitudes compared with healthy controls, and their P300 amplitudes of F3 electrodes were correlated negatively to their scores on the 24-item Hamilton Depression Rating Scale, the Snaith-Hamilton Pleasure Scale, and the nine-item Patient Health Questionnaire. P300 amplitudes of P4 electrodes were correlated negatively with their scores on the Dysfunctional Attitude Scale. P300 source activation of depressed patients before antidepressant treatment was reduced in the left superior parietal lobule and the precuneus compared with healthy controls and depressed patients after treatment. No difference was found between healthy controls and depressed patients after treatment. The left superior parietal lobule and the precuneus might be therapeutic targets of depression. PMID- 29239977 TI - Increased resting-state brain entropy in Alzheimer's disease. AB - Entropy analysis of resting-state functional MRI (R-fMRI) is a novel approach to characterize brain temporal dynamics and facilitates the identification of abnormal brain activity caused by several disease conditions. However, Alzheimer's disease (AD)-related brain entropy mapping based on R-fMRI has not been assessed. Here, we measured the sample entropy and voxel-wise connectivity of the network degree centrality (DC) of the intrinsic brain activity acquired by R-fMRI in 26 patients with AD and 26 healthy controls. Compared with the controls, AD patients showed increased entropy in the middle temporal gyrus and the precentral gyrus and also showed decreased DC in the precuneus. Moreover, the magnitude of the negative correlation between local brain activity (entropy) and network connectivity (DC) was increased in AD patients in comparison with healthy controls. These findings provide new evidence on AD-related brain entropy alterations. PMID- 29239978 TI - PICU Length of Stay: Factors Associated With Bed Utilization and Development of a Benchmarking Model. AB - OBJECTIVES: ICU length of stay is an important measure of resource use and economic performance. Our primary aims were to characterize the utilization of PICU beds and to develop a new model for PICU length of stay. DESIGN: Prospective cohort. The main outcomes were factors associated with PICU length of stay and the performance of a regression model for length of stay. SETTING: Eight PICUs. PATIENTS: Randomly selected patients (newborn to 18 yr) from eight PICUs were enrolled from December 4, 2011, to April 7, 2013. Data consisted of descriptive, diagnostic, physiologic, and therapeutic information. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The mean length of stay for was 5.0 days (SD, 11.1), with a median of 2.0 days. The 50.6% of patients with length of stay less than 2 days consumed only 11.1% of the days of care, whereas the 19.6% of patients with length of stay 4.9-19 days and the 4.6% with length of stay greater than or equal to 19 days consumed 35.7% and 37.6% of the days of care, respectively. Longer length of stay was observed in younger children, those with cardiorespiratory disease, postintervention cardiac patients, and those who were sicker assessed by Pediatric Risk of Mortality scores receiving more intensive therapies. Patients in the cardiac ICU stayed longer than those in the medical ICU. The length of stay model using descriptive, diagnostic, severity, and therapeutic factors performed well (patient-level R-squared of 0.42 and institution-level R-squared of 0.76). Standardized (observed divided by expected) length of stay ratios at the individual sites ranged from 0.87 to 1.09. CONCLUSIONS: PICU bed utilization was dominated by a minority of patients. The 5% of patients staying the longest used almost 40% of the bed days. The multivariate length of stay model used descriptive, diagnostic, therapeutic, and severity factors and has potential applicability for internal and external benchmarking. PMID- 29239979 TI - Monitoring Haloperidol Plasma Concentration and Associated Adverse Events in Critically Ill Children With Delirium: First Results of a Clinical Protocol Aimed to Monitor Efficacy and Safety. AB - OBJECTIVES: As delirium in critically ill children is increasingly recognized, more children are treated with the antipsychotic drug haloperidol, while current dosing guidelines are lacking solid evidence and appear to be associated with a high risk of adverse events. We aim to report on the safety and efficacy of a recently implemented clinical dose-titration protocol with active monitoring of adverse events. DESIGN: From July 2014 until June 2015, when a potential delirium was identified by regular delirium scores and confirmed by a child psychiatrist, haloperidol was prescribed according to the Dutch Pediatric Formulary. Daily, adverse events were systematically assessed, haloperidol plasma concentrations were measured, and delirium symptoms followed. Dependent on the clinical response, plasma concentration, and adverse event, the dose was adjusted. SETTING: A 28-bed tertiary PICU in the Netherlands. PATIENTS: All patients admitted to the PICU diagnosed with delirium. INTERVENTION: Treatment with haloperidol according to a dose-titration protocol MEASUREMENTS AND MAIN RESULTS:: Thirteen children (median age [range] 8.3 yr [0.4-13.8 yr]) received haloperidol, predominantly IV (median dose [range] 0.027 mg/kg/d [0.005-0.085 mg/kg/d]). In all patients, pediatric delirium resolved, but five of 13 patients developed possible adverse event. These were reversed after biperiden (n = 2), discontinuing (n = 3), and/or lowering the dose (n = 3). Plasma concentrations were all below the presumed therapeutic threshold of 3-12 ug/L. CONCLUSIONS: Prospective systematic monitoring of adverse event in critically ill children receiving haloperidol revealed a significant proportion of possible adverse events. Adverse event developed despite low plasma concentrations and recommended dose administration in the majority of the patients. Our data suggest that haloperidol can potentially improve pediatric delirium, but it might also put patients at risk for developing adverse events. PMID- 29239982 TI - Postexercise Hypotension and Heart Rate Variability Responses Subsequent to Traditional, Paired Set, and Superset Training Methods. AB - The purpose of this study was to compare training volume, post-exercise hypotension (PEH) and heart rate variability (HRV) responses to different strength training methods. Thirteen trained men volunteered for this study. Three training methods were completed in a randomized design, which included: Traditional Set (TS) - three successive sets for the lying bench press (LBP), lat pulldown (LPD), incline 45 degrees bench press (BP45), seated close-grip row (SCR), triceps extension (TE), and biceps curl (BC), with a 90 sec. rest interval between sets and exercises; Paired Set (PS) - three paired sets for the LBP-LPD, BP45-SCR, and TE-BC, with a 90 sec. rest interval between sets and exercises; and Super-Set (SS) - three super-sets for the LBP-LPD, BP45-SCR, and TE-BC. During the SS session, no rest was permitted between paired sets, followed by 180 sec. rest after each super-set. Ten repetition maximum (RM) loads were adopted for all exercises. Blood pressure and HRV were measured at baseline, immediately post session, and at 10 min. intervals until 60 min. post session. Significantly greater training volume was noted under the SS method (8608.6 +/- 2062.2 kg) versus the TS method (7527.5 +/- 2365.1kg), respectively. Significantly greater training volume was also observed under the PS method (8262.3 +/- 2491.2kg) versus the TS method (p <= 0.05). No main effects for HRV and PEH were noted between protocols (p > 0.05). However, similar PEH responses intra-protocol were observed for the TS, PS and SS methods (p <= 0.05). Considering the duration of the PEH intra-protocol, large effect sizes were noted for the SS and PS methods versus the TS method in diastolic and mean blood pressure. Therefore, both the PS and SS methods may be an alternative to the TS method to achieve greater total work and training volume with a tendency towards a longer PEH response. PMID- 29239981 TI - Effect of Practice on Performance and Pacing Strategies During an Exercise Circuit Involving Load Carriage. AB - Burdon, CA, Park, J, Tagami, K, Groeller, H, and Sampson, JA. Effect of practice on performance and pacing strategies during an exercise circuit involving load carriage. J Strength Cond Res 32(3): 700-707, 2018-Pacing is critical for athletic endeavors, and the strategies used by athletes are often modified after practice. The importance of practice when completing occupational assessments has been established; however, the effect of load carriage and discrete subtask activities on strategies to modulate physical exertion to complete a work task simulation is currently unknown. Therefore, we sought to investigate the effect of practice on pacing strategies used to complete a physiological aptitude assessment circuit. Twenty-five participants completed an assessment designed for firefighters on 3 occasions. The circuit comprised 6 disparate tasks (including unilateral load carriage, static holds and fire-hose drags) with lap and task completion times recorded. Pacing strategies were examined relative to the effect of practice throughout (globally) and within the assessment (discrete tasks). By the second visit, overall test performance and discrete task performance of the first, fourth, and fifth tasks improved, respectively, by 12.6% (95% confidence interval: +/-3.6%, p < 0.01), 12.4% (+/-6.0%, p < 0.01), 11.7% (+/-4.9%, p < 0.01), and 17.8% (+/-10.0%, p < 0.03). Compared with visit 1, significant improvements in performance were observed on the second and third visit. However, no significant additional improvement was noted between visits 2 and 3. Therefore, to reliably assess performance of the occupational test, 1 practice session (2 visits) is required. Practice is important to allow individuals to optimize their pacing strategy for successful performance. PMID- 29239980 TI - Derivation and Internal Validation of a Mortality Prediction Tool for Initial Survivors of Pediatric In-Hospital Cardiac Arrest. AB - OBJECTIVES: To develop a clinical prediction score for predicting mortality in children following return of spontaneous circulation after in-hospital cardiac arrest. DESIGN: Observational study using prospectively collected data. SETTING: This was an analysis using data from the Get With The Guidelines-Resuscitation registry between January 2000 and December 2015. PATIENTS: Pediatric patients (< 18 yr old) who achieved return of spontaneous circulation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality. Patients were divided into a derivation (3/4) and validation (1/4) cohort. A prediction score was developed using a multivariable logistic regression model with backward selection. Patient and event characteristics for the derivation cohort (n = 3,893) and validation cohort (n = 1,297) were similar. Seventeen variables associated with the outcome remained in the final reduced model after backward elimination. Predictors of in-hospital mortality included age, illness category, pre-event characteristics, arrest location, day of the week, nonshockable pulseless rhythm, duration of chest compressions, and interventions in place at time of arrest. The C-statistic for the final score was 0.77 (95% CI, 0.75-0.78) in the derivation cohort and 0.77 (95% CI, 0.74-0.79) in the validation cohort. The expected versus observed mortality plot indicated good calibration in both the derivation and validation cohorts. The score showed a stepwise increase in mortality with an observed mortality of less than 15% for scores 0-9 and greater than 80% for scores greater than or equal to 25. The model also performed well for neurologic outcome and in sensitivity analyses for events within the past 5 years and for patients with or without a pulse at the onset of chest compressions. CONCLUSIONS: We developed and internally validated a prediction score for initial survivors of pediatric in-hospital cardiac arrest. This prediction score may be useful for prognostication following cardiac arrest, stratifying patients for research, and guiding quality improvement initiatives. PMID- 29239983 TI - Effects of 2% Dehydration on Lactate Concentration During Constant-Load Cycling. AB - Green, JM, Miller, B, Simpson, J, Dubroc, D, Keyes, A, Neal, K, Gann, J, and Andre, T. Effects of 2% dehydration on lactate concentration during constant-load cycling. J Strength Cond Res 32(7): 2066-2071, 2018-The lactate [La] threshold (LT) can predict endurance performance potential. Dehydration may alter LT. This study examined effects of dehydration on [La] response during constant-load cycling. Recreationally fit (V[Combining Dot Above]O2peak = 48.7 +/- 5.2 ml.kg.min) male participants (n = 9) completed 2 * 40-minute constant-load cycling trials; euhydrated (HYD) and after previous evening passive (water bath) dehydration (2% body weight, DEH) (HYD and DEH counterbalanced). Lactate, heart rate (HR), 10-point Omni ratings of perceived exertion (RPE), and rectal temperature (Trec) were measured after warm-up (WU) and at 10, 20, 30, and 40 minutes. Before cycling, urine specific gravity (USG) was measured and participants estimated perceived recovery status (PRS). Urine specific gravity DEH (1.027 +/- 0.004) was significantly greater than HYD (1.013 +/- 0.007). After WU, [La] was significantly greater (all time points) for DEH (~4.1 mmol.L) vs. HYD (~3.5 mmol.L) with similar results for HR (DEH: ~167, HYD: ~158 b.min). For DEH, RPE was significantly greater (~1 unit) at 20, 30, and 40 minutes, and Trec was significantly greater at 30 and 40 minutes (~0.4 degrees C). DEH (vs. HYD) also resulted in significantly different resting HR (93 +/- 6, vs. 85 +/- 7 b.min), significantly greater session RPE (7.7 +/- 1.1 vs. 5.3 +/- 1.1), and significantly lower subjective feelings of recovery (PRS = 6.4 +/- 2.9, vs. 9.0 +/- 1.5). Current results indicate systematic changes in [La] and associated physiological responses result from previous day dehydration. Hydration status should be a concern in paradigms where [La] assessment is used. PMID- 29239984 TI - Profiling Inflammatory Markers During the Competitive Season and Post Season in Collegiate Wrestlers. AB - : The purpose of this study was to determine if biological markers of muscle damage and inflammation coincide with subjective measures of muscle fatigue and sleep quality among Division I collegiate wrestlers. The goal was to provide practitioners with noninvasive techniques to evaluate a wrestlers inflammatory state. METHODS: Subjects from the Central Michigan University Division I collegiate wrestling team (n=6) were analyzed on six separate occasions throughout the course of the competitive season and post season. Biological measurements (creatine kinase, Il-6, TNF-alpha, Il-1beta, Il-10) and subjective measurements (fatigue, muscle soreness, sleep quality) were performed. RESULTS: The self-reported level of muscle soreness and fatigue was significantly higher from pre-season through mid-season, but leveled off late into the season. Creatine kinase followed a similar pattern early into the season compared to pre season, and decreased at the end of season. Plasma TNF-alpha and IL-8 levels increased modestly late into season compared to pre-season. Sleep quality correlated with plasma levels of IL-8 (r2=0.120, p<0.05). CONCLUSIONS: Subjects experienced muscle soreness and fatigue early in the competitive season, along with an increase in markers of muscle damage. This may indicate an adaptive response to the training load. Low grade systemic inflammation increased late into the season, and correlated with poor sleep quality. Based on these data, wrestlers may benefit by additional recovery time early into the season to prevent muscle fatigue and damage. As the season progresses, low-grade inflammation may be prevented or monitored by tracking the quality of sleep. PMID- 29239985 TI - Training Load, Physical Performance, Biochemical Markers, and Psychological Stress During A Short Preparatory Period in Brazilian Elite Male Volleyball Players. AB - The aim of this study was to assess the relationship between training load (TL) and physical performance, biochemical markers, and psychological stress during a short preparatory period (PP) in Brazilian elite male volleyball players. Twelve volleyball players from a team competing in the Brazilian Men's Volleyball Super League were enrolled (26.9 +/- 4.6 years). Countermovement Jump (CMJ), Creatine Kinase (CK), Testosterone (T), Cortisol (Cr), T/Cr ratio, and Recovery and Stress Questionnaire for Athletes (RESTQ-Sport) were collected at baseline, after 2, 4, and 6 week. TL was quantified daily using the Rating of Perceived Exertion (RPE). Differences were noted between Total Weekly TL (TWTL) (F3,33 = 50.907; p = 0.0001), CK (F3,33 = 16.157; p = 0.0001), and T (F3,33 = 3.283; p = 0.03). No differences were seen in CMJ (F3,33 = 1.821; p = 0.16), Cr (F3,33 = 2.409; p = 0.08), or T/Cr ratio (F3,33 = 1.527; p = 0.23). The RESTQ-Sport demonstrated differences between moments in Social Stress (F3,33 = 2.297; p = 0.04; Eta = 0.25), Success (F3,33 = 4.350; p = 0.01; Eta = 0.19), General Well-being (F3,33 = 4.465; p = 0.01; Eta = 0.36), and Injury (F3,33 = 2.792; p = 0.05; Eta = 0.62). The results showed a significant correlations of small to moderate magnitude between TWTL and CK (r = 0.32; p = 0.05). In conclusion, a short PP in volleyball leads to increased TL, CK level, and psychological stress. TL was related with the increase of CK, suggesting muscle damage without increased of physical performance. PMID- 29239986 TI - Practical Model of Low-Volume Paddling-Based Sprint Interval Training Improves Aerobic and Anaerobic Performances in Professional Female Canoe Polo Athletes. AB - Sheykhlouvand, M, Khalili, E, Gharaat, M, Arazi, H, Khalafi, M, and Tarverdizadeh, B. Practical model of low-volume paddling-based sprint interval training improves aerobic and anaerobic performances in professional female canoe polo athletes. J Strength Cond Res 32(8): 2375-2382, 2018-Brief, intense exercise training using running and cycling as exercise interventions may induce aerobic and anaerobic adaptations in athletes from a wide range of sports. However, this has not been studied extensively for those sports in which the upper body is predominantly involved. Our purpose was to examine the effects of kayak paddling based sprint interval training (SIT) on cardiorespiratory fitness and anaerobic performance. Sixteen professional female canoe polo athletes (age = 27.6 +/- 1.9 years; height = 165.7 +/- 5.2 cm; body mass = 62.6 +/- 8.5 kg; body mass index = 22.8 kg.m; body fat = 23.8 +/- 4.9%) were randomized to either an intense exercise training consisting of sets of 5 * 5-second maximum sprint efforts interspersed by a 10-second recovery between each sprint (3, 4, 5, and 6 sets/session from first to fourth week, respectively, with 3 minutes of rest between each set), performed 3 times per week for 4 weeks (n = 8), or a usual training control group (n = 8). Before and after the training period, aerobic and anaerobic measurements were assessed using a kayak specific test and Wingate protocol, respectively. Training increased V[Combining Dot Above]O2peak, O2 pulse, anaerobic threshold, peak, and mean power output in the SIT group compared with the control group (p <= 0.05) who showed no changes in these variables when tested 4 weeks apart without SIT. Paddling-based SIT was a potent stimulus and time-efficient strategy to induce rapid adaptations in aerobic and anaerobic performances in professional female canoe polo athletes who can use this training method to achieve fitness in a short period. PMID- 29239987 TI - Body Composition of Women's Ice Hockey Players: Comparison of Estimates Using Skinfolds and Idxa. AB - The purpose of this study was to compare percent fat (% Fat) estimates from anthropometric equations using skinfolds (SKF) in women's ice hockey players to estimates obtained from Lunar iDXA. Data were collected on 19 elite female Swedish hockey players (mean age +/- SD = 18.4 +/- 2.4 y). Four skinfolds (SKF) (triceps, abdominal, suprailiac, and thigh) were measured within two hours of iDXA assessments. The % Fat estimates from iDXA and four anthropometric equations were compared using paired t-tests, and a one-way ANOVA was used to compare % Fat estimates from the anthropometric equations. Bland Altman analyses were used to assess agreement between % Fat estimates from SKF and iDXA. The significance level was set a priori at p<0.05. The % Fat estimates from anthropometric equations were significantly lower than those from iDXA (mean +/- SD: 26.85 +/- 4.93%, p=0.000). Bland Altman analyses indicated mean differences of -7.96 to 10.13 percentage points between anthropometric equations and iDXA. Estimates of % Fat from anthropometric equations (range: 16.72% to 18.89%) were within the range reported in earlier studies using the Sum of 7 SKF. Thus, SKF offer a reasonable alternative to iDXA for this population, but result in underestimates of % Fat relative to iDXA. Strength and conditioning coaches should use the same body composition assessment method consistently, and interpret the results with caution, as they are estimates and not true values. PMID- 29239988 TI - Effect of Boards in Small-Sided Street Soccer Games on Movement Pattern and Physiological Response in Recreationally Active Young Men. AB - The present study investigated whether street soccer might be proposed as an alternative to recreational small-sided games on grass as a health-enhancing activity, and specifically the effects of the boards surrounding the pitch. Eleven recreationally active young males (28.4+/-4.2 (+/-SD) yrs, 19.9+/-4.2% body fat, 47.7+/-6.0 mlminkg), after familiarization, completed one to two sessions of 20x13-m 3v3 street soccer games with boards (WB) and one to two sessions without boards (WOB) in a randomized order. Movement pattern was measured using GPS and heart rate recordings, blood sampling and RPE scales were used to evaluate exercise intensity and physiological strain. Total number of accelerations (19%) and Player Load (18%) were higher (p < 0.05) in WB than in WOB, whereas total distance covered (12%), high-speed running (59%) and peak speed (11%) were lower (p < 0.05) in WB than in WOB. Moreover, HRmean was higher in WB than in WOB (85.7+/-5.4 vs. 81.3+/-8.2%HRmax, p = 0.012, ES = 0.64), whereas time with HR>90%HRmax did not differ between WB and WOB (42+/-34 vs. 32+/ 30%, p = 0.243, ES = 0.32). Plasma ammonia increased more in WB than in WOB, with no differences found in mean and peak blood lactate. RPE was higher after WB than after WOB (7.1+/-1.0 vs. 5.5+/-1.2, p < 0.001, ES = 1.39). In conclusion, intensity was sufficiently high in both game formats to expect short- and long term health improvements as a result of regular participation. Boards affected movement pattern and physiological demands, producing higher number of accelerations, Player Load, average heart rate, plasma ammonia, and rating of perceived exertion, but lower total distance, number of intense runs and peak speed. PMID- 29239989 TI - A Systematic Review of the Association Between Physical Fitness and Musculoskeletal Injury Risk: Part 3 - Flexibility, Power, Speed, Balance, and Agility. AB - We performed a systematic review and evaluation of the existing scientific literature on the association between flexibility, power, speed, balance, and agility, and musculoskeletal injury (MSK-I) risk in military and civilian populations. MEDLINE, EBSCO, EMBASE, and the Defense Technical Information Center were searched for original studies published from 1970 through 2015 that examined associations between these physical fitness measures (flexibility, power, speed, balance, and agility) and MSK-I. Methodological quality and strength of the evidence were determined following criteria adapted from previously published systematic reviews. Twenty-seven of 4,229 citations met our inclusion criteria. Primary findings indicate there is (a) moderate evidence that hamstring flexibility, as measured by performance on a sit-and-reach test or active straight-leg raise test assessed with goniometry, and ankle flexibility, assessed with goniometry, are associated with MSK-I risk; (b) moderate evidence that lower body power, as measured by performance on a standing broad jump or vertical jump with no countermovement, is associated with MSK-I risk; (c) moderate evidence that slow sprint speed is associated with MSK-I risk; (d) moderate evidence that poor performance on a single-leg balance test is associated with increased risk for ankle sprain; and (e) insufficient evidence that agility is associated with MSK-I risk. Several measures of flexibility, power, speed, and balance are risk factors for training-related MSK-I in military and civilian athletic populations. Importantly, these findings can be useful for military, first responder, and athletic communities who are seeking evidence-based metrics for assessing or stratifying populations for risk of MSK-I. PMID- 29239990 TI - Changes in Player Activity Profiles Following the 2015 Fih Rule Changes in Elite Women's Hockey. AB - The aim of this study was to compare the player activity profiles of elite international women hockey players pre (2014) and post (2015) the 2015 FIH match rule changes at team and positional levels. The match activity profiles (n=400) of 19 female hockey players (Age 23+/-4 years, mass 63.6+/-5.5 kg, VO2max 57+/-6 ml.kg.min in 2014, 58+/-6 ml.kg.min in 2015) were recorded during competitive international matches in 2014 (match n=12) and 2015 (match n=13) using 10Hz GPS units. The practical utility of an effect was only classified as substantial when there was a >75% likelihood that the +/-90% CI of the ES was equal to or greater than the small (ES +/- 0.2) reference value. Mean match time decreased by over two minutes from 71.72+/-1.38 to 69.40+/-4.72mins. There were increases at the team level in relative substitutions (SUB), relative distance (RD), High Speed Running (HSR - 3.08-5.27m.s) and surges (S), with a fall in Low Speed Running (LSR- 0-3.05m.s) between 2014 and 2015. There were no changes in the between position differences observed from 2014 to 2015. Within-positions, there were relative increases in RD for all positions, HSR and S for midfield, and in SUB and S in forwards. The 2015 FIH rule changes appear to have increased the general intensity of international women's hockey. However the different facets of physical performance did not change uniformly across team positions. Therefore specific modifications to conditioning practises for each position may be warranted to more accurately reflect match demands. PMID- 29239991 TI - A multiple repeated sprint ability test with four changes of direction for badminton players (part 2): predicting skill level with anthropometry, strength, shuttlecock and displacement velocity. AB - The goal of this study was: (i) to assess general and specific lower and upper limb force, shuttlecock velocity, displacement ability and the anthropometric characteristics of badminton players at five skill levels, and (ii) to predict individual players' number of points. We divided 83 participants into groups of novice (n=15), intermediate (n=16), skilled (n=23), highly skilled (n=14) and elite (n=15) players. The number of points scored for each player performing tournaments (excluding novices) during the entire season was used as a continuous and dependent variable after logarithmic transformation for correlational study. Anthropometric measurements of height, mass, percentage of fat and muscle were recorded, along with shuttlecock maximal velocity during smashes. Upper limb power and lower limb force were recorded during jumps and handgrip strength. We also assessed players' ability to move quickly around the court through an on court multiple repetition sprint ability in badminton (MRSAB) test with four changes of direction. All variables were combined in a multiple regression model. The main findings were that the major contributor to skill level is shuttlecock velocity (r=0.86), the time taken to move during the MRSAB test (r=0.85) and the squat jump height (r=0.53). Anthropometric factors contribute only a little to the individual score point (2%). Finally, the multiple regression model reveals that log(number of points)= 4.91 + 0.042 x Shuttle velocity - 0.029 x MRSABTime - 0.001 x Squat Jump height, with r=0.86 and a relative respective contribution of each variable of 86%, 13% and 1%. PMID- 29239992 TI - Comparison of Resistance-Based Walking Cardiorespiratory Test to The Bruce Protocol. AB - Cardiorespiratory fitness is assessed through graded exercise tests that determine the maximum amount of sustained mechanical work that an individual can perform while also providing health and fitness related information. This manuscript describes a novel method to perform graded exercise tests that uses posteriorly directed resistive forces. The purpose of this investigation is to validate a novel resistance based test in comparison to a traditional speed and incline based test in a cohort of non-impaired individuals. Twenty non-impaired individuals, 8 males, 12 females, mean age 28.4+/- 9.6, range 20-54 years old. Participants performed two maximal exercise tests. The speed and incline based test used the Bruce protocol and increased treadmill incline and speed every three minutes. The resistance based test used a robotic device interfaced with the treadmill that provided specified horizontal resistive forces at the center of mass calculated to match each Bruce Protocol stage while individuals walked at 1.1 m/s. Participants obtained ~3% higher maximum VO2 measure using the speed and incline based method (dependent t-test p=0.08). VO2 peaks between tests were strongly correlated (r=0.93, p<0.001). Peak values of secondary physiologic measures (i.e., max heart rate, respiratory exchange ratio) were within 3% between tests. We found a significant linear relationship between mass-specific work rate and measured VO2 stage-by-stage for both tests, but no significant difference between each linear fit (p=0.84). These data suggest horizontal resistive forces while walking on a treadmill, can be used to increase aerobic effort in a way that closely simulates work rates of the Bruce Protocol. PMID- 29239993 TI - Hypoxia During Resistance Exercise Does Not Affect Physical Performance, Perceptual Responses, or Neuromuscular Recovery. AB - Scott, BR, Slattery, KM, Sculley, DV, and Dascombe, BJ. Hypoxia during resistance exercise does not affect physical performance, perceptual responses, or neuromuscular recovery. J Strength Cond Res 32(8): 2174-2182, 2018-This study aimed to determine whether performing resistance exercise in hypoxia affects markers of physical performance, perceptual responses, and neuromuscular function. Fourteen male subjects (age: 24.6 +/- 2.7 years; height: 179.7 +/- 5.9 cm; body mass: 84.6 +/- 11.6 kg) with >2 years resistance training experience performed moderate-load resistance exercise in 2 conditions: normoxia (FIO2 = 0.21) and hypoxia (FIO2 = 0.16). Resistance exercise comprised 3 sets of 10 repetitions of back squats and deadlifts at 60% of 1 repetition maximum (1RM), with 60 seconds inter-set rest. Physical performance was assessed by quantifying velocity and power variables during all repetitions. Perceptual ratings of perceived exertion, physical fatigue, muscle soreness, and overall well-being were obtained during and after exercise. Neuromuscular performance was assessed by vertical jump and isometric mid-thigh pull (IMTP) tasks for up to 48 hours after exercise. Although physical performance declined across sets, there were no differences between conditions. Similarly, perceived exertion and fatigue scores were not different between conditions. Muscle soreness increased from baseline at 24 and 48 hours after exercise in both conditions (p <= 0.001). Jump height and IMTP peak force were decreased from baseline immediately after exercise (p <= 0.026), but returned to preexercise values after 24 hours. These findings suggest that hypoxic resistance exercise does not affect exercise performance or perceived exercise intensity. In addition, neuromuscular recovery and perceptual markers of training stress were not affected by hypoxia, suggesting that hypoxic resistance training may not add substantially to the training dose experienced. PMID- 29239994 TI - Effects of Judo Training on Bones: A Systematic Literature Review. AB - The aim of this study was to provide a systematic literature review on the osteogenic effects of judo (PROSPERO: CRD42016041803). The online search was conducted according to the inclusion criteria: observational studies and clinical/interventional trials in English from inception to June 2016; bone health, mineral density (BMD), diameters, impact force and turnover markers (BTM) outcomes. Thirty-four studies were included and graded for their methodological quality ("fair" quality: 79.4%). The most used assessment method (44.1%) was X ray absorptiometry. A positive association between judo and bone health/status emerged. Findings support site-specific BMD accrual in children, adolescents, adult athletes, and in pre- and post-menopausal women practitioners. BTM revealed a hypermetabolic status in high-level judo athletes. The osteogenic stimuli of judo seem to protect athletes from alterations in bone metabolic balance due to weight loss cycling. Sexual dimorphism was found between judoka in bone diameters and mass, and significant differences in bone breadths emerged between elite and non-elite judoka. The fall techniques reduced bone impact force and velocity respect 'natural' fall. Further longitudinal, cross-sectional and interventional researches are required. This paper provides useful information on bone for health sport scientists, coaches, and practitioners, stimulating future research lines on judo. In particular, coaches and physical trainers should consider to introduce judo fall techniques in their training plans to prevent fall-related injuries, especially relevant in the older population. Conversely, coaches are urged to carefully control weight cycling dietary habits of their athletes, which can produce serious metabolic responses on bones. PMID- 29239995 TI - Development of Anaerobic Fitness in Top-Level Competitive Youth Ice Hockey Players. AB - Leiter, JR, Cordingley, DM, and MacDonald, PB. Development of anaerobic fitness in top-level competitive youth ice hockey players. J Strength Cond Res 32(9): 2612-2615, 2018-Ice hockey is a physiologically complex sport involving both the anaerobic and aerobic energy systems. The purpose of this study was to evaluate the anaerobic power output (PO) of top-level competitive youth hockey players. It was hypothesized that with each successive increase in age, there would be an associated change in anaerobic PO. Two hundred and fifty-one male hockey players between the ages of 13-17 years participated in this study. All athletes completed a 30-second Wingate test as part of a preseason physiological and fitness combine. A 1-way analysis of variance was performed to compare peak PO (POpeak), average PO (POavg), and fatigue index between all age groups. A Tukey's post hoc test was used to determine changes in immediately successive age groups for all variables. Age categories were grouped as 13 years old (yrs) (n = 72), 14 yrs (n = 68), 15 yrs (57) and 16 yrs (n = 54, including 11 athletes 17 yrs). Absolute POpeak significantly increased with all age increases. Relative POpeak, absolute POavg, and relative POavg increased between the ages of 13 and 14 years, and 14 and 15 years, but not between the ages 15 and 16 years. There were no changes in fatigue index between any successive age groups. Anaerobic PO increases with an increase in age with no associated change in fatigue index. Athletes, coaches, and parents can use this normative data to help prepare the player for upcoming seasons in which there may be an increase in level or age class. PMID- 29239996 TI - Upper-Body Strength Measures and Pop-Up Performance of Stronger and Weaker Surfers. AB - The primary purpose of this study was to investigate the reliability of the isometric push-up (IPU), dynamic push-up (DPU), and force plate pop-up (FP POP) as measures of upper-body isometric and dynamic strength qualities in surfing athletes. Furthermore, the study aimed to compare pop-up performance between stronger and weaker surfers. Eighteen female (n=9) and male (n=9) surfers (age=28.1+/-6.4 yrs, mass=69.6+/-10.4 kg, height=172.5+/-6.7 cm) completed a battery of upper-body strength assessments, of which exhibited high between-day reliability: (IPU, (CV%=4.7, ICC=0.96), DPU (CV%=5.0, ICC=0.90), FP POP (CV%=4.4, ICC=0.90). Participants were subsequently split into stronger (n=9) and weaker (n=9) surfers based on normalized peak force (PF) attained in the IPU. Pop-up performance was measured both in the water and during the FP POP, and was referred to as time to pop (TTP). Significant between group differences were observed for normalized PF during IPU (d=1.59, p<0.01) and DPU (d=0.94 p=0.04). Although not significant, there was a large magnitude difference in FP POP (d=0.80, p=0.08) and FP TTP (d=0.85, p=0.07). Significant correlations were identified between normalized IPU PF and normalized DPU FP (r=0.69, p=0.03) and FP TTP (r=0.73, p=0.02) in the stronger group. The weaker group exhibited a significant inverse correlation between normalized IPU PF and in water TTP (r= 0.77, p<0.01). The results suggest improvements in pop-up performance may be elicited by improving dynamic strength for stronger surfers, whereas pop-up performance in weaker surfers may be elicited by improving maximum strength. The upper-body strength assessments provided a novel insight into strength qualities that are associated with in water performance of surfers (TTP). PMID- 29239997 TI - Predisposing Risk Factors and Stress Fractures in Division I Cross Country Runners. AB - The purpose of this study was to explore factors associated with increased stress fractures in collegiate cross country runners. Participants in this study were 42 male and female cross country runners at a Division I university. Each athlete completed a questionnaire regarding smoking status, vitamin/mineral intake, previous stress fracture history, birth control usage, menstrual status, and demographic information. Nutritional assessment via a 3-day food record and measurements of whole body, lumbar spine, and hip bone mineral densities (BMD) were also conducted on each athlete. Results indicated that 40% of the female and 35% of the male runners reported a history of stress fracture, and that all of these did not meet the recommended daily energy intake or adequate intakes for calcium or Vitamin D required for their amount of training. Two-tailed t-test found statistically higher incidences of lumbar spine BMD in males and females whose daily calcium and Vitamin D intakes were below minimum requirements as well as for women whose caloric intake was below the required level. When data on the lumbar spine was evaluated, 31% of participants (31.8% of the male and 30% of the female runners) were identified as having osteopenia and 4.8% with osteoporosis. Results warrant a need for future longitudinal studies. PMID- 29239998 TI - Seasonal Changes in Functional Fitness and Neurocognitive Assessments in Youth Ice Hockey Players. AB - Deficits in balance and strength combined with differing rates of sensory and motor neural development may increase risk of sports related injury in youth. This study evaluated changes in functional fitness and concussion status over the course of a competitive season in youth ice-hockey players, and examined the relationship between these variables and injury occurrence. Thirty-six participants (8.9 +/- 1.1 years) completed pre and post-season assessments including anthropometric measurements, the Functional Movement Screen (FMS), Lower Quarter Y-Balance Test (YBT-LQ), and a computerized neurocognitive assessment (ImPACT). Paired samples t-tests were used to compare pre and post season data. Independent samples t-tests were used to compare FMS, YBT-LQ, and ImPACT scores between injured and uninjured participants at baseline. The mean composite score of the FMS was not statistically different between pre (15.1 +/- 1.8) and post-season (15.6 +/- 2.3, p<0.16). The YBT-LQ composite score showed a decrease in reach distance scores between pre (86.10 +/- 6.00) and post-season (83.20 +/- 5.40, p<0.001). Neurocognitive assessment scores improved in both the injured and uninjured participants. There were no significant relationships between FMS scores, YBT-LQ, and injury incidence. Results from our study provide insight into changes in functional fitness levels and neurocognitive scores over the course of a season in youth ice-hockey players. These findings provide insight into expected changes over the course of a season, and provide context for injury risk monitoring by coaches. PMID- 29239999 TI - Care Management to Reduce Disparities and Control Hypertension in Primary Care: A Cost-effectiveness Analysis. AB - BACKGROUND: Project ReD CHiP (reducing disparities and controlling hypertension in primary care) care management was a clinic-based intervention that aimed to improve blood pressure control through improved care coordination and provide self-management support to patients from racially and socioeconomically. OBJECTIVE: To evaluate the cost-effectiveness of ReD CHiP care management versus standard care to treat hypertension in diverse communities. RESEARCH DESIGN: Microsimulation model from a health care sector perspective over 15 years. We used the published literature to inform our model including the ReD CHiP trial and the age-specific and race-specific cardiovascular disease risk equations. Deterministic and probabilistic sensitivity analyses were conducted to assess the uncertainty. SUBJECTS: Primary prevention in a racially diverse setting. MEASURES: Costs per quality-adjusted life years (QALYs) to produce an incremental cost-effectiveness ratio (ICER). RESULTS: ReD CHiP had an increase of $2114 and 0.04 QALYs. The ICER was $52,850/QALY. Predominately African American (ICER: $48,250/QALY) and elderly populations (ie, age 65+) derived value from ReD CHiP (ICER: $39,525/QALY). The value of ReD CHiP varied with changes in the reduction in systolic blood pressure (5 mm Hg reduction, ICER: $133,300/QALY; 15 mm Hg reduction, ICER: $18,767/QALY). Probabilistic sensitivity analysis indicated that ReD CHiP CM was cost-effective in over 90% of simulations, based on a willingness to-pay of $100,000/QALY. CONCLUSIONS: ReD CHiP care management is cost-effective to prevent negative consequences of hypertension. African American and elderly patients have more favorable ICERs, recommending targeted interventions to improve health equity among vulnerable patient populations. PMID- 29240000 TI - Complete Versus Staged Repair for Neonates With Tetralogy of Fallot: Establishment and Validation of a Cohort of 2235 Patients Using Detailed Surgery Sequence Review of Health Care Administrative Data. AB - BACKGROUND: The surgical strategy for neonates with tetralogy of Fallot (TOF) consists of complete or staged repair. Assessing the comparative effectiveness of these approaches is facilitated by a large multicenter cohort. We propose a novel process for cohort assembly using the Pediatric Health Information System (PHIS), an administrative database that contains clinical and billing data for inpatient and emergency department stays from tertiary children's hospitals. METHODS: A 4 step process was used to identify neonates with TOF: (1) screen neonates in PHIS with International Classification of Diseases-9 (ICD-9) diagnosis or procedure codes for TOF; (2) include patients with TOF procedures before 30 days of age; (3) exclude patients with missing 2-year follow-up data; (4) analyze patients' 2 year surgery sequence patterns, exclude patients inconsistent with a treatment strategy for TOF, and designate patients as complete or staged repair. Manual chart review at 1 PHIS center was performed to validate this process. RESULTS: Between January 2004 and March 2015, 5862 patients were identified in step 1. Step 2 of cohort assembly excluded 3425 patients (58%); step 3 excluded 148 patients (3%); and step 4 excluded 54 patients (1%). The final cohort consisted of 2235 neonates with TOF from 45 hospitals. Manual chart review of 336 patients showed a positive predictive value for accurate PHIS identification of 44% after step 1 and 97% after step 4. CONCLUSIONS: This systematic cohort identification algorithm resulted in a high positive predictive value to appropriately categorize patients. This carefully assembled cohort offers a unique opportunity for future studies in neonatal TOF outcomes. PMID- 29240002 TI - Practices, attitudes, and knowledge about Crohn's disease and smoking cessation among gastroenterologists. AB - OBJECTIVE: Cigarette smoking is one of the most important, modifiable environmental factors in Crohn's disease (CD) and screening for tobacco use is an official recommendation and quality measure in the care of CD patients. The objective of this study was to learn more about gastroenterologists' practices, opinions, and knowledge in this area. PATIENTS AND METHODS: A 15 question survey was sent through email to two national gastroenterology distribution lists. Questions were written in multiple choice formats and were designed to collect information about gastroenterologists' practices, attitudes, and knowledge regarding smoking cessation in CD patients. Responses were stratified by practice setting, experience, and inflammatory bowel disease-focus. Responses were anonymous and were collected in a secure, online database. RESULTS: A total of 141 respondents completed the survey. Overall, 89% of participants screened their CD patients for smoking more than 75% of the time. In all, 62% provided smoking cessation counseling more than 75% of the time. Overall, 94% of respondents felt comfortable discussing the benefits of smoking cessation with their patients. In all, 56% felt comfortable discussing smoking cessation strategies with their patients. Overall, 88% of respondents agreed that gastroenterologists should provide smoking cessation counseling; however, 43 and 11% agreed that the gastroenterologist should be the primary counselor and primary prescriber of cessation-related pharmacotherapy, respectively. CONCLUSION: Surveyed gastroenterologists agree that smoking cessation is an important part of the care of CD patients and this is reflected in their screening practices. Counseling occurs irregularly and many gastroenterologists do not feel comfortable discussing cessation strategies. Future guidelines should provide further guidance on the gastroenterologist's role in smoking cessation counseling for CD patients. PMID- 29240001 TI - Celiac disease is uncommon in irritable bowel syndrome in the USA. AB - BACKGROUND AND AIMS: Routine serologic testing for celiac disease (CD) may be useful in irritable bowel syndrome (IBS) patients, but this is controversial. We aimed to compare the prevalence of unrecognized CD in a large cohort of patients with and without IBS. PARTICIPANTS AND METHODS: This is a family case-control IBS study conducted at a single US academic medical center. Stored serum and DNA were available. Tissue transglutaminase (TTg) immunoglobulin A was performed, followed by indirect immunofluorescence testing for endomysial antibodies with positive or weakly positive TTg results. Individuals were considered to have CD if both results were positive. chi and Fisher's exact tests were used to compare prevalence between the two groups. RESULTS: Serum samples were studied from 533 cases and 531 controls. In all, 80% of participants were female, with a median age of 50 years; 65% of cases and 0% controls met the Rome criteria for IBS. Previous serological testing for CD had occurred in 142 (27%) cases and 13 (2%) controls, but none had CD on subsequent testing. Six (1.1%) cases versus five (0.9%) controls had positive or weakly positive TTg test. Six cases (1.1%) versus three (0.6%) controls were confirmed to have CD by endomysial antibody (P=0.51). CONCLUSION: No difference in the prevalence of CD between patients with IBS and patients without IBS at a tertiary medical center was observed. Our findings do not support routine celiac serologic or genetic testing in patients with IBS in all US populations. PMID- 29240003 TI - The difference in endoscopic yield in patients with either iron-deficiency anemia or anemia with normal ferritin. AB - OBJECTIVE: Current guidelines recommend a gastroduodenoscopy (GDS) and colonoscopy in patients with iron-deficiency anemia (IDA). However, in daily practice, patients with nonferriprive anemia are also referred for endoscopy. The aim of this study is to compare the diagnostic yield of colonoscopy and GDS in patients with IDA and non-IDA. PATIENTS AND METHODS: A retrospective single center cohort study was carried out from January 2013 till February 2016 that included 917 patients with anemia. We compared the endoscopic yield in patients with IDA versus patients with anemia otherwise. Multivariate regression analyses were carried out to identify predictive factors for the diagnostic yield of GDS and colonoscopy. RESULTS: The yield of both GDS (25%) and colonoscopy (30%) was comparable in IDA and non-IDA patients. However, in patients without known gastrointestinal medical history and without concomitant indications for endoscopy (N=373), the diagnostic yield of GDS was three times higher in IDA patients compared with non-IDA patients (P<0.01). The diagnostic yield for colonoscopy was not significantly different between the two groups. Age and sex were recurrent predictive variables in the outcome of both GDS and colonoscopies. CONCLUSION: We recommend IDA as well as non-IDA as indications for GDS and colonoscopy. Only in patients without gastrointestinal history or localizing complaints a significant difference in the diagnostic yield is found between IDA and non-IDA patients. In this group, upper endoscopy can be omitted in non-IDA patients as they were three times less likely to have a bleeding source found on GDS compared with IDA patients. PMID- 29240004 TI - Synchronizing Gait with Cardiac Cycle Phase Alters Heart Rate Response during Running. AB - : Timing foot strike to occur in synchrony with cardiac diastole may reduce left ventricular afterload and promote coronary and skeletal muscle perfusion. PURPOSE: This study aimed to assess heart rate (HR) and metabolic responses to running when foot strikes are timed to occur exclusively during 1) the systolic phase of the cardiac cycle or 2) the diastolic phase. METHODS: Ten elite male distance runners performed a testing session on a treadmill at 4.72 m.s while matching their steps to an auditory tone and wearing a chest strap that transmitted accelerometer and ECG signals. Testing comprised eight prompted 3-min stages, where a real-time adaptive auditory tone guided subjects to step with each ECG R-wave (systolic stepping) or alternatively, at 45% of each R-R interval (diastolic stepping), followed by a 3-min unprompted control stage. Metabolic variables were measured continuously. RESULTS: HR (P < 0.001) and minute ventilation (P < 0.001) were significantly lower during diastolic stepping compared with systolic stepping, whereas O2 pulse (P < 0.001) was correspondingly significantly higher during diastolic stepping. CONCLUSION: Synchronizing foot strikes when running to the diastolic portion of the cardiac cycle results in a significantly reduced HR and minute ventilation compared with stepping during systole. This cardiac and ventilatory response to diastolic stepping may be beneficial to distance running performance. PMID- 29240005 TI - Efficacy of a Dual-ring Wound Protector for Prevention of Surgical Site Infections After Pancreaticoduodenectomy in Patients With Intrabiliary Stents: A Randomized Clinical Trial. AB - OBJECTIVE: To evaluate the efficacy of a dual-ring wound protector for preventing incisional surgical site infection (SSI) among patients with preoperative biliary stents undergoing pancreaticoduodenectomy (PD). METHODS AND ANALYSIS: This study was a parallel, dual-arm, double-blind randomized controlled trial. Adult patients with a biliary stent undergoing elective PD at 2 tertiary care institutions were included (February 2013 to May 2016). Patients were randomly assigned to receive a surgical dual-ring wound protector or no wound protector, and also the current standard of care. The main outcome measure was incisional SSI, as defined by the Centers for Disease Control and Prevention criteria, within 30 days of the index operation. RESULTS: A total of 107 patients were recruited (mean age 67.2 years; standard deviation 12.9; 65% male). No significant differences were identified between the intervention and control groups (age, sex, body mass index, preoperative comorbidities, American Society of Anesthesiologists class, prestent cholangitis). There was a significant reduction in the incidence of incisional SSI in the wound protector group (21.1% vs 44.0%; relative risk reduction 52%; P = 0.010). Patients with completed PD also displayed a decrease in incisional SSI with use of the wound protector compared with those palliated surgically (27.3% vs 48.7%; P = 0.04). Multivariate analysis did not identify any significant modifying factor relationships (estimated blood loss, duration of surgery, hospital site, etc.) (P > 0.05). CONCLUSION: Among adult patients with intrabiliary stents, the use of a dual-ring wound protector during PD significantly reduces the risk of incisional SSI. PMID- 29240006 TI - Surgical Consultation as Social Process: Implications for Shared Decision Making. AB - OBJECTIVE: This qualitative study examines surgical consultation as a social process and assesses its alignment with assumptions of the shared decision-making (SDM) model. SUMMARY OF BACKGROUND DATA: SDM stresses the importance of patient preferences and rigorous discussion of therapeutic risks/benefits based on these preferences. However, empirical studies have highlighted discrepancies between SDM and realities of surgical decision making. Qualitative research can inform understanding of the decision-making process and allow for granular assessment of the nature and causes of these discrepancies. METHODS: We observed consultations between 3 general surgeons and 45 patients considering undergoing 1 of 2 preference-sensitive elective operations: (1) hernia repair, or (2) cholecystectomy. These patients and surgeons also participated in semi-structured interviews. RESULTS: By the time of the consultation, patients and surgeons were predisposed toward certain decisions by preceding events occurring elsewhere. During the visit, surgeons had differential ability to arbitrate surgical intervention and construct the severity of patients' conditions. These upstream dynamics frequently displaced the centrality of the risk/benefit-based consent discussion. CONCLUSION: The influence of events preceding consultation suggests that decision-making models should account for broader spatiotemporal spans. Given surgeons' authority to define patients' conditions and control service provision, SDM may be premised on an overestimation of patients' power to alter the course of decision making once in a specialist's office. Considering the subordinate role of the risk/benefit discussion in many surgical decisions, it will be important to study if and how the social process of decision making is altered by SDM-oriented decision aids that foreground this discussion. PMID- 29240008 TI - Genome-wide Discovery of a Novel Gene-expression Signature for the Identification of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma. AB - OBJECTIVE: This study aimed to develop a gene-expression signature for identification of lymph node (LN) metastasis in esophageal squamous cell carcinoma (ESCC) patients. SUMMARY OF BACKGROUND DATA: LN metastasis is recognized as the most important independent risk factor for therapeutic decision making of ESCC patients. METHODS: A bioinformatic approach was used to analyze RNA sequencing profiles of ESCC patients, and to develop a gene-expression signature for identifying LN metastasis. The robustness of this panel was assessed in 2 independent patient cohorts (n = 56 and 224). RESULTS: We initially prioritized a 16-gene signature out of the total 20,531 mRNAs. The model estimated by these 16 genes discriminated LN status with an area under the curve (AUC) of 0.77 [95% confidence interval (95% CI), 0.68-0.87, 5-fold cross validation]. Subsequently, a reduced and optimized 5-gene panel was trained in a clinical cohort, which effectively distinguished ESCC patients with LN metastasis (cohort-1: AUC, 0.74; 95% CI, 0.58-0.89; cohort-2, T1-T2: AUC, 0.74; 95% CI, 0.63 0.86), and was significantly superior to preoperative computed tomography (AUC, 0.61; 95% CI, 0.50-0.72). Furthermore, a combination signature comprising of the 5-gene panel together with the lymphatic vessel invasion (LVI) and venous invasion (VI) demonstrated a significantly improved diagnostic performance compared with individual clinical variables, in both cohorts (cohort-1: AUC, 0.87; 95% CI, 0.78-0.96; cohort-2: AUC, 0.76; 95% CI, 0.65-0.88). CONCLUSION: Our novel 5-gene panel is a robust diagnostic tool for LN metastasis, especially in early-T stage ESCC patients, with a promising clinical potential. PMID- 29240009 TI - Gastrointestinal Symptoms in Children and Adolescents With Neurofibromatosis Type 1. AB - OBJECTIVES: Neurofibromatosis type 1 (NF1) is a complex genetic disorder characterized by symptoms of the skin and nervous system. A previous study indicated that constipation is common in children with NF1. The aim of the present study was to investigate the phenotype and prevalence of gastrointestinal (GI) symptoms in a population of 4 to 17-year-olds with NF1 compared with their unaffected siblings. METHODS: GI symptoms were assessed with a web-based, parent or self-administered, validated, Rome III diagnostic questionnaire. Participants were recruited from 1 of 2 Danish National Centers of Expertise for NF1. Logistic regression was used to estimate the prevalence of functional dyspepsia, irritable bowel syndrome (IBS), and constipation in each group and the groups were compared using odds ratio (OR). RESULTS: We compared 102 NF1 patients (median age 10.3 years) and 46 of their unaffected siblings (median age 10 years). The overall likelihood of having GI symptoms usually attributed to either functional dyspepsia, IBS, or constipation was 30.4% in patients versus 10.9% in siblings, OR 3.58 (95% confidence interval 1.30 to 9.79). The prevalence of constipation was 22.5% in patients and 4.3% in siblings, OR 6.41 (95% confidence interval 1.45 to 28.24). The use of laxatives was 16% (n = 16) in patients and 2% (n = 1) in siblings. CONCLUSIONS: Overall, GI symptoms attributed to functional dyspepsia, IBS or constipation are more common in 4 to 17-year-olds with NF1 when compared with their unaffected siblings. The high prevalence indicates that GI dysfunction in NF1 is not functional but may be part of the underlying NF1 disorder. PMID- 29240007 TI - Alternative Fistula Risk Score for Pancreatoduodenectomy (a-FRS): Design and International External Validation. AB - OBJECTIVE: The aim of this study was to develop an alternative fistula risk score (a-FRS) for postoperative pancreatic fistula (POPF) after pancreatoduodenectomy, without blood loss as a predictor. BACKGROUND: Blood loss, one of the predictors of the original-FRS, was not a significant factor during 2 recent external validations. METHODS: The a-FRS was developed in 2 databases: the Dutch Pancreatic Cancer Audit (18 centers) and the University Hospital Southampton NHS. Primary outcome was grade B/C POPF according to the 2005 International Study Group on Pancreatic Surgery (ISGPS) definition. The score was externally validated in 2 independent databases (University Hospital of Verona and University Hospital of Pennsylvania), using both 2005 and 2016 ISGPS definitions. The a-FRS was also compared with the original-FRS. RESULTS: For model design, 1924 patients were included of whom 12% developed POPF. Three predictors were strongly associated with POPF: soft pancreatic texture [odds ratio (OR) 2.58, 95% confidence interval (95% CI) 1.80-3.69], small pancreatic duct diameter (per mm increase, OR: 0.68, 95% CI: 0.61-0.76), and high body mass index (BMI) (per kg/m increase, OR: 1.07, 95% CI: 1.04-1.11). Discrimination was adequate with an area under curve (AUC) of 0.75 (95% CI: 0.71-0.78) after internal validation, and 0.78 (0.74-0.82) after external validation. The predictive capacity of a-FRS was comparable with the original-FRS, both for the 2005 definition (AUC 0.78 vs 0.75, P = 0.03), and 2016 definition (AUC 0.72 vs 0.70, P = 0.05). CONCLUSION: The a FRS predicts POPF after pancreatoduodenectomy based on 3 easily available variables (pancreatic texture, duct diameter, BMI) without blood loss and pathology, and was successfully validated for both the 2005 and 2016 POPF definition. PMID- 29240010 TI - Well Preserved Renal Function in Children With Untreated Chronic Liver Disease. AB - OBJECTIVES: On the basis of studies with hepatorenal syndrome, it is widely regarded that renal function is impacted in chronic liver disease (CLD). Therefore, we investigated renal function in children with CLD. METHODS: In a retrospective study of 277 children with CLD, renal function was investigated as glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), measured as clearance of inulin and para-amino hippuric acid or clearance of iohexol. The data were analyzed with regard to different subgroups of liver disease and to the grade of damage. RESULTS: Hyperfiltration (>+2 SD of controls) was found in the subgroups of progressive familial intrahepatic cholestasis (44%), glycogenosis (75%), and acute fulminant liver failure (60%). Patients with biliary atresia, most other patients with metabolic disease and intrahepatic cholestasis, and those with vascular anomalies and cryptogenic cirrhosis had normal renal function. Decreased renal function was found in patients with Alagille's syndrome (64% < -2 SD). Increased GFR and ERPF was found in patients with elevated transaminases, low prothrombin level, high bile acid concentration, and high aspartate-aminotransferase-to-platelet ratio. CONCLUSIONS: Most children with CLD had surprisingly well preserved renal function and certain groups had even hyperfiltration. The finding that children with decompensated liver disease and ongoing liver failure had stable kidney function suggests that no prognostic markers of threatening hepatorenal syndrome were at hand. Moreover, estimation of GFR based on serum creatinine fails to reveal hyperfiltration. PMID- 29240011 TI - Fecal Calprotectin Test Performed at Home: A Prospective Study of Pediatric Patients With Inflammatory Bowel Disease. AB - OBJECTIVES: Measuring fecal calprotectin (FC) in a laboratory is time-consuming and that is why home tests have been developed. We studied the use of an FC home test in pediatric patients with inflammatory bowel disease (PIBD) in real-life settings. METHODS: The patients were asked to perform the IBDoc FC home test monthly for 6 months and to report their clinical disease activity at testing. Clinical decision-making, however, was guided by routine FC enzyme-linked immunosorbent assay (ELISA) for patients with raised IBDoc values. Spare frozen samples were analyzed using ELISA and IBDoc in the laboratory. The participants completed a questionnaire about FC testing at the start and end of the study. RESULTS: Of the 52 patients, 35 (67%) ages 5 to 18 years completed the study, and 197 home tests were performed. Of these, 15% failed, mainly because of technical reasons. Just under half of the patients (47%) considered home testing comparable or superior to routine testing. In contrast, the parents were unsatisfied (61%), mostly because the IBDoc results were significantly different from ELISA and they found the phone application difficult to handle but whenever the IBDoc was performed by a laboratory professional it was comparable with ELISA, suggesting that practical issues hampered home testing. Despite their reservations, more than 80% of parents felt that home testing would improve disease management. CONCLUSIONS: PIBD patients and their families were interested in FC home monitoring and willing to adopt testing as a part of their disease management, but this approach requires thorough guidance. PMID- 29240013 TI - Equitable Education for Introverts: Providing Learning Opportunities That Prepare Nursing Students to Be Leaders. PMID- 29240012 TI - Surgical Treatment of Chronic Elbow Dislocation Allowing for Early Range of Motion: Operative Technique and Clinical Results. AB - OBJECTIVES: To describe the surgical treatment and patient outcomes of chronic elbow dislocations. DESIGN: Retrospective review. SETTING: Two tertiary referral centers. PATIENTS/PARTICIPANTS: All patients with surgically treated chronic elbow dislocation with no associated articular fracture from January 2009 to January 2015. INTERVENTION: Review of patient demographics, injury chronicity, surgical technique, and patient outcomes. MAIN OUTCOME MEASUREMENT: Clinical outcomes included elbow range of motion and complications. Radiographic outcomes included the presence of heterotopic ossification. Patient-reported outcomes included the Mayo Elbow Performance Index (MEPI) and the Summary Outcome Determination (SOD). RESULTS: Thirty-two patients with mean follow-up of 22 months (range, 13-41 months) were included. The mean dislocation duration was 6 months (range, 1-34 months). The mean preoperative range of motion was 8 degrees (range, 0-30 degrees). There were no infections or recurrent dislocations. One patient developed transient ulnar nerve palsy postoperatively. There were no cases of new or progressive heterotopic ossification. The mean postoperative extension was 31 degrees (range, 0-75 degrees), and the mean postoperative flexion was 132 degrees (range, 95-150 degrees); the mean final arc of motion was 101 degrees (range, 50-140 degrees). The mean postoperative MEPI was 93 (range, 70-100), and the mean SOD score was 9 (range, 6-10). Using the MEPI, 97% (31/32 patients) had good or excellent outcome. There was no difference in flexion/extension arc or MEPI scores between groups of elbows older and younger than 17 years or dislocations less or more than 3 months. CONCLUSION: This is the largest case series of surgically treated patients with chronic elbow dislocation. Using our surgical technique, 97% of patients had good or excellent outcome with a low complication rate. Open reduction of chronic elbow dislocation can be accomplished while permitting early motion with minimal recurrent dislocation risk. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29240014 TI - Classroom Participation: A Model of Feminist Pedagogy. AB - Nursing faculty need to provide students with problem-solving skills during their formative academic years, and feminist pedagogy supported by classroom participation may foster these skills. Through the lens of feminist pedagogy, factors that influence classroom participation of nursing students were identified using the College and University Classroom Environment Inventory. Nursing students reported higher levels of attendance and punctuality compared with preparation and contribution to class discussion and favored personalization and equity over innovation and individualization in the classroom. PMID- 29240015 TI - Evaluating the Clinical Judgment of Prelicensure Nursing Students in the Clinical Setting. AB - Assessing clinical judgment for safe nursing practice is a challenge. In this study, the Lasater Clinical Judgment Rubric (LCJR) was used to evaluate clinical judgment of junior and senior nursing students in the clinical setting. Juniors demonstrated an accomplished level on the total scale and all 4 subscales, whereas seniors had exemplary clinical judgment on the total scale and 3 of 4 subscales. The study provides evidence in support of the use of the LCJR to assess students' clinical judgment in the clinical practice setting. PMID- 29240017 TI - Successful Removal of Intracardiac Thrombus With a Poole Tip Suction Device Through the Inferior Vena Cava of a Patient With Cardiovascular Collapse During Liver Transplant: A Case Report. AB - Intracardiac thrombus occurs in 1.2%-6.3% of patients undergoing orthotopic liver transplant and is associated with a high mortality rate. The pathophysiology and risk factors for development of this complication are not well understood. No consensus treatment guidelines exist, and specific therapies are associated with serious risks. We present the timely and successful use of a Poole tip surgical suction device advanced into the right atrium through a cavotomy created in the inferior vena cava to remove a large right atrial thrombus during liver transplant. The thrombus was identified with transesophageal echocardiography and was causing cardiovascular collapse. PMID- 29240018 TI - Allergic Reaction Caused by a Lip Balm-Flavored Facemask Used During Inhalational Induction: A Case Report. AB - Flavoring a facemask with a lip balm for inhalational induction in children is a common practice. However, most anesthesia providers are unaware of potential complications and the management of allergic reactions caused by lip balm. We describe the occurrence of allergic reaction to lip balm-flavored facemask in a child who underwent an inhalational anesthetic induction. The facial rash resolved completely without complications after administration of an antihistamine and steroid. PMID- 29240020 TI - Association study of FGF18 with developmental dyslexia in Chinese population. AB - Developmental dyslexia (DD) is a neurobiological disorder featured by reading disabilities. In recent years, genome-wide approaches provided new perspectives to discover novel candidate genes of DD. In a previous study, rs9313548 located downstream of FGF18 showed borderline genome-wide significant association with DD. Herein, we selected rs9313548 and 11 independent tag single nucleotide polymorphisms covering gene region of FGF18 to perform association analysis with DD among 978 Chinese dyslexic cases and 998 controls recruited from elementary schools. However, we did not observe any single nucleotide polymorphism exceeding significant threshold. Our preliminary results suggested that FGF18 might not be a susceptibility gene for DD in Chinese population. PMID- 29240021 TI - Differences in Seizure Expression Between Magnetic Seizure Therapy and Electroconvulsive Shock. AB - OBJECTIVE: Evidence suggests that magnetic seizure therapy (MST) results in fewer side effects than electroconvulsive treatment, both in humans treated with electroconvulsive therapy (ECT) as well as in the animal preclinical model that uses electroconvulsive shock (ECS). Evidence suggests that MST results in fewer cognitive side effects than ECT. Although MST offers enhanced control over seizure induction and spread, little is known about how MST and ECT seizures differ. Seizure characteristics are associated with treatment effect. This study presents quantitative analyses of electroencephalogram (EEG) power after electrical and magnetic seizure induction and anesthesia-alone sham in an animal model. The aim was to test whether differential neurophysiological characteristics of the seizures could be identified that support earlier observations that the powers of theta, alpha, and beta but not delta frequency bands were lower after MST when compared with those after ECS. METHODS: In a randomized, sham-controlled trial, 24 macaca mulatte received 6 weeks of daily sessions while scalp EEG was recorded. Electroencephalogram power was quantified within delta, theta, alpha, and beta frequency bands. RESULTS: Magnetic seizure therapy induced lower ictal expression in the theta, alpha and beta frequencies than ECS, but MST and ECS were indistinguishable in the delta band. Magnetic seizure therapy showed less postictal suppression than ECS. Increasing electrical dosage increased ictal power, whereas increasing MST dosage had no effect on EEG expression. CONCLUSIONS: Magnetic seizure therapy seizures have less robust electrophysiological expression than ECS, and these differences are largest in the alpha and beta bands. The relevance of these differences in higher frequency bands to clinical outcomes deserves further exploration. SIGNIFICANCE: Contrasting EEG in ECS and MST may lead to insights on the physiological underpinnings of seizure-induced amnesia and to finding ways to reduce cognitive side effects. PMID- 29240022 TI - Vagally Mediated Postictal Asystole During Electroconvulsive Therapy. PMID- 29240023 TI - Immediate Effects of Transcranial Direct Current Stimulation on Obsession-Induced Anxiety in Refractory Obsessive-Compulsive Disorder: A Pilot Study. AB - OBJECTIVE: Studies have shown that transcranial direct current stimulation (tDCS) has immediate effects on brain activity. The aim of this study was to investigate the potential use of tDCS to regulate obsession-induced anxiety immediately after symptom provocation in patients with refractory obsessive-compulsive disorder (OCD). METHODS: Twelve patients with refractory OCD received cathode, anode, and sham transcranial direct current stimulation over the medial prefrontal cortex conjugant to pharmacological treatment in a crossover design. Before and after the DC stimulation, patients graded the intensity of their anxiety after a short exposure to a provoking stimulus using the visual analogue scale. Clinical questionnaires assessing symptoms severity were also applied before each stimulation mode. RESULTS: We found a statistically significant decrease in the severity of the obsession-induced anxiety (decreased visual analogue scale) as a result of cathode tDCS in comparison with the anode and sham stimulation. Reduction in obsession-induced anxiety was consistent, yet short lasting, and was independent of symptom severity. CONCLUSIONS: Cathode tDCS could be potentially used to regulate obsession-induced anxiety in refractory OCD patients. Further studies are warranted to confirm our results as well as to determine whether tDCS can achieve prolonged benefits in OCD and be of aid in behavioral treatments based on exposure. PMID- 29240025 TI - Hypovitamininosis D in Childhood Cancer Survivors: Importance of Vitamin D Supplementation and Measurement Over Different Points of Time. AB - This observational retrospective cross-sectional and case-controlled study measures levels of 25-hydroxy-vitamin D (25-OH-VD) in pediatric cancer survivors at different intervals and assesses the effect of 2 supplementation regimens over a period of 12 months. Sixty-eight patients were included in this quasi experimental study, of which 32 were boys and 36 were girls. A control group of 30 healthy children were included. It was found that initial 25-OH-VD levels were insufficient (<30 ng/mL) in 61 patients (89.7%). Yet, no significant difference between the levels of 25-OH-VD in these patients as compared with the healthy control group was evidenced. However, 25-OH-VD levels were significantly higher at 18 months in patients who were supplemented with oral 50,000 IU/month vitamin D during the 12 months in comparison with patients supplemented with 1000 IU/day. Our findings indicate that pediatric cancer survivors who require frequent monitoring of their 25-OH-VD levels yielded better results when supplemented with higher doses of vitamin D over longer periods of time. A course of oral vitamin D supplementation regimen of 50,000 IU/month gave effective results with excellent compliance and no reports of any adverse or harmful effects. PMID- 29240024 TI - Delayed Methotrexate Clearance Despite Carboxypeptidase-G2 (Glucarpidase) Administration in 2 Patients With Toxic Methotrexate Levels. AB - High-dose methotrexate has been a treatment for osteosarcoma; however, its nephrotoxic effects are considerable. Carboxypeptidase-G2 (glucarpidase) was approved by the US Food and Drug Administration in 2012 for treatment of toxic methotrexate levels. We report our experience using glucarpidase under compassionate use before Food and Drug Administration approval in 2 patients who had delayed methotrexate clearance and prolonged kidney injury despite glucarpidase administration. Our results show that patients with methotrexate toxicity may require repeated doses of glucarpidase in addition to supportive measures, such as dialysis. PMID- 29240026 TI - Gemtuzumab Ozogamicin Containing Chemotherapy for Relapsed or Refractory Acute Myeloid Leukemia (AML) in Children. PMID- 29240027 TI - Congenital Hemophilia A Presenting With Hashimoto's Encephalopathy and Myocarditis: The First Reported Case. AB - Here, we report a case of hemophilia A with myocarditis, encephalopathy, and spontaneous intramedullary hemorrhage. A 14-month-old male infant presented with loss of consciousness, generalized tonic-clonic convulsions, and cardiac failure. The neurological examination was normal. Myocarditis was diagnosed. After administration of fresh frozen plasma, the aPTT did not return to normal. The factor VIII (FVIII) level was 10.2% the normal level, and the patient was diagnosed with hemophilia A. The cerebrospinal fluid (CSF) evaluation was unremarkable, with the exception of elevated CSF protein levels. An electroencephalogram revealed diffuse slowing of background activity. The spinal MRI revealed chronic bleeding in areas of the medulla spinalis. Tests for the antibodies associated with autoimmune encephalitis were negative. Anti thyroglobulin (THG) (11.8 U/mL [normal, 0 to 4 U/mL]) and anti-thyroid peroxidase (TPO) (53.9 U/mL [normal, 0 to 9 U/mL]) antibodies were present in the serum. The patient received 1 g/kg intravenous immunoglobulin G (IVIG) for 2 days based on a diagnosis of myocarditis and Hashimoto's encephalopathy. After the first month of treatment his clinical findings were negative. He developed an inhibitor to FVIII 1 month after initiation of FVIII replacement therapy. Hemophilia A has various clinical presentations. Autoimmunity may lead to early inhibitor development in patients with hemophilia. PMID- 29240028 TI - Genotype-phenotype Correlation of beta-Thalassemia in Croatian Patients: A Specific HBB Gene Mutations. AB - An analysis of genotype-phenotype correlation was performed for 14 patients with beta-thalassemia who had been registered in Referral Centre for hematology and oncology of the University Hospital Centre, Zagreb, Croatia. HBB gene mutations were determined using a gene-specific Q5 High-Fidelity PCR analysis with direct DNA sequencing of amplified transcripts. Mahidol score index used for classification of thalassemia severity was found to be low for all the patients enrolled in the study, indicating a mild beta-thalassemia phenotype with no signs of disease progression. Most of the patients have already described gene mutations: IVS-II-666 C>T (HBB:c.316-185C>T) and IVS-II-16 G>C (HBB:c.315+16G>C). Each of the aforementioned mutations was found in (11/14; 78,57%) and (10/14; 71,43%) of our patients, respectively. Recently published HBB:c.9T>C mutation was found in 8 of 14 (57,14%) in our study group. IVSII-74 T>G (HBB:c.315+74T>G) is a worldwide mutation found in 6 of 14 (42.86%) of our patients. All these mutations occur among Croatian children with no obvious Indian/Near Eastern/Iranian ancestry. We also identified 7 de novo mutations (c.316-135het_dupT, c.316 133A>G, c.93-54G>A, c.316-68_316-67het_insCGG, c.316-342delA, c.316-312delT, c.316-209delT) of mild severity phenotype according to Mahidol classification score index. We did not find children or adults with thalassemia major severity phenotype. PMID- 29240029 TI - Thiamylal Plus Pentazocine Shows Similar Efficacy as Ketamine Plus Midazolam for Painful Procedures in Children With Leukemia. AB - This retrospective study compared the use of thiamylal plus pentazocine (TP) to ketamine plus midazolam (KM) in children with leukemia who were undergoing bone marrow aspiration and/or intrathecal chemotherapy. A total of 268 procedures in 35 children with leukemia were retrospectively analyzed for efficacy and adverse events. All procedures were successfully completed without severe adverse events. TP induced significantly faster sedation. The incidents of desaturation were significantly greater in the TP group, but were transient and recovered by oxygen supplementation alone. Therefore, TP can be a useful combination with a similar efficacy as KM for painful procedures in children. PMID- 29240030 TI - A Case of Familial Mediterranean Fever Having Intermittent Leukopenia. AB - Familial Mediterranean fever (FMF) is a genetically inherited autoinflammatory disorder characterized by inflammatory attacks and may result in amyloidosis as a severe complication. Elevation of acute phase reactants, including leukocytosis, is seen during attack periods. Here we describe a 13-year-old female patient with a very rare clinical presentation of FMF, who would experience FMF attacks when she did not regularly take her colchicine. During these attacks she had leukopenia and neutropenia instead of leukocytosis. The leukocyte count returned to normal when she continued the medication and avoided attacks. Ethnicity and clinical signs are important in leukopenic patientsand should be investigated for FMF to avoid unnecessary procedures and complications. PMID- 29240031 TI - Thoracic Actinomycosis With Infiltration of the Spine: An Oncological Pitfall. AB - Thoracic actinomycosis with involvement of the vertebral column and chest wall is rare in children and may resemble malignant tumors. A 12-year-old girl was admitted to our clinic having B-symptoms, cachexia, and painful scoliosis (Karnofsky index 20%). Imaging showed a large thoracic left-sided paravertebral tumor with infiltration of the vertebrae, destruction of the chest wall and multiple intrapulmonary nodules. Initially, Ewing sarcoma was suspected and chemotherapy started without previous biopsies. Definite diagnosis of actinomycosis was established later upon histopathologic examination and successfully treated by beta-lactam antibiotics. Collectively, this case illustrates that actinomycosis can be an oncological pitfall and possible differential diagnosis. PMID- 29240032 TI - Primary Pediatric Cutaneous T-Cell Lymphoproliferative Disorders: 3 New Cases. AB - Primary cutaneous lymphoproliferative disorders are a composite group of diseases with considerable differences in histopathologic, immunophenotypic, and clinical features. They are exceedingly rare in children and in the literature only few cases are reported with extremely different therapeutic approaches. Because of the rarity of cutaneous lymphomas we consider crucial to increase the knowledge of these diseases providing every single case. We present 3 pediatric cases of primary cutaneous T-cell lymphomas occurred to our center with different features and therapeutic approach. PMID- 29240033 TI - Paraneoplastic Cytopenia in Ovarian Germ Cell Tumor: A Novel Presentation. AB - We report on the case of a 12-year-old girl, who presented with an ovarian germ cell tumor and cytopenia (anemia and thrombocytopenia) as an associated paraneoplastic syndrome, which gradually regressed after the tumor's removal. This report adds to the previously described paraneoplastic syndromes potentially associated with ovarian germ cell tumor. PMID- 29240034 TI - Management of Refractory Pediatric Kaposiform Hemangioendothelioma With Sirolimus and Aspirin. AB - Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor characterized by aggressive local invasion and a syndrome of platelet trapping known as Kasabach Merritt phenomenon that, through deposition of platelet derived growth factors, may perpetuate the growth of the tumor. Although many cases of KHE are successfully treated with local control or low-intensity chemotherapy, some cases are often refractory even to aggressive treatment. Herein, we describe a patient with a refractory, recurrent KHE despite multiple attempts at local control and intensive chemotherapy, that ultimately was successfully treated with rationally designed and low-intensity combination therapy of sirolimus and aspirin. PMID- 29240035 TI - Acinic Cell Carcinoma of the Parotid Gland in Children and Adolescents. AB - Acinic cell carcinoma of the parotid gland is a rare low-grade malignant neoplasm. Data on children are sparse. For the present study, the database of a tertiary pediatric medical center was reviewed for all patients with parotid gland acinic cell carcinoma diagnosed and treated between 2004 and 2013. Clinical, histologic, treatment, and outcome parameters were collected from the medical files. Four patients were identified, 3 female and 1 male, aged 13.5 to 18 years (median 15.7) at diagnosis. One patient had a family history of parotid tumor and 1 of hypothyroidism/hyperthyroidism. Two patients had L-thyroxin treated Hashimoto thyroiditis, and 1 had a thyroid nodule. All presented with a localized parotid mass and negative lymph nodes. Treatment consisted of partial parotidectomy, with no damage to the facial nerve. Histology confirmed the diagnosis of acinic cell carcinoma with low proliferation rate (Ki67 immunostaining 1% to 8%). No evidence of disease was found on any patient with a median follow-up at 83 months (range, 32 to 93 mo) from presentation. In our experience, the prognosis of pediatric parotid gland acinic cell carcinoma is good, and surgery alone is sufficient for treatment of early stage tumors. This is the first report of findings of a family history of thyroid disease and/or thyroid abnormalities in patients with parotid gland acinic cell carcinoma. PMID- 29240036 TI - Solid Pseudopapillary Neoplasm of the Pancreas in Children and Adults: A National Study of 369 Patients. AB - BACKGROUND: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor in children, with current evidence limited to single-center studies. We examined treatment and clinical outcomes for pediatric and adult SPN with a national data set. METHODS: The 2004 to 2013 National Cancer Data Base was queried to identify all patients diagnosed with SPN. The cohort was stratified by age (pediatric and adult) defined as below 18 years and 18 years and above, respectively. Baseline characteristics and unadjusted outcomes were compared. RESULTS: We identified 21 pediatric and 348 adult patients with SPN. Both groups displayed similar demographic composition. Patients were commonly female (90.5% [pediatric] vs. 85.9% [adult], P=0.56) and white (66.7% vs. 68.3%, P=0.74). Tumor location was similar between adults and children. Median tumor size was similar between children and adults (5.9 vs. 4.9 cm, P=0.41). Treatment strategies did not vary between groups. Partial pancreatectomy was the most common resection strategy (71.4% vs. 53.1%, P=0.80). Both groups experienced low mortality (0.0% vs. 0.7% at 5 y, P=0.31). CONCLUSIONS: This study provides the largest comparison of pediatric and adult SPN to date. Children with SPN have similar disease severity at presentation, receive similar treatments, and demonstrate equivalent postoperative outcomes compared with their adult counterparts. PMID- 29240037 TI - Fetal Anemia Causing Hydrops Fetalis From an Alpha-Globin Variant: Homozygous Hemoglobin Constant Spring. AB - BACKGROUND: Fetal anemia is often assumed to be due to red cell alloimmunization and Parvovirus infection, and can lead to hydrops fetalis and death in utero. Other causes, such as mutations of hemoglobin alpha, are less commonly considered. METHODS: We report 7 cases with fetal anemia causing hydrops fetalis. Serial Doppler ultrasound for measurement peak systolic velocity (PSV) of middle cerebral artery (MCA) was used for evaluation of fetal anemia. Fetal anemia is suggested if the MCA/PSV ratio is >1.5 multiple of median. Cordocentesis was performed subsequently to find the cause of fetal anemia and check fetal hemoglobin for consideration of intrauterine infusion. Investigations for fetal anemia include complete blood count, blood morphology, and blood group of mother and fetus, reticulocyte counts, red cell indices, screening for thalassemia, hemoglobin typing, acid elution test, parvovirus B 19 serology, and TORCH titer (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, and syphilis). Intrauterine infusion, using irradiated prestorage filtered red cell with hematocrit level of 80%, is indicated if fetal hemoglobin is <10 g/dL. RESULT: Seven cases with fetal anemia were prenatally diagnosed from gestational ages 20 to 34 weeks. Initial hematocrit in these cases varied from 9% to 17.2%. In each case, causes of anemia were determined using the investigations listed above. All cases underwent uneventfully up to 3 intrauterine transfusions. DNA study for thalassemia demonstrated homozygous Constant Spring (CS) in 5 cases, homozygous CS with heterozygous E in 1 case, and compound heterozygous CS and Pakse in 1 case. The perinatal outcomes were normal term in 5 cases, preterm in 2 cases. Low birth weight was determined in 2 cases. The screening for thalassemia major, including the osmotic fragility and dichlorophenol indophenol precipitation test (DCIP), is not helpful for detecting hemoglobin variants such as Constant Spring or Pakse. SUMMARY: This study emphasizes homozygous Constant Spring and compound heterozygous CS and Pakse as a cause of hydrops fetalis. Proper management for the fetus after diagnosis can lead to a good fetal outcome. Prevention control programs should include screening of parents for the heterozygous state. PMID- 29240038 TI - Prevalence of Hypertension (HTN) and Cardiovascular Risk Factors in a Hospitalized Pediatric Hemophilia Population. AB - Improved life expectancy in hemophilia has led to a greater interest in age related disorders. Hypertension (HTN) as well as cardiovascular disease have been increasingly reported in hemophilic adults but there is currently very limited data in the pediatric population. We conducted a cross-sectional study using data from the 2012 National Health Cost and Utilization Project database to determine the prevalence of HTN and associated cardiovascular risk factors in a hospitalized pediatric hemophilia population, between the ages of 0 to 21 years, in comparison with the general pediatric population. The prevalence of HTN was significantly higher in children with hemophilia (CWH) in comparison with the general pediatric population (1.71% vs. 1.02%, P-value=0.005). When adjusting the analysis for sex, the prevalence of HTN in the hemophilia cohort remained higher, although not statistically significant (1.52% vs. 1.22%, P-value=0.2568). When examining the concomitant presence of >=1 cardiovascular risk factors in the hypertensive subgroups, CWH had a higher prevalence of obesity (2.64% vs. 1.32%, P-value <0.0001). Interestingly, diabetes mellitus was more prevalent in nonhemophilic children (1.47% vs. 0.56%, P-value=0.0015). These data suggest that cardiovascular risk factors need to be closely monitored in CWH, and a better preventive strategy is likely needed to identify those hemophilic patients at higher risk of developing cardiovascular disease in adulthood. PMID- 29240039 TI - An overview of low back pain and occupational exposures to whole-body vibration and mechanical shocks. AB - This paper offers an overview of the relation of low back pain (LBP) to occupational exposures to whole-body vibration (WBV) and mechanical shocks. LBP is a condition of multifactorial origin and is a very common health problem in the general population. Among occupational risk factors, epidemiological studies of driving occupations have provided evidence for strong associations between LBP and occupational exposures to WBV and mechanical shocks. Since it is hard to separate the contribution of WBV exposure to disorders in the lower back from that of other individual, ergonomic or psychosocial risk factors, a quantitative exposure-response relationship for WBV cannot be outlined precisely. Experimental research has provided biodynamic support to the findings of epidemiological studies, showing that in controlled laboratory conditions exposure to WBV can cause mechanical overload to the human spine. The EU Directive on mechanical vibration has established daily exposure action and limit values to protect the workers against the risk from WBV. There is some evidence that the EU exposure limit values are excessive, so much so that an elevated risk of LBP has been found for WBV exposures beneath the EU limit values. In the Italian arm of the EU VIBRISKS prospective cohort study of professional drivers, measures of internal lumbar load (compressive and shear peak forces), calculated by means of anatomy based finite-element models, were found better predictors of the occurrence over time of low back disorders than the metrics of external exposure suggested by the EU Directive on mechanical vibration. Further biodynamic and epidemiological studies are needed to validate the findings of the VIBRISKS study. PMID- 29240040 TI - Effects of the work limitations on the career path of a cohort of health workers. AB - BACKGROUND: The median age of the workforce, and of healthcare workers in particular, is increasing, resulting in a reduced work capacity. This may prompt the occupational physician to issue fitness for work limitations. OBJECTIVES: To examine the health surveillance data collected over 20 years on the employees of a large healthcare institution to identify the effects of the limitations imposed on their career paths. METHODS: The database of health surveillance records gathered over the years was analysed using the same dedicated software. Fourteen types of limitations were classified via a "text mining" treatment. 3,653 subjects were selected, divided in two groups (A: with a limitation and B: without limitation) comprised of 655 and 2,998 subjects, respectively. The subjects were then ranked on the basis of departments and tasks involved. We also evaluated the number of departmental changes for each worker and the corresponding rate of change for the three groups A, B and B post-limitation. RESULTS: Limitations have been increasing in parallel with the aging of workers, in particular those relating to Manual Load Handling/Posture (MLH/P). The limitations due to Allergy/Latex lasted longer, and in a greater proportion than MLH/P, particularly when compared to the limitation for Shift Work and those for "Other Limitations" that were shrinking faster. CONCLUSIONS: There is a clear relationship between certain types of limitations/prescriptions and workers' ages. It is necessary to carry out an assessment of the association with the work performed in order to implement age management strategies aimed at maintaining work capacity in aging workers. PMID- 29240041 TI - Reduction of excavation face collapse risk in tunnelling. AB - : Two large road tunnels, recently developed near Florence, showed instabilities of the excavation face which subsequently caused sixteen collapses. Due to the risk for workers' safety, the public authority for occupational health and safety (ASL) has monitored the failure rate and other background variables in order to assess the possible correlations between risk reductions, its own actions, and those of the various safety actors involved. OBJECTIVES: To evaluate if the interventions carried out by the design team were able to reduce the risks of collapse and which of the ASL actions and/or which other factors were more effective in changing the attitudes of the parties involved, leading to a more expensive but safer project variant. RESULTS: After adoption of the second of two project variants, no more collapses were observed. No correlation was found between trend of ASL inspections and observed variation of collapse rate. Conversely, the adoption of strongly coercive measures and investigation reporting by local media coincided with periods of risk reduction, even if the low number of events does not allow for statistical evaluation. CONCLUSIONS: These findings appear to be coherent with the ratio of the cost of penalties related to health and safety infringements (thousands of euros) to the overall cost of the safer project variant (a hundred times greater). The safer variant required 7% more labour but avoided forced interruptions caused by the collapses, allowing a 13% faster excavation rate. PMID- 29240042 TI - Range of motion limitations of the upper body in obese female workers. AB - BACKGROUND: The prevalence of obesity is increasing worldwide, and the economic consequences of an increased percentage of obese workers are relevant in terms of health costs and absences from work. Obesity is associated with reduced participation in the workforce, increased absence from work, disability and health costs, lower salaries and reduced productivity. OBJECTIVES: We aimed at quantifying the limitations in range of motion (ROM) of the upper limb and the trunk of obese workers during basic occupational tasks. METHODS: One group of 15 obese female subjects (BMI: 42.10+/-9.10 kg/m2) and one control group of 13 normal-weight female subjects were recruited. Three group of tasks were selected as representative of basic occupational movements: 1) upper limb movements (reaching, abduction-adduction, frontal elevation); 2) trunk movements (lateral bending, rotation); 3) whole body movement (target task). RESULTS: We observed significant range of motion limitations in lateral and frontal upper arm elevation. Statistically significant difference in terms of center of pressure (the point of application of the ground reaction force measured by means of force platform) excursions was observed for lateral bending and trunk rotation tasks. CONCLUSIONS: Our results show that obese subjects have significant range of motion limitations of the upper body during basic occupational activities. This study provides quantitative evidence of these limitations of obese workers and may serve occupational specialists to allocate them to adequate jobs and reduce the rate of work-related musculoskeletal disorders. PMID- 29240043 TI - Nurses Work Functioning Questionnaire (NWFQ): refinement and validation of the Italian version. AB - BACKGROUND: The availability of an assessment measure for work impairment in nurses, or nursing students, is of crucial importance for early detection of workers/students at risk. Recently, a new measure, the Nurses Work Functioning Questionnaire (NWFQ), has become available, but there is no validated Italian version. OBJECTIVES: The aim of this study was to develop and validate an Italian version of the NWFQ. METHODS: We evaluated the factor structure, the internal consistency, and the convergent and discriminant construct validity with respect to organizational justice and job strain of the Italian NWFQ using data from 645 nursing students. RESULTS: Results suggested that a single-factor, 34-item measurement model could be a more parsimonious alternative (CFI=.915, TLI=.910, RMSEA=.039 e CFI=.907, TLI=.901, RMSEA=.046 in in two random subsamples; median factor loading .50, range .26-.63) to the original seven-factor structure. The score on this version of the NWFQ showed excellent internal consistency and construct validity, as higher scores were significantly associated with lower perceived distributive (r=-.30) and interpersonal justice (r=-.43), decision latitude (r=-.33), and social support (r=-.58). CONCLUSIONS: The Italian refinement of the NWFQ seems to have adequate psychometric properties and it is thus suitable for the assessment of impairment of work functioning in nursing students. PMID- 29240044 TI - Sinonasal cancer in a worker exposed to chromium in an unusual industrial sector. AB - BACKGROUND: Occupational exposure to chromium is carcinogenic for human respiratory system. Due to the low incidence of sinonasal malignancies, there is still a paucity of evidence to confirm that chromium(VI) exposure is a cause of nasal cancer. OBJECTIVES: To report on a sinonasal cancer (SNC) of rare occupational origin, increasing the awareness on epidemiological knowledge of occupational exposures to chromium compounds. METHODS: We describe a case of a 64 year-old chrome plater who worked in the galvanic industry in the early 1970s. After a latency period of 39 years, he was diagnosed with sinonasal undifferentiated carcinoma (SNUC). A brief review of the literature was conducted. RESULTS: A thorough occupational history revealed a 4-year-long occupational exposure to chromium(VI) during a magnesium cylinder plating process involved in computer production. The patient underwent endoscopic endonasal removal of the SNUC. He is alive with no evidence of disease at 40-month follow up. Our literature review identified 8 papers concerning 40 cases of chrome induced sinonasal tumors. The maximum relative risk of SNC developing in chromium exposed workers was 15.4. CONCLUSIONS: When dealing with patients diagnosed with SNC, the possibility of an underlying occupational risk is worth further investigation. Because chromium exposure is rare, and the incidence of SNUC is low, any information emerging on clinical and exposure-related aspects of SNCs in chrome plating workers can contribute to adding evidence on the possible causal relationship between chromium and sinonasal malignancies. PMID- 29240045 TI - Pier Diego Siccardi (1880-1917) and the "Clinica del Lavoro" in the trench warfare. AB - BACKGROUND: The year 2017 marks the centenary of the death of the Italian scientist Pier Diego Siccardi (1880-1917), one of Luigi Devoto's assistants at the "Clinica del Lavoro" in Milan. OBJECTIVES: To commemorate Siccardi and to describe the activities of the physicians of the "Clinica del Lavoro" during World War I. METHODS: A comprehensive analysis was conducted on scientific papers written by Pier Diego Siccardi and by other physicians belonging to the Clinica del Lavoro, in the period 1915-1918. RESULTS: During the Great War, the Clinica del Lavoro became a military hospital, even though it indirectly maintained a role in Occupational Health, assisting women who had started to work to replace the men sent to the front. Devoto and his assistants were drafted as Army doctors, but continued their research activities while at the front; focusing on the diseases that affected the soldiers, mainly infections. Bleeding fevers and jaundice were endemic among Italian troops, but their etiology was unknown. Pier Diego Siccardi identified this syndrome as an infection caused by a spirochete, and was the first one to isolate the infectious agent. Siccardi prematurely died of the same disease as a consequence of a laboratory accident, which provided further confirmation for his research. CONCLUSIONS: The heroic life of Siccardi and his tragic death testify the important activities of the scientists of the "Clinica del Lavoro" in the years of the Great War. PMID- 29240046 TI - What is the origin of the Italian term "medico competente"? AB - BACKGROUND: The meaning of the term "medico competente" - usually adopted in Italy to indicate the occupational physician - is little known. OBJECTIVES: To describe the origins of the word "medico competente" in Italy. METHODS: We conducted a comprehensive analysis of the Italian legislation from the end of the nineteenth century to the present day. RESULTS: In the United Kingdom, occupational physicians were originally named as "certifying surgeon" (1833) and "appointed surgeon" (1860). In Italy, the term "medico delegato" was introduced to indicate the physician who visited child laborers (1886), while the word "medico competente" was first used in some propaganda leaflets of the Clinica del Lavoro of Milan in 1910. This term was officially used in Italian legislation in 1927 and was preferred to "medico di fabbrica" (factory physician) in the post World War II period. Since 1982, the term "medico competente" has started to be considered as a synonym of occupational physician in Italian laws. CONCLUSIONS: The name "medico competente" appears to derive from a legislative imposition rather than from a voluntary choice developed in a medical and scientific context. Nowadays, Italian occupational physicians should be stimulated to find scientific, ethical, and professional meanings in this term, so helping to enhance their figure in modern society. PMID- 29240048 TI - Why patients are afraid of opioid analgesics: a study on opioid perception in patients with chronic pain. AB - INTRODUCTION Opiophobia is deemed one of the key barriers in effective pain management. OBJECTIVES The study aimed to assess the overall perception of opioids in cancer patients treated for chronic pain, as well as to determine the nature of their most common related fears. PATIENTS AND METHODS The study included 100 palliative care patients who suffered from chronic cancer or noncancer pain. Initially, they had to complete a survey exploring their knowledge on analgesics and potential fear of using opioids. The second phase was based on in-depth interviews with 10 palliative care patients suffering from cancer pain who were reluctant to use opioids. RESULTS Of the 100 patients, 43 expressed concerns over commencing the treatment with opioids. Fear was reported more often in patients already on strong opioids, who either overtly expressed it (group C) or not (group B), as compared with patients treated with weak opioids (group A) (50%, 48%, and 19% of groups C, B, and A, respectively). The main concerns were drug addiction, fear of death or dying, and undesirable side effects. A qualitative study revealed similar types of fear among patients expressing concerns prior to being put on strong opioids. CONCLUSIONS Opiophobia seems to be common among palliative care patients (up to 50%) treated with strong opioids. They mainly fear drug addiction, undesirable effects, and death or dying. Better awareness of patients' preconceptions about opioids may become instrumental to alleviating their suffering through enhanced pain management. PMID- 29240047 TI - Synthesis and DFT Calculations of Novel Vanillin-Chalcones and Their 3-Aryl-5-(4 (2-(dimethylamino)-ethoxy)-3-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1 carbaldehyde Derivatives as Antifungal Agents. AB - Novel (E)-1-(aryl)-3-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl) prop-2-en-1 ones 4 were synthesized by a Claisen-Schmidt reaction of 4-(2 (dimethylamino)ethoxy)-3-methoxy-benzaldehyde (2) with several acetophenone derivatives 3. Subsequently, cyclocondensation reactions of chalcones 4 with hydrazine hydrate afforded the new racemic 3-aryl-5-(4-(2-(dimethylamino)ethoxy) 3-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbaldehydes 5 when the reaction was carried out in formic acid. The antifungal activity of both series of compounds against eight fungal species was determined. In general, chalcone derivatives 4 showed better activities than pyrazolines 5 against all tested fungi. None of the compounds 4a-g and 5a-g showed activity against the three Aspergillus spp. In contrast, most of the compounds 4 showed moderate to high activities against three dermatophytes (MICs 31.25-62.5 ug/mL), being 4a followed by 4c the most active structures. Interestingly, 4a and 4c possess fungicidal rather than fungistatic activities, with MFC values between 31.25 and 62.5 MUg/mL. The comparison of the percentages of inhibition of C. neoformans by the most active compounds 4, allowed us to know the role played by the different substituents of the chalcones' A-ring. Also the most anti-cryptococcal compounds 4a-c and 4g, were tested in a second panel of five clinical C. neoformans strains in order to have an overview of their inhibition capacity not only of standardized but also of clinical C. neoformans strains. DFT calculations showed that the electrophilicity is the main electronic property to explain the differences in antifungal activities for the synthesized chalcones and pyrazolines compounds. Furthermore, a quantitative reactivity analysis showed that electron-withdrawing substituted chalcones presented the higher electrophilic character and hence, the greater antifungal activities among compounds of series 4. PMID- 29240049 TI - [Use of local thrombolysis in patients with massive pulmonary thromboembolism and moderate-to-severe pulmonary hypertension]. AB - Presented herein are the results of treating a total of 110 patients with acute massive pulmonary thromboembolism. The patients included in the study were divided into 2 groups depending on the degree of severity of pulmonary hypertension. All patients underwent interventional treatment, i.e., endovascular mechanical fragmentation with local thrombolysis. Both short- and long-term outcomes were then analysed. Performing local thrombolysis made it possible to achieve regression of clinical manifestations of acute respiratory insufficiency in more than 98% of patients. Stabilization of the clinical condition in the early postoperative period was accompanied by improvement of haemodynamics of the right heart in the remote terms of follow up after the intervention. There were 2 (1.8%) lethal outcomes resulting from progression of acute cardiovascular insufficiency. Clinically significant haemorrhage was observed in 1 (0.8%) case and was successfully arrested by conservative therapy. It was shown that local thrombolysis contributed not only to improving perfusion of the lesser circulation, a reduction of pressure in pulmonary arteries and the right heart, but also to a decrease or normalization of the linear dimensions of the right auricle and right ventricle, as well as prevented the formation of chronic postembolic pulmonary hypertension in more than 90% of patients. It was also demonstrated that while performing this type of treatment, the initial level of pulmonary hypertension did not influence either the prognosis or the outcome of the disease. PMID- 29240050 TI - [Antithrombotic therapy after bypass grafting below the inguinal ligament]. AB - The importance of antithrombotic therapy following reconstructive operations on arteries below the inguinal ligament is beyond question. The pharmaceutical market offers a wide variety of antiaggregant and anticoagulant agents, with many studies (including randomised and multicenter ones) performed worldwide on the problem of choosing optimal antithrombotic therapy in the postoperative period after arterial reconstructions. Nevertheless, the problem of selecting adequate antithrombotic therapy after shunting operations remains undetermined. Presented in the article is a review of foreign studies on the problem concerned. This is followed by discussing the results of many large international studies, including such trials as the BOA and CASPAR. Based on the findings obtained in these studies, Cochrane reviews, European and American guidelines, the authors express their opinion on the algorithms of choosing an appropriate variant of antithrombotic therapy during the postoperative period in patients after arterial reconstructions below the inguinal ligament. PMID- 29240051 TI - Influence of autophagy on the genesis and development of atherosclerosis and its risk factors. AB - Autophagy is a highly conservative process of degeneration during which intracellular components including soluble macromolecules (e. g., nucleic acids, proteins, carbohydrates and lipids) and dysfunctional organelles (e. g., mitochondria, peroxisomes, and the endoplasmatic reticulum) are degraded by a lysosome. Autophagy serves as a dynamic system of recycling proving cells with energy and building components. Because of it in cells of an organism new proteins and membranes can form contributing to survival of the individual under starvation conditions. Autophagy plays an important role in the genesis and development of multifactorial pathogenesis including atherosclerosis and its risk factors. The present article examines both a pathogenic and protective role of autophagy in such pathological processes. The article can be useful to molecular biologists and biochemists, as well as to professionals involved in the problems of atherosclerosis and cardiovascular diseases. PMID- 29240052 TI - [Assessment of endothelial dysfunction for prevention of complications in patients with lesions of peripheral arteries]. AB - BACKGROUND: Severity of endothelial dysfunction and impairments of the vasomotor function of arteries correlate with the degree of the development of atherosclerosis and the risk of cardiovascular complications. To date, poorly studied still remains the problem concerning alteration of the regulatory function of the endothelium in patients diagnosed with pronounced atherosclerotic lesions of peripheral arteries, as well as the impact of a surgical intervention on indices of endothelial dysfunction. PATIENTS AND METHODS: Presented in the article are the results of preoperative study of the endothelial function by means of peripheral arterial tonometry (PAT) using the Endo PATTM 2000 device (Itamar Medical Ltd.) in a total of 74 patients undergoing surgical treatment at the Institute of Surgery named after A.V. Vishnevsky. The male-to-female ratio in the studied group was 1:2.52, with the patients' average age amounting to 67?}8 years. Of the 74 patients, 21 were subjected to a repeat examination performed at terms varying from 2 to 23 months postoperatively. Of these, 17 (80.95%) patients took statins. Fourteen (66.7%) patients had endured an operative intervention on carotid arteries and seven (33.3%) had been operated on for lesions of lower-limb arteries. RESULTS: The statistical analysis of the obtained findings revealed no significant differences of the indices of the endothelial function in the studied group between the genders, depending on age, smoking or taking statins. Neither were there statistically significant differences in the reactive hyperaemia index (RHI) amongst the patients with the involvement of one or several arterial basins. We did not reveal a direct relationship or regularity of the effect of a surgical intervention on the RHI values in the operated patients. This might be explained by the fact that the method of PAT to a greater degree assesses the state of the microvascular bed rather than that of large arteries. PMID- 29240053 TI - [Method of preventive ultrasound diagnosis of venous thrombosis]. AB - AIM: The purpose of the study was to work out a method of preventive diagnosis of venous thromboses by means of ultrasonographic duplex scanning (USDS). PATIENTS AND METHODS: A total of 306 people were examined. Of these, 146 patients presented with acute venous thrombosis, 108 subjects suffered from varicose veins, and 52 were apparently healthy people composing the control group. All those enrolled into the study were examined by means of USDS, with the D-dimer level determined. RESULTS: The obtained findings made it possible to discover and duly describe an ultrasonographic phenomenon of the presence of echo-positive inclusions in the zone of valvular sinuses, which was called the phenomenon of spontaneous echo contrast (SEC). This was followed by working out a classification of this phenomenon, describing two degrees thereof. Degree 1 SEC reflects the fact that the area of valvular sinuses is the most thrombogenic zone. Degree 2 SEC is characterised as a pathological, being simultaneously pre thrombotic, condition and may serve as one of the earliest predictors of the development of venous thrombosis. A close correlation was established between the degree 2 SEC phenomenon, the presence of venous thrombosis and the values of the D-dimer level (r=0.89, p<0.01). CONCLUSION: Ultrasonographic examination of valvular sinuses is a simple, readily available and reproducible method of screening and may thus be used for preventive diagnosis of acute venous thromboses. The findings of this study make it possible to form risk groups by the development of deep vein thrombosis, as well as to initiate timely measures on prevention of the pathology concerned. PMID- 29240054 TI - [Endovascular interventions in treatment of patients with acute impairment of mesenteric blood circulation]. AB - The authors share herein their experience of treating a total of eight patients with acute impairment of mesenteric blood circulation, describing both technical and instrumental peculiarities of interventions on the superior mesenteric artery. Technical success defined as restoration of the main blood flow through the superior mesenteric artery was achieved in seven (87.5%) patients. Of these, two (25%) patients required laparotomy and intestinal resection, with the scope of resection being significantly reduced in one case after endovascular thrombectomy. A further two (25%) patients developed respiratory distress syndrome as a complication of reperfusion syndrome. There were two (25%) lethal outcomes. A conclusion was drawn that endovascular interventions might be regarded as an independent method of treatment of patients presenting with acute impairment of the mesenteric blood flow in the stage of intestinal ischaemia. Besides, this technique makes it possible in case of the development of intestinal gangrene to dramatically diminish the scope of intestinal necrotic lesion. PMID- 29240055 TI - [Endovascular treatment of acute mesenteric ischaemia in thrombosis of superior mesenteric artery]. AB - The article deals with the problems related to acute impairment of mesenteric blood circulation, known as a nosological entity associated with an extremely high mortality rate. The authors point out that there are currently no common approaches to appropriate management of the pathology concerned and define the role of modern minimally invasive methods, which roentgenosurgical interventions belong to, making it possible to rapidly, safely and efficiently cope with the problem of thrombosis of mesenteric vessels, as well as to decrease lethality and improve the prognosis in this cohort of patients. Also presented herein is a detailed description of a clinical case report regarding successful endovascular treatment of a patient suffering from acute thrombosis of the superior mesenteric artery. This is followed by assessing efficacy and safety of the method employed, and, finally, suggesting tactical solutions in treatment of patients presenting with acute pathology of mesenteric vessels. PMID- 29240056 TI - [Hybrid intervention for a multilevel aneurysmatic lesion of the aorta in a patient with multifocal atherosclerosis]. AB - A multilevel aneurysmatic lesion of the aorta is a rare pathology. The authors describe herein a clinical case report regarding stage-wise treatment of a patient presenting with aneurysms of the thoracic and abdominal portions of the aorta and a haemodynamically significant lesion of coronary and carotid arteries. Strategy of surgical management was decided upon collegially. Successful endoprosthetic repair of the aneurysm of the thoracic portion of the aorta required closure of the left carotid artery with a graft, which, taking into consideration an existing occlusion of the right internal carotid artery, demanded preliminary carotid-subclavian bypass grafting. The clinical course of progressing angina pectoris (75% stenosis of the anterior descending artery with a poststenotic aneurysm) also increased the risk of the surgical stage. The authors provide a detailed description of the planning procedure, stages, and technical aspects of the operations performed. No complications were encountered. The duration of the follow up period amounted to 15 months. There was regression of the symptomatic manifestations, accompanied and followed by complete thrombosis of the aneurysmatic zones stented. A hybrid approach demonstrated efficacy and safety in staged treatment of complicated combined pathology of the aorta and its branches. PMID- 29240057 TI - [Experience with using cyanoacrylate glue in endovascular treatment of varicose veins]. AB - The method of cyanoacrylate-mediated obliteration of subcutaneous veins is known to be an alternative to thermal endovascular obliteration and eliminates the need for tumescent anaesthesia. This technique is based on glue-induced damage to the venous intima, followed by immune response according to the delayed-type hypersensitivity principle. The authors report herein their first experience with using cyanoacrylate-mediated embolization in treatment of patients presenting with varicose veins. The operation was carried out using the VenaSeal closure system (Medtronic). Under ultrasonographic guidance, we performed cyanoacrylate mediated obliteration of the trunk of the great saphenous vein, without tumescence. The procedure turned out to be well tolerated, with no pain in the zone of cyanoacrylate obliteration reported by the patients in the postoperative period. By means of ultrasonographic control carried out within 1-month of follow up we assessed obliteration of the vein, with the diameter of the obliterated portion amounting to 0.3-0.4 cm. No phlebitis, allergic reactions, nor evidence of deep vein thrombosis were observed. We also performed a morphological study of the removed suprafascial segment of the vein, containing the cyanoacrylate adhesive. The obtained findings demonstrated detachment and destruction of the intima, swelling and loosening of the media, as well active degranulation of mast cells, thus making it possible to suppose the presence of toxic damage to the venous wall induced by cyanoacrylate glue. Hence, the experience thus gained appears to be unequivocally suggestive of remarkable simplicity of performing cyanoacrylate-mediated embolization whose indisputable advantages include the painless nature of the procedure and no need for tumescent anaesthesia. In order to assess efficacy and safety of this technique, further studies are required. PMID- 29240058 TI - [Venous thromboembolic complications in patients with cardiovascular implantable electronic devices]. AB - The problem of venous thromboembolic complications (VTECs) in patients with cardiovascular implantable electronic devices (CIEDs) is extremely important today because of an annually increasing number of surgical interventions for life threatening arrhythmias and chronic heart failure. There are hitherto no clearly defined reliable risk factors for VTECs due to heterogeneity of the available literature data. Some sources point to elevated thrombus formation in patients with a large number of electrodes, in repeat operative interventions, in the presence of a temporary pacemaker, in implantation on the left side, silicon cover of an electrode, others refute these facts. Still undetermined remains the choice of antithrombotic therapy for prevention and treatment of VTECs in this cohort of patients. Implantation of a VTEC may be accompanied by thrombosis of deep veins of the upper extremities up to the development of total occlusion of veins. In rare cases, thrombosis extends proximally, there appears superior vena cava syndrome which may require surgical treatment. Diagnosis of these diseases is complicated by their symptom-free course in the majority of cases. The most dangerous VTEC is pulmonary thromboembolism very commonly not accompanied by clinical symptomatology or taking its course under the mask of other more frequent diseases. Despite the fact that pulmonary thromboembolism with a source in the system of the superior vena cava is rarely massive, it may lead to the development of chronic postembolic pulmonary hypertension and to decreased quality of life. The article contains a review of the present-day literature and a clinical case report concerning the development of VTECs in a patient with a CIED in the form of thrombosis of the right internal jugular, subclavian and brachiocephalic veins, pulmonary embolism of small branches of the right pulmonary artery, suppuration of the pacemaker's bed and sepsis. Therapy with antibiotics, low-molecular-weight heparins, antiplatelet drugs and anti inflammatory agents with regular sanitation of the pacemaker's bed turned out effective. PMID- 29240059 TI - [Vein morphology after endovenous laser coagulation at different power and similar linear density of energy]. AB - The purpose of the study was to assess the depth of damage to the venous wall after endovenous laser coagulation (EVLC) at different power of the unit - 5, 7 and 10 W and similar linear density of energy (LDE) - approximately 70 J/cm. Our prospective comparative morphological study with blinding included a total of 30 patients subjected to EVLC of the great saphenous vein using the unit with a wavelength of 1,470 nm and radial light guides with automatic traction. The patients were divided into three groups, each comprising 10 patients. The unit's power (W) during EVLC and velocity of light guide traction (mm/s) in group one amounted to 5 and 0.7 (LDE - 71.4 J/cm), in group two to 7 and 1.0 (LDE - 70 J/cm) and in group tree to 10 and 1.5 (LDE - 66.7 J/cm), respectively. The coagulated veins were then procured from mini approaches and subjected to three sections made at a distance of 2 mm from each other. Specimens were stained with haematoxylin-eosin and picrofuxin according to the van Gieson technique. Then, in four places of each section (at 3, 6, 9 and 12 hours) we assessed the depth of the damage to the venous wall and calculated the average percentage of alteration - the ratio of the depth of the lesion to the venous wall thickness. The average depth of damage to the venous wall (MUm) amounted in the first group to 122.9 ?m, in the second group to 182.9 MUm, and in the third group to 267 MUmm. The index of alteration (%) averagely amounted: in group one to 25.7, in group two to 37.9 and in group three (at a power of 10 W) to 55.5 (p=0.0001 when comparing each of the groups (the Kruskal-Wallis test)). Hence, despite an inconsiderable decrease of the LDE from the first to the third group, as power increased, the depth and percentage of damage to venous walls increased statistically significantly. It follows from the above-mentioned that: 1) an increase in power (from 5 to 10 W) of the unit during EVLC at comparable LDE (approximately 70 J/cm) leads to a deeper damage of the venous wall; 2) it is necessary to carry out a clinical study aimed at comparing different modes of coagulation, with the assessment of the frequency of recanalization and the level of pain syndrome. PMID- 29240060 TI - [Conservative treatment of chronic diseases of lower limb veins: major risks of poor patient compliance]. AB - Presented herein are the results of the Russian part of the International Research Programme 'VEIN ACT' aimed at studying approaches to conservative treatment of chronic vein diseases in the Russian Federation, assessing its efficacy and safety, as well as monitoring the patient compliance. Also discussed are the regimen and results of conservative therapy, depending on patients' gender, age and body mass index, as well as the level of adherence to various methods of treatment in the cohorts concerned. High efficacy of conservative therapy in all patients was confirmed. However, the regimen of drug therapy needs to be adjusted depending on the disease severity, especially in patients of a more advanced age and those with obesity. The lowest patient compliance was observed in relation to compression treatment. The existing situation may be improved by be means of appropriate recommendations and a possible decrease of the level and degree of compression. This should of course be done carefully and attentively, with obligatorily taking into consideration the patients' age and body mass index. PMID- 29240061 TI - [Hybrid treatment of patients with aneurysms and dissections of the aortic arch and descending portion of the thoracic aorta]. AB - The authors share herein their experience with hybrid surgical treatment of 21 patients presenting with lesions of the aortic arch and descending thoracic aorta. Aortic pathology included dissection of the thoracoabdominal aorta (n=15), a sacciform aneurysm of the aortic arch (n=5), and a spindle-shaped aneurysm of the distal portions of the aortic arch (n=1). The first stage consisted of the following operations: transposition of the left subclavian artery into the left common carotid artery (n=9; 42.8%), partial debranching (n=11; 52.5%), and total debranching (n=1; 4.7%). The second stage consisted in implantation of a stent graft: to the thoracic aorta in 18 (85.8%) cases, and to the thoracic and abdominal portions of the aorta in 3 (14.2%) cases. The most significant complications of the immediate postoperative period included acute cerebral circulation impairment (n=1) and local dissection of the ascending aorta (n=1). Type I endoleaks were observed in 4 (19%) patients, type II endoleaks in 1 (4.7%), and type III endoleaks in 1 (4.7%). The mean duration of the follow up after discharge from hospital amounted to 11.6+/-7.9 months. In 4 patients after 6 months the findings of the control MSCT angiography showed no significant changes of the endoleaks. 1-year patency of the shunted branches of the aortic arch amounted to 95.2%. The cumulative survival rate amounted to 95.2%. PMID- 29240062 TI - [Carotid revascularization in type 2 diabetes mellitus. Significance of chronic hyperglycaemia]. AB - Patients with type 2 diabetes mellitus (type 2 DM) are typically prone to the development of cerebral atherosclerosis. Presented herein are the results of examination of patients suffering from ischaemic cerebrovascular diseases on the background of type 2 DM subjected to open surgical or endovascular interventions. In patients with cerebrovascular pathology and type 2 DM, atherosclerosis progresses on the background of chronic hyperglycaemia combined with dyslipidaemia, leading to increased incidence of the development of cerebral circulatory impairments and detection of the indications for carrying out angioreconstructive operations on the internal carotid arteries. The presence of type 2 DM is associated with increased risk for the development of ischaemic lesions of the brain matter while performing carotid endarterectomy and endovascular interventions which are associated with higher values of glycaemia (8.0 mmol/l) and glycated haemoglobin (7.8-8 %) prior to the operation. PMID- 29240063 TI - [Simultaneous operation in a patient with stenosis of the extracranial portion and an intracranial aneurysm of the internal carotid artery]. AB - Presented herein is a clinical case report concerning surgical treatment of a patient with a rare combination of two pathologies, i. e., a haemodynamically significant stenosis of the extracranial portion and a sacciform aneurysm of the communicative portion of the right internal carotid artery on the background of multifocal atherosclerosis. The patient underwent a simultaneous operation consisting in clipping of the sacciform arterial aneurysm of the communicative portion of the right internal carotid artery and carotid endarterectomy on the right. The chosen surgical policy ensured effective prevention of the development of ischaemic stroke and rupture of the arterial aneurysm, whose risks would have been high in staged treatment and sequentially performing two operations. PMID- 29240064 TI - [Aneurysmal lesions of the extracranial segment of the internal carotid artery]. AB - The article contains a review of the literature devoted to the state-of-the-art data concerning management of patients presenting with an aneurysmal lesion of the extracranial segment of the internal carotid artery. This is followed by describing two clinical case reports regarding aneurysms of the extracranial segment of the internal carotid artery and the outcomes of endovascular treatment. PMID- 29240065 TI - [Secondary reconstructions after endovascular treatment of a woman with critical lower limb ischaemia]. AB - Primary endovascular interventions carried out according to the indications determined by the TASC II guidelines have proved successful in treatment of patients presenting with critical lower limb ischaemia. However, performing secondary and complicated reconstructions requires an individual approach with the assessment of all possible risks involved. Presented herein is a clinical case report regarding repeat reconstruction in a woman with critical lower limb ischaemia after a previously performed endovascular intervention. PMID- 29240066 TI - Peculiarities of vitalization of grafts made of porous polytetrafluoroethylene in reconstruction of major veins (an experimental study). AB - Increased incidence of locally disseminated malignant neoplasms with invasion of major veins compels modern surgery to search for an optimal material for reconstruction of major veins. Presented herein are the results of an experimental study aimed at exploring patency and peculiarities of vitalization of grafts made of porous polytetrafluoroethylene (7th generation, 2010) manufactured by the Closed Joint Stock Company 'Research and Production Complex 'Ecoflon' (St. Petersburg, Russia) with an internal diameter measuring 4.0 mm and used for reconstruction of major veins and arteries with a follow up period up to 270 days. Vitalization of porous polytetrafluoroethylene grafts in the venous position is comparable to that in the arterial position, having similar patterns. Both in the arterial and venous position, vitalization of the graft proceeds at the expense of 'crawling' of the neointima from the anastomoses to the centre of the graft. To distinctive peculiarities of vitalization of grafts in the venous position belong statistically significantly larger thickness of the neointima in the venous position at all stages of the study, lack of statistically significant difference of the neointimal thickness near the edges and in the central part of the graft in the venous position at 270 days. Neither thromboses nor haemodynamically meaningful stenoses of the porous polytetrafluoroethylene grafts and anastomoses in the venous position, despite low velocity of blood flow and its laminar pattern, were observed at any terms of follow up. The obtained findings are indicative of the possibility and validity of using porous polytetrafluoroethylene grafts for reconstruction of major veins in clinical practice. PMID- 29240067 TI - [Myocardial protection during left-ventricular reconstruction in patients with an ejection fraction below 30]. AB - Surgical reconstruction of the left ventricle is an effective method of treatment for ischaemic cardiomyopathy. One of the conditions of successful intervention is correctly choosing a method of intraoperative myocardial protection. Currently, two techniques of myocardial protection are used: cardioplegic cardiac arrest and continuous myocardial perfusion on the beating heart. A series of experimental studies demonstrated that myocardial oxygen requirements in ischaemic cardiomyopathy during permanent perfusion are three times higher than during cardioplegic cardiac arrest. However, the technique of continuous myocardial perfusion in conditions of the beating heart makes it possible to prevent ischaemia of the most sensitive subendocardial layers of the myocardium. In order to determine optimal strategy of myocardial protection during surgical reconstruction of the left ventricle we retrospectively assessed therapeutic outcomes in a total of 136 patients presenting with ischaemic cardiomyopathy, an ejection fraction below 30%, and an end-systolic volume index of more than 100 ml/m2. The patients were divided into two groups: group 1 (n=44) subjected to reconstruction of the left ventricle performed on the beating heart and group 2 (n=92) undergoing surgery in conditions of cardioplegic cardiac arrest. We examined early and medium-term clinical and echocardiographic results (30-day mortality, postoperative complications, medium-term survival, and probability of the development of major adverse cardiac and cerebrovascular events (MACCE)). It was determined that short- and medium-term clinical and echocardiographic results of surgical reconstruction of the left ventricle in patients with an ejection fraction less than 30% do not depend on the method of myocardial protection (continuous myocardial perfusion in conditions of the beating heart or crystalloid cardioplegia). PMID- 29240068 TI - [Treatment of a woman with phlegmasia cerulea dolens complicated by massive pulmonary thromboembolism and intestinal haemorrhage]. AB - Acute thrombosis of the lower limb deep veins remains one of the most common vascular diseases. It is characterised by formation of thrombotic masses in the system of the deep veins of the lower extremities. A serious complication associated with deep vein thrombosis is pulmonary embolism. In rare cases, under certain conditions a massive and disseminated blockade of the venous outflow with thrombotic masses may lead to ischaemia of the extremity with the formation of superficial and deep necroses and later on to gangrene. One of the main components of management is long-term administration of anticoagulants, which in a series of cases may result in the development of gastrointestinal haemorrhage which in its turn requires discontinuation of anticoagulants. Described herein is a clinical case report concerning treatment of a woman presenting with deep vein thrombosis and the development of phlegmasia cerulean dolens complicated by massive pulmonary artery thromboembolism on the background of intestinal bleeding. PMID- 29240069 TI - [Urapidil as a drug of choice for decreasing arterial pressure in surgical practice]. AB - Arterial hypertension as a complication of the perioperative period is encountered in 6-20% of patients undergoing general surgical interventions. This article provides a detailed discussion of epidemiology and pathophysiological aspects of arterial hypertension in surgical patients, as well as physiology and the classification of the receptor complex participating in regulation of arterial pressure. Special attention is paid to clinical trials dedicated to using Urapidil (Ebrantil(r)) which belongs to the group of alpha1-adrenoblockers. PMID- 29240070 TI - [Method of forming a distal anastomosis with an autovenous cuff]. AB - Presented herein is a brief review of the world literature dedicated to methods of formation of composite arterial anastomoses in the femoropopliteal-tibial region The most justified is considered the use of a composite shunt formed proximally from a synthetic vascular graft made of polytetrafluoroethylene and distally with an extension from a portion of the suitable for reconstruction autovein (the so-called autovenous cuff of patch). The use of an autovenous cuff is more physiological since it provides closer correspondence of the diameters of the distal anastomosis being applied between the artery and autovenous extension, as well as contributes to creation of more adequate haemodynamic conditions in the shunt. Also analysed is the technique of performing the previously suggested anastomoses, demonstrating their main disadvantages. This is followed by describing a new original method of formation of a distal anastomosis using an autovenous insert, showing its advantages, with the main amongst them being the presence of only two vascular sutures and a decrease in the possibility of the onset and development of turbulence in the zone of the anastomosis. A conclusion is drawn that the suggested method contributes to decreasing the duration of the main stage of the operation, decreases the probability of technical defects and reduces the risk for the development of postoperative complications associated with impairments of the processes of haemodynamics in the zone of the anastomosis formed. PMID- 29240071 TI - [Remote results of open surgical and endovascular treatment of internal carotid artery stenoses]. AB - The article is a review containing a comparative analysis of the remote results in patients presenting with carotid artery atherosclerosis and treated by means of either stenting or carotid endarterectomy. More than ten international randomized studies have up to now been conducted. Some of them prove the advantage of using either carotid endarterectomy or stenting of carotid arteries, others show equivalence of both methods of treatment. Carotid endarterectomy is currently a preferred operation for carotid artery stenoses, with lower incidence of the development of postoperative strokes and restenoses in the remote period. But stenting is an alternative technique in patients with high operative risk. Therefore, the question of choosing an appropriate type of the intervention should be decided upon for each patient individually. A more definite conclusion to be made on advantages of carotid endarterectomy over endovascular angioplasty, or vice versa, requires further studying therapeutic outcomes during a longer follow-up period. PMID- 29240072 TI - [Varicose veins of small pelvis as a cause of vulvar varicosity and varicose veins of lower extremities]. AB - The article is a literature review presenting modern data on applied anatomy of the pelvic veins, diagnosis and treatment of pelvic varicose veins, pelviperineal reflux and vulvar varicosity, lower limb varicose veins, which were caused by pathological reflux from varicose pelvic veins. Presented is the information on tactical approaches in treatment of combined varicose veins of the pelvis and lower limbs, surgical decision-making for correction of pelviperineal reflux, methods of operative and phlebosclerosing interventions on pelvic and superficial veins of the perineum and lower limbs. PMID- 29240073 TI - [On the problem of lumbar sympathectomy]. PMID- 29240074 TI - BET bromodomain inhibitors synergize with ATR inhibitors in melanoma. AB - This corrects the article DOI: 10.1038/cddis.2017.383. PMID- 29240075 TI - A systematic analysis of online marketing materials used by providers of expanded carrier screening. AB - PURPOSE: Expanded carrier screening (ECS) for a large number of recessive disorders is available to prospective parents through commercial providers. This study aimed to analyze the content of marketing materials on ECS providers' websites. METHODS: To identify providers of ECS tests, we undertook a comprehensive online search, reviewed recent academic literature on commercial carrier screening, and consulted with colleagues familiar with the current ECS landscape. The identified websites were archived in April 2017, and inductive content analysis was performed on website text, brochures and educational materials, and video transcripts. RESULTS: We identified 18 ECS providers, including 16 commercial genetic testing companies. Providers typically described ECS as an important family planning tool. The content differed in both the tone used to promote ECS and the accuracy and completeness of the test information provided. We found that most providers offered complimentary genetic counseling to their consumers, although this was often optional, limited to the posttest context, and, in some cases, appeared to be available only to test-positive individuals. CONCLUSION: The quality of ECS providers' websites could be improved by offering more complete and accurate information about ECS and their tests. Providers should also ensure that all carrier couples receive posttest genetic counseling to inform their subsequent reproductive decision making. PMID- 29240076 TI - From public health genomics to precision public health: a 20-year journey. AB - In this paper, we review the evolution of the field of public health genomics in the United States in the past two decades. Public health genomics focuses on effective and responsible translation of genomic science into population health benefits. We discuss the relationship of the field to the core public health functions and essential services, review its evidentiary foundation, and provide examples of current US public health priorities and applications. We cite examples of publications to illustrate how Genetics in Medicine reflected the evolution of the field. We also reflect on how public-health genomics is contributing to the emergence of "precision public health" with near-term opportunities offered by the US Precision Medicine (AllofUs) Initiative. PMID- 29240077 TI - Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a single-center experience. AB - PurposeTo describe the frequency and nature of differences in variant classifications between clinicians and genetic testing laboratories.MethodsRetrospective review of variants identified through genetic testing ordered in routine clinical care by clinicians in the Stanford Center for Inherited Cardiovascular Disease. We compared classifications made by clinicians, the testing laboratory, and other laboratories in ClinVar.ResultsOf 688 laboratory classifications, 124 (18%) differed from the clinicians' classifications. Most differences in classification would probably affect clinical care of the patient and/or family (83%, 103/124). The frequency of discordant classifications differed depending on the testing laboratory (P < 0.0001) and the testing laboratory's classification (P < 0.00001). For the majority (82/124, 66%) of discordant classifications, clinicians were more conservative (less likely to classify a variant pathogenic or likely pathogenic). The clinicians' classification was discordant with one or more submitter in ClinVar in 49.1% (28/57) of cases, while the testing laboratory's classification was discordant with a ClinVar submitter in 82.5% of cases (47/57, P = 0.0002).ConclusionThe clinical team disagreed with the laboratory's classification at a rate similar to that of reported disagreements between laboratories. Most of this discordance was clinically significant, with clinicians tending to be more conservative than laboratories in their classifications. PMID- 29240078 TI - ERRATUM: Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics. AB - This corrects the article DOI: 10.1038/gim.2017.84. PMID- 29240079 TI - Response to Metcalfe et al. PMID- 29240081 TI - Analytical expressions of the imaging and aberration coefficients of a general form surface. AB - A theoretical development is presented in this paper for describing and understanding the imaging and aberrations of a general form surface. The development is based on the Taylor expansion of an arbitrary ray trace from the object reference plane to the image reference plane, which is called the base mapping of the general form surface in this paper. The base mapping is expressed as two Taylor series of the object and pupil coordinates and the imaging and aberration coefficients in the third-order scope are derived and presented as analytical expressions relevant to the optic parameters, invoking no approximations. The situation with tilted object and observing plane is also considered, and the mapping from a tilted object to a tilted observing plane is derived via simple mathematical manipulations based on the base mapping. PMID- 29240080 TI - Reinterpretation of sequence variants: one diagnostic laboratory's experience, and the need for standard guidelines. AB - PurposeThe advent of next-generation sequencing resulted in substantial increases in the number of variants detected, interpreted, and reported by molecular genetics diagnostic laboratories. Recent publications have provided standards for the interpretation of sequence variants, but there are currently no standards regarding reinterpretation of these variants. Recognizing that significant changes in variant classification may occur over time, many genetics diagnostic laboratories have independently developed practices for variant reinterpretation. The purpose of this study is to describe our laboratory approach to variant reinterpretation.MethodsWe surveyed eight genetics diagnostic laboratories in Canada and the United States.ResultsEach laboratory had differing protocols, but most felt that clinically relevant changes to variant classifications should be communicated to ordering providers. Based on results of this survey and our experience, we developed a cost-effective and resource-efficient approach to variant reinterpretation.ConclusionOngoing variant reinterpretation is required to maintain the highest standards for delivering genetics laboratory services. Our approach to variant reinterpretation offers an efficient solution that does not compromise accuracy or timely delivery of genetics laboratory services. PMID- 29240082 TI - Study on the mathematical relationship existing between single-photon laser Doppler flowmetry and diffuse correlation spectroscopy with static background. AB - In the present contribution, the theoretical relationship existing between the blood flow index measured by diffuse correlation spectroscopy and single-photon laser-Doppler flowmetry (SP-LDF) is investigated. A specific mathematical description that accounts for the properties of single-photon detectors for SP LDP was developed. Static background has also been considered and, to the best of our knowledge, this has never been included before in SP-LDF analytical theories. The comparisons were realized for two SP-LDF implementations: for "classical" and "fast" algorithms. "Classical" SP-LDF is not sensitive to small changes on the number of detected speckles and coherence length of the laser, usually described by a unique parameter "beta." This is a strong point when assessing blood flow index, e.g., in humans, where "beta" is particularly difficult to be determined in real time. The proposed theory may be utilized, e.g., to investigate other SP LDF setups and optical/physiological parameter ranges or, generally, to optimize real SP-LDF instrumentation. PMID- 29240083 TI - Evolution properties of partially coherent standard and elegant Hermite-Gaussian beams in uniaxial crystals. AB - The propagation properties of a partially coherent elegant Hermite-Gaussian beam (EHGB) and a partially coherent standard Hermite-Gaussian beam (SHGB) in uniaxial crystals orthogonal to the optical axis are studied. The propagation expression for the cross-spectral density of the partially coherent EHGB and SHGB propagating in a uniaxial crystal is derived. With the help of the derived formula, some analyses are illustrated by numerical examples related to the evolution properties of the spectral density, the spectral degree of coherence, and the effective beam width of the partially coherent EHGB and SHGB in a uniaxial crystal. It is shown that propagation properties of the partially coherent EHGB and SHGB in an isotropic crystal are much different from the evolution properties in an anisotropic crystal. The evolution behavior of spectral density and the spectral degree of coherence depends on the parameters of the uniaxial crystals (the ratio of extraordinary and ordinary refractive indices), and beam parameters including the coherence length and the beam order, as well as the propagation distance. PMID- 29240084 TI - Theoretical modeling and design of photonic structures in zeolite nanocomposites for gas sensing. Part I: surface relief gratings. AB - The suitability of holographic structures fabricated in zeolite nanoparticle polymer composite materials for gas sensing applications has been investigated. Theoretical modeling of the sensor response (i.e., change in hologram readout due to a change in refractive index modulation or thickness as a result of gas adsorption) of different sensor designs was carried out using Raman-Nath theory and Kogelnik's coupled wave theory. The influence of a range of parameters on the sensor response of holographically recorded surface and volume photonic grating structures has been studied, namely the phase difference between the diffracted and probe beam introduced by the grating, grating geometry, thickness, spatial frequency, reconstruction wavelength, and zeolite nanoparticle refractive index. From this, the optimum fabrication conditions for both surface and volume holographic gas sensor designs have been identified. Here, in part I, results from theoretical modeling of the influence of design on the sensor response of holographically inscribed surface relief structures for gas sensing applications is reported. PMID- 29240085 TI - Far zone behavior of light waves on scattering from an arbitrary-orientated ellipsoidal random particle. AB - The behavior of light waves on scattering from an ellipsoidal quasi-homogeneous particle with arbitrary orientation is discussed within the accuracy of the first order Born approximation. It is shown that the orientation of a particle plays an important role for the spectral density and for the spectral degree of coherence of the scattered field. Numerical result shows that, when the ellipsoidal particle features rotational symmetry, the profile of the far zone distribution is governed by the polar angle of a particle's orientation, while the orientation of the far zone distribution is governed by the azimuthal angle of a particle's orientation. PMID- 29240086 TI - Scintillation and bit error rate analysis of a phase-locked partially coherent flat-topped array laser beam in oceanic turbulence. AB - In this paper, the performance of underwater wireless optical communication (UWOC) links, which is made up of the partially coherent flat-topped (PCFT) array laser beam, has been investigated in detail. Providing high power, array laser beams are employed to increase the range of UWOC links. For characterization of the effects of oceanic turbulence on the propagation behavior of the considered beam, using the extended Huygens-Fresnel principle, an analytical expression for cross-spectral density matrix elements and a semi-analytical one for fourth-order statistical moment have been derived. Then, based on these expressions, the on axis scintillation index of the mentioned beam propagating through weak oceanic turbulence has been calculated. Furthermore, in order to quantify the performance of the UWOC link, the average bit error rate (BER) has also been evaluated. The effects of some source factors and turbulent ocean parameters on the propagation behavior of the scintillation index and the BER have been studied in detail. The results of this investigation indicate that in comparison with the Gaussian array beam, when the source size of beamlets is larger than the first Fresnel zone, the PCFT array laser beam with the higher flatness order is found to have a lower scintillation index and hence lower BER. Specifically, in the sense of scintillation index reduction, using the PCFT array laser beams has a considerable benefit in comparison with the single PCFT or Gaussian laser beams and also Gaussian array beams. All the simulation results of this paper have been shown by graphs and they have been analyzed in detail. PMID- 29240087 TI - Simulation of Raman scattering including detector parameters and sampling volume. AB - Raman spectroscopy can be employed to measure the chemical composition of a sample, which can in turn be used to extract biological information. The aim of this paper is to introduce an efficient simulation technique for Raman spectroscopy in turbid (scattering) media taking into account relevant detector parameters and the sampling volume. We simulate the process of photon motion in turbid media by means of the Monte Carlo (MC) method. The numerical simulation of Raman scattering consists of two stages: calculation of the photon fluence at each point of the medium and subsequent generation of the corresponding amount of Raman photons at each point. The developed model allows simulation of both confocal and optical fiber probe Raman setups. In more detail, the model efficiently simulates Raman signals for different single and multi-layer phantoms and geometries, including focused and collimated (i.e., the fiber-based case) excitation laser beams as well as different values for the numerical aperture and the excitation beam radius. In the future, our results offer the potential to improve the design of Raman systems for in vivo applications in biomedical research. PMID- 29240088 TI - Contrast enhanced quarter-Talbot images. AB - In this paper a rigorous mathematical approach to the near-field diffraction of 1D periodic structures at quarter-Talbot distances is presented. At the beginning of the paper, we present a mathematical investigation on the behavior of periodic functions under squaring by the aid of Fourier analysis. We determine sufficient conditions for a periodic function in which its fundamental period is halved by squaring. We show that if Fourier expansion of a given periodic function includes only coefficients with odd indexes, and minimum difference of the indexes is 2, then its fundamental period halves by squaring. This result is clarified by considering some typical periodic functions. Based on the presented mathematical results, we explain the formation of halved-period sub-images at quarter-Talbot distances from the 1D periodic structures in the near-field diffraction. In this work, 1D periodic structures are categorized into two classes in terms of their Fourier expansion forms. We show that Fourier expansion of a given 1D periodic structure may include Fourier coefficients either with both even and odd indexes or only with odd indexes plus the DC term. For clarifying the matter, the near field diffractions from four sets of structures are considered, including parabolic and triangular gratings; sawtooth and Ronchi gratings; two- and three level binary gratings; and sin-sinusoidal and cos-sinusoidal gratings. It is shown that, for all of these sets, by excluding even-order Fourier coefficients from the Fourier expansions, except the DC term, the value of intensity contrasts decreases at quarter-Talbot distances. We show that, in addition to the consistency of the presented approach for analyzing quarter-Talbot images with the conventional fractional Talbot formulation, it also reveals new details on the subject. As a direct address to the potential applications of the work, we show that high-contrast sub-images of a binary grating can be produced at quarter Talbot distances only by choosing suitable opening numbers and that it can be used in various domains such as lithography. PMID- 29240089 TI - Fast actual-size vectorial simulation of concave diffraction gratings with structural randomness. AB - In this study, an actual-size concave grating with structural randomness is numerically analyzed. Numerical electromagnetic analyses that solve Maxwell's equations can provide rigorous diffracted fields including the polarization characteristics. However, because of high computational costs, actual-size gratings with no periodicity have seldom been analyzed. We apply the difference field boundary element method (DFBEM) for the analyses of actual-size concave gratings with 10,000 random blazed grooves. The DFBEM provides vectorial diffracted or scattered waves with very low computational resources. First, we estimate the accuracy of the computation results, and then we show some relations between the degree of randomness and the diffraction efficiency, including the polarization dependency. PMID- 29240090 TI - Generation of a dark spot beyond the diffraction limit with a radially polarized vortex beam. AB - We propose and demonstrate that a dark spot can be generated by a radially polarized beam with a first-order vortex after phase modulation by an optimal binary phase element. The distance between two mainlobe intensity peaks along the radial direction is 0.62lambda on the focal plane. The proposed system is easy to implement in practice and has low energy loss, since it uses phase-only modulation. Then, the fluorescent spot is calculated for stimulated emission depletion microscopy when a radially polarized beam works as the pump beam. The FWHM of the fluorescent spot can achieve 0.008lambda for a saturated case. This is much smaller than that achieved using a circular polarized vortex erase beam (0.0422lambda) or an azimuthally polarized erase beam with optimizing amplitude phase modulation (0.0279lambda). PMID- 29240091 TI - Hyperspectral image compression approaches: opportunities, challenges, and future directions: discussion. AB - This paper establishes a review of the recent study in the field of hyperspectral (HS) image compression approaches. Recently, image compression techniques have achieved significant advances from diverse types of coding standards/approaches. HS image compression requires an unconventional coding technique because of its unique, multiple-dimensional structure. The data redundancy exists in both inter band and intra-band methods. The survey summarizes current literature in inter- and intra-band compression methods. The challenges, opportunities, and future research possibilities regarding HS image compression are further discussed. The experimental results are also provided for validity and applicability of the existing HS image compression techniques. PMID- 29240092 TI - Light scattering by periodic rough surfaces: equivalent jump conditions. AB - We present an interface model based on two-scale homogenization to predict the coherent scattering of light by a periodic rough interface between air and a dielectric. Contrary to previous approaches where the roughnesses are replaced by a layer filled with an equivalent medium, our modeling yields effective jump conditions applying across the region containing the roughnesses. The validity of the model is inspected by comparison with direct numerics and with experimental measurements on an air/silicium rough interface near the Brewster angle. It is shown that the interface model reproduces accurately the shift in the Brewster phenomenon without any adjustable parameter, which is of practical importance in retrieval methods to get thickness or filling fraction with reliable physical values. PMID- 29240093 TI - Monte Carlo method to model optical coherence propagation in random media. AB - The traditional Monte Carlo technique of photon transport in random media describes only single point properties of light, such as its intensity. Here we demonstrate an approach that extends these capabilities to simulations involving properties of spatial coherence, a two-point characteristic of light. Numerical experiments illustrate the use of this Monte Carlo technique for describing the propagation of partially spatially coherent light through random multiply scattering media. PMID- 29240095 TI - Application of derivative matrices of skew rays to direct and inverse problems of Risley and tilting orthogonal double-prism systems. AB - Risley systems and tilting orthogonal double-prism systems are optical systems consisting of two prisms in series. The analysis of such systems typically involves both direct and inverse problems. Problems of the former type can be easily solved using ray-tracing equations. However, inverse problems are comparatively more difficult if the search direction is not properly given prior to iteration. In the present study, the two optical systems are modeled using the homogeneous coordinate notation. A method is then proposed for solving the direct and inverse problems of both optical systems using a ray-tracing approach and the first- and second-order derivative matrices of the skew rays. In addition, four optimization methods based on the two derivative matrices are proposed for determining the search direction in the inverse problem. Eight illustrative examples are given. It is shown that the proposed method can not only determine the scan patterns and sensitivity coefficients in the direct problem, but also determine the search direction in the inverse problem. PMID- 29240094 TI - Improvement in error propagation in the Shack-Hartmann-type zonal wavefront sensors. AB - Estimation of the wavefront from measured slope values is an essential step in a Shack-Hartmann-type wavefront sensor. Using an appropriate estimation algorithm, these measured slopes are converted into wavefront phase values. Hence, accuracy in wavefront estimation lies in proper interpretation of these measured slope values using the chosen estimation algorithm. There are two important sources of errors associated with the wavefront estimation process, namely, the slope measurement error and the algorithm discretization error. The former type is due to the noise in the slope measurements or to the detector centroiding error, and the latter is a consequence of solving equations of a basic estimation algorithm adopted onto a discrete geometry. These errors deserve particular attention, because they decide the preference of a specific estimation algorithm for wavefront estimation. In this paper, we investigate these two important sources of errors associated with the wavefront estimation algorithms of Shack-Hartmann type wavefront sensors. We consider the widely used Southwell algorithm and the recently proposed Pathak-Boruah algorithm [J. Opt.16, 055403 (2014)JOOPDB0150 536X10.1088/2040-8978/16/5/055403] and perform a comparative study between the two. We find that the latter algorithm is inherently superior to the Southwell algorithm in terms of the error propagation performance. We also conduct experiments that further establish the correctness of the comparative study between the said two estimation algorithms. PMID- 29240096 TI - Spatial coherence of fields from generalized sources in the Fresnel regime. AB - Analytic expressions of the spatial coherence of partially coherent fields propagating in the Fresnel regime in all but the simplest of scenarios are largely lacking, and calculation of the Fresnel transform typically entails tedious numerical integration. Here, we provide a closed-form approximation formula for the case of a generalized source obtained by modulating the field produced by a Gauss-Shell source model with a piecewise constant transmission function, which may be used to model the field's interaction with objects and apertures. The formula characterizes the coherence function in terms of the coherence of the Gauss-Schell beam propagated in free space and a multiplicative term capturing the interaction with the transmission function. This approximation holds in the regime where the intensity width of the beam is much larger than the coherence width under mild assumptions on the modulating transmission function. The formula derived for generalized sources lays the foundation for the study of the inverse problem of scene reconstruction from coherence measurements. PMID- 29240097 TI - Analytical and graphical ray-tracing techniques based on a classical principle for photon refraction. AB - In this work, a new classical principle that can explain the refraction of a single photon path at the boundary between two different media is proposed. This principle leads to the two well-known laws of refraction and also to a simple linear form of Snell's law. This linear form not only played a vital role in simplifying the mathematics of analytical ray tracing, but also led to a unified common form for the meridional ray-tracing formulas. Also, it works as a basic rule for a new graphical ray-tracing technique. In a previous work [J. Opt. Soc. Am. A.34, 335 (2017)JOAOD60740-323210.1364/JOSAA.34.000335], new exact ray tracing formulas were derived. All of these formulas are rewritten, in the current work, in terms of that linear form of Snell's law that revealed their common mathematical form. The meridional exact formula of a thick lens is generalized to include a whole system of spherical surfaces. From the latter, all the other exact ray-tracing formulas can be easily derived. As an application, a single exact meridional formula for a ball lens and a formula for its longitudinal spherical aberration are derived. Also, we present a new ray-tracing procedure for skew rays propagating through a system of spherical surfaces that can be centered, decentered, and/or tilted without the need to determine the point of incidence or the normal to the surface. Finally, and also based on that linear form of Snell's law, a new graphical ray-tracing technique that is simpler than the classical one is presented. PMID- 29240098 TI - Reduced-basis boundary element method for fast electromagnetic field computation. AB - In this work, we combine conventional boundary element method (BEM) with the reduced-basis method (RBM) and propose a reduced-basis boundary element method (RB-BEM) to realize efficient modeling for parameterized electromagnetic scattering problems of dielectric scatterers. The RB-BEM allows for splitting the modeling process into a parameter-independent offline part and parameter dependent online part, and replacing the high-dimensional original model obtained by conventional BEM with a low-dimensional reduced-basis model to improve computational efficiency of the online part. We also propose an improved greedy algorithm based on multi-grid to improve the computational efficiency of the offline part. The numerical experiments indicate that the efficiency of the improved greedy algorithm is several times higher than that of the standard one, and the solving efficiency of the reduced-basis model is several times to dozens of times higher than that of the original model with a prescribed approximation accuracy. PMID- 29240099 TI - Two years of tutorials: editorial. AB - Editor-in-Chief P. Scott Carney gives an update on JOSA A tutorials. PMID- 29240100 TI - Herpin effective media resonant underlayers and resonant overlayer designs for ultra-high NA interference lithography. AB - Dielectric waveguide resonant underlayers are employed in ultra-high NA interference photolithography to effectively double the depth of field. Generally a single high refractive index waveguiding layer is employed. Here multilayer Herpin effective medium methods are explored to develop equivalent multilayer waveguiding layers. Herpin equivalent resonant underlayers are shown to be suitable replacements provided at least one layer within the Herpin trilayer supports propagating fields. In addition, a method of increasing the intensity incident upon the photoresist using resonant overlayers is also developed. This method is shown to greatly enhance the intensity within the photoresist making the use of thicker, safer, non-absorbing, low refractive index matching liquids potentially suitable for large-scale applications. PMID- 29240101 TI - Vector polynomials for direct analysis of circular wavefront slope data: erratum. AB - We provide a correction to Eq. (4) in J. Opt. Soc. Am. A34, 1908 (2017)JOAOD60740 323210.1364/JOSAA.34.001908. PMID- 29240102 TI - On the "unreasonable" effectiveness of transport of intensity imaging and optical deconvolution. AB - The effectiveness of reconstructive imaging using the homogeneous transport of intensity equation may be regarded as "unreasonable," because it has been shown to significantly increase signal-to-noise ratio while preserving spatial resolution, compared to equivalent conventional absorption-based imaging techniques at the same photon fluence. We reconcile this surprising behavior by analyzing the propagation of noise in typical in-line holography experiments. This analysis indicates that novel imaging techniques may be designed that produce high signal-to-noise images at low radiation doses without sacrificing spatial resolution. PMID- 29240103 TI - Polarization properties of Ince-Gaussian laser beams. AB - A consistent theoretical description of the polarization properties of Ince-Gauss (IG) laser beams is provided by constructing paraxial IG solutions to Maxwell equations. We confirm this description experimentally by recording both the dominant and cross-polarization components. Moreover, by experimentally confirming the evolution of the dominant and cross-polarization components as functions of ellipticity parameters, our paper extends further support to a unified treatment of the three (Laguerre-Gauss, Hermite-Gauss, and IG) families of paraxial laser beams. PMID- 29240104 TI - Validity of the Kirchhoff approximation for the scattering of electromagnetic waves from dielectric, doubly periodic surfaces. AB - Accuracy of Kirchhoff approximation (KA) for rough-surface electromagnetic wave scattering is studied by comparison with accurate numerical solutions in the context of three-dimensional dielectric surfaces. The Kirchhoff tangent plane approximation is examined without resorting to the principle of stationary phase. In particular, it is shown that this additional assumption leads to zero cross polarized backscattered power, but not the tangent plane approximation itself. Extensive numerical results in the case of a bisinusoidal surface are presented for a wide range of problem parameters: height-to-period, wavelength, incidence angles, and dielectric constants. In particular, this paper shows that the range of validity inherent in the KA includes surfaces whose curvature is not only much smaller, but also comparable to the incident wavelength, with errors smaller than 5% in total reflectivity, thus presenting a detailed and reliable source for the validity of the KA in a three-dimensional fully polarimetric formulation. PMID- 29240105 TI - Sensitivity enhancement of a conventional gold grating assisted surface plasmon resonance sensor by using a bimetallic configuration. AB - A surface plasmon resonance (SPR)-based refractive index sensor using a silver grating fabricated over the gold film is proposed. The performance of the sensor has been evaluated on the basis of sensitivity, full width half maximum (FWHM), and dip strength of the reflection spectrum. Rigorous coupled wave analysis has been utilized to study the effect of grating parameters on sensing performance. Our systematic analysis exhibits that inappropriate grating parameters may lead to poor performance of the sensor. Sensitivity of the conventional gold grating (grating engraved in gold) assisted SPR sensor is obtained to be 321 degrees /RIU. Further, we have shown that sensitivity and FWHM could be improved by using a bimetallic structure that consists of a silver grating on a thin gold film and thereby increases the quality factor. Sensitivity of the proposed structure is 346 degrees /RIU with a quality factor more than 97.46 RIU-1. PMID- 29240106 TI - Electro-optically induced topological reactions of optical indicatrix orientation and polarization state defects. AB - We have studied the behavior of topological defects (TDs) of the optical indicatrix orientation and polarization state, which appear when a divergent optical beam propagates through LiNbO3 crystals under an external electric field. We have found that the topological reaction of the splitting of a central TD of optical indicatrix orientation, which occurs under the electric field EX, proceeds according to a scheme 1=1/2+1/2. This reaction splits a doubly charged optical vortex into two singly charged vortices. An increase in the electric field strength leads to angular displacement of the optical vortices, thus making it possible to operate spatial positions of the optical vortices via a Pockels effect. We have found that the lateral TDs with the strengths +/-1/2 represent the defects of the polarization state and are not caused by defects of optical indicatrix orientation. They form topological dipoles and generate optical vortices. These topological dipoles undergo no topological reactions in the external electric field. PMID- 29240107 TI - Designing a low-threshold quantum-dot laser based on a slow-light photonic crystal waveguide. AB - We numerically investigate and design a compact electrically pumped edge-emitting photonic crystal waveguide (PCW) quantum dot (QD) laser operating at room temperature. Use of a narrowband folded directional coupler as the output mirror has made the proposed structure an edge-emitting single-mode laser. Moreover, we propose a set of rate equations to model the performance of the PCW-QD laser. In the proposed model, we take the effects of the homogeneous and inhomogeneous broadenings and the slow-light effects on the modal gain and loss coefficient into account. Simulations show that threshold current as low as ~26 MUA can be achieved for the PCW-QD laser with a 50-MUm-long cavity and output power in the range of micro-watts. The proposed low-threshold edge-emitting PCW-QD laser is a promising light source for the off-chip and on-chip photonic network applications. PMID- 29240108 TI - Wavelength measurement by Fourier analysis of interference fringes through a plane parallel plate. AB - When a diverging laser beam passed through a plane parallel glass plate, interference fringes were observed; analysis of these fringes provided accurate estimation of the source wavelength. The fringes had a unique angular range of uniform fringe density. Fourier transform of the fringes in this range directly provided wavelength information. Reference lasers were used to establish a calibration between the fringe density and wavenumber, with which we estimated the wavelength of a test laser. An accuracy of 4.5*10-5 was obtained, which is better than that of conventional grating spectrometers, while providing a much broader free spectral range. Our method has unique features, such as extreme simplicity of the setup, fast analysis, and low cost, which are great advantages in practical wavelength meter applications. PMID- 29240109 TI - Carry-free full-symbol one-step modified signed-digit addition. AB - Optical computing has advantages over electronic computing because it can carry much more information and process more data bits. Providing that carry-look-ahead is applied in optical computing in the same way electronic computing accomplishes addition calculation, it will be more inefficient because of the delay caused by a large number of serial carries. On the basis of the research on relations among the augend, addend, results, and the redundancy of modified signed-digit (MSD) number, the implementation method of carry-free one-step MSD addition is presented. Meanwhile, the corresponding logical light path scheme is designed in this paper. Extensive experimental results show that the proposed implementation method of one-step addition is correct, and the designed light path scheme is reasonable. PMID- 29240110 TI - Optimizing alignment and growth of low-loss YAG single crystal fibers using laser heated pedestal growth technique. AB - The effect of misalignments of different optical components in the laser heated pedestal growth apparatus have been modeled using Zemax optical design software. By isolating the misalignments causing the non-uniformity in the melt zone, the alignment of the components was fine-tuned. Using this optimized alignment, low loss YAG single crystal fibers of 120 MUm diameter were grown, with total attenuation loss as low as 0.5 dB/m at 1064 nm. PMID- 29240111 TI - Frequency-modulated multifunction lidar for anemometry, range finding, and velocimetry-1. Theory and signal processing. AB - Original waveforms and optimized signal processing are proposed for frequency modulated continuous-wave lidar for range finding, velocimetry, and laser anemometry. For range finding, the aim of this signal processing is to extend lidar range and reduce ambiguities. Moreover, the effect of moderate atmospheric turbulence on lidar efficiency is analyzed for infinite and finite targets, taking into account wind-induced bistatism. For laser anemometry, the aim is to measure air speed at the shortest distance farther than the rotor-induced turbulent volume around the helicopter and to avoid parasitic echoes coming from clouds or hard targets in the vicinity of a helicopter. PMID- 29240112 TI - Frequency-modulated multifunction lidar for anemometry, range finding, and velocimetry-2. Experimental results. AB - Frequency-modulated continuous-wave lidar is evaluated for range finding, velocimetry, and laser anemometry. An original signal processing and waveform calibration for range finding leads to a reduction of computational effort while preserving capability for long-range measurement. Multiple target distance measurement is also demonstrated. For laser anemometry, the aim is to avoid parasitic echoes in the vicinity of a helicopter and to measure the air speed at the shortest distance farther than the rotor-induced turbulent volume around the helicopter. Flight tests of this functionality and vortex ring state warning are demonstrated. PMID- 29240113 TI - Homogeneous-material-based calibration method for correcting laser-induced breakdown spectroscopy measurement-error bias in the case of dust pollution. AB - A calibration method based on homogeneous material for correcting laser-induced breakdown spectroscopy (LIBS) measurement-error bias in the case of dust pollution under laboratory conditions is proposed. The measured plasma spectra of the sample can be corrected by measuring the spectral integral of the homogeneous material. Thus, we can effectively minimize the dust pollution effect on LIBS and guarantee its precision. Results show that the mean absolute errors of CaO, MgO, Fe2O3, Al2O3, and SiO2 in cement samples are decreased notably from 1.02%, 0.06%, 0.15%, 0.57%, and 0.80% to 0.41%, 0.02%, 0.04%, 0.35%, and 0.39%, respectively. Combination of this calibration method with the traditional optical dustproof methods will significantly extend the LIBS equipment maintenance cycle and make preliminary preparations for the next practical industrial application. PMID- 29240114 TI - Analysis of high-resolution electro-optical beam steering by long-range surface plasmon resonance using a ZnSe prism. AB - A proposal on high-resolution electro-optical beam steering is conceptualized analytically using a long-range surface plasmon resonance configuration comprising a liquid crystal layer of E44 for 1550 nm wavelength. With the tuning of the refractive index of E44 through variations of applied voltage from 0 to 10 V, an optical beam steering can be attained considering the composite effect of spatial and angular Goos-Hanchen and Imbert-Fedorov shifts. As compared with the existing beam shift processes in MUrad by mechanical means, here, the computed angular resolution is 3.40 nrad. The proposed idea finds a new avenue in the field of pulse generation, optical sensor applications, and atomic force microscopy, mitigating existing drawbacks. PMID- 29240115 TI - Infrared image enhancement algorithm based on adaptive histogram segmentation. AB - Contrast enhancement plays a crucial role in infrared image pre-processing. Compared with the increasingly popular local-mapping enhancement methods, the global-mapping enhancement methods have a unique feature that reserves the thermal distribution information, which is vital in some temperature-sensitive applications. However, the main challenge of the global-mapping methods is how to enhance the contrast effectively without suffering from over-enhancement of the background and noise. To this end, we propose a novel global-mapping enhancement algorithm in this paper. First, the histogram is divided into several sub histograms adaptively based on the heat conduction theory. By designing a metric called AHV, the background and non-background sub-histograms are distinguished, and then enhanced separately where more grayscales are allocated to non background sub-histograms than background sub-histograms. Meanwhile, the property of the human visual system described by Weber's law is also taken into consideration during the grayscale redistribution. The qualitative and quantitative comparisons with state-of-the-art methods on several databases demonstrate the advantages of our proposed method. PMID- 29240116 TI - Laser-induced breakdown spectroscopy for three-dimensional elemental mapping of composite materials synthesized by additive technologies. AB - Three-dimensional multi-elemental mapping of composite wear-resistant coatings by laser-induced breakdown spectroscopy has been demonstrated for the first time, to the best of our knowledge. Individual clads of 1560 nickel alloy reinforced with tungsten carbide were synthesized by a co-axial laser cladding technique. Electron energy dispersive x-ray spectroscopy revealed elemental maps for major elements (W, Ni, Co, Cr, Fe) but failed to measure silicon and carbon. Laser induced breakdown spectroscopy was utilized for elemental mapping of carbon and all other elements of interest. It was demonstrated that three-dimensional elemental profiling for a few tens of micrometers requires substantial laser spot overlapping during the scanning procedure in order to achieve good accuracy of depth measurements. Elemental maps for nickel, iron, chromium, silicon, tungsten, and carbon were quantified for 900 MUm*900 MUm*45 MUm volume with 30 MUm lateral and 4 MUm depth resolution in the case of tungsten carbide particles in nickel alloy. PMID- 29240117 TI - Scanning resonator microscopy integrating phase sensitive detection. AB - Scanning resonator microscopy (SRM) is a scanning probe technique that uses a small, optical resonator attached to the end of a conventional atomic force microscopy cantilever to simultaneously measure optical and topography properties of sample surfaces. In SRM, whispering gallery mode (WGM) resonances excited in the attached optical resonator shift in response to changes in surface refractive index (RI), providing a mechanism for mapping RI with high spatial resolution. In our initial report, the SRM tip was excited with a fixed excitation wavelength during sample scanning, which limits the approach. An improved method based on a wavelength modulation coupled with phase sensitive detection is reported here. This results in real-time characterization of WGM spectral shifts while eliminating complications arising from measurements based solely on signal intensity. This improved approach, combined with a modified tip design enabling integration of smaller resonators, is shown to enhance signal-to-noise and lead to sub-100 nm spatial resolution in the SRM optical image. The improved capabilities are demonstrated through measurements on thin dielectric and polymer films. PMID- 29240118 TI - Accurate calibration of a multi-camera system based on flat refractive geometry. AB - Multi-camera systems are widely applied in many fields, but the camera calibration is particularly important and difficult. In the application of a multi-camera system, it is very common for multiple cameras to be distributed on both sides of the measured object with overlapping field of view. In this paper, we present a novel calibration method for a multi-camera system based on flat refractive geometry. All cameras in the system can acquire calibration images of a transparent glass calibration board (TGCB) at the same time. The application of TGCB leads to a refractive phenomenon that can generate calibration error. The theory of flat refractive geometry is employed to eliminate the error. The proposed method combines the camera projection model with flat refractive geometry to determine the intrinsic and extrinsic camera parameters. The bundle adjustment method is employed to minimize the reprojection error and obtain optimized calibration results. The simulation is performed with zero-mean Gaussian noise of the standard deviation changes from 0 to 0.4 pixels, and the results show that the error of rotation angle is less than 5.6e-3 deg, and the error of translation is less than 4.6e-3 mm. The four-camera calibration results of real data show that the mean value and standard deviation of the reprojection error of our method are 4.3411e-05 and 0.4553 pixels, respectively. Both the simulative and real experiments show that the proposed method is accurate and feasible. PMID- 29240119 TI - Focusing anomalies with binary diffractive optical elements. AB - Binary diffractive optics have been extensively studied to date as tools for arbitrary laser beam shaping and experimentally implemented with etched transparent optics and spatial light modulators. Here we demonstrate that a simple one-step binary optic is able to enhance the intensity of a focused beam, displaying some counterintuitive focusing anomalies. We explain these effects by considering the optical aberrations in binary diffractive optics and outline how this may be exploited for further improvements in refractive/diffractive combinations for super-resolution microscopy. PMID- 29240120 TI - 1.7 MUm band narrow-linewidth tunable Raman fiber lasers pumped by spectrum sliced amplified spontaneous emission. AB - A 1.7 MUm band tunable narrow-linewidth Raman fiber laser based on spectrally sliced amplified spontaneous emission (SS-ASE) and multiple filter structures is proposed and experimentally demonstrated. In this scheme, an SS-ASE source is employed as a pump source in order to avoid stimulated Brillouin scattering. The ring configuration includes a 500 m long high nonlinear optical fiber and a 10 km long dispersion shifted fiber as the gain medium. A segment of un-pumped polarization-maintaining erbium-doped fiber is used to modify the shape of the spectrum. Furthermore, a nonlinear polarization rotation scheme is applied as the wavelength selector to generate lasers. A high-finesse ring filter and a ring filter are used to narrow the linewidth of the laser, respectively. We demonstrate tuning capabilities of a single laser over 28 nm between 1652 nm and 1680 nm by adjusting the polarization controller (PC) and tunable filter. The tunable laser has a 0.023 nm effective linewidth with the high-finesse ring filter. The stable multi-wavelength laser operation of up to four wavelengths can be obtained by adjusting the PC carefully when the pump power increases. PMID- 29240121 TI - Dynamic modulation of wideband slow light with continuous group index in polymer filled photonic crystal waveguide. AB - The dynamic modulation of wide bandwidth and low-dispersion slow light with continuous variation of group index ng is realized in a polymer-filled photonic crystal waveguide (PF-PCW) with optimal structure. By adjusting the unified radius of air holes under a different refractive index of polymer in the first two rows of holes adjacent to the defect, the structure optimization of PF-PCW is first studied, then the fixed optimal structure is obtained. In the optimal photonic crystal waveguide with hole radius r0=0.328a, a fixed refractive index n1=1.74 of polymer in the first-row holes, and by adjusting refractive index n2, the flattened wideband slow light with large normalized delay bandwidth product of group index from 17.15 to 55.65 has been demonstrated. Then, by filling polymer with electro-optic effect into the second-row holes, the dynamic modulation of the optimized slow light in PF-PCW is investigated. The simulation shows that the center operating frequency slightly shifts linearly to a higher one, and the average group index increases exponentially from 33.943 to 75.546 with a normalized delay bandwidth product larger than 0.3089 as the applied voltage increases. The modulation sensitivity of the average group index is about 0.3467/V when applied voltages vary from 0 V to 120 V. These results open the possibility for the dynamic control of slow light according to the practical requirements of flexibility and tunability. PMID- 29240122 TI - Spectral response characteristics of the transmission-mode aluminum gallium nitride photocathode with varying aluminum composition. AB - In order to research spectral response characteristics of transmission-mode nanostructure aluminum gallium nitride (AlGaN) photocathodes, the AlGaN photocathodes materials with varied aluminum (Al) composition were grown by metalorganic chemical vapor deposition (MOCVD) and its optical properties were measured. The Al compositions of each AlGaN film of the photocathodes were analyzed from their adsorption properties curves; their thickness was also calculated by the matrix formula of thin-film optics. The nanostructure AlGaN photocathodes were activated with the Caesium-Oxygen (Cs-O) alternation, and after the photocathode was packaged in vacuum, their spectrum responses were measured. The experimental results showed that the trend of spectrum response curves first increased and then decreased along with the increasing of the incident light wavelength. The peak spectrum response value was 17.5 mA/W at 255 nm, and its quantum efficiency was 8.5%. The lattice defects near the interface of the AlGaN heterostructure could impede the electron motion crossing this region and moving toward the photocathode surface; this was a factor that reduces the electron emission performance of the photocathodes. Also, the experimental result showed that the thickness of each AlGaN layer affected the electron diffusion characteristics; this was a key factor that influenced the spectrum response performance. PMID- 29240123 TI - Detecting crop population growth using chlorophyll fluorescence imaging. AB - For both field and greenhouse crops, it is challenging to evaluate their growth information on a large area over a long time. In this work, we developed a chlorophyll fluorescence imaging-based system for crop population growth information detection. Modular design was used to make the system provide high intensity uniform illumination. This system can perform modulated chlorophyll fluorescence induction kinetics measurement and chlorophyll fluorescence parameter imaging over a large area of up to 45 cm*34 cm. The system can provide different lighting intensity by modulating the duty cycle of its control signal. Results of continuous monitoring of cucumbers in nitrogen deficiency show the system can reduce the judge error of crop physiological status and improve monitoring efficiency. Meanwhile, the system is promising in high throughput application scenarios. PMID- 29240124 TI - Mueller matrix polarimetry on plasma sprayed thermal barrier coatings for porosity measurement. AB - Yttria-stabilized zirconia (YSZ) is the most widely used material for thermal plasma sprayed thermal barrier coatings (TBCs) used to protect gas turbine engine parts in demanding operation environments. The superior material properties of YSZ coatings are related to their internal porosity level. By quantifying the porosity level, tighter control on the spraying process can be achieved to produce reliable coatings. Currently, destructive measurement methods are widely used to measure the porosity level. In this paper, we describe a novel nondestructive approach that is applicable to classify the porosity level of plasma sprayed YSZ TBCs via Mueller matrix polarimetry. A rotating retarder Mueller matrix polarimeter was used to measure the polarization properties of the plasma sprayed YSZ coatings with different porosity levels. From these measurements, it was determined that a sample's measured depolarization ratio is dependent on the sample's surface roughness and porosity level. To this end, we correlate the depolarization ratio with the samples' surface roughness, as measured by a contact profilometer, as well as the total porosity level, in percentage measured using a micrograph and stereological analysis. With the use of this technique, a full-field and rapid measurement of porosity level can be achieved. PMID- 29240125 TI - Wide-angle absorption of visible light from simple bilayers. AB - Color-selective absorption of light is a very significant operation used in numerous applications, from photonic sensing and switching to optical signal modulation and energy harnessing. We demonstrate angle-insensitive and polarization-independent absorption by thin bilayers comprising ordinary bulk media: dielectrics, semiconductors, and metals. Several highly efficient designs for each color of the visible spectrum are reported, and their internal fields' distributions reveal the resonance mechanism of absorption. The proposed bilayer components are realizable, since various physical or chemical deposition methods can be used for their effective fabrication. The absorption process is found to exhibit endurance with respect to the longitudinal dimension of the planar structure, which means that the same designs could be successfully utilized in non-planar configurations composed of arbitrary shapes. PMID- 29240126 TI - Analysis of long-term visual quality with numerical 3D ray tracing after corneal crosslinking treatment. AB - A numerical 3D ray tracing model was used to evaluate the long-term visual effects of two regimens of corneal crosslinking (CXL) treatment of 48 patients with the corneal degeneration keratoconus. The 3D ray tracing analyses were based on corneal elevation data measured by Scheimpflug photography. Twenty-two patients were treated with standard CXL applied uniformly across the corneal surface, whereas 26 patients underwent a customized, refined treatment only at local zones on the cornea (photorefractive intrastromal CXL; PiXL). Spot diagrams, spot root-mean-square (RMS) values, and Strehl ratios were evaluated for the patients prior to and 1, 3, 6, and 12 months after treatment. It was found that the group of patients treated with PiXL, on average, tended to attain a long-term improvement of the corneal optical performance, whereas only minor changes of the optical parameters were found for group treated with standard CXL. Our results confirmed that standard CXL treatment stabilizes the corneal optical quality over time, and thus halts the progression of the corneal degeneration. In addition to stabilization, the results showed that a significantly higher proportion of subjects treated with PiXL improved in RMS, 3, 6, and 12 months after treatment, compared to with CXL (p<0.05). This finding indicates that the PiXL treatment might improve optical quality over time. PMID- 29240127 TI - Optimal design for the support structure of a cavity mirror in a chemical oxygen iodine laser resonator. AB - The dynamic characteristics of the cavity mirror support structure strongly influence the quality of the output beam. However, the contradiction between excellent dynamic performance and light weight make the design process challenging. To cope with the problems encountered in the original design of a chemical oxygen iodine laser system, this paper presents a two-dimensional adjustable support structure based on spherical constraints with large specific stiffness in the initial design phase. Subsequently, a two-level optimization strategy containing a macro design and a detailed design is adopted to optimize the initial structure. At the macro design stage, a two-step topology optimization procedure is introduced, in which the scale of the optimization model is dramatically reduced using the independent continuous mapping algorithm to improve the calculation speed in the first step, and the gray elements are eliminated using the bi-directional evolutionary structural optimization method to clearly obtain the optimal topology in the second step. This method is verified to overcome the defect of low efficiency, while still eliminating gray elements. At the detailed design stage, an adaptive surrogate model and the multi objective design optimization method are employed to seek the best compromise between the lower weight and higher dynamic performance. The results from the application to the example of the cavity mirror support structure show that the mass is reduced by 41.8%, and the dynamic performance requirement is fulfilled. PMID- 29240128 TI - Integrated Lloyd's mirror on planar waveguide facet as a spectrometer. AB - A low-cost and simple Fourier transform spectrometer based on the Lloyd's mirror configuration is proposed in order to have a very stable interferogram. A planar waveguide coupled to a fiber injection is used to spatially disperse the optical beam. A second beam superposed to the previous one is obtained by a total reflection of the incident beam on a vertical glass face integrated in the chip by dicing with a specific circular precision saw. The interferogram at the waveguide output is imaged on a near-infrared camera with an objective lens. The contrast and the fringe period are thus dependent on the type and the fiber position and can be optimized to the pixel size and the length of the camera. Spectral resolution close to lambda/Deltalambda=80 is reached with a camera with 320 pixels of 25 MUm width in a wavelength range from O to L bands. PMID- 29240129 TI - Tunable single-longitudinal-mode Ho:YAG laser pumped by a 1.13 MUm diode laser. AB - We demonstrate a tunable single-longitudinal-mode Ho:YAG laser pumped by a 1.13 MUm diode. With two intracavity Fabry-Perot etalons, the maximum single longitudinal-mode output power of 102 mW at 2129.6 nm is obtained. The wavelength is tuned from 2119.7 to 2131.5 nm by precisely rotating two etalons. The measured beam quality factors M2 are 1.29 and 1.28 in the x and y directions, respectively. PMID- 29240130 TI - Ultra-compact beam splitter and filter based on a graphene plasmon waveguide. AB - This paper presents a sheet of graphene-ribbon waveguide as a simple and ultra compact splitter and filter in the mid-infrared waveband. The central wavelength of the graphene surface plasmons (GSPs) and the coupling intensity of this splitter can be tuned by changing the physical parameters, such as the chemical potential, the width of the waveguide, the gap between neighboring graphene ribbons, the refractive index of the substrate, the carrier relaxation time, etc. The effects of these parameters on GSP waves and beam-splitter specifications are numerically depicted based on the finite-difference time-domain method. This proposed structure can be used to construct an ultra-compact fast-tunable beam splitter, filter, modulator, and switch in the mid-infrared range. PMID- 29240131 TI - Exposure-fusion-based dot-grid image acquisition and recognition for sheet metal strain analysis. AB - Dot-grid images are usually captured for grid strain analysis during sheet metal forming. Due to the strong reflective characteristic of the metallic surfaces, the recorded dot-grid images often have poor quality, low positioning accuracy, and low recognition rate. Therefore, an exposure-fusion-based dot-grid image acquisition and recognition approach is proposed. First, multiple dot-grid images are captured at different exposure levels. Subsequently, the recorded multi exposure dot-grid images are fused into a new high-quality dot-grid image based on exposure fusion technology. Finally, a dot-grid image recognition procedure is developed to detect the dot-grids in the new dot-grid image. Both synthetic and real dot-grid images were tested to verify the performance of the novel approach. When synthetic dot-grid images were tested, the maximum positioning error was up to 6.044 pixels if they were recognized in the traditional way, whereas the maximum positioning error was reduced to 0.132 pixels if the novel approach was adopted. When real dot-grid images were tested, the lowest recognition rate is only 50.52% if they were recognized in the traditional way. Nevertheless, the recognition rate can reach about 91% if the novel approach was employed. These experimental results show the superiorities of the novel approach. PMID- 29240132 TI - Improvement of high-power laser performance for super-smooth optical surfaces using electrorheological finishing technology. AB - Laser-induced damage threshold (LIDT) is a key parameter for optical components heavily influenced by the surface roughness in high-power laser uses. Present polishing technologies often bring about directional micro waviness to the optical surfaces due to path effect. Roughness features of a K9 glass surface were studied in this paper. A new evaluating restriction for power spectral density specification was established, and the off-specification frequency contents were found out. Then the electromagnetic simulation of light field modulation was carried out, and the field enhancement factor reached 12.04, verifying the impact of these contents on the laser damage performance of optical components. To restrain the modulation effect by the textures, electrorheological finishing (ERF) technology was proposed, and the processing was undertaken on the K9 surface. Roughness data converged to minimal Ra 1.00 nm, and the angular spectrum decreased in expected ranges. ERF proved to be effective in eliminating the directional textures and restraining the light intensity modulation of the textures. As a result, the LIDTs of optical components can be improved by ERF processing. PMID- 29240133 TI - Alignment error analysis of detector array for spatial heterodyne spectrometer. AB - Spatial heterodyne spectroscopy (SHS) is a new spatial interference spectroscopy which can achieve high spectral resolution. The alignment error of the detector array can lead to a significant influence with the spectral resolution of a SHS system. Theoretical models for analyzing the alignment errors which are divided into three kinds are presented in this paper. Based on these models, the tolerance angle of these errors has been given, respectively. The result of simulation experiments shows that when the angle of slope error, tilt error, and rotation error are less than 1.21 degrees , 1.21 degrees , 0.066 degrees respectively, the alignment reaches an acceptable level. PMID- 29240134 TI - Spectral characterization of a supercontinuum source based on nonlinear broadening in an aqueous K2ZnCl4 salt solution. AB - We report on investigations concerning the shot-to-shot spectral stability properties of a supercontinuum source based on nonlinear processes such as self phase modulation and optical wave-breaking in a highly concentrated K2ZnCl4 double salt solution. The use of a liquid medium offers both damage resistance and high third-order optical nonlinearity. Approximately 40 MUJ pulses spanning a spectral range between 390 and 960 nm were produced with 3.8% RMS energy stability, using infrared input pulses of 500+/-50 fs FWHM durations and 2.42+/ 0.04 mJ energies with an RMS stability of 2%. The spectral stability was quantified via acquiring single-shot spectra and studying shot-to-shot variation across a spectral range of 200-1100 nm, as well as by considering spectral correlations. The regional spectral correlation variations were indicative of nonlinear processes leading to sideband generation. Spectral stability and efficiency of energy transfer into the supercontinuum were found to weakly improve with increasing driver pulse energy, suggesting that the nonlinear broadening processes are more stable when driven more strongly, or that self guiding effects in a filament help to stabilize the supercontinuum generation. PMID- 29240135 TI - Long-period fiber grating: a specific design for biosensing applications. AB - In this paper, a detailed investigation on the modeling of long-period fiber grating (LPFG) sensors is discussed with the aim of providing a more realistic solution for their use in biosensing. Add-layer sensitivity, i.e., sensitivity of the sensor to an additional layer adhered onto the fiber surface, is quantified and a clear and complete analysis about the influence of the average thickness of the deposited biological sensing layers, as well as the change in refractive index of these layers, on the resonant wavelength of the cladding modes of an LPFG is provided. Add-layer sensitivity of LPFG sensors close to mode transition (MT) and also at turn-around point (TAP) are taken into account. Adsorbed layer thicknesses, as estimated from measured wavelength shifts of the LPFG, are found to have a good match with the values obtained through other measurement techniques. PMID- 29240136 TI - Bit-rate-transparent optical return-to-zero-to-nonreturn-to-zero format conversion based on linear spectral phase filtering of the RZ signal. AB - We propose a novel and simple design for all-optical bit-rate-transparent return to-zero (RZ)-to-nonreturn-to-zero (NRZ) telecommunication data format conversion based on linear spectral phase filtering of the RZ signal. The proposed concept is numerically analyzed and experimentally validated through successful format conversion of a 640 Gbit/s coherent RZ signal into the equivalent NRZ time-domain data using a simple phase filter realized by a commercial optical waveshaper. PMID- 29240137 TI - High-quality-factor double Fabry-Perot plasmonic nanoresonator. AB - Fabry-Perot (FP)-like resonances have been widely described in nanoantennas. In the original FP resonator, a third mirror can be added, resulting in a multimirror interferometer. However, in the case of a combination of nanoantennas, it has been reported that each cavity behaves independently. Here, we evidence the interferences between two FP absorbing nanoantennas through a common mirror, which has a strong impact on the optical behavior. While the resonance wavelength is only slightly shifted, the level of absorption reaches nearly 100%. Moreover, the quality factor increases up to factor 7 and can be chosen by geometric design over a range from 11 to 75. We demonstrate, thanks to a simple analytical model, that this coupling can be ascribed to a double FP cavity resonance, with the unique feature that each cavity is separately coupled to the outer medium. PMID- 29240138 TI - Schottky graphene/Si photodetector based on metal-dielectric hybrid hollow-core photonic crystal fibers. AB - This Letter presents a new family of Schottky graphene/silicon (Si) photodetectors (PDs) based on hollow-core photonic crystal fibers (HPCFs), working at both optical communication and room temperature. The proposed structure has the advantage of plasmonic HPCFs in a slow-light regime, and the absorption mechanism is based on an internal photoemission effect. The main feature of this structure is that the enhanced electric field is strongly localized in the hollow core of the guided core mode with the surface plasmon modes at the surface metal wires embedded in the photonic crystal structure. For the proposed graphene/silicon Schottky PD, numerical simulation predicts responsivity of ~0.39 A/W, and continuous-wave sensitivity of -59 dBm, which reveals substantial improvements compared to that of typical metal/Si Schottky PDs. PMID- 29240140 TI - On-chip Brillouin purification for frequency comb-based coherent optical communications. AB - In this Letter, for the first time, to the best of our knowledge, we harness on chip Brillouin scattering for narrowband amplification and spectral purification of frequency comb lines for coherent optical communications. A parametrically generated optical frequency comb with a low carrier-to-noise power ratio was filtered through narrowband Brillouin amplification utilizing the same comb as the optical pump. This was achieved on a photonic chip to enable successful transmission of an advanced modulation format signal: 64-level quadrature amplitude modulation. 96 Gb/s data were modulated on two polarizations on multiple comb lines across 1532.9-1557.5 nm, demonstrating the scalability of this concept for operation in wavelength division multiplexing applications. The small form factor of the photonic chip reduces the polarization drifts when compared to optical fibers and paves the way for photonic integration. PMID- 29240139 TI - High-reflection Mo/Be/Si multilayers for EUV lithography. AB - The effect of Be layers on the reflection coefficients of Mo/Be/Si multilayer mirrors in the extreme ultraviolet (EUV) region is reported. Samples were studied using laboratory and synchrotron based reflectometry, and high-resolution transmission electron microscopy. The samples under study have reflection coefficients above 71% at 13.5 nm and more than 72% at 12.9 nm in a near normal incidence mode. Calculations show that by optimizing the thickness of the Be layer it should be possible to increase the reflection coefficient by another 0.5 1%. These results are of considerable interest for EUV lithography. PMID- 29240141 TI - Quantification of laser-induced damage growth using fractal analysis. AB - Lateral and longitudinal laser damage growth under subsequent irradiations at 351 nm in the nanosecond range from micrometric to millimetric scales is presented herein. Atypical behavior has been observed, showing the growth in the longitudinal direction, whereas the lateral growth does not evolve. We propose the use of fractal analysis to describe the evolution of the bulk damage morphology. The results indicate first a dependence between the damage fractal dimension and the laser parameters, such as the fluence and the pulse duration. Next, it seems from observations that the damage morphology modifications drive the growth rate changes. PMID- 29240142 TI - Dual-wavelength digital holography with a low-coherence light source based on a quantum dot film. AB - This Letter proposes a dual-wavelength, low-coherence digital holography system with a single light source, which utilizes a quantum dot (QD) film as a wavelength converter. By changing the size of the QDs, the proposed method easily yields higher and more uniform illumination of any target wavelength, compared with bandpass-filtered light-emitting diodes. Fabrication parameters of the QD film for better conversion efficiency are discussed. Using this light source with the dual-wavelength reconstruction method extends the efficiency and range of nanoscale three-dimensional height measurements. PMID- 29240143 TI - Refractionless propagation of discretized light. AB - Light refraction, i.e., the bending of the path of a light wave at the interface between two different dielectric media, is ubiquitous in optics. Refraction arises from the different speeds of light and is unavoidable in continuous media, according to Snell's Law. Here we show rather counterintuitively that omnidirectional refractionless propagation can be observed for discretized light crossing a tilted interface separating two homogeneous waveguide lattices. PMID- 29240144 TI - 1.25 GHz sine wave gating InGaAs/InP single-photon detector with a monolithically integrated readout circuit. AB - InGaAs/InP single-photon detectors (SPDs) are the key devices for applications requiring near-infrared single-photon detection. The gating mode is an effective approach to synchronous single-photon detection. Increasing gating frequency and reducing the module size are important challenges for the design of such a detector system. Here we present for the first time, to the best of our knowledge, an InGaAs/InP SPD with 1.25 GHz sine wave gating (SWG) using a monolithically integrated readout circuit (MIRC). The MIRC has a size of 15 mm*15 mm and implements the miniaturization of avalanche extraction for high frequency SWG. In the MIRC, low-pass filters and a low-noise radio frequency amplifier are integrated based on the technique of low temperature co-fired ceramic, which can effectively reduce the parasitic capacitance and extract weak avalanche signals. We then characterize the InGaAs/InP SPD to verify the functionality and reliability of the MIRC, and the SPD exhibits excellent performance with 27.5% photon detection efficiency, a 1.2 kcps dark count rate, and 9.1% afterpulse probability at 223 K and 100 ns hold-off time. With this MIRC, one can further design miniaturized high-frequency SPD modules that are highly required for practical applications. PMID- 29240145 TI - Micro-scale roughening of glass substrates using carbon nanotube-driven templates for enhancements in white luminescence characteristics. AB - A novel way of roughening the surface of a glass substrate using a carbon nanotube-driven template is introduced to enhance the white luminescence characteristics of a printed (Ba,Sr,Ca)2SiO4:Eu2+ yellow silicate phosphor layer. The distribution of closed pores in the template layer induces selective etching and micro-scale roughening. As a result, a substantial improvement of ~22.5% in the luminous efficacy was achieved when both sides of the substrate were roughened. This is attributed to the reductions of both the total internal reflection of rays at the glass-air interface and the specular reflection at the phosphor-glass interface. PMID- 29240146 TI - Hybrid unidirectional meta-coupler for vertical incidence to a high-refractive index waveguide in telecom wavelength. AB - Unidirectional optical manipulation, especially the coupling from a vertical light beam to a waveguide unidirectionally, is desirable in photonic integration. We first propose a hybrid unidirectional meta-coupler for vertical incidence to a high-refractive-index waveguide in telecom wavelength, a periodic plasmonic metasurface composed of metal-insulator-metal unit cells is used for phase matching. Three designs are given for devices working around wavelengths 0.85, 1.31, and 1.55 MUm. The simulated coupling efficiencies are all around 70%, and the 1 dB coupling bandwidths are 29, 82, and 105 nm, respectively. Our approach paves the way for the applications of optical metasurfaces to planar lightwave circuits. PMID- 29240147 TI - Bismuth-doped all-fiber mode-locked laser operating at 1340 nm. AB - We demonstrate a 1340 nm mode-locked Bismuth (Bi)-doped fiber laser without any saturable absorber. The effect of pump power on pulse width is studied, and a variation from 1.5 to 3 ns is reported. The output of the mode-locked Bi-doped fiber laser is further amplified using a master oscillator power amplifier configuration, and a peak power of 1.15 W is achieved. Soliton bunching is observed, and a true pulse width of 1.2 ps is reported from the measured autocorrelation trace. Stable operation of the mode-locked laser is verified from the radio-frequency spectrum with a fundamental repetition rate of 6.3 MHz, and SNR of 65 dB. PMID- 29240148 TI - Direct write micro/nano optical fibers by near-field melt electrospinning. AB - A simple fabrication method of micro/nano-optical fibers (MNOFs) based on near field melt electrospinning (NMES) is proposed in this Letter. Single fibers with diameters ranging from 500 nm to 6 MUm were directly written by near-field electrospinning of molten poly(methyl methacrylate) (PMMA). The morphology and transmission characteristics of single PMMA MNOFs were experimentally measured. The results showed that PMMA MNOFs have the advantages of smooth surfaces, uniform diameters, and low loss. As an example of one-step fabrication for MNOF devices, a planar helical MNOF structure was directly written and optically characterized. To demonstrate the versatility of the NMES process, in combination with the microfluidic technique, a liquid refractive index-sensing chip was fabricated and tested. Our results demonstrate that the proposed fabrication method has strong potential in the direct writing of patterned optical devices and heterogeneous integrated devices. PMID- 29240149 TI - Full C-band Si photonic crystal waveguide modulator. AB - The slow-light effect in silicon lattice-shifted photonic crystal waveguide (LSPCW) Mach-Zehnder modulators allows compact phase shifters, while limiting the working spectrum Deltalambda. We optimized the structural parameters of the LSPCW and extended Deltalambda to cover the full C-band in exchange for moderately decreasing the group index ng. We obtained Deltalambda=42 nm with ng=8-9 in a fabricated device and observed 25 Gbps eye opening in the 200 MUm modulator in the full C-band. PMID- 29240150 TI - Position-resolved Raman spectra from a laser-trapped single airborne chemical droplet. AB - It could be very useful to detect and monitor the molecules and molecular reactions located at different positions within a microsized particle as they respond to various micro-local environments. In this Letter, a particular optical trap using two focusing counterpropagating hollow beams was able to stably trap both absorbing and nonabsorbing particles in air for lengthy observation. A technique that can measure the Raman spectra from different submicrometer positions of a laser-trapped single airborne particle was developed. Spontaneous and stimulated Raman scattering spectra originating from different positions of a diethyl phthalate droplet were recorded, and the strong Raman scattering signals are the result of cavity-enhanced effects and the localized strong light illumination. PMID- 29240151 TI - Wavefront sensing with a thin diffuser. AB - We propose and implement a broadband, compact, and low-cost wavefront sensing scheme by simply placing a thin diffuser in the close vicinity of a camera. The local wavefront gradient is determined from the local translation of the speckle pattern. The translation vector map is computed thanks to a fast diffeomorphic image registration algorithm and integrated to reconstruct the wavefront profile. The simple translation of speckle grains under local wavefront tip/tilt is ensured by the so-called "memory effect" of the diffuser. Quantitative wavefront measurements are experimentally demonstrated, both for the few first Zernike polynomials and for phase-imaging applications requiring high resolution. We finally provided a theoretical description of the resolution limit that is supported experimentally. PMID- 29240152 TI - Design of nanowire-induced nanocavities in photonic crystal disks. AB - We propose a novel type of nanowire (NW)-induced nanocavity based on photonic crystal disks, and we investigate its design by three-dimensional finite difference time-domain calculations. We detail the confinement principle used in such a cavity and discuss the influence of geometric and material parameters on the cavity performance. Finally, we report on an optimized design presenting a quality factor Q=7.2*104, a mode volume as small as Vm=2.2(lambda/nrNW)3, and a large confinement factor of the electric field energy in the NW Gamma=65%, which shows good prospects for the realization of efficient NW-based nanolasers operating in the ultraviolet and visible ranges. PMID- 29240153 TI - Effect of pulse asymmetry and nonlinear chirp on the accuracy of ultrafast pulsed laser interferometry. AB - Ultrafast pulsed laser interferometry (PLI) can measure picometer displacements at sub-nanosecond time scales, such as acoustic waves and vibrations in microstructures. In this Letter, the effects of pulse characteristics on the accuracy of PLI are investigated through measurements and modeling. The results show that the effective wavelength of PLI, lambdaeff, varies significantly as a function of overlap between the interfering pulses due to pulse asymmetry and nonlinear chirp. This variation presents a serious limitation on the accuracy of PLI if unaddressed. However, it is shown that a continuous-wave laser interferometer can be used to determine lambdaeff with an uncertainty near 0.01%, making it possible to use PLI for accurate displacement measurements. PMID- 29240154 TI - Great photoluminescence enhancement in Al-sputtered Zn0.78Mg0.22O films. AB - Zn0.78Mg0.22O thin films were grown on a-plane sapphire substrates by plasma assisted molecular beam epitaxy. Compared with ZnO, the crystal quality of Zn0.78Mg0.22O thin films degrades significantly, which results in low internal quantum efficiency (etaint). Besides improving the quality of Zn0.78Mg0.22O, an effective method has been used to enhance the internal quantum efficiency and the UV emission of Zn0.78Mg0.22O by sputtering Al nanoparticles. Taking advantage of the resonant coupling between UV emission of Zn0.78Mg0.22O film and Al nanoparticle surface plasmons (SPs), a 59-fold enhancement of the UV emission and a 3.5-fold enhancement of etaint has been achieved under the optimized sputtering time. Moreover, the enhancement ratio is stable after two months. It paves a facile way in fabricating high-efficiency UV optoelectronic devices. PMID- 29240155 TI - All-optical control of ultrahigh-Q silica microcavities with iron oxide nanoparticles. AB - We propose and experimentally demonstrate, to the best of our knowledge, the first all-optical control scheme of ultrahigh-quality (Q)-factor silica microcavities, which can maintain their Q factors over 108 during the tuning process. For silica microcavities, the resonance tunability is very important and is also challenging for many applications. However, almost all previous works on resonance tuning deteriorate the Q factors of silica microcavities at different levels, and evidently these schemes are not suitable for applications in which ultrahigh Q factors are required. In this work, based on the proposed silica microbottle cavity and iron oxide nanoparticles, we realize all-optical control of the silica microcavity and maintain its Q factor of around 1.2*108 during the tuning process. A tuning range of 85.9 GHz (0.68 nm) and a tuning sensitivity of 13.6 GHz/mW are obtained, and it is possible to realize full tunability by bridging the azimuthal free spectral range using six adjacent q-series modes. Moreover, all-optical control of the reflection spectrum is also carried out. This work will broaden the applications of ultrahigh-Q silica microcavities in nonlinear optics, microwave photonics, cavity optomechanics, and cavity quantum electrodynamics. PMID- 29240156 TI - Experimental demonstration of critical coupling of whispering gallery mode cavities on a Bloch surface wave platform. AB - We experimentally demonstrate critical coupling of whispering gallery mode (WGM) disk resonators implemented on a Bloch surface wave platform using scanning near field optical microscopy. The studied structure is a 60 nm thick TiO2 WGM disk cavity (radius of 100 MUm) operating within the C-band telecommunication wavelength. An extinction ratio of 26 dB and a quality factor of 2200 are measured. Such a high extinction ratio verifies the critical coupling of the WGM resonator. This result paves the way to planar optical signal processing devices based on the proposed geometry, for which a critical coupling condition is a guarantee of optimum performance. PMID- 29240157 TI - High-performance Ge-on-Si photodetector with optimized DBR location. AB - We investigated the Ge-on-Si photodetector's performance enhancement by optimizing the detector length, therefore, the location of the distributed Bragg reflector (DBR). Since the unabsorbed signal light in the photodetector oscillates between the germanium and silicon layers, but the DBR is on the silicon layer, the optimized location of the DBR will result in shorter devices, with increased bandwidth, reduced dark current, and consistent responsivity. The 5 MUm long photodetector with an optimized DBR location shows responsivity of 0.72 A/W, at least 31.7 GHz 3 dB bandwidth; the dark current is only 7 nA at 1550 nm. PMID- 29240158 TI - Steering optical comb frequencies by rotating the polarization state. AB - We demonstrate a new approach to steer the frequencies of a nonlinear polarization-rotation mode-locked laser, where a specially designed intrcavity electro-optic modulator tunes the polarization state of the laser signal. This approach not only results in the broadband associated with high performance, but also results in a large dynamic range associated with good robustness. Our experimental results show that frequency control dynamic ranges are at least one order of magnitude larger than those of the previous ultra-fast frequency control techniques, reaching hundreds of hertz and hundreds of megahertz for repetition rate (fr) and carrier-envelope-offset frequency (fceo), respectively. PMID- 29240159 TI - Sodium guide star laser pulsed at Larmor frequency: erratum. AB - We correct an improper statement on the geomagnetic field of an astronomical telescope site in our original paper [Opt. Lett.42, 4351 (2017)OPLEDP0146 959210.1364/OL.42.004351]. PMID- 29240160 TI - Single-shot, real-time carrier-envelope phase measurement and tagging based on stereographic above-threshold ionization at short-wave infrared wavelengths. AB - A high-precision, single-shot, and real-time carrier-envelope phase (CEP) measurement at 1.8 MUm laser wavelength based on stereographic photoelectron spectroscopy is presented. A precision of the CEP measurement of 120 mrad for each and every individual laser shot for a 1 kHz pulse train with randomly varying CEP is demonstrated. Simultaneous to the CEP measurement, the pulse lengths are characterized by evaluating the spatial asymmetry of the measured above-threshold ionization (ATI) spectra of xenon and referenced to a standard pulse-duration measurement based on frequency-resolved optical gating. The validity of the CEP measurement is confirmed by implementing phase tagging for a CEP-dependent measurement of ATI in xenon with high energy resolution. PMID- 29240161 TI - Hilbert's Hotel in polarization singularities. AB - We demonstrate theoretically how the creation of polarization singularities by the evolution of a fractional nonuniform polarization optical element involves the peculiar mathematics of countably infinite sets in the form of "Hilbert's Hotel." Two distinct topological processes can be observed, depending on the structure of the fractional optical element. PMID- 29240162 TI - Traveling wave-like Fabry-Perot resonator-based add-drop filters. AB - We have proposed and studied a novel channel add-drop filter (ADF) based on a single Fabry-Perot resonator. The resonator consists of two mode-conversion Bragg grating reflectors separated by a wide waveguide that laterally coupled to two narrow waveguides. It behaves like a traveling-wave resonator where fields are coupled to the buses in one direction. Compact and narrowband ADFs are achieved with dropping efficiencies higher than 95%, as shown by the three-dimensional finite-difference time-domain simulations. In addition, the proposed device is applied to realize an eight-channel add-drop multiplexer in the C-band by cascading the ADFs with adjusted channel wavelengths. PMID- 29240163 TI - Raman dissipative soliton fiber laser pumped by an ASE source. AB - The mode locking of a Raman fiber laser with an amplified spontaneous emission (ASE) pump source is investigated for performance improvement. Raman dissipative solitons with a compressed pulse duration of 1.05 ps at a repetition rate of 2.47 MHz are generated by utilizing nonlinear polarization rotation and all-fiber Lyot filter. A signal-to-noise ratio as high as 85 dB is measured in a radio-frequency spectrum, which suggests excellent temporal stability. Multiple-pulse operation with unique random static distribution is observed for the first time, to the best of our knowledge, at higher pump power in mode-locked Raman fiber lasers. PMID- 29240164 TI - Detuned Brillouin amplification of OTDR signals with an enhanced signal-to-noise ratio. AB - The technique known as external Brillouin amplification of Rayleigh scattering is characterized in the detuning regime. When employed as an amplifier of OTDR signals, it is shown that the signal-to-noise ratio is significantly improved for optimum pump Stokes detuning, leading to enhanced nanostrain sensitivity. This effect is due to the Brillouin bandwidth dependence on the Stokes power. PMID- 29240165 TI - Extreme ultraviolet light source at a megahertz repetition rate based on high harmonic generation inside a mode-locked thin-disk laser oscillator. AB - We demonstrate a compact extreme ultraviolet (XUV) source based on high-harmonic generation (HHG) driven directly inside the cavity of a mode-locked thin-disk laser oscillator. The laser is directly diode-pumped at a power of only 51 W and operates at a wavelength of 1034 nm and a 17.35 MHz repetition rate. We drive HHG in a high-pressure xenon gas jet with an intracavity peak intensity of 2.8*1013 W/cm2 and 320 W of intracavity average power. Despite the high-pressure gas jet, the laser operates at high stability. We detect harmonics up to the 17th order (60.8 nm, 20.4 eV) and estimate a flux of 2.6*108 photons/s for the 11th harmonic (94 nm, 13.2 eV). Due to the power scalability of the thin-disk concept, this class of compact XUV sources has the potential to become a versatile tool for areas such as attosecond science, XUV spectroscopy, and high-resolution imaging. PMID- 29240166 TI - Topological cascade laser for frequency comb generation in PT-symmetric structures. AB - The cascade of resonant PT-symmetric topological structures is shown to emit laser light with a frequency comb spectrum. We consider optically active topological lattices supporting edge modes at regularly spaced frequencies. When the amplified resonances in the PT-broken regime match the edge modes of the topological gratings, we predict the emission of discrete laser lines. A proper design enables the engineering of the spectral features for specific applications. Topological protection makes the system very well suited for a novel generation of compact frequency comb emitters for spectroscopy, metrology, and quantum information. PMID- 29240167 TI - Diffraction symmetry of binary Fourier elements with feature sizes on the order of the illumination wavelength and effects of fabrication errors. AB - When building spot array binary Fourier diffractive optical elements (DOEs) having feature sizes on the order of the wavelength, we noticed remarkable variations in the experimental diffraction efficiency compared to the simulation results. Even with the use of high-cost electron beam lithography and rigorous Fourier modal method simulations, there appear to be no publications, to the best of our knowledge, showing close agreement in diffraction efficiency between the simulation and experimental results. In this Letter, we show that the diffraction symmetry of binary Fourier DOEs can be an efficient and consistent metric for evaluating the limit of the thin-element approximation and the effects of fabrication errors. PMID- 29240168 TI - Partially coherent diffraction-free vortex beams with a Bessel-mode structure. AB - A new family of partially coherent beams carrying optical vortices is introduced. Any member of this family represents an incoherent superposition of fully coherent orthogonal Bessel modes with the same helical wavefront and is notable for its diffraction-free propagation. It is shown analytically and experimentally that such beams can be approximately generated in the Fourier-transforming optical system with a computer-controlled liquid-crystal spatial light modulator. PMID- 29240169 TI - All-fiber interferometer-based repetition-rate stabilization of mode-locked lasers to 10-14-level frequency instability and 1-fs-level jitter over 1 s. AB - We report on all-fiber Michelson interferometer-based repetition-rate stabilization of femtosecond mode-locked lasers down to 1.3*10-14 frequency instability and 1.4 fs integrated jitter in a 1 s time scale. The use of a compactly packaged 10 km long single-mode fiber (SMF)-28 fiber link as a timing reference allows the scaling of phase noise at a 10 GHz carrier down to -80 dBc/Hz at 1 Hz Fourier frequency. We also tested a 500 m long low-thermal sensitivity fiber as a reference and found that, compared to standard SMF-28 fiber, it can mitigate the phase noise divergence by ~10 dB/dec in the 0.1-1 Hz Fourier frequency range. These results suggest that the use of a longer low thermal-sensitivity fiber may achieve sub-femtosecond integrated timing jitter with sub-10-14-level frequency instability in repetition rate by a simple and robust all-fiber-photonic method. PMID- 29240171 TI - Direct writing of plane-by-plane tilted fiber Bragg gratings using a femtosecond laser. AB - In this Letter, we report a flexible, plane-by-plane direct write inscription method for the development of tailored, tilted fiber Bragg gratings using a femtosecond laser. Compared to ultraviolet or femtosecond laser inscription based on the phase mask, interferometric, or point-by-point methods, the presented approach is far more flexible and offers several advantages. Laser inscription is made through the fiber coating, while the grating planes are controlled to minimize birefringence, with precise control over the wavelength location and strength of cladding modes. Tenth-order gratings were produced in the C+L bands so that higher-order gratings could be studied at shorter wavelengths. In particular, we show that the refractometric sensitivity depends on the grating order, ranging from ~28 nm/refractive index unit (RIU) at ~1510 nm to ~13 nm/RIU at ~1260 nm. PMID- 29240170 TI - Jones matrix microscopy from a single-shot intensity measurement. AB - Quantitative measurement of Jones matrix elements is crucial for the study of light polarization with the wide range of applications. Here, we propose and experimentally demonstrate a novel method of Fourier space sharing to determine spatially resolved all four elements of the Jones matrix from a single-intensity frame. This is achieved by applying a holographic approach and making use of two triangular polarization Sagnac interferometers in the sample and reference arms. The proposed technique is flexible to adjust carrier frequencies in order to meet the varying demand of different anisotropic samples. A Jones matrix microscopy system is developed and applied to transparent samples. Experimental implementation of the proposed technique is demonstrated by determining the Jones matrix elements of commercially available known samples and liquid crystal droplets. PMID- 29240172 TI - Ultra-compact polarization-independent directional couplers utilizing a subwavelength structure. AB - Ultra-compact polarization-independent directional couplers are proposed and demonstrated on the silicon-on-insulator (SOI) platform. By using the subwavelength structure in the coupling region, the coupling strength is greatly enhanced only for TE polarization, so that the coupling strength could be equivalent between TE and TM polarizations. Both complete coupling and 3 dB splitting have been demonstrated. The coupling length could be as short as ~3.75 MUm. The measured excess losses and polarization dependence losses are <~1 and <~0.5 dB. PMID- 29240173 TI - Phase transition through the splitting of self-dual spectral singularity in optical potentials. AB - We consider optical media, which feature antilinear symmetries. We show that (i) spectral singularities of such media (if any) are always self-dual, i.e., correspond to coherent perfect absorber lasers; (ii) under the change of a system parameter, the self-dual spectral singularity may split into a pair of isolated complex conjugate eigenvalues, which corresponds to an unconventional and overlooked, in the most of the previous studies, scenario of the phase transition (known as parity-time [PT]-symmetry breaking in systems obeying PT symmetry); (iii) if the antilinear symmetry is local, i.e., does not involve any spatial reflection, then no spectral singularity is possible. Our findings are illustrated with several examples including a PT-symmetric bilayer and other complex potentials discussed in recent literature. PMID- 29240174 TI - All-fiber second-order optical vortex generation based on strong modulated long period grating in a four-mode fiber. AB - We propose an effective all-fiber method to generate a high-order optical vortex (OV) via twisting a strong modulated long-period fiber grating (LPFG) written in a four-mode fiber (4MF). With a special design and optimization of the procedures of CO2-laser irradiation, an LPFG with strong period deformation is achieved in the 4MF. Based on this LPFG, we can directly convert the linear polarization (LP) fiber fundamental mode (LP01) to the high-order LP core mode (LP21) with efficiency of 99.7% and then transform the LP21 mode into a high-order OV mode (+/-2 order). This is the first time, to the best of our knowledge, that +/-2 order OV modes have been experimentally generated with just one fiber grating in an all-fiber-system. PMID- 29240175 TI - Radiation-induced birefringence variations in polarization-maintaining fibers. AB - Gamma radiation-induced birefringence (RIB) variations in a solid core photonic crystal polarization-maintaining fiber (Pc-PMF) and a Panda PMF (Pa-PMF) are investigated. Experiments show that the birefringence of the fibers changes approximately linearly with a radiation dose over the range from 0 to 400 krad(Si), with negative slope coefficients of 8.91*10-10/krad(Si) and 4.38*10 9/krad(Si) for the Pc-PMF and Pa-PMF, respectively. Models of RIB variations for the two fibers are established, and the theoretical results agree well with the experimental ones. PMID- 29240176 TI - Highly efficient optical parametric amplifier tunable from near- to mid-IR for driving extreme nonlinear optics in solids. AB - We have developed a robust optical parametric amplifier (OPA) based on three AgGaS2-crystal pumping by a Cr:Forsterite GW femtosecond laser system, generating 150 fs pulses in dual bands of 1.6-2.0 MUm (signal wave) and 3.5-5.5 MUm (idler wave). By introducing a negative prechirp to the pump, a combined efficiency in two waves of greater than 10% was achieved, with signal energy up to 110 MUJ and idler energy up to 43 MUJ. Operation parameters of the system (intensity up to 90 TW/cm2) make OPA a promising tool for driving nonlinear optical phenomena, including generation of optical harmonics and laser-induced extreme states of matter in solids and liquids. As a proof of principle, we generated harmonics up to the sixth order and sum frequencies in 5 mm thick polycrystalline ZnSe. PMID- 29240177 TI - Photo-bleaching mechanism of the BAC-Si in bismuth/erbium co-doped optical fibers. AB - Photo-bleaching of the silica-related bismuth active center (BAC-Si) in bismuth/erbium co-doped optical fibers is investigated. By analyzing dynamic spectral characteristics of BAC-Si, the photo-bleaching of the BAC-Si is found to be linked to the escape of an excited electron from the bismuth site in the BAC Si. This mechanism of BAC-Si bleaching linked to an escaping excited electron is further confirmed with both photo-bleaching experiments by different laser pump wavelengths and a potential energy model describing the loss of an excited electron. Additionally, the temperature effect on the photo-bleaching, which is in good agreement with the above findings, is observed and discussed. PMID- 29240178 TI - Exploring the self-mode locking of the 2 MUm Tm:YAG laser with suppression of the self-pulsing dynamic. AB - A continuous-wave (cw) self-mode-locked Tm:YAG laser at 2015 nm is successfully demonstrated by suppressing the self-pulsing behavior. By using rate equations to simulate the laser temporal dynamic, the theoretical analysis indicates that the reabsorption-induced self-pulsing for the Tm:YAG laser can be suppressed with sufficient pump power. It is experimentally confirmed that at absorbed powers higher than 6 W, the self-pulsing can be eliminated and a cw self-mode-locked pulse is generated instead of the Q-switched mode locking. At an absorbed power of 6.8 W, the output power of the self-mode-locked Tm:YAG laser reaches 1.22 W with corresponding pulse duration of 3 ps and a repetition rate of 3.376 GHz. PMID- 29240179 TI - Widely tunable optical parametric oscillation in a Kerr microresonator. AB - We report on the first experimental demonstration of widely tunable parametric sideband generation in a Kerr microresonator. Specifically, by pumping a silica microsphere in the normal dispersion regime, we achieve the generation of phase matched four-wave mixing sidebands at large frequency detunings from the pump. Thanks to the role of higher-order dispersion in enabling phase matching, small variations of the pump wavelength translate into very large and controllable changes in the wavelengths of the generated sidebands: we experimentally demonstrate over 720 nm of tunability using a low-power continuous-wave pump laser in the C-band. We also derive simple theoretical predictions for the phase matched sideband frequencies and discuss the predictions in light of the discrete cavity resonance frequencies. Our experimentally measured sideband wavelengths are in very good agreement with theoretical predictions obtained from our simple phase-matching analysis. PMID- 29240180 TI - Experimental study of the mode instability onset threshold in high-power FA-LPF lasers. AB - We report here on an experimental investigation of the temporal behavior of transverse mode instabilities into "fully aperiodic large-pitch fibers" (FA-LPFs) operated in high-power continuous-wave laser configuration. To ensure an effective transverse single-mode emission into FA-LPFs, a perfect index matching between the active core and the background cladding materials (Deltan=0) is required. The original design of such fibers enables an effective transverse single-mode emission by strengthening the higher-order mode delocalization out of the gain region, even for high heat load levels, consequently leading to the improvement of the beam spatial quality. The study was conducted over fibers of various gain region diameters, from 58 to 100 MUm, for a refractive index mismatch Deltan of about +8*10-5. The emitted beam is characterized using both M2 measurements and time traces to study the changeover of a stable temporal behavior to an unstable one. PMID- 29240181 TI - Chirped-pulse-based broadband RF channelization implemented by a mode-locked laser and dispersion. AB - Based on chirped pulses, a wideband radio frequency (RF) channelized receiver that can easily support hundreds of channels is proposed. The mixing chirped pulses and its own delayed copy produces an equivalent RF local oscillation (LO). The LO frequency can be changed by simply setting the delay between the two paths. Channelized receiving of broadband RF signals can be realized by parallel delay line arrays. Meanwhile, the use of in-phase/quadrature demodulation avoids the extra optical or electrical filtering as well as image interference. A receiver with channel spacing of 100 MHz, covering the spectrum from DC to 18.4 GHz is experimentally demonstrated. The performances, including signal-to-noise ratio, frequency response, spurious-free dynamic range, and image rejection, are analyzed. PMID- 29240182 TI - Flexible design method for freeform lenses with an arbitrary lens contour. AB - A method is presented that allows the design of freeform lenses with an arbitrary contour in a flexible and robust manner. The method is based on the generation of two equi-flux grids representing the source and target beams, with two separate curl-free mappings from an equi-spatial rectangular grid. Because the source and target grids are generated independently from one another, one can map arbitrary complex source beams with certain contours onto arbitrary complex target beams within other contours with high convergence probability. The method is illustrated by calculating a triangular freeform lens that reshapes a triangular beam from a Lambertian source into a uniform pentagonal irradiance distribution on a target plane. PMID- 29240183 TI - Experimental generation of linearly chirped 350 GHz band pulses with a bandwidth beyond 60 GHz. AB - We present in this Letter the experimental generation of linear frequency modulated (LFM) terahertz pulses with large bandwidths by using an optical interferometer-based photonic scheme and cutting-edge terahertz transceiver technology. The LFM pulses exhibiting a bandwidth in excess of 60 GHz centered at 350 GHz are successfully generated in the experiment, which represents the first demonstration of large time-bandwidth products (TBWPs) in the terahertz region above 300 GHz, to the best of our knowledge. The achieved TBWP of up to 527 has great potential in many prospective applications such as high-resolution radar sensing and imaging. PMID- 29240184 TI - Characterization of two ultrashort laser pulses using interferometric imaging of self-diffraction. AB - Noncollinear pulse characterization methods can be applied to over-octave spanning waveforms, but geometrical effects in the nonlinear medium such as beam smearing and critical sensitivity to beam alignment hinder their accurate application. Here, a method is introduced for the temporal and spatial characterization of two pulses by interferometric, spectrally resolved imaging of self-diffraction. Geometrical effects are resolved by the method and, therefore, do not limit the accuracy. Two methods for quantitative pulse retrieval are presented. One method is analytical and very fast; the other method is iterative and more robust if applied to noisy data. PMID- 29240185 TI - Perfect broadband invisibility in isotropic media with gain and loss. AB - We offer a simple route to perfect omnidirectional invisibility in a spectral band of desired width. Our approach is based on the observation that in two dimensions a complex potential v(x,y) is invisible for incident plane waves with a wavenumber not exceeding a pre-assigned value alpha, provided that its Fourier transform with respect to y, which we denote by v~(x,Ky), vanishes for Ky<=2alpha. We can fulfill this condition for potentials modeling the permittivity profile of an optical slab. Such a slab is perfectly invisible for any transverse electric wave whose wavenumber is in the range [0,alpha]. Our results also apply to transverse magnetic waves propagating in a medium with a relative permittivity epsilon^(x,y) that is a smooth bounded function with a positive real part. PMID- 29240186 TI - Effects of defocus and other quadratic errors on OTF. AB - Even for the simplest nontrivial aberration, defocus, and for a circular pupil, there is no theoretical closed-form expression for the optical transfer function (OTF). By using a simple approximation, we provide a simple yet accurate approximation for the OTF of a defocused system. We generalize this approach to generic quadratic aberrations, including astigmatism. PMID- 29240187 TI - Variable Stripe Length method: influence of stripe length choice on measured optical gain. AB - The Variable Stripe Length (VSL) method is a very popular tool to measure the optical gain in thin film active devices. However, over the last decade experimental and theoretical evidence has been reported that cast doubt upon its reliability and that seriously discourages its application. Continuing in the path of highlighting the uncertainties associated with this method, this Letter soundly demonstrates that the particular choice of stripe lengths in the VSL measurements profoundly influences the optical gains retrieved by this method. Thus, a single set of VSL data may render gain values that differ by tens of cm 1. The observed gain variability is ascribed to a combination of unavoidable experimental noise and incorrect assumptions in the analytical treatment (small signal approximation). PMID- 29240188 TI - Modeling the sensitivity dependence of silicon-photonics-based ultrasound detectors. AB - With recent advances in optical technology, interferometric sensing has grown into a highly versatile approach for ultrasound detection, with many interferometric detectors relying on optical waveguides to achieve high levels of sensitivity and miniaturization. In this Letter, we establish a practical model for assessing the sensitivity of silicon-photonics waveguides to acoustic waves. The analysis is performed for different polarizations, waveguide dimensions, and acoustic wave types. Our model was validated experimentally in the acoustic frequency band of 1-13 MHz by measuring the sensitivities of the two polarization modes in a silicon strip waveguide. Both the experimental results and theoretical prediction show that the transverse-magnetic polarization achieves a higher sensitivity and suppression of surface acoustic waves compared to the transverse electric polarization for the geometries studied. PMID- 29240189 TI - Intensity noise coupling in soliton fiber oscillators. AB - We present an experimental and numerical study on the spectrally resolved pump-to output intensity noise coupling in soliton fiber oscillators. In our study, we observe a strong pump noise coupling to the Kelly sidebands, while the coupling to the soliton pulse is damped. This behavior is observed in erbium-doped as well as holmium-doped fiber oscillators and confirmed by numerical modeling. It can be seen as a general feature of laser oscillators in which soliton pulse formation is dominant. We show that spectral blocking of the Kelly sidebands outside the laser cavity can improve the intensity noise performance of the laser dramatically. PMID- 29240190 TI - Multilayered analog optical differentiating device: performance analysis on structural parameters. AB - Analogy optical devices (AODs) able to do mathematical computations have recently gained strong research interest for their potential applications as accelerating hardware in traditional electronic computers. The performance of these wavefront processing devices is primarily decided by the accuracy of the angular spectral engineering. In this Letter, we show that the multilayer technique could be a promising method to flexibly design AODs according to the input wavefront conditions. As examples, various Si-SiO2-based multilayer films are designed that can precisely perform the second-order differentiation for the input wavefronts of different Fourier spectrum widths. The minimum number and thickness uncertainty of sublayers for the device performance are discussed. A technique by rescaling the Fourier spectrum intensity has been proposed in order to further improve the practical feasibility. These results are thought to be instrumental for the development of AODs. PMID- 29240191 TI - Modal instability induced by stimulated Raman scattering in high-power Yb-doped fiber amplifiers. AB - Modal instability (MI) and stimulated Raman scattering (SRS) are the main obstacles in the power scaling of fiber lasers and amplifiers. In the power scaling of a high-power ytterbium (Yb)-doped master oscillator power amplifier system, a new type of MI has occurred. Experimentally, it is shown that just at the onset of the SRS effect, MI takes place, and the degradation of the beam quality is observed. By the spectra and beam quality measurements, it is revealed that this type of MI can be mitigated firmly by suppressing the SRS effect in high-power Yb-doped fiber amplifiers. PMID- 29240192 TI - Wavelength-modulated planar laser-induced fluorescence for imaging gases. AB - This work presents the development of wavelength-modulated planar laser-induced fluorescence (WM-PLIF) and its initial application to infrared imaging of carbon monoxide in a laminar flame. A continuous-wave quantum-cascade laser producing 50 mW near 4.8 MUm was injection-current modulated at 1 kHz and scanned across the P(20) transition of CO at 20 Hz. The corresponding infrared-laser-induced fluorescence from 2065 cm-1 to 2155 cm-1 was imaged orthogonal to the laser sheet using a high-speed IR camera, and digital lock-in detection of the WM-PLIF first-harmonic signal (SF,1f) was performed to provide high-fidelity, background free imaging of CO. Images of the peak-SF,1f signal are presented for a laminar CO-H2 diffusion flame in air at atmospheric pressure. We demonstrate that this technique is sensitive enough to image nascent CO in flames and present a strategy for simulating the WM-PLIF harmonic signals. PMID- 29240193 TI - Off-axis tilt compensation in common-path digital holographic microscopy based on hologram rotation. AB - We present a simple and effective compensation method for the off-axis tilt in common-path digital holographic microscopy (CPDHM) by introducing a rotating operation on the hologram. The proposed method mainly requires a digital reference hologram (DRH), which is a rotated version of the original one; it is assumed to be easy to obtain by rotating the specimen's hologram 180 degrees . In this way, the off-axis tilt could be removed by subtracting the retrieved phase of DRH from the retrieved phase of the original hologram, but without any complex spectrum centering judgment, fitting procedures, or prior knowledge of the system. This highly automatic and efficient performance makes our approach available for real-time quantitative phase imaging (QPI), although it limits the field of view (FOV) of the specimen. Some experimental results of microlens array and phase plate demonstrate the feasibility and effectiveness of the proposed method. PMID- 29240194 TI - Tens of hertz narrow-linewidth laser based on stimulated Brillouin and Rayleigh scattering. AB - We proposed and demonstrated a linewidth compression method of a laser based on stimulated Brillouin scattering (SBS) and a Rayleigh backscattering structure (RBS). The relationship between the output SBS laser linewidth and the input pump linewidth was studied theoretically and experimentally. It is shown that the narrower linewidth of the pump laser leads to the narrower bandwidth of the SBS gain and, finally, the bandwidth of the SBS will tend to its intrinsic value as the linewidth of a pump laser narrower than 10 kHz; then the linewidth of an SBS fiber ring laser would tend to 200 Hz. In order to further reduce its linewidth with low cost, RBS and a simple dual-cavity feedback structure were added and, finally, a ~75 Hz narrow-linewidth laser with a side-mode suppression ratio of 70 dB was obtained. PMID- 29240195 TI - Sub-Rayleigh resolution ghost imaging by spatial low-pass filtering. AB - A sub-Rayleigh resolution ghost imaging experiment is performed via post detection spatial low-pass filtering of the instantaneous intensity. A super resolution reconstructed image has been achieved, in which the spatial resolution can exceed the Rayleigh diffraction limit by more than a factor of two. The resolution depends on the filter threshold, and the Rayleigh limit can be exceeded for a wide choice of threshold values. The setup is simple and easy to implement, which is an advantage for practical applications. PMID- 29240196 TI - Chromatic aberration compensation in numerical reconstruction of digital holograms by Fresnel-Bluestein propagation. AB - In this Letter, we present a method for chromatic compensation in numerical reconstruction of digitally recorded holograms based on Fresnel-Bluestein propagation. The proposed technique is applied to correct the chromatic aberration that arises in the reconstruction of RGB holograms of both millimeter- and micrometer-sized objects. The results show the feasibility of this strategy to remove the wavelength dependence of the size of the numerically propagated wavefields. PMID- 29240197 TI - Self-tuning optical resonator. AB - We demonstrate a nonlinear optical resonator that tunes itself onto resonance with an input beam. In a monolithic Fabry-Perot cavity implemented in rubidium doped periodically poled potassium titanyl phosphate, an intensity-dependent refractive index produces line pulling by multiple free-spectral ranges (FSRs). In this condition, the cavity passively maintains optical resonance in the face of FSR-scale excursions of the drive laser frequency: when one resonant operating point becomes unstable, the resonator rapidly transitions to another resonant operating point. We demonstrate stable second-harmonic generation with no active feedback to the laser or cavity. The self-tuning effect appears to be supported by a very strong, previously unreported optical nonlinearity. PMID- 29240198 TI - Editorial: Optics Letters-40 Years and Beyond. AB - Editor-in-Chief Xi-Cheng Zhang reflects on the past and present of Optics Letters and looks ahead to its future. PMID- 29240199 TI - Late Dental Implant Failures Associated with Retained Root Fragments: Case Reports with Histologic and SEM Analysis. AB - Interest has recently developed in the purposeful retention of root fragments with their periodontal apparatus to support bone and soft tissue at immediate implant sites in the esthetic zone. This methodology is designed to avoid bone grafting, connective tissue grafts, and the use of membranes and may have short term benefits in terms of tissue preservation. However, it is not completely without long-term risks. At times, implants may be unintentionally placed into edentulous sites where root fragments remain. This report presents two cases of long-term failure postloading associated with unintentionally retained root fragments. Histologic evaluation evidenced retained root fragments in close association with dental implants and the surrounding bone. Scanning electron microscopic evaluation revealed that the failed implant surfaces were infiltrated by bacterial deposits and calculus. Clinicians should exercise caution when placing dental implants in sites with retained root fragments, as long-term risks may be associated with this therapy. PMID- 29240200 TI - Immediate Placement of Ultrawide-Diameter Implants in Molar Sockets: Description of a Recommended Technique. AB - Immediate implant placement is performed less frequently in molar extraction sockets than in single root sockets. This is mainly due to the tripodal anatomical configuration of molar roots, which is perceived as complex and therefore unsuitable. The mechanical burden of molar sites, combined with much larger socket dimensions, make it amenable to the use of ultrawide-diameter dental implants. This article describes a practical, sequenced technique that can be used predictably for immediate implant placement in maxillary and mandibular first molar sockets, using a dry skull model for clarification. This detailed description is based on the experience of more than 580 clinical cases over a 10 year period. PMID- 29240201 TI - Coronally Advanced Flap with Site-Specific Application of Connective Tissue Graft for the Treatment of Multiple Adjacent Gingival Recessions: A 3-Year Follow-Up Case Series. AB - The aim of this study was to evaluate the short- (1 year) and longer-term (3 years) effectiveness of a surgical procedure combining coronally advanced flap (CAF) with site-specific application of connective tissue graft (CTG) in the treatment of multiple gingival recessions (MGR). A total of 60 periodontally healthy subjects with esthetic complaints due to excessive tooth length presenting multiple (at least three) Miller Class I and II gingival recession defects (>= 1 mm) affecting adjacent teeth in the maxilla and mandible were enrolled in the study. All recessions were treated with CAF. The CTG was applied in gingival defects with a baseline keratinized tissue height (KTH) < 1 mm or with KTH between 1 and 2 mm and gingival thickness < 1 mm. Complete root coverage (CRC) was obtained in 98.5% (263 of 267 recessions) and in 94.7% (256 of 267 recessions) of the sites at the 1- and 3-year follow-up visits, respectively. No statistically significant differences were found at 1 and 3 years in terms of CRC between sites with or without CTG and between sites belonging to the maxilla or mandible. A greater increase in KTH at 3 years was demonstrated in sites treated with CTG. This was ascribed to the tendency of the mucogingival line to regain its genetically determined position and not to graft exposure. The present study demonstrated that the proposed surgical technique combining CAF with site specific application of CTG was an effective treatment modality for the management of MGR, obtaining 93% CRC in the CAF-treated sites and 100% CRC in the sites treated with CAF + CTG at 3 years. PMID- 29240202 TI - Effectiveness of Two Different Lingual Flap Advancing Techniques for Vertical Bone Augmentation in the Posterior Mandible: A Comparative, Split-Mouth Cadaver Study. AB - Vertical ridge augmentation in the posterior mandible is a technique-sensitive procedure that requires adequate anatomical knowledge and precise surgical skills to minimize the risk of complications. One of the most important but also challenging aspects of the surgical technique is proper flap management to allow for passive flap closure and reduce the chances of postoperative complications affecting deep anatomical spaces. This article presents a detailed description of a novel lingual flap advancement technique and its validation via a split-mouth, comparative study using a cadaver model. A total of 12 fresh cadaver heads presenting bilateral posterior mandibular edentulism were selected. Sides were randomized to receive a classic lingual flap release technique (control) or the modified technique presented here, which involves the intentional preservation of the mylohyoid muscle attachment to the mandible. Vertical flap release was measured at three different zones using standard forces. The mean difference between the test and control group in zones I (retromolar pad area), II (middle area), and III (premolar area) was 8.273 +/- 1.794 mm (standard error of the mean [SEM] = 0.5409 mm), 10.09 +/- 2.948 mm (SEM = 0.8889 mm), and 10.273 +/- 2.936 mm (SEM = 0.8851 mm), respectively, reaching very strong statistical significance (P < .0001) in all three zones. PMID- 29240203 TI - Scar Tissue Formation Following Alveolar Ridge Preservation: A Case Control Study. AB - The aim of this retrospective case control study was to compare a porcine collagen matrix (Mucograft Seal, Geistlich) with a free gingival punch graft with respect to size, invagination, and color of resulting soft tissue scar formation. Following definition of inclusion and exclusion criteria, 22 patients were retrospectively included in this study. The patients were divided into two groups. In group A, the extraction socket was filled with bovine bone mineral (Bio-Oss, Geistlich) and covered with a free gingival punch graft. In group B, the extraction socket was filled with bovine bone mineral (Bio-Oss) and covered with porcine collagen matrix. After final prosthetic reconstruction (18 implant retained crowns and 4 fixed partial dentures), two independent examiners evaluated the size, invagination, and color of the soft tissue scar using a modified scar-evaluation scale originally developed for dermal wounds (lower values correspond to less scarring). Patient satisfaction was recorded using a questionnaire. Patient records were screened for frequency and costs of scar removal treatment. The average scar score for groups A and B was 1.33 and 4.3, respectively, revealing significantly less scarring in group B (P = .000295). Frequency and costs of scar removal treatment were statistically significantly higher in Group A (P = .000234). Patient satisfaction was not statistically significantly different between the treatment groups (P = .711 for group A and P = .809 for group B. The results suggest that alveolar ridge preservation using bovine bone mineral and porcine collagen matrix leads to less scar tissue formation when compared with bovine bone mineral and free gingival punch grafts from the palate. PMID- 29240204 TI - Buccal-Lingual Bone Remodeling in Immediately Loaded Fresh Socket Implants: A Cone Beam Computed Tomography Study. AB - The aim of this study was to evaluate buccal-lingual bone remodeling after fresh socket implant placement and immediate loading at 3 years of follow-up by cone beam computed tomography (CBCT). A total of 96 implants were placed in fresh sockets in anterior maxillary regions and immediately loaded. The sockets were divided into two groups related to buccal bone thickness: group A, with a buccal bone thickness > 1 mm, and group B, with a thickness <= 1 mm. The CBCT scans were performed before tooth extractions and 3 years after implant placement, and measurements were assessed. At 3 years, all fresh sockets in both groups presented considerable buccal-palatal crestal reduction. In both groups, statistically significant (P < .05) bone loss was found between time points. There was no statistically significant difference in bone reduction between groups at 3 years of follow-up. Nevertheless, sockets with vertical axis presented more bone volume reduction than those with axis parallel to buccal bone after implant placement. PMID- 29240205 TI - Regenerative Treatment of Periodontal Intrabony Defects Using Autologous Dental Pulp Stem Cells: A 1-Year Follow-Up Case Series. AB - The present case series aimed to explore the potential clinical benefits of the application of dental pulp stem cells (DPSCs) in the regenerative treatment of deep intrabony defects. A total of 11 isolated intrabony defects in 11 chronic periodontitis patients were accessed with a minimally invasive flap and filled with DPSCs loaded on a collagen sponge. A tooth requiring extraction for impaction or malpositioning was used as an autologous source for DPSCs. An average clinical attachment level gain of 4.7 +/- 1.5 mm associated with a residual mean probing depth (PD) of 3.2 +/- 0.9 mm and remarkable stability of the gingival margin was observed at 1 year. Complete pocket closure (PD < 3 mm) was achieved in 63.6% of the experimental sites. Clinical outcomes were supported by the radiographic analysis showing a bone fill of 3.6 +/- 1.9 mm. PMID- 29240206 TI - Peri-implantitis Management in the Esthetic Zone in a Periodontally Compromised Patient: Five-Year Results Including Cone Beam Computed Tomography. AB - A 59-year-old woman was referred for specialist treatment due to peri-implantitis affecting four implants in the anterior maxilla. On presentation, probing depths were up to 12 mm with bleeding on probing/suppuration and extensive peri-implant bone loss. There was a history of treated chronic periodontitis. Nonsurgical management was followed by regenerative peri-implant surgery. Peri-implant probing depths reduced to a maximum of 5 mm and remained stable throughout the 5 year follow-up period. Cone beam computed tomography at 2 years postoperatively confirmed the presence of regenerated peri-implant tissue and integration with the pre-existing peri-implant bone. PMID- 29240207 TI - Incision Design and Soft Tissue Management to Maintain or Establish an Interproximal Papilla Around Integrated Implants: A Case Series. AB - Maintenance or reconstruction of interproximal papilla for a successful dental implant restoration can be challenging. To date, the results from various surgical and prosthetic techniques to maintain or regenerate papilla adjacent to dental implants have been unpredictable. To maintain the quality of the soft tissue around an implant, the blood supply must be preserved and formation of scar tissue must be minimized during surgery. Therefore, incision design is vital to producing an esthetic and successful dental implant restoration. In this study, specific incision designs and soft tissue management techniques were used to preserve or create interproximal papilla around single or adjacent implants. PMID- 29240208 TI - Effect of Different Intraradicular Posts on the Color of the Buccal Gingiva at Teeth Restored with Zirconia Crowns. AB - The purpose of this study was to test whether prosthetic treatment with different intraradicular posts influences the color of the buccal gingiva at teeth restored with zirconia crowns. A total of 31 patients in need of a full-coverage single crown at an endodontically treated premolar, canine, or incisor in the maxilla or the mandible were included. The patients were randomly assigned to receive composite build-ups using titanium (Ti), zirconia (Zi), or glass-fiber (Gf) posts or a build-up using no post at all (NP). All the teeth were restored with veneered zirconia single crowns. Spectrophotometric color measurements of the buccal gingiva were taken at the test teeth prior to and after the prosthetic treatment, and at the contralateral vital control tooth. The differences of the color components DeltaL, Deltaa, and Deltab and the total color difference DeltaE between the test tooth prior to and after treatment and between the test and control tooth were calculated. The color differences were analyzed to determine whether they varied from 0 and 3.7, the threshold for detection by the human eye. Analysis of variance was performed to compare DeltaE, DeltaL, Deltaa, and Deltab in the four post groups. The prosthetic treatment induced a significant color change DeltaE in all the groups (Ti: DeltaE1 = 6.4 +/- 1.9; Zi: 7.1 +/- 2.0; Gf: 6.2 +/- 3.5; NP: 6.6 +/- 3.5). There was no significant difference between Ti, Zi, Gf, and NP with respect to DeltaE, DeltaL, Deltaa, and Deltab. Gingival color DeltaE differed significantly between the test and control teeth before (Ti: DeltaE = 6.8 +/- 3.0; Zi: 9.0 +/- 3.5; Gf: 5.7 +/- 2.1; NP: 8.2 +/- 2.8) and after prosthetic treatment (Ti: DeltaE = 6.0 +/- 2.8; Zi: 7.1 +/- 2.9; Gf: 7.2 +/ 3.0; NP: 6.9 +/- 2.6). The use of different intraradicular posts (titanium, zirconia, glass fiber) or no post at all did not influence the color of the buccal gingiva at teeth restored with zirconia crowns. There was a significant gingival color difference between endodontically treated teeth and vital control teeth, both before and after prosthetic treatment. PMID- 29240209 TI - Effect of Deproteinized Bovine Bone Mineral at Implant Dehiscence Defects Grafted by the Sandwich Bone Augmentation Technique. AB - The aim of this study was to compare the amount of radiographic horizontal buccal bone thickness (BBT) at implant dehiscence defects grafted with the sandwich bone augmentation (SBA) and modified sandwich bone augmentation (MSBA) techniques. Compared to the SBA technique, the MSBA approach involved an additional outer layer of deproteinized bovine bone mineral (DBBM) to maintain the space for bone regeneration for longer periods. A total of 19 patients, each with a buccal implant dehiscence defect, were recruited. The control group was treated with SBA technique (n = 10), while the test group was treated with MSBA technique. Cone beam computed tomography (CBCT) scans, taken at three time points (before and immediately after implant surgery, and 6 months post-treatment) were used to assess the BBT at the implant platform (-1.8 mm), the rough-smooth junction (0 mm), and 2, 4, 6, 8, and 10 mm apical to the rough-smooth junction. At 6 months postsurgery, the mean BBT in control and test groups was 1.69 +/- 0.38 mm and 2.55 +/- 0.21 mm, respectively. Mean BBT was significantly greater in the test group at 2, 4, 6, and 8 mm apical to the rough-smooth junction. There was no statistical difference in the mean BBT at the implant platform, the rough-smooth junction, and 10 mm apical to the rough-smooth junction between the two groups (P > .05). Within the limitations of this study, it was concluded that the additional layer of DBBM enhanced BBT along the implant, except at the smooth collar. PMID- 29240210 TI - Three-Dimensional Bone Augmentation and Immediate Implant Placement via Transcrestal Sinus Lift: Five-Year Clinical Outcomes. AB - This study proposed a surgical technique that solves three-dimensional conditions of extreme bone atrophy. A total of 278 surgeries with transcrestal sinus lift and fresh frozen allogenous bone blocks were performed. A total of 1,024 implants were placed. After 60 months of observation, 969 implants were considered grade I (successful), 24 grade II (satisfactory survival), and 8 grade III (compromised survival). The cumulative success and survival rates, respectively, were 94.6% and 97.7%. This innovative procedure is very effective in selected cases. Fresh frozen human bone allografts have been shown to be a reliable biomaterial to increase bone volume with simultaneous dental implant placement. PMID- 29240211 TI - Retrospective Analysis of the Outcome of Ridge Preservation with Anorganic Bovine Bone Minerals: Microcomputed Tomographic Assessment of Wound Healing in Grafted Extraction Sockets. AB - A total of 68 extraction sockets were grafted with anorganic bovine bone mineral and covered by dense polytetrafluoroethylene membrane. Quantitative analysis of three-dimensional microcomputed tomography imaging of core samples retrieved after a mean of 21.0 +/- 14.2 weeks revealed 40.1% bone volume fraction (bone volume [BV]/total volume [TV]) and 12% residual graft. Evidence of de novo bone formation was observed in the form of discrete islands of newly formed bone in direct apposition to graft particles, separated from parent bone. Anterior sockets exhibited a significantly higher percentage of residual graft compared to premolar sockets (P = .05). The BV/TV and percentage of residual graft correlated well with histomorphometric analysis of the same sites, but not with implant outcomes. PMID- 29240212 TI - Accuracy of Implants Placed with Surgical Guides: Thermoplastic Versus 3D Printed. AB - This study was conducted to evaluate the accuracy of implants placed using two different guided implant surgery materials: thermoplastic versus three dimensionally (3D) printed. A cone beam computed tomography (CBCT) scan previously obtained and selected for single-tooth implant replacement was converted into a Digital Imaging and Communications in Medicine (DICOM) file. All models were planned and exported for printing using BlueSkyBio Plan Software with the DICOM files. A total of 20 3D-printed mandibular quadrant jaws replicating the CBCT were printed by Right Choice Milling, as was the control model to accept the control implant. Previously, 10 thermoplastic and 10 3D-printed surgical guides had been made by the same lab technician at Right Choice Milling. One Nobel Biocare implant with a trilobe connection was placed per guide and replica jaw model pair. Implants were placed using the thermoplastic and 3D-printed surgical guides, representing the two test groups, following the Nobel Biocare guided surgical protocol. A total of 21 CBCT scans were then taken, one for the control implant and one for each test implant. The CBCT volume was converted to a DICOM file and transferred to Invivo5 software version 5.4 (Anatomage). The DICOM file of each test implant was superimposed over the DICOM file of the control. The deviation of the head of the implant, the deviation of the apex of the implant, and the angle of deviation were evaluated from measurements on the superimposition of the control and test implants. Mann-Whitney U test was used to test the null hypotheses at alpha = .05 and a confidence interval of 95%. Descriptive statistics were used for the average +/- standard deviation. The implants placed with the thermoplastic surgical guides showed an average of 3.40 degrees of angular deviation compared to 2.36 degrees for implants placed with the 3D-printed surgical guides (P = .143). The implants placed with the thermoplastic surgical guides showed an average of 1.33 mm of deviation at the head of the implant compared to 0.51 mm for implants placed with the 3D-printed surgical guides (P < 0.001). The implants placed with the thermoplastic surgical guides showed an average of 1.6 mm of deviation at the apex of the implant compared to 0.76 mm for implants placed with the 3D-printed surgical guides (P < .001). There was no significant difference in the angular deviations of implants placed with thermoplastic surgical guides compared to those placed with the 3D printed surgical guide. However, the locations of the implant head and implant apex were significantly more accurate for the implants placed with the 3D-printed surgical guides compared to those placed with the thermoplastic surgical guides. PMID- 29240213 TI - Minimally Invasive Treatment of an Ankylosed, Severely Discolored, and Intruded Central Incisor with a Masking Ceramic Veneer: A Clinical Report. AB - Dental therapy of traumatically ankylosed maxillary anterior teeth with an additional slight root resorption represents a great challenge for the restorative team and requires intensive planning and communication between patient, dentist, orthodontist, periodontist, and dental technician. The inhibition of vertical growth often makes dental intervention indispensable. Porcelain laminate veneers have been successfully used for more than two decades, mainly on anterior teeth, and was the minimally invasive treatment option for the present case report. Preprosthetic planning with a digital approach of the width length ratio and the red-white esthetics were important prerequisites for a satisfactory treatment result. The treatment goal was clarified using a wax-up and a corresponding template for intraoral verification with a mock-up. The template also served as a preparation guide. Despite all risk factors, including the endodontic treatment, the 3-mm intruded position, and the slight root resorption, the patient and the restorative team decided to restore the situation with two feldspathic-ceramic veneers to provide an esthetic, time-saving, nonsurgical process for the patient. PMID- 29240214 TI - Impact of Dental Implant Surface Modifications on Adhesion and Proliferation of Primary Human Gingival Keratinocytes and Progenitor Cells. AB - The success of dental implants depends mainly on osseointegration and gingival sealing. Therefore, early attachment and spreading of epithelial cells might be critical for a positive outcome. Research in dental implant materials has primarily focused on surface roughness, defined by the average roughness (Ra) index, as it promotes the process of osseointegration. This study explored its influence on soft tissue attachment by looking mainly at adhesion, proliferation, and spreading of primary human cells belonging to the epithelial lineage. Characterized human gingival keratinocytes, gingival and epithelial progenitor cells were seeded on machined (S1; Ra = 0.3 to 0.6 MUm), Ti-Unite (S2; Ra = 1.2 MUm), and SLA (S3; Ra = 2 MUm) implants. Cell adhesion with early proliferation and spreading were evaluated by combining a biochemical vitality test with imaging analyses. Findings showed that adhesion was significantly higher on S1 (36% +/- 2%) and S2 (44% +/- 7%) than on S3 (23% +/- 6%), while early proliferation was slightly improved on S1. The resulting data, obtained through an innovative and easily reproducible in vitro method, suggest that implant surface roughness affects epithelial cell adhesion and proliferation. PMID- 29240215 TI - A New Prognostication System for Dental Implants. AB - Given the popularity of dental implants, determining their prognosis is an integral component of dental practice. An accurate prognosis is crucial to development of an appropriate treatment plan and may require alterations as overall status or the status of implants or natural teeth change. The importance of an established set of factors for determining implant prognosis would be highlighted in dentist-patient communication and in interdisciplinary collaboration. The main objective of the proposed prognostication system is short and long-term success of dental implants. The aim of this study was to review evidence-based prognostic factors including surgical, peri-implant, prosthetic, and overall considerations in implant dentistry and to propose a new prognostication system. A blind survey was taken by 67 prosthodontists, periodontists, and oral surgeons at three dental schools to assess the importance of each consideration based on clinical experience and available evidence. The results supported incorporation of the comprehensive review of evidence-based prognostic factors into the proposed dynamic system for dental implant prognostication. PMID- 29240216 TI - Pigmentation on Gingiva: A Diagnostic Dilemma. AB - Pigmentation on gingiva can be physiologic or pathologic. Gingival pigmentation is present from birth in certain individuals. However, sudden occurrence of pigmentation suggests some systemic association. In the present case, a patient was referred by a physician for biopsy of the tissue along with gingival depigmentation. The depigmentation procedure was performed in both arches, and the biopsy specimen was sent for histopathologic examination. This case highlights the importance of biopsy of gingival pigmentation with a history of sudden occurrence. A biopsy is warranted to distinguish pathologic pigmentation from physiologic. PMID- 29240217 TI - Interdependence of free zinc changes and protein complex assembly - insights into zinc signal regulation. AB - Cellular zinc (Zn(ii)) is bound with proteins that are part of the proteomes of all domains of life. It is mostly utilized as a catalytic or structural protein cofactor, which results in a vast number of binding architectures. The Zn(ii) ion is also important for the formation of transient protein complexes with a Zn(ii) dependent quaternary structure that is formed upon cellular zinc signals. The mechanisms by which proteins associate with and dissociate from Zn(ii) and the connection with cellular Zn(ii) changes remain incompletely understood. In this study, we aimed to examine how zinc protein domains with various Zn(ii)-binding architectures are formed under free Zn(ii) concentration changes and how formation of the Zn(ii)-dependent assemblies is related to the protein concentration and reactivity. To accomplish these goals we chose four zinc domains with different Zn(ii)-to-protein binding stoichiometries: classical zinc finger (ZnP), LIM domain (Zn2P), zinc hook (ZnP2) and zinc clasp (ZnP1P2) folds. Our research demonstrated a lack of changes in the saturation level of intraprotein zinc binding sites, despite various peptide concentrations, while homo- and heterodimers indicated a concentration-dependent tendency. In other words, at a certain free Zn(ii) concentration, the fraction of a formed dimeric complex increases or decreases with subunit concentration changes. Secondly, even small or local changes in free Zn(ii) may significantly affect protein saturation depending on its architecture, function and subcellular concentration. In our paper, we indicate the importance of interdependence of free Zn(ii) availability and protein subunit concentrations for cellular zinc signal regulation. PMID- 29240223 TI - Holy flux: spatial and temporal variation in massive pulses of emerging insect biomass from western U.S. rivers. PMID- 29240224 TI - Metabolic characterization of anaerobic fungi provides a path forward for bioprocessing of crude lignocellulose. AB - The conversion of lignocellulose-rich biomass to bio-based chemicals and higher order fuels remains a grand challenge, as single-microbe approaches often cannot drive both deconstruction and chemical production steps. In contrast, consortia based bioprocessing leverages the strengths of different microbes to distribute metabolic loads and achieve process synergy, product diversity, and bolster yields. Here, we describe a biphasic fermentation scheme that combines the lignocellulolytic action of anaerobic fungi isolated from large herbivores with domesticated microbes for bioproduction. When grown in batch culture, anaerobic fungi release excess sugars from both cellulose and crude biomass due to a wealth of highly expressed carbohydrate active enzymes (CAZymes), converting as much as 49% of cellulose to free glucose. This sugar-rich hydrolysate readily supports growth of Saccharomyces cerevisiae, which can be engineered to produce a range of value-added chemicals. Further, construction of metabolic pathways from transcriptomic data reveals that anaerobic fungi do not catabolize all sugars that their enzymes hydrolyze from biomass, leaving other carbohydrates such as galactose, arabinose, and mannose available as nutritional links to other microbes in their consortium. Although basal expression of CAZymes in anaerobic fungi is high, it is drastically amplified by cellobiose breakout products encountered during biomass hydrolysis. Overall, these results suggest that anaerobic fungi provide a nutritional benefit to the rumen microbiome, which can be harnessed to design synthetic microbial communities that compartmentalize biomass degradation and bioproduct formation. PMID- 29240225 TI - Modeling electron competition among nitrogen oxides reduction and N2 O accumulation in hydrogenotrophic denitrification. AB - Hydrogenotrophic denitrification is a novel and sustainable process for nitrogen removal, which utilizes hydrogen as electron donor, and carbon dioxide as carbon source. Recent studies have shown that nitrous oxide (N2 O), a highly undesirable intermediate and potent greenhouse gas, can accumulate during this process. In this work, a new mathematical model is developed to describe nitrogen oxides dynamics, especially N2 O, during hydrogenotrophic denitrification for the first time. The model describes electron competition among the four steps of hydrogenotrophic denitrification through decoupling hydrogen oxidation and nitrogen reduction processes using electron carriers, in contrast to the existing models that couple these two processes and also do not consider N2 O accumulation. The developed model satisfactorily describes experimental data on nitrogen oxides dynamics obtained from two independent hydrogenotrophic denitrifying cultures under various hydrogen and nitrogen oxides supplying conditions, suggesting the validity and applicability of the model. The results indicated that N2 O accumulation would not be intensified under hydrogen limiting conditions, due to the higher electron competition capacity of N2 O reduction in comparison to nitrate and nitrite reduction during hydrogenotrophic denitrification. The model is expected to enhance our understanding of the process during hydrogenotrophic denitrification and the ability to predict N2 O accumulation. PMID- 29240226 TI - Engineering and cytosolic delivery of a native regulatory protein and its variants for modulation of ERK2 signaling pathway. AB - The modulation of a cell signaling process using a molecular binder followed by an analysis of the cellular response is crucial for understanding its role in the cellular function and developing pharmaceuticals. Herein, we present the modulation of the ERK2-mediated signaling pathway through the cytosolic delivery of a native regulatory protein for ERK2, that is, PEA-15 (phosphoprotein enriched in astrocytes, 15 kDa), and its engineered variants using a bacterial toxin-based delivery system. Based on biochemical and structural analyses, PEA-15 variants with different phosphorylation sites and a high affinity for ERK2 were designed. Semi-rational approach led to about an 830-fold increase in the binding affinity of PEA-15, resulting in more effective modulation of the ERK2-mediated signaling. Our approach enabled an understanding of the cellular function of the ERK2 mediated signaling process and the effect of PEA-15 phosphorylation on its action as an ERK2 blocker. We demonstrated the utility and potential of our approach by showing an efficient cytosolic delivery of these PEA-15 variants and the effective suppression of cell proliferation through the inhibition of the ERK2 function. The present approach can be used broadly for modulating the cell signaling processes and understanding their roles in cellular function, as well as for the development of therapeutics. PMID- 29240227 TI - Advances in applications of rhamnolipids biosurfactant in environmental remediation: A review. AB - The objective of this review is to provide a comprehensive overview of the advances in the applications of rhamnolipids biosurfactants in soil and ground water remediation for removal of petroleum hydrocarbon and heavy metal contaminants. The properties of rhamnolipids associated with the contaminant removal, that is, solubilization, emulsification, dispersion, foaming, wetting, complexation, and the ability to modify bacterial cell surface properties, were reviewed in the first place. Then current remediation technologies with integration of rhamnolipid were summarized, and the effects and mechanisms for rhamnolipid to facilitate contaminant removal for these technologies were discussed. Finally rhamnolipid-based methods for remediation of the sites co contaminated by petroleum hydrocarbons and heavy metals were presented and discussed. The review is expected to enhance our understanding on environmental aspects of rhamnolipid and provide some important information to guide the extending use of this fascinating chemical in remediation applications. PMID- 29240228 TI - Chromatographic methods in HIV medicine: Application to therapeutic drug monitoring. AB - HIV antiretroviral therapy spans several different drug classes, meant to combat various aspects of viral infection and replication. Many authors have argued the benefits of therapeutic drug monitoring (TDM) for the HIV patient including compliance assurance and assessment of appropriate drug concentrations; however, the array of drug chemistries and combinations makes TDM an arduous task. HPLC-UV and LC-MS/MS are both frequent instruments for the quantification of HIV drugs in biological matrices with investigators striving to balance sensitivity and affordability. Plasma, the dominant matrix for these analyses, is prepared using protein precipitation, liquid-liquid extraction or solid-phase extraction depending on the specific complement of analytes. Despite the range of polarities found in drug classes relevant to HIV therapeutics, most chromatographic separations utilize a hydrophobic column (C18 ). Additionally, as the clinically relevant samples for these assays are infected with HIV, along with possible co infections, another important aspect of sample preparation concerns viral inactivation. Although not routine in clinical practice, many published analytical methods from the previous two decades have demonstrated the ability to conduct TDM in HIV patients receiving various medicinal combinations. This review summarizes the analytical methods relevant to TDM of HIV drugs, while highlighting respective challenges. PMID- 29240229 TI - Thermoactivation of a cellobiohydrolase. AB - We have measured activity and substrate affinity of the thermostable cellobiohydrolase, Cel7A, from Rasamsonia emersonii over a broad range of temperatures. For the wild type enzyme, which does not have a Carbohydrate Binding Module (CBM), higher temperature only led to moderately increased activity against cellulose, and we ascribed this to a pronounced, temperature induced desorption of enzyme from the substrate surface. We also tested a "high affinity" variant of R. emersonii Cel7A with a linker and CBM from a related enzyme. At room temperature, the activity of the variant was similar to the wild type, but the variant was more accelerated by temperature and about two-fold faster around 70 degrees C. This better thermoactivation of the high-affinity variant could not be linked to differences in stability or the catalytic process, but coincided with less desorption as temperature increased. Based on these observations and earlier reports on moderate thermoactivation of cellulases, we suggest that better cellulolytic activity at industrially relevant temperatures may be attained by engineering improved substrate affinity into enzymes that already possess good thermostability. PMID- 29240230 TI - LC-MS/MS profiling of polyphenol-enriched leaf, stem and root extracts of Korean Humulus japonicus Siebold & Zucc and determination of their antioxidant effects. AB - Polyphenols from ethyl acetate extracts from the leaves, stems and roots of Korean Humulus japonicus were comprehensively profiled using liquid chromatography-electrospray ionization-tandem mass spectrometry. A total of 36 polyphenols were detected, of which 26 were structurally characterized based on their [M - H]- peak, tandem mass spectrometry fragmentation pattern, UV-vis absorption and published data. Validation data provided satisfactory results for the evaluated parameters. The determination coefficients were >=0.9812. The limits of detection and quantification were 0.017-0.573 and 0.056-1.834 mg/L, respectively, indicating good performance limits. The accuracy (expressed as percentage recovery) at 50 and 100 mg/L was 71.4-99.7 and 75.1-105.1%, with precisions (expressed as relative standard deviation) of 1.5-7.3 and 0.8-4.1%, respectively, indicating acceptable accuracy and precision values. The leaves were rich in total polyphenols (3089.9 +/- 6.4 mg/kg of fresh sample) followed by the stems (1313.9 +/- 6.4 mg/kg of fresh sample) and roots (655.2 +/- 2.7 mg/kg of fresh sample). Antioxidant activity, determined by alpha,alpha-diphenyl-beta picrylhydrazyl, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) scavenging activity and ferric reducing antioxidant power assay, revealed the lowest EC50 value for the leaf extracts, indicating a higher scavenging activity in this tissue followed by the roots and stems. Overall, the results indicated that H. japonicus is rich in polyphenols and could be a potential alternative to Humulus lupulus (hop plant) in the brewery industry. PMID- 29240231 TI - The issue of HPLC determination of endogenous lipoic acid in human plasma. AB - Lipoic acid (LA) is used extensively as a therapeutic agent for the treatment of various diseases. Many methods have been reported for the determination of LA plasma levels and its metabolites after its supplementation, but available information concerning endogenous plasma levels is still scarce. Studies which directly focused on determining the endogenous plasma levels provided highly controversial results, <4.9 nmol/L or 143.7-197.0 nmol/L. The main aim of this study was to verify the levels of free LA in the plasma of 40 individuals (17 women, 23 men). This group was nonsupplemented with LA and met the conditions for incorporation into the blood donors register. We measured the levels of LA using an HPLC method with very sensitive coulometric detection after previous sample preparation including deproteination and solid-phase extraction with a Phenyl cartridge. Our limit of detection was 1.85 nmol/L and was better than the values reported in studies that directly focused on determining the endogenous plasma levels of LA: 2.4 and 4.9 nmol/L respectively. However, the levels of free LA in the plasma of nonsupplemented voluntary blood donors were not detectable in all cases. The presented results of our study show that endogenous concentrations of LA are <1.85 nmol/L. PMID- 29240232 TI - Trends in self-reported oral health of US adults: National Health and Nutrition Examination Survey 1999-2014. AB - OBJECTIVE: Single-item self-reported oral health (SROH) is a convenient and reliable measure for the assessment of population-based oral health. However, little is known about trends and its associations among US adults. This study investigated trends in SROH (aged 20+ years) and the associated factors among adults living in the United States. METHODS: Self-reported oral health data for 41 621 adults aged 20+ years from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2014 were analysed. Survey-weighted descriptive statistics were computed to provide nationally representative estimates. Multivariable logistic regression was performed separately for each survey period with SROH as the primary outcome. Independent variables included were age, gender, race/ethnicity, education level and family poverty income ratio or PIR. Pooled survey-weighted multivariable logistic regression was also performed to consider possible time-changing effects. RESULTS: The survey-weighted proportions of "excellent or very good" in SROH increased from 27% in 1999-2000 (n = 4873) to 38% in 2013-2014 (n = 5765). Separate multivariable logistic analyses for each survey period suggested that females, Whites (vs Mexican and Black Americans) as well as respondents from high family PIR had higher odds of reporting their oral health as "excellent or very good" (P < .05). The pooled multivariable logistic model confirmed results in the separate logistic regression, and respondents in the more recent survey periods had higher probabilities of reporting "excellent or very good" oral health. Respondents aged 50-59 years were found to have relatively lower probabilities of reporting "excellent or very good" oral health, while people aged 20-29 years had higher probabilities than those aged 30-39 years. Compared to respondents with lower education, those with higher education were more likely to report their oral health as excellent or very good. CONCLUSIONS: Self-reported oral health improved from 1999 to 2014. In general, respondents who were young, female, White, had higher education or higher income or were surveyed in more recent years reported excellent or very good oral health. PMID- 29240233 TI - Blue honeysuckle (Lonicera caerulea subsp. edulis (Turcz. ex Herder) Hulten.) berries and changes in their ingredients across different locations. AB - BACKGROUND: Interest in organic blue honeysuckle berries has increased in recent years. They are rich in various health-promoting compounds which are sensitive to different environmental factors and are modified during the growing season. RESULTS: Honeysuckle berries from different locations differed significantly in their contents of primary and secondary metabolites. The location Ogulin, with the highest altitude and consequently high UV radiation, had the highest phenolic content (259.85 mg per 100 g). Additionally, Vukovski Vrh, with the lowest temperature, had the highest ascorbic acid content (36.83 mg per 100 g), while Smartno pri Litiji and Visnja Gora, with the highest precipitation, had the highest organic acid contents (885.85 and 850.01 mg per 100 g respectively). A combination of stressful environmental conditions of temperature, water source and light intensity led to the highest saponin content in Visnja Gora (695 mg per 100 g), the highest tannin content in Dolnje Impolje (134 mg per 100 g) and the highest sugar content (2585.45 mg per 100 g) in Vucetinac. CONCLUSION: The contents of bioactive substances were influenced by various environmental factors such as temperature, UV radiation, altitude, light intensity and fruit ripening stage. Different compounds respond distinctly to different environmental factors. (c) 2017 Society of Chemical Industry. PMID- 29240235 TI - Three-dimensional digital reconstruction of skin epidermis and dermis. AB - This study describes how three-dimensional (3D) human skin tissue is reconstructed, and provides digital anatomical data for the physiological structure of human skin tissue based on large-scale thin serial sections. Human skin samples embedded in paraffin were cut serially into thin sections and then stained with hematoxylin-eosin. Images of serial sections obtained from lighting microscopy were scanned and aligned by the scale-invariant feature transform algorithm. 3D reconstruction of the skin tissue was generated using Mimics software. Fibre content, porosity, average pore diameter and specific surface area of dermis were analysed using the ImageJ analysis system. The root mean square error and mutual information based on the scale-invariant feature transform algorithm registration were significantly greater than those based on the manual registration. Fibre distribution gradually decreased from top to bottom; while porosity showed an opposite trend with irregular average pore diameter distribution. A specific surface area of the dermis showed a 'V' shape trend. Our data suggested that 3D reconstruction of human skin tissue based on large-scale serial sections could be a valuable tool for providing a highly accurate histological structure for analysis of skin tissue. Moreover, this technology could be utilized to produce tissue-engineered skin via a 3D bioprinter in the future. PMID- 29240234 TI - Prospective study feasibility: Screening of antenatal total abnormal pulmonary venous return. AB - INTRODUCTION: Total abnormal pulmonary venous return is a heart defect often missed prenatally, yet at birth, it is a surgical emergency. Antenatal detection could be improved by sonographic visualization of the anastomosis of 2 pulmonary veins in a sinus into the left atrium. The objective of this study is to evaluate the feasibility of this screening method. METHOD: Prospective observational study. Five operators selected one representative image taken during morphological ultrasound screening. Anonymized images were later assessed for quality by an expert. Both the operator and the expert were asked to rate the picture and collect clinical data. Feasibility corresponded to the percentage of images judged satisfactory by the expert; reliability corresponded to the percentage judged satisfactory by both the expert and the sonographer. RESULTS: A total of 192 patients were included. Feasibility was 73% (95% confidence interval, 67.1%-79.7%) and reliability was 81.4% (95% confidence interval, 75.9% 86.9%). There was no learning curve. CONCLUSION: This study confirms that visualization of the 2 pulmonary veins in a sinus into the left atrium at midtrimester screening is simple and reproducible. The next stage is to evaluate the sensitivity and specificity as a screening test of total abnormal pulmonary venous return and whether that would improve morbidity and mortality. PMID- 29240236 TI - Evaluation of osteoblast differentiation and function when cultured on mesoporous bioactive glass adsorbed with testosterone. AB - Mesoporous bioactive glass (MBG), a kind of porous materials with great osteoconductive and osteoinductive ability, shows promising application in bone tissue engineering due to its high specific surface area, orderly channel structure, and large pore volume. Here we reported that the proliferation, differentiation, and mineralization were promoted in MC3T3-E1 cells cultured on MBG which adsorbed with testosterone (MBG/T). We found that transcriptional activity of Runx2 which is a critical transcription factor is increased in MC3T3 E1 cells cultured on MBG/T. Intriguingly, we observed that ERK phosphorylation was enhanced in MC3T3-E1 cells cultured on MBG/T. We showed that activated Runx2 in MC3T3-E1 cells cultured on MBG/T is through Erk1/2 phosphorylation. Consistent with this result, we also found that the expression of osteoblastic marker genes were increased. Therefore, we concluded that osteoblast differentiation and mineralization was enhanced after cells cultured on MBG/T through Erk1/2 activated Runx2 pathway. Our findings provided that MBG/T is a potential material in the process of bone repair. PMID- 29240237 TI - Nonisolated diaphragmatic hernia in Simpson-Golabi-Behmel syndrome. AB - OBJECTIVE: Congenital diaphragmatic hernia (CDH) is associated with Simpson Golabi-Behmel syndrome (SGBS), but few cases diagnosed prenatally have been reported. The aim of this series is to highlight the association of nonisolated CDH with SGBS type I on prenatal ultrasound and emphasize the importance of genetic testing, fetal autopsy, and family history in confirming this diagnosis. METHOD: Retrospective review of 3 cases of SGBS type I in a single tertiary care centre. Family history, fetal ultrasound, autopsy findings, and genetic testing for GPC3 was performed for each case. RESULTS: Fetal ultrasound findings in the second trimester were CDH, omphalocele, increased nuchal fold, renal anomaly, and cleft lip and palate. Fetal autopsy confirmed the prenatal ultrasound findings and also showed dysmorphic facial features and premalignant lesions on renal and gonadal histology. Microarray and DNA analysis of the GPC3 gene confirmed the diagnosis of SGBS type I in each case. CONCLUSION: Nonisolated CDH in a male fetus suggests a diagnosis of SGBS type I. Fetal autopsy, pedigree analysis, and genetic testing for GPC3 are all essential to confirming the diagnosis. The histological findings of ovotestes and nephroblastomatosis indicate that cancer predisposition is established early in fetal life. PMID- 29240239 TI - Double Seropositive Myasthenia Gravis: A 5-Year Follow-Up. PMID- 29240238 TI - Evaluation of microfiltration and heat treatment on the microbiological characteristics, phenolic composition and volatile compound profile of pomegranate (Punica granatum L.) juice. AB - BACKGROUND: Since processing technology and storage may influence the sensory and nutritional value as well as the shelf life of pomegranate juice (PJ), mild technologies based on microfiltration may be a promising alternative to heat treatments for fruit juice preservation. In this study, physicochemical and microbiological properties of raw (RPJ), microfiltered (MPJ) and cloudy pasteurized (PPJ) PJ were compared over a period of 4 weeks. RESULTS: Data demonstrated that microfiltration was comparable to pasteurization in guaranteeing microbiological stability of the juice, avoiding spoilage of the final product. After treatment, PPJ showed the highest amounts of gallic acid (GA) and ellagic acid derivatives (EAs). During storage, the amount of ellagitannins, EAs and GA similarly decreased in all types of juice. Trends towards variations of monomeric anthocyanins in MPJ and variations of polymeric and copigmented anthocyanins in both MPJ and PPJ were found over storage. CONCLUSION: The optimization of pretreatments and filtration parameters can lead to the industrial scale-up of microfiltration technology for the development of high-quality non-heat-treated PJ. (c) 2017 Society of Chemical Industry. PMID- 29240240 TI - Ultrasound-triggered effects of the microbubbles coupled to GDNF- and Nurr1 loaded PEGylated liposomes in a rat model of Parkinson's disease. AB - The purpose of this study was to investigate ultrasound-triggered effects of the glial cell line-derived neurotrophic factor (GDNF) + nuclear receptor-related factor 1 (Nurr1)-polyethylene glycol (PEG)ylated liposomes-coupled microbubbles (PLs-GDNF + Nurr1-MBs) on behavioral impairment and neuron loss in a rat model of Parkinson's disease (PD). The unloaded PEGylated liposomes-coupled microbubbles (PLs-MBs) were characterized for zeta potential, particle size, and concentration. 6-hydroxydopamine (6-OHDA) was used to establish the PD rat model. Rotational, climbing pole, and suspension tests were used to detect behavioral impairment. The immunohistochemical staining of tyrosine hydroxylase (TH) and dopamine transporter (DAT) was used to assess the neuron loss. Western blot and quantitative real-time PCR (qRT-PCR) analysis were used to measure the expression levels of GDNF and Nurr1. The particle size of PLs-MBs was gradually increased, while the concentration and absolute zeta potential were gradually decreased as the time prolongs. 6-OHDA increased amphetamine-induced rotations and loss of dopaminergic neurons as compared to sham group. Interestingly, PLs-GDNF-MBs or PLs-Nurr1-MBs decreased rotations and increased the TH and DAT immunoreactivity. Combined of both genes resulted in a robust reduction in the rotations and a greater increase of the dopaminergic neurons. The delivery of PLs-GDNF + Nurr1 MBs into the brains using magnetic resonance imaging (MRI)-guided focused ultrasound may be more efficacious for the treatment of PD than the single treatment. PMID- 29240242 TI - The 9p21 locus: A potential therapeutic target and prognostic marker in breast cancer. AB - Breast cancer is an important cause of cancer related mortality in women. Despite extensive efforts to identify valid biomarkers for risk stratification, there are relatively few with proven clinical utility. It is recognized that genetic factors play a major role in determining susceptibility to breast cancer. Recent genome-wide-association-studies and gene expression analysis have demonstrated that a locus on chromosome 9p21, which contains three genes; CDKN2B (encoding p15ink4b), CDKN2A (encoding p16ink4a and p14ARF) and the 3' end of CDKN2BAS (an antisense noncoding RNA in the INK4 locus [ANRIL]) are associated with an increased risk of this malignancy. ANRIL has a post transcriptional modulatory activity, which has been shown to perturb the expression of nearby genes and may play an important role in coordinating tissue remodeling through regulation of cell proliferation, apoptosis, aging, extra-cellular matrix remodeling, and inflammatory response. However, the role of ANRIL is not well understood in breast cancer. Hypermethylation of the p14ARF and p16INK4a genes is found in some tumor types. Nevertheless, further studies are necessary to confirm the clinical utility of these putative markers in risk stratification, or assessing prognosis. In this review, we have summarized the prognostic and therapeutic potential of the p14ARF and p16INK4a genes in patients with breast cancer. PMID- 29240241 TI - Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion. AB - Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management. PMID- 29240243 TI - Fabrication and evaluation of 3D printed BCP scaffolds reinforced with ZrO2 for bone tissue applications. AB - Fused deposition modeling (FDM) is a promising 3D printing and manufacturing step to create well interconnected porous scaffold designs from the computer-aided design (CAD) models for the next generation of bone scaffolds. The purpose of this study was to fabricate and evaluate a new biphasic calcium phosphate (BCP) scaffold reinforced with zirconia (ZrO2 ) by a FDM system for bone tissue engineering. The 3D slurry foams with blending agents were successfully fabricated by a FDM system. Blending materials were then removed after the sintering process at high temperature to obtain a targeted BCP/ZrO2 scaffold with the desired pore characteristics, porosity, and dimension. Morphology of the sintered scaffold was investigated with SEM/EDS mapping. A cell proliferation test was carried out and evaluated with osteosarcoma MG-63 cells. Mechanical testing and cell proliferation evaluation demonstrated that 90% BCP and 10% ZrO2 scaffold had a significant effect on the mechanical properties maintaining a structure compared that of only 100% BCP with no ZrO2 . Additionally, differentiation studies of human mesenchymal stem cells (hMSCs) on BCP/ZrO2 scaffolds in static and dynamic culture conditions showed increased expression of bone morphogenic protein-2 (BMP-2) when cultured on BCP/ZrO2 scaffolds under dynamic conditions compared to on BCP control scaffolds. The manufacturing of BCP/ZrO2 scaffolds through this innovative technique of a FDM may provide applications for various types of tissue regeneration, including bone and cartilage. PMID- 29240244 TI - Prenatal diagnosis of urinary tract anomalies, a cohort study in the Northern Netherlands. AB - OBJECTIVE: To describe prevalence, time of diagnosis, and type of birth in children and fetuses with urinary tract (UT) anomalies after the introduction of the anomaly scan in the Netherlands in 2007. METHODS: We selected, from a population-based congenital anomaly registry, children and fetuses with UT anomalies born between 2008 and 2014. Cases were defined according to type of UT anomaly and whether isolated or with associated anomalies. Information was collected on time of diagnosis and type of birth. RESULTS: We included 487 cases. Total prevalence increased from 34.0 in 2008 to 42.3 per 10 000 births in 2014, mainly by an increase in anomalies of the collecting system. Almost 70% presented as isolated. Anomalies of the renal parenchyma were more often associated with genetic or other anomalies (47.3%) than anomalies of the collecting system (19.0%). The proportion of prenatally diagnosed cases increased from 59.3% in 2008 to 80.9% in 2014. Termination of pregnancy occurred in 14.8%, of which the majority were UT anomalies associated with a genetic disorder or other anomalies. CONCLUSION: In the period after the introduction of the anomaly scan, we observed an increasing prevalence of anomalies of the collecting system, but no increase in termination of pregnancies. PMID- 29240245 TI - Structure and composition of Unio pictorum shell: arguments for the diversity of the nacroprismatic arrangement in molluscs. AB - Mollusc shells are complex organomineral structures, the arrangement and composition depending on the species. Most studies are dedicated to shells composed of an aragonite nacreous and a calcite prismatic layer, so the nacreous prismatic model based on Pinctada and Atrina-Pinna. Here, we studied the micro- and nanostructure, the mineralogy and composition of a nacroprismatic bivalve species: Unio pictorum. The prismatic layer of Unio is aragonite, and the inner structure of the prismatic units strongly differs from those of the calcitic layers. The shape of the prisms varies depending on their growth stage. The first layers of nacre are similar to those of gastropods (columnar nacre), then evolve towards the typical bivalve arrangement (sheet nacre). Na, Sr, Mg, P and S are present in both prisms and nacre. The organic prismatic envelopes are rich in sulphur amino acids, whereas organic sulphate is present within the prisms and the nacreous tablets. P is present as phosphate, probably a mixture of organic and mineral complex. Chemical distribution maps confirm the absence of an organic membrane between the nacre and the prisms. The comparison of the structure, mineralogy and composition of Unio pictorum and different species show the diversity of nacroprismatic shells, and that these features are taxonomically dependent. PMID- 29240246 TI - Hyperthermia enhances radiosensitivity of colorectal cancer cells through ROS inducing autophagic cell death. AB - Hyperthermia (HT) enhances the anti-cancer effects of radiotherapy (RT), but the precise biochemical mechanisms involved are unclear. This study was aim to investigate if mild HT sensitizes colorectal cancer cells to RT through reactive oxygen species (ROS)-inducing autophagic cell death in a mice model of HCT116 human colorectal cancer. HCT116 mice model were randomly divided into five groups: mock group, hyperthermia group (HT), radiotherapy group (RT), HT + RT group, and HT + RT +N-acetyl L-cysteine (NAC) group (HT + CT + NAC). After four weeks of treatment, cancer growth inhibition, rate and mitochondrial membrane potential were measured with MTT and JC-1 assays, respectively, while ROS were estimated fluorimetrically. The relationship of these parameters to expressions of autophagy-related genes Beclin1, LC3B, and mTOR was analyzed. Gene expression was measured by Real-Time polymerase chain reaction (RT-PCR). There were significant increases in ROS levels and mitochondrial membrane potential in the HT + RT group. ROS levels in the HT + RT group increased more significantly than in any other group. In contrast, ROS levels in the HT + RT + NAC group were significantly decreased relative to the HT + RT group. The number of autophagic bodies in HT + RT group was higher than that of mock group. There were significant increases in the expression of Beclin1 and LC3B genes, while mTOR expression was significantly decreased in the HT + CT group. Treatment with NAC reversed the pattern of these changes. These results indicate that HT enhances the radiosensitivity of colorectal cancer cells to RT through ROS inducing autophagic cell death. PMID- 29240247 TI - Do we still need oral food challenges for the diagnosis of food allergy? AB - Food challenges are standard in the diagnosis in patients suspected of being allergic to food. However, their role is regularly questioned due to the time required to perform them, and to their cost and the inherent risk of severe reactions. Food challenges have been challenged by recent advances defining threshold values for food-specific IgE helping to predict the probability of having symptoms to the suspected food. Also, identification of major allergens to various highly allergenic foods such as peanuts or tree nuts has contributed to an increased accuracy of IgE testing. Altogether, these new data have contributed to a better definition of the role of oral food challenges in the diagnosis of food allergy. Oral food challenges are not outdated and remain the gold standard in the diagnosis of food allergy. PMID- 29240248 TI - Sperm binding to porcine oviductal cells is mediated by SRCR domains contained in DMBT1. AB - The oviduct is an organ in which a subpopulation of sperm is stored in a reservoir, preserving its fertilizing potential. In porcine, two oviductal proteins have been identified in relation to sperm binding, Annexin A2 and Deleted in Malignant Brain Tumor 1 (DMBT1). DMBT1 is a multifunctional, multidomain glycoprotein, and the characteristics of all of its domains, as well as its carbohydrates, make them candidates for sperm binding. In this work, we challenge sperm for binding to pig oviductal cells on primary culture, after treatment with antibodies specific for the different domains present in DMBT1. Only anti-SRCR antibodies produced inhibition of sperm binding to cells. Thus, SRCR is the main domain in DMBT1 promoted sperm binding to form the reservoir in the oviduct, and this function is probably elicited through the polypeptide itself. PMID- 29240249 TI - Exosomal miR-6803-5p as potential diagnostic and prognostic marker in colorectal cancer. AB - Accumulating data have suggested exosome-delivered microRNAs (miRNAs) play critical role in carcinogenesis and cancer progression. However, little is known about the influence of exosomal miR-6803-5p on the development and prognosis of colorectal cancer (CRC). Levels of serum exosomal miR-6803-5p were determined by microarray analysis and verified by quantitative real-time PCR (qRT-PCR). Outcomes of overall survival (OS) and disease-free survival (DFS) of CRC patients were estimated by Kaplan-Meier analysis. We used cox regression analysis to investigate the association between exosomes-encapsulated miR-6803-5p and the clinicopathological factors of CRC patients. The exosomal miR-6803-5p was significantly increased in serum samples from patients with CRC in contrast to healthy controls. Significantly higher levels of serum exosomal miR-6803-5p were observed in CRC patients at later TNM stage or with lymph node metastasis as well as liver metastasis. Patients with elevated levels of serum exosomal miR-6803-5p had much poorer OS and DFS. Cox regression analysis revealed high levels of exosomal miR-6803-5p was associated with poor prognosis in CRC independent of other confounding factors. Thus, exosomal miR-6803-5p is a potential diagnostic and prognostic biomarker for patients with CRC. PMID- 29240250 TI - Microrna-139-5p inhibits epithelial-mesenchymal transition and fibrosis in post menopausal women with interstitial cystitis by targeting LPAR4 via the PI3K/Akt signaling pathway. AB - The study explores whether miR-139-5p targeting LPAR4 affects epithelial mesenchymal transition (EMT) and fibrosis in post-menopausal women with interstitial cystitis (IC) via the PI3K/Akt signaling pathway. Bladder tissues of IC and normal bladder tissues were collected. The pathology of bladder tissues was observed by HE, Masson and Picrosirius red staining. LPAR4 positive expression rate were determined by IHC. ELISA was performed to detect the levels of IL-6, IL-8, IL-10, and TNF-alpha. Rat IC models were randomized into seven different groups. miR-139-5p, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, P13K, Akt, E cadherin, N-cadherin, Vimentin, TGF-beta1, and CTGF expression were determined by RT-qPCR and Western blotting. Dual luciferase reporter gene assay verified that LPAR4 is a target gene of miR-139-5p. Fibrosis was a pathological manifestation of IC. The IC group showed higher LPAR4, PI3K, Akt, p-PI3K, p-Akt, N-cadherin, Vimentin, TGF-beta1, and CTGF expression but lower miR-139-5p and E-cadherin expression than the normal group. The levels of IL-6, IL-8, IL-10, and TNF-alpha expression decreased while HB-EGF increased in the IC group in comparison of the normal group. Compared with the blank and NC groups, E-cadherin expression was increased in the miR-139-5p mimic and siRNA-LPAR4 groups, while LPAR4, PI3K, Akt, p-P13K, p-Akt, N-cadherin, Vimentin, TGF-beta1, and CTGF expression were decreased. An opposite trend was found in the miR-139-5p inhibitor group. The miR 139-5p decreased in the miR-139-5p inhibitor + siRNA-LPAR4 and miR-139-5p inhibitor + wortmannin groups. Conclusively, miR-139-5p targeting LPAR4 inhibits EMT and fibrosis in post-menopausal IC women through the PI3K/Akt signaling pathway. PMID- 29240251 TI - Progenitor cells from different zones of human cartilage and their correlation with histopathological osteoarthritis progression. AB - Cell-based therapies development for the treatment of osteoarthritis (OA) requires an understanding of the disease progression and attributes of the cells resident in cartilage. This study focused on quantitative assessment of the concentration and biological potential of stem and progenitor cells resident in different zones of cartilage displaying macroscopic Outerbridge grade 1-2 OA, and their correlation with OA progression based on established histologic scoring system. Lateral femoral condyles were collected from 15 patients with idiopathic OA and varus knees undergoing total knee arthroplasty. Superficial(Csp , top ~ 500 um) and deep cartilage(Cdp ) was separated. Chondrogenic Connective Tissue Progenitors (CTP-C) were assayed by standardized Colony-Forming-Unit assay using automated image analysis (ColonyzeTM ) based on ASTM standard F-2944-12. Cell concentration (cells/mg) was significantly greater in Csp (median: 7,000; range: 3,440-17,600) than Cdp (median: 5,340; range: 3,393-9,660), p = 0.039. Prevalence (CTPs/million cells) was not different between Csp (median: 1,274; range: 0 3,898) and Cdp (median:1,365; range:0-6,330), p = 0.42. In vitro performance of CTP-C progeny varied widely within and between patients, manifest by variation in colony size and morphology. Mean histopathological Mankin score was 4.7 (SD = 1.2), representing mild to moderate OA. Tidemark breach by blood vessels was associated with lower Csp cell concentration (p = 0.02). Matrix degradation was associated with lower Cdp cell and CTP-C concentration (p = 0.015 and p = 0.095, respectively), independent of articular surface changes. These findings suggest that the initiation of OA may occur in either superficial or deep zones. The pathological changes affect CTP-Cs in Csp and Cdp cartilage zones differently. The heterogeneity among the available CTP-Cs in Csp and Cdp suggests performance based selection to optimize cell-sourcing strategies for therapy. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1728-1738, 2018. PMID- 29240252 TI - Ganoderma microsporum immunomodulatory protein induces apoptosis and potentiates mitomycin C-induced apoptosis in urinary bladder urothelial carcinoma cells. AB - Current chemotherapy and immunotherapy treatments followed by transurethral resection for urinary bladder urothelial carcinoma (UC) usually suffer from poor prognosis and high recurrence rate. Design and modification of current formulation with the novel adjuvants are needed. A recombinant protein derived from Ganoderma microsporum named as Ganoderma microsporum immunomodulatory protein (GMIP) was used to treat UC cells. We found GMIP elicits a dose-dependent and time-dependent anti-UC cell proliferation effect, with a half-maximal inhibition concentration (IC50 ) comparable to mitomycin C (MMC), a commonly used chemotherapy agent. After GMIP treatment, UC cells showed apoptotic phenomenon including cell cycle arrest in the G1 phase, elevated sub-G1 population, mitochondrial membrane potential loss, up-regulated p21 expression, p21 nuclear translocation, caspase activation, and PARP cleavage in a p53-independent but p21 mediated pathways. Unlike lung cancer cells, GMIP treated UC cells showed no autophagic scheme including Beclin-1, an autophagy to apoptosis switch marker, was not cleaved by caspase 3 and slight LC3B-II accumulation. Also, the classic autophagic inhibitor, chloroquine had no effect in GMIP-mediated cell death made us conclude that GMIP induced apoptosis through caspase activation but not autophagy in UC cells. Additionally, GMIP showed synergistic effects with MMC in killing UC cells and thus decreased the concentration of MMC usage to reach the comparable apoptotic effects. Our results delineate novel strategies for treatment of UC by GMIP alone or in combination with MMC application and provide a promising therapeutic cocktail for better treatment of urinary bladder urothelial carcinoma. PMID- 29240253 TI - Outcome following second allogeneic hematopoietic cell transplantation: A single center experience. AB - OBJECTIVE: Second allogeneic hematopoietic cell transplantation (HCT) may be indicated following relapse or graft failure following first HCT. Our retrospective single-center study sought to investigate parameters that influence post-second allogeneic HCT survival. METHOD: We investigated 92 patients who underwent second allogeneic HCT between 1980 and 2016 for relapse or graft failure following first HCT. Median age at second HCT was 41 years (range 16-68), performed for relapse in 59 patients (64%) and for graft failure in 33 patients (36%). RESULTS: On univariate analysis, 3-year OS of the entire cohort was 35% (95% CI=25-45). Eastern Cooperative Oncology Group (ECOG) score (3-year OS 48% for ECOG 0-1, 18% for ECOG 2-3, P=.0006), second HCT indication (3-year OS 43% for relapse, 20% for graft failure, P=.02), time from first HCT to relapse/graft failure (3-year OS for <12months 21%, for >=12months 46%, P=.009), and conditioning intensity (3-year OS for MA 42% vs other regimens 23%, P=.08) significantly influenced OS. Multivariable analysis confirmed ECOG score (HR=2.15 for ECOG 2-3, 95% CI=1.32-3.51, P=.002) and second HCT indication (HR=1.67 for graft failure, 95% CI=1.02-2.75, P=.04) to independently influence survival. CONCLUSION: Second HCT may offer long-term survival particularly to patients with good performance status who relapse post-first HCT. PMID- 29240254 TI - NF-kappaB-regulated miR-155, via repression of QKI, contributes to the acquisition of CSC-like phenotype during the neoplastic transformation of hepatic cells induced by arsenite. AB - Chronic exposure to arsenite can cause various human tumors. For the initiation and recurrence of human liver cancer, the acquisition of CSC-like properties is essential. In various cancers, microRNAs (miRNAs) act as regulators in induction of CSC-like properties. Liver cancers over-express miR-155, but the mechanism relating miR-155 and arsenite-induced liver cancer is unknown. Here, we show that long-term exposure of L-02 cells to arsenite increases miR-155 levels by activation of NF-kappaB and leads to the acquisition of CSC-like properties. In spheroids formed from arsenite-transformed L-02 cells, the levels of miR-155 positively relate to the levels of CD90, EpCAM, and OCT4. Inhibition of miR-155, by reduction of SOX2 and OCT4, results in suppression of spheroid formation. Luciferase reporter assays indicate that QKI is a target of miR-155. Inhibition of QKI expression by miR-155 promotes arsenite-induced acquisition of CSC-like properties, whereas QKI over-expression has the opposite effect. Collectively, the findings demonstrate that miR-155, driven by NF-kappaB, reduces QKI expression and is involved in acquisition of the CSC-like phenotype during neoplastic transformation of hepatic cells induced by arsenite. PMID- 29240256 TI - Covalent Bonding and Charge Shift Bonds: Comment on "The Carbon-Nitrogen Bonds in Ammonium Compounds Are Charge Shift Bonds". AB - The paper by Gershoni-Poranne and Chen (R. Gershoni-Poranne, P. Chen, Chem. Eur. J. 2017, 23, 4659) gives an incorrect definition of covalent bonding. Furthermore, the assignment of so-called charge shift bonds in ammonium compounds has no physical foundation and is conceptually redundant. PMID- 29240255 TI - Extracting unresolved coupling constants from complex multiplets by a real-time J upscaled SERF experiment. AB - The measurement of small homonuclear coupling constants is often prevented by either their small size and/or overlap with other signal splittings. Here, we present a real-time method to extract such couplings without interference from other splittings, with a resolution that is beyond conventional NMR spectra. In this real-time J-upscaled SERF experiment, homonuclear coupling is removed by slice-selective pure shift NMR, whereas scalar coupling to only one selected signal is reintroduced by selective refocusing. The remaining couplings are enhanced by real-time J-upscaling during interruptions of the FID data acquisition. The resulting spectrum is not only simplified by the restriction of the scalar coupling but also its resolution enhanced. This improved resolution results from a reduction of signal broadening due to magnetic field inhomogeneities from 2 different sources: slice-selective excitation and the spin echo type J-upscaling element. PMID- 29240257 TI - Altered expression of telomere-associated genes in leukocytes among BRCA1 and BRCA2 carriers. AB - Telomere dysfunction resulting from telomere shortening and deregulation of shelterin components has been linked to the pathogenesis of age-related disorders, including cancer. Recent evidence suggests that BRCA1/2 (BRCA1 and BRCA2) tumor suppressor gene products play an important role in telomere maintenance. Although telomere shortening has been reported in BRCA1/2 carriers, the direct effects of BRCA1/2 haploinsufficiency on telomere maintenance and predisposition to cancer development are not completely understood. In this study, we assessed the telomere-associated and telomere-proximal gene expression profiles in peripheral blood leukocytes from patients with a BRCA1 or BRCA2 mutation, compared to samples from sporadic and familial breast cancer individuals. We found that 25 genes, including TINF2 gene (a negative regulator of telomere length), were significantly differentially expressed in BRCA1 carriers. Leukocyte telomere length analysis revealed that BRCA1/2 carriers had relatively shorter telomeres than healthy controls. Further, affected BRCA1/2 carriers were well differentiated from unaffected BRCA1/2 carriers by the expression of telomere-proximal genes. Our results link BRCA1/2 haploinsufficiency to changes in telomere length, telomere-associated as well as telomere-proximal gene expression. Thus, this work supports the effect of BRCA1/2 haploinsufficiency in the biology underlying telomere dysfunction in cancer development. Future studies evaluating these findings will require a large study population. PMID- 29240258 TI - DNA and RNA binding by the Wilms' tumour gene 1 (WT1) protein +KTS and -KTS isoforms-From initial observations to recent global genomic analyses. AB - The Wilms' tumour gene 1 protein (WT1) is a zinc finger transcription factor found indispensable for foetal development. WT1 has also been implicated in the development of tumours in several organ systems, including acute myeloid leukaemia (AML). Four main WT1 isoforms come from 2 alternative splice events. One alternative splice results in the inclusion or exclusion of 3 amino acids, KTS, between zinc fingers 3 and 4 in the WT1 protein. The KTS insert has been extensively investigated due to the functional implications for DNA and RNA binding. In this review, we provide an overview of the research into the isoforms containing or lacking the KTS insert in leukaemic cells, as well as the research into the binding patterns of the WT1 -KTS and +KTS isoforms to DNA and RNA. Finally, we connect the results of the DNA binding research to the ChIP-CHIP and ChIP-Seq investigations into the global genomic binding of the WT1 protein that have recently been performed. PMID- 29240259 TI - Dissipative particle dynamic simulation and experimental assessment of the impacts of humic substances on aqueous aggregation and dispersion of engineered nanoparticles. AB - Comprehensive experimental quantification and mapping of the aggregation and dispersion state of engineered nanoparticles (NPs) in the presence of humic substances is a great challenge. Dissipative particle dynamic (DPD) simulation was adopted to investigate the aggregation and dispersion mechanisms of NPs in the presence of a humic substance analog. Twelve different types of NPs including 2 metal-based NPs, 7 metal oxide-based NPs, and 3 carbon-based NPs in pure water (pH 3.0) and algae medium (pH 8.0) in the presence of a humic substance analogy were selected for experimental verification of the DPD simulation results. In agreement with results obtained with dynamic light scattering and phase analysis light scattering techniques, the simulations demonstrated that the presence of humic substances reduced the aggregation extent of the NPs. The DPD simulations showed that the stability and dispersity of the NPs increased first, and then decreased with increasing concentrations of humic substances. Moreover, there existed a concentration of humic substances where the NPs became more stable and more dispersed, which was experimentally verified in the case of all the NPs in the pure water and in the algae medium. Furthermore, theory and simulation indicate that both hydrophobic and hydrogen interaction play an important role in controlling the formation of NP aggregates in the presence of humic substances. Electrostatic interaction and steric repulsion are the main mechanisms underlying the effects of humic substances on the aqueous dispersion stability of NPs. Environ Toxicol Chem 2018;37:1024-1031. (c) 2017 SETAC. PMID- 29240260 TI - Sohlh1 suppresses glioblastoma cell proliferation, migration, and invasion by inhibition of Wnt/beta-catenin signaling. AB - Glioblastoma (GBM) is the most aggressive and highly invasive type of astrocytic tumors. Despite advances in diagnosis and therapy, the prognosis and survival time remain poor. Identifying key mediators of tumor cell proliferation, migration, and invasion is crucial to the development of new and more effective therapies. In this paper, we report the novel role of Spermatogenesis- and oogenesis- specific basic helix-loop-helix transcription factor1 (Sohlh1) in the inhibition of Wnt/beta-catenin signaling and aggressive behaviors in GBM cells. Immunohistochemistry was performed to examine the expression of Sohlh1 and related proteins in astrocytomas. Human glioblastoma U87 and U251 cellswere transfected with appropriate plasmids and/or siRNAs to evaluate their functions on cell proliferation, migration, and invasion. Western blot and TOPflash luciferase assay were used to determine the involvement of Wnt/beta-catenin signaling pathway in Sohlh1-mediated cellular activities in glioblastomas. We observed that Sohlh1 was downregulated in astrocytomas. The reduction in Sohlh1 expression was inversely correlated with the degree of malignancy in astrocytomas. In GBM cell lines, cellular proliferation, migration, and invasion were significantly enhanced after Sohlh1 knockdown, but significantly inhibited after Sohlh1 overexpression. These functional effects of Sohlh1 were achieved by upregulating GSK3beta and inhibiting Wnt/beta-catenin signaling. Our findings provide novel mechanistic insights of Sohlh1 in malignant progression of astrocytomas, suggesting that the level of Sohlh1 expression may be a predictor of astrocytoma behavior and further, Sohlh1 may serve as a potential therapeutic target for GBM. PMID- 29240261 TI - Mitochondrial dysfunction RAD51, and Ku80 proteolysis promote apoptotic effects of Dinaciclib in Bcl-xL silenced cells. AB - In the present study, we investigated the effect of CDK inhibitors (ribociclib, palbociclib, seliciclib, AZD5438, and dinaciclib) on malignant human glioma cells for cell viability, apoptosis, oxidative stress, and mitochondrial function using various assays. None of the CDK inhibitors induced cell death at a clinically relevant concentration. However, low nanomolar concentrations of dinaciclib showed higher cytotoxic activity against Bcl-xL silenced cells in a time- and concentration-dependent manner. This effect was not seen with other CDK inhibitors. The apoptosis-inducing capability of dinaciclib in Bcl-xL silenced cells was evidenced by cell shrinkage, mitochondrial dysfunction, DNA damage, and increased phosphatidylserine externalization. Dinaciclib was found to disrupt mitochondrial membrane potential, resulting in the release of cytochrome c, AIF, and smac/DIABLO into the cytoplasm. This was accompanied by the downregulation of cyclin-D1, D3, and total Rb. Dinaciclib caused cell cycle arrest in a time- and concentration-dependent manner and with accumulation of cells in the sub-G1 phase. Our results also revealed that dinaciclib, but not ribociclib or palbociclib or seliciclib or AZD5438 induced intrinsic apoptosis via upregulation of the levels of pro-apoptotic proteins (Bax and Bak), resulting in the activation of caspases and cleavage of PARP. We also found an additional mechanism for the dinaciclib-induced augmentation of apoptosis due to abrogation RAD51-cyclin D1 interaction, specifically proteolysis of the DNA repair proteins RAD51 and Ku80. Our results suggest that successfully interfering with Bcl-xL function may restore sensitivity to dinaciclib and could hold the promise for an effective combination therapeutic strategy. PMID- 29240262 TI - Flow cytometric analysis of cerebrospinal fluid in adult patients with acute lymphoblastic leukemia during follow-up. AB - OBJECTIVE: To explore the value of flow cytometric (FCM) analysis of cerebrospinal fluid (CSF) in the diagnosis of central nervous system involvement in adult patients with acute lymphoblastic leukemia (ALL) during follow-up. METHODS: A total of 2871 CSF samples from 357 adult patients with newly diagnosed ALL between the year of 2009 and 2015 were analyzed retrospectively. These patients were divided into 3 groups according to CSF results, FCM+/conventional cytology (CC)+ group, FCM+/CC- group, and FCM-/CC- group, respectively. The overall survival (OS) of the three groups was analyzed. RESULTS: Fifteen (4.2%) and 26 (7.3%) patients' CSF samples were FCM+/CC+ and FCM+/CC-, respectively. The remaining 316 (88.5%) patients' samples were FCM-/CC-. The 2-year OS for the FCM+/CC+, FCM+/CC-, and FCM-/CC- groups was 40.0%, 20.6%, and 64.2%, respectively (P < .001). There was no statistically significant difference in OS between FCM+/CC+ and FCM+/CC- patients (P = .195). In multivariate analysis, a high WBC count and LDH level were independent risk factors for central nervous system involvement in adult patients with ALL. CONCLUSIONS: FCM demonstrated a superior sensitivity over conventional cytology in the diagnosis of central nervous system involvement in adult patients with ALL. FCM+/CC- patients showed a similar survival with FCM+/CC+ patients, suggesting that an isolated FCM-positive status holds clinical significance. PMID- 29240263 TI - Cytochemical flow analysis of intracellular G6PD and aggregate analysis of mosaic G6PD expression. AB - BACKGROUND: Medicines that exert oxidative pressure on red blood cells (RBC) can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Due to X-chromosome inactivation, females heterozygous for G6PD with 1 allele encoding a G6PD-deficient protein and the other a normal protein produce 2 RBC populations each expressing exclusively 1 allele. The G6PD mosaic is not captured with routine G6PD tests. METHODS: An open-source software tool for G6PD cytofluorometric data interpretation is described. The tool interprets data in terms of % bright RBC, or cells with normal G6PD activity in specimens collected from 2 geographically and ethnically distinct populations, an African American cohort (USA) and a Karen and Burman ethnic cohort (Thailand) comprising 242 specimens including 89 heterozygous females. RESULTS: The tool allowed comparison of data across 2 laboratories and both populations. Hemizygous normal or deficient males and homozygous normal or deficient females cluster at narrow % bright cells with mean values of 96%, or 6% (males) and 97%, or 2% (females), respectively. Heterozygous females show a distribution of 10-85% bright cells and a mean of 50%. The distributions are associated with the severity of the G6PD mutation. CONCLUSIONS: Consistent cytofluorometric G6PD analysis facilitates interlaboratory comparison of cellular G6PD profiles and contributes to understanding primaquine-associated hemolytic risk. PMID- 29240264 TI - Longitudinal vitamin D deficiency is inversely related to mite sensitization in early childhood. AB - BACKGROUND: There are few studies addressing the longitudinal analysis of vitamin D deficiency and its impact on the development of atopic diseases in early childhood. METHODS: We investigated 155 children who regularly followed up at our clinic for 5 years as subjects enrolled in a birth cohort study. The pattern of vitamin D levels from birth to 5 years of age was clustered using K-means method in R software. Absolute eosinophil count (AEC), and total serum and specific immunoglobulin E antibodies against food (egg white, milk, and wheat) and inhalant allergens (Dermatophagoides pteronyssinus, Dermatophagoides farina, and Cladosporium herbarum) were measured at 1.5, 3, 4 and 5 years of age. RESULTS: A total of 137 children with serum samples obtained over at least 3 time points during the follow-up period were recruited. Using K-means clustering, the dynamic changes in vitamin D levels were significantly stratified into 3 clusters (cluster A, >=30 ng/mL, n = 61; cluster B, 20-29.9 ng/mL, n = 53; cluster C, <20 ng/mL, n = 23). Despite no statistical association with atopic diseases, a persistent vitamin D deficiency appeared to be associated with eosinophilia at age 3, and total serum and mite-specific immunoglobulin E (IgE) levels at age 4. Furthermore, an associated higher prevalence of mite sensitization at age 4 was significantly associated with the risk of allergic rhinitis and asthma. CONCLUSIONS: Vitamin D deficiency is inversely associated with AEC and mite specific IgE levels, which may potentially increase susceptibility to develop allergies including rhinitis and asthma in early childhood. PMID- 29240265 TI - Bone Mineral Density and Its Serial Changes Are Associated With PTH Levels in Pseudohypoparathyroidism Type 1B Patients. AB - Bone responsiveness to serum parathyroid hormone (PTH) in pseudohypoparathyroidism 1B (PHP1B) is controversial. Forty-eight PHP1B patients diagnosed by molecular analysis were recruited from 2000 to 2016 from the Peking Union Medical College Hospital. Fifty-five sex-matched nonsurgical hypoparathyroidism (NS-HP) patients were selected and included for comparison. Basic information, laboratory test, and dual-energy X-ray absorptiometry (DXA) results were collected. Linear regression was performed to identify independent predictors of lumbar spine (LS), femoral neck (FN), and total hip (TH) bone mineral density (BMD) Z-scores in PHP1B patients. BMD and related markers were compared between PHP and NS-HP patients. Longitudinal observation of 10 PHP1B patients was performed. The BMD Z-score for the LS (1.14 +/- 1.41) was higher than that for the FN (-0.20 +/- 1.00, p < 0.001) and the TH (0.03 +/- 1.06, p < 0.001) in PHP1B patients. Despite lower serum calcium levels in untreated patients (1.72 mmol/L in untreated patients versus 2.14 mmol/L in treated patients, p = 0.024), the PTH levels as well as BMD Z-scores were comparable between treated and untreated patients at baseline. PTH was a negative predictor for LS-BMD Z-score (B = -0.004, p = 0.028) for sporadic PHP1B patients, and a similar result was obtained for all the PHP1B patients (B = -0.002, p = 0.053). Z scores for FN- and LS-BMDs after treatment increased by 0.31 +/- 0.10 and 0.58 +/ 0.12, respectively, where the increase in LS-BMD correlated with a decrease in PTH (r = -0.72, p = 0.044). All BMD Z-scores were significantly lower in PHP1B patients than in IHP patients for the FN, LS, and TH (-0.20 +/- 1.00 versus 1.57 +/- 1.07, 1.14 +/- 1.41 versus 1.96 +/- 1.32, 0.03 +/- 1.06 versus 1.67 +/- 1.01, respectively, all p < 0.05). Skeletal tissue in PHP1B patients responds to PTH, where heterogenous sensitivities to PTH may exist in different regions of bone. Therefore, it is reasonable to normalize PTH levels when treating PHP1B to avoid negative effects of PTH on bone. (c) 2017 American Society for Bone and Mineral Research. PMID- 29240266 TI - Posaconazole oral dose and plasma levels in pediatric hematology-oncology patients. AB - BACKGROUND: Posaconazole is a triazole with limited pharmacokinetic information in children. This study assessed the correlation between posaconazole oral solution daily dosage/kg/body weight and trough plasma level. METHODS: A total of 97 hematology-oncology pediatric patients with >=1 posaconazole plasma concentration level (PPC) assessment in the first 6 weeks after the start of posaconazole treatment were included. RESULTS: Posaconazole was used as prophylaxis in 84 of 97 (87%) patients and as therapy in 13 of 97 (13%). The median daily dose/kg/bw ranged from 10 to 12 mg in the prophylaxis group and 12.5 to 16.5 mg in the therapy group. The median value of PPC for the prophylaxis group was 0.9 and 0.8 MUg/mL at the first and second/third determinations, respectively. Posaconazole prophylaxis failed in 4 of 84 patients (5%). The median value of PPC for the therapy group was 1.5 and 1.4 MUg/mL at the first/second and the third determination, respectively. Posaconazole-related side effects were reported in 6 patients and all regressed with the suspension of the drug. In the prophylaxis group, the use of proton-pump inhibitors was significantly associated with a lower PPC, P = 0.04. CONCLUSIONS: Posaconazole may be a valuable antifungal agent in children despite the incomplete knowledge of its pharmacokinetic characteristics. PMID- 29240267 TI - Acute oral dose of sodium nitrite causes redox imbalance and DNA damage in rat kidney. AB - Sodium nitrite (NaNO2 ) is widely used as a food additive and preservative in fish and meat products. We have evaluated the effect of a single acute oral dose of NaNO2 on oxidative stress parameters, antioxidant capacity, and DNA in rat kidney. Male Wistar rats were divided into four groups and given single oral dose of NaNO2 at 20, 40, 60, and 75 mg/kg body weight; untreated rats served as the control group. All animals in NaNO2 -treated groups showed marked alterations in various parameters of oxidative stress as compared to the control group. This included increase in lipid peroxidation, protein oxidation, hydrogen peroxide levels, and decrease in reduced glutathione content and antioxidant capacity. Administration of NaNO2 also increased DNA damage as evident from release of free nucleotides and confirmed by comet assay. It also led to greater cross-linking of DNA to proteins. Histological analysis showed marked morphological changes in the kidney of NaNO2 -treated animals. These alterations could be due to increased free radical generation or direct chemical modification by reaction intermediates. Our results suggest that nitrite-induced nephrotoxicity is mediated through redox imbalance and results in DNA damage. PMID- 29240268 TI - Assessment of procoagulant potential in patients with reactive thrombocytosis and its association with platelet count. AB - OBJECTIVE: We aimed to determine hemostatic changes and characterize the procoagulant potential among patients with reactive thrombocytosis (RT). METHODS: Sixty patients with RT (median platelet count 718 * 109 /L) and 20 healthy persons were tested for complete blood count, C-reactive protein, von Willebrand factor (VWF), factor VIII and fibrinogen, and thrombin generation. Platelet studies, including light transmission aggregometry and Cone and Plate(let) Analyzer, were also conducted. Reticulated platelets and platelet P-selectin expression were measured using flow cytometry. RESULTS: Compared to patients with mild thrombocytosis (platelet count 500-700 * 109 /L; n = 27), those with moderate-to-severe thrombocytosis (platelet count >700 * 109 /L; n = 33) had significantly higher fibrinogen, factor VIII, and VWF antigen and activity levels; higher endogenous thrombin potential, peak thrombin generation and velocity index levels, and shorter time-to-peak thrombin level. VWF antigen and activity, fibrinogen, and factor VIII were positively associated with platelet count, whereas VWF activity/antigen ratio was inversely correlated. In a multivariate analysis of RT and control participants, only platelet count predicted endogenous thrombin potential with a positive-linear correlation. No patients developed acquired von Willebrand syndrome. CONCLUSIONS: As determined by thrombin generation, RT was associated with in vitro prothrombotic tendency, which correlated with platelet count. This may explain the increased thromboembolic risk previously reported in patients with RT. PMID- 29240269 TI - Reductive Amination by Photoredox Catalysis and Polarity-Matched Hydrogen Atom Transfer. AB - The excitation of a RuII photosensitizer in the presence of ascorbic acid leads to the reduction of iminium ions to electron-rich alpha-aminoalkyl radical intermediates, which are rapidly converted into reductive amination products by thiol-mediated hydrogen atom transfer (HAT). As a result, the reductive amination of carbonyl compounds with amines by photoredox catalysis proceeds in good to excellent yields and with broad substrate scope and good functional group tolerance. The three key features of this work are 1) the rapid interception of electron-rich alpha-aminoalkyl radical intermediates by polarity-matched HAT in a photoredox reaction, 2) the method of reductive amination by photoredox catalysis itself, and 3) the application of this new method for temporally and spatially controlled reactions on a solid support, as demonstrated by the attachment of a fluorescent dye on an activated cellulose support by photoredox-catalyzed reductive amination. PMID- 29240271 TI - Chromatin-level regulation of the fragmented dothistromin gene cluster in the forest pathogen Dothistroma septosporum. AB - Genes required for fungal secondary metabolite production are usually clustered, co-regulated and expressed in stationary growth phase. Chromatin modification has an important role in co-regulation of secondary metabolite genes. The virulence factor dothistromin, a relative of aflatoxin, provided a unique opportunity to study chromatin level regulation in a highly fragmented gene cluster that is switched on during early exponential growth phase. We analysed three histone modification marks by ChIP-qPCR and gene deletion in the pine pathogen Dothistroma septosporum to determine their effects on dothistromin gene expression across a time course and at different loci of the dispersed gene cluster. Changes in gene expression and dothistromin production were associated with changes in histone marks, with higher acetylation (H3K9ac) and lower methylation (H3K9me3, H3K27me3) during early exponential phase at the onset of dothistromin production. But while H3K27me3 directly influenced dothistromin genes dispersed across chromosome 12, effects of H3K9 acetylation and methylation were orchestrated mainly through a centrally located pathway regulator gene DsAflR. These results revealed that secondary metabolite production can be controlled at the chromatin-level despite the genes being dispersed. They also suggest that patterns of chromatin modification are important in adaptation of a virulence factor for a specific role in planta. PMID- 29240270 TI - The Dynamic Equilibrium of Hexakis(pentafluoroethyl)distannane Adducts [XSn(C2 F5 )3 {Sn(C2 F5 )3 }]- (X=Cl, Br, I, Sn(C2 F5 )3 ). AB - The tin-tin bond cleavage of hexaorganodistannanes by nucleophiles is a long known reaction and widely used for stannate formation or stannyl group transfer. Herein, we detail our experiments to provide analytical evidence for the existence of the reasonably stable anionic complexes [XSn(C2 F5 )3 {Sn(C2 F5 )3 }]- (X=Cl, Br, I, Sn(C2 F5 )3 ) derived from hexakis(pentafluoroethyl)distannane. NMR investigations at low temperature lend further mechanistic insights. Thus, by detection of the imposing ion [Sn(C2 F5 )3 {Sn(C2 F5 )3 }2 ]- , one can surmise that the chemistry of Sn2 (C2 F5 )6 has more in common with the isolobal iodine than with classical distannanes. PMID- 29240272 TI - Amino acid deprivation and central carbon metabolism regulate the production of outer membrane vesicles and tubes by Francisella. AB - Francisella tularensis is a highly virulent Gram-negative bacterial pathogen that causes the zoonotic disease tularemia. F. novicida, a model tularemia strain, produces spherical outer membrane vesicles (OMV), as well as novel tubular vesicles and extensions of the cell surface. These OMV and tubes (OMV/T) are produced in a regulated manner and contain known virulence factors. Mechanisms by which bacterial vesicles are produced and regulated are not well understood. We performed a genetic screen in F. novicida to decipher the molecular basis for regulated OMV/T formation, and identified both hypo- and hyper-vesiculating mutants. Mutations in fumA and tktA, involved in central carbon metabolism, and in FTN_0908 and FTN_1037, of unknown function, resulted in severe defects in OMV/T production. Cysteine deprivation was identified as the signal that triggers OMV/T formation in F. novicida during growth in rich medium. We also found that fully virulent F. tularensis produces OMV/T in a similarly regulated manner. Further analysis revealed that OMV/T production is responsive to deprivation of essential amino acids in addition to cysteine, and that the hypo-vesiculating mutants are defective in responding to this signal. Thus, amino acid starvation, such as encountered by Francisella during host cell invasion, regulates the production of membrane-derived structures. PMID- 29240273 TI - Endothelial dysfunction may promote keloid growth. AB - Keloid is a cutaneous fibroproliferative disorder. It results from impaired wound healing that generates persistent inflammation and extensive deposition of collagen fibers in the wound/scar. Keloids tend to be worse in hypertensive patients. The present prospective cross-sectional study assessed whether endothelial dysfunction, which occurs in hypertension, associates with keloid formation and progression. This study included randomly selected patients with keloids who were assessed for surgical keloid treatment in 2013-2014. A series of nonkeloid patients admitted to the hospital was also recruited during this period. To measure endothelial function, all patients underwent digital reactive hyperemia peripheral arterial tonometry. Test results were expressed as reactive hyperemia index (RHI) and augmentation index (AI). In total, 57 patients with keloids and 19 nonkeloid controls were recruited. Keloid patients did not differ from the controls in terms of demographic or clinical variables, but had significantly worse RHI and AI values. Moreover, poor RHI and AI values associated with keloid development on binomial logistic regression. The keloid patients were then divided into four groups depending on whether their keloids started at age 0-12, 13-18, 19-29, or >=30 years. Patients whose keloids arose before and well after puberty tended to have lower RHI than the controls, but these differences did not achieve statistical significance. However, these two groups did have significantly poorer AI values than the controls. Thus, endothelial dysfunction could cause keloid formation and/or aggravation. This indicates that vascular endothelial cells are important for wound healing. PMID- 29240274 TI - Complement factor H gene polymorphism rs6677604 and the risk, severity and progression of IgA nephropathy: A systematic review and meta-analysis. AB - AIM: Studies reporting the association between complement factor H gene rs6677604 polymorphism and susceptibility to IgA nephropathy (IgAN) had yielded inconsistent results. We performed a systematic review and meta-analysis to clarify the association between rs6677604 and IgAN susceptibility, disease severity and chronic progression. METHODS: A comprehensive database search was performed to identify eligible studies. Meta-analyses were performed for rs6677604 allele frequency, genotypes and the association with IgAN susceptibility. RESULTS: 10 studies were included in the systematic review. Among them, four studies containing 10 distinct datasets (15,617 cases and 31,957 controls) were included in the meta-analysis. The pooled frequency of the minor allele (A) was significantly higher in Europeans than in Asians across both IgAN cases and controls, and the frequency of the minor allele (A) in IgAN cases was also significantly lower than that in controls across both European and Asian subgroups. Significant associations were detected between rs6677604 and risk of developing IgAN, when comparing allele A vs. G, genotype AA vs. GG, genotype AA vs. AG and genotype AG vs. GG. In analysis stratified by ethnicity, significant association was only observed in Europeans but not in Asians when comparing AA vs. GG or AA vs. AG. CONCLUSION: Our pooled analysis showed a significant association between rs6677604-(A) allele and IgAN susceptibility, supporting the importance of complement activation in the pathogenesis of IgAN. The presence of rs6677604-(A) allele may be associated with a decreased the risk of IgAN in Europeans, but the association was not confirmed in Asians. PMID- 29240275 TI - Metabolic stress induces modifications in the epigenetic program of preimplantation bovine embryos. AB - The mammalian embryo is sensitive to and adapts to its metabolic environment. The mother's metabolic health and nutrient availability, for example, can modulate the oviductal fluid composition and thus embryo development. In this project, we induced energetic stress in bovine embryos during early culture to observe the epigenetic responses associated with metabolic stress, using a treatment paradigm known to decrease blastocyst rates. Embryos were generated using oocytes from slaughtered cows, and then exposed to an elevated glucose concentration (5 vs. 0.2 mM in control conditions) for the first 3 days post-fertilization, followed by normal media until the blastocyst stage. The EmbryoGENE platform was then used to identify DNA methylation differences between the two treatments. Probes (450,000) were then analyzed based on their genome location and methylation differences. Our results revealed that elevated glucose led to hypomethylation close to telomeric regions and methylation changes on genomic regions associated with energy metabolism. PMID- 29240276 TI - A Keggin Polyoxometalate Shows Water Oxidation Activity at Neutral pH: POM@ZIF-8, an Efficient and Robust Electrocatalyst. AB - Keggin-type polyoxometalate anions [XM12 O40 ]n- are versatile, as their applications in interdisciplinary areas show. The Keggin anion [CoW12 O40 ]6- turns into an efficient and robust electrocatalyst upon its confinement in the well-defined void space of ZIF-8, a metal-organic framework (MOF). [H6 CoW12 O40 ]@ZIF-8 is so stable to water oxidation that it retains its initial activity even after 1000 catalytic cycles. The catalyst has a turnover frequency (TOF) of 10.8 mol O2 (mol Co)-1 s-1 , one of the highest TOFs for electrocatalytic oxygen evolution at neutral pH. Controlled experiments rule out the chances of formation and participation of CoOx in this electrocatalyic water oxidation. PMID- 29240277 TI - How perceived feelings of "wellness" influence the decision-making of people with predialysis chronic kidney disease. AB - AIMS AND OBJECTIVES: To identify the subjective meanings attached to decisions made by people living with chronic kidney disease as they consider their transition to renal replacement therapy. BACKGROUND: Within the challenging world of chronic illness, people draw upon their temporal life experiences to help them make the best or most balanced primary healthcare decisions. Understanding the risks and benefits associated with these decisions has been an area of intense interest in health research. DESIGN: An exploratory qualitative descriptive design. METHOD: A convenience sample of twelve people, at stages 3B to 5 of chronic kidney disease, attending two predialysis renal clinics in Sydney, Australia, consented to be interviewed. The semi-structured interviews centred on their decision-making experiences as they considered their transition to renal replacement therapy. RESULTS: Three themes emerged from participant narratives which have been framed into the following questions: (i) Do I need renal replacement therapy? (ii) What is the "right" renal replacement therapy for me? and (iii) When should I start renal replacement therapy? Decisions about the transition to renal replacement therapy were impacted upon by the participants' perceived feelings of wellness and the belief that renal replacement therapy would not be needed at any time in the foreseeable future. CONCLUSION: This study highlights the importance of optimising person-centred care and raises important issues for the education and management of people with chronic kidney disease in the predialysis stages of the illness. RELEVANCE TO CLINICAL PRACTICE: In order to facilitate the transition to renal replacement therapy, renal clinicians have a responsibility to more fully understand the patient journey during the predialysis stages of chronic kidney disease. A clearer understanding of patients' perceptions and decision-making experiences creates a space for mutual understanding. This is essential for the future development and implementation of collaborative, person-centred educational strategies and long-term renal healthcare outcomes. PMID- 29240279 TI - Nagoya Gold Medal: E. W. Meijer / Nagoya Silver Medal: H. Suga / Prelog Medal and Lectureship: S. B. H. Kent / Tajima Prize: X. Hu. PMID- 29240278 TI - Predictors of returns to the emergency department after head and neck surgery. AB - BACKGROUND: Thirty-day hospital readmissions have become a measure of quality of care. Many readmissions enter through the emergency department. The purposes of this study were to determine the rate, risk factors, and costs of 30-day returns to the emergency department (30dEDRs) after head and neck surgery. METHODS: All adult patients undergoing head and neck surgery at the University of Florida from 2012 to 2014 were reviewed. Univariate and multivariate logistic regression analyses were performed to identify risk factors for 30dEDRs. RESULTS: We found 1065 patients who underwent 1173 procedures. There were 88 cases (7.5%) that resulted in 30dEDRs and 55 patients (4.7%) who had 30-day unplanned readmissions (30dURs). Significant predictors of 30dEDRs included: smoking; hypothyroidism; and intensive care unit (ICU) stays. Significant predictors of readmission from an emergency department visit were Charlson Comorbidity Index (CCI) and cancer stage. Total costs of 30dEDRs and any subsequent readmissions topped $500 000. CONCLUSION: The rate of 30dEDRs after head and neck surgery is low; however, these visits increase the hospitals' financial burden as well as patient morbidity. Predictors of 30dEDRs may be utilized to formulate preventative measures. PMID- 29240280 TI - Enantioselective Iridium-Catalyzed Phthalide Formation through Internal Redox Allylation of Phthalaldehydes. AB - An inside job: Enantioselective phthalide synthesis was achieved through internal redox allylation of o-phthalaldehydes. Oxidative esterification is balanced by reductive carbonyl addition to achieve an overall redox-neutral process. This method enabled formal syntheses of ent-spirolaxine methyl ether and CJ-12,954. PMID- 29240281 TI - Comparative analysis of 2 robotic thyroidectomy procedures: Transoral versus bilateral axillo-breast approach. AB - BACKGROUND: The surgical outcomes of a single surgeon's initial cases of transoral robotic thyroidectomy (TORT) were compared with the surgeon's initial cases of a bilateral axillo-breast approach (BABA) robotic thyroidectomy. METHODS: The medical reports were retrospectively reviewed. The BABA robotic thyroidectomies were performed between 2008 and 2009, and TORTs were performed between 2012 and 2016. RESULTS: Each group comprised 50 patients. Operative time for total thyroidectomy was shorter, the pain scores were lower, and hospital stays were shorter in the TORT group than in the BABA robotic thyroidectomy group. There were no significant differences between groups in either vocal cord palsy or hypoparathyroidism rates. There were 9 cases of mental nerve injury in the first 12 cases of TORT, but none subsequently. CONCLUSION: The TORT procedure could be performed safely and showed comparable outcomes with BABA robotic thyroidectomy in selected patients. Therefore, TORT may be an alternative approach for patients who prefer a scar-free thyroidectomy. PMID- 29240282 TI - Bis(perchlorocatecholato)silane-A Neutral Silicon Lewis Super Acid. AB - No neutral silicon Lewis super acids are known to date. We report on the synthesis of bis(perchlorocatecholato)silane and verify its Lewis super acidity by computation (DLPNO-CCSD(T)) and experiment (fluoride abstraction from SbF6- ). The exceptional affinity towards donors is further demonstrated by, for example, the characterization of an unprecedented SiO4 F2 dianion and applied in the first hydrodefluorination reaction catalyzed by a neutral silicon Lewis acid. Given the strength and convenient access to this new Lewis acid, versatile applications might be foreseen. PMID- 29240283 TI - Proximal tubular epithelial cells preferentially endocytose covalently-modified albumin compared to native albumin. AB - AIM: Albumin can be covalently modified at surface lysine residues and thus the circulation contains a mixture of native albumin (i.e. not modified) and albumin with varying degrees of modification. Uptake and lysosomal degradation of glomerular filtered albumin by proximal tubular cells via the megalin scavenger receptor is considered an important mechanism to limit albumin loss in the urine. However, whether this is a general mechanism of tubular uptake of albumin or if this is restricted to modified albumin is unknown. To address this question, we investigated the uptake of modified versus native albumin by proximal tubular cells. METHODS: A well-characterised proximal tubular cell model of albumin uptake was used to compare the uptake of modified albumin (covalent labelling of lysine residues with fluorescent probes) to that of native recombinant human albumin (rHA) labelled with 14 C during protein synthesis (14 C-rHA). RESULTS: Opossum kidney (OK) cells showed significant uptake of fluorescence-labelled albumin via an endocytosis mechanism. This uptake was inhibited by an equimolar ratio of different types of covalently modified albumin; however, purified bovine serum albumin and rHA failed to compete with the uptake of fluorescence-labelled albumin. In contrast, OK cells failed to endocytose native 14 C-rHA despite efficiently endocytosing covalently modified rHA. CONCLUSION: Our studies show that OK cells preferentially endocytose covalently-modified albumin compared to native albumin. This apparent selectivity of the megalin scavenger receptor complex suggests a specific role for this pathway in the removal of modified albumin from the circulation. PMID- 29240284 TI - Extracellular matrix/stromal vascular fraction gel conditioned medium accelerates wound healing in a murine model. AB - Conditioned medium (CM) is a new treatment modality in regenerative medicine and has shown a successful outcome in wound healing. We recently introduced extracellular matrix/stromal vascular fraction gel (ECM/SVF-gel), an adipose derived stem cell and adipose native extracellular matrix-enriched product for cytotherapy. This study aimed to evaluate the effect of CM from ECM/SVF-gel (Gel CM) on wound healing compared with the conventional CM from adipose tissue (Adi CM) and stem cell (SVF-CM). In vitro wound healing effect of three CMs on keratinocytes and fibroblasts was evaluated in terms of proliferation property, migratory property, and extracellular matrix production. In vivo, two full thickness wounds were created on the back of each mice. The wounds were randomly divided to receive Gel-CM, Adi-CM, SVF-CM, and PBS injection. Histologic observations and collagen content of wound skin were made. Growth factors concentration in three CMs was further quantified. In vitro, Gel-CM promoted the proliferation and migration of keratinocytes and fibroblasts and enhanced collagen I synthesis in fibroblasts compared to Adi-CM and SVF-CM. In vivo, wound closure was faster, and dermal and epidermal regeneration was improved in the Gel CM-treated mice compared to that in Adi-CM and SVF-CM-treated mice. Moreover, The growth factors concentration (i.e., vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor, and transforming growth factor-beta) in Gel-CM were significantly higher than those in Adi-CM and SVF-CM. Gel-CM generated under serum free conditions significantly enhanced wound healing effect compared to Adi-CM and SVF-CM by accelerating cell proliferation, migration, and production of ECM. This improved trophic effect may be attributed to the higher growth factors concentration in Gel-CM. Gel-CM shows potential as a novel and promising alternative to skin wound healing treatment. But limitations include the safety and immunogenicity studies of Gel-CM still remain to be clearly clarified and more data on mechanism study are needed. PMID- 29240285 TI - Significance of measured intraoperative portal vein flows after thrombendvenectomy in deceased donor liver transplantations with portal vein thrombosis. PMID- 29240286 TI - Peptidoglycan hydrolysis mediated by the amidase AmiC and its LytM activator NlpD is critical for cell separation and virulence in the phytopathogen Xanthomonas campestris. AB - The essential stages of bacterial cell separation are described as the synthesis and hydrolysis of septal peptidoglycan (PG). The amidase, AmiC, which cleaves the peptide side-chains linked to the glycan strands, contributes critically to this process and has been studied extensively in model strains of Escherichia coli. However, insights into the contribution of this protein to other processes in the bacterial cell have been limited. Xanthomonas campestris pv. campestris (Xcc) is a phytopathogen that causes black rot disease in many economically important plants. We investigated how AmiC and LytM family regulators, NlpD and EnvC, contribute to virulence and cell separation in this organism. Biochemical analyses of purified AmiC demonstrated that it could hydrolyse PG and its activity could be potentiated by the presence of the regulator NlpD. We also established that deletion of the genes encoding amiC1 or nlpD led to a reduction in virulence as well as effects on colony-forming units and cell morphology. Moreover, further genetic and biochemical evidence showed that AmiC1 and NlpD affect the secretion of type III effector XC3176 and hypersensitive response (HR) induction in planta. These findings indicate that, in addition to their well studied role(s) in cell separation, AmiC and NlpD make an important contribution to the type III secretion (T3S) and virulence regulation in this important plant pathogen. PMID- 29240287 TI - Comparative study of femtosecond laser-assisted cataract surgery and conventional phacoemulsification in vitrectomized eyes. AB - IMPORTANCE: To compare the safety and outcomes of femtosecond laser-assisted cataract surgery (FLACS) and conventional phacoemulsification in post-vitrectomy eyes. BACKGROUND: To compare visual outcomes and adverse outcomes of FLACS and conventional phacoemulsification in vitrectomized eyes. DESIGN: Single surgeon, retrospective study set in a private clinic in Auckland, New Zealand. Patients selected in a chronological manner, without masking or randomization. PARTICIPANTS: Only patients undergoing cataract extraction following vitrectomy were included. METHODS: The last 25 surgeries performed prior to acquisition of the femtosecond laser and the first 25 surgeries performed following acquisition of the femtosecond laser were included. Patient demographic data, preoperative and postoperative visual acuities were collected. Intraoperative and postoperative complications were compared. Follow-up ranged from 1 to 74 months. MAIN OUTCOME MEASURES: The main outcome measures are postoperative visual outcomes and intra- and postoperative complications for both groups. RESULTS: Results of FLACS compared to conventional phacoemulsification are as follows: preoperative logMAR best corrected visual acuity (BCVA) (0.63 vs. 0.69), postoperative logMAR BCVA (0.17 vs. 0.19), posterior capsule complications (0% vs. 12%, P = 0.235), cystoid macular oedema (CMO) (12% vs. 20%, P = 0.705) and postoperative neodymium-doped yttrium aluminium garnet (Nd:YAG) capsulotomy (16% vs. 48%, P = 0.032). CONCLUSIONS AND RELEVANCE: FLACS demonstrates comparable visual outcomes to conventional phacoemulsification. Whilst outcomes measured were not statistically significant, except postoperative YAG capsulotomy, FLACS showed a trend towards a better intraoperative and postoperative safety profile. Femtosecond laser offers a theoretical advantage in reducing complication rates in post-vitrectomy eyes, further larger studies are needed. PMID- 29240288 TI - 3D printing of the choroidal vessels and tumours based on optical coherence tomography. PMID- 29240289 TI - DNAzyme Feedback Amplification: Relaying Molecular Recognition to Exponential DNA Amplification. AB - Technologies capable of linking DNA amplification to molecular recognition are very desirable for ultrasensitive biosensing applications. We have developed a simple but powerful isothermal DNA amplification method, termed DNAzyme feedback amplification (DFA), that is capable of relaying molecular recognition to exponential DNA amplification. The method incorporates both an RNA-cleaving DNAzyme (RCD) and rolling circle amplification (RCA) carried out by a special DNA polymerase using a circular DNA template. DFA begins with a stimulus-dependent RCA reaction, producing tandemly linked RCDs in long-chain DNA products. These RCDs cleave an RNA-containing DNA sequence to form additional primers that hybridize to the circular DNA molecule, giving rise to DNA assemblies that act as the new inputs for RCA. The RCA reaction and the cleavage event keep on feeding each other autonomously, resulting in exponential growth of repetitive DNA sequences that can be easily detected. This method can be used for the detection of both nucleic acid based targets and non-nucleic acid analytes. In this article, we discuss the conceptual framework of the feedback amplification approach, the essential features of this method as well as remaining challenges and possible solutions. PMID- 29240290 TI - Bioorthogonal Cycloadditions with Sub-Millisecond Intermediates. AB - Tetrazine- and sydnone-based click reactions have emerged as important bioconjugation strategies with fast kinetics and N2 or CO2 as the only byproduct. Mechanistic studies of these reactions have focused on the initial rate determining cycloaddition steps. The subsequent N2 or CO2 release from the bicyclic intermediates has been approached mainly through computational studies, which have predicted lifetimes of femtoseconds. In the present study, bioorthogonal cycloadditions involving N2 or CO2 extrusion have been examined experimentally at the single-molecule level by using a protein nanoreactor. At the resolution of this approach, the reactions appeared to occur in a single step, which places an upper limit on the lifetimes of the intermediates of about 80 MUs, which is consistent with the computational work. PMID- 29240291 TI - New 4-Amino-1,2,3-Triazole Inhibitors of Indoleamine 2,3-Dioxygenase Form a Long Lived Complex with the Enzyme and Display Exquisite Cellular Potency. AB - Indoleamine-2,3 dioxygenase 1 (IDO1) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO1 has become an attractive target for cancer treatment. A novel series of highly cell potent IDO1 inhibitors based on a 4 amino-1,2,3-triazole core have been identified. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a noncompetitive kinetic mechanism of action with respect to the tryptophan substrate. In co-complex crystal structures, the compounds bind in the tryptophan pocket and make a direct ligand interaction with the haem iron of the porphyrin cofactor. It is proposed that these data can be rationalised by an ordered binding mechanism, in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long lived complex with the enzyme, which partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO1-targeted drugs. PMID- 29240292 TI - Molecular mechanism for the red blood cell senescence clock. AB - Lacking protein synthesis machinery and organelles necessary for autophagy or apoptosis, aged red blood cells (RBCs) are marked by circulating auto-antibodies for macrophage-mediated clearance. The antigen recognized by these auto antibodies is the major protein of the RBC membrane, Band 3. To ensure regulation and specificity in clearance, the molecular "clock" must mark senescent cells in a way that differentiates them from younger cells, to prevent premature clearance. Predominant models of Band 3 senescence signaling are reviewed, and merits are discussed in light of the recently published crystal structure of the Band 3 membrane domain. (c) 2017 IUBMB Life, 70(1):32-40, 2018. PMID- 29240293 TI - Transvenous pacemaker implantation after the bidirectional Glenn operation for patients with complex congenital disease. AB - INTRODUCTION: The bidirectional Glenn operation for congenital heart disease produces anatomical constraints to conventional transvenous pacemaker implantation. An iliac approach, although not previously described in this population, is potentially a preferable alternative to a thoracotomy for epicardial pacing. METHODS AND RESULTS: A single-center retrospective review was performed for all patients that underwent transvenous pacemaker implantation following the bidirectional Glenn operation with partial biventricular repair. Follow-up data, implant indications, and techniques were recorded. Five patients underwent a transvenous iliac approach (median age 26.9 years, interquartile range [IQR] 25.8-27.6). Pacing indications included AV block in 3 patients (2 requiring cardiac resychronization therapy) and sinus node dysfunction in 2. Implanted leads were atrial in 4 and ventricular in 3 (1 of the latter was placed in the coronary sinus). In two cases, transvenous leads were tunneled to a preexisting epicardial abdominal generator. Median follow-up was 4.1 years (range 1.0-16.7 years). One patient underwent device revision for lead position-related groin discomfort; a second patient developed atrial lead failure following a Maze operation and underwent lead replacement by the iliac approach. Patients were not routinely anticoagulated postprocedure given lead position in the subpulmonary circulation. At last follow-up, all patients were alive. One patient underwent heart transplantation 6 months after implant with only partial resolution of pacing-induced cardiomyopathy. CONCLUSIONS: Trans-iliac pacemaker placement may be an effective alternative to surgery for patients requiring permanent pacing after the Glenn operation. PMID- 29240294 TI - Hydrogen Evolution Activity of Ruthenium Phosphides Encapsulated in Nitrogen- and Phosphorous-Codoped Hollow Carbon Nanospheres. AB - RuPx nanoparticles (NPs) encapsulated in uniform N,P-codoped hollow carbon nanospheres (RuPx @NPC) have been synthesized through a facile route in which aniline-pyrrole copolymer nanospheres are used to disperse Ru ions followed by a gas phosphorization process. The as-prepared RuPx @NPC exhibits a uniform core shell hollow nanospherical structure with RuPx NPs as the core and N,P-codoped carbon (NPC) as the shell. This strategy integrates many advantages of hollow nanostructures, which provide a conductive substrate and the doping of a nonmetal element. At high temperatures, the obtained thin NPC shell can not only protect the highly active phase of RuPx NPs from aggregation and corrosion in the electrolyte but also allows variation in the electronic structures to improve the charge-transfer rate greatly by N,P codoping. The optimized RuPx @NPC sample at 900 degrees C exhibits a Pt-like performance for the hydrogen evolution reaction (HER) and long-term durability in acidic, alkaline, and neutral solutions. The reaction requires a small overpotential of only 51, 74, and 110 mV at 10 mA cm-2 in 0.5 m H2 SO4 , 1.0 m KOH, and 1.0 m phosphate-buffered saline, respectively. This work provides a new way to design unique phosphide-doped carbon heterostructures through an inorganic-organic hybrid method as excellent electrocatalysts for HER. PMID- 29240295 TI - Highlights on the Road towards Highly Emitting Solid-State Luminophores: Two Classes of Thiazole-Based Organoboron Fluorophores with the AIEE/AIE Effect. AB - Developing a novel, small-sized molecular building block that may be capable of emitting light in the solid state is a challenging task and has rarely been reported in the literature. BF2 -containing dyes seem to be promising candidates towards this aim. Two series of new N^NBF2 complexes showing aggregation-induced emission (AIE) and aggregation-induced emission enhancement (AIEE) were designed and synthesized by means of a new protocol, which improved on the traditional method by employing microwave irradiation. The optical and photophysical properties of the BF2 complexes were investigated in depth. The synthesized complexes showed fluorescence in both solution and the solid state and, in a mixture of tetrahydrofuran/water, may aggregate into fluorescent nanoparticles. The experimental investigation was supported by quantum mechanical calculations. Their availability, stability, large Stokes shifts, and aggregation capabilities, along with their solid-state emission capability, render this new class of BF2 complexes promising AIEE/AIE fluorophores for further applications in the fields of fluorescence imaging and materials science. PMID- 29240296 TI - Bacteriophage effectively kills multidrug resistant Staphylococcus aureus clinical isolates from chronic rhinosinusitis patients. AB - BACKGROUND: Bacteriophage (phage) therapy has been proposed as an alternative to antibiotics. Phages have been shown to kill antibiotic resistant Staphylococcus aureus strains; however, it is unknown whether stress-induced antibiotic tolerance affects S. aureus susceptibility to phages. Our objective was to determine the effectiveness of 2 phages currently in clinical development, against antibiotic-resistant and induced antibiotic-tolerant clinical S. aureus isolates. METHODS: Antibiotic tolerant S. aureus strains were induced by incubation with increasing concentrations of gentamicin, mupirocin, and ciprofloxacin over time and their susceptibility to 2 clinically relevant phages (Sa83 and Sa87) was assessed. In addition, phage susceptibility was tested in relation to the antibiotic sensitivity of 65 clinical S. aureus isolates, harvested from the sinonasal cavities of chronic rhinosinusitis (CRS) patients. Phage sensitivity was assessed using a plaque spot assay and by measuring optical density values to observe planktonic S. aureus growth in the presence of the phage. Alamar Blue assays were used to assess biofilm viability after phage treatment. RESULTS: Frequency of antibiotic resistance amongst clinical S. aureus isolates was 90.7% (59/65) with 13 of 65 (20.0%) identified as multidrug resistant. Tolerance to gentamicin, mupirocin, and ciprofloxacin was rapidly induced by incubation with increasing concentrations of respective antibiotics. There was no significant difference in phage sensitivity between antibiotic sensitive and resistant/tolerant S. aureus clinical isolates in planktonic and biofilm form. CONCLUSION: Clinical S. aureus isolates from CRS patients have a high (20%) incidence of multidrug resistance. Antibiotic resistance or tolerance did not affect phage susceptibility of those isolates. PMID- 29240297 TI - Shared CaM- and S100A1-binding epitopes in the distal TRPM4 N terminus. AB - The transient receptor potential channel of melastatin 4 (TRPM4) belongs to a group of large ion receptors that are involved in countless cell signalling cascades. This unique member is ubiquitously expressed in many human tissues, especially in cardiomyocytes, where it plays an important role in cardiovascular processes. Transient receptor potential channels (TRPs) are usually constituted by intracellular N- and C- termini, which serve as mediators affecting allosteric modulation of channels, resulting in the regulation of the channel function. The TRPs tails contain a number of conserved epitopes that specifically bind the intracellular modulators. Here, we identify new binding sites for the calmodulin (CaM) and S100 calcium-binding protein A1 (S100A1), located in the very distal part of the TRPM4 N terminus. We have used chemically synthesized peptides of the TRPM4, mimicking the binding epitopes, along with fluorescence methods to determine and specify CaM- and S100A1-binding sites. We have found that the ligands binding epitopes at the TRPM4 N terminus overlap, but the interacting mechanism of both complexes is probably different. The molecular models supported by data from the fluorescence method confirmed that the complexes formations are mediated by the positively charged (R139, R140, R144) and hydrophobic (L134, L138, V143) residues present at the TRPM4 N terminus-binding epitopes. The data suggest that the molecular complexes of TRPM4/CaM and TRPM4/S100A1 would lead to the modulation of the channel functions. PMID- 29240298 TI - Diabetic macular edema, innovative technologies and economic impact: New opportunities for the Lombardy Region healthcare system? AB - PURPOSE: Diabetic macular edema (DME) is a leading cause of vision loss and blindness. The aim of this study was to evaluate the economic benefits of introducing additional alternative technologies (Dexamethasone intravitreal implant - DEX - and Aflibercept injections), compared with the historical scenario of Ranibizumab intravitreal injections. METHODS: A 3-year budget impact model was developed, taking into consideration the perspective of the Lombardy Region Healthcare Service (LRHS). Total administration costs (real-life data retrieved from clinical practice at three Departments of Ophthalmology) as well as costs related to the management of potential adverse events (information collected from the literature) were analysed. RESULTS: Over a 36-month horizon, the results showed that a higher consumption of DEX could lead to significant economic savings for the Regional Healthcare Service, ranging from a minimum of 4.35% (if DEX were used only in the second-line of treatment) to a maximum of 12.97% (if DEX were used in both the first-line and second-line), including the potential impact of adverse events. Therapy costs with Aflibercept and Ranibizumab were similar. CONCLUSIONS: This study demonstrates that concentrating all eligible patients within the Ranibizumab regimen is unlikely to represent a cost-effective strategy. Indeed, significant economic advantages would be achieved by introducing the other licensed alternatives, Dexamethasone implant and Aflibercept, thus optimising DME Italian healthcare expenditure. The results demonstrate DEX as an advantageous technological alternative for the target population affected by DME, both as a first- and second-line treatment option, reducing the economic burden of the pathology for the Regional/National Health Service. PMID- 29240299 TI - The effect of haemopoietic stem cell transplantation on the ocular phenotype in mucopolysaccharidosis type I (Hurler). AB - PURPOSE: To determine whether the ocular phenotype in patients with mucopolysaccharidosis type I (MPSI) Hurler is affected by the efficacy of previous haemopoietic stem cell transplantation (HSCT). DESIGN: A retrospective cohort study of patients with MPSI who had undergone treatment with HSCT. METHODS: Ocular phenotype was documented for each patient and compared to levels of biomarkers representing efficacy of previous transplantation. MAIN OUTCOME MEASURES: Assessment of visual acuity (VA), severity of corneal clouding and the presence of optic neuropathy or retinopathy. Biomarker assessment included dermatan sulphate/chondroitin sulphate (DS/CS) ratio and iduronidase enzyme level. RESULTS: Severe corneal clouding was significantly greater in patients with lower iduronidase levels (p = 0.023) and raised DS/CS ratio (R2 = 0.28 p = 0.043). Better VA was related to a higher iduronidase levels (R2 = 0.15, p = 0.004) and lower DS/CS ratio (R2 = 0.38, p = 0.001). CONCLUSION: Improved ocular phenotypes in MPSI are associated with markers signifying efficacy of prior transplant. Early and effective HSCT may result in a better visual prognosis and reduction in ocular complications for patients with MPSI. PMID- 29240300 TI - Genomic origin and nuclear localization of TERRA telomeric repeat-containing RNA: from Darkness to Dawn. AB - Long noncoding RNAs, produced from distinct regions of the chromosomes, are emerging as new key players in several important biological processes. The long noncoding RNAs add a new layer of complexity to cellular regulatory pathways, from transcription to cellular trafficking or chromatin remodeling. More than 25 years ago, the discovery of a transcriptional activity at telomeres of protozoa ended the long-lasting belief that telomeres were transcriptionally silent. Since then, progressively accumulating evidences established that production of TElomeric Repeat-containing RNA (TERRA) was a general feature of eukaryotic cells. Whether TERRA molecules always originate from the telomeres or whether they can be transcribed from internal telomeric repeats as well is however still a matter of debate. Whether TERRA transcripts always localize to telomeres and play similar roles in all eukaryotic cells is also unclear. We review the studies on TERRA localization in the cell, its composition and some aspects of its transcriptional regulation to summarize the current knowledge and controversies about the genomic origin of TERRA, with a focus on human and mouse TERRA. PMID- 29240301 TI - The Terracol and Ardouin developmental model of frontal sinus drainage pathway and surrounding spaces: a radiologic validation. AB - BACKGROUND: The complexity of the frontal sinus drainage pathway (FSDP) can be challenging even for expert surgeons. Several classifications have been proposed to simplify the understanding of FSDP, whose anatomical variability can be simplified based on the knowledge of its developmental mechanisms. METHODS: Cone beam computed tomography studies performed at the Unit of Radiology of the University of Brescia between March and November 2012 were retrospectively analyzed. FSDP was classified as medial or lateral to the vertical portion of the uncinate process and the following anatomical variants were studied: agger nasi cell, Kuhn's cells, suprabullar cell, supraorbital ethmoid cell, suprabullar frontal cell, and frontal septal cell. The developmental model of the FSDP proposed by Terracol and Ardouin was analyzed and expected associations between the position of the drainage pathway and anatomical variants were formulated. Statistical associations between anatomical variants and the position of FSDP were calculated and compared with expected associations to validate the developmental model. RESULTS: The anatomical variants of FSDP statistically validated the developmental model of Terracol and Ardouin. CONCLUSION: Knowledge of the possible developmental patterns of FSDP helps the surgeon in the understanding of the complexity of the frontoethmoidal region. PMID- 29240303 TI - Discovery of novel negletein derivatives as potent anticancer agents for acute myeloid leukemia. AB - Baicalin and its aglycone baicalein derived from Scutellaria baicalensis exhibited potent anticancer effects in various types of cancer cell lines. However, the unfavorable pharmaceutical properties became the main obstacle for their potential clinical development. With the aim of development of novel anticancer agents based on the skeleton of baicalin, a series of novel negletein derivatives were designed and synthesized. Among them, compound 8 (FZU-02,006) with an N,N-dimethylamino ethoxyl moiety at the C-6 position exhibited significant enhanced antiproliferative effect against HL-60 cells in vitro through regulating multisignaling pathways. These results revealed that compound 8 with the improved aqueous solubility (as HCl salt, >1 mg/ml) and enhanced antileukemia potency might serve as a promising lead for further development. PMID- 29240302 TI - Correlation between sinus and lung cultures in lung transplant patients with cystic fibrosis. AB - BACKGROUND: Lung transplantation has revolutionized the treatment of end-stage pulmonary disease due to cystic fibrosis. However, infection of the transplanted lungs can lead to serious complications, including graft failure and death. Although many of these patients have concurrent sinusitis, it is unclear whether bacteria from the sinuses can infect the allograft. METHODS: This is a single institution retrospective study of all patients who underwent lung transplantation for cystic fibrosis from 2005 to 2015 at Duke University Hospital. Pre- and posttransplant nasal and pulmonary cultures obtained via nasal endoscopy and bronchoalveolar lavage (BAL), respectively, were analyzed. RESULTS: A total of 141 patients underwent 144 lung transplants. Sinus cultures were available for 76 patients (12 pretransplant, 42 posttransplant, 22 both pre- and posttransplant). Pretransplant BAL cultures were available for 139 patients, and posttransplant BAL cultures were available for all patients. Pseudomonas aeruginosa (PsA) and methicillin-resistant Staphylococcus aureus (MRSA) were the most common organisms cultured. There was a significant correlation between pretransplant sinus and posttransplant BAL cultures for PsA (p = 0.003), MRSA (p = 0.013), and Burkholderia cepacia (p = 0.001). CONCLUSION: There was a high correlation between pretransplant sinus cultures and posttransplant BAL cultures for PsA, MRSA, and Burkholderia sp. This suggests that the paranasal sinuses may act as a reservoir for allograft colonization in patients with cystic fibrosis. Further studies are needed to determine whether treatment of sinusitis affects allograft colonization and transplant outcomes. PMID- 29240304 TI - Weight status, diet quality, perceived stress, and functional health of caregivers of children with autism spectrum disorder. AB - PURPOSE: Caring for children with autism spectrum disorder (ASD) can be highly demanding and can put significant strain on caregivers. To date, little is known about the extent to which caregivers of children with ASD experience increased levels of stress which may adversely affect health outcomes. The purpose of this secondary analysis was to compare caregivers of children with ASD and caregivers of typically developing children (TDC) in weight status, diet quality, perceived stress related to the parenting role, and functional health and well-being. DESIGN AND METHODS: Caregivers of 25 children with ASD and 30 TDC completed the 2005 Block Food Frequency Questionnaire, the 36-item Short Form of the Parenting Stress Index (PSI/SF), and the Short Form Health Survey (SF-36) and had their heights and weights measured during an onsite visit. Diet quality was assessed using the Healthy Eating Index (HEI)-2010 and its dietary components and conformance to the 2010 Dietary Guidelines for Americans. RESULTS: ASD caregivers did not differ significantly from TDC caregivers in body mass index or overweight/obesity prevalence (p >= .28), even when controlling for covariates. In univariate analyses, ASD caregivers consumed significantly fewer empty calories from solid fats, alcohol, and added sugars than TDC caregivers (p = .03), but they did not differ significantly in any other dietary outcomes including nutrient adequacy (p >= .10) and mean total HEI scores (p = .20). ASD caregivers, when compared to TDC caregivers, reported significantly greater parenting stress for the subscales difficult child and parent-child dysfunctional interaction as well as total stress (p < .001). In addition, 56% of ASD caregivers compared with 6.7% of TDC caregivers showed clinically significant levels of stress (p < .0001); a finding which remained statistically significant when controlling for covariates. ASD and TDC caregivers did not differ significantly in any SF-36 health domains related to functional health and well being (p >= .10). PRACTICE IMPLICATIONS: Despite higher reported levels of stress, ASD caregivers did not differ significantly from TDC caregivers in diet- and health-related outcomes. Nurses and other health professionals should use comprehensive screening tools to assess overall caregiver stress and levels of resilience. PMID- 29240305 TI - Surgical anatomy of the round window-Implications for cochlear implantation. AB - BACKGROUND: The round window is an important portal for the application of active hearing aids and cochlear implants. The anatomical and topographical knowledge about the round window region is a prerequisite for successful insertion for a cochlear implant electrode. OBJECTIVE OF REVIEW: To sum up current knowledge about the round window anatomy and to give advice to the cochlear implant surgeon for optimal placement of an electrode. TYPE OF REVIEW: Systematic Medline search. SEARCH STRATEGY: Search term "round window[Title]" with no date restriction. Only publications in the English Language were included. All abstracts were screened for relevance, that is a focus on surgical anatomy of the round window. The search results were supplemented with hand searching of selected reviews and reference lists from included studies. EVALUATION METHOD: Subjective assessment. RESULTS: There is substantial variability in size and shape of the round window. The round window is regarded as the most reliable surgical landmark to safely locate the scala tympani. Factors affecting the optimal trajectory line for atraumatic electrode insertion are anatomy of the round window, the anatomy of the intracochlear hook region and the variable orientation and size of the cochlea's basal turn. CONCLUSIONS: The very close relation to the sensitive inner ear structures necessitates a thorough anatomic knowledge and careful insertion technique, especially when implanting patients with residual hearing. In order to avoid electrode migration between the scalae and to achieve protect the modiolus and the basilar membrane, it is recommended to aim for an electrode insertion vector from postero-superior to antero-inferior. PMID- 29240308 TI - Genetics and nursing: A whole new ball game or back to basics? PMID- 29240307 TI - Use and limitations of offsite consequence analysis tools from South Korea and the United States in hydrogen fluoride accidental release. AB - We investigated the characteristics and limitations in the event of hydrofluoric acid (HF) leakage by comparing and analyzing the offsite consequence analysis (OCA) tools based on the chemical plant operating conditions. We reviewed the tools Korea Offsite Risk Assessment (KORA) from South Korea and Risk Management Plan*Comp (RMP*CompTM) and Areal Location of Hazardous Atmospheres (ALOHA) from the United States. The scenario studied was based on a leak event from a 50% HF aqueous solution storage tank, and the operating conditions taken into consideration were the operating temperature and dike installation conditions. The results from the OCA differed; KORA presented a smaller range of offsite impact than did ALOHA. The offsite impact ranges of KORA and ALOHA increased as the operating temperature and dike installation area increased. However, RMP*Comp differed greatly in its offsite impact range results in the operating temperature range of 25 degrees C to 30 degrees C. Moreover, in the alternative scenario, a limitation existed in that the offsite impact range was not changed by the dike installation conditions. The offsite impact range analyzed via KORA and ALOHA reflected the reality of an HF leak accident better than that analyzed via RMP*Comp. Therefore, it is more reasonable to use KORA and ALOHA instead of RMP*Comp in OCA. Moreover, users should realize that ALOHA has a somewhat wider range of offsite impact than KORA does in OCA. The separation distance from the storage tank when installing a dike is effective between 1 and 1.5 m in consideration of securing the minimum workspace for workers. Integr Environ Assess Manag 2018;14:205-211. (c) 2017 SETAC. PMID- 29240306 TI - Diabetic macular oedema treated with intravitreal anti-vascular endothelial growth factor - 2-4 years follow-up of visual acuity and retinal thickness in 566 patients following Danish national guidelines. AB - PURPOSE: To investigate long-term functional and anatomical outcomes, discontinuation patterns, drug switching and rates of nonimprovement in patients treated with ranibizumab pro re nata (PRN) regimen for diabetic macular oedema (DME) according to the Danish national guidelines. METHODS: Retrospective cohort study of 566 eyes in 566 patients with centre-involved DME who started intravitreal treatment with ranibizumab between January 2011 and December 2013 in the Greater Copenhagen region. Data were retrieved from a database and patient records between January 2011 and March 2016 and analysed using mixed-model statistics. RESULTS: At the conclusion of follow-up, 24.6% were in active ranibizumab follow-up, 25.4% had switched to other intravitreal pharmacotherapy, 31.6% had been discontinued because of disease stability, 13.8% had been lost to follow-up, 1.4% had been discontinued because of low visual acuity (VA), and 3.2% had died. At baseline, mean best-corrected visual acuity (BCVA) and mean central subfield thickness (CST) were 64.9 (+/-15.0) letters and 400.2 (+/-120.3) MUm. Mean change in BCVA and mean change in CST from baseline to 3, 12, 24, 36 and 48 months of follow-up were +3.9, +3.5, +2.7, +1.8, +2.3 letters and -97.4, -102.6, 106.9, -105.9, -131.6 MUm, respectively. Mean number of injections was 6.1 in year 1 and 1.8 in year 4. In 93 patients, drug switching to aflibercept showed no difference between the two drugs on BCVA or CST. In 79 patients, CST decreased <10% compared to baseline during the first year. CONCLUSION: In a single-centre clinical setting, 566 patients treated for DME with ranibizumab according to the Danish national guidelines were followed for up to 4 years. Best-corrected visual acuity (BCVA) outcomes are in the low end of clinical studies, but studied on a wider population and achieved with fewer injections. PMID- 29240309 TI - Comparison of two peripheral mononuclear cell isolation protocols for flow cytometry crossmatching. AB - In clinical organ transplantation, flow cytometry crossmatching can be performed on total blood with a hemolysis step or after a preliminary mononuclear cell separation step using a standard Ficoll-Hypaque protocol. Here, we compared the Ficoll-Hypaque step with a faster technique for isolating mononuclear cells (the SepMate tube), using the same samples (collected and stored at room temperature for 0, 24, 48 or 72 hours). We found that the SepMate separation protocol is easily applied to flow cytometry crossmatching (with or without pronase treatment), provided that the samples have been stored at room temperature for 48 hours or less. Conversely, the Ficoll-Hypaque protocol should be used if the samples have been stored for more than 48 hours at room temperature. PMID- 29240310 TI - Diagnostic accuracy of high-resolution T2-weighted MRI vs contrast-enhanced T1 weighted MRI to screen for cerebellopontine angle lesions in symptomatic patients. AB - OBJECTIVE: To evaluate diagnostic accuracy of high-resolution T2-weighted MRI (T2w) for detecting cerebellopontine angle (CPA) lesions compared to a combined protocol including gadolinium enhanced T1-weighted MRI (GdT1w). SETTING: Department of Radiology & Nuclear Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands. PARTICIPANTS: A random sample of MRIs from 350 patients (700 CPAs) with asymmetrical audiovestibular complaints was used, acquired between 2013 and 2016. MAIN OUTCOME MEASURES: Sensitivity, specificity, positive and negative predictive values of T2w results compared to GdT1w and, in patients with any suggestion of CPA pathology, to the complete examination (T1w, GdT1w and T2w). Inter-rater agreement between an experienced neuroradiologist and a less experienced observer was calculated. RESULTS: Results of 678 CPAs in 340 patients were analysed. On T2w, the neuroradiologist identified all 27 lesions >2 mm in size out of a total of 30 CPA lesions (sensitivity: 90% [95% CI: 73.5% 97.9%]). Negative predictive value reached 99.5% (95% CI: 98.7-99.9). One missed lesion of 2 mm would have been detected in clinical practice, as this was one of 14 patients for which additional GdT1w would have been ordered based on T2w alone, increasing sensitivity to 93% (95% CI: 77.9%-99.2%) and negative predictive value to 99.7% (95% CI: 98.9%-100%). Inter-rater agreement for T2w was 98% (95% CI: 96.4-98.8). CONCLUSION: T2w has a very high diagnostic accuracy for the presence of CPA lesions in patients with asymmetrical audiovestibular complaints. However, in a screening protocol with T2w only, smallest vestibular schwannomas as well as rare differential diagnoses that probably only would be detected on GdT1w may remain unnoticed. PMID- 29240311 TI - Systemic changes in photosynthesis and reactive oxygen species homeostasis in shoots of Arabidopsis thaliana infected with the beet cyst nematode Heterodera schachtii. AB - Photosynthetic efficiency and redox homeostasis are important for plant physiological processes during regular development as well as defence responses. The second-stage juveniles of Heterodera schachtii induce syncytial feeding sites in host roots. To ascertain whether the development of syncytia alters photosynthesis and the metabolism of reactive oxygen species (ROS), chlorophyll a fluorescence measurements and antioxidant responses were studied in Arabidopsis thaliana shoots on the day of inoculation and at 3, 7 and 15 days post inoculation (dpi). Nematode parasitism caused an accumulation of superoxide and hydrogen peroxide molecules in the shoots of infected plants at 3 dpi, probably as a result of the observed down-regulation of antioxidant enzymes. These changes were accompanied by an increase in RNA and lipid oxidation markers. The activities of antioxidant enzymes were found to be enhanced on infection at 7 and 15 dpi, and the content of anthocyanins was elevated from 3 dpi. The fluorescence parameter Rfd , defining plant vitality and the photosynthetic capacity of leaves, decreased by 11% only at 7 dpi, and non-photochemical quenching (NPQ), indicating the effectiveness of photoprotection mechanisms, was about 16% lower at 3 and 7 dpi. As a result of infection, the ultrastructure of chloroplasts was changed (large starch grains and plastoglobules), and more numerous and larger peroxisomes were observed in the mesophyll cells of leaves. We postulate that the joint action of antioxidant enzymes/molecules and photochemical mechanisms leading to the maintenance of photosynthetic efficiency promotes the fine-tuning of the infected plants to oxidative stress induced by parasitic cyst nematodes. PMID- 29240312 TI - Garden terror-Case series of twenty-eight serious ear injuries caused by yucca plants. PMID- 29240313 TI - Deconvolution of images from 3D printed cells in layers on a chip. AB - Layer-by-layer cell printing is useful in mimicking layered tissue structures inside the human body and has great potential for being a promising tool in the field of tissue engineering, regenerative medicine, and drug discovery. However, imaging human cells cultured in multiple hydrogel layers in 3D-printed tissue constructs is challenging as the cells are not in a single focal plane. Although confocal microscopy could be a potential solution for this issue, it compromises the throughput which is a key factor in rapidly screening drug efficacy and toxicity in pharmaceutical industries. With epifluorescence microscopy, the throughput can be maintained at a cost of blurred cell images from printed tissue constructs. To rapidly acquire in-focus cell images from bioprinted tissues using an epifluorescence microscope, we created two layers of Hep3B human hepatoma cells by printing green and red fluorescently labeled Hep3B cells encapsulated in two alginate layers in a microwell chip. In-focus fluorescent cell images were obtained in high throughput using an automated epifluorescence microscopy coupled with image analysis algorithms, including three deconvolution methods in combination with three kernel estimation methods, generating a total of nine deconvolution paths. As a result, a combination of Inter-Level Intra-Level Deconvolution (ILILD) algorithm and Richardson-Lucy (RL) kernel estimation proved to be highly useful in bringing out-of-focus cell images into focus, thus rapidly yielding more sensitive and accurate fluorescence reading from the cells in different layers. (c) 2017 American Institute of Chemical Engineers Biotechnol. Prog., 34:445-454, 2018. PMID- 29240314 TI - Treatment of incarcerated hernia in adults. AB - Of the 14,000 hernias operated annually in Finland, approximately 5 to 6% are treated as emergencies usually due to incarceration. Compared with elective hernia operations, emergency operations carry an increased risk of complications and death, especially in elderly patients and those with comorbidities. The risk of hernia recurrence is higher after an emergency procedure. In an emergency situation, a solution resulting in the best immediate and long-term outcome should be selected for each patient. Sometimes it is best to treat only the acute incarceration, whereas in some cases a hernia repair with good and lasting outcome can be safely performed already during the acute situation. Besides the nature of the hernia itself, the decisions are affected by the general condition and underlying disease of the patient, as well as the surgeon's experience. Emergency hernia surgery requires experience, as suboptimal solutions will complicate any repair operations that may be required later. PMID- 29240315 TI - Molecular Drug-Susceptibility Test for Tuberculosis. PMID- 29240316 TI - Assessment of Health Inequalities Among Older People Using the EPICES Score: A Composite Index of Social Deprivation. AB - BACKGROUND: Most of the indicators commonly used to assess social deprivation are poorly suited to study health inequalities in older people. The EPICES (Evaluation of Deprivation and Inequalities in Health Examination Centres) score is a new composite index commonly used to measure individual deprivation. OBJECTIVE: To assess the relationships between health indicators and the EPICES score in older people. Design, Setting, and participants: We performed a cross sectional study using the data from the 2008 ESPS Survey (Health, HealthCare and Insurance Survey). Of the 4235 survey respondents aged 60 and over in 2008, 2754 completed the 11 items of the EPICES score and were included in the study. MAIN OUTCOMES AND MEASURES: Deprivation was measured using the EPICES score. Health indicators were: Disability, physical performance, cognitive decline, self perceived health status, and health-care use and participation in prevention programs (missing teeth not replaced, healthcare renunciation, no hemoccult test [60-75 years] and no mammography [60-75 years]). RESULTS: Of the 4235 survey respondents aged 60 and over in 2008, 2754 completed the 11 items of the EPICES score and were included in the study. The mean age was 70.5+/- 8.2 years. 52.8% were women. 25.8% were living in poor households. According to the EPICES score, 35.1% were deprived. The EPICES score is linked to all the health indicators assessed in this study: Physical disability, cognitive decline; lifestyle and health care accessibility. These relationships increase steadily with the level of social deprivation. For example, the risk of having difficulties in walking 500m without help or an assistive device is multiplied by 13 (RR=13.5 [7.9-20.8]) in the elderly of quintile 5 (maximum precariousness). Limitations: The observational nature limits inferences about causality.CONCLUSION: The EPICES score is linked to health indicators. It could be a useful instrument to assess health inequalities in older people living in the community. PMID- 29240317 TI - Inflammations of the mammary gland. AB - Breast inflammation, i.e. mastitis is an entity with a variable etiology and severity, typically affecting women of fertile age. In most cases, anamnesis reveals the etiology of the disease, bacterial puerperal mastitis associated with breastfeeding being the most common. Periductal mastitis is a breast inflammation typically associated with smoking in women of 40 to 50 years of age, localized to the region of the areola. Granulomatous mastitis and other rare breast inflammations usually require specialized care. Regardless of etiology, treatment of acute inflammation depends on the clinical picture and, with the exception of puerperal mastitis, emergency ultrasound imaging is often necessary in order to detect an abscess and drain it. In all cases of mastitis, the possibility of underlying malignancy as well as inflammatory breast cancer should be kept in mind. If specialized care is required, breast inflammation is treated in a breast, general or plastic surgery unit. PMID- 29240318 TI - Ketamine in the treatment of acute pain. AB - Ketamine is an old anesthetic agent that relieves pain by reducing central sensitization in the central nervous system. This is advantageous for patients suffering from severe pain prior to surgery or are using a strong opioid. The S enantiomer of ketamine used for anesthesia is more powerful than racemic ketamine. The ideal dose of ketamine for pain relief is not yet known, and its adverse effects on the central nervous system, including hallucinations, sedation, and diplopia have limited its use in pain management. The significance of these effects at low doses is probably less than expected, particularly if benzodiazepines or an alpha-2 agonist, such as dexmedetomidine, are administered in addition to ketamine. PMID- 29240320 TI - Time has not passed for the tilt table test. AB - INTRODUCTION: The tilt table test is used for determining the loss of consciousness, and in the case of reflex syncope, for gaining insight into the circulatory mechanism. In 2015, all tilt tests within the Hospital District of Helsinki and Uusimaa (HUS) were performed in the clinical physiology unit of the HUS Medical Imaging Center at Peijas Hospital. METHODS: The patients' medical history, circulation monitor printouts, and medical reports were recorded from all tilt tests carried out during 2015. Positive tilt tests were classified according to the VASIS classification and the elapsed time to loss of consciousness was observed. RESULTS: Among a total of 133 patients, abnormal upright tolerance was found in 30 per cent of the patients. The average time to loss of consciousness was 35.2 minutes. The most common mechanism of syncope was mixed reaction (60.0%), whereas vasovagal reaction (22.5%), cardioinhibitory reaction (10.0%), and lacking stroke volume response (7.5%) were less common. CONCLUSIONS: Practices of referral for the tilt table test vary among the different units of HUS. In our material, the cardioinhibitory reaction was less common than in previous studies. PMID- 29240319 TI - Frailty and Health-Related Quality of Life in End Stage Renal Disease Patients of All Ages. AB - BACKGROUND: Frailty is associated with worse health-related quality of life (HRQOL) in older adults and worse clinical outcomes in adults of all ages with end stage renal disease (ESRD). It is unclear whether frail adults of all ages with ESRD are more likely to experience worse HRQOL. OBJECTIVE: The goal of this study was to identify factors associated with worsening HRQOL in this population. DESIGN, SETTING AND MEASUREMENTS: We studied 233 adults of all ages with ESRD enrolled (11/2009-11/2013) in a longitudinal cohort study. Frailty status was measured at enrollment and HRQOL was reported (Excellent, Very Good, Good, Fair or Poor) at the initial assessment and follow-up (median follow-up 9.4 months). We studied factors associated with Fair/Poor HRQOL at follow-up using logistic regression and factors associated with HRQOL change using multinomial regression. All models were adjusted for age, sex, race, education, BMI, diabetes status, history of a previous transplant, type of dialysis and time between assessments. RESULTS: Fair/Poor HRQOL was reported by 28% at initial assessment and 33% at follow-up. 47.2% of participants had stable HRQOL, 22.8% better HRQOL, and 30.0% worse HRQOL at follow-up (P<0.001). In adjusted models, only frailty was associated with Fair/Poor HRQOL at follow-up (OR: 2.79, 95% CI: 1.32-5.90) and worsening HRQOL at follow-up (RR: 2.91, 95%CI: 1.08-7.80). CONCLUSIONS: Frail adults of all ages with ESRD are more likely to experience fair/poor HRQOL and worsening HRQOL over time. Frailty represents a state of decreased physiologic reserve that impacts not only clinical outcomes but also the patient-centered outcome of HRQOL. PMID- 29240321 TI - Medicare Program: Hospital Outpatient Prospective Payment and Ambulatory Surgical Center Payment Systems and Quality Reporting Programs. Final rule with comment period. AB - This final rule with comment period revises the Medicare hospital outpatient prospective payment system (OPPS) and the Medicare ambulatory surgical center (ASC) payment system for CY 2018 to implement changes arising from our continuing experience with these systems. In this final rule with comment period, we describe the changes to the amounts and factors used to determine the payment rates for Medicare services paid under the OPPS and those paid under the ASC payment system. In addition, this final rule with comment period updates and refines the requirements for the Hospital Outpatient Quality Reporting (OQR) Program and the ASC Quality Reporting (ASCQR) Program. PMID- 29240322 TI - Osteosclerosis associated with hepatitis C. AB - We describe the first Finnish case of hepatitis C associated osteosclerosis. In which the patient's bone symptoms and bone density were resolved with hepatitis C treatment. Suspecting the possibility of osteosclerosis underlying bone pains in a hepatitis C patient is well-founded, although osteoporotic fractures are a more common problem. PMID- 29240323 TI - The Fate of FDA Postapproval Studies. PMID- 29240324 TI - Current Care Guideline: Heart failure. AB - Treatment of heart failure depends on etiology, left ventricular function and severity of symptoms. Appropriate diagnosis and treatment requires close collaboration between health care providers. In heart failure with reduced ejection fraction, pharmacological treatment and device therapies are based on solid scientific evidence. Less data exist on treatment of heart failure with preserved ejection fraction, where management of underlying diseases contributing to the syndrome is the primary goal. Patient education and self-care may reduce the need for hospitalizations and improve quality of life. Physical exercise reduces symptoms and improves exercise tolerance. PMID- 29240325 TI - Tort Law--Expert Testimony in Asbestos Litigation--District of South Carolina Holds the Every Exposure Theory Insufficient to Demonstrate Specific Causation Even If Legal Conclusions are Scientifically Sound.--Haskins v. 3m Co., Nos. 2:15 cv-02086, 3:15-cv-02123, 2017 WL 3118017 (D.S.C. July 21, 2017). PMID- 29240326 TI - Health Seeking in Men: A Concept Analysis. AB - This article describes the analysis of the concept of health seeking in men. Menhave shorter life expectancies and utilize health services less often than women,leading to poor health outcomes, but a gendered basis for health seeking remainspoorly defined. Walker and Avant's framework was used to guide this conceptanalysis. Literature published in English from 1990-2015 was reviewed. Thematicanalysis identified attributes, antecedents, and consequences of the concept.Based on the analysis, a contemporary definition for health seeking in men wasconstructed, rooted in the concept of health. The definition is based on the conceptanalysis and the defining attributes that were identified. This analysis provides adefinition specifically for health seeking in American men, making it more specificand gender-based than the parent concept of "health." This concept analysis providesconceptual clarity that can guide development of a conceptual frameworkthat may be uniquely relevant to providers in urology. Further exploration willuncover specific cultural, social, sexual, and geographic perspectives. PMID- 29240327 TI - Adult Patients with Developmental Disorders: Are You Prepared? PMID- 29240328 TI - Ciprofloxacin Resistance: A Review of Patients in East London Undergoing Prostate Biopsy. AB - Transrectal ultrasound guided biopsy of the prostate remains the gold standardinvestigation to diagnose prostate cancer. Although post-biopsy complicationsare relatively rare, the risk of sepsis associated with the procedure means thatprophylactic antibiotics are paramount. The most widely used antibiotic regimenincludes a quinolone, such as ciprofloxacin. Resistance to quinolone antibioticsis rising. In this small pilot study, the incidence of quinolone resistance was 18%in our population of patients attending the prostate biopsy clinic. PMID- 29240329 TI - Hazardous Drugs in the Urology Workplace: Focus on Intravesical Medications. AB - The Society of Urologic Nurses and Associates (SUNA) and the AmericanUrological Association (AUA) collaborated to develop a standard operating procedurein 2015 for instillation of intravesical cytotoxic, immunotherapeutic, and/ortherapeutic drugs for patients with urothelial carcinoma of the bladder and interstitialcystitis. This is a synthesis of the standard operating procedure in the contextof hazardous drug administration, including indications for administration,guidelines, and principles of hazardous drugs in the clinical setting, peri-treatmentconcerns, and patient and staff education. PMID- 29240330 TI - Regulating Black-Box Medicine. AB - Data drive modern medicine. And our tools to analyze those data are growing ever more powerful. As health data are collected in greater and greater amounts, sophisticated algorithms based on those data can drive medical innovation, improve the process of care, and increase efficiency. Those algorithms, however, vary widely in quality. Some are accurate and powerful, while others may be riddled with errors or based on faulty science. When an opaque algorithm recommends an insulin dose to a diabetic patient, how do we know that dose is correct? Patients, providers, and insurers face substantial difficulties in identifying high-quality algorithms; they lack both expertise and proprietary information. How should we ensure that medical algorithms are safe and effective? Medical algorithms need regulatory oversight, but that oversight must be appropriately tailored. Unfortunately, the Food and Drug Administration (FDA) has suggested that it will regulate algorithms under its traditional framework, a relatively rigid system that is likely to stifle innovation and to block the development of more flexible, current algorithms. This Article draws upon ideas from the new governance movement to suggest a different path. FDA should pursue a more adaptive regulatory approach with requirements that developers disclose information underlying their algorithms. Disclosure would allow FDA oversight to be supplemented with evaluation by providers, hospitals, and insurers. This collaborative approach would supplement the agency's review with ongoing real world feedback from sophisticated market actors. Medical algorithms have tremendous potential, but ensuring that such potential is developed in high quality ways demands a careful balancing between public and private oversight, and a role for FDA that mediates--but does not dominate--the rapidly developing industry. PMID- 29240332 TI - Nurses: The Professionals Who Improvise to Improve our World PMID- 29240331 TI - The Association of the Braden Scale Score and Postoperative Morbidity Following Urogynecologic Surgery. AB - The Braden scale is a widely used tool to assess pressure ulcer risk.Preoperative Braden scores were significantly associated with postoperativemorbidity among women undergoing urogynecologic surgery for stress incontinenceand pelvic organ prolapse. PMID- 29240333 TI - Tele-Continence Care: A Novel Approach for Providers . AB - Urinary incontinence (UI), typically a sensitive and personal concern, has beenamendable to healthcare interventions via telehealth applications. Telehealth hasbeen identified as a method capable of providing care to rural locations based onits ability to eliminate the need for patient and/or healthcare provider travel. Thepurpose of this project was to determine if telehealth improved follow up visitrates among rural dwelling patients with UI. Additional data were collected toassess the effect of treatment recommendations, patient perception of this experience,and healthcare team opinion of telehealth implementation. Results reflectan improvement in follow-up rates, effectiveness of the treatment plan, patientsatisfaction, and healthcare team support. PMID- 29240334 TI - Do in vitro fertilization treatments result in healthy babies? AB - In Finland, the proportion of children born as a result of in vitro fertilization treatments is annually approximately 3.3%, and the percentage proportion of the population is growing. Their general somatic health status and cognitive development do not differ from spontaneously fertilized children. In vitro fertilization treatments are, however, associated with a slightly elevated risk of preterm delivery, low birth weight and structural abnormalities. The risk of childhood cancer does not appear to be increased in IVF children. The in vitro fertilization process affects the embryonic epigenome, which organizes itself during early embryonic development. These changes may influence the phenotype and health profile of the unborn child. The effect of in vitro fertilization treatments on an individual's long-term health is poorly understood, requiring prospective follow-up studies with sufficiently large datasets. In vitro fertilization treatments are the most effective way to treat infertility, and the treatments are generally safe both for the future mother and the baby being born. PMID- 29240335 TI - Caring communication - The impact of interpersonal communication between physician and patient. Can smileys measure the quality of communication? AB - The importance of communication in medical practice is widely recognized, but what is good communication in patient encounter? Feedback and surveys based on patient experience or "smileys" provide a narrow and often too insignificant view of communication. In addition to patient experience, communication benefits the information gathering by the physician and the patient, the patient's ability to promote his/her recovery, the physician's coping with workload, and the effectiveness of health care. In order to evaluate communication and improve it, one has to recognize the criteria and objectives of good communication. Medical communication that supports the rehabilitation of patients is reasonably good and responsible communication. PMID- 29240336 TI - Identifying Unmet Care Needs of Patients with Prostate Cancer To Assist with Their Success in Coping. AB - In the United Kingdom, our Health Needs Assessment survey return rate of 42% identified unmet needs in subjects with prostate cancer. Subjects reported the greatest unmet need was related to erectile dysfunction. Other unmet needs were related to incontinence, tiredness, hot flashes, lower urinary tract symptoms, rectal bleeding, and relationship issues. PMID- 29240337 TI - Nucleic acid diagnostic approaches in parasitology. AB - Nucleic acid diagnostic technologies are partly replacing traditional microscopy and antigen detection methods in parasitological diagnostics. In particular, the diagnostics of parasitic diarrhea is undergoing a transformation due to the application of polymerase chain reaction (PCR) tests. Diagnostics of malaria is still based on microscopy, but rapid nucleic acid tests are emerging. Laboratories of clinical microbiology in Finland currently provide PCR tests e.g. for intestinal protozoa, Toxoplasma and Trichomonas. Nucleic acid diagnostic methods are superior in specificity and sensitivity, but may give false positive results after a treated infection. PMID- 29240338 TI - Healthcare Costs Associated with Hydrophilic-Coated And Non-Coated Urinary Catheters for Intermittent Use In the United States. AB - This health economic evaluation simulated a cohort to compare hydrophilic coatedto non-coated catheters for intermittent catheterization. By using a Markovmodel, lifetime costs and catheter-related complications were investigated.Results determined that the use of hydrophilic-coated catheters save money andreduce treatment-related complications. PMID- 29240339 TI - Traumatic hip dislocation in pediatric patients. AB - Traumatic hip dislocations constitute approximately 5% of all pediatric dislocations and typically result from high-energy trauma. However, pediatric hip dislocations can also occur as a result of minor energy due to flexibility of the joint structures of the immature hip. Children with a posteriorly dislocated hip present with the injured hip in flexion, adduction and internal rotation. Spontaneous relocation of hip dislocation is frequent and a thorough physical examination of the whole lower extremity is always required to reduce the chance of missing hip dislocation/subluxation. Dislocated hips should be emergently repositioned under general anesthesia. MRI is indicated after reduction and in patients after spontaneous relocation if labral interposition is suspected in plain radiographs. PMID- 29240340 TI - Update on Current Care guideline: Memory Disorders. AB - Any complaint about memory should be examined. Diagnosis is based on international criteria. Basic evaluation consists of medical history, clinical evaluation, cognitive tests and brain imaging. When a diagnosis of Alzheimer's disease (AD), AD with cerebrovascular disease or with Lewy Body disease (LBD), or Dementia associated with Parkinson's disease or LBD is made, evidence-based medical therapy (acetylcholine esterase inhibitor or memantine) is indicated as a part of comprehensive care. In frontotemporal degenerations, these drugs are ineffective. For severe behavioural disorders, other psychoactive medications can be applied if non-pharmacological treatments are not sufficient. PMID- 29240341 TI - Finland establishing the internet of genomics and health data. AB - Genomic data, i.e. measurement of variation in the complete genome has revolutionized genetic research and changed our understanding of the pathogenetic mechanisms of diseases. Genomic data in combination with Finnish special strengths - population history, the nation's comprehensive health records and a strong research tradition in genetic epidemiology - has made Finland a testing laboratory for diseases of public health importance. At the same time, genomic research has changed into statistical evaluation of large masses of data - big data. New research knowledge is now descending to the prevention and treatment of diseases, and this will affect future medical practices. In this reform, Finland has a chance to be a key player. The change is, however, global, and the world will not wait that Finland is ready, but instead we have to take care of it ourselves. When successful, new kind of research will help better allocate health care resources, provide more individualized care and stimulate businesses based on new technology. PMID- 29240342 TI - A Nurse-Driven Protocol for Removal of Indwelling Urinary Catheters Across a Multi-Hospital Academic Healthcare System. AB - Catheter-associated urinary tract infections (CAUTIs) are one of the most common hospital-acquired infections in the United States. Because of persistently high CAUTI rates despite evidence-based interventions, we designed and implemented a performance improvement nurse-driven removal protocol for indwelling urinary catheters. Post-implementation, both catheter utilization and CAUTIs decreased significantly at the one hospital with the highest baseline rates; at the two hospitals with low baseline rates, the impact of the protocol varied. This project highlights important steps in developing and implementing a nurse-driven removal protocol across a multi-hospital academic healthcare system. PMID- 29240344 TI - Application to the Evidence Base: A Nurse-Driven Protocol for Removal of Indwelling Urinary Catheters Across a Multi-Hospital Academic Healthcare System. PMID- 29240343 TI - Assessment of multifactorial coronary artery disease by utilizing genomic data. AB - The scientific advances in the past few years have enabled individualized prevention and treatment of diseases on the basis of genome-wide information. For example, dozens of genomic regions affecting the risk for coronary artery disease have been identified. Both Finnish and international longitudinal studies show that the risk assessment of coronary artery disease can be significantly improved if the estimate is based both on the newly discovered hereditary risk factors and the long-recognized traditional risk factors, e.g. age, gender, smoking, blood pressure, and serum lipid levels. In this review, by using coronary artery disease as an example, we present recent research aiming at enhancing the use of genome information in combination with traditional risk factors for the assessment of the risk for common disease of public health importance. We introduce the KardioKompassi tool, developed by us, which comprehensively utilizes the genetic profile of an individual in combination with conventional health information to assess the risk for coronary artery disease. We also discuss the prospects and opportunities provided by the newly developed next generation risk prediction tools to promote health." PMID- 29240345 TI - Applications of genomic medicine in the treatment of diseases. AB - Individualized medicine, based on a detailed mapping of the patient's disease mechanisms, is becoming an essential part of treatment for an increasing number of diseases. In the past few years, the possibility to determine the abnormal genome and transcriptome of diseased cells at a reasonable cost has been the major advance. The vast amount of data accumulated from one patient will set requirements for data extraction tools, in order to have the essential information affecting the treatment of the patient information quickly and reliably at the disposal of attending physicians. A computerized decision support system connected to the information systems of the hospital is an integral part of individualized treatment. Although the application of genomic and other profiling information is challenging, individualization of medication provides great promises more effective and safer treatment. PMID- 29240346 TI - Empowering Our Youth: Initiating Sexual Health Education on the Inpatient Unit for the Chronically Ill Pediatric Patient. AB - Chronicaly ill pre-teens and adolescents often spend months as inpatients while undergoing treatment. This population includes but is not limited to oncology, transplant, physically disabled, and medically fragile pediatric patients. Sexual health education is often considered less important than the complex disease states and medical issues faced by pediatric inpatients. Many clinicians fail to realize the value of providing this guidance as a necessary part of the physical and psychosocial health of these young patients. Chronically ill youth lack normal social interactions while hospitalized and may have body image issues related to physical disabilities. A need for sexual health education stems from the high sexually transmitted disease prevalence in this population. Lack of formal provider education on sexual health, provider discomfort in discussing sexual health topics, and overlooking the importance of adolescent sexual health have delayed integration of sexual education into inpatient teaching, discharge planning, and outpatient follow up. With few guidelines and minimal published research on this topic, clinicians and parents often have no experience, education, or guidance to provide this specific knowledge effectively. The goal of this discussion of sexual health education for chronically ill adolescents is to highlight the need for additional research, improved training for healthcare providers, and development of evidence-based guidelines in the inpatient and outpatient settings. PMID- 29240347 TI - Genomic data into everyday work of a medical practitioner - digital tools for decision-making. AB - Recent technological development has enabled fast and cost-effective simultaneous analyses of several gene variants or sequence of even the whole genome. For medical practitioners this has created challenges although genomic information may be clinically useful in new applications such as finding out individual risk for diseases influenced by as many as 50,000 variable DNA regions or in detecting pharmacogenetic risks prior to prescribing a medicine. New digital tools have paved the way for utilization of genomic data via easy access and clear clinical interpretation for both doctor and patient. In this review we describe some of these tools and applications for clinical use. PMID- 29240348 TI - Avoiding Same-Day Cystoscopy Cancellations by Veterans: Nurse-Led Education Improved Efficiency for Cystoscopy in VA Urology Clinics. AB - Same-day cancellation of outpatient cystoscopy was recognized as a growing problem in a New Mexico Veterans Administration regional urology clinic. A multidisciplinary team initiated a performance improvement project using the VA TAMMCS method to address the problem. The resulting changes in patient education significantly reduced cystoscopy cancellations and improved overall patient satisfaction. PMID- 29240349 TI - Nurse-Initiated Telephone Follow Up after Ureteroscopic Stone Surgery. AB - This article presents findings of a quality improvement (QI) project using theDMAIC (define, measure, analyze, improve, and control) model designed todecrease the rate of emergency department (ED) visits and nurse advice linecalls after ureteroscopic stone surgery. Results indicated that nurse initiated follow-up phone calls can decrease ED visits. PMID- 29240350 TI - Data systems, genomic data and expertise of doctors. AB - Introduction of genomic data into health care requires willingness from physicians to adopt decision support systems as well as genomic information as part of their work. In the interview study, doctors' expectations about data systems and genomic data, as well as challenges for their utilization, are brought into light. Besides technical functionality, linking of data systems and the new knowledge mediated by them for clinicians also requires that doctors understand them as part of their professional expertise and thus useful. PMID- 29240351 TI - Improving the Patient Experience in the Urology Office: An Evidence-Based Tool Kit to Impact Staff Perception Of Patient Satisfaction. AB - Researchers evaluated the effectiveness of an educational intervention, which included use of an evidence-based tool kit for healthcare providers to improve patient satisfaction. Findings demonstrated improved staff perceptions of their actions influencing patient experiences, use of standardized patient care processes, and increased patient experience scores. PMID- 29240352 TI - Baseline Vulnerability and Inpatient Frailty Status in Relation to Adverse Outcomes in a Surgical Cohort. AB - This study aimed to derive measures of baseline vulnerability and inpatient frailty in elderly surgical patients and to study their association with adverse post-operative outcomes. Data from comprehensive geriatric assessment of 208 general surgical and orthopaedic patients aged 70 and over admitted to four acute hospitals in Queensland, Australia, were analysed to derive a baseline and inpatient Frailty Index (FI). The association of these indices with adverse outcomes was examined in logistic regression. The mean (SD) baseline FI was 0.19 (0.09) compared to 0.26 (0.12) on admission, with a predominant increase in domains related to functional status. Both baseline and inpatient FI were significant predictors of one year mortality, inpatient delirium, and a composite adverse outcome, after adjusting for age, sex and acuity of surgery. In summary, detecting baseline frailty pre-hospitalisation may be useful to trigger the implementation of supportive and preventative measures in hospital. PMID- 29240353 TI - Frailty in General Practice. PMID- 29240358 TI - Editorial. PMID- 29240357 TI - The Effects of a Take-Home Educational Video on Patient Knowledge Retention, Anxiety, Satisfaction, and Provider Time. AB - Patient anxiety related to prostate cancer surgery may lead to reduced patient satisfaction. Repeated reinforcement of pre-operative education to reduce anxiety greatly impacts provider time. Improved knowledge retention of what to expect postoperatively may reduce patient anxiety. This quality improvement project demonstrated that a take-home educational video supports patient knowledge retention, reduces patient anxiety, increases patient satisfaction, and saves postoperative provider time PMID- 29240359 TI - Cystectomy-Enhanced Recovery Program: Nursing Implications. AB - Cystectomy is a complex procedure with a tenuous perioperative course. Enhanced recovery programs (ERPs) are bundle strategies, developed to enhance the recovery of surgical patients. This article outlines the components of an ERP for cystectomy patients from a nursing implementation perspective. PMID- 29240360 TI - Decision-Making in Prostate Cancer - Choosing Active Surveillance Over Other Treatment Options: A Literature Review. AB - A literature review was done using the Cognitive-Social Health Information Processing (C-SHIP) framework to identify how and why men diagnosed with prostate cancer choose active surveillance over other treatment options. Findings indicated men who choose active surveillance have a stronger preference for active or collaborative decision-making than those who choose other treatments. Men primarily choose active surveillance to avoid the side effects of incontinence and erectile dysfunction. This literature review informed the study by Bayliss, Duff, Strieker, and Walker (2016) and found physician recommendation to be the most influential factor when patients make a treatment decision. PMID- 29240361 TI - ADVANCED PRACTICE NURSING. A LEVEL IN ITS OWN RIGHT. PMID- 29240362 TI - Confidence of Nursing Personnel in Their Understanding Of the Psychosocial Impact of Prostate Cancer. AB - Nurses must be equipped with skills to support men diagnosed with prostate cancer. Implementation of a unit-specific, evidence-based education program had significant, positive effects on the confidence of nurses who care for veterans who experience a psychosocial impact of prostate cancer treatment. PMID- 29240363 TI - Symptoms Control for Patients with Superficial Bladder Cancers Before and After TURBT and Intravesical Epirubicin Instillation. AB - Bladder cancer is one of the most common cancers among urologic cancers.Intravesical instillation following transurethral resection of bladder tumor(TURBT) is used as a treatment of bladder cancer. According to results of thisstudy, before and after intravesical instillations following TURBT have no effecton symptom outcomes of patients with superficial bladder cancer. PMID- 29240364 TI - Wife Caregiver Experiences in the Patient with Prostate Cancer at Home. AB - This study explored the caregiving experiences of wives of patients with prostatecancer. Twenty wives revealed those older, educated, or married longer wereless burdened by caregiving, but needed more information. Findings contributenew dimensions in caregiving for patients with prostate cancer and their wives. PMID- 29240365 TI - MEMBER ONLY COLLECTIVE AGREEMENTS: WHY NOT? AB - For those active in industrial relations there is quite a well-known book titled From the Folks Who Brought You the Weekend: A Short, Illustrated History of Labor in the United States. The books' thesis or focus was firstly to remind readers of the many struggles in the USA by trade unions to obtain and protect basic working conditions American workers, now take for granted, and secondly to reinforce the important and enduring relationship between unions and their members. PMID- 29240367 TI - Application to the Evidence Base: Wife Caregiver Experiences in the Patient with Prostate Cancer at Home . PMID- 29240366 TI - CAREER CHANGE INTO NURSING. REAPS REWARD. PMID- 29240368 TI - COCOA (Theobroma cacao) Polyphenol-Rich Extract Increases the Chronological Lifespan of Saccharomyces cerevisiae. AB - BACKGROUND: Saccharomyces cerevisiae is a model organism with conserved aging pathways. Yeast chronological lifespan experiments mimic the processes involved in human non-dividing tissues, such as the nervous system or skeletal muscle, and can speed up the search for biomolecules with potential anti-aging effects before proceeding to animal studies. OBJECTIVE: To test the effectiveness of a cocoa polyphenol-rich extract (CPE) in expanding the S. cerevisiae chronological lifespan in two conditions: in the stationary phase reached after glucose depletion and under severe caloric restriction. MEASUREMENTS: Using a high throughput method, wild-type S. cerevisiae and its mitochondrial manganese dependent superoxide dismutase null mutant (sod2Delta) were cultured in synthetic complete dextrose medium. After 2 days, 0, 5 and 20 mg/ml of CPE were added, and viability was measured throughout the stationary phase. The effects of the major components of CPE were also evaluated. To determine yeast lifespan under severe caloric restriction conditions, cultures were washed with water 24 h after the addition of 0 and 20 mg/ml of CPE, and viability was followed over time. RESULTS : CPE increased the chronological lifespan of S. cerevisiae during the stationary phase in a dose-dependent manner. A similar increase was also observed in (sod2Delta). None of the major CPE components (theobromine, caffeine, maltodextrin, (-)-epicatechin, (+)-catechin and procyanidin B2) was able to increase the yeast lifespan. CPE further increased the yeast lifespan under severe caloric restriction. CONCLUSION: CPE increases the chronological lifespan of S. cerevisiae through a SOD2-independent mechanism. The extract also extends yeast lifespan under severe caloric restriction conditions. The high-throughput assay used makes it possible to simply and rapidly test the efficacy of a large number of compounds on yeast aging, requiring only small amounts, and is thus a convenient screening assay to accelerate the search for biomolecules with potential anti-aging effects. PMID- 29240369 TI - THE MORAL SIGNIFICANCE OF ANTIMICROBIAL RESISTANCE. AB - On 14 April 2016, ABC News and The 7:30 Report both reported the case of a 46 year old man who died from hepatitis B believed to have been contracted from another patient while on dialysis at a Melbourne hospital (http://www.abc.net.au/7:30/content/2015/s4443575.htm). PMID- 29240370 TI - Testicular Torsion: Current Evaluation and Management. AB - Testicular torsion is a urologic emergency, requiring prompt identification and management. Understanding the risk factors, presentation, and management is essential to decrease delays in diagnosis and intervention. This review discusses the prevalence, pathophysiology, management, and outcomes of testicular torsion. PMID- 29240371 TI - Meeting the Needs of the Complex Older Adult Patient with Urinary Retention: A Case Study. AB - This article presents a case study of how a homebound older adult patient with urinary retention is managed by a patient-centered medical home/transitional care model. A description of how a root cause analysis can effectively improve outcomes is also provided. PMID- 29240372 TI - DEVELOPING A CULTURE OF RESEARCH IN COMMUNITY NURSING. AB - In today's demanding clinical environments it is challenging for nurses to undertake research, Barriers include time, limited self-belief and confidence, commitment, limited knowledge of the research process, and lack of administrative support. Yet nurses are curious and many have ideas to improve clinical care and patient outcomes. This paper discusses how a community nursing service, Sydney District Nursing, has developed a congenial and collegial process to improve the culture of nursing research, and to support its nurses to undertake research and develop quality improvement projects. PMID- 29240373 TI - Early Recognition and Management of Rare Kidney Stone Disorders. AB - Kidney stones, especially those that present in childhood/adolescence, may be due to rare inherited disorders such as cystinuria. Early recognition and prompt treatment can help reduce or even prevent the serious long-term complications of these rare stone disorders. PMID- 29240374 TI - Case Study - Case Studies in Cystinuria. AB - The diagnosis and treatment of patients with rare inherited metabolic disorders associated with recurrent and often obstructive kidney stones are important to the prevention of chronic kidney disease or end stage renal disease. Two case studies in this article describe the diagnosis and management of cystinuria, the most common rare kidney stone disorder. PMID- 29240376 TI - STUDENT PERCEPTIONS OF PRIMARY HEALTHCARE. AB - Reviews of undergraduate nursing courses reveal variability in what is being taught regarding primary healthcare (Betony & Yarwood, 2013; Keleher et al. 2010). In an investigation of the perceptions of final year students and recent graduates about underlying conceptual frameworks. Anderson et al. (2015) found students and graduates value primary healthcare as part of their curriculum. PMID- 29240375 TI - An Integrative Review of Current Research on the Role of the Female Urinary Microbiota in Overactive Bladder Symptoms. AB - This integrative review explores current evidence on microbiota of the female urinary tract as it relates to overactive bladder (OAB) symptoms. Six articles were identified for review. Findings suggest a possible link between the female urinary microbiome and OAB symptom presentation. PMID- 29240378 TI - TRAUMA-INFORMED CARE AND PRACTICE IN NURSING. AB - Trauma comes in many guises--from accidents, natural disasters (single incident trauma) to complex trauma such as child abuse and growing up with domestic violence. Illness, medical procedures, treatments and hospitalization are themselves often traumatic, with recent traumas compounding those experienced previously. PMID- 29240377 TI - GAY MEN AND TYPE 2 DIABETES STUDY. AB - Australia's first study of gay men with type 2 diabetes is underway at Victoria University. PMID- 29240379 TI - REGIONAL WOUNDS. VICTORIA. AB - Regional Wounds Victoria (RWV) are a collaborative of nine nurse consultants who cover 96% of Victoria's land mass that services 30% of Victoria's home and community care clients. They work alongside staff in the District Nursing Services and high level care Public Sector Residential Aged Care Services, targeting all aspects of the management of chronic and complex wounds. PMID- 29240380 TI - THE VALUE OF HEALTH PROMOTION PROGRAMS FOR OLDER PEOPLE WITH CHRONIC CONDITIONS IN THE COMMUNITY. AB - The Ottawa Charter of Health Promotion (WHO, 1996) advocates that health promotion occurs when people are able to improve and practice more successful control over their health. The concept of health promotion was founded on the notion of community action, raising awareness and instilling community accountability and involvement in one's own actions. PMID- 29240381 TI - RE-ENGINEERING PRIMARY HEALTHCARE NURSING AS A FIRST CAREER CHOICE. AB - In line with international models and critical to the primary healthcare nursing workforce, the Australian Primary Health Care Nursing Association (APNA) has been funded by the Commonwealth Department of Health to develop an Education and Career Framework and Toolkit for primary healthcare nurses. The aim of the project is to improve the recruitment and retention of nurses and to re-engineer primary healthcare as a first choice career option. PMID- 29240382 TI - IMPORTANCE OF PREVENTATIVE HAND HYGIENE PRACTICES IN COMMUNITY NURSING. WOUND MANAGEMENT. AB - Hand hygiene, when undertaken correctly, is the most effective preventative measure in reducing the spread of microorganisms that cause healthcare associated infections (WHO, 2009; NICE, 2012). PMID- 29240383 TI - THE GLAMOROUS ROLE OF A COMMUNITY STOMAL THERAPIST. AB - Stomal therapy nursing is rarely described as glamorous. Indeed sometimes the stomal therapist is referred to as "The BAG" lady -- a label I personally hold in high regard. PMID- 29240384 TI - MAKING THE MOVE TO PRIMARY HEALTHCARE -- UNEARTHING THE EXPERIENCES OF ACUTE CARE NURSES TRANSITIONING TO PHC EMPLOYMENT. AB - There wouldn't be a nurse who hasn't experienced that sinking feeling when waking up on the day they are about to start work in a new position. PMID- 29240385 TI - THE NEED FOR MORE OCCUPATIONAL HEALTH NURSING RESEARCH IN AUSTRALIAN INDUSTRY. AB - Occupational Health Nurse Robyn Stone is researching health outcomes from worker health assessment and worker health intervention programs in an Australian manufacturing industry. PMID- 29240386 TI - EVALUATION OF A NURSE-LED HYPERTENSION MANAGEMENT INTERVENTION IN AUSTRALIAN GENERAL PRACTICE: THE IMPRESS INTERVENTION. AB - Hypertension is currently the most frequently seen condition in Australian general practice (Britt et al. 2015). Of the 4.6 million Australians living with hypertension, many struggle to keep their blood pressure under control and are at increased risk of renal failure, cardiovascular disease and premature death (Australian Institute of Health and Welfare, 2015; Cadilhac et al. 2012). The General Practice Nurse (GPN) has a significant role to play in supporting self management and lifestyle risk factor reduction. PMID- 29240388 TI - THE LINK NURSE ROLE IN END OF LIFE CARE IN AGED CARE. AB - The care of older people at the end of life is a key element of primary and community care. The Decision Assist -- Palliative Care Linkages project aimed to improve end of life care given to older Australians through establishing linkages between aged care and specialist palliative care services. PMID- 29240387 TI - THE NATURE OF COLLABORATION IN GENERAL PRACTICE. AB - It is anticipated that over the next decade, demand for primary care services will exceed the capacity of the general practice workforce (Crettenden et al. 2014). Collaboration may help alleviate workforce stressors by ensuring that the most appropriate team member delivers care in an efficient and timely manner (Wagner et al. 2001). PMID- 29240389 TI - HOW'S YOUR HEART? SEIZING OPPORTUNITIES TO ENGAGE NURSES IN COMMUNITY HEALTH PROMOTION EARLY IN THEIR CAREERS. AB - Opportunities for student nurses to consolidate their new clinical skills and engage in health promotion in the community setting at the beginning of their careers are not common. PMID- 29240390 TI - PRIMARY MENTAL HEALTHCARE FOR AUSTRALIANS: MENTAL HEALTH NURSES LEADING THE WAY. AB - In 2008, the World Health Organization (WHO) released a report on integrating primary health into primary care. The key message of the report was 'integrating mental health services into primary care is the most viable way of ensuring that people get the mental healthcare they need' (WHO, 2008, p1). PMID- 29240391 TI - RESEARCH: PATIENT DETERIORATION -- PATIENT SAFETY. AB - Inadequate management of deteriorating patients is of international concern. In order to tackle this issue there has been an increasing effort to upskill nursing and medical staff (Australian Commission on Safety and Quality in Healthcare, 2012). PMID- 29240392 TI - THE LOW DOWN ON LONG-ACTING REVERSIBLE CONTRACEPTIVES IN PRIMARY HEALTHCARE. AB - Effective primary healthcare (PHC) is meant to support people to manage their health issues in the community, resulting in less hospitalization, fewer health inequalities and better health outcomes for all people. This being said, unplanned pregnancy remains an urgent and pressing key health issue in Australia. PMID- 29240393 TI - PARENTING EFFECTIVELY DESPITE: THE MATERNAL EARLY CHILDHOOD SUSTAINED. HOME VISITING PROGRAM. AB - Nurse led home visiting programs as an intervention to invest in children's health and wellbeing is considered a useful and effective way to deliver a health and parenting service (US Department of Health and Human Services, 2014). PMID- 29240394 TI - Correction to Porous Aromatic Frameworks for Size-Selective Halogenation of Aryl Compounds. PMID- 29240395 TI - Narrow Band Gap Conjugated Polyelectrolytes. AB - Two essential structural elements define a class of materials called conjugated polyelectrolytes (CPEs). The first is a polymer framework with an electronically delocalized, pi-conjugated structure. This component allows one to adjust desirable optical and electronic properties, for example the range of wavelengths absorbed, emission quantum yields, electron affinity, and ionization potential. The second defining feature is the presence of ionic functionalities, which are usually linked via tethers that can modulate the distance of the charged groups relative to the backbone. These ionic groups render CPEs distinct relative to their neutral conjugated polymer counterparts. Solubility in polar solvents, including aqueous media, is an immediately obvious difference. This feature has enabled the development of optically amplified biosensor protocols and the fabrication of multilayer organic semiconductor devices through deposition techniques using solvents with orthogonal properties. Important but less obvious potential advantages must also be considered. For example, CPE layers have been used to introduce interfacial dipoles and thus modify the effective work function of adjacent electrodes. One can thereby modulate the barriers for charge injection into semiconductor layers and improve the device efficiencies of organic light-emitting diodes and solar cells. With a hydrophobic backbone and hydrophilic ionic sites, CPEs can also be used as dispersants for insoluble materials. Narrow band gap CPEs (NBGCPEs) have been studied only recently. They contain backbones that comprise electron-rich and electron-poor fragments, a combination that leads to intramolecular charge transfer excited states and enables facile oxidation and reduction. One particularly interesting combination is NBGCPEs with anionic sulfonate side groups, for which spontaneous self-doping in aqueous media is observed. That no such doping is observed with cationic NBGCPEs indicates that the interplay between electrostatic forces and the redox chemistry of the organic semiconducting chain is essential for stabilizing the polaronic states and increasing the conductivity of the bulk. Capitalizing upon the properties of NBGCPEs has resulted in a range of new applications. When doped, they can be introduced as interlayers in organic and perovskite solar cells. Single-walled carbon nanotubes can be n- or p-doped with NBGCPEs, depending on whether the same backbone contains attached cationic or anionic side groups, respectively. The resulting dispersions can be used to fabricate flexible thermoelectric devices in which the n- and p-semiconductor legs are nearly identical in terms of chemical composition. Electrostatic interactions with negatively charged cell walls, in combination with the long-wavelength absorption and high photothermal efficiencies, have been used to create effective agents for photothermal killing of bacteria. Additionally, recent results have shown that cationic NBGCPEs can effectively n-dope graphene and that this doping is temperature-dependent. The preferential charge carriers can therefore be chosen to be electrons or holes depending on the applied temperature. PMID- 29240396 TI - Casting a Wider Net: Rational Synthesis Design of Low-Dimensional Bulk Materials. AB - The discovery of novel magnetic and electronic properties in low-dimensional materials has led to the pursuit of hierarchical materials with specific substructures. Low-dimensional solids are highly anisotropic by nature and show promise in new quantum materials leading to exotic physical properties not realized in three-dimensional materials. We have the opportunity to extend our synthetic strategy of the flux-growth method to designing single crystalline low dimensional materials in bulk. The goal of this Account is to highlight the synthesis and physical properties of several low-dimensional intermetallic compounds containing specific structural motifs that are linked to desirable magnetic and electrical properties. We turned our efforts toward intermetallic compounds consisting of antimony nets because they are closely linked to properties such as high carrier mobility (the velocity of an electron moving through a material under a magnetic field) and large magnetoresistance (the change in resistivity with an applied magnetic field), both of which are desirable properties for technological applications. The SmSb2 structure type is of particular interest because it is comprised of rectangular antimony nets and rare earth ions stacked between the antimony nets in a square antiprismatic environment. LnSb2 (Ln = La-Nd, Sm) have been shown to be highly anisotropic with SmSb2 exhibiting magnetoresistance of over 50000% for H?c axis and ~2400% for H?ab. Using this structure type as an initial building block, we envision the insertion of transition metal substructures into the SmSb2 structure type to produce ternary materials. We describe compounds adopting the HfCuSi2 structure type as an insertion of a tetrahedral transition metal-antimony subunit into the LnSb2 host structure. We studied LnNi1-xSb2 (Ln = Y, Gd-Er), where positive magnetoresistance reaching above 100% was found for the Y, Gd, and Ho analogues. We investigated the influence of the transition metal sublattice by substituting Ni into Ce(Cu1-xNix)ySb2 (y < 0.8) and found that the material is highly anisotropic and metamagnetic transitions appear at ~0.5 and 1 T in compounds with higher Ni concentration. Metamagnetism is characterized by a sharp increase in the magnetic response of a material with increasing applied magnetic field, which was also observed in LnSb2 (Ln = Ce-Nd). We also endeavored to study materials that possess a transition metal sublattice with the potential for geometric frustration. An example is the La2Fe4Sb5 structure type, which consists of antimony square nets and an iron-based network arranged in nearly equilateral triangles, a feature found in magnetically frustrated systems. We discovered spin glass behavior in Ln2Fe4Sb5 (Ln = La-Nd, Sm) and evidence that the transition metal sublattice contributes to the magnetic interactions of Ln2Fe4Sb5. We investigated the magnetic properties of Pr2Fe4-xCoxSb5 (x < 2.3) and found that as the Co concentration increases, a second magnetic transition leads from a localized to an itinerant system. The La2Fe4Sb5 structure type is quite robust and allows for the incorporation of other transition metals, thereby making it an excellent candidate to study competing magnetic interactions in lanthanide containing intermetallic compounds. In this manuscript, we aim to share our experiences of bulk intermetallic compounds to inspire the development of new low dimensional materials. PMID- 29240397 TI - Functionalization of SiO2 Surfaces for Si Monolayer Doping with Minimal Carbon Contamination. AB - Monolayer doping (MLD) involves the functionalization of semiconductor surfaces followed by an annealing step to diffuse the dopant into the substrate. We report an alternative doping method, oxide-MLD, where ultrathin SiO2 overlayers are functionalized with phosphonic acids for doping Si. Similar peak carrier concentrations were achieved when compared with hydrosilylated surfaces (~2 * 1020 atoms/cm3). Oxide-MLD offers several advantages over conventional MLD, such as ease of sample processing, superior ambient stability, and minimal carbon contamination. The incorporation of an oxide layer minimizes carbon contamination by facilitating attachment of carbon-free precursors or by impeding carbon diffusion. The oxide-MLD strategy allows selection of many inexpensive precursors and therefore allows application to both p- and n-doping. The phosphonic acid functionalized SiO2 surfaces were investigated using X-ray photoelectron spectroscopy and attenuated total reflectance Fourier transform infrared spectroscopy, whereas doping was assessed using electrochemical capacitance voltage and Hall measurements. PMID- 29240398 TI - Efficient Flame Detection and Early Warning Sensors on Combustible Materials Using Hierarchical Graphene Oxide/Silicone Coatings. AB - Design and development of smart sensors for rapid flame detection in postcombustion and early fire warning in precombustion situations are critically needed to improve the fire safety of combustible materials in many applications. Herein, we describe the fabrication of hierarchical coatings created by assembling a multilayered graphene oxide (GO)/silicone structure onto different combustible substrate materials. The resulting coatings exhibit distinct temperature-responsive electrical resistance change as efficient early warning sensors for detecting abnormal high environmental temperature, thus enabling fire prevention below the ignition temperature of combustible materials. After encountering a flame attack, we demonstrate extremely rapid flame detection response in 2-3 s and excellent flame self-extinguishing retardancy for the multilayered GO/silicone structure that can be synergistically transformed to a multiscale graphene/nanosilica protection layer. The hierarchical coatings developed are promising for fire prevention and protection applications in various critical fire risk and related perilous circumstances. PMID- 29240399 TI - Trapping Structural Coloration by a Bioinspired Gyroid Microstructure in Solid State. AB - In theory, gyroid photonic crystals in butterfly wings exhibit advanced optical properties as a result of their highly interconnected microstructures. Because of the difficulties in synthesizing artificial gyroid materials having periodicity corresponding to visible wavelengths, human-made visible gyroid photonic crystals are still unachievable by self-assembly. In this study, we develop a physical approach-trapping of structural coloration (TOSC)-through which the visible structural coloration of an expanded gyroid lattice in a solvated state can be preserved in the solid state, thereby allowing the fabrication of visible wavelength gyroid photonic crystals. Through control over the diffusivity and diffusive distance for solvent evaporation, the single-molecular-weight gyroid block copolymer photonic crystal can exhibit desired structural coloration in the solid state without the need to introduce any additives, namely, evapochromism. Also, greatly enhanced reflectivity is observed arising from the formation of porous gyroid nanochannels, similar to those in butterfly wings. As a result, TOSC facilitates the fabrication of the human-made solid gyroid photonic crystal featuring tunable and switchable structural coloration without the synthesis to alter the molecular weight. It appears to be applicable in the fields of optical communication, energy, light-emission, sensors, and displays. PMID- 29240400 TI - Electrochemical Oxidation of Chlorine-Doped Co(OH)2 Nanosheet Arrays on Carbon Cloth as a Bifunctional Oxygen Electrode. AB - The primary challenge of developing clean energy conversion/storage systems is to exploit an efficient bifunctional electrocatalyst both for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) with low cost and good durability. Here, we synthesized chlorine-doped Co(OH)2 in situ grown on carbon cloth (Cl-doped Co(OH)2) as an integrated electrode by a facial electrodeposition method. The anodic potential was then applied to the Cl-doped Co(OH)2 in an alkaline solution to remove chlorine atoms (electro-oxidation (EO)/Cl-doped Co(OH)2), which can further enhance the electrocatalytic activity without any thermal treatment. EO/Cl-doped Co(OH)2 exhibits a better performance both for ORR and OER in terms of activity and durability because of the formation of a defective structure with a larger electrochemically active surface area after the electrochemical oxidation. This approach provides a new idea for introducing defects and developing active electrocatalyst. PMID- 29240401 TI - Reduction of Graphene Oxide Thin Films by Cobaltocene and Decamethylcobaltocene. AB - Reduced graphene oxide (RGO) films have been prepared by immersion of graphene oxide (GO) films at room temperature in nonaqueous solutions containing simple, outer-sphere metallocene reductants. Specifically, solutions of cobaltocene, cobaltocene and trifluoroacetic acid (TFA), and decamethylcobaltocene each showed activity for the rapid reduction of GO films cast on a wide variety of substrates. Each reactant increased the conductivity of the films by several orders of magnitude, with RGO films prepared with either decamethylcobaltocene or cobaltocene and TFA possessing the highest conductivities (~104 S m-1). X-ray photoelectron spectroscopy suggested that while all three reagents lowered the content of carbon-oxygen functionalities, solutions of cobaltocene and TFA were the most effective at reducing the material to sp2 carbon. Separately, Raman spectra and atomic force micrographs indicated that RGO films prepared with decamethylcobaltocene consisted of the largest graphitic domains and lowest macroscopic roughness. Cumulatively, the data suggest that the outer-sphere reductants can affect the conversion to RGO but the reactivity and mechanism depend on the standard potential of the reductant and the availability of protons. This work both demonstrates a new way to prepare high-quality RGO films on a wide range of substrate materials without annealing and motivates future work to elucidate the chemistry of RGO synthesis through the tunability of outer sphere reductants such as metallocenes. PMID- 29240402 TI - Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. AB - Enzymes of the ALDH1A subfamily of aldehyde dehydrogenases are crucial in regulating retinoic acid (RA) signaling and have received attention as potential drug targets. ALDH1A2 is the primary RA-synthesizing enzyme in mammalian spermatogenesis and is therefore considered a viable drug target for male contraceptive development. However, only a small number of ALDH1A2 inhibitors have been reported, and information on the structure of ALDH1A2 was limited to the NAD-liganded enzyme void of substrate or inhibitors. Herein, we describe the mechanism of action of structurally unrelated reversible and irreversible inhibitors of human ALDH1A2 using direct binding studies and X-ray crystallography. All inhibitors bind to the active sites of tetrameric ALDH1A2. Compound WIN18,446 covalently reacts with the side chain of the catalytic residue Cys320, resulting in a chiral adduct in ( R) configuration. The covalent adduct directly affects the neighboring NAD molecule, which assumes a contracted conformation suboptimal for the dehydrogenase reaction. The reversible inhibitors interact predominantly through direct hydrogen bonding interactions with residues in the vicinity of Cys320 without affecting NAD. Upon interaction with inhibitors, a large flexible loop assumes regular structure, thereby shielding the active site from solvent. The precise knowledge of the binding modes provides a new framework for the rational design of novel inhibitors of ALDH1A2 with improved potency and selectivity profiles. PMID- 29240403 TI - Multivalent Glycomimetics with Affinity and Selectivity toward Fucose-Binding Receptors from Emerging Pathogens. AB - Bacterial and fungal pathogens involved in lung infection in cystic fibrosis patients utilize a particular family of glycan-binding proteins, characterized by the presentation of six fucose-binding sites on a ring-shaped scaffold. These lectins are attractive targets for anti-infectious compounds that could interfere in the recognition of host tissues by pathogens. The design of a cyclopeptide based hexavalent structure allowed for the presentation of six fucose residues. The synthetic hexavalent compound displays liable geometry resulting in high avidity binding by lectins from Aspergillus fumigatus and Burkholderia ambifaria. Replacing the fucose residue with a conformationally constrained fucomimetic does not alter the affinity and provides fine specificity with no binding to other fucose-specific lectins. PMID- 29240405 TI - RE(SO4)[B(OH)4](H2O), RE(SO4)[B(OH)4](H2O)2, and RE(SO4)[B(OH)4](H2O).H2O: Rare Earth Borate-Sulfates Featuring Three Types of Layered Structures. AB - Using hydrothermal reactions, three series of rare-earth borate-sulfates, namely, RE(SO4)[B(OH)4](H2O) (RE = La (1), Sm (2), Eu (3)), RE(SO4)[B(OH)4](H2O)2 (RE = Pr (4), Nd (5), Sm (6), Eu (7), Gd (8)), and RE(SO4)[B(OH)4](H2O).H2O (RE = Tb (9), Dy (10), Ho (11), Er (12), Tm (13), Yb (14), Lu (15), Y (16)), have been synthesized, which represent the first rare-earth borate-sulfate mixed-anion compounds. All these compounds possess the same fundamental building anionic units of SO4 and B(OH)4 tetrahedra; however, they exhibit three different types of two-dimensional (2D) layered structures composed of 1D RE-B-O and RE-S-O chains. The rare-earth borate chains are similar in all compounds, while the rare earth sulfate chains differ in each type of compound due to the various coordination modes of sulfate groups. On the basis of the measured UV-vis diffuse reflectance spectra, the optical band gaps of compounds 2, 3, 6, and 7 are estimated to be 4.66, 4.53, 4.62, and 4.50 eV, respectively. Luminescence studies show that compounds 2, 3, 6, and 7 exhibit strong emission in the orange or red regions. Furthermore, thermal analysis and magnetic susceptibility measurements for these four representative compounds have also been performed. PMID- 29240404 TI - Conservation of Specificity in Two Low-Specificity Proteins. AB - Many regulatory proteins bind peptide regions of target proteins and modulate their activity. Such regulatory proteins can often interact with highly diverse target peptides. In many instances, it is not known if the peptide-binding interface discriminates targets in a biological context, or whether biological specificity is achieved exclusively through external factors such as subcellular localization. We used an evolutionary biochemical approach to distinguish these possibilities for two such low-specificity proteins: S100A5 and S100A6. We used isothermal titration calorimetry to study the binding of peptides with diverse sequence and biochemistry to human S100A5 and S100A6. These proteins bound distinct, but overlapping, sets of peptide targets. We then studied the peptide binding properties of orthologs sampled from across five amniote species. Binding specificity was conserved along all lineages, for the last 320 million years, despite the low specificity of each protein. We used ancestral sequence reconstruction to determine the binding specificity of the last common ancestor of the paralogs. The ancestor bound the entire set of peptides bound by modern S100A5 and S100A6 proteins, suggesting that paralog specificity evolved via subfunctionalization. To rule out the possibility that specificity is conserved because it is difficult to modify, we identified a single historical mutation that, when reverted in human S100A5, gave it the ability to bind an S100A6 specific peptide. These results reveal strong evolutionary constraints on peptide binding specificity. Despite being able to bind a large number of targets, the specificity of S100 peptide interfaces is likely important for the biology of these proteins. PMID- 29240406 TI - Radical Deuteration with D2O: Catalysis and Mechanistic Insights. AB - Selective incorporation of deuterium atoms into molecules is of high interest for labeling purposes and for optimizing properties of drug candidates. A mild and environmentally benign method for the deuteration of alkyl iodides via radical pathway using D2O as source of deuterium has been developed. The reaction is initiated and mediated by triethylborane in the presence of dodecanethiol as a catalyst. This method is compatible with a wide range of functional groups and provides the monodeuterated products in good yields and with a high level of deuterium incorporation. It opens promising opportunities for the development of enantioselective radical reactions. Moreover, a revision of the mechanism of the deoxygenation reaction of xanthates using R3B and water (Wood deoxygenation) is presented. PMID- 29240407 TI - Membrane Determinants Affect Fibrillation Processes of beta-Sheet Charged Peptides. AB - Assembly of fibrillar peptide structures is dependent both upon their intrinsic propensities toward beta-structure formation, as well as on structural modulation by external molecular factors. beta-sheet structures may either be designed to form useful assemblies or be the undesired consequence of protein denaturation to toxic amyloid structures in several neurodegenerative diseases. Membrane bilayers have been implicated as primary initiators and modulators of amyloid fibrillation and the reasons for this effect are yet to be elucidated. Here, we employed a set of three charged peptides having the tendency to form beta-sheet fibrils, to investigate the effect of zwitterionic and negatively charged bilayer vesicles on their assembly structures. Microscopic and spectroscopic experiments revealed intimate relationship between peptide/membrane charges and fibrillation properties. Electrostatic attraction was apparent between oppositely charged peptides and vesicles; however, such interactions did not appear to significantly modulate fibril morphologies of either the net anionic peptide or the cationic one. Yet, a dramatic structural effect was observed when the nominal zwitterionic peptide underwent fibrillation in the presence of negatively charged vesicles. Assemblies of this peptide display a net positive charge, which facilitated the counterionic interactions with the vesicles. Furthermore, these interactions templated a unique twisted fiber morphology demonstrating the dramatic effect membrane-mediated interactions exert on fibril morphologies. PMID- 29240409 TI - From Experiments to a Fast Easy-to-Use Computational Methodology to Predict Human Aldehyde Oxidase Selectivity and Metabolic Reactions. AB - Aldehyde oxidase (AOX) is a molibdo-flavoenzyme that has raised great interest in recent years, since its contribution in xenobiotic metabolism has not always been identified before clinical trials, with consequent negative effects on the fate of new potential drugs. The fundamental role of AOX in metabolizing xenobiotics is also due to the attempt of medicinal chemists to stabilize candidates toward cytochrome P450 activity, which increases the risk for new compounds to be susceptible to AOX nucleophile attack. Therefore, novel strategies to predict the potential liability of new entities toward the AOX enzyme are urgently needed to increase effectiveness, reduce costs, and prioritize experimental studies. In the present work, we present the most up-to-date computational method to predict liability toward human AOX (hAOX), for applications in drug design and pharmacokinetic optimization. The method was developed using a large data set of homogeneous experimental data, which is also disclosed as Supporting Information . PMID- 29240408 TI - Isobaric Tags for Relative and Absolute Quantification (iTRAQ)-Based Untargeted Quantitative Proteomic Approach To Identify Change of the Plasma Proteins by Salbutamol Abuse in Beef Cattle. AB - Salbutamol, a selective beta2-agonist, endangers the safety of animal products as a result of illegal use in food animals. In this study, an iTRAQ-based untargeted quantitative proteomic approach was applied to screen potential protein biomarkers in plasma of cattle before and after treatment with salbutamol for 21 days. A total of 62 plasma proteins were significantly affected by salbutamol treatment, which can be used as potential biomarkers to screen for the illegal use of salbutamol in beef cattle. Enzyme-linked immunosorbent assay measurements of five selected proteins demonstrated the reliability of iTRAQ-based proteomics in screening of candidate biomarkers among the plasma proteins. The plasma samples collected before and after salbutamol treatment were well-separated by principal component analysis (PCA) using the differentially expressed proteins. These results suggested that an iTRAQ-based untargeted quantitative proteomic strategy combined with PCA pattern recognition methods can discriminate differences in plasma protein profiles collected before and after salbutamol treatment. PMID- 29240410 TI - Determining the Relative Susceptibility of Four Prion Protein Genotypes to Atypical Scrapie. AB - Atypical scrapie is a sheep prion (PrPSc) disease whose epidemiology is consistent with a sporadic origin and is associated with specific polymorphisms of the normal cellular prion protein (PrPC). To determine the relative amounts of PrP polymorphisms present in atypical scrapie, total PrP was digested with chymotrypsin to generate characteristic peptides spanning relevant polymorphisms at positions 136, 141, 154, 171, and 172 of sheep PrPC. A multiple reaction monitoring method (MRM), employing 15N-labeled internal standards, was used to detect and quantify these polymorphisms present in both the PrPSc and PrPC from heterozygous (ALRRY and ALHQY or ALRQD or AFRQY) atypical scrapie-infected or uninfected control sheep. Both polymorphisms of the full length and truncated (C1) natively expressed PrPC are produced in equal amounts. The overall amount of PrPC present in the infected or uninfected animals was similar. PrPSc isolated from heterozygotes was composed of significant amounts of both PrP polymorphisms, including the ALRRY polymorphism which is highly resistant to classical scrapie. Thus, an atypical scrapie infection does not result from an overexpression of sheep PrPC. The replication of all atypical scrapie prions occurs at comparable rates, despite polymorphisms at positions 141, 154, 171, or 172. PMID- 29240411 TI - Singlet Fission Involves an Interplay between Energetic Driving Force and Electronic Coupling in Perylenediimide Films. AB - Due to its ability to offset thermalization losses in photoharvesting systems, singlet fission has become a topic of research interest. During singlet fission, a high energy spin-singlet state in an organic semiconductor divides its energy to form two lower energy spin-triplet excitations on neighboring chromophores. While key insights into mechanisms leading to singlet fission have been gained recently, developing photostable compounds that undergo quantitative singlet fission remains a key challenge. In this report, we explore triplet exciton production via singlet fission in films of perylenediimides, a class of compounds with a long history of use as industrial dyes and pigments due to their photostability. As singlet fission necessitates electron transfer between neighboring molecules, its rate and yield depend sensitively on their local arrangement. By adding different functional groups at their imide positions, we control how perylenediimides pack in the solid state. We find inducing a long axis displacement of ~3 A between neighboring perylenediimides gives a maximal triplet production yield of 178% with a fission rate of ~245 ps despite the presence of an activation barrier of ~190 meV. These findings disagree with Marcus theory predictions for the optimal perylenediimide geometry for singlet fission, but do agree with Redfield theory calculations that allow singlet fission to occur via a charge transfer-mediated superexchange mechanism. Unfortunately, triplets produced by singlet fission are found to decay over tens of nanoseconds. Our results highlight that singlet fission materials must be designed to not only produce triplet excitons but to also facilitate their extraction. PMID- 29240412 TI - Integration of On-Column Chemical Reactions in Protein Characterization by Liquid Chromatography/Mass Spectrometry: Cross-Path Reactive Chromatography. AB - Profiling of complex proteins by means of mass spectrometry (MS) frequently requires that certain chemical modifications of their covalent structure (e.g., reduction of disulfide bonds), be carried out prior to the MS or MS/MS analysis. Traditionally, these chemical reactions take place in the off-line mode to allow the excess reagents (the majority of which interfere with the MS measurements and degrade the analytical signal) to be removed from the protein solution prior to MS measurements. In addition to a significant increase in the analysis time, chemical reactions may result in a partial or full loss of the protein if the modifications adversely affect its stability, e.g,, making it prone to aggregation. In this work we present a new approach to solving this problem by carrying out the chemical reactions online using the reactive chromatography scheme on a size exclusion chromatography (SEC) platform with MS detection. This is achieved by using a cross-path reaction scheme, i.e., by delaying the protein injection onto the SEC column (with respect to the injection of the reagent plug containing a disulfide-reducing agent), which allows the chemical reactions to be carried out inside the column for a limited (and precisely controlled) period of time, while the two plugs overlap inside the column. The reduced protein elutes separately from the unconsumed reagents, allowing the signal suppression in ESI to be avoided and enabling sensitive MS detection. The new method is used to measure fucosylation levels of a plasma protein haptoglobin at the whole protein level following online reduction of disulfide-linked tetrameric species to monomeric units. The feasibility of top-down fragmentation of disulfide containing proteins is also demonstrated using beta2-microglobulin and a monoclonal antibody (mAb). The new online technique is both robust and versatile, as the cross-path scheme can be readily expanded to include multiple reactions in a single experiment (as demonstrated in this work by oxidatively labeling mAb on the column, followed by reduction of its disulfide bonds and MS analysis of the extent of oxidation within each chain of the molecule). PMID- 29240413 TI - Reversible Twisting of Primary Amides via Ground State N-C(O) Destabilization: Highly Twisted Rotationally Inverted Acyclic Amides. AB - Since the seminal studies by Pauling in 1930s, planarity has become the defining characteristic of the amide bond. Planarity of amides has central implications for the reactivity and chemical properties of amides of relevance to a range of chemical disciplines. While the vast majority of amides are planar, nonplanarity has a profound effect on the properties of the amide bond, with the most common method to restrict the amide bond relying on the incorporation of the amide function into a rigid cyclic ring system. In a major departure from this concept, here, we report the first class of acyclic twisted amides that can be prepared, reversibly, from common primary amides in a single, operationally trivial step. Di-tert-butoxycarbonylation of the amide nitrogen atom yields twisted amides in which the amide bond exhibits nearly perpendicular twist. Full structural characterization of a range of electronically diverse compounds from this new class of twisted amides is reported. Through reactivity studies we demonstrate unusual properties of the amide bond, wherein selective cleavage of the amide bond can be achieved by a judicious choice of the reaction conditions. Through computational studies we evaluate structural and energetic details pertaining to the amide bond deformation. The ability to selectively twist common primary amides, in a reversible manner, has important implications for the design and application of the amide bond nonplanarity in structural chemistry, biochemistry and organic synthesis. PMID- 29240414 TI - Trace Element Removal in Distributed Drinking Water Treatment Systems by Cathodic H2O2 Production and UV Photolysis. AB - As water scarcity intensifies, point-of-use and point-of-entry treatment may provide a means of exploiting locally available water resources that are currently considered to be unsafe for human consumption. Among the different classes of drinking water contaminants, toxic trace elements (e.g., arsenic and lead) pose substantial operational challenges for distributed drinking water treatment systems. Removal of toxic trace elements via adsorption onto iron oxides is an inexpensive and robust treatment method; however, the presence of metal-complexing ligands associated with natural organic matter (NOM) often prevents the formation of iron precipitates at the relatively low concentrations of dissolved iron typically present in natural water sources, thereby requiring the addition of iron which complicates the treatment process and results in a need to dispose of relatively large amounts of accumulated solids. A point-of-use treatment device consisting of a cathodic cell that produced hydrogen peroxide (H2O2) followed by an ultraviolet (UV) irradiation chamber was used to decrease colloid stabilization and metal-complexing capacity of NOM present in groundwater. Exposure to UV light altered NOM, converting ~6 MUM of iron oxides into settable forms that removed between 0.5 and 1 MUM of arsenic (As), lead (Pb), and copper (Cu) from solution via adsorption. After treatment, changes in NOM consistent with the loss of iron-complexing carboxylate ligands were observed, including decreases in UV absorbance and shifts in the molecular composition of NOM to higher H/C and lower O/C ratios. Chronoamperometric experiments conducted in synthetic groundwater revealed that the presence of Ca2+ and Mg2+ inhibited intramolecular charge-transfer within photoexcited NOM, leading to substantially increased removal of iron and trace elements. PMID- 29240415 TI - Identifying Plant Stress Responses to Roxarsone in Soybean Root Exudates: New Insights from Two-Dimensional Correlation Spectroscopy. AB - Roxarsone (ROX) is an organoarsenic feed additive of increasing interest used in the poultry industry. Soybean responses to ROX stress were investigated in root exudates (REs) using two-dimensional correlation spectroscopy (2D-COS) with fluorescence and Fourier transform infrared spectra. Environmentally relevant ROX concentrations caused negligible toxicity to crop growth and photosynthesis activity but blackened soybean roots at high concentrations. 2D-COS analysis revealed that the protein-like fluorophore and C?C and C?O, aliphatic OH, and polysaccharide C-O-H moieties in soybean REs were most sensitive to ROX stress. Heterospectral 2D-COS results suggested that aromatic, amide I, quinone, ketone, and aliphatic functional groups were the foundational components of protein-like and short-wavelength excited humic-like fluorophores in soybean REs. Carboxyl and phenolic moieties were related to the long-wavelength excited humic-like fluorophore. Overall, 2D-COS combined with molecular-based spectral analysis of REs provided an innovative approach to characterize the physiological responses of crops to contaminants at sublethal levels. PMID- 29240416 TI - Electrical Properties and Oxygen Stoichiometry of Ba1-xSrxTiO3-delta Ceramics. AB - Ba1-xSrxTiO3 solid solutions prepared by a solid-state reaction in air at 1200 1400 degrees C, followed by slow cooling to room temperature at the end of the reaction, were essentially oxygen-stoichiometric and p-type. Their conductivity increased reversibly when either p(O2) in the surrounding atmosphere was increased or a dc bias as small as 1 V was applied across the samples. The enhanced p-type conductivity is attributed to the creation of mobile holes on underbonded oxide ions. The same samples quenched from >~1400 degrees C were increasingly oxygen deficient and n-type. They showed reduced conductivity with either a dc bias or increased p(O2), attributed to the trapping of mobile electrons. These materials provide a rare example of a switch between n-type and p-type conductivity, in the same material, linked to oxygen stoichiometry variation. In both n- and p-type materials, the samples responded to external stimuli in a way similar to that of a leaky capacitor; polarization processes at sample surfaces led first to charge storage and second to a reversible change in bulk electrical properties. PMID- 29240417 TI - Modifying the Formulation of Abamectin To Promote Its Efficacy on Southern Root Knot Nematode (Meloidogyne incognita) under Blending-of-Soil and Root-Irrigation Conditions. AB - The southern root-knot nematode (RKN), Meloidogyne incognita, is the most disastrous and prevalent nematode threat to the production of crops, especially vegetables. In the current study, second-stage juveniles (J2) of M. incognita were collected from five regions near Tai'an, China. The toxicity of abamectin to these J2 had insignificant differences, with LC50 values of approximately 2 mg/L. Two pesticide application approaches (i.e., blending-of-soil and root-irrigation) were adopted in pot experiments; blending-of-soil was more beneficial for promoting the efficacy of abamectin on the RKN of tomatoes. Abamectin microcapsule suspension exhibited superiority to emulsifiable concentrate (EC) at dosages of 5 and 10 mg active ingredient per plant integrating efficacy, root length, plant height, the fresh weight of roots, and the fresh weight of stems + leaves. Adsorption, leaching, and mobility of abamectin in the soil also verified bioactivity test results. Modifying the formulation of abamectin can promote its efficacy on RKN under different application approaches. PMID- 29240419 TI - Application of Classical Thermodynamics to Conductivity in Nonpolar Media: Experimental Confirmation. AB - We previously proposed ( Gourdin-Bertin , S. and Chassagne , C. J. Chem. Phys. 2016 , 144 ( 24) ) a simple theoretical model to account for the evolution of conductivity with dielectric permittivity in nonpolar media. In this article, we validate the theory experimentally for the case of an ionogenic species kept at a constant chemical potential (i.e., in equilibrium with a nondissolved salt, in contrast to previously published conductivity measurements carried out as a function of various fully dissolved salt concentrations). To our knowledge, it is the first time that this type of experiment has been performed explicitly. PMID- 29240418 TI - Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766). AB - Demonstrating intracellular protein target engagement is an essential step in the development and progression of new chemical probes and potential small molecule therapeutics. However, this can be particularly challenging for poorly studied and noncatalytic proteins, as robust proximal biomarkers are rarely known. To confirm that our recently discovered chemical probe 1 (CCT251236) binds the putative transcription factor regulator pirin in living cells, we developed a heterobifunctional protein degradation probe. Focusing on linker design and physicochemical properties, we generated a highly active probe 16 (CCT367766) in only three iterations, validating our efficient strategy for degradation probe design against nonvalidated protein targets. PMID- 29240420 TI - Iodine-Promoted Aromatization of p-Menthane-Type Phytocannabinoids. AB - Treatment with iodine cleanly converts various p-menthane-type phytocannabinoids and their carboxylated precursors into cannabinol (CBN, 1a). The reaction is superior to previously reported protocols in terms of simplicity and substrate range, which includes not only tricyclic tetrahydrocannabinols such as Delta9-THC (2a) but also bicyclic phytocannabinoids such as cannabidiol (CBD, 3a). Lower homologues from the viridin series (2c and 3c, respectively) afforded cannabivarin (CBV), a non-narcotic compound that, when investigated against a series of ionotropic (thermo-TRPs) biological end-points of phytocannabinoids, retained the submicromolar TRPA1-activating and TRPM8-inhibiting properties of CBN, while also potently activating TRPV2. Treatment with iodine provides an easy access to CBN (1a) from crude extracts and side-cuts of the purification of Delta9-THC and CBD from respectively narcotic Cannabis sativa (marijuana) and fiber hemp, substantially expanding the availability of this compound and, in the case of fiber hemp, dissecting it from narcotic phytocannabinoids. PMID- 29240421 TI - Photochemistry of Fe:H2O Adducts in Argon Matrixes: A Combined Experimental and Theoretical Study in the Mid-IR and UV-Visible Regions. AB - The photochemistry of Fe:H2O adducts is of interest in fields as diverse as catalysis and astrochemistry. Industrially, iron can be used as a catalyst to convert H2O to H2, whereas in the interstellar medium it may be an important component of dust grains, influencing the chemistry on their icy surfaces. This study consisted of the deposition and spectral characterization of binary systems of atomic iron with H2O in cryogenic argon matrixes. In this way, we were able to obtain information about the interaction of the two species; we observed the formation of adducts of iron monomers and dimers with water molecules in the mid IR and UV-visible spectral domains. Upon irradiation with a UV radiation source, the iron species were inserted into the water molecules to form HFeOH and HFe2OH, leading in some cases to the formation of FeO possibly accompanied by the production of H2. DFT and correlated multireference wave function calculations confirmed our attributions. This combination of IR and UV-visible spectroscopy with theoretical calculations allowed us to determine, for the first time, the spectral characteristics of iron adducts and their photoproducts in the UV visible and in the OH stretching region of the mid-IR domain. PMID- 29240422 TI - High in Vivo Stability of 64Cu-Labeled Cross-Bridged Chelators Is a Crucial Factor in Improved Tumor Imaging of RGD Peptide Conjugates. AB - Although the importance of bifunctional chelators (BFCs) is well recognized, the chemophysical parameters of chelators that govern the biological behavior of the corresponding bioconjugates have not been clearly elucidated. Here, five BFCs closely related in structure were conjugated with a cyclic RGD peptide and radiolabeled with Cu-64 ions. Various biophysical and chemical properties of the Cu(II) complexes were analyzed with the aim of identifying correlations between individual factors and the biological behavior of the conjugates. Tumor uptake and body clearance of the 64Cu-labeled bioconjugates were directly compared by animal PET imaging in animal models, which was further supported by biodistribution studies. Conjugates containing propylene cross-bridged chelators showed higher tumor uptake, while a closely related ethylene cross-bridged analogue exhibited rapid body clearance. High in vivo stability of the copper chelator complex was strongly correlated with high tumor uptake, while the overall lipophilicity of the bioconjugate affected both tumor uptake and body clearance. PMID- 29240423 TI - Correlated Molecular Orbital Theory Study of the Al + CO2 Reaction. AB - Density functional theory (DFT) and correlated molecular orbital electronic structure calculations were used to study the Al + CO2 -> AlO + CO reaction on the electronic ground-state potential-energy surface (PES). Geometries were optimized using DFT (M11/jun-cc-pV(Q+d)Z) and more accurate energies were obtained using the composite Weizmann-1 theory with Brueckner doubles (W1BD). The results comprise the most complete, most systematic characterization of the Al + CO2 reaction surface to date and are based on consistent application of high level methods for all stationary points identified. The pathways from Al + CO2 to AlO + CO on the electronic ground-state PES all involve formation of one or more stable AlCO2 complexes denoted eta-AlCO2, trans-AlCO2, and C2v-AlCO2, among which eta-AlCO2 and C2v-AlCO2 are the least and most stable, respectively. We report a new minimum-energy pathway for the overall reaction, namely formation of eta AlCO2 from reactants and dissociation of that same complex to products via a bond insertion reaction that passes through a fourth (weakly metastable) AlCO2 complex denoted cis-OAlCO. Natural Bond Orbital analysis was applied to study trends in charge distribution and the degree of charge transfer in key structures along the minimum-energy pathway. The process of aluminum insertion into CO2 is discussed in the context of analogous processes for boron and first-row transition metals. PMID- 29240425 TI - Energy Landscape and Pathways for Transitions between Watson-Crick and Hoogsteen Base Pairing in DNA. AB - The recent discovery that Hoogsteen (HG) base pairs are widespread in DNA across diverse sequences and positional contexts could have important implications for understanding DNA replication and DNA-protein recognition. While evidence is emerging that the Hoogsteen conformation could be a thermodynamically accessible conformation of the DNA duplex and provide a means to expand its functionality, relatively little is known about the molecular mechanism underlying the Watson Crick (WC) to HG transition. In this Perspective, we describe pathways and kinetics for this transition at an atomic level of detail, using the energy landscape perspective. We show that competition between the duplex conformations results in a double funnel landscape, which explains some recent experimental observations. The interconversion pathways feature a number of intermediates, with a variable number of WC and HG base pairs. The relatively slow kinetics, with possible deviations from two-state behavior, suggest that this conformational switch is likely to be a challenging target for both simulation and experiment. PMID- 29240426 TI - p-Carborane Conjugation in Radical Anions of Cage-Cage and Cage-Phenyl Compounds. AB - Optical electron transfer (intervalence) transitions in radical anions of p carborane oligomers attest to delocalization of electrons between two p carboranes cages or a p-carborane and a phenyl ring. Oligomers of the 12 vertex p carborane (C2B10H12) cage, [12], with up to 3 cages were synthesized, as well as p-carboranes with one or two trimethylsilylphenyl groups, [6], attached to the carbon termini. Pulse radiolysis in tetrahydrofuran produced radical anions, determined redox potentials by equilibria and measured their absorption spectra. Density functional theory computations provided critical insight into the optical electron transfer bands and electron delocalization. One case, [6-12-6], showed both Robin-Day class II and III transitions. The class III transition resulted from a fully delocalized excess electron across both benzene rings and the central p-carborane, with an electronic coupling Hab = 0.46 eV between the cage and either benzene. This unprecedented finding shows that p-carborane bridges are not simply electron withdrawing insulators. In other cases with more than ~1/2 of the excess electron localized on a [12], large cage distortions were triggered, producing a partially open cage with a nido-like structure. This resulted in class II transitions with similar Hab but massive reorganization energies. The computations also predicted delocalization in radical cations, but complexities in cation formation allowed only tentative experimental support of the predictions. The results with anions provide clear evidence for carborane conjugation that might be exploited in molecular wire materials, which are classically composed of all pi-conjugated molecules. PMID- 29240424 TI - SOMO-HOMO Level Inversion in Biologically Important Radicals. AB - Conventionally, the singly occupied molecular orbital (SOMO) of a radical species is considered to be the highest occupied molecular orbital (HOMO), but this is not the case always. In this study, we considered a number of radicals from smallest diatomic anion radicals such as superoxide anion radical to one-electron oxidized DNA related base radicals that show the SOMO is energetically lower than one or more doubly occupied molecular orbitals (MOs) (SOMO-HOMO level inversion). The electronic configurations are calculated employing the B3LYP/6-31++G** method, with the inclusion of aqueous phase via the integral equation formalism of the polarized continuum model solvation model. From the extensive study of the electronic configurations of radicals produced by one-electron oxidation or reduction of natural-DNA bases, bromine-, sulfur-, selenium-, and aza-substituted DNA bases, as well as 20 diatomic molecules, we highlight the following important findings: (i) SOMO-HOMO level inversion is a common phenomenon in radical species. (ii) The more localized spin density in sigma-orbital on a single atom (carbon, nitrogen, oxygen, sulfur, or selenium), the greater the gap between HOMO and SOMO. (iii) In species with SOMO-HOMO level inversion, one-electron oxidation takes place from HOMO not from the SOMO, which produces a molecule in its triplet ground state. Oxidation of aqueous superoxide anion producing triplet molecular oxygen is one example of many. (iv) These results are for conventional radicals and in contrast with those reported for distonic radical anions in which SOMO HOMO gaps are smaller for more localized radicals and the orbital inversions vanish in water. Our findings yield new insights into the properties of free radical systems. PMID- 29240428 TI - Structures and Heats of Formation of Simple Alkaline Earth Metal Compounds II: Fluorides, Chlorides, Oxides, and Hydroxides for Ba, Sr, and Ra. AB - Geometry parameters, vibrational frequencies, heats of formation, bond dissociation energies, cohesive energies, and selected fluoride affinities (difluorides) are predicted for the late alkaline earth (Sr, Ba, and Ra) oxides, fluorides, chlorides, and hydroxides at the coupled cluster theory CCSD(T) level. Additional corrections (scalar relativistic and pseudopotential corrections, vibrational zero-point energies, and atomic spin-orbit effects) were included to accurately calculate the total atomization energies and heats of formation following the Feller-Peterson-Dixon methodology. The calculated values are compared to the experimental data where available. In some cases, especially for Ra compounds, there are no experimental results, or the experimental energetics and geometries are not reliable or have very large error bars. All of the Sr, Ba, and Ra difluorides, dichlorides, and dihydroxides are bent structures with the OMO bond angles decreasing going down the group. The cohesive energies of bulk Be dihalides are predicted to be quite low, while those of Ra are relatively large. The fluoride affinities show that the difluorides are moderately strong Lewis acids and that such trifluorides may form under the appropriate experimental conditions. PMID- 29240427 TI - Base-Controlled Regioselective Functionalization of Chloro-Substituted Quinolines. AB - We prepared a number of di- and trifunctionalized quinolines by selective metalation of chloro-substituted quinolines with metal amides followed by reaction with different electrophiles. Metalation of the C-3 position of the quinolinic ring with lithium diisopropylamide at -70 degrees C is easy to achieve, whereas reaction with lithium-magnesium and lithium-zinc amides affords C-2 or C-8 functionalized derivatives in a regioselective fashion. These complementary methods could be rationalized by DFT calculations and are convenient strategies toward the synthesis of bioactive quinoline derivatives such as chloroquine analogues. PMID- 29240429 TI - Stabilizing Nanocrystalline Oxide Nanofibers at Elevated Temperatures by Coating Nanoscale Surface Amorphous Films. AB - Nanocrystalline materials often exhibit extraordinary mechanical and physical properties but their applications at elevated temperatures are impaired by the rapid grain growth. Moreover, the grain growth in nanocrystalline oxide nanofibers at high temperatures can occur at hundreds of degrees lower than that would occur in corresponding bulk nanocrystalline materials, which would eventually break the fibers. Herein, by characterizing a model system of scandia stabilized zirconia using hot-stage in situ scanning transmission electron microscopy, we discover that the enhanced grain growth in nanofibers is initiated at the surface. Subsequently, we demonstrate that coating the fibers with nanometer-thick amorphous alumina layer can enhance their temperature stability by nearly 400 degrees C via suppressing the surface-initiated grain growth. Such a strategy can be effectively applied to other oxide nanofibers, such as samarium doped ceria, yttrium-stabilized zirconia, and lanthanum molybdate. The nanocoatings also increase the flexibility of the oxide nanofibers and stabilize the high-temperature phases that have 10 times higher ionic conductivity. This study provides new insights into the surface-initiated grain growth in nanocrystalline oxide nanofibers and develops a facile yet innovative strategy to improve the high-temperature stability of nanofibers for a broad range of applications. PMID- 29240430 TI - Electron-Phonon Coupling Constant of Metallic Overlayers from Specular He Atom Scattering. AB - He atom scattering has been shown to be a sensitive probe of electron-phonon interaction properties at surfaces. Here it is shown that measurements of the thermal attenuation of the specular He atom diffraction peak (the Debye-Waller effect) can determine the electron-phonon coupling constant, lambda, for ultrathin films of metal overlayers on various close-packed metal substrates. Values of lambda obtained for single and multiple monolayers of alkali metals, and for Pb layers on Cu(111), extrapolated to large thicknesses, agree favorably with known bulk values. This demonstrates that He atom scattering can measure the electron-phonon coupling strength as a function of film thickness on a layer-by layer basis. PMID- 29240431 TI - Solar Photothermal Disinfection using Broadband-Light Absorbing Gold Nanoparticles and Carbon Black. AB - A simple heat treatment, perhaps the most globally recognized point-of-use water sterilization method, is seemingly effective against all major pathogens of concern, but bulk water boiling is not energy efficient or sustainable. Herein, we present the first application of solar-to-thermal converting nanomaterials for the direct inactivation of bacteria and viruses in drinking water through the application of Au nanorods, carbon black, and Au nanorod-carbon black composite materials as light absorbers. With broad absorption bands spanning the visible and near-infrared wavelengths, at sufficient concentrations, these nanoparticles induce multiple scattering events, increasing photon absorption probability and concentrating the light within a small spatial domain, leading to localized, intense heating that inactivates microorganisms in close proximity. Moving toward practical device design, we have developed a facile silane immobilization approach to fabricate films with densely packed layers of photothermal nanomaterials. Our results suggest that upon irraditaion with simulated solar light, these films can thermally inactivate bacteria and viruses, as demonstrated through the inactivation of surrogate organisms Escherichia coli K-12, and bacteriophages MS2 and PR772. PMID- 29240432 TI - Directing Nanoscale Optical Flows by Coupling Photon Spin to Plasmon Extrinsic Angular Momentum. AB - As any physical particle or object, light undergoing a circular trajectory features a constant extrinsic angular momentum. Within strong curvatures, this angular momentum can match the spin momentum of a photon, thus providing the opportunity of a strong spin-orbit interaction. Using this effect, we demonstrate tunable symmetry breaking in the coupling of light into a curved nanoscale plasmonic waveguide. The helicity of the impinging optical wave controls the power distribution between the two counter-propagating subwavelength guided modes including unidirectional waveguiding. We found experimentally that up to 95% of the incoupled light can be selectively directed into one of the two propagation directions of a nanoscale waveguide. This approach offers new degrees of freedom in the manipulation of subdiffraction optical modes and thus appealing new prospects for the development of advanced, deeply subwavelength optical functionalities. PMID- 29240433 TI - High-Density Modification of H-Terminated Si(111) Surfaces Using Short-Chain Alkynes. AB - H-Si(111)-terminated surfaces were alkenylated via two routes: through a novel one-step gas-phase hydrosilylation reaction with short alkynes (C3 to C6) and for comparison via a two-step chlorination and Grignard alkenylation process. All modified surfaces were characterized by static water contact angles and X-ray photoelectron spectroscopy (XPS). Propenyl- and butenyl-coated Si(111) surfaces display a significantly higher packing density than conventional C10-C18 alkyne derived monolayers, showing the potential of this approach. In addition, propyne chemisorption proceeds via either of two approaches: the standard hydrosilylation at the terminal carbon (lin) at temperatures above 90 degrees C and an unprecedented reaction at the second carbon (iso) at temperatures below 90 degrees C. Molecular modeling revealed that the packing energy of a monolayer bonded at the second carbon is significantly more favorable, which drives iso attachment, with a dense packing of surface-bound iso-propenyl chains at 40% surface coverage, in line with the experiments at <90 degrees C. The highest density monolayers are obtained at 130 degrees C and show a linear attachment of 1-propenyl chains with 92% surface coverage. PMID- 29240434 TI - Fibrinogen Motif Discriminates Platelet and Cell Capture in Peptide-Modified Gold Micropore Arrays. AB - Human blood platelets and SK-N-AS neuroblastoma cancer-cell capture at spontaneously adsorbed monolayers of fibrinogen-binding motifs, GRGDS (generic integrin adhesion), HHLGGAKQAGDV (exclusive to platelet integrin alphaIIbbeta3), or octanethiol (adhesion inhibitor) at planar gold and ordered 1.6 MUm diameter spherical cap gold cavity arrays were compared. In all cases, arginine/glycine/aspartic acid (RGD) promoted capture, whereas alkanethiol monolayers inhibited adhesion. Conversely only platelets adhered to alanine/glycine/aspartic acid (AGD)-modified surfaces, indicating that the AGD motif is recognized preferentially by the platelet-specific integrin, alphaIIbbeta3. Microstructuring of the surface effectively eliminated nonspecific platelet/cell adsorption and dramatically enhanced capture compared to RGD/AGD modified planar surfaces. In all cases, adhesion was reversible. Platelets and cells underwent morphological change on capture, the extent of which depended on the topography of the underlying substrate. This work demonstrates that both the nature of the modified interface and its underlying topography influence the capture of cancer cells and platelets. These insights may be useful in developing cell-based cancer diagnostics as well as in identifying strategies for the disruption of platelet cloaks around circulating tumor cells. PMID- 29240435 TI - Electrostatic Self-Assembly Enabling Integrated Bulk and Interfacial Sodium Storage in 3D Titania-Graphene Hybrid. AB - Room-temperature sodium-ion batteries have attracted increased attention for energy storage due to the natural abundance of sodium. However, it remains a huge challenge to develop versatile electrode materials with favorable properties, which requires smart structure design and good mechanistic understanding. Herein, we reported a general and scalable approach to synthesize three-dimensional (3D) titania-graphene hybrid via electrostatic-interaction-induced self-assembly. Synchrotron X-ray probe, transmission electron microscopy, and computational modeling revealed that the strong interaction between titania and graphene through comparably strong van der Waals forces not only facilitates bulk Na+ intercalation but also enhances the interfacial sodium storage. As a result, the titania-graphene hybrid exhibits exceptional long-term cycle stability up to 5000 cycles, and ultrahigh rate capability up to 20 C for sodium storage. Furthermore, density function theory calculation indicated that the interfacial Li+, K+, Mg2+, and Al3+ storage can be enhanced as well. The proposed general strategy opens up new avenues to create versatile materials for advanced battery systems. PMID- 29240436 TI - High-Resolution Infrared Spectra of the nu1 Fundamental Bands of Mono-Substituted 13C Propyne Isotopologues. AB - We present a combined experimental and ab initio study on the jet-cooled high resolution infrared spectra of the nu1 (acetylenic stretch) fundamental band for three isotopologues of propyne: 13CH312C=12CH, 12CH313C=12CH, and 12CH312C=13CH. The experimental spectra are recorded in natural abundance using a continuous supersonic expansion of regular propyne diluted in argon and helium, in combination with continuous wave cavity ring-down spectroscopy (cw-CRDS). The fully rotationally resolved K' = 0 and 1 subbands of all three monosubstituted 13C isotopologues have been measured near 3330 cm-1, and their spectroscopic analysis is presented here for the first time. The assignment of the bands and perturbation analysis are assisted by high level ab initio calculations at the CCSD(T) level of theory, from which vibrational frequencies, rotational constants, and Fermi resonances are predicted for each isotopologue. PMID- 29240437 TI - Catalyst-Controlled [3 + 2] and [4 + 2] Annulations of Oximes with Propargyl Alcohols: Divergent Access to Indenamines and Isoquinolines. AB - Rhodium(III)- and iridium(III)-catalyzed C-H activation of oximes and coupling with propargyl alcohols is discussed. Depending on the catalyst, the reaction pathway switched between [3 + 2] and [4 + 2] annulations, thus giving divergent access to indenamines and isoquinolines in a one-pot and atom-economical manner. The hydroxyl group in the tertiary propargyl alcohol substrate was found to be crucial in controlling chemoselectivity. Five-membered rhodacycle and iridacycle intermediates have also been identified for mechanism hypotheses. PMID- 29240438 TI - Magnetically Controlled Atomic-Plasmonic Fano Resonances. AB - Following the efforts of size reduction and the integration of light and vapor systems, great promise is held in the integration of vapor and confined electromagnetic waves. By confining light to nanoscale dimensions, fundamental properties of light-vapor interactions may vary significantly. For example, the state of polarization may be modified as compared with weakly focused beams. Specifically, in transverse magnetic modes, the existence of a longitudinal field component, which is in quadrature to the transverse field, generates a "circular like" polarized light. Here, by taking advantage of this very property, we study the interaction of confined light and vapor in a coupled system of plasmons and atomic vapors in the presence of magnetic fields. Our results show that the spectroscopic nature and Fano resonances of the hybrid plasmonic-atomic system are greatly altered. In parallel, we also exploit the existence of the atoms in proximity to the plasmonic mode to probe the polarization state of the electromagnetic field and reveal the longitudinal-to-transverse ratio between the plasmonic modes components in the near field. Interestingly, our system maps the amplitude and phase information of the electromagnetic modes to the spectral domain. As such, combining magnetic fields with the coupled plasmonic-atomic system has the potential for future applications in high spatial resolution magnetometry, near-field vectorial imaging, and magnetically induced switching and tuning. PMID- 29240439 TI - Defining Metabolic and Nonmetabolic Regulation of Histone Acetylation by NSAID Chemotypes. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known for their effects on inflammatory gene expression. Although NSAIDs are known to impact multiple cellular signaling mechanisms, a recent finding is that the NSAID salicylate can disrupt histone acetylation, in part through direct inhibition of the lysine acetyltransferase (KAT) p300/CBP. While salicylate is a relatively weak KAT inhibitor, its CoA-linked metabolite is more potent; however, the ability of NSAID metabolites to inhibit KAT enzymes biochemically and in cells remains relatively unexplored. Here we define the role of metabolic and nonmetabolic mechanisms in inhibition of KAT activity by NSAID chemotypes. First, we screen a small panel of NSAIDs for biochemical inhibition of the prototypical KAT p300, leading to the finding that many carboxylate-containing NSAIDs, including ibuprofen, are able to function as weak inhibitors. Assessing the inhibition of p300 by ibuprofen-CoA, a known NSAID metabolite, reveals that linkage of ibuprofen to CoA increases its biochemical potency toward p300 and other KAT enzymes. In cellular studies, we find that carboxylate-containing NSAIDs inhibit histone acetylation. Finally, we exploit the stereoselective metabolism of ibuprofen to assess the role of its acyl-CoA metabolite in regulation of histone acetylation. This unique strategy reveals that formation of ibuprofen-CoA and histone acetylation are poorly correlated, suggesting metabolism may not be required for ibuprofen to inhibit histone acetylation. Overall, these studies provide new insights into the ability of NSAIDs to alter histone acetylation, and illustrate how selective metabolism may be leveraged as a tool to explore the influence of metabolic acyl-CoAs on cellular enzyme activity. PMID- 29240440 TI - Electrical Tuning of Interlayer Exciton Gases in WSe2 Bilayers. AB - van der Waals heterostructures formed by stacking two-dimensional atomic crystals are a unique platform for exploring new phenomena and functionalities. Interlayer excitons, bound states of spatially separated electron-hole pairs in van der Waals heterostructures, have demonstrated potential for rich valley physics and optoelectronics applications and been proposed to facilitate high-temperature superfluidity. Here, we demonstrate highly tunable interlayer excitons by an out of-plane electric field in homobilayers of transition metal dichalcogenides. Continuous tuning of the exciton dipole from negative to positive orientation has been achieved, which is not possible in heterobilayers due to the presence of large built-in interfacial electric fields. A large linear field-induced redshift up to ~100 meV has been observed in the exciton resonance energy. The Stark effect is accompanied by an enhancement of the exciton recombination lifetime by more than two orders of magnitude to >20 ns. The long recombination lifetime has allowed the creation of an interlayer exciton gas with density as large as 1.2 * 1011 cm-2 by moderate continuous-wave optical pumping. Our results have paved the way for the realization of degenerate exciton gases in atomically thin semiconductors. PMID- 29240441 TI - Integrating Ab Initio Simulations and X-ray Photoelectron Spectroscopy: Toward A Realistic Description of Oxidized Solid/Liquid Interfaces. AB - Many energy storage and conversion devices rely on processes that take place at complex interfaces, where structural and chemical properties are often difficult to probe under operating conditions. A primary example is solar water splitting using high-performance photoelectrochemical cells, where surface chemistry, including native oxide formation, affects hydrogen generation. In this Perspective, we discuss some of the challenges associated with interrogating interface chemistry, and how they may be overcome by integrating high-level first principles calculations of explicit interfaces with ambient pressure X-ray photoelectron spectroscopy and direct spectroscopic simulations. We illustrate the benefit of this combined approach toward insights into native oxide chemistry at prototypical InP/water and GaP/water interfaces. This example suggests a more general roadmap for obtaining a realistic and reliable description of the chemistry of complex interfaces by combining state-of-the-art computational and experimental techniques. PMID- 29240442 TI - Optical Antenna-Based Fluorescence Correlation Spectroscopy to Probe the Nanoscale Dynamics of Biological Membranes. AB - The plasma membrane of living cells is compartmentalized at multiple spatial scales ranging from the nano- to the mesoscale. This nonrandom organization is crucial for a large number of cellular functions. At the nanoscale, cell membranes organize into dynamic nanoassemblies enriched by cholesterol, sphingolipids, and certain types of proteins. Investigating these nanoassemblies known as lipid rafts is of paramount interest in fundamental cell biology. However, this goal requires simultaneous nanometer spatial precision and microsecond temporal resolution, which is beyond the reach of common microscopes. Optical antennas based on metallic nanostructures efficiently enhance and confine light into nanometer dimensions, breaching the diffraction limit of light. In this Perspective, we discuss recent progress combining optical antennas with fluorescence correlation spectroscopy (FCS) to monitor microsecond dynamics at nanoscale spatial dimensions. These new developments offer numerous opportunities to investigate lipid and protein dynamics in both mimetic and native biological membranes. PMID- 29240443 TI - Photoluminescence of Zero-Dimensional Perovskites and Perovskite-Related Materials. AB - Zero-dimensional (0-D) perovskites and perovskite-related materials are an emerging class of optoelectronic materials exhibiting strong excitonic properties and, quite often, high photoluminescence (PL) in the solid state. Here we highlight two different classes of 0-D perovskites with contrasting structural and optical properties, focusing mainly on the less explored but rapidly growing bulk quantum materials termed as 0-D perovskite-related materials (0-D PRMs), whose PL properties are quite intriguing and a topic of recent debate. We attempt to present here a comprehensive picture to rationalize the contrasting properties of the 0-D PRMs and provide an understanding of the mechanism of exciton dynamics and PL of this class of materials. We hope that exciting PL and tunable composition of these systems will help design of new materials with versatile optical properties suited for practical applications. PMID- 29240444 TI - Regio- and Diastereodivergent [4 + 2] Cycloadditions with Cyclic 2,4-Dienones. AB - By employing activated alkenes with bulky alpha-functional groups, such as alpha cyano-alpha,beta-unsaturated ketones and Meldrum's acid-based alkenes, a previously unreported cross-trienamine pathway of cyclic 2,4-dienones is adopted to deliver gamma',delta-regioselective [4 + 2] cycloadducts catalyzed by cinchona derived amines. In addition, a diastereodivergent [4 + 2] cycloaddition reaction is realized with Z-configured 4-alkylideneisoxazol-5(4H)-ones under similar catalytic conditions, even through a three- or four-component cascade process with simple starting materials. PMID- 29240445 TI - Agglomeration-Free Preparation of Modified Silica Nanoparticles for Emulsion Polymerization-A Well Scalable Process. AB - To prepare modified silica nanospheres for emulsion polymerization, a new agglomeration-free change of dispersion media has been developed. Nanosized silica spheres were synthesized by the Stober method and directly modified with a silane coupling agent. To prepare these particles for subsequent polymerization, the dispersion medium was changed in a two-step process from ethanol to water without agglomeration of the particles. The emulsion polymerization leads to hemispherical single-core-structured silica-polystyrene composite particles. The thickness of the polymer shell can be altered by varying the amount of styrene. The developed change of dispersion media provides nonagglomerated modified silica particles for the encapsulation with polystyrene and enables the synthesis of narrowly distributed single-core composite particles. The developed process is a promising approach for the preparation of nanoparticles for subsequent polymerization and can be scaled-up for industrial applications. PMID- 29240446 TI - Magnetic Control of the Chiroptical Plasmonic Surfaces. AB - A major challenge facing plasmon nanophotonics is the poor dynamic tunability. A functional nanophotonic element would feature the real-time sizable tunability of transmission, reflection of light's intensity or polarization over a broad range of wavelengths, and would be robust and easy to integrate. Several approaches have been explored so far including mechanical deformation, thermal, or refractive index effects, and all-optical switching. Here we devise an ultrathin chiroptical surface, built on two-dimensional nanoantennas, where the chiral light transmission is controlled by the externally applied magnetic field. The magnetic field-induced modulation of the far-field chiroptical response with this surface exceeds 100% in the visible and near-infrared spectral ranges, opening the route for nanometer-thin magnetoplasmonic light-modulating surfaces tuned in real time and featuring a broad spectral response. PMID- 29240447 TI - Tunable UV-Emitters through Graphene Plasmonics. AB - Control over the spontaneous emission of light through tailored optical environments remains a fundamental paradigm in nanophotonics. The use of highly confined plasmons in materials such as graphene provides a promising platform to enhance transition rates in the IR-THz by many orders of magnitude. However, such enhancements involve near-field plasmon modes or other kinds of near-field coupling like quenching, and it is challenging to use these highly confined modes to harness light in the far-field due to the difficulty of plasmonic outcoupling. Here, we propose that through the use of radiative cascade chains in multilevel emitters, IR plasmons can be used to enhance far field spectra in the visible and UV range, even at energies greater than 10 eV. Combining Purcell-enhancement engineering, graphene plasmonics, and radiative cascade can result in a new type of UV emitter whose properties can be tuned by electrically doping graphene. Varying the distance between the emitter and the graphene surface can change the strength of the far-field emission lines by 2 orders of magnitude. We also find that the dependence of the far-field emission on the Fermi energy is potentially extremely sharp at the onset of interband transitions, allowing the Fermi energy to effectively serve as a "switch" for turning on and off certain plasmonic and far-field emissions. PMID- 29240448 TI - Pediatric Care Providers, Family, and Friends as Sources of Breastfeeding Support Beyond Infancy. AB - OBJECTIVE: To examine women's perceptions about support from pediatric primary care providers (PCPs), family, and friends for breastfeeding beyond 12 months, which is an increasing common practice. STUDY DESIGN: Women who breastfed at least one child beyond 12 months completed an online questionnaire distributed via La Leche League USA (2013). Questionnaire content focused on sources of support for breastfeeding beyond 12 months, support ratings, and participant characteristics. Bivariate statistics and multivariable log-binomial regression compared ratings of support across sources, by PCP sex, and with breastfeeding duration. RESULTS: Of 48,379 eligible U.S. women, about half discussed their decision to breastfeed beyond infancy with their child's PCP. In contrast, almost all (91.4%) did so with their spouse, partner, or significant other. Women were consistently more comfortable discussing their decision to breastfeed for more than a year with their family and closest friend than they were with their child's PCP (all p < 0.001). Three-fourths of PCPs were rated as supportive, but 11.1% were somewhat or very unsupportive. Female pediatricians received similar ratings as males (adjusted risk ratio = 1.01, 95% confidence interval: 1.00, 1.03). Thirty-eight percent of women who reported their PCP was unsupportive changed PCPs. CONCLUSION: Family and PCP support is likely to be important for the growing proportion of U.S. mother-child dyads who are breastfeeding beyond 12 months. Many, but not all, women rated their child's PCP as supportive, and lack of support was a reason women reported for changing PCPs. Evidence-based interventions in primary care to support breastfeeding beyond infancy are needed. PMID- 29240450 TI - Letter in response to 'Tp-e interval and Tp-e/QT ratio before and after catheter ablation in patients with premature ventricular complexes'. PMID- 29240449 TI - miR-19-5p Enhances Tumorigenesis in Human Colorectal Cancer Cells by Targeting TSPYL5. AB - The cancer suppressor gene, testis-specific protein Y-encoded-like 5 (TSPYL5), has been implicated in various cancers, including colorectal cancer (CRC). In this study, we investigated the role of TSPYL5 in the development of CRC in vitro. First, we used bioinformatics to predict the binding target of TSPYL5, and found that the microRNA, miR-19-5p, bound to the 3' untranslated region (UTR) of TSPYL5. This interaction was further validated by the dual-luciferase assay. Second, we found that overexpressed TSPYL5 enhanced apoptosis in HT29 cells and reduced cell proliferation, reduced cell migration/invasion, and most of the cells accumulated in the G0/G1 phase of the cell cycle. These effects were reversed after addition of miR-19-5p mimics. Third, knocking down expression of miR-19-5p also increased apoptosis, and reduced cell proliferation, migration, and invasion in HT29 cells. We speculate that miR-19-5p induces the degradation of TSPYL5 by binding to its 3'UTR. Our results suggest that increasing the expression of TSPYL5 in HT29 cells or inhibiting miR-19-5p promotes apoptosis of HT29 cells. Thus, miR-19-5p could be used as biomarkers of CRC, with potential implications for diagnosis and therapeutic intervention. PMID- 29240451 TI - HPE as a Field: Implications for the Production of Compelling Knowledge. AB - ISSUE: Research in education, including health professions education, has long struggled with the competing concerns of academic and practice-based stakeholders. Inspired partially by the work of Stokes and other theorists in science and technology studies, we propose that discussions about compelling research in health professions education might be usefully advanced by considering what it would mean if the community framed itself as a knowledge producing field instead of aligning itself with either disciplinary or practical interests. EVIDENCE: Efforts to foreground disciplinary or practical interests in education research have been unproductive, leading to the privileging of one group's expertise at the expense of the other. Currently proposed principles and practices for responding to the divergence between these interests, such as knowledge translation or practitioner inquiry, have yielded comparatively little in the way of mutual satisfaction. IMPLICATIONS: As a field, health professions education research would not privilege either disciplinary or practical interests, nor would it attempt any sort of definitive blueprint for resolution to the tension. Rather it would regard these interests as inherently interconnected and, therefore, always in tension to varying degrees. The challenge for a field is not to resolve that tension but to harness it in productive ways through collaboration, negotiation, and compromise, through ever shifting engagements that will not necessarily be comfortable but will nonetheless foster knowledge that resonates with all parts of the community. PMID- 29240452 TI - Breastfeeding Peer Support Program Increases Breastfeeding Duration Rates Among Middle- to High-Income Women. AB - BACKGROUND: Research has shown that women with low socioeconomic status and lack of breastfeeding support often breastfeed for shorter durations. Little research has been done on the effects of a breastfeeding peer support program for women from middle- to high-socioeconomic status. OBJECTIVE: The objective of this project was to determine whether a breastfeeding peer support program would increase breastfeeding duration rates among middle- to high-socioeconomic status women. MATERIALS AND METHODS: One hundred thirteen women were recruited from local OB/GYN offices to participate in a breastfeeding peer support program that included prenatal visits, phone calls, and anticipatory breastfeeding guidance throughout the infants' first year of life. RESULTS: Factors associated with a significant increase (p < 0.05) in breastfeeding duration included marital status, mother's ethnicity, mother's medical history, and delivery type. Mothers who remained enrolled in the study had the following breastfeeding duration rates: 85% at 6 months and 65% at 12 months. These are all higher than current national goals and statewide rates. CONCLUSION: Results indicate that consistent breastfeeding support during the infants' first year of life may increase breastfeeding duration rates for women of higher socioeconomic status. PMID- 29240453 TI - Medical Students' Implicit Bias and the Communication of Norms in Medical Education. AB - ISSUE: Medical educators should consider how institutional norms influence medical students' perceptions of implicit bias. Understanding normative structures in medical education can shed light on why this influence is associated with students' resistance to implicit bias. EVIDENCE: Extant research across diverse fields of study uncovers and theorizes layers of norms and normative systems and how they are related to ethical behavior. This review bridges the fields of communication, bioethics, and medical education, constructing an organized foundation and common language by which researchers can build effective educational interventions. First, the nature and effects of implicit bias are described. Second, the nature of normative systems in medical education is explicated. Concepts from the fields of education and communication are transferred to medical education. Third, the structure of the communication of norms in medical education is revealed, through theoretical research in bioethics and empirical medical education research. IMPLICATIONS: Recommendations are provided for medical educators to improve activities intended to encourage reflection on implicit bias. These recommendations include reframing educational activities as endeavors in "personal" development and uncovering and transforming those normative structures that encourage resistance to implicit bias. PMID- 29240454 TI - A Comparison of the Expectations and Experiences of Medical Students From High-, Middle-, and Low-Income Countries Participating in Global Health Clinical Electives. AB - : Phenomenon: Global health education (GHE) is expanding to include socioculturally and resource-different settings, with the goal of developing a workforce with members who can promote health equity locally and globally. GHE is also no longer limited to students from high-income countries (HICs). However, it is unknown whether the motivations and experiences of medical students from HICs and from low- and middle-income countries (LMICs) participating in GHE clinical electives through institutional partnerships are similar or different. Such an understanding is needed to design programs that meet the needs of participants and effectively train them in the principles and practice of global health. APPROACH: This was a cross-sectional, mixed-methods survey of LMIC students from partner sites rotating at one U.S. medical school, and U.S. students from one medical school rotating at partner sites, between 2010 and 2015. Variables included demographic characteristics of participants, components of the curriculum at the home institution, and components of the away rotation, including perceptions of its content and impact. Content analysis was used to identify themes in the responses provided to open-ended questions. FINDINGS: In all, 63 of 84 (75%) LMIC and 61 of 152 (40%) U.S. students participated. Recall of predeparture training was low for both LMIC and U.S. students (44% and 55%, respectively). Opportunities to experience different healthcare systems, resource different settings, and cultural exposure emerged as motivators for both groups. Both groups noted differences in doctor-patient relationships, interactions between colleagues, and use of diagnostic testing. U.S. respondents were more likely to perceive differences in the impact of social determinants of health and ethical issues. Both groups felt that their experience affected their interactions with patients and perspectives on education, but U.S. students were more likely to mention perspectives on healthcare delivery and social determinants of health, whereas LMIC respondents noted impacts on career goals. Insights: These results argue that GHE is not restricted to resource-constrained settings and that students from LMICs have similar reasons for participation as those from HICs. LMIC students also identified a lack of emphasis on GHE topics like social determinants of health during GH electives, which could diminish the effectiveness of these experiences. Both U.S. and LMIC students emphasized the cultural component of their GHE experience but had different perceptions regarding core tenets of GHE, such as the social determinants of health and health equity, during these experiences. PMID- 29240455 TI - Development and Evaluation of a Student-Initiated Test Preparation Program for the USMLE Step 1 Examination. AB - PROBLEM: Studies have documented performance on the United States Medical Licensing Examination(r) (USMLE) Step 1 exam as an important factor that residency program directors consider when deciding which applicants to interview and rank. Therefore, success on this exam, though only one aspect of applicant evaluation, is important in determining future career prospects for medical students. Unfortunately, mean test scores at the University of Illinois College of Medicine at Chicago (UIC) have historically been below the national average. INTERVENTION: This retrospective and quasi-experimental mixed-methods study describes the development, evaluation, and effects of a student-initiated USMLE Step 1 preparatory program at UIC. The program provided second year students with First Aid for the USMLE Step 1 at the beginning of the academic year, as well as a six month subscription to the USMLE World question bank midyear. In addition, optional peer review sessions covering basic sciences and organ systems were taught by high-performing upperclassmen. The goals of the program were to raise mean USMLE Step 1 exam scores and increase the percentage of students passing the exam on their first time. CONTEXT: The program premiered during the 2012-13 academic year. Data from this cohort as well as four others (N = 830; 2010-2014 examinees) were gathered. Performances between preintervention (2010-12 examinees) and postintervention (2013-14 examinees) cohorts of students were compared. Focus groups and interviews with staff and students were conducted, recorded, and analyzed to investigate the impact that the program had on student interactions and perceptions of the learning environment. OUTCOME: There was a significant difference in exam performance pre- versus postintervention, with average USMLE Step 1 scores improving by 8.82 points following the implementation of the student-initiated program, t(5.61) = 828, p < .001. The average first attempt pass rate also increased significantly by 8%, chi2(1) = 23.13, p < .001. Taking age, sex, Medical College Admission Test(r) scores, and undergraduate grade point average into account, students who participated in the program scored 6.57 points higher than students who did not participate in the program (R2 = 0.3), F(5, 886) = 76.71, p < .01, and had higher odds of passing USMLE Step 1 (odds ratio = 3.08, SE = 1.07, p < .01). Students and staff commented on the sense of community and empowerment the program created as well as the unique student-driven nature of the program. LESSONS LEARNED: This study demonstrates the efficacy of a student-initiated curriculum and provides guidance for development and implementation of examination preparatory efforts at other institutions. PMID- 29240456 TI - Trainees' Perceptions of Feedback: Validity Evidence for Two FEEDME (Feedback in Medical Education) Instruments. AB - : Construct: Medical educators consider feedback a core component of the educational process. Effective feedback allows learners to acquire new skills, knowledge, and attitudes. Learners' perceptions of feedback are an important aspect to assess with valid methods in order to improve the feedback skills of educators and the feedback culture. BACKGROUND: Although guidelines for delivering effective feedback have existed for several decades, medical students and residents often indicate that they receive little feedback. A recent scoping review on feedback in medical education did not reveal any validity evidence on instruments to assess learner's perceptions of feedback. The purpose of our study was to gather validity evidence on two novel FEEDME (Feedback in Medical Education) instruments to assess medical students' and residents' perceptions of the feedback that they receive. APPROACH: After the authors developed an initial instrument with 54 items, cognitive interviews with medical students and residents suggested that 2 separate instruments were needed, one focused on the feedback culture (FEEDME-Culture) and the other on the provider of feedback (FEEDME-Provider). A Delphi study with 17 medical education experts and faculty members assessed content validity. The response process was explored involving 31 medical students and residents at 2 academic institutions. Exploratory factor analysis and reliability analyses were performed on completed instruments. RESULTS: Two Delphi consultation rounds refined the wording of items and eliminated several items. Learners found both instruments easy and quick to answer; it took them less than 5 minutes to complete. Learners preferred an electronic format of the instruments over paper. Factor analysis revealed a two- and three-factor solution for the FEEDME-Culture and FEEDME-Provider instruments, respectively. Cronbach's alpha was greater than 0.80 for all factors. Items on both instruments were moderately to highly correlated (range, r = .3-.7). CONCLUSIONS: Our results provide preliminary validity evidence of 2 novel feedback instruments. After further validation of both FEEDME instruments, sharing the results of the FEEDME-Culture instrument with educational leaders and faculty may improve the culture of feedback on specific educational rotations and at the institutional level. The FEEDME-Provider instrument could be useful for faculty development targeting feedback skills. Additional research studies could assess whether both instruments may be used to help learners receive feedback and prompt reflective learning. PMID- 29240457 TI - Urinary peptidomics in kidney disease and drug research. AB - INTRODUCTION: Due to its close connection with the renal system, urine is considered a valuable source of information in kidney disease research. Peptidomics methods focus on the discovery of endogenous peptides, given their wide range of biological functions and diagnostic and therapeutic potential. Representing a non-invasive and sensitive method, technological prospects of urinary peptidomics should be evaluated in the context of drug discovery and research. Areas covered: This review describes urinary peptidomics with focus on its application in drug research in the field of kidney diseases. The authors provide an overview of current achievements and potential future applications. Expert opinion: The urinary peptidome is a dynamically changing source of information, able to reflect sudden and long-term changes affecting the renal system. Studies utilizing urinary peptidomics techniques have demonstrated their value in patient stratification and detection of early pathological changes in kidney disease. Serving as a liquid biopsy, urinary peptides are an invaluable tool for drug response monitoring. Nevertheless, peptidomics is largely underexplored in drug research in general, as evidenced by the scarce number of scientific publications on this topic. Further progress will be driven by the successful validation of current discoveries and continued efforts to improve the translation of results into therapeutic applications. PMID- 29240458 TI - Genome-Wide Analysis of Uveal Melanoma Metastasis-Associated LncRNAs and Their Functional Network. AB - Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Up to 50% of primary UM cases will develop distant metastasis, but no effective therapies are currently available. The present study aimed to characterize the expression profile of the long noncoding RNAs (lncRNAs) and screen the potential metastasis-associated lncRNAs in UM. A genome-wide analysis of the transcriptome was performed on 11 primary UM tissues (6 metastasized and 5 nonmetastasized) through RNA sequencing. A total of 40,878 lncRNAs were detected in UM, 4,983 of which were novel candidates. We identified 329 differentially expressed lncRNAs (DELs) and 802 differentially expressed mRNAs (DEMs) by comparing the transcriptome profile between metastasized and nonmetastasized UM group. The DEL DEM coexpression network revealed that the RP11-551L14.4, TCONS_00004101, and TCONS_00004845 DELs had the highest connectivity with the DEMs, coexpressed with 225, 28, and 10 DEMs, respectively, whereas the SPOCD1, PEA15, and SLC44A3 DEMs were most closely connected with the DELs, and were coexpressed with 89, 27, and 22 DELs, respectively. Moreover, 17 and 743 DEMs were targeted by the DELs through cis- or trans-action, respectively. These targeted DEMs were significantly enriched in D-Arginine and D-ornithine metabolism and glycerolipid metabolism of Kyoto Encyclopedia of Genes and Genomes pathways, and enriched in bradykinin receptor activity and haptoglobin binding of gene ontology biological processes. Quantitative real-time PCR confirmed the sequencing data. These findings have provided new insights into the molecular mechanism of UM metastasis and paved the way for further investigations regarding lncRNA in UM. PMID- 29240459 TI - Downregulated expression of hsa_circ_0074362 in gastric cancer and its potential diagnostic values. AB - AIM: To explore the diagnostic value of hsa_circ_0074362 in the screening of gastric cancer. METHODS: The expression levels of hsa_circ_0074362 in 127 gastric cancer tissues and paired adjacent normal tissues, 83 gastritis tissues and six gastric cancer cell lines were first detected by quantitative reverse transcription-polymerase chain reaction. Then, the relationship between its levels and clinicopathological factors of patients with gastric cancer was analyzed. Finally, a receiver operating characteristic curve was established. RESULTS: Hsa_circ_0074362 levels were significantly downregulated in gastric cancer tissues, gastritis tissues and gastric cancer cell lines. Its levels were associated with lymphatic metastasis. CONCLUSION: Hsa_circ_0074362 probably plays a role in the initiation of gastric cancer and may be a potential biomarker of gastric cancer. PMID- 29240460 TI - Two Adolescent Cases of Psychotropic-Related Nonaffective Oniomania. PMID- 29240461 TI - Clinicopathological significance of Bmi-1 overexpression in esophageal cancer: a meta-analysis. AB - AIM: The clinicopathological effects of Bmi-1 expression in esophageal cancer remain widely disputed. Our aim was to clarify this relationship. METHODS: Available studies were retrieved from diverse databases. Review Manager 5.3 and Stata 12.0 software were used to identify correlations between Bmi-1 expression and the clinicopathological features of esophageal cancer. RESULTS: From 16 studies, 1523 esophageal cancer patients were analyzed. Meta-analysis demonstrated that Bmi-1 overexpression was associated with differentiation (p = 0.03), tumor/node/metastasis stage (p = 0.02), depth of invasion (p = 0.0006) and lymph node metastasis (p = 0.008). CONCLUSION: The expression of Bmi-1 is associated with the progression and invasion of esophageal cancer. PMID- 29240462 TI - My Journey With Health Education & Behavior. PMID- 29240463 TI - Assessing the Validity of a Multidisciplinary Mini-Clinical Evaluation Exercise. AB - : Construct: The purpose of this study was to provide validity evidence for the mini-clinical evaluation exercise (mini-CEX) as an assessment tool for clinical skills in the workplace. BACKGROUND: Previous research has demonstrated validity evidence for the mini-CEX, but most studies were carried out in internal medicine or single disciplines, therefore limiting generalizability of the findings. If the mini-CEX is to be used in multidisciplinary contexts, then validity evidence should be gathered in similar settings. The purpose of this study was to gather further validity evidence for the mini-CEX but in a broader context. Specifically we sought to explore the effects of discipline and rater type on mini-CEX scores, internal structure, and the relationship between mini-CEXs and OSCEs in a multidisciplinary context. APPROACH: During clerkship, medical students completed eight different rotations (family medicine, internal medicine, surgery, psychiatry, pediatrics, emergency, anesthesiology and obstetrics and gynecology). During each rotation, mini-CEX forms and a written examination were completed. Two multidisciplinary OSCEs (in Clerkship Year 3 and start of Year 4) assessed clinical skills. The reliability of the mini-CEX was assessed using Generalizability analyses. To assess the influence of discipline and rater type, mean scores were analyzed using a factorial analysis of variance. The total mini CEX score was correlated to scores from the students' respective OSCEs and corresponding written exams. RESULTS: Eighty-two students met inclusion criteria for a total of 781 ratings (average of 9.82 mini-CEX forms per student). There was a significant effect of discipline (p < .001, = .16), and faculty provided lower scores than nonfaculty raters (7.12 vs. 7.41; p = .002, = .02). The g coefficient was .53 when discipline was included as a facet and .23 when rater type was a facet. There were low, but statistically significant correlations between the mini-CEX and scores for the 4th-year OSCE Total Score and the OSCE communication scores, r(80) = .40, p < .001 and r(80) = .29, p = .009. The mini CEX was not correlated with the written examination scores for any of the disciplines. CONCLUSIONS: Our results provide conflicting findings for validity evidence for the mini-CEX. Mini-CEX ratings were correlated to multidisciplinary OSCEs but not written examinations, supporting the validity argument. However, reliability of the mini-CEX was low to moderate, and error accounted for the greatest amount of variability in scores. There was variation in scores due to discipline and resident raters gave higher scores than faculty. These results should be considered when considering the use of the mini-CEX in different contexts. PMID- 29240465 TI - Efficacy of Lactic Acid, Lactic Acid-Acetic Acid Blends, and Peracetic Acid To Reduce Salmonella on Chicken Parts under Simulated Commercial Processing Conditions. AB - The poultry processing industry has been undergoing a series of changes as it modifies processing practices to comply with new performance standards for chicken parts and comminuted poultry products. The regulatory approach encourages the use of intervention strategies to prevent and control foodborne pathogens in poultry products and thus improve food safety and protect human health. The present studies were conducted to evaluate the efficacy of antimicrobial interventions for reducing Salmonella on inoculated chicken parts under simulated commercial processing conditions. Chicken pieces were inoculated by immersion in a five-strain Salmonella cocktail at 6 log CFU/mL and then treated with organic acids and oxidizing agents on a commercial rinsing conveyor belt. The efficacy of spraying with six different treatments (sterile water, lactic acid, acetic acid, buffered lactic acid, acetic acid in combination with lactic acid, and peracetic acid) at two concentrations was evaluated on skin-on and skin-off chicken thighs at three application temperatures. Skinless chicken breasts were used to evaluate the antimicrobial efficacy of lactic acid and peracetic acid. The color stability of treated and untreated chicken parts was assessed after the acid interventions. The lactic acid and buffered lactic acid treatments produced the greatest reductions in Salmonella counts. Significant differences between the control and water treatments were identified for 5.11% lactic acid and 5.85% buffered lactic acid in both skin-on and skin-off chicken thighs. No significant effect of treatment temperature for skin-on chicken thighs was found. Lactic acid and peracetic acid were effective agents for eluting Salmonella cells attached to chicken breasts. PMID- 29240464 TI - Analysis of Agreement of Retinal-Layer Thickness Measures Derived from the Segmentation of Horizontal and Vertical Spectralis OCT Macular Scans. AB - PURPOSE: Optical coherence tomography (OCT) is a reliable method used to quantify discrete layers of the retina. Spectralis OCT is a device used for this purpose. Spectralis OCT macular scan imaging acquisition can be obtained on either the horizontal or vertical plane. The vertical protocol has been proposed as favorable, due to postulated reduction in confound of Henle's fibers on segmentation-derived metrics. Yet, agreement of the segmentation measures of horizontal and vertical macular scans remains unexplored. Our aim was to determine this agreement. MATERIALS AND METHODS: Horizontal and vertical macular scans on Spectralis OCT were acquired in 20 healthy controls (HCs) and 20 multiple sclerosis (MS) patients. All scans were segmented using Heidelberg software and a Johns Hopkins University (JHU)-developed method. Agreement was analyzed using Bland-Altman analyses and intra-class correlation coefficients (ICCs). RESULTS: Using both segmentation techniques, mean differences (agreement at the cohort level) in the thicknesses of all macular layers derived from both acquisition protocols in MS patients and HCs were narrow (<1 um), while the limits of agreement (LOA) (agreement at the individual level) were wider. Using JHU segmentation mean differences (and LOA) for the macular retinal nerve fiber layer (RNFL) and ganglion cell layer + inner plexiform layer (GCIP) in MS were 0.21 um (-1.57-1.99 um) and -0.36 um (-1.44-1.37 um), respectively. CONCLUSIONS: OCT segmentation measures of discrete retinal-layer thicknesses derived from both vertical and horizontal protocols on Spectralis OCT agree excellently at the cohort level (narrow mean differences), but only moderately at the individual level (wide LOA). This suggests patients scanned using either protocol should continue to be scanned with the same protocol. However, due to excellent agreement at the cohort level, measures derived from both acquisitions can be pooled for outcome purposes in clinical trials. PMID- 29240466 TI - Developing an infrastructure to support clinical academic careers. AB - Research and evidence-based practice underpins the delivery of high-quality patient care. Developing the research capacity and capability of nurses, midwives and allied health professionals requires a robust emphasis and the necessary support infrastructure to encourage and develop practitioners to follow a clinical academic career pathway. Clinical academic partnerships between higher education and healthcare institutions can offer a blend of required expertise with mutual benefits. This article reports on a recent Florence Nightingale Foundation and Council of Deans of Health Leadership Scholarship improvement project to establish an infrastructure to support the development of clinical academic roles to enhance the provision of evidence-based patient care in the North East of Scotland. PMID- 29240467 TI - Changing practice for hip arthroplasty and its implications. AB - This overview provides insight into changes in clinical practice and the implications for nursing staff and clinicians who are involved in the management of patients undergoing primary total hip arthroplasty. The review highlights commonly used surgical approaches, their advantages, their associated risks and how to manage complications if they occur. PMID- 29240468 TI - A dual role focusing on continence and safeguarding: collaboration is key. PMID- 29240469 TI - Raising mental health literacy. PMID- 29240470 TI - The overlooked population. PMID- 29240471 TI - Nurse-led clinics for atrial fibrillation: managing risk factors. AB - Atrial fibrillation (AF) is the most common and sustained cardiac arrhythmia rated by cardiologists as one of the most difficult conditions to manage. Traditionally, AF management has focused on the three pillars of rate control, rhythm control and anticoagulation. However, more recently, cardiovascular risk factor management in AF has emerged as a fourth and essential pillar, delivering improved patient outcomes. In the UK, AF is a condition that is often managed poorly, with patients reporting a lack of understanding of their condition and treatment options. Many aspects of assessment and communication in AF management are time consuming. Failure to address those aspects may negatively affect the quality of care. Nurse-led clinics can contribute significantly in the areas of patient education and sustained follow-up care, improving outcomes and addressing current deficiencies in AF risk-factor management due to scarcity of medical resources. This article discusses the major cardiovascular risk factors associated with AF, drawing on evidence from the literature, and considers the effectiveness and implications for practice of introducing community-based nurse led clinics for risk-factor management in patients with AF. PMID- 29240472 TI - Can we improve care and save money? AB - Sam Foster, Chief Nurse, Oxford University Hospitals, considers the Secretary of State for Health's argument that safe care costs less. PMID- 29240473 TI - Stoma care in a time of financial pressures: can we cut the costs? AB - Andrew Bird, Lead Stoma Care Nurse Specialist, Colorectal and Stoma Care, Surgery Division, Queen's Medical Centre Campus, Nottingham University Hospitals NHS Trust, Andrew.Bird@nuh.nhs.uk. PMID- 29240474 TI - The Government's progress in promoting choice in end-of-life care. AB - Emeritus Professor Alan Glasper, University of Southampton, discusses the effectiveness of measures to deliver personalisation and choice in care for people nearing the end of life. PMID- 29240475 TI - Avoiding emergency stoma surgery with the use of sugar. AB - George Theofanis, Mahmud Saedon, Soo Hua Kho, Francesk Mulita, Stylianos Germanos and Edmund Leung discuss the use of sugar as an aid to reducing a stomal prolapse. PMID- 29240476 TI - The state of care in England: time for a post-match analysis. AB - John Tingle, Associate Professor (Teaching and Scholarship), Nottingham Trent University, discusses the Care Quality Commission's annual assessment of health and social care in England. PMID- 29240477 TI - Time for a measuring stick. PMID- 29240478 TI - Celebrating advancing practice. AB - Julia Williams, Senior Lecturer-Adult Nursing, Postgraduate Diploma Programme Lead, Buckinghamshire New University, julia.williams@bucks.ac.uk. PMID- 29240480 TI - Parastomal hernia: the need for consistency in prevention and management. AB - Wendy Osborne, Educational Officer, ASCN UK, and Clinical Lead Ostomy Division, Coloplast Ltd, summarises the ASCN UK parastomal hernia workshop, which took place at the ASCN UK 2017 annual conference. PMID- 29240479 TI - Nursing and the barriers to sustainable health care: a literature review. AB - OBJECTIVES: global warming poses a serious threat to human health, yet healthcare organisations and staff have been relatively slow to engage with sustainable healthcare practices. This review of the literature seeks to frame what is already known about nurses and their views on global warming and sustainable health care. DESIGN: 11 primary research articles were sourced from a search of five mainstream databases. These articles were subject to a basic thematic analysis. RESULTS: six themes were identified: sustainability, endemic blindness to global issues, environmental numbness, social norms, priority assigned to sustainability, and psychology of responsibility and blame. CONCLUSION: from the literature reviewed, there are a number of social, cultural and psychological barriers that have led to widespread inaction. This article recommends further research to understand the psychological barriers in more depth as this is a poorly understood area. PMID- 29240481 TI - From staff nurse to nurse consultant: Spiritual care part 9: Judaism. AB - John Fowler, Educational Consultant, explores the considerations for clinically based nurses when caring for patients who follow Judaism. PMID- 29240482 TI - Response to Time for a measuring stick. PMID- 29240483 TI - Evaluating a nurse scholarship programme: realising potential. AB - Evaluation is an integral component of any nurse education programme and ideally requires a multi-method approach. This article describes both the formative and summative evaluation of the St Mark's Burdett nurse scholarship from the perspective of the health professionals involved. During the nursing scholar's specialty placements, their achievements were recorded alongside a more detailed insight into their ongoing development during weekly supervision sessions. The summative evaluation comprised recording their attendance at taught study days, progress in academic modules and one-to-one interviews. A survey was also conducted to gather feedback about the scholarship. The evaluation indicated that this programme helped the nursing scholars gain exposure to a broad range of gastrointestinal nursing clinical environments, provided them with the resources needed to continue to develop academically and professionally, and helped them to achieve career progression in specialist nursing. PMID- 29240484 TI - A specialist in research and practice. AB - Gabrielle Thorpe, Lecturer in Nursing Sciences, University of East Anglia and Honorary Colorectal & Stoma Care Specialist Nurse, Norfolk and Norwich University Hospitals NHS Foundation Trust, Gabrielle.Thorpe@uea.ac.uk. PMID- 29240485 TI - Preparing for future incapacity. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, discusses the options available for those preparing for the future when ill health may affect their capacity to make decisions about their care. PMID- 29240486 TI - ASCN UK Guideline: parastomal hernias. PMID- 29240487 TI - Treating chronic constipation and faecal incontinence using transanal irrigation. PMID- 29240488 TI - Encouraging political participation among the next generation. AB - Elizabeth Rosser, acting Executive Dean, Deputy Dean for Education and Professional Practice, and Professor of Nursing at Bournemouth University, discusses how nurses can be encouraged to be politically engaged. PMID- 29240489 TI - Recognising and assessing care needs in patients with dementia: the three Ds. AB - Aysha Mendes, Freelance Journalist, specialising in health, psychology and nursing, aysha.freelance@gmail.com. PMID- 29240491 TI - Sir Adolphe Abrahams: physician and Olympics medical officer. PMID- 29240492 TI - Interprofessional bedside teaching: setting up a novel teaching programme. AB - BACKGROUND: An ageing population and health-care advances mean that patients have increasingly complex medical health and social needs, requiring a multidisciplinary team. However, despite working as an interprofessional team, team members still largely train in professional silos. Furthermore health-care professionals report a poor understanding of the skills of colleagues from different professions. This article describes the set up and outcomes of a novel interprofessional bedside teaching programme. METHODS: An in-centre interprofessional teacher training course was established to facilitate interprofessional bedside teaching, along with supported ward-based sessions to apply the skills. RESULTS: Three in-centre courses and five workplace sessions have run, with forty-five and twenty-eight interprofessional participants respectively. Statistically significant improvements in confidence facilitating interprofessional teaching were seen, with participants more likely to teach at the bedside and involve the multidisciplinary team. CONCLUSIONS: This article shows evidence of a teaching programme which improves the confidence of the multidisciplinary team in facilitating interprofessional bedside teaching. PMID- 29240493 TI - Atopic dermatitis. PMID- 29240494 TI - Prehabilitation. PMID- 29240496 TI - Clinical News. PMID- 29240495 TI - Stenotrophomonas maltophilia CSF infection in infants after neurosurgery. PMID- 29240498 TI - A challenging skin lesion. PMID- 29240497 TI - Adjuvant analgesics in spinal surgery. AB - Peri- and postoperative pain control can present a challenge to any doctor, particularly in the setting of spinal surgery. The use of adjuvant pain agents and multimodal analgesia is changing the face of modern anaesthesia and offering clinicians more avenues to control perioperative pain. This article discusses the use of adjuvant medications and some of the evidence surrounding their use in spinal surgery. PMID- 29240499 TI - Disseminated nocardiosis in a liver transplant patient. PMID- 29240500 TI - Bisphosphonate-related proximal femoral insufficiency fractures. PMID- 29240501 TI - Delivering the future hospital. PMID- 29240502 TI - Should thoracic epidurals be routinely sited in patients having cardiac surgery? PMID- 29240503 TI - Best practice in care for preterm infants. PMID- 29240504 TI - Listeria infection presenting as myositis and rhabdomyolysis, needing renal replacement. PMID- 29240505 TI - Hoarseness in children. AB - Hoarseness or dysphonia are terms used to describe a change in the quality of the voice. The voice quality can be raspy, breathy, strained, fatigued, rough, tremulous or weak. There may be a change in pitch, restriction of range, voice breaks, decreased projection, or abnormal resonance. It is important to remember that a voice disorder is not a disease in itself but rather a presentation of an underlying pathology. Clinicians' knowledge of paediatric hoarseness is limited as it can be difficult to examine children using fibreoptic laryngoscopy and the child may not comprehend the need for detailed examination. However, paediatric flexible naso-laryngoscopy provides a dynamic view of the laryngeal anatomy and function. Recent advances in diagnostic equipment, pharmacology and therapeutics mean that this problem can be managed more successfully but it still remains a challenge. This article discusses the presentation, aetiology and management of hoarseness in children. PMID- 29240506 TI - Preventing peripheral venous catheter-related Staphylococcus aureus bacteraemia. PMID- 29240507 TI - Neonatal jaundice: aetiology, diagnosis and treatment. AB - A significant proportion of term and preterm infants develop neonatal jaundice. Jaundice in an otherwise healthy term infant is the most common reason for readmission to hospital. Jaundice is caused by an increase in serum bilirubin levels, largely as a result of breakdown of red blood cells. Bilirubin is conveyed in the blood as 'unconjugated' bilirubin, largely bound to albumin. The liver converts bilirubin into a conjugated form which is excreted in the bile. Very high levels of unconjugated bilirubin are neurotoxic. Phototherapy is a simple and effective way to reduce the bilirubin level. Most term babies have 'physiological' jaundice which responds to a short period of phototherapy, and requires no other treatment. A few babies have rapidly rising bilirubin levels which place them at risk of kernicterus. Current management of jaundice in the UK is guided by the NICE guideline. Any infant with high serum bilirubin or a rapidly rising bilirubin level needs to be treated urgently to avoid neurotoxicity. High levels of conjugated bilirubin in a term baby can indicate biliary atresia, and babies with persisting jaundice must have their level of conjugated bilirubin measured. Preterm infants on long-term parenteral nutrition may develop conjugated jaundice which generally improves with the introduction of enteral feed and weaning of intravenous nutrition. PMID- 29240508 TI - Medical complications of bulimia nervosa. AB - Bulimia nervosa is a psychiatric disorder with many different medical sequelae. This article reviews the principal medical complications associated with bulimia nervosa, and emphasizes the importance of a timely approach to diagnosis and management. PMID- 29240509 TI - Mild bleeding disorders: what every clinician should know. AB - Patients with mild bleeding disorders are under-recognized and frequently present to general physicians. The underlying reasons for bleeding are multifactorial. There is little evidence to guide diagnostic and management decision making in patients with mild bleeding disorders. This article outlines different types of mild bleeding disorders, with a particular focus on bleeding associated with low levels of von Willebrand factor and mild platelet defects. It gives practical, evidence-based advice on the investigation and management of patients with a suspected or known mild bleeding disorder, considering the scenarios of an acute bleed, stable outpatient, peri-surgical management and thrombosis. Patients with a mild bleeding disorder have variable bleeding because of the interplay of genetic and environmental factors. The clinical history remains of utmost importance in their general management. Liaison with a specialist centre, multidisciplinary assessment and a careful judgement of the balance of risk in each individual circumstance is required to safely manage these patients. PMID- 29240510 TI - Equipment needs for premature babies in special care or intensive care. AB - Neonates who require additional care, be it in a special care baby unit, neonatal intensive care unit or just on the labour ward, may need specific equipment to allow the team to care for them accurately and safely. This article outlines some of the specific types of equipment which may be needed. PMID- 29240511 TI - Meeting the nutritional needs of premature babies: their future is in our hands. AB - The goals of early nutrition in preterm infants are to provide all the necessary vital nutrients, achieve extra-uterine growth rates similar to fetuses of the same gestational age, and support functional neurodevelopmental outcomes that are comparable to those of infants born at term. It is vital to provide nutrition that will maximally support brain growth and development, but over-feeding with accelerated growth, fat accumulation and long-term metabolic consequences should also be avoided. Because the morbidity associated with prematurity increases nutritional and energetic demands, the basic approach is of providing early intensive nutrition. Protein is the main driving force for growth and brain development. Since deficits in protein occur from the first day of extra-uterine life, sufficient quantities of parenteral amino acids should be provided from the first hours of life. With protein and carbohydrates, enough energy should also be provided, via concomitant early administration of intravenous lipid emulsions. Early initiation of enteral feeding with advancement to full enteral nutrition is associated with better maturation of the gut and better neuro-developmental outcomes. Human milk is the best food for preterm babies, although enrichment may be needed. PMID- 29240512 TI - Percutaneous image-guided lung biopsy. PMID- 29240513 TI - Examination of a third nerve palsy. PMID- 29240514 TI - Menopausal asthma-much ado about nothing? An observational study. AB - OBJECTIVE: Menopausal asthma is considered a distinct asthma phenotype. Our aim was to identify potential specific features of asthma in postmenopausal women in a cohort of Polish females. METHODS: Asthma severity and control, pulmonary function, exhaled nitric oxide (FENO), peripheral blood and induced sputum (IS) differential cell count were compared in three groups: women with premenopausal asthma (group 1), menopausal women with pre-existing asthma (group 2A) and menopausal women with asthma onset in the perimenopausal or menopausal period (group 2B). RESULTS: We enrolled 27 women to group 1, 13 to group 2A and 16 to group 2B. Asthma severity and control, blood eosinophil count and FENO did not differ among the groups. Menopausal women had a higher incidence of irreversible airway obstruction (84.6% in group 2A and 56.2% in group 2B vs. 22.2% in group 1, p < 0.001 and p = 0.03, respectively). The proportion of patients with sputum eosinophilia was highest in menopausal women with pre-existing asthma, although the difference did not reach statistical significance (88.9% in group 2A vs. 66.7% in group 2B and 65.0% in group 1, respectively, p = 0.86). CONCLUSIONS: Menopausal women with asthma are characterized by an increased incidence of irreversible airway obstruction regardless of disease duration. This may indicate that age may contribute to pulmonary function impairment in asthmatic women independently of their hormonal status at the time of asthma diagnosis. Our results failed to confirm the presence of specific asthma features which would allow to distinguish the phenotype of menopausal asthma. PMID- 29240515 TI - Binding modes of hERG blockers: an unsolved mystery in the drug design arena. PMID- 29240516 TI - Association Between Duration of Reproductive Years and Metabolic Syndrome. AB - BACKGROUND: The incidence of metabolic syndrome (MetS) has gradually increased in recent years. MetS has been associated with age at menarche and menopause; however, the association between MetS and the reproductive span remains unclear. MATERIALS AND METHODS: This study examined MetS and the reproductive span among 1,214 participants of the 2014 Korea National Health and Nutrition Examination Surveys, a stratified, complex, multistage, probability cluster survey conducted by the Division of Chronic Disease Surveillance of the Korea Center for Disease Control and Prevention since 1998. MetS was defined by using the joint interim statement of the International Diabetes Federation; National Heart, Lung, and Blood Institute; and American Heart Association. The reproductive span or duration of reproductive years was calculated from age at menarche to age at menopause for postmenopausal women. RESULTS: The prevalence of MetS in this study was 36% (437 of 1,214). In multivariate analysis adjusted for age, longer reproductive years were associated with a higher prevalence of MetS (odds ratio [OR] 1.059, 95% confidence interval [CI] 1.055-1.063). However, after adjusting for covariates (age, residential area, income, dyslipidemia medication, education, current smoking, regular exercise, alcohol consumption, body mass index, years after menopause, aspartate aminotransferase, alanine aminotransferase, and white and red blood cell counts), longer reproductive years were associated with a lower prevalence of MetS (OR 0.751, 95% CI 0.745-0.747). CONCLUSION: Longer reproductive years were significantly associated with a decreased prevalence of MetS. PMID- 29240517 TI - Sensory Processing Patterns in Autism, Attention Deficit Hyperactivity Disorder, and Typical Development. AB - AIMS: The purpose of this study was to examine sensory processing in children ages 3-14 years with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and typical development (TD) using the Sensory Profile 2nd Edition (Dunn, 2014). METHODS: Participants included 239 children (ASD = 77; ADHD = 78; TD = 84) matched on age and gender. Multivariate analysis of covariance was used to compare the extent to which the three grsoups differed on sensory processing patterns (i.e., sensitivity, avoiding, registration, seeking) and sensory systems (i.e., auditory, visual, touch, movement, body position, oral, conduct, attention, social). We also examined the effect of chronological age. RESULTS: Children with ASD and ADHD did not differ in sensory processing patterns which were elevated as compared to a TD group. Children with ASD showed the highest rate of oral processing differences, followed by ADHD and TD. Children with ADHD had higher visual processing scores than children with ASD and TD. Older children had lower scores for seeking, auditory, visual, movement, touch, and conduct than younger children, regardless of diagnosis. CONCLUSIONS: Findings suggest that sensory features may be an area of overlap of behaviors in ASD and ADHD, which may have implications for intervention approaches for children with these conditions. PMID- 29240518 TI - Does Dosage Matter? A Pilot Study of Hand-Arm Bimanual Intensive Training (HABIT) Dose and Dosing Schedule in Children with Unilateral Cerebral Palsy. AB - AIM: We compared the efficacy of hand-arm bimanual intensive training (HABIT) in two doses (90 vs. 45 hours) and two schedules of the same dose (90 vs. 2 * 45 hours) on hand and daily functioning. METHOD: Eighteen children with unilateral cerebral palsy were randomized to receive 6 hours of daily training over 3 weeks, totaling 90 hours (Group 90, n = 9) or receive 6 hours of daily training over 1.5 weeks, totaling 45 hours (Group 2 * 45, n = 9). After 6 months, Group 2 * 45 received an additional 45 hours. Hand (Jebsen-Taylor Test of Hand Function, Assisting Hand Assessment) and daily functioning tests (Canadian Occupational Performance Measure, Pediatric Evaluation of Disability Inventory) were administered before, immediately after, and 6 months after interventions. RESULTS: Both groups demonstrated significant improvements in hand and daily functioning after 90 hours (Group 90) or the first 45 hours (Group 2 * 45), without differences between groups. However, more children from Group 90 obtained smallest detectable differences in the Assisting Hand Assessment. The addition of the second bout of 45 hours (Group 2 * 45) did not lead to further improvements. CONCLUSIONS: As this study was powered to test for large differences between groups, future investigations on larger samples will be needed to compare differences at the two dosage levels. PMID- 29240519 TI - Don't Want to Look Dumb? The Role of Theories of Intelligence and Humanlike Features in Online Help Seeking. AB - Numerous studies have shown that individuals' help-seeking behavior increases when a computerized helper is endowed with humanlike features in nonachievement contexts. In contrast, the current research suggests that anthropomorphic helpers are not universally conducive to help-seeking behavior in contexts of achievement, particularly among individuals who construe help seeking as a display of incompetence (i.e., entity theorists). Study 1 demonstrated that when entity theorists received help from an anthropomorphized (vs. a nonanthropomorphized) helper, they were more concerned about negative judgments from other people, whereas incremental theorists were not affected by anthropomorphic features. Study 2 showed that when help was provided by an anthropomorphized (vs. a nonanthropomorphized) helper, entity theorists were less likely to seek help, even at the cost of lower performance. In contrast, incremental theorists' help-seeking behavior and task performance were not affected by anthropomorphism. This research deepens the current understanding of the role of anthropomorphic computerized helpers in online learning contexts. PMID- 29240520 TI - Draft Whole Genome Sequence Analyses on Pseudomonas syringae pv. actinidiae Hypersensitive Response Negative Strains Detected from Kiwifruit Bleeding Sap Samples. AB - Kiwifruit bleeding sap samples, collected in Italian and Chilean orchards from symptomatic and asymptomatic plants, were evaluated for the presence of Pseudomonas syringae pv. actinidiae, the causal agent of bacterial canker. The saps were sampled during the spring in both hemispheres, before the bud sprouting, during the optimal time window for the collection of an adequate volume of sample for the early detection of the pathogen, preliminarily by molecular assays, and then through its direct isolation and identification. The results of molecular analyses showed more effectiveness in the P. syringae pv. actinidiae detection when compared with those of microbiological analyses through the pathogen isolation on the nutritive and semiselective media selected. The bleeding sap analyses allowed the isolation and identification of two hypersensitive response (HR) negative and hypovirulent P. syringae pv. actinidiae strains from different regions in Italy. Moreover, multilocus sequence analysis (MLSA) and whole genome sequence (WGS) were carried out on selected Italian and Chilean P. syringae pv. actinidiae virulent strains to verify the presence of genetic variability compared with the HR negative strains and to compare the variability of selected gene clusters between strains isolated in both countries. All the strains showed the lack of argK and coronatine gene clusters as reported for the biovar 3 P. syringae pv. actinidiae strains. Despite the biologic differences obtained in the tobacco bioassays and in pathogenicity assays, the MLSA and WGS analyses did not show significant differences between the WGS of the HR negative and HR positive strains; the difference, on the other hand, between PAC_ICE sequences of Italian and Chilean P. syringae pv. actinidiae strains was confirmed. The inability of the hypovirulent strains IPV-BO 8893 and IPV-BO 9286 to provoke HR in tobacco and the low virulence shown in this host could not be associated with mutations or recombinations in T3SS island. PMID- 29240521 TI - Challenges with modelling anxiety disorders: a possible hindrance for drug discovery. PMID- 29240522 TI - Stakeholder views addressing the development and uptake of powered wheelchair assistive technology. AB - PURPOSE: The objective of this research is to identify stakeholder views with regard to the development of effective powered wheelchair assistive technologies more suited to the user and carer needs, whilst also meeting the requirements for other stakeholders, such that developers can be better guided towards producing solutions which have a better chance of getting to the market place and hence to the end user. METHOD: A questionnaire was designed to collect the views of all stakeholders and circulated to a statistically representative number of them. The question rating data were then checked for correlation between groups, and within groups, to establish validity. RESULTS: The 74 stakeholders across the eight classes who responded had a good correlation between each other, with a cross class "Pearson's correlation" ranging between 0.7 and 0.95, and the "Fleiss's Kappa reliability of agreement" within each class ranging between 0.07 and 0.36. CONCLUSIONS: This research has identified that all stakeholders should be involved in the development of the technology and that some may benefit in 'role reversal' to help understand user problems and stakeholder concerns more clearly. Cost was a significant barrier to the uptake of appropriate technology, and training of users and carers was a major issue. Furthermore, development should not increase user isolation and the impact on the user must be monitored for 'quality of life'. Technical support and training should be given to the user and their carers, and equipment must be adaptive to meet the changing needs of the user. Implications for Rehabilitation Improved acceptance and use of technology by the user and their carers. Reduced rejection of appropriate provision. Improved mobility and interaction with others. Improved quality of life for users and carers. PMID- 29240523 TI - Injectable-platelet rich fibrin using the low speed centrifugation concept improves cartilage regeneration when compared to platelet-rich plasma. AB - The aim of the present study was to evaluate the effect of injectable platelet rich fibrin (i-PRF) on cultivated chondrocytes and osteochondral regeneration in critical-sized osteochondral defect of the rabbit's knee in comparison to autologous platelet-rich plasma (PRP). Chondrocytes were first investigated for their ability to proliferate and differentiate in response to PRP and i-PRF. Thereafter, full-thickness critical-sized osteochondral defects 5 mm in diameter and 5 mm in depth were created in the knee joint of 12 adult female New Zealand White rabbits. Defects were regenerated with either PRP or i-PRF and compared to control. Animals were sacrificed at 4 and 12 weeks postoperatively and evaluated histologically by macroscopic and microscopic examination for cartilage regeneration. i-PRF significantly promoted chondrocyte proliferation and mRNA levels of Sox9, collagen type II, and aggrecan when compared to PRP and control. Histological analysis revealed that at 4 weeks, macroscopic ICRS scores from the i-PRF group were significantly enhanced when compared to the PRP and control groups. At 12 weeks post surgery, the microscopic ICRS scores demonstrated that the i-PRF group significantly improved cartilage regeneration when compared to PRP. In conclusion, the use of i-PRF using the low speed centrifugation concept significantly promoted chondrocyte activity and further improved cartilage regeneration when compared to PRP. The histological results revealed early and better cartilage regeneration within 4 weeks postoperatively when i-PRF was utilized and the results were maintained at 12 weeks. Future clinical studies are now needed investigating the regenerative potential of i-PRF in comparison to PRP for knee regeneration. PMID- 29240524 TI - Professionals learning together with patients: An exploratory study of a collaborative learning Fellowship programme for healthcare improvement. AB - Improving the quality of healthcare involves collaboration between many different stakeholders. Collaborative learning theory suggests that teaching different professional groups alongside each other may enable them to develop skills in how to collaborate effectively, but there is little literature on how this works in practice. Further, though it is recognised that patients play a fundamental role in quality improvement, there are few examples of where they learn together with professionals. To contribute to addressing this gap, we review a collaborative fellowship in Northwest London, designed to build capacity to improve healthcare, which enabled patients and professionals to learn together. Using the lens of collaborative learning, we conducted an exploratory study of six cohorts of the year long programme (71 participants). Data were collected using open text responses from an online survey (n = 31) and semi-structured interviews (n = 34) and analysed using an inductive open coding approach. The collaborative design of the Fellowship, which included bringing multiple perspectives to discussions of real world problems, was valued by participants who reflected on the safe, egalitarian space created by the programme. Participants (healthcare professionals and patients) found this way of learning initially challenging yet ultimately productive. Despite the pedagogical and practical challenges of developing a collaborative programme, this study indicates that opening up previously restricted learning opportunities as widely as possible, to include patients and carers, is an effective mechanism to develop collaborative skills for quality improvement. PMID- 29240525 TI - Building U.S. Capacity to Review and Prevent Maternal Deaths. AB - In the United States, the risk of death during and up to a year after pregnancy from pregnancy-related causes increased from ~10 deaths per 100,000 live births in the early 1990s to 17 deaths per 100,000 live births in 2013. While vital statistics-based surveillance systems are useful for monitoring trends and disparities, state and local maternal mortality review committees (MMRCs) are best positioned to both comprehensively assess deaths to women during pregnancy and the year after the end of pregnancy, and identify opportunities for prevention. Although the number of committees that exist has increased over the last several years, both newly formed and long-established committees struggle to achieve and sustain progress toward reviewing and preventing deaths. We describe the key elements of a MMRC; review a logic model that represents the general inputs, activities, and outcomes of a fully functional MMRC; and describe Building U.S. Capacity to Review and Prevent Maternal Deaths, a recent multisector initiative working to remove barriers to fully functional MMRCs. Increased standardization of review committee processes allows for better data to understand the multiple factors that contribute to maternal deaths and facilitates the collaboration that is necessary to eliminate preventable maternal deaths in the United States. PMID- 29240526 TI - Wells syndrome secondary to influenza vaccination: A case report and review of the literature. AB - Vaccinations have been shown repeatedly to be extremely safe with low incidence of complications. Given the rarity, these adverse events, they must be reported and examined cautiously. This case report illustrates the first case of an adult presenting with Wells syndrome that developed soon after vaccination with the thiomersal, a common preservative, containing influenza vaccine. Wells syndrome, also known as eosinophilic cellulitis, is an uncommon dermatologic condition of unknown etiology. Lesions in patients with Wells syndrome (eosinophilic cellulitis) progress over a few days to become large indurated plaques with associated edema and erythema. Although the etiology of Wells syndrome remains unknown, certain precipitants have been described in the literature, including but not limited to parasitic infections, contact dermatitis, Churg-Strauss disease and various medications. This article describes a possible sensitivity to thiomersal, as well as describes other cases that have reported a similar sensitivity secondary to receiving thiomersal-containing vaccines. PMID- 29240528 TI - Associations Between Sexual Risk-Related Behaviors and School-Based Education on HIV and Condom Use for Adolescent Sexual Minority Males and Their Non-Sexual Minority Peers. AB - PURPOSE: With HIV and sexually transmitted disease (STD) rates disproportionately high among adolescent sexual minority males (ASMM), it is important to understand how school-based sexual health education may relate to sexual risk-related behavior among this population. This analysis explores reported HIV/AIDS- and condom-related education and sexual risk-related behaviors among ASMM and their adolescent non-sexual-minority male (non-ASMM) peers. METHODS: Students (n = 11,681) from seven Florida high schools completed paper-and-pencil questionnaires. A matched analytic sample of ASMM and non-ASMM students was created by using propensity score-matching techniques (n = 572). Logistic regressions controlling for individual and school characteristics examined reporting having been taught about AIDS or HIV in school, having been taught in school about using condoms, condom use at last sex, HIV/STD testing, and associations between these variables. RESULTS: Compared with matched non-ASMM peers, ASMM students were less likely to report having been taught about AIDS or HIV in school (odds ratio [OR] = 0.58, P = 0.04) and having used a condom at last sex (OR = 0.39, P < 0.01), but were more likely to report having been tested for HIV or STDs (OR = 1.88, P = 0.02). There were no significant differences for reporting having been taught in school about using condoms. Among non-ASMM, reporting having been taught in school about using condoms was associated with a greater likelihood of condom use at last sex (OR = 4.78, P < 0.01); this was not seen for ASMM. CONCLUSIONS: Differential reports of receiving HIV/AIDS education and differential associations between condom-related education and condom use in ASMM and non-ASMM suggest that sexual health education in schools may not be resonating with ASMM and non-ASMM in the same way. PMID- 29240527 TI - Depressive Symptom Prevalence and Predictors in the First Half of Pregnancy. AB - INTRODUCTION: Major depression during the peripartum (MDP) period carries significant public health impact due to the potential adverse effects on maternal, infant, and family outcomes. METHODS: As part of a larger longitudinal study, this cross-sectional observational study sought to build upon the current literature on the prevalence and predictors of depression in the early second trimester of pregnancy, as related to generally accepted risk factors and other less explored risk factors. RESULTS: The findings from this study suggest that in this sample of 230 black and white women at ~14 weeks gestation, ~19% endorsed depressive symptoms and that the most important predictors of depression in pregnancy were a preconception history of a mental health issue (e.g., lifetime depressive episode) and perceived stress. Other relevant predictors were pregnancy-related anxiety, income, and stressful life events. CONCLUSION/CLINICAL RELEVANCE: It is important for clinicians not only to screen for MDP during prenatal visits by asking about current depressive, stress, and anxiety symptoms but also to identify patients at risk for MDP by asking simple questions about history of preconception/lifetime episodes of depression and stressful life events. Given the variance accounted for by lifetime depression, additional research into how clinicians may approach this important topic is warranted. For example, checklists given in the waiting room may be less likely to elicit endorsement compared with conversations aimed to normalize the range of depressive histories that may have relevance to obstetric health. PMID- 29240529 TI - Cross-sectional associations between gender-linked personality traits and use of weight-loss and muscle-building products among U.S. young adults. AB - This study examined the cross-sectional associations between gender-linked personality traits and use of products for weight loss and muscle building using data from young adults participating in Wave III of the National Longitudinal Study of Adolescent to Adult Health who completed the short-form Bem Sex-Role Inventory (n = 3,343). Among men, a higher score on the masculinity scale was associated with greater odds of diet pill use, legal performance-enhancing substance (PES) use, and illicit PES use, while a higher score on the femininity scale was associated with lower odds of illicit PES use. These findings can inform interventions for men with weight/shape concerns. PMID- 29240530 TI - Mobile Integrated Healthcare Intervention and Impact Analysis with a Medicare Advantage Population. AB - Mobile Integrated Healthcare (MIH) is a patient-centered, innovative delivery model offering on-demand, needs-based care and preventive services, delivered in the patient's home or mobile environment. An interprofessional MIH clinical team delivered a care coordination program for a Medicare Advantage Preferred Provider Organization that was risk assigned prior to intervention to target the highest risk members. Using claims and eligibility data, 6 months of pre-program experience and 6 months of program-influenced experience from the intervention cohort was compared to a propensity score-matched comparison cohort to measure impact. The intervention led to a reduction in inpatient and emergency department utilization, resulting in net savings amount totals of $2.4 million over the 6 months of the program. After accounting for the costs of implementing the program, the intervention produced a return on investment of 2.97. Additionally, high patient activation and experience lend strength to this MIH intervention as a promising model to reduce utilization and costs while keeping patient satisfaction high. PMID- 29240531 TI - Enhancing Dignity for Older Inpatients: The Photograph-Next-to-the-Bed Study. AB - OBJECTIVES: Older inpatients compromised by illness and cognitive decline may be stripped of physical and cultural identifiers, making them vulnerable to erosion of dignity. This study explored the experiences of patients, carers and clinical staff in response to a simple intervention that could enhance the dignity of care for older inpatients. METHODS: All patients in a rehabilitation ward were encouraged to have a photograph of themselves next to their bed. Of those who participated, focus groups were recruited for patients, family members and staff to explore their reflections. Discussions were transcribed and analyzed using a deductive approach to capture evolving themes relating to patient care. RESULTS: All groups reported that the photograph provided "connection" and means of communication between patients and staff. Staff spoke positively of gaining additional insights into patients' lives. Benefits included enrichment of inter personal relationships between patients and staff, between staff and families and between patients themselves. CONCLUSIONS: A bedside photograph improved connections between staff, patients and carers, promoting patients' dignity of identity. CLINICAL IMPLICATIONS: Displaying a bedside photograph as a visual reminder of the patient in the pre-illness state helps preservation of an individual's dignity, a core concept in patient-centered care. PMID- 29240532 TI - Norms and stigma around unintended pregnancy in Alabama: Associations with recent contraceptive use and dual method use among young women. AB - BACKGROUND: The role of unintended pregnancy norms and stigma in contraceptive use among young women is understudied. This study investigated relationships between anticipated reactions from others, perceived stigma, and endorsed stigma concerning unintended pregnancy, with any and dual contraceptive use in this population. METHODS: From November 2014 to October 2015, young women aged 18-24 years (n = 390) and at risk for unintended pregnancy and sexually transmitted infections participated in a survey at a university and public health clinics in Alabama. Multivariable regression models examined associations of unintended pregnancy norms and stigma with contraceptive use, adjusted for demographic and psychosocial characteristics. RESULTS: Compared to nonusers, more any and dual method users, were White, nulliparous, and from the university and had higher income. In adjusted models, anticipated disapproval of unintended pregnancy by close others was associated with greater contraceptive use (adjusted Odds Ratio [aOR] = 1.54, 95 percent confidence interval [CI] = 1.03-2.30), and endorsement of stigma concerning unintended pregnancy was associated with lower odds of dual method use (aOR = 0.71, 95 percent CI = 0.51-1.00). CONCLUSION: Unintended pregnancy norms and stigma were associated with contraceptive behavior among young women in Alabama. Findings suggest the potential to promote effective contraceptive use in this population by leveraging close relationships and addressing endorsed stigma. PMID- 29240533 TI - Investigation of Perceptual-Motor Behavior Across the Expert Athlete to Disabled Patient Skill Continuum can Advance Theory and Practical Application. AB - A framework is presented of how theoretical predictions can be tested across the expert athlete to disabled patient skill continuum. Common-coding theory is used as the exemplar to discuss sensory and motor system contributions to perceptual motor behavior. Behavioral and neural studies investigating expert athletes and patients recovering from cerebral stroke are reviewed. They provide evidence of bi-directional contributions of visual and motor systems to perceptual-motor behavior. Majority of this research is focused on perceptual-motor performance or learning, with less on transfer. The field is ripe for research designed to test theoretical predictions across the expert athlete to disabled patient skill continuum. Our view has implications for theory and practice in sports science, physical education, and rehabilitation. PMID- 29240534 TI - Non-Pharmacological Approaches to Pain Management in Residential Aged Care: a Pre Post-Test Study. AB - OBJECTIVES: The project aimed to evaluate a pain management program (PMP) using non-pharmacological approaches at five residential aged care facilities (RACFs) in Australia. METHODS: The PMP involved a physiotherapist implementing four sessions per week of treatments (massage therapy, TENS, exercises and stretching, or combinations of these). Ninety-five participants were recruited (average age, 83 years; SD = 7.6; 38% men, 62% women; 56% with dementia). Sessions lasted approximately 10 minutes, and residents' levels of pain were recorded using a 5 point scale before and after each treatment. The intervention period for each participant was the first consecutive 8 weeks in which they received the intervention. RESULTS: Data analyses showed: (1) a small but statistically significant decrease in the number of as required (PRN) medications; and (2) a decrease in average pain ratings from pre-session to post-session from 2.4 (some to moderate pain) to 1.1 (a little pain). Notably, residents with dementia received lower pain ratings than those without. CONCLUSIONS: Non-pharmacological approaches to pain in residential care settings are effective, especially when two or more are combined. Staff working in residential care settings should rely on best practice to recognise pain in residents with dementia. CLINICAL IMPLICATIONS: Non-pharmacological interventions may be effective in reducing pain and reliance on PRN medications in residential care settings, especially when two or more are used. Staff working in residential aged care settings should be provided with training in pain assessment and management, with particular attention to residents with dementia. PMID- 29240535 TI - Factors associated with waterpipe tobacco smoking among Lebanese women. AB - INTRODUCTION: Waterpipe tobacco smoking (WTS) has become a serious public health threat in the Middle East and beyond. OBJECTIVES: To estimate the prevalence rates of cigarette and WTS among Lebanese women and describe characteristics associated with each behavior. METHODS: Secondary analysis of women's health data obtained in a national survey in 2010. RESULTS: Of 2,255 selected women, 78 percent reported no or past long-term WTS. Among the 12 percent of regular waterpipe smokers, 40 percent were light users (mean three waterpipe heads weekly), while 60 percent were heavy users (mean of 11 heads per week). About 70 percent were never or past long-term cigarette smokers. Younger age, location within Greater Beirut (GB) and having professional employment were significantly associated with use of WTS. Older age, GB location, lower education, and ever married were significantly associated with cigarette smoking. CONCLUSIONS: WTS is becoming a socially normative behavior among empowered professional women, who can spare the time and expense to engage in this behavior in easily accessible cafes, which prohibit cigarette smoking. Public health implications: Government, media, and NGO campaigns against smoking should target waterpipe use, not only in Lebanon but also across the Arab world and among Arab communities in the Diaspora with messages different from anti-cigarette campaigns. PMID- 29240536 TI - Dementia Awareness Campaign in the Latino Community: A Novel Community Engagement Pilot Training Program with Promotoras. AB - OBJECTIVES: To create a curriculum about Alzheimer's disease and dementia, and to train Promotoras affiliated with a local community education and health advocacy organization, in order to raise awareness and knowledge of what dementia is, and how it can be recognized, in persons of Hispanic/Latino descent. METHODS: Community based participatory research (CPBR) model was used to create materials, implement training, and engage/empower Promotoras to educate the local community. RESULTS: Pre-post findings indicated a positive learning experience for the Promotoras and willingness to share new dementia information with their community. One year post-evaluative survey with a subset showed outreach to an average of 15-25 community members, indicating positive reception of this new information. CONCLUSIONS: CPBR model is a successful education and outreach tool with Latino communities. Our Dementia Awareness Campaign was a success with the first 20 Promotoras trained; at present we plan to train additional groups in nearby communities with significant Hispanic/Latino populations. CLINICAL IMPLICATIONS: In order to get Latinos to seek early detection, we need to first educate them about dementia, win trust, and encourage treatment-seeking. Early intervention, diagnosis, and prevention will benefit from educational campaigns using the CBPR model. PMID- 29240537 TI - Infertility and self-rated health among Malawian women. AB - BACKGROUND: Infertility is prevalent and stigmatized in sub-Saharan Africa. Self rated health, a subjective indicator that has been consistently related to objectively measured health, may be useful in evaluating the relationship between women's infertility and health. METHODS: Data were from surveys conducted from July 2014 to January 2015 with women aged 15-39 years (n = 915) as part of the initial assessment in a cohort study in Lilongwe district, Malawi. We first assessed correlates of self-reported infertility among women in rural Malawi. We then used multiple logistic regression to examine associations between infertility and self-rated health. RESULTS: Of women surveyed, 20 percent had a history of infertility. Compared to women who had not experienced infertility, women with a history of infertility were older (p = 0.05), less educated (p = 0.01), and more likely to report depressive symptoms (p = 0.02) and forced first intercourse (p = 0.02) and to have been previously diagnosed with a sexually transmitted infection (p = 0.05). However, women with a history of infertility were not significantly more likely to report poor self-rated health (adjusted odds ratio: 1.69; 95 percent confidence interval: 0.70-4.07). CONCLUSION: Infertility was prevalent in our sample of Malawian women but was not significantly related to self-rated health, an instrument widely used in public health research. PMID- 29240538 TI - Pathways to Infidelity: The Roles of Self-Serving Bias and Betrayal Trauma. AB - This study employed a structural equation modeling (SEM) approach to examine the interrelationships between the self-serving bias and various known predictors of sexual infidelity. Specifically, we sought to generate a path model depicting how the following variables jointly predict sexual infidelity perpetration: (1) insecure attachment, (2) pathological narcissism, (3) sexual narcissism, (4) primary psychopathy, (5) self-serving attributions for retaliatory infidelity, and (6) sexual betrayal victimization. We developed a structural model describing various pathways to sexual infidelity perpetration based on these six variables. Three pathways to infidelity were discovered. In the first pathway, anxious and avoidant attachment predicted primary psychopathy, and self-justification for retaliatory infidelity mediated the relationship between primary psychopathy and infidelity perpetration. In the second pathway, anxious attachment predicted sexual narcissism, which predicted self-justification for retaliatory infidelity, which in turn predicted infidelity perpetration. In the third pathway, being a victim of sexual betrayal directly predicted sexual infidelity perpetration. In fact, suffering sexual betrayal was the best predictor of sexual infidelity perpetration. The clinical implications of these findings are discussed. PMID- 29240539 TI - Is BRAF V600E Mutation the Explanation for Age-Associated Mortality Risk in Patients With Papillary Thyroid Cancer? PMID- 29240540 TI - Patient Age-Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer. AB - Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC. PMID- 29240541 TI - Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. AB - Purpose Retrospective studies suggest that metastasis-directed therapy (MDT) for oligorecurrent prostate cancer (PCa) improves progression-free survival. We aimed to assess the benefit of MDT in a randomized phase II trial. Patients and Methods In this multicenter, randomized, phase II study, patients with asymptomatic PCa were eligible if they had had a biochemical recurrence after primary PCa treatment with curative intent, three or fewer extracranial metastatic lesions on choline positron emission tomography-computed tomography, and serum testosterone levels > 50 ng/mL. Patients were randomly assigned (1:1) to either surveillance or MDT of all detected lesions (surgery or stereotactic body radiotherapy). Surveillance was performed with prostate-specific antigen (PSA) follow-up every 3 months, with repeated imaging at PSA progression or clinical suspicion for progression. Random assignment was balanced dynamically on the basis of two factors: PSA doubling time (<= 3 v > 3 months) and nodal versus non-nodal metastases. The primary end point was androgen deprivation therapy (ADT)-free survival. ADT was started at symptomatic progression, progression to more than three metastases, or local progression of known metastases. Results Between August 2012 and August 2015, 62 patients were enrolled. At a median follow-up time of 3 years (interquartile range, 2.3-3.75 years), the median ADT-free survival was 13 months (80% CI, 12 to 17 months) for the surveillance group and 21 months (80% CI, 14 to 29 months) for the MDT group (hazard ratio, 0.60 [80% CI, 0.40 to 0.90]; log-rank P = .11). Quality of life was similar between arms at baseline and remained comparable at 3-month and 1-year follow-up. Six patients developed grade 1 toxicity in the MDT arm. No grade 2 to 5 toxicity was observed. Conclusion ADT-free survival was longer with MDT than with surveillance alone for oligorecurrent PCa, suggesting that MDT should be explored further in phase III trials. PMID- 29240542 TI - Phase II Study of Everolimus in Patients With Thymoma and Thymic Carcinoma Previously Treated With Cisplatin-Based Chemotherapy. AB - Purpose No effective salvage treatments are available for patients with advanced/recurrent thymoma (T) or thymic carcinoma (TC) who have progressed after platinum-based chemotherapy. This study evaluated the activity of everolimus in patients with advanced/recurrent T or TC previously treated with cisplatin containing chemotherapy. Patients and Methods This was a single-arm, single stage, open-label, multicenter, phase II trial. Patients received oral everolimus 10 mg/d until disease progression, unacceptable toxicity, or patient refusal. A Fleming phase II trial was designed. The null hypothesis of a true disease control rate (DCR) of 40% was tested against a one-sided alternative of a true DCR of 60% (alpha = beta = 0.10): If disease control were achieved in >= 21 of the first 41 evaluable patients, everolimus could be recommended for further evaluation. Progression-free survival, overall survival, and safety were also evaluated. Results From 2011 to 2013, 51 patients were enrolled (T, n = 32; TC, n = 19). Complete remission was observed in one patient with TC, partial response in five patients (T, n = 3; TC, n = 2), and stable disease in 38 patients (T, n = 27; TC, n= 11), with a DCR of 88% (T,: 93.8%; TC, 77.8%). With a median follow up of 25.7 months, median progression-free survival was 10.1 months (T,: 16.6 months; TC, 5.6 months), and median overall survival was 25.7 months (T, not reached; TC, 14.7 months). Fourteen patients had a serious drug-related adverse event; of these patients, nine permanently discontinued treatment. Three patients died of pneumonitis while in the study. Immunohistochemical positivity for p4E BP1 or insulin-like growth factor-1 receptor was statistically significantly related to a shorter survival. Conclusion Everolimus may induce durable disease control in a high percentage of patients with T or TC, albeit with a potential high risk of fatal pneumonitis. PMID- 29240543 TI - STOMPing Out Hormone-Sensitive Metastases With Local Therapies in Prostate Cancer. PMID- 29240544 TI - Expected Time to Return to Athletic Participation After Stress Fracture in Division I Collegiate Athletes. AB - BACKGROUND: Few studies have documented expected time to return to athletic participation after stress fractures in elite athletes. HYPOTHESIS: Time to return to athletic participation after stress fractures would vary by site and severity of stress fracture. STUDY DESIGN: Retrospective cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: All stress fractures diagnosed in a single Division I collegiate men's and women's track and field/cross-country team were recorded over a 3-year period. Site and severity of injury were graded based on Kaeding Miller classification system for stress fractures. Time to return to full unrestricted athletic participation was recorded for each athlete and correlated with patient sex and site and severity grade of injury. RESULTS: Fifty-seven stress fractures were diagnosed in 38 athletes (mean age, 20.48 years; range, 18 23 years). Ten athletes sustained recurrent or multiple stress fractures. Thirty seven injuries occurred in women and 20 in men. Thirty-three stress fractures occurred in the tibia, 10 occurred in the second through fourth metatarsals, 3 occurred in the fifth metatarsal, 6 in the tarsal bones (2 navicular), 2 in the femur, and 5 in the pelvis. There were 31 grade II stress fractures, 11 grade III stress fractures, and 2 grade V stress fractures (in the same patient). Mean time to return to unrestricted sport participation was 12.9 +/- 5.2 weeks (range, 6-27 weeks). No significant differences in time to return were noted based on injury location or whether stress fracture was grade II or III. CONCLUSION: The expected time to return to full unrestricted athletic participation after diagnosis of a stress fracture is 12 to 13 weeks for all injury sites. CLINICAL RELEVANCE: Athletes with grade V (nonunion) stress fractures may require more time to return to sport. PMID- 29240545 TI - Screen viewing time and externalising problems in pre-school children in Northern Thailand. AB - OBJECTIVES: There are increasing reports of younger children accessing media and screen. This study aims to describe screen use in pre-school children and its association with externalising problems. METHODS: A cross-sectional study of pre schoolers aged two to five years was conducted. Their caregivers were asked to provide data regarding screen use by their children and themselves. The Child Behaviour Checklist (CBCL) was completed by caregivers to assess their child's behaviour. RESULTS: Participants included 200 caregivers of pre-school children. There were 47% of pre-schoolers who had used at least three types of media. When comparing the 0-1, >1 to 2, and >2 hours per day of screen viewing time groups, the children who had experienced more screen time also had significantly more background media and their caregivers had more screen time (p < 0.001). The externalising problem scores increased with more screen viewing time, although the relationship was not statistically significant. However, age and gender of the child were factors associated with externalising problems from the multiple linear regression analysis (p = 0.03). CONCLUSION: Pre-schoolers with more screen viewing time did not have a significantly greater externalising problem score than those with less screen time. A longitudinal study with a larger sample size would provide more information. PMID- 29240546 TI - The psychosocial themes of children with a congenital heart defect. AB - Children living with a congenital heart defect (CHD) carry the burden of a condition affecting their biological, psychological, and social functioning. Even though the physical heartbeats of these children might be inaudible and defective, their intra- and inter-personal 'stories in sound' need to be heard and understood. The aim of this research study was to explore these 'stories in sound' in children diagnosed with CHD. A qualitative, exploratory, descriptive study using thematic analysis was conducted. Semi-structured interviews were conducted with six boys and three girls between the ages of eight and fourteen years, who were diagnosed with CHD. The developmental psychopathology model (DPM) served as a conceptual framework. Five main themes emerged and were related to (i) the participants' understanding of their cardiac diagnoses; (ii) the participants' perceptions regarding their post-operative cardiac statuses; (iii) the participants' psychological experiences related to their cardiac statuses; (iv) the effects of living with CHD on their social functioning; and (v) a unique relationship to their chronic cardiac condition. Within each of these themes, thirteen subthemes were identified. The article concludes that an age-appropriate understanding of CHD and post-operative cardiac status is important, as children's perceptions have implications for their psychosocial experiences and acceptance of living with CHD. These children need comprehensive support from health care professionals. PMID- 29240547 TI - Implementing CDC's Level of Care Assessment Tool (LOCATe): A National Collaboration to Improve Maternal and Child Health. AB - Perinatal regionalization, or risk-appropriate care, is an approach that classifies facilities based on capabilities to ensure women and infants receive care at a facility that aligns with their risk. The CDC designed the Levels of Care Assessment Tool (LOCATe) to assist jurisdictions working in risk-appropriate care in assessing a facility's level of maternal and neonatal care aligned with the most current American College of Obstetricians and Gynecologists/Society for Maternal-Fetal Medicine (ACOG/SMFM) and American Academy of Pediatrics (AAP) guidelines. LOCATe produces standardized assessments for each hospital that participates and facilitates conversations among stakeholders in risk-appropriate care. This article describes how public health departments implement and use LOCATe in their jurisdictions. PMID- 29240549 TI - Interpreter-mediated Cognitive Assessments: Who Wins and Who Loses? AB - OBJECTIVES: The number of people with dementia from culturally and linguistically diverse (CALD) backgrounds is increasing dramatically in Australia. Accurate cognitive assessments of people from CALD backgrounds can be achieved with the use of skilled interpreters. This study aimed to explore the experience of interpreter-mediated assessments from the perspectives of clinicians, interpreters and carers. METHODS: Consultations with interpreters, clinicians and carers were conducted through individual interviews and focus groups. The consultations explored participants' experiences of interpreter-mediated assessments, including perception of the interpreting process, roles of interpreters, and challenges associated with interpreter-mediated assessments. RESULTS: Four themes emerged across groups: (1) the importance of having professional interpreters, (2) different perceptions of the roles of interpreters, (3) clinicians' feelings of having less control over assessments, and (4) particular challenges associated with cognitive assessments. CONCLUSIONS: Finding from this study highlight the important role that interpreters play in cognitive assessments with immigrants. However, there appears to be different perceptions of the role between clinicians and interpreters. When these different understandings are not resolved, they will lead to tension between clinicians and interpreters. These findings highlight the importance of relational aspects in interpreter-mediated assessment and suggest that the negotiation of the relationships between clinicians and interpreters is an important factor that determines the effectiveness and accuracy of these assessments. CLINICAL IMPLICATIONS: This study highlights the need for clinicians and interpreters education of roles of all parties in interpreter-mediated cognitive assessment. Areas to be covered in education could include: common misunderstandings of interpreters roles, and practice tips on how to improve communications in assessments, such as briefing before and after the assessment. Such education will enable more accurate assessment and less stress for patients and their families. PMID- 29240550 TI - The relationship between menopausal symptoms and sexual function. AB - Sexual function could be affected by several factors in postmenopausal women. This cross-sectional study aimed to investigate the relationship between the severity of menopausal symptoms and sexual function. The study was conducted among 405 postmenopausal women aged 40-65 years, in Chalous and Noshahr, Iran, from October 2013 to May 2014. The participants were selected using a multistage sampling method. The instruments used for data collection were the Female Sexual Function Index (FSFI), the Menopause Rating Scale (MRS), and a demographics questionnaire. The relationship between the severity of menopausal symptoms and sexual function was examined using Pearson's correlation coefficient and multiple linear and logistic regressions. The mean unadjusted FSFI and MRS scores were 24.11 and 12.45, respectively; and 61.0 percent of the participants had female sexual dysfunction (FSD) (FSFI <=26.55). A significant negative correlation was observed between the MRS scores (total and all subscales) and the total scores for FSFI (p < 0.001). The results of the logistic regression analysis showed that with every unit increase in the total score of MRS, the likelihood of sexual dysfunction was 9.6 percent greater. We conclude that menopausal symptoms need to be considered in the design of health initiatives aimed at postmenopausal women's sexual function. PMID- 29240551 TI - Time-Varying Effects of Parental Alcoholism on Depression. AB - INTRODUCTION: Children of alcoholic parents are at increased risk for lifetime depression. However, little is known about how this risk may change in magnitude across age, especially in mid-adulthood and beyond. METHODS: We used a nationally representative sample (N = 36,057) of US adults from the National Epidemiologic Survey on Alcohol and Related Conditions, wave III. After adjusting for demographic characteristics, we examined the relationship between parental alcoholism and outcomes of 1) major depressive disorder, Diagnostic and Statistical Manual of Mental Disorders-5th edition (DSM-5) and 2) DSM-5 persistent depressive disorder. To examine continuous moderation of this relationship across participants' age, we used time-varying effect models. RESULTS: Parental alcoholism was associated in general with a higher risk for both major depressive disorder (odds ratio [OR], 1.98, 95% confidence interval [CI], 1.85-2.11; P < .001) and persistent depressive disorder (OR, 2.28, 95% CI, 2.04-2.55; P < .001). The association between parental alcoholism and major depressive disorder was stable and positive across age, but the association with persistent depressive disorder significantly declined among older adults; respondents older than 73 years old were not at increased risk for persistent depressive disorder. CONCLUSIONS: Findings from this study show that the risk of parental alcoholism on depression is significant and stable among individuals of a wide age range, with the exception of a decline in persistent depressive risk among older adults. These findings highlight the importance of screening for depression among adults with parental alcoholism. PMID- 29240552 TI - Prevalence of and Trends in Diabetes Among Veterans, United States, 2005-2014. AB - Diabetes is a highly prevalent chronic disease among US adults, and its prevalence among US veterans is even higher. This study aimed to examine the prevalence of and trends in diabetes in US veterans by using data from the US National Health and Nutrition Examination Survey from 2005 through 2014. The overall prevalence of diabetes and undiagnosed diabetes was 20.5% and 3.4%, respectively, and increased from 15.5% in 2005-2006 to 20.5% in 2013-2014 (P = .04). Effective prevention and intervention approaches are needed to lower diabetes prevalence among US veterans and ultimately improve their health status. PMID- 29240553 TI - Promoting Children's Physical Activity in Low-Income Communities in Colorado: What Are the Barriers and Opportunities? AB - INTRODUCTION: Colorado has the highest rate of adult physical activity in the United States. However, children in Colorado have a lower rate of physical activity relative to other states, and the rate is lowest among children in low income households. We conducted focus groups, surveys, and interviews with parents, youth, and stakeholders to understand barriers to physical activity among children in low-income households in Colorado and to identify opportunities to increase physical activity. METHODS: From April to July 2016, we recruited participants from 5 communities in Colorado with high rates of poverty, inactivity, and obesity; conducted 20 focus groups with 128 parents and 42 youth; and interviewed 8 stakeholders. All focus group participants completed intake surveys. We analyzed focus group and interviews by using constant comparison. RESULTS: We identified 12 themes that reflect barriers to children's physical activity. Within the family context, barriers included parents' work schedules, lack of interest, and competing commitments. At the community level, barriers included affordability, traffic safety, illicit activity in public spaces, access to high-quality facilities, transportation, neighborhood inequities, program availability, lack of information, and low community engagement. Survey respondents most commonly cited lack of affordable options and traffic safety as barriers. Study participants also identified recommendations for addressing these barriers. Providing subsidized transportation, improving parks and recreation centers, and making better use of existing facilities were all proposed as opportunities to improve children's physical activity levels. CONCLUSION: In this formative study of Colorado families, participants confirmed barriers to physical activity that previous research on low-income communities has documented, and these varied by geographic location. Participants proposed a set of solutions for addressing barriers and endorsed community input as an essential first step for planning community-level health initiatives. PMID- 29240554 TI - Effects of a Tobacco-Free Work Site Policy on Employee Tobacco Attitudes and Behaviors, Travis County, Texas, 2010-2012. AB - BACKGROUND: The adoption of tobacco-free policies in behavioral health settings is an important step in reducing staff tobacco use as well as the high rates of tobacco use among people with mental illness and behavioral disorders. Studies have demonstrated the importance of staff support when implementing tobacco-free workplace policies, but there is limited research examining tobacco use prevalence among staff and staff attitude before and after policy adoption. COMMUNITY CONTEXT: Integral Care, a local authority for behavioral health and developmental disabilities in Austin, Texas, and Austin Public Health embarked on a comprehensive planning process before implementing a 100% tobacco-free campus policy. The objectives were 1) assess staff tobacco use and attitudes toward a tobacco-free policy, 2) communicate policy to staff, 3) provide staff education and training, and 4) provide cessation resources. METHODS: Integral Care and Austin Public Health conducted a web-based employee survey 6 months before and 6 and 12 months after implementation of the policy to measure tobacco use prevalence and attitudes among employees. OUTCOME: Employees had significant improvements in tobacco use prevalence and attitudes toward the tobacco-free policy from pre-implementation to post-implementation. Tobacco use prevalence among staff decreased from 27.6% to 13.8%, and support for the policy increased from 60.6% to 80.3% at 12 months post-implementation. INTERPRETATION: Adoption of 100% tobacco-free campus policies in behavioral health settings can result in significant reductions in staff tobacco use. Leadership should provide staff with education, training, and cessation support before adoption of tobacco-free work site policies to ensure success. PMID- 29240556 TI - Crazy Making: The Institutional Relations of Undergraduate Nursing in the Reproduction of Biomedical Psychiatry. AB - Undergraduate mental health nursing education has been extensively discussed among nursing scholars, educators, and curriculum experts. While various perspectives have weighed in on mental health nursing education in Canada, little attention has been paid to understanding the relationship between biomedical psychiatry and undergraduate nursing education. Using institutional ethnography, this article examines the social and textual relations which characterize this relationship. Beginning in the everyday teaching and learning work of faculty members and nursing students in a collaborative baccalaureate nursing program, the social organization of mental health nursing education is explicated and the textual processes are outlined. Findings suggest the presence of an institutional and discursive dominance of mental health nursing education by biomedical psychiatry. Implications for nursing education and recommendations to better balance mental health nursing education are outlined. PMID- 29240555 TI - Daily Sugar-Sweetened Beverage Consumption, by Disability Status, Among Adults in 23 States and the District of Columbia. AB - INTRODUCTION: Information on dietary intake, including sugar-sweetened beverages (SSBs), for adults with disabilities is limited. Such information can inform interventions to prevent chronic disease and promote health among adults with disabilities. The objective of this study was to describe the associations between SSB consumption and disability among adults. METHODS: We examined data on adults aged 18 years or older in 23 states and the District of Columbia who participated in the 2013 Behavioral Risk Factor Surveillance System (n = 150,760). Participants who reported a limitation in any activity caused by physical, mental, or emotional problems or who reported use of special equipment were considered to have a disability (n = 41,199). Participants were classified as daily SSB consumers (>=1 time/d) and non-daily SSB consumers (<1 time/d). Multivariable logistic regression was used to examine associations between daily SSB intake and disability after controlling for sociodemographic characteristics. An interaction effect between disability and obesity status was tested to consider obesity status as a potential effect modifier. RESULTS: The prevalence of drinking SSBs at least once daily was significantly higher among adults with disabilities (30.3%) than among adults without disabilities (28.6%) (P = .01). After controlling for sociodemographic characteristics, among nonobese adults, the odds of daily SSB intake were significantly higher among adults with disabilities than among adults without disabilities (adjusted odds ratio = 1.27, P < .001). Among obese adults, daily SSB intake was not associated with disability status (adjusted odds ratio = 0.97; P = .58). CONCLUSION: Our findings highlight the need for increased awareness of SSB consumption among adults with disabilities. PMID- 29240557 TI - Impact of motion compensation and partial volume correction for 18F-NaF PET/CT imaging of coronary plaque. AB - Recent studies have suggested that 18F-NaF-PET enables visualization and quantification of plaque micro-calcification in the coronary tree. However, PET imaging of plaque calcification in the coronary arteries is challenging because of the respiratory and cardiac motion as well as partial volume effects. The objective of this work is to implement an image reconstruction framework, which incorporates compensation for respiratory as well as cardiac motion (MoCo) and partial volume correction (PVC), for cardiac 18F-NaF PET imaging in PET/CT. We evaluated the effect of MoCo and PVC on the quantification of vulnerable plaques in the coronary arteries. Realistic simulations (Biograph TPTV, Biograph mCT) and phantom acquisitions (Biograph mCT) were used for these evaluations. Different uptake values in the calcified plaques were evaluated in the simulations, while three 'plaque-type' lesions of 36, 31 and 18 mm3 were included in the phantom experiments. After validation, the MoCo and PVC methods were applied in four pilot NaF-PET patient studies. In all cases, the MoCo-based image reconstruction was performed using the STIR software. The PVC was obtained from a local projection (LP) method, previously evaluated in preclinical and clinical PET. The results obtained show a significant increase of the measured lesion-to-background ratios (LBR) in the MoCo + PVC images. These ratios were further enhanced when using directly the tissue-activities from the LP method, making this approach more suitable for the quantitative evaluation of coronary plaques. When using the LP method on the MoCo images, LBR increased between 200% and 1119% in the simulated data, between 212% and 614% in the phantom experiments and between 46% and 373% in the plaques with positive uptake observed in the pilot patients. In conclusion, we have built and validated a STIR framework incorporating MoCo and PVC for 18F-NaF PET imaging of coronary plaques. First results indicate an improved quantification of plaque-type lesions. PMID- 29240558 TI - A modified microdosimetric kinetic model for relative biological effectiveness calculation. AB - In the heavy ion therapy, not only the distribution of physical absorbed dose, but also the relative biological effectiveness (RBE) weighted dose needs to be taken into account. The microdosimetric kinetic model (MKM) can predict the RBE value of heavy ions with saturation-corrected dose-mean specific energy, which has been used in clinical treatment planning at the National Institute of Radiological Sciences. In the theoretical assumption of the MKM, the yield of the primary lesion is independent of the radiation quality, while the experimental data shows that DNA double strand break (DSB) yield, considered as the main primary lesion, depends on the LET of the particle. Besides, the beta parameter of the MKM is constant with LET resulting from this assumption, which also differs from the experimental conclusion. In this study, a modified MKM was developed, named MMKM. Based on the experimental DSB yield of mammalian cells under the irradiation of ions with different LETs, a RBEDSB (RBE for the induction of DSB)-LET curve was fitted as the correction factor to modify the primary lesion yield in the MKM, and the variation of the primary lesion yield with LET is considered in the MMKM. Compared with the present the MKM, not only the alpha parameter of the MMKM for mono-energetic ions agree with the experimental data, but also the beta parameter varies with LET and the variation trend of the experimental result can be reproduced on the whole. Then a spread out Bragg peaks (SOBP) distribution of physical dose was simulated with Geant4 Monte Carlo code, and the biological and clinical dose distributions were calculated, under the irradiation of carbon ions. The results show that the distribution of clinical dose calculated with the MMKM is closed to the distribution with the MKM in the SOBP, while the discrepancy before and after the SOBP are both within 10%. Moreover, the MKM might overestimate the clinical dose at the distal end of the SOBP more than 5% because of its constant beta value, while a minimal value of beta is calculated with the MMKM at this position. Besides, the discrepancy of the averaged cell survival fraction in the SOBP calculated with the two models is more than 15% at the high dose level. The MMKM may provide a reference for the accurate calculation of the RBE value in heavy ion therapy. PMID- 29240560 TI - Nematicity, magnetism and superconductivity in FeSe. AB - Iron-based superconductors are well known for their complex interplay between structure, magnetism and superconductivity. FeSe offers a particularly fascinating example. This material has been intensely discussed because of its extended nematic phase, whose relationship with magnetism is not obvious. Superconductivity in FeSe is highly tunable, with the superconducting transition temperature, T c, ranging from 8 K in bulk single crystals at ambient pressure to almost 40 K under pressure or in intercalated systems, and to even higher temperatures in thin films. In this topical review, we present an overview of nematicity, magnetism and superconductivity, and discuss the interplay of these phases in FeSe. We focus on bulk FeSe and the effects of physical pressure and chemical substitutions as tuning parameters. The experimental results are discussed in the context of the well-studied iron-pnictide superconductors and interpretations from theoretical approaches are presented. PMID- 29240559 TI - Fluorescence detection, enumeration and characterization of single circulating cells in vivo: technology, applications and future prospects. AB - There are many diseases and biological processes that involve circulating cells in the bloodstream, such as cancer metastasis, immunology, reproductive medicine, and stem cell therapies. This has driven significant interest in new technologies for the study of circulating cells in small animal research models and clinically. Most currently used methods require drawing and enriching blood samples from the body, but these suffer from a number of limitations. In contrast, 'in vivo flow cytometry' (IVFC) refers to set of technologies that allow study of cells directly in the bloodstream of the organism in vivo. In recent years the IVFC field has grown significantly and new techniques have been developed, including fluorescence microscopy, multi-photon, photo-acoustic, and diffuse fluorescence IVFC. In this paper we review recent technical advances in IVFC, with emphasis on instrumentation, contrast mechanisms, and detection sensitivity. We also describe key applications in biomedical research, including cancer research and immunology. Last, we discuss future directions for IVFC, as well as prospects for broader adoption by the biomedical research community and translation to humans clinically. PMID- 29240562 TI - Occurrence of Impaired Physical Performance in Memory Clinic Patients With Cerebral Small Vessel Disease. AB - Cerebral small vessel disease (CSVD) occurs often in memory clinic patients. Apart from cognitive deficits, these patients can express physical decline, which predicts adverse health outcomes. In this study, we investigated the cooccurrence of clinically relevant impairments in physical performance and CSVD in memory clinic patients. We included 131 patients with vascular brain injury, mild cognitive impairment or Alzheimer disease with available 3T MRI and physical performance scores. CSVD was visually rated according to 3 subtypes and as a total burden score, composed of the presence of white matter hyperintensities (WMH), lacunar infarcts (LI), and cerebral microbleeds (MB). Physical performance was assessed with the Short Physical Performance Battery (SPPB), covering gait speed, balance, and chair stand performance. CSVD markers and impaired physical performance both occurred often. High total CSVD burdens cooccurred with impaired chair stand performances [odds ratio (OR) 2.67; 95% confidence interval (CI) (1.12-6.34)]. WMH cooccurred with impaired SPPB scores (OR, 3.76; 95% CI, 1.68 8.44), impaired gait speeds (OR, 4.11; 95% CI, 1.81-9.31) and impaired chair stand performances (OR, 5.62; 95% CI, 2.29-13.80). In memory clinic patients, high burdens of CSVD, particularly WMH, often cooccur with impairments in physical performance. The presence of WMH should alert clinicians to the presence of these, clinically relevant, physical impairments. PMID- 29240563 TI - Impact of Methylprednisolone on Postoperative Quality of Recovery and Delirium in the Steroids in Cardiac Surgery Trial: A Randomized, Double-blind, Placebo controlled Substudy: Erratum. PMID- 29240561 TI - Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set (UDS). AB - INTRODUCTION: The neuropsychological battery of the Uniform Data Set (UDSNB) was implemented in 2005 by the National Institute on Aging (NIA) Alzheimer Disease Centers program to measure cognitive performance in dementia and mild cognitive impairment due to Alzheimer Disease. This paper describes a revision, the UDSNB 3.0. METHODS: The Neuropsychology Work Group of the NIA Clinical Task Force recommended revisions through a process of due diligence to address shortcomings of the original battery. The UDSNB 3.0 covers episodic memory, processing speed, executive function, language, and constructional ability. Data from 3602 cognitively normal participants in the National Alzheimer Coordinating Center database were analyzed. RESULTS: Descriptive statistics are presented. Multivariable linear regression analyses demonstrated score differences by age, sex, and education and were also used to create a normative calculator available online. DISCUSSION: The UDSNB 3.0 neuropsychological battery provides a valuable non proprietary resource for conducting research on cognitive aging and dementia. PMID- 29240565 TI - Platelets-to-lymphocyte ratio is a good predictor of liver fibrosis and insulin resistance in hepatitis C virus-related liver disease. AB - BACKGROUND: Hepatitis C virus (HCV) is a global health problem that is complicated by liver fibrosis and insulin resistance (IR). AIM: The aim of this study was to validate neutrophils-to-lymphocytes ratio (NLR) and platelets-to lymphocytes ratio (PLR) as indirect biomarkers of liver fibrosis and IR in HCV patients. PATIENTS AND METHODS: One hundred and fifty patients were enrolled. Physical examination, BMI, liver function tests, serum creatinine, complete blood count, serum HCV RNA count by PCR, and abdominal ultrasonography were performed. Transient elastography measurement using FibroScan was performed. Patients were classified into those with mild fibrosis (F1-F3) and significant fibrosis (F4). IR was defined as homeostasis model assessment of IR more than 2. NLR and PLR were calculated. RESULTS: The average age of the patients was 47.21+/-10.51 years, mainly men (n=119; 79.3%), and 87.3% (n=131) had IR and 44.7% (n=67) had significant fibrosis. PLR was lower in patients with IR (74.95+/-37.90 vs. 94.71+/-31.45; P=0.032) unlike the NLR, which was comparable (P>0.05). Patients with significant fibrosis had lower PLR (66.43+/-39.38 vs. 86.35+/-33.85; P=0.001) unlike NLR (P>0.05). PLR (cutoff>=77.47) had 78.9% sensitivity, 60.3% specificity, 22.4% positive predictive value, and 95.2% negative predictive value for non-IR (P=0.008). At a cutoff of at least 63.71, PLR had 73.5% sensitivity, 61.2% specificity, 70.1% positive predictive value, and 65.1% negative predictive value for nonsignificant fibrosis (P=0.001). Age and PLR (odds ratio=0.99; 95% confidence interval=0.976-0.999) were predictors of IR, whereas age, total bilirubin, serum albumin, liver stiffness, and PLR (odds ratio=0.98; 95% confidence interval=0.974-0.994) were predictors of significant fibrosis. CONCLUSION: PLR is useful in distinguishing the patients with significant fibrosis or IR unlike NLR. PMID- 29240564 TI - Evaluating different criteria for defining a complete ambulatory blood pressure monitoring recording: data from the Jackson Heart Study. AB - OBJECTIVE: We determined differences in the prevalence of blood pressure (BP) phenotypes and the association of these phenotypes with left ventricular hypertrophy (LVH) for individuals who fulfilled and did not fulfill various criteria used for defining a complete ambulatory blood pressure monitoring (ABPM) recording. METHODS: We analyzed data for 1141 participants from the Jackson Heart Study. Criteria evaluated included having greater than or equal to 80% of planned readings with more than or equal to one reading per hour (Spanish ABPM Registry criteria), more than or equal to 70% of planned readings with a minimum of 20 daytime and seven nighttime readings (2013 European Society of Hypertension criteria), greater than or equal to 14 daytime and greater than or equal to seven nighttime readings (2003 European Society of Hypertension criteria), more than or equal to 10 daytime and more than or equal to 5 nighttime readings (International Database of Ambulatory Blood Pressure in Relation to Cardiovascular Outcome criteria), and greater than or equal to 14 daytime readings (UK National Institute of Health and Clinical Excellence criteria). RESULTS: Between 45.0% (Spanish ABPM Registry) and 91.8% (UK National Institute of Health and Clinical Excellence) of the participants fulfilled the different criteria for a complete ABPM recording. Across the various criteria evaluated, 55.5-57.8% of participants had nocturnal hypertension and 62.8-66.8% had nondipping systolic BP. Among participants with clinic-measured systolic/diastolic BP of more than or equal to 140/90 mmHg, 22.9-26.5% had white-coat hypertension. The prevalence of daytime, 24-h, sustained, and masked hypertension differed by up to 2% for participants fulfilling each criterion. The association of BP phenotypes with LVH was similar for participants who fulfilled versus those who did not fulfill different criteria (each P>0.05). CONCLUSION: Irrespective of the criteria used for defining a complete ABPM recording, the prevalence of BP phenotypes and their association with LVH were similar. PMID- 29240566 TI - A practical clinical approach to utilize cardiopulmonary exercise testing in the evaluation and management of coronary artery disease: a primer for cardiologists. AB - PURPOSE OF REVIEW: There is growing clinical interest for the use of cardiopulmonary exercise testing (CPET) to evaluate patients with or suspected coronary artery disease (CAD). With mounting evidence, this concise review with relevant teaching cases helps to illustrate how to integrate CPET data into real world patient care. RECENT FINDINGS: CPET provides a novel and purely physiological basis to identify cardiac dysfunction in symptomatic patients with both obstructive-CAD and nonobstructive-CAD (NO-CAD). In many cases, abnormal cardiac response on CPET may be the only objective evidence of potentially undertreated ischemic heart disease. When symptomatic patients have NO-CAD on coronary angiogram, they are still at increased risk for cardiovascular events. This problem appears to be more common in women than men and may warrant more aggressive risk factor modification. As the main intervention is lifestyle (diet, smoking cessation, exercise) and medical therapy (statins, angiotensin-converting enzyme inhibitors, beta-blockers), serial CPET testing enables close surveillance of cardiovascular function and is responsive to clinical status. SUMMARY: CPET can enhance outpatient evaluation and management of CAD. Diagnostically, it can help to identify physiologically significant obstructive-CAD and NO-CAD in patients with normal routine cardiac testing. CPET may be of particular value in symptomatic women with NO-CAD. Prognostically, precise quantification of improvements in exercise capacity may help to improve long-term lifestyle and medication adherence for this chronic condition. PMID- 29240567 TI - Theoretical Evaluation and Experimental Validation of Localized Therapeutic Hypothermia Application to Preserve Residual Hearing After Cochlear Implantation. AB - OBJECTIVES: Cochlear implantation surgery has been shown to result in trauma to inner ear sensory structures, resulting in loss of residual hearing. Localized therapeutic hypothermia has been shown in clinical care to be a neuroprotective intervention. Previously, we have shown in an experimental model that localized hypothermia protects cochlear hair cells and residual hearing function against surgical and cochlear implantation trauma. Using experimental temperature measurements carried out in human cadaver temporal bones and a finite element model of the inner ear, the present study examined the temperature distribution of a custom-designed hypothermia delivery system in the human inner ear organs. DESIGN: The efficacy of the hypothermia probe and resulting heat distribution across human cochlea and surrounding tissues were modeled in three-dimensional in COMSOL. The geometry and dimensions of inner ear and temporal bones were derived from computed tomographic and magnetic resonance imaging images. Model predictions were compared with experimental observations from five human temporal bones. RESULTS: In both the modeling and experimental studies, the cochlear temperature was lowered by 4 to 6 degrees C on the round window from a baseline of 37 degrees C within 16 to 18 minutes. The model simulations showed uniformly distributed cooling across the cochlea. This study provides insight for design, operation, and protocols for efficacious delivery of mild therapeutic hypothermia to the human cochlea that may significantly benefit patients undergoing surgical cochlear implantation by preserving residual hearing. CONCLUSION: There was a close correlation between the results of the numerical simulations and experimental observations in this study. Our custom-designed system is capable of effectively providing mild therapeutic hypothermia locally to the human cochlea. When combined with results from in vivo animal experiments, the present study suggests that the application of localized therapeutic hypothermia may hold potential for patients with an aim to preserve residual hearing after cochlear implantation. PMID- 29240569 TI - Paediatric procedural sedation and analgesia by emergency physicians in a country with a recent establishment of emergency medicine. AB - OBJECTIVES: Paediatric patients receive less procedural sedation and analgesia (PSA) in the emergency department compared with adults, especially in countries where emergency medicine is at an early stage of development. The objectives of this study were to evaluate the adverse events and efficacy of paediatric PSA in a country with a recent establishment of emergency medicine and to describe which factors aided implementation. METHODS: This is a prospective, multicentre, observational study of paediatric patients undergoing PSA by the first trained emergency physicians (EPs) in The Netherlands. A standardized data collection form was used at all participating hospitals to collect data on adverse events, amnesia, pain scores, and procedure completion. A survey was used to interpret which factors had aided PSA implementation. RESULTS: We recorded 351 paediatric PSA. The mean age was 9.5 years (95% confidence interval: 9.1-10.0). Esketamine was most frequently used (42.4%), followed by propofol (34.7%). The adverse event rate was low (3.0%). Amnesia was present in 86.8%. The median pain score was 2 (out of 10) for patients without amnesia. Procedures were successfully completed in 93.9% of the cases. CONCLUSION: Paediatric PSA provided by the first EPs in The Netherlands showed appropriate levels of sedation and analgesia with a high rate of procedure completion and a low rate of adverse events. Our paper suggests that EPs provided with a proper infrastructure of mentorship, training and guidelines can implement effective paediatric PSA. PMID- 29240568 TI - The Epidemiology of Pediatric Head Injury Treated Outside of Hospital Emergency Departments. AB - BACKGROUND: Although head trauma-related deaths, hospitalizations, and emergency department visits are well characterized, few studies describe pediatric patients presenting outside of emergency departments. We compared the epidemiology and extent of healthcare-seeking pediatric (0-17 years) patients presenting in outpatient settings with those of patients seeking nonhospitalized emergency department care. METHODS: We used MarketScan Medicaid and commercial claims, 2004 2013, to identify patients managed in two outpatient settings (physician's offices/clinics, urgent care) and the emergency department. We then examined differences in demographic and injury-specific factors, Centers for Disease Control and Prevention-defined head trauma diagnoses, the extent of and reasons for post-index visit ambulatory care use within 30/90/180 days, and annual and monthly variations in head trauma trends. Outpatient incidence rates in 2013 provided estimates of the nationwide US outpatient burden. RESULTS: A total of 1,683,097 index visits were included, representing a nationwide burden in 2013 of 844,660 outpatient cases, a number that encompassed 51% of healthcare-seeking head trauma that year and that substantially increased in magnitude from 2004 to 2013. Two-thirds (68%) were managed in outpatient settings. While demographic distributions varied with index-visit location, injury-specific factors were comparable. Seasonal spikes appeared to coincide with school sports. CONCLUSIONS: There is an urgent need to better understand the natural history of head trauma in the >800,000 pediatric patients presenting each year for outpatient care. These outpatient injuries, which are more than double the number of head trauma cases recorded in the hospital-affiliated settings, illustrate the potential importance of expanding inclusion criteria in surveillance and prevention efforts designed to address this critical issue. PMID- 29240570 TI - Severity of button batteries ingestions: data from French Poison Control Centres between 1999 and 2015. AB - BACKGROUND: Although the ingestion of button batteries is an infrequent situation, it leads to a significant risk of causing serious damage. OBJECTIVE: This study was carried out to describe all the cases of button battery ingestion recorded by the French Poison Control Centers over 16 years. PATIENTS AND METHODS: All the cases of button battery ingestion were recorded from 1 January 1999 to the end of June 2015, analysed (age, sex, number of ingested button batteries, clinical signs and treatments) and graded for severity according to the poisoning severity score. RESULTS: The incidence of button batteries ingestions was constant over the 16-year period, with an average of 266+/-98.5 cases per year and a total of 4030 cases. Nevertheless, 21 cases were severe and two deaths occurred. Interestingly, for the two patients who died, the battery was stuck in the oesophagus and they presented anorexia and/or dysphagia, abdominal pain and fever and in one case, a melena 3 weeks after ingestion. Importantly, these symptoms were observed even if the battery was expelled in one fatal case. CONCLUSION: Ingestions of button batteries still occur and may cause serious damage, especially in children, and if the button battery is stuck in the oesophagus as it might cause severe symptoms. Patients who have ingested a button battery must be directed to the emergency department for medical evaluation, even if the button battery has been expelled from the body and even more if gastrointestinal symptoms are present. PMID- 29240572 TI - Preventing Falls and Fall-Related Injuries in State Veterans Homes: Virtual Breakthrough Series Collaborative. AB - This article reports on improved processes and outcomes from a virtual breakthrough series quality improvement collaborative to reduce preventable falls and fall-related injuries in 23 State Veterans Homes. Participating teams implemented 24 interventions (process changes); the most common was the postfall huddle. Teams reduced falls and fall-related injuries. This project highlights the importance of leadership support, interdisciplinary team involvement, and collaboration as essential components of fall prevention work. PMID- 29240571 TI - Developing the Clinical Nurse Leader Survey Instrument: A Modified Delphi Study. AB - Clinical nurse leader (CNL)-integrated care delivery is an emerging nursing model, with growing adoption in diverse health systems. To generate a robust evidence base for this promising nursing model, it is necessary to measure CNL practice to explicitly link it to observed quality and safety outcome improvements. This study used a modified Delphi approach with an expert CNL panel to develop and test the face, content, and construct validity of the CNL Practice Survey instrument. PMID- 29240573 TI - Making Wise Choices in Health Provision: Initial Exploration of Nurse Perceptions in Israel. AB - Overuse of health services drives up costs while affecting quality of care. It can also harm patients physically and psychologically through invoking duplicate testing, unnecessary procedures, and psychological stress. The purpose of this study was to understand nurses' perceptions of health care overuse. Nurses perceived that physicians' main considerations when ordering tests are to get additional data to strengthen the diagnosis and "just to be safe." Fear of litigation and patients' desires were important factors. Implementing interventions to reduce overuse will create a more efficient and effective system. PMID- 29240574 TI - Evaluation of Retinal Changes in Progressive Supranuclear Palsy and Parkinson Disease. AB - BACKGROUND: Differentiating Parkinson disease (PD) from progressive supranuclear palsy (PSP) can be challenging early in the clinical course. The aim of our study was to see if specific retinal changes could serve as a distinguishing feature. METHODS: We used spectral domain optical coherence tomography (SD-OCT) with automatic segmentation to measure peripapillary nerve fiber layer thickness and the thickness and volume of retinal layers at the macula. RESULTS: Thicknesses of superior peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell layer, inner plexiform layer, inner nuclear layer, and macular volume were more affected in PSP compared with PD (P < 0.05). Thicker inferotemporal pRNFL and lower macular volume were detected in levodopa users compared with nonusers in patients with PD. CONCLUSIONS: PD and PSP are associated with distinct changes in retinal morphology, which can be assessed with SD-OCT. PMID- 29240575 TI - Horner Syndrome as the Only Focal Neurologic Manifestation of Hypothalamic Hemorrhage. AB - A 70-year-old woman suffered an anterior dorsal hypothalamic hemorrhage that caused an ipsilateral Horner syndrome (HS) as the only focal neurologic manifestation. This is only the second reported case of hypothalamic hemorrhage producing HS. Because HS was the sole focal neurologic manifestation, its confirmation with topical apraclonidine drops was a valuable clue toward prompt localization of the patient's confusional state. PMID- 29240576 TI - Temporary Lumbar Drain as Treatment for Pediatric Fulminant Idiopathic Intracranial Hypertension: Comment. PMID- 29240577 TI - Temporary Lumbar Drain as Treatment for Pediatric Fulminant Idiopathic Intracranial Hypertension: Response. PMID- 29240578 TI - Case of Bilateral Sequential Nonarteritic Ishemic Optic Neuropathy After Rechallenge With Sildenafil: Comment. PMID- 29240579 TI - Should Conjunctival Biopsy Be Performed for Definitive Diagnosis of Sarcoidosis? PMID- 29240580 TI - Prognostic Significance of Periadnexal Extension in Cutaneous Melanoma and its Implications for Pathologic Reporting and Staging. AB - Tumor thickness is the strongest predictor of outcome for clinically localized melanoma. Therefore, accurate assessment is critical for appropriate staging, reliable estimation of prognosis, and management. When melanoma extends alongside skin adnexal structures more deeply than the main tumor mass (periadnexal extension), it is currently unknown whether the prognosis is more accurately reflected by the deepest point of periadnexal tumor extension or the main tumor mass. This study sought to address this question. Survival outcomes of 257 primary cutaneous melanoma patients with periadnexal extension diagnosed between 2005 and 2015 and managed at Melanoma Institute Australia were identified and compared with a control cohort of 514 patients who were matched for tumor thickness, sex, age, mitotic rate, ulceration status, and year of diagnosis but lacked periadnexal extension. The incidence of periadnexal extension at Melanoma Institute Australia was 1.5% (257/16,692 cutaneous melanomas diagnosed between 2005 and 2015). The patient characteristics between the 2 groups were otherwise very similar; median Breslow thickness was 0.9 mm for the periadnexal group and 1.0 mm for the control group. The median extension beyond the Breslow thickness in the tumors with periadnexal extension was 0.45 mm (mean, 0.4 mm). Median follow-up was 46 months for the periadnexal group and 44 months for the control group. Measures of clinical outcomes all showed trends for improved survival in the periadnexal extension group; these were melanoma-specific survival (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.44, 1.38), overall survival (HR, 0.91; 95% CI, 0.59, 1.41), disease-free survival (HR, 0.68; 95% CI, 0.45, 1.03), and distant disease-free survival (HR, 0.69; 95% CI, 0.4, 1.17), although none were statistically significant. There was a higher rate of sentinel lymph node (SLN) metastasis in the periadnexal group versus the control group in patients whose tumors were >1 mm thick (24/100=24% vs. 23/187=12.3%). Periadnexal extension was significantly associated with SLN metastasis on univariate logistic regression analysis (odds ratio [95% CI], 2.25 [1.20, 4.24], P=0.01). If the periadnexal extension had been included in the measurement of tumor thickness, 42.8% of patients would have been upstaged to a higher American Joint Committee on Cancer T category. The findings of this study indicate that periadnexal involvement that extends more deeply than the thickness of the main tumor mass increases the risk of SLN metastasis in tumours >1 mm thick, however, does not worsen clinical outcomes overall, and tumor thickness measurements should not include deeper foci of periadnexal tumor. PMID- 29240581 TI - Cutaneous Melanocytoma With CRTC1-TRIM11 Fusion: Report of 5 Cases Resembling Clear Cell Sarcoma. AB - We report 5 cases of primary intradermal nodular unpigmented tumors with a melanocytic immunophenotype associated with a novel CRTC1-TRIM11 fusion. Clinically, the cutaneous nodules were slowly growing in 3 women and 2 men (25 to 82 y old, median, 28 y) with no specific topography. Lesion size ranged from 4 to 12 mm (median, 5 mm). The tumors were strictly located in the dermis with a nodular pattern. The cells were arranged in confluent nests and fascicules. Central fibronecrotic areas were present in 2 cases. Cells were medium to large, sometimes multinucleated, and presented a spindled and epithelioid cytology with prominent nucleoli. Cytonuclear atypia was constant, and mitotic activity in hotspot areas ranged from 1 to 5/mm2. Immunohistochemistry found a constant positivity with S100, MiTF, and Sox10, and a heterogenous staining by MelanA or HMB45. NTRK1 was strongly positive in 3 cases. In all cases, RNA sequencing found an invariable CRTC1(e1)-TRIM11(e2) fusion, confirmed by fluorescent in situ hybridization techniques with a TRIM11 break-apart probe. In 4/4 cases, nuclear TRIM11 expression was positive by immunohistochemistry. Fluorescent in situ hybridization techniques showed no rearrangement of NTRK1 or EWSR1, and array comparative genomic hybridization displayed no alteration (1 case) or only a whole chromosome 7 gain (2 cases) when performed. No relapse or metastatic event was observed during follow-up [3 to 72 months (median, 14 mo)]. Cutaneous clear cell sarcoma was the main differential diagnosis. Overlapping morphologic features previously described in primary dermal melanomas and paraganglioma-like melanocytic tumors were present. The CRTC1-TRIM11 fusion appears to be specific of an unpigmented nodular tumor combining a melanocytic phenotype and low-grade tumor behavior. PMID- 29240582 TI - The Morphologic Spectrum of Sertoliform Cystadenoma of the Rete Testis: A Series of 15 Cases. AB - Sertoliform cystadenoma of the rete testis (SCRT) is rare with only 9 cases reported to date in the literature, none with follow-up. Four large genitourinary pathology consult services were searched. We identified 15 cases of SCRT. Men were 21 to 84 years old (mean, 46 y) and had testicular discomfort or mass. Other findings were seminoma (n=1), spermatocele (n=2), hydrocele (n=1), varicocele (n=1), and scrotal hematoma (n=1). Eight had preoperative serum tumor markers, which were normal. Tumors ranged from 0.3 to 4 cm (mean, 1.5 cm). All of them were well circumscribed with solid and cystic features and occupied on average, 73% of the rete (20% to 100%). The tumors were mostly confined within dilated channels of the rete testis and showed classic features consisting of: (1) tubules with well-formed lumina in 87% of cases; (2) well-formed tubules with no lumina in 87% of cases; and (3) cords/nests in hyalinized or myxoid stroma in 73% of cases. Other patterns included: (1) solid/sheet growth in 26% of cases; (2) individual cells in 13% of cases; (3) festoons in 13% of cases; (4) branching tubules in 7% of cases; and (5) papillary in 7% of cases. Cells were cuboidal with round to oval nuclei with small nucleoli, except at the periphery where projections into rete tubules had a more columnar appearance. In the festooning pattern, nuclei were pseudostratified and columnar with prominent nucleoli and nuclear grooves. In 4 cases, tumor extended into adjacent seminiferous tubules surrounded by dense peritubular fibrosis, with in some cases small cysts lined by flattened epithelium containing pale lightly granular material. All cases lacked necrosis and significant atypia. Mitoses ranged from 0 to 2 per 10 high-power field. Follow-up ranged from 4 to 170 months with mean of 97 months. For the 13 cases with information, all patients were alive, except for 3 who died of either unrelated causes (9.2 and 10 y) or of unknown cause (4.8 y at age 89 y). We performed immunohistochemistry for steroidogenic factor 1 and inhibin in 4 of our cases, where 3 (75%) were positive for both markers. We also describe 2 additional cases which morphologically resembled SCRT but had more atypical features. This study highlights that SCRT has variable morphology. We also verify the benign nature of the lesion and its lack of association with any syndromes. PMID- 29240583 TI - Site-specific Differences in Colonic Adenocarcinoma: KRAS Mutations and High Tumor Budding Are More Frequent in Cecal Adenocarcinoma. AB - Recent literature indicates that adenocarcinomas of the cecum differ with respect to molecular alterations compared with noncecal proximal colon adenocarcinomas and that cecal tumor site may be a prognostically relevant variable. We compared molecular alterations, histopathologic features, and disease-specific survival in a series of 328 colonic adenocarcinomas identified over a 2-year period and stratified by tumor location (cecum, right colon, and left colon). Overall, cecal adenocarcinomas demonstrated the highest frequency of molecular abnormalities with 74% harboring either a KRAS exon 2 or 3 mutation, a BRAF mutation, or DNA mismatch repair protein deficiency. KRAS mutations were more frequently seen in the cecum compared with all other tumor sites (P=0.03). KRAS mutations were identified in 46% of cecal adenocarcinomas compared with only 25% of adenocarcinomas of the right colon (P=0.004). Cecal adenocarcinomas more frequently displayed adverse histopathologic features, in particular high tumor budding (31%), compared with tumors of the right colon (18%; P=0.04) and tumors of the left colon (17%; P=0.02). Overall stage was the most important independent predictor of disease-specific survival in the multivariable analysis; however, cecal tumor site and high tumor budding were also predictive of poor survival, particularly in patients with stage III or IV tumors. In conclusion, cecal adenocarcinomas are characterized by a high frequency of KRAS mutations compared with noncecal right colon tumors, frequently display high tumor budding, and may be a prognostically relevant variable, particularly in patients with stage III or IV disease. PMID- 29240584 TI - Dermatofibrosarcoma Protuberans of Distal Extremities and Acral Sites: A Clinicopathologic Analysis of 27 Cases. AB - Dermatofibrosarcoma protuberans (DFSP) of the distal extremities and acral sites are extremely rare and incompletely characterized. Twenty-seven DFSP occurring in these sites were retrieved from our collective archives and reevaluated. Tumors occurred in 16 males and 11 females. Median age at presentation was 42.5 years (range, 7 to 78 y). Lesions involved the foot (18 with 6 in the toes and 2 on the plantar foot), distal ankle (4), hand (4 with 2 in the thumbs), and wrist (1). All cases showed predominantly classic DFSP morphology and were diffusely CD34 positive. Myxoid change, melanin pigmented, and giant cell fibroblastoma foci were each present in 1 case, respectively. Fibrosarcomatous change was present in 3 cases. Fluorescent in situ hybridization demonstrated PDGFB gene rearrangement in 9 of 10 tested cases. Clinical follow-up was available in 21 cases (median, 36.1 mo; range, 1 to 152 mo) and revealed 4 local recurrences. Four patients underwent digital amputation for unresectable recurrent disease. An additional patient underwent multiple resections with positive margins and elected to receive imatinib mesylate therapy. After a 2-year course, the patient has no evidence of residual disease (40 mo). No metastases were documented in any of the cases studied. The natural history of DFSP of distal extremities and acral sites is similar to that of its counterparts elsewhere. A high index of suspicion, careful morphologic examination for key histologic features of DFSP, and in selected cases, molecular studies to identify the pathognomonic COL1A1-PDGFB gene fusion should facilitate the distinction of these rare, locally aggressive neoplasms from morphologic mimics that may arise in distal extremities and acral sites. PMID- 29240585 TI - The Cicatrix: The Functional Stage of Wound Healing. PMID- 29240586 TI - Insights into the Pathophysiology of Hypertrophic Scars and Keloids: How Do They Differ? AB - GENERAL PURPOSE: To provide information about the clinical presentation of hypertrophic scars and keloids based on their varied structural components. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After completing this continuing education activity, you should be able to: ABSTRACT: Hypertrophic scars and keloids are firm, raised, erythematous plaques or nodules that manifest when the cicatrix fails to properly heal. They result from pathologic wound healing and often cause pain and decreased quality of life. The appearance of such cosmetically unappealing scars affects the confidence and self-esteem of many patients. These scars can also cause dysfunction by interfering with flexion and extension across joints. Both possess some unique and distinct histochemical and physiologic characteristics that set them apart morphologically and at the molecular level. While these entities have been the focus of research for many years, differentiating between them remains challenging for clinicians.This article reviews the clinical presentation of aberrant scars and illustrates how they can be differentiated. It outlines their pathophysiology and emphasizes the unique molecular mechanisms underlying each disorder. It also examines how altered expression levels and the distribution of several factors may contribute to their unique clinical characteristics and presentation. Further research is needed to elucidate optimal treatments and preventive measures for these types of aberrant scarring. PMID- 29240587 TI - Reclaiming Autologous Amputated Tissue for Limb Salvage of a Diabetic Foot Burn with Underlying Critical Limb Ischemia. AB - BACKGROUND: Diabetes mellitus is a worldwide pandemic that impacts more than 387 million people, with 29 million individuals affected in the United States alone. Diabetic patients have a 25% lifetime risk of developing a diabetic foot ulcer (DFU). Having a DFU is associated with a risk of recurrence approaching 70%. In addition, 1 in 6 patients with DFU will have a lower-limb amputation, with an associated increase in mortality ranging from 47% to 70%. Therefore, limb salvage is critical in patients with DFU. CASE STUDY: This article describes the case of a 70-year-old man with diabetes mellitus, end-stage renal disease, and peripheral arterial occlusive disease who presented with a 1.5% total-body-surface-area, third-degree burn to the left hallux with dry gangrene extending to the midfoot. Ankle brachial indexes were 0.66 on the left and 0.64 on the right. Toe pressures on the left were absent because of extensive dry gangrene. His right foot had a prior transmetatarsal amputation. Using a retrograde pedal approach, a chronic total occlusion of the left posterior tibial artery was recanalized with balloon angioplasty. He then underwent a transmetatarsal amputation with closure, except that the plantar medial side could not be closed without tension. Therefore, an autologous full-thickness skin graft, from the amputation specimen, was used to bridge the defect. DISCUSSION: At 32-week follow-up, the wound was healed, the graft had fully incorporated, and the patient was ambulating well using custom orthotic footwear. The creative use of amputated tissue to assist with wound coverage has not been well described in the literature. PMID- 29240588 TI - Survey Results from the Philippines: NPUAP Changes in Pressure Injury Terminology and Definitions. AB - OBJECTIVE: To determine the opinions of healthcare clinicians in the Philippines regarding the 2016 National Pressure Ulcer Advisory Panel (NPUAP) terminology changes and revised staging definitions. DESIGN AND SETTING: A survey methodology was used in Manila, Philippines. Convenience samples of healthcare clinicians of varying disciplines and employment settings were invited to participate in this research. INTERVENTIONS: A survey was administered at key intervals regarding the revised NPUAP terminology changes and revised staging definitions. The survey was administered before and after an interactive, basic 2-day wound course was conducted. MAIN RESULTS: Results revealed strong support for the 2016 NPUAP terminology change from pressure ulcer to pressure injury and the revised staging definitions. CONCLUSIONS: Since the NPUAP changed its terminology and revised the staging definitions, the wound care community has been responding to those changes. Because pressure injuries are a global health concern, the opinions of clinicians outside the United States are equally valuable. The healthcare clinicians in the Philippines surveyed appear to embrace the new terminology changes and revised staging definitions put forth by the NPUAP. PMID- 29240589 TI - Infrared Skin Thermometry: Validating and Comparing Techniques to Detect Periwound Skin Infection. AB - OBJECTIVE: Diagnosis of wound infection can be challenging because it relies on a combination of clinical signs and symptoms that are often nonspecific. Increased periwound cutaneous temperature is a classic sign of deep and surrounding wound infection, and its quantitative measurement is one of the most reliable and valid clinical signs of deep and surrounding skin infection at the bedside. Skin surface temperature differences may be detected using commercially available noncontact infrared thermometers. However, techniques to detect temperature using noncontact infrared thermometers vary, and no studies have evaluated these methods. Two such measurement techniques include the "4-point" and "whole-wound" scanning methods. This study assessed the ability of different infrared thermometers using the aforementioned techniques to detect clinically meaningful differences in periwound cutaneous temperatures used in the diagnosis of wound infection. METHODS: A prospective cohort study was conducted from 2015 to 2016 of consenting adult patients 18 years or older with an open wound attending a regional wound care clinic. One hundred patients with wounds underwent surface temperature measurement. Infection was not a specific inclusion criterion as the primary objective was to conduct a comparative assessment of infrared thermometry devices. Demographic data (age, height, weight, gender, and ethnicity) were also collected. Each wound was measured using 4 different noncontact infrared thermometers: Exergen DermaTemp 1001 (Exergen Corporation, Watertown, Massachusetts), Mastercraft Digital Temperature Reader (Mastercraft, Toronto, Ontario, Canada), Mastercool MSC52224-A (Mastercool Inc, Randolph, New Jersey), and Etekcity ETC-8250 Temperature Heat Pen (Etekcity, Anaheim, California). Data analysis was based on a comparison of 4 periwound skin surface temperature measurement differences (DeltaT in degrees Fahrenheit) between the wound site and an equivalent contralateral control site. OUTCOME MEASURES: The primary outcome of the ability of each thermometer to detect a clinically significant difference in temperature was assessed with chi analysis. Paired t tests were conducted to compare the DeltaT measurements of each specific thermometry device between the 2 measurement techniques. Pearson product moment correlation coefficients were calculated for the temperature DeltaT for both measuring techniques for all devices to determine level of agreement. A 1-way analysis of variance was conducted to compare temperature measurements among the infrared thermometry devices. MAIN RESULTS: There was no significant difference in the ability of each thermometer to detect a clinically meaningful difference of 3 degrees F by either the 4-point (P = .10) or whole-wound techniques (P = .67). When a definition of 4 degrees F was used, results were similar (4-point, P = .15; whole wound, P = .20). Comparisons among devices and techniques showed strong correlations (>0.80). Etekcity ETC-8250 and the 4-point measurement compared with the Exergen device using the whole-wound technique had a correlation coefficient of 0.72. Spearman rho demonstrated a similarly high degree of correlation between techniques and devices, and only the Etekcity ETC-8250 device had a coefficient of 0.71 to 0.90 when compared with others. Paired t testing for each thermometry device comparing measurement techniques for raw temperatures DeltaT demonstrated no significant difference (P > .05). No statistical differences among the DeltaT values for the 3 different thermometers were noted when using the whole-wound method (P = .095). Similarly, no significant differences among the DeltaT values were noted for the 4 different thermometers when using the 4-point method (P = .10). CONCLUSIONS: The results of this study demonstrate that both the 4-point and whole-wound methods of temperature acquisition using cost-efficient infrared thermometers provide accurate and similar results in clinical wound care settings. PMID- 29240590 TI - Reverse Sural Adipofascial Flaps with Acellular Dermal Matrix and Negative Pressure Wound Therapy. AB - The reverse sural adipofascial flap (RSAF) is used to reconstruct challenging wounds of the foot and ankle. It offers several advantages over the traditional reverse sural flap, including less venous congestion. To complete the reconstruction, split-thickness skin grafting (STSG) may be done immediately or in a delayed fashion; however, both scenarios result in suboptimal take rates and prolonged healing. An acellular dermal matrix (ADM; Integra; Ethicon Inc, Somerville, New Jersey) and negative-pressure wound therapy (NPWT) combined with RSAF followed by delayed STSG may decrease wound healing time.In this study, 8 patients underwent reconstruction of lower-extremity wounds with RSAF. Four patients underwent RSAF with immediate STSG, and 4 underwent RSAF with placement of the ADM and a vacuum-assisted closure device, with STSG at a later date.The 4 patients who underwent RSAF and immediate STSG had an average time to heal of 141.2 days, and 2 patients required reoperation. The 4 patients who underwent RSAF with an ADM and NPWT had an average time to heal of 104.5 days, and 1 patient required reoperation. Average time until STSG was 41.5 days. The latter group demonstrated a reduction in time to heal by an average of 36.7 days, or 25%. All 8 patients achieved successful wound closure.The RSAF is a durable option for complex lower-extremity reconstruction. Interim placement of ADM and NPWT may increase STSG take rates. Using this technique in conjunction with RSAF may decrease the overall healing time compared with RSAF with immediate STSG. PMID- 29240591 TI - Beware: Medicare Is Enforcing the Use of Modifiers for "Always Therapy" Services. PMID- 29240592 TI - 2018 Checklist: Organizing Your Department for the New Year. PMID- 29240593 TI - Insights into the Pathophysiology of Hypertrophic Scars and Keloids: How Do They Differ? PMID- 29240595 TI - Reproducibility of Central Corneal Thickness Measurements in Healthy and Glaucomatous Eyes. PMID- 29240594 TI - Preventive Effect of a Microclimate-Regulating System on Pressure Ulcer Development: A Prospective, Randomized Controlled Trial in Dutch Nursing Homes. AB - OBJECTIVE: Prevention of pressure ulcers (PrUs) is based on relieving pressure, diminishing shear stress, and controlling the skin's microclimate. Based on the recommendations in the most recent guideline for prevention of PrUs, a pressure relieving, shear stress-diminishing, and microclimate-controlling skin interface multilayer support system (Bedcare; Sense Textile, 's-Hertogenbosch, the Netherlands) has been developed for use on top of a viscoelastic foam mattress (Formafoam, Kabelfabriek Eupen, Belgium). The aim of this study was to test the PrU preventive effect of this system compared with a viscoelastic foam mattress alone. METHODS: A multicenter, prospective, randomized controlled trial was executed in 21 nursing homes in the Netherlands. Residents with a Braden score less than 16, a life expectancy of more than 3 months, and no PrUs during the last 3 months were asked to participate and included after informed consent. Residents were divided into 2 groups. The control group received a new high quality viscoelastic foam mattress covered with a cotton sheet. The intervention group received the same new mattress, in combination with the newly developed multilayer system. Research nurses followed the participating residents for 12 weeks. The outcome parameter was the development of PrUs. RESULTS: Two hundred six residents participated in the study. Both groups had comparable demographics (eg, age, Braden score, care dependency, incontinence). In the control group, 5% of the residents developed a category 2, 3, or 4 PrU, and 9% in the intervention group did. These results were not statistically significant. CONCLUSIONS: This study shows that the multilayer system (Mini Overlay System, barrier mattress cover, and Stay and Transfer Sheet), when used as an integral system and in combination with a viscoelastic foam mattress, has no added value over the viscoelastic foam mattress/cotton sheet. PMID- 29240597 TI - Trabeculectomy With Mitomycin-C: Outcomes and Risk Factors for Failure in Primary Angle-closure Glaucoma. AB - PURPOSE: There are no reported large series of trabeculectomy with mitomycin-C (MMC) in Western patients with primary angle-closure glaucoma (PACG). Our study evaluates long-term tonometric outcomes of trabeculectomy in PACG. MATERIALS AND METHODS: This is a retrospective cohort study. The primary outcomes were the Kaplan-Meier success rates on survival analyses using 3 criteria, with or without adjunctive medication: (A) intraocular pressure (IOP) <=18 mm Hg and IOP reduction of 20%; (B) IOP<=15 mm Hg and IOP reduction 25%; and (C) IOP<=12 mm Hg and IOP reduction 30%. In total, 136 eyes (102 patients) with PACG who underwent trabeculectomy MMC were included. The Cox proportional hazard regression analysis was used to identify risk factors for failure with multivariate analysis (P<0.05). RESULTS: The qualified success rates (+/-SD) after 1, 3, and 5 years of follow-up for criterion A were 92% (+/-2.2%), 78% (+/-3.8%), and 72% (+/-4.3%); for criterion B, 86% (+/-3.0%), 65% (+/-4.4%), and 59% (+/-4.7%); and for criterion C, 62% (+/-4.2%), 40% (+/-4.5%), and 32% (+/-4.4%). Baseline factors associated with failure were: family history, absence of laser peripheral iridotomy, higher IOP, and presence of a crystalline lens. CONCLUSIONS: Trabeculectomy with MMC effectively reduces IOP in PACG. Long-term IOP reduction is achieved for target IOP levels in the mid-teens. Presence of a crystalline lens, lack of iridotomy and higher preoperative IOP were associated with higher risks of failure. PMID- 29240599 TI - Prevalence and Visual Outcome of Glaucoma With Uveitis in a Thai Population. PMID- 29240598 TI - Intraluminal Deposits Found in Glaucoma Tube Shunts Via Anterior Segment Ocular Coherence Tomography. AB - PURPOSE: To describe and characterize a novel observation of intraluminal deposits of glaucoma tube shunts (TS) using spectral domain (SD) ocular coherence topography (OCT). PATIENTS AND METHODS: Fifteen TS in 11 patients diagnosed with primary open-angle, neovascular, aphakic, and uveitic glaucomas. Both Ahmed (n=11) and Baerveldt (n=4) TS were examined with 5-line raster anterior segment SD-OCT imaging. RESULTS: The exposed tubes of 2 patients had highly reflective intraluminal deposits in the corresponding exposed areas. Seven tubes without exposure had a thin rim of highly reflective material. Six tubes were clear of luminal deposits. The most common diagnosis in the study was uveitic glaucoma which occurred in 5 of the 15 eyes (33%). The next most common diagnosis was primary open-angle glaucoma which occurred in 4 of the 15 eyes (25%). There were 2 nonvalved Baerveldt tubes in each group. The mean duration of TS implantation was 15.0 months in the deposit group and 33.7 months in the group without luminal deposits. The majority of patients in each group were using eye drops at presentation (88.9% deposit, 83.3% clear), and the average intraocular pressure was 20.2 mm Hg in the deposit group and 19.0 mm Hg in the clear group. CONCLUSIONS: Anterior segment OCT imaging may be used to evaluate TS integrity. Intraluminal deposits in TS may occur as a natural response to implanted drainage device, possibly as an inflammatory response. PMID- 29240600 TI - Meibomian Gland Performance in Glaucomatous Patients With Long-term Instillation of IOP-lowering Medications. AB - PURPOSE: To investigate the meibomian gland (MG) performance in patients with glaucoma under topical intraocular pressure (IOP)-lowering medications. MATERIALS AND METHODS: This was a cross-sectional case-control study. Patients with glaucoma under different dosages and instillation periods of topical IOP-lowering medications were included. A total of 30 eyes out of 30 healthy participants and 85 eyes out of 85 patients with glaucoma were analyzed. The burden of instilling antiglaucoma agents [burden of antiglaucoma (BAG)] was simply scored for each participant based on the number, formula, frequency, and duration of topical IOP lowering medications used. All participants completed the MG and tear assessments, including Standard Patient Evaluation of Eye Dryness questionnaire, lipid layer thickness, MG secretion and dropout, Schirmer test, tear break-up time, and blinking patterns. RESULTS: Patients with glaucoma had significantly lower Standard Patient Evaluation of Eye Dryness scores, thinner lipid layer thickness, worse mebium quality, and lower MG secretion compared with healthy participants. Among the patients with glaucoma, MG loss ratio (P=0.006) and meiboscale (P=0.017) were significantly correlated with the BAG score. Compared with the low BAG group (score <80), the high BAG group (score >=80) had significantly shorter tear break-up time (P=0.047), lower MG density (P=0.032), higher MG loss ratio (P=0.011), and higher meiboscale (P=0.036). CONCLUSIONS: Patients with a higher BAG agents had more unstable tear films and more severe MG dropout. Therefore, MG disease should be particularly observed in patients with glaucoma following a higher BAG regimen. PMID- 29240601 TI - Efficacy of Transanal Drainage Tube Placement After Modified Posterior Pelvic Exenteration for Primary Ovarian Cancer. AB - OBJECTIVE: The aim of this study was to investigate the clinical usefulness of the placement of a transanal drainage tube (TDT) to prevent anastomotic leakage after a modified posterior pelvic exenteration (MPPE) for the treatment of primary ovarian cancer. METHODS: We performed a retrospective review of all the consecutive patients who had undergone an MPPE for primary ovarian, tubal, or peritoneal cancer between October 2012 and November 2016 at our institution. Patient-related, disease-related, and surgery-related data were collected. RESULTS: One hundred five patients who underwent an MPPE were included in this study. A TDT was placed in all the patients. A diverting ileostomy was created during cytoreductive surgery in 7 patients (7%). Those who underwent a diverting ileostomy tended to have a greater degree of surgical invasiveness, as was reflected by a longer operative time, a serious loss of blood, and a large quantity of intraoperative blood transfusion. Anastomotic leakage occurred in 1 patient (1%), and a diverting ileostomy was created for this patient. CONCLUSIONS: Transanal drainage tube placement seems to be an effective and safe procedure that can decrease the rate of anastomotic leakage and the need for a diverting stoma after MPPE for ovarian cancer. However, some patients inevitably require a diverting stoma despite the TDT placement. PMID- 29240602 TI - Unclassified Variants of BRCA1 and BRCA2 in Korean Patients With Ovarian Cancer. AB - OBJECTIVE: The aim of the present study was to investigate unclassified variants (UVs) in BRCA1 and 2 of Korean patients with ovarian cancer. METHODS: We retrospectively analyzed 138 patients diagnosed with ovarian/fallopian tubal/peritoneal cancer between January 2013 and January 2016, whose BRCA genetic test results and clinical characteristics were available for review. Patient peripheral blood lymphocyte specimens were assessed for BRCA mutations and variations by direct sequencing. Identified UVs were classified according to several algorithms. RESULTS: The results of genetic testing revealed 31 (22.5%, 31/138) pathogenic BRCA mutations (24 BRCA1, 7 BRCA2 mutations). The BRCA1 c.390C>A mutation was observed in 4 patients (12.9%, 4/31). Thirty-four (24.6%, 34/138) BRCA UVs were identified in 33 patients. Of these, the BRCA1 c.4883T>C and BRCA2 c.8187G>T variants were each detected in 4 patients (4/34, 11.8%). According to the used algorithms and cosegregation test, the BRCA1 c.5339T>C and BRCA2 c.8437_8439delGGA variants were both predicted to be likely pathogenic. CONCLUSIONS: The 2 identified likely pathogenic UVs require further verification with clinical evidence. Clarifying the clinical significance of UVs is an increasingly important step for cancer treatment in the current era of precision medicine. PMID- 29240603 TI - What Is the Optimal Adjuvant Treatment Sequence for Node-Positive Endometrial Cancer? Results of a National Cancer Database Analysis. AB - OBJECTIVE: The optimal sequence of administering chemotherapy (CT) and radiation treatment (RT) in women with node-positive endometrial carcinoma (EC) remains controversial. We used the National Cancer Database to evaluate overall survival (OS) in women with advanced EC receiving different sequences of adjuvant therapy. METHODS: The National Cancer Database was queried for female adults with International Federation of Gynecology and Obstetrics 2009 stage IIIC1 to IIIC2 EC diagnosed from 2004 to 2012 treated with hysterectomy and adjuvant CT and RT. Overall survival was compared between sequential treatment (CT followed by RT) and concurrent treatment (CT and RT within 4 weeks). chi tests assessed differences by sequence and various clinical variables. Log-rank test and Cox proportional hazards models evaluated OS. Risk factors related to OS were identified by univariate and multivariate analyses. RESULTS: Of 1826 patients, 67% (1218) received sequential treatment and 33% (608) received concurrent treatment. The median follow-up was 49.2 months. The sequential treatment group had a better 5-year OS (67% [95% confidence interval = 64%-70%]) than the concurrent treatment group (62% [95% confidence interval = 57%-66%]) (P = 0.004). On multivariate analysis, the strongest predictors of worse OS were increasing age (hazard ratio [HR] = 1.04 [1.02-1.06], P = 0.0003), type 2 versus type 1 EC (HR = 1.60 [1.06-2.43], P = 0.03), grade 3 versus 1 (HR = 2.64 [1.23-5.67], P = 0.01), residual disease or positive margin versus negative margin (HR = 2.25 [1.43-3.56], P = 0.0005), and concurrent versus sequential treatment (HR = 1.67 [1.15-2.40], P = 0.006). CONCLUSIONS: This study suggests that upfront CT followed by RT may be a better treatment sequence for adjuvant therapy in women with advanced EC. PMID- 29240604 TI - Potential Significance of Peptidome in Human Ovarian Cancer for Patients With Ascites. AB - OBJECTIVE: Ovarian cancer (OC) is one of the lethal gynecological malignancies. Most women affected by OC with malignant ascites will relapse. Peptidomics, as an emerging branch of proteomics, is more applied in screening of disease biomarkers, diagnosis, treatment, and monitoring. However, there is still little in-depth analysis about peptidomics study in OC with malignant ascites. METHODS: A comparative peptidomic profiling of ascites fluid between 6 OC patients and 6 benign gynecological conditions using liquid chromatography-tandem mass spectrometry was analyzed. Afterward, the Ingenuity Pathway Analysis was performed to reveal the potential function of peptide-protein precursors. RESULTS: A total of 4388 nonredundant peptides were identified, 104 of which were significantly differentially expressed in the ascites fluid of OC and benign gynecological conditions (>2-fold changes and P < 0.05): 52 peptides were upregulated while 52 peptides were downregulated. These peptides were imported into the Ingenuity Pathway Analysis and identified putative roles in OC. CONCLUSIONS: We identified the peptidome patterns of patients with OC and benign gynecological conditions, and these differentially expressed that peptides might play an important role during occurrence and development of OC and will be in hope to explore bioactive peptides in the pathogenesis of OC. PMID- 29240605 TI - Platelet-Derived Growth Factor D Is a Prognostic Biomarker and Is Associated With Platinum Resistance in Epithelial Ovarian Cancer. AB - OBJECTIVE: This study aimed to investigate whether platelet-derived growth factor D (PDGF-D) is a prognostic biomarker and is associated with platinum resistance in epithelial ovarian cancer, which has not been studied by others previously. METHODS: In this study, we detected expression of PDGF-D in ovarian cancer tissues through immunohistochemistry and Western blotting. Furthermore, we analyzed the association between PDGF-D expression and clinicopathological features including prognosis in epithelial ovarian cancer. Statistical analyses were performed by using chi test, log-rank test, Cox regression test, and Kaplan Meier method. RESULTS: High PDGF-D expression is positively correlated with International Federation of Gynecology and Obstetrics stage (P < 0.001), histologic grade (P < 0.001), lymph node metastasis (P = 0.022), and poor prognosis (P < 0.001). Platelet-derived growth factor D in platinum-resistant cases is overexpressed compared with that in platinum-sensitive cases (P < 0.001). Obstetrics stage (P = 0.029) and PDGF-D overexpression (P < 0.001) are independently correlated with platinum resistance. CONCLUSIONS: Our study indicates that PDGF-D overexpression is an independent predictor of platinum based chemotherapy resistance and that it may also be a potential biomarker for targeted therapy and poor prognosis. PMID- 29240607 TI - The Clinical Impact of Cardiology Consultation Prior to Major Vascular Surgery. AB - OBJECTIVE: To understand statewide variation in preoperative cardiology consultation prior to major vascular surgery and to determine whether consultation was associated with differences in perioperative myocardial infarction (poMI). SUMMARY BACKGROUND DATA: Medical consultation prior to major vascular surgery is obtained to reduce perioperative risk. Despite perceived benefit of preoperative consultation, evidence is lacking specifically for major vascular surgery on the effect of preoperative cardiac consultation. METHODS: Patient and clinical data were obtained from a statewide vascular surgery registry between January 2012 and December 2014. Patients were risk stratified by revised cardiac risk index category and compared poMI between patients who did or did not receive a preoperative cardiology consultation. We then used logistic regression analysis to compare the rate of poMI across hospitals grouped into quartiles by rate of preoperative cardiology consultation. RESULTS: Our study population comprised 5191 patients undergoing open peripheral arterial bypass (n = 3037), open abdominal aortic aneurysm repair (n = 332), or endovascular aneurysm repair (n = 1822) at 29 hospitals. At the patient level, after risk stratification by revised cardiac risk index category, there was no association between cardiac consultation and poMI. At the hospital level, preoperative cardiac consultation varied substantially between hospitals (6.9%-87.5%, P <0.001). High preoperative consulting hospitals (rate >66%) had a reduction in poMI (OR, 0.52; confidence interval: 0.28-0.98; P <0.05) compared with all other hospitals. These hospitals also had a statistically greater consultation rate with a variety of medical specialties. CONCLUSIONS: Preoperative cardiology consultation for vascular surgery varies greatly between institutions, and does not appear to impact poMI at the patient level. However, reduction of poMI was noted at the hospitals with the highest rate of preoperative cardiology consultation as well as a variety of medical services, suggesting that other hospital culture effects play a role. PMID- 29240608 TI - Metabolic Profile of Ex Vivo Lung Perfusate Yields Biomarkers for Lung Transplant Outcomes. AB - OBJECTIVE: To identify potential biomarkers during ex vivo lung perfusion (EVLP) using metabolomics approach. SUMMARY BACKGROUND DATA: EVLP increases the number of usable donor lungs for lung transplantation (LTx) by physiologic assessment of explanted marginal lungs. The underlying paradigm of EVLP is the normothermic perfusion of cadaveric lungs previously flushed and stored in hypothermic preservation fluid, which allows the resumption of active cellular metabolism and respiratory function. Metabolomics of EVLP perfusate may identify metabolic profiles of donor lungs associated with early LTx outcomes. METHODS: EVLP perfusate taken at 1and 4 hperfusion were collected from 50 clinical EVLP cases, and submitted to untargeted metabolic profiling with mass spectrometry. The findings were correlated with early LTx outcomes. RESULTS: Following EVLP, 7 cases were declined for LTx. In the remaining transplanted cases, 9 cases developed primary graft dysfunction (PGD) 3. For the metabolic profile at EVLP 1h, a logistic regression model based on palmitoyl-sphingomyelin, 5 aminovalerate, and decanoylcarnitine yielded a receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.987 in differentiating PGD 3 from Non-PGD 3 outcomes. For the metabolic profile at EVLP-4h, a logistic regression model based on N2-methylguanosine, 5-aminovalerate, oleamide, and decanoylcarnitine yielded a ROC curve with AUC 0.985 in differentiating PGD 3 from non-PGD 3 outcomes. CONCLUSIONS: Metabolomics of EVLP perfusate revealed a small panel of metabolites highly correlated with early LTx outcomes, and may be potential biomarkers that can improve selection of marginal lungs on EVLP. Further validation studies are needed to confirm these findings. PMID- 29240606 TI - Genetic studies of human neuropathic pain conditions: a review. AB - Numerous studies have shown associations between genetic variants and neuropathic pain disorders. Rare monogenic disorders are caused by mutations of substantial effect size in a single gene, whereas common disorders are likely to have a contribution from multiple genetic variants of mild effect size, representing different biological pathways. In this review, we survey the reported genetic contributors to neuropathic pain and submit them for validation in a 150,000 participant sample of the U.K. Biobank cohort. Successfully replicated association with a neuropathic pain construct for 2 variants in IL10 underscores the importance of neuroimmune interactions, whereas genome-wide significant association with low back pain (P = 1.3e-8) and false discovery rate 5% significant associations with hip, knee, and neck pain for variant rs7734804 upstream of the MAT2B gene provide evidence of shared contributing mechanisms to overlapping pain conditions at the molecular genetic level. PMID- 29240609 TI - Effects of Propofol on Cellular Bioenergetics in Human Skeletal Muscle Cells. AB - OBJECTIVES: Propofol may adversely affect the function of mitochondria and the clinical features of propofol infusion syndrome suggest that this may be linked to propofol-related bioenergetic failure. We aimed to assess the effect of therapeutic propofol concentrations on energy metabolism in human skeletal muscle cells. DESIGN: In vitro study on human skeletal muscle cells. SETTINGS: University research laboratories. SUBJECTS: Patients undergoing hip surgery and healthy volunteers. INTERVENTIONS: Vastus lateralis biopsies were processed to obtain cultured myotubes, which were exposed to a range of 1-10 MUg/mL propofol for 96 hours. MEASUREMENTS AND MAIN RESULTS: Extracellular flux analysis was used to measure global mitochondrial functional indices, glycolysis, fatty acid oxidation, and the functional capacities of individual complexes of electron transfer chain. In addition, we used [1-C]palmitate to measure fatty acid oxidation and spectrophotometry to assess activities of individual electron transfer chain complexes II-IV. Although cell survival and basal oxygen consumption rate were only affected by 10 MUg/mL of propofol, concentrations as low as 1 MUg/mL reduced spare electron transfer chain capacity. Uncoupling effects of propofol were mild, and not dependent on concentration. There was no inhibition of any respiratory complexes with low dose propofol, but we found a profound inhibition of fatty acid oxidation. Addition of extra fatty acids into the media counteracted the propofol effects on electron transfer chain, suggesting inhibition of fatty acid oxidation as the causative mechanism of reduced spare electron transfer chain capacity. Whether these metabolic in vitro changes are observable in other organs and at the whole-body level remains to be investigated. CONCLUSIONS: Concentrations of propofol seen in plasma of sedated patients in ICU cause a significant inhibition of fatty acid oxidation in human skeletal muscle cells and reduce spare capacity of electron transfer chain in mitochondria. PMID- 29240610 TI - First case of nonalcoholic steatohepatitis in a child with del(1p36) and dup (Xp22): review of the literature. PMID- 29240611 TI - Clinical and molecular characterization of the first familial report of 1p32 microdeletion. AB - Structural rearrangements of chromosome band 1p31p32 are rare, and their phenotypic consequences remain poorly delineated. Up to 12 patients with learning difficulties, developmental delay, multiple congenital anomalies and microdeletion of the chromosome band 1p31p32 have been described. Inheritance of this deletion has not been reported previously. We describe the inheritance of the 1p32 deletion and discuss the relevance of this deletion to the described phenotype. The differences in clinical and molecular characteristics between the proband and other published reports are reviewed. Patients were evaluated in Genetics Clinic with history, examination and investigation. The existing literature on interstitial deletions of 1p was reviewed. Here, we report on a three-generation family, where the index patient was an adult female with learning difficulty, dysmorphic features, microcephaly, ambiguous genitalia, congenital hip dislocation and brachydactyly in whom a maternally inherited 1.45 Mbp interstitial deletion was detected at 1p32.3. Both her mother and maternal grandmother have learning difficulties and dysmorphic features. There are 14 OMIM genes in the deleted region including LRP8 and DMRTB1. The NFIA gene is not deleted in this family. The first report of a familial 1p32 microdeletion in three generations of a family carrying the smallest reported a deletion involving this region and brachydactyly as a previously unreported feature. PMID- 29240612 TI - Extracellular Matrix Applications in the Treatment of Open Fractures With Complex Wounds and Large Soft Tissue Defects. AB - Use of biologic scaffolds such as extracellular matrix (ECM) is a promising trend in the treatment of complex wounds in orthopedic trauma patients. In this clinical series we describe the technique of the successful application of porcine urinary bladder ECM products in the treatment of open fractures of the extremities with complex wounds and large soft tissue defects. The clinical outcomes demonstrated that even in challenging cases where local flap coverage of bone or neurovascular structures is not possible, sequential xenograft implantation allowed us to achieve a stable soft tissue envelope. Different forms of ECM products are easy to apply in the presence of orthopedic hardware. In certain wounds, complete closure can be achieved even without subsequent skin grafting. We recommend relatively earlier application of xenograft. PMID- 29240613 TI - Assessing the Knowledge, Skills, and Abilities of Public Health Professionals in Big City Governmental Health Departments. AB - OBJECTIVE: To identify essential knowledge, skills, and abilities (KSAs) for and characterize gaps in KSAs of professionals working in large, urban health departments. DESIGN: A survey was disseminated to potentially eligible supervisors within 26 of 28 health departments in the largest, most urban jurisdictions in the country. A supervisor was eligible to participate if he or she supervised at least 1 staff member whose highest level of education was a master's degree. SETTING AND PARTICIPANTS: A total of 645 eligible supervisors participated in the workforce survey for a response rate of 27.1% and cooperation rate of 55.2%. MAIN OUTCOME MEASURE(S): Supervisors were asked to rate the importance of KSAs to their masters-level staffs' work and indicate their staffs' proficiency. RESULTS: Fifty-eight percent of supervisors reported supervising staff with a master of public health/master of science in public health degree. More than 30% of supervisors indicated that all of the 30 KSAs were essential. Four of the top 10 KSAs rated as essential by supervisors pertained to the ability to communicate. The top skills gaps perceived by supervisors were professional staffs' ability to apply quality improvement concepts to their work (38.0%), understanding of the political system (37.7%), and ability to anticipate changes (33.8%). CONCLUSIONS: Public health practitioners receive training in methods, theories, and evidence-based approaches, yet further investment in the workforce is necessary to advance population health. A focus should be placed developing strategic skills rather than advancing narrow specialties. Findings from this research can guide the creation and implementation of training curricula and professional development programs offered within local health departments or targeted to their staff, as well as satisfaction of accreditation requirements. By focusing on building strategic skills, we can ensure a public health workforce that is equipped with the KSAs necessary to practice Public Health 3.0 and leaders who are able to serve as their communities' chief health strategists. PMID- 29240614 TI - A Measure of the Potential Impact of Hospital Community Health Activities on Population Health and Equity. AB - CONTEXT: Many hospitals in the United States are exploring greater investment in community health activities that address upstream causes of poor health. OBJECTIVE: Develop and apply a measure to categorize and estimate the potential impact of hospitals' community health activities on population health and equity. DESIGN, SETTING, AND PARTICIPANTS: We propose a scale of potential impact on population health and equity, based on the cliff analogy developed by Jones and colleagues. The scale is applied to the 317 activities reported in the community health needs assessment implementation plan reports of 23 health care organizations in the Minneapolis-St Paul, Minnesota, metropolitan area in 2015. MAIN OUTCOME MEASURE: Using a 5-point ordinal scale, we assigned a score of potential impact on population health and equity to each community health activity. RESULTS: A majority (50.2%) of health care organizations' community health activities are classified as addressing social determinants of health (level 4 on the 5-point scale), though very few (5.4%) address structural causes of health equity (level 5 on the 5-point scale). Activities that score highest on potential impact fall into the topic categories of "community health and connectedness" and "healthy lifestyles and wellness." Lower-scoring activities focus on sick or at-risk individuals, such as the topic category of "chronic disease prevention, management, and screening." Health care organizations in the Minneapolis-St Paul metropolitan area vary substantially in the potential impact of their aggregated community health activities. CONCLUSIONS: Hospitals can be significant contributors to investment in upstream community health programs. This article provides a scale that can be used not only by hospitals but by other health care and public health organizations to better align their community health strategies, investments, and partnerships with programming and policies that address the foundational causes of population health and equity within the communities they serve. PMID- 29240615 TI - Enhancement and Suppression of Ionization in Drug Analysis Using HPLC-MS/MS in Support of Therapeutic Drug Monitoring: A Review of Current Knowledge of Its Minimization and Assessment. AB - High-performance liquid chromatography coupled with tandem mass spectrometry is commonly used for quantitation of analytes in biological matrices, because of the selectivity, sensitivity, and high throughput offered by this technique. However, the presence of both suppression and enhancement of ionization (SEI) by matrix components is an increasingly recognized impediment to accurate results. The existence of SEI indicates that ionization efficiency is a result of the chemical environment seen by both the analyte and internal standard during ion formation. SEI is influenced by the type and the make of ion source used, mobile-phase composition, extent of sample preparation, and the ability to chromatographically separate other compounds that may influence ionization of the analyte and/or internal standard. A comprehensive review of the phenomenon of SEI in high performance liquid chromatography coupled with tandem mass spectrometry was conducted, and a summary of salient papers relating to therapeutic agents in biological matrices is presented. Suggestions for approaches to minimize, normalize, or assess SEI and its deleterious effect on accuracy and sensitivity, and hence the validity of quantitative results, are provided. Consideration is also given to a strategy to test for SEI, including the number of samples from different sources that are required to adequately test for SEI. PMID- 29240617 TI - "The future depends on what you do today". PMID- 29240616 TI - Clozapine and Norclozapine Concentrations in Paired Human Plasma and Serum Samples. AB - BACKGROUND: Plasma and serum are often used interchangeably for therapeutic drug monitoring (TDM) purposes, and concentrations of some drugs are reported to be lower in serum than in plasma when collected into blood collection tubes containing a gel separator. TDM is recommended for clozapine, although few studies have compared concentrations between plasma and serum. Therefore, we investigated the comparability of dipotassium ethylenediaminetetraacetic acid human plasma and serum from blood collection tubes containing a gel separator for the measurement of clozapine and norclozapine. METHODS: Whole blood from patients (N = 93) prescribed clozapine was collected into a polypropylene Vacuette dipotassium ethylenediaminetetraacetic acid-containing blood collection tube (Greiner Bio-One), and a polypropylene Vacuette serum separator blood collection tube (Greiner Bio-One) containing a clotting activator (silica particles) and a polymer gel. RESULTS: Mean clozapine concentrations were significantly (P <= 0.05) lower in serum (0.37 mg/L) than in plasma (0.39 mg/L), as were concentrations of norclozapine (0.17 and 0.18 mg/L, respectively). Bland-Altman plots indicated mean serum clozapine and norclozapine were 0.018 mg/L (5.3%) and 0.004 mg/L (3.6%), respectively, lower in serum than plasma. CONCLUSIONS: Despite the finding that clozapine and norclozapine were significantly higher in plasma than in serum when obtained from blood collected into Vacuette serum separator collection tubes, this difference is insignificant in the clinical interpretation of clozapine and norclozapine TDM results. PMID- 29240618 TI - Diagnosing and treating ADHD in adults. PMID- 29240619 TI - Primary care management of ulcerative colitis. PMID- 29240620 TI - Urinary incontinence: Pelvic floor muscle and behavioral training for women. AB - Primary care NPs play a significant role in recognizing and implementing strategies for urinary incontinence (UI) management. The American College of Physicians recommends pelvic floor muscle and behavioral training as initial treatment for UI. This article provides practical tips that can help improve urinary continence. PMID- 29240621 TI - 30th Annual APRN Legislative Update: Improving access to healthcare one state at a time. AB - The Annual Legislative Update describes recent legislative changes to practice, reimbursement, and prescriptive authority that have the most impact on NPs and other advanced practice nurses across the country. PMID- 29240623 TI - Improving HPV vaccination rates among young males in rural areas of the United States. AB - Human papillomavirus (HPV) vaccination occurs more frequently among females ages 11 to 18 than their male counterparts. The purpose of this quality improvement project is to identify reasons why parents/guardians either choose or decline HPV immunization and increase rates of vaccination among males ages 11 to 18 in rural areas of the United States. PMID- 29240624 TI - Perpetuating our profession: Nurturing NP students. PMID- 29240625 TI - Orbital Shear Stress Regulates Differentiation and Barrier Function of Primary Renal Tubular Epithelial Cells. AB - Primary cells cultured in vitro gradually lose features characteristic of the in vivo phenotype. Culture techniques that help maintain cell-specific phenotype are advantageous for development of tissue engineered and bioartificial organs. Here we evaluated the phenotype of primary human renal tubular epithelial cells subjected to fluid shear stress by culturing the cells on an orbital shaker. Transepithelial electrical resistance (TEER), cell density, and gene and protein expression of proximal tubule-specific functional markers were measured in cells subjected to orbital shear stress. Cells cultured on an orbital shaker had increased TEER, higher cell density, and enhanced tubular epithelial specific gene and protein expression. This is likely due at least in part to the mechanical stress applied to the apical surface of the cells although other factors including increased nutrient and oxygen delivery and improved mixing could also play a role. These results suggest that orbital shaker culture may be a simple approach to augmenting the differentiated phenotype of cultured renal epithelial cells. PMID- 29240626 TI - First Report of Biventricular Percutaneous Impella Ventricular Assist Device Use in Pediatric Patients. AB - There is a growing interest in the use of percutaneously delivered ventricular assist devices (PVAD) in the pediatric patient population. A 16 year old female and 18 year old male both status post heart transplantation presented with evidence of graft rejection and acute severe global systolic and diastolic heart failure necessitating hemodynamic catheterization and inotropic support. Both underwent percutaneous Impella CP LVAD (Abiomed, Danvers, MA) placement with close monitoring of right ventricular function. Although pulmonary artery wedge pressure (PAWP) improved, persistently elevated central venous pressures (CVP) and ongoing renal and liver injury prompted insertion of Impella RP RVAD. Explantation of bilateral devices was achieved within 4 days in the 18 year old patient. He would go on to require total artificial heart support before successful retransplantation. Despite bilateral PVAD support and antirejection medications, our 16 year old patient went on to develop multisystem organ failure and ultimately passed away after withdrawal of life-sustaining therapies. We report the first description of biventricular percutaneous Impella VAD for the treatment of acute decompensated heart failure in a pediatric institution. This innovative VAD option for older children/adolescents represents a less-invasive advancement in mechanical support technology with potential applicability across the pediatric population. PMID- 29240627 TI - Extracorporeal Membrane Oxygenation Bridges Inoperable Patients to Definitive Cardiac Operation. AB - Extracorporeal membrane oxygenation (ECMO) offers an opportunity for patient recovery through complete cardiopulmonary support but is associated with complications that limit duration and overall utility. We examine the role of ECMO as a potential bridge to high-risk cardiac surgery in otherwise inoperable cases. This study reports a retrospective, multi-institution experience examining all patients for whom ECMO was used preoperatively as a bridge to definitive cardiac surgery without exception. A consecutive patient database (December 2011 through August 2017) was utilized. European System for Cardiac Risk Evaluation (EuroSCORE) 2 was calculated as a metric of patient acuity and risk assessment. Observed and expected mortality were compared. Twelve adult patients fit inclusion criteria and were supported with ECMO during the study period. There were five males and seven females. Average age was 56 (39-77) years. All 12 patients were supported with venoarterial ECMO for cardiogenic shock. This was done in preparation for corrective conventional cardiac surgery. Definitive cardiac surgical procedures included complex valve (n = 5), left ventricular assist device (n = 3), coronary artery bypass grafting (CABG; n = 2), CABG/ventricular septal defect repair (n = 1), and mitral valve replacement/CABG (n = 1). Average time of ECMO support was 200 (range 113-379) hours. Three patients were decannulated from ECMO at the conclusion of definitive cardiac surgery. Risk assessed by Logistic EuroSCORE 2 ranged from 64% to 89%. Average EuroSCORE 2-predicted mortality representing all 12 patients was 77%. Thirty day mortality was 25% (3/12), and hospital mortality was 33% (4/12). Seven patients are still alive today, with a mean survival of 37 (range 2-64) months. Two deaths were associated with gastrointestinal bleeding and two with evolving liver failure. Mean difference between the EuroSCORE 2 prediction model and actual observed 30 day mortality rate was 42.33 (95% CI 36.86-47.98) with a two-tailed, one-sample t test value of p < 0.001. ECMO can successfully be utilized as a bridge to conventional cardiac surgical procedures in critically ill patients, with a historically high mortality. PMID- 29240628 TI - Circulatory Support with Extracorporeal Membrane Oxygenation and/or Impella for Cardiogenic Shock During Myocardial Infarction. AB - Temporary mechanical circulatory support (TCS) is recommended for patients with profound cardiogenic shock (CS). Extracorporeal membrane oxygenation (ECMO) and Impella are possible TCS devices, but the device choice and the implantation timing are not definitely established, specifically during acute myocardial infarction. We have analyzed the respective use of ECMO or Impella (2.5, CP, or 5.0) for CS following acute myocardial infarction, from a cohort of patients who underwent TCS within 72 hours after admission for emergency percutaneous coronary intervention (PCI) from January 2009 to April 2015. Among 88 TCS-treated patients, 42 had early TCS: 23 ECMO and 19 Impella. Cardiac management, including PCI, was similar between the two groups, but ECMO patients were sicker than Impella patients (higher blood lactate level at ICU admission, higher vasoactive inotroic and ENCOURAGE scores before TCS implantation, p <= 0.02). Three patients (7%) have had TCS implantation before admission, but TCS was implanted mostly in cathlab (43%, 1 during PCI, 13 just after PCI) or soon after ICU admission (50%, n = 21). Modification of the initial TCS choice was required in 10 cases (24%) for assistance upgrading in case of Impella (n = 4) or for left ventricle unloading in case of ECMO (n = 6). Extracorporeal membrane oxygenation is the technique of choice in case of profound CS, whereas Impella devices seem more appropriate for less severe hemodynamic compromise. Interestingly, the combination of both techniques may help to overcome the limits inherent to each device. PMID- 29240629 TI - Measuring Contractility During Mechanical Circulatory Support Would Be a Strong Plus. PMID- 29240630 TI - In Vitro Characterization of the Pittsburgh Pediatric Ambulatory Lung. AB - Acute and chronic respiratory failure are a significant source of pediatric morbidity and mortality. Current respiratory support options used to bridge children to lung recovery or transplantation typically render them bedridden and can worsen long-term patient outcomes. The Pittsburgh Pediatric Ambulatory Lung (P-PAL) is a wearable pediatric blood pump and oxygenator (0.3 m surface area) integrated into a single compact unit that enables patient ambulation. The P-PAL is intended for long-term use and designed to provide up to 90% of respiratory support in children weighing 5-25 kg. Computational fluid dynamics and numerical gas exchange modeling were used to design the P-PAL and predict its performance. A P-PAL prototype was then used to obtain pressure versus flow curves at various impeller rotation rates using a blood analog fluid. In vitro oxygen exchange rates were obtained in blood in accordance with ISO standard 7199. The normalized index of hemolysis (NIH) was measured over a 6 hour period at blood flow rates of 1 and 2.5 L/min. The P-PAL provided blood flows of 1-2.5 L/min against the pressure drop associated with its intended-use pediatric cannulas. The oxygen exchange rate reached a maximum of 108 ml/min at a blood flow rate of 2.5 L/min and met our respiratory support design target. Device-induced hemolysis was low with NIH values of 0.022-0.027 g/100 L in the intended blood flow rate range. In conclusion, the current P-PAL design met our pumping, oxygenation, and hemolysis specifications and has the potential to improve treatment for pediatric respiratory failure. PMID- 29240631 TI - In Vivo 5 Day Animal Studies of a Compact, Wearable Pumping Artificial Lung. AB - Recent studies show improved outcomes in ambulated lung failure patients. Ambulation still remains a challenge in these patients. This necessitates development of more compact and less cumbersome respiratory support specifically designed to be wearable. The Paracorporeal Ambulatory Assist Lung (PAAL) is being designed for providing ambulatory support in lung failure patients during bridge to transplant or recovery. We previously published in vitro and acute in vivo results of the PAAL. This study further evaluates the PAAL for 5 days. Five-day in vivo studies with the PAAL were conducted in 50-60 kg sheep after heparinization (activated clotting time range: 190-250 s) and cannulation with a 27 Fr. Avalon Elite dual-lumen cannula. The animals were able to move freely in a stanchion while device flow, resistance, and hemodynamics were recorded hourly. Oxygenation and hemolysis were measured daily. Platelet activation, blood chemistry, and comprehensive blood counts are reported for preoperatively, on POD 0, and POD 5. Three animals survived for 5 days. No study termination resulted from device failure. One animal was terminated on POD 0 and one animal was terminated at POD 3. The device was operated between 1.93 and 2.15 L/min. Blood left the device 100% oxygenated. Plasma-free hemoglobin ranged 10.8-14.5 mg/dl. CD62-P expression was under 10%. Minimal thrombus was seen in devices at explant. Chronic use of the PAAL in awake sheep is promising based on our study. There were no device-related complications over the study course. This study represents the next step in our pathway to eventual clinical translation. PMID- 29240632 TI - Methods for Sexually Transmitted Disease Prevention Programs to Estimate the Health and Medical Cost Impact of Changes in Their Budget. AB - BACKGROUND: The purpose of this article was to describe methods that sexually transmitted disease (STD) programs can use to estimate the potential effects of changes in their budgets in terms of disease burden and direct medical costs. METHODS: We proposed 2 distinct approaches to estimate the potential effect of changes in funding on subsequent STD burden, one based on an analysis of state level STD prevention funding and gonorrhea case rates and one based on analyses of the effect of Disease Intervention Specialist (DIS) activities on gonorrhea case rates. We also illustrated how programs can estimate the impact of budget changes on intermediate outcomes, such as partner services. Finally, we provided an example of the application of these methods for a hypothetical state STD prevention program. RESULTS: The methods we proposed can provide general approximations of how a change in STD prevention funding might affect the level of STD prevention services provided, STD incidence rates, and the direct medical cost burden of STDs. In applying these methods to a hypothetical state, a reduction in annual funding of US $200,000 was estimated to lead to subsequent increases in STDs of 1.6% to 3.6%. Over 10 years, the reduction in funding totaled US $2.0 million, whereas the cumulative, additional direct medical costs of the increase in STDs totaled US $3.7 to US $8.4 million. CONCLUSIONS: The methods we proposed, though subject to important limitations, can allow STD prevention personnel to calculate evidence-based estimates of the effects of changes in their budget. PMID- 29240633 TI - Sexually Transmitted Infection Testing of HIV-Positive Medicare and Medicaid Enrollees Falls Short of Guidelines. AB - BACKGROUND: Men who have sex with men with HIV have high sexually transmitted infection (STI) incidence. Thus, the Centers for Disease Control and Prevention (CDC) recommends at least yearly STI screening of HIV-infected individuals. METHODS: We calculated testing rates for syphilis, chlamydia, and gonorrhea among HIV-positive Californians with Medicare or Medicaid insurance in 2010. Logistic regressions estimated how testing for each bacterial STI relates to demographic and provider factors. RESULTS: Fewer than two-thirds of HIV-positive Medicare and fewer than three-quarters of Medicaid enrollees received a syphilis test in 2010. Screenings for chlamydia or gonorrhea were less frequent: approximately 30% of Medicare enrollees were tested for chlamydia or gonorrhea in 2010, but higher proportions of Medicaid enrollees were tested (45%-46%). Only 34% of HIV-positive Medicare enrollees who were tested for syphilis were also screened for chlamydia or gonorrhea on the same day. Nearly half of Medicaid enrollees were tested for all 3 STIs on the same day. Patients whose providers had more HIV experience had higher STI testing rates. CONCLUSIONS: Testing rates for chlamydia and gonorrhea infection are low, despite the increase in these infections among people living with HIV and their close association with HIV transmission. Interventions to increase STI testing include the following: prompts in the medical record to routinely conduct syphilis testing on blood drawn for viral load monitoring, opt out consent for STI testing, and provider education about the clinical importance of STIs among HIV-positive patients. Last, it is crucial to change financial incentives that discourage nucleic acid amplification testing for rectal chlamydia and gonorrhea infections. PMID- 29240634 TI - Improvement Still Needed in Sexually Transmitted Disease Testing Among HIV Positive Medicaid Enrollees. PMID- 29240635 TI - The Etiology of Male Urethral Discharge in Zimbabwe: Results from the Zimbabwe STI Etiology Study. AB - INTRODUCTION: Sexually transmitted infections (STIs) are managed syndromically in most developing countries. In Zimbabwe, men presenting with urethral discharge are treated with a single intramuscular dose of kanamycin or ceftriaxone in combination with a week's course of oral doxycycline. This study was designed to assess the current etiology of urethral discharge and other STIs to inform current syndromic management regimens. METHODS: We conducted a study among 200 men with urethral discharge presenting at 6 regionally diverse STI clinics in Zimbabwe. Urethral specimens were tested by multiplex polymerase chain reaction testing for Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, and Trichomonas vaginalis. In addition, serologic testing for syphilis and HIV was performed. RESULTS: Among the 200 studied men, one or more pathogens were identified in 163 (81.5%) men, including N. gonorrhoeae in 147 (73.5%), C. trachomatis in 45 (22.5%), T. vaginalis in 8 (4.0%), and M. genitalium in 7 (3.5%). Among all men, 121 (60%) had a single infection, 40 (20%) had dual infections, and 2 (1%) had 3 infections. Among the 45 men with C. trachomatis, 36 (80%) were coinfected with N. gonorrhoeae. Overall, 156 (78%) men had either N. gonorrhoeae or C. trachomatis identified. Of 151 men who consented to HIV testing, 43 (28.5%) tested positive. There were no differences in HIV status by study site or by urethral pathogen detected. CONCLUSIONS: Among men presenting at Zimbabwe STI clinics with urethral discharge, N. gonorrhoeae and C. trachomatis are the most commonly associated pathogens. Current syndromic management guidelines seem to be adequate for the treatment for symptomatic men, but future guidelines must be informed by ongoing monitoring of gonococcal resistance. PMID- 29240636 TI - The Etiology of Genital Ulcer Disease and Coinfections With Chlamydia trachomatis and Neisseria gonorrhoeae in Zimbabwe: Results From the Zimbabwe STI Etiology Study. AB - BACKGROUND: In many countries, sexually transmitted infections (STIs) are treated syndromically. Thus, patients diagnosed as having genital ulcer disease (GUD) in Zimbabwe receive a combination of antimicrobials to treat syphilis, chancroid, lymphogranuloma venereum (LGV), and genital herpes. Periodic studies are necessary to assess the current etiology of GUD and assure the appropriateness of current treatment guidelines. MATERIALS AND METHODS: We selected 6 geographically diverse clinics in Zimbabwe serving high numbers of STI cases to enroll men and women with STI syndromes, including GUD. Sexually transmitted infection history and risk behavioral data were collected by questionnaire and uploaded to a Web based database. Ulcer specimens were obtained for testing using a validated multiplex polymerase chain reaction (M-PCR) assay for Treponema pallidum (TP; primary syphilis), Haemophilus ducreyi (chancroid), LGV-associated strains of Chlamydia trachomatis, and herpes simplex virus (HSV) types 1 and 2. Blood samples were collected for testing with HIV, treponemal, and nontreponemal serologic assays. RESULTS: Among 200 GUD patients, 77 (38.5%) were positive for HSV, 32 (16%) were positive for TP, and 2 (1%) were positive for LGV-associated strains of C trachomatis. No H ducreyi infections were detected. No organism was found in 98 (49.5%) of participants. The overall HIV positivity rate was 52.2% for all GUD patients, with higher rates among women compared with men (59.8% vs 45.2%, P < 0.05) and among patients with HSV (68.6% vs 41.8%, P < 0.0001). Among patients with GUD, 54 (27.3%) had gonorrhea and/or chlamydia infection. However, in this latter group, 66.7% of women and 70.0% of men did not have abnormal vaginal or urethral discharge on examination. CONCLUSIONS: Herpes simplex virus is the most common cause of GUD in our survey, followed by T. pallidum. No cases of chancroid were detected. The association of HIV infections with HSV suggests high risk for cotransmission; however, some HSV ulcerations may be due to HSV reactivation among immunocompromised patients. The overall prevalence of gonorrhea and chlamydia was high among patients with GUD and most of them did not meet the criteria for concomitant syndromic management covering these infections. PMID- 29240637 TI - The Boomerang Lift: A Three-Step Compartment-Based Approach to the Youthful Cheek. AB - Autologous fat grafting is an important tool for plastic surgeons treating the aging face. Malar augmentation with fat is often targeted to restore the youthful facial contour and provides support to the lower eyelid. The existence of distinct facial fat compartments suggests that a stepwise approach may be appropriate in this regard. The authors describe a three-step approach to malar augmentation using targeted deep malar fat compartmental augmentation, termed the "boomerang lift." Clinical patients undergoing autologous fat grafting for malar augmentation were injected in three distinct deep malar fat compartments: the lateral sub-orbicularis oculi fat, the medial sub-orbicularis oculi fat, and the deep medial cheek (n = 9). Intraoperative three-dimensional images were taken at baseline and following compartmental injections (Canfield VECTRA H1). Images were overlaid between the augmented and baseline captures, and the three-dimensional surface changes were analyzed, which represented the resulting "augmentation zone." Three-dimensional analysis demonstrated a unique pattern for the augmentation zone consistent across patients. The augmentation zone resembled a boomerang, with the short tail supporting the medial lower lid and the long tail extending laterally along the zygomatic arch. The upper border was restricted by the level of the nasojugal interface, and the lower border was defined medially by the nasolabial fold and laterally by the level of the zygomaticocutaneous ligament. Lateral and medial sub-orbicularis oculi fat injections defined the boundaries of the boomerang shape, and injection to the deep medial cheek provided maximum projection. This is the first description of deep malar augmentation zones in clinical patients. Three-dimensional surface imaging was ideal for analyzing the surface change in response to targeted facial fat grafting. The authors' technique resulted in a reproducible surface shape, which they term the boomerang lift. PMID- 29240638 TI - Antibiotic Prophylaxis after Immediate Breast Reconstruction: The Reality of Its Efficacy. AB - BACKGROUND: Numerous techniques are used to prevent infection after immediate implant-based breast reconstruction. Postoperative antibiotic prophylaxis is commonly prescribed to decrease the risk of reconstructive failure, despite conflicting evidence regarding its effectiveness. The authors studied whether postoperative antibiotic prophylaxis decreases the risk of infection-related explantation in the setting of immediate prosthesis-based breast reconstruction. METHODS: Using Truven MarketScan databases, the authors identified all patients who underwent immediate implant reconstruction between January of 2010 and June of 2014 with at least 6 months of follow-up. Postoperative antibiotic prophylaxis was defined as any oral antibiotic course to be taken postoperatively based on prescriptions filled within 14 days preoperatively through 24 hours after discharge. Reconstructive failure, defined as explantation because of infection, was the primary outcome. Secondary outcomes of interest included wound complications, infection, and readmission for infection. Multivariable regression analyses controlled for demographic variables/comorbidities. RESULTS: Of the 7443 patients, 6049 (81 percent) filled prescriptions for postoperative antibiotic prophylaxis. These patients were equally likely to develop a wound complication (OR, 0.93; 95 percent CI, 0.71 to 1.23) or infection (OR, 0.89; 95 percent CI, 0.70 to 1.14), undergo explantation because of infection (OR, 0.82; 95 percent CI, 0.57 to 1.18), or require readmission for infection (OR, 1.21; 95 percent CI, 0.82 to 1.78) compared with those who did not receive antibiotics. There was no significant difference in the risk of infection-related outcomes based on postoperative antibiotic prophylaxis duration. CONCLUSIONS: Postoperative antibiotic prophylaxis was not associated with a reduced risk of infection or explantation following prosthesis-based breast reconstruction. Given rising rates of antibiotic resistance, focusing instead on technical considerations and the management of comorbid conditions may more effectively enhance the safety of breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29240639 TI - Absorbable Antibiotic Beads Prophylaxis in Immediate Breast Reconstruction. AB - BACKGROUND: Breast reconstruction with tissue expanders is the most common mode of reconstruction following mastectomy. Infection necessitating tissue expander removal is a significant complication leading to patient distress and increased health care costs. METHODS: Over 3 years, 127 breast reconstructions with tissue expanders were performed by a single surgeon. Fifty-nine of these reconstructions were performed using a standardized protocol in which patients washed with chlorhexidine several days before surgery and received intravenous antibiotics preoperatively. Intraoperatively, the submuscular pocket was irrigated with triple-antibiotic solution and the skin was prepared again with povidone-iodine before expander placement. This group was referred to as the preintervention group. Sixty-eight of the reconstructions were performed using the standardized protocol with the addition of biodegradable antibiotic beads (Stimulan with vancomycin and gentamicin) in the submuscular pocket. This group made up the postintervention group. The primary outcome was the rate of infection necessitating tissue expander removal. RESULTS: The rate of tissue expander loss caused by infection was 11.9 percent in the preintervention group and 1.5 percent in the postintervention group (p = 0.024). Higher body mass index was associated with a statistically significant increase in infections necessitating expander removal. CONCLUSION: The use of absorbable antibiotic beads in the submuscular pocket reduced the risk of periprosthetic implant infection necessitating implant removal by 8-fold. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29240640 TI - Indocyanine Green Angiography Use in Breast Reconstruction: A National Analysis of Outcomes and Cost in 110,320 Patients. AB - BACKGROUND: Indocyanine green angiography has gained popularity in breast reconstruction for its ability to assess mastectomy skin and tissue flap viability. The authors aim to analyze trends and outcomes associated with indocyanine green angiography use in breast reconstruction. METHODS: Using 2012 to 2014 data from the Healthcare Cost and Utilization Project National Inpatient Sample, Agency for Healthcare Research and Quality, the authors identified breast reconstructions performed with or without indocyanine green angiography use. Trends over time were assessed using the Cochran-Armitage test. Outcomes were assessed using logistic regression and generalized linear modeling. RESULTS: Over the study period, 110,320 patients underwent breast reconstruction: 107,005 (97.0 percent) without and 3315 (3.0 percent) with indocyanine green angiography use. Usage increased over time: 750 patients (1.9 percent) in 2012, increasing to 1275 patients (3.7 percent) in 2013 (p < 0.001). Smokers (p = 0.018), hypertensive patients (p = 0.046), obese patients (p < 0.001), and those with a higher comorbidity index (p < 0.001) were more likely to undergo indocyanine green angiography. Autologous reconstruction was more frequently combined with its use compared with tissue expander reconstruction (4.5 percent versus 2.1 percent; p < 0.001). There was a significant increase in the odds of debridement associated with its use (OR, 1.404; p < 0.001; 95 percent CI, 1.201 to 1.640). CONCLUSIONS: Indocyanine green angiography use in breast reconstruction has increased in recent years and is associated with higher debridement rates. These rates may indicate changing trends for clinicians when deciding whether to debride tissue during breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29240641 TI - Low-Dose Insulin as an Antiscarring Therapy in Breast Surgery: A Randomized Controlled Trial. AB - BACKGROUND: The role of insulin in expediting wound healing is firmly established within the context of major trauma and burns; however, only limited clinical evidence exists as to its effects on scar formation. This study aims to build on previous laboratory work to examine the potential antiscarring properties of insulin in a clinical environment. METHODS: Ninety-one patients undergoing bilateral aesthetic breast operations were recruited to receive low-dose insulin and placebo injections to the medial 3 cm of their submammary incisions within the context of a randomized, intrapatient, placebo-controlled trial, and scar quality was assessed at 3-, 6-, and 12-month reviews using the Manchester Scar Scale. RESULTS: Across the cohort at 12-month review, the insulin-treated scars had lower scar scores (p = 0.055) compared with placebo. Subgroup analysis of individuals with heavier scars showed that median scar scores were significantly lower for the insulin-treated scars with regard to both scar contour (p = 0.048) and scar distortion (p = 0.045). CONCLUSIONS: Subcutaneous insulin injections reduced the appearance of scarring in this study compared with placebo. The greatest effect was seen in those participants who showed heavier scars and, as such, insulin has a role as an antiscarring therapy in individuals likely to be affected by heavier scarring. Further research is required to more precisely delineate which subjects may benefit most from this treatment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 29240642 TI - Body Mass's Impact on Response to Fixed-Dose Vasopressin in Patients With Septic Shock. AB - INTRODUCTION: The effect of patient weight and body mass index (BMI) on hemodynamic response to vasoactive medications is not fully understood. In titratable vasopressors, this effect is less likely a concern due to the ability to titrate dose to response; however, with the use of fixed-dose vasopressin, patient weight and BMI may impact response. METHODS: This was a single-center, retrospective cohort of patients who received fixed-dose vasopressin for septic shock for at least 6 h with concomitant catecholamines in the medical, surgical, or neurosciences intensive care unit (ICU) at a tertiary care center. The association of weight- and BMI-adjusted vasopressin dose with change in catecholamine dose and change in mean arterial pressure (MAP) were evaluated using Spearman's correlation. Patients were further stratified by World Health Organization BMI categories to evaluate secondary outcomes. RESULTS: There were 938 patients included with a median weight of 86.3 (70.6-106.6) kg and BMI of 29.5 (24.9-36.2) kg/m. There was no correlation between weight-adjusted vasopressin dose and change in catecholamine dose (r = -0.05, P = 0.13) or change in MAP (r = 0.04, P = 0.31) 2 h after initiation of vasopressin. Similarly, no correlation was found when evaluating change in catecholamine dose or MAP at 6 and 12 h after vasopressin initiation (all P values >0.05). Comparable findings were observed when evaluating correlations between BMI-adjusted vasopressin dose with change in MAP and catecholamine dose at all time points (all P values >0.05). BMI groupings were balanced with 238 patients (25.4%) having a BMI less than 25, 254 patients (27.1%) having BMI 25 to 30, 182 patients (19.4%) having BMI 30 to 35, and 264 patients (28.1%) having BMI more than 35. The median duration of mechanical ventilation and ICU free days were 3.99 (1.50-5.07) and 0 (0-1.6) days, respectively, with no differences observed when stratified by BMI (P = 0.59 and P = 0.83, respectively). In-hospital mortality was 64.8% and there was no difference among BMI groups (P = 0.35). CONCLUSIONS: In this large cohort of septic shock patients, adjusting vasopressin dose for weight and BMI did not impact changes in catecholamine doses or MAP. Duration of mechanical ventilation, ICU free days, and mortality after vasopressin initiation were not affected by BMI. PMID- 29240643 TI - Temporally Distinct Regulation of Pathways Contributing to Cardiac Proteostasis During the Acute and Recovery Phases of Sepsis. AB - BACKGROUND: Cardiac dysfunction is a common manifestation of sepsis and is associated with early increases in inflammation and decreases in myocardial protein synthesis. However, little is known regarding the molecular mechanisms regulating protein homeostasis during the recovery phase after the removal of the septic nidus. Therefore, the purpose of this study was to investigate diverse signal transduction pathways that regulate myocardial protein synthesis and degradation. METHODS: Adult male C57BL/6 mice were used to identify potential mechanisms mediating the acute (24 h) effect of cecal ligation and puncture as well as long-term changes that manifest during the chronic (10 days) recovery phase. RESULTS: Sepsis acutely decreased cardiac protein synthesis that was associated with reduced phosphorylation of S6K1/S6 but not 4E-BP1. Sepsis also decreased proteasome activity, although with no change in MuRF1 and atrogin-1 mRNA expression. Sepsis acutely increased apoptosis (increased caspase-3 and PARP cleavage), autophagosome formation (increased LC3B-II), and canonical inflammasome activity (increased NLRP3, TMS1, cleaved caspase-1). In contrast, during the recovery phase, independent of a difference in food consumption, global protein synthesis was increased, the early repression in proteasome activity was restored to basal levels, whereas stimulation of apoptosis, autophagosome formation, and the canonical inflammasome pathway had abated. However, during recovery there was a selective stimulation of the noncanonical inflammasome pathway as evidenced by activation of caspase-11 with cleavage of Gasdermin D. CONCLUSIONS: These data demonstrate a temporally distinct homeostatic shift in the cardiac proteostatic response to acute infection and recovery. PMID- 29240644 TI - Monocyte Function and Clinical Outcomes in Febrile and Afebrile Patients With Severe Sepsis. AB - INTRODUCTION: Absence of fever is associated with higher mortality in septic patients, but the reason for this is unknown. Immune dysfunction may be a potential link between failure to mount a fever and poor outcomes. The purpose of this study was to evaluate monocyte function and clinical surrogates of immunity (i.e., mortality and acquisition of secondary infections) in febrile and afebrile septic patients. METHODS: Single-center, prospective cohort study of 92 critically ill septic patients. Patients were categorized into febrile (>=38.0 degrees C) and afebrile (<38.0 degrees C) groups based on temperature measurements within 24 hours of sepsis diagnosis. HLA-DR expression and LPS induced TNF-alpha production were quantified on days 1-2, days 3-4, and days 6-8 after sepsis diagnosis. A repeated measures mixed models analysis was used to compare these markers between the two groups. RESULTS: Forty-four patients (47.8%) developed a fever within 24 h of sepsis diagnosis. There were no significant differences in HLA-DR expression or LPS-induced TNF-alpha production between febrile and afebrile patients at any individual time point. However, HLA DR expression significantly increased between days 1-2 and days 6-8 (median difference 8118 [IQR 1,662, 9,878] antibodies/cell, P = 0.002) in febrile patients, but not in afebrile patients (median difference 403 [-3,382, 3,507] antibodies/cell, P = 0.25). Afebrile patients demonstrated higher 28-day mortality (37.5% vs 18.2%) and increased acquisition of secondary infections (35.4% vs. 15.9%). CONCLUSIONS: Absence of fever is associated with suppressed HLA-DR expression over time, a finding suggestive of monocyte dysfunction in sepsis, as well as worse clinical outcomes. PMID- 29240646 TI - Genetic and Environmental Contributions to Sleep Quality and Low Back Pain: A Population-Based Twin Study. AB - OBJECTIVE: The aim of the study was to estimate the extent to which the co occurrence of poor sleep quality and low back pain is due to the same genetic and/or environmental risk factors or due to a causal association. METHODS: Cross sectional data on sleep quality (Pittsburgh Sleep Quality index) and low back pain were collected in a population-based sample of adult twins (N = 2134) registered with the Murcia Twin Registry. Bivariate analysis and structural equation modeling were used. RESULTS: The phenotypic correlation between sleep quality and low back pain was 0.23 (95% confidence interval [CI] = 0.17-0.28). The best-fitting bivariate model included additive genetic and unique environmental factors. Genetic factors accounted for 26% (95% CI = 10-40) and 34% (95% CI = 25-43) of the variability of low back pain and sleep quality, respectively. The correlation between the genetic factors underlying each trait was rG of 0.33 (95% CI = 0.03-0.66), and this overlap of genetic factors explained 42.5% of the phenotypic correlation. On the other hand, nonshared environmental factors of each variable were only fairly correlated rE of 0.19 (95% CI = 0.06-0.31), although this overlap explained 57.5% of the phenotypic correlation. In addition, twins in monozygotic pairs with poorer sleep quality presented more often with low back pain than their co-twins (rho^ = 0.25, p < .0001). CONCLUSIONS: The data are compatible with a causal effect of sleep quality on low back pain (or the reverse effect), because the correlations between the genetic and unique environmental factors for each trait were significant and there was a significant correlation between the monozygotic twins' difference scores. Apart from environmental factors that affect both characteristics, there are many individual-specific events that influence low back pain but differ from those influencing sleep quality. PMID- 29240645 TI - Resveratrol Downregulates Biomarkers of Sepsis Via Inhibition of Proteasome's Proteases. AB - Lipopolysaccharide (LPS) is the main agonist of gram-negative bacteria and initiates inflammation. We recently reported that plasmas from sepsis patients revealed increased levels of following group of biomarkers; VCAM-1, ICAM1, CRP, resistin, and proteasome LMP subunits. Our objective here was to compare effects of resveratrol (shown to be a nonspecific proteasome inhibitor by us) and a known LMP7 inhibitor (ONX-0914, specific inhibitor) on proteasome's activities, as well as on inflammatory markers mentioned above in human blood monocytes. Using fluorescence-based assays on blood monocytes purified proteasomes, resveratrol (0 100 MUM) inhibited all three protease activities, predominantly LMP7. Similarly, resveratrol inhibited all three protease activities using cell-based luminescence assay. In contrast, ONX-0914 was more selective and potent for LMP7 activity. Resveratrol and ONX-0914, both significantly inhibited expression of LPS-induced biomarkers mentioned above in CD14 monocytes. Moreover, resveratrol itself, as well as in combination with LPS, accumulated pIkappaBalpha in CD14 monocytes. Collectively, our data suggest that resveratrol is a less potent inhibitor of all three; CT-like (predominantly LMP7), T-like and PA protease activities and is less toxic to human monocytes than ONX-0914 (a selector inhibitor of only LMP7) as observed by an autophagy detection kit. Also, resveratrol reduces LPS-induced inflammatory cytokine expression by decreasing the translocation of NF-kappaB due to an increase in inhibitor pIkappaBalpha. Therefore, resveratrol can be used to curb inflammation in diseased states like sepsis and other disorders. PMID- 29240647 TI - Stagnation Syndrome: Relevance of the Multilayers of Illness Experiences in Chinese Medicine to the Understanding of Functional Somatic Syndrome. PMID- 29240648 TI - Reliable new measures capturing low-frequency fluctuations from resting-state functional MRI. AB - Resting-state functional MRI (rsfMRI) is one of the most important neuroimaging modalities for investigating alterations in the resting-state networks of the human brain, given that abnormal neural activity during the resting state is associated with neurological disorders. However, neuroimaging results obtained from rsfMRI have rarely been replicated with repeated measurements. Therefore, we aimed to develop new measures to extract highly reliable and reproducible functional neuroimaging metrics from rsfMRI data. Preprocessed rsfMRI data from 30 patients with 10 sessions of rsfMRI scans taken within 1 month were obtained from the Consortium for Reliability and Reproducibility. We developed a time domain measure to capture low-frequency fluctuation (LFF) using a general linear model with three different periodic regressors: boxcar, triangular, and sinusoidal functions. Then, test-retest reliability for the proposed methods was evaluated using the intraclass correlation (ICC). Our approaches for evaluating LFF from rsfMRI data significantly identified the default mode network areas (corrected P<0.05). The regression model with the sinusoidal basis function produced the most reliable results (ICC=0.6) compared with the boxcar (ICC=0.32) or triangular (ICC=0.34) functions. Taken together, the proposed methods successfully identified the default mode network regions. In addition, our results suggest that new functional metrics aiming to extract LFF components by modeling rsfMRI time-series data might provide a reliable biomarker to identify neurological disorders accompanying abnormal functional activity. PMID- 29240649 TI - Electronic Fetal Monitoring Documentation: Connecting Points for Quality Care and Communication. AB - Contemporaneous, complete, and objective documentation is the foundation for continuity of patient care and facilitates communication between all levels of healthcare clinicians. The impact of electronic fetal monitoring on obstetric safety has become a high priority, with documentation being essential to evaluating care quality. Over several decades, electronic fetal monitoring documentation has reached a higher level of precision because paper is being replaced with health information technology that incorporates system's features such as checklists, drop-down boxes, and decision analysis. The intent of this article is to provide a synopsis of important concepts regarding electronic fetal monitoring documentation and liability-reduction strategies for perinatal nurses. PMID- 29240650 TI - Oxytocin Use in Labor: Legal Implications. AB - Oxytocin is one of the most commonly used medications in obstetrics and has been associated with claims of negligence in cases of adverse outcomes. Errors involving intravenous oxytocin administration for induction or augmentation of labor are most commonly dose related and include failure to avoid or treat tachysystole or failure to asses or treat a fetal heart rate pattern indicative of disruption in oxygenation. Clinicians should be knowledgeable regarding pharmacokinetics of oxytocin and the effect of uterine contractions on fetal oxygenation as well as safe titration of oxytocin to achieve the desired effect while minimizing harm. PMID- 29240651 TI - Acute Impact of Different Exercise Modalities on Arterial and Platelet Function. AB - PURPOSE: Acute coronary syndromes and ischemic stroke are associated with arterial events involving platelets, the endothelium, and atherosclerosis. Although regular physical activity is associated with lower risk of cardiovascular events and mortality, risk is transiently increased during and immediately after participation in an acute bout of exercise. No previous study has investigated the acute impact of exercise on platelet activation and arterial function in the same participants; it is also unknown if responses are dependent on exercise modality. We hypothesized that commonly adopted, yet physiologically distinct, modalities of exercise ("aerobic" vs "resistance") have differing effects on in vivo platelet activation and conduit artery diameter. METHODS: Eight apparently healthy middle-age (53.5 +/- 1.6 yr) male subjects took part in four 30-min experimental interventions (aerobic exercise, resistance exercise, combined aerobic/resistance exercise, or no-exercise), in random order. Blood samples were collected, and the measurement of brachial artery diameter by ultrasound was performed before, immediately after, and 1 h after each intervention. Platelet activation was determined by the positive binding of antibodies to surface receptors exposed on activated platelets (anti-CD62P and PAC-1). RESULTS: Brachial artery diameter increased immediately after all three exercise modalities (P < 0.001) and remained above preexercise levels 1 h after resistance exercise and after combined aerobic/resistance exercise. No changes were observed in markers of in vivo platelet activation with any experimental protocol. CONCLUSIONS: These data suggest that postexercise enhancement in arterial function may mitigate the acute impact of exercise on platelet activation. PMID- 29240652 TI - Interindividual Responses of Appetite to Acute Exercise: A Replicated Crossover Study. AB - PURPOSE: Acute exercise transiently suppresses appetite, which coincides with alterations in appetite-regulatory hormone concentrations. Individual variability in these responses is suspected, but replicated trials are needed to quantify them robustly. We examined the reproducibility of appetite and appetite regulatory hormone responses to acute exercise and quantified the individual differences in responses. METHODS: Fifteen healthy, recreationally active men completed two control (60-min resting) and two exercise (60-min fasted treadmill running at 70% peak oxygen uptake) conditions in randomized sequences. Perceived appetite and circulating concentrations of acylated ghrelin and total peptide YY (PYY) were measured immediately before and after the interventions. Interindividual differences were explored by correlating the two sets of response differences between exercise and control conditions. Within-participant covariate adjusted linear mixed models were used to quantify participant-condition interactions. RESULTS: Compared with control, exercise suppressed mean acylated ghrelin concentrations and appetite perceptions (all ES = 0.62-1.47, P < 0.001) and elevated total PYY concentrations (ES = 1.49, P < 0.001). For all variables, the standard deviation of the change scores was substantially greater in the exercise versus control conditions. Moderate-to-large positive correlations were observed between the two sets of control-adjusted exercise responses for all variables (r = 0.54-0.82, P <= 0.036). After adjusting for baseline measurements, participant-condition interactions were present for all variables (P <= 0.053). CONCLUSIONS: Our replicated crossover study allowed, for the first time, the interaction between participant and acute exercise response in appetite parameters to be quantified. Even after adjustment for individual baseline measurements, participants demonstrated individual differences in perceived appetite and hormone responses to acute exercise bouts beyond any random within subject variability over time. PMID- 29240654 TI - Peripheral Artery Disease Symptomatology and Ischemia. PMID- 29240655 TI - Evaluation of a Person-Centered, Theory-Based Intervention to Promote Health Behaviors. AB - BACKGROUND: Effective promotion of health behaviors requires strong interventions. Applying person-centered approaches and concepts synthesized from two motivational theories could strengthen the effects of such interventions. OBJECTIVES: The aim of the study was to report the effect sizes, fidelity, and acceptability of a person-centered, health behavior intervention based on self regulation and self-determination theories. METHODS: Using a pre- and postintervention design, with a 4-week follow-up, advanced practice registered nurses made six weekly contacts with 52 volunteer participants. Most participants were educated White women. Advanced practice registered nurses elicited participant motives and particular goals for either healthy diet or physical activity behaviors. Minutes and type of activity and servings of fat and fruit/vegetables were assessed. RESULTS: Effect sizes for engaging in moderate aerobic activity and in fruit/vegetable and fat intake were 0.53, 0.82, and 0.57, respectively. The fidelity of delivery was 80-97% across contacts, and fidelity of participants' receipt of intervention components was supported. Participant acceptance of the intervention was supported by positive ratings on aspects of relevance and usefulness. DISCUSSION: To advance the science of health behavior change and improve client health status, person-centered approaches and concepts synthesized from motivational theories can be applied and tested with a randomized, controlled design and diverse samples to replicate and extend this promising behavioral intervention. PMID- 29240656 TI - Hospital-Acquired Pressure Injury: Risk-Adjusted Comparisons in an Integrated Healthcare Delivery System. AB - BACKGROUND: Although healthcare organizations have decreased hospital-acquired pressure injury (HAPI) rates, HAPIs are not eliminated, driving further examination in both nursing and health services research. OBJECTIVE: The objective was to describe HAPI incidence, risk factors, and risk-adjusted hospital variation within a California integrated healthcare system. METHODS: Inpatient episodes were included in this retrospective cohort if patients were hospitalized between January 1, 2013, and June 30, 2015. The primary outcome was development of a HAPI over time. Predictors included cited HAPI risk factors in addition to incorporation of a longitudinal comorbidity burden (Comorbidity Point Score, Version 2 [COPS2]), a severity-of-illness score (Laboratory-Based Acute Physiology Score, Version 2 [LAPS2]), and the Braden Scale for Predicting Pressure Ulcer Risk. RESULTS: Analyses included HAPI inpatient episodes (n = 1661) and non-HAPI episodes (n = 726,605). HAPI incidence was 0.57 per 1,000 patient days (95% CI [0.019, 3.805]) and 0.2% of episodes. A multivariate Cox proportional hazards model showed significant (p < .001) hazard ratios (HRs) for the change from the 25th to the 75th percentile for age (HR = 1.36, 95% CI [1.25, 1.45]), higher COPS2 scores (HR = 1.10, 95% CI [1.04, 1.16]), and higher LAPS2 scores (HR = 1.38, 95% CI [1.28, 1.50]). Female gender, an emergency room admission for a medical reason, and higher Braden scores showed significant protective HRs (HR < 1.00, p < .001). After risk adjustment, significant variation remained among the 35 hospitals. DISCUSSION: Results prompt the consideration of age, severity of illness (LAPS2), comorbidity indexes (COPS2), and the Braden score as important predictors for HAPI risk. HAPI rates may be low; however, because of significant individual site variation, HAPIs remain an area to explore through both research and quality improvement initiatives. PMID- 29240657 TI - Inequalities in Health Services Usage in a National Health System Scheme: The Case of a Southern Social European Region. AB - BACKGROUND: Health services can reduce inequalities caused by other determinants of health or increase them due to the effect of the inverse care law-the principle that the availability of good quality care tends to vary inversely with the need for it in the population served. OBJECTIVE: The purpose of the research was to describe inequalities in the use of nursing services, medical services in primary care, specialist care, and services not fully covered by the Basque public health system in Spain. METHODS: A cross-sectional study of adults aged at least 25 years who completed the 2013 Basque Health Survey (N = 10,454) was conducted. Age-standardized prevalence and prevalence ratios for use of services that are covered and noncovered in the health system were computed. The association of health services usage with socioeconomic variables was estimated using a Poisson regression model with robust variance. The relative index of inequality (RII) was used to measure the magnitude of socioeconomic status inequalities in health service use. All analyses were carried out separately for men and women. RESULTS: Individuals with lower socioeconomic status were more likely to use primary care (RII = 0.87, 95% CI [0.79, 0.97]) and less likely to use specialist services (RII = 0.82, 95% CI [0.75, 0.89]). Across noncovered health services, inequalities between the highest and lowest social groups were significant in all cases and especially marked in men's use of physiotherapists (RII = 0.46, 95% CI [0.35, 0.61]) and podiatrists (RII = 0.24, 95%CI [0.15, 0.38]). DISCUSSION: There are significant inequalities in primary and specialist health service use based on individual socioeconomic status, particularly for services that are not provided free of charge within the existing health system. This suggests that health service systems that are not explicitly designed to provide universal access may actually amplify preexisting social and health inequalities within their target populations. PMID- 29240658 TI - Nursing Activities for Patients With Chronic Disease in Primary Care Settings: A Practice Analysis. AB - BACKGROUND: Nurses in primary care organizations play a central role for patients with chronic disease. Lack of clarity in role description may be associated with underutilization of nurse competencies that could benefit the growing population of patients with chronic disease. OBJECTIVE: The purpose of the research was to describe nursing activities in primary care settings with patients with chronic disease. METHODS: A Web-based survey was sent to nurses practicing in Family Medicine Groups in the Canadian Province of Quebec. Participants rated the frequency with which they carried out nursing activities in five domains: (a) global assessment, (b) care and case management, (c) health promotion, (d) nurse physician collaboration, and (e) planning services for patients with chronic disease. Findings were summarized with descriptive statistics (means, standard deviations, and ranges). RESULTS: The survey was completed by 266 of the 322 nurses who received the survey (82.6%). Activities in the health promotion and global assessment of the patient domains were carried out most frequently. Planning services for patients with chronic disease were least frequently performed. DISCUSSION: This study provides a broad description of nursing activities with patients with chronic disease in primary care. The findings provide a baseline for clinicians and researchers to document and improve nursing activities for optimal practice for patients with chronic disease. PMID- 29240659 TI - Using a Wireless Electroencephalography Device to Evaluate E-Health and E Learning Interventions. AB - BACKGROUND: Measuring engagement and other reactions of patients and health professionals to e-health and e-learning interventions remains a challenge for researchers. OBJECTIVE: The aim of this pilot study was to assess the feasibility and acceptability of using a wireless electroencephalography (EEG) device to measure affective (anxiety, enjoyment, relaxation) and cognitive (attention, engagement, interest) reactions of patients and healthcare professionals during e health or e-learning interventions. METHODS: Using a wireless EEG device, we measured patient (n = 6) and health professional (n = 7) reactions during a 10 minute session of an e-health or e-learning intervention. The following feasibility and acceptability indicators were assessed and compared for patients and healthcare professionals: number of eligible participants who consented to participate, reasons for refusal, time to install and calibrate the wireless EEG device, number of participants who completed the full 10-minute sessions, participant comfort when wearing the device, signal quality, and number of observations obtained for each reaction. The wireless EEG readings were compared to participant self-rating of their reactions. RESULTS: We obtained at least 75% of possible observations for attention, engagement, enjoyment, and interest. EEG scores were similar to self-reported scores, but they varied throughout the sessions, which gave information on participants' real-time reactions to the e health/e-learning interventions. Results on the other indicators support the feasibility and acceptability of the wireless EEG device for both patients and professionals. DISCUSSION: Using the wireless EEG device was feasible and acceptable. Future studies must examine its use in other contexts of care and explore which components of the interventions affected participant reactions by combining wireless EEG and eye tracking. PMID- 29240660 TI - Healthcare Provider Views on Transitioning From Task Shifting to Advanced Practice Nursing in Tanzania. AB - BACKGROUND: The Tanzanian health sector suffers from shortages of healthcare workers as well as uneven distribution of healthcare workers in urban and rural areas. Task shifting-delegation of tasks from professionals to other healthcare team members with less training, such as medical attendants-is practiced, compromising quality of care. Advanced practice nursing is underutilized. OBJECTIVE: The purpose of this study was to explore the views of nurses and physicians on current responses to shortages of healthcare workers and the potential for utilization of advanced practice nurses. METHODS: A descriptive, qualitative design was used. Purposeful sampling was used to select 20 participants. An in-depth interview guide was used to obtain information. Interviews were conducted in Swahili or English. Content analysis was used to identify themes. RESULTS: Shortage of human resources in rural primary healthcare facilities was identified as a major rationale for implementation of the advanced practice nurse practitioner role because the current health providers in rural health facilities are less trained and doctors are not ready to work in these settings. Opposition from physicians is expected during the course of implementing the nurse practitioner role. Professional bodies and government should reach consensus before the implementation of this role in such a way that they should agree on scope and standards of practice of nurse practitioners in Tanzania. CONCLUSION: Shortage of human resources for health is greater in rural primary healthcare facilities. Task shifting in Tanzania is neither effective nor legally recognized. Transition to advanced practice nursing roles-particularly the nurse practitioner role-can facilitate provision of optimal care. Nurse practitioners should be prepared to work in rural primary healthcare facilities. PMID- 29240661 TI - Physical Restraint Use With Elderly Patients: Perceptions of Nurses and Nursing Assistants in Spanish Acute Care Hospitals. AB - BACKGROUND: Physical restraint is often used during the hospitalization of elderly people. However, this procedure is associated with adverse outcomes; therefore, it is necessary to be aware of the circumstances that promote restraint use, such as the perceptions of professionals who use it. OBJECTIVES: The purpose of the research was to determine the situations in which nursing staff considered the use of physical restraint as most important and to evaluate the possible associations with the sociodemographic and professional variables. METHODS: A descriptive cross-sectional multicenter study was carried out in 52 units of eight Spanish acute hospitals. A survey of registered nurses and nursing assistants was used to collect data related to sociodemographic characteristics, experience, training in restraint use, and the Perception of Restraint Use Questionnaire (PRUQ)-which assesses the perceived importance of reasons frequently given for the use of physical restraint. RESULTS: The sample comprised 508 registered nurses and 347 nursing assistants. Almost all (98%) had used physical restraint, and 82% thought their training in the use of physical restraint was insufficient. Nursing assistants scored higher than registered nurses (p < .005, d = .68) on PRUQ total score and individual item scores, suggesting they thought the factors were more important in restraint use. Both registered nurses and nursing assistants considered restraint as most important in the prevention of falls and in the removal of medical devices such as intravenous lines and urinary catheters. Associations between PRUQ total score and other variables (unit type, sociodemographic factors, hospital) were nonsignificant. DISCUSSION: The professionals considered restraint as very important in preventing safety problems. In order to improve the quality of care, it is essential to identify the factors that can have an effect on the application of physical restraint. Educational programs are of fundamental importance, but to be more effective in reducing the use of physical restraint, they should address commonly held views on rationale for restraint use and be accompanied by institutional policies promoting a restraint-free environment. PMID- 29240663 TI - Increased Efficiency of Solar Cells Protected by Hydrophobic and Hydrophilic Anti Reflecting Nanostructured Glasses. AB - We investigated the fabrication of large-area (cm2) nanostructured glasses for solar cell modules with hydrophobic and hydrophilic properties using soft lithography and colloidal lithography. Both of these techniques entail low-cost and ease of nanofabrication. We explored the use of simple 1D and 2D nanopatterns (nanowires and nanocones) and the effect of introducing disorder in the nanostructures. We observed an increase in the transmitted light for ordered nanostructures with a maximum value of 99% for wavelengths >600 nm when ordered nanocones are fabricated on the two sides of the solar glass. They produced an increment in the efficiency of the packaged solar cell with respect to the glass without nanostructures. On the one hand, the wettability properties showed that the ordering of the nanostructures improved the hydrophobicity of the solar glasses and increased their self-cleaning capacity. On the other hand, the disordered nanostructures improved the hydrophilic properties of solar glasses, increasing their anti-fogging capacity. The results show that by selecting the appropriate nanopattern, the wettability properties (hydrophobic or hydrophilic) can be easily improved without decreasing the efficiency of the solar cell underneath. PMID- 29240662 TI - Essential Oils from Neotropical Piper Species and Their Biological Activities. AB - The Piper genus is the most representative of the Piperaceae reaching around 2000 species distributed in the pantropical region. In the Neotropics, its species are represented by herbs, shrubs, and lianas, which are used in traditional medicine to prepare teas and infusions. Its essential oils (EOs) present high yield and are chemically constituted by complex mixtures or the predominance of main volatile constituents. The chemical composition of Piper EOs displays interspecific or intraspecific variations, according to the site of collection or seasonality. The main volatile compounds identified in Piper EOs are monoterpenes hydrocarbons, oxygenated monoterpenoids, sesquiterpene hydrocarbons, oxygenated sesquiterpenoids and large amounts of phenylpropanoids. In this review, we are reporting the biological potential of Piper EOs from the Neotropical region. There are many reports of Piper EOs as antimicrobial agents (fungi and bacteria), antiprotozoal (Leishmania spp., Plasmodium spp., and Trypanosoma spp.), acetylcholinesterase inhibitor, antinociceptive, anti-inflammatory and cytotoxic activity against different tumor cells lines (breast, leukemia, melanoma, gastric, among others). These studies can contribute to the rational and economic exploration of Piper species, once they have been identified as potent natural and alternative sources to treat human diseases. PMID- 29240664 TI - alpha-Pyrone Polyketides from Streptomyces ambofaciens BI0048, an Endophytic Actinobacterial Strain Isolated from the Red Alga Laurencia glandulifera. AB - Four new (1-4) and six previously reported (5-10) alpha-pyrone polyketides, along with benzoic acid, hydrocinnamic acid, and (E)-cinnamic acid, were isolated from the organic extract resulting from the cultivation of the algicolous strain Streptomyces ambofaciens BI0048, which in turn was isolated from the inner tissues of the red alga Laurencia glandulifera. The structure elucidation of the isolated natural products was based on extensive analysis of their spectroscopic data (NMR, MS, UV, IR). Compounds 1-10 were evaluated for their antibacterial and cytotoxic activities against two multidrug-resistant strains of Staphylococcus aureus and one strain of Escherichia coli, as well as two human cancer cell lines. PMID- 29240665 TI - Airborne or Fomite Transmission for Norovirus? A Case Study Revisited. AB - Norovirus infection, a highly prevalent condition associated with a high rate of morbidity, comprises a significant health issue. Although norovirus transmission mainly occurs via the fecal-oral and vomit-oral routes, airborne transmission has been proposed in recent decades. This paper re-examines a previously described norovirus outbreak in a hotel restaurant wherein airborne transmission was originally inferred. Specifically, the original evidence that suggested airborne transmission was re-analyzed by exploring an alternative hypothesis: could this outbreak instead have occurred via fomite transmission? This re-analysis was based on whether fomite transmission could have yielded similar attack rate distribution patterns. Seven representative serving pathways used by waiters were considered, and the infection risk distributions of the alternative fomite transmission routes were predicted using a multi-agent model. These distributions were compared to the reported attack rate distribution in the original study using a least square methods approach. The results show that with some reasonable assumptions of human behavior patterns and parameter values, the attack rate distribution corresponded well with that of the infection risk via the fomite route. This finding offers an alternative interpretation of the transmission routes that underlay this particular norovirus outbreak and an important consideration in the development of infection control guidelines and the investigation of similar norovirus outbreaks in future. PMID- 29240666 TI - Induction of Inflammation In Vivo by Electrocardiogram Sensor Operation Using Wireless Power Transmission. AB - Prolonged monitoring by cardiac electrocardiogram (ECG) sensors is useful for patients with emergency heart conditions. However, implant monitoring systems are limited by lack of tissue biocompatibility. Here, we developed an implantable ECG sensor for real-time monitoring of ventricular fibrillation and evaluated its biocompatibility using an animal model. The implantable sensor comprised transplant sensors with two electrodes, a wireless power transmission system, and a monitoring system. The sensor was inserted into the subcutaneous tissue of the abdominal area and operated for 1 h/day for 5 days using a wireless power system. Importantly, the sensor was encapsulated by subcutaneous tissue and induced angiogenesis, inflammation, and phagocytosis. In addition, we observed that the levels of inflammation-related markers increased with wireless-powered transmission via the ECG sensor; in particular, levels of the Th-1 cytokine interleukin-12 were significantly increased. The results showed that induced tissue damage was associated with the use of wireless-powered sensors. We also investigated research strategies for the prevention of adverse effects caused by lack of tissue biocompatibility of a wireless-powered ECG monitoring system and provided information on the clinical applications of inflammatory reactions in implant treatment using the wireless-powered transmission system. PMID- 29240667 TI - Enabling Factors for Sustaining Open Defecation-Free Communities in Rural Indonesia: A Cross-Sectional Study. AB - Community Approaches to Total Sanitation (CATS) programmes, like the Sanitasi Total Berbasis Masyarakat (STBM) programme of the Government of Indonesia, have played a significant role in reducing open defecation though still little is known about the sustainability of the outcomes. We assessed the sustainability of verified Open Defecation Free (ODF) villages and explored the association between slippage occurrence and the strength of social norms through a government conducted cross-sectional data collection in rural Indonesia. The study surveyed 587 households and held focus group discussions (FGDs) in six ODF villages two years after the government's ODF verification. Overall, the slippage rate (i.e., a combination of sub-optimal use of a latrine and open defecation at respondent level) was estimated to be 14.5% (95% CI 11.6-17.3). Results of multivariate logistic regression analyses indicated that (1) weaker social norms, as measured by respondents' perceptions around latrine ownership coverage in their community, (2) a lack of all-year round water access, and (3) wealth levels (i.e., not being in the richest quintile), were found to be significantly associated with slippage occurrence. These findings, together with qualitative analysis, concluded that CATS programmes, including a combination of demand creation, removal of perceived constraints through community support mechanisms, and continued encouragement to pursue higher levels of services with post-ODF follow-up, could stabilize social norms and help to sustain longer-term latrine usage in study communities. Further investigation and at a larger scale, would be important to strengthen these findings. PMID- 29240669 TI - Experimental and Theoretical Studies on the Adsorption and Desorption Mechanisms of Chromate Ions on Cross-Linked Chitosan. AB - In this work, chitosan bead materials were modified by cross-linking with epichlorohydrin (EP) and glutaraldehyde (GA) for the removal of heavy metals in wastewater. Using these cross-linked chitosan materials, the dependence of adsorption of chromate anions on pH was investigated experimentally and theoretically. The experimental results show that the adsorption process of the chromate (Cr) ions greatly depends on the pH of the solution, with the chitosan modified by cross-linking being an efficient adsorbent for chromate. On the other hand, quantum chemistry calculations were conducted to find out the factor determining the pH dependence of the adsorption efficiency of chromate ions on the dimer chitosan molecule, and show results similar to those found in the experiment. Both the experimental and numerical results show that the total charge numbers of the adsorbent and the adsorbate species and their relative molecular geometries are crucial in determining the adsorption efficiency. PMID- 29240668 TI - Heat Shock Proteins in Vascular Diabetic Complications: Review and Future Perspective. AB - Heat shock proteins (HSPs) are a large family of proteins highly conserved throughout evolution because of their unique cytoprotective properties. Besides assisting protein refolding and regulating proteostasis under stressful conditions, HSPs also play an important role in protecting cells from oxidative stress, inflammation, and apoptosis. Therefore, HSPs are crucial in counteracting the deleterious effects of hyperglycemia in target organs of diabetes vascular complications. Changes in HSP expression have been demonstrated in diabetic complications and functionally related to hyperglycemia-induced cell injury. Moreover, associations between diabetic complications and altered circulating levels of both HSPs and anti-HSPs have been shown in clinical studies. HSPs thus represent an exciting therapeutic opportunity and might also be valuable as clinical biomarkers. However, this field of research is still in its infancy and further studies in both experimental diabetes and humans are required to gain a full understanding of HSP relevance. In this review, we summarize current knowledge and discuss future perspective. PMID- 29240670 TI - Well-Being and Associated Factors among Women in the Gender-Segregated Country. AB - Well-being is an essential measure that contributes to the evaluation of the health and quality of life of populations. In 1948, the World Health Organization (WHO) defined health as physical, mental and social well-being. A cross-sectional survey was conducted in Riyadh, Saudi Arabia, between July and September 2015. Women aged 18 years old and above were invited to participate in the study. The data were collected using the WHO's Well-Being Index questionnaire. Univariate and multivariate logistic regression models were fitted to identify factors that are significantly associated with well-being. A total of 900 women completed the survey. Approximately 58% of the women reported moderate to high (>=50) score of well-being, whereas 41.7% reported ill-being/likely depression. Experiencing violence, living in unfavorable physical conditions and reporting morbidities were shown to be significantly associated with low levels of subjective well being (ill-being) (p < 0.0001). Our study revealed a significant percentage of low levels of well-being among women in Riyadh, Saudi Arabia, and identified the factors associated with them. Further research in this domain is recommended to better investigate additional causes of the low levels of well-being hence help in planning and guiding necessary interventions. PMID- 29240671 TI - Microwave-Enhanced Photolysis of Norfloxacin: Kinetics, Matrix Effects, and Degradation Pathways. AB - Degradation of norfloxacin (NOR) was studied using a combination of microwave and UV irradiation methods (MW/UV process). Remarkable synergistic effect was found between MW and UV light. The removal rate with the MW/UV process was much faster than that with UV light irradiation only. Degradation of NOR followed second order kinetics and ~72% of NOR could be removed in the first 5 min of MW/UV reaction. Influence of inorganic ions (cations (K+, Mg2+, Ca2+, Cu2+) and anions (Cl-, SO42-, NO3-, CO32-)), humic acid (HA) and surfactants (cation, anion, and non-ionic) on the degradation of NOR by the MW/UV process was investigated. Among the ions, Cu2+ and NO3- ions inhibited the degradation of NOR. The presence of HA and surfactants in water showed a slight inhibition on the NOR removal. Furthermore, the NOR degradation in the MW/UV process was primarily caused by the .OH-photosensitization steps. Seven intermediates formed by the oxidation of NOR were identified and three reaction pathways were proposed. Removals of NOR in tap water (TW), synthetic wastewater (WW), river water (RW), and seawater (SW) were also studied, which demonstrated that the MW/UV process was an effective oxidation technology for degrading fluoroquinolone antibiotics in different water matrices. PMID- 29240672 TI - Amount, Distribution, and Quality of Protein Intake Are Not Associated with Muscle Mass, Strength, and Power in Healthy Older Adults without Functional Limitations-An enable Study. AB - To maintain muscle mass in older age, several aspects regarding the amount and distribution of protein intake have been suggested. Our objective was to investigate single and combined associations of daily protein intake, evenness of protein distribution across the three main meals, number of meals providing >=0.4 g protein/kg body weight (BW), and number of meals providing >=2.5 g leucine, with muscle mass, strength, and power in successful agers. In this cross sectional study in 97 healthy community-dwelling adults without functional limitations aged 75-85 years, protein intake was assessed using 7-day food records. Muscle mass, leg muscle strength, leg muscle power, and handgrip strength were measured according to standardized protocols. Mean daily protein intake was 0.97 +/- 0.28 g/kg BW and the coefficient of variance between main meals was 0.53 +/- 0.19. Per day, 0.72 +/- 0.50 meals providing >=0.4 g protein/kg BW and 1.11 +/- 0.76 meals providing >=2.5 g leucine were consumed. No correlations between single or combined aspects of protein intake and skeletal muscle index, leg muscle power, leg muscle strength, or handgrip strength were observed (Spearman's r of -0.280 to 0.291). In this sample of healthy older adults without functional limitations, aspects of protein intake were not associated with muscle mass, strength, or power. PMID- 29240673 TI - Urinary Fractional Excretion of Phosphorus in Dogs with Spontaneous Chronic Kidney Disease. AB - The increase of urinary fractional excretion of phosphorus (uFEP) may indicate phosphorus retention before the onset of hyperphosphatemia in the early stages of chronic kidney disease (CKD). The hypothesis of this study is whether uFEP may increase during the early stage of CKD as a compensatory mechanism to prevent hyperphosphatemia as well as whether hyperphosphatemia in the late stages is associated with increase or decrease in uFEP in dogs with naturally occurring CKD; therefore, the aim of this study was to determine the uFEP in CKD dogs with different stages. Forty-nine CKD dogs were included, and they were divided into stage 1 (serum creatinine < 1.4 mg/dL), stage 2 (serum creatinine 1.5 to 2.0 mg/dL), stage 3 (serum creatinine 2.1 to 5.0 mg/dL) and stage 4 (serum creatinine > 5.0 mg/dL), according to the IRIS staging criteria. The stage 3 was subdivided into stage 3-A (serum creatinine 2.1 to 3.5 mg/dL) and stage 3-B (serum creatinine 3.6 to 5.0 mg/dL). The control group comprised 10 dogs, and uFEP <= 40% was considered as normal. A progressive increase in uFEP along the progression of CKD was found. However, similar results of uFEP levels were observed in late CKD, since there were no differences between stages 3 (A, B) and 4. Interestingly, some CKD dogs with stage 4 showed normal or reduced uFEP, besides hyperphosphatemia; conversely, some dogs in early CKD had increased uFEP values and normophosphatemia. Our findings suggest that uFEP may act as a compensatory mechanism to avoid the onset of hyperphosphatemia in early CKD, but not in later stages. uFEP assessment may be considered as an additional tool for the diagnostic and monitoring of phosphate disorders in dogs with CKD, since it may help to identify disturbances of phosphorus balance. More studies are needed to elucidate the role of uFEP in phosphorus homeostasis in dogs with CKD. PMID- 29240675 TI - Improvement of Gaofen-3 Absolute Positioning Accuracy Based on Cross-Calibration. AB - The Chinese Gaofen-3 (GF-3) mission was launched in August 2016, equipped with a full polarimetric synthetic aperture radar (SAR) sensor in the C-band, with a resolution of up to 1 m. The absolute positioning accuracy of GF-3 is of great importance, and in-orbit geometric calibration is a key technology for improving absolute positioning accuracy. Conventional geometric calibration is used to accurately calibrate the geometric calibration parameters of the image (internal delay and azimuth shifts) using high-precision ground control data, which are highly dependent on the control data of the calibration field, but it remains costly and labor-intensive to monitor changes in GF-3's geometric calibration parameters. Based on the positioning consistency constraint of the conjugate points, this study presents a geometric cross-calibration method for the rapid and accurate calibration of GF-3. The proposed method can accurately calibrate geometric calibration parameters without using corner reflectors and high precision digital elevation models, thus improving absolute positioning accuracy of the GF-3 image. GF-3 images from multiple regions were collected to verify the absolute positioning accuracy after cross-calibration. The results show that this method can achieve a calibration accuracy as high as that achieved by the conventional field calibration method. PMID- 29240674 TI - Evaluation of the Cytotoxicity and Genotoxicity of Flavonolignans in Different Cellular Models. AB - Flavonolignans are the main components of silymarin, which represents 1.5-3% of the dry fruit weight of Milk thistle (Silybum marianum L. Gaernt.). In ancient Greece and Romania, physicians and herbalists used the Silybum marianum to treat a range of liver diseases. Besides their hepatoprotective action, silymarin flavonolignans have many other healthy properties, such as anti-platelet and anti inflammatory actions. The aim of this study was to evaluate the toxic effect of flavonolignans on blood platelets, peripheral blood mononuclear cells (PBMCs) and human lung cancer cell line-A549-using different molecular techniques. We established that three major flavonolignans: silybin, silychristin and silydianin, in concentrations of up to 100 uM, have neither a cytotoxic nor genotoxic effect on blood platelets, PMBCs and A549. We also saw that silybin and silychristin have a protective effect on cellular mitochondria, observed as a reduction of spontaneous mitochondrial DNA (mtDNA) damage in A549, measured as mtDNA copies, and mtDNA lesions in ND1 and ND5 genes. Additionally, we observed that flavonolignans increase the blood platelets' mitochondrial membrane potential and reduce the generation of reactive oxygen species in blood platelets. Our current findings show for the first time that the three major flavonolignans, silybin, silychristin and silydianin, do not have any cytotoxicity and genotoxicity in various cellular models, and that they actually protect cellular mitochondria. This proves that the antiplatelet and anti inflammatory effect of these compounds is part of our molecular health mechanisms. PMID- 29240676 TI - From Ion Current to Electroosmotic Flow Rectification in Asymmetric Nanopore Membranes. AB - Asymmetrically shaped nanopores have been shown to rectify the ionic current flowing through pores in a fashion similar to a p-n junction in a solid-state diode. Such asymmetric nanopores include conical pores in polymeric membranes and pyramidal pores in mica membranes. We review here both theoretical and experimental aspects of this ion current rectification phenomenon. A simple intuitive model for rectification, stemming from previously published more quantitative models, is discussed. We also review experimental results on controlling the extent and sign of rectification. It was shown that ion current rectification produces a related rectification of electroosmotic flow (EOF) through asymmetric pore membranes. We review results that show how to measure and modulate this EOF rectification phenomenon. Finally, EOF rectification led to the development of an electroosmotic pump that works under alternating current (AC), as opposed to the currently available direct current EOF pumps. Experimental results on AC EOF rectification are reviewed, and advantages of using AC to drive EOF are discussed. PMID- 29240677 TI - Amniotic Fluid Arginine from Gestational Weeks 13 to 15 Is a Predictor of Birth Weight, Length, and Head Circumference. AB - Arginine is a constituent of proteins and a precursor for polyamines and nitric oxide, and is essential for placentation, angiogenesis, and growth. Maternal plasma arginine concentrations are found to be lower in pregnancies complicated by fetal growth restriction, and arginine supplementation in later pregnancy is reported to increase birth weight. We measured arginine and the metabolites asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) in the amniotic fluid obtained in pregnancy weeks 13 to 15 from 363 pregnancies with a documented normal outcome and related the concentrations to birth weight, length, and head circumference. Arginine was higher in the amniotic fluid from female (mean 40.8 (SD 10.6) umol/L) compared to male fetuses (37.4 (SD 11.2) umol/L, p = 0.003). Despite the gender difference, arginine in the amniotic fluid from gestational weeks 13-15 was the strongest predictor for birth weight, length, and head circumference. ADMA was a strong predictor for birth weight and length, SDMA for birth weight, while Arg/ADMA and Arg/SDMA only predicted head circumference in multiple linear regression models. Due to increased arginine demands, pregnancy is considered a state of relative arginine deficiency. Our findings reflect the importance of a good maternal arginine status in early pregnancy, an observation that should be evaluated in an intervention study. PMID- 29240678 TI - Risk Factors Associated with Preterm Neonatal Mortality: A Case Study Using Data from Mt. Hope Women's Hospital in Trinidad and Tobago. AB - Preterm neonatal mortality contributes significantly to the high incidence of death among children under five years of age. Neonatal mortality also serves as an indicator of maternal health in society. The aim of the study is to examine the risk factors for preterm neonatal mortality at the neonatal intensive care unit (NICU) at Mount Hope Women's Hospital in Trinidad and Tobago (MHWH). In this retrospective study, we included infants (N = 129), born < 37 weeks gestational age, between 1 January and 31 December 2015. Two binary logistic regression models (infant and maternal variables) were constructed to identify predictors of preterm neonatal mortality. Roughly 12% of the infants died after being admitted to the NICU. The binary logistic regression (infant model) had an excellent fit (area under the curve (AUC): 0.904, misclassification rate: 11.7%) whilst the maternal binary logistic model had a fair fit (AUC: 0.698). Birth weight, length of time on the ventilator and obstetric complications proved to significantly influence the odds of preterm neonatal death. The estimated models show that improvement in neonatal as well as maternal variables has direct impact on preterm neonatal mortality. PMID- 29240679 TI - Fiber-Optic Sensor-Based Remote Acoustic Emission Measurement in a 1000 degrees C Environment. AB - Recently, the authors have proposed a remote acoustic emission (AE) measurement configuration using a sensitive fiber-optic Bragg grating (FBG) sensor. In the configuration, the FBG sensor was remotely bonded on a plate, and an optical fiber was used as the waveguide to propagate AE waves from the adhesive point to the sensor. The previous work (Yu et al., Smart Materials and Structures 25 (10), 105,033 (2016)) has clarified the sensing principle behind the special remote measurement system that enables accurate remote sensing of AE signals. Since the silica-glass optical fibers have a high heat-resistance exceeding 1000 degrees C, this work presents a preliminary high-temperature AE detection method by using the optical fiber-based ultrasonic waveguide to propagate the AE from a high temperature environment to a room-temperature environment, in which the FBG sensor could function as the receiver of the guided wave. As a result, the novel measurement configuration successfully achieved highly sensitive and stable AE detection in an alumina plate at elevated temperatures in the 100 degrees C to 1000 degrees C range. Due to its good performance, this detection method will be potentially useful for the non-destructive testing that can be performed in high temperature environments to evaluate the microscopic damage in heat-resistant materials. PMID- 29240680 TI - Evaluation on the Photosensitivity of 2,2'-Azobis(2,4-Dimethyl)Valeronitrile with UV. AB - Azo compounds have high exothermic characteristics and low thermal stability, which have caused many serious thermal accidents around the world. In general, different locations (e.g., equatorial or polar regions) have different UV intensities. If the azo compound exists in an inappropriately stored or transported condition, the decrease in thermal stability may cause a thermal hazard or ageing. 2,2'-Azobis(2,4-dimethyl)valeronitrile (ADVN) is investigated with respect to the thermal stability affected by UV exposure at 0, 6, 12, and 24 h. When ADVN is exposed to 24 h of UV (100 mW/m2 and 254 nm), T0 is not only advanced, but the mass loss is also increased during the main decomposition stage. In addition, the apparent activation energy and integral procedural decomposition temperature (IPDT) of ADVN exposed to 24 h of UV is calculated by kinetic models. Therefore, the prevention mechanism, thermal characteristics, and kinetic parameters are established in our study. We should isolate UV contacting ADVN under any situations, avoiding ADVN being aged or leading to thermal runaway. This study provided significant information for a safer process under changing UV exposure times for ADVN. Furthermore, the research method may serve as an important benchmark for handling potentially hazardous chemicals, such as azo compounds described herein. PMID- 29240681 TI - Mercury Hair Concentration among Primary School Children in Malaysia. AB - The main concern regarding mercury exposure is the adverse health effect on the developing nervous system. The objective of this cross-sectional study was to determine hair mercury levels and their association with socio-demographic characteristics, complaints about mercury poisoning symptoms and the fish consumption pattern among children in Malaysia. A cross-sectional study was conducted among 215 school children aged 11 years old. Hair was collected from the children and the total mercury was analyzed using oxygen combustion-gold amalgamation atomic absorption spectrophotometry. Anthropometric data, a fish consumption questionnaire and mercury poisoning symptoms were collected during a personal interview. The mean hair mercury level among primary school children was 0.63 +/- 0.59 ug/g with the geometric mean of 0.47 ug/g. A total of 14% of respondents had hair mercury levels above 1 ug/g. A multiple binary logistic regression analysis outlined that fish consumption of at least one meal per week increased the likelihood of having a high mercury level (odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3-10.4). This study confirms the existence of a mercury burden among Malaysian children and the level is high compared to other regional studies. This study provides important baseline data regarding the mercury level among children in Malaysia. PMID- 29240682 TI - Recombinant PrP and Its Contribution to Research on Transmissible Spongiform Encephalopathies. AB - The misfolding of the cellular prion protein (PrPC) into the disease-associated isoform (PrPSc) and its accumulation as amyloid fibrils in the central nervous system is one of the central events in transmissible spongiform encephalopathies (TSEs). Due to the proteinaceous nature of the causal agent the molecular mechanisms of misfolding, interspecies transmission, neurotoxicity and strain phenomenon remain mostly ill-defined or unknown. Significant advances were made using in vivo and in cellula models, but the limitations of these, primarily due to their inherent complexity and the small amounts of PrPSc that can be obtained, gave rise to the necessity of new model systems. The production of recombinant PrP using E. coli and subsequent induction of misfolding to the aberrant isoform using different techniques paved the way for the development of cell-free systems that complement the previous models. The generation of the first infectious recombinant prion proteins with identical properties of brain-derived PrPSc increased the value of cell-free systems for research on TSEs. The versatility and ease of implementation of these models have made them invaluable for the study of the molecular mechanisms of prion formation and propagation, and have enabled improvements in diagnosis, high-throughput screening of putative anti prion compounds and the design of novel therapeutic strategies. Here, we provide an overview of the resultant advances in the prion field due to the development of recombinant PrP and its use in cell-free systems. PMID- 29240684 TI - Optimal Multi-Type Sensor Placement for Structural Identification by Static-Load Testing. AB - Assessing ageing infrastructure is a critical challenge for civil engineers due to the difficulty in the estimation and integration of uncertainties in structural models. Field measurements are increasingly used to improve knowledge of the real behavior of a structure; this activity is called structural identification. Error-domain model falsification (EDMF) is an easy-to-use model based structural-identification methodology which robustly accommodates systematic uncertainties originating from sources such as boundary conditions, numerical modelling and model fidelity, as well as aleatory uncertainties from sources such as measurement error and material parameter-value estimations. In most practical applications of structural identification, sensors are placed using engineering judgment and experience. However, since sensor placement is fundamental to the success of structural identification, a more rational and systematic method is justified. This study presents a measurement system design methodology to identify the best sensor locations and sensor types using information from static-load tests. More specifically, three static-load tests were studied for the sensor system design using three types of sensors for a performance evaluation of a full-scale bridge in Singapore. Several sensor placement strategies are compared using joint entropy as an information-gain metric. A modified version of the hierarchical algorithm for sensor placement is proposed to take into account mutual information between load tests. It is shown that a carefully-configured measurement strategy that includes multiple sensor types and several load tests maximizes information gain. PMID- 29240683 TI - Development and Validation of the Brief Folate-Specific Food Frequency Questionnaire for Young Women's Diet Assessment. AB - The tools enabling brief assessment of folate intake may be of great value for public health purposes. The aim of the presented study was to design a brief folate-specific food frequency questionnaire for Central and Eastern European population of women, as well as to assess the validity and reproducibility of the designed Folate-Intake Calculation-Food Frequency Questionnaire (Fol-IC-FFQ) on a group of Polish women aged 20-30 years. Participants collected 3-day dietary records and completed the Fol-IC-FFQ twice (FFQ1: directly after the dietary record; and FFQ2: six weeks later). The analysis included an assessment of validity (comparison of the results of FFQ1 and 3-day dietary record) and of reproducibility (comparison of the results of FFQ1 and FFQ2). In assessment of validity, a Bland-Altman index of 5.3% was observed. In assessment of reproducibility, a Bland-Altman index of 2.7% was observed, the share of individuals classified into the same intake adequacy category was over 85%, the share of individuals classified into the same tertile was almost 75%, the weighted kappa statistic indicated substantial agreement (0.67) and correlation was significant (p = 0.0000; R = 0.7995). Assessment of the Fol-IC-FFQ revealed a satisfactory level of validity and very good level of reproducibility in the population of young Polish women. The Fol-IC-FFQ may be considered a valid tool for the assessment of folate intake in young Polish women and a promising tool for the assessment of folate intake in young women in Central and Eastern Europe. PMID- 29240686 TI - Marketing Animal-Friendly Products: Addressing the Consumer Social Dilemma with Reinforcement Positioning Strategies. AB - This article presents a conceptual framework that aims to encourage consumer animal-friendly product choice by introducing positioning strategies for animal friendly products. These strategies reinforce the animal welfare with different types of consumption values and can therefore reduce consumers' social dilemma, which is a major barrier to animal-friendly consumer choices. The article suggests how animal-friendly products can use various types of consumption values (functional, sensory, emotional, social, epistemic and situational) to create an attractive position relative to their competitors. It also explains why some consumer segments, such as those with a specific thinking style, may experience a stronger effect of some strategies, giving directions on how to approach different types of consumers. Finally, building on research asserting that animal welfare is a credence product attribute, the article proposes moderating effects of two factors that help consumers to evaluate the credibility of animal welfare claims, namely corporate social responsibility strategy and the role of stakeholders. Here it concludes that companies selling animal-friendly products need to be aware of the impact of their overall strategy on the effectiveness of positioning strategies for individual products and that, to gain consumer trust, they may need to collaborate with relevant stakeholders, such as media or animal interest organizations. PMID- 29240685 TI - Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aalpha, Bbeta, and gamma Chains. AB - Fibrinogen is a highly pleiotropic protein that is involved in the final step of the coagulation cascade, wound healing, inflammation, and angiogenesis. Heterozygous mutations in Aalpha, Bbeta, or gamma fibrinogen-chain genes (FGA, FGB, FGG) have been described as being responsible for fibrinogen deficiencies (hypofibrinogenemia, hypo-dysfibrinogenemia, dysfibrinogenemia) and for more rare conditions, such as fibrinogen storage disease and hereditary renal amyloidosis. Instead, biallelic mutations have been associated with afibrinogenemia/severe hypofibrinogenemia, i.e., the severest forms of fibrinogen deficiency, affecting approximately 1-2 cases per million people. However, the "true" prevalence for these conditions on a global scale is currently not available. Here, we defined the mutational burden of the FGA, FGB, and FGG genes, and estimated the prevalence of inherited fibrinogen disorders through a systematic analysis of exome/genome data from ~140,000 individuals belonging to the genome Aggregation Database. Our analysis showed that the world-wide prevalence for recessively inherited fibrinogen deficiencies could be 10-fold higher than that reported so far (prevalence rates vary from 1 in 106 in East Asians to 24.5 in 106 in non Finnish Europeans). The global prevalence for autosomal-dominant fibrinogen disorders was estimated to be ~11 in 1000 individuals, with heterozygous carriers present at a frequency varying from 3 every 1000 individuals in Finns, to 1-2 every 100 individuals among non-Finnish Europeans and Africans/African Americans. Our analysis also allowed for the identification of recurrent (i.e., FGG p.Ala108Gly, FGG-Thr47Ile) or ethnic-specific mutations (e.g., FGB-p.Gly103Arg in Admixed Americans, FGG-p.Ser245Phe in Africans/African Americans). PMID- 29240687 TI - Decreasing Inappropriate Use of Antibiotics in Primary Care in Four Countries in South America-Cluster Randomized Controlled Trial. AB - High antibiotic prescribing and antimicrobial resistance in patients attending primary care have been reported in South America. Very few interventions targeting general practitioners (GPs) to decrease inappropriate antibiotic prescribing have been investigated in this region. This study assessed the effectiveness of online feedback on reducing antibiotic prescribing in patients with suspected respiratory tract infections (RTIs) attending primary care. The aim was to reduce antibiotic prescribing in patients with acute bronchitis and acute otitis media. Both are RTIs for which antibiotics have a very limited effect. A cluster randomized two-arm control trial was implemented. Healthcare centres from Bolivia, Argentina, Paraguay and Uruguay participating in the quality improvement program HAPPY AUDIT were randomly allocated to either intervention or control group. During ten consecutive weeks, GPs in the intervention group received evidence-based online feedback on the management of suspected RTIs. In patients with acute bronchitis, the intervention reduced the antibiotic prescribing rate from 71.6% to 56% (control group from 61.2% to 52%). In patients with acute otitis media, the intervention reduced the antibiotic prescribing from 94.8% to 86.2% (no change in the control group). In all RTIs, the intervention reduced antibiotic prescribing rate from 37.4% to 28.1% (control group from 29% to 27.2%). Online evidence-based feedback is effective for reducing antibiotic prescribing in patients with RTIs attending primary care in South America. PMID- 29240688 TI - Oral Plasmacytoma in a Dog. AB - A 6-year-old male Pit bull mix dog presented for bleeding from the mouth persisting for five days. A clinical evaluation revealed a 2 * 3 cm soft tissue mandibular mass at the crown of the first premolar, as well as a non-regenerative anemia and hyperproteinemia. Cytologic and histopathologic evaluations of the mass were compatible with an oral plasmacytoma. PMID- 29240689 TI - Investigating beta-N-Methylamino-l-alanine Misincorporation in Human Cell Cultures: A Comparative Study with Known Amino Acid Analogues. AB - Misincorporation of beta-N-methylamino-l-alanine (BMAA) into proteins has been proposed to be a mechanism of toxicity to explain the role of BMAA in neurodegenerative disease development. However, studies have shown that all detectable BMAA can be removed from proteins by SDS-PAGE purification and that the toxicity of l-canavanine cannot be reproduced in prokaryotes or in a rat pheochromocytoma cell line, strongly indicating that the misincorporation hypothesis of BMAA should be re-investigated. The aim of this study was therefore to determine if BMAA misincorporates into proteins in cells of human origin with subsequent misincorporation-type toxicity. Almost complete loss of viability in response to exposure to l-4-fluorophenylalanine and l-m-tyrosine was observed in all of the cell lines, corresponding to a concentration-dependent increase of the analogues in protein extracts from exposed cells. In contrast, BMAA exposure resulted in slight toxicity in one of the cell lines but the observed toxicity was not the result of misincorporation of BMAA into proteins, as no BMAA was detected in any of the SDS-PAGE purified protein extracts that were obtained from the cells following BMAA exposure. The results show that BMAA is not misincorporated into human proteins and that misincorporation is not a valid mechanism of toxicity. PMID- 29240691 TI - Absence of Correlation between Chimeric RNA and Aging. AB - Chimeric RNAs have been recognized as a phenomenon not unique to cancer cells. They also exist in normal physiology. Aging is often characterized by deregulation of molecular and cellular mechanisms, including loss of heterochromatin, increased transcriptional noise, less tight control on alternative splicing, and more stress-induced changes. It is thus assumed that chimeric RNAs are more abundant in older people. In this study, we conducted a preliminary investigation to identify any chimeric RNAs with age-based trends in their expression levels in blood samples. A chimeric RNA candidate list generated by bioinformatic analysis indicated the possibility of both negative and positive trends in the expression of chimeric RNAs. Out of this candidate list, five novel chimeric RNAs were successfully amplified in multiple blood samples and then sequenced. Although primary smaller sample sizes displayed some weak trends with respect to age, analysis of quantitative PCR data from larger sample sizes showed essentially no relationship between expression levels and age. Altogether, these results indicate that, contradictory to the common assumption, chimeric RNAs as a group are not all higher in older individuals and that placing chimeric RNAs in the context of aging will be a much more complex task than initially anticipated. PMID- 29240692 TI - Acoustic Anomalies and Fast Relaxation Dynamics of Amorphous Progesterone as Revealed by Brillouin Light Scattering. AB - The amorphous state of pharmaceuticals has attracted much attention due to its high bioavailability and other advantages. The stability of the amorphous state in relation with the local molecular mobility is important from both fundamental and practical points of view. The acoustic properties of amorphous progesterone, one of the representative steroid hormones, were investigated by using a Brillouin inelastic light scattering technique. The Brillouin spectrum of the longitudinal acoustic mode exhibited distinct changes at the glass transition and the cold-crystallization temperatures. The acoustic dispersions of the longitudinal sound velocity and the acoustic absorption coefficient were attributed to the fast and possibly the secondary relaxation processes in the glassy and supercooled liquid states, while the structural relaxation process was considered as the dominant origin for the significant acoustic damping observed even in the liquid phase. The persisting acoustic dispersion in the liquid state was attributed to the single-molecule nature of the progesterone which does not exhibit hydrogen bonds in the condensed states. PMID- 29240690 TI - High-Throughput Sequencing of Small RNA Transcriptomes in Maize Kernel Identifies miRNAs Involved in Embryo and Endosperm Development. AB - Maize kernel development is a complex biological process that involves the temporal and spatial expression of many genes and fine gene regulation at a transcriptional and post-transcriptional level, and microRNAs (miRNAs) play vital roles during this process. To gain insight into miRNA-mediated regulation of maize kernel development, a deep-sequencing technique was used to investigate the dynamic expression of miRNAs in the embryo and endosperm at three developmental stages in B73. By miRNA transcriptomic analysis, we characterized 132 known miRNAs and six novel miRNAs in developing maize kernel, among which, 15 and 14 miRNAs were commonly differentially expressed between the embryo and endosperm at 9 days after pollination (DAP), 15 DAP and 20 DAP respectively. Conserved miRNA families such as miR159, miR160, miR166, miR390, miR319, miR528 and miR529 were highly expressed in developing embryos; miR164, miR171, miR393 and miR2118 were highly expressed in developing endosperm. Genes targeted by those highly expressed miRNAs were found to be largely related to a regulation category, including the transcription, macromolecule biosynthetic and metabolic process in the embryo as well as the vitamin biosynthetic and metabolic process in the endosperm. Quantitative reverse transcription-PCR (qRT-PCR) analysis showed that these miRNAs displayed a negative correlation with the levels of their corresponding target genes. Importantly, our findings revealed that members of the miR169 family were highly and dynamically expressed in the developing kernel, which will help to exploit new players functioning in maize kernel development. PMID- 29240693 TI - Estimated Dietary Intakes of Toxic Elements from Four Staple Foods in Najran City, Saudi Arabia. AB - Exposure of the inhabitants of Najran area in Saudi Arabia to the toxic elements As, Cd, Cr, and Pb through foods has not been previously investigated. Exposure to such elements is an important public health issue, so the study described here was performed with the aim of determining estimated dietary intakes (EDIs) for these metals in Najran area. The As, Cd, Cr, and Pb concentrations in four staple foods (rice, wheat, red meat, and chicken) were determined by inductively coupled plasma-mass spectrometry. A food frequency questionnaire (FFQ) was completed by 80 study participants. These data were used to estimate dietary intakes of the metals in the four staple foods. The mean As, Cd, Cr, and Pb EDIs in the four food types were 1.1 * 10-6-2.6 * 10-5, 1.42 * 10-5-2.2 * 10-4, 3.4 * 10-4-8.0 * 10-4, and 2.3 * 10-5-2.1 * 10-3 mg/kg bw day, respectively. Hazard Quotients (HQ) for all elements did not exceed one. The highest Pb concentration was found for chicken and the source of this toxic element in this food needs to be investigated in the future. The lowest As concentration was found for wheat highest in rice. The EDIs for all elements in the four food types were below the provisional tolerable weekly intakes set by the World Health Organization (WHO). PMID- 29240694 TI - Centralized Networks to Generate Human Body Motions. AB - We consider continuous-time recurrent neural networks as dynamical models for the simulation of human body motions. These networks consist of a few centers and many satellites connected to them. The centers evolve in time as periodical oscillators with different frequencies. The center states define the satellite neurons' states by a radial basis function (RBF) network. To simulate different motions, we adjust the parameters of the RBF networks. Our network includes a switching module that allows for turning from one motion to another. Simulations show that this model allows us to simulate complicated motions consisting of many different dynamical primitives. We also use the model for learning human body motion from markers' trajectories. We find that center frequencies can be learned from a small number of markers and can be transferred to other markers, such that our technique seems to be capable of correcting for missing information resulting from sparse control marker settings. PMID- 29240695 TI - Energy Efficient Real-Time Scheduling Using DPM on Mobile Sensors with a Uniform Multi-Cores. AB - In wireless sensor networks (WSNs), sensor nodes are deployed for collecting and analyzing data. These nodes use limited energy batteries for easy deployment and low cost. The use of limited energy batteries is closely related to the lifetime of the sensor nodes when using wireless sensor networks. Efficient-energy management is important to extending the lifetime of the sensor nodes. Most effort for improving power efficiency in tiny sensor nodes has focused mainly on reducing the power consumed during data transmission. However, recent emergence of sensor nodes equipped with multi-cores strongly requires attention to be given to the problem of reducing power consumption in multi-cores. In this paper, we propose an energy efficient scheduling method for sensor nodes supporting a uniform multi-cores. We extend the proposed T-Ler plane based scheduling for global optimal scheduling of a uniform multi-cores and multi-processors to enable power management using dynamic power management. In the proposed approach, processor selection for a scheduling and mapping method between the tasks and processors is proposed to efficiently utilize dynamic power management. Experiments show the effectiveness of the proposed approach compared to other existing methods. PMID- 29240696 TI - Metalaxyl Degradation by Mucorales Strains Gongronella sp. and Rhizopus oryzae. AB - In this study, the degradation of metalaxyl was investigated in the presence of two Mucorales strains, previously isolated from soil subjected to repeated treatments with this fungicide and selected after enrichment technique. Fungal strains were characterised by a polyphasic approach using phylogenetic analysis of the Internal Transcribed Spacer (ITS) gene region, phenotypic characterisation by Matrix-Assisted Laser Desorption Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF MS) spectral analysis, and growth kinetics experiments. The strains were identified as Gongronella sp. and Rhizopus oryzae. The fungal growth kinetics in liquid cultures containing metalaxyl fits with Haldane model. Under laboratory conditions, the ability of Gongronella sp. and R. oryzae cultures to degrade metalaxyl was evaluated in liquid cultures and soil experiments. Both species were able to: (a) use metalaxyl as the main carbon and energy source; and (b) degrade metalaxyl in polluted soils, with rates around 1.0 mg kg-1 d-1. This suggests these strains could degrade metalaxyl in soils contaminated with this fungicide. PMID- 29240697 TI - Cymantrenyl-Nucleobases: Synthesis, Anticancer, Antitrypanosomal and Antimicrobial Activity Studies. AB - The synthesis of four cymantrene-5-fluorouracil derivatives (1-4) and two cymantrene-adenine derivatives (5 and 6) is reported. All of the compounds were characterized by spectroscopic methods and the crystal structure of two derivatives (1 and 6), together with the previously described cymantrene-adenine compound C was determined by X-ray crystallography. While the compounds 1 and 6 crystallized in the triclinic P-1 space group, compound C crystallized in the monoclinic P21/m space group. The newly synthesized compounds 1-6 were tested together with the two previously described cymantrene derivatives B and C for their in vitro antiproliferative activity against seven cancer cell lines (MCF-7, MCF-7/DX, MDA-MB-231, SKOV-3, A549, HepG2m and U-87-MG), five bacterial strains Staphylococcus aureus (methicillin-sensitive, methicillin-resistant and vancomycin-intermediate strains), Staphylococcus epidermidis, and Escherichia coli, including clinical isolates of S. aureus and S. epidermidis, as well as against the protozoan parasite Trypanosoma brucei. The most cytotoxic compounds were derivatives 2 and C for A549 and SKOV-3 cancer cell lines, respectively, with 50% growth inhibition (IC50) values of about 7 uM. The anticancer activity of the cymantrene compounds was determined to be due to their ability to induce oxidative stress and to trigger apoptosis and autophagy in cancer cells. Three derivatives (1, 4 and 5) displayed promising antitrypanosomal activity, with GI50 values in the low micromolar range (3-4 uM). The introduction of the 5 fluorouracil moiety in 1 enhanced the trypanocidal activity when compared to the activity previously reported for the corresponding uracil derivative. The antibacterial activity of cymantrene compounds 1 and C was within the range of 8 64 ug/mL and seemed to be the result of induced cell shrinking. PMID- 29240698 TI - Sequential Growth of Uniform beta-NaYF4@beta-NaLnF4 (Ln = Y, Lu, Yb) Microcrystals with Luminescent Properties of Multicolor Tuning and Dual-Mode Emission. AB - We synthesized the uniform core-shell microstructured compounds with hexagonal phase NaYF4:Er/Yb microrods as the core and hexagonal phase NaLnF4 (NaYbF4, NaLuF4:Yb/Tm, NaYF4:Yb/Er, NaYF4:Eu) as the shell based on the hydrothermal reaction. These microscale core-shell structures provided a platform for the spatially confining optical process while possessing high luminescence efficiency. The thickness of the shell could be controlled by adjusting the amounts of shell precursor, which significantly affected the intensity of the shell dopant ions emission and the emission color of core-shell upconversion luminescence (UCL). The uniform NaYF4@NaLnF4 (Ln = Y, Lu, Yb) microrods, with a series of rare-earth ions doped into the core and shell layer at various doping concentrations, achieved color-tuning of the upconversion (UC) emission and dual mode emission at the single-microcrystal level, thus allowing the efficient utilization of core-shell microcrystals in the photonics and security labeling. This study suggests a new class of luminescent materials in the microscopic field. PMID- 29240699 TI - Is a "Good Death" at the Time of Animal Slaughter an Essentially Contested Concept? AB - The phrase "essentially contested concept" (ECC) entered the academic literature in 1956 in an attempt to better characterize certain contentious concepts of political theory. Commonly identified examples of contested concepts are morality, religion, democracy, science, nature, philosophy, and certain types of creative products such as the novel and art. The structure proposed to identify an ECC has proven useful in a wide variety of deliberative discourse in the social, political, and religious arenas where seemingly intractable but productive debates are found. Where a strongly held moral position is contradicted by law, a portion of the citizenry see the law as illegitimate and do not feel compelled to respect it. This paper will attempt to apply the analytic structure of ECC to the concept of animal wellbeing at the time of slaughter specifically a "good death." The results of this analysis supports an understanding that the current slaughter debate is a disagreement in moral belief and normative moral theory. The parties to the dispute have differing visions of the "good." The method of slaughter is not an essentially contested concept where further discourse is likely to result in a negotiated resolution. The position statements of veterinary organizations are used as an example of current discourse. PMID- 29240700 TI - High-Speed Video System for Micro-Expression Detection and Recognition. AB - Micro-expressions play an essential part in understanding non-verbal communication and deceit detection. They are involuntary, brief facial movements that are shown when a person is trying to conceal something. Automatic analysis of micro-expression is challenging due to their low amplitude and to their short duration (they occur as fast as 1/15 to 1/25 of a second). We propose a fully micro-expression analysis system consisting of a high-speed image acquisition setup and a software framework which can detect the frames when the micro expressions occurred as well as determine the type of the emerged expression. The detection and classification methods use fast and simple motion descriptors based on absolute image differences. The recognition module it only involves the computation of several 2D Gaussian probabilities. The software framework was tested on two publicly available high speed micro-expression databases and the whole system was used to acquire new data. The experiments we performed show that our solution outperforms state of the art works which use more complex and computationally intensive descriptors. PMID- 29240701 TI - 25th Conference of GP2A. AB - The 25th Conference of GP2A was held on 31 August and 1 September 2017 in Liverpool, UK, with the aim of exchange of ideas and experience, particularly amongst young medicinal chemists. Topics included bioactive compounds from plants and lichens, and design and development of drugs. Abstracts of invited lectures, proffered oral presentations, flash presentations and posters presented during the meeting are collected in this report. PMID- 29240702 TI - The Platonic Receptacle (Hypodoche), Whitehead's Philosophy, and Genome Evolution. AB - The discovery of a universal genetic code utilized by all existing organisms became the backbone of biology. The coding capacity underwent changes during evolution, but its main fluctuation results from its different reading and regulation. The genetic code thus represents a sort of receptacle of living organism evolution. In this article, we propose an analogy between the genetic code and a broader Platonic hypodoche, a concept that Alfred North Whitehead used to explain various aspects of science. PMID- 29240703 TI - Bioactive Compounds from the Stems of Clausena lansium. AB - In view of the significant neuroprotective effect of Clausena lansium, we continued to separate the n-butanol and the water extracts from the stems of C. lansium in order to find the leading compounds with significant activity. Two new phenolic glycosides, Clausenolside A-B (1-2), one new pair of phenolic enantiomers (3a, 3b), and two new monoterpenoids, clausenapene A-B (4-5), together with twelve known analogues (6-17) were isolated from the stems of C. lansium. Compounds 1-17 were obtained from C. lansium for the first time. Compounds 3a, 3b, 4, 16, and 17 showed strong or moderate potential neuroprotective effects on inhibited PC12 cell injury induced by okadaic acid, and compound 9 exhibited strong potential hepatoprotective activities. Their structures were elucidated on the basis of spectroscopic analyses, including UV, IR, NMR experiments, and electronic circular dichroism (ECD) spectra. PMID- 29240705 TI - Two-Ply Composite Membranes with Separation Layers from Chitosan and Sulfoethylcellulose on a Microporous Support Based on Poly(diphenylsulfone-N phenylphthalimide). AB - Two-ply composite membranes with separation layers from chitosan and sulfoethylcellulose were developed on a microporous support based on poly(diphenylsulfone-N-phenylphthalimide) and investigated by use of X-ray diffraction and scanning electron microscopy methods. The pervaporation properties of the membranes were studied for the separation of aqueous alcohol (ethanol, propan-2-ol) mixtures of different compositions. When the mixtures to be separated consist of less than 15 wt % water in propan-2-ol, the membranes composed of polyelectrolytes with the same molar fraction of ionogenic groups ( NH3+ for chitosan and -SO3- for sulfoethylcellulose) show high permselectivity (the water content in the permeate was 100%). Factors affecting the structure of a non-porous layer of the polyelectrolyte complex formed on the substrate surface and the contribution of that complex to changes in the transport properties of membranes are discussed. The results indicate significant prospects for the use of chitosan and sulfoethylcellulose for the formation of highly selective pervaporation membranes. PMID- 29240704 TI - Prevalence of Chlamydia trachomatis Infection and Its Association with Sexual Behaviour and Alcohol Use in the Population Living in Separated and Segregated Roma Settlements in Eastern Slovakia. AB - The aim of the study was to explore sexual behaviour and the occurrence of Chlamydia trachomatis (CT) infection in the population living in Roma settlements compared to the majority population in Slovakia and to assess the association between alcohol use and sexual behaviour within both populations. A cross sectional population-based Hepa-Meta study was conducted in Slovakia in 2011. The final sample comprised 452 Roma and 403 non-Roma respondents. The occurrence of CT was detected by direct proof of the pathogen by PCR. The association between alcohol use and the prevalence of risky sexual behaviour were assessed using a logistic regression. First intercourse at age 15 or younger was reported by 27.9% of Roma (vs. 4.5% of non-Roma); 93.4% of Roma (vs. 77.9% of non-Roma) used condom inconsistently, 22.8% of Roma (vs. 43.9% of non-Roma) used a condom for protection from unwanted pregnancies and only 8.8% of Roma (vs. 21.8% of non Roma) due to protection against infectious diseases. However, Roma reported having had five or more sexual partners less often compared to the majority (11.5% of Roma vs. 20.6% of non-Roma). Binge drinking at least once a month was associated with a higher number of sexual partners in both groups, but not with condom non-use. The prevalence of CT infection in the Roma population was higher (3.8%) compared to non-Roma (2.7%); however, the difference was not statistically significant. Our study found no differences in the prevalence of CT infection between Roma and non-Roma despite differences in sexual behaviour. Roma begin their sexual life earlier and have unprotected sex more often, but on the other hand, they seem to be much more restrained in terms of the number of sexual partners compared to the majority population. PMID- 29240706 TI - Multi-Objective Optimization Algorithm to Discover Condition-Specific Modules in Multiple Networks. AB - The advances in biological technologies make it possible to generate data for multiple conditions simultaneously. Discovering the condition-specific modules in multiple networks has great merit in understanding the underlying molecular mechanisms of cells. The available algorithms transform the multiple networks into a single objective optimization problem, which is criticized for its low accuracy. To address this issue, a multi-objective genetic algorithm for condition-specific modules in multiple networks (MOGA-CSM) is developed to discover the condition-specific modules. By using the artificial networks, we demonstrate that the MOGA-CSM outperforms state-of-the-art methods in terms of accuracy. Furthermore, MOGA-CSM discovers stage-specific modules in breast cancer networks based on The Cancer Genome Atlas (TCGA) data, and these modules serve as biomarkers to predict stages of breast cancer. The proposed model and algorithm provide an effective way to analyze multiple networks. PMID- 29240707 TI - Molecular Mechanisms of Zinc Oxide Nanoparticle-Induced Genotoxicity Short Running Title: Genotoxicity of ZnO NPs. AB - BACKGROUND: Zinc oxide nanoparticles (ZnO NPs) are among the most frequently applied nanomaterials in consumer products. Evidence exists regarding the cytotoxic effects of ZnO NPs in mammalian cells; however, knowledge about the potential genotoxicity of ZnO NPs is rare, and results presented in the current literature are inconsistent. OBJECTIVES: The aim of this review is to summarize the existing data regarding the DNA damage that ZnO NPs induce, and focus on the possible molecular mechanisms underlying genotoxic events. METHODS: Electronic literature databases were systematically searched for studies that report on the genotoxicity of ZnO NPs. RESULTS: Several methods and different endpoints demonstrate the genotoxic potential of ZnO NPs. Most publications describe in vitro assessments of the oxidative DNA damage triggered by dissoluted Zn2+ ions. Most genotoxicological investigations of ZnO NPs address acute exposure situations. CONCLUSION: Existing evidence indicates that ZnO NPs possibly have the potential to damage DNA. However, there is a lack of long-term exposure experiments that clarify the intracellular bioaccumulation of ZnO NPs and the possible mechanisms of DNA repair and cell survival. PMID- 29240708 TI - Landscape of Research Areas for Zeolites and Metal-Organic Frameworks Using Computational Classification Based on Citation Networks. AB - The field of porous materials is widely spreading nowadays, and researchers need to read tremendous numbers of papers to obtain a "bird's eye" view of a given research area. However, it is difficult for researchers to obtain an objective database based on statistical data without any relation to subjective knowledge related to individual research interests. Here, citation network analysis was applied for a comparative analysis of the research areas for zeolites and metal organic frameworks as examples for porous materials. The statistical and objective data contributed to the analysis of: (1) the computational screening of research areas; (2) classification of research stages to a certain domain; (3) "well-cited" research areas; and (4) research area preferences of specific countries. Moreover, we proposed a methodology to assist researchers to gain potential research ideas by reviewing related research areas, which is based on the detection of unfocused ideas in one area but focused in the other area by a bibliometric approach. PMID- 29240710 TI - A Novel Concrete-Based Sensor for Detection of Ice and Water on Roads and Bridges. AB - Hundreds of people are killed or injured annually in the United States in accidents related to ice formation on roadways and bridge decks. In this paper, a novel embedded sensor system is proposed for the detection of black ice as well as wet, dry, and frozen pavement conditions on roads, runways, and bridges. The proposed sensor works by detecting changes in electrical resistance between two sets of stainless steel poles embedded in the concrete sensor to assess surface and near-surface conditions. A preliminary decision algorithm is developed that utilizes sensor outputs indicating resistance changes and surface temperature. The sensor consists of a 102-mm-diameter, 38-mm-high, concrete cylinder. Laboratory results indicate that the proposed sensor can effectively detect surface ice and wet conditions even in the presence of deicing chlorides and rubber residue. This sensor can further distinguish black ice from ice that may exist within concrete pores. PMID- 29240709 TI - Prevalence of Albuminuria in Children Living in a Rural Agricultural and Fishing Subsistence Community in Lake Chapala, Mexico. AB - The occurrence of Chronic Kidney Disease (CKD) of unknown etiology in autochthonous child populations residing along the Lake Chapala lakeshore is endemic (Jalisco, Mexico). The objective of this study was to determine the prevalence of albuminuria in the pediatric population and to measure the glomerular filtration rate in children with two positive albuminuria tests. Urinary albumin was measured in 394 children. Subjects with two or more positive albuminuria test donated blood samples for the determination of serum biomarkers. From a rural community with 565 children under the age of 17 years, 394 (69.7%) participated with first morning urine samples. A total of 180 children were positive (with two or more positive albuminuria tests). The prevalence of albuminuria among the children participating in the study was 45.7%. Of the 180 children with persistent albuminuria, 160 (88.9%) were tested for serum creatinine, urea, and cystatin C. The 68.1% of the children studied, were found in stages 3a and 3b of the Kidney Disease Improving Global Outcomes (KDIGO) classification (mean glomerular filtration rate (GFR) 51.9 and 38.4 mL/min/1.73 m2 respectively). The lowest frequencies were for classifications 1 and 4. None of the subjects was classified as grade 5. The prevalence of albuminuria in children from this rural community is 3-5 times higher than reported in international literature. Regarding GFR, more than 50% of children studied are under 60 mL/min/1.73 m2. It is a priority to find the causes of albuminuria and CKD in this Mexican region. PMID- 29240711 TI - NAD1 Controls Defense-Like Responses in Medicago truncatula Symbiotic Nitrogen Fixing Nodules Following Rhizobial Colonization in a BacA-Independent Manner. AB - Legumes form endosymbiotic interaction with host compatible rhizobia, resulting in the development of nitrogen-fixing root nodules. Within symbiotic nodules, rhizobia are intracellularly accommodated in plant-derived membrane compartments, termed symbiosomes. In mature nodule, the massively colonized cells tolerate the existence of rhizobia without manifestation of visible defense responses, indicating the suppression of plant immunity in the nodule in the favur of the symbiotic partner. Medicago truncatulaDNF2 (defective in nitrogen fixation 2) and NAD1 (nodules with activated defense 1) genes are essential for the control of plant defense during the colonization of the nitrogen-fixing nodule and are required for bacteroid persistence. The previously identified nodule-specific NAD1 gene encodes a protein of unknown function. Herein, we present the analysis of novel NAD1 mutant alleles to better understand the function of NAD1 in the repression of immune responses in symbiotic nodules. By exploiting the advantage of plant double and rhizobial mutants defective in establishing nitrogen-fixing symbiotic interaction, we show that NAD1 functions following the release of rhizobia from the infection threads and colonization of nodule cells. The suppression of plant defense is self-dependent of the differentiation status of the rhizobia. The corresponding phenotype of nad1 and dnf2 mutants and the similarity in the induction of defense-associated genes in both mutants suggest that NAD1 and DNF2 operate close together in the same pathway controlling defense responses in symbiotic nodules. PMID- 29240712 TI - Developing an Agent-Based Drug Model to Investigate the Synergistic Effects of Drug Combinations. AB - The growth and survival of cancer cells are greatly related to their surrounding microenvironment. To understand the regulation under the impact of anti-cancer drugs and their synergistic effects, we have developed a multiscale agent-based model that can investigate the synergistic effects of drug combinations with three innovations. First, it explores the synergistic effects of drug combinations in a huge dose combinational space at the cell line level. Second, it can simulate the interaction between cells and their microenvironment. Third, it employs both local and global optimization algorithms to train the key parameters and validate the predictive power of the model by using experimental data. The research results indicate that our multicellular system can not only describe the interactions between the microenvironment and cells in detail, but also predict the synergistic effects of drug combinations. PMID- 29240713 TI - Nb-Based Zeolites: Efficient bi-Functional Catalysts for the One-Pot Synthesis of Succinic Acid from Glucose. AB - The one-pot production of succinic acid from glucose was investigated in pure hot water as solvent using Nb (0.02 and 0.05 moles%)-Beta zeolites obtained by a post synthesis methodology. Structurally, they are comprised of residual framework Al acid sites, extra-framework isolated Nb (V) and Nb2O5 pore-encapsulated clusters. The Nb-modified Beta-zeolites acted as bi-functional catalysts in which glucose is dehydrated to levulinic acid (LA) which, further, suffers an oxidation process to succinic acid (SA). After the optimization of the reaction conditions, that is, at 180 degrees C, 18 bar O2, and 12 h reaction time, the oxidation of glucose occurred with a selectivity to succinic acid as high as 84% for a total conversion. PMID- 29240714 TI - Spiro[pyrrolidine-3,3'-oxindoles] and Their Indoline Analogues as New 5-HT6 Receptor Chemotypes. AB - Synthetic derivatives of spiro[pyrrolidinyl-3,3'-oxindole] alkaloids (coerulescine analogues) were investigated as new ligands for aminergic G-protein coupled receptors (GPCRs). The chemical starting point 2'-phenylspiro[indoline 3,3'-pyrrolidin]-2-one scaffold was identified by virtual fragment screening utilizing ligand- and structure based methods. As a part of the hit-to-lead optimization a structure-activity relationship analysis was performed to explore the differently substituted 2'-phenyl-derivatives, introducing the phenylsulphonyl pharmacophore and examining the corresponding reduced spiro[pyrrolidine-3,3'-indoline] scaffold. The optimization process led to ligands with submicromolar affinities towards the 5-HT6 receptor that might serve as viable leads for further optimization. PMID- 29240715 TI - The Role of Motion Concepts in Understanding Non-Motion Concepts. AB - This article discusses a specific type of metaphor in which an abstract non motion domain is described in terms of a motion event. Abstract non-motion domains are inherently different from concrete motion domains. However, motion domains are used to describe abstract non-motion domains in many metaphors. Three main reasons are suggested for the suitability of motion events in such metaphorical descriptions. Firstly, motion events usually have high degrees of concreteness. Secondly, motion events are highly imageable. Thirdly, components of any motion event can be imagined almost simultaneously within a three dimensional space. These three characteristics make motion events suitable domains for describing abstract non-motion domains, and facilitate the process of online comprehension throughout language processing. Extending the main point into the field of mathematics, this article discusses the process of transforming abstract mathematical problems into imageable geometric representations within the three-dimensional space. This strategy is widely used by mathematicians to solve highly abstract and complex problems. PMID- 29240716 TI - Impedance Spectroscopy Analysis and Equivalent Circuit Modeling of Graphene Oxide Solutions. AB - The optical and electrical characteristics of a graphene oxide solution (GS) with different graphene oxide (GO) concentrations in de-ionized water are investigated via the electrochemical impedance spectroscopy (EIS) method. The measurement results produced by the EIS for the GS are represented with both Bode and Nyquist plots in a frequency range from 1 kHz to 10 MHz. Using these results, we develop an equivalent circuit model as a function of the GO concentration, representing the GS as a mixed circuit of two-dimensional (2D) GO dispersed in parallel in de ionized (DI) water. The underlying physics of the current-flowing behavior in the GS are explained and interpreted using empirical circuit models; the circuit model also shows that highly resistive GO becomes conductive in GS form in the DI water. The findings in this work should draw new attention toward GSes and related applications, including functional composite materials, catalysts, and filter membranes. PMID- 29240717 TI - A Novel Antibiotic Mechanism of l-Cyclopropylalanine Blocking the Biosynthetic Pathway of Essential Amino Acid l-Leucine. AB - The unusual amino acid l-cyclopropylalanine was isolated from the mushroom Amanita virgineoides after detection in an anti-fungal screening test. l Cyclopropylalanine was found to exhibit broad-spectrum inhibition against fungi and bacteria. The anti-fungal activity was found to be abolished in the presence of the amino acid l-leucine, but not any other amino acids, indicating that l cyclopropylalanine may block the biosynthesis of the essential amino acid l leucine, thereby inhibiting fungal and bacteria growth. Further biochemical studies found l-cyclopropylalanine indeed inhibits alpha-isopropylmalate synthase (alpha-IMPS), the enzyme that catalyzes the rate-limiting step in the biosynthetic pathway of l-leucine. Inhibition of essential l-leucine synthesis in fungal and bacteria organisms, a pathway absent in host organisms such as humans, may represent a novel antibiotic mechanism to counter the ever-increasing problem of drug resistance to existing antibiotics. PMID- 29240718 TI - Construction of Luminogen Exhibiting Multicolored Emission Switching through Combination of Twisted Conjugation Core and Donor-Acceptor Units. AB - Stimuli responsive luminescent materials, especially those exhibiting multicolor emission switching, have potential application in sensor, optical recording, security ink, and anti-counterfeit label. Through combination of twisted conjugation core and donor and acceptor units, a luminogen (2-(bis(4-(carbazol-9 yl)phenyl)methylene)malononitrile (1) was synthesized. Luminogen 1 can form three kinds of crystals emitting green (1GC, lambdaem = 506 nm, PhiF = 19.8%), yellow green (1YC, lambdaem = 537 nm, PhiF = 17.8%), and orange (1OC, lambdaem = 585 nm, PhiF = 30.0%) light upon 365 nm UV illumination. The emission of amorphous solid of 1 (1Am) overlaps with that of 1OC (lambdaem = 585 nm), with quantum yield of 13.9%, which is seldom reported. Emission of 1 can be switched among green, yellow-green, and orange through morphology modulation upon exposure to thermal, solvent vapor, or mechanical stimuli. Finally, its potential application in optical recording was also investigated. PMID- 29240719 TI - Pericardial Effusion as a Presenting Symptom of Hashimoto Thyroiditis: A Case Report. AB - Background: Hashimoto thyroiditis (HT) is the most frequent cause of acquired hypothyroidism in paediatrics. HT is usually diagnosed in older children and adolescents, mainly in females and is rare in infants and toddlers with cardiac involvement, including pericardial effusion, that can be found in 10% to 30% of adult HT cases. In this paper, a child with HT and pericardial effusion as the most important sign of HT is described. Case presentation: A four-year-old male child suffering for a few months from recurrent abdominal pain sometimes associated with vomiting underwent an abdominal ultrasound scan outside the hospital. This led to the identification of a significant pericardial effusion. At admission, his family history revealed that both his mother and maternal grandmother suffered from HT and that both were treated with l-thyroxine (LT4). The clinical examination did not reveal any pathological signs other than a palpable thyroid. His weight was 21 kg (78th percentile), his height was 101.8 cm (12th percentile) and his body max index (BMI) was 20.26 (96th percentile). On a chest radiograph, his heart had a globular appearance and the lung fields were normal. An echocardiography confirmed and determined the effusion amount (max, 23 mm; 600 mL) with light impairment of the heart kinetics. The ECG showed sinus bradycardia with a normal ST tract. Based on the blood test results, an infectious cause of the pericardial fluid excess was considered unlikely. Thyroid function testing revealed very high thyrotropin (TSH, 487 MUIU/mL; normal range, 0.340-5.600 MUIU/mL) and low serum-free thyroxine (fT4, 0.04 ng/dL; normal range, 0.54-1.24 ng/dL) levels. High thyroid peroxidase antibody titres in the blood were evidenced (>1500 UI/L; normal values, 0.0-9.0 UI/L). The thyroid ultrasound was consistent with thyroiditis. HT was diagnosed, and LT4 replacement therapy with levothyroxine sodium 1.78 ug/kg/die was initiated, with a gradual increase of the administered dose. The treatment was successful because a complete regression of the effusion after one month was evidenced, with a substantial modification towards normality of the thyroid function tests. One year later, the substitutive therapy led to complete normalization of the thyroid function indexes. A slight reduction of weight (BMI, 17.60 for age) and an increase of the velocity of height growth were evidenced. Conclusions: When fluid is identified in the pericardial space and pericarditis of unknown origin is diagnosed, the thyroid function should be immediately evaluated to prescribe substitutive hormonal therapy if necessary and thereby avoid overt hypothyroidism development and the risk of cardiac tamponade. PMID- 29240720 TI - Enhanced Reduction of Few-Layer Graphene Oxide via Supercritical Water Gasification of Glycerol. AB - A sustainable and effective method for de-oxygenation of few-layer graphene oxide (FLGO) by glycerol gasification in supercritical water (SCW) is described. In this manner, reduction of FLGO and valorization of glycerol, in turn catalyzed by FLGO, are achieved simultaneously. The addition of glycerol enhanced FLGO oxygen removal by up to 59% due to the in situ hydrogen generation as compared to the use of SCW only. Physicochemical characterization of the reduced FLGO (rFLGO) showed a high restoration of the sp2-conjugated carbon network. FLGO sheets with a starting C/O ratio of 2.5 are reduced by SCW gasification of glycerol to rFLGO with a C/O ratio of 28.2, above those reported for hydrazine-based methods. Additionally, simultaneous glycerol gasification resulted in the concurrent production of H2, CO, CH4 and valuable hydrocarbons such as alkylated and non alkylated long chain hydrocarbon (C12-C31), polycyclic aromatic hydrocarbons (PAH), and phthalate, phenol, cresol and furan based compounds. PMID- 29240721 TI - Extreme Environment Sensing Using Femtosecond Laser-Inscribed Fiber Bragg Gratings. AB - The femtosecond laser-induced fiber Bragg grating is an effective sensor technology that can be deployed in harsh environments. Depending on the optical fiber chosen and the inscription parameters that are used, devices suitable for high temperature, pressure, ionizing radiation and strain sensor applications are possible. Such devices are appropriate for aerospace or energy production applications where there is a need for components, instrumentation and controls that can function in harsh environments. This paper will present a review of some of the more recent developments in this field. PMID- 29240723 TI - Identification of Key Genes and Pathways in Tongue Squamous Cell Carcinoma Using Bioinformatics Analysis. AB - BACKGROUND Tongue squamous cell carcinoma (TSCC) is a major type of oral cancers and has remained an intractable cancer over the past decades. The aim of this study was to identify differentially expressed genes (DEGs) during TSCC and reveal their potential mechanisms. MATERIAL AND METHODS The gene expression profiles of GSE13601 were downloaded from the GEO database. The GSE13601 dataset contains 57 samples, including 31 tongue SCC samples and 26 matched normal mucosa samples. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed; Cytoscape software was used for the protein-protein interaction (PPI) network and module analysis of the DEGs. RESULTS We identified a total of 1,050 upregulated DEGs (uDEGs) and 702 downregulated DEGs (dDEGs) of TSCC. The GO analysis results showed that uDEGs were significantly enriched in the following biological processes (BP): signal transduction, positive or negative regulation of cell proliferation, and negative regulation of cell proliferation. The dDEGs were significantly enriched in the following biological processes: signal transduction, cell adhesion, and apoptotic process. The KEGG pathway analysis showed that uDEGs were enriched in metabolic pathways, pathways in cancer, and PI3K-Akt signaling pathway, while the dDEGs were enriched in focal adhesion and ECM-receptor interaction. The top centrality hub genes RAC1, APP, EGFR, KNG1, AGT, and HRAS were identified from the PPI network. Module analysis revealed that TSCC was associated with significant pathways, including neuroactive ligand-receptor interaction, calcium signaling pathway, and chemokine signaling pathway. CONCLUSIONS The present study identified key genes and signal pathways, which deepen our understanding of the molecular mechanisms of carcinogenesis and development of the disease, and might be used as diagnostic and therapeutic molecular biomarkers for TSCC. PMID- 29240726 TI - Notes from the Field: Tuberculosis Control Activities After Hurricane Harvey - Texas, 2017. PMID- 29240724 TI - Large Outbreak of Neisseria meningitidis Serogroup C - Nigeria, December 2016 June 2017. AB - On February 16, 2017, the Ministry of Health in Zamfara State, in northwestern Nigeria, notified the Nigeria Centre for Disease Control (NCDC) of an increased number of suspected cerebrospinal meningitis (meningitis) cases reported from four local government areas (LGAs). Meningitis cases were subsequently also reported from Katsina, Kebbi, Niger, and Sokoto states, all of which share borders with Zamfara State, and from Yobe State in northeastern Nigeria. On April 3, 2017, NCDC activated an Emergency Operations Center (EOC) to coordinate rapid development and implementation of a national meningitis emergency outbreak response plan. After the outbreak was reported, surveillance activities for meningitis cases were enhanced, including retrospective searches for previously unreported cases, implementation of intensified new case finding, and strengthened laboratory confirmation. A total of 14,518 suspected meningitis cases were reported for the period December 13, 2016-June 15, 2017. Among 1,339 cases with laboratory testing, 433 (32%) were positive for bacterial pathogens, including 358 (82.7%) confirmed cases of Neisseria meningitidis serogroup C. In response, approximately 2.1 million persons aged 2-29 years were vaccinated with meningococcal serogroup C-containing vaccines in Katsina, Sokoto, Yobe, and Zamfara states during April-May 2017. The outbreak was declared over on June 15, 2017, after high-quality surveillance yielded no evidence of outbreak-linked cases for 2 consecutive weeks. Routine high-quality surveillance, including a strong laboratory system to test specimens from persons with suspected meningitis, is critical to rapidly detect and confirm future outbreaks and inform decisions regarding response vaccination. PMID- 29240722 TI - G Protein-Coupled Receptors at the Crossroad between Physiologic and Pathologic Angiogenesis: Old Paradigms and Emerging Concepts. AB - G protein-coupled receptors (GPCRs) have been implicated in transmitting signals across the extra- and intra-cellular compartments, thus allowing environmental stimuli to elicit critical biological responses. As GPCRs can be activated by an extensive range of factors including hormones, neurotransmitters, phospholipids and other stimuli, their involvement in a plethora of physiological functions is not surprising. Aberrant GPCR signaling has been regarded as a major contributor to diverse pathologic conditions, such as inflammatory, cardiovascular and neoplastic diseases. In this regard, solid tumors have been demonstrated to activate an angiogenic program that relies on GPCR action to support cancer growth and metastatic dissemination. Therefore, the manipulation of aberrant GPCR signaling could represent a promising target in anticancer therapy. Here, we highlight the GPCR-mediated angiogenic function focusing on the molecular mechanisms and transduction effectors driving the patho-physiological vasculogenesis. Specifically, we describe evidence for the role of heptahelic receptors and associated G proteins in promoting angiogenic responses in pathologic conditions, especially tumor angiogenesis and progression. Likewise, we discuss opportunities to manipulate aberrant GPCR-mediated angiogenic signaling for therapeutic benefit using innovative GPCR-targeted and patient tailored pharmacological strategies. PMID- 29240727 TI - Health and Development at Age 19-24 Months of 19 Children Who Were Born with Microcephaly and Laboratory Evidence of Congenital Zika Virus Infection During the 2015 Zika Virus Outbreak - Brazil, 2017. AB - In November 2015, the Brazilian Ministry of Health (MOH) declared the Zika virus outbreak a public health emergency after an increase in microcephaly cases was reported in the northeast region of the country (1). During 2015-2016, 15 states in Brazil with laboratory-confirmed Zika virus transmission reported an increase in birth prevalence of microcephaly (2.8 cases per 10,000 live births), significantly exceeding prevalence in four states without confirmed transmission (0.6 per 10,000) (2). Although children with microcephaly and laboratory evidence of Zika virus infection have been described in early infancy (3), their subsequent health and development have not been well characterized, constraining planning for the care and support of these children and their families. The Brazilian MOH, the State Health Secretariat of Paraiba, and CDC collaborated on a follow-up investigation of the health and development of children in northeastern Brazil who were reported to national surveillance with microcephaly at birth. Nineteen children with microcephaly at birth and laboratory evidence of Zika virus infection were assessed through clinical evaluations, caregiver interviews, and review of medical records. At follow-up (ages 19-24 months), most of these children had severe motor impairment, seizure disorders, hearing and vision abnormalities, and sleep difficulties. Children with microcephaly and laboratory evidence of Zika virus infection have severe functional limitations and will require specialized care from clinicians and caregivers as they age. PMID- 29240728 TI - State Laws Regarding Indoor Public Use, Retail Sales, and Prices of Electronic Cigarettes - U.S. States, Guam, Puerto Rico, and U.S. Virgin Islands, September 30, 2017. AB - Electronic cigarettes (e-cigarettes) are the most frequently used tobacco product among U.S. youths, and past 30-day e-cigarette use is more prevalent among high school students than among adults (1,2). E-cigarettes typically deliver nicotine, and the U.S. Surgeon General has concluded that nicotine exposure during adolescence can cause addiction and can harm the developing adolescent brain (2). Through authority granted by the Family Smoking Prevention and Tobacco Control Act, the Food and Drug Administration (FDA) prohibits e-cigarette sales to minors, free samples, and vending machine sales, except in adult-only facilities (3). States, localities, territories, and tribes maintain broad authority to adopt additional or more stringent requirements regarding tobacco product use, sales, marketing, and other topics (2,4). To understand the current e-cigarette policy landscape in the United States, CDC assessed state and territorial laws that 1) prohibit e-cigarette use and conventional tobacco smoking indoors in restaurants, bars, and worksites; 2) require a retail license to sell e cigarettes; 3) prohibit e-cigarette self-service displays (e.g., requirement that products be kept behind the counter or in a locked box); 4) establish 21 years as the minimum age of purchase for all tobacco products, including e-cigarettes (tobacco-21); and 5) apply an excise tax to e-cigarettes. As of September 30, 2017, eight states, the District of Columbia (DC), and Puerto Rico prohibited indoor e-cigarette use and smoking in indoor areas of restaurants, bars, and worksites; 16 states, DC, and the U.S. Virgin Islands required a retail license to sell e-cigarettes; 26 states prohibited e-cigarette self-service displays; five states, DC, and Guam had tobacco-21 laws; and eight states, DC, Puerto Rico, and the U.S. Virgin Islands taxed e-cigarettes. Sixteen states had none of the assessed laws. A comprehensive approach that combines state-level strategies to reduce youths' initiation of e-cigarettes and population exposure to e-cigarette aerosol, coupled with federal regulation, could help reduce health risks posed by e-cigarettes among youths (2,5). PMID- 29240729 TI - Introduction of Inactivated Poliovirus Vaccine and Impact on Vaccine-Associated Paralytic Poliomyelitis - Beijing, China, 2014-2016. AB - When included in a sequential polio vaccination schedule, inactivated polio vaccine (IPV) reduces the risk for vaccine-associated paralytic poliomyelitis (VAPP), a rare adverse event associated with receipt of oral poliovirus vaccine (OPV). During January 2014, the World Health Organization (WHO) recommended introduction of at least 1 IPV dose into routine immunization schedules in OPV using countries (1). The Polio Eradication and Endgame Strategic Plan 2013-2018 recommended completion of IPV introduction in 2015 and globally synchronized withdrawal of OPV type 2 in 2016 (2). Introduction of 1 dose of IPV into Beijing's Expanded Program on Immunization (EPI) on December 5, 2014 represented China's first province-wide IPV introduction. Coverage with the first dose of polio vaccine was maintained from 96.2% to 96.9%, similar to coverage with the first dose of diphtheria and tetanus toxoids and pertussis vaccine (DTP) (96.5% 97.2%); the polio vaccine dropout rate (the percentage of children who received the first dose of polio vaccine but failed to complete the series) was 1.0% in 2015 and 0.4% in 2016. The use of 3 doses of private-sector IPV per child decreased from 18.1% in 2014, to 17.4% in 2015, and to 14.8% in 2016. No cases of VAPP were identified during 2014-2016. Successful introduction of IPV into the public sector EPI program was attributed to comprehensive planning, preparation, implementation, robust surveillance for adverse events after immunization (AEFI), and monitoring of vaccination coverage. This evaluation provided information that helped contribute to the expansion of IPV use in China and in other OPV-using countries. PMID- 29240730 TI - QuickStats: Percentage* of Visits by Patients Aged >=18 Years to Office-Based Physicians? Made by Patients with >=2 Selected Diagnosed Chronic Conditions,S by Physician Specialty Category and Patient Age Group - National Ambulatory Medical Care Survey, 2015. AB - In 2015, the percentage of office-based physician visits by adults with two or more diagnosed chronic conditions was 53.1% for primary care physicians, 38.5% for medical specialists, and 23.9% for surgeons. This pattern was observed for each of the age groups studied. The percentage of visits increased with age group, regardless of specialty category. PMID- 29240731 TI - Notes from the Field: Monitoring Out-of-State Patients During a Hurricane Response Using Syndromic Surveillance - Tennessee, 2017. PMID- 29240732 TI - Endoscopic Resection for Early-Stage Esophageal Cancer, Are We There for Squamous As Well? AB - Superficial esophageal squamous cell cancer (SESCC) is often managed with esophagectomy with or without chemoradiotherapy. Esophagectomy has a significant complication rate and is not an option for many patients. In the current issue, a retrospective single center study evaluated 66 patients with SESCC. With endoscopic resection followed by adjuvant chemoradiotherapy, the reported 1-, 3- and 5-year overall survival rates were 98%, 87% and 75% respectively, comparable to survival rates after esophagectomy or definitive chemoradiotherapy. This study suggests a key role for endoscopic management in SESCC, and provides important data on the combination of endoscopic management plus adjuvant chemoradiation. PMID- 29240733 TI - Use of TAI-FISH to visualize neural ensembles activated by multiple stimuli. AB - Researchers in behavioral neuroscience have long sought imaging techniques that can identify and distinguish neural ensembles that are activated by sequentially applied stimuli at single-cell resolution across the whole brain. Taking advantage of the different kinetics of immediate-early genes' mRNA and protein expression, we addressed this problem by developing tyramide-amplified immunohistochemistry-fluorescence in situ hybridization (TAI-FISH), a dual-epoch neural-activity-dependent labeling protocol. Here we describe the step-by-step procedures for TAI-FISH on brain sections from mice that were sequentially stimulated by morphine (appetitive first stimulus) and foot shock (aversive second stimulus). We exemplify our approach by FISH-labeling the neural ensembles that were activated by the second stimulus for the mRNA expression of c-fos, a well-established marker of neural activation. We labeled neuronal ensembles activated by the first stimulus using fluorescence immunohistochemistry (IHC) for the c-fos protein. To further improve the temporal separation of the c-fos mRNA and protein signals, we provide instructions on how to enhance the protein signals using tyramide signal amplification (TSA). Compared with other dual-epoch labeling techniques, TAI-FISH provides better temporal separation of the activated neural ensembles and is better suited to investigation of whole-brain responses. TAI-FISH has been used to investigate neural activation patterns in response to appetitive and aversive stimuli, and we expect it to be more broadly utilized for visualizing brain responses to other types of stimuli, such as sensory stimuli or psychiatric drugs. From first stimulation to image analysis, TAI-FISH takes ~9 d to complete. PMID- 29240735 TI - Improved health and welfare will flow from reductions in drinking. PMID- 29240734 TI - Transient expression of human antibodies in mammalian cells. AB - Recombinant expression of antibody molecules in mammalian cells offers important advantages over traditionally utilized bacterial expression, including glycosylation required for antibody functionality and markedly reduced levels of endotoxin contamination. Advances in transient mammalian expression systems enable high yields (>100 mg/liter) that now allow for effective recombinant antibody production at a reasonable cost. Here, we provide step-by-step protocols for the design and recombinant expression of full-length IgG antibodies and antibody-derived constructs (including Fab, Fc-fusions and bispecifics) in mammalian cells. Antibody constructs are designed by combining antibody variable domains, generated by phage display or derived from human/humanized monoclonals, with constant regions. The constructs are then expressed from mammalian vectors, secreted into culture media, purified by affinity chromatography and characterized by biolayer interferometry. This article provides detailed protocols, sequences and strategies that allow the expression and purification of endotoxin-free antibody reagents suitable for testing in animal models within a 3 week time frame. PMID- 29240736 TI - Management of coronary artery disease in patients on dialysis. AB - AIMS: Coronary artery disease is common in patients with end-stage renal failure (ESRF). However, there is little evidence that revascularisation improves outcomes, compared with medical management. This study assessed survival and cardiovascular outcomes in patients with ESRF undergoing coronary angiography and then having coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention (PCI) or medical management. METHODS: Survival and major adverse cardiac events (MACE) were examined in all patients with ESRF who underwent coronary angiography at Auckland City Hospital between 2003 and 2012. Outcomes of patients who underwent revascularisation (CABG or PCI) were compared with those managed medically. RESULTS: Two hundred and eighty-eight patients with ESRF had a total of 382 diagnostic coronary angiograms. Ninety-one (32%) patients underwent revascularisation (61 PCI, 30 CABG), with the other 197 (68%) treated medically or requiring no specific cardiac treatment. The median survival was 3.3 (IQR 2.1 5.3) years in patients undergoing CABG, 2.9 (IQR 1.5-5.4) years in patients treated with PCI and 2.9 (IQR 1.3-5.5) years in patients managed medically. There was no significant difference in survival between treatment modalities in the entire cohort, nor in the 108 patients with triple vessel disease. Similarly, there was no difference in the incidence of major adverse cardiac events, comparing medical management with revascularisation. CONCLUSION: There was no apparent survival advantage with revascularisation by either CABG or PCI, compared with medical management, in patients with ESRF undergoing coronary angiography. This study confirms the poor prognosis of patients with ESRF and coronary disease. Observational studies cannot control for all potential confounders; randomised trial data are needed to guide optimal management of this high-risk patient cohort. PMID- 29240738 TI - Outcome of acute hospital admission for non-specific low back pain: what is the role of MRI? AB - BACKGROUND: Low back pain is a common worldwide condition, affecting most people during their lifetime. Various imaging modalities are being used to assist clinicians in diagnosing and thus, aid in formulating a suitable management plan. Extensive research has been carried out in assessing this condition due to its high prevalence, with many guidelines published internationally. AIM: To determine whether MRI imaging influences the management of patients admitted with acute, non-specific low back pain between 1 January 2013 and 31 December 2015. METHOD: A total of 209 patients who met the inclusion criteria were included in the study. Suitable patients were initially identified from the ward admission book. Subsequently, relevant data regarding patient admission and management within the two-year period were obtained from the hospital patient management system, including radiology reports. RESULTS: Out of the 209 patients included in this study, 131 patients (63%) had an MRI as part of the diagnostic process. Most patients were managed non-operatively with only 41 (20%) out of the 209 patients having undergone acute surgery while an inpatient. In this subgroup, 38 had an MRI done prior to surgery. Among the 168 patients who were treated non operatively, including epidural steroid injection, 13 patients (8%) had elective surgery within one year from their initial presentation. CONCLUSION: Use of MRI can aid in the early diagnosis and facilitate faster rehabilitation for patients. It can also potentially reduce patient stay in hospital and result in significant cost savings for the healthcare system. Imaging guidelines should be developed in the assessment of patients with low back pain in an acute hospital setting. PMID- 29240737 TI - Morbidity from intentional self-harm among Pacific peoples in New Zealand 1996 2015. AB - AIM: The aim of this study was to describe trends in intentional self-harm for Pacific peoples in New Zealand by reviewing official data over the period 1996 2015. METHOD: Publicly funded hospitalisations where the external cause was intentional self-harm were examined and areas of interest were identified and are presented. RESULTS: Over a 19-year period (1996-2015), there were 1,608 intentional self-harm events for Pacific peoples (2.8%) out of 58,643 intentional self-harm events nationally for New Zealand's total population. CONCLUSION: This study has been able to delineate Pacific ethnic-specific information not previously available for a prolonged period of 19 years. There are differences in Pacific peoples' experiences between ethnic groups. Furthermore, disparities persist between Pacific and non-Pacific. This study exposes priority areas for more targeted interventions according to ethnic, socioeconomic status, gender and age variations. PMID- 29240739 TI - Office design and health: a systematic review. AB - AIM: To carry out a systematic review of recent research into the effects of workplace design, comparing individual with shared workspaces, on the health of employees. METHODS: The research question was "Does workplace design (specifically individual offices compared with shared workspaces) affect the health of workers?" A literature search limited to articles published between 2000 and 2017 was undertaken. A systematic review was carried out, and the findings of the reviewed studies grouped into themes according to the primary outcomes measured in the studies. RESULTS: The literature search identified 15 relevant studies addressing health effects of shared or open-plan offices compared with individual offices. Our systematic review found that, compared with individual offices, shared or open-plan office space is not beneficial to employees' health, with consistent findings of deleterious effects on staff health, wellbeing and productivity. Our findings are also consistent with those of earlier reviews. CONCLUSION: These findings have public health implications for the New Zealand workforce. Decisions about workplace design should include weighing the short-term financial benefits of open-plan or shared workspaces against the significant harms, including increased sickness absence, lower job satisfaction and productivity, and possible threats to recruitment and retention of staff. PMID- 29240741 TI - A retrospective audit of the characteristics and treatment outcomes in patients with diabetes-related charcot neuropathic osteoarthropathy. AB - AIMS: To review the characteristics, management and outcomes one year after diagnosis in patients with diabetes related charcot neuropathic osteoarthropathy (CN) treated at the Diabetes Podiatry service, Waitemata District Health Board (WDHB) between 2000-2014. METHODS: Patients with diabetes and recorded diagnosis of CN were identified from the podiatry service records. Clinical details were retrospectively obtained from WDHB databases and patient medical records. RESULTS: Forty-one patients were included, 31 had type 2 diabetes, 10 had type 1 diabetes. At presentation, the median duration of all-type diabetes was 15 years. The median time from symptom onset to diagnosis was 17 weeks. Symptoms at presentation were: oedema (49%), warmth (73%), erythema (17%), swelling (90%) and pain (60%). Concomitant ulcers were present in 32%, deformities 83%, osteomyelitis 2% and septic arthritis 2%. Mean time to ambulation in modified shoes was 21.3 weeks (+/-11.5). Complication rates one year from diagnosis for ulcers, osteomyelitis, amputations and all-cause mortality were 34%, 2%, 2% and 5% respectively. CONCLUSION: Time to diagnosis of CN was shorter than previously reported, though the high rate of deformities still suggests a significant delay in diagnosis. Increased education of healthcare professionals and people with diabetes-related neuropathy is important to ensure early diagnosis and appropriate management to reduce deformities and complications. PMID- 29240742 TI - Paediatric testicular tumours in a New Zealand centre. AB - AIM: This is a 12-year, single-centre retrospective review of paediatric testicular tumours and review of the world literature on paediatric testicular tumours. The aim was to identify presenting features, the range of pathology and management of such tumours in comparison with other published series. METHODS: The hospital's pathology database was searched for all testicular and paratesticular tissue submitted for patients younger than 16 years of age during the 12-year study period January 2000 to December 2011, and patients with testicular tumours identified. A detailed review of clinical records was then completed and summary statistics calculated. RESULTS: There were 33 tumours and 22 (66.7%) were malignant. The most common tumour was mature teratoma. No tumours presented with a twisted gonad. The mean incidence per year was 2.75 cases. This is comparable to other reported series worldwide (median 1.92, range 1.7-6.3). CONCLUSION: Testicular tumours in children are rare. In our centre, mature teratoma was the most common tumour, and malignant testicular tumours did not present with torsion. Our experience in managing gonadal tumours is similar to that published by major centres for paediatric surgery across the world. There is scope to develop the practice of testis-sparing surgery. PMID- 29240740 TI - Characteristics of and differences between Pasifika women and New Zealand European women diagnosed with breast cancer in New Zealand. AB - AIM: Breast cancer in New Zealand-based Pasifika women is a significant issue. Although Pasifika women have a lower incidence of breast cancer compared to New Zealand European women, they have higher breast cancer mortality and lower five year survival. The aim of this study was to describe the characteristics and tumour biology of Pasifika women and to compare New Zealand European women to identify what factors impact on early (Stage 1 and 2) vs advanced stage (Stage 3 and 4) at diagnosis. METHOD: Data on all Pasifika and New Zealand European women diagnosed with breast cancer (C50) during the period 1 June 2000 to 31 May 2013 was extracted from the Auckland and Waikato Breast Cancer Registries. Descriptive tables and Chi-square test were used to examine differences in characteristics and tumour biology between Pasifika and New Zealand European women. Logistic regression was used to identify factors that contributed to an increased risk of advanced stage at diagnosis. RESULTS: A significantly higher proportion of Pasifika women had advanced disease at diagnosis compared to New Zealand European women (33.3% and 18.3%, respectively). Cancer biology in Pasifika women was more likely to be: 1) HER2+, 2) ER/PR negative and 3) have a tumour size of >=50mm. Pasifika women live in higher deprivation areas of 9-10 compared to New Zealand European women (55% vs 14%, respectively) and were less likely to have their cancer identified through screening. Logistic regression showed that if Pasifika women were on the screen-detected pathway they had similar odds (not sig.) of having advanced disease at diagnosis to New Zealand European women. CONCLUSION: Mode of detection, deprivation, age and some biological factors contributed to the difference in odds ratio between Pasifika and New Zealand European women. For those of screening age, adherence to the screening programme and improvements in access to earlier diagnosis for Pasifika women under the current screening age have the potential to make a substantial difference in the number of Pasifika women presenting with late-stage disease. PMID- 29240743 TI - Potential for public health success in tackling the hepatitis C virus epidemic. AB - New Zealand and Australia both now have the potential for a major public health success in controlling the hepatitis C virus epidemic. The burden of advanced liver disease and drug-related harm is increasing. However, a new range of anti viral therapies have become available which offer a potential cure for most people with few side-effects. The epidemic is potentially preventable and hepatitis C is now curable. Although public health strategies for blood-borne viruses have been updated, they fall short of what is needed and should be upgraded with more emphasis on prevention, in order to achieve control of this epidemic. PMID- 29240744 TI - An osteoarthritis model of care should be a national priority for New Zealand. AB - Osteoarthritis is highly prevalent, disabling and costly to the person and the community. The burden of this chronic condition is predicted to increase dramatically over the coming decades. Healthcare spending on osteoarthritis is unsustainable and action is needed to improve care delivery. At present, there is an over-emphasis on surgical and pharmacological interventions, despite evidence supporting conservative treatments such as exercise, weight loss and education. While clinical guidelines provide recommendations regarding best practice (ie, what to do), they fail to address how to operationalise these recommendations into clinical practice. Models of care (MoCs) can help bridge the evidence practice gap by outlining evidence-informed interventions as well as how to implement them within a local system. However, New Zealand has no osteoarthritis MoC. The Mobility Action Programme, funded by the Ministry of Health, is delivering evidence-informed, multi-disciplinary care for osteoarthritis through local initiatives. Although the programme remains under evaluation it presents an opportunity to inform development of a national osteoarthritis MoC for New Zealand. A policy framework, such as a MoC, is needed to scale up successful programs and deliver best practice care nationwide. Ultimately, addressing the burden of osteoarthritis will require system-wide approaches involving public policy responses to target primary prevention. PMID- 29240745 TI - Waking up to poor vision after a night out. PMID- 29240746 TI - The Quality Improvement Residency: a model to address the lack of pre registration education in quality improvement in New Zealand healthcare professionals. PMID- 29240747 TI - Research opportunities for medical students: how much time do you have? PMID- 29240748 TI - Funding public healthcare is an investment, not a cost. PMID- 29240749 TI - Mesh abdominal wall hernia surgery is safe and effective-the harm New Zealand media has done: response to Dr Steven Kelly's article. PMID- 29240750 TI - Timeliness of melanoma management. PMID- 29240751 TI - New Zealand's legal action against IQOS postponed, consultation with Big Tobacco follows: a response from the Ministry of Health. PMID- 29240752 TI - Effect of early dietary energy restriction and phosphorus level on subsequent growth performance, intestinal phosphate transport, and AMPK activity in young broilers. AB - We aimed to determine the effect of low dietary energy on intestinal phosphate transport and the possible underlying mechanism to explain the long-term effects of early dietary energy restriction and non-phytate phosphorus (NPP). A 2 * 3 factorial experiment, consisting of 2 energy levels and 3 NPP levels, was conducted. Broiler growth performance, intestinal morphology in 0-21 days and 22 35 days, type IIb sodium-phosphate co-transporter (NaPi-IIb) mRNA expression, adenylate purine concentrations in the duodenum, and phosphorylated adenosine monophosphate-activated protein kinase (AMPK-alpha) activity in 0-21 days were determined. The following results were obtained. (1) Low dietary energy (LE) induced a high feed conversion ratio (FCR) and significantly decreased body weight gain in young broilers, but LE induced significantly higher compensatory growth in low NPP (LP) groups than in the high or medium NPP groups (HP and MP). (2) LE decreased the villus height (VH) in the intestine, and LE-HP resulted in the lowest crypt depth (CD) and the highest VH:CD ratio in the initial phase. However, in the later period, the LE-LP group showed an increased VH:CD ratio and decreased CD in the intestine. (3) LE increased ATP synthesis and decreased AMP:ATP ratio in the duodenal mucosa of chickens in 0-21 days, and LP diet increased ATP synthesis and adenylate energy charges but decreased AMP production and AMP:ATP ratio. (4) LE led to weaker AMPK phosphorylation, higher mTOR phosphorylation, and higher NaPi-IIb mRNA expression. Thus, LE and LP in the early growth phase had significant compensatory and interactive effect on later growth and intestinal development in broilers. The effect might be relevant to energy status that LE leads to weaker AMPK phosphorylation, causing a lower inhibitory action toward mTOR phosphorylation. This series of events stimulates NaPi-IIb mRNA expression. Our findings provide a theoretical basis and a new perspective on intestinal phosphate transport regulation, with potential applications in broiler production. PMID- 29240753 TI - Virulence, pathology, and pathogenesis of Pteropine orthoreovirus (PRV) in BALB/c mice: Development of an animal infection model for PRV. AB - BACKGROUND: Cases of acute respiratory tract infection caused by Pteropine orthoreovirus (PRV) of the genus Orthoreovirus (family: Reoviridae) have been reported in Southeast Asia, where it was isolated from humans and bats. It is possible that PRV-associated respiratory infections might be prevalent in Southeast Asia. The clinical course of PRV is not fully elucidated. METHODS: The virulence, pathology, and pathogenesis of two PRV strains, a human-borne PRV strain (isolated from a patient, who returned to Japan from Bali, Indonesia in 2007) and a bat-borne PRV (isolated from a bat [Eonycteris spelaea] in the Philippines in 2013) were investigated in BALB/c mice using virological, pathological, and immunological study methods. RESULTS: The intranasal inoculation of BALB/c mice with human-borne PRV caused respiratory infection. In addition, all mice with immunity induced by pre-inoculation with a non-lethal dose of PRV were completely protected against lethal PRV infection. Mice treated with antiserum with neutralizing antibody activity after inoculation with a lethal dose of PRV showed a reduced fatality rate. In this mouse model, bat-borne PRV caused respiratory infection similar to human-borne PRV. PRV caused lethal respiratory disease in an animal model of PRV infection, in which BALB/c mice were used. CONCLUSIONS: The BALB/c mouse model might help to accelerate research on the virulence of PRV and be useful for evaluating the efficacy of therapeutic agents and vaccines for the treatment and prevention of PRV infection. PRV was shown for the first time to be a causative virus of respiratory disease on the basis of Koch's postulations by the additional demonstration that PRV caused respiratory disease in mice through their intranasal inoculation with PRV. PMID- 29240754 TI - Maternal death review and outcomes: An assessment in Lagos State, Nigeria. AB - The objective of the study was to investigate the results of Maternal and Perinatal Death Surveillance and Response (MPDSR) conducted in three referral hospitals in Lagos State, Nigeria over a two-year period and to report the outcomes and the lessons learned. MPDRS panels were constituted in the three hospitals, and beginning from January 2015, we conducted monthly MPDSR in the three hospitals using a nationally approved protocol. Data on births and deaths and causes of deaths as identified by the MPDSR panels were collated in the hospitals. The results show that over a 21-month period (January 1, 2015 September 30, 2016), maternal mortality ratio (MMR) remained high in the hospitals. Although there was a trend towards an increase in MMR in Lagos Island Maternity Hospital and Gbagada General Hospital, and a trend towards a decline in Ajeromi Hospital, none of these trends were statistically significant. Eclampsia, primary post-partum haemorrhage, obstructed labour and puerperal sepsis were the leading obstetric causes of death. By contrast, delay in arrival in hospital, the lack of antenatal care and patients' refusal to receive recommended treatment were the patients' associated causes of death, while delay in treatment, poor use of treatment protocols, lack of equipment and lack of skills by providers to use available equipment were the identified facility-related causes of death. Failure to address the patients and facility-related causes of maternal mortality possibly accounted for the persistently high maternal mortality ratio in the hospitals. We conclude that interventions aimed at redressing all causes of maternal deaths identified in the reviews will likely reduce the maternal mortality ratios in the hospitals. PMID- 29240755 TI - Integrating transcriptomics and metabolomics to characterize the regulation of EPA biosynthesis in response to cold stress in seaweed Bangia fuscopurpurea. AB - Bangia fuscopurpurea is a traditional mariculture crop having high nutritional value, eicosapntemacnioc acid (EPA) production, and protein content. As an intertidal species, it can tolerate drastic changes in abiotic factors such as temperature, hydration, and light radiation; however, genomic information on the evolutionary aspect and mechanism of EPA enrichment in B. fuscopurpurea and the role of EPA in cold tolerance in this species remain elusive. We conducted transcriptome profile analysis in B. fuscopurpurea to investigate the biological functions of genes associated with resistance to various environment factors. We identified 41,935 unigenes that were assembled and applied to public databases to define their functional annotation (NR, GO, KEGG, KOG, and SwissProt). We further identified genes that encoded key enzymes in EPA biosynthesis; five paralogous genes encoding delta5 desaturase were detected in B. fuscopurpurea. Fatty acid profiling and gene expression analysis of B. fuscopurpurea grown under cold stress were simultaneously performed. The EPA content was increased by 29.8% in the samples grown at 4 degrees C, while the total amount of fatty acids remained unchanged. Moreover, all the EPA biosynthesis-related desaturase and elongase genes were upregulated under cold stress. Thus, we hypothesized that diverse EPA biosynthesis pathways and significant increase in gene copy numbers of fatty acid desaturases, together with the concomitant elevation in the transcriptional level of genes associated with fatty acid metabolism, lead to EPA accumulation and subsequently affect membrane fluidity, contributing to cold stress resistance in B. fuscopurpurea. Our findings not only provide a fundamental genetic background for further research in B. fuscopurpurea, but also have important implications for screening and genetic engineering of algae and plants for EPA production. PMID- 29240756 TI - Elastic K-means using posterior probability. AB - The widely used K-means clustering is a hard clustering algorithm. Here we propose a Elastic K-means clustering model (EKM) using posterior probability with soft capability where each data point can belong to multiple clusters fractionally and show the benefit of proposed Elastic K-means. Furthermore, in many applications, besides vector attributes information, pairwise relations (graph information) are also available. Thus we integrate EKM with Normalized Cut graph clustering into a single clustering formulation. Finally, we provide several useful matrix inequalities which are useful for matrix formulations of learning models. Based on these results, we prove the correctness and the convergence of EKM algorithms. Experimental results on six benchmark datasets demonstrate the effectiveness of proposed EKM and its integrated model. PMID- 29240757 TI - RCT of an integrated CBT-HIV intervention on depressive symptoms and HIV risk. AB - Depression and depressive symptoms mediate the association between drug use and HIV risk. Yet, there are few interventions that target depressive symptoms and HIV risk for people who use drugs (PWUD). This study was a randomized controlled trial of an integrated cognitive behavioral therapy and HIV prevention intervention to reduce depressive symptoms, injection risk behaviors and increase condom use in a sample of urban people who used heroin or cocaine in the prior 6 months. A total of 315 individuals aged 18-55, who self-reported at least one HIV drug and sex risk behavior and scored >=16 and <40 on the Centers for Epidemiologic Studies-Depression (CES-D) scale were randomized using a two-block design, stratified by sex to ensure equivalent numbers, to a 10 session intervention arm (n = 162) or a single session control arm (n = 153). The outcomes of interest were decreases in CES-D score and injection risk behaviors and increases in condom use. The sample was majority African American (85%) and unemployed (94%). Nearly half (47%) reported injection in the prior 6 months and only 19% were taking medication for depression. Follow-up assessments were conducted at 6 and 12 months. Retention at 12 months was 94%. Intervention arm was associated with statistically significantly lower CES-D score at 12 month compared to control. No differences were observed between arms in injection risk. At 6 month, intervention was associated with greater odds of condom use with non main partner. These findings suggest the potential role of the integrated intervention in reducing depressive symptoms, but weak impact on HIV risk. This trial is registered with ClinicalTrials.gov under the title "Neighborhoods, Networks, Depression, and HIV Risk" number NCT01380613. PMID- 29240759 TI - Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer. AB - The molecular symmetry of multimeric proteins is generally determined by using X ray diffraction techniques, so that the basic question as to whether this symmetry is perfectly preserved for the same protein in solution remains open. In this work, human transthyretin (TTR), a homotetrameric plasma transport protein with two binding sites for the thyroid hormone thyroxine (T4), is considered as a case study. Based on the crystal structure of the TTR tetramer, a hypothetical D2 symmetry is inferred for the protein in solution, whose functional behavior reveals the presence of two markedly different Kd values for the two T4 binding sites. The latter property has been ascribed to an as yet uncharacterized negative binding cooperativity. A triple mutant form of human TTR (F87M/L110M/S117E TTR), which is monomeric in solution, crystallizes as a tetrameric protein and its structure has been determined. The exam of this and several other crystal forms of human TTR suggests that the TTR scaffold possesses a significant structural flexibility. In addition, TTR tetramer dynamics simulated using normal modes analysis exposes asymmetric vibrational patterns on both dimers and thermal fluctuations reveal small differences in size and flexibility for ligand cavities at each dimer-dimer interface. Such small structural differences between monomers can lead to significant functional differences on the TTR tetramer dynamics, a feature that may explain the functional heterogeneity of the T4 binding sites, which is partially overshadowed by the crystal state. PMID- 29240758 TI - Increased gamma band activity for lateral interactions in humans. AB - Collinear facilitation of contrast sensitivity supported by lateral interactions within primary visual cortex is implicated in contour and object perception, with neural correlates in several frequency bands. Although higher component of the ERP power spectrum, the gamma-band, is postulated to reflect object representation, attention and memory, its neuronal source has been questioned, suggesting it is an artifact reflecting saccadic eye movements. Here we explored the gamma-band activity during collinear facilitation with no saccade-related confounds. We used single-trial spectral analysis of ERP in occipital channels in a time-window of nearly complete saccadic suppression and discarded sporadic trials containing saccades, in order to avoid saccadic artifacts. Although converging evidence suggests that gamma-band oscillations emerge from local excitatory-inhibitory balance involving GABAergic inhibition, here we show activity amplification during facilitatory collinear interactions, presumably dominated by excitations, in the gamma-band 150-350 milliseconds following onset of low near-threshold contrast stimulus. This result highlights the potential role of gamma-band oscillations in neuronal encoding of basic processes in visual perception. Thus, our findings suggest that gamma-band ERP spectrum analysis may serve as a useful and reliable tool for exploring basic perception, both in normal adults and in special populations. PMID- 29240760 TI - Novel linear motif filtering protocol reveals the role of the LC8 dynein light chain in the Hippo pathway. AB - Protein-protein interactions (PPIs) formed between short linear motifs and globular domains play important roles in many regulatory and signaling processes but are highly underrepresented in current protein-protein interaction databases. These types of interactions are usually characterized by a specific binding motif that captures the key amino acids shared among the interaction partners. However, the computational proteome-level identification of interaction partners based on the known motif is hindered by the huge number of randomly occurring matches from which biologically relevant motif hits need to be extracted. In this work, we established a novel bioinformatic filtering protocol to efficiently explore interaction network of a hub protein. We introduced a novel measure that enabled the optimization of the elements and parameter settings of the pipeline which was built from multiple sequence-based prediction methods. In addition, data collected from PPI databases and evolutionary analyses were also incorporated to further increase the biological relevance of the identified motif hits. The approach was applied to the dynein light chain LC8, a ubiquitous eukaryotic hub protein that has been suggested to be involved in motor-related functions as well as promoting the dimerization of various proteins by recognizing linear motifs in its partners. From the list of putative binding motifs collected by our protocol, several novel peptides were experimentally verified to bind LC8. Altogether 71 potential new motif instances were identified. The expanded list of LC8 binding partners revealed the evolutionary plasticity of binding partners despite the highly conserved binding interface. In addition, it also highlighted a novel, conserved function of LC8 in the upstream regulation of the Hippo signaling pathway. Beyond the LC8 system, our work also provides general guidelines that can be applied to explore the interaction network of other linear motif binding proteins or protein domains. PMID- 29240762 TI - Rethinking 3R strategies: Digging deeper into AnimalTestInfo promotes transparency in in vivo biomedical research. AB - In the European Union (EU), animal welfare is seen as a matter of great importance. However, with respect to animal experimentation, European citizens feel quite uninformed. The European Directive 2010/63/EU for the protection of laboratory animals aims for greater transparency and requires that a comprehensible, nontechnical summary (NTS) of each authorised research project involving animals is published by the respective Member State. However, the NTSs remain sleeping beauties if their contents are not easily and systematically accessible. The German web-based NTS database AnimalTestInfo is a unique channel for scientists to communicate their work, and provides the opportunity for large scale analyses of planned animal studies to inform researchers and the public. For an in-depth meta-analysis, we classified the duly completed NTSs submitted to AnimalTestInfo in 2014 and 2015 according to the International Classification of Diseases and Related Health Problems (ICD) system. Indexing the NTSs with ICD codes provided a fine-grained overview of the prospective uses of experimental animals. Using this approach, transparency, especially for highly controversial animal research involving, for example, nonhuman primates, is fostered, as it enables pinpointing the envisaged beneficiary down to the level of the addressed disease. Moreover, research areas with many planned projects involving animals can be specified in detail. The development of 3R (replacement, reduction, and refinement) measures in these research areas may be most efficient, as a large number of experimental animals would benefit from it. Indexing NTSs with ICD codes can support governments and funding agencies in advancing target-oriented funding of 3R research. Data drawn from NTSs can provide a basis for the development, validation, and implementation of directed 3R strategies as well as guidance for rethinking the role of animal research models. PMID- 29240761 TI - Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes. AB - Microorganisms in the placenta have been linked to adverse pregnancy outcomes as well as neonatal illness. Inflammation in the placenta has been identified as a contributing factor in this association, but the underlying biological mechanisms are not yet fully understood. The placental epigenome may serve as an intermediate between placental microbes and inflammation, contributing to adverse outcomes in the offspring. In the present study, genome-wide DNA methylation (n = 486,428 CpG sites) of 84 placentas was analyzed in relation to 16 species of placental microorganisms using samples collected from the Extremely Low Gestation Age Newborns (ELGAN) cohort. A total of n = 1,789 CpG sites, corresponding to n = 1,079 genes, displayed differential methylation (q<0.1) in relation to microorganisms. The altered genes encode for proteins that are involved in immune/inflammatory responses, specifically the NF-kappaB signaling pathway. These data support bacteria-dependent epigenetic patterning in the placenta and provide potential insight into mechanisms that associate the presence of microorganisms in the placenta to pregnancy and neonatal outcomes. This study lays the foundation for investigations of the placental microbiome and its role in placental function. PMID- 29240763 TI - Costs of task allocation with local feedback: Effects of colony size and extra workers in social insects and other multi-agent systems. AB - Adaptive collective systems are common in biology and beyond. Typically, such systems require a task allocation algorithm: a mechanism or rule-set by which individuals select particular roles. Here we study the performance of such task allocation mechanisms measured in terms of the time for individuals to allocate to tasks. We ask: (1) Is task allocation fundamentally difficult, and thus costly? (2) Does the performance of task allocation mechanisms depend on the number of individuals? And (3) what other parameters may affect their efficiency? We use techniques from distributed computing theory to develop a model of a social insect colony, where workers have to be allocated to a set of tasks; however, our model is generalizable to other systems. We show, first, that the ability of workers to quickly assess demand for work in tasks they are not currently engaged in crucially affects whether task allocation is quickly achieved or not. This indicates that in social insect tasks such as thermoregulation, where temperature may provide a global and near instantaneous stimulus to measure the need for cooling, for example, it should be easy to match the number of workers to the need for work. In other tasks, such as nest repair, it may be impossible for workers not directly at the work site to know that this task needs more workers. We argue that this affects whether task allocation mechanisms are under strong selection. Second, we show that colony size does not affect task allocation performance under our assumptions. This implies that when effects of colony size are found, they are not inherent in the process of task allocation itself, but due to processes not modeled here, such as higher variation in task demand for smaller colonies, benefits of specialized workers, or constant overhead costs. Third, we show that the ratio of the number of available workers to the workload crucially affects performance. Thus, workers in excess of those needed to complete all tasks improve task allocation performance. This provides a potential explanation for the phenomenon that social insect colonies commonly contain inactive workers: these may be a 'surplus' set of workers that improves colony function by speeding up optimal allocation of workers to tasks. Overall our study shows how limitations at the individual level can affect group level outcomes, and suggests new hypotheses that can be explored empirically. PMID- 29240766 TI - Estimated clinical impact of the Xpert MTB/RIF Ultra cartridge for diagnosis of pulmonary tuberculosis: A modeling study. AB - BACKGROUND: The Xpert MTB/RIF (Xpert) assay offers rapid and accurate diagnosis of tuberculosis (TB) but still suffers from imperfect sensitivity. The newer Xpert MTB/RIF Ultra cartridge has shown improved sensitivity in recent field trials, but at the expense of reduced specificity. The clinical implications of switching from the existing Xpert cartridge to the Xpert Ultra cartridge in different populations remain uncertain. METHODS AND FINDINGS: We developed a Markov microsimulation model of hypothetical cohorts of 100,000 individuals undergoing diagnostic sputum evaluation with Xpert for suspected pulmonary TB, in each of 3 emblematic settings: an HIV clinic in South Africa, a public TB center in India, and an adult primary care setting in China. In each setting, we used existing data to project likely diagnostic results, treatment decisions, and ultimate clinical outcomes, assuming use of the standard Xpert versus Xpert Ultra cartridge. Our primary outcomes were the projected number of additional unnecessary treatments generated, the projected number of TB deaths averted, and the projected number of unnecessary treatments generated per TB death averted, if standard Xpert were switched to Xpert Ultra. We also simulated alternative approaches to interpreting positive results of the Ultra cartridge's semi quantitative trace call. Extensive sensitivity and uncertainty analyses were performed to evaluate the drivers and generalizability of projected results. In the Indian TB center setting, replacing the standard Xpert cartridge with the Xpert Ultra cartridge was projected to avert 0.5 TB deaths (95% uncertainty range [UR]: 0, 1.3) and generate 18 unnecessary treatments (95% UR: 10, 29) per 1,000 individuals evaluated-resulting in a median ratio of 38 incremental unnecessary treatments added by Ultra per incremental death averted by Ultra compared to outcomes using standard Xpert (95% UR: 12, indefinite upper bound). In the South African HIV care setting-where TB mortality rates are higher and Ultra's improved sensitivity has greater absolute benefit-this ratio improved to 7 unnecessary treatments per TB death averted (95% UR: 2, 43). By contrast, in the Chinese primary care setting, this ratio was much less favorable, at 372 unnecessary treatments per TB death averted (95% UR: 75, indefinite upper bound), although the projected number of unnecessary treatments using Xpert Ultra was lower (with a possibility of no increased overtreatment) when using specificity data only from lower-burden settings. Alternative interpretations of the trace call had little effect on these ratios. Limitations include uncertainty in key parameters (including the clinical implications of false-negative results), the exclusion of transmission effects, and restriction of this analysis to adult pulmonary TB. CONCLUSIONS: Switching from the standard Xpert cartridge to the Xpert Ultra cartridge for diagnosis of adult pulmonary TB may have different consequences in different clinical settings. In settings with high TB and HIV prevalence, Xpert Ultra is likely to offer considerable mortality benefit, whereas in lower prevalence settings, Xpert Ultra will likely result in considerable overtreatment unless the possibility of higher specificity of Ultra in lower-prevalence settings in confirmed. The ideal use of the Ultra cartridge may therefore involve a more nuanced, setting-specific approach to implementation, with priority given to populations in which the anticipated prevalence of TB (and HIV) is the highest. PMID- 29240765 TI - Drug resistance and treatment failure in leishmaniasis: A 21st century challenge. AB - Reevaluation of treatment guidelines for Old and New World leishmaniasis is urgently needed on a global basis because treatment failure is an increasing problem. Drug resistance is a fundamental determinant of treatment failure, although other factors also contribute to this phenomenon, including the global HIV/AIDS epidemic with its accompanying impact on the immune system. Pentavalent antimonials have been used successfully worldwide for the treatment of leishmaniasis since the first half of the 20th century, but the last 10 to 20 years have witnessed an increase in clinical resistance, e.g., in North Bihar in India. In this review, we discuss the meaning of "resistance" related to leishmaniasis and discuss its molecular epidemiology, particularly for Leishmania donovani that causes visceral leishmaniasis. We also discuss how resistance can affect drug combination therapies. Molecular mechanisms known to contribute to resistance to antimonials, amphotericin B, and miltefosine are also outlined. PMID- 29240767 TI - MITF - A controls branching morphogenesis and nephron endowment. AB - Congenital nephron number varies widely in the human population and individuals with low nephron number are at risk of developing hypertension and chronic kidney disease. The development of the kidney occurs via an orchestrated morphogenetic process where metanephric mesenchyme and ureteric bud reciprocally interact to induce nephron formation. The genetic networks that modulate the extent of this process and set the final nephron number are mostly unknown. Here, we identified a specific isoform of MITF (MITF-A), a bHLH-Zip transcription factor, as a novel regulator of the final nephron number. We showed that overexpression of MITF-A leads to a substantial increase of nephron number and bigger kidneys, whereas Mitfa deficiency results in reduced nephron number. Furthermore, we demonstrated that MITF-A triggers ureteric bud branching, a phenotype that is associated with increased ureteric bud cell proliferation. Molecular studies associated with an in silico analyses revealed that amongst the putative MITF-A targets, Ret was significantly modulated by MITF-A. Consistent with the key role of this network in kidney morphogenesis, Ret heterozygosis prevented the increase of nephron number in mice overexpressing MITF-A. Collectively, these results uncover a novel transcriptional network that controls branching morphogenesis during kidney development and identifies one of the first modifier genes of nephron endowment. PMID- 29240764 TI - Selection for long and short sleep duration in Drosophila melanogaster reveals the complex genetic network underlying natural variation in sleep. AB - Why do some individuals need more sleep than others? Forward mutagenesis screens in flies using engineered mutations have established a clear genetic component to sleep duration, revealing mutants that convey very long or short sleep. Whether such extreme long or short sleep could exist in natural populations was unknown. We applied artificial selection for high and low night sleep duration to an outbred population of Drosophila melanogaster for 13 generations. At the end of the selection procedure, night sleep duration diverged by 9.97 hours in the long and short sleeper populations, and 24-hour sleep was reduced to 3.3 hours in the short sleepers. Neither long nor short sleeper lifespan differed appreciably from controls, suggesting little physiological consequences to being an extreme long or short sleeper. Whole genome sequence data from seven generations of selection revealed several hundred thousand changes in allele frequencies at polymorphic loci across the genome. Combining the data from long and short sleeper populations across generations in a logistic regression implicated 126 polymorphisms in 80 candidate genes, and we confirmed three of these genes and a larger genomic region with mutant and chromosomal deficiency tests, respectively. Many of these genes could be connected in a single network based on previously known physical and genetic interactions. Candidate genes have known roles in several classic, highly conserved developmental and signaling pathways-EGFR, Wnt, Hippo, and MAPK. The involvement of highly pleiotropic pathway genes suggests that sleep duration in natural populations can be influenced by a wide variety of biological processes, which may be why the purpose of sleep has been so elusive. PMID- 29240768 TI - The association between the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) rs1044396 and Internet gaming disorder in Korean male adults. AB - The primary aim of this study was to investigate the genetic predisposition of Internet gaming disorder (IGD), and the secondary aim was to compare the results to those of alcohol dependence (AD). Two independent case-control studies were conducted. A total of 30 male participants with IGD, diagnosed according to the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, and 30 sex-matched controls participated in study 1. We designed targeted exome sequencing (TES) to test for 72 candidate genes that have been implicated in the pathogenesis of addiction. The genes included seven neurotransmitter (dopamine, serotonin, glutamate, r-aminobutyric acid (GABA), norepinephrine, acetylcholine, and opioid) system genes. A total of 31 male in patients with AD and 29 normal male controls (NC) were enrolled in study 2. The same 72 genes included in study 1 and ten additional genes related to alcohol metabolic enzyme were selected as the target genes, and we identified the genetic variants using the same method (TES). The IGD group had a lower frequency of the T allele of rs1044396 in the nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4), and this variant represents a protective allele against IGD. However, we did not find a significant difference in the polymorphisms of the 72 genes that encode neurotransmitter systems between the AD and NC groups. This study demonstrated that rs1044396 of CHRNA4 was significantly associated with IGD. PMID- 29240769 TI - Specific excitatory connectivity for feature integration in mouse primary visual cortex. AB - Local excitatory connections in mouse primary visual cortex (V1) are stronger and more prevalent between neurons that share similar functional response features. However, the details of how functional rules for local connectivity shape neuronal responses in V1 remain unknown. We hypothesised that complex responses to visual stimuli may arise as a consequence of rules for selective excitatory connectivity within the local network in the superficial layers of mouse V1. In mouse V1 many neurons respond to overlapping grating stimuli (plaid stimuli) with highly selective and facilitatory responses, which are not simply predicted by responses to single gratings presented alone. This complexity is surprising, since excitatory neurons in V1 are considered to be mainly tuned to single preferred orientations. Here we examined the consequences for visual processing of two alternative connectivity schemes: in the first case, local connections are aligned with visual properties inherited from feedforward input (a 'like-to-like' scheme specifically connecting neurons that share similar preferred orientations); in the second case, local connections group neurons into excitatory subnetworks that combine and amplify multiple feedforward visual properties (a 'feature binding' scheme). By comparing predictions from large scale computational models with in vivo recordings of visual representations in mouse V1, we found that responses to plaid stimuli were best explained by assuming feature binding connectivity. Unlike under the like-to-like scheme, selective amplification within feature-binding excitatory subnetworks replicated experimentally observed facilitatory responses to plaid stimuli; explained selective plaid responses not predicted by grating selectivity; and was consistent with broad anatomical selectivity observed in mouse V1. Our results show that visual feature binding can occur through local recurrent mechanisms without requiring feedforward convergence, and that such a mechanism is consistent with visual responses and cortical anatomy in mouse V1. PMID- 29240770 TI - Emergence of melioidosis in the Indian Ocean region: Two new cases and a literature review. AB - Melioidosis is a disease caused by bacteria called B. pseudomallei. Infections can develop after contact with standing water. This disease can reach all the organs and especially the lungs. It is associated with a high mortality rate (up to 50%). Melioidosis is endemic in northern Australia and in Southeast Asia. Nevertheless, B. pseudomallei may be endemic in the Indian Ocean region and in Madagascar in particular, so clinicians and microbiologists should consider acute melioidosis as a differential diagnosis in the Indian Ocean region, in particular from Madagascar. PMID- 29240771 TI - A master equation approach to actin polymerization applied to endocytosis in yeast. AB - We present a Master Equation approach to calculating polymerization dynamics and force generation by branched actin networks at membranes. The method treats the time evolution of the F-actin distribution in three dimensions, with branching included as a directional spreading term. It is validated by comparison with stochastic simulations of force generation by actin polymerization at obstacles coated with actin "nucleation promoting factors" (NPFs). The method is then used to treat the dynamics of actin polymerization and force generation during endocytosis in yeast, using a model in which NPFs form a ring around the endocytic site, centered by a spot of molecules attaching the actin network strongly to the membrane. We find that a spontaneous actin filament nucleation mechanism is required for adequate forces to drive the process, that partial inhibition of branching and polymerization lead to different characteristic responses, and that a limited range of polymerization-rate values provide effective invagination and obtain correct predictions for the effects of mutations in the active regions of the NPFs. PMID- 29240772 TI - Monitoring of arrhythmia and sudden death in a hemodialysis population: The CRASH ILR Study. AB - INTRODUCTION: It has been suggested that sudden cardiac death (SCD) contributes around 50% of cardiovascular and 27% of all-cause mortality in hemodialysis patients. The true burden of arrhythmias and arrhythmic deaths in this population, however, remains poorly characterised. Cardio Renal Arrhythmia Study in Hemodialysis (CRASH-ILR) is a prospective, implantable loop recorder single centre study of 30 established hemodialysis patients and one of the first to provide long-term ambulatory ECG monitoring. METHODS: 30 patients (60% male) aged 68+/-12 years receiving hemodialysis for 45+/-40 months with varied etiology (diabetes 37%, hypertension 23%) and left ventricular ejection fraction (LVEF) 55+/-8% received a Reveal XT implantable loop recorder (Medtronic, USA) between August 2011 and October 2014. ECG data from loop recorders were transmitted at each hemodialysis session using a remote monitoring system. Primary outcome was SCD or implantation of a (tachy or bradyarrhythmia controlling) device and secondary outcome, the development of arrhythmia necessitating medical intervention. RESULTS: During 379,512 hours of continuous ECG monitoring (mean 12,648+/-9,024 hours/patient), there were 8 deaths-2 SCD and 6 due to generalised deterioration/sepsis. 5 (20%) patients had a primary outcome event (2 SCD, 3 pacemaker implantations for bradyarrhythmia). 10 (33%) patients reached an arrhythmic primary or secondary end point. Median event free survival for any arrhythmia was 2.6 years (95% confidence intervals 1.6-3.6 years). CONCLUSIONS: The findings confirm the high mortality rate seen in hemodialysis populations and contrary to initial expectations, bradyarrhythmias emerged as a common and potentially significant arrhythmic event. PMID- 29240773 TI - Polypyridylruthenium(II) complexes exert anti-schistosome activity and inhibit parasite acetylcholinesterases. AB - BACKGROUND: Schistosomiasis affects over 200 million people and there are concerns whether the current chemotherapeutic control strategy (periodic mass drug administration with praziquantel (PZQ)-the only licenced anti-schistosome compound) is sustainable, necessitating the development of new drugs. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the anti-schistosome efficacy of polypyridylruthenium(II) complexes and showed they were active against all intra mammalian stages of S. mansoni. Two compounds, Rubb12-tri and Rubb7-tnl, which were among the most potent in their ability to kill schistosomula and adult worms and inhibit egg hatching in vitro, were assessed for their efficacy in a mouse model of schistosomiasis using 5 consecutive daily i.v. doses of 2 mg/kg (Rubb12 tri) and 10 mg/kg (Rubb7-tnl). Mice treated with Rubb12-tri showed an average 42% reduction (P = 0.009), over two independent trials, in adult worm burden. Liver egg burdens were not significantly decreased in either drug-treated group but ova from both of these groups showed significant decreases in hatching ability (Rubb12-tri-68%, Rubb7-tnl-56%) and were significantly morphologically altered (Rubb12-tri-62% abnormal, Rubb7-tnl-35% abnormal). We hypothesize that the drugs exerted their activity, at least partially, through inhibition of both neuronal and tegumental acetylcholinesterases (AChEs), as worms treated in vitro showed significant decreases in activity of these enzymes. Further, treated parasites exhibited a significantly decreased ability to uptake glucose, significantly depleted glycogen stores and withered tubercules (a site of glycogen storage), implying drug-mediated interference in this nutrient acquisition pathway. CONCLUSIONS/SIGNIFICANCE: Our data provide compelling evidence that ruthenium complexes are effective against all intra-mammalian stages of schistosomes, including schistosomula (refractory to PZQ) and eggs (agents of disease transmissibility). Further, the results of this study suggest that schistosome AChE is a target of ruthenium drugs, a finding that can inform modification of current compounds to identify analogues which are even more effective and selective against schistosomes. PMID- 29240775 TI - Ornithine decarboxylase as a therapeutic target for endometrial cancer. AB - Ornithine Decarboxylase (ODC) a key enzyme in polyamine biosynthesis is often overexpressed in cancers and contributes to polyamine-induced cell proliferation. We noted ubiquitous expression of ODC1 in our published endometrial cancer gene array data and confirmed this in the cancer genome atlas (TCGA) with highest expression in non-endometrioid, high grade, and copy number high cancers, which have the worst clinical outcomes. ODC1 expression was associated with worse overall survival and increased recurrence in three endometrial cancer gene expression datasets. Importantly, we confirmed these findings using quantitative real-time polymerase chain reaction (qRT-PCR) in a validation cohort of 60 endometrial cancers and found that endometrial cancers with elevated ODC1 had significantly shorter recurrence-free intervals (KM log-rank p = 0.0312, Wald test p = 5.59e-05). Difluoromethylornithine (DFMO) a specific inhibitor of ODC significantly reduced cell proliferation, cell viability, and colony formation in cell line models derived from undifferentiated, endometrioid, serous, carcinosarcoma (mixed mesodermal tumor; MMT) and clear cell endometrial cancers. DFMO also significantly reduced human endometrial cancer ACI-98 tumor burden in mice compared to controls (p = 0.0023). ODC-regulated polyamines (putrescine [Put] and/or spermidine [Spd]) known activators of cell proliferation were strongly decreased in response to DFMO, in both tumor tissue ([Put] (p = 0.0006), [Spd] (p<0.0001)) and blood plasma ([Put] (p<0.0001), [Spd] (p = 0.0049)) of treated mice. Our study indicates that some endometrial cancers appear particularly sensitive to DFMO and that the polyamine pathway in endometrial cancers in general and specifically those most likely to suffer adverse clinical outcomes could be targeted for effective treatment, chemoprevention or chemoprevention of recurrence. PMID- 29240776 TI - Microbiological profile and risk factors for in-hospital mortality of infective endocarditis in tertiary care hospitals of south Vietnam. AB - OBJECTIVES: We aimed to evaluate the microbiological characteristics and risk factors for mortality of infective endocarditis in two tertiary hospitals in Ho Chi Minh City, south Vietnam. MATERIALS AND METHODS: A retrospective study of 189 patients (120 men, 69 women; mean age 38 +/- 18 years) with the diagnosis of probable or definite infective endocarditis (IE) according to the modified Duke Criteria admitted to The Heart Institute or Tam Duc Hospital between January 2005 and December 2014. RESULTS: IE was related to a native valve in 165 patients (87.3%), and prosthetic valve in 24 (12.7%). Of the 189 patients in our series, the culture positive rate was 70.4%. The most common isolated pathogens were Streptococci (75.2%), Staphylococci (9.8%) followed by gram negative organism (4.5%). The sensitivity rate of Streptococci to ampicillin, ceftriaxone or vancomycin was 100%. The rate of methicillin resistant Staphylococcus aureus was 40%. There was a decrease in penicillin sensitivity for Streptococci over three eras: 2005-2007 (100%), 2008-2010 (94%) and 2010-2014 (84%). The in-hospital mortality rate was 6.9%. Logistic regression analysis found prosthetic valve and NYHA grade 3 or 4 heart failure and vegetation size of more than 15 mm as strong predictors of in-hospital mortality. CONCLUSION: Streptococcal species were the major pathogen of IE in the recent years with low rates of antimicrobial resistance. Prosthetic valve involvement, moderate or severe heart failure and vegetation size of more than 15 mm were independent predictors for in-hospital mortality in IE. PMID- 29240777 TI - Nonlinear spectral mixture effects for photosynthetic/non-photosynthetic vegetation cover estimates of typical desert vegetation in western China. AB - Desert vegetation plays significant roles in securing the ecological integrity of oasis ecosystems in western China. Timely monitoring of photosynthetic/non photosynthetic desert vegetation cover is necessary to guide management practices on land desertification and research into the mechanisms driving vegetation recession. In this study, nonlinear spectral mixture effects for photosynthetic/non-photosynthetic vegetation cover estimates are investigated through comparing the performance of linear and nonlinear spectral mixture models with different endmembers applied to field spectral measurements of two types of typical desert vegetation, namely, Nitraria shrubs and Haloxylon. The main results were as follows. (1) The correct selection of endmembers is important for improving the accuracy of vegetation cover estimates, and in particular, shadow endmembers cannot be neglected. (2) For both the Nitraria shrubs and Haloxylon, the Kernel-based Nonlinear Spectral Mixture Model (KNSMM) with nonlinear parameters was the best unmixing model. In consideration of the computational complexity and accuracy requirements, the Linear Spectral Mixture Model (LSMM) could be adopted for Nitraria shrubs plots, but this will result in significant errors for the Haloxylon plots since the nonlinear spectral mixture effects were more obvious for this vegetation type. (3) The vegetation canopy structure (planophile or erectophile) determines the strength of the nonlinear spectral mixture effects. Therefore, no matter for Nitraria shrubs or Haloxylon, the non linear spectral mixing effects between the photosynthetic / non-photosynthetic vegetation and the bare soil do exist, and its strength is dependent on the three dimensional structure of the vegetation canopy. The choice of linear or nonlinear spectral mixture models is up to the consideration of computational complexity and the accuracy requirement. PMID- 29240774 TI - Pharmacological inactivation does not support a unique causal role for intraparietal sulcus in the discrimination of visual number. AB - The "number sense" describes the intuitive ability to quantify without counting. Single neuron recordings in non-human primates and functional imaging in humans suggest the intraparietal sulcus is an important neuroanatomical locus of numerical estimation. Other lines of inquiry implicate the IPS in numerous other functions, including attention and decision making. Here we provide a direct test of whether IPS has functional specificity for numerosity judgments. We used muscimol to reversibly and independently inactivate the ventral and lateral intraparietal areas in two monkeys performing a numerical discrimination task and a color discrimination task, roughly equilibrated for difficulty. Inactivation of either area caused parallel impairments in both tasks and no evidence of a selective deficit in numerical processing. These findings do not support a causal role for the IPS in numerical discrimination, except insofar as it also has a role in the discrimination of color. We discuss our findings in light of several alternative hypotheses of IPS function, including a role in orienting responses, a general cognitive role in attention and decision making processes and a more specific role in ordinal comparison that encompasses both number and color judgments. PMID- 29240778 TI - Biopsychosocial predictors of perceived life expectancy in a national sample of older men and women. AB - Perceived life expectancy (PLE) is predictive of mortality risk in older adults, but the factors that may contribute to mental conceptions of PLE are unknown. We aimed to describe the sociodemographic, biomedical, behavioral, and psychological predictors of self-reported PLE estimates among older English adults. Data were from 6662 adults aged 50-79 years in the population-based English Longitudinal Study of Ageing (cross-sectional sample from 2012/13). PLE was assessed in the face-to-face study interview ("What are the chances you will live to be age x or more?" where x = current age plus 10-15 years). Responses were categorized as 'low' (0-49%), 'medium' (50-74%), and 'high' (75-100%). Adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) for low vs. high PLE were estimated using population-weighted modified Poisson regression with robust error variance. Overall, 1208/6662 (18%) participants reported a low PLE, 2806/6662 (42%) reported a medium PLE, and 2648/6662 (40%) reported a high PLE. The predictors of reporting a low PLE included older age (PR = 1.64; 95% CI: 1.50 1.76 per 10 years), male sex (PR = 1.14; 95% CI: 1.02-1.26), being a smoker (PR = 1.39; 95% CI: 1.22-1.59 vs. never/former smoker), and having a diagnosis of cancer or diabetes. A low sense of control over life was associated with low PLE, as was low satisfaction with life and worse self-rated health. Those with a higher perceived social standing were less likely to report a low PLE (PR = 0.90; 95% CI: 0.87-0.93 per 10-point increase, out of 100). This study provides novel insight into potential influences on older adults' expectations of their longevity, including aspects of psychological well-being. These results should be corroborated to better determine their implications for health-related decision making, planning, and behavior among older adults. PMID- 29240779 TI - Impact of maternal high fat diet on hypothalamic transcriptome in neonatal Sprague Dawley rats. AB - Maternal consumption of a high fat diet during early development has been shown to impact the formation of hypothalamic neurocircuitry, thereby contributing to imbalances in appetite and energy homeostasis and increasing the risk of obesity in subsequent generations. Early in postnatal life, the neuronal projections responsible for energy homeostasis develop in response to appetite-related peptides such as leptin. To date, no study characterises the genome-wide transcriptional changes that occur in response to exposure to high fat diet during this critical window. We explored the effects of maternal high fat diet consumption on hypothalamic gene expression in Sprague Dawley rat offspring at postnatal day 10. RNA-sequencing enabled discovery of differentially expressed genes between offspring of dams fed a high fat diet and offspring of control diet fed dams. Female high fat diet offspring displayed altered expression of 86 genes (adjusted P-value<0.05), including genes coding for proteins of the extra cellular matrix, particularly Collagen 1a1 (Col1a1), Col1a2, Col3a1, and the imprinted Insulin-like growth factor 2 (Igf2) gene. Male high fat diet offspring showed significant changes in collagen genes (Col1a1 and Col3a1) and significant upregulation of two genes involved in regulation of dopamine availability in the brain, tyrosine hydroxylase (Th) and dopamine reuptake transporter Slc6a3 (also known as Dat1). Transcriptional changes were accompanied by increased body weight, body fat and body length in the high fat diet offspring, as well as altered blood glucose and plasma leptin. Transcriptional changes identified in the hypothalamus of offspring of high fat diet mothers could alter neuronal projection formation during early development leading to abnormalities in the neuronal circuitry controlling appetite in later life, hence priming offspring to the development of obesity. PMID- 29240780 TI - FilaminA and Formin2 regulate skeletal, muscular, and intestinal formation through mesenchymal progenitor proliferation. AB - The effects of actin dependent molecular mechanisms in coordinating cellular proliferation, migration and differentiation during embryogenesis are not well understood. We have previously shown that actin-binding Filamin A (FlnA) and actin-nucleating Formin 2 (Fmn2) influence the development of the brain causing microcephaly in mice. In this study, we broaden this phenotype to explore the effects of these two proteins in the development of extra-CNS organ systems, including the gut, muscle, and skeleton. We observed defects in rib and sternum midline closure leading to thoracoabdominal schisis in FlnA+Fmn2 knockout mice, reminiscent of the pentalogy of Cantrell syndrome. These mice exhibit shortened guts, as well as thinned thoracic muscle mass. Immunostaining showed these changes are partially caused by a decrease in the number of presumptive mesenchymal proliferating cells with loss of either FlnA or FlnA+Fmn2. This proliferation defect appears to be in part due to delayed differentiation in these regions. While both FlnA and FlnA+Fmn2 mice show reduced cell death relative to WT control, increased caspase staining was seen in the double null relative to FlnA null suggesting that this could also contribute to the FlnA+Fmn2 phenotype. Therefore FlnA and Fmn2 are likely essential to cell proliferation, differentiation and cell death in a variety of tissues and organs, further reiterating the importance of vesicle trafficking in regulation of development. PMID- 29240781 TI - Comparing mail-in self-collected specimens sent via United States Postal Service versus clinic-collected specimens for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae in extra-genital sites. AB - OBJECTIVES: To evaluate the concordance between clinic-collected extra-genital specimens and self-collected mailed-in extra-genital specimens among participants seeking sexually transmitted infection testing at a free clinic in Hollywood, CA. METHODS: A convenience sample of 210 men who have sex with men were enrolled between February 29, 2016 and December 21, 2016 and received mail-in testing kits for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG). All testing was performed using the GeneXpert(r) CT/NG (Cepheid, Sunnyvale, CA). RESULTS: From the 210 mail-in kits distributed, 149 mail-in kits (71.0%) were returned to the laboratory, resulting in 145 pairs (clinic-collected and mail-in) of rectal test results and 148 pairs of pharyngeal test results for both CT and NG detection. The concordance was 95.0% for all CT rectal tests, 99.3% for all CT pharyngeal tests, 95.7% for all NG rectal tests, and 97.2% for all NG pharyngeal tests. CONCLUSION: Roughly two-thirds of mail-in test kits were returned and concordance was generally high, however more than one-third of positive results were missed in mail-in samples. The prevalence of potential false-negative results among mail in samples warrants caution when implementing mail-in STI testing strategies. PMID- 29240782 TI - Conservation and divergence of Starch Synthase III genes of monocots and dicots. AB - Starch Synthase (SS) plays an important role in extending the alpha-1,4 glucan chains during starch biosynthesis by catalyzing the transfer of the glucosyl moiety from ADP-glucose to the non-reducing end of a pre-existing glucan chain. SS has five distinct isoforms of which SSIII is involved in the formation of longer glucan chain length. Here we report identification and detailed characterization of 'true' orthologs of the well-characterized maize SSIII (ZmSSIII), among six monocots and two dicot species. ZmSSIII orthologs have nucleotide sequence similarity ranging from 56-81%. Variation in gene size among various orthologs ranged from 5.49 kb in Arabidopsis to 11.62 kb in Brachypodium and the variation was mainly due to intron size and indels present in the exons 1 and 3. Number of exons and introns were highly conserved among all orthologs however. While the intron number was conserved, intron phase showed variation at group, genera and species level except for intron 1 and 5. Several species, genera, and class specific cis-acting regulatory elements were identified in the promoter region. The predicted protein size of the SSIII orthologs ranged from 1094 amino acid (aa) in Arabidopsis to 1688 aa in Brachypodium with sequence identity ranging from 60%-89%. The N-terminal region of the protein was highly variable whereas the C-terminal region containing the Glycosyltransferase domain was conserved with >80% sequence similarity among the orthologs. In addition to confirming the known motifs, eleven novel motifs possibly providing species, genera and group specific functions, were identified in the three carbohydrate binding domains. Despite of significant sequence variation among orthologs, most of the motifs and their relative distances are highly conserved among the orthologs. The 3-D structure of catalytic region of SSIII orthologs superimposed with higher confidence confirming the presence of similar binding sites with five unidentified conserved regions in the catalytic (glycosyltransferase) domain including the pockets involved in catalysis and binding of ligands. Homeologs of wheat SSIII gene showed tissue and developmental stage specific expression pattern with the highest expression recorded in developing grains. PMID- 29240783 TI - Fluctuation-driven price dynamics and investment strategies. AB - Investigation of the driven mechanism of the price dynamics in complex financial systems is important and challenging. In this paper, we propose an investment strategy to study how dynamic fluctuations drive the price movements. The strategy is successfully applied to different stock markets in the world, and the result indicates that the driving effect of the dynamic fluctuations is rather robust. We investigate how the strategy performance is influenced by the market states and optimize the strategy performance by introducing two parameters. The strategy is also compared with several typical technical trading rules. Our findings not only provide an investment strategy which extends investors' profits, but also offer a useful method to look into the dynamic properties of complex financial systems. PMID- 29240784 TI - Effects of calcium channel blockers comparing to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with hypertension and chronic kidney disease stage 3 to 5 and dialysis: A systematic review and meta analysis. AB - BACKGROUND: Calcium channel blocker (CCB) or two renin angiotensin aldosterone system blockades (RAAS), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are major potent and prevalently used as initial antihypertensive agents for mild to moderate hypertension, but no uniform agreement as to which antihypertensive drugs should be given for initial therapy, especially among chronic kidney disease (CKD) patients. DESIGN: A systematic review and meta-analysis comparing CCBs and the two RAAS blockades for hypertensive patients with CKD stage 3 to 5D. The inclusion criteria for this systematic review was RCT that compared the effects of CCBs and the two RAAS blockades in patients with hypertension and CKD. The exclusion criteria were (1) renal transplantation, (2) CKD stage 1 or 2, (3) combined therapy (data cannot be extracted separately). Outcomes were blood pressure change, mortality, heart failure, stroke or cerebrovascular events, and renal outcomes. RESULTS: 21 randomized controlled trials randomized 9,492 patients with hypertensive and CKD into CCBs and the two RAAS blockades treatments. The evidence showed no significant differences in blood presser change, mortality, heart failure, stroke or cerebrovascular events, and renal outcomes between CCBs group and the two RAAS blockades group. The publication bias of pooled mean blood presser change that was detected by Egger's test was non-significant. CONCLUSIONS: CCBs has similar effects on long term blood pressure, mortality, heart failure, stroke or cerebrovascular events, and renal function to RAAS blockades in patients CKD stage 3 to 5D and hypertension. PMID- 29240785 TI - DEET as a feeding deterrent. AB - The insect repellent N,N-diethyl-3-methylbenzamide (DEET), is a multimodal compound that acts as a spatial repellent as well as an irritant (contact repellent), thus being perceived by the insect's olfactory and gustatory systems as an odorant and a tastant, respectively. Soon after DEET was developed, almost 6 decades ago, it was reported that it reduced mosquito feeding on blood mixed with this repellent. It is now known that the mosquito proboscis senses contact repellents with the tips (labella) of the labium, which remain in direct contact with the outer layers of the skin, while the stylets, including the feeding deterrent sensor (labrum), penetrate the skin. We designed a behavioral assay that allowed us to measure feeding deterrence without complications from contact or spatial repellency. Using the southern house mosquito, Culex quinquefasciatus, we demonstrate here that when DEET was mixed with blood and covered by Parafilm(r) layers, the mean number of landings and duration of contacts with surfaces covering blood mixed with DEET or blood plus solvent (dimethyl sulfoxide) did not differ significantly thus implying that DEET did not leak to the outer surface. The feeding times, however, were significantly different. When blood was mixed either with 0.1 or 1% DEET, female southern house mosquitoes spent significantly (P<0.0001) less time feeding than the time spent feeding on blood mixed only with the solvent. By contrast, significant differences in the mean times of feeding on blood containing 1% picaridin and blood plus solvent were significant at 5%, but not at 1% level. Like DEET, the contact repellent and insecticide, permethrin, caused a significant (P<0.0001) reduction in feeding time. We, therefore, concluded, that in this context, DEET, permethrin, and, to a lesser extent, picaridin, act as feeding deterrents. PMID- 29240786 TI - Time trend analysis (2009-2016) of antimicrobial susceptibility in Neisseria gonorrhoeae isolated in Italy following the introduction of the combined antimicrobial therapy. AB - INTRODUCTION: Neisseria gonorrhoeae (NG) antimicrobial susceptibility trends to azithromycin, cefixime and ceftriaxone were analyzed, from 2009 to 2016, to monitor changing antimicrobial susceptibility concomitant with the change in prescribing practice in 2012 from cefixime, or ceftriaxone, to ceftriaxone plus azithromycin. Patient characteristics predictive to be infected by antibiotic resistant N. gonorrhoeae were estimated. Finally, the protocol for the treatment of gonorrhoea, in comparison with the international guidelines, was also evaluated. MATERIALS AND METHODS: Data on NG antimicrobial resistance were obtained from a network of sexually transmitted diseases clinics and other laboratories in 12 cities in Italy. We tested the 1,433 gonococci for antimicrobial susceptibility to azithromycin, cefixime and ceftriaxone using a gradient diffusion method. Logistic-regression methods with cluster robust standard errors were used to investigate the association of resistance categories with demographic and clinical patient characteristics and to assess changes in prescribing practices. To minimize bias due to missing data, all statistical models were fitted to data with forty rounds of multiple imputation, using chained equations. RESULTS: The percentage of isolates resistant to cefixime was 17.10% in 2009 and declined up to 1.39% in 2016; at the same time, those resistant to azithromycin was 23.68% in 2009 and 3.00% in 2012. Starting from 2013, azithromycin resistant gonococci tended to increase up to 7.44% in 2016. No ceftriaxone resistant isolates were observed. By multivariate analysis, the men who have sex with women (MSW) and women had a proportional adjusted OR of resistance of 1.25 (95%CI: 0.90; 1.73) and 1.67 (95%CI: 1.16; 2.40), respectively, in comparison with men who have sex with men (MSM). An aOR of resistance of 0.48 (95%CI: 0.21; 1.12) among NG isolated in the pharynx, compared with those isolated in genital sites, was calculated. The proportional aOR of resistance was 0.58 (95%CI: 0.38; 0.89) for presence vs absence of co-infection and 2.00 (95%CI: 1.36; 2.96) for past history vs no history of gonorrhoea.Finally, at least for the period 2013-2016, the older, subjects with anorectal or pharyngeal gonorrhoea infection, subjects with a co-infection, subjects with a previous gonorrhoea infection were not always correctly treated. CONCLUSIONS: Overall, our findings suggest the shifts in N. gonorrhoeae susceptibility to cefixime and azithromycin in the time frame period. First of all, the increasing rate of azithromycin resistance in 2015-2016 in NG isolated in the country need to be monitor in the future. Finally, extensive information on treatment regimens may be useful to asses treatment adherence particularly for the older subjects, subjects with an anorectal or pharyngeal infection, subjects with a co-infection and subjects with a previous history of gonorrhoea. Gonorrhoea treatment strategy should be based on the evidence obtained by the local antimicrobial surveillance system and data about treatment failures. PMID- 29240787 TI - BRD3/4 inhibition and FLT3-ligand deprivation target pathways that are essential for the survival of human MLL-AF9+ leukemic cells. AB - In the present work we aimed to identify targetable signaling networks in human MLL-AF9 leukemias. We show that MLL-AF9 cells critically depend on FLT3-ligand induced pathways as well as on BRD3/4 for their survival. We evaluated the in vitro and in vivo efficacy of the BRD3/4 inhibitor I-BET151 in various human MLL AF9 (primary) models and patient samples and analyzed the transcriptome changes following treatment. To further understand the mode of action of BRD3/4 inhibition, we performed ChIP-seq experiments on the MLL-AF9 complex in THP1 cells and compared it to RNA-seq data of I-BET151 treated cells. While we could confirm a consistent and specific downregulation of key-oncogenic drivers such as MYC and BCL2, we found that the majority of I-BET151-responsive genes were not direct MLL-AF9 targets. In fact, MLL-AF9 specific targets such as the HOXA cluster, MEIS1 and other cell cycle regulators such as CDK6 were not affected by I-BET151 treatment. Furthermore, we also highlight how MLL-AF9 transformed cells are dependent on the function of non-mutated hematopoietic transcription factors and tyrosine kinases such as the FLT3-TAK1/NF-kB pathway, again impacting on BCL2 but not on the HOXA cluster. We conclude that BRD3/4 and the FLT3-TAK1/NF-kB pathways collectively control a set of targets that are critically important for the survival of human MLL-AF9 cells. PMID- 29240788 TI - Enhanced heart failure, mortality and renin activation in female mice with experimental dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is the major cause of heart failure affecting both women and men. Limited clinical studies show conflicting data in sex-related differences in the progression of dilated cardiomyopathy and heart failure (HF) outcomes. We examined the comparative sex-related progression of cardiomyopathy and the development of HF (at 4, 7, 13 weeks of age) in a well-established, transgenic mouse model of DCM that recapitulates the progressive stages of human HF. By 13 weeks of age, female mice with DCM had more severe left ventricular systolic dysfunction, left ventricular dilation and wall thinning (P<0.001 for all) than age-matched male mice with DCM. Female mice also had greater lung edema (P<0.001), cardiac fibrosis (P<0.01) and pleural effusions, which were not rescued by ovariectomy. By comparison to DCM male mice at 13 weeks, these pathological changes in female mice with DCM, were associated with significant increases in plasma active renin (P<0.01), angiotensin II (P<0.01) and aldosterone levels (P<0.001). In comparison to DCM male mice, DCM female mice also showed differential expression of the natriuretic peptide system with lower corin and higher ANP, BNP and cGMP levels at 13 weeks of age. We conclude, that female mice with experimental DCM have an accelerated progression of cardiomyopathy and HF, which was not corrected by early ovariectomy. These alterations are associated with early renin activation with increased angiotensin II and aldosterone levels, and altered expression of the natriuretic peptide system. PMID- 29240789 TI - How to quantitatively evaluate safety of driver behavior upon accident? A biomechanical methodology. AB - How to evaluate driver spontaneous reactions in various collision patterns in a quantitative way is one of the most important topics in vehicle safety. Firstly, this paper constructs representative numerical crash scenarios described by impact velocity, impact angle and contact position based on finite element (FE) computation platform. Secondly, a driver cabin model is extracted and described in the well validated multi-rigid body (MB) model to compute the value of weighted injury criterion to quantitatively assess drivers' overall injury under certain circumstances. Furthermore, based on the coupling of FE and MB, parametric studies on various crash scenarios are conducted. It is revealed that the WIC (Weighted Injury Criteria) value variation law under high impact velocities is quite distinct comparing with the one in low impact velocities. In addition, the coupling effect can be elucidated by the fact that the difference of WIC value among three impact velocities under smaller impact angles tends to be distinctly higher than that under larger impact angles. Meanwhile, high impact velocity also increases the sensitivity of WIC under different collision positions and impact angles. Results may provide a new methodology to quantitatively evaluate driving behaviors and serve as a significant guiding step towards collision avoidance for autonomous driving vehicles. PMID- 29240791 TI - Cross-sectional interactions between quality of the physical and social environment and self-reported physical activity in adults living in income deprived communities. AB - BACKGROUND: Understanding the environmental determinants of physical activity in populations at high risk of inactivity could contribute to the development of effective interventions. Socioecological models of activity propose that environmental factors have independent and interactive effects of physical activity but there is a lack of research into interactive effects. OBJECTIVES: This study aimed to explore independent and interactive effects of social and physical environmental factors on self-reported physical activity in income deprived communities. METHODS: Participants were 5,923 adults in Glasgow, United Kingdom. Features of the social environment were self-reported. Quality of the physical environment was objectively-measured. Neighbourhood walking and participation in moderate physical activity [MPA] on >=5 days/week was self reported. Multilevel multivariate logistic regression models tested independent and interactive effects of environmental factors on activity. RESULTS: 'Social support' (walking: OR:1.22,95%CI = 1.06-1.41,p<0.01; MPA: OR:0.79,95%CI = 0.67 0.94,p<0.01), 'social interaction' (walking: OR:1.25,95%CI = 1.10-1.42,p<0.01; MPA: OR:6.16,95%CI = 5.14-7.37,p<0.001) and 'cohesion and safety' (walking: OR:1.78,95%CI = 1.56-2.03,p<0.001; MPA: OR:1.93,95%CI = 1.65-2.27,p<0.001), but not 'trust and empowerment', had independent effects on physical activity. 'Aesthetics of built form' (OR:1.47,95%CI = 1.22-1.77,p<0.001) and 'aesthetics and maintenance of open space' (OR:1.32, 95%CI = 1.13-1.54,p<0.01) were related to walking. 'Physical disorder' (OR:1.63,95%CI = 1.31-2.03,p<0.001) had an independent effect on MPA. Interactive effects of social and physical factors on walking and MPA were revealed. CONCLUSIONS: Findings suggest that intervening to create activity-supportive environments in deprived communities may be most effective when simultaneously targeting the social and physical neighbourhood environment. PMID- 29240792 TI - Optimized maritime emergency resource allocation under dynamic demand. AB - Emergency resource is important for people evacuation and property rescue when accident occurs. The relief efforts could be promoted by a reasonable emergency resource allocation schedule in advance. As the marine environment is complicated and changeful, the place, type, severity of maritime accident is uncertain and stochastic, bringing about dynamic demand of emergency resource. Considering dynamic demand, how to make a reasonable emergency resource allocation schedule is challenging. The key problem is to determine the optimal stock of emergency resource for supplier centers to improve relief efforts. This paper studies the dynamic demand, and which is defined as a set. Then a maritime emergency resource allocation model with uncertain data is presented. Afterwards, a robust approach is developed and used to make sure that the resource allocation schedule performs well with dynamic demand. Finally, a case study shows that the proposed methodology is feasible in maritime emergency resource allocation. The findings could help emergency manager to schedule the emergency resource allocation more flexibly in terms of dynamic demand. PMID- 29240790 TI - Single-cell RNA sequencing reveals intrinsic and extrinsic regulatory heterogeneity in yeast responding to stress. AB - From bacteria to humans, individual cells within isogenic populations can show significant variation in stress tolerance, but the nature of this heterogeneity is not clear. To investigate this, we used single-cell RNA sequencing to quantify transcript heterogeneity in single Saccharomyces cerevisiae cells treated with and without salt stress to explore population variation and identify cellular covariates that influence the stress-responsive transcriptome. Leveraging the extensive knowledge of yeast transcriptional regulation, we uncovered significant regulatory variation in individual yeast cells, both before and after stress. We also discovered that a subset of cells appears to decouple expression of ribosomal protein genes from the environmental stress response in a manner partly correlated with the cell cycle but unrelated to the yeast ultradian metabolic cycle. Live-cell imaging of cells expressing pairs of fluorescent regulators, including the transcription factor Msn2 with Dot6, Sfp1, or MAP kinase Hog1, revealed both coordinated and decoupled nucleocytoplasmic shuttling. Together with transcriptomic analysis, our results suggest that cells maintain a cellular filter against decoupled bursts of transcription factor activation but mount a stress response upon coordinated regulation, even in a subset of unstressed cells. PMID- 29240793 TI - Dental implants in Sjogren's syndrome patients: A systematic review. AB - OBJECTIVES: The Sjogren's syndrome (SS) is a chronic autoimmune disease that affects salivation and consequently the health of oral tissues. The aim of this systematic review was to investigate the implant survival rate, marginal bone loss (MBL) and biological complications of dental implants in SS patients. MATERIALS AND METHODS: Eligibility criteria included prospective and retrospective cohort studies, controlled clinical trials, and randomized clinical trials (RCTs). An electronic search without date or language restrictions was carried out in MEDLINE, Cochrane, Web of Science, and LILACS until June 2017. In addition, manual search and in the grey literature were also conducted. The search process, data analysis, and quality assessment were performed by two independent reviewing authors. The protocol of this systematic review was registered in PROSPERO under number CRD42016053277. RESULTS: The search and selection process yielded 6 studies, published between 1997 and 2016. An average of 93.7% survival in a mean period of 3.97 years of follow-up was observed. A low number of MBL and biological complications were reported by the studies. All the studies analyzed observed an improvement in life quality of subjects with SS and rehabilitated through dental implants. CONCLUSIONS: With the limitations of this review and based on the available data, the dental implant therapy in SS patients seems to present high implant survival rate, low MBL and low biological complications. In addition, all included studies observed an increase in the quality of life of SS patients who were rehabilitated through dental implants. PMID- 29240795 TI - The MsmX ATPase plays a crucial role in pectin mobilization by Bacillus subtilis. AB - Carbohydrates from plant cell walls are often found as heteropolysaccharides intertwined with each other. For competitive advantage against other microorganisms, and ability to fully exploit available carbon and energy sources, Bacillus subtilis possesses a high number of proteins dedicated to the uptake of mono- and oligosaccharides. Here, we characterize transporter complexes, belonging to the ATP-binding cassette (ABC) superfamily, involved in the uptake of oligosaccharides commonly found in pectin. The uptake of these carbohydrates is shown to be MsmX-dependent, assigning a key role in pectin mobilization for MsmX, a multipurpose ATPase serving several distinct ABC-type I sugar importers. Mutagenesis analysis of the transmembrane domains of the AraNPQ MsmX-dependent importer revealed putative residues for MsmX interaction. Interestingly however, although MsmX is shown to be essential for energizing various ABC transporters we found that a second B. subtilis ATPase, YurJ, is able to complement its function when placed in trans at a different locus of the chromosome. PMID- 29240794 TI - Radiocesium contamination and estimated internal exposure doses in edible wild plants in Kawauchi Village following the Fukushima nuclear disaster. AB - Kawauchi Village, in Fukushima Prefecture, is located within a 30-km radius of the nuclear disaster site of the Fukushima Daiichi Nuclear Power Plant (FDNPP). "Sansai" (edible wild plants) in this village have been evaluated by gamma spectrometry after the residents had returned to their homes, to determine the residents' risk of internal exposure to artificial radionuclides due to consumption of these plants. The concentrations of radiocesium (cesium-134 and cesium-137) were measured in all 364 samples collected in spring 2015. Overall, 34 (9.3%) samples exceeded the regulatory limit of 100 Bq/kg established by Japanese guidelines, 80 (22.0%) samples registered between 100 Bq/kg and 20 Bq/kg, and 250 (68.7%) registered below 20 Bq/kg (the detection limit). The internal effective doses from edible wild plants were sufficiently low (less than 1 mSv/y), at 3.5+/-1.2 MUSv/y for males and 3.2+/-0.9 MUSv/y for females (2.7+/ 1.5 MUSv/y for children and 3.7+/-0.7 MUSv/y for adults in 2015). Thus, the potential internal exposure doses due to consumption of these edible wild plants were below the applicable radiological standard limits for foods. However, high radiocesium levels were confirmed in specific species, such as Eleutherococcus sciadophylloides ("Koshiabura") and Osmunda japonica (Asian royal fern, "Zenmai"). Consequently, a need still might exist for long-term follow-up such as environmental monitoring, physical and mental support to avoid unnecessary radiation exposure and to remove anxiety about adverse health effects due to radiation. The customs of residents, especially the "satoyama" (countryside) culture of ingesting "sansai," also require consideration in the further reconstruction of areas such as Kawauchi Village that were affected by the nuclear disaster. PMID- 29240796 TI - Improving the quality of child anthropometry: Manual anthropometry in the Body Imaging for Nutritional Assessment Study (BINA). AB - Anthropometric data collected in clinics and surveys are often inaccurate and unreliable due to measurement error. The Body Imaging for Nutritional Assessment Study (BINA) evaluated the ability of 3D imaging to correctly measure stature, head circumference (HC) and arm circumference (MUAC) for children under five years of age. This paper describes the protocol for and the quality of manual anthropometric measurements in BINA, a study conducted in 2016-17 in Atlanta, USA. Quality was evaluated by examining digit preference, biological plausibility of z-scores, z-score standard deviations, and reliability. We calculated z-scores and analyzed plausibility based on the 2006 WHO Child Growth Standards (CGS). For reliability, we calculated intra- and inter-observer Technical Error of Measurement (TEM) and Intraclass Correlation Coefficient (ICC). We found low digit preference; 99.6% of z-scores were biologically plausible, with z-score standard deviations ranging from 0.92 to 1.07. Total TEM was 0.40 for stature, 0.28 for HC, and 0.25 for MUAC in centimeters. ICC ranged from 0.99 to 1.00. The quality of manual measurements in BINA was high and similar to that of the anthropometric data used to develop the WHO CGS. We attributed high quality to vigorous training, motivated and competent field staff, reduction of non measurement error through the use of technology, and reduction of measurement error through adequate monitoring and supervision. Our anthropometry measurement protocol, which builds on and improves upon the protocol used for the WHO CGS, can be used to improve anthropometric data quality. The discussion illustrates the need to standardize anthropometric data quality assessment, and we conclude that BINA can provide a valuable evaluation of 3D imaging for child anthropometry because there is comparison to gold-standard, manual measurements. PMID- 29240797 TI - A mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases. AB - Neurodegenerative diseases are becoming prevalent as the population ages. Geniposide could inhibit oxidative stress, reduce apoptosis, protect neuron, and has been used for therapy of the neurodegenerative diseases. The bioavailability of geniposide by nasal route is greater than that by oral administration. However, mucociliary clearance is a rate-limiting factor for nasal route administration. The objective of this study was to develop and evaluate a mucoadhesive, thermoreversible in situ nasal gel of geniposide. The poloxamers (P407, P188) and the hydroxypropyl methylcellulose were used as thermoreversible and mucoadhesive polymers, respectively. Borneol was used as a permeation enhancer. The hydrogel was prepared with the cold method and optimized by the response surface methodology-central composite design. Gelation temperature, pH, clarity, gel strength, mucoadhesive strength, in vitro and ex vivo release kinetics of formulations were evaluated. The optimized amounts of poloxamer407 (P407), poloxamer188 (P188) and hydroxypropyl methylcellulose were determined to be 19.4-20.5%, 1.1-4.0% and 0.3-0.6% respectively. The second-order polynomial equation in terms of actual factors indicated a satisfactory correlation between the independent variables and the response (R2 = 0.9760). An ANOVA of the empirical second-order polynomial model indicated the model was significant (P<0.01). P407, P188, P407*P188, P4072 and P1882 were significant model terms. The effects of P407 on gelation temperature were greater than those of other independent variables. The pH values of all the formulations were found to be within 6.3-6.5 which was in the nasal physiological pH range 4.5-6.5. The drug content, gel strength, mucoadhesive strength of the optimized formulations were 97-101%, 25-50 sec and 4000-6000 dyn/cm2 respectively. The in vitro release kinetics of cumulative release of geniposide was fitted to the zero-order model. The ex vivo cumulative release kinetics of geniposide was fitted to the Weibull model. This study concludes that the release of geniposide is controlled by gel corrosion, and that the permeation of geniposide is time-dependent. The more residence time, mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases is of compliance and potential application. PMID- 29240798 TI - The cost of comorbidities in treatment for HIV/AIDS in California. AB - BACKGROUND: Antiretroviral therapy has increased longevity for people living with HIV (PLWH). As a result, PLWH increasingly experience the common diseases of aging and the resources needed to manage these comorbidities are increasing. This paper characterizes the number and types of comorbidities diagnosed among PLWH covered by Medicare and examines how non-HIV comorbidities relate to outpatient, inpatient, and pharmaceutical expenditures. METHODS: The study examined Medicare expenditures for 9767 HIV-positive Californians enrolled in Medicare in 2010 (7208 persons dually covered by Medicare and Medicaid and 2559 with Medicare only). Costs included both out of pocket costs and those paid by Medicare and Medicaid. Comorbidities were determined by examining diagnosis codes. FINDINGS: Medicare expenditures for Californians with HIV averaged $47,036 in 2010, with drugs accounting for about 2/3 of the total and outpatient costs 19% of the total. Inpatient costs accounted for 18% of the total. About 64% of the sample had at least one comorbidity in addition to HIV. Cross-validation showed that adding information on comorbidities to the quantile regression improved the accuracy of predicted individual expenditures. Non-HIV comorbidities relating to health habits-diabetes, hypertension, liver disease (hepatitis C), renal insufficiency-are common among PLWH. Cancer was relatively rare, but added significantly to cost. Comorbidities had little effect on pharmaceutical costs, which were dominated by the cost of antiretroviral therapy, but had a major effect on hospital admission. CONCLUSIONS: Comorbidities are prevalent among PLWH and add substantially to treatment costs for PLWH. Many of these comorbidities relate to health habits that could be addressed with additional prevention in ambulatory care, thereby improving health outcomes and ultimately reducing costs. PMID- 29240800 TI - Effect of long-term dietary sphingomyelin supplementation on atherosclerosis in mice. AB - Sphingomyelin (SM) levels in the circulation correlate positively with atherosclerosis burden. SM is a ubiquitous component of human diets, but it is unclear if dietary SM increases circulating SM levels. Dietary choline increases atherosclerosis by raising circulating trimethylamine N-oxide (TMAO) levels in mice and humans. As SM has a choline head group, we ask in this study if dietary SM accelerates atherosclerotic lesion development by increasing circulating SM and TMAO levels. Three studies were performed: (Study 1) C57BL/6 mice were maintained on a high fat diet with or without SM supplementation for 4 weeks prior to quantification of serum TMAO and SM levels; (Study 2) atherosclerosis was studied in apoE-/- mice after 16 weeks of a high fat diet without or with SM supplementation and (Study 3) apoE-/- mice were maintained on a chow diet for 19 weeks without or with SM supplementation and antibiotic treatment prior to quantification of atherosclerotic lesions and serum TMAO and SM levels. SM consumption did not increase circulating SM levels or atherosclerosis in high fat fed apoE-/- mice. Serum TMAO levels in C57BL/6 mice were low and had no effect atherosclerosis lesion development. Dietary SM supplementation significantly reduced atherosclerotic lesion area in the aortic arch of chow-fed apoE-/- mice. This study establishes that dietary SM does not affect circulating SM levels or increase atherosclerosis in high fat-fed apoE-/- mice, but it is anti-atherogenic in chow-fed apoE-/- mice. PMID- 29240801 TI - Student satisfaction and loyalty in Denmark: Application of EPSI methodology. AB - Monitoring and managing customers' satisfaction are key features to benefit from today's competitive environment. In higher education context, only a few studies are available on satisfaction and loyalty of the main customers who are the students, which signifies the need to investigate the field more thoroughly. The aim of this research is to measure the strength of determinants of students' satisfaction and the importance of antecedents in students' satisfaction and loyalty in Denmark. Our research model is the modification of European Performance Satisfaction Index (EPSI), which takes the university's image direct effects on students' expectations into account from students' perspective. The structural equation model of student satisfaction and loyalty has been evaluated using partial least square path modelling. Our findings confirm that the EPSI framework is applicable on student satisfaction and loyalty among Danish universities. We show that all the relationships among variables of the research model are significant except the relationship between quality of software and students' loyalty. Results further verify the significance of antecedents in students' satisfaction and loyalty at Danish universities; the university image and student satisfaction are the antecedents of student loyalty with a significant direct effect, while perceived value, quality of hardware, quality of software, expectations, and university image are antecedents of student satisfaction. Eventually, our findings may be of an inspiration to maintain and improve students' experiences during their study at the university. Dedicating resources to identified important factors from students' perception enable universities to attract more students, make them highly satisfied and loyal. PMID- 29240799 TI - Inappropriate self-medication among adolescents and its association with lower medication literacy and substance use. AB - BACKGROUND: While self-medication is common, inappropriate self-medication has potential risks. This study assesses inappropriate self-medication among adolescents and examines the relationships among medication literacy, substance use, and inappropriate self-medication. METHOD: In 2016, a national representative sample of 6,226 students from 99 primary, middle, and high schools completed an online self-administered questionnaire. Multiple logistic regression analysis was used to examine factors related to inappropriate self-medication. RESULTS: The prevalence of self-medication in the past year among the adolescents surveyed was 45.8%, and the most frequently reported drugs for self-medication included nonsteroidal anti-inflammatory drugs or pain relievers (prevalence = 31.1%), cold or cough medicines (prevalence = 21.6%), analgesics (prevalence = 19.3%), and antacids (prevalence = 17.3%). Of the participants who practiced self medication, the prevalence of inappropriate self-medication behaviors included not reading drug labels or instructions (10.1%), using excessive dosages (21.6%), and using prescription and nonprescription medicine simultaneously without advice from a health provider (polypharmacy) (30.3%). The results of multiple logistic regression analysis showed that after controlling for school level, gender, and chronic diseases, the participants with lower medication knowledge, lower self efficacy, lower medication literacy, and who consumed tobacco or alcohol were more likely to engage in inappropriate self-medication. CONCLUSION: Lower medication literacy and substance use were associated with inappropriate self medication among adolescents. PMID- 29240802 TI - Systemic factors related to soluble (pro)renin receptor in plasma of patients with proliferative diabetic retinopathy. AB - (Pro)renin receptor [(P)RR], a new component of the tissue renin-angiotensin system (RAS), plays a crucial role in inflammation and angiogenesis in the eye, thus contributing to the development of proliferative diabetic retinopathy (PDR). In this study, we investigated systemic factors related to plasma levels of soluble form of (P)RR [s(P)RR] in patients with PDR. Twenty type II diabetic patients with PDR and 20 age-matched, non-diabetic patients with idiopathic macular diseases were enrolled, and plasma levels of various molecules were measured by enzyme-linked immunosorbent assays. Human retinal microvascular endothelial cells were stimulated with several diabetes-related conditions to evaluate changes in gene expression using real-time quantitative PCR. Of various systemic parameters examined, the PDR patients had significantly higher blood sugar and serum creatinine levels than non-diabetic controls. Protein levels of s(P)RR, prorenin, tumor necrosis factor (TNF)-alpha, complement factor D (CFD), and leucine-rich alpha-2-glycoprotein 1 (LRG1) significantly increased in the plasma of PDR subjects as compared to non-diabetes, with positive correlations detected between s(P)RR and these inflammatory molecules but not prorenin. Estimated glomerular filtration rate and serum creatinine were also correlated with plasma s(P)RR, but not prorenin, levels. Among the inflammatory molecules correlated with s(P)RR in the plasma, TNF-alpha, but not CFD or LRG1, application to retinal endothelial cells upregulated the mRNA expression of (P)RR but not prorenin, while stimulation with high glucose enhanced both (P)RR and prorenin expression. These findings suggested close relationships between plasma s(P)RR and diabetes-induced factors including chronic inflammation, renal dysfunction, and hyperglycemia in patients with PDR. PMID- 29240803 TI - Bone edema on magnetic resonance imaging is highly associated with low bone mineral density in patients with ankylosing spondylitis. AB - OBJECTIVE: This study aimed to assess the relationship between bone marrow edema (BME) on magnetic resonance imaging (MRI) and bone mineral density (BMD) in patients with ankylosing spondylitis (AS). METHODS: The study included 333 patients with AS who underwent BMD measurements and axial MRI. Additionally, 106 normal controls were included. The modified New York criteria were used as the classification criteria of AS. Clinical, laboratory, and imaging data were collected and analyzed. Lumbar spine and proximal femur BMD were assessed using dual-energy X-ray absorptiometry. Low BMD was defined by a Z-score <=-2. The Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index was used to assess inflammation at the sacroiliac joint (SIJ) and spine. RESULTS: Among the 333 patients, the male:female ratio was 4.6:1, mean patient age was 28.5+/-10.6 years, and mean disease duration was 7.3+/-6.8 years. The prevalences of low BMD, osteopenia, and osteoporosis were significantly higher among AS patients than among controls (19.8%, 62.8%, and 5.7% vs. 4.7%, 33.0%, and 0%, respectively, P = 0.000). The BMD values were significantly lower and prevalences of low BMD at both the spine and femur were significantly higher among patients with BME on MRI than among those without BME. Multivariate logistic regression analysis showed that male sex (OR 3.87, 95% CI 1.21-7.36, P = 0.023), high ASDAS-CRP score (OR 2.83, 95% CI 1.36-4.76, P = 0.015), the presence of BME on sacroiliac MRI (OR 2.83, 95% CI 1.77-6.23, P = 0.000) and spinal MRI (OR 4.06, 95% CI 1.96-8.46, P = 0.000), and high grade of sacroiliitis (OR 2.93, 95% CI 1.82-4.45, P = 0.002) were risk factors for low BMD (any site). The SPARCC scores of the SIJ were negatively correlated with femoral BMD (r = -0.22, 95% CI -0.33 to -0.10, P = 0.000). Additionally, the SPARCC scores of the spine were negatively correlated with BMD values (r = -0.23, 95% CI -0.36 to -0.09, P = 0.003) and Z-scores (r = 0.24, 95% CI -0.36 to -0.12, P = 0.001) at the spine. CONCLUSION: Low BMD is common in AS patients. BME on MRI is highly associated with low BMD at both the spine and femur. PMID- 29240804 TI - Different involvement of medial prefrontal cortex and dorso-lateral striatum in automatic and controlled processing of a future conditioned stimulus. AB - Recent studies support the idea that stimulus processing in latent inhibition can vary during the course of preexposure. Controlled attentional mechanisms are said to be important in the early stages of preexposure, while in later stages animals adopt automatic processing of the stimulus to be used for conditioning. Given this distinction, it is possible that both types of processing are governed by different neural systems, affecting differentially the retrieval of information about the stimulus. In the present study we tested if a lesion to the dorso lateral striatum or to the medial prefrontal cortex has a selective effect on exposure to the future conditioned stimulus (CS). With this aim, animals received different amounts of exposure to the future CS. The results showed that a lesion to the medial prefrontal cortex enhanced latent inhibition in animals receiving limited preexposure to the CS, but had no effect in animals receiving extended preexposure to the CS. The lesion of the dorso-lateral striatum produced a decrease in latent inhibition, but only in animals with an extended exposure to the future conditioned stimulus. These results suggest that the dorsal striatum and medial prefrontal cortex play essential roles in controlled and automatic processes. Automatic attentional processes appear to be impaired by a lesion to the dorso-lateral striatum and facilitated by a lesion to the prefrontal cortex. PMID- 29240805 TI - Poly-victimization in a Norwegian adolescent population: Prevalence, social and psychological profile, and detrimental effects. AB - BACKGROUND: This study focuses on poly-victimization, with the aim of providing a realistic estimation of the prevalence of lifetime victimization in a Norwegian adolescent population (ages 18-19 years). METHODS: Based upon the concept from previous research, we applied measures of child poly-victimization on Norwegian data obtained from a national youth survey in 2015 (N = 4,531) to arrive at an estimation of its prevalence. We used variables that measure individual characteristics such as gender and educational aspiration and socio-economic factors such as parents' education level and home economic situation to derive a social and psychological profile of victimization and poly-victimization among young people. Finally, we estimated the effects of poly-victimization on mental health such as symptoms of depression, anxiety and trauma. RESULTS: Our study identified a poly-victimization prevalence of 8.6% among young people, i.e. they were exposed to three of all four forms of violence investigated by our study: non-physical violence, witnessing violence against parents, physical violence and sexual abuse. Adolescents of poly-victimization are six times more likely to report depression and anxiety and trauma when compared with those without victimization. CONCLUSIONS: Poly-victimization is a phenomenon that heavily burdens many young people across many national contexts. Poly-victims clearly tend to develop depression, anxiety, and posttraumatic stress symptoms. The early detection of sexual abuse, physical violence, and bullying victimization is of critical importance and preventive measures could consider addressing family factors through parental educational programs. PMID- 29240806 TI - The structure of salt marsh soil mesofauna food webs - The prevalence of disturbance. AB - Mesofauna taxa fill key trophic positions in soil food webs, even in terrestrial marine boundary habitats characterized by frequent natural disturbances. Salt marshes represent such boundary habitats, characterized by frequent inundations increasing from the terrestrial upper to the marine pioneer zone. Despite the high abundance of soil mesofauna in salt marshes and their important function by facilitating energy and carbon flows, the structure, trophic ecology and habitat related diet shifts of mesofauna species in natural salt marsh habitats is virtually unknown. Therefore, we investigated the effects of natural disturbance (inundation frequency) on community structure, food web complexity and resource use of soil mesofauna using stable isotope analysis (15N, 13C) in three salt marsh zones. In this intertidal habitat, the pioneer zone is exposed to inundations twice a day, but lower and upper salt marshes are less frequently inundated based on shore height. The mesofauna comprised 86 species / taxa dominated by Collembola, Oribatida and Mesostigmata. Shifts in environmental disturbances influenced the structure of food webs, diversity and density declined strongly from the land to the sea pointing to the importance of increasing levels of inundation frequency. Accordingly, the reduced diversity and density was associated by a simplification of the food web in the pioneer zone as compared to the less inundated lower and upper salt marsh with a higher number of trophic levels. Strong variations in delta15N signatures demonstrated that mesofauna species are feeding at multiple trophic levels. Primary decomposers were low and most mesofauna species functioned as secondary decomposers or predators including second order predators or scavengers. The results document that major decomposer taxa, such as Collembola and Oribatida, are more diverse than previously assumed and predominantly dwell on autochthonous resources of the respective salt marsh zone. The results further suggest that Mesostigmata mostly adopt an intraguild predation lifestyle. The high trophic position of a large number of predators suggests that intraguild predation is of significant importance in salt marsh food webs. Presumably, intraguild predation contributes to stabilizing the salt marsh food web against disturbances. PMID- 29240807 TI - Diversification of the insulin-like growth factor 1 gene in mammals. AB - Insulin-like growth factor 1 (IGF1), a small, secreted peptide growth factor, is involved in a variety of physiological and patho-physiological processes, including somatic growth, tissue repair, and metabolism of carbohydrates, proteins, and lipids. IGF1 gene expression appears to be controlled by several different signaling cascades in the few species in which it has been evaluated, with growth hormone playing a major role by activating a pathway involving the Stat5b transcription factor. Here, genes encoding IGF1 have been evaluated in 25 different mammalian species representing 15 different orders and ranging over ~180 million years of evolutionary diversification. Parts of the IGF1 gene have been fairly well conserved. Like rat Igf1 and human IGF1, 21 of 23 other genes are composed of 6 exons and 5 introns, and all 23 also contain recognizable tandem promoters, each with a unique leader exon. Exon and intron lengths are similar in most species, and DNA sequence conservation is moderately high in orthologous exons and proximal promoter regions. In contrast, putative growth hormone-activated Stat5b-binding enhancers found in analogous locations in rodent Igf1 and in human IGF1 loci, have undergone substantial variation in other mammals, and a processed retro-transposed IGF1 pseudogene is found in the sloth locus, but not in other mammalian genomes. Taken together, the fairly high level of organizational and nucleotide sequence similarity in the IGF1 gene among these 25 species supports the contention that some common regulatory pathways had existed prior to the beginning of mammalian speciation. PMID- 29240808 TI - Altered cerebral hemodyamics and cortical thinning in asymptomatic carotid artery stenosis. AB - Cortical thinning is a potentially important biomarker, but the pathophysiology in cerebrovascular disease is unknown. We investigated the association between regional cortical blood flow and regional cortical thickness in patients with asymptomatic unilateral high-grade internal carotid artery disease without stroke. Twenty-nine patients underwent high resolution anatomical and single delay, pseudocontinuous arterial spin labeling magnetic resonance imaging with partial volume correction to assess gray matter baseline flow. Cortical thickness was estimated using Freesurfer software, followed by co-registration onto each patient's cerebral blood flow image space. Paired t-tests assessed regional cerebral blood flow in motor cortex (supplied by the carotid artery) and visual cortex (indirectly supplied by the carotid) on the occluded and unoccluded side. Pearson correlations were calculated between cortical thickness and regional cerebral blood flow, along with age, hypertension, diabetes and white matter hyperintensity volume. Multiple regression and generalized estimating equation were used to predict cortical thickness bilaterally and in each hemisphere separately. Cortical blood flow correlated with thickness in motor cortex bilaterally (p = 0.0002), and in the occluded and unoccluded sides individually; age (p = 0.002) was also a predictor of cortical thickness in the motor cortex. None of the variables predicted cortical thickness in visual cortex. Blood flow was significantly lower on the occluded versus unoccluded side in the motor cortex (p<0.0001) and in the visual cortex (p = 0.018). On average, cortex was thinner on the side of occlusion in motor but not in visual cortex. The association between cortical blood flow and cortical thickness in carotid arterial territory with greater thinning on the side of the carotid occlusion suggests that altered cerebral hemodynamics is a factor in cortical thinning. PMID- 29240809 TI - Interaction mode of CIDE family proteins in fly: DREP1 and DREP3 acidic surfaces interact with DREP2 and DREP4 basic surfaces. AB - Cell death-inducing DNA fragmentation factor 45 (DFF45)-like effector (CIDE) domains were initially identified as protein interaction modules in apoptotic nucleases and are now known to form a highly conserved family with diverse functions that range from cell death to lipid homeostasis. In the fly, four CIDE domain-containing proteins (DFF-related protein [DREP]-1-4) and their functions, including interaction relationships, have been identified. In this study, we introduced and investigated acidic side-disrupted mutants of DREP1, DREP2, and DREP3. We discovered that the acidic surface patches of DREP1 and DREP3 are critical for the homo-dimerization. In addition, we found that the acidic surface sides of DREP1 and DREP3 interact with the basic surface sides of DREP2 and DREP4. Our current study provides clear evidence demonstrating the mechanism of the interactions between four DREP proteins in the fly. PMID- 29240810 TI - Forest loss in New England: A projection of recent trends. AB - New England has lost more than 350,000 ha of forest cover since 1985, marking a reversal of a two-hundred-year trend of forest expansion. We a cellular land cover change model to project a continuation of recent trends (1990-2010) in forest loss across six New England states from 2010 to 2060. Recent trends were estimated using a continuous change detection algorithm applied to twenty years of Landsat images. We addressed three questions: (1) What would be the consequences of a continuation of the recent trends in terms of changes to New England's forest cover mosaic? (2) What social and biophysical attributes are most strongly associated with recent trends in forest loss, and how do these vary geographically? (3) How sensitive are projections of forest loss to the reference period-i.e. how do projections based on the period spanning 1990-to-2000 differ from 2000-to-2010, or from the full period, 1990-to-2010? Over the full reference period, 8201 ha yr-1 and 468 ha yr-1 of forest were lost to low- and high-density development, respectively. Forest loss was concentrated in suburban areas, particularly near Boston. Of the variables considered, 'distance to developed land' was the strongest predictor of forest loss. The next most important predictor varied geographically: 'distance to roads' ranked second in the more developed regions in the south and 'population density' ranked second in the less developed north. The importance and geographical variation in predictor variables were relatively stable between reference periods. In contrast, there was 55% more forest loss during the 1990-to-2000 reference period compared to the 2000-to-2010 period, highlighting the importance of understanding the variation in reference periods when projecting land cover change. The projection of recent trends is an important baseline scenario with implications for the management of forest ecosystems and the services they provide. PMID- 29240811 TI - Whole-genome analyses of human adenovirus type 55 emerged in Tibet, Sichuan and Yunnan in China, in 2016. AB - Three outbreaks of acute respiratory disease occurred at military camps in 2016 at Tibet, Sichuan and Yunnan province, China. The pathogen induced these three outbreaks were all confirmed as HAdV-55 by genotype-specific PCR. The outbreak in Tibet was the first report that HAdV-55 occurred in the high altitude (HA, above sea level 3658 m). This study aims to determine the gene variation and evolution characteristics of these viral strains. Three strains of adenoviruses, LS89/Tibet/2016 (GenBank accession no. KY002683), SF04/SC/2016 (GenBank accession no. KY002684) and KM03/YN/2016 (GenBank accession no. KY002685) were obtained and confirmed by wholegenome sequencing. No multi-gene fragments recombination were found in these isolated HAdV-55 virus compared with previous reported HAdV-55 strains in China. The outbreaks in Tibet and in Sichuan continuously occurred. Virus isolated from Tibet (LS89/Tibet/2016) and Sichuan (SF04/SC/2016) had a similar mutation pattern and had a closer genetic evolutionary distance than KM03/YN/2016 strain, which indicates that the pathogens causing these two outbreaks may be of the same origin. Moreover, we found that heating was an effective way to inactive these viruses, which provide valuable information for the development of HAdV-55 vaccines. Our data provide new information for genetic evolution of HAdV-55, and contribute to the prevention and control of HAdV-55 infection in the future. PMID- 29240812 TI - Effects of vaspin on pancreatic beta cell secretion via PI3K/Akt and NF-kappaB signaling pathways. AB - Vaspin (visceral adipose tissue-derived serine protease inhibitor) is a recently discovered adipokine that has been implicated in diabetes mellitus and other metabolic disorders. However, the effects of vaspin on pancreatic beta cell function and related mechanisms are not fully understood. Thus, the present study was performed to investigate the effects of vaspin on pancreatic beta cell function and the potential underlying mechanisms. Both in vitro (rat insulinoma cells, INS-1) and in vivo (high fat diet fed rats) experiments were conducted. The results showed that vaspin significantly increased INS-1 cell secretory function. Potential mechanisms were explored using inhibitors, western blot and real-time PCR techniques. We found that vaspin increased the levels of IRS-2 mRNA and IRS-2 total protein, while decreased the serine phosphorylation level of IRS 2 protein. Moreover, vaspin increased the Akt phosphorylation protein level which was reversed by PI3K inhibitor ly294002. In addition, vaspin increased the phosphorylation levels of mTOR and p70S6K, which was inhibited by rapamycin. Meanwhile, we found that the NF-kappaB mRNA and protein levels were reduced after vaspin treatment, similar to the effect of NF-kappaB inhibitor TPCK. Furthermore, vaspin increased the glucose stimulated insulin secretion (GSIS) level, lowered blood glucose level and improved the glucose tolerance and insulin sensitivity of high fat diet fed rats. Hyperglycemic clamp test manifested that vaspin improved islet beta cell function. Together, these findings provide a new understanding of the function of vaspin on pancreatic beta cell and suggest that it may serve as a potential agent for the prevention and treatment of type 2 diabetes. PMID- 29240813 TI - Feature reliability determines specificity and transfer of perceptual learning in orientation search. AB - Training can modify the visual system to produce a substantial improvement on perceptual tasks and therefore has applications for treating visual deficits. Visual perceptual learning (VPL) is often specific to the trained feature, which gives insight into processes underlying brain plasticity, but limits VPL's effectiveness in rehabilitation. Under what circumstances VPL transfers to untrained stimuli is poorly understood. Here we report a qualitatively new phenomenon: intrinsic variation in the representation of features determines the transfer of VPL. Orientations around cardinal are represented more reliably than orientations around oblique in V1, which has been linked to behavioral consequences such as visual search asymmetries. We studied VPL for visual search of near-cardinal or oblique targets among distractors of the other orientation while controlling for other display and task attributes, including task precision, task difficulty, and stimulus exposure. Learning was the same in all training conditions; however, transfer depended on the orientation of the target, with full transfer of learning from near-cardinal to oblique targets but not the reverse. To evaluate the idea that representational reliability was the key difference between the orientations in determining VPL transfer, we created a model that combined orientation-dependent reliability, improvement of reliability with learning, and an optimal search strategy. Modeling suggested that not only search asymmetries but also the asymmetric transfer of VPL depended on preexisting differences between the reliability of near-cardinal and oblique representations. Transfer asymmetries in model behavior also depended on having different learning rates for targets and distractors, such that greater learning for low-reliability distractors facilitated transfer. These findings suggest that training on sensory features with intrinsically low reliability may maximize the generalizability of learning in complex visual environments. PMID- 29240814 TI - Towards the identification of Idiopathic Parkinson's Disease from the speech. New articulatory kinetic biomarkers. AB - Although a large amount of acoustic indicators have already been proposed in the literature to evaluate the hypokinetic dysarthria of people with Parkinson's Disease, the goal of this work is to identify and interpret new reliable and complementary articulatory biomarkers that could be applied to predict/evaluate Parkinson's Disease from a diadochokinetic test, contributing to the possibility of a further multidimensional analysis of the speech of parkinsonian patients. The new biomarkers proposed are based on the kinetic behaviour of the envelope trace, which is directly linked with the articulatory dysfunctions introduced by the disease since the early stages. The interest of these new articulatory indicators stands on their easiness of identification and interpretation, and their potential to be translated into computer based automatic methods to screen the disease from the speech. Throughout this paper, the accuracy provided by these acoustic kinetic biomarkers is compared with the one obtained with a baseline system based on speaker identification techniques. Results show accuracies around 85% that are in line with those obtained with the complex state of the art speaker recognition techniques, but with an easier physical interpretation, which open the possibility to be transferred to a clinical setting. PMID- 29240815 TI - Evolution-guided adaptation of an adenylation domain substrate specificity to an unusual amino acid. AB - Adenylation domains CcbC and LmbC control the specific incorporation of amino acid precursors in the biosynthesis of lincosamide antibiotics celesticetin and lincomycin. Both proteins originate from a common L-proline-specific ancestor, but LmbC was evolutionary adapted to use an unusual substrate, (2S,4R)-4-propyl proline (PPL). Using site-directed mutagenesis of the LmbC substrate binding pocket and an ATP-[32P]PPi exchange assay, three residues, G308, A207 and L246, were identified as crucial for the PPL activation, presumably forming together a channel of a proper size, shape and hydrophobicity to accommodate the propyl side chain of PPL. Subsequently, we experimentally simulated the molecular evolution leading from L-proline-specific substrate binding pocket to the PPL-specific LmbC. The mere change of three amino acid residues in originally strictly L proline-specific CcbC switched its substrate specificity to prefer PPL and even synthetic alkyl-L-proline derivatives with prolonged side chain. This is the first time that such a comparative study provided an evidence of the evolutionary relevant adaptation of the adenylation domain substrate binding pocket to a new sterically different substrate by a few point mutations. The herein experimentally simulated rearrangement of the substrate binding pocket seems to be the general principle of the de novo genesis of adenylation domains' unusual substrate specificities. However, to keep the overall natural catalytic efficiency of the enzyme, a more comprehensive rearrangement of the whole protein would probably be employed within natural evolution process. PMID- 29240816 TI - The "sociotype" construct: Gauging the structure and dynamics of human sociality. AB - Exploring the pertinence of a "sociotype" construct, established along the conceptual chain genotype-phenotype-sociotype, is the essential purpose of the present paper. Further, by following the sociotype's conceptual guidelines, a new psychometric indicator has been developed in order to gauge the level of social interaction around each individual-the sociotype questionnaire (SOCQ). A first version of this questionnaire has been elaborated by gathering data about the different classes of social bonds (family, friends, acquaintances, and work/study colleagues) in general population and about the dynamic update of these bonds via face-to-face conversation and other modes of interaction. A specific fieldwork was undertaken, involving 1,075 participants, all of them Spanish adults (with diverse social and regional backgrounds). The data obtained were analyzed by means of the correlational method with an analytical cross-sectional design: the number of factors and the consistency and reliability of the resulting scales were evaluated and correlated. The new sociotype indicator resulting from that fieldwork, in spite of its limitations, seems to be valid and reliable, as well as closely associated with widely used metrics of loneliness and psychological distress. It is interesting that the construct noticeably varies throughout the life course and circumstances of individuals, based on their gender and age, and adjusting to the different situations of social networking. This is the first study, to the best of our knowledge, which has tried to reach both a theoretical and an operational formulation of the sociotype construct, by establishing an ad hoc psychometric questionnaire. We think that the information provided by this operational definition opens a new direction of work that could be useful to guide the development and evaluation of programs aimed at improving and strengthening social networking in people at risk, especially for the elderly. PMID- 29240817 TI - More visual mind wandering occurrence during visual task performance: Modality of the concurrent task affects how the mind wanders. AB - Mind wandering has been considered as a mental process that is either independent from the concurrent task or regulated like a secondary task. These accounts predict that the form of mind wandering (i.e., images or words) should be either unaffected by or different from the modality form (i.e., visual or auditory) of the concurrent task. Findings from this study challenge these accounts. We measured the rate and the form of mind wandering in three task conditions: fixation, visual 2-back, and auditory 2-back. Contrary to the general expectation, we found that mind wandering was more likely in the same form as the task. This result can be interpreted in light of recent findings on overlapping brain activations during internally- and externally-oriented processes. Our result highlights the importance to consider the unique interplay between the internal and external mental processes and to measure mind wandering as a multifaceted rather than a unitary construct. PMID- 29240819 TI - Use of thermal analysis coupled with differential scanning calorimetry, quadrupole mass spectrometry and infrared spectroscopy (TG-DSC-QMS-FTIR) to monitor chemical properties and thermal stability of fulvic and humic acids. AB - Thermogravimetry-coupled with differential scanning calorimetry, quadrupole mass spectrometry, and Fourier-transform infrared spectroscopy (TG-DSC-QMS-FTIR)-was applied to monitor the thermal stability (in an N2 pyrolytic atmosphere) and chemical properties of natural polymers, fulvic (FA) and humic acids (HA), isolated from chemically different soils. Three temperature ranges, R1, 40-220 degrees C; R2, 220-430 degrees C; and R3, 430-650 degrees C, were distinguished from the DSC data, related to the main thermal processes of different structures (including transformations without weight loss). Weight loss (DeltaM) estimated from TG curves at the above temperature intervals revealed distinct differences within the samples in the content of physically adsorbed water (at R1), volatile and labile functional groups (at R2) as well as recalcitrant and refractory structures (at R3). QMS and FTIR modules enabled the chemical identification (by masses and by functional groups, respectively) of gaseous species evolved during thermal decomposition at R1, R2 and R3. Variability in shape, area and temperature of TG, DSC, QMS and FTIR peaks revealed differences in thermal stability and chemical structure of the samples between the FAs and HAs fractions of different origin. The statistical analysis showed that the parameters calculated from QMS (areas of m/z = 16, 17, 18, 44), DSC (MaxDSC) and TG (DeltaM) at R1, R2 and R3 correlated with selected chemical properties of the samples, such as N, O and COOH content as well as E2/E6 and E2/E4 indexes. This indicated a high potential for the coupled method to monitor the chemical changes of humic substances. A new humification parameter, HTD, based on simple calculations of weight loss at specific temperature intervals proved to be a good alternative to indexes obtained from other methods. The above findings showed that the TG-DSC QMS-FTIR coupled technique can represent a useful tool for the comprehensive assessment of FAs and HAs properties related to their various origin. PMID- 29240818 TI - Genetic dissection of main and epistatic effects of QTL based on augmented triple test cross design. AB - The use of heterosis has considerably increased the productivity of many crops; however, the biological mechanism underpinning the technique remains elusive. The North Carolina design III (NCIII) and the triple test cross (TTC) are powerful and popular genetic mating design that can be used to decipher the genetic basis of heterosis. However, when using the NCIII design with the present quantitative trait locus (QTL) mapping method, if epistasis exists, the estimated additive or dominant effects are confounded with epistatic effects. Here, we propose a two step approach to dissect all genetic effects of QTL and digenic interactions on a whole genome without sacrificing statistical power based on an augmented TTC (aTTC) design. Because the aTTC design has more transformation combinations than do the NCIII and TTC designs, it greatly enriches the QTL mapping for studying heterosis. When the basic population comprises recombinant inbred lines (RIL), we can use the same materials in the NCIII design for aTTC-design QTL mapping with transformation combination Z1, Z2, and Z4 to obtain genetic effect of QTL and digenic interactions. Compared with RIL-based TTC design, RIL-based aTTC design saves time, money, and labor for basic population crossed with F1. Several Monte Carlo simulation studies were carried out to confirm the proposed approach; the present genetic parameters could be identified with high statistical power, precision, and calculation speed, even at small sample size or low heritability. Additionally, two elite rice hybrid datasets for nine agronomic traits were estimated for real data analysis. We dissected the genetic effects and calculated the dominance degree of each QTL and digenic interaction. Real mapping results suggested that the dominance degree in Z2 that mainly characterize heterosis showed overdominance and dominance for QTL and digenic interactions. Dominance and overdominance were the major genetic foundations of heterosis in rice. PMID- 29240820 TI - Age-related nomograms for antral follicle count and anti-Mullerian hormone for subfertile Chinese women in Singapore. AB - BACKGROUND: Antral follicle count (AFC) and anti-Mullerian hormone (AMH) are known as the most reliable markers of a woman's ovarian reserve and are related to age. There is currently no specific local age-related centile charts for AFC and AMH. Therefore, we aim to examine the relationship between AFC and AMH with age and construct age-related nomograms among a subfertile Asian population. METHODS: This is a study involving Chinese women who had their AFC and AMH measured as part of their subfertility screening from December 2010 until November 2014 in KK Women's and Children's Hospital, Singapore. Ordinary least squares regression analysis was used to estimate the relationship of AFC and AMH with age, while age-related AFC and AMH nomograms for the 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentiles were produced using the lambda-mu-sigma method. RESULTS: A total of 1,009 women, aged 26 to 44 year-old, were included. On average, the AFC and AMH decreased respectively by 0.79 follicle (95% confidence interval -0.93, -0.64) and 0.38 ng/mL (95% confidence interval -0.43, -0.32) per year of age. The age-related nomograms of AFC showed an approximately linear pattern, inversely correlated with age, regardless of the percentile. For AMH, the pattern is linear for the 75th percentile and below but shows a slightly accelerating decline for the 90th and 97th percentile. Overall, there were large inter-individual variations in AFC and AMH up to about 40 year-old. CONCLUSION: The declines of AFC and AMH over age are mostly linear among subfertile Chinese women in Singapore. The age-related AFC and AMH nomograms could be used as a reference chart by fertility practitioners. However, future validation with longitudinal data is required. PMID- 29240822 TI - Acne keloidalis nuchae in Asian: A single institutional experience. AB - Acne keloidalis nuchae, a type of folliculitis involving the back of the neck, is common in black men, although rare cases have been reported in patients of other ethnicities. We analyzed the clinicopathological features of acne keloidalis nuchae in 17 Asians. Patients' age at the time of presentation ranged from 20 to 69 years. Most patients experienced the disease over 2 years (range, 3 months-20 years); follow-up data were available for 11 (65%) patients (range, 2-95 months). Nine (53%) patients had comorbidities, but none had a history of other skin disease or a family history of acne keloidalis nuchae. Macroscopically, seven (41%) patients had multiple erythematous pustulopapular lesions, and 10 (59%) had a single large plaque. Histopathologically, deep scarring folliculitis containing naked hair shafts was identified. In all cases, inflammation was most severe in the upper two-thirds of the dermis, and the differences in pustulopapular and plaque lesions were more prominent in the peri-inflammation area. Of the seven patients with plaque lesions treated with steroids alone or steroids and cryotherapy, three experienced plaque reduction. Acne keloidalis nuchae occurring in Asian patients frequently present with typical clinicopathological features, and therefore in spite of very low incidence the diagnosis of this disease entity should be considered in idiopathic scarring folliculitis of the posterior neck. PMID- 29240821 TI - Tumor necrosis factor-alpha antagonist diminishes osteocytic RANKL and sclerostin expression in diabetes rats with periodontitis. AB - Type 1 diabetes with periodontitis shows elevated TNF-alpha expression. Tumor necrosis factor (TNF)-alpha stimulates the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and sclerostin. The objective of this study was to determine the effect of TNF-alpha expression of osteocytic RANKL and sclerostin in type 1 diabetes rats with periodontitis using infliximab (IFX), a TNF-alpha antagonist. Rats were divided into two timepoint groups: day 3 and day 20. Each timepoint group was then divided into four subgroups: 1) control (C, n = 6 for each time point); 2) periodontitis (P, n = 6 for each time point); 3) diabetes with periodontitis (DP, n = 8 for each time point); and 4) diabetes with periodontitis treated with IFX (DP+IFX, n = 8 for each time point). To induce type 1 diabetes, rats were injected with streptozotocin (50 mg/kg dissolved in 0.1 M citrate buffer). Periodontitis was then induced by ligature of the mandibular first molars at day 7 after STZ injection (day 0). IFX was administered once for the 3 day group (on day 0) and twice for the 20 day group (on days 7 and 14). The DP group showed greater alveolar bone loss than the P group on day 20 (P = 0.020). On day 3, higher osteoclast formation and RANKL positive osteocytes in P group (P = 0.000 and P = 0.011, respectively) and DP group (P = 0.006 and P = 0.017, respectively) than those in C group were observed. However, there was no significant difference in osteoclast formation or RANKL-positive osteocytes between P and DP groups. The DP+IFX group exhibited lower alveolar bone loss (P = 0.041), osteoclast formation (P = 0.019), and RANKL positive osteocytes (P = 0.009) than that of the DP group. On day 20, DP group showed a lower osteoid area (P = 0.001) and more sclerostin-positive osteocytes (P = 0.000) than P group. On days 3 and 20, the DP+IFX group showed more osteoid area (P = 0.048 and 0.040, respectively) but lower sclerostin-positive osteocytes (both P = 0.000) than DP group. Taken together, these results suggest that TNF alpha antagonist can diminish osteocytic RANKL/sclerostin expression and osteoclast formation, eventually recovering osteoid formation. Therefore, TNF alpha might mediate alveolar bone loss via inducing expression of osteocytic RANKL and sclerostin in type 1 diabetes rats with periodontitis. PMID- 29240823 TI - Facebook Addiction Disorder (FAD) among German students-A longitudinal approach. AB - The present study aimed to investigate Facebook Addiction Disorder (FAD) in a German student sample over a period of one year. While mean FAD level did not increase during the investigation period, a significant increase was shown in the number of participants reaching the critical cutoff score. FAD was significantly positively related to the personality trait narcissism and to negative mental health variables (depression, anxiety, and stress symptoms). Furthermore, FAD fully mediated the significant positive relationship between narcissism and stress symptoms, which demonstrates that narcissistic people can be specifically at risk to develop FAD. Present results give a first overview of FAD in Germany. Practical applications for future studies and limitations of present results are discussed. PMID- 29240824 TI - High abundance of ArfGAP1 found in the mossy fibers in hilus of the dentate gyrus region of the mouse brain. AB - The Arf GTPase-activating protein ArfGAP1 and its brain-specific isoform ArfGAP1B play an important role in neurotransmission. Here we analyzed the distribution of ArfGAP1 in the mouse brain. We found high levels of ArfGAP1 in the mouse dentate gyrus where it displayed especially elevated level in the polymorph layer (hilus). Importantly, the ArfGAP1 signal follows the pathway of the granular cell axons so-called mossy fibers which extend from the dentate gyrus to CA3 via stratum lucidum and partially stratum oriens. Additionally, we identified differential expression of ArfGAP1 in the isocortex. Thus, staining with anti ArfGAP1 antibodies allows distinction between cortical cell layers 1, 2, 3 and 5 from 4 and 6. Taken together, our data suggest that ArfGAP1 can be used as a specific marker of the dentate mossy fibers and as for visualization of cortical layers in immunohistochemical studies. PMID- 29240825 TI - False friends: Phagocytes as Trojan horses in microbial brain infections. PMID- 29240826 TI - PamR, a new MarR-like regulator affecting prophages and metabolic genes expression in Bacillus subtilis. AB - B. subtilis adapts to changing environments by reprogramming its genetic expression through a variety of transcriptional regulators from the global transition state regulators that allow a complete resetting of the cell genetic expression, to stress specific regulators controlling only a limited number of key genes required for optimal adaptation. Among them, MarR-type transcriptional regulators are known to respond to a variety of stresses including antibiotics or oxidative stress, and to control catabolic or virulence gene expression. Here we report the characterization of the ydcFGH operon of B. subtilis, containing a putative MarR-type transcriptional regulator. Using a combination of molecular genetics and high-throughput approaches, we show that this regulator, renamed PamR, controls directly its own expression and influence the expression of large sets of prophage-related and metabolic genes. The extent of the regulon impacted by PamR suggests that this regulator reprograms the metabolic landscape of B. subtilis in response to a yet unknown signal. PMID- 29240827 TI - Diagnostic accuracy research in glaucoma is still incompletely reported: An application of Standards for Reporting of Diagnostic Accuracy Studies (STARD) 2015. AB - BACKGROUND: Research has shown a modest adherence of diagnostic test accuracy (DTA) studies in glaucoma to the Standards for Reporting of Diagnostic Accuracy Studies (STARD). We have applied the updated 30-item STARD 2015 checklist to a set of studies included in a Cochrane DTA systematic review of imaging tools for diagnosing manifest glaucoma. METHODS: Three pairs of reviewers, including one senior reviewer who assessed all studies, independently checked the adherence of each study to STARD 2015. Adherence was analyzed on an individual-item basis. Logistic regression was used to evaluate the effect of publication year and impact factor on adherence. RESULTS: We included 106 DTA studies, published between 2003-2014 in journals with a median impact factor of 2.6. Overall adherence was 54.1% for 3,286 individual rating across 31 items, with a mean of 16.8 (SD: 3.1; range 8-23) items per study. Large variability in adherence to reporting standards was detected across individual STARD 2015 items, ranging from 0 to 100%. Nine items (1: identification as diagnostic accuracy study in title/abstract; 6: eligibility criteria; 10: index test (a) and reference standard (b) definition; 12: cut-off definitions for index test (a) and reference standard (b); 14: estimation of diagnostic accuracy measures; 21a: severity spectrum of diseased; 23: cross-tabulation of the index and reference standard results) were adequately reported in more than 90% of the studies. Conversely, 10 items (3: scientific and clinical background of the index test; 11: rationale for the reference standard; 13b: blinding of index test results; 17: analyses of variability; 18; sample size calculation; 19: study flow diagram; 20: baseline characteristics of participants; 28: registration number and registry; 29: availability of study protocol; 30: sources of funding) were adequately reported in less than 30% of the studies. Only four items showed a statistically significant improvement over time: missing data (16), baseline characteristics of participants (20), estimates of diagnostic accuracy (24) and sources of funding (30). CONCLUSIONS: Adherence to STARD 2015 among DTA studies in glaucoma research is incomplete, and only modestly increasing over time. PMID- 29240828 TI - Ten simple rules for writing a career development award proposal. PMID- 29240829 TI - CELSR2 is a candidate susceptibility gene in idiopathic scoliosis. AB - A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c.G6859A change in exon 21 (NM_001408), leading to a predicted p.V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance. PMID- 29240830 TI - A low fat diet ameliorates pathology but retains beneficial effects associated with CPT1b knockout in skeletal muscle. AB - Inhibiting fatty acid oxidation is one approach to lowering glucose levels in diabetes. Skeletal muscle specific Carnitine Palmitoyltransferase 1b knockout mice (Cpt1bm-/-) comprise a model of impaired fat oxidation; and have decreased fat mass and enhanced glucose disposal and muscle oxidative capacity compared to controls. However, unfavorable effects occur relative to controls when Cpt1bm-/- mice are fed a 25% fat diet, including decreased activity and fat free mass and increased intramuscular lipid and serum myoglobin. In this study we explore if a low fat, high carbohydrate diet can ablate the unfavorable effects while maintaining the favorable phenotype in Cpt1bm-/- mice. Mice were fed either 10% fat (low fat) or 25% fat (chow) diet. Body composition was measured biweekly and indirect calorimetry was performed. Low fat diet abolishes the decreased activity, fat, and fat free mass seen in Cpt1bm-/- mice fed chow diet. Low fat diet also reduces serum myoglobin levels in Cpt1bm-/- mice and diminishes differences in IGF-1 seen between Cpt1bm-/- mice and control mice fed chow diet. Glucose tolerance tests reveal that glucose clearance is improved in Cpt1bm-/- mice relative to controls regardless of diet, and serum analysis shows increased levels of muscle derived FGF21. Electron microscopic analyses and measurements of mRNA transcripts show increased intramuscular lipids, FGF21, mitochondrial and oxidative capacity markers regardless of diet. The favorable metabolic phenotype of Cpt1bm-/- mice therefore remains consistent regardless of diet; and a combination of a low fat diet and pharmacological inhibition of CPT1b may offer remedies to reduce blood glucose. PMID- 29240832 TI - Correction: Short-term leprosy forecasting from an expert opinion survey. AB - [This corrects the article DOI: 10.1371/journal.pone.0182245.]. PMID- 29240831 TI - Comparative transcriptome profiling of virulent and non-virulent Trypanosoma cruzi underlines the role of surface proteins during infection. AB - Trypanosoma cruzi, the protozoan that causes Chagas disease, has a complex life cycle involving several morphologically and biochemically distinct stages that establish intricate interactions with various insect and mammalian hosts. It has also a heterogeneous population structure comprising strains with distinct properties such as virulence, sensitivity to drugs, antigenic profile and tissue tropism. We present a comparative transcriptome analysis of two cloned T. cruzi strains that display contrasting virulence phenotypes in animal models of infection: CL Brener is a virulent clone and CL-14 is a clone that is neither infective nor pathogenic in in vivo models of infection. Gene expression analysis of trypomastigotes and intracellular amastigotes harvested at 60 and 96 hours post-infection (hpi) of human fibroblasts revealed large differences that reflect the parasite's adaptation to distinct environments during the infection of mammalian cells, including changes in energy sources, oxidative stress responses, cell cycle control and cell surface components. While extensive transcriptome remodeling was observed when trypomastigotes of both strains were compared to 60 hpi amastigotes, differences in gene expression were much less pronounced when 96 hpi amastigotes and trypomastigotes of CL Brener were compared. In contrast, the differentiation of the avirulent CL-14 from 96 hpi amastigotes to extracellular trypomastigotes was associated with considerable changes in gene expression, particularly in gene families encoding surface proteins such as trans-sialidases, mucins and the mucin associated surface proteins (MASPs). Thus, our comparative transcriptome analysis indicates that the avirulent phenotype of CL-14 may be due, at least in part, to a reduced or delayed expression of genes encoding surface proteins that are associated with the transition of amastigotes to trypomastigotes, an essential step in the establishment of the infection in the mammalian host. Confirming the role of members of the trans-sialidase family of surface proteins for parasite differentiation, transfected CL-14 constitutively expressing a trans-sialidase gene displayed faster kinetics of trypomastigote release in the supernatant of infected cells compared to wild type CL-14. PMID- 29240834 TI - Discovery of carbamate degrading enzymes by functional metagenomics. AB - Bioremediation of pollutants is a major concern worldwide, leading to the research of new processes to break down and recycle xenobiotics and environment contaminating polymers. Among them, carbamates have a very broad spectrum of uses, such as toxinogenic pesticides or elastomers. In this study, we mined the bovine rumen microbiome for carbamate degrading enzymes. We isolated 26 hit clones exhibiting esterase activity, and were able to degrade at least one of the targeted polyurethane and pesticide carbamate compounds. The most active clone was deeply characterized. In addition to Impranil, this clone was active on Tween 20, pNP-acetate, butyrate and palmitate, and on the insecticide fenobucarb. Sequencing and sub-cloning of the best target revealed a novel carboxyl-ester hydrolase belonging to the lipolytic family IV, named CE_Ubrb. This study highlights the potential of highly diverse microbiota such as the ruminal one for the discovery of promiscuous enzymes, whose versatility could be exploited for industrial uses. PMID- 29240835 TI - Scientific research on animal biodiversity is systematically biased towards vertebrates and temperate regions. AB - Over the last 25 years, research on biodiversity has expanded dramatically, fuelled by increasing threats to the natural world. However, the number of published studies is heavily weighted towards certain taxa, perhaps influencing conservation awareness of and funding for less-popular groups. Few studies have systematically quantified these biases, although information on this topic is important for informing future research and conservation priorities. We investigated: i) which animal taxa are being studied; ii) if any taxonomic biases are the same in temperate and tropical regions; iii) whether the taxon studied is named in the title of papers on biodiversity, perhaps reflecting a perception of what biodiversity is; iv) the geographical distribution of biodiversity research, compared with the distribution of biodiversity and threatened species; and v) the geographical distribution of authors' countries of origin. To do this, we used the search engine Web of Science to systematically sample a subset of the published literature with 'biodiversity' in the title. In total 526 research papers were screened-5% of all papers in Web of Science with biodiversity in the title. For each paper, details on taxonomic group, title phrasing, number of citations, study location, and author locations were recorded. Compared to the proportions of described species, we identified a considerable taxonomic weighting towards vertebrates and an under-representation of invertebrates (particularly arachnids and insects) in the published literature. This discrepancy is more pronounced in highly cited papers, and in tropical regions, with only 43% of biodiversity research in the tropics including invertebrates. Furthermore, while papers on vertebrate taxa typically did not specify the taxonomic group in the title, the converse was true for invertebrate papers. Biodiversity research is also biased geographically: studies are more frequently carried out in developed countries with larger economies, and for a given level of species or threatened species, tropical countries were understudied relative to temperate countries. Finally, biodiversity research is disproportionately authored by researchers from wealthier countries, with studies less likely to be carried out by scientists in lower-GDP nations. Our results highlight the need for a more systematic and directed evaluation of biodiversity studies, perhaps informing more targeted research towards those areas and taxa most depauperate in research. Only by doing so can we ensure that biodiversity research yields results that are relevant and applicable to all regions and that the information necessary for the conservation of threatened species is available to conservation practitioners. PMID- 29240833 TI - Vagal nerve stimulation triggers widespread responses and alters large-scale functional connectivity in the rat brain. AB - Vagus nerve stimulation (VNS) is a therapy for epilepsy and depression. However, its efficacy varies and its mechanism remains unclear. Prior studies have used functional magnetic resonance imaging (fMRI) to map brain activations with VNS in human brains, but have reported inconsistent findings. The source of inconsistency is likely attributable to the complex temporal characteristics of VNS-evoked fMRI responses that cannot be fully explained by simplified response models in the conventional model-based analysis for activation mapping. To address this issue, we acquired 7-Tesla blood oxygenation level dependent fMRI data from anesthetized Sprague-Dawley rats receiving electrical stimulation at the left cervical vagus nerve. Using spatially independent component analysis, we identified 20 functional brain networks and detected the network-wise activations with VNS in a data-driven manner. Our results showed that VNS activated 15 out of 20 brain networks, and the activated regions covered >76% of the brain volume. The time course of the evoked response was complex and distinct across regions and networks. In addition, VNS altered the strengths and patterns of correlations among brain networks relative to those in the resting state. The most notable changes in network-network interactions were related to the limbic system. Together, such profound and widespread effects of VNS may underlie its unique potential for a wide range of therapeutics to relieve central or peripheral conditions. PMID- 29240836 TI - Is quality of life different between diabetic and non-diabetic people? The importance of cardiovascular risks. AB - BACKGROUND: To analyse and compare the impact of cardiovascular risk factors and disease on health-related quality of life (HRQoL) in people with and without diabetes living in the community. METHODS: We used data of 1,905 people with diabetes and 19,031 people without diabetes from the last Spanish National Health Survey (years 2011-2012). The HRQoL instrument used was the EuroQol 5D-5L, based on time trade-off scores. Matching methods were used to assess any differences in the HRQoL in people with and without diabetes with the same characteristics (age, gender, education level, and healthy lifestyle), according to cardiovascular risk factors and diseases. Disparities were also analysed for every dimension of HRQoL: mobility, daily activities, personal care, pain/discomfort, and anxiety/depression. RESULTS: There were no significant differences in time trade off scores between people with and without diabetes when cardiovascular risk factors or established cardiovascular disease were not present. However, when cardiovascular risk factors were present, the HRQoL score was significantly lower in people with diabetes than in those without. This difference was indeed greater when cardiovascular diseases were present. More precisely, people with diabetes and any of the cardiovascular risk factors, who have not yet developed any cardiovascular disease, report lower HRQoL, 0.046 TTO score points over 1 (7.93 over 100 in the VAS score) compared to those without diabetes, and 0.14 TTO score points of difference (14.61 over 100 in the VAS score) if cardiovascular diseases were present. In fact, when the three risk factors were present in people with diabetes, HRQoL was significantly lower (0.10 TTO score points over 1 and 10.86 points over 100 in VAS score), obesity being the most influential risk factor. CONCLUSIONS: The presence of established cardiovascular disease and/or cardiovascular risk factors, specially obesity, account for impaired quality of life in people with diabetes. PMID- 29240837 TI - The impact of self-avatars on trust and collaboration in shared virtual environments. AB - A self-avatar is known to have a potentially significant impact on the user's experience of the immersive content but it can also affect how users interact with each other in a shared virtual environment (SVE). We implemented an SVE for a consumer virtual reality system where each user's body could be represented by a jointed self-avatar that was dynamically controlled by head and hand controllers. We investigated the impact of a self-avatar on collaborative outcomes such as completion time and trust formation during competitive and cooperative tasks. We used two different embodiment levels: no self-avatar and self-avatar, and compared these to an in-person face to face version of the tasks. We found that participants could finish the task more quickly when they cooperated than when they competed, for both the self-avatar condition and the face to face condition, but not for the no self-avatar condition. In terms of trust formation, both the self-avatar condition and the face to face condition led to higher scores than the no self-avatar condition; however, collaboration style had no significant effect on trust built between partners. The results are further evidence of the importance of a self-avatar representation in immersive virtual reality. PMID- 29240838 TI - Recognized focused practice: Does sub-specialty designation offer value to the neurosurgeon? AB - Vehicles for life-long assessment such as Maintenance of Certification tend to focus on generalist neurosurgical knowledge. However, as neurosurgeons advance in their careers, they tend to narrow their practice and increase volumes in certain specific types of operations. Failing to test the type of procedures most relevant to the practitioner is a lost opportunity to improve the knowledge and practice of the individual neurosurgeon. In this study, we assess the neurosurgical community's appetite for designations of board-recognized Recognized Focused Practice (RFP). We administered a validated, online, confidential survey to 4,899 neurosurgeons (2,435 American Board of Neurological Surgery (ABNS) Diplomates participating in MOC, 1,440 Diplomates certified prior to 1999 (grandfathered), and 1,024 retired Diplomates). We received 1,449 responses overall (30% response rate). A plurality of respondents were in practice 11-15 years (18.5%), in private practice (40%) and participate in MOC (61%). 49% of respondents felt that a RFP designation would not be helpful. For the 30% who felt that RFP would be helpful, 61.3% felt that it would support recognition by their hospital or practice, it would motivate them to stay current on medical knowledge (53.4%), or it would help attract patients (46.4%;). The most popular suggestions for RFP were Spine (56.2%), Cerebrovascular (62.9%), Pediatrics (64.1%), and Functional/Stereotactic (52%). A plurality of neurosurgeons (35.7%) felt that RFP should recognize neurosurgeons with accredited and non-accredited fellowship experience and sub-specialty experience. Ultimately, Recognized Focused Practice may provide value to individual neurosurgeons, but the neurosurgical community shows tepid interest for pursuing this designation. PMID- 29240840 TI - A simplified model of biosonar echoes from foliage and the properties of natural foliages. AB - Foliage echoes could play an important role in the sensory ecology of echolocating bats, but many aspects of their sensory information content remain to be explored. A realistic numerical model for these echoes could support the development of hypotheses for the relationship between foliage properties and echo parameters. In prior work by the authors, a simple foliage model based on circular disks distributed uniformly in space has been developed. In the current work, three key simplifications used in this model have been examined: (i) representing leaves as circular disks, (ii) neglecting shading effects between leaves, and (iii) the uniform spatial distribution of the leaves. The target strengths of individual leaves and shading between them have been examined in physical experiments, whereas the impact of the spatial leaf distribution has been studied by modifying the numerical model to include leaf distributions according to a biomimetic model for natural branching patterns (L-systems). Leaf samples from a single species (leatherleaf arrowwood) were found to match the relationship between size and target strength of the disk model fairly well, albeit with a large variability part of which could be due to unaccounted geometrical features of the leaves. Shading between leaf-sized disks did occur for distances below 50 cm and could hence impact the echoes. Echoes generated with L-system models in two distinct tree species (ginkgo and pine) showed consistently more temporal inhomogeneity in the envelope amplitudes than a reference with uniform distribution. However, these differences were small compared to effects found in response to changes in the relative orientation of simulated sonar beam and foliage. These findings support the utility of the uniform leaf distribution model and suggest that bats could use temporal inhomogeneities in the echoes to make inferences regarding the relative positioning of their sonar and a foliage. PMID- 29240839 TI - The soluble loop BC region guides, but not dictates, the assembly of the transmembrane cytochrome b6. AB - Studying folding and assembly of naturally occurring alpha-helical transmembrane proteins can inspire the design of membrane proteins with defined functions. Thus far, most studies have focused on the role of membrane-integrated protein regions. However, to fully understand folding pathways and stabilization of alpha helical membrane proteins, it is vital to also include the role of soluble loops. We have analyzed the impact of interhelical loops on folding, assembly and stability of the heme-containing four-helix bundle transmembrane protein cytochrome b6 that is involved in charge transfer across biomembranes. Cytochrome b6 consists of two transmembrane helical hairpins that sandwich two heme molecules. Our analyses strongly suggest that the loop connecting the helical hairpins is not crucial for positioning the two protein "halves" for proper folding and assembly of the holo-protein. Furthermore, proteolytic removal of any of the remaining two loops, which connect the two transmembrane helices of a hairpin structure, appears to also not crucially effect folding and assembly. Overall, the transmembrane four-helix bundle appears to be mainly stabilized via interhelical interactions in the transmembrane regions, while the soluble loop regions guide assembly and stabilize the holo-protein. The results of this study might steer future strategies aiming at designing heme-binding four-helix bundle structures, involved in transmembrane charge transfer reactions. PMID- 29240842 TI - Analysis of ecological thresholds in a temperate forest undergoing dieback. AB - Positive feedbacks in drivers of degradation can cause threshold responses in natural ecosystems. Though threshold responses have received much attention in studies of aquatic ecosystems, they have been neglected in terrestrial systems, such as forests, where the long time-scales required for monitoring have impeded research. In this study we explored the role of positive feedbacks in a temperate forest that has been monitored for 50 years and is undergoing dieback, largely as a result of death of the canopy dominant species (Fagus sylvatica, beech). Statistical analyses showed strong non-linear losses in basal area for some plots, while others showed relatively gradual change. Beech seedling density was positively related to canopy openness, but a similar relationship was not observed for saplings, suggesting a feedback whereby mortality in areas with high canopy openness was elevated. We combined this observation with empirical data on size- and growth-mediated mortality of trees to produce an individual-based model of forest dynamics. We used this model to simulate changes in the structure of the forest over 100 years under scenarios with different juvenile and mature mortality probabilities, as well as a positive feedback between seedling and mature tree mortality. This model produced declines in forest basal area when critical juvenile and mature mortality probabilities were exceeded. Feedbacks in juvenile mortality caused a greater reduction in basal area relative to scenarios with no feedback. Non-linear, concave declines of basal area occurred only when mature tree mortality was 3-5 times higher than rates observed in the field. Our results indicate that the longevity of trees may help to buffer forests against environmental change and that the maintenance of old, large trees may aid the resilience of forest stands. In addition, our work suggests that dieback of forests may be avoidable providing pressures on mature and juvenile trees do not pass critical thresholds. PMID- 29240841 TI - Microcystin-LR does not induce alterations to transcriptomic or metabolomic profiles of a model heterotrophic bacterium. AB - Microcystins are secondary metabolites produced by several freshwater, bloom forming cyanobacterial species. Microcystin-producing cyanobacteria co-occur with a complex community of heterotrophic bacteria. Though conflicting, studies suggest that microcystins affect the physiology of heterotrophic bacteria by inducing oxidative stress and increasing cell envelope permeability. Based on these observations, we hypothesized that exposure to microcystin should induce differential expression in genes responding to oxidative and envelope stress and trigger shifts in metabolite pools. We tested this hypothesis by exposing Escherichia coli MG1655 to 1 and 10 mg/L microcystin-LR and monitored global changes to gene expression, cellular metabolite pools, and lipid composition using RNA-sequencing and UPLC-MS. Contrary to reported studies, we observed no evidence that microcystin-LR induced oxidative or cell envelope stress in E. coli under the tested conditions. Our results suggest a potential difference in mechanism by which microcystin-LR interacts with heterotrophic bacteria vs. cyanobacteria. PMID- 29240843 TI - Behavior of bacteriome symbionts during transovarial transmission and development of the Asian citrus psyllid. AB - The Asian citrus psyllid Diaphorina citri Kuwayama (Hemiptera: Liviidae) is a serious pest worldwide, transmitting Candidatus Liberibacter spp. (Alphaproteobacteria), the causative agents of a devastating citrus disease known as huanglongbing or greening disease. In a symbiotic organ called the bacteriome, D. citri possesses an organelle-like defensive symbiont, Candidatus Profftella armatura (Betaproteobacteria), and a nutritional symbiont, Ca. Carsonella ruddii (Gammaproteobacteria). Drastically reduced symbiont genomes and metabolic complementarity among the symbionts and D. citri indicate their mutually indispensable association. Moreover, horizontal gene transfer between the Profftella and Liberibacter lineages suggests ecological and evolutionary interactions between the bacteriome symbiont and the HLB pathogen. Using fluorescence in situ hybridization, we examined the behavior of Profftella and Carsonella during transovarial transmission and the development of D. citri. In the bacteriomes of sexually-mature female adults, symbionts transformed from an extremely elongated tubular form into spherical or short-rod forms, which migrated toward the ovary. The symbionts then formed mosaic masses, which entered at the posterior pole of the vitellogenic oocytes. After anatrepsis, Carsonella and Profftella migrated to the central and peripheral parts of the mass, respectively. Following the appearance of host nuclei, the mass cellularized, segregating Carsonella and Profftella in the central syncytium and peripheral uninucleate bacteriocytes, respectively. Subsequently, the uninucleate bacteriocytes harboring Profftella assembled at the posterior pole, while the syncytium, containing Carsonella, sat on the anterior side facing the germ band initiating katatrepsis. During dorsal closure, the syncytium was divided into uninuclear bacteriocytes, which surrounded the mass of bacteriocytes containing Profftella. Once fully surrounded, the bacteriocyte mass containing Profftella was fused into a syncytium. Prior to hatching, a pair of wing-like protrusions arose from both lateral sides of the bacteriome, which continued to grow throughout the nymphal stages. These findings provide a foundation for better understanding the intricate relationship between D. citri and its microbiota. PMID- 29240844 TI - Correction: Computational and biological evidences on the serotonergic involvement of SeTACN antidepressant-like effect in mice. AB - [This corrects the article DOI: 10.1371/journal.pone.0187445.]. PMID- 29240846 TI - Characterization of conditions and determination of practical tips for mtDNA level estimation in various human cells. AB - Determination of mtDNA copy number in the cell is crucial to understand many cellular processes. Recently, the number of studies with the use of mitochondrial DNA (mtDNA) content as the determinant of mitochondrial abnormalities increased greatly and is still growing, therefore, optimization of technical conditions for this analysis is crucial. Despite using similar laboratory protocols, some results cannot be compared between research centers, thus causing discrepancies in the assessment of mtDNA content. The aim of this work was to test which conditions of biological sample collection and storage affect estimation of mtDNA level relative to the nuclear DNA (nDNA) in the blood samples and dermal fibroblasts. We found that the time and temperature of sample storage, as well as the type of the blood sample (whole blood or leukocytes) influence the estimate of mtDNA/nDNA ratio in the blood. In the case of dermal fibroblasts collected from healthy control and Huntington disease patients, our data indicate that the passage number of cells is essential to obtain reliable results. PMID- 29240845 TI - Ras GAP-related and C-terminal domain-dependent localization and tumorigenic activities of IQGAP1 in melanoma cells. AB - IQGAP1 interacts with a number of binding partners through a calponin homology domain (CHD), a WW motif, IQ repeats, a Ras GAP-related domain (GRD), and a conserved C-terminal (CT) domain. Among various biological and cellular functions, IQGAP1 is known to play a role in actin cytoskeleton dynamics during membrane ruffling and lamellipodium protrusion. In addition, phosphorylation near the CT domain is thought to control IQGAP1 activity through regulation of intramolecular interaction. In a previous study, we discovered that IQGAP1 preferentially localizes to retracting areas in B16F10 mouse melanoma cells, not areas of membrane ruffling and lamellipodium protrusion. Nothing is known of the domains needed for retraction localization and very little is known of IQGAP1 function in the actin cytoskeleton of melanoma cells. Thus, we examined localization of IQGAP1 mutants to retracting areas, and characterized knock down phenotypes on tissue culture plastic and physiologic-stiffness hydrogels. Localization of IQGAP1 mutants (S1441E/S1443D, S1441A/S1443A, DeltaCHD, DeltaGRD or DeltaCT) to retracting and protruding cell edges were measured. In retracting areas there was a decrease in S1441A/S1443A, DeltaGRD and DeltaCT localization, a minor decrease in DeltaCHD localization, and normal localization of the S1441E/S1443D mutant. In areas of cell protrusion just behind the lamellipodium leading edge, we surprisingly observed both DeltaGRD and DeltaCT localization, and increased number of microtubules. IQGAP1 knock down caused loss of cell polarity on laminin-coated glass, decreased proliferation on tissue culture polystyrene, and abnormal spheroid growth on laminin-coated hydrogels. We propose that the GRD and CT domains regulate IQGAP1 localization to retracting actin networks to promote a tumorigenic role in melanoma cells. PMID- 29240848 TI - Hospitalists in the ICU: Necessary But Not Sufficient. AB - BACKGROUND: OBJECTIVE: DESIGN, SETTING, PATIENTS: INTERVENTION: MEASUREMENTS: CONCLUSIONS: PMID- 29240847 TI - Characterizing Hospitalist Practice and Perceptions of Critical Care Delivery. AB - BACKGROUND: Intensivist shortages have led to increasing hospitalist involvement in critical care delivery. OBJECTIVE: To characterize the practice of hospitalists practicing in the intensive care unit (ICU) setting. DESIGN: Survey of hospital medicine physicians. SETTING: This survey was conducted as a needs assessment for the ongoing efforts of the Critical Care Task Force of the Society of Hospital Medicine Education Committee. PARTICIPANTS: Hospitalists in the United States. INTERVENTION: An iteratively developed, 25-item, webbased survey. MEASUREMENTS: Results were compiled from all respondents then analyzed in subgroups. Various items were examined for correlations. RESULTS: A total of 425 hospitalists completed the survey. Three hundred and twenty-five (77%) provided critical care services, and 280 (66%) served as primary physicians in the ICU. Hospitalists were significantly more likely to serve as primary physicians in rural ICUs (85% of rural respondents vs 62% of nonrural; P < .001 for association). Half of the rural hospitalists who were primary physicians for ICU patients felt obliged to practice beyond their scope, and 90% at least occasionally perceived that they had insufficient support from board-certified intensivists. Among respondents serving as primary physicians for ICU patients, 67% reported at least moderate difficulty transferring patients to higher levels of ICU care. Difficulty transferring patients was the only item significantly correlated with the perception of being expected to practice beyond one's scope (P < .05 for association). CONCLUSIONS: Hospitalists frequently deliver critical care services without adequate training or support, most prevalently in rural hospitals. Without major changes in intensivist staffi ng or patient distribution, this is unlikely to change. PMID- 29240849 TI - The Association of Frailty with Discharge Disposition for Hospitalized Community Dwelling Elderly Patients. AB - BACKGROUND: OBJECTIVE: DESIGN, SETTING, PATIENTS: INTERVENTION: MEASUREMENTS: CONCLUSIONS: PMID- 29240850 TI - Hospitalist and Internal Medicine Leaders' Perspectives of Early Discharge Challenges at Academic Medical Centers. AB - Improving early discharges may improve patient flow and increase hospital capacity. We conducted a national survey of academic medical centers addressing the prevalence, importance, and effectiveness of early-discharge initiatives. We assembled a list of hospitalist and general internal medicine leaders at 115 US based academic medical centers. We emailed each institutional representative a 30 item online survey regarding early-discharge initiatives. The survey included questions on discharge prioritization, the prevalence and effectiveness of early discharge initiatives, and barriers to implementation. We received 61 responses from 115 institutions (53% response rate). Forty-seven (77%) "strongly agreed" or "agreed" that early discharge was a priority. "Discharge by noon" was the most cited goal (n = 23; 38%) followed by "no set time but overall goal for improvement" (n = 13; 21%). The majority of respondents reported early discharge as more important than obtaining translators for non-English-speaking patients and equally important as reducing 30-day readmissions and improving patient satisfaction. The most commonly reported factors delaying discharge were availability of postacute care beds (n = 48; 79%) and patient-related transport complications (n = 44; 72%). The most effective early discharge initiatives reported involved changes to the rounding process, such as preemptive identification and early preparation of discharge paperwork (n = 34; 56%) and communication with patients about anticipated discharge (n = 29; 48%). There is a strong interest in increasing early discharges in an effort to improve hospital throughput and patient flow. PMID- 29240851 TI - Off Target But Hitting the Mark. AB - BACKGROUND: OBJECTIVE: DESIGN, SETTING, PATIENTS: INTERVENTION: MEASUREMENTS: CONCLUSIONS: PMID- 29240852 TI - The Epidemiology and Clinical Associations of Portal Vein Thrombosis in Hospitalized Patients With Cirrhosis: A Nationwide Analysis From the National Inpatient Sample. AB - BACKGROUND: OBJECTIVE: DESIGN, SETTING, PATIENTS: INTERVENTION: MEASUREMENTS: CONCLUSIONS: PMID- 29240853 TI - The Evaluation of Medical Inpatients Who Are Admitted on Long-term Opioid Therapy for Chronic Pain. AB - Individuals who are on long-term opioid therapy (LTOT) for chronic noncancer pain are frequently admitted to the hospital with acute pain, exacerbations of chronic pain, or comorbidities. Consequently, hospitalists find themselves faced with complex treatment decisions in the context of uncertainty about the effectiveness of LTOT as well as concerns about risks of overdose, opioid use disorders, and adverse events. Our multidisciplinary team sought to synthesize guideline recommendations and primary literature relevant to assessing medical inpatients on LTOT, with the objective of assisting practitioners in balancing effective pain treatment and opioid risk reduction. We identified no primary studies or guidelines specific to assessing medical inpatients on LTOT. Recommendations from outpatient guidelines on LTOT and guidelines on pain management in acute-care settings include the following: evaluate both pain and functional status, differentiate acute from chronic pain, investigate the preadmission course of opioid therapy, obtain a psychosocial history, screen for mental health conditions, screen for substance use disorders, check state prescription drug monitoring databases, order urine drug immunoassays, detect use of sedative hypnotics, and identify medical conditions associated with increased risk of overdose and adverse events. Although approaches to assessing medical inpatients on LTOT can be extrapolated from related guidelines, observational studies, and small studies in surgical populations, more work is needed to address these critical topics for inpatients on LTOT. PMID- 29240854 TI - Upregulation of Extracellular Matrix Genes Corroborates Clinical Efcacy of Human Fibroblast-Derived Growth Factors in Skin Rejuvenation. AB - Skin care products may use various active ingredients to support skin rejuvenation including growth factors and other molecules that help to regenerate extracellular matrix (ECM) and promote skin repair. The biological effect of skin care products with a strong anti-aging claim was assessed in gene expression analyses using an in vitro human skin model. Application of products containing human fibroblast-derived growth factors resulted in signifcant upregulation of genes encoding ECM components including collagens and elastin. Human fibroblasts cultured under hypoxic conditions show increased gene expression of stem cell markers, and their conditioned media could possibly further support skin rejuvenation. Furthermore, a double-blind, randomized, placebo-controlled study was con-ducted in subjects with moderate to severe facial photodamage to assess the cosmetic clinical efficacy of a product containing human fibroblast-derived growth factors. The test product group demonstrated significantly greater reductions in the appearance of fne lines/wrinkles, coarse line/wrinkles, and overall photodamage, compared to the placebo group. Altogether, the results suggest that human fibroblast-derived growth factors support skin rejuvenation by stimulating dermal fibroblasts to generate ECM. PMID- 29240855 TI - Lawrence Transfer Factor: Transference of Specific Immune Memory by Dialyzable Leukocyte Extract from a CD8+ T Cell Line. AB - Lawrence transfer factor (TF) is defined as dialyzable leukocyte extract (DLE) that can transfer antigen-specific cell-mediated immunity from a person testing positive for the antigen in a delayed type hypersensitivity skin test manner to a person negative for the same antigen.A recent article by Myles et al1 has identified a DLE isolated from an established CD8+ T cell line capable of transferring antigen-specific immunity. The DLE contains a portion of the beta chain of the T cell receptor and additional nucleotide and protein factors that are being subjected to further modern biochemical analysis.After months of study that included interviews of TF physician-scientists, we conclude that an antigen specific TF exists for most, if not all, antigens. By working from a CD8+ T cell line with modern biochemical technology, it should be possible to identify and patent products capable of treating infectious diseases, antigen-responsive cancers, and autoimmune disorders. PMID- 29240856 TI - Combining Topical Psoriasis Treatment to Enhance Systemic and Phototherapy: A Review of the Literature. AB - Psoriasis is a chronic inflammatory skin disease that affects millions of people in the United States as well as worldwide. While there is currently no cure for psoriasis, many treatment options are available. Topical therapies are the mainstay for the majority of patients who have limited or mild psoriasis. Among these medications, topical vitamin D analogs (eg, calcipotriene) and corticosteroids (eg, betamethasone), and these drugs in combination, are the most widely prescribed psoriasis drugs and are the cornerstone of topical therapies. For patients with more severe disease, phototherapy, conventional systemic agents, and biologics are often indicated. Currently, the goal of treatment is to control the clinical symptoms of the skin, reduce systemic disease potential, and improve the patient's quality of life. Despite the availability of various therapeutic options for psoriasis, many patients go untreated, and even among those who are treated, many do not achieve complete resolution of the disease. The new consensus is to treat to a target of 1% or less of body surface area involvement. Innovative treatment strategies are needed to meet this goal and patients' desire to achieve clear skin. Combination therapies are widely used by physicians, and adjunctive topical therapies used with other antipsoriatic regimens have been demonstrated to provide many clinical benefits. This article reviews the most recently published clinical evidence of adjunctive use of topical agents with biologics, conventional systemic agents, and phototherapy, to better establish the role of topical agents in combination therapy for the treatment of psoriasis. PMID- 29240857 TI - The Latest Drugs and Small Molecule Inhibitors for Skin and Hair. AB - Biologic drugs, a novel class of agents engineered to target specific mediators of inflammation, and small-molecule inhibitors that penetrate the cell membrane to interact with targets inside a cell represent the cutting-edge of pharmacological biomedical therapeutics. Clinical studies have already demonstrated the effectiveness of this new generation of drugs in treating a variety of medical illnesses and conditions that were refractory to traditional treatments. This review aims to describe the latest available or currently in development drugs, biologic agents, and small molecule inhibitors for treatment of psoriasis, rosacea, alopecia areata, and atopic dermatitis. PMID- 29240858 TI - A Novel Multifactorial Approach to Developing Mild Laundry Detergents and Assessing Their Relative Mildness AB - INTRODUCTION: Dermatologists are becoming more aware of the irritant and allergic potential of laundry detergents that incorporate harsh surfactants and potentially sensitizing ingredients. It is difficult however for the physician to distinguish one laundry detergent from another because the only distinguishing feature advertised tends to be the lack of dyes and fragrances.DESIGN: A new objective method was developed for measuring the harshness of laundry detergents using a three-pronged laboratory testing approach consisting of zein, corneosurfametry, and cytokine testing. Combing these methods, a Detergent Mildness Index was created which conveniently provides a single value by which products can be compared.RESULTS: A new mild laundry detergent was formulated with ingredients carefully selected by dermatologists who are experts in con-tact dermatitis. The irritancy potential of the formula was measured using the Detergent mildness index score. Compared to 11 other commercial laundry detergents marketed for sensitive skin, the new formula is measurably the mildest formula.DISCUSSION: The Detergent Mildness Index provides dermatologists with an objective method to compare commercial laundry deter-gents. Currently the only method available is patch testing, this new test is able to more finely differentiate between products and thus enables more informed recommendations on laundry detergent choices for their patients with sensitive skin. PMID- 29240859 TI - Real-World Clinical Experience With Apremilast in a Large US Retrospective Cohort Study of Patients With Moderate to Severe Plaque Psoriasis. AB - OBJECTIVE: To examine real-world use and patient outcomes with apremilast, an oral PDE4 inhibitor, in the dermatology practice set-ting for treatment of patients with moderate to severe plaque psoriasis.

METHODS: This retrospective, multicenter, longitudinal, observational cohort study used Modernizing Medicine's electronic medi-cal record (EMR) database of 5000 US dermatology providers. There were 7517 adults aged >=18 years with a psoriasis diagnosis (ICD-9, ICD-10) who received apremilast therapy from October 1, 2015, to January 31, 2016, and were included in efficacy and safety analyses. Among patients who switched from non-apremilast to apremilast monotherapy, the majority (74.2%) switched from prior topical treatment. RESULTS: At apremilast initiation, in systemic-naive and systemic-experienced patients, mean (SD) Physician Global Assessment (PGA) was 2.79 (0.13) and 2.48 (0.15); mean (SD) psoriasis-affected body surface area (BSA) was 17.85% (2.27) and 12.93% (2.59); and mean itch numeric rating scale (NRS; 0=no itch, 10=worst itch possible) score was 4.14 and 3.82, respectively. Within 6 months of apremilast initiation, PGA decreased (mean [SD]) in systemic-naive patients (-1.71 [0.19], P less than0.001) and systemic experienced patients (-1.02 [0.18], P less than 0.001); 26.8% (systemic-naive) and 25.5% (systemic-experienced) of patients achieved a PGA score of 0 or 1. Likewise, statistically significant reductions in BSA were noted in systemic naive patients (~62% reduction from baseline; P less than 0.01) and systemic experienced patients (~60% reduction from baseline; P=0.002). Mean itch NRS decreased to 2.38 in systemic-naive patients (P=0.139) and 0.0 in systemic experienced patients (P=0.034). Of 160 patients with >=1 assessment of patient perceived overall treatment effectiveness, 138 (86.2%) strongly/somewhat agreed apremilast was effective in clearing their skin of psoriasis. For safety analyses, body weight was available in the EMR database and decreased in systemic naive patients (-1.75 kg) and systemic-experienced patients (-1.09 kg). CONCLUSIONS: Findings support the effectiveness of apremilast in patients with moderate to severe psoriasis in dermatology clinical practices. Patients perceived apremilast to be effective. PMID- 29240860 TI - Cost Per Additional Responder Associated With Ixekizumab and Etanercept in the Treatment of Moderate-to-Severe Psoriasis. AB - BACKGROUND: Newer psoriasis treatments can achieve greater levels of efficacy than older systemic therapies; however, current psoriasis costs are substantial. We sought to estimate costs per additional responder associated with ixekizumab and etanercept, versus placebo, using efficacy data from phase 3 clinical trials (UNCOVER-2 and UNCOVER-3).METHODS: In UNCOVER-2/UNCOVER-3, patients received subcutaneous placebo, etanercept 50 mg twice weekly (BIW), or ixekizumab one 80 mg injection every 2 weeks (Q2W) after a 160-mg starting dose. Twelve-week induction-phase Psoriasis Area and Severity Index (PASI) 75, PASI 90, and PASI 100 response rates for ixekizumab, etanercept, and placebo were obtained from pooled data from the overall and United States (US) subgroup intention-to-treat (ITT) populations, and used to calculate numbers needed to treat (NNTs) to achieve one additional PASI 75, PASI 90, or PASI 100 response for ixekizumab Q2W and etanercept BIW versus placebo. Twelve-week drug costs per patient were calculated based on the UNCOVER-2/UNCOVER-3 dosing schedule and wholesale acquisition costs. Mean costs per additional responder for PASI 75, PASI 90, and PASI 100 for each treatment versus placebo were calculated for pooled UN-COVER 2/UNCOVER-3 overall and US subgroup ITT populations.RESULTS: Pooled overall ITT population: costs per additional PASI 75, PASI 90, or PASI 100 responder were US $37,540, US $46,299, or US $80,710 for ixekizumab Q2W and US $57,533, US $120,720, or US $404,695 for etanercept BIW, respectively. US subgroup ITT population: costs per additional PASI 75, PASI 90, or PASI 100 responder were US $38,165, US $49,740, or US $93,536 for ixekizumab Q2W and US $69,580, US $140,881, or US $631,875 for etanercept BIW, respectively. CONCLUSIONS: Twelve week costs per additional responder were lower for ixekizumab Q2W than for etanercept BIW across all levels of clearance (PASI 75, PASI 90, and PASI 100) in the pooled UNCOVER-2/UNCOVER-3 overall and US subgroup ITT populations. PMID- 29240861 TI - A Systematic Review of Lower Lip Anatomy, Mechanics of Local Flaps, and Special Considerations for Lower Lip Reconstruction. AB - Reconstruction of defects of the lower lip can be very challenging. The aim of this review is to analyze the unique characteristics of lower lip anatomy and provide a systematic approach for lower lip reconstruction. A review of current literature was performed using the PubMed database. Articles analyzing the anatomic and histologic characteristics of the lower lip, mechanics of local faps, and different lower lip reconistruction techniques were included. Articles focused on lower lip reconstruction with free faps were excluded. The orbicularis oris has been described as the main supportive mechanism, however, a number of other structures have been shown to provide mechanical support to the lower lip, including septations of connective tissue extending from the epithelium to the orbicularis oris, a fbroelastic meshwork located in the mentolabial sulcus, and subdermal muscular fibers with dermal terminations in the area of the modiolus. Depending on the location, size, and depth of the wound, a number of reconstruction options are available. Preservation of the competency of orbicularis oris, relation-ship of the modiolus with associated muscles, and sensation, are critical components of functional reconstruction. Primary closure and local faps are assessed for these 3 components and analysis is provided. In conclusion, knowledge of the static and dynamic structural support of the lower lip, as well as the characteristics of different reconstructive options, is imperative for optimal functional and aesthetic outcomes. PMID- 29240862 TI - "Deep Heating" Noninvasive Skin Tightening Devices: Review of Effectiveness and Patient Satisfaction. AB - Non-surgical aesthetic devices intended for treatment of lax and loose skin have gained popularity due to their ability to non-invasively improve patient's aesthetic condition and its low side effect profile. This study is intended to review available peer reviewed literature about Ultherapy, ThermaCool, and Exilis Ultra 360 non-invasive skin tightening devices to compare their treatment efficacy and patient subjective satisfaction. PMID- 29240863 TI - Long-Term Follow-up of Onychomycosis Patients Treated With Efinaconazole AB - BACKGROUND: Onychomycosis is a common disease that remains difficult to treat despite the introduction of new topical agents. Clinical trials on efinaconazole and tavaborole included 48 weeks' daily treatment regimens with a 4-week follow up. It has been suggested that either a longer treatment regimen or longer follow up would lead to even better results, primarily due to the time taken for the diseased nail to grow out, especially in those patients with more severe disease. OBJECTIVE: To investigate the impact of a longer follow-up period on the efficacy of efinaconazole 10% topical solution in patients with moderate-to-severe onychomycosis. METHODS: &Single center, open-labeled study in 23 subjects aged 18 80 years with a clinical and mycological diagnosis of moderate-to-severe dermatophyte toenail onychomycosis (40-75% clinical involvement). Subjects were treated with efinaconazole 10% solution, once-daily for 48 weeks, with two 12 week post-treatment follow-ups (at week 60 and 72). Primary efficacy endpoint was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture). Secondary endpoints included mycologic cure rates and treatment success (defined as those patients who had at least a 50% improvement in affected toenail from baseline). RESULTS: Twenty-two subjects completed the study. Mean baseline age 59.4 years (range, 37-77), predominance of male subjects (73.9%). Median baseline severity 50% affected target toenail. At week 72, two subjects were complete cures and 56.5% of subjects achieved treatment success. There were no complete cures at week 48, but 39.1% achieved treatment success. Mycologic cure rates were 91.3% at week 48. Median percent affected target toenail reduced to 40%, and further to 25% (week 48 and 72, respectively). Treatment was well tolerated, with no adverse events related to medication. CONCLUSIONS: This single-center phase 4 study supports previous data showing good efficacy and tolerability of efinaconazole in moderately severe onychomycosis. Continued reduction in disease severity post treatment suggest that a longer follow-up of patients treated with efinaconazole would afford better efficacy results, as indicated by greater treatment success, and increase in number of subjects who became complete cures. PMID- 29240864 TI - Patient Awareness of Local Drug Price Variation and the Factors That Influence Pharmacy Choice: A Cross-sectional Survey Study AB - BACKGROUND: High out-of-pocket drug expenditures are increasingly common in dermatology. Patients may not be aware that prices vary among pharmacies and consequently may not shop for the lowest cost. OBJECTIVE: To determine what factors influence pharmacy choice and the effect of providing local prescription prices on pharmacy selection. We hypothesized that patients do not "shop around" due to lack of knowledge of price variation and would choose a pharmacy based on costs if educated on price disparity.METHODS: Between July and August 2016, we administered a cross-sectional anonymous survey to adults visiting four outpatient clinics at an academic tertiary care center in Washington, D.C. Participants answered questions before and after viewing a list of prescription drug prices from local pharmacies.RESULTS: 287 surveys were administered to a convenience sample of adults (age >= 18 and literate in English). Of the 287 participants, 218 fully completed the survey; 55.1% were women and 40.5% were over age 40. When considering a cost savings of $10-25, 65% would switch pharmacies if the distance were the same, and 21.3% would switch if the distance were 45-minutes further. After price education, fewer participants felt that drug price knowledge would ultimately influence pharmacy choice (P less than 0.0001). However, respondents' intended frequency of researching price online, calling a pharmacy to ask about price, and comparing price between pharmacies before filling a prescription all increased, compared to prior self-reported frequencies (P less than 0.001). Specifically, participants with $75,000-$99,999 income were more likely to compare prices than those with income below $45,000 (odds ratio [OR], 4.62; 95% confidence interval [CI], 1.24-17.28).CONCLUSION: In this study, pharmacy choice was more influenced by convenience than cost prior to drug price education. However, price education ultimately impacted intent to research prescription drug prices before selecting a pharmacy. Thus, knowledge of drug pricing may be useful in creating cost savings for patients. PMID- 29240865 TI - Mast Cell Burden in a Patient With Cutaneous Disease AB - Mastocytosis is a disease characterized by the abnormal clonal proliferation of mast cells in skin and/or extracutaneous organs, often relating to activating mutations of c-KIT. Histopathology special stains, such as Giemsa, Leder, and Toluidine blue, are key for the diagnosis of cutaneous mastocytosis (CM). In adults, skin lesions can be associated with systemic disease. Tryptase is a diagnostic marker in mastocytosis and thought to reflect the burden of mast cell disease. In this report, we present a case of cutaneous mast cell disease with associated findings of elevated serum tryptase and mast cell infiltration of the bone marrow consistent with indolent systemic mastocytosis. PMID- 29240866 TI - Pityriasis Folliculorum: Response to Topical Ivermectin AB - Pityriasis folliculorum has been described as a dry type of rosacea with extensive proliferation of Demodex folliculorum in pilosebaceous follicles of the skin. This skin condition is frequently difficult to manage, with various treatment options showing mixed efficacy. Oral ivermectin, a macrocyclic lactone parasiticide with anti-inflammatory and anti-parasitic effects, is one of the leading treatment modalities for demodicosis. Topical ivermectin has recently been FDA approved as therapy for rosacea. We present the case of a woman with pityriasis folliculorum who showed significant improvement from using topical ivermectin with no adverse events related to treatment. PMID- 29240867 TI - Management of Late-Onset, Recurrent Facial Nodular Reaction After Poly-L-Lactic (PLLA) Injections AB - Despite a well-established safety profile for poly-L-lactic acid (PLLA), known complications of nodules, papules and granulomas can occur. The author presents a case of late-onset facial nodules after treatment with PLLA dermal filler for facial volumization. The late-onset nodules appeared 16 months post-initial injection and were initially treated with intralesional steroids followed by 5 fluorouracil, and oral corticosteroids. It took over a year of treatment with oral corticosteroids and periodic intralesional steroid injections for the nodules to resolve. The author describes in detail the course of the nodules as well as the clinical management. PMID- 29240868 TI - Effectiveness of the Mohs and Close Technique in Increasing the Efficiency of a Mohs Micrographic Surgery. AB - Editor's note: JDD welcomes Letters to the Editor that discuss controversy surrounding a recently published article. Letters being considered for publication may be sent to the authors of the original article, who may be given the opportunity to reply. Letters will be published at the discretion of the Editors. PMID- 29240869 TI - Recalcitrant Diffuse Cutaneous Sarcoidosis With Perianal Involvement Responding to Adalimumab. AB -

Recalcitrant cutaneous sarcoidosis with perianal involvement is rare. To our knowledge we present the first documented case of cutaneous sarcoidosis with perianal involvement successfully treated with adalimumab.

J Drugs Dermatol. 2017;16(12):1305-1306.

. PMID- 29240870 TI - Practitioners Take Huge Risks Dealing With Rogue Drug Compounders. AB - . PMID- 29240871 TI - A rare phenotype of heterozygous Danon disease mimicking apical hypertrophic cardiomyopathy. PMID- 29240872 TI - Worldwide reporting of fatal outcomes after ticagrelor to the US Food and Drug Administration. PMID- 29240873 TI - Preliminary Results of the Use of a Stabilized Hypochlorous Acid Solution in the Management of Ralstonia Pickettii Biofilm on Silicone Breast Implants. AB - Background: Ralstonia Pickettii biofilms are associated with pocket infections following breast implant surgeries. Biofilm protects bacteria most topically applied antimicrobial irrigations. Objectives: To evaluate the effectiveness of four antimicrobial solutions on the planktonic form and established biofilm of Ralstonia Pickettii grown on 3 different types of silicone breast implants. Methods: Time kill assays at clinical concentrations of chlorhexidine gluconate, povidone iodine, triple-antibiotic solution, and a 0.025% hypochlorous acid solution stabilized in amber glass were evaluated. Normal saline was the control. Three types of silicone implants, two with a textured surface and one smooth surface, were selected. Planktonic assays were performed after implants were soaked for one, five, 30, and 120 minute time points. Biofilm assays were performed after 5 and 120 minutes of implant soak time. Both tests evaluated cell forming units (CFU/mL). Results: Triple antibiotic solution had no effect on R. pickettii and was dropped from the study. Remaining solutions showed total kill of planktonic bacteria at one minute. Saline control showed no significant effect on biofilm as anticipated. Stabilized hypochlorous acid was the only solution tested capable of eradicating R. pickettii biofilm on all implant surfaces tested within the first five minute soak time. Conclusions: Noncytotoxic, 0.025% hypochlorous acid in normal saline, stabilized in amber glass, successfully eradicated Ralstonia pickettii in planktonic and mature biofilm on three types of silicone implants during initial five minute soak time and may be the preferred antimicrobial solution for pocket lavage. This preliminary study requires further investigation. Leaching and implant compatibility testing is currently in progress. PMID- 29240875 TI - The expanding roles of Argonautes: RNA interference, splicing and beyond. AB - Argonaute (AGO) protein family is highly conserved in eukaryotes and prokaryotes, reflecting its evolutionarily indispensible role in maintaining normal life cycle of the organisms. Small RNA-guided, AGO-dependent RNA interference (RNAi) is a well-studied pathway for gene expression regulation, which can be performed at transcriptional, posttranscriptional or translational level. In addition to RNAi, growing pieces of evidence point to a novel role of AGOs in pre-mRNA (messenger RNA precursor) splicing in animals. Many noncoding RNAs (ncRNAs) share common structural features with protein-coding genes, indicating that these ncRNAs might be subject to AGO-mediated splicing. Finally, we provide a comprehensive view that RNAi, transcription and RNA splicing are highly interactive processes, all of which involve several key factors such as AGOs. In this regard, the AGO proteins contribute to orchestrate an exquisite gene regulatory network in vivo. However, more research efforts are needed to reach a thorough understanding of the AGO activities. PMID- 29240876 TI - Machine learning for classifying tuberculosis drug-resistance from DNA sequencing data. AB - Motivation: Correct and rapid determination of Mycobacterium tuberculosis (MTB) resistance against available tuberculosis (TB) drugs is essential for the control and management of TB. Conventional molecular diagnostic test assumes that the presence of any well-studied single nucleotide polymorphisms is sufficient to cause resistance, which yields low sensitivity for resistance classification. Summary: Given the availability of DNA sequencing data from MTB, we developed machine learning models for a cohort of 1839 UK bacterial isolates to classify MTB resistance against eight anti-TB drugs (isoniazid, rifampicin, ethambutol, pyrazinamide, ciprofloxacin, moxifloxacin, ofloxacin, streptomycin) and to classify multi-drug resistance. Results: Compared to previous rules-based approach, the sensitivities from the best-performing models increased by 2-4% for isoniazid, rifampicin and ethambutol to 97% (P < 0.01), respectively; for ciprofloxacin and multi-drug resistant TB, they increased to 96%. For moxifloxacin and ofloxacin, sensitivities increased by 12 and 15% from 83 and 81% based on existing known resistance alleles to 95% and 96% (P < 0.01), respectively. Particularly, our models improved sensitivities compared to the previous rules-based approach by 15 and 24% to 84 and 87% for pyrazinamide and streptomycin (P < 0.01), respectively. The best-performing models increase the area-under-the-ROC curve by 10% for pyrazinamide and streptomycin (P < 0.01), and 4-8% for other drugs (P < 0.01). Availability and implementation: The details of source code are provided at http://www.robots.ox.ac.uk/~davidc/code.php. Contact: david.clifton@eng.ox.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29240874 TI - Wheat genetic resources in the post-genomics era: promise and challenges. AB - Background: Wheat genetic resources have been used for genetic improvement since 1876, when Stephen Wilson (Transactions and Proceedings of the Botanical Society of Edinburgh 12: 286) consciously made the first wide hybrid involving wheat and rye in Scotland. Wide crossing continued with sporadic attempts in the first half of 19th century and became a sophisticated scientific discipline during the last few decades with considerable impact in farmers' fields. However, a large diversity of untapped genetic resources could contribute in meeting future wheat production challenges. Perspectives and Conclusion: Recently the complete reference genome of hexaploid (Chinese Spring) and tetraploid (Triticum turgidum ssp. dicoccoides) wheat became publicly available coupled with on-going international efforts on wheat pan-genome sequencing. We anticipate that an objective appraisal is required in the post-genomics era to prioritize genetic resources for use in the improvement of wheat production if the goal of doubling yield by 2050 is to be met. Advances in genomics have resulted in the development of high-throughput genotyping arrays, improved and efficient methods of gene discovery, genomics-assisted selection and gene editing using endonucleases. Likewise, ongoing advances in rapid generation turnover, improved phenotyping, envirotyping and analytical methods will significantly accelerate exploitation of exotic genes and increase the rate of genetic gain in breeding. We argue that the integration of these advances will significantly improve the precision and targeted identification of potentially useful variation in the wild relatives of wheat, providing new opportunities to contribute to yield and quality improvement, tolerance to abiotic stresses, resistance to emerging biotic stresses and resilience to weather extremes. PMID- 29240878 TI - Pulmonary sarcomatoid carcinoma: an analysis of a rare cancer from the Surveillance, Epidemiology, and End Results database. AB - OBJECTIVES: Pulmonary sarcomatoid carcinoma (PSC) is a rare malignant neoplasm that accounts for a small percentage of non-small-cell lung carcinoma (NSCLC). At least 10% of PSCs has a spindle and/or giant cell component, which is often associated with a poor prognosis. We reviewed the Surveillance, Epidemiology, and End Results (SEER) database for the clinicopathological characteristics and surgical outcomes of PSCs. METHODS: The SEER database (1973-2013) was queried for PSC. A comparison between PSC and other NSCLC patients was performed. Cox regression for overall survival (OS) and logistic regression for node-positive predictors were performed. A propensity-matched (1:2) analysis (including age, gender, grade and stage) among surgically treated cases was done to compare OS in PSC versus other NSCLCs. RESULTS: A total of 955 899 NSCLC patients were identified; of these, 4987 patients had been diagnosed with PSC (0.52%). Men represented 60.9% of cases, with a median age of 68 years. The median size of the tumour was 5 cm and 3.5 cm in PSCs and NSCLCs, respectively (P < 0.001). PSC patients had significantly less Stage I, more high-grade tumours, advanced T stage, N+ disease and M1 disease (P < 0.001). In the PSC cohort, the most significant predictor of N+ disease on multivariate analysis was advanced T stage (P < 0.001). Predictors of OS in Stages I/II PSC on multivariate analysis were advanced age [P < 0.001, hazard ratio (HR) = 1.03], male gender (P = 0.024, HR = 1.25), carcinosarcoma (P = 0.002, HR = 1.76), grade (P = 0.033, HR = 1.81), T stage (P = 0.003, HR = 1.75), N status (P = 0.001, HR = 1.90) and surgical resection (P < 0.001, HR = 0.58). Among matched surgically resected cohorts, a poorer prognosis for OS was evident in PSCs in early stages (I/II) than in other NSCLCs (P = 0.009). CONCLUSIONS: PSC patients present with more advanced stage and with worse survival outcomes than other NSCLC patients. While surgical resection conveys a survival advantage in PSC, this group represents a population at a high risk for relapse and should be evaluated for novel adjuvant therapies. PMID- 29240877 TI - Prepouch Ileitis After Ileal Pouch-anal Anastomosis: Patterns of Presentation and Risk Factors for Failure of Treatment. AB - Background and Aims: There is a lack in the literature about prepouch ileitis [PI], in particular regarding risk factors associated with failure of the medical treatment. Aim of the study is to analyse the characteristics of PI patients and to compare those who required surgery with those who were successfully treated with conservative therapy. Methods: All cases presenting a diagnosis of PI were included and analysed. Patients eventually requiring surgery were compared with those who were managed conservatively, for symptoms of presentation, endoscopic characteristics, and rate of response to medical treatment. A sub-analysis of outcomes based on the final histology was performed. Results: The overall incidence of PI among 1286 patients was 4.4% [57], after a median of 6.8 years from pouch surgery. Symptoms included increased frequency [26.4%], outlet obstruction [21%], and bleeding [15.8%]. Afferent limb stenosis affected 49.1% of patients. The comparison showed that patients requiring surgery had a higher rate of Crohn's disease and indeterminate colitis [42.1 vs 0% and 15.8 vs 2.6%, p < 0.0001], outlet obstruction as main symptom [47.4 vs 7.9%, p = 0.0023], and afferent limb stenosis [73.7 vs 36.8%, p = 0.008] at endoscopy. Rate of failure of medical treatment at 5 years was 8.2% in patients with ulcerative colitis and 75% in the presence of both indeterminate colitis and Crohn's disease [p < 0.0001]. Conclusions: Crohn's disease, indeterminate colitis, and stenosis with outlet obstruction are risk factors for failure of treatment after diagnosis of PI. Early aggressive therapy and surgery should be considered in these cases. PMID- 29240879 TI - Importance of post-approval real-word evidence. PMID- 29240882 TI - Surgical ablation for atrial fibrillation in mitral valve disease: impact of the maze procedure. PMID- 29240881 TI - Nrf2 promotes mutant K-ras/p53-driven pancreatic carcinogenesis. AB - The Keap1-Nrf2 system contributes to the maintenance of homeostasis by regulating oxidative stress responses in normal tissues and organs, and is exploited in various cancers for proliferation, survival and acquisition of therapy resistance. Pancreatic cancer remains one of the intractable cancers, despite the improved clinical outcomes of other types of cancer, due to its invasive and refractory nature to therapeutic intervention. The current study aimed to clarify the contribution of Nrf2 to pancreatic carcinogenesis using a pancreas-specific mutant K-ras and p53 (KPC) mouse model. Deletion of Nrf2 in KPC mice (KPCN) decreased the formation of precancerous lesions as well as the development of invasive pancreatic cancer. The pancreatic tumor-derived cancer cell lines from KPCN mouse showed decreased expression of glutathione S-transferases (GST), UDP glucuronosyltransferases (UGT) and ABC transporters. Along with these biochemical changes, cell lines from KPCN mice revealed increased sensitivity to oxidative stress and chemotherapeutic agent. The current study revealed that Nrf2 contributes to pancreatic carcinogenesis in a way distinct from the chemoresistance of lung and esophagus, and that Nrf2 could be a novel therapeutic target of pancreatic cancer. PMID- 29240880 TI - Assessment of Histological Remission in Ulcerative Colitis: Discrepancies Between Daily Practice and Expert Opinion. AB - Background and Aims: Histological remission [HR] is a potential treatment target in ulcerative colitis [UC]. Limited 'real world' data are available on the reliability of histological scoring when assessing minimal histological inflammation. The aim of this study was to investigate the reliability of UC histological scores in colonic biopsies showing mucosal healing [MH] and limited histological inflammation, and to compare the 'daily practice' histological assessment with expert reviews by gastrointestinal [GI] pathologists. Methods: We performed a retrospective single-centre study. Colonic biopsies from UC patients with MH [Mayo score <= 1] were included. All biopsies assessed in daily practice were reassessed by three blinded GI pathologists using three histological scores (Geboes score [GS], Riley score [RS], Harpaz [Gupta] Index [HGI]) and a global visual scale [GVS]. We evaluated inter- and intra-observer variation between GI pathologists and correlations between scores including the initial histological assessment using Cronbach's alpha and Spearman rho analysis. Results: In total, 270 biopsies from 39 UC patients were included. The inter-observer concordance for all histological indexes was substantial to almost perfect [GS 0.84; HGI 0.61; GVS 0.74, RS 0.91]. Correlation between the RS and GS was almost perfect [R = 0.86], but we found no correlation between the primary histological assessment and reassessment by GI pathologists. Conclusions: Current UC histological scores reliably assess limited histological inflammation in UC patients. The discrepancy between the initial histological assessment and the reassessment by dedicated GI pathologists suggests a gap between daily practice and academic expertise. This issue may limit the implementation of HR as a treatment target for UC in daily practice. PMID- 29240883 TI - Is a fatty liver (always or ever) bad for the heart? PMID- 29240885 TI - A chest tube misplaced in the heart? AB - A 69-year-old patient with a malignant right pleural effusion experienced an inadvertent chest tube insertion through the hepatic vein, which ended up in the right ventricle. This rare complication occurred using a 14-Fr Thal-Quick chest tube (Seldinger method). The chest tube was successfully removed in a non operative approach. PMID- 29240886 TI - Pope Francis champions Huntington's disease. PMID- 29240884 TI - A proposal for a comprehensive risk scoring system for predicting postoperative complications in octogenarian patients with medically operable lung cancer: JACS1303. AB - OBJECTIVES: Although some retrospective studies have reported clinicopathological scoring systems for predicting postoperative complications and survival outcomes for elderly lung cancer patients, optimized scoring systems remain controversial. METHODS: The Japanese Association for Chest Surgery (JACS) conducted a nationwide multicentre prospective cohort and enrolled a total of 1019 octogenarians with medically operable lung cancer. Details of the clinical factors, comorbidities and comprehensive geriatric assessment were recorded for 895 patients to develop a comprehensive risk scoring (RS) system capable of predicting severe complications. RESULTS: Operative (30 days) and hospital mortality rates were 1.0% and 1.6%, respectively. Complications were observed in 308 (34%) patients, of whom 81 (8.4%) had Grade 3-4 severe complications. Pneumonia was the most common severe complication, observed in 27 (3.0%) patients. Five predictive factors, gender, comprehensive geriatric assessment75: memory and Simplified Comorbidity Score (SCS): diabetes mellitus, albumin and percentage vital capacity, were identified as independent predictive factors for severe postoperative complications (odds ratio = 2.73, 1.86, 1.54, 1.66 and 1.61, respectively) through univariate and multivariate analyses. A 5-fold cross validation was performed as an internal validation to reconfirm these 5 predictive factors (average area under the curve 0.70). We developed a simplified RS system as follows: RS = 3 (gender: male) + 2 (comprehensive geriatric assessment 75: memory: yes) + 2 (albumin: <3.8 ng/ml) + 1 (percentage vital capacity: <=90) + 1 (SCS: diabetes mellitus: yes). CONCLUSIONS: The current series shows that octogenarians can be successfully treated for lung cancer with surgical resection with an acceptable rate of severe complications and mortality. We propose a simplified RS system to predict severe complications in octogenarian patients with medically operative lung cancer. Trial Registration Number: JACS1303 (UMIN000016756). PMID- 29240887 TI - Associations between unemployment and heavy episodic drinking from adolescence to midlife in Sweden and Finland. AB - Background: Unemployment and alcohol use have often been found to correlate and to act as risk factors for each other. However, only few studies have examined these associations at longitudinal settings extending over several life phases. Moreover, previous studies have mostly used total consumption or medical diagnoses as the indicator, whereas subclinical measures of harmful alcohol use, such as heavy episodic drinking (HED), have been used rarely. The aim of this study was to examine the associations between HED and unemployment from adolescence to midlife in two Nordic countries. Methods: Participants of separate cohort studies from Sweden and Finland were recruited at age 16 in 1981/1983 and followed up at ages 21/22, 30/32 and 43/42, (n = 1080/2194), respectively. Cross lagged autoregressive models were used to determine associations between HED and unemployment. Results: In the Swedish cohort, HED at ages 16 and 30 in men and HED at age 21 in women were associated with subsequent unemployment. In the Finnish cohort, we found corresponding associations at age 16 in women and at age 22 in men. However, the gender differences were not statistically significant. The associations from unemployment to HED were non-significant in both genders, in both cohorts and at all ages. Conclusions: Our results suggest that heavy drinkers are more likely to experience unemployment in subsequent years. The associations from HED to unemployment seem to exist through the life course from adolescence to midlife. More emphasis should be put on reducing alcohol related harms in order to improve labour-market outcomes. PMID- 29240888 TI - Barriers to contacting general practice with alarm symptoms of colorectal cancer: a population-based study. AB - Background: A prerequisite for general practitioners (GPs) being able to refer patients with cancer alarm symptoms for further investigations is that individuals present to the GP. Knowledge of barriers to help-seeking is, however, sparse. Objectives. The aim of this study was to analyse associations between the experience of recent-onset alarm symptom of colorectal cancer and four different barriers towards GP contact. Methods: A nationwide web-based cohort survey was conducted in 100000 individuals aged 20 years or above, randomly selected from the Danish Civil Registration System. Items regarding experience of four predefined alarm symptoms of colorectal cancer (rectal bleeding, abdominal pain, change in stool texture and change in stool frequency), decisions about contact to GPs and barriers towards GP contact were included. Results: A total of 37455 respondents over 40 years (51.8%) completed the questionnaire. The proportion of individuals with no contact to the GP varied between 69.8% and 79.8% for rectal bleeding and change in stool frequency, respectively. The most widely reported barriers were being worried about wasting the doctor's time and being too busy to make time to visit the doctor. Men with rectal bleeding significantly more often reported being worried about what the doctor might find. The proportion of individuals who reported barriers was, in general, higher among the youngest age group. Conclusion: Barriers to contacting the GP were frequent when experiencing alarm symptoms of colorectal cancer. Reporting the different barriers was significantly associated with gender and age. PMID- 29240890 TI - Drug Development for Multidrug-Resistant Bacteria: Why Compromise? PMID- 29240889 TI - GeoBoost: accelerating research involving the geospatial metadata of virus GenBank records. AB - Summary: GeoBoost is a command-line software package developed to address sparse or incomplete metadata in GenBank sequence records that relate to the location of the infected host (LOIH) of viruses. Given a set of GenBank accession numbers corresponding to virus GenBank records, GeoBoost extracts, integrates and normalizes geographic information reflecting the LOIH of the viruses using integrated information from GenBank metadata and related full-text publications. In addition, to facilitate probabilistic geospatial modeling, GeoBoost assigns probability scores for each possible LOIH. Availability and implementation: Binaries and resources required for running GeoBoost are packed into a single zipped file and freely available for download at https://tinyurl.com/geoboost. A video tutorial is included to help users quickly and easily install and run the software. The software is implemented in Java 1.8, and supported on MS Windows and Linux platforms. Contact: gragon@upenn.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29240892 TI - High-density lipoprotein (HDL) and infections: a versatile culprit. PMID- 29240893 TI - Risk and Reputation: Obstetricians, Cesareans, and Consent. AB - When physicians performed cesarean sections in the nineteenth century, they customarily sought agreement from all present before proceeding. In contrast, after the introduction of electronic fetal monitoring in the late 1960s, obstetricians obtained permission for a cesarean by offering a choice that ensured consent-give birth by cesarean or give birth vaginally to a damaged or dead baby. This article argues that the manner in which physicians obtained consent for cesareans in the nineteenth century was one factor that kept the cesarean rate low, while the manner in which physicians obtained consent in the late twentieth and early twenty-first centuries was one factor driving up the cesarean rate. The dissimilar approaches to consent did serve a common purpose, however. Each preserved physicians' reputations. With the surgery likely to end in a woman's death in the nineteenth century, consensus ensured that a bad outcome would be a shared burden. And because the fetal monitor, in exaggerating the risks of vaginal birth, changed the nature of the malpractice climate for obstetricians, the late-twentieth-century approach to consent similarly protected physicians. As one early twenty-first-century obstetrician quipped, "You don't get sued for doing a C-section. You get sued for not doing a C-section." PMID- 29240891 TI - Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation. AB - Context: The etiology of primary ovarian insufficiency (POI) remains unknown in most cases. Objective: We sought to identify the genes causing POI. Design: The study was a familial genetic study. Setting: The study was performed at two academic institutions. Patients: We identified a consanguineous Yemeni family in which four daughters had POI. A brother had azoospermia. Intervention: DNA was subjected to whole genome sequencing. Shared regions of homozygosity were identified using Truploidy and prioritized using the Variant Annotation, Analysis, and Search Tool with control data from 387 healthy subjects. Imaging and quantification of protein localization and mitochondrial function were examined in cell lines. Main Outcome: Homozygous recessive gene variants shared by the four sisters. Results: The sisters shared a homozygous stop gain mutation in exon 6 of PSMC3IP (c.489 C>G, p.Tyr163Ter) and a missense variant in exon 1 of CLPP (c.100C>T, p.Pro34Ser). The affected brother also carried the homozygous PSMC3IP mutation. Functional studies demonstrated mitochondrial fragmentation in cells infected with the CLPP mutation. However, no abnormality was found in mitochondrial targeting or respiration. Conclusions: The PSMC3IP mutation provides additional evidence that mutations in meiotic homologous recombination and DNA repair genes result in distinct female and male reproductive phenotypes, including delayed puberty and primary amenorrhea caused by POI (XX gonadal dysgenesis) in females but isolated azoospermia with normal pubertal development in males. The findings also suggest that the N-terminal missense mutation in CLPP does not cause substantial mitochondrial dysfunction or contribute to ovarian insufficiency in an oligogenic manner. PMID- 29240894 TI - Mucosal HIV Shedding During ART. PMID- 29240895 TI - Surgical ablation for atrial fibrillation in mitral valve disease: impact of the maze procedure-authors' response. PMID- 29240896 TI - Dechorionation and Permeabilization of Podisus nigrispinus (Heteroptera: Pentatomidae) Eggs: Limiting Factors for Cryopreservation. AB - Cryopreservation protocols have been developed for eggs of Diptera, Lepidoptera, and Hymenoptera; however, for Heteroptera, such as Podisus nigrispinus Dallas, 1851 (Pentatomidae), no procedures have been described yet. The objective of this study was to evaluate the processes of dechorionation and permeabilization on the viability of eggs of P. nigrispinus with different embryonic ages. In the laboratory, embryos of 24, 48, 72, and 96 h of age were submitted to sodium hydroxide, sodium hypochlorite, isopropyl, and hexane solutions for dechorionation and permeabilization. The experiment was carried out in a 4 * 8 factorial scheme. Sodium hydroxide affects embryo viability; however, 96-h-old embryos showed higher viability when compared with 24, 48, and 72-h-old embryos. Microscope observations showed that, after the treatments, the chorion of P. nigrispinus eggs was reduced to 5.11 +/- 0.30 um. These solutions for dechorionation and permeabilization of P. nigrispinus eggs together with embryonic age affect the viability of embryos to be cryopreserved. PMID- 29240897 TI - Factors influencing women in physical activity programs in Malaysia. AB - The majority of research on factors associated with women participation in physical activity (PA) has been in developed countries with limited research in developing countries. Few women in Malaysia are active at the recommended levels for health, and activity rates are less than developed countries. Little research has focused specially on physically active Malaysian women and the factors that contribute to them becoming and staying active in PA programs. This lack of knowledge hinders the tailored development and implementation of PA programs to meet their needs. The aim of this study was to identify the factors of participation in PA programs for Malaysian women. The social-ecological model was used to investigate and theme the factors. Focus group discussion was conducted with participants in six PA programs targeted specifically to women. Thirty-seven women were involved in the focus group discussion, with ages ranging from 19 to 82 years. Inductive and deductive content analysis was conducted from verbatim transcripts using NVivo. Inductive content analysis allowed raw data and second order themes to emerge. Findings revealed social support structures, tailored programs for women, and location were key contributors that encouraged women to participate in these programs. The similarity in contributors between women in non-western and western countries signifies a prime opportunity for bi-lateral relationships to be formed to enable the enhancement of program development relevant to different ethnicities and cultures within or across countries. PMID- 29240898 TI - Natural History of Contralateral Nodules After Lobectomy in Patients With Papillary Thyroid Carcinoma. AB - Background: Bilateral thyroid nodularity is considered an indication for total thyroidectomy in papillary thyroid carcinoma (PTC). However, the natural history and outcome of contralateral nodules have never been studied. Objective: To investigate the natural history of nonsuspicious contralateral nodules after lobectomy for PTC. Methods: We included patients who had one or more solid nodules (>=3 mm) in the contralateral lobe with benign cytology before surgery or small nonsuspicious nodules per ultrasonography. Results: One hundred and twelve patients were included. Median age was 57 years, and median size of the PTC (initial lobectomy) was 8 mm (range, 0.5 to 28 mm). On the contralateral side, the median size of nodules was 7 mm (range, 3 to 30 mm). Thirty-three nodules (29%) had fine-needle aspiration (FNA) before surgery, and all were benign. After a median follow-up of 6 years, median growth was zero (range, -20 to 19 mm). Twenty-six nodules (23%) increased >=3 mm in size (median, 6 mm; range, 4 to 19 mm). Twenty patients (18%) developed new nodules. Twelve patients (11%) underwent completion thyroidectomy for growth (three), suspicious FNA (seven; Bethesda III to V), malignancy (one), or unknown reason (one). Overall, according to the completion thyroidectomy specimen, six patients (5%) were diagnosed with contralateral PTC (five micro-PTCs, one 20 mm), and all were without evidence of disease at the end of follow-up. There were no surgical difficulties or local complications during completion surgery. Conclusions: Lobectomy for low-risk patients with a small PTC and nonsuspicious contralateral thyroid nodule(s) is a reliable and safe initial treatment option. In the few patients who required completion thyroidectomy, treatment with surgery and radioiodine was effective. PMID- 29240899 TI - Patient perceptions of receiving test results via online portals: a mixed-methods study. AB - Objective: Online portals provide patients with access to their test results, but it is unknown how patients use these tools to manage results and what information is available to promote understanding. We conducted a mixed-methods study to explore patients' experiences and preferences when accessing their test results via portals. Materials and Methods: We conducted 95 interviews (13 semistructured and 82 structured) with adults who viewed a test result in their portal between April 2015 and September 2016 at 4 large outpatient clinics in Houston, Texas. Semistructured interviews were coded using content analysis and transformed into quantitative data and integrated with the structured interview data. Descriptive statistics were used to summarize the structured data. Results: Nearly two-thirds (63%) did not receive any explanatory information or test result interpretation at the time they received the result, and 46% conducted online searches for further information about their result. Patients who received an abnormal result were more likely to experience negative emotions (56% vs 21%; P = .003) and more likely to call their physician (44% vs 15%; P = .002) compared with those who received normal results. Discussion: Study findings suggest that online portals are not currently designed to present test results to patients in a meaningful way. Patients experienced negative emotions often with abnormal results, but sometimes even with normal results. Simply providing access via portals is insufficient; additional strategies are needed to help patients interpret and manage their online test results. Conclusion: Given the absence of national guidance, our findings could help strengthen policy and practice in this area and inform innovations that promote patient understanding of test results. PMID- 29240900 TI - Evaluation of differential pulmonary perfusion using 99mTc macroaggregated albumin after the Fontan procedure. AB - OBJECTIVES: The Fontan procedure [total cavopulmonary connection (TCPC)] is the final palliation for patients with univentricular physiology. We studied differential perfusion ratio and percentage uptake of a radiotracer in different zones of each lung following TCPC. METHODS: Between July 2015 and June 2017, 45 patients underwent 99mTc macroaggregated albumin lung perfusion scan at a mean follow-up period of 49.3 +/- SD 26.1 days following TCPC. Differential perfusion ratio and percentage uptake of the radiotracer in the upper, middle and lower zones of each lung were calculated. RESULTS: Post-foot injection [inferior vena cava (IVC) injection], preferential flow to the lungs was as follows: left lung (n = 13, 30.2%), right lung (n = 13, 30.2%) and uniformly to both lungs (n= 17, 39.6%). Post-arm injection [superior vena cava (SVC) injection], preferential flow to the lungs was as follows: left lung (n = 13, 30.2%), right lung (n = 22, 51.2%) and uniformly to both lungs (n= 8, 18.6%). The middle zone was perfused the most in both lungs. Total lower zone mean perfusion was higher than the upper zone following both SVC injection and IVC injection (34.1 +/- SD 5.3% vs 17. +/- SD 4.1% and 33 +/- SD 5.0% vs 17.5 +/- SD 4.1%, respectively). In patients with bilateral SVC, post-IVC injection, 6 (75%) patients had preferential flow to the right lung, whereas post-SVC injection, preferential flow to the left lung was visualized in 7 (87.5%) patients. CONCLUSIONS: Following TCPC, IVC blood was distributed uniformly in both lungs. SVC blood preferentially perfused the right lung. The middle zone was perfused the most in both lungs. PMID- 29240901 TI - Daily Social Interactions and the Biological Stress Response: Are There Age Differences in Links Between Social Interactions and Alpha-Amylase? AB - Background and Objectives: According to the strength and vulnerability integration (SAVI) model, older people are better able to avoid negative social interactions than younger people, but when they do experience negative interactions, they are equally or more emotionally and physiologically reactive than younger people. Less is known about the links between daily negative and positive social encounters and the sympathetic adrenal medullary system (a key stress pathway) and whether there are age differences in these links. This study considers whether negative and positive social interactions are associated with diurnal alpha-amylase (a measure of the sympathetic adrenal medullary system) and whether there are differences in these links by age. Research Design and Methods: Participants were from the Daily Health, Stress, and Relationship Study, which includes a random sample of 89 individuals (aged 40-95) who completed 14 days of daily diary interviews and provided saliva samples four times a day (wake, 30 min after wake, lunch, and bedtime) for four of those days that were assayed for alpha-amylase. Results: Days in which people reported more negative interactions were associated with flatter morning declines in alpha-amylase, indicating greater stress. Links between positive interactions and diurnal alpha-amylase varied by age group. Discussion and Implications: Findings are consistent with the SAVI model indicating that older adults respond differently to social stimuli than younger people. PMID- 29240902 TI - Dose Dependency and a Functional Cutoff for TPO-Antibody Positivity During Pregnancy. AB - Objective: To investigate a dose dependency of thyroperoxidase antibody (TPOAb) concentrations in relation to thyroid function and premature delivery and define a population-based, pregnancy-specific, functional cutoff for TPOAb positivity. Design: Individual participant meta-analysis of three prospective birth cohorts: the Amsterdam Born Children and their Development study, and the Holistic Approach to Pregnancy. Setting: Population-based studies in the Netherlands (2002 to 2014). Participants: A total of 11,212 pregnant women (<20 weeks' gestation). Main Outcome Measures: Thyrotropin (TSH) and FT4 concentrations, premature delivery. Results: In all cohorts, there was a dose-dependent positive association of TPOAb concentrations with TSH concentrations, as well as a dose dependent negative association with FT4 concentrations during early pregnancy (all P < 0.0001). There was a dose-dependent association of TPOAb concentrations with the risk of premature delivery, which was also modified by TSH concentrations. Women with TPOAb concentrations from the 92nd percentile upward had a higher TSH and a higher risk of a TSH >2.5 mU/L (range, 19.4% to 51.3%). Stratified analyses showed that women with TPOAb concentrations below manufacturer cutoffs already had a higher risk of premature delivery, especially when TSH concentrations were high or in the high-normal range. Conclusions: This study demonstrated a dose-dependent relationship between TPOAbs and thyroid function as well as the risk of premature delivery. Furthermore, our results indicate that the currently used cutoffs for TPOAb positivity may be too high. Furthermore, the use of a population-based cutoff for TPOAbs may identify women with a clinically relevant extent of thyroid autoimmunity and a higher risk of premature delivery but that would not be considered TPOAb positive or eligible for treatment otherwise. PMID- 29240904 TI - Prostate cancers that 'Wnt' respond to abiraterone. PMID- 29240903 TI - Declining Mortality Rates in HIV-Infected People Who Inject Drugs During a Seek and-Treat Initiative in Vancouver, Canada, 1996-2014: A Prospective Cohort Study. AB - We estimated rates and predictors of death among a community-recruited prospective cohort of 961 human immunodeficiency virus (HIV)-infected people who inject drugs in Vancouver, Canada, between 1996 and 2014. The results demonstrated significant declines in age-adjusted all-cause and HIV-related mortality rates since 2010, coincident with the scale-up of a community-wide "seek-and-treat" campaign. PMID- 29240905 TI - Coronary autoregulation and assessment of stenosis severity without pharmacological vasodilation. AB - For identification of myocardial ischaemia by non-invasive imaging or invasive physiological assessment, administration of a vasodilating or positive inotropic agent is often considered indispensable to exhaust the cardiac compensation mechanisms. Indeed, microcirculatory dilatation is needed for assessment of myocardial perfusion or coronary blood flow. However, three different modalities exist that quantify myocardial ischaemia without recourse to pharmacological stress agents, using either myocardial contrast echocardiography, imaging of myocardial blood volume or invasive coronary pressure measurement with the instantaneous wave-free ratio (iFR). The theoretical framework of these vasodilator-free modalities revolves around the two innate mechanisms that protect the myocardium from ischaemia at rest: coronary autoregulation and arteriogenesis. Coronary autoregulation and metabolic dilatation form the putative processes that regulate microvascular tone and constitute of a complex interplay between metabolic factors, myogenic control, and endothelium-based control that each interact with coronary arterioles of a different size. Arteriogenesis describes the development of large calibre collateral arteries from a pre-existing network, triggered by occlusive coronary artery disease. Following these descriptions, the fundamental principles and the existing evidence of these three diagnostic modalities are reviewed. Emphasis is placed on iFR, which is clinically best applicable. Instantaneous wave-free ratio has proven to be an effective method to determine the haemodynamic significance of coronary stenoses in two recent large randomized clinical trials, together enrolling over 4500 patients. Ultimately, this review aims to clarify the theoretical rationale and to describe the clinical implications of functional stenosis assessment under resting conditions. PMID- 29240906 TI - Differential Inhibition of Helicoverpa armigera (Lep.: Noctuidae) Gut Digestive Trypsin by Extracted and Purified Inhibitor of Datura metel (Solanales: Solanaceae). AB - The cotton bollworm, Helicoverpa armigera Hubner (Lep: Noctuidae), is an economically important pest of numerous major food crops worldwide. Protease inhibitors from plants, expressed constitutively in transgenic crops, have potential for pest management as an alternative to chemical pesticides. In this study, a protease inhibitor was isolated, purified, and characterized from Datura metel L. seeds. The purity of the isolated inhibitor was confirmed by reverse phase high-performance liquid chromatography, and activity staining showed one major peak and one clear activity band for the protein. Electrophoretic studies following gel filtration and ion-exchange chromatography revealed two and one bands for purified proteins, respectively. Partial biochemical characterizations of the purified inhibitor were determined. Maximum inhibitory activity was observed at 40-45 degrees C (optimal temperature) when tested against gut extracts of fourth to sixth instar H. armigera larvae. Thermo-stability of the trypsin inhibitor against sixth instar larval midgut trypsin was observed up to 50 degrees C when incubated for 30 min and 2 h. Among metal ions tested, Fe2+, Cu2+, and Mn2+ were found to decrease the trypsin inhibitory activity, whereas Hg2+, Mg2+, K+, Zn2+, Na+, Ca2+, and Cd2+ were found to significantly increase the inhibitory effect. This trypsin inhibitor showed competitive inhibition where the apparent value of Michaelis-Menten Km increased, but the value of Vmax remained unchanged. PMID- 29240907 TI - Primary care for refugees and newly arrived migrants in Europe: a qualitative study on health needs, barriers and wishes. AB - Background: In order to provide effective primary care for refugees and to develop interventions tailored to them, we must know their needs. Little is known of the health needs and experiences of recently arrived refugees and other migrants throughout their journey through Europe. We aimed to gain insight into their health needs, barriers in access and wishes regarding primary health care. Methods: In the spring of 2016, we conducted a qualitative, comparative case study in seven EU countries in a centre of first arrival, two transit centres, two intermediate-stay centres and two longer-stay centres using a Participatory Learning and Action research methodology. A total of 98 refugees and 25 healthcare workers participated in 43 sessions. Transcripts and sessions reports were coded and thematically analyzed by local researchers using the same format at all sites; data were synthesized and further analyzed by two other researchers independently. Results: The main health problems of the participants related to war and to their harsh journey like common infections and psychological distress. They encountered important barriers in accessing healthcare: time pressure, linguistic and cultural differences and lack of continuity of care. They wish for compassionate, culturally sensitive healthcare workers and for more information on procedures and health promotion. Conclusion: Health of refugees on the move in Europe is jeopardized by their bad living circumstances and barriers in access to healthcare. To address their needs, healthcare workers have to be trained in providing integrated, compassionate and cultural competent healthcare. PMID- 29240908 TI - Pulmonary alveolar proteinosis. PMID- 29240909 TI - Cohort Profile Update: The 1993 Pelotas (Brazil) Birth Cohort follow-up at 22 years. PMID- 29240910 TI - Genetic Predisposition to Obesity and Medicare Expenditures. AB - Background: The relationship between obesity and health expenditures is not well understood. We examined the relationship between genetic predisposition to obesity measured by a polygenic risk score for body mass index (BMI) and Medicare expenditures. Methods: Biennial interview data from the Health and Retirement Survey for a nationally representative sample of older adults enrolled in fee-for service Medicare were obtained from 1991 through 2010 and linked to Medicare claims for the same period and to Genome-Wide Association Study (GWAS) data. The study included 6,628 Medicare beneficiaries who provided 68,627 complete person year observations during the study period. Outcomes were total and service specific Medicare expenditures and indicators for expenditures exceeding the 75th and 90th percentiles. The BMI polygenic risk score was derived from GWAS data. Regression models were used to examine how the BMI polygenic risk score was related to health expenditures adjusting for demographic factors and GWAS-derived ancestry. Results: Greater genetic predisposition to obesity was associated with higher Medicare expenditures. Specifically, a 1 SD increase in the BMI polygenic risk score was associated with a $805 (p < .001) increase in annual Medicare expenditures per person in 2010 dollars (~15% increase), a $370 (p < .001) increase in inpatient expenses, and a $246 (p < .001) increase in outpatient services. A 1 SD increase in the polygenic risk score was also related to increased likelihood of expenditures exceeding the 75th percentile by 18% (95% CI: 10%-28%) and the 90th percentile by 27% (95% CI: 15%-40%). Conclusion: Greater genetic predisposition to obesity is associated with higher Medicare expenditures. PMID- 29240911 TI - Caloric Restriction Research: New Perspectives on the Biology of Aging. PMID- 29240912 TI - Taking Obesity in Older Adults Seriously. PMID- 29240914 TI - Spotlight on recently published ICVTS articles. PMID- 29240913 TI - The 2017 EACTS guidelines on perioperative medication in adult cardiac surgery and patient blood management. PMID- 29240915 TI - The Paramedian Supracerebellar-Transtentorial Approach for a Tentorial Incisura Meningioma: 3-Dimensional Operative Video. PMID- 29240916 TI - Study on the anti-endotoxin effect of sinomenine using an Agilent genome array. AB - Background: Endotoxin is a significant contributing factor underlying the occurrence of fever, diarrhea, inflammation, edema, coagulation, shock and other syndromes associated with gram-negative bacterial infections. To date, there is no effective treatment for endotoxemia. Aim: The aim of this study was to characterize differentially expressed genes in sinomenine-treated and lipopolysaccharide (LPS)-induced endothelial cells by microarray analysis and to determine the potential pharmacological activity of sinomenine. Design: The cultured cells of five treatment groups (n = 3) were collected. Participants: total RNA was extracted and subjected to Agilent Porcine 4 * 44 K whole genome microarray. Methods: Kyoto encyclopedia of genes and genomes and gene ontology software were applied to screen and analyze differentially regulated genes. Results: The results showed that 723 differentially regulated genes were identified including 410 up-regulated genes and 313 down-regulated genes in therapy group vs. LPS group. Ten genes may be key controlled genes in the pathogenesis of LPS, including five up-regulated genes (ARG1, TLR2, IL1A, VCAM1, DKK3) and five down-regulated genes (HABP2, ID1, CHDH, GPX3, PTGFR), which primarily contribute to biological processes such as inflammatory response, vascular lesion, metabolic process and cell cycle. IL1A and FMO3 were considered as potent target genes. Conclusion: Global gene expression profile analysis showed that sinomenine might effectively be useful to regulate inflammatory responses as part of future anti-endotoxin therapies. PMID- 29240917 TI - Leisure centre entrance charges and physical activity participation in England. AB - Reducing or eliminating the cost to the public of using leisure facilities is one tool that local authorities have available to reduce inequalities in physical activity (PA). There is limited evidence about the effect of leisure entrance charges and their impact on participation. This study aimed to ascertain how facility pricing influenced the decisions people made about how to pay and what to pay for and how, in turn, these decisions impacted on participation for different groups. A total of 83 members of the public living in 4 local authorities in the North West of England were involved in focus groups or individual interviews. The results show that cost was a key factor which influenced PA participation in low income neighbourhoods. In practise, however, the majority of service users navigated the range of prices or payment options to find one that was suitable rather than simply reporting whether leisure was affordable or not. Whilst pre-paid options (e.g. direct debit memberships) encouraged participation, entrance charges incurred each time an individual participated had a negative impact on frequency but were a convenient way of paying for occasional use or for people who were unable to afford a pre-paid option. Free access also helped people who could not afford pre-paid membership to exercise regularly as well as incentivizing non-users to try activities. The research concluded that policies that include components of free access and offer more flexible payment options are most likely to contribute to reducing inequalities in PA. PMID- 29240918 TI - Evaluation of the Natural Zeolite Lethal Effects on Adults of the Bean Weevil Under Different Temperatures and Relative Humidity Regimes. AB - We studied the insecticidal activity of different concentrations of very high quality natural zeolites (zeolitic rock containing 92 wt% clinoptilolite) applied on dry beans. The test species was adult bean weevils Acanthoscelides obtectus (Say; Coleoptera: Bruchidae), and the variables included different temperatures and humidity regimes. At certain natural zeolite concentrations the adult mortality approached 100% within the first day of exposure. The lethal natural zeolite concentration for 50% adult mortality (LD50) was 1.1 g/kg dry beans 1 d after exposure. The temperature had no significant effects on the insecticidal potential of the tested natural zeolite formulations. The lethal time (LT) for 50% adult mortality (LT50), at a concentration of 0.5 g/kg dry beans was 106.429, 101.951, and 90.084 min at 15, 20, and 25 degrees C, respectively. It did not differ significantly. In contrast, relative humidity (RH) and exposure time as well as their interactions had a significant effect on natural zeolite formulation and insecticidal potential. At a constant concentration of 0.5 g/kg dry beans and 25 degrees C at 23%, 34%, 53%, and 88% RH the LT50 ranged from 61.6 to 75.9 min; at 72% RH the LT50 was 110.6 min. The results indicate that natural zeolite at low concentrations is promising for the control of the bean weevil under different temperatures and RH regimes. PMID- 29240920 TI - An appeal for a more evidence based approach to biopesticide safety in the EU. AB - EFSA responded to our perspective article on the safe use of the insect pathogen Bacillus thrurigiensis (Bt). In doing so they admitted that there is no direct evidence to suggest that B. thuringiensis can cause diarrhoea. They nevertheless continue to repeat the assertion that Bt cannot be distinguished from Bacillus cereus, even though nearly all Bt strains, and certainly all biopesticide strains, can be distinguished from B. cereus using multi-locus sequencing typing. EFSA also continue to repeat the unsupported and speculative hypothesis that Bt strains could be capable of causing cryptic infections in humans. This hypothesis is very much against the weight of all available safety and epidemiological data. Moreover, genotyping schemes of B. cereus group clinical infections also show that biopesticide strains have never been associated with human infections. Our position that Bt biopesticides and Bt isolates from the clade dominated by invertebrate pathogens are incapable of causing infections in humans is well supported by the international community of scientists familiar with the data on the safety of Bt after more than four decades of extensive use in agriculture and forestry. PMID- 29240919 TI - Genome-wide dose-dependent inhibition of histone deacetylases studies reveal their roles in enhancer remodeling and suppression of oncogenic super-enhancers. AB - Histone deacetylase inhibitors (HDACIs) are known to alter gene expression by both up- and down-regulation of protein-coding genes in normal and cancer cells. However, the exact regulatory mechanisms of action remain uncharacterized. Here we investigated genome wide dose-dependent epigenetic and transcriptome changes in response to HDACI largazole in a transformed and a non-transformed cell line. Exposure to low nanomolar largazole concentrations (=GI50) triggered a general decrease in mRNA accumulation. Largazole induces elevation of histone H3 acetylation at Lys-9 and Lys-27 along many gene bodies but does not correlate with up- or down-regulation of the associated transcripts. A higher dose of largazole results in more RNA polymerase II pausing at the promoters of actively transcribed genes and cell death. The most prevalent changes associated with transcriptional regulation occur at distal enhancer elements. Largazole promotes H3K27 acetylation at a subset of poised enhancers and unexpectedly, we also found active enhancers that become decommissioned in a dose and cell type dependent manner. In particular, largazole decreases RNA polymerase II accumulation at super-enhancers (SEs) and preferentially suppresses SE-driven transcripts that are associated with oncogenic activities in transformed cells. PMID- 29240921 TI - Cry1 Bt Susceptibilities of Fall Armyworm (Lepidoptera: Noctuidae) Host Strains. AB - The fall armyworm, Spodoptera frugiperda (Smith; Lepidoptera: Noctuidae), is a highly polyphagous, multivoltine pest of commercial crops including corn (Zea mays L.), cotton (Gossypium spp. L.), rice (Oryza sativa L.), and pasture grasses. Fall armyworm has become a growing concern in agricultural communities across the Americas as field populations in many locales have evolved resistance to several Cry1 toxins derived from the bacterium Bacillus thuringiensis Berliner (Bt). An often overlooked aspect of fall armyworm biology is the existence of two host strains, the 'rice' and 'corn' strains. There has been little research devoted to the characterization of fall armyworm host strains, although there is evidence that the rice and corn-strains may differ in their tolerances to Bt toxins expressed by transgenic plants. In this study, diet-based bioassays were conducted to compare the susceptibilities of one rice-strain, two corn-strains, and one rice-corn hybrid population to Cry1Ab, Cry1Ac, and Cry1F protein. Results indicate that the corn-strains and hybrid populations are more tolerant to the Bt toxins, especially to Cry1F, than the rice-strain population. Results from this study, when combined with existing techniques for host strain identification, may aid in the development of regional insect resistance management programs for fall armyworm. PMID- 29240924 TI - Effect of omega-3 fatty acids on cognition: an updated systematic review of randomized clinical trials. AB - Context: The increasing number of studies on the effects of n-3 long-chain polyunsaturated fatty acids (LC-PUFAs) on health, particularly cognition, in the last 5 years reflects the growing interest in this area of research. Objective: The aim for this systematic review was to evaluate the scientific evidence published in the last 5 years (2012-2017) on the effects of n-3 LC-PUFA intake on cognition, cognitive development, and cognitive decline to determine whether n-3 LC-PUFAs support cognitive development and prevent cognitive decline. Data Sources: The PubMed database was searched. Study Selection: The 51 articles included in this systematic review reported on healthy individuals with mild or moderate cognitive impairment and patients with Alzheimer's disease. Risk of bias was assessed using Cochrane methodology. Data Extraction: The number of study participants, the type of study, the type and dose of n-3 LC-PUFAs, and the key results are reported here. Results: Current evidence indicates that n-3 LC-PUFAs administered during pregnancy or breastfeeding have no effect on the skills or cognitive development of children in later stages of development. Evidence regarding the improvement of cognitive function during childhood and youth or in attention deficit/hyperactivity disorder is inconclusive. Moreover, it is still unclear if n-3 LC-PUFAs can improve cognitive development or prevent cognitive decline in young or older adults. PMID- 29240925 TI - Reply to Paul and Leibovici. PMID- 29240923 TI - Neutrophil activation signature in juvenile idiopathic arthritis indicates the presence of low-density granulocytes. AB - Objective: JIA is an autoimmune, inflammatory disease with involvement of innate and adaptive immune responses. However, the role of neutrophils in JIA pathogenesis remains unclear. This study aimed to identify and validate neutrophil gene expression signatures in JIA using public microarray datasets and new clinical samples. Methods: Three suitable datasets were analysed by significance analysis of microarray and Ingenuity. Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from a new cohort of JIA patients and healthy paediatric controls (HCs). Gene expression was validated using quantitative PCR. Serum concentrations of proteins were measured using ELISA. Low density granulocytes (LDGs) in JIA and HC PBMCs were quantified by flow cytometry using forward/side-scatter properties. Results: Ingenuity identified transcriptional regulation (false discovery rate < 0.05) by G-CSF, GM-CSF and IL 8 along with expression of neutrophil granule protein genes including ELANE, MPO, MMP8 and MMP9 in datasets from JIA PBMCs. LDG counts were elevated in JIA compared with HCs (2.5% vs 1.4%; P = 0.007). Transcripts for MMP8 (P = 0.005), MPO (P = 0.0124) and Fcgamma Receptor 1B (FCgammaR1B) (P = 0.0417) were significantly higher in JIA compared with HC neutrophils. MMP9 protein levels were lower in systemic JIA patient sera [355.95 ng/ml (s.d. 250.03)] compared with HCs [675.41 ng/ml (s.d. 181.17); P = 0.007], but levels of elastase, MPO and MMP8 were not significantly different. Conclusion: LDGs are elevated in JIA and contribute to the transcriptomic profile of JIA PBMCs. JIA neutrophils express higher levels of MMP8 and FCGR1B, which may be implicated in disease pathology through the release of proteases and reactive oxygen metabolites, causing systemic inflammation and damage to joints. PMID- 29240922 TI - Prevalence, Magnitude, and Correlates of HIV-1 Genital Shedding in Women on Antiretroviral Therapy. AB - Background: Genital human immunodeficiency virus (HIV) RNA shedding can continue despite HIV being undetectable in blood, and can be associated with transmission. Methods: We included African women on antiretroviral therapy (ART). Linear and generalized linear mixed models were used to compare the magnitude and prevalence of genital shedding, respectively, by time since ART initiation. Multivariable logistic regression with generalized estimating equations was used to assess predictors of genital shedding among women with undetectable plasma viral load (VL). Results: Among 1114 women, 5.8% of visits with undetectable plasma VL and 23.6% of visits with detectable VL had genital shedding. The proportion of visits with genital shedding decreased with time since ART initiation but the magnitude of shedding remained unchanged when plasma VL was undetectable (P = .032). Prevalence of shedding did not vary by time since ART initiation when plasma VL was detectable (P = .195), though the magnitude of shedding significantly increased (P = .04). Predictors of genital shedding were HIV disease stage, antiretroviral regimen, and genital ulcers or cervical tenderness. Discussion: In addition to ART, reducing immune activation through prevention and treatment of HIV-related conditions and genital tract infections may decrease the risk of HIV 1 shedding and potential transmission. PMID- 29240927 TI - Commentary: Introduction to an historical reprint: Heredity and environment in early 20th century genetics: Major Leonard Darwin's advice to eugenists. PMID- 29240926 TI - ExoCET: exonuclease in vitro assembly combined with RecET recombination for highly efficient direct DNA cloning from complex genomes. AB - The exponentially increasing volumes of DNA sequence data highlight the need for new DNA cloning methods to explore the new information. Here, we describe 'ExoCET' (Exonuclease Combined with RecET recombination) to directly clone any chosen region from bacterial and mammalian genomes with nucleotide precision into operational plasmids. ExoCET combines in vitro exonuclease and annealing with the remarkable capacity of full length RecET homologous recombination (HR) to retrieve specified regions from genomic DNA preparations. Using T4 polymerase (T4pol) as the in vitro exonuclease for ExoCET, we directly cloned large regions (>50 kb) from bacterial and mammalian genomes, including DNA isolated from blood. Employing RecET HR or Cas9 cleavage in vitro, the directly cloned region can be chosen with nucleotide precision to position, for example, a gene into an expression vector without the need for further subcloning. In addition to its utility for bioprospecting in bacterial genomes, ExoCET presents straightforward access to mammalian genomes for various applications such as region-specific DNA sequencing that retains haplotype phasing, the rapid construction of optimal, haplotypic, isogenic targeting constructs or a new way to genotype that presents advantages over Southern blotting or polymerase chain reaction. The direct cloning capacities of ExoCET present new freedoms in recombinant DNA technology. PMID- 29240928 TI - 'Common things are common'. PMID- 29240929 TI - The Genome and Adult Somatic Transcriptome of the Mormyrid Electric Fish Paramormyrops kingsleyae. AB - Several studies have begun to elucidate the genetic and developmental processes underlying major vertebrate traits. Few of these traits have evolved repeatedly in vertebrates, preventing the analysis of molecular mechanisms underlying these traits comparatively. Electric organs have evolved multiple times among vertebrates, presenting a unique opportunity to understand the degree of constraint and repeatability of the evolutionary processes underlying novel vertebrate traits. As there is now a completed genome sequence representing South American electric eels, we were motivated to obtain genomic sequence from a linage that independently evolved electric organs to facilitate future comparative analyses of the evolution and development of electric organs. We report here the sequencing and de novo assembly of the genome of the mormyrid Paramormyrops kingsleyae using short-read sequencing. In addition, we have completed a somatic transcriptome from 11 tissues to construct a gene expression atlas of predicted genes from this assembly, enabling us to identify candidate housekeeping genes as well as genes differentially expressed in the major somatic tissues of the mormyrid electric fish. We anticipate that this resource will greatly facilitate comparative studies on the evolution and development of electric organs and electroreceptors. PMID- 29240931 TI - Microsurgical Fenestration of Thalamic Cyst Along With Third Ventriculostomy and Septal Fenestration via the Interhemispheric Transcallosal Approach: 3 Dimensional Operative Video. PMID- 29240930 TI - Britain Breathing: using the experience sampling method to collect the seasonal allergy symptoms of a country. AB - Objective: Allergies are increasing, but the reasons for this are unclear. Although environmental factors are thought to be important, there is a lack of data on how they contribute to symptom development. To understand this relationship better, we need accurate data about both symptoms and environmental factors. Our objective here is to ascertain whether experience sampling is a reliable approach for collecting allergy symptom data in the general population, allowing us to map symptoms and understand etiology. Materials and Methods: We conducted a 32-week cross-sectional study where individuals reported their seasonal allergy symptoms and severity via a mobile application. Symptom geographical location and timestamp were also collected automatically. Results: The experience sampling method reliably infers the incidence of seasonal allergies as indicated by the strong correlation (r = 0.93, P < .003) between the reported lack of wellness and the number of antihistamines prescribed by General Practitioners. Discussion and Conclusion: The project has resulted in the first dataset to map allergy symptoms over time and place and reveals periods of peak hay fever symptoms in the UK. PMID- 29240932 TI - Homogenization of Populations in the Wildflower, Texas Bluebonnet (Lupinus texensis). AB - Wildflower seeds are routinely spread along highways and thoroughfares throughout North America as part of federal beautification policy, but the genetic effect of the introduction of these cultivated populations on wild populations of the same species is unknown. Interbreeding may occur between these seeded and wild populations, resulting in several possible outcomes. Here we sample 187 individuals in 12 matched pairs of neighboring wild and seeded populations of the Texas bluebonnet (Lupinus texensis), a species popular in commercially available wildflower seed mixes used by both the Texas Department of Transportation and the public. We use genotyping by sequencing to identify 11741 genome-wide single nucleotide polymorphisms, as well as a smaller number of SNPs from the chloroplast genome, to analyze population structure and genetic diversity within and between the populations. We find a striking lack of population structure both between wild and seeded populations and amongst wild populations. STRUCTURE analyses indicate that all populations are apparently panmictic. This pattern may be explained by extensive swamping of wild populations by seeded germplasm and increased dispersal of semi-domesticated seed across this species' core native range by humans. We discuss the possible negative and positive ramifications of homogenization on the evolutionary future of this popular wildflower species. PMID- 29240933 TI - Recruitment of UvrBC complexes to UV-induced damage in the absence of UvrA increases cell survival. AB - Nucleotide excision repair (NER) is the primary mechanism for removal of ultraviolet light (UV)-induced DNA photoproducts and is mechanistically conserved across all kingdoms of life. Bacterial NER involves damage recognition by UvrA2 and UvrB, followed by UvrC-mediated incision either side of the lesion. Here, using a combination of in vitro and in vivo single-molecule studies we show that a UvrBC complex is capable of lesion identification in the absence of UvrA. Single-molecule analysis of eGFP-labelled UvrB and UvrC in living cells showed that UV damage caused these proteins to switch from cytoplasmic diffusion to stable complexes on DNA. Surprisingly, ectopic expression of UvrC in a uvrA deleted strain increased UV survival. These data provide evidence for a previously unrealized mechanism of survival that can occur through direct lesion recognition by a UvrBC complex. PMID- 29240935 TI - Letter: The Use of Vancomycin Powder for Surgical Prophylaxis Following Craniotomy. PMID- 29240934 TI - A peculiar IclR family transcription factor regulates para-hydroxybenzoate catabolism in Streptomyces coelicolor. AB - In Streptomyces coelicolor, we identified a para-hydroxybenzoate (PHB) hydroxylase, encoded by gene pobA (SCO3084), which is responsible for conversion of PHB into PCA (protocatechuic acid), a substrate of the beta-ketoadipate pathway which yields intermediates of the Krebs cycle. We also found that the transcription of pobA is induced by PHB and is negatively regulated by the product of SCO3209, which we named PobR. The product of this gene is highly unusual in that it is the apparent fusion of two IclR family transcription factors. Bioinformatic analyses, in vivo transcriptional assays, electrophoretic mobility shift assays (EMSAs), DNase I footprinting, and isothermal calorimetry (ITC) were used to elucidate the regulatory mechanism of PobR. We found that PobR loses its high affinity for DNA (i.e., the pobA operator) in the presence of PHB, the inducer of pobA transcription. PHB binds to PobR with a KD of 5.8 MUM. Size exclusion chromatography revealed that PobR is a dimer in the absence of PHB and a monomer in the presence of PHB. The crystal structure of PobR in complex with PHB showed that only one of the two IclR ligand binding domains was occupied, and defined how the N-terminal ligand binding domain engages the effector ligand. PMID- 29240936 TI - Grit, Illness-Related Distress, and Psychosocial Outcomes in College Students With a Chronic Medical Condition: A Path Analysis. AB - Objective: Adolescents and young adults (AYAs) with chronic medical conditions are at increased risk for a host of negative psychosocial outcomes, including depressive and anxious symptoms. Although studies have shown that illness appraisals (e.g., illness intrusiveness [II] and illness uncertainty [IU]) demonstrate consistent associations with such outcomes, few studies have examined positive factors that may relate to better psychosocial outcomes and appraisals. The present study evaluated grit (i.e., perseverance and passion for long-term goals), a novel construct in pediatric psychology, as a positive factor that relates to reduced untoward effects of II and IU on psychosocial outcomes in AYAs with chronic medical conditions. Methods: College students with a chronic medical condition (N = 120) completed questionnaires online, including measures of grit, II, IU, depression, anxiety, and emotional well-being (EWB). Results: The overall path analysis demonstrated that increased grit is directly associated with decreased depressive and anxious symptoms and increased EWB (p < .05). Further, analyses indicated that the positive association between grit and psychosocial outcomes is partially mediated by illness appraisals (p < .05). Conclusions: This study identified grit as a positive personal asset among AYAs with chronic medical conditions. By introducing a novel construct to the AYA literature, the study expands on the integration of positive psychology and pediatric psychology and underscores the need for greater research on the role of grit in chronic medical condition populations. PMID- 29240937 TI - Cord sign in cerebral venous thrombosis. PMID- 29240939 TI - Dual pathology may be masked by iron replacement therapy. PMID- 29240940 TI - State of the art in eukaryotic nitrogenase engineering. AB - Improving the ability of plants and plant-associated organisms to fix and assimilate atmospheric nitrogen has inspired plant biotechnologists for decades, not only to alleviate negative effects on nature from increased use and availability of reactive nitrogen, but also because of apparent economic benefits and opportunities. The combination of recent advances in synthetic biology and increased knowledge about the biochemistry and biosynthesis of the nitrogenase enzyme has made the seemingly remote and for long unreachable dream more possible. In this review, we will discuss strategies how this could be accomplished using biotechnology, with a special focus on recent progress on engineering plants to express its own nitrogenase. PMID- 29240942 TI - Overexpression of PDR16 confers resistance to complex sphingolipid biosynthesis inhibitor aureobasidin A in yeast Saccharomyces cerevisiae. AB - Sphingolipids are essential for normal cell growth of yeast Saccharomyces cerevisiae. Aureobasidin A (AbA), an antifungal drug, inhibits Aur1, an enzyme catalyzing the synthesis of inositol phosphorylceramide, and induces a strong growth defect in yeast. In this study, we screened for multicopy suppressor genes that confer resistance to AbA, and identified PDR16. In addition, it was found that PDR17, a paralog of PDR16, also functions as a multicopy suppressor. Pdr16 and Pdr17 belong to a family of phosphatidylinositol transfer proteins; however, cells overexpressing the other members of the family hardly exhibited resistance to AbA. Overexpression of a lipid-binding defective mutant of Pdr16 did not confer the resistance to AbA, indicating that the lipid-binding activity is essential for acquiring resistance to AbA. When expression of the AUR1 gene was repressed by a tetracycline-regulatable promoter, the overexpression of PDR16 or PDR17 did not suppress the growth defect caused by the AUR1 repression. Quantification analysis of complex sphingolipids revealed that in AbA-treated cells, but not in cells in which AUR1 was repressed by the tetracycline regulatable promoter, the reductions of complex sphingolipid levels were suppressed by the overexpressed PDR16. Thus, it was indicated that the overexpression of PDR16 reduces the effectiveness of AbA against intracellular Aur1 activity. PMID- 29240941 TI - Management of the Pine Processionary Moth, Thaumetopoea pityocampa (Lepidoptera: Thaumetopoeidae), in Urban and Suburban Areas: Trials With Trunk Barrier and Adhesive Barrier Trap Devices. AB - In urban and suburban areas larvae of the pine processionary moth, Thaumetopoea pityocampa (Denis and Schiffermuller), cause serious defoliation to Cedrus, Pinus, and Pseudotsuga trees and health problems to humans and domestic or farm animals by their urticating setae. In this study, we present the results of biennial trials (2015-2016) on the management of T. pityocampa infestations using commercial or LIFE-PISA prototype trunk barrier and adhesive trap devices in Greece (Attica and Volos), Spain (Valencia), and Italy (Molise). In Attica, for both 2015 and 2016, the commercial trunk barrier trap devices captured significantly more T. pityocampa wintering migrant larvae compared to the adhesive barrier trap devices, indicating their high capture capacity. The total performance of the trunk barriers trap devices was 99.8% in 2015 and 99.6% in 2016. In Volos and Valencia, no significant differences were recorded between captures in commercial and LIFE-PISA prototype trunk barrier trap devices. In the tests that were conducted in Molise, the commercial trunk barrier trap devices exhibited high effectiveness in capturing the wintering migrant larvae during their procession, before they reach the ground for pupation. Moreover, significantly fewer male adults were captured by pheromone trap devices during summer 2016 in comparison with 2015 in the experimental area. Similarly, significantly fewer nests were formed on the experimental area trees in winter 2016 and 2017 compared with 2015. Our results show the potential of the trunk barrier trap devices in the management of T. pityocampa numbers after long-term application in urban and suburban areas. PMID- 29240943 TI - Commentary: Giuseppe Campani (1635-1715, Rome, Italy): the First Use of a Microscope in Medicine and Surgery. AB - Giuseppe Campani (1635-1715) was a polymath in Rome, Italy, during the Scientific Revolution in the XVIIth century. In particular, he forged the screw barrel microscope and was manufacturing his own lenses for microscopes and telescopes. He mastered the art of lens grinding. Those lenses have been analyzed with modern methods and turned out to be of extremely good quality, shining light on the fact that Giuseppe Campani mastered the theories of optics. Moreover, in a letter that Giuseppe Campani sent to Pope Innocent XI, he clearly described the use of a microscope for the examination of wounds of legs. This letter dates back to 15 August 1686 and is the first evidence of the use of microscopes to analyze wounds, sores, and anatomic specimens in medical and surgical settings. MG Yasargil previously showed the lithography accompanying this letter and was the first to recognize its great importance. We accessed this original letter in the Vatican Library, and for the first time we have translated it from Latin to English in order to unveil its significance in the context of the Scientific Revolution and the history of medicine and surgery. PMID- 29240944 TI - A Right to Access to Emergency Health Care: The European Court of Human Rights Pushes the Envelope. AB - This article argues that the European Court of Human Rights (ECtHR) seems to have recently acknowledged that there is a right to access to emergency health care in the member states of the Council of Europe. The Chamber of the ECtHR found that a state's failure to design a regulatory framework that guarantees access to health care in emergency situations violates the substantial limb of Article 2 European Convention on Human Rights (ECHR) that protects the right to life. It is argued that the newly established requirements seem to be reasonable but that there seem to be no sufficient safeguards to ensure that the ECtHR does not substitute its own assessment for that of medical professionals. PMID- 29240945 TI - Transcript profiling indicates a widespread role for bacterial-type phosphoenolpyruvate carboxylase in malate-accumulating sink tissues. AB - Phosphoenolpyruvate carboxylase (PEPC) is an important regulatory enzyme situated at a key branch point of central plant metabolism. Plant genomes encode several plant-type PEPC (PTPC) isozymes, along with a distantly related bacterial-type PEPC (BTPC). BTPC is expressed at high levels in developing castor oil seeds where it tightly interacts with co-expressed PTPC polypeptides to form unusual hetero-octameric Class-2 PEPC complexes that are desensitized to allosteric inhibition by L-malate. Analysis of RNA-Seq and microarray transcriptome datasets revealed two distinct patterns of tissue-specific BTPC expression in vascular plants. Species such as Arabidopsis thaliana, strawberry, rice, maize, and poplar mainly exhibited pollen- or floral-specific BTPC expression. By contrast, BTPC transcripts were relatively abundant in developing castor, cotton, and soybean seeds, cassava tubers, as well as immature tomato, cucumber, grape, and avocado fruit. Immunoreactive 118 kDa BTPC polypeptides were detected on immunoblots of cucumber and tomato fruit extracts. Co-immunoprecipitation established that as in castor, BTPCs physically interact with endogenous PTPCs to form Class-2 PEPC complexes in tomato and cucumber fruit. We hypothesize that Class-2 PEPCs simultaneously maintain rapid anaplerotic PEP carboxylation and respiratory CO2 refixation in diverse, biosynthetically active sinks that accumulate high malate levels. PMID- 29240948 TI - Early Cyclical Neuromuscular Electrical Stimulation Improves Strength and Trophism by Akt Pathway Signaling in Partially Paralyzed Biceps Muscle After Spinal Cord Injury in Rats. AB - Background: Electrical stimulation is often used to treat weakness in people with spinal cord injury (SCI); however its efficacy for increasing strength and trophism is weak, and the mechanisms underlying the therapeutic benefits are unknown. Objective: The purpose of this study was to analyze the effects of neuromuscular electrical stimulation (NMES) on muscle function, trophism, and the Akt pathway signaling involved in muscular plasticity after incomplete SCI in rats. Design: This was an experimental study. Methods: Twenty-one adult female Wistar rats were divided into sham, SCI, and SCI plus NMES groups. In injured animals, SCI hemisection was induced by a surgical procedure at the C5-C7 level. The 5-week NMES protocol consisted of biceps brachii muscle stimulation 5 times per week, initiated 48 h after injury. Forepaw function and strength, biceps muscle trophism, and the expression of phosphorylated Akt, p70S6K, and GSK-3beta cellular anabolic pathway markers in stimulated muscle tissue were assessed. Results: There was an increase in bicep muscle strength in the NMES group compared with the untreated SCI group, from postoperative day 21 until the end of the evaluation period. Also, there was an increase in muscle trophism in the NMES group compared with the SCI group. Forelimb function gradually recovered in both the SCI group and the NMES group, with no differences between them. Regarding muscle protein expression, the NMES group had higher values for phospho-Akt, phospho-p70S6K, and phospho-GSK-3beta than did the SCI group. Limitations: The experimental findings were limited to an animal model of incomplete SCI and may not be fully generalizable to humans. Conclusions: Early cyclical NMES therapy was shown to increase muscle strength and induce hypertrophy after incomplete SCI in a rat model, probably by increasing phospho-Akt, phospho-p70S6K, and phospho GSK-3beta signaling protein synthesis. PMID- 29240947 TI - A FTH1 gene:pseudogene:microRNA network regulates tumorigenesis in prostate cancer. AB - Non-coding RNAs play a vital role in diverse cellular processes. Pseudogenes, which are non-coding homologs of protein-coding genes, were once considered non functional evolutional relics. However, recent studies have shown that pseudogene transcripts can regulate their parental transcripts by sequestering shared microRNAs (miRNAs), thus acting as competing endogenous RNAs (ceRNAs). In this study, we utilize an unbiased screen to identify the ferritin heavy chain 1 (FTH1) transcript and multiple FTH1 pseudogenes as targets of several oncogenic miRNAs in prostate cancer (PCa). We characterize the critical role of this FTH1 gene:pseudogene:miRNA network in regulating tumorigenesis in PCa, whereby oncogenic miRNAs downregulate the expression of FTH1 and its pseudogenes to drive oncogenesis. We further show that impairing miRNA binding and subsequent ceRNA crosstalk completely rescues the slow growth phenotype in vitro and in vivo. Our results also demonstrate the reciprocal regulation between the pseudogenes and intracellular iron levels, which are crucial for multiple physiological and pathophysiological processes. In summary, we describe an extensive gene:pseudogene network comprising multiple miRNAs and multiple pseudogenes derived from a single parental gene. The network could be regulated through multiple mechanisms to modulate iron storage in various signaling pathways, the deregulation of which results in PCa development and progression. PMID- 29240949 TI - Nitric oxide production in plants: an update. AB - Nitric oxide (NO) is a key signaling molecule in plant physiology. However, its production in photosynthetic organisms remains partially unresolved. The best characterized NO production route involves the reduction of nitrite to NO via different non-enzymatic or enzymatic mechanisms. Nitrate reductases (NRs), the mitochondrial electron transport chain, and the new complex between NR and NOFNiR (nitric oxide-forming nitrite reductase) described in Chlamydomonas reinhardtii are the main enzymatic systems that perform this reductive NO production in plants. Apart from this reductive route, several reports acknowledge the possible existence of an oxidative NO production in an arginine-dependent pathway, similar to the nitric oxide synthase (NOS) activity present in animals. However, no NOS homologs have been found in the genome of embryophytes and, despite an increasing amount of evidence attesting to the existence of NOS-like activity in plants, the involved proteins remain to be identified. Here we review NO production in plants with emphasis on the presentation and discussion of recent data obtained in this field. PMID- 29240950 TI - What Did You Do Today? Variability in Daily Activities is Related to Variability in Daily Cognitive Performance. AB - Objectives: Are the activities we do each day related to fluctuations in our daily cognitive performance? Positive longitudinal associations between cognitive, physical, and social activities and cognitive ability in adulthood are well established. However little is known about how this relationship may operate at the daily level. Methods: Community-dwelling participants 60-90 years of age (M = 69.41; n = 146) reported their activity participation and completed cognitive tests online for 7 consecutive days. Results: Multilevel models showed that daily activities covaried with daily cognitive performance, indicating fluctuations in the activities that a person engaged in across the week were associated with corresponding changes in their daily speed, memory, and reasoning. This was strongest for social activities where on days when individuals engaged in more routine activities with social-private characteristics than usual, they had higher memory scores and responded faster. Discussion: This information could be particularly relevant to the daily lives of older adults, especially those experiencing cognitive decline. PMID- 29240946 TI - Chemistry, mechanism and clinical status of antisense oligonucleotides and duplex RNAs. AB - RNA plays a central role in the expression of all genes. Because any sequence within RNA can be recognized by complementary base pairing, synthetic oligonucleotides and oligonucleotide mimics offer a general strategy for controlling processes that affect disease. The two primary antisense approaches for regulating expression through recognition of cellular RNAs are single stranded antisense oligonucleotides and duplex RNAs. This review will discuss the chemical modifications and molecular mechanisms that make synthetic nucleic acid drugs possible. Lessons learned from recent clinical trials will be summarized. Ongoing clinical trials are likely to decisively test the adequacy of our current generation of antisense nucleic acid technologies and highlight areas where more basic research is needed. PMID- 29240951 TI - Using the comet assay and lysis conditions to characterize DNA lesions from the acrylamide metabolite glycidamide. AB - The alkaline comet assay and a cell-free system were used to characterise DNA lesions induced by treatment with glycidamide (GA), a metabolite of the food contaminant acrylamide. DNA lesions induced by GA were sensitively detected when the formamidopyrimidine-DNA-glycosylase (Fpg) enzyme was included in the comet assay. We used LC-MS to characterise modified bases from GA-treated naked DNA with and without subsequent Fpg treatment. N7-GA-Guanine and N3-GA-Adenine aglycons were detected in the supernatant showing some depurination of adducted bases; treatment of naked DNA with Fpg revealed no further increase in the adduct yield nor occurrence of other adducted nucleobases. We treated human lymphocytes with GA and found large differences in DNA lesion levels detected with Fpg, depending on the duration and the pH of the lysis step. These lysis-dependent variations in GA-induced Fpg sensitive sites paralleled those observed after treatment of cells with methyl methane sulfonate (MMS). On the other hand, oxidative lesions (8-oxoGuanine) induced by a photoactive compound (Ro 12-9786) plus light, and also DNA strand breaks induced by X-rays, were detected largely independently of the lysis conditions. The results suggest that the GA-induced lesions are predominantly N7-GA-dG adducts slowly undergoing imidazole ring opening at pH 10 as in the standard lysis procedure; such structures are substrate for Fpg leading to strand breaks. The data suggest that the characteristic alkaline lysis dependence of some DNA lesions may be used to study specific types of DNA modifications. The comet assay is increasingly used in regulatory testing of chemicals; in this context, lysis-dependent variations represent a novel approach to obtain insight in the molecular nature of a genotoxic insult. PMID- 29240952 TI - Diversity and complexity of flavodiiron NO/O2 reductases. AB - Flavodiiron proteins (FDPs) are a family of enzymes endowed with nitric oxide (NO) or oxygen reductase activities, forming the innocuous nitrous oxide (N2O) or water molecules, respectively. FDPs are widespread in the three life kingdoms, and have a modular nature, being each monomer minimally constituted by a metallo beta-lactamase-like domain containing a catalytic diiron centre, followed by a flavodoxin one, with a flavin mononucleotide. Since their discovery, additional domains have been found in FDPs, attached to the C-terminus, and containing either extra metal (iron) centers or extra flavin binding modules. Following an extensive analysis of genomic databases, we identified novel domain compositions, and proposed a new classification of FDPs in eight classes based on the nature and number of extra domains. PMID- 29240953 TI - Influence of excess branched-chain amino acid uptake by Streptococcus mutans in human host cells. AB - Oral streptococci, including cariogenic bacterium Streptococcus mutans, comprise a large percentage of human supragingival plaque, which contacts both tooth surfaces and gingiva. Eukaryotic cells are able to take up macromolecules and particles, including bacteria, by endocytosis. Increasing evidence indicates endocytosis may be used as an entry process by bacteria. We hypothesized that some endocytosed bacteria might survive and obtain nutrients, such as amino acids, until they are killed. To verify this hypothesis, we focused on bacterial utilization of branched-chain amino acids (BCAAs; isoleucine, leucine and valine) in host cells. A branched-chain aminotransferase, IlvE (EC 2.6.1.42), has been suggested to play an important role in internal synthesis of BCAAs in S. mutans UA159. Therefore, we constructed an ilvE-deficient S. mutans 109c strain and confirmed that it had similar growth behavior as reported previously. 14C radioactive leucine uptake assays showed that ilvE-deficient S. mutans took up more leucine both inside and outside of host cells. We further clarified that a relative decrease of BCAAs in host cells caused enhanced endocytic and autophagic activity. In conclusion, S. mutans is endocytosed by host cells and may survive and obtain nutrients, such as BCAAs, inside the cells, which might affect cellular functions of host cells. PMID- 29240954 TI - Dosing down with biologic therapies: a systematic review and clinicians' perspective. PMID- 29240955 TI - Pine wilt disease causes cavitation around the resin canals and irrecoverable xylem conduit dysfunction. AB - Physiological mechanisms of irreversible hydraulic dysfunction in seedlings infected with pine wilt disease (PWD) are still unclear. We employed cryo scanning electron microscopy (cryo-SEM) to investigate the temporal and spatial changes in water distribution within the xylem of the main stem of 2-year-old Japanese black pine seedlings infested by pine wood nematodes (PWNs). Our experiment was specifically designed to compare the water relations among seedlings subjected to the following water treatment and PWN combinations: (i) well-watered versus prolonged drought (no PWNs); and (ii) well-watered with PWNs versus water-stressed with PWNs (four treatments in total). Cryo-SEM imaging observations chronicled the development of patchy cavitations in the xylem tracheids of the seedlings influenced by PWD. With the progression of drought, many pit membranes of bordered pits in the xylem of the main stem were aspirated with the decrease in water potential without xylem cavitation, indicating that hydraulic segmentation may exist between tracheids. This is the first study to demonstrate conclusively that explosive and irreversible cavitations occurred around the hydraulically vulnerable resin canals with the progression of PWD. Our findings provide a more comprehensive understanding of stressors on plant-water relations that may eventually better protect trees from PWD and assist with the breeding of trees more tolerant to PWD. PMID- 29240957 TI - Non-coding RNAs in cardiac fibrosis: emerging biomarkers and therapeutic targets. AB - Non-coding RNAs (ncRNAs) are a class of RNA molecules that do not encode proteins. ncRNAs are involved in cell proliferation, apoptosis, differentiation, metabolism, and other physiological processes as well as the pathogenesis of diseases. Cardiac fibrosis is increasingly recognized as a common final pathway in advanced heart diseases. Many studies have shown that the occurrence and development of cardiac fibrosis is closely related to the regulation of ncRNAs. This review will highlight recent updates regarding the involvement of ncRNAs in cardiac fibrosis, and their potential as emerging biomarkers and therapeutic targets. PMID- 29240958 TI - Short- and long-term effects of hemodialysis on platelet and monocyte activity markers of atherosclerosis in patients with end-stage renal disease. AB - BACKGROUND: In hemodialysis (HD) patients cardiovascular events represent the predominant cause of mortality. Since platelet and monocyte activity markers play an important role in cardiovascular mortality, this study assessed the influence of HD on these markers. METHODS: Forty one HD patients (25 male, 16 female) were included. Blood samples were obtained before and after a single HD session at baseline and again after an elapsed period of 114 +/- 21 days (91-175 days) on maintenance hemodialysis. Surface expression of CD40L and CD62P on platelets, tissue factor binding on monocytes and platelet-monocyte aggregates were measured by flow cytometry. Plasma levels of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFa) and soluble CD40L were analyzed by enzyme linked immunosorbent assay. RESULTS: Tissue factor on monocytes was significantly increased after a single HD session at baseline (p = 0.041), whereas platelet-monocyte aggregates, the expression of CD40L and CD62P on platelets did not change significantly. After a mean of 114 +/- 21 days of HD therapy, tissue factor on monocytes (p < 0.0001), platelet-monocytes aggregates (p < 0.0001), plasma levels of MCP-1 (p = 0.012) and TNFa (p = 0.046) were significantly decreased compared to baseline values. In contrast, platelet surface expression of CD40L and CD62P as well as plasma levels of sCD40L and IL-6 were not attenuated significantly. There was no significant correlation detected between the markers examined and the cumulative time on hemodialysis. CONCLUSIONS: Platelet and monocyte activity markers assessed in this study do not appear to be significantly increased by HD therapy. Therefore, these markers probably cannot be accountable for increased cardiovascular mortality in chronic HD patients. PMID- 29240956 TI - MAP kinases associate with high molecular weight multiprotein complexes. AB - Plant responses to the environment and developmental processes are mediated by a complex signaling network. The Arabidopsis thaliana mitogen-activated protein kinases (MAPKs) MPK3 and MPK6 and their orthologs in other plants are shared signal transducers that respond to many developmental and environmental signals and thus represent highly connected hubs in the cellular signaling network. In animals, specific MAPK signaling complexes are assembled which enable input specific protein-protein interactions and thus specific signaling outcomes. In plants, not much is known about such signaling complexes. Here, we report that MPK3, MPK6, and MPK10 orthologs in tomato, tobacco, and Arabidopsis as well as tomato MAPK kinase 4 (MKK4) associate with high molecular weight (~250-550 kDa) multiprotein complexes. Elicitation by the defense-associated peptides flg22 and systemin resulted in phosphorylation and activation of the monomeric MAPKs, whereas the complex-associated MAPKs remained unphosphorylated and inactive. In contrast, treatment of tomato cells with a phosphatase inhibitor resulted in association of phosphorylated MPK1/2 with the complex. These results demonstrate that plant MAPKs and MAPKKs dynamically assemble into stable multiprotein complexes and this may depend on their phosphorylation status. Identification of the constituents of these multiprotein complexes promises a deeper understanding of signaling dynamics. PMID- 29240959 TI - Evaluation of left ventricular function in overweight children and teenagers with arterial hypertension and white coat hypertension. AB - BACKGROUND: Obesity in childhood is strongly associated with elevated arterial blood pressure and risk of hypertension. The aim of the study was the evaluation of left ventricular function in hypertensive and white coat hypertensive overweight children and teenagers. METHODS: The study group consisted of 74 overweight patients aged 10.3 +/- 3.1 years (range: 6-16 years) diagnosed as hypertensive in standard blood pressure measurement. The control group consisted of 31 normotensive and normoweight children. Ambulatory blood pressure monitoring (ABPM) and echocardiographic assessment of the left ventricular mass and function were performed in all participants. RESULTS: Using ABPM hypertension was confirmed in 20 children (27%). In the 54 remaining children (73%) white coat hypertension was diagnosed. The analysis of echocardiographic parameters revealed higher left ventricular mass index (LVMI) in hypertensive overweight than in normotensive normoweight children (47.5 +/- 9.2 g/m2.7 vs. 39.8 +/- 12.1 g/m2.7; p < 0.05) and no difference between overweight hypertensive and WCH-hypertensive groups. The deceleration time of mitral early filling (DCT) was longer in hypertensive normoweight children than in normotensive overweight patients (219.5 +/- 110.3 ms vs. 197.8 +/- 65.8 ms; p < 0.05). A significant correlation between systolic pressure load (SBPL) and DCT (r = 0.57) and moderate correlation between SBPL and LVMI (r: 0.48) as well as between LVMI and isovolumetric relaxation time (r = 0.37) were found. CONCLUSIONS: In overweight children the diagnosis of hypertension should be confirmed in ambulatory blood pressure monitoring because of the high prevalence of white coat hypertension. Periodic echocardiographic examinations should be recommended in overweight children with increased systolic blood pressure load and decreased systolic nocturnal deep because of the possibility of left ventricular function impairment. PMID- 29240960 TI - Variant rs2200733 and rs10033464 on chromosome 4q25 are associated with increased risk of atrial fibrillation after catheter ablation: Evidence from a meta analysis. AB - BACKGROUND: Common genetic polymorphisms at chromosome 4q25 were associated with increased susceptibility to atrial fibrillation (AF). However, it remained controversial whether these variants could be used as risk predictors for AF recurrence after catheter ablation. We therefore performed a metaanalysis to quantify the association between rs2200733 C>T/rs10033464 G>T and AF recurrence. METHODS: Relevant studies were systematically retrieved from PubMed, Web of Science, Elsevier database and Cochrane library through November 2016. Data were abstracted and pooled using Stata 12.0 software. RESULTS: A total of 2,145 patients undergoing catheter ablation were included. Patients with rs2200733 TT or TT+CT showed an overall increased susceptibility to AF recurrence (homozygous model [TT vs. CC]: odds ratio [OR] = 2.03, 95% confidence interval [CI] 1.49 2.76, p = 0.000; dominant model [TT+TC vs. CC]: OR = 1.48, 95% CI 1.17-1.87, p = 0.001; recessive model [TT vs. TC+CC]: OR = 1.88, 95% CI 1.12-3.15, p = 0.017). Subgroup analysis also identified a positive relation in Caucasians and late recurrence of AF in allelic, homozygous and dominant comparison. Moreover, a significant increased risk of AF recurrence was observed in patients with rs10033464 TG or TT+TG (heterozygous model [TG vs. GG]: OR = 1.46, 95% CI 1.01 2.12, p = 0.047; dominant model [TT+TG vs. GG]: OR = 1.51, 95% CI 1.04-2.17, p = 0.029). CONCLUSIONS: After catheter ablation, rs2200733 (TT or TT+TC) and rs10033464 (TT+TG or TG) were associated with increased risk of AF recurrence. PMID- 29240961 TI - Anomalous origin of culprit coronary arteries in acute coronary syndromes. AB - BACKGROUND: To describe a series of acute coronary syndrome (ACS) patients in whom anomalous origin of culprit coronary artery (AOCCA) was diagnosed. Percutaneous coronary interventions (PCI) in AOCCA are performed very infrequently. METHODS: Electronic databases from three high-volume tertiary cardiac centers were retrospectively searched for the presence of AOCCA in ACS. RESULTS: Different types of AOCCA in ACS were identified in 20 patients. The most frequent AOCCA was left circumflex coronary artery (LCx) originating from right coronary artery (RCA) or directly from the right coronary sinus (RCS), n = 13, followed by high/atypical RCA, n = 3, LCA originating from RCS (n = 3) with either RCA-AOCCA (n = 1) or left anterior descending coronary artery (LAD)-AOCCA (n = 1) or RCA originating from left sinus of Valsalva, (n = 1), LAD originating from RCA (n = 1). In 1 ST-elevation myocardial infarction (STEMI)-patient RCA AOCCA cannulation was unsuccessful, in 1 non-STEMI-patient AOCCA was missed, 1 ACS-patient was treated surgically and 1 ACS-patient was treated conservatively (both patients with non-STEMI). In the remaining patients PCI was successfully performed. CONCLUSIONS: The most frequently encountered AOCCA is LCx branching off from RCA. AOCCA may either be difficult to cannulate and PCI aborted even in STEMI, or missed, especially when the intermediate branch from LCA is mimicking proper LCx. PMID- 29240962 TI - Long-term outcomes after percutaneous revascularization of complex coronary bifurcation lesions using a dedicated self-expanding biolimus-eluting stent system. AB - BACKGROUND: To evaluate long-term clinical outcomes after treatment of complex bifurcation lesions with the AXXESS dedicated self-expanding biolimus A9-eluting bifurcation stent. METHODS: Between 2004 and 2013, 123 patients with complex bifurcation lesions were treated in a single-center with the AXXESS stent in the proximal main vessel (MV) and additional drug-eluting stents in branches when required. Median follow-up was 5 years. Primary endpoint was the rate of major adverse cardiac events (MACE). Secondary endpoints included MACE components (cardiac death, non-periprocedural clinical myocardial infarction [MI], target lesion revascularization [TLR] and definite/probable stent thrombosis [ST]) as well as all-cause death, target vessel revascularization (TVR) and non-TVR. RESULTS: During follow-up, 11 (8.9%) patients experienced a MACE, of whom 2 (1.6%) suffered cardiac death, 2 (1.6%) had a non-periprocedural clinical MI requiring TLR, and 7 (5.7%) underwent elective TLR. No definite/probable ST was observed. All-cause death occurred in 9 (7.3%) patients, TVR in 11 (8.9%) and non TVR in 11 (8.9%). Patients treated for left main (LM) bifurcation lesions were more likely to experience MACE than non-LM bifurcation lesions (25% vs. 6.5%, p = 0.04). CONCLUSIONS: Percutaneous revascularization of complex bifurcation lesions with the AXXESS stent is safe and provides excellent long-term results, especially in non-LM lesions. PMID- 29240963 TI - Proximal buddy in jail technique: A bail out technique to increase guide support. AB - BACKGROUND: During percutaneous coronary intervention, "buddy-in-jail" technique is often used to facilitate stent delivery in complex coronary artery lesions. However, the safety and efficacy of this tech-nique when used with different jailed wire and applied in different target vessel lesions remain elusive. The aim of this retrospective study was to analyze the effectiveness of "buddy-in jail" technique in the tortuous and rigid lesions of both the common and neighboring coronary arteries. The effectiveness between hydrophilic-coated and non-hydrophilic-coated guide wire as jailed wires was also compared. METHODS: The "buddy-in-jail" technique was applied in 15 patients after failed balloon or stent delivery into the target vessel lesion from June 2014 to December 2016. The safety and effectiveness of the "bud-dy-in-jail" technique was compared in the tortuous and rigid lesions of both the common and neighbor-ing coronary arteries and between hydrophilic-coated and non-hydrophilic-coated "jailed" wires. RESULTS: Stent delivery was successful in 13 (86.7%) patients with the use of "buddy-in-jail" technique. The success rate was similar to the group using the common artery (87.5%) as a "buddy" vessel and the group using a neighboring artery (85.7%) as a "buddy" vessel (p > 0.05), and between hydrophilic- -coated (100%) and non-hydrophilic-coated "jailed" wire (77.8%) group (p > 0.05). All wires were successfully extracted without complications. CONCLUSIONS: The "buddy in-jail" technique offers a potential alternative approach for the distal stent delivery in both the common and neighboring coronary arteries. Also, both hydrophilic and non-hydro-philic-coated wire could be safely and effectively used as "jailed" wire. PMID- 29240964 TI - Psycho-emotional disorders as incoming risk factors for myocardial infarction with non-obstructive coronary arteries. AB - BACKGROUND: There is an emerging field underlying the myocardial infarction (MI) with non-obstruc-tive coronary arteries (MINOCA). The aim of this study was to evaluate the impact of psycho-emotional disorders and social habits in MINOCA patients. METHODS: The study included 95 consecutive patients diagnosed of MINOCA and 178 patients with MI and obstructive lesions. MINOCA patients were included when they fulfilled the three main criteria: accomplishment of the Third Universal Definition of Myocardial Infarction, absence of obstructive coronary arteries and no clinically overt specific cause for the acute presentation. RESULTS: MINOCA patients had a higher frequency of previous psychiatric illnesses than the obstructive coronary arteries group (29.7% vs. 12.9%, p = 0.001). MINOCA patients recognized emotional stress in 75.7% of the cases, while only 32.1% of the obstructive related group did (p < 0.001). The relation-ship remained after excluding takotsubo syndrome from the analysis (26 cases, 27.4%): psychiatric diseases (27.9% vs. 12.9%, p < 0.01) and recognition of emotional stress (70.8% vs. 32.1%, p < 0.001). Social habits which could act as stress modulating showed no significant relation with MINOCA. CONCLUSIONS: Psycho-emotional disorders are related to MINOCA and they could act as risk fac-tor. This relationship is maintained after excluding takotsubo from the analysis. (Cardiol J 2018; 25, 1: 24-31). PMID- 29240965 TI - Clinical impact of repolarization changes in supine versus upright body position. AB - BACKGROUND: The impact of postural changes on various electrocardiography (ECG) characteristics has only been assessed in a few small studies. This large prospective trial was conducted to confirm or refute preliminary data and add important results with immediate impact on daily clinical practice. METHODS: ECGs in supine and upright position from 1028 patients were analyzed. Evaluation was made according to changes in T-wave vector and direction, ST-segment deviation, heart rate, QT interval and QTc interval was performed. Findings were correlated with the medical history of patients. RESULTS: Positional change from supine to upright resulted in a significantly increased heart rate (8.05 +/- 7.71 bpm) and a significantly increased QTc interval after Bazetts (18 +/- 23.45 ms) and Fridericas (8.84 +/- 17.30) formula. In the upright position significantly more T waves turned negative (14.7%) than positive (5.7%). ST elevation was recorded in only 0.4% and ST depression in not more than 0.2% of all patients. CONCLUSIONS: The majority of the patients do not show significant morphological changes in their ECG by changing the body position from supine to upright. Changes of QTc time instead, are significant and the interval might be overestimated in upright. Therefore assessment of the QTc interval should strictly be done in a supine position. PMID- 29240966 TI - Sustainable Carbon/Carbon Supercapacitors Operating Down to -40 degrees C in Aqueous Electrolyte Made with Cholinium Salt. AB - Cholinium chloride at a concentration of 5 mol kg-1 in water is proposed as a low cost and environmentally friendly aqueous electrolyte, enabling extension of the operating range of carbon/carbon supercapacitors (SCs) down to -40 degrees C. This solution has a pH close to neutrality (pH 6.1) and high conductivity of 88 mS cm-1 at 24 degrees C. The supercapacitors demonstrate a high capacitance of 126 F g-1 (per mass of one electrode) and long life span at voltages up to 1.5 V. At -40 degrees C, the carbon/carbon SCs display excellent electrochemical characteristics with only slightly reduced capacitance of 106 F g-1 and negligible ohmic losses. As compared to previous works, where antifreezing additives were introduced in traditional neutral electrolytes, the low solubility of the salt and related poor conductivity of the solution is no longer an issue, which makes cholinium salt aqueous solutions very promising for SCs operating at sub-ambient temperature conditions. PMID- 29240967 TI - Cryptogenic hepatocellular carcinoma (HCC) had worse overall survival of disease than viral HCC patients. PMID- 29240968 TI - Monitoring of spoilage-associated microbiota on modified atmosphere packaged beef and differentiation of psychrophilic and psychrotrophic strains. AB - AIMS: This study aimed to explore the discriminatory power of MALDI-TOF MS as a high-throughput method to monitor growth dynamics of meat-spoiling bacteria on modified atmosphere packaged (MAP) beef and to differentiate psychrophilic and psychrotrophic spoilage-associated strains. METHODS AND RESULTS: MAP beef steaks were incubated for 21 days at constant 4 and 10 degrees C. Development of headspace gas composition, pH, CFU and spoilage-associated microbial composition were monitored. MALDI-TOF MS exhibited high discriminatory power for reliable, high-throughput identification of spoilage-associated, psychrotrophic microbiota. Microbiota development was highly dependent on initial abundance of specific species. Organoleptic onset of spoilage was concomitant with an alteration of headspace atmosphere and pH. Screening for psychrophiles at 4 degrees C on beef revealed the abundance of Leuconostoc gelidum subsp. gelidum TMW2.1998 with characteristic psychrophilic growth behaviour. CONCLUSIONS: We suggest that control of initial contaminants is crucial to predict the onset of spoilage and that headspace atmosphere and pH are important parameters with spoilage indicative potential. SIGNIFICANCE AND IMPACT OF THE STUDY: MALDI-TOF MS proved suitable for high-resolution monitoring of psychrotrophic and psychrophilic spoilage-associated microbiota and enables improved insights in the spoilage progress. The presence of psychrophilic strains on beef is the likely causative for unexplained spoilage events. PMID- 29240969 TI - Well-Defined Heterobimetallic Reactivity at Unsupported Ruthenium-Indium Bonds. AB - The hydride complex [Ru(IPr)2 (CO)H][BArF4 ], 1, reacts with InMe3 with loss of CH4 to form [Ru(IPr)2 (CO)(InMe)(Me)][BArF4 ], 4, featuring an unsupported Ru-In bond with unsaturated Ru and In centres. 4 reacts with H2 to give [Ru(IPr)2 (CO)(eta2 -H2 )(InMe)(H)][BArF4 ], 5, while CO induces formation of the indyl complex [Ru(IPr)2 (CO)3 (InMe2 )][BArF4 ], 7. These observations highlight the ability of Me to shuttle between Ru and In centres and are supported by DFT calculations on the mechanism of formation of 4 and its reactions with H2 and CO. An analysis of Ru-In bonding in these species is also presented. Reaction of 1 with GaMe3 also involves CH4 loss but, in contrast to its In congener, sees IPr transfer from Ru to Ga to give a gallyl complex featuring an eta6 interaction of one aryl substituent with Ru. PMID- 29240970 TI - Rumen bacteria at work: bioaugmentation strategies to enhance biogas production from cow manure. AB - AIMS: To investigate the effects of different bioaugmentation strategies for enhancing the biogas production from cow manure and evaluate microbial community patterns. METHODS AND RESULTS: Co-inoculation with cow rumen fluid and cow rumen derived enriched microbial consortia was evaluated in anaerobic batch tests at 36 degrees C and 41 degrees C. Singular addition of both rumen fluid and enriched bioaugmentation culture had a promising enhancement on methane yields; however, the highest methane yield (311 ml CH4 per gram VS at 41 degrees C) was achieved when the anaerobic seed sludge was co-inoculated together with rumen fluid and enriched bioaugmentation culture. Bacterial community profiles were investigated by Ion PGM Platform, and specific lignocellulolytic bacteria dynamics in batch tests were assessed by qPCR. The temperature had minor effects on the abundance of bacterial community; in which Bacteroidetes and Firmicutes were the most abundant phyla in all digesters. Furthermore, Rikenellaceae, Clostridiaceae, Porphyromonadaceae, Bacteroidaceae and Ruminococcaceae played a crucial role during the anaerobic degradation of cow manure. There was an important impact of Firmicutes flavefaciens and Ruminococcus albus at 41 degrees C, which in turn positively affected the methane production. CONCLUSION: The degree of enhancement in biogas production can be upgraded by the co-inoculation of rumen-derived bioaugmentation culture with anaerobic seed sludge with high methanogenic activity. SIGNIFICANCE AND IMPACT OF THE STUDY: A close look at the biotic interactions and their associations with abiotic factors might be valuable for evaluating rumen-related bioaugmentation applications. PMID- 29240971 TI - Functional limitation of the masticatory system in patients with bulbar involvement in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) with bulbar dysfunction affects the motor neurons responsible for controlling the muscles in the jaw, face, soft palate, pharynx, larynx and tongue. This cross-sectional study aimed to determine the functional limitation of the jaw in patients with ALS and bulbar dysfunction who had upper motor neuron (UMN), lower motor neuron (LMN) or balanced involvement. One hundred and fifty-three patients with ALS and 23 controls were included. All participants answered using the 8-item Jaw Functional Limitation Scale (JFLS-8). Patients with ALS were grouped by neurologic examination as follows: non-bulbar ALS, bulbar UMN-predominant ALS; bulbar LMN-predominant ALS; and bulbar balanced (UMN + LMN) ALS. Jaw limitation between the different groups was compared using the Kruskal-Wallis test. Patients with non-bulbar ALS had similar mandibular limitations to healthy participants. Only patients with balanced UMN and LMN bulbar manifestations reported greater difficulties in chewing soft food or in jaw mobility compared to the non-bulbar ALS group. Patients with bulbar involvement also had greater difficulties in chewing tough food or chicken and in swallowing and talking compared to the non-bulbar group, regardless of whether UMN or LMN predominant. No significant differences were found between the groups in smiling and yawning difficulties. Bulbar involvement in patients with ALS is associated with functional limitation of the masticatory system. However, balanced bulbar UMN and LMN involvement is associated with the worst impairments in chewing soft food and in opening the jaw widely. PMID- 29240972 TI - Evidence for Dynamic Chemical Kinetics at Individual Molecular Ruthenium Catalysts. AB - Catalytic cycles are typically depicted as possessing time-invariant steps with fixed rates. Yet the true behavior of individual catalysts with respect to time is unknown, hidden by the ensemble averaging inherent to bulk measurements. Evidence is presented for variable chemical kinetics at individual catalysts, with a focus on ring-opening metathesis polymerization catalyzed by the second generation Grubbs' ruthenium catalyst. Fluorescence microscopy is used to probe the chemical kinetics of the reaction because the technique possesses sufficient sensitivity for the detection of single chemical reactions. Insertion reactions in submicron regions likely occur at groups of many (not single) catalysts, yet not so many that their unique kinetic behavior is ensemble averaged. PMID- 29240973 TI - A Breathing Atom-Transfer Radical Polymerization: Fully Oxygen-Tolerant Polymerization Inspired by Aerobic Respiration of Cells. AB - The first well-controlled aqueous atom-transfer radical polymerization (ATRP) conducted in the open air is reported. This air-tolerant ATRP was enabled by the continuous conversion of oxygen to carbon dioxide catalyzed by glucose oxidase (GOx), in the presence of glucose and sodium pyruvate as sequential sacrificial substrates. Controlled polymerization using initiators for continuous activator regeneration (ICAR) ATRP of oligo(ethylene oxide) methyl ether methacrylate (OEOMA, Mn =500) yielded polymers with low dispersity (1.09<=D<=1.29) and molecular weights (MWs) close to theoretical values in the presence of pyruvate. Without added pyruvates, lower MWs were observed due to generation of new chains by H2 O2 formed by reaction of O2 with GOx. Successful chain extension of POEOMA500 macroinitiator with OEOMA300 (D<=1.3) and Bovine Serum Albumin bioconjugates (D<=1.22) confirmed a well-controlled polymerization. The reactions in the open air in larger scale (25 mL) were also successful. PMID- 29240974 TI - Increased xylose affinity of Hxt2 through gene shuffling of hexose transporters in Saccharomyces cerevisiae. AB - AIMS: Optimizing D-xylose transport in Saccharomyces cerevisiae is essential for efficient bioethanol production from cellulosic materials. We have used a gene shuffling approach of hexose (Hxt) transporters in order to increase the affinity for D-xylose. METHODS AND RESULTS: Various libraries were transformed to a hexose transporter deletion strain, and shuffled genes were selected via growth on low concentrations of D-xylose. This screening yielded two homologous fusion proteins (fusions 9,4 and 9,6), both consisting of the major central part of Hxt2 and various smaller parts of other Hxt proteins. Both chimeric proteins showed the same increase in D-xylose affinity (8.1 +/- 3.0 mmol l-1 ) compared with Hxt2 (23.7 +/- 2.1 mmol l-1 ). The increased D-xylose affinity could be related to the C terminus, more specifically to a cysteine to proline mutation at position 505 in Hxt2. CONCLUSIONS: The Hxt2C505P mutation increased the affinity for D-xylose for Hxt2, thus providing a way to increase D-xylose transport flux at low D xylose concentration. SIGNIFICANCE AND IMPACT OF THE STUDY: The gene shuffling protocol using the highly homologues hexose transporters family provides a powerful tool to enhance the D-xylose affinity of Hxt transporters in S. cerevisiae, thus providing a means to increase the D-xylose uptake flux at low D xylose concentrations. PMID- 29240975 TI - Macroecological patterns of sexual size dimorphism in turtles of the world. AB - Sexual size dimorphism (SSD) is a well-documented phenomenon in both plants and animals; however, the ecological and evolutionary mechanisms that drive and maintain SSD patterns across geographic space at regional and global scales are understudied, especially for reptiles. Our goal was to examine geographic variation of turtle SSD and to explore ecological and environmental correlates using phylogenetic comparative methods. We use published body size data on 135 species from nine turtle families to examine how geographic patterns and the evolution of SSD are influenced by habitat specialization, climate (annual mean temperature and annual precipitation) and climate variability, latitude, or a combination of these predictor variables. We found that geographic variation, magnitude and direction of turtle SSD are best explained by habitat association, annual temperature variance and annual precipitation. Use of semi-aquatic and terrestrial habitats was associated with male-biased SSD, whereas use of aquatic habitat was associated with female-biased SSD. Our results also suggest that greater temperature variability is associated with female-biased SSD. In contrast, wetter climates are associated with male-biased SSD compared with arid climates that are associated with female-biased SSD. We also show support for a global latitudinal trend in SSD, with females being larger than males towards the poles, especially in the families Emydidae and Geoemydidae. Estimates of phylogenetic signal for both SSD and habitat type indicate that closely related species occupy similar habitats and exhibit similar direction and magnitude of SSD. These global patterns of SSD may arise from sex-specific reproductive behaviour, fecundity and sex-specific responses to environmental factors that differ among habitats and vary systematically across latitude. Thus, this study adds to our current understanding that while SSD can vary dramatically across and within turtle species under phylogenetic constraints, it may be driven, maintained and exaggerated by habitat type, climate and geographic location. PMID- 29240976 TI - Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events. AB - BACKGROUND: Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. Adding a second antiplatelet drug to aspirin may produce additional benefit for people at high risk and people with established cardiovascular disease. This is an update to a previously published review from 2011. OBJECTIVES: To review the benefit and harm of adding clopidogrel to aspirin therapy for preventing cardiovascular events in people who have coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or were at high risk of atherothrombotic disease, but did not have a coronary stent. SEARCH METHODS: We updated the searches of CENTRAL (2017, Issue 6), MEDLINE (Ovid, 1946 to 4 July 2017) and Embase (Ovid, 1947 to 3 July 2017) on 4 July 2017. We also searched ClinicalTrials.gov and the WHO ICTRP portal, and handsearched reference lists. We applied no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials comparing over 30 days use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in people with coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease. We excluded studies including only people with coronary drug-eluting stent (DES) or non-DES, or both. DATA COLLECTION AND ANALYSIS: We collected data on mortality from cardiovascular causes, all-cause mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, major and minor bleeding. The overall treatment effect was estimated by the pooled risk ratio (RR) with 95% confidence interval (CI), using a fixed-effect model (Mantel-Haenszel); we used a random-effects model in cases of moderate or severe heterogeneity (I2 >= 30%). We assessed the quality of the evidence using the GRADE approach. We used GRADE profiler (GRADE Pro) to import data from Review Manager to create a 'Summary of findings' table. MAIN RESULTS: The search identified 13 studies in addition to the two studies in the previous version of our systematic review. Overall, we included data from 15 trials with 33,970 people. We completed a 'Risk of bias' assessment for all studies. The risk of bias was low in four trials because they were at low risk of bias for all key domains (random sequence generation, allocation concealment, blinding, selective outcome reporting and incomplete outcome data), even if some of them were funded by the pharmaceutical industry.Analysis showed no difference in the effectiveness of aspirin plus clopidogrel in preventing cardiovascular mortality (RR 0.98, 95% CI 0.88 to 1.10; participants = 31,903; studies = 7; moderate quality evidence), and no evidence of a difference in all-cause mortality (RR 1.05, 95% CI 0.87 to 1.25; participants = 32,908; studies = 9; low quality evidence).There was a lower risk of fatal and non-fatal myocardial infarction with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 0.78, 95% CI 0.69 to 0.90; participants = 16,175; studies = 6; moderate quality evidence). There was a reduction in the risk of fatal and non-fatal ischaemic stroke (RR 0.73, 95% CI 0.59 to 0.91; participants = 4006; studies = 5; moderate quality evidence).However, there was a higher risk of major bleeding with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 1.44, 95% CI 1.25 to 1.64; participants = 33,300; studies = 10; moderate quality evidence) and of minor bleeding (RR 2.03, 95% CI 1.75 to 2.36; participants = 14,731; studies = 8; moderate quality evidence).Overall, we would expect 13 myocardial infarctions and 23 ischaemic strokes be prevented for every 1000 patients treated with the combination in a median follow-up period of 12 months, but 9 major bleeds and 33 minor bleeds would be caused during a median follow-up period of 10.5 and 6 months, respectively. AUTHORS' CONCLUSIONS: The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infarction and ischaemic stroke, and an increased risk of major and minor bleeding compared with aspirin alone. According to GRADE criteria, the quality of evidence was moderate for all outcomes except all-cause mortality (low quality evidence) and adverse events (very low quality evidence). PMID- 29240977 TI - Broadband homonuclear decoupled HSQMBC methods. AB - Long-range heteronuclear coupling constants convey invaluable information for stereochemical and conformational analysis of molecules from synthetic and natural origin. Here, we report a real-time Zangger-Sterk CPMG-HSQMBC method for the precise and direct measurement of multiple-bond heteronuclear couplings. It is demonstrated that the real-time acquisition strategy combined with multiple slice selective excitation can provide substantial improvement in sensitivity (or reduction of experimental time) as compared to other variants of broadband homonuclear decoupled HSQMBC methods published previously. Scope and limitations of the different strategies applied for decoupling are reviewed. Moreover, practical guidelines for the choice of the most appropriate method are also presented. Applications are given on a metal complex incorporating P-heterocycles and two diglycosyl-selenides for the extraction of n J(1 H, 31 P) and n J(1 H, 77 Se), respectively. PMID- 29240978 TI - Biomimicry of volatile-based microbial control for managing emerging fungal pathogens. AB - Volatile organic compounds (VOCs) are known to be produced by a wide range of micro-organisms and for a number of purposes. Volatile-based microbial inhibition in environments such as soil is well-founded, with numerous antimicrobial VOCs having been identified. Inhibitory VOCs are of interest as microbial control agents, as low concentrations of gaseous VOCs can elicit significant antimicrobial effects. Volatile organic compounds are organic chemicals typically characterized as having low molecular weight, low solubility in water, and high vapour pressure. Consequently, VOCs readily evaporate to the gaseous phase at standard temperature and pressure. This contact-independent antagonism presents unique advantages over traditional, contact-dependent microbial control methods, including increased surface exposure and reduced environmental persistence. This approach has been the focus of our recent research, with positive results suggesting it may be particularly promising for the management of emerging fungal pathogens, such as the causative agents of white-nose syndrome of bats and snake fungal disease, which are difficult or impossible to treat using traditional approaches. Here, we review the history of volatile-based microbial control, discuss recent progress in formulations that mimic naturally antagonistic VOCs, outline the development of a novel treatment device, and highlight areas where further work is needed to successfully deploy VOCs against existing and emerging fungal pathogens. PMID- 29240980 TI - A Simple and Efficient Method of Extracting DNA from Aged Bones and Teeth. AB - DNA is often difficult to extract from old bones and teeth due to low levels of DNA and high levels of degradation. This study established a simple yet efficient method for extracting DNA from 20 aged bones and teeth (approximately 60 years old). Based on the concentration and STR typing results, the new method of DNA extraction (OM) developed in this study was compared with the PrepFilerTM BTA Forensic DNA Extraction Kit (BM). The total amount of DNA extracted using the OM method was not significantly different from that extracted using the commercial kit (p > 0.05). However, the number of STR loci detected was significantly higher in the samples processed using the OM method than using the BM method (p < 0.05). This study aimed to establish a DNA extraction method for aged bones and teeth to improve the detection rate of STR typing and reduce costs compared to the BM technique. PMID- 29240979 TI - Brief Exposures to the Taste of Ethanol (EtOH) and Quinine Promote Subsequent Acceptance of EtOH in a Paradigm that Minimizes Postingestive Consequences. AB - BACKGROUND: Aversion to the orosensory properties of concentrated ethanol (EtOH) solutions is often cited as a primary barrier to initiation of drinking and may contribute to abstention. These aversive properties include gustatory processes which encompass both bitter-like taste qualities and trigeminal-mediated irritation. Chronic intermittent EtOH access (CIA) results in substantial and persistent increases in EtOH consumption, but the degree to which this facilitation involves sensory responding to EtOH and other bitter stimuli is currently undetermined. METHODS: Long-Evans rats were given brief-access licking tests designed to examine the immediate, taste-guided assessment of the palatability of EtOH and quinine solutions. Rats were assessed once in a naive state and again following previous brief-access exposure, or following 4 weeks of CIA. The relationship between the sensitivity to the aversive orosensory properties of EtOH and quinine following EtOH access and the impact of antecedent quinine exposure on the acceptance of EtOH were determined in 2 parallel studies. RESULTS: Both brief access to EtOH and 4-week CIA resulted in substantial rightward shifts in the concentration-response function of brief-access EtOH licking, indicating that EtOH exposure increased acceptance of the taste of EtOH. The initial sensitivity to the aversive orosensory properties of EtOH and quinine was positively correlated in naive rats, such that rats that were initially more accepting of quinine were also more accepting of EtOH. Rats that sampled quinine immediately prior to tasting EtOH exhibited successive positive contrast in that they were more accepting of highly concentrated EtOH, relative to a water-control group. CONCLUSIONS: Increased EtOH acceptance following exposure is, at least in part, facilitated by a decrease in its aversive sensory properties. Both long- and short-term access increase the palatability of the taste of EtOH in brief access licking tests. Moreover, the sensitivity to the bitterness of quinine was predictive of acceptance of EtOH indicating some commonality in the sensory mechanisms that mediate the initial acceptance of the 2 stimuli. Accordingly, immediate prior exposure to quinine results in increased acceptance of EtOH, suggesting that successive positive contrast between oral stimuli may contribute to increased alcohol consumption. PMID- 29240981 TI - Sulfoxide-Induced Homochiral Folding of ortho-Phenylene Ethynylenes (o-OPEs) by Silver(I) Templating: Structure and Chiroptical Properties. AB - A new family of homochiral silver complexes based on carbophilic interactions with ortho-phenylene ethynylene (o-OPE) scaffolds containing up to two silver atoms are described. These compounds represent a unique class of complexes with chirality at the metal. Chiral induction is based on the inclusion of chiral sulfoxides, which allow efficient transfer of chirality to the helically folded o OPE, leading to circularly polarized luminescence (CPL)- and vibrational circular dichroism (VCD)-active compounds. In the presence of silver(I) cations, carbophilic interactions dominate, which promote helical structures with a defined helicity. This is one of the very scarce examples of the use of such interactions in the attractive field of abiotic foldamers. The switching event has been extensively studied by using different chiroptical techniques, including circular dichroism, CPL, and VCD, and represents one of the few CPL switches described in the literature. PMID- 29240982 TI - Multidimensional Bone Density Phenotyping Reveals New Insights Into Genetic Regulation of the Pediatric Skeleton. AB - Osteoporosis is a complex disease with developmental origins. It is therefore important to understand the genetic contribution to pediatric areal bone mineral density (aBMD). Individual skeletal site phenotyping has been primarily used to identify pediatric aBMD loci. However, this approach is limited because there is a degree of aBMD discordance across skeletal sites. We therefore applied a novel multidimensional phenotyping approach to further understand the genetic regulation of pediatric aBMD. Our sample comprised a prospective, longitudinal cohort of 1293 children of European ancestry (52% female; up to seven annual measurements). Principal components analysis was applied to dual-energy X-ray absorptiometry-derived aBMD Z-scores for total hip, femoral neck, spine, and distal radius to generate multidimensional aBMD phenotypes (ie, principal component scores). We tested the association between a genetic score (percentage of bone lowering alleles at 63 loci) and each principal component. We also performed a genomewide association study (GWAS) using the multiethnic baseline data (n = 1885) to identify novel loci associated with these principal components. The first component (PC1) reflected a concordant phenotypic model of the skeleton (eg, higher loading score = higher BMD across all sites). In contrast, PC2 was discordant for distal radius versus spine and hip aBMD, and PC3 was discordant for spine versus distal radius and hip aBMD. The genetic score was associated with PC1 (beta = -0.05, p = 3.9 * 10-10 ), but was not associated with discordant PC2 or PC3. Our GWAS discovered variation near CPED1 that associated with PC2 (rs67991850, p = 2.5 * 10-11 ) and near RAB11FIP5 (rs58649746, p = 4.8 * 10-9 ) that associated with PC3. In conclusion, an established bone fragility genetic summary score was associated with a concordant skeletal phenotype, but not discordant skeletal phenotypes. Novel associations were observed for the discordant multidimensional skeletal phenotypes that provide new biological insights into the developing skeleton. (c) 2017 American Society for Bone and Mineral Research. PMID- 29240984 TI - Pentacene Excitons in Strong Electric Fields. AB - Electroluminescence spectroscopy of organic semiconductors in the junction of a scanning tunneling microscope (STM) provides access to the polarizability of neutral excited states in a well-characterized molecular geometry. We study the Stark shift of the self-trapped lowest singlet exciton at 1.6 eV in a pentacene nanocrystal. Combination of density functional theory (DFT) and time-dependent DFT (TDDFT) with experiment allows for assignment of the observation to a charge transfer (CT) exciton. Its charge separation is perpendicular to the applied field, as the measured polarizability is moderate and the electric field in the STM junction is strong enough to dissociate a CT exciton polarized parallel to the applied field. The calculated electric-field-induced anisotropy of the exciton potential energy surface will also be of relevance to photovoltaic applications. PMID- 29240983 TI - Human UGT2B7 is the major isoform responsible for the glucuronidation of clopidogrel carboxylate. AB - Clopidogrel is predominantly hydrolyzed to clopidogrel carboxylic acid (CCA) by carboxylesterase 1, and subsequently CCA is glucuronidated to clopidogrel acyl glucuronide (CAG) by uridine diphosphate-glucuronosyltransferases (UGTs); however, the UGT isoenzymes glucuronidating CCA remain unidentified to date. In this study, the glucuronidation of CCA was screened with pooled human liver microsomes (HLMs) and 7 human recombinant UGT (rUGT) isoforms. Results indicated that rUGT2B7 exhibited the highest catalytical activity for the CCA glucuronidation as measured with a mean Vmax value of 120.9 pmol/min/mg protein, 3- to 12-fold higher than that of the other rUGT isoforms tested. According to relative activity factor approach, the relative contribution of rUGT2B7 to CCA glucuronidation was estimated to be 58.6%, with the minor contributions (3%) from rUGT1A9. Moreover, the glucuronidation of CCA followed Michaelis-Menten kinetics with a mean Km value of 372.9 MUM and 296.4 MUM for pooled HLMs and rUGT2B7, respectively, showing similar affinity for both. The formation of CAG was significantly inhibited by azidothymidine and gemfibrozil (well-characterized UGT2B7 substrates) in a concentration-dependent manner, or by fluconazole (a typical UGT2B7-selective inhibitor) in a time-dependent manner, for both HLMs and rUGT2B7, respectively. In addition, CCA inhibited azidothymidine glucuronidation (catalyzed almost exclusively by UGT2B7) by HLMs and rUGT2B7 in a concentration dependent manner, indicating that CCA is a substrate of UGT2B7. These results reveal that UGT2B7 is the major enzyme catalyzing clopidogrel glucuronidation in the human liver, and that there is the potential for drug-drug interactions between clopidogrel and the other substrate drugs of UGT2B7. PMID- 29240985 TI - Serological responses to revaccination with hepatitis A virus (HAV) vaccines among HIV-positive individuals whose anti-HAV antibody waned after primary vaccination. AB - BACKGROUND: Among HIV-positive individuals, seroprotection for hepatitis A virus (HAV) following primary vaccination may wane with time. However, seroresponses to HAV revaccination are rarely investigated among HIV-positive patients who have lost protective antibodies after primary vaccination. METHODS: During the outbreak of acute hepatitis A in Taiwan after June 2015, HAV-seronegative, HIV positive individuals were advised to receive two doses of HAV vaccines at 24 weeks apart. A retrospective 1:2 matched case-control study was conducted to compare the seroresponses at weeks 4, 24, 28 and 48 of HAV vaccination between those who underwent revaccination after having lost protective antibodies (case patients) and those who underwent primary vaccination (controls). RESULTS: Seventy-five case patients and 150 matched controls were included. The serological response rates were consistently higher among the case patients than controls: 88.1% vs 10.5% at week 4 following the first dose of HAV vaccination (P < .001); 93.3% vs 46.0% at week 24 (immediately before the second dose; P < .001); 98.7% vs 62.7% at week 28 (4 weeks after the second dose; P < .001) and 98.7% vs 92.7% at week 48 (P = .06). The anti-HAV antibody titres as reflected by the semi-quantitative assay for the case patients were also significantly higher than the controls at weeks 24, 28 and 48 following HAV vaccination. CONCLUSIONS: We demonstrated faster and better serological responses to HAV revaccination among the HIV-positive individuals who had lost their anti-HAV antibodies after primary vaccination. Single dose of HAV revaccination may provide rapid and sufficient seroresponses for HAV during the outbreak of acute hepatitis A. PMID- 29240987 TI - NMR Study of Rcf2 Reveals an Unusual Dimeric Topology in Detergent Micelles. AB - The Saccharomyces cerevisiae mitochondrial respiratory supercomplex factor 2 (Rcf2) plays a role in assembly of supercomplexes composed of cytochrome bc1 (complex III) and cytochrome c oxidase (complex IV). We expressed the Rcf2 protein in Escherichia coli, refolded it, and reconstituted it into dodecylphosphocholine (DPC) micelles. The structural properties of Rcf2 were studied by solution NMR, and near complete backbone assignment of Rcf2 was achieved. The secondary structure of Rcf2 contains seven helices, of which five are putative transmembrane (TM) helices, including, unexpectedly, a region formed by a charged 20-residue helix at the C terminus. Further studies demonstrated that Rcf2 forms a dimer, and the charged TM helix is involved in this dimer formation. Our results provide a basis for understanding the role of this assembly/regulatory factor in supercomplex formation and function. PMID- 29240988 TI - Photoinduced Cobalt(III)-Trifluoromethyl Bond Activation Enables Arene C-H Trifluoromethylation. AB - Visible-light capture activates a thermodynamically inert CoIII -CF3 bond for direct C-H trifluoromethylation of arenes and heteroarenes. New trifluoromethylcobalt(III) complexes supported by a redox-active [OCO] pincer ligand were prepared. Coordinating solvents, such as MeCN, afford green, quasi octahedral [(S OCO)CoIII (CF3 )(MeCN)2 ] (2), but in non-coordinating solvents the complex is red, square pyramidal [(S OCO)CoIII (CF3 )(MeCN)] (3). Both are thermally stable, and 2 is stable in light. But exposure of 3 to low-energy light results in facile homolysis of the CoIII -CF3 bond, releasing . CF3 radical, which is efficiently trapped by TEMPO. or (hetero)arenes. The homolytic aromatic substitution reactions do not require a sacrificial or substrate-derived oxidant because the CoII by-product of CoIII -CF3 homolysis produces H2 . The photophysical properties of 2 and 3 provide a rationale for the disparate light stability. PMID- 29240986 TI - The Essential Elements of a Risk Governance Framework for Current and Future Nanotechnologies. AB - Societies worldwide are investing considerable resources into the safe development and use of nanomaterials. Although each of these protective efforts is crucial for governing the risks of nanomaterials, they are insufficient in isolation. What is missing is a more integrative governance approach that goes beyond legislation. Development of this approach must be evidence based and involve key stakeholders to ensure acceptance by end users. The challenge is to develop a framework that coordinates the variety of actors involved in nanotechnology and civil society to facilitate consideration of the complex issues that occur in this rapidly evolving research and development area. Here, we propose three sets of essential elements required to generate an effective risk governance framework for nanomaterials. (1) Advanced tools to facilitate risk-based decision making, including an assessment of the needs of users regarding risk assessment, mitigation, and transfer. (2) An integrated model of predicted human behavior and decision making concerning nanomaterial risks. (3) Legal and other (nano-specific and general) regulatory requirements to ensure compliance and to stimulate proactive approaches to safety. The implementation of such an approach should facilitate and motivate good practice for the various stakeholders to allow the safe and sustainable future development of nanotechnology. PMID- 29240990 TI - Wnt signaling loss accelerates the appearance of neuropathological hallmarks of Alzheimer's disease in J20-APP transgenic and wild-type mice. AB - Alzheimer's disease (AD) is a neurodegenerative pathology characterized by aggregates of amyloid-beta (Abeta) and phosphorylated tau protein, synaptic dysfunction, and spatial memory impairment. The Wnt signaling pathway has several key functions in the adult brain and has been associated with AD, mainly as a neuroprotective factor against Abeta toxicity and tau phosphorylation. However, dysfunction of Wnt/beta-catenin signaling might also play a role in the onset and development of the disease. J20 APPswInd transgenic (Tg) mouse model of AD was treated i.p. with various Wnt signaling inhibitors for 10 weeks during pre symptomatic stages. Then, cognitive, biochemical and histochemical analyses were performed. Wnt signaling inhibitors induced severe changes in the hippocampus, including alterations in Wnt pathway components and loss of Wnt signaling function, severe cognitive deficits, increased tau phosphorylation and Abeta1-42 peptide levels, decreased Abeta42/Abeta40 ratio and Abeta1-42 concentration in the cerebral spinal fluid, and high levels of soluble Abeta species and synaptotoxic oligomers in the hippocampus, together with changes in the amount and size of senile plaques. More important, we also observed severe alterations in treated wild-type (WT) mice, including behavioral impairment, tau phosphorylation, increased Abeta1-42 in the hippocampus, decreased Abeta1-42 in the cerebral spinal fluid, and hippocampal dysfunction. Wnt inhibition accelerated the development of the pathology in a Tg AD mouse model and contributed to the development of Alzheimer's-like changes in WT mice. These results indicate that Wnt signaling plays important roles in the structure and function of the adult hippocampus and suggest that inhibition of the Wnt signaling pathway is an important factor in the pathogenesis of AD. Read the Editorial Highlight for this article on page 356. PMID- 29240991 TI - Consequences of Sphaeropsis tip blight disease for the phytohormone profile and antioxidative metabolism of its pine host. AB - Phytopathogenic fungi infections induce plant defence responses that mediate changes in metabolic and signalling processes with severe consequences for plant growth and development. Sphaeropsis tip blight, induced by the endophytic fungus Sphaeropsis sapinea that spreads from stem tissues to the needles, is the most widespread disease of conifer forests causing dramatic economic losses. However, metabolic consequences of this disease on bark and wood tissues of its host are largely unexplored. Here, we show that diseased host pines experience tissue dehydration in both bark and wood. Increased cytokinin and declined indole-3 acetic acid levels were observed in both tissues and increased jasmonic acid and abscisic acid levels exclusively in the wood. Increased lignin contents at the expense of holo-cellulose with declined structural biomass of the wood reflect cell wall fortification by S. sapinea infection. These changes are consistent with H2 O2 accumulation in the wood, required for lignin polymerization. Accumulation of H2 O2 was associated with more oxidized redox states of glutathione and ascorbate pools. These findings indicate that S. sapinea affects both phytohormone signalling and the antioxidative defence system in stem tissues of its pine host during the infection process. PMID- 29240992 TI - Heart rate recovery and diastolic blood pressure ratio on the treadmill test predict an induction and recurrence of vasovagal syncope. AB - Background/Aims: The induction and recurrence of syncope is a concerning situation that could be unpredicted in the vasovagal syncope (VVS). We investigated a simple predictor for the induced and recurrent VVS during Head-Up table-tilt Test (HUT) and clinically follow-up. Methods: The 143 consecutive patients with VVS (age 31 +/- 19 years, 33 male) who referred by a cardiologist or neurologist and had undergone an echocardiogram, HUT, and a treadmill exercise test (TMT) were recruited and clinically follow-up. Patients were divided into two groups based on the result of HUT and TMT. The data was analyzed and compared between VVS patients and control 141 patients without VVS who were enrolled in the same study period (age 40 +/- 5 years, 117 male). Results: The heart rate recovery (HRR), recovery systolic blood pressure (RecSBP), recovery diastolic blood pressure (RecDBP), HRR/RecSBP and HRR/RecDBP were significantly different between controls and VVS during the TMT. Within VVS, even if, baseline characteristics were similar between negative and positive HUT (n = 92 vs. n = 51). HRR (31 +/- 10 vs. 35 +/- 10), HRR/RecSBP (0.24 +/- 0.09 vs. 0.28 +/- 0.09) and HRR/RecDBP (0.49 +/- 0.18 vs. 0.58 +/- 0.19) were significantly different between negative and positive HUT results. Especially, HRR/RecSBP and HRR/RecDBP were significantly correlated with induced syncope with a sensitivity and specificity ([60%, 83%] cut-off, 0.31; [72%, 80%] cut-off, 0.63). In the Cox regression, HRR/ RecDBP were significantly associated with recurrence of VVS with hazard ratio of 3.29 (confidence interval, 0.95 to 11.3; p = 0.049). Conclusions: HRR/RecDBP may be a useful predictor for induction during HUT and recurrence during follow-up in the VVS. PMID- 29240993 TI - Quantifying Bioavailability of Pyrene Associated with Dissolved Organic Matter of Various Molecular Weights to Daphnia magna. AB - Dissolved organic matter (DOM) is a key environmental factor for the bioavailability of hydrophobic organic compounds (HOCs) in natural waters. However, the bioavailability of DOM-associated HOCs is not clear. In this research, pyrene was selected as a model HOC, and its freely dissolved concentration (Cfree) was maintained by passive dosing systems. The immobilization and pyrene content in the tissues excluding gut of Daphnia magna were examined to quantify the bioavailability of DOM-associated pyrene. The results indicated that DOM promoted the bioavailability of pyrene when the Cfree of pyrene was kept constant, and the bioavailability of pyrene associated with DOM of various molecular weights was ordered as middle molecular weight (5 000-10 000 Da) DOM > lower molecular weight (<1 000, 1 000-3 000, and 3 000-5 000 Da) DOM > higher molecular weight (>10 000 Da) DOM. The influencing mechanisms of DOM molecular weight were related with the partition of pyrene between DOM and water, the uptake routes of DOM by D. magna, and the desorption or release of pyrene from DOM in the gut of D. magna. The findings obtained in this research suggest that the bioavailability of DOM-associated HOCs should be taken into account for the eco-environmental risk assessment of HOCs in water systems. PMID- 29240994 TI - Using Mutations for Pesticide Resistance to Identify the Cause of Toxicity in Environmental Samples. AB - Traditional Toxicity Identification Evaluations (TIE) are applied to identify causal agents in complex environmental samples showing toxicity and rely upon physical or chemical manipulation of samples. However, mutations conferring toxicant resistance provide the opportunity for a novel biologically based TIE. Populations within the Hyalella azteca complex from pesticide-affected waterways were 2 and 3 orders of magnitude more resistant to the pyrethroid cyfluthrin and the organophosphate chlorpyrifos, respectively, than laboratory-cultured H. azteca widely used for toxicity testing. Three resistant populations, as well as laboratory-cultured, nonresistant H. azteca, were exposed to urban and agricultural runoff. Every sample causing death or paralysis in the nonresistant individuals had no effect on pyrethroid-resistant individuals, providing strong evidence that a pyrethroid was the responsible toxicant. The lack of toxicity to chlorpyrifos-sensitive, but pyrethroid-resistant, individuals suggested chlorpyrifos was not a likely toxicant, a hypothesis supported by chemical analysis. Since these mutations that confer resistance to pesticides are highly specific, toxicity to wild-type, but not resistant animals, provides powerful evidence of causality. It may be possible to identify strains resistant to even a wider variety of toxicants, further extending the potential use of this biologically based TIE technique beyond the pyrethroid and organophosphate resistant strains currently available. PMID- 29240995 TI - Monochromophoric Design Strategy for Tetrazine-Based Colorful Bioorthogonal Probes with a Single Fluorescent Core Skeleton. AB - Fluorogenic bioorthogonal probes are ideal for fluorescent imaging in live cell conditions. By taking advantage of the dual functionality of tetrazine (Tz), as a bioorthogonal reaction unit as well as a fluorescence quencher, a fluorophore-Tz conjugate (FLTz) has been utilized for fluorescent live cell imaging via inverse electron-demand Diels-Alder (iEDDA) type bioorthogonal reactions. However, most FLTz strategies rely on a donor-acceptor-type energy transfer mechanism, which limits red-shifting of probes' emission wavelength without deterioration of the fluorescent turn-on/off ratio. To address this constraint, herein we present a monochromophoric design strategy for making a series of FLTzs spanning a broad range of emission colors. For the systematic comparison of design strategies with minimized structural differences, we selected indolizine-based emission-tunable Seoul-Fluor (SF) as a model fluorophore system. As a result, by inducing strong electronic coupling between Tz and pi-conjugation systems of an indolizine core, we efficiently quench the fluorescence of SF-tetrazine conjugates (SFTzs) and achieved more than 1000-fold enhancement in fluorescence after iEDDA reaction with trans-cyclooctene (TCO). Importantly, we were able to develop a series of colorful SFTzs with a similar turn-on/off ratio regardless of their emission wavelength. The applicability as bioorthogonal probes was demonstrated with fluorescence bioimaging of innate microtubule and mitochondria using docetaxel TCO and triphenylphosphonium-TCO in live cells without washing steps. We believe this study could provide new insight for the reliable and generally applicable molecular design strategy to develop bioorthogonal fluorogenic probes having an excellent turn-on ratio, regardless of their emission wavelength. PMID- 29240996 TI - Transfer Mechanism, Uptake Kinetic Process, and Bioavailability of P, Cu, Cd, Pb, and Zn in Macrophyte Rhizosphere Using Diffusive Gradients in Thin Films. AB - The transfer-uptake-bioavailability of phosphorus (P), Cu, Cd, Zn, and Pb in rhizosphere of Zizania latifolia (ZL) and Myriophyllum verticiilaturn (MV) cultivated in rhizoboxes in Lake Erhai (China) is evaluated by DGT (diffusive gradients in thin films) technique. DGT induced fluxes in sediments (DIFS) model reveals that resupply ability (r), liable pool size in sediment solid (kd), kinetic parameter (k-1), or response time (Tc) control the diffusion-resupply characters of P and Cu (standing for four metals) in rhizosphere interface. The linear fitting curves of element content in ZL or MV roots (Croot) against DGT (CDGT), porewater (C0), or sediment concentration demonstrate that Croot for five elements can be predicted by CDGT more effectively than the other methods. (I) DOC (dissolved organic carbon) in porewater controlled by OM (organic matter) in solid plus pH for Cu and Cd or (II) DOP/DTP ratio in porewater (between dissolved organic P and dissolved total P) for P controlled by Fe-bound P and OM in solid, can affect phytoavailability in rhizosphere. They lead to (I) the larger slope (s) and the linear regression coefficient (R2) in the first part than those for the complete fitting curve (ZL or MV root against CDGT(Cu) or C0(Cu) and MV root against CDGT(Cd)) or (II) the outliers above or below the fitting curve (ZL root (P) against C0(P) or CDGT(P)) and the larger R2 without outliers. DGT-rhizobox DIFS should be a reliable tool to research phytoremediation mechanism of macrophytes. PMID- 29240997 TI - In Situ Quantification of [Re(CO)3]+ by Fluorescence Spectroscopy in Simulated Hanford Tank Waste. AB - A pretreatment protocol is presented that allows for the quantitative conversion and subsequent in situ spectroscopic analysis of [Re(CO)3]+ species in simulated Hanford tank waste. In this test case, the nonradioactive metal rhenium is substituted for technetium (Tc-99), a weak beta emitter, to demonstrate proof of concept for a method to measure a nonpertechnetate form of technetium in Hanford tank waste. The protocol encompasses adding a simulated waste sample containing the nonemissive [Re(CO)3]+ species to a developer solution that enables the rapid, quantitative conversion of the nonemissive species to a luminescent species which can then be detected spectroscopically. The [Re(CO)3]+ species concentration in an alkaline, simulated Hanford tank waste supernatant can be quantified by the standard addition method. In a test case, the [Re(CO)3]+ species was measured to be at a concentration of 38.9 MUM, which was a difference of 2.01% from the actual concentration of 39.7 MUM. PMID- 29240999 TI - Friction- and Wear-Reducing Properties of Multifunctional Small Molecules. AB - Nitrogen- and oxygen-containing compounds were designed empirically and subsequently synthesized, and their rheology, friction, and wear performance as multifunctional base oils (MFBOs) were evaluated. Two of the compounds displayed good viscosity/rheology profiles without the addition of polymeric viscosity modifiers, displaying high viscosity indexes (VIs) above 200. Furthermore, all three MFBOs had lower coefficients of friction compared to well-established and accepted benchmarks. The most significant advancement is their impressive wear improvement by a factor of 5.5 to 70 compared to either of the benchmarks, which is attributed to the polar nature of the base oil which promotes boundary lubrication with metal surfaces. Moreover, these compounds were easily synthesized in one step from commercial starting materials. This work demonstrates that a careful design could provide the features/performance/functions of base oil, rheology modifiers (or VI improvers), and antiwear and friction-reducing additives, all-in one molecule. PMID- 29240998 TI - Orthogonality and Burdens of Heterologous AND Gate Gene Circuits in E. coli. AB - Synthetic biology approaches commonly introduce heterologous gene networks into a host to predictably program cells, with the expectation of the synthetic network being orthogonal to the host background. However, introduced circuits may interfere with the host's physiology, either indirectly by posing a metabolic burden and/or through unintended direct interactions between parts of the circuit with those of the host, affecting functionality. Here we used RNA-Seq transcriptome analysis to quantify the interactions between a representative heterologous AND gate circuit and the host Escherichia coli under various conditions including circuit designs and plasmid copy numbers. We show that the circuit plasmid copy number outweighs circuit composition for their effect on host gene expression with medium-copy number plasmid showing more prominent interference than its low-copy number counterpart. In contrast, the circuits have a stronger influence on the host growth with a metabolic load increasing with the copy number of the circuits. Notably, we show that variation of copy number, an increase from low to medium copy, caused different types of change observed in the behavior of components in the AND gate circuit leading to the unbalance of the two gate-inputs and thus counterintuitive output attenuation. The study demonstrates the circuit plasmid copy number is a key factor that can dramatically affect the orthogonality, burden and functionality of the heterologous circuits in the host chassis. The results provide important guidance for future efforts to design orthogonal and robust gene circuits with minimal unwanted interaction and burden to their host. PMID- 29241000 TI - Possible Existence of alpha-Sheets in the Amyloid Fibrils Formed by a TTR105-115 Mutant. AB - Herein, we combine several methods to characterize the fibrils formed by a TTR105 115 mutant in which Leu111 is replaced by the unnatural amino acid aspartic acid 4-methyl ester. We find that this mutant peptide exhibits significantly different aggregation behavior than the wild-type peptide: (1) it forms fibrils with a much faster rate, (2) its fibrils lack the long-range helical twists observed in TTR105-115 fibrils, (3) its fibrils exhibit a giant far-UV circular dichroism signal, and (4) its fibrils give rise to an unusual amide I' band consisting of four distinct and sharp peaks. On the basis of these results and also several previous computational studies, we hypothesize that the fibrils formed by this TTR mutant peptide contain both beta- and alpha-sheets. PMID- 29241001 TI - Synthesis of Conformationally-Locked cis- and trans-Bicyclo[4.4.0] Mono-, Di-, and Trioxadecane Modifications of Galacto- and Glucopyranose; Experimental Limiting 3JH,H Coupling Constants for the Estimation of Carbohydrate Side Chain Populations and Beyond. AB - Hexopyranose side chains populate three staggered conformations, whose proportions can be determined from the three sets of ideal limiting 3JH5,H6R and 3JH5,H6S coupling constants in combination with the time-averaged experimental coupling constants. Literature values for the limiting coupling constants, obtained by the study of model compounds, the use of the Haasnoot-Altona and related equations, or quantum mechanical computations, can result in computed negative populations of one of the three ideal conformations. Such values arise from errors in the limiting coupling constants and/or from the population of nonideal conformers. We describe the synthesis and analysis of a series of cis- and trans-fused mono-, di-, and trioxabicyclo[4.4.0]octane-like compounds. Correction factors for the application of data from internal models (-CH(OR) CH(OR)-) to terminal systems (-CH(OR)-CH2(OR)) are deduced from comparison of further models, and applied where necessary. Limiting coupling constants so derived are applied to the side chain conformations of three model hexopyranosides, resulting in calculated conformer populations without negative values. Although, developed primarily for hexopyranose side chains, the limiting coupling constants are suitable, with the correction factors presented, for application to the side chains of higher carbon sugars and to conformation analysis of acyclic diols and their derivatives in a more general sense. PMID- 29241003 TI - Chiral Coalition in Helical Sense Enhancement of Copolymers: The Role of the Absolute Configuration of Comonomers. AB - Both the role of the absolute configuration and the tendency of a chiral monomer to promote a certain helical scaffold in a poly(phenylacetylene) (PPA) have been evaluated to study the communication between two chiral monomers within a copolymer chain. Nineteen different PPA copolymer series-47 helical copolymers altogether-were prepared to explore the existence of a chiral-to-chiral communication mechanism. From the data obtained, we found that communication between two different chiral monomers emerges when both exhibit two special features: (a) a different conformational composition-one must exist in a single low-energy conformation ("chiral Sergeant") and the other must present two conformers ("chiral Soldier")-and (b) the induction of a similar scaffold in the PPA, either cis-cisoidal or cis-transoidal. In the selected systems, the chiral Soldier includes the 4-ethynylanilide (para position) of either (R)- or (S)-2 methoxy-2-phenylacetic acid pendants characterized by their conformational flexibility (equilibrium between synperiplanar and antiperiplanar conformations). The chiral Sergeant contains the same chiral groups but linked to the backbone in meta position [3-ethynylanilide of (R)- or (S)-2-methoxy-2-phenylacetic acid] and is selected on the basis of its restricted antiperiplanar conformation. Incorporation of a very small amount (1%) of the Sergeant into a chain composed of just the Soldier transforms the originally axially racemic chain into a helix with strong sense preference (either M or P) that is determined by the absolute configuration of the Soldier. PMID- 29241004 TI - Intrinsic Size Effect in Scaffolded Porous Calcium Silicate Particles and Mechanical Behavior of Their Self-Assembled Ensembles. AB - Scaffolded porous submicron particles with well-defined diameter, shape, and pore size have profound impacts on drug delivery, bone-tissue replacement, catalysis, sensors, photonic crystals, and self-healing materials. However, understanding the interplay between pore size, particle size, and mechanical properties of such ultrafine particles, especially at the level of individual particles and their ensemble states, is a challenge. Herein, we focus on porous calcium-silicate submicron particles with various diameters-as a model system-and perform extensive 900+ nanoindentations to completely map out their mechanical properties at three distinct structural forms from individual submicron particles to self assembled ensembles to pressure-induced assembled arrays. Our results demonstrate a notable "intrinsic size effect" for individual porous submicron particles around ~200-500 nm, induced by the ratio of particle characteristic diameter to pore characteristic size distribution. Increasing this ratio results in a brittle to-ductile transition where the toughness of the submicron particles increases by 120%. This size effect becomes negligible as the porous particles form superstructures. Nevertheless, the self-assembled arrays collectively exhibit increasing elastic modulus as a function of applied forces, while pressure induced compacted arrays exhibit no size effect. This study will impact tuning properties of individual scaffolded porous particles and can have implications on self-assembled superstructures exploiting porosity and particle size to impart new functionalities. PMID- 29241002 TI - The Future of Multiplexed Eukaryotic Genome Engineering. AB - Multiplex genome editing is the simultaneous introduction of multiple distinct modifications to a given genome. Though in its infancy, maturation of this field will facilitate powerful new biomedical research approaches and will enable a host of far-reaching biological engineering applications, including new therapeutic modalities and industrial applications, as well as "genome writing" and de-extinction efforts. In this Perspective, we focus on multiplex editing of large eukaryotic genomes. We describe the current state of multiplexed genome editing, the current limits of our ability to multiplex edits, and provide perspective on the many applications that fully realized multiplex editing technologies would enable in higher eukaryotic genomes. We offer a broad look at future directions, covering emergent CRISPR-based technologies, advances in intracellular delivery, and new DNA assembly approaches that may enable future genome editing on a massively multiplexed scale. PMID- 29241005 TI - Spatiotemporal Control of TGF-beta Signaling with Light. AB - Cells employ signaling pathways to make decisions in response to changes in their immediate environment. Transforming growth factor beta (TGF-beta) is an important growth factor that regulates many cellular functions in development and disease. Although the molecular mechanisms of TGF-beta signaling have been well studied, our understanding of this pathway is limited by the lack of tools that allow the control of TGF-beta signaling with high spatiotemporal resolution. Here, we developed an optogenetic system (optoTGFBRs) that enables the precise control of TGF-beta signaling in time and space. Using the optoTGFBRs system, we show that TGF-beta signaling can be selectively and sequentially activated in single cells through the modulation of the pattern of light stimulations. By simultaneously monitoring the subcellular localization of TGF-beta receptor and Smad2 proteins, we characterized the dynamics of TGF-beta signaling in response to different patterns of blue light stimulations. The spatial and temporal precision of light control will make the optoTGFBRs system as a powerful tool for quantitative analyses of TGF-beta signaling at the single cell level. PMID- 29241007 TI - Sulfur-Doped Laser-Induced Porous Graphene Derived from Polysulfone-Class Polymers and Membranes. AB - Graphene based materials have profoundly impacted research in nanotechnology, and this has significantly advanced biomedical, electronics, energy, and environmental applications. Laser-induced graphene (LIG) is made photothermally and has enabled a rapid route for graphene layers on polyimide surfaces. However, polysulfone (PSU), poly(ether sulfone) (PES), and polyphenylsulfone (PPSU) are highly used in numerous applications including medical, energy, and water treatment and they are critical components of polymer membranes. Here we show LIG fabrication on PSU, PES, and PPSU resulting in conformal sulfur-doped porous graphene embedded in polymer dense films or porous substrates using reagent- and solvent-free methods in a single step. We demonstrate the applicability as flexible electrodes with enhanced electrocatalytic hydrogen peroxide generation, as antifouling surfaces and as antimicrobial hybrid membrane-LIG porous filters. The properties and surface morphology of the conductive PSU-, PES-, and PPSU-LIG could be modulated using variable laser duty cycles. The LIG electrodes showed enhanced hydrogen peroxide generation compared to LIG made on polyimide, and showed exceptional biofilm resistance and potent antimicrobial killing effects when treated with Pseudomonas aeruginosa and mixed bacterial culture. The hybrid PES-LIG membrane-electrode ensured complete elimination of bacterial viability in the permeate (6 log reduction), in a flow-through filtration mode at a water flux of ~500 L m-2 h-1 (2.5 V) and at ~22 000 L m-2 h-1 (20 V). Due to the widespread use of PSU, PES, and PPSU in modern society, these functional PSU-, PES-, and PPSU-LIG surfaces have great potential to be incorporated into biomedical, electronic, energy and environmental devices and technologies. PMID- 29241006 TI - Toxoid Vaccination against Bacterial Infection Using Cell Membrane-Coated Nanoparticles. AB - As nanoparticles exhibit unique properties attractive for vaccine development, they have been progressively implemented as antigen delivery platforms and immune potentiators. Recently, cell membrane-coated nanoparticles have provided a novel approach for intercepting and neutralizing bacterial toxins by leveraging their natural affinity to cellular membranes. Such toxin-nanoparticle assemblies, termed nanotoxoids, allow rapid loading of different types of toxins and have been investigated for their ability to effectively confer protection against bacterial infection. This topical review will cover the current progress in antibacterial vaccine nanoformulations and highlight the nanotoxoid platform as a novel class of nanoparticulate vaccine. We aim to provide insights into the potential of nanotoxoids as a platform that is facile to implement and can be broadly applied to help address the rising threat of super pathogens. PMID- 29241008 TI - Efficient Steplike Carrier Multiplication in Percolative Networks of Epitaxially Connected PbSe Nanocrystals. AB - Carrier multiplication (CM) is a process in which a single photon excites two or more electrons. CM is of interest to enhance the efficiency of a solar cell. Until now, CM in thin films and solar cells of semiconductor nanocrystals (NCs) has been found at photon energies well above the minimum required energy of twice the band gap. The high threshold of CM strongly limits the benefits for solar cell applications. We show that CM is more efficient in a percolative network of directly connected PbSe NCs. The CM threshold is at twice the band gap and increases in a steplike fashion with photon energy. A lower CM efficiency is found for a solid of weaker coupled NCs. This demonstrates that the coupling between NCs strongly affects the CM efficiency. According to device simulations, the measured CM efficiency would significantly enhance the power conversion efficiency of a solar cell. PMID- 29241009 TI - The Nitric Oxide Dimer Reaction in Carbon Nanopores. AB - When confined within nanoporous carbons (activated carbon fibers or carbon nanotubes) having pore widths of about 1 nm, nitric oxide is found to react completely to form the dimer, (NO)2, even though almost no dimers are present in the bulk gas phase in equilibrium with the pore phase. Moreover, the yield of dimer is unchanged upon varying the temperature over the range studied in the experiments. Earlier molecular simulation studies showed a significant increase in dimer formation in carbon nanopores, but the dimer yield was considerably less than that found in the experiments, and decreased rapidly as the temperature was raised. Here, we report an ab initio and molecular simulation study of this reaction in both slit-shaped pores and single-walled carbon nanotubes. The ab initio calculations show that the nitric oxide dimer forms a weak chemical bond with the carbon, and the bonding energy is more than 20 times stronger than the van der Waals energy assumed in the previous studies. When this is accounted for, the predicted dimer yield is in good agreement with the experimental values, as is its temperature dependence. We also report results for the pressure tensor components for this confined reactive mixture. Local tangential pressures near the pore walls are as high as millions of bar, reflecting the strong nanoscale forces. PMID- 29241010 TI - Mechanisms of Arsenic Sequestration by Prosopis juliflora during the Phytostabilization of Metalliferous Mine Tailings. AB - Phytostabilization is a cost-effective long-term bioremediation technique for the immobilization of metalliferous mine tailings. However, the biogeochemical processes affecting metal(loid) molecular stabilization and mobility in the root zone remain poorly resolved. The roots of Prosopis juliflora grown for up to 36 months in compost-amended pyritic mine tailings from a federal Superfund site were investigated by microscale and bulk synchrotron X-ray absorption spectroscopy (XAS) and multiple energy micro-X-ray fluorescence imaging to determine iron, arsenic, and sulfur speciation, abundance, and spatial distribution. Whereas ferrihydrite-bound As(V) species predominated in the initial bulk mine tailings, the rhizosphere speciation of arsenic was distinctly different. Root-associated As(V) was immobilized on the root epidermis bound to ferric sulfate precipitates and within root vacuoles as trivalent As(III)-(SR)3 tris-thiolate complexes. Molar Fe-to-As ratios of root epidermis tissue were two times higher than the 15% compost-amended bulk tailings growth medium. Rhizoplane associated ferric sulfate phases that showed a high capacity to scavenge As(V) were dissimilar from the bulk-tailings mineralogy as shown by XAS and X-ray diffraction, indicating a root-surface mechanism for their formation or accumulation. PMID- 29241011 TI - Silver-Free Palladium-Catalyzed C(sp3)-H Arylation of Saturated Bicyclic Amine Scaffolds. AB - Herein, we report a silver-free Pd(II)-catalyzed C(sp3)-H arylation of saturated bicyclic and tricyclic amine scaffolds. The reaction provides good yields using a range of aryl iodides and aryl bromides including functionalized examples bearing aldehydes, ketones, esters, free phenols, and heterocycles. The methodology has been applied to medicinally relevant scaffolds. Two of the intermediate palladium complexes in the catalytic cycle have been prepared and characterized, and a mechanism is proposed. Removal of the directing group proceeded with good yield under relatively mild conditions. PMID- 29241012 TI - Investigation of the Electronic Excited-State Equilibrium Geometries of Three Molecules Undergoing ESIPT: A RI-CC2 and TDDFT Study. AB - Energy minima on the potential energy surfaces of the ground and excited states have been characterized for three photoactive molecules that undergo excited state intramolecular proton transfer: 3-hydroxychromone, N-salicylideneaniline, and 2-(2-hydroxyphenyl)benzothiazole. Both the CC2 method and the TDDFT methodology with different exchange-correlation (XC) functionals differing by the amount of Hartree-Fock (HF) exchange have been employed. Besides the analysis of the structures along the reaction paths, this study has compared the TDDFT and CC2 results to provide guidelines for selecting the best XC functionals. Several geometrical parameters as well as the excitation energies are found to vary monotonically with the amount of HF exchange. Systematically, this study has addressed the ground-state geometries, those of the excited states, and their variations upon excitation, showing that the M06 XC functional provides the closest agreement with the CC2 results. Still, large differences of geometries have been observed between the different levels of approximation, mostly for the excited states: (i) Not all methods locate the same number of minima, (ii) the bond length variations upon excitation might be reversed, and (iii) the H-bond network can be modified from one level to another, changing the keto/enol character. Moreover, TDDFT/M06 and B3LYP-35 vertical excitation energies are in good agreement with the CC2 values. All in all, these results call for being cautious when using these optimized geometries for predicting the spectroscopic signatures of these compounds to understand the processes that take place during photoexcitation. PMID- 29241013 TI - libreta: Computerized Optimization and Code Synthesis for Electron Repulsion Integral Evaluation. AB - A new library called libreta for the evaluation of electron repulsion integrals (ERIs) over segmented and contracted Gaussian functions is developed. Our libreta is optimized from three aspects: (1) The Obara-Saika, Dupuis-Rys-King, and McMurchie-Davidson method are all employed. The recurrence relations involved are optimized by tree-search for each combination of angular momenta, and in the best case, 50% of the intermediates can be eliminated to reduce the computational cost. (2) The optimized codes for recurrence relations are combined with different contraction orders, each of which is suitable for ERIs of different angular momenta and contraction patterns. In practice, libreta will determine and use the best scheme to evaluate each ERI. (3) libreta is also optimized at the coding level. For example, with common subexpression elimination and local memory access, the performance can be increased by about 6% and 20%, respectively. The performance was compared with libint2. For both popular segmented and contracted basis sets, libreta can be faster than libint2 by 7.2-912.0%. For basis sets of heavy elements that contain Gaussian basis functions of large contraction degrees, the performance can be increased 20-30 times. We also tested the performance of libreta in direct self-consistent field (SCF) calculations and compared it with NWChem. In most cases, the average time for one SCF iteration by libreta is less than NWChem by 144.2-495.9%. Finally, we discuss the origin of redundancies occurring in the recurrence relations and derive an upper bound of the least number of intermediates required to be calculated in a McMurchie Davidson recurrence, which is confirmed by ours as well as previous authors' results. We expect that libreta can become a useful tool for theoretical and computational chemists to develop their own algorithms rapidly. PMID- 29241014 TI - An Observational Study of the Efficacy of Cisatracurium Compared with Vecuronium in Patients with or at Risk for Acute Respiratory Distress Syndrome. AB - RATIONALE: The neuromuscular blocking agent cisatracurium may improve mortality for patients with moderate-to-severe acute respiratory distress syndrome (ARDS). Other neuromuscular blocking agents, such as vecuronium, are commonly used and have different mechanisms of action, side effects, cost, and availability in the setting of drug shortages. OBJECTIVES: To determine whether cisatracurium is associated with improved outcomes when compared with vecuronium in patients at risk for and with ARDS. METHODS: Using a nationally representative database, patients who were admitted to the ICU with a diagnosis of ARDS or an ARDS risk factor, received mechanical ventilation, and were treated with a continuous infusion of neuromuscular blocking agent for at least 2 days within 2 days of hospital admission were included. Patients were stratified into two groups: those who received cisatracurium or vecuronium. Propensity matching was used to balance both patient- and hospital-specific factors. Outcomes included hospital mortality, duration of mechanical ventilation, ICU and hospital duration, and discharge location. MEASUREMENTS AND MAIN RESULTS: Propensity matching successfully balanced all covariates for 3,802 patients (1,901 per group). There was no significant difference in mortality (odds ratio, 0.932; P = 0.40) or hospital days (-0.66 d; P = 0.411) between groups. However, patients treated with cisatracurium had fewer ventilator days (-1.01 d; P = 0.005) and ICU days (-0.98 d; P = 0.028) but were equally likely to be discharged home (odds ratio, 1.19; P = 0.056). CONCLUSIONS: When compared with vecuronium, cisatracurium was not associated with a difference in mortality but was associated with improvements in other clinically important outcomes. These data suggest that cisatracurium may be the preferred neuromuscular blocking agent for patients at risk for and with ARDS. PMID- 29241016 TI - Reply to Morice and Hart: Increased Propensity for Pneumonia with Fluticasone in Chronic Obstructive Pulmonary Disease. PMID- 29241015 TI - Airway Epithelial Progenitors and the Natural History of Chronic Obstructive Pulmonary Disease. PMID- 29241017 TI - Older Adult Multitasking Performance Using a Gaze-Contingent Useful Field of View. AB - Objective We implemented a gaze-contingent useful field of view paradigm to examine older adult multitasking performance in a simulated driving environment. Background Multitasking refers to the ability to manage multiple simultaneous streams of information. Recent work suggests that multitasking declines with age, yet the mechanisms supporting these declines are still debated. One possible framework to better understand this phenomenon is the useful field of view, or the area in the visual field where information can be attended and processed. In particular, the useful field of view allows for the discrimination of two competing theories of real-time multitasking, a general interference account and a tunneling account. Methods Twenty-five older adult subjects completed a useful field of view task that involved discriminating the orientation of lines in gaze contingent Gabor patches appearing at varying eccentricities (based on distance from the fovea) as they operated a vehicle in a driving simulator. In half of the driving scenarios, subjects also completed an auditory two-back task to manipulate cognitive workload, and during some trials, wind was introduced as a means to alter general driving difficulty. Results Consistent with prior work, indices of driving performance were sensitive to both wind and workload. Interestingly, we also observed a decline in Gabor patch discrimination accuracy under high cognitive workload regardless of eccentricity, which provides support for a general interference account of multitasking. Conclusion The results showed that our gaze-contingent useful field of view paradigm was able to successfully examine older adult multitasking performance in a simulated driving environment. Application This study represents the first attempt to successfully measure dynamic changes in the useful field of view for older adults completing a multitasking scenario involving driving. PMID- 29241018 TI - Older women exhibit greater airway 8-isoprostane responses to strenuous exercise compared with older men and younger controls. AB - Development of late-onset respiratory diseases is associated with elevated 8 isoprostane, a marker of oxidative stress, in the airways. However, sex differences exist in development of these diseases. Using an exhaustive exercise bout as a physiological stressor may elucidate whether there is a sex difference with aging in pre- to postexercise airway 8-isoprostane generation. The purpose of this study was to determine whether older women exhibit a greater airway 8 isoprostane response to exhaustive exercise compared with older men and younger controls. Thirty-six individuals completed the study (12 postmenopausal older women (OW) and 12 age-matched older men (OM), 65 +/- 4 years of age; and 12 younger controls (YC), 21 +/- 2 years of age). Baseline measurements included exhaled breath condensate (EBC) for assessment of airway 8-isoprostane and standard pulmonary function tests (PFTs) to assess forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, and forced expiratory flow at 25%-75% of FVC. Subjects then performed a peak oxygen uptake test to exhaustion on a cycle ergometer. Immediately postexercise, PFTs and EBC were performed. The generation of airway 8-isoprostane from pre- to postexercise was greater in OW compared with OM and YC (p < 0.01), increasing ~74% +/- 77% in OW, while decreasing in OM (~12% +/- 50%) and YC (~20.9% +/- 30%). The OW exhibited a greater airway 8-isoprostane response to exhaustive exercise compared with OM and YC, which may suggest that sex differences in oxidative stress generation following exhaustive exercise may provide a mechanistic rationale for sex differences in late-onset respiratory diseases. PMID- 29241019 TI - Quantitative Analysis of a Multiplexed Immunofluorescence Panel in T-Cell Lymphoma. AB - Immunohistochemistry (IHC) provides clinically useful information on protein expression in cancer cells. However, quantification of colocalizing signals using conventional IHC and visual scores is challenging. Here we describe the application of quantitative immunofluorescence in angioimmunoblastic T-cell lymphoma (AITL), a peripheral T-cell lymphoma characterized by cellular heterogeneity that impedes IHC interpretation and quantification. A multiplexed immunofluorescence (IF) panel comprising T- and B-lymphocyte markers along with T follicular helper (TFH) markers was validated for appropriate cellular localization in sections of benign tonsillar tissue and tested in two samples of AITL, using a Vectra microscope for spectral imaging and InForm software for analysis. We measured the percentage positivity of the TFH markers, BCL6 and PD1, in AITL CD4-positive cells to be approximately 26% and 45%, with 12% coexpressing both markers. The pattern is similar to CD4 cells within the germinal center of normal tonsils and clearly distinct from extragerminal CD4 cells. This study demonstrates the feasibility of automated and quantitative imaging of a multiplexed panel of cellular markers in formalin-fixed, paraffin-embedded tissue sections of a cellularly heterogenous lymphoma. Multiplexed IF allows the simultaneous scoring of markers in malignant and immune cell populations and could potentially increase accuracy for establishment of diagnostic thresholds. PMID- 29241020 TI - An Automatic Lab-on-Disc System for Blood Typing. AB - A blood-typing assay is a critical test to ensure the serological compatibility of a donor and an intended recipient prior to a blood transfusion. This article presents a lab-on-disc blood-typing system to conduct a total of eight assays for a patient, including forward-typing tests, reverse-typing tests, and irregular antibody tests. These assays are carried out in a microfluidic disc simultaneously. A blood-typing apparatus was designed to automatically manipulate the disc. The blood type can be determined by integrating the results of red blood cell (RBC) agglutination in the microchannels. The experimental results of our current 40 blood samples show that the results agree with those examined in the hospital. The accuracy reaches 97.5%. PMID- 29241021 TI - Increased Propensity for Pneumonia with Fluticasone in Chronic Obstructive Pulmonary Disease. PMID- 29241022 TI - Evolution as an ecosystem process: insights from genomics. AB - Evolution is a fundamental ecosystem process. The study of genomic variation of organisms can not only improve our understanding of evolutionary processes, but also of contemporary and future ecosystem dynamics. We argue that integrative research between the fields of genomics and ecosystem ecology could generate new insights. Specifically, studies of biodiversity and ecosystem functioning, evolutionary rescue, and eco-evolutionary dynamics could all benefit from information about variation in genome structure and the genetic architecture of traits, whereas genomic studies could benefit from information about the ecological context of evolutionary dynamics. We propose new ways to help link research on functional genomic diversity with (reciprocal) interactions between phenotypic evolution and ecosystem change. Despite numerous challenges, we anticipate that the wealth of genomic data being collected on natural populations will improve our understanding of ecosystems. PMID- 29241023 TI - Ergovaline does not alter the severity of ryegrass staggers induced by lolitrem B. AB - AIM: To investigate a possible interaction between lolitrem B and ergovaline by comparing the incidence and severity of ryegrass staggers in sheep grazing ryegrass (Lolium perenne) containing lolitrem B or ryegrass containing both lolitrem B and ergovaline. METHODS: Ninety lambs, aged approximately 6 months, were grazed on plots of perennial ryegrass infected with either AR98 endophyte (containing lolitrem B), standard endophyte (containing lolitrem B and ergovaline) or no endophyte, for up to 42 days from 2 February 2010. Ten lambs were grazed on three replicate plots per cultivar. Herbage samples were collected for alkaloid analysis and lambs were scored for ryegrass staggers (scores from 0 5) weekly during the study. Any animal which was scored >=4 was removed from the study. RESULTS: Concentrations of lolitrem B did not differ between AR98 and standard endophyte-infected pastures during the study period (p=0.26), and ergovaline was present only in standard endophyte pastures. Ryegrass staggers was observed in sheep grazing both the AR98 and standard endophyte plots, with median scores increasing in the third week of the study. Prior to the end of the 42-day grazing period, 22 and 17 animals were removed from the standard endophyte and AR98 plots, respectively, because their staggers scores were >=4. The cumulative probability of lambs having scores >=4 did not differ between animals grazing the two pasture types (p=0.41). CONCLUSIONS AND CLINICAL RELEVANCE: There was no evidence for ergovaline increasing the severity of ryegrass staggers induced by lolitrem B. In situations where the severity of ryegrass staggers appears to be greater than that predicted on the basis of concentrations of lolitrem B, the presence of other tremorgenic alkaloids should be investigated. PMID- 29241024 TI - Age- and Gender-Associated Liver Physiological T1rho Dynamics Demonstrated with a Clinically Applicable Single-Breathhold Acquisition. AB - To understand women's and men's physiological ranges of liver T1rho relaxation time measured with a single breathhold black blood sequence, this healthy volunteer study was conducted in 62 women (mean age, 38.9 y; range, 18-75 y) and 34 men (mean age, 44.7 y; range, 24-80 y). Approval from the institutional ethics committee was obtained. Magnetic resonance imaging was performed with a 3.0T scanner with six spin-lock times of 0, 10, 20, 25, 35, and 50 ms and a single breathhold of 12 s per slice acquisition. Six slices were acquired for each examination. The results demonstrated that the female liver T1rho value ranged between 35.07 and 51.97 ms and showed an age-dependent decrease, with younger women having a higher measurement. The male liver T1rho value ranged between 34.94 and 43.39 ms, with no evidential age dependence. Postmenopausal women had similar liver T1rho values as men. For women, there was a trend that the liver T1rho value could be 4% to 5% lower during the menstrual phase than during the nonmenstrual phase. For both women and men, no evidential association was seen between body mass index and liver T1rho. PMID- 29241025 TI - Antimicrobial usage and risk of retreatment for mild to moderate clinical mastitis cases on dairy farms following on-farm bacterial culture and selective therapy. AB - AIMS: To assess antimicrobial usage for treatment of mild to moderate clinical mastitis, and risk of retreatment, following implementation of an on-farm bacterial culture system and selective therapy based on culture results, and to assess compliance with treatment decision tree protocols and the level of agreement between results from on-farm culture and laboratory-based microbiology methods. MATERIALS AND METHODS: Herdowners from seven dairy herds were asked to collect milk samples from cases of mild to moderate clinical mastitis between July 2015 and May 2016. All samples were cultured on-farm using a commercially available selective media and were also submitted for laboratory-based culture. Within sequential pairs of cows with mastitis, half were assigned to be treated without regard to culture results (Blanket group), and half were treated based on the on-farm culture results (Selective group) according to decision tree diagrams provided to the farmers. Culture results, treatments, and retreatments for clinical mastitis were recorded. The sum of the daily doses of antimicrobials used per cow, the number of retreatments and interval to first retreatment were compared between treatment groups. RESULTS: The geometric mean sum of daily doses for quarters assigned to the Selective (1.72 (95% CI=1.55-1.90)) group was lower than for the Blanket (2.38 (95% CI=2.17-2.60)) group (p=0.005). The percentage of cows retreated for clinical mastitis did not differ between the Selective (21.7 (95% CI=10.5-25.9)%) and Blanket (26.1 (95% CI=20.9-31.3)%) groups (p=0.13), and there was no difference between groups in the hazard that cows would be retreated within 60 days of enrolment (hazard ratio=0.82 (95% CI=0.39-1.69); p=0.59). Compliance with the treatment protocols was higher amongst quarters assigned to the Selective (199/233; 85.4%) compared with the Blanket (171/249; 68.7%) group (p<0.001), and varied between farms from 64-94%. The overall agreement between results from on-farm and laboratory culture was 188/331 (56.9%; kappa=0.31; p<0.001), but varied between farms from 44.7-88.2% (p<0.001). CONCLUSIONS: Use of on-farm culture with selective antimicrobial therapy resulted in approximately 25% lower antimicrobial usage, but was not associated with an increase in the proportion of cows retreated for clinical mastitis. CLINICAL RELEVANCE: This study has demonstrated that on-farm culture and selective therapy based on culture results can be implemented on-farm. However, farms varied in their implementation of both the treatment protocols and microbiology procedures. Where such systems are to be used on-farm, specific training and on-going monitoring is required. PMID- 29241026 TI - Reliability of a new test food to assess masticatory function. AB - OBJECTIVE: This study assessed the reliability and validity of masticatory function assessment using a new test food, Optozeta. DESIGN: Thirty-five adults participated in the cross-sectional clinical part of the study; ten of them performed a retest. They performed two free-style masticatory tests consisting of five trials of 20 cycles each chewing three pieces of Optosil or Optozeta placed in a latex bag. Optozeta was created by mixing 50% Optosil with 50% of Zetalabor. Masticatory performance, masticatory laterality and chewing rate were assessed. Reliability and construct validity were assessed using the intraclass correlation coefficient (ICC) and Spearman correlations, respectively. RESULTS: Higher ICC values were observed for each aspect of masticatory function as assessed using Optozeta compared with Optosil. All the participants showed a lower median particle size value using Optozeta than Optosil. For each masticatory parameter, a high correlation was observed between using Optosil or Optozeta. CONCLUSIONS: Optozeta seems to have good construct validity and appears to be more reliable than Optosil as a test food to assess masticatory function. PMID- 29241027 TI - When forensic odontology met biochemistry: Multidisciplinary approach in forensic human identification. AB - When human remains are found, the priority of the investigation is to ascertain the identity of the deceased. A positive identification is a key factor in providing closure for the family of the deceased; it is also required to issue the death certificate and therefore, to settle legal affairs. Moreover, it is difficult for any forensic investigation involving human remains to be solved without the determination of an identity. Therefore, personal identification is necessary for social, legal and forensic reasons. In the last thirty years forensic odontology has experienced an important transformation, from primarily involving occasional dental identification into a broader role, contributing to the determination of the biological profile. In the same way, "DNA fingerprinting" has evolved not only in terms of improving its technology, but also in its application beyond the "classical": helping with the estimation of sex, age and ancestry. As these two forensic disciplines have developed independently, their pathways have crossed several times through human identification operations, especially the ones that require a multidisciplinary approach. Thus, the aim of this review is to describe the contributions of both forensic odontology and molecular biology/biochemistry to human identification, demonstrating how a multidisciplinary approach can lead to a better and more efficient identification. PMID- 29241028 TI - A latent class analysis of PTSD symptoms among inner city primary care patients. AB - OBJECTIVES: Examine evidence for different subclasses of posttraumatic stress disorder (PTSD) symptoms in a sample of trauma exposed, low-income, predominantly African American men and women. Assess the relationship between PTSD subclasses with major depressive disorder (MDD) and types of trauma experienced. METHOD: Latent class analysis (LCA) using a multivariate normal mixture model on the 17 item PTSD Symptom Scale (PSS) was used to identify latent subclasses of PTSD symptoms (N = 5063). RESULTS: LCA suggested four subclasses of PTSD symptoms: (1) High severity and comorbidity (n = 932, 92.2% current PTSD, 88.7% MDD, 82% both), characterized by high PTSD symptoms, depression, and comorbidity of PTSD and MDD; (2) Moderate severity (n = 1179, 56.5% current PTSD, 53.9% MDD, 34.5% both), which had high avoidance and hyper-vigilance symptoms compared to the other symptoms; (3) Low PTSD and high depression (n = 657, 12.8% current PTSD, 49.9% MDD, 8.8% both) which had high insomnia but otherwise low PTSD symptoms and high depression; and (4) Resilient (n = 2295, 2.0% current PTSD, 16.4% MDD, and 0.6% both) characterized by low mean scores on all PTSD symptoms and depression. CONCLUSIONS: The results suggest avoidance and hyper-vigilance are important symptoms in PTSD development and insomnia may be an important indicator for depression. The combination of severe insomnia, avoidance, and hyper-vigilance may be key symptoms for comorbidity of PTSD and MDD. Future studies should focus on these symptoms to better target people at high risk for developing PTSD or MDD. PMID- 29241029 TI - Activated human B cells stimulate COX-2 expression in follicular dendritic cell like cells via TNF-alpha. AB - In spite of the potential importance of cyclooxygenase (COX)-2 expression in the germinal center, its underlying cellular and molecular mechanisms are largely unknown. COX-2 is the key enzyme generating pleiotropic prostaglandins. Based on our previous findings, we hypothesized that lymphocytes would stimulate COX-2 expression in follicular dendritic cell (FDC) by liberating cytokines. In this study, we examined the effect of tonsillar lymphocytes on COX-2 expression in FDC like cells by immunoblotting. B but not T cells induced COX-2 protein in a time- and dose-dependent manner. Sub-fractionation analysis of B cell subsets revealed that activated but not resting B cells were responsible for the COX-2 induction. Confocal microscopy of frozen tonsils demonstrated that FDCs indeed express COX-2 in situ, in line with the in vitro results. To identify the stimulating molecule, we added neutralizing antibodies to the coculture of FDC-like cells and B cells. COX-2 induction in FDC-like cells was markedly inhibited by TNF-alpha neutralizing antibody. Finally, the actual production of TNF-alpha by activated B cells was confirmed by an enzyme immunoassay. The current study implies an unrecognized cellular interaction between FDC and B cells leading to COX-2 expression during immune inflammatory responses. PMID- 29241030 TI - Expression profiles of genes involved in TLRs and NLRs signaling pathways of water buffaloes infected with Fasciola gigantica. AB - Infection of ruminants and humans with Fasciola gigantica is attracting increasing attention due to its economic impact and public health significance. However, little is known of innate immune responses during F. gigantica infection. Here, we investigated the expression profiles of genes involved in Toll-like receptors (TLRs) and NOD-like receptors (NLRs) signaling pathways in buffaloes infected with 500F. gigantica metacercariae. Serum, liver and peripheral blood mononuclear cell (PBMC) samples were collected from infected and control buffaloes at 3, 10, 28, and 70days post infection (dpi). Then, the levels of 12 cytokines in serum samples were evaluated by ELISA. Also, the levels of expression of 42 genes, related to TLRs and NLRs signaling, in liver and PBMCs were determined using custom RT2 Profiler PCR Arrays. At 3 dpi, modest activation of TLR4 and TLR8 and the adaptor protein (TICAM1) was detected. At 10 dpi, NF kappaB1 and Interferon Regulatory Factor signaling pathways were upregulated along with activation of TLR1, TLR2, TLR6, TLR10, TRAF6, IRF3, TBK1, CASP1, CD80, and IFNA1 in the liver, and inflammatory response with activated TLR4, TLR9, TICAM1, NF-kappaB1, NLRP3, CD86, IL-1B, IL-6, and IL-8 in PBMCs. At 28 dpi, there was increase in the levels of cytokines along with induction of NLRP1 and NLRP3 inflammasomes-dependent immune responses in the liver and PBMCs. At 70 dpi, F. gigantica activated TLRs and NLRs, and their downstream interacting molecules. The activation of TLR7/9 signaling (perhaps due to increased B-cell maturation and activation) and upregulation of NLRP3 gene were also detected. These findings indicate that F. gigantica alters the expression of TLRs and NLRs genes to evade host immune defenses. Elucidation of the roles of the downstream effectors interacting with these genes may aid in the development of new interventions to control disease caused by F. gigantica infection. PMID- 29241031 TI - The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-kappaB and PI3K/Akt/mTOR pathways. AB - The aim of present study was to evaluate the protective effects of dexmedetomidine (DEX) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and investigate its possible mechanisms mediated by HMGB1. In vivo, pulmonary pathology observation and myeloperoxidase (MPO) activity were also examined to evaluate the protective effect of DEX in the lungs. Tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) in bronchoalveolar lavage fluid (BALF), serum and lung tissues LPS-induced rats were detected. The oxidative indices including superoxide dismutase (SOD), Malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in serum were also determined. Additionally, nitric oxide (NO), TNF-alpha, IL-6 and IL-1beta, MDA, SOD and GSH-Px in the supernatants of LPS-induced BEAS-2B cells were measured. Furthermore, we detected the protein expression of high mobility group box-1 protein (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiating factor 88 (MyD88), inhibitor of NF-kappaB (IkappaBalpha), p-IkappaBalpha, nuclear factor kappa-B (NF-kappaB), p-NF-kappaB, phosphatidylinositol 3'-kinase (PI3K), p-PI3K, protein kinase B (Akt), p-Akt, mammalian target of rapamycin (mTOR) and p-mTOR in LPS-induced ALI rats and LPS-induced BEAS-2B cells. Immunohistochemical and immunofluorescence analyses of HMGB1 in lung tissues or BEAS-2B cells were also conducted to evaluate the mechanisms of DEX. DEX effectively attenuated pulmonary pathology, and ameliorated the levels of MPO, SOD, MDA, GSH-Px, TNF-alpha, IL-6, IL-1beta and NO in LPS-stimulated rats and BEAS-2B cells. Additionally, treatment with DEX inhibited the expression of HMGB1, TLR4, MyD88, p-IkappaB, p-NF-kappaB, p-PI3K, p-Akt and p-mTOR in vivo and in vitro. Immunohistochemical and immunofluorescence analyses also showed that DEX suppressed HMGB1 levels in lung sections and BEAS-2B cells. Treatment with glycyrrhizin, an inhibitor of HMGB1, confirmed that HMGB1 was involved in the mechanism of DEX on LPS-induced ALI. The transfection of HGMB1 siRNA also confirmed these findings in vitro. In conclusion, the present study showed that DEX exerted a protective effect on LPS induced ALI rats likely through the HMGB1-mediated TLR4/NF-kappaB and PI3K/Akt/mTOR pathways. PMID- 29241032 TI - Biomimetic elastomeric, conductive and biodegradable polycitrate-based nanocomposites for guiding myogenic differentiation and skeletal muscle regeneration. AB - Artificial muscle-like biomaterials have gained tremendous interests owing to their broad applications in regenerative medicine, wearable devices, bioelectronics and artificial intelligence. Unfortunately, key challenges are still existed for current materials, including biomimetic viscoelasticity, biocompatibility and biodegradation, multifunctionality. Herein, for the first time, we develop highly elastomeric, conductive and biodegradable poly (citric acid-octanediol-polyethylene glycol)(PCE)-graphene (PCEG) nanocomposites, and demonstrate their applications in myogenic differentiation and guiding skeletal muscle tissue regeneration. In PCEG nanocomposites, PCE provides the biomimetic elastomeric behavior, and the addition of reduced graphene oxide (RGO) endows the enhanced mechanical strength and conductivity. The highly elastomeric behavior, significantly enhanced modulus (400%-800%), strength (200%-300%) of PCEG nanocomposites with controlled biodegradability and electrochemical conductivity were achieved. The myoblasts proliferation and myogenic differentiation were significantly improved by PCEG nanocomposite. Significantly high in vivo biocompatibility of PCEG nanocomposites was observed when implanted in the subcutaneous tissue for 4 weeks in rats. PCEG nanocomposites could significantly enhance the muscle fibers and blood vessels formation in vivo in a skeletal muscle lesion model of rat. This study may provide a novel strategy to develop multifunctional elastomeric nanocomposites with high biocompatibility for potential soft tissue regeneration and stretchable bioelectronic devices. PMID- 29241033 TI - The elimination of positive priming with increasing prime duration reflects a transition from perceptual fluency to disfluency rather than bias against primed words. AB - With immediate repetition priming of forced choice perceptual identification, short prime durations produce positive priming (i.e., priming the target leads to higher accuracy, while priming the foil leads to lower accuracy). Many theories explain positive priming following short duration primes as reflecting increased perceptual fluency for the primed target (i.e., decreased identification latency). However, most studies only examine either accuracy or response times, rather than considering the joint constraints of response times and accuracy to properly address the role of decision biases and response caution. This is a critical oversight because several theories propose that the transition to negative priming following a long duration prime reflects a decision strategy to compensate for the effect of increased perceptual fluency. In contrast, the nROUSE model of Huber and O'Reilly (2003) explains this transition as reflecting perceptual habituation, and thus a change to perceptual disfluency. We confirmed this prediction by applying a sequential sampling model (the diffusion race model) to accuracy and response time distributions from a new single item same different version of the priming task. In this way, we measured strategic biases and perceptual fluency in each condition for each subject. The nROUSE model was only applied to accuracy from the original forced-choice version of the priming task. This application of nROUSE produced separate predictions for each subject regarding the degree of fluency and disfluency in each condition, and these predictions were confirmed by the drift rate parameters (i.e., fluency) from the response time model in contrast to the threshold parameters (i.e., bias). PMID- 29241034 TI - Sweet! Helicobacter Sugar Calms Intestinal Macrophages. AB - In the absence of IL-10, Helicobacter hepaticus (Hh) induces colitis. In this issue of Cell Host & Microbe, Danne et al. (2017) report that Hh produces a polysaccharide that induces an anti-inflammatory response in macrophages, providing a potential clue as to why this bacterium is normally tolerated by the immune system. PMID- 29241035 TI - Crossed Wires: Interspecies Interference Blocks Pathogen Colonization. AB - Commensal bacteria protect against invading pathogens using many strategies. In this issue of Cell Host & Microbe, Paharik et al. (2017) find that a commensal blocks Staphylococcus aureus colonization by producing a signal to shut down virulence. PMID- 29241036 TI - Plasmodium Peekaboo: PK4 Mediates Parasite Latency. AB - In this issue of Cell Host & Microbe, Zhang et al. (2017) show that translational repression through eIF2alpha phosphorylation mediated by PK4 kinase activity plays a key role in artemisinin resistance in recrudescent malaria infections. Targeting this druggable process could extend the lifespan of current frontline treatments. PMID- 29241037 TI - The Mammalian Gut as a Matchmaker. AB - Dynamics of phages and bacteria in the gut may play key roles in human health. In this issue of Cell Host & Microbe, De Sordi et al. (2017) provide insights into phage-bacteria interactions, finding that microbial communities contribute to phage persistence in the mammalian gut by supplying new hosts. PMID- 29241038 TI - Through the Scope Darkly: The Gut Mycobiome Comes into Focus. AB - The gut microbiome is comprised of microbes from multiple kingdoms, including bacteria, but also fungi, viruses, and perhaps other agents. In this issue of Cell Host & Microbe, Jiang et al. (2017) reveal that fungal monocolonization after antibiotic-mediated depletion of intestinal bacteria prevents colitis and influenza, thus highlighting beneficial roles of fungi. PMID- 29241039 TI - Route Connection: Mouth to Intestine in Colitis. AB - In a recent study published in Science, Atarashi et al. (2017) showed that Klebsiella strains isolated from the saliva of Crohn's disease patients can induce Th1 cell responses to promote colitis. Their findings highlight the importance of the oral cavity as a potential reservoir for bacteria that can promote intestinal disease. PMID- 29241040 TI - A Large Polysaccharide Produced by Helicobacter hepaticus Induces an Anti inflammatory Gene Signature in Macrophages. AB - Interactions between the host and its microbiota are of mutual benefit and promote health. Complex molecular pathways underlie this dialog, but the identity of microbe-derived molecules that mediate the mutualistic state remains elusive. Helicobacter hepaticus is a member of the mouse intestinal microbiota that is tolerated by the host. In the absence of an intact IL-10 signaling, H. hepaticus induces an IL-23-driven inflammatory response in the intestine. Here we investigate the interactions between H. hepaticus and host immune cells that may promote mutualism, and the microbe-derived molecule(s) involved. Our results show that H. hepaticus triggers early IL-10 induction in intestinal macrophages and produces a large soluble polysaccharide that activates a specific MSK/CREB dependent anti-inflammatory and repair gene signature via the receptor TLR2. These data identify a host-bacterial interaction that promotes mutualistic mechanisms at the intestinal interface. Further understanding of this pathway may provide novel prevention and treatment strategies for inflammatory bowel disease. PMID- 29241041 TI - Inhibiting the Plasmodium eIF2alpha Kinase PK4 Prevents Artemisinin-Induced Latency. AB - Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent infection, resulting in treatment failure. A subset of parasites is thought to undergo ART induced latency, but the mechanisms remain unknown. Here, we report that ART treatment results in phosphorylation of the parasite eukaryotic initiation factor 2alpha (eIF2alpha), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2alpha correlates with high rates of recrudescence following ART, and inhibiting eIF2alpha dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2alpha phosphorylation is mediated by the Plasmodium eIF2alpha kinase, PK4. Overexpression of a PK4 dominant-negative or pharmacological inhibition of PK4 blocks parasites from entering latency and abolishes recrudescence after ART treatment of infected mice. These results show that translational control underlies ART-induced latency and that interference with this stress response may resolve the clinical problem of recrudescent infection. PMID- 29241042 TI - The Adenovirus E1A C Terminus Suppresses a Delayed Antiviral Response and Modulates RAS Signaling. AB - The N-terminal half of adenovirus e1a assembles multimeric complexes with host proteins that repress innate immune responses and force host cells into S-phase. In contrast, the functions of e1a's C-terminal interactions with FOXK, DCAF7, and CtBP are unknown. We found that these interactions modulate RAS signaling, and that a single e1a molecule must bind all three of these host proteins to suppress activation of a subset of IFN-stimulated genes (ISGs). These ISGs were otherwise induced in primary respiratory epithelial cells at 12 hr p.i. This delayed activation of ISGs required IRF3 and coincided with an ~10-fold increase in IRF3 from protein stabilization. The induced IRF3 bound to chromatin and localized to the promoters of activated ISGs. While IRF3, STAT1/2, and IRF9 all greatly increased in concentration, there were no corresponding mRNA increases, suggesting that e1a regulates the stabilities of these key activators of innate immune responses, as shown directly for IRF3. PMID- 29241043 TI - Posttranscriptional m6A Editing of HIV-1 mRNAs Enhances Viral Gene Expression. PMID- 29241044 TI - Cooperative broadband spin echoes through optimal control. AB - The Hahn echo sequence is one of the most common building blocks in magnetic resonance, consisting of an excitation pulse and a refocusing pulse. Conventional approaches to improve the performance of echo experiments focused on the optimization of individual pulses, compensating their own imperfections. Here we present an approach to concurrently design both pulses such that they also compensate each others imperfections. The fact that for such cooperative pulses the individual pulses do not need to be perfect provides additional degrees of freedom, resulting in improved overall Hahn echo performance. Single-scan cooperative pulses are compared to conventional approaches by simulations as well as experiments. PMID- 29241045 TI - Overhauser effects in non-conducting solids at 1.2 K. AB - Recently, it was observed that protons in non-conducting solids doped with 1,3 bisdiphenylene-2-phenylallyl (BDPA) or its sulfonated derivative (SA-BDPA) can be polarized through Overhauser effects via resonant microwave irradiation. These effects were present under magic angle spinning conditions in magnetic fields between 5 and 18.8 T and at temperatures near 100 K. This communication reports similar effects in static samples at 6.7 T and, more importantly, at temperatures as low as 1.2 K, in a different dynamic regime than in the previous study. Our results provide new information towards understanding the mechanism of the Overhauser effect in non-conducting solids. We discuss possible origins of the fluctuations that can give rise to an Overhauser effect at such low temperatures. PMID- 29241046 TI - Increase in post activation potentiation in females following a cycling warmup. AB - Post activation potentiation (PAP) is a phenomenon in which muscular force is acutely enhanced as a result of prior contractile activity. The net augmentation is dependent upon the intensity of the preceding conditioning contraction influencing calcium release and phosphorylation of the regulatory myosin light chain. This phenomenon has been recorded after various types of conditioning contractions, however the interaction of a warmup on PAP remains uncertain and whether this differs between males and females requires consideration. We investigated the effect of a cycling warmup on twitch contractile properties and PAP of the plantar flexors on males and in females using oral contraceptives. A maximal voluntary contraction (MVC) of the plantar flexors preceded and followed a 10-min cycling warmup, where supramaximal twitches were administered prior to, during and after the conditioning contractions. Twitch contractile properties of peak tension (PT), time to peak tension (TPT), half relaxation time (HRT) and contraction duration (CD) were compared between resting and potentiated twitches before and after the warmup. Ultrasonography was used to measure in vivo Achilles tendon architecture. Males were ~30% stronger, but voluntary activation did not differ from females (p = .37). In males and females PT increased following the conditioning MVC (p = .03). The degree of potentiation was higher following the warmup in females (25.01%, p = .02) but not males (p = .24). TPT, HRT and contraction duration (p < .05) were faster after the warmup and in males (p < .001). Achilles tendon elongation was unchanged by the warmup (p = .11). Ten minutes of a cycling warmup reduced TPT, HRT, and CD in both males and females without altering the tendon. The degree of PAP was higher in females than males following the warmup. This difference might be associated with altered calcium kinetics of females on oral contraceptives as well as higher proportion of type I fibres in the active muscles. PMID- 29241047 TI - Knee misalignment and exercise amount: Predictive value for chronic low back pain in young competitive athletes. AB - Sports medical examinations of juvenile athletes provide an opportunity for preventive measures against sports-related diseases. Determining the leg axis deviation as a risk factor for future constraints may offer approaches for such measures. Data were obtained from 789 youth athletes: 166 with coronal plane knee misalignment and 623 without. After a seven-year period, 64 participants (m: 33, f: 31) from both groups were reassessed for the incidence of nonspecific chronic low back pain (CLBP). To distinguish participants with increased risk for CLBP, contingency tables for comparison of expected and joint frequency distribution testing and receivers operating characteristic (ROC) analyses for the weekly training time were conducted. Subjects with an initial diagnosed knee misalignment showed increased risk for the development of CLBP (CHI2 = 4.2, p < .05, OR = 3.4) compared to participants without knee misalignment. In athletes with knee misalignment, ROC analysis revealed an optimal cut-off of 6.75 h/w (AUC = 0.8; Chi2 = 4.2, p < .05, OR = 8.0). In athletes without leg axis deviation, no association to training volume was detected. Our results suggest a predictive value of knee misalignment on the later occurrence of CLBP in young competitive athletes and underline the importance of an examination of the motor system during sports medical assessments in youth athletes. Training volume of almost more than 7 h a week enhances this risk. PMID- 29241048 TI - Impact of serum albumin levels on long-term all-cause, cardiovascular, and cardiac mortality in patients with first-onset acute myocardial infarction. AB - BACKGROUND: To evaluate the association of serum albumin (SA) with long-term all cause, cardiovascular, and cardiac mortality in patients with first-onset acute myocardial infarction (AMI). METHODS: The cohort study enrolled 2305 patients with first-onset AMI. The median follow-up was of 1088days (3years). Impacts of SA on long-time mortality after AMI were determined using multivariate Cox proportional hazard regression analysis with backward selection. RESULTS: The patients were divided into three categories by SA tertiles (<=3.62, 3.63-4.08, >4.08g/dl). High tertile group was used as reference, the adjusted HRs for all cause death were 1.21 (P=0.338) and 1.74 (P=0.003) for intermediate and low tertile, respectively (p-for-trend=0.001); The equivalent values for cardiovascular death were 1.13 (P=0.588) and 1.64 (P=0.022), respectively (p-for trend=0.009); The corresponding values for cardiac death were 1.07 (P=0.806) and 1.59 (P=0.048), respectively (p-for-trend=0.022). Moreover, adjusted HRs per 1 g/dl decrease in SA concentrations were 1.66 (P=0.001) for all-cause death, 1.47 (P=0.024) for cardiovascular death, and 1.61 (P=0.012) for cardiac death. CONCLUSIONS: Low SA level (<=3.62g/dl) on admission was an independent predictor of long-term all-cause, cardiovascular, and cardiac mortality in patients with first-onset AMI. There was a dose-response relationship between decreased SA concentrations and increased long-term all-cause, cardiovascular, and cardiac mortality. PMID- 29241049 TI - Prenatal maternal mood patterns predict child temperament and adolescent mental health. AB - BACKGROUND: This study quantifies the dynamics of maternal mood focusing on unpredictability, and to assess if greater unpredictability of prenatal maternal mood predicts child temperament and internalizing symptoms through early adolescence. METHODS: The association between prenatal mood predictability and child internalizing symptoms were assessed in two longitudinal cohorts (N's = 227 and 180). Maternal mood was assessed repeatedly during pregnancy as early as 15 weeks' gestation. Predictability of maternal mood was calculated by applying Shannon's entropy to the distribution of responses on mood questionnaires. Maternal reports of child negative affectivity (a predictor of later internalizing) were collected at 6, 12, 24 months and 7 years of age. Child self reports of anxiety symptoms were collected at 10 years and reports of depression symptoms at 13 years. RESULTS: Fetal exposure to more elevated maternal mood entropy predicted higher levels of child negative affectivity at 12 months (r = .36; p < 01), 24 months (r = .31; p < 01) and 7 years (r = .32; p < 01) of age. In addition, children exposed to higher prenatal maternal mood entropy, reported higher levels of anxiety symptoms at 10 years (r = .24; p < 01) and elevated depressive symptoms at 13 years (r = .29; p < .01). These associations persisted after adjusting for maternal pre and postnatal mood valence (e.g. depression levels) and for other relevant demographic characteristics. CONCLUSIONS: Our findings provide strong support for the notion that patterns of maternal mood influence the developing brain. More specifically, they suggest that prenatal maternal mood predictability may be a critical predictor of developmental mental health trajectories and should be considered when assessing early life influences on lifespan mental health. PMID- 29241050 TI - Cytokine alterations in panic disorder: A systematic review. AB - BACKGROUND: Panic disorder (PD) occurs in 3.4-4.7% of the general population. Although accumulating evidence suggests that some inflammatory processes play a role in the pathophysiology of mental disorders, very few studies have evaluated cytokine levels in patients with PD. The aim of the present study was to systematically review the characteristic cytokine profile of PD patients and discuss some possibilities for future trials on this common and disabling disorder. METHODS: A comprehensive literature search was carried out in PubMed and Web of Science databases (search terms: "panic disorder" or "panic attacks" and IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13, TNF-alpha and INF-gamma). RESULTS: Eleven studies involving measurements of cytokines in PD patients were included in this review article. Increased serum levels of some inflammatory markers such as IL-6, IL-1beta and IL-5 were reported in PD patients compared with control subjects. There are some conflicting results regarding IL-2, IL-12, and INF-gamma in association with PD. LIMITATIONS: There are discrepant findings in the existing literature regarding PD and cytokines. A significant portion of the recognized heterogeneity may be attributable to variability in assay procedures. The discrepant findings may also have been due to differences in the study populations. CONCLUSIONS: Cytokines induce the production of acute-phase proteins and are linked to neurogenesis, modification of the HPA axis, microglial activation, tryptophan metabolism and an imbalance in excitatory and inhibitory neurotransmission. Investigation of inflammatory biomarkers in PD could contribute to understanding the pathophysiological mechanisms in this debilitating disorder. PMID- 29241051 TI - Determination of lipid profiles in serum of obese ponies before and after weight reduction by using multi-one-dimensional thin-layer chromatography. AB - Obesity is a key component of equine metabolic syndrome, which is highly associated with laminitis. Feed restriction and/or exercise are known to alleviate the detrimental effects of insulin resistance in obese ponies. However, little is known about changes in the serum lipid patterns due to weight reduction and its association with disease outcomes. Therefore, the lipid patterns in the serum of 14 mature ponies before and after a 14-week body weight reduction program (BWRP) were investigated by multi-one-dimensional thin-layer chromatography (MOD-TLC). Additionally, sensitivity to insulin (SI), body condition scores (BCS) and cresty neck scores (CNS) were measured. A BWRP resulted in a significant loss of body weight (P<0.001), which was associated with beneficial decreases in BCS and CNS (both, P<0.001). Serum lipid compositions revealed significantly increased free fatty acid (FFA), sphingomyelin (SM; both P<0.001), total cholesterol (C) and cholesterol ester (CE) (both P<0.01) and triacylglycerol (TG; P<0.05) densities. Improvement of SI after the BWRP was associated with increases in neutral lipids (C, CE and TG, all P<0.01), FFA and the phospholipid SM (both, P<0.001). The results show that a BWRP in obese ponies was effective and associated with changes in the concentrations of neutral lipids and the phospholipid SM, indicating that SM may play a role in insulin signaling pathways and thus in the pathogenesis of insulin resistance and the progression of metabolic syndrome in obese ponies. PMID- 29241052 TI - Hydroxyapatite-chitosan based bioactive hybrid biomaterials with improved mechanical strength. AB - Composites consisting of hydroxyapatite (HA) and chitosan (CTS) have recently been intensively studied. In this work, a novel inorganic-organic (I/O) HA/CTS materials in the form of granules were prepared through a simple solution-based chemical method. During the synthesis of these hybrids, the electrostatic complexes between positively charged, protonated amine groups of chitosan and the negative phosphate species (HPO42- and H2PO4-) were formed. Our biocomposites belong to the class I of hybrids, which was confirmed by FTIR studies. XRD analysis revealed that the obtained materials consisted of hydroxyapatite as the only crystalline phase. Homogeneous dispersion of the components in HA/CTS composites was confirmed. The use of 17wt% and 23wt% of chitosan resulted in approximately 12-fold and 16-fold increase in the compressive strength of HA/CTS as compared to the non-modified HA material. During incubation of the studied materials in SBF, pH of the solution remained close to the physiological one. Formation of apatite layer on their surfaces indicated bioactive nature of the developed biomaterials. PMID- 29241054 TI - Effect of auxiliary group for p-type organic dyes in NiO-based dye-sensitized solar cells: The first principal study. AB - Auxiliary acceptor groups play a crucial role in D-A-pi-A structured organic dyes. In this paper, we designed three D-A-pi-A structured organic molecules based on the prototype dye QT-1, named ME18-ME20, and further investigated their electronic and optical properties with density functional theory (DFT) and time dependent DFT (TDDFT). The calculated results indicate that the scope and intensity of dyes' absorption spectra have some outstanding changes by inserting auxiliary groups. ME20 has not only 152nm redshifts to long wave orientation, but also 78% increased oscillator strength compared to QT-1, and its absorption spectrum broadens region even up to 1400nm. Then, we studied the reason that the effect of the introduced different auxiliary acceptor groups in these dyes through their ground states geometries and energy levels, electron transfer and recombination rate. PMID- 29241053 TI - Excitation of triplet states of hypericin in water mediated by hydrotropic cromolyn sodium salt. AB - Hypericin (Hyp) is a hydrophobic pigment found in plants of the genus Hypericum which exhibits low levels of solubility in water. This work shows that the solubility of Hyp can be significantly increased through the addition of cromolyn disodium salt (DSCG). Performed studies using UV-VIS absorption and fluorescence spectroscopies demonstrate that Hyp remains in a predominantly biologically photodynamic active monomeric form in the presence of DSCG at concentrations ranging from 4.6*10-3 to 1.2*10-1mol.L-1. The low association constant between Hyp and DSCG (Ka=71.7+/-2M-1), and the polarity value of 0.3 determined for Hyp in a DSCG-water solution, lead to a suggestion that the monomerization of Hyp in aqueous solution can be explained as a result of the hydrotropic effect of DSCG. This hydrotropic effect is most likely a result of interactions between two relative rigid aromatic rings of DSCG and a delocalized charge on the surface of the Hyp molecule. The triplet-triplet (T-T) electronic transition observed in is Hyp in the presence of DSCG suggests a possible production of reactive oxygen species once Hyp is irradiated with visible light in a DSCG aqueous solution. PMID- 29241055 TI - pH-Dependent reversible crystal transformation of 1-carboxymethyl-1-methyl pyrrolidinium bromides and their spectroscopic fingerprint. AB - In this work, two 1-carboxymethyl-1-methyl-pyrrolidinium bromides (N methylpyrrolidine betaine hydrobromides) with the stoichiometry of betaine:hydrobromic acid as 1:1 and 2:1, denoted as CMPRHBr-I and CMPRHBr-II, respectively, were prepared and crystallographically determined. The large difference in these two structures is the type of hydrogen bonds, resulting in the different thermal stability. A strong OH?Br hydrogen bond was observed in CMPRHBr-I, whereas O?H?O hydrogen bond in CMPRHBr-II. Both these two crystals can mutually transform by changing the pH value of the aqueous solution. Vibrational spectroscopic studies shows that these two structures can be easily distinguished by the characteristic bands such as nuCO stretching vibration and the D-type bands. Our studies indicate that it should be cautious of the structural change as this type of organic salts was purified and recrystallized. PMID- 29241056 TI - Segmentation of arterial walls in intravascular ultrasound cross-sectional images using extremal region selection. AB - Intravascular Ultrasound (IVUS) is an intra-operative imaging modality that facilitates observing and appraising the vessel wall structure of the human coronary arteries. Segmentation of arterial wall boundaries from the IVUS images is not only crucial for quantitative analysis of the vessel walls and plaque characteristics, but is also necessary for generating 3D reconstructed models of the artery. The aim of this study is twofold. Firstly, we investigate the feasibility of using a recently proposed region detector, namely Extremal Region of Extremum Level (EREL) to delineate the luminal and media-adventitia borders in IVUS frames acquired by 20 MHz probes. Secondly, we propose a region selection strategy to label two ERELs as lumen and media based on the stability of their textural information. We extensively evaluated our selection strategy on the test set of a standard publicly available dataset containing 326 IVUS B-mode images. We showed that in the best case, the average Hausdorff Distances (HD) between the extracted ERELs and the actual lumen and media were 0.22 mm and 0.45 mm, respectively. The results of our experiments revealed that our selection strategy was able to segment the lumen with ?0.3 mm HD to the gold standard even though the images contained major artifacts such as bifurcations, shadows, and side branches. Moreover, when there was no artifact, our proposed method was able to delineate media-adventitia boundaries with 0.31 mm HD to the gold standard. Furthermore, our proposed segmentation method runs in time that is linear in the number of pixels in each frame. Based on the results of this work, by using a 20 MHz IVUS probe with controlled pullback, not only can we now analyze the internal structure of human arteries more accurately, but also segment each frame during the pullback procedure because of the low run time of our proposed segmentation method. PMID- 29241057 TI - FE analysis of surface acoustic wave transmission in composite piezoelectric wedge structures. AB - The paper numerically investigates the transmission of harmonic surface acoustic waves (SAWs) across the perfectly bonded and perfectly sliding contacts between two 90 degrees -wedges, at least one of which possessing piezoelectric properties. The finite element method in frequency domain is used. The structures are constructed of lithium niobate, fused quartz, silicon and gallium arsenide. The SAW is always incident from lithium niobate. The dependences of the transmission coefficient on the combination of materials and the orientation of the lithium niobate, as well as on the height of the step at the interface between the two parts of the structure are computed and analyzed. This step can appear in the process of fabrication of the composite substrate. The obtained results demonstrate that SAWs are able to transmit fairly efficiently across a wedge-like contact. Therefore such structures can be useful, in particular, in cases when it is advantageous to generate a SAW in one strongly piezoelectric material and observe its action, e.g., due to the transmitted surface normal displacement in another material like in SAW-driven microfluidics. PMID- 29241058 TI - A novel robotic arm driven by sandwich piezoelectric transducers. AB - In this work, a novel robotic arm driven by sandwich piezoelectric transducers is proposed. The proposed robotic arm is composed of three arms and four joints. Each arm consists of a sandwich piezoelectric transducer and an H-shaped hollow frame. The sandwich piezoelectric transducer utilizes frictional force to drive the joints on its both sides to rotate simultaneously. The joint between two arms can be driven to rotate in two perpendicular directions by two sandwich piezoelectric transducers. The rotation of joints results in the arm motion. Utilizing the finite element method, the optimized geometrical parameters of the sandwiched piezoelectric transducer are obtained, and the operating principle is demonstrated. A prototype of the robotic arm is also fabricated and assembled, it is 573 g in weight and 412 mm in length, and the maximum rotation angle of each joint is 160 degrees . The mechanical characteristics of the robotic arm prototype are investigated by experiments. The results indicate that, when the excitation frequency of one sandwich piezoelectric transducer is 37.4 kHz, the arms on its two sides rotate in opposite directions with an average rotational velocity of 320 deg/s at 330 Vpp, a resolution of 100 MUrad at 230 Vpp, and a startup and shutdown response time of 40 ms and 30 ms at 230 Vpp, respectively. PMID- 29241059 TI - Moxidectin residues in lamb tissues: Development and validation of analytical method by UHPLC-MS/MS. AB - The development and validation of a throughput method for the quantitation of moxidectin residues in lamb target tissues (muscle, kidney, liver and fat) was conducted using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). To achieve higher recovery of the analyte from the matrices, a modified QuEChERS method was used for sample preparation. The chromatographic separation was achieved using a Zorbax Eclipse Plus C18 RRHD column with a mobile phase comprising 5mM ammonium formate solution +0.1% formic acid (A) and acetonitrile +0.1% formic acid (B) in a linear gradient program. Method validation was performed based on the Commission Decision 2002/657/EC and VICH GL49. To quantify the analyte, matrix-matched analytical curves were constructed with spiked blank tissues, with a limit of quantitation of 5ngg-1 and limit of detection of 1.5ngg-1 for all matrices. The linearity, decision limit, detection capability accuracy, and inter- and intra-day repeatability of the method are reported. The method was successfully applied to incurred lamb tissue samples (muscle, liver, kidney and fat) in a concentration range from 5 to 200MUgkg-1, which demonstrated its suitability for monitoring moxidectin residues in lamb tissues in health surveillance programs, as well as for pharmacokinetics and residue depletion studies. PMID- 29241060 TI - A novel electrochemical cytosensor for selective and highly sensitive detection of cancer cells using binding-induced dual catalytic hairpin assembly. AB - Rare cancer cells in body fluid could be useful biomarkers for noninvasive diagnosis of cancer. However, detection of these rare cells is currently challenging. In this work, a binding-induced dual catalytic hairpin assembly (DCHA) electrochemical cytosensor was developed for highly selective and sensitive detection of cancer cells. The fuel probe, released by hybridization between the capture probe and catalytic hairpin assembly (CHA) products of target cell-responsive reaction, initiated dual CHA recycling, leading to multiple CHA products. Furthermore, the hybridization between fuel probe and capture probe decreased non-specific CHA products, improving the signal-to-noise ratio and detection sensitivity. Under the optimal conditions, the developed cytosensor was able to detect cells down to 30 cells mL-1 (S/N = 3) with a linear range from 50 to 100,000 cells mL-1 and was capable of distinguishing target cells from normal cells in clinical blood samples. PMID- 29241062 TI - A paper-supported aptasensor based on upconversion luminescence resonance energy transfer for the accessible determination of exosomes. AB - Exosomes, as potential cancer diagnostic markers have received close attention in recent years. However, there is still a lack of simple and convenient methods to detect and quantitate exosomes. Herein, we used a simple paper-supported aptasensor based on luminescence resonance energy transfer (LRET) from upconversion nanoparticles (UCNPs) to gold nanorods (Au NRs) for the accessible determination of exosomes. When exosomes are present, the two sections of the aptamer can combine with the CD63 protein on the surface of exosomes and form a conjugation to close the distance between UCNPs and Au NRs, which initiates the LRET and promotes luminescence quenching. These variations can be monitored by the homemade image system, and the green channel intensities of obtained colored images were extracted with photoshop software to quantify the luminescence. As a result, the quenching of the luminescence of the UCNPs is linearly correlated to the concentration of the exosomes (in the range of 1.0 * 104 ~ 1.0 * 108 particles/MUL), enabling the detection and quantification of the exosomes. Such approach can reach a low detection limit of exosomes (1.1 * 103 particles/MUL) and effectively reduce the background signal by using UCNPs as a luminescent material. This study provides an efficient and practical approach to the detection of exosomes, which should lead to point-of-care testing in clinical applications. PMID- 29241063 TI - Red warning for air pollution in China: Exploring residents' perceptions of the first two red warnings in Beijing. AB - Air pollution early warnings have been issued in China to mitigate the effects of high pollution days. Public perceptions and views about early warning signals can affect individual behaviors and play a major role in the public's response to air pollution risks. This study examined public attitudes and responses to the first two red warnings for air pollution in Beijing in 2015. An online survey was sent out, and 664 respondents (response rate = 90%) provided their perspectives on the red warnings. Descriptive statistics, sign tests and binary logit models were used to analyze the data. More than half of the respondents reported that their life and work were affected by the red warning in December 2015. In contrast to their perceptions about the second red warning period, the public thought that the first red warning should have been issued earlier and that the number of consecutive days of warnings should have been reduced. The respondents also recommended that instead of reducing the number of red warnings, the red warning emergency measures should be adjusted. Specifically, the public preferred the installation of air purifiers in schools rather than closing schools and strengthening road flushing and dust pollution controls over restrictions on driving. Data analyses were conducted to examine the affected groups and different groups' perceptions of the necessity of implementing emergency measures. The results indicated that men and more educated respondents were more likely to be affected by driving limitations, and men were less supportive of these limitations. The age and education of respondents were significantly negatively associated with the opinion that schools should be closed, whereas wealthier respondents were more supportive of school closings. The finding of a negative attitude among the public toward the first two red warnings may be used to help local governments modify protective measures and pollution mitigation initiatives to increase acceptance. PMID- 29241061 TI - ScFv-modified graphene-coated IDE-arrays for 'label-free' screening of cardiovascular disease biomarkers in physiological saline. AB - Fatty-acid binding proteins (FABP) and myeloperoxidases (MPO) are associated with many chronic conditions in humans and considered to be important biomarkers for diagnosis of cardiac diseases. Here we assemble a new electrical biosensor platform based on graphene-coated interdigitated electrode arrays (IDE-arrays) towards ultrafast, label-free screening of heart type-FABP and MPO. Arrays of nanoscale (nanoIDE) and microscale (microIDE) electrode-arrays were fabricated on wafer-scale by combining nanoimprint and photolithography processes. Chemical vapor deposition grown multilayer graphene was transferred onto nano/microIDE arrays and used as a high surface-to-volume ratio electrical transducer. Novel biofunctional layers of specially engineered anti-h-FABP and anti-MPO single chain fragment variables (scFv) were immobilized onto graphene-coated IDE-array sensor platform for electrical detection of h-FABP and MPO in physiological saline. scFv fragments show increased sensitivity in comparison to the state-of the-art competitive ELISA for their higher affinity towards target analytes. Deploying FABP and MPO specific scFvs as receptor molecules onto our high sensitivity graphene-coated IDE-arrays with identical sensor characteristics and assays covering clinically relevant concentrations in physiological saline, we demonstrate realization of a simple and versatile biosensor platform capable of high performance cardiac-bioassays for point-of-care applications. PMID- 29241064 TI - Kitchen PM2.5 concentrations and child acute lower respiratory infection in Bhaktapur, Nepal: The importance of fuel type. AB - BACKGROUND: Globally, solid fuels are used by about 3 billion people for cooking and a smaller number use kerosene. These fuels have been associated with acute lower respiratory infection (ALRI) in children. Previous work in Bhaktapur, Nepal, showed comparable relationships of biomass and kerosene cooking fuels with ALRI in young children, compared to those using electricity for cooking. We examine the relationship of kitchen PM2.5 concentrations to ALRI in those households. METHODS: ALRI cases and age-matched controls were enrolled from a cohort of children 2-35 months old. 24-h PM2.5 was measured once in each participant's kitchen. The main analysis was carried out with conditional logistic regression, with PM2.5 measures specified both continuously and as quartiles. RESULTS: In the kitchens of 393 cases and 431 controls, quartiles of increasing PM2.5 concentration were associated with a monotonic increase in odds ratios (OR): 1.51 (95% CI: 1.00, 2.27), 2.22 (1.47, 3.34), 2.48 (1.63, 3.77), for the 3 highest exposure quartiles. The general kitchen concentration-response shape across all stoves was supralinear. There was evidence for increased risk with biomass stoves, but the slope for kerosene stoves was steeper, the highest quartile OR being 5.36 (1.35, 21.3). Evidence for increased risk was also found for gas stoves. CONCLUSION: Results support previous reports that biomass and kerosene cooking fuels are both ALRI risk factors, but suggests that PM2.5 from kerosene is more potent on a unit mass basis. Further studies with larger sample sizes and preferably using electricity as the baseline fuel are needed. PMID- 29241065 TI - Associations between maternal triclosan concentrations in early pregnancy and gestational diabetes mellitus, impaired glucose tolerance, gestational weight gain and fetal markers of metabolic function. AB - BACKGROUND: Triclosan is a phenolic biocide used in a multitude of consumer products and in health care settings. It is widely detected in the American and Canadian populations and has been shown in animal models to act as an endocrine disrupting agent. However, there has been little examination to date of the effects of triclosan exposure in pregnancy on perinatal metabolic outcomes in human populations. METHODS: Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a Canadian pregnancy cohort, we measured associations of first-trimester urinary triclosan concentrations with total gestational weight gain, gestational diabetes mellitus and impaired glucose tolerance in pregnancy, and fetal markers of metabolic function. Leptin and adiponectin were measured in plasma from umbilical cord blood samples in term neonates and categorized into low (< 10th percentile), intermediate (10th-90th percentile) and high (> 90th percentile) levels. Triclosan concentrations were grouped into quartiles and associations with study outcomes were examined using logistic regression models with adjustment for maternal age, race/ethnicity, pre pregnancy BMI, education and urinary specific gravity. Restricted cubic spline analysis was performed to help assess linearity and shape of any dose-response relationships. All analyses for leptin and adiponectin levels were performed on the entire cohort as well as stratified by fetal sex. RESULTS: Triclosan measures were available for 1795 MIREC participants with a live born singleton birth. Regression analyses showed a non-significant inverse association between triclosan concentrations and leptin levels above the 90th percentile that was restricted to female fetuses (OR for highest quartile of triclosan compared to lowest quartile = 0.4 (95% CI 0.2-1.1), p-value for trend across quartiles = 0.02). Triclosan concentrations in the second quartile were associated with elevated odds of adiponectin below the 10th percentile in male fetuses (OR for Q2 compared to Q1 = 2.5, 95% CI 1.1-5.9, p-value for trend across quartiles = 0.93). No significant linear associations between triclosan concentrations and leptin or adiponectin levels in overall or sex-specific analyses were observed from restricted cubic spline analyses. No significant associations were observed in adjusted analyses between triclosan concentrations and gestational diabetes mellitus, impaired glucose tolerance or gestational weight gain. CONCLUSIONS: This study does not support an association between triclosan concentrations in pregnancy and fetal metabolic markers, glucose disorders of pregnancy, or excessive gestational weight gain. PMID- 29241066 TI - Agronomic efficiency of phosphate fertilizers produced by the re-use of a metallurgical acid residue. AB - The production of fertilizers with industrial wastes reduces the environmental impacts of waste disposal and improves environmental sustainability by generating added-value products. Our objective with this study was to evaluate the agronomic performance and potential soil/plant contamination with heavy metals of alternative phosphate (P) fertilizers, obtained from the acidulation of phosphate rocks (PR) by a metallurgical acidic waste. Seven P fertilizers were evaluated: three PR (Araxa, Patos, and Bayovar), their respective acidulated products (PAPR), and triple superphosphate fertilizer (TSP). A greenhouse trial was carried out to test the agronomic performances of fertilizers in a sequentially cultivated maize-soybean-white oat. The reaction of PR with acid waste was effective to increase their solubility and improve plant yield and P uptake compared to their natural PR. There was a cumulative recovery by plants of 1.4 and 8.1% of added P via PR and PAPR, respectively. No increase in heavy metal (Cd, Pb, Cr, and Ni) availability in soil or accumulation in shoots was observed, indicating that the PAPR were environmentally safe. The usage of acid waste to produce P fertilizers therefore represents a strategic way to employ marginal products for the production of fertilizers. PMID- 29241067 TI - Weed seed spread and its prevention: The role of roadside wash down. AB - Vehicles are one of the major vectors of long-distance weed seed spread. Viable seed removed from vehicles at roadside wash down facilities was studied at five locations in central Queensland, Australia over a 3-year period. Seed from 145 plant species, belonging to 34 different families, were identified in the sludge samples obtained from the wet particulate matter collection pit of the wash down facilities. Most of the species were annual forbs (50%) with small or very small seed size (<2 mm in diameter). A significant amount of seed from the highly invasive, parthenium weed was observed in these samples. More parthenium weed seed were found in the Rolleston facility and in the spring, but its seed was present in all facilities and in all seasons. The average number of viable seed found within every ton of dry particulate matter removed from vehicles was ca. 68,000. Thus, a typical wash down facility was removing up to ca. 335,000 viable seed from vehicles per week, of which ca. 6700 were parthenium weed seed. Furthermore, 61% of these seed (ca. 200,000) were from introduced species, and about half of these (35% of total) were from species considered to be weeds. Therefore, the roadside wash down facilities found throughout Queensland can remove a substantial amount of viable weed seed from vehicles, including the invasive parthenium weed, and the use of such facilities should be strongly encouraged. PMID- 29241068 TI - Long-term projections of temperature-related mortality risks for ischemic stroke, hemorrhagic stroke, and acute ischemic heart disease under changing climate in Beijing, China. AB - BACKGROUND: Changing climates have been causing variations in the number of global ischemic heart disease and stroke incidences, and will continue to affect disease occurrence in the future. OBJECTIVES: To project temperature-related mortality for acute ischemic heart disease, and ischemic and hemorrhagic stroke with concomitant climate warming. METHODS: We estimated the exposure-response relationship between daily cause-specific mortality and daily mean temperature in Beijing. We utilized outputs from 31 downscaled climate models and two representative concentration pathways (RCPs) for the 2020s, 2050s, and 2080s. This strategy was used to estimate future net temperature along with heat- and cold-related deaths. The results for predicted temperature-related deaths were subsequently contrasted with the baseline period. RESULTS: In the 2080s, using the RCP8.5 and no population variation scenarios, the net total number of annual temperature-related deaths exhibited a median value of 637 (with a range across models of 434-874) for ischemic stroke; this is an increase of approximately 100% compared with the 1980s. The median number of projected annual temperature related deaths was 660 (with a range across models of 580-745) for hemorrhagic stroke (virtually no change compared with the 1980s), and 1683 (with a range across models of 1351-2002) for acute ischemic heart disease (a slight increase of approximately 20% compared with the 1980s). In the 2080s, the monthly death projection for hemorrhagic stroke and acute ischemic heart disease showed that the largest absolute changes occurred in summer and winter while the largest absolute changes for ischemic stroke occurred in summer. CONCLUSIONS: We projected that the temperature-related mortality associated with ischemic stroke will increase dramatically due to climate warming. However, projected temperature related mortality pertaining to acute ischemic heart disease and hemorrhagic stroke should remain relatively stable over time. PMID- 29241069 TI - MiR-208a-3p aggravates autophagy through the PDCD4-ATG5 pathway in Ang II-induced H9c2 cardiomyoblasts. AB - Pathological cardiac hypertrophy is the main determinant of the development of heart failure, for which there is often no effective therapy. The dysregulation of autophagy is implicated in hypertrophy, but the mechanism linking these processes is unclear. In this study, we characterized the regulatory role of miR 208a-3p in autophagy in H9c2 cardiomyoblasts induced by Angiotensin II (Ang II). We found that miR-208a-3p was up-regulated in Ang II-induced H9c2 cardiomyoblasts and in starvation-induced autophagy. The overexpression of miR-208a-3p increased Ang II-induced autophagy, and this was accompanied by the inhibition of programmed cell death protein (PDCD4) and upregulation of autophagy protein 5 (ATG5). A dual-luciferase report assay confirmed the direct binding between miR 208a-3p and PDCD4. PDCD4 knockdown up-regulated autophagy, and its overexpression down-regulated this process. Moreover, the PDCD4-mediated regulation of autophagy was modulated by ATG5. Taken together, these findings indicate that miR-208a-3p promotes autophagy during Ang II-induced hypertrophy and provide a basis for the development of therapies for hypertrophic-induced cardiac dysfunction. PMID- 29241070 TI - Protocatechuic acid ameliorates high glucose-induced extracellular matrix accumulation in diabetic nephropathy. AB - Protocatechuic acid (PCA), a phenolic compound of anthocyanins, was reported to possess various pharmacologic properties, including anti-oxidant, anti inflammatory, anti-apoptosis, anti-diabetic and anti-tumor activities. However, the role of PCA in diabetic nephropathy remains elusive. The present study was conducted to evaluate the effects of PCA on extracellular matrix (ECM) accumulation in high glucose (HG)-induced human mesangial cells (MCs) and explore the possible mechanism. Our results demonstrated that PCA obviously inhibited HG induced proliferation of MCs in a dose-dependent manner. In addition, PCA effectively reduced the protein expression levels of type IV collagen, laminin and fibronectin induced by HG, as well as decreased the levels of ROS and MDA in HG-stimulated MCs. Mechanistic studies showed that PCA efficiently down-regulated the phosphorylation level of p38 MAPK in HG-stimulated MCs. Taken together, our present study demonstrated that PCA protects MCs against HG damage might via inhibition of the p38 MAPK signaling pathway. Thus, PCA might be a beneficial agent for the prevention and treatment of diabetic nephropathy. PMID- 29241071 TI - Insights on ornithine decarboxylase silencing as a potential strategy for targeting retinoblastoma. AB - Ornithine Decarboxylase (ODC) is a key enzyme involved in polyamine synthesis and is reported to be up regulated in several cancers. However, the effect of ODC gene silencing in retinoblastoma is to be understood for utilization in therapeutic applications. Hence, in this study, a novel siRNA (small interference RNA) targeting ODC was designed and validated in Human Y79 retinoblastoma cells for its effects on intracellular polyamine levels, Matrix Metalloproteinase 2 & 9 activity and Cell cycle. The designed siRNA showed efficient silencing of ODC mRNA expression and protein levels in Y79 cells. It also showed significant reduction of intracellular polyamine levels and altered levels of oncogenic LIN28b expression. By this study, a regulatory loop is proposed, wherein, ODC silencing in Y79 cells to result in decreased polyamine levels, thereby, leading to altered protein levels of Lin28b, MMP-2 and MMP-9, which falls in line with earlier studies in neuroblastoma. Thus, by this study, we propose ODC silencing as a prospective strategy for targeting retinoblastoma. PMID- 29241072 TI - Combined efficacy of oseltamivir, isoprinosine and ellagic acid in influenza A(H3N2)-infected mice. AB - Influenza pathogenesis comprises a complex cascade of impaired cellular processes resulting from the viral replication and exaggerated immune response accompanied by reactive oxygen species (ROS) burst and oxidative stress, destructing membranous structures and tissues. By classical virological and biochemical methods we compared and evaluated the therapeutic effects of 2.5mg/kg/day of the antiviral drug - oseltamivir (OS), 500mg/kg/day of the immune modulator - isoprinosine (IP) and 500mg/kg/day of the antioxidant agent ellagic acid (EA) with a focus on their combined activities in influenza H3N2 virus-infected mice. The survival, lung pathology and titers, as well as the oxidative stress biomarker thiobarbituric acid reactive substances (TBARS) in the lungs, liver and blood plasma, correlated to the activities of the antioxidant enzymes superoxide dismutase (SOD) and glutathione reductase (GR) were assessed. We found that the viral inhibitor applied together with the immune modulator and the antioxidant exhibited strong therapeutic effects on the survival of the influenza-challenged mice. That effect was mostly pronounced for the triple combination - protection index (PI) of 75.2%, mean survival time (MST) extended by 5.8 days compared to the PBS control and significant reduction of the lung titers by 1.38 Deltalg; 2.3 scores lower lung pathology and 8 times reduction of the accumulated TBARS in the lungs and liver on the 5-th day p.i. The enzymatic assays revealed that this combination demonstrated very good protection against the damaging superoxide radicals (83% efficiency of SOD, in comparison to healthy controls 100%). The double combinations of OS with IP and EA also showed protective effects according to the virological analysis - PI of 53.1% and 54.5%. Ten times higher GR activity was observed when the combination EA+OS and monotherapy of EA were applied (96% in comparison to healthy controls 100%). The best antioxidant effect in blood plasma was observed in the EA+IP group - 4 times reduction in the TBARS-content compared to infected controls but it did not have any efficacy on the survival and lung injury. PMID- 29241073 TI - Resveratrol inhibits proliferation, migration and invasion via Akt and ERK1/2 signaling pathways in renal cell carcinoma cells. AB - Recent studies have shown that resveratrol (RES) inhibits cancer cell growth, migration and invasion. Here, we evaluated RES in two human renal cell carcinoma (RCC) cell lines, ACHN and A498. We investigated the effects of RES on proliferation, cell morphology, colony formation, migration, and invasion. We used a proliferation assay to demonstrate that RES inhibited cell growth with IC50 values 132.9+/-1.064MUM in ACHN, and 112.8+/-1.191MUM in A498, respectively. Using inverted contrast microscopy, we showed that RES reduced cell-to-cell contact and inhibited formation of filopodia. A wound healing assay showed that RES inhibited migration of RCC cells. A Transwell assay showed that RES inhibited RCC migration and invasion. Western blot analysis showed that RES suppresses expression of N-cadherin, Vimentin, Snail, MMP-2, MMP-9, p-Akt and p-ERK1/2, but increased expression of E-cadherin and TIMP-1. In the presence of PD98059, the inhibitor of ERK1/2 pathway, we repeated all of the above experiments, showed that RES acted via the ERK1/2 pathway. Taken together, our results suggested that RES suppressed RCC cell proliferation, migration, and invasion in a concentration and time-dependent manner. These effects likely resulted from inactivation of the Akt and ERK1/2 signaling pathways. PMID- 29241074 TI - SALL4 promotes osteoblast differentiation by deactivating NOTCH2 signaling. AB - BACKGROUND: The Spalt-Like Transcription Factor 4 (SALL4) is reported to regulate cell proliferation, migration and invasion. However, the roles of SALL4 in osteoblast differentiation are unclear. This study was aimed to explore the underlying mechanism of SALL4 in osteoporosis. METHODS: Firstly, the expression of SALL4 was assessed in vivo and in vitro at various stages of development of rats (E14, E20, postnatal 2, 4, and 9 day) or different incubation time (0, 6, 9, 12 and 15 day) of C2C12 and MC3T3-E1 cells. Then, alkaline phosphatase (ALP) activities and positive cells percentages were respectively detected after oeSall4 or siSall4 transfection. Cell differentiation related markers and chondrogenesis-related genes expressions in C2C12 cells were tested by western blot assay and qRT-PCR. Finally, the connection and interaction between SALL4 and NOTCH2 were studied. RESULTS: The results showed that SALL4 expression was increased in vivo and in vitro with the growth of rats or the incubation of cells. SALL4 overexpression promoted osteoblast differentiation; on the contrary, SALL4 knockdown inhibited osteoblast differentiation. Moreover, SALL4 participated in the middle and late stages of cell differentiation. Then, SALL4 and NOTCH2 interacted with each other. NOTCH2 expression was decreased both in vivo and in vitro, and negatively regulated by SALL4. Besides, SALL4 overexpression suppressed NOTCH2 target genes expressions and nuclear entry, while deactivated NOTCH2 signaling. CONCLUSIONS: Our study found that SALL4 played very important roles in the process of osteoblast differentiation by deactivating NOTCH2 signaling. These findings might provide a new insight for treatment of osteoporosis. PMID- 29241075 TI - Assessment of arsenic oxidation potential of Microvirga indica S-MI1b sp. nov. in heavy metal polluted environment. AB - Arsenic oxidizing alpha-proteobacterial strain Microvirga indica S-MI1b sp. nov. was isolated from metal industry soil and has the ability to oxidize 15 mM of arsenite [As(III)] completely in 39 h. The strain S-MI1b resists to different heavy metals and it oxidizes arsenite in presence of Li, Pb, Hg, Sb(III), Cd, Cr(VI), Ni, and exhibited growth inhibitory effect in presence of Hg, Cu, and Cd at higher concentration. The morphology of Microvirga indica S-MI1b changed in presence of heavy metals however there was no accumulation of As(III) in the cells. The study showed that Microvirga indica S-MI1b can oxidize arsenite at broad pH ranges from 4.0 to 9.0 with optimum at pH 7.0. The kinetic studies of arsenite oxidation by strain S-MI1b signified that it has greater affinity towards As(III). The arsenite oxidase activity of cells grown in presence of Li and Cr(VI) supported the cell culture studies. This is first report on biotransformation of arsenite by Microvirga genus and also arsenite oxidation in presence of heavy metals. PMID- 29241076 TI - Magnifying ion mobility spectrometry-mass spectrometry measurements for biomolecular structure studies. AB - Ion mobility spectrometry-mass spectrometry (IMS-MS) provides information about the structures of gas-phase ions in the form of a collision cross section (CCS) with a neutral buffer gas. Indicating relative ion size, a CCS value alone is of limited utility. Although such information can be used to propose different conformer types, finer details of structure are not captured. The increased accessibility of IMS-MS measurements with commercial instrumentation in recent years has ballooned its usage in combination with separate measurements to provide enhanced data from which greater structural inferences can be drawn. This short review presents recent outstanding developments in scientific research that employs complementary measurements that when combined with IMS-MS data are used to characterize the structures of a wide range of compounds. PMID- 29241077 TI - Pectoral nerve blocks to improve analgesia after breast cancer surgery: A prospective, randomized and controlled trial. AB - STUDY OBJECTIVE: To evaluate the analgesic efficacy of ultrasound guided combined pectoral nerve blocks I and II in patients scheduled for surgery for breast cancer. DESIGN: Prospective, randomized, control trial. SETTING: Operating rooms in a tertiary care hospital of Northern India. PATIENTS: Sixty American Society of Anesthesiologists status I to II adult women, aged 18-70years were enrolled in this study. INTERVENTIONS: Patients were randomized into two groups (30 patients in each group), PECS (P) group and control (C) group. In group P, patients received both general anesthesia and ultrasound guided combined pectoral nerve blocks (PECS I and II). In group C, patients received only general anesthesia. MEASUREMENTS: We noted pain intensity at rest and during abduction of the ipsilateral upper limb, incidence of postoperative nausea and vomiting; patient's satisfaction with postoperative analgesia and maximal painless abduction at different time intervals in both groups. MAIN RESULTS: There was significant decrease in the total amount of fentanyl requirement in the in P group {(140.66+/ 31.80MUg) and (438+/-71.74MUg)} in comparison to C group {(218.33+/-23.93MUg) and (609+/-53.00MUg)} during intraoperative and post-operative period upto 24h respectively. The time to first analgesic requirement was also more in P group (44.33+/-17.65min) in comparison to C group (10.36+/-4.97min) during post operative period. There was less limitation of shoulder movement (pain free mobilization) on the operative site at 4h and 5h after surgery in P group in comparison to C group. However there was no difference in the incidence of post operative nausea and vomiting (22 out of 30 patients in group P and 20 out of 30 patients in group C) but patients in group P had a better satisfaction score with postoperative analgesia than C group having a p value of <0.001(Score 1; 5 VS 20; Score 2; 12 VS 9; Score 3; 13 VS 1). CONCLUSIONS: Ultrasound guided combined pectoral nerve blocks are an effective modality of analgesia for patients undergoing breast surgeries during perioperative period. CLINICAL TRIAL REGISTRATION: CTRI/2015/12/006457. PMID- 29241078 TI - Heteropolytungstate-decorated core-shell magnetic nanoparticles: A covalent strategy for polyoxometalate-based hybrid nanomaterials. AB - Amino-functionalized core-shell magnetic nanoparticles have been covalently grafted with Polyoxometalates (POMs). These multifunctional nanocomposites have been obtained through the coupling of heteropolytungstate-based hybrids bearing carboxylic acid functions with aminopropyl functions that decorate the core-shell nanoparticles. The physical properties of the resulting materials have been studied by a large set of techniques. The very good nanostructuration of the POMs at the surface of the obtained nanoparticles have thus been directly observed by high-resolution transmission electronic microscopy (HR-TEM). Furthermore, the hyperthermia properties of these nanocomposites have been also considered as a function of the size of the magnetic core. Finally, the stability of these suspensions in organic media makes them particularly interesting in the frame of their processing or their potential use as nanocatalysts. PMID- 29241079 TI - Prenatal and childhood perfluoroalkyl substances exposures and children's reading skills at ages 5 and 8years. AB - BACKGROUND: Exposure to perfluoroalkyl substances (PFASs) may impact children's neurodevelopment. OBJECTIVE: To examine the association of prenatal and early childhood serum PFAS concentrations with children's reading skills at ages 5 and 8years. METHODS: We used data from 167 mother-child pairs recruited during pregnancy (2003-2006) in Cincinnati, OH, quantified prenatal serum PFAS concentrations at 16+/-3weeks of gestation and childhood sera at ages 3 and 8years. We assessed children's reading skills using Woodcock-Johnson Tests of Achievement III at age 5years and Wide Range Achievement Test-4 at age 8years. We used general linear regression to quantify the covariate-adjusted associations between natural log-transformed PFAS concentrations and reading skills, and used multiple informant model to identify the potential windows of susceptibility. RESULTS: Median serum PFASs concentrations were PFOS>PFOA>PFHxS>PFNA in prenatal, 3-year, and 8-year children. The covariate-adjusted general linear regression identified positive associations between serum PFOA, PFOS and PFNA concentrations and children's reading scores at ages 5 and 8years, but no association between any PFHxS concentration and reading skills. The multiple informant model showed: a) Prenatal PFOA was positively associated with higher children's scores in Reading Composite (beta: 4.0, 95% CI: 0.6, 7.4 per a natural log unit increase in exposure) and Sentence Comprehension (beta: 4.2, 95% CI: 0.5, 8.0) at age 8years; b) 3-year PFOA was positively associated with higher children's scores in Brief Reading (beta: 7.3, 95% CI: 0.9, 13.8), Letter Word Identification (beta: 6.6, 95% CI: 1.1, 12.0), and Passage Comprehension (beta: 5.9, 95% CI: 1.5, 10.2) at age 5years; c) 8-year PFOA was positively associated with higher children's Word Reading scores (beta: 5.8, 95% CI: 0.8, 10.7) at age 8years. Prenatal PFOS and PFNA were positively associated with children's reading abilities at age 5years, but not at age 8years; 3-year PFOS and PFNA were positively associated with reading scores at age 5years. But PFHxS concentrations, at any exposure windows, were not associated with reading skills. CONCLUSION: Prenatal and childhood serum PFOA, PFOS and PFNA concentrations were positively associated with better children's reading skills at ages 5 and 8years, but no association was found between serum PFHxS and reading skills. PMID- 29241081 TI - Does misuse lead to a disorder? The misuse of prescription tranquilizer and sedative medications and subsequent substance use disorders in a U.S. longitudinal sample. AB - OBJECTIVES: We used two waves of National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) data and examined whether the misuse of prescription tranquilizers or sedatives at Wave 1 was associated with either continued misuse, tranquilizer/sedative use disorder, or other substance use disorder (SUD) at Wave 2. METHODS: Prospective data were analyzed from structured diagnostic interviews using the Alcohol Use disorders and Associated Disabilities Interview Schedule: DSM-IV Version (AUDADIS-DSM-IV). A nationally representative sample of 34,653 of U.S. adults, 18years or older at Wave 1 (2001-2002), were re-interviewed at Wave 2 (2004-2005). After applying the survey weights, the sample represented a population that was 52% female, 71% White, 12% Hispanic, 11% African American, 4% Asian and 2% Native American or other. RESULTS: An estimated 79% of adults who engaged in tranquilizer or sedative misuse at Wave 1 had stopped using these drugs at Wave 2. Only a small percentage (4.3%) of misusers at Wave 1 had a tranquilizer or sedative use disorder at Wave 2. However, 45% (45.0%) of misusers at Wave 1 had at least one other SUD at Wave 2. Among those in remission from a sedative or tranquilizer use disorder at Wave 1, 4.8% had a tranquilizer or sedative use disorder while 34.7% had at least one other SUD at Wave 2. CONCLUSIONS: Most adults who engaged in the misuse of prescription tranquilizers or sedatives ceased using within 3years; however, their prior misuse was associated with higher prevalence of having a SUD three years later. PMID- 29241082 TI - The effect of N-acetylcysteine and working memory training on cocaine use, craving and inhibition in regular cocaine users: correspondence of lab assessments and Ecological Momentary Assessment. AB - INTRODUCTION: Effective treatment for cocaine use disorder should dampen hypersensitive cue-induced motivational processes and/or strengthen executive control. Using a randomized, double-blind, placebo-controlled intervention, the primary aim of this study was to investigate the effect of N-Acetylcysteine (NAC) and working memory (WM)-training to reduce cocaine use and craving and to improve inhibition assessed in the laboratory and during Ecological Momentary Assessment (EMA). The second aim was to examine correspondence between laboratory and EMA data. METHODS: Twenty-four of 38 cocaine-using men completed a 25-day intervention with 2400mg/day NAC or placebo and WM-training as well as two lab visits assessing cocaine use, craving and inhibition (Stop Signal task). Additionally, cocaine use, craving and cognition (Stroop task) were assessed using EMA during treatment, with 26 participants completing 819 assessments. RESULTS: Cocaine problems according to the Drug Use Disorder Identification Test (DUDIT) decreased more after NAC than after placebo, and the proportion of cocaine-positive urines at lab-visit 2 was lower in the NAC group. No NAC effects were found on craving. For cocaine use and craving, results from the lab data were generally similar to EMA results. NAC also showed some effects on cognitive control: improved inhibition assessed with the Stop Signal task in the lab, and decreased classic Stroop performance during EMA. There were no significant effects of number of completed WM-training sessions. CONCLUSIONS: Overall this study revealed mixed findings regarding the treatment of cocaine use disorders with NAC and WM-training. The effect of NAC on inhibition should be further investigated. PMID- 29241080 TI - Paternal urinary concentrations of organophosphate flame retardant metabolites, fertility measures, and pregnancy outcomes among couples undergoing in vitro fertilization. AB - BACKGROUND: Use of organophosphate flame retardants (PFRs) has increased over the past decade following the phase out of some brominated flame retardants, leading to increased human exposure. We recently reported that increasing maternal PFR exposure is associated with poorer pregnancy outcomes among women from a fertility clinic. Because a small epidemiologic study previously reported an inverse association between male PFR exposures and sperm motility, we sought to examine associations of paternal urinary concentrations of PFR metabolites and their partner's pregnancy outcomes. METHODS: This analysis included 201 couples enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2005-2015) who provided one or two urine samples per IVF cycle. In both the male and female partner, we measured five urinary PFR metabolites [bis(1,3 dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP) and bis(1 chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). The sum of the molar concentrations of the urinary PFR metabolites was calculated. We used multivariable generalized linear mixed models to evaluate the association of urinary concentrations of paternal PFR metabolites with IVF outcomes, accounting for multiple in vitro fertilization (IVF) cycles per couple. Models were adjusted for year of IVF treatment cycle, primary infertility diagnosis, and maternal urinary PFR metabolites as well as paternal and maternal age, body mass index, and race/ethnicity. RESULTS: Detection rates were high for paternal urinary concentrations of BDCIPP (84%), DPHP (87%) and ip-PPP (76%) but low for tb-PPP (12%) and zero for BCIPP (0%). We observed a significant 12% decline in the proportion of fertilized oocytes from the first to second quartile of male urinary SigmaPFR and a 47% decline in the number of best quality embryos from the first to third quartile of male urinary BDCIPP in our adjusted models. An 8% decline in fertilization was observed for the highest compared to lowest quartile of urinary BDCIPP concentrations (95% CI: 0.01, 0.12, p-trend=0.06). CONCLUSIONS: Using IVF as a model to investigate human reproduction and pregnancy outcomes, we found that paternal urinary concentrations of BDCIPP were associated with reduced fertilization. In contrast to previously reported findings for the female partners, the paternal urinary PFR metabolites were not associated with the proportion of cycles resulting in successful implantation, clinical pregnancy, and live birth. These results indicate that paternal preconception exposure to TDCIPP may adversely impact successful oocyte fertilization, whereas female preconception exposure to SigmaPFRs may be more relevant to adverse pregnancy outcomes. PMID- 29241083 TI - A review of the value of human epidermal growth factor receptor 2 (HER2)-targeted therapies in breast cancer. AB - The cost of cancer drugs continues to escalate with the rapid development and approval of novel therapies, especially over the course of the last decade. In human epidermal growth factor receptor 2 (HER2)-positive breast cancer, the survival benefits gained by new treatments have been undeniably substantial. It is important to assess the financial value of these therapies for decision making at both the societal and individual level. This information is key for managing resources in resource-limited health care systems, while at the same time supporting patient decision-making and conversations between patient and physicians on cost versus benefit. In this article, we perform a systematic review of cost-effectiveness analyses that have been completed to date on HER2 targeted agents, focussing on those that correlate with standard of care therapy. Our discussion also highlights potential strategies to overcome several limitations associated with measuring value for anticancer drugs. PMID- 29241084 TI - Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08). AB - BACKGROUND: KRAS mutation occurs in ~40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. RESULTS: Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily * 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3-75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). CONCLUSIONS: Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570. PMID- 29241085 TI - Salting-out assisted liquid-liquid extraction coupled with hydrophilic interaction chromatography for the determination of biguanides in biological and environmental samples. AB - A new salting-out assisted liquid-liquid extraction (SALLE) sample preparation method for the determination of the polar anti-diabetic biguanide drugs (metformin, buformin and phenformin) in blood plasma, urine and lake water samples were developed. The SALLE was performed by mixing samples (plasma (0.2mL), urine or lake water (1.0mL)) with acetonitrile (0.4mL for plasma, 0.5mL for urine or lake water), sodium hydroxide powder was then added for the phase separation. The effects of type of salting-out reagent, type of extraction solvent, volumes of acetonitrile and sample, amount of sodium hydroxide, vortexing and centrifugation times on the extraction efficiency were investigated. The upper layer, containing the biguanides, was directly injected into a HPLC unit using ZIC-HILIC column (150mm*2.1mm*3.5MUm) and was detected at 236nm. The method was validated and calibration curves were linear with r2>0.99 over the range of 20-2000MUgL-1 for plasma and 5-2000MUgL-1 for urine and lake water samples. The limits of detection were in the range (3.8-5.6)MUgL-1, (0.8 1.5)MUgL-1 and (0.3-0.8)MUgL-1 for plasma, urine and lake water, respectively. The accuracies in the three matrices were within 87.3-103%, 87.4-109%, 82.2-109% of the nominal concentration for metformin, buformin and phenformin, respectively. The relative standard deviation for inter- and intra -day precision were in the range of 1.0-17% for all analytes in the three matrices. PMID- 29241087 TI - Development of a fast HPLC-DAD method for simultaneous quantitation of three immunosuppressant drugs in whole blood samples using intelligent chemometrics resolving of coeluting peaks in the presence of blood interferences. AB - The present study describes a fast high performance liquid chromatography-diode array detection analytical methodology for quantification of tacrolimus, everolimus and cyclosporine A in whole blood samples, with minimum sample preparation steps. A short isocratic chromatographic elution was coupled with second-order calibration using multivariate curve resolution to stablish a smart and green methodology. Due to presence of matrix effect, a sample-added calibration strategy was used for quantification purposes. The serious issues related to background drift, chromatographic shifts and co-elution of non calibrated blood components, were resolved by a proper background correction and multivariate curve resolution-alternating least squares (MCR/ALS) methods The main features of this study were based on the fact that the acquired data matrices were handled intelligently and all features of the concerned target analytes were taken into account. Satisfactory resolution and quantification results in the presence of matrix interferences were achieved and the second order advantage was fully exploited. The average recoveries in therapeutic concentration ranges were 102+/-10%, 99+/-11% and 104+/-12% for TAC, EVR and CsA, with average relative prediction errors of less than 7%. Considering the advantages of the present strategy, such as increased selectivity, sensitivity and sufficiency of lower limit of quantification through multivariate advantage, simplicity of sample treatment steps, a fast elution pattern and also a low-cost instrumentation compared with LC-MS/MS, the proposed method has the significant merits as an alternative for simultaneous therapeutic monitoring of immunosuppressants. PMID- 29241086 TI - Practical aspects of the automated preparation of aqueous two phase systems for the analysis of biological macromolecules. AB - A robust strategy for the automated preparation of aqueous two-phase systems (ATPS) using a liquid handling sample processor was developed using gravimetric methods: to determine the accuracy of preparation. The major robotic control parameters requiring adjustment were; speed of aspiration and dispense; delay times following aspiration and dispense alongside measures to control cross contamination during phase sampling. In general mixture compositions of both polymer/polymer and polymer/salt mixtures could be prepared with a target bias accuracy of less than 5%. However, we found that the bias accuracy with which systems of defined TLL and MR could be constructed was highly dependent on the tie line length of the ATPS and the geometrical form of the ATPS co-existence curve. For systems with a very low degree of curvature (PEG/salt systems here) increases in bias (accuracy) are appreciable at relatively long tie line lengths. Where the degree of curvature is more pronounced (PEG/dextran systems) closer approach to the critical point was possible without major effect on bias/accuracy. Application of the strategy to the measurement of the partitioning of phosphorylated and dephosphorylated forms of the model protein ovalbumin are reported. Differences in partition of phosphorylated (native) forms and dephosphorylated forms could be demonstrated. In a PEG/salt system this was manifest as a substantial decrease in solubility based on overall protein recovery derived from accurate knowledge of the system mass ratio. In a PEG/dextran system differences in partition coefficient could be demonstrated between phosphorylated and dephosphorylated forms. PMID- 29241088 TI - Development of an LC-MS method to quantify coproporphyrin I and III as endogenous biomarkers for drug transporter-mediated drug-drug interactions. AB - Coproporphyrins are proposed as endogenous biomarkers of hepatic Organic Anion Transporting Polypeptide (OATP)1B functional activity. In this study, a new sample extraction method based on a mixed-mode anion exchange sorbent (SPE clean up using Oasis 30mg Max 96 well plates) was developed for absolute quantification of coproporphyrin I and III (CP-I and CP-III) in human plasma. Chromatographic separation was performed with an Ace Excel 2 C18 PFP, 3MUm, 2.1*150mm, maintained at 60 degrees C. A 10mM ammonium formate containing 0.1% HCOOH and acetonitrile (100%) was used as mobile phase A and B, respectively. Mass transition, m/z 655.3 >596.3 was selected to monitor CP-I and CP-III, while m/z 659.3->600.3 transition was used for the stable isotope labelled internal standard. Optimization of the liquid chromatography tandem mass spectrometry method ensured a lower limit of quantification (LLOQ) of 20pg/mL. Both CP-I and CP-III had extraction recoveries of 70%. The calibration range was 0.02-100ng/mL for both CP-I and CP-III, yielding calibration curves with correlation coefficients greater than 0.988. Inter day precision (CV<9%) and accuracy (84.3-103.9%) complied with the recommendation of the European Bioanalytical Forum. The optimized method was used to analyse plasma samples originating from three independent clinical studies. Obtained CP-I and CP-III plasma baseline levels in healthy volunteers were in good agreement with previously published data. Moreover, CP-I and CP-III plasma levels in human subjects dosed with a clinically confirmed OATP inhibitor were significantly increased compared to their baseline levels. These data demonstrate the potential of CP-I and CP-III as endogenous biomarkers to predict the drug drug interaction (DDI) related to hepatic OATP1B inhibition. Stability of CP-I and CP-III in plasma and solvents under different processing and storage conditions was also evaluated. PMID- 29241089 TI - Association of psychosis with antiphospholipid antibody syndrome: A systematic review of clinical studies. AB - OBJECTIVE: In this systematic review, we reviewed the association between Antiphospholipid antibody syndrome (APS) and psychosis and focused on the prevalence, clinical presentation, immunologic and neurological workup, treatment options, and clinical outcomes. METHODOLOGY: We performed this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA)'s guidelines. We searched eight databases for potential articles and manually searched references and relevant articles of included studies. We included all articles reporting psychotic symptoms in patients with APS. Article quality was assessed using an adapted version of the Cancer Council Australia tool for case-series. RESULTS: We included 23 articles of 454 articles found. The mean patient age at presentation was 39years and most patients were women. Delusions and hallucinations were the common clinical manifestations of APS-associated psychosis. Findings on neuroimaging were attributed to APS associated thrombosis in most cases. Most patients had a complete resolution of psychotic symptoms. CONCLUSION: APS-associated psychosis is rare. Later age of onset for psychosis, sudden onset, female sex, and comorbid medical and psychiatric symptoms should raise the suspicions for the presence of APS. APS associated psychosis may have a favorable prognosis. However, further studies need to validate this conclusion. PMID- 29241090 TI - Attachment style and filial obligation in the burden of caregivers of dementia patients. AB - Insecure attachment styles have been known to predict greater burden in caregivers of dementia patients. However, it has not been tested how filial obligation, which refers to one's sense of duty on helping elderly parents and is especially pronounced in Asian cultures, is involved in that relationship. We sought to identify whether the association between attachment style and caregiver burden differs according to the degree of filial obligation in caregivers of dementia patients. To assess filial obligation in Korean participants, a Korean filial obligation measure was developed. Ninety-eight Korean female caregivers of dementia patients reported their attachment style, filial obligation, burden, and patient behavioral symptoms. Patients' cognitive abilities, daily activity levels, and global dementia severities were obtained from hospital records. When adjusting for caregiver and patient characteristics, greater attachment anxiety predicted higher burden, corroborating literature findings. However, the association of attachment avoidance with burden was contingent on filial obligation: When obligation was high, greater avoidance associated with lower burden, which contrasts with previous negative implications of attachment insecurity. This implies a buffering role of attachment avoidance among those highly obligated. In addition, obligation positively predicted burden among those low in avoidance. This study is the first one to investigate and find conditional associations between attachment style, filial obligation, and caregiver burden. Given that filial obligation tends to be higher in caregivers of Eastern countries, this study provides quantitative evidence that the caregiving process may be different for them. PMID- 29241091 TI - The effectiveness of group Otago exercise program on physical function in nursing home residents older than 65years: A randomized controlled trial. AB - AIM: To examine whether the 6-months group-based Otago exercise program is more effective than usual care on physical function and functional independence in nursing home residents older than 65 years. METHODS: An observer-blind randomized controlled study included 77 independently walking, cognitively unimpaired residents aged 78.4+/-7.6years, of which 66.2% were female. Physical function was assessed at baseline, after 3 and 6months of the Otago exercise program by three performance tests: Berg Balance Scale (BBS), Timed Up and Go (TUG) and Chair Rising Test (CRT), and functional independence by the motor Functional Independence Measure (mFIM). RESULTS: Significant within participant effects of time in EG for BBS, TUG and CRT (p<0.001) and for mFIM (p=0.010) were found. Between participant effects of groups on BBS, TUG, CRT and mFIM values were not significant. Changes in values of performed three tests regarding physical function were significantly different in EG and CG (p<0.001), as well as for functional independence test (mFIM) (p=0.019). In EG the values got better, while in CG values worsened. Effect sizes of change in the EG were higher for BBS, TUG and CRT compared to mFIM. CONCLUSION: The Otago exercise program was shown as effective in improving balance, functional mobility, lower limbs muscle strength and functional independence, indicating that it could help in slowing of disability progression. PMID- 29241093 TI - Quantitative analysis of drugs in hair by UHPLC high resolution mass spectrometry. AB - Liquid chromatographic methods coupled to high resolution mass spectrometry are increasingly used to identify compounds in various matrices including hair but there are few recommendations regarding the parameters and their criteria to identify a compound. In this study we present a method for the identification and quantification of a range of drugs and discuss the parameters used to identify a compound with high resolution mass spectrometry. Drugs were extracted from hair by incubation in a buffer:solvent mixture at 37 degrees C during 18h. Analysis was performed on a chromatographic system comprised of an Agilent 6550 QTOF coupled to a 1290 Infinity UHPLC system. High resolution accurate mass data were acquired in the All Ions mode and exported into Mass Hunter Quantitative software for quantitation and identification using qualifier fragment ions. Validation included selectivity, matrix effects, calibration range, within day and between day precision and accuracy. The analytes were 7-amino-flunitrazepam, 7-amino clonazepam, 7-amino-nitrazepam, acetylmorphine, alimemazine, alprazolam, amphetamine, benzoylecgonine, buprenorphine, diazepam, ethylmorphine, fentanyl, hydroxyzine, ketobemidone, codeine, cocaine, MDMA, methadone, methamphetamine, morphine, oxycodone, promethazine, propiomazine, propoxyphene, tramadol, zaleplone, zolpidem, and zopiclone. As proof of concept, hair from 29 authentic post mortem cases were analysed. The calibration range was established between 0.05ng/mg to 5.0ng/mg for all analytes except fentanyl (0.02-2.0), buprenorphine (0.04-2.0), and ketobemidone (0.05-4.0) as well as for alimemazine, amphetamine, cocaine, methadone, and promethazine (0.10-5.0). For all analytes, the accuracy of the fortified pooled hair matrix was 84-108% at the low level and 89-106% at the high level. The within series precisions were between 1.4 and 6.7% and the between series precisions were between 1.4 and 10.1%. From the 29 autopsy cases, 121 positive findings were encountered from 23 of the analytes in concentrations similar to those previously published. We conclude that the developed method proved precise and accurate and that it had sufficient performance for the purpose of detecting regular use of drugs or treatment with prescription drugs. To identify a compound we recommend the use of ion ratios as a complement to instrument software "matching scores". PMID- 29241094 TI - Adhesion of human monocytes to oxygen- and nitrogen- containing plasma polymers: Effect of surface chemistry and protein adsorption. AB - The interactions between monocytes and biomaterials can potentially be modulated by controlling the chemical and structural surface properties of biomaterials. The objective of this study was to determine the effect of plasma-deposited functional organic coatings on monocyte adhesion and differentiation into macrophages. Organic coatings with varying oxygen and nitrogen concentration were prepared by low-pressure plasma co-polymerization of binary gas mixtures combining a hydrocarbon (butadiene/ethylene) and a heteroatom-containing gas (carbon dioxide/ammonia) to deposit either oxygen or nitrogen-containing coatings. The deposition parameters controlled the composition of the coatings and, consequently, the surface charge (between 26 mV and -28 mV) and wettability. The adhesion of myeloid leukemia cell lines U937 and NB4 as well as human monocytes to plasma polymerized coatings, was tested using cell culture medium with and without fetal bovine serum. The results showed that the concentration of [-NH2] and [-COOH] on the surface of the plasma polymers, controls the adhesion of U937 and NB4 cell lines to the coatings. Thus, above a certain composition threshold, i.e. [-NH2]=2.6-3.0% and [-COOH]=1.2-1.57 nmol/cm2, the surface facilitates adhesion of both cell lines, irrespective of the culture medium used. Based on qualitative observations the number of monocytes adhering to the coatings was proportional to the concentration of functional groups at the surface of the coatings. The surface plasmon resonance results, in line with cell culture experiments, indicated that the presence of albumin on the surfaces with [-NH2] and [-COOH] above the determined critical concentration may be an indicator of monocyte adhesion to these plasma polymers. PMID- 29241092 TI - Trehalose protects against oxidative stress by regulating the Keap1-Nrf2 and autophagy pathways. AB - Dysfunction of autophagy, which regulates cellular homeostasis by degrading organelles and proteins, is associated with pathogenesis of various diseases such as cancer, neurodegeneration and metabolic disease. Trehalose, a naturally occurring nontoxic disaccharide found in plants, insects, microorganisms and invertebrates, but not in mammals, was reported to function as a mechanistic target of the rapamycin (mTOR)-independent inducer of autophagy. In addition, trehalose functions as an antioxidant though its underlying molecular mechanisms remain unclear. In this study, we showed that trehalose not only promoted autophagy, but also increased p62 protein expression, in an autophagy-independent manner. In addition, trehalose increased nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in a p62-dependent manner and enhance expression of its downstream antioxidant factors, heme oxygenase-1 (Ho-1) and nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (Nqo1). Moreover, treatment with trehalose significantly reduced amount of reactive oxygen species. Collectively, these results suggested that trehalose can function as a novel activator of the p62-Keap1/Nrf2 pathway, in addition to inducing autophagy. Therefore, trehalose may be useful to treat many chronic diseases involving oxidative stress and dysfunction of autophagy. PMID- 29241095 TI - Mathematical modeling approaches to describe the dynamics of protein adsorption at solid interfaces. AB - Protein adsorption on solid surfaces play a crucial role in many biological applications. While extensive experimental studies have revealed the dynamics of protein adsorption in detail using newly developed experimental techniques, mathematical modeling approaches provide illustrative insight of such complex processes, which are often difficult to describe experimentally. To advance our understanding of dynamic protein behaviors at interfaces between proteins and solid surfaces, there are needs for additional information about such complex phenomena, especially conformational changes in protein mixture system. In this review, we will briefly describe competitive protein adsorption process (known as 'Vroman effect') and provide a brief overview of some important mathematical modeling approaches to advance our knowledge of the dynamic adsorption/desorption processes and highlight the need for experimental methods to determine the extent of conformational changes and the rate of conformational change of adsorbed proteins at the surfaces. PMID- 29241097 TI - Corrigendum to "The study of zinc ions binding to casein" [Colloids and Surfaces B: Biointerfaces 120 (2014) 21-27]. PMID- 29241096 TI - Study of non-covalent interactions on dendriplex formation: Influence of hydrophobic, electrostatic and hydrogen bonds interactions. AB - The interaction of a double stranded small interference RNA (siRNA Nef) with cationic carbosilane dendrimers of generations 1-3 with two different ammonium functions at the periphery ([-NMe2R]+, R=Me, (CH2)2OH) has been studied by experimental techniques (zeta potential, electrophoresis, single molecule pulling experiments) and molecular dynamic calculations. These studies state the presence of different forces on dendriplex formation, depending on generation and type of ammonium group. Whilst for higher dendrimers electrostatic forces mainly drive the stability of dendriplexes, first generation compounds can penetrate into siRNA strands due to the establishment of hydrophobic interactions. Finally, in the particular case of first generation dendrimer [G1O3(NMe2(CH2)2OH))6]6+; the presence of hydroxyl groups reinforces dendriplex stability by hydrogen bonds formation. However, since these small dendrimers do not cover the RNA, only higher generation derivatives protect RNA from degradation. PMID- 29241098 TI - Under-ascertainment, under-reporting and timeliness of Iranian communicable disease surveillance system for zoonotic diseases. AB - OBJECTIVES: The important steps in controlling infectious diseases are fast detection, proper treatment and on-time reporting of cases to the appropriate authorities. This study was conducted to evaluate the quality of Iranian communicable diseases surveillance system (CDSS) for zoonotic diseases in rural areas of Fars province (Iran's third largest province). STUDY DESIGN: The three most important evaluation indices of CDSS, namely under-ascertainment, under reporting and timeliness, for the three most common zoonotic diseases were measured using independent data source obtained from door-to-door interviews and patients' medical records. METHODS: Interviews were conducted with 48,771 households in rural areas of Fars province from April 2014 to March 2015. The medical and registration data were obtained from the CDSS and medical or health centres. RESULTS: Under-ascertainment, total under-reporting and timeliness (delay from the time of onset of symptoms to the time of visiting a medical or health centre, to the time of reporting visited cases to the highest level of CDSS) for leishmaniasis were 19.6%, 42.5% and 81.61 days (48.95 due to system delay), respectively. The corresponding indices for brucellosis were 0%, 41.8% and 56.5 days (22 due to system delay), respectively. For animal bite, the corresponding indices were 7.83%, 13.07% and less than 72 h, respectively (no system delay). CONCLUSIONS: Although the status of case reporting and timeliness of surveillance system in public sectors providing medical services are clearly better than those of the private sectors, the indices are far from the level needed by CDSS to be able to detect and handle epidemics on time. Training health personnel, especially physicians, from public and private sectors to secure their cooperation along with routine and indebt evaluation are necessary to improve CDSS in Iran. PMID- 29241099 TI - Perceptual-motor regulation in locomotor pointing while approaching a curb. AB - Locomotor pointing is a task that has been the focus of research in the context of sport (e.g. long jumping and cricket) as well as normal walking. Collectively, these studies have produced a broad understanding of locomotor pointing, but generalizability has been limited to laboratory type tasks and/or tasks with high spatial demands. The current study aimed to generalize previous findings in locomotor pointing to the common daily task of approaching and stepping on to a curb. Sixteen people completed 33 repetitions of a task that required them to walk up to and step onto a curb. Information about their foot placement was collected using a combination of measures derived from a pressure-sensitive walkway and video data. Variables related to perceptual-motor regulation were analyzed on an inter-trial, intra-step and inter-step level. Similar to previous studies, analysis of the foot placements showed that, variability in foot placement decreased as the participants drew closer to the curb. Regulation seemed to be initiated earlier in this study compared to previous studies, as shown by a decreasing variability in foot placement as early as eight steps before reaching the curb. Furthermore, it was shown that when walking up to the curb, most people regulated their walk in a way so as to achieve minimal variability in the foot placement on top of the curb, rather than a placement in front of the curb. Combined, these results showed a strong perceptual-motor coupling in the task of approaching and stepping up a curb, rendering this task a suitable test for perceptual-motor regulation in walking. PMID- 29241100 TI - The effect of spatial auditory landmarks on ambulation. AB - The maintenance of balance and posture is a result of the collaborative efforts of vestibular, proprioceptive, and visual sensory inputs, but a fourth neural input, audition, may also improve balance. Here, we tested the hypothesis that auditory inputs function as environmental spatial landmarks whose effectiveness depends on sound localization ability during ambulation. Eight blindfolded normal young subjects performed the Fukuda-Unterberger test in three auditory conditions: silence, white noise played through headphones (head-referenced condition), and white noise played through a loudspeaker placed directly in front at 135 centimeters away from the ear at ear height (earth-referenced condition). For the earth-referenced condition, an additional experiment was performed where the effect of moving the speaker azimuthal position to 45, 90, 135, and 180 degrees was tested. Subjects performed significantly better in the earth referenced condition than in the head-referenced or silent conditions. Performance progressively decreased over the range from 0 degrees to 135 degrees but all subjects then improved slightly at the 180 degrees compared to the 135 degrees condition. These results suggest that presence of sound dramatically improves the ability to ambulate when vision is limited, but that sound sources must be located in the external environment in order to improve balance. This supports the hypothesis that they act by providing spatial landmarks against which head and body movement and orientation may be compared and corrected. Balance improvement in the azimuthal plane mirrors sensitivity to sound movement at similar positions, indicating that similar auditory mechanisms may underlie both processes. These results may help optimize the use of auditory cues to improve balance in particular patient populations. PMID- 29241101 TI - Marjolin's ulcer in a 20 years old split thickness skin graft on the knee-A case report. AB - OBJECTIVE: Marjolin's Ulcer (MU) is a rare cutaneous neoplasm arising in cikatrical tissue. Due to its typical clinical presentation as a non-healing lesion in scar tissue, the diagnosis can be delayed and even overlooked. METHODS AND RESULTS: We present the case of an elderly woman who developed an ulcerated, exophytic lesion in a split thickness skin graft (STSG) on the lateral aspect of the left knee. Histology showed a radically excised highly differentiated squamous cell carcinoma (SCC) with keratine pearls and a component of basocellular carcinoma (BCC). The histological picture combined with the location and long time interval since the primary surgery made the diagnosis of MU highly likely. DISCUSSION: Considering the risk of metastasis and mortality it is important to recognize the diagnosis and initiate adequate treatment. CONCLUSION: The diagnosis of MU is clinical and confirmed by pathology. The typical long delay from the primary lesion to the malignant transformation might occlude the diagnosis. As such, a thorough anamnesis is essential in a non- healing ulcerated lesion in a cikatrical area to adequately diagnose and treat the condition. PMID- 29241102 TI - Utility of hepatobiliary scintigraphy for recurrent reflux cholangitis following choledochojejunostomy: A case report. AB - INTRODUCTION: Reflux cholangitis is a frequent complication of Roux-en-Y choledochojejunostomy. PRESENTATION OF CASE: A 68-year-old male underwent left lobectomy of the liver, bile duct resection and choledochojejunostomy for intrahepatic cholangiocarcinoma located in Segment 2 of the liver, 40mm in diameter with a lymph node metastasis 5 years ago. He had frequent recurrences of postoperative reflux cholangitis and hepatic abscesses and was treated with antibiotics each time. Postoperative adjuvant chemotherapy was scheduled, but due to recurrent cholangitis it was difficult. Although double balloon endoscopy for endoscopic retrograde cholangiography was performed, no stenosis was found in the choledochojejunostomy anastomosis, and no defect suspected of calculus and stenosis were found by contrast. Antibiotics had to be administered for a long time because it recurred when antibiotics were discontinued. This time, a tumor 2.0cm in diameter was detected in segment 7 of the liver on follow - up computed tomography. The preoperative diagnosis was recurrent Intrahepatic cholangiocarcinoma. Hepatobiliary scintigraphy was carried out in preparation for concomitant treatment of his reflux cholangitis. Retention in the blind loop of the choledochojejunostomy was retarded, and the excretion was delayed. Therefore, hepatectomy and resection of the blind loop were performed. We confirmed improvement of stasis in the blind loop on postoperative hepatobiliary scintigraphy. The postoperative course was uneventful, and antibiotics were not required. DISCUSSION: Hepatobiliary scintigraphy may be able to clarify the mechanism underlying reflux cholangitis. CONCLUSION: Hepatobiliary scintigraphy was useful for the treatment of recurrent reflux cholangitis in this case. PMID- 29241104 TI - The relationship between self-compassion and the risk for substance use disorder. AB - OBJECTIVE: This study explored the relationship between substance use disorder risk and self-compassion and posits a model for how the two are related through the mitigation of suffering. METHOD: Study participants were recruited using social media to complete an online survey that included a basic socio-demographic survey and two validated instruments, the Self-Compassion Survey and the National Institute on Drug Abuse (NIDA) Alcohol Smoking and Substance Involvement Screening Test (ASSIST), which screens for substance use disorder (SUD) risk. Established cut scores for ASSIST were used to divide participants into low, moderate and high-risk groups. RESULTS: Participants (n=477) were 31 years old on average, almost evenly split by gender, mostly non-Hispanic white, slightly more likely to be single and to hold an Associate's degree or higher. Overall, 89% of participants reported using drugs and/or alcohol in their lifetime. SUD risk was distributed between low risk (52%), moderate risk (37%) and a smaller percentage of high risk (11%). Self-compassion was inversely related to SUD risk. The low risk group had a higher mean self-compassion score (M=2.86, SD=0.75) than the people who were high risk (M=2.25, SD=0.61) (t(298)=5.58 p<0.0001). Bivariate Pearson correlations showed strong associations between high risk and all self compassion subscales, as well as low risk and five of the subscales. CONCLUSIONS: This study suggests SUD risk has an inverse relationship to self-compassion. Raising self-compassion may be a useful addition to substance use disorder prevention and treatment interventions. PMID- 29241103 TI - Prevalence and correlates of benzodiazepine use and misuse among young adults who use prescription opioids non-medically. AB - BACKGROUND: Benzodiazepine use dramatically increases the risk of unintentional overdose among people who use opioids non-medically. However, little is known about the patterns of co-occurring benzodiazepine and opioid use among young adults in the United States. METHODS: The Rhode Island Young Adult Prescription Drug Study (RAPiDS) was a cross-sectional study from January 2015-February 2016. RAPiDS recruited 200 young adults aged 18-29 who reported past 30-day non-medical prescription opioid (NMPO) use. Using Wilcoxon rank sum test and Fisher's exact test, we examined correlates associated with regular prescribed and non-medical use (defined as at least monthly) of benzodiazepines among NMPO users in Rhode Island. RESULTS: Among participants, 171 (85.5%) reported lifetime benzodiazepine use and 125 (62.5%) reported regular benzodiazepine use. Nearly all (n=121, 96.8%) reported non-medical use and 43 (34.4%) reported prescribed use. Compared to the 75 participants who did not regularly use benzodiazepines, participants who reported regular use were more likely to be white (66.3% vs. 58.0%, p=0.03), have ever been incarcerated (52.8% vs. 37.3%, p=0.04), and have ever been diagnosed with a psychiatric disorder (bipolar: 29.6% vs. 16.0%, p=0.04; anxiety: 56.8 vs. 36.0%, p=0.01). Although the association was marginally significant, accidental overdose was higher among those who were prescribed the benzodiazepine they used most frequently compared to those who were not (41.9% vs. 24.4%, p=0.06). CONCLUSION: Benzodiazepine use and misuse are highly prevalent among young adult NMPO users. Harm reduction and prevention programs for this population are urgently needed. PMID- 29241105 TI - How alcohol use problem severity affects the outcome of brief intervention delivered in-person versus through computer-generated feedback letters. AB - OBJECTIVE: The aim was to test if people with different alcohol use problem severity benefitted differentially from brief alcohol interventions delivered in person versus through computer-generated feedback letters. METHODS: Nine hundred sixty-one 18-64year old general hospital inpatients with at-risk alcohol use (mean age=40.9years [standard deviation=14.1], 75% men) were randomized to a) in person counseling, b) computer-generated individualized feedback letters, or c) assessment only. Both interventions were delivered on the ward and 1 and 3 months later. Outcome was the change in the self-reported alcohol use per day at 6-, 12 , 18-, and 24-month follow-up. The Alcohol Use Disorder Identification Test (AUDIT) score was tested as a moderator of the effect of in-person counseling and computer-generated feedback letters, with higher AUDIT scores indicating more severe alcohol problems. RESULTS: Compared to assessment only, computer-generated feedback letters more strongly reduced alcohol use over 24 months among persons with AUDIT scores of about 8 and lower (ps <0.05). In-person counseling tended to be superior over assessment only among persons scoring high on the AUDIT, but differences were not statistically significant. Six-, 12-, and 18-month differences between in-person counseling and computer-generated feedback letters were significant (ps<0.05) for persons with AUDIT scores below 7.1-7.7. The differences between both interventions attenuated at 24-month follow-up. CONCLUSIONS: Computer-based intervention delivery may be superior over in-person delivery for people with low levels of alcohol use problem severity, whereas those with more severe alcohol problems may require more intensive care. PMID- 29241106 TI - Differentials and trends in emergency department visits due to alcohol intoxication and co-occurring conditions among students in a U.S. public university. AB - BACKGROUND: Few studies have explored the epidemiology of students presenting to the emergency department (ED) as a consequence of hazardous drinking. This study examined differentials and trends in ED visits following alcohol intoxication and co-occurring conditions among students presenting to a major U.S. university health system. METHODS: The ED electronic medical records from academic years 2010-2015 were queried for student visits and their records were linked to the university's student admission datasets. Student alcohol-related visits were identified based on ICD-9 codes. Student characteristics and trends in the rate of alcohol intoxication per 100 ED student visits were analyzed. A random sample of 600 student clinical records were reviewed to validate diagnostic codes. RESULTS: There were 9616 student ED visits (48% males) to the ED of which 1001 (10.4%) visits involved alcohol intoxication. Two thirds of ED visits with alcohol intoxication had a co-occurring diagnosis, with injuries (24%) being the most common condition. The rate of alcohol intoxication varied greatly by student demographics and campus-related factors. There was a linear increase in the rate of alcohol intoxication from 7.9% in 2009-10 to 12.3% in 2014-15 (p<0.01). The increase was greater among female students, students below 20 years of age, Asian students, and student athletes. In the sample reviewed, only two thirds of ED visits with alcohol intoxication were recorded by diagnostic codes. CONCLUSION: The rate of ED visits following alcohol intoxication varied by student demographic characteristics and campus-related factors with a rising trend over the study period. PMID- 29241107 TI - Nationwide analysis on the impact of socioeconomic land use factors and incidence of urothelial carcinoma. AB - BACKGROUND: Incidence rates for urothelial carcinoma (UC) have been reported to differ between countries within the European Union (EU). Besides occupational exposure to chemicals, other substances such as tobacco and nitrite in groundwater have been identified as risk factors for UC. We investigated if regional differences in UC incidence rates are associated with agricultural, industrial and residential land use. METHODS: Newly diagnosed cases of UC between 2003 and 2010 were included. Information within 364 administrative districts of Germany from 2004 for land use factors were obtained and calculated as a proportion of the total area of the respective administrative district and as a smoothed proportion. Furthermore, information on smoking habits was included in our analysis. Kulldorff spatial clustering was used to detect different clusters. A negative binomial model was used to test the spatial association between UC incidence as a ratio of observed versus expected incidence rates, land use and smoking habits. RESULTS: We identified 437,847,834 person years with 171,086 cases of UC. Cluster analysis revealed areas with higher incidence of UC than others (p=0.0002). Multivariate analysis including significant pairwise interactions showed that the environmental factors were independently associated with UC (p<0.001). The RR was 1.066 (95% CI 1.052-1.080), 1.066 (95% CI 1.042 1.089) and 1.067 (95% CI 1.045-1.093) for agricultural, industrial and residential areas, respectively, and 0.996 (95% CI 0.869-0.999) for the proportion of never smokers. CONCLUSION: This study displays regional differences in incidence of UC in Germany. Additionally, results suggest that socioeconomic factors based on agricultural, industrial and residential land use may be associated with UC incidence rates. PMID- 29241108 TI - The efficacy of posterior hemivertebra resection with lumbosacral fixation and fusion in the treatment of congenital scoliosis: A more than 2-year follow-up study. AB - OBJECTIVE: Hemivertebrae (HV) located at the lower lumbar or lumbosacral region often produce early trunk imbalance and long compensatory curves. Because of the biomechanical characteristics of the lumbosacral junction, the rate of instrumentation failures at the region has always been high. Our study aimed to evaluate the results of posterior HV resection with lumbosacral fixation and fusion in the treatment of congenital scoliosis and to make a preliminary analysis of the possible risk factors for instrument failures. PATIENTS AND METHODS: From 2010 to 2015, 17 patients (7 males and 10 females) with congenital scoliosis underwent HV resection with lumbosacral fixation and fusion in our department. The mean patient age was 13.2+/-4.4years at surgery, and the mean follow-up time was 37.6+/-4.6months. Clinical outcomes and related complications were assessed by reviewing medical records, operative notes, radiographic data, and scores on the SRS-22 questionnaire. RESULTS: The mean Cobb angle of the segmental curve was 37.5 degrees +/-12.7 degrees preoperatively, 7.9 degrees +/ 5.5 degrees postoperatively, and 7.9 degrees +/-5.3 degrees at the latest follow-up. The mean Cobb angle of the cranial compensatory curve was 39.2 degrees +/-17.2 degrees , 9.1 degrees +/-9.5 degrees , and 9.5 degrees +/-10.8 degrees , respectively. Trunk balance was improved in both the coronal (59.6%) and sagittal (58.6%) planes after surgery, and remained stable at the latest follow-up. Three domains of SRS-22, including self-image, mental health, and satisfaction, were significantly improved at the latest follow-up compared with preoperative status. Complications included one transient neurologic impairment, one superficial wound infection, and two implant failures. CONCLUSIONS: Early posterior HV resection with short lumbosacral fixation and fusion is effective in the treatment of HV located at lower lumbar or lumbosacral region. Delayed surgical intervention may lead to longer fusion and fixation. A long lumbosacral construct using only S1 pedicle screws as distal anchors tends to accompany a high rate of implant failures. PMID- 29241109 TI - Pharmacokinetic studies of naproxen amides of some amino acid esters with promising colorectal cancer chemopreventive activity. AB - Naproxen (nap) is belonging to Non-steriodal anti-inflammatory drugs (NSAIDs) group of drugs that characterized by their free carboxylic group. The therapeutic activity of nap is usually accompanied by GI untoward side effects. Recently synthesized naproxen amides of some amino acid esters prodrugs to mask the free carboxylic group were reported. Those prodrugs showed a promising colorectal cancer chemopreventive activity. The current study aims to investigate the fate and hydrolysis of the prodrugs kinetically in different pH conditions, simulated gastric and intestinal fluids with pHs of 1.2, 5.5 and 7.4 in vitro at 37 degrees C. The effect of enzymes on the hydrolysis of prodrugs was also studied through incubation of these prodrugs at 37 degrees C in human plasma and rat liver homogenates. The pharmacokinetic parameters of selected prodrugs and the liberated nap were studied after oral and intraperitoneal administration in male wistar rats. The results showed the hydrolysis of naproxen amides of amino acid esters to nap through two steps first by degradation of the ester moiety to form the amide of nap with amino acid and the second was through the degradation of the amide link to liberate nap. The two reactions were followed and studied kinetically where K1 and K2 (rate constants of degradation) is reported. The hydrolysis of prodrugs was faster in liver homogenates than in plasma. The relative bioavailability of the liberated nap in vivo was higher in case of prodrug containing ethyl glycinate moiety than that occupied l-valine ethyl ester moiety. Each of nap. prodrugs containing ethyl glycinate and l-valine ethyl ester moieties appears promising in liberating nap, decreasing direct GI side effect and consequently their colorectal cancer chemopreventive activity. PMID- 29241111 TI - Modelling sulfate reduction in anaerobic digestion: Complexity evaluation and parameter calibration. AB - A comparative analysis of five different structures of sulfate reduction (SR) models for anaerobic digestion (AD) was conducted to evaluate their accuracy to provide model developers and users with better information to decide on the optimum degree of complexity. The models evaluated differ in terms of the number/type of sulfate reducing bacterial activities considered based on the electron donors used. A systematic calibration of the evaluated models against a large set of experimental data was also conducted using a very recent parameter calibration method. Results indicate that a simple model incorporating both acetate utilizing and hydrogen utilizing sulfate reducing bacterial activities (the MAH model) achieves a good balance between performance and complexity in terms of prediction errors against experimental data. All the models evaluated provided acceptable predictions except the model including only hydrogen utilizing sulfate reducing bacterial activity. More complex model structures are recommended only if required in specific experimental cases. PMID- 29241110 TI - Design, synthesis, and initial evaluation of affinity-based small molecular probe for detection of WDR5. AB - WDR5, a subunit of the SET/MLL complex, plays critical roles in various biological progresses and are abnormally expressed in many cancers. Here we report the design, synthesis, and biochemical characterization of a new chemical tool to capture WDR5 protein. The probe is a biotinylated version of compound 30 that is a potent WDR5 inhibitor we previously reported. Importantly, the probe displayed high affinity to WDR5 protein in vitro binding potency and showed the ability in specifically and real time monitoring WDR5 protein. Further, the biotinylated tag of the probe enabled selectively "chemoprecipitation" of WDR5 from whole cell lysates of MV4-11. This probe provided a new approach to identify the overexpressed WDR5 protein in different cancer cells and applications to proteomic analysis of WDR5 and WDR5-binding partners. PMID- 29241112 TI - Chromium isotope fractionation during Cr(VI) reduction in a methane-based hollow fiber membrane biofilm reactor. AB - Chromium (Cr) isotope fractionation analysis is a promising tool for monitoring Cr(VI) reduction in natural aqueous systems. In addition, large amounts of CH4 in natural aqueous sediments are oxidized to CO2 through methanotrophs, thereby mitigating emissions to the atmosphere. However, the investigations on the Cr(VI) reduction process with methanotrophs, and the associated Cr isotope fractionation patterns are scarce. In this study, we have shown that Cr(VI) reduction can occur in the presence of CH4 as the sole electron donor in a hollow-fiber membrane reactor (HfMBR) after direct bacteria enrichment from sediment samples. Products of the methane oxidation by the methanotrophs are used by microbes to reduce Cr(VI) as shown by the progressive increase in delta53Cr with time in the CH4 feed reactor. The isotope fractionation factor (epsilon) of -2.62 +/- 0.200/00 was obtained from the application of the Rayleigh distillation model. The results of Cr isotope fractionation analysis also explained the decrease of Cr(VI) concentration in the N2 feed reactor, where the delta53Cr values remained steady in the first two weeks but significantly increased in the last two weeks, indicating that physical adsorption and subsequent Cr(VI) reduction occurred. This study extended the application of Cr isotope fractionation, showing the suitability of this method for clarifying different Cr(VI) removal processes. PMID- 29241113 TI - Concentrating molasses distillery wastewater using biomimetic forward osmosis (FO) membranes. AB - Treatment of sugarcane molasses distillery wastewater is challenging due to the presence of complex phenolic compounds (melanoidins and polyphenols) having antioxidant properties. Due to zero liquid discharge regulations, Indian distilleries continue to explore effective treatment options. This work examines the concentration of distillery wastewater by forward osmosis (FO) using aquaporin biomimetic membranes and magnesium chloride hexahydrate (MgCl2.6H2O) as draw solution. The operational parameters viz. feed solution and draw solution flow rate and draw solution concentration were optimized using 10% v/v melanoidins model feed solution. This was followed by trials with distillery wastewater. Under the conditions of this work, feed and draw flow rates of 1 L/min and draw solution concentration of 2M MgCl2.6H2O for melanoidins model solution and 3M MgCl2.6H2O for distillery wastewater were optimal for maximum rejection. Rejection of 90% melanoidins, 96% antioxidant activity and 84% COD was obtained with melanoidins model feed, with a corresponding water flux of 6.3 L/m2h. With as-received distillery wastewater, the rejection was similar (85-90%) to the melanoidins solution, but the water flux was lower (2.8 L/m2h). Water recovery from distillery wastewater over 24 h study period was higher with FO (70%) than reported for RO (35-45%). Repeated use of the FO membrane over five consecutive 24 h cycles with fresh feed and draw solutions and periodic cleaning showed consistent average water flux and rejection of the feed constituents. PMID- 29241115 TI - Predictors of justice system involvement: Maltreatment and education. AB - Decades of research have established that experience of abuse and/or neglect in childhood is related to negative outcomes, such as juvenile delinquency. Existing research has shown that involvement in child welfare services is also related to juvenile delinquency, particularly for children who are victims of neglect. Research has also identified educational factors such as chronic absenteeism as significant predictors of involvement in the juvenile justice system. However, little research has investigated the combined influence of educational factors, child abuse, and involvement in child protective services on justice system involvement. The current study examined the influence of educational factors and involvement in child protective services on justice system involvement. The study utilized records from an educational database of children who attended a school within a county of Mississippi in any year from 2003 through 2013. Cases were then matched with records from the county Youth Court, Law Enforcement agencies, and Child Protection Services. A multivariate logistic regression controlling for gender, race, current age, and time at risk was conducted to involvement in the justice system. In general, educational factors were stronger predictors of justice system involvement than allegations of maltreatment. PMID- 29241114 TI - Understanding the impact of cationic polyacrylamide on anaerobic digestion of waste activated sludge. AB - Previous investigations showed that cationic polyacrylamide (cPAM), a flocculant widely used in wastewater pretreatment and waste activated sludge dewatering, deteriorated methane production during anaerobic digestion of sludge. However, details of how cPAM affects methane production are poorly understood, hindering deep control of sludge anaerobic digestion systems. In this study, the mechanisms of cPAM affecting sludge anaerobic digestion were investigated in batch and long term tests using either real sludge or synthetic wastewaters as the digestion substrates. Experimental results showed that the presence of cPAM not only slowed the process of anaerobic digestion but also decreased methane yield. The maximal methane yield decreased from 139.1 to 86.7 mL/g of volatile suspended solids (i.e., 1861.5 to 1187.0 mL/L) with the cPAM level increasing from 0 to 12 g/kg of total suspended solids (i.e., 0-236.7 mg/L), whereas the corresponding digestion time increased from 22 to 26 d. Mechanism explorations revealed that the addition of cPAM significantly restrained the sludge solubilization, hydrolysis, acidogenesis, and methanogenesis processes. It was found that ~46% of cAPM was degraded in the anaerobic digestion, and the degradation products significantly affected methane production. Although the theoretically biochemical methane potential of cPAM is higher than that of protein and carbohydrate, only 6.7% of the degraded cPAM was transformed to the final product, methane. Acrylamide, acrylic acid, and polyacrylic acid were found to be the main degradation metabolites, and their amount accounted for ~50% of the degraded cPAM. Further investigations showed that polyacrylic acid inhibited all the solubilization, hydrolysis, acidogenesis, and methanogenesis processes while acrylamide and acrylic acid inhibited the methanogenesis significantly. PMID- 29241116 TI - "Body self" in the shadow of childhood sexual abuse: The long-term implications of sexual abuse for male and female adult survivors. AB - Childhood sexual abuse (CSA) may have long-term negative outcomes for victims' body representations. In this study we examined a model in which the relation between CSA and an individual's discomfort when in close proximity to others is mediated by disrupted body boundaries, and the relation between CSA and body shame is mediated by body self-objectification. Since most of these variables were conceptualized and assessed primarily among women, gender differences regarding the proposed model were examined. Study participants were 843 college/university students (536 women and 307 men). Results from structural equation modeling analyses indicated that in both genders, disrupted body boundaries mediated the relations between CSA and an individual's discomfort when in close proximity to others, as well as between CSA and body shame. Body self objectification was not associated with history of CSA. Finally, we discuss the role these findings may play in the detrimental long-term effects of CSA on both male and female survivors, and refer to their common underlying mechanism. PMID- 29241117 TI - Influence of direct and alternating current electric fields on efficiency promotion and leaching risk alleviation of chelator assisted phytoremediation. AB - Direct and alternating current electric fields with various voltages were used to improve the decontamination efficiency of chelator assisted phytoremediation for multi-metal polluted soil. The alleviation effect of electric field on leaching risk caused by chelator application during phytoremediation process was also evaluated. Biomass yield, pollutant uptake and metal leaching retardation under alternating current (AC) and direct current (DC) electric fields were compared. The biomass yield of Eucalyptus globulus under AC fields with various voltages (2, 4 and 10 V) were 3.91, 4.16 and 3.67kg, respectively, significantly higher than the chelator treatment without electric field (2.71kg). Besides growth stimulation, AC fields increased the metal concentrations of plant tissues especially in aerial parts manifested by the raised translocation factor of different metals. Direct current electric fields with low and moderate voltages increased the biomass production of the species to 3.45 and 3.12kg, respectively, while high voltage on the contrary suppressed the growth of the plants (2.66kg). Under DC fields, metal concentrations elevated obviously with increasing voltages and the metal translocation factors were similar under all voltages. Metal extraction per plant achieved the maximum value under moderate voltage due to the greatest biomass production. DC field with high voltage (10V) decreased the volume of leachate from the chelator treatment without electric field from 1224 to 56mL, while the leachate gathered from AC field treatments raised from 512 to 670mL. DC field can retard the downward movement of metals caused by chelator application more effectively relative to AC field due to the constant water flow and electroosmosis direction. Alternating current field had more promotive effect on chelator assisted phytoremediation efficiency than DC field illustrated by more metal accumulation in the species. However, with the consideration of leaching risk, DC field with moderate voltage was the optimal supplementary technique for phytoremediation. PMID- 29241118 TI - PLHINT: A knowledge-driven computational approach based on the intermolecular H bond interactions at the protein-ligand interface from docking solutions. AB - The tendency of docking scoring functions to generate crystal close conformations of ligands bound to protein structures face limitations in not reproducing the exact crystal intermolecular contacts in dock poses. Intermolecular H bond contacts enumerated at the protein-docked ligand interface can be used to train scoring models and improve virtual screening performance. There is a need to incorporate additional knowledge of protein-ligand H bond contacts in extension to crystal contacts from docking solutions within the reproducibility efficiency of the docking program. A computational approach PLHINT (Protein-ligand H bond interaction pattern) is presented here which extracts intermolecular H bond interactions from native-like docked ligand poses, transform into the scoring scheme and apply over the virtual screening results of database molecules. The basic premise of the PLHINT approach is to score the most observed H bond patterns with the high score to achieve high recovery rates. Tested on ten diverse DUD-E benchmark datasets, the approach has demonstrated better overall performance and ligand enrichment competency over virtual screening results generated by three genetic algorithm-based docking programs viz. AutoDock Vina, FlexAID and PLANTS. Furthermore, the approach has successfully recovered the poor and random virtual screening results with better enrichments. PMID- 29241119 TI - Bench to bedside review: Possible role of vitamin D in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a group of dysfunctions in social interaction, communication, and behaviors. Studies have demonstrated that vitamin D deficiency during pregnancy and in individuals increased the risk of ASD. A genetic polymorphism study has pinpointed that genotype AA/A-allele of GC rs4588 in children is associated with ASD, which encodes the vitamin D binding protein. Translating the mentioned points into clinical practice, several clinical trials have demonstrated that vitamin D supplementation can improve the core symptoms in children with ASD. One paper also showed that possible prophylactic effect for the reoccurrence of ASD by vitamin D supplement during pregnancy and early childhood. Herein, this review aims to address the recent advances in this field and to clarify the possible role of vitamin D in ASD. PMID- 29241120 TI - A study on the association of mood disorders and gluten-related diseases. AB - Our study aimed to evaluate the presence of antibodies related to gluten intolerance in patients with mood disorders. A total of 60 patients with a diagnosis of bipolar disorder or depressive disorder were recruited. Fourty-eight subjects randomly selected among unrelated family members were included as controls. Celiac disease-associated antibodies were assayed both in the patients and controls. Mean values of IgA/IgG anti-gliadin antibodies, IgA/IgG anti deamidated gliadin peptide antibodies and IgA anti-transglutaminase (tTG) antibodies were not different between patients and controls. However, a significant difference was found for anti-tTG IgG antibodies. Even if both in controls and in patients the mean anti-tTG IgG value was below the cutoff, the estimates produced by the statistical model showed that each unit increase in the anti-tTG IgG antibody value corresponded to an approximately 5% increased chance of having a mood disorder. The patient group showed a more frequent presence of symptoms associated to non-celiac gluten sensitivity. However, as there was neither any correlation between antibody levels and gastrointestinal symptoms, nor with the intensity of the psychiatric symptoms, it may be conceivable that the increase in anti-tTG IgG antibodies is not disorder-related but possibly an outcome of the psychiatric disorder itself. PMID- 29241121 TI - Nanotitania crystals induced efficient photocatalytic color degradation, antimicrobial and larvicidal activity. AB - Textile industries release tonnes of harmful toxic dyes into the environment, causing severe effects on living organisms, including humans. Mosquitoes vectors spread important diseases which cause millions of human deaths worldwide. To control mosquitoes a number of synthetic mosquitocidal agents have been employed but all these pesticides pose harmful effects to human health and non-target species and also led to resistance development in treated vectors. Microbial strains are also developing resistance to the available antibiotics, this currently represents a major public health challenge. The current study is focused on the green synthesis of titanium dioxide nanoparticles (TiO2 NPs) using aqueous leaf extracts of Euphorbia hirta. Results suggested an efficient remedy for the above mentioned problems using TiO2 NPs against the dye degradation, mosquito larvae and bacterial pathogens. The fabrication of TiO2 NPs was confirmed by UV-visible spectroscopy, the biomolecules involved in the synthesis process were evidenced by Fourier transform infra-red spectroscopy (FT-IR), the crystalline structure was observed by using X-ray powder diffraction (XRD) analysis. Spherical shaped TiO2NPs were recorded using field emission scanning electron microscopy (FESEM). Energy dispersive X-ray spectroscopy (EDX) results showed the elemental composition of TiO2 NPs. Enhanced rate of photocatalytic dye degradation efficacy was recorded in in methylene blue (95.8%) followed by crystal violet (86.7%). Antibacterial activity assays indicated growth inhibition was highest in Staphylococcus epidermidis and Proteus vulgaris. The LC50 of TiO2 NPs and E. hirta extract on Aedes aegypti larvae were 13.2mg/l and 81.2mg/l, while on Culex quinquefasciatus they were 6.89mg/l and 46.1mg/l respectively. Overall, based on the results of the present study, the green engineered nanotitania could be considered as novel and promising photocatalytic, antibacterial, and mosquitocidal agent. PMID- 29241122 TI - Modulation by neighboring cells of the responses and fate of melanoma cells irradiated with UVA. AB - UVA radiation, which accounts for about 95% of the solar spectrum, contributes to and may be the etiological factor of skin cancers of which malignant melanoma is the most aggressive. UVA causes oxidative stress in various types of cells in the skin, keratinocyte, melanocytes, and fibroblasts, which is responsible for its cytotoxic effect. Here we used a transwell system to explore how the responses of melanoma cells to a low dose of UVA (20kJ/m2, ~10% of the minimal erythema dose) are influenced by neighboring co-cultured melanoma cells or fibroblasts. This dose had a low toxicity for melanoma cells, but after irradiation, co-culture with non-irradiated melanoma cells caused a strong decline in their viability and an increased frequency of apoptosis, whereas co-culture with fibroblast exerted a protective effect on irradiated melanoma cells. At the same time, the presence of non-irradiated cells, especially fibroblasts, decreased the level of UVA-induced reactive oxygen and nitrogen species. Interleukins efficiently produced by fibroblasts seem to be main players in these effects. Our studies reveal that coexistence of fibroblasts with melanoma cells may strongly modulate the direct action and may change bystander effects exerted by UVA light. Similar modulation of the effect of UVA on melanoma cells in vivo by bystander-like signaling from neighboring cells would have consequences for the development of malignant melanoma. PMID- 29241123 TI - Effects of arbuscular mycorrhizal inoculation and biochar amendment on maize growth, cadmium uptake and soil cadmium speciation in Cd-contaminated soil. AB - Experiments conducted to understand how arbuscular mycorrhizal (AM) inoculation or biochar application affect plant growth and heavy metal uptake have thus far looked at single applications of either soil amendment. There is little evidence of their synergistic effects, in particular for plants grown in cadmium (Cd) contaminated soil. We conducted a mesocosm experiment to investigate the effect of AM inoculation (Glomus intraradices BEG 141) and/or wheat-straw biochar amendment on maize (Zea mays L. cv. Hongdan No. 897) growth, antioxidant enzymatic activities, and Cd uptake, as well as soil Cd speciation under applications of 0, 3, 6 mg Cd per kg soil. Applying either AM inoculant or biochar alone significantly increased maize growth and reduced Cd uptake. Furthermore, solo AM inoculation alleviating Cd stress more fully than biochar, in turn facilitating maize growth and decreasing soil Cd translocation into plant tissue. Still, solo biochar amendment was more effective at inducing soil alkalinization and contributing to Cd immobilization. Adding biochar together with AM inoculant significantly promoted fungal populations compared to a control. Amending soil with AM inoculant and biochar together produced the largest increase in maize growth and decrease in tissue Cd concentrations. This effect was additive, with 79.1% greater biomass, 51.42%, 82.91%, 43.96% higher activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and 50.06%, 67.19%, 58.04% and 76.19% lower Cd concentrations in roots, stems, leaves, and ears, respectively, at a 6 mg kg-1 Cd contamination rate. The combined treatment also had a synergistic effect on inducing soil alkalinization and causing Cd immobilization, and decreasing Cd phytoavailability and post harvest transfer risks. These results suggest that AM inoculation in combination with biochar application may be applicable not only for maize production but also for phytostabilization of Cd-contaminated soil. PMID- 29241124 TI - Struvite formation and decomposition characteristics for ammonia and phosphorus recovery: A review of magnesium-ammonia-phosphate interactions. AB - Struvite (MgNH4PO4.6H2O) forms in aqueous systems with high ammonia and phosphate concentrations. However, conditions that result into struvite formation are highly dependent on the ionic compositions, temperature, pH, and ion speciation characteristics. The primary ions involved in struvite formation have complex interactions and can form different crystals depending on the ionic levels, pH and temperature. Struvite as well as struvite analogues (with substitution of monovalent cations for NH4+ or divalent cations for Mg2+) as well as other crystals can form simultaneously and result in changes in crystal morphology during crystal growth. This review provides the results from experimental and theoretical studies on struvite formation and decomposition studies. Characteristics of NH4+ or divalent cations for Mg2+ were evaluated in comparison to monovalent and divalent ions for formation of struvite and its analogues. Struvite crystals forming in wastewater systems are likely to contain crystals other than struvite due to ionic interactions, pH changes, temperature effects and clustering of ions during nucleation and crystal growth. Decomposition of struvite occurs following a series of reactions depending on the rate of heating, temperature and availability of water during heating. PMID- 29241125 TI - The enhancement and inhibition of mercury reduction by natural organic matter in the presence of Shewanella oneidensis MR-1. AB - Reduction-oxidation (Redox) processes of mercury (Hg) are of significant importance in influencing Hg speciation, bioavailability, and fate in anoxic environments where natural organic matter (NOM) and dissimilatory metal reducing bacteria (DMRB) are widely observed. However, the redox reaction between Hg and NOM, has not yet been studied in the presence of S. oneidensis MR-1 in anoxic environments. We have found that the reduction rate of mercuric mercury [Hg(II)] in the presence of Elliott soil humic acid (ESHA) was 0.02 h-1. It was faster than the rate (0.01 h-1) in the direct microbial Hg(II) reduction, suggesting that ESHA acts as an electron transfer mediator between cells and Hg, which enhances Hg(II) reduction under anoxic conditions. The overall rate of Hg(II) reduction in the presence of ESHA is determined by the rate of electron transfer from S. oneidensis MR-1 to ESHA (rate-limiting step) since the rate of electron transfer from reduced ESHA to Hg(II) was so rapid. In the reaction between S. oneidensis MR-1 and a variety of NOM analogs, the production rate of elemental mercury [Hg (0)] was linearly correlated with the free radical concentrations and aromaticities in reduced NOM analogs. However, at the high ESHA concentrations or cell contents, Hg(II) reduction might be inhibited by thiol functional groups in reduced ESHA and on cells. We suggest that the presence of NOM, cell concentration and NOM source can significantly affect the redox processes of Hg and therefore, have important implications for elucidating Hg redox processes under environmentally relevant complex conditions. PMID- 29241126 TI - The chronic exposure to abamectin causes spatial memory deficit and depressive behavior in mice. AB - It is known that abamectin (ABA), which is a component belonging to the group of avermectins, has been broadly used as biopesticide. Although its effect on non target aquatic organisms is known, knowledge about its impacts on terrestrial animals such as mammals remains incipient. Thus, we aim at investigating the effects (phycical and neural-behavioral) from the chronic exposure (90 days) to ABA (1/10 of LD50) on Swiss and C57Bl/6J mice from both sexes. Accordingly, at the end of the experimental period the animals were subjected to the following tests: Novel Object Recognition Test (NORT), Morris Water Maze (MWM), Tail Suspension Test (TST), and Forced Swimming Test (FST). We showed that the new object recognition indexes in the NORT test sessions did not differ between experimental groups; however, animals exposed to ABA, regardless of sex or strain, recorded longer latency time to find the quadrant holding the platform in the MWM training sessions, as well as stayed shorter in this quadrant. Such results highlight the negative effect of the pesticide on the animals' spatial memory evocation, without evident influence from their genetic status and sex. With regard to TST, we also did not observe differences in immobility time between groups; however, Swiss mice (males and females) presented depressive behavior in the FST, and apparent influence from their genetic status in their responses during the test. Therefore, our study confirms the neurotoxic potential of ABA and is pioneer in reporting memory deficit and depressive behavior in mammal experimental models. PMID- 29241127 TI - High-strength N-methyl-2-pyrrolidone-containing process wastewater treatment using sequencing batch reactor and membrane bioreactor: A feasibility study. AB - N-methyl-2-pyrrolidone (NMP) is widely used as a solvent in polymeric membrane fabrication process, its elimination from the process wastewater (normally at a high concentration > 1000 mg/L) prior to discharge is essential because of environmental concern. This study investigated the feasibility of treating high strength NMP-containing process wastewater in a sequencing batch reactor (SBR; i.e., batch feeding and intermittent aerobic/anoxic condition) and a membrane bioreactor (MBR; i.e., continuous feeding and aeration), respectively. The results showed that the SBR with the acclimated sludge was capable of removing >90% of dissolved organic carbon (DOC) and almost 98% of NMP within 2 h. In contrast, the MBR with the acclimated sludge showed a decreasing NMP removal efficiency from 100% to 40% over 15-day operation. The HPLC and LC-MS/MS analytical results showed that NMP degradation in SBR and MBR could undergo different pathways. This may be attributed to the dissimilar bacterial community compositions in the SBR and MBR as identified by 16s rRNA gene sequencing analysis. Interestingly, the NMP-degrading capability of the activated sludge derived from MBR could be recovered to >98% after they were operated at the SBR mode (batch feeding mode with intermittent aerobic/anoxic condition). This study reveals that SBR is probably a more feasible process to treat high-strength NMP containing wastewater, but residual NMP metabolites in the SBR effluent need to be post-treated by an oxidation or adsorption process in order to achieve zero discharge of toxic chemicals. PMID- 29241128 TI - Mobility of polivinylpyrrolidone coated silver nanoparticles in tropical soils. AB - Experiments in saturated soil columns were performed to investigate the transport and retention of 25 nm and 75 nm silver nanoparticles stabilized with polyvinylpyrrolidone (PVP-AgNPs) in two Brazilian soils (sandy and sandy-clay). The normalized concentration of the PVP-AgNPs was obtained through a flow injection analysis method based on the surface plasmon ressonance effect of the metallic nanoparticles. The use of the ultraviolet-visible spectroscopy (UV-Vis) allows a rapid and low-cost analysis. The obtained breakthrough curves (BCs) were modeled with a deterministic model of solute transport in steady conditions of water flow and considering two regions of non-physical equilibrium; this model allowed the determination of the hydrodynamic parameters. It was found that the process occurs in condition of non-equilibrium, with a low mass transfer for larger NP, and that the process is predominantly advective and affected by the pore size of the soil packed in the columns. The BCs for PVP-AgNPs obtained by UV Vis spectroscopy were compared with the BCs obtained by ICP-MS and with BCs of the bromide anion, confirming that the nanoparticles have a low retention and few modifications when transported through the soil column. These PVP-AgNPs are highly mobile and can be transported through the studied tropical soils, representing a potential environmental problem, due to the possibility of these materials reaching groundwater. On the contrary, the conservative behavior of PVP AgNPs in the studied tropical soils, indicates its potential use as tracers, substituting the bromide anion which has been demonstrated to be not a good tracer in the same conditions. PMID- 29241129 TI - Improving biocathode community multifunctionality by polarity inversion for simultaneous bioelectroreduction processes in domestic wastewater. AB - Bioelectrochemical systems (BESs) have been tentatively applied for wastewater treatment processes, but the complex composition of wastewater could lead to difficulties in establishing functional biofilm or result in performance instability. Few studies have investigated the enrichment of biocathode with domestic wastewater (DW) and the function. A biocathode with multi-pollutant removal capabilities was enriched based on polarity inverted bioanode, which was established with DW. The biocathode function was examined using model pollutants (nitrate, nitrobenzene and Acid Orange 7) supplemented as sole or mixed electron acceptors. When compared to the anaerobic control treatment, the biofilm demonstrated significantly enhanced reduction abilities in the open circuit. For the closed circuit, their removal efficiencies were further enhanced for both the sole and mixed substrates conditions. The bioanodes community structure and diversity markedly changed after operating for 50 d as biocathodes. The biocathode multifunctionality and stability could be related to the maintenance of organic matters fermentative bacteria (mainly belonging to Bacteroidetes, Firmicutes and Synergistetes) and the enrichment of versatile pollutant-reducing bacteria (e.g. Pseudomonas, Thauera and Comamonas from Proteobacteria). Other pollutants, such as perchlorate, sulfate, heavy metals, and halogenated organics, may also work as potential electron acceptors. This study provides a new strategy to improve the biocathode community multifunctionality for simultaneous bioelectroreduction, which can be combined with other wastewater treatment processes in actual application. PMID- 29241130 TI - Calculation of Thallium's toxicity coefficient in the evaluation of potential ecological risk index: A case study. AB - As a common pollutive metal element, Tl is very biotoxic. The potential ecological risk index (RI) proposed by Hakanson is one of the commonest methods for evaluation of ecological risk of a metal in sedimentary environment of a water body. According to the calculation principle proposed by Hakanson, the toxicity coefficient of Tl was calculated, and determined as 10 in this paper. In addition, the environmental risk of Tl in the surface sediment of the Beijing Hangzhou Grand Canal (Zaozhuang Section) was evaluated by RI method, enrichment factor method, etc. The South-to-North Water Diversion Project which benefits four billion people is the largest inter-basin water transfer project in China. The Zaozhuang Section is a significant water conveyance line of this project. We found that the Tl concentrations were 0.46-0.70 MUg g-1 with the mean value of 0.61 MUg g-1 and were higher than the local background value. The highest contents of Tl occurred in the middle of Zaozhuang section and Tai'erzhuang District, but the enrichment degree of it was much higher in the entrance of Nansihu Lake. The grain size and Al oxides/hydroxides were main factors which controlled the distribution of Tl. Analysis of enrichment factors indicated that Tl in sediments possessed obvious source of human activities which were mainly from combustion of fossil fuels such as coal and mining of mineral resources. As a whole, however, the research region has low Tl content, so Tl has a small probability of environmental pollution. PMID- 29241131 TI - Subcellular distribution and chemical form of phosphorus involved in alleviating phosphorus toxicity of the phosphorus-accumulator Polygonum hydropiper. AB - Polygonum hydropiper is a dominant plant species in Shifang phosphorus (P) mine area and is a promising P-accumulator used for P-phytoextraction. To date, little information is available on the physiological response involved in alleviating P toxicity of P. hydropiper under high P. A pot experiment was carried out to investigate growth, P subcellular distribution, chemical forms in two ecotypes of P. hydropiper under high levels (1, 4, and 8 mmol P L-1) of inorganic P (Pi) and organic P (Po), supplied as KH2PO4 and myo-inositol hexaphosphoric acid dodecasodium salt, respectively. The mining ecotype (ME) showed a greater ability to tolerate high P than the non-mining ecotype (NME), as shown by its superior growth with undamaged leaf anatomical structure. The ME showed 1.3-2.2 times greater shoot P accumulation than the NME. More than 93% of P accumulated in tissue cell wall and soluble fraction. The increasing P treatments increased all tissue P forms, especially Pi form. The ME showed significantly higher ester P, nucleic P and insoluble P in tissues than the NME at 8 mmol L-1; however, it demonstrated lower Pi, expect for roots at 5 weeks. The percentages of Pi and nucleic P in roots of the ME were higher than other P forms, and the percentages of nucleic P dominated in the leaves. Probably, the combination of preferential distribution of P in cell wall and soluble fraction in tissues and storage of P in low activity as nucleic P in leaves allows the ME to adapt high P. PMID- 29241132 TI - Cadmium mobility, uptake and anti-oxidative response of water spinach (Ipomoea aquatic) under rice straw biochar, zeolite and rock phosphate as amendments. AB - Agricultural soils contamination with cadmium (Cd) has become a serious concern through anthropogenic activities. The possible environmental friendly solutions for Cd are required to address its mobility through various cost effective amendments. This study aims to evaluate the impact of rice straw biochar (BC), zeolite (ZE) and rock phosphate (RP) stabilizers to minimize the potential risk of Cd mobility and its uptake by water spinach in acidic soil through pot experiment. Concentration of Cd in TCLP and CaCl2 extract gradually decreased with the increase of amendments (BC, ZE and RP) rates. The increase in BC addition from 1.5% to 3% significantly decreased CaCl2-extractable Cd by 65.78% 72.89% and TCLP extractable Cd by 31.16%-37.66% respectively, over control. Whereas, RP addition decreases 53.4%-65.18% and 11.68%-19.48% in CaCl2 and TCLP extractable Cd respectively, as compared to control soil. The addition of BC, ZE and RP decreased Cd uptake by 22.91%-61.82% with 1.5% and 3% application rate, respectively. Moreover, the antioxidant enzymes activity i.e., superoxide dismutase (SOD) and peroxidase (POD) decreased with the addition of BC, ZE and RP under Cd stress. In conclusion, rice straw biochar could be highly recommended as a safe stabilizer to immobilize Cd in polluted agricultural soils. PMID- 29241133 TI - Oxidation of beta-blockers by birnessite: Kinetics, mechanism and effect of metal ions. AB - Manganese dioxides are ubiquitous in natural waters, soils, and sediments and play an important role in oxidative transformation of organic pollutants. This work presents the kinetics of the oxidation of selected beta-blockers, betaxolol, metoprolol, and atenolol by birnessite (delta-MnO2) as a function of concentration of the beta-blocker, dosage of delta-MnO2, and solution pH. The values of pseudo-first-order rate constants (kobs) of beta-blockers decreased in the order betaxolol > atenolol > metoprolol, which was positively correlated with their acid dissociation constants (Ka). Effect of series of metal ions (Fe3+, Cr3+, Al3+, Pb2+, Cu2+, Zn2+, Ni2+, Cd2+, Mg2+, and Ca2+) on the degradation of beta-blockers by delta-MnO2 was systematically examined. All of these metal ions inhibited the oxidation reaction under the same constant ionic strength. The inhibition efficiency was positively correlated with the logarithm of stability constant of metal ions in aqueous solution (logKMeOH). By LC-ESI-MS/MS analyses, the oxidation of beta-blockers primarily involved hydroxylation and cleavage of the parent molecules to the short branched chain compounds. An electron transfer mechanism for the oxidation of beta-blockers by delta-MnO2 was proposed. The oxidation was initiated by the electron transfer from the nonbonding electrons on nitrogen (N-electrons) of beta-blockers to delta-MnO2, followed by transformation of radical intermediates. These findings will help to understand the oxidation processes of beta-blockers and predict the effect of metal ions on the removal of pollutants by delta-MnO2 in the environment. PMID- 29241134 TI - Effects of the herbicides linuron and S-metolachlor on Perez's frog embryos. AB - Presence of pesticides in the environment and their possible effects on aquatic organisms are of great concern worldwide. The extensive use of herbicides in agricultural areas are one of the factors contributing to the known decline of amphibian populations. Thus, as non-target species, amphibians can be exposed in early life stages to herbicides in aquatic systems. In this context, this study aims to evaluate effects of increasing concentrations of two maize herbicides, linuron and S-metolachlor on embryos of the Perez' frog (Pelophylax perezi) during 192 h. Apical endpoints were determined for each herbicide: mortality, hatching rate, malformations and length. Frog embryos presented a LC50 of 21 mg/l linuron and 37.5 mg/l S-metolachlor. Furthermore, sub-lethal concentrations of both herbicides affected normal embryonic development, delaying hatching, decreasing larvae length and causing several malformations. Length of larvae decreased with increasing concentrations of each herbicide, even at the lower concentrations tested. Malformations observed in larvae exposed to both herbicides were oedemas, spinal curvature and deformation, blistering and microphtalmia. Overall, these results highlight the need to assess adverse effects of xenobiotics to early life stages of amphibians regarding beside mortality the embryonic development, which could result in impairments at later stages. However, to unravel mechanisms involved in toxicity of these herbicides further studies regarding lower levels of biological organisation such as biochemical and genomic level should be performed. PMID- 29241135 TI - Characterization of uranium redox state in organic-rich Eocene sediments. AB - The presence of organic matter (OM) has a profound impact on uranium (U) redox cycling, either limiting or promoting the mobility of U via binding, reduction, or complexation. To understand the interactions between OM and U, we characterised U oxidation state and speciation in nine OM-rich sediment cores (18 samples), plus a lignite sample from the Mulga Rock polymetallic deposit in Western Australia. Uranium was unevenly dispersed within the analysed samples with 84% of the total U occurring in samples containing >21 wt % OM. Analyses of U speciation, including x-ray absorption spectroscopy and bicarbonate extractions, revealed that U existed predominately (~71%) as U(VI), despite the low pH (4.5) and nominally reducing conditions within the sediments. Furthermore, low extractability by water, but high extractability by a bi-carbonate solution, indicated a strong association of U with particulate OM. The unexpectedly high proportion of U(VI) relative to U(IV) within the OM-rich sediments implies that OM itself does not readily reduce U, and the reduction of U is not a requirement for immobilizing uranium in OM-rich deposits. The fact that OM can play a significant role in limiting the mobility and reduction of U(VI) in sediments is important for both U-mining and remediation. PMID- 29241136 TI - Submillimeter-scale heterogeneity of labile phosphorus in sediments characterized by diffusive gradients in thin films and spatial analysis. AB - Sediments have a heterogeneous distribution of labile redox-sensitive elements due to a drastic downward transition from oxic to anoxic condition as a result of organic matter degradation. Characterization of the heterogeneous nature of sediments is vital for understanding of small-scale biogeochemical processes. However, there are limited reports on the related specialized methodology. In this study, the monthly distributions of labile phosphorus (P), a redox-sensitive limiting nutrient, were measured in the eutrophic Lake Taihu by Zr-oxide diffusive gradients in thin films (Zr-oxide DGT) on a two-dimensional (2D) submillimeter level. Geographical information system (GIS) techniques were used to visualize the labile P distribution at such a micro-scale, showing that the DGT-labile P was low in winter and high in summer. Spatial analysis methods, including semivariogram and Moran's I, were used to quantify the spatial variation of DGT-labile P. The distribution of DGT-labile P had clear submillimeter-scale spatial patterns with significant spatial autocorrelation during the whole year and displayed seasonal changes. High values of labile P with strong spatial variation were observed in summer, while low values of labile P with relatively uniform spatial patterns were detected in winter, demonstrating the strong influences of temperature on the mobility and spatial distribution of P in sediment profiles. PMID- 29241137 TI - Improving post-detonation energetics residues estimations for the Life Cycle Environmental Assessment process for munitions. AB - The Life Cycle Environmental Assessment (LCEA) process for military munitions tracks possible environmental impacts incurred during all phases of the life of a munition. The greatest energetics-based emphasis in the current LCEA process is on manufacturing. A review of recent LCEAs indicates that energetics deposition on ranges from detonations and disposal during training is only peripherally examined through assessment of combustion products derived from closed-chamber testing or models. These assessments rarely report any measurable energetic residues. Field-testing of munitions for energetics residues deposition has demonstrated that over 30% of some energetic compounds remain after detonation, which conflicts with the LCEA findings. A study was conducted in the open environment to determine levels of energetics residue deposition and if combustion product results can be correlated with empirical deposition results. Energetics residues deposition, post-detonation combustion products, and fine aerosolized energetics particles following open-air detonation of blocks of Composition C4 (510 g RDX/block) were quantified. The deposited residues amounted to 3.6 mg of energetic per block of C4, or less than 0.001% of the original energetics. Aerial emissions of energetics were about 7% of the amount of deposited energetics. This research indicates that aerial combustion products analysis can provide a valuable supplement to energetics deposition data in the LCEA process but is insufficient alone to account for total residual energetics. This study demonstrates a need for the environmental testing of munitions to quantify energetics residues from live-fire training. PMID- 29241138 TI - Effects of fluoride on synapse morphology and myelin damage in mouse hippocampus. AB - To investigate the fluoride-induced neurotoxicity on mice hippocampus, healthy adult mice were exposed to 25, 50, and 100 mg NaF/L for 60 days. The results showed that medium and high fluoride administration induced ultrastructural alterations in the structure of neuron synapse, including indistinct and short synaptic cleft, and thickened postsynaptic density (PSD). The significant reduced mRNA expressions of proteolipid protein (PLP) in medium and high fluoride groups suggested that myelin damage occurred in hippocampus. The myelin damage in turn was determined by the increased myelin-associated glycoprotein (MAG) level, which is naturally released by injured myelin, in high fluoride group, compared to the medium fluoride group. In addition, high fluoride exposure also reduced the mRNA and protein levels of cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), and neural cell adhesion molecule (NCAM). These findings suggested that the alteration in synaptic structure and myelin damage may partly be due to adverse effects of fluoride on the neurotrophy and neuron adhesion in mice hippocampus. PMID- 29241139 TI - Mussels and clams from the italian fish market. is there a human exposition risk to metals and arsenic? AB - Seafood is associated with many beneficial effects on human health. However, the overall level of contaminants in biota has increased over the last two centuries and seafood is one of the source of oral exposition to contaminants. Therefore, this work aimed to evaluate cadmium, lead, mercury, arsenic, chromium and nickel presence in mussels and clams, from the Italian market, and the associated risk. The samples were from five different FAO areas. Analyses were carried out using inductively-coupled plasms-mass spectrometry. The sample concentrations were below the maximum levels stated by Commission Regulation (EC) 1881/2006, except one mussel sample, which was non-compliant for cadmium (2.13 +/- 0.20 mg kg-1). For arsenic, nickel and chromium, maximum levels are not stated by the European Union. In this study, arsenic ranged from 1.29 to 13.35 mg kg-1 and nickel ranged from 1, and BMDL10 for lung bladder and skin cancer in all mussel samples was overcome, in the 100% and 25% of mussel and clam samples, respectively. PMID- 29241140 TI - Ammonium haloacetates - An alternative to glyphosate? AB - This study shows the design, synthesis and evaluation of eco(phyto)toxic and herbicidal activities of quaternary ammonium salts (QASs), derived from haloacetic acids, in context of the search for safer alternatives to the commonly used herbicide, N-(phosphonomethyl)glycine (glyphosate). The structure of the investigated QASs refers to the heteroatom sequence in the anion of glyphosate in which the (P-C)-N nitrogen atom was replaced by one or more halogens (F, Cl). The ecotoxicity of the synthesized QASs was tested against luminescent marine bacteria Vibrio fischeri (Microtox(r) test) and the crustaceans Heterocypris incongruens (Ostracodtoxkit FTM). The phytotoxic effect of QASs was also studied with respect to spring barley (Hordeum vulgare) and common radish (Raphanus sativus L. radicula Pers.), whereas herbicidal activity was investigated in relation to popular weeds species gallant soldier (Galinsoga parviflora Cav.) and common sorrel (Rumex acetosa L.). The results showed that toxicity of the synthesized QASs depends on a number of halo-substituents, especially for bioluminescent bacteria Vibrio fischeri for which EC50 values were those varying the most. Phytotoxicity tests proved that the investigated QASs had a similar high, toxic effect both on monocotyledonous and dicotyledonous plants with exception of DIPA - DCA. Moreover, their herbicidal activity against common sorrel was comparable to glyphosate. PMID- 29241141 TI - Plasma exchange in severe acute relapses of multiple sclerosis - Results from a Portuguese cohort. AB - BACKGROUND: Relapses in Multiple Sclerosis (MS) are often associated with significant disability impairment which is resultant from poor response to corticosteroids. In such severe cases, plasma exchange (PLEX) may be used, although only a few studies with MS patients have been reported. Our objective was to evaluate the effectiveness of PLEX in severe relapses of MS. METHODS: Retrospective study of MS patients treated with PLEX in acute relapses. Data regarding EDSS, annualized relapse rate (ARR), treatment with corticosteroids, number of PLEX sessions, adverse events, and gadolinium enhancement in brain MRI were analysed. RESULTS: Included 46 patients, 76.09% female (n = 35) with mean age of 38.76 years and mean disease duration of 5.99 years, of which 84.78% had a Relapsing Remitting MS (n = 39), 15.22% Secondary Progressive MS (n = 7). The previous ARR was 1.1 and in 28.26% of the cases (n = 13) PLEX was used in the relapse that led to MS diagnosis. The majority of relapses had motor impairment (69.6%, n = 32), with a median EDSS increase of 1.5 points from baseline (maximum of 6.5) and higher than 1.5 points in 45.65% of cases (n = 21). Brain MRI was available in 69.57% of the cases (n = 32), and gadolinium enhancing lesions were present in 68.75% of cases (n = 22). Corticosteroids were used before PLEX in all patients for a mean of 6.09 days, without any immediate benefit in 41.30% of cases (n = 19), with the remaining cases showing only mild disability recovery. After a mean of 7.39 PLEX sessions, there was clinical benefit with complete EDSS recovery in 41.30% of patients (n = 19), and partial in 39.13% (n = 18). There were no adverse events related to PLEX in 89.13% of patients (n = 41) and in the remaining patients the reported adverse events included deep venous thrombosis (n = 1), anaemia (n = 1), fever (n = 1), hypoalbuminemia (n = 1) and arterial hypotension (n = 1). CONCLUSION: Our results support the use of PLEX in severe relapses unresponsive to corticosteroids, since it was an effective and relatively safe treatment for most of our patients. PMID- 29241142 TI - Unmet needs, burden of treatment, and patient engagement in multiple sclerosis: A combined perspective from the MS in the 21st Century Steering Group. AB - BACKGROUND: Patient engagement is vital in multiple sclerosis (MS) in order to optimise outcomes for patients, society and healthcare systems. It is essential to involve all stakeholders in potential solutions, working in a multidisciplinary way to ensure that people with MS (PwMS) are included in shared decision-making and disease management. To start this process, a collaborative, open environment between PwMS and healthcare professionals (HCPs) is required so that similarities and disparities in the perception of key areas in patient care and unmet needs can be identified. With this patient-centred approach in mind, in 2016 the MS in the 21st Century Steering Group formed a unique collaboration to include PwMS in the Steering Group to provide a platform for the patient voice. METHODS: The MS in the 21st Century initiative set out to foster engagement through a series of open-forum joint workshops. The aims of these workshops were: to identify similarities and disparities in the perception and prioritisation in three key areas (unmet needs, the treatment burden in MS, and factors that impact patient engagement), and to provide practical advice on how the gaps in perception and understanding in these key areas could be bridged. RESULTS: Combined practical advice and direction are provided here as eight actions: 1. Improve communication to raise the quality of HCP-patient interaction and optimise the limited time available for consultations. 2. Heighten the awareness of 'hidden' disease symptoms and how these can be managed. 3. Improve the dialogue surrounding the benefit versus risk issues of therapies to help patients become fully informed and active participants in their healthcare decisions. 4. Provide accurate, lucid information in an easily accessible format from reliable sources. 5. Encourage HCPs and multidisciplinary teams to acquire and share new knowledge and information among their teams and with PwMS. 6. Foster greater understanding and awareness of challenges faced by PwMS and HCPs in treating MS. 7. Collaborate to develop local education, communication and patient-engagement initiatives. 8. Motivate PwMS to become advocates for self-management in MS care. CONCLUSION: Our study of PwMS and HCPs in the MS in the 21st Century initiative has highlighted eight practical actions. These actions identify how differences and gaps in unmet needs, treatment burden, and patient engagement between PwMS and HCPs can be bridged to improve MS disease management. Of particular interest now are patient-centred educational resources that can be used during time limited consultations to enhance understanding of disease and improve communication. Actively bridging these gaps in a joint approach enables PwMS to take part in shared decision-making; with improved communication and reliable information, patients can make informed decisions with their HCPs, as part of their own personalised disease management. PMID- 29241143 TI - Perceptions about supervised injection facilities among people who inject drugs in Philadelphia. AB - BACKGROUND: People who inject drugs (PWID) are at high risk for infectious diseases, skin and soft tissue infections, and overdose. However, these harms are all avoidable when sterile injection equipment, hygienic places to inject, and medical care are accessible. Unfortunately, many PWID in the U.S lack these resources. The most vulnerable are forced to inject in public spaces, where individual risks are high and communal harms are sometimes many. Supervised Injection Facilities (SIFs) are an established intervention for reducing these harms. Despite positive experiences in other countries, little research explores how PWID in the U.S. perceive the value of such facilities. METHODS: We conducted a freelisting exercise with PWID (n=42) and healthcare providers (n=20) at a syringe exchange program (SEP) that provides comprehensive clinical and social services in Philadelphia to inform in-depth semi-structured interviews with PWID (n=19) at the same location. RESULTS: Participants expressed support for a potential SIF as a valuable public health intervention. They suggested that an SIF would improve PWID health while reducing the public disorder associated with injecting drugs in public. The latter was especially important to participants without stable housing, whose decision to inject furtively in secluded places was often motivated by desire not to upset community members, and particularly children. These participants acknowledged that such seclusion elevated the risk of fatal overdose. Despite similarly positive perceptions about an SIF, participants with stable housing reported that they would prefer to continue injecting at home. CONCLUSION: Results both confirm and extend prior research about PWID and SIFs. Participants expressed support for SIFs as in prior survey research in the U.S. and in other countries. Facility location and housing status were identified as important determinants of facility use. Results extend prior research by illuminating PWID perceptions in the U.S. including motivations grounded in concern for public order. PMID- 29241144 TI - The diverse reasons for using Novel Psychoactive Substances - A qualitative study of the users' own perspectives. AB - BACKGROUND: The increasing number of legally ambiguous and precarious Novel Psychoactive Substances (NPS) constitutes a challenge for policy makers and public health. Scientific and more in-depth knowledge about the motivations for using NPS is scarce and often consist of predetermined, non-systematic, or poorly described reasons deduced from top-down approaches. Therefore, the aim of the present study was to explore and characterize the users' self-reported reasons for NPS use inductively and more comprehensively. METHODS: The self-reported reasons of a self-selected sample of 613 international NPS users were collected via an online survey promoted at the international drug discussion forum bluelight.org and later analyzed qualitatively using inductive thematic analysis. RESULTS: The analysis showed that the participants used NPS because these compounds reportedly: 1) enabled safer and more convenient drug use, 2) satisfied a curiosity and interest about the effects, 3) facilitated a novel and exciting adventure, 4) promoted self-exploration and personal growth, 5) functioned as coping agents, 6) enhanced abilities and performance, 7) fostered social bonding and belonging, and 8) acted as a means for recreation and pleasure. The consumption of NPS was also driven by 9) problematic and unintentional use. CONCLUSION: The present study contributed to a more comprehensive understanding of the users' own and self-reported reasons for using NPS, which needs to be acknowledged not only in order to minimize drug related harm and drug user alienation but also to improve prevention efforts and reduce the potentially counter-intuitive effects of strictly prohibitive policies. PMID- 29241145 TI - Wet-chemical etching of atom probe tips for artefact free analyses of nanoscaled semiconductor structures. AB - We introduce an innovative specimen preparation method employing the selectivity of a wet-chemical etching step to improve data quality and success rates in the atom probe analysis of contemporary semiconductor devices. Firstly, on the example of an SiGe fin embedded in SiO2 we demonstrate how the selective removal of SiO2 from the final APT specimen significantly improves accuracy and reliability of the reconstructed data. With the oxide removal, we eliminate the origin of shape artefacts, i.e. the formation of a non-hemispherical tip shape, that are typically observed in the reconstructed volume of complex systems. Secondly, using the same approach, we increase success rates to ~90% for the damage-free, 3D site-specific localization of short (250 nm), vertical Si nanowires at the specimen apex. The impact of the abrupt emitter radius change that is introduced by this specimen preparation method is evaluated as being minor using field evaporation simulation and comparison of different reconstruction schemes. The Ge content within the SiGe fin as well as the 3D boron distribution in the Si NW as resolved by atom probe analysis are in good agreement with TEM/EDS and ToF-SIMS analysis, respectively. PMID- 29241146 TI - ISeeYou - Evaluation of a woman-centred care pilot project in Bachelor midwifery education and research. AB - AIM: to evaluate the ISeeYou project that aims to equip first year Bachelor midwifery students to support them in their learning of providing woman-centred care. METHODS: the project has an ethnographic design. First year midwifery students buddied up to one woman throughout her continuum of the childbirth process and accompanied her during her antenatal and postnatal care encounters. Participant-observation was utilised by the students to support their learning. The Client Centred Care Questionnaire (CCCQ) was administered to collect data about women's care experiences. The project was evaluated using the SWOT model. MAIN FINDINGS: 54 first year students completed the project and observed and evaluated on average eight prenatal visits and two postnatal visits. Students gained insight into women's lived experiences during the childbirth process and of received care throughout this period. Students reported that this was meaningful and supported and enhanced their comprehension of women-centred care. Logistic issues (lectures, travel, time) and being conscious of their role as an 'outsider' sometimes constrained, but never hindered, the students in meeting the requirements of the project. Overall, the project provided students with opportunities to expand competencies and to broaden their outlook on midwifery care. CONCLUSION: the project offers students unique and in-depth experiences supporting and augmenting their professional competencies and their personal, professional and academic development. PMID- 29241148 TI - Obesity exacerbates the acute metabolic side effects of olanzapine. AB - Olanzapine is a second-generation antipsychotic used in the management of schizophrenia and various off-label conditions. The acute metabolic responses of olanzapine recapitulate many of the side effects associated with obesity. Obesity rates are high in the schizophrenic population, but it is unknown whether pre existing obesity-associated metabolic dysfunction augments the acute side effects of olanzapine. To address this question, we compared the responses to olanzapine in lean and high-fat diet-induced (HFD) obese mice. Four weeks of HFD (60%kcal from fat) led to obese, hyperglycemic, and insulin resistant mice. Olanzapine induced hyperglycemia and systemic insulin resistance were exacerbated in HFD induced obese mice. Olanzapine also profoundly inhibited insulin signalling in skeletal muscle and liver, which appears to be exacerbated by obesity. The greater olanzapine-induced hyperglycemia may also result from increased hepatic glucose output in obese mice as pyruvate challenge led to significantly higher blood glucose concentrations, with associated increases in hepatic content of gluconeogenic enzymes. Olanzapine also suppressed RER while acutely increasing oxygen consumption in obese mice. A single olanzapine treatment reduced physical activity for up to 24h, regardless of obesity. Considering obesity is very common in the schizophrenic population, these data suggest that previous research may be under-estimating the severity of olanzapine's acute side effects. PMID- 29241147 TI - Combined enzymatic and metabolic analysis of grapevine cell responses to elicitors. AB - Elicitors trigger plant defense responses, including phytoalexin production and cell-wall reinforcement. Primary metabolism plays an important role in these responses as it fuels the associated energetic costs and provides precursors for the synthesis of the numerous secondary metabolites involved in defenses against pathogens. In this context, we aimed to determine whether oligosaccharidic elicitors differing in their capacity to activate defense-associated secondary metabolism in grapevine would differently impact primary metabolism. To answer this question, cell suspensions were treated with two elicitors: an oligogalacturonide, and the beta-glucan laminarin. Enzymatic activity assays together with targeted (HPLC) and global (GC-MS) analyses of metabolites were next performed to compare their impact on plant primary or secondary metabolism. The results showed that the oligogalacturonide, which induced the highest level of the phytoalexin resveratrol and the highest activity of stilbene synthase, also induced the highest activity of shikimate hydroxycinnamoyltransferase, a key enzyme involved in the synthesis of lignin. The oligogalacturonide-induced defenses had a significant impact on primary metabolism 24 h following elicitor treatment, with a reduced abundance of pyruvate and 2-oxoglutarate, together with an increase of a set of metabolites including carbohydrates and amino acids. Interestingly, an accumulation of galacturonate and gentiobiose was observed in the oligogalacturonide- and laminarin-treated cells, respectively, suggesting that both elicitors are rapidly hydrolyzed in grapevine cell suspension cultures. PMID- 29241150 TI - Assessment of the Roche Linear Array HPV Genotyping Test within the VALGENT framework. AB - BACKGROUND: Cervical cancer screening programs are switching from cytology-based screening to high-risk (hr) HPV testing. Only clinically validated tests should be used in clinical practice. OBJECTIVES: To assess the clinical performance of the Roche Linear Array HPV genotyping test (Linear Array) within the VALGENT-3 framework. STUDY DESIGN: The VALGENT framework is designed for comprehensive comparison and clinical validation of HPV tests that have limited to extended genotyping capacity. The Linear Array enables type-specific detection of 37 HPV types. For the purpose of this study, Linear Array results were designated as positive only if one of the 13 hrHPV types also included in the Hybrid Capture 2 (HC2) was detected. The VALGENT-3 framework comprised 1600 samples obtained from Slovenian women (1300 sequential cases from routine cervical cancer screening enriched with 300 cytological abnormal samples). Sensitivity for cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) (n=127) and specificity for 28days into LPS-treated mice caused ALI. The filtered supernatant resulted in significantly ameliorated mouse ALI. MPs that accumulate during RCC storage prime the PMN respiratory burst and cause ALI in a two-event mouse model. PMID- 29241159 TI - Oxymatrine prevents synovial inflammation and migration via blocking NF-kappaB activation in rheumatoid fibroblast-like synoviocytes. AB - The fibroblast-like synoviocytes (FLSs) has the aggressive phenotype, which is very important for cartilage destruction in rheumatoid arthritis (RA). To the pathology of RA, the increased FLSs migration, activation and proliferation are essential factors. Oxymatrine is a traditional Chinese herb, which is the extraction from the root of Sophora flavescens and regarded as quinolizidine alkaloid compounds and has been shown to inhibit inflammation, proliferation and migration in vitro or vivo. However, whether oxymatrine effects in the treatment of RA FLSs is undefined. In our study, the inhibition of oxymatrine in RA FLSs inflammation, proliferation and migration in RA FLS are evaluated. We found that oxymatrine decreased the IL-6 and IL-8 expression and the proliferation, migration and invasion of RA FLSs. We also evaluated the molecular mechanisms and we found the effect of oxymatrine on NF-kappaB activation. The results showed that oxymatrine inhibited the activity of NF-kappaB. And the treatment activity of oxymatrine on collagen-induced arthritis (CIA) was further explored by us. Thus, we conclude that oxymatrine may protect joint destruction of RA by inhibiting synoviocyte activation, migration, invasion, and proliferation. PMID- 29241161 TI - Troxerutin Protects Against Myocardial Ischemia/Reperfusion Injury Via Pi3k/Akt Pathway in Rats. AB - BACKGROUND/AIMS: Troxerutin, also known as vitamin P4, has been commonly used in the treatment of chronic venous insufficiency (CVI) disease. However, its effect on in vivo myocardial ischemia/reperfusion (I/R) injury, a model that closely mimics acute myocardial infarction in humans, is still unknown. METHODS: The myocardial I/R injury rat model was created with troxerutin preconditioning. Myocardial infarct size was evaluated by the Evans blue-TTC method. Hemodynamic parameters, including the heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP), maximal rate of rise in blood pressure in the ventricular chamber (+dp/dt max), and maximal rate of decline in blood pressure in the ventricular chamber (-dp/dt max) were monitored. Serum TNF-alpha and IL-10 were determined by ELISA kit. Cell apoptosis was detected by MTT method. RESULTS: Troxerutin preconditioning significantly reduced myocardial infarct size, improved cardiac function, and decreased the levels of creatine kinase (CK), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in the I/R injury rat model. The serum and mRNA levels of TNF-alpha and IL 10 as well as some apoptosis markers (Bax, Caspase 3) also decreased. Moreover, troxerutin pretreatment markedly increased the phosphorylation of Akt, and blocking PI3K activity by LY294002 abolished the protective effect of troxerutin on I/R injury. CONCLUSION: Troxerutin preconditioning protected against myocardial I/R injury via the PI3K/Akt pathway. PMID- 29241162 TI - In Vitro and In Vivo Activity of Fomitopsis Pinicola (Sw. Ex Fr.) Karst Chloroform (Fpkc) Extract Against S180 Tumor Cells. AB - BACKGROUND/AIMS: Non-toxic fomitopsis is has been traditionally used in folk medicine in many countries for its anti-inflammatory and anti-vascular disease activities. The present study investigates the antitumor effect of Fomitopsis pinicola (Sw. Ex Fr.) Karst chloroform extract (FPKc) on S180 tumor cells in vitro and in vivo and we determined the underlying mechanisms. METHODS: HPLC was employed to analyze the constituents of FPKc. In-vitro 3-(4,5-Dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to quantify the growth inhibition of FPKc; Propidium iodide (PI) exclusion assay and scanning electron microscopy (SEM) were used to observe the damage on the cell membrane and the changes of the cell morphology; Staining with Hoechst 33342/propidium iodide (HO/PI) and the application of the Annexin V-FITC/PI analysis permitted to observe the cell death triggered by FPKc; DNA damage and cell cycle arrest were detected by flow cytometry; Rhodamine 123 (RH123) and Cytochrome C were used as dyes to investigate the alterations of the mitochondria. In-vivo tumor inhibition and mice survival time were determined. RESULTS: The results of the HPLC assay indicated that FPKc might contain DA (dehydroeburiconic acid), PA (pachymic acid), and ES (ergosterol), at percentages of 0.25%, 17.8%, and 10.5%, respectively. Concerning the study of the biological function, the results showed that FPKc exhibited preferential and significant suppression of proliferation on specific cell lines including S180, HL-60, U937, K562, SMMC-7721, and Eca-109 cells, which induced plasma membrane and cell morphology damages, triggering S180 tumor-cells late apoptosis and leading to DNA damage and S phase arrest. Mitochondria were suspected to play a vital role in these changes. In vivo data indicated that FPKc inhibited the solid tumor growth and prolonged the survival time of tumor-bearing mice. Moreover, FPKc provoked only little damage on normal cells in vitro and also on normal tissues in vivo. CONCLUSION: FPKc inhibited S180 tumor cells growth and prolonged the lifespan of mice. In vitro, we found that FPKc induced S180 tumor cells apoptosis and cell cycle arrest, possibly via the mitochondrial pathway. PMID- 29241163 TI - Diagnosis and Management of Necrotizing Enterocolitis: An International Survey of Neonatologists and Pediatric Surgeons. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a serious complication of prematurity. Currently, there is limited evidence to guide investigation and treatment strategies. OBJECTIVES: To evaluate the parameters used to diagnose or exclude NEC, and to identify differences between neonatologists and pediatric surgeons. METHODS: A scenario-based survey was sent to neonatologists and pediatric surgeons. RESULTS: 173 physicians from 26 countries completed the survey (55% neonatologists and 45% pediatric surgeons). Bloody stools, abdominal tenderness, low platelet counts, and increased lactate levels increased the likelihood of NEC for 82, 72, 56, and 45% of respondents, respectively. Intestinal pneumatosis, portal venous gas, and pneumoperitoneum on X-ray increased the likelihood of NEC for 99, 98, and 92% of respondents, respectively. Clinical examination and laboratory tests were insufficient to exclude NEC, but normal intestinal movements and normal gut wall thickness on ultrasonography decreased the likelihood of NEC for 38 and 33% of respondents, respectively. Neonatologists more frequently relied on increased gastric residuals and abdominal distension to diagnose NEC (p = 0.04 and p = 0.03, respectively), whereas pediatric surgeons more frequently reported that absence of bloody stools helped to exclude NEC (p = 0.04). In a deteriorating patient with suspected NEC, 39% of respondents would broaden the antibiotic spectrum, and 42% would recommend a laparotomy. CONCLUSION: Our results indicate a wide variation in the management of NEC, with significant differences between neonatologists and pediatric surgeons. A better appreciation of the relative significance and weighting that should be applied to the clinical features and investigations should reduce the variation in interpretation that appears to exist. PMID- 29241164 TI - Peritoneal Dialysis Catheter Revision and Replacement by Nephrologist for Peritoneal Dialysis Catheter Malfunction. AB - BACKGROUND: Catheter malfunction is an important cause of technique failure for peritoneal dialysis (PD) patients, and is commonly managed by surgeons or intervention radiologists. We reviewed our experience in catheter revision or replacement by nephrologists. METHOD: We reviewed the clinical outcome and complication rate of 95 consecutive patients who had PD catheter malfunction, with catheter revision or replacement by nephrologist. RESULT: Amongst the 95 patients, 32 had catheter revision, 24 catheter replacement via the original wound, and 39 catheter replacement via a new mini-laparotomy wound. Catheter survival was 71.6% at 1 month and 48.4% at 6 months; technique survival was 88.4% at 1 month and 77.4% at 6 months. When the 3 types of procedure were analyzed separately, technique survival at 1 month was 96.8, 75.0, and 89.7%, respectively, for patients who received catheter revision, catheter replacement via the original wound, and catheter replacement via a new mini-laparotomy wound (p = 0.0002), although their catheter survival rates were not significantly different. Also, 2 patients had bleeding that required urgent surgical exploration, 2 had wound infection, and 8 had peritonitis within 4 weeks after the surgery. CONCLUSION: PD catheter revision and replacement by nephrologist has an acceptable catheter survival and a reasonable complication rate. Given that prompt intervention is an important consideration, catheter revision and replacement by nephrologist is a suitable method for the management of catheter malfunction. PMID- 29241165 TI - SC1 Promotes MiR124-3p Expression to Maintain the Self-Renewal of Mouse Embryonic Stem Cells by Inhibiting the MEK/ERK Pathway. AB - BACKGROUND/AIMS: Self-renewal is one of the most important features of embryonic stem (ES) cells. SC1 is a small molecule modulator that effectively maintains the self-renewal of mouse ES cells in the absence of leukemia inhibitory factor (LIF), serum and feeder cells. However, the mechanism by which SC1 maintains the undifferentiated state of mouse ES cells remains unclear. METHODS: In this study, microarray and small RNA deep-sequencing experiments were performed on mouse ES cells treated with or without SC1 to identify the key genes and microRNAs that contributed to self-renewal. RESULTS: SC1 regulates the expressions of pluripotency and differentiation factors, and antagonizes the retinoic acid (RA) induced differentiation in the presence or absence of LIF. SC1 inhibits the MEK/ERK pathway through Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and pathway reporting experiments. Small RNA deep-sequencing revealed that SC1 significantly modulates the expression of multiple microRNAs with crucial functions in ES cells. The expression of miR124-3p is upregulated in SC1-treated ES cells, which significantly inhibits the MEK/ERK pathway by targeting Grb2, Sos2 and Egr1. CONCLUSION: SC1 enhances the self-renewal capacity of mouse ES cells by modulating the expression of key regulatory genes and pluripotency associated microRNAs. SC1 significantly upregulates miR124-3p expression to further inhibit the MEK/ ERK pathway by targeting Grb2, Sos2 and Egr1. PMID- 29241166 TI - The Clinical Efficacy of Radium-223 for Bone Metastasis in Patients with Castration-Resistant Prostate Cancer: An Italian Clinical Experience. AB - BACKGROUND/AIM: Prostate cancer frequently causes bone metastases and skeletal events that impair quality of life (QoL) and survival. The alpha emitter radium 223 is a new drug that improves treatment in men with castration-resistant prostate cancer (CRPC) and bone metastases. Our aim was to evaluate the effectiveness of radium-223. SUBJECTS AND METHODS: In this retrospective study we enrolled 48 subjects. Pain reduction, alkaline phosphatase (ALP), time to first symptomatic skeletal event, and QoL were the variables we evaluated. RESULTS: Radium-223 was well tolerated, with a manageable toxicity profile and a modest objective response rate. A considerable difference in serum ALP levels before and after treatment was observed, with a significant correlation between pain relief and QoL, which showed a value of R2 to 0.44 with a slope of 1.50 (p = 0.0021). CONCLUSIONS: Radium-223 showed a clinical benefit, with a reduction in pain symptoms in 58% of patients. Radium-223 was shown to be an effective and well tolerated therapeutic option in patients with metastatic CRPC progressing after docetaxel plus prednisone treatment. PMID- 29241167 TI - Nutritional Screening and Clinical Outcome in Hospitalized Patients with Crohn's Disease. AB - BACKGROUND/AIMS: Hospitalized patients with Crohn's disease (CD) can develop severe nutritional deficits. However, the nutritional screening tools with the most utility for such patients are still unknown. METHODS: Nutritional status of 40 CD patients was assessed on admission using several screening tools and laboratory tests. Their validity was evaluated in relation to length of hospital stay (LOS) and intestinal resection. Receiver operating characteristic analysis was performed to predict prolonged LOS (>=28 days). RESULTS: Prolonged LOS was correlated with each of the following screening parameters: Subjective Global Assessment, Nutrition Risk Screening 2002 (NRS 2002), Onodera's Prognostic Nutritional Index (O-PNI), Controlling Nutritional Status, serum albumin level, and weight loss. These parameters were not correlated with intestinal resection. Evaluation of prognostic yield showed cutoff values of serum albumin 3.3 g/dL (AUC 0.797, sensitivity 57.1%, specificity 89.5%) and O-PNI 36.5 (0.749, 71.4%, 73.7%). By combining the serum albumin cutoff value and NRS 2002 score, patients were divided into 4 groups, with a prolonged LOS rate of 68.2% in the group with the worst prognosis. CONCLUSIONS: A combination of serum albumin (given the simplicity of testing) and NRS 2002 as nutritional screening tools may be useful for hospitalized CD patients. PMID- 29241168 TI - Epidemiology of Intracranial Gliomas. AB - Gliomas are the most common primary intracranial neoplasms, which cause significant mortality and morbidity that is disproportionate to their relatively rare incidence. Many potential risk factors for glioma have been studied to date, but only few provide explanation for the number of brain tumor cases identified. The most significant findings include increased risk due to exposure to ionizing radiation and decreased risk with the history of allergy or atopic diseases. The potential effect of the cellular phone usage has been evaluated extensively, but the results remain inconclusive. A very small proportion of gliomas can be attributed to inherited genetic disorders. Additionally, recent analyses using the genome-wide association study design have identified several inherited genomic risk variants. PMID- 29241169 TI - Imaging of Intracranial Gliomas. AB - Combined use of contemporary radiological modalities, particularly integration of structural, metabolic, and functional imaging, provides optimal multifaceted information for detailed characterization of intracranial gliomas. It allows differentiation of the tumor from non-neoplastic pathology, its non-invasive histopathological typing and grading, prediction of patient prognosis and clinical course of the disease, detailed planning of surgical resection or biopsy, critical postoperative assessment of the residual lesion, effective surveillance during follow-up with evaluation of effectiveness of the adjuvant therapy and timely identification of recurrence, and even insights into molecular signatures of the neoplasms. Therefore, advanced neuroimaging is one of the most important cornerstones of the modern neuro-oncology. PMID- 29241170 TI - Rationale for Aggressive Resection and General Surgical Principles for Intracranial Gliomas. AB - Given the infiltrative nature of gliomas, controversy has long persisted over the value of their aggressive surgical removal. Nevertheless, in recent decades, the balance of opinion in neurosurgical oncology has shifted from a more nihilistic view that led to many patients' receiving stereotactic biopsy or very limited debulking of lesions for tissue diagnosis only, to more extensive tumor resections which relieve mass effect, lower intracranial pressure, reduce accompanying brain edema, and attenuate dependence on steroids. Achieving a clinically significant cytoreduction makes adjuvant therapy more successful, and ultimately helps to preserve or improve neurological function. Moreover, increased extent of brain tumor removal results in prolongation of progression free survival and overall survival of patients and improves their quality of life. The beneficial effect of high resection rate may be noted even in selected cases of recurrent neoplasms. However, optimizing an aggressive surgical strategy for intracranial gliomas requires specific skills, availability of advanced intraoperative technological modalities, and the presence of a highly qualified multidisciplinary team of medical professionals for pre-, intra-, and postoperative care of such patients. PMID- 29241171 TI - Virtual Reality Surgical Simulation: Implications for Resection of Intracranial Gliomas. AB - Surgical simulation has the potential to play important roles in surgical training and preoperative planning. The advent of virtual reality (VR) with tactile haptic feedback has revolutionized surgical simulation, creating a novel environment for residents to learn manual skills without compromising patient safety. This concept is particularly relevant in neurosurgical training where the acquired skill set demands performance of technically challenging tasks under pressure and where the consequences of error are significant. The evolution of VR simulation is discussed here within the context of neurosurgical training and its implications for resection of intracranial gliomas. VR holds the promise of providing a useful educational tool for neurosurgical residents to hone their surgical skills and for neurosurgeons to rehearse specific segments of the surgery prior to the actual operation. Also discussed are several important issues related to simulation and simulation-based training that will need to be addressed before widespread adoption of VR simulation as a useful technology. PMID- 29241172 TI - Neurophysiological Monitoring and Awake Craniotomy for Resection of Intracranial Gliomas. AB - Aggressive resection of intracranial gliomas has a positive impact on patients' prognosis, but is associated with a risk of neurological complications. For preservation of brain functions and avoidance of major postoperative morbidity various methods of intraoperative neurophysiological monitoring have been introduced into clinical practice. At present, somatosensory evoked potentials (SSEP), motor evoked potentials (MEP), visual evoked potentials (VEP), brainstem auditory evoked potentials (BAEP), and electrocorticography (ECoG) are used routinely during neurosurgical procedures. To maximize the efficacy of these neurophysiological techniques, it is most preferable to apply total intravenous anesthesia with continuous infusion of propofol and opioids and avoidance of long acting muscle relaxants. Surgery for brainstem gliomas requires specific mapping with direct electrical stimulation (DES), corticobulbar tract MEP monitoring, and free-running electromyography (EMG) of the various muscles innervated by the cranial nerves. Awake craniotomy and intraoperative mapping of language and sensorimotor functions with DES allow precise identification of the functionally important neuronal structures and have become standard techniques for removal of cerebral neoplasms affecting eloquent cortical areas and subcortical pathways. Overall, contemporary neurophysiology plays a very important role in guidance of brain tumor surgery, in which it helps to maximize the extent of resection and to minimize the risk of permanent neurological morbidity. PMID- 29241173 TI - Surgical Management of Gliomas in Eloquent Cortex. AB - Gliomas located in eloquent cortex impose a unique surgical obstacle. The oncological benefit of aggressive resection must be balanced with preservation of functional tissue and optimization of surgical outcome. Technical advances in preoperative functional imaging, refinement of intraoperative mapping, and conceptual understanding of cerebral plasticity have significantly improved the outcome of this patient population. PMID- 29241174 TI - Surgery of Insular Gliomas. AB - For a long time, surgery within the insular lobe, especially in cases of intrinsic tumors, was considered as too dangerous. Even though such interventions are still challenging, resection of insular glioma became more popular during the past decade. First of all, this has happened due to better understanding of the functional anatomy of this complex brain region, combined with an improved knowledge of its connectivity. Furthermore, development of advanced intraoperative techniques, especially functional brain mapping with direct electrical stimulation, resulted in increased safety of procedures. Finally, recent evidence-based data from multiple clinical studies strongly support early maximal safe resection of both low- and high-grade gliomas. These conceptual and methodological advances led neurosurgeons to envision surgical strategy for insular gliomas in a more systematic manner. PMID- 29241175 TI - Surgery of Critically Located Intracranial Gliomas. AB - Management of deep-seated and midline gliomas originating from thalamus, hypothalamus, basal ganglia, and brainstem presents significant challenges. Aggressive resection of such tumors is frequently impossible due to excessive morbidity and mortality rates; thus, combinations of both surgical and non surgical treatment options should be always considered. In each individual case, there should be reasonable clinical judgment with regard to the optimal outcome providing the best possible prognosis for the patient, with high quality of life and minimal risk of complications. PMID- 29241176 TI - Surgery of Intracranial Gliomas in Children. AB - Gliomas are the most common type of brain cancer in the pediatric patients, constituting about 50% of all childhood intracranial tumors. This is a highly heterogeneous group, varying from the benign WHO histopathological grades I and II to malignant WHO grades III and IV. The histology and location are significant prognostic factors, which influence the decision for surgical intervention, as well as the extent of possible tumor removal. In low-grade gliomas, surgery remains the initial option and should be directed at gross total resection in favorable locations, such as the cerebral hemispheres and the cerebellum. Management of high-grade gliomas (HGG), which are less common in children compared to adults, continue to pose a significant challenge. In non-brainstem HGG, the goal is safe maximal tumor removal, while it generally does not play any role in diffuse intrinsic pontine gliomas. Treatment must, thus, be individualized in the majority of cases of HGG. Surgery for gliomas in children continues to be aided by technological advancements facilitating tumor resection and improving patient safety and outcomes. PMID- 29241177 TI - Surgical Management of Recurrent Intracranial Gliomas. AB - In cases of recurrent gliomas, the treatment options are limited and not yet standardized. Choices usually include re-operation, systemic chemotherapy, salvage re-irradiation, and supportive care, which can be used either separately or in combination. From a surgical perspective, management of recurrent brain tumor poses a significant challenge, as the desire to attain aggressive lesion resection must be balanced against the need to preserve neurological functions and to maximize the quality of life. Additionally, specific practical difficulties in performing repeat craniotomies and significant risk of perioperative morbidity in such cases necessitate careful selection of the optimal candidates for surgery. PMID- 29241178 TI - Role of Biopsies in the Management of Intracranial Gliomas. AB - Gliomas encompass a wide spectrum of various histopathological entities with different management strategies and associated prognoses. In many cases, initial biopsy of the brain lesion is required, since definitive diagnosis forms the foundation for treatment decision-making. Tissue sampling can be attained during stereotactic, open, or endoscopic procedures and, overall, provides >90% diagnostic yield, while it may be significantly lower (60-70%) in small (<1 cm3) and/or heterogeneous lesions. In the majority of the modern series, the morbidity rates do not exceed 2.5%. In experienced hands biopsy can be safely attained in any regions of the brain, including eloquent cortex, deep-seated structures, and the brainstem. PMID- 29241179 TI - Rs739837 Polymorphism in MiR-885-3p Binding Site Within 3'-Untranslated Region of Vitamin D Receptor is Associated with a Decreased Risk of Pressure Ulcers. AB - BACKGROUND/AIMS: Accumulative evidence has shown that miR-885-3p plays a crucial role in human carcinogenesis. From miRNA database, we also found that rs739837 polymorphism in miR-885-3p binding site within 3'-untranslated region of Vitamin D receptor (VDR), compromising the suppressive effect of miR-885-3p on VDR. Moreover, Vitamin D is involved in controlling the cell immune response and may play a role in pressure ulcers development. However, whether this polymorphism is actually linked with pressure ulcers remains unclear. The aim of the present study was to investigate the potential association between the rs739837 polymorphism and pressure ulcers, and to explore molecular mechanism of VDR in pressure ulcers. METHODS: Luciferase assays were performed to validate the relationship between miR-885 and VDR, which was confirmed by western-blotting analysis. The relationship between rs739837 and the risk of pressure ulcers was explored using logistic regression analysis. RESULTS: We first conducted statistical analysis to explore the association between the rs739837 genotype and risk of pressure ulcers, and found that the polymorphism genotype was significantly associated with the risk of pressure ulcers (OR 0.68, 95% CI 0.43 0.95, P value = 0.02). We then searched the miRNA database online and identified VDR as a direct target. We established the negative regulatory relationship between miR-885-3p and VDR using luciferase assays. Meanwhile, we transfected cells with scramble control, miR-885-3p mimics, VDR siRNA and miR-885-3p inhibitors. The results further confirmed the negative regulatory relationship between miR-885-3p and VDR. CONCLUSION: VDR is a virtual target of miR-885-3p, and rs739837 might be a predictive biomarker for the risk of pressure ulcers. PMID- 29241180 TI - High Mobility Group Box1 Inhibitor Glycyrrhizic Acid Attenuates Kidney Injury in Streptozotocin-Induced Diabetic Rats. AB - BACKGROUND/AIMS: High mobility group box 1 (HMGB1) is an important mediator of the inflammatory response. It has been implicated in the pathogenesis of autoimmune diseases, atherosclerosis, and obesity. However, the effects of HMGB1 on diabetic nephropathy remain unclear. Here, we investigated the potential roles and mechanisms of an HMGB1 inhibitor, glycyrrhizic acid (GA), in renal injury with the streptozotocin (STZ)-induced rat model. METHODS: The diabetic rat was generated by intraperitoneal injection of STZ and then treated with the HMGB1 inhibitor GA or saline for 8 weeks. Rats were randomly divided into three groups: the normal control and saline group (Control), the diabetic rats with saline group (Diabetic) and the diabetic rats plus GA group (Diabetic+GA). Peripheral blood was obtained for measurements of blood glucose, TNF-a, IL-6 and IL-1beta. The mRNA levels of proinflammatory cytokines (TNF-a, IL-6 and IL-1beta), chemokines (MCP-1), intercellular adhesion molecules (ICAM-1) and TGF-beta1 in the kidneys were evaluated by quantitative real-time PCR. The protein levels of phosphorylated(p) and total(t) p38 MAPK, JNK, ERK, and NF-kappaB were measured by western blot. RESULTS: We found that diabetic rats showed obvious renal lesions, an elevated urinary albumin/creatinine ratio (UACR) and increased expression levels of TGF-beta1 and Col-IV in the kidneys, accompanied by significantly enhanced expression levels of HMGB1, receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR-4) in the kidney tissue. Furthermore, the GA treatment significantly reduced the UAC levels, ameliorated renal injury, and decreased the TNF-alpha, 1L-6, IL-1beta, MCP-1, ICAM-1, TGF-beta1 and Col-IV levels. Importantly, the expression levels of HMGBI, RAGE and TLR4 in the kidney tissues of the diabetic rats were also inhibited by the GA treatment. Furthermore, the GA treatment significantly reduced the phosphorylation levels of ERK and p38 MAPK and suppressed NF-kappaB translocation from the cytoplasm to the nucleus. CONCLUSION: Our findings indicate that the HMGB1 inhibitor GA may improve renal injury and inflammatory responses in diabetic rats by regulating RAGE/TLR4-related ERK and p38 MAPK/NF-kappaB activation. PMID- 29241181 TI - Sex Determination and Sex Chromosomes in Amphibia. AB - Sex chromosomes in most amphibians are homomorphic (undifferentiated) in both sexes and are characterized by frequent turnover. This is in sharp contrast to sex chromosomes in 2 major vertebrate groups, the mammals and birds, where they are heteromorphic in one sex and are highly conserved. Sex-determining mechanisms in anuran amphibians, particularly in relation to the turnover of sex-determining genes and sex chromosomes, are summarized and their evolution is discussed. PMID- 29241182 TI - Serum Biomarker Identification by Mass Spectrometry in Acute Aortic Dissection. AB - BACKGROUND/AIMS: Aortic dissection (AD) is also known as intramural hematoma. This study aimed to screen peripheral blood biomarkers of small molecule metabolites for AD using high-performance liquid chromatography-mass spectrometry (HPLC-MS). METHODS: Sera from 25 healthy subjects, 25 patients with well established AD, and 25 patients with well-established hypertension were investigated by HPLC-MS to detect metabolites, screen differentially expressed metabolites, and analyze metabolic pathways. RESULTS: Twenty-six and four metabolites were significantly up- and down-regulated in the hypertensive patients compared with the healthy subjects; 165 metabolites were significantly up-regulated and 109 significantly down-regulated in the AD patients compared with the hypertensive patients. Of these metabolites, 35 were up-regulated and 105 down-regulated only in AD patients. The metabolites that were differentially expressed in AD are mainly involved in tryptophan, histidine, glycerophospholipid, ether lipid, and choline metabolic pathways. As AD alters the peripheral blood metabolome, analysis of peripheral blood metabolites can be used in auxiliary diagnosis of AD. CONCLUSION: Eight metabolites are potential biomarkers for AD, 3 of which were differentially expressed and can be used for auxiliary diagnosis of AD and evaluation of treatment effectiveness. PMID- 29241183 TI - Leptin Suppresses Glutamate-Induced Apoptosis Through Regulation of ERK1/2 Signaling Pathways in Rat Primary Astrocytes. AB - BACKGROUND/AIMS: Leptin is a hormone expressed by adipose tissue that regulates body energy homeostasis and weight loss by activating leptin receptors in the hypothalamus. Leptin receptors are also expressed in astrocytes. An anti apoptosis effect of leptin in brain has recently been reported. However, the anti apoptosis mechanism of leptin in the brain is unknown. METHODS: To investigate whether leptin exerts protective effects against glutamate-induced apoptosis in astrocytes, we performed cell viability assays and apoptosis assays using rat primary astrocytes. Intracellular signaling pathways involved in anti-apoptosis effects of leptin were analyzed by immunoblotting together with a leptin mutant (S120A/T121A) with antagonist function and pharmacological inhibitors. RESULTS: We found that glutamate-induced apoptosis in rat primary astrocytes was significantly decreased by treatment with leptin. Leptin inhibited glutamate induced phosphorylation of ERK1/2 in astrocytes. The leptin S120A/T121A mutant did not inhibit glutamate-induced ERK1/2 phosphorylation and ERK1/2-mediated apoptosis. CONCLUSIONS: Collectively, our results provide initial evidence that leptin exerts an anti-apoptotic effect against glutamate toxicity through activation of intracellular signaling pathways which reverse glutamate-induced ERK1/2 phosphorylation in primary astrocytes. Therefore, our findings suggest that leptin might be considered a candidate for potential therapeutic applications in glutamate-induced brain excitotoxicity. PMID- 29241184 TI - Peritonitis in Children on Chronic Peritoneal Dialysis: The Experience of a Large National Pediatric Cohort. AB - BACKGROUND: We performed this study to evaluate the incidence, risk factors, microbiology, treatment, and outcome of peritonitis in pediatric Peritoneal dialysis (PD) patients at a nationwide prospective study. METHODOLOGY: Patients younger than 18 years recruited in the BRAZPD II study from 2004 to 2011, who presented their first peritonitis episode, were included in the study. RESULTS: We found 125 first episodes of peritonitis in 491 children PD patients (0.43 episodes/patient-year). Patients free of peritonitis episode constituted 75.6% in 1 year. Culture-negative episodes were very high (59.2%) and gram-positive (GP) bacteria were the most commonly found organisms (58.8%). First-generation cephalosporin was the initial choice to cover GP (40.5%) and aminoglycosides was the most prescribed antibiotics used for gram-negative agents (27.5%). Treatment failure was 26.4%. Technique failure (TF) occurred in 12.1% and peritonitis was the main cause (65.1%). Pseudomonas (p = 0.04) and negative cultures (p < 0.001) were identified as predictors of TF. CONCLUSION: Peritonitis remains a common complication of PD in children and negative cultures and pseudomonas had a negative impact on TF. PMID- 29241185 TI - Treatment Step 1 for Asthma Should Not Be Left Blank, and SABA-Only Might Not Be a Treatment Step 1 Option for Asthma. PMID- 29241187 TI - Contents Vol. 17, 2017. PMID- 29241186 TI - Strengthening Gastric Cancer Therapy by Trastuzumab-Conjugated Nanoparticles with Simultaneous Encapsulation of Anti-MiR-21 and 5-Fluorouridine. AB - BACKGROUND/AIMS: MicroRNA-21 is an oncogenic miR (oncomiR) frequently elevated in gastric cancer (GC). Overexpression of miR-21 decreases the sensitivity of GC cells to 5-fluorouridine (5-Fu) and trastuzumab, a humanized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2). Receptor-mediated endocytosis plays a crucial role in the delivery of biotherapeutics including anti-miRNA oligonucleotides (AMOs). This study is a continuation of earlier findings involving poly(epsilon-caprolactone) (PCL)-poly (ethylene glycol) (PEG) nanoparticles (PEG-PCL NPs), which were coated with trastuzumab to target GC with HER2 receptor over-expression using anti-miRNA-21 (AMO-21) and 5-Fu. METHODS: HER PEG-PCL NPs were prepared by one-step carbodiimide coupling using 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride (EDAc) and Sulfo-NHS in aqueous phase. Covalent coupling of amino groups at the surface of PEG-PCL with the carboxyl groups of trastuzumab was analyzed by X-ray photoelectron spectroscopy (XPS). AMO-21/5-Fu NPs were formulated by a double-emulsion solvent evaporation technique. The cell line specificity, cellular uptake and AMO-21 delivery were investigated through the rhodamine-B-labeled 6-carboxyfluorescein (FAM)-AMO-21 PEG-PCL NPs coated with or without the antibody in both Her2-positive (NUGC4) and negative GC cells (SGC7901) visualized by fluorescence microscopy. The cytotoxicity of the HER-PEG-PCL NPs encapsulating AMO-21 was evaluated by MTT and apoptosis. Real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to examine miR-21 and phosphatase and tensin homolog (PTEN) and Sprouty2 expression in GC cell lines. The antitumor effects of AMO-21/5-Fu NPs were compared with other groups in xenograft gastric cancer mice. RESULTS: The antibody conjugates significantly enhanced the cellular uptake of NPs. The AMO 21/5-Fu NPs effectively suppressed the target miRNA expression in GC cells, which further up-regulated PTEN and Sprouty2. As a result, the sensitivity of HER2 expressing gastric cancer to trastuzumab and 5-Fu were enhanced both in vitro and in vivo. The approach enhanced the targeting by trastuzumab as well as antibody dependent cellular cytotoxicity (ADCC) of immune effector cells Conclusions: Taken together, the results provide insight into the biological and clinical potential of targeted AMO-21 and 5-Fu co-delivery using modified trastuzumab for GC treatment. PMID- 29241189 TI - Lord Adrian, MD, PRS, OM. AB - Edgar Douglas Adrian was an outstandingly brilliant, Nobel prize-winning neurophysiologist. He is remembered for developing the all-or-none principle of muscle contraction, and for explaining the minutiae of motor and sensory nerve transmission. He showed that the afferent effect in a neuron depends on the pattern in time of the impulses travelling in it, thereby providing a quantitative basis of nervous behaviour. With Sir Charles Sherrington, he was awarded the Nobel Prize in 1932 for discoveries on the functions of the neurons. PMID- 29241190 TI - CircRNA Expression Profile in Early-Stage Lung Adenocarcinoma Patients. AB - BACKGROUND/AIMS: Lung adenocarcinoma, a form of non-small cell lung cancer with high lethality at an advanced stage, is becoming more common in women, non- or never-smokers, and even young adults. At present, there are still no effective early diagnosis methods for patients to be cured in a timely manner. Circular RNAs (circRNAs), which are stable and conserved non-coding RNA in mammalian cells, have been reported to be widely involved in the processes of cancer disease. However, it is still a puzzle as to which specific circRNAs are involved in the development of early-stage lung adenocarcinoma. METHODS: Tumor samples and paired adjacent normal tissues from 4 patients with early-stage lung adenocarcinoma were selected to investigate the expression profile of circRNAs by using a high-throughput circRNA microarray. Bioinformatic analyses were conducted to screen those differentially expressed circRNAs. qRT-PCR and sequencing were performed to assure the microarray data. RESULTS: A total of 357 circRNAs were dysregulated in the tumor samples, which suggests potential roles in lung cancer. qRT-PCR detection showed that five selected circRNAs were identical to the microarray data, and the potential circRNA-miRNA interactions were predicted. CONCLUSION: This work illustrates that clusters of circRNAs are aberrantly expressed in early-stage lung adenocarcinoma, which might offer potential targets for the early diagnosis of this disease and new genetic insights into lung cancer. PMID- 29241191 TI - Evaluation of Behavioral and Susceptibility Patterns in Premenopausal Women with Recurrent Urinary Tract Infections: A Case Control Study. AB - Recurrent urinary tract infections (UTI) are a major source of morbidity and healthcare costs. Risk factors associated with recurrence rates in premenopausal women can be attributed to patient lifestyle behavior. The aim of this study was to assess hygienic risk factors, determine pathogen distribution, and susceptibility patterns in premenopausal women with recurrent UTI. This was case control study in which a face-to-face interview was conducted to obtain information from premenopausal women with recurrent UTI. Microbiology cultures and susceptibility results were obtained to analyze pathogen distribution and resistance. In this study, 214 cases and 230 controls were compared and the following practices were associated with increased risk of recurrent UTI in multivariable analysis: washing genitals from back to front (OR 1.64 [95% CI 1.05 2.56]), not voiding within 15 min after intercourse (OR 2.81 [95% CI 1.72-4.66]), not drinking water after intercourse (OR 1.69 [95% CI 1.12-2.58]), using any soap to clean after urination (OR 2.11 [95% CI 1.42-3.17]). Escherichia coli were the most prevalent pathogens isolated (66.4%), followed by Klebsiella spp. (12.6%), Pseudomonas aeruginosa (12.1%), and Proteus spp., (6.6%). This study identified several modifiable sexual and hygienic practices associated with recurrent UTI in premenopausal women. Continuous surveillance of antimicrobial susceptibility patterns is important to overcome resistance. PMID- 29241192 TI - MicroRNA-92a-3p Regulates Aggrecanase-1 and Aggrecanase-2 Expression in Chondrogenesis and IL-1beta-Induced Catabolism in Human Articular Chondrocytes. AB - BACKGROUND/AIMS: Aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) are secreted enzymes belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family that play significant roles in the progression of osteoarthritis (OA). Here, we aimed to determine whether the expression of ADAMTS-4/5 in chondrogenesis and inflammation is regulated by microRNA-92a-3p (miR-92a-3p). METHODS: MiR-92a-3p and ADAMTS-4/5 expressions were determined by quantitative polymerase chain reaction (qPCR). To investigate the repressive effect of miR-92a-3p on ADAMTS-4/5 expression, chondrogenic human mesenchymal stem cells (hMSCs) and human chondrocytes were transfected with mature miR-92a-3p or an antisense inhibitor (anti-miR-92a-3p), respectively. ADAMTS-4/5 protein production was quantified by enzyme-linked immunosorbent assay (ELISA), and miR 92a-3p involvement in IL-1beta-mediated catabolic effects was examined by immunoblotting. The roles of activated MAP kinases (MAPK) and nuclear factor (NF) kappaB were evaluated by using specific inhibitors. Interaction between miR-92a 3p and its putative binding site in the 3'-untranslated region (3'-UTR) of ADAMTS 4/5 mRNA was confirmed by luciferase reporter assay. RESULTS: miR-92a-3p expression was elevated in chondrogenic hMSCs, with significantly lower expression in OA cartilage than in normal cartilage. Stimulation with IL-1beta significantly reduced miR-92a-3p expression in primary human chondrocytes (PHCs). Transfection of chondrocytes with miR-92a-3p downregulated IL-1beta-induced ADAMTS-4/5 expression, and the activity of a reporter construct containing the 3' UTR of human ADAMTS-4/5 mRNA. MiR-92a-3p expression was suppressed upon IL-1beta induced activation of MAPK and NF-kappaB in chondrocytes. CONCLUSION: MiR-92a-3p is an important regulator of ADAMTS-4/5 in human chondrocytes and may contribute to the development of OA. PMID- 29241194 TI - [Kombinierte Anwendung von Strahlentherapie und adjuvanter Therapie mit einem Mistelextrakt (Viscum album L.) zur Behandlung des oralen malignen Melanoms beim Hund: Eine retrospektive Studie]. AB - Hintergrund: Orale maligne Melanome (OMM) des Hundes zeichnen sich durch schnelles Wachstum, lokale Invasion und hohe Metastasierungsraten aus. Extrakte auf Basis von Viscum album L. (VAE) werden zunehmend in der Krebstherapie sowohl in der Human- als auch in der Veterinarmedizin eingesetzt. Ziel unserer Studie war es zu untersuchen, inwieweit die adjuvante Therapie mit VAE eine therapeutische Option zur Behandlung von OMM ist. Besonderes Augenmerk galt dabei der Uberlebenszeit und moglichen Nebenwirkungen. Tiere und Methoden: 26 Hunde mit OMM, die in einem der grobetaten veterinaronkologischen Zentren der Schweiz allesamt eine Strahlentherapie erhielten (teilweise nach operativer Tumorresektion) wurden in die retrospektive Studie eingeschlossen: 18 Hunde wurden mit VAE behandelt (1 ml VAE (Iscador(r)) in ansteigenden Konzentrationen von 0,1 bis 20 mg/ml subkutan 3-mal pro Woche (VAE-Gruppe), 8 erhielten keine adjuvante Behandlung (Vergleichsgruppe). Wir verglichen die Grobetaenentwicklung der OMM sowie die Uberlebenszeit. Ergebnisse: Patienten mit Bestrahlung und adjuvanter VAE-Therapie zeigten mit 236 Tagen eine signifikant langere mediane Uberlebenszeit im Vergleich zu Patienten mit Bestrahlung, aber ohne adjuvante VAE Therapie (49 Tage; Log-Rank-Test: p = 0,0047). Die VAE-Therapie verlangerte die Uberlebenszeit um mehr als zwei Drittel (Hazard Ratio (HR) = 0,30, 95% Konfidenzintervall (KI) 0,11-0,86; p = 0,024), wahrend ein hoheres Tumorstadium gemabeta UICC (Union internationale contre le cancer) einen statistischen Trend zur Verdopplung des Sterberisikos zeigte (UICC-Stadium III/IV vs. I/II: HR = 2,12, 95%-KI 0,88-5,12; p = 0,095). Zwei Patienten zeigten milde Nebenwirkungen wahrend der VAE-Behandlung. Einer der beiden zeigte 1 Tag lang ein selbstlimitiertes Fieber, bei dem anderen Patienten reduzierten wir die Dosis von einem konzentrierteren zu einem weniger konzentrierten VAE (Serie 0) aufgrund von Mudigkeit, die daraufhin verschwand. Schlussfolgerungen: VAE ist eine sichere, nebenwirkungsarme Behandlung und scheint sich positiv auf die Uberlebenszeit von Hunden mit OMM auszuwirken. Somit ist dieser therapeutische Ansatz es wert, vermehrt bei der adjuvant zur Strahlentherapie eingesetzten Behandlung des OMM in Betracht gezogen zu werden. Die verglichenen Gruppen waren jedoch klein, divers und nicht konsistent hinsichtlich aller prognostischen Parameter. Eine prospektive Studie mit einer grobetaeren Studienpopulation ware daher von Interesse. PMID- 29241193 TI - Comparative Analysis on Low- and Standard-Dose Regimes of Alteplase Thrombolytic Therapy for Acute Ischemic Stroke: Efficacy and Safety. AB - OBJECTIVE: This study analyzed the efficacy and safety of low-dose and standard dose alteplase intravenous thrombolytic therapy for acute ischemic stroke (AIS). METHODS: Patients with AIS who underwent intravenous alteplase thrombolysis from July 2012 to December 2016 were retrospectively analyzed and correspondingly divided into low-dose (0.6-0.89 mg/kg) group and standard-dose group (0.9 mg/kg) according to alteplase dosage. The clinical outcome was evaluated by modified Rankin Scale (mRS) at 90 days after onset. The safety index was the mortality at 90 days after onset and the incidence of symptomatic intracranial hemorrhage (SICH) within 7 days. RESULTS: A total of 1,486 patients were included (1,115 cases in low-dose group and 371 cases in standard-dose group). There were no significant differences in baseline data between the 2 groups. As mRS, good outcome rate as well as mortality rate in both groups had no significant difference (36.1 vs. 37.6%; chi2 = 10.882, p = 0.890; 5.5 vs. 7.3%; chi2 = 2.163, p = 0.076), but the incidence of SICH in low-dose group was significantly lower than that of the standard-dose group (2.2 vs. 5.9%; chi2 = 3.157, p = 0.001). CONCLUSION: The efficacy of low-dose alteplase intravenous thrombolytic therapy for AIS was equivalent to the standard-dose regimen but with higher safety. PMID- 29241195 TI - Nursing Intervention on the Compliance of Hemodialysis Patients with End-Stage Renal Disease: A Meta-Analysis. AB - BACKGROUND: Dialysis is imperative for patients with end-stage renal disease (ESRD); however, compliance ensures its efficacy. Nursing intervention has been considered to improve compliance. This meta-analysis is aimed at exploring the effects of nursing intervention on dialysis compliance. METHODS: A search was performed in the PubMed, Cochrane, and Embase databases for relevant original research articles. Studies were included or excluded based on the simultaneous consideration of quality as ranked by Jadad score and the compliance with predefined selection criteria. RESULTS: A total of 817 participants were included. The results showed that nursing intervention led to significantly higher compliance with dialysis than in standard care. A pilot analysis evidenced that different intervention strategies, including educational, cognitive, and behavioral approaches, had limited effects on dialysis compliance. CONCLUSION: Nursing intervention is beneficial for raising dialysis compliance, providing evidence of the need to strengthen nursing care for ESRD patients administered with dialysis in daily clinical practice. PMID- 29241196 TI - Calycosin Inhibits the Migration and Invasion of Human Breast Cancer Cells by Down-Regulation of Foxp3 Expression. AB - BACKGROUND/AIMS: Calycosin, a phytoestrogenic compound, has recently emerged as a promising antitumor drug. It has been shown that calycosin suppresses growth and induces apoptosis of breast cancer cells. However, the effect of calycosin on migration and invasion of breast cancer cells and the underlying molecular mechanisms have not been elucidated. METHODS: Human breast cancer cells MCF-7 and T47D were treated with, or without, different doses (0, 6.25, 12.5, 25, 50, 100 or 150 MUM) of calycosin, and the viability of different groups was determined by MTT assay. Next, the inhibitory effect of higher doses (50, 100 or 150 MUM) of calycosin on migration and invasion of the two cell lines was determined by wound healing and transwell assay. The relative expression levels of forkhead box P3 (Foxp3), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in MCF-7 and T47D cells were determined by quantitative RT-PCR and Western blot. RESULTS: Treatment with lower doses (6.25 or 12.5 MUM) promoted proliferation of breast cancer cells, but with higher doses significantly reduced the viability of MCF-7 and T47D cells. Furthermore, higher doses of calycosin were found to inhibit migration and invasion of the two cell lines in a dose dependent manner. Additionally, treatment with a higher dose of calycosin significantly reduced the expression levels of Foxp3, followed by down-regulation of VEGF and MMP-9 in both MCF-7 and T47D breast cancer cells. CONCLUSION: Treatment with a higher dose of calycosin tends to reduce migration and invasion capacity of human breast cancer cells, by targeting Foxp3-mediated VEGF and MMP-9 expression. PMID- 29241197 TI - Renoprotective Effects of Metformin. AB - BACKGROUND/AIMS: It has become clear that metformin exerts pleiotropic actions beyond its glucose-lowering agent effect. In this review, we summarise the state of the art concerning the potential renoprotective effects of metformin in vitro, animal models and clinical nephrology. METHODS: A literature search was performed in PUBMED, ScienceDirect, between January 1957 and March 2017 using the following keywords: "metformin," "nephroprotection," "renoprotection," "survival," "renal failure," "chronic kidney diseases," "fibrosis," "polycystic kidney disease" and "microalbuminuria." RESULTS: A recent review of 17 observational studies concluded that metformin use appeared associated with reduced all-cause mortality in patients with CKD. Metformin has been shown to exert positive effects on the kidney in vitro and animal models representing different types of renal diseases, from acute kidney injury to chronic kidney disease. A retrospective cohort study from the Scientific Registry of Transplant Recipients indicated that metformin was associated with lower adjusted hazards for living donor and deceased donor allograft survival at 3 years posttransplant, and with lower mortality. CONCLUSION: Based on experimental evidence and some relevant clinical observations, metformin seems to be a promising drug in the treatment of progressive renal damage. RCT studies are the next essential step. PMID- 29241198 TI - FAM3A Protects Against Glutamate-Induced Toxicity by Preserving Calcium Homeostasis in Differentiated PC12 Cells. AB - BACKGROUND/AIMS: Stroke is the leading cause of adult disability, and glutamate induced dysregulation of intracellular Ca2+ homeostasis is a key mechanism. FAM3A is the first member of the family with sequence similarity 3 (FAM3) gene family, and its biological function remains largely unknown. We have recently reported that FAM3A exerts protective effects against oxidative stress and mitochondrial dysfunction in HT22 cells. METHODS: Here, we investigated the protective effects of FAM3A using a glutamate-induced neuronal injury model in nerve growth factor (NGF)-differentiated PC12 cells. The protective effects were determined by measuring lactate dehydrogenase (LDH) release, apoptosis and mitochondrial oxidative stress. Ca2+ imaging was performed to detect changes in intracellular Ca2+ concentration in PC12 cells. The related molecular mechanisms were investigated by fluorescence staining, coimmunoprecipitation (Co-IP) and western blotting. RESULTS: Upregulation of FAM3A by lentivirus transfection markedly decreased LDH release, inhibited apoptosis and reduced mitochondrial oxidative stress, which were accompanied by alleviated intracellular Ca2+ levels as measured by calcium imaging. The results of western blotting showed that FAM3A significantly decreased the surface expression of metabotropic glutamate receptor 1/5 (mGluR1/5), with no effect on the expression of N-methyl-d-aspartic acid receptor (NMDAR) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunits. FAM3A overexpression also inhibited the intracellular Ca2+ release mediated by mGluR1/5 and inositol 1,4,5-trisphosphate receptor (IP3R), but not the ryanodine receptor (RyR). In addition, FAM3A significantly attenuated the store-operated calcium entry (SOCE) induced by thapsigargin (Tg), but the expression of SOCE-related proteins was not altered. The results of coimmunoprecipitation (Co-IP) showed that FAM3A disrupted the interaction of stromal interaction molecule 1 (STIM1) with Orai1 triggered by glutamate. CONCLUSION: These results suggest that the upregulation of FAM3A protects against glutamate-induced dysfunction of Ca2+ homeostasis not only by inhibiting mGluR1/5 dependent endoplasmic reticulum (ER) Ca2+ release, but also by attenuating SOCE mediated by the STIM1-Orai1 interaction. PMID- 29241200 TI - Atypical Hemolytic Uremic Syndrome Associated with Complement Factor H Mutation and IgA Nephropathy: A Case Report Successfully Treated with Eculizumab. AB - We present a rare case of IgA nephropathy in a patient who developed atypical hemolytic uremic syndrome (aHUS) associated with a complement factor H (CFH) gene mutation, and who was successfully treated with eculizmab. A 76-year-old man was admitted as the patients had thrombotic microangiopathies findings. The patient was treated with plasma exchange, hemodialysis and methylprednisolone. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 level was not decreased. Light microscopy findings were consistent with hemolytic uremic syndrome and immunofluorescence analysis revealed IgA and C3 were detected. Genetic analysis revealed that mutation of p.Arg1215Gln in CFH was identified. The diagnosis of aHUS was confirmed and eculizmab therapy was currently effective for 5 months. PMID- 29241199 TI - Change in Hemoglobin Trajectory and Darbepoetin Dose Approaching End-Stage Renal Disease: Data from the Trial to Reduce Cardiovascular Events with Aranesp Therapy Trial. AB - BACKGROUND: The pathogenesis of chronic kidney disease associated anemia is multifactorial and includes decreased production of erythropoietin (EPO), iron deficiency, inflammation, and EPO resistance. To better understand the trajectory of these parameters, we described temporal trends in hemoglobin (Hb), ferritin, transferrin saturation, C-reactive protein (CRP), and darbepoetin dosing in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT). METHODS: We performed a post hoc analysis of 4,038 participants in TREAT. Mixed effects linear regression models were used to determine the trajectory of parameters of interest prior to end-stage renal disease (ESRD). Likelihood ratio tests were used to determine the overall differences in biomarker values and differences in trajectories between those who did and did not develop ESRD. RESULTS: Hb declined precipitously in the year prior to the development of ESRD (irrespective of treatment assignment), and was on average 1.15 g/dL (95% CI -1.26 to -1.04) lower in those who developed ESRD versus those who did not, at the time of ESRD/end of follow-up. Simultaneously, the mean darbepoetin dose and CRP concentration increased, while serum ferritin and transferrin saturations were >140 MUg/L and 20%, respectively. CONCLUSIONS: Our analyses provide descriptive insights regarding the temporal changes of Hb, darbepoetin dose, and related parameters as ESRD approaches in participants of TREAT. Hb declined as much as 1-2 years prior to the development of ESRD, without biochemical evidence of iron deficiency. The most precipitous decline occurred in the months immediately prior to ESRD, despite administration of escalating doses of darbepoetin and in parallel with an increase in CRP. PMID- 29241201 TI - Cot Death: History of an Iatrogenic Disaster. AB - Since antiquity, cot death has been explained as accidental suffocation, overlaying, or smothering. Parents were blamed for neglect or drunkenness. A cage called arcuccio was invented around 1570 to protect the sleeping infant. Up to the 19th century, accidents were registered as natural causes of death. From 1830, accidental suffocation became unacceptable for physicians and legislators, and "natural" explanations for the catastrophe were sought, with parents being consoled rather than blamed. Two assumed causes had serious consequences: thymus hyperplasia was irradiated, causing thyroid cancer, and the concept of central apnea was widely accepted, which led to home monitors and distracted from epidemiological evidence. Prone sleeping originated in the 1930s and from 1944, it was associated with cot death. However, from the 1960s, many authors recommended prone sleeping for infants, and many countries adopted the advice. A worldwide epidemic followed, peaking at 20/00 in England and Wales and 50/00 in New Zealand in the 1980s. Although epidemiological evidence was available by 1970, the first intervention was initiated in the Netherlands in 1989. Cot death disappeared almost entirely wherever prone sleeping was avoided. This strongly supports the assumption that prone sleeping has the greatest influence on the disorder, and that the epidemic resulted from wrong advice. PMID- 29241202 TI - Ghrelin is Negatively Correlated with Iron in the Serum in Human and Mice. AB - BACKGROUND/AIMS: The studies in the patients with iron deficiency anemia (IDA) implied the existence of the association of ghrelin with iron or hepcidin levels in the plasma under the pathophysiological conditions. We hypothesized that fasting may be able to affect iron metabolism via ghrelin under the physiological conditions. METHODS: We investigated the effects of fasting on serum ghrelin and iron contents in healthy volunteers (23-31 years) and C57BL/6 male mice (8-week olds) under the physiological conditions. RESULTS: Fasting induced a significant elevation in both total ghrelin and acylated ghrelin and a reduction in iron levels in the serum of both human and mice. Correlation analysis demonstrated that total ghrelin or acylated ghrelin is negatively correlated with iron in the serum in human and mice. CONCLUSION: Ghrelin has a role to reduce serum iron under the conditions of fasting. PMID- 29241203 TI - Genome-Wide Transcriptome Analysis of Estrogen Receptor-Positive and Human Epithelial Growth Factor Receptor 2-Positive Breast Cancers by Ribonucleic Acid Sequencing. AB - AIM: The aim is to identify complex pathogenesis of breast cancer subtypes and disclose the whole landscape of altered transcriptional activities in these cancers. METHODS: We downloaded raw expression data from public database, and performed transcriptome analysis of 8 estrogen receptor-positive (ER+) breast cancer tissue samples, 8 human epithelial growth factor receptor 2-positive (HER2+) breast cancer tissue samples, and 3 normal breast tissues by identification, functional annotation, and prediction of upstream regulators and cell-surface biomarkers of differentially expressed genes (DEGs). RESULTS: We identified over 5,000 DEGs in each of ER+ and HER2+ breast cancers compared to normal tissues. Functional enrichment analysis of shared DEGs indicated significant changes in the regulation of immune -systems in the 2 subtypes. We further identified 1,871 DEGs between the 2 subtypes and disclosed great tumor heterogeneity. We identified 533 shared upregulated genes and predicted 17 upstream transcription factors, as well as identified differentially expressed cell-surface biomarkers for distinguishing our ER+ and HER2+ breast cancers. Further analysis also highlighted the limitation of the usage of HER2 alone in breast cancer classification. CONCLUSION: Our findings in ER+ and HER2+ breast cancers provided novel insights into heterogeneous transcriptional activities underlying complex mechanisms of oncogenesis in breast cancers. PMID- 29241204 TI - Achieve Your Goals Together. The Easy and Reasonable Way to Treat Chronic Kidney Disease-Mineral Bone Disorder. PMID- 29241205 TI - Glaucocalyxin B Alleviates Lipopolysaccharide-Induced Parkinson's Disease by Inhibiting TLR/NF-kappaB and Activating Nrf2/HO-1 Pathway. AB - BACKGROUND/AIMS: Parkinson's disease (PD) is a common neurodegenerative disease in the old population, characterized by dopaminergic neuron loss, inflammation and oxidative stress injury in the substantia nigra. Glaucocalyxin B (GLB), an ent-kauranoid diterpenoid isolated from Rabdosia japonica, has anti-inflammation and anti-tumor effects. However, its effects on PD remain unclear. METHODS: PD was introduced in rats via injection of lipopolysaccharide (LPS) into cerebral corpus striatum, and GLB was given intracerebroventricularly to these rats. Their walking, climbing and sensory states were detected by Stepping, Whisker and Cylinder Tests. The expression of tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), CD11b and ionized calcium binding adaptor molecule (IBA)-1 were detected by immunohischemical staining. The levels of a series of inflammatory factors, oxidative stress-related factors and apoptosis-related factors were measured by real-time PCR, immunoblotting and ELISA. In addition, Toll-like receptor (TLR)/nuclear factor kappa B (NF-kappaB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathways were investigated to illustrate the underlying mechanism. In vitro, microglial cells exposed to LPS were treated with GLB. RESULTS: The injection of LPS caused walking, climbing and sensory disturbances in rats, induced inflammation, oxidative stress response and apoptosis, and activated TLR/NF-kappaB and Nrf2/ HO 1 pathways in the cerebral tissue. GLB administration attenuated LPS-induced alterations. The TLR/NF-kappaB pathway was deactivated and Nrf2/HO-1 was activated after application of GLB. In vitro, cytotoxic effects induced by the conditioned medium derived from microglial cells exposed to LPS in PC12 cells were attenuated by GLB. CONCLUSION: GLB suppresses LPS-induced PD symptoms by modification of TLR/NF-kappaB and Nrf2/HO-1 pathways in vivo and in vitro. PMID- 29241206 TI - A Multicenter Experience with Long-Acting Somatostatin Analogues in Patients with Congenital Hyperinsulinism. AB - BACKGROUND/AIMS: Congenital hyperinsulinism (CHI) is a rare disease characterized by recurrent severe hypoglycemia. In the diffuse form of CHI, pharmacotherapy is the preferred choice of treatment. Long-acting somatostatin analogues have been used in children as off-label medication. However, the efficacy, outcomes, and adverse effect profiles of long-acting somatostatin analogues have not been described in multicentered studies. The aim of this retrospective study is to summarize the experience with long-acting somatostatin analogues in a large group of children with CHI. METHODS: Data were obtained retrospectively from 27 patients with CHI who received long-acting somatostatin analogues in 6 different centers in Europe. These included information on glycemic stability, auxology, and adverse effect profile in clinical follow-up assessments. RESULTS: Blood glucose control improved in most patients (89%). No life-threatening side effects occurred. Thirteen patients (48%) experienced side effects; in 3 patients (11%), the side effects were the main reason for discontinuation of the treatment. The most frequent side effect was elevated liver enzymes (n = 10, 37%). CONCLUSION: Long-acting somatostatin analogues are effective in glycemic control of patients with CHI. However, in 37% of all patients increased liver enzymes were observed. It is important to monitor liver function in all patients receiving long-acting somatostatin analogue therapy. PMID- 29241207 TI - Disease Remission in Children and Adolescents with Intermediate Uveitis: A Survival Analysis. AB - PURPOSE: To report the incidence rate (IR) of remission in pediatric noninfectious intermediate uveitis (IU). METHODS: Longitudinal retrospective cohort study, including 19 patients (32 eyes) between 1985 and 2014, followed-up until loss or January 2016. Remission was defined following the Standardization of Uveitis Nomenclature workshop criteria, prolonged remission as a remission spanning 12 months and until the end of follow-up, and relapse as recurrence of inflammatory activity in an eye in remission. RESULTS: Median follow-up time was 6.3 years. IRs (95% confidence interval) for remission, relapse, and prolonged remission were 18.6 (13.1-26.5), 32.3 (20.6-50.7), and 6.7 (3.8-11.9) episodes per 100 eye-years, respectively. 48% of eyes relapsed in the first year following remission. 25 and 50% of eyes achieved prolonged remission after 5 and 10 years of follow-up, respectively. CONCLUSIONS: Inflammatory relapses may be frequent in noninfectious IU affecting children and adolescents, appearing early after remission. Also, prolonged remission seems infrequent, being achieved late during follow-up. PMID- 29241209 TI - Lateral Medullary Infarction Caused by Oriental Acupuncture. PMID- 29241208 TI - Exosomes from MiR-126-Overexpressing Adscs Are Therapeutic in Relieving Acute Myocardial Ischaemic Injury. AB - BACKGROUND/AIMS: Recent studies have indicated that exosomes play an important role in adipose-derived stem cell (ADSC) transplant-mediated ischaemic heart disease therapy. However, the treatment effect is not obvious. The aim of this study is to investigate whether ADSC-derived exosomes enriched with microRNA (miR)-126 have a more protective effect on acute myocardial infarction (AMI). METHODS: Exosomes were characterized by transmission electron microscopy, and the exosome particles were further examined using nanoparticle tracking analyses. A rat model of myocardial infarction and in vitro model of hypoxia-induced H9c2 myocardial cell injury were established to study the protective mechanism of exosomes from miR-126-overexpressing ADSCs. RESULTS: The in vitro results showed that exosomes derived from miR-126-overexpressing ADSCs decreased H9c2 myocardial cell injury by reducing inflammation factor expression during hypoxia induction. The miR-126-enriched exosomes also decreased the expression of fibrosis-related proteins of H9c2 cells under hypoxic conditions. Matrigel(r) and Transwell(r) assays showed that miR-126-enriched exosomes significantly promoted microvascular generation and migration, respectively. In vivo studies confirmed that exosomes derived from ADSCs significantly decreased the myocardial injury area of infarction, especially after miR-126-enriched exosome treatment. Cardiac fibrosis and inflammatory cytokine expression were also decreased after treatment with miR 126-enriched exosomes. However, blood vessel formation was promoted in the infarction region of AMI rats. CONCLUSIONS: The results suggested that the expression of miR-126-enhanced ADSC-derived exosomes prevented myocardial damage by protecting myocardial cells from apoptosis, inflammation, fibrosis, and increased angiogenesis. PMID- 29241210 TI - Combination Cyclophosphamide/Glucocorticoids Provide Better Tolerability and Outcomes versus Glucocorticoids Alone in Patients with Sjogren's Associated Chronic Interstitial Nephritis. AB - BACKGROUND: Steroid therapy has become an effective option for patients with primary Sjogren's syndrome with tubulointerstitial nephritis (TIN), while the use of cytotoxic agents is still debated. Our study aimed to compare the clinical outcomes of patients treated with cyclophosphamide (CTX) combined with glucocorticoids with those of patients treated with glucocorticoids alone. METHODS: All patients with primary Sjogren's syndrome with chronic TIN admitted to the Division of Nephrology, Ruijin Hospital, from January 1, 2002, to April 30, 2016, and treated with steroids alone or combined with CTX were included. The immunological prognosis, improvements of renal function, and acquired tubular defects of the patients were retrospectively compared between the 2 therapeutic groups. RESULTS: A total of 70 cases were included. Of these, 36 were diagnosed by renal biopsy. A total of 56 patients were treated with glucocorticoids alone, while 14 patients received glucocorticoids combined with CTX. There were no significant differences in clinical characteristics and laboratory parameters between the 2 therapeutic groups at baseline. Compared with patients in the steroid group, patients in the CTX group showed better estimated glomerular filtration rate (eGFR) improvement (21.35 +/- 19.63 vs. 2.72 +/- 19.11 mL/min/1.73 m2, p = 0.006) but a similar decline in immunoglobulin G (IgG; 450 [interquartile range, IQR 910] vs.176 [IQR 1,910] mg/dL, p = 0.93) at 12 months of follow-up. CTX therapy was associated with better eGFR improvement (beta = 12.96 [2.95-22.97]) even after adjusting for dry mouth, anti-Sjogren's-syndrome related antigen A and anti-Sjogren's-syndrome-related antigen B positivity, hemoglobin, initial steroid dose, and baseline eGFR by linear regression analyses. Subgroup analyses revealed that the beneficial effects of CTX therapy on renal function were only observed in patients with baseline IgG >=1,560 mg/dL or eGFR <90 mL/min/1.73 m2. The urine alpha1-microglobulin improvement was better in the CTX group than in the steroid group at 12 months of follow-up (beta = 1.29, 95% CI 0.56-2.02, p = 0.001). CONCLUSIONS: CTX therapy is suggested for primary Sjogren's syndrome patients with chronic TIN, especially those with higher IgG levels and abnormal renal function at baseline. PMID- 29241211 TI - The Role of Pannexin3-Modified Human Dental Pulp-Derived Mesenchymal Stromal Cells in Repairing Rat Cranial Critical-Sized Bone Defects. AB - BACKGROUND/AIMS: Human dental pulp-derived mesenchymal stromal cells (hDPSCs) are promising seed cells for tissue engineering due to their easy accessibility and multi-lineage differentiation. Pannexin3 (Panx3) plays crucial roles during bone development and differentiation. The aim of the present study was to investigate the effect of Panx3 on osteogenesis of hDPSCs and the underlying mechanism. METHODS: Utilizing qRT-PCR, Western blot, and immunohistochemistry, we explored the change of Panx3 during osteogenic differentiation of hDPSCs. Next, hDPSCs with loss (Panx3 knockdown) and gain (Panx3 overexpression) of Panx3 function were developed to investigate the effects of Panx3 on osteogenic differentiation of hDPSC and the underlying mechanism. Finally, a commercial beta-TCP scaffold carrying Panx3-modified hDPSCs was utilized to evaluate bone defect repair. RESULTS: Panx3 was upregulated during osteogenic differentiation in a time dependent manner. Panx3 overexpression promoted osteogenic differentiation of hDPSCs, whereas depletion of Panx3 resulted in a decline of differentiation, evidenced by upregulated expression of mineralization-related markers, increased alkaline phosphatase (ALP) activity, and enhanced ALP and Alizarin red staining. Panx3 was found to interact with the Wnt/beta-catenin signaling pathway, forming a negative feedback loop. However, Wnt/beta-catenin did not contribute to enhancement of osteogenic differentiation as observed in Panx3 overexpression. Moreover, Panx3 promoted osteogenic differentiation of hDPSCs via increasing ERK signaling pathway. Micro-CT and histological staining results showed that Panx3 modified hDPSCs significantly improved ossification of critical-sized bone defects. CONCLUSION: These findings suggest that Panx3 is a crucial modulator of hDPSCs differentiation. PMID- 29241212 TI - Serum Magnesium Abnormality and Influencing Factors of Serum Magnesium Level in Peritoneal Dialysis Patients: A Single-Center Study in Northern China. AB - BACKGROUND/AIMS: Both hypomagnesemia and hypermagnesemia have been associated with cardiovascular diseases, bone diseases, and mortality in dialysis patients. We aimed to investigate the prevalence of and influencing factors for abnormal serum Mg levels in patients on peritoneal dialysis (PD). METHODS: A cross sectional study in Peking University People's Hospital recorded the demographic information, clinical characteristics, and laboratory data. Data were assessed and compared with the results from 2 other studies in China. RESULTS: Of 180 enrolled PD patients, the primary diseases were glomerulonephritis (38.3%) and diabetic nephropathy (38.3%). Mean serum Mg concentration was 1.02 +/- 0.16 mmol/L; 67% had normal serum Mg concentrations, and 33% had hypermagnesemia. CONCLUSIONS: Hypermagnesemia is likely to occur in patients with higher serum phosphate, lower intact parathyroid hormone, and lower high-sensitivity C reactive protein levels. Serum Mg level distributions in PD patients vary throughout China, may have different potential causes (such as geographical location and dietary habits) and should be further studied. PMID- 29241214 TI - Nasalance Variability in 3- to 5-Year-Old Children during Production of Speech Stimulus in Three Vowel Contexts. AB - OBJECTIVE: The purpose of this study was to determine whether age and vowel contexts influence test-retest nasalance score variability in typically developing Korean children. PARTICIPANTS: Forty-five 3- to 5-year-old children with normal speech and resonance participated in the study. METHODS: All subjects were asked to repeat three 4-syllable speech stimuli in high, low, or mixed vowel contexts twice after the examiner. An immediate test-retest nasalance score was assessed with no headgear change. Test and retest variability in nasalance scores was examined based on the absolute difference in nasalance scores of the first and second repetition for each stimulus. RESULTS: A significant main effect of the vowel context on variability in nasalance scores was found, but the effect of age on nasalance variability was not significant. Mean absolute difference in nasalance scores for the stimuli in the high vowel contexts was significantly greater than for the stimuli in the low and mixed vowel contexts. CONCLUSIONS: The results suggested that variability in nasalance scores might not decrease with age and tend to show considerable individual variations. Increased variability in nasalance scores in the high vowel context might be associated with aerodynamic and acoustic characteristics resulting from physiological aspects of the vowel /i/. PMID- 29241213 TI - Antibiotics-Induced Obesity: A Mitochondrial Perspective. AB - Antibiotics are the first line of treatment against infections and have contributed immensely to reduce the morbidity and mortality rates. Recently, extensive use of antibiotics has led to alterations of the gut microbiome, predisposition to various diseases and most importantly, increase in the emergence of antibiotic-resistant bacteria, which poses a major threat to global public health. Another major issue faced worldwide due to unregulated use of antibiotics in children as well as in adults is the influence of metabolism and body weight homeostasis, leading to obesity. Apart from the involvement of biosocial causes influencing diet, physical activity, and antibiotic use, pathogenesis of obesity is linked to interconnected functional alterations in cells, tissues and organs due to biochemical, epigenetic and genetic factors. Mitochondrial dysfunction is one such factor, which is becoming the primary focus of various aspects of research on multifactorial complex diseases and is providing new perspectives on etiology, biomarker-based diagnosis, and drug sensitivity. Through this review, we have made an attempt to present the interplay between use of antibiotics, obesity, and associated mitochondrial dysfunction. This may provide insights into the molecular basis, genetic predisposition and environmental triggers, which in turn may have potential clinical applications in the management of antibiotic use. PMID- 29241215 TI - Erratum. PMID- 29241216 TI - Melanoma Screening. PMID- 29241217 TI - Multinodular and Vacuolating Neuronal Tumor of the Cerebrum: A Benign Nonaggressive Cerebral Lesion. PMID- 29241218 TI - Analysis of the Cariogenic Potential of Various Almond Milk Beverages using a Streptococcus mutans Biofilm Model in vitro. AB - To evaluate the cariogenic properties of almond milk beverages, 6 almond milks, along with soy and whole bovine milk, were analyzed for their abilities to support Streptococcus mutans biofilm formation and acid production, and their capacity to buffer changes in pH. Biofilm formation by S. mutans was analyzed using an in vitro 96-well plate model and measured by crystal violet staining. Acid production by S. mutans was evaluated by a colorimetric L-lactate assay and pH measurement of bacterial cultures. Buffering capacity was assessed by a pH titration assay. Soy milk supported the most biofilm growth, while the least was observed with unsweetened almond milk (both p < 0.001). Among almond milks, sucrose-sweetened milk led to the highest level of biofilm formation (p < 0.001), while the least was observed with unsweetened milk (p < 0.05). Sucrose-sweetened almond milk yielded the lowest pH (4.56 +/- 0.66), followed by soy milk and bovine milk; the highest pH was with unsweetened almond milk (6.48 +/- 0.5). When analyzed by pH titration, the unsweetened almond milk displayed the weakest buffering capacity while bovine milk showed the highest (p < 0.001). These results suggest that the almond milk beverages, except those that are sweetened with sucrose, possess limited cariogenic properties, while soy milk exhibits the most cariogenic potential. As milk alternatives become increasingly popular, dentists must counsel their patients that almond milks, especially sucrose sweetened varieties, have cariogenic potential. For patients who are lactose intolerant or suffer from milk allergy, almond milks may be a better alternative than soy-based products. PMID- 29241219 TI - YAP Inhibits the Apoptosis and Migration of Human Rectal Cancer Cells via Suppression of JNK-Drp1-Mitochondrial Fission-HtrA2/Omi Pathways. AB - BACKGROUND/AIMS: The Hippo-Yap pathway is associated with tumor development and progression. However, little evidence is available concerning its role in cancer cell apoptosis and migration via mitochondrial homeostasis. Here, we identify mitochondrial fission as a regulator of the Hippo-Yap pathway in human rectal cancer tumorigenesis and metastasis. METHODS: In this study, we performed loss-of function assays concerning Yap in RCC via shRNA. Cellular viability and apoptosis were measured via MTT, the TUNEL assay and trypan blue staining. Mitochondrial function was assessed via JC1 staining, the mPTP opening assay, mitochondrial respiratory function analysis, electron microscopy and immunofluorescence analysis of HtrA2/Omi. Mitophagy and mitochondrial fission were assessed via western blots and immunofluorescence. Cell migration was evaluated via the Transwell assay, wound-healing assay and immunofluorescence analysis of F-actin. The interaction between JNK and Yap was detected via co-immunoprecipitation and Yap recombinant mutagenic plasmid transfection. Western blots were used to analyze signaling pathways in conjunction with JNK inhibitors or HtrA2/Omi siRNA. RESULTS: Yap is upregulated in human rectal cancer cells, where its expression correlates positively with cell survival and migration. Functional studies established that silencing of Yap drove JNK phosphorylation, which induced Drp1 activation and translocation to the surface of mitochondria, initiating mitochondrial fission. Excessive mitochondrial fission mediated HtrA2/Omi leakage from the mitochondria into the cytoplasm, where HtrA2/Omi triggered cellular apoptosis via the mitochondrial apoptosis pathway. Moreover, released HtrA2/Omi also phosphorylated cofilin and inhibited cofilin-mediated F-actin polymerization. F-actin collapse perturbed lamellipodia formation and therefore impaired cellular migration and invasion. CONCLUSION: Collectively, our results demonstrate that Hippo-Yap can serve as a tumor promoter in human rectal cancer and acts by restricting JNK/Drp1/mitochondrial fission/ HtrA2/Omi, with potential implications for new approaches to human rectal cancer therapy. PMID- 29241220 TI - High-Risk Human Papillomavirus in Oral Cancer: Clinical Implications. AB - Oral cancer is the eleventh most common cancer globally, with well-established major risk factors of tobacco, areca nut, alcohol, and high-risk human papillomavirus (HR-HPV) types 16 and 18. HR-HPV16/18 are the etiologic agents of cervical cancers and a proportion of oropharyngeal cancers. HPV-associated oropharyngeal and oral cancers show better prognosis and response to therapy. However, the picture of HR-HPV16/18 and the clinical implications of oral cancers are not clear with the majority of reports combining oral cancer data with head and neck cancers. The current review compiles the global prevalence of HR HPV16/18 in oral cancers, highlighting the unique clinical and molecular pathologic features, prognosis and therapeutic strategies in the prevention and management of HPV-positive oral cancers. The potential for the use of de intensified therapy and prophylactic prevention in HPV-positive oral cancer patients is highlighted. PMID- 29241221 TI - Diagnosis, Risk Assessment, and Treatment Decisions for Occlusal Caries: A Survey from the Danish Public Dental Health Service. AB - This study validates a case-based survey method and analyzes the extent to which Danish dental professionals apply current concepts and strategies for occlusal caries management in children, adolescents, and young adults. A case-based, precoded questionnaire consisting of 10 clinical cases/patients with 26 teeth/occlusal surfaces was developed. The cases were set up in a PowerPoint presentation and color printed as a booklet illustrating patients with different patterns of caries activity, severity, and risk. A total of 69 dental professionals participated. Content and face validity of the survey method was established using a panel of experts. The panel also assessed the reliability of the method using a test-retest procedure (kappa >= 0.80) and acting as benchmark. Measurements of agreement between dental professional and benchmark assessments showed substantial agreement for overall caries activity and risk assessment of patients and for clinical and radiographic severity of occlusal lesions (kappa = 0.61-0.67). For assessment of caries lesion activity on occlusal surfaces, the agreement was moderate (kappa = 0.50). Regarding treatment decisions, dental professionals showed substantial agreement when indicating restorative treatments (kappa = 0.68). Multivariate logistic regression analysis showed a significant influence of various patient-, lesion-, and participant-related variables in the assessment of caries risk, caries activity and severity, and treatment decision. In conclusion, Danish dental professionals participating in the study apply reasonably well current concepts on overall caries activity and risk assessment, clinical and radiographic severity of occlusal lesions, and, to a certain extent, assessment of caries lesion activity on occlusal surfaces. Nonoperative treatment decisions had a high priority among Danish professionals. PMID- 29241223 TI - Tumour sidedness and intrinsic subtypes in patients with stage II/III colon cancer: analysis of NSABP C-07 (NRG Oncology). AB - BACKGROUND: We tested the association of colon tumour sidedness with prognosis and with molecular subtypes recently shown to be predictive of oxaliplatin benefit in stage III colon cancer. METHODS: NSABP/NRG C-07 trial (N=1603) was used to determine association of tumour sidedness with molecular subtypes and recurrence-free survival (RFS) and overall survival (OS). RESULTS: Sidedness was associated with molecular subtypes except stem-like/CMS4 subtype. Patients with stage III, left-sided tumours showed superior OS but not RFS. Sidedness was not associated with prediction of oxaliplatin benefit when combined with 5-Fu+LV. However, greater benefit from oxaliplatin was observed in a small subset of stage III patients with left-sided, enterocyte-subtype tumours (interaction HR=0.17, P=0.01). CONCLUSIONS: Sidedness was associated with molecular subtypes and was predictive of OS in stage III colon cancer but was not predictive of RFS or oxaliplatin benefit in C-07. Molecular subtypes may provide more predictive value for oxaliplatin benefit than tumour sidedness. PMID- 29241222 TI - Flavopiridol enhances ABT-199 sensitivity in unfavourable-risk multiple myeloma cells in vitro and in vivo. AB - BACKGROUND: The BCL-2-specific BH3-mimetic ABT-199 (venetoclax) has been reported to be principally active against favourable-risk multiple myeloma (MM) cells, prompting efforts to extend its activity to include more resistant, higher-risk MM subsets. METHODS: Effects of the CDK9 inhibitor flavopiridol (FP; alvocidib) on responses to ABT-199 were examined in MM cells. Cell death and protein expression were evaluated by western blot and immunofluorescence. Xenograft models were used to study combination effects in vivo. RESULTS: FP synergistically increased ABT-199 lethality in both ABT-199-sensitive and insensitive MM cells. FP blocked CDK9 activation/positive transcription elongation factor B phosphorylation, downregulated MCL-1, increased BCL-2/MCL-1 ratios, and upregulated BIM. MCL-1 ectopic expression or knockdown in MM cells significantly diminished or increased ABT-199 sensitivity, respectively. CDK9 knockdown triggered MCL-1 downregulation and increased ABT-199 activity, whereas BIM knockdown significantly reduced FP/ABT-199 lethality. FP also enhanced ABT 199 lethality in unfavourable prognosis primary MM cells. HS-5 cell co-culture failed to protect MM cells from the FP/ABT-199 regimen, suggesting circumvention of microenvironmental signals. Finally, FP/ABT-199 significantly increased survival in systemic xenograft and immune-competent MM models while exhibiting minimal toxicity. CONCLUSIONS: These findings argue that CDK9 inhibitors, for example, FP may increase the antimyeloma activity of ABT-199, including in unfavourable-risk MM minimally responsive to ABT-199 alone. PMID- 29241229 TI - Back to the future: occupational diver training in Australia. AB - The Australian Diver Accreditation Scheme (ADAS) had its genesis in the 1990s in response to a need to produce occupational divers who were trained to international standards with the necessary skills to safely undertake complex work in high-risk environments. Well-trained dive teams who are 'fit-for-purpose' can be regarded as the highest level of risk control in preventing accidents and workplace morbidity. Without such training, work site risks are not detected, with potentially disastrous consequences. In September 2017, the only civilian ADAS level 3 and 4 training facility in Australia, The Underwater Centre Tasmania (TUCT), closed its doors. The reasons for TUCT closure were multifactorial. However, the loss of higher level training capability in this country and its benefits to industry will have a future adverse impact. As industry pushes for more complex diving to improve productivity, Australian occupational diver training processes are becoming 'streamlined' and are losing parity with international benchmarks. This is a potentially fatal combination. PMID- 29241230 TI - Influence of repetitive diving in saltwater on pressure equalization and Eustachian tube function in recreational scuba divers. AB - INTRODUCTION: We investigated in a prospective, observational trial the feasibility of using the Eustachian tube function test (ETFT) to measure the effect of repetitive pressure exposure during open seawater dives on Eustachian tube function. METHODS: The study included 28 adult divers during six consecutive days of diving in the Red Sea. Participants underwent otoscopy and ETFT before the first dive, between each dive and after the last dive. ETFT included regular tympanometry (R-tymp), tympanometry after Valsalva (V-tymp) and after swallowing (S-tymp). The R-tymp was obtained as 'baseline' peak pressure. After a Valsalva, the peak pressure should shift (positively), revealing a positive shift of the tympanic membrane. This pressure shift is defined here as R-VdP. The changes in compliance and peak pressure were recorded and correlated with otoscopic findings and diving experience. Middle ear barotrauma was scored using the Edmonds modified TEED scale. RESULTS: The 28 participants performed 437 dives. Positive shift of pressure in the middle ear was evident with significant changes from day one to day three (P < 0.0001). Divers with barotrauma showed significantly lower values of R-tymp peak pressure and significantly higher negative R-VdP, compared to divers with normal otoscopic findings (P < 0.05). Diving experience significantly correlated with R-tymp peak pressure and prevalence of middle ear barotrauma. CONCLUSION: Significant changes in middle ear pressure and pressure equalization from repeated pressure exposure in saltwater were seen using ETFT. Repetitive, multi-day diving led to significantly decreased compliance and increased R-tymp peak pressure (overpressure) in the middle ear. Most profound changes were observed in less and intermediate experienced divers. PMID- 29241232 TI - Thromboelastographic assessment of the impact of mexiletine on coagulation abnormalities induced by air or normal saline intravenous injections in conscious rats. AB - BACKGROUND: Thromboelastography (TEG) in venous air embolism (VAE) has been poorly studied. We induced coagulation abnormalities by VAE in a rat model, assessed by TEG with and without mexiletine, a lidocaine analogue local anesthetic. METHODS: Twenty-three Sprague Dawley rats instrumented under isoflurane anesthesia and allowed to recover five days prior to the experiments were randomized into three experimental groups: 1) VAE (n = 6); 2) VAE and mexiletine (n = 9); and 3) normal saline (NS) alone (control group, n = 8). Blood samples were collected at baseline, one hour (h) and 24 h in all groups and analyzed by TEG to record the R, K, angle alpha and MA parameters. RESULTS: In Group 1, VAE decreased significantly R at 1 h (31%), K at 1 h (59%) and 24 h (34%); alpha increased significantly at 1 h (30%) and 24 h (22%). While R returned to baseline values within 24 h, K, MA and alpha did not. In group-2 (Mexiletine + VAE), K and R decreased at 1 h (48% and 29%, respectively) and at 24 h the changes were non-significant. Angle alpha increased at 1 h (28%) and remained increased for 24 h (25%). In group 3 (NS), only R was temporarily affected. MA increased significantly at 24 h only in the VAE alone group. CONCLUSION: As expected, VAE produced a consistent and significant hypercoagulable response diagnosed/confirmed by TEG. Mexiletine prevented the MA elevation seen with VAE and corrected R and K time at 24 h, whereas angle alpha remained unchanged. Mexiletine seemed to attenuate the hypercoagulability associated with VAE in this experiment. These results may have potential clinical applications and deserve further investigation. PMID- 29241231 TI - Influence of repetitive diving in freshwater on pressure equalization and Eustachian tube function in recreational scuba divers. AB - INTRODUCTION: We investigated the effect of repetitive pressure exposure during freshwater dives on Eustachian tube function and the middle ear, assessed by the Eustachian tube function test (ETFT). METHODS: This prospective observational cohort study included 23 divers over three consecutive days of diving in freshwater lakes in Nordhausen, Germany. Participants underwent otoscopy and ETFT before the first dive, between each dive and after the last dive. ETFT included regular tympanometry (R-tymp), tympanometry after Valsalva (V-tymp) and after swallowing (S-tymp). The peak pressure difference between the R-tymp and the V tymp (R-VdP) defined effectiveness of pressure equalization after Valsalva manoeuvres. We evaluated the change in compliance and peak pressure and correlated the results to the otoscopic findings and diving experience. RESULTS: Twenty-three divers performed 144 dives. Middle ear barotrauma was assessed using the Edmonds modification of the TEED scoring system. In the ETFT, the R-tymp peak pressure displayed a negative shift from day one to three (P = 0.001) and differed significantly between the experience groups (P = 0.01). R-VdP did not change significantly on any of the three days of diving (all P > 0.05). Participants without MEBt showed significantly lower R-tymp values than did those with barotrauma (P = 0.019). CONCLUSION: Repetitive pressure exposure during three consecutive days of freshwater diving led to a negative shift of the peak pressure in the middle ear. Less experienced divers showed significantly higher middle ear peak pressure and higher pressure differences after equalization manoeuvres. Higher middle ear peak pressure was also associated with a higher prevalence of barotrauma. PMID- 29241233 TI - Hyperbaric oxygen in the treatment of acute retinal artery occlusion. AB - INTRODUCTION: Acute retinal artery occlusion (ARAO) is a major cause of sudden, painless visual loss, often leaving no useful vision in the affected eye. Its incidence is cited at 0.85 per 100,000 persons per year but may be higher because of under-reporting. The natural history is difficult to study, but a spontaneous resolution rate of < 1-8% for acute, non-arteritic ARAO has been cited. Occurrence in an only eye is devastating for the patient. There is currently no consensus regarding management of ARAO and little evidence to support any treatment modality. Despite only limited case series, hyperbaric oxygen treatment (HBOT) is recommended for ARAO by the Undersea and Hyperbaric Medical Society (UHMS) and by the European Committee for Hyperbaric Medicine. METHODS: Between early 2003 and December 2012, all ARAO patients presenting to Christchurch Hospital were referred for consideration of HBOT. These 31 consecutive patients' medical records were reviewed retrospectively. The time delay from onset of visual loss to commencing HBOT; the presenting visual acuity; various demographic data; the HBOT administered and the outcome visual acuity were documented. RESULTS: All 31 patients underwent at least one HBOT (median 4, range 1-7) at a pressure of 203-284 kPa for 1.5 to 2.0 h. One patient's treatment was terminated after 60 min at their request; another declined further HBOT and one suffered middle ear barotrauma. Thirteen patients also received anticoagulants at the discretion of the referring ophthalmologist. Twenty three patients had temporarily improved vision with the first HBOT. Seven patients had permanent, good visual recovery (6/18 or better; Snellen chart); and two only modest improvement (6/60). All nine patients who improved permanently were treated within 10 hours of symptom onset. CONCLUSIONS: Where available, HBOT is indicated for ARAO. Our protocol may not have been aggressive enough and the UHMS protocol is recommended. A multi-centre, randomised controlled trial is feasible, but would be logistically difficult and expensive and may be ethically unsupportable given the lack of alternative, effective treatments. PMID- 29241234 TI - Lost at sea: the medicine, physiology and psychology of prolonged immersion. AB - In most countries, immersion represents the second most common cause of accidental death in children and the third in adults. Between 2010 and 2013, 561 deaths worldwide involving recreational divers were recorded by the Divers Alert Network. Consequently, there is no room for complacency when diving. Being lost at sea is a diver's worst nightmare. In 2006, a diver was lost at sea off the coast of New Zealand for 75 hours. It is unprecedented that, after such a long time immersed in temperate (16-17 degrees C) waters, he was found and survived. His case is presented and utilised to illustrate the many physiological and psychological factors involved in prolonged immersion and what might determine survival under such circumstances. We also briefly review options for enhancing diver location at sea and a few issues related to search and rescue operations are discussed. PMID- 29241235 TI - Personality and behavioural outcomes in diving: current status and recommendations for future research. AB - This paper provides a brief overview of the shift from studies describing the personality profiles of divers to studies exploring associations between personality variables and diving performance in terms of behavioural outcomes. The personality associations that were investigated include performance during training, panic proneness, diving injuries, susceptibility to inert gas narcosis, and the behaviour of tourist divers. The paper concludes with a number of suggested directions for further research on personality and diving that may provide tangible benefits in terms of both enhanced safety and improved performance underwater. PMID- 29241236 TI - Diving and antidepressants. AB - Psychoactive drugs pose a risk to both the diver and his or her buddy. Little is known about the safety of diving with antidepressants. Amongst the potential interactions with the diving environment are: somnolence; convulsions; a bleeding tendency (potentially worsening decompression illness, DCI), alterations to glucose metabolism and psychiatric side effects. Fluoxetine may potentially reduce the inflammatory process associated with DCI. This article presents guidelines for recreational diving in combination with antidepressants. These guidelines were endorsed at a meeting of the Dutch Association for Diving Medicine in 2015 and are solely based on 'expert' opinion. PMID- 29241237 TI - Delayed hyperbaric intervention in life-threatening decompression illness. AB - Arterial gas embolism is a catastrophic event. Bubbles in the arterial circulation may lodge in the brain and cause infarction in the affected area and/or in a coronary vessel causing acute myocardial ischaemia. There is no well defined window of time beyond which a response to hyperbaric oxygen is not expected. Major improvement may occur if the patient is treated as soon as possible, but is less likely in divers with severe decompression illness who have delayed intervention. We report on a 51-year-old, male rebreather diver who suffered loss of consciousness and cardiovascular collapse within minutes of a 30 metre deep dive at a remote Micronesian dive site. Recompression treatment did not start for six days for reasons to be presented, during which time he remained deeply comatose, cardiovascularly unstable and intubated on ventilator support. Despite this, following aggressive hyperbaric treatment over many days he made a functional recovery. At one year post injury, he is leading a functional life but has not returned to his previous occupation as a diver and suffers from moderately severe tinnitus and impaired right ear hearing and occasional mild speech problems. He is undertaking a number of on-line courses with a view to re employment. PMID- 29241238 TI - Hyperbaric oxygen-associated seizure leading to stroke. AB - Oxygen toxicity seizures are a well-known complication of hyperbaric oxygen treatment (HBOT). Until now, there have not been any reported cases of an acute ischaemic event (stroke) as the result of a HBOT-associated oxygen toxicity seizure. We report an event in which a seizure and stroke occurred together and consider that the stroke may have been caused by seizure-induced demand ischaemia. This challenges the generally held view that oxygen toxicity seizures in the clinical hyperbaric setting are benign. A discussion of the literature on the subject of seizure-induced brain injury is included. Risk factors for cerebrovascular disease should be taken into consideration in determining treatment pressures for HBOT, as reducing pressure reduces seizure risk. PMID- 29241239 TI - A New EHR Training Curriculum and Assessment for Pediatric Residents. AB - Background Conventional classroom Electronic Health Record (EHR) training is often insufficient for new EHR users. Studies suggest that enhanced training with a hands-on approach and closely supported clinical use is beneficial.Objectives Our goals were to develop an enhanced EHR learning curriculum for Post Graduate Year 1 (PGY1) residents and measure changes in EHR skill proficiency, efficiency, and self-efficacy.Methods A novel three-phase, multimodal enhanced EHR curriculum was designed for a cohort of PGY1 residents. After basic training, residents began phase 1 of enhanced training, including demonstrations, live practice, and order set review. Phase 2 involved skills-oriented assignments, role playing, and medication entry. Phase 3 included shadowing, scribing histories, and supervised order entry. Residents' EHR skills and attitudes were measured and compared before and after the enhanced curriculum via proficiency test and a survey of efficiency and self-efficacy.Results Nineteen of 26 PGY1 residents participated in the study (73%). There was significant improvement in mean proficiency scores and two of the five individual proficiency scores. There were significant improvements in most efficiency survey responses from pre- to postintervention. For the self-efficacy presurvey, many PGY1s reported to be "very" or "somewhat confident" performing each of the five tasks, and perceptions did not improve or worsened on most postsurvey responses. The greatest resource was the time required to design and deliver the enhanced training.Conclusion An enhanced training curriculum along with a proficiency assessment was developed and described here. An enhanced training curriculum significantly improved PGY1 EHR efficiency and some measures of proficiency but not self-efficacy. This intervention may support improved EHR-related clinic workflows, which ultimately could enable residents and preceptors to prioritize patient care and time for clinical education. PMID- 29241240 TI - Clinical Practice Informs Secure Messaging Benefits and Best Practices. AB - Background Clinical care team members in Department of Veterans' Affairs (VA) facilities nationwide are working to integrate the use of Secure Messaging (SM) into care delivery and identify innovative uses. Identifying best practices for proactive use of SM is a key factor in its successful implementation and sustained use by VA clinical care team members and veterans.Objectives A collaborative project solicited input from VA clinical care teams about their local practices using SM to provide access to proactive patient-centered care for veterans and enhance workflow.Methods This project implemented a single-item cross-sectional qualitative electronic survey via internal e-mail to local coordinators in all 23 Veterans Integrated Service Networks (VISNs). Content analysis was used to manage descriptive data responses. Descriptive statistics described sample characteristics.Results VA clinical care team members across 15 of 23 VISNs responded to the questionnaire. Content analysis of 171 responses produced two global domains: (1) benefits of SM and (2) SM best practices. Benefits of SM use emphasize enhanced and efficient communication and increased access to care. Care team members incorporate SM into their daily clinical practices, using it to provide services before, during, and after clinical encounters as a best practice. SM users suggest improvements in veteran care, clinical team workflow, and efficient use of health resources. Clinical team members invested in the successful implementation of SM integrate SM into their daily practices to provide meaningful and useful veteran-centered care and improve workflow.Conclusion VA clinical care team members can use SM proactively to create an integrated SM culture. With adequate knowledge and motivation to proactively use this technology, all clinical team members within the VA system can replicate best practices shared by other clinical care teams to generate meaningful and useful interactions with SM to enrich veterans' health care experience. PMID- 29241241 TI - Quantifying the Effect of Data Quality on the Validity of an eMeasure. AB - Objective The objective of this study was to demonstrate the utility of a healthcare data quality framework by using it to measure the impact of synthetic data quality issues on the validity of an eMeasure (CMS178-urinary catheter removal after surgery).Methods Data quality issues were artificially created by systematically degrading the underlying quality of EHR data using two methods: independent and correlated degradation. A linear model that describes the change in the events included in the eMeasure quantifies the impact of each data quality issue.Results Catheter duration had the most impact on the CMS178 eMeasure with every 1% reduction in data quality causing a 1.21% increase in the number of missing events. For birth date and admission type, every 1% reduction in data quality resulted in a 1% increase in missing events.Conclusion This research demonstrated that the impact of data quality issues can be quantified using a generalized process and that the CMS178 eMeasure, as currently defined, may not measure how well an organization is meeting the intended best practice goal. Secondary use of EHR data is warranted only if the data are of sufficient quality. The assessment approach described in this study demonstrates how the impact of data quality issues on an eMeasure can be quantified and the approach can be generalized for other data analysis tasks. Healthcare organizations can prioritize data quality improvement efforts to focus on the areas that will have the most impact on validity and assess whether the values that are reported should be trusted. PMID- 29241242 TI - Automated Screening of Emergency Department Notes for Drug-Associated Bleeding Adverse Events Occurring in Older Adults. AB - Objective To conduct research to show the value of text mining for automatically identifying suspected bleeding adverse drug events (ADEs) in the emergency department (ED).Methods A corpus of ED admission notes was manually annotated for bleeding ADEs. The notes were taken for patients >= 65 years of age who had an ICD-9 code for bleeding, the presence of hemoglobin value <= 8 g/dL, or were transfused > 2 units of packed red blood cells. This training corpus was used to develop bleeding ADE algorithms using Random Forest and Classification and Regression Tree (CART). A completely separate set of notes was annotated and used to test the classification performance of the final models using the area under the ROC curve (AUROC).Results The best performing CART resulted in an AUROC on the training set of 0.882. The model's AUROC on the test set was 0.827. At a sensitivity of 0.679, the model had a specificity of 0.908 and a positive predictive value (PPV) of 0.814. It had a relatively simple and intuitive structure consisting of 13 decision nodes and 14 leaf nodes. Decision path probabilities ranged from 0.041 to 1.0. The AUROC for the best performing Random Forest method on the training set was 0.917. On the test set, the model's AUROC was 0.859. At a sensitivity of 0.274, the model had a specificity of 0.986 and a PPV of 0.92.Conclusion Both models accurately identify bleeding ADEs using the presence or absence of certain clinical concepts in ED admission notes for older adult patients. The CART model is particularly noteworthy because it does not require significant technical overhead to implement. Future work should seek to replicate the results on a larger test set pulled from another institution. PMID- 29241243 TI - Core Components for a Clinically Integrated mHealth App for Asthma Symptom Monitoring. AB - Background mHealth apps may be useful tools for supporting chronic disease management.Objective Our aim was to apply user-centered design principles to efficiently identify core components for an mHealth-based asthma symptom monitoring intervention using patient-reported outcomes (PROs).Methods We iteratively combined principles of qualitative research, user-centered design, and "gamification" to understand patients' and providers' needs, develop and refine intervention components, develop prototypes, and create a usable mobile app to integrate with clinical workflows. We identified anticipated benefits and burdens for stakeholders.Results We conducted 19 individual design sessions with nine adult patients and seven clinicians from an academic medical center (some were included multiple times). We identified four core intervention components: (1) Invitation-patients are invited by their physicians. (2) Symptom checks patients receive weekly five-item questionnaires via the app with 48 hours to respond. Depending on symptoms, patients may be given the option to request a call from a nurse or receive one automatically. (3) Patient review-in the app, patients can view their self-reported data graphically. (4) In-person visit physicians have access to patient-reported symptoms in the electronic health record (EHR) where they can review them before in-person visits. As there is currently no location in the EHR where physicians would consistently notice these data, recording a recent note was the best option. Benefits to patients may include helping decide when to call their provider and facilitating shared decision making. Benefits to providers may include saving time discussing symptoms. Provider organizations may need to pay nurses extra, but those costs may be offset by reduced visits and hospitalizations.Conclusion Recent systematic reviews show inconsistent outcomes and little insight into functionalities required for mHealth asthma interventions, highlighting the need for systematic intervention design. We identified specific features for adoption and engagement that meet the stated needs of users for asthma symptom monitoring. PMID- 29241244 TI - Physician Beliefs about the Meaningful Use of the Electronic Health Record: A Follow-Up Study. AB - Background There is continuing interest in how physicians are responding to the meaningful use of the electronic health record (EHR) incentive program. However, little research has been done on physician beliefs about the meaningful use of the EHR.Objective This study aims to conduct a follow-up study of physician beliefs about the meaningful use of the EHR.Methods Online survey of physicians at two academic medical centers (AMCs) in the northeast who were participating in the meaningful use of the EHR incentive program and were using an internally developed EHR was conducted.Results Of the 2,033 physicians surveyed, 1,075 completed the survey for an overall response rate of 52.9%. Only one-fifth (20.5%) of the physicians agreed or strongly agreed that meaningful use of the EHR would help them improve quality of care, and only a quarter (25.2%) agreed or strongly agreed that the meaningful use of the EHR would improve the care that their organization delivers. Physician satisfaction with the outpatient EHR was the strongest predictor of self-efficacy with achieving stage 2 of the meaningful use of the EHR incentive program (odds ratio: 2.10, 95% confidence interval: 1.61, 2.75, p < 0.001). Physicians reported more negative beliefs in stage 2 than stage 1 across all belief items. For example, 28.1% agreed or strongly agreed that the meaningful use of the EHR would decrease medical errors in stage 2 as compared with 35.9% in stage 1 (p < 0.001).Conclusion Only one-fifth of the physicians in our study believed that the meaningful use of the EHR would improve quality of care, patient-centeredness of care, or the care they personally provide. Primary care physicians expressed more negative beliefs about the meaningful use of the EHR in stage 2 than in stage 1. These findings show that physicians continue to express negative beliefs about the meaningful use of the EHR. These ongoing negative beliefs are concerning for both implementation and policy. PMID- 29241245 TI - Better Usability and Technical Stability Could Lead to Better Work-Related Well Being among Physicians. AB - Background and Objective Finnish physicians have been increasingly dissatisfied with poor usability of the electronic patient record (EPR) systems, which they have identified as an overload factor in their work. Our aim is to specify which factors in EPRs are associated with work-related well-being of physicians.Methods A web-based questionnaire was sent to Finnish physicians younger than 65 years; the responses (n = 3,781) represent one-fourth of these. This was a repetition of a survey in 2010, where this questionnaire was used for the first time. In addition to statements assessing usability, there were questions measuring time pressure and job control. The relation between usability and work well-being was investigated with hierarchical multivariate regression analyses: With time pressure and job control as dependent variables, EPR usability assessments and physicians' background information were used as independent variables.Results In the multivariate analyses, technical problems that are often experienced in the EPR were related to higher time pressure and lower job control. Active participation in the development of the EPR system was related to stronger time pressure and stronger job control. In addition, use of several systems daily and the experience of time-consuming documentation of patient information for statistical purposes (billing, national registries, and reporting) were related to higher time pressure, while those with longer experience with the EPR system and those experiencing easy-to-read nursing records reported higher job control.Conclusion To relieve time pressure and increase sense of job control experienced by physicians, usability, integrations, and stability of the EPR systems should be improved: fewer login procedures, easier readability of nursing records, and decreased need for separate documentation for statistical purposes. Physician participation in the EPR development would increase the feeling of job control, but would add the time pressure. Hence, time for developmental work should be arranged. PMID- 29241246 TI - Health Information Exchange for Continuity of Maternal and Neonatal Care Supporting: A Proof-of-Concept Based on ISO Standard. AB - Background Around the world, people receive care at various institutions; therefore, clinical information is recorded either on paper or distributed on different information systems with reduced capabilities for sharing data. One approach to handling the complex nature of the health information systems and making it interoperable is the two-level modeling, and the ISO 13606 standard is an option to support this model. A regionally governed EHR program in Brazil proposed to use the ISO 13606 standard and archetypes. This program includes an EHR repository for consolidating the longitudinal electronic record of patients' health.Objective This article aims to present the results and lessons learned from a proof-of-concept (POC) for integrating the Maternal and Neonatal Healthcare Information System (SISMater) developed by the Federal University of Minas Gerais (UFMG) with the EHR system developed by the Department of Healthcare for the State of Minas Gerais (SES/MG).Methods The design of the architecture and software development were driven by the content to be exchanged between the SISMater system and the EHR system and the usage of XML transformation to translate an ISO 13606 EHR extract and vice versa. This POC did not include tests related to revision objects according to ISO 13606 reference model.Results The software architecture and software components required for this POC were proposed and tested. The EHR system validated the syntax and semantic and persisted the extract in the EHR repository. Complete results can be accessed at https://github.com/pocppsus/repository.Conclusion The approach for using XML transformations could make easier the process for ISO 13606 noncompliant EMR systems to exchange EHR data with the SES/MG EHR system. PMID- 29241247 TI - Usability Evaluation of Electronic Health Record System around Clinical Notes Usage-An Ethnographic Study. AB - Background A substantial gap exists between current Electronic Health Record (EHR) usability and potential optimal usability. One of the fundamental reasons for this discrepancy is poor incorporation of a User-Centered Design (UCD) approach during the Graphical User Interface (GUI) development process.Objective To evaluate usability strengths and weaknesses of two widely implemented EHR GUIs for critical clinical notes usage tasks.Methods Twelve Internal Medicine resident physicians interacting with one of the two EHR systems (System-1 at Location-A and System-2 at Location-B) were observed by two usability evaluators employing an ethnographic approach. User comments and observer findings were analyzed for two critical tasks: (1) clinical notes entry and (2) related information-seeking tasks. Data were analyzed from two standpoints: (1) usability references categorized by usability evaluators as positive, negative, or equivocal and (2) usability impact of each feature measured through a 7-point severity rating scale. Findings were also validated by user responses to a post observation questionnaire.Results For clinical notes entry, System-1 surpassed System-2 with more positive (26% vs. 12%) than negative (12% vs. 34%) usability references. Greatest impact features on EHR usability (severity score pertaining to each feature) for clinical notes entry were: autopopulation (6), screen options (5.5), communication (5), copy pasting (4.5), error prevention (4.5), edit ability (4), and dictation and transcription (3.5). Both systems performed equally well on information-seeking tasks and features with greatest impacts on EHR usability were navigation for notes (7) and others (e.g., looking for ancillary data; 5.5). Ethnographic observations were supported by follow-up questionnaire responses.Conclusion This study provides usability-specific insights to inform future, improved, EHR interface that is better aligned with UCD approach. PMID- 29241248 TI - Providing Patients with Implantable Cardiac Device Data through a Personal Health Record: A Qualitative Study. PMID- 29241249 TI - Health IT Usability Focus Section: Data Use and Navigation Patterns among Medical ICU Clinicians during Electronic Chart Review. AB - Background A detailed understanding of electronic health record (EHR) workflow patterns and information use is necessary to inform user-centered design of critical care information systems. While developing a longitudinal medical record visualization tool to facilitate electronic chart review (ECR) for medical intensive care unit (MICU) clinicians, we found inadequate research on clinician EHR interactions.Objective We systematically studied EHR information use and workflow among MICU clinicians to determine the optimal selection and display of core data for a revised EHR interface.Methods We conducted a direct observational study of MICU clinicians performing ECR for unfamiliar patients during their routine daily practice at an academic medical center. Using a customized manual data collection instrument, we unobtrusively recorded the content and sequence of EHR data reviewed by clinicians.Results We performed 32 ECR observations among 24 clinicians. The median (interquartile range [IQR]) chart review duration was 9.2 (7.3-14.7) minutes, with the largest time spent reviewing clinical notes (44.4%), laboratories (13.3%), imaging studies (11.7%), and searching/scrolling (9.4%). Historical vital sign and intake/output data were never viewed in 31% and 59% of observations, respectively. Clinical notes and diagnostic reports were browsed >=10 years in time for 60% of ECR sessions. Clinicians viewed a median of 7 clinical notes, 2.5 imaging studies, and 1.5 diagnostic studies, typically referencing a select few subtypes. Clinicians browsed a median (IQR) of 26.5 (22.5-37.25) data screens to complete their ECR, demonstrating high variability in navigation patterns and frequent back-and-forth switching between screens. Nonetheless, 47% of ECRs begin with review of clinical notes, which were also the most common navigation destination.Conclusion Electronic chart review centers around the viewing of clinical notes among MICU clinicians. Convoluted workflows and prolonged searching activities indicate room for system improvement. Using study findings, specific design recommendations to enhance usability for critical care information systems are provided. PMID- 29241250 TI - Health IT Usability Focus Section: Adapting EHR-Based Medication Instructions to Comply with Plain Language Guidance-A Randomized Experiment. AB - Objective Patient instructions are generally written by clinicians. However, clinician-centered language is challenging for patients to understand; in the case of pediatric medication instructions, consequences can be serious. Using examples of clinician-written medication instructions from an electronic health record, we conducted an experiment to determine whether parental misinterpretations would be reduced by instructions that followed best practices for plain language.Methods We selected examples of dosing instructions from after visit summaries in a commercial electronic health record. A demographically diverse sample of parents and adult caregivers was recruited from an online panel to participate in an English-language experiment, in which they received a comprehension questionnaire with either original after-visit summary instructions or instructions revised to comply with federal and other sources of plain language guidance.Results Nine-hundred and fifty-one respondents completed the experiment; 50% were women, the mean age was 36 years, and 38% had less than a 4 year college education. The revisions were associated with an 8 percentage point increase in correct answers overall (from 55% to 63%, p < 0.001), although revisions were not equally effective for all instructions. Health literacy and health numeracy were strong and independent predictors of comprehension. Overall, mistakes on comprehension questions were common, with respondents missing an average of 41% (6.1 of 15) of questions.Conclusion In this experimental study, a relatively simple intervention of revising text was associated with a modest reduction in frequency of misinterpretations of medication instructions. As a supplement to more intensive high-touch interventions, revising electronic health record output to replace complex language with patient-centered language in an automated fashion is a potentially scalable solution that could reduce medication administration errors by parents. PMID- 29241251 TI - Association between Search Behaviors and Disease Prevalence Rates at 18 U.S. Children's Hospitals. AB - Background Usage of online resources by clinicians in training and practice can provide insight into knowledge gaps and inform development of decision support tools. Although online information seeking is often driven by encountered patient problems, the relationship between disease prevalence and search rate has not been previously characterized.Objective This article aimed to (1) identify topics frequently searched by pediatric clinicians using UpToDate (http://www.uptodate.com) and (2) explore the association between disease prevalence rate and search rate using data from the Pediatric Health Information System.Methods We identified the most common search queries and resources most frequently accessed on UpToDate for a cohort of 18 children's hospitals during calendar year 2012. We selected 64 of the most frequently searched diseases and matched ICD-9 data from the PHIS database during the same time period. Using linear regression, we explored the relationship between clinician query rate and disease prevalence rate.Results The hospital cohort submitted 1,228,138 search queries across 592,454 sessions. The majority of search sessions focused on a single search topic. We identified no consistent overall association between disease prevalence and search rates. Diseases where search rate was substantially higher than prevalence rate were often infectious or immune/rheumatologic conditions, involved potentially complex diagnosis or management, and carried risk of significant morbidity or mortality. None of the examined diseases showed a decrease in search rate associated with increased disease prevalence rates.Conclusion This is one of the first medical learning needs assessments to use large-scale, multisite data to identify topics of interest to pediatric clinicians, and to examine the relationship between disease prevalence and search rate for a set of pediatric diseases. Overall, disease search rate did not appear to be associated with hospital disease prevalence rates based on ICD-9 codes. However, some diseases were consistently searched at a higher rate than their prevalence rate; many of these diseases shared common features. PMID- 29241252 TI - Residents' Insights and Ideas about Screen-Sharing in Primary Care Clinics. AB - Background Previous studies described attending physicians' perceptions of the benefits and downsides of having the electronic health record (EHR) in the room during a clinical encounter. The perspective of residents has received little attention.Objective The goal of this project was to solicit internal medicine residents' perception of EHR use in primary care clinic visits. In this report, we focus on residents' perception of screen-sharing.Methods We conducted qualitative, semistructured interviews of internal medicine residents. Interviews were audiorecorded, transcribed, and anonymized. Using a deductive approach to data analysis, we coded the transcripts to identify themes of interest.Results We included 21 residents. We identified eight themes related to screen-sharing. We identified opportunities, facilitators and barriers, and outcomes related to screen-sharing. We conceptualized the outcomes, facilitators, and barriers as falling into four categories: structural, patient based, physician based, and interactional.Conclusion Wider dissemination and adoption of curricula designed to teach residents how to incorporate EHR into the clinical encounter is needed. In addition, our study demonstrates the need to focus this training, at least in part, on screen-sharing and management of sensitive information disclosure. PMID- 29241253 TI - Leveraging the Electronic Health Record to Get Value from Referrals. PMID- 29241254 TI - Patient Self-Management of Asthma Using Mobile Health Applications: A Systematic Review of the Functionalities and Effects. AB - Objective The aim of this systematic review was to summarize the evidence regarding the effects of mobile health applications (mHealth apps) for self management outcomes in patients with asthma and to assess the functionalities of effective interventions.Methods We systematically searched Medline, Scopus, and the Cochrane Central Register of Controlled Trials. We included English-language studies that evaluated the effects of smartphone or tablet computer apps on self management outcomes in asthmatic patients. The characteristics of these studies, effects of interventions, and features of mHealth apps were extracted.Results A total of 10 studies met all the inclusion criteria. Outcomes that were assessed in the included studies were categorized into three groups (clinical, patient reported, and economic). mHealth apps improved asthma control (five studies) and lung function (two studies) from the clinical outcomes. From the patient-reported outcomes, quality of life (three studies) was statistically significantly improved, while there was no significant impact on self-efficacy scores (two studies). Effects on economic outcomes were equivocal, so that the number of visits (in two studies) and admission and hospitalization-relevant outcomes (in one study) statistically significantly improved; and in four other studies, these outcomes did not improve significantly. mHealth apps features were categorized into seven categories (inform, instruct, record, display, guide, remind/alert, and communicate). Eight of the 10 mHealth apps included more than one functionality. Nearly all interventions had the functionality of recording user entered data and half of them had the functionality of providing educational information and reminders to patients.Conclusion Multifunctional mHealth apps have good potential in the control of asthma and in improving the quality of life in such patients compared with traditional interventions. Further studies are needed to identify the effectiveness of these interventions on outcomes related to medication adherence and costs. PMID- 29241257 TI - ? PMID- 29241258 TI - [Changes of Motor Balance in the Course of an Inpatient Psychosomatic Rehabilitation]. AB - Aim of the study For many rehabilitants both the motor balance and the feeling of being emotionally stable and in balance are essential preconditions for participation in employment and society. The goal of this study was to capture changes in motor balance in the course of an inpatient psychosomatic rehabilitation and to set them in relation to changes in mental variables. Methods 118 patients of a psychosomatic clinic (49.3+/-8.6 years; 75.4 % women) were examined at the beginning and the end of rehabilitation. To measure motor balance the balance test (GGT) of Bos, Wydra and Karisch, the timed up and go test (TUG), eight tasks of standing balance on an unstable surface as well as eight tasks on a stable surface were used. As psychological variables, self esteem (MSWS), degree of depressive (BDI-II) and anxiety symptoms (BAI) were measured. Results The motor balance ability, assessed by the GGT (d=1,37), the TUG (d=0,56), tasks of standing balance on an unstable surface (d=1,48) as well as on a stable surface (d=0.67), increased significantly in the course of rehabilitation and was also reflected in the self-evaluation of motor balance (d=0,97). Correlations in the change of motor and mental variables were particularly evident between the balance tasks on an unstable and a stable surface and different scales of the MSWS. Conclusion In the course of rehabilitation, an improvement in psychological symptoms as well as the balance ability was found, however, contrary to our expectations, no significant correlations were observed. At the first view it seems like there would be no relationship between psychological factors and the motor balance of the patients. However it should be noted that motor balance was examined in a standardized situation in which the patients were not exposed to any particular psychological distress. Observations during the conduct of the study suggest that changes in motor balance could be shown rather in observable characteristics of postural control (for example in contraction and relaxation) than in the number of fulfilled tasks. The motor balance tests were not only accepted very well by the rehabilitants but often also provoked self-reflection processes on topics such as balance and stability in a psychosomatic sense. Further research both on the factors influencing the motor balance ability as well as on their relation to the improvement in activity and participation appears promising. PMID- 29241259 TI - [Competence Based Catalogue of Learning Objectives for Rehabilitation, Physical Medicine, Naturopathic Treatment - Revised Version - Joint Recommendations of the German Society of Rehabilitation Science and the German Society of Physical Medicine and Rehabilitation]. AB - Since the first publication of learning objectives for the interdisciplinary subject "Rehabilitation, Physical Medicine, Naturopathic Treatment" in undergraduate medical education in 2004 a revision is reasonable due to heterogenous teaching programmes in the faculties and the introduction of the National Competence Based Catalogue of Learning Objectives in Medicine as well as the "Masterplan Medical Education 2020". Therefore the German Society of Rehabilitation Science and the German Society of Physical Medicine and Rehabilitation started a structured consensus process using the DELPHI-method to reduce the learning objectives and arrange them more clearly. Objectives of particular significance are emphasised. All learning objectives are assigned to the cognitive and methodological level 1 or to the action level 2. The learning objectives refer to the less detailed National Competence Based Catalogue of Learning Objectives in Medicine. The revised learning objectives will contribute to further progress in competence based and more homogenous medical teaching in core objectives of Rehabilitation, Physical Medicine, and Naturopathic Treatment in the faculties. PMID- 29241260 TI - ? PMID- 29241261 TI - Erratum: Risk Factors for Dystonia after Selective Dorsal Rhizotomy in Nonwalking Children and Adolescents with Bilateral Spasticity. PMID- 29241262 TI - Phenotypic and Genotypic Heterogeneity of RRM2B Variants. AB - OBJECTIVES: Genotype and phenotype of RRM2B mutation have become increasingly heterogeneous. This review aims at summarizing recent advances concerning the genotypic and phenotypic variability of RRM2B mutations. METHOD: The review evaluated clinical and instrumental data of 82 patients carrying a mutation in the RRM2B gene reported in 18 publications with regard to onset, frequency, and type of clinical manifestations and genetic findings. RESULTS: The review showed marked variety of clinical manifestations and marked variety of age at onset. Organs predominantly affected in RRM2B mutation carriers are the skeletal muscle, the brain, and the kidneys. Additionally affected may be the eyes, ears, endocrine organs, heart, gastro-intestinal tract, bone marrow, or the peripheral nerves. So far 43 mutations in 81 patients have been reported. Diagnosing RRM2B associated disease requires demonstration of an appropriate phenotype and a RRM2B mutation. Various clinical manifestations are accessible to various invasive or noninvasive therapeutic measures. The outcome of RRM2B-associated mitochondrial disorders is highly variable ranging from early death to survival into adulthood. CONCLUSIONS: Phenotype and genotype in RRM2B mutation carriers are more widespread than anticipated. Particularly in patients with chronic progressive external ophthalmoplegia, ptosis, limb muscle weakness, muscle hypotonia, renal tubulopathy, ataxia, deafness, and lactic acidosis, a RRM2B mutation should be considered. PMID- 29241263 TI - Systematic Review of Oral Therapy for the Treatment of Symptoms of Bladder Pain Syndrome: The Brazilian Guidelines. AB - Interstitial cystitis (IC), including bladder pain syndrome (BPS), is a chronic and debilitating disease that mainly affects women. It is characterized by pelvic pain associated with urinary urgency, frequency, nocturia and negative urine culture, with normal cytology. In 2009, the Society for Urodynamics and Female Urology (SUFU) defined the term IC/BPS as "an unpleasant sensation (pain, pressure, and discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms for more than 6 weeks duration, in the absence of infection or other identifiable causes." This is the definition used by the American Urological Association (AUA) in the most recent guidelines on IC/BPS. Interstitial cystitis may be sufficiently severe to have a devastating effect on the quality of life, but it may also be associated with moderate symptoms whose effects are less debilitating. Although there are several clinical trials to assess oral and intravesical therapies, the treatment for IC remains far from ideal. This systematic assessment evaluates published randomized clinical trials on oral medications used to treat symptoms of BPS. This study was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) method. Two independent reviewers screened the studies to determine their inclusion or exclusion and to perform the methodological analysis. The inclusion criteria included randomized studies published between April of 1988 and April of 2016 that used oral medications to treat symptoms of BPS or IC. According to the systematic review performed, we should consider pentosan polysulfate as one of the best options of oral drugs for the treatment of BPS symptoms. However, this drug is not an available option in Brazil. Orally administered amitriptyline is an efficacious medical treatment for BPS, and it should be the first treatment offered. PMID- 29241264 TI - [Smoke-free psychiatry in Germany: A closer look]. AB - OBJECTIVE: In order to protect non-smokers, the federal states of Germany have adopted a law that provides for extensive smoking bans. In many of these federal laws, acute psychiatric facilities are treated as an exception. Therefore, it is often up to the institutions themselves to develop and enforce regulations. The aim of this study was to evaluate the situation in acute psychiatric facilities. METHODS: The survey was created on the basis of previously evaluated questionnaires and consisted of 53 questions. A total of 289 hospitals were contacted. Participants were invited to take part in the survey via e-mail. RESULTS: 59 hospitals (20.4 %) participated in the survey. Binding regulations were in place in 48 (81.4 %) hospitals, in 26 (44.1 %), smoking was prohibited on open wards. Three hospitals (5.1 %) strictly prohibited smoking on locked wards. Stop-smoking medication was available in 31 (55.3 %) hospitals. 19 (32.2 %) offered smoking cessation interventions. 22 (37.3 %) hospitals have set up a working group on the subject. CONCLUSION: Currently, the issue of smoking in psychiatric facilities does not receive enough attention. The physical and mental health of psychiatric patients would benefit from a smoke-free policy. In order to achieve this, psychiatric staff and patients need appropriate support. PMID- 29241265 TI - Retroperitoneoscopic Resection of a Lumbosacral Plexus Schwannoma: Case Report and Literature Review. AB - BACKGROUND AND STUDY AIMS: Schwannomas are benign tumors derived from the Schwann cells of the peripheral nerve sheath that rarely affect the retroperitoneum. When symptomatic, surgical resection is usually recommended via open surgery or the laparoscopic transperitoneal approach. We discuss the retroperitoneoscopic resection of lumbosacral plexus schwannomas through an illustrative case and literature review. A new management classification is also proposed. PATIENTS: A 61-year-old woman affected by schwannomatosis presented with neuropathic pain in her right inguinocrural area for the past 4 years before admission. Preoperative imaging revealed a 2-cm right retroperitoneal tumor lateral to the psoas muscle. The diagnosis of a schwannoma of the ilioinguinal nerve was then suggested. The patient underwent complete tumor resection through retroperitoneoscopy, and no recurrence was observed over the long term. A review of the relevant literature revealed that surgical strategy depends on tumor location, and therefore patients are divided into three groups by tumor position to guide trocar placement: type 1 (paravertebral or over the psoas muscle), type 2 (lateral to the psoas muscle), and type 3 (sacral or pelvic). RESULTS: Four patients were classified as type 1, one as type 2, and three as type 3, thereby guiding trocar placement to a lateral, anterior, or inferior montage, respectively. CONCLUSIONS: Retroperitoneoscopy is a minimally invasive technique that offers some potential advantages in approaching retroperitoneal masses. This new classification is useful to group patients and thus provide guidance on the best retroperitoneoscopic surgical strategy. PMID- 29241266 TI - Cerebellopontine Angle Schwannoma and Meningioma in Contiguity: Surgical Implications in Neurofibromatosis. AB - Concurrent occurrence of brain tumors in the same location is very unusual and has been noted in patients with neurofibromatosis. Two lesions, occurring in close contact but of different histology, are called contiguous tumors. Schwannoma and meningioma are the two common histologies reported to present as contiguous tumor. We present two patients with contiguous tumors in the cerebellopontine angle. The magnetic resonance imaging characteristics in both cases demonstrate important findings that should be identified to raise the possibility of contiguous tumors. We discuss the surgical implications in identifying the facial nerve in this complex tumor morphology and steps we took to preserve function. Variable displacement of the facial nerve in the presence of multiple tumors needs to be kept in mind during surgical management and can be significantly aided by intraoperative monitoring. PMID- 29241267 TI - Congenital Intracerebral Pial Arteriovenous Fistula: A Case Report. AB - Pial arteriovenous fistula (AVF) is an extremely rare intracranial vascular lesion. The pediatric type of AVF has a high percentage of varix, leading to mass effect with symptoms. We report a 12-year-old boy who was admitted due to sudden confusion and urinary incontinence. Computed tomography, magnetic resonance imaging, and magnetic resonance angiography (MRA) confirmed the diagnosis of congenital pial AVF. Digital subtraction angiography (DSA) revealed the lesion originating from the left middle cerebral artery and draining into the superior sagittal sinus. The AVF was successfully obliterated with six microcoils and 2.5 mL ethylene vinyl alcohol copolymer using a middle cerebral artery approach. This patient was discharged without neurologic deficits. The AVF became smaller and ultimately disappeared on the DSA and MRA at follow-up. PMID- 29241268 TI - Lacking Benefit of Intraoperative High-Dose Dexamethasone in Instrumented Surgery for Cervical Spondylotic Myelopathy. AB - BACKGROUND: Our objective was to investigate the effect of intraoperative dexamethasone administration on wound healing, complications, and clinical outcome in patients with posterior surgery for cervical spondylotic myelopathy (CSM). METHODS: We conducted a retrospective study of patients with CSM undergoing dorsal instrumentation and decompression of the cervical spine. The senior surgeon decided if administration of dexamethasone (40 mg intravenously) was indicated. Patients were divided into two groups: dexamethasone group (DG) and non-dexamethasone group (nDG). All patients were monitored for pre- and postoperative neurologic symptoms and complications. Clinical follow-up was evaluated with the Neck Disability Index (NDI) and the modified Japanese Orthopaedic Association (mJOA) score. RESULTS: A total of 49 patients were included (DG, 25; nDG, 24). DG and nDG patients showed no significant differences in pre- and postoperative findings. Five patients in the DG had wound healing complications compared with patients in the nDG (p = 0.021), and one died due to infection. Apart from that, we did not observe any significant differences between the two groups regarding complications, neurologic symptoms, and follow up (NDI and mJOA). CONCLUSION: Intraoperative dexamethasone administration had no influence on the postoperative outcome and follow-up. A significantly higher rate of wound infections was detected in the DG. These data support the hypothesis that intraoperative dexamethasone bolus application in CSM lacks benefit. PMID- 29241269 TI - Comparison of Percutaneous Endoscopic Lumbar Diskectomy and Open Lumbar Microdiskectomy for Recurrent Lumbar Disk Herniation. AB - OBJECTIVE: To establish the appropriateness of transforaminal percutaneous endoscopic lumbar diskectomy (PELD) by comparing it with open lumbar microdiskectomy (OLM) for surgical treatment of recurrent lumbar disk herniation. METHODS: We retrospectively analyzed 83 patients who underwent revision surgery (group A: PELD, 35 cases; group B: OLM, 48 cases) for recurrent lumbar disk herniation between March 2009 and April 2014. All of the patients were followed > 12 months. To evaluate outcomes, we checked the leg and back visual analog scale (VAS), Oswestry Disability Index (ODI), complications, and recurrence for all patients. RESULTS: The mean improvement of VAS for leg was 5.97 +/- 0.98 for group A and 5.62 +/- 1.42 for group B (p = 0.194). The mean improvement of VAS for back pain was 2.71 +/- 1.30 for group A and 2.29 +/- 1.41 for group B (p = 0.168). The mean improvement of ODI scores was 28.86 +/- 3.93 for group A and 28.00 +/- 4.22 for group B (p = 0.350). Total surgery-related complications were none for group A and nine for group B (p = 0.009). Group A had one subject with surgery-related neurologic symptoms and group B had four (p = 0.391). Recurrence occurred in two patients in group A and seven patients in group B (p = 0.291). CONCLUSION: PELD and OLM have favorable clinical outcomes in patients with recurrent lumbar disk herniation, and PELD results in fewer complications compared with OLM. Therefore, PELD may be a better alternative to OLM for patients with recurrent lumbar disk herniation. PMID- 29241270 TI - Endoscopic Third Ventriculostomy before Posterior Fossa Tumor Surgery in Adult Patients. AB - OBJECTIVE: Obstructive hydrocephalus in patients with posterior fossa tumors is frequently seen. Treatment options include immediate tumor removal or prior cerebrospinal fluid (CSF) diversion procedures. The necessity and feasibility of an ETV in these situations has not yet been proven in adult patients. METHODS: We retrospectively reviewed our prospectively maintained database for ETVs before surgery of posterior fossa tumors in adults. The primary focus of data analyses was the question of whether the ETV was suitable to treat the acute situation of hydrocephalus without an increased rate of complications due to the special anatomical situation with a posterior fossa tumor. We also analyzed whether any further CSF diverting procedures were necessary. RESULTS: A total of 40 adult patients who underwent an ETV before posterior fossa tumor surgery were analyzed. Overall, 33 patients (82.5%) had clinical signs of hydrocephalus, and all of them improved in their clinical course after ETV. Seven patients (17.5%) did not demonstrate clinical signs of hydrocephalus, but ETV was performed with prophylactic or palliative intent in six patients and one patient, respectively. No complications were observed due to ETV itself. No permanent shunting procedure was necessary in a mean follow-up of 76.5 months. Early additional CSF diverting procedures (redo ETV, external ventricular drain) were performed in five patients (12.5%). CONCLUSION: The present series confirms the feasibility and safety of ETV before posterior fossa tumor surgery in adult patients. If patients had symptomatic hydrocephalus before tumor surgery, an ETV can be performed, followed by early elective tumor surgery. A prophylactic ETV in asymptomatic patients is not advised. Early elective tumor surgery should be performed in these patients. PMID- 29241271 TI - How Reliable Is Pupillary Evaluation Following Subarachnoid Hemorrhage? Effect of Oculomotor Nerve Degeneration Secondary to Posterior Communicating Artery Vasospasm: First Experimental Study. AB - BACKGROUND AND STUDY AIM: Basic neurophysiologic principles of the light reflex are well known. However, the effects of degenerated axon densities of oculomotor nerves (OMNs) secondary to posterior communicating artery (PComA) vasospasm following subarachnoid hemorrhage (SAH) have not been investigated. Our aim was to study this subject. METHODS: This study was conducted on 19 rabbits. There was a control group of five animals, a sham group of five animals in which saline was injected into the cisterna magna and a study group of nine animals in which homologous blood was injected into the cisterna magna. Pupillary diameters were measured for 1 week, then the animals were decapitated. The normal and degenerated axon densities of the OMNs were examined by stereological methods. Vasospasm indexes (VSIs) of posterior communicating arteries (PComAs) supplying OMNs were estimated and analyzed statistically. RESULTS: The pupillary diameter was 5.439 +/- 368 um, and the mean axon density of the OMNs was 0.924 +/- 324/mm3 in the control group. The pupillary diameter and degenerated axon density of the OMNs in animals of the sham group were 6.980 +/- 0.370 um and 36 +/- 8/mm3, respectively. The pupillary diameter was 9.942 +/- 653 um, and degenerated axon density of the OMNs was 265 +/- 57/mm3 in animals with SAH. The mean VSI values of PComAs were 0.927 +/- 0.224 in the control group, 1.542 +/- 0.257 in the sham group, and 2.321 +/- 0.324 in the SAH group. CONCLUSION: We found a linear relationship between the axon density of the OMNs and pupillary diameters. High degenerated neuron density in the OMNs may be responsible for an unresponsive pupillary that has not been mentioned in the literature. PMID- 29241272 TI - Oral Cavity Infection: An Underestimated Source of Pyogenic Spondylodiscitis? AB - BACKGROUND: The incidence of pyogenic spondylodiscitis is increasing; however, the source of infection often remains obscure. We analyzed predisposing factors, pathogens, and outcome of patients undergoing surgical and/or conservative treatment of spondylodiscitis with a focus on the diagnostic work-up including a comprehensive maxillofacial assessment. PATIENTS: The analysis of prognostic factors comprised comorbidities, nicotine dependence, symptom duration, and oral cavity peculiarities. After a standardized diagnostic work-up, a detailed examination of the oral cavity was also performed. The outcome analysis included assessment of the patients' clinical status. RESULTS: Forty-one patients with pyogenic spondylodiscitis were investigated of whom 24% had undergone spinal surgery within 4 weeks before the infection. A total of 29% of patients were found to have a concomitant bacterial oral cavity disease, and in 22% the definitive source of infection remained unidentified. Among the 12 patients with oral cavity infections, 10 patients had periodontitis; 8, root canal pathologies; 6, periapical lesions, and another 8 patients, caries. In 25% of these patients, typical oral cavity pathogens were found in the intervertebral disk. The prevalence of oral cavity infections was associated with a history of nicotine dependence (p = 0.003). All other analyzed comorbidities did not differ compared with patients without an oral cavity focus. CONCLUSION: Oral cavity infections appear to be a frequent source of pyogenic spondylodiscitis, with smoking its most relevant associated risk factor. In case of an unidentified infection focus, a detailed diagnostic work-up including a mandatory maxillofacial assessment is strongly recommended. PMID- 29241273 TI - Transforaminal Percutaneous Endoscopic Lumbar Diskectomy for Downmigrated Disk Herniations: Lever-Up, Rotate, and Tilt Technique. AB - BACKGROUND AND STUDY AIMS: Although transforaminal percutaneous endoscopic lumbar diskectomy (PELD) offers certain advantages in the treatment of disk herniations, it used to be limited to nonmigrated or low-migrated herniations. With improvements in endoscopic spinal surgery, the range of indications for PELD has expanded. Various techniques including transforaminal and interlaminar approaches for migrated disk herniations are described in the literature. This study describes a transforaminal PELD approach to address downmigrated intracanal soft disk herniations effectively using the lever-up, rotate, and tilt technique. PATIENTS AND METHODS: We performed a retrospective review of 18 patients who had been operated on with the described technique between October 2012 and December 2015. We assessed clinical outcomes using the visual analog scale (VAS) for back and leg pain and the Oswestry Disability Index (ODI) preoperatively at their respective clinical visits and postoperatively at the patients' final follow-up examinations. RESULTS: The mean preoperative VAS scores for back and leg pain were 3.75 + 1.34 (range: 2-6) and 8.3 + 0.6 (range: 8-10), respectively. The mean preoperative ODI was 67.3 + 15.3 (range: 48-90). The mean VAS scores for back and leg pain improved to 1.38 + 1.58 (range: 0-6) and 1.19 + 0.75 (range: 0-3), respectively, at the last follow-up. The mean ODI also improved to 14.1 + 6.2 (range: 8-30) at the last follow-up. All differences between the preoperative and last follow-up scores were statistically significant (p < 0.05), Two surgeries failed because of a remnant disk fragment. CONCLUSIONS: The lever-up, rotate, and tilt technique for transforaminal PELD is an effective maneuver to treat downmigrated disk herniations in selected patients by experienced surgeons. PMID- 29241274 TI - Accuracy of Coronal Plane Mechanical Alignment in a Customized, Individually Made Total Knee Replacement with Patient-Specific Instrumentation. AB - The objective of this study was to evaluate the accuracy of a customized individually made total knee implant used in conjunction with patient-specific cutting guides in restoring coronal plane mechanical axis alignment using computer-assisted surgery (CAS). A consecutive series of 63 total knee arthroplasty (TKA) patients were prospectively measured with intraoperative CAS. The patient-specific instruments and implants were created utilizing a preoperative CT scan. CAS system was used for all patients, to determine mechanical alignment. Bone cuts were made using the patient-specific instruments. Both bone cuts and final coronal mechanical alignment were recorded utilizing the navigation system for the assessment.The patient-specific instruments and implants provided perfect neutral coronal mechanical alignment (0 degrees ) in 53 patients. The remaining 10 patients had a postoperative alignment within +/- 2 degrees of neutral. The average preoperative deformity was 5.57 degrees versus 0.18 degrees postoperatively (p < 0.0001). The mean correction angle was 5.68 degrees . No patients had postoperative extension deficits as measured with CAS (7.50 degrees pre-op for 40/63 patients). Customized, individually made total knee implant with patient-specific cutting jigs showed results that are comparable to those of CAS systems in this study. This technology restores the neutral coronal mechanical axis very accurately, while offering unique benefits such as improved implant fit and restoration of the patient's J-curves, which require further investigation. PMID- 29241275 TI - Correction: Endoscopic subtypes of colorectal laterally spreading tumors (LSTs) and the risk of submucosal invasion: a meta-analysis. PMID- 29241276 TI - Multiband mucosectomy for the treatment of challenging non-pedunculated colorectal polyps. AB - BACKGROUND AND STUDY AIMS: Endoscopic mucosal resection is the gold standard treatment for non-pedunculated colorectal polyps; however, some specific situations (location behind folds, scarred or flat morphology) can make this technique challenging. We aimed to assess the efficacy and safety of multiband mucosectomy (MBM) for resection of non-pedunculated colorectal polyps. PATIENTS AND METHODS: This was a retrospective study of patients in whom MBM was performed to resect large non-pedunculated colorectal polyps. All procedures were carried out using the Shooter multiband ligator kit (Cook Medical, Limerick, Ireland). A 3-month follow-up colonoscopy was performed in all patients. RESULTS: 10 patients underwent MBM for resection of 10 large (median 33.5 mm) non-pedunculated polyps. A total of 45 MBM sessions were carried out to resect all of the lesions using on average one rubber band per 1.5 cm2 of resected tissue. Complete resection was possible in 9 out of 10 lesions, although en bloc resection was only feasible in one lesion. Follow-up colonoscopy revealed residual adenoma in just one patient. No major complications were registered. CONCLUSIONS: In this small series of patients, MBM proved to be a safe and effective endoscopic resection technique for challenging non-pedunculated colorectal polyps. PMID- 29241277 TI - Dual Energy Computed Tomography in Musculoskeletal Imaging, with Focus on Fragility Fractures of the Pelvis. AB - Dual energy computed tomography (DECT) is a constantly evolving technology, which opens up new diagnostic possibilities. It is particularly valuable for musculoskeletal (MSK) imaging. Due to the lack of recognition and availability of dual energy scanners, routine use is only established in a few centres. The intention of this review is to show the possibilities and fields of applications of the DECT in MSK imaging, as well as to describe technical principles and typical indications. We mainly focus on the use of DECT in the context of fragility fractures of the pelvis. The use of the DECT in pelvic fractures of the elderly could combine the advantages of CT diagnostics - fast and continuous availability, lower costs by dispensing with a supplementary MRI examination - and the high sensitivity of MRI to oedema in fragility fractures. Furthermore, the latest DECT scanners are dose neutral, so that these examinations can also be carried out without increased radiation exposure. PMID- 29241278 TI - Epigenetic Regulation of the Nitric Oxide Pathway, 17-alpha Hydroxyprogesterone Caproate, and Recurrent Preterm Birth. AB - OBJECTIVE: We sought to evaluate nitric oxide pathway placental gene expression and the epigenome (CpG methylation) among women receiving 17-alpha hydroxyprogesterone caproate (17-OHPC) with and without recurrent preterm birth (PTB). STUDY DESIGN: This was a case-control study. We prospectively recruited women with >= 1 prior singleton spontaneous PTB <34 weeks receiving 17-OHPC. DNA and RNA were isolated from placentas. RNA abundance (gene expression) and the methylome were analyzed for 84 genes in nitric oxide pathways. Women with recurrent PTB <34 weeks (cases) were compared with those delivering at term (controls). Statistical analysis included multivariable models with Bonferroni's corrected p-values. RESULTS: In this study, 17 women met inclusion criteria; 7 preterm cases (delivered at 22.6 +/- 2.9 weeks) and 10 term controls (delivered at 38.5 +/- 0.8 weeks). Groups had similar PTB history, race/ethnicity, and socioeconomic risk factors for PTB. Twenty-seven nitric oxide genes displayed differential expression (p < 0.05 and q < 0.10) when comparing placentas from preterm cases and term controls; all were downregulated in preterm cases. Eight hundred sixty corresponding CpG sites were differentially methylated between the preterm cases and term controls (Bonferroni's p-value <0.05). CONCLUSION: CpG methylation and gene expression patterns in nitric oxide pathway genes differ among placentas from recurrent PTB compared with term birth following 17-OHPC exposure. PMID- 29241279 TI - Does Early Artificial Rupture of Membranes Speed Labor in Preterm Inductions? AB - OBJECTIVE: In full-term patients, early artificial rupture of membranes (AROMs) decreases time in labor. We assessed the impact of early AROM in preterm patients undergoing indicated induction of labor. STUDY DESIGN: We conducted a retrospective cohort study of all patients undergoing indicated preterm induction (23-34 weeks) at a single tertiary care center from 2011 to 2014. Early AROM was defined as <4 cm and late AROM was defined as >=4 cm. The primary outcomes evaluated were cesarean delivery and time in labor. Secondary outcomes were chorioamnionitis and a composite of maternal and neonatal adverse outcomes. RESULTS: Of the 149 women included, 65 (43.6%) had early AROM. Early AROM was associated with an increased time from the start of induction to delivery (25.7 +/- 13.0 vs. 19.0 +/- 10.3 hours, p < 0.01) and with an increase in the risk of cesarean (53.4 vs. 22.6%, adjusted odds ratio: 3.5, 95% confidence interval: 1.60 7.74). Early AROM was not associated with an increased risk of chorioamnionitis or adverse maternal or fetal outcomes. CONCLUSION: In this observational cohort, early AROM was associated with an increased risk of cesarean. A randomized controlled trial is necessary to determine the optimal timing of AROM in preterm patients requiring delivery. PMID- 29241280 TI - Sex Difference in Mortality for Premature and Low Birth Weight Neonates: A Systematic Review. AB - OBJECTIVE: Advances in neonatology have made possible the survival of neonates with lower gestational ages and birth weights. Nevertheless, findings remain of a sex difference in mortality for premature and low birth weight (LBW) neonates with male sex often associated with poorer outcome (the "male disadvantage"). Through literature review, this article will seek clarification of the existing evidence regarding the association between sex and mortality at discharge from neonatal intensive care units (NICUs) for premature and LBW neonates. METHODS: A systematic review was conducted in Medline and Google Scholar with subsequent search of study reference lists. RESULTS: The database search yielded 349 articles and an additional 11 were identified from study reference lists. A final 32 studies were reviewed. Of these, 26 studies demonstrated worse male mortality outcome and 6 studies reported no sex difference in mortality. CONCLUSION: The majority of reviewed studies found poorer male mortality outcome. A small number of studies maintained a null association between sex and mortality. This indicates male premature and LBW neonates experience higher risk of mortality by discharge compared with females, an observation which may inform clinical decision making in the NICU. PMID- 29241281 TI - [The Circadian Clock is Now Ticking Even in Stockholm - Nobel Prize in Medicine 2017]. PMID- 29241282 TI - [Mozart's Death: Dr. Closset and a Political Plot]. PMID- 29241284 TI - ["Life is short". Rejuvenation and immortality from a historical perspective]. AB - To be young and immortal: That is the dream of humanity. Medical and civilizing progress have led to a life expectancy unthinkable a few centuries ago. Physicians wonder where it will all end. And after all, does it make sense to live forever? A look back in history and literature can help to relativize (post) modern utopias. PMID- 29241283 TI - [There is no Season for Gifts]. AB - Gifts and payments from pharmaceutical manufacturers to medical doctors constitute a conflict of interest, which may lead to an undue influence on prescribing behavior. In Germany, 35 research-based pharmaceutical companies, organized in the "Verband der forschenden Arzneimittelhersteller (VfA)" paid ? 562 million to medical doctors and hospitals in 2016. Of these, ? 356 million were paid for clinical trials and non-interventional studies, ? 105 million for sponsored presentations and CME and ? 101 million went to hospitals and other organizations for sponsoring, consulting and events. This article gives a short review on the different kinds of interactions, discusses psychological mechanisms and legal aspects of accepting gifts and recommends not to accept any gifts and donations from pharmaceutical companies to avoid undue influences on prescribing behavior. There are many ways to keep up to date using independent sources of information, and independent CME-events are growing in number - examples are given. PMID- 29241285 TI - ? PMID- 29241286 TI - [Humor in Medicine - The Art of Leaping Over the Shadows]. AB - Humor and laughter are integral parts of human life and communication - and so of course they occur in medical contacts.Humor is defined as a personality based cognitive emotional style of processing situations, characterized by the ability to find positive aspects even in negative situations, and the ability to communicate this point of view to others and to cheer them up. Humor can support healing processes and coping with illness. Humor and jokes reduce anxiety and stress (for patients and doctors). Humorous people have a more realistic, flexible and less fearful behaviour. Humor helps to overcome negative experience. Humor can help the patient to gain new views towards the disease and a healthy distance towards occurring symptoms. Humor improves the relationship between patient and doctor. But beware: jokes can also be used to express fears, aggression or shame. Therefore it is worthwhile to listen carefully to what patients want to express. Humor reduces the risk of burnout. In contact with patients, it is important to give their humor room, to use it and respond to it, more than making jokes. Humor can be trained. Humor training and creation of a humorous atmosphere in health care facilities should also be supported by health insurance funds, institutions' sponsors and public authorities. PMID- 29241287 TI - [Where and How does Yoga Work? - A Scientific Overview]. AB - As a traditional health care system, yoga combines physical activity, breathing techniques and meditation. It is increasingly used as a preventive or therapeutic means. Yoga has been researched in hundreds of randomized controlled trials. Positive effects are especially found for chronic pain conditions, hypertension, depression and in supportive cancer care. While there are case reports of serious adverse events associated with yoga, the risk seems to be extremely low and comparable to other forms of physical activity. Yoga can thus be considered as a safe and effective adjunct therapy for a number of conditions. PMID- 29241288 TI - [Aromatherapy - From Traditional and Scientific Evidence into Clinical Practice]. AB - Essential oils (EOs), also known as volatile oils, are concentrated natural plant products which contain volatile aroma compounds. Most EOs are derived by steam distillation, a tradition which can be traced back as many as 5000 years. They possess unique properties which result in various possibilities for application, also in modern medical contexts. Areas for medical aromatherapy include respiratory diseases, pain management or stress alleviation, amongst many others. Different modes of application exist: The rich ingredients can be absorbed by the body by anointment, gentle massage, inhalation, or oral intake of capsules. Also the risks of EO application in medical contexts should be considered, such as rare allergic reactions, overdosing, poor substance quality or overestimation of the effectiveness. PMID- 29241289 TI - [Radiology in the Light of Evolutionary Cognitive Theory]. AB - An X-ray photograph is not adapted to the human a priori intuition: it is not colored, it is two-dimensional, has no depth and no perspective. A radiograph is composed by about 100 gradations of grey, of which the human eye cannot resolve more than 30. Projection radiography has a cardinal problem: the superposition of normal and pathological structures. Apart from visual physiology, visual psychology plays an essential role in diagnosis: expectation and stereotyped thinking influence the interpretation of visual perception. X-ray findings are to be compared with anamnesis, laboratory values, clinical data and always with good judgement - this was already known in 1913. Plato sketched a cave analogy that describes the difficulties of interpreting "shadows" - with very interesting parallels to radiology. PMID- 29241290 TI - ? PMID- 29241291 TI - [Alcohol is an Unsafe Product]. AB - Alcohol is a hazardous product. Its consumption depends on the society's drinking norms. These are set by advertising industries on the one hand, and forces of public health and medical services on the other hand. Germany is one of the countries with high alcohol consumption. According to epidemiological evidence, alcohol-attributable diseases include more than 200 diagnostic entities. Medical practitioners may help to reduce alcohol consumption. Data revealed that brief intervention, including computer-generated feedback in medical practice, is efficient in reducing consumption. It relieves the physician of counseling responsibilities. PMID- 29241293 TI - In Vivo Delivery of Nanoparticles into Plant Leaves. AB - Plant nanobiotechnology is an interdisciplinary field at the interface of nanotechnology and plant biology that aims to utilize nanomaterials as tools to study, augment or impart novel plant functions. The delivery of nanoparticles to plants in vivo is a key initial step to investigate plant nanoparticle interactions and the impact of nanoparticles on plant function. Quantum dots are smaller than plant cell wall pores, have versatile surface chemistry, bright fluorescence and do not photobleach, making them ideal for the study of nanoparticle uptake, transport, and distribution in plants by widely available confocal microscopy tools. Herein, we describe three different methods for quantum dot delivery into leaves of living plants: leaf lamina infiltration, whole shoot vacuum infiltration, and root to leaf translocation. These methods can be potentially extended to other nanoparticles, including nanosensors and drug delivery nanoparticles. (c) 2017 by John Wiley & Sons, Inc. PMID- 29241292 TI - The In Situ Enzymatic Screening (ISES) Approach to Reaction Discovery and Catalyst Identification. AB - The importance of discovering new chemical transformations and/or optimizing catalytic combinations has led to a flurry of activity in reaction screening. The in situ enzymatic screening (ISES) approach described here utilizes biological tools (enzymes/cofactors) to advance chemistry. The protocol interfaces an organic reaction layer with an adjacent aqueous layer containing reporting enzymes that act upon the organic reaction product, giving rise to a spectroscopic signal. ISES allows the experimentalist to rapidly glean information on the relative rates of a set of parallel organic/organometallic reactions under investigation, without the need to quench the reactions or draw aliquots. In certain cases, the real-time enzymatic readout also provides information on sense and magnitude of enantioselectivity and substrate specificity. This article contains protocols for single-well (relative rate) and double-well (relative rate/enantiomeric excess) ISES, in addition to a colorimetric ISES protocol and a miniaturized double-well procedure. (c) 2017 by John Wiley & Sons, Inc. PMID- 29241294 TI - Early-Stage Formulation Considerations. AB - When a drug candidate-i.e., a new chemical entity (NCE) or new molecular entity (NME)-is discovered, there is a requirement to identify a vehicle for in vitro and/or in vivo evaluation to assess the activity and/or toxicity of the compound (here we refer to the biologically active compound as the active pharmaceutical ingredient: API). Ideally, this vehicle will not impart any biological activity or any toxicity that would mask or confound the effects of the API. At this early stage in development, and given the high attrition rates of drug candidates in discovery, it does not make sense to fully characterize the API-speed and cost are generally the driving factors. This chapter provides guidance for the development of early-stage test articles (i.e., drug products containing APIs intended to be used for the in vitro and/or in vivo evaluation) and not necessarily formulations that are intended to progress into clinical evaluation. (c) 2017 by John Wiley & Sons, Inc. PMID- 29241295 TI - In Vitro Selection and Characterization of DNA Aptamers to a Small Molecule Target. AB - Aptamers, synthetic oligonucleotide-based molecular recognition probes, have found use in a wide array of biosensing technologies based on their tight and highly selective binding to a variety of molecular targets. However, the inherent challenges associated with the selection and characterization of aptamers for small molecule targets have resulted in their underrepresentation, despite the need for small molecule detection in fields such as medicine, the environment, and agriculture. This protocol describes the steps in the selection, sequencing, affinity characterization, and truncation of DNA aptamers that are specific for small molecule targets. (c) 2017 by John Wiley & Sons, Inc. PMID- 29241296 TI - Evolving Aptamers with Unnatural Base Pairs. AB - A novel technology, genetic alphabet expansion, has rapidly advanced through the successful creation of unnatural base pairs that function as a third base pair in replication. Recently, genetic alphabet expansion has been applied to some practical areas. Among them, the application to DNA aptamer generation is a good example of the broad utility of this technology. A hydrophobic unnatural base pair, Ds-Px, which exhibits high fidelity in replication as a third base pair, has been applied to an evolutionary engineering method called SELEX (Systematic Evolution of Ligands by EXponential enrichment) to generate DNA aptamers that bind to targets. A few Ds bases in DNA aptamers significantly increase the binding affinity to targets, enabling the use of DNA aptamers as an alternative to antibodies. This protocol describes the ExSELEX (genetic alphabet Expansion for SELEX) method to generate Ds-containing DNA aptamers. (c) 2017 by John Wiley & Sons, Inc. PMID- 29241297 TI - Selecting a suitable surgical treatment for hepatic angiomyolipoma: a retrospective analysis of 92 cases. AB - BACKGROUND: Hepatic angiomyolipoma (HAML) is a rare and difficult-to-diagnose liver tumour. The aim of this study was to summarize experiences in the management of HAML and to recommend a practical treatment strategy. METHODS: We retrospectively studied 92 patients who were diagnosed with HAML and analysed the clinical presentation, histopathological features and treatment of the tumours encountered at our institute from May 2009 to June 2016. RESULTS: The patients included 67 females and 25 males who underwent at least one radiographic examination. Sixty-eight patients underwent radical hepatectomy, two patients underwent liver biopsy, and 22 patients were treated with radiofrequency ablation after liver biopsy. The tumour cells correspondingly expressed both melanoma cell markers (HMB45, MART-1) and smooth muscle cell markers. Two patients were found to have tumour recurrence (2/92, 2.2%) after radical hepatectomy, and none of the patients died. CONCLUSION: Diagnosis of HAML depends on pathological findings. The treatment strategy for HAML should be selected according to the tumour size, liver biopsy, location and clinical symptoms of HAML. Patients should be followed closely after surgery because of the malignant potential of HAML. PMID- 29241298 TI - Etiology of Salinity and Water Origin, the Main Dilemma of Badab Sourt, a Unique Travertine Spring. AB - Badab Sourt travertine-depositing springs in the north of Iran, naturally create a unique surreal landscape containing a range of stepped travertine terraces, similarly found only in a few other places on earth. This site comprises of three travertine saline springs with different values of salinity and discharge (SP1 , SP2 , and SP3 ) and one non-travertine fresh karstic spring (SP4 ) within a distance of about 300 m. The etiology behind this salinity and the water origin are the main research's dilemma that were investigated using geological, hydrochemical, and stable isotopic techniques. Based on the topography and isotopic results, the carbonate formations in northern (Khoshyeilagh and Mobarak) and southern (Cretaceous limestone) parts of the springs potentially provide the initial hydraulic gradient for deep circulation of the water and CO2 . However, geological studies indicate that the hydraulic connectivity of the Cretaceous formation to the travertine springs is interrupted by impermeable geological formations. Based on the proposed conceptual hydrogeological model and mass balance calculations, the SP4 spring is locally recharged from the nearby karstic area of Khoshyeilagh formation through shallow, short and steep groundwater flow circulation that is completely different from the travertine springs. The travertine spring (SP1 ) is recharged from more distant areas having higher altitudes on Mobarak and Khoshyeilagh limestone and circulate more deeply before emerging on the surface. The SP2 and SP3 springs can derive from the mixing of the saline water (SP1 ) and fresh water (SP4 ). The dissolution of interlayers of halite in Shemshak formation is concluded as the main source of salinity. This is the first research article in detail to survey hydrogeology of the travertine springs in Iran. PMID- 29241299 TI - NMR elucidation of monomer-dimer transition and conformational heterogeneity in histone-like DNA binding protein of Helicobacter pylori. AB - Helicobacter pylori (H. pylori) colonizes under harsh acidic/oxidative stress conditions of human gastrointestinal tract and can survive there for infinitely longer durations of host life. The bacterium expresses several harbinger proteins to facilitate its persistent colonization under such conditions. One such protein in H. pylori is histone-like DNA binding protein (Hup), which in its homo-dimeric form binds to DNA to perform various DNA dependent cellular activities. Further, it also plays an important role in protecting the genomic DNA from oxidative stress and acidic denaturation. Legitimately, if the binding of Hup to DNA is suppressed, it will directly impact on the survival of the bacterium, thus making Hup a potential therapeutic target for developing new anti-H. pylori agents. However, to inhibit the binding of Hup to DNA, it is necessary to gain detailed insights into the molecular and structural basis of Hup-dimerization and its binding mechanism to DNA. As a first step in this direction, we report here the nuclear magnetic resonance (NMR) assignments and structural features of Hup at pH 6.0. The study revealed the occurrence of dynamic equilibrium between its monomer and dimer conformations. The dynamic equilibrium was found to shifting towards dimer both at low temperature and low pH; whereas DNA binding studies evidenced that the protein binds to DNA in its dimeric form. These preliminary investigations correlate very well with the diverse functionality of protein and will form the basis for future studies aiming to develop novel anti-H. pylori agents employing structure-based-rational drug discovery approach. PMID- 29241300 TI - Prevalence of fluoroquinolone-resistant rectal flora in patients undergoing transrectal ultrasound-guided prostate needle biopsy: A prospective multicenter study. AB - OBJECTIVES: To estimate the prevalence of fluoroquinolone-resistant rectal flora in patients undergoing transrectal ultrasound-guided prostate needle biopsy and to identify the high-risk groups. METHODS: From January 2015 to March 2016, rectal swabs of 557 men who underwent transrectal ultrasound-guided prostate needle biopsy were obtained from five institutions. Clinical variables, including demographics, rectal swab culture results and infectious complications, were evaluated. Univariable and multivariable analyses were used to identify the risk factors for fluoroquinolone resistance of rectal flora and infectious complications. RESULTS: The incidence of fluoroquinolone-resistant and extended spectrum beta-lactamase production was 48.1 and 11.8%, respectively. The most common fluoroquinolone-resistant bacteria was Escherichia coli (81% of total fluoroquinolone-resistant bacteria, 39% of total rectal flora), and 16 (2.9%) patients had infectious complications. Univariable and multivariable analysis of clinical parameters affecting fluoroquinolone resistance showed no factor associated with fluoroquinolone resistance of rectal flora. The clinical parameter related to infectious complications after prostate biopsy was a history of operation within 6 months (relative risk 6.60; 95% confidence interval 1.99 21.8, P = 0.002). CONCLUSIONS: These findings suggest that a risk-based approach by history taking cannot predict antibiotic resistance of rectal flora, and physicians should consider targeted antibiotic prophylaxis or extended antibiotic prophylaxis for Korean patients undergoing transrectal ultrasound-guided prostate biopsy because of high antibiotic resistance of rectal flora. PMID- 29241301 TI - How to evaluate "true" bladder contractility? Measurement of the area under the curve of Watts factor could provide a new approach to true bladder contractility. PMID- 29241302 TI - Complications of chest drain insertion in a patient with pleural plaques. PMID- 29241304 TI - Circadian Patterns of Rats in Their Home Cages Detected Using a Video Tracking System. AB - The diurnal rhythm is the common event in nature and specially shows in the behavioral patterns.Using the infrared sensor or photo beam detector to detect this 24-h rhythmicity in behaviors of mammalian,including in the rats and mice, is also the common way. The photo-sensory detecting mean is friendlyand its advantage is unrestricted by light density and light-dark transition. However, this kind ofequipment is cost-expensive and uneasy to fit for home cage in rodents. In this study, we tried to usethe video-tracking system to detect the rhythmic activity of rats in their home cages. Adult maleSprague-Dawley rats, weighing 250-280 g, were used in this study and individual was kept in itsown cage. Combined with the infrared sensitive charge-coupled device (CCD) camera and withautomatically lights-off sensitive infrared illuminants as the accessory device, we found that animalsexhibited the circadian locomotor activity in either light-dark cycles or constant darkness conditions.Moreover, the rhythmic patterns of locomotion in animals were affected by the one-hour exposure ofwhite light under the constant darkness condition. The phase-advanced effects were found by thevideo tracking system. In summary, the video tracking system is the useful way to detect the rhythmicactivity, especially in long-term circadian rhythmicity, in rats. PMID- 29241303 TI - Body fluid status assessment by bio-impedance analysis in patients presenting to the emergency department with dyspnea. AB - BACKGROUND/AIMS: Fluid retention occurs in patients with heart failure, accounting for dyspnea. We investigated the diagnostic implication of body fluid status, assessed by bio-impedance analysis (BIA), in acute heart failure (AHF) among patients who presented with dyspnea. METHODS: A total of 100 patients who presented with dyspnea and suspected with AHF were analyzed in this study. We enrolled 50 AHF and 50 non-AHF patients discriminated through echocardiographic analysis and Framingham criteria and were matched by age and sex. Body composition was analyzed using a multifrequency BIA. RESULTS: AHF patients demonstrated higher extracellular water (ECW)/total body water (TBW) compared with non-AHF patients (0.412 +/- 0.017 vs. 0.388 +/- 0.023, p < 0.001). A significant difference of ECW/TBW between AHF patients and nonAHF patients was noted when the upper extremities, trunk, and lower extremities were analyzed (all p < 0.001, respectively). ECW/TBW was not different between patients with reduced ejection fraction (EF) and preserved EF along body compartments. The best cut-off value to predict AHF was > 0.412 at lower extremities with sensitivity and specificity of 0.780 and 0.960. The ECW/TBW of the lower extremities (ECW/TBWL) was correlated with log B-type natriuretic peptide (BNP) levels (r = 0.603, p < 0.001) and also improved the net reclassification improvement and integrated discriminated improvement when added to log BNP level. Multivariate analysis revealed that ECW/TBWL > 0.412 had an independent association with AHF patients (p = 0.011). CONCLUSION: The ECW/TBWL was higher in patients with dyspnea caused by AHF than their counterparts and demonstrated an independent diagnostic implication. It may be a promising marker to diagnose AHF at bedside. PMID- 29241305 TI - Serum Glutamine Levels as a Potential Diagnostic Biomarker in Sepsis following Surgery for Peritonitis. AB - Few diagnostic biomarkers for sepsis after emergency peritonitis surgery are available toclinicians, and, thus, it is important to develop new biomarkers for patients undergoing this procedure.We investigated whether serum glutamine and selenium levels could be diagnostic biomarkers of sepsisin individuals recovering from emergency peritonitis surgery. From February 2012 to March 2013,patients who had peritonitis diagnosed at the emergency department and underwent emergencysurgery were screened for eligibility. Serum glutamine and selenium levels were obtained at pre-operative,post-operative and recovery time points. The average level of pre-operation serum glutamine wassignificantly different from that on the recovery day (0.317 +/- 0.168 vs. 0.532 +/- 0.155 mM, P < 0.001);moreover, serum glutamine levels were unaffected by surgery. Selenium levels were significantlylower on the day of surgery than they were at recovery (106.6 +/- 36.39 vs. 130.68 +/- 56.98 ng/mL, P = 0.013);no significant difference was found between pre-operation and recovery selenium levels. Unlikeselenium, glutamine could be a sepsis biomarker for individuals with peritonitis. We recommendincluding glutamine as a biomarker for sepsis severity assessment in addition to the commonly usedclinical indicators. PMID- 29241306 TI - Combined and Isolated Effects of Alcohol Intake and One Night of Sleep Deprivation on Mood States, Hormonal and Inflammatory Responses in Healthy Male Adults:a Crossover Randomized Controlled Trial. AB - Alcohol (ALC) intake and sleep deprivation (SDP) are conditions that cause changes in thephysiological status. However, the relationship between biological markers and mood states is notentirely clear yet. The purpose of the study was to compare isolated and combined effects of ALCintake and SDP on hormonal and inflammatory responses and in changes in the state of mood. Also,we intended to explain possible changes in mood states through biochemical variations using multiplestepwise regression analysis. Ten healthy male were randomized in four situations: (1) placebo intake+ normal sleep (PLA + SLE); (2) ALC intake + SLE; (3) PLA intake + SDP; (4) ALC intake + SDP.While subjects ingested ALC (1 g/kg of beer), PLA intake was a non-alcoholic beer. The subjects hadone night of SLE or were subjected to SDP in the lab for 8 h. After each experimental condition, morningblood samples were taken for assessments of serum levels of glucose, cortisol, testosterone, epinephrine,interleukin-6 (IL-6), interleukin-10 (IL-10) and C-reactive protein (CRP). The subjects were alsoasked to fill in a Profile of Mood State questionnaire. The results showed that the glucose level wassignificant lower in ALC + SDP compared to the PLA + SLE condition. Total Mood Disturbance waslower in ALC + SDP and PLA + SDP compared to the PLA + SLE condition. Fatigue was higher underSDP conditions compared to PLA + SLE. Vigor was lower under the ALC + SDP condition comparedto the PLA + SLE condition. Regression analysis showed that Total Mood Disturbance and fatigueunder ALC + SDP were associated with changes in the cortisol levels. Our results showed that combinedand isolated ALC intake and one night of SDP did not change the hormonal and inflammatoryresponses tested, and the combined effects caused a reduction in the glucose levels. Vigor, fatigue andTotal Mood Disturbance were affected by each condition. Furthermore, Total Mood Disturbance andfatigue were possibly explained by changes in the cortisol levels in the combined condition. PMID- 29241307 TI - The Mechanism of Mitochondria-Mediated Pathway in the Apoptosis of Platelets in Immune-Induced Bone Marrow Failure. AB - Excessive platelet apoptosis is one of the pathogenic causes of immune-induced bone marrowfailure (BMF). The aim of the present study was to explore the role of mitochondria-mediated pathwayin the apoptosis of platelets in immune-induced BMF. An immune-induced BMF model was establishedin mice, which were randomly divided into three groups: normal control (CTL) group, BMF group andcyclosporine (CSA) group (n = 10 in each group). Mice were given 0.027 g/kg CSA daily in the CSAgroup. Platelet count (PLT), mitochondrial transmembrane potential (DeltaPsim), cytochrome C (CytC),phosphatidylserine (PS), calcium ion (Ca2+) and expression of proteins of the mitochondrial apoptoticpathway, including Bak, Bax, caspase-3, caspase-8 and caspase-9, was examined and compared.Compared with the CTL group, the BMF group had significantly a lower level of PLC and DeltaPsim, buthigher levels of CytC, PS, Ca2+ and higher expression levels of Bak, Bax, cleaved caspase-9 and cleavedcaspase-3 (P < 0.05). CSA restored the above changes in the BMF model (P < 0.05). Further studiesshowed that intravenous injection of the caspase-9 inhibitor Z-LE(OMe)HD(OMe)-fluoromethylketone(FMK) into the mice could significantly inhibit apoptosis of the platelets and the effect of CSAtreatment when compared to the BMF group, and exerted a better protective effect from apoptosis ifthe caspase-9 inhibitor was combined with the CSA treatment. These results revealed that plateletapoptosis may play an important role in the reduction of platelet of immune-induced BMF probablythrough the mitochondrial pathway. PMID- 29241308 TI - Infusion of Porcine-Derived Amniotic Fluid Stem Cells for Treatment of Experimental Colitis in Mice. AB - Recently, stem cells have offered an alternative treatment for inflammatory bowel disease (IBD)or colitis to overcome the poor outcomes associated with current therapies. Amniotic fluid-derivedstem cells (AFSCs) have the potential for the regeneration of impaired organs and the recovery ofnormal physiologic functions of damaged tissues without ethical concerns or risk of tumor formation.In this work, we aimed to examine the therapeutic effects of infusion of porcine AFSCs (pAFSCs) indextran sulfate sodium (DSS)-induced colitis in mice. Treatment with pAFSCs was shown to inhibitthe shortening of the colon after induction of colitis and dramatically ameliorated the body weightlossinduced by the DSS treatment. In addition, pAFSCs could also reduce the extent of the inflamedarea represented by epithelial mesenchymal transformation in the colitis mice. The levels of theinflammatory cytokines interleukin 6 (IL-6) and interferon gamma (IFN-gamma) were also reduced incolitis mice transplanted with pAFSCs. In conclusion, pAFSCs can ameliorate experimental colitis inmice, suggesting that they may be a potential treatment for IBD or colitis. PMID- 29241309 TI - Involvement of Endothelial Nitric Oxide Synthase Activation in Midkine-Mediated Central Hypotensive Effects. AB - The growth factor midkine (MK) has been implicated in various biologic and pathologic events.It has been shown that the peripheral influence of MK on cardiovascular regulation is due to aninfluence on the renin-angiotensin system (RAS). The nucleus tractus solitarii (NTS) is the primaryintegrative center for cardiovascular control and other autonomic functions in the central nervoussystem. However, the signaling mechanisms involved in MK-mediated cardiovascular effects in theNTS remain unclear. In this study, we investigated whether the RAS and/or N-methyl-D-aspartate(NMDA) receptor-calmodulin-endothelial nitric oxide synthase (eNOS) signaling pathways were bothinvolved in MK-mediated blood pressure (BP) regulation in the NTS of Wistar-Kyoto (WKY) rats.Intra-NTS microinjection and immunoblot analysis were used to evaluate the signal pathway. WKY ratswere anesthetized with urethane. Unilateral microinjection of MK (600 fmol) into the NTS produceda dose-dependent decrease in BP and heart rate (HR). The depressor effects were observed beforeand after microinjection of the angiotensin-converting enzyme (ACE) inhibitor lisinopril (2.4 fmol),or the angiotensin receptor blockers (ARB) inhibitor valsartan (7.5 pmol). However, lisinopril andvalsartan did not diminish the MK-mediated cardiovascular effects in the NTS. Microinjection ofthe NMDA receptor antagonist MK801 (1 nmol) or the NOS inhibitor N-nitro l-arginine methyl ester(L-NAME), (33 nmol), into the NTS attenuated the MK-induced hypotensive effects. Pretreatment withan eNOS inhibitor N5-iminoethyl-l-ornithine (L-NIO) (6 nmol) attenuated the MK-inducedhypotensive effects. In this study, the data showed that MK might play a role in centralcardiovascular regulation in the NTS. These results suggest that MK decreased BP and HR in the NTSprobably acting via the NMDA receptor-calmodulin eNOS signaling pathway. PMID- 29241310 TI - Indocyanine green fluorescence-guided sentinel lymph node identification in urologic cancers: a systematic review and meta-analysis. AB - INTRODUCTION: To date, bilateral pelvic lymph node dissection (PLND) represents the most accurate and reliable staging procedure for the detection of lymph node invasion in prostate cancer and bladder cancer. However, the procedure is not devoid of complications. In this field, Indocyanine green fluorescence-guided sentinel lymph node (SLN) identification is an emerging and promising technique, as accurate staging of urologic cancer could be enhanced by a thorough evaluation of the sentinel lymph nodes. Aim of the present review is to analyze available evidence and perform a metanalysis on ICG-guided SLN detection for urologic malignancies. EVIDENCE ACQUISITION: A systematic review to assess the clinical value of Indocyanine green for the identification of sentinel lymphatic drainage for bladder, prostate, kidney and penile cancers was undertaken, with a meta analysis to generate pooled detection rate concerning patients (clinical sensitivity) and nodes basin (technical sensitivity) separately. Studies reporting on the use of Indocyanine green for the detection of SLNs from the bladder, prostate and penile cancers were included. EVIDENCE SYNTHESIS: A total of 10 clinical trials were included. Using the fixed effects model and the random effects model, the pooled patient detection rates and their 95% confidence intervals (95% CI) were 0.88 (0.82-0.92) and 0.92 (0.84-0.96), respectively. The pooled nodes detection rates were 0.71 (95% CI: 0.68-0.74) using the fixed effect model and 0.75 (95% CI: 0.56-0.87) using the random effect model. Significant heterogeneities existed among studies for patients and for nodes (I2=0.66, P<0.001 and I2=0.96, P<0.001, respectively). Significant publication bias was found in patient detection rate (P<0.001) and in nodes detection rate (P<0.001). CONCLUSIONS: SLN mapping in bladder and prostate cancer is a method with a high detection rate, although its specificity to predict LN invasion remains poor. Large, well-constructed trails are needed to assess the impact of ICG fluorescence guided SLN dissection on uro-oncologic surgery. PMID- 29241311 TI - A larger detrusor wall thickness increases the risk of non muscle invasive bladder cancer recurrence and progression: result from a multicenter observational study. AB - BACKGROUND: Recent experimental study showed a higher incidence of bladder cancer in presence of bladder detrusor muscle thickening. The aim of this study is to assess whether a higher detrusor muscle thickness (DWT) may be a risk factor of recurrence of non-muscle invasive urothelial bladder cancer (NMIBC). METHODS: Men with histologically-confirmed diagnosis of NMIBC were prospectively enrolled in 4 centers between December 2015 and April 2017. DWT was measured by ultrasound and DWT>2.5 mm was used as threshold for detrusor muscle thickening. Patients underwent to adjuvant local treatment in according to their progression and recurrence risk computed by European Organization Research and Treatment of Cancer (EORTC) Score for NMIBC. Every three months cystoscopy and urinary cytology were used to detect disease recurrence and progression. The main clinic pathological variables were compared between patients with DWT<=2.5 mm and DWT>2.5 mm. RESULTS: One hundred patients (49.8%) with DWT >2.5 mm were significantly older, had larger and more tumors and experienced more prior NMIBC than 101 (50.2%) patients with a DWT<=2.5 mm. Recurrence and progression disease occurred more often and briefly in patients with a detrusor muscle thickening. At univariate analysis, DWT>2.5 was a predictive risk factors of cancer recurrence and progression, respectively: OR 4.9 (95% CI: 2.5-9.5) P=0.001 and OR 2.21 (95% CI: 1.71-4.73), P=0.001. Enclosing DWT in EORTC risk calculator significantly increased by 3% and 1% recurrence and progression risk assessment, respectively. CONCLUSIONS: Detrusor muscle thickening may have a role in NMIBC course with a higher recurrence rate, however further confirmatory and elucidating studies are required. PMID- 29241312 TI - Selective clamping during laparoscopic partial nefrectomy: the use of near infrared fluorescence guidance. AB - BACKGROUND: Near infrared fluorescence (NIRF) is being investigated as a helpful tool to enhance segmental arterial clamping in robotics. Available experiences with NIRF during standard laparoscopy are anecdotal. The aim of the study was to perform a single-center feasibility and results analysis of laparoscopic partial nephrectomy (LPN) performed using NIRF-guided selective clamping. METHODS: May 2016-December 2016: 15 patients diagnosed with a renal mass suitable for nephron sparing approach consecutively underwent LPN with NIRF-guidance technique. Demographic data, tumor characteristics; perioperative data; functional data; pathologic data; postoperative complications as classified according to the Clavien system were prospectively collected. Serum creatinine (SCr) and eGFR were assessed by serial measurements; 99mTc-MAG-3 nuclear renal scan was performed too. The measures were conducted preoperatively and at the 3rd postoperative month. RESULTS: No complications were recorded. Use of NIRF guidance did not influence the safety of the procedure. Operative time was not significantly increased with respect to the medians reported in the literature for LPN. Blood losses were negligible. NIRF-guidance allowed for successful selective clamping in 11 cases (73.3%). In one case NIRF guidance allowed for the super-selective closing of the tumor-feeding artery. In 4 cases (26.7%) selective ischemia was impossible and clamping of the main renal artery was chosen. CONCLUSIONS: NIRF guidance was successfully applied during laparoscopic PN, offering the surgeon additional information about kidney anatomy and perfusion. Our experience demonstrated the potential benefits of the new technology. The clinically relevance of selective clamping on functional outcomes is still a matter of debate. PMID- 29241313 TI - Hormonal treatment and quality of life of prostate cancer patients: new evidence. AB - Androgen deprivation therapy (ADT) is the mainstay of treatment of patients with relapsed or metastatic hormone-sensitive prostatic carcinoma. The dramatic reduction of serum testosterone levels induced by ADT produces multiple side effects as vasomotor flushing, sexual dysfunction, fatigue, impairment of cognitive function, reduced quality of sleep, gynecomastia and anemia, that are able to decrease health-related quality of life (QoL). In addition, hormonal therapy can interfere with bone metabolism and induce metabolic and cardiovascular complications. Recently, new-generation hormonal therapies, such as abiraterone and enzalutamide, have been tested and approved in castration resistant prostatic cancer patients and current studies are moving forward to the earlier use of these two drugs. In this evolving scenario, the management of hormonal therapy toxicity, given the long duration of treatment and the potentially high impact of side effects on patients' functional status and quality of life, is a critical challenge for clinicians. A correct information of patients before the initiation of treatment, together with the adoption of preventive measures, could help to ameliorate their quality of life. The aim of this review is to describe the impact on quality of life of endocrine treatment side effects and analyze possible interventions to alleviate them. PMID- 29241314 TI - Perioperative antithrombotic therapy in patients undergoing endoscopic urologic surgery: where do we stand with current literature? AB - The number of patients on chronic anticoagulant or antiplatelet therapy requiring endoscopic urological surgery is increasing worldwide. Therefore, there is a strong demand to standardize the perioperative treatment of this cohort of patients, both from a surgical and cardiological point of view, balancing the risks of bleeding versus thrombosis, and the important possible clinical and medical legal repercussions therein. Although literature is scarce and the quality of evidence quite low, in line with other surgical specialties, guidelines and recommendations for the management of urological patients have begun to emerge. The aim of this review is to analyze current available literature and evidence on the most common endoscopic procedures performed in this high-risk group of patients, focusing on the perioperative management. In particular, to analyze the most frequently performed endoscopic procedures for the treatment of benign prostate enlargement (transurethral resection of the prostate, Thulium, Holmium and greenlight laser prostatectomy), bladder cancer (transurethral resection of the bladder), upper urinary tract urothelial cancer, and nephrolithiasis. Despite the lack of randomized studies, regardless of individual patient considerations, studies would support continuation of acetylsalicylic acid, which is recommended by cardiologists, in patients with intermediate/high risk of coronary thrombosis. In contrast, multiple studies found that bridging with light weight molecular weight heparin can potentially lead to more bleeding than continuation of the anticoagulant(s) and antiplatelet therapy, and caution with bridging is advised. All urologists should familiarize themselves with emerging guidelines and recommendations, and always be prepared to discuss specific cases or scenarios in a dedicated multidisciplinary team. PMID- 29241315 TI - Natural antioxidant extracts as food preservatives. AB - The food industry is becoming more specialized and processing methods are continuously being developed to meet consumer needs. Consumers demand products that are safe and preferably free of synthetic additives. These additives are associated with health effects, in most cases without reasonable justification. Consequently, consumers are looking for clearly labelled products that guarantee the absence of synthetic additives. This has led to the need to search for natural additives, which the food industry claims arenatural antioxidant preservatives. The sources of natural antioxidants can be extremely varied, because practically all plants contain antioxidants that allow them to protect themselves from solar radiation and pests, as well as to regulate the production of chemical energy. However, the best alternatives for the food industry are fruits and spices, because they are already foods themselves. This article will describe fruits and spices considered as important sources of phenolic antioxidants. The main medicinal properties are related to phenolic compounds and their uses as additives, depending on their chemical structure. PMID- 29241316 TI - Effect of jasmonic acid and yeast extract elicitation on low-molecular antioxidants and antioxidant activity of marjoram (Origanum majorana L.). AB - BACKGROUND: Elicitation, which is a way of inducing plant secondary metabolism, may be an effective method for improving the quality of plant food. The aim of this study was to determine how the application of jasmonic acid (as an abiotic elicitor) and yeast extract (as a biotic elicitor) influences the production of some bioactive compounds in marjoram and the antioxidant activity of this herb. METHODS: Elicitation with 0.01 µM and 1 µM jasmonic acid as well as 0.1% and 1% yeast extracts was used for improving the health-benefiting quality of marjoram. The study focused on the effects of eliciting the level of some phytochemicals and the antioxidant activity of marjoram. RESULTS: There were no significant differences in total phenolic content between the elicited and control plants. In turn, the elicitation with 0.1% and 1% yeast extracts caused 1.8- and 2.5-fold increases in the ascorbic acid content in marjoram leaves, respectively. Both biotic and abiotic elicitation resulted in elevation of chlorophyll content, but only the abiotic elicitor (jasmonic acid) caused a significant increase (by over 50%) in the carotenoid content of marjoram leaves. The antiradical activity of marjoram was increased by the abiotic and biotic elicitation, whereas only the abiotic elicitation resulted in improving the reducing power of this herb. CONCLUSIONS: In conclusion, biotic and abiotic elicitation could be an effective strategy for improving the level of some phytochemicals, as well as the antioxidant activity of marjoram. A particularly valuable finding obtained in this study is that natural elicitors e.g. yeast extract can be equally effective in elevating the content of some bioactive compounds in herbs e.g. marjoram as an abiotic one. PMID- 29241317 TI - Optimization of soymilk, mango nectar and sucrose solution mixes for better quality of soymilk based beverage. AB - BACKGROUND: Soy milk-based beverages play an important role as a healthy food alternative for human consumption. However, the ‘beany’ flavor and chalky mouth feel of soy milk often makes it unpalatable to consumers. The objective of the present study is to optimize a blend of soy milk, mango nectar and sucrose solution for the best quality soy milk-based beverage. METHODS: This study was designed to develop a soy milk blended beverage, with mango nectar and sucrose solutions, with the best physicochemical and sensory properties. Fourteen combinations of formulations were determined by D-optimal mixture simplex lattice design, by using Design expert. The blended beverages were prepared by mixing the three basic ingredients with the range of 60−100% soy milk, 0–25% mango nectar and 0–15% sucrose solution. The prepared blended beverage was analyzed for selected physicochemical and sensory properties. The statistical significance of the terms in the regression equations were examined by Analysis of Variance (ANOVA) for each response and the significance test level was set at 5% (p < 0.05). RESULTS: The results showed that, as the proportion of mango nectar and sucrose solution increased, total color change, total soluble solid, gross energy, titratable acidity, and beta-carotene contents increased but with a decrease in moisture , ash, protein, ether extract, minerals and phytic acid contents was observed. Fi- nally, numerical optimization determined that 81% soy milk, 16% Mango nectar and 3% sugar solution will give by a soy milk blended beverage with the best physicochemical and sensory properties, with a desirability of 0.564. CONCLUSIONS: Blending soy milk with fruit juice such as mango is beneficial, as it improves sensory as well as selected nutritional parameters. PMID- 29241318 TI - Polyphenolic content, antiradical activity, stability and microbiological quality of elderberry (Sambucus nigra L.) extracts. AB - BACKGROUND: The pharmaceutical and food industries expect detailed knowledge on the physicochemical properties of elderberry fruit extracts, their stability and microbiological quality, as well as the polyphenol content in elderberry cultivars. The characteristics of the extracts might be additionally modified by citric acid, which improves the stability of anthocyanins and protects processed fruits and syrups from pathogenic microorganisms. The choice of the method with citric acid was a consequence of the physicochemical charac teristics of elderberry pigments, which are not stable under the effect of light in alcoholic solutions. The aim of study was to analyze the properties of elderberry fruit extracts regarding polyphenol content and antiradical activity, as well as their stability and microbiological quality. METHODS: The plant material consisted of fruit from four cultivars (Alleso, Korsor, Sampo, Samyl) of black elderberry (Sambucus nigra L.). The following were determined in fruit extracts: polyphe- nolic content (HPLC), antiradical activity (ABTS and DPPH) and stability and microbiological quality. RESULTS: The HPLC analysis of polyphenols demonstrated that the extracts from fruits collected from cv. Samyl had the highest 3 sambubioside cyanidin content and those from cv. Korsor contained the highest quantity of 3-glucoside cyanidin. The extracts from cv. Sampo fruit had a dominant 3-sambubioside-5-gluco- side cyanidin and 3,5-diglucoside cyanidin content. The highest quercetin (5.92 mg 100 mg-1 of extract) and caffeic acid (1.21 mg 100 mg-1 of extract) content was found in fruit extracts from cv. Alleso. The cultivars Samyl and Korsor had a higher level of anthocyanins and higher antiradical activity (ABTS) in fruit extracts than cv. Alleso and Sampo. The antiradical activity (DPPH) of fruit extracts from elderberry cultivars as- sessed in this research was similar. The degradation index for all fruit extracts was similar (DI = 1.035). The microbiological species detected in extracts were classified as moulds (Penicillum sp., Aspergillus sp.) and yeasts (Rhodotorula sp., Torulopsis sp., Trichosporon sp., Saccharomyces sp.). CONCLUSIONS: The research findings may support the selection of certain cultivars for industrial applications. The high stability of anthocyanins and low level of microbiological impurities in elderberry extracts ensure the high quality of such a raw material in food and pharmaceutical processing. PMID- 29241319 TI - Effects of six substances on the growth and freeze-drying of Lactobacillus delbrueckii subsp. bulgaricus. AB - BACKGROUND: The efficacy of Lactobacillus delbrueckii subsp. bulgaricus as starter cultures for the dairy industry depends largely on the number of viable and active cells. Freeze-drying is the most convenient and successful method to preserve the bacterial cells. However, not all strains survived during freeze drying. METHODS: The effects of six substances including NaCl, sorbitol, mannitol, mannose, sodium glutamate, betaine added to the MRS medium on the growth and freeze-drying survival rate and viable counts of Lb. delbrueckii subsp. bulgaricus were studied through a single-factor test and Plackett-Burman design. Subsequently, the optimum freeze-drying conditions of Lb. delbrueckii subsp. bulgaricus were determined. RESULTS: Lb. delbrueckii subsp. bulgaricus survival rates were up to the maximum of 42.7%, 45.4%, 23.6%, while the concentrations of NaCl, sorbitol, sodium glutamate were 0.6%, 0.15%, 0.09%, respectively. In the optimum concentration, the viable counts in broth is 6.1, 6.9, 5.13 (×108 CFU/mL), respectively; the viable counts in freeze-drying power are 3.09, 5.2, 2.7 (×1010 CFU/g), respectively. CONCLUSIONS: Three antifreeze factors including NaCl, sorbitol, sodium glutamate have a positive effect on the growth and freeze-drying of Lb. delbrueckii subsp. bulgaricus. The results are beneficial for developing Lb. delbrueckii subsp. bulgaricus. PMID- 29241320 TI - Influence of marinades on shear force, structure and sensory properties of home style jerky. AB - BACKGROUND: Products from dried meat have been sold for many years as snack foods. The most important sensory attributes of this type of food are texture and flavour, determined by the selection of the raw material and the effect of numerous technological factors. The aim of the study was to investigate the structure, sen- sory and mechanical properties of meat snacks produced under non commercial conditions using wild boar, roe deer and beef as raw material. METHODS: Jerky was prepared from Longissimus muscle treated (24 h, 4°C) with the follow- ing marinades before drying at 55°C for 6 h: (a) spices, (b) lemon & honey marinade, (c) marinating with balsamic vinegar marinade, (d) dipping into pineapple marinade, and (e) using ginger marinade. The jerky’s shear and work forces, structure and sensory properties were compared. RESULTS: An increase in sensory properties and a decrease in WB parameters as a consequence in muscle structural elements changes were found in all marinate treated samples compared to the control. The greatest changes were observed when the meat was soaked with pineapple marinade before drying. Lower ones were observed when ginger and balsamic vinegar marinades were applying, and the lowest when jerky was produced using lemon & honey. Roe deer jerky, compared to wild boar and beef, received better scores for texture, and worse for overall acceptability. CONCLUSIONS: Marinades containing proteolytic enzymes or characterized by a low pH could be used as tenderizers in jerky production from initially tough meat such as wild boar, and marinades based on lemon & honey and also vinegar could be used for flavoring tender meat with an intense aroma, such as roe deer meat. PMID- 29241321 TI - The suitability of different probiotic strains for the production of fruit-whey beverages. AB - BACKGROUND: When designing new probiotic products, one of the most important aspects is the selection of bacterial strains with high survival rates in the matrix of the product concerned. The aim of the present research was to evaluate the potential of selected strains of probiotic bacteria for the production of fruit-whey beverages. METHODS: Orange, apple and blackcurrant whey beverages were produced, and each was inoculated with one of the following probiotic strains: Bifidobacterium lactis HN019TM; Lactobacillus aci- dophilus NCFM®; Lactobacillus paracasei Lpc-37TM; Lactobacillus rhamnosus HN001TM. The count of probiotic bacteria as well as pH and total acidity were evaluated at the 1st, 7th, 14th, 21st and 28th day of storage. RESULTS: Beverages containing L. paracasei Lpc-37TM or L. rhamnosus HN001TM were characterized by a sig- nificantly higher average number of viable cells (7.02 or 7.05 log cfu/g, respectively) than products with lactis HN019TM or L. acidophilus NCFM® (6.43 or 6.37 log cfu/g, respectively). The use of L. paracasei Lpc-37 and L. rhamnosus HN001 strains in orange and apple drinks allows the recommended count for probiotic products, 106 cfu/g for 28 days of storage, to be exceeded. Survival of the B. lactis HN019 strain fulfills the above requirements only in the orange drink. The L. acidophilus NCFM® strain was found to be the least suitable for the production of beverages, as it did not reach 6 log cfu/g in any products after 28 days of stor- age. The highest average number of bacteria was found in the orange beverages (7.14 log cfu/g). In terms of bacteria viability, blackcurrant juice was the least suitable for the production of whey probiotic drinks, due to its high acidity. CONCLUSIONS: The results of the present study indicate that careful selection of the fruit juice component, especially in terms of its acidity, is key to designing successful probiotic fruit-whey beverages. Other factors which should be taken into account to ensure a sufficient number of live probiotic cells, i.e. their therapeutic level in fruit-whey drinks, are the choice of probiotic strain and determination of the maximal shelf life. PMID- 29241322 TI - Modulatory effects of dietary supplementation by Vernonia amygdalina on high-fat diet-induced obesity in Wistar rats. AB - BACKGROUND: Obesity is a growing public health problem arising from energy imbalance. The effect of 10% dietary incorporation of Vernonia amygdalina (VA) leaves into high-fat diets on some biological markers of adiposity and dyslipidaemia was investigated. METHODS: Experimental diets consisted of the following – CD (control diet); HFD (high-fat diet); and HFD- VA (HFD containing 10% Vernonia amygdalina leaves) supplementation. Fifteen male Wistar rats were randomly divided into three groups of five animals each. After twelve weeks of feeding, serum lipid profile, blood glucose concentrations, body weight, adiposity index, feed intake, fecal loss and relative organ weight were investigated. RESULTS: Vernonia amygdalina (VA) inhibited HFD-induced weight gain and adiposity in rats. HFD-induced obese rats showed a significant increase in the levels of serum TG and TC compared to rats on a normal diet. However, the levels of serum TG, TC, LDL-C in HFDVA rats reduced significantly relative to the levels in HFD rats. Our results indicate that HFDVA reversed fatty infiltration leading to decreased body weight and fat tissue mass in the rats. CONCLUSIONS: These results suggested that incorporation of Vernonia amygdalina into high-fat diets may have therapeutic potentials for obesity and related metabolic disorders. Further studies to explore its possibility as an alternative pharmacologic agent to treat obesity are warranted. PMID- 29241323 TI - Serum 25-hydroxyvitamin D concentrations and selected diet components in postmenopausal women. AB - BACKGROUND: Nutrition and lifestyle factors play an important role in the development and maintenance of peak bone mass and the prevention of bone degradation. The aim of the present study was to assess 25-hydroxy- cholecalciferol [25(OH)D] serum concentration in postmenopausal women during the winter period and the supply of selected components in their diet. METHODS: The study was conducted on a group of 35 women aged 54–77, using a question- naire, including a 24-hour recall related to a subject’s nutrient consumption. Serum concentrations of 25(OH) D were determined. Body composition was assessed with bioelectrical impedance analysis. RESULTS: Mean 25(OH)D serum concentration was found to be 61.2% of the minimum healthy level, according to the reference values. The supply of vitamin D and calcium covered 36.2% and 56.7% of RDA respectively. Correlation analysis has shown a significant inverse relationship between 25(OH)D serum con- centration and body fat (p < 0.05). CONCLUSIONS: The study indicates a decreased serum concentration of 25(OH)D in postmenopausal women during the winter period and a low supply of vitamin D and calcium in their diet. Nutrition education should be introduced to the adult population to prevent bone fractures. PMID- 29241324 TI - Repeatedly heated palm kernel oil induces hyperlipidemia, atherogenic indices and hepatorenal toxicity in rats: Beneficial role of virgin coconut oil supplementation. AB - BACKGROUND: The literature reports that the health benefits of vegetable oil can be deteriorated by repeated heating, which leads to lipid oxidation and the formation of free radicals. Virgin coconut oil (VCO) is emerging as a functional food oil and its health benefits are attributed to its potent polyphenolic compounds. We investigated the beneficial effect of VCO supplementation on lipid profile, liver and kidney markers in rats fed repeatedly heated palm kernel oil (HPO). METHODS: Rats were divided into four groups (n = 5). The control group rats were fed with a normal diet; group 2 rats were fed a 10% VCO supplemented diet; group 3 administered 10 ml HPO/kg b.w. orally; group 4 were fed 10% VCO + 10 ml HPO/kg for 28 days. Subsequently, serum markers of liver damage (ALT, AST, ALP and albumin), kidney damage (urea, creatinine and uric acid), lipid profile and lipid ratios as cardiovascular risk indices were evaluated. RESULTS: HPO induced a significant increase in serum markers of liver and kidney damage as well as con- comitant lipid abnormalities and a marked reduction in serum HDL-C. The lipid ratios evaluated for atherogenic and coronary risk indices in rats administered HPO only were remarkably higher than control. It was observed that VCO supplementation attenuated the biochemical alterations, including the indices of cardiovascular risks. CONCLUSIONS: VCO supplementation demonstrates beneficial health effects against HPO-induced biochemical alterations in rats. VCO may serve to modulate the adverse effects associated with consumption of repeatedly heated palm kernel oil. PMID- 29241325 TI - Nanoscale Organic-Inorganic Hybrid Photosensitizers for Highly Effective Photodynamic Cancer Therapy. AB - Recently, photodynamic therapy (PDT) has attracted significant attention as a minimally invasive approach for cancer treatment. Clinical applications of current photosensitizers are often limited by their poor water solubility, low singlet oxygen (1O2) quantum yields, long-term toxicity, instability, and complex nanostructures. Here, we report a rational design of polyhedral oligomeric silsesquioxanes (POSSs)-based porphyrin (PPP5000) used as an intrinsically nanoscale photosensitizer. In this strategy, inorganic 3D rigid block POSSs not only act as antiaggregate units but also provide conjugating reactive sites for further chemical modification. Without an additional carrier and formulation process, PPP5000 intrinsically shows high water solubility (~40 mg/mL), good PDT efficiency, and more excellent anticancer performance compared to tetra(hydroxyphenyl)porphyrin (the parent compound of m-THPC, Foscan). Considering the organic nature of porphyrin and the biodegradable property of inorganic POSS scaffolds at physiological conditions, the present work may lead to a new generation of biodegradable and intrinsic PDT agents with overall performance superior to conventional agents in terms of 1O2 production efficiency, water solubility, structurally stability, photostability, and biocompatibility. PMID- 29241326 TI - The Associative Memory, Water Mediated, Structure and Energy Model (AWSEM) Amylometer: Predicting Amyloid Propensity and Fibril Topology Using an Optimized Folding Landscape Model. AB - Amyloids are fibrillar protein aggregates with simple repeated structural motifs in their cores, usually beta-strands but sometimes alpha-helices. Identifying the amyloid-prone regions within protein sequences is important both for understanding the mechanisms of amyloid-associated diseases and for understanding functional amyloids. Based on the crystal structures of seven cross-beta amyloidogenic peptides with different topologies and one recently solved cross alpha fiber structure, we have developed a computational approach for identifying amyloidogenic segments in protein sequences using the Associative memory, Water mediated, Structure and Energy Model (AWSEM). The AWSEM-Amylometer performs favorably in comparison with other predictors in predicting aggregation-prone sequences in multiple data sets. The method also predicts well the specific topologies (the relative arrangement of beta-strands in the core) of the amyloid fibrils. An important advantage of the AWSEM-Amylometer over other existing methods is its direct connection with an efficient, optimized protein folding simulation model, AWSEM. This connection allows one to combine efficient and accurate search of protein sequences for amyloidogenic segments with the detailed study of the thermodynamic and kinetic roles that these segments play in folding and aggregation in the context of the entire protein sequence. We present new simulation results that highlight the free energy landscapes of peptides that can take on multiple fibril topologies. We also demonstrate how the Amylometer methodology can be straightforwardly extended to the study of functional amyloids that have the recently discovered cross-alpha fibril architecture. PMID- 29241327 TI - A Spectral Shift-Based Electrochemiluminescence Sensor for Hydrogen Sulfide. AB - Classic electrochemiluminescence (ECL) assays relying on the change in luminescence intensity face a challenge in the quantitative analysis of complex samples. Here, we report the design and implementation of a new sensing strategy, using the maximum luminescence wavelength (lambdamax) shift as the readout to achieve quantitative detection. This approach includes an ECL luminophore (RuSiO2@GO) and a H2S-sensitive inner filter absorber (CouMC). The absorbance of CouMC illustrates a dependence on the H2S concentration, which induces a change in the maximum luminescence wavelength (Deltalambdamax) of the ECL luminophore. Both experimental and simulated results suggest that the spectral shift of ECL effectively avoids the interference of the total luminescence intensity fluctuations, enabling a highly reliable quantitative analysis. This spectral shift-based ECL assay strategy offers a wide application potential by extending types of ECL luminophores and absorptive chemodosimeters, based on an inner filter effect. PMID- 29241328 TI - Dimeric Porphyrin Small Molecules for Efficient Organic Solar Cells with High Photoelectron Response in the Near-Infrared Region. AB - Small molecules (SMs) with elongated backbones are promising for achieving a higher photovoltaic performance. Herein, a dimeric porphyrin small molecule, ZnP2 DPP, consisting of two porphyrin units linked with an ethynylene as the core and two diketopyrrolopyrrole (DPP) units as the arms is designed and synthesized as an electron donor for solution-processed bulk-heterojunction (BHJ) organic solar cells (OSCs). A significantly enhanced power conversion efficiency of 8.45% with an impressive short-circuit current density (Jsc) up to 19.65 mA cm-2 is achieved for the BHJ OSCs based on ZnP2-DPP under AM 1.5G irradiation (100 mW cm-2) compared to that for the OSCs based on the dimeric porphyrin linked with bis ethynylenes reported previously. Furthermore, the devices show broad photoelectron responses up to 1000 nm with high near-infrared external quantum efficiency up to 66% at 780 nm. This is the first study reporting SM OSCs displaying such a large Jsc of about 20 mA cm-2 simultaneously with a considerably high and deep photoelectron response of up to 1000 nm. PMID- 29241329 TI - Epitope Binning Assay Using an Electron Transfer-Modulated Aptamer Sensor. AB - Surface plasmon resonance and quartz crystal microbalance are workhorses of protein-DNA interaction research for over 20 years, providing ways to quantitatively determine the protein-DNA binding. However, the cost, necessary technical expertise, and severe nonspecific adsorption poses barriers to their use. Convenient and effective techniques for the measurement of protein-DNA binding affinity and the epitope binning between DNA and proteins for developing highly sensitive detection platform remain challenging. Here, we develop a binding-induced alteration in electron transfer kinetics of the redox reporter labeled (methylene blue) on DNA aptamer to measure the binding affinity between prostate-specific antigen (PSA) and aptamer. We demonstrate that the binding of PSA to aptamer decreases the electron transfer rate of methylene blue for ~45%. Further, we identify the best pairwise selection of aptamers for developing sandwich assay by sorting from 10 pairwise modes with the PSA detection limit of 500 ng/mL. Our study provides promising ways to analyze the binding affinity between ligand and receptor and to sort pairwise between aptamers or antibodies for the development of highly sensitive sandwich immunoassays. PMID- 29241330 TI - Ultrasensitive and Highly Stable Resistive Pressure Sensors with Biomaterial Incorporated Interfacial Layers for Wearable Health-Monitoring and Human-Machine Interfaces. AB - Flexible piezoresistive sensors have huge potential for health monitoring, human machine interfaces, prosthetic limbs, and intelligent robotics. A variety of nanomaterials and structural schemes have been proposed for realizing ultrasensitive flexible piezoresistive sensors. However, despite the success of recent efforts, high sensitivity within narrower pressure ranges and/or the challenging adhesion and stability issues still potentially limit their broad applications. Herein, we introduce a biomaterial-based scheme for the development of flexible pressure sensors that are ultrasensitive (resistance change by 5 orders) over a broad pressure range of 0.1-100 kPa, promptly responsive (20 ms), and yet highly stable. We show that employing biomaterial-incorporated conductive networks of single-walled carbon nanotubes as interfacial layers of contact-based resistive pressure sensors significantly enhances piezoresistive response via effective modulation of the interlayer resistance and provides stable interfaces for the pressure sensors. The developed flexible sensor is capable of real-time monitoring of wrist pulse waves under external medium pressure levels and providing pressure profiles applied by a thumb and a forefinger during object manipulation at a low voltage (1 V) and power consumption (<12 MUW). This work provides a new insight into the material candidates and approaches for the development of wearable health-monitoring and human-machine interfaces. PMID- 29241331 TI - Photodissociation Dynamics of Benzaldehyde-d5 at 205 nm:The H Atom Production Channel. AB - Photodissociation dynamics of benzaldehyde-d5 (C6D5CHO) at 205 nm was investigated by measuring laser-induced fluorescence spectra of fragment H atoms. From the Doppler-broadened spectra, center-of-mass translational energy release into the C6D5CO + H channel was obtained as 68.8 +/- 5.8 kJ/mol with the absolute quantum yield, 0.17 +/- 0.03. The observed translational energy was successfully estimated from two-dimensional potential energy surfaces along the C-H dissociation coordinate and the CCO bent angle and the out-of-plane H angle, respectively calculated at the B3LYP/cc-pVDZ level. The dissociation of H should take place along the triplet surface via intersystem crossing from S1 after internal conversion from the initially excited S3 state and on the triplet surface, the dissociation proceeds along the CCO bent-linear-bent configuration with H being planar to nonplanar pathway. PMID- 29241332 TI - Variability in Lignin Composition and Structure in Cell Walls of Different Parts of Macauba (Acrocomia aculeata) Palm Fruit. AB - The lignins from different anatomical parts of macauba (Acrocomia aculeata) palm fruit, namely stalks, epicarp, and endocarp, were studied. The lignin from stalks was enriched in S-lignin units (S/G 1.2) and beta-ether linkages (84% of the total) and was partially acylated at the gamma-OH of the lignin side-chains (26% lignin acylation), predominantly with p-hydroxybenzoates and acetates. The epicarp lignin was highly enriched in G-lignin units (S/G 0.2) and consequently depleted in beta-ethers (65%) and enriched in condensed structures such as phenylcoumarans (24%) and dibenzodioxocins (3%). The endocarp lignin was strikingly different from the rest and presented large amounts of piceatannol units incorporated into the polymer. This resulted in a lignin polymer depleted in beta-ethers but enriched in condensed structures and linked piceatannol moieties. The incorporation of piceatannol into the lignin polymer seems to have a role in seed protection. PMID- 29241333 TI - Online HPLC-ESI-HRMS Method for the Analysis and Comparison of Different Dissolved Organic Matter Samples. AB - Natural dissolved organic matter (DOM) is an ultracomplex mixture that is essential to global carbon cycling but is poorly understood because of its complexity. The most powerful tool for the DOM characterization is high resolution mass spectrometry (HRMS) generally combined to direct infusion (DI) as sample introduction. Liquid chromatography (LC) represents a compelling alternative to DI; however, state-of-the-art techniques involve only offline LC HRMS approaches, which have important logistical drawbacks that make DOM analysis more challenging. This study introduces a new method based on online coupling of liquid chromatography to high resolution mass spectrometry, able to overcome the disadvantages of usual approaches. It is characterized by high reproducibility (% Bray-Curtis dissimilarity among replicates ~ 2.5%), and it reduces transient complexity and contaminant interferences, thus increasing the signal-to-noise ratio (S/N), leading to the identification of an overall larger number of formulas in the mixture. Moreover, the application of an in silico fractionation prior to the statistical analysis allows an easy, flexible, fast, and detailed comparison of DOM samples from a variety of sources with a single chromatographic run. PMID- 29241334 TI - Magnetically Bistable Nitrenes: Matrix Isolation of Furoylnitrenes in Both Singlet and Triplet States and Triplet 3-Furylnitrene. AB - Two simple acylnitrenes, 2-furoylnitrene (2) and 3-furoylnitrene (6), were generated through 266 nm laser photolysis of the corresponding azides. Both are magnetically bistable in cryogenic matrices, as evidenced by the direct observation of the closed-shell singlet state with IR spectroscopy in solid Ne, Ar, Kr, Xe, and N2 matrices (3-40 K) and the triplet state in toluene (10 K) with EPR spectroscopy (32: |D/hc| = 1.48 cm-1 and |E/hc| = 0.029 cm-1; 36: |D/hc| = 1.39 cm-1 and |E/hc|c = 0.039 cm-1). Subsequent visible-light and UV laser irradiations led to the formation of furyl isocyanates (3 and 7) and ring-opening product 3-cyanoacrolein (9-E and 9-Z), respectively, in which the elusive 3 furylnitrene (38) was also identified by IR and EPR spectroscopy (|D/hc| = 1.12 cm-1 and |E/hc| = 0.005 cm-1). PMID- 29241335 TI - Taxation on Innovation. PMID- 29241340 TI - A Single-Center Experience With Tacrolimus LCP (Envarsus XR) in Pancreas Transplant Recipients. PMID- 29241339 TI - A novel model for a hub-and-spoke spinal service and improvements in the treatment of spinal pathology in a rural hospital setting. AB - INTRODUCTION: We present a unique pathway for care aimed specifically at spinal patients. As a result of the shift of the spoke direction from the existing hub and-spoke model, patient care is being redirected successfully with great benefit to a rural department. Within the rural community, it is the spoke that is the main locality to which patients present and at which they are treated. Subspecialty procurement is often more central and located in tertiary referral centres outside of a rural position. This in itself can prove difficult to patients and their relatives because subspecialty treatment, when required, is often only accessed at tertiary referral centers, which can present travel difficulties to patients and their relatives. This is at a time of great vulnerability for patients and families when what is required is more stability and familiarity. METHODS: We conducted a retrospective cohort study between 15 December 2014 and 21 September 2016. We examined the number of patients that had been seen and treated in both an inpatient and outpatient setting after a change of departmental policy and the introduction of two designated spinal consultants into a rural trauma and orthopaedic hospital in the county of Suffolk in eastern England. Before this introduction, patients were transferred out from this rural setting where inpatient management was required and/or seen in outpatient departments in more central (hub) locations. Over this time, 1413 patients were seen on an elective basis by two spinal consultants and 199 by one of those consultants on an emergency basis. RESULTS: This has led to a fruitful integration of spinal care in the rural hospital setting with the introduction of a first-line on-call service, specialist spinal onsite support with commissioned outpatient and trauma facilities, thereby increasing the facilities in the rural hospital setting on a background of continued support from the hub specialist centre. CONCLUSIONS: This novel approach improves support for existing trauma and orthopaedic surgery departments, increases commissioned facilities within the rural hospital setting and improves the care received on a more local level by patients developing spinal pathologies. This subspecialty service was previously only available within the more central, large city-based hub hospital. After the introduction of a subspecialty spine service, facilities within this spoke rural hospital have increased and access to these services is more available locally to the rural community. This has improved patient care dramatically. PMID- 29241341 TI - Abaloparatide: Review of a Next-Generation Parathyroid Hormone Agonist. AB - OBJECTIVE: To review the efficacy, safety, and economics of abaloparatide in the treatment of postmenopausal osteoporosis. DATA SOURCES: PubMed (1966 to October 2017), Clinicaltrials.gov (October 2017), and Scopus (1970 to October 2017) were searched using abaloparatide, Tymlos, BA058, PTHrP 1-34 analog, and parathyroid hormone-related peptide 1-34 analog. STUDY SELECTION AND DATA EXTRACTION: Human studies published in peer-reviewed publications in English were the primary sources for efficacy, safety, and economic data. DATA SYNTHESIS: In the 2 randomized, published clinical studies of 24 weeks and 18 months duration, bone mineral density changes were higher for abaloparatide (lumbar spine, 6.7%-11.2%; femoral head, 3.1%-3.2%; total hip, 2.6%-4.2%) compared with placebo (lumbar spine, 0.6%-1.6%; femoral head, -0.4% to 0.8%; total hip, -0.1% to 0.4%; P < 0.05) and compared with teriparatide in the 24-week study (total hip 2.6% vs +0.5%, P < 0.05). New vertebral and nonvertebral fractures occurred in 0.6% and 2.7% of patients on abaloparatide compared with 4.2% and 4.7% on placebo in the 18-month study ( P < 0.05). Abaloparatide appears to have a somewhat higher risk for adverse effects, discontinuation as a result of adverse effects, and serious or severe adverse effects than teriparatide, but teriparatide has a higher risk for hypercalcemia. Pharmacoeconomic modeling appears to favor abaloparatide if differences in efficacy and cost are maintained. CONCLUSION: Abaloparatide, which has less effect on osteoclasts, is an alternative to teriparatide in patients with postmenopausal osteoporosis who are at high risk for fractures or who have failed antiresorptive therapy based on initial clinical studies and economic modeling. PMID- 29241342 TI - Evaluating the Impact of the Addition of Cladribine to Standard Acute Myeloid Leukemia Induction Therapy. AB - BACKGROUND: Treatment for acute myeloid leukemia (AML) has remained relatively unchanged over the past few decades. Although recent drug approvals have provided an increase in the number of treatment options in AML, further optimization of standard induction therapy is still necessary. The most commonly utilized induction options have been well studied, but there is a paucity of literature comparing the combination of idarubicin with cytarabine and cladribine. OBJECTIVE: To assess the clinical effectiveness of the addition of cladribine to idarubicin and cytarabine (7+3 IA) induction therapy in the treatment of AML. METHODS: This retrospective, propensity score-matched cohort study evaluated 37 patients with previously untreated AML who received either 7+3 IA or idarubicin, cytarabine, and cladribine (7+3+5 IAC) as induction therapy. The primary end point of this study was complete response (CR), with secondary end points including hospital length of stay (LOS), and adverse event rates. RESULTS: After propensity score matching, odds of reaching CR in the 7+3+5 IAC cohort were increased by 33% (95% CI = 1.09-1.55; P < 0.01) compared with the 7+3 IA cohort. Patients who received cladribine were also found to have a reduction in hospital LOS by 3.5 days (95% CI = 0.07-6.85; P = 0.045) without an increase in adverse event rates. CONCLUSION: The addition of cladribine to the 7+3 IA regimen may improve clinical outcomes when used as initial induction therapy, without increasing the incidence of adverse event rates. PMID- 29241343 TI - Can Biologic Augmentation Improve Clinical Outcomes Following Microfracture for Symptomatic Cartilage Defects of the Knee? A Systematic Review. AB - Objective To perform a systematic review of clinical outcomes following microfracture augmented with biological adjuvants (MFX+) compared with microfracture (MFX) alone. Design The MEDLINE, Scopus, and Cochrane databases were searched for clinical studies on MFX+ for chondral defects of the knee. Study characteristics and clinical outcome score data were collected. Subjective synthesis was performed using data from randomized controlled studies to determine effect size of MFX+ procedures performed with either injectable or scaffold-based augmentation compared with MFX alone. Results A total of 18 articles reporting on 625 patients (491 MFX+, 134 MFX) were identified. Six studies were level II evidence and 1 study was level I evidence. Mean patient age range was 26 to 51 years, and mean follow-up ranged from 2 to 5 years. All studies demonstrated significant improvement in reported clinical outcome scores at follow-up after MFX+ therapy, and 87% of patients reported satisfaction with treatment. The most commonly reported treatment complication was postoperative stiffness (3.9% of patients). Subjective synthesis on randomized controlled trials demonstrated that 2/2 injectable MFX+ interventions had significantly greater improvements in International Knee Documentation Committee Subjective Knee Form (IKDC; P = 0.004) and Knee injury and Osteoarthritis Outcome Score (KOOS; P = 0.012) scores compared with MFX alone, while 2/2 trials on scaffolding MFX+ adjuvants showed comparable postoperative improvements. Conclusions MFX+ biological adjuvants are safe supplements to marrow stimulation for treating cartilage defects in the adult knee. Early literature is heterogenous and extremely limited in quality. Individual trials report both equivalent and superior clinical outcomes compared with MFX alone, making definitive conclusions on the efficacy of MFX+ difficult without higher quality evidence. PMID- 29241345 TI - Effects of attentional focus on motor learning in children with autism spectrum disorder. AB - Inability to acquire a new motor skill is a common motor difficulty in children with autism spectrum disorder. The purpose of this study is to examine whether the motor learning benefits of an external focus of attention for typically developing children and children with intellectual disabilities could also be applied to children with autism spectrum disorder. Children ( N = 65; mean age = 10.01 years) diagnosed with high-functioning autism spectrum disorder were randomly assigned into one of the three groups: external focus ( n = 22), internal focus ( n = 22), and control ( n = 21). They were required to throw beanbags at a static target for 50 acquisition trials, 10 retention trials, and 10 transfer trials. While all three groups learnt the skills in a similar manner during the acquisition phase, the internal focus group demonstrated more robust motor performance than the external focus group and the control group in both retention and transfer tests, while there was no difference between the external focus group and the control group in both retention and transfer tests. The findings provide evidence that internal focus of attention may be more effective for facilitating motor learning in children with autism spectrum disorder. However, further study is needed to determine the factors contributing to this finding. PMID- 29241344 TI - Sustainability of rare earth elements chain: from production to food - a review. AB - Rare earth elements (REE) are a group of chemical elements that include lanthanoids (lanthanum to lutetium), scandium and yttrium. In the last decades, the REE demand in the industry and other areas has increased significantly. In general, REE have shown low concentrations in soils, plants, water and atmosphere, but they may accumulate in such environments due to anthropogenic inputs. In areas where there is REE contamination, the slow accumulation of these elements in the environment could become problematic. Many studies have shown environmental areas contaminated with REE and their toxic effects. Thus, it is important to review, in order to improve the current understanding of these elements in the environment, showing the effects of REE exposure in mining, soil, water, plants and food. Besides, there are few suppliers and a limited quantity of these elements in the world. This paper suggests options to improve the sustainability management of REE chain. PMID- 29241346 TI - Individual characteristics of students with autism spectrum disorders and school refusal behavior. AB - This study compared social, executive, emotional, and behavioral characteristics of students with autism spectrum disorder who did and did not display school refusal behavior. The participants were 62 students with autism spectrum disorder without intellectual disability aged 9-16 years attending inclusive schools. Parents first completed questionnaires assessing social and executive functioning as well as emotional and behavioral problems. They then documented their child's school refusal behavior for a period of 20 days. Compared to students without school refusal behavior (n = 29), students with school refusal behavior (n = 33) were significantly less socially motivated; displayed more deficits in initiating tasks or activities, in generating ideas, responses, or problem-solving strategies; and displayed more withdrawn and depressive symptoms. Assessing social and executive functioning, as well as emotional problems, may help professionals provide tailored interventions for students with autism spectrum disorder and school refusal behavior, which will further be valuable in recognizing characteristics associated with school refusal behavior. PMID- 29241347 TI - Hospital-Based Clinicians' Perceptions of Geographic Cohorting: Identifying Opportunities for Improvement. AB - Members of the Society of Hospital Medicine were surveyed about geographic cohorting (GCh); 369 responses were analyzed, two thirds of which were from GCh participants. Improved collaboration with the bedside nurse, increased nonclinical interactions, decreased paging interruptions, and improved efficiency were perceived by >50%. Narrowed clinical expertise, increased fragmentation, increased face-to-face interruptions, and an adverse impact on camaraderie within the hospitalist group were reported by 25% to 50%. Academic practices were associated with positive perceptions while higher patient loads were associated with negative perceptions. Comments on GCh benefits invoked improvements in (1) interprofessional collaboration, (2) efficiency, (3) patient-centeredness, (4) nursing satisfaction, and (5) GCh mediated facilitation of other interventions. GCh downsides included (1) professional and personal dissatisfaction, (2) concerns about providing suboptimal care, and (3) implementation barriers. GCh is receiving attention. Although it facilitates important benefits, it is perceived to mediate unintended consequences, which should be addressed in redesign efforts. PMID- 29241348 TI - The Voice of Autoimmunity: Antisynthetase Syndrome Manifesting as Vocal Fold Bamboo Nodes. AB - OBJECTIVES: To describe a case of vocal fold bamboo nodes leading to the diagnosis of antisynthetase syndrome, a rare autoimmune disorder. To highlight the link between these laryngeal lesions and autoimmunity. METHODS: A case of vocal fold bamboo nodes in a patient with long-standing interstitial lung disease is presented. The presence of these characteristic lesions prompted a rheumatologic workup that led to the diagnosis of a rare autoimmune disorder. RESULTS: The patient was ultimately diagnosed with antisynthetase syndrome, a rare condition characterized by inflammatory myositis and interstitial lung disease. She was treated with steroids and immunosuppressive agents with improvement in her symptoms and clinical findings. CONCLUSIONS: Vocal fold bamboo nodes are pathognomonic signs of autoimmunity. Management consists primarily of medical treatment of the underlying systemic disorder. Intralesional steroid injection or phonomicrosurgical excision may be considered for refractory cases. PMID- 29241349 TI - Distribution and Clustering of Cutaneous T-Cell Lymphoma (CTCL) Cases in Canada During 1992 to 2010. AB - BACKGROUND: Clustering of patients with cutaneous T-cell lymphoma (CTCL) was reported in several jurisdictions around the world. This rare cancer is known to affect spouses and in some cases multiple members of the same family. These combined results suggest the existence of external disease triggers/promoters. We recently conducted the first comprehensive analysis of CTCL incidence and mortality in Canada, which revealed case clustering in several regions. OBJECTIVES: To extend our previous analysis on CTCL incidence across Canada and to provide all the collected data on CTCL patient incidence in Canada during the period of 1992 to 2010. METHODS: Clinical parameters for patients with CTCL in Canada were analyzed using 2 independent population-based cancer registries: Canadian Cancer Registry and Le Registre Quebecois du Cancer. The CTCL incidence rates were examined on different geographical levels, including provinces/territories, cities, and forward sortation areas. RESULTS: Our findings further corroborate our earlier observations of higher CTCL incidence in Newfoundland and Labrador, maritime provinces (Nova Scotia and New Brunswick), and prairie provinces (Manitoba and Saskatchewan). Also, most cities with high CTCL incidence were located in these provinces. Extensive mapping of high incidence postal codes supports case clustering in a number of communities that are located in the proximity of industrial centres and seaports. CONCLUSIONS: Detailed analysis of CTCL incidence in Canada is critical to fully understand the burden of this disease in our country, to begin the search for a possible external trigger for this lymphoma, and to reform how health care resources are distributed throughout the country to better serve Canadian patients with CTCL. PMID- 29241350 TI - Platelet Volume Measurements-EDTA, Citrate, or Both? PMID- 29241351 TI - Association Between Plasma Trans-Fatty Acid Concentrations and Measures of Glucose Homeostasis and Cardiovascular Risk Factors in Adults in NHANES 1999 2000. AB - There is limited evidence on the association between plasma trans-fatty acids (TFAs) and cardiometabolic risk factors. Therefore, we examined the association between plasma TFA concentrations and glucose homeostasis and cardiovascular (CV) risk factors in adult Americans from the 1999 to 2000 National Health and Nutrition Examination Survey participants. Derivatized TFAs were separated by capillary gas chromatography. Of the 1678 participants, 46.5% were men. The mean age was 50.5 years overall, with no significant difference between men and women ( P = .101). In age-, sex- and race-adjusted analyses, mean waist circumference, fat-free mass, fat mass, C-peptide, insulin, hemoglobin A1c (HbA1c), homeostatic model assessment of insulin resistance (HOMA-IR), serum triglycerides (TGs), and total cholesterol (TC) increased across increasing quarters of TFAs (for all P < .001), while mean serum high-density lipoprotein cholesterol decreased across increasing quarters of plasma TFAs ( P < .001). In multivariable adjusted linear regressions, there remained significant positive associations between all plasma TFAs and body mass index, waist circumference, fat-free mass, fat mass, C peptide, insulin, fasting blood glucose, HOMA-IR, HbA1c, TGs, low-density lipoprotein cholesterol, and TC ( P < .001). In conclusion, our findings support a possible association between plasma TFAs concentrations and measures of glucose homeostasis and several CV risk factors. PMID- 29241352 TI - Rhabdomyolysis and elevated liver enzymes after rapid correction of hyponatremia due to pneumonia and concurrent use of aripiprazole: A case report. PMID- 29241353 TI - Role of Proline in Pathogen and Host Interactions. AB - SIGNIFICANCE: Proline metabolism has complex roles in a variety of biological processes, including cell signaling, stress protection, and energy production. Proline also contributes to the pathogenesis of various disease-causing organisms. Understanding the mechanisms of how pathogens utilize proline is important for developing new strategies against infectious diseases. Recent Advances: The ability of pathogens to acquire amino acids is critical during infection. Besides protein biosynthesis, some amino acids, such as proline, serve as a carbon, nitrogen, or energy source in bacterial and protozoa pathogens. The role of proline during infection depends on the physiology of the host/pathogen interactions. Some pathogens rely on proline as a critical respiratory substrate, whereas others exploit proline for stress protection. CRITICAL ISSUES: Disruption of proline metabolism and uptake has been shown to significantly attenuate virulence of certain pathogens, whereas in other pathogens the importance of proline during infection is not known. Inhibiting proline metabolism and transport may be a useful therapeutic strategy against some pathogens. Developing specific inhibitors to avoid off-target effects in the host, however, will be challenging. Also, potential treatments that target proline metabolism should consider the impact on intracellular levels of Delta1-pyrroline-5-carboxylate, a metabolite intermediate that can have opposing effects on pathogenesis. FUTURE DIRECTIONS: Further characterization of how proline metabolism is regulated during infection would provide new insights into the role of proline in pathogenesis. Biochemical and structural characterization of proline metabolic enzymes from different pathogens could lead to new tools for exploring proline metabolism during infection and possibly new therapeutic compounds. Antioxid. Redox Signal. 00, 000-000. PMID- 29241355 TI - Follow-Up Study of Youth Who Received EIBI as Young Children. AB - Although early intensive behavioral intervention (EIBI) has been clearly shown to be evidence-based, there is very little information available regarding long-term outcomes, especially from community effectiveness studies. We present data on cognitive, adaptive, and autism severity measures from four time points (pre- and post-EIBI and two follow-up points) for a sample of 21 youth, currently aged 16 years on average (range = 13-20) who received EIBI as young children and who have been out of EIBI for a mean of 10 years (range = 8.5-14). Results show heterogeneous outcomes and a general pattern of stability since the end of EIBI, suggesting gains made in EIBI are maintained. PMID- 29241356 TI - The Impact of Experiential Avoidance and Event Centrality in Trauma-Related Rumination and Posttraumatic Stress. AB - Cognitive control strategies like rumination often increase posttraumatic stress disorder (PTSD) symptoms. However, extant research has provided equivocal results when attempting to explain why this phenomenon occurs. The current study explored several mechanisms that may clarify such findings. For this study, 193 trauma exposed community members completed measures of PTSD, rumination, experiential avoidance, and event centrality. Elevated reports of rumination were associated with greater PTSD symptomology, experiential avoidance, and event centrality. Results suggest that rumination indirectly influenced PTSD symptom severity through experiential avoidance. This pattern held true regardless of whether a trauma survivor viewed their reported trauma as central or peripheral to their personal identity. These data suggest that the link between ruminating about a traumatic experience and enhanced PTSD symptomology may be partially explained by increasingly restrictive cognitive patterns and enhanced avoidance of aversive internal stimuli. Furthermore, they provide preliminary evidence to suggest that rumination and experiential avoidance are strongly associated with one another (and subsequent PTSD symptomology) among trauma survivors, regardless of how central a traumatic event is to an individual's personal narrative. Such findings support clinical interventions like exposure, which progressively support new learning in response to feared or unwanted experiences in service of expanding an individual's cognitive and behavioral repertoires. PMID- 29241354 TI - Contemporary management of high-grade gliomas. AB - High-grade gliomas, including glioblastoma, are the most common malignant brain tumors in adults. Despite intensive efforts to develop new therapies for these diseases, treatment options remain limited and prognosis is poor. Recently, there have been important advances in our understanding of the molecular basis of glioma, leading to refinements in our diagnostic and management approach. There is new evidence to guide the treatment of elderly patients. A multitude of new agents have been investigated, including targeted therapies, immunotherapeutics and tumor-treating fields. This review summarizes the key findings from this research, and presents a perspective on future opportunities to advance the field. PMID- 29241357 TI - Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. AB - OBJECTIVE: Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties. The authors assessed the safety and effectiveness of CBD in patients with schizophrenia. METHOD: In an exploratory double-blind parallel-group trial, patients with schizophrenia were randomized in a 1:1 ratio to receive CBD (1000 mg/day; N=43) or placebo (N=45) alongside their existing antipsychotic medication. Participants were assessed before and after treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Assessment of Cognition in Schizophrenia (BACS), the Global Assessment of Functioning scale (GAF), and the improvement and severity scales of the Clinical Global Impressions Scale (CGI-I and CGI-S). RESULTS: After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms (PANSS: treatment difference=-1.4, 95% CI=-2.5, -0.2) and were more likely to have been rated as improved (CGI-I: treatment difference=-0.5, 95% CI=-0.8, -0.1) and as not severely unwell (CGI-S: treatment difference=-0.3, 95% CI=-0.5, 0.0) by the treating clinician. Patients who received CBD also showed greater improvements that fell short of statistical significance in cognitive performance (BACS: treatment difference=1.31, 95% CI=-0.10, 2.72) and in overall functioning (GAF: treatment difference=3.0, 95% CI=-0.4, 6.4). CBD was well tolerated, and rates of adverse events were similar between the CBD and placebo groups. CONCLUSIONS: These findings suggest that CBD has beneficial effects in patients with schizophrenia. As CBD's effects do not appear to depend on dopamine receptor antagonism, this agent may represent a new class of treatment for the disorder. PMID- 29241358 TI - Criticisms of Kraepelin's Psychiatric Nosology: 1896-1927. AB - Emil Kraepelin's psychiatric nosology, proposed in the 5th and 6th editions of his textbook published in 1896 and 1899, did not quickly gain worldwide acceptance, but was instead met with substantial and sustained criticism. The authors review critiques of Kraepelin's work published in his lifetime by Adolf Meyer, Friedrich Jolly, Eugenio Tanzi, Alfred Hoche, Karl Jaspers, and Willy Hellpach. These critics made six major points. First, Kraepelin's new categories of dementia praecox and manic-depressive insanity were too broad and too heterogeneous. Second, his emphasis on course of illness was misconceived, as the same disease can result in brief episodes or a chronic course. Third, the success of his system was based on the quality of his textbooks and his academic esteem, rather than on empirical findings. Fourth, his focus on symptoms and signs led to neglect of the whole patient and his or her life story. Fifth, Kraepelin's early emphasis on experimental psychology did not bear the expected fruit. Sixth, Kraepelin was committed to the application of the medical disease model. However, because of the many-to-many relationship between brain pathology and psychiatric symptoms, true natural disease entities may not exist in psychiatry. Most of the ongoing debates about Kraepelin's nosology have roots in these earlier discussions and would be enriched by a deeper appreciation of their historical contexts. As authoritative as Kraepelin was, and remains today, his was only one among many voices, and attention to them would be well repaid by a deeper understanding of the fundamental conceptual challenges in our field. [AJP at 175: Remembering Our Past As We Envision Our Future April 1927: In Memoriam: Emil Kraepelin, M.D. Meyer provides an admiring but not uncritical overview of Kraepelin's career and contributions to psychiatry. "It was the unflinchingly psychiatric orientation of the man," he wrote, "that impressed and attracted physicians and students." (Am J Psychiatry 1927; 83:748-755 )]. PMID- 29241360 TI - Interfragmentary Compression Forces Vary Based on Scaphoid Bone Screw Type and Fracture Location. AB - BACKGROUND: The objective of this study was to determine the interfragmentary compression forces generated in a foam model as a function of headless compression screw type (fully threaded and central threadless) and fracture location. METHODS: Eighty-eight polyurethane foam models were fixed across a simulated transverse fracture with either a fully threaded screw or a central threadless screw. The location of the transverse fracture varied along the length of the foam model in 2 mm increments for 11 fracture locations. The force generated at the fracture site upon fixation was utilized to determine the interfragmentary compression. Interfragmentary compression was compared using a paired t test and 2-way analysis of variance, with significance set at P < .05. RESULTS: Interfragmentary compression was found to vary based on fracture location and screw type. The fully threaded screw generated significantly greater compression for fracture locations at 12 mm and 18 mm from the top edge of the foam model, while the central threadless screw generated significantly greater compression for fractures located 2 mm from the top edge of the foam model. CONCLUSIONS: The central threadless screw and the fully threaded screw had different fracture locations where maximum compression force occurred. The fully threaded screw generated greater compression force toward the screw center due to greater thread purchase. However, the central threadless screw generated greater compression at the most proximal fracture location due to its greater thread pitch toward the screw head. Maximizing interfragmentary compression may aid in reducing nonunion rates associated with the internal fixation of proximal scaphoid fractures. PMID- 29241359 TI - Antidepressant Outcomes Predicted by Genetic Variation in Corticotropin-Releasing Hormone Binding Protein. AB - OBJECTIVE: Genetic variation within the hypothalamic-pituitary-adrenal (HPA) axis has been linked to risk for depression and antidepressant response. However, these associations have yet to produce clinical gains that inform treatment decisions. The authors investigated whether variation within HPA axis genes predicts antidepressant outcomes within two large clinical trials. METHOD: The test sample comprised 636 patients from the International Study to Predict Optimized Treatment in Depression (iSPOT-D) who completed baseline and 8-week follow-up visits and for whom complete genotyping data were available. The authors tested the relationship between genotype at 16 candidate HPA axis single nucleotide polymorphisms (SNPs) and treatment outcomes for three commonly used antidepressants (escitalopram, sertraline, and extended-release venlafaxine), using multivariable linear and logistic regression with Bonferroni correction. Response and remission were defined using the Hamilton Depression Rating Scale. Findings were then validated using the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study of outcome predictors in treatment-naive patients with major depression. RESULTS: The authors found that the rs28365143 variant within the corticotropin-releasing hormone binding protein (CRHBP) gene predicted antidepressant outcomes for remission, response, and symptom change. Patients homozygous for the G allele of rs28365143 had greater remission rates, response rates, and symptom reductions. These effects were specific to drug class. Patients homozygous for the G allele responded significantly better to the selective serotonin reuptake inhibitors escitalopram and sertraline than did A allele carriers. In contrast, rs28365143 genotype was not associated with treatment outcomes for the serotonin norepinephrine reuptake inhibitor venlafaxine. When patients were stratified by race, the overall effect of genotype on treatment response remained. In the validation sample, the GG genotype was again associated with favorable antidepressant outcomes, with comparable effect sizes. CONCLUSIONS: These findings suggest that a specific CRHBP SNP, rs28365143, may have a role in predicting which patients will improve with antidepressants and which type of antidepressant may be most effective. The results add to the foundational knowledge needed to advance a precision approach to personalized antidepressant choices. PMID- 29241361 TI - Clinical and Radiological Outcomes Comparing Percutaneous Chevron-Akin Osteotomies vs Open Scarf-Akin Osteotomies for Hallux Valgus. AB - BACKGROUND: Minimally invasive surgeries have gained popularity due to less soft tissue trauma and better wound healing. To date, limited studies have compared the outcomes of percutaneous and open osteotomies. This study aims to investigate the clinical and radiological outcomes of percutaneous chevron-Akin osteotomies vs open scarf-Akin osteotomies at 24-month follow-up. METHOD: We reviewed a prospectively collected database in a tertiary hospital hallux valgus registry. Twenty-nine feet that underwent a percutaneous technique were matched to 58 feet that underwent open scarf and Akin osteotomies. Clinical outcome measures assessed included visual analog scale (VAS) scores, American Orthopaedic Foot & Ankle Society Hallux Metatarsophalangeal-Interphalangeal score (AOFAS Hallux MTP IP), and Short Form 36 (SF-36) Health Survey. Radiological outcomes included hallux valgus angle (HVA) and intermetatarsal angle (IMA). All patients were prospectively followed up at 6 and 24 months. RESULTS: Both groups showed comparable clinical and radiological outcomes at the 24-month follow-up. However, the percutaneous group demonstrated less pain in the perioperative period ( P < .001). There were significant differences in the change in HVA between the groups but comparable radiological outcomes in IMA at the 24-month follow-up. The percutaneous group demonstrated shorter length of operation ( P < .001). There were no complications in the percutaneous group but 3 wound complications in the open group. CONCLUSIONS: We conclude that clinical and radiological outcomes of third-generation percutaneous chevron-Akin osteotomies were comparable with open scarf and Akin osteotomies at 24 months but with significantly less perioperative pain, shorter length of operation, and less risk of wound complications. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 29241362 TI - Simplified teixobactin analogues to target superbugs. AB - Ishwar Singh speaks to Benjamin Walden, Commissioning Editor. Ishwar Singh is Senior Lecturer in biological chemistry at the School of Pharmacy, University of Lincoln. Prior to Lincoln, he had held many prestigious fellowships such as the Alexander von Humboldt fellowship, Germany; and Senior Research Fellowship, DANIDA, Denmark and CSIR, India. He is an organic chemist. He has developed bioconjugations for DNA, RNA and polymer modifications. He is currently leading research in novel antimicrobials based on rational design against clinically important resistant bacteria (such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, mycobacteria, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa), biologics delivery, peptides, sequence-selective DNA cross linking, nanoparticles modifications for drug delivery and diagnostic applications. PMID- 29241363 TI - Science, state, and spirituality: Stories of four creationists in South Korea. AB - This paper presents an analysis of the birth and growth of scientific creationism in South Korea by focusing on the lives of four major contributors. After creationism arrived in Korea in 1980 through the global campaign of leading American creationists, including Henry Morris and Duane Gish, it steadily grew in the country, reflecting its historical and social conditions, and especially its developmental state with its structured mode of managing science and appropriating religion. We argue that while South Korea's creationism started with the state-centered conservative Christianity under the government that also vigilantly managed scientists, it subsequently constituted some technical experts' efforts to move away from the state and its religion and science through their negotiation of a new identity as Christian intellectuals ( chisigin). Our historical study will thus explain why South Korea became what Ronald Numbers has called "the creationist capital of the world." PMID- 29241364 TI - Health benefits of pistachios consumption. AB - The health benefits of nuts, mainly in relation to the improvement of dysmetabolic conditions such as obesity, type 2 diabetes mellitus and the related cardiovascular diseases, have been widely demonstrated. Compared to other nuts, pistachios have a lower fat and caloric content, and contain the highest levels of unsaturated fatty acids, potassium, gamma-tocopherol, phytosterols and xanthophyll carotenoids, all substances that are well known for their antioxidant and anti-inflammatory actions. This variety of nutrients contributes to the growing body of evidence that the consumption of pistachios improves health, leading to a greater potential of healthy antioxidant and anti-inflammatory activity, glycemic control, and endothelial function. The present review examines the nutrients and phytochemicals present in pistachios as well as the potential health benefits of including pistachios in a diet. PMID- 29241367 TI - Differentiation of conjunctiva mesenchymal stem cells into secreting islet beta cells on plasma treated electrospun nanofibrous scaffold. AB - Transplantation of stem cells using biocompatible nanofibrous scaffolds is a promising therapeutic method for treating Diabetic Mellitus. The aim of this study was to derive insulin-producing cells (IPCs) from conjunctiva-derived mesenchymal stem cell (CJMSCs) and to compare the functionality of differentiated IPCs in a three-dimensional (3D) culture with 2D. Furthermore, the effects of hydrophobicity of scaffold on IPCs differentiation were examined. Scanning electron microscopy (SEM), quantitative real times PCR (qPCR), Immunostaining and flow cytometry were used to analyze fabricated scaffold and the presence of IPCs. Functional maturity of differentiated cells was determined by measuring insulin release and the creation of IPCs was confirmed via gene and protein expression. In this study, the induced CJMSCs were morphologically similar to pancreatic islet-like cells. The expression of the islet-associated genes (glucagon, insulin and Pdx-1) and the insulin release (2.5-fold) in 3D-cultured cells was significantly higher than the 2D. The expression of IPCs genes was significantly higher in CJMSCs differentiated on plasma-treated nanofibers compared to those on untreated scaffolds. In conclusion, the results show that CJMSCs might be a new source for Diabetic Mellitus therapy and the nanofibrous scaffold could be used as a potential cell carrier for islet tissue engineering. PMID- 29241366 TI - Accuracy of dental development for estimating the pubertal growth spurt in comparison to skeletal development: a systematic review and meta-analysis. AB - OBJECTIVES: This study aimed to search for scientific evidence concerning the accuracy of dental development for estimating the pubertal growth spurt. METHODS: It was conducted according to the statements of PRISMA. An electronic search was performed in six databases, including the grey literature. The PICOS strategy was used to define the eligibility criteria and only observational studies were selected. RESULTS: Out of 1,416 identified citations, 10 articles fulfilled the criteria and were included in this systematic review. The association between dental development and skeletal maturity was considered strong in seven studies, and moderate in two, although the association with the pubertal growth spurt had been verified in only four articles. According to half of the studies, the tooth that provided the greater association with the ossification centres was the lower canine. The meta-analysis performed also indicated a positive association, being stronger in females [0.725 (0.649-0.808)]. However, when the method used for dental evaluation was considered, it was possible to verify greater correlation coefficients for Nolla [0.736 (0.666-0.814)] than for Demirjian [0.631 (0.450 0.884)], at the boys sample. The heterogeneity test reached high values (Q = 51.00), suggesting a potential bias within the studies. CONCLUSIONS: Most of individual studies suggested a strong correlation between dental development and skeletal maturation, although the association with the peakof pubertal growth spurtwas clearly cited only in some of them. However, due to the high heterogeneity found among the studies included in this meta-analysis, a pragmatic recommendation about the use of dental stages is not possible. PMID- 29241365 TI - Gabapentin for the treatment of alcohol use disorder. AB - INTRODUCTION: Alcohol misuse is the fifth leading risk factor for premature death and disability worldwide. Fewer than 10% of afflicted Americans receive pharmacological treatment for alcohol use disorder. Gabapentin is a calcium channel GABAergic modulator that is widely used for pain. Studies showing reduced drinking and decreased craving and alcohol-related disturbances in sleep and affect in the months following alcohol cessation suggest therapeutic potential for alcohol use disorder. Areas covered: Human laboratory and clinical studies assessing gabapentin for alcohol use disorder are reviewed. Data were obtained by searching for English peer-reviewed articles on PubMed, reference lists of identified articles, and trials registered on clinicaltrials.gov. Additionally, the mechanism of action of gabapentin specific to alcohol use disorder, and studies of gabapentin for alcohol withdrawal and non-alcohol substance use disorders are summarized. Expert opinion: Alcohol use disorder represents a challenge and large, unmet medical need. Evidence from single-site studies lend support to the safety and efficacy of gabapentin as a novel treatment for alcohol use disorder, with unique benefits for alcohol-related insomnia and negative affect, relative to available treatments. Proprietary gabapentin delivery systems may open a path to pivotal trials and registration of gabapentin as a novel treatment for alcohol use disorder. PMID- 29241368 TI - Gastrointestinal perforation in light chain amyloidosis in the era of novel agent therapy - a case series and review of the literature. AB - Gastrointestinal (GI) perforation is remarkably rare in patients with light chain (AL) amyloidosis and has not yet been reported in patients with AL amyloidosis treated with novel agents. Only 24 cases of GI perforation have previously been reported in the setting of AL amyloidosis of which 15 had available information in English. All 15 did not receive novel agent therapy and six died early after experiencing GI perforation. This study reports the characteristics and outcome of AL patients that developed GI perforation in the era of novel agent treatment. Seven patients were reviewed. In two patients, GI perforation was the presenting symptom of AL amyloidosis, whereas five patients developed GI perforations following initiation of an anti-AL therapy (three after bortezomib-based, 1 after lenalidomide-based and 1 after thalidomide-based therapy). All patients underwent surgery and survived the perforation. Treatment was renewed following surgery in six of seven patients, with no further GI complications. In conclusion, GI perforation in AL amyloidosis is rare and mostly reported after treatment initiation. Urgent surgery appears to be lifesaving and renewal of the anti-AL novel therapy appears to be safe, with no significant risk for re-perforation or GI toxicity. Prognosis in these patients is related to severity of the disease and response to therapy rather than the development of GI perforation. PMID- 29241369 TI - Oxygen saturation measurements in telemonitoring of patients with COPD: a systematic review. AB - INTRODUCTION: Telemonitoring applications are expected to become a key component in future healthcare. Despite the frequent use of SpO2 measurements in telemonitoring of patients with chronic obstructive pulmonary disease (COPD), no profound overview is available about these measurements. Areas covered: A systematic search identified 71 articles that performed SpO2 measurements in COPD telemonitoring. The results indicate that long-term follow-up of COPD patients using daily SpO2 spot checks is practically feasible. Very few studies specified protocols for performing these measurements. In many studies, deviating SpO2 values were used to raise alerts that led to immediate action from healthcare professionals. However, little information was available about the exact implementation and performance of these alerts. Therefore, no firm conclusions can be drawn about the real value of SpO2 measurements. Future research could optimize performance of alerts using individualized, time-dependent thresholds or predictive algorithms to account for individual differences and SpO2 baseline changes. Additionally, the value of performing continuous measurements should be examined. Expert commentary: Standardization of the measurements, data science techniques and advancing technology can still boost performance of telemonitoring applications. All these opportunities should be thoroughly explored to assess the real value of SpO2 in COPD telemonitoring. PMID- 29241370 TI - Identification of structural requirements and prediction of inhibitory activity of natural flavonoids against Zika virus through molecular docking and Monte Carlo based QSAR Simulation. AB - There has been growing interest in the research of flavonoids due to their potential antiviral activities. Recently, some natural flavonoids have shown potential inhibitory activity against zika virus NS3-NS2B protease. In order to accelerate the drug discovery efforts using flavonoids, a Monte Carlo simulation based QSAR method has been applied to find out the structural requirements for the inhibitory activity. The best QSAR model was obtained using SMILES descriptors and HSG descriptors with 1EC connectivity with the following statistical parameters: R2 = 0.9569 and Q2 = 0.9050 for the test set. The best model was further utilised for the prediction of inhibitory activity of some other natural flavonoids. Four flavonoids (amentoflavone, fisetin, isorhamnetin and theaflavin-3-gallate) have shown higher predicted inhibitory activity and further validated by performing docking analysis. This study may help in understanding and performing natural flavonoids-based drug discovery against zika virus. PMID- 29241371 TI - Capitalizing on technology for developing communication skills in autism spectrum disorder: a single case study. AB - PURPOSE: In this case study, we discuss the application of a patient-centred clinical approach that led to the use of an assisted communication platform to combat severe communicative deficit in a child with autism spectrum disorder (ASD). METHODS: Initial assessment at four years of age revealed that the patient had rudimentary communication skills, with significant sensory integration dysfunction manifested as oral, olfactory, and tactile seeking behaviours; self stimulatory behaviour; and complete dependence on caregiver for activities of daily living. Intensive, multi-disciplinary intervention resulted in minimal improvement in communicative skills and sensory seeking over six months. Subsequently, a tailor-made picture-assisted communication training with the mother as the communication facilitator was adopted. This approach was abandoned due to the patient's poor response and mother's low acceptance of picture-based interaction. A preference for printed material was observed in the patient. Accordingly, further management was focused on employing a computer-based interactive platform that the patient was taught to use over the course of a few months as a part of augmentative and alternative communication (AAC) intervention program. This resulted in a remarkable improvement in the child's skills that now allowed for a better intentional communication of his thoughts and needs. CONCLUSIONS: This study highlights the importance of revisiting conventional rehabilitation strategies for communicative deficits and tailoring them according to the patient's needs and preferences. It also emphasises that besides excellent observation skills, clinicians must be willing to consider technology based approaches in patients responding poorly to traditional approaches in order to develop effective interventional programmes. Implication for Rehabilitation The current study highlights the importance of exploring the application of technology based intervention for building communication skills in the early stages of rehabilitation for persons with communicative deficit. It also emphasises the need for excellent observation skills among clinicians so that the peculiar interests of children with ASD may be applied in designing training programmes to overcome communication barriers. Additionally, clinicians should familiarise themselves with the latest assistive technology-based rehabilitation approaches and be willing to explore newer approaches if traditional ones fail to yield satisfactory outcomes. Use of technology-based interventions to reduce dependence among persons with disability would be beneficial, both socially and economically, in developing countries with limited resources. PMID- 29241372 TI - Maturation of bone-conduction transcranial and forehead attenuation using a measure of sound pressure in the ear canal. AB - OBJECTIVE: Although it is understood that bone-conduction (BC) hearing is different between infants and adults, few studies have attempted to explain why these differences exist. The main objective in this study was to better understand how properties of the developing skull contribute to the maturation of BC sensitivity through an indirect measurement of BC attenuation across the skull. DESIGN: Estimation of transcranial and forehead attenuation of pure-tone BC stimuli was conducted using sound pressure in the ear canal for a transducer placed on the skull ipsi- and contralateral to the probe ear and at the forehead. STUDY SAMPLE: Seventy-six individuals participated in the study, including 59 infants and children (1 month-7 years) and 17 adults. RESULTS: BC attenuation was greatest for young infants, and decreased throughout maturation. Attenuation from the forehead to the ipsilateral temporal bone was also greater compared to the transcranial measures for infants and children older than 10 months. CONCLUSIONS: These results provide evidence that physical maturation of the skull contributes to infant-adult differences in BC attenuation. Clinicians may consider these results, in combination with previous studies using physiological measures, when fitting infants and young children with bone-anchored hearing systems. PMID- 29241373 TI - Agreement between the 'point of care' tests for microalbuminuria and HbA1c performed in mexican family medicine units and the results of standard laboratory tests. AB - The albumin-creatinine ratio is considered an indicator of microalbuminuria, precursor to chronic kidney disease, while HbA1c is used to measure glycemic control. Given the prevalence of diabetes-related nephropathy, spot testing of albumin has long been recommended as a preventative measure, for the timely detection of microalbuminuria. However, many countries do not have this testing available in primary care, and sometimes not even in second- and third-level care. The objective of this study was to compare agreement of the microalbuminuria and HbA1c results obtained in the laboratory with 'gold standard' techniques, with those obtained on site with a 'Point of Care' DCA VantageTM device by Siemens. Results for the albumin-creatinine ratio and HbA1c from the Siemens DCA VantageTM point of care device were compared with those from standard laboratory tests in 25 family medicine units in Mexico City and Toluca, State of Mexico, in patients diagnosed with type-2 diabetes. Agreement between the albumin values of the 2 tests was 0.745 (CI 95% 0.655-0.812). Agreement between the two measurement techniques for HbA1c was 0.970 (CI 95% 0.966-0.973). The results obtained were sufficiently comparative (Ri= 0.74 for albumin creatinine ratio and Ri = 0.97 for HbA1c) to justify the use of the point of care device. Given the high agreement between the point of care device and laboratory tests, this device could be used to identify chronic kidney disease and glycemic control for more adequate treatment in patients with diabetes, especially in remote areas. PMID- 29241374 TI - Pharmacokinetic drug evaluation of empagliflozin plus linagliptin for the treatment of type 2 diabetes. AB - INTRODUCTION: Type 2 diabetes mellitus has become a growing epidemic and therefore efficient treatment strategies that target its management are needed. The treatment of diabetic patients often requires the combination of antidiabetic drug classes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) block glucose reabsorption in the proximal renal tubules. Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glucose metabolism by blocking the enzyme that degrades incretins leading to increased insulin secretion. Areas covered: The aim of the review is to present the available data on pharmacokinetic properties/pharmacodynamics, metabolic and cardiovascular effects of empagliflozin plus linagliptin combination. Expert opinion: Both empagliflozin and linagliptin have established safety and efficacy in the treatment of diabetes. Available data demonstrate the absence of pharmacological interactions when the two drugs are given together. The complementary mechanisms of action would be expected to provide additive benefits on carbohydrate metabolism variables, but the results from clinical trials have shown that the empagliflozin/linagliptin combination provides only mild improvements of glycated hemoglobin compared with either monotherapy. However, the single-tablet formulation of empagliflozin/linagliptin is expected to provide better compliance and thus improved glycaemic control coupled with a favourable safety profile. Thus, the fixed-dose combination of empagliflozin/linagliptin has the capacity to both effectively and safely manage diabetic patients. PMID- 29241375 TI - Peritoneal dissemination of ovarian cancer: role of MUC16-mesothelin interaction and implications for treatment. AB - INTRODUCTION: Peritoneal dissemination is a particular form of malignant progression in ovarian cancer, preceding hematogenic or lymphatic dissemination. Thus, prevention of peritoneal implantation of cancer cells is envisioned to inhibit neoplastic dissemination and therefore prolong disease remission and patient's survival. Areas covered: An extended review on the role of MUC16 (CA125) and mesothelin (MSLN), expressed in a high percentage of ovarian carcinomas, indicate that this duet is relevant for the contact between cancer cells and mesothelial cells in homotypic (cancer cell-cancer cell) and heterotypic (cancer cell-mesothelial cell) interactions. This review discusses the reasons underlying the clinical failure of immunotherapeutic strategies targeting MUC16. Clinical data on MSLN targeting agents such as antibody-based immunotoxins or antibody drug conjugates are also reviewed. The promising anti tumor effect of CAR-T cells directed to MUC16 or MSLN is emphasized. New emerging strategies specifically disrupting the MUC16-MSLN interaction are at the forefront of this review, including TRAIL ligands bound to MSLN targeting MUC16 expressing cells and single chain monoclonal antibodies and immunoadhesins recognizing MSLN-MUC16 binding domains. Expert commentary: Based on existing evidences the authors advocate that agents targeting MUC16-MSLN may add to the therapeutic armamentarium directed to abrogate peritoneal homing of ovarian cancer. PMID- 29241376 TI - Non-endoscopic biopsy techniques: a review. AB - INTRODUCTION: Diseases of the stomach and small intestine account for approximately 20% of all gastrointestinal (GI)-related mortality. Biopsy of the stomach and small intestine remains a key diagnostic tool for most of the major diseases that affect the GI tract. While endoscopic means for obtaining biopsy is generally the standard of care, it has several limitations that make it less ideal for pediatric patients and in low resource areas of the world. Therefore, non-endoscopic means for obtaining biopsy samples is of interest in these settings. Areas covered: We review non-endoscopic biopsy techniques reported thus far, and critically examine their merits and demerits regarding their suitability for obtaining biopsy samples in non-sedated subjects. Expert commentary: Esophagogastroduodenoscopy (EGD) is the current standard for acquiring biopsy from the GI tract, however, its limitations include subject sedation, expensive endoscopy infrastructure, expert personnel, and a small but significant risk of complications. A less costly, minimally-invasive and non-endoscopic means for obtaining biopsy samples is therefore of interest for addressing these issues. Such a technology would be of significant impact in low- and middle-income countries where conducting endoscopy is challenging. PMID- 29241377 TI - Current and future immunotherapies for thyroid cancer. AB - INTRODUCTION: Cancer immunotherapies were approved in recent years, including immune checkpoint inhibitors. Experience with ipilimumab (CTLA-4 antagonist), nivolumab and pembrolizumab (PD-1 antagonists), and atezolizumab (PD-L1 antagonist) has shown that the impact on overall survival in cancer patients is paramount. Immune checkpoint inhibitors target the immune system and they can be applied across multiple cancers; the response rate is ranging from 20 to 40%. Many studies have shown that thyroid cancer (TC) cells produce cytokines and chemokines, inducing several tumor-promoting effects. Targeting and/or lowering cytokines and chemokines concentrations within the tumor microenvironment would produce a therapeutic benefit. In TC, increased Treg and PD-1+ T cell frequencies are indicative of aggressive disease and PD-L1 expression correlates with a greater risk of recurrence. Area covered: After performing a literature search, a few pioneering studies have evaluated immunotherapy in thyroid cancer. More recently a case has been described involving anaplastic thyroid cancer treated with vemurafenib and nivolumab, with substantial regression and complete radiographic and clinical remission. Expert commentary: The use of immune checkpoint inhibitors in aggressive TC has not yet been extensively investigated and further studies in a large number of TC patients are urgently needed. PMID- 29241378 TI - Equivalence of glatiramer acetate products: challenges in assessing pharmaceutical equivalence and critical clinical performance attributes. AB - INTRODUCTION: This review discusses the challenges to characterize and evaluate the peptide based drug glatiramer acetate (GA) and its follow-on products used for treatment of multiple sclerosis patients. Areas covered: GA is a highly complex mixture of peptides consisting of four amino acids. The various (physico) chemical approaches and bioassays used for characterizing this complex drug product are described. It is not possible to link data from preclinical performance to outcomes observed in clinical trials as no critical attributes suitable for predicting the clinical performance in MS patients have been identified yet. The limited insight into the precise mechanism(s) of action of GA may explain why these critical clinical performance attributes still have not been identified. Expert opinion: The complexity of GA and lack of understanding of critical clinical performance attributes leads to a number of issues to be resolved as they hamper industry and regulatory bodies in designing and evaluating follow-on/generic applications of GA. The following questions are waiting to be addressed: Preclinical characterization vs clinical outcome: what is the relation? What are possible biomarkers? How to choose the right patient group? What is the experience with existing follow-on versions? Is there a place for GA 'betters'? How to evaluate existing and draft new guidance documents and pharmacopoeial monographs? PMID- 29241380 TI - Erratum. PMID- 29241379 TI - Prevalence of anti-nuclear autoantibodies in subjects exposed to natural asbestiform fibers: a cross-sectional study. AB - Fluoro-edenite (FE) is an asbestiform mineral fiber spotted in the lava rocks excavated from a stone quarry in Biancavilla (Italy). The derived material had been employed locally for building purposes. Previous studies found evidence that exposure to asbestos may induce autoimmunity, with frequency of anti-nuclear autoantibodies (ANA). The aim of this study was to explore the relationship between FE exposure and autoimmune responses in an exposed population. For the study, 60 subjects living in the area of Biancavilla and 60 subjects as control group were randomly invited to participate. A free medical check, including spirometry and a high-resolution computer tomography chest scan, was given to all participants. ANA were determined by indirect immunofluorescence. On medical check, no subject showed any sign and/or symptoms of illness. Prevalence for samples positive to ANA were 70% (n = 42) and 25% (n = 15), respectively, for exposed and non-exposed subjects (p < 0.05). The presence of pleural plaques (PP) was found in 21 (30%) of the exposed subjects and in 2 (3%) of the non-exposed participants. PP subjects were always ANAs positive. In conclusion, as already it was observed with exposure to asbestos fibers, levels of ANA seemed to significantly increase in subjects who had been exposed to FE. Furthermore, all subjects showing PP were also ANA-positive. This first finding in subjects exposed to FE should encourage researchers to further investigate associations between autoimmune unbalance and environmental exposure to asbestiform fibers. PMID- 29241381 TI - Prevalence, characteristics and risk factors of pressure ulcers in public and private hospitals care units and nursing homes in France. AB - OBJECTIVE: The aim of this study conducted in 2014 was to describe the prevalence of pressure ulcers in different types of French hospital unit at the national level to compare them with data from the 1994 and 2004 study. METHODS: This cross sectional study was conducted over a single day. All care units were invited to participate by drawing lots stratified by region in successive waves until 1,200 agreements were obtained. Lots were drawn for towns with more than 10,000 inhabitants. All public- and private-sector hospital facilities in each town drawn by lot were invited to participate in the survey. RESULTS: 776 hospital services throughout France took part and accommodated 21,538 patients: 12,752 women (59.2%) and 8,786 men (40.8%). Of these patients, 1,753 (8.1%; IC95% = 7.7; 8.5) had pressure ulcers. The pressure-ulcer rate was 7.8% (IC95% = [7.3; 8.3] (n = 997)) for hospitalized women and 8.6% (IC95% = [8.0; 9.2] (n = 756)) for men (p = 0.0381). The 8.1% level reported in 2014 therefore points to a reduction in pressure-ulcer prevalence; 8.6% in 1994 and 8.9% in 2004. CONCLUSIONS: The actions performed daily by healthcare professionals to prevent pressure ulcers, supported by research and training programs, including those by PERSE, are having a real impact over time. PMID- 29241382 TI - Causes of Mortality in ICU-Acquired Weakness. AB - BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is a common complication of critical illness and is associated with increased mortality, longer mechanical ventilation and longer hospital stay. Little is known about the causes of mortality in patients with ICU-AW. In this study, we aimed to give an overview of the causes of death in a population diagnosed with ICU-AW during hospital admission. METHODS: Data from a prospective cohort study in the mixed medical-surgical ICU of the Academic Medical Center in Amsterdam were used. Patients were included when mechanically ventilated for more than 48 hours. Intensive care unit-acquired weakness was defined as a mean medical research council score <4. Baseline data and data on the time of death were collected. RESULTS: Fifty-three patients were included. Irreversible shock with multiple organ failure (MOF) was the most common cause of death (28/53 of patients; 26 patients with septic shock and 2 patients with hypovolemic shock). Most common site of sepsis was abdominal (38.5%) and pulmonary (19.2%). On admission to the ICU, 53% had a do-not-resuscitate code. In 74% of the patients, further treatment limitations were implemented during their ICU stay. CONCLUSION: In this cohort of patients with ICU-AW, most patients died of irreversible shock with MOF, caused by sepsis. PMID- 29241383 TI - The effect of prophylactic oral tranexamic acid plus buccal misoprostol on blood loss after vaginal delivery: a randomized controlled trial. AB - OBJECTIVE: The objective of this study is to evaluate the effect of prophylactic oral tranexamic acid (TA) plus buccal misoprostol on the amount of blood loss after vaginal delivery in women at low risk for post-partum hemorrhage (PPH). MATERIALS AND METHODS: The study was a randomized open label clinical trial conducted in a tertiary University Hospital between January 2016 and June 2017. We included women who delivered vaginally with a singleton pregnancy. They were randomized into three groups: group I (women received 10 IU oxytocin IV after delivery of the baby), group II (women received 600 ug buccal misoprostol after delivery of the baby), and group III (women received 1000 mg oral TA at the end of the first stage of labor plus 600 ug buccal misoprostol after delivery of the baby). In each group, pre- and post-delivery pulse rate, blood pressure, temperature, and hemoglobin level were evaluated. Additionally, the amount of blood loss, need for blood transfusion, need for additional uterotonics, and side effects of the study medications were recorded. RESULTS: There was a statistically significant lower hemoglobin level and higher blood loss in the misoprostol group compared with oxytocin group and TA plus misoprostol group (p = .0001). There was a statistically significant higher hemoglobin level and lower blood loss in the TA plus misoprostol group compared with the oxytocin group (p = .004 and .043, respectively). PPH occurred in 16.7% of women in the misoprostol group compared 1.7% in the oxytocin group and no cases of PPH in the TA plus misoprostol group (p = .0001). CONCLUSIONS: In settings like rural area or home delivery in which oxytocin is not available, alternative oral TA plus buccal misoprostol may be considered as an effective line in prevention of PPH. PMID- 29241384 TI - Effects of ciprofloxacin and quercetin on fetal brain development: a biochemical and histopathological study. AB - PURPOSE: Teratogens cause birth defects and malformations while human development is being completed. In pregnancy, urinary tract infection (UTI) is a common health problem caused by bacteria. The fluoroquinolones such as ciprofloxacin, levofloxacin, moxifloxacin, and gemifloxacin can treat various types of bacterial infections successfully. The aim of this study is to determine whether the use of ciprofloxacin during pregnancy causes oxidative stress on brain tissues of the fetus, and whether quercetin contributes to prevent this damage if stress has already occurred. MATERIALS AND METHODS: In our study, 22 young female Wistar albino rats weighing 250 g were used. Rats were mated overnight in separate plastic cages. Female rats were regarded as pregnant when a vaginal plug was observed, and these were divided into four groups of control, ciprofloxacin, quercetin, and cipro + quercetin. Two daily i.p. 20 mg/kg doses of ciprofloxacin were administered to ciprofloxacin group between 7 and 17 d of pregnancy. Throughout the study, daily (20 d) 20 mg/kg quercetin was dissolved in corn oil and administered to the quercetin group by oral gavage. Rats were fed ad libitum throughout the study. Fetuses were taken by C-section on the 20th day of pregnancy. Thereafter, the brain tissues were subjected to histological assessments and biochemical analyzes. RESULTS: The experimental groups were compared with the control group; ciprofloxacin affected fetal development, especially caused damage to neurons in brain tissue and cause hemorrhagic defects. And also, it was determined that many parameters were affected such as antioxidant parameters, enzyme levels and levels of malondialdehyde (MDA) (a marker of lipid peroxidation). Quercetin is a member of flavonoid with strong antioxidant properties, and our results indicate that the use of ciprofloxacin in pregnancy can result damage to fetal brain tissue. CONCLUSIONS: Unlike these results when some parameters are evaluated it is understood that this harmful effects suppressed by quercetin. PMID- 29241385 TI - Incarcerated Women's Experiences and Perceptions of Participating in Research. AB - The research process within prisons has largely considered researchers' perspectives. Only one known study explicitly examined incarcerated persons' perceptions and no known studies have explored incarcerated persons' experiences with research on sensitive topics. This study examines incarcerated women's experiences with participating in research on victimization. A thematic analysis was conducted on responses to open-ended questions about participating in a research study from 227 women in two prisons who participated in a study about victimization. Women prisoners were overwhelmingly positive about participating in the research study with the vast majority willing to participate in a future study. Participants believed participating in the study provided opportunities for them to share their story, heal, reflect, grow, and help others. Some women mentioned that discussing certain topics created uncomfortable emotions and memories. Participants perceived benefits of participating in research. Implications for research in prisons are presented. PMID- 29241386 TI - Modified risk associations of lipoproteins and apolipoproteins by chronic low grade inflammation. AB - INTRODUCTION: Lipoproteins and the apolipoproteins (apo) that they carry are major determinants of cardiovascular diseases (CVD) as well as metabolic, renal and inflammatory chronic disorders either directly or through mediation of risk factors. The notion that elevated low-density lipoprotein cholesterol (LDL-C) and apoB levels are related to the acquisition of CVD and, high-density lipoprotein cholesterol (HDL-C) and apoA-I indicate protection against CVD has been challenged in the past decade. Advanced age, adiposity, ethnicity or impaired glucose intolerance rendered autoimmune activation in an environment of pro inflammatory state/oxidative stress and may disrupt the linear risk association between lipoproteins. Areas covered: This review summarizes the modified risk associations of lipoproteins and apolipoprotein by an environment of chronic systemic low-grade inflammation with special emphasis on the non-linear relationship of lipoprotein(a) [Lp(a)], a biomarker of renewed interest in cardiometabolic risk. Expert commentary: It seems that autoimmune activation in an environment of pro-inflammatory state/oxidative stress not only disrupts the linear risk association between lipoproteins, but also may cause interference in immunoassays. Hence, methodological improvement in immunoassays and much further research focusing on population segments susceptible to a pro-inflammatory state is necessary for further advances in knowledge. PMID- 29241387 TI - Predictors of emotional distress in pregnant women: the mediating role of relationship intimacy. AB - BACKGROUND: Assessment and treatment of emotional distress during pregnancy show that worries during pregnancy and interpersonal relationships with partners are the important factors determining psychological health. AIMS: The present study aimed to investigate the impact of worries during pregnancy, relationship intimacy, and marital satisfaction on anxiety, depression, and stress symptoms in pregnant women, as well as to analyse the mediating effect of relationship intimacy between marital satisfaction and emotional distress. METHOD: During their second and third trimester of pregnancy, 200 Portuguese women were recruited during childbirth preparation consultations and completed the Cambridge Worry Scale (CWS), the Personal Assessment of Intimacy in Relationships Scale (PAIR), the Marital Life Areas Satisfaction Evaluation Scale (MLASES), and the Depression, Anxiety, and Stress Scale (DASS-21). RESULTS: Hierarchical multiple regression analyses showed that being unemployed or on sick leave, being younger, having a history of miscarriage, having more worries during pregnancy, and declaring low-relationship intimacy were the main predictors of emotional distress. Relationship intimacy mediated the relation of marital satisfaction to anxiety and depression symptoms. CONCLUSIONS: This study highlights the importance of the worries during pregnancy and relationship intimacy in shaping pregnant women's emotional distress, and identifies both as targets of intervention. PMID- 29241388 TI - Hypercalcemia-Induced Pancreatitis in Pregnancy Following Calcium Carbonate Ingestion. AB - BACKGROUND: Calcium carbonate is often used to relieve Gastroesophageal Reflux Disease (GERD) in pregnant patients. This report describes a potentially serious complication. CASE: A pregnant female presented at 34 weeks gestation with abdominal pain, nausea, and vomiting. Home medications included an unquantifiable amount of calcium carbonate 500 mg due to constant consumption for GERD. Laboratory findings included elevated calcium, amylase, lipase, and triglyceride level. Pancreatitis was diagnosed and abdominal ultrasound excluded gallstones. Despite hydration, lipase rose and emergency cesarean section was performed. Hypercalcemia was managed by intravenous fluid administration. After delivery, pancreatitis resolved. CONCLUSION: Pancreatitis developed in pregnant patient with hypercalcemia due to excessive calcium carbonate ingestion and resolved after delivery of the fetus, fluid resuscitation, and return of calcium level to normal. PMID- 29241389 TI - Euglycemic Diabetic Ketoacidosis Associated With Sodium-Glucose Cotransporter Type 2 Inhibitors in Patients With Type 2 Diabetes Mellitus Receiving Oral Therapy. AB - INTRODUCTION AND OBJECTIVE: Postmarketing reports and warnings of serious adverse events such as diabetic ketoacidosis (DKA) have raised concern regarding the safety of sodium-glucose cotransporter 2 inhibitors (SGLT2i). This report describes 2 cases of symptomatic SGLT2i-associated euglycemic DKA (euDKA) leading to hospitalization in patients with type 2 diabetes mellitus (DM) previously well controlled on oral medications. CASE REPORTS: Subject 1 is a 55-year-old female admitted with euDKA precipitated by infection and managed with intravenous insulin. This case was notable for a delayed diagnosis of euDKA and lack of clinical improvement despite withholding dapagliflozin. Subject 2 is a 62-year old male admitted with euDKA precipitated by infection. His clinical condition improved rapidly and euDKA responded to withdrawal of empagliflozin alone. DISCUSSION: Applying the Naranjo adverse medication reaction probability scale to each case (subject 1 score = 3 points; subject 2 score = 4 points) suggests these are possible adverse reactions to SGLT2i. Data from randomized controlled trials suggest DKA events in adults with type 2 DM receiving SGLT2i are rare and similar to placebo. However, data from a large cohort suggest these events occur more frequently and are associated with a 2-fold increased risk of DKA. CONCLUSION: This class of medications may be associated with a higher real-world risk of DKA in adults with type 2 DM than previously reported. Patients prescribed these medications should receive vigilant assessment for features of traditional DKA as well as euDKA. PMID- 29241390 TI - Public health impact of pneumococcal conjugate vaccine infant immunization programs: assessment of invasive pneumococcal disease burden and serotype distribution. AB - INTRODUCTION: Pneumococcal conjugate vaccine (PCV) impact studies have reported substantial reductions in the incidence of invasive pneumococcal disease (IPD) after implementation of childhood PCV programs. Heterogeneity in surveillance systems, local epidemiology and PCV programs hampers comparisons between studies. We aimed to better understand the impact of childhood PCV programs on overall IPD and serotype distribution. Areas covered: We analyzed the impact of PCV programs on the incidence of overall IPD, and the distribution of vaccine serotypes (VT) and non-vaccine serotypes (NVT) in children <5 years and adults >=65 years old. We retrieved datasets from observational post-marketing studies and surveillance reports from countries with high-quality surveillance data available for at least 2 years before PCV program initiation and 3 years after higher-valent PCV implementation. We harmonized pre- and post-PCV analysis periods and assessment methods. Expert commentary: After introduction of pediatric PCV programs, the residual overall IPD burden in children was low and in a narrow range across countries with high vaccination coverage, irrespective of differences in PCV programs and pneumococcal epidemiology. Effects on overall IPD were more variable in the elderly. Whereas IPD was mainly due to VTs before PCV introduction, NVTs are the major contributor today in children and adults. PMID- 29241391 TI - Analysis of cystic hygroma diagnosed in the prenatal period: 5-years' experience at a tertiary hospital in Southeastern Turkey. AB - PURPOSE: Our aim was to evaluate the association of cystic hygroma (CH) with fetal malformations and also to investigate the outcome of fetuses with CH diagnosed in the prenatal period. METHODS: We divided the CH patients into two main groups as isolated CH or CH associated with the congenital structural abnormality (CSA) by measuring the thickness of CH and showing other fetal abnormalities. Pregnancy outcomes were recorded as spontaneous abortion, elective termination, intrauterine death, live birth, postnatal death, and lost to follow up. RESULTS: There were 74 cases of fetal CH including 19 in CSA-CH group and 55 in isolated-CH group diagnosed between 11 and 21 weeks' gestation. Karyotype analysis of these 28 patients revealed 18 (64.2%) normal karyotypes. Pregnancy outcomes included 54 elective terminations, five postnatal deaths, one spontaneous abortion, six live births, four intrauterine deaths, and four patients were lost to follow-up. CONCLUSION: In the presence of any CSA concurrent with CH, prognosis may be considered as poor and any additional help of fetal karyotyping is questionable. But fetal karyotyping may be advocated in counseling patients with isolated CH, in which a better prognosis and resolvement of CH may be expected in case of a normal karyotype. PMID- 29241392 TI - The hidden agenda of predatory journals: A warning call for junior researchers and student authors. PMID- 29241393 TI - Multidimensional approach for the proper management of a complex chronic patient with chronic obstructive pulmonary disease. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is frequently associated with comorbidities occurring either independently or as consequences of COPD. Areas covered: This review examines the interactions between the pathophysiology of COPD and the most frequent comorbidities, and highlights the need for multidimensional clinical strategies to manage COPD patients with comorbidities. Expert commentary: Most COPD patients need to be approached in a complex and multifactorial scenario. The diagnosis of COPD is necessarily based on the presence of chronic respiratory symptoms and poorly reversible airflow obstruction, but exacerbations and comorbidities need to be considered in the evaluation of disease severity and prognosis in individual patients. More importantly, defining the precise relationship between COPD and comorbidities for each patient is the basis for a correct therapeutic approach. PMID- 29241394 TI - Neoadjuvant therapy offers longer survival than upfront surgery for poorly differentiated and higher stage pancreatic cancer. AB - BACKGROUND: Neoadjuvant therapy for pancreatic cancer remains controversial. Our aim was to assess differences in survival, disease recurrence and histopathological tumor characteristics between patients treated with neoadjuvant therapy followed by subsequent surgery and patients undergoing upfront surgery. MATERIAL AND METHODS: Out of 399 consecutive pancreatic ductal adenocarcinoma (PDAC) patients operated at Helsinki University Hospital in 2000-2015, 75 borderline resectable patients were treated with neoadjuvant therapy. Resectable propensity scored patients (n = 150) underwent upfront surgery. Neoadjuvant therapy consisted of folfirinox, single gemcitabine or combined with cisplatin, nab-paclitaxel or capecitabine with or without radiation. Survival was calculated with Kaplan-Meier and compared with the Breslow test. Survival was determined from the start of treatment, being the first day of treatment for patients treated with neoadjuvant therapy and the date of surgery for others. RESULTS: Between 2000 and 2015 median disease-specific survival (DSS) [34 vs. 26 months, p = .016] and disease-free survival (DFS) [22 vs. 13 months, p = .001] were longer in patients treated with neoadjuvant therapy than in those undergoing upfront surgery. Survival differences were not significant in the 2000s but were, in turn, among patients treated in the 2010s with better survival for patients treated with neoadjuvant therapy [DSS 35 vs. 26 months, p = .008 and DFS 25 vs. 13 months, p = .001]. Especially patients with poorly differentiated G3 tumors [DSS 30 vs. 11 months, p = .004 and DFS 21 vs. 7 months, p = .001] and higher stage IIB-III [DSS 34 vs. 20 months, p = .006 and DFS 21 vs. 10 months, p = .001] had longer survival when treated with neoadjuvant therapy. CONCLUSIONS: PDAC patients treated with neoadjuvant therapy had longer DSS and DFS than those undergoing upfront surgery. Neoadjuvant therapy benefits especially borderline resectable patients with higher stage and poorly differentiated tumors. PMID- 29241395 TI - Oxytocin regulates social approach. AB - The physical space individuals share is known as interpersonal space. As social creatures, people tend to approach others actively and explore the environment around them, opting for different space preferences with different people. In the current study, we sought to examine the role of oxytocin (OT) in regulating active social interpersonal space preferences. Contrary to previous studies that reported a preference for increased space following intranasal OT, we predicted that following OT administration individuals would exhibit increased active approach towards a protagonist. Accordingly, we measured active approach towards friends and strangers. The results indicated that OT increased social approach, particularly to strangers, suggesting that the OT system plays a major role in regulating social approach, depending on type of protagonist. The results are in line with the social salience and anxiety reduction hypotheses showing that OT increases approach to strangers. PMID- 29241396 TI - Critical Thresholds of Intracranial Pressure-Derived Continuous Cerebrovascular Reactivity Indices for Outcome Prediction in Noncraniectomized Patients with Traumatic Brain Injury. AB - The aim of the study was to compare intracranial pressure (ICP)-derived cerebrovascular reactivity indices in their ability to predict six-month outcome, and to determine/compare critical thresholds related to outcome for each index in adult noncraniectomized traumatic brain injury (TBI). Using a retrospective cohort of nondecompressive craniectomy (non-DC) patients with TBI, we performed univariate and multi-variate binary logistic regression outcome analysis of: pressure reactivity index (PRx), pulse amplitude index (PAx), and a newly described index (RAC) calculated as the regression coefficient between ICP waveform amplitude and cerebral perfusion pressure (CPP). Finally, we performed sequential chi-square threshold analysis for each index as it related to six month binary outcomes. Outcome was assessed via dichotomized Glasgow Outcome Scores (GOS): (A) favorable (GOS 4 or 5) versus unfavorable (GOS 3 or less), (B) alive versus dead. There were 358 non-DC patients with TBI included in all aspects of the analysis. In an analysis of the entire recording period for all patients using univariate binary logistic regression, the areas under the curves (AUCs) for favorable versus unfavorable outcome were: PRx (0.573, p < 0.0001), PAx (0.606, p < 0.0001), and RAC (0.655, p < 0.0001). Similarly, the AUCs for alive versus dead outcome were: PRx (0.651, p < 0.0001), PAx (0.705, p < 0.0001), and RAC (0.722, p < 0.0001). RAC displayed superior AUC statistics compared with PRx and PAx, using both univariate and multi-variate regression. RAC displayed more stable critical thresholds related to six-month outcomes. Thresholds for both favorable versus unfavorable and alive versus dead outcomes for PRx, PAx, and RAC across the entire recording period were: +0.35 and +0.35, 0 and +0.25, 0.10 and -0.05, respectively. In non-DC patients with TBI, RAC appears to be superior to PRx and PAx in six-month outcome prediction, using both univariate and multi-variate logistic regression. Further, RAC displayed more stable critical thresholds associated with binary outcomes at six months. Further analysis of RAC in TBI is required. PMID- 29241397 TI - Static Characteristics of a New Three-Dimensional Linear Homeomorphic Saccade Model. AB - A linear homeomorphic saccade model that produces 3D saccadic eye movements consistent with physiological and anatomical evidence is introduced. Central to the model is the implementation of a time-optimal controller with six linear muscles and pulleys that represent the saccade oculomotor plant. Each muscle is modeled as a parallel combination of viscosity [Formula: see text] and series elasticity [Formula: see text] connected to the parallel combination of active state tension generator [Formula: see text], viscosity element [Formula: see text], and length tension elastic element [Formula: see text]. Additionally, passive tissues involving the eyeball include a viscosity element [Formula: see text], elastic element [Formula: see text], and moment of inertia [Formula: see text]. The neural input for each muscle is separately maintained, whereas the effective pulling direction is modulated by its respective mid-orbital constraint from the pulleys. Initial parameter values for the oculomotor plant are based on anatomical and physiological evidence. The oculomotor plant uses a time-optimal, 2D commutative neural controller, together with the pulley system that actively functions to implement Listing's law during both static and dynamic conditions. In a companion paper, the dynamic characteristics of the saccade model is analyzed using a time domain system identification technique to estimate the final parameter values and neural inputs from saccade data. An excellent match between the model estimates and the data is observed, whereby a total of 20 horizontal, 5 vertical, and 64 oblique saccades are analyzed. PMID- 29241398 TI - Effects of Exposure and Vowel Space Distribution on Phonetic Drift: Evidence from American English Learners of French. AB - Recent work by Chang has shown that even at the very earliest stages of second language (L2) acquisition, the phonetic implementation of speakers' native English phoneme categories is slightly modified by contact with L2 Korean, which is referred to as "phonetic drift." This study investigates whether rapid phonetic drift generalizes to another pairing of languages. We examined naive American English learners of French, who were recorded producing both American English and French vowels after one and six weeks of a study abroad program in Paris. In addition, the Study Abroad group is compared with proficient American English L1 speakers of French who have been residents of Paris for at least five years, to investigate the impact of long-term use of an L2 on the vowel categories of L1. Whereas the Study Abroad group showed no evidence of phonetic drift after six weeks, the Paris Residents' American English vowel space shifted along F1 and several English vowels demonstrated clear movement toward French monolingual norms. A closer look at the high vowels provides insight into how phonetic categories are influenced both by drift and by a pressure to keep vowel categories distinct between the languages. The results are also discussed with respect to potential effects of the size of the vowel inventory and the amount of input required to cause phonetic drift. PMID- 29241399 TI - Identifying the source of food-borne disease outbreaks: An application of Bayesian variable selection. AB - Early identification of contaminated food products is crucial in reducing health burdens of food-borne disease outbreaks. Analytic case-control studies are primarily used in this identification stage by comparing exposures in cases and controls using logistic regression. Standard epidemiological analysis practice is not formally defined and the combination of currently applied methods is subject to issues such as response misclassification, missing values, multiple testing problems and small sample estimation problems resulting in biased and possibly misleading results. In this paper, we develop a formal Bayesian variable selection method to account for misclassified responses and missing covariates, which are common complications in food-borne outbreak investigations. We illustrate the implementation and performance of our method on a Salmonella Thompson outbreak in the Netherlands in 2012. Our method is shown to perform better than the standard logistic regression approach with respect to earlier identification of contaminated food products. It also allows relatively easy implementation of otherwise complex methodological issues. PMID- 29241400 TI - Bayesian nonparametric inference for the three-class Youden index and its associated optimal cutoff points. AB - The three-class Youden index serves both as a measure of medical test accuracy and a criterion to choose the optimal pair of cutoff values for classifying subjects into three ordinal disease categories (e.g. no disease, mild disease, advanced disease). We present a Bayesian nonparametric approach for estimating the three-class Youden index and its corresponding optimal cutoff values based on Dirichlet process mixtures, which are robust models that can handle intricate features of distributions for complex data. Results from a simulation study are presented and an application to data from the Trail Making Test to assess cognitive impairment in Parkinson's disease patients is detailed. PMID- 29241401 TI - Who Lives Alone During Old Age? Trends in the Social and Functional Disadvantages of Sweden's Solitary Living Older Adults. AB - This study identifies specific social and functional disadvantages associated with living alone during old age in Sweden and assesses whether these associations have changed during recent decades. Data came from repeated cross sectional surveys of Swedish adults aged 77+ during 1992-2014. Findings indicate that several types of disadvantage are consistently associated with the probability of living alone including financial insecurity and having never married for women and having never married and mobility impairment for men. Also for older men, low education has become an increasing strong determinant of living alone. These findings suggest that older adults who live alone are a subgroup that is particularly, and in some cases increasingly, vulnerable with respect to social and functional status. This has important policy implications related to addressing the needs of this growing subgroup as well as methodological implications for studies on the health effects of living alone. PMID- 29241402 TI - A review on management of spent lithium ion batteries and strategy for resource recycling of all components from them. AB - The wide use of lithium ion batteries (LIBs) has brought great numbers of discarded LIBs, which has become a common problem facing the world. In view of the deleterious effects of spent LIBs on the environment and the contained valuable materials that can be reused, much effort in many countries has been made to manage waste LIBs, and many technologies have been developed to recycle waste LIBs and eliminate environmental risks. As a review article, this paper introduces the situation of waste LIB management in some developed countries and in China, and reviews separation technologies of electrode components and refining technologies of LiCoO2 and graphite. Based on the analysis of these recycling technologies and the structure and components characteristics of the whole LIB, this paper presents a recycling strategy for all components from obsolete LIBs, including discharge, dismantling, and classification, separation of electrode components and refining of LiCoO2/graphite. This paper is intended to provide a valuable reference for the management, scientific research, and industrial implementation on spent LIBs recycling, to recycle all valuable components and reduce the environmental pollution, so as to realize the win-win situation of economic and environmental benefits. PMID- 29241404 TI - In Vivo Measurement of Surface Pressures and Retraction Distances Applied on Abdominal Organs During Surgery. AB - This study undertook the in vivo measurement of surface pressures applied by the fingers of the surgeon during typical representative retraction movements of key human abdominal organs during both open and hand-assisted laparoscopic surgery. Surface pressures were measured using a flexible thin-film pressure sensor for 35 typical liver retractions to access the gall bladder, 36 bowel retractions, 9 kidney retractions, 8 stomach retractions, and 5 spleen retractions across 12 patients undergoing open and laparoscopic abdominal surgery. The maximum and root mean square surface pressures were calculated for each organ retraction. The maximum surface pressures applied to these key abdominal organs are in the range 1 to 41 kPa, and the average maximum surface pressure for all organs and procedures was 14 +/- 3 kPa. Surface pressure relaxation during the retraction hold period was observed. Generally, the surface pressures are higher, and the rate of surface pressure relaxation is lower, in the more confined hand-assisted laparoscopic procedures than in open surgery. Combined video footage and pressure sensor data for retraction of the liver in open surgery enabled correlation of organ retraction distance with surface pressure application. The data provide a platform to design strategies for the prevention of retraction injuries. They also form a basis for the design of next-generation organ retraction and space creation surgical devices with embedded sensors that can further quantify intraoperative retraction forces to reduce injury or trauma to organs and surrounding tissues. PMID- 29241403 TI - Social support and verbal interaction are differentially associated with cognitive function in midlife and older age. AB - Social engagement is associated with healthy aging and preserved cognition. Two dimensions of engagement, verbal interactions and perceived support, likely impact cognition via distinct mechanistic pathways. We explored the cognitive benefit of each construct among enrollees (N = 1,052, mean age = 60.2 years) in the Wisconsin Registry for Alzheimer's Prevention study, who provide neuropsychological and sociobehavioral data at two-year intervals. Outcomes included six cognitive factor scores representing key domains of executive function and memory. Key predictors included self-reported perceived social support and weekly verbal interaction. Results indicated that after adjusting for lifestyle covariates, social support was positively associated with Speed and Flexibility and that verbal interactions were associated with Verbal Learning and Memory. These findings suggest that support, which may buffer stress, and verbal interaction, an accessible, aging-friendly form of environmental enrichment, are uniquely beneficial. Both are integral in the design of clinical and community interventions and programs that promote successful aging. PMID- 29241405 TI - Cell Clusters Are Indicative of Stem Cell Activity in the Degenerate Intervertebral Disc: Can Their Properties Be Manipulated to Improve Intrinsic Repair of the Disc? AB - The aim of this study was to examine the complexity of the stem cell populations in the intervertebral disc (IVD) and understand their role in disc degeneration, with a view of determining whether the resident stem cells could be developed for therapeutic purposes to combat IVD degeneration. Stem cells have been isolated from disc and paradiscal tissues, including the notochord, annulus fibrosus (AF), nucleus pulposus (NP), cartilaginous endplate (CEP), ligamentum flavum, and vertebral body. Resident AF and NP cells are relatively sparsely distributed occurring as single or occasional doublet cells surrounded by an extensive extracellular matrix (ECM). Small clusters of 4-12 cells also occur close to annular lesions in experimental ovine and canine disc degeneration, these are indicative of an attempted repair response by resident stem cells. The rat IVD also has notochordal and peripheral cell populations in the outer AF, which express CS sulfation motifs (7-D-4, 4-C-3, 3-B-3[-]) characteristic of activated stem cells, the murine IVD also has a cell population in the outer AF adjacent to the vertebral growth plate with characteristics of a progenitor cell population. These have also been observed in rabbit, minipig, ovine, and human IVDs. Chondroid cell nests in the ovine NP may represent a progenitor/stem cell reserve. Such human chondroid cells express CS sulfation motifs (7-D-4, 4-C-3, 3 B-3[-]), cytokeratin-8 and 19, and CD cell surface markers typical of stem cells, including OCT3/4, CD105, CD90, STRO-1, NOTCH1, and JAGGED1. Similar stem cell populations are present in grade IV degenerate human IVDs. A greater understanding of the biology of this chondroid cell population may identify them as a therapeutic resource. A resident therapeutic cell type adapted to the demanding IVD environment may be advantageous in repair strategies. PMID- 29241406 TI - Outpatient clinics treating substance use disorders in Northwest Russia and Northern Norway: a descriptive comparative study. AB - Both in Norway and Russia a considerable portion of the population have substance use disorders. However, the knowledge about outpatient services treating substance use disorders in Norway and Russia is limited. This study will describe and compare outpatient clinics treating substance use disorders in Arkhangelsk in Northwest Russia and in Bodo and Tromso in Northern Norway on availability, accessibility and treated prevalence (patients treated in one year). The managers (N=3) of the outpatient clinics (N=3) were interviewed with the European Service Mapping Schedule (ESMS) and the International Classification of Mental Health Care (ICMHC). The interviews were supplemented by e-mail and phone calls. The treatment in Arkhangelsk was mainly biologically oriented (medical), while a greater variety of methods was available in Bodo and Tromso. The clinic in Russia was a drop-in clinic, while in Norway patients needed a referral to get an appointment in the clinic. Patients treated in Arkhangelsk (treated prevalence) was 1662, while in Bodo it was 233 and in Tromso 220. The present study revealed great differences between the clinics involved in accessibility, availability and treated prevalence. Cultural traditions and budgeting of the mental health care system could explain some of the findings. PMID- 29241407 TI - Reflections on labelling and counting. PMID- 29241408 TI - Response to Professor Whitely, concerning "Evaluation of sodium tetradecyl sulfate and polidocanol as sclerosants for leg telangiectasia based on histological evaluation with clinical correlation". PMID- 29241409 TI - Letter Re: Evaluation of sodium tetradecyl sulfate and polidocanol as sclerosants for leg telangiectasia based on histological evaluation with clinical correlation. PMID- 29241411 TI - Prediction of zinc binding sites in proteins using sequence derived information. AB - Zinc is one the most abundant catalytic cofactor and also an important structural component of a large number of metallo-proteins. Hence prediction of zinc metal binding sites in proteins can be a significant step in annotation of molecular function of a large number of proteins. Majority of existing methods for zinc binding site predictions are based on a data-set of proteins, which has been compiled nearly a decade ago. Hence there is a need to develop zinc-binding site prediction system using the current updated data to include recently added proteins. Herein, we propose a support vector machine-based method, named as ZincBinder, for prediction of zinc metal-binding site in a protein using sequence profile information. The predictor was trained using fivefold cross validation approach and achieved 85.37% sensitivity with 86.20% specificity during training. Benchmarking on an independent non-redundant data-set, which was not used during training, showed better performance of ZincBinder vis-a-vis existing methods. Executable versions, source code, sample datasets, and usage instructions are available at http://proteininformatics.org/mkumar/znbinder/. PMID- 29241410 TI - Co-relation of overall survival with peripheral blood-based inflammatory biomarkers in advanced stage non-small cell lung cancer treated with anti programmed cell death-1 therapy: results from a single institutional database. PMID- 29241412 TI - Tonsillotomy versus tonsillectomy in adults suffering from tonsil-related afflictions: a systematic review. AB - OBJECTIVE: Tonsillotomy has emerged as an alternative for tonsillectomy in treating patients with tonsil-related afflictions. Tonsillotomy provides favourable outcomes in children, but treatment of choice in adults remains unclear. This systematic review sought to evaluate the current literature on the efficacy and adverse events of tonsillotomy compared to tonsillectomy in adults. METHODS: A Medline and Cochrane search was conducted for randomized clinical trials (RCTs) and cohort studies comparing tonsillotomy to tonsillectomy in adults. Risk of bias was assessed. Outcome measures were efficacy of the procedure in resolving the initial tonsil-related symptoms (tonsillitis, obstructive sleep apnoea, tonsil stones, halitosis, dysphagia), procedure-related complications, recovery time, post-operative use of analgesics, patient satisfaction, and operating time. RESULTS: In total nine papers were included. These trials had a high risk of bias and the inter-comparability of results was poor. The reported studies found generally a similar efficacy for both interventions. With regard to pain, the use of analgesics, patient satisfaction and operation time, the results were generally in favour of tonsillotomy. Post operative haemorrhages were more frequent after tonsillectomy. CONCLUSION: Current evidence suggests an equal efficacy of tonsillotomy and tonsillectomy in adults and a preference for tonsillotomy in terms of pain, analgesics use, patient-satisfaction, operation time and post-operative complications. PMID- 29241413 TI - Novel missense mutations in gidB gene associated with streptomycin resistance in Mycobacterium tuberculosis: insights from molecular dynamics. AB - Streptomycin was the first antibiotic used for the treatment of tuberculosis by inhibiting translational proof reading. Point mutation in gidB gene encoding S adenosyl methionine (SAM)-dependent 7-methylguanosine (m7G) methyltransferase required for methylation of 16S rRNA confers streptomycin resistance. As there was no structural substantiation experimentally, gidB protein model was built by threading algorithm. In this work, molecular dynamics (MD) simulations coupled with binding free energy calculations were performed to outline the mechanism underlying high-level streptomycin resistance associated with three novel missense mutants including S70R, T146M, and R187M. Results from dynamics analyses suggested that the structure distortion in the binding pocket of gidB mutants modulate SAM binding affinity. At the structural level, these conformational changes bring substantial decrease in the number of residues involved in hydrogen bonding and dramatically reduce thermodynamic stability of mutant gidB-SAM complexes. The outcome of comparative analysis of the MD simulation trajectories revealed lower conformational stability associated with higher flexibility in mutants relative to the wild-type, turns to be major factor driving the emergence of drug resistance toward antibiotic. This study will pave way toward design and development of resistant defiant gidB inhibitors as potent anti-TB agents. PMID- 29241414 TI - Molecular mechanisms of allosteric probe dependence in MU opioid receptor. AB - Allostery is one of the most important features of proteins. It greatly contributes to the complexity of life, since it enables possibility of precise tuning of protein function, as well as performing more than one function per protein. Probe dependence is one of the unique features of allostery. It allows a protein to respond differently to the same allosteric modulator when different drugs or transmitters are bound. Unfortunately, allosteric mechanisms are difficult to investigate experimentally. Instead, they can be reproduced artificially in simulations. We simulated in silico a native-like cell membrane fragment with an active-state human MU opioid receptor (MOR) in order to investigate diverse effects of a receptor's positive allosteric modulator on various agonists. Particular emphasis on native-likeness of the environment was put. We managed to reproduce the experimentally observed effects, which allowed us to take deeper insight into their underlying mechanisms. We found an allosteric pathway in the receptor, leading from the ligand binding site to the intracellular, effector site. We observed that the modulator affected the pathway, inducing different resultant responses for full and partial agonists. PMID- 29241415 TI - Biomechanically determined hand force limits protecting the low back during occupational pushing and pulling tasks. AB - Though biomechanically determined guidelines exist for lifting, existing recommendations for pushing and pulling were developed using a psychophysical approach. The current study aimed to establish objective hand force limits based on the results of a biomechanical assessment of the forces on the lumbar spine during occupational pushing and pulling activities. Sixty-two subjects performed pushing and pulling tasks in a laboratory setting. An electromyography-assisted biomechanical model estimated spinal loads, while hand force and turning torque were measured via hand transducers. Mixed modelling techniques correlated spinal load with hand force or torque throughout a wide range of exposures in order to develop biomechanically determined hand force and torque limits. Exertion type, exertion direction, handle height and their interactions significantly influenced dependent measures of spinal load, hand force and turning torque. The biomechanically determined guidelines presented herein are up to 30% lower than comparable psychophysically derived limits and particularly more protective for straight pushing. Practitioner Summary: This study utilises a biomechanical model to develop objective biomechanically determined push/pull risk limits assessed via hand forces and turning torque. These limits can be up to 30% lower than existing psychophysically determined pushing and pulling recommendations. Practitioners should consider implementing these guidelines in both risk assessment and workplace design moving forward. PMID- 29241416 TI - Culture, Masculine Honor, and Violence Toward Women. AB - Prior research has connected the cultural ideology of honor to intrasexual violence between men and to attitudes supporting intersexual aggression in response to perceived honor violations by female romantic partners. We extend this research to show that honor ideology is also associated with an increased likelihood of men actually engaging in violent and sexually coercive behaviors toward women. Extending previous research on honor-based schemas and scripts linked to relationship violence, comparisons between honor states and non-honor states in the United States show that official rape and domestic homicide rates by White male perpetrators (Study 1) and experiences of rape and violence in relationships anonymously reported by White female teenagers (Study 2) were higher in honor states, controlling for a variety of potential confounds. These results extend prior laboratory research on honor-based schemas and scripts into the realm of extreme, real-world behaviors. PMID- 29241417 TI - Neuropsychiatric manifestations are not uncommon in Indian lupus patients and negatively affect quality of life. AB - Objectives The objectives of this paper are to look at the prevalence of neuropsychiatric manifestations and assess their impact on quality of life in North Indian lupus patients. Methods The study included consecutive patients with systemic lupus erythematosus (SLE) who were older than 18 years and met the SLICC 2012 criteria. A diagnosis of a neuropsychiatric syndrome was made as per ACR 1999 definitions. Manifestations occurring at any point in time after the diagnosis of SLE were considered if a reliable history and medical records were available. Quality of life was assessed by EuroQol-5D questionnaire. Means were compared by student t test for normally distributed data. Comparison of quality of life between groups was performed by the Kruskal-Wallis test and Mann-Whitney U test. Results This study included 101 patients of SLE with mean (+/-SD) age of 32.3 +/- 10.0 years and a majority ( n = 92) were females. Mean (+/-SD) age of diagnosis of SLE was 27.8 +/- 9.2 years and disease duration (after diagnosis) was 4.6 +/- 4.5 years. Thirty-three patients had neuropsychiatric manifestations with a total of 42 events. The most common manifestation was headache (10%) followed by anxiety disorder (5%) and peripheral neuropathy (9%). Other NPSLE syndromes observed in the study are seizure (4%), cognitive dysfunction (4%), depression (4%), acute confusional state (2%), autonomic neuropathy (2%), movement disorder (1%), and mononeuritis multiplex (1%). On comparing the groups of NPSLE, nephritis, and neither, there was a significant difference in mobility, self-care, pain, and worry. On post hoc test, there was a significant difference between the NPSLE and neither group. Conclusion Neuropsychiatric manifestations significantly affect quality of life in North Indian SLE patients. PMID- 29241418 TI - Isolation and Characterization of Bone Marrow Mesenchymal Stromal Cell Subsets in Culture Based on Aldehyde Dehydrogenase Activity. AB - Mesenchymal stromal cells (MSCs) have particular properties that allow their use as therapeutic strategies for several cell-based applications. Historically, bone marrow (BM)-MSCs are isolated by culture adherence since specific cell surface markers are yet to be developed. This original work aimed to identify and characterize isolating expanded BM-MSCs based on their aldehyde dehydrogenase (ALDH) activity known to be a hallmark of stem cells and relevant for their isolation. We thus isolated by fluorescence-activated cell sorting technology two functionally different populations of BM-MSCs depending on their ALDH activity (ALDH+ and ALDH-). Transcriptome analysis and profiling clearly demonstrated that both populations of BM-MSCs present distinct pattern of genes related to the main properties of MSCs (proliferation, response to hypoxia, angiogenesis, phenotype, stemness, multilineage, hematopoiesis, immunomodulation) in an ALDH activity dependent manner. Both BM-MSC populations look to significantly differ in terms of biological responses and functionalities. More functional analyses are needed to understand and characterize the properties of these ALDH populations. Collectively, our results highlight ALDH activity as a potential feature for isolating and segregating functional and/or competent subset of BM-MSC populations, which may account for better and more efficient therapeutic issue. PMID- 29241419 TI - Genomics England's implementation of its public engagement strategy: Blurred boundaries between engagement for the United Kingdom's 100,000 Genomes project and the need for public support. AB - The United Kingdom's 100,000 Genomes Project has the aim of sequencing 100,000 genomes from National Health Service patients such that whole genome sequencing becomes routine clinical practice. It also has a research-focused goal to provide data for scientific discovery. Genomics England is the limited company established by the Department of Health to deliver the project. As an innovative scientific/clinical venture, it is interesting to consider how Genomics England positions itself in relation to public engagement activities. We set out to explore how individuals working at, or associated with, Genomics England enacted public engagement in practice. Our findings show that individuals offered a narrative in which public engagement performed more than one function. On one side, public engagement was seen as 'good practice'. On the other, public engagement was presented as core to the project's success - needed to encourage involvement and ultimately recruitment. We discuss the implications of this in this article. PMID- 29241420 TI - Molecular modeling and dynamic simulations of agglutinin-like family members from Candida albicans: New insights into potential targets for the treatment of candidiasis. AB - Infections by Candida albicans in immune compromised patients cause significant morbidity and mortality. In the search for potential molecular targets for drug development, the family of agglutinin-like proteins (Als) in C. albicans have been identified due to numerous attributes associated with high virulence, most prominently due to their role in adherence. Here, molecular models of individual members of the Als family illustrated common and unique structure features. Additionally, dynamic simulations were performed to display regions of high mobility. The results showed variations between Als members in the fluctuation of the A1B1 protein loop, which is located at the entrance to the peptide binding cavity, suggesting that this feature may be a factor contributing to observed differences in affinities to ligands and adhesion properties. Molecular docking results further suggested that ligand affinity could be influenced by movements in the A1B1 loop. In addition, a new site was identified in Als in an area adjacent to the peptide binding cavity that could serve as a new binding site for the design of future anti-adhesion ligands that provide increased specificity inhibiting Als proteins from C. albicans. PMID- 29241421 TI - The Effect of Zinc Supplementation on Sleep Quality of ICU Nurses: A Double Blinded Randomized Controlled Trial. AB - This study examined the effect of zinc supplementation on the sleep quality (SQ) of intensive care unit (ICU) nurses. In a double-blind, randomized controlled trial, 54 ICU nurses were randomly assigned to the intervention group ( n = 27) that received 220 mg zinc sulfate capsules every 72 hours for 1 month and the control group ( n = 26) that received placebo. Sleep quality of ICU nurses was measured by calculating the total quality sleep score using the Pittsburgh Sleep Quality Index (PSQI). The serum zinc level was a secondary outcome. All measurements were calculated at both baseline and 1 month after intervention. The total PSQI, subjective SQ, and sleep latency scores for the intervention group were significantly lower than the control group, which means that the SQ of ICU nurses in the intervention group improved from baseline. The serum zinc level of the intervention group at the end of the study was significantly higher than the control group, which means that zinc supplementation improved participants' serum zinc level. Based on these findings, the researcher suggested that zinc supplementation could be associated with better SQ, subjective SQ, and sleep latency in this group of workers. PMID- 29241422 TI - Factors Associated With Injury Among Employees at a U.S. Army Hospital. AB - The purpose of this study was to investigate injury incidence and factors associated with injury among employees at a large U.S. Army hospital to inform injury prevention planning and health promotion education efforts. Demographics, health behaviors, and injury history were collected by survey from hospital employees between October and December 2014. Descriptive statistics were reported and factors associated with injury were determined using multiple logistic regression. Respondents (380; 56% females, 44% males; 54% active duty military, 45% civilians) reported a prevalence of unhealthy behaviors (e.g., not enough exercise [58%] and poor sleeping habits [49%]). Nearly half of respondents (47%) reported at least one occupational injury in the past 12 months. Leading mechanisms of injuries were repetitive overuse (36%), falls (15%), and single twisting movement/overexertion (14%). Leading activities at the time of injury were physical training (24%), walking/hiking (15%), and lifting or moving objects (11%). Factors associated with injury included active duty military status, less education, tobacco use, overuse of alcohol or drugs, and stress. Health education efforts and materials intended for hospital staff should incorporate identified modifiable injury risk factors (e.g., alcohol and drug use, stress, tobacco use, poor sleep). Injury prevention initiatives should focus on physical training, walking/hiking, and lifting. Establishment of surveillance and routine review of employee injury, illness, and health behavior data are recommended to monitor program effects and collect data necessary to inform future prevention priorities and planning. PMID- 29241423 TI - Reconsolidation of Traumatic Memories for PTSD: A randomized controlled trial of 74 male veterans. AB - DESIGN: A randomized waitlist-controlled design (n = 74) examined the efficacy of Reconsolidation of Traumatic Memories (RTM) among male veterans with current month flashbacks and nightmares. Volunteers were randomly assigned to immediate treatment (three 120-minute sessions of RTM), or to a 3-week waiting condition before receiving the RTM treatment. Blinded psychometricians evaluated the symptoms at intake, 2 weeks, and 6 weeks post. Wait-listed participants were re evaluated and then treated. Sixty-five volunteers completed the treatment. RESULTS: Of those treated, 46 (71%) lost DSM diagnosis for post-traumatic stress disorder (PTSD) by one of the following definitions: 42 persons (65%) were in complete remission (PTSD Symptom Scale Interview (PSS-I) <= 20 and DSM criteria not met). Four others (6%) lost the DSM diagnosis or were otherwise sub-clinical by dichotomous criteria (PSS-I < 20 and absence of flashbacks and nightmares) but non-ambiguous on the PTSD Checklist Military Version measures. Within-group RTM effect sizes (Hedges' g) for PSS-I score changes ranged from 1.45 to 2.3. The between-group comparison between the treatment group and the untreated controls was significant (p < .001) with an effect size equivalent to two standard deviations (g = 2.13; 95% CI [1.56, 2.70]). Patient satisfaction with the intervention was high. CONCLUSIONS: RTM shows promise as a brief, cost-effective intervention for PTSD characterized primarily by intrusive symptoms. Clinical or methodological significance of this article: The article provides evidence to support a fast (5 hours or fewer) robust intervention for PTSD characterized by intrusive symptoms including current-month flashbacks, nightmares, and accompanied by sympathetic arousal in response to trauma narratives. The intervention is well tolerated and has demonstrated efficacy up to one year. PMID- 29241426 TI - Causal inference with measurement error in outcomes: Bias analysis and estimation methods. AB - Inverse probability weighting estimation has been popularly used to consistently estimate the average treatment effect. Its validity, however, is challenged by the presence of error-prone variables. In this paper, we explore the inverse probability weighting estimation with mismeasured outcome variables. We study the impact of measurement error for both continuous and discrete outcome variables and reveal interesting consequences of the naive analysis which ignores measurement error. When a continuous outcome variable is mismeasured under an additive measurement error model, the naive analysis may still yield a consistent estimator; when the outcome is binary, we derive the asymptotic bias in a closed form. Furthermore, we develop consistent estimation procedures for practical scenarios where either validation data or replicates are available. With validation data, we propose an efficient method for estimation of average treatment effect; the efficiency gain is substantial relative to usual methods of using validation data. To provide protection against model misspecification, we further propose a doubly robust estimator which is consistent even when either the treatment model or the outcome model is misspecified. Simulation studies are reported to assess the performance of the proposed methods. An application to a smoking cessation dataset is presented. PMID- 29241427 TI - Risk Factor Knowledge, Perceived Threat, and Protective Health Behaviors: Implications for Type 2 Diabetes Control in Rural Communities. AB - Purpose The purpose of this study was to explore how perceived threat of type 2 diabetes (T2D) is shaped by risk factor knowledge and promotes the engagement of protective health behaviors among rural adults. Methods Participants (N = 252) completed a cross-sectional mixed-mode survey. Chi-squared analyses were computed to examine differences in perceived threat by demographic factors and knowledge of T2D risk factors. Logistic regressions were conducted to examine the relationship between T2D perceived threat and engagement in physical activity and health screenings. Results Perceived threat and knowledge of T2D risk factors were high. Perceived susceptibility was significantly higher among women, whites, and respondents with high body mass index (BMI). Respondents reporting physical activity most/almost every day had low perceived susceptibility to T2D. Perceived severity was significantly higher among respondents with high BMI. Blood cholesterol and glucose screenings were associated with greater T2D perceived susceptibility and severity. Higher BMI was associated with receiving a blood glucose screening. Conclusion Health education specialists and researchers should further explore the implications of using audience segmented fear appeal messages to promote T2D control through protective health behaviors. PMID- 29241428 TI - State-Targeted Funding and Technical Assistance to Increase Access to Medication Treatment for Opioid Use Disorder. AB - OBJECTIVE: As the United States grapples with an opioid epidemic, expanding access to effective treatment for opioid use disorder is a major public health priority. Identifying effective policy tools that can be used to expand access to care is critically important. This article examines the relationship between state-targeted funding and technical assistance and adoption of three medications for treating opioid use disorder: oral naltrexone, injectable naltrexone, and buprenorphine. METHODS: This study draws from the 2013-2014 wave of the National Drug Abuse Treatment System Survey, a nationally representative, longitudinal study of substance use disorder treatment programs. The sample includes data from 695 treatment programs (85.5% response rate) and representatives from single state agencies in 49 states and Washington, D.C. (98% response rate). Logistic regression was used to examine the relationships of single-state agency targeted funding and technical assistance to availability of opioid use disorder medications among treatment programs. RESULTS: State-targeted funding was associated with increased program-level adoption of oral naltrexone (adjusted odds ratio [AOR]=3.14, 95% confidence interval [CI]=1.49-6.60, p=.004) and buprenorphine (AOR=2.47, 95% CI=1.31-4.67, p=.006). Buprenorphine adoption was also correlated with state technical assistance to support medication provision (AOR=1.18, 95% CI=1.00-1.39, p=.049). CONCLUSIONS: State-targeted funding for medications may be a viable policy lever for increasing access to opioid use disorder medications. Given the historically low rates of opioid use disorder medication adoption in treatment programs, single-state agency targeted funding is a potentially important tool to reduce mortality and morbidity associated with opioid disorders and misuse. PMID- 29241429 TI - Behavioral Health Coverage Under the Affordable Care Act: What Can We Learn From Marketplace Products? AB - OBJECTIVE: The 2008 federal parity law and the 2010 Affordable Care Act (ACA) sought to expand access to behavioral health services. There was concern that health plans might discourage enrollment by individuals with behavioral health conditions who tend to be higher cost. This study compared behavioral health benefits available in the group insurance market (nonmarketplace) to those sold through the ACA marketplaces to check for evidence of less generous behavioral health coverage in marketplace plans. METHODS: Data were from a 2014 nationally representative survey of commercial health plans regarding behavioral health services (80% response rate). The sample included the most common silver marketplace product and, as a comparison, the most common nonmarketplace product of the same type (for example, health maintenance organization or preferred provider organization) from each health plan (N=106 marketplace and nonmarketplace pairs, or 212 products). RESULTS: Marketplace and nonmarketplace products were similar in terms of coverage, prior authorization, and continuing review requirements. Marketplace products were more likely to employ narrow and tiered behavioral health provider networks. Narrow and tiered networks were more common in state than in federal marketplaces. CONCLUSIONS: Provider network design is a tool that health plans may use to control cost and possibly discourage enrollment by high-cost users, including those with behavioral health conditions. The ACA was successful in ensuring robust behavioral health coverage in marketplace plans. As the marketplaces evolve or are replaced, these data provide an important baseline to which future systems can be compared. PMID- 29241430 TI - Past-Year Treatment Utilization Among Individuals Meeting DSM-5 PTSD Criteria: Results From a Nationally Representative Sample. AB - OBJECTIVE: Little is known regarding treatment utilization among individuals meeting DSM-5 criteria for posttraumatic stress disorder (PTSD). METHODS: Data were analyzed from the third wave of the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative sample using DSM-5 criteria. RESULTS: Factors related to increased odds of PTSD treatment utilization for individuals meeting lifetime criteria included some college education versus less than a high school degree (odds ratio [OR]=3.17), having health insurance versus no insurance (OR=2.86), having a comorbid phobia disorder versus not having a phobia disorder (OR=1.36), and greater PTSD symptom count (OR=1.11). Older age (OR=.40), identifying as black or Asian versus white non-Hispanic (OR=.70 and OR=.28, respectively), and greater social functioning (OR=.98) were associated with decreased odds of PTSD treatment utilization. CONCLUSIONS: Results highlight factors that may be useful in identifying population subgroups with PTSD that are at risk for underutilization of services. PMID- 29241431 TI - The Impact of a Peer Navigator Program in Addressing the Health Needs of Latinos With Serious Mental Illness. AB - OBJECTIVE: The impact of a peer navigator program (PNP) on efforts to address the health needs of Latinos with serious mental illness was examined in a randomized controlled trial. METHODS: Latinos with a serious mental illness (N=110) were randomly assigned to the PNP (integrated care with a peer navigator [PN]) or to a treatment-as-usual control group (integrated care without a PN) for one year. Data on service engagement (scheduled and received appointments) were assessed weekly, and self-reports of recovery, empowerment, and quality of life were collected at baseline and at four, eight, and 12 months. RESULTS: Findings from group * trial analyses of covariance (ANCOVAs) found main and interaction effects for scheduled and achieved appointments, showing better engagement for the PNP group compared with the control group over the course of the study. Significant interactions were found for recovery, empowerment, and quality of life, showing greater improvement for the PNP group compared with the control group over year 1 of the study (multivariate ANCOVA; F=3.27, df=9 and 98, p<.01). CONCLUSIONS: In the-field navigation by peers seems to enhance service engagement, recovery, and quality of life. Whether these results occurred because navigators helped overcome barriers to treatment-regardless of whether they were peers per se-needs to be examined in future research. PMID- 29241432 TI - Correlates of Reduced Violent Behavior Among Patients Receiving Intensive Treatment for Posttraumatic Stress Disorder. AB - OBJECTIVE: Posttraumatic stress disorder (PTSD) has been linked to violent behavior, especially among military personnel returning from service in a war zone. Little is known, however, about whether the extent of violent behavior among persons with PTSD changes in response to intensive treatment or about the predictors and correlates of any such change. METHODS: The study examined data from over 35,000 U.S. military veterans treated in specialized intensive Veterans Health Administration PTSD programs. Data were collected at program entry and four months after discharge. Variables studied documented sociodemographic and biographical data, program participation, and clinical factors such as PTSD symptom severity and substance use. Violence was assessed by a self-report measure that addressed property damage, threatening behavior, and physical assault. RESULTS: Violence declined significantly between program entry and four month postdischarge, with a moderate effect size. Most of the variance was explained by baseline levels of violence; those who reported the most violent behavior at baseline showed the largest reductions four months after discharge. The reduction in violence was more strongly correlated with reductions in patients' PTSD symptomatology and substance use than with their incarceration history or with other sociodemographic and biographical variables. CONCLUSIONS: Although an observational study cannot identify specific causes of reductions in violent behavior, these data suggest that the short-term support, shelter, and asylum that formed part of intensive treatment are associated with reduced violent behavior and that such services play an important role in the spectrum of care for war-related PTSD. PMID- 29241434 TI - Clinical Consensus Recommendations for Urine Testing of Adherence to Antipsychotics Among People With Serious Mental Illness. AB - OBJECTIVE: This study developed clinical recommendations for the use of proven urine testing technologies to assess antipsychotic medication adherence among people with serious mental illness. METHODS: Guided by the RAND/UCLA Appropriateness Method, researchers conducted a literature review and semistructured interviews and convened an expert panel to develop clinical consensus recommendations for the use of urine monitoring to assess antipsychotic medication adherence. RESULTS: The expert panel identified six circumstances in which urine monitoring was recommended at initial evaluation and five scenarios in which monitoring was recommended after initial evaluation. Conducting monitoring at the site where psychiatric medication is prescribed and providing education prior to testing and feedback after testing were recommended. CONCLUSIONS: A consensus was reached on clinical recommendations for use of urine monitoring at intake and during ongoing treatment. There was strong agreement that monitoring can be used to improve assessment and thence clinical care and outcomes. PMID- 29241433 TI - Long-Run Trends in Antidepressant Use Among Youths After the FDA Black Box Warning. AB - OBJECTIVE: In October 2004, the Food and Drug Administration directed pharmaceutical companies to issue a black box warning about the potential link between the use of antidepressants and suicidal ideation among children. This study analyzed long-run trends in antidepressant use among children before and after the black box warning for those with and without severe psychological impairment. METHODS: The analysis used data from the Medical Expenditure Panel Survey for children ages five to 17, covering years 2000-2011 (N=75,819). The study used multivariate probit models to compare the changes in the rate of any antidepressant use in the early (2004-2007) and late (2008-2011) postwarning years with the rate in the prewarning years (2002-2003). Recycled predictions methods were used to estimate yearly predicted probabilities of use. RESULTS: After adjustment for all covariates, there was a .5% statistically significant decline in the probability of using any antidepressants during the early postwarning years (2004-2007) compared with prewarning years. In the long run (2008-2011), however, there was no statistically significant difference. Five years after the black box warning, the adjusted rates of use increased to their prewarning levels (2.29% in 2003 and 2.26% in 2009). The initial impact of the warning differed between the severe and nonsevere populations, with a significant effect on those with nonsevere psychological impairment. CONCLUSIONS: The return to the rates before the black box warning raises concern that the impact of the warning may have dissipated over time. More frequent updates of the warning might be necessary. PMID- 29241436 TI - Integrated Primary Care in Assertive Community Treatment. AB - Assertive community treatment (ACT) has the potential to serve as a medical home for adults with serious mental illness, a population that experiences some of the most significant health disparities in the United States. Using site visit methodology, the authors describe partnerships that were created between five ACT programs and federally qualified health centers (FQHCs) to provide integrated behavioral health and primary care. The authors examined rates of screening for common chronic conditions. The programs used three distinct approaches: two programs colocated ACT teams at an FQHC, two programs employed primary care providers who split their time between the FQHC and the ACT program, and one program embedded a primary care provider within the ACT team. Effective communication between staffs may be more important than type of partnership in determining integration success. PMID- 29241435 TI - Potential Benefits of Incorporating Peer-to-Peer Interactions Into Digital Interventions for Psychotic Disorders: A Systematic Review. AB - OBJECTIVE: Peer-to-peer interactions and support groups mitigate experiences of social isolation and loneliness often reported by individuals with psychotic disorders. Online peer-to-peer communication can promote broader use of this form of social support. Peer-to-peer interactions occur naturally on social media platforms, but they can negatively affect mental health. Recent digital interventions for persons with psychotic disorders have harnessed the principles of social media to incorporate peer-to-peer communication. This review examined the feasibility, acceptability, and preliminary efficacy of recent digital interventions in order to identify strategies to maximize benefits of online peer to-peer communication for persons with psychotic disorders. METHODS: An electronic database search of PubMed, EMBASE, PsycINFO, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Health Technology Assessment Database was conducted in February 2017 and yielded a total of 1,015 results. Eight publications that reported data from six independent trials and five interventions were reviewed. RESULTS: The technology supporting peer-to-peer communication varied greatly across studies, from online forums to embedded social networking. When peer-to-peer interactions were moderated by facilitators, retention, engagement, acceptability, and efficacy were higher than for interventions with no facilitators. Individuals with psychotic disorders were actively engaged with moderated peer-to-peer communication and showed improvements in perceived social support. Studies involving service users in intervention design showed higher rates of acceptability. CONCLUSIONS: Individuals with psychotic disorders value and benefit from digital interventions that include moderated peer-to-peer interactions. Incorporating peer-to-peer communication into digital interventions for this population may increase compliance with other evidence-based therapies by producing more acceptable and engaging online environments. PMID- 29241437 TI - The Swiss Mental Health Care System. AB - The United States and Switzerland are among the world's wealthiest countries. Both are highly innovative and entrepreneurial, ranking high in global competitiveness and innovation and with similar liberal economies. This column highlights features of the health care system in Switzerland, a country with an exclusively private health insurance system, with federally mandated universal health insurance. Residents can choose from about 58 insurance companies. Switzerland regulates these companies and negotiates reimbursement rates. The Swiss model of health care and its provision of comprehensive psychiatric and substance abuse treatment could inform policy as the United States considers major changes to its health care laws. Switzerland could serve as an example for developing a mental health care model that ensures appropriate services, with a high density of psychiatric inpatient facilities and mental health care providers, while maintaining affordable care. PMID- 29241438 TI - Realizing E-Prescribing's Potential to Reduce Outpatient Psychiatric Medication Errors. AB - Preliminary evidence from observational and cohort studies suggests that replacement of paper- and phone-based medication prescriptions with electronic prescribing systems in ambulatory settings is associated with decreased medication errors. However, problems from traditional prescribing also occur with e-prescribing (such as incorrect medication dose and instructions or wrong patient), as do some new problems (a confusing user interface leading to prescribing the wrong medication). The authors present four steps for reducing medication errors in outpatient psychiatric settings: continuing to implement e prescribing, streamlining user interfaces, improving interoperability among various e-prescribing and retail pharmacy systems, and using education and advocacy to achieve these goals. PMID- 29241439 TI - Family Decision Making and Self-Determination Among Consumers With Schizophrenia in China: Cross-Cultural Implications. AB - OBJECTIVES: Self-determination is viewed as an important ingredient of successful recovery in psychiatric rehabilitation. The concept of autonomy, a key component of self-determination, may be of less importance in Chinese cultures, whereby an individual's choices may be in conflict with the family's expectations. This study aimed to develop an instrument to measure opinions about self-determination among Chinese consumers and their family members. METHODS: A 27-item questionnaire, the Consumer and Family Decision Making Scale (CFDMS), was constructed to measure consumers' and family members' views of self-determination in various aspects of daily life. A total of 364 (182 consumers of psychiatric services with a diagnosis of schizophrenia and 182 of their family members) participated in the study. RESULTS: The CFDMS was found to possess good psychometric properties and appears to be a reliable and valid instrument for assessment of consumers' decision making. (The Cronbach's alphas of psychiatric care and treatment factor, personal and social function factor, community and daily living factor, and money management factor were as follows: .86, .89, .87 and .76. The respective test-retest reliabilities were as follows: .81, .89, .80, and .88). Chinese consumers preferred autonomous decision making in regard to personal and social functioning and community and daily living but preferred to defer decisions regarding psychiatric care and treatment and money management to others. Family members and consumers had similar views. CONCLUSIONS: Deferring decisions to family members is common in Chinese families. The emphasis on autonomy in Western health care may need to be reconsidered in the treatment of Chinese consumers. Chinese families have a strong influence on treatment decisions, and providers must respect this style and remain nonjudgmental when dealing with situations or decisions that may be contradictory to their own culture and values. PMID- 29241440 TI - Primary Care-Mental Health Integration in the VA: Shifting Mental Health Services for Common Mental Illnesses to Primary Care. AB - OBJECTIVE: Primary care-mental health integration (PC-MHI) aims to increase access to general mental health specialty (MHS) care for primary care patients thereby decreasing referrals to non-primary care-based MHS services. It remains unclear whether new patterns of usage of MHS services reflect good mental health care. This study examined the relationship between primary care clinic engagement in PC-MHI and use of different MHS services. METHODS: This was a retrospective longitudinal cohort study of 66,638 primary care patients with mental illnesses in 29 Southern California Veterans Affairs clinics (2008-2013). Regression models used clinic PC-MHI engagement (proportion of all primary care clinic patients who received PC-MHI services) to predict relative rates of general MHS visits and more specialized MHS visits (for example, visits for serious mental illness services), after adjustment for year and clinic fixed effects, other clinic interventions, and patient characteristics. RESULTS: Patients were commonly diagnosed as having depression (35%), anxiety (36%), and posttraumatic stress disorder (22%). For every 1 percentage point increase in a clinic's PC-MHI engagement rate, patients at the clinic had 1.2% fewer general MHS visits per year (p<.001) but no difference in more specialized MHS visits. The reduction in MHS visits occurred among patients with depression (-1.1%, p=.01) but not among patients with psychosis; however, the difference between the subsets was not statistically significant. CONCLUSIONS: Primary care clinics with greater engagement in PC-MHI showed reduced general MHS use rates, particularly for patients with depression, without accompanying reductions in use of more specialized MHS services. PMID- 29241441 TI - Antibody separation using lectin modified poly(HEMA-EDMA) hydrogel membranes. AB - Herein we describe the synthesis of Concanavalin A-poly(2-hydroxyethyl methacrylate-ethylene dimethacrylate) hydrogel membranes (via photopolymerization technique) for antibody separation from aqueous solutions. Different characterization techniques including Scanning Electron Microscopy, Fourier Transform Infrared Spectroscopy, Elemental Analysis and swelling tests revealed the highly rough morphology and spherical shape of the synthetized membranes. Attached amount of IMEO (salinization agent) onto polymeric structure and Con A binding capacity were found to be 10.85 mol/g and 3.52 mg/g, respectively. Optimum conditions for IgG adsorption such as adsorption capacity, pH and reusability profile of HMs were judiciously characterized. Maximum IgG adsorption capacity of hydrogel membrane was found to be as 26.81 mg/g. Adsorbed IgG was eluted successfully by using 2.0 M of NaCl solution. Reusability profiles of hydrogel membrane in five adsorption-desorption cycles revealed that there was no significant decrease in IgG adsorption capacity at the end of the 5th reuse. The hydrogel membranes reported here hold considerable promise as an effective sorbent system for IgG adsorption with good stability and efficient repeated usage. PMID- 29241442 TI - Age differences in negative and positive expectancy bias in comorbid depression and anxiety. AB - Anxious individuals report disproportionately negative expectations concerning the future, termed the negative expectancy bias. In contrast, ageing is associated with an inflated expectancy for positive future events. A recent study [Steinman, S. A., Smyth, F. L., Bucks, R. S., MacLeod, C., & Teachman, B. A. (2013). Anxiety-linked expectancy bias across the adult lifespan. Cognition and Emotion, 27, 345-355. doi: 10.1080/02699931.2012.711743 ] found using an interpretation bias task, a negative expectancy bias in young adults and positive expectancy bias in older adults with high trait anxiety. Extending this, the current study examined expectancy bias for positive, negative and ambiguously emotionally toned information in younger and older adults with clinical levels of depression and anxiety to community control groups, thus allowing examination of both disorder status and age on biases. Clinical participants reported a pervasive tendency to expect negative events relative to positive regardless of whether the current scenarios were positive, negative or ambiguous. Older adults showed greater expectancy for future positive scenarios when the initial scenario was negative or ambiguous. Age moderated the negative expectancy bias shown by clinical participants for ambiguous scenarios. Clinical disorders in older adults attenuated the positive expectancy bias that was otherwise strong in community participants. These findings provide further evidence for age differences in processing of emotionally toned information, with older adults showing a greater expectancy for positive future events. PMID- 29241443 TI - Characterization of Molecular Changes in Endometrium Associated With Chronic Use of Progesterone Receptor Modulators: Ulipristal Acetate Versus Mifepristone. AB - Ulipristal acetate (UPA) is a selective progesterone receptor modulator (PRM), which is used as an emergency contraceptive in women. Recent studies demonstrated the efficacy of an UPA contraceptive vaginal ring (UPA-CVR) as a blocker of ovulation. However, the endometrium of women exposed to UPA over a 6-month period display glandular changes, termed PRM-associated endometrial changes (PAECs). We, therefore, investigated whether UPA-induced PAECs are associated with altered expression of the transcription factor heart- and neural crest derivatives expressed protein 2 (HAND2) whose downregulation is observed in endometrial epithelial hyperplasia and cancer. Our results showed that while exposure to mifepristone, a well-known PRM, leads to suppression of endometrial HAND2 expression, long-term exposure to UPA-CVR did not cause downregulation of this marker. Further studies, using human primary endometrial stromal cells, confirmed that whereas mifepristone-mediated suppression of HAND2 elevated the levels of its downstream target fibroblast growth factor 18, UPA did not significantly alter the expression of this growth factor. A rationale for the differential regulation of HAND2 by these PRMs was provided by our observation that mifepristone-bound progesterone receptors turn over at a faster rate than those bound to UPA. Collectively, these results support the selective effects of different PRMs and indicate that chronic exposure to UPA does not alter the HAND2 pathway whose dysregulation is linked to complex atypical endometrial hyperplasia and cancer. The results from this study involving a limited number of clinical samples should pave the way for a larger study to determine the safety of UPA for long-term use. PMID- 29241444 TI - Willingness to pay for flexible working conditions of people with type 2 diabetes: discrete choice experiments. AB - BACKGROUND: The increasing number of people with chronic diseases challenges workforce capacity. Type 2 diabetes (T2D) can have work-related consequences, such as early retirement. Laws of most high-income countries require workplaces to provide accommodations to enable people with chronic disabilities to manage their condition at work. A barrier to successful implementation of such accommodations can be lack of co-workers' willingness to support people with T2D. This study aimed to examine the willingness to pay (WTP) of people with and without T2D for five workplace initiatives that help individuals with type 2 diabetes manage their diabetes at work. METHODS: Three samples with employed Danish participants were drawn from existing online panels: a general population sample (n = 600), a T2D sample (n = 693), and a matched sample of people without diabetes (n = 539). Participants completed discrete choice experiments eliciting their WTP (reduction in monthly salary, ?/month) for five hypothetical workplace initiatives: part-time job, customized work, extra breaks with pay, and time off for medical consultations with and without pay. WTP was estimated by conditional logits models. Bootstrapping was used to estimate confidence intervals for WTP. RESULTS: There was an overall WTP for all initiatives. Average WTP for all attributes was 34 ?/month (95% confidence interval [CI]: 27-43] in the general population sample, 32 ?/month (95% CI: 26-38) in the T2D sample, and 55 ?/month (95% CI: 43-71) in the matched sample. WTP for additional breaks with pay was considerably lower than for the other initiatives in all samples. People with T2D had significantly lower WTP than people without diabetes for part-time work, customized work, and time off without pay, but not for extra breaks or time off with pay. CONCLUSIONS: For people with and without T2D, WTP was present for initiatives that could improve management of diabetes at the workplace. WTP was lowest among people with T2D. Implementation of these initiatives seems feasible and may help unnecessary exclusion of people with T2D from work. PMID- 29241445 TI - Shifting cancer care towards Multidisciplinarity: the cancer center certification program of the German cancer society. AB - BACKGROUND: Over the last decades numerous initiatives have been set up that aim at translating the best available medical knowledge and treatment into clinical practice. The inherent complexity of the programs and discrepancies in the terminology used make it difficult to appreciate each of them distinctly and compare their specific strengths and weaknesses. To allow comparison and stimulate dialogue between different programs, we in this paper provide an overview of the German Cancer Society certification program for multidisciplinary cancer centers that was established in 2003. MAIN BODY: In the early 2000s the German Cancer Society assessed the available information on quality of cancer care in Germany and concluded that there was a definite need for a comprehensive, transparent and evidence-based system of quality assessment and control. This prompted the development and implementation of a voluntary cancer center certification program that was promoted by scientific societies, health-care providers, and patient advocacy groups and based on guidelines of the highest quality level (S3). The certification system structures the entire process of care from prevention to screening and multidisciplinary treatment of cancer and places multidisciplinary teams at the heart of this program. Within each network of providers, the quality of care is documented using tumor-specific quality indicators. The system started with breast cancer centers in 2003 and colorectal cancer centers in 2006. In 2017, certification systems are established for the majority of cancers. Here we describe the rationale behind the certification program, its history, the development of the certification requirements, the process of data collection, and the certification process as an example for the successful implementation of a voluntary but powerful system to ensure and improve quality of cancer care. CONCLUSION: Since 2003, over 1 million patients had their primary tumors treated in a certified center. There are now over 1200 sites for different tumor entities in four countries that have been certified in accordance with the program and transparently report their results from multidisciplinary treatment for a substantial proportion of cancers. This led to a fundamental change in the structure of cancer care in Germany and neighboring countries within one decade. PMID- 29241446 TI - Narrowing the spectrum: the new frontier of precision antimicrobials. AB - Antibiotics have become the standard of care for bacterial infections. However, rising rates of antibiotic-resistant infections are outpacing the development of new antimicrobials. Broad-spectrum antibiotics also harm beneficial microbial communities inhabiting humans. To combat antibiotic resistance and protect these communities, new precision antimicrobials must be engineered to target specific pathogens. PMID- 29241447 TI - Six-year survival of reimplanted talus after isolated total talar extrusion: a case report. AB - BACKGROUND: Open total extrusion of the talus without concomitant fracture is an extremely rare injury. We present 6-year follow-up data of a patient treated using a temporary spanning external fixator and less invasive single K-wire fixation. CASE PRESENTATION: A 55-year-old Asian man who had a totally extruded talus without fracture underwent immediate reimplantation surgery. A spanning external fixator with single antegrade K-wire fixation was applied to maintain the reimplanted talus. During 6 years of follow-up, he could walk without aids and could squat, corresponding to an American Orthopaedic Foot and Ankle Society score of 85. We found that the suspect lesion that was evident at 6 months after surgery had disappeared at 12 months postoperatively on the basis of sequential follow-up magnetic resonance imaging. There was no evidence of osteonecrosis of the dislocated talus at the final follow-up. CONCLUSIONS: In patients with a totally extruded talus, a surgical strategy including immediate reimplantation of the talus and a temporary spanning fixator with single K-wire fixation might be useful to allow early mobilization around the ankle joint and to prevent additional damage of the foot without significant complications. PMID- 29241448 TI - Stranger in a strange land: the experiences of immigrant researchers. AB - Continuing with our Q&A series discussing issues of diversity in STEM fields, Genome Biology spoke with three researchers on their experiences as immigrants. PMID- 29241449 TI - The small dense LDL particle/large buoyant LDL particle ratio is associated with glucose metabolic status in pregnancy. AB - BACKGROUND: The lipoprotein subfraction particle profile can be used to improve clinical assessments of cardiovascular disease risk and contribute to early detection of atherogenic dyslipidemia. Lipid alterations in gestational diabetes have been extensively studied, but the results have been inconsistent. Here, we investigated serum lipoprotein subfraction particle levels and their association with glucose metabolic status in pregnancy. METHODS: Twenty-eight pregnant women with gestational diabetes and 56 pregnant women with normal glucose tolerance matched for body mass index were enrolled in this study. We assessed fasting serum lipid concentrations and lipoprotein subfraction particle levels in participants between 24 and 28 weeks of gestation. RESULTS: The level of low density lipoprotein (LDL) cholesterol was significantly lower in women with gestational diabetes than in those with normal glucose tolerance, but the triglyceride and high-density lipoprotein (HDL) cholesterol levels of the two groups were similar. Lipoprotein particle analysis showed that very-low-density lipoprotein (VLDL) particle number and the small dense LDL particle/large buoyant LDL particle (sdLDL-P/lbLDL-P) ratio were significantly higher in women with gestational diabetes than in those with normal glucose tolerance (P = 0.013 and P = 0.015, respectively). In multivariate analysis, fasting glucose was independently and positively associated with sdLDL-P/lbLDL-P ratio even after adjustment for maternal age, gestational weight gain, BMI and LDL cholesterol (standardized Beta = 0.214, P = 0.029). CONCLUSIONS: The sdLDL-P/lbLDL-P ratio is higher in GDM compared with non-diabetic pregnant women, and positively and independently associated with fasting glucose in pregnant women. PMID- 29241451 TI - Energetic performance analysis of staged palliative surgery in tricuspid atresia using vector flow mapping. AB - BACKGROUND: Staged palliative surgery markedly shifts the balance of volume load on a single ventricle and pulmonary vascular bed. Blalock-Taussig shunt necessitates a single ventricle eject blood to both the systemic and pulmonary circulation. On the contrary, bidirectional cavopulmonary shunt release the single ventricle from pulmonary circulation. CASE PRESENTATION: We report a case of tricuspid atresia patient who underwent first palliative surgery and second palliative surgery. Volume loading condition was assessed by energetic parameters (energy loss, kinetic energy) intraoperatively using vector flow mapping. These energetic parameters can simply indicate the volume loading condition. CONCLUSION: Vector flow mapping was useful tool for monitoring volume loading condition in congenital heart disease surgery. PMID- 29241450 TI - Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. AB - BACKGROUND: Compared with World Health Organization-defined acute myeloid leukaemia (AML) not otherwise specified, patients with AML with myelodysplasia related changes (AML-MRC) are generally older and more likely to have poor-risk cytogenetics, leading to poor response and prognosis. More than one-half of all older (>=65 years) patients in the phase 3 AZA-AML-001 trial had newly diagnosed AML-MRC. METHODS: We compared clinical outcomes for patients with AML-MRC treated with azacitidine or conventional care regimens (CCR; induction chemotherapy, low dose cytarabine, or supportive care only) overall and within patient subgroups defined by cytogenetic risk (intermediate or poor) and age (65-74 years or >=75 years). The same analyses were used to compare azacitidine with low-dose cytarabine in patients who had been preselected to low-dose cytarabine before they were randomized to receive azacitidine or CCR (ie, low-dose cytarabine). RESULTS: Median overall survival was significantly prolonged with azacitidine (n = 129) versus CCR (n = 133): 8.9 versus 4.9 months (hazard ratio 0.74, [95%CI 0.57, 0.97]). Among patients with intermediate-risk cytogenetics, median overall survival with azacitidine was 16.4 months, and with CCR was 8.9 months (hazard ratio 0.73 [95%CI 0.48, 1.10]). Median overall survival was significantly improved for patients ages 65-74 years treated with azacitidine compared with those who received CCR (14.2 versus 7.3 months, respectively; hazard ratio 0.64 [95%CI 0.42, 0.97]). Within the subgroup of patients preselected to low-dose cytarabine before randomization, median overall survival with azacitidine was 9.5 months versus 4.6 months with low-dose cytarabine (hazard ratio 0.77 [95%CI 0.55, 1.09]). Within the low-dose cytarabine preselection group, patients with intermediate-risk cytogenetics who received azacitidine had a median overall survival of 14.1 months versus 6.4 months with low-dose cytarabine, and patients aged 65-74 years had median survival of 14.9 months versus 5.2 months, respectively. Overall response rates were similar with azacitidine and CCR (24.8% and 17.3%, respectively), but higher with azacitidine versus low-dose cytarabine (27.2% and 13.9%). Adverse events were generally comparable between the treatment arms. CONCLUSIONS: Azacitidine may be the preferred treatment for patients with AML-MRC who are not candidates for intensive chemotherapy, particularly patients ages 65-74 years and those with intermediate-risk cytogenetics. TRIAL REGISTRATION: This study was registered at clinicalTrials.gov on February 16, 2010 ( NCT01074047 ). PMID- 29241452 TI - Pancreatic schwannoma: a case report and an updated 40-year review of the literature yielding 68 cases. AB - BACKGROUND: Pancreatic schwannoma is a rare tumor. Preoperative diagnosis of pancreatic schwannoma is challenging due to its tendency to mimic other lesions of the pancreas. We describe a case of pancreatic schwannoma and present a review of the cases currently reported in the English literature to identify characteristics of pancreatic schwannoma on imaging. CASE PRESENTATION: A 53-year old male presented with a history of intermittent periumbilical abdominal pain and lower back pain for 1 week. Based on ultrasound (US) and computed tomography (CT) findings, we made a preoperative diagnosis of solid pseudopapillary tumor and performed a standard pancreaticoduodenectomy. Pathological examination showed that the tumor was composed of spindle cells with a palisading arrangement, and immunohistochemistry revealed strong positive staining for S-100 protein, which was consistent with a diagnosis of pancreatic schwannoma. At the 8-month follow up visit, the patient was doing well without recurrent disease, and his abdominal pain had resolved. CONCLUSIONS: Although pancreatic schwannoma is rare, it should be included in the list of differential diagnoses of pancreatic masses, both solid and cystic. A tumor size larger than 6.90 cm, vascular encasement, or visceral invasion should elicit suspicion of malignant transformation. PMID- 29241454 TI - Effects of sociodemographic characteristics and patients' health beliefs on tuberculosis treatment adherence in Ethiopia: a structural equation modelling approach. AB - BACKGROUND: Patients' beliefs are a major factor affecting tuberculosis (TB) treatment adherence. However, there has been little use of Health Belief Model (HBM) in determining the pathway effect of patients' sociodemographic characteristics and beliefs on TB treatment adherence. Therefore, this study was aimed at determining the effect of sociodemographic characteristics and patients' health beliefs on TB treatment adherence based on the HBM concept in Ethiopia. METHODS: A cross-sectional study was conducted in Addis Ababa, Ethiopia among TB patients undertaking treatment. Thirty health centres were randomly selected and one hospital was purposely chosen. Six hundred and ninety-eight TB patients who had been on treatment for 1-2 month, were aged 18 years or above, and had the mental capability to provide consent were enrolled consecutively with non probability sampling technique from the TB registration book until required sample size achieved. Structured questionnaires were used to collect data. Structural equation modelling was employed to assess the pathway relationship between sociodemographic characteristics, patients' beliefs, and treatment adherence. RESULTS: Of the 698 enrolled participants, 401 (57.4%) were male and 490 (70.2%) were aged 35 years and below. The mean age of participants was 32 (+/ 11.7) and the age range was 18-90 years. Perceived barrier/benefit was shown to be a significant direct negative effect on TB treatment adherence (beta = -0.124, P = 0.032). In addition, cue to action (beta = -0.68, P <= 0.001) and psychological distress (beta = 0.08, P < 0.001) were shown significant indirect effects on TB treatment adherence through perceived barrier/benefit. CONCLUSIONS: Interventions intended to decrease perceived barriers and maximize perceived benefits should be implemented to enhance TB treatment adherence. In addition, it is crucial that counselling is incorporated with the regular directly observed therapy program. Motivators (cue to actions) such as friends, family, healthcare workers, and the media could be used to promote TB treatment adherence. PMID- 29241453 TI - Bile acid is a significant host factor shaping the gut microbiome of diet-induced obese mice. AB - BACKGROUND: Intestinal bacteria are known to regulate bile acid (BA) homeostasis via intestinal biotransformation of BAs and stimulation of the expression of fibroblast growth factor 19 through intestinal nuclear farnesoid X receptor (FXR). On the other hand, BAs directly regulate the gut microbiota with their strong antimicrobial activities. It remains unclear, however, how mammalian BAs cross-talk with gut microbiome and shape microbial composition in a dynamic and interactive way. RESULTS: We quantitatively profiled small molecule metabolites derived from host-microbial co-metabolism in mice, demonstrating that BAs were the most significant factor correlated with microbial alterations among all types of endogenous metabolites. A high-fat diet (HFD) intervention resulted in a rapid and significant increase in the intestinal BA pool within 12 h, followed by an alteration in microbial composition at 24 h, providing supporting evidence that BAs are major dietary factors regulating gut microbiota. Feeding mice with BAs along with a normal diet induced an obese phenotype and obesity-associated gut microbial composition, similar to HFD-fed mice. Inhibition of hepatic BA biosynthesis under HFD conditions attenuated the HFD-induced gut microbiome alterations. Both inhibition of BAs and direct suppression of microbiota improved obese phenotypes. CONCLUSIONS: Our study highlights a liver-BA-gut microbiome metabolic axis that drives significant modifications of BA and microbiota compositions capable of triggering metabolic disorders, suggesting new therapeutic strategies targeting BA metabolism for metabolic diseases. PMID- 29241455 TI - Inclusion of men in maternal and safe motherhood services in inner-city communities in Ghana: evidence from a descriptive cross-sectional survey. AB - BACKGROUND: There has been a growing realisation of the need to enhance men's inclusion in maternal and safe motherhood services, especially in low-income settings. However, empirical studies on the extent to which men are involved in maternal and safe motherhood services especially in poor inner-city communities are lacking. The purpose of this study was to describe the level of men's inclusion in maternal and safe-motherhood services in inner-city communities in Ghana, and to assess the barriers of men's involvement. METHODS: A descriptive cross-sectional quantitative survey was conducted among a total of 256 randomly selected adult men in Chorkor, an inner-city fishing community in Accra, the capital city of Ghana. A multistage sampling strategy was used to select houses, households and respondents. Descriptive statistical techniques were used to analyse the data. Data analysis was done with the aid of SPSS version 20. RESULTS: Although almost all (96.6%) respondents knew the meaning of family planning, as high as 236(92.2%) have never accompanied their wives/partners to clinics to seek family planning services. Also 242(94.5%) and 251(98%) of men, respectively, knew the importance of antenatal services and supervised delivery. However, only 114(44.5%) of men ever accompanied their wives/partners to seek skilled delivery services. Men's involvement was hindered by barriers such as attitude of health workers, long waiting time and socio-cultural beliefs. CONCLUSION: The study revealed a gap between men's awareness of the importance of maternal and safe motherhood services and their actual involvement in accessing these services with their female partners. There is a need to create a supportive environment that encourages men to be involved in maternal health services to help reduce maternal/neonatal morbidity and mortality. PMID- 29241456 TI - Designer rhamnolipids by reduction of congener diversity: production and characterization. AB - BACKGROUND: Rhamnolipids are biosurfactants featuring surface-active properties that render them suitable for a broad range of industrial applications. These properties include their emulsification and foaming capacity, critical micelle concentration, and ability to lower surface tension. Further, aspects like biocompatibility and environmental friendliness are becoming increasingly important. Rhamnolipids are mainly produced by pathogenic bacteria like Pseudomonas aeruginosa. We previously designed and constructed a recombinant Pseudomonas putida KT2440, which synthesizes rhamnolipids by decoupling production from host-intrinsic regulations and cell growth. RESULTS: Here, the molecular structure of the rhamnolipids, i.e., different congeners produced by engineered P. putida are reported. Natural rhamnolipid producers can synthesize mono- and di-rhamnolipids, containing one or two rhamnose molecules, respectively. Of each type of rhamnolipid four main congeners are produced, deviating in the chain lengths of the beta-hydroxy-fatty acids. The resulting eight main rhamnolipid congeners with variable numbers of hydrophobic/hydrophilic residues and their mixtures feature different physico-chemical properties that might lead to diverse applications. We engineered a microbial cell factory to specifically produce three different biosurfactant mixtures: a mixture of di- and mono-rhamnolipids, mono-rhamnolipids only, and hydroxyalkanoyloxy alkanoates, the precursors of rhamnolipid synthesis, consisting only of beta-hydroxy-fatty acids. To support the possibility of second generation biosurfactant production with our engineered microbial cell factory, we demonstrate rhamnolipid production from sustainable carbon sources, including glycerol and xylose. A simple purification procedure resulted in biosurfactants with purities of up to 90%. Finally, through determination of properties specific for surface active compounds, we were able to show that the different mixtures indeed feature different physico-chemical characteristics. CONCLUSIONS: The approach demonstrated here is a first step towards the production of designer biosurfactants, tailor-made for specific applications by purposely adjusting the congener composition of the mixtures. Not only were we able to genetically engineer our cell factory to produce specific biosurfactant mixtures, but we also showed that the products are suited for different applications. These designer biosurfactants can be produced as part of a biorefinery from second generation carbon sources such as xylose. PMID- 29241459 TI - To Mia or not to Mia: stepwise evolution of the mitochondrial intermembrane space disulfide relay. AB - The disulfide relay system found in the intermembrane space (IMS) of mitochondria is an essential pathway for the import and oxidative folding of IMS proteins. Erv1, an essential member of this pathway, has been previously found to be ubiquitously present in mitochondria-containing eukaryotes. However, the other essential protein, Mia40, was found to be absent or not required in some organisms, raising questions about how the disulfide relay functions in these organisms. A recent study published in BMC Biology demonstrates for the first time that some Erv1 proteins can function in oxidative folding independently of a Mia40 protein, providing for the first time strong evidence that the IMS disulfide relay evolved in a stepwise manner.See research article: 10.1186/s12915 017-0445-8. PMID- 29241457 TI - Impaired regeneration in calpain-3 null muscle is associated with perturbations in mTORC1 signaling and defective mitochondrial biogenesis. AB - BACKGROUND: Previous studies in patients with limb-girdle muscular dystrophy type 2A (LGMD2A) have suggested that calpain-3 (CAPN3) mutations result in aberrant regeneration in muscle. METHODS: To gain insight into pathogenesis of aberrant muscle regeneration in LGMD2A, we used a paradigm of cardiotoxin (CTX)-induced cycles of muscle necrosis and regeneration in the CAPN3-KO mice to simulate the early features of the dystrophic process in LGMD2A. The temporal evolution of the regeneration process was followed by assessing the oxidative state, size, and the number of metabolic fiber types at 4 and 12 weeks after last CTX injection. Muscles isolated at these time points were further investigated for the key regulators of the pathways involved in various cellular processes such as protein synthesis, cellular energy status, metabolism, and cell stress to include Akt/mTORC1 signaling, mitochondrial biogenesis, and AMPK signaling. TGF-beta and microRNA (miR-1, miR-206, miR-133a) regulation were also assessed. Additional studies included in vitro assays for quantifying fusion index of myoblasts from CAPN3-KO mice and development of an in vivo gene therapy paradigm for restoration of impaired regeneration using the adeno-associated virus vector carrying CAPN3 gene in the muscle. RESULTS: At 4 and 12 weeks after last CTX injection, we found impaired regeneration in CAPN3-KO muscle characterized by excessive numbers of small lobulated fibers belonging to oxidative metabolic type (slow twitch) and increased connective tissue. TGF-beta transcription levels in the regenerating CAPN3-KO muscles were significantly increased along with microRNA dysregulation compared to wild type (WT), and the attenuated radial growth of muscle fibers was accompanied by perturbed Akt/mTORC1 signaling, uncoupled from protein synthesis, through activation of AMPK pathway, thought to be triggered by energy shortage in the CAPN3-KO muscle. This was associated with failure to increase mitochondria content, PGC-1alpha, and ATP5D transcripts in the regenerating CAPN3-KO muscles compared to WT. In vitro studies showed defective myotube fusion in CAPN3-KO myoblast cultures. Replacement of CAPN3 by gene therapy in vivo increased the fiber size and decreased the number of small oxidative fibers. CONCLUSION: Our findings provide insights into understanding of the impaired radial growth phase of regeneration in calpainopathy. PMID- 29241458 TI - Inhibition of the IGF signaling pathway reverses cisplatin resistance in ovarian cancer cells. AB - BACKGROUND: This study was aimed at investigating whether metformin can reverse the resistance of ovarian cancer cells to cisplatin and exploring the underlying mechanism. METHODS: Ovarian cancer cell proliferation in vitro was evaluated using a CCK-8 assay. The resistance index of platinum-resistant ovarian cancer cells was determined and cell cycle and apoptosis rate determined by annexin V/propidium iodide double-staining in CP70 cells. Western blotting was used to determine IGF1, IGF1R, AKT, p-IGF1, p-IGF1R, p-AKT, and MRP2 levels in cells treated with different concentrations of metformin and LY29400, an inhibitor of the insulin-like growth factor pathway. Changes in gene expression levels of MRP2, IGF1, IGF1R, and AKT were determined by fluorescence real-time quantitative PCR assay of CP70 cells treated with metformin. Tumors of human ovarian cancer cell lines CP70 and A2780 were established by subcutaneous transplantation of cells in nude mice and the effect of metformin on MRP2 expression and tumor inhibition assessed. RESULTS: The IC50 value of cisplatin in CP70 cells decreased significantly as metformin concentration increased (P < 0.05). The cell cycle distribution in CP70 cells changed with metformin treatment; the percentage of cells in the G0/G1 phase, as well as the natural apoptosis rate was significantly increased with metformin treatment (P < 0.05). IGF1, IGF1R, AKT p-IGF1, p-IGF1R, and p-Akt protein expression was enhanced dose-dependently with metformin, and was also significantly changed by treatment of CP70 cells with 0 mM metformin +10 mM LY294002. Moreover, changes in the expression of MRP2, IGF1, IGF1R, and AKT was metformin-concentration dependent, and was significantly different from that in the untreated control group (P < 0.05). In nude mice, the tumor volumes of the cisplatin-treated groups were significantly less than in the control group, and was further suppressed by co-treatment with cisplatin and metformin (P < 0.05), indicating that these 2 drugs had a synergistic effect on tumor inhibition. CONCLUSION: Metformin can improve the sensitivity of ovarian cancer CP70 cells to cisplatin in a concentration-dependent manner by activating the AKT signaling pathway, inhibiting the IGF1R signaling pathway, and reducing MRP2 expression. PMID- 29241461 TI - Mapping a shared genetic basis for neurodevelopmental disorders. AB - Distinct neurodevelopmental disorders have a common genetic etiology that explains the high degree of comorbidity among these disorders. A recent study sought to identify copy number variants across five neurodevelopmental disorders, and detected an enrichment for chromosome 9p24.3 duplication encompassing DOCK8 and KANK1 in affected individuals. Such large-scale studies will help uncover additional causative and modifier loci within common pathways, which will enable the development of therapeutic targets for the treatment of multiple disorders.See related research 10.1186/s13073-017-0494-1. PMID- 29241460 TI - Fractal analysis of left ventricular trabeculations is associated with impaired myocardial deformation in healthy Chinese. AB - BACKGROUND: Left ventricular (LV) non-compaction (LVNC) is defined by extreme LV trabeculation, but is measured variably. Here we examined the relationship between quantitative measurement in LV trabeculation and myocardial deformation in health and disease and determined the clinical utility of semi-automated assessment of LV trabeculations. METHODS: Cardiovascular magnetic resonance (CMR) was performed in 180 healthy Singaporean Chinese (age 20-69 years; males, n = 91), using balanced steady state free precession cine imaging at 3T. The degree of LV trabeculation was assessed by fractal dimension (FD) as a robust measure of trabeculation complexity using a semi-automated technique. FD measures were determined in healthy men and women to derive normal reference ranges. Myocardial deformation was evaluated using feature tracking. We tested the utility of this algorithm and the normal ranges in 10 individuals with confirmed LVNC (non compacted/compacted; NC/C ratio > 2.3 and >=1 risk factor for LVNC) and 13 individuals with suspected disease (NC/C ratio > 2.3). RESULTS: Fractal analysis is a reproducible means of assessing LV trabeculation extent (intra-class correlation coefficient: intra-observer, 0.924, 95% CI [0.761-0.973]; inter observer, 0.925, 95% CI [0.821-0.970]). The overall extent of LV trabeculation (global FD: 1.205 +/- 0.031) was independently associated with increased indexed LV end-diastolic volume and mass (sbeta = 0.35; p < 0.001 and sbeta = 0.13; p < 0.01, respectively) after adjusting for age, sex and body mass index. Increased LV trabeculation was independently associated with reduced global circumferential strain (sbeta = 0.17, p = 0.013) and global diastolic circumferential and radial strain rates (sbeta = 0.25, p < 0.001 and sbeta = -0.15, p = 0.049, respectively). Abnormally high FD was observed in all patients with a confirmed diagnosis of LVNC. Five out of 13 individuals with suspected LVNC had normal FD, despite NC/C > 2.3. CONCLUSION: This study defines the normal range of LV trabeculation in healthy Chinese that can be used to make or refute a diagnosis of LVNC using the fractal analysis tool, which we make freely available. We also show that increased myocardial trabeculation is associated with higher LV volumes, mass and reduced myocardial strain. PMID- 29241462 TI - [Neurogenic thoracic outlet syndrome]. AB - Neurogenic thoracic outlet syndrome (nTOS) is a type of thoracic outlet syndrome (TOS) where compression of the brachial plexus is responsible for development of upper-extremity, head and neck symptoms. We present a 16-year-old and a 34-year old patient with nTOS. Diagnosis in both cases was done by following the recently published reporting standards for (n)TOS. After this multidisciplinary diagnostic work-up we performed a transaxillary thoracic outlet decompression (TOD). Due to lack of literature, difficult nomenclature and complexity of diagnosis and treatment, diagnosis of nTOS is often delayed. Recent experience shows that treatment of nTOS is safe and effective, both in the short term and the long term. PMID- 29241463 TI - [Myocardial contusion following trauma]. AB - BACKGROUND: Myocardial contusion is a potentially life threatening condition, which should be considered in patients with a compatible thoracic trauma. Guidelines for diagnosis and determination of management are non-existent. CASE DESCRIPTION: A 51-year-old man arrived at the accident and emergency department with thoracic trauma after being knocked down by a bus. A myocardial contusion was diagnosed based on the ECG and elevated high-sensitivity (hs) troponin levels. Cardiac ultrasound revealed no abnormalities. No complications occurred during 48 hours of cardiac monitoring. CONCLUSION: In patients with thoracic trauma, a combination of ECG abnormalities and raised hs troponin levels indicates myocardial contusion. Cardiac ultrasound is required in these patients if they are haemodynamically instable or suffer clinical deterioration. Observation using cardiac rhythm monitoring is necessary in all patients with myocardial contusion, because of the risk of complications such as life threatening cardiac arrhythmias. PMID- 29241464 TI - [Diagnostic approach and treatment of primary hyperparathyroidism]. AB - - Primary hyperparathyroidism (PHPT) is characterised by elevated serum calcium levels due to elevated levels, or insufficient suppression, of parathyroid hormone (PTH).- The incidence of PHPT has increased in recent years. This is mainly the result of more frequently performed routine measurements of serum calcium, e.g. as part of postmenopausal screening.- The classically described features of PHPT - bones and stones - are not always observed and most patients are asymptomatic.- Diagnosis of PHPT is only established by biochemical testing, not by imaging.- Ultrasound and technetium-99m sestamibi SPECT-CT are the first choice imaging modalities. These investigations are necessary to localize the parathyroid adenomas and thereby facilitate minimal invasive parathyroidectomy (MIP). PMID- 29241465 TI - [Delayed umbilical cord separation]. AB - We present the case report of a preterm infant with delayed umbilical cord separation. At the age of four weeks the umbilical cord separation had still not occurred. The umbilical cord tissue sometimes seemed wet and did not dry completely. There were no signs of immunodeficiency. An ultrasound of the abdomen showed a small urachal cyst. No further intervention was indicated. PMID- 29241466 TI - [How can gentlemen of standing grow old healthily? Plemp and his De togatorum valetudine tuenda commentatio (1670)]. AB - In 1670, the Professor of Medicine V.F. Plemp from the Belgian University of Leuven published a book explaining in an entertaining fashion how elderly gentlemen in positions of authority could live for a long time in good health but still have enjoyable lives. In writing this book the author manifested himself as a 17th century forerunner of the modern fitness and wellness movement. Plemp was a humanist who believed in the renaissance of Antiquity, and his medical revelations originate largely from ancient Roman sources. He also skilfully intertwined his health advice with descriptions of Greek and Roman customs and mores. PMID- 29241467 TI - [Bioresorbable coronary scaffolds: follow-up]. AB - Bioresorbable scaffolds have been developed as an alternative to current metal stents. Despite earlier acceptable short-term results, the recently published AIDA study found that the most-used resorbable scaffold (Absorb) presents an almost threefold increased risk of stent thrombosis than the metal XIENCE stent, short-term as well as long-term. Acute and subacute stent thrombosis probably occur because of inadequate dual antiplatelet therapy, suboptimal implantation technique or both. Late stent thrombosis is probably affected by absorption related stent-strut discontinuity and factors affecting blood flow. Implantation protocols consisting of adequate pre-dilation, correct sizing and post-dilation have been proposed to reduce the risk of stent thrombosis. In addition, it recommended to treat patients with dual antiplatelet therapy for up to 3 years after placement. The resorbable scaffold is currently being studied further in controlled clinical studies. With new insights and future technical improvements, the bioresorbable scaffold may still be the next revolution in the area of coronary stents. PMID- 29241468 TI - [Addendum to the Dutch guideline for minor head/brain injury]. AB - - After introduction of the Dutch guideline for 'Care for patients with minor head/brain injury' (LTH guideline) in 2010, the number of CT scans has increased. Some of these scans were for patients with only trivial trauma and may not have been necessary.- In addition, since this guideline was implemented, there have been changes in the use of anticoagulants and platelet aggregation inhibitors. Non-vitamin-K-dependent oral anticoagulants (NOACs) and platelet aggregation inhibitors, or combinations of these, are prescribed more often.- These two factors have led the Netherlands Society of Neurology to initiate a request for modification of the LTH guideline for adults in two ways: (a) identification of minimal or trivial trauma for which no CT scan is required and (b) inclusion of NOACs and platelet aggregation inhibitors, or combinations of these, in the guideline. PMID- 29241469 TI - [Social obstetrics: a level playing field when it comes to a healthy start]. AB - Next to foetal growth, embryonic development during the first weeks of pregnancy is associated not only with the health of the newborn, but also with health and disease in later life. In the Netherlands, large disparities exist in perinatal health. These are not only related to medical risks but also to an accumulation of risks related to lifestyle and the social environment. The effects of poverty on perinatal health appear to be substantial. These new insights should lead to a renewal of pregnancy-related care in the form of the implementation of preconception care and 'social obstetrics', into which medical and social domains of care should be integrated. University Medical Centres should apply the results of research in a more proactive manner and organise such societal valorisation programmes in cooperation with local authorities. PMID- 29241470 TI - [Social issues in the doctor's clinic]. AB - Doctors are confronted with issues that arise in society. These social issues can affect patients' health. Solving these problems requires more than just prescribing a pill, as illustrated by the cases of three patients. The first patient is a 42-year-old male with cardiac symptoms, chronic lower back pain and an excessive use of tranquillizers. The welfare worker intervened and his demand for health care and use of tranquillizers diminished. The second patient is a 53 year-old female with symptoms of chronic back pain, migraine and depression. A labour dispute concerning her health eventually led to a referral to a project named 'social hospital', but actual assistance never took place due to the patient's alleged lack of time to participate. The third case concerns an 86-year old female with postherpetic neuralgia who also suffered from loneliness. The patient's named welfare worker tried to get in touch with her, but the patient kept her at a distance. These three cases illustrate that it is very important to get to know the social network in a community in order to refer patients with social issues to the right person or place. Furthermore, prevention and early intervention strategies should be applied where possible. Doctors and local governments must act together in order to succeed in solving patient ill health as a result of social issues. PMID- 29241471 TI - [Patients also have responsibility for prevention]. AB - Patient organisations should be more visible in the societal debate about prevention, alongside fulfilling their more traditional tasks such as education, peer support and lobbying for their interests. Despite appreciating the medical care he received, the author also personally experienced a lack of attention for life-style interventions (e.g. a salt-free diet, exercise) in the care provided. Since 2012, awareness among European patient groups is rising about the importance of nutrition, which is evolving from being considered as a simple necessity to being an essential component of disease management. EU patient groups are participating in the EU-wide national 'Optimal Nutritional Care for All' campaigns. They perceive prevention as a way to decrease lifestyle diseases in the long term, and to economise on health-care costs. Dedicated, enthusiastic politicians are required if this transformation is to take place; they also need reduce the socio-economic differences in society that negatively impact on health and life-expectancy. PMID- 29241472 TI - [Health advocacy in medical student education]. AB - The introduction of the CanMEDS method to qualify training and ongoing education for healthcare providers in terms of competencies has provided a clear framework for medical schools' curricula. Different roles are outlined, and one of these is health advocacy. Physicians are accountable to society to use their knowledge and expertise to improve health. Even before the introduction of CanMEDS, physicians took responsibility for improving health by tackling issues in society that negatively affected the health of many; one obvious example is the provision of clean water and sewage systems to prevent epidemics of infectious diseases such as cholera. The role of the health advocate is now addressed within medical education in graduate and postgraduate medical training curricula. If they are to be really effective, trainers should provide proper role models on how to be a health advocate; even though each doctor does not have to become a politician to change the world, all doctors should look further than the individual patient in their surgery. PMID- 29241473 TI - [Chris, Arie and Piet: three politically active Dutch physicians in the 20th century]. AB - Chris Mol, Arie Querido and Piet Muntendam were three socially and politically active medical doctors in the 20th century. Inspired by different sources (Catholicism, and the social democratic and progressive-liberal movements), these doctors strove to improve public health in the Netherlands. Up to about 1940 they were primarily traditional doctors caring for individual patients. After World War Two their scope widened, eventually to the wider society. The life histories of the three main characters are remarkably intertwined. Querido and Muntendam were classmates at secondary school and university, while Mol and Muntendam frequently met in Parliament between 1950 and 1960. At the end of his career Querido published two historiographies on public health institutions, which were commissioned by Muntendam and Mol. Chris, Arie and Piet passed away in 1979, 1985 and 1986. PMID- 29241474 TI - Optimising design and cost-effective implementation of future pan-African dietary studies: a review of existing economic integration and nutritional indicators for scenario-based profiling and clustering of countries. AB - Most of the African countries are undergoing a complex nutrition and epidemiologic transition associated with a rapid increase in the prevalence of diverse non-communicable diseases. Despite this alarming situation, the still limited and fragmented resources available in Africa impede the implementation of effective action plans to tackle the current and projected diet-disease burden. In order to address these common needs and challenges, the African Union is increasingly supporting continental approaches and strategies as reflected in the launching of the Agenda 2063 and the African regional nutrition strategy 2015 2025, among others. To assure the successful implementation of pan-African nutritional and health initiatives, cost-effective approaches considering similarities/disparities in economy, regional integration, development and nutritional aspects between countries are needed. In the absence of pre-existing models, we reviewed regional economic integration and nutritional indicators (n 13) available in international organisations databases or governmental agencies websites, for fifty-two African countries. These indicators were used to map the countries according to common languages (e.g. Arabic, English, French, Portuguese), development status (e.g. human development index), malnutrition status (e.g. obesity) and diet (e.g. staples predominantly based on either cereals or tubers). The review of the indicators showed that there exist similarities between African countries that can be exploited to benefit the continent with cross-national experiences in order to avoid duplication of efforts in the implementation of future pan-African health studies. In addition, including present and future nutrition surveillance programmes in Africa into national statistical systems might be cost-effective and sustainable in the longer term. PMID- 29241475 TI - Israeli National Policy for Carbapenem-Resistant Enterobacteriaceae Screening, Carrier Isolation and Discontinuation of Isolation. AB - Since 2006, Israel has been confronting an outbreak of carbapenem-resistant Enterobacteriaceae (CRE), and in 2007 Israel implemented a national strategy to contain spread. The intervention was initially directed toward acute-care hospitals and later expanded to include an established reservoir of carriage in long-term-care hospitals. It included regular reporting of CRE cases to a central registry and daily oversight of management of the outbreak at the institutional level. Microbiological methodologies were standardized in clinical laboratories nationwide. Uniform requirements for carrier screening and isolation were established, and a protocol for discontinuation of carrier status was formulated. In response to the evolving epidemiology of CRE in Israel and the continued need for uniform guidelines for carrier detection and isolation, the Ministry of Health in 2016 issued a regulatory circular updating the requirements for CRE screening, laboratory diagnosis, molecular characterization, and carrier isolation, as well as reporting and discontinuation of isolation in healthcare institutions nationwide. The principal elements of the circular are contained herein. Infect Control Hosp Epidemiol 2018;39:85-89. PMID- 29241476 TI - INAHTA IMPACT STORY: LEGISLATIVE AND ACCREDITATION REQUIREMENTS FOR OFFICE-BASED SURGERY IN AUSTRALIA. AB - BACKGROUND: There is growing trend for some surgical procedures previously performed in hospitals to be done in alternative settings, including office-based facilities. There has been some safety concerns reported in the media, which document serious adverse events following procedures performed in an office-based setting. To understand the current regulatory oversight of surgery in this setting ASERNIP-S conducted a review of the legislative and accreditation process governing these facilities in Australia. METHODS: Using rapid review methodology, internet searches targeted government Web sites for relevant publicly-available documents. Use of consolidated versions of legislative instruments ensured currency of information. Standards were sourced directly from the issuing authorities or those that oversee the accreditation process. RESULTS: Within Australia, healthcare facilities for surgery and their licensing are defined by each state and territory, which results in significant jurisdictional variation. These variations relate to the need for anesthesia beyond conscious sedation and listing of procedures in legislative instruments. In 2013, Australia adopted National Safety and Quality Health Service standards (NSQHS standards) for the accreditation of hospitals and day surgery centers; however, there is no NSQHS standard for office-based facilities. The main legislative driver for compliance is access to reimbursement schemes for service delivery. CONCLUSIONS: The legislative and accreditation framework creates a situation whereby healthcare facilities that provide services outside the various legal definitions of surgery and those not covered by a reimbursement scheme, can operate without licensing and accreditation oversight. This situation exposes patients to potential increased risk of harm when receiving treatment in such unregulated facilities. PMID- 29241477 TI - INSIGHTS FROM THE FRONT LINES: A COLLECTION OF STORIES OF HTA IMPACT FROM INAHTA MEMBER AGENCIES. AB - This mini-theme contains six stories of health technology assessment (HTA) impact from member agencies of The International Network of Agencies for Health Technology Assessment (INAHTA), which were originally shared at the 2015 and 2016 INAHTA Congresses. The INAHTA impact story sharing is an innovative network activity where member agency representatives share experiences of HTA impact in a loosely structured story format. Through this process, members gain insights from other agencies on new ways of thinking about and approaching HTA impact assessment. A guide is provided to members to prepare their story, and the best story receives the David Hailey Award for Best Impact Story. This mini-theme contains stories of HTA impact from six member agencies in different parts of the world: the Health Assessment Division of the Ministry of Public Health (Uruguay), the Institute of Quality and Efficiency in Health Care (Germany), the Health Information and Quality Authority (Ireland), the Finnish Office for Health Technology Assessment (Finland), the Australian Safety and Efficacy Register of New Interventional Procedures-Surgical (Australia), and the Institut national d'excellence en sante et en services sociaux (Canada). Across the papers, common themes emerge about the importance of appropriate engagement of stakeholders and the broadening scope of HTA beyond reimbursement decision making. PMID- 29241478 TI - MicroRNA-296 Targets Specificity Protein 1 to Suppress Cell Proliferation and Invasion in Cervical Cancer. AB - Cervical cancer is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths in women worldwide. MicroRNA-296 (miR-296) is aberrantly expressed in a variety of human cancer types. However, the expression levels, biological roles, and underlying molecular mechanisms of miR 296 in cervical cancer remain unclear. This study aimed to detect miR-296 expression in cervical cancer and evaluate its roles and underlying mechanisms in cervical cancer. This study demonstrated that miR-296 was significantly downregulated in cervical cancer tissues and cell lines. Restoring the expression of miR-296 inhibited the proliferation and invasion of cervical cancer cells. Moreover, miR-296 directly targeted the 3'-untranslated regions of specificity protein 1 (SP1) and decreased its endogenous expression at both the mRNA and protein levels. Similar to induced miR-296 expression, SP1 knockdown suppressed the proliferation and invasion of cervical cancer cells. Besides, resumption expression of SP1 rescued the tumor-suppressing roles of miR-296 in cervical cancer. These results indicated that miR-296 may act as a tumor suppressor in cervical cancer by directly targeting SP1. Therefore, SP1 may be developed as a therapeutic target for the treatment of patients with this malignancy. PMID- 29241480 TI - Children, poverty and health promotion in Australia. PMID- 29241481 TI - Advancing evaluation practice in health promotion. PMID- 29241482 TI - Improving the translation of health promotion interventions using effectiveness implementation hybrid designs in program evaluations. AB - Bridging the gap between research-based evidence and public health policy and practice is a considerable challenge to public health improvement this century, requiring a rethinking of conventional approaches to health research production and use. Traditionally the process of research translation has been viewed as linear and unidirectional, from epidemiological research to identify health problems and determinants, to efficacy and effectiveness trials and studies of strategies to maximise the implementation and dissemination of evidence-based interventions in practice. A criticism of this approach is the considerable time it takes to achieve translation of health research into practice. Hybrid evaluation designs provide one means of accelerating the research translation process by simultaneously collecting information regarding intervention impacts and implementation and dissemination strategy. However, few health promotion research trials employ such designs and often fail to report information to enable assessment of the feasibility and potential impact of implementation and dissemination strategies. In addition to intervention effects, policy makers and practitioners also want to know the impact of implementation strategies. This commentary will define the three categories of effectiveness-implementation hybrid designs, describe their application in health promotion evaluation, and discuss the potential implications of more systematic use of such designs for the translation of health promotion and evaluation.So what?Greater use of effectiveness-implementation hybrid designs may accelerate research translation by providing more practice- and policy-relevant information to end-users, more quickly. PMID- 29241483 TI - National Trends and Outcomes in Isolated Tricuspid Valve Surgery. AB - BACKGROUND: Severe isolated disease of the tricuspid valve (TV) is increasing and results in intractable right heart failure. However, isolated TV surgery is rarely performed, and there are little data describing surgical outcomes. OBJECTIVES: The purpose of this study was to evaluate contemporary utilization trends and in-hospital outcomes for isolated TV surgery in the United States. METHODS: Patients age >18 years who underwent TV repair or replacement from 2004 to 2013 were identified using the National Inpatient Sample. Patients with congenital heart disease, with endocarditis, and undergoing concomitant cardiac operations except for coronary bypass surgery were excluded. RESULTS: Over a 10 year period, a total of 5,005 isolated TV operations were performed nationally. Operations per year increased from 290 in 2004 to 780 in 2013 (p < 0.001 for trend). In-hospital mortality was 8.8% and did not vary across the study period. Adjusted in-hospital mortality for TV replacement was significantly higher than TV repair (odds ratio: 1.91; 95% confidence interval: 1.18 to 3.09; p = 0.009). CONCLUSIONS: Isolated TV surgery is rarely performed, although utilization has increased over time. However, despite an increase in surgical volume, operative mortality has not changed. Mortality is greatest in patients undergoing valve replacement. Given the increasing prevalence of isolated TV disease in the population, research into optimal surgical timing and patient selection is critical. PMID- 29241484 TI - Isolated Tricuspid Valve Surgery. PMID- 29241486 TI - Primary Prevention of Atherosclerosis: Time to Take a Selfie? PMID- 29241485 TI - Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors. AB - BACKGROUND: Absence of cardiovascular risk factors (CVRFs) is traditionally considered low risk for atherosclerosis; however, individuals without CVRFs, as currently defined, still have events. OBJECTIVES: This study sought to identify predictors of subclinical atherosclerosis in CVRF-free individuals. METHODS: Participants from the PESA (Progression of Early Subclinical Atherosclerosis) study (n = 4,184) without conventional CVRFs were evaluated (n = 1,779; 45.0 +/- 4.1 years, 50.3% women). CVRF freedom was defined as no current smoking and untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dl, total cholesterol <240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, and high-density lipoprotein cholesterol >=40 mg/dl. A subgroup with optimal CVRFs (n = 740) was also defined as having blood pressure <120/80 mm Hg, fasting glucose <100 mg/dl, glycosylated hemoglobin <5.7%, and total cholesterol <200 mg/dl. We evaluated ultrasound-detected carotid, iliofemoral, and abdominal aortic plaques; coronary artery calcification; serum biomarkers; and lifestyle. Adjusted odds ratios (with 95% confidence interval) and ordinal logistic regression models were used. RESULTS: Subclinical atherosclerosis (plaque or coronary artery calcification) was present in 49.7% of CVRF-free participants. Together with male sex and age, LDL-C was independently associated with atherosclerosis presence and extent, in both the CVRF-free and CVRF-optimal groups (odds ratio [*10 mg/dl]: 1.14 to 1.18; p < 0.01 for all). Atherosclerosis presence and extent was also associated in the CVRF-free group with glycosylated hemoglobin levels. CONCLUSIONS: Many CVRF-free middle-aged individuals have atherosclerosis. LDL-C, even at levels currently considered normal, is independently associated with the presence and extent of early systemic atherosclerosis in the absence of major CVRFs. These findings support more effective LDL-C lowering for primordial prevention, even in individuals conventionally considered at optimal risk. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318). PMID- 29241488 TI - Do We Need a Trial of DES Versus CABG Surgery in Diabetic Patients With ACS? PMID- 29241487 TI - Surgical Versus Percutaneous Coronary Revascularization in Patients With Diabetes and Acute Coronary Syndromes. AB - BACKGROUND: Randomized trial data support the superiority of coronary artery bypass grafting (CABG) surgery over percutaneous coronary intervention (PCI) in diabetic patients with multivessel coronary artery disease (MV-CAD). However, whether this benefit is seen in a real-world population among subjects with stable ischemic heart disease (SIHD) and acute coronary syndromes (ACS) is unknown. OBJECTIVES: The main objective of this study was to assess the generalizability of the FREEDOM (Future REvascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multi-vessel Disease) trial in real world practice among patients with diabetes mellitus and MV-CAD in residents of British Columbia, Canada. Additionally, the study evaluated the impact of mode of revascularization (CABG vs. PCI with drug-eluting stents) in diabetic patients with ACS and MV-CAD. METHODS: In a large population-based database from British Columbia, this study evaluated major cardiovascular outcomes in all diabetic patients who underwent coronary revascularization between 2007 and 2014 (n = 4,661, 2,947 patients with ACS). The primary endpoint (major adverse cardiac or cerebrovascular events [MACCE]) was a composite of all-cause death, nonfatal myocardial infarction, and nonfatal stroke. The risk of MACCE with CABG or PCI was compared using multivariable adjustment and a propensity score model. RESULTS: At 30-days post-revascularization, for ACS patients the odds ratio for MACCE favored CABG 0.49 (95% confidence interval [CI]: 0.34 to 0.71), whereas among SIHD patients MACCE was not affected by revascularization strategy (odds ratio: 1.46; 95% CI: 0.71 to 3.01; pinteraction <0.01). With a median follow-up of 3.3 years, the late (31-day to 5-year) benefit of CABG over PCI no longer varied by acuity of presentation, with a hazard ratio for MACCE in ACS patients of 0.67 (95% CI: 0.55 to 0.81) and the hazard ratio for SIHD patients of 0.55 (95% CI: 0.40 to 0.74; pinteraction = 0.28). CONCLUSIONS: In diabetic patients with MV-CAD, CABG was associated with a lower rate of long-term MACCE relative to PCI for both ACS and SIHD. A well-powered randomized trial of CABG versus PCI in the ACS population is warranted because these patients have been largely excluded from prior trials. PMID- 29241490 TI - Short QT Syndrome and Hydroquinidine: Rare Diseases and Unavailable Drugs. PMID- 29241489 TI - Hydroquinidine Prevents Life-Threatening Arrhythmic Events in Patients With Short QT Syndrome. AB - BACKGROUND: Short QT syndrome (SQTS) is a rare and life-threatening arrhythmogenic syndrome characterized by abbreviated repolarization. Hydroquinidine (HQ) prolongs the QT interval in SQTS patients, although whether it reduces cardiac events is currently unknown. OBJECTIVES: This study investigated whether long-term treatment with HQ reduces the occurrence of life threatening arrhythmic events (LAE) (cardiac arrest or sudden cardiac death) in SQTS patients. METHODS: In this cohort study on consecutive SQTS patients, 2 analyses were performed: 1) a matched-period analysis for the occurrence of LAE in 17 SQTS patients who received long-term HQ; and 2) a comparison of the annual incidence of LAE off- and on-HQ in 16 SQTS patients who survived a cardiac arrest. RESULTS: A total of 17 patients (82% male, age 29 +/- 3 years, QTc before treatment 331 +/- 3 ms) received HQ therapy (584 +/- 53 mg/day). Therapy was stopped in 2 cases (12%) due to gastrointestinal intolerance, and 15 patients continued treatment for 6 +/- 1 year. QTc prolongation was observed in all patients (by 60 +/- 6 ms; p < 0.001). We compared the occurrence of LAE during 6 +/- 1 years before and after HQ, observing that patients on HQ experienced a reduction in both the rate of LAE from 40% to 0% (p = 0.03) and the number of LAE per patient from 0.73 +/- 0.3 to 0 (p = 0.026). Furthermore, the annual rate of LAE in the 16 patients with a previous cardiac arrest dropped from 12% before HQ to 0 on therapy (p = 0.028). CONCLUSIONS: We demonstrated for the first time that treatment with HQ was associated with a lower incidence of LAE in SQTS patients. These data point to the importance that quinidine, that in several countries has been removed from the market, remains available worldwide for patients with SQTS. In the present study, therapy with HQ has been proven to be safe, with a relatively low rate of side effects. PMID- 29241491 TI - Data Sharing and Cardiology: Platforms and Possibilities. AB - Sharing deidentified patient-level research data presents immense opportunities to all stakeholders involved in cardiology research and practice. Sharing data encourages the use of existing data for knowledge generation to improve practice, while also allowing for validation of disseminated research. In this review, we discuss key initiatives and platforms that have helped to accelerate progress toward greater sharing of data. These efforts are being prompted by government, universities, philanthropic sponsors of research, major industry players, and collaborations among some of these entities. As data sharing becomes a more common expectation, policy changes will be required to encourage and assist data generators with the process of sharing the data they create. Patients also will need access to their own data and to be empowered to share those data with researchers. Although medicine still lags behind other fields in achieving data sharing's full potential, cardiology research has the potential to lead the way. PMID- 29241492 TI - Mechanical Intervention for Aortic Valve Stenosis in Patients With Heart Failure and Reduced Ejection Fraction. AB - The risk and benefit of mechanical interventions in valvular heart disease have been primarily described among patients with normal ejection fraction. The advent of nonsurgical mechanical interventions for aortic stenosis (transcatheter aortic valve replacement) may alter the risk-benefit ratio for patients who would otherwise be at increased risk for valve surgery. This review describes the epidemiology and pathophysiology of aortic stenosis with heart failure and reduced ejection fraction and summarizes the current registry and clinical trial data applicable to this frequently encountered high-risk group. It concludes with discussion of ongoing trials, new approaches, emerging indications, and a potential clinical algorithm incorporating optimal mechanical intervention for patients with aortic stenosis and concomitant reduced ejection fraction. PMID- 29241493 TI - Improved Survival After Implementation of a Large-Scale Regional Dedicated Aortic Network. PMID- 29241494 TI - Heart Failure and Ischemic Heart Disease in Patients With Rheumatoid Arthritis. PMID- 29241495 TI - Statistical Analyses of Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction. PMID- 29241496 TI - Flow-Mediated Dilation of Brachial Artery as a Screening Tool for Anthracycline Induced Cardiotoxicity. PMID- 29241497 TI - Reply: Statistical Analyses of Arginine-Nitric Oxide Metabolites and Cardiac Dysfunction. PMID- 29241498 TI - The Anticoagulation Conundrum of Mechanical Heart Valves in Pregnancy: Should DOACs Be Considered? PMID- 29241499 TI - Reply: The Anticoagulation Conundrum of Mechanical Heart Valves in Pregnancy: Should DOACs Be Considered? PMID- 29241500 TI - A review of postoperative pain assessment records of nurses. PMID- 29241501 TI - CYP2D6 drug-gene and drug-drug-gene interactions among patients prescribed pharmacogenetically actionable opioids. AB - PURPOSE: When codeine and tramadol are used for pain management, it is imperative that nurses are able to assess for potential drug-gene and drug-drug-gene interactions that could adversely impact drug metabolism and ultimately pain relief. Both drugs are metabolized through the CYP2D6 metabolic pathway which can be affected by medications as well the patient's own pharmacogenotype. The purpose of this brief report is to identify drug-gene and drug-drug-gene interactions in 30 adult patients prescribed codeine or tramadol for pain. METHODS: We used three data sources: (1) six months of electronic health record data on the number and types of medications prescribed to each patient; (2) each patient's CYP2D6 pharmacogenotype, and (3) published data on known CYP2D6 gene drug and drug-drug-gene interactions. RESULTS: Ten patients (33%) had possible drug-gene or drug-drug-gene interactions. Five patients had CYP2D6 drug-gene interactions indicating they were not good candidates for codeine or tramadol. In addition, five patients had potential CYP2D6 drug-drug-gene interactions with either codeine or tramadol. CONCLUSION: Our findings from this exploratory study underscores the importance of assessing and accounting for drug-gene and drug drug-gene interactions in patients prescribed codeine or tramadol. PMID- 29241502 TI - Recruitment and retention of a challenging population: Lessons learned and design implications. AB - PURPOSE: The purpose of this article is share the lessons learned from recruiting and retaining adults with type 2 diabetes and solid tumor cancer into a longitudinal study exploring the relationship among chemotherapy, glycemic control, and symptoms. DESIGN/METHODS: Twelve-week longitudinal study, recruited thirty-four adults 21years or older with pre-existing type 2 diabetes and a solid tumor cancer, from three community based cancer centers who were eligible to receive outpatient chemotherapy. METHODS: Fisher's Exact Test (categorical variables) and Logistic Regression (continuous variables) were used to evaluate factors associated with participant withdrawal. A dichotomous attrition variable was created to identify those who dropped out of the study before the final week and those who completed. RESULTS: Thirteen of the 34 participants completed the study. Symptom severity, baseline HbA1c and metastases were all identified as being factors that potentially influenced attrition. Recruitment was improved once recruiters were hired at each of the cancer centers and adjustments made to the inclusion criteria. CONCLUSIONS/IMPLICATIONS FOR RESEARCH: Several design elements need to be considered to address attrition in future including the use of recruiters, inclusion and exclusion criteria, consent timing, data collection schedules, participant characteristics, participant burden, and support person identification. PMID- 29241503 TI - Psychometric properties of belief measures about osteoporosis and its control. AB - BACKGROUND AND PURPOSE: Osteoporosis (OP) is a chronic health condition with potentially serious consequences. Although preventive behaviors are important to control OP, many people do not engage in such behaviors. Although beliefs about preventive behaviors for OP influence such behaviors, we could not find psychometrically strong measures of such beliefs for use in planned research. Our initial study was done to assess the content validity, clarity, and internal consistency of belief measures regarding behaviors to control OP: perceived competence, perceived susceptibility, and perceived severity, based on relevant theories. METHODS: Using a descriptive design, we recruited five clinicians to rate proposed measures for content validity. We also recruited fifty-one older adults from five different counties in a Midwestern state to respond to proposed measures so we could assess clarity and internal consistency reliability. RESULTS: The content validity indices of items varied from 0.60-1.00. The content validity indices of scales varied from 0.73-1.00. For reliability, the final Cronbach's alphas were 0.79-0.96. CONCLUSIONS: Addressing a gap in research, we have documented good psychometric properties of belief measures regarding OP and its control. In describing our search for psychometrically sound measures, we have raised issues for future researchers to consider prior to adopting use of existing measures. Nurses can use these measures to assess and address the accuracy of patients' beliefs either individually or in groups. Researchers can use these measures to examine whether or not psycho-educational interventions influence beliefs about OP and its control. PMID- 29241504 TI - The effects of mindfulness-based stress reduction on hospital nursing staff. PMID- 29241505 TI - Knowledge, behaviours, training and attitudes of nurses during preparation and administration of intravenous medications in intensive care units (ICU). A multicenter Italian study. AB - BACKGROUND: Medication errors can put at risk the life of patients hospitalized in the ICUs. These errors occur more frequently in the ICUs due to their peculiar medical framework. There is not much information about the knowledge, attitudes, behaviours and training needs of the nurses who work in ICUs towards the medication errors. OBJECTIVE: This study aims at describing the knowledge, attitudes, behaviours and training needs of the Italian nurses who work in ICUs towards the use of IV drugs, and identifying the strategies that nurses can adopt to prevent the occurrence of medication errors. MATERIALS AND METHODS: Cross sectional study. The survey was carried out through a self-administrated questionnaire and it was addressed to 529 Italian nurses who work in the ICUs of Southern, Centre and Northern Italy hospitals (average age of the sample 39.9, SD=9.1, 68.1% females). The questionnaire, made of 36 items divided into 7 sections, was validated after the results of the pilot study. RESULTS: The study highlighted the importance of the role, behaviours and knowledge of the nurses to prevent the medication errors. The results of the multivariate analysis of the multicentre study show a relation among correct behaviours and positive attitudes, even if it is not statistically significant. Worth mentioning is the fact that the achievement of a university degree affects negatively the correct behaviours (OR 0.56, 95% CI 0.34-0.95), as well as the years of work (OR 0.97, 95% CI 0.94-0.99). CONCLUSIONS: The results of this multicentre study are encouraging. Nurses who have a good command of the English language (sufficient, good, and excellent) dedicate more than an hour per week to the bibliography update. Extending and deepening the knowledge of the nurses in a cyclical way might be an effective strategy to keep a high level of security of the drugs in the ICUs. The study highlighted that almost all the surveyed nurses (93%) are aware that an adequate knowledge of the drugs dosage calculation is essential to reduce the occurrence of medication errors in the drugs preparation phase. PMID- 29241506 TI - Quality of life and self-care in elderly patients with cardiovascular diseases: The effect of a Traditional Chinese Medicine health educational intervention. AB - AIMS: To explore the effects of a Traditional Chinese Medicine health educational intervention on the quality of life and self-care agency of elderly patients living with chronic cardiovascular disease. BACKGROUND: Cardiovascular disease is a leading cause of morbidity and mortality worldwide. The secondary prevention and treatment for chronic cardiovascular disease emphasize the importance of lifestyle modification. However, behavior-changing is difficult and individual choices are influenced by broader environmental factors. The lifestyle intervention for the purpose of self-care enhancing should be considered the driving force from the cultural element. METHODS: The study was conducted from April 2014 to October 2014. Ninety-eight community dwelling individuals with chronic cardiovascular disease were recruited from Shaoxing and randomized. 48 participants were in the intervention group with a 6-month Traditional Chinese Medicine health education and 50 participants were in the control group with routine care. The main measurements included health-related quality of life and self-care agency, which was assessed by the Short Form-36 Chinese version and the Exercise of Self-Care Agency Scale respectively, and were measured at the baseline and post intervention (6months after baseline). RESULTS: After 6months of intervention, the quality of life and self-care agency in the intervention group were significantly improved. CONCLUSIONS: The traditional Chinese medicine health education is an effective method for promoting quality of life and self care agency in cardiovascular disease patients. It could be applied as adjunctive care for cardiovascular disease patients self-care supporting. PMID- 29241507 TI - Validation of the Symptom Status Questionnaire-Heart Failure in Korean patients. AB - AIM: The purpose of this study was to examine the psychometric properties of the Korean version of the Symptom Status Questionnaire-Heart Failure (SSQ-HF) in patients with heart failure (HF). Specific aims were to examine 1) reliability and item homogeneity, using Cronbach's alpha and item analyses; and 2) validity, using factor analysis and known relationships of depressive symptoms and perceived control to HF symptoms. BACKGROUND: HF symptoms are among the strongest factors affecting health-related quality of life (HRQOL), and can lead to hospitalization. Therefore, it is important to assess and manage HF symptoms using a reliable and valid instrument. However, there is no such instrument for Korean patients with HF. METHODS: Data on HF symptoms, sociodemographic and clinical characteristics, and covariates such as depressive symptoms, perceived control, and self-care maintenance were collected from 119 patients (mean age: 65.0years; 58.8% males). Cronbach's alpha was used to test reliability, and factor analysis and multiple regression analyses were used to test validity. RESULTS: Cronbach's alpha was 0.76, supporting reliability. In factor analysis, a single-factor structure emerged, and the loading coefficients of all items were >0.45, supporting construct validity. In addition, as hypothesized, depressive symptoms and perceived control were significantly associated with HF symptoms, further supporting validity. CONCLUSIONS: The reliability and validity of the Korean version of the SSQ-HF were supported among Korean HF patients. Clinicians and researchers can use the SSQ-HF to assess and manage common HF symptoms. PMID- 29241510 TI - Exploring Jordanian women's experience of first pelvic examination. PMID- 29241509 TI - Increasing awareness of protection from sexual abuse in children with mild intellectual disabilities: An education study. AB - Sexual abuse is an important problem for children and particularly those with intellectual disabilities. Increasing awareness of sexual abuse could help these children to protect themselves from such a potential encounter. The study was conducted to raise awareness about sexual abuse in children with intellectual disabilities with 15 children who had mild intellectual disabilities as a pre posttest experimental design. Informative pictures, designed according to age and intellectual level, suitable stories linked with these pictures and homework, were used in an educational setting. It was determined that there was a significant difference relating to the scores for all the subjects before and after the assignment (p<0.05). After education, awareness of them in protecting from a possible sexual abuse increased with protection educations for intellectual disabilities children, as desired. PMID- 29241508 TI - The use of multiple languages in a technology-based intervention study: A discussion paper. AB - BACKGROUND AND OBJECTIVES: With an increasing number of racial/ethnic minorities in the U.S., nursing research frequently involves the use of multiple languages, especially to promote the understanding of educational materials related to nursing care. Furthermore, with a recent emphasis on innovation in health-related research, the use of technology is prominent in nursing research. However, practical issues in the use of multiple languages, especially in technology-based intervention studies, have rarely been reported and/or discussed in nursing literature. The purpose of this paper is to identify practical issues in conducting a technology-based intervention study using multiple languages among Asian American breast cancer survivors. METHODS: In a large-scale technology based breast cancer intervention study, research team members wrote memos on issues in translation process and plausible reasons for the issues. Then, the memos and written records were analyzed using a content analysis. By using individual words as the unit of analysis, line-by-line coding was done, and idea categories representing practical issues were extracted from the codes. RESULTS: Six themes representing the practical issues were extracted. Issues were found in recruiting and retaining bilingual research team members; maintaining consistency in translation process; keeping cultural and conceptual equivalence; repeating IRB protocol modifications; finding and using existing translated versions; and arranging technological aspects related to electronic multiple-language versions. CONCLUSION: The use of multiple languages in a technology-based intervention study is feasible. However, it is necessary to effectively manage unforeseen challenges through various strategies. PMID- 29241511 TI - Increasing patient recall of nurse leader rounding. AB - Nursing staff in a medical/surgical acute care 34-bed hospital unit were challenged by low percentages of patients able to recall nurse leader rounding activity (NLR). NLR occurred daily for all patients, yet many did not recall visits by nursing leaders when surveyed at discharge. Care giver credibility suffered as non-nursing executives questioned if NLR consistently occurred. Several mechanisms were used to facilitate patient NLR recall: scripted NLR verbiage/keywords, nursing uniform leadership insignia and white lab coats, sharing of business cards, handwritten notes on patient communication white boards, multimedia leadership insignia on leader e-tablets, and visits with family members: patient NLR recall did not improve. Nurses designed low effort, active learning, spaced repetition exchanges using the hospital nurse call system in reverse to distinguish NLR from other care-related activity. A pilot study saw NLR recall climb from a baseline measurement of 37.5% (n=88) to 88% (n=93) following implementation. Mann-Whitney U confirmed significant findings (U=2018.5, p<0.001). Patient age and cognitive impairment were confirmed as confounding factors. Binary logistic regression analysis confirmed intervention effects exceeded confounding effects. Findings were consistent with subsequent patient survey results provided by a third party. PMID- 29241512 TI - Development of post hip replacement comfort scale. AB - AIM: To develop and psychometrically test the Post Hip Replacement Comfort Scale (PHRCS). BACKGROUND: Evaluation of the patient comfort after hip replacement surgery is highly important in order to increase the quality of patient care. The review of the relevant literature shows that a scale that specifically measures the patient comfort after hip replacement surgery is absent. DESIGN: Methodological design was used. This study included the development of the scale and tested the psychometric properties of the scale. METHOD: 180 patients who had been hip replacement surgery recruited from three education and research hospitals' orthopedic and trauma departments from January 2014 to December 2015. The study was conducted in three phases. In phase 1, scale items were developed based on the literature review and other comfort scales. In phase 2, the trial was applied with data collection forms. Phase 3 was conducted to evaluate the reliability and validity of the finalized inventory using item analysis. RESULTS: The Cronbach's alpha coefficient value is 0.758. Test-retest results found positive and meaningful correlation between the scores of the scales, indicating the reliability of the scale. Scope, surface, criterion and construct validity analysis confirmed the validity of the scale. There were 26 items in the final scale. In our study, the average patient comfort score was 3.64+/-0.43 (from 1 to 5). CONCLUSION: The PHRCS is recommended for evaluating patients' comfort after hip replacement surgery and examining the effects of nursing interventions on patients' comfort. PMID- 29241513 TI - Nurses' compliance with isolation precautions and the affecting factors. AB - PURPOSE: This study aims at identifying nurses' compliance with isolation precautions and the affecting factors. METHODS: The present study is descriptive and relational in nature. Data were collected through Descriptive Features Form and The Isolation Precautions Compliance Scale (TIPCS), which was developed in Turkey in 2010. RESULTS: Isolation Precautions Compliance Scale mean score of the 130 nurses participating in the study was found 76.55+/-8.48. Statistically significant differences were found between the groups in terms of nurses' gender, working unit, duration of working, type of isolation applied, and problems experienced in isolation practices (p<0.05, p<0.01). There was a positive and significant relationship between the Isolation Precautions Compliance Scale scores and age, education level, and duration of working. CONCLUSION: The nurses participating in the study were found to have generally good compliance with isolation precautions; and the scale mean scores of the nurses working in intensive care units were higher than the nurses working in clinics. PMID- 29241514 TI - Team Science and Team Research: How Are They the Same? PMID- 29241515 TI - Barriers to family presence during resuscitation and strategies for improving nurses' invitation to families. PMID- 29241517 TI - The COPD exacerbation experience: A qualitative descriptive study. PMID- 29241516 TI - Factors affecting self-care behavior in Koreans with COPD. AB - BACKGROUND: Despite the importance of self-care in people with COPD, little is known about the effect of symptoms and symptom clusters on self-care behavior in people with exacerbated COPD. This study was designed to describe their level of self-care and to examine factors associated with self-care behavior, including symptoms and symptom clusters. METHODS: For this cross-sectional descriptive study, the researcher recruited Koreans with exacerbated COPD (N=71) from three tertiary care hospitals. Self-care behavior was measured with Alberto Chronic Obstructive Pulmonary Disease Self-care Behavior Inventory. Descriptive and inferential statistics were used to analyze the data from structured interviews, questionnaires, and clinical measures. RESULTS: Mean score of self-care behavior was 119.30. Level of education, comorbidities, emergency department visits during past year, general health perception, and education about exacerbation and symptom management explained 43.9% of total variance in self-care behavior. When individual symptoms were added to the regression model, anxiety accounted for the largest change in total variance in self-care behavior. When a symptom cluster group variable was added to the regression model, change in total variance in self-care behavior was significantly greater than change in variance from individual symptoms. CONCLUSION: Study results indicate that nurses should assess level of self-care in people with COPD and provide them with appropriate education to improve their self-care behavior. Further, it will remind nurses to heed symptom levels and other variables that affect self-care behavior. COPD patients with a lower level of multiple symptoms should be targeted for intervention to improve self-care. PMID- 29241518 TI - Influence of anthropometric parameters on breastmilk provision in preterm infants. AB - OBJECTIVE: To explore how growth trends may relate to maternal provision of breastmilk to preterm infants in the Neonatal Intensive Care Unit (NICU). DESIGN: Non-experimental, retrospective, descriptive. SETTING: Level III, 40-bed suburban neonatal intensive care unit (NICU). PARTICIPANTS: 94 preterm infants (<37 post menstrual age) admitted to the NICU between September 2011 and May 2013. METHODS: This retrospective chart review explored the relationship between infant growth during hospitalization and maternal provision of breastmilk at discharge. Growth data were collected including standard weekly growth measurements from birth through hospital discharge. In addition, average growth over time or growth velocity was assessed for weight (g/kg/d), head circumference (cm/d) and length (cm/d). Growth parameters at birth and discharge were plotted using the Olsen 2010 Growth Calculator for Preterm Infants to obtain standardized assessments of growth percentiles. Key growth factors were examined against the primary investigational outcomes of continued breastmilk provision at discharge and length of hospital stay. Variables included infant characteristics, number of daily direct-to-breast feedings (identified as traditional oral breastfeeding), and maternal characteristics. Statistical tests included student t-test and chi square. Logistic regression models were used to evaluate data and multiple regression was used to examine growth variables. RESULT: In this cohort, 44% of mothers continued to provide breastmilk at the time of infant discharge. Growth velocity was a significant predictor of continued provision of breastmilk at discharge (p=0 0.002, OR 1.39). Ponderal index, combined with other variables were highly predictive of length of stay (p<0.001, R2=0.858). Those infants whose first oral feed was direct-to-breast (versus bottle) were more likely to still be receiving breastmilk at discharge (adj OR 5.3). CONCLUSION: First oral feed being direct-to-breast and higher growth velocity are supportive of continued breastmilk provision throughout hospitalization. These results highlight a need for additional breastfeeding support for mother-infants dyads who provided a bottle as the first oral feed or with poorer growth progression. PMID- 29241519 TI - The Positive Thinking Skills Scale: A screening measure for early identification of depressive thoughts. AB - BACKGROUND: Depression is currently considered the second leading cause of disability worldwide. Positive thinking is a cognitive process that helps individuals to deal with problems more effectively, and has been suggested as a useful strategy for coping with adversity, including depression. The Positive Thinking Skills Scale (PTSS) is a reliable and valid measure that captures the frequency of use of positive thinking skills that can help in the early identification of the possibility of developing depressive thoughts. However, no meaningful cutoff score has been established for the PTSS. AIM: To establish a cutoff score for the PTSS for early identification of risk for depression. METHODS: This study used a receiver operating characteristic (ROC) curve to establish a PTSS cutoff score for risk for depression, using the Center for Epidemiological Studies-Depression Scale (CES-D) as the gold standard measure. RESULTS: In a sample of 109 caregivers, the ROC showed that the cutoff score of PTSS that best classify the participants is 13.5. With this PTSS score, 77.8% of the subjects with low CES-D are classify correctly, and 69.6% of the subjects with high CES-D are classify correctly. Since the PTSS score should be integer numbers, functionally the cutoff would be 13. CONCLUSION: The study showed that a cut off score of 13 is a point at which referral, intervention, or treatment would be recommended. Consequently, this can help in the early identification of depressive symptoms that might develop because of the stress of caregiving. PMID- 29241520 TI - Evaluation of a WeChat-based dementia-specific training program for nurses in primary care settings: A randomized controlled trial. AB - Community nurses play a crucial role in early detection and timely diagnosis of dementia. However, they are usually not prepared for the role through their formal education, particularly in low- and middle-income countries due to undeveloped nursing curriculum in dementia care. This paper describes a two-arm cluster-randomized controlled trial to improve community nurses' knowledge, attitudes, and practice changes using an innovative and interactive mobile phone applet-based activity in primary care settings. The intervention sites received dementia-specific training and control sites received care training for older people with disability. Both groups completed measures assessing dementia knowledge, attitudes, and intentions to make changes to achieve early detection and a timely diagnosis of dementia immediately after training and at 3-month follow-up. The intervention group provided feedback immediately after training and at 3-month follow-up. The main results show that the intervention group demonstrated significant improvement in dementia knowledge and attitudes from baseline immediately after training and at the 3-month follow-up. The intervention group also showed more intentions to make changes to achieve early detection of dementia. Feedback suggested the program was well-received. Overall, the program showed acceptability and feasibility in improving nurses' dementia knowledge, attitudes, and intentions to achieve early detection of dementia. PMID- 29241521 TI - What drives pregnant women's decisions to accept the pertussis vaccine? AB - The aims of this study were to identify factors associated with pregnant women's intention to receive the pertussis vaccine during pregnancy, using the Health Belief Model; while comparing between pregnant native-born Israeli women and Israeli women born in the former Soviet Union. Convenience and snowball sampling methods were used to recruit 200 pregnant Israeli native-born women and women born in the former Soviet Union. Data were collected using a cross-sectional questionnaire survey. Regression results revealed that susceptibility to pertussis, seriousness of pertussis, perceived benefits of the vaccine, knowledge of risk factors of pertussis, and general health motivation together explained 76% of the variance of women's intention to receive the pertussis vaccine. Perceived benefits of the vaccine was the most significant factor affecting pregnant women's intention to receive the pertussis vaccine during pregnancy (p<0.05). Native-born women had higher intention to be vaccinated and more positive health beliefs (p<0.05). PMID- 29241522 TI - Comparison of standardized and customized SBAR communication tools to prevent nursing home resident transfer. PMID- 29241523 TI - Acculturative stress in Korean Americans. AB - BACKGROUND: Acculturative stress is known to contribute to chronic diseases among many immigrants and yet this association in Korean Americans remains unclear. AIM: The study purpose was to examine the level of acculturative stress in Korean Americans and to determine if correlations existed with personal and physiological factors. METHODS: An exploratory, cross-sectional, descriptive study was conducted in a sample of 107 Korean American adults. Data on acculturative stress and personal factors were collected using a survey questionnaire in addition to a direct measure of physiological factors (i.e., body mass index and blood pressure). RESULTS: All 107 participants were first generation Koreans. Most participants were women (66.4%), with a mean age of 53.9+/-10.7, married (88.8%), and with a college education (84.2%). Acculturative stress was associated with a number of personal factors (i.e., arrival age, years of U.S education, years of U.S. residency, English proficiency), and the personal factors of gender, age, employment status, and years of U.S. residency were associated with the physiological factors. No statistically significant associations were found between acculturative stress and physiological factors. CONCLUSIONS: The mean acculturative stress score in this study was higher than findings from prior studies of Korean immigrants in the United States or Canada, with the rates of obesity and hypertension higher than prior reports of Korean Americans or Koreans residing in Korea. Future study is necessary with a larger sample from a variety of different geographic areas of the United States to examine further the impact of acculturative stress on physiological factors during the process of acculturation. PMID- 29241524 TI - Validity of the current risk assessment scale for pressure ulcers in intensive care (EVARUCI) and the Norton-MI scale in critically ill patients. AB - OBJECTIVE: The objective of this study was to evaluate the validity of risk detection scales EVARUCI and Norton-MI (modified by INSALUD) to detect critical adult patients with the risk of developing pressure ulcers (PU) in an intensive care unit (ICU). DESIGN: The authors have conducted a descriptive, prospective study at the ICU in their hospital from 2008 to 2014. The evaluations of both scales were registered daily by nurses from the unit. PATIENTS: Adult patients admitted into the ICU. MAIN OUTCOMES MEASURE: The study measured the sensitivity, specificity, positive predictive values (PPV) and negative predictive values (NPV) of each of the scores for both scales and areas under curve (AUC) of receiver operating characteristics (ROC). MAIN RESULTS: The authors have evaluated a total of 2534 patients. For the cut-off point recommended by the authors in the scale Norton-MI (PC 14), a sensitivity of 94,05% (93,28-94,82) was obtained, specificity of 40,47% (39,72-41,22), VPP 26,22% and VPN 96,80%. For EVARUCI (CP 10) a sensitivity of 80,43% (79,15-81,72), specificity 64,41 (63,68 65,14), VPP 33,71% and VPN of 93,60%. The ABC-COR was 0,774 with a 95% CI of 0,766 to 0,781 for the scale of Norton-MI and 0.756 with a 95% CI of 0,749 to 0,764 for EVARUCI. CONCLUSION: Both scales are valid to help predict the risk of developing PU in critical patients. The sensitivity and ABC-COR are very similar for EVARUCI and Norton-Mi. The authors state they do not have any financial interests linked to this article. PMID- 29241525 TI - Exploring why nurses transition from acute care to primary health care employment. PMID- 29241526 TI - Uncertainty and quality of life of Malaysian women with breast cancer: Mediating role of coping styles and mood states. AB - PURPOSE: This study aimed to investigate the relationship between uncertainty in illness and quality of life, and examine the mediating role of coping strategies and mood states in this relationship among breast cancer patients. METHODS: A convenience sample of 135 Malaysian women with breast cancer completed questionnaires measuring uncertainty in illness, mood states (i.e. anxiety and depression), quality of life, and copying styles. RESULTS: The results showed an inverse correlation between uncertainty and quality of life after controlling for the effects of age, cancer stage and time since diagnosis. Moreover, the negative association between illness uncertainty and quality of life was mediated by coping strategies and mood states. CONCLUSION: The findings revealed that breast cancer patients experiencing a high level of uncertainty more likely use avoidant and less likely use active emotional coping strategies which in turn amplifies anxiety and depression and undermines their quality of life. While some interventions to reduce the adverse consequences of uncertainty are recommended, the findings indicated the need for targeted psychological interventions seeking to gradually shift cancer patients' coping strategies from avoidant to active emotional coping. PMID- 29241527 TI - Equine-assisted therapy intervention studies targeting physical symptoms in adults: A systematic review. PMID- 29241528 TI - The care dependency of patients after laparoscopic abdominal surgery and associated factors in China. AB - PURPOSE: The outcome after laparoscopic surgery is dependent on self-care behaviors. Whether or not the patients after laparoscopic abdominal surgery in China are care-dependent is still unclear. Thus, the studies try to analyze influence factors of care dependence on patients with laparoscopic abdominal surgery, to provide reference for personalized care for the patient. METHODS: In our study, two hundreds and forty-two cases were selected and investigated by using the exercise of self-care agency scale and care dependency scale. And correlation analyses between care dependency and self-care agency, age or hospital stay duration was made by Spearman correlation analysis. The analysis of associated factors was made by multivariable linear regression model. RESULTS: The mean age of participants is 42.12+/-12.67 (ranged from 18 to 73years), and 134 patients (55.37%) in the study were older than 50years. Among the 242 participants, 59.09% is male. Our data found that the average self-care agency score was 115.72+/-30.13. And 64.88% participates are in the median level of self care agency. Care dependency correlated with self-care agency (r=-0.85, P=0.009), age (r=-0.71, P=0.001) and hospital stay duration (r=-0.69, P=0.003) negatively. The linear regression was found between gender, age, educational level, days of hospital stay and care dependency. The model is care dependency=99.533+5.02*(gender)-0.795*(age)+0.512*(educational level)-0.239*(days of hospital stay). CONCLUSION: Patients after laparoscopic surgery take notice of self-care. Gender, age, educational level and days of hospital stay affect care dependence. PMID- 29241529 TI - Development and testing of a goals of care intervention in advanced heart failure. AB - AIM: The purpose of this paper is to describe the conceptual framework for a goals of care (GoC) intervention, elements, and findings of intervention feasibility, acceptability, and benefits from both patients with heart failure (HF) and their providers. BACKGROUND: Receiving care at a mechanical circulatory support center for advanced HF offers new opportunities for treatment, making the implementation of a GoC intervention timely and crucial in helping patients determine next steps in HF treatment. METHODS: The GoC intervention was designed using a self-management framework, incorporating the concepts of self-efficacy, patient activation, and patient motivation. At the conclusion of the study, open ended exit interviews were conducted with patients and providers. Content analysis was used to derive the feasibility, acceptability, and benefits of the intervention. RESULTS: Forty-one patients with HF, with average age 58.2+/ 11.3years, LVEF=30.3+/-9.7%, and New York Heart Association Functional Class (NYHA FC)=2.4+/-0.8, and nine HF providers participated in the study. Patient benefits from the intervention included enhanced communication with their provider and family members, increased confidence to have a conversation with the provider, and refreshed HF knowledge. Provider benefits from the intervention were facilitating a conversation with the patient and learning new information about the patient's goals and values. CONCLUSION: The GoC intervention provides an avenue to align patient goals and values with treatment choices in the context of advanced heart failure, so that patient quality of life is enhanced and costs of care can be reduced. PMID- 29241530 TI - ATP Citrate Lyase Regulates Myofiber Differentiation and Increases Regeneration by Altering Histone Acetylation. AB - ATP citrate lyase (ACL) plays a key role in regulating mitochondrial function, as well as glucose and lipid metabolism in skeletal muscle. We report here that ACL silencing impairs myoblast and satellite cell (SC) differentiation, and it is accompanied by a decrease in fast myosin heavy chain isoforms and MYOD. Conversely, overexpression of ACL enhances MYOD levels and promotes myogenesis. Myogenesis is dependent on transcriptional but also other mechanisms. We show that ACL regulates the net amount of acetyl groups available, leading to alterations in acetylation of H3(K9/14) and H3(K27) at the MYOD locus, thus increasing MYOD expression. ACL overexpression in murine skeletal muscle leads to improved regeneration after cardiotoxin-mediated damage. Thus, our findings suggest a mechanism for regulating SC differentiation and enhancing regeneration, which might be exploited for devising therapeutic approaches for treating skeletal muscle disease. PMID- 29241531 TI - lncRNA Panct1 Maintains Mouse Embryonic Stem Cell Identity by Regulating TOBF1 Recruitment to Oct-Sox Sequences in Early G1. AB - Long noncoding RNAs (lncRNAs) have been implicated in diverse biological processes, including embryonic stem cell (ESC) maintenance. However, their functional mechanisms remain largely undefined. Here, we show that the lncRNA Panct1 regulates the transient recruitment of a putative X-chromosome-encoded protein A830080D01Rik, hereafter referred to as transient octamer binding factor 1 (TOBF1), to genomic sites resembling the canonical Oct-Sox motif. TOBF1 physically interacts with Panct1 and exhibits a cell-cycle-specific punctate localization in ESCs. At the chromatin level, this correlates with its recruitment to promoters of pluripotency genes. Strikingly, mutating an octamer like motif in Panct1 RNA abrogates the strength of TOBF1 localization and recruitment to its targets. Taken together, our data reveal a tightly controlled spatial and temporal pattern of lncRNA-mediated gene regulation in a cell-cycle dependent manner and suggest that lncRNAs might function as barcodes for identifying genomic addresses for maintaining cellular states. PMID- 29241533 TI - A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity. AB - The mosquito-borne flaviviruses include important human pathogens such as dengue, Zika, West Nile, and yellow fever viruses, which pose a serious threat for global health. Recent genetic screens identified endoplasmic reticulum (ER)-membrane multiprotein complexes, including the oligosaccharyltransferase (OST) complex, as critical flavivirus host factors. Here, we show that a chemical modulator of the OST complex termed NGI-1 has promising antiviral activity against flavivirus infections. We demonstrate that NGI-1 blocks viral RNA replication and that antiviral activity does not depend on inhibition of the N-glycosylation function of the OST. Viral mutants adapted to replicate in cells deficient of the OST complex showed resistance to NGI-1 treatment, reinforcing the on-target activity of NGI-1. Lastly, we show that NGI-1 also has strong antiviral activity in primary and disease-relevant cell types. This study provides an example for advancing from the identification of genetic determinants of infection to a host directed antiviral compound with broad activity against flaviviruses. PMID- 29241532 TI - Glucocorticoid Receptor Binding Induces Rapid and Prolonged Large-Scale Chromatin Decompaction at Multiple Target Loci. AB - Glucocorticoids act by binding to the glucocorticoid receptor (GR), which binds to specific motifs within enhancers of target genes to activate transcription. Previous studies have suggested that GRs can promote interactions between gene promoters and distal elements within target loci. In contrast, we demonstrate here that glucocorticoid addition to mouse bone-marrow-derived macrophages produces very rapid chromatin unfolding detectable by fluorescence in situ hybridization (FISH) at loci associated with GR binding. Rapid chromatin decompaction was generally not dependent on transcription at those loci that are known to be inducible in both mouse and human macrophages and was sustained for up to 5 days following ligand removal. Chromatin decompaction was not dependent upon persistent GR binding, which decayed fully after 24 hr. We suggest that sustained large-scale chromatin reorganization forms an important part of the response to glucocorticoid and might contribute to glucocorticoid sensitivity and resistance. PMID- 29241534 TI - Integrating Extracellular Flux Measurements and Genome-Scale Modeling Reveals Differences between Brown and White Adipocytes. AB - White adipocytes are specialized for energy storage, whereas brown adipocytes are specialized for energy expenditure. Explicating this difference can help identify therapeutic targets for obesity. A common tool to assess metabolic differences between such cells is the Seahorse Extracellular Flux (XF) Analyzer, which measures oxygen consumption and media acidification in the presence of different substrates and perturbagens. Here, we integrate the Analyzer's metabolic profile from human white and brown adipocytes with a genome-scale metabolic model to predict flux differences across the metabolic map. Predictions matched experimental data for the metabolite 4-aminobutyrate, the protein ABAT, and the fluxes for glucose, glutamine, and palmitate. We also uncovered a difference in how adipocytes dispose of nitrogenous waste, with brown adipocytes secreting less ammonia and more urea than white adipocytes. Thus, the method and software we developed allow for broader metabolic phenotyping and provide a distinct approach to uncovering metabolic differences. PMID- 29241535 TI - Strict Independence of Parallel and Poly-synaptic Axon-Target Matching during Visual Reflex Circuit Assembly. AB - The use of sensory information to drive specific behaviors relies on circuits spanning long distances that wire up through a range of axon-target recognition events. Mechanisms assembling poly-synaptic circuits and the extent to which parallel pathways can "cross-wire" to compensate for loss of one another remain unclear and are crucial to our understanding of brain development and models of regeneration. In the visual system, specific retinal ganglion cells (RGCs) project to designated midbrain targets connected to downstream circuits driving visuomotor reflexes. Here, we deleted RGCs connecting to pupillary light reflex (PLR) midbrain targets and discovered that axon-target matching is tightly regulated. RGC axons of the eye-reflex pathway avoided vacated PLR targets. Moreover, downstream PLR circuitry is maintained; hindbrain and peripheral components retained their proper connectivity and function. These findings point to a model in which poly-synaptic circuit development reflects independent, highly stringent wiring of each parallel pathway and downstream station. PMID- 29241536 TI - Infrabarrels Are Layer 6 Circuit Modules in the Barrel Cortex that Link Long Range Inputs and Outputs. AB - The rodent somatosensory cortex includes well-defined examples of cortical columns-the barrel columns-that extend throughout the cortical depth and are defined by discrete clusters of neurons in layer 4 (L4) called barrels. Using the cell-type-specific Ntsr1-Cre mouse line, we found that L6 contains infrabarrels, readily identifiable units that align with the L4 barrels. Corticothalamic (CT) neurons and their local axons cluster within the infrabarrels, whereas corticocortical (CC) neurons are densest between infrabarrels. Optogenetic experiments showed that CC cells received robust input from somatosensory thalamic nuclei, whereas CT cells received much weaker thalamic inputs. We also found that CT neurons are intrinsically less excitable, revealing that both synaptic and intrinsic mechanisms contribute to the low firing rates of CT neurons often reported in vivo. In summary, infrabarrels are discrete cortical circuit modules containing two partially separated excitatory networks that link long-distance thalamic inputs with specific outputs. PMID- 29241537 TI - Nucleus Accumbens Dopamine Signaling Regulates Sexual Preference for Females in Male Mice. AB - Sexual preference for the opposite sex is a fundamental behavior underlying reproductive success, but the neural mechanisms remain unclear. Here, we examined the role of dopamine signaling in the nucleus accumbens core (NAcc) in governing chemosensory-mediated preference for females in TrpC2-/- and wild-type male mice. TrpC2-/- males, deficient in VNO-mediated signaling, do not display mating or olfactory preference toward females. We found that, during social interaction with females, TrpC2-/- males do not show increased NAcc dopamine levels, observed in wild-type males. Optogenetic stimulation of VTA-NAcc dopaminergic neurons in TrpC2-/- males during exposure to a female promoted preference response to female pheromones and elevated copulatory behavior toward females. Additionally, we found that signaling through the D1 receptor in the NAcc is necessary for the olfactory preference for female-soiled bedding. Our study establishes a critical role for the mesolimbic dopaminergic system in governing pheromone-mediated responses and mate choice in male mice. PMID- 29241538 TI - An Elongin-Cullin-SOCS Box Complex Regulates Stress-Induced Serotonergic Neuromodulation. AB - Neuromodulatory cells transduce environmental information into long-lasting behavioral responses. However, the mechanisms governing how neuronal cells influence behavioral plasticity are difficult to characterize. Here, we adapted the translating ribosome affinity purification (TRAP) approach in C. elegans to profile ribosome-associated mRNAs from three major tissues and the neuromodulatory dopaminergic and serotonergic cells. We identified elc-2, an Elongin C ortholog, specifically expressed in stress-sensing amphid neuron dual ciliated sensory ending (ADF) serotonergic sensory neurons, and we found that it plays a role in mediating a long-lasting change in serotonin-dependent feeding behavior induced by heat stress. We demonstrate that ELC-2 and the von Hippel Lindau protein VHL-1, components of an Elongin-Cullin-SOCS box (ECS) E3 ubiquitin ligase, modulate this behavior after experiencing stress. Also, heat stress induces a transient redistribution of ELC-2, becoming more nuclearly enriched. Together, our results demonstrate dynamic regulation of an E3 ligase and a role for an ECS complex in neuromodulation and control of lasting behavioral states. PMID- 29241539 TI - Functional and Molecular Characterization of Mechanoinsensitive "Silent" Nociceptors. AB - Mechanical and thermal hyperalgesia (pain hypersensitivity) are cardinal signs of inflammation. Although the mechanism underlying thermal hyperalgesia is well understood, the cellular and molecular basis of mechanical hyperalgesia is poorly described. Here, we have identified a subset of peptidergic C-fiber nociceptors that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli when exposed to the inflammatory mediator nerve growth factor (NGF). Strikingly, NGF did not affect mechanosensitivity of other nociceptors. We show that these mechanoinsensitive "silent" nociceptors are characterized by the expression of the nicotinic acetylcholine receptor subunit alpha-3 (CHRNA3) and that the mechanically gated ion channel PIEZO2 mediates NGF induced mechanosensitivity in these neurons. Retrograde tracing revealed that CHRNA3+ nociceptors account for ~50% of all peptidergic nociceptive afferents innervating visceral organs and deep somatic tissues. Hence, our data suggest that NGF-induced "un-silencing" of CHRNA3+ nociceptors significantly contributes to the development of mechanical hyperalgesia during inflammation. PMID- 29241540 TI - Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms. AB - The central mechanism by which neurotensin (Nts) potentiates weight loss has remained elusive. We leveraged chemogenetics to reveal that Nts-expressing neurons of the lateral hypothalamic area (LHA) promote weight loss in mice by increasing volitional activity and restraining food intake. Intriguingly, these dual weight loss behaviors are mediated by distinct signaling pathways: Nts action via NtsR1 is essential for the anorectic effect of the LHA Nts circuit, but not for regulation of locomotor or drinking behavior. Furthermore, although LHA Nts neurons cannot reduce intake of freely available obesogenic foods, they effectively restrain motivated feeding in hungry, weight-restricted animals. LHA Nts neurons are thus vital mediators of central Nts action, particularly in the face of negative energy balance. Enhanced action via LHA Nts neurons may, therefore, be useful to suppress the increased appetitive drive that occurs after lifestyle-mediated weight loss and, hence, to prevent weight regain. PMID- 29241541 TI - Adipose KLF15 Controls Lipid Handling to Adapt to Nutrient Availability. AB - Adipose tissue stores energy in the form of triglycerides. The ability to regulate triglyceride synthesis and breakdown based on nutrient status (e.g., fed versus fasted) is critical for physiological homeostasis and dysregulation of this process can contribute to metabolic disease. Whereas much is known about hormonal control of this cycle, transcriptional regulation is not well understood. Here, we show that the transcription factor Kruppel-like factor 15 (KLF15) is critical for the control of adipocyte lipid turnover. Mice lacking Klf15 in adipose tissue (AK15KO) display decreased adiposity and are protected from diet-induced obesity. Mechanistic studies suggest that adipose KLF15 regulates key genes of triglyceride synthesis and inhibits lipolytic action, thereby promoting lipid storage in an insulin-dependent manner. Finally, AK15KO mice demonstrate accelerated lipolysis and altered systemic energetics (e.g., locomotion, ketogenesis) during fasting conditions. Our study identifies adipose KLF15 as an essential regulator of adipocyte lipid metabolism and systemic energy balance. PMID- 29241542 TI - MICU2 Restricts Spatial Crosstalk between InsP3R and MCU Channels by Regulating Threshold and Gain of MICU1-Mediated Inhibition and Activation of MCU. AB - Ca2+ entry into mitochondria is mediated by the Ca2+ uniporter-channel complex containing MCU, the Ca2+-selective pore, and associated regulatory proteins. The roles of MICU proteins are controversial. MICU1 was proposed to be necessary for MCU activity, whereas subsequent studies suggested it inhibits the channel in the low-cytoplasmic Ca2+ ([Ca2+]c) regime, a mechanism referred to as "gatekeeping," that imposes a [Ca2+]c threshold for channel activation at ~1-3 MUM. Here, we measured MCU activity over a wide range of quantitatively controlled and recorded [Ca2+]c. MICU1 alone can mediate gatekeeping as well as highly cooperative activation of MCU activity, whereas the fundamental role of MICU2 is to regulate the threshold and gain of MICU1-mediated inhibition and activation of MCU. Our results provide a unifying model for the roles of the MICU1/2 heterodimer in MCU channel regulation and suggest an evolutionary role for MICU2 in spatially restricting Ca2+ crosstalk between single inositol 1,4,5-trisphosphate receptor (InsP3R) and MCU channels. PMID- 29241543 TI - ppGpp Controls Global Gene Expression in Light and in Darkness in S. elongatus. AB - The bacterial and plant stringent response involves production of the signaling molecules guanosine tetraphosphate and guanosine pentaphosphate ((p)ppGpp), leading to global reorganization of gene expression. The function of the stringent response has been well characterized in stress conditions, but its regulatory role during unstressed growth is less studied. Here, we demonstrate that (p)ppGpp-deficient strains of S. elongatus have globally deregulated biosynthetic capacity, with increased transcription rate, translation rate, and cell size in unstressed conditions in light and impaired viability in darkness. Synthetic restoration of basal guanosine tetraphosphate (ppGpp) levels is sufficient to recover transcriptional balance and appropriate cell size in light and to rescue viability in light/dark conditions, but it is insufficient to enable efficient dark-induced transcriptional shutdown. Our work underscores the importance of basal ppGpp signaling for regulation of cyanobacterial physiology in the absence of stress and for viability in energy-limiting conditions, highlighting that basal (p)ppGpp level is essential in cyanobacteria in the environmental light/dark cycle. PMID- 29241545 TI - The Germline Linker Histone dBigH1 and the Translational Regulator Bam Form a Repressor Loop Essential for Male Germ Stem Cell Differentiation. AB - Drosophila spermatogenesis constitutes a paradigmatic system to study maintenance, proliferation, and differentiation of adult stem cell lineages. Each Drosophila testis contains 6-12 germ stem cells (GSCs) that divide asymmetrically to produce gonialblast cells that undergo four transit-amplifying (TA) spermatogonial divisions before entering spermatocyte differentiation. Mechanisms governing these crucial transitions are not fully understood. Here, we report the essential role of the germline linker histone dBigH1 during early spermatogenesis. Our results suggest that dBigH1 is a general silencing factor that represses Bam, a key regulator of spermatogonia proliferation that is silenced in spermatocytes. Reciprocally, Bam represses dBigH1 during TA divisions. This double-repressor mechanism switches dBigH1/Bam expression from off/on in spermatogonia to on/off in spermatocytes, regulating progression into spermatocyte differentiation. dBigH1 is also required for GSC maintenance and differentiation. These results show the critical importance of germline H1s for male GSC lineage differentiation, unveiling a regulatory interaction that couples transcriptional and translational repression. PMID- 29241544 TI - Dissociation of Rad51 Presynaptic Complexes and Heteroduplex DNA Joints by Tandem Assemblies of Srs2. AB - Srs2 is a superfamily 1 (SF1) helicase and antirecombinase that is required for genome integrity. However, the mechanisms that regulate Srs2 remain poorly understood. Here, we visualize Srs2 as it acts upon single-stranded DNA (ssDNA) bound by the Rad51 recombinase. We demonstrate that Srs2 is a processive translocase capable of stripping thousands of Rad51 molecules from ssDNA at a rate of ~50 monomers/s. We show that Srs2 is recruited to RPA clusters embedded between Rad51 filaments and that multimeric arrays of Srs2 assemble during translocation on ssDNA through a mechanism involving iterative Srs2 loading events at sites cleared of Rad51. We also demonstrate that Srs2 acts on heteroduplex DNA joints through two alternative pathways, both of which result in rapid disruption of the heteroduplex intermediate. On the basis of these findings, we present a model describing the recruitment and regulation of Srs2 as it acts upon homologous recombination intermediates. PMID- 29241546 TI - Neutrophils and Snail Orchestrate the Establishment of a Pro-tumor Microenvironment in Lung Cancer. AB - Understanding the immune compartment of tumors facilitates the development of revolutionary new therapies. We used a Kras(G12D)-driven mouse model of lung cancer to establish an immune signature and identified a contribution of Gr1+ neutrophils to disease progression. Depletion experiments showed that Gr1+ cells (1) favor tumor growth, (2) reduce T cell homing and prevent successful anti-PD1 immunotherapy, and (3) alter angiogenesis, leading to hypoxia and sustained Snail expression in lung cancer cells. In turn, Snail accelerated disease progression and increased intratumoral Cxcl2 secretion and neutrophil infiltration. Cxcl2 was produced mainly by neutrophils themselves in response to a factor secreted by Snail-expressing tumor cells. We therefore propose a vicious cycle encompassing neutrophils and Snail to maintain a deleterious tumor microenvironment. PMID- 29241547 TI - CAR T Cells Releasing IL-18 Convert to T-Bethigh FoxO1low Effectors that Exhibit Augmented Activity against Advanced Solid Tumors. AB - Adoptive therapy with chimeric antigen receptor (CAR)-redirected T cells has achieved remarkable efficacy in the treatment of hematopoietic malignancies. However, eradicating large solid tumors in advanced stages of the disease remains challenging. We explored augmentation of the anti-tumor immune reaction by establishing an acute inflammatory reaction. Systematic screening indicates that IL-18 polarizes CAR T cells toward T-bethigh FoxO1low effectors with an acute inflammatory response. CAR T cells engineered with inducible IL-18 release exhibited superior activity against large pancreatic and lung tumors that were refractory to CAR T cells without cytokines. IL-18 CAR T cell treatment was accompanied by an overall change in the immune cell landscape associated with the tumor. More specifically, CD206- M1 macrophages and NKG2D+ NK cells increased in number, whereas Tregs, suppressive CD103+ DCs, and M2 macrophages decreased, suggesting that "iIL18 TRUCKs" can be used to sensitize large solid tumor lesions for successful immune destruction. PMID- 29241548 TI - Diverging mRNA and Protein Networks in Activated Microglia Reveal SRSF3 Suppresses Translation of Highly Upregulated Innate Immune Transcripts. AB - Uncontrolled microglial activation may lead to the development of inflammation induced brain damage. Here, we uncover a ribosome-based mechanism/checkpoint involved in control of the innate immune response and microglial activation. Using an in vivo model system for analysis of the dynamic translational state of microglial ribosomes, with mRNAs as input and newly synthesized peptides as an output, we find a marked dissociation of microglia mRNA and protein networks following innate immune challenge. Highly upregulated and ribosome-associated mRNAs were not translated, resulting in two distinct microglial molecular signatures, a highly specialized pro-inflammatory mRNA signature and an immunomodulatory/homeostatic protein signature. We find that this is due to specific translational suppression of highly expressed mRNAs through a 3' UTR mediated mechanism involving the RNA-binding protein SRSF3. This discovery suggests avenues for therapeutic modulation of innate immune response in resident microglia. PMID- 29241549 TI - Trafficking-Mediated STING Degradation Requires Sorting to Acidified Endolysosomes and Can Be Targeted to Enhance Anti-tumor Response. AB - STING is an endoplasmic reticulum (ER)-associated transmembrane protein that turns on and quickly turns off downstream signaling as it translocates from the ER to vesicles. How STING signaling is attenuated during trafficking remains poorly understood. Here, we show that trafficking-mediated STING degradation requires ER exit and function of vacuolar ATPase complex. Late-stage STING vesicles are sorted to Rab7-positive endolysosomes for degradation. Based on analysis of existing structures, we also identified the helix amino acid 281 (aa281)-297 as a motif required for trafficking-mediated STING degradation. Immuno-electron microscopy (EM) reveals the size and clustering of STING vesicles and topology of STING on the vesicle. Importantly, blockade of trafficking mediated STING degradation using bafilomycin A1 specifically enhanced cyclic guanosine monophosphate (GMP)-AMP (cGAMP)-mediated immune response and anti-tumor effect in mice. Together, our findings provide biochemical and imaging evidence for STING degradation by the lysosome and pinpoint trafficking-mediated STING degradation as a previously unanticipated therapeutic target for enhancing STING signaling in cancer therapy. PMID- 29241550 TI - Structural Determination of the Broadly Reactive Anti-IGHV1-69 Anti-idiotypic Antibody G6 and Its Idiotope. AB - The heavy chain IGHV1-69 germline gene exhibits a high level of polymorphism and shows biased use in protective antibody (Ab) responses to infections and vaccines. It is also highly expressed in several B cell malignancies and autoimmune diseases. G6 is an anti-idiotypic monoclonal Ab that selectively binds to IGHV1-69 heavy chain germline gene 51p1 alleles that have been implicated in these Ab responses and disease processes. Here, we determine the co-crystal structure of humanized G6 (hG6.3) in complex with anti-influenza hemagglutinin stem-directed broadly neutralizing Ab D80. The core of the hG6.3 idiotope is a continuous string of CDR-H2 residues starting with M53 and ending with N58. G6 binding studies demonstrate the remarkable breadth of binding to 51p1 IGHV1-69 Abs with diverse CDR-H3, light chain, and antigen binding specificities. These studies detail the broad expression of the G6 cross-reactive idiotype (CRI) that further define its potential role in precision medicine. PMID- 29241551 TI - Sorting Tubules Regulate Blood-Brain Barrier Transcytosis. AB - Transcytosis across the blood-brain barrier (BBB) regulates key processes of the brain, but the intracellular sorting mechanisms that determine successful receptor-mediated transcytosis in brain endothelial cells (BECs) remain unidentified. Here, we used Transferrin receptor-based Brain Shuttle constructs to investigate intracellular transport in BECs, and we uncovered a pathway for the regulation of receptor-mediated transcytosis. By combining live-cell imaging and mathematical modeling in vitro with super-resolution microscopy of the BBB, we show that intracellular tubules promote transcytosis across the BBB. A monovalent construct (sFab) sorted for transcytosis was localized to intracellular tubules, whereas a bivalent construct (dFab) sorted for degradation formed clusters with impaired transport along tubules. Manipulating tubule biogenesis by overexpressing the small GTPase Rab17 increased dFab transport into tubules and induced its transcytosis in BECs. We propose that sorting tubules regulate transcytosis in BECs and may be a general mechanism for receptor mediated transport across the BBB. PMID- 29241552 TI - A Single-Cell RNA Sequencing Study Reveals Cellular and Molecular Dynamics of the Hippocampal Neurogenic Niche. AB - Adult neurogenesis in the murine dentate gyrus occurs in a specialized microenvironment that sustains the generation of neurons during life. To fully understand adult neurogenesis, it is essential to determine the neural stem cell (NSC) and progenitor developmental stages, their molecular determinants, and the niche cellular and molecular composition. We report on a single-cell RNA sequencing study of the hippocampal niche, performed by isolating all the non neuronal cell populations. Our analysis provides a comprehensive description of the dentate gyrus cells, and it allows the identification of exclusive cell-type specific markers. We define the developmental stages and transcriptional dynamics of NSCs and progenitors, and we find that, while NSCs represent a heterogeneous cellular continuum, progenitors can be grouped into distinct subtypes. We determine the oligodendrocyte lineage and transcriptional dynamics, and we describe the microglia transcriptional profile and activation state. The combined data constitute a valuable resource to understand regulatory mechanisms of adult neurogenesis. PMID- 29241553 TI - Comprehensive Proteomic Characterization of Ontogenic Changes in Hematopoietic Stem and Progenitor Cells. AB - Hematopoietic stem and progenitor cells (HSPCs) in the fetus and adult possess distinct molecular landscapes that regulate cell fate and change their susceptibility to initiation and progression of hematopoietic malignancies. Here, we applied in-depth quantitative proteomics to comprehensively describe and compare the proteome of fetal and adult HSPCs. Our data uncover a striking difference in complexity of the cellular proteomes, with more diverse adult specific HSPC proteomic signatures. The differential protein content in fetal and adult HSPCs indicate distinct metabolic profiles and protein complex stoichiometries. Additionally, adult characteristics include an arsenal of proteins linked to viral and bacterial defense, as well as protection against ROS induced protein oxidation. Further analyses show that interferon alpha, as well as Neutrophil elastase, has distinct functional effects in fetal and adult HSPCs. This study provides a rich resource aimed toward an enhanced mechanistic understanding of normal and malignant hematopoiesis during fetal and adult life. PMID- 29241554 TI - Primary Patient-Derived Cancer Cells and Their Potential for Personalized Cancer Patient Care. AB - Personalized cancer therapy is based on a patient's tumor lineage, histopathology, expression analyses, and/or tumor DNA or RNA analysis. Here, we aim to develop an in vitro functional assay of a patient's living cancer cells that could complement these approaches. We present methods for developing cell cultures from tumor biopsies and identify the types of samples and culture conditions associated with higher efficiency of model establishment. Toward the application of patient-derived cell cultures for personalized care, we established an immunofluorescence-based functional assay that quantifies cancer cell responses to targeted therapy in mixed cell cultures. Assaying patient derived lung cancer cultures with this method showed promise in modeling patient response for diagnostic use. This platform should allow for the development of co clinical trial studies to prospectively test the value of drug profiling on tumor biopsy-derived cultures to direct patient care. PMID- 29241557 TI - Editorial overview: Antimicrobials. PMID- 29241558 TI - Editorial overview: Bacterial systems biology. PMID- 29241555 TI - Inhibiting the Ca2+ Influx Induced by Human CSF. AB - One potential therapeutic strategy for Alzheimer's disease (AD) is to use antibodies that bind to small soluble protein aggregates to reduce their toxic effects. However, these therapies are rarely tested in human CSF before clinical trials because of the lack of sensitive methods that enable the measurement of aggregate-induced toxicity at low concentrations. We have developed highly sensitive single vesicle and single-cell-based assays that detect the Ca2+ influx caused by the CSF of individuals affected with AD and healthy controls, and we have found comparable effects for both types of samples. We also show that an extracellular chaperone clusterin; a nanobody specific to the amyloid-beta peptide (Abeta); and bapineuzumab, a humanized monoclonal antibody raised against Abeta, could all reduce the Ca2+ influx caused by synthetic Abeta oligomers but are less effective in CSF. These assays could be used to characterize potential therapeutic agents in CSF before clinical trials. PMID- 29241556 TI - Hepatic Dysfunction Caused by Consumption of a High-Fat Diet. AB - Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver dysfunction and low-grade inflammation during the development of diet-induced metabolic syndrome. We validated these model findings with additional experiments on mouse liver sections. In total, we present an integrative systems biology study of diet induced hepatic insulin resistance that uncovered molecular features promoting the development and maintenance of metabolic disease. PMID- 29241559 TI - miR393 inhibits in vitro shoot regeneration in Arabidopsis thaliana via repressing TIR1. AB - A large number of genes are involved in the control of shoot regeneration from in vitro cultured plant material. The abundance of the miR393 was different between regenerable and non-regenerable calli induced from Arabidopsis thaliana explants. The regenerability of root explants derived from p35S:miR393a (the miR393a over expressing line) was shown here to be poorer than that of the wild type (WT). Also, explants derived from plants engineered to constitutively express MIM393 (a mutated form of miR393) had an enhanced level of shoot regeneration. The number of newly formed shoot apical meristems (SAMs) was smaller in p35S:miR393a, while it was larger in p35S:MIM393, compared to the WT, indicating that miR393a inhibited shoot regeneration via repressing the de novo formation of SAMs. The capacity to regenerate shown by plants harboring mTIR1 (a form of TIR1 not cleavable by miR393) was similar to that shown by lines constitutively expressing MIM393, while regenerability of tir1-1 (a loss-of-function mutant) was similar to p35S:miR393a. miR393a and TIR1 were both transcribed at high levels in the initiation sites of nascent shoot apical meristems. Thus, the miR393-TIR1 molecular regulation pathway appears to be a component of the regulatory control over shoot regeneration from in vitro culture. PMID- 29241560 TI - RNA sequencing and analysis of three Lupinus nodulomes provide new insights into specific host-symbiont relationships with compatible and incompatible Bradyrhizobium strains. AB - Nitrogen fixation in the legume root-nodule symbiosis has a critical importance in natural and agricultural ecosystems and depends on the proper choice of the symbiotic partners. However, the genetic determinism of symbiotic specificity remains unclear. To study this process, we inoculated three Lupinus species (L. albus, L. luteus, L. mariae-josephae), belonging to the under-investigated tribe of Genistoids, with two Bradyrhizobium strains (B. japonicum, B. valentinum) presenting contrasted degrees of symbiotic specificity depending on the host. We produced the first transcriptomes (RNA-Seq) from lupine nodules in a context of symbiotic specificity. For each lupine species, we compared gene expression between functional and non-functional interactions and determined differentially expressed (DE) genes. This revealed that L. luteus and L. mariae-josephae (nodulated by only one of the Bradyrhizobium strains) specific nodulomes were richest in DE genes than L. albus (nodulation with both microsymbionts, but non functional with B. valentinum) and share a higher number of these genes between them than with L. albus. In addition, a functional analysis of DE genes highlighted the central role of the genetic pathways controlling infection and nodule organogenesis, hormones, secondary, carbon and nitrogen metabolisms, as well as the implication of plant defence in response to compatible or incompatible Bradyrhizobium strains. PMID- 29241561 TI - Arabidopsis mTERF6 is required for leaf patterning. AB - To enhance our understanding of the roles of mitochondrial transcription termination factors (mTERFs) in plants, we have taken a reverse genetic approach in Arabidopsis thaliana. One of the mutants isolated carried a novel allele of the mTERF6 gene, which we named mterf6-5. mTERF6 is a chloroplast and mitochondrial localised protein required for the maturation of chloroplast isoleucine tRNA. The mterf6-5 plants are pale and exhibit markedly reduced growth, and altered leaf and chloroplast development. Our qRT-PCR analyses revealed mis-expression of several plastid, mitochondrial and nuclear genes in mterf6-5 plants. Synergistic phenotypes were observed in double mutant combinations of mterf6-5 with alleles of other mTERF genes as well as with scabra3-2, affected in the plastid RpoTp RNA polymerase; these observations suggest a functional relationship between mTERF6, other mTERFs and SCA3. The mterf6-5 mutation also enhanced the leaf dorsoventral polarity defects of the asymmetric leaves1-1 (as1-1) mutant, which resulted in radial leaves. This interaction seemed specific of the impaired mTERF6 function because mutations in the mTERF genes MDA1 or TWR-1/mTERF9 did not result in radialised leaves. Furthermore, the mterf6-5 mutation dramatically increased the leaf phenotype of as2-1 and caused lethality early in vegetative development. Our results uncover a new role for mTERF6 in leaf patterning and highlight the importance of mTERFs in plant development. PMID- 29241563 TI - Two metallocarboxypeptidase inhibitors are implicated in tomato fruit development and regulated by the Inner No Outer transcription factor. AB - The TCMP-1 and TCMP-2 genes of tomato code for metallocarboxypeptidase inhibitors and show sequential, tightly regulated expression patterns during flower and fruit development. In particular, TCMP-1 is highly expressed in flower buds before anthesis, while TCMP-2 in ripe fruits. Their expression pattern suggests that they might play a role in fruit development. Here, to investigate their function, we altered their endogenous levels by generating transgenic plants harbouring a chimeric gene expressing the TCMP-1 coding sequence under the control of the TCMP-2 promoter. The expression of the transgene caused an earlier fruit setting with no visible phenotypic effects on plant and fruit growth. The altered TCMP-1 regulation determines an increased level of TCMP-1 in the fruit and unexpected changes in the levels of both TCMPs in flower buds before anthesis, suggesting a mechanism of transcriptional cross-regulation. We in silico analysed TCMPs promoter regions for the presence of common cis acting elements related to ovary/fruit development and we found that both promoters contain putative binding sites for INNER NO OUTER (INO), a transcription factor implicated in ovule development. By chromatin immunoprecipitation, we proved that INO binds to TCMP-1 and TCMP-2 promoters, thereby representing a candidate regulatory factor for coordinated control of TCMPs. PMID- 29241565 TI - Gene mapping and transcriptome profiling of a practical photo-thermo-sensitive rice male sterile line with seedling-specific green-revertible albino leaf. AB - Abnormal environment weather can cause rice photoperiod-thermo-sensitive genic male sterile (PTGMS) lines fertile or partially fertile and thus cause the mixture of true hybrids with selfing seeds. Seedling-specific green-revertible albino leaf color mutant can be used to distinguish the real hybrids. Besides, it can also be used as an ideal material to research the development of chloroplast and biosynthesis of chlorophyll. The phenotype of leaf color mutants includes light green, yellowing, albino, green-revertible albino. Gene mutations affecting the synthesis and degradation of photosynthetic pigments, lycopene and heme, the differentiation and development of chloroplast, gibberellins (GAs) biosynthesis, can change the leaf color. We have created a PTGMS line with seedling-specific green-revertible albino leaf named W01S. The leaf phenotype, pollen sterility and fertility, agronomic traits, heredity, gene mapping and RNA-Seq of the differentially expressed genes between albino and green-revertible leaves were investigated. The results showed that W01S is a practical PTGMS line as Pei'ai 64S. The mutation of candidate gene Os03g0594100 (ent-isokaurene C2-hydroxylase like) in W01S can be related to the biosynthesis of GAs, indole acetic acids, ethylene. PMID- 29241564 TI - Chrysanthemum MADS-box transcription factor CmANR1 modulates lateral root development via homo-/heterodimerization to influence auxin accumulation in Arabidopsis. AB - Root system architecture is an important agronomic trait by which plants both acquire water and nutrients from the soil and adapt to survive in a complex environment. The adaptation of plant root systems to environmental constraints largely depends on the growth and development of lateral roots (LRs). MADS-box transcription factors (TFs) are important known regulators of plant growth, development, and response to environmental stimuli. However, the potential mechanisms by which they regulate LRs development remain poorly understood. Here, we identified a MADS-box chrysanthemum gene CmANR1, homologous to the Arabidopsis gene AtANR1, which plays a key role in the regulation of LR development. qRT-PCR assays indicated that CmANR1 was primarily expressed in chrysanthemum roots and was rapidly induced by exposure to high nitrate concentrations. Ectopic expression of CmANR1 in Arabidopsis significantly increased the number and length of emerged LRs compared to the wild-type (col) control, but had no obvious affect on primary root (PR) development. We also found that CmANR1 positively influenced auxin accumulation in LRs at least partly by improving auxin biosynthesis and transport, thereby promoting LR development. Furthermore, we found that ANR1 formed homo- and heterodimers through interactions with itself and AGL21 at its C terminal domain. Overall, our findings provide considerable new information about the mechanisms by which the chrysanthemum MADS-box TF CmANR1 mediates LR development by directly altering auxin accumulation. PMID- 29241566 TI - A catechol oxidase AcPPO from cherimoya (Annona cherimola Mill.) is localized to the Golgi apparatus. AB - Cherimoya (Annona cherimola) is an exotic fruit with attractive organoleptic characteristics. However, it is highly perishable and susceptible to postharvest browning. In fresh fruit, browning is primarily caused by the polyphenol oxidase (PPO) enzyme catalyzing the oxidation of o-diphenols to quinones, which polymerize to form brown melanin pigment. There is no consensus in the literature regarding a specific role of PPO, and its subcellular localization in different plant species is mainly described within plastids. The present work determined the subcellular localization of a PPO protein from cherimoya (AcPPO). The obtained results revealed that the AcPPO- green fluorescent protein co-localized with a Golgi apparatus marker, and AcPPO activity was present in Golgi apparatus enriched fractions. Likewise, transient expression assays revealed that AcPPO remained active in Golgi apparatus-enriched fractions obtained from tobacco leaves. These results suggest a putative function of AcPPO in the Golgi apparatus of cherimoya, providing new perspectives on PPO functionality in the secretory pathway, its effects on cherimoya physiology, and the evolution of this enzyme. PMID- 29241567 TI - Pectic enzymes as potential enhancers of ascorbic acid production through the D galacturonate pathway in Solanaceae. AB - The increase of L-Ascorbic Acid (AsA) content in tomato (Solanum lycopersicum) is a common goal in breeding programs due to its beneficial effect on human health. To shed light into the regulation of fruit AsA content, we exploited a Solanum pennellii introgression line (IL12-4-SL) harbouring one quantitative trait locus that increases the content of total AsA in the fruit. Biochemical and transcriptomic analyses were carried out in fruits of IL12-4-SL in comparison with the cultivated line M82 at different stages of ripening. AsA content was studied in relation with pectin methylesterase (PME) activity and the degree of pectin methylesterification (DME). Our results indicated that the increase of AsA content in IL12-4-SL fruits was related with pectin de methylesterification/degradation. Specific PME, polygalacturonase (PG) and UDP-D glucuronic-acid-4-epimerase (UGlcAE) isoforms were proposed as components of the D-galacturonate pathway leading to AsA biosynthesis. The relationship between AsA content and PME activity was also exploited in PMEI tobacco plants expressing a specific PME inhibitor (PMEI). Here we report that tobacco PMEI plants, altered in PME activity and degree of pectin methylesterification, showed a reduction in low methylesterified pectic domains and exhibited a reduced AsA content. Overall, our results provide novel biochemical and genetic traits for increasing antioxidant content by marker-assisted selection in the Solanaceae family. PMID- 29241568 TI - The AtMC4 regulates the stem cell homeostasis in Arabidopsis by catalyzing the cleavage of AtLa1 protein in response to environmental hazards. AB - The AtLa1 protein is an RNA binding factor that initiates the translation of WUSCHEL (WUS) mRNA in Arabidopsis. The AtLa1 protein can regulate the stem cell homeostasis via the nuclear-to-cytoplasmic translocation in response to environmental hazards. However, the translocation mechanism of AtLa1 protein remains to be elucidated. In the present study, we have explored the role of AtMC4 protein in the subcellular translocation of AtLa1 protein. Our results showed that the AtLa1 protein is a substrate of AtMC4 protein. The AtMC4 protein can interact with AtLa1 protein and catalyze the cleavage of the C-terminal nuclear localization signal peptide of AtLa1 protein. The AtMC4 protein is mainly distributed in the cytoplasm. In the presence of environmental stresses, the cytoplasmic-to-nuclear translocation of AtMC4 protein is enhanced with the result that more AtLa1 protein can be cleaved and transported from nucleus to cytoplasm, where AtLa1 protein further initiates the translation of WUS mRNA. By contrast, knockdown of AtMC4 expression inhibits the nuclear-to-cytoplasmic translocation of AtLa1 protein and the WUS protein translation. Based on these results, we conclude that the AtMC4 protein regulates stem cell homeostasis by catalyzing the cleavage of AtLa1 protein in response to environmental hazards. PMID- 29241569 TI - Structure-function relationships in photosynthetic membranes: Challenges and emerging fields. AB - Oxygenic photosynthesis is a fundamental biological process that shaped the earth's biosphere. The process of energy transformation is hosted in highly specialized thylakoid membranes that adjust their architecture in response to environmental cues at different structural levels leading to the adjustment of photosynthetic functions. This review presents structure-function dynamics ranging from the whole membrane system over the mesoscopic level (protein ensembles) down to interactions between lipids and protein complexes. On the whole membrane level, thylakoid membranes constantly change their overall shape (e.g. membranes swell and shrink or destack and stack) that controls vital functions of energy transformation. Furthermore, the physical connection and transition between stacked grana thylakoid and unstacked membrane regions that determines mass transport between these sub-compartments is a crucial open question. On the mesoscopic level, it turns out that reorganizations between disordered and ordered protein arrangements is central for light harvesting and lateral diffusion processes. It has to be unraveled how changes in mesoscopic protein organization are controlled. Finally, dynamic physicochemical properties of the lipid bilayer can determine the structure and organization of photosynthetic membrane proteins, a field that is highly neglected so far. This review focusses on open questions and challenging problems in photosynthesis research. PMID- 29241570 TI - ZmNST3 and ZmNST4 are master switches for secondary wall deposition in maize (Zea mays L.). AB - Secondary walls are the most abundant biomass produced by plants, and they consist mainly of lignin, cellulose and hemicellulose. Understanding how secondary wall biosynthesis is regulated could potentially provide genetic tools for engineering biomass components, especially in maize and Sorghum bicolor. Although many works have focused on secondary wall biosynthesis in dicotyledons, little has been reported for these monocotyledons. In this study, we cloned two NAC transcriptional factor genes, ZmNST3 and ZmNST4, and analyzed their functions in maize secondary wall formation process. ZmNST3 and ZmNST4 were expressed specifically in secondary wall-forming cells, expression of ZmNST3/4 can restore the pendent phenotype of Arabidopsis nst1nst3 double mutant. ZmNST3/4 overexpressing Arabidopsis and maize displayed a thickened secondary wall in the stem, and knockdown maize showed defective secondary wall deposition. ZmNST3/4 could regulate the expression of ZmMYB109/128/149. Our results revealed that ZmNST3/4 are master switches of the maize secondary wall biosynthesis process and provides new evidence that the secondary wall regulatory pathway is conserved in different plant species. PMID- 29241571 TI - RMR (Receptor Membrane RING-H2) type 1 and 2 show different promoter activities and subcellular localizations in Arabidopsis thaliana. AB - Soluble vacuolar proteins reach their compartments of final accumulation through the binding with specific transmembrane cargo receptors. In Arabidopsis thaliana two different families of receptors have been characterized. The AtVSRs (Vacuolar Sorting Receptor), which are known to be involved in the protein sorting to lytic vacuoles (LV), and the AtRMRs (Receptor Membrane RING-H2), for which there is less evidence for a role in the traffic to the protein storage vacuole (PSV). In this study we investigated the localization and tissue expression of two RMRs (AtRMR1 and 2) in their species of origin, A. thaliana. Our experiments using leaf protoplasts and transgenic plants supported previous results of subcellular localization in Nicotiana benthamiana that visualized AtRMR1 and 2 in the cisternae of endoplasmic reticulum (ER) and in the trans-Golgi network (TGN), respectively. The promoter activities of AtRMR1 and AtRMR2 detected in transgenic A. thaliana lines suggest that the expression of these two receptors only partially overlap in some organs and tissues. These results suggest that AtRMR1 and 2 are not functionally redundant, but could also interact and participate in the same cellular process in tissues with an overlapping expression. PMID- 29241572 TI - Genome-wide association mapping of QTL underlying seed oil and protein contents of a diverse panel of soybean accessions. AB - To investigate the genetic basis of variation in oil and protein contents in soybean seeds, a diverse collection of 421 mainly Chinese soybean cultivars was genotyped using 1536 SNPs, mostly from candidate genes related to acyl-lipid metabolism and from regions harboring known QTL. Six significant associations were identified for each of seed oil and protein contents which individually explained 2.7-5.9% of the phenotypic variance. Six associations occurred in or near known QTL and the remaining are putative novel QTL. Ten significant associations influenced the oil content without decreasing protein content, and vice versa. One SNP was pleiotropic, with opposite effects on oil and protein contents. The genetic region covering Map-6076 and-6077 was shown to be involved in controlling oil content in soybean by integrating the results of association mapping with information on known QTL and tissue-specific expression data. This region was subject to strong selection during the genetic improvement of soybean. Our results not only confirm and refine the map positions of known QTL but also contribute to a further elucidation of the genetic architecture of protein and oil contents in soybean seeds by identifying new associations exhibiting pleiotropic effects on seed protein and oil contents. PMID- 29241573 TI - Gaps and opportunities for nutrition research in relation to non-communicable diseases in Arab countries: Call for an informed research agenda. AB - Effective public health nutrition interventions are needed to curb the escalating prevalence of non-communicable diseases (NCDs) in many Arab countries. In order to generate the scientific evidence needed for the success of these interventions, an informed research agenda should be developed. The purpose of this review is to identify gaps and opportunities for research on nutrition and NCDs among Arab countries, which is an important step towards the formulation of this research agenda. Published papers that addressed nutrition and NCDs in Arab countries between the years 2006 and 2015 were reviewed (n=824). The main gaps identified were related to the predominance of laboratory-based studies with few cohort and intervention studies, and the small percentage of articles examining dietary patterns. While food frequency questionnaires were the main dietary assessment method used, only 35% were validated. Very few studies included children and the majority considered nutrition in isolation, excluding other environmental factors. Opportunities identified included the promising momentum in studying nutrition and NCDs among Arab countries, evidenced by an increasing number of articles published over the years, that may be guided in future nutrition research to fill the identified gaps. In addition, the higher number of articles in high-income countries coupled with the impact of papers in middle income countries suggests an opportunity of synergistic collaboration among these countries. The identified gaps and opportunities in this review may serve as basis for Arab countries to start developing a research agenda in the area of nutrition and NCDs. PMID- 29241574 TI - Glucose-mediated inactivation of AMP-activated protein kinase reduces the levels of L-type amino acid transporter 1 mRNA in C2C12 cells. AB - Branched chain amino acids (BCAAs) have protective effects against muscle atrophy. Although plasma BCAA concentrations are higher in patients with diabetes than in healthy subjects, diabetes is related to sarcopenia. We hypothesized that high glucose concentration reduces the quantity of BCAA transporters, and consequently, the effects of BCAAs are diminished despite their high levels. We examined whether glucose reduces the expression of L-type amino acid transporter 1 (LAT1), which transports neutral amino acids, including BCAA, in C2C12 myocytes. Glucose reduced LAT1 mRNA level by 80% in the C2C12 cells, compared with that in the glucose-free control cells. Regarding LAT1-related transporters, glucose also reduced the level of sodium-dependent neutral amino acid transporter 2 mRNA, but not that of 4F2 heavy chain. Although fructose reduced LAT1 mRNA levels, 2-deoxyglucose exhibited low effectiveness in reducing LAT1 mRNA level; galactose and mannitol had no effect. These results suggest a relationship between ATP produced during glycolysis and LAT1 mRNA levels. In fact, the AMP activated protein kinase (AMPK) inhibitor dorsomorphin reduced LAT1 mRNA levels in the absence of glucose, whereas the AMPK activator 5-Aminoimidazole-4 carboxamide-1-beta-d-ribofuranoside increased LAT1 mRNA levels even in the presence of glucose. Consistent with these findings, glucose reduced the levels of phospho-AMPKalpha (Thr172) compared with that in the glucose-free control. These findings indicate that glucose inactivates AMPK, leading to a reduction in LAT1 mRNA levels in the C2C12 cells. This glucose-induced reduction in LAT1 expression may explain the unresponsiveness to BCAA in the patients with diabetes. PMID- 29241575 TI - Dietary supplementation with myo-inositol reduces hepatic triglyceride accumulation and expression of both fructolytic and lipogenic genes in rats fed a high-fructose diet. AB - Excessive fructose ingestion drastically enhances hepatic lipid accumulation. The most prominent form of inositol-myo-inositol (MI)-remarkably reduces high sucrose induced hepatic triglyceride (TG) accumulation. Because MI is a major and strong lipotrope, we hypothesized in this study that MI improves fatty liver more induced by excessive ingestion of fructose than sucrose. Rats were fed a high glucose diet (HGD), a high-fructose diet (HFD), or an HFD supplemented with 0.2% MI for 12 days. Hepatic levels of TG and mRNAs for fructolysis (ketohexokinase and aldolase B), lipogenesis (pyruvate kinase, liver, and RBC; glucose-6 phosphate dehydrogenase; acetyl-CoA carboxylase alpha; fatty acid synthase; and stearoyl-CoA desaturase 1), and a key transcription factor for lipogenesis carbohydrate-responsive element-binding protein-were significantly increased in the HFD group compared with the HGD group, and the increase was markedly decreased by MI supplementation. Similarly, HFD-induced pyruvate kinase, liver, and RBC and fatty acid synthase protein levels in the liver were reduced by MI treatment. On the other hand, hepatic levels of mRNAs for beta-oxidation (acyl CoA synthetase and carnitine palmitoyltransferase 1a) did not differ among the 3 groups. Taken together, this study showed that MI supplementation decreases the expression of fructolytic/lipogenic genes and lipogenic proteins as well as TG accumulation in high fructose-induced fatty liver in rats. PMID- 29241576 TI - Anthocyanin-rich plum juice reduces ambulatory blood pressure but not acute cognitive function in younger and older adults: a pilot crossover dose-timing study. AB - Consumption of anthocyanins from fruit sources may exert protection against hypertension and improve cognition. However, the effect of dose timing in studies is rarely considered. We hypothesized that timed-dose consumption of juice from an anthocyanin-rich Japanese plum variety (Queen Garnet plum, QGP) will have acute and dose-timing effects on cardiovascular responses, cognition, and urinary anthocyanin excretion profiles. Our study objective was to investigate the impact of plum juice on these health parameters. Twelve older (65+ years) and 12 younger (18-45 years) adults participated in an acute crossover study. Participants received, randomly, either 1 * 300 mL or 3 * 100 mL plum juice over 3 hours on 2 different occasions with a 2-week washout period. A battery of cognitive tasks was administered at 0 and 6 hours on each study day. Blood pressure (BP) and urinary anthocyanin/metabolite excretion profiles were measured over 24 hours. Area under the curve for BP was calculated (0-6 hours). A significant reduction in BP and cardiovascular responses was observed in both age groups which was more obvious in the older age group on the single dose for systolic BP, diastolic BP, mean arterial pressure, and heart rate (P values = .035, .028, .017, and .006, respectively). No significant difference was observed between dose-timing regimens for either age group. There was no observed effect on cognition. Native QGP anthocyanins, as well as methylated/glucuronidated metabolites, were detected in urine with no significant differences between age groups or dose timing. High anthocyanin plum juice significantly reduced BP, but dose timing did not appear to be a significant factor in the potential acute BP-lowering effect of QGP juice. PMID- 29241577 TI - Caulerpa okamurae extract inhibits adipogenesis in 3T3-L1 adipocytes and prevents high-fat diet-induced obesity in C57BL/6 mice. AB - Seaweeds are considered a potential source of antiobesity agents. Because Caulerpa, a seaweed, has been consumed for food in Japan, China, South Korea, and Australia, we hypothesized that Caulerpa okamurae may have antiobesity effects in an animal model of high-fat diet (HFD)-induced obesity in C57BL/6 mice. Herein, we found that the ethanolic extract of C okamurae (COE) significantly inhibited lipid accumulation and reduced the expression of the master regulator of adipogenesis, peroxisome proliferator-activated receptor-gamma, sterol regulatory element binding protein-1c, and CCAAT/enhancer-binding protein-alpha in 3T3-L1 adipocytes. Moreover, COE significantly decreased body weight, fat weight, and liver weight in HFD-fed mice. This effect is comparable to that of positive control Garcinia cambogia extract, which has been approved by the Korean Food and Drug Administration as a weight loss food supplement in South Korea. Similarly, markers of weight gain such as free fatty acids, triglyceride, total cholesterol, glucose, and insulin in the plasma and free fatty acid, triglyceride, total cholesterol, and total lipid in the liver are significantly reduced in COE treated HFD-fed mice. We found significantly reduced peroxisome proliferator activated receptor-gamma, CCAAT/enhancer-binding protein-alpha, fatty acid synthase, sterol regulatory element binding protein-1c, cluster of differentiation 36, and acetyl-CoA synthetase in the adipose tissue of COE treated HFD-fed mice. In conclusion, our results demonstrated that COE is effective in preventing body weight gain and fat accumulation and reduces plasma and hepatic lipid profiles. Together, these findings suggest that C okamurae may be used as a possible treatment option for the management of obesity and associated metabolic disorders. PMID- 29241578 TI - Polymorphisms in the leptin (rs7799039) gene are associated with an increased risk of excessive gestational weight gain but not with leptin concentration during pregnancy. AB - Single nucleotide polymorphisms (SNPs) in leptin (LEP) and leptin receptor (LEPR) have been shown to be linked to obesity-related metabolic markers and phenotype. Therefore, we hypothesized that the LEP-rs7799039 and LEPR-rs1137101 SNPs are related to the risk of pre-pregnancy overweight/obesity (body mass index >=25 kg/m2) as well as to excessive gestational weight gain (GWG) and high concentrations of leptin throughout pregnancy. We investigated a prospective cohort of 147 Brazilian pregnant women through weeks 5-13, 20-26, and 30-36 of gestation. Genetic variants of LEP and LEPR were analyzed by real-time polymerase chain reaction and leptin by enzyme-linked immunosorbent assay. Statistical analyses included multiple linear regression, linear mixed effects, and Poisson regression models. Genotype AA carriers for the LEP-rs7799039 gene maintained a lower body weight throughout pregnancy compared with those with genotypes GG or GA + GG (betaAAvsGG = -7.91 kg; 95% confidence interval [CI], -14.21 to -1.61; P = .01; and betaAAvsGA + GG = -7.66 kg; 95% CI, -14.07 to -1.25; P = .02). The A allele was significantly associated with an increased risk for excessive GWG (relative riskLEP-GAvsGG, 2.16; 95% CI, 1.23-3.80; and relative riskLEP-AAvsGG, 2.37; 95% CI, 1.04-5.39). Neither the LEP-rs7799039 nor LEPR-rs1137101 SNP was significantly associated with pre-pregnancy overweight/obesity risk and leptin concentrations during pregnancy. In conclusion, our results indicate that women who had the AA genotype for LEP-rs7799039 displayed a lower body weight throughout pregnancy compared with GG or GA + GG carriers. LEP-rs7799039 was significantly associated with an increased risk for excessive GWG, but the results do not support significant associations of the LEP-rs7799039 and LEPR rs1137101 polymorphisms with pre-pregnancy overweight/obesity risk and leptin concentrations throughout pregnancy. PMID- 29241579 TI - Punicalagin from pomegranate promotes human papillary thyroid carcinoma BCPAP cell death by triggering ATM-mediated DNA damage response. AB - Punicalagin (PUN), a component derived from pomegranate, is well known for its anticancer activity. Our previous work revealed that PUN induces autophagic cell death in papillary thyroid carcinoma cells. We hypothesized that PUN triggers DNA damage associated with cell death because DNA damage was reported as an inducer of autophagy. Our results showed that PUN treatment caused DNA breaks as evidenced by the significant enhancement in the phosphorylation of H2A.X. However, reactive oxygen species and DNA conformational alteration, 2 common inducing factors in DNA damage, were not involved in PUN-induced DNA damage. The phosphorylation of ataxia-telangiectasia mutated gene-encoded protein (ATM) but not ataxia telangiectasia and Rad3-related protein (ATR) was up-regulated in a time- and dosage-dependent manner after PUN treatment. KU-55933, an inhibitor of ATM, inhibited the phosphorylation of ATM induced by PUN and reversed the decreased cell viability caused by PUN. Thus, we demonstrated that PUN induces cell death of papillary thyroid carcinoma cells by triggering ATM-mediated DNA damage response, which provided novel mechanisms and potential targets for the better understanding of the anticancer actions of PUN. PMID- 29241580 TI - In vitro-fermented raw and roasted walnuts induce expression of CAT and GSTT2 genes, growth inhibition, and apoptosis in LT97 colon adenoma cells. AB - Walnuts are rich in bioactive compounds such as polyunsaturated fatty acids, polyphenols, and dietary fiber. Therefore, the consumption of walnuts can contribute to a healthy diet and may reduce the risk for colon cancer. Heat treatment like roasting may change the chemical composition of walnuts and therefore their chemopreventive properties. Therefore, the hypothesis of the present study is that different roasting conditions (RCs) alter the chemopreventive effects of walnuts. Thus, the aim of the present study was to investigate whether different RCs (RC1=139.7 degrees C/25 min, RC2=154.5 degrees C/20 min, and RC3=185.5 degrees C/25 min) alter the chemopreventive effects of walnuts. Raw and roasted walnuts were subjected to in vitro digestion and fermentation. After treatment of LT97 colon adenoma cells with fermentation supernatants (FSs), expression of CAT, SOD2, GPx1, GSTP1, and GSTT2 genes as well as cell growth and apoptosis was examined. In comparison to the fermentation blank control, walnut FS particularly increased mRNA levels of CAT 1.7-fold and GSTT2 3.1-fold, whereas GPx1 levels were significantly decreased 0.6-fold. Walnut FS decreased growth of adenoma cells in a time- and dose-dependent manner. In particular, higher concentrations of walnut FS (5%) significantly increased the number of early apoptotic cells 2.0-fold and induced caspase-3 activity 6.8-fold compared with the blank control. The roasting process had no direct impact on the observed effects. In sum, our results indicate that walnuts exhibit chemopreventive effects regarding the risk for colon cancer development by inducing expression of genes involved in detoxification (CAT, GSTT2) and by inducing growth inhibition and apoptosis in colon adenoma cells unaffected by moderate roasting. PMID- 29241581 TI - Iron-induced chelation alleviates the potential allergenicity of ovotransferrin in a BALB/c mouse model. AB - Ovotransferrin (OVT) is one of the main egg allergens with 2 iron-binding sites. Several studies have demonstrated that iron-chelation decreased the allergenicity of milk allergen and birch pollen allergens. Therefore, we hypothesized that iron chelation could also reduce the allergenicity of OVT. Apo-OVT (iron-free OVT, the natural state in egg white) and Holo-OVT (iron-chelated OVT) were prepared, and the allergenicity of them were assessed and compared using a BALB/c mouse model as well as dendritic cells (DCs) based on antigen uptake. Mice were orally sensitized with Apo-OVT or Holo-OVT using cholera toxin as adjuvant. Clinical signs of allergy, morphological structure of jejunum, specific antibody levels, mast cell protease-1 (mMCP-1) concentrations, cytokines and antigen uptake by DCs were determined after the mice were challenged with Apo-OVT or Holo-OVT. Results showed that both Apo-OVT and Holo-OVT induced intestinal allergy, but no systematic allergic symbols were observed. Serum levels of mouse mast cell protease-1 (mMCP-1) and specific IgE in Apo-OVT group were lower than in control group, and no significant difference between Apo-OVT group and Holo-OVT group (P>.05). The levels of OVT-specific IgG and IgG1, as well as the Th-1 cytokine interferon gamma and Th2-type cytokine interleukin-13 in Holo-OVT sensitized mice were significantly decreased compared to Apo-OVT group (P<.05), while no significant difference with control group (P>.05). However, DCs took in less Apo OVT than Holo-OVT. Overall, iron-induced chelation could alleviate the potential allergenicity of OVT in vivo. PMID- 29241582 TI - Whey protein supplementation 2 hours after a lower protein breakfast restores plasma essential amino acid availability comparable to a higher protein breakfast in overweight adults. AB - Amino acids from meals peak in the plasma at ~180 minutes postprandial. Conversely, amino acids from rapidly digestible whey protein appear in the plasma within 15 minutes and peak at 60 minutes postprandial. Therefore, we hypothesized that consuming a 20-g whey protein snack 2 hours after a standard mixed macronutrient, lower protein breakfast (10 g) would result in peak and composite postprandial plasma essential amino acid (EAA) responses that were not different from consuming a 30-g protein breakfast alone. Using a randomized, crossover design, 12 subjects (6 men, 6 women; age: 29 +/- 1 y; BMI: 26.0 +/- 1.0 kg/m2; mean +/- SE) completed three 330-minute trials in which they consumed breakfasts containing (i) 10 g of protein (10-PRO, control), (ii) 30 g of protein (30-PRO), and (iii) 10 g of protein followed by 20 g of whey protein isolate 120 minutes later (10/20-PRO). For both 30-PRO and 10/20-PRO, EAA peaked 180 minutes after breakfast, with greater peak concentrations for 10/20-PRO than 30-PRO (Tukey adjusted, P < .0001). Essential amino acid positive incremental areas under the curve (iAUCpos) over 300 minutes were not different between 30-PRO and 10/20-PRO. Consuming a rapidly digested whey protein snack 2 hours after a slowly digested, lower protein breakfast resulted in a greater peak plasma EAA concentration but comparable plasma EAA availability than consuming a single higher protein breakfast. PMID- 29241583 TI - Surviving Naegleria fowleri infections: Response. PMID- 29241585 TI - Detection of Velocity and Diffusion Coefficient Change Points in Single-Particle Trajectories. AB - The position-time trajectory of a biological subject moving in a complex environment contains rich information about how it interacts with the local setting. Whether the subject be an animal or an intracellular endosomal vesicle, the two primary modes of biological locomotion are directional movement and random walk, respectively characterized by velocity and diffusion coefficient. This contribution introduces a method to quantitatively divide a single-particle trajectory into segments that exhibit changes in the diffusion coefficient, velocity, or both. With the determination of these two physical parameters given by the maximum likelihood estimators, the relative precisions are given as explicit functions of the number of data points and total trajectory time. The method is based on rigorous statistical tests and does not require any presumed kinetics scheme. Results of extensive characterizations, extensions to 2D and 3D trajectories, and applications to common scenarios are also discussed. PMID- 29241584 TI - A Schizophrenia-Linked KALRN Coding Variant Alters Neuron Morphology, Protein Function, and Transcript Stability. AB - BACKGROUND: Large-scale genetic studies have revealed that rare sequence variants, including single nucleotide variants (SNVs), in glutamatergic synaptic genes are enriched in schizophrenia patients. However, the majority are too rare to show any association with disease and have not been examined functionally. One such SNV, KALRN-P2255T, displays a penetrance that greatly exceeds that of previously identified schizophrenia-associated SNVs. Therefore, we sought to characterize its effects on the function of kalirin (Kal)-9, a dual Ras-related C3 botulinum toxin substrate 1 and Ras homologue gene family, member A (RhoA) guanine nucleotide exchange factor, upregulated in human schizophrenia brain tissue. METHODS: Kal9 was overexpressed in primary rat cortical neurons or human embryonic kidney 293 (HEK293) cells. The effects of the P2255T variant on dendritic branching, dendritic spine morphology, protein and messenger RNA stability, and catalytic activity were examined. RESULTS: Kal9-P2255T leads to diminished basal dendritic branching and dendritic spine size, compared with wild type Kal9. The P2255T SNV directly affected Kal9 protein function, causing increased RhoA activation in HEK293 cells, but had no effect on Ras-related C3 botulinum toxin substrate 1 activation. Consistent with human postmortem findings, we found that Kal9-P2255T protein levels were higher than those of wild type Kal9 in neurons. Increased messenger RNA stability was detected in HEK293 cells, indicating that this was the cause of the higher protein levels. When analyzed together, increased intrinsic RhoA guanine nucleotide exchange factor catalytic activity combined with increased messenger RNA expression led to net enhancement of RhoA activation, known to negatively impact neuronal morphology. CONCLUSIONS: Taken together, our data reveal a novel mechanism for disease associated SNVs and provide a platform for modeling morphological changes in mental disorders. PMID- 29241586 TI - Influence of membrane cholesterol on monocyte chemotaxis. AB - Cholesterol content influences several important physiological functions due to its effect on membrane receptors. In this work, we tested the hypothesis that cellular cholesterol alters chemotactic response of monocytes to Monocyte Chemoattractant Protein-1 (MCP-1) due to their effect on the receptor, CCR2. We used Methyl-beta-cyclodextrin (MbetaCD) to alter the baseline cholesterol in human monocytic cell line THP-1, and evaluated their chemotactic response to MCP 1. Compared to untreated cells, cholesterol enrichment increased the number of monocytes transmigrated in response to MCP-1 while depletion had opposite effect. Using imaging flow cytometry, we established that these differences were due to alterations in expression levels, but not the surface distribution, of CCR2. PMID- 29241588 TI - Reanalyzing neurocognitive data on the role of the motor system in speech perception within COSMO, a Bayesian perceptuo-motor model of speech communication. AB - While neurocognitive data provide clear evidence for the involvement of the motor system in speech perception, its precise role and the way motor information is involved in perceptual decision remain unclear. In this paper, we discuss some recent experimental results in light of COSMO, a Bayesian perceptuo-motor model of speech communication. COSMO enables us to model both speech perception and speech production with probability distributions relating phonological units with sensory and motor variables. Speech perception is conceived as a sensory-motor architecture combining an auditory and a motor decoder thanks to a Bayesian fusion process. We propose the sketch of a neuroanatomical architecture for COSMO, and we capitalize on properties of the auditory vs. motor decoders to address three neurocognitive studies of the literature. Altogether, this computational study reinforces functional arguments supporting the role of a motor decoding branch in the speech perception process. PMID- 29241587 TI - Associations between infant fungal and bacterial dysbiosis and childhood atopic wheeze in a nonindustrialized setting. AB - BACKGROUND: Asthma is the most prevalent chronic disease of childhood. Recently, we identified a critical window early in the life of both mice and Canadian infants during which gut microbial changes (dysbiosis) affect asthma development. Given geographic differences in human gut microbiota worldwide, we studied the effects of gut microbial dysbiosis on atopic wheeze in a population living in a distinct developing world environment. OBJECTIVE: We sought to determine whether microbial alterations in early infancy are associated with the development of atopic wheeze in a nonindustrialized setting. METHODS: We conducted a case control study nested within a birth cohort from rural Ecuador in which we identified 27 children with atopic wheeze and 70 healthy control subjects at 5 years of age. We analyzed bacterial and eukaryotic gut microbiota in stool samples collected at 3 months of age using 16S and 18S sequencing. Bacterial metagenomes were predicted from 16S rRNA data by using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States and categorized by function with Kyoto Encyclopedia of Genes and Genomes ontology. Concentrations of fecal short-chain fatty acids were determined by using gas chromatography. RESULTS: As previously observed in Canadian infants, microbial dysbiosis at 3 months of age was associated with later development of atopic wheeze. However, the dysbiosis in Ecuadorian babies involved different bacterial taxa, was more pronounced, and also involved several fungal taxa. Predicted metagenomic analysis emphasized significant dysbiosis-associated differences in genes involved in carbohydrate and taurine metabolism. Levels of the fecal short-chain fatty acids acetate and caproate were reduced and increased, respectively, in the 3-month stool samples of children who went on to have atopic wheeze. CONCLUSIONS: Our findings support the importance of fungal and bacterial microbiota during the first 100 days of life on the development of atopic wheeze and provide additional support for considering modulation of the gut microbiome as a primary asthma prevention strategy. PMID- 29241589 TI - Corrigendum to "Acknowledging attributes that enable the career academic nurse to thrive in the tertiary education sector: A qualitative systematic review" [Nurse Educ. Today 45, October 2016, 212-218]. PMID- 29241590 TI - Corrigendum to "Structural stigma and all-cause mortality in sexual minority populations" [Soc. Sci. Med. 103 (2014) 33-41]. PMID- 29241592 TI - Lancaster's Technique of Cataract Extraction. PMID- 29241593 TI - Rapid differential diagnosis of diabetes insipidus in a 7-month-old infant: The copeptin approach. AB - INTRODUCTION: Diabetes insipidus is characterized by hypoosmotic polyuria related to deficiency of arginine-vasopressin (AVP) secretion (central diabetes insipidus, CDI) or renal insensitivity to AVP (nephrogenic diabetes insipidus, NDI). The water deprivation test with assessment of AVP activity is currently the gold standard for differential diagnosis in patients presenting polyuria polydipsia syndrome. Nevertheless, it can be dangerous without proper surveillance and its interpretation may be challenging. Other markers have been suggested. Direct quantification of circulating AVP is not sufficient for diagnosis: vasopressin is unstable, analysis is complex. AVP comes from prohormone preprovasopressin with concomitant release of copeptin (C-terminal moiety) in the equimolar ratio. Copeptin is stable in vitro, with easy and rapid measurement (<4h). Past studies have shown greater sensitivity and specificity of copeptin versus AVP to discriminate etiologies of polyuria in adults, but its value has not been demonstrated in infants yet. OBSERVATION: A 7-month-old infant presented polyuria-polydipsia syndrome with poor weight gain. Laboratory tests pointed out hypernatremia (170mmol/L) and blood hyperosmolarity (330mOsm/L) with inappropriate urinary hypoosmolarity (168mOsm/L). Plasmatic copeptin measurement was found at a very high level, 303pmol/L (1-14pmol/L). DdAVP administration did not improve the polyuria, confirming the final diagnosis of NDI. Hyperhydration with a hypoosmolar diet normalized the hydration status and circulating levels of copeptin within 1 week. CONCLUSION: Copeptin, a stable peptide reflecting AVP secretion, could be a safer and faster biomarker for etiological diagnosis of polyuria-polydipsia syndrome in children. Before regularization of hydration status, a single baseline measurement may be enough to discriminate NDI from other etiologies without the water deprivation test. PMID- 29241591 TI - Preliminary Report on Effects of Photocoagulation Therapy. PMID- 29241595 TI - Re 'Provision of information to consumers about the calorie content of alcoholic drinks: did the responsibility deal pledge by alcohol retailers and producers increase the availability of calorie information?' PMID- 29241594 TI - Comparison of the effect of allopurinol and febuxostat on urinary 2,8 dihydroxyadenine excretion in patients with Adenine phosphoribosyltransferase deficiency (APRTd): A clinical trial. AB - INTRODUCTION: Adenine phosphoribosyltransferase (APRT) deficiency is a rare, but significant, cause of kidney stones and progressive chronic kidney disease. The optimal treatment has not been established. The purpose of this pilot study was to compare the effect of the xanthine oxidoreductase inhibitors allopurinol and febuxostat on urinary 2,8-dihydroxyadenine (DHA) excretion in APRT deficiency patients. MATERIALS AND METHODS: Patients listed in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, currently receiving allopurinol therapy, were invited to participate. The trial endpoint was the 24-h urinary DHA excretion following treatment with allopurinol (400mg/day) and febuxostat (80mg/day). Urinary DHA was measured using a novel ultra-performance liquid chromatography - electrospray tandem mass spectrometry assay. RESULTS: Eight of the 10 patients invited completed the study. The median (range) 24-h urinary DHA excretion was 116 (75-289) mg at baseline, and 45 (13-112) mg after 14days of allopurinol therapy (P=0.036). At the end of the febuxostat treatment period, 4 patients had urinary DHA below detectable limits (<20ng/mL) compared with none of the participants following allopurinol treatment (P=0.036). The other 4 participants had a median 24-h urinary DHA excretion of 13.2 (10.0-13.4) mg at the completion of febuxostat therapy (P=0.036). CONCLUSION: Urinary DHA excretion in APRT deficiency patients decreased with conventional doses of both allopurinol and febuxostat. Febuxostat was, however, significantly more efficacious than allopurinol in reducing DHA excretion in the prescribed doses. This finding, which may translate into improved outcomes of patients with APRT deficiency, should be confirmed in a larger sample. PMID- 29241596 TI - Essentials of Statistical Methods for Assessing Reliability and Agreement in Quantitative Imaging. AB - Quantitative imaging is increasing in almost all fields of radiological science. Modern quantitative imaging biomarkers measure complex parameters including metabolism, tissue microenvironment, tissue chemical properties or physical properties. In this paper, we focus on measurement reliability assessment in quantitative imaging. We review essential concepts related to measurement such as measurement variability and measurement error. We also discuss reliability study methods for intraobserver and interobserver variability, and the applicable statistical tests including: intraclass correlation coefficient, Pearson correlation coefficient, and Bland-Altman graphs and limits of agreement, standard error of measurement, and coefficient of variation. PMID- 29241598 TI - Organ donation after controlled cardiac death under Maastricht category iii: Ethical implications and end of life care. AB - The decrease in potential donation after brain death has resulted in a need to evaluate alternative sources. Donation after cardiac death is a good option. The objectives of this article are to describe the Maastricht type iii controlled organ donation characteristics and to determine end-of-life care and the role of nurses in the donation process. In this type of donation, cardiocirculatory arrest is predictable after the limitation of life sustaining treatments. These are patients for whom there are no effective therapy options and, in the context of an organised and planned practice involving all the professionals involved in the care of the patient, the decision is made, in consultation with the family, to withdraw life support measures. This limitation of life sustaining treatments is never carried out with the aim of making a Maastricht iii donation, but to avoid prolonging the dying process through useless and possibly degrading interventions. The obligation of the health team is to provide a dignified death and this not only includes the absence of pain, but the patient and their family must be guaranteed a feeling of calmness and serenity. Once the decision has been taken to withhold or withdraw measures, the nurse has an important role in the implementation of a palliative care plan in where physicians, nurses and patients/families should be involved and whose focus should be on patients' dignity and comfort, considering their physical, psychological and spiritual needs. PMID- 29241597 TI - Understanding Patient Preference in Female Pelvic Imaging: Transvaginal Ultrasound and MRI. AB - RATIONALE AND OBJECTIVES: Women with pelvic pain or abnormal uterine bleeding may undergo diagnostic imaging. This study evaluates patient experience in transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI) and explores correlations between preference and symptom severity. MATERIALS AND METHODS: Institutional review board approval was obtained for this Health Insurance Portability and Accountability Act-compliant prospective study. Fifty premenopausal women with pelvic symptoms evaluated by recent TVUS and MRI and without history of gynecologic cancer or hysterectomy were included. A phone questionnaire used validated survey instruments including Uterine Fibroid Symptoms Quality of Life index, Testing Morbidities Index, and Wait Trade Off for TVUS and MRI examinations. RESULTS: Using Wait Trade Off, patients preferred TVUS over MRI (3.58 vs 2.80 weeks, 95% confidence interval [CI] -1.63, 0.12; P = .08). Summary test utility of Testing Morbidities Index for MRI was worse than for TVUS (81.64 vs 87.42, 95%CI 0.41, 11.15; P = .03). Patients reported greater embarrassment during TVUS than during MRI (P <.0001), but greater fear and anxiety both before (P <.0001) and during (P <.001) MRI, and greater mental (P = .02) and physical (P = .02) problems after MRI versus TVUS. Subscale correlations showed physically inactive women rated TVUS more negatively (R = -0.32, P = .03), whereas women with more severe symptoms of loss of control of health (R = -0.28, P = .04) and sexual dysfunction (R = -0.30, P = .03) rated MRI more negatively. CONCLUSION: Women with pelvic symptoms had a slight but significant preference for TVUS over MRI. Identifying specific distressing aspects of each test and patient factors contributing to negative perceptions can direct improvement in both test environment and patient preparation. Improved patient experience may increase imaging value. PMID- 29241599 TI - Participation of clinical nurses in the practical education of undergraduate nursing students. AB - OBJECTIVE: To evaluate the level of participation of clinical nurses from Castellon where Universitat JaumeI nursing students do their clinical clerkship. To identify the variables that may influence clinical nurses' participation in students' clinical mentorship. METHOD: This observational, cross-sectional and descriptive study was conducted by applying the validated Involvement, Motivation, Satisfaction, Obstacles and Commitment (IMSOC) questionnaire. The variables collected were: age, work environment and previous training. The study was conducted between January and December 2014. RESULTS: The sample included 117 nurses. The overall mean questionnaire score was 122.838 (standard deviation: +/ 18.692; interquartile range 95%: 119.415-126.26). The variable "previous training for mentorship students" was statistically significant in the overall score and for all dimensions (P<.05). Primary care nurses obtained better scores in the dimension Implication than professionals working at other care levels. CONCLUSIONS: The level of participation of the clinical nurses from Castellon is adequate. The previous training that professionals receive for mentoring students improves both their level of participation and primary care level. Extending this research to other national and international environments is recommended. PMID- 29241600 TI - Adding clarity to the universal health coverage picture. PMID- 29241601 TI - Universal health care in Bangladesh-promises and perils. PMID- 29241603 TI - A need for overhaul of policy on contraception and abortion in India. PMID- 29241602 TI - The incidence of abortion and unintended pregnancy in India, 2015. AB - BACKGROUND: Reliable information on the incidence of induced abortion in India is lacking. Official statistics and national surveys provide incomplete coverage. Since the early 2000s, medication abortion has become increasingly available, improving the way women obtain abortions. The aim of this study was to estimate the national incidence of abortion and unintended pregnancy for 2015. METHODS: National abortion incidence was estimated through three separate components: abortions (medication and surgical) in facilities (including private sector, public sector, and non-governmental organisations [NGOs]); medication abortions outside facilities; and abortions outside of facilities and with methods other than medication abortion. Facility-based abortions were estimated from the 2015 Health Facilities Survey of 4001 public and private health facilities in six Indian states (Assam, Bihar, Gujarat, Madhya Pradesh, Tamil Nadu, and Uttar Pradesh) and from NGO clinic data. National medication abortion drug sales and distribution data were obtained from IMS Health and six principal NGOs (DKT International, Marie Stopes International, Population Services International, World Health Partners, Parivar Seva Santha, and Janani). We estimated the total number of abortions that are not medication abortions and are not obtained in a health facility setting through an indirect technique based on findings from community-based study findings in two states in 2009, with adjustments to account for the rapid increase in use of medication abortion since 2009. The total number of women of reproductive age and livebirth data were obtained from UN population data, and the proportion of births from unplanned pregnancies and data on contraceptive use and need were obtained from the 2015-16 National Family Health Survey-4. FINDINGS: We estimate that 15.6 million abortions (14.1 million-17.3 million) occurred in India in 2015. The abortion rate was 47.0 abortions (42.2 52.1) per 1000 women aged 15-49 years. 3.4 million abortions (22%) were obtained in health facilities, 11.5 million (73%) abortions were medication abortions done outside of health facilities, and 0.8 million (5%) abortions were done outside of health facilities using methods other than medication abortion. Overall, 12.7 million (81%) abortions were medication abortions, 2.2 million (14%) abortions were surgical, and 0.8 million (5%) abortions were done through other methods that were probably unsafe. We estimated 48.1 million pregnancies, a rate of 144.7 pregnancies per 1000 women aged 15-49 years, and a rate of 70.1 unintended pregnancies per 1000 women aged 15-49 years. Abortions accounted for one third of all pregnancies, and nearly half of pregnancies were unintended. INTERPRETATION: Health facilities can have a greater role in abortion service provision and provide quality care, including post-abortion contraception. Interventions are needed to expand access to abortion services through better equipping existing facilities, ensuring adequate and continuous supplies of medication abortion drugs, and by increasing the number of trained providers. In view of how many women rely on self-administration of medication abortion drugs, interventions are needed to provide women with accurate information on these drugs and follow-up care when needed. Research is needed to test interventions that improve knowledge and practice in providing medication abortion, and the Indian Government at the national and state level needs to prioritise improving policies and practice to increase access to comprehensive abortion care and quality contraceptive services that prevent unintended pregnancy. FUNDING: Government of UK Department for International Development (until 2015), the David and Lucile Packard Foundation, the John D. and Catherine T. MacArthur Foundation, and the Ford Foundation. PMID- 29241604 TI - Informality and health: universal health coverage in the era of SDGs. PMID- 29241605 TI - Investigating the sexual transmission of Zika virus. PMID- 29241606 TI - Revisiting strategies to eliminate mother-to-child transmission of syphilis. PMID- 29241607 TI - Measuring women's empowerment: a need for context and caution. PMID- 29241608 TI - Measuring women's empowerment: a need for context and caution. PMID- 29241609 TI - Measuring women's empowerment: a need for context and caution - Authors' reply. PMID- 29241610 TI - Epidemiological data for hepatitis D in Africa. PMID- 29241611 TI - Epidemiological data for hepatitis D in Africa. PMID- 29241612 TI - Epidemiological data for hepatitis D in Africa - Authors' reply. PMID- 29241613 TI - Early antenatal care visit as indicator for health equity monitoring. PMID- 29241614 TI - Improving quality of antenatal care through provision of medical supply kits. PMID- 29241616 TI - Community health workers for blood pressure control in Nepal. PMID- 29241615 TI - Provision of medical supply kits to improve quality of antenatal care in Mozambique: a stepped-wedge cluster randomised trial. AB - BACKGROUND: High levels of maternal and newborn mortality and morbidity remain a daunting reality in many low-income countries. Several interventions delivered during antenatal care have been shown to improve maternal and newborn outcomes, but stockouts of medical supplies at point of care can prevent implementation of these services. We aimed to evaluate whether a supply chain strategy based on the provision of kits could improve quality of care. METHODS: We did a pragmatic, stepped-wedge, cluster-randomised controlled trial at ten antenatal care clinics in Mozambique. Clinics were eligible if they were not already implementing the proposed antenatal care package; they served at least 200 new pregnant women per year; they had Maternal and Child Health (MCH) nurses; and they were willing to participate. All women attending antenatal care visits at the participating clinics were included in the trial. Participating clinics were randomly assigned to shift from control to intervention on prespecified start dates. The intervention involved four components (kits with medical supplies, a cupboard to store these supplies, a tracking sheet to monitor stocks, and a one-day training session). The primary outcomes were the proportion of women screened for anaemia and proteinuria, and the proportion of women who received mebendazole in the first antenatal care visit. The intervention was delivered under routine care conditions, and analyses were done according to the intention-to-treat principle. This trial is registered with the Pan African Clinical Trial Registry, number PACTR201306000550192. FINDINGS: Between March, 2014, and January, 2016, 218 277 antenatal care visits were registered, with 68 598 first and 149 679 follow-up visits. We found significant improvements in all three primary outcomes. In first visits, 5519 (14.6%) of 37 826 women were screened for anaemia in the control period, compared with 30 057 (97.7%) of 30 772 in the intervention period (adjusted odds ratio 832.40; 99% CI 666.81-1039.11; p<0.0001); 3739 (9.9%) of 37 826 women were screened for proteinuria in the control period, compared with 29 874 (97.1%) of 30 772 in the intervention period (1875.18; 1447.56-2429.11; p<0.0001); and 17 926 (51.4%) of 34 842 received mebendazole in the control period, compared with 24 960 (88.2%) of 28 294 in the intervention period (1.88; 1.70-2.09; p<0.0001). The effect was immediate and sustained over time, with negligible heterogeneity between sites. INTERPRETATION: A supply chain strategy that resolves stockouts at point of care can result in a vast improvement in quality during antenatal care visits, when compared with the routine national process for procurement and distribution of supplies. FUNDING: Government of Flanders and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction. PMID- 29241617 TI - Effectiveness of a lifestyle intervention led by female community health volunteers versus usual care in blood pressure reduction (COBIN): an open-label, cluster-randomised trial. AB - INTRODUCTION: Elevated blood pressure greatly contributes to cardiovascular deaths in low-income and middle-income countries. We aimed to investigate the effectiveness of a population-level intervention led by existing community health workers in reducing the burden of hypertension in a low-income population. METHODS: We did a community-based, open-label, two-group, cluster-randomised controlled trial in Nepal. Using computer-generated codes, we randomly assigned (1:1) 14 clusters to a lifestyle intervention led by female community health volunteers (FCHVs) or usual care (control group). In the intervention group, 43 FCHVs provided home visits every 4 months for lifestyle counselling and blood pressure monitoring. Eligible participants had been involved in a previous population-based survey, were aged 25-65 years, did not have plans to migrate outside the study area, and were not severely ill or pregnant. The primary outcome was mean systolic blood pressure at 1 year. We included all participants who remained in the trial at 1 year in the primary analysis. This trial is registered with ClinicalTrials.gov, number NCT02428075. FINDINGS: Between April 1, 2015, and Dec 31, 2015, we recruited 1638 participants (939 assigned to intervention; 699 assigned to control). At 1 year, 855 participants remained in the intervention group (425 were normotensive, 175 were prehypertensive, and 255 had hypertension) and 613 remained in the control group (305 were normotensive, 128 were prehypertensive, and 180 had hypertension). The mean systolic blood pressure at 1 year was significantly lower in the intervention group than in the control group for all cohorts: the difference was -2.28 mm Hg (95% CI -3.77 to 0.79, p=0.003) for participants who were normotensive, -3.08 mm Hg (-5.58 to 0.59, p=0.015) for participants who were prehypertensive, and -4.90 mm Hg (-7.78 to -2.00, p=0.001) for participants who were hypertensive. INTERPRETATION: A simple, FCHV-led lifestyle intervention coupled with monitoring of blood pressure is effective for reduction of blood pressure in individuals with hypertension and ameliorates age-related increases in blood pressure in adults without hypertension in the general population of Nepal. FUNDING: Aarhus University, Jayanti Memorial Trust. PMID- 29241619 TI - Problems with the WHO guidelines for management of childhood pneumonia. PMID- 29241618 TI - Appropriateness of clinical severity classification of new WHO childhood pneumonia guidance: a multi-hospital, retrospective, cohort study. AB - BACKGROUND: Management of pneumonia in many low-income and middle-income countries is based on WHO guidelines that classify children according to clinical signs that define thresholds of risk. We aimed to establish whether some children categorised as eligible for outpatient treatment might have a risk of death warranting their treatment in hospital. METHODS: We did a retrospective cohort study of children aged 2-59 months admitted to one of 14 hospitals in Kenya with pneumonia between March 1, 2014, and Feb 29, 2016, before revised WHO pneumonia guidelines were adopted in the country. We modelled associations with inpatient mortality using logistic regression and calculated absolute risks of mortality for presenting clinical features among children who would, as part of revised WHO pneumonia guidelines, be eligible for outpatient treatment (non-severe pneumonia). FINDINGS: We assessed 16 162 children who were admitted to hospital in this period. 832 (5%) of 16 031 children died. Among groups defined according to new WHO guidelines, 321 (3%) of 11 788 patients with non-severe pneumonia died compared with 488 (14%) of 3434 patients with severe pneumonia. Three characteristics were strongly associated with death of children retrospectively classified as having non-severe pneumonia: severe pallor (adjusted risk ratio 5.9, 95% CI 5.1-6.8), mild to moderate pallor (3.4, 3.0-3.8), and weight-for-age Z score (WAZ) less than -3 SD (3.8, 3.4-4.3). Additional factors that were independently associated with death were: WAZ less than -2 to -3 SD, age younger than 12 months, lower chest wall indrawing, respiratory rate of 70 breaths per min or more, female sex, admission to hospital in a malaria endemic region, moderate dehydration, and an axillary temperature of 39 degrees C or more. INTERPRETATION: In settings of high mortality, WAZ less than -3 SD or any degree of pallor among children with non-severe pneumonia was associated with a clinically important risk of death. Our data suggest that admission to hospital should not be denied to children with these signs and we urge clinicians to consider these risk factors in addition to WHO criteria in their decision making. FUNDING: Wellcome Trust. PMID- 29241620 TI - Trends in, and projections of, indicators of universal health coverage in Bangladesh, 1995-2030: a Bayesian analysis of population-based household data. AB - BACKGROUND: Many countries are implementing health system reforms to achieve universal health coverage (UHC) by 2030. To understand the progress towards UHC in Bangladesh, we estimated trends in indicators of the health service and of financial risk protection. We also estimated the probability of Bangladesh's achieving of UHC targets of 80% essential health-service coverage and 100% financial risk protection by 2030. METHODS: We estimated the coverage of UHC indicators-13 prevention indicators and four treatment indicators-from 19 nationally representative population-based household surveys done in Bangladesh from Jan 1, 1991, to Dec 31, 2014. We used a Bayesian regression model to estimate the trend and to predict the coverage of UHC indicators along with the probabilities of achieving UHC targets of 80% coverage of health services and 100% coverage of financial risk protection from catastrophic and impoverishing health payments by 2030. We used the concentration index and relative index of inequality to assess wealth-based inequality in UHC indicators. FINDINGS: If the current trends remain unchanged, we estimated that coverage of childhood vaccinations, improved water, oral rehydration treatment, satisfaction with family planning, and non-use of tobacco will achieve the 80% target by 2030. However, coverage of four antenatal care visits, facility-based delivery, skilled birth attendance, postnatal checkups, care seeking for pneumonia, exclusive breastfeeding, non-overweight, and adequate sanitation were not projected to achieve the target. Quintile-specific projections showed wide wealth-based inequality in access to antenatal care, postnatal care, delivery care, adequate sanitation, and care seeking for pneumonia, and this inequality was projected to continue for all indicators. The incidence of catastrophic health expenditure and impoverishment were projected to increase from 17% and 4%, respectively, in 2015, to 20% and 9%, respectively, by 2030. Inequality analysis suggested that wealthiest households would disproportionately face more financial catastrophe than the most disadvantaged households. INTERPRETATION: Despite progress, Bangladesh will not achieve the 2030 UHC targets unless the country scales up interventions related to maternal and child health services, and reforms health financing systems to avoid high dependency on out-of-pocket payments. The introduction of a national health insurance system, increased public funding for health care, and expansion of community-based clinics in rural areas could help to move the country towards UHC. FUNDING: Japan Ministry of Health, Labour, and Welfare. PMID- 29241621 TI - Confocal super-resolution imaging of the glomerular filtration barrier enabled by tissue expansion. AB - The glomerular filtration barrier, has historically only been spatially resolved using electron microscopy due to the nanometer-scale dimensions of these structures. Recently, it was shown that the nanoscale distribution of proteins in the slit diaphragm can be resolved by fluorescence based stimulated emission depletion microscopy, in combination with optical clearing. Fluorescence microscopy has advantages over electron microscopy in terms of multiplex imaging of different epitopes, and also the amount of volumetric data that can be extracted from thicker samples. However, stimulated emission depletion microscopy is still a costly technique commonly not available to most life science researchers. An imaging technique with which the glomerular filtration barrier can be visualized using more standard fluorescence imaging techniques is thus desirable. Recent studies have shown that biological tissue samples can be isotropically expanded, revealing nanoscale localizations of multiple epitopes using confocal microscopy. Here we show that kidney samples can be expanded sufficiently to study the finest elements of the filtration barrier using confocal microscopy. Thus, our result opens up the possibility to study protein distributions and foot process morphology on the effective nanometer-scale. PMID- 29241622 TI - Higher blood urea nitrogen is associated with increased risk of incident diabetes mellitus. AB - Experimental evidence suggests that higher levels of urea may increase insulin resistance and suppress insulin secretion. However, whether higher levels of blood urea nitrogen (BUN) are associated with increased risk of incident diabetes mellitus in humans is not known. To study this, we built a national cohort of 1,337,452 United States Veterans without diabetes to characterize the association of BUN and risk of incident diabetes. Over a median follow-up of 4.93 years, there were 172,913 cases of incident diabetes. In joint risk models of estimated glomerular filtration rate (eGFR) and BUN. there was no association between eGFR and the risk of incident diabetes in those with a BUN of 25 mg/dl or less. However, the risk was significantly increased in those with a BUN over 25 mg/dl at all eGFR levels, even in those with an eGFR of 60 ml/min/1.73m2 or more (hazard ratio 1.27; confidence interval 1.24-1.31). The risk of incident diabetes was highest in those with BUN over 25 mg/dL and an eGFR under 15 ml/min/1.73m2 (1.68; 1.51-1.87). Spline analyses of the relationship between BUN and risk of incident diabetes showed that risk was progressively higher as BUN increased. In models where eGFR was included as a continuous covariate, compared to a BUN of 25 mg/dl or less, a BUN over 25 mg/dl was associated with increased risk of incident diabetes (1.23; 1.21-1.25). Every 10 ml/min/1.73m2 decrease in eGFR was not associated with risk of incident diabetes (1.00; 1.00-1.01). Two-stage residual inclusion analyses showed that, independent of the impact of eGFR, every 10 mg/dL increase in BUN concentration was associated with increased risk of incident diabetes (1.15; 1.14-1.16). Thus, higher levels of BUN are associated with increased risk of incident diabetes mellitus. PMID- 29241623 TI - Knockout of the interleukin-36 receptor protects against renal ischemia reperfusion injury by reduction of proinflammatory cytokines. AB - IL-36, a newly named member of the IL-1 cytokine family, includes 3 isoforms, IL 36alpha, IL-36beta, and IL-36gamma, all of which bind to a heterodimer containing the IL-36 receptor (IL-36R). Little is known about the role of the IL-36 axis in acute kidney injury (AKI) pathogenesis. Therefore, we evaluated IL-36 function in the bilateral renal ischemia-reperfusion injury model of AKI using IL-36R knockout and wild-type mice. IL-36R was found to be expressed in the kidney, mainly in proximal tubules. In IL-36R knockout mice, plasma creatinine, blood urea nitrogen, and IL-6 levels after ischemia-reperfusion injury were significantly lower than those in wild-type mice. Immunohistological analysis revealed mild tubular injury. IL-36alpha/beta/gamma levels were increased after ischemia-reperfusion injury, and IL-36alpha was expressed in lymphocytes and proximal tubular cells, but post-ischemia-reperfusion injury mRNA levels of IL-6 and TNF-alpha were low in IL-36R knockout mice. In primary cultures of renal tubular epithelial cells, IL-36alpha treatment upregulated NF-kappaB activity and Erk phosphorylation. Notably, in patients with AKI, urine IL-36alpha levels were increased, and IL-36alpha staining in renal biopsy samples was enhanced. Thus, IL 36alpha/IL-36R blockage could serve as a potential therapeutic target in AKI. PMID- 29241624 TI - The macrophage phenotype and inflammasome component NLRP3 contributes to nephrocalcinosis-related chronic kidney disease independent from IL-1-mediated tissue injury. AB - Primary/secondary hyperoxalurias involve nephrocalcinosis-related chronic kidney disease (CKD) leading to end-stage kidney disease. Mechanistically, intrarenal calcium oxalate crystal deposition is thought to elicit inflammation, tubular injury and atrophy, involving the NLRP3 inflammasome. Here, we found that mice deficient in NLRP3 and ASC adaptor protein failed to develop nephrocalcinosis, compromising conclusions on nephrocalcinosis-related CKD. In contrast, hyperoxaluric wild-type mice developed profound nephrocalcinosis. NLRP3 inhibition using the beta-hydroxybutyrate precursor 1,3-butanediol protected such mice from nephrocalcinosis-related CKD. Interestingly, the IL-1 inhibitor anakinra had no such effect, suggesting IL-1-independent functions of NLRP3. NLRP3 inhibition using 1,3-butanediol treatment induced a shift of infiltrating renal macrophages from pro-inflammatory (CD45+F4/80+CD11b+CX3CR1+CD206-) and pro fibrotic (CD45+F4/80+CD11b+CX3CR1+CD206+TGFbeta+) to an anti-inflammatory (CD45+F4/80+CD11b+CD206+TGFbeta-) phenotype, and prevented renal fibrosis. Finally, in vitro studies with primary murine fibroblasts confirmed the non redundant role of NLRP3 in the TGF-beta signaling pathway for fibroblast activation and proliferation independent of the NLRP3 inflammasome complex formation. Thus, nephrocalcinosis-related CKD involves NLRP3 but not necessarily via intrarenal IL-1 release but rather via other biological functions including TGFR signaling and macrophage polarization. Hence, NLRP3 may be a promising therapeutic target in hyperoxaluria and nephrocalcinosis. PMID- 29241627 TI - [Faecal microbiota transplant in a child with very early onset inflammatory bowel disease]. PMID- 29241626 TI - C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis. AB - The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C5aR1 in these responses has not been described. Here, we use murine models to dissect the role of C5aR1 in the generation of anti-myeloperoxidase autoimmunity and the effector responses resulting in renal injury. The genetic absence or pharmacological inhibition of C5aR1 results in reduced autoimmunity to myeloperoxidase with an attenuated Th1 response, increased Foxp3+ regulatory T cells and reduction in generation of myeloperoxidase-ANCA. These changes are mediated by C5aR1 on dendritic cells, which promotes activation, and thus myeloperoxidase autoimmunity and glomerulonephritis. We also use renal intravital microscopy to determine the effect of C5aR1 inhibition on ANCA induced neutrophil dysfunction. We found that myeloperoxidase-ANCA induce neutrophil retention and reactive oxygen species burst within glomerular capillaries. These pathological behaviors are abrogated by C5aR1 inhibition. Thus, C5aR1 inhibition ameliorates both autoimmunity and intra-renal neutrophil activation in ANCA-associated vasculitis. PMID- 29241625 TI - Vinculin is required to maintain glomerular barrier integrity. AB - Cell-matrix interactions and podocyte intercellular junctions are key for maintaining the glomerular filtration barrier. Vinculin, a cytoplasmic protein, couples actin filaments to integrin-mediated cell-matrix adhesions and to cadherin-based intercellular junctions. Here, we examined the role of vinculin in podocytes by the generation of a podocyte-specific knockout mouse. Mice lacking podocyte vinculin had increased albuminuria and foot process effacement following injury in vivo. Analysis of primary podocytes isolated from the mutant mice revealed defects in cell protrusions, altered focal adhesion size and signaling, as well as impaired cell migration. Furthermore, we found a marked mislocalization of the intercellular junction protein zonula occludens-1. In kidney sections from patients with focal segmental glomerulosclerosis, minimal change disease and membranous nephropathy, we observed dramatic differences in the expression levels and localization of vinculin. Thus, our results suggest that vinculin is necessary to maintain the integrity of the glomerular filtration barrier by modulating podocyte foot processes and stabilizing intercellular junctions. PMID- 29241628 TI - [Care of the newborn with perinatal asphyxia candidate for therapeutic hypothermia during the first six hours of life in Spain]. AB - INTRODUCTION: The process of care and assistance from birth to the starting of therapeutic hypothermia (TH) is crucial in order to improve its effectiveness and prevent the worsening of hypoxic-ischaemic injury. METHODS: A national cross sectional study carried out in 2015 by use of a questionnaire sent to all level iii units on the care of the newborn>=35 weeks gestation within the first hours of life after a perinatal asphyxia event. According to clinical practice guidelines, the quality of care was compared between the hospitals that carried out or did not carry out TH, and according to the level of care. RESULTS: A total of 89/90 hospitals participated, of which 57/90 performed TH. They all used resuscitation protocols and turned off the radiant warmer after stabilisation. All of them performed glucose and blood gas analysis, monitored the central temperature, put the newborn on a diet, and performed at least two examinations for the diagnosis of hypoxic-ischaemic encephalopathy. Greater than one-third (35%) of hospitals did not have amplitude-integrated electroencephalogram, and 6/57 were TH-hospitals. The quality of care among hospitals with and without TH was similar, childbirth being better in those that performed TH, and those with a higher level of care. Level IIIc hospitals had higher scores than the others. The TH-hospitals mentioned not always having neonatologists with experience in neurological assessment and interpretation of amplitude-integrated electroencephalogram (25%), or in brain ultrasound (62%). CONCLUSIONS: In response to the recommendations of the asphyxiated newborn, there is a proper national health care standard with differences according to the level of care and whether TH is offered. More amplitude-integrated electroencephalogram devices are necessary, as well as more neonatologists trained in the evaluations that will be require by the newborn with hypoxic-ischaemic encephalopathy. PMID- 29241630 TI - [Expert opinion on DRESS and viruses: Answer]. PMID- 29241631 TI - [On the attractiveness of a university-hospital career in medicine: Obstacles and solutions. The teachers' perspective]. PMID- 29241632 TI - Can false memory for critical lures occur without conscious awareness of list words? AB - We examined whether the DRM false memory effect can occur when list words are presented below the perceptual identification threshold. In four experiments, subjects showed robust veridical memory for studied words and false memory for critical lures when masked list words were presented at exposure durations of 43 ms per word. Shortening the exposure duration to 29 ms virtually eliminated veridical recognition of studied words and completely eliminated false recognition of critical lures. Subjective visibility ratings in Experiments 3a and 3b support the assumption that words presented at 29 ms were subliminal for most participants, but were occasionally experienced with partial awareness by participants with higher perceptual awareness. Our results indicate that a false memory effect does not occur in the absence of conscious awareness of list words, but it does occur when word stimuli are presented at an intermediate level of visibility. PMID- 29241629 TI - The expression of Mirc1/Mir17-92 cluster in sputum samples correlates with pulmonary exacerbations in cystic fibrosis patients. AB - INTRODUCTION: Cystic fibrosis (CF) is a multi-organ disorder characterized by chronic sino-pulmonary infections and inflammation. Many patients with CF suffer from repeated pulmonary exacerbations that are predictors of worsened long-term morbidity and mortality. There are no reliable markers that associate with the onset or progression of an exacerbation or pulmonary deterioration. Previously, we found that the Mirc1/Mir17-92a cluster which is comprised of 6 microRNAs (Mirs) is highly expressed in CF mice and negatively regulates autophagy which in turn improves CF transmembrane conductance regulator (CFTR) function. Therefore, here we sought to examine the expression of individual Mirs within the Mirc1/Mir17-92 cluster in human cells and biological fluids and determine their role as biomarkers of pulmonary exacerbations and response to treatment. METHODS: Mirc1/Mir17-92 cluster expression was measured in human CF and non-CF plasma, blood-derived neutrophils, and sputum samples. Values were correlated with pulmonary function, exacerbations and use of CFTR modulators. RESULTS: Mirc1/Mir17-92 cluster expression was not significantly elevated in CF neutrophils nor plasma when compared to the non-CF cohort. Cluster expression in CF sputum was significantly higher than its expression in plasma. Elevated CF sputum Mirc1/Mir17-92 cluster expression positively correlated with pulmonary exacerbations and negatively correlated with lung function. Patients with CF undergoing treatment with the CFTR modulator Ivacaftor/Lumacaftor did not demonstrate significant change in the expression Mirc1/Mir17-92 cluster after six months of treatment. CONCLUSIONS: Mirc1/Mir17-92 cluster expression is a promising biomarker of respiratory status in patients with CF including pulmonary exacerbation. PMID- 29241633 TI - Polyploidy and nuclear phenotype characteristics of cardiomyocytes from diabetic adult and normoglycemic aged mice. AB - The frequency of polyploid nuclei in the aging human heart is in sharp contrast with that in the human liver. An inverse pattern exists between the mouse heart and liver cells. Ploidy degrees in mouse hepatocytes under hyperglycemic conditions are elevated to higher levels than those in aged hepatocytes. In this study, image analysis cytometry was used to investigate the effect of diabetes and aging on Feulgen-DNA quantities, ploidy degrees, nuclear shapes and chromatin texture in mouse cardiomyocytes compared to previously reported data for mouse hepatocytes. Adult, non-obese diabetic (NOD) hyperglycemic and normoglycemic females and 56-week-old normoglycemic BALB/c females were used. A small percentage (~7%) of the cardiomyocyte nuclei in severely hyperglycemic NOD adult mice possessed higher ploidy values than those in the 8-week-old normoglycemic mice. Surprisingly, the Feulgen-DNA values and the frequency of nuclei belonging to the 4C and 8C ploidy classes were even higher (~6%) in normoglycemic NOD specimens than in age-matched hyperglycemic NOD specimens. Additionally, a pronounced elongated nuclear shape was observed especially in adult normoglycemic NOD mice. In conclusion, NOD mice, irrespective of their glycemic level, exhibit a moderate increase in ploidy degrees within cardiomyocyte nuclei during the adult lifetime. As expected, aging did not affect the Feulgen-DNA values and the ploidy degrees of cardiomyocytes in BALB/c mice. The differences in ploidy degrees and chromatin textures such as absorbance variability and entropy, between adult NOD and aged BALB/c mice are consistent with other reports, indicating dissimilarities in chromatin functions between diabetes and aging. PMID- 29241634 TI - Impact of post craniectomy cranioplasty on cerebral perfusion and clinical outcome. PMID- 29241635 TI - Atrial fibrillation: Location, location, location-Does it matter? PMID- 29241637 TI - [Health and determinants of health in second generations of international immigrants: Social inequalities in health since childhood?] AB - OBJECTIVE: To analyse the social inequalities in health between children and youth population of an immigrant origin from low-income countries and those of native origin in the Basque Country. METHOD: Cross-sectional descriptive study using data from the Basque Country Health Survey 2013. Variables of health, behaviours and life conditions were used as the outcome variables. Prevalence ratios were calculated using robust Poisson models. RESULTS: The children with immigrant parents had poorer self-rated health, a higher prevalence of obesity, spent more hours in sedentary activities and lived in households with greater economic difficulties. The differences persisted even after adjusting for social class and educational level of parents. CONCLUSIONS: A migrant background is a highly relevant axis of health inequalities and has an influence beyond a generation. Given this reality, it is necessary to implement effective and suitable measures to ensure life with good health conditions and to reduce social inequalities in health, not only in childhood but through the entire life cycle. PMID- 29241636 TI - Urban-rural differences in mortality for atrial fibrillation hospitalizations in the United States. AB - BACKGROUND: Cardiovascular outcomes vary between urban and rural hospitals, with worse outcomes in rural settings. OBJECTIVE: The purpose of this study was to examine whether in-hospital mortality for hospitalization for atrial fibrillation (AF) varied between urban and rural hospitals. METHODS: A cross-sectional examination of patients who were hospitalized for AF was performed in the National Inpatient Sample between 2012 and 2014 to compare in-hospital mortality in patients admitted to urban vs rural hospitals. Patients with a principal International Classification of Diseases, Ninth Revision discharge diagnosis of AF were included. Hospitals were classified as urban or rural on the basis of core-based statistical areas. In-hospital mortality was defined as death due to any cause during hospitalization. RESULTS: A total of 248,731 (mean age 69 years; 78% white; 48% women) admissions for AF were identified. Of these, 218,946 (88%) were from urban hospitals and 29,785 (12%) were from rural hospitals. Patients admitted to rural hospitals had a 17% increased risk of death as compared with those admitted to urban hospitals in a multivariable model, which accounted for differences in patient characteristics and potential confounders (odds ratio 1.17; 95% confidence interval 1.04-1.32). Similar results were obtained in a propensity score-matched analysis and in subgroup analyses by sex, race, and region. CONCLUSION: In-hospital mortality of AF is higher in rural hospitals than in urban hospitals. Further research is needed to understand this finding and to develop targeted strategies to reduce mortality in patients admitted for AF in rural hospitals. PMID- 29241638 TI - Medical treatment of a female patient with complicated Klippel-Trenaunay syndrome. PMID- 29241639 TI - Facial Cutaneous Larva Migrans Acquired in Spain. PMID- 29241640 TI - Association of anti-cyclic citrullinated protein antibodies, erosions, and rheumatoid factor with disease activity and work productivity: A patient registry study. AB - OBJECTIVES: To evaluate associations between the presence of anti-cyclic citrullinated protein antibodies (anti-CCP) and rheumatoid factor (RF) and other outcomes, including joint erosions and both clinical and economic endpoints, in patients with rheumatoid arthritis (RA). METHODS: Data from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS), a prospective registry of adult RA patients with established or recent-onset RA, were analyzed. Logistic regression models were constructed to test associations between anti CCP/RF seropositivity and erosive disease and the presence of anti-CCP/RF seropositivity plus erosive disease and (1) RA severity; (2) hospitalizations; (3) durable medical equipment (DME) use; and (4) worker productivity (e.g., employment status). Covariates in these models included patient age, gender, race, body mass index (BMI), number of comorbidities, and treatment. RESULTS: Among 1309 registrants, those who were positive (vs. negative) for anti-CCP were 2.72 times more likely to have erosions (OR = 2.72; 95% CI: 1.77-4.18; P < 0.001). Individuals positive (vs. negative) for RF were 36% more likely to have erosions (95% CI: 0.88-2.08; P = 0.162). Patients with anti-CCP seropositivity and erosions were significantly more likely to: (1) have higher disease activity as measured by the Disease Activity Score in 28 joints C-reactive protein (DAS28 CRP >= 2.6); (2) be hospitalized; (3) use DME; and (4) be unemployed, disabled, or long-term disabled. CONCLUSIONS: For the first time in a "real-world" setting including patients with both recent-onset and chronic RA, this study demonstrated that the combination of anti-CCP seropositivity and erosions were significantly associated with more adverse clinical and health-economic consequences, including a lower probability of low disease activity and higher health resource utilization, despite use of biologic disease-modifying antirheumatic drugs by many patients. This dual presentation may signal a need for more intensive therapies, even when observed in patients with chronic, as well as recent-onset, RA. Trial registration [Brigham and Women's Hospital (BWH) Rheumatoid Arthritis Sequential Study; Registry URL: https://clinicaltrials.gov/ct2/show/NCT01793103; ClinicalTrials.gov Identifier NCT01793103]. PMID- 29241641 TI - The Systemic Sclerosis Questionnaire (SySQ): Validation of the translation of the original German version into Spanish and its relationship to the disease and to quality of life. AB - OBJECTIVE: Translation, transculturation and validity of the self-administered questionnaire for functionality (Systemic Sclerosis Questionnaires [SySQ]) for use in Spanish patients with systemic sclerosis and its relationship to the severity of the disease and to quality of life. PATIENTS AND METHODS: We conducted an observational analytical study to perform a cross-cultural validation of the self-administered questionnaire on functionality in scleroderma. The validity of the form and content was evaluated by an expert panel. The method included: a) adaptation into Spanish of the construct for translation and back translation, and transculturation; b) internal consistency with the SySQ (Cronbach's alpha), and c) reproducibility was assessed taking into account all occasions in which the test was performed with Cohen's kappa. Additionally, we calculated the Spearman correlation coefficient with the Medsger severity scale, Health Assessment Questionnaire score and SF-36 score. RESULTS: We included 70 patients with systemic sclerosis: age 17-78 (51+/-12) years, 65 (93%) were women, diffuse/limited subtype 64/36%, disease duration of 0.5-40 years. Optimal internal consistency for all categories of the final version of SySQ (Cronbach's alpha of 0.961) and intraobserver reliability in 2 tests over a 2-week interval (Cohen's kappa coefficient 0.618) and optimal interobserver reliability in 2 tests on the same day (Cohen's kappa coefficient 0.911). Moderate correlation between functionality by SySQ and by Health Assessment Questionnaire (r=0.573, P<.0001). Inverse correlation between SySQ and quality of life mental health domain SF-36 (r=-0.435, P<.001) and physical domain SF-36 (r= 0.638, P<.001). Medsger severity scale (tendon, heart, lung, vascular) also showed significant correlation with SySQ. CONCLUSIONS: SySQ in this validated Spanish version is a suitable instrument to measure functional status in patients with systemic sclerosis. Reduced functionality is related to greater tendon and peripheral vascular involvement and to a poorer quality of life. PMID- 29241642 TI - Clinical guidelines for male lower urinary tract symptoms and benign prostatic hyperplasia: Importance of periodic updates based on available evidence. PMID- 29241643 TI - A 3-Dimensional Approach for Analysis in Orthognathic Surgery-Using Free Software for Voxel-Based Alignment and Semiautomatic Measurement. AB - PURPOSE: In orthognathic surgery, the repeatability of 3-dimensional (3D) measurements is limited by the need for manual reidentification of reference points, which can incorporate errors greater than 1 mm for every 4 repeated measurements. This report describes a semiautomatic approach to decrease the manual reidentification error. This study evaluated the repeatability of surgical outcome measurements using the semiautomatic approach. Furthermore, a step-by step guide is provided to enable researchers and clinicians to perform the 3D analysis by themselves. MATERIALS AND METHODS: Evaluating surgical outcome consists of 2 parts. First, the scans are aligned at the anterior cranial base. Second, a semiautomatic approach is used to place 3 dental reference points at exactly the same sites of the pre- and postoperative maxilla. Because the maxilla is repositioned during surgery but otherwise unaltered, the reference points should be identical if the pre- and postoperative scans are aligned at the maxilla. Therefore, the authors propose the insertion of reference points on the preoperative scan and then repositioning a copy of the preoperative reference points relative to the postoperative scan. To align the reference points on the postoperative scan, the hard palate is used as a mutual maxillary reference structure. A reproducibility test was performed in 10 participants by analyzing the difference between repeated measurements. RESULTS: Repeated linear measurements differed by less than 0.1 mm along all 3 axes (standard deviations, <0.1 mm). The 2 largest differences between repeated measurements were 0.33 mm along the superoinferior axis and 0.29 along the anteroposterior axis. Repeated rotational measurements differed by less than 0.1 degrees around all 3 axes (standard deviations, <=0.1 degrees ). CONCLUSION: The semiautomatic approach showed excellent linear and angular repeatability. The algorithm can be implemented in the clinical evaluation of orthognathic surgical outcome and postoperative relapse. PMID- 29241644 TI - Decline of rotavirus-coded hospitalizations in children under 5 years: A report from Japan where rotavirus vaccines are self-financed. AB - OBJECTIVES: To estimate the trend in incidence of rotavirus gastroenteritis (RVGE) hospitalization among children aged <5 years in Japan during pre- and post vaccine periods (2009-2011 and 2012-2015). STUDY DESIGN: This retrospective observational study used a health insurance claims database (constructed by Japan Medical Data Center Co., Ltd.). Rotavirus vaccine became commercially available in 2011. We analyzed data of all children aged <5 years between January 2009 and December 2015. We estimated the incidence rate (IR) of RVGE hospitalization per 1000 person-years from 2009 to 2015 and incidence rate ratio (IRR) of post vaccine years compared with the averaged pre-vaccine years. IRs and IRRs were also estimated by age group. Primary analysis was limited to the rotavirus season (January to June) of each year. RESULTS: The IR was 6.3-9.3 in pre-vaccine years, 2.3 in 2014, and 3.0 in 2015; the decline was estimated to be 71% in 2014 and 61% in 2015 (p<0.01). By age group, reduction in hospitalizations began in 2013 among children <1 year old, followed by children aged 1 to <5 years in 2014. In the 2014 season, a 65% reduction in RVGE hospitalization was observed in children aged 36 to <60 months, although this age group was unlikely to be vaccinated. CONCLUSIONS: A substantial decline of RVGE hospitalization in 2014 and its persistence was observed among children aged <5 years in Japan after introduction of rotavirus vaccine, although not included in the national immunization program. Indirect effects of rotavirus vaccination were suggested in the 2014 season. PMID- 29241645 TI - Healthcare worker's attitude to seasonal influenza vaccination in the South Tyrolean province of Italy: barriers and facilitators. AB - BACKGROUND: Seasonal influenza vaccination (SIV) is an effective and safe way to prevent influenza. Public health institutions around the world consequently recommend SIV to certain groups at risk, including healthcare worker's (HCWs). Even if SIV is free of charge, the vaccination coverage rate remains low, however. The aim of this study was to gain information on the sociodemographics, lifestyle and knowledge of HCWs associated with their attitude to SIV, also investigating the differences between different professional categories of HCW. METHODS: A cross-sectional study was conducted over six consecutive weeks from October to December 2016. It was based on an anonymous online questionnaire administered to all employees (N = 9633) of the South Tyrolean Health Service. Coverage rates and attitudes to SIV were assessed by type of HCW. A logistic regression analysis was run to test the associations between SIV in the winter of 2015/2016 and potential predictors of the HCWs' attitude to vaccination. RESULTS: In all, 4091 employees (42.4% of the total) took part in the study. Statistically significant differences emerged between the different healthcare professions in terms of their reported vaccination rates and their attitudes to SIV. Among the different types of HCW, physicians had the highest rate of vaccination uptake. There were sociocultural and lifestyle factors associated with SIV in HCWs, as well as these worker's professional roles and the ward where they worked. All the professionals agreed that specific training was the best way to improve HCW vaccination rates. CONCLUSION: Low compliance with SIV among HCWs is attributable to numerous factors, some of which relate to their attitude to health issues. Commitment and accountability to patients and society should be further developed in HCWs. Specific training and information, also through informal scientific channels, should be provided to improve their knowledge of influenza and attitude to vaccination. PMID- 29241646 TI - HIV population-level adaptation can rapidly diminish the impact of a partially effective vaccine. AB - BACKGROUND: Development of an HIV vaccine might be essential to ending the HIV/AIDS pandemic. However, vaccines can result in the emergence and spread of vaccine-resistant strains. Indeed, analyses of breakthrough infections in the HIV phase 3 vaccine trial RV144 identified HIV genotypes with differential rates of transmission in vaccine and placebo recipients. We hypothesized that, for HIV vaccination programs based on partially effective vaccines similar to RV144, HIV adaptation will rapidly diminish the expected vaccine impact. METHODS AND FINDINGS: Using two HIV epidemic models, we simulated large-scale vaccination programs and, critically, included HIV strain diversity with respect to the vaccine response. We show here that rapid population-level viral adaptation can lead to decreased overall vaccine efficacy and substantially fewer infections averted by vaccination, when comparing scenarios with and without viral evolution (with outcomes depending on vaccination coverage, vaccine efficacy against the sensitive allele, and the initial resistant allele frequency). Translating this to the epidemic in South Africa, a scenario with 70% vaccination coverage may result in 250,000 infections (non-averted by vaccination) within 10 years of vaccine rollout that are due solely to HIV adaptation, all else being equal. CONCLUSIONS: These findings suggest that approaches to HIV vaccine development, program implementation, and epidemic modeling may require attention to viral adaptation in response to vaccination. PMID- 29241647 TI - Safety of currently licensed hepatitis B surface antigen vaccines in the United States, Vaccine Adverse Event Reporting System (VAERS), 2005-2015. AB - INTRODUCTION: Currently four recombinant hepatitis B (HepB) vaccines are in use in the United States. HepB vaccines are recommended for infants, children and adults. We assessed adverse events (AEs) following HepB vaccines reported to the Vaccine Adverse Event Reporting System (VAERS), a national spontaneous reporting system. METHODS: We searched VAERS for reports of AEs following single antigen HepB vaccine and HepB-containing vaccines (either given alone or with other vaccines), from January 2005 - December 2015. We conducted descriptive analyses and performed empirical Bayesian data mining to assess disproportionate reporting. We reviewed serious reports including reports of special interest. RESULTS: VAERS received 20,231 reports following HepB or HepB-containing vaccines: 10,291 (51%) in persons <2 years of age; 2588 (13%) in persons 2-18 years and 5867 (29%) in persons >18 years; for 1485 (7.3%) age was missing. Dizziness and nausea (8.4% each) were the most frequently reported AEs following a single antigen HepB vaccine: fever (23%) and injection site erythema (11%) were most frequent following Hep-containing vaccines. Of the 4444 (22%) reports after single antigen HepB vaccine, 303 (6.8%) were serious, including 45 deaths. Most commonly reported cause of death was Sudden Infant Death Syndrome (197). Most common non-death serious reports following single antigen HepB vaccines among infants aged <1 month, were nervous system disorders (15) among children aged 1 23 months; infections and infestation (8) among persons age 2-18 years blood and lymphatic systemic disorders; and general disorders and administration site conditions among persons age >18 years. Most common vaccination error following single antigen HepB was incorrect product storage. CONCLUSIONS: Review current U.S.-licensed HepB vaccines administered alone or in combination with other vaccines did not reveal new or unexpected safety concerns. Vaccination errors were identified which indicate the need for training and education of providers on HepB vaccine indications and recommendations. PMID- 29241648 TI - Different effects of caffeine on behavioral neurophenotypes of two zebrafish populations. AB - Caffeine is a substance present in several foods and drinks of common western diet. Although high caffeine concentrations induce anxiogenic properties in various species, the influence of the different baselines of anxiety levels on caffeine-mediated responses is poorly understood. The short-fin wild-type (WT) and leopard (leo) zebrafish populations present significant behavioral differences, in which leo shows exacerbated anxiety-like responses. Since behavioral neurophenotyping may be easily assessed in adult zebrafish by associating temporal and spatial three-dimensional reconstructions of locomotion, we investigated the effects of caffeine on exploration and anxiety-like behavior of WT and leo zebrafish. Moreover, the whole-body cortisol content was assessed in the absence and presence of caffeine. For this purpose, animals were acutely exposed to caffeine (25, 50, 100 and 200mg/L) for 15min and further tested in the novel tank. Endpoint data and 3D reconstruction plots revealed that caffeine was anxiogenic in both WT and leo populations by altering vertical swimming, freezing, and erratic movements depending on the concentration. Prominent anxiogenic effects during habituation to novelty were observed in WT, suggesting a fundamental role of the phenotype in caffeine-mediated neurobehavioral responses. Although untreated leo showed higher baseline cortisol levels than control WT, caffeine increased whole-body cortisol in both populations. Moreover, caffeine induced aberrant swimming profiles in WT and leo following 200mg/L exposure, which could reflect nonspecific toxicity and/or seizure-like behaviors. Collectively, our novel findings show that caffeine effects in zebrafish differ in a population-dependent manner. PMID- 29241649 TI - The structure of the mental lexicon: What primary progressive aphasias reveal. AB - Like recursive syntax, a structured mental lexicon is specific to the human species but its internal organization remains unclear. It is thought to contain information about the semantic, syntactic (e.g., gender) and formal (orthographic/phonological) features of a word. Previous studies suggested that these three components might be separated at the behavioral level and that they might be implemented by temporal cortices. However, the available investigations are based on case reports or small-cohort studies with patients demonstrating post-stroke aphasia, and they did not contrast the three lexical components in a directly comparable way. Similarly, functional imaging studies with healthy adults did not compare the lexical components but explored them separately using various tasks. Here we assessed the three components with comparable tasks in a relatively large cohort of 20 patients with primary progressive aphasia (PPA), namely logopenic and semantic PPA, which have been shown to affect the temporal cortex. The same tasks were also applied to 23 healthy adults. We thereby primarily aimed at showing multiple intra-lexical dissociations at the behavioral level to demonstrate the existence of a threefold segregation within the mental lexicon. We also sought to confirm the temporal-cortical involvement in the implementation of the lexical components and to characterize differential lexical breakdown in PPA. Lexical components were explored with three implicit processing tasks (semantic, syntactic-gender, word-form priming) and with three explicit matching tasks (semantic, syntactic-gender, word-form). Our results indicate that the three components are functionally segregated as evidenced by multiple dissociations at the group level, and the individual level, thus substantiating the existence of a threefold structure of the mental lexicon. Cortical thickness analyses showed damage to the left lateral temporal cortex in the entire PPA cohort suggesting that lexical components are anatomically segregated within this cortical region. Our results also refine previous proposals about lexical deficits in PPA by demonstrating differential damage to all three components of the lexicon in semantic and logopenic PPA, which might have an impact on PPA diagnosis and language rehabilitation strategies. PMID- 29241650 TI - Regional gray matter volume mediates the relationship between maternal emotional warmth and gratitude. AB - Researchers have examined how parenting behavior influences individuals' brain structure and behavioral development, primarily among people who have experienced maltreatment. However, information relating to the anatomical structure associated with the parenting behavior in young healthy individuals who have not experienced maltreatment is scant. Gratitude is an important aspect of human sociality. Both the extent to which parenting behavior influences gratitude and the neural basis of the relationship between parenting behavior and gratitude are unclear. Thus, in the present study, the primary aim was to use voxel-based morphometry (VBM) to investigate the neuroanatomical basis of parenting behavior in young healthy participants. The results showed a significant negative correlation between the maternal emotional warmth and both the dorsal medial prefrontal cortex (dmPFC) and the lateral rostral prefrontal cortex. Then, we used mediation analysis to investigate the neural basis of the relationship between parenting behavior and gratitude. The results revealed that the volume of the lateral rostral prefrontal cortex mediates the relationship between the maternal emotional warmth and gratitude. Together, these findings suggest that the family environment, specifically parenting behavior, might be associated with the gray matter volume of brain structure. Further, the lateral rostral prefrontal cortex might have an important role in the relationship between the maternal emotional warmth and gratitude. PMID- 29241651 TI - Distinct roles of prelimbic and infralimbic proBDNF in extinction of conditioned fear. AB - Brain-derived neurotrophic factor (BDNF) has been investigated for its positive role in regulation of fear acquisition and memory. The precursor of BDNF, proBDNF, has been identified as different protein from its mature form. The prelimbic (PL) and infralimbic (IL) sub-regions of the medial prefrontal cortex (mPFC) are functionally distinct in fear behavior. However, the role of PL and IL proBDNF in fear memory is unclear. Here, through the infusion of cleavage resistant proBDNF and its antibody, we identified the dissociable roles of PL and IL proBDNF in fear expression and extinction memory as well as explored proBDNF's potential mechanism of action. The results suggest that the infusion of proBDNF in the IL facilitates induction of fear extinction, while infusion in the PL depresses fear expression. Blocking proBDNF by using its antibody disrupted the acquisition of fear extinction in the IL, but not the PL. Furthermore, proBDNF induced extinction was sufficient for extinguishing new and older memories, and required NR2B, but not NR2A, -containing NMDA receptors. We also observed extinction-related proBDNF expression increased in the PL and IL during successful fear expression and extinction, respectively. Importantly, enhanced proBDNF was required for maintaining an extinguished behavior. The extinction effects of proBDNF did not involve degrading the original fear memory. Therefore, proBDNF in the IL and PL differentially contribute to the inhibitory control of fear extinction behavior. Our findings provide a strong link between proBDNF activity and deficits in fear extinction, a hallmark of several psychiatric disorders. PMID- 29241652 TI - Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults. AB - The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double-blind, randomized, placebo-controlled, 4-way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event-related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 MUg roflumilast. Specifically, immediate recall performance on the VLT increased 2-3 words, accompanied by an enhanced P600 peak during word presentation at the third learning trial. No side effects typical for PDE4-Is were reported for the lowest and effective dose of 100 MUg roflumilast. The current proof-of-concept study shows for the first time the potential of low-dose roflumilast administration as a memory enhancer in humans. PMID- 29241653 TI - Synaptic adaptations to chronic ethanol intake in male rhesus monkey dorsal striatum depend on age of drinking onset. AB - One in 12 adults suffer with alcohol use disorder (AUD). Studies suggest the younger the age in which alcohol consumption begins the higher the probability of being diagnosed with AUD. Binge/excessive alcohol drinking involves a transition from flexible to inflexible behavior likely involving the dorsal striatum (caudate and putamen nuclei). A major focus of this study was to examine the effect of age of drinking onset on subsequent chronic, voluntary ethanol intake and dorsal striatal circuitry. Data from rhesus monkeys (n = 45) that started drinking as adolescents, young adults or mature adults confirms an age-related risk for heavy drinking. Striatal neuroadaptations were examined using whole-cell patch clamp electrophysiology to record AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) and GABAA receptor-mediated miniature inhibitory postsynaptic currents (mIPSCs) from medium-sized spiny projection neurons located in the caudate or putamen nuclei. In controls, greater GABAergic transmission (mIPSC frequency and amplitude) was observed in the putamen compared to the caudate. With advancing age, in the absence of ethanol, an increase in mIPSC frequency concomitant with changes in mIPSC amplitude was observed in both regions. Chronic ethanol drinking decreased mIPSC frequency in the putamen regardless of age of onset. In the caudate, an ethanol drinking-induced increase in mIPSC frequency was only observed in monkeys that began drinking as young adults. Glutamatergic transmission did not differ between the dorsal striatal subregions in controls. With chronic ethanol drinking there was a decrease in the postsynaptic characteristics of rise time and area of mEPSCs in the putamen but an increase in mEPSC frequency in the caudate. Together, the observed changes in striatal physiology indicate a combined disinhibition due to youth and ethanol leading to abnormally strong activation of the putamen that could contribute to the increased risk for problem drinking in younger drinkers. PMID- 29241654 TI - Ginsenoside Rb1 confers neuroprotection via promotion of glutamate transporters in a mouse model of Parkinson's disease. AB - Ginsenoside Rb1 has been demonstrated to protect dopaminergic (DA) neurons from death in vitro. However, the neuroprotective effects and underlying mechanism of Rb1 in treating Parkinson's disease (PD) remain uncharacterized. In this study, we explored the effects of Rb1 on the movement disorder and the underlying mechanisms based on the glutamatergic transmission and excitotoxicity in the 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Here, for the first time, we report that Rb1 treatment ameliorates motor deficits, prevents DA neuron death, and suppresses alpha-synuclein expression and astrogliosis in the MPTP mouse model of PD. Rb1 attenuates glutamate excitotoxicity by upregulating glutamate transporter expression and function, and modulating the nigrostriatal and cortico-nigral glutamatergic transmission pathways. Our results demonstrate that Rb1 increases glutamate transporter expression via nuclear translocation of nuclear factor-kappa B, regulates glutamate receptor expression and promotes synaptic protein expression. These results indicate that Rb1 suppresses glutamate excitotoxicity and modulates synaptic transmission to improve the impairments in motor functions of the MPTP model of PD, suggesting that Rb1 may serve as a potential therapeutic agent for PD. PMID- 29241657 TI - Density-driven transport of gas phase chemicals in unsaturated soils. AB - Variations of gas phase density are responsible for advective and diffusive transports of organic vapors in unsaturated soils. Laboratory experiments were conducted to explore dense gas transport (sulfur hexafluoride, SF6) from different source densities through a nitrogen gas-dry soil column. Gas pressures and SF6 densities at transient state were measured along the soil column for three transport configurations (horizontal, vertically upward and vertically downward transport). These measurements and others reported in the literature were compared with simulation results obtained from two models based on different diffusion approaches: the dusty gas model (DGM) equations and a Fickian-type molar fraction-based diffusion expression. The results show that the DGM and Fickian-based models predicted similar dense gas density profiles which matched the measured data well for horizontal transport of dense gas at low to high source densities, despite the pressure variations predicted in the soil column were opposite to the measurements. The pressure evolutions predicted by both models were in trend similar to the measured ones for vertical transport of dense gas. However, differences between the dense gas densities predicted by the DGM and Fickian-based models were discernible for vertically upward transport of dense gas even at low source densities, as the DGM-based predictions matched the measured data better than the Fickian results did. For vertically downward transport, the dense gas densities predicted by both models were not greatly different from our experimental measurements, but substantially greater than the observations obtained from the literature, especially at high source densities. Further research will be necessary for exploring factors affecting downward transport of dense gas in soil columns. Use of the measured data to compute flux components of SF6 showed that the magnitudes of diffusive flux component based on the Fickian-type diffusion expressions in terms of molar concentration, molar fraction and mass density fraction gradient were almost the same. However, they were greater than the result computed with the mass fraction gradient for >24% and the DGM-based result for more than one time. As a consequence, the DGM-based total flux of SF6 was in magnitude greatly less than the Fickian result not only for horizontal transport (diffusion-dominating) but also for vertical transport (advection and diffusion) of dense gas. Particularly, the Fickian-based total flux was more than two times in magnitude as much as the DGM result for vertically upward transport of dense gas. PMID- 29241656 TI - Adipose-derived stem cells decrease pain in a rat model of oxaliplatin-induced neuropathy: Role of VEGF-A modulation. AB - Oxaliplatin therapy of colorectal cancer induces a dose-dependent neuropathic syndrome in 50% of patients. Pharmacological treatments may offer limited relief; scientific efforts are needed for new therapeutic approaches. Therefore we evaluated in a preclinical setting the pain relieving properties of mesenchymal stem cells and its secretome. Rat adipose stem cells (rASCs) were administered in a rat model of oxaliplatin-induced neuropathy. A single intravenous injection of rASCs reduced oxaliplatin-dependent mechanical hypersensitivity to noxious and non-noxious stimuli taking effect 1 h after administration, peaking 6 h thereafter and lasting 5 days. Cell-conditioned medium was ineffective. Repeated rASCs injections every 5 days relieved pain each time with a comparable effect. Labeled rASCs were detected in the bloodstream 1 and 3 h after administration and found in the liver 24 h thereafter. In oxaliplatin-treated rats, the plasma concentration of vascular endothelial growth factor (pan VEGF-A) was increased while the isoform VEGF165b was upregulated in the spinal cord. Both alterations were reverted by rASCs. The anti-VEGF-A monoclonal antibody bevacizumab (intraperitoneally) reduced oxaliplatin-dependent pain. Studying the peripheral and central role of VEGF165b in pain, we determined that the intraplantar and intrathecal injection of the growth factor induced a pro-algesic effect. In the oxaliplatin neuropathy model, the intrathecal infusion of bevacizumab, anti-rat VEGF165b antibody and rASCs reduced pain. Adult adipose mesenchymal stem cells could represent a novel approach in the treatment of neuropathic pain. The regulation of VEGF-A is suggested as an effective mechanism in the complex response orchestrated by stem cells against neuropathy. PMID- 29241655 TI - Citalopram restores short-term memory deficit and non-cognitive behaviors in APP/PS1 mice while halting the advance of Alzheimer's disease-like pathology. AB - Alzheimer's disease (AD) is the most common cause of dementia. In addition to cognitive impairments, deficits in non-cognitive behaviors are also common neurological sequelae in AD. Here, we show that complex behavioral deficits in 7 month-old APPswe/PSEN1dE9 (APP/PS1) mice include impairments in object recognition, deficient social interaction, increased depression and buried marbles. Citalopram, one of the selective serotonin reuptake inhibitors (SSRIs), ameliorated the amyloid deposition in AD patients and transgenic animal models. After treatment for 4 weeks, citalopram rescued the deficits in short-term memory, sociability and depression in these mice. Further immunohistochemical analysis showed chronic citalopram treatment significantly attenuated beta amyloid deposition and microglial activation in the brains of APP/PS1 mice as demonstrated previously. Parvalbumin (PV) interneurons, which are the primary cellular subtype of GABAergic neurons and considered indispensable for short-term memory and social interaction, also contributed to the progress of depression. Additionally, we found the citalopram could significantly increase the PV positive neurons in the cortex of APP/PS1 mice without alteration in the hippocampus, which might contribute to the improvement of behavioral performance. Our findings suggest that citalopram might be a potential candidate for the early treatment of AD. PMID- 29241658 TI - Spatiotemporal Bayesian networks for malaria prediction. AB - Targeted intervention and resource allocation are essential for effective malaria control, particularly in remote areas, with predictive models providing important information for decision making. While a diversity of modeling technique have been used to create predictive models of malaria, no work has made use of Bayesian networks. Bayes nets are attractive due to their ability to represent uncertainty, model time lagged and nonlinear relations, and provide explanations. This paper explores the use of Bayesian networks to model malaria, demonstrating the approach by creating village level models with weekly temporal resolution for Tha Song Yang district in northern Thailand. The networks are learned using data on cases and environmental covariates. Three types of networks are explored: networks for numeric prediction, networks for outbreak prediction, and networks that incorporate spatial autocorrelation. Evaluation of the numeric prediction network shows that the Bayes net has prediction accuracy in terms of mean absolute error of about 1.4 cases for 1 week prediction and 1.7 cases for 6 week prediction. The network for outbreak prediction has an ROC AUC above 0.9 for all prediction horizons. Comparison of prediction accuracy of both Bayes nets against several traditional modeling approaches shows the Bayes nets to outperform the other models for longer time horizon prediction of high incidence transmission. To model spread of malaria over space, we elaborate the models with links between the village networks. This results in some very large models which would be far too laborious to build by hand. So we represent the models as collections of probability logic rules and automatically generate the networks. Evaluation of the models shows that the autocorrelation links significantly improve prediction accuracy for some villages in regions of high incidence. We conclude that spatiotemporal Bayesian networks are a highly promising modeling alternative for prediction of malaria and other vector-borne diseases. PMID- 29241659 TI - A novel method for predicting kidney stone type using ensemble learning. AB - The high morbidity rate associated with kidney stone disease, which is a silent killer, is one of the main concerns in healthcare systems all over the world. Advanced data mining techniques such as classification can help in the early prediction of this disease and reduce its incidence and associated costs. The objective of the present study is to derive a model for the early detection of the type of kidney stone and the most influential parameters with the aim of providing a decision-support system. Information was collected from 936 patients with nephrolithiasis at the kidney center of the Razi Hospital in Rasht from 2012 through 2016. The prepared dataset included 42 features. Data pre-processing was the first step toward extracting the relevant features. The collected data was analyzed with Weka software, and various data mining models were used to prepare a predictive model. Various data mining algorithms such as the Bayesian model, different types of Decision Trees, Artificial Neural Networks, and Rule-based classifiers were used in these models. We also proposed four models based on ensemble learning to improve the accuracy of each learning algorithm. In addition, a novel technique for combining individual classifiers in ensemble learning was proposed. In this technique, for each individual classifier, a weight is assigned based on our proposed genetic algorithm based method. The generated knowledge was evaluated using a 10-fold cross-validation technique based on standard measures. However, the assessment of each feature for building a predictive model was another significant challenge. The predictive strength of each feature for creating a reproducible outcome was also investigated. Regarding the applied models, parameters such as sex, acid uric condition, calcium level, hypertension, diabetes, nausea and vomiting, flank pain, and urinary tract infection (UTI) were the most vital parameters for predicting the chance of nephrolithiasis. The final ensemble-based model (with an accuracy of 97.1%) was a robust one and could be safely applied to future studies to predict the chances of developing nephrolithiasis. This model provides a novel way to study stone disease by deciphering the complex interaction among different biological variables, thus helping in an early identification and reduction in diagnosis time. PMID- 29241660 TI - Effects of glenohumeral internal rotation deficit on baseball pitching among pitchers of different ages. AB - BACKGROUND: Previous studies have reported that glenohumeral internal rotation deficit (GIRD) may increase the risk of shoulder injury. However, the effects of GIRD on baseball pitching among pitchers of different age groups are still unclear. METHODS: The study participants were 24 high school and 24 university pitchers. For each age group, the pitchers were evenly divided into a GIRD group and a normal group. The pitching motion of each participant was captured using a motion analysis system at a sampling frequency of 300 Hz. The kinematics and kinetics of the throwing shoulder and trunk were quantified, and statistical differences between the groups were examined by 2-sample t tests. RESULTS: For both age groups, significant differences were observed in shoulder external rotations of the GIRD and normal groups. Compared with the university pitchers in the normal group, the university pitchers with GIRD exhibited a greater shoulder loading and did more internal rotation work in the acceleration phase. The high school pitchers with GIRD showed a larger trunk tilt and less trunk rotation than the university pitchers with GIRD. However, the university pitchers with GIRD exhibited a larger shoulder posterior force and horizontal adduction torque than the high school pitchers with GIRD. CONCLUSION: Pitchers with GIRD do change their pitching motions, and the greater resulting shoulder joint loading predisposes them to a greater risk of shoulder injury, especially among university pitchers. PMID- 29241661 TI - Glenoid component loosening associated with increased critical shoulder angle at midterm follow-up. AB - BACKGROUND: Glenoid component loosening is a common failure mode of total shoulder arthroplasty (TSA). A larger critical shoulder angle (CSA) may cause superior glenoid component loading and more rapid component loosening. The purpose of this study was to define the relationship between the CSA and glenoid component loosening in midterm follow-up after TSA. METHODS: We conducted a retrospective study of 61 primary TSAs for osteoarthritis with an average follow up of 5.0 +/- 2.2 years without surgical revision. Standard true anteroposterior radiographs postoperatively and at longest follow-up were graded in a blinded and repetitive nature for pegged glenoid radiolucent lines and measured for the CSA. An "at-risk" glenoid was defined as grade 3 or higher lucency. RESULTS: The average CSA was 32 degrees +/- 5 degrees , median midterm lucency grade was 2 (range, 0-5), and median progression of lucency grade was 1 (range, -1 to 4). At midterm follow-up, 20% of TSAs were grade 3 or higher mean glenoid lucency, with an average CSA of 36 degrees . There was a statistically significant correlation between CSA and both glenoid lucency grade (odds ratio, 1.20 per degree CSA) and progression of lucency grade (odds ratio, 1.24). An increase in CSA of 10 degrees was associated with a 6.2-fold increased odds of having an at-risk glenoid. CONCLUSION: This study identifies the CSA as a risk factor for glenoid component loosening after TSA. Our findings suggest that the CSA may be a modifiable factor during surgery to improve glenoid component outcomes. PMID- 29241662 TI - An edge-based SIR model for sexually transmitted diseases on the contact network. AB - Sexually transmitted diseases, which are infections through sexual contact, pose severe public health threat nowadays. In this paper, we develop a novel model for such diseases on a bipartite random contact network. Our model is precise with arbitrary initial conditions, which makes it suitable to study preventative vaccination strategies. We derive the reproduction number and show that R0=1 is the disease threshold. An implicit formula for the final epidemic size is also derived, and we show that the formula gives a unique positive final epidemic size when the reproduction number is larger than unity. We find that the final size in either sex is heavily influenced by the degree distribution of the opposite sex. PMID- 29241663 TI - Model selection for integrated pest management with stochasticity. AB - In Song and Xiang (2006), an integrated pest management model with periodically varying climatic conditions was introduced. In order to address a wider range of environmental effects, the authors here have embarked upon a series of studies resulting in a more flexible modeling approach. In Akman et al. (2013), the impact of randomly changing environmental conditions is examined by incorporating stochasticity into the birth pulse of the prey species. In Akman et al. (2014), the authors introduce a class of models via a mixture of two birth-pulse terms and determined conditions for the global and local asymptotic stability of the pest eradication solution. With this work, the authors unify the stochastic and mixture model components to create further flexibility in modeling the impacts of random environmental changes on an integrated pest management system. In particular, we first determine the conditions under which solutions of our deterministic mixture model are permanent. We then analyze the stochastic model to find the optimal value of the mixing parameter that minimizes the variance in the efficacy of the pesticide. Additionally, we perform a sensitivity analysis to show that the corresponding pesticide efficacy determined by this optimization technique is indeed robust. Through numerical simulations we show that permanence can be preserved in our stochastic model. Our study of the stochastic version of the model indicates that our results on the deterministic model provide informative conclusions about the behavior of the stochastic model. PMID- 29241664 TI - Distinguishing three subtypes of hematopoietic cells based on gene expression profiles using a support vector machine. AB - Hematopoiesis is a complicated process involving a series of biological sub processes that lead to the formation of various blood components. A widely accepted model of early hematopoiesis proceeds from long-term hematopoietic stem cells (LT-HSCs) to multipotent progenitors (MPPs) and then to lineage-committed progenitors. However, the molecular mechanisms of early hematopoiesis have not been fully characterized. In this study, we applied a computational strategy to identify the gene expression signatures distinguishing three types of closely related hematopoietic cells collected in recent studies: (1) hematopoietic stem cell/multipotent progenitor cells; (2) LT-HSCs; and (3) hematopoietic progenitor cells. Each cell in these cell types was represented by its gene expression profile among a total number of 20,475 genes. The expression features were analyzed by a Monte-Carlo Feature Selection (MCFS) method, resulting in a feature list. Then, the incremental feature selection (IFS) and a support vector machine (SVM) optimized with a sequential minimum optimization (SMO) algorithm were employed to access the optimal classifier with the highest Matthews correlation coefficient (MCC) value of 0.889, in which 6698 features were used to represent cells. In addition, through an updated program of MCFS method, seventeen decision rules can be obtained, which can classify the three cell types with an overall accuracy of 0.812. Using a literature review, both the rules and the top features used for building the optimal classifier were confirmed to be commonly used or potential biological markers for distinguishing the three cell types of HSPCs. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. PMID- 29241666 TI - Identification of human circadian genes based on time course gene expression profiles by using a deep learning method. AB - Circadian genes express periodically in an approximate 24-h period and the identification and study of these genes can provide deep understanding of the circadian control which plays significant roles in human health. Although many circadian gene identification algorithms have been developed, large numbers of false positives and low coverage are still major problems in this field. In this study we constructed a novel computational framework for circadian gene identification using deep neural networks (DNN) - a deep learning algorithm which can represent the raw form of data patterns without imposing assumptions on the expression distribution. Firstly, we transformed time-course gene expression data into categorical-state data to denote the changing trend of gene expression. Two distinct expression patterns emerged after clustering of the state data for circadian genes from our manually created learning dataset. DNN was then applied to discriminate the aperiodic genes and the two subtypes of periodic genes. In order to assess the performance of DNN, four commonly used machine learning methods including k-nearest neighbors, logistic regression, naive Bayes, and support vector machines were used for comparison. The results show that the DNN model achieves the best balanced precision and recall. Next, we conducted large scale circadian gene detection using the trained DNN model for the remaining transcription profiles. Comparing with JTK_CYCLE and a study performed by Moller Levet et al. (doi: https://doi.org/10.1073/pnas.1217154110), we identified 1132 novel periodic genes. Through the functional analysis of these novel circadian genes, we found that the GTPase superfamily exhibits distinct circadian expression patterns and may provide a molecular switch of circadian control of the functioning of the immune system in human blood. Our study provides novel insights into both the circadian gene identification field and the study of complex circadian-driven biological control. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. PMID- 29241665 TI - Structure and energetic basis of overrepresented lambda light chain in systemic light chain amyloidosis patients. AB - Amyloid formation and deposition of immunoglobulin light-chain proteins in systemic amyloidosis (AL) cause major organ failures. While the kappa light-chain is dominant (lambda/kappa=1:2) in healthy individuals, lambda is highly overrepresented (lambda/kappa=3:1) in AL patients. The structural basis of the amyloid formation and the sequence preference are unknown. We examined the correlation between sequence and structural stability of dimeric variable domains of immunoglobulin light chains using molecular dynamics simulations of 24 representative dimer interfaces, followed by energy evaluation of conformational ensembles for 20 AL patients' light chain sequences. We identified a stable interface with displaced N-terminal residues, provides the structural basis for AL protein fibrils formation. Proline isomerization may cause the N-terminus to adopt amyloid-prone conformations. We found that lambda light-chains prefer misfolded dimer conformation, while kappa chain structures are stabilized by a natively folded dimer. Our study may facilitate structure-based small molecule and antibody design to inhibit AL. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. PMID- 29241668 TI - Neutrophil-to-Lymphocyte Ratio is a strong predictor of atherosclerotic carotid plaques in older adults. AB - BACKGROUND AND AIMS: The Neutrophil-to-Lymphocyte Ratio (NLR), an index of systemic inflammation, has been reported to be associated with subclinical atherosclerosis, but its predictive role of the presence of carotid atherosclerotic plaques remains undefined. This study aims to assess this association which gives additional value to this biomarker, with respect to the main risk factors, in the prediction of carotid atherosclerosis in older adults. METHODS AND RESULTS: We recruited 324 patients, aged >=65 years, without hematopoietic disorders, and/or history of malignancies, evidence of acute infections, chronic inflammatory status, and history of glucocorticoid therapy within the past three months, hospitalized in the Unit of Internal Medicine, University of Catania, Catania, Italy from January 2014 to December 2016. All patients underwent blood sampling for white blood cell, neutrophil, lymphocyte and platelet counts, and for measurements of inflammatory markers, NLR was calculated as the ratio of the absolute neutrophil count to the absolute lymphocyte count. Patients also underwent carotid scan by ultrasonography (US) to evaluate abnormalities of carotid wall. NLR resulted a strong predictor of the presence of carotid plaques. NLR > 2.4 predicted with 80% probability carotid plaques (p < 0.01), while NLR > 3.68 gave 97% probability (p = 0.013). Furthermore, NLR > 2.4 was associated with an average presence of 2.86 carotid plaques (p < 0.001). Fibrinogen and CRP performed well, but with lesser significance, as predictors of the presence of carotid plaques (p = 0.002). CONCLUSION: NLR is a strong predictor of the presence and the number of carotid atherosclerotic plaques. Its use could be useful to identify the risk of harboring carotid plaques. PMID- 29241669 TI - Cytokine contributions to alterations of the volatile metabolome induced by inflammation. AB - Several studies demonstrate that inflammation affects body odor. Volatile signals associated with inflammation induced by pyrogens like LPS are detectable both by conspecifics and chemical analyses. However, little is known about the mechanisms which translate detection of a foreign molecule or pathogen into a unique body odor, or even how unique that odor may be. Here, we utilized C57BL/6J trained mice to identify the odor of LPS-treated conspecifics to investigate potential pathways between LPS-induced inflammation and changes in body odor, as represented by changes in urine odor. We hypothesized that the change in volatile metabolites could be caused directly by the pro-inflammatory cytokine response mediated by TNF or IL-1beta, or by the compensatory anti-inflammatory response mediated by IL-10. We found that trained biosensors generalized learned LPS associated odors to TNF-induced odors, but not to IL-1beta or IL-10-induced odors. Analyses of urine volatiles using headspace gas chromatography revealed distinct profiles of volatile compounds for each treatment. Instrumental discrimination relied on a mixture of compounds, including 2-sec-butyl-4,5 dihydrothiazole, cedrol, nonanal, benzaldehyde, acetic acid, 2-ethyl-1-hexanol, and dehydro-exo-brevicomin. Although interpretation of LDA modeling differed from behavioral testing, it does suggest that treatment with TNF, IL-1beta, and LPS can be distinguished by their resultant volatile profiles. These findings indicate there is information found in body odors on the presence of specific cytokines. This result is encouraging for the future of disease diagnosis via analysis of volatiles. PMID- 29241671 TI - Mkp-1 protects mice against toxin-induced liver damage by promoting the Nrf2 cytoprotective response. AB - The present study was undertaken to investigate the possible protective effect of mitogen-activated protein kinase phosphatase 1 (Mkp-1) on toxin-induced hepatic injury. Here, we uncovered a positive feedback loop between Mkp-1, a dual threonine/tyrosine phosphatase, and nuclear factor erythroid 2-related factor 2 (Nrf2), a crucial regulator of the defense system in the liver. Mkp-1-/- mice exhibited decreased protein levels of Nrf2, phase II gene products, and reduced glutathione (GSH) in the liver. Induction of detoxifying enzymes by the Nrf2 activator butylated hydroxyanisole (BHA) or sulforaphane, was attenuated in the liver and small intestines of Mkp-1-/- mice, indicating that the Nrf2 signaling pathway is impaired as a result of Mkp-1 deficiency. Mkp-1-/- mice suffered more severe liver injury after a single exposure to hepatotoxin carbon tetrachloride (CCl4) than their wild-type (WT) counterparts. BHA partially rescued the CCl4 induced liver damage in WT mice, but not in Mkp-1-/- mice, suggesting the requirement of Mkp-1 in the activation of Nrf2 signaling against the liver injury. Mechanistically, Mkp-1 upregulated Nrf2 through a direct interaction with the Neh2 domain in the transcription factor, while Nrf2 enhanced the expression of Mkp-1 mRNA by binding to the ARE site at -1719 to -1710bp in the Mkp-1 promoter. Our results reveal novel role of Mkp-1 in the maintenance of redox homeostasis in the liver. Thus, strategies aimed at augmenting Mkp-1 expression may be beneficial in protecting the liver and may provide novel therapeutic approaches to toxin-induced liver injury. PMID- 29241667 TI - Correlates of ideal cardiovascular health in European adolescents: The HELENA study. AB - BACKGROUND AND AIMS: The ideal cardiovascular health (iCVH) construct consists of 4 health behaviors (smoking status, body mass index, physical activity and diet) and 3 health factors (total cholesterol, blood pressure and fasting glucose). A greater number of iCVH components in adolescence are related to better cardiovascular health, but little is known about the correlates of iCVH in adolescents. Thus, the aim of the study was to examine correlates of iCVH in European adolescents. METHODS AND RESULTS: The study comprised 637 European adolescents with complete iCVH data. Participants were part of the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study, a cross sectional, multicenter study conducted in 9 different European countries. Correlates investigated were sex and age, family affluence scale, maternal education, geographic location, sleep time, television viewing, duration of pregnancy, birth weight and breastfeeding. Younger adolescents, those whose mothers had medium/high education or those who watched television less than 2 h per day had a greater number of iCVH components compared to those who were older, had a mother with low education or watched television 2 h or more daily (P <= 0.01). CONCLUSION: Since in our study older adolescents had worse iCVH than younger adolescents, early promotion of cardiovascular health may be important. Future studies may also investigate the usefulness of limiting television viewing to promote iCVH. Finally, since adolescents of mothers with low education had poorer iCVH, it may be of special interest to tailor public health promotion to adolescents from families with low socioeconomic status. PMID- 29241673 TI - Adverse Effects of "Teachable Moment" Interventions in Lung Cancer: Why Prudence Matters. PMID- 29241672 TI - Catatonia with schizophrenia: From ECT to rTMS. AB - BACKGROUND: Electroconvulsive therapy is indicated in cases of catatonic schizophrenia following a failure of the challenge test with lorazepam or Zolpidem(r). Some patients need maintenance treatment with ECT. Repetitive Transcranial Magnetic Stimulation (rTMS) and anodal Transcranial direct-current stimulation (tDCS) might be effective against catatonia. OBJECTIVE: Consider an alternative to ECT for a refractory patient. REVIEW: Twenty-one articles were identified mainly based on case reports series were found using search on Medline, Google Scholar, PsychInfo, CAIRNS. Key words were:"catatonia", and "rTMS", and more generally with"ECT","tDCS","Zolpidem(r)". At the end there were only six case reports with rTMS and three with tDCS. We discussed the alternative to ECT and follow up rTMS strategies illustrated by these case reports. FINDINGS: Patients mean age was 35; numbers of previous ECT vary from zero to 556; the most common motor threshold (MT) is 80%, with two patients with 110%, the most common treatment placement is L DLPFC. In one of them, ECT was the only acute-state or maintenance treatment effective in this patient, who underwent 556 ECT sessions over 20 years. High-frequency rTMS was considered as a possible alternative, given the potential adverse effects of chronic maintenance ECT in a patient with comorbid epilepsy. rTMS treatment was 3-4*/week and over time extended to once every two weeks. A persistent objective improvement in catatonia was observed on the Bush-Francis Catatonia Rating Scale. CONCLUSION: rTMS is helpful for acute and maintenance treatment for catatonic schizophrenia who both failed multiple pharmacologic interventions and had safety concerns with continuing maintenance ECT. Clinicians should consider rTMS as a potential treatment option for refractory catatonia. PMID- 29241670 TI - Glia- and tissue-specific changes in the Kynurenine Pathway after treatment of mice with lipopolysaccharide and dexamethasone. AB - Behavioral symptoms associated with mood disorders have been intimately linked with immunological and psychological stress. Induction of immune and stress pathways is accompanied by increased tryptophan entry into the Kynurenine (Kyn) Pathway as governed by the rate-limiting enzymes indoleamine/tryptophan 2,3 dioxygenases (DO's: Ido1, Ido2, Tdo2). Indeed, elevated DO expression is associated with inflammation- and stress-related depression symptoms. Here we examined central (brain, astrocyte and microglia) and peripheral (lung, liver and spleen) DO expression in mice treated intraperitoneally with lipopolysaccharide (LPS) and dexamethasone (DEX) to model the response of the Kyn Pathway to inflammation and glucocorticoids. LPS-induced expression of cytokines in peripheral tissues was attenuated by DEX, confirming inflammatory and anti inflammatory responses, respectively. Increased Kyn levels following LPS and DEX administration verified Kyn Pathway activation. Expression of multiple mRNA isoforms for each DO, which we have shown to be differentially utilized and regulated, were quantified including reference/full-length (FL) and variant (v) transcripts. LPS increased Ido1-FL in brain (~1000-fold), a response paralleled by increased expression in both astrocytes and microglia. Central Ido1-FL was not changed by DEX; however, LPS-induced Ido1-FL was decreased by DEX in peripheral tissues. In contrast, DEX increased Ido1-v1 expression by astrocytes and microglia, but not peripheral tissues. In comparison, brain Ido2 was minimally induced by LPS or DEX. Uniquely, Ido2-v6 was LPS- and DEX-inducible in astrocytes, suggesting a unique role for astrocytes in response to inflammation and glucocorticoids. Only DEX increased central Tdo2 expression; however, peripheral Tdo2 was upregulated by either LPS or DEX. In summary, specific DO isoforms are increased by LPS and DEX, but LPS-dependent Ido1 and Ido2 induction are attenuated by DEX only in the periphery indicating that elevated DO expression and Kyn production within the brain can occur independent of the periphery. These findings demonstrate a plausible interaction between immune activation and glucocorticoids associated with depression. PMID- 29241674 TI - Ethnomedicinal plant diversity in Thailand. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Plants have provided medicine to humans for thousands of years, and in most parts of the world people still use traditional plant-derived medicine. Knowledge related to traditional use provides an important alternative to unavailable or expensive western medicine in many rural communities. At the same time, ethnomedicinal discoveries are valuable for the development of modern medicine. Unfortunately, globalization and urbanization causes the disappearance of much traditional medicinal plant knowledge. AIM OF THE STUDY: To review available ethnobotanical knowledge about medicinal plants in Thailand and to estimate its diversity. METHODS: Information about ethnomedicinal uses of plants in Thailand was extracted from 64 scientific reports, books, and theses produced between 1990 and 2014. Plant identifications in the primary sources were updated to currently accepted names following The Plant List website and the species were assigned to family following the Angiosperm Phylogeny Website. Use Values (UV) were calculated to estimate the importance of medicinal plant species (UVs) and families (UVf). Medicinal use categories, plant parts used, preparations of the medicine, and their applications were noted for each use report. RESULTS: We found 16,789 use reports for 2187 plant species in 206 families. These data came from 19 ethnic groups living in 121 villages throughout Thailand. The health conditions most commonly treated with medicinal plants were in the categories digestive system disorders, infections/infestations, nutritional disorders, muscular-skeletal system disorders, and genitourinary system disorders. Plant families with very high use values were Fabaceae, Asteraceae, Acanthaceae, Lamiaceae, and Zingiberaceae and species with very high use values were Chromolaena odorata (L.) R.M.King & H.Rob., Blumea balsamifera (L.) DC., and Cheilocostus speciosus (J.Koenig) C.D.Specht. Stems and leaves were the most used plant parts, but also other parts of the plants were used in medicinal recipes. The most common way of using the medicinal plants was as a decoction in water. CONCLUSION: We found 2187 plant species that were used in traditional medicine in Thailand. Of these a few hundred had high use values, suggesting that they may produce bioactive compounds with strong physiological effects. PMID- 29241676 TI - Breast cancer and synchronous multiple myeloma as a diagnostic challenge: Case report and review of literature. AB - Multiple myeloma is a hematological malignancy, which sometimes creates difficulties in diagnosis, based on the presence of monoclonal protein in serum/urine and plasmocyte infiltration in the bone marrow, and on the other hand, synchronous cancers are also a diagnostic challenge. We present a case report of a patient with concurrent breast cancer and multiple myeloma. A 68-year old woman was admitted to the hospital with diagnosis of left breast cancer in first stage of the disease. In the past, she had had several episodes of thrombocytopenia, leucocytosis, and mild anaemia, which were followed by hematologist in outpatient setting. She was operated and started adjuvant chemotherapy. During treatment, episodes of hematological abnormalities were observed. After completion of the chemotherapy for breast cancer, the patient was observed and short time after that multiple myeloma was diagnosed as a synchronous cancer. Patient was first treated for breast cancer, then subsequently for multiple myeloma (2 lines therapy: CTD and VMP). We describe diagnostic problems with multiple myeloma; however, they could be caused by curation of breast cancer, which might have supressed the proliferation of plasmocytes and could delay the diagnosis. All symptoms of multiple myeloma were interpreted as a secondary effect of chemotherapy. Review of the literature shows the clinical approaches in such situations. PMID- 29241675 TI - Effect of Telmisartan on Preventing Learning and Memory Deficits Via Peroxisome Proliferator-Activated Receptor-gamma in Vascular Dementia Spontaneously Hypertensive Rats. AB - BACKGROUND: This study aimed to explore the effect of telmisartan (TEL), as a partial peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, in vascular dementia (VaD) rats induced by middle cerebral artery occlusion (MCAO). METHODS: Spontaneously hypertensive rats were divided into 6 groups: the sham group, model group, TEL-treated groups (1, 5, and 10 mg/kg), and TEL + GW9662 (10 mg/kg + 1 mg/kg). Using the MCAO method established the VaD rat model. Cognitive function was detected through the Morris water maze test, and matrix metalloproteinase 2 (MMP2) or matrix metalloproteinase 9 (MMP9), acetylcholinesterase (AChE), choline acetyltransferase (ChAT), and synaptophysin (SYN) in the hippocampus of rats were measured by the immunohistochemical method. RESULTS: In the Morris water maze test, the spatial memory ability was significantly impaired in the model group and improved in the TEL groups (1, 5, and 10 mg/kg), but the improvement effect of TEL on spatial memory was inhibited by GW9662, a PPAR-gamma antagonist. Compared with the sham group, the expression levels of MMP2, MMP9, and AChE increased and the expression levels of ChAT and SYN decreased significantly in the model group. Interestingly, TEL (1, 5, and 10 mg/kg) significantly reduced the expression levels of MMP2, MMP9, and AChE and significantly improved the expression levels of ChAT and SYN in a dose-dependent manner. However, cotreatment with GW9662 inhibited the TEL-mediated improvement effects on MMPs, the cholinergic system, and SYN. CONCLUSION: This study suggested that TEL had improvement effects in VaD rats via the PPAR-gamma pathway. PMID- 29241677 TI - Newborn screening of congenital adrenal hyperplasia. PMID- 29241679 TI - Origins and Predictors of Friendships in 6- to 8-Year-Old Children Born at Neonatal Risk. AB - OBJECTIVE: To test effects of gestational age (GA), early social experiences, and child characteristics on children's friendships and perceived peer acceptance. STUDY DESIGN: As part of the prospective Bavarian Longitudinal Study (1147 children, 25-41 weeks GA), children's friendships (eg, number of friends, frequency of meeting friends) and perceived peer acceptance were assessed before school entry (6 years of age) and in second grade (8 years of age) using child and parent reports. The parent-infant relationship was evaluated during the 5 months after birth. Child characteristics (ie, height, motor impairment, cognitive ability, behavioral problems) were measured at 6 years of age. Multiple regressions estimated effects of GA, parent-infant relationship, and child characteristics. RESULTS: Overall, children with higher GA had more friends, spent more time with friends, and were more accepted by peers at 6 years of age. Better parent-infant relationships, higher cognitive abilities, and fewer motor and behavioral problems predicted more friendships and higher peer acceptance after adjusting for sex, socioeconomic status, multiples, siblings, and special schooling. Across all GA groups, number of friends (child report: mean change, 1.77; 95% CI, 1.57-1.96) and peer acceptance (child report: mean change, 0.14; 95% CI, 0.09-0.19; parent report: mean change, 0.14; 95% CI, 0.11-0.17) increased with age, but the increase in number of friends was higher among preterm children (ie, interaction effect age*GA group: P = .034). CONCLUSIONS: Our results provide evidence of a dose-response effect of low GA on children's friendships and perceived peer acceptance. Improvements in early parenting and motor, cognitive, and behavioral development may facilitate friendships and peer acceptance for all children across the gestation spectrum. PMID- 29241680 TI - Race Effects of Inhaled Nitric Oxide in Preterm Infants: An Individual Participant Data Meta-Analysis. AB - OBJECTIVE: To assess whether inhaled nitric oxide (iNO) improves survival without bronchopulmonary dysplasia (BPD) for preterm African American infants. STUDY DESIGN: An individual participant data meta-analysis was conducted, including 3 randomized, placebo-controlled trials that enrolled infants born at <34 weeks of gestation receiving respiratory support, had at least 15% (or a minimum of 10 infants in each trial arm) of African American race, and used a starting iNO of >5 parts per million with the intention to treat for 7 days minimum. The primary outcome was a composite of death or BPD. Secondary outcomes included death before discharge, postnatal steroid use, gross pulmonary air leak, pulmonary hemorrhage, measures of respiratory support, and duration of hospital stay. RESULTS: Compared with other races, African American infants had a significant reduction in the composite outcome of death or BPD with iNO treatment: 49% treated vs 63% controls (relative risk, 0.77; 95% CI, 0.65-0.91; P = .003; interaction P = .016). There were no differences between racial groups for death. There was also a significant difference between races (interaction P = .023) of iNO treatment for BPD in survivors, with the greatest effect in African American infants (P = .005). There was no difference between racial groups in the use of postnatal steroids, pulmonary air leak, pulmonary hemorrhage, or other measures of respiratory support. CONCLUSION: iNO therapy should be considered for preterm African American infants at high risk for BPD. iNO to prevent BPD in African Americans may represent an example of a racially customized therapy for infants. PMID- 29241678 TI - Language Dysfunction in Pediatric Epilepsy. PMID- 29241681 TI - Validation of Scratching Severity as an Objective Assessment for Itch. AB - There are currently no simple, standardized, objective assessments of itch for clinical trials and practice. We sought to validate and test the severity of scratching as an objective measure of itch (4-point ordinal scale ranging from 0 [not present] to 3 [very prominent] based on the observation of scratching lesions). We performed a prospective outpatient study using questionnaires and evaluations by a dermatologist in adults with atopic dermatitis (n = 261). Severity of scratching best correlated with patient-reported global atopic dermatitis severity (Kendall tau = 0.336, P < 0.0001), numeric rating scale of itch in the past 24 hours (tau = 0.266, P = 0.0010) and 3 days (tau = 0.296, P < 0.0001). Severity of scratching showed responsiveness over time. Patients experiencing improvement of scratching severity of 1 point or greater had significantly lower itch based on numeric rating scale in the past 3 days (Wilcoxon rank sum test, P = 0.0175), 5-D itch scale (P = 0.0146), and Patient Oriented Eczema Measure scores (P = 0.0146). There was a significant decrease in scratching severity for patients experiencing itch improvement of 4 points or greater in the past 3 days on the numeric rating scale (Fisher exact test, P = 0.0026), Patient-Oriented Eczema Measure (P < 0.0001), and Dermatology Life Quality Index (P = 0.0285). Severity of scratching may be a useful endpoint in clinical trials and practice across the gamut of pruritic disorders. Future studies are needed to validate severity of scratching in other pruritic disease. PMID- 29241682 TI - Editorial: Get inspired - Lessons learned from evolution of thyroid hormone signaling in developmental processes. PMID- 29241683 TI - Notch pathway signaling in the skin antagonizes Merkel cell development. AB - Merkel cells are mechanosensitive skin cells derived from the epidermal lineage whose development requires expression of the basic helix-loop-helix transcription factor Atoh1. The genes and pathways involved in regulating Merkel cell development during embryogenesis are poorly understood. Notch pathway signaling antagonizes Atoh1 expression in many developing body regions, so we hypothesized that Notch signaling might inhibit Merkel cell development. We found that conditional, constitutive overexpression of the Notch intracellular domain (NICD) in mouse epidermis significantly decreased Merkel cell numbers in whisker follicles and touch domes of hairy skin. Conversely, conditional deletion of the obligate NICD binding partner RBPj in the epidermis significantly increased Merkel cell numbers in whisker follicles, led to the development of ectopic Merkel cells outside of touch domes in hairy skin epidermis, and altered the distribution of Merkel cells in touch domes. Deletion of the downstream Notch effector gene Hes1 also significantly increased Merkel cell numbers in whisker follicles. Together, these data demonstrate that Notch signaling regulates Merkel cell production and patterning. PMID- 29241684 TI - Aortofemoral Reconstruction for an Infected Graft Using Thrombosed Femoral Veins. AB - INTRODUCTION: Treatment of an infected aortic prosthesis is difficult and the ideal graft material is subject to debate. REPORT: A case of infected aortic prosthesis treated using bilateral thrombosed superficial femoral veins (SFVs) is presented. Bilateral reversed SFVs were cut longitudinally at both proximal ends about 3-4 cm and were sutured side by side. The operating time was 5 h. No sign of recurrent infection was observed when the patient suffered a myocardial infarction and died 6 months post-operatively. DISCUSSION: Thrombosed SFVs may be considered as a therapeutic option for infected aortic graft replacement. PMID- 29241686 TI - RANKL and RANK: From Mammalian Physiology to Cancer Treatment. AB - The tumor necrosis factor (TNF) receptor RANK (TNFRSF11A) and its ligand RANKL (TNFSF11) regulate osteoclast development and bone metabolism. They also control stem cell expansion and proliferation of mammary epithelial cells via the sex hormone progesterone. As such, RANKL and RANK have been implicated in the onset of hormone-induced breast cancer. Recently, RANK/RANKL were identified as crucial regulators for BRCA1 mutation-driven breast cancer. Current prevention strategies for BRCA1 mutation carriers are associated with wide-ranging risks; therefore, the search for alternative, non-invasive strategies is of paramount importance. We summarize here the functions of the RANKL/RANK pathway in mammalian physiology and focus on its recently uncovered role in breast cancer. We propose that anti RANKL therapy should be pursued as a preventative strategy for breast cancer. PMID- 29241687 TI - Mechanisms of Carrier Formation during Clathrin-Independent Endocytosis. AB - Clathrin-independent endocytosis (CIE) mediates the cellular uptake of many extracellular ligands, receptors, and pathogens, including several life threatening bacterial toxins and viruses. So far, our understanding of CIE carrier formation has lagged behind that of clathrin-coated vesicles. Impediments have been the imprecise definition of some CIE pathways, the lack of specific cargoes being transported and of exclusive cytosolic markers and regulators. Notwithstanding these limitations, three distinct molecular mechanisms by which CIE carriers form can be defined. Cargo capture by cytosolic proteins is the main mechanism used by fast endophilin-mediated endocytosis (FEME) and interleukin 2 receptor (IL-2R) endocytosis. Acute signaling-induced membrane remodeling drives macropinocytosis. Finally, extracellular lipid or cargo clustering by the glycolipid-lectin (GL-Lect) hypothesis mediates the uptake of Shiga and cholera toxins and receptors by the CLIC/GEEC pathway. Here, we review these mechanisms and highlight current gaps in knowledge that will need to be addressed to complete our understanding of CIE. PMID- 29241685 TI - Fenestrated Thoracic Endovascular Aortic Repair Using Physician Modified Stent Grafts for Acute Type B Aortic Dissection with Unfavourable Landing Zone. AB - OBJECTIVES: The aim was to evaluate the early results of fenestrated thoracic endovascular aortic repair (fTEVAR) using physician modified stent grafts (PMSGs) to revascularise aortic branches for acute type B aortic dissection (ABAD) with unfavourable proximal landing zone. METHODS: Twenty consecutive patients who underwent fenestrated TEVAR using PMSGs between November 2015 and December 2016 were retrospectively reviewed. Pre-, intra-, and post-operative clinical data were recorded. RESULTS: The median patient age was 53 years (range, 18-83 years), and 16 of the 20 (80%) patients were men. Indications were complicated ABAD with unfavourable proximal landing zones, including inadequate proximal landing zone (n = 4), retrograde dissection extending to the left subclavian artery (LSA) (n = 13), and retrograde haematoma involving the LSA (n = 3). Twenty PMSGs (Medtronic Valiant stent grafts, n = 4; Relay thoracic stent grafts, n = 10; Ankura thoracic stent grafts, n = 6) were deployed. One LSA fenestration was created in 19 patients, and one LSA fenestration combined with a left common carotid artery (LCCA) scallop was created in one patient. Branch stents consist of a covered stent for the LSA (n = 7), an uncovered stent for the LSA (n = 14), and an uncovered stent for the LCCA (n = 1). The median duration for stent graft modifications was 40 min (range 30-60 min). The mean interval between symptom onset and treatment was 5 +/- 3 days (range, 1-10 days). The initial technical success rate was 90% (18 of 20). Partial coverage of the LCCA in one patient resolved after uncovered chimney stent implantation in the LCCA. Type III endoleak between the LSA covered stent and the PMSG occurred in this patient 1 week post fTEVAR and resolved after re-intervention with deployment of an Amplatzer occluder device across the site of the leak. A chimney stent was deployed to solve the misalignment of the LSA in another patient. The mean operation time was 101 +/- 48 min, and fluoroscopy time was 24 +/- 16 min. There were no in hospital deaths and no peri-operative neurological complications. The median length of stay was 9 +/- 6 days (range, 5-26 days). One patient had a left brachial artery (LBA) pseudoaneurysm at the puncture site that required open repair. One patient presented renal deterioration post-operatively and recovered uneventfully after conservative therapy. All patients survived at a mean follow up of 6.95 months (range, 2-14 months). During follow-up, no post-operative complications occurred and all target vessels remained patent. No fenestration related Type I or III endoleaks were observed. CONCLUSIONS: fTEVAR using PMSGs may be a viable alternative for patients who present with ABAD without healthy proximal landing zones and who are unable to wait for a custom made fenestrated device. PMID- 29241688 TI - Event-triggered containment control for second-order multi-agent systems with sampled position data. AB - This paper is concerned with the problem of event-triggered containment control for second-order multi-agent systems with sampled position data. First, a distributed event-triggered containment control protocol is designed, which utilizes the sampled position data only and allows the event-triggering condition to be intermittently examined at constant sampling instants. Then, based on the algebraic graph theory and matrix theory, a sufficient condition on the communication topology, the controller gains, and the sampling period is derived so as to achieve containment control. Finally, a numerical example is provided to verify the theoretical results. PMID- 29241690 TI - Nuclear positioning in skeletal muscle. AB - Skeletal muscle cells possess a unique cellular architecture designed to fulfill their contractile function. Muscle cells (also known as myofibers) result from the fusion of hundreds of myoblasts and grow into a fiber of several centimeters in length. Cellular structures gradually become organized during muscle development to raise a mature contractile cell. A hallmark of this singular cell architecture is the position of nuclei at the periphery of the myofiber, below the plasma membrane. Nuclei in myofibers are evenly distributed except in specialized regions like the neuromuscular or myotendinous junctions. Disruption of nuclear positioning results in hindered muscle contraction and occurs in a multitude of muscle disorders as well as in regenerative myofibers. We will explore in this review the step by step nuclear migrations during myogenesis for nuclei to reach their evenly distributed anchored position at the periphery. PMID- 29241692 TI - In vitro inhibitory effects of major bioactive constituents of Andrographis paniculata, Curcuma longa and Silybum marianum on human liver microsomal morphine glucuronidation: A prediction of potential herb-drug interactions arising from andrographolide, curcumin and silybin inhibition in humans. AB - This study aimed to investigate the liver microsomal inhibitory effects of silybin, silychristin, andrographolide, and curcumin by using morphine as an in vitro UGT2B7 probe substrate, and predict the magnitude of the herb-drug interaction arising from these herbal constituents' inhibition in vivo. Studies were performed in the incubation with and without bovine serum albumin (BSA). Andrographolide and curcumin showed a marked inhibition on morphine 3- and 6 glucuronidation with IC50 of 50&87 and 96&111 MUM, respectively. In the presence of 2%BSA, andrographolide also showed a strong inhibition on morphine 3- and 6 glucuronidation (IC50 4.4&21.6 MUM) whereas curcumin showed moderate inhibition (IC50 338&333 MUM). In the absence and presence of 2%BSA, morphine 3- and 6 glucuronidation was moderately inhibited by silybin (IC50 583&862 and 1252&1421 MUM, respectively), however was weakly inhibited by silychristin (IC50 3527&3504 and 1124&1530 MUM, respectively). The Ki of andrographolide, curcumin and silybin on morphine 3- and 6-glucuronidation were 7.1&9.5, 72.7&65.2, and 224.5&159.7 MUM, respectively, while the respective values generated from the system containing 2%BSA were 2.4&3.1, 96.4&108.8, and 366.3&394.5 MUM. Using the in vitro and in vivo extrapolation approach, andrographolide was herbal component that may have had a potential interaction in vivo when it was co-administered with morphine. PMID- 29241691 TI - Nuclear positioning in migrating fibroblasts. AB - The positioning and movement of the nucleus has recently emerged as an important aspect of cell migration. Understanding of nuclear positioning and movement has reached an apogee in studies of fibroblast migration. Specific nuclear positioning and movements have been described in the polarization of fibroblast for cell migration and in active migration in 2D and 3D environments. Here, we review recent studies that have uncovered novel molecular mechanisms that contribute to these events in fibroblasts. Many of these involve a connection between the nucleus and the cytoskeleton through the LINC complex composed of outer nuclear membrane nesprins and inner nuclear membrane SUN proteins. We consider evidence that appropriate nuclear positioning contributes to efficient fibroblast polarization and migration and the possible mechanism through which the nucleus affects cell migration. PMID- 29241693 TI - Biological mechanisms beyond network analysis via mathematical modeling: Comment on "Network science of biological systems at different scales: A review" by Marko Gosak et al. PMID- 29241689 TI - Nuclear movement in fungi. AB - Nuclear movement within a cell occurs in a variety of eukaryotic organisms including yeasts and filamentous fungi. Fungal molecular genetic studies identified the minus-end-directed microtubule motor cytoplasmic dynein as a critical protein for nuclear movement or orientation of the mitotic spindle contained in the nucleus. Studies in the budding yeast first indicated that dynein anchored at the cortex via its anchoring protein Num1 exerts pulling force on an astral microtubule to orient the anaphase spindle across the mother daughter axis before nuclear division. Prior to anaphase, myosin V interacts with the plus end of an astral microtubule via Kar9-Bim1/EB1 and pulls the plus end along the actin cables to move the nucleus/spindle close to the bud neck. In addition, pushing or pulling forces generated from cortex-linked polymerization or depolymerization of microtubules drive nuclear movements in yeasts and possibly also in filamentous fungi. In filamentous fungi, multiple nuclei within a hyphal segment undergo dynein-dependent back-and-forth movements and their positioning is also influenced by cytoplasmic streaming toward the hyphal tip. In addition, nuclear movement occurs at various stages of fungal development and fungal infection of plant tissues. This review discusses our current understanding on the mechanisms of nuclear movement in fungal organisms, the importance of nuclear positioning and the regulatory strategies that ensure the proper positioning of nucleus/spindle. PMID- 29241694 TI - Design and Application of a Novel Patient-Specific Three-Dimensional Printed Drill Navigational Guiding in Atlantoaxial Pedicle Screw Placement. AB - PURPOSE: To explore accuracy and clinical efficacy of a novel patient-specific three-dimensional (3D) printed drill navigational guiding template in atlantoaxial pedicle screw placement. METHODS: A retrospective analysis of 49 patients with atlantoaxial vertebral fractures and dislocations was performed. Patients were divided into a 3D printed navigational guiding template group (n = 25) and traditional group (n = 14). Safety of screw position was assessed, and accuracy of 2 screw placement methods was compared. Accuracy of screw placement was assessed by comparing differences between preoperative designed channel transverse angle and postoperative actual screw placement angle. Two groups were compared to find differences between operative time, intraoperative blood loss, screw placement time, number of fluoroscopy examinations, visual analog scale score, and Japanese Orthopaedic Association score. RESULTS: There were statistically significant differences between the guiding template group and traditional group in operative time, intraoperative blood loss, screw placement time, and number of fluoroscopy examinations. No statistically significant differences were found between groups in transverse and sagittal angles with ideal values. There were statistically significant differences between preoperative and 1-week, 1-month, 3-month, 6-month, and 1-year postoperative visual analog scale and Japanese Orthopaedic Association scores in the same group, whereas there were no statistically significant differences between the groups. CONCLUSIONS: Use of the novel patient-specific 3D printed drill navigational guiding template in surgical treatment of atlantoaxial fracture and dislocation can improve accuracy of pedicle screw placement and safety of the surgery, can reduce surgical risks, and can obtain satisfactory clinical curative effects. PMID- 29241695 TI - Percutaneous Full-Endoscopic Anterior Transcorporeal Procedure for Cervical Disc Herniation: A Novel Procedure and Early Follow-Up Study. AB - OBJECTIVE: To describe the surgical technique of percutaneous full-endoscopic anterior transcorporeal cervical discectomy (PEATCD) in detail and report the clinical outcomes and radiologic changes in patients with cervical intervertebral disc herniation (CIVDH). METHODS: A novel procedure, PEATCD, was performed on 36 patients with CIVDH between June 2015 and June 2016. A retrospective study of these patients was carried out over a follow-up period of 12-24 months. The visual analog scale scores, Japanese Orthopedic Association (JOA) scores, and improvement rates (IRs) of the JOA scores were used to evaluate neurologic symptoms. Radiologic follow-up included magnetic resonance imaging, computed tomography scan, and standard radiographs. RESULTS: All patients reported immediate postoperative relief of neck and arm pain compared with the recorded preoperative levels of discomfort, and the JOA scores improved gradually during the follow-up period. The IRs of the neurologic evaluations ranged from 60% to 100%, the average being 85.47% +/- 9.32%. The decrease in the intervertebral disc height was statistically significant (P < 0.0001), and there were no adverse clinically related symptoms. No collapse of the drilled vertebrae was recorded, and the bone defects showed significant decreases within 3 months after the operation. There were no surgery-related complications. CONCLUSIONS: PEATCD combines the benefits of an anterior transcorporeal approach with endoscopy, preserves the cervical motion segment and causes less damage to the disc, and significantly decreases surgical trauma. Therefore, PEATCD is a safe, effective, minimally invasive, alternative procedure for patients with CIVDH. PMID- 29241696 TI - Serious Concomitant Injuries in Pediatric Patients with Severe Traumatic Brain Injury. AB - BACKGROUND: Severe traumatic brain injury (TBI) is a leading cause of death among children. Although several studies have reported the negative effects of concomitant injuries on mortality in adults with TBI, their effect on pediatric patients remains unclear. Our objective was to describe the effect of serious concomitant injuries on outcomes in pediatric patients with severe TBI. METHODS: We identified pediatric patients (<18 years) with severe TBI between 2004 and 2015, through the Japan Trauma Data Bank. We excluded patients who had cardiopulmonary arrest on arrival and those whose main outcome (mortality) was missed from the analyses. Two groups with severe TBI were compared on the basis of the presence of serious concomitant injuries (maximum Abbreviated Injury Scale score >=3 in regions other than the head) and adjusted for potential confounders using multiple logistic regression analysis. RESULTS: One-thousand-and-thirty four participants were eligible for analysis, of which 472 had serious concomitant injuries. Pediatric patients with a serious concomitant injury had higher mortality. The probability difference was 11.5 (95% confidence interval [CI]: 6.1%-16.9%), which was greater than the mortality of 1.5 (95% CI: 1.2% 1.8%) observed in patients with a serious injury but not TBI. The presence of a serious concomitant injury was significantly associated with increased mortality, even after adjusting for possible confounders (adjusted odds ratio, 2.01; 95% CI, 1.40-2.89; P < 0.001). CONCLUSION: Serious concomitant injuries are associated with higher mortality in pediatric patients with severe TBI, as a direct consequence, as well as due to concomitant injuries potentiating TBI pathobiology. PMID- 29241697 TI - Opening the black box of endocrine disruption of brain development: Lessons from the characterization of Bisphenol A. AB - Bisphenol A (BPA) is among the best-studied endocrine disrupting chemicals, known to act via multiple steroid hormone receptors to mediate a myriad of cellular effects. Pre-, peri-, and postnatal BPA exposure have been linked to a variety of altered behaviors in multiple model organisms, ranging from zebrafish to frogs to mammalian models. Given that BPA can cross the human placental barrier and has been found in the serum of human fetuses during gestation, BPA has been postulated to adversely affect ongoing neurodevelopment, ultimately leading to behavioral disorders later in life. Indeed, the brain has been identified as a key developmental target for BPA disruption. Despite these known associations between gestational BPA exposure and adverse developmental outcomes, as well as an extensive body of evidence existing in the literature, the mechanisms by which BPA induces its cellular- and tissue-specific effects on neurodevelopmental processes still remains poorly understood at a mechanistic level. In this review we will briefly summarize the effects of gestational BPA exposure on neural developmental mechanisms and resulting behaviors, and then present suggestions for how we might address gaps in our knowledge to develop a fuller understanding of endocrine neurodevelopmental disruption to better inform governmental policy against the use of BPA or other endocrine disruptors. PMID- 29241698 TI - Telephone triage and midwifery: A scoping review. AB - BACKGROUND: Midwives use telephone triage to provide advice and support to childbearing women, and to manage access to maternity services. Telephone triage practises are important in the provision of accurate, timely and appropriate health care. Despite this, there has been very little research investigating this area of midwifery practice. AIM: To explore midwives and telephone triage practises; and to discuss the relevant findings for midwives managing telephone calls from women. METHODS: A five-stage process for conducting scoping reviews was employed. Searches of relevant databases as well as grey literature, and reference lists from included studies were carried out. FINDINGS: A total of 11 publications were included. Thematic analysis was used to identify key concepts. We grouped these key concepts into four emergent themes: purpose of telephone triage, expectations of the midwife, challenges of telephone triage, and achieving quality in telephone triage. DISCUSSION: Telephone triage from a midwifery perspective is a complex multi-faceted process influenced by many internal and external factors. Midwives face many challenges when balancing the needs of the woman, the health service, and their own workloads. Primary research in this area of practice is limited. CONCLUSION: Further research to explore midwives' perceptions of their role, investigate processes and tools midwives use, evaluate training programs, and examine outcomes of women triaged is needed. PMID- 29241699 TI - Sterile water injections for childbirth pain: An evidenced based guide to practice. AB - BACKGROUND: About 30% of women in labour suffer from lower back pain. Studies of sterile water injections for management of low back pain have consistently shown this approach to be effective. The objective of this evidence-based guide is to facilitate the clinical use of sterile water injections to relieve lower back pain in labouring women. METHODS: To identify relevant publications our search strategy was based on computerised literature searches in scientific databases. The methodological quality of each study was assessed using the modified version of the Jadad scale, 12 studies were included. FINDINGS: Recommendations regarding the clinical use of sterile water injections for pain relief in labour are reported in terms of the location of injection administration, various injection techniques, number of injections used, amount of sterile water in each injection and adverse effects. DISCUSSION: Both injection techniques provide good pain relief for lower back pain during labour. The subcutaneous injection technique is possibly less painful than the intracutaneous technique administered, but we are unsure if this impacts on effectiveness. The effect seems to be related to the number of injections and the amount of sterile water in each injection. CONCLUSION: The recommendation at present, based on the current state of knowledge, is to give four injections. Notwithstanding the differences in injection technique and number of injections the method appears to provide significant levels of pain relief and can be repeated as often as required with no adverse effect (apart from the administration pain) on the woman or her foetus. PMID- 29241700 TI - Characterization of the coating and tablet core roughness by means of 3D optical coherence tomography. AB - This study demonstrates the use of optical coherence tomography (OCT) to simultaneously characterize the roughness of the tablet core and coating of pharmaceutical tablets. OCT is a high resolution non-destructive and contactless imaging methodology to characterize structural properties of solid dosage forms. Besides measuring the coating thickness, it also facilitates the analysis of the tablet core and coating roughness. An automated data evaluation algorithm extracts information about coating thickness, as well as tablet core and coating roughness. Samples removed periodically from a pan coating process were investigated, on the basis of thickness and profile maps of the tablet core and coating computed from about 480,000 depth measurements (i.e., 3D data) per sample. This data enables the calculation of the root mean square deviation, the skewness and the kurtosis of the assessed profiles. Analyzing these roughness parameters revealed that, for the given coating formulation, small valleys in the tablet core are filled with coating, whereas coarse features of the tablet core are still visible on the final film-coated tablet. Moreover, the impact of the tablet core roughness on the coating thickness is analyzed by correlating the tablet core profile and the coating thickness map. The presented measurement method and processing could be in the future transferred to in-line OCT measurements, to investigate core and coating roughness during the production of film-coated tablets. PMID- 29241701 TI - Production of cocrystals in an excipient matrix by spray drying. AB - Spray drying is a well-established scale-up technique for the production of cocrystals. However, to the best of our knowledge, the effect of introducing a third component into the feed solution during the spray drying process has never been investigated. Cocrystal formation in the presence of a third component by a one-step spray drying process has the potential to reduce the number of unit operations which are required to produce a final pharmaceutical product (e.g. by eliminating blending with excipient). Sulfadimidine (SDM), a poorly water soluble active pharmaceutical ingredient (API), and 4-aminosalicylic acid (4ASA), a hydrophilic molecule, were used as model drug and coformer respectively to form cocrystals by spray drying in the presence of a third component (excipient). The solubility of the cocrystal in the excipient was measured using a thermal analysis approach. Trends in measured solubility were in agreement with those determined by calculated Hansen Solubility Parameter (HSP) values. The ratio of cocrystal components to excipient was altered and cocrystal formation at different weight ratios was assessed. Cocrystal integrity was preserved when the cocrystal components were immiscible with the excipient, based on the difference in Hansen Solubility Parameters (HSP). For immiscible systems (difference in HSP > 9.6 MPa0.5), cocrystal formation occurred even when the proportion of excipient was high (90% w/w). When the excipient was partly miscible with the cocrystal components, cocrystal formation was observed post spray drying, but crystalline API and coformer were also recovered in the processed powder. An amorphous dispersion was formed when the excipient was miscible with the cocrystal components even when the proportion of excipient used as low (10% w/w excipient). For selected spray dried cocrystal-excipient systems an improvement in tableting characteristics was observed, relative to equivalent physical mixtures. PMID- 29241702 TI - Effect of high pressure homogenization on the structure and the interfacial and emulsifying properties of beta-lactoglobulin. AB - The effect of high pressure homogenization (HPH) on the structure of beta lactoglobulin (beta-lg) was studied by combining spectroscopic, chromatographic, and electrophoretic methods. The consequences of the resulting structure modifications on oil/water (O/W) interfacial properties were also assessed. Moderated HPH treatment (100 MPa/4 cycles) showed no significant modification of protein structure and interfacial properties. However, a harsher HPH treatment (300 MPa/5 cycles) induced structural transformation, mainly from beta-sheets to random coils, wide loss in lipocalin core, and protein aggregation via intermolecular disulfide bridges. HPH-modified beta-lg displayed higher surface hydrophobicity leading to a faster adsorption rate at the interface and an earlier formation of an elastic interfacial film at Cbeta-lg = 0.1 wt%. However, no modification of the interfacial properties was observed at Cbeta-lg = 1 wt%. At this protein concentration, the prior denaturation of beta-lg by HPH did not modify the droplet size of nanoemulsions prepared with these beta-lg solutions as the aqueous phases. A slightly increased creaming rate was however observed. The effects of HPH and heat denaturations appeared qualitatively similar, but with differences in their extent. PMID- 29241703 TI - The artificial membrane insert system as predictive tool for formulation performance evaluation. AB - In view of the increasing interest of pharmaceutical companies for cell- and tissue-free models to implement permeation into formulation testing, this study explored the capability of an artificial membrane insert system (AMI-system) as predictive tool to evaluate the performance of absorption-enabling formulations. Firstly, to explore the usefulness of the AMI-system in supersaturation assessment, permeation was monitored after induction of different degrees of loviride supersaturation. Secondly, to explore the usefulness of the AMI-system in formulation evaluation, a two-stage dissolution test was performed prior to permeation assessment. Different case examples were selected based on the availability of in vivo (intraluminal and systemic) data: (i) a suspension of posaconazole (Noxafil(r)), (ii) a cyclodextrin-based formulation of itraconazole (Sporanox(r)), and (iii) a micronized (Lipanthyl(r)) and nanosized (Lipanthylnano(r)) formulation of fenofibrate. The obtained results demonstrate that the AMI-system is able to capture the impact of loviride supersaturation on permeation. Furthermore, the AMI-system correctly predicted the effects of (i) formulation pH on posaconazole absorption, (ii) dilution on cyclodextrin-based itraconazole absorption, and (iii) food intake on fenofibrate absorption. Based on the applied in vivo/in vitro approach, the AMI-system combined with simple dissolution testing appears to be a time- and cost-effective tool for the early stage evaluation of absorption-enabling formulations. PMID- 29241704 TI - Development and characterization of an anthropomorphic breast phantom for permanent breast seed implant brachytherapy credentialing. AB - PURPOSE: To develop an anthropomorphic breast phantom for use in credentialing of permanent breast seed implant brachytherapy. METHODS AND MATERIALS: A representative external contour and target volume was used as the basis of mold manufacturing for anthropomorphic breast phantom development. Both target and normal tissue were composed of gel-like materials that provide suitable computed tomography and ultrasound contrast for brachytherapy delivery. The phantoms were evaluated for consistency in construction (target location) and Hounsfield unit (computed tomography contrast). For both target and normal tissue, the speed of sound was measured and compared to the image reconstruction algorithm's expectation value. Five phantoms were imaged preimplant and postimplant to assess interphantom similarity as well as to evaluate the uncertainty in quantifying seed position. RESULTS: The average Hounsfield units of the target and normal tissue gels is -146 +/- 5 and 23 +/- 1, respectively. The average speed of sound of the target and normal tissue gels is 1485 +/- 7 m/s and 1558 +/- 9 m/s, respectively, resulting in an estimated 0.4 mm uncertainty in image guidance. The registration/deformation uncertainty was determined to be 0.8 mm. The standard combined uncertainty in assessing seed position spatial accuracy, also including a 0.9 mm estimate based on literature for seed localization, is estimated to be 1.3 mm. CONCLUSIONS: The development of the anthropomorphic breast phantom and evaluation of both the consistency as well as overall seed position uncertainty illustrates the suitability of this phantom for use in brachytherapy end-to-end delivery and implant accuracy evaluation. When evaluating a user's implant accuracy, we estimate a standard combined uncertainty of 1.3 mm. PMID- 29241705 TI - Characterizing the impact of adaptive planning on image-guided perineal interstitial brachytherapy for gynecologic malignancies. AB - PURPOSE: To determine the dosimetric impact of organ and implant motion/deformation in the context of adaptive planning in image-guided gynecologic brachytherapy using a 3-fraction transperineal approach. METHODS AND MATERIALS: Twenty-six patients were analyzed. Each patient was treated with three fractions given over a 24-h period using a single insertion. A planning CT scan (+/-MRI) was acquired before the first fraction. A verification scan was taken within 1 h following the second fraction. A single plan was delivered for Fractions 1 and 2 with an adaptive plan delivered for Fraction 3. Two evaluation frameworks were established. Framework 1 investigated the effects of motion/deformation from both implant and organs. Framework 2 investigated the impact of implant motion/deformation alone. Differences in high-risk clinical target volume (HRCTV) D90%, V100%, and bladder/rectum D2cc were assessed. RESULTS: From implant to verification, the HRCTV D90% and V100% decreased significantly (5.0%, p < 0.01; 3.1%, p < 0.01) and rectal D2cc was significantly higher (12.2%, p = 0.02). Adaptive planning recouped these changes. Implant changes resulted in a reduction in HRCTV dose and coverage, but no significant effect was seen in the bladder or rectum. CONCLUSIONS: Adaptive planning represents an important aspect of perineal-based interstitial image-guided brachytherapy given in three fractions; its absence would result in plan degradation. PMID- 29241706 TI - Placement of an absorbable rectal hydrogel spacer in patients undergoing low-dose rate brachytherapy with palladium-103. AB - PURPOSE: Rates of rectal toxicity after low-dose-rate (LDR) brachytherapy for prostate cancer are dependent on rectal dose, which is associated with rectal distance from prostate and implanted seeds. Placement of a hydrogel spacer between the prostate and rectum has proven to reduce the volume of the rectum exposed to higher radiation dose levels in the setting of external beam radiotherapy. We present our findings with placing a rectal hydrogel spacer in patients following LDR brachytherapy, and we further assess the impact of this placement on dosimetry and acute rectal toxicity. METHODS AND MATERIALS: Between January 2016 and April 2017, 74 patients had placement of a hydrogel spacer, immediately following a Pd-103 seed-implant procedure. Brachytherapy was delivered as follows: as a monotherapy to 26 (35%) patients; as part of planned combination therapy with external beam radiotherapy to 40 (54%) patients; or as a salvage monotherapy to eight (11%) patients. Postoperative MRI was used to assess separation achieved with rectal spacer. Acute toxicity was assessed retrospectively using Radiation Oncology Therapy Group radiation toxicity grading system. Rectal dosimetry was compared with a consecutive cohort of 136 patients treated with seed implantation at our institution without a spacer, using a 2 tailed paired Student's t test (p < 0.05 for statistical significance). RESULTS: On average, 11.2-mm (SD 3.3) separation was achieved between the prostate and the rectum. The resultant mean rectal volume receiving 100% of prescribed dose (V100%), dose to 1 cc of rectum (D1cc), and dose to 2 cc of rectum (D2cc) were 0 (SD 0.05 cc), 25.3% (SD 12.7), and 20.5% (SD 9.9), respectively. All rectal dosimetric parameters improved significantly for the cohort with spacer placement as compared with the nonspacer cohort. Mean prostate volume, prostate V100 and dose to 90% of gland (D90) were 29.3 cc (SD 12.4), 94.0% (SD 3.81), and 112.4% (SD 12.0), respectively. Urethral D20, D5cc, and D1cc were 122.0% (SD 17.27), 133.8% (SD 22.8), and 144.0% (SD 25.4), respectively. After completing all treatments, at the time of first the followup, 7 patients reported acute rectal toxicity-6 experiencing Grade 1 rectal discomfort and 1 (with preexisting hemorrhoids) experiencing Grade 1 bleeding. CONCLUSIONS: Injection of rectal spacer is feasible in the post-LDR brachytherapy setting and reduces dose to the rectum with minimal toxicity. Prostate and urethral dosimetries do not appear to be affected by the placement of a spacer. Further studies with long-term followup are warranted to assess the impact on reduction of late rectal toxicity. PMID- 29241707 TI - Expression of the DJ-1 protein in the serum of Chinese patients with Parkinson's disease. AB - DJ-1 is one of the important genes found in Parkinson's disease (PD). Studies have shown that the DJ-1 protein levels are elevated in the cerebrospinal fluid (CSF) and plasma of sporadic PD patients, and the DJ-1 protein levels in the CSF and plasma may serve as biomarkers of PD. However, Japanese scholars previously reported that there was no difference in the levels of the DJ-1 protein in serum between sporadic PD patients and controls. Therefore, whether the serum DJ-1 protein levels are different between PD patients and controls in Chinese patients as well as whether serum DJ-1 protein can serve as a biomarker of PD are unknown. The present study aimed to determine whether there was a difference in serum DJ-1 protein levels between Chinese PD patients and controls. The subjects included 18 primary PD patients and 7 controls. Blood was collected by venipuncture, and serum was collected by centrifugation after the blood was coagulated. The serum DJ-1 protein levels were detected by both Western blot and ELISA. There were differences in the serum DJ-1 protein levels among different individuals. The serum DJ-1 concentration in PD patients was 11.3+/-10.1ng/ml, and that in controls was 18.1+/-12.8ng/ml (P>0.05). In conclusion, similar to the study conducted by Japanese scholars, we found no significant difference in the serum DJ-1 protein levels between PD patients and controls in Chinese subjects. The levels of the DJ-1 protein in serum may not be a biomarker of PD. In addition, there may be differences in the serum DJ-1 protein levels between Chinese and Japanese patients. PMID- 29241708 TI - Contribution of CB1Rs in anxiety-related behaviors but not locomotor deficits induced by methamphetamine. AB - Several lines of evidence have indicated that Methamphetamine (METH) exposure leads to neurodegenerative changes in the dopaminergic neurons and subsequently may predispose users to motor deficit. On the other hand, there is a reciprocal regulation between the endocannabinoid and the dopaminergic systems. Previous studies also showed that the endocannabinoids are involved in the signaling mechanisms of various brain regions related to motor and cognitive functions. The cerebellum seems as a rational target to investigate the action of cannabinoids on motor coordination because of the high concentration of the cannabinoid receptor in the molecular layer of it and other regions involved in motor activity. The behavioral effects of systemic CBR agonist (3mg/kg/day WIN55,212-2) and antagonist (10mg/kg SR141716A) treatment on METH-induced motor deficits in rats were assessed using open field, rota-rod, and grip tests. Our results show that motor coordination and muscle strength significantly decreased in the animals received METH (5mg/kg, daily*3days) as compared to the saline groups. Pretreatment with neither WIN55,212-2 nor SR141716A had no effects on impairments induced by METH. Meanwhile, motor activity and anxiety-related behaviors significantly increased in the animals that received METH and pretreatment with SR141716A significantly attenuated anxiety-related behaviors induced by METH. In sum, our findings show that anxiety-related behaviors induced by METH can be affected by CB1R manipulation and provide evidence that antagonism of CB1R at high dose cannot reverse the deteriorative METH-induced locomotion changes. PMID- 29241709 TI - Regulation of Pleiotrophin and Fyn in the striatum of rats undergoing L-DOPA induced dyskinesia. AB - L-DOPA is the gold standard pharmacological therapy for symptomatic treatment of Parkinson's disease (PD), however, its long-term use is associated with the emergence of L-DOPA-induced dyskinesia (LID). Understanding the underlying molecular mechanisms of LID is crucial for the development of newer and more effective therapeutic approaches. In previous publications, we have shown that Pleiotrophin (PTN), a developmentally regulated trophic factor, is up-regulated by L-DOPA in the striatum of dopamine denervated rats. We have also shown that both mRNA and protein levels of RPTPzeta/beta, a PTN receptor, were upregulated in the same experimental condition and expressed in striatal medium spiny neurons. The PTN-RPTPzeta/beta intracellular pathway has not been fully explored and it might be implicated in the striatal plastic changes triggered by L-DOPA treatment. RPTPzeta/beta is part of the postsynaptic density zone and modulates Fyn, a Src tyrosine kinase that regulates the NR2A and NR2B subunits of the NMDA receptor and has been singled out as a key molecule in the development of LID. In this study, we evaluated the changes in PTN and Fyn protein levels and Fyn phosphorylation status in the 6-OHDA rat model of PD rendered dyskinetic with L DOPA. We found an increase in the number of PTN immunoreactive neurons, no changes in the amount of total Fyn but a significant increase in Fyn phosphorylation in the dorsolateral striatum of dyskinetic rats. Our results support the idea that both PTN and Fyn may be involved in the development of LID, further contributing to the understanding of its molecular mechanisms. PMID- 29241710 TI - New insights into the gene expression associated to amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is the most prevalent neuromuscular disease worldwide. It is a lethal and progressive neurodegenerative disease, principally affecting motor neurons; patient clinical characteristics are muscle weakness, dysphagia and respiratory failure. The mean age is related to family history (40years, familial ALS or FALS) or with no family history (50years), but it is more common in people aged 60-69years. The cause of ALS is not known and it is not known yet why it affects some people and not others. However expert consensus is that molecular alterations in different cells are involved in the development and progression of the disease. For example, motor neuron death is caused by a variety of cellular defects, including the processing of RNA molecules, water channels, and calcium levels, increasing evidence that these alterations of cells in the nervous system play an important role in ALS. Here we will systematically examine different genes (AQP1, SLC14A1, MT1X, DSCR1L1, PCP4, UCHL1, GABRA1, EGR1, OLFM1 and VSNL1) that are "up or down" regulated in the motor cortex and spinal cord and their association with ALS risk. These could be novel biomarkers associated with ALS risk. We built an interaction Network with Cytoscape, this was used to identify pathways, miRNA and drugs associated to ALS. The most important affected pathway is PI3K-Akt signaling. Thirteen microRNAs (miRNA-19B1, miRNA-107, miRNA-124-1, miRNA-124-2, miRNA-9-2, miRNA-29A, miRNA-9-3, miRNA-328, miRNA-19B2, miRNA-29B2, miRNA-124-3, miRNA-15A and miRNA-9-1) and four drugs (Estradiol, Acetaminophen, Progesterone and resveratrol) for new possible treatments were identified. PMID- 29241712 TI - Among the topics of this issue: Health literacy and interpreter-mediated communication. PMID- 29241711 TI - l-Carnitine and heart disease. AB - Cardiovascular disease (CVD) is a key cause of deaths worldwide, comprising 15 17% of healthcare expenditure in developed countries. Current records estimate an annual global average of 30 million cardiac dysfunction cases, with a predicted escalation by two-three folds for the next 20-30years. Although beta-blockers and angiotensin-converting-enzymes are commonly prescribed to control CVD risk, hepatotoxicity and hematological changes are frequent adverse events associated with these drugs. Search for alternatives identified endogenous cofactor l carnitine, which is capable of promoting mitochondrial beta-oxidation towards a balanced cardiac energy metabolism. l-Carnitine facilitates transport of long chain fatty acids into the mitochondrial matrix, triggering cardioprotective effects through reduced oxidative stress, inflammation and necrosis of cardiac myocytes. Additionally, l-carnitine regulates calcium influx, endothelial integrity, intracellular enzyme release and membrane phospholipid content for sustained cellular homeostasis. Carnitine depletion, characterized by reduced expression of "organic cation transporter-2" gene, is a metabolic and autosomal recessive disorder that also frequently associates with CVD. Hence, exogenous carnitine administration through dietary and intravenous routes serves as a suitable protective strategy against ventricular dysfunction, ischemia reperfusion injury, cardiac arrhythmia and toxic myocardial injury that prominently mark CVD. Additionally, carnitine reduces hypertension, hyperlipidemia, diabetic ketoacidosis, hyperglycemia, insulin-dependent diabetes mellitus, insulin resistance, obesity, etc. that enhance cardiovascular pathology. These favorable effects of l-carnitine have been evident in infants, juvenile, young, adult and aged patients of sudden and chronic heart failure as well. This review describes the mechanism of action, metabolism and pharmacokinetics of l-carnitine. It specifically emphasizes upon the beneficial role of l-carnitine in cardiomyopathy. PMID- 29241713 TI - Effects of superficial heating and insulation on walking speed in people with hereditary and spontaneous spastic paraparesis: A randomised crossover study. AB - OBJECTIVES: Cooling of the lower limb in people with Hereditary and Spontaneous Spastic Paraparesis (pwHSSP) has been shown to affect walking speed and neuromuscular impairments. The investigation of practical strategies, which may help to alleviate these problems is important. The potential of superficial heat to improve walking speed has not been explored in pwHSSP. Primary objective was to explore whether the application of superficial heat (hot packs) to lower limbs in pwHSSP improves walking speed. Secondary objective was to explore whether wearing insulation after heating would prolong any benefits. METHODS: A randomised crossover study design with 21 pwHSSP. On two separate occasions two hot packs and an insulating wrap (Neo-GTM) were applied for 30minutes to the lower limbs of pwHSSP. On one occasion the insulating wrap was maintained for a further 30minutes and on the other occasion it was removed. Measures of temperature (skin, room and core), walking speed (10 metre timed walk) and co ordination (foot tap time) were taken at baseline (T1), after 30 mins (T2) and at one hour (T3). RESULTS: All 21 pwHSSP reported increased lower limb stiffness and decreased walking ability when their legs were cold. After thirty minutes of heating, improvements were seen in walking speed (12.2%, P<0.0001, effect size 0.18) and foot tap time (21.5%, P<0.0001, effect size 0.59). Continuing to wear insulation for a further 30minutes gave no additional benefit; with significant improvements in walking speed maintained at one hour (9.9%, P>0.001) in both conditions. CONCLUSIONS: Application of 30minutes superficial heating moderately improved walking speed in pwHSSP with effects maintained at 1hour. The use of hot packs applied to lower limbs should be the focus of further research for the clinical management of pwHSSP who report increased stiffness of limbs in cold weather and do not have sensory deficits. PMID- 29241714 TI - Morphological-molecular characterization and phylogenetic relationships of a new Trichuris species (Nematoda: Trichuridae) parasitic on Holochilus chacarius (Cricetidae: Sigmodontinae) from the Chaco ecoregion (Argentina). AB - A new Trichuris species isolated from Holochilus chacarius (Cricetidae: Sigmodontinae) from the Chaco ecoregion in Argentina is described based on morphological characteristics and mitochondrial (cox1, cob) and nuclear (ITS2) markers. The new species is distinguished from 27 species of Trichuris from North and South American rodents based on morphological and biometrical features, such as the absence of a spicular tube, presence of a cylindrical spicular sheath, non protrusive vulva, length of spicule, and proximal and distal cloacal tube. In addition, the results based on three molecular markers of the new species and three Trichuris species previously analysed from sigmodontine rodents: Trichuris pardinasi, Trichuris navonae and Trichuris bainae confirmed that the specimens here studied belong to a different species. Molecular data are further used to discuss the phylogenetic relationships among the Trichuris species of rodents from Argentina. The combined analysis of mitochondrial genes (cox1 and cob) revealed four clades corresponding with four different species of Trichuris. T. navonae (Akodontini rodents) and T. massoiai n. sp. as a sister group related to T. bainae (Oryzomyini rodents) and separated of T. pardinasi (Phyllotini rodents). PMID- 29241715 TI - Engaging Patients in Decisions About Cancer Screening: Exploring the Decision Journey Through the Use of a Patient Portal. AB - INTRODUCTION: Engaging patients to make informed choices is paramount but difficult in busy practices. This study sought to engage patients outside the clinical setting to better understand how they approach cancer screening decisions, including their primary concerns and their preferences for finalizing their decision. METHODS: Twelve primary care practices offering patients an online personal health record invited eligible patients to complete a 17-item online interactive module. Among 11,458 registered users, invitations to complete the module were sent to adults aged 50-74 years who were overdue for colorectal cancer screening and to women aged 40-49 years and men aged 55-69 who had not undergone a recent mammogram or prostate-specific antigen test, respectively. RESULTS: The module was started by 2,355 patients and completed by 903 patients. Most respondents (76.8%) knew they were eligible for screening. Preferred next steps were talking to the clinician (76.6%), reading/research (28.6%), and consulting trusted friends/family (16.4%). Priority topics included how much screening improves life expectancy, comparative test performance, and the prevalence/health risks of the cancer. Leading fears were getting cancer/delayed detection (79.2%), abnormal results (40.5%), and testing complications (39.1%), the last referring to false test results, medical complications, or unnecessary treatments. Men eligible for prostate-specific antigen screening were more likely than women eligible for mammography to express concerns about testing complications and to prioritize weighing pros and cons over gut feelings (p<0.05). CONCLUSIONS: Although this sample was predisposed to screening, most patients wanted help in finalizing their decision. Many wanted to weigh the pros and cons and expressed fears of potential harms from screening. Understanding how patients approach decisions may help design more effective engagement strategies. PMID- 29241716 TI - Dog Ownership and Mortality in England: A Pooled Analysis of Six Population-based Cohorts. AB - INTRODUCTION: Dog ownership may be associated with reduced risk for cardiovascular disease. However, data are scant on the relationship between dog ownership and all-cause and cause-specific mortality risk. METHODS: Data from six separate cohorts (1995-1997, 2001-2002, 2004) of the Health Survey for England were pooled and analyzed in 2017. Participants were 59,352 adults (mean age 46.5, SD=17.9 years) who consented to be linked to the National Death Registry. Living in a household with a dog was reported at baseline. Outcomes included all-cause and cardiovascular disease mortality (determined using ICD-9 codes 390-459, ICD 10 codes I01-I99). Multilevel Weibull survival analysis was used to examine the associations between dog ownership and mortality, adjusted for various sociodemographic and lifestyle variables. Potential effect modifiers, including age, sex, education, living circumstances, longstanding illness, and prior diagnosis of cardiovascular disease, were also examined. RESULTS: During 679,441 person-years of follow-up (mean 11.5, SD=3.8 years), 8,169 participants died from all causes and 2,451 from cardiovascular disease. In the fully adjusted models, there was no statistically significant association between dog ownership and mortality outcomes (hazard ratio=1.03, 95% CI=0.98, 1.09, for all-cause mortality; and hazard ratio=1.07, 95% CI=0.96, 1.18, for cardiovascular disease mortality) and no significant effect modification. CONCLUSIONS: There is no evidence for an association between living in a household with a dog and all cause or cardiovascular disease mortality in this large sample. These results should be interpreted in light of limitations in the measurement of dog ownership and its complexity in potential long-term health implications. Future studies should measure specific aspects of ownership, such as caring responsibilities and temporality. PMID- 29241717 TI - Provider Discussions of Genetic Tests With U.S. Women at Risk for a BRCA Mutation. AB - INTRODUCTION: The U.S. Preventive Services Task Force recommends that primary care providers screen unaffected women with a family history of BRCA mutation associated cancers, but without a personal history of BRCA-related cancer, for referral to genetic counseling and potential genetic testing. METHODS: The 2015 National Health Interview Survey was analyzed in January 2017 to determine the rates at which unaffected adult women with a positive family history of BRCA related cancers, assessed using the Family History Screen-7, reported discussing genetic testing with a provider, using genetic counseling services, and having genetic testing for increased cancer risk. Clinical correlates associated with these outcomes were assessed using multivariable logistic regression (AOR with 95% CI). RESULTS: Among unaffected Family History Screen-7 screen-positive women, 9.5% reported discussing genetic testing with a provider, 5.1% reported genetic counseling, and 2.7% reported uptake of genetic testing. Younger women (aged 18 39 and 40-49 years) were more likely to discuss genetic testing than women aged >=60 years (AOR=1.50, 95% CI=1.09, 2.06 and AOR=1.64, 95% CI=1.15, 2.33, respectively). Women of black race (AOR=1.50, 95% CI=1.09, 2.07) and women with greater than a high school education (AOR=1.85, 95% CI=1.41, 2.43) were more likely to discuss genetic testing than women of white race and women with a high school education or less, respectively. Among a higher risk subgroup with an even stronger family history of BRCA-associated cancers, 18.5% of women reported discussions. CONCLUSIONS: Despite a decade-old U.S. Preventive Services Task Force recommendation, few unaffected women at risk for BRCA-associated cancer report discussing genetic testing with a provider. PMID- 29241718 TI - SES, Heart Failure, and N-terminal Pro-b-type Natriuretic Peptide: The Atherosclerosis Risk in Communities Study. AB - INTRODUCTION: Compared with coronary heart disease and stroke, the association between SES and the risk of heart failure is less well understood. METHODS: In 12,646 participants of the Atherosclerosis Risk in Communities Study cohort free of heart failure history at baseline (1987-1989), the association of income, educational attainment, and area deprivation index with subsequent heart failure related hospitalization or death was examined while accounting for cardiovascular disease risk factors and healthcare access. Because SES may affect threshold of identifying heart failure and admitting for heart failure management, secondarily the association between SES and N-terminal pro-b-type natriuretic peptide (NT proBNP) levels, a marker reflecting cardiac overload, was investigated. Analysis was conducted in 2016. RESULTS: During a median follow-up of 24.3 years, a total of 2,249 participants developed heart failure. In a demographically adjusted model, the lowest-SES group had 2.2- to 2.5-fold higher risk of heart failure compared with the highest SES group for income, education, and area deprivation. With further adjustment for time-varying cardiovascular disease risk factors and healthcare access, these associations were attenuated but remained statistically significant (e.g., hazard ratio=1.92, 95% CI=1.69, 2.19 for the lowest versus highest income), with no racial interaction (p>0.05 for all SES measures). Similarly, compared with high SES, low SES was associated with both higher baseline level of NT-proBNP in a multivariable adjusted model (15% higher, p<0.001) and increase over time (~1% greater per year, p=0.023). CONCLUSIONS: SES was associated with clinical heart failure as well as NT-proBNP levels inversely and independently of traditional cardiovascular disease factors and healthcare access. PMID- 29241719 TI - Nativity Disparities in Human Papillomavirus Vaccination Among U.S. Adults. AB - INTRODUCTION: Several studies have identified disparities in human papillomavirus (HPV)-related outcomes by nativity status (i.e., U.S.- versus foreign-born). However, few studies have explored whether vaccination differences exist by nativity status. Vaccination disparities have the potential to exacerbate HPV related cancer disparities in the long term if left unaddressed. Therefore, the authors investigated whether there were significant differences in HPV vaccination initiation (one or more doses) and completion (three or more doses) between U.S.-born and foreign-born men and women. METHODS: Using the 2011 to 2015 waves of the National Health Interview Survey, data from 15,967 U.S. men aged 18 32 years and 23,794 U.S. women aged 18-35 years were analyzed in February 2017. Multivariable logistic regression models were fit to determine whether nativity status predicted (1) HPV vaccination initiation and (2) HPV vaccination completion separately among men and women after adjusting for demographic, socioeconomic, and healthcare factors. RESULTS: Compared with those born in the U.S., foreign-born men and women had lower prevalence of HPV vaccine initiation and completion. Furthermore, after controlling for covariates, foreign-born men (OR=0.63, 95% CI=0.47, 0.85) and women (OR=0.57, 95% CI=0.49, 0.66) had significantly lower adjusted odds of HPV vaccination initiation compared with their U.S.-born counterparts. Additionally, foreign-born women had significantly lower adjusted odds of HPV vaccination completion (OR=0.56, 95% CI=0.46, 0.69). CONCLUSIONS: The demographic, socioeconomic, and healthcare factors included in this study did not appear to account fully for observed disparities. Future research is needed to understand other factors that may contribute to nativity status disparities in HPV vaccination. PMID- 29241720 TI - Physician Training in Cancer Prevention and Control: A Population Health Imperative. AB - Cancer is the second leading cause of morbidity and mortality in the U.S. Although reducing the number of new cancer cases is a national health goal, the continuing growth of the older adult population ensures that the burden of cancer will increase. Despite documentation of the shortage of oncologists to meet the growing need, relatively limited attention has been focused on increasing the physician workforce trained in the prevention and control of cancer. The existing physician workforce with such specialized training in cancer prevention and control is small, aging, increasing at a low rate, and likely to decrease because of an imbalance between retiring physicians and new entrants. This commentary addresses the imperative for increasing the number of physicians trained in preventive medicine with a specialization in cancer prevention and control by first providing a brief overview of U.S. cancer morbidity and mortality, then describing the status of, and trends in, physician training in cancer prevention and control, and concluding by suggesting opportunities for bolstering physician training in cancer prevention and control. PMID- 29241721 TI - Screening for Alcohol Misuse: Practices Among U.S. Primary Care Providers, DocStyles 2016. AB - INTRODUCTION: Excessive alcohol use is associated with car crashes, violence, and multiple disease conditions, including fetal alcohol spectrum disorders. The U.S. Preventive Services Task Force (USPSTF) recommends that primary care providers screen all adults and conduct brief counseling interventions with those who misuse alcohol. The USPSTF prefers use of three screening tools that measure alcohol consumption (Alcohol Use Disorders Identification Test, Alcohol Use Disorders Identification Test-Consumption, and National Institute on Alcohol Abuse and Alcoholism Single Question) because these tools detect the full spectrum of alcohol misuse in adults. This study estimated the prevalence of primary care provider screening practices for alcohol misuse and examined factors associated with using a USPSTF-preferred screening tool. METHODS: In 2016, a cross-sectional analysis was conducted on self-reported 2016 DocStyles data to estimate the prevalence of different screening tools used by 1,506 primary care providers-family practitioners, internists, obstetrician/gynecologists, and nurse practitioners. Adjusted prevalence ratios were calculated using logistic regression to examine the association between provider attributes and use of USPSTF-preferred screening tools. RESULTS: In this study, 96% of providers reported screening patients for alcohol misuse. Among those that screened, 38% used a USPSTF-preferred screening tool. Provider specialty, awareness of USPSTF guidelines, and mode of administering screening tool were associated with using a preferred screening tool. CONCLUSIONS: Although most primary care providers reported screening for alcohol misuse, about two thirds did not use a tool capable of detecting the full spectrum of alcohol misuse. Using suitable screening tools will better identify patients who misuse alcohol and increase the opportunity for appropriate intervention, ultimately helping to reduce the burden from the many conditions associated with excessive alcohol consumption. PMID- 29241722 TI - Higher-Calorie Menu Items Eliminated in Large Chain Restaurants. AB - INTRODUCTION: Large chain restaurants have reduced calories in their new menu items. No research has examined the calorie content of items eliminated from these menus. METHODS: Data are from the MenuStat project (2012-2015), which includes 66 of the 100 largest U.S. chain restaurants (n=27,238 items), to compare: (1) mean calories for items on the menu in all years compared with those dropped after 2012 and (2) mean calories for items new in 2013 or 2014 that stayed on the menu compared with items new in 2013 or 2014 that were dropped. The data were analyzed in 2016. RESULTS: Menu items that were dropped from the menu relative to those on the menu in all years had 71 more calories (p=0.02). New items that were dropped relative to new items that stayed on the menu had 52 more calories (p=0.04). CONCLUSIONS: Items dropped from chain restaurant menus are significantly higher in calories than items that remain on the menu. Eliminating higher-calorie items from restaurant menus may have a significant and positive impact on population health by reducing calorie intake without relying on individual behavior, which is very resistant to change. PMID- 29241723 TI - Intrapersonal and Environmental Correlates of Bicycling in U.S. Adults. AB - INTRODUCTION: Bicycling is a health-promoting physical activity, but little is known about the factors that influence this behavior in the U.S. The objective of this cross-sectional study was to identify multilevel ecologic correlates of bicycling behaviors in a nationally representative sample of U.S. adults. METHODS: This analysis, conducted in 2016-2017, utilized data from the 2012 National Survey of Bicyclist and Pedestrian Attitudes and Behaviors (n=7,509; N=246,155,593). Weighted logistic regression models were utilized to examine the association between intrapersonal, perceived environment, and objective environment variables and total, recreation, and transportation bicycling. RESULTS: Significant differences were identified when bicyclists were compared with non-bicyclists. Respondents whose most recent ride was for recreation had significantly higher odds of being male, younger, white, and college educated, and significantly lower odds of being retired or a homemaker. Respondents who reported that their most recent ride was for transportation had significantly higher odds of being male, younger, and a student, and had significantly lower odds of being a high school graduate. Transportation riders also had significantly higher odds of perceived presence of a bike lane or path within one quarter mile of their residence, and living in a more rural area. CONCLUSIONS: In the U.S., recreation bicycling is a choice-based behavior, whereas transportation bicycling may be more influenced by the perceived and objective built environment. Interventions should consider how to make recreation and transportation bicycling more accessible and affordable to all individuals. PMID- 29241724 TI - Measures of SES for Electronic Health Record-based Research. AB - INTRODUCTION: Although infrequently recorded in electronic health records (EHRs), measures of SES are essential to describe health inequalities and account for confounding in epidemiologic research. Medical Assistance (i.e., Medicaid) is often used as a surrogate for SES, but correspondence between conventional SES and Medical Assistance has been insufficiently studied. METHODS: Geisinger Clinic EHR data from 2001 to 2014 and a 2014 questionnaire were used to create six SES measures: EHR-derived Medical Assistance and proportion of time under observation on Medical Assistance; educational attainment, income, and marital status; and area-level poverty. Analyzed in 2016-2017, associations of SES measures with obesity, hypertension, type 2 diabetes, chronic rhinosinusitis, fatigue, and migraine headache were assessed using weighted age- and sex-adjusted logistic regression. RESULTS: Among 5,550 participants (interquartile range, 39.6-57.5 years, 65.9% female), 83% never used Medical Assistance. All SES measures were correlated (Spearman's p<=0.4). Medical Assistance was significantly associated with all six health outcomes in adjusted models. For example, the OR for prevalent type 2 diabetes associated with Medical Assistance was 1.7 (95% CI=1.3, 2.2); the OR for high school versus college graduates was 1.7 (95% CI=1.2, 2.5). Medical Assistance was an imperfect proxy for SES: associations between conventional SES measures and health were attenuated <20% after adjustment for Medical Assistance. CONCLUSIONS: Because systematically collected SES measures are rarely available in EHRs and are unlikely to appear soon, researchers can use EHR-based Medical Assistance to describe inequalities. As SES has many domains, researchers who use Medical Assistance to evaluate the association of SES with health should expect substantial unmeasured confounding. PMID- 29241725 TI - Value of water enema computed tomography in elderly symptomatic patients. AB - BACKGROUND AND STUDY AIMS: Colonoscopy remains the gold standard for the examination of the colon. However, its use in the elderly is not well tolerated, and there is often a need for general anaesthesia, thus increasing the risk, especially if there are co-morbidities. Water enema computed tomography has been suggested to be a satisfactory alternative as a non-invasive, fast and effective means for the diagnosis of colorectal supra-centimetric lesions. The aim of our study was to assess the performance of water enema computed tomography as first line examination by calculating its negative predictive value (NPV) for the diagnosis of supra-centimetric lesions in symptomatic elderly referred to colonoscopy. PATIENTS AND METHODS: This was a prospective study including 57 symptomatic patients older than 65 years. All patients were explored by water enema computed tomography at first, followed by colonoscopy, and responded to a questionnaire on the tolerance to the preparation and both procedures. RESULTS: The mean age of patients was 73 years. The M:F sex ratio was 1.59. The most frequent indication for colonoscopy was bowel disorders associated with abdominal pain (30%). Water enema computed tomography allowed the diagnosis of tumours (n = 2), polyps (n = 6), diverticulosis (n = 7), inflammatory wall thickening (n = 1) and extra-colic lesions (n = 28). NPV of water enema computed tomography for supra-centimetric lesions was 96.5%. Sensitivity and specificity were 87.3% and 98%, respectively. However, for sub-centimetric lesions, water enema computed tomography had a low sensitivity estimated at 6%, specificity at 89.9%, positive predictive value at 91.9% and NPV at 27.7%. CONCLUSION: Water enema computed tomography has proven to be a valuable and non-invasive method indicated as a first-line examination in case of colonic symptoms in the elderly to diagnose supra-centimetric lesions. PMID- 29241726 TI - Prevalence and risk factors of hepatitis D virus infection in patients with chronic hepatitis B infection attending the three main tertiary hospitals in Libya. AB - BACKGROUND AND STUDY AIMS: Globally, More than 350 million individuals are chronically infected with hepatitis B virus (HBV), and >20 million of them are co infected with hepatitis D virus (HDV). The aim of this study was to determine the pattern of HDV infection in patients with chronic hepatitis B in three main tertiary hospitals in Tripoli and Benghazi, Libya. PATIENTS AND METHODS: This cross sectional and descriptive study was conducted on 162 patients with chronic hepatitis B positive for more than six months) who were followed up at hepatitis clinics of the three main tertiary hospitals in Tripoli city (88 patients from Tripoli Medical Centre and Tripoli Central Hospital) and Benghazi city (74 patients from Aljomhoria Hospital) during the period from January 2010 to June 2012. HBV and HDV markers were detected by enzyme linked fluorescent assay (ELFA) or enzyme-linked immunosorbent assay and HBV-DNA was quantified by real-time PCR techniques. RESULTS: The mean age of patients was 36,92 +/- 15,35. One hundred and three (63.6%) of them were males and 59 (36,4%) were females. Four patients (2,5%) were tested positive for anti-HD antibodies, all of them have had clinical and/or histological diagnosis of cirrhosis. In multivariable regression analysis, age (p = .04), elevation of serum ALT (p = .03), elevation of serum AST (p = .04), and presence of cirrhosis (p = .003) were significantly related to HDV seropositivity. CONCLUSION: Although the study demonstrated that Libya has low to moderate prevalence of HDV (2,5%), it is important for policy makers and health care providers to continue the preventive measures for HDV spread, and HBV prevention program including utilization of HBV vaccine. Furthermore, it is imperative to screen chronic HBV patients for HDV for close observation for early diagnosis of subsequent development of liver cirrhosis. Moreover, further epidemiologic and genetic studies are needed to explore the trend for HDV infection in Libya. PMID- 29241727 TI - Simple classifiers for molecular subtypes of colorectal cancer. AB - BACKGROUND AND STUDY AIM: Colorectal cancer (CRC) is a heterogeneous disease entity with a diverse biological pathogenesis. This study aims to validate the two studies published in 2013 which established a separate CRC molecular subtype classification by utilizing a rapidly accessible miniclassifier, and verify a simplified version thereof. PATIENTS AND METHODS: Participants diagnosed with CRC (n = 568) were subtyped in three classifications for characteristic, and prognostic purposes. Colorectal cancer subtypes (CCS) were classified as: i) CCS1 (CDX2+, microsatellite stable (MSS)/microsatellite instability (MSI)-low), ii) CCS2 (MSI-high), and iii) CCS3 (FRMD6/ZEB1/HTR2B +, CDX2-, MSS/MSI-low]. Simplified CCS (SiCCS) subtypes were grouped as: i) CDX2 (CDX2+, MSS/MSI-low, ZEB1 <= 2), ii) MSI-H (MSI-high, CDX2/FRMD6/ZEB1/HTR2B +/-), and iii) ZEB1 (ZEB1 >= 2, CDX2-, MSS/MSI-low). New molecular classification (NMC) subtypes were defined as: i) enterocyte (E-C) (MUC2 +), ii) goblet-like (G-L) (MUC2 + and TFF3 +), iii) transit-amplifying (T-A) (CFTR +), and iv) stem-like (S-L) (ZEB1 +). RESULTS: In total, 53.5% (n = 304) CCS, 58.3% (n = 331) SiCCS, and 37.7% (n = 214) NMC tumours could be evaluated. CCS2 and MSI-H CRCs had the most favourable survival outcome, whereas the CCS3, ZEB1 and S-L subtypes showed the poorest prognosis. A significant overlap between CCS3, ZEB1, and S-L tumours was demonstrated. CONCLUSION: There is still a need for a consensus gene expression based subtyping classification system for CRCs, thereby allowing the categorization of most CRC tumours. This study reveals that a simple and rapidly accessible process could replace the complicated, costly and mostly inapproachable methods clinical practices that have been introduced in the majority of previous studies. PMID- 29241728 TI - An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome. AB - BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare disorder caused by biallelic mutations in the lysosomal trafficking regulator gene (LYST), resulting in formation of giant lysosomes or lysosome-related organelles in several cell types. The disease is characterized by immunodeficiency and a fatal hemophagocytic lymphohistiocytosis caused by impaired function of cytotoxic lymphocytes, including natural killer (NK) cells. OBJECTIVE: We sought to determine the underlying biochemical cause of the impaired cytotoxicity of NK cells in patients with CHS. METHODS: We generated a human cell model of CHS using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology. We used a combination of classical techniques to evaluate lysosomal function and cell activity in the model system and super-resolution microscopy to visualize F actin and lytic granules in normal and LYST-deficient NK cells. RESULTS: Loss of LYST function in a human NK cell line, NK92mi, resulted in inhibition of NK cell cytotoxicity and reproduced other aspects of the CHS cellular phenotype, including the presence of significantly enlarged lytic granules with defective exocytosis and impaired integrity of endolysosomal compartments. The large granules had an acidic pH and normal activity of lysosomal enzymes and were positive for the proteins essential for lytic granule exocytosis. Visualization of the actin meshwork openings at the immunologic synapse revealed that the cortical actin acts as a barrier for secretion of such large granules at the cell cell contact site. Decreasing the cortical actin density at the immunologic synapse or decreasing the lytic granule size restored the ability of LYST deficient NK cells to degranulate and kill target cells. CONCLUSION: The cortical actin and granule size play significant roles in NK cell cytotoxic function. We present evidence that the periodicity of subsynaptic actin is an important factor limiting the release of large lytic granules from NK cells from patients with CHS and could be a novel target for pharmaceutical intervention. PMID- 29241730 TI - Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders. PMID- 29241732 TI - PGAM5 regulates PINK1/Parkin-mediated mitophagy via DRP1 in CCCP-induced mitochondrial dysfunction. AB - Mitochondrial dynamics and mitophagy are critical processes for regulating mitochondrial homeostasis. Phosphoglycerate mutase family member 5 (PGAM5) is a mitochondrial protein that plays crucial roles in apoptosis and necroptosis, but the roles of PGAM5 in mitochondrial dynamics and mitophagy remain unclear. In this study, we investigated the role of PGAM5 in carbonyl cyanide m chlorophenylhydrazone (CCCP)-induced mitochondrial damage and the correlation between mitochondrial dynamics and mitophagy using SH-SY5Y cells. We found that CCCP decreased mitochondrial membrane potential, resulting in mitochondrial dysfunction. CCCP increased PGAM5, dynamin-related protein 1 (DRP1), and optic atrophy 1 (OPA1) expression of the mitochondrial fraction in a time-dependent manner. Knockdown of PGAM5 inhibited DRP1 translocation without a change in OPA1 expression in CCCP-treated cells. Furthermore, knockdown of PGAM5 and DRP1 significantly blocked the increase of PTEN-induced putative protein kinase 1 (PINK1) and Parkin expression in the mitochondrial fraction of CCCP-treated cells. Interestingly, CCCP did not alter PINK1/Parkin expression in the mitochondrial fraction of OPA1 knockdown cells. Inhibiting mitophagy by PGAM5 knockdown accelerated CCCP-induced apoptosis. CCCP treatment also results in PINK1 stabilization on the mitochondrial membrane, which subsequently increases Parkin recruitment from the cytosol to abnormal mitochondria. In addition, we found that CCCP increased the level of mitochondrial LC3II, indicating that Parkin recruitment of PINK1 is a result of mitophagy. We propose that activation of PGAM5 is associated with DRP1 recruitment and PINK1 stabilization, which contribute to the modulation of mitophagy in CCCP-treated cells with mitochondrial dysfunction. In conclusion, we demonstrated that PGAM5 regulates PINK1-Parkin-mediated mitophagy, which can exert a neuroprotective effect against CCCP-induced apoptosis. PMID- 29241731 TI - Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination activating gene 2 mouse model is not hindered by inflammation and immune dysregulation. AB - BACKGROUND: Omenn syndrome (OS) is a rare severe combined immunodeficiency associated with autoimmunity and caused by defects in lymphoid-specific V(D)J recombination. Most patients carry hypomorphic mutations in recombination activating gene (RAG) 1 or 2. Hematopoietic stem cell transplantation is the standard treatment; however, gene therapy (GT) might represent a valid alternative, especially for patients lacking a matched donor. OBJECTIVE: We sought to determine the efficacy of lentiviral vector (LV)-mediated GT in the murine model of OS (Rag2R229Q/R229Q) in correcting immunodeficiency and autoimmunity. METHODS: Lineage-negative cells from mice with OS were transduced with an LV encoding the human RAG2 gene and injected into irradiated recipients with OS. Control mice underwent transplantation with wild-type or OS-untransduced lineage-negative cells. Immunophenotyping, T-dependent and T-independent antigen challenge, immune spectratyping, autoantibody detection, and detailed tissue immunohistochemical analyses were performed. RESULTS: LV-mediated GT allowed immunologic reconstitution, although it was suboptimal compared with that seen in wild-type bone marrow (BM)-transplanted OS mice in peripheral blood and hematopoietic organs, such as the BM, thymus, and spleen. We observed in vivo variability in the efficacy of GT correlating with the levels of transduction achieved. Immunoglobulin levels and T-cell repertoire normalized, and gene corrected mice responded properly to challenges in vivo. Autoimmune manifestations, such as skin infiltration and autoantibodies, dramatically improved in GT mice with a vector copy number/genome higher than 1 in the BM and 2 in the thymus. CONCLUSIONS: Our data show that LV-mediated GT for patients with OS significantly ameliorates the immunodeficiency, even in an inflammatory environment. PMID- 29241733 TI - Autophagy regulates high concentrations of iodide-induced apoptosis in SH-SY5Y cells. AB - To date, there are many people residing in areas with high levels of iodide in water. Our previous epidemiological study showed that exposure to high iodine in drinking water significantly reduced the intelligence of children although the mechanisms remain unclear. To explore whether high concentrations of iodide may cause cytotoxic effect and the role of autophagy in the high iodide-induced apoptosis, human neuroblastoma cells (SH-SY5Y cells) were exposed to high concentrations of iodide. Morphological phenotypes, cell viability, Hoechst 33258 staining, the expression levels of apoptosis and autophagy-related proteins were detected. A possible effect of an inhibitor (3-methyladenine, 3-MA) or an inducer (rapamycin) of autophagy on high iodide-induced apoptosis also was examined. Results indicated that high iodide changed cellular morphology, decreased cell viability and increased the protein's expression level of apoptosis and autophagy. In addition, high iodide-induced apoptosis was enhanced by inhibition of autophagy and inhibited by activation of autophagy in SH-SY5Y cells. Collectively, high concentrations of iodide are toxic to SH-SY5Y cells, as well as induce apoptosis and autophagy. Furthermore, autophagy plays a regulatory role in high concentrations of iodide-induced apoptosis in SH-SY5Y cells. PMID- 29241729 TI - Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. AB - BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8 95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen. PMID- 29241734 TI - Maduramicin-activated protein phosphatase 2A results in extracellular signal regulated kinase 1/2 inhibition, leading to cytotoxicity in myocardial H9c2 cells. AB - Maduramicin, a polyether ionophore antibiotic used as an anticoccidial agent in poultry industry, has been reported to be toxic to animals and humans if improperly used or by accident, resulting in heart failure, skeletal muscle degeneration and even death. However, the molecular mechanism underlying its cardiotoxicity remains elusive. Mitogen activated protein kinases (MAPKs) and protein phosphatases signaling pathways have been documented to be involved in the cell survival regulation. The present study was set to investigate the role of above pathways in maduramicin-induced myocardial cytotoxicity. Here we observed that maduramicin inhibited cell proliferation and reduced cell viability in H9c2 cells. Furthermore, we found that maduramicin suppressed extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in a concentration-dependent manner. Ectopic expression of constitutively active MKK1 partially prevented the cytotoxicity of maduramicin. Moreover, we showed that maduramicin concentration dependently activated protein phosphatase 2A (PP2A) by decreasing its phosphorylation and increasing its methylation. Inhibition of PP2A with okadaic acid attenuated maduramicin's toxicity. Overexpression of dominant negative PP2A partially rescued cells from maduramicin-inhibited ERK1/2 contributing to its cytotoxicity. The results indicate that maduramicin activates PP2A and consequently inhibits ERK1/2, leading to cytotoxicity in H9c2 cells. Our data suggest that manipulation of PP2A-ERK1/2 pathway may be a potential approach to prevent maduramicin-induced cardiotoxicity. PMID- 29241735 TI - Editorial Comment. PMID- 29241736 TI - Covariate balance for no confounding in the sufficient-cause model. AB - PURPOSE: To show conditions of covariate balance for no confounding in the sufficient-cause model and discuss its relationship with exchangeability conditions. METHODS: We consider the link between the sufficient-cause model and the counterfactual model, emphasizing that the target population plays a key role when discussing these conditions. Furthermore, we incorporate sufficient causes within the directed acyclic graph framework. We propose to use each of the background factors in sufficient causes as representing a set of covariates of interest and discuss the presence of covariate balance by comparing joint distributions of the relevant background factors between the exposed and the unexposed groups. RESULTS: We show conditions for partial covariate balance, covariate balance, and full covariate balance, each of which is stronger than partial exchangeability, exchangeability, and full exchangeability, respectively. This is consistent with the fact that the sufficient-cause model is a "finer" model than the counterfactual model. CONCLUSIONS: Covariate balance is a sufficient, but not a necessary, condition for no confounding irrespective of the target population. Although our conceptualization of covariate imbalance is closely related to the recently proposed counterfactual-based definition of a confounder, the concepts of covariate balance and confounder should be clearly distinguished. PMID- 29241737 TI - Derivatization of honokiol by integrated acetylation and methylation for improved cutaneous delivery and anti-inflammatory potency. AB - A set of honokiol derivatives was synthesized to evaluate skin permeation and bioactivity. The reaction for derivatization included acetylation and methylation. The anti-inflammatory activity against neutrophils and macrophages was examined. The experimental setup for the assessment of cutaneous absorption was the in vitro Franz diffusion assembly. Honokiol and its derivatives significantly downregulated superoxide anion and elastase production in neutrophils, with honokiol showing the greatest inhibition. All derivatives could be completely hydrolyzed to the parent compounds after passing into the skin. The skin deposition of honokiol at an infinite dose (3mM) was 0.33nmol/mg 4'-O acetylhonokiol (AH), and 2,4'-diacetylhonokiol (DAH) exhibited comparable or less absorption than honokiol. The integrated acetylation and methylation (2-O-acetyl 4'-O-methylhonokiol, AMH) led to a 10.5-fold improvement of absorption compared to honokiol. AMH was advantageous for the targeted cutaneous treatment due to the high skin deposition and minimal penetration across the skin (8.40nmol/cm2 compared to 93.49nmol/cm2 for honokiol). The predicted therapeutic index for superoxide and interleukin (IL)-6 inhibition was much higher for topically applied AMH than for the other penetrants tested. The total polarity surface and hydrogen bond acceptor number calculated by molecular modeling were the parameters used to anticipate the cutaneous absorption. Our data suggest that AMH is a potent and safe candidate for cutaneous inflammation therapy. PMID- 29241738 TI - Expression of autophagy-related markers at the surgical margin of oral squamous cell carcinoma correlates with poor prognosis and tumor recurrence. AB - Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide, and is associated with poor prognosis. Autophagy is a programmed cell survival mechanism involved in physiologic processes and various diseases including cancer. However, the relationship between autophagy and cancer is controversial. Several studies have claimed that the expression of autophagy-related proteins, namely microtubule-associated protein light chain3 (LC3) and p62/SQSTM1 (p62), is associated with poor prognosis in OSCC. In this study, we evaluated the expression of the autophagy-related markers LC3A/B and p62 by immunohistochemistry in 71 OSCC patient samples, especially focusing on surgical margins. Results were correlated with clinical characteristics. The expression of LC3A and LC3B was correlated with tumor recurrence and poor overall survival based on multivariate analysis, whereas the expression of p62 was correlated with only tumor recurrence and not prognosis. Thus, we suggest that the expression of autophagy-related markers at the surgical margins might be an indicator of local recurrence and poor prognosis in human OSCC. These results will aid in the development of new therapeutics and diagnostics for OSCC. PMID- 29241739 TI - BRAF and KRAS mutations in tubular apocrine adenoma and papillary eccrine adenoma of the skin. AB - Tubular apocrine adenoma (TAA) and papillary eccrine adenoma (PEA) are benign sweat gland tumors. Their names imply that they exhibit apocrine and eccrine differentiation, respectively. However, morphologically they are very similar and are often indistinguishable. The molecular pathogenesis of either tumor is poorly understood at present. On the basis of an index case of nipple adenoma that was morphologically reminiscent of cutaneous TAA/PEA and harbored a BRAFV600E mutation, we investigated whether a similar genetic change is also present in TAA/PEA. BRAF, RAS, and PIK3CA mutation analyses, and BRAFV600E-specific immunohistochemistry were performed for 24 TAAs/PEAs, 10 eccrine poromas, 7 apocrine cystadenomas, 2 TAA-like adenomas associated with nevus sebaceus, and one apocrine adenoma probably arising in anogenital mammary-like glands (AGMLGs). The results demonstrated that BRAFV600E mutations were present in TAAs (9/15, 60%) and PEAs (7/9, 78%), but not in other neoplasms. Two additional TAAs harbored KRASG12D mutations. In addition, a KRASG12C mutation was identified in one nevus sebaceus-associated TAA-like adenoma. The speculated AGMLG-related apocrine adenoma had a PIK3CAH1047R mutation. We concluded that activating BRAF and KRAS mutations were commonly present in TAAs/PEAs, indicating that in addition to a morphological resemblance, they are closely related genetically. Therefore, they could be considered to be united as a single entity. By contrast, the apocrine adenoma probably arising in AGMLG harbored a PIK3CA mutation, which is also commonly present in hidradenoma papilliferum. Further studies are necessary to determine whether the pathogenesis of AGMLG-related tumors is similar to breast tumors. PMID- 29241740 TI - Aberrant Pax-8 expression in well-differentiated papillary mesothelioma and malignant mesothelioma of the peritoneum: a clinicopathologic study. AB - Serous ovarian neoplasms can overlap morphologically with peritoneal mesothelial proliferations, including well-differentiated papillary mesothelioma (WDPM) and malignant epithelioid mesothelioma (MM). Accurate histologic classification of these neoplasms is important for clinical management. The Pax-8 protein is commonly used for differentiating peritoneal MM from serous carcinoma, but the diagnostic value of Pax-8 for distinguishing WDPM from borderline or low-grade serous tumors is unknown. We used immunohistochemistry staining to assess Pax-8 expression in 33 WDPMs, 34 peritoneal MMs, 48 pleural MMs, 11 adenomatoid tumors, 5 peritoneal inclusion cysts, and 51 benign/reactive mesothelium specimens. Staining was noted in 20 WDPMs (61%), with 17 showing strong and diffuse nuclear staining and 3 patchy/focal staining. Calretinin was expressed in 33 cases (100%), whereas focal BerEP4 staining was noted in 2 of 29 cases (7%). In contrast, 4 peritoneal MM (12%) were Pax-8 positive (3 diffuse and 1 focal staining). All adenomatoid tumors and peritoneal inclusion cysts were negative for Pax-8. Of the 48 pleural MM cases, 2 (4%) showed focal weak to moderate nuclear labeling for Pax-8, and 2 cases (4%) of reactive mesothelium demonstrated focal and scattered Pax-8 staining. Pax-8 appears to be a useful marker for distinguishing MM from gynecologic malignancies but is not reliable for distinguishing WDPM from borderline or low-grade gynecologic lesions. PMID- 29241741 TI - Vasitis nodosa and related lesions: a modern immunohistochemical staining profile with special emphasis on novel diagnostic dilemmas. AB - Vasitis nodosa is a benign proliferation of vas deferens epithelium, thought to be a response to trauma or obstruction, usually vasectomy. Although histologic features mimic malignancy, diagnosis is usually straightforward due to the clinical context. We analyzed 21 specimens with vasitis or epididymitis nodosa with antibodies to PAX8, CD10, p63, alpha-methyl-acyl-coA-racemase (AMACR), GATA3, prostein, NKX3.1, and prostate-specific antigen (PSA). Two diagnostically problematic cases included (1) florid bladder muscle involvement after prostatectomy and (2) involvement of the ampulla and ejaculatory duct in a radical prostatectomy specimen. Vasitis nodosa was excluded in 3 additional histologic mimics (2 post-treatment prostate cancers and 1 bladder cancer). PAX8 yielded consistent positive (100%) nuclear staining in the proliferative glands of vasitis nodosa, often stronger and more uniform than native vas deferens. CD10 labeling was common but also labeled secretions and other structures. Labeling for p63 was often basally located in glands with a multilayered appearance, but often markedly attenuated or lacking in the proliferative glands compared to native epithelium. AMACR positivity was variable but often present (19/21). PSA, prostein, and NKX3.1 were consistently negative. Rare problematic cases of vasitis nodosa include "invasion" of the ejaculatory duct at the prostate and involvement of bladder muscle after prostatectomy. The proliferative vasitis nodosa glands often have a prostate cancer-like staining pattern with variable AMACR positivity and negative or patchy p63. However, reliable positivity for PAX8, patchy GATA3, and negative staining for PSA, NKX3.1, and prostein aid in distinguishing from prostate cancer and tubular variants of bladder cancer. PMID- 29241742 TI - Diagnostic utility of histone H3.3 G34W, G34R, and G34V mutant-specific antibodies for giant cell tumors of bone. AB - Giant cell tumors of bone (GCTBs) are characterized by mononuclear stromal cells and osteoclast-like giant cells; up to 95% have H3F3A gene mutation. The RANKL inhibitor denosumab, when used for the treatment of GCTB, leads to histological changes such as new bone formation and giant cell depletion. Here we assessed the diagnostic utility of immunohistochemical staining with the antibodies against histone H3.3 G34W, G34R and G34V mutant proteins for GCTB and other histologically similar bone and joint lesions. H3.3 G34W, G34R and G34V expressions were detected in mononuclear stromal cells in 47/51 (92%), 1/51 (2%) and 3/51 (6%) cases of primary GCTBs, respectively, in a mutually exclusive manner. All recurrent/metastatic GCTBs (n=14), post-denosumab GCTBs (n=8) and secondary malignant GCTBs (n=2) were positive for H3.3 G34W. The immunohistochemical results were essentially correlated with the H3F3A genotype determined by mutation analysis. In post-denosumab GCTBs, H3.3 G34W expression was seen in immature bone-forming cells. H3.3 G34W, G34R and G34V were negative in 121/122 cases of non-GCTB, including chondroblastoma, osteosarcoma, primary aneurysmal bone cyst and other giant cell-rich lesions. The exception was a single case of undifferentiated high-grade pleomorphic sarcoma that was positive for H3.3 G34W, suggesting the possibility of sarcomatous overgrowth of primary malignant GCTB. Therefore, H3.3 G34W/R/V mutant-specific antibodies are useful surrogate markers for the H3F3A genotype and helpful for the diagnosis of GCTB and its variants. The expression of H3.3 G34W mutant protein in post-denosumab GCTB suggests that neoplastic stromal cells may play a role in new bone formation. PMID- 29241743 TI - Glaucoma after Lens-Sparing Vitrectomy for Advanced Retinopathy of Prematurity. AB - PURPOSE: To report the incidence of, and factors related to, glaucoma after lens sparing vitrectomy (LSV) surgery in advanced retinopathy of prematurity (ROP). DESIGN: Retrospective case series at a single tertiary referral pediatric vitreoretinal practice. PARTICIPANTS: Four hundred and one eyes from 270 patients were included. METHODS: The medical records of patients who underwent LSV for stage 4A, 4B, and 5 ROP were retrospectively reviewed. Data were collected from patient charts including gender, gestational age at birth, birthweight, stage of ROP at presentation, prior treatment (laser or cryotherapy), subsequent retinal surgeries, presence of glaucoma, time to glaucoma (interval between LSV and the onset of glaucoma), date of lensectomy (if performed), and retinal attachment status at last visit. Lensectomy was considered as a time-dependent covariate in the analysis. MAIN OUTCOME MEASURES: Incidence of glaucoma and potential risk factors for time to glaucoma. RESULTS: Among 401 eyes with advanced ROP, 40 eyes (10.0%) had glaucoma during a mean of 3.06+/-4.11 years of follow-up. The incidence of glaucoma was 6.9% (17/247) in stage 4A, 12.0% (16/133) in stage 4B, and 33.3% (7/21) in stage 5 ROP. Twenty-one percent of eyes (87/401) required lensectomy at a mean of 1.23+/-2.19 years after LSV. In univariate analysis, having stage 5 ROP (vs. stage 4 ROP) and presence of lensectomy were found to be significantly associated with time to glaucoma (hazard ratio = 6.76, 95% confidence interval = 2.19-20.88, P = 0.001; hazard ratio = 3.06, 95% confidence interval = 1.56-6.0, P = 0.001, respectively). In multivariate analysis, lensectomy was the only significant independent factor associated with time to glaucoma (hazard ratio = 2.76, 95% confidence interval = 1.371-5.581, P = 0.004). CONCLUSIONS: Patients with more severe ROP had a higher incidence of glaucoma after lens-sparing vitrectomy. If a patient required lensectomy owing to progression of ROP and/or presence of lens opacity, then the hazard of having glaucoma significantly increased compared with those without lensectomy. PMID- 29241744 TI - Fragility of Results in Ophthalmology Randomized Controlled Trials: A Systematic Review. AB - PURPOSE: Evidence-based medicine is guided by our interpretation of randomized controlled trials (RCTs) that address important clinical questions. Evaluation of the robustness of statistically significant outcomes adds a crucial element to the global assessment of trial findings. The purpose of this systematic review was to determine the robustness of ophthalmology RCTs through application of the Fragility Index (FI), a novel metric of the robustness of statistically significant outcomes. DESIGN: Systematic review. METHODS: A literature search (MEDLINE) was performed for all RCTs published in top ophthalmology journals and ophthalmology-related RCTs published in high-impact journals in the past 10 years. Two reviewers independently screened 1811 identified articles for inclusion if they (1) were a human ophthalmology-related trial, (2) had a 1:1 prospective study design, and (3) reported a statistically significant dichotomous outcome in the abstract. All relevant data, including outcome, P value, number of patients in each group, number of events in each group, number of patients lost to follow-up, and trial characteristics, were extracted. The FI of each RCT was calculated and multivariate regression applied to determine predictive factors. RESULTS: The 156 trials had a median sample size of 91.5 (range, 13-2593) patients/eyes, and a median of 28 (range, 4-2217) events. The median FI of the included trials was 2 (range, 0-48), meaning that if 2 non events were switched to events in the treatment group, the result would lose its statistical significance. A quarter of all trials had an FI of 1 or less, and 75% of trials had an FI of 6 or less. The FI was less than the number of missing data points in 52.6% of trials. Predictive factors for FI by multivariate regression included smaller P value (P < 0.001), larger sample size (P = 0.001), larger number of events (P = 0.011), and journal impact factor (P = 0.029). CONCLUSIONS: In ophthalmology trials, statistically significant dichotomous results are often fragile, meaning that a difference of only a couple of events can change the statistical significance. An application of the FI in RCTs may aid in the interpretation of results and assessment of quality of evidence. PMID- 29241745 TI - Skin and the metabolic syndrome. PMID- 29241746 TI - Important considerations for legislation banning commercial tanning beds among minors. PMID- 29241747 TI - Pathophysiology of the metabolic syndrome. AB - The metabolic syndrome-otherwise called syndrome X, insulin resistance syndrome, Reaven syndrome, and "the deadly quartet"-is the name given to the aggregate of clinical conditions comprising central and abdominal obesity, systemic hypertension, insulin resistance (or type 2 diabetes mellitus), and atherogenic dyslipidemia. It is a prothrombotic and proinflammatory state characterized by increased inflammatory cytokine activity. In addition to inflammatory dermatoses such as psoriasis, lichen planus, and hidradenitis suppurativa, metabolic syndrome is also commonly associated with accelerated atherosclerotic cardiovascular disease, hyperuricemia/gout, chronic kidney disease, and obstructive sleep apnea. Current therapeutic options for metabolic syndrome are limited to individual treatments for hypertension, hyperglycemia, and hypertriglyceridemia, as well as dietary control measures and regular exercise. PMID- 29241748 TI - Psoriasis and the metabolic syndrome. AB - Chronic plaque psoriasis is an immune-mediated inflammatory skin disease that is strongly associated with the clinical features of the metabolic syndrome (MetS), including abdominal obesity, hypertension, atherogenic dyslipidemia, type 2 diabetes, insulin resistance, and nonalcoholic fatty liver disease. The strength of these associations has been repeatedly confirmed by several observational studies. In particular, the prevalence of MetS in patients with psoriasis ranges from 20% to 50%, with a risk of having MetS is at least double in psoriatic patients compared with nonpsoriatic control individuals. MetS is also more common in patients with severe psoriasis than in those with mild skin disease. Emerging evidence now suggests that psoriasis and MetS share multiple metabolic risk factors, genetic background, and pathogenic pathways. The association between psoriasis and MetS has important clinical implications. Systemic conventional treatments should be used with caution in psoriatic patients with MetS, because they could adversely affect the coexisting metabolic disorders, especially in the case of their chronic use. Biologics appear to have a different safety profile compared with conventional treatments, and so they are usually tolerated. Collectively, dermatologists should pay close attention to the early recognition of coexisting metabolic disorders and give appropriate pharmacologic and nonpharmacologic (hypocaloric diet and regular exercise) recommendations to their patients. PMID- 29241749 TI - Acne vulgaris: The metabolic syndrome of the pilosebaceous follicle. AB - Acne vulgaris is an epidemic inflammatory disease of the human sebaceous follicle and represents the most common skin disease affecting about 85% of adolescents in Westernized populations. Acne vulgaris is primarily a disease of wealthy countries and exhibits higher prevalence rates in developed compared with developing countries. No acne has been found in non-Westernized populations still living under Paleolithic dietary conditions constraining hyperglycemic carbohydrates, milk, and dairy products. The high prevalence rates of adolescent acne cannot be explained by the predominance of genetic factors but by the influence of a Western diet that overstimulates the key conductor of metabolism, the nutrient- and growth factor-sensitive kinase mTORC1. Increased mTORC1 activity has been detected in lesional skin and sebaceous glands of acne patients compared with acne-free controls. Increased mTORC1 signaling is a characteristic feature of insulin resistance, obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. Acne vulgaris is a family member of mTORC1-driven diseases of civilization and represents the MetS of the sebaceous follicle. PMID- 29241750 TI - Historical perspectives of the metabolic syndrome. AB - The metabolic syndrome (MetS) or insulin resistance syndrome is a constellation of obesity-related metabolic derangements predisposing to type 2 diabetes and cardiovascular disease. In 1998, WHO defined the first criteria of MetS. Three years later, the user-friendly National Cholesterol Education Program criteria of MetS were proposed. Different criteria were issued by the International Diabetes Federation in 2005, making abdominal obesity a necessary component. Several international societies, including The International Diabetes Federation, jointly adopted the revised National Cholesterol Education Program criteria as harmonizing criteria of MetS in 2009. WHO warned the next year that MetS has limited practical utility as a management tool. Adipose tissue inflammation has been shown to be a fundamental mechanism of metabolic derangements, associated with ectopic lipid deposit and mitochondrial dysfunction in skeletal muscle and the liver. PMID- 29241751 TI - Hidradenitis suppurativa and the metabolic syndrome. AB - The association of the metabolic syndrome (MetS) and its components with immune mediated chronic inflammatory disorders has attracted much interest within the last two decades. In addition to the well-established association of psoriasis with MetS, recent data point to an association between MetS and hidradenitis suppurativa, as well. The association of hidradenitis suppurativa with MetS and its components, such as diabetes, obesity, and dyslipidemia, has been consistently identified in controlled studies. This relationship is not only limited to older individuals but also applicable to younger patients and those with mild disease. This review documents the link between these disorders and discusses its practical implications, mainly highlighting the importance of prevention and routine screening for early diagnosis to prevent cardiovascular related morbidity. PMID- 29241752 TI - Acanthosis nigricans and the metabolic syndrome. PMID- 29241753 TI - Alopecia and the metabolic syndrome. AB - Hair loss is a common condition that affects most people at some point in their lives. It can exist as an isolated problem or with other diseases and conditions. Androgenetic alopecia (AGA) and its association with the metabolic syndrome (MetS) have received increasing interest since 1972, when the first link between cardiovascular risk factors and hair loss was raised. We have reviewed studies concerning the relationship between alopecia and MetS. Many studies have investigated the relationship among AGA and MetS and its individual components, particularly in men, where a disproportionately large number of these studies supports this association. AGA has also been associated with other metabolic related conditions, including coronary artery disease, polycystic ovary syndrome, and Cushing syndrome, as well as several nutritional deficiencies, all of which have led to many clinicians advocating for the screening of MetS and cardiovascular risk factors in patients who present with AGA. PMID- 29241754 TI - Atopic dermatitis and the metabolic syndrome. AB - Atopic dermatitis is a common chronic inflammatory skin disease affecting about 10% to 20% of the general population. Disturbances in lipid metabolism contribute to defective lipid lamellae of the stratum corneum. The relationship of the metabolic syndrome and atopic dermatitis, on the contrary, remains unclear, because there are contradictory results from various trials. PMID- 29241755 TI - Autoimmune skin diseases and the metabolic syndrome. AB - The metabolic syndrome represents an important association of cutaneous maladies with cardiovascular illnesses. Chronic inflammation, shared risk factors (ie, smoking and alcohol consumption), treatment (ie, immunosuppressive agents and drugs that alter the lipid profile), and shared genetic risk loci have been proposed to the cause metabolic syndrome and cardiovascular morbidity of autoimmune diseases. There are many possible inflammatory mediators that are suggested to play a role in insulin resistance pathogenesis, such as tumor necrosis factor-alpha, interleukin-6, leptin, and adiponectin. These mediators are also abnormal in autoimmune skin disorders. We discuss several autoimmune skin diseases, connective tissue diseases, bullous diseases, vitiligo, psoriasis, lichen planus, chronic urticaria, and atopic dermatitis. PMID- 29241756 TI - Gynecologic and andrologic dermatology and the metabolic syndrome. AB - The relationship of sex hormones to obesity and inflammation has been extensively studied. Research on endogenous and exogenous sex steroids, including studies on animal models of metabolic syndrome (MetS), has indicated that sex hormones are involved in metabolic pathways relevant to MetS. Lower testosterone levels in men and higher levels in women increase risks of MetS and type 2 diabetes mellitus (T2DM). Lower levels of sex hormone-binding globulin increase risks of MetS and T2DM in both sexes. Skin diseases that are sex hormone mediated, such as polycystic ovary syndrome, acanthosis nigricans, acne vulgaris, and pattern alopecia, have been associated with insulin resistance. Insulin resistance increases the risk for metabolic and potentially cardiovascular complications, and patients with such skin diseases should be followed for a prolonged time to determine whether they develop these complications. Early intervention may help delay or prevent the onset of T2DM and decrease cardiovascular risks. PMID- 29241757 TI - Cutaneous manifestations of obesity and themetabolic syndrome. AB - The cutaneous manifestations of obesity and the associated metabolic syndrome (MetS) may present with a wide variety of cutaneous findings, including acanthosis nigricans, acrochordon, cellulitis, psoriasis, hidradenitis suppurativa, acne, and hirsutism. Being aware of such clinical signs and the underlying systemic disorders may facilitate earlier diagnoses, thereby permitting earlier of therapy initiation and prevention of long-term sequelae. In this process, dermatologists are key figures in the early detection of MetS and its clinical manifestations. PMID- 29241758 TI - Cutaneous manifestations of diabetes mellitus and the metabolic syndrome. AB - Metabolic diseases are commonly encountered in the Western world. Cutaneous manifestations are common in metabolic disorders, such as diabetes mellitus (DM) and the metabolic syndrome (MetS), and metabolic diseases may manifest with specific skin findings. MetS and DM share a common mechanism in their etiopathogenesis. As a result, the skin findings associated with these two diseases partially overlap. Several skin findings in DM and MetS may be the first clinical features of the disease, and early diagnosis facilitates treatment, thereby helping in preventing long-term complications. In this review, MetS and skin manifestations associated with DM are discussed. PMID- 29241759 TI - Genetics and the metabolic syndrome. AB - Originally coined as "syndrome X" in 1988 by Gerald Reaven (1928), the metabolic syndrome (MetS) encompasses a constellation of risk factors, the coincidence of which amounts to an increased cardiovascular and diabetic risk. Rising numbers of dermatoses are being recognized as cutaneous markers of MetS. Dermatologists should look beyond treating the cutaneous condition and quantify the associated increase in cardiovascular risk. The original dermatosis associated with obesity was acanthosis nigricans-described in 1889 by Paul Gerson Unna (1850-1929) and Sigmund Pollitzer (1859-1937). Over the last 20 years, clear associations between psoriasis, hidradenitis suppurativa, and MetS have also emerged. Several studies have shown synergistic improvement in the cutaneous pathology after treatment of components of MetS. This suggests common causalities and is a burgeoning area of research. We review the available evidence about the genetics underlying psoriasis, hidradenitis suppurativa, and acanthosis nigricans. Despite the strong clinical associations, the underlying genetic basis for a link to MetS remains unclear. PMID- 29241760 TI - Miscellaneous skin disease and the metabolic syndrome. AB - The link between the metabolic syndrome (MetS) and skin diseases is increasingly important, with new associations being discovered. The association between MetS and psoriasis or MetS and hidradenitis suppurativa is well known, although the relationship between MetS and various autoimmune or inflammatory diseases has only recently attracted interest. Some inflammatory skin diseases, such as vitiligo, scleredema, recurrent aphthous stomatitis, Behcet disease, rosacea, necrobiosis lipoidica, granuloma annulare, skin tags, knuckle pads, and eruptive xanthomas, have possible associations with MetS. In this review, we examine the state of knowledge involving the relationship between MetS and these dermatologic diseases. PMID- 29241761 TI - Spatial distribution and optimal harvesting of an age-structured population in a fluctuating environment. AB - We analyze a spatial age-structured model with density regulation, age specific dispersal, stochasticity in vital rates and proportional harvesting. We include two age classes, juveniles and adults, where juveniles are subject to logistic density dependence. There are environmental stochastic effects with arbitrary spatial scales on all birth and death rates, and individuals of both age classes are subject to density independent dispersal with given rates and specified distributions of dispersal distances. We show how to simulate the joint density fields of the age classes and derive results for the spatial scales of all spatial autocovariance functions for densities. A general result is that the squared scale has an additive term equal to the squared scale of the environmental noise, corresponding to the Moran effect, as well as additive terms proportional to the dispersal rate and variance of dispersal distance for the age classes and approximately inversely proportional to the strength of density regulation. We show that the optimal harvesting strategy in the deterministic case is to harvest only juveniles when their relative value (e.g. financial) is large, and otherwise only adults. With increasing environmental stochasticity there is an interval of increasing length of values of juveniles relative to adults where both age classes should be harvested. Harvesting generally tends to increase all spatial scales of the autocovariances of densities. PMID- 29241763 TI - Eltrombopag reduces clinically relevant thrombocytopenic events in higher risk MDS and AML. PMID- 29241762 TI - Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial. AB - BACKGROUND: Thrombocytopenia is a life-threatening complication in patients with advanced myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). In this study (ASPIRE), we aimed to assess eltrombopag, an oral thrombopoietin receptor agonist, for thrombocytopenia (grade 4) treatment in adult patients with advanced MDS or AML. METHODS: ASPIRE consisted of an open-label, double-blind phase for 8 weeks and a randomised, double-blind phase (parts 1 and 2, reported here) for 12 weeks, and an open-label extension (part 3). Eligible patients were men and women aged 18 years or older, with intermediate-2 or high-risk MDS or AML, with bone marrow blasts of 50% or less, and had either grade 4 thrombocytopenia due to bone marrow insufficiency (platelet counts <25 * 109 per L) or grade 4 thrombocytopenia before platelet transfusion, with 25 * 109 platelets per L or greater after transfusion. Additionally, eligible patients had at least one of the following within the screening period of 4 weeks: platelet transfusion, symptomatic bleeding, or platelet count of less than 10 * 109 per L. During part 1, patients received eltrombopag, and dose-escalation criteria for part 2 were determined. In part 2, we randomly allocated patients 2:1 using an interactive voice-response system to eltrombopag or placebo, stratified by baseline platelet count (<10 * 109 platelets per L vs >=10 * 109 platelets per L) and disease (MDS vs AML). In parts 1 and 2, patients received supportive standard of care and initiated eltrombopag or placebo at 100 mg per day (50 mg per day for patients of east-Asian heritage) to a maximum of 300 mg per day (150 mg per day for patients of east-Asian heritage). The part 2 primary objective was assessed by a composite primary endpoint of clinically relevant thrombocytopenic events (CRTE) during weeks 5-12, defined as one of the following events, either alone or in combination: grade 3 or worse haemorrhagic adverse events; platelet counts of less than 10 * 109 per L; or platelet transfusions. Efficacy analyses were based on intention to treat; clinically meaningful efficacy was defined as 30% absolute difference between groups. This trial is registered with ClinicalTrials.gov, number NCT01440374. FINDINGS: In part 1, 17 patients received eltrombopag and 11 patients completed treatment; four experienced significantly increased platelet counts, and ten had reduced platelet transfusion requirements. In part 2 we randomly allocated 145 patients to receive supportive care plus eltrombopag (n=98) or placebo (n=47); similar proportions had MDS (50 [51%] patients to eltrombopag, 22 (47%) patients to placebo) or AML (48 [49%] patients to eltrombopag, 25 [53%] patients to placebo). Average weekly CRTE proportions from weeks 5-12 were significantly lower with eltrombopag (54% [95% CI 43-64]) than with placebo (69% [57-80], odds ratio [OR] 0.20, 95% CI 0.05-0.87; p=0.032) although the difference between treatment groups was less than 30%. The most common grade 3 and grade 4 adverse events were fatigue (six [6%] in the eltrombopag group and one [2%] in the placebo group), hypokalaemia (six [6%] and two [4%]), pneumonia (five [5%] and five [11%]), and febrile neutropenia (five [5%] and six [13%]). Serious adverse events were reported in 56 (58%) eltrombopag treated patients and 32 (68%) placebo-treated patients. Seven eltrombopag recipients and two placebo recipients had serious adverse events that were suspected to be study drug-related (eltrombopag: acute kidney injury, arterial thrombosis, bone pain, diarrhoea, myocardial infarction, pyrexia, retinal vein occlusion, n=1 each; placebo: vomiting, white blood cell count increased, n=1 each). Two eltrombopag recipients (arterial thrombosis n=1; myocardial infarction n=1) and no placebo recipients experienced fatal serious adverse events suspected to be study drug-related. INTERPRETATION: No new safety concerns were noted with eltrombopag and the trial met the primary objective of a reduction in CRTEs; eltrombopag might be a treatment option for thrombocytopenic patients with AML or MDS who are ineligible for other treatment and who are not receiving disease modifying treatment. FUNDING: Novartis Pharma AG. PMID- 29241764 TI - Determining the effects of green chemistry synthesized Ag-nisin nanoparticle on macrophage cells. AB - Bacteriocins are low molecular weight substances produced through post transcriptional changes. These molecules are easily degraded in mammalian gut by proteolytic enzymes especially protease. Nisin is a peptide with 34 aa and its structure contains a pentacyclic lanthionine and 4 beta metyllanthionine residues. Different formulations have been designed for nisin. Since "green synthesis" is a progressive method to prepare anti-microbial and anti-cancer compounds, this study aimed at green synthesis of nisin metal compounds to be used lower concentration still exerting nisin effects. For this purpose, a 1 mg/ml nisin solution was added to a 1 mM silver nitrate solution and incubated to synthesis nano Ag-nisin, then the optical density of new solution was detected using UV spectroscopy. To determine biomolecules in the Ag-nisin solution, the FTIR method was employed. The size and morphology of Ag-nisin was measured by TEM. The toxicity, inflammatory cytokines production, and intracellular ROS quantity was evaluated using MTT, ELISA and flow-cytometry. XRD pattern indicated the silver crystals in Ag-nisin solution. In addition, FTRI findings showed that the carbonyl groups of amino acid are potently able to bind to metal nanoparticles, cover, and prevent them from particle agglomeration. Treating macrophage cells with 10, 25, 50 and 100 MUg/ml of Ag-nisin had no significant effect on the cell viability and intracellular ROS quantity compared to the control group. In addition, different concentrations of Ag-nisin had no effect on the IL-10 and TNF-alpha levels but caused an increased level of IL-12 in comparison with the control group. In the current study, for the first time, green synthesize was used to prepare Ag-nisin particles. The synthesized nanoparticle is able to induce inflammatory activity via increasing IL-12 without any change in the TNF-alpha level in macrophage cells. PMID- 29241765 TI - Oliveria decumbens essential oil: Chemical compositions and antimicrobial activity against the growth of some clinical and standard strains causing infection. AB - Oliveria decumbens as a valuable medicinal plant is extensively used in traditional medicine. clinical and standard strains causing infection resistance to antimicrobial agents, is one of the important problems in medicine. The aim of this study was to investigate the antibacterial activities and phytochemical analysis of Oliveria decumbens essential oil on the growth of some clinical and standard strains causing infection (Pseudomonas aerogenes, Escherichia coli, Streptococcus pyogenes and Staphylococcus epidermidis). Oliveria decumbens essential oil composition was identified by gas chromatography/mass spectrometry. Phytochemical analysis (alkaloids, saponins, flavone and phenolic) essential oil of the Oliveria decumbens were appraised based on qualitative methods. Several methods (disk diffusion, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)) were used to appraise the antibacterial activity of the Oliveria decumbens essential oil. Thymol (28.45%) was the major compound of Oliveria decumbens essential oil. The total phenolics content (TPC) of the essential oil positively correlated with antioxidant activity (AA). The TPC and AA of Oliveria decumbens essential oil was equal to 92.45 +/- 0.70 MUg GAE/mg and 164.45 +/- 1.20 MUg/ml, respectively. The MIC of Oliveria decumbens essential oil ranged from 1 to 8 mg/ml depending on the type of bacteria (clinical and standard strains). The MBC of Oliveria decumbens essential oil varied from 1 mg/ml to 16 mg/ml. The smallest inhibition zone diameter (IZD) on different Oliveria decumbens essential oil concentrations on P. aeruginosa. Results indicate that Oliveria decumbens essential oil can prove to be an important source of AA and antibacterial and may be used for the treatment of infection diseases. PMID- 29241766 TI - Integron mediated bacterial resistance and virulence on clinical pathogens. AB - Integron was recognized as mobile elements responsible for the emergence and diffusion of antibiotic resistance, virulence and pathogenicity. The existence of resistant integron in pathogens may consequently lead to the increasing number of clinical failures in bacterial mediated diseases, as well as the expenses. In this study, a total of 22 clinical pathogens (including E. faecalis, S. aureus, K. pneumoniae, Enterobacter, P. aeruginosa and Acinetobacter) were subjected to the identification of class 1-class 3 integrons and drug resistant gene cassettes by high flux LAMP method. According to the results, the clinical isolates were screened as carrying class 1 integron with dfrA12-orfF-aadA2 cassette array, class 1 integron with dfrA17-aadA5 cassette array, class 1 integron with aadA2 cassette, class 1 integron with blaVIM2 cassette, class 1 and class 2 integron with dfrA1-sat1-aadA1 and dfrA12-orfF-aadA2 cassette arrays simultaneously, which was accordantly with the previous data. The optimized high flux LAMP assay was proceeded in water bath at 65 degrees C for 60 min and determined by naked eye, with the time consumption restricted within 2.5 h. Prior to conventional PCR method, the high flux LAMP assay was demonstrated as a highly-specific and highly sensitive method. This study offered a valid LAMP method in resistance integrons detection for laboratory use, which was time-saving and easy-determination. PMID- 29241767 TI - Effects of prolonged exposure to moderate static magnetic field and its synergistic effects with alkaline pH on Enterococcus faecalis. AB - Static magnetic field (SMF) has been shown to biologically affect various microorganisms, but its effects on Enterococcus faecalis, which is associated with multiple dental infections, have not been reported yet. Besides, Enterococcus faecalis was found to be resistant to the alkaline environment provided by a major dental antimicrobial, calcium hydroxide. Therefore, the antibacterial activity of prolonged exposure to moderate SMF (170 mT) and its possible synergistic activity with alkaline pH (pH = 9) were evaluated in the study. The ability to form a biofilm under these conditions was examined by crystal violet assay. Real-time quantitative PCR was performed to evaluate the relative expression of stress (dnaK and groEL) and virulence (efaA, ace, gelE and fsrC) related genes. As the results indicated, cell proliferation was inhibited after 120 h of SMF exposure. What's more, the combined treatment of SMF and alkaline pH showed significantly improved antimicrobial action when compared to single SMF and alkaline pH treatment for more than 24 h and 72 h respectively. However, the ability to form a biofilm was also enhanced under SMF and alkaline pH treatments. SMF can induce stress response by up-regulating the expression of dnaK and elevate virulence gene expression (efaA and ace). These responses were more significant and more genes were up-regulated including groEL, gelE and fsrC when exposed to SMF and alkaline pH simultaneously. Hence, combination of SMF and alkaline pH could be a promising disinfection strategy in dental area and other areas associated with Enterococcus faecalis infections. PMID- 29241768 TI - Zika virus: The transboundary pathogen from mosquito and updates. AB - Zika virus (ZIKV) is a mosquito-borne flavivirus that was relatively obscure until outbreaks started in 2013. ZIKV is associated with neurological manifestations such as Guillan-Barre Syndrome in adult and microcephaly in the newborn population. Although the majority of disease mechanisms of ZIKV is unclear, some information was updated with new scientific evidence. Currently, there are no approved drugs or vaccine that can be used for therapy during ZIKV infection. Based on the transmission mechanism of ZIKV, vector control and safe sex seem to be the most effective available preventive measures against ZIKV spread. This study summarized the current ZIKV epidemiology, the status of the existing pathogenic mechanism of ZIKV, the development of potential compounds and vaccines against ZIKV, and the control efforts against ZIKV. PMID- 29241770 TI - Total cholesterol and stroke mortality in middle-aged and elderly adults: A prospective cohort study. AB - BACKGROUND AND AIMS: The association between cholesterol and stroke has been inconsistent. This study aimed to examine the association between total cholesterol (TC) and mortality from total stroke and stroke subtypes. METHODS: 503,340 Korean adults aged 40-80 years without a history of heart disease or stroke participated in routine health examinations in 2002 and 2003, and were followed up until 2013. Adjusted hazard ratios (HRs) for stroke (I60-I69) mortality were calculated. RESULTS: Nonlinear associations for total stroke (U curve) and hemorrhagic stroke (L-curve), especially intracerebral hemorrhage (ICH), but a linear association for ischemic stroke, were found. In the range <200 mg/dL, TC was inversely associated with stroke mortality (HR per 39 mg/dL [1 mmol/L] increase = 0.88 [95% CI = 0.80-0.95]), mainly due to hemorrhagic stroke (HR = 0.78 [0.68-0.90]), especially ICH (HR = 0.72 [0.62-0.85]). In the upper range (200-349 mg/dL), TC was positively associated with stroke mortality (HR = 1.09 [1.01-1.16]); ICH and subarachnoid hemorrhage mortality showed no inverse association. The associations were generally similar in middle-aged (40-64 years) and elderly (>=65 years) adults and, in the upper range, each 1 mmol/L (39 mg/dL) higher TC was associated with 11% higher mortality from stroke (95% CI = 2%-21%) in the elderly. Both middle-aged (39%) and elderly (23%) adults had higher ischemic stroke mortality associated with TC >=240 mg/dL, compare to <200 mg/dL. CONCLUSIONS: TC level around 200 mg/dL was associated with the lowest risk of overall stroke in the elderly and middle-aged adults. No stroke subtype including ICH, was inversely associated with TC in the range >=200 mg/dL. PMID- 29241769 TI - Antibacterial activity of Artemisia asiatica essential oil against some common respiratory infection causing bacterial strains and its mechanism of action in Haemophilus influenzae. AB - The main objective of the current study was to investigate the chemical composition of the essential oil of Artemisia asiatica together with investigating the antibacterial effects it exerts on several common respiratory infection causing bacteria including Haemophilus influenzae. Its mechanism of action was studied using various state-of-the-art assays like scanning electron microscopy, DNA, RNA and protein leakage assays, growth curve assays etc. The essential oil was extracted from the leaves of A. asiatica by supercritical CO2 fluid extraction technology. Chemical composition of essential oils was analyzed by gas chromatography-mass-spectrometry (GC-MS). The antibacterial activity was evaluated against 6 bacteria by the paper disc diffusion method. The minimum inhibitory concentration (MIC) and minimum bactericide concentration (MBC) values of the essential oil were estimated by agar dilution method. The antibacterial mechanism was evaluated by growth curve, the integrity of cell membrane and scanning electronmicroscope (SEM). Gas chromatographic analysis of the A. asiatica essential oil led to the identification of 16 chemical constituents accounting for 97.2% of the total oil composition. The major components were found to be Piperitone, (z)-davanone, p-cymene and 1, 8-cineole. The essential oil showed maximum growth inhibition against Haemophilus influenzae with a zone of inhibition of 24.5 mm and MIC/MBC values of 1.9/4.5 mg/mL respectively. Bacteria treated with the essential oil led to a rapid decrease in the number of viable cells. On adding the essential oil of A. asiatica to the bacterial culture, the constituents of the bacterial cell got released into the medium and this cell constituent release increased with increasing doses of the essential oil. SEM showed that the bacterial cells treated with the essential oil showed damaged cell wall, deformed cell morphology and shrunken cells. PMID- 29241771 TI - Alopecia areata: Disease characteristics, clinical evaluation, and new perspectives on pathogenesis. AB - Alopecia areata (AA) is a common, inflammatory, nonscarring type of hair loss. Significant variations in the clinical presentation of AA have been observed, ranging from small, well-circumscribed patches of hair loss to a complete absence of body and scalp hair. Patients affected by AA encompass all age groups, sexes, and ethnicities, and may experience frustration with the unpredictable nature of their disease for which there is currently no definitive treatment. The cause of AA remains incompletely understood, though it is believed to result-at least in part-from a loss of immune privilege in the hair follicle, autoimmune-mediated hair follicle destruction, and the upregulation of inflammatory pathways. Patients with AA frequently experience marked impairment in psychological well being, self-esteem, and may be more likely to suffer from psychiatric comorbidities. Part one of this two-part continuing medical education series describes the epidemiology, clinical evaluation, prognosis, and recent advancements in the understanding of the pathogenesis of AA. PMID- 29241772 TI - Location of skin lesions in Henoch-Schonlein purpura and its association with significant renal involvement. AB - BACKGROUND: Henoch-Schonlein purpura (HSP) is a small vessel IgA-predominant vasculitis. OBJECTIVE: To describe adult patients with HSP and determine if the distribution of skin lesions (ie, purpura above the waist or purpura below the waist only), is a predictor of significant renal involvement at the time of the skin biopsy and the months following. METHODS: A retrospective study on renal function from 72 adult patients with skin-biopsy proven HSP. Longitudinal renal data were analyzed after HSP diagnosis by using baseline renal function for comparison. RESULTS: Statistical analysis adjusted for sex, age, and baseline creatinine revealed a trend between HSP lesions only on the upper and lower extremities and long-term renal involvement (4.767, P = .067). Moreover, in another analysis adjusted for age and baseline creatinine, lesions located only on the upper and lower extremities significantly increased the odds of having long-term significant renal involvement (6.55, P = .049) in men. LIMITATIONS: This retrospective study used patient information that was subject to selection bias. CONCLUSION: In patients with HSP, skin lesion distribution on the extremities might be predictive of significant long-term renal involvement and might be critical for risk stratification and development of personalized diagnostics and therapeutics. PMID- 29241773 TI - Alopecia areata: An appraisal of new treatment approaches and overview of current therapies. AB - Many therapies are available for the treatment of alopecia areata, including topical, systemic, and injectable modalities. However, these treatment methods produce variable clinical outcomes and there are no currently available treatments that induce and sustain remission. When making management decisions, clinicians must first stratify patients into pediatric versus adult populations. Disease severity should then be determined (limited vs extensive) before deciding the final course of therapy. The second article in this continuing medical education series describes the evidence supporting new treatment methods, among them Janus kinase inhibitors. We evaluate the evidence concerning the efficacy, side effects, and durability of these medications. An overview of conventional therapy is also provided with new insights gleaned from recent studies. Finally, future promising therapeutic options that have not yet been fully evaluated will also be presented. PMID- 29241774 TI - Trends in Medicare spending on topical immunomodulators and chemotherapies. PMID- 29241775 TI - Retrospective effects of the American Joint Committee on Cancer's eighth edition guidelines for staging melanoma. PMID- 29241776 TI - Heterogeneous spectrum of acral melanoma: A clinicoprognostic study of 213 acral melanomas according to tumor site. PMID- 29241777 TI - Micromelanomas identified with time-lapse total body photography and dermoscopy. PMID- 29241778 TI - Metastatic melanoma after solid organ transplantation: An interdisciplinary, institution-based review of management with systemic and targeted therapies. PMID- 29241779 TI - Interrater reliability for histopathologic diagnosis of keratinocyte carcinomas. PMID- 29241780 TI - Trends in US sunscreen formulations: Impact of increasing spray usage. PMID- 29241781 TI - Nifedipine cream versus sildenafil cream for patients with secondary Raynaud phenomenon: A randomized, double-blind, controlled pilot study. PMID- 29241782 TI - A novel treatment for limited mouth opening due to facial fibrosis: A case series. PMID- 29241783 TI - Botulinum toxin type A for the treatment of localized recalcitrant chronic pruritus. PMID- 29241784 TI - Ivermectin versus permethrin in the treatment of scabies: A systematic review and meta-analysis of randomized controlled trials. PMID- 29241785 TI - Cantharidin for treatment of facial molluscum contagiosum: A retrospective review. PMID- 29241786 TI - Health care utilization for psoriasis in the United States differs by race: An analysis of the 2001-2013 Medical Expenditure Panel Surveys. PMID- 29241787 TI - Prognosis, treatment, and disease outcomes in frontal fibrosing alopecia: A retrospective review of 92 cases. PMID- 29241788 TI - Efficacy of topical diphenylcyclopropenone maintenance treatment for patients with alopecia areata: A retrospective study. PMID- 29241789 TI - Vitamin D deficiency in patients with alopecia areata: A systematic review and meta-analysis. PMID- 29241790 TI - Cancer risks among patients with alopecia areata: A population-based case-control study in Korea. PMID- 29241791 TI - Decreased risk of vitiligo in organ transplant recipients: A population-based cohort study. PMID- 29241793 TI - Hidradenitis suppurativa burden of disease tool: Pilot testing of a disease specific quality of life questionnaire. PMID- 29241792 TI - Activation of melanocytes in idiopathic guttate hypomelanosis after 5 fluorouracil infusion using a tattoo machine: Preliminary analysis of a randomized, split-body, single blinded, placebo controlled clinical trial. PMID- 29241794 TI - Drug-associated hidradenitis suppurativa: A systematic review of case reports. PMID- 29241795 TI - Romance, love, and sex in the dermatology department and residency program. PMID- 29241796 TI - Examining specimens brought in by a patient with delusional parasitosis. PMID- 29241797 TI - Romance, love, and sex in the dermatology department and residency program: More than a disruptive influence. PMID- 29241798 TI - Reply to: "Romance, love, and sex in the dermatology department and residency program: More than a disruptive influence". PMID- 29241799 TI - Vitiligo-like depigmentation in patients receiving programmed cell death-1 inhibitor reflects active vitiligo. PMID- 29241800 TI - Vitiligo-like lesions in patients receiving anti-programmed cell death-1 therapies are distinct from spontaneously occurring active vitiligo. PMID- 29241801 TI - Acknowledging the pseudo "fringe sign" in frontal fibrosing alopecia has diagnostic and prognostic implications. PMID- 29241803 TI - Reply to: "Updated diagnostic criteria for frontal fibrosing alopecia". PMID- 29241802 TI - Updated diagnostic criteria for frontal fibrosing alopecia. PMID- 29241804 TI - Reply to: "Rosacea and alcohol intake". PMID- 29241805 TI - Innovative modification of the USB dermatoscope for mucoscopy. PMID- 29241806 TI - Ultrasonography-guided curettage of poly-DL-lactic acid filler granulomas. PMID- 29241807 TI - Use of the inverted parachute retraction suture for epidermal cyst removal. PMID- 29241808 TI - Radiofrequency-assisted subcision for postacne scars. PMID- 29241810 TI - PC-FACS. AB - PC-FACS (Fast Article Critical Summaries for Clinicians in Palliative Care) provides hospice and palliative care clinicians with concise summaries of the most important findings from more than 100 medical and scientific journals. If you have colleagues who would benefit from receiving PC-FACS, please encourage them to join the AAHPM ataahpm.org. Comments from readers are welcomed atpc facs@aahpm.org. PMID- 29241809 TI - Chemotherapy Use, End-of-Life Care, and Costs of Care Among Patients Diagnosed With Stage IV Pancreatic Cancer. AB - CONTEXT: For patients with metastatic cancer and limited life expectancy, potential benefits of chemotherapy must be balanced against harms to quality of life near death and increased out-of-pocket costs of care. OBJECTIVES: To evaluate the association between chemotherapy use by patients with Stage IV pancreatic cancer and health care use and Medicare and out-of-pocket costs in the last 30 days of life. METHODS: We conducted a retrospective cohort study of 3825 patients aged 66 years or older when diagnosed with Stage IV pancreatic cancer in 2006-2011, using the linked Surveillance, Epidemiology, and End Results-Medicare data. Using a propensity score matched sample, we examined associations between initiation of chemotherapy shortly after the metastatic diagnosis (and secondarily, continued chemotherapy use in the last 30 days of life) and health care use and costs (both Medicare payment and patient out-of-pocket costs) in the last 30 days of life. RESULTS: Chemotherapy use was associated with increased rates of hospital admissions (45.0% vs. 29.2%, P < 0.001), emergency department visits (41.3% vs. 27.2%, P < 0.001), and death in a hospital (14.2% vs. 9.1%, P < 0.001); fewer days in hospice care (11.5 days vs. 15.7 days, P < 0.001); and more than 50% increase in patient out-of-pocket costs for care ($1311.5 vs. $841.0, P < 0.001) in the last 30 days of life. Among patients who initiated chemotherapy, more stark differences in these outcomes were found by whether patients received chemotherapy in the last 30 days of life. CONCLUSION: Chemotherapy use among older patients diagnosed with metastatic pancreatic cancer was associated with substantially increased use of health care and higher patient out-of-pocket costs near death. PMID- 29241811 TI - Syk and Src-targeted anti-inflammatory activity of aripiprazole, an atypical antipsychotic. AB - Aripiprazole (ARP) is a partial agonist of dopamine D2 receptors that is commonly prescribed to treat schizophrenia and bipolar disorder. The anti-inflammatory effect of ARP was recently documented in a few studies, but its molecular mechanisms have not been fully elucidated. In this study, peptidoglycan (PGN) treated macrophages (RAW264.7 cells), reporter gene assay, an overexpression strategy, immunoprecipitation, and immunoblotting analysis were employed to clarify the anti-inflammatory mechanism of ARP. ARP was found to dose-dependently inhibit production of nitric oxide (NO) and prostaglandin E2 (PGE2) without exhibiting cytotoxicity. In agreement with this result, ARP was found to suppress the mRNA expression levels of inflammatory genes such as cyclooxygenase-2 (COX 2), inducible NO synthase (iNOS), and tumor necrosis factor (TNF)-alpha. Luciferase assay and immunoblotting analysis with nuclear fractions showed that activator protein-1 (AP-1) and nuclear factor (NF)-kappaB are targeted by ARP. Similar to these data, c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 4 (MKK4), MKK7, and transforming growth factor beta-activated kinase 1 (TAK1) for AP-1 activation, and inhibitor of kappaBalpha (IkappaBalpha), IkappaBalphakinase alpha/beta (IKKalpha/beta), AKT, phosphatidylinositide 3 kinases (PI3K), spleen tyrosine kinase (Syk), and Src for NF-kappaB activation were revealed to be inhibited by ARP treatment. These results suggest that ARP can suppress inflammatory responses triggered by Gram positive bacteria through suppression of both AP-1 and NF-kappaB pathways. PMID- 29241812 TI - Exploiting the therapeutic potential of ready-to-use drugs: Repurposing antibiotics against amyloid aggregation in neurodegenerative diseases. AB - Neurodegenerative diseases are chronic and progressive disorders that affect specific regions of the brain, causing gradual disability and suffering that results in a complete inability of patients to perform daily functions. Amyloid aggregation of specific proteins is the most common biological event that is responsible for neuronal death and neurodegeneration in various neurodegenerative diseases. Therapeutic agents capable of interfering with the abnormal aggregation are required, but traditional drug discovery has fallen short. The exploration of new uses for approved drugs provides a useful alternative to fill the gap between the increasing incidence of neurodegenerative diseases and the long-term assessment of classical drug discovery technologies. Drug re-profiling is currently the quickest possible transition from bench to bedside. In this way, experimental evidence shows that some antibiotic compounds exert neuroprotective action through anti-aggregating activity on disease-associated proteins. The finding that many antibiotics can cross the blood-brain barrier and have been used for several decades without serious toxic effects makes them excellent candidates for therapeutic switching towards neurological disorders. The present review is, to our knowledge, the first extensive evaluation and analysis of the anti-amyloidogenic effect of different antibiotics on well-known disease associated proteins. In addition, we propose a common structural signature derived from the antiaggregant antibiotic molecules that could be relevant to rational drug discovery. PMID- 29241813 TI - Prenatal stress challenge impairs fetal lung development and asthma severity sex specifically in mice. AB - Allergic asthma is an increasing health problem worldwide. Interestingly, prenatal challenges such as stress have been associated with an increased risk for asthma during childhood. The underlying pathogenesis of how prenatal stress increases the risk for asthma still remains unclear. Potential targets could be that the fetal immune ontogeny or fetal lung development are compromised by prenatal challenges. Here, we aimed to identify whether prenatal stress challenge affects fetal lung development in mice. C57BL/6 pregnant mice were challenged with sound stress and fetal lung development was assessed histologically. Whilst prenatal stress challenge did not profoundly affect lung development in male fetuses, it resulted in less extensive terminal sacs, surrounded by thicker mesenchymal tissue in female fetuses. Thus, prenatal stress disrupted fetal lung development sex-specifically. Interestingly, upon prenatal stress challenge, the airway hyperresponsiveness and eosinophilic inflammation- two hallmarks of asthma - were significantly increased in adult female offspring, whilst regulatory CD4+ T cells were reduced. These findings strongly underpin the sex-specific association between s challenged fetal development and a sex-specific altered severity of asthma in adult offspring. Our model now allows to identify maternal markers through which the risk for asthma and possible other diseases is vertically transferred before birth in response to challenges. Such identification then opens avenues for primary disease prevention. PMID- 29241814 TI - A new method to locate the radial head "safe zone" on computed tomography axial views. AB - PURPOSE: Direct location of the "safe zone" on a CT axial view is impossible because the radial head is circular in shape. Previous "safe zone" location methods are not appropriate if the physician is unable to visualize the actual radial head. This study aims to introduce a new method to locate the "safe zone" on CT. METHODS: CT scans were performed on 20 intact cadaveric upper limbs from 20 different corpses in full pronation and supination. The DICOM-format raw data were then re-sliced and analyzed in Mimics 17.0 (Materialise, Belgium). The radial interosseous border (IB) is shaped like a droplet on the axial view; its axis was selected as our reference line (RL). A parallel line in the radial head axial slice was created, and its position relative to the "safe zone" was studied. Deviation in RL direction was evaluated. RESULTS: Safe-zone scope was 114.41 degrees +/-11.99. The rotation angle from the RL to the safe-zone's anterior and posterior border was 215.03 degrees +/-5.99 and 100.62 degrees +/ 8.12, respectively. Rotation direction (clockwise or anti-clockwise) depended on relative radius-ulna position. The safe zone was located by determining these two borders. The reference line's direction was stable in the upper half of the IB; its distance to the radial head fovea was 77.33 degrees mm+/-6.24. CONCLUSIONS: The radial head "safe zone" can be located on CT axial view based on the upper half of the IB using this new method. The method is clinically applicable to determine whether postoperative elbow malrotation results from plate impingement. PMID- 29241815 TI - Litigation in orthopedic surgery: What can we do to prevent it? Systematic analysis of 126 legal actions involving four university hospitals in France. AB - INTRODUCTION: Orthopedic surgery produces 20% of medical malpractice claims. However only a few studies have examined the reasons for and consequences of these disputes, and they have usually been limited to a single hospital. This led us to perform a retrospective analysis of the claims at four teaching hospitals in northwestern France. The goals were (1) to describe the circumstances that led to these claims and recommend ways to prevent them, and (2) to describe the conduct of the proceedings and their financial and social outcomes. HYPOTHESIS: A systematic analysis of litigation cases will provide accurate information on the circumstances leading to these claims. METHODS: The study included 126 disputes settled between 2000 and 2010 and related to orthopedic or trauma care given at one of four teaching hospitals in northwestern France. The method of recourse, grounds of the complaint, type of surgical procedure, expert findings and amount of the award were systematically analyzed. RESULTS: Of these 126 cases, 54 (43%) of them were submitted to the French CRCI (regional conciliation and compensation commission), 48 (39%) to the French administrative courts and 51 (41%) were settled amicably. Multiple methods of recourse were used in 21% of cases (n=27/126). The average length of administrative court proceedings was 36.7+/-27 months [4-102], which was significantly longer than the CRCI proceedings (22.7+/ 17.9 months [3-80]) or out-of-court settlement (23.7+/-21.5 months [0-52]) (p<0.0001). Damages were sought for medical error or treatment-related risk in 67.5% of the complaints (n=85/126), and for failure to inform in 15.8% of cases (n=20/126). There was a suspected surgical site infection in 79.3% of cases (n=100/126). There were multiple grounds for complaint in 68.3% of cases (n=86/126). Poor communication between the physician and patient was identified in 26.2% of cases (n=33/126). Damages were awarded in 25% of cases (n=31/126), with an average award of ?58,303+/-?91,601 [0-357,970]. CONCLUSION: The primary grounds for legal action are infection-related complications combined with a deterioration in the doctor-patient relationship. Disputes could be prevented by continuing efforts to combat hospital-acquired infections and providing better communications training. LEVEL OF PROOF: IV (retrospective study). PMID- 29241816 TI - Triple-bundle anatomical reconstruction using the coracoacromial ligament and the short head of biceps tendon to stabilize chronic acromioclavicular joint dislocations: A cadaver feasibility study. AB - INTRODUCTION: In cases of chronic acromioclavicular joint separation, the biomechanical properties of anatomical reconstructions are closer to the native configuration than the Weaver-Dunn procedure. Consequently, the radiological and clinical outcomes are better. However, an additional incision is needed to harvest the graft, which increases the procedure's morbidity. HYPOTHESIS: Triple bundle reconstruction can be performed with the coracoacromial ligament (CAL) and the semi conjoined tendon (SCT). MATERIAL AND METHODS: Bilateral dissection was performed on the upper limb of six fresh-frozen cadavers. Measurements useful to the procedure were taken on one limb, specifically the minimum graft length needed and the available length. The surgical procedure was performed on the other limb. The proximally based SCT was passed through the base of the coracoid process, then divided into two strips tightened from the superior aspect of the coracoid process to the clavicular insertion points of the conoid and trapezoid ligaments. The CAL was detached from the coracoid process and then secured in the medullary canal of the clavicle, after its lateral one-quarter was resected (i.e., 10mm). RESULTS: The mean length of the SCT was 101.7+/-7.6mm (95.1-114.5) and the mean length of the CAL was 35.3+/-4.7mm (28.7-42.5). The SCT length needed for this reconstruction was 58+/-4.3mm (51.5-62) medially and 60.3+/-4.6mm (54.3-66.3) laterally. The procedure was feasible in all six cadavers with an average excess length of 39.9+/-5.7mm (32.2-47) for the conoid bundle, 37.6+/-5mm (31-45.1) for the trapezoid ligament and 6+/-2.7mm (3-9.5) for the CAL. DISCUSSION: Triple-bundle anatomical reconstruction using the SCT and CAL is feasible. However, the strength of this construct must be evaluated biomechanically before it can be used clinically. LEVEL OF EVIDENCE: Not applicable - cadaver study. PMID- 29241817 TI - Salvage of congenital pseudarthrosis of the tibia by the induced membrane technique followed by a motorised lengthening nail. AB - An 18-year-old male with neurofibromatosis type I was treated for congenital pseudarthrosis of the tibia using the Masquelet induced-membrane technique with internal fixation by retrograde implantation of a transplantar intramedullary nail. Bone healing was obtained at the expense of malunion with external rotation and 5.5cm of lower limb shortening. A motorised intramedullary-lengthening nail (Fitbone(r), Wittenstein, Igersheim, Germany) was implanted. This treatment was successful in correcting the rotational malalignment and limb length discrepancy. The motorised nail Fitbone(r) may be a valid option for treating complex cases of limb length discrepancy, including those combined with limb deformities. PMID- 29241818 TI - Treatment of intra-articular fracture of distal radius fractures with fluoroscopic only or combined with arthroscopic control: A prospective tomodensitometric comparative study of 40 patients. AB - BACKGROUND: Considering articular distal radius fractures treated with volar plate, we hypothesized that articular radio-carpal displacement was better reduced with arthroscopic control than with only fluoroscopic control. METHODS: Forty patients with similar articular radius fracture (type C according to AO classification) and high functional needs were treated with volar plate fixation. They were divided in two comparative groups: 20 patients in Fluoroscopic group and 20 patients in Arthroscopic group. Pre and postoperative radiographs and tomodensitometric images were analysed by an independent observer. We evaluate extra and intra-articular displacements according to "Patient Accident Fracture" classification. RESULTS: We observed a better reduction of the radio-carpal step off and gap in the arthroscopic group, with a statistically significant difference (p<0.05). The index of postoperative intra-articular reduction was better in the fluoroscopic group (5.5) than in the arthroscopic group (2.2) with a significant difference (p<0.05). CONCLUSIONS: According to these results, arthroscopy is useful to perform a better articular radio-carpal reduction in distal radius fracture. LEVEL OF EVIDENCE: Level 3. PMID- 29241819 TI - Cyclophostin and Cyclipostins analogues, new promising molecules to treat mycobacterial-related diseases. AB - The progression of mycobacterial diseases requires the development of new therapeutics. This study evaluated the efficacy and selectivity of a panel of Cyclophostin and Cyclipostins analogues (CyCs) against various bacteria and mycobacteria. The activity 26 CyCs was first assayed by the agar plate method. Compounds exhibiting 50-100% growth inhibition were then selected to determine their minimum inhibitory concentrations (MICs) by the resazurin microtiter assay (REMA). The best drug candidate was further tested against clinical mycobacterial isolates and bacteria responsible for nosocomial infections, including 6 Gram negative bacteria, 5 Gram-positive bacteria, 29 rapid-growing mycobacteria belonging to the Mycobacterium chelonae-abscessus clade and 3 slow-growing mycobacteria (Mycobacterium marinum, Mycobacterium bovis BCG and Mycobacterium tuberculosis). Among the 26 CyCs tested, 10 were active and their inhibitory activity was exclusively restricted to mycobacteria. The best candidate (CyC17) was further tested against 26 clinical strains and showed high selectivity for mycobacteria, with MICs (<2-40 ug/mL) comparable with those of most classical antimicrobials used to treat M. abscessus infections. Together, these results support the fact that such CyCs represent a new family of potent and selective inhibitors against mycobacteria. This is of particular interest for future chemotherapeutic developments against mycobacterial-associated infections, especially against M. abscessus, the most drug-resistant mycobacterial species. PMID- 29241820 TI - Outcomes of adjunctive therapy with intrathecal or intraventricular administration of colistin for post-neurosurgical meningitis and ventriculitis due to carbapenem-resistant acinetobacter baumannii. AB - The efficacy and safety of intrathecal (ITH) or intraventricular (IVT) colistin in addition to intravenous (IV) colistin for meningitis and ventriculitis due to carbapenem-resistant Acinetobacter baumannii (CRAB) is unclear. In this retrospective observational study of 40 patients with post-neurosurgical meningitis and ventriculitis due to CRAB, 33 patients without concomitant infection received appropriate dosage regimens of IV colistin. Of the 33 patients, 17 received additional ITH/IVT colistin and 16 received only IV colistin. The 14-day, 30-day and in-hospital mortality rates were nominally lower for patients who received ITH/IVT colistin adjunctive therapy versus patients who received only IV colistin (24% vs. 38%, 29% vs. 56% and 29% vs. 56%, respectively). The costs of treatment were significantly lower, the lengths of hospital and intensive care unit (ICU) stay were significantly shorter, and the number of ventilator days was significantly less among patients who received ITH/IVT colistin compared with patients who did not receive ITH/IVT colistin. The initial Acute Physiology and Chronic Health Evaluation (APACHE) II and Glasgow Coma Scale (GCS) scores were associated with 30-day mortality with odds ratios (95% confidence intervals) of 1.21 (1.08-1.46) and 0.77 (0.44-0.85), respectively. Chemical meningitis from ITH/IVT colistin was mild and resolved spontaneously. Treatment of post-neurosurgical CRAB meningitis and ventriculitis with ITH/IVT colistin as an adjunct to IV colistin was associated with shorter lengths of hospital and ICU stay and a trend to lower mortality, especially among severely ill patients. PMID- 29241821 TI - Isoniazid and rifampicin concentrations in children with tuberculosis with either a daily or intermittent regimen: implications for the revised RNTCP 2012 doses in India. AB - Suboptimal plasma drug concentrations in antitubercular therapy (ATT) may lead to delayed treatment response and the emergence of acquired drug resistance. This study aimed (i) to determine and compare plasma concentrations of isoniazid (INH) and rifampicin (RIF) in children treated for tuberculosis receiving a daily or intermittent ATT regimen and (ii) to study the effect of INH and RIF exposure on clinical outcome at the end of therapy (EOT). A total of 41 children aged 2-16 years initiated on either a daily or three-times weekly (intermittent) ATT regimen were recruited into the study. Towards the end of the intensive phase, blood specimens were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 4 and 6 h post-dose. Concentrations of INH and RIF were analysed using validated liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography assays, respectively. The maximum plasma concentration (Cmax), the area under the concentration-time curve from 0-6 h (AUC0-6h) and treatment outcome were determined. Ninety-two percent of patients had an INH Cmax > 3 ug/mL. Seventy-seven percent of patients had a RIF Cmax < 8 ug/mL and 28% of patients had a RIF AUC0-24h < 13 mg ? h/L. INH and RIF exposure did not differ between daily and intermittent ATT regimens on the day of administration. All children had a favourable outcome at EOT. Since 77% of children had low RIF exposure, we recommend routine use of therapeutic drug monitoring to prevent relapse and to support implementation of the revised RNTCP 2012 doses. PMID- 29241822 TI - Neural correlates of gentle skin stroking in early infancy. AB - Physical expressions of affection play a foundational role in early brain development, but the neural correlates of affective touch processing in infancy remain unclear. We examined brain responses to gentle skin stroking, a type of tactile stimulus associated with affectionate touch, in young infants. Thirteen term-born infants aged 11-36days, recruited through the FinnBrain Birth Cohort Study, were included in the study. Soft brush strokes, which activate brain regions linked to somatosensory as well as socio-affective processing in children and adults, were applied to the skin of the right leg during functional magnetic resonance imaging. We examined infant brain responses in two regions-of-interest (ROIs) known to process gentle skin stroking - the postcentral gyrus and posterior insular cortex - and found significant responses in both ROIs. These results suggest that the neonate brain is responsive to gentle skin stroking within the first weeks of age, and that regions linked to primary somatosensory as well as socio-affective processing are activated. Our findings support the notion that social touch may play an important role in early life sensory processing. Future research will elucidate the significance of these findings for human brain development. PMID- 29241823 TI - Reply to Saeid Safiri's Letter to the Editor: Risk factors for laryngeal penetration-aspiration in patients with acute traumatic cervical spinal cord injury. PMID- 29241824 TI - Risk factors for laryngeal penetration-aspiration in patients with acute traumatic cervical spinal cord injury: methodological issues. PMID- 29241826 TI - Trabecular health of vertebrae based on anisotropy in trabecular architecture and collagen/apatite micro-arrangement after implantation of intervertebral fusion cages in the sheep spine. AB - Healthy trabecular bone shows highly anisotropic trabecular architecture and the preferential orientation of collagen and apatite inside a trabecula, both of which are predominantly directed along the cephalocaudal axis. This makes trabecular bone stiff in the principally loaded direction (cephalocaudal axis). However, changes in these anisotropic trabecular characteristics after the insertion of implant devices remain unclear. We defined the trabecular architectural anisotropy and the preferential orientation of collagen and apatite as parameters of trabecular bone health. In the present study, we analyzed these parameters after the implantation of two types of intervertebral fusion cages, open and closed box-type cages, into sheep spines for 2 and 4months. Alteration and evolution of trabecular health around and inside the cages depended on the cage type and implantation duration. At the boundary region, the values of trabecular architectural anisotropy and apatite orientation for the closed-type cages were similar to those for isotropic conditions. In contrast, significantly larger anisotropy was found for open-type cages, indicating that the open-type cage tended to maintain trabecular anisotropy. Inside the open-type cage, trabecular architectural anisotropy and apatite orientation significantly increased with time after implantation. Assessing trabecular anisotropy might be useful for the evaluation of trabecular health and the validation and refinement of implant designs. PMID- 29241825 TI - Sex hormones are negatively associated with vertebral bone marrow fat. AB - CONTEXT: Higher bone marrow fat (BMF)1 is associated with osteoporosis and reduced hematopoiesis. Exogenous estradiol reduces BMF in older women, but effects of endogenous sex hormones are unknown. OBJECTIVE: To determine if endogenous sex hormones are associated with BMF in older men and women. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Participants using medications that may affect BMF were excluded. MAIN OUTCOME MEASURES: Vertebral BMF was measured with magnetic resonance spectroscopy. Estradiol, testosterone and sex hormone binding globulin were measured on archived serum. Linear regression models were adjusted for age, total percent body fat and visit window. RESULTS: Analyses included 244 men and 226 women, mean age 81.5 (SD 4.1) years. Mean BMF was 54.1% (SD 8.6) (men) and 54.7% (SD 8.1) (women). In adjusted models, per 1pg/ml increase in total estradiol, there was a statistically significant 0.26% decrease in BMF in men (95% CI: -0.41, -0.11) and a non-significant 0.20% decrease in women (95% CI: -0.55, 0.15), with no evidence of interaction by gender (p=0.88). Per 10ng/dl increase in total testosterone, there was a significant 0.10% decrease in BMF in men (95% CI: -0.17, -0.03) and a non-significant 0.13% (95% CI: -0.79, 0.53) decrease in women, with no evidence of interaction by gender (p=0.97). CONCLUSION: Higher bone marrow fat is associated with lower total estradiol and testosterone levels in older men, with a similar but statistically non significant association in older women. Sex hormone levels appear to play a role in the regulation of bone marrow fat in older adults. PMID- 29241827 TI - Prevalence and risk factors for kidney stones in fibrodysplasia ossificans progressiva. AB - The worldwide prevalence and risk factors for kidney stones in patients with fibrodysplasia ossificans progressiva (FOP) are unknown. We conducted a survey of 383 patient-members of the International Fibrodysplasia Ossificans Progressiva Association, comprising the entire global membership of the international FOP community. Two hundred seven patients from 31 nations and 6 continents (54%) responded. Nineteen of 207 respondents had kidney stones, revealing a worldwide prevalence of 9.2%. In a confirmatory follow-up study of subjects participating in a longitudinal FOP natural history study, 9 of 114 individuals reported a history of kidney stones (7.9%). In both study populations patients with kidney stones were found to be more functionally impaired compared to those without nephrolithiasis. The prevalence of kidney stones in the adult FOP population of the Unites States was 15.8% (9/57 individuals) compared to a sex- and age weighted prevalence of 4.5% (p=4*10-5) in the general population. Although geographical variation exists, patients with FOP have an approximately three-fold greater prevalence of kidney stones than the general population. This unusually high prevalence may be due to high bone turnover from chronic immobilization, or to unknown mechanistic effects of the activating FOP mutation in activin A receptor, type I/activin-like kinase-2 (ACVR1/ALK2), increasing the disease burden and morbidity in this already disabling condition. PMID- 29241830 TI - Editors in Chief Overview. PMID- 29241828 TI - Acute and chronic rapamycin use in patients with Fibrodysplasia Ossificans Progressiva: A report of two cases. AB - Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection. In both patients, FOP progressed despite the use of rapamycin. This report highlights the real-world use of rapamycin in two FOP patients and provides insight into the use of rapamycin in clinical trials for the management of FOP. PMID- 29241831 TI - Change of Editor in Chief. PMID- 29241829 TI - The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology. AB - INTRODUCTION: An animal model of late-onset Alzheimer's disease is needed to research what causes degeneration in the absence of dominant genetic insults and why the association cortex is particularly vulnerable to degeneration. METHODS: We studied the progression of tau and amyloid cortical pathology in the aging rhesus macaque using immunoelectron microscopy and biochemical assays. RESULTS: Aging macaques exhibited the same qualitative pattern and sequence of tau and amyloid cortical pathology as humans, reaching Braak stage III/IV. Pathology began in the young-adult entorhinal cortex with protein kinase A-phosphorylation of tau, progressing to fibrillation with paired helical filaments and mature tangles in oldest animals. Tau pathology in the dorsolateral prefrontal cortex paralleled but lagged behind the entorhinal cortex, not afflicting the primary visual cortex. DISCUSSION: The aging rhesus macaque provides the long-sought animal model for exploring the etiology of late-onset Alzheimer's disease and for testing preventive strategies. PMID- 29241832 TI - Editorial. PMID- 29241833 TI - Editorial overview: Preface to 'a tribute to professor Norman Bowery'. PMID- 29241834 TI - Efficacy and Safety of Oral and Transdermal Opioid Analgesics for Musculoskeletal Pain in Older Adults: A Systematic Review of Randomized, Placebo-Controlled Trials. AB - : This systematic review with meta-analysis was performed to evaluate the efficacy and safety of using opioid analgesics in older adults with musculoskeletal pain. We searched Cochrane Library, MEDLINE, EMBASE, Web of Science, AMED, CINAHL, and LILACS for randomized controlled trials with mean population age of 60 years or older, comparing the efficacy and safety of opioid analgesics with placebo for musculoskeletal pain conditions. Reviewers extracted data, assessed risk of bias, and evaluated the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Random effects models were used to calculate standardized mean differences (when different scales were used across trials), mean differences and odds ratios with respective 95% confidence intervals (CIs). Meta-regressions were carried out to assess the influence of opioid analgesic daily dose and treatment duration on our main outcomes. We included 23 randomized placebo-controlled trials in the meta analysis. Opioid analgesics had a small effect on decreasing pain intensity (standardized mean difference = -.27; 95% CI = -.33 to -.20) and improving function (standardized mean difference = -.27, 95% CI = -.36 to -.18), which was not associated with daily dose or treatment duration. The odds of adverse events were 3 times higher (odds ratio = 2.94; 95% CI = 2.33-3.72) and the odds of treatment discontinuation due to adverse events 4 times higher (odds ratio = 4.04; 95% CI = 3.10-5.25) in patients treated with opioid analgesics. The results show that in older adults suffering from musculoskeletal pain, using opioid analgesics had only a small effect on pain and function at the cost of a higher odds of adverse events and treatment discontinuation. For this specific population, the opioid-related risks may outweigh the benefits. PERSPECTIVE: The systematic review shows that, in older adults suffering from musculoskeletal conditions, opioid analgesics have only a small effect on pain and disability. Conversely, this population is at higher risk of adverse events. The results may reflect age-related physiological changes in pain processing, pharmacokinetics, and pharmacodynamics. PMID- 29241835 TI - The Effect of a Statewide Mandatory Prescription Drug Monitoring Program on Opioid Prescribing by Emergency Medicine Providers Across 15 Hospitals in a Single Health System. AB - : Prescription drug monitoring programs (PDMPs) enable registered prescribers to obtain real-time information on patients' prescription history of controlled medications. We sought to describe the effect of a state-mandated PDMP on opioid prescribing by emergency medicine providers. We retrospectively analyzed electronic medical records of 122,732 adult patients discharged with an opioid prescription from 15 emergency departments in a single health system in Pennsylvania from July 2015 to March, 2017. We used an interrupted time series design to evaluate the percentage of patients discharged each month with an opioid prescription before and after state law-mandated PDMP use on August 25, 2016. From August (pre-PDMP) to September, 2016 (post-PDMP), the opioid prescribing rate decreased from 12.4% (95% confidence interval [CI], 10.8%-14.1%) to 10.2% (95% CI, 8.8%-11.8%). For each month between September 2016 to March 2017, there was a mean decline of .46% (95% CI, -.38% to -.53%) in the percentage of patients discharged with an opioid prescription. There was heterogeneity in opioid prescribing across hospitals as well as according to patient diagnosis. PERSPECTIVE: This study examined the effect of a state-mandated PDMP on opioid prescribing among emergency medicine providers from 15 different hospitals in a single health system. Findings support current PDMP mandates in reducing opioid prescriptions, which could curb the prescription opioid epidemic and may ultimately reduce abuse, misuse, and overdose death. PMID- 29241836 TI - Opposite Effects of Stress on Pain Modulation Depend on the Magnitude of Individual Stress Response. AB - : The effect of acute stress on pain threshold and intolerance threshold are reported as producing either hypoalgesia or hyperalgesia. Yet, the contribution of individual stress reactivity in this respect has not been established. The aim was to test 2 pain modulation paradigms under acute stress manipulation, to our knowledge, for the first time, to study whether stress differentially affects pain modulation, and whether the effect is related to individual stress response. Participants were 31 healthy subjects. Conditioned pain modulation (CPM) and pain adaptation were measured before and after inducing an acute stress response using the Montreal Imaging Stress Task. Subjects' stress response was evaluated according to salivary cortisol, autonomic function, and perceived stress and anxiety. The Montreal Imaging Stress Task induced a validated stress response. On a group level, stress induced reduction in CPM magnitude and increase in pain adaptation compared with baseline. These responses correlated with stress reactivity. When the group was subdivided according to stress reactivity, only high stress responders exhibited reduced CPM whereas only low stress responders exhibited increased pain adaptation. The results suggest that acute stress may induce opposite effects on pain modulation, depending on individual stress reactivity magnitude, with an advantage to low stress responders. PERSPECTIVE: This study evaluated the effect of acute stress on pain modulation. Pain modulation under stress is affected by individual stress responsiveness; decreased CPM occurs in high stress responders whereas increased pain adaptation occurs in low stress responders. Identification of high stress responders may promote better pain management. PMID- 29241837 TI - Kinases in synaptic development and neurological diseases. AB - Neuronal morphogenesis and synapse development is essential for building a functioning nervous system, and defects in these processes are associated with neurological disorders. Our understanding of molecular components and signalling events that contribute to neuronal development and pathogenesis is limited. Genes associated with neurodevelopmental and neurodegenerative diseases provide entry points for elucidating molecular events that contribute to these conditions. Several protein kinases, enzymes that regulate protein function by phosphorylating their substrates, are genetically linked to neurological disorders. Identifying substrates of these kinases is key to discovering their function and providing insight for possible therapies. In this review, we describe how various methods for kinase-substrate identification helped elucidate kinase signalling pathways important for neuronal development and function. We describe recent advances on roles of kinases TAOK2, TNIK and CDKL5 in neuronal development and the converging pathways of LRRK2, PINK1 and GAK in Parkinson's Disease. PMID- 29241838 TI - Telomerase level increase is related to n-3 polyunsaturated fatty acid efficacy in first episode schizophrenia: Secondary outcome analysis of the OFFER randomized clinical trial. AB - Schizophrenia is associated with shortening of the lifespan mainly due to cardiovascular events, cancer and chronic obstructive pulmonary disease. Both telomere attrition and decrease of telomerase levels were observed in schizophrenia. Polyunsaturated fatty acids (PUFA) influence multiple biochemical mechanisms which are postulated to accelerate telomere shortening and limit the longevity of patients with schizophrenia. Intervention studies based on add-on therapy with n-3 polyunsaturated fatty acids (n-3 PUFA) in patients with schizophrenia did not assess the changes in telomerase levels. A randomized placebo-controlled trial named OFFER was designed to compare the efficacy of a 26 week intervention composed of either 2.2g/day of n-3 PUFA or olive oil placebo with regard to symptom severity in first-episode schizophrenia patients. The secondary outcome measure of the study was to describe the association between the clinical effect of n-3 PUFA and changes in telomerase levels. Seventy-one patients aged 16-35 were enrolled in the study and randomly assigned to the study arms. The Positive and Negative Syndrome Scale (PANSS) was used to assess the change in symptom severity. Telomerase levels of peripheral blood mononuclear cells (PBMC) were assessed at three points: at baseline and at weeks 8 and 26 of the intervention. A significantly greater increase in PBMC telomerase levels in the intervention group compared to placebo was observed (p<0.001). Changes in telomerase levels significantly and inversely correlated with improvement in depressive symptoms and severity of the illness. The efficacy of a six-month intervention with n-3 PUFA observed in first-episode schizophrenia may be related to an increase in telomerase levels. PMID- 29241839 TI - The theta burst transcranial magnetic stimulation over the right PFC affects electroencephalogram oscillation during emotional processing. AB - Prefrontal cortex (PFC) plays an important role in emotional processing and therefore is one of the most frequently targeted regions for non-invasive brain stimulation such as repetitive transcranial magnetic stimulation (rTMS) in clinical trials, especially in the treatment of emotional disorders. As an approach to enhance the effectiveness of rTMS, continuous theta burst stimulation (cTBS) has been demonstrated to be efficient and safe. However, it is unclear how cTBS affects brain processes related to emotion. In particular, psychophysiological studies on the underlying neural mechanisms are sparse. In the current study, we investigated how the cTBS influences emotional processing when applied over the right PFC. Participants performed an emotion recognition Go/NoGo task, which asked them to select a GO response to either happy or fearful faces after the cTBS or after sham stimulation, while 64-channel electroencephalogram (EEG) was recorded. EEG oscillation was examined using event related spectral perturbation (ERSP) in a time-interval between 170 and 310ms after face stimuli onset. In the sham group, we found a significant difference in the alpha band between response to happy and fearful stimuli but that effect did not exist in the cTBS group. The alpha band activity at the scalp was reduced suggesting the excitatory effect at the brain level. The beta and gamma band activity was not sensitive to cTBS intervention. The results of the current study demonstrate that cTBS does affect emotion processing and the effect is reflected in changes in EEG oscillations in the alpha band specifically. The results confirm the role of prefrontal cortex in emotion processing. We also suggest that this pattern of cTBS results elucidates mechanisms by which mood improvement in depressive disorders is achieved using cTBS intervention. PMID- 29241840 TI - Three big things in neuropalliative care: Communication, personhood and uncertainty. PMID- 29241841 TI - Dorsal Wrist Plication for Midcarpal Instability. AB - PURPOSE: Midcarpal instability (MCI) is a cause of chronic wrist pain for which treatment remains controversial. This study's purpose was to determine the outcome of a treatment algorithm for MCI that included immobilization and surgical interventions. METHODS: We prospectively enrolled 23 consecutive patients (12 males, average age 27 years) with 27 symptomatic wrists. All had generalized wrist pain with an average duration of 22 months. All had MCI and a catch-up clunk that reproduced the symptoms. Initial treatment was full immobilization for 6 weeks. When necessary, recurrence after immobilization was treated with an anatomically based surgical procedure to plicate the dorsal capsule and extrinsic ligaments to stabilize the midcarpal joint. Failure of surgical plication was followed by 4-corner intercarpal arthrodesis when necessary. Patients were observed for instability, grip strength, wrist motion, and Patient-Rated Wrist Evaluation. RESULTS: For 22 wrists there was partial relief of symptoms with full-time cast or orthosis immobilization; however, symptoms quickly returned with mobilization. The other wrists had previously been immobilized and patients refused further nonsurgical care. All patients underwent surgical plication of the dorsum of the wrists. Postoperative follow-up (35 months) showed statistically significant improvements in grip strength and Patient-Rated Wrist Evaluation scores. All patients had improved pain at final follow-up. Most improvement was in female patients aged under 25 years, with hypermobility and without major traumatic or work-related injuries. This contrasted with poorer outcomes in men aged over 25years who had moderate or severe trauma that was mostly work-related. Instability recurred in 2 patients who then had a 4-corner arthrodesis. CONCLUSIONS: Immobilization was not successful in controlling pain and recurrence of instability in patients with MCI. Surgical midcarpal capsular plication was less effective in men with posttraumatic instability. The capsular plication procedure was successful in young female patients with ligament laxity and a history of only minor or repetitive trauma and no history of major trauma. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29241842 TI - Functional Impact of Congenital Hand Differences: Early Results From the Congenital Upper Limb Differences (CoULD) Registry. AB - PURPOSE: To characterize the functional, emotional, and social impact of congenital upper limb differences on affected children and families before treatment, using validated functional outcome instruments. METHODS: From June 2014 to March 2016, 586 children with congenital upper limb differences from 2 pediatric hospitals were enrolled in the Congenital Upper Limb Differences registry. Demographic, clinical, and radiographic data were collected, and diagnoses categorized according to the Oberg-Manske-Tonkin classification. Functional outcomes were assessed in 301 patients using the Pediatric Outcomes Data Collection Instrument (PODCI) and Patient-Reported Outcomes Measurement Information System (PROMIS) upper extremity (UE) function, pain, anxiety, depression, and peer relationships modules. RESULTS: The cohort had high median PODCI scores in all domains, ranging from 83 to 100 in children and adolescents. Patients had decreased PROMIS UE scores compared with population norms; however, they showed low scores for pain, anxiety, depression and higher scores in the peer relationship domain, respectively. Patients with entire limb involvement had higher PROMIS pain scores and lower PODCI UE and global functioning than those with differences limited only to the hand. Compared with those with bilateral involvement, patients with unilateral differences reported higher scores for PODCI sports global functioning, better PROMIS UE function, and lower pain scores. Additional orthopedic conditions and medical comorbidities negatively influenced all PODCI scores and PROMIS pain and UE function domains. CONCLUSIONS: Children with congenital hand differences report decreased upper limb function but better peer relationships and positive emotional states compared with population norms. CLINICAL RELEVANCE: The Congenital Upper Limb Differences registry is a valid source of information related to congenital upper limb differences in clinical practice. With continuous enrollment and longitudinal follow-up, the registry will increase the understanding of UE function and psychosocial aspects of health in pediatric population. PMID- 29241843 TI - Quantifying the Effect of Diabetes on Surgical Hand and Forearm Infections. AB - PURPOSE: Diabetes has long been established as a risk factor for hand and forearm infections. The purpose of this study was to review the effect of glycemic factors on outcomes among diabetic patients with surgical upper-extremity infections. We hypothesized that diabetic inpatients may benefit from stronger peri-infection glycemic control. METHODS: A prospective cohort study enrolled diabetic and nondiabetic surgical hand and forearm infections over 3 years. Glycemic factors included baseline glycosylated hemoglobin, blood glucose (BG) at presentation, and inpatient BG. Poor baseline control was defined as glycosylated hemoglobin of 9.0% or greater and poor inpatient control as average BG of 180 mg/dL or greater. The main outcome of interest was the need for repeat therapeutic drainage. Multivariable logistic regression quantified the association between diabetic factors and this outcome. RESULTS: The study involved 322 patients: 76 diabetic and 246 nondiabetic. Diabetic infections were more likely than nondiabetic infections to result from idiopathic mechanisms, occur in the forearm, and present as osteomyelitis, septic arthritis, and necrotizing fasciitis. Diabetic microbiology was more likely polymicrobial and fungal. After first drainage, diabetic patients were more likely to require repeat drainage and undergo eventual amputation. Among diabetic patients, poor inpatient control was associated with need for repeat drainage. CONCLUSIONS: Diabetes exacerbates the burden of surgical upper-extremity infections: specifically, more proximal locations, deeper involved anatomy at presentation, broader pathogenic microbiology, increased need for repeat drainage, and higher risk for amputation. Among diabetic patients, poor inpatient glycemic control is associated with increased need for repeat drainage. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic I. PMID- 29241844 TI - Efficacy and safety of routine aspiration thrombectomy during primary PCI for ST segment elevation myocardial infarction: A meta-analysis of large randomized controlled trials. AB - BACKGROUND: Recent randomized controlled trials (RCTs) have questioned the clinical efficacy and safety of routine aspiration thrombectomy (AT) during primary percutaneous coronary intervention (PCI). A systematic synthesis of these randomized data is hence very timely to address this clinical equipoise. METHODS: We performed a meta-analysis of the larger (>150 patients) RCTs that compared AT with only primary PCI. Procedural endpoints were myocardial blush grade (MBG) score of 0 or 1 and ST-segment resolution (STR) >50%. Midterm endpoints were mortality, reinfarction, target vessel revascularization, and stroke >30 days after the procedure. RESULTS: We identified 11 large RCTs, with 10,309 patients randomized to AT and 10,296 to routine strategy (RT). While AT was associated with significantly improved myocardial perfusion, as demonstrated by the MBG score (OR = 0.69; p = 0.010), and improved rates of STR >50% (OR = 1.41; p = 0.006), there were no differences in mortality (OR = 0.89; p = 0.76), reinfarction (OR = 0.9; p = 0.47), target vessel revascularization (TVR; OR = 1.06; p = 0.67), and stroke rates (OR = 1.49; p = 0.29) >30 days after the procedure. CONCLUSION: Our meta-analysis of 20,605 patients who participated in large RCTs demonstrates improved MBG scores and STR >50% with AT compared with only PCI, but no differences were observed in mortality, reinfarction, TVR, and stroke rates at 30 days. Our study supports the latest ACC/AHA/SCAI focused update document that recommends against the routine use of AT during primary PCI. PMID- 29241845 TI - CRISPR/Cas9-mediated knockout of two eye pigmentation genes in the brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae). AB - The brown planthopper Nilaparvata lugens is one of the most destructive insect pests in Asia, demonstrating high fertility and causing huge crop losses by sucking sap of rice as well as transmitting viruses. However, functional genomic studies on N. lugens are seriously constrained by lack of genetic tools. Here, we employed two eye pigmentation genes to generate germ-line mutations in N. lugens using the CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR associated) system. We showed that injection of single guide RNA of the cinnabar gene of N. lugens (Nl-cn) into pre-blastoderm eggs induced insertion and deletion (indels) in the founder generation (G0), which were heritably transmitted to the following G1 generation, leading to bright red compound eyes and ocelli. Mutations of N. lugens white (Nl-w) generated a high mutant rate of up to 27.3%, resulting in mosaic eyes consisting of white and lightly pigmented ommatidia in both G0 and G1 individuals. The specificity of CRISPR/Cas9-mediated mutagenesis was further bolstered by PCR and RNA interference-based knockdown analysis. These results show that CRISPR/Cas9-mediated gene editing is achievable in a hemipteran insect, offering a valuable tool for the study of functional genomics and pest management in this planthopper species. PMID- 29241846 TI - The Joint Action on Health Workforce Planning and Forecasting: Results of a European programme to improve health workforce policies. AB - Health workforce (HWF) planning and forecasting is faced with a number of challenges, most notably a lack of consistent terminology, a lack of data, limited model-, demand-based- and future-based planning, and limited inter country collaboration. The Joint Action on Health Workforce Planning and Forecasting (JAHWF, 2013-2016) aimed to move forward on the HWF planning process and support countries in tackling the key challenges facing the HWF and HWF planning. This paper synthesizes and discusses the results of the JAHWF. It is shown that the JAHWF has provided important steps towards improved HWF planning and forecasting across Europe, among others through the creation of a minimum data set for HWF planning and the 'Handbook on Health Workforce Planning Methodologies across EU countries'. At the same time, the context-sensitivity of HWF planning was repeatedly noticeable in the application of the tools through pilot- and feasibility studies. Further investments should be made by all actors involved to support and stimulate countries in their HWF efforts, among others by implementing the tools developed by the JAHWF in diverse national and regional contexts. Simultaneously, investments should be made in evaluation to build a more robust evidence base for HWF planning methods. PMID- 29241847 TI - Recurrent symptoms after per-oral endoscopic myotomy in achalasia: Redo, dilate, or operate? A call for a tailored approach. PMID- 29241848 TI - Gastroscopy and gastric cancer-related mortality: Time to change recommendations regarding screening? PMID- 29241849 TI - Early ERCP for severe cholangitis? Of course! PMID- 29241850 TI - Guidewire cannulation in ERCP: from zero to hero! PMID- 29241851 TI - Sphincter of Oddi dysfunction: the never-ending story has come to a conclusion. PMID- 29241852 TI - Devices for adenoma detection rate: Holy Grail or training tool? PMID- 29241853 TI - Postsurgery risk for nonmalignant colorectal polyps: the ultimate call. PMID- 29241854 TI - Is it safe to wait 10 years after a negative baseline screening colonoscopy result? PMID- 29241855 TI - Assessment of trainees' performance in colonoscopy. PMID- 29241856 TI - Is it noninferiority? PMID- 29241857 TI - Response. PMID- 29241858 TI - Safety of lumen-apposing metal stents for pancreatic fluid drainage: waiting for a clear answer. PMID- 29241859 TI - Response. PMID- 29241861 TI - Response. PMID- 29241860 TI - Post-ERCP pancreatitis in patients with type 2 diabetes mellitus. PMID- 29241862 TI - Can a multidisciplinary approach improve the care of patients with benign biliary strictures? PMID- 29241863 TI - Response. PMID- 29241864 TI - Unearthing the significance of buried intestinal metaplasia. PMID- 29241865 TI - Endoscopic eradication therapy and the test of time. PMID- 29241866 TI - Measurement of the response-ratio of an ionization chamber filled with dry air to that filled with P-10 gas in the calibration of gas monitors. AB - We developed a new method to determine the response ratio of an ionization chamber (Ohkura ionization chamber: type I-4096 01/06) filled with dry air to that filled with P-10 gas. The response-ratio was obtained by comparing the output currents of the ionization chamber after introduction of radioactive gasses of identical activities contained in two small vessels. The obtained ratio was 0.690 +/- 0.003, which agreed with the results obtained by other methods. PMID- 29241867 TI - Slow-growing subcutaneous lesion: The value of ultrasound. PMID- 29241868 TI - Macrophage activation syndrome induced by prolonged treatment with liposomal amphotericin B. PMID- 29241869 TI - Primary colo-colic intussusception as cause of intestinal obstruction. PMID- 29241870 TI - Disseminated Propionibacterium acnes infection in a 42-year-old HIV-positive man. PMID- 29241871 TI - Systemic reaction and mediastinal involvement secondary to breast implant rupture. PMID- 29241872 TI - Fat necrosis and subcutaneous abscesses due to apomorphine. PMID- 29241873 TI - Reply. PMID- 29241874 TI - Feohifomicosis in a renal and pulmonary transplant patient. PMID- 29241875 TI - Antibiotics policy: The arrival of antimicrobial stewardship programmes. PMID- 29241876 TI - Update in ethiopathogeny, diagnosis and treatment of the IgG4 related disease. AB - IgG4 related disease (IgG4-RD) is probably an autoimmune pathology of unknown etiology. Diverse interactions participate in its pathogen between the adaptive and innate immune systems, activating lymphocytes B and T which trigger the inflammatory cascade, which culminates in fibrosis of the organs and their malfunction. It can affect a multitude of organs simultaneously. The diagnosis is based on the correlation of clinical findings with anatomopathological results (lymphoplasmocitary infiltrate, storiform fibrosis, obliterative phlebitis and IgG4+plasmatic cell count) and with the presence of elevated IgG4 in serum, depending on the criteria used. Corticoids and rituximab are among the few validated treatments available. There are multiple biomarkers and treatments in development. In this review, we aim to go over the principal pathogenic and clinical characteristics of IgG4-RD, as well as its handling, in accordance with the available scientific evidence. PMID- 29241877 TI - Adult onset Still's Disease. AB - Adult onset Still's disease is a rare systemic condition at the crossroads between auto-inflammatory syndromes and autoimmune diseases, with considerable heterogeneity in terms of clinical presentation, evolution and severity. This article reviews the main advances and lesser known aspects of this entity related to its clinical spectrum (atypical cutaneous lesions, unusual manifestations, macrophage activation syndrome, disease phenotypes), the emerging controversy around its association with delayed malignancy, the search for new biomarkers for its diagnosis, evaluation of prognosis (clinical factors, prognostic indexes and biomarkers to identify patients at risk of severe organ failure or life threatening complications), and the determinants in the choice of biological treatment. PMID- 29241878 TI - Reply. PMID- 29241879 TI - Usefulness of the N-terminal pro brain natriuretic peptide as short-term prognostic factor for mortality in the elderly patients with infection seen in emergency departments. PMID- 29241880 TI - Short-term prognostic value of NT-proBNT in acute infection. PMID- 29241881 TI - ISPOR Code of Ethics 2017 (4th Edition). AB - As the leading health economics and outcomes research (HEOR) professional society, ISPOR has a responsibility to establish a uniform, harmonized international code for ethical conduct. ISPOR has updated its 2008 Code of Ethics to reflect the current research environment. This code addresses what is acceptable and unacceptable in research, from inception to the dissemination of its results. There are nine chapters: 1 - Introduction; 2 - Ethical Principles respect, beneficence and justice with reference to a non-exhaustive compilation of international, regional, and country-specific guidelines and standards; 3 - Scope HEOR definitions and how HEOR and the Code relate to other research fields; 4 - Research Design Considerations primary and secondary data related issues, e.g., participant recruitment, population and research setting, sample size/site selection, incentive/honorarium, administration databases, registration of retrospective observational studies and modeling studies; 5 - Data Considerations privacy and data protection, combining, verification and transparency of research data, scientific misconduct, etc.; 6 - Sponsorship and Relationships with Others (roles of researchers, sponsors, key opinion leaders and advisory board members, research participants and institutional review boards (IRBs) / independent ethics committees (IECs) approval and responsibilities); 7 - Patient Centricity and Patient Engagement new addition, with explanation and guidance; 8 - Publication and Dissemination; and 9 - Conclusion and Limitations. PMID- 29241882 TI - Next Edition of the ISPOR Code of Ethics: Is It Setting Us up for the Era of Digitized Health Care? PMID- 29241883 TI - The Role of Noncomparative Evidence in Health Technology Assessment Decisions. AB - BACKGROUND: Many health technology assessment (HTA) agencies express a preference for randomized controlled trial evidence when appraising health technologies; nevertheless, it is not always feasible or ethical to conduct such comparative trials. OBJECTIVES: To assess the role of noncomparative evidence in HTA decision making. METHODS: The Web sites of the National Institute for Health and Care Excellence (NICE) in the United Kingdom, the Canadian Agency for Drugs and Technologies in Health (CADTH) in Canada, and the Institute for Quality and Efficiency in Health Care (Institut fur Qualitat und Wirtschaftlichkeit im Gesundheitswesen [IQWiG]) in Germany were searched for single HTA reports (published between January 2010 and December 2015). The product, indication, outcome, and clinical evidence presented (comparative/noncomparative) were double extracted, with any discrepancies reconciled. A noncomparative study was defined as any study not presenting results against another treatment (including placebo or best supportive care), regardless of phase or setting, including dose-ranging studies. RESULTS: A total of 549 appraisals were extracted. Noncomparative evidence was considered in 38% (45 of 118) of NICE submissions, 13% (34 of 262) of CADTH submissions, and 12% (20 of 169) of IQWiG submissions. Evidence submissions based exclusively on noncomparative evidence were presented in only 4% (5 of 118) of NICE appraisals, 6% (16 of 262) of CADTH appraisals, and 4% (6 of 169) of IQWiG appraisals. Most drugs appraised solely on the basis of noncomparative evidence were indicated for cancer or hepatitis C. Positive outcome rates (encompassing recommended/restricted/added-benefit decisions) for submissions presenting only noncomparative evidence were similar to overall recommendation rates for CADTH (69% vs. 68%, respectively), but were numerically lower for NICE (60% vs. 84%, respectively) and IQWiG (17% vs. 38%, respectively) (P > 0.05 for all). CONCLUSIONS: Noncomparative studies can be viewed as acceptable clinical evidence by HTA agencies when these study designs are justifiable and when treatment effect can be convincingly demonstrated, but their use is currently limited. PMID- 29241884 TI - The Use of Decomposition Methods in Real-World Treatment Benefits Evaluation for Patients with Type 2 Diabetes Initiating Different Injectable Therapies: Findings from the INITIATOR Study. AB - BACKGROUND: Determining characteristics of patients likely to benefit from a particular treatment could help physicians set personalized targets. OBJECTIVES: To use decomposition methodology on real-world data to identify the relative contributions of treatment effects and patients' baseline characteristics. METHODS: Decomposition analyses were performed on data from the Initiation of New Injectable Treatment Introduced after Antidiabetic Therapy with Oral-only Regimens (INITIATOR) study, a real-world study of patients with type 2 diabetes started on insulin glargine (GLA) or liraglutide (LIRA). These analyses investigated relative contributions of differences in baseline characteristics and treatment effects to observed differences in 1-year outcomes for reduction in glycated hemoglobin A1c (HbA1c) and treatment persistence. RESULTS: The greater HbA1c reduction seen with GLA compared with LIRA (-1.39% vs. -0.74%) was primarily due to differences in baseline characteristics (HbA1c and endocrinologist as prescribing physician; P < 0.050). Patients with baseline HbA1c of 9.0% or more or evidence of diagnosis codes related to mental illness achieved greater HbA1c reductions with GLA, whereas patients with baseline polypharmacy (6-10 classes) or hypogylcemia achieved greater reductions with LIRA. Decomposition analyses also showed that the higher persistence seen with GLA (65% vs. 49%) was mainly caused by differences in treatment effects (P < 0.001). Patients 65 years and older, those with HbA1c of 9.0% or more, those taking three oral antidiabetes drugs, and those with polypharmacy of more than 10 classes had higher persistence with GLA; patients 18 to 39 years and those with HbA1c of 7.0% to less than 8.0% had higher persistence with LIRA. CONCLUSIONS: Although decomposition does not demonstrate causal relationships, this method could be useful for examining the source of differences in outcomes between treatments in a real-world setting and could help physicians identify patients likely to respond to a particular treatment. PMID- 29241885 TI - Cost Effectiveness of the Angiotensin Receptor Neprilysin Inhibitor Sacubitril/Valsartan for Patients with Chronic Heart Failure and Reduced Ejection Fraction in the Netherlands: A Country Adaptation Analysis Under the Former and Current Dutch Pharmacoeconomic Guidelines. AB - OBJECTIVES: To describe the adaptation of a global health economic model to determine whether treatment with the angiotensin receptor neprilysin inhibitor LCZ696 is cost effective compared with the angiotensin-converting enzyme inhibitor enalapril in adult patients with chronic heart failure with reduced left ventricular ejection fraction in the Netherlands; and to explore the effect of performing the cost-effectiveness analyses according to the new pharmacoeconomic Dutch guidelines (updated during the submission process of LCZ696), which require a value-of-information analysis and the inclusion of indirect medical costs of life-years gained. METHODS: We adapted a UK model to reflect the societal perspective in the Netherlands by including travel expenses, productivity loss, informal care costs, and indirect medical costs during the life-years gained and performed a preliminary value-of-information analysis. RESULTS: The incremental cost-effectiveness ratio obtained was ?17,600 per quality-adjusted life-year (QALY) gained. This was robust to changes in most structural assumptions and across different subgroups of patients. Probability sensitivity analysis results showed that the probability that LCZ696 is cost effective at a ?50,000 per QALY threshold is 99.8%, with a population expected value of perfect information of ?297,128. On including indirect medical costs of life-years gained, the incremental cost-effectiveness ratio was ?26,491 per QALY gained, and LCZ696 was 99.46% cost effective at ?50,000 per QALY, with a population expected value of perfect information of ?2,849,647. CONCLUSIONS: LCZ696 is cost effective compared with enalapril under the former and current Dutch guidelines. However, the (monetary) consequences of making a wrong decision were considerably different in both scenarios. PMID- 29241886 TI - PCSK9 Inhibitors Show Value for Patients and the US Health Care System. AB - BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were approved by the US Food and Drug Administration (FDA) as cholesterol-lowering therapies for patients with familial hypercholesterolemia or atherosclerotic cardiovascular disease. OBJECTIVES: To estimate the long-term health and economic value of PCSK9 inhibitors for Americans (51 years and older). METHODS: We conducted simulations using the Future Elderly Model, an established dynamic microsimulation model to project the lifetime outcomes for the US population aged 51 years and older. Health effects estimates and confidence intervals from published meta-analysis studies were used to project changes in life expectancy, quality-adjusted life-years, and lifetime medical spending resulting from the use of PCSK9 inhibitors. We considered two treatment scenarios: 1) current FDA eligibility and 2) an extended eligibility scenario that includes patients with no pre-existing cardiovascular disease but at high risk. We assumed that the price of PCSK9 inhibitors was discounted by 35% in the first 12 years and by 57% thereafter, with gradual uptake of the drug in eligible populations. RESULTS: Use of PCSK9 inhibitors by individuals covered by current FDA approval would extend life expectancy at the age of 51 years by an estimated 1.1 years and would yield a lifetime net value of $5800 per person. If use was extended to those at high risk for cardiovascular disease, PCSK9 inhibitors would generate a lifetime net benefit of $14,100 per person. CONCLUSIONS: Expanded access to PCSK9 inhibitors would offer positive long-term net value for patients and the US health care system at the current discounted prices. PMID- 29241887 TI - Basal Insulin Regimens for Adults with Type 1 Diabetes Mellitus: A Cost-Utility Analysis. AB - OBJECTIVES: To assess the cost-effectiveness of basal insulin regimens for adults with type 1 diabetes mellitus in England. METHODS: A cost-utility analysis was conducted in accordance with the National Institute for Health and Care Excellence reference case. The UK National Health Service and personal and social services perspective was used and a 3.5% discount rate was applied for both costs and outcomes. Relative effectiveness estimates were based on a systematic review of published trials and a Bayesian network meta-analysis. The IMS CORE Diabetes Model was used, in which net monetary benefit (NMB) was calculated using a threshold of L20,000 per quality-adjusted life-year (QALY) gained. A wide range of sensitivity analyses were conducted. RESULTS: Insulin detemir (twice daily) [iDet (bid)] had the highest mean QALY gain (11.09 QALYs) and NMB (L181,456) per patient over the model time horizon. Compared with the lowest cost strategy (insulin neutral protamine Hagedorn once daily), it had an incremental cost effectiveness ratio of L7844/QALY gained. Insulin glargine (od) [iGlarg (od)] and iDet (od) were ranked as second and third, with NMBs of L180,893 and L180,423, respectively. iDet (bid) remained the most cost-effective treatment in all the sensitivity analyses performed except when high doses were assumed (>30% increment compared with other regimens), where iGlarg (od) ranked first. CONCLUSIONS: iDet (bid) is the most cost-effective regimen, providing the highest QALY gain and NMB. iGlarg (od) and iDet (od) are possible options for those for whom the iDet (bid) regimen is not acceptable or does not achieve required glycemic control. PMID- 29241889 TI - Comparing Methods for Estimating Direct Costs of Adverse Drug Events. AB - OBJECTIVES: To estimate how direct health care costs resulting from adverse drug events (ADEs) and cost distribution are affected by methodological decisions regarding identification of ADEs, assigning relevant resource use to ADEs, and estimating costs for the assigned resources. METHODS: ADEs were identified from medical records and diagnostic codes for a random sample of 4970 Swedish adults during a 3-month study period in 2008 and were assessed for causality. Results were compared for five cost evaluation methods, including different methods for identifying ADEs, assigning resource use to ADEs, and for estimating costs for the assigned resources (resource use method, proportion of registered cost method, unit cost method, diagnostic code method, and main diagnosis method). Different levels of causality for ADEs and ADEs' contribution to health care resource use were considered. RESULTS: Using the five methods, the maximum estimated overall direct health care costs resulting from ADEs ranged from Sk10,000 (Sk = Swedish krona; ~?1,500 in 2016 values) using the diagnostic code method to more than Sk3,000,000 (~?414,000) using the unit cost method in our study population. The most conservative definitions for ADEs' contribution to health care resource use and the causality of ADEs resulted in average costs per patient ranging from Sk0 using the diagnostic code method to Sk4066 (~?500) using the unit cost method. CONCLUSIONS: The estimated costs resulting from ADEs varied considerably depending on the methodological choices. The results indicate that costs for ADEs need to be identified through medical record review and by using detailed unit cost data. PMID- 29241888 TI - Incremental Costs and Cost Effectiveness of Intensive Treatment in Individuals with Type 2 Diabetes Detected by Screening in the ADDITION-UK Trial: An Update with Empirical Trial-Based Cost Data. AB - BACKGROUND: There is uncertainty about the cost effectiveness of early intensive treatment versus routine care in individuals with type 2 diabetes detected by screening. OBJECTIVES: To derive a trial-informed estimate of the incremental costs of intensive treatment as delivered in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care Europe (ADDITION) trial and to revisit the long-term cost-effectiveness analysis from the perspective of the UK National Health Service. METHODS: We analyzed the electronic primary care records of a subsample of the ADDITION-Cambridge trial cohort (n = 173). Unit costs of used primary care services were taken from the published literature. Incremental annual costs of intensive treatment versus routine care in years 1 to 5 after diagnosis were calculated using multilevel generalized linear models. We revisited the long-term cost-utility analyses for the ADDITION-UK trial cohort and reported results for ADDITION-Cambridge using the UK Prospective Diabetes Study Outcomes Model and the trial-informed cost estimates according to a previously developed evaluation framework. RESULTS: Incremental annual costs of intensive treatment over years 1 to 5 averaged L29.10 (standard error = L33.00) for consultations with general practitioners and nurses and L54.60 (standard error = L28.50) for metabolic and cardioprotective medication. For ADDITION-UK, over the 10-, 20-, and 30-year time horizon, adjusted incremental quality-adjusted life-years (QALYs) were 0.014, 0.043, and 0.048, and adjusted incremental costs were L1,021, L1,217, and L1,311, resulting in incremental cost-effectiveness ratios of L71,232/QALY, L28,444/QALY, and L27,549/QALY, respectively. Respective incremental cost-effectiveness ratios for ADDITION-Cambridge were slightly higher. CONCLUSIONS: The incremental costs of intensive treatment as delivered in the ADDITION-Cambridge trial were lower than expected. Given UK willingness-to-pay thresholds in patients with screen-detected diabetes, intensive treatment is of borderline cost effectiveness over a time horizon of 20 years and more. PMID- 29241892 TI - Forecasting the Long-Term Clinical and Economic Outcomes of Lumacaftor/Ivacaftor in Cystic Fibrosis Patients with Homozygous phe508del Mutation. AB - OBJECTIVES: To forecast lifetime outcomes and cost of lumacaftor/ivacaftor combination therapy in patients with cystic fibrosis (CF) with homozygous phe508del mutation from the US payer perspective. METHODS: A lifetime Markov model was developed from a US payer perspective. The model included five health states: 1) mild lung disease (percent predicted forced expiratory volume in 1 second [FEV1] >70%), 2) moderate lung disease (40% <= FEV1 <= 70%), 3) severe lung disease (FEV1 < 40%), 4) lung transplantation, and 5) death. All inputs were derived from published literature. We estimated lumacaftor/ivacaftor's improvement in outcomes compared with a non-CF referent population as well as CF specific mortality estimates. RESULTS: Lumacaftor/ivacaftor was associated with additional 2.91 life-years (95% credible interval 2.55-3.56) and additional 2.42 quality-adjusted life-years (QALYs) (95% credible interval 2.10-2.98). Lumacaftor/ivacaftor was associated with improvements in survival and QALYs equivalent to 27.6% and 20.7%, respectively, for the survival and QALY gaps between CF usual care and their non-CF peers. The incremental lifetime cost was $2,632,249. CONCLUSIONS: Lumacaftor/ivacaftor increased life-years and QALYs in CF patients with the homozygous phe508del mutation and moved morbidity and mortality closer to that of their non-CF peers but it came with higher cost. PMID- 29241890 TI - Value of Information Analysis of Multiparameter Tests for Chemotherapy in Early Breast Cancer: The OPTIMA Prelim Trial. AB - BACKGROUND: Precision medicine is heralded as offering more effective treatments to smaller targeted patient populations. In breast cancer, adjuvant chemotherapy is standard for patients considered as high-risk after surgery. Molecular tests may identify patients who can safely avoid chemotherapy. OBJECTIVES: To use economic analysis before a large-scale clinical trial of molecular testing to confirm the value of the trial and help prioritize between candidate tests as randomized comparators. METHODS: Women with surgically treated breast cancer (estrogen receptor-positive and lymph node-positive or tumor size >=30 mm) were randomized to standard care (chemotherapy for all) or test-directed care using Oncotype DXTM. Additional testing was undertaken using alternative tests: MammaPrintTM, PAM-50 (ProsignaTM), MammaTyperTM, IHC4, and IHC4-AQUATM (NexCourse BreastTM). A probabilistic decision model assessed the cost-effectiveness of all tests from a UK perspective. Value of information analysis determined the most efficient publicly funded ongoing trial design in the United Kingdom. RESULTS: There was an 86% probability of molecular testing being cost-effective, with most tests producing cost savings (range -L1892 to L195) and quality-adjusted life year gains (range 0.17-0.20). There were only small differences in costs and quality-adjusted life-years between tests. Uncertainty was driven by long-term outcomes. Value of information demonstrated value of further research into all tests, with Prosigna currently being the highest priority for further research. CONCLUSIONS: Molecular tests are likely to be cost-effective, but an optimal test is yet to be identified. Health economics modeling to inform the design of a randomized controlled trial looking at diagnostic technology has been demonstrated to be feasible as a method for improving research efficiency. PMID- 29241891 TI - Cost Effectiveness of Candida Polymerase Chain Reaction Detection and Empirical Antifungal Treatment among Patients with Suspected Fungal Peritonitis in the Intensive Care Unit. AB - BACKGROUND: Mortality from intra-abdominal candidiasis in intensive care units (ICUs) is high. It takes many days for peritoneal-fluid fungal culture to become positive, and the recommended empirical antifungal therapy involves excessive costs. Polymerase chain reaction (PCR) should produce results more rapidly than fungal culture. OBJECTIVES: To perform a cost-effectiveness analysis of the combination of several diagnostic and therapeutic strategies to manage Candida peritonitis in non-neutropenic adult patients in ICUs. METHODS: We constructed a decision tree model to evaluate the cost effectiveness. Cost and effectiveness were taken into account in a 1-year time horizon and from the French National Health Insurance perspective. Six strategies were compared: fluconazole or echinocandin as an empirical therapy, plus diagnosis by fungal culture or detection by PCR of all Candida species, or use of PCR to detect most fluconazole resistant Candida species (i.e., Candida krusei and Candida glabrata). RESULTS: The use of fluconazole empirical treatment and PCR to detect all Candida species is more cost effective than using fluconazole empirical treatment without PCR (incremental cost-effectiveness ratio of ?40,055/quality-adjusted life-year). Empirical treatment with echinocandin plus PCR to detect C. krusei and C. glabrata is the most effective strategy, but has an incremental cost effectiveness ratio of ?93,776/quality-adjusted life-year. If the cost of echinocandin decreases, then strategies involving PCR plus empirical echinocandin become more cost-effective. CONCLUSIONS: Detection by PCR of all Candida species and of most fluconazole-resistant Candida species could improve the cost effectiveness of fluconazole and echinocandin given to non-neutropenic patients with suspected peritoneal candidiasis in ICUs. PMID- 29241893 TI - Value of Implementation of Strategies to Increase the Adherence of Health Professionals and Cancer Survivors to Guideline-Based Physical Exercise. AB - BACKGROUND: To increase the adherence of health professionals and cancer survivors to evidence-based physical exercise, effective implementation strategies (ISTs) are required. OBJECTIVES: To examine to what extent these ISTs provide value for money and which IST has the highest expected value. METHODS: The net benefit framework of health economic evaluations is used to conduct a value-of-implementation analysis of nine ISTs. Seven are directed to health professionals and two to cancer survivors. The analysis consists of four steps: 1) analyzing the expected value of perfect implementation (EVPIM); 2) assessing the estimated costs of the various ISTs; 3) comparing the ISTs' costs with the EVPIM; and 4) assessing the total net benefit (TNB) of the ISTs. These steps are followed to identify which strategy has the greatest value. RESULTS: The EVPIM for physical exercise in the Netherlands is ?293 million. The total costs for the ISTs range from ?34,000 for printed educational materials for professionals to ?120 million for financial incentives for patients, and thus all are cost effective. The TNB of the ISTs that are directed to professionals ranges from ?5.7 million for printed educational materials to ?30.9 million for reminder systems. Of the strategies that are directed to patients, only the motivational program had a positive net benefit of ?100.4 million. CONCLUSIONS: All the ISTs for cancer survivors, except for financial incentives, had a positive TNB. The largest improvements in adherence were created by a motivational program for patients, followed by a reminder system for professionals. PMID- 29241895 TI - Development and Validation of the AFImpact: An Atrial Fibrillation-Specific Measure of Patient-Reported Health-Related Quality of Life. AB - BACKGROUND: Improvement in health-related quality of life is a key therapeutic goal of disease management in atrial fibrillation (AF). OBJECTIVES: To describe the development of the AFImpact, an AF-specific health-related quality-of-life patient-reported outcome measure. METHODS: Development and validation of the AFImpact comprised a qualitative stage, consisting of a literature review and concept elicitation interviews (91 patients with AF), item generation, and cognitive debriefing (30 patients with AF), and a quantitative stage, consisting of evaluation of the instrument's psychometric properties (313 patients with AF). Preliminary responsiveness to change was assessed in 118 patients undergoing cardioversion. RESULTS: On the basis of the literature review and concept elicitation interviews, 75 items were generated. Factor analyses guided a reduction to 18 items. Three domains were confirmed: vitality (7 items), emotional distress (8 items), and sleep (3 items). The 18-item AFImpact demonstrated high item convergent and discriminant validity. Cronbach alpha coefficients showed high internal consistency reliability. Test-retest reliability of individual items in stable patients (n = 33) was satisfactory, with intraclass correlation coefficients ranging from 0.61 to 0.86. All three AFImpact domain scores differentiated patients who reported different levels of overall health, thereby supporting known-groups validity. Scores for each item improved after cardioversion, with effect sizes ranging from -0.19 to -0.65. CONCLUSIONS: Psychometric evaluations support the reliability and validity of the AFImpact as a patient-reported outcome instrument to measure the impact of AF, with preliminary results in patients undergoing cardioversion supporting responsiveness to change. PMID- 29241894 TI - Effects of Transitioning to Medicare Part D on Access to Drugs for Medical Conditions among Dual Enrollees with Cancer. AB - OBJECTIVES: To evaluate the impact of transitioning from Medicaid to Medicare Part D drug coverage on the use of noncancer treatments among dual enrollees with cancer. METHODS: We leveraged a representative 5% national sample of all fee-for service dual enrollees in the United States (2004-2007) to evaluate the impact of the removal of caps on the number of reimbursable prescriptions per month (drug caps) under Part D on 1) prevalence and 2) average days' supply dispensed for antidepressants, antihypertensives, and lipid-lowering agents overall and by race (white and black). RESULTS: The removal of drug caps was associated with increased use of lipid-lowering medications (days' supply 3.63; 95% confidence interval [CI] 1.57-5.70). Among blacks in capped states, we observed increased use of lipid-lowering therapy (any use 0.08 percentage points; 95% CI 0.05-0.10; and days' supply 4.01; 95% CI 2.92-5.09) and antidepressants (days' supply 2.20; 95% CI 0.61-3.78) and increasing trends in antihypertensive use (any use 0.01 percentage points; 95% CI 0.004-0.01; and days' supply 1.83; 95% CI 1.25-2.41). The white-black gap in the use of lipid-lowering medications was immediately reduced (-0.09 percentage points; 95% CI -0.15 to -0.04). We also observed a reversal in trends toward widening white-black differences in antihypertensive use (level -0.08 percentage points; 95% CI -0.12 to -0.05; and trend -0.01 percentage points; 95% CI -0.02 to -0.01) and antidepressant use (-0.004 percentage points; 95% CI -0.01 to -0.0004). CONCLUSIONS: Our findings suggest that the removal of drug caps under Part D had a modest impact on the treatment of hypercholesterolemia overall and may have reduced white-black gaps in the use of lipid-lowering and antidepressant therapies. PMID- 29241896 TI - An Exploratory Study on Using Principal-Component Analysis and Confirmatory Factor Analysis to Identify Bolt-On Dimensions: The EQ-5D Case Study. AB - OBJECTIVE: Generic preference-based measures such as the EuroQol five-dimensional questionnaire (EQ-5D) are used in economic evaluation, but may not be appropriate for all conditions. When this happens, a possible solution is adding bolt-ons to expand their descriptive systems. Using review-based methods, studies published to date claimed the relevance of bolt-ons in the presence of poor psychometric results. This approach does not identify the specific dimensions missing from the Generic preference-based measure core descriptive system, and is inappropriate for identifying dimensions that might improve the measure generically. This study explores the use of principal-component analysis (PCA) and confirmatory factor analysis (CFA) for bolt-on identification in the EQ-5D. METHODS: Data were drawn from the international Multi-Instrument Comparison study, which is an online survey on health and well-being measures in five countries. Analysis was based on a pool of 92 items from nine instruments. Initial content analysis provided a theoretical framework for PCA results interpretation and CFA model development. PCA was used to investigate the underlining dimensional structure and whether EQ 5D items were represented in the identified constructs. CFA was used to confirm the structure. CFA was cross-validated in random halves of the sample. RESULTS: PCA suggested a nine-component solution, which was confirmed by CFA. This included psychological symptoms, physical functioning, and pain, which were covered by the EQ-5D, and satisfaction, speech/cognition,relationships, hearing, vision, and energy/sleep which were not. These latter factors may represent relevant candidate bolt-ons. CONCLUSIONS: PCA and CFA appear useful methods for identifying potential bolt-ons dimensions for an instrument such as the EQ-5D. PMID- 29241897 TI - Nephrectomy Complication Is a Risk Factor of Clinically Meaningful Decrease in Health Utility among Living Kidney Donors. AB - OBJECTIVES: To assess the clinically relevant change in health state utility (HSU) in living kidney donors and whether this change value is constant across measures and clinical conditions and is useful for health economics studies. We aimed to 1) measure the change in the HSU score for living kidney donors from before donation to 3 months after donation and 2) estimate the minimal important decrease (MIDe) in the HSU score for living kidney donors and its associated clinical factors. METHODS: Data from a prospective multicenter observational study measuring quality of life of kidney donors by the three-level EuroQol five dimensional questionnaire (EQ-5D-3L) and the six-dimensional health state short form (SF-6D) before donation and at 3 months after donation provided HSU scores. Two methods were used to derive the MIDe: the anchor-based method and the distribution-based (standard error of measurement) method. Logistic regression was used to identify clinical factors associated with the MIDe after donation. RESULTS: In total, 228 and 216 donors completed the EQ-5D-3L and the SF-6D, respectively. Mean HSU scores were 0.932 and 0.823 before donation and 0.895 and 0.764 at 3 months after donation. HSU scores were significantly decreased at 3 months, and 18.5% of donors rated their global health as "somewhat worse." By the EQ-5D-3L and the SF-6D, the MIDe was estimated at -0.113 and -0.116 with the anchor-based method and -0.075 and -0.077 with the distribution-based method. Risk of decreased HSU score was significantly associated with clinical complications but only marginally with surgical technique. CONCLUSIONS: A short term clinically relevant decrease in HSU was significantly associated with clinical complications in kidney donors. Preventing perioperative complications is of prime importance in kidney donation. PMID- 29241898 TI - Patient Preferences for Device-Aided Treatments Indicated for Advanced Parkinson Disease. AB - BACKGROUND: Effective treatment for advanced Parkinson disease (PD) uncontrolled with oral medication includes device-aided therapies such as deep brain stimulation (DBS) and continuous levodopa-carbidopa infusion to the duodenum via a portable pump. OBJECTIVE: Our objective was to quantify patient preferences for attributes of these device-aided treatments. METHODS: We administered a Web enabled survey to 401 patients in the United States. A discrete-choice experiment (DCE) was used to evaluate patients' willingness to accept tradeoffs among efficacy, tolerability, and convenience of alternative treatments. DCE data were analyzed using random-parameters logit. Best-worst scaling (BWS) was used to elicit the relative importance of device-specific attributes. Conditional logit was used to analyze the BWS data. We tested for differences in preferences among subgroups of patients. RESULTS: Improving ability to think clearly was twice as important as a 6-hour-per-day improvement in control of movement symptoms. After controlling for efficacy, treatment delivered via portable infusion pump was preferred over DBS, and both devices were preferred to oral therapy with poor symptom control. Patients were most concerned about device attributes relating to risk of stroke, difficulty thinking, and neurosurgery. Avoiding surgery to insert a wire in the brain was more important than avoiding surgery to insert a tube into the small intestine. Some differences in preferences among subgroups were statistically, but not qualitatively, significant. CONCLUSIONS: This study clarifies the patient perspective in therapeutic choices for advanced PD. These findings may help improve communication between patients and providers and also provide evidence on patient preferences to inform regulatory and access decisions. PMID- 29241899 TI - Comparison of Oral Anticoagulants for Stroke Prevention in Nonvalvular Atrial Fibrillation: A Multicriteria Decision Analysis. AB - BACKGROUND: Decision on the most appropriate oral anticoagulation therapy for stroke prevention in patients with nonvalvular atrial fibrillation is difficult because multiple treatment options are available, and these vary in their clinical effects and relevant nonclinical characteristics. OBJECTIVES: To use a multicriteria decision analysis (MCDA) to compare the oral anticoagulants apixaban, dabigatran, edoxaban, rivaroxaban, and vitamin K antagonist (VKAs; specifically warfarin) in patients with nonvalvular atrial fibrillation. METHODS: We identified the evaluation criteria through a targeted literature review and clinical judgment. The final evaluation model included nine clinical events and four other criteria. We ranked possibly fatal clinical event criteria on the basis of the differences in risks of fatal events and the corresponding window of therapeutic opportunity, as observed in clinical trials. Clinical judgment was used to rank other criteria. Full criteria ranking was used to calculate centroid weights, which were combined with individual treatment performances to estimate the overall value score for each treatment. RESULTS: Using such an MCDA, dabigatran yielded the highest overall value, approximately 6% higher than that of the second-best treatment, apixaban. Dabigatran also had the highest first rank probability (0.72) in the probabilistic sensitivity analysis. Rivaroxaban performed worse than the other non-VKA oral anticoagulants, but better than VKAs (with both having 0.00 first-rank probability). The results were insensitive to changes in model structure. CONCLUSIONS: When all key oral anticoagulant value criteria and their relative importance are investigated in an MCDA, dabigatran appears to rank the highest and warfarin the lowest. PMID- 29241900 TI - A (Latent) Class of Their Own: Response Patterns in Trading Off Quantity and Quality of Life in Time Trade-Off Exercises. AB - BACKGROUND: Conflicting results regarding associations of time trade-off (TTO) valuations with respondent characteristics have been reported, mostly on the basis of regression analyses. Alternative approaches, such as the latent class analysis (LCA), may add to the further understanding of variations in TTO responses. OBJECTIVES: To identify whether subgroups of respondents can be identified on the basis of their responses to TTO exercises and to investigate which respondent characteristics are associated with membership of the identified subgroups. METHODS: Members of the Dutch general public, aged 18 to 65 years, completed a Web-based questionnaire concerning sociodemographic characteristics, three TTO exercises valuing health states described using the domains of the EuroQol five-dimensional questionnaire, and preference for quality versus quantity of life. LCA was used to identify patterns in the responses. Predictive variables were included in the final LCA model to identify the particular respondent characteristics that predict subgroup membership. RESULTS: The sample consisted of 1067 respondents. Four latent classes were identified in the responses to TTO exercises. Two were high traders, focusing on quality of life and trading off a relatively high number of years. The other two were low traders, focusing on length of life. Predictive analyses revealed significant differences between subgroups in terms of age, sex, subjective life expectancy, and preference for quantity over quality of life. CONCLUSIONS: We showed that distinct classes of respondents can be discerned in TTO responses from the general public, distinguishing subgroups of low and high traders. More research in this area should confirm our findings and investigate their implications for health state valuation exercises. PMID- 29241901 TI - Comparison of Timed Automata with Discrete Event Simulation for Modeling of Biomarker-Based Treatment Decisions: An Illustration for Metastatic Castration Resistant Prostate Cancer. AB - BACKGROUND: With the advent of personalized medicine, the field of health economic modeling is being challenged and the use of patient-level dynamic modeling techniques might be required. OBJECTIVES: To illustrate the usability of two such techniques, timed automata (TA) and discrete event simulation (DES), for modeling personalized treatment decisions. METHODS: An early health technology assessment on the use of circulating tumor cells, compared with prostate-specific antigen and bone scintigraphy, to inform treatment decisions in metastatic castration-resistant prostate cancer was performed. Both modeling techniques were assessed quantitatively, in terms of intermediate outcomes (e.g., overtreatment) and health economic outcomes (e.g., net monetary benefit). Qualitatively, among others, model structure, agent interactions, data management (i.e., importing and exporting data), and model transparency were assessed. RESULTS: Both models yielded realistic and similar intermediate and health economic outcomes. Overtreatment was reduced by 6.99 and 7.02 weeks by applying circulating tumor cell as a response marker at a net monetary benefit of -?1033 and -?1104 for the TA model and the DES model, respectively. Software-specific differences were observed regarding data management features and the support for statistical distributions, which were considered better for the DES software. Regarding method-specific differences, interactions were modeled more straightforward using TA, benefiting from its compositional model structure. CONCLUSIONS: Both techniques prove suitable for modeling personalized treatment decisions, although DES would be preferred given the current software-specific limitations of TA. When these limitations are resolved, TA would be an interesting modeling alternative if interactions are key or its compositional structure is useful to manage multi-agent complex problems. PMID- 29241902 TI - Scientific Evidence in Health Technology Assessment Reports: An In-Depth Analysis of European Assessments on High-Risk Medical Devices. AB - BACKGROUND: The aim of this study was to examine the scientific evidence on clinical effectiveness and safety used in health technology assessments (HTAs) of high-risk medical devices (MDs) in Europe. METHODS: We applied a systematic approach to identify European institutions involved in HTA and to select reports assessing MDs considered high-risk according to the definition in the new German health care regulation S137h. Reports published between 2010 and 2015 were considered in our subsequent analysis. We used a structured tool based on widely accepted methodologic principles from Drummond's framework to extract key information on the clinical evidence considered in the reports. RESULTS: Out of 1376 identified reports, 93 were eligible for analysis. All reports based their assessment primarily on direct evidence, in most cases (68%) identified through an independent systematic literature search. In more than half the identified studies considered in the reports, clinical evidence for demonstration of effectiveness and safety was of moderate or low quality. Even when systematic reviews and randomized controlled trials were available for assessment, most studies showed an unclear or high risk of bias. CONCLUSIONS: This study confirms that the quality of scientific evidence used in HTA of high-risk MDs is low and therefore the use of evidence needs improvement. The European Commission recently updated the regulation on MDs but mainly focused on the safety of materials and the CE (Conformite Europeene [European Conformity]) mark. Our results show that additional changes are necessary, specifically with regard to the marketing authorization process of MDs, with stricter quality requirements based on methodologically robust trials, possibly in combination with other evidence sources. PMID- 29241903 TI - Effect of Dipeptidyl Peptidase-4 Inhibitors on Heart Failure: A Network Meta Analysis. AB - BACKGROUND: Previous meta-analyses evaluating the effectiveness of individual dipeptidyl peptidase-4 (DPP-4) inhibitors on the risk of heart failure (HF) were limited because of the small number of trials with direct comparisons between two treatments. METHODS: A Bayesian network meta-analysis was performed to investigate the relationship between DPP-4 inhibitors and the risk of HF in patients with type-2 diabetes mellitus. The primary outcome was the occurrence of HF or hospital admission for HF. RESULTS: Fifty randomized controlled trials were identified. Relative to placebo, no increased risk of HF events was seen for vildagliptin (risk ratio [RR] 0.71; 95% confidence interval [CI] 0.25-1.68), sitagliptin (RR 0.86; CI 0.43-1.57), or saxagliptin (RR 0.84; 95% CI 0.33-1.61), but alogliptin was associated with a higher risk of HF (RR 2.13; 95% CI 1.06 6.26). Vildagliptin and sitagliptin were associated with a significantly decreased risk of HF compared with alogliptin. Vildagliptin had the highest probability to be the safest option with regard to the risk of HF (49.18%), followed by saxagliptin (26.56%), sitagliptin (20.76%), linagliptin (0.25%), and alogliptin (0.12%). A statistically significant inconsistency was noted in some comparisons. CONCLUSIONS: The risk of HF needs to be taken into account when prescribing DPP-4 inhibitors. Evidence suggests that vildagliptin may be the least harmful agent with regard to the risk of HF. However, a statistically significant inconsistency was identified in the Bayesian network meta-analysis. Therefore, further studies are warranted to evaluate the cardiovascular safety of DPP-4 inhibitors. PMID- 29241904 TI - Letter to the Editor: Emerging Guidelines for Patient Engagement in Research. PMID- 29241905 TI - Author Response: Patient Engagement. PMID- 29241906 TI - Rare presentation of sarcoidosis: Multimodal imaging diagnosis of cardiac involvement. AB - We report a case of sarcoidosis with an unusual presentation, initially manifesting as bilateral pulmonary embolism and then as a cardiac form of the disease with an ominous clinical event consisting of sustained ventricular tachycardia. The diagnosis was established by clinical and magnetic resonance criteria despite normal conventional echocardiographic study. Detailed functional assessment provided by tracking techniques (speckle tracking echocardiography and cardiac magnetic resonance tissue tracking) enabled the detection of regional deformation abnormalities, indicating prominent circumferential strain and epicardial layer alterations, partly matching the structural changes depicted by distribution of delayed enhancement. We find this case notable for various issues it raises concerning diagnosis and management of cardiac sarcoidosis. These are mainly related to recent developments in imaging modalities that enable non invasive identification of structural and functional abnormalities in this condition early, before overt deterioration in left ventricular ejection fraction. Information from different imaging modalities and tools provide information that could potentially assist preclinical diagnosis, with possible prognostic implications. PMID- 29241907 TI - A systematic review of massive transfusion protocol in obstetrics. AB - Post-partum obstetric haemorrhage is a leading cause of mortality among Japanese women, generally treated with haemostatic measures followed by supplementary transfusion. Commonly used in the setting of severe trauma, massive transfusion protocols (MTPs), preparations of red blood cell concentrate (RBC) and fresh frozen plasma (FFP) with additional supplements, have proved effective in decreasing patient mortality following major obstetric bleeding events. Although promising, the optimal configuration of RBC and FFP utilized for obstetric bleeding needs to be verified. Here, we conducted a systematic literature review to define the optimal ratio of RBC to FFP for transfusion therapy during instances of obstetric bleeding. Our analysis extracted four retrospective, observational studies, all demonstrating that an FFP/RBC ratio of >=1 was associated with improved patient outcomes following obstetric haemorrhage. We therefore conclude that, from the standpoint of haemostatic resuscitation, an FFP/RBC ratio of >=1 is a necessary condition for optimal clinical management during MTP administration in the field of obstetrics. Hence, we further propose an optimized MTP strategy to be utilized in the setting of severe obstetric bleeding. PMID- 29241908 TI - Laboratory and clinical significance of macroprolactinemia in women with hyperprolactinemia. AB - The role of macroprolactinemia in women with hyperprolactinemia is currently controversial and can lead to clinical dilemmas, depending upon the origin of macroprolactin, the presence of hyperprolactinemic symptoms and monomeric prolactin (PRL) levels. Macroprolactinemia is mostly considered an extrapituitary phenomenon of mild and asymptomatic hyperprolactinemia associated with normal concentrations of monomeric PRL and a predominance of macroprolactin confined to the vascular system, which is biologically inactive. Patients can therefore be reassured that macroprolactinemia should be considered a benign clinical condition, resistant to antiprolactinemic drugs, and that no diagnostic investigations or prolonged follow-up should be necessary. However, a significant proportion of macroprolactinemic patients appears to suffer from hyperprolactinemia-related symptoms and radiological pituitary findings commonly associated with true hyperprolactinemia. The symptoms of hyperprolactinemia are correlated to the levels of monomeric PRL excess, which may be explained as coincidental, by dissociation of macroprolactin, or by physiological, pharmacological and pathological causes. The excess of monomeric PRL levels in such cases is of primarily importance and the diagnosis of macroprolactinemia is misleading or inadequate. However, macroprolactinemia of pituitary origin associated with radiological findings of pituitary adenomas may rarely occur with similar hyperprolactinemic manifestations, exclusively due to bioactivity of macroprolactin. Therefore, in such cases with hyperprolactinemic signs and pituitary findings, macroprolactinemia should be considered a pathological biochemical condition of hyperprolactinemia. Accordingly, individualized diagnostic investigations with the introduction of dopamine agonists, or other treatment with prolonged follow-up, should be mandatory. The review analyses the laboratory and clinical significance of macroprolactinemia in hyperprolactinemic women suggesting clinically useful diagnostic and treatment strategies. PMID- 29241909 TI - Effect of hyoscine butyl-bromide on the duration of active phase of labor: A randomized-controlled trial. AB - OBJECTIVE: Hyoscine butyl bromide (HBB) is known for its antispasmodic action and has been in use for over five decades, there is however no consensus on its effectiveness in the labor process. The aim of this study was to determine the effect of HBB on the duration of the active phase of labor. MATERIALS AND METHODS: A randomized double-blind placebo-controlled clinical trial involving 160 parturient who received either intravenous Hyoscine butyl-bromide (20 mg in 1 ml; n = 80) or intravenous normal saline (1 ml, n = 80). The mean duration of active phase of labor was compared between the two groups. RESULTS: The observed mean duration of the active phase of labor was significantly shorter (P = 0.001) in the Hyoscine butyl-bromide group (365.11 +/- 37.32 min, range = 280-490) than in the Placebo group (388.46 +/- 51.65 min, range = 280-525). There was no significant difference between the two groups in the mean duration of the second and third stages of labor (20.46 +/- 10.46 vs. 23.38 +/- 18.95 min, P = 0.43 and 8.96 +/- 4.34 vs. 9.23 +/- 5.92 min, P = 0.75, respectively). The mean 1-min APGAR scores were also comparable (8.08 +/- 1.54 vs. 7.64 +/- 1.60, P = 0.08). The mean postpartum blood loss was significantly less in the Hyoscine butyl bromide group (303 +/- 96.52 vs. 368 +/- 264.19 ml, P = 0.04). CONCLUSION: Hyoscine butyl-bromide was effective in shortening the duration of the active phase of labor. It was also associated with significantly less postpartum blood loss. PMID- 29241910 TI - Prenatal diagnosis of Down syndrome: A 13-year retrospective study. AB - OBJECTIVE: The aim of this study is to summarize the experience on prenatal diagnosis of Down syndrome. MATERIALS AND METHODS: The study includes a retrospective data analysis of 157 prenatally detected cases of Down syndrome, routinely diagnosed among 6448 prenatal investigations performed during a 13-year period (2002-2014) in a single tertiary center. RESULTS: The prevalence of diagnosed Down syndrome cases was 2.4%. Maternal age alone was indication for prenatal diagnosis in 47 cases (45.2%), increased first-/second-trimester biochemical screening test in 34 cases (21.7%), abnormal ultrasound examination in 69 cases (43.9%), positive familial history for chromosomal abnormalities in four cases, and high risk for trisomy 21 revealed by cell-free DNA testing in three cases. Ultrasound anomalies were present in total of 94 fetuses (59.8%). The most common abnormality was cystic hygroma found in 46 cases (29.3%). A regular form of Down syndrome (trisomy 21) was found in 147 cases (93.6%), Robertsonian translocation in six cases (3.8%), and mosaic form in four cases (2.6%). CONCLUSION: In prenatal diagnosis of Down syndrome noninvasive screening methods are important for estimation of individual risks, in both, young population of woman and older mothers, while conventional and molecular cytogenetic methods are essential for definite diagnosis and proper genetic counseling. PMID- 29241911 TI - A comparison of mean corpuscular volume (MCV) between thalassemia-carrier and non thalassemia-carrier pregnant women receiving highly active antiretroviral therapy (HAART). AB - OBJECTIVE: HIV-infected treatment with antiretroviral drugs is one of the common causes of macrocytosis. In patients receiving highly active antiretroviral therapy (HAART), the mean corpuscular volume (MCV) can be shifted from microcytic to normocytic or macrocytic after treatment and significantly affected the thalassemia screening. This study aimed to compare MCV between thalassemia carrier and non-thalassemia-carrier antiretroviral drug-naive, HIV-infected, pregnant women receiving HAART. The results will support the couples at risk identification in prenatal control of severe thalassemia disease. MATERIALS AND METHODS: A retrospective cohort study was conducted in antiretroviral drug-naive, HIV-infected, pregnant women who received HAART between January 2008 and December 2015 in Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand. Changes in MCV were compared between the thalassemia and non-thalassemia carriers. RESULTS: Of 74 pregnant women who were exposed to HAART for at least 4 weeks, increased MCV levels were significantly greater in the non-thalassemia carriers group (n = 58) than in the thalassemia-carrier group (n = 16) (16.60 +/- 12.55 fL and 15.61 +/- 9.67 fL, respectively; p < 0.001). Pre-HAART exposure, sensitivity of MCV was 83.3% for thalassemia carriers screening using MCV <80 fL. Post-HAART exposure, sensitivity of MCV was 33.3%, and the false negative rate was 66.7%. CONCLUSION: Post-HAART exposure, MCV increased substantially in both the thalassemia and non thalassemia carriers. Using MCV <80 fL as the cutoff for diagnosing thalassemia, false negative results were observed in two thirds of the thalassemia carriers who were exposed to HAART for at least 4 weeks; therefore, the screening test should be interpreted with caution. PMID- 29241912 TI - Radiofrequency ablation for selective reduction in complex monochorionic multiple pregnancies: A case series. AB - OBJECTIVE: To determine the safety and efficacy of radiofrequency ablation (RFA) for selective fetal reduction in complex monochorionic multiple pregnancies. MATERIALS AND METHODS: From July 2011 to January 2015, data on all cases treated with RFA were collected prospectively in our hospital. Indications, procedure details, cause of fetal demise and pregnancy outcomes were analyzed. Sonography and magnetic resonance imaging were performed to detect fetal brain damage. Information regarding development after birth was collected according to the Gesell Development Schedule(r). RESULTS: There were 22 cases of twins (6 presenting with twin-twin transfusion syndrome, 10 with malformations, 4 with selective intrauterine growth restriction, and 2 with twin reversed arterial perfusion sequence); and 11 cases of triplets (9 dichorionictriamniotic, 2 monochorionictriamniotic). All surgeries were completed with one puncture. No maternal complications presented during RFA procedure, and the PPROM rate before 32 w was 9% (3/33). There were 3 cases of intrauterine fetal demise and 4 twin cases where pregnancy was terminated. The fetal survival rate was 77% (17/22) in twins, 91% (20/22) in triplets. Total fetal survival rate was 84% (37/44). The neurodevelopmental follow-up investigations showed no abnormalities in any of the survivors. CONCLUSION: RFA for selective fetal reduction in complex monochorionic multiple pregnancies is effective, minimally invasive, and safe. PMID- 29241913 TI - The comparison of umbilical cord arterial blood lactate and pH values for predicting short-term neonatal outcomes. AB - OBJECTIVE: Current clinical practice of assessing neonatal condition is based on evaluation of umbilical cord arterial blood pH value rather than lactate. However, evidence shows that lactate is direct and more predictive measurement than pH or at least of equal importance. This study is to assess and compare umbilical cord arterial lactate and pH values for predicting short-term neonatal outcomes. MATERIALS AND METHODS: A retrospective cohort study was conducted at the tertiary level hospital, were arterial umbilical cord blood sampling was collected according to the standard procedures. Neonatal morbidity was registered if at least one of the following conditions was noted: Apgar score at 1 min after delivery was 6 or lower, resuscitation performed, including assisted ventilation and requirement of admission to neonatal intensive care unit. Mothers-newborns pairs were allocated into two groups: newborns exposed to perinatal hypoxia (group 1) and observed as healthy newborns (group 2). Receiver operating characteristics curves (ROC) were generated to assess the predictive ability of pH and lactate for the short-term neonatal outcomes. RESULTS: 901 neonates born at >=37 weeks of gestation were included. Newborns exposed to perinatal hypoxia (group 1) encompassed 39 (4.3%) patients, and observed as healthy (group 2) - 862 (95.7%). Arterial umbilical cord blood pH in group 1 was 7.160 +/- 0.126 as compared to 7.314 +/- 0.083 in group 2; p < 0.001. Mean arterial lactate was significantly higher in group 1 than group 2 (6.423 +/- 2.335 as compared to 3.600 +/- 1.833; p < 0.001). The difference between areas under ROC curves representing pH and lactate was not significant (0.848 and 0.831 respectively; p = 0.6132). CONCLUSION: Umbilical cord arterial lactate and pH predicted short term neonatal outcomes with similar efficacies. PMID- 29241914 TI - Estrogen receptor and laminin genetic polymorphism among women with pelvic organ prolapse. AB - OBJECTIVE: Laminin is a connective tissue component. The LAMC1 gene encodes for gamma-1 chain of laminin, which is associated with familial clustering of POP. The ERalpha gene which encodes for cellular estrogen receptor has also been associated with POP. The aim of this study was to evaluate a possible correlation between polymorphism in these genes and the risk for developing POP. MATERIALS AND METHODS: Blood samples were drawn from 33 women with advanced POP (study group) and 33 women without POP (control group). DNA was extracted, and the presence of the rs10911193 C/T mutation in LAMC1 and of the rs2228480 G/A mutation in ERalpha was detected using the PCR technique. RESULTS: 26 samples were available for each group regarding ERalpha. 33 samples were available for each group, regarding LAMC1. The prevalence of homozygotes for the ERalpha rs2228480 G/A mutation was 19.2% and 0% among women with and without POP, respectively (OR 39.77, 95% CI 1.93-817.0, P = 0.00046). The prevalence of heterozygotes for this mutation was 83.3% and 11.5%, respectively (OR 19.2, 95% CI 4.15-88.6, P < 0.0001). The prevalence of homozygotes for the LAMC1 gene rs10911193 C/T mutation was 3.6% and 6.1% among women with and without POP (NS), while the respective for heterozygotes for this mutation was 21.4% and 33.3% (NS). CONCLUSIONS: Polymorphism in the ERalpha gene is associated with an increased risk for advanced POP. However, polymorphism in the LAMC1 gene does not seem to be associated with such risk. PMID- 29241915 TI - Predictors of failure of the commonly used single-dose methotrexate protocol for treating tubal ectopic pregnancies. AB - OBJECTIVES: This study identified patients who would benefit from an earlier additional medical intervention and/or continuing close surveillance even if commonly used parameters indicated sufficient medical treatment to determine markers of treatment failure. MATERIALS AND METHODS: A retrospective analysis of patients with a preliminary diagnosis of ectopic pregnancy treated with the single-dose methotrexate protocol. Group 1: cases cured with a single dose of methotrexate; Group 2: cases who required more than one dose of methotrexate or surgery following the first dose. Demographics, clinical/sonographic findings, observation period, and beta-human chorionic gonadotropin (hCG) levels were compared among the two groups. Thresholds were defined and a regression analysis was performed to define independent predictors of failure. RESULTS: Data from 120 patients were analyzed: Group 1 (n = 92); Group 2 (n = 28). beta-hCG levels measured at all time points, and day (0-4) and day (4-7) changes, presence of adnexial masses, and infertility were significantly different among the two groups. Only the day (0-4) and day (4-7) changes in beta-hCG levels were independent predictors of failure. CONCLUSION: Day (0-4) thresholds or newly defined day (4-7) thresholds were not more sensitive than the conventional day (4 7) criteria. Day (0-4) beta-hCG levels increased by more than 9.7% in half the patients who required additional methotrexate doses or surgery despite fulfillment of the conventional day (4-7) criteria. In contrast, no cases of treatment failure were observed if the day (0-4) decrease was >26.6%. PMID- 29241916 TI - Etiology and management of primary amenorrhoea: A study of 102 cases at tertiary centre. AB - OBJECTIVE: To determine the prevalence of etiologic causes of primary amenorrhea in Indian population. MATERIALS AND METHODS: A retrospective study was performed using 102 complete medical records of women with primary amenorrhea who attended the Gynaecologic Endocrinology Clinic, Department of Obstetrics and Gynaecology, AIIMS, New Delhi from September 2012 to September 2015. Cases were analysed according to clinical profile, development of secondary sexual characteristics, physical examination, pelvic and rectal examination, X-ray of chest and lumbo sacral spine, hormone profile, pelvic USG, MRI, and cytogenetic study including karyotype. RESULTS: The three most common causes of primary amenorrhea were Mullerian anomalies (47%), gonadal dysgenesis (20.5%), and hypogonadotropic hypogonadism (14.7%) in the present study. There were 3 cases of Turner syndrome (45,XO), 5 cases of Swyer's syndrome (46,XY) and 2 cases of Androgen insensitivity syndrome (46,XY). One case had pituitary macroadenoma and eight cases (7.8%) were of genital tuberculosis. CONCLUSIONS: The present study has currently been the largest case series of primary amenorrhea from North India. Mullerian anomaly is the most prevalent etiological factor leading to amenorrhoea followed by gonadal dysgenesis in our study. Racial, genetic and environmental factors could play role in the cause of primary amenorrhea. PMID- 29241917 TI - Pueraria mirifica inhibits 17beta-estradiol-induced cell proliferation of human endometrial mesenchymal stem cells. AB - OBJECTIVE: The notion that the human endometrium may contain a population of stem cells has recently been proposed. The mesenchymal stem cells (MSCs) in the endometrium are believed to be responsible for the remarkable regenerative ability of endometrial cells. Estrogens influence the physiological and pathological processes of several hormone-dependent tissues, such as the endometrium. Pueraria mirifica (PM) is a herbal plant that contains several phytoestrogens, including isoflavones, lignans, and coumestans, and is known to exert an estrogenic effect on animal models. The present study investigated the effects of PM on the proliferation of human endometrial MSCs (hEN-MSCs). MATERIALS AND METHODS: The hEN-MSCs were isolated from human endometrial tissue. The surface markers of these hEN-MSCs were identified through reverse transcription-polymerase chain reaction analysis. The proliferation potential of hEN-MSCs was measured through a cell proliferation assay. Multilineage differentiation ability was confirmed through Oil red O and von Kossa staining. RESULTS: This study demonstrated that 17beta-estradiol-responsive MSCs with Oct 4, CD90, and CD105 gene expression can be derived from the human endometrium and that PM exerts biological effects on hEN-MSCs, specifically, enhanced cell growth rate, through the estrogen receptor. Furthermore, PM at 1500 and 2000 MUg/mL significantly increased cell proliferation compared with the vehicle control, and PM concentration at 1000 MUg/mL significantly inhibited the enhanced cell growth rate induced by 17beta-estradiol in hEN-MSCs. CONCLUSION: This study provides new insights into the possible biological effects of PM on the proliferation of hEN MSCs. PMID- 29241919 TI - Does the "freeze-all" policy allow for a better outcome in assisted reproductive techniques than the use of fresh embryo transfers? - A retrospective study on cumulative live birth rates. AB - OBJECTIVE: There are increasing concerns regarding the adverse effects associated with control ovarian hyperstimulation (COH) in both endometrial and uterine environments. With the "segmentation treatment policy" of assisted reproductive techniques (ART), endometrial problems may be obviated through embryo cryopreservation. However, it remains unclear if the "freeze-all policy" offers a better outcome when compared with fresh embryo transfer (ET). To clarify this, we compared the cumulative live birth rates (CLBRs) between these two patient populations. MATERIALS AND METHODS: This is a retrospective study on 853 patients undergoing ovarian stimulation and ART (including IVF/ICSI) during the period from January 2012 to June 2014 in Taichung Veterans General Hospital, Taiwan, ROC. We followed up with these patients through to November 2016. Patients whose embryos were not completely transferred back were excluded. The study group ('freeze-all') included 84 patients whose cycles were performed initially without fresh ET, but were later given frozen-thawed ET. The control group ('fresh ET') had 625 patients whose cycles were performed with fresh ET, followed by frozen thawed ET. Basic parameters and CLBRs were statistically compared between these two groups. RESULTS: The CLBRs in the study group were significantly higher than those in the control group (64.3% vs. 45.8%, p = 0.001). Subgroup analysis revealed that when the number of oocyte pick up (OPU) is between 4 and 15, the CLBRs in the study group were significantly better (58.3% vs. 40.9%, p = 0.042). For those with OPU <4 or OPU >15 the CLBRs were similar in these two groups (OPU < 4: study vs. control 23.1% vs. 18.8% respectively, p = 0.713; OPU>15: study vs. control 85.7% vs. 80.8% respectively, p = 0.625) CONCLUSION: The Freeze-all policy improved the ART outcome for normal responders. PMID- 29241918 TI - Human amniotic fluid stem cells have better potential in early second trimester of pregnancy and can be reprogramed to iPS. AB - OBJECTIVE: To study the difference of amniotic fluid stem cell potential at different gestational age. MATERIALS AND METHODS: Second trimester amniocentesis was performed during 15 to 22nd week of gestational age in a single medical center from 2015 to 2016. Early second trimester amniotic fluid stem cells (E AFS) and later one (L-AFS) were defined 15-18th week, and 19-22nd week, respectively. Cell characteristics, surface markers and ability to form induced pluripotent stem cells (iPS) were studied. RESULTS: All the amniotic fluid stem cells samples could be isolated and cultured from second trimester amniocentesis. E-AFS showed more Ckit + cell, shorted doubling time, smaller cell size and higher cell density compared to L-AFS. Both groups had the same stem cell surface markers with highly expression of CD44, CD73, CD90, and CD105, negative for CD45. They can easily be reprogramed into amniotic fluid stem cell derived iPS via standard induction. CONCLUSION: Human amniotic fluid stem cells could be isolated from early or late second trimester amniocentesis with the similar stem cell surface markers presentation, especially in mesenchymal stem cells markers. However, the cells from early second trimester amniocentesis have more Ckit + number and more potential characteristics compared to late second trimester amniocentesis. Both E-AFS and L-AFS could form the iPS easily which lead to the future disease modeling study. PMID- 29241920 TI - Learning curve in concurrent application of laparoscopic and robotic-assisted hysterectomy with lymphadenectomy in endometrial cancer. AB - OBJECTIVE: To evaluate the concurrent interaction of laparoscopic and robotic assisted surgery in the initial learning period of endometrial cancer staging. MATERIALS AND METHODS: A retrospective cohort study was performed for the first 44 consecutive patients with endometrial cancer underwent laparoscopic (LSS) or robotic-assisted staging surgery (RSS) from February 2012 to October 2015 by a single surgeon in a tertiary care referral hospital. Demographics, diagnosis, perioperative variables, and complications were recorded. Quality of surgery was determined by the number of lymph nodes dissected and learning curve was estimated by operative time with respect to chronologic order of operation. RESULTS: Twenty-four patients received LSS and 20 patients received RSS. RSS required longer operative time, but obtained more total number of lymph nodes compared with LSS (286.9 vs. 201.9 min (p < 0.001); 26.2 vs. 20.7 (p < 0.05), respectively. There were no difference in blood loss, number of para-aortic nodes removed, complications and hospital stay between the two types of surgery. An additive model based on tumor grade, body mass index, estimated blood loss and chronological order of operation was constructed to fit operative time of these two types of surgery. Proficiency of achievement was not observed for LSS and was 6 for RSS. CONCLUSIONS: Operative time was longer but Lymph node dissection was easier in RSS. Learning curve for LSS to maintain similar surgical quality as RSS was not observed. The concurrent use of robotic platform in the initial practice of minimally invasive staging surgery could optimize surgical technique for LSS. PMID- 29241921 TI - Relationship between fetal heart rate patterns and a time course for evaluation of fetal well-being: "the 30 minutes rule" for decision of mechanical delivery. AB - OBJECTIVE: To predict acidosis in fetus showing deceleration associated with non reassuring fetal status during delivery, we examined the relationship between duration of the deceleration and umbilical arterial pH. MATERIALS AND METHODS: A total of 19,907 deliveries in eight facilities of the Juntendo Perinatal Care Group, 895 cases of vaginal deliveries with level 3 decelerations were selected for the subjects of this study. The cut-off point of time when the umbilical arterial pH fell below 7.20 in all cases of level 3 and for each deceleration type were examined. The explanatory variables were the pH and pO2 of umbilical arterial gas and the time from onset of the level 3 pattern to delivery. From receiver operating characteristic (ROC) analysis using these variables, the critical point indicating low Apgar score was set at an umbilical arterial pH < 7.20. RESULTS: The cut-off point of time when the umbilical arterial pH fell below 7.2 was 33.5 min for all cases of level 3, and 604 cases of severe variable decelerations with normal baseline variability and normal baseline heart rates, the cut-off point was 33.5 min as well. For 108 cases of late decelerations, there was no significant cut-off point for either the mild or severe cases. Mild prolonged deceleration showed the cut-off point of 34.5 min. CONCLUSIONS: We confirmed the time indices for predicting and preventing acidosis in fetuses showing decelerations. To prevent fetal acidosis, the decision related to proper timing for performing assisted delivery by considering the time course is important. PMID- 29241922 TI - Single incision anterior apical mesh and sacrospinous ligament fixation in pelvic prolapse surgery at 36 months follow-up. AB - OBJECTIVE: To compare the clinical efficacy, recurrence, complications and quality of life changes 3 years after Elevate-A/single incision mesh surgery anterior apical (SIM A) and sacrospinous ligament fixation (SSF) in the management of pelvic organ prolapse (POP). MATERIALS AND METHODS: A prospective cohort study, 139 women, underwent transvaginal surgery for anterior and/or apical POP > stage 2, 69 patients had SIM A and 70 patients had SSF. The objective cure was defined as POP <= stage 1 anterior, apical according to POP-Q. Subjective cure is patient's negative feedback to question 2 and 3 of pelvic organ prolapse distress inventory 6 (POPDI-6). Patient's satisfaction was reported using validated quality of life questionnaires. Multi-channel urodynamic study was used to report any voiding problems related to the prolapse surgery 6 months after surgery. RESULTS: 119 patients completed a minimum of 3 years follow up. 89.8% is the overall prolapse correction success rate for SIM A and 73.3% for SSF group (p = 0.020), and 96.6% versus 73.4% at the anterior vaginal compartment respectively (p <= 0.001). Statistically significant difference was noticed in apical compartment with 98.3% with SIM A and 85.0% with SSF (p = 0.009). The subjective success rate, 86.4% in the SIM A and 70.0% in the SSF arm (p = 0.030) was significantly noted. Only, Pelvic Organ Prolapse Distress Inventory-6 (POPDI 6) showed significant improvement. Operation time and intra-operative blood loss tend to be more with SIM A. CONCLUSION: SIM A has better 3 years objective and subjective cure rate than SSF in the anterior and/or apical compartment prolapse. PMID- 29241923 TI - Maternal serum placental growth factor combined with second trimester aneuploidy screening to predict small-for-gestation neonates without preeclampsia. AB - OBJECTIVE: To investigate the role of maternal serum placenta growth factor (PlGF) and quadruple test parameters in predicting the risk of small for gestational age (SGA) infants of mothers without preeclampsia. MATERIALS AND METHODS: We prospectively enrolled 300 pregnant patients who underwent blood sampling at 15-18 weeks gestation and followed them until delivery. Cases with SGA neonate delivery (n = 100) were compared with matched AGA neonate controls (n = 200). The plasma PlGF and quadruple markers were measured by enzyme-linked immunosorbent assay. The results were analyzed with Mann-Whitney U tests, and regression analysis was used to develop a model for the prediction of SGA. RESULTS: Women who delivered SGA neonates had decreased levels of PlGF (median 0.71 MoM versus 0.7 MoM; p < 0.01), hCG (median 0.97 MoM versus 1.06 MoM; p = 0.046) and uE3 (median 0.92 MoM versus 1.04 MoM) compared to the AGA group. AFP, hCG and inhibin-A levels did not differ significantly. A PlGF concentration <0.37 MoM had a sensitivity of 28.0% (95% CI: 19.5-37.9) and a specificity of 89.5% (95% CI: 84.4-93.4) for the prediction of SGA neonates without PE. CONCLUSION: SGA neonates in the absence of PE could potentially be identified at 15-18 weeks of pregnancy. PMID- 29241925 TI - A community-based epidemiological survey of overactive bladder and voiding dysfunction in female Taiwanese residents aged 40 years and above. AB - OBJECTIVE: This is part of a three-year study designed to evaluate the natural history of lower urinary tract symptoms in local community residents aged 40 years and above in central Taiwan. We evaluated the prevalence of overactive bladder (OAB) and voiding dysfunction (VD) in female residents using validated questionnaires. MATERIALS AND METHODS: A structured questionnaire containing groups of different questionnaires was translated into Chinese and each one was validated separately. A trained research assistant interviewed the participants and assisted in filling in the questionnaires. Residents were recorded to have OAB if the total OABSS score was?4. Urge urinary incontinence (UUI) was defined as urine leakage preceded by the feeling of urgency which is slightly or more distressful. VD was defined as feeling of difficulty in emptying the bladder which is slightly or more distressful. RESULTS: A total of 2411 community residents aged 40 years and above who completed all the questionnaires in the initial survey were recruited, of which 1469(60.9%) were women. The prevalence of OAB, UUI and VD were 33.1%, 26.8% and 28.3% respectively in the female community residents. Age?60 (OR, 1.5; 95%CI, 1.1-2.0), menopause (OR1.4; 95% CI, 1.0-1.9) and a history of diabetes mellitus (OR, 1.8; 95% CI, 1.2-2.8) were the risk factors for OAB. Age?60 (OR, 1.4; 95%CI, 1.0-1.9), BMI ?25 (OR, 1.3; 95% CI, 1.0 1.7) and instrument deliveries (OR, 1.5; 95% CI, 1.0-2.1) were the risk factors for VD. CONCLUSION: Our results imply that the prevalence of overactive bladder and voiding difficulty are high in female community residents aged ? 40 years in central Taiwan. PMID- 29241924 TI - Effects of growth hormone plus gonadotropins on controlled ovarian stimulation in infertile women of advanced age, poor responders, and previous in vitro fertilization failure patients. AB - OBJECTIVE: To investigate the effects of growth hormone (GH) cotreatment in ovarian stimulation in infertile women of advanced age, poor responders, and patients with one or more previous IVF treatment failures. MATERIALS AND METHODS: We conducted a retrospective observational study of 436 patients undergoing GH cotreatment in ovarian stimulation. The first arm included 134 infertile women of advanced age. The second arm included 236 patients with one or more IVF previous treatment failures, and the third arm included 66 younger poor responders. Main outcome measures were the number of oocytes and embryos, quality of embryos, and implantation and pregnancy rates. RESULTS: In infertile women of advanced age, GH plus ovarian stimulation yielded no statistical differences in the numbers of oocytes and embryos, quality of embryo, and rates of implantation and pregnancy. In the second arm, the mature oocyte number (8.2 vs. 6.8), implantation rate (16.1% vs. 0%), and pregnancy rate (33.9% vs. 0%) in the GH cotreatment group differed significantly from those in the control group; the rate of good-quality embryos in the GH cotreatment group improved from 35.5% +/- 31.1%-41.4% +/- 30.6% in this arm. Similar results were observed in the third arm; in this arm, the clinical pregnancy rate was 30.3% in the GH cotreatment group and 6.1% in the control group. CONCLUSION: No significant differences were observed in infertile women of advanced age, which may be due to the low GH dose. The GH adjuvant therapy for patients with one or more previous IVF treatment failures and for poor responders significantly improved the oocyte and embryo numbers as well as implantation and pregnancy rates. PMID- 29241926 TI - Effect of non-ablative laser treatment on overactive bladder symptoms, urinary incontinence and sexual function in women with urodynamic stress incontinence. AB - OBJECTIVE: To investigate the effects of non-ablative laser treatment on overactive bladder (OAB) syndromes, stress urinary incontinence and sexual function in women with urodynamic stress incontinence (USI). MATERIALS AND METHODS: Between April 2015 and June 2015, consecutive patients with USI with OAB syndromes underwent two sessions of Erbium:YAG laser treatment in a tertiary hospital. Patients received validated urological questionnaires, urodynamic studies, 1-h pad test and measurement of vaginal pressure before, one and three months after laser treatment. Questionnaires at 12 months were completed by telephone interview. Adverse effects and patients' satisfaction were also assessed. RESULTS: We included 30 patients with a mean age of 52.6 +/- 8.8 years. Three months after therapy, mean 1-h pad test significantly decreased (P = 0.039). Significant improvement in OAB symptoms in four questionnaires were noted at three months post treatment, but not sustained for 12 months in two of them. Three months after therapy, mean vaginal pressure significantly improved (P = 0.009). Of 24 (82.7%) sexually active patients, 62.5% (15/24) and 54.2% (13/24) of their sexual partners reported improved sexual gratification three months later. No major adverse effects were noticed. CONCLUSIONS: Erbium:YAG laser treatment can resolve USI and coexistent OAB symptoms three months after therapy. Sexual experience is also improved. However, repeated laser therapy may be necessary after six months. PMID- 29241927 TI - Prenatal diagnosis of a 1.6-Mb 4p16.3 interstitial microdeletion encompassing FGFRL1 and TACC3 associated with bilateral cleft lip and palate of Wolf Hirschhorn syndrome facial dysmorphism and short long bones. AB - OBJECTIVE: We present prenatal diagnosis of a 4p16.3 interstitial microdeletion associated with bilateral cleft lip and palate and short long bones on prenatal ultrasound, and we discuss the genotype-phenotype correlation. MATERIALS AND METHODS: A 32-year-old woman underwent amniocentesis at 22 weeks of gestation because of bilateral cleft lip and palate and short limbs on prenatal ultrasound. Conventional cytogenetic analysis was performed on cultured amniocytes and parental bloods. Oligonucleotide array comparative genomic hybridization (aCGH) was performed on the DNAs extracted from uncultured amniocytes, parental bloods and umbilical cord. Metaphase fluorescence in situ hybridization (FISH) was performed on cultured amniocytes. RESULTS: Amniocentesis revealed a karyotype of 46,XY. The parental karyotypes were normal. aCGH analysis on uncultured amniocytes revealed a 1.66-Mb interstitial microdeletion at 4p16.3 encompassing 23 Online Mendelian Inheritance of in Man (OMIM) genes including FGFRL1 and TACC3. The parents did not have such a deletion. The pregnancy was subsequently terminated, and a malformed fetus was delivered with typical Wolf-Hirschhorn syndrome (WHS) facial appearance and bilateral cleft lip and palate. aCGH analysis of the umbilical cord confirmed the prenatal diagnosis with a result of arr 4p16.3 (72,447-1,742,649) * 1.0 [GRCh37 (hg19)]. Metaphase FISH analysis of cultured amniocytes confirmed a 4p16.3 microdeletion. CONCLUSION: Haploinsufficiency of FGFRL1 and TACC3 at 4p16.3 can be associated with bilateral cleft lip and palate of WHS facial dysmorphism and short long bones. Prenatal diagnosis of facial cleft with short long bones should raise a suspicion of chromosome microdeletion syndromes. PMID- 29241928 TI - Uses of FloSeal(c) in obstetric hemorrhage: Case series and literature review. AB - OBJECTIVE: FloSeal(c) has been shown to be an alternative and effective method of hemostasis. The current study examines the various uses of FloSeal(c) in obstetric hemorrhage and gives an overview of the literature. CASE REPORTS: In this retrospective case review, a total of 11 cases with obstetric hemorrhage were reviewed throughout a period of one year. All but one case was successful in using FloSeal(c) in arresting the bleeding with hysterectomy avoided. FloSeal(c) can be considered when bleeding occurs locally at the placental bed, bladder base, adhesiolysis site, vaginal tears or at suture holes. CONCLUSION: FloSeal(c) was a quick and effective alternative for hemostasis and should be considered when conventional hemostatic techniques fails or is impractical. PMID- 29241929 TI - Fertility outcomes following pelvic embolization in women with acquired uterine arteriovenous malformation. AB - OBJECTIVE: Acquired uterine arteriovenous malformation (UAVM) is a rare, life threatening disease. Angiography with uterine arterial embolization (UAE) is the diagnostic tool and a choice of fertility-sparing treatment. Here, we present a series of five successful pregnancies after embolization of UAVM. CASE REPORTS: Three reproductive aged women were treated for UAVM, resulting in five successful pregnancies. Their past history suggested that three cases had had previous uterine procedures, including second trimester abortion and elective dilatation and curettage. Intermittent heavy vaginal bleeding was the primary symptom of UAVM. One patient with anemia had two ineffective embolizations and achieved a singleton pregnancy after the third embolization. However, intrauterine fetal demise with severe fetal growth retardation was noted on the 28th gestation week. The other two women had temporary ovulation disorder after UAE. After Clomiphene Citrate (CC) treatment, successful pregnancies were achieved and carried to term uneventfully. CONCLUSION: UAE is an acceptable method for preserving fertility and treatment in women with symptomatic UAVMs. PMID- 29241930 TI - Prenatal diagnosis and molecular cytogenetic characterization of low-level mosaicism for tetrasomy 18p at amniocentesis in a pregnancy with a favorable outcome. AB - OBJECTIVE: We present prenatal diagnosis of low-level mosaicism for tetrasomy 18p at amniocentesis in a pregnancy with a favorable outcome. CASE REPORT: A 40-year old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Amniocentesis revealed a de novo supernumerary isochromosome 18p in eight of 39 colonies of cultured amniocytes. The karyotype was 47,XX,+i(18)(p10)[8]/46,XX[31]. Array comparative genomic hybridization (aCGH) analysis using uncultured amniocytes revealed arr 18p11.32p11.21 [hg 19] (148,963 14,081,887) * 2-3. Repeat amniocentesis was performed at 20 weeks of gestation. Interphase fluorescence in situ hybridization (FISH) analysis showed four 18p11.22-specific probe (RP11-918F20) signals in 11.7% (12/103 cells) of uncultured amniocytes. aCGH analysis on uncultured amniocytes did not detect genomic imbalance in chromosome 18. The parental karyotypes were normal. Polymorphic DNA marker analysis excluded uniparental disomy 18. Cytogenetic analysis of cultured amniocytes at repeat amniocentesis revealed a karyotype of 47,XX,+i(18)(p10)[2]/46,XX[12]. Prenatal ultrasound was unremarkable. The pregnancy was carried to 38 weeks of gestation, and a 2742-g phenotypically normal female baby was delivered with a cord blood karyotype of 46,XX. When examined at 8 months of age, the infant was normal in growth and psychomotor development. Interphase FISH analysis on 21 uncultured urinary cells revealed normal signals in all cells and no mosaic tetrasomy 18p. CONCLUSION: Low-level mosaic tetrasomy 18p at amniocentesis without ultrasound abnormalities can be associated with a favorable outcome. PMID- 29241931 TI - Prenatal diagnosis of low-level mosaicism for trisomy 13 at amniocentesis associated with a favorable outcome. AB - OBJECTIVE: We present prenatal diagnosis of low-level mosaicism for trisomy 13 at amniocentesis associated with a favorable outcome. CASE REPORT: A 35-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+13[5]/46,XY[20]. Oligonucleotide array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed arr [GRCh37] (13)*3 [0.10], (X,Y)*1 compatible with trisomy 13 mosaicism. Prenatal ultrasound was unremarkable. Repeat amniocentesis was performed at 21 weeks of gestation. Interphase fluorescence in situ hybridization (FISH) analysis on uncultured amniocytes revealed a mosaic trisomy 13 level of 10% (10/100 cells). aCGH analysis on uncultured amniocytes revealed a result of arr 13q12.11q34 (20,407,323-115,092,619)*2.1 with a log2 ratio of 0.06 compatible with a 10% level of mosaicism. Polymorphic DNA marker analysis excluded uniparental disomy 13. The parental karyotypes were normal. Conventional cytogenetic analysis using cultured amniocytes at repeat amniocentesis revealed a karyotype of 46,XY in 23/23 colonies. The pregnancy was carried to 37 weeks of gestation, and a 3600-g phenotypically normal male baby was delivered. When examined at 8 months of age, the infant was doing well and was normal in psychomotor and growth development. The peripheral blood had a karyotype of 46,XY, and interphase FISH analysis on uncultured urinary cells revealed a mosaic trisomy 13 level of 4.4% (2/45 cells). CONCLUSION: Low-level true mosaicism for trisomy 13 at amniocentesis without ultrasound abnormalities can be associated with a favorable fetal outcome. PMID- 29241932 TI - Prenatal diagnosis of an 8q22.2-q23.3 deletion associated with bilateral cleft lip and palate and intrauterine growth restriction on fetal ultrasound. AB - OBJECTIVE: We present prenatal diagnosis of an interstitial 8q22.2-q23.3 deletion associated with bilateral cleft lip and palate and intrauterine growth restriction (IUGR) on fetal ultrasound. CASE REPORT: A 29-year-old, primigravid woman underwent elective amniocentesis at 17 weeks of gestation because of anxiety. Amniocentesis revealed a karyotype of 46, XX. However, level II ultrasound at 21 weeks of gestation revealed a fetus with IUGR and bilateral cleft lip and palate. Repeat amniocentesis was performed at 21 weeks of gestation, and array comparative genomic hybridization using uncultured amniocytes revealed a 13.5-Mb interstitial deletion of 8q22.2-q23.3 encompassing 37 Online Mendelian Inheritance of in Man (OMIM) genes including SPAG1, GRHL2, NCALD, RRM2B and ZFPM2. Polymorphic DNA marker analysis determined a paternal origin of the deletion. The pregnancy was subsequently terminated, and a malformed fetus was delivered with a depressed nose and bilateral cleft lip and palate. CONCLUSION: Prenatal diagnosis of facial cleft with IUGR should raise a suspicion of subtle chromosome deletions. PMID- 29241933 TI - Prenatal diagnosis and molecular cytogenetic characterization of an interstitial deletion of 18q12.1-q12.3 encompassing DTNA, CELF4 and SETBP1. AB - OBJECTIVE: We present prenatal diagnosis and molecular cytogenetic characterization of an interstitial deletion of 18q12.1-q12.3. CASE REPORT: A 35 year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 46,XX,del(18)(q12.1q12.3). The fetal ultrasound was unremarkable. The woman underwent repeat amniocentesis at 20 weeks of gestation. Array comparative genomic hybridization (aCGH) using uncultured amniocytes revealed a 10.76-Mb interstitial deletion 18q12.1-q12.3 or arr 18q12.1q12.3 (31,944,347-42,704,784) * 1.0 encompassing 19 Online Mendelian Inheritance of in Man (OMIM) genes including DTNA, CELF4 and SETBP1. Metaphase fluorescence in situ hybridization analysis on cultured amniocytes confirmed an 18q proximal interstitial deletion. The parental karyotypes were normal. Polymorphic DNA marker analysis determined a paternal origin of the deletion. The pregnancy was subsequently terminated at 24 weeks of gestation, and a 650-g fetus was delivered with characteristic facial dysmorphism. CONCLUSION: aCGH analysis and polymorphic DNA marker analysis at amniocentesis are useful for determination of the deleted genes and the parental origin of the de novo deletion, and the acquired information is helpful for genetic counseling. PMID- 29241934 TI - Fetoplacental cytogenetic discrepancy in a pregnancy with fetal mosaic tetrasomy 12p and Pallister-Killian syndrome detected by amniocentesis. AB - OBJECTIVE: We present fetoplacental cytogenetic discrepancy in a pregnancy with prenatally detected mosaic tetrasomy 12p by amniocentesis. CASE REPORT: A 34-year old woman underwent amniocentesis at 17 weeks of gestation because of advanced maternal age. Cytogenetic analysis of cultured amniocytes revealed a karyotype of 47,XX,+i(12)(p10)[7]/46,XX[16]. Array comparative genomic hybridization (aCGH) analysis of the DNA extracted from cultured amniocytes revealed arr (12p)*3, (X)*2. Prenatal ultrasound findings were unremarkable. The pregnancy was subsequently terminated, and a fetus was delivered with facial dysmorphism consistent with the clinical features of Pallister-Killian syndrome (PKS). Postnatal cytogenetic analysis of the cultured cells from umbilical cord, skin, cord blood and placenta revealed 47,XX,+i(12)(p10)[6]/46,XX[34] in umbilical cord, 47,XX,+i(12)(p10)[11]/46,XX[29] in skin, 47,XX,+i(12)(p10)[3]/46,XX[47] in cord blood and 46,XX[40] in placenta. The mosaic tetrasomy 12p levels of the umbilical cord, skin, cord blood and placenta were 15%, 27.5%, 6% and 0%, respectively. aCGH analysis of the DNA extracted from uncultured cord blood and placenta revealed arr 12p13.33p11.1 (230,421-34,756,209)*3.0 in cord blood but no genomic imbalance in placenta. Polymorphic DNA marker analysis showed a maternal origin of the supernumerary isochromosome 12p in cord blood but biparental inheritance with equal fluorescent activity in placenta. CONCLUSION: Pregnancy with fetal PKS and mosaic tetrasomy 12p may present fetoplacental cytogenetic discrepancy. Therefore, genetic analysis on placenta alone may fail to detect fetal mosaic tetrasomy 12p associated with PKS. PMID- 29241935 TI - Identification of a c.544C>T mutation in WDR34 as a deleterious recessive allele of short rib-polydactyly syndrome. AB - OBJECTIVE: Single-nucleotide polymorphism (SNP) microarrays and whole-exome sequencing (WES) are tools to precisely diagnose rare autosomal recessive (AR) diseases. In this study, SNP chip and WES were used to identify a mutated location in WDR34 in a baby born to consanguineous parents. CASE REPORT: The baby, born at 36 gestational weeks had a small thoracic cage, symmetric short proximal bones, and polydactyly. Radiography showed short ribs with reduced lung volume and pulmonary opacities, compatible with asphyxiating thoracic dystrophy or short rib-polydactyly syndrome (SRPS). At 4 months of age, she died of pulmonary hypoplasia and sepsis. SNP microarray and evaluation tool confirmed WDR34 as the candidate gene. WES detected an AR mutation at c.554C > T [p.Arg182Trp] in WDR34. CONCLUSION: This study was the first to identify c.544C > T [p.Arg182Trp] mutation in WDR34 in a patient with SRPS. According to the database, the homozygous mutation of c.544C > T in WDR34 was deleterious and the prevalence of heterozygous mutation was relatively higher in Asian population. More studies of this mutation in patients with SRPS are required. PMID- 29241936 TI - Teriparatide and denosumab treatment for pregnancy and lactation-associated osteoporosis with multiple vertebral fractures: A case study. AB - OBJECTIVE: Pregnancy and lactation-associated osteoporosis (PLO) is a rare disease, which can lead to vertebral fractures in women of reproductive age. No treatment strategy for PLO has been established. Here we report a case of PLO treated with teriparatide followed by denosumab, in which remarkable improvement in bone mineral density (BMD) was achieved. CASE REPORT: A 27-year-old woman experienced severe back pain two weeks after her first delivery. PLO was diagnosed from her low BMD and multiple vertebral compression fractures. She was treated with teriparatide for 6 months, followed by denosumab. After 1 year, her BMD increase from baseline was 16.5% in L2~4 and her pain had been relieved. CONCLUSION: In addition to weaning, administration of teriparatide followed by denosumab led to remarkable improvement in the patient's symptoms and BMD. Therefore, we regard this method as a promising choice for the treatment of PLO. PMID- 29241937 TI - Treatment of fetal congenital chylothorax: Report of eight cases at a mainland Chinese medical center. PMID- 29241938 TI - Asymptomatic uterine rupture detected at cesarean section: Some different viewpoints. PMID- 29241939 TI - Response to Correspondence "Asymptomatic uterine rupture detected at cesarean section: Some different viewpoints". PMID- 29241940 TI - Plant-Soil Feedback: Bridging Natural and Agricultural Sciences. AB - In agricultural and natural systems researchers have demonstrated large effects of plant-soil feedback (PSF) on plant growth. However, the concepts and approaches used in these two types of systems have developed, for the most part, independently. Here, we present a conceptual framework that integrates knowledge and approaches from these two contrasting systems. We use this integrated framework to demonstrate (i) how knowledge from complex natural systems can be used to increase agricultural resource-use efficiency and productivity and (ii) how research in agricultural systems can be used to test hypotheses and approaches developed in natural systems. Using this framework, we discuss avenues for new research toward an ecologically sustainable and climate-smart future. PMID- 29241941 TI - Finding Evolutionary Processes Hidden in Cryptic Species. AB - Cryptic species could represent a substantial fraction of biodiversity. However, inconsistent definitions and taxonomic treatment of cryptic species prevent informed estimates of their contribution to biodiversity and impede our understanding of their evolutionary and ecological significance. We propose a conceptual framework that recognizes cryptic species based on their low levels of phenotypic (morphological) disparity relative to their degree of genetic differentiation and divergence times as compared with non-cryptic species. We discuss how application of a more rigorous definition of cryptic species in taxonomic practice will lead to more accurate estimates of their prevalence in nature, better understanding of their distribution patterns on the tree of life, and increased abilities to resolve the processes underlying their evolution. PMID- 29241942 TI - An imaging-based analysis of lipid deposits on contact lens surfaces. AB - PURPOSE: To evaluate whether LipidTOX could stain lipid deposits on contact lens (CL) surfaces and compare lipid deposition patterns on various CL surfaces using an imaging method. METHODS: Ten CLs each of six silicone hydrogel materials and one hydrogel material were incubated in cholesteryl oleate solution (5.60mg/ml) for 12hours. The CLs were then separately stained with Oil Red O and LipidTOX and imaged under a fluorescence microscope. Twenty worn senofilcon A CLs from both eyes of ten participants were also stained similarly. The area of deposition was calculated using Fiji software. Median deposition areas were compared between various materials using the Kruskal-Wallis test. The Mann-Whitney U test was used to compare the median deposition areas in the same material using the two dyes and also to compare the median deposition areas on worn and doped senofilcon A CLs. RESULTS: LipidTOX staining needed fewer steps than Oil Red O for staining the deposits. There was no statistically significant difference between the median areas of lipid deposition among the CL materials using either Oil Red O (p=0.42) or LipidTOX (p=0.21). However, significantly different median deposition areas were found between in vitro and ex vivo stained senofilcon A CLs using both Oil Red O (p=0.002) and LipidTOX (p=0.029). CONCLUSIONS: LipidTOX can stain lipid deposits on contact lens surfaces and is simpler to use than Oil Red O. Lipid deposition in the central 2mm diameter zone did not significantly differ between various commercial CL materials. PMID- 29241943 TI - Gender Disparities in Park Use and Physical Activity among Residents of High Poverty Neighborhoods in Los Angeles. AB - INTRODUCTION: Physical inactivity is more prevalent among women than men and is related to poor health outcomes. Neighborhood parks constitute an important resource for physical activity (PA), however, previous studies of park users have found fewer women being physically active. METHODS: We conducted a hierarchical mixed-effect regression analysis of the independent associations between gender and park use and PA among a population-based sample in high-poverty neighborhoods in Los Angeles. Data sources included 1) structured interviews with adults (>=18 years of age) in randomly selected households within 1 mile of study parks (n = 2,973), 2) systematic observations of study parks (n = 48), and 3) neighborhood characteristics from the 2010 U.S. Census. RESULTS: After controlling for race/ethnicity, education, body mass index of 30 kg/m2 or greater, health status, proximity to park, having children under the age of 18, perceived park safety, estimated screen time, and park- and neighborhood-level variables, statistically significant differences were found between women and men on all outcomes. Compared with men, women reported fewer park visits in the past week (-0.28 times/week; p < .001) and shorter durations of a typical park visit (-11.11 min/visit; p < .001). Women were also less likely than men to report levels of PA that meet national guidelines (>=150 minutes of moderate to vigorous PA per week; risk difference = -0.06; p < .01) or to exercise in the park (risk difference = 0.13; p < .001) or elsewhere (risk difference = -0.13; p < .001). CONCLUSIONS: Women living in high-poverty neighborhoods use parks less for PA than men. Improved park-level design, programming, and other policy interventions may be needed to mitigate disparities in park use and PA for all. PMID- 29241944 TI - Fracture resistance and failure modes of polymer infiltrated ceramic endocrown restorations with variations in margin design and occlusal thickness. AB - PURPOSE: The purpose of this in vitro study was to assess the effect of varying the margin designs and the occlusal thicknesses on the fracture resistance and mode of failures of endodontically treated teeth restored with polymer infiltrated ceramic endocrown restorations. METHODS: Root canal treated mandibular molars were divided into four groups (n=8) and were prepared to receive Computer-Aided Design/Computer-Aided Manufacturing (CAD/CAM) fabricated polymer infiltrated ceramic endocrowns (ENAMIC blocks). Group B2 represents teeth prepared with a butt joint design receiving endocrowns with 2mm occlusal thickness and the same for group B3.5 but with 3.5mm occlusal thickness. Group S2 represents teeth prepared with 1mm shoulder finish line receiving endocrowns with 2mm occlusal thickness and the same for group S3.5 but with 3.5mm occlusal thickness. After cementation and thermal aging, fracture resistance test was performed and failure modes were observed. RESULTS: Group S3.5 showed the highest mean fracture load value (1.27+/-0.31kN). Endocrowns with shoulder finish line had significantly higher mean fracture resistance values than endocrowns with butt margin (p<0.05). However, the results were not statistically significant regarding the restoration thickness. Evaluation of the fracture modes revealed no statistically significant difference between the modes of failure of tested groups. CONCLUSIONS: For the restoration of endodontically treated teeth, adding a short axial wall and shoulder finish line can increase the fracture resistance. However, further investigations, especially the fatigue behavior, are needed to ensure this effect applies with small increases of restoration thickness. PMID- 29241945 TI - Micro-computed tomography for evaluating alveolar bone resorption induced by hyperocclusion. AB - PURPOSE: Occlusal trauma, resulting in the destruction of alveolar bone, is a form of periodontal disease caused by excessive mechanical stress (MS) during hyperocclusion. Previously, we showed that CC chemokine ligand (CCL) 2/CCR2 receptor axis plays a crucial role in MS-dependent osteoclastogenesis. However, in the previous work, we were unable to precisely measure changes in alveolar bone profiles. In the present study, we sought to establish a precise method for evaluating alveolar bone resorption induced by hyperocclusion using micro computed tomography. METHODS: Under anesthesia, a stainless steel wire was attached to the molars of 5-week-old C57/BL6 wild-type (WT) mice, CCL2-/- mice, and CCR2-/-mice to induce occlusal force overload. At days 0 and 7, hard tissue samples were harvested and analyzed by micro-computed tomography. RESULTS: In the WT mice, bone mineral density of the alveolar bone was significantly decreased at day 7 as compared with day 0, with marked alveolar bone resorption observed. Similarly, significant alveolar bone resorption was observed in the CCL2-/- and CCR2-/- mice at day 7 as compared with day 0. CONCLUSIONS: Micro-computed tomographic images can be used to measure changes in bone mineral density in a mouse model of hyperocclusion. This method may be useful for further investigating bone changes in other periodontal disease research fields. PMID- 29241946 TI - Youth With Psychogenic Non-Syncopal Collapse Have More Somatic and Psychiatric Symptoms and Lower Perceptions of Peer Relationships Than Youth With Syncope. AB - BACKGROUND: Little is known about somatic and psychiatric symptoms and perceived peer relationships of patients with psychogenic nonsyncopal collapse. OBJECTIVE: This study aimed to compare somatic and psychiatric symptoms and other elements potentially related to functional neurological symptom disorders between youth with psychogenic nonsyncopal collapse and those with neurally mediated syncope. METHODS: Before testing, patients completed a structured interview and questionnaire addressing current symptoms, previous psychiatric diagnoses, referrals, diagnostic testing, prescribed medications, and patient self-ratings of anxiety, depression, and perceived peer relationships. RESULTS: Compared with patients with syncope (n = 60), patients with psychogenic nonsyncopal collapse (n = 60) had higher ratings for lightheadedness and vertigo, more abdominal pain, more chronic headaches, more fatigue, more sleep disturbances, more prescriptions for antidepressant medicines, more encephalograms performed, more referrals to psychiatry, and more psychiatric diagnoses including anxiety, depression, posttraumatic stress disorder, previous nonfainting conversion disorders, and eating disorders (all p < 0.05). Patients with psychogenic nonsyncopal collapse rated their anxiety (10.5 +/- 7.7 versus 5.9 +/- 5.8, p < 0.001) and depression (8.7 +/- 8.3 versus 3.1 +/- 5, p < 0.001) symptoms higher and their peer relationships (37 +/- 12.3 versus 47.6 +/- 7.9, p < 0.001) lower than patients with syncope. Peer relationships remained significantly lower (p = 0.001) when analyzed with anxiety and depression. CONCLUSION: Patients with psychogenic nonsyncopal collapse have more symptom complaints and perceptions of poorer peer social interactions than patients with syncope. These results broaden our understanding of the biopsychosocial profile that increases an individual's vulnerability to psychogenic nonsyncopal collapse specifically and to functional neurological symptom disorders in general. PMID- 29241947 TI - Effects of Sublingual Glyceryl Trinitrate Administration on the Quality of Preprocedure CT Angiography Performed to Plan Prostate Artery Embolization. AB - PURPOSE: To determine the effects of sublingual glyceryl trinitrate (GTN) on the quality of planning computed tomography (CT) angiography performed prior to prostate artery embolization (PAE). MATERIALS AND METHODS: A retrospective cohort study was performed on patients who had previously undergone CT angiography before a procedure for PAE at our institution. Early CT angiography studies for PAE at our single center had initially been performed without GTN. These were compared to subsequent CT angiography studies that had been performed with GTN, after a previously implemented change in practice. Prostate arteries were examined by 2 blinded observers for peak enhancement (Hounsfield units [HU]) and lumen diameter. In addition, assessors' interpretation of the prostate artery origin from CT angiography was compared with the true anatomy demonstrated at the time of procedure. RESULTS: A total of 16 patients, corresponding to 32 prostate arteries, were examined on CT angiography. Mean diameter of the prostate artery was found to be significantly greater in those receiving GTN (2.2 mm vs. 1.6 mm, P < .001). Peak prostate artery enhancement was also greater in the GTN group (218 HU vs 173 HU, P = 0.042). Observers correctly identified the prostate artery origin more frequently in the GTN group; however, this difference was not statistically significant (56% vs 25%, odds ratio = 3.9, P = .149). CONCLUSIONS: The administration of sublingual GTN immediately prior to CT angiography is associated with a significant increase in prostate artery diameter and peak opacification. This was not associated with a statistically significant increase in the ability of observers to correctly identify the origin of the prostate artery. PMID- 29241948 TI - Risk management training programme: A perspective from the European side of the Atlantic. PMID- 29241949 TI - A severe but reversible reduction in insulin sensitivity is observed in patients with insulinoma. AB - BACKGROUND: Hypoglycemic manifestations are highly variable in patients with an insulinoma and largely independent of tumour size and severity of insulin hypersecretion. OBJECTIVES: We investigated the clinical, biological and tumoral characteristics of insulinomas in a large monocentric series of patients and we evaluated their insulin sensitivity before and after successful pancreatic surgery. PATIENTS AND METHODS: This was a retrospective analysis of 40 patients treated for an insulinoma between 1982 and 2012 in our academic hospital. Insulin sensitivity and beta cell function were evaluated by a HOMA test outside hypoglycaemic episodes in a large subset of these patients. RESULTS: The mean age at onset of symptoms was 48.8+/-20.1 years and the mean age at diagnosis was 50.7+/-19.9 years. Neuroglycopenic symptoms were observed in 90% of patients. The most effective preoperative imaging technique to localize the tumour was endoscopic ultrasound. Insulin sensitivity was greatly reduced in patients with insulinoma (38.9%+/-22.3%), while beta cells function was increased (359.0+/ 171.5%), but to a variable extent (range: 110.6-678.6%). After complete resection of the tumour and remission of hypoglycemic episodes, insulin sensitivity increased in all evaluated subjects (72.8+/-36.7%) and normalized in the majority. CONCLUSION: Although neuroglycopenic symptoms are present in most patients, diagnosis of insulinoma is often delayed. Endoscopic ultrasound remains the most sensitive preoperative technique to localize the tumour. We also show that in response to chronic hyperinsulinemia, patients with insulinoma develop protective mechanisms responsible for a marked insulin resistance, which is reversible after complete resection of the tumour. PMID- 29241950 TI - Unilateral aggressive pheochromocytoma revealed by a massive intraperitoneal hemorrhage five years after an initial presentation suggesting an adrenal hematoma. PMID- 29241951 TI - European recommendations for the management of adrenal incidentalomas: A debate on patients follow-up. PMID- 29241952 TI - Downregulation of common cytokine receptor gamma chain inhibits inflammatory responses in macrophages stimulated with Riemerella anatipestifer. AB - Th17-cell-mediated inflammation is affected by the soluble form of common cytokine receptor gamma chain (gammac). We previously suggested that inflammatory cytokines including interleukin (IL)-17A are associated with Riemerella anatipestifer infection, which a harmful bacterial pathogen in ducks. Here, the expression profiles of membrane-associated gammac (dugammac-a) and soluble gammac (dugammac-b) in R. anatipestifer-stimulated splenic lymphocytes and macrophages, and in the spleens and livers of R. anatipestifer-infected ducks, were investigated. In vitro and in vivo results indicated that the expression levels of both forms of gammac were increased, showing that marked increases were detected in the expression of the dugammac-b form rather than the dugammac-a form. Treatment with gammac-specific siRNA downregulated mRNA expression of Th17 related cytokines, including IL-17A and IL-17F, in duck splenic macrophages stimulated with R. anatipestifer, whereas the expressions of interferon (IFN) gamma and IL-2 were enhanced. The results showed that the upregulation of gammac, especially the dugammac-b form, was associated with expression of Th17-related cytokines during R. anatipestifer infection. PMID- 29241954 TI - Structural characterization of ribT from Bacillus subtilis reveals it as a GCN5 related N-acetyltransferase. AB - In bacteria, biosynthesis of riboflavin occurs through a series of enzymatic steps starting with one molecule of GTP and two molecules of ribulose-5 phosphate. In Bacillus subtilis (B. subtilis) the genes (ribD/G, ribE, ribA, ribH and ribT) which are involved in riboflavin biosynthesis are organized in an operon referred as rib operon. All the genes of rib operon are characterized functionally except for ribT. The ribT gene with unknown function is found at the distal terminal of rib operon and annotated as a putative N-acetyltransferase. Here, we report the crystal structure of ribT from B. subtilis (bribT) complexed with coenzyme A (CoA) at 2.1 A resolution determined by single wavelength anomalous dispersion method. Our structural study reveals that bribT is a member of GCN5-related N-acetyltransferase (GNAT) superfamily and contains all the four conserved structural motifs that have been in other members of GNAT superfamily. The members of GNAT family transfers the acetyl group from acetyl coenzyme A (AcCoA) to a variety of substrates. Moreover, the structural analysis reveals that the residues Glu-67 and Ser-107 are suitably positioned to act as a catalytic base and catalytic acid respectively suggesting that the catalysis by bribT may follow a direct transfer mechanism. Surprisingly, the mutation of a non conserved amino acid residue Cys-112 to alanine or serine affected the binding of AcCoA to bribT, indicating a possible role of Cys-112 in the catalysis. PMID- 29241953 TI - Innate immune responses in the Chinese oak silkworm, Antheraea pernyi. AB - Innate immunity, the evolutionarily conserved defense system, has been extensively analyzed in insect models over recent decades. The significant progress in this area has formed our dominant conceptual framework of the innate immune system, but critical advances in other insects have had a profound impact on our insights into the mystery of innate immunity. In recent years, we focused on the immune responses in Antheraea pernyi, an important commercial silkworm species reared in China. Here, we review the immune responses of A. pernyi based on immune-related gene-encoded proteins that are divided into five categories, namely pattern recognition receptors, hemolymph proteinases and their inhibitors, prophenoloxidase, Toll pathway factors and antimicrobial peptides, and others. Although the summarized information is limited since the research on A. pernyi immunity is in its infancy, we hope to provide evidence for further exploration of innate immune mechanisms. PMID- 29241955 TI - Determination of caffeine, theobromine and theophylline in Mate beer and Mate soft drinks by high-performance thin-layer chromatography. AB - Mate beer and Mate soft drinks are beverages produced from the dried leaves of Ilex paraguariensis (Yerba Mate). In Yerba Mate, the xanthine derivatives caffeine, theobromine and theophylline, also known as methylxanthines, are important active components. The presented method for the determination of caffeine, theobromine and theophylline in Mate beer and Mate soft drinks by high performance thin-layer chromatography with ultraviolet detection (HPTLC-UV) offers a fully automated and sensitive determination of the three methylxanthines. Filtration of the samples was followed by degassing, dilution with acetonitrile in the case of Mate beers for protein precipitation, and centrifugation before the extracts were analyzed by HPTLC-UV on LiChrospher silica gel plates with fluorescence indicator and acetone/toluene/chloroform (4:3:3, v/v/v) as the mobile phase. For quantitation, the absorbance was scanned at 274nm. Limits of detection and quantitation were 1 and 4ng/zone, respectively, for caffeine, theobromine and theophylline. With recoveries close to 100% and low standard deviations reliable results were guaranteed. Experimental Mate beers as well as Mate beers and Mate soft drinks from the market were analyzed for their concentrations of methylxanthines. PMID- 29241956 TI - Magnetic sporopollenin-cyanopropyltriethoxysilane-dispersive micro-solid phase extraction coupled with high performance liquid chromatography for the determination of selected non-steroidal anti-inflammatory drugs in water samples. AB - A facile dispersive-micro-solid phase extraction (D-MU-SPE) method coupled with HPLC for the analysis of selected non-steroidal anti-inflammatory drugs (NSAIDs) in water samples was developed using a newly prepared magnetic sporopollenin cyanopropyltriethoxysilane (MS-CNPrTEOS) sorbent. Sporopollenin homogenous microparticles of Lycopodium clavatum spores possessed accessible functional groups that facilitated surface modification. Simple modification was performed by functionalization with 3-cyanopropyltriethoxysilane (CNPrTEOS) and magnetite was introduced onto the biopolymer to simplify the extraction process. MS CNPrTEOS was identified by infrared spectrometrywhile the morphology and the magnetic property were confirmed by scanning electron microscopy (SEM) and vibrating sample magnetometer (VSM), respectively. To maximize the extraction performance of ketoprofen, ibuprofen, diclofenac and mefenamic acid using the proposed MS-CNPrTEOS, important D-MU-SPE parameters were comprehensively optimized. The optimum extraction conditions were sorbent amount, 40 mg; extraction time, 5 min; desorption time; 5 min; sample volume, 15 mL; sample pH 2.0; and salt addition, 2.5% (w/v). The feasibility of the developed method was evaluated using spiked tap water, lake water, river water and waste water samples. Results showed that ketoprofen and ibuprofen were linear in the range of 1.0-1000 MUg L-1 whilst diclofenac and mefenamic acid were linear in the range 0.8-500 MUg L-1. The results also showed good detection limits for the studied NSAIDs in the range of 0.21-0.51 MUg L-1 and good recoveries for spiked water samples in the range of 85.1-106.4%. The MS-CNPrTEOS proved a promising dispersive sorbent and applicable to facile and rapid assay of NSAIDs in water samples. PMID- 29241957 TI - Evaluation of adsorption selectivity of immunoglobulins M, A and G and purification of immunoglobulin M with mixed-mode resins. AB - This study investigated adsorption selectivity of immunoglobulin M (IgM), immunoglobulin A (IgA) and immunoglobulin (IgG) on four mixed-mode resins with the functional ligands of 4-mercatoethyl-pyridine (MEP), 2-mercapto-1 methylimidazole (MMI), 5-aminobenzimidazole (ABI) and tryptophan-5 aminobenzimidazole (W-ABI), respectively. IgM purification processes with mixed mode resins were also proposed. All resins showed typical pH-dependent adsorption, and high adsorption capacity was found at pH 5.0-8.0 with low adsorption capacity under acidic conditions. Meanwhile, high selectivity of IgM/IgA and IgM/IgG was obtained with ABI-4FF and MMI-4FF resins at pH 4.0-5.0, which was used to develop a method for IgM, IgA and IgG separation by controlling loading and elution pH. Capture of monoclonal IgM from cell culture supernatant with ABI-4FF resins was studied and high purity (~99%) and good recovery (80.8%) were obtained. Moreover, IgM direct separation from human serum with combined two step chromatography (ABI-4FF and MMI-4FF) was investigated, and IgM purity of 65.2% and a purification factor of 28.3 were obtained after optimization. The antibody activity of IgM was maintained after purification. The results demonstrated that mixed-mode chromatography with specially-designed ligands is a promising way to improve adsorption selectivity and process efficiency of IgM purification from complex feedstock. PMID- 29241958 TI - Time to appendectomy for acute appendicitis: A systematic review. AB - OBJECTIVE: The goal of this systematic review by the American Pediatric Surgical Association Outcomes and Evidence-Based Practice Committee was to develop recommendations regarding time to appendectomy for acute appendicitis in children within the context of preventing adverse events, reducing cost, and optimizing patient/parent satisfaction. METHODS: The committee selected three questions that were addressed by searching MEDLINE, Embase, and the Cochrane Library databases for English language articles published between January 1, 1970 and November 3, 2016. Consensus recommendations for each question were made based on the best available evidence for both children and adults. RESULTS: Based on level 3-4 evidence, appendectomy performed within 24h of admission in patients with acute appendicitis does not appear to be associated with increased perforation rates or other adverse events. Based on level 4 evidence, time from admission to appendectomy within 24h does not increase hospital cost or length of stay (LOS). Data are currently limited to determine an association between the timing of appendectomy and parent/patient satisfaction. CONCLUSIONS: There is a paucity of high-quality evidence in the literature regarding timing of appendectomy for patients with acute appendicitis and its association with adverse events or resource utilization. Based on available evidence, appendectomy performed within the first 24h from presentation is not associated with an increased risk of perforation or adverse outcomes. TYPE OF STUDY: Systematic Review of Level 1-4 studies. PMID- 29241959 TI - The Journal of Pediatric Surgery: Its First 50 Years. AB - This article is based on the Journal of Pediatric Surgery Lecture at the 2017 meeting of the British Association of Pediatric Surgeons. This lecture was renamed The Jay L. Grosfeld /Journal of Pediatric Surgery Lecture in honor of Dr. Jay L. Grosfeld who was Editor-in-Chief of the Journal of Pediatric Surgery (JPS) from 1994 until his passing in 2016. The first part of this paper recounts the first 50years of JPS starting with the efforts of Drs. Koop and Gans to start a Journal devoted to Pediatric Surgery. The second part of the paper reviews the top ten citations in the first 50years of JPS. Finally, the last part of the article discusses what the future may hold for JPS. PMID- 29241960 TI - Trends in common surgical procedures at children's and nonchildren's hospitals between 2000 and 2009. AB - PURPOSE: Though growth in children's surgical expenditures has been documented, procedure-specific differences in volume and costs at children's hospitals (CH) and non-hildren's hospitals (NCH) have not been explored. Our purpose was to compare trends in volume and costs of common pediatric surgical procedures between CH and NCH. METHODS: We performed a review of the 2000-2009 Kids' Inpatient Database identifying all cases of appendectomy for uncomplicated appendicitis (AP), tonsillectomy and adenoidectomy (TA), fundoplication (FP), humeral fracture repair (HFR), pyloromyotomy (PYL), and cholecystectomy (CHOLE). Trends in case volume and costs were examined at CH versus NCH. RESULTS: The proportion of surgical care at CH increased for all procedures from 2000 to 2009. TA and CHOLE demonstrated higher costs per case at CH. Positive growth over time in cost per case at CH was seen for AP and FP, with the cost per case of FP increasing by 21% between 2006 and 2009. CONCLUSIONS: The proportion of surgeries performed at CH is continuing to grow alongside proportionate increases in costs, however costs for certain procedures are higher at CH than NCH. Further investigation is needed to explore cost containment at CH while still maintaining specialized, high quality surgical care. LEVEL OF EVIDENCE: Level III. PMID- 29241961 TI - Management of neonates with right-sided aortic arch and esophageal atresia: International survey on IPEG AND ESPES members' experience. AB - AIM: The optimum surgical approach of neonates with right-sided aortic arch (RAA) and esophageal atresia (EA)/tracheoesophageal fistula (TEF) is still an unsolved question. In order to propose an operative algorithm in the era of endoscopic surgery, we performed an international survey to know the current practice between pediatric endoscopic surgeons. Two of the most important societies in endoscopic pediatric surgery were queried: the International Pediatric Endosurgery Group (IPEG) and the European Society of Paediatric Endoscopic Surgeons (ESPES). MATERIALS AND METHODS: During December 2016, an anonymous online-based survey was sent to all IPEG and ESPES members, collecting data regarding perioperative management and surgical repair of EA/TEF with RAA. RESULTS: 144 surgeons from 23 countries completed the questionnaire. 69.2% of respondents were IPEG members, 30.8% were ESPES members. 71.5% of members who answered the survey had more than 10years of surgical experience. A preoperative echocardiography was almost uniformly performed (93.1%). 31.9% of the surveyed surgeons had never treated an EA/TEF with RAA. The remaining 98 surveyed surgeons had managed 279 cases of EA/TEF with RAA. Thoracotomy was considered the preferred approach for 54.2% of the surgeons, and 51.9% chose a right-sided approach. When RAA was an intraoperative finding, 76% would perform a contralateral thoracotomy if difficulties arose. Thoracoscopy was preferred by 45.8% of surgeons. If RAA was suspected preoperatively, 63.1% preferred to attempt a left-sided thoracoscopy and only 24.2% would change their approach to a thoracotomy. If RAA was an intraoperative finding and a safe surgical repair could not be achieved through right-sided thoracoscopy, 51.5% of them chose to perform a left sided thoracoscopy, rather than convert to thoracotomy. CONCLUSIONS: Preoperative echocardiography performed by experienced examiners helps in surgical planning. Preoperative diagnosis of RAA should not discourage thoracoscopic repair, which is increasingly becoming more popular for the correction of EA/TEF. In case of an unexpected intraoperative diagnosis of RAA or operative difficulties when approaching through the right side, thoracoscopy offers a less aggressive approach. LEVEL OF EVIDENCE: V. PMID- 29241962 TI - Engineering and repair of diaphragm using biosheet (a collagenous connective tissue membrane) in rabbits. AB - BACKGROUND: Prosthetic patches can be used to repair large congenital diaphragmatic hernia defects but may be associated with infection, recurrence, and thoracic deformity. Biosheets (collagenous connective tissue membranes) have been used in regenerative medicine. We evaluated the efficacy of Biosheets in a rabbit model. METHODS: Biosheets were prepared by embedding silicone plates in dorsal subcutaneous pouches of rabbits for 4weeks. In group 1 (n=11), Gore-Tex(r) sheets (1.8*1.8cm) were implanted into a diaphragmatic defect. In group 2 (n=11), Seamdura(r), a bioabsorbable artificial dural substitute, was implanted in the same manner. In group 3 (n=14), biosheets were autologously transplanted into the diaphragmatic defects. All rabbits were euthanized 3months after transplantation to evaluate their graft status. RESULTS: Herniation of liver was observed in 5 rabbits (45%) in group 1, 8 (73%) in group 2, and 3 (21%) in group 3. A significant difference was noted between groups 2 and 3 (P=0.017). Biosheets had equivalent burst strength and modulus of elasticity as native diaphragm. Muscular tissue regeneration in transplanted biosheets in group 3 was confirmed histologically. CONCLUSION: Biosheets may be applied to diaphragmatic repair and replacement of diaphragmatic muscular tissue. LEVEL OF EVIDENCE: Level III. PMID- 29241963 TI - Negative pressure wound therapy in pediatric surgery: How and when to use. AB - INTRODUCTION: Negative pressure wound therapy (NPWT) has been widely adopted to treat laparostomy, abdominal compartment syndrome (ACS) and complicated wounds associated with tissue loss. The method presents specific aspects, advantages and indications in Pediatrics. Our aim is to review the evidence available about NPWT in children. METHODS: Active search for papers about NPWT in Pediatric patients. Papers referring to orthopedic problems, wound complications after Cardiac Surgery or burns were excluded. RESULTS: The method shows good results to treat ACS, complicated wounds and abdominal wall malformations in neonates, including prematures. Periwound skin protection, monitoring of fluid losses and fine tuning of negative pressure levels according to age are necessary. Less pain, quicker recovery, less frequent dressing changes, possible recovery of exposed surgical hardware, granulation and shrinkage of the wound are advantages of the method over other kinds of dressing. NPWT is contraindicated over blood vessels and exposed nerves. Debridement is needed before usage over necrotic areas. Enteric fistulae are not contraindications. Complications are rare, mainly foam retention and dermatitis/skin maceration. The possibility of fistulae being caused by NPWT remains debatable. CONCLUSION: NPWT is widely used in Pediatrics, including neonates and premature, but the evidence available about the method is scarce and low quality. Complications are uncommon and mostly manageable. A possible causal relationship between NPWY and enteric fistula remains unclear. Adult devices and parameters have been adapted to children's use. Extra care is needed to protect the delicate tissues of Pediatric patients. Comparative research to define differential costs, indications and advantages of the method, specific indications and limits of NWTP in Pediatrics is needed. TYPE OF STUDY: Review. EVIDENCE LEVEL: IV. PMID- 29241964 TI - George Macaulay: A short biography and his place in the history of congenital diaphragmatic hernia. AB - George Macaulay (1716-1766) was a Scot admired for his work as an obstetric physician, philanthropist, author, and feminist, but whom history has largely forgotten. In a time rampant with misogyny, Macaulay empathized with women, discouraged sexism within institutions, and contributed to the training of midwives. He spent much of his career working at the British Lying-in Hospital in London. Perhaps most importantly, he worked tirelessly for this hospital, contributed to various medical innovations, and reported several medical cases throughout his career, including that of congenital diaphragmatic hernia, almost a century before the anatomist whose eponymous name it bears. The purpose of this article is to reappraise the life, achievements, and specifically, the role of George Macaulay in our understanding of CDH. PMID- 29241965 TI - Perinatal hemorrhage from ulceration of the umbilical cord: A potentially catastrophic association with duodenal and jejunal obstruction. AB - PURPOSE: The purpose of this study is to review published reports and contribute new cases of umbilical cord ulceration (UCU) with perinatal hemorrhage into the amniotic cavity in the setting of duodenal or jejunal obstruction because knowledge of this sequence is poorly disseminated and could be lifesaving. METHODS: Published reports of UCU with hemorrhage associated with congenital duodenal or jejunal obstruction were reviewed. Chart review was conducted for the cases encountered at our institutions between January 2008 and March 2017. We noted perinatal complications, method of delivery, gestational age, birth weight, gender, number, location, and pathologic description of umbilical cord ulcers, and outcome. RESULTS: Thirty-one reports and 7 new cases were studied. Perinatal complications included: preterm labor or preterm premature rupture of membranes: 63%; fetal distress: 95%; mean gestational age: 33weeks; premature gestation: 95%; bloody amniotic fluid: 90%. Pathological analysis of UCUs revealed solitary, multifocal, helical and punched-out lesions. There were 12 neonatal deaths (32%), and 12 intrauterine deaths (32%). Survival rate was 37%. CONCLUSIONS: UCU with perinatal hemorrhage is associated with duodenal and jejunal obstruction. Knowing the typical clinical signs of this potential catastrophic complication could prompt lifesaving delivery. TYPE OF STUDY: Prognostic LEVEL OF EVIDENCE: IV. PMID- 29241966 TI - Streptococcus anginosus is associated with postoperative intraabdominal collections in appendicitis. AB - AIM OF STUDY: Streptococcus anginosus group (SA) (formerly Streptococcus milleri) are pathogens recognised to have a high risk of postoperative collection in appendicitis, although little data exist specifically in children. We performed a retrospective review of all microbiological data from appendicectomies to assess whether there was an association in children. METHODS: A retrospective case note review of patients admitted to a paediatric tertiary centre coded for appendicitis from January 2015 to October 2016 was completed. Initial length of stay (LOS), cumulative hospital days, histology, microbiology, and radiology reports were recorded. The postoperative antibiotic regimen was based on surgeon's choice and not standardised. MAIN RESULTS: 231 children were identified, and 18 were excluded. In the remainder, 169 (78.9%) had positive microbiology cultures, and of these 45 were positive for SA (26.6%). There was no significant variation in monthly incidence (P=0.58). Patients with SA+ve cultures were associated with complicated appendicitis on histology (P=0.01), longer LOS and cumulative hospital days (P=0.001), and increased likelihood of developing postoperative collections (P=0.001). The relative risk of developing a postoperative collection with SA+ve cultures was 2.40. There was no difference in time to presentation, histology, or intervention between SA and non-SA patients who developed collections. All SA cultures were sensitive to penicillin and erythromycin. CONCLUSION: SA cultured from intraoperative serial swabs is associated with an increased risk of developing postoperative collection (2.40). Using this information with standardisation of antimicrobial management may reduce the rate of postoperative complications in paediatric appendicitis. LEVEL OF EVIDENCE: Level II prognosis study. PMID- 29241967 TI - Survey of the American Pediatric Surgical Association on cannulation practices in pediatric ECMO. AB - AIMS: Extracorporeal membrane oxygenation (ECMO) is a commonly used modality of life support for children with cardiopulmonary failure. Consensus on pediatric cannulation strategies and management does not currently exist. The goal of this study was to investigate individual surgeon approaches towards ECMO cannulations in children. METHODS: A 21-question online survey was developed and disseminated to the American Pediatric Surgical Association (APSA) membership. Participant responses were summarized as counts and percentages. Effect of ECMO volume and surgeon experience on responses was assessed. RESULTS: There were 252 APSA members who participated in this study for a response rate of 21%, with 225 (89.3%) performing ECMO. Sixty respondents (28.3%) reported using neck vessels exclusively for cannulation regardless of age or weight of the patient. After neck decannulation, 13 (6.6%) repaired the carotid artery for all patients, and 21 (10.7%) repaired only for children older than 5years. Of those performing femoral cannulation, 56 (26.4%) would perform at 5years or older and 66 (31.1%) at 12years. The most common challenge for femoral cannulation was the need for distal perfusion (n=119; 59.8%). Assistance from vascular surgery was requested by 32 (16.4%) for distal perfusion catheter placement, and by 79 (40.5%) for decannulation. Regarding femoral cannulation, lack of training was more likely to be a challenge if performing <5 cannulations per year (25.2% vs 12.5%; p=0.03). Surgeons with <10years of experience were more likely to consult vascular surgery compared to those with >10years of experience (18.5% vs 8%; p=0.03). CONCLUSION: Considerable variation exists in individual surgeon cannulation practices in pediatric ECMO, in particular in the management of school age and adolescent VA ECMO. Mixed approaches across several ECMO management case study questions indicate that further work is needed to evaluate specific risks with cannulations in children. LEVEL OF EVIDENCE: IV. PMID- 29241968 TI - Case-control analysis of leucine-rich repeat kinase 2 protective variants in Alzheimer's disease. AB - Amyloid is the main pathological substrate of Alzheimer's disease (AD) and has been described in leucine-rich repeat kinase 2 (LRRK2) carriers with Parkinson's disease. LRRK2 has been linked with amyloid precursor protein pathways in neurodegeneration. Two common LRRK2 variants, R1398H and N551K, have been shown to be protective in multiple Parkinson's disease cohorts. We hypothesized that R1398H and N551K may be protective in AD. In a case-control study involving 1390 subjects (719 controls and 671 AD cases), R1398H was demonstrated in 16.8% of AD cases compared to 16.7% in controls (odds ratio = 1.01, 95% confidence interval = 0.76-1.34, p = 0.94), whereas N551K was demonstrated in 17.3% of AD cases compared to 17.2% of controls (odds ratio = 1.00, 95% confidence interval = 0.76 1.32, p = 0.98). Overall, these results suggest that LRRK2 R1398H or N551K variants do not appear to modulate the risk of AD. PMID- 29241969 TI - Relation of Ectopic Fat with Atherosclerotic Cardiovascular Disease Risk Score in South Asians Living in the United States (from the Mediators of Atherosclerosis in South Asians Living in America [MASALA] Study). AB - Few studies have investigated the association between ectopic fat from different depots and cardiovascular risk scores and their components in the same population, and none have investigated these relations in South Asians. In a cross-sectional analysis of 796 participants in the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study who had measurements of visceral, subcutaneous, pericardial, hepatic, and intermuscular fat from abdominal and cardiac computed tomography scans, we used linear regression to determine the associations of 1 standard deviation difference in each ectopic fat depot with pooled cohort risk score and its components. Pericardial and visceral fat were more strongly associated with the pooled cohort risk score (3.1%, 95% confidence interval [CI] 2.5 to 3.7, and 2.7%, 95% CI 2.1 to 3.3, respectively) and components than intermuscular fat (2.3%, 95% CI 1.7 to 3.0); subcutaneous fat was inversely associated with the pooled cohort risk score (-2.6%, 95% CI -3.2 to 1.9) and hepatic fat attenuation was not linearly associated with the pooled cohort risk score when mutually adjusted (-0.3%, 95% CI -0.9 to 0.4). Associations for risk factor components differed by fat depot. In conclusion, subcutaneous and hepatic fat may have different functions than fat stored in other depots in South Asians. Determining whether these relations are heterogeneous by race may help elucidate the mechanisms underlying CVD disparities. PMID- 29241970 TI - Identification of a Folate Receptor-Targeted Near-Infrared Molecular Contrast Agent to Localize Pulmonary Adenocarcinomas. AB - Non-small cell lung cancer (NSCLC) is the number one cancer killer in the United States. Despite attempted curative surgical resection, nearly 40% of patients succumb to recurrent disease. High recurrence rates may be partially explained by data suggesting that 20% of NSCLC patients harbor synchronous disease that is missed during resection. In this report, we describe the use of a novel folate receptor-targeted near-infrared contrast agent (OTL38) to improve the intraoperative localization of NSCLC during pulmonary resection. Using optical phantoms, fluorescent imaging with OTL38 was associated with less autofluorescence and greater depth of detection compared to traditional optical contrast agents. Next, in in vitro and in vivo NSCLC models, OTL38 reliably localized NSCLC models in a folate receptor-dependent manner. Before testing intraoperative molecular imaging with OTL38 in humans, folate receptor-alpha expression was confirmed to be present in 86% of pulmonary adenocarcinomas upon histopathologic review of 100 human pulmonary resection specimens. Lastly, in a human feasibility study, intraoperative molecular imaging with OTL38 accurately identified 100% of pulmonary adenocarcinomas and allowed for identification of additional subcentimeter neoplastic processes in 30% of subjects. This technology may enhance the surgeon's ability to identify NSCLC during oncologic resection and potentially improve long-term outcomes. PMID- 29241972 TI - Towards machine learned quality control: A benchmark for sharpness quantification in digital pathology. AB - Pathology is on the verge of a profound change from an analog and qualitative to a digital and quantitative discipline. This change is mostly driven by the high throughput scanning of microscope slides in modern pathology departments, reaching tens of thousands of digital slides per month. The resulting vast digital archives form the basis of clinical use in digital pathology and allow large scale machine learning in computational pathology. One of the most crucial bottlenecks of high-throughput scanning is quality control (QC). Currently, digital slides are screened manually to detected out-of-focus regions, to compensate for the limitations of scanner software. We present a solution to this problem by introducing a benchmark dataset for blur detection, an in-depth comparison of state-of-the art sharpness descriptors and their prediction performance within a random forest framework. Furthermore, we show that convolution neural networks, like residual networks, can be used to train blur detectors from scratch. We thoroughly evaluate the accuracy of feature based and deep learning based approaches for sharpness classification (99.74% accuracy) and regression (MSE 0.004) and additionally compare them to domain experts in a comprehensive human perception study. Our pipeline outputs spacial heatmaps enabling to quantify and localize blurred areas on a slide. Finally, we tested the proposed framework in the clinical setting and demonstrate superior performance over the state-of-the-art QC pipeline comprising commercial software and human expert inspection by reducing the error rate from 17% to 4.7%. PMID- 29241971 TI - Blocking Stemness and Metastatic Properties of Ovarian Cancer Cells by Targeting p70S6K with Dendrimer Nanovector-Based siRNA Delivery. AB - Metastasis is the cause of most (>90%) cancer deaths and currently lacks effective treatments. Approaches to understanding the biological process, unraveling the most effective molecular target(s), and implementing nanotechnology to increase the therapeutic index are expected to facilitate cancer therapy against metastasis. Here, we demonstrate the potential advantages of bringing these three approaches together through the rational design of a small interfering RNA (siRNA) that targets p70S6K in cancer stem cells (CSCs) in combination with dendrimer nanotechnology-based siRNA delivery. Our results demonstrated that the generation 6 (G6) poly(amidoamine) dendrimer can be used as a nanovector to effectively deliver p70S6K siRNA by forming uniform dendriplex nanoparticles that protect the siRNA from degradation. These nanoparticles were able to significantly knock down p70S6K in ovarian CSCs, leading to a marked reduction in CSC proliferation and expansion without obvious toxicity toward normal ovarian surface epithelial cells. Furthermore, treatment with the p70S6K siRNA/G6 dendriplexes substantially decreased mesothelial interaction, migration and invasion of CSCs in vitro, as well as tumor growth and metastasis in vivo. Collectively, these results suggest that p70S6K constitutes a promising therapeutic target, and the use of siRNA in combination with nanotechnology-based delivery may constitute a new approach for molecularly targeted cancer therapy to treat metastasis. PMID- 29241973 TI - Pattern based classification of endocervical adenocarcinoma: a review. AB - While endocervical adenocarcinoma is comprised of several histological subtypes, the most common subtype is human papillomavirus-associated usual type, and management of these tumours is primarily determined by FIGO (International Federation of Gynecology and Obstetrics) stage, a clinically based staging system. Early stage cervical cancer is determined by the pathological evaluation of tumour microscopic measurement (depth of invasion), which can be particularly challenging because of the lack of a defined point of origin. Yet important treatment decisions, cone versus radical surgery, are based on this imperfect system, resulting in overtreatment and related morbidities in many patients for whom it may not be necessary. There is a growing consensus, however, for a more conservative approach, one that reduces morbidity and prevents loss of fertility in these (often young) patients. This movement has been supported, in part, by the development of a morphology based risk stratification system which was devised in order to recognise those tumours that, while invasive, could potentially be treated more conservatively. In this review, we provide the reader with the background and rationale for a more conservative approach in treating endocervical adenocarcinoma, summarise the risk stratification system, and review the system's utility and reproducibility. In addition, we comment on recent updates that attempt to further refine the system. The application of this morphology based classification could help identify a subset of patients with endocervical adenocarcinoma (who would otherwise undergo radical surgery based on FIGO staging alone) that have good clinical outcomes and could be treated more conservatively. PMID- 29241974 TI - Endometriosis-associated ovarian neoplasia. AB - This article reviews the most relevant pathological and molecular features of ovarian tumours that are associated with endometriosis. Endometriosis is a common condition, affecting 5-15% of all women, and it has been estimated that 0.5-1% of cases are complicated by neoplasia. The most common malignant tumours in this setting are endometrioid adenocarcinoma and clear cell adenocarcinoma, each accounting for approximately 10% of ovarian carcinomas in Western countries. A minority of cases are associated with Lynch syndrome. These carcinomas are often confined to the ovaries at presentation in which case they have relatively favourable outcomes. However, high-stage tumours, particularly clear cell carcinomas, generally have a poor prognosis and this partly reflects relative resistance to current treatment. Histological diagnosis is straightforward in the majority of cases but some variants, for example endometrioid carcinomas with sex cord-like appearances or oxyphil cells, may create diagnostic difficulty. Similarly, clear cell carcinomas can show a range of architectural and cytological patterns that overlap with other tumours, both primary and metastatic, involving the ovaries. Endometriosis-associated borderline tumours are less common, and they often show mixed patterns of differentiation (seromucinous tumours). Atypical endometriosis may represent an intermediate step in neoplastic progression and some of these lesions demonstrate immunohistological and molecular alterations similar to those observed in endometriosis-related tumours. ARID1A mutations are relatively common in all of these tumours, but each has additional characteristic molecular alterations which are likely to be of increasing clinical relevance as targeted therapies are developed. Less is known of the pathogenesis of rarer endometriosis-associated ovarian tumours including endometrioid stromal sarcoma, mesodermal (Mullerian) adenosarcoma, and carcinosarcoma. This article also briefly reviews the issue of synchronous endometrioid carcinomas of the endometrium and the ovary, including the most recent developments on pathogenesis. PMID- 29241976 TI - Physician gender and apologies in clinical interactions. AB - OBJECTIVE: We examine whether patients have a preference for affective (i.e., focused on patient's emotions) or cognitive (i.e., focused on the process that led to the error) apologies that are dependent on the apologizing physician's gender. We hypothesize patients will prefer gender-congruent apologies (i.e., when females offer affective apologies and males offer cognitive apologies). METHODS: We randomly assigned analogue patients (APs: participants instructed to imagine they were a patient) to read a scenario in which a female or male physician makes an error and provides a gender-congruent or incongruent apology. APs reported on their perceptions of the physician and legal intentions. RESULTS: An apology-type and gender congruency effect was found such that APs preferred apologies congruent with the gender of the apologizing physician. An indirect effect of congruency on legal intentions through physician perceptions was confirmed (b=-0.24, p=0.02). CONCLUSION: Our results suggest that physician gender plays a role in patient reactions to different apology types. PRACTICE IMPLICATIONS: Apology trainings should incorporate how physician characteristics can influence how patients assess and respond to apologies. PMID- 29241975 TI - Positive emotion communication: Fostering well-being at end of life. AB - OBJECTIVE: Little is known about positive emotion communication (PEC) in end-of life care. This study aims to identify types and patterns of PEC among hospice nurses, caregivers, and patients. METHODS: A coding system based on positive psychology theory was applied as a secondary analysis to audio recordings of hospice nurse home visits with cancer patients and family caregivers, collected as part of a prospective longitudinal study. Eighty recordings (4 visits from 20 triads) were coded for humor, connection, praise, positive focus, gratitude, taking joy/savoring, and perfunctory statements. RESULTS: Descriptive statistics revealed the greatest proportion of PEC was made by nurses. Humor was most frequently used across all speakers. Cluster analysis revealed four PEC visit types: Savor/Take Joy; Humor; Perfunctory; and Other-focused Expressions of Positive Emotions. Linear mixed effect regression was used to estimate the trajectory of PEC over time, but no significant change was found. CONCLUSION: We found that positive emotions are common in nurse, caregiver and patient communication at end-of-life and do not decline closer to death. PRACTICE IMPLICATION: This study is among the first to explore PEC at end-of-life, and offers a way to bring strengths-based approaches into end of life communication research. PMID- 29241977 TI - Patients with IPF and lung cancer: diagnosis and management. PMID- 29241978 TI - Acalabrutinib in mantle cell lymphoma. PMID- 29241980 TI - [Embryotoxon in Axenfeld-Rieger syndrome in an infant]. PMID- 29241979 TI - Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. AB - BACKGROUND: Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity. METHODS: In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926. FINDINGS: From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1 2) previous therapies. At a median follow-up of 15.2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62-80), 67% (58-75), and 87% (79-92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 [38%]), diarrhoea (38 [31%]), fatigue (34 [27%]), and myalgia (26 [21%]). The most common grade 3 or worse adverse events were neutropenia (13 [10%]), anaemia (11 [9%]), and pneumonia (six [5%]). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13.8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]). INTERPRETATION: Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population. FUNDING: Acerta Pharma, a member of the AstraZeneca Group. PMID- 29241981 TI - Uptake of iron (III)-ethylenediamine-N, N, N', N'-tetraacetic acid complex by phosphatidylcholine lipid film. Part II. Effect of film curvature. AB - Mixed micelles formed in a ternary-solute aqueous solution of NaOH, iron (III) ethylenediamine-N, N, N', N'-tetraacetic acid complex (Fe-EDTA) and 1,2 diheptanoyl-sn-glycero-3-phosphatidyl choline (DHPC) were studied and compared with the mixed adsorbed film reported in Part I of this series to clarify the effect of the curvature of molecular assemblies on the interactions between their Fe-EDTA and DHPC constituents. The critical micelle concentrations (CMCs), surface tension at the CMC, and solution pH were measured as functions of the mole fractions of NaOH and DHPC. Rigorous thermodynamic equations were derived, in which the overall proton dissociation equilibria of Fe-EDTA and DHPC were taken into consideration, and applied to experimental data to obtain phase diagrams of micelle formation and the micelle-adsorbed film equilibrium. It was found that when the bulk solution was strongly acidic, Fe-EDTA was incorporated in the micelles. However, the adsorbed film was more Fe-EDTA-enriched than the micelle. These findings imply that a flat cell membrane is more permeable to an iron complex than a cell membrane with positive curvature. PMID- 29241982 TI - Monocyte profile in peripheral blood of gestational diabetes mellitus patients. AB - OBJECTIVE: Gestational diabetes Mellitus has been considered an inflammatory disease involving different cells and mediators in its development. The role of innate immune cells in GDM physiopathology remains unclear, therefore this study was conducted to assess monocyte profile in GDM patients. DESIGN: This was a case control study including 20 glucose-tolerant pregnant women (controls) and 18 GDM patients. METHODS: Flow cytometry was used to assess peripheral blood monocytes subsets (classical, intermediate, non-classical), the expression of TLR4 and CCR2 chemokine receptor (CD192) and cytokines (TNFA, IL6, IL10) secretion by monocytes subsets. In addition, sCD14 serum levels were evaluated by ELISA. RESULTS: We observed increased percentage of CD14+ cells, decreased frequency of intermediate monocytes (CD14+CD16+), and lower percentage of circulating monocytes (classical, intermediate and non-classical) that express TLR4 in the diabetic group compared to controls. Soluble CD14+ serum levels were higher in GDM patients compared to controls. There were no differences in the expression of the CCR2 chemokine receptor and cytokines (TNFA, IL6 and IL10) secretion between the studied groups. CONCLUSIONS: Our results demonstrated that GDM patients present impaired monocyte profile in the peripheral blood, suggesting that these cells are involved in GDM physiopathology. PMID- 29241984 TI - GesEPOC Guidelines In The Elderly: Still A Long Way To Go. PMID- 29241983 TI - Pediatric Interstitial Lung Disease: an Ongoing Challenge. PMID- 29241985 TI - The Effect of a Basic Basket on Tuberculosis Treatment Outcome in the Huambo Province, Angola. PMID- 29241987 TI - Boys, Biceps, and Bradycardia: The Hidden Dangers of Muscularity-Oriented Disordered Eating. AB - The recognition of eating disorders (EDs) in males represents an ongoing challenge for physicians. This challenge is particularly complex in the case of EDs that are oriented toward muscularity, as opposed to thinness, which current diagnostic criteria do not accommodate. Nevertheless, EDs in males, and muscularity-oriented disordered eating (MODE) in particular, are increasingly prevalent and are likely to be encountered in clinical practice. We report the case of a 16-year-old male who presented with medical instability, requiring hospitalization, in the context of MODE. Importantly, this patient did not meet formal diagnostic criteria for a specific ED, and behavioral symptoms were deemed goal oriented in the context of high school wrestling pursuits. This case highlights the challenges of identifying MODE and the medical risks associated therein. Pediatricians are encouraged to screen for MODE in adolescent males reporting body image concerns. PMID- 29241986 TI - The Effects of Gender- and Sexuality-Based Harassment on Lesbian, Gay, Bisexual, and Transgender Substance Use Disparities. AB - PURPOSE: We tested three competing models about whether gender- and sexuality based harassment at school have nonindependent, additive, or interactive effects on adolescents' electronic cigarette use (i.e., vaping), cigarette smoking, alcohol use, and heavy episodic drinking (HED). We also tested whether harassment mediated substance use disparities between lesbian, gay, bisexual, transgender (LGBT) adolescents and their cisgender heterosexual peers. METHODS: We analyzed cross-sectional data from the 2013-2014 California Healthy Kids Survey, including 316,766 students in grades 7, 9, and 11 from more than 1,500 middle and high schools. We used logistic regression models and interaction terms to estimate associations of past-year gender- and sexuality-based harassment at school on past-month substance use, and the Karlson-Holm-Breen method to test whether harassment mediated LGBT disparities in substance use. RESULTS: Vaping, smoking, drinking, HED, and gender- and sexuality-based harassment were higher for transgender adolescents than for cisgender males and females, and for adolescents who were lesbian, gay, or bisexual only versus heterosexual only. Gender- and sexuality-based harassments were independently associated with greater odds of using each substance in every grade. These two types of harassment had positive interactions with each other for vaping in grade 11, smoking in grade 11, and HED in grades 9 and 11. Gender- and sexuality-based harassment significantly mediated many of the LGBT disparities in substance use. CONCLUSIONS: Gender- and sexuality based harassment at school independently or interactively produced LGBT disparities in substance use. Reducing these types of discrimination in schools will likely mitigate these disparities. PMID- 29241988 TI - Disparities in operative outcomes in patients with comorbid mental illness. AB - BACKGROUND: Patients with mental health disorders have worse medical outcomes and experience excess mortality compared with those without a mental health comorbidity. This study aimed to evaluate the relationship between mental health comorbidities and surgical outcomes. METHODS: This retrospective cohort study used the National Inpatient Sample (2009-2011) to select patients who underwent one of the 4 most common general surgery procedures (cholecystectomy and common duct exploration, colorectal resection, excision and lysis of peritoneal adhesions, and appendectomy). Patients with a concurrent mental health diagnosis were identified. Multivariable logistic regression examined outcomes, including prolonged length of stay, in-hospital mortality, and postoperative complications. RESULTS: Of the 579,851 patients included, 38,702 patients (6.7%) had a mental health diagnosis. Mood disorders were most prevalent (58.7%), followed by substance abuse (23.8%). After adjustment for confounders, including sex, race, number of comorbidities, admission status, open operations, insurance, and income quartile, we found that having a mental health diagnosis conferred a 40% greater odds of including prolonged length of stay (OR 1.41, P < .001) and increased odds of any complication (OR 1.18, P < .001). Odds of death were slightly less in the mental health diagnosis cohort. CONCLUSIONS: General surgery patients with comorbid mental disease experience a greater incidence of postoperative complications and longer hospitalizations. Recognizing these disparate outcomes is the first step in understanding how to optimize care for this frequently marginalized population. PMID- 29241989 TI - Similar degree of intimal hyperplasia in surgically detected stenotic and nonstenotic arteriovenous fistula segments: a preliminary report. AB - BACKGROUND: Intimal hyperplasia has been historically associated with improper venous remodeling and stenosis after creation of an arteriovenous fistula. Recently, however, we showed that intimal hyperplasia by itself does not explain the failure of maturation of 2-stage arteriovenous fistulas. We seek to evaluate whether intimal hyperplasia plays a role in the development of focal stenosis of an arteriovenous fistula. METHODS: This study compares intimal hyperplasia lesions in stenotic and nearby nonstenotic segments collected from the same arteriovenous fistula. Focal areas of stenosis were detected in the operating room in patients (n= 14) undergoing the second-stage vein transposition procedure. The entire vein was inspected, and areas of stenosis were visually located with the aid of manual palpation and hemodynamic changes in the vein peripheral and central to the narrowing. Stenotic and nonstenotic segments were documented by photography before tissue collection (14 tissue pairs). Intimal area and thickness, intima-media thickness, and intima to media area ratio were measured in hematoxylin and eosin stained cross-sections followed by pairwise statistical comparisons. RESULTS: The intimal area in stenotic and nonstenotic segments ranged from 1.25 to 11.61 mm2 and 1.29 to 5.81 mm2, respectively. There was no significant difference between these 2 groups (P=.26). Maximal intimal thickness (P=.22), maximal intima-media thickness (P=.13), and intima to media area ratio (P=.73) were also similar between both types of segments. CONCLUSION: This preliminary study indicates that postoperative intimal hyperplasia by itself is not associated with the development of focal venous stenosis in 2-stage fistulas. PMID- 29241990 TI - Influence of metformin and insulin on myocardial substrate oxidation under conditions encountered during cardiac surgery. AB - BACKGROUND: The influence of diabetic therapies on myocardial substrate selection during cardiac surgery is unknown but may be important to ensure optimal surgical outcomes. We hypothesized that metformin and insulin alter myocardial substrate selection during cardiac surgery and may affect reperfusion cardiac function. METHODS: Rat hearts (n = 8 per group) were evaluated under 3 metabolic conditions: normokalemia, cardioplegia, or bypass. Groups were perfused with Krebs-Henseleit buffer in the presence of no additives, metformin, insulin, or both insulin and metformin. Perfusion buffer containing physiologic concentrations of energetic substrates with different carbon-13 (13C) labeling patterns were used to determine substrate oxidation preferences using 13C magnetic resonance spectroscopy and glutamate isotopomer analysis. Rate pressure product and oxygen consumption were measured. RESULTS: Myocardial function was not different between groups. For normokalemia, ketone oxidation was reduced in the presence of insulin and the combination of metformin and insulin reduced fatty acid oxidation. Metformin reduced fatty acid and ketone oxidation during cardioplegia. Fatty acid oxidation was increased in the bypass group compared with all other conditions. CONCLUSION: Metformin and insulin affect substrate utilization and reduce fatty acid oxidation before reperfusion. These alterations in substrate oxidation did not affect myocardial function in otherwise normal hearts. PMID- 29241991 TI - Pancreatic cyst fluid glucose: rapid, inexpensive, and accurate diagnosis of mucinous pancreatic cysts. AB - BACKGROUND: The most widely accepted biochemical test for preoperative differentiation of mucinous from benign, nonmucinous pancreatic cysts is cyst fluid carcinoembryonic antigen. However, the diagnostic accuracy of carcinoembryonic antigen ranges from 70% to 86%. Based on previous work, we hypothesize that pancreatic cyst fluid glucose may be an attractive alternative to carcinoembryonic antigen. METHODS: Pancreatic cyst fluid was collected during endoscopic or operative intervention. Diagnoses were pathologically confirmed. Glucose and carcinoembryonic antigen were measured using a patient glucometer and automated analyzer/enzyme-linked immunosorbent assay. Sensitivity, specificity, accuracy, and receiver operator characteristic analyses were performed. RESULTS: Cyst fluid samples from 153 patients were evaluated (mucinous: 25 mucinous cystic neoplasms, 77 intraductal papillary mucinous neoplasms, 4 ductal adenocarcinomas; nonmucinous: 21 serous cystic neoplasms, 9 cystic neuroendocrine tumors, 14 pseudocysts, 3 solid pseudopapillary neoplasms). Median cyst fluid glucose was lower in mucinous versus nonmucinous cysts (19 vs 96 mg/dL; P < .0001). With a threshold of <= 50 mg/dL, cyst fluid glucose was 92% sensitive, 87% specific, and 90% accurate in diagnosing mucinous pancreatic cysts. In comparison, cyst fluid carcinoembryonic antigen with a threshold of >192 ng/mL was 58% sensitive, 96% specific, and 69% accurate. Area under the curve for glucose and CEA were similar at 0.91 and 0.92. CONCLUSION: Cyst fluid glucose has significant advantages over carcinoembryonic antigen and should be considered for use as a routine diagnostic test for pancreatic mucinous cysts. PMID- 29241992 TI - Educational content and the use of social media at US departments of surgery. AB - BACKGROUND: The growth of the social media platform Twitter has prompted many to consider its potential as an educational tool. Little is known about how surgery training programs are utilizing this resource and whether this platform can provide educational content effectively. We sought to determine national utilization of Twitter by departments of surgery in the United States and evaluate if educationally driven content heightened engagement with the Twitter followers. METHODS: We conducted a cross-sectional analysis of social media presence for all Accreditation Council for Graduation Medical Education accredited general surgery training programs between October 1, 2016 and December 31, 2016. Each tweet was characterized as either promotional or educational. Metrics related to account engagement, including impressions (number of times a tweet is seen) and retweets (number of times a tweet is shared), were compared. These results were compared against a single departmental account focused primarily on educational content. RESULTS: Thirty-two departmental Twitter accounts were identified from the 272 programs approached associated with accredited general surgery training programs. Training programs posted a median of 1.0 unique tweets (interquartile range: 0.6-2.3) per week. Tweets were primarily promotional (81% of posts) and generated marginal engagement with followers (3.4 likes/tweet; 1.5 retweets/tweet). In contrast, a single, resident run departmental account at our institution (University of Michigan) focused on educational content generated consistent, educational content (19.6 unique tweets/week, 48% of which were educational), which resulted in increased engagement with followers (11.4 likes/tweet; 5.9 retweets/tweet) compared to other accounts. CONCLUSION: Though Twitter is being widely adopted widely by departments of surgery, it is primarily utilized for promotional content. Use of educational content may improve engagement from followers. PMID- 29241994 TI - Discussion. PMID- 29241993 TI - Preoperative pain in patient with an inguinal hernia predicts long-term quality of life. AB - BACKGROUND: Patients presenting for inguinal hernia repair report a wide range of pain. We hypothesized that patients presenting with less preoperative pain would experience a greater improvement in long-term quality of life after an inguinal hernia repair. METHODS: A total of 54 patients underwent either laparoscopic or open inguinal hernia repair and completed the Short Form 12 (SF-12) survey both preoperatively and 6 to 12 months after their repair. The physical and mental component scores (PCS and MCS) were calculated from the SF-12. Patients also completed an analog surgical pain scale. t Tests and analyses of covariance were used. A preoperative surgical pain scale score of >12 was representative of moderate to severe pain. RESULTS: Regardless of preoperative pain, there was improvement in long-term PCS quality of life (45.4 +/- 11.3 vs 50.1 +/- 9.1; P < .0001) that was not noted when assessing MCS quality of life (55.0 +/- 8.3 vs 54.7 +/- 9.4; P = .76). Patients who reported no or a low amount of preoperative pain experienced improved PCS quality of life compared with patients who reported moderate to severe preoperative pain (P = .048). This relationship was not noted with MCS (P = .16). CONCLUSION: This study suggests that patients presenting for inguinal hernia repair with no or low pain are more likely to experience improved physical function quality of life as a result of the herniorrhaphy. PMID- 29241995 TI - Discussion. PMID- 29241996 TI - Fracture-related mortality in southern Sweden: A multiple cause of death analysis, 1998-2014. AB - PURPOSE: To assess fracture-related mortality among adults (aged >=20years) in southern Sweden using multiple causes of death approach. METHODS: All death certificates (n=201 488) in adults recorded in the region of Skane from 1998 to 2014 were examined. We identified fracture-related deaths and computed mortality rates by sex, age group, and fracture site. Temporal trends were evaluated using joinpoint regression and associated causes were identified by age- and sex adjusted observed/expected ratios. RESULTS: Fractures were mentioned on 6 226 (3.1%) death certificates, with majority of these occurred among women (60%) and those aged>=80years (77%). While hip was the most common site overall (61% of all fracture-related deaths), skull was the most common site in people <60years (60% of all fracture-related deaths). Proportion of death certificates mentioning fracture was stable in women but increased by 0.4% (95% CI: 0.1 to 0.6) in men between 1998-2002 and 2010-2014. The mean age at death was higher in death certificates mentioning fracture than those without and this gap widened over time. The mean age-standardized fracture-related mortality rate was 18.8 (14.0) per 100 000 person-year in men (women) and declined by 1.5% (1.3%) per year during 1998-2014. Injuries (84.6%) and cardiovascular disorders (64.6%) were the most common comorbidities on death certificates mentioning fracture. CONCLUSIONS: Fracture is a contributing cause of death in more than 3% of all deaths in southern Sweden with hip in lead among older and skull fracture among younger people. There was a slight increase in proportion of deaths associated with fracture in men but not women during the study period. PMID- 29241997 TI - Quadrilateral plate fractures of the acetabulum: Proposition for a novel classification system. AB - BACKGROUND: Currently, there is no definition or classification system for quadrilateral plate (QLP) fractures; the aim was to anatomically and radiologically characterise the QLP, propose a definition and classify QLP fractures. METHODS: This study included an anatomical component and a radiological component. The anatomical study aimed at defining the characteristics of the QLP; the QLP was identified using four articulating bony pelvis specimens. A titanium mesh was placed on the specimens' quadrilateral surface; standard anteroposterior and oblique views were obtained, and axial CT images, to determine the radiological landmarks. The radiological study included the review of images of patients with QLP fractures; fractures involving the QLP were identified in a series of 609 consecutive patients with acetabular fractures. RESULTS: We considered QLP fractures where the QLP is separated from both columns of the acetabulum; this was found in 16% (98 cases). They were mostly encountered with associated both columns fractures (60 cases; 61%), Separation of the QLP could be complete or incomplete, or simple or comminuted, so QLP fractures were divided into three types: QLP1, simple with incomplete separation; QLP2, comminuted with incomplete separation; QLP3, comminuted with complete separation (QLP4), simple with complete separation. CONCLUSION: The QLP was characterised, and a definition and classification system; Cairo University Hospitals (CUH) Classification was proposed for these fractures. We believe that this classification may prove useful in the future for the identification and management of these fractures. PMID- 29241998 TI - The prevalence and morphology of the corona mortis (Crown of death): A meta analysis with implications in abdominal wall and pelvic surgery. AB - PURPOSE: Corona mortis is a highly variable vascular connection between the obturator and external iliac or inferior epigastric arteries or veins located behind the superior pubic ramus in the retropubic space (space of Retzius). Due to the significant variation in this collateral circulation, detailed anatomical knowledge of the corona mortis is vital to enhance the prevention of possible iatrogenic errors in hernia repair and other pubic surgical procedures. The aim of our meta-analysis was to provide comprehensive data on the prevalence, anatomical characteristics, and ethnic variations of the corona mortis vessel. METHODS: An extensive search was conducted through the major electronic databases to identify eligible articles. Data extracted included investigative method, prevalence of the corona mortis vessels among hemi-pelvises (overall, arterial only, venous only, and combined), distance from the corona mortis to pubic symphysis, and assessment of gender, side, laterality, and ethnicity subgroups. RESULTS: A total of 21 studies (n=2184 hemi-pelvises) were included in the meta analysis. The overall prevalence of the corona mortis in hemi-pelvises is high (49.3%). A venous corona mortis is more prevalent than an arterial corona mortis (41.7% vs. 17.0%). The corona mortis is more common in Asia (59.3%) than in Europe (42.8%) and North America (44.3%). CONCLUSIONS: As a corona mortis is present in an about half of all hemi-pelvises, it is important to consider the possibilities of its presence when undertaking surgical procedures and plan accordingly to avoid injuries. All surgeons operating in the retropubic region should have a thorough understanding of the anatomical characteristics and surgical implications of a corona mortis. PMID- 29241999 TI - Burn! How implicit and explicit attitudes predict early adolescents' "hot sauce" aggression toward classroom peers. AB - The current study examined to what extent early adolescents' implicit and explicit evaluations of a classmate predict (a) their own aggressive behavior toward that classmate and (b) their classmate's aggressive behavior toward them. Implicit and explicit peer evaluations were assessed among 148 early adolescents (78 boys and 70 girls; Mage = 11.1 years) with an approach-avoidance task and a likeability rating. Adolescents' aggression was measured by the number of grams of hot sauce administered to the peer in a "taste test." The analyses with the actor-partner interdependence model showed that girls' implicit attitude predicted aggression toward their partner and that boys' implicit attitude predicted their partner's aggression toward them. Explicit attitudes did not predict "hot sauce" aggression. The current study demonstrates that implicit evaluation of a peer can in fact be even more impactful than explicit evaluation in social interactions among peers. PMID- 29242000 TI - Social recovery therapy in combination with early intervention services for enhancement of social recovery in patients with first-episode psychosis (SUPEREDEN3): a single-blind, randomised controlled trial. AB - BACKGROUND: Provision of early intervention services has increased the rate of social recovery in patients with first-episode psychosis; however, many individuals have continuing severe and persistent problems with social functioning. We aimed to assess the efficacy of early intervention services augmented with social recovery therapy in patients with first-episode psychosis. The primary hypothesis was that social recovery therapy plus early intervention services would lead to improvements in social recovery. METHODS: We did this single-blind, phase 2, randomised controlled trial (SUPEREDEN3) at four specialist early intervention services in the UK. We included participants who were aged 16-35 years, had non-affective psychosis, had been clients of early intervention services for 12-30 months, and had persistent and severe social disability, defined as engagement in less than 30 h per week of structured activity. Participants were randomly assigned (1:1), via computer-generated randomisation with permuted blocks (sizes of four to six), to receive social recovery therapy plus early intervention services or early intervention services alone. Randomisation was stratified by sex and recruitment centre (Norfolk, Birmingham, Lancashire, and Sussex). By necessity, participants were not masked to group allocation, but allocation was concealed from outcome assessors. The primary outcome was time spent in structured activity at 9 months, as measured by the Time Use Survey. Analysis was by intention to treat. This trial is registered with ISRCTN, number ISRCTN61621571. FINDINGS: Between Oct 1, 2012, and June 20, 2014, we randomly assigned 155 participants to receive social recovery therapy plus early intervention services (n=76) or early intervention services alone (n=79); the intention-to-treat population comprised 154 patients. At 9 months, 143 (93%) participants had data for the primary outcome. Social recovery therapy plus early intervention services was associated with an increase in structured activity of 8.1 h (95% CI 2.5-13.6; p=0.0050) compared with early intervention services alone. No adverse events were deemed attributable to study therapy. INTERPRETATION: Our findings show a clinically important benefit of enhanced social recovery on structured activity in patients with first-episode psychosis who received social recovery therapy plus early intervention services. Social recovery therapy might be useful in improving functional outcomes in people with first-episode psychosis, particularly in individuals not motivated to engage in existing psychosocial interventions targeting functioning, or who have comorbid difficulties preventing them from doing so. FUNDING: National Institute for Health Research. PMID- 29242001 TI - Social functioning in patients with first-episode psychosis. PMID- 29242002 TI - Corrigendum to "Deletion of NADH oxidase in Listeria monocytogenes promotes the bacterial infection of brain" [Free Radic. Biol. Med. 112 (2017) 608-615]. PMID- 29242003 TI - More research on pharmacist-led programmes to improve COPD medication adherence still needed. PMID- 29242004 TI - Point-of-Care Devices Using Disease Biomarkers To Diagnose Neurodegenerative Disorders. AB - Neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases are highly prevalent and immensely destructive to the health and well being of individuals and their families across the globe. Neurodegenerative diseases are characterized by the gradual loss of neural tissue in the central nervous system. Clearly, early diagnosis of the onset of neurodegeneration is vital and beneficial. Current diagnostic methods rely heavily on symptoms or autopsy results, thus overlooking early diagnosis, the only opportunity for amelioration. However, appropriately selected and used biomarker diagnostics provide a solution. This article reviews the development and application of biomarker-related diagnostics for neurodegenerative disease with specific recommendations for point-of-care (POC) methodology. These advantageous approaches may offer a solution to existing obstacles and limitations to neurodegenerative disease treatment. PMID- 29242005 TI - A Case of Successful MitraClip Placement in a Patient With Severe Mitral Regurgitation After Failed Mitral Valve Ring Annuloplasty. PMID- 29242006 TI - Perioperative Considerations in the Management of Pheochromocytoma: The Details Behind the Changing Dogma. PMID- 29242007 TI - Extracorporeal Membrane Oxygenation (ECMO)-Assisted Surgery for Mediastinal Goiter Removal. PMID- 29242008 TI - Immune responses to peptides containing homocitrulline or citrulline in the DR4 transgenic mouse model of rheumatoid arthritis. AB - Antibodies to proteins/peptides containing citrulline are hallmarks of Rheumatoid Arthritis (RA). These antibodies are strongly associated with the expression of the Shared Epitope (SE). RA patients also generate antibodies to homocitrulline containing proteins/peptides (also referred to as anti-carbamylated protein antibodies (Anti-CarP)). This study was undertaken to investigate the relationship between homocitrulline and citrulline immune responses using an established mouse model of RA: DR4-transgenic (DR4tg) mice that express the human SE. C57BL/6 (B6) and DR4tg (on a B6 background) mice were immunized subcutaneously with a homocitrullinated peptide (HomoCitJED). Splenic T cell proliferation was evaluated by 3H-thymidine incorporation assay. Antibodies to homocitrullinated and citrullinated antigens were screened by enzyme-linked immunosorbent assay (ELISA). Antibody cross-reactivity was examined by inhibition with HomoCitJED and its citrullinated counterpart peptide, CitJED (the number of homocitrullines in HomoCitJED is equal to the number of citrullines in CitJED). HomoCitJED-immunized DR4tg mice developed early T and B cell responses to HomoCitJED and late responses to CitJED. These mice also developed anti-CCP2 antibodies. In some mice, antibodies to HomoCitJED were also reactive to CitJED. B6 mice immunized with HomoCitJED developed late T and B cell responses to HomoCitJED, but did not generate responses to citrullinated antigens. Unlike DR4tg mice, anti-HomoCitJED antibodies from B6 mice did not react to CitJED. In conclusion, DR4tg mice immunized with HomoCitJED developed immune responses to CitJED, indicating cross-reactivity. CitJED immune responses were dependent on the SE. HomoCitJED responses occurred in the absence of the SE (B6 mice); however, they developed earlier in DR4tg SE-expressing mice. PMID- 29242009 TI - Tendon displacements during voluntary and involuntary finger movements. AB - In the human hand, independent movement control of individual fingers is limited. One potential cause for this is mechanical connections between the tendons and muscle bellies corresponding to the different fingers. The aim of this study was to determine the tendon displacement of the flexor digitorum superficialis (FDS) of both the instructed and the neighboring, non-instructed fingers during single finger flexion movements. In nine healthy subjects (age 22-29 years), instructed and non-instructed FDS finger tendon displacement of the index, middle and ring finger was measured using 2D ultrasound analyzed with speckle tracking software in two conditions: active flexion of all finger joints with all fingers free to move and active flexion while the non-instructed fingers were restricted. Our results of the free movement protocol showed an average tendon displacement of 27 mm for index finger flexion, 21 mm for middle finger flexion and 17 mm for ring finger flexion. Displacements of the non-instructed finger tendons (~12 mm) were higher than expected based of the amount of non-instructed finger movement. In the restricted protocol, we found that, despite minimal joint movements, substantial non-instructed finger tendon displacement (~9 mm) was still observed, which was interpreted as a result of tendon strain. When this strain component was subtracted from the tendon displacement of the non-instructed fingers during the free movement condition, the relationship between finger movement and tendon displacement of the instructed and non-instructed finger became comparable. Thus, when studying non-instructed finger tendon displacement it is important to take tendon strain into consideration. PMID- 29242011 TI - Altered Mental Status in an Elderly Male. PMID- 29242010 TI - Heart Rate Variability Analysis in Patients Who Have Bradycardia Presenting to the Emergency Department with Chest Pain. AB - BACKGROUND: Heart rate variability (HRV) is a noninvasive method to measure the function of the autonomic nervous system. It has been used to risk stratify patients with undifferentiated chest pain in the emergency department (ED). However, bradycardia can have a modifying effect on HRV. OBJECTIVE: In this study, we aimed to determine how bradycardia affected HRV analysis in patients who presented with chest pain to the ED. METHODS: Adult patients presenting to the ED at Singapore General Hospital with chest pain were included in the study. Patients with non-sinus rhythm on electrocardiogram (ECG) were excluded. HRV parameters, including time domain, frequency domain, and nonlinear variables, were analyzed from a 5-min ECG segment. Occurrence of a major adverse cardiac event ([MACE], e.g., acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, or mortality) within 30 days of presentation to the ED was also recorded. RESULTS: A total of 797 patients were included for analysis with 248 patients (31.1%) with 30-day MACE and 135 patients with bradycardia (16.9%). Compared to non-bradycardic patients, bradycardic patients had significant differences in all HRV parameters suggesting an increased parasympathetic component. Among non-bradycardic patients, comparing those who did and did not have 30-day MACE, there were significant differences predominantly in time domain variables, suggesting decreased HRV. In bradycardic patients, the same analysis revealed significant differences in predominantly frequency-domain variables suggesting decreased parasympathetic input. CONCLUSIONS: Chest pain patients with bradycardia have increased HRV compared to those without bradycardia. This may have important implications on HRV modeling strategies for risk stratification of bradycardic and non-bradycardic chest pain patients. PMID- 29242012 TI - Outcomes of Immunocompetent Children Presenting with Fever and Neutropenia. AB - BACKGROUND: Neutropenia may alarm clinicians and prompt extensive evaluation in children with fever, even in immunocompetent patients. OBJECTIVE: Our aim was to determine outcomes in previously healthy febrile children presenting to the emergency department with severe neutropenia. METHODS: We reviewed data from infants and children aged 3-36 months with fever and severe neutropenia, defined as a peripheral neutrophil count <500 * 103/MUL, at our institution between January 1, 2012 and December 31, 2015. We compared our results to those from a similar study of children with a peripheral neutrophil count of 500-1000 * 103/MUL. RESULTS: Severe neutropenia was recorded in 52 patients; severe bacterial infection (SBI) was found in 1 (1.9%), but none had a positive blood culture. Incidence of SBI was not different from that found in a study of similar patients with moderate neutropenia. CONCLUSIONS: Immunocompetent patients with fever and severe neutropenia do not carry a higher risk for SBI compared to patients with fever and moderate neutropenia. Such patients could potentially be followed closely with serial blood counts to ensure bone marrow recovery, without the use of antibiotics. PMID- 29242013 TI - Blink and You Will Miss It! An Important Consideration in Facial Burns. PMID- 29242015 TI - Food allergy: setting the scene for tolerance induction. PMID- 29242014 TI - Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial. AB - BACKGROUND: Despite progress in single food oral immunotherapy, there is little evidence concerning the safety and efficacy of treating individuals with multiple food (multifood) allergies. We did a pilot study testing whether anti-IgE (omalizumab) combined with multifood oral immunotherapy benefited multifood allergic patients. METHODS: We did a blinded, phase 2 clinical trial at Stanford University. We enrolled participants, aged 4-15 years, with multifood allergies validated by double-blind, placebo-controlled food challenges to their offending foods. Inclusion criteria included a positive skin prick test of 6 mm or more (wheal diameter, above the negative control), a food-specific serum IgE concentration of more than 4 kU/L for each food, or both, and a positive double blind, placebo-controlled food challenge at 500 mg or less of food protein. Exclusion criteria included eosinophilic oesophagitis and severe asthma. Participants were randomised (3:1) with a block size of four, to receive multifood oral immunotherapy to two to five foods, together with omalizumab (n=36) or placebo (n=12). 12 individuals who fulfilled the same inclusion and exclusion criteria were included as controls. These individuals were not randomised and received neither omalizumab nor oral immunotherapy. Omalizumab or placebo was administered subcutaneously for 16 weeks, with oral immunotherapy starting at week 8, and was stopped 20 weeks before the exit double-blind, placebo-controlled food challenge at week 36. The primary endpoint was the proportion of participants who passed double-blind, placebo-controlled food challenges to at least two of their offending foods. This completed trial is registered with ClinicalTrials.gov, number NCT02643862. FINDINGS: Between March 25, 2015, and Aug 18, 2016, 165 participants were assessed for eligibility, of whom 84 did not meet the inclusion criteria and 21 declined to participate. We enrolled and randomised 48 eligible participants and the remaining 12 patients were included as nonrandomised, untreated controls. At week 36, a significantly greater proportion of the omalizumab-treated (30 [83%] of 36) versus placebo (four [33%] of 12) participants passed double-blind, placebo-controlled food challenges to 2 g protein for two or more of their offending foods (odds ratio 10.0, 95% CI 1.8-58.3, p=0.0044). All participants completed the study. There were no serious or severe (grade 3 or worse) adverse events. Participants in the omalizumab group had a significantly lower median per-participant percentage of oral immunotherapy doses associated with any adverse events (27% vs 68%; p=0.0082). The most common adverse events in both groups were gastrointestinal events. INTERPRETATION: In multifood allergic patients, omalizumab improves the efficacy of multifood oral immunotherapy and enables safe and rapid desensitisation. FUNDING: US National Institutes of Health (NIH). PMID- 29242016 TI - HbA1C variability and hypoglycemia hospitalization in adults with type 1 and type 2 diabetes: A nested case-control study. AB - AIMS: To determine association between HbA1C variability and hypoglycemia requiring hospitalization (HH) in adults with type 1 diabetes (T1D) and type 2 diabetes (T2D). METHODS: Using nested case-control design in electronic health record data in England, one case with first or recurrent HH was matched to one control who had not experienced HH in incident T1D and T2D adults. HbA1C variability was determined by standard deviation of >=3 HbA1C results. Conditional logistic models were applied to determine association of HbA1C variability with first and recurrent HH. RESULTS: In T1D, every 1.0% increase in HbA1C variability was associated with 90% higher first HH risk (95% CI, 1.25 2.89) and 392% higher recurrent HH risk (95% CI, 1.17-20.61). In T2D, a 1.0% increase in HbA1C variability was associated with 556% higher first HH risk (95% CI, 3.88-11.08) and 573% higher recurrent HH risk (95% CI,1.59-28.51). In T2D for first HH, the association was the strongest in non-insulin non-sulfonylurea users (P<0.0001); for recurrent HH, the association was stronger in insulin users than sulfonylurea users (P=0.07). The HbA1C variability-HH association was stronger in more recent years in T2D (P<=0.004). CONCLUSIONS: HbA1C variability is a strong predictor for HH in T1D and T2D. PMID- 29242017 TI - Global curriculum in research literacy for the surgical oncologist. AB - BACKGROUND: The ability to provide optimal care to cancer patients depends on awareness of current evidence-based practices emanating from research or involvement in research where circumstances permit. The significant global variations in cancer-related research activity and its correlation to cancer specific outcomes may have an influence on the care provided to cancer patients and their outcomes. The aim of this project is to develop a global curriculum in research literacy for the surgical oncologist. MATERIALS AND METHODS: The leadership of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in research literacy for the Surgical Oncologist. RESULTS: A global curriculum in research literacy is developed to incorporate the required domains considered to be essential to interpret the published research or become involved in research activity where circumstances permit. The purpose of this curriculum is to promote research literacy for the surgical oncologist, wherever they are based. It does not mandate direct research participation which may not be feasible due to restrictions within the local health-care delivery environment, socio-economic priorities and the educational environment of the individual institution where they work. CONCLUSIONS: A global curriculum in research literacy is proposed which may promote research literacy or encourage involvement in research activity where circumstances permit. It is hoped that this will enhance cancer-related research activity, promote awareness of optimal evidence-based practices and improve outcomes for cancer patients globally. PMID- 29242018 TI - Current practice in cytoreductive surgery and HIPEC for metastatic peritoneal disease: Spanish multicentric survey. AB - INTRODUCTION: Radical Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC), has been proposed as the current standard of treatment for metastatic peritoneal disease by several tumors. Despite its widely utilization, there seems to be a great variability in their organization, clinical practice, and safety among centers. AIM OF THE STUDY: To obtain updated information on clinical practice in different perioperative areas of the CRS HIPEC. PATIENTS AND METHODS: All 25 members of the Spanish Surface Peritoneal Malignancy (GECOP), were invited to answer an online survey, to describe their usual practice in different perioperative areas of the CRS-HIPEC. RESULTS: Survey was responded by 100% of centers. This study represents more than 800 patients treated annually. Seventy per cent of respondents perform CRS-HIPEC for more than 5 years. The most frequent technique was Coliseum (88%). Routinely non-invasive monitoring of cardiac output is used by 92% of centers. More than 50% of centers administer oxaliplatin (74%), or mitomycin-C (65%) in colorectal cancer; cisplatin in gastric cancer (73%) and mesothelioma (74%). Ovarian cancer is treated with cisplatin and various combinations, in 64% or paclitaxel in 54.5%. Spillage protocol was available in 100% centers. CONCLUSIONS: Data showed an important variability in volume of patients per center, selection of cytostatic agents, professional training and safety measures applied. The standardization of CRS/HIPEC procedures based on the best available evidence, the individualization of patients and the consensus among professionals, constitute an important part of the basis that will allow us to improve results of this complex procedure. PMID- 29242020 TI - Selective inhibition of beta-N-acetylhexosaminidases by thioglycosyl naphthalimide hybrid molecules. AB - To develop selective inhibitors for beta-N-acetylhexosaminidases which are involved in a myriad of physiological processes, a series of novel thioglycosyl naphthalimide hybrid inhibitors were designed, synthesized and evaluated for inhibition activity against glycosyl hydrolase family 20 and 84 (GH20 and GH84) beta-N-acetylhexosaminidases. These compounds which incorporate groups with varied sizes and lengths at the linker region between thioglycosyl moiety and naphthalimide moiety are designed to improve the selectivity and stacking interactions. The GH84 human O-GlcNAcase (hOGA) was sensitive to the subtle changes in the linker region and the optimal choice is a small size linker with six atoms length. And the GH20 insect beta-N-acetylhexosaminidase OfHex1 could tolerate compounds with a hydrophobic bulky linker. Especially, the compound 5c (hOGA, Ki = 3.46 MUM; OfHex1, Ki > 200 MUM) and the compound 6f (hOGA, Ki > 200 MUM; OfHex1, Ki = 21.81 MUM) displayed high selectivity. The molecular docking results indicated that the inhibition mechanism was different between the two families due to their different structural characteristics beyond the active sites. These results provide some promising clues to improve selectivity of potent molecules against beta-N-acetylhexosaminidases. PMID- 29242019 TI - Global variations in the level of cancer-related research activity and correlation to cancer-specific mortality: Proposal for a global curriculum. AB - INTRODUCTION: The aim of this study was to analyze global variations in the level of cancer-related research activity and correlate this with cancer-specific mortality. METHODS: The SCOPUS database was explored to obtain data relating to the number of cancer-related publications per country. Cancer-specific mortality rates were obtained from the World Health Organization. Global variations in the level of scholarly activity were analyzed and correlated with variations in cancer-specific mortality. RESULTS: Data for 142 countries were obtained and significant variations in the level of research activity was noted. The level of research activity increased with rising socio-economic status. The United States was the most prolific country with 222,300 publications followed by Japan and Germany. Several countries in different regions of the world had a low level of research activity. An inverse relationship between the level of research activity and cancer-specific mortality was noted. This relationship persisted even in countries with a low level of research activity. The socioeconomic status of a nation and geographic location (continent) had a mixed influence with an overall apparent correlation with cancer-related research activity. CONCLUSION: This study demonstrates significant global variation in the level of cancer-related research activity and a correlation with cancer-specific mortality. The presence of a minimum set of standards for research literacy, as proposed by the European Society of Surgical Oncology and the Society of Surgical Oncology may contribute to enhanced research activity and improve outcomes for cancer patients worldwide. PMID- 29242022 TI - Diversity and Inclusion: Now Radiology Must Walk the Walk. PMID- 29242021 TI - Activatable fluorescent probes in fluorescence-guided surgery: Practical considerations. AB - Fluorescence-guided imaging during surgery is a promising technique that is increasingly used to aid surgeons in identifying sites of tumor and surgical margins. Of the two types of fluorescent probes, always-on and activatable, activatable probes are preferred because they produce higher target-to-background ratios, thus improving sensitivity compared with always-on probes that must contend with considerable background signal. There are two types of activatable probes: 1) enzyme-reactive probes that are normally quenched but can be activated after cleavage by cancer-specific enzymes (activity-based probes) and 2) molecular-binding probes which use cancer targeting moieties such as monoclonal antibodies to target receptors found in abundance on cancers and are activated after internalization and lysosomal processing (binding-based probes). For fluorescence-guided intraoperative surgery, enzyme-reactive probes are superior because they can react quickly, require smaller dosages especially for topical applications, have limited side effects, and have favorable pharmacokinetics. Enzyme-reactive probes are easier to use, fit better into existing work flows in the operating room and have minimal toxicity. Although difficult to prove, it is assumed that the guidance provided to surgeons by these probes results in more effective surgeries with better outcomes for patients. In this review, we compare these two types of activatable fluorescent probes for their ease of use and efficacy. PMID- 29242024 TI - Continuity and diversity. PMID- 29242023 TI - Open Access Journal Policies: A Systematic Analysis of Radiology Journals. AB - OBJECTIVE: The open access movement has pushed for greater access to scientific knowledge by expanding access to scientific journal articles. There is limited information about the extent to which open access policies have been adopted by radiology journals. We performed a systematic analysis to ascertain the proportion of radiology journals with open access options. MATERIALS AND METHODS: A search was performed with the assistance of a clinical informationist. Full and mixed English-language diagnostic and interventional radiology Web of Science journals (impact factors > 1.0) were included. Nuclear medicine, radiation oncology, physics, and solicitation-only journals were excluded. Primary outcome was open access option (yes or no) with additional outcomes including presence or absence of embargo, complete or partial copyright transfer, publication fees, and self-archiving policies. Secondary outcomes included journal citations, journal impact factors, immediacy, Eigenfactor, and article influence scores. Independent double readings were performed with differences resolved by consensus, supplemented by contacting editorial staff at each journal. RESULTS: In all, 125 journals were identified; review yielded 49 journals (39%, mean impact factor of 2.61). Thirty-six of the journals had open access options (73.4%), and four journals were exclusively open access (8.2%). Twelve-month embargoes were most commonly cited (90.6%) with 28.6% of journals stating that they did not require a complete transfer of copyright. Prices for open access options ranged from $750 to $4,000 (median $3,000). No statistically significant differences were found in journal impact measures comparing journals with open access options to journals without open access options. CONCLUSIONS: Diagnostic and interventional radiology journals have widely adopted open access options with a few radiology journals being exclusively open access. PMID- 29242025 TI - Efficacy of the split-thickness labial flap method for soft tissue management in anterior ridge horizontal augmentation procedures: A clinical prospective study in the anterior maxilla. AB - OBJECTIVE: To introduce a novel method of split-thickness labial flap in maxillary anterior ridge horizontal augmentation and to evaluate its efficacy and morbidity. MATERIALS AND METHODS: 230 patients were selected to receive either particulate or onlay grafting. A split-thickness labial flap was applied to cover the grafted area and close the wound. The incidence of postsurgical complications and the level of patient discomfort were evaluated. A visual analog scale was used to quantify the amount of pain and swelling in the patients. RESULTS: In all 375 surgical sites, passive primary closure was achieved with the split-thickness labial flap method. Membrane exposure after surgery was seen in 6 cases in the onlay group and in 4 in the particulate group. No long-lasting pain (>1 week), paresthesia, or signs of infection occurred during the follow-up period of 6 months. The mean pain and swelling scores in the particulate graft group (2.75 +/ 3.01 and 2.02 +/- 2.51, respectively) were lower than the scores in the onlay graft group (3.18 +/- 2.79 and 3.85 +/- 2.25, respectively). CONCLUSIONS: The flap advancement technique presented in this study facilitates clinically passive primary closure. This technique can be used successfully in both particulate and onlay horizontal graft procedures. PMID- 29242026 TI - The localization and risk factors of squamous cell carcinoma in the oral cavity: A retrospective study of 1501 cases. AB - Head and neck cancer is the tenth leading cause of cancer mortality. Ninety percent of tumours in the oral cavity are squamous cell carcinomas. Information about the exact localisation of OSCC is missing in the literature. In the present study, we retrospectively analysed a total of 1501 OSCC patients, who were treated between 1975 and 2009. The purpose of this study was to examine the localisation of OSCC tumours and to analyse the influence of various parameters on tumour localisation. 71.5% of these patients were male and 28.5% were female. The mean age was 60 years. The most common sites of OSCC occurrence were the floor of the mouth and the anterior base of the mouth. The hard palate was the most affected anatomical area of the maxilla. Descriptive statistical analysis, chi-square testing and a multivariate analysis using a multinomial logistical model showed a significant correlation of younger age and female gender with tumour occurrence in the maxilla and the tongue. We provide a very detailed anatomical mapping of OSCC. PMID- 29242027 TI - Muller glial cells of the primate foveola: An electron microscopical study. AB - Previous studies on the ultrastructure of the primate foveola suggested the presence of an inverted cone-like structure which is formed by 25-35 specialized Muller cells overlying the area of high photoreceptor density. We investigated the ultrastructure of the Muller cells in the foveola of a human and macaque retina. Sections through the posterior poles of an eye of a 40 years-old human donor and an eye of an adult cynomolgus monkey (Macaca fascicularis) were investigated with transmission electron microscopy. The foveola consisted of an inner layer (thickness, 5.5-12 MUm) which mainly contained somata (including nuclei) and inner processes of Muller cells; this layer overlaid the central Henle fibers and outer nuclear layer. The inner layer contained numerous watery cysts and thin lamelliform and tubular Muller cell processes which spread along the inner limiting membrane (ILM). The cytoplasm of the outer Muller cell processes became increasingly dispersed and electron-lucent in the course towards the outer limiting membrane. The ILM of the foveola was formed by a very thin basal lamina (thickness, <40 nm) while the basal lamina of the parafovea was thick (0.9-1 MUm). The data show that there are various conspicuous features of foveolar Muller cells. The numerous thin Muller cell processes below the ILM may smooth the inner surface of the foveola (to minimize image distortion resulting from varying light refraction angles at an uneven retinal surface), create additional barriers to the vitreous cavity (compensating the thinness of the ILM), and provide mechanical stability to the tissue. The decreasing density of the outer process cytoplasm may support the optical function of the foveola. PMID- 29242028 TI - Blockade of KCa3.1: A novel target to treat TGF-beta1 induced conjunctival fibrosis. AB - Postoperative conjunctival fibrosis is common in patients after glaucoma filtration surgery. The calcium activated potassium (KCa3.1) channel has been shown to inhibit fibrosis in many non-ocular tissues. However, its potential in treating ocular fibrosis remains unknown. We tested the anti-fibrotic potential of TRAM34, a selective blocker of KCa3.1 channel, in treating conjunctival fibrosis. Primary human conjunctival fibroblast (HCF) cultures derived from donor tissues. Myofibroblasts causing conjunctival fibrosis were generated by growing HCFs in the presence of TGFbeta1 for 72 h. KCa3.1 mRNA and protein expression in HCF was examined with PCR and western blot. The anti-fibrotic potential of TRAM34 was examined by measuring fibrotic gene expression with quantitative PCR (qPCR), immunofluorescence, and western blotting in HCFs in +/- TGFbeta1 (5 ng/ml) and TRAM34 (0-25 MUM). The cytotoxicity of Tram34 was analyzed with trypan blue assay and its role in Smad signaling was studied with immunofluorescence. Expression of KCa3.1 mRNA and protein was detected in HCFs and TGFbeta1 treatment to HCFs significantly increased expression of KCa3.1. TRAM34 treatment attenuated transcription of fibrotic markers, alphaSMA (p < .001), fibronectin (p < .05), collagen I (p < .001) and collagen IV (p < .001) in TGFbeta1-induced HCFs. Further, TRAM34 significantly inhibited TGFbeta1-stimulated alphaSMA protein expression (p < .01) and nuclear translocation of fibrotic Smad2/3 in HCFs and showed no significant cytotoxicity (p < .05). The KCa3.1 potassium channel plays a significant role in the prevention of conjunctival fibrosis and TRAM34 has potential to control post surgical bleb fibrosis in patients. In vivo studies are warranted. PMID- 29242029 TI - Modernizing Human Cancer Risk Assessment of Therapeutics. AB - Cancer risk assessment of therapeutics is plagued by poor translatability of rodent models of carcinogenesis. In order to overcome this fundamental limitation, new approaches are needed that enable us to evaluate cancer risk directly in humans and human-based cellular models. Our enhanced understanding of the mechanisms of carcinogenesis and the influence of human genome sequence variation on cancer risk motivates us to re-evaluate how we assess the carcinogenic risk of therapeutics. This review will highlight new opportunities for applying this knowledge to the development of a battery of human-based in vitro models and biomarkers for assessing cancer risk of novel therapeutics. PMID- 29242030 TI - Large retropharyngeal haematoma. Airway management with Airtraq(r) laryngoscope. AB - Retropharyngeal haematoma is a life-threatening clinical situation that can lead to a potential obstruction of the upper airway and requires rapid diagnosis. Clinicaly, it can be presented in different ways, depending on its size and growing speed. The first measure is to protect and manage the airway: in most cases this is a difficult airway situation. A retropharyngeal haematoma can be formed due to a previous traumatic history, with or without associated cervical fracture. Treatment of the haematoma is conservative in most cases, with close monitoring until it is reabsorbed in 3-4 weeks, although they can sometimes require surgical evacuation. We present the case of a patient who developed a large retropharyngeal haematoma after minor cervical trauma and describe an approach of the airway using the Airtraq(r) disposable optical laryngoscope. PMID- 29242031 TI - Prognosis and predictors of mortality in critically ill elderly patients. AB - OBJECTIVES: to evaluate mortality of patients>=80 years admitted to the Surgical Intensive Care Unit (SICU), global hospital mortality and factors related to it. MATERIAL AND METHODS: observational retrospective study of patients>=80 years admitted to SICU between June 2012 and June 2015. RESULTS: a total of 299 patients were included, 54 of them died in the SICU (18.1%) and 80 patients (26.8%) died during their hospital stay. SICU mortality was independently related to age (OR=1.125; 95%CI: 1.042-1.215; P=.003), SAPS II (OR=1.026; 95% CI: 1.008 1.044; P=.004), need for renal replacement therapy (RRT) (OR=1.960; 95%CI: 1.046 3.671; P=.036) and need for mechanical ventilation for more than 24hours (OR=2.834; 95%CI: 1.244-6.456; P=.013). Factors independently related to hospital mortality were age (OR=1.125; 95%CI: 1.054-1.192; P<.001), SOFA score (OR=1.154; 95% CI: 1.079-1.235; P<.001), need for RRT (OR=1.924; 95%CI: 1.121-3.302; p=0.018) and need for mechanical ventilation for more than 24hours (OR=3.144; 95% CI: 1.771-5.584; P<.001). CONCLUSIONS: In critically ill patients over 80 years hospital mortality was independently related to age, SOFA score, RRT need and need for mechanical ventilation for more than 24hours. Our results raise important issues about end-of-life care and life-sustaining interventions in elderly, critically ill patients. PMID- 29242032 TI - Gene Phenotypes: The Role Can't Be Ignored in Etiology of Dental Caries. PMID- 29242033 TI - The evidence and rationale for the perioperative use of loop diuretics during kidney transplantation: A comprehensive review. AB - PURPOSE: Loop diuretics (LD) attenuate ischemic injury in nephrons. They are thought to decrease delayed graft function (DGF) during kidney transplantation (KT). This review aimed to summarize the current evidence for the perioperative use of LD during KT. METHODS: We performed an analysis of all articles that were published since the inception of Medline and Embase: 26 studies were selected for inclusion. Scope was LD use during the perioperative phase of KT only. RESULTS: Six animal studies demonstrated mixed results in terms of renal function and survival. Of the 20 studies performed in humans, 4 were randomized clinical trials. The risk of bias was mostly unclear. Evidence supporting the role of LD to increase diuresis was mixed and to prevent DGF was weak. There was poor evidence to support LD use to improve initial and long-term graft function. No data on patient survival could be found. Overall, there was a lack of any robust clinical evidence for LD use perioperatively during KT. IMPLICATIONS: There is poor evidence to support the perioperative use of LD during KT. Well-designed trials are needed to further explore their safety and efficacy, and we summarize several rationales. Pragmatic rationales include volume management. There is evidence to suggest that LD have a vasodilatory effect, and decrease edema, congestion and oxygen requirements. Lastly, there are several theoretical rationales to explore LD use during KT, in particular, attenuating ischemia reperfusion injury and modulating autophagy. PMID- 29242034 TI - Dendritic cells in the regulation of immunity and inflammation. AB - As potent antigen-presenting cells, dendritic cells (DCs) comprise the most heterogeneous cell population with significant cellular phenotypic and functional plasticity. They form a sentinel network to modulate immune responses, since intrinsic cellular mechanisms and complex external, environmental signals endow DCs with the distinct capacity to induce protective immunity or tolerance to self. Interactions between DCs and other cells of the immune system mediate this response. This interactive response depends on DC maturation status and subtype, as well as the microenvironment of the tissue location and DC-intrinsic regulators. Dysregulated DCs can initiate and perpetuate various immune disorders, which creates attractive therapeutic targets. In this review, we provide a detailed outlook on DC ontogeny and functional specialization. We highlight recent advances on the regulatory role that DCs play in immune responses, the putative molecular regulators that control DC functional responding and the contribution of DCs to inflammatory disease physiopathology. PMID- 29242035 TI - Outcomes of liver-first strategy and classical strategy for synchronous colorectal liver metastases in Sweden. AB - BACKGROUND: Patients with synchronous colorectal liver metastases (sCRLM) are increasingly operated with liver resection before resection of the primary cancer. The aim of this study was to compare outcomes in patients following the liver-first strategy and the classical strategy (resection of the bowel first) using prospectively registered data from two nationwide registries. METHODS: Clinical, pathological and survival outcomes were compared between the liver first strategy and the classical strategy (2008-2015). Overall survival was calculated. RESULTS: A total of 623 patients were identified, of which 246 were treated with the liver-first strategy and 377 with the classical strategy. The median follow-up was 40 months. Patients chosen for the classical strategy more often had T4 primary tumours (23% vs 14%, P = 0.012) and node-positive primaries (70 vs 61%, P = 0.015). The liver-first patients had a higher liver tumour burden score (4.1 (2.5-6.3) vs 3.6 (2.2-5.1), P = 0.003). No difference was seen in five year overall survival between the groups (54% vs 49%, P = 0.344). A majority (59%) of patients with rectal cancer were treated with the liver-first strategy. CONCLUSION: The liver-first strategy is currently the dominant strategy for sCRLM in patients with rectal cancer in Sweden. No difference in overall survival was noted between strategies. PMID- 29242036 TI - Seven new sesquineolignans isolated from the seeds of hawthorn and their neuroprotective activities. AB - Seven new sesquineolignans (1-7) were isolated from the 70% ethanolic extract of the hawthorn seeds. Their structures were established by comprehensive spectroscopic analyses including 1D, 2D NMR, CD and HRESIMS data. The neuroprotective activity of the isolated sesquilignans towards H2O2-induced damage in human neuroblastoma SH-SY5Y cells was investigated. All of these sesquineolignans exhibited significant neuroprotective activity towards damaged SH-SY5Y cells, compared with the positive control (Trolox). Among them, 6 displayed the most potent neuroprotective ability with the survival rate of 90.74% at the concentration of 50MUM. Moreover, Hoechst 33258 staining and Annexin V/PI analysis proved that 6 could protect damaged SH-SY5Y cells through inhibiting cellular apoptosis. PMID- 29242037 TI - Unusual metal complex of cadinane sesquiterpene alkaloid and new neolignan glycosides from Alangium alpinum. AB - One unusual metal complex of cadinane sesquiterpene alkaloid (1), one new cadinane sesquiterpene alkaloid (2) and two new neolignan glycosides (3-4) along with six known cadinane sesquiterpene derivatives (5-10), nineteen known phenolic glycosides (11-29) were isolated from the aerial parts of Alangium alpinum. Structures of new crystals of metal complex were characterized by X-Ray diffraction and ICP-AES analysis. Other new compounds were elucidated by combined use and detailed analysis of HR-ESIMS, 1D and 2D NMR and CD spectroscopic method. In addition, all isolated compounds were tested for their inhibitory effects against TNF-alpha induced NF-kappaB activation in Hela cells and NO production in RAW 264.7 macrophages. PMID- 29242038 TI - NMR-based phytochemical analysis of Vitis vinifera cv Falanghina leaves. Characterization of a previously undescribed biflavonoid with antiproliferative activity. AB - Vitis vinifera cv Falanghina is an ancient grape variety of Southern Italy. A thorough phytochemical analysis of the Falanghina leaves was conducted to investigate its specialised metabolite content. Along with already known molecules, such as caftaric acid, quercetin-3-O-beta-d-glucopyranoside, quercetin 3-O-beta-d-glucuronide, kaempferol-3-O-beta-d-glucopyranoside and kaempferol-3-O beta-d-glucuronide, a previously undescribed biflavonoid was identified. For this last compound, a moderate bioactivity against metastatic melanoma cells proliferation was discovered. This datum can be of some interest to researchers studying human melanoma. The high content in antioxidant glycosylated flavonoids supports the exploitation of grape vine leaves as an inexpensive source of natural products for the food industry and for both pharmaceutical and nutraceutical companies. Additionally, this study offers important insights into the plant physiology, thus prompting possible technological researches of genetic selection based on the vine adaptation to specific pedo-climatic environments. PMID- 29242039 TI - Potassium oxalate oral rinses for long-term relief from dentinal hypersensitivity: Three randomised controlled studies. AB - OBJECTIVES: To evaluate effectiveness of oral rinses containing dipotassium oxalate monohydrate (KOX) in relieving dentinal hypersensitivity (DH) after 8 w use adjunctive to brushing. METHODS: Three 8-week, randomised, controlled, double blind, parallel-group, single-centre studies were conducted in adults with DH. In each study, participants were randomised to one of two experimental rinses or a placebo in a matrix design, such that each experimental rinse was evaluated in two studies. Rinses A (pH 4.5) and B (pH 7.0) contained 1.5% KOX and were fluoride-free; Rinse C (pH 4.5) contained 2.0% KOX and 45 ppm fluoride as NaF; the placebo rinse (pH 4.5) did not contain KOX or fluoride. Participants brushed with a fluoride dentifrice for 1 min, briefly rinsed with water, then rinsed with their assigned oral rinse for 1 min twice daily for 8 w. DH was assessed at baseline and following 4 and 8 w use by response to an evaporative (air) stimulus (evaluated by Schiff sensitivity score and a 10-point visual rating scale) and a tactile stimulus (Yeaple probe). RESULTS: All rinses in each study were associated with statistically significant improvements from baseline in measures of DH after 4 and 8 w treatment. However, between-treatment comparisons were inconsistent across the studies, with only Study 3 demonstrating a significant difference between the experimental (Rinses B and C) and placebo rinses. A number of treatment-related adverse events (all mild) were reported. CONCLUSIONS: Rinses containing 1.5-2.0% KOX did not consistently demonstrate a benefit over placebo in relieving DH after 8 w use. CLINICAL SIGNIFICANCE: While favourable results were found in one of the investigations, this suite of studies shows that the possibility of inconsistent results exists even with the best designed and executed trials. PMID- 29242040 TI - Valuing the delivery of dental care: Heterogeneity in patients' preferences and willingness-to-pay for dental care attributes. AB - OBJECTIVES: To examine the amount of heterogeneity in patients' preferences for dental care, what factors affect their preferences, and how much they would be willing to pay for improvement in specific dental care attributes. METHODS: A discrete choice experiment (DCE) was used to elicit patients' preferences. Three alternative dental care services that differed in the type of care provider, treatment explanation, dental staff behavior, waiting time and treatment cost were described to patients. Patients (n=265) were asked to choose their preferred alternative. The study was conducted at a public dental clinic of the School of Dental Medicine, University of Zagreb. Mixed logit and latent class models were used for analysis. RESULTS: On average, the patients would be willing to pay ?45 for getting a detailed explanation of treatment over no explanation. This was the most valued attribute of dental care, followed by dental staff behavior with marginal willingness-to-pay (WTP) of ?28. Dental care provided by the faculty members and private dental care were valued similarly, while student-provided care was valued ?23 less. Patients also disliked longer waiting time in the office, but this was the least important attribute. Four classes of patients with distinct preferences for dental care were identified. Older and/or more educated patients tended to give relatively less importance to treatment explanation. Higher education was also associated with a higher propensity to substitute faculty dental care with the private care providers. CONCLUSIONS: Large heterogeneity in patients' preferences was detected. Understanding their preferences may improve the delivery of dental care. CLINICAL SIGNIFICANCE: Dental care providers should pay particular attention to providing a detailed treatment explanation to their patients. Dental care for older and/or more educated patients should be more attentive to interpersonal characteristics. Faculty dental care provided by faculty members could be price competitive to private care, and student-provided care more affordable. PMID- 29242042 TI - Neoadjuvant chemotherapy in breast cancer: more than just downsizing. PMID- 29242043 TI - Sweep-tone evoked stimulus frequency otoacoustic emissions in humans: Development of a noise-rejection algorithm and normative features. AB - In recent years, there has been a growing interest to measure stimulus frequency otoacoustic emissions (SFOAEs) using sweep tones. While there are several advantages of the sweep-tone technique, one of the major problems with sweep-tone methodologies is the lack of an objective analysis procedure that considers and rejects individual noisy recordings or noisy segments. A new efficient data driven method for rejecting noisy segments in SFOAE analysis is proposed and the normative features of SFOAEs are characterized in fifty normal-hearing young adults. The automated procedure involved phase detrending with a low-order polynomial and application of median and interquartile ranges for data outlier rejection from individual recordings. The SFOAE level and phase were analyzed using the least-squared fit method, and the noise floor was estimated using the error of the mean of the sweep level. Overall, the results of this study demonstrated the effectiveness of the automated noise rejection procedure and described the normative features of sweep-tone evoked SFOAEs in human adults. PMID- 29242044 TI - What Interventions Are Most Effective for Emergency Contraception? PMID- 29242041 TI - Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. AB - BACKGROUND: Neoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials. METHODS: We obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality). FINDINGS: Patients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5-14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21.4% for NACT versus 15.9% for adjuvant chemotherapy (5.5% increase [95% CI 2.4-8.6]; rate ratio 1.37 [95% CI 1.17-1.61]; p=0.0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38.2% for NACT vs 38.0% for adjuvant chemotherapy; rate ratio 1.02 [95% CI 0.92 1.14]; p=0.66), breast cancer mortality (34.4% vs 33.7%; 1.06 [0.95-1.18]; p=0.31), or death from any cause (40.9% vs 41.2%; 1.04 [0.94-1.15]; p=0.45). INTERPRETATION: Tumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered-eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy. FUNDING: Cancer Research UK, British Heart Foundation, UK Medical Research Council, and UK Department of Health. PMID- 29242045 TI - Defining the Applicant Pool for Postgraduate Year-2 Categorical General Surgery Positions. AB - OBJECTIVE: In the spring of 2010, a categorical general surgery postgraduate year (PGY)-2 position became available at our academic medical center secondary to attrition of a PGY-1 resident. We sought to study the unique characteristics of applicants to that position and to describe the selection process with hopes to stimulate additional studies about the unique challenges of recruiting applicants into advanced standing positions. DESIGN: Applications were received via e-mail and reviewed to characterize the applicant pool. An Excel spreadsheet was used to organize data. Characteristics assessed included United States Medical Licensing Examination (USMLE) scores, Educational Commission for Foreign Medical Graduates status, Alpha Omega Alpha Honor Society status, sex, academic performance, number of case logs, volunteer and job experience, leadership roles, research experience including submissions, and advanced degrees. These characteristics were compared to those of the PGY-1 applicants through the Match that year. SETTING: Academic medical center. PARTICIPANTS: Applicants for a categorical general surgery PGY-2 position in 2010. RESULTS: A total of 129 applicants provided the requested documents. There were 104 males, 25 females, no Alpha Omega Alpha Honor Society candidates, and 82 international candidates. Of all, 46 candidates experienced academic difficulties. Quantitative averages include USMLE 1: 214.17, USMLE 2: 215.74, American Board of Surgery In Training Examination (ABSITE) percentile = 51.96, ABSITE 2 = 46.00, grand total case log: 192.10. Advanced degrees included 2 MBAs, 6 MPHs, and 7 nonphysiology MSs. The selection process to fill the position started on 3/25/2010 when the announcement was published and ended on 5/11/2010 when the offer of acceptance was sent. The selected applicant integrated well with the peers and just graduated from our residency as one of the leaders of the graduating class. CONCLUSIONS: Although the attrition rate in general surgery remains high, there is a dearth of literature about how best to replace residents. The hardship of replacing residents highlights the importance of studying this group to improve the recruitment process and the quality of replacement residents. The selection process was time consuming and presented its own challenges given the lack of a computerized system for screening. It lasted nearly 7 weeks requiring faculty time commitment to mine through application data/e-mails, correspond with applicants, conduct interviews, and ultimately select an applicant for the position. This is the first study to investigate the applicant pool to advanced standing positions in general surgery and we present it as a pilot study to stimulate further research efforts. PMID- 29242047 TI - Trans-esophageal endobronchial ultrasound-guided needle aspiration (EUS-B-NA): A road map for the chest physician. AB - The endobronchial ultrasound (EBUS) scope has been increasingly used in the gastrointestinal tract (EUS-B). Scientific data proves its efficacy and safety to provide a complete lung cancer staging, when combined with EBUS-TBNA, and in the diagnosis of para-esophageal lesions. There are multiple barriers to start performing EUS-B but probably the most important ones are related to knowledge and training, so new operators should follow a structured training curriculum. This review aims to reflect the best current knowledge regarding EUS-B and provide a road map to assist those who are incorporating the technique into their clinical practice. PMID- 29242046 TI - The feasibility and acceptability of self-testing for proteinuria during pregnancy: A mixed methods approach. AB - OBJECTIVE: To investigate feasibility and acceptability of self-testing for proteinuria during pregnancy. STUDY DESIGN: Mixed methods approach which included: an accuracy study where pregnant women (n = 100) and healthcare professionals (n = 96) tested seven synthetic protein samples and completed a questionnaire, a feasibility study where pregnant women who were self-monitoring their blood pressure were asked to self-test for proteinuria (n = 30), and an online questionnaire about women's experiences of self-testing (n = 200). MAIN OUTCOME MEASURES: Sensitivity and specificity of testing and questionnaire results. RESULTS: There were no significant differences in the accuracy of synthetic sample testing by pregnant women (sensitivity 0.81 (95% confidence intervals (CI) 0.78-0.85), specificity 0.93 (95% CI 0.91-0.95)) and healthcare professionals: (sensitivity 0.83 (95% CI 0.79-0.86), specificity 0.92 (95% CI 0.90-0.94)). Automated readers had significantly better sensitivity (0.94 (0.91 0.97) (p <= .001 in each case), but worse specificity 0.78 (0.69-0.85). Similar results were gained using self-tested urine samples compared to staff-testing using a reference standard of laboratory urine protein-creatinine ratio (uPCR). Women who completed the online survey with experience of self-testing (n = 39, 20%) generally found it easy, and with support from healthcare professionals felt it improved involvement in their care and reduced anxiety. CONCLUSIONS: Self testing for proteinuria by pregnant women had similar accuracy to healthcare professional testing and was acceptable to both groups. Self-testing of urine combined with self-monitoring of blood pressure could provide a useful adjunct to clinic-based surveillance for the detection of pre-eclampsia. Such novel strategies warrant further research. PMID- 29242048 TI - Simplified immobilisation method for histidine-tagged enzymes in poly(methyl methacrylate) microfluidic devices. AB - Poly(methyl methacrylate) (PMMA) microfluidic devices have become promising platforms for a wide range of applications. Here we report a simple method for immobilising histidine-tagged enzymes suitable for PMMA microfluidic devices. The 1-step-immobilisation described is based on the affinity of the His-tag/Ni-NTA interaction and does not require prior amination of the PMMA surface, unlike many existing protocols. We compared it with a 3-step immobilisation protocol involving amination of PMMA and linking NTA via a glutaraldehyde cross-linker. These methods were applied to immobilise transketolase (TK) in PMMA microfluidic devices. Binding efficiency studies showed that about 15% of the supplied TK was bound using the 1-step method and about 26% of the enzyme was bound by the 3-step method. However, the TK-catalysed reaction producing l-erythrulose performed in microfluidic devices showed that specific activity of TK in the device utilising the 1-step immobilisation method was approximately 30% higher than that of its counterpart. Reusability of the microfluidic device produced via the 1-step method was tested for three cycles of enzymatic reaction and at least 85% of the initial productivity was maintained. The device could be operated for up to 40 h in a continuous flow and on average 70% of the initial productivity was maintained. The simplified immobilisation method required fewer chemicals and less time for preparation of the immobilised microfluidic device compared to the 3-step method while achieving higher specific enzyme activity. The method represents a promising approach for the development of immobilised enzymatic microfluidic devices and could potentially be applied to combine protein purification with immobilisation. PMID- 29242049 TI - Rational library design by functional CDR resampling. AB - Successful antibody discovery relies on diversified libraries, where two aspects are implied, namely the absolute number of unique clones and the percentage of functional clones. Instead of pursuing the absolute quantity thresholded by current display technology, we have sought to maximize the effective diversity by improving functional clone percentage. With the combined effort of bioinformatics, structural biology, molecular immunology and phage display technology, we devised a bioinformatic pipeline to construct and validate libraries via combinatorial assembly of sequences from a database of experimentally validated antibodies. Furthermore, we showed that the libraries constructed as such yielded a significantly increased success rate against different antigen types and generated over 20-fold more unique hits per targets compared with libraries based on traditional degenerate nucleotide methods. Our study indicated that predefined CDR sequences with optimized CDR-framework compatibility could be a productive direction of functional library construction for in vitro antibody development. PMID- 29242051 TI - Bamboo Nodes on a Series of 15 Patients: Vocal Fold Lesion as a Sign of Autoimmune Disease and Microphonotrauma. AB - OBJECTIVES: Bamboo nodes are band-like submucosal deposits of the middle third of the vocal fold. They are often related to connective tissue disorders, but can also precede them. The aim of this study was to report our experience with conservative treatment of those rare lesions. METHODS: This is a retrospective series of 15 patients consulting for hoarseness and presenting bamboo nodes from 2010 to 2016. RESULTS: All patients were women of mean age of 38 years with a moderate or high degree of daily vocal effort. Nine patients (60%) presented with known autoimmune disease at the phoniatric appointment. The other patients (40%) benefited from a systematic biological research for autoimmune disease, which retrieved two poorly symptomatic connective tissue disorders. Patients were clinically improved by speech therapy (53%) or by an optimization or introduction of immunosuppressive treatment (46%). A spontaneous improvement was observed for three patients after voice rest (one after retirement, one after professional change, and last one after resuming professional singing). In our series, no phonosurgery was performed. The vocal profile at last appointment found a moderate Voice Handicap Index at 35.3/120, a low maximum time of phonation at 13.6 seconds, and a high jitter at 1.4, sign of instability of the vibrator. CONCLUSION: This series emphasizes the importance of diagnosing bamboo nodes in middle-aged female presenting an autoimmune disease. Vice versa for each patient with bamboo nodes, a systematic autoimmune check-up has to be realized to detect a biological asymptomatic autoimmune disease. PMID- 29242050 TI - Mutant FGFR3 associated with SADDAN disease causes cytoskeleton disorganization through PLCgamma1/Src-mediated paxillin hyperphosphorylation. AB - K650M/E substitutions in the Fibroblast growth factor receptor 3 (FGFR3) are associated with Severe Achondroplasia with Developmental Delay and Acanthosis Nigricans (SADDAN) and Thanatophoric Dysplasia type II (TDII), respectively. Both SADDAN and TDII present with affected endochondral ossification marked by impaired chondrocyte functions and growth plate disorganization. In vitro, K650M/E substitutions confer FGFR3 constitutive kinase activity leading to impaired biosynthesis and accumulation of immature receptors in endoplasmic reticulum (ER)/Golgi. From those compartments, both SADDAN-FGFR3 and TDII-FGFR3 receptors engender uncontrolled signalling, activating PLCgamma1, signal transducer and activator of transcription 1, 3 and 5 (STAT1/3/5) and ERK1/2 effectors. Here, we investigated the impact of SADDAN-FGFR3 and TDII-FGFR3 signalling on cytoskeletal organization. We report that SADDAN-FGFR3, but not TDII-FGFR3, affects F-actin organization by inducing tyrosine hyperphosphorylation of paxillin, a key regulator of focal adhesions and actin dynamics. Paxillin phosphorylation was upregulated at tyrosine 118, a functional target of Src and FAK kinases. By using Src-deficient cells and a Src kinase inhibitor, we established a role played by Src activation in paxillin hyperphosphorylation. Moreover, we found that SADDAN-FGFR3 induced FAK phosphorylation at tyrosines 576/577, suggesting its involvement as a Src co activator in paxillin phosphorylation. Interestingly, paxillin hyperphosphorylation by SADDAN-FGFR3 caused paxillin mislocalization and partial co-localization with the mutant receptor. Finally, the SADDAN-FGFR3 double mutant unable to bind PLCgamma1 failed to promote paxillin hyperphosphorylation, pointing to PLCgamma1 as an early player in mediating paxillin alterations. Overall, our findings contribute to elucidate the molecular mechanism leading to cell dysfunctions caused by SADDAN-FGFR3 signalling. PMID- 29242052 TI - Endoscopic and Phoniatric Evaluation in Singing Students. AB - OBJECTIVES: In To analyze laryngostroboscopic findings and ENT/phoniatric examination results in a group of singing students and in a control group of non singing subjects to emphasize the importance of ENT/phoniatric examination and of laryngostroboscopy before taking up singing. METHODS: 56 singing students and 60 healthy euphonic non-singer volunteers were recruited. In each subject a perceptual assessment and a self-assessment (VHI) of the voice were performed. The singing students filled out the Singing-VHI. All subjects underwent flexible fiberoptic endoscopy and laryngostroboscopy. All subjects were evaluated through the Reflux Symptom Index (RSI) and the Reflux Finding Score (RFS). RESULTS: At laryngostroboscopy, 60.7% of students presented pathological findings, versus 20% of controls (P < 0.0001). Incomplete glottic closure (35.7% vs. 13.3%), supraglottic hypertonus (16.1% vs. 5%), organic lesions (bilateral nodules, cysts, sulcus vergeture) (17.9% vs. 3.3%), posterior erythema (16.1% vs. 5%) and laryngeal edema (14.3% vs 3.3%) were more frequent in the students. The most common symptoms in singers were phonasthenia (37.5 % vs 6.7%; P = 0.0001) and mucus sensation (17.9% vs. 5%, P = 0.03). S-VHI showed higher values in students with pathological laryngostroboscopy (P < 0.0001). Finally, average RSI and RFS were higher in students. CONCLUSIONS: Due to the high percentage of organic and functional voice disorders in singing students, it would be desirable that every subject who is going to start singing underwent an ENT/phoniatric investigation with videostrobolaryngoscopy to ascertain vocal folds healthy condition. PMID- 29242053 TI - Automatic activation mapping and origin identification of idiopathic outflow tract ventricular arrhythmias. AB - PURPOSE: Activation mapping is used to guide ablation of idiopathic outflow tract ventricular arrhythmias (OTVAs). Isochronal activation maps help to predict the site of origin (SOO): left vs right outflow tract (OT). We evaluate an algorithm for automatic activation mapping based on the onset of the bipolar electrogram (EGM) signal for predicting the SOO and the effective ablation site in OTVAs. METHODS: Eighteen patients undergoing ablation due to idiopathic OTVAs were studied (12 with left ventricle OT origin). Right ventricle activation maps were obtained offline with an automatic algorithm and compared with manual annotation maps obtained during the intervention. Local activation time (LAT) accuracy was assessed, as well as the performance of the 10ms earliest activation site (EAS) isochronal area in predicting the SOO. RESULTS: High correlation was observed between manual and automatic LATs (Spearman's: 0.86 and Lin's: 0.85, both p<0.01). The EAS isochronal area were closely located in both map modalities (5.55 +/- 3.56mm) and at a similar distance from the effective ablation site (0.15+/-2.08mm difference, p=0.859). The 10ms isochronal area longitudinal/perpendicular diameter ratio measured from automatic maps showed slightly superior SOO identification (67% sensitivity, 100% specificity) compared with manual maps (67% sensitivity, 83% specificity). CONCLUSIONS: Automatic activation mapping based on the bipolar EGM onset allows fast, accurate and observer-independent identification of the SOO and characterization of the spreading of the activation wavefront in OTVAs. PMID- 29242054 TI - Brugada phenocopy induced by severe pneumothorax. AB - A Brugada phenocopy has been defined as a clinical situation that presents with an abnormal electrocardiogram identical to any of the electrocardiographic patterns found in Brugada syndrome in the absence of the characteristic congenital genetic abnormalities. The first confirmed case of type 1 Brugada phenocopy associated with severe left pneumothorax is presented. A provocative test with ajmaline, which proved to be negative, was performed to confirm the diagnosis. The presence of ST-segment elevation in the context of pneumothorax is most infrequent. PMID- 29242056 TI - In search of the 'best' rapid response early warning system - The journey has just begun. PMID- 29242055 TI - Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Posttreatment in Rhesus Macaques. AB - Nonhuman primates currently serve as the best experimental model for Lyme disease because of their close genetic homology with humans and demonstration of all three phases of disease after infection with Borrelia burgdorferi. We investigated the pathology associated with late disseminated Lyme disease (12 to 13 months after tick inoculation) in doxycycline-treated (28 days; 5 mg/kg, oral, twice daily) and untreated rhesus macaques. Minimal to moderate lymphoplasmacytic inflammation, with a predilection for perivascular spaces and collagenous tissues, was observed in multiple tissues, including the cerebral leptomeninges, brainstem, peripheral nerves from both fore and hind limbs, stifle synovium and perisynovial adipose tissue, urinary bladder, skeletal muscle, myocardium, and visceral pericardium. Indirect immunofluorescence assays that combined monoclonal (outer surface protein A) and polyclonal antibodies were performed on all tissue sections that contained inflammation. Rare morphologically intact spirochetes were observed in the brains of two treated rhesus macaques, the heart of one treated rhesus macaque, and adjacent to a peripheral nerve of an untreated animal. Borrelia antigen staining of probable spirochete cross sections was also observed in heart, skeletal muscle, and near peripheral nerves of treated and untreated animals. These findings support the notion that chronic Lyme disease symptoms can be attributable to residual inflammation in and around tissues that harbor a low burden of persistent host-adapted spirochetes and/or residual antigen. PMID- 29242057 TI - Quality of audio-assisted versus video-assisted dispatcher-instructed bystander cardiopulmonary resuscitation: A systematic review and meta-analysis. AB - AIM: This study aimed to conduct a systematic review and meta-analysis comparing the effect of video-assistance and audio-assistance on quality of dispatcher instructed cardiopulmonary resuscitation (DI-CPR) for bystanders. METHODS: Five databases were searched, including PubMed, Cochrane library, Embase, Scopus and NIH clinical trial, to find randomized control trials published before June 2017. Qualitative analysis and meta-analysis were undertaken to examine the difference between the quality of video-instructed and audio-instructed dispatcher instructed bystander CPR. RESULTS: The database search yielded 929 records, resulting in the inclusion of 9 relevant articles in this study. Of these, 6 were included in the meta-analysis. Initiation of chest compressions was slower in the video-instructed group than in the audio-instructed group (median delay 31.5 s; 95% CI: 10.94-52.09). The difference in the number of chest compressions per minute between the groups was 19.9 (95% CI: 10.50-29.38) with significantly faster compressions in the video-instructed group than in the audio-instructed group (104.8 vs. 80.6). The odds ratio (OR) for correct hand positioning was 0.8 (95% CI: 0.53-1.30) when comparing the audio-instructed and video-instructed groups. The differences in chest compression depth (mm) and time to first ventilation (seconds) between the video-instructed group and audio-instructed group were 1.6 mm (95% CI: -8.75, 5.55) and 7.5 s (95% CI: -56.84, 71.80), respectively. CONCLUSIONS: Video-instructed DI-CPR significantly improved the chest compression rate compared to the audio-instructed method, and a trend for correctness of hand position was also observed. However, this method caused a delay in the commencement of bystander-initiated CPR in the simulation setting. PMID- 29242058 TI - Endovascular cooling versus standard femoral catheters and intravascular complications: A propensity-matched cohort study. AB - BACKGROUND: Targeted temperature management (TTM) contributes to improved neurological outcome in adults who have been successfully resuscitated after cardiac arrest with shockable rhythm. Endovascular cooling catheters are widely used to induce and maintain targeted temperature in the ICU. The aim of the study was to compare the risk of complications with cooling catheters and standard central venous catheters. MATERIALS AND METHODS: In this prospective single centre cohort study, we included all patients admitted to an intensive care unit for successfully resuscitated cardiac arrest that required endovascular TTM (Coolgard(r), ZollTM Medical corporation, MA, USA), between August 2012 and November 2014, inclusive. We matched the endovascular cooling catheter cohort with a retrospective historical cohort of 512 central femoral venous catheters from the 3SITES trial to compare thrombotic and infectious complications. RESULTS: Overall, 108 patients were included in the cooling cohort, of which 89 had ultrasound doppler. The duration of catheterization was 4.9 days in the control group versus 4.2 days in the TTM group (p = 0.08). After propensity-score matching, there were significantly more thrombotic complications in the cooling (n = 75) than in the control (n = 75) group (12 of 75 (16%) versus 0 of 75 (0%), respectively, p = 0.005), and 4 patients presented major complications. There were 8 colonized catheters in each group (11%) (p > 0.99), and none of the patients had a catheter-related bloodstream infection. CONCLUSIONS: In our propensity-score matched study, endovascular cooling catheters were associated with an increased risk of venous catheter-related thrombosis compared to standard central venous catheters. PMID- 29242059 TI - Usefulness of underwater endoscopic submucosal dissection in saline solution with a monopolar knife for colorectal tumors (with videos). AB - BACKGROUND AND AIMS: Generally, colorectal endoscopic submucosal dissection (ESD) is performed with a monopolar knife with CO2 supply from an endoscope. There are few case reports about underwater ESD (UESD) in saline solution with a bipolar knife. The usefulness and safety of UESD in saline solution with a monopolar knife are unclear. The present study aimed to investigate the usefulness and safety of UESD in saline solution with a monopolar knife for colorectal tumors. METHODS: This retrospective, observational study on UESD for colorectal tumors included 26 colorectal tumors from 24 patients treated with UESD at our department between October 2015 and February 2017. The characteristics of patients, factors associated with ESD difficulty, treatment results, and variations in blood test data before and after UESD were analyzed. RESULTS: En bloc resection was successful in all lesions without any serious adverse events. The median major diameter of the resected specimens was 30 mm (interquartile range [IQR], 28-35) and of the tumor 22.5 mm (IQR, 17.8-25.3). The median procedure time was 60 minutes (IQR, 45-111) and median speed of dissection 10.4 mm2/min (IQR, 6.4-12.2). No cases of perforation occurred. Post-ESD bleeding occurred in only 1 case, and endoscopic hemostasis was achieved. There was no case of electrolyte imbalance requiring treatment after UESD. CONCLUSIONS: UESD in saline solution with a monopolar knife for colorectal tumors is useful and safe. UESD has potential advantages that should be further assessed. PMID- 29242060 TI - Higher Programmatic Volume in Neonatal Heart Surgery Is Associated With Lower Early Mortality. AB - BACKGROUND: The early results of congenital heart surgery in neonates remain a challenge. We sought to determine the nature of the association between annual center volume of neonatal cardiac surgery and operative mortality using a multicenter cohort. METHODS: The dataset consists of 27,556 neonatal procedures performed between 1999 and 2015 in 90 centers participating in the European Congenital Heart Surgeons Association database. Centers with mean annual volume load of six or more that submitted data for at least 3 consecutive years were included. World Bank annual gross national index per capita was utilized as an indicator of temporal national affluence. Multilevel logistic regression was used to create a model including the significant risk factors and to calculate odds ratios for operative mortality. Iterative modeling of the dataset incrementally excluding centers with lower annual caseload was used to identify the relationship between annual volume and mortality. RESULTS: In the model thus calculated including The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) mortality score, operative weight and age, noncardiac genetic anomalies, and annual volume of operations were independent risk factors for operative mortality in the analysis of the entire cohort. In the model containing these variables, annual gross national index and year of surgery were not significantly associated with mortality. In the iterative process, annual volume ceased to be a risk factor when units operating on fewer than 60 neonates annually were excluded. CONCLUSIONS: In neonatal congenital heart surgery, the risk of operative death decreased with the increase of volume load. The cutoff point in this cohort was a mean annual volume of 60 neonatal operations per year. PMID- 29242061 TI - Phosphorylation of Ser-525 in betaPix impairs Nox1-activating ability in Caco-2 cells. AB - betaPix activates Nox1, an O2--generating NADPH oxidase, through Rac activation. In this study, we found that S525E mutation of betaPix eliminated its Nox1 activating ability in transfected Caco-2 cells. Unexpectedly, affinity for Rac was not diminished but rather enhanced by S525E mutation, and guanine nucleotide exchange factor (GEF) activity was not altered. The N-terminal fragment (amino acids 1-400) showed similar Rac-binding and GEF activity to wild-type betaPix. In contrast, the C-terminal fragment (amino acids 408-646) had higher Rac-binding activity, particularly for Rac-GTP, than wild-type betaPix, and showed no GEF activity. These data suggest that a second Rac-binding site within the C-terminal region is opened by phosphorylation of Ser-525. The site may bind not only Rac GDP but also Rac-GTP released from the N-terminal catalytic region, which interrupts Rac-GTP translocation to the membrane where Nox1 resides. If one considers that S340E mutation enhances Nox1 activation (Kaito et al., 2014), the present study suggests that betaPix can also play an inhibitory role in O2- production, depending on the sites of phosphorylation. PMID- 29242062 TI - Rationale and design of the SAIL trial for intramuscular injection of allogeneic mesenchymal stromal cells in no-option critical limb ischemia. AB - BACKGROUND: Critical limb ischemia (CLI) represents the most severe form of peripheral artery disease and has an immense impact on quality of life, morbidity, and mortality. A considerable proportion of CLI patients are ineligible for revascularization, leaving amputation as the only option. Mesenchymal stromal cells (MSCs), because of their vasculoregenerative and immunomodulatory characteristics, have emerged as a potential new treatment. METHODS: The primary objective of this trial is to investigate whether intramuscular administration of allogeneic bone marrow (BM)-derived MSCs is safe and potentially effective. The SAIL (allogeneic mesenchymal Stromal cells for Angiogenesis and neovascularization in no-option Ischemic Limbs) trial is a double-blind, placebo-controlled randomized clinical trial to investigate the effect of allogeneic BM-MSCs in patients with CLI who are not eligible for conventional revascularization. A total of 66 patients will be included and randomized (1:1) to undergo 30 intramuscular injections with either BM-MSCs (5 * 106 MSCs per injection) or placebo in the ischemic lower extremity. Primary outcome, that is, therapy success, a composite outcome consisting of mortality, limb status, clinical status, and changes in pain score, will be assessed at 6 months. All study-related procedures will take place in the University Medical Center Utrecht in The Netherlands. CONCLUSIONS: If our results indicate that intramuscular allogeneic BM-MSC therapy for CLI is safe and potentially effective, this will have important consequences for treatment of patients with CLI. A large multicenter clinical trial with longer follow-up focusing on hard end points should then be initiated to confirm these findings. PMID- 29242063 TI - Simple classification and clinical outcomes of angiographic dissection after balloon angioplasty for femoropopliteal disease. AB - OBJECTIVE: Angiographic dissection is considered to be associated with restenosis. However, little is known about the impact of the severity of angiographic dissection on future restenosis. METHODS: A total of 319 consecutive de novo femoropopliteal lesions were treated by balloon angioplasty alone. All of these lesions were divided into three groups: group A, no angiographic dissection; group B, mild dissection, the width of the dissection was less than one-third of the lumen; and group C, severe dissection, the width of the dissection was more than one-third of the lumen. Kaplan-Meier analysis estimated the primary patency rate at 3 years between the groups. RESULTS: The primary patency rates at 3 years were 66.0% in group A, 63.8% in group B, and 32.5% in group C (log-rank, P < .001). Cox proportional hazards analysis revealed that a lesion length >100 mm (hazard ratio, 1.734; 95% confidence interval, 1.099-2.735; P = .018) and severe angiographic dissection (hazard ratio, 1.956; 95% confidence interval, 1.276-2.997; P = .002) were predictors of primary patency loss at 3 years. When the lesions were divided into two groups according to the lesion length >100 mm or not, angiographic dissection had a larger impact on restenosis in a long lesion >100 mm (<=100 mm: 65.5% in group A, 75.6% in group B, and 48.0% in group C [log-rank, P = .015]; >100 mm: 68.8% in group A, 42.5% in group B, and 24.2% in group C [log-rank, P = .017]). CONCLUSIONS: Severe angiographic dissection was associated with future restenosis after balloon angioplasty for femoropopliteal lesions, but mild angiographic dissection was not. Angiographic dissection had more impact on future restenosis particularly in treated long lesions. Stents might not be necessary in short lesions with mild dissection. PMID- 29242064 TI - Hypoxia-inducible factor 1 in clinical and experimental aortic aneurysm disease. AB - OBJECTIVE: Mural angiogenesis and macrophage accumulation are two pathologic hallmarks of abdominal aortic aneurysm (AAA) disease. The heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) is an essential regulator of angiogenesis and macrophage function. In this study, we investigated HIF-1 expression and activity in clinical and experimental AAA disease. METHODS: Human aortic samples were obtained from 24 AAA patients and six organ donors during open abdominal surgery. Experimental AAAs were created in 10-week-old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase (PPE). Expression of HIF-1alpha and its target gene messenger RNA (mRNA) levels were assessed in aneurysmal and control aortae. The HIF-1alpha inhibitors 2 methoxyestradiol and digoxin, the prolyl hydroxylase domain-containing protein (PHD) inhibitors cobalt chloride and JNJ-42041935, and the vehicle alone as control were administered daily to mice at varying time points beginning before or after PPE infusion. Influences on experimental AAA formation and progression were assessed by serial transabdominal ultrasound measurements of aortic diameter and histopathologic analysis at sacrifice. RESULTS: The mRNA levels for HIF 1alpha, vascular endothelial growth factor A, glucose transporter 1, and matrix metalloproteinase 2 were significantly increased in both human and experimental aneurysm tissue. Tissue immunostaining detected more HIF-1alpha protein in both human and experimental aneurysmal aortae compared with respective control aortae. Treatment with either HIF-1alpha inhibitor, beginning before or after PPE infusion, prevented enlargement of experimental aneurysms. Both HIF-1alpha inhibition regimens attenuated medial elastin degradation, smooth muscle cell depletion, and mural angiogenesis and the accumulation of macrophages, T cells, and B cells. Whereas mRNA levels for PHD1 and PHD2 were elevated in experimental aneurysmal aortae, pharmacologic inhibition of PHDs had limited effect on experimental aneurysm progression. CONCLUSIONS: Expression of HIF-1alpha and its target genes is increased in human and experimental AAAs. Treatment with HIF 1alpha inhibitors limits experimental AAA progression, with histologic evidence of attenuated mural leukocyte infiltration and angiogenesis. These findings underscore the potential significance of HIF-1alpha in aneurysm pathogenesis and as a target for pharmacologic suppression of AAA disease. PMID- 29242065 TI - Preliminary results of endovascular aneurysm sealing from the multicenter Italian Research on Nellix Endoprosthesis (IRENE) study. AB - OBJECTIVE: Because of advances in technology and experience of the operator, endovascular aneurysm repair (EVAR) has supplanted open repair to treat abdominal aortic aneurysm (AAA). The low 30-day mortality and morbidity of EVAR make the endovascular approach particularly suitable for patients at high surgical risk. However, endoleak or endograft migration requiring secondary intervention or open surgical conversion is a limitation of EVAR. The Nellix system (Endologix, Inc, Irvine, Calif) has been designed to seal the entire AAA to overcome these limitations with EVAR. We report the results of a retrospective, multicenter study with endovascular aneurysm sealing (EVAS) aimed to assess technical success, procedure-related mortality, complications, and reinterventions. METHODS: This study included patients selected for elective treatment with the Nellix device per the endovascular repair protocol at 16 Italian vascular centers. All patients were enrolled in a postoperative surveillance imaging program including duplex ultrasound investigations, computed tomography, and magnetic resonance controls following local standards of care. RESULTS: From 2013 to 2015, there were 335 patients (age, 75.5 +/- 7.4 years; 316 men) who underwent elective EVAS. In 295 cases (88.0%), EVAS was performed under standard instructions for use of the Nellix system. Preoperative aneurysm diameter was 55.5 +/- 9.4 mm (range, 46-65 mm). The inferior mesenteric artery and lumbar arteries emerging from the AAA were patent in 61.8% and 81.3% of cases, respectively. Chimney grafts were electively carried out in eight cases (2.4%). One (0.3%) intraprocedural type IB endoleak was observed and promptly corrected. Device deployment was successful in all patients, with no perioperative mortality. Early (<=30 days) complications included 1 (0.3%) type IA endoleak, 2 (0.6%) type II endoleaks (0.6%), 2 (0.6%) stent occlusions (0.6%), 3 (0.9%) distal embolizations, and 2 (0.2%) femoral artery dissections. Six (2.9%) patients underwent reinterventions. At 1-year follow-up, complications included 3 (1.1%) type II endoleaks, 4 (1.4%) type IA endoleaks, 1 (0.3%) type IB endoleak, 2 (0.7%) distal stent migrations, 5 (1.8%) distal embolizations, and 1 (0.3%) stent occlusion. Twelve patients (3.7%) underwent reinterventions, including four (1.4%) surgical conversions due to aortoduodenal fistula (1), endograft infection (1), and type IA endoleak that was unsuccessfully treated percutaneously (2). Two AAA-related deaths occurred. Freedom from aneurysm-related reintervention was 98.3% at 1-month and 94.7% at 12-month follow-up. CONCLUSIONS: The preliminary results of this real-world multicenter study showed that EVAS with Nellix for the management of AAAs appears feasible. This device platform is associated with acceptable procedure-related mortality and low overall complication and reintervention rates. Definitive conclusions on the value of this novel device await long-term follow-up data. PMID- 29242066 TI - External polytetrafluoroethylene reinforcement of varicose autologous vein grafts in peripheral bypass surgery produces durable bypass function. AB - OBJECTIVE: Use of autologous veins as peripheral bypass graft may become critical in the presence of significant varicose degeneration of the harvested vein. External support of such dilated veins with standard polytetrafluoroethylene (PTFE) prostheses was recommended as an option to use these veins for peripheral bypass. A single-center experience with this technique regarding long-term graft function, secondary reinterventions, and potential graft degeneration is presented. METHODS: Between January 1995 and January 2006, there were 54 patients with varicose veins who underwent 57 consecutive infrainguinal vein bypass operations with PTFE reinforcement in 57 limbs. Indications for surgery consisted of disabling claudication (5), chronic critical ischemia (40), popliteal aneurysm (11), and acute ischemia (1). Grafts were observed with duplex ultrasound scan supplemented by additional angiography in case of recurrent ischemia, with prospective documentation of follow-up data in a computerized vascular database. Graft patency, limb salvage, and possible degeneration of the vein grafts were retrospectively analyzed. RESULTS: Mean follow-up was 79 months (range, 1-219 months). The 30-day mortality was 2%. Secondary procedures to maintain or to restore bypass patency were necessary in 12 grafts (21%). Primary, primary assisted, and secondary patency rates were 54%, 73%, and 73% after 5 years for all bypasses, with a limb salvage rate for limbs operated on for chronic critical or acute ischemia of 83%. Significant stenosis of a reinforced vein segment was detected in one case after 56 months, with subsequent replacement of the vein graft with a biologic vascular prosthesis. CONCLUSIONS: Good late graft patency and limb salvage combined with a low rate of late vein graft degeneration justify the use of external PTFE reinforcement of varicose vein segments in infrainguinal bypass surgery. PMID- 29242067 TI - Severe contralateral carotid stenosis or occlusion does not have an impact on risk of ipsilateral stroke after carotid endarterectomy. AB - OBJECTIVE: This study evaluates the impact of severe (>70%) contralateral carotid stenosis or occlusion (SCSO) on outcomes after carotid endarterectomy (CEA). METHODS: Clinical data for all patients undergoing CEA at a single center were prospectively gathered and retrospectively reviewed, with the sample population stratified according to the presence of SCSO. Perioperative outcomes of CEA in the presence of SCSO were analyzed using univariate and multivariate methods. RESULTS: During a 17-year study period, 2945 CEAs were performed on 1843 patients, including 736 (25%) patients with SCSO. Patients identified with SCSO had a higher rate of positive intraoperative electroencephalographic changes (30% vs 16%; P < .0001) and use of an intraoperative shunt (40% vs 28%; P < .0001). Univariate analysis identified SCSO as a risk factor for any stroke (2.8% vs 1.5%; P = .02), death (2.2% vs 1.1%; P = .02), and any stroke/death (4.3% vs 2.4%; P < .0079) but not ipsilateral stroke (1.5% vs 1.2%; P = .38). Multivariable regression demonstrated SCSO as an independent predictor of any stroke (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.0-3.3; P = .05) and any stroke/death (OR, 1.7; 95% CI, 1.1-2.7; P = .02), without increasing risk of ipsilateral stroke (OR, 1.3; 95% CI, 0.6-2.7; P = .54). The presence of SCSO was also associated with a higher risk of late mortality (hazard ratio, 1.3; 95% CI, 1.1-1.4; P < .01). CONCLUSIONS: Although the presence of SCSO is a risk factor for any stroke/death with CEA, it does not increase the risk of ipsilateral stroke. These data suggest that increased attention to perioperative medical and hemodynamic management should be especially considered in this cohort of patients as the observed strokes do not occur in the territory at risk from the surgical procedure. PMID- 29242068 TI - Hybrid repair of abdominal aortic aneurysm in a patient with poliomyelitis related deformities. AB - A 63-year-old man presented with an asymptomatic infrarenal abdominal aortic aneurysm. He had scoliosis and atrophic right leg change as sequelae of poliomyelitis. The patient was not a candidate for endovascular aneurysm repair because of anatomic unsuitability. An open surgical repair was performed by the retroperitoneal approach because of severe scoliosis and left lateral aneurysm deviation. To minimize contralateral exposure, the Viabahn stent graft (W. L. Gore & Associates, Flagstaff, Ariz) was inserted in the right external iliac artery and anastomosed with the right expanded polytetrafluoroethylene graft limb. I report the successful hybrid repair of infrarenal abdominal aortic aneurysm using the modified Viabahn open revascularization technique. PMID- 29242069 TI - Large-vessel vasculitis in human immunodeficiency virus-infected patients. AB - OBJECTIVE: The objective of this study was to describe large-vessel vasculitis (LVV) in patients with human immunodeficiency virus (HIV) infection. It is a retrospective single-center study conducted between 2000 and 2015 through a university hospital of 11 HIV-infected patients with LVV. METHODS: The characteristics and outcome of 11 HIV-infected patients with LVV (7 patients fulfilled international criteria for Takayasu arteritis, 5 patients had histologic findings of vasculitis, and 5 patients had imaging features of aortitis) were analyzed and compared with those of 82 patients with LVV but without HIV infection. RESULTS: Concerning the HIV-infected patients with LVV (n = 11), the mean age was 40 years (range, 36-56 years), and 55% of patients were female. At diagnosis of LLV, the mean initial CD4 cell count was 455 cells/mm3 (range, 166-837 cells/mm3), and the median HIV viral load was 9241 copies. Vascular lesions were located in the aorta (n = 7), in supra-aortic trunks (n = 7), and in digestive arteries (n = 3). Inflammatory aorta infiltrates showed a strong expression of interferon-gamma and interleukin 6. In HIV-negative LVV patients (n = 82), the median age was 42 years, and 88% of the patients were women. Thirty patients had an inflammatory syndrome. Seventy patients had been treated with glucocorticosteroids and 57 with immunosuppressive treatments. Compared with their negative counterparts, HIV-positive patients with LVV were more frequently male (P = .014), had more vascular complications (ie, Ishikawa score; P = .017), and had more frequent revascularization (P = .047). After a mean follow-up of 96 months, four relapses of vasculitis were reported, and one patient died. Regardless of the HIV virologic response, antiretroviral therapy improved LVV in only one case. CONCLUSIONS: LVV in HIV-infected patients is a rare and severe entity. PMID- 29242070 TI - Anesthetic type and hospital outcomes after carotid endarterectomy from the Vascular Quality Initiative database. AB - OBJECTIVE: Studies on the safety of carotid endarterectomy (CEA) under different anesthetic techniques are sometimes contradictory. The aim of this study was to compare real-world outcomes of CEA under general anesthesia (GA) vs regional or local anesthesia (RA/LA). METHODS: A retrospective analysis of the Vascular Quality Initiative database (2003-2017) was performed. Primary outcomes included perioperative stroke, death, and myocardial infarction (MI) occurring during the hospital stay. Univariate and multivariate analyses were used. To minimize selection bias and to evaluate comparable groups, patients were matched on baseline variables using coarsened exact matching. RESULTS: Of 75,319 CEA cases, 6684 (8.9%) were performed under RA/LA. These patients were more likely to be older (median age, 72 vs 71 years) and male (62.5% vs 60.2%), with higher American Society of Anesthesiologists class (class 3-5, 94.2% vs 93.0%) than those undergoing CEA-GA (all P < .001). CEA-GA had higher crude rates of in hospital cardiac outcomes including MI mainly diagnosed clinically or on electrocardiography (0.5% vs 0.2%; P = .01), dysrhythmia (1.6% vs 1.2%; P < .001), acute congestive heart failure (CHF; 0.5% vs 0.2%; P < .001), and hemodynamic instability (27.0% vs 20.0%; P < .001) compared with CEA-RA/LA. No difference in perioperative stroke or death was seen between the two groups. On multivariate analysis, CEA-GA was associated with twice the odds of in-hospital MI (adjusted odds ratio [aOR], 1.95; 95% confidence interval [CI], 1.06-3.59; P = .03), 4 times the odds of acute CHF (aOR, 3.92; 95% CI, 1.84-8.34; P < .001), and 1.5 times the odds of hemodynamic instability (aOR, 1.54; 95% CI, 1.44-1.66; P < .001). Patients undergoing CEA-GA had 1.8 times the odds of staying in the hospital for >1 day (aOR, 1.80; 95% CI, 1.67-1.93; P < .001). Coarsened exact matching confirmed our results. Risk factors associated with increased cardiac complications (MI and CHF) under GA included female gender, increased age, Medicaid insurance, history of smoking, medical comorbidities (such as hypertension, diabetes, coronary artery disease, and CHF), prior ipsilateral carotid intervention, and urgent/emergent procedures. CONCLUSIONS: Patients undergoing CEA under GA have higher odds of postoperative MI, acute CHF, and hemodynamic instability compared with those undergoing CEA under RA/LA. They are also more likely to stay in the hospital for >1 day. However, the overall risk of cardiac adverse events after CEA was low, which made the differences clinically irrelevant. The choice of anesthesia approach to CEA should be driven by the team's experience and the patient's risk factors and preference. PMID- 29242071 TI - Impact of acute postoperative limb ischemia after cardiac and thoracic aortic surgery. AB - OBJECTIVE: Acute limb ischemia (ALI) is the cause of significant morbidity and mortality. Although ALI after cardiac surgery is associated with high rates of morbidity and mortality, there are no robust, controlled analyses of the risk factors and outcomes of ALI in this setting. We aimed to identify risk factors for and to delineate outcomes after ALI in patients undergoing cardiac surgery. METHODS: We performed a retrospective review of prospectively collected data on patients undergoing cardiac surgery at our institution between 2002 and 2012. RESULTS: Between 2002 and 2012, there were 11,343 patients who underwent major open cardiac surgery, with 156 cases of ALI for an incidence of 1.4%. In a multivariable model, significant risk factors for ALI included body surface area (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.18-0.92), current smoking status (OR, 2.2; 95% CI, 1.3-3.7), peripheral arterial disease (OR, 2.5; 95% CI, 1.6-3.7), nonelective operative status (OR, 1.9-5.0; 95% CI, 1.2-19.7), use of extracorporeal membrane oxygenation (OR, 5.6; 95% CI, 2.5-11.6) or intra-aortic balloon pump (OR, 4.7; 95% CI, 2.9-7.5), and valve operation (OR, 2.1; 95% CI, 1.1-4.0). There were 105 (67%) patients who developed ALI who required an operation, and 27 (17%) required an amputation on the index admission. ALI was associated with a significant reduction in long-term survival (hazard ratio, 3.72; 95% CI, 2.97-4.65; P < .0001). CONCLUSIONS: ALI is associated with significant morbidity and mortality, and it is also associated with reduced long term survival. Those patients with the risk factors described require extra vigilance to limit the risk of ALI and should be managed in accordance with the patient's overall clinical condition and goals of care. PMID- 29242072 TI - Therapeutic angiogenesis by local sustained release of microRNA-126 using poly lactic-co-glycolic acid nanoparticles in murine hindlimb ischemia. AB - OBJECTIVE: Recent studies demonstrate that microRNAs show promising potential, including angiogenesis, in therapeutic intervention. MicroRNA-126 (miR-126) is reported to regulate angiogenesis by blocking Sprouty-related EVH1 domain containing protein 1 (SPRED1), an endogenous inhibitor of vascular endothelial cell growth factor. In this study, we investigated the angiogenic effects of the sustained release of miR-126 loaded with poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) in a murine hindlimb ischemia model. METHODS: We induced mice hindlimb ischemia through femoral artery excision. We randomly assigned the mice to two groups and performed an intramuscular injection of miR-126-loaded PLGA NPs (miR-126) or scrambled miR-loaded PLGA NPs (control) shortly after induction of ischemia. RESULTS: The miR-126 expression levels in the ischemic limb at 3 days after treatment were significantly higher in mice treated with miR-126-loaded PLGA NPs than in those with scrambled miR, indicating the fair efficiency of local miR transduction (control vs miR-126: 0.33 +/- 0.12 vs 0.74 +/- 0.42; P < .05; n = 6). Laser Doppler perfusion imaging revealed that limb blood flow in mice treated with miR-126-loaded PLGA NPs was significantly higher at 14 days after treatment (sham vs control vs miR-126: 0.62 +/- 0.09 vs 0.58 +/- 0.05 vs 0.72 +/- 0.07; P < .001; n = 12). Immunohistochemical analysis indicated that CD31-positive cell density and alpha-smooth muscle actin-positive vessel density were significantly higher in miR-126-treated mice (control vs miR-126: 0.33 +/- 0.12 vs 0.74 +/- 0.42; P < .05; n = 6). SPRED1 messenger RNA expression levels were significantly lower in miR-126-treated mice (control vs miR-126: 1.00 +/- 0.05 vs 0.81 +/- 0.07; P < .05; n = 6). Western blotting indicated that protein levels of pERK/ERK mediated by SPRED1 were significantly higher in miR-126 treated mice (control vs miR-126: 0.29 +/- 0.10 vs 0.54 +/- 0.21; P < .05; n = 6). CONCLUSIONS: This study suggests that sustained release of miR-126-loaded PLGA NPs might be an effective method in therapeutic angiogenesis for hindlimb ischemia. PMID- 29242073 TI - Abbreviated atovaquone-proguanil prophylaxis regimens in travellers after leaving malaria-endemic areas: A systematic review. AB - BACKGROUND: We evaluated existing data on the prophylactic efficacy of atovaquone proguanil (AP) in order to determine whether prophylaxis in travellers can be discontinued on the day of return from a malaria-endemic area instead of seven days after return as per currently recommended post-travel schedule. METHODS: PubMed and Embase databases were searched to identify relevant studies. This PROSPERO-registered systematic review followed PRISMA guidelines. The search strategy included terms or synonyms relevant to AP combined with terms to identify articles relating to prophylactic use of AP and inhibitory and half-life properties of AP. Studies considered for inclusion were: randomized controlled trials, cohort studies, quasi-experimental studies, open-label trials, patient control studies, cross-sectional studies; as well as case-series and non-clinical studies. Data on study design, characteristics of participants, interventions, and outcomes were extracted. Primary outcomes considered relevant were prophylactic efficacy and prolonged inhibitory activity and half-life properties of AP. RESULTS: The initial search identified 1,482 publications, of which 40 were selected based on screening. Following full text review, 32 studies were included and categorized into two groups, namely studies in support of the current post-travel regimen (with a total of 2,866 subjects) and studies in support of an alternative regimen (with a total of 533 subjects). CONCLUSION: There is limited direct and indirect evidence to suggest that an abbreviated post travel regimen for AP may be effective. Proguanil, however, has a short half-life and is essential for the synergistic effect of the combination. Stopping AP early may result in mono-prophylaxis with atovaquone and possibly select for atovaquone resistant parasites. Furthermore, the quality of the studies in support of the current post-travel regimen outweighs the quality of the studies in support of an alternative short, post-travel regimen, and the total sample size of the studies to support stopping AP early comprises a small percentage of the total sample size of the studies performed to establish the efficacy of the current AP regimen. Additional research is required - especially from studies evaluating impact on malaria parasitaemia and clinical illness and conducted among travellers in high malaria risk settings - before an abbreviated regimen can be recommended in current practice. PROSPERO REGISTRATION NUMBER: CRD42017055244. PMID- 29242074 TI - Genome-wide identification and validation of new reference genes for transcript normalization in developmental and post-harvested fruits of Actinidia chinensis. AB - The appropriate reference genes are important and essential for reliable results of transcript normalization in real-time qRT-PCR. In the current study, we identified 1203 stably expressed genes from 35,286 genes' expression profiles in developmental fruits of Actinidia chinensis. We manually selected six candidate genes and assessed their expression levels, using two sets of fruit samples of A. chinensis: flesh fruits at four developmental stages and post-harvested fruits. The expression stability of these six genes was assessed by three independent algorithms: geNorm, NormFinder, and BestKeeper. Statistical results indicated these six genes can serve as internal control in both developmental and post harvested fruits. Among these genes, UBQ_CONJ_E2 (Ubiquitin-conjugating enzyme E2 36) and TUB_FCB (Tubulin folding cofactor B) were the two best reference genes identified in this study. The identification and validation of these reference genes can be helpful for elucidating the studies of fruit development and post harvested fruits' storage in A. chinensis and other fruit crops of Actinidiaceae. PMID- 29242075 TI - Molecular drug resistance profiles of Mycobacterium tuberculosis from sputum specimens using ion semiconductor sequencing. AB - The increasing burden of multidrug resistant (MDR)-TB, defined by resistance to rifampin (RFP) and isoniazid (INH), and extensively drug resistant-TB, defined by MDR-TB with additional resistance to fluoroquinolones (FQs) and more than one second-line injectable drug, is a serious impediment to global TB control. We evaluated the feasibility of full-length gene analysis including inhA, katG, rpoB, pncA, rpsL embB, eis, and gyrA using a semiconductor NGS with the Ion AmpliSeq TB panel to directly analyse 34 sputum specimens confirmed by phenotypic DST: INH, RFP, ethambutol (EMB), pyrazinamide (PZA), amikacin, kanamycin, streptomycin (SM), FQs including ofloxacin, moxifloxacin, and levofloxacin. The molecular drug resistance profiles showed "very good" and "substantial" strength of agreement for the phenotypic DST results of RFP and EMB, PZA, SM, FQs resistance with specificities of 96%, and 88%, 97%, 100% and sensitivities of 100%, and 88%, 60%, 67%, respectively. The strength of agreement for the detection of resistance to INH was "substantial", compared between katG mutation and phenotypic INH only. Ion semiconductor NGS could make possible detection of several uncommon or novel amino acid changes in the full coding regions of these eight genes. However, molecular drug resistant profile should be complemented and validated by subsequent phenotypic DST studies at the same time. PMID- 29242076 TI - Evaluation of colorimetric assays for determination of H2O2in planta during fungal wood decomposition. AB - Hydrogen peroxide (H2O2) plays a critical role in generating oxygen radicals as fungi attack and deconstruct plant cell walls. Its concentrations in planta, however, are often low during decomposition and evade detection by traditional methods. Here, we compared relevant methods and selected the best based on detection limits and selectivity. PMID- 29242078 TI - Reply to: "The PNPLA3 SNP rs738409:G allele is associated with increased liver disease-associated mortality but reduced overall mortality in a population-based cohort". PMID- 29242077 TI - Vaccine-type mutations identified in Varicella zoster virus passaged in cell culture. AB - Varicella-zoster virus (VZV) is a causative agent for chickenpox and shingles. Comparative genomic sequence analysis of clinical and vaccine strains suggested potential sites responsible for attenuation. In this study, low and high passages of two VZV clinical strains cultured in human fibroblast cells were compared for genomic DNA sequences and growth characteristics. Mutations were detected at 187 and 162 sites in the strain YC01 and YC02, respectively. More than 86% of mutations were found in open reading frames, and ORF62 exhibited highest frequency of mutations. T to C and A to G transitions accounted for more 90% of all possible substitutions. Forty mutations were common to two strains, including 27 in ORF62. Mutations found in attenuated vaccine strains were also detected at 7 positions. Both high and low passage strains were infectious and grew similarly in human fibroblast cells. In guinea pig cells, however, high passage strain remained infectious while low passage strain lost infectivity. This study may provide new insight into the attenuating mutations associated with in vitro passaging of VZV. PMID- 29242079 TI - The PNPLA3 SNP rs738409:G allele is associated with increased liver disease associated mortality but reduced overall mortality in a population-based cohort. PMID- 29242081 TI - A mass spectrometry based method and a software tool to assess degradation status of serum samples to be used in proteomics for biomarker discovery. PMID- 29242080 TI - Feasibility and Acceptability of Mindfulness for Survivors of Homicide and Their Providers. AB - PURPOSE: This study uses participatory research methods with survivors of homicide and their service providers to explore the feasibility and acceptability of a culturally adapted mindfulness intervention for stress reduction and resilience in homicide survivors. PROCEDURES: Our mixed methods approach included: (a) previewing a Mindfulness-Based Stress Reduction program with providers and survivors; (b) using their iterative feedback during focus groups to revise the curriculum; and (c) studying the acceptability of the adapted curriculum for survivors through focus group and standardized data collection. FINDINGS: We learned that providers use mindfulness for self-care and both providers and survivors view the approach for survivors as promising. Based on attendance, participation, and focus group data, the adapted curriculum was both feasible and acceptable. Survivors' reports suggested most experienced improved emotion regulation, feelings of empowerment, and better coping. CONCLUSIONS: Culturally adapted mindfulness programs may support healing for homicide survivors and possibly other low-income people of color with significant trauma backgrounds. Further investigation is needed to rigorously assess outcomes and specific effects, both positive and negative, of mindfulness in this and other more diversified populations. PMID- 29242083 TI - Medical abortion pills have the potential to change everything about abortion. PMID- 29242082 TI - Is a lower-dose, subcutaneous contraceptive injectable containing depot medroxyprogesterone acetate likely to impact women's risk of HIV? PMID- 29242084 TI - Predictors of timing of pregnancy discovery. AB - OBJECTIVE: Earlier pregnancy discovery is important in the context of prenatal and abortion care. We evaluated characteristics associated with later pregnancy discovery among women seeking abortion care. STUDY DESIGN: Data come from a survey of women seeking abortion care at four family planning facilities in Utah. The participants completed a survey during the state-mandated abortion information visit they are required to complete prior to having an abortion. The outcome in this study was pregnancy discovery before versus after 6 weeks since respondents' last menstrual period (LMP). We used logistic regression to estimate the relationship between sociodemographic and health-related independent variables of interest and pregnancy discovery before versus after 6 weeks. RESULTS: Among the 458 women in the sample, 28% discovered their pregnancy later than 6 weeks since LMP. Most (n=366, 80%) knew the exact date of their LMP and a significant minority estimated it (n=92, 20%). Those who estimated the date of their LMP had higher odds of later pregnancy discovery than those who knew the exact date (adjusted odds ratio (aOR)=1.81[1.07-3.07]). Those who used illicit drugs weekly, daily, or almost daily had higher odds of later pregnancy discovery (aOR=6.33[2.44, 16.40]). CONCLUSION: Women who did not track their menstrual periods and those who frequently used drugs had higher odds of discovering their pregnancies later. IMPLICATIONS: Women who estimated the date of their LMP and who frequently used drugs may benefit from strategies to help them recognize their pregnancies earlier and link them to care when they discover their pregnancies later. PMID- 29242085 TI - Self-assessment of medical abortion outcome using symptoms and home pregnancy testing. AB - OBJECTIVES: We aimed to evaluate compliance with a strategy to enable medical abortion patients to assess treatment outcome on their own and decide whether to seek clinical follow-up. STUDY DESIGN: We enrolled women undergoing medical abortion with mifepristone and misoprostol at three clinics in the United States. Each participant was instructed to perform a multilevel pregnancy test (MLPT) 7 days after mifepristone ingestion and to contact the clinic immediately if the test indicated a possible ongoing pregnancy or if specified symptoms occurred. A telephone call was scheduled 14 days after mifepristone ingestion to evaluate participants who had not contacted the clinic earlier. RESULTS: Of the 343 enrolled participants, 90 (26%) did not provide sufficient follow-up information for analysis of compliance with instructions. Of the 253 (74%) who did, 218 (86%) implemented the self-assessment strategy as instructed, 20 (7.9%) failed to report a non-reassuring MLPT result, 4 (1.6%) failed to promptly report symptoms that the study clinician subsequently judged to require evaluation, and 11 (4.3%) did not perform the MLPT. We ascertained abortion outcomes for 239 (70%) of the enrolled women, of whom three were diagnosed with ongoing pregnancies. One other participant was hospitalized for bleeding. All four women had implemented the strategy correctly. Of the 219 enrolled participants (64%) who provided opinions, 170 (78%) indicated that most could use the MLPT to decide whether they are "OK" after an abortion. We did not ascertain opinions from 124 enrolled participants (36%). CONCLUSIONS: At least two thirds of enrolled participants correctly implemented a strategy using symptom evaluation and a MLPT to assess their own medical abortion outcomes. No ongoing pregnancies occurred in women documented not to have implemented the strategy as intended. Perceived feasibility of the self-assessment approach was high. Implications Statement The common practice of scheduling a clinical contact after every medical abortion may not be necessary to ensure safety; enabling patients to determine for themselves whether or not a contact is needed can be a reasonable approach. PMID- 29242086 TI - Women's experiences of their preabortion ultrasound image printout. AB - OBJECTIVES: We know little about women's interest in and experiences with a printout of their preabortion ultrasound image. METHODS: We conducted a mixed methods study at a large-volume abortion-providing facility where patients are offered the opportunity to receive their ultrasound printout, using 2 years of abstracted medical chart data on demographics and printout acceptance and interviews with patients about whether they took a printout and, if they did, why and what they did with it. We analyzed chart data using multivariable logistic regression to examine predictors of printout acceptance and interviews using elaborative coding and modified grounded theory. RESULTS: We abstracted data from 5342 charts and interviewed 23 women. Thirty-eight percent of all patients and 61% of interviewees accepted the printout. Predictors of accepting the printout included being younger, being nonwhite, having a partner who is a boyfriend or friend, and not having a support person at the visit. Interviewees reported that they accepted the printout simply because it was offered, out of curiosity and as part of confirming their abortion decision. They described various uses for the printout, including sharing with others, consulting before their abortion appointment, retaining as a keepsake and nothing at all. CONCLUSIONS: Some abortion patients are interested in receiving a printout of their ultrasound image and find it useful. Women accept a printout for a range of reasons and use it in various ways; there is no singular experience or use of the printout. IMPLICATIONS: We find no evidence that taking a printout of the preabortion ultrasound image causes emotional distress, nor did we find that it was expressly important for any patient's experience. Providers should consider providing interested patients with a printout, if they have the capability to do so, when they request one. PMID- 29242087 TI - Complications with use of misoprostol for abortion in Madagascar: between ease of access and lack of information. AB - OBJECTIVE: The objective was to learn what complications some women experienced in Madagascar following use of misoprostol for abortion and what treatment they received post misoprostol use. STUDY DESIGN: This was a qualitative study in 2015 2016 among women who had experienced complications after use of misoprostol, with or without additional methods, for abortion; what information they received before use; what dosage and regimens they used; what complications they experienced; and what treatment they received postuse. We initially conducted in depth, semistructured interviews with 60 women who had undergone an abortion that resulted in complications. The results presented here are based on interviews with the subset of 19 women who had used misoprostol. RESULTS: The 19 women were aged 16-40, with an average age of 21-26 at interview and average age of 18-21 at abortion. To obtain an abortion, they sought advice from partners, friends, family members, and/or traditional practitioners and health care providers. Misoprostol was easily accessible through the formal and informal sectors, but the dosages and regimens the women used on the advice of others were extremely variable, did not match WHO guidelines and were apparently ineffective, resulting in failed abortion, incomplete abortion, heavy bleeding/hemorrhage, strong pain and/or infection. CONCLUSIONS: This study provides data on complications from the use of misoprostol as an abortifacient in Madagascar. Health care providers need training in correct misoprostol use and how to treat complications. Law and policy reforms are needed to support such training and to ensure the provision of safe abortion services in the public health system. IMPLICATIONS: Health care providers who provide abortion care and treatment of abortion complications need training in correct misoprostol use and treatment of complications. Women and pharmacy workers also need this information. Law and policy reforms are needed to allow training and provision of safe services. Further research is needed on the extent and impact of incorrect misoprostol administration. PMID- 29242088 TI - Voluntarily induced vomiting - A yoga technique to enhance pulmonary functions in healthy humans. AB - Vomiting is a complex autonomic reflex orchestrated by several neurological centres in the brain. Vagus, the cranial nerve plays a key role in regulation of vomiting. Kunjal Kriya (Voluntarily Induced Vomiting), is a yogic cleansing technique which involves voluntarily inducing vomiting after drinking saline water (5%) on empty stomach. This study was designed with an objective to understand the effect of voluntary induced vomiting (ViV) on pulmonary functions in experienced practitioners and novices and derive its possible therapeutic applications. Eighteen healthy individuals volunteered for the study of which nine had prior experience of ViV while nine did not. Pulmonary function tests were performed before and after 10 min of rest following ViV. Analysis of Covariance was performed adjusted for gender and baseline values. No significant changes were observed across genders. The results of the present study suggest a significant increase in Slow Vital Capacity [F(1,13) = 5.699; p = 0.03] and Forced Inspiratory Volume in 1st Second [p = 0.02] and reduction in Expiratory Reserve Volume [F(1,13) = 5.029; p = 0.04] and Respiratory Rate [F(1,13) = 3.244, p = 0.09]. These changes suggest the possible role of ViV in enhancing the endurance of the respiratory muscles, decreased airway resistance, better emptying of lungs and vagal predominance respectively. We conclude that ViV when practiced regularly enhances the endurance of the respiratory muscles and decreases airway resistance. These findings also indicate need for scientific understanding of ViV in the management of motion sickness and restrictive pulmonary disorders like bronchitis and bronchial asthma. PMID- 29242089 TI - Cocos nucifera in combination with metformin for modulation of diabetic symptoms in streptozotocin induced diabetic rats. AB - BACKGROUND: Cocos nucifera, belonging to Arecaceae family, holds quite an importance in the Indian traditional medicinal system. C.nucifera inflorescence (CnI) has been reported in the literature to be useful in the treatment of diarrhoea, dysentery, diabetes, and dyspepsia. In this study, we aimed to evaluate the efficacy of CnI as an adjuvant with metformin in ameliorating Type-2 diabetes mellitus (T2-DM). OBJECTIVE: To evaluate antidiabetic activity of CnI in combination with metformin in Streptozotocin (STZ) induced diabetic rats. MATERIALS AND METHODS: Diabetes was induced in male Wistar rats using streptozotocin (45 mg/kg; i.p.). Plasma glucose level (PGL) was estimated after 72 h of STZ injection. Ethanolic extract of CnI (250 mg/kg and 500 mg/kg) per se and in combination with metformin (22.5 mg/kg) was administered orally once daily to rats for a period of 28 days. PGL level was estimated on 7th, 14th and 21st day followed by Oral Glucose Tolerance Test (OGTT) and PGL both on the 28th day of treatment. DPPH assay was performed to evaluate antioxidant activity of CnI extract. RESULTS: Extract of CnI (250 mg/kg and 500 mg/kg alone and the combination of extract (250 mg/kg) along with metformin (22.5 mg/kg) significantly decreased PGL (p < 0.0001) on 7th, 14th, 21st and 28th days. Histopathological analysis of pancreatic tissue showed that treatment with CnI extract per se and in combination with metformin improved the damaged architecture of pancreas. CONCLUSION: The combination therapy of CnI and metformin produced a significant antidiabetic effect than that of the extract alone and provides a scientific rationale for their use in antidiabetic therapy as an adjuvant. PMID- 29242090 TI - The effect of Brahmi vati and Sarpagandha Ghana vati in management of essential hypertension - A randomized, double blind, controlled clinical study. AB - BACKGROUND: Essential hypertension (EHTN) is emerging as one of the most prevalent disorder with higher rate of complications, morbidity and mortality. Brahmi vati, an Ayurvedic medicine is explored for its efficacy in the management of EHTN. METHODS: 68 patients of age group 20-60 years, of either sex meeting the JNC 7 criteria of EHTN were randomly divided into two groups, group A and group B. Group A and group B received capsule Brahmi vati 500 mg and capsule Sarpagandha Ghana vati 500 mg respectively twice a day for 30 days. Assessments were done through various variables like systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), lipid profiles, Hamilton anxiety rating scale, 2 weeks sleep diary, serum creatinine, hemoglobin, total leukocyte count and erythrocyte sedimentation rate. Follow up visit was on every 15th day. RESULTS: Study showed that both Brahmi vati and Sarpagandha Ghanavati produced significant improvement in most of the variables and were comparable. Significant improvements were seen in various variables like SBP, DBP, MAP, Hamilton anxiety rating scale, subjective sleep profiles and total cholesterol. However Brahmi vati showed significant increase in weight and Body Mass Index (BMI). SarpagandhaGhanavati produced reduction in total cholesterol and LDL. Both groups showed good safety profile evaluated through serum creatinine assessment. CONCLUSION: Clinical efficacy of Sarpagandha Ghana vati and Brahmi vati on EHTN showed that both were effective, safe and comparable. Both were comprehensively effective in management of EHTN. PMID- 29242092 TI - Zika virus and microcephaly: where do we go from here? PMID- 29242091 TI - Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study. AB - BACKGROUND: A Zika virus epidemic emerged in northeast Brazil in 2015 and was followed by a striking increase in congenital microcephaly cases, triggering a declaration of an international public health emergency. This is the final report of the first case-control study evaluating the potential causes of microcephaly: congenital Zika virus infection, vaccines, and larvicides. The published preliminary report suggested a strong association between microcephaly and congenital Zika virus infection. METHODS: We did a case-control study in eight public maternity hospitals in Recife, Brazil. Cases were neonates born with microcephaly, defined as a head circumference of 2 SD below the mean. Two controls without microcephaly were matched to each case by expected date of delivery and area of residence. We tested the serum of cases and controls and the CSF of cases for detection of Zika virus genomes with quantitative RT-PCR and for detection of IgM antibodies with capture-IgM ELISA. We also tested maternal serum with plaque reduction neutralisation assays for Zika and dengue viruses. We estimated matched crude and adjusted odds ratios with exact conditional logistic regression to determine the association between microcephaly and Zika virus infection. FINDINGS: We screened neonates born between Jan 15 and Nov 30, 2016, and prospectively recruited 91 cases and 173 controls. In 32 (35%) cases, congenital Zika virus infection was confirmed by laboratory tests and no controls had confirmed Zika virus infections. 69 (83%) of 83 cases with known birthweight were small for gestational age, compared with eight (5%) of 173 controls. The overall matched odds ratio was 73.1 (95% CI 13.0-infinity) for microcephaly and Zika virus infection after adjustments. Neither vaccination during pregnancy or use of the larvicide pyriproxyfen was associated with microcephaly. Results of laboratory tests for Zika virus and brain imaging results were available for 79 (87%) cases; within these cases, ten were positive for Zika virus and had cerebral abnormalities, 13 were positive for Zika infection but had no cerebral abnormalities, and 11 were negative for Zika virus but had cerebral abnormalities. INTERPRETATION: The association between microcephaly and congenital Zika virus infection was confirmed. We provide evidence of the absence of an effect of other potential factors, such as exposure to pyriproxyfen or vaccines (tetanus, diphtheria, and acellular pertussis, measles and rubella, or measles, mumps, and rubella) during pregnancy, confirming the findings of an ecological study of pyriproxyfen in Pernambuco and previous studies on the safety of Tdap vaccine administration during pregnancy. FUNDING: Brazilian Ministry of Health, Pan American Health Organization, and Enhancing Research Activity in Epidemic Situations. PMID- 29242094 TI - Cochrane Qualitative and Implementation Methods Group guidance series-paper 1: introduction. PMID- 29242093 TI - Efficacy and safety of chemotherapy in older versus non-older patients with advanced gastric cancer: A real-world data, non-inferiority analysis. AB - OBJECTIVE: Advanced gastric cancer (AGC) is a common neoplasm in older adults. Nevertheless, there are few specific management data in the literature. The aim of this study was to assess non-inferiority of survival and efficacy-related outcomes of chemotherapy used in older vs non-older patients with AGC. MATERIALS AND METHODS: We recruited 1485 patients from the AGAMENON registry of AGC treated with polychemotherapy between 2008-2017. A statistical analysis was conducted to prove non-inferiority for overall survival (OS) associated with the use of chemotherapy schedules in individuals >=70 vs.<70years. The fixed-margin method was used (hazard ratio [HR]<1.176) that corresponds to conserving at least 85% efficacy. RESULTS: 33% (n=489) of the cases analyzed were >=70 years. Two-agent chemotherapies and combinations with oxaliplatin (48% vs. 29%) were used more often in the older patients, as were modified schedules and/or lower doses. Toxicity grade 3-4 was comparable in both groups, although when looking at any grade, there were more episodes of enteritis, renal toxicity, and fatigue in older patients. In addition, toxicity was a frequent cause for discontinuing treatment in older patients. The response rate was similar in both groups. After adjusting for confounding factors, the non-inferiority of OS associated with schedules administered to the older vs. younger subjects was confirmed: HR 1.02 (90% CI, 0.91-1.14), P (non inferiority)=0.018, as well as progression-free survival: HR 0.97 (90% CI, 0.87-1.08), P(non-inferiority)=0.001. CONCLUSION: In this AGC registry, the use of chemotherapy with schedules adapted to patients >=70 years provided efficacy that was not inferior to that seen in younger cases, with comparable adverse effects. PMID- 29242095 TI - Cochrane Qualitative and Implementation Methods Group guidance series-paper 5: methods for integrating qualitative and implementation evidence within intervention effectiveness reviews. AB - The Cochrane Qualitative and Implementation Methods Group develops and publishes guidance on the synthesis of qualitative and mixed-method evidence from process evaluations. Despite a proliferation of methods for the synthesis of qualitative research, less attention has focused on how to integrate these syntheses within intervention effectiveness reviews. In this article, we report updated guidance from the group on approaches, methods, and tools, which can be used to integrate the findings from quantitative studies evaluating intervention effectiveness with those from qualitative studies and process evaluations. We draw on conceptual analyses of mixed methods systematic review designs and the range of methods and tools that have been used in published reviews that have successfully integrated different types of evidence. We outline five key methods and tools as devices for integration which vary in terms of the levels at which integration takes place; the specialist skills and expertise required within the review team; and their appropriateness in the context of limited evidence. In situations where the requirement is the integration of qualitative and process evidence within intervention effectiveness reviews, we recommend the use of a sequential approach. Here, evidence from each tradition is synthesized separately using methods consistent with each tradition before integration takes place using a common framework. Reviews which integrate qualitative and process evaluation evidence alongside quantitative evidence on intervention effectiveness in a systematic way are rare. This guidance aims to support review teams to achieve integration and we encourage further development through reflection and formal testing. PMID- 29242096 TI - Risk Factors for Short-term Complications After Rotator Cuff Repair in the United States. AB - PURPOSE: To use a population-level dataset to evaluate the rate of 30-day complications after rotator cuff repair, and to evaluate the risk factors for complication and unplanned hospital readmission. METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program from 2011 to 2015 to identify patients who underwent rotator cuff repair and concomitant procedures using Current Procedural Terminology codes. Postoperative complications and unplanned hospital readmissions were identified. Patient demographics, medical comorbidities, and perioperative variables were used in a multivariate logistic regression model to identify the risk factors for infection, any complication, and unplanned hospital readmission. RESULTS: A total of 23,741 patients were identified who underwent rotator cuff repair. Overall, 1.39% of patients experienced at least 1 complication, with 0.66% minor complications and 0.85% major complications. Unplanned readmission occurred in 1.16% of patients. Infection was the most common complication, occurring in 0.3% of patients (n = 72), and was the most common reason for return to the operating room. Open rotator cuff repair and male gender were independent risk factors for all outcomes. Increased age and numerous medical comorbidities were associated with the risk of any complication or unplanned hospital readmission. CONCLUSIONS: Rotator cuff repair has a low incidence of short-term complications. Infection was the most common complication. Open repair, male gender, increased age, and medical comorbidities all significantly increased the risk of complications and hospital readmission. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29242098 TI - Complex aortic coarctation and a bicuspid aortic valve with severe stenosis in a 68 year-old woman. PMID- 29242097 TI - Emerging trends in the immunotherapy of pancreatic cancer. AB - Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the U.S., claiming approximately 43,000 lives every year. Much like other solid tumors, PC evades the host immune surveillance by manipulating immune cells to establish an immunosuppressive tumor microenvironment (TME). Therefore, targeting and reinstating the patient's immune system could serve as a powerful therapeutic tool. Indeed, immunotherapy has emerged in recent years as a potential adjunct treatment for solid tumors including PC. Immunotherapy modulates the host's immune response to tumor-associated antigens (TAAs), eradicates cancer cells by reducing host tolerance to TAAs and provides both short- and long-term protection against the disease. Passive immunotherapies like monoclonal antibodies or engineered T-cell based therapies directly target tumor cells by recognizing TAAs. Active immunotherapies, like cancer vaccines, on the other hand elicit a long-lasting immune response via activation of the patient's immune cells against cancer cells. Several immunotherapy strategies have been tested for anti-tumor responses alone and in combination with standard care in multiple preclinical and clinical studies. In this review, we discuss various immunotherapy strategies used currently and their efficacy in abrogating self-antigen tolerance and immunosuppression, as well as their ability to eradicate PC. PMID- 29242099 TI - Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction. AB - BACKGROUND: MOTS-c is one of the newly identified mitochondrial-derived peptides which play a role in regulating metabolic homeostasis. The current study aimed to investigate whether circulating MOTS-c levels are also associated with endothelial dysfunction(ED) in patients without significant structural coronary lesions. METHODS: Forty patients undergoing coronary angiography and endothelial function testing for clinical indications of recurrent angina with no structural coronary lesions were included in the study. They were divided into two groups based on coronary blood flow response to intracoronary acetylcholine (ACh) as normal endothelial function (>= 50% increase from baseline) or ED, (n=20 each). Aortic plasma samples were collected at the time of catheterization for analysis of circulating MOTS-c levels by ELISA. The effect of MOTS-c on vascular reactivity was assessed in organ chambers using aortic rings collected from rats and renal artery stenosis (RAS) mice. RESULTS: Baseline characteristics were similar between the two groups. MOTS-c plasma levels were lower in patients with ED compared with patients with normal endothelial function (p=0.007). Furthermore, plasma MOTS-c levels were positively correlated with microvascular (p=0.01) and epicardial (p=0.02) coronary endothelial function. Although MOTS-c did not have direct vasoactive effects, pretreating aortic rings from rats or RAS mice with MOTS-c (2MUg/ml) improved vessel responsiveness to ACh compared with vessels without MOTS-c treatment. CONCLUSION: Lower circulating endogenous MOTS-c levels in human subjects are associated with impaired coronary endothelial function. In rodents, MOTS-c improves endothelial function in vitro. Thus, MOTS-c represents a novel potential therapeutic target in patients with ED. PMID- 29242100 TI - Takotsubo is not a cardiomyopathy. AB - Unraveling the mechanisms underlying Takotsubo (TTS) leads to question the current inclusion of the condition within the spectrum of cardiomyopathies. Indeed, the clinical presentation and pathophysiology of TTS clearly differ from cardiomyopathies, i.e. diseases of heart muscle unexplained by abnormal loading conditions or coronary artery disease, which cannot recover spontaneously and may cause sudden death often in minimally symptomatic individuals or result in a gradual deterioration in ventricular function and end-stage heart failure. Furthermore, the term 'cardiomyopathy' can no longer be applied when functional or morphologic abnormalities of the coronary arteries leading to acute myocardial ischemia are deemed responsible for left ventricular (LV) systolic dysfunction. After 27years of investigation, time has come to recognize that patients with TTS do suffer from severe myocardial ischemia and fulfill all criteria of acute coronary syndromes, i.e. acute chest pain, typical electrocardiographic changes, cardiac troponin rise, as well as LV wall motion abnormalities. Accordingly, we propose that TTS should be labeled as an acute 'syndrome' to be included more appropriately within the spectrum of ischemic heart disease. With regard to the term 'stress', it may imply that the catecholamine surge is essential to produce the typical transient myocardial injury. Thus, the terminology 'Takotsubo (stress) syndrome' would more accurately reflect recent advances in the pathophysiology. PMID- 29242101 TI - Epigenetic silencing of EVL/miR-342 in multiple myeloma. AB - miR-342-3p, localized to 14q32, is a tumor suppressor miRNA implicated in multiple cancers. As the promoter region of its host gene, EVL, is embedded in a CpG island, we postulated that miR-342-3p is an intronic miRNA co-regulated with its host gene by promoter DNA methylation in multiple myeloma (MM). By methylation-specific polymerase chain reaction, verified by quantitative bisulfite pyrosequencing, methylation of EVL/miR-342 was absent in all healthy controls (n = 10) and 12 of 15 (80%) human myeloma cell lines (HMCLs), but partially methylated in 3 of 15 (20%) HMCLs, including KMS-12-PE, OCI-MY5, and RPMI-8226R. In HMCLs, by real-time quantitative reverse transcription-polymerase chain reaction, methylation of EVL/miR-342 correlated with lower expression of both EVL (P = 0.013) and miR-342-3p (P = 0.023). Moreover, in KMS-12-PE and RPMI 8226R cells, both partially methylated for EVL/miR-342, 5-AzadC treatment led to demethylation of EVL/miR-342 and re-expression of miR-342-3p. Upon removal of 5 AzadC, continuous culture resulted in restoration of EVL/miR-342 methylation and downregulation of miR-342-3p. In primary samples, methylation of EVL/miR-342 was detected in 1 of 18 (5.6%) monoclonal gammopathy of undetermined significance (MGUS), 8 of 63 (12.7%) diagnostic MM, and 5 of 30 (16.7%) relapsed MM. EVL/miR 342 methylation was preferentially detected in IgD MM but not found to impact survival. Collectively, in MM, miR-342-3p is an intronic miRNA regulated by promoter DNA methylation of its host gene, EVL, in a tumor-specific manner. Methylation of EVL/miR-342 was present in consecutive stages of myelomagenesis including MGUS, diagnostic MM, and relapsed MM. PMID- 29242102 TI - Shock Reduction With Antitachycardia Pacing Before and During Charging for Fast Ventricular Tachycardias in Patients With Implantable Defibrillators. AB - INTRODUCTION AND OBJECTIVES: Fast ventricular tachycardias in the ventricular fibrillation zone in patients with an implantable cardioverter-defibrillator are susceptible to antitachycardia pacing (ATP) termination. Some manufacturers allow programming 2 ATP bursts: before charging (BC) and during (DC) charging. The aim of this study was to describe the safety and effectiveness of ATP BC and DC for fast ventricular tachycardias in the ventricular fibrillation zone in patients with an implantable cardioverter-defibrillator in daily clinical practice. METHODS: Data proceeded from the multicenter UMBRELLA trial, including implantable cardioverter-defibrillator patients followed up by the CareLink monitoring system. Fast ventricular tachycardias in the ventricular fibrillation zone until a cycle length of 200ms with ATP BC and/or ATP DC were included. RESULTS: We reviewed 542 episodes in 240 patients. Two ATP bursts (BC/DC) were programmed in 291 episodes (53.7%, 87 patients), while 251 episodes (46.3%, 153 patients) had 1 ATP burst only DC. The number of episodes terminated by 1 ATP DC was 139, representing 55.4% effectiveness (generalized estimating equation adjusted 60.4%). There were 256 episodes terminated by 1 or 2 ATP (BC/DC), representing 88% effectiveness (generalized estimating equation-adjusted 79.3%); the OR for ATP effectiveness BC/DC vs DC was 2.5, 95%CI, 1.5-4.1; P <.001. Shocked episodes were 112 (45%) for ATP DC vs 35 (12%) for ATP BC/DC, representing an absolute reduction of 73%. The mean shocked episode duration was 16seconds for ATP DC vs 19seconds for ATP BC/DC (P=.07). CONCLUSIONS: The ATP DC in the ventricular fibrillation zone for fast ventricular tachycardia is moderately effective. Adding an ATP burst BC increases the overall effectiveness, reduces the need for shocks, and does not prolong episode duration. PMID- 29242103 TI - The neural network for face recognition: Insights from an fMRI study on developmental prosopagnosia. AB - Face recognition is supported by collaborative work of multiple face-responsive regions in the brain. Based on findings from individuals with normal face recognition ability, a neural model has been proposed with the occipital face area (OFA), fusiform face area (FFA), and face-selective posterior superior temporal sulcus (pSTS) as the core face network (CFN) and the rest of the face responsive regions as the extended face network (EFN). However, little is known about how these regions work collaboratively for face recognition in our daily life. Here we focused on individuals suffering developmental prosopagnosia (DP), a neurodevelopmental disorder specifically impairing face recognition, to shed light on the infrastructure of the neural model of face recognition. Specifically, we used a variant of global brain connectivity method to comprehensively explore resting-state functional connectivity (FC) among face responsive regions in a large sample of DPs (N = 64). We found that both the FCs within the CFN and those between the CFN and EFN were largely reduced in DP. Importantly, the right OFA and FFA served as the dysconnectivity hubs within the CFN, i.e., FCs concerning these two regions within the CFN were largely disrupted. In addition, DPs' right FFA also showed reduced FCs with the EFN. Moreover, these disrupted FCs were related to DP's behavioral deficit in face recognition, with the FCs from the FFA to the anterior temporal lobe (ATL) and pSTS the most predictive. Based on these findings, we proposed a revised neural model of face recognition demonstrating the relatedness of interactions among face-responsive regions to face recognition. PMID- 29242104 TI - Structural network differences in chronic muskuloskeletal pain: Beyond fractional anisotropy. AB - Chronic musculoskeletal pain is a condition that influences central nervous system structure. In this study, we combined novel structural neuroimaging techniques, using well-validated software packages including FSL, Mrtrix3, and DSI Studio, to characterize brain grey (GM) and white matter (WM) differences in chronic musculoskeletal pain participants (n = 74), compared to age-matched pain free controls (n = 31). In participants with chronic pain, we identified significantly higher volume in subcortical GM structures using voxel-based morphometry (FSLVBM). These differences were most prominent in the caudate, amygdala, and the hippocampus. At the same time, volume was lower in the dorsolateral prefrontal cortex, as well as the primary motor and sensory regions in patients with chronic pain. To delineate WM microstructural differences of neuronal (e.g., activity-dependent myelin remodeling) and non-neuronal (e.g., neuroinflammation) origins, we utilized Mrtrix3 software pipelines to investigate WM fiber complexity, density, and cross-section. Whole-brain analyses revealed lower WM fiber complexity within the corpus callosum and the anterior limb of the left internal capsule. Whole brain and region of interest analyses revealed fiber complexity differences within the salience and the sensorimotor networks. In contrast, we detected non-neuronal white matter density differences within the dorsal attention network: density was lower in the inferior fronto-occipital fasciculus and the splenium of the corpus callosum in chronic musculoskeletal pain. Consistent with the involvement of the dorsal attention network, WM tractography analysis, conducted with DSI Studio and Network Based Statistics, revealed higher connectivity from the superior parietal lobule to the hippocampus in patients with chronic pain. No differences were detected in measures of fiber cross-section, suggesting the absence of neuronal degeneration in chronic pain. The combination of multiple neuroimaging techniques in this study offers a unique window into the structural differences within the chronic pain brain and provides the first evidence of microstructural variations in fiber complexity and density. PMID- 29242106 TI - The effects of dopaminergic D2-like receptor stimulation upon behavioral and neural correlates of renewal depend on individual context processing propensities. AB - Renewal is defined as the recovery of an extinguished response when the contexts of extinction and recall differ. Prominent hippocampal activity during context related extinction can predict renewal. Dopaminergic antagonism during extinction learning impaired extinction and reduced hippocampal activation, without affecting renewal. However, to what extent dopaminergic stimulation during extinction influences hippocampal processing and renewal is as yet unknown. In this fMRI study, we investigated the effects of the dopamine D2-like agonist bromocriptine upon renewal in an associative learning task, in hippocampus and ventromedial PFC. We observed significant differences between bromocriptine (BROMO) and placebo (PLAC) treatments in the subgroups showing (REN) and lacking (NoREN) renewal: the renewal level of BROMO REN was significantly higher, and associated with more prominent hippocampal activation during extinction and recall, compared to PLAC REN and BROMO NoREN. Results suggest that an interaction between D2like-agonist-induced enhancement of hippocampal activity and a pre existing tendency favoring context processing contributed to the higher renewal levels. In contrast, ventromedial prefrontal activation was unchanged, indicating that increased hippocampal context processing and not prefrontal response selection constituted the central driving force behind the high renewal levels. The findings demonstrate that hippocampal dopamine is important for encoding and providing of context information, and thus crucially involved in the renewal effect. PMID- 29242105 TI - Affective and non-affective touch evoke differential brain responses in 2-month old infants. AB - Caressing touch is an effective way to communicate emotions and to create social bonds. It is also one of the key mediators of early parental bonding. The caresses are generally thought to represent a social form of touching and indeed, slow, gentle brushing is encoded in specialized peripheral nerve fibers, the C tactile (CT) afferents. In adults, areas such as the posterior insula and superior temporal sulcus are activated by affective, slow stroking touch but not by fast stroking stimulation. However, whether these areas are activated in infants, after social tactile stimulation, is unknown. In this study, we compared the total hemoglobin responses measured with diffuse optical tomography (DOT) in the left hemisphere following slow and fast stroking touch stimulation in 16 2 month-old infants. We compared slow stroking (optimal CT afferent stimulation) to fast stroking (non-optimal CT stimulation). Activated regions were delineated using two methods: one based on contrast between the two conditions, and the other based on voxel-based statistical significance of the difference between the two conditions. The first method showed a single activation cluster in the temporal cortex with center of gravity in the middle temporal gyrus where the total hemoglobin increased after the slow stroking relative to the fast stroking (p = 0.04 uncorrected). The second method revealed a cluster in the insula with an increase in total hemoglobin in the insular cortex in response to slow stroking relative to fast stroking (p = 0.0005 uncorrected; p = 0.04 corrected for multiple comparisons). These activation clusters encompass areas that are involved in processing of affective, slow stroking touch in the adult brain. We conclude that the infant brain shows a pronounced and adult-like response to slow stroking touch compared to fast stroking touch in the insular cortex but the expected response in the primary somatosensory cortex was not found at this age. The results imply that emotionally valent touch is encoded in the brain in adult like manner already soon after birth and this suggests a potential for involvement of touch in bonding with the caretaker. PMID- 29242107 TI - Ability of emergency medicine residents in the diagnosis of CHF with a preserved ejection fraction by echocardiogram. PMID- 29242109 TI - Short National Early Warning Score - Developing a Modified Early Warning Score. AB - INTRODUCTION: Early Warning Score (EWS) systems have been developed for detecting hospital patients clinical deterioration. Many studies show that a National Early Warning Score (NEWS) performs well in discriminating survival from death in acute medical and surgical hospital wards. NEWS is validated for Portugal and is available for use. A simpler EWS system may help to reduce the risk of error, as well as increase clinician compliance with the tool. OBJECTIVES: The aim of the study was to evaluate whether a simplified NEWS model will improve use and data collection. METHODS: We evaluated the ability of single and aggregated parameters from the NEWS model to detect patients' clinical deterioration in the 24h prior to an outcome. There were 2 possible outcomes: Survival vs Unanticipated intensive care unit admission or death. We used binary logistic regression models and Receiver Operating Characteristic Curves (ROC) to evaluate the parameters' performance in discriminating among the outcomes for a sample of patients from 6 Portuguese hospital wards. RESULTS: NEWS presented an excellent discriminating capability (Area under the Curve of ROC (AUCROC)=0.944). Temperature and systolic blood pressure (SBP) parameters did not contribute significantly to the model. We developed two different models, one without temperature, and the other by removing temperature and SBP (M2). Both models had an excellent discriminating capability (AUCROC: 0.965; 0.903, respectively) and a good predictive power in the optimum threshold of the ROC curve. CONCLUSIONS: The 3 models revealed similar discriminant capabilities. Although the use of SBP is not clearly evident in the identification of clinical deterioration, it is recognized as an important vital sign. We recommend the use of the first new model, as its simplicity may help to improve adherence and use by health care workers. PMID- 29242108 TI - A multi-level intervention in worksites to increase fruit and vegetable access and intake: Rationale, design and methods of the 'Good to Go' cluster randomized trial. AB - BACKGROUND: Fruit and vegetable (F&V) consumption is an important contributor to chronic disease prevention. However, most Americans do not eat adequate amounts. The worksite is an advantageous setting to reach large, diverse segments of the population with interventions to increase F&V intake, but research gaps exist. No studies have evaluated the implementation of mobile F&V markets at worksites nor compared the effectiveness of such markets with or without nutrition education. METHODS: This paper describes the protocol for Good to Go (GTG), a cluster randomized trial to evaluate F&V intake change in employees from worksites randomized into three experimental arms: discount, fresh F&V markets (Access Only arm); markets plus educational components including campaigns, cooking demonstrations, videos, newsletters, and a web site (Access Plus arm); and an attention placebo comparison intervention on physical activity and stress reduction (Comparison). Secondary aims include: 1) Process evaluation to determine costs, reach, fidelity, and dose as well as the relationship of these variables with changes in F&V intake; 2) Applying a mediating variable framework to examine relationships of psychosocial factors/determinants with changes in F&V consumption; and 3) Cost effectiveness analysis of the different intervention arms. DISCUSSION: The GTG study will fill important research gaps in the field by implementing a rigorous cluster randomized trial to evaluate the efficacy of an innovative environmental intervention providing access and availability to F&V at the worksite and whether this access intervention is further enhanced by accompanying educational interventions. GTG will provide an important contribution to public health research and practice. Trial registration number NCT02729675, ClinicalTrials.gov. PMID- 29242110 TI - Initiation of Traditional Cigarette Smoking after Electronic Cigarette Use Among Tobacco-Naive US Young Adults. AB - BACKGROUND: Although electronic cigarettes (e-cigarettes) may help some smokers quit, some young adult never-smokers are now using e-cigarettes recreationally, potentially increasing their risk for initiation of smoking. We aimed to determine the association between baseline e-cigarette use and subsequent initiation of cigarette smoking among initially never-smoking young adults. METHODS: We conducted a prospective cohort study with assessments at baseline (March 2013) and follow-up (October 2014). We used sampling frames representing 97% of the US population to recruit a nationally representative sample of never smoking young adults aged 18 to 30 years. The independent variable was baseline ever use of e-cigarettes. The main outcome measure was initiation of traditional cigarette smoking between baseline and 18-month follow-up. RESULTS: Baseline surveys were completed by 1506 never-smoking young adults, of whom 915 (60.8%) completed follow-up. There were no demographic differences between responders and nonresponders. After applying survey weights-which accounted for both nonresponse and overcoverage or undercoverage-2.5% of the represented population of never smokers (801,010 of 32,040,393) used e-cigarettes at baseline. Cigarette smoking was initiated by 47.7% of e-cigarette users and 10.2% of nonusers (P = .001). In fully adjusted multivariable models, e-cigarette use at baseline was independently associated with initiation of smoking at 18 months (adjusted odds ratio, 6.8; 95% confidence interval, 1.7-28.3). Results remained similar in magnitude and statistically significant in all sensitivity analyses. CONCLUSIONS: Baseline e-cigarette use was independently associated with initiation of traditional cigarette smoking at 18 months. This finding supports policy and educational interventions designed to decrease use of e-cigarettes among nonsmokers. PMID- 29242111 TI - Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure: A National LymphoCare Study and Center for International Blood and Marrow Transplant Research Analysis. AB - Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within 2 years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup. ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within 2 years of frontline chemoimmunotherapy. We identified 2 groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT) and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment; 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in 5 year OS between the 2 groups (60% versus 67%, respectively; P = .16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (<=1 year of ETF; n = 123) had higher 5-year OS than those without autoHCT (73% versus 60%, P = .05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (hazard ratio, .63; 95% confidence interval, .42 to .94; P = .02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within 1 year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF. PMID- 29242112 TI - BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling: Summary and Recommendations from the Organizing Committee. AB - The Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling was convened on December 1, 2016 at the American Society of Hematology meeting to discuss the emerging data and technologies for minimal residual disease assessment and immune profiling in myeloma. Particular emphasis was placed on developing strategies to incorporate these techniques into clinical trial design. This document reviews the literature, summarizes the topics discussed in the workshop, and provides recommendations for integration of these techniques into future clinical trial design. PMID- 29242113 TI - Professionals' knowledge, attitude and referral behaviour of preimplantation genetic diagnosis for hereditary breast and ovarian cancer. AB - Hereditary breast and ovarian cancer caused by a BRCA1/2 mutation is the most frequent indication for preimplantation genetic diagnosis (PGD) in the Netherlands. The extent to which involved professionals are informed about this option, however, is unclear. The few available international studies mostly represent a limited range of professionals, and suggest that their knowledge about PGD for hereditary cancer syndromes is sparse and referral for PGD is based on limited understanding. A cross-sectional survey assessing awareness, knowledge, acceptability and PGD-referral for BRCA was completed by 188 professionals involved in the field of breast and ovarian cancer or reproduction. One-half of professionals were aware of PGD for BRCA, and most had a low to moderate level of knowledge. A total of 86% considered PGD for BRCA acceptable and 48% had referred patients with BRCA for PGD. Awareness and knowledge was higher among professionals who worked at a university hospital (compared with a general hospital). Knowledge of PGD was positively associated with discussing and referring for PGD, and PGD acceptability was associated with previous awareness. Although PGD counselling is the primary responsibility of the geneticist, other involved professionals may be gatekeepers as patients rely on them for raising awareness and referral. PMID- 29242114 TI - Biostimulation of nutrient additions on indigenous microbial community at the stage of nitrogen limitations during composting. AB - Microorganisms can play a crucial role in the efficiency for composting, which are essential for converting the organic wastes into a well-stabilized, value added product. However, the activity of most of the key functional microorganisms were inhibited due to the limited special nutrient substances or other physiochemical factors during composting, which further affected the quality of compost. The study was conducted to investigate the effects of enriched ammonium (NH4+-N) and organic nitrogen (Org-N) on indigenous microbial community and whether nitrogen (N) nutrient additions could modify the special species during composting. The results showed that the abundance and structure of bacterial community had distinctly diverse responses to different N nutritional treatments (no nutrient addition, NH4+-N addition, and Org-N addition). The addition of N sources enhanced the abundance of corresponding uncultured indigenous species negatively related to the factor of NH4+ and Org-N in redundancy analysis (RDA) during composting but the effect of NH4+ was more significant than Org-N. Nonmetric multidimensional scaling ordination (NMDS) demonstrated that both the two N additions changed bacterial community but had different duration for affecting bacterial composition. Conclusively, an optimized method for regulating the key stains with special biological capacity is proposed by controlling the single limiting-nutrient factor sharply decreasing at one of composting stages and negatively related to the key species in RDA. PMID- 29242115 TI - Using factorial experimental design to evaluate the separation of plastics by froth flotation. AB - This paper proposes the use of factorial experimental design as a standard experimental method in the application of froth flotation to plastic separation instead of the commonly used OVAT method (manipulation of one variable at a time). Furthermore, as is common practice in minerals flotation, the parameters of the kinetic model were used as process responses rather than the recovery of plastics in the separation products. To explain and illustrate the proposed methodology, a set of 32 experimental tests was performed using mixtures of two polymers with approximately the same density, PVC and PS (with mineral charges), with particle size ranging from 2 to 4 mm. The manipulated variables were frother concentration, air flow rate and pH. A three-level full factorial design was conducted. The models establishing the relationships between the manipulated variables and their interactions with the responses (first order kinetic model parameters) were built. The Corrected Akaike Information Criterion was used to select the best fit model and an analysis of variance (ANOVA) was conducted to identify the statistically significant terms of the model. It was shown that froth flotation can be used to efficiently separate PVC from PS with mineral charges by reducing the floatability of PVC, which largely depends on the action of pH. Within the tested interval, this is the factor that most affects the flotation rate constants. The results obtained show that the pure error may be of the same magnitude as the sum of squares of the errors, suggesting that there is significant variability within the same experimental conditions. Thus, special care is needed when evaluating and generalizing the process. PMID- 29242116 TI - Wood waste decomposition in landfills: An assessment of current knowledge and implications for emissions reporting. AB - Large quantities of wood products have historically been disposed of in landfills. The fate of this vast pool of carbon plays an important role in national carbon balances and accurate emission reporting. The Republic of Ireland, like many EU countries, utilises the 2006 Intergovernmental Panel on Climate Change (IPCC) guidelines for greenhouse gas reporting in the waste sector, which provides default factors for emissions estimation. For wood products, the release of carbon is directly proportional to the decomposition of the degradable organic carbon fraction of the product, for which the IPCC provides a value of 0.5 (50%). However, in situ analytic results of the decomposition rates of carbon in landfilled wood do not corroborate this figure; suggesting that carbon emissions are likely overestimated. To assess the impact of this overestimation on emission reporting, carbon decomposition values obtained from literature and the IPCC default factor were applied to the Irish wood fraction of landfilled waste for the years 1957-2016 and compared. Univariate analysis found a statistically significant difference between carbon (methane) emissions calculated using the IPCC default factor and decomposition factors from direct measurements for softwoods (F = 45.362, p = <.001), hardwoods (F = 20.691, p = <.001) and engineered wood products (U = 4.726, p = <.001). However, there was no significant difference between emissions calculated using only the in situ analytic decomposition factors, regardless of time in landfill, location or subsequently, climate. This suggests that methane emissions from the wood fraction of landfilled waste in Ireland could be drastically overestimated; potentially by a factor of 56. The results of this study highlight the implications of emission reporting at a lower tierand prompts further research into the decomposition of wood products in landfills at a national level. PMID- 29242117 TI - Design, implementation, and evaluation of an Internet of Things (IoT) network system for restaurant food waste management. AB - Catering companies around the world generate tremendous amounts of waste; those in China are no exception. The paper discusses the design, implementation, and evaluation of a sensor-based Internet of Things (IoT) network technology for improving the management of restaurant food waste (RFW) in the city of Suzhou, China. This IoT-based system encompasses the generation, collection, transportation and final disposal of RFW. The Suzhou case study comprised four steps: (1) examination of the required functionality of an IoT-enabled system in the specific context of Suzhou; (2) configuration of the system architecture, both software and hardware components, according to the identified functionality; (3) installation of the components of the IoT system at the facilities of the stakeholders across the RFW generation-collection-transportation-disposal value chain; and (4) evaluation of the performance of the entire system, based on data from three years of operation. The results show that the system had a strong impact. Positive results include: (1) better management of RFW generation, as evidenced by a 20.5% increase in RFW collected via official channels and a 207% increase in the number of RFW generators under official contract; (2) better law enforcement in response to RFW malpractice, enabled by the monitoring capabilities of the IoT system; and (3) an overall reduction in illicit RFW activities and better process optimization across the RFW value chain. Negative results include: (1) Radio-frequency identification (RFID) tags need to be renewed often due to the frequent handling of waste bins, thus increasing operating costs; (2) dynamic/automatic weight sensors had a higher degree of error than the more time-consuming static/manual weighing method; and (3) there were disagreements between the city's government agencies about how to interpret data from the IoT system, which led to some inefficiencies in management. In sum, the Suzhou IoT system enabled data-driven management of RFW and had a net positive impact for the stakeholders involved. PMID- 29242118 TI - Activation of transglutaminase 2 by nerve growth factor in differentiating neuroblastoma cells: A role in cell survival and neurite outgrowth. AB - NGF (nerve growth factor) and tissue transglutaminase (TG2) play important roles in neurite outgrowth and modulation of neuronal cell survival. In this study, we investigated the regulation of TG2 transamidase activity by NGF in retinoic acid induced differentiating mouse N2a and human SH-SY5Y neuroblastoma cells. TG2 transamidase activity was determined using an amine incorporation and a peptide cross linking assay. In situ TG2 activity was assessed by visualising the incorporation of biotin-X-cadaverine using confocal microscopy. The role of TG2 in NGF-induced cytoprotection and neurite outgrowth was investigated by monitoring hypoxia-induced cell death and appearance of axonal-like processes, respectively. The amine incorporation and protein crosslinking activity of TG2 increased in a time and concentration-dependent manner following stimulation with NGF in N2a and SH-SY5Y cells. NGF mediated increases in TG2 activity were abolished by the TG2 inhibitors Z-DON (Z-ZON-Val-Pro-Leu-OMe; Benzyloxycarbonyl (6-Diazo-5-oxonorleucinyl)-l-valinyl-l-prolinyl-l-leucinmethylester) and R283 (1,3,dimethyl-2[2-oxo-propyl]thio)imidazole chloride) and by pharmacological inhibition of extracellular signal-regulated kinases 1 and 2 (ERK1/2), protein kinase B (PKB) and protein kinase C (PKC), and removal of extracellular Ca2+. Fluorescence microscopy demonstrated NGF induced in situ TG2 activity. TG2 inhibition blocked NGF-induced attenuation of hypoxia-induced cell death and neurite outgrowth in both cell lines. Together, these results demonstrate that NGF stimulates TG2 transamidase activity via a ERK1/2, PKB and PKC-dependent pathway in differentiating mouse N2a and human SH-SY5Y neuroblastoma cells. Furthermore, NGF-induced cytoprotection and neurite outgrowth are dependent upon TG2. These results suggest a novel and important role of TG2 in the cellular functions of NGF. PMID- 29242119 TI - Pharmacological modulation of AMPA receptor phosphorylation by dopamine and muscarinic receptor agents in the rat medial prefrontal cortex. AB - Two key transmitters in the medial prefrontal cortex (mPFC), dopamine and acetylcholine, are believed to interact with each other to modulate local glutamatergic transmission, although molecular mechanisms underlying their crosstalk are poorly understood. Here we investigated effects of pharmacological manipulations of dopamine and muscarinic receptors on phosphorylation of alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the adult rat mPFC in vivo. We found that an agonist selective for Galphas-coupled dopamine D1 receptors, SKF81297, increased AMPA receptor GluA1 subunit phosphorylation at a protein kinase A-sensitive site (S845), while SKF81297 had no effect on GluA1 phosphorylation at S831. An agonist for Galphai/o-coupled dopamine D2 receptors, quinpirole, also increased S845 but not S831 phosphorylation. When coinjected, the two agonists induced an additive increase in S845 phosphorylation. The D1 receptor antagonist SCH23390 blocked the SKF81297/quinpirole-stimulated S845 phosphorylation. The D2 antagonist eticlopride also partially blocked S845 responses to SKF81297/quinpirole. VU0152100, a positive allosteric modulator selective for Galphai/o-coupled muscarinic M4 receptors, reduced the S845 phosphorylation induced by SKF81297 and quinpirole injected alone or together. In contrast, coinjection of subthreshold doses of tropicamide, an M4 antagonist, and SKF81297 facilitated S845 phosphorylation. Additionally, coadministered SFK81297 and quinpirole increased the abundance of mPFC GluA1 at extrasynaptic sites. These data reveal that both D1 and D2 receptors upregulate GluA1 phosphorylation in mPFC neurons probably via a direct and indirect mechanism, respectively. The indirect mechanism involves M4 receptors which generally counteract the effect of dopamine on GluA1 phosphorylation. PMID- 29242120 TI - Osteoprotective effects of salidroside in ovariectomized mice and diabetic mice. AB - Salidroside, an active constituent from the root of Rhodiola rosea L., has multiple pharmacological effects, such as anti-cancer, anti-inflammatory and anti oxidative properties, etc. However, its protective effect on bone tissue via regulating calcium homeostasis is yet to be determined. This study was performed to investigate if salidroside could protect against bone injuries induced by estrogen deficiency or hyperglycemia through modulating calcium homeostasis. Ovariectomized (OVX) mice and diabetic mice were treated with salidroside (20mg/kg) for 6 weeks. Safranin O staining and micro-CT were performed on the distal metaphysis of femur. The calcium content in serum, urine and femur was measured, and the mRNA and protein expressions of regulators in kidney were determined by PCR and immunoblotting, respectively. Treatment with salidroside increased bone calcium level and decreased urinary calcium excretion, consequently attenuating the deteriorations of trabecular bone in both OVX mice and diabetic mice. 25-Hydroxyvitamin D-24 hydroxylase expression was down regulated and vitamin D receptor expression was up-regulated in kidney of both OVX mice and diabetic mice upon to salidroside treatment, which also inhibited the ovariectomy-induced decrease in expression of renal transcellular calcium transporters and the diabetes-induced enhancement in renal calcium-sensing receptor (CaSR) expression. Taken together, salidroside exerted osteoprotective effects by improving calcium homeostasis via regulating vitamin D metabolism and transcellular calcium transporters as well as modulating CaSR expression in kidney. PMID- 29242121 TI - Postinduction butorphanol administration alters oxygen consumption to improve blood gases in etorphine-immobilized white rhinoceros. AB - OBJECTIVE: To investigate the effects of postinduction butorphanol administration in etorphine-immobilized white rhinoceros on respiration and blood gases. STUDY DESIGN: Randomized crossover study. ANIMALS: A group of six sub-adult male white rhinoceros. METHODS: Etorphine, or etorphine followed by butorphanol 12 minutes after recumbency, was administered intramuscularly [2.5 mg etorphine, 25 mg butorphanol (1000-1250 kg), or 3.0 mg etorphine, 30 mg butorphanol (1250-1500 kg)]. Sampling started at 10 minutes after initial recumbency, and was repeated at 5 minute intervals for 25 minutes. Arterial blood gases, limb muscle tremors, expired minute ventilation and respiratory frequency were measured at each sampling point. Calculated values included alveolar-arterial oxygen gradient [ [Formula: see text] ], expected respiratory minute volume (Ve), tidal volume (Vt), oxygen consumption ( [Formula: see text] ) and carbon dioxide production ( [Formula: see text] ). RESULTS: Etorphine administration resulted in an initial median (range) hypoxaemia [arterial partial pressure of oxygen 25.0 (23.0-28.0) mmHg], hypercapnia [arterial partial pressure of carbon dioxide 76.2 (67.2-81.2) mmHg], increased [Formula: see text] [41.7 (36.6-45.1) mmHg, [Formula: see text] [11.1 (10.0-12.0) L minute-1] and muscle tremors. Butorphanol administration was followed by rapid, although moderate, improvements in arterial partial pressure of oxygen [48.5 (42.0-51.0) mmHg] and arterial partial pressure of carbon dioxide [62.8 (57.9-75.2) mmHg]. In rhinoceros administered butorphanol, [Formula: see text] [4.4 (3.6-5.1) L minute-1] and [Formula: see text] [4.2 (3.8-4.4) L minute 1] were lower than in those not administered butorphanol. Increased arterial oxygen tension was associated with lower oxygen consumption (p=0.002) which was positively associated with lower muscle tremor scores (p<0.0001). CONCLUSIONS AND CLINICAL RELEVANCE: Hypoxaemia and hypercapnia in etorphine-immobilized rhinoceros resulted from an increased [ [Formula: see text] ] and increased [Formula: see text] and [Formula: see text] associated with muscle tremors. Rather than being associated with changes in Ve, it appears that improved blood gases following butorphanol administration were a consequence of decreased [Formula: see text] associated with reduced muscle tremoring. PMID- 29242122 TI - Promoting Student Integrity: Ethical Issues in the Digital Age. PMID- 29242123 TI - Ensemble of random forests One vs. Rest classifiers for MCI and AD prediction using ANOVA cortical and subcortical feature selection and partial least squares. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly and affects approximately 30 million individuals worldwide. Mild cognitive impairment (MCI) is very frequently a prodromal phase of AD, and existing studies have suggested that people with MCI tend to progress to AD at a rate of about 10-15% per year. However, the ability of clinicians and machine learning systems to predict AD based on MRI biomarkers at an early stage is still a challenging problem that can have a great impact in improving treatments. METHOD: The proposed system, developed by the SiPBA-UGR team for this challenge, is based on feature standardization, ANOVA feature selection, partial least squares feature dimension reduction and an ensemble of One vs. Rest random forest classifiers. With the aim of improving its performance when discriminating healthy controls (HC) from MCI, a second binary classification level was introduced that reconsiders the HC and MCI predictions of the first level. RESULTS: The system was trained and evaluated on an ADNI datasets that consist of T1-weighted MRI morphological measurements from HC, stable MCI, converter MCI and AD subjects. The proposed system yields a 56.25% classification score on the test subset which consists of 160 real subjects. COMPARISON WITH EXISTING METHOD(S): The classifier yielded the best performance when compared to: (i) One vs. One (OvO), One vs. Rest (OvR) and error correcting output codes (ECOC) as strategies for reducing the multiclass classification task to multiple binary classification problems, (ii) support vector machines, gradient boosting classifier and random forest as base binary classifiers, and (iii) bagging ensemble learning. CONCLUSIONS: A robust method has been proposed for the international challenge on MCI prediction based on MRI data. The system yielded the second best performance during the competition with an accuracy rate of 56.25% when evaluated on the real subjects of the test set. PMID- 29242124 TI - Kinetic characterization and structural modeling of an NADP+-dependent succinic semialdehyde dehydrogenase from Anabaena sp. PCC7120. AB - Succinic semialdehyde dehydrogenases (SSADH) of cyanobacteria played a pivotal role in completing the cyanobacterial tricarboxylic acid cycle. The structural information of cofactor preference and catalysis for SSADH from cyanobacteria is currently available. However, the detailed kinetics of SSADH from cyanobacteria were not characterized yet. In this study, an all3556 gene encoding SSADH from Anabaena sp. PCC7120 (ApSSADH) was amplified and the recombinant ApSSADH was purified homogenously. Kinetic analysis showed that ApSSADH was an NADP+ dependent SSADH, which utilized NADP+ and succinic semialdehyde (SSA) as its preferred substrates and the activity of ApSSADH was inhibited by its substrate of SSA. At the same time, the Ser157 residue was found to function as the determinant of cofactor preference. Further study demonstrated that activity and substrate inhibition of ApSSADH would be greatly reduced by the mutation of the residues at the active site. Bioinformatic analysis indicated that those residues were highly conserved throughout the SSADHs. To our knowledge this is the first report exploring the detailed kinetics of SSADH from cyanobacteria. PMID- 29242125 TI - Optimization for pectinase-assisted extraction of polysaccharides from pomegranate peel with chemical composition and antioxidant activity. AB - In this work, based on response surface methodology (RSM), an optimized method of extracting water-soluble polysaccharide from pomegranate peel (PPP) with pectinase was proposed. Additionally, the chemical composition and the antioxidant activities of the extracted PPP were studied. The effects of three factors of enzymolysis time, ratio of liquid to solid and dosage of enzyme on the PPP yield were investigated. The experimental results showed that the optimal conditions were as following: enzymolysis time 19.70 min, ratio of liquid to solid 20.5:1(mL/g), dosage of enzyme 0.68%. Under the best conditions, the maximum PPP yield was 27.3 +/- 0.08%. FT-IR and GC-MS revealed that PPP was the typical acidic heteropolysaccharides and mainly consisted of d-mannose (19.30%), d-galactose (47.93%) and l-arabinose (23.08%). Moreover, the antioxidant activity assay in vitro showed that PPP exhibited strong reducing power and good scavenging activities on superoxide anion, hydroxyl, and DPPH radicals. The PPP extracted with pectinase had excellent antioxidant properties and could be developed into a new type of dietary supplement or functional food. PMID- 29242126 TI - Significance of elevated Prohibitin 1 levels in Multiple Sclerosis patients lymphocytes towards the assessment of subclinical disease activity and its role in the central nervous system pathology of disease. AB - Multiple Sclerosis (MS) is an autoimmune-neurodegenerative disorder managed therapeutically by modulating lymphocytes activity which has potential in disease management. Prohibitin 1(PHB) that controls the reactive oxygen species (ROS) and present on the activated lymphocytes have significance in the therapy of MS as esters of fumaric acid that regulates ROS is in phase II/III clinical trials. Thus, we evaluated the expression levels of PHB1 in experimental autoimmune encephalomyelitis (EAE), the animal model of MS and on MS patient's lymphocytes. PHB levels in brain tissue of EAE animals were determined by immunoblotting and on blood lymphocytes from MS relapse, Remission, Optic Neuritis, Neurological controls and Healthy volunteers by FACS using anti-PHB and anti-CD45 antibodies. We observed significant elevation of PHB in EAE brains (91.0 +/- 17.59%) vs controls (29.8 +/- 12.9%) (p = 0.01) and on lymphocytes of MS patients in acute (73.5 +/- 11.20%) or relapsing (69.3 +/- 17.33%) phase compared to remission (45.9 +/- 8.08%) [p = 0.034 acute vs remission; p = 0.004 relapse vs remission]. Up regulation of PHB in relapsing vs remission MS patients imply the potential use of PHB to clinically evaluate subclinical disease status towards prognosis of an oncoming relapse. Elevated PHB levels in EAE brains signify the role of PHB in regulating ROS and implies PHB's role in oxidative stress. PMID- 29242127 TI - Investigation of antibacterial properties of novel papain immobilized on tannic acid modified Ag/CuFe2O4 magnetic nanoparticles. AB - The non-toxic CuFe2O4 magnetic nanoparticles have been solvothermally synthesized, characterized and used as an efficient magnetic precursor for papain immobilization and then investigated antibacterial properties of them. For increasing the antibacterial activity, the silver nanoparticles were doped on CuFe2O4 magnetic nanoparticles. All prepared samples exhibited stronger antibacterial properties against Gram-positive bacteria (Staphyloccocus aureus) than Gram-negative bacteria (Escherichia coli). However, it was determined that the Ag/CuFe2O4 had a more vigorous antibacterial property against the Staphyloccocus aureus bacteria by calculating the inhibition diameter of 25 +/- 0.1 mm in the synthesized samples. Also, the antibacterial activity increased by immobilization of papain. PMID- 29242128 TI - Performance of 5 different displays in the detection of artificial incipient and recurrent caries-like lesions. AB - OBJECTIVES: The aim of this study was to assess whether auto-calibrating medical grade monitors perform better than off-the-shelf monitors and tablet computers in detecting artificial incipient and recurrent caries-like lesions. STUDY DESIGN: Sixty extracted teeth (30 premolars and 30 molars) were selected. All molars received class II amalgam and composite restorations. A 7-mm2 area on the crowns of half of the teeth was demineralized. Phantoms consisting of 4 teeth were created. Three observers using a 5-point scale evaluated digital periapical radiographs for the presence of caries on 5 displays: 2 autocalibrating medical grade monitors, 2 tablets, and 1 off-the-shelf monitor. Sensitivity, specificity, accuracy, and receiver operating curve data were calculated and verified through analysis of variance and Tukey tests. Observer agreements were assessed using Cohen's kappa test. RESULTS: Intraobserver agreement ranged from 0.347 to 0.612 (molars) and 0.617 to 0.811 (premolars). Interobserver agreement ranged from 0.239 to 0.559 (molars) and 0.657 to 0.858 (premolars). The performances of tablets and the off-the-shelf monitor were similar to medical monitors when the same tooth groups were compared. Medical-grade monitors presented fewer statistically significant differences when different lesions where compared within the same display and restorative material. CONCLUSIONS: Evaluations of similar lesions were not significantly different among the 3 types of displays. However, the autocalibrating medical-grade monitors performed better when incipient and recurrent lesions were compared. PMID- 29242129 TI - Comparison between peri-implant bone level changes of implants placed during and 3 months after iliac bone grafting. AB - OBJECTIVE: The aim of this study was to compare the peri-implant bone level changes of implants placed during and 3 months after bone grafting from the iliac crest. STUDY DESIGN: A total of 103 implants were placed: 42 during the grafting and 61 at 3 months after the grafting procedure. All patients were grafted with iliac bone from the anterosuperior iliac crest. Bone resorption was evaluated with cone beam computed tomography in all patients at their last control visit. Periodontal health was assessed via the gingival and plaque indices and pocket depths around the dental implants. RESULTS: Mean bone resorption values at the buccal, lingual, mesial, and distal sides of the implants were 1.08 mm, 0.36 mm, 0.30 mm, and 0.25 mm, respectively, in the delayed group, and 1.87 mm, 1.25 mm, 0.92 mm, and 1.23 mm, respectively, in the simultaneous group; the differences between the groups were significant. There were no significant between-group differences in the gingival or plaque indices or pocket depths. The mean follow up period was 29 months. CONCLUSIONS: For reconstructing atrophic jaws, bone grafting from the iliac crest and implant placement after 3 months is a reliable technique with a high success rate and less bone resorption. PMID- 29242130 TI - Calcified carotid artery atheromas in panoramic radiographs are associated with a first myocardial infarction: a case-control study. AB - OBJECTIVE: The aim of this case-control study was to investigate whether patients with a first myocardial infarction (MI) had a higher prevalence of calcified carotid artery atheromas (CCAAs) on panoramic radiographs (PRs) than age-, gender , and residential area-matched controls without MI. STUDY DESIGN: Six hundred ninety-six cases with a first MI and 696 controls were included in this substudy of the Swedish multicentre PAROKRANK study. All participants underwent panoramic radiography, and the PRs were evaluated for CCAAs. RESULTS: The prevalence of CCAAs detected by PR was 33.8% (235 of 696) in cases and 27.6% (192 of 696) in controls (odds ratio [OR] 1.24; 95% confidence interval [CI] 1.04-1.44; P = .012). Among males, 32.7% of cases (184 of 562) and 26.5% of controls (149 of 562) displayed CCAAs on PRs (OR 1.24; 95% CI 1.03-1.48; P = .022). Among both genders, bilateral CCAAs were significantly more common among cases than among controls (P = .002). CONCLUSIONS: Cases with recent MIs had a significantly higher prevalence of CCAAs on PRs compared with controls without MIs. This difference between groups was more pronounced for bilateral CCAAs. These findings supported the hypothesis that CCAA detection could serve as a risk indicator for future MIs. PMID- 29242131 TI - Knowledge Translation: The Bridging Function of Cochrane Rehabilitation. AB - Cochrane Rehabilitation is aimed to ensure that all rehabilitation professionals can apply Evidence Based Clinical Practice and take decisions according to the best and most appropriate evidence in this specific field, combining the best available evidence as gathered by high-quality Cochrane systematic reviews, with their own clinical expertise and the values of patients. This mission can be pursued through knowledge translation. The aim of this article is to shortly present what knowledge translation is, how and why Cochrane (previously known as Cochrane Collaboration) is trying to reorganize itself in light of knowledge translation, and the relevance that this process has for Cochrane Rehabilitation and in the end for the whole world of rehabilitation. It is well known how it is difficult to effectively apply in everyday life what we would like to do and to apply the scientific knowledge in the clinical field: this is called the know-do gap. In the field of evidence-based medicine, where Cochrane belongs, it has been proven that high-quality evidence is not consistently applied in practice. A solution to these problems is the so-called knowledge translation. In this context, Cochrane Rehabilitation is organized to provide the best possible knowledge translation in both directions (bridging function), obviously toward the world of rehabilitation (spreading reviews), but also to the Cochrane community (production of reviews significant for rehabilitation). Cochrane is now strongly pushing to improve its knowledge translation activities, and this creates a strong base for Cochrane Rehabilitation work, focused not only on spreading the evidence but also on improving its production to make it more meaningful for the world of rehabilitation. PMID- 29242132 TI - Molecular characterization, expression and functional analysis of NOD1, NOD2 and NLRC3 in Nile tilapia (Oreochromis niloticus). AB - The nucleotide-binding oligomerization domain proteins NOD1, NOD2 and NLRC3 are cytoplasmic pattern recognition receptors (PRRs) of the Nod-like receptor (NLR) family. In the present study, the Nile tilapia (Oreochromis niloticus) NOD1 (ntNOD1), NOD2 (ntNOD2) and NLRC3 (ntNLRC3) genes were cloned and characterized. The full-length ntNOD1, ntNOD2 and ntNLRC3 genes were 3924, 3886 and 4574 bp, encoding 941, 986 and 1130 amino acids, respectively. The three Nod-like receptors have a NACHT domain and a C-terminal leucine-rich repeat (LRR) domain. In addition, ntNOD1 and ntNOD2 have a N-terminal CARD domain (ntNOD2 has two). Phylogenetic analysis showed that the three NLRs are highly conserved. Tissue expression analysis of the three receptors revealed that the highest mRNA and protein levels of ntNOD1, ntNOD2 and ntNLRC3 were in the spleen. The expression patterns of NLRs during embryonic development showed that the expression levels of ntNOD2 and ntNLRC3 significantly increased from 2 to 8 days post-fertilization (dpf). The expression levels of ntNOD1 significantly increased from 2 to 6 dpf, decreased at 7 dpf and then increased at 8 dpf. Upon stimulation with an intraperitoneal injection of Streptococcus agalactiae, expression levels of the ntNOD1, ntNOD2 and ntNLRC3 mRNA and protein were clearly altered in the blood, spleen, kidney, intestine and gill. Furthermore, after cotransfection with an NF kappaB reporter plasmid, NF-kappaB activation in ntNOD1-overexpressing 293T cells significantly increased compared with that in control cells, before or after i EDPA-stimulation. By contrast, compared with control, ntNOD2 and ntNLRC3 had no effect on NF-kappaB activation in 293T cells, when their potential ligands were not stimulated. However, after MDP-stimulation, ntNOD2 and ntNLRC3 overexpression increased NF-kappaB activation in 293T cells. NOD1 and NLRC3 were uniformly distributed throughout the cytoplasm in 293T cells, whereas NOD2 was distributed throughout the cytoplasm and nucleus. Our results indicate that the three Nod like receptors are functionally conserved and may play pivotal roles in defense against pathogens such as Streptococcus agalactiae. PMID- 29242133 TI - Role of aloin in the modulation of certain immune parameters in skin mucus of an Indian major carp, Labeo rohita. AB - Enhancement of immune system seems to be the most promising method of preventing fish diseases. Several herbal products have immunostimulant properties, and are environmental friendly, economical and can act against a broad spectrum of pathogens. Present study was designed with an aim to evaluate the role of aloin, extracted from a herb Aloe barbadensis, in the modulation of certain immune parameters in an Indian major carp, Labeo rohita. Fishes were divided into control, vehicle control and aloin treated groups. Experiments were conducted for 7 days and fishes from the three groups were analyzed at 2d, 4d, 6d and 8d. The results demonstrated that at different intervals, L. rohita administered with aloin showed a significant increase in the activity of enzymes - lysozyme, protease, carboxylesterase, alkaline phosphatase, acid phosphatase, catalase and peroxidase, and non-enzymatic factors hemagglutinin and alternate complement compared with that of the controls. Thus, it can be concluded that administration of aloin is beneficial in enhancing the immune response and hence it can be used as potent immunostimulant in aquaculture. PMID- 29242134 TI - Non-contrast estimation of diffuse myocardial fibrosis with dual energy CT: A phantom study. AB - BACKGROUND: Estimation of diffuse myocardial fibrosis, substrate for adverse events such as heart failure and arrhythmias in patients with various cardiac disorders, is presently done by histopathology or cardiac magnetic resonance. We sought to develop a non-contrast method to estimate the amount of diffuse myocardial fibrosis leveraging dual energy computed tomography (DECT) in phantoms and a suitable small animal model. METHODS AND RESULTS: Phantoms consisted of homogenized bovine myocardium with varying amounts of Type 1 collagen. Fifteen mice underwent sham surgery, no procedure, or transverse aortic constriction (TAC) for 5 or 8 weeks to produce moderate or severe fibrosis, respectively. Phantoms and ex vivo mouse hearts were imaged on a single source, DECT scanner equipped with kVp switching. Monochromatic images were reconstructed at 40-140 keV. Linear discriminant analysis (LDA) was performed on mean myocardial CT numbers derived from single energy (70 keV) images as well as images reconstructed across multiple energies. Classification of myocardial fibrosis severity as low, moderate or severe was more often correct using the multi-energy CT/LDA approach vs. single energy CT/LDA in both phantoms (80.0% vs. 70.0%) and mice (93.3% vs. 33.3%). CONCLUSIONS: DECT myocardial imaging with multi-energy analysis better classifies myocardial fibrosis severity compared to a single energy-based approach. Non-contrast DECT can accurately and non-invasively estimate the extent of diffuse myocardial fibrosis in phantom and animal models. These data support further evaluation of this approach for in vivo myocardial fibrosis estimation. PMID- 29242135 TI - Quantitative image mean squared displacement (iMSD) analysis of the dynamics of profilin 1 at the membrane of live cells. AB - Image mean square displacement analysis (iMSD) is a method allowing the mapping of diffusion dynamics of molecules in living cells. However, it can also be used to obtain quantitative information on the diffusion processes of fluorescently labelled molecules and how their diffusion dynamics change when the cell environment is modified. In this paper, we describe the use of iMSD to obtain quantitative data of the diffusion dynamics of a small cytoskeletal protein, profilin 1 (pfn1), at the membrane of live cells and how its diffusion is perturbed when the cells are treated with Cytochalasin D and/or the interactions of pfn1 are modified when its actin and polyphosphoinositide binding sites are mutated (pfn1-R88A). Using total internal reflection fluorescence microscopy images, we obtained data on isotropic and confined diffusion coefficients, the proportion of cell areas where isotropic diffusion is the major diffusion mode compared to the confined diffusion mode, the size of the confinement zones and the size of the domains of dynamic partitioning of pfn1. Using these quantitative data, we could demonstrate a decreased isotropic diffusion coefficient for the cells treated with Cytochalasin D and for the pfn1-R88A mutant. We could also see changes in the modes of diffusion between the different conditions and changes in the size of the zones of pfn1 confinements for the pfn1 treated with Cytochalasin D. All of this information was acquired in only a few minutes of imaging per cell and without the need to record thousands of single molecule trajectories. PMID- 29242136 TI - Anxiolytic effect of CPEB1 knockdown on the amygdala of a mouse model of inflammatory pain. AB - Anxiety disorders are a category of mental disorders characterized by feelings of anxiety, stress, and fear attached to various sources. However, their pathogenesis is complicated and has not been fully elucidated. The amygdala is a vital brain region that regulates anxiety and mental disorders. Cytoplasmic polyadenylation element binding protein 1 (CPEB1) mediates the extension of the mRNA polyadenylation tail and facilitates the translation of target RNA. CPEB1 is closely related to neuronal diseases, such as Fragile X Syndrome, learning and memory disorders, and chronic pain. In this study, the role of CPEB1 in anxiety development was determined in a pain-mediated anxiety mouse model. The anxiety model was established in mice by injecting with Complete Freund's Adjuvant (CFA) into the hindpaw. CFA injection then led to anxiety-like behaviors and increased the CPEB1 levels in the mouse basolateral amygdala (BLA). CPEB1 enhancement facilitated the translation of GluA1, GluN2A, GluN2B, PSD95, and GABA receptors, which disturbed the E/I balance in the BLA as shown by enhanced excitatory presynaptic release and reduced inhibitory presynaptic release. CPEB1 knockdown with AAV-CPEB1-shRNA alleviated the anxiety-like behaviors but not the pain-like behaviors by enhancing inhibitory transmission in the BLA of model mice. The data suggest that CPEB1 participates in anxiety development by regulating excitatory/inhibitory synaptic transmission in the BLA. PMID- 29242137 TI - Sleep deprivation decreases neuronal excitability and responsiveness in rats both in vivo and ex vivo. AB - Sleep deprivation has severe consequences for higher nervous functions. Its effects on neuronal excitability may be one of the most important factors underlying functional deterioration caused by sleep loss. In the present work, excitability changes were studied using two complementary in vivo and ex vivo models. Auditory evoked potentials were recorded from freely-moving animals in vivo. Amplitude of evoked responses showed a near-continuous decrease during deprivation. Prevention of sleep also reduced synaptic efficacy ex vivo, measured from brain slices derived from rats that underwent sleep deprivation. While seizure susceptibility was not affected significantly by sleep deprivation in these preparations, the pattern of spontaneous seizure activity was altered. If seizures developed, they lasted longer and tended to contain more spikes in slices obtained from sleep-deprived than from control rats. Current-source density analysis revealed that location and sequence of activation of local cortical networks recruited by seizures did not change by sleep deprivation. Moderate differences seen in the amplitude of individual sinks and sources might be explained by smaller net transmembrane currents as a consequence of decreased excitability. These findings contradict the widely accepted conception of synaptic homeostasis suggesting gradual increase of excitability during wakefulness. Our results also indicate that decreased neuronal excitability caused by sleep deprivation is preserved in slices prepared from rats immediately after deprivation. This observation might mean new opportunities to explore the effects of sleep deprivation in ex vivo preparations that allow a wider range of experimental manipulations and more sophisticated methods of analysis than in vivo preparations. PMID- 29242138 TI - A High Prevalence of Food Insecurity Among University Students in Appalachia Reflects a Need for Educational Interventions and Policy Advocacy. AB - OBJECTIVES: To measure prevalence and correlates of food insecurity among college students in Appalachia, compare food-insecure and food-secure students on correlates, and identify predictor variables. DESIGN: Cross-sectional, online questionnaire. SETTING: University in Appalachia. PARTICIPANTS: Nonprobability, random sample of 1,093 students (317 male [30.1%]; 723 females [68.4%]). MAIN OUTCOME MEASURES: Food insecurity, coping strategies, money expenditure, academic progress, and demographics. ANALYSIS: Correlational, chi-square, and regression. RESULTS: A total of 239 students experienced low food security (21.9%) whereas 266 had experienced very low food security (24.3%) in the past 12 months. Predictor variables were higher money expenditure and coping strategy scale scores, lower grade point averages, male gender, receiving financial aid, fair or poor self-rated health status, and never cooking for self or others. These variables accounted for 48.1% of variance in food security scores. Most frequently used coping strategies included purchasing cheap, processed food (n = 282; 57.4%), stretching food (n = 199; 40.5%), and eating less healthy meals to eat more (n = 174; 35.4%). CONCLUSIONS AND IMPLICATIONS: Food-insecure students need interventions that teach budgeting skills and how to purchase and prepare healthy foods, as well as policies that increase access to food resource assistance. PMID- 29242139 TI - Mothers of Obese Children Use More Direct Imperatives to Restrict Eating. AB - OBJECTIVE: To examine the association of mother and child characteristics with use of direct imperatives to restrict eating. METHODS: A total of 237 mother child dyads (mean child age, 70.9 months) participated in a video-recorded, laboratory-standardized eating protocol with 2 large portions of cupcakes. Videos were reliably coded for counts of maternal direct imperatives to restrict children's eating. Anthropometrics were measured. Regression models tested the association of participant characteristics with counts of direct imperatives. RESULTS: Child obese weight status and maternal white non-Hispanic race/ethnicity were associated with greater levels of direct imperatives to restrict eating (p = .0001 and .0004, respectively). CONCLUSIONS AND IMPLICATIONS: Mothers of obese children may be using more direct imperatives to restrict eating so as to achieve behavioral compliance to decrease their child's food intake. Future work should consider the effects direct imperatives have on children's short- and long-term eating behaviors and weight gain trajectories. PMID- 29242140 TI - Impacts of a Vegetable Cooking Skills Program Among Low-Income Parents and Children. AB - OBJECTIVE: To evaluate the impact of a vegetable-focused cooking skills and nutrition program on parent and child psychosocial measures, vegetable liking, variety, and home availability. DESIGN: Baseline and postcourse surveys collected 1-week after the course. SETTING: Low-income communities in Minneapolis-St Paul. PARTICIPANTS: Parent-child dyads (n = 89; one third each Hispanic, African American, and white) with complete pre-post course data; flyer and e-mail recruitment. INTERVENTION(S): Six 2-hour-weekly sessions including demonstration, food preparation, nutrition education lessons, and a meal. MAIN OUTCOME MEASURES: Parental cooking confidence and barriers, food preparation/resource management, child self-efficacy and cooking attitudes, vegetable liking, vegetable variety, and vegetable home availability. ANALYSIS: Pre-post changes analyzed with paired t test or Wilcoxon signed-rank tests. Results were significant at P < .05. RESULTS: Increased parental cooking confidence (4.0 to 4.4/5.0), healthy food preparation (3.6 to 3.9/5.0), child self-efficacy (14.8 to 12.4; lower score = greater self-efficacy), vegetable variety (30 to 32/37 for parent, 22 to 24/37 for child), and home vegetable availability (16 to 18/35) (all P < .05). CONCLUSIONS AND IMPLICATIONS: A short-term evaluation of a vegetable-focused cooking and nutrition program for parents and children showed improvements in psychosocial factors, variety, and home availability. PMID- 29242141 TI - Molecular and epidemiological evidence of patient-to-patient hepatitis C virus transmission in a Scottish emergency department. AB - BACKGROUND: Transmission of hepatitis C virus (HCV) in the healthcare setting is rare. Routine infection prevention and control measures mean that this should be a preventable 'never event'. AIM: To investigate the diagnosis of acute healthcare-associated HCV infection. METHODS: Epidemiological and molecular investigation of a case of acute HCV infection associated with nosocomial exposure. FINDINGS: Detailed investigation of the treatment history of a patient with acute HCV infection identified transmission from a co-attending patient in an emergency department as the likely source; this possibility was confirmed by virus sequence analysis. The precise route of transmission was not identified, though both patient and source had minimally invasive healthcare interventions. Review of infection, prevention and control identified potentially contributory factors in the causal pathway including hand hygiene, inappropriate use of personal protective equipment, and blood contamination of the surface of the departmental blood gas analyser. CONCLUSION: We provide molecular and epidemiological evidence of HCV transmission between patients in an emergency department that was made possible by environmental contamination. Patients with HCV infection are higher users of emergency care than the general population and a significant proportion of those affected remain unknown and/or infectious. Equipment, departmental design, staff behaviour, and patient risk require regular review to minimize the risk of nosocomial HCV transmission. PMID- 29242142 TI - Use of a Penicillin Allergy Screening Algorithm and Penicillin Skin Testing for Transitioning Hospitalized Patients to First-Line Antibiotic Therapy. AB - BACKGROUND: Penicillin allergy is the most commonly reported antibiotic allergy. Avoidance of beta-lactam antibiotics in hospitalized patients leads to the use of second-line therapies. OBJECTIVE: The utility of a penicillin allergy history algorithm (PAHA) and subsequent penicillin skin testing (PST) in transitioning hospitalized patients from second- to first-line antibiotic therapy is described. METHODS: Through an electronic medical record report, pharmacists identified adult inpatients with penicillin allergy receiving moxifloxacin, intravenous vancomycin, aztreonam, daptomycin, or linezolid, in which a beta-lactam antibiotic was preferred. The PAHA was administered to identify patients for PST. Skin-test negative patients were transitioned to first-line beta-lactam antibiotic therapy. RESULTS: Fifty patients consented to the study. Historical reactions included hives (16 patients, 32%), angioedema (15, 30%), anaphylaxis (6, 12%), unknown (6, 12%), rash (6, 12%), and dyspnea (1, 2%). Pre-PST antibiotic regimens included vancomycin (82%), aztreonam (22%), moxifloxacin (6%), daptomycin (4%), and/or linezolid (2%). Forty-seven patients (94%) were skin-test negative and were subsequently transitioned to a beta-lactam antibiotic. Two patients were skin-test positive and one was histamine nonreactive. No patients experienced an immediate adverse reaction when challenged with a penicillin-based antibiotic. A total of 982 days of second-line antibiotic therapy and at least 23 hospital days to administer the antibiotic were avoided. CONCLUSIONS: The use of the PAHA and subsequent PST is a safe, effective multidisciplinary intervention that facilitates the transition to beta lactam antibiotics. Our approach is unique in that it prioritizes patients based on the use of second-line antibiotics, and then applies an algorithm to determine eligibility for PST. PMID- 29242143 TI - Increased ratio of pollock roe-specific IgE to salmon roe-specific IgE levels is associated with a positive reaction to cooked pollock roe oral food challenge. AB - BACKGROUND: Anaphylaxis and immediate-type fish roe allergies have been reported worldwide, and, in Japan, fish roe is the sixth most common food allergen. No oral food challenges (OFCs) have used pollock roe (PR), which is reported to have high cross-reactivity with salmon roe (SR). Therefore, we administered an OFC using cooked PR to evaluate PR- and SR-specific immunoglobulin E (IgE) levels and allergic reactions in patients with PR sensitivity. METHODS: This retrospective study evaluating patient characteristics and responses to OFCs was conducted with 10-20 g of cooked PR, between April 2006 and November 2016. RESULTS: We assessed 51 patients (median age: 6.8 years). All had PR sensitization, 6 (12%) with a history of immediate reactions to PR, and 18 (35%) of immediate reactions to SR. Median PR-specific and SR-specific IgE values were 3.4 kUA/L and 9.9 kUA/L, respectively. Seven patients (14%) had a positive OFC. There was no anaphylaxis. Induced symptoms were mild and included localized urticaria, throat pruritus, intermittent cough, and mild abdominal pain. We treated one patient with mild abdominal pain with oral antihistamines. There were no significant differences in history of immediate reaction to PR and PR-specific IgE titers between OFC positive and OFC-negative patients, although significant differences were found for PR-specific IgE titers adjusted for SR-specific IgE (p = 0.025) and PR specific IgE/SR-specific IgE ratio (p = 0.009). CONCLUSIONS: Increased PR specific IgE/SR-specific IgE ratio or PR-specific IgE levels adjusted for SR specific IgE levels were risk factors for OFC positivity. PMID- 29242144 TI - Recent advances in understanding the roles of blood platelets in the pathogenesis of allergic inflammation and bronchial asthma. AB - Platelets play an essential role in hemostasis to minimize blood loss due to traumatic injury. In addition, they contain various immune-associated molecules and contribute to immunological barrier formation at sites of vascular injury, thereby protecting against invading pathogens. Platelets are also crucially involved in development of allergic diseases, including bronchial asthma. Platelets in asthmatics are more activated than those in healthy individuals. By using a murine asthma model, platelets were shown to be actively involved in progression of the disease, including in airway eosinophilia and airway remodeling. In the asthmatic airway, pathological microvascular angiogenesis, a component of airway remodeling, is commonly observed, and the degree of abnormality is significantly associated with disease severity. Therefore, in order to repair the newly formed and structurally fragile blood vessels under inflammatory conditions, platelets may be continuously activated in asthmatics. Importantly, platelets constitutively express IL-33 protein, an alarmin cytokine that is essential for development of bronchial asthma. Meanwhile, the concept of development of allergic diseases has recently changed dramatically, and allergy researchers now share a belief in the centrality of epithelial barrier functions. In particular, IL-33 released from epithelial barrier tissue at sites of eczema can activate the antigen-non-specific innate immune system as an alarmin that is believed to be necessary for subsequent antigen-specific acquired immunological responses. From this perspective, we propose in this review a possible mechanism for how activated platelets act as an alarmin in development of bronchial asthma. PMID- 29242145 TI - ETosis-derived DNA trap production in middle ear effusion is a common feature of eosinophilic otitis media. PMID- 29242147 TI - Shared and divergent neural reactivity to non-drug operant response outcomes in current smokers and ex-smokers. AB - Addiction to cigarettes presents with considerable health risks and induces high costs on healthcare resources. While the majority of cigarette smokers endorse the desire to quit, only a small percentage of quit attempts lead to full abstinence. Failure to achieve abstinence may arise from maladaptive reactivity in fronto-striatal regions that track positive and negative valence outcomes, thus biasing the choice to smoke in the presence of alternative, non-drug reinforcement. Alternatively, long-term nicotine abstinence may reveal neural substrates of adaptive valence outcome processing that promote and maintain smoking cessation. The present study set out to examine the neural correlates of operant response outcomes in current smokers, ex-smokers and matched controls using a monetary incentive delay task during functional MRI. Here we report that compared to controls, both current smokers and ex-smokers showed significantly less activation change in the left amygdala during positive response outcomes, and in the anterior cingulate cortex, during both positive and negative response outcomes. Ex-smokers, however, demonstrated significantly greater activation change compared to smokers and controls in the right amygdala during negative response outcomes. Activation change in the anterior cingulate cortex and middle frontal gyrus of smokers was significantly negatively correlated with nicotine dependence and cigarette pack-years. These results suggest a pattern of shared and divergent reactivity in current smokers and ex-smokers within corticolimbic regions that track both positive and negative operant response outcomes. Exaggerated adaptive processing in ex-smokers may promote long-term smoking cessation through amplified negative valence outcome monitoring. PMID- 29242146 TI - Control of oocyte meiotic maturation in C. elegans. AB - In virtually all sexually reproducing animals, oocytes arrest in meiotic prophase and resume meiosis in a conserved biological process called meiotic maturation. Meiotic arrest enables oocytes, which are amongst the largest cells in an organism, to grow and accumulate the necessary cellular constituents required to support embryonic development. Oocyte arrest can be maintained for a prolonged period, up to 50 years in humans, and defects in the meiotic maturation process interfere with the faithful segregation of meiotic chromosomes, representing the leading cause of human birth defects and female infertility. Hormonal signaling and interactions with somatic cells of the gonad control the timing of oocyte meiotic maturation. Signaling activates the CDK1/cyclin B kinase, which plays a central role in regulating the nuclear and cytoplasmic events of meiotic maturation. Nuclear maturation encompasses nuclear envelope breakdown, meiotic spindle assembly, and chromosome segregation whereas cytoplasmic maturation involves major changes in oocyte protein translation and cytoplasmic organelles and is less well understood. Classically, meiotic maturation has been studied in organisms with large oocytes to facilitate biochemical analysis. Recently, the nematode Caenorhabditis elegans is emerging as a genetic paradigm for studying the regulation of oocyte meiotic maturation. Studies in this system have revealed conceptual, anatomical, and molecular links to oocytes in all animals including humans. This review focuses on the signaling mechanisms required to control oocyte growth and meiotic maturation in C. elegans and discusses how the downstream regulation of protein translation coordinates the completion of meiosis and the oocyte-to-embryo transition. PMID- 29242148 TI - Whole-bacterium SELEX of DNA aptamers for rapid detection of E.coli O157:H7 using a QCM sensor. AB - The rapid detection of foodborne pathogens is critical to ensure food safety. The objective of this study is to select aptamers specifically bound to Escherichia coli O157:H7 using the whole-bacterium SELEX (Systematic Evolution of Ligands by Exponential Enrichment) and apply the selected aptamer to a QCM (quartz crystal microbalance) sensor for rapid and sensitive detection of target bacteria. A total of 19 rounds of selection against live E. coli O157:H7 and 6 rounds of counter selection against a mixture of Staphylococcus aureus, Listeria monocytogenes, and Salmonella Typhimurium, were performed. The aptamer pool from the last round was cloned and sequenced. One sequence S1 that appeared 16 times was characterized and a dissociation constant (Kd) of 10.30nM was obtained. Subsequently, a QCM aptasensor was developed for the rapid detection of E. coli O157:H7. The limit of detection (LOD) and the detection time of the aptasensor was determined to be 1.46*103 CFU/ml and 50min, respectively. This study demonstrated that the ssDNA aptamer selected by the whole-bacterium SELEX possessed higher sensitivity than previous work and the potential use of the constructed QCM aptasensor in rapid screening of foodborne pathogens. PMID- 29242149 TI - Serial excision with power-stretching of the skin in giant melanocytic nevi therapy. PMID- 29242150 TI - Free flap reconstruction for trauma in the early post-partum period. PMID- 29242151 TI - Resveratrol induces sumoylated COX-2-dependent anti-proliferation in human prostate cancer LNCaP cells. AB - Cyclooxygenase (COX)-2 has been implicated in cancer development. However, resveratrol-induced nuclear accumulation of COX-2 enhances p53-dependent anti proliferation in different types of cancers. Treatment with resveratrol leads to phosphorylation and nuclear translocation of mitogen-activated protein kinase (ERK1/2), and accumulation of nuclear COX-2 to complex with pERK1/2 and p53. The consequence is Ser-15 phosphorylation of p53 (pSer15-p53), and induction of anti proliferation in cancer cells. We investigated the mechanisms by which resveratrol-inducible COX-2 facilitates p53-dependent anti-proliferation in prostate cancer LNCaP cells. Resveratrol treatment caused nuclear accumulation and complexing of ERK1/2, pSer15-p53 and COX-2 which was activated ERK1/2 dependent. Knockdown of SUMO-1 by shRNA also reduced nuclear accumulation of COX 2. Inhibition of nuclear accumulation by the COX-2 specific inhibitor, NS-398, inhibited co-localization of nuclear COX-2 and SUMO-1. Similar results were observed in the PD98059-treated cells. Finally, inhibition of SUMO-1 expression also reduced resveratrol-induced expression of pro-apoptotic genes but increased the expression of proliferative genes. In summary, these results demonstrate that inducible COX-2 associates with phosphorylated ERK1/2 to induce the phosphorylation of Ser-15 in p53 and then complexes with p53 and SUMO-1 which binds to p53-responsive pro-apoptotic genes to enhance their expression. The inhibition of COX-2 expression and activity significantly blocks the pro apoptotic effect of resveratrol. PMID- 29242152 TI - Human umbilical cord-derived mesenchymal stem cells protect from hyperoxic lung injury by ameliorating aberrant elastin remodeling in the lung of O2-exposed newborn rat. AB - The incidence and mortality rates of bronchopulmonary dysplasia (BPD) remain very high. Therefore, novel therapies are imminently needed to improve the outcome of this disease. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) show promising therapeutic effects on oxygen-induced model of BPD. In our experiment, UC-MSCs were intratracheally delivered into the newborn rats exposed to hyperoxia, a well-established BPD model. This study demonstrated that UC-MSCs reduce elastin expression stimulated by 90% O2 in human lung fibroblasts-a (HLF a), and inhibit HLF-a transdifferentiation into myofibroblasts. In addition, the therapeutic effects of UC-MSCs in neonatal rats with BPD, UC-MSCs could inhibit lung elastase activity and reduce aberrant elastin expression and deposition in the lung of BPD rats. Overall, this study suggested that UC-MSCs could ameliorate aberrant elastin expression in the lung of hyperoxia-induced BPD model which may be associated with suppressing increased TGFbeta1 activation. PMID- 29242153 TI - Characterization of Staphylococcus epidermidis Polynucleotide phosphorylase and its interactions with ribonucleases RNase J1 and RNase J2. AB - Polynucleotide phosphorylase catalyzes both 3'-5' exoribonuclease and polyadenylation reactions. The crystal structure of Staphylococcus epidermidis PNPase revealed a bound phosphate in the PH2 domain of each protomer coordinated by three adjacent serine residues. Mutational analysis suggests that phosphate coordination by these serine residues is essential to maintain the catalytic center in an active conformation. We note that PNPase forms a complex with RNase J1 and RNase J2 without substantially altering either exo-ribonuclease or polyadenylation activity of this enzyme. This decoupling of catalytic activity from protein-protein interactions suggests that association of these endo- or exo ribonucleases with PNPase could be more relevant for cellular localization or concerted targeting of structured RNA for recycling. PMID- 29242154 TI - High expression of diffuse panbronchiolitis critical region 1 gene promotes cell proliferation, migration and invasion in pancreatic ductal adenocarcinoma. AB - Diffuse panbronchiolitis critical region 1 (DPCR1) is located in the major histocompatibility complex (MHC) class I. It was reported to be downregulated in invasive pituitary adenoma compared with that in non-invasive tumors, but upregulated in the precursor of gastric carcinogenesis. However, the direct effect of DPCR1 on cancer cells has rarely been reported, and the role DPCR1 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The clinical sample validation and public data analysis of the present study demonstrated that DPCR1 was upregulated markedly in PDAC and this high expression was negatively correlated with the patient prognosis. Functionally, knocking down DPCR1 in PDAC cell lines inhibited cell proliferation, migration and invasion in vitro. Tumor xenograft experiments further showed that suppression of DPCR1 inhibited tumor growth in vivo. In addition, the results of RNA deep sequencing and qRT-PCR assay showed that DPCR1 participated in PADC progression by regulating nuclear factor kappa B signaling pathway, suggesting that it might be a novel oncogene in tumor progression and a potential therapeutic target in PDAC as well. PMID- 29242155 TI - A quantitative comparison of points of departure between 28-day and 90-day repeated dose studies with a proposed extrapolation factor. AB - The influence of exposure duration on chemical toxicity has important implications for risk assessment. Although a default 10-fold extrapolation factor is commonly applied when the toxicological dataset includes a subchronic (90-day) study but lacks studies of chronic duration, little consensus has been reached on an appropriate extrapolation factor to apply when the dataset includes a 28-day study but lacks studies of longer durations. The goal of the present assessment was to identify a 28-day to 90-day extrapolation factor by analyzing distributions of ratios of No-Observed-Adverse-Effect Levels (NOAELs) and Benchmark Doses (BMDs) derived from 28-day and 90-day studies. The results of this analysis suggest that a default 10-fold extrapolation factor in chemical risk assessment applications is sufficient to account for the uncertainty associated with evaluating human health risk based on results from a 28-day study in the absence of results from a 90-day study. This analysis adds significantly to the growing body of literature interpreting the influence of exposure duration on chemical toxicity that will likewise facilitate discussions on the future state of testing requirements in the international regulatory community. PMID- 29242156 TI - An avian reproduction study historical control database: A tool for data interpretation. AB - Avian reproduction studies are a regulatory requirement for pesticides in many regions. The data often require careful interpretation due to the nature of the study design. Here we present the historical control dataset for bobwhite quail and mallard duck reproduction studies performed at the Evans Analytical Group LLC avian toxicology laboratory over the period 1985-2016. The analysis demonstrates the stability of reproductive parameters over time and good agreement to normal control ranges as required by the regulatory test guidelines. The major source of variation is shown to be within study variation. Power analyses confirm the generally good power properties of the test design. Recommendations for the use of historical control data for the interpretation of avian reproduction studies are made. We believe the analysis and evaluation presented here can facilitate the development of practical guidance that can be implemented in regulatory programmes requiring this test. PMID- 29242157 TI - Determination of Green's function for three-dimensional traction force reconstruction based on geometry and boundary conditions of cell culture matrices. AB - : Cell migration plays a particular important role in the initiation and progression of many physical processes and pathological conditions such as tumor invasion and metastasis. Three-dimensional traction force microscopy (TFM) of high resolution and high accuracy is being developed in an effort to unveil the underlying mechanical process of cell migration in a vivo-like environment. Linear elasticity-based TFM (LETM) as a mainstream approach relies on the Green's function (that relates traction forces to matrix deformation), of which the inherent boundary conditions and geometry of the matrix could remarkably affect the result as suggested by previous 2D studies. In this study, we investigated this close linkage in 3D environment, via modeling of a cell sensing a close-by fixed boundary of a 3D matrix surrounding it, and comparing the reconstructed traction forces from three different solutions of the Green's function, including a fully matching solution derived using the adapted Mindlin's approach. To increase fidelity in the estimate of traction forces for extreme conditions such as a sparse sampling of deformation field or targeting small focal adhesions, we numerically solved the singularity problem of the Green's function in a non conventional way to avoid exclusion of singular point regions that could contain representative deformation indicators for such extreme conditions. A single case experimental study was conducted for a multi-cellular structure of endothelial cells that just penetrated into the gel at the early stage of angiogenesis. STATEMENT OF SIGNIFICANCE: This study focused on the fundamental issue regarding extension of linear elasticity-based TFM to deal with physically realistic matrices (where cells are encapsulated), which concerns determination of the Green's function matching their geometry and boundary conditions. To increase fidelity in the estimate of traction forces for extreme conditions such as a sparse sampling of deformation field or targeting small focal adhesions, we numerically solved the singularity problem of the Green's function to avoid exclusion of singular point regions that could contain representative deformation indicators for such extreme conditions. The proposed approach to adapting the Green's function for the specific 3D cell culture situation was examined in a single case experimental study of endothelial cells in sprouting angiogenesis. PMID- 29242158 TI - Additively manufactured biodegradable porous magnesium. AB - : An ideal bone substituting material should be bone-mimicking in terms of mechanical properties, present a precisely controlled and fully interconnected porous structure, and degrade in the human body to allow for full regeneration of large bony defects. However, simultaneously satisfying all these three requirements has so far been highly challenging. Here we present topologically ordered porous magnesium (WE43) scaffolds based on the diamond unit cell that were fabricated by selective laser melting (SLM) and satisfy all the requirements. We studied the in vitro biodegradation behavior (up to 4 weeks), mechanical properties and biocompatibility of the developed scaffolds. The mechanical properties of the AM porous WE43 (E = 700-800 MPa) scaffolds were found to fall into the range of the values reported for trabecular bone even after 4 weeks of biodegradation. Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), electrochemical tests and uCT revealed a unique biodegradation mechanism that started with uniform corrosion, followed by localized corrosion, particularly in the center of the scaffolds. Biocompatibility tests performed up to 72 h showed level 0 cytotoxicity (according to ISO 10993-5 and -12), except for one time point (i.e., 24 h). Intimate contact between cells (MG-63) and the scaffolds was also observed in SEM images. The study shows for the first time that AM of porous Mg may provide distinct possibilities to adjust biodegradation profile through topological design and open up unprecedented opportunities to develop multifunctional bone substituting materials that mimic bone properties and enable full regeneration of critical-size load-bearing bony defects. STATEMENT OF SIGNIFICANCE: The ideal biomaterials for bone tissue regeneration should be bone-mimicking in terms of mechanical properties, present a fully interconnected porous structure, and exhibit a specific biodegradation behavior to enable full regeneration of bony defects. Recent advances in additive manufacturing have resulted in biomaterials that satisfy the first two requirements but simultaneously satisfying the third requirement has proven challenging so far. Here we present additively manufactured porous magnesium structures that have the potential to satisfy all above-mentioned requirements. Even after 4 weeks of biodegradation, the mechanical properties of the porous structures were found to be within those reported for native bone. Moreover, our comprehensive electrochemical, mechanical, topological, and biological study revealed a unique biodegradation behavior and the limited cytotoxicity of the developed biomaterials. PMID- 29242159 TI - An implantable depot capable of in situ generation of micelles to achieve controlled and targeted tumor chemotherapy. AB - : Camptothecin (CPT)-containing promicelle polymers (PMCPT) based on 4-armed poly(ethylene glycol) (PEG) were developed previously to self-assemble into folate-targeted and glutathione (GSH)-sensitive micelles (MCPT). To address severe systemic toxicity and lack of tumor specificity implicated in the intravenous administration of MCPT, a micelle-generating depot has been developed by blend electrospinning of PEG-poly(lactide) (PELA) copolymers, PMCPT and polyethylene oxide (PEO). Upon implantation of the depot onto a tumor, PMCPT are sustainably released to self-assemble into MCPT on the tumor site. The release of PMCPT is adjusted by varying PEO/PELA ratios and reaches in the range of 23-92% after 30 days of incubation. By making use of the aggregation-induced emission (AIE) features of tetraphenylethylene (TPE) derivatives, the release process of TPE-containing promicelle polymers (PMTPE) from the depot and the spontaneous formation of micelles (MTPE) have been monitored from the self-assembly-induced fluorescence light-up both in vitro and in vivo. Compared with intravenous injection of MCPT, the micelle-generating depot has significantly enhanced micelle accumulation in the tumor for an extended period of time and resulted in stronger tumor inhibitory efficacy, reduced systemic toxicity and more effective inhibition of tumor metastasis, demonstrating great potential for targeted cancer therapy with sustained efficacy. STATEMENT OF SIGNIFICANCE: The promicelle polymer-co-electrospun fibers are developed to form a micelle-generating depot after implantation onto the tumor. The promicelle polymers are continuously released and simultaneously self-assemble into folate-targeted and glutathione sensitive micelles, ensuring sustained micelle delivery for more than 30 days. The process of micelle formation in the tumor tissue is visualized in vivo for the first time based on the mechanism of aggregation-induced emission. This in situ micelle formation also prevents premature drug release and rapid clearance from the bloodstream. In addition, these fibers deliver anti-cancer agents directly within tumor cells via dual selectivity (i.e. spatially selective accumulation in tumor tissues via implantation and selective internalization into tumor cells via folate receptor-mediated endocytosis) and on-demand drug release in response to cytosol GSH. They exhibit superior tumor inhibitory efficacy with minimal systemic toxicity, and prevent from malignant metastasis of cancer cells. PMID- 29242161 TI - Preparation of dexamethasone-loaded biphasic calcium phosphate nanoparticles/collagen porous composite scaffolds for bone tissue engineering. AB - : Although bone is regenerative, its regeneration capacity is limited. For bone defects beyond a critical size, further intervention is required. As an attractive strategy, bone tissue engineering (bone TE) has been widely investigated to repair bone defects. However, the rapid and effective bone regeneration of large non-healing defects is still a great challenge. Multifunctional scaffolds having osteoinductivity and osteoconductivity are desirable to fasten functional bone tissue regeneration. In the present study, biomimetic composite scaffolds of collagen and biphasic calcium phosphate nanoparticles (BCP NPs) with a controlled release of dexamethasone (DEX) and the controlled pore structures were prepared for bone TE. DEX was introduced in the BCP NPs during preparation of the BCP NPs and hybridized with collagen scaffolds, which pore structures were controlled by using pre-prepared ice particulates as a porogen material. The composite scaffolds had well controlled and interconnected pore structures, high mechanical strength and a sustained release of DEX. The composite scaffolds showed good biocompatibility and promoted osteogenic differentiation of hMSCs when used for three-dimensional culture of human bone marrow-derived mesenchymal stem cells. Subcutaneous implantation of the composite scaffolds at the dorsa of athymic nude mice demonstrated that they facilitated the ectopic bone tissue regeneration. The results indicated the DEX-loaded BCP NPs/collagen composite scaffolds had high potential for bone TE. STATEMENT OF SIGNIFICANCE: Scaffolds play a crucial role for regeneration of large bone defects. Biomimetic scaffolds having the same composition of natural bone and a controlled release of osteoinductive factors are desirable for promotion of bone regeneration. In this study, composite scaffolds of collagen and biphasic CaP nanoparticles (BCP NPs) with a controlled release nature of dexamethasone (DEX) were prepared and their porous structures were controlled by using ice particulates. In vitro cell culture and in vivo implantation experiments demonstrated the composite scaffolds exerted synergistic effects on the osteogenic differentiation of hMSCs and bone regeneration. The composite scaffolds also showed promotive effect on the formation of capillary blood vessels in the regenerated bone. This study is the first research to prepare DEX loaded BCP NPs/collagen porous composite scaffolds. The superior performance of the composite scaffolds indicates the composite scaffolds should be useful for bone tissue engineering. PMID- 29242160 TI - The impact of functional groups of poly(ethylene glycol) macromers on the physical properties of photo-polymerized hydrogels and the local inflammatory response in the host. AB - : Poly(ethylene glycol) (PEG) can be functionalized and modified with various moieties allowing for a multitude of cross-linking chemistries. Here, we investigate how vinyl sulfone, acrylate, and maleimide functional end groups affect hydrogel formation, physical properties, viability of encapsulated cells, post-polymerization modification, and inflammatory response of the host. We have shown that PEG-VS hydrogels, in the presence of a co-monomer, N-vinyl-2 pyrrolidone (NVP), form more efficiently than PEG-Ac and PEG-Mal hydrogels, resulting in superior physical properties after 6 min of ultraviolet light exposure. PEG-VS hydrogels exhibited hydrolytic stability and non-fouling characteristics, as well as the ability to be modified with biological motifs, such as RGD, after polymerization. Additionally, unmodified PEG-VS hydrogels resulted in lesser inflammatory response, cellular infiltration, and macrophage recruitment after implantation for 28 days in mice. These findings show that altering the end group chemistry of PEG macromer impacts characteristics of the photo-polymerized network. We have developed a tunable non-degradable PEG system that is conducive for cell or tissue encapsulation and evokes a minimal inflammatory response, which could be utilized for future immunoisolation applications. STATEMENT OF SIGNIFICANCE: The objective of this study was to develop a tunable non-degradable PEG system that is conducive for encapsulation and evokes a minimal inflammatory response, which could be utilized for immunoisolation applications. This study has demonstrated that reactive functional groups of the PEG macromers impact free radical mediated network formation. Here, we show PEG-VS hydrogels meet the design criteria for an immunoisolating device as PEG-VS hydrogels form efficiently via photo polymerization, impacting bulk properties, was stable in physiological conditions, and elicited a minimal inflammatory response. Further, NVP can be added to the precursor solution to expedite the cross-linking process without impacting cellular response upon encapsulation. These findings present an additional approach/chemistry to encapsulate cells or tissue for immunoisolation applications. PMID- 29242162 TI - NF-kappaB signaling is key in the wound healing processes of silk fibroin. AB - : Silk fibroin (SF) is a well-studied biomaterial for tissue engineering applications including wound healing. However, the signaling mechanisms underlying the impact of SF on this phenomenon have not been determined. In this study, through microarray analysis, regulatory genes of NF-KB signaling were activated in SF-treated NIH3T3 cells along with other genes. Immunoblot analysis confirmed the activation of the NF-KB signaling pathway as SF induced protein expression levels of IKKalpha, IKKbeta, p65, and the degradation of IkappaBalpha. The treatment of NIH3T3 cells with SF also increased the expression of cyclin D1, vimentin, fibronectin, and vascular endothelial growth factor (VEGF). The expression of these factors by SF treatment was abrogated when NF-KB was inhibited by a pharmacological inhibitor Bay 11-7082. Knockdown of NF-KB using siRNA of IKKalpha and IKKbeta also inhibited the SF-induced wound healing response of the NIH3T3 cells in a wound scratch assay. Collectively, these results indicated that SF-induced wound healing through the canonical NF-kappaB signaling pathway via regulation of the expression of cyclin D1, vimentin, fibronectin, and VEGF by NIH3T3 cells. Using an in vivo study with a partial thickness excision wound in rats we demonstrated that SF-induced wound healing via NF-kappaB regulated proteins including cyclin D1, fibronectin, and VEGF. The in vitro and in vivo data suggested that SF induced wound healing via modulation of NF-KB signaling regulated proteins. STATEMENT OF SIGNIFICANCE: Silk fibroin has been effectively used as a dressing for wound treatment for more than a century. However, mechanistic insight into the basis for wound healing via silk fibroin has not been elucidated. Here we report a key mechanism involved in silk fibroin induced wound healing both in vitro and in vivo. Using genetic- and protein-level analyses, NF-kappaB signaling was found to regulate silk fibroin induced wound healing by modulating target proteins. Thus, the NF-kappaB signaling pathway may be utilized as a therapeutic target during the formulation of silk fibroin-based biomaterials for wound healing and tissue engineering. PMID- 29242163 TI - Changes of DNA topology affect the global transcription landscape and allow rapid growth of a Bacillus subtilis mutant lacking carbon catabolite repression. AB - Bacteria are able to prioritize preferred carbon sources from complex mixtures. This is achieved by the regulatory phenomenon of carbon catabolite repression. To allow the simultaneous utilization of multiple carbon sources and to prevent the time-consuming adaptation to each individual nutrient in biotechnological applications, mutants lacking carbon catabolite repression can be used. However, such mutants often exhibit pleiotropic growth defects. We have isolated and characterized mutations that overcome the growth defect of Bacillus subtilis ccpA mutants lacking the major regulator of catabolite repression, in particular their glutamate auxotrophy. Here we show, that distinct mutations affecting the essential DNA topoisomerase I (TopA) cause glutamate prototrophy of the ccpA mutant. These suppressing variants of the TopA enzyme exhibit increased activity resulting in enhanced relaxation of the DNA. Reduced DNA supercoiling results in enhanced expression of the gltAB operon encoding the biosynthetic glutamate synthase. This is achieved by a significant re-organization of the global transcription network accompanied by re-routing of metabolism, which results in inactivation of the glutamate dehydrogenase. Our results provide a link between DNA topology, the global transcriptional network, and glutamate metabolism and suggest that specific topA mutants may be well suited for biotechnological purposes. PMID- 29242164 TI - Rapid allopolyploid radiation of moonwort ferns (Botrychium; Ophioglossaceae) revealed by PacBio sequencing of homologous and homeologous nuclear regions. AB - Polyploidy is a major speciation process in vascular plants, and is postulated to be particularly important in shaping the diversity of extant ferns. However, limitations in the availability of bi-parental markers for ferns have greatly limited phylogenetic investigation of polyploidy in this group. With a large number of allopolyploid species, the genus Botrychium is a classic example in ferns where recurrent polyploidy is postulated to have driven frequent speciation events. Here, we use PacBio sequencing and the PURC bioinformatics pipeline to capture all homeologous or allelic copies of four long (~1 kb) low-copy nuclear regions from a sample of 45 specimens (25 diploids and 20 polyploids) representing 37 Botrychium taxa, and three outgroups. This sample includes most currently recognized Botrychium species in Europe and North America, and the majority of our specimens were genotyped with co-dominant nuclear allozymes to ensure species identification. We analyzed the sequence data using maximum likelihood (ML) and Bayesian inference (BI) concatenated-data ("gene tree") approaches to explore the relationships among Botrychium species. Finally, we estimated divergence times among Botrychium lineages and inferred the multi labeled polyploid species tree showing the origins of the polyploid taxa, and their relationships to each other and to their diploid progenitors. We found strong support for the monophyly of the major lineages within Botrychium and identified most of the parental donors of the polyploids; these results largely corroborate earlier morphological and allozyme-based investigations. Each polyploid had at least two distinct homeologs, indicating that all sampled polyploids are likely allopolyploids (rather than autopolyploids). Our divergence time analyses revealed that these allopolyploid lineages originated recently within the last two million years-and thus that the genus has undergone a recent radiation, correlated with multiple independent allopolyploidizations across the phylogeny. Also, we found strong parental biases in the formation of allopolyploids, with individual diploid species participating multiple times as either the maternal or paternal donor (but not both). Finally, we discuss the role of polyploidy in the evolutionary history of Botrychium and the interspecific reproductive barriers possibly involved in these parental biases. PMID- 29242165 TI - Molecular phylogeny and divergence of the map turtles (Emydidae: Graptemys). AB - The map turtles (genus Graptemys) comprise a morphologically diverse clade that forms a major component of the southeastern US hotspot of chelonian diversity. Map turtles have experienced both recent and rapid diversification resulting in long-standing uncertainty regarding species boundaries and phylogenetic relationships within the genus as well as timing of their divergence. We present a phylogeny for the group that includes geographically representative sampling for all described species and subspecies. We make use of an empirical prior on rates of molecular evolution to estimate divergence times with a molecular clock under a coalescent framework. Together, the phylogeny and divergence time estimates suggest that diversification has been both more recent and more rapid than has so far been suspected. We provide a well-supported evolutionary framework for Graptemys that is necessary for understanding map turtle diversity, biogeography, and for conservation of this threatened clade of turtles. PMID- 29242166 TI - Genomic data resolve gene tree discordance in spiderhunters (Nectariniidae, Arachnothera). AB - Reduced representation genomic sequencing methods efficiently gather sequence data from thousands of loci throughout the genome. These data can be used to test previous phylogenetic hypotheses produced from limited numbers of mitochondrial and nuclear loci that often reveal intriguing, but conflicting, results. In this paper, we use phylogenomic data to revisit recent molecular phylogenetic work that clarified many taxonomic relationships within spiderhunters, but also questioned the monophyly of this distinctive genus of sunbirds (AVES: Nectariniidae; Arachnothera). DNA sequence data were produced by target-capture sequencing of ultraconserved elements (UCEs) to infer the evolutionary history of 11 species of Arachnothera and six outgroups, including the Purple-naped Sunbird (Hypogramma hypogrammicum), which previous work suggested might lie within Arachnothera. Although we recovered many different gene tree topologies, concatenated and coalescent methods of analysis converged on a species tree that strongly supports the monophyly of Arachnothera, with Hypogramma as its sister taxon. PMID- 29242168 TI - AKT1 distinctively suppresses MyD88-depenedent and TRIF-dependent Toll-like receptor signaling in a kinase activity-independent manner. AB - We found that AKT1, a primary effector molecule of PI3K-AKT signaling, distinctively suppressed Toll-like receptor (TLR)-mediated MyD88-dependent and Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF)-dependent signaling by inhibiting NF-kappaB activation and IRF3 activity independently of its kinase activity. In AKT1 knockout RAW264.7 cells, lipopolysaccharide (LPS)-induced transcription and protein production of cytokines including IL-1beta and TNF alpha (regulated by the MyD88-dependent pathway), as well as IFN-beta and RANTES (C-C motif chemokine ligand 5: CCL-5; regulated by the TRIF-dependent pathways) was enhanced compared to wild type cells. In response to LPS stimulation, AKT1 knockout cells also exhibited enhanced NF-kappaB and IFN-beta promoter activities, which were reduced to a level comparable to that in wild type cells by complementation with either AKT1 or its kinase-dead mutant (AKT1-KD). Expression of AKT1 or AKT1-KD similarly suppressed NF-kappaB and IFN-beta promoter activities induced by LPS and other TLR ligands in wild type cells. Analysis of NF-kappaB activation caused by transient expression of proteins involved in the MyD88-dependent pathway in TLR signaling revealed that AKT1 suppressed signaling that occurs between activation of IKKbeta and that of NF kappaB. In contrast, AKT1 appeared to suppress the IFN-beta promoter through inhibition of IRF3 activity itself. These results demonstrate a novel, non-kinase function of AKT1 that inhibits TLR signaling, and suggest the multifunctional nature of AKT1. PMID- 29242167 TI - Membrane-initiated nuclear trafficking of the glucocorticoid receptor in hypothalamic neurons. AB - Glucocorticoid binding to the intracellular glucocorticoid receptor (GR) stimulates the translocation of the GR from the cytosol to the nucleus, which leads to the transactivation or transrepression of gene transcription. However, multiple lines of evidence suggest that glucocorticoid signaling can also be initiated from the plasma membrane. Here, we provide evidence for membrane initiated glucocorticoid signaling by a membrane-impermeant dexamethasone-bovine serum albumin (Dex-BSA) conjugate, which induced GR nuclear trafficking in hypothalamic neurons in vitro and in vivo. The GR nuclear translocation induced by a membrane-impermeant glucocorticoid suggests trafficking of an unliganded GR. The membrane-initiated GR trafficking was not blocked by inhibiting ERK MAPK, p38 MAPK, PKA, Akt, Src kinase, or calcium signaling, but was inhibited by Akt activation. Short-term exposure of hypothalamic neurons to dexamethasone (Dex) activated the glucocorticoid response element (GRE), suggesting transcriptional transactivation, whereas exposure to the Dex-BSA conjugate failed to activate the GRE, suggesting differential transcriptional activity of the liganded compared to the unliganded GR. Microarray analysis revealed divergent transcriptional regulation by Dex-BSA compared to Dex. Together, our data suggest that signaling from a putative membrane glucocorticoid receptor induces the trafficking of unliganded GR to the nucleus, which elicits a pattern of gene transcription that differs from that of the liganded receptor. The differential transcriptional signaling by liganded and unliganded receptors may contribute to the broad range of genetic regulation by glucocorticoids, and may help explain some of the different off-target actions of glucocorticoid drugs. PMID- 29242169 TI - C60 fullerenes disrupt cellular signalling leading to TRPC4 and TRPC6 channels opening by the activation of muscarinic receptors and G-proteins in small intestinal smooth muscles. AB - The effect of water-soluble pristine C60 fullerene nanoparticles (C60NPs) on receptor-operated cation channels formed by TRPC4/C6 proteins in ileal smooth muscle cells was investigated for the first time. Activation of these channels subsequent to acetylcholine binding to the expressed in these cells M2 and M3 muscarinic receptors represents the key event in the parasympathetic control of gastrointestinal smooth muscle motility and cholinergic excitation-contraction coupling. Experiments were performed on single collagenase-dispersed mouse ileal myocytes using patch-clamp techniques with symmetrical 125mM Cs+ solutions and [Ca2+]i 'clamped' at 100nM in order to isolate the muscarinic cation current (mICAT). The current was induced by intracellular infusion of 200MUM GTPgammaS, which activates G-proteins directly, i.e. bypassing the muscarinic receptors. C60NPs applied at 10-6M at peak response to activation of G-proteins caused mICAT inhibition by 47.0+/-3.5% (n=9). The inhibition developed rather slowly, with the time constant of 119+/-16s, was voltage-independent and irreversible. Thus, C60NPs are unlikely to cause any direct block of TRPC4/C6 channels; rather, they may accumulate in the membrane and disrupt G-protein signalling leading to mICAT generation. C60NPs may represent a novel class of biocompatible molecules for the treatment of disorders associated with enhanced gastrointestinal motility. PMID- 29242170 TI - A shift in the IL-6/STAT3 signalling pathway imbalance towards the SHP2 pathway in severe asthma results in reduced proliferation process. AB - BACKGROUND: Bronchial fibroblasts are the main structural cells responsible for extracellular matrix production and turnover in lung tissue. They play a key role in airway remodelling in asthma through different cytokines including interleukin (IL-6). OBJECTIVE: To decipher IL-6 signalling in bronchial fibroblasts obtained from severe eosinophilic asthmatics compared to mild asthmatics and healthy controls. METHODS: Human bronchial fibroblasts were isolated from bronchial biopsies of mild and severe eosinophilic asthmatics and non-atopic healthy controls. IL-6 was assessed by qRT-PCR and ELISA. Phosphorylated STAT3, SHP2 and p38/MAPK were evaluated by Western blot. Chemical inhibitors for SHP2 and p38 were used. Fibroblast proliferation was evaluated by BrdU incorporation test. RESULTS: IL-6 release was significantly increased in fibroblasts from mild and severe asthmatics compared to healthy controls. Fibroblasts from severe asthmatics showed a reduced STAT3 activation compared to mild asthmatics and healthy controls. Constitutive activation of phosphatase SHP2 was found to negatively regulate IL-6 induced STAT3 phosphorylation in fibroblasts from severe asthmatics. This effect was accompanied by a decrease in fibroblast proliferation rate due to the activated p38/mitogen-activated protein kinase. SHP2 and p38/MAPK specific inhibitors (PHPS1 and SB212190) significantly induce a restoration of STAT3 phosphorylation, IL-6 target gene expression and cell proliferation. CONCLUSION: These data show dysregulated IL-6 signalling in bronchial fibroblasts derived from severe eosinophilic asthmatic subjects involving the protein tyrosine phosphatase SHP2 and p38MAPK. Collectively, our data provides new insights into the mechanisms by which bronchial fibroblasts regulate airway remodelling in severe asthma. PMID- 29242171 TI - Down-regulation of stearoyl-CoA desaturase-1 increases susceptibility to palmitic acid-induced lipotoxicity in human trophoblast cells. AB - In early pregnancy, adequate dietary factors are important for the growth of human trophoblast cells, followed by placental development. Although stearoyl-CoA desaturase 1 (SCD1) is expected to relieve palmitic acid (PA)-induced lipotoxicity by regulating diacylglycerol and ceramide, its function is unclear in human trophoblast cells. The aim was to investigate inhibitory effects of SCD1 activity on PA-induced trophoblast cell death. PA induces cell death and inhibits the invasion of human trophoblast cells (HTR8/SVneo). In addition, we demonstrate that SCD1 has a protective role against PA in human trophoblast cells by regulating AKT-mediated signaling pathway and mitochondrial membrane potential. The knockdown of SCD1 enhances the proapoptotic activity of PA in HTR8/SVneo cells. Lastly, we investigated microRNA expression predicted to target SCD1 and diacylglycerol O-acyltransferase 1 (DGAT1) by PA. Collectively, the results suggest potential roles of SCD1 and DGAT1 in alleviating the toxicity of PA and maintaining lipid homeostasis for normal placentation. PMID- 29242172 TI - Curcumin enhances LXRalpha in an AMP-activated protein kinase-dependent manner in human macrophages. AB - Liver X receptor alpha (LXRalpha) is a nuclear receptor involved in cholesterol homeostasis. Curcumin, a traditional Chinese derivative from the rhizomes of Curcuma longa and a well-known AMP-activated protein kinase (AMPK) activator, possess hypocholesterolemic activity, however, the possible link between AMPK and cholesterol is unknown. In this study, we have investigated whether curcumin regulates metabolic changes in cholesterol metabolism via LXRalpha in THP-1 human macrophages, the cells implicated in atheroma plaques formation. Results showed that curcumin induced AMPK phosphorylation, increased LXRalpha mRNA and protein expression. Curcumin up-regulated mRNA expression of genes involved in cholesterol transport and metabolism as ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, and the sterol response element binding protein 1c (SREBP1c). On the other hand, this increased LXRalpha mRNA and protein expression was reverted when AMPK was inhibited by its chemical inhibitor, compound C. Transfection with AMPK alpha1 and alpha2 siRNA decreased the LXRalpha mRNA expression and its target genes. Curcumin treatment inhibited cell migration and was also able to promote reverse cholesterol transport in THP-1 cells. This enhanced reverse cholesterol transport might be related to the up-regulating of ABCA1 and ABCG1 mRNA expression by activating AMPK-LXRalpha signaling in THP-1 cells. This study describes a possible mechanism for understanding the hypocholesterolemic effects of curcumin and expand knowledge about the LXRalpha regulation by AMPK. PMID- 29242173 TI - Exploring Determinants of Patient Adherence to a Portal-Supported Oncology Rehabilitation Program: Interview and Data Log Analyses. AB - BACKGROUND: Telemedicine applications often do not live up to their expectations and often fail once they have reached the operational phase. OBJECTIVE: The objective of this study was to explore the determinants of patient adherence to a blended care rehabilitation program, which includes a Web portal, from a patient's perspective. METHODS: Patients were enrolled in a 12-week oncology rehabilitation treatment supported by a Web portal that was developed in cooperation with patients and care professionals. Semistructured interviews were used to analyze thought processes and behavior concerning patient adherence and portal use. Interviews were conducted with patients close to the start and the end of the treatment. Besides, usage data from the portal were analyzed to gain insights into actual usage of the portal. RESULTS: A total of 12 patients participated in the first interview, whereas 10 participated in the second round of interviews. Furthermore, portal usage of 31 patients was monitored. On average, 11 persons used the portal each week, with a maximum of 20 in the seventh week and a drop toward just one person in the weeks in the follow-up period of the treatment. From the interviews, it was derived that patients' behavior in the treatment and use of the portal was primarily determined by extrinsic motivation cues (eg, stimulation by care professionals and patient group), perceived severity of the disease (eg, physical and mental condition), perceived ease of use (eg, accessibility of the portal and the ease with which information is found), and perceived usefulness (eg, fit with the treatment). CONCLUSIONS: The results emphasized the impact that care professionals and fellow patients have on patient adherence and portal usage. For this reason, the success of blended care telemedicine interventions seems highly dependent on the willingness of care professionals to include the technology in their treatment and stimulate usage among patients. PMID- 29242174 TI - Standard Anatomic Terminologies: Comparison for Use in a Health Information Exchange-Based Prior Computed Tomography (CT) Alerting System. AB - BACKGROUND: A health information exchange (HIE)-based prior computed tomography (CT) alerting system may reduce avoidable CT imaging by notifying ordering clinicians of prior relevant studies when a study is ordered. For maximal effectiveness, a system would alert not only for prior same CTs (exams mapped to the same code from an exam name terminology) but also for similar CTs (exams mapped to different exam name terminology codes but in the same anatomic region) and anatomically proximate CTs (exams in adjacent anatomic regions). Notification of previous same studies across an HIE requires mapping of local site CT codes to a standard terminology for exam names (such as Logical Observation Identifiers Names and Codes [LOINC]) to show that two studies with different local codes and descriptions are equivalent. Notifying of prior similar or proximate CTs requires an additional mapping of exam codes to anatomic regions, ideally coded by an anatomic terminology. Several anatomic terminologies exist, but no prior studies have evaluated how well they would support an alerting use case. OBJECTIVE: The aim of this study was to evaluate the fitness of five existing standard anatomic terminologies to support similar or proximate alerts of an HIE-based prior CT alerting system. METHODS: We compared five standard anatomic terminologies (Foundational Model of Anatomy, Systematized Nomenclature of Medicine Clinical Terms, RadLex, LOINC, and LOINC/Radiological Society of North America [RSNA] Radiology Playbook) to an anatomic framework created specifically for our use case (Simple ANatomic Ontology for Proximity or Similarity [SANOPS]), to determine whether the existing terminologies could support our use case without modification. On the basis of an assessment of optimal terminology features for our purpose, we developed an ordinal anatomic terminology utility classification. We mapped samples of 100 random and the 100 most frequent LOINC CT codes to anatomic regions in each terminology, assigned utility classes for each mapping, and statistically compared each terminology's utility class rankings. We also constructed seven hypothetical alerting scenarios to illustrate the terminologies' differences. RESULTS: Both RadLex and the LOINC/RSNA Radiology Playbook anatomic terminologies ranked significantly better (P<.001) than the other standard terminologies for the 100 most frequent CTs, but no terminology ranked significantly better than any other for 100 random CTs. Hypothetical scenarios illustrated instances where no standard terminology would support appropriate proximate or similar alerts, without modification. CONCLUSIONS: LOINC/RSNA Radiology Playbook and RadLex's anatomic terminologies appear well suited to support proximate or similar alerts for commonly ordered CTs, but for less commonly ordered tests, modification of the existing terminologies with concepts and relations from SANOPS would likely be required. Our findings suggest SANOPS may serve as a framework for enhancing anatomic terminologies in support of other similar use cases. PMID- 29242175 TI - Developing mHealth Messages to Promote Postmenstrual Regulation Contraceptive Use in Bangladesh: Participatory Interview Study. AB - BACKGROUND: Abortions are restricted in Bangladesh, but menstrual regulation is an approved alternative, defined as a procedure of regulating the menstrual cycle when menstruation is absent for a short duration. Use of contraception after menstrual regulation can reduce subsequent unintended pregnancy, but in Bangladesh, the contraceptive method mix is dominated by short-term methods, which have higher discontinuation and failure rates. Mobile phones are a channel via which menstrual regulation clients could be offered contraceptive support after leaving the clinic. OBJECTIVE: This study aimed to support the development of a mobile phone intervention to support postmenstrual regulation family planning use in Bangladesh. It explored what family planning information women want to receive after having a menstrual regulation procedure, whether they would like to receive this information via their mobile phone, and if so, what their preferences are for the way in which it is delivered. METHODS: We conducted participatory interviews with 24 menstrual regulation clients in Dhaka and Sylhet divisions in Bangladesh. Women were recruited from facilities in urban and peri urban areas, which included public sector clinics supported by Ipas, an international nongovernmental organization (NGO), and NGO clinics run by Marie Stopes. Main themes covered in the interviews were factors affecting the use of contraception, what information and support women want after their menstrual regulation procedure, how respondents would prefer to receive information about contraception, and other key issues for mobile health (mHealth) interventions, such as language and privacy. As part of the in-depth interviews, women were shown and played 6 different messages about contraception on the research assistant's phone, which they were given to operate, and were then asked to give feedback. RESULTS: Women were open to both receiving messages about family planning methods on their mobile phones and talking to a counselor about family planning methods over the phone after their menstrual regulation. Women most commonly wanted information about the contraceptive method they were currently using and wanted this information to be tailored to their particular needs. Women preferred voice messages to text and liked the interactive voice message format. When asked to repeat and identify the main points of the messages, women demonstrated good understanding of the content. Women did not seem too concerned with privacy or with others reading the messages and welcomed including their husbands in speaking to a counselor. CONCLUSIONS: This study found that menstrual regulation clients are very interested in receiving information on their phones to support family planning use and wanted more information about the method of contraception they were using. Participatory voicemail was the preferred modality. PMID- 29242176 TI - Chinese Cardiovascular Disease Mobile Apps' Information Types, Information Quality, and Interactive Functions for Self-Management: Systematic Review. AB - BACKGROUND: China has a large population with cardiovascular disease (CVD) that requires extensive self-management. Mobile health (mHealth) apps may be a useful tool for CVD self-management. Little is currently known about the types and quality of health information provided in Chinese CVD mobile apps and whether app functions are conducive to promoting CVD self-management. OBJECTIVE: We undertook a systematic review to evaluate the types and quality of health information provided in Chinese CVD mobile apps and interactive app functions for promoting CVD self-management. METHODS: Mobile apps targeting end users in China with CVD conditions were selected in February 2017 through a multi-stage process. Three frameworks were used to evaluate the selected apps: (1) types of health information offered were assessed using our Health Information Wants framework, which encompasses 7 types of information; (2) quality of information provided in the apps was assessed using the 11 guidelines recommended by the National Library of Medicine of the National Institutes of Health; and (3) types of interactive app functions for CVD self-management were assessed using a 15-item framework adapted from the literature, including our own prior work. RESULTS: Of 578 apps identified, 82 were eligible for final review. Among these, information about self-care (67/82, 82%) and information specifically regarding CVD (63/82, 77%) were the most common types of information provided, while information about health care providers (22/82, 27%) and laboratory tests (5/82, 6%) were least common. The most common indicators of information quality were the revealing of apps' providers (82/82, 100%) and purpose (82/82, 100%), while the least common quality indicators were the revealing of how apps' information was selected (1/82, 1%) and app sponsorship (0/82, 0%). The most common interactive functions for CVD self-management were those that enabled user interaction with the app provider (57/82, 70%) and with health care providers (36/82, 44%), while the least common interactive functions were those that enabled lifestyle management (13/82, 16%) and psychological health management (6/82, 7%). None of the apps covered all 7 types of health information, all 11 indicators of information quality, or all 15 interactive functions for CVD self-management. CONCLUSIONS: Chinese CVD apps are insufficient in providing comprehensive health information, high-quality information, and interactive functions to facilitate CVD self management. End users should exercise caution when using existing apps. Health care professionals and app developers should collaborate to better understand end users' preferences and follow evidence-based guidelines to develop mHealth apps conducive to CVD self-management. PMID- 29242177 TI - Implementing a Mental Health Care Program and Home-Based Training for Mothers of Children With Autism Spectrum Disorder in an Urban Population in Bangladesh: Protocol for a Feasibility Assessment Study. AB - BACKGROUND: Mothers of children with autism spectrum disorder (ASD) have reported a higher level of depression than mothers of children with other neurodevelopmental disorders in both developed and developing countries. Mothers are the lifetime caregivers of children with ASD, and a high burden of depression can negatively impact their ability to provide care. However, access to mental health services in primary care is limited, given the scarcity of qualified providers in Bangladesh. OBJECTIVE: We aim to pilot the feasibility of integrating mental health services for the mothers of children with ASD attending schools offering ASD care and improve skills of mothers for child care through a home-based training program. METHODS: The study will be conducted in two selected schools in Dhaka in Bangladesh that have been offering services for ASD for more than 10 years. A female psychologist will be deployed at the schools to offer nonpharmacological services for all mothers having a depressive episode. Referral for pharmacological treatment will be made at the discretion of supervising psychiatrists. An ASD special educator will provide training to the mothers for enhancing their child care skills at home on a monthly basis. The proposed intervention package will be implemented over a period of 4-6 months, and the feasibility of the intervention will be assessed through a pre- and postintervention evaluation by obtaining the perspectives of various stakeholders involved in the implementation of mental health services and maternal training. The primary outcome will include assessment of acceptability, adaptability, demand, practicality, implementation, and integration of the package intervention in the school settings. The secondary outcomes will include assessment of: 1) the prevalence of maternal depression; 2) children's behavioral, social, and communication skills; and 3) the intervention participation costs incurred by institutions and families. RESULTS: Between February and March 2017, 188 mothers of children with ASD were screened for depression following a written informed consent. Based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), the Structured Clinical Interview for the DSM-IV (SCID-1) was administered to 66 mothers. In-depth interviews were conducted with 10 mothers and 8 various stakeholders. Between January-June 2017, the team finalized a draft psychosocial counseling module and a maternal training module. Between April-May 2017, mental health services were provided by psychologists to 41 mothers who attended the counseling centers at each school. Three special educators have been trained in June 2017 to initiate training of the participating mothers. CONCLUSIONS: This is the first study of a mental health intervention for mothers of children with ASD to reduce their burden of depression and improve the outcomes of their children. The findings will inform the provision of services for children with ASD and their mothers in Bangladesh and similar settings. PMID- 29242178 TI - Deciding How to Stay Independent at Home in Later Years: Development and Acceptability Testing of an Informative Web-Based Module. AB - BACKGROUND: Seniors with loss of autonomy may face decisions about whether they should stay at home or move elsewhere. Most seniors would prefer to stay home and be independent for as long as possible, but most are unaware of options that would make this possible. OBJECTIVE: The study aimed to develop and test the acceptability of an interactive website for seniors, their caregivers, and health professionals with short interlinked videos presenting information about options for staying independent at home. METHODS: The approach for design and data collection varied, involving a multipronged, user-centered design of the development process, qualitative interviews, and end-user feedback to determine content (ie, needs assessment) in phase I; module development (in English and French) in phase II; and survey to test usability and acceptability with end users in phase III. Phase I participants were a convenience sample of end users, that is, seniors, caregivers, and professionals with expertise in modifiable factors (eg, day centers, home redesign, equipment, community activities, and finances), enabling seniors to stay independent at home for longer in Quebec and Alberta, Canada. Phase II participants were bilingual actors; phase III participants included phase I participants and new participants recruited through snowballing. Qualitative interviews were thematically analyzed in phase II to determine relevant topics for the video-scripts, which were user-checked by interview participants. In phase III, the results of a usability questionnaire were analyzed using descriptive statistics. RESULTS: In phase I, interviews with 29 stakeholders, including 4 seniors, 3 caregivers, and 22 professionals, showed a need for a one-stop information resource about options for staying independent at home. They raised issues relating to 6 categories: cognitive autonomy, psychological or mental well-being, functional autonomy, social autonomy, financial autonomy, and people involved. A script was developed and evaluated by participants. In phase II, after 4 days in a studio with 15 bilingual actors, 30 videos were made of various experts (eg, family doctor, home care nurse, and social worker) presenting options and guidance for the decision-making process. These were integrated into an interactive website, which included a comments tool for visitors to add information. In phase III (n=21), 8 seniors (7 women, mean age 75 years), 7 caregivers, and 6 professionals evaluated the acceptability of the module and suggested improvements. Clarity of the videos scored 3.6 out of 4, length was considered right by 17 (separate videos) and 13 participants (all videos together), and 18 participants considered the module acceptable. They suggested that information should be tailored more, and that seniors may need someone to help navigate it. CONCLUSIONS: Our interactive website with interlinked videos presenting information about options for staying independent at home was deemed acceptable and potentially helpful by a diverse group of stakeholders. PMID- 29242179 TI - Individual Differences in the Relationship Between Attachment and Nomophobia Among College Students: The Mediating Role of Mindfulness. AB - BACKGROUND: There is a growing interest in nomophobia, which is defined as the fear of being out of cellular phone contact, or "feelings of discomfort or anxiety experienced by individuals when they are unable to use their mobile phones or utilize the affordances these devices provide". However, only limited research can be found in terms of its determinants at present. Contemporary literature suggests that the relationships among attachment styles, mindfulness, and nomophobia have not been investigated. OBJECTIVE: This study aims to investigate the mediating effect of mindfulness on the relationship between attachment and nomophobia. In addition, the study also focuses on gender differences in attachment, mindfulness, and nomophobia. A theory-based structural model was tested to understand the essentials of the associations between the constructs. METHODS: The Experiences in Close Relationships Scale, Nomophobia Questionnaire, and Mindful Attention Awareness Scale were used to collect data from undergraduate students (N=450; 70.9% women [319/450]; mean age=21.94 years [SD 3.61]). Two measurement models (ie, attachment and mindfulness) and a structural model were specified, estimated, and evaluated. RESULTS: The structural equation model shows that the positive direct effects of avoidant (.13, P=.03) and anxious attachment (.48, P<.001) on nomophobia were significant. The negative direct effects of avoidant (-.18, P=.01) and anxious attachment ( .33, P<.001) on mindfulness were also significant. Moreover, mindfulness has a significant negative effect on nomophobia for women only (-.13, P=.03). Finally, the Sobel test showed that the indirect effects of avoidant and anxious attachment on nomophobia via mindfulness were significant (P<.001). The direct and indirect effects of anxious attachment, avoidant attachment, and mindfulness altogether accounted for 33% of the total variance in nomophobia. Gender comparison results show that there is a significant difference in attachment based on gender (F2,447=6.97, P=.01, Wilk lambda=.97, partial eta2=.03). Women (mean 68.46 [SD 16.96]) scored significantly higher than men (mean 63.59 [SD 15.97]) in anxious attachment (F1=7.93, P=.01, partial eta2=.02). Gender differences in mindfulness were not significant (F4,448=3.45, P=.69). On the other hand, results do show significant gender differences in nomophobia (F4,445=2.71, P=.03, Wilk lambda=.98, partial eta2=.02) where women scored significantly higher than men. CONCLUSIONS: In general, individuals who are emotionally more dependent and crave more closeness and attention in the relationship tend to display higher levels of fear or discomfort when they have no access to their mobile phones. However, gender has a differential impact on the relationship between avoidant attachment and nomophobia. This study establishes the impact of mindfulness on nomophobia for women; therefore, future studies should test the effectiveness of mindfulness-based therapy approaches and confirm whether they are effective and efficient. On the basis of significant gender difference in nomophobia and attachment, we conclude that gender should be taken into account in mindfulness-based treatments dealing with nomophobia. PMID- 29242180 TI - Development and Usability Evaluation of an Art and Narrative-Based Knowledge Translation Tool for Parents With a Child With Pediatric Chronic Pain: Multi Method Study. AB - BACKGROUND: Chronic pain in childhood is increasingly being recognized as a significant clinical problem for children and their families. Previous research has identified that families want information about the causes of their child's chronic pain, treatment options, and effective strategies to help their child cope with the pain. Unfortunately, parents have reported that finding this information can be challenging. OBJECTIVE: The aim of this study was to actively work together with children attending a pediatric chronic pain clinic and their parents to develop, refine, and evaluate the usability of an art and narrative based electronic book (e-book) for pediatric chronic pain. METHODS: A multiphase, multi-method research design employing patient engagement techniques was used to develop, refine, and evaluate the usability of an art and narrative based e-book for pediatric chronic pain management to facilitate knowledge translation for parents with a child with chronic pain. The multiple phases included the following: (1) qualitative interviews to compile parents' narratives using qualitative interviews; (2) qualitative data analysis; (3) development of an e book prototype; (4) expert clinician feedback; (5) parent usability evaluation, knowledge change, and confidence in knowledge responses using an electronic survey; (6) e-book refinement; and (7) dissemination of the e-book. RESULTS: A 48 page e-book was developed to characterize the experiences of a family living with a child with chronic pain. The e-book was a composite narrative of the parent interviews and encompassed descriptions of the effects the condition has on each member of the family. This was merged with the best available research evidence on the day-to-day management of pediatric chronic pain. The e-book was vetted for clinical accuracy by expert pediatric pain clinicians. All parents that participated in the usability evaluation (N=14) agreed or strongly agreed the content of the e-book was easy to understand and stated that they would recommend the e-book to other families who have children with chronic pain. Our research identified up to a 21.4% increase in knowledge after using the e-book, and paired t tests demonstrated a statistically significant difference in confidence in answering two of the five knowledge questions (chronic pain is a disease involving changes in the nervous system; the use of ibuprofen is usually effective at controlling chronic pain); t13=0.165, P=.001 and t13=0.336, P=.002, respectively, after being exposed to the e-book. CONCLUSIONS: Our results demonstrate that parents positively rated an e-book developed for parents with a child with chronic pain. Our results also identify that overall, parents' knowledge increased after using the e-book, and confidence in their knowledge about chronic pain and its management increased in two aspects after e-book exposure. These results suggest that art and narrative-based knowledge translation interventions may be useful in transferring complex health information to parents. PMID- 29242181 TI - A Data Model for Teleconsultation in Managing High-Risk Pregnancies: Design and Preliminary Evaluation. AB - BACKGROUND: Teleconsultation is a guarantor for virtual supervision of clinical professors on clinical decisions made by medical residents in teaching hospitals. Type, format, volume, and quality of exchanged information have a great influence on the quality of remote clinical decisions or tele-decisions. Thus, it is necessary to develop a reliable and standard model for these clinical relationships. OBJECTIVE: The goal of this study was to design and evaluate a data model for teleconsultation in the management of high-risk pregnancies. METHODS: This study was implemented in three phases. In the first phase, a systematic review, a qualitative study, and a Delphi approach were done in selected teaching hospitals. Systematic extraction and localization of diagnostic items to develop the tele-decision clinical archetypes were performed as the second phase. Finally, the developed model was evaluated using predefined consultation scenarios. RESULTS: Our review study has shown that present medical consultations have no specific structure or template for patient information exchange. Furthermore, there are many challenges in the remote medical decision making process, and some of them are related to the lack of the mentioned structure. The evaluation phase of our research has shown that data quality (P<.001), adequacy (P<.001), organization (P<.001), confidence (P<.001), and convenience (P<.001) had more scores in archetype-based consultation scenarios compared with routine-based ones. CONCLUSIONS: Our archetype-based model could acquire better and higher scores in the data quality, adequacy, organization, confidence, and convenience dimensions than ones with routine scenarios. It is probable that the suggested archetype-based teleconsultation model may improve the quality of physician-physician remote medical consultations. PMID- 29242182 TI - GMC cuts junior doctors' registration fees. PMID- 29242183 TI - Frequency of a diagnosis of glaucoma in individuals who consume coffee, tea and/or soft drinks. AB - AIMS: To evaluate the association between consumption of coffee, tea or soft drinks, and glaucoma in the participants of the 2005-2006 National Health and Nutrition Examination Survey (NHANES). METHODS: The exposures of interest of this retrospective cross-sectional study were caffeinated and decaffeinated coffee, iced tea, hot tea and soft drinks. The outcome of interest was a clinical diagnosis of glaucoma based on the Rotterdam criteria. Analysis of the correlation between the frequency of consumption of each type of beverage and glaucoma was performed using logistic regression modelling while controlling for age, body mass index, gender, ethnicity, smoking status and diabetes. Data were weighted using the multistage NHANES sampling design. RESULTS: Among a total of 1678 survey participants, the overall prevalence of glaucoma was 5.1% (n=84). Most participants were non-Hispanic white (n=892; 53.2%). There were no statistically significant associations between consumption of caffeinated and decaffeinated coffee, iced tea and soft drinks, and glaucoma. Participants who consumed at least one cup of hot tea daily had a 74% decreased odds of having glaucoma compared with those who did not consume hot tea (adjusted OR=0.26, 95% CI 0.09 to 0.72, P=0.004 for trend); however, no statistically significant association existed for decaffeinated hot tea and glaucoma. CONCLUSION: In NHANES, participants who consumed hot tea daily were less likely to have glaucoma than those who did not consume hot tea. No significant associations were found between the consumption of coffee, iced tea, decaffeinated tea and soft drinks, and glaucoma risk. This study is limited by its cross-sectional design and use of multiple statistical testing, and larger prospective studies are needed to investigate the proposed association between tea consumption and decreased glaucoma risk. PMID- 29242185 TI - Will the Antarctic tardigrade Acutuncus antarcticus be able to withstand environmental stresses related to global climate change? AB - Because conditions in continental Antarctica are highly selective and extremely hostile to life, its biota is depauperate, but well adapted to live in this region. Global climate change has the potential to impact continental Antarctic organisms because of increasing temperatures and ultraviolet radiation. This research evaluates how ongoing climate changes will affect Antarctic species, and whether Antarctic organisms will be able to adapt to the new environmental conditions. Tardigrades represent one of the main terrestrial components of Antarctic meiofauna; therefore, the pan-Antarctic tardigrade Acutuncus antarcticus was used as model to predict the fate of Antarctic meiofauna threatened by climate change. Acutuncus antarcticus individuals tolerate events of desiccation, increased temperature and UV radiation. Both hydrated and desiccated animals tolerate increases in UV radiation, even though the desiccated animals are more resistant. Nevertheless, the survivorship of hydrated and desiccated animals is negatively affected by the combination of temperature and UV radiation, with the hydrated animals being more tolerant than desiccated animals. Finally, UV radiation has a negative impact on the life history traits of successive generations of A. antarcticus, causing an increase in egg reabsorption and teratological events. In the long run, A. antarcticus could be at risk of population reductions or even extinction. Nevertheless, because the changes in global climate will proceed gradually and an overlapping of temperature and UV increase could be limited in time, A. antarcticus, as well as many other Antarctic organisms, could have the potential to overcome global warming stresses, and/or the time and capability to adapt to the new environmental conditions. PMID- 29242184 TI - Sex Differences in Treatments, Relative Survival, and Excess Mortality Following Acute Myocardial Infarction: National Cohort Study Using the SWEDEHEART Registry. AB - BACKGROUND: This study assessed sex differences in treatments, all-cause mortality, relative survival, and excess mortality following acute myocardial infarction. METHODS AND RESULTS: A population-based cohort of all hospitals providing acute myocardial infarction care in Sweden (SWEDEHEART [Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies]) from 2003 to 2013 was included in the analysis. Excess mortality rate ratios (EMRRs), adjusted for clinical characteristics and guideline-indicated treatments after matching by age, sex, and year to background mortality data, were estimated. Although there were no sex differences in all-cause mortality adjusted for age, year of hospitalization, and comorbidities for ST-segment-elevation myocardial infarction (STEMI) and non STEMI at 1 year (mortality rate ratio: 1.01 [95% confidence interval (CI), 0.96 1.05] and 0.97 [95% CI, 0.95-0.99], respectively) and 5 years (mortality rate ratio: 1.03 [95% CI, 0.99-1.07] and 0.97 [95% CI, 0.95-0.99], respectively), excess mortality was higher among women compared with men for STEMI and non-STEMI at 1 year (EMRR: 1.89 [95% CI, 1.66-2.16] and 1.20 [95% CI, 1.16-1.24], respectively) and 5 years (EMRR: 1.60 [95% CI, 1.48-1.72] and 1.26 [95% CI, 1.21 1.32], respectively). After further adjustment for the use of guideline-indicated treatments, excess mortality among women with non-STEMI was not significant at 1 year (EMRR: 1.01 [95% CI, 0.97-1.04]) and slightly higher at 5 years (EMRR: 1.07 [95% CI, 1.02-1.12]). For STEMI, adjustment for treatments attenuated the excess mortality for women at 1 year (EMRR: 1.43 [95% CI, 1.26-1.62]) and 5 years (EMRR: 1.31 [95% CI, 1.19-1.43]). CONCLUSIONS: Women with acute myocardial infarction did not have statistically different all-cause mortality, but had higher excess mortality compared with men that was attenuated after adjustment for the use of guideline-indicated treatments. This suggests that improved adherence to guideline recommendations for the treatment of acute myocardial infarction may reduce premature cardiovascular death among women. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02952417. PMID- 29242186 TI - Biased IGH VDJ gene repertoire and clonal expansions in B cells of chronically hepatitis C virus-infected individuals. AB - Patients chronically infected with hepatitis C virus (HCV) frequently develop mixed cryoglobulinemia (MC), a monoclonal expansion of immunoglobulin M (IgM)+ autoreactive B cells, and also have an increased B-cell lymphoma risk. Whether HCV infection also impacts the B-cell compartment and the B-cell receptor repertoire in patients not affected by MC or lymphomas is poorly understood. Flow cytometric analysis of peripheral blood B cells of 30 MC-negative HCV-infected patients and 15 healthy controls revealed that frequencies of class-switched memory B cells were increased in the patients, whereas frequencies of transitional and naive B cells were decreased. For 22 HCV+ patients and 7 healthy controls, we performed high-throughput sequencing of immunoglobulin heavy chain VDJ rearrangements of naive, mature CD5+, IgM+ memory, and class-switched memory B cells. An increased usage of several IGHV genes, including IGHV1-69 and IGHV4 59, which are closely linked to MC and HCV-associated lymphomas, was specifically seen among IgM+ memory B cells of the patients. Moreover, many, and partly very large, expanded clones were seen predominantly among IgM+ memory B cells of all HCV-infected patients analyzed. Thus, chronic HCV infection massively disturbs the B-cell compartment even in patients without clinically detectable B-cell lymphoproliferation and generates many large B-cell clones, especially among non class-switched memory B cells. Because B-cell clones in MC and lymphomas derive from this B-cell subset, this establishes IgM+ memory B cells as a general target of lymphoproliferation in HCV+ patients, affecting apparently all patients. PMID- 29242187 TI - Altered plasma clot properties increase the risk of recurrent deep vein thrombosis: a cohort study. AB - It has been demonstrated that fibrin clots generated from plasma samples obtained from patients with prior thromboembolic events are denser and less susceptible to lysis. Such a prothrombotic fibrin clot phenotype has been suggested as a new risk factor for venous thromboembolism, but its prognostic value is unclear. To assess whether abnormal clot properties can predict recurrent deep vein thrombosis (DVT), we studied 320 consecutive patients aged 18 to 70 years following the first-ever DVT. Plasma clot properties were evaluated after 3 months of anticoagulant treatment since the index event. A mean duration of anticoagulation was 10 months (range, 4-20). Recurrent DVT was observed in 77 patients (25%; 6.6%/year) during a median follow-up of 44 months. Recurrences of DVT were associated with faster formation (-9% lag phase) of denser fibrin networks (-12% fibrin clot permeability [Ks]) and 4% higher maximum absorbance of plasma clots that displayed impaired fibrinolytic degradation (+25% prolonged clot lysis time [CLT]) and a 5% slower rate of increase in D-dimer levels during clot degradation (D-Drate; all P < .05). Proximal DVT alone, higher C-reactive protein, D-dimer, peak thrombin, lower Ks, shorter lag phase, decreased D-Drate, and prolonged CLT were independent predictors of recurrences (all P < .05). Individuals characterized by low Ks (<=7.3 * 10-9 cm2) and prolonged CLT (>96 min) were at the highest risk of recurrent DVT (odds ratio, 15.8; 95% confidence interval, 7.5-33.5). Kaplan-Meier curves showed that reduced Ks and prolonged CLT predicted recurrent DVT. We demonstrate that unfavorably altered clot properties may predict recurrent DVT after anticoagulation withdrawal. PMID- 29242188 TI - Saturation mutagenesis reveals manifold determinants of exon definition. AB - To illuminate the extent and roles of exonic sequences in the splicing of human RNA transcripts, we conducted saturation mutagenesis of a 51-nt internal exon in a three-exon minigene. All possible single and tandem dinucleotide substitutions were surveyed. Using high-throughput genetics, 5560 minigene molecules were assayed for splicing in human HEK293 cells. Up to 70% of mutations produced substantial (greater than twofold) phenotypes of either increased or decreased splicing. Of all predicted secondary structural elements, only a single 15-nt stem-loop showed a strong correlation with splicing, acting negatively. The in vitro formation of exon-protein complexes between the mutant molecules and proteins associated with spliceosome formation (U2AF35, U2AF65, U1A, and U1-70K) correlated with splicing efficiencies, suggesting exon definition as the step affected by most mutations. The measured relative binding affinities of dozens of human RNA binding protein domains as reported in the CISBP-RNA database were found to correlate either positively or negatively with splicing efficiency, more than could fit on the 51-nt test exon simultaneously. The large number of these functional protein binding correlations point to a dynamic and heterogeneous population of pre-mRNA molecules, each responding to a particular collection of binding proteins. PMID- 29242189 TI - Secreted heme peroxidase from Dictyostelium discoideum: Insights into catalysis, structure, and biological role. AB - Oxidation of halides and thiocyanate by heme peroxidases to antimicrobial oxidants is an important cornerstone in the innate immune system of mammals. Interestingly, phylogenetic and physiological studies suggest that homologous peroxidases are already present in mycetozoan eukaryotes such as Dictyostelium discoideum This social amoeba kills bacteria via phagocytosis for nutrient acquisition at its single-cell stage and for antibacterial defense at its multicellular stages. Here, we demonstrate that peroxidase A from D. discoideum (DdPoxA) is a stable, monomeric, glycosylated, and secreted heme peroxidase with homology to mammalian peroxidases. The first crystal structure (2.5 A resolution) of a mycetozoan peroxidase of this superfamily shows the presence of a post translationally-modified heme with one single covalent ester bond between the 1 methyl heme substituent and Glu-236. The metalloprotein follows the halogenation cycle, whereby compound I oxidizes iodide and thiocyanate at high rates (>108 m-1 s-1) and bromide at very low rates. It is demonstrated that DdPoxA is up regulated and likely secreted at late multicellular development stages of D. discoideum when migrating slugs differentiate into fruiting bodies that contain persistent spores on top of a cellular stalk. Expression of DdPoxA is shown to restrict bacterial contamination of fruiting bodies. Structure and function of DdPoxA are compared with evolutionary-related mammalian peroxidases in the context of non-specific immune defense. PMID- 29242190 TI - The Rv2633c protein of Mycobacterium tuberculosis is a non-heme di-iron catalase with a possible role in defenses against oxidative stress. AB - The Rv2633c gene in Mycobacterium tuberculosis is rapidly up-regulated after macrophage infection, suggesting that Rv2633c is involved in M. tuberculosis pathogenesis. However, the activity and role of the Rv2633c protein in host colonization is unknown. Here, we analyzed the Rv2633c protein sequence, which revealed the presence of an HHE cation-binding domain common in hemerythrin-like proteins. Phylogenetic analysis indicated that Rv2633c is a member of a distinct subset of hemerythrin-like proteins exclusive to mycobacteria. The Rv2633c sequence was significantly similar to protein sequences from other pathogenic strains within that subset, suggesting that these proteins are involved in mycobacteria virulence. We expressed and purified the Rv2633c protein in Escherichia coli and found that it contains two iron atoms, but does not behave like a hemerythrin. It migrated as a dimeric protein during size-exclusion chromatography. It was not possible to reduce the protein or observe any evidence for its interaction with O2 However, Rv2633c did exhibit catalase activity with a kcat of 1475 s-1 and Km of 10.1 +/- 1.7 mm Cyanide and azide inhibited the catalase activity with Ki values of 3.8 MUm and 37.7 MUm, respectively. Rv2633c's activity was consistent with a role in defenses against oxidative stress generated during host immune responses after M. tuberculosis infection of macrophages. We note that Rv2633c is the first example of a non-heme di-iron catalase, and conclude that it is a member of a subset of hemerythrin-like proteins exclusive to mycobacteria, with likely roles in protection against host defenses. PMID- 29242191 TI - The inducible microRNA-203 in fish represses the inflammatory responses to Gram negative bacteria by targeting IL-1 receptor-associated kinase 4. AB - Innate immune responses are the first defense against pathogenic invaders. Activation and termination of these immune responses are regulated by several mechanisms. MicroRNAs (miRNAs), a group of small non-coding RNAs, have been implicated in the regulation of a spectrum of both physiological and pathological conditions, including immune responses. Although the immune regulatory miRNA networks in higher vertebrates have been well described, regulation of these responses in fish species is poorly understood. In the present study, we investigated the role of the miRNA miR-203 involved in inflammatory responses in miiuy croaker (Miichthys miiuy). We found that the Gram-negative bacterium Vibrio anguillarum and lipopolysaccharide significantly up-regulated host miR-203 expression. The increased miR-203 expression suppressed the production of inflammatory cytokines and thereby prevented mounting of a full immune response. Mechanistically, we identified and validated IL-1 receptor-associated kinase 4 (IRAK4) as a target of miR-203. We observed that miR-203 post-transcriptionally controls IRAK4 expression and thereby inhibits the activation of nuclear factor kappaB (NF-kappaB) signaling. In summary, our findings reveal that miR-203 in fish is a critical suppressor of innate immune responses to bacterial infection by suppressing a feedback to IRAK4-NF-kappaB-mediated signaling. PMID- 29242192 TI - The ubiquitin E3 ligase CHIP promotes proteasomal degradation of the serine/threonine protein kinase PINK1 during staurosporine-induced cell death. AB - Mutations in the gene for the serine/threonine protein kinase PTEN-induced putative kinase 1 (PINK1) are the second most frequent cause of autosomal recessive Parkinson's disease (PD). Via its kinase activity, PINK1 regulates neuronal cell survival and mitochondrial quality control. Numerous reports have revealed that PINK1 has diverse and physiologically significant functions, and therefore its activity should be tightly regulated. However, the molecular mechanisms regulating PINK1 stability and the modulator(s) involved have not been elucidated. In this study, we demonstrate that the ubiquitin E3 ligase carboxyl terminus of Hsp70-interacting protein (CHIP) promotes PINK1 ubiquitination and decreases its steady-state levels. Moreover, PINK1 levels were strongly reduced in HEK293 and SH-SY5Y cells exposed to the apoptosis-inducer staurosporine. Of note, we found that this reduction resulted from CHIP-mediated PINK1 ubiquitination. Accordingly, siRNA-mediated CHIP knockdown reduced susceptibility to staurosporine-induced cell death. Taken together, these findings suggest that CHIP plays a role in negative regulation of PINK1 stability and may suppress PINK1's cytoprotective effect during staurosporine-induced mammalian cell death. We propose that this PINK1 regulatory pathway might contribute to Parkinson's disease pathogenesis. PMID- 29242194 TI - George Man Burrows and the anguished birth of general practice. PMID- 29242193 TI - Crystal structure of murine 4-1BB and its interaction with 4-1BBL support a role for galectin-9 in 4-1BB signaling. AB - 4-1BB (CD137) is a TNF receptor superfamily (TNFRSF) member that is thought to undergo receptor trimerization upon binding to its trimeric TNF superfamily ligand (4-1BBL) to stimulate immune responses. 4-1BB also can bind to the tandem repeat-type lectin galectin-9 (Gal-9), and signaling through mouse (m)4-1BB is reduced in galectin-9 (Gal-9)-deficient mice, suggesting a pivotal role of Gal-9 in m4-1BB activation. Here, using sulfur-SAD phasing, we determined the crystal structure of m4-1BB to 2.2-A resolution. We found that similar to other TNFRSFs, m4-1BB has four cysteine-rich domains (CRDs). However, the organization of CRD1 and the orientation of CRD3 and CRD4 with respect to CRD2 in the m4-1BB structure distinctly differed from those of other TNFRSFs. Moreover, we mapped two Asn residues within CRD4 that are N-linked glycosylated and mediate m4-1BB binding to Gal-9. Kinetics studies of m4-1BB disclosed a very tight nanomolar binding affinity to m4-1BBL with an unexpectedly strong avidity effect. Both N- and C terminal domains of Gal-9 bound m4-1BB, but with lower affinity compared with m4 1BBL. Although the TNF homology domain (THD) of human (h)4-1BBL forms non covalent trimers, we found that m4-1BBL formed a covalent dimer via 2 cysteines absent in h4-1BBL. As multimerization and clustering is a prerequisite for TNFR intracellular signaling, and as m4-1BBL can only recruit two m4-1BB monomers, we hypothesize that m4-1BBL and Gal-9 act together to aid aggregation of m4-1BB monomers to efficiently initiate m4-1BB signaling. PMID- 29242195 TI - Key Programme Science lessons from an HIV prevention 'Learning Site' for sex workers in Mombasa, Kenya. AB - OBJECTIVES: In 2013, Kenya's National AIDS and STI Control Programme established a Learning Site (LS) in Mombasa County to support and strengthen capacity for HIV prevention programming within organisations working with sex workers. A defining feature of LS was the use of a Programme Science approach throughout its development and implementation. We provide an overview of the key components of LS, present findings from 23 months of programme monitoring data, and highlight key Programme Science lessons from its implementation and monitoring. METHODS: Routine monitoring data collected from September 2013 through July 2015 are presented. Individual-level service utilisation data were collected monthly and indicators of interest were analysed over time to illustrate trends in enrolment, programme coverage and service utilisation among sex workers in Mombasa County. RESULTS: Over the monitoring period, outreach programme enrolment occurred rapidly; condom distribution targets were met consistently; rates of STI screening remained high and diagnoses declined; and reporting of and response to violent incidents increased. At the same time, enrolment in LS clinics was relatively low among female sex workers, and HIV testing at LS was low among both female and male sex workers. CONCLUSION: Lessons learnt from operationalising the Programme Science framework through the Mombasa LS can inform the development and implementation of similar LS in different geographical and epidemiological contexts. Importantly, meaningful involvement of sex workers in the design, implementation and monitoring processes ensures that overall programme performance is optimised in the context of local, 'on-the-ground' realities. Additionally, learnings from LS highlight the importance of introducing enhanced monitoring and evaluations systems into complex programmes to better understand and explain programme dynamics over time. PMID- 29242196 TI - A novel assessment of the traction forces upon settlement of two typical marine fouling invertebrates using PDMS micropost arrays. AB - Marine biofouling poses a severe threat to maritime and aquaculture industries. To prevent the attachment of marine biofouling organisms on man-made structures, countless cost and effort was spent annually. In particular, most attention has been paid on the development of efficient and environmentally friendly fouling resistant coatings, as well as larval settlement mechanism of several major biofouling invertebrates. In this study, polydimethylsiloxane (PDMS) micropost arrays were utilized as the settlement substrata and opposite tractions were identified during early settlement of the barnacle Amphibalanus amphitrite and the bryozoan Bugula neritina The settling A. amphitrite pushed the periphery microposts with an average traction force of 376.2 nN, while settling B. neritina pulled the periphery microposts with an average traction force of 205.9 nN. These micropost displacements are consistent with the body expansion of A. amphitrite during early post-settlement metamorphosis stage and elevation of wall epithelium of B. neritina during early pre-ancestrula stage, respectively. As such, the usage of micropost array may supplement the traditional histological approach to indicate the early settlement stages or even the initiation of larval settlement of marine fouling organisms, and could finally aid in the development of automatic monitoring platform for the real-time analysis on this complex biological process. PMID- 29242197 TI - JAK signaling regulates germline cyst breakdown and primordial follicle formation in mice. AB - In female mammals, primordial follicles consist of two types of cells, namely, oocytes and pregranulosa cells that surround the oocytes. The size of the primordial follicle pool determines the reproductive ability of female mammals. However, the underlying mechanisms controlling primordial follicle assembly remain unclear. In this study, we show that oocyte-derived Janus kinase (JAK) signaling is vital for germline cyst breakdown and primordial follicle formation in vitro JAK2 and JAK3 activity is increased while germline cysts are breaking down. Inhibition of either JAK2 or JAK3 prevents germline cyst breakdown and primordial follicle formation. We further show that specific suppression of JAK2 delays germ cell loss through the downregulation of p53, but has no influence on pregranulosa cell proliferation. Alternatively, specific inhibition of JAK3 decreases pregranulosa cell proliferation by downregulating Notch2 signaling, implying that JAK3 acts on pregranulosa cells by controlling the extracellular secretion of oocyte-derived factors. In summary, our results indicate that JAK signaling contributes to germline cyst breakdown and primordial follicle formation by regulating oocyte loss and pregranulosa cell proliferation in the fetal mouse ovary. Our findings contribute to a better understanding of the molecular mechanism of mammalian folliculogenesis. PMID- 29242198 TI - An attenuated quadruple gene mutant of Mycobacterium tuberculosis imparts protection against tuberculosis in guinea pigs. AB - Previously we had developed a triple gene mutant of Mycobacterium tuberculosis (MtbDeltamms) harboring disruption in three genes, namely mptpA, mptpB and sapM Though vaccination with MtbDeltamms strain induced protection in the lungs of guinea pigs, the mutant strain failed to control the hematogenous spread of the challenge strain to the spleen. Additionally, inoculation with MtbDeltamms resulted in some pathological damage to the spleens in the early phase of infection. In order to generate a strain that overcomes the pathology caused by MtbDeltamms in spleen of guinea pigs and controls dissemination of the challenge strain, MtbDeltamms was genetically modified by disrupting bioA gene to generate MtbDeltammsb strain. Further, in vivo attenuation of MtbDeltammsb was evaluated and its protective efficacy was assessed against virulent M. tuberculosis challenge in guinea pigs. MtbDeltammsb mutant strain was highly attenuated for growth and virulence in guinea pigs. Vaccination with MtbDeltammsb mutant generated significant protection in comparison to sham-immunized animals at 4 and 12 weeks post-infection in lungs and spleen of infected animals. However, the protection imparted by MtbDeltammsb was significantly less in comparison to BCG immunized animals. This study indicates the importance of attenuated multiple gene deletion mutants of M. tuberculosis for generating protection against tuberculosis. PMID- 29242200 TI - Considering Cultures and Consequences: The Relevance of Bacteremia in Infant UTIs. PMID- 29242199 TI - Organ-specific lymphatic vasculature: From development to pathophysiology. AB - Recent discoveries of novel functions and diverse origins of lymphatic vessels have drastically changed our view of lymphatic vasculature. Traditionally regarded as passive conduits for fluid and immune cells, lymphatic vessels now emerge as active, tissue-specific players in major physiological and pathophysiological processes. Lymphatic vessels show remarkable plasticity and heterogeneity, reflecting their functional specialization to control the tissue microenvironment. Moreover, alternative developmental origins of lymphatic endothelial cells in some organs may contribute to the diversity of their functions in adult tissues. This review aims to summarize the most recent findings of organotypic differentiation of lymphatic endothelial cells in terms of their distinct (patho)physiological functions in skin, lymph nodes, small intestine, brain, and eye. We discuss recent advances in our understanding of the heterogeneity of lymphatic vessels with respect to the organ-specific functional and molecular specialization of lymphatic endothelium, such as the hybrid blood lymphatic identity of Schlemm's canal, functions of intestinal lymphatics in dietary fat uptake, and discovery of meningeal lymphatic vasculature and perivascular brain lymphatic endothelial cells. PMID- 29242202 TI - Calcific Aortic Valve Disease: Insights Into the Genetics of Vascular Ageing. PMID- 29242203 TI - Hydroxyurea for SCA in Africa: no malaria harm. PMID- 29242201 TI - Familial Aggregation of Aortic Valvular Stenosis: A Nationwide Study of Sibling Risk. AB - BACKGROUND: Aortic valvular stenosis (AS) is the most common cause of cardiac valvular replacement surgery. During the last century, the pathogenesis of AS has undergone transitions in developed countries, from rheumatic heart disease to a degenerative calcific pathogenesis. Although a familial component has been described for a subset of cases with a bicuspid valve, data are limited on the overall familial aggregation of this disease. METHODS AND RESULTS: Contemporary information on 6 117 263 Swedish siblings, of which 13 442 had a clinical diagnosis of AS, was collected from the nationwide Swedish Multi-Generation Register and the National Patient Register. A total of 4.8% of AS cases had a sibling history of AS. Having at least 1 sibling with AS was associated with a hazard ratio of 3.41 (95% confidence interval, 2.23-5.21) to be diagnosed with AS in an adjusted model. Individuals with >1 sibling with AS had an exceptionally high risk (hazard ratio, 32.84) but were uncommon (34 siblings from 11 sibships). In contrast, spouses of subjects with AS were only slightly more likely to be diagnosed with AS compared with subjects without spousal AS (hazard ratio 1.16 for husbands and 1.18 for wives). CONCLUSIONS: A sibling history of clinically diagnosed AS was associated with increased risk of AS. Spouses of patients with AS only had a modest risk increase, suggesting that shared adult environmental factors contribute less to the development of AS than genetic factors. PMID- 29242204 TI - SETD2: a complex role in blood malignancy. PMID- 29242205 TI - Of pools, oceans, and the Dead Sea. PMID- 29242206 TI - On PAR with aPC to target inflammasomes. PMID- 29242207 TI - Complement and coagulation: so close, yet so far. PMID- 29242208 TI - HSCT cures ADA2 deficiency. PMID- 29242209 TI - Circulating hypergranular neoplastic cells: not always leukemic promyelocytes. PMID- 29242211 TI - Danica Chen: From early learning to aging research. AB - Chen studies the cellular and genetic mechanisms that control organismal aging. PMID- 29242213 TI - Phosphorus redox reactions as pinch hitters in microbial metabolism. PMID- 29242212 TI - Nuclear option prevents hyperinfection in the Strongyloides worm war. PMID- 29242210 TI - Reversible immortalisation enables genetic correction of human muscle progenitors and engineering of next-generation human artificial chromosomes for Duchenne muscular dystrophy. AB - Transferring large or multiple genes into primary human stem/progenitor cells is challenged by restrictions in vector capacity, and this hurdle limits the success of gene therapy. A paradigm is Duchenne muscular dystrophy (DMD), an incurable disorder caused by mutations in the largest human gene: dystrophin. The combination of large-capacity vectors, such as human artificial chromosomes (HACs), with stem/progenitor cells may overcome this limitation. We previously reported amelioration of the dystrophic phenotype in mice transplanted with murine muscle progenitors containing a HAC with the entire dystrophin locus (DYS HAC). However, translation of this strategy to human muscle progenitors requires extension of their proliferative potential to withstand clonal cell expansion after HAC transfer. Here, we show that reversible cell immortalisation mediated by lentivirally delivered excisable hTERT and Bmi1 transgenes extended cell proliferation, enabling transfer of a novel DYS-HAC into DMD satellite cell derived myoblasts and perivascular cell-derived mesoangioblasts. Genetically corrected cells maintained a stable karyotype, did not undergo tumorigenic transformation and retained their migration ability. Cells remained myogenic in vitro (spontaneously or upon MyoD induction) and engrafted murine skeletal muscle upon transplantation. Finally, we combined the aforementioned functions into a next-generation HAC capable of delivering reversible immortalisation, complete genetic correction, additional dystrophin expression, inducible differentiation and controllable cell death. This work establishes a novel platform for complex gene transfer into clinically relevant human muscle progenitors for DMD gene therapy. PMID- 29242215 TI - Talazoparib Bests Chemo for Breast Cancer. AB - Patients with advanced or metastatic HER2-negative breast cancer and germline BRCA1/2 mutations may benefit from talazoparib, according to data from a phase III trial. Compared with chemotherapy, the investigational PARP inhibitor induced some complete responses, prolonged progression-free survival, and improved patients' overall quality of life. PMID- 29242214 TI - Expressed Gene Fusions as Frequent Drivers of Poor Outcomes in Hormone Receptor Positive Breast Cancer. AB - We sought to uncover genetic drivers of hormone receptor-positive (HR+) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR+ breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR+ breast cancer. Collectively, our findings identify expressed gene fusions as frequent and potentially actionable drivers in HR+ breast cancer.Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336-53. (c)2017 AACR.See related commentary by Natrajan et al., p. 272See related article by Liu et al., p. 354This article is highlighted in the In This Issue feature, p. 253. PMID- 29242216 TI - Complete Genome Sequence of the New Urolithin-Producing Bacterium Gordonibacter urolithinfaciens DSM 27213T. AB - Gordonibacter urolithinfaciens DSM 27213T was isolated from human feces and is able to metabolize ellagic acid (a dietary phenolic compound present in various fruits) to urolithins. Here, we report the finished and annotated genome sequence of this organism. PMID- 29242217 TI - Draft Genome Sequence of Glycomyces fuscus TRM 49117, Isolated from a Hypersaline Soil Sample. AB - Glycomyces spp. are rare actinomycetes that are potential antibiotic producers. Here, we report the draft genome sequence of Glycomyces fuscus TRM 49117. This is the first genome report of a bacterium belonging to the genus Glycomyces The genome information of G. fuscus will contribute to studies on the structure and function of antibiotics. PMID- 29242218 TI - Draft Genome Sequence of Immunobiotic Lactobacillus rhamnosus Strain IBL027, a Potential Adjuvant for Mucosal Vaccine Development. AB - The genome sequence of the immunomodulatory strain Lactobacillus rhamnosus strain IBL027 is described here. The reads were assembled into contigs with a total size 2,898,501 bp. The genome information will be useful for further specific genetic studies of this strain to evaluate its immunomodulatory and biotechnological properties as a vaccine adjuvant. PMID- 29242219 TI - Draft Genome Sequence of Loktanella cinnabarina Strain XM1 Isolated from Coastal Surface Water. AB - We report here the draft genome sequence of Loktanella cinnabarina strain XM1, which was isolated from coastal surface water and shared 99.43% 16S rRNA gene sequence identity with the deep-sea bacterium L. cinnabarina LL-001T The estimated genome size of strain XM1 is 3,782,785 bp, with a G+C content of 67.9%. PMID- 29242220 TI - Genome Sequence Analysis of a G2P[4] Group A Rotavirus Strain with an Unusual Canine-Origin NSP1 A15 Genotype. AB - Here, we disclose the complete genomic sequence of a rare rotavirus group A G2P[4]-I2-R2-C2-M2-A15-N2-T2-E2-H2 strain detected in a fecal specimen from a rotaviral acute gastroenteritis patient who had previously received the Rotarix vaccine. PMID- 29242221 TI - Species-Wide Collection of Escherichia coli Isolates for Examination of Genomic Diversity. AB - Pathogenic and nonpathogenic Escherichia coli strains present a vast genomic diversity. We report the genome sequences of 2,244 E. coli isolates from multiple animal and environmental sources. Their phylogenetic relationships and potential risk to human health were examined. PMID- 29242222 TI - Complete Genome Sequence of Roe Deer Picobirnavirus Strain PBV/roe_deer/SLO/D38 14/2014. AB - Picobirnaviruses (PBVs) have been detected in feces from various animal species and humans. Here, we report the complete genome sequence of the PBV/roe_deer/SLO/D38-14/2014 strain, which is the first PBV detected in roe deer, providing additional knowledge about the high diversity and host range of PBVs. PMID- 29242223 TI - Whole-Genome Sequences of Three Streptococcus macedonicus Strains Isolated from Italian Cheeses in the Veneto Region. AB - We report here the genome sequences of three Streptococcus macedonicus strains isolated from different cheeses in the Veneto region of Italy. The presented data aim at increasing the scarce genomic information available for this species, which is frequently encountered in fermented foods and appears to be a promising technological microorganism. PMID- 29242224 TI - Draft Genome Sequence of the First NDM-4-Producing Escherichia coli Strain (AK1), Isolated from Sewage Water of a North Indian Hospital. AB - We report here the draft genome sequence of the first isolated NDM-4-producing Escherichia coli strain, isolated from sewage water at a North Indian hospital. The genome has an assembly size of 5,076,053 bp, arranged in 129 contigs, with 5,271 genes and a G+C content of 50.47%. PMID- 29242225 TI - First Report of a Whole-Genome Shotgun Sequence of a Clinical Enterococcus faecalis Sequence Type 6 Strain from South Africa. AB - Enterococcus faecalis is a lactic acid-producing Gram-positive bacterium commonly found in the intestinal tract of humans and animals; it is implicated in multidrug-resistant nosocomial infections. The draft genome of this E. faecalis sequence type 6 (ST6) strain consists of 3,215,228 bp, with 37.20% GC content, 3,048 predicted coding sequences, and 61 RNA genes. PMID- 29242226 TI - Complete Genome Sequence of Hyperthermophilic Archaeon Thermococcus sp. EXT12c, Isolated from the East Pacific Rise 9 degrees N. AB - We report the genome sequence of Thermococcus sp. EXT12c isolated from a deep-sea hydrothermal vent at the East Pacific Rise 9 degrees N. Microbes in the genus Thermococcus are able to grow anaerobically at high temperature, around neutral pH, and some of them under high hydrostatic pressure. PMID- 29242227 TI - Complete Genome Sequence of the Kiwifruit Pathogen Pseudomonas syringae pv. actinidiae Biovar 5, Originating from Japan. AB - We present the first complete genome sequence of a copper-resistant biovar 5 strain of a bacterial pathogen of kiwifruit, Pseudomonas syringae pv. actinidiae. Comparison with the genome sequence of a copper-sensitive biovar 5 isolate indicates that copper resistance is encoded on a plasmid. PMID- 29242228 TI - BMSCs ameliorate septic coagulopathy by suppressing inflammation in cecal ligation and puncture-induced sepsis. AB - Sepsis is an aggressive and life-threatening systemic inflammatory response with a high mortality. Inflammation and coagulation play crucial roles in the pathogenesis of sepsis in a mutually promoting manner. Unlike other single-target molecular therapies that have no obvious effects on clinical sepsis, bone marrow stromal cell (BMSC) therapy offers a broader spectrum of activities ranging from immune and inflammation suppression to tissue regeneration. In this report, we demonstrate that BMSC injection attenuates septic coagulopathy. It decreased the mortality, mitigated lung injury and reduced the surge of proinflammatory factors in mice with sepsis induced by cecal ligation and puncture (CLP). An in vitro cell model also revealed that co-culture with BMSCs reduced secretion of proinflammatory factors and injury of endothelial cells in response to lipopolysaccharide (LPS), an endotoxin of gram-negative bacteria. Together, our results demonstrate that BMSCs suppress sepsis-induced inflammation, endothelial dysfunction and defective coagulation. PMID- 29242229 TI - Emerging role of the plant ERF transcription factors in coordinating wound defense responses and repair. AB - Plants react to wounding through the activation of both defense and repair pathways, but how these two responses are coordinated is unclear. Here, we put forward the hypothesis that diverse members of the subfamily X of the plant specific ethylene response factor (ERF) transcription factors coordinate stress signaling with the activation of wound repair mechanisms. Moreover, we highlight the observation that tissue repair is strongly boosted through the formation of a heterodimeric protein complex that comprises ERF and transcription factors of the GRAS domain type. This interaction turns ERFs into highly potent and stress responsive activators of cell proliferation. The potency to induce stem cell identity suggests that these heterodimeric transcription factor complexes could become valuable tools to increase crop regeneration and transformation efficiency. PMID- 29242230 TI - Paracrine brassinosteroid signaling at the stem cell niche controls cellular regeneration. AB - Stem cell regeneration is crucial for both cell turnover and tissue healing in multicellular organisms. In Arabidopsis roots, a reduced group of cells known as the quiescent center (QC) act as a cell reservoir for surrounding stem cells during both normal growth and in response to external damage. Although cells of the QC have a very low mitotic activity, plant hormones such as brassinosteroids (BRs) can promote QC divisions. Here, we used a tissue-specific strategy to investigate the spatial signaling requirements of BR-mediated QC divisions. We generated stem cell niche-specific receptor knockout lines by placing an artificial microRNA against BRI1 (BRASSINOSTEROID INSENSITIVE 1) under the control of the QC-specific promoter WOX5. Additionally, QC-specific knock-in lines for BRI1 and its downstream transcription factor BES1 (BRI1-EMS-SUPPRESOR1) were also created using the WOX5 promoter. By analyzing the roots of these lines, we show that BES1-mediated signaling cell-autonomously promotes QC divisions, that BRI1 is essential for sensing nearby inputs and triggering QC divisions and that DNA damage promotes BR-dependent paracrine signaling in the stem cell niche as a prerequisite to stem cell replenishment. PMID- 29242231 TI - The ER membrane protein complex is a transmembrane domain insertase. AB - Insertion of proteins into membranes is an essential cellular process. The extensive biophysical and topological diversity of membrane proteins necessitates multiple insertion pathways that remain incompletely defined. Here we found that known membrane insertion pathways fail to effectively engage tail-anchored membrane proteins with moderately hydrophobic transmembrane domains. These proteins are instead shielded in the cytosol by calmodulin. Dynamic release from calmodulin allowed sampling of the endoplasmic reticulum (ER), where the conserved ER membrane protein complex (EMC) was shown to be essential for efficient insertion in vitro and in cells. Purified EMC in synthetic liposomes catalyzed the insertion of its substrates in a reconstituted system. Thus, EMC is a transmembrane domain insertase, a function that may explain its widely pleiotropic membrane-associated phenotypes across organisms. PMID- 29242232 TI - RALF4/19 peptides interact with LRX proteins to control pollen tube growth in Arabidopsis. AB - The communication of changes in the extracellular matrix to the interior of the cell is crucial for a cell's function. The extracellular peptides of the RAPID ALKALINIZATION FACTOR (RALF) family have been identified as ligands of receptor like kinases of the CrRLK1L subclass, but the exact mechanism of their perception is unclear. We found that Arabidopsis RALF4 and RALF19 redundantly regulate pollen tube integrity and growth, and that their function depends on pollen expressed proteins of the LEUCINE-RICH REPEAT EXTENSIN (LRX) family, which play a role in cell wall development but whose mode of action is not understood. The LRX proteins interact with RALFs, monitoring cell wall changes, which are communicated to the interior of the pollen tube via the CrRLK1L pathway to sustain normal growth. PMID- 29242233 TI - Quantum liquid droplets in a mixture of Bose-Einstein condensates. AB - Quantum droplets are small clusters of atoms self-bound by the balance of attractive and repulsive forces. Here, we report on the observation of droplets solely stabilized by contact interactions in a mixture of two Bose-Einstein condensates. We demonstrate that they are several orders of magnitude more dilute than liquid helium by directly measuring their size and density via in situ imaging. We show that the droplets are stablized against collapse by quantum fluctuations and that they require a minimum atom number to be stable. Below that number, quantum pressure drives a liquid-to-gas transition that we map out as a function of interaction strength. These ultradilute isotropic liquids remain weakly interacting and constitute an ideal platform to benchmark quantum many body theories. PMID- 29242235 TI - Mechanically robust, readily repairable polymers via tailored noncovalent cross linking. AB - Expanding the range of healable materials is an important challenge for sustainable societies. Noncrystalline, high-molecular-weight polymers generally form mechanically robust materials, which, however, are difficult to repair once they are fractured. This is because their polymer chains are heavily entangled and diffuse too sluggishly to unite fractured surfaces within reasonable time scales. Here we report that low-molecular-weight polymers, when cross-linked by dense hydrogen bonds, yield mechanically robust yet readily repairable materials, despite their extremely slow diffusion dynamics. A key was to use thiourea, which anomalously forms a zigzag hydrogen-bonded array that does not induce unfavorable crystallization. Another key was to incorporate a structural element for activating the exchange of hydrogen-bonded pairs, which enables the fractured portions to rejoin readily upon compression. PMID- 29242234 TI - Arabidopsis pollen tube integrity and sperm release are regulated by RALF mediated signaling. AB - In flowering plants, fertilization requires complex cell-to-cell communication events between the pollen tube and the female reproductive tissues, which are controlled by extracellular signaling molecules interacting with receptors at the pollen tube surface. We found that two such receptors in Arabidopsis, BUPS1 and BUPS2, and their peptide ligands, RALF4 and RALF19, are pollen tube-expressed and are required to maintain pollen tube integrity. BUPS1 and BUPS2 interact with receptors ANXUR1 and ANXUR2 via their ectodomains, and both sets of receptors bind RALF4 and RALF19. These receptor-ligand interactions are in competition with the female-derived ligand RALF34, which induces pollen tube bursting at nanomolar concentrations. We propose that RALF34 replaces RALF4 and RALF19 at the interface of pollen tube-female gametophyte contact, thereby deregulating BUPS-ANXUR signaling and in turn leading to pollen tube rupture and sperm release. PMID- 29242236 TI - Near-Field Ultrasound Imaging During Radiofrequency Catheter Ablation: Tissue Thickness and Epicardial Wall Visualization and Assessment of Radiofrequency Ablation Lesion Formation and Depth. AB - BACKGROUND: Safe and successful radiofrequency catheter ablation depends on creation of transmural lesions without collateral injury to contiguous structures. Near-field ultrasound (NFUS) imaging through transducers in the tip of an ablation catheter may provide important information about catheter contact, wall thickness, and ablation lesion formation. METHODS AND RESULTS: NFUS imaging was performed using a specially designed open-irrigated radiofrequency ablation catheter incorporating 4 ultrasound transducers. Tissue/phantom thickness was measured in vitro with varying contact angles. In vivo testing was performed in 19 dogs with NFUS catheters positioned in 4 chambers. Wall thickness measurements were made at 222 sites (excluding the left ventricle) and compared with measurements from intracardiac echocardiography. Imaging was used to identify the epicardium with saline infusion into the pericardial space at 39 sites. In vitro, the measured exceeded actual tissue/phantom thickness by 13% to 20%. In vivo, NFUS reliably visualized electrode-tissue contact, but sensitivity of epicardial imaging was 92%. The chamber wall thickness measured by NFUS correlated well with intracardiac echocardiography (r=0.86; P<0.0001). Sensitivity of lesion identification by NFUS was 94% for atrial and 95% for ventricular ablations. NFUS was the best parameter to predict lesion depth in right and left ventricle (r=0.47; P<0.0001; multiple regression P=0.0025). Lesion transmurality was correctly identified in 87% of atrial lesions. CONCLUSIONS: NFUS catheter imaging reliably assesses electrode-tissue contact and wall thickness. Its use during radiofrequency catheter ablation may allow the operator to assess the depth of ablation required for transmural lesion formation to optimize power delivery. PMID- 29242237 TI - Near-Field Ultrasound Imaging of Ablation Lesion Formation: More Than Meets the Eye? PMID- 29242238 TI - Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model. AB - RATIONALE: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, whereas TL in skeletal muscle represents a minimally replicative tissue. OBJECTIVE: We measured LTL and muscle TL (MTL) in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD. METHODS AND RESULTS: Our Discovery Cohort comprised 259 individuals aged 63+/-14 years (mean+/-SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTL adjusted for muscle biopsy site (MTLA) was longer than LTL and the LTL-MTLA gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL (P=0.005), but not MTLA (P=0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTLA) was wider (P=0.0003), and the TL ratio between leukocytes and muscle (LTL/MTLA) was smaller (P=0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals. CONCLUSIONS: This first study to apply the blood-and-muscle TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02176941. PMID- 29242241 TI - Colors of Myocardial Infarction: Can They Predict the Future? PMID- 29242239 TI - Defining Quality in Cardiovascular Imaging: A Scientific Statement From the American Heart Association. AB - The aims of the current statement are to refine the definition of quality in cardiovascular imaging and to propose novel methodological approaches to inform the demonstration of quality in imaging in future clinical trials and registries. We propose defining quality in cardiovascular imaging using an analytical framework put forth by the Institute of Medicine whereby quality was defined as testing being safe, effective, patient-centered, timely, equitable, and efficient. The implications of each of these components of quality health care are as essential for cardiovascular imaging as they are for other areas within health care. Our proposed statement may serve as the foundation for integrating these quality indicators into establishing designations of quality laboratory practices and developing standards for value-based payment reform for imaging services. We also include recommendations for future clinical research to fulfill quality aims within cardiovascular imaging, including clinical hypotheses of improving patient outcomes, the importance of health status as an end point, and deferred testing options. Future research should evolve to define novel methods optimized for the role of cardiovascular imaging for detecting disease and guiding treatment and to demonstrate the role of cardiovascular imaging in facilitating healthcare quality. PMID- 29242240 TI - Persistence of Infarct Zone T2 Hyperintensity at 6 Months After Acute ST-Segment Elevation Myocardial Infarction: Incidence, Pathophysiology, and Prognostic Implications. AB - BACKGROUND: The incidence and clinical significance of persistent T2 hyperintensity after acute ST-segment-elevation myocardial infarction (STEMI) is uncertain. METHODS AND RESULTS: Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI: NCT02072850). Two hundred eighty-three STEMI patients (mean age, 59+/-12 years; 75% male) had cardiac magnetic resonance with T2 mapping performed at 2 days and 6 months post-STEMI. Persisting T2 hyperintensity was defined as infarct T2 >2 SDs from remote T2 at 6 months. Infarct zone T2 was higher than remote zone T2 at 2 days (66.3+/-6.1 versus 49.7+/-2.1 ms; P<0.001) and 6 months (56.8+/-4.5 versus 49.7+/-2.3 ms; P<0.001). Remote zone T2 did not change over time (mean change, 0.0+/-2.7 ms; P=0.837), whereas infarct zone T2 decreased (-9.5+/-6.4 ms; P<0.001). At 6 months, T2 hyperintensity persisted in 189 (67%) patients, who were more likely to have Thrombus in Myocardial Infarction flow 0 or 1 in the culprit artery (P=0.020), incomplete ST-segment resolution (P=0.037), and higher troponin (P=0.024). Persistent T2 hyperintensity was associated with NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration (0.57 on a log scale [0.42-0.72]; P=0.004) and the likelihood of adverse left ventricular remodeling (>20% change in left ventricular end-diastolic volume; 21.91 [2.75-174.29]; P=0.004). Persistent T2 hyperintensity was associated with all-cause death and heart failure, but the result was not significant (P=0.051). DeltaT2 was associated with all-cause death and heart failure (P=0.004) and major adverse cardiac events (P=0.013). CONCLUSIONS: Persistent T2 hyperintensity occurs in two thirds of STEMI patients. Persistent T2 hyperintensity was associated with the initial STEMI severity, adverse remodeling, and long-term health outcome. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850. PMID- 29242242 TI - NHS will need 190 000 more doctors unless productivity improves, workforce plan warns. PMID- 29242243 TI - An Infrared Dye-Conjugated Virus-like Particle for the Treatment of Primary Uveal Melanoma. AB - The work outlined herein describes AU-011, a novel recombinant papillomavirus like particle (VLP) drug conjugate and its initial evaluation as a potential treatment for primary uveal melanoma. The VLP is conjugated with a phthalocyanine photosensitizer, IRDye 700DX, that exerts its cytotoxic effect through photoactivation with a near-infrared laser. We assessed the anticancer properties of AU-011 in vitro utilizing a panel of human cancer cell lines and in vivo using murine subcutaneous and rabbit orthotopic xenograft models of uveal melanoma. The specificity of VLP binding (tumor targeting), mediated through cell surface heparan sulfate proteoglycans (HSPG), was assessed using HSPG-deficient cells and by inclusion of heparin in in vitro studies. Our results provide evidence of potent and selective anticancer activity, both in vitro and in vivo AU-011 activity was blocked by inhibiting its association with HSPG using heparin and using cells lacking surface HSPG, indicating that the tumor tropism of the VLP was not affected by dye conjugation and cell association is critical for AU-011 mediated cytotoxicity. Using the uveal melanoma xenograft models, we observed tumor uptake following intravenous (murine) and intravitreal (rabbit) administration and, after photoactivation, potent dose-dependent tumor responses. Furthermore, in the rabbit orthotopic model, which closely models uveal melanoma as it presents in the clinic, tumor treatment spared the retina and adjacent ocular structures. Our results support further clinical development of this novel therapeutic modality that might transform visual outcomes and provide a targeted therapy for the early-stage treatment of patients with this rare and life threatening disease. Mol Cancer Ther; 17(2); 565-74. (c)2017 AACR. PMID- 29242245 TI - More new treatments for cystic fibrosis. PMID- 29242244 TI - Current status of paediatric and neonatal organ donation in the UK. PMID- 29242247 TI - CHIP Regulates Aquaporin-2 Quality Control and Body Water Homeostasis. AB - The importance of the kidney distal convoluted tubule (DCT) and cortical collecting duct (CCD) is highlighted by various water and electrolyte disorders that arise when the unique transport properties of these segments are disturbed. Despite this critical role, little is known about which proteins have a regulatory role in these cells and how these cells can be regulated by individual physiologic stimuli. By combining proteomics, bioinformatics, and cell biology approaches, we found that the E3 ubiquitin ligase CHIP is highly expressed throughout the collecting duct; is modulated in abundance by vasopressin; interacts with aquaporin-2 (AQP2), Hsp70, and Hsc70; and can directly ubiquitylate the water channel AQP2 in vitro shRNA knockdown of CHIP in CCD cells increased AQP2 protein t1/2 and reduced AQP2 ubiquitylation, resulting in greater levels of AQP2 and phosphorylated AQP2. CHIP knockdown increased the plasma membrane abundance of AQP2 in these cells. Compared with wild-type controls, CHIP knockout mice or novel CRISPR/Cas9 mice without CHIP E3 ligase activity had greater AQP2 abundance and altered renal water handling, with decreased water intake and urine volume, alongside higher urine osmolality. We did not observe significant changes in other water- or sodium-transporting proteins in the gene modified mice. In summary, these results suggest that CHIP regulates AQP2 and subsequently, renal water handling. PMID- 29242248 TI - Causes of Death after a Hospitalization with AKI. AB - Mortality after AKI is high, but the causes of death are not well described. To better understand causes of death in patients after a hospitalization with AKI and to determine patient and hospital factors associated with mortality, we conducted a population-based study of residents in Ontario, Canada, who survived a hospitalization with AKI from 2003 to 2013. Using linked administrative databases, we categorized cause of death in the year after hospital discharge as cardiovascular, cancer, infection-related, or other. We calculated standardized mortality ratios to compare the causes of death in survivors of AKI with those in the general adult population and used Cox proportional hazards modeling to estimate determinants of death. Of the 156,690 patients included, 43,422 (28%) died in the subsequent year. The most common causes of death were cardiovascular disease (28%) and cancer (28%), with respective standardized mortality ratios nearly six-fold (5.81; 95% confidence interval [95% CI], 5.70 to 5.92) and eight fold (7.87; 95% CI, 7.72 to 8.02) higher than those in the general population. The highest standardized mortality ratios were for bladder cancer (18.24; 95% CI, 17.10 to 19.41), gynecologic cancer (16.83; 95% CI, 15.63 to 18.07), and leukemia (14.99; 95% CI, 14.16 to 15.85). Along with older age and nursing home residence, cancer and chemotherapy strongly associated with 1-year mortality. In conclusion, cancer-related death was as common as cardiovascular death in these patients; moreover, cancer-related deaths occurred at substantially higher rates than in the general population. Strategies are needed to care for and counsel patients with cancer who experience AKI. PMID- 29242249 TI - Acidosis and Deafness in Patients with Recessive Mutations in FOXI1. AB - Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients. PMID- 29242250 TI - A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection. AB - Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor specific antibody (DSA)-positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, -4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24 month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR. PMID- 29242251 TI - Equal Opportunity, Equal Work: Increasing Women's Participation in the U.S. President's Malaria Initiative Africa Indoor Residual Spraying Project. AB - BACKGROUND: One of the primary control measures for malaria transmission is indoor residual spraying (IRS). Historically, few women have worked in IRS programs, despite the income-generating potential. Increasing women's roles in IRS requires understanding the barriers to women's participation and implementing measures to address them. The U.S. President's Malaria Initiative (PMI) Africa Indoor Residual Spraying (AIRS) Project is the largest implementer of IRS globally. To address gender inequity in IRS operations, PMI AIRS assessed the barriers to the participation of women and developed and implemented policies to address these barriers. METHODS: The PMI AIRS Project initially identified barriers through a series of informal assessments with key stakeholders. PMI AIRS then implemented a series of gender-guided policies, starting in 2015, in Benin, Ethiopia, Ghana, Mali, Madagascar, Mozambique, Rwanda, Senegal, Zambia, and Zimbabwe. The policies included adapting physical work environments to ensure privacy for women; ensuring the safety of women in the workplace; guaranteeing safety and job security of women during pregnancy; and encouraging qualified women to apply for supervisory positions. The project collected routine programmatic data on staff, spray quality, and spray efficiency; data from 2012 through the end of 2015 were analyzed (up through 1 year after implementation of the gender policies). In addition, PMI AIRS conducted surveys in 2015, 2016, and 2017 before and after the spray campaigns in 4 countries to determine changes in gender norms among spray operators through questions about decision making and agency. RESULTS: The PMI AIRS Project increased women's employment with the program. Specifically, women's employment increased overall from 23% in 2012 to 29% in 2015, with a 2015 range from 16% (Mali) to 40% (Madagascar). Growth among supervisor roles was even stronger, with the percentage of women in supervisory roles increasing from 17% in 2012 to 46% in 2015, with a 2015 range from 9% (Mali) to 50% (Madagascar). While the data showed that in most countries women sprayed fewer houses per day than men in 2015, the differences were not meaningful, ranging from 0.1 to 1.2 households per day. Gender norms shifted toward more egalitarian views in 2 of the 4 countries with survey data. CONCLUSION: Preliminary results suggest the PMI AIRS Project gender policies are increasing the engagement of women in all aspects of spray operations, especially in supervisory roles. Expansion of these policies to all countries implementing IRS and to malaria control implementation more broadly is recommended. PMID- 29242252 TI - Correction for Mounce et al., "A Conserved Gammaherpesvirus Protein Kinase Targets Histone Deacetylases 1 and 2 To Facilitate Viral Replication in Primary Macrophages". PMID- 29242253 TI - Correction for Subba-Reddy et al., "VPg-Primed RNA Synthesis of Norovirus RNA Dependent RNA Polymerases by Using a Novel Cell-Based Assay". PMID- 29242254 TI - Correction for Ver et al., "The Cellular Factor NXP2/MORC3 Is a Positive Regulator of Influenza Virus Multiplication". PMID- 29242255 TI - Correction for Hraber et al., "Panels of HIV-1 Subtype C Env Reference Strains for Standardized Neutralization Assessments". PMID- 29242256 TI - Manual review of electronic medical records as a reference standard for case definition development: a validation study. AB - BACKGROUND: The Canadian Primary Care Sentinel Surveillance Network (CPCSSN) previously carried out a validation study of case definitions for 8 chronic diseases (diabetes mellitus, hypertension, osteoarthritis, depression, dementia, chronic obstructive pulmonary disease, parkinsonism and epilepsy) using direct review of "raw" electronic medical record data. Although effective, this method is time-consuming and can present methodological and organizational challenges. We aimed to determine whether the processed and standardized data contained with the CPCSSN database might function as a reference standard for case definition validation. METHODS: Using a traditional validation study design, we compared the case identification results of the chart reviews for the 8 chronic diseases with the results of a manual review of the CPCSSN processed data for the same conditions in the same patient sample. Patients were randomly sampled from the June 30, 2012 CPCSSN database, with oversampling of patients with rare conditions. RESULTS: We analyzed data for 1906 patients. Manual review of the CPCSSN records for case ascertainment yielded sensitivity ranging from 77.5% (95% confidence interval [CI] 73.3%-81.6%) for depression to 97.2% (95% CI 95.4% 99.0%) for diabetes. Specificity was high for all definitions (range 93.1% [95% CI 91.4%-94.7%] to 99.4% [95% CI 99.0%-99.8%]). Positive predictive values and negative predictive values also showed high accuracy of the manual CPCSSN record review relative to review of the raw chart data. INTERPRETATION: The use of CPCSSN records as the reference standard to validate case definitions substantially reduces the burden on sentinel physicians and clinic managers as well as on researchers while offering a reference standard that is a reasonable substitution for chart review. PMID- 29242257 TI - Atopobium and Fusobacterium as novel candidates for sarcoidosis-associated microbiota. AB - Sarcoidosis is a granulomatous disease that mainly affects the lung. A role of microbial factors in disease pathogenesis is assumed, but has not been investigated systematically in a large cohort.This cross-sectional study compared the lung microbiota of 71 patients with sarcoidosis, 15 patients with idiopathic pulmonary fibrosis (non-infectious controls) and 10 healthy controls (HCs). Next generation sequencing of 16S DNA was used on bronchoalveolar lavage samples to characterise the microbial composition, which was analysed for diversity and indicator species. Host genotypes for 13 known sarcoidosis risk variants were determined and correlated with microbial parameters.The microbial composition differed significantly between sarcoidosis and HC samples (redundancy analysis ANOVA, p=0.025) and between radiographic Scadding types. Atopobium spp. was detected in 68% of sarcoidosis samples, but not in HC samples. Fusobacterium spp. was significantly more abundant in sarcoidosis samples compared with those from HCs. Mycobacteria were found in two of 71 sarcoidosis samples. Host-genotype analysis revealed an association of the rs2076530 (BTNL2) risk allele with a decrease in bacterial burden (p=0.002).Our results indicate Scadding type dependent microbiota in sarcoidosis BAL samples. Atopobium spp. and Fusobacterium spp. were identified as sarcoidosis-associated bacteria, which may enable new insights into the pathogenesis and treatment of the disease. PMID- 29242258 TI - ERS statement: interventional bronchoscopy in children. AB - Paediatric airway endoscopy is accepted as a diagnostic and therapeutic procedure, with an expanding number of indications and applications in children. The aim of this European Respiratory Society task force was to produce a statement on interventional bronchoscopy in children, describing the evidence available at present and current clinical practice, and identifying areas deserving further investigation. The multidisciplinary task force panel performed a systematic review of the literature, focusing on whole lung lavage, transbronchial and endobronchial biopsy, transbronchial needle aspiration with endobronchial ultrasound, foreign body extraction, balloon dilation and occlusion, laser-assisted procedures, usage of airway stents, microdebriders, cryotherapy, endoscopic intubation, application of drugs and other liquids, and caregiver perspectives. There is a scarcity of published evidence in this field, and in many cases the task force had to resort to the collective clinical experience of the committee to develop this statement. The highlighted gaps in knowledge underline the need for further research and serve as a call to paediatric bronchoscopists to work together in multicentre collaborations, for the benefit of children with airway disorders. PMID- 29242260 TI - The potential effects of pregnancy in a patient with idiopathic pulmonary arterial hypertension responding to calcium channel blockade. PMID- 29242261 TI - Dual responses of CD14 methylation to distinct environments: a role in asthma and allergy. PMID- 29242259 TI - Chest computed tomography-derived low fat-free mass index and mortality in COPD. AB - Low fat-free mass index (FFMI) is an independent risk factor for mortality in chronic obstructive pulmonary disease (COPD) not typically measured during routine care. In the present study, we aimed to derive fat-free mass from the pectoralis muscle area (FFMPMA) and assess whether low FFMIPMA is associated with all-cause mortality in COPD cases. We used data from two independent COPD cohorts, ECLIPSE and COPDGene.Two equal sized groups of COPD cases (n=759) from the ECLIPSE study were used to derive and validate an equation to calculate the FFMPMA measured using bioelectrical impedance from PMA. We then applied the equation in COPD cases (n=3121) from the COPDGene cohort, and assessed survival. Low FFMIPMA was defined, using the Schols classification (FFMI <16 in men, FFMI <15 in women) and the fifth percentile normative values of FFMI from the UK Biobank.The final regression model included PMA, weight, sex and height, and had an adjusted R2 of 0.92 with fat-free mass (FFM) as the outcome. In the test group, the correlation between FFMPMA and FFM remained high (Pearson correlation=0.97). In COPDGene, COPD cases with a low FFMIPMA had an increased risk of death (HR 1.6, p<0.001).We demonstrated COPD cases with a low FFMIPMA have an increased risk of death. PMID- 29242262 TI - Standardised classification of the aetiology of bronchiectasis using an objective algorithm. PMID- 29242263 TI - Temporal trajectories of novel object recognition performance in mice exposed to intermittent hypoxia. AB - Intermittent hypoxia is one of the major perturbations of sleep-disordered breathing and has been causally implicated in neurocognitive deficits. However, the reversibility of such deficits is unclear.Male C57BL/6J mice were exposed to either intermittent hypoxia or room air for 3-240 days, and then half were randomly selected and allowed to recover in normoxic conditions for the same duration of the previous exposure. A novel object recognition (NOR) test was performed.NOR performance was stable over time in room air. Intermittent hypoxia induced significant reductions in recognition index that progressed over the first 45 days and stabilised thereafter. Normoxic recovery of recognition index was essentially complete and indistinguishable from room air in mice exposed to shorter intermittent hypoxia times (<90 days). However, significant residual deficits emerged after normoxic recovery following prolonged intermittent hypoxia exposures (p<0.01). In addition, gradual attenuation of the magnitude of recovery in recognition index occurred with increasingly longer intermittent hypoxia exposures (MANOVA p<0.0001).Intermittent hypoxia during the resting period reduces NOR performance in a time-dependent fashion. Reversal of NOR performance deficits is unlikely after prolonged intermittent hypoxia duration. These findings suggest that early recognition of sleep apnoea and effective treatment are critical for restoration of the adverse cognitive effects of the disease. PMID- 29242264 TI - Prognostic value of right ventricular dilatation in patients with low-risk pulmonary embolism. AB - The prognosis of multidetector computed tomography (MDCT) assessed right ventricular dilatation (RVD) is unclear in patients with pulmonary embolism (PE) and a simplified Pulmonary Embolism Severity Index (sPESI) of 0. We investigated in these patients whether MDCT-assessed RVD, defined by a right to left ventricular ratio (RV/LV) >=0.9 or >=1.0, is associated with worse outcomes.We combined data from three prospective cohorts of patients with PE. The main study outcome was the composite of 30-day all-cause mortality, haemodynamic collapse or recurrent PE in patients with sPESI of 0.Among 779 patients with a sPESI 0, 420 (54%) and 299 (38%) had a RV/LV >=0.9 and >=1.0 respectively. No difference in primary outcome was observed, 0.95% (95% CI 0.31-2.59) versus 0.56% (95% CI 0.10 2.22; p=0.692) and 1.34% (95% CI 0.43-3.62) versus 0.42% (95% CI 0.07-1.67; p=0.211) with RV/LV >=0.9 and >=1.0 respectively. Increasing the RV/LV threshold to >=1.1, the outcome occurred more often in patients with RVD (2.12%, 95% CI 0.68-5.68 versus 0.34%, 95% CI 0.06-1.36; p=0.033).MDCT RV/LV ratio of >=0.9 and >=1.0 in sPESI 0 patients is frequent but not associated with a worse prognosis but higher cut-off values might be associated with worse outcome in these patients. PMID- 29242265 TI - To progress understanding of disease triggers and modifiers in sarcoidosis, stratification is the key. PMID- 29242266 TI - Always think of the right ventricle, even in "low-risk" pulmonary embolism. PMID- 29242267 TI - "Infertility in an adult cohort with primary ciliary dyskinesia: phenotype-gene association." Gert Jan Vanaken, Laurence Bassinet, Mieke Boon, Rahma Mani, Isabelle Honore, Jean-Francois Papon, Harry Cuppens, Martine Jaspers, Natalie Lorent, Andre Coste, Estelle Escudier, Serge Amselem, Bernard Maitre, Marie Legendre and Sophie Christin-Maitre. Eur Respir J 2017; 50: 1700314. PMID- 29242268 TI - Preterm Birth, Poverty, and Cognitive Development. AB - BACKGROUND: Preterm birth and childhood poverty each adversely impact children's cognitive development and academic outcomes. In this study, we investigated whether the relationships between preterm and early term birth and children's cognitive scores at 3, 5, and 7 years old were modified by childhood poverty. METHODS: This study was conducted by using data on singletons born at 24 to 40 weeks' gestation enrolled in the Millennium Cohort Study in the United Kingdom. Linear regression models were used to test independent and joint associations of gestational age (early or moderate preterm, late preterm, or early term compared with term) and childhood poverty (<60% of median UK income) with children's cognitive scores. Presence of additive interaction between gestational age and poverty was tested by using interaction terms. RESULTS: Children born preterm (<37 weeks) or early term (37-38 weeks) tended to score more poorly on cognitive assessments than children born at term (39-40 weeks). The estimated deficits were ~0.2 to 0.3 SD for early or moderate preterm, 0.1 SD for late preterm, and 0.05 SD for early term compared with term. Children living in poverty scored 0.3 to 0.4 SD worse than children not living in poverty on all assessments. For most assessments, the estimated effects of the 2 factors were approximately additive, with little or no evidence of interaction between gestational age and poverty. CONCLUSIONS: Although children born preterm who lived in poverty had the poorest cognitive outcomes, living in poverty did not magnify the adverse effect of being preterm on cognitive development. PMID- 29242269 TI - SIADH in Systemic JIA Resolving After Treatment With an IL-6 Inhibitor. AB - Interleukin-6 (IL-6) is implicated in the pathogenesis of both systemic juvenile idiopathic arthritis (SJIA) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but the 2 have not been previously described as occurring together. We report a case of a 6-year-old girl with symptoms of arthralgia, daily fevers, evanescent rash, lymphadenopathy, and laboratory evaluation showing elevated inflammatory markers, consistent with SJIA. At presentation, the patient had hyponatremia with a sodium level of 128 mEq/L. She had low serum osmolality with elevated urine osmolality, consistent with SIADH. Hyponatremia improved temporarily during times of fluid restriction as expected in SIADH, but did not resolve until SJIA was treated successfully with tocilizumab, an IL-6 receptor antibody that inhibits IL-6 activity. The positive response to treatment with tocilizumab supports the role of IL-6 in the pathogenesis of both SJIA and SIADH. Patients with SJIA should be monitored for SIADH to avoid complications of untreated hyponatremia. PMID- 29242270 TI - Intermedin Enlarges the Vascular Lumen by Inducing the Quiescent Endothelial Cell Proliferation. AB - OBJECTIVE: Intermedin plays an important role in vascular remodeling and significantly improves blood perfusion, but the precise mechanism remains unclear. Herein, we aimed to define whether vascular lumen enlargement is responsible for the intermedin-increased blood perfusion and explore the underlying cellular and molecular mechanisms. APPROACH AND RESULTS: To study the role of intermedin, we generated the IMD-KO (Adm2-/-) mice using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) system. Intermedin significantly promoted vascular lumen enlargement in vitro (fibrin beads assay) and in vivo (murine retinas), which contributed to the improved blood perfusion in both physiological (retinal) and pathological (tumor) angiogenic models. We designed experiments to calculate the endothelial cell (EC) size and found that the lumen enlargement is because of EC proliferation but not because of a change in cell shape. ECs that construct vessel walls are considered quiescent cells because they are in a state of contact inhibition and show reduced responsiveness to VEGF (vascular endothelial growth factor). Using immunoprecipitation, Western blot assay, and fluorescent microscopy, we found that intermedin induced the formation of a signaling complex containing CRLR (calcitonin receptor-like receptor)/beta-arr1 (beta-arrestin1)/Src in ECs and promoted it internalizing into cytoplasm in a clathrin-dependent manner to activate downstream ERK1/2 (extracellular signal-regulated kinase 1/2). Importantly, this effect was not abrogated by cell-cell contacts of ECs. Through this mechanism, intermedin could reactivate the quiescent ECs to proliferate, resulting in continuous lumen expanding and a more effective blood perfusion. CONCLUSIONS: Our findings suggest a novel mechanism that may explain how quiescent ECs overcome the contact inhibition and regain the ability to proliferate for continuous vascular lumen enlargement. PMID- 29242272 TI - Correction: Reliability of an automatic classifier for brain enlarged perivascular spaces burden and comparison with human performance. PMID- 29242271 TI - SNRK (Sucrose Nonfermenting 1-Related Kinase) Promotes Angiogenesis In Vivo. AB - OBJECTIVE: SNRK (sucrose nonfermenting 1-related kinase) is a novel member of the AMPK (adenosine monophosphate-activated protein kinase)-related superfamily that is activated in the process of angiogenesis. Currently, little is known about the function of SNRK in angiogenesis in the physiological and pathological conditions. APPROACH AND RESULTS: In this study, in Snrk global heterozygous knockout mice, retina angiogenesis and neovessel formation after hindlimb ischemia were suppressed. Consistently, mice with endothelial cell (EC)-specific Snrk deletion exhibited impaired retina angiogenesis, and delayed perfusion recovery and exacerbated muscle apoptosis in ischemic hindlimbs, compared with those of littermate wide-type mice. Endothelial SNRK expression was increased in the extremity vessel samples from nonischemic human. In ECs cultured in hypoxic conditions, HIF1alpha (hypoxia inducible factor 1alpha) bound to the SNRK promoter to upregulate SNRK expression. In the nuclei of hypoxic ECs, SNRK complexed with SP1 (specificity protein 1), and together, they bound to an SP1 binding motif in the ITGB1 (beta1 integrin) promoter, resulting in enhanced ITGB1 expression and promoted EC migration. Furthermore, SNRK or SP1 deficiency in ECs ameliorated hypoxia-induced ITGB1 expression and, consequently, inhibited EC migration and angiogenesis. CONCLUSIONS: Taken together, our data have revealed that SNRK/SP1-ITGB1 signaling axis promotes angiogenesis in vivo. PMID- 29242274 TI - Sema4D/PlexinB1 inhibition ameliorates blood-brain barrier damage and improves outcome after stroke in rats. AB - The inflammatory process in stroke is the major contributor to blood-brain barrier (BBB) breakdown. Previous studies indicated that semaphorin 4D (Sema4D), an axon guidance molecule, initiated inflammatory microglial activation and disrupted endothelial function in the CNS. However, whether Sema4D disrupts BBB integrity after stroke remains unclear. To study the effect of Sema4D on BBB disruption in stroke, rats were subjected to transient middle cerebral artery occlusion and targeted injection of lentivirus-mediated clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene disruption of PlexinB1. We found that Sema4D synchronously increased with BBB permeability and accumulated in the perivascular area after stroke. Suppressing Sema4D/PlexinB1 signaling in the periinfarct cortex significantly decreased BBB permeability as detected by MRI and fibrin deposition, and thereby improved stroke outcome. In vitro, we confirmed that Sema4D disrupted BBB integrity and endothelial tight junctions. Moreover, we found that Sema4D induced pericytes to acquire a CD11b positive phenotype and express proinflammatory cytokines. In addition, Sema4D inhibited AUF1-induced proinflammatory mRNA decay effect. Taken together, our data provides evidence that Sema4D disrupts BBB integrity and promotes an inflammatory response by binding to PlexinB1 in pericytes after transient middle cerebral artery occlusion. Our study indicates that Sema4D may be a novel therapeutic target for treatment in the acute phase of stroke.-Zhou, Y.-F., Li, Y.-N., Jin, H.-J., Wu, J.-H., He, Q.-W., Wang, X.-X., Lei, H., Hu, B. Sema4D/PlexinB1 inhibition ameliorates blood-brain barrier damage and improves outcome after stroke in rats. PMID- 29242273 TI - RBPJ mediates uterine repair in the mouse and is reduced in women with recurrent pregnancy loss. AB - Unexplained recurrent pregnancy loss (uRPL) is associated with repeated embryo loss and endometrial repair with elevated endometrial expression of inflammatory cytokines, including IFN-gamma. Notch signaling through its transcription factor recombination signal binding protein Jkappa (RBPJ) regulates mechanisms including the immune response and repair after tissue injury. Initially, null mutation of RBPJ in the mouse uterus ( Pgrcre/+Rbpjf/f; Rbpj c-KO) results in subfertility, but we have found that these mice become infertile after pregnancy as a result of dysfunctional postpartum uterine repair, including delayed endometrial epithelial and myometrial regeneration. RNA sequencing of postpartum uterine repair sites revealed global up-regulation of inflammatory pathways, including IFN signaling. Consistent with elevated IFN-gamma, macrophages were recruited and polarized toward an M1-cytotoxic phenotype, which is associated with preventing repair and promoting further tissue injury. Through embryo transfer experiments, we show that dysfunctional postpartum repair directly impairs future embryo implantation in Rbpj c-KO mice. Last, we clinically correlated our findings from the Rbpj c-KO mouse in women diagnosed with uRPL. Reduced RBPJ in women with uRPL was associated with increased levels of IFN-gamma. The data, taken together, indicate that RBPJ regulates inflammation during endometrial repair, which is essential for future pregnancy potential, and its dysregulation may serve as an unidentified contributor to uRPL in women.-Strug, M. R., Su, R.-W., Kim, T. H., Mauriello, A., Ticconi, C., Lessey, B. A., Young, S. L., Lim, J. M., Jeong, J. W., Fazleabas, A. T. RBPJ mediates uterine repair in the mouse and is reduced in women with recurrent pregnancy loss. PMID- 29242275 TI - IGFBP7 regulates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells via Wnt/beta-catenin signaling pathway. AB - Insulin-like growth factor-binding protein 7 (IGFBP7), a low-affinity IGF binder, may play an important role in bone metabolism. However, its function in osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (BMSCs) remains unclear. Therefore, we investigated its effects on osteogenic differentiation. Overexpression of IGFBP7 enhanced the expression of osteo specific genes and proteins, and IGFBP7 knockdown decreased osteogenesis-specific markers. More mineral deposits and higher alkaline phosphatase activity were observed after the up-regulation of IGFBP7. Moreover, beta-catenin levels were up regulated by the overexpression of IGFBP7 or the addition of extracellular IGFBP7 protein and were reduced by the depletion of IGFBP7. The increase in osteogenic differentiation due to the overexpression of IGFBP7 was partially decreased by specific Wnt/beta-catenin signaling inhibitors. Using a rat tibial osteotomy model, a sheet of IGFBP7-overexpressing BMSCs improved bone healing, as demonstrated by imaging, biomechanical, and histologic analyses. Taken together, these findings indicate that IGFBP7 regulates the osteogenic differentiation of BMSCs partly via the Wnt/beta-catenin signaling pathway.-Zhang, W., Chen, E., Chen, M., Ye, C., Qi, Y., Ding, Q., Li, H., Xue, D., Gao, X., Pan, Z. IGFBP7 regulates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells via Wnt/beta-catenin signaling pathway. PMID- 29242276 TI - Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs. AB - Butyrate can improve gut functions, whereas histone deacetylase inhibitors might alleviate neurocognitive alterations. Our aim was to assess whether oral butyrate could modulate brain metabolism and plasticity and if this would relate to gut function. Sixteen pigs were subjected to sodium butyrate (SB) supplementation via beverage water or water only [control (C)]. All pigs had blood sampled after 2 and 3 wk of treatment, and were subjected to a brain positron emission tomography after 3 wk. Animals were euthanized after 4 wk to sample pancreas, intestine, and brain for gut physiology and anatomy measurements, as well as hippocampal histology, Ki67, and doublecortin (DCX) immunohistochemistry. SB compared with C treatment triggered basal brain glucose metabolism changes in the nucleus accumbens and hippocampus ( P = 0.003), increased hippocampal granular cell layer volume ( P = 0.006), and neurogenesis (Ki67: P = 0.026; DCX: P = 0.029). After 2 wk of treatment, plasma levels of glucose, insulin, lactate, glucagon-like peptide 1, and peptide tyrosine tyrosine remained unchanged. After 3 wk, plasma levels of lactate were lower in SB compared with C animals ( P = 0.028), with no difference for glucose and insulin. Butyrate intake impacted very little gut anatomy and function. These results demonstrate that oral SB impacted brain functions with little effects on the gut.-Val-Laillet, D., Guerin, S., Coquery, N., Nogret, I., Formal, M., Rome, V., Le Normand, L., Meurice, P., Randuineau, G., Guilloteau, P., Malbert, C.-H., Parnet, P., Lalles, J.-P., Segain, J.-P. Oral sodium butyrate impacts brain metabolism and hippocampal neurogenesis, with limited effects on gut anatomy and function in pigs. PMID- 29242277 TI - Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity. AB - Obesity-mediated inflammation is a major cause of insulin resistance, and macrophages play an important role in this process. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum chaperone that modulates unfolded protein response (UPR), and mice with GRP78 heterozygosity were resistant to diet-induced obesity. Here, we show that mice with macrophage selective ablation of GRP78 (Lyz- GRP78-/-) are protected from skeletal muscle insulin resistance without changes in obesity compared with wild-type mice after 9 wk of high-fat diet. GRP78-deficient macrophages demonstrated adapted UPR with up-regulation of activating transcription factor (ATF)-4 and M2-polarization markers. Diet-induced adipose tissue inflammation was reduced, and bone marrow derived macrophages from Lyz- GRP78-/- mice demonstrated a selective increase in IL-6 expression. Serum IL-13 levels were elevated by >4-fold in Lyz- GRP78-/- mice, and IL-6 stimulated the myocyte expression of IL-13 and IL-13 receptor. Lastly, recombinant IL-13 acutely increased glucose metabolism in Lyz- GRP78-/- mice. Taken together, our data indicate that GRP78 deficiency activates UPR by increasing ATF-4, and promotes M2-polarization of macrophages with a selective increase in IL-6 secretion. Macrophage-derived IL-6 stimulates the myocyte expression of IL-13 and regulates muscle glucose metabolism in a paracrine manner. Thus, our findings identify a novel crosstalk between macrophages and skeletal muscle in the modulation of obesity-mediated insulin resistance.-Kim, J. H., Lee, E., Friedline, R. H., Suk, S., Jung, D. Y., Dagdeviren, S., Hu, X., Inashima, K., Noh, H. L., Kwon, J. Y., Nambu, A., Huh, J. R., Han, M. S., Davis, R. J., Lee, A. S., Lee, K. W., Kim, J. K. Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity. PMID- 29242280 TI - Results of Fertility-Sparing Surgery for Expansile and Infiltrative Mucinous Ovarian Cancers. AB - BACKGROUND: No series had been reported focusing on the results of fertility sparing surgery in stage I mucinous ovarian cancers according to histotype (infiltrative vs. expansile). Investigating such outcomes was the aim of the present study. MATERIALS AND METHODS: The present study was a retrospective analysis of patients treated conservatively with preservation of the uterus and contralateral ovary from 1976 to 2016. The pathology of the tumors was reviewed by two expert pathologists according to the 2014 World Health Organization (WHO) classification criteria. Oncologic and fertility results were analyzed. RESULTS: Twenty-one patients fulfilled the inclusion criteria, twelve with expansile and nine with infiltrative cancer. All patients had a unilateral tumor and underwent unilateral salpingo-oophorectomy in one-step (n = 6) or two-step (n = 15) surgeries. All but one had complete peritoneal staging surgery based on cytology, omentectomy, and random peritoneal biopsies. Ten had nodal staging surgery. The International Federation of Gynecology and Obstetrics stages were IA (n = 9), IC1 (n = 6), and IC2 (n = 6); the nuclear grades were grade 1 (n = 9), grade 2 (n = 5), and grade 3 (n = 1). Two patients recurred (one expansile and one infiltrative type) 19 and 160 months after surgery, respectively. One stage IA, nuclear grade 2 expansile tumor recurred on the spared ovary; the patient remains alive. The other stage IA infiltrative tumor recurred as peritoneal spread; the patient is alive with disease. Six patients became pregnant; four with expansile tumors and two with infiltrative tumors. CONCLUSION: The type of mucinous cancer has no impact on the oncologic outcome in this series of patients treated conservatively. Fertility-sparing surgery should be considered for early-stage infiltrative-type tumors. IMPLICATIONS FOR PRACTICE: According to the most recently updated World Health Organization classification guidelines, mucinous cancers should be classified as either expansile or infiltrative. The infiltrative type has a poorer prognosis, but there are no data about the safety of fertility-sparing surgery (FSS) in this context. A collection of 21 cases reviewed by two expert pathologists this study is the first devoted to the conservative treatment of mucinous tumors according to both subtypes. The key result was that the type of mucinous cancer has no impact on the oncologic outcome; thus, FSS may be considered in both subtypes. PMID- 29242281 TI - FDA Benefit-Risk Assessment of Osimertinib for the Treatment of Metastatic Non Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor T790M Mutation. AB - : On March 30, 2017, the U.S. Food and Drug Administration (FDA) approved osimertinib for the treatment of patients with metastatic, epidermal growth factor receptor (EGFR) T790M mutation-positive, non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed following EGFR tyrosine kinase inhibitor (TKI) therapy. Approval was based on demonstration of a statistically significant difference in the primary endpoint of progression-free survival (PFS) when comparing osimertinib with chemotherapy in an international, multicenter, open-label, randomized trial (AURA3). In this confirmatory trial, which enrolled 419 patients, the PFS hazard ratio for osimertinib compared with chemotherapy per investigator assessment was 0.30 (95% confidence interval 0.23-0.41), p < .001, with median PFS of 10.1 months in the osimertinib arm and 4.4 months in the chemotherapy arm. Supportive efficacy data included PFS per blinded independent review committee demonstrating similar PFS results and an improved confirmed objective response rate per investigator assessment of 65% and 29%, with estimated median durations of response of 11.0 months and 4.2 months, in the osimertinib and chemotherapy arms, respectively. Patients received osimertinib 80 mg once daily and had a median duration of exposure of 8 months. The toxicity profile of osimertinib compared favorably with the profile of other approved EGFR TKIs and chemotherapy. The most common adverse drug reactions (>20%) in patients treated with osimertinib were diarrhea, rash, dry skin, nail toxicity, and fatigue. Herein, we review the benefit-risk assessment of osimertinib that led to regular approval, for patients with metastatic NSCLC harboring EGFR TKI whose disease has progressed on or after EGFR TKI therapy. IMPLICATIONS FOR PRACTICE: Osimertinib administered to metastatic non-small cell lung cancer (NSCLC) patients harboring an EGFR T790M mutation, who have progressed on or following EGFR TKI therapy, demonstrated a substantial improvement over platinum-based doublet chemotherapy as well as durable intracranial responses. The ability to test for the T790M mutation in plasma using the FDA-approved cobas EGFR Mutation Test v2 (Roche, Basel, Switzerland) identifies patients with NSCLC tumors not amenable to biopsy. Since a 40% false negative rate has been observed with the circulating tumor DNA test, re evaluation of the feasibility of tissue biopsy is recommended to identify patients with a false-negative plasma test result who may benefit from osimertinib. PMID- 29242279 TI - Molecular Biomarkers of Primary and Acquired Resistance to T-Cell-Mediated Immunotherapy in Cancer: Landscape, Clinical Implications, and Future Directions. AB - : The emergence of immunotherapy has revolutionized cancer treatment in recent years. Inhibitors of immune checkpoints, including antibodies against cytotoxic T lymphocyte-associated protein 4, programmed cell death protein 1, and programmed death ligand 1, have demonstrated notable efficacy in certain advanced cancers. Unfortunately, many patients do not benefit from these therapies and either exhibit primary resistance to treatment or develop acquired mechanisms of resistance after initially responding to therapy. Here, we review the genomic and immune traits that may promote resistance to T-cell-mediated immunotherapy, with a focus on identifying potential biomarkers that could eventually be used in the clinical setting to guide treatment selection. We summarize the clinical evidence for these markers and discuss how current understanding of resistance mechanisms can inform future studies and aid clinical decision-making in order to derive maximum benefit from immunotherapy. IMPLICATIONS FOR PRACTICE: Immunotherapy has rapidly progressed as a treatment modality for multiple cancers, but it is still unclear which patients are likely to benefit from these therapies. Studies of resistance mechanisms have only recently started to identify biomarkers that can help predict patient outcomes. This review summarizes the available clinical data in regard to immunotherapy resistance, with a focus on molecular biomarkers that may be useful in guiding clinical decision-making. It discusses possible applications of these biomarkers and highlights opportunities for further clinical discovery. PMID- 29242282 TI - Patient-Reported Comorbidity and Survival in Older Adults with Cancer. AB - BACKGROUND: Our ability to optimize the care of older adults with cancer and comorbid illnesses is insufficient because most clinical trials lack systematic measurement. The primary purpose of this study was to evaluate the association between patient-reported comorbidity and all-cause mortality using various comorbidity scoring algorithms. MATERIALS AND METHODS: The Carolina Senior Registry was linked with the North Carolina Central Cancer Registry to obtain mortality data. Comorbidity was assessed using the patient-reported Older Americans Resources and Services Questionnaire subscale that assesses 13 specific conditions and the degree to which each impairs activities. Multivariable Cox proportional hazard regression models were used to evaluate the association between comorbidities and all-cause mortality. RESULTS: The study sample included 539 patients; the median age was 72 years, 72% were female, and 47% had breast cancer. Overall, 92% reported >=1 comorbid condition, with a mean of 2.7 conditions (range 0-10), with arthritis and hypertension the most common (52% and 50%, respectively). Approximately 60% reported a functional limitation related to comorbidity. After adjusting for time from diagnosis to geriatric assessment, age, cancer type, and stage, the risk of death increased by 5% for each unit increase in comorbidity burden score (adjusted hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.01-1.10) and 12% for each comorbid condition impacting function (HR = 1.12, 95% CI: 1.02-1.23). CONCLUSION: Comorbid conditions in older adults with cancer are highly prevalent and associated with all-cause mortality, particularly those conditions that impair function. Routine comorbidity assessment should be included in clinical trials and can be measured via a simple one-page patient-reported questionnaire. IMPLICATIONS FOR PRACTICE: In order to optimize and personalize the care of older adults with cancer, systematic measurement of comorbidities is necessary in both clinical trials and routine practice. Patient-reported comorbid conditions in older adults with cancer are highly prevalent and are associated with increased risk of all-cause mortality, particularly for those conditions that impair function. Comorbidity can be systematically measured via a one-page patient-reported questionnaire and should be incorporated into future clinical trials and considered for use in oncology clinics to aid in assessing older adults with cancer. PMID- 29242284 TI - Putting rising emergency hospital admissions for children into perspective: how do international comparisons help? PMID- 29242285 TI - Redundancy and cooperation in Notch intercellular signaling. AB - During metazoan development, Notch signaling drives spatially coordinated differentiation by establishing communication between adjacent cells. This occurs through either lateral inhibition, in which adjacent cells acquire distinct fates, or lateral induction, in which all cells become equivalent. Notch signaling is commonly activated by several distinct ligands, each of which drives signaling with a different efficiency upon binding to the Notch receptor of adjacent cells. Moreover, these ligands can also be distinctly regulated by Notch signaling. Under such complex circumstances, the overall spatial coordination becomes elusive. Here, we address this issue through both mathematical and computational analyses. Our results show that when two ligands have distinct efficiencies and compete for the same Notch receptor, they cooperate to drive new signaling states, thereby conferring additional robustness and evolvability to Notch signaling. Counterintuitively, whereas antagonistically regulated ligands cooperate to drive and enhance the response that is expected from the more efficient ligand, equivalently regulated ligands coordinate emergent spatial responses that are dependent on both ligands. Our study highlights the importance of ligand efficiency in multi-ligand scenarios, and can explain previously reported complex phenotypes. PMID- 29242283 TI - Phase II Study of BEZ235 versus Everolimus in Patients with Mammalian Target of Rapamycin Inhibitor-Naive Advanced Pancreatic Neuroendocrine Tumors. AB - LESSONS LEARNED: Treatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.The hypothesis of dual targeting of the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents. BACKGROUND: This phase II study investigated whether targeting the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naive to mTOR inhibitor therapy. METHODS: Patients with advanced pNET were randomized (1:1) to oral BEZ235 400 mg twice daily or oral everolimus 10 mg once daily on a continuous dosing schedule. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, overall response rate (ORR), overall survival (OS), and time to treatment failure. RESULTS: Enrollment in this study was terminated early (62 enrolled of the 140 planned). The median PFS was 8.2 months (95% confidence interval [CI]: 5.3 to not evaluable [NE]) with BEZ235 versus 10.8 months (95% CI: 8.1-NE) with everolimus (hazard ratio 1.53; 95% CI: 0.72-3.25). The most commonly reported all-grade adverse events (>50% of patients regardless of study treatment relationship) with BEZ235 were diarrhea (90.3%), stomatitis (74.2%), and nausea (54.8%). CONCLUSION: BEZ235 treatment in mTOR inhibitor-naive patients with advanced pNET did not demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile. PMID- 29242286 TI - HOP-1 Presenilin Deficiency Causes a Late-Onset Notch Signaling Phenotype That Affects Adult Germline Function in Caenorhabditis elegans. AB - Functionally redundant genes present a puzzle as to their evolutionary preservation, and offer an interesting opportunity for molecular specialization. In Caenorhabditis elegans, either one of two presenilin genes (sel-12 or hop-1) facilitate Notch activation, providing the catalytic subunit for the gamma secretase proteolytic enzyme complex. For all known Notch signaling events, sel 12 can mediate Notch activation, so the conservation of hop-1 remains a mystery. Here, we uncover a novel "late-onset" germline Notch phenotype in which HOP-1 deficient worms fail to maintain proliferating germline stem cells during adulthood. Either SEL-12 or HOP-1 presenilin can impart sufficient Notch signaling for the establishment and expansion of the germline, but maintenance of an adult stem cell pool relies exclusively on HOP-1-mediated Notch signaling. We also show that HOP-1 is necessary for maximum fecundity and reproductive span. The low-fecundity phenotype of hop-1 mutants can be phenocopied by switching off glp-1/Notch function during the last stage of larval development. We propose that at the end of larval development, dual presenilin usage switches exclusively to HOP-1, perhaps offering opportunities for differential regulation of the germline during adulthood. Additional defects in oocyte size and production rate in hop-1 and glp-1 mutants indicate that the process of oogenesis is compromised when germline Notch signaling is switched off. We calculate that in wild-type adults, as much as 86% of cells derived from the stem cell pool function to support oogenesis. This work suggests that an important role for Notch signaling in the adult germline is to furnish a large and continuous supply of nurse cells to support the efficiency of oogenesis. PMID- 29242287 TI - The Local Coexistence Pattern of Selfing Genotypes in Caenorhabditis elegans Natural Metapopulations. AB - To study the interplay of rare outcrossing and metapopulation structure, we focus on the nematode Caenorhabditis elegans Its remarkably low outcrossing rate is at the extreme end of the spectrum for facultative selfing organisms. At the demographic level, C. elegans natural populations undergo boom and bust dynamics on ephemeral resources, with the dauer diapause larva acting as the dispersal form. Here we investigate the small-scale genetic structure of C. elegans populations in two localities over several years, using 2b restriction-associated DNA sequencing of nearly 1000 individuals. We find a remarkably small number of genome-wide haplotypes, almost exclusively in the homozygous state, confirming the low effective outcrossing rate. Most strikingly, the major haplotypes in a locality remain intact and do not effectively recombine over several years. From the spatial pattern of diversity, we estimate that each subpopulation or deme is seeded by a mean of 3-10 immigrating individuals. Populations are thus formed by clones that compete at two levels, within a subpopulation and at the metapopulation level. We test for the presence of local phenotypic variation in pathogen resistance and dauer larva nictation, which could possibly explain the maintenance of different genotypes by heterogeneous selection in different local environments or lifecycles. This study is the first to address the local spatiotemporal genetic structure of C. elegans on feeding substrates. We conclude that these animals coexist as competing homozygous clones at the smallest population scale as well as in the metapopulation. PMID- 29242278 TI - AMPK in skeletal muscle function and metabolism. AB - Skeletal muscle possesses a remarkable ability to adapt to various physiologic conditions. AMPK is a sensor of intracellular energy status that maintains energy stores by fine-tuning anabolic and catabolic pathways. AMPK's role as an energy sensor is particularly critical in tissues displaying highly changeable energy turnover. Due to the drastic changes in energy demand that occur between the resting and exercising state, skeletal muscle is one such tissue. Here, we review the complex regulation of AMPK in skeletal muscle and its consequences on metabolism ( e.g., substrate uptake, oxidation, and storage as well as mitochondrial function of skeletal muscle fibers). We focus on the role of AMPK in skeletal muscle during exercise and in exercise recovery. We also address adaptations to exercise training, including skeletal muscle plasticity, highlighting novel concepts and future perspectives that need to be investigated. Furthermore, we discuss the possible role of AMPK as a therapeutic target as well as different AMPK activators and their potential for future drug development. Kjobsted, R., Hingst, J. R., Fentz, J., Foretz, M., Sanz, M.-N., Pehmoller, C., Shum, M., Marette, A., Mounier, R., Treebak, J. T., Wojtaszewski, J. F. P., Viollet, B., Lantier, L. AMPK in skeletal muscle function and metabolism. PMID- 29242288 TI - A Role for Monomethylation of Histone H3-K27 in Gene Activity in Drosophila. AB - Polycomb repressive complex 2 (PRC2) is a conserved chromatin-modifying enzyme that methylates histone H3 on lysine-27 (K27). PRC2 can add one, two, or three methyl groups and the fully methylated product, H3-K27me3, is a hallmark of Polycomb-silenced chromatin. Less is known about functions of K27me1 and K27me2 and the dynamics of flux through these states. These modifications could serve mainly as intermediates to produce K27me3 or they could each convey distinct epigenetic information. To investigate this, we engineered a variant of Drosophila melanogaster PRC2 which is converted into a monomethyltransferase. A single substitution, F738Y, in the lysine-substrate binding pocket of the catalytic subunit, E(Z), creates an enzyme that retains robust K27 monomethylation but dramatically reduced di- and trimethylation. Overexpression of E(Z)-F738Y in fly cells triggers desilencing of Polycomb target genes significantly more than comparable overexpression of catalytically deficient E(Z), suggesting that H3-K27me1 contributes positively to gene activity. Consistent with this, normal genomic distribution of H3-K27me1 is enriched on actively transcribed Drosophila genes, with localization overlapping the active H3-K36me2/3 chromatin marks. Thus, distinct K27 methylation states link to either repression or activation depending upon the number of added methyl groups. If so, then H3-K27me1 deposition may involve alternative methyltransferases beyond PRC2, which is primarily repressive. Indeed, assays on fly embryos with PRC2 genetically inactivated, and on fly cells with PRC2 chemically inhibited, show that substantial H3-K27me1 accumulates independently of PRC2. These findings imply distinct roles for K27me1 vs. K27me3 in transcriptional control and an expanded machinery for methylating H3-K27. PMID- 29242290 TI - A Failsafe for Sensing Chromatid Tension in Mitosis with the Histone H3 Tail in Saccharomyces cerevisiae. AB - Mitotic fidelity is ensured by achieving biorientation on all paired chromosomes. The key signal for proper chromosome alignment is the tension between sister chromatids created by opposing poleward force from the spindles. In the budding yeast, the tension-sensing function requires that the Shugoshin protein, Shugoshin 1, be recruited to the centromeres and the neighboring pericentric regions. Concerted actions integrating proteins at centromeres and pericentromeres create highly specific Shugoshin 1 domains on mitotic chromosomes. We have previously reported that an important regulatory region on histone H3, termed the tension-sensing motif (TSM), is responsible for retaining Shugoshin 1 at pericentromeres. The TSM is negatively regulated by the acetyltransferase Gcn5p, but the underlying mechanism was elusive. In this work, we provide evidence that, when the TSM function is impaired, the histone H3 tail adopts a role that complements the damaged TSM to ensure faithful mitosis. This novel function of the H3 tail is controlled by Gcn5p, which targets selective lysine residues. Mutations to K14 and K23 ameliorate the mitotic defects resulting from TSM mutations. The restoration of faithful segregation is accompanied by regaining Shugoshin 1 access to the pericentric regions. Our data reveal a novel pathway for mitotic Shugoshin 1 recruitment and further reinforce the active role played by chromatins during their segregation in mitosis. PMID- 29242289 TI - Mild Telomere Dysfunction as a Force for Altering the Adaptive Potential of Subtelomeric Genes. AB - Subtelomeric regions have several unusual characteristics, including complex repetitive structures, increased rates of evolution, and enrichment for genes involved in niche adaptation. The adaptive telomere failure hypothesis suggests that certain environmental stresses can induce a low level of telomere failure, potentially leading to elevated subtelomeric recombination that could result in adaptive mutational changes within subtelomeric genes. Here, we tested a key prediction of the adaptive telomere failure hypothesis-that telomere dysfunction mild enough to have little or no overall effect on cell fitness could still lead to substantial increases in the mutation rates of subtelomeric genes. Our results show that a mutant of Kluyveromyces lactis with stably short telomeres produced a large increase in the frequency of mutations affecting the native subtelomeric beta-galactosidase (LAC4) gene. All lac4 mutants examined from strains with severe telomere dysfunction underwent terminal deletion/duplication events consistent with being due to break-induced replication. In contrast, although cells with mild telomere dysfunction also exhibited similar terminal deletion and duplication events, up to 50% of lac4 mutants from this background unexpectedly contained base changes within the LAC4 coding region. This mutational bias for producing base changes demonstrates that mild telomere dysfunction can be well suited as a force for altering the adaptive potential of subtelomeric genes. PMID- 29242291 TI - The X-linked 1.688 Satellite in Drosophila melanogaster Promotes Specific Targeting by Painting of Fourth. AB - Repetitive DNA, represented by transposons and satellite DNA, constitutes a large portion of eukaryotic genomes, being the major component of constitutive heterochromatin. There is a growing body of evidence that it regulates several nuclear functions including chromatin state and the proper functioning of centromeres and telomeres. The 1.688 satellite is one of the most abundant repetitive sequences in Drosophila melanogaster, with the longest array being located in the pericentromeric region of the X-chromosome. Short arrays of 1.688 repeats are widespread within the euchromatic part of the X-chromosome, and these arrays were recently suggested to assist in recognition of the X-chromosome by the dosage compensation male-specific lethal complex. We discovered that a short array of 1.688 satellite repeats is essential for recruitment of the protein POF to a previously described site on the X-chromosome (PoX2) and to various transgenic constructs. On an isolated target, i.e., an autosomic transgene consisting of a gene upstream of 1.688 satellite repeats, POF is recruited to the transgene in both males and females. The sequence of the satellite, as well as its length and position within the recruitment element, are the major determinants of targeting. Moreover, the 1.688 array promotes POF targeting to the roX1-proximal PoX1 site in trans Finally, binding of POF to the 1.688-related satellite-enriched sequences is conserved in evolution. We hypothesize that the 1.688 satellite functioned in an ancient dosage compensation system involving POF targeting to the X-chromosome. PMID- 29242292 TI - Comparative Oligo-FISH Mapping: An Efficient and Powerful Methodology To Reveal Karyotypic and Chromosomal Evolution. AB - Developing the karyotype of a eukaryotic species relies on identification of individual chromosomes, which has been a major challenge for most nonmodel plant and animal species. We developed a novel chromosome identification system by selecting and labeling oligonucleotides (oligos) located in specific regions on every chromosome. We selected a set of 54,672 oligos (45 nt) based on single copy DNA sequences in the potato genome. These oligos generated 26 distinct FISH signals that can be used as a "bar code" or "banding pattern" to uniquely label each of the 12 chromosomes from both diploid and polyploid (4* and 6*) potato species. Remarkably, the same bar code can be used to identify the 12 homeologous chromosomes among distantly related Solanum species, including tomato and eggplant. Accurate karyotypes based on individually identified chromosomes were established in six Solanum species that have diverged for >15 MY. These six species have maintained a similar karyotype; however, modifications to the FISH signal bar code led to the discovery of two reciprocal chromosomal translocations in Solanum etuberosum and S. caripense We also validated these translocations by oligo-based chromosome painting. We demonstrate that the oligo-based FISH techniques are powerful new tools for chromosome identification and karyotyping research, especially for nonmodel plant species. PMID- 29242293 TI - Variable impairment of platelet functions in patients with severe, genetically linked immune deficiencies. AB - In patients with dysfunctions of the Ca2+ channel ORAI1, stromal interaction molecule 1 (STIM1) or integrin-regulating kindlin-3 (FERMT3), severe immunodeficiency is frequently linked to abnormal platelet activity. In this paper, we studied platelet responsiveness by multiparameter assessment of whole blood thrombus formation under high-shear flow conditions in 9 patients, including relatives, with confirmed rare genetic mutations of ORAI1, STIM1 or FERMT3. In platelets isolated from 5 out of 6 patients with ORAI1 or STIM1 mutations, store-operated Ca2+ entry (SOCE) was either completely or partially defective compared to control platelets. Parameters of platelet adhesion and aggregation on collagen microspots were impaired for 4 out of 6 patients, in part related to a low platelet count. For 4 patients, platelet adhesion/aggregation and procoagulant activity on von Willebrand Factor (VWF)/rhodocytin and VWF/fibrinogen microspots were impaired independently of platelet count, and were partly correlated with SOCE deficiency. Measurement of thrombus formation at low shear rate confirmed a greater impairment of platelet functionality in the ORAI1 patients than in the STIM1 patient. For 3 patients/relatives with a FERMT3 mutation, all parameters of thrombus formation were strongly reduced regardless of the microspot. Bone marrow transplantation, required by 2 patients, resulted in overall improvement of platelet function. We concluded that multiparameter assessment of whole blood thrombus formation in a surface-dependent way can detect: i) additive effects of low platelet count and impaired platelet functionality; ii) aberrant ORAI1-mediated Ca2+ entry; iii) differences in platelet activation between patients carrying the same ORAI1 mutation; iv) severe platelet function impairment linked to a FERMT3 mutation and bleeding history. PMID- 29242295 TI - The use of romiplostim in treating chemotherapy-induced thrombocytopenia in patients with solid tumors. PMID- 29242294 TI - In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation. AB - T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day -1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-alpha production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400). PMID- 29242296 TI - Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement. PMID- 29242297 TI - Loss of 5-hydroxymethylcytosine is a frequent event in peripheral T-cell lymphomas. PMID- 29242298 TI - A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia. AB - Primary therapy resistance is a major problem in acute myeloid leukemia treatment. We set out to develop a powerful and robust predictor for therapy resistance for intensively treated adult patients. We used two large gene expression data sets (n=856) to develop a predictor of therapy resistance, which was validated in an independent cohort analyzed by RNA sequencing (n=250). In addition to gene expression markers, standard clinical and laboratory variables as well as the mutation status of 68 genes were considered during construction of the model. The final predictor (PS29MRC) consisted of 29 gene expression markers and a cytogenetic risk classification. A continuous predictor is calculated as a weighted linear sum of the individual variables. In addition, a cut off was defined to divide patients into a high-risk and a low-risk group for resistant disease. PS29MRC was highly significant in the validation set, both as a continuous score (OR=2.39, P=8.63.10-9, AUC=0.76) and as a dichotomous classifier (OR=8.03, P=4.29.10-9); accuracy was 77%. In multivariable models, only TP53 mutation, age and PS29MRC (continuous: OR=1.75, P=0.0011; dichotomous: OR=4.44, P=0.00021) were left as significant variables. PS29MRC dominated all models when compared with currently used predictors, and also predicted overall survival independently of established markers. When integrated into the European LeukemiaNet (ELN) 2017 genetic risk stratification, four groups (median survival of 8, 18, 41 months, and not reached) could be defined (P=4.01.10-10). PS29MRC will make it possible to design trials which stratify induction treatment according to the probability of response, and refines the ELN 2017 classification. PMID- 29242300 TI - Blood cytokine concentrations in pediatric patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. AB - Patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma often present with B-symptoms or hemophagocytosis and generate an anti-tumor immune response. Specific serum cytokine levels or profiles may reflect the tumor burden, non-specific immune stimulation by the tumor or differences in the strength of the patients' anti-lymphoma immunity. We systematically correlated pretreatment concentrations of 25 cytokines with clinical and biological characteristics in a well-characterized cohort of 119 uniformly treated pediatric patients with anaplastic large cell lymphoma. Fifteen patients with anaplastic large cell lymphoma in remission and 11 patients with low-stage B-cell lymphoma served as controls. Concentrations of interleukin-9, interleukin-10, interleukin 17a, hepatocyte growth factor, soluble interleukin-2 receptor, and soluble CD30 were significantly higher in initial sera of patients than in the sera of subjects from both control groups, indicating an anaplastic large cell lymphoma type cytokine signature. The levels of interleukin-6, interferon-gamma, interferon gamma-induced protein, and soluble interleukin-2 receptor correlated with the stage, initial general condition, minimal disseminated disease, anaplastic lymphoma kinase-antibody titers, and the risk of relapse among patients with anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Only interleukin-6 showed an independent prognostic value in multivariate analyses. Pretreatment cytokine profiles in patients with anaplastic large cell lymphoma reflect a tumor signature as well as tumor burden and also differences in the strength of the patients' immune response. PMID- 29242299 TI - Allogeneic stem cell transplantation benefits for patients >= 60 years with acute myeloid leukemia and FLT3 internal tandem duplication: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. AB - Intermediate-risk cytogenetic acute myeloid leukemia with an internal tandem duplication of FLT3 (FLT3-ITD) is associated with a high risk of relapse, and is now a standard indication for allogeneic stem cell transplantation. Nevertheless, most studies supporting this strategy have been performed in young patients. To address the benefit of allogeneic transplantation in the elderly, we made a selection from the European Society for Blood and Marrow Transplantation registry of de novo intermediate-risk cytogenetic acute myeloid leukemia harboring FLT3 ITD in patients aged 60 or over and transplanted from a related or unrelated donor between January 2000 and December 2015. Two hundred and ninety-one patients were identified. Most patients received a reduced-intensity conditioning (82%), while donors consisted of an unrelated donor in 161 (55%) patients. Two hundred and twelve patients received their transplantation in first remission, 37 in second remission and 42 in a more advanced stage of the disease. The 2-year leukemia-free survival rate was 56% in patients in first remission, 22% in those in second remission and 10% in patients with active disease, respectively (P<0.005). Non-relapse mortality for the entire cohort was 20%. In multivariate analysis, disease status at transplantation was the most powerful predictor of worse leukemia-free survival, graft-versus-host disease and relapse-free survival, and overall survival. In this elderly population, age was not associated with outcome. Based on the current results, allogeneic transplantation translates into a favorable outcome in fit patients >= 60 with FLT3-ITD acute myeloid leukemia in first remission, similarly to current treatment recommendations for younger patients. PMID- 29242301 TI - In vitro and in vivo evidence for uncoupling of B-cell receptor internalization and signaling in chronic lymphocytic leukemia. AB - B-cell receptor activation, occurring within lymph nodes, plays a key role in the pathogenesis of chronic lymphocytic leukemia and is linked to prognosis. As well as activation of downstream signaling, receptor ligation triggers internalization, transit to acidified endosomes and degradation of ligand receptor complexes. Herein, we investigated the relationship between these two processes in normal and leukemic B cells. We found that leukemic B cells, particularly anergic cases lacking the capacity to initiate downstream signaling, internalize and accumulate ligand in acidified endosomes more efficiently than normal B cells. Furthermore, ligation of either surface CD79B, a B-cell receptor component required for downstream signaling, or surface Immunoglobulin M (IgM) by cognate agonistic antibody, showed that the two molecules internalize independently of each other in leukemic but not normal B cells. Since association with surface CD79B is required for surface retention of IgM, this suggests that uncoupling of B-cell receptor internalization from signaling may be due to the dissociation of these two molecules in leukemic cells. A comparison of lymph node with peripheral blood cells from chronic lymphocytic leukemia patients showed that, despite recent B-cell receptor activation, lymph node B cells expressed higher levels of surface IgM. This surprising finding suggests that the B-cell receptors of lymph node- and peripheral blood-derived leukemic cells might be functionally distinct. Finally, long-term therapy with the Bruton's tyrosine kinase inhibitors ibrutinib or acalabrutinib resulted in a switch to an anergic pattern of B-cell receptor function with reduced signaling capacity, surface IgM expression and more efficient internalization. PMID- 29242303 TI - Ibrutinib does not affect ristocetin-induced platelet aggregation evaluated by light transmission aggregometry in chronic lymphocytic leukemia patients. PMID- 29242302 TI - A distinct subtype of Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorder: adult patients with chronic active Epstein-Barr virus infection-like features. AB - The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16-86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever (P=0.005), but greater frequency of skin lesions (P<0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease (P<0.001 and P=0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis (P=0.0087, P=0.0236, and P=0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival (P=0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed. PMID- 29242304 TI - Unsatisfactory efficacy in randomized study of reduced-dose CPX-351 for medically less fit adults with newly diagnosed acute myeloid leukemia or other high-grade myeloid neoplasm. PMID- 29242305 TI - Worldwide study of hematopoietic allogeneic stem cell transplantation in pyruvate kinase deficiency. PMID- 29242306 TI - NHS publishes estimates of avoidable deaths in hospitals. PMID- 29242307 TI - Ozone-induced eosinophil recruitment to airways is altered by antigen sensitization and tumor necrosis factor-alpha blockade. AB - Ozone is an atmospheric pollutant that causes lung inflammation and airway hyperresponsiveness. Ozone's effects occur in two distinct phases that are mediated by different populations of eosinophils. In the acute phase 1 day after exposure, mature airway-resident eosinophils alter parasympathetic nerve function that results in airway hyperresponsiveness. At this time point, the severity of hyperresponsiveness correlates with the number of eosinophils in close proximity to airway nerves, but not with eosinophils in bronchoalveolar lavage. Three days later, newly divided eosinophils are recruited to airways by a tumor necrosis factor-alpha-dependent mechanism. These new eosinophils paradoxically attenuate ozone-induced airway hyperresponsiveness. Ozone's effects on airway tissue eosinophils and nerve-associated eosinophils 3 days after exposure are unknown. Thus, we tested ozone's effects on eosinophils in airway subepithelium and around airway nerves 1 and 3 days after ozone in nonsensitized and ovalbumin-sensitized guinea pigs with or without the tumor necrosis factor-alpha antagonist, etanercept, and compared changes in eosinophils with ozone-induced airway hyperresponsiveness. More eosinophils were present in small, noncartilaginous airways and along small airway nerves compared to large cartilaginous airways in all treatment groups. The number of airway and nerve-associated eosinophils were unaffected 1 day after ozone exposure, whereas significantly fewer airway eosinophils were present 3 days later. Airway and nerve-associated eosinophils were also decreased in small airways 3 days after ozone in sensitized animals. These changes were blocked by etanercept. Airway eosinophils, but not nerve associated or bronchoalveolar lavage eosinophils correlated with airway hyperresponsiveness 3 days after ozone. Our findings indicate ozone causes persistent alterations in airway eosinophils and reinforce the importance of characterizing eosinophils' effects within distinct airway compartments. PMID- 29242309 TI - Physiological differences between a noncontinuous and a continuous endurance training protocol in recreational runners and metabolic demand prediction. AB - This study investigated the physiological difference in recreational runners between a noncontinuous and a continuous endurance training protocol. It also aimed to determine physiological surrogate that could monitor metabolic demand of prolonged running in real-time. For data collection, a total of 18 active male recreational runners were recruited. Physiological (HR, RR, RER, VO2, BLa), and overall perceptual (RPEO) responses were recorded against three designed test sessions. Session 1 included VO2submax test to determine critical speed (CS) at anaerobic threshold (AT). Session 2 was the noncontinuous CS test until exhaustion, having 4:1 min work-to-rest ratio at CS, whereas session 3 was the continuous CS test till exhaustion. As 1-min recovery during session 2 may change fatigue behavior, it was hypothesized that it will significantly change the physiological stress and hence endurance outcomes. Results reported average time to exhaustion (TTE) was 37.33(9.8) mins for session 2 and 23.28(9.87) mins for session 3. Participants experienced relatively higher metabolic demand (BLa) 6.78(1.43) mmol.l-1 in session 3 as compared to session 2 (5.52(0.93) mmol.l-1). RER was observed to increase in session 3 and decrease in session 2. Student's paired t-test only reported a significant difference in TTE, VO2, RER, RPEO, and BLa at "End" between session 2 and 3. Reported difference in RPEO and %HRmax at "AT" were 5 (2.2) and 89.8 (2.60)% during session 2 and 6 (2.5) and 89.8 (2.59)% during session 3, respectively. Regression analysis reported strong correlation of %HRmax (adj. R-square = 0.588) with BLa than RPEO (adj. R-square = 0.541). The summary of findings suggests that decreasing RER increased TTE and reduced BLa toward "End" during session 2 which might have helped to have better endurance. The %HRmax was identified to be used as a better noninvasive surrogate of endurance intensity estimator. PMID- 29242308 TI - Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone. AB - Inhalation of ozone (O3), a gaseous air pollutant, causes lung injury, lung inflammation, and airway hyperresponsiveness. Macrophages, mast cells, and neutrophils contribute to one or more of these sequelae induced by O3 Furthermore, each of these aforementioned cells express chemokine (C-C motif) receptor-like 2 (Ccrl2), an atypical chemokine receptor that facilitates leukocyte chemotaxis. Given that Ccrl2 is expressed by cells essential to the development of O3-induced lung pathology and that chemerin, a Ccrl2 ligand, is increased in bronchoalveolar lavage fluid (BALF) by O3, we hypothesized that Ccrl2 contributes to the development of lung injury, lung inflammation, and airway hyperresponsiveness induced by O3 To that end, we measured indices of lung injury (BALF protein, BALF epithelial cells, and bronchiolar epithelial injury), lung inflammation (BALF cytokines and BALF leukocytes), and airway responsiveness to acetyl-beta-methylcholine chloride (respiratory system resistance) in wild type and mice genetically deficient in Ccrl2 (Ccrl2-deficient mice) 4 and/or 24 hours following cessation of acute exposure to either filtered room air (air) or O3 In air-exposed mice, BALF chemerin was greater in Ccrl2-deficient as compared to wild-type mice. O3 increased BALF chemerin in mice of both genotypes, yet following O3 exposure, BALF chemerin was greater in Ccrl2-deficient as compared to wild-type mice. O3 increased indices of lung injury, lung inflammation, and airway responsiveness. Nevertheless, no indices were different between genotypes following O3 exposure. In conclusion, we demonstrate that Ccrl2 modulates chemerin levels in the epithelial lining fluid of the lungs but does not contribute to the development of O3-induced lung pathology. PMID- 29242311 TI - Simple technique for aiding thoracic CT scanning of cats without general anaesthesia PMID- 29242310 TI - Approaches to neuromodulation for schizophrenia. AB - Based on the success of deep brain stimulation (DBS) for treating movement disorders, there is growing interest in using DBS to treat schizophrenia (SZ). We review the unmet needs of patients with SZ and the scientific rationale behind the DBS targets proposed in the literature in order to guide future development of DBS to treat this vulnerable patient population. SZ remains a devastating disorder despite treatment. Relapse, untreated psychosis, intolerable side effects and the lack of effective treatment for negative and cognitive symptoms contribute to poor outcome. Novel therapeutic interventions are needed to treat SZ and DBS is emerging as a potential intervention. Convergent genetic, pharmacological and neuroimaging evidence implicating neuropathology associated with psychosis is consistent with SZ being a circuit disorder amenable to striatal modulation with DBS. Many of the DBS targets proposed in the literature may modulate striatal dysregulation. Additional targets are considered for treating tardive dyskinesia and negative and cognitive symptoms. A need is identified for the concurrent development of neurophysiological biomarkers relevant to SZ pathology in order to inform DBS targeting. Finally, we discuss the current clinical trials of DBS for SZ, and their ethical considerations. We conclude that patients with severe symptoms despite treatment must have the capacity to consent for a DBS clinical trial in which risks can be estimated, but benefit is not known. In addition, psychiatric populations should have access to the potential benefits of neurosurgical advances. PMID- 29242312 TI - Husbandry procedures at the point of lambing with reference to perinatal lamb mortality. PMID- 29242313 TI - Dissection of Glomerular Transcriptional Profile in Patients With Diabetic Nephropathy: SRGAP2a Protects Podocyte Structure and Function. AB - Podocytes play a pivotal role in maintaining glomerular filtration function through their interdigitated foot processes. However, the mechanisms that govern the podocyte cytoskeletal rearrangement remain unclear. Through analyzing the transcriptional profile of renal biopsy specimens from patients with diabetic nephropathy (DN) and control donors, we identify SLIT-ROBO rhoGTPase-activating protein 2a (SRGAP2a) as one of the main hub genes strongly associated with proteinuria and glomerular filtration in type 2 DN. Immunofluorescence staining and Western blot analysis revealed that human and mouse SRGAP2a is primarily localized at podocytes and largely colocalized with synaptopodin. Moreover, podocyte SRGAP2a is downregulated in patients with DN and db/db mice at both the mRNA and the protein level. SRGAP2a reduction is observed in cultured podocytes treated with tumor growth factor-beta or high concentrations of glucose. Functional and mechanistic studies show that SRGAP2a suppresses podocyte motility through inactivating RhoA/Cdc42 but not Rac1. The protective role of SRGAP2a in podocyte function also is confirmed in zebrafish, in which knockdown of SRGAP2a, a SRGAP2 ortholog in zebrafish, recapitulates podocyte foot process effacement. Finally, increasing podocyte SRGAP2a levels in db/db mice through administration of adenovirus-expressing SRGAP2a significantly mitigates podocyte injury and proteinuria. The results demonstrate that SRGAP2a protects podocytes by suppressing podocyte migration. PMID- 29242315 TI - Manganese Is a Plant's Best Friend: Intracellular Mn Transport by the Transporter NRAMP2. PMID- 29242314 TI - Reduced Expression of APUM24, Encoding a Novel rRNA Processing Factor, Induces Sugar-Dependent Nucleolar Stress and Altered Sugar Responses in Arabidopsis thaliana. AB - Ribosome biogenesis is one of the most energy-consuming events in the cell and must therefore be coordinated with changes in cellular energy status. Here, we show that the sugar-inducible gene ARABIDOPSIS PUMILIO PROTEIN24 (APUM24) encodes a Pumilio homology domain-containing protein involved in pre-rRNA processing in Arabidopsis thaliana Null mutation of APUM24 resulted in aborted embryos due to abnormal gametogenesis and embryogenesis, whereas reduced expression of APUM24 caused several phenotypes characteristic of ribosome biogenesis or function related mutants. APUM24 interacted with other pre-rRNA processing factors and a putative endonuclease for the removal of the internal transcribed spacer 2 (ITS2) of pre-rRNA in the nucleolus. The APUM24-containing complex also interacted with ITS2, and reduced APUM24 expression caused the overaccumulation of processing intermediates containing ITS2. Thus, APUM24 likely functions as an ITS2 removal associated factor. Most importantly, the apum24 knockdown mutant was hypersensitive to highly concentrated sugar, and the mutant showed sugar dependent overaccumulation of processing intermediates and nucleolar stress (changes in nucleolar size). Furthermore, reduced APUM24 expression diminished sugar-induced promotion of leaf and root growth. Hence, a breakdown in the coordinated expression of ribosome biogenesis-related genes with energy status may induce nucleolar stress and disturb proper sugar responses in Arabidopsis. PMID- 29242316 TI - Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies. AB - Purpose: Response to standard oncologic treatment is limited in colorectal cancer. The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing; however, drug discovery is currently limited by the lack of translation of CMS to preclinical models.Experimental Design: We analyzed CMS in primary colorectal cancers, cell lines, and patient-derived xenografts (PDX). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n = 459 drugs) to analyze subtype-specific drug sensitivities.Results: The distinct molecular and clinicopathologic characteristics of each CMS group were validated in a single-hospital series of 409 primary colorectal cancers. The new, cancer cell-adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model.Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group. Clin Cancer Res; 24(4); 794-806. (c)2017 AACR. PMID- 29242317 TI - Enzyme-free nucleic acid dynamical systems. AB - Chemistries exhibiting complex dynamics-from inorganic oscillators to gene regulatory networks-have been long known but either cannot be reprogrammed at will or rely on the sophisticated enzyme chemistry underlying the central dogma. Can simpler molecular mechanisms, designed from scratch, exhibit the same range of behaviors? Abstract chemical reaction networks have been proposed as a programming language for complex dynamics, along with their systematic implementation using short synthetic DNA molecules. We developed this technology for dynamical systems by identifying critical design principles and codifying them into a compiler automating the design process. Using this approach, we built an oscillator containing only DNA components, establishing that Watson-Crick base pairing interactions alone suffice for complex chemical dynamics and that autonomous molecular systems can be designed via molecular programming languages. PMID- 29242319 TI - The nanoscale circuitry of battery electrodes. AB - Developing high-performance, affordable, and durable batteries is one of the decisive technological tasks of our generation. Here, we review recent progress in understanding how to optimally arrange the various necessary phases to form the nanoscale structure of a battery electrode. The discussion begins with design principles for optimizing electrode kinetics based on the transport parameters and dimensionality of the phases involved. These principles are then used to review and classify various nanostructured architectures that have been synthesized. Connections are drawn to the necessary fabrication methods, and results from in operando experiments are highlighted that give insight into how electrodes evolve during battery cycling. PMID- 29242318 TI - Single-stranded DNA and RNA origami. AB - Self-folding of an information-carrying polymer into a defined structure is foundational to biology and offers attractive potential as a synthetic strategy. Although multicomponent self-assembly has produced complex synthetic nanostructures, unimolecular folding has seen limited progress. We describe a framework to design and synthesize a single DNA or RNA strand to self-fold into a complex yet unknotted structure that approximates an arbitrary user-prescribed shape. We experimentally construct diverse multikilobase single-stranded structures, including a ~10,000-nucleotide (nt) DNA structure and a ~6000-nt RNA structure. We demonstrate facile replication of the strand in vitro and in living cells. The work here thus establishes unimolecular folding as a general strategy for constructing complex and replicable nucleic acid nanostructures, and expands the design space and material scalability for bottom-up nanotechnology. PMID- 29242322 TI - France nabs foreign climate science talent. PMID- 29242321 TI - Satellites trace Afghanistan's lost empires. PMID- 29242324 TI - Swedish plastics study fabricated, panel finds. PMID- 29242323 TI - Ice-shrouded life sees daylight. PMID- 29242325 TI - Why fossil scientists are suing Trump over monuments move. PMID- 29242326 TI - Sudan seeks a science revival. PMID- 29242327 TI - Not so fast. PMID- 29242328 TI - A matter of trust. PMID- 29242329 TI - Breaking the deadlock on ivory. PMID- 29242330 TI - Closing the tubulin detyrosination cycle. PMID- 29242331 TI - How plants differ in toxin-sensitivity. PMID- 29242332 TI - Rethinking digital manufacturing with polymers. PMID- 29242333 TI - Speeding up crystallization. PMID- 29242334 TI - Fotis Kafatos (1940-2017). PMID- 29242335 TI - A new data effort to inform career choices in biomedicine. PMID- 29242336 TI - Improving regulation of microbiota transplants. PMID- 29242337 TI - Speak out against tuition waiver taxes. PMID- 29242338 TI - Retinoic acid's reproducible future. PMID- 29242339 TI - Lessons learned from cetacean tragedies. PMID- 29242340 TI - Anomalous spin correlations and excitonic instability of interacting 2D Weyl fermions. AB - The Coulomb interaction in systems of quasi-relativistic massless electrons has an unscreened long-range component at variance with conventional correlated metals. We used nuclear magnetic resonance (NMR) measurements to reveal unusual spin correlations of two-dimensional Weyl fermions in an organic material, causing a divergent increase of the Korringa ratio by a factor of 1000 upon cooling, in marked contrast to conventional metallic behavior. Combined with model calculations, we show that this divergence stems from an interaction-driven velocity renormalization that almost exclusively suppresses zero-momentum spin fluctuations. At low temperatures, the NMR relaxation rate shows an unexpected increase; numerical analyses show that this increase corresponds to internode excitonic fluctuations, a precursor to a transition from massless to massive quasiparticles. PMID- 29242341 TI - Purcell effect for active tuning of light scattering from semiconductor optical antennas. AB - Subwavelength, high-refractive index semiconductor nanostructures support optical resonances that endow them with valuable antenna functions. Control over the intrinsic properties, including their complex refractive index, size, and geometry, has been used to manipulate fundamental light absorption, scattering, and emission processes in nanostructured optoelectronic devices. In this study, we harness the electric and magnetic resonances of such antennas to achieve a very strong dependence of the optical properties on the external environment. Specifically, we illustrate how the resonant scattering wavelength of single silicon nanowires is tunable across the entire visible spectrum by simply moving the height of the nanowires above a metallic mirror. We apply this concept by using a nanoelectromechanical platform to demonstrate active tuning. PMID- 29242342 TI - Disorder-induced optical transition from spin Hall to random Rashba effect. AB - Disordered structures give rise to intriguing phenomena owing to the complex nature of their interaction with light. We report on photonic spin-symmetry breaking and unexpected spin-optical transport phenomena arising from subwavelength-scale disordered geometric phase structure. Weak disorder induces a photonic spin Hall effect, observed via quantum weak measurements, whereas strong disorder leads to spin-split modes in momentum space, a random optical Rashba effect. Study of the momentum space entropy reveals an optical transition upon reaching a critical point where the structure's anisotropy axis vanishes. Incorporation of singular topology into the disordered structure demonstrates repulsive vortex interaction depending on the disorder strength. The photonic disordered geometric phase can serve as a platform for the study of different phenomena emerging from complex media involving spin-orbit coupling. PMID- 29242343 TI - Monitoring and manipulating Higgs and Goldstone modes in a supersolid quantum gas. AB - Higgs and Goldstone modes are collective excitations of the amplitude and phase of an order parameter that is related to the breaking of a continuous symmetry. We directly studied these modes in a supersolid quantum gas created by coupling a Bose-Einstein condensate to two optical cavities, whose field amplitudes form the real and imaginary parts of a U(1)-symmetric order parameter. Monitoring the cavity fields in real time allowed us to observe the dynamics of the associated Higgs and Goldstone modes and revealed their amplitude and phase nature. We used a spectroscopic method to measure their frequencies, and we gave a tunable mass to the Goldstone mode by exploring the crossover between continuous and discrete symmetry. Our experiments link spectroscopic measurements to the theoretical concept of Higgs and Goldstone modes. PMID- 29242344 TI - Activation of surface lattice oxygen in single-atom Pt/CeO2 for low-temperature CO oxidation. AB - To improve fuel efficiency, advanced combustion engines are being designed to minimize the amount of heat wasted in the exhaust. Hence, future generations of catalysts must perform at temperatures that are 100 degrees C lower than current exhaust-treatment catalysts. Achieving low-temperature activity, while surviving the harsh conditions encountered at high engine loads, remains a formidable challenge. In this study, we demonstrate how atomically dispersed ionic platinum (Pt2+) on ceria (CeO2), which is already thermally stable, can be activated via steam treatment (at 750 degrees C) to simultaneously achieve the goals of low temperature carbon monoxide (CO) oxidation activity while providing outstanding hydrothermal stability. A new type of active site is created on CeO2 in the vicinity of Pt2+, which provides the improved reactivity. These active sites are stable up to 800 degrees C in oxidizing environments. PMID- 29242345 TI - Eudicot plant-specific sphingolipids determine host selectivity of microbial NLP cytolysins. AB - Necrosis and ethylene-inducing peptide 1-like (NLP) proteins constitute a superfamily of proteins produced by plant pathogenic bacteria, fungi, and oomycetes. Many NLPs are cytotoxins that facilitate microbial infection of eudicot, but not of monocot plants. Here, we report glycosylinositol phosphorylceramide (GIPC) sphingolipids as NLP toxin receptors. Plant mutants with altered GIPC composition were more resistant to NLP toxins. Binding studies and x-ray crystallography showed that NLPs form complexes with terminal monomeric hexose moieties of GIPCs that result in conformational changes within the toxin. Insensitivity to NLP cytolysins of monocot plants may be explained by the length of the GIPC head group and the architecture of the NLP sugar-binding site. We unveil early steps in NLP cytolysin action that determine plant clade-specific toxin selectivity. PMID- 29242346 TI - Structural basis of membrane disruption and cellular toxicity by alpha-synuclein oligomers. AB - Oligomeric species populated during the aggregation process of alpha-synuclein have been linked to neuronal impairment in Parkinson's disease and related neurodegenerative disorders. By using solution and solid-state nuclear magnetic resonance techniques in conjunction with other structural methods, we identified the fundamental characteristics that enable toxic alpha-synuclein oligomers to perturb biological membranes and disrupt cellular function; these include a highly lipophilic element that promotes strong membrane interactions and a structured region that inserts into lipid bilayers and disrupts their integrity. In support of these conclusions, mutations that target the region that promotes strong membrane interactions by alpha-synuclein oligomers suppressed their toxicity in neuroblastoma cells and primary cortical neurons. PMID- 29242348 TI - My children help my science. PMID- 29242347 TI - Comprehensive computational design of ordered peptide macrocycles. AB - Mixed-chirality peptide macrocycles such as cyclosporine are among the most potent therapeutics identified to date, but there is currently no way to systematically search the structural space spanned by such compounds. Natural proteins do not provide a useful guide: Peptide macrocycles lack regular secondary structures and hydrophobic cores, and can contain local structures not accessible with l-amino acids. Here, we enumerate the stable structures that can be adopted by macrocyclic peptides composed of l- and d-amino acids by near exhaustive backbone sampling followed by sequence design and energy landscape calculations. We identify more than 200 designs predicted to fold into single stable structures, many times more than the number of currently available unbound peptide macrocycle structures. Nuclear magnetic resonance structures of 9 of 12 designed 7- to 10-residue macrocycles, and three 11- to 14-residue bicyclic designs, are close to the computational models. Our results provide a nearly complete coverage of the rich space of structures possible for short peptide macrocycles and vastly increase the available starting scaffolds for both rational drug design and library selection methods. PMID- 29242349 TI - Efficacy and Safety of ITCA 650, a Novel Drug-Device GLP-1 Receptor Agonist, in Type 2 Diabetes Uncontrolled With Oral Antidiabetes Drugs: The FREEDOM-1 Trial. AB - OBJECTIVE: ITCA 650 (exenatide in osmotic mini-pump) continuously delivers exenatide subcutaneously for 3-6 months. Two doses of ITCA 650 were compared with placebo in patients with uncontrolled type 2 diabetes. RESEARCH DESIGN AND METHODS: This 39-week, phase 3, double-blind, placebo-controlled trial randomized 460 patients aged 18-80 years with glycated hemoglobin (HbA1c) 7.5-10% [58-86 mmol/mol] 1:1:1 to placebo, ITCA 650 40 MUg/day, or ITCA 650 60 MUg/day. Primary end point was change in HbA1c at 39 weeks. RESULTS: Least squares (LS) mean change from baseline HbA1c was -1.1% [-12.2 mmol/mol] and -1.2% [-13.2 mmol/mol] for ITCA 650 40 and 60 MUg/day, respectively (P < 0.001 vs. placebo -0.1% [-1.3 mmol/mol]). In a prespecified analysis, greater HbA1c reductions occurred in patients not receiving sulfonylureas (SUs) versus those receiving SUs (-1.7% vs. 1.2% [-18.6 and -13.1 mmol/mol]). At week 39, HbA1c <7% [53 mmol/mol] was attained in 37%, 44%, and 9% of ITCA 650 40 MUg/day, ITCA 650 60 MUg/day, and placebo groups, respectively (P < 0.001 each dose vs. placebo). LS mean change from baseline body weight was -2.3 kg and -3.0 kg for ITCA 650 40 and 60 MUg/day, respectively (P <= 0.015 vs. placebo -1.0 kg). Nausea was the most common adverse event (AE) and subsided over time. Discontinuation for gastrointestinal AEs occurred in 7.2% with ITCA and 1.3% with placebo. Most AEs associated with procedures to place and remove ITCA 650 were mild and transient. CONCLUSIONS: ITCA 650 significantly reduced HbA1c and weight compared with placebo and was well tolerated in patients with uncontrolled type 2 diabetes on oral antidiabetes medications. PMID- 29242351 TI - Second Arterial Versus Venous Conduits for Multivessel Coronary Artery Bypass Surgery in California. AB - BACKGROUND: Whether a second arterial conduit improves outcomes after multivessel coronary artery bypass grafting remains unclear. Consequently, arterial conduits other than the left internal thoracic artery are seldom used in the United States. METHODS: Using a state-maintained clinical registry including all 126 nonfederal hospitals in California, we compared all-cause mortality and rates of stroke, myocardial infarction, repeat revascularization, and sternal wound infection between propensity score-matched cohorts who underwent primary, isolated multivessel coronary artery bypass grafting with the left internal thoracic artery, and who received a second arterial conduit (right internal thoracic artery or radial artery, n=5866) or a venous conduit (n=53 566) between 2006 and 2011. Propensity score matching using 34 preoperative characteristics yielded 5813 matched sets. A subgroup analysis compared outcomes between propensity score-matched recipients of a right internal thoracic artery (n=1576) or a radial artery (n=4290). RESULTS: Second arterial conduit use decreased from 10.7% in 2006 to 9.1% in 2011 (P<0.0001). However, receipt of a second arterial conduit was associated with significantly lower mortality (13.1% versus 10.6% at 7 years; hazard ratio, 0.79; 95% confidence interval [CI], 0.72-0.87), and lower risks of myocardial infarction (hazard ratio, 0.78; 95% CI, 0.70-0.87) and repeat revascularization (hazard ratio, 0.82; 95% CI, 0.76-0.88). In comparison with radial artery grafts, right internal thoracic artery grafts were associated with similar mortality rates (right internal thoracic artery 10.3% versus radial artery 10.7% at 7 years; hazard ratio, 1.10; 95% CI, 0.89-1.37) and individual risks of cardiovascular events, but the risk of sternal wound infection was increased (risk difference, 1.07%; 95% CI, 0.15-2.07). CONCLUSIONS: Second arterial conduit use in California is low and declining, but arterial grafts were associated with significantly lower mortality and fewer cardiovascular events. A right internal thoracic artery graft offered no benefit over that of a radial artery, but did increase risk of sternal wound infection. These findings suggest surgeons should consider lowering their threshold for using arterial grafts, and the radial artery may be the preferred second conduit. PMID- 29242350 TI - NT-proBNP (N-Terminal pro-B-Type Natriuretic Peptide)-Guided Therapy in Acute Decompensated Heart Failure: PRIMA II Randomized Controlled Trial (Can NT-ProBNP Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?). AB - BACKGROUND: The concept of natriuretic peptide guidance has been extensively studied in patients with chronic heart failure (HF), with only limited success. The effect of NT-proBNP (N-terminal probrain natriuretic peptide)-guided therapy in patients with acute decompensated HF using a relative NT-proBNP target has not been investigated. This study aimed to assess whether NT-proBNP-guided therapy of patients with acute decompensated HF using a relative NT-proBNP target would lead to improved outcomes compared with conventional therapy. METHODS: We conducted a prospective randomized controlled trial to study the impact of in-hospital guidance for acute decompensated HF treatment by a predefined NT-proBNP target (>30% reduction from admission to discharge) versus conventional treatment. Patients with acute decompensated HF with NT-proBNP levels >1700 ng/L were eligible. After achieving clinical stability, 405 patients were randomized to either NT-proBNP-guided or conventional treatment (1:1). The primary end point was dual: a composite of all-cause mortality and HF readmissions in 180 days and the number of days alive out of the hospital in 180 days. Secondary end points were all-cause mortality within 180 days, HF readmissions within 180 days, and a composite of all-cause mortality and HF readmissions within 90 days. RESULTS: Significantly more patients in the NT-proBNP-guided therapy group were discharged with an NT-proBNP reduction of >30% (80% versus 64%, P=0.001). Nonetheless, NT proBNP-guided therapy did not significantly improve the combined event rate for all-cause mortality and HF readmissions (hazard ratio, 0.96; 95% confidence interval, 0.72-1.37; P=0.99) or the median number of days alive outside of the hospital (178 versus 179 days for NT-proBNP versus conventional patients, P=0.39). Guided therapy also did not significantly improve any of the secondary end points. CONCLUSIONS: The PRIMA II trial (Can NT-ProBNP-Guided Therapy During Hospital Admission for Acute Decompensated Heart Failure Reduce Mortality and Readmissions?) demonstrates that the guidance of HF therapy to reach an NT-proBNP reduction of >30% after clinical stabilization did not improve 6-month outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.trialregister.nl. Unique identifier: NTR3279. PMID- 29242352 TI - Predicting Risk in Patients Hospitalized for Acute Decompensated Heart Failure and Preserved Ejection Fraction: The Atherosclerosis Risk in Communities Study Heart Failure Community Surveillance. AB - BACKGROUND: Risk-prediction models specifically for hospitalized heart failure with preserved ejection fraction are lacking. METHODS AND RESULTS: We analyzed data from the ARIC (Atherosclerosis Risk in Communities) Study Heart Failure Community Surveillance to create and validate a risk score predicting mortality in patients >=55 years of age admitted with acute decompensated heart failure with preserved ejection fraction (ejection fraction >=50%). A modified version of the risk-prediction model for acute heart failure developed from patients in the EFFECT (Enhanced Feedback for Effective Cardiac Treatment) study was used as a composite predictor of 28-day and 1-year mortalities and evaluated together with other potential predictors in a stepwise logistic regression. The derivation sample consisted of 1852 hospitalizations from 2005 to 2011 (mean age, 77 years; 65% women; 74% white). Risk scores were created from the identified predictors and validated in hospitalizations from 2012 to 2013 (n=821). Mortality in the derivation and validation sample was 11% and 8% at 28 days and 34% and 31% at 1 year. The modified EFFECT score, including age, systolic blood pressure, blood urea nitrogen, sodium, cerebrovascular disease, chronic obstructive pulmonary disease, and hemoglobin, was a powerful predictor of mortality. Another important predictor for both 28-day and 1-year mortalities was hypoxia. The risk scores were well calibrated and had good discrimination in the derivation sample (area under the curve: 0.76 for 28-day and 0.72 for 1-year mortalities) and validation sample (area under the curve: 0.73 and 0.71, respectively). CONCLUSIONS: Mortality after acute decompensation in patients with heart failure with preserved ejection fraction is high, with one third of patients dying within a year. A prediction tool may allow for greater discrimination of the highest risk patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00005131. PMID- 29242353 TI - Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload-Induced Heart Failure. AB - BACKGROUND: Energy starvation and the shift of energy substrate from fatty acids to glucose is the hallmark of metabolic remodeling during heart failure progression. However, ketone body metabolism in the failing heart has not been fully investigated. METHODS AND RESULTS: Microarray data analysis and mitochondrial isobaric tags for relative and absolute quantification proteomics revealed that the expression of D-beta-hydroxybutyrate dehydrogenase I (Bdh1), an enzyme that catalyzes the NAD+/NADH coupled interconversion of acetoacetate and beta-hydroxybutyrate, was increased 2.5- and 2.8-fold, respectively, in the heart after transverse aortic constriction. In addition, ketone body oxidation was upregulated 2.2-fold in transverse aortic constriction hearts, as determined by the amount of 14CO2 released from the metabolism of [1-14C] beta-hydroxybutyrate in isolated perfused hearts. To investigate the significance of this augmented ketone body oxidation, we generated heart-specific Bdh1-overexpressing transgenic mice to recapitulate the observed increase in basal ketone body oxidation. Bdh1 transgenic mice showed a 1.7-fold increase in ketone body oxidation but did not exhibit any differences in other baseline characteristics. When subjected to transverse aortic constriction, Bdh1 transgenic mice were resistant to fibrosis, contractile dysfunction, and oxidative damage, as determined by the immunochemical detection of carbonylated proteins and histone acetylation. Upregulation of Bdh1 enhanced antioxidant enzyme expression. In our in vitro study, flow cytometry revealed that rotenone-induced reactive oxygen species production was decreased by adenovirus-mediated Bdh1 overexpression. Furthermore, hydrogen peroxide-induced apoptosis was attenuated by Bdh1 overexpression. CONCLUSIONS: We demonstrated that ketone body oxidation increased in failing hearts, and increased ketone body utilization decreased oxidative stress and protected against heart failure. PMID- 29242354 TI - Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations. AB - Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1 (7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide] and WEE1 inhibitor AZD1775 [2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4 methylpiperazin-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one] using simultaneous and sequential dosing schedules. Simultaneous treatment synergistically reduced melanoma cell survival and tumor growth. In contrast, sequential treatment was antagonistic and had a minimal tumor inhibitory effect compared with individual agents. Mechanistically, simultaneous targeting of AKT and WEE1 enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating transcription factors p53 and forkhead box M1, which was not observed with sequential treatment. Thus, this study identifies a rapid approach to assess the drug combinations with a mechanistic basis for selection, which suggests that combining AKT and WEE1 inhibitors is needed for maximal efficacy. PMID- 29242355 TI - The Bioactive Protein-Ligand Conformation of GluN2C-Selective Positive Allosteric Modulators Bound to the NMDA Receptor. AB - N-methyl-d-aspartate (NMDA) receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit selective positive allosteric modulators of NMDA receptor function have therapeutically relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NMDA receptors that contain the GluN2C subunit have structural determinants of activity that reside between the GluN2C amino terminal domain and the GluN2C agonist binding domain, suggesting a unique site of action. Here we use molecular biology and homology modeling to identify residues that line a candidate binding pocket for GluN2C selective pyrrolidinones. We also show that occupancy of only one site in diheteromeric receptors is required for potentiation. Both GluN2A and GluN2B can dominate the sensitivity of triheteromeric receptors to eliminate the actions of pyrrolidinones, thus rendering this series uniquely sensitive to subunit stoichiometry. We experimentally identified NMR-derived conformers in solution, which combined with molecular modeling allows the prediction of the bioactive binding pose for this series of GluN2C-selective positive allosteric modulators of NMDA receptors. These data advance our understanding of the site and nature of the ligand-protein interaction for GluN2C-selective positive allosteric modulators for NMDA receptors. PMID- 29242357 TI - Reply. PMID- 29242358 TI - Beware of Multiphase CTA Interpretation. PMID- 29242356 TI - Pre-treatment growth and IGF-I deficiency as main predictors of response to growth hormone therapy in neural models. AB - Mathematical models have been applied in prediction of growth hormone treatment effectiveness in children since the end of 1990s. Usually they were multiple linear regression models; however, there are also examples derived by empirical non-linear methods. Proposed solution consists in application of machine learning technique - artificial neural networks - to analyse this problem. This new methodology, contrary to previous ones, allows detection of both linear and non linear dependencies without assuming their character a priori The aims of this work included: development of models predicting separately growth during 1st year of treatment and final height as well as identification of important predictors and in-depth analysis of their influence on treatment's effectiveness. The models were derived on the basis of clinical data of 272 patients treated for at least 1 year, 133 of whom have already attained final height. Starting from models containing 17 and 20 potential predictors, respectively for 1st year and final height model, we were able to reduce their number to 9 and 10. Basing on the final models, IGF-I concentration and earlier growth were indicated as belonging to most important predictors of response to GH therapy, while results of GH secretion tests were automatically excluded as insignificant. Moreover, majority of the dependencies were observed to be non-linear, thus using neural networks seems to be reasonable approach despite it being more complex than previously applied methods. PMID- 29242360 TI - Imaging of Anaplastic Thyroid Carcinoma. AB - Anaplastic thyroid carcinoma is fatal if unresectable. However, improved survival has been reported after gross total resection and multimodality therapy. In this report, we describe the contrast-enhanced high-resolution CT characteristics of anaplastic thyroid carcinoma in 57 patients. Anaplastic thyroid carcinoma presented as a large neck mass with necrosis in 82% of cases. The tumors demonstrated common extrathyroidal extension (91%). Sixty-two percent of tumors demonstrated calcification. Visceral space invasion involved the esophagus (62%), trachea (57%), and larynx (29%). Carotid artery encasement was present in 42%, and 43% involved the internal jugular vein. Sixty-three percent had lateral compartment lymphadenopathy; 58% of these nodes were necrotic, and 11% were cystic. No metastatic nodes had calcification. Central compartment lymphadenopathy was seen in 56% of cases, and lateral retropharyngeal lymphadenopathy was detected in 12%. Knowledge of these imaging features aids in guiding the approach to the initial tissue diagnosis with either fine-needle aspiration or core biopsy, assessing the feasibility of surgical resection, and determining prognosis. PMID- 29242359 TI - Combining Quantitative Susceptibility Mapping with Automatic Zero Reference (QSM0) and Myelin Water Fraction Imaging to Quantify Iron-Related Myelin Damage in Chronic Active MS Lesions. AB - BACKGROUND AND PURPOSE: A hyperintense rim on susceptibility in chronic MS lesions is consistent with iron deposition, and the purpose of this study was to quantify iron-related myelin damage within these lesions as compared with those without rim. MATERIALS AND METHODS: Forty-six patients had 2 longitudinal quantitative susceptibility mapping with automatic zero reference scans with a mean interval of 28.9 +/- 11.4 months. Myelin water fraction mapping by using fast acquisition with spiral trajectory and T2 prep was obtained at the second time point to measure myelin damage. Mixed-effects models were used to assess lesion quantitative susceptibility mapping and myelin water fraction values. RESULTS: Quantitative susceptibility mapping scans were on average 6.8 parts per billion higher in 116 rim-positive lesions compared with 441 rim-negative lesions (P < .001). All rim-positive lesions retained a hyperintense rim over time, with increasing quantitative susceptibility mapping values of both the rim and core regions (P < .001). Quantitative susceptibility mapping scans and myelin water fraction in rim-positive lesions decreased from rim to core, which is consistent with rim iron deposition. Whole lesion myelin water fractions for rim-positive and rim-negative lesions were 0.055 +/- 0.07 and 0.066 +/- 0.04, respectively. In the mixed-effects model, rim-positive lesions had on average 0.01 lower myelin water fraction compared with rim-negative lesions (P < .001). The volume of the rim at the initial quantitative susceptibility mapping scan was negatively associated with follow-up myelin water fraction (P < .01). CONCLUSIONS: Quantitative susceptibility mapping rim-positive lesions maintained a hyperintense rim, increased in susceptibility, and had more myelin damage compared with rim-negative lesions. Our results are consistent with the identification of chronic active MS lesions and may provide a target for therapeutic interventions to reduce myelin damage. PMID- 29242361 TI - Measuring Cerebral and Cerebellar Glutathione in Children Using 1H MEGA-PRESS MRS. AB - BACKGROUND AND PURPOSE: Glutathione is an important antioxidant in the human brain and therefore of interest in neurodegenerative disorders. The purpose of this study was to investigate the feasibility of measuring glutathione in healthy nonsedated children by using the 1H Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence at 3T and to compare glutathione levels between the medial parietal gray matter and the cerebellum. MATERIALS AND METHODS: Glutathione was measured using MEGA-PRESS MRS (TR = 1.8 seconds, TE = 131 ms) in the parietal gray matter (35 * 25 * 20 mm3) of 6 healthy children (10.0 +/- 2.4 years of age; range, 7-14 years; 3 males) and in the cerebellum of 11 healthy children (12.0 +/ 2.7 years of age; range, 7-16 years; 6 males). A postprocessing pipeline was developed to account for frequency and phase variations in the edited ON and nonedited OFF spectra. Metabolites were quantified with LCModel and reported both as ratios and water-scaled values. Glutathione was quantified in the ON-OFF spectra, whereas total NAA, total Cho, total Cr, mIns, Glx, and taurine were quantified in the OFF spectra. RESULTS: We found significantly higher glutathione, total Cho, total Cr, mIns, and taurine in the cerebellum (P < .01). Glx and total NAA were significantly higher in the parietal gray matter (P < .01). There was no significant difference in glutathione/total Cr (P = .93) between parietal gray matter and cerebellum. CONCLUSIONS: We demonstrated that glutathione measurement in nonsedated children is feasible. We found significantly higher glutathione in the cerebellum compared with the parietal gray matter. Metabolite differences between the parietal gray matter and cerebellum agree with published MRS data in adults. PMID- 29242362 TI - Feasibility of Permanent Stenting with Solitaire FR as a Rescue Treatment for the Reperfusion of Acute Intracranial Artery Occlusion. AB - BACKGROUND AND PURPOSE: The Solitaire FR can be used not only as a tool for mechanical thrombectomy but also as a detachable permanent stent. Our aim was to assess the feasibility and safety of permanent stent placement with the Solitaire FR compared with other self-expanding stents for intracranial artery recanalization for acute ischemic stroke. MATERIALS AND METHODS: From January 2011 through January 2016, we retrospectively selected 2979 patients with acute ischemic stroke. Among them, 27 patients who underwent permanent stent placement (13 patients with the Solitaire FR [Solitaire group] and 14 patients with other self-expanding stents [other stent group]) were enrolled. The postprocedural modified TICI grade and angiographic and clinical outcomes were assessed. The safety and efficacy of permanent stent placement of the Solitaire FR for acute large-artery occlusion were evaluated. RESULTS: Stent placement was successful in all cases. Modified TICI 2b-3 reperfusion was noted in 84.6% of the Solitaire group and in 78.6% of the other stent group. Procedural time was significantly shorter in the Solitaire group than in the other stent group (P = .022). Shorter procedural time was correlated with favorable outcome (rho = 0.46, P = .035). No significant differences were found in the modified TICI grade, NIHSS score, mRS, and hemorrhagic transformation rate between the 2 groups. The acute in-stent thrombosis rate at discharge was significantly lower when a glycoprotein IIb/IIIa inhibitor was injected during the procedure (P = .013). CONCLUSIONS: Permanent stent placement with the Solitaire FR compared with other self-expanding stents appears to be feasible and safe as a rescue tool for refractory intra-arterial therapy. PMID- 29242363 TI - Diagnostic Accuracy of Amino Acid and FDG-PET in Differentiating Brain Metastasis Recurrence from Radionecrosis after Radiotherapy: A Systematic Review and Meta Analysis. AB - BACKGROUND: Current studies that analyze the usefulness of amino acid and FDG-PET in distinguishing brain metastasis recurrence and radionecrosis after radiation therapy are limited by small cohort size. PURPOSE: Our aim was to assess the diagnostic accuracy of amino acid and FDG-PET in differentiating brain metastasis recurrence from radionecrosis after radiation therapy. DATA SOURCES: Studies were retrieved from PubMed, Embase, and the Cochrane Library. STUDY SELECTION: Fifteen studies were included from the literature. Each study used PET to differentiate radiation necrosis from tumor recurrence in contrast-enhancing lesions on follow up brain MR imaging after treating brain metastasis with radiation therapy. DATA ANALYSIS: Data were analyzed with a bivariate random-effects model. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were pooled, and a summary receiver operating characteristic curve was fit to the data. DATA SYNTHESIS: The overall pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of PET were 0.85, 0.88, 7.0, 0.17, and 40, respectively. The area under the receiver operating characteristic curve was 0.93. On subgroup analysis of different tracers, amino acid and FDG-PET had similar diagnostic accuracy. Meta regression analysis demonstrated that the method of quantification based on patient, lesion, or PET scan (based on lesion versus not, P = .07) contributed to the heterogeneity. LIMITATIONS: Our study was limited by small sample size, and 60% of the included studies were of retrospective design. CONCLUSIONS: Amino acid and FDG-PET had good diagnostic accuracy in differentiating brain metastasis recurrence from radionecrosis after radiation therapy. PMID- 29242364 TI - Optimal Fat Suppression in Head and Neck MRI: Comparison of Multipoint Dixon with 2 Different Fat-Suppression Techniques, Spectral Presaturation and Inversion Recovery, and STIR. AB - BACKGROUND AND PURPOSE: Uniform complete fat suppression is essential for identification and characterization of most head and pathology. Our aim was to compare the multipoint Dixon turbo spin-echo fat-suppression technique with 2 different fat-suppression techniques, including a hybrid spectral presaturation with inversion recovery technique and an inversion recovery STIR technique, in head and neck fat-suppression MR imaging. MATERIALS AND METHODS: Head and neck MR imaging datasets of 72 consecutive patients were retrospectively reviewed. All patients were divided into 2 groups based on the type of fat-suppression techniques used (group A: STIR and spectral presaturation with inversion recovery gadolinium-T1WI; group B: multipoint Dixon T2 TSE and multipoint Dixon gadolinium T1WI TSE). Objective and subjective image quality and scan acquisition times were assessed and compared between multipoint Dixon T2 TSE versus STIR and multipoint Dixon gadolinium-T1WI TSE versus spectral presaturation with inversion recovery gadolinium-T1WI using the Mann-Whitney U test. RESULTS: A total of 64 patients were enrolled in the study (group A, n = 33 and group B, n = 31). Signal intensity ratios were significantly higher for multipoint Dixon T2 and gadolinium T1WI techniques compared with STIR (P < .001) and spectral presaturation with inversion recovery gadolinium-T1WI (P < .001), respectively. Two independent blinded readers revealed that multipoint Dixon T2 and gadolinium-T1WI techniques had significantly higher overall image quality (P = .022 and P < .001) and fat suppression grades (P < .013 and P < .001 across 3 different regions) than STIR and spectral presaturation with inversion recovery gadolinium-T1WI, respectively. The scan acquisition time was relatively short for the multipoint Dixon technique (2 minutes versus 4 minutes 56 seconds for the T2-weighted sequence and 2 minutes versus 3 minutes for the gadolinium-T1WI sequence). CONCLUSIONS: The multipoint Dixon technique offers better image quality and uniform fat suppression at a shorter scan time compared with STIR and spectral presaturation with inversion recovery gadolinium-T1WI techniques. PMID- 29242365 TI - Improved Precision of Automatic Brain Volume Measurements in Patients with Clinically Isolated Syndrome and Multiple Sclerosis Using Edema Correction. AB - BACKGROUND AND PURPOSE: The presence of edema will result in increased brain volume, which may obscure progressing brain atrophy. Similarly, treatment-induced edema reduction may appear as accelerated brain tissue loss (pseudoatrophy). The purpose of this study was to correlate brain tissue properties to brain volume, to investigate the possibilities for edema correction and the resulting improvement of the precision of automated brain volume measurements. MATERIALS AND METHODS: A group of 38 patients with clinically isolated syndrome or newly diagnosed MS were imaged at inclusion and after 1, 2, and 4 years using an MR quantification sequence. Brain volume, relaxation rates (R1 and R2), and proton density were measured by automated software. RESULTS: The reduction of normalized brain volume with time after inclusion was 0.273%/year. The mean SDs were 0.508%, 0.526%, 0.454%, and 0.687% at baseline and 1, 2, and 4 years. Linear regression of the relative change of normalized brain volume and the relative change of R1, R2, and proton density showed slopes of -0.198 (P < .001), 0.156 (P = .04), and 0.488 (P < .001), respectively. After we applied the measured proton density as a correction factor, the mean SDs decreased to 24.2%, 4.8%, 33.3%, and 17.4%, respectively. The observed atrophy rate reduced from 0.273%/year to 0.238%/year. CONCLUSIONS: Correlations between volume and R1, R2, and proton density were observed in the brain, suggesting that a change of brain tissue properties can affect brain volume. Correction using these parameters decreased the variation of brain volume measurements and may have reduced the effect of pseudoatrophy. PMID- 29242369 TI - The Affordable Care Act, Medicaid Expansion, and Disparities in Kidney Disease. PMID- 29242368 TI - Lessons from CKD-Related Genetic Association Studies-Moving Forward. AB - Over the past decade, genetic association studies have uncovered numerous determinants of kidney function in the general, diabetic, hypertensive, CKD, ESRD, and GN-based study populations (e.g., IgA nephropathy, membranous nephropathy, FSGS). These studies have led to numerous novel and unanticipated findings, which are helping improve our understanding of factors and pathways affecting both normal and pathologic kidney function. In this review, we report on major discoveries and advances resulting from this rapidly progressing research domain. We also predict some of the next steps the nephrology community should embrace to accelerate the identification of genetic and molecular processes leading to kidney dysfunction, pathophysiologically based disease subgroups, and specific therapeutic targets, as we attempt to transition toward a more precision-based medicine approach. PMID- 29242370 TI - Striving to Achieve an Integrated Home Dialysis System: A Report from the Ontario Renal Network Home Dialysis Attrition Task Force. PMID- 29242366 TI - The landscape of human mutually exclusive splicing. AB - Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA-Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila Finally, MXEs are significantly enriched in pathogenic mutations and their spatio-temporal expression might predict human disease pathology. PMID- 29242367 TI - Subspecies in the global human gut microbiome. AB - Population genomics of prokaryotes has been studied in depth in only a small number of primarily pathogenic bacteria, as genome sequences of isolates of diverse origin are lacking for most species. Here, we conducted a large-scale survey of population structure in prevalent human gut microbial species, sampled from their natural environment, with a culture-independent metagenomic approach. We examined the variation landscape of 71 species in 2,144 human fecal metagenomes and found that in 44 of these, accounting for 72% of the total assigned microbial abundance, single-nucleotide variation clearly indicates the existence of sub-populations (here termed subspecies). A single subspecies (per species) usually dominates within each host, as expected from ecological theory. At the global scale, geographic distributions of subspecies differ between phyla, with Firmicutes subspecies being significantly more geographically restricted. To investigate the functional significance of the delineated subspecies, we identified genes that consistently distinguish them in a manner that is independent of reference genomes. We further associated these subspecies-specific genes with properties of the microbial community and the host. For example, two of the three Eubacterium rectale subspecies consistently harbor an accessory pro inflammatory flagellum operon that is associated with lower gut community diversity, higher host BMI, and higher blood fasting insulin levels. Using an additional 676 human oral samples, we further demonstrate the existence of niche specialized subspecies in the different parts of the oral cavity. Taken together, we provide evidence for subspecies in the majority of abundant gut prokaryotes, leading to a better functional and ecological understanding of the human gut microbiome in conjunction with its host. PMID- 29242371 TI - Commentary on Lessons from CKD-Related Genetic Association Studies-Moving Forward. PMID- 29242372 TI - Life Expectancy Gains for Patients with ESRD. PMID- 29242373 TI - Changes in Excess Mortality from End Stage Renal Disease in the United States from 1995 to 2013. AB - BACKGROUND AND OBJECTIVES: Individuals with ESRD have a very high risk of death. Although mortality rates have decreased over time in ESRD, it is unknown if improvements merely reflect parallel increases in general population survival. We, therefore, examined changes in the excess risk of all-cause mortality-over and above the risk in the general population-among people treated for ESRD in the United States from 1995 to 2013. We hypothesized that the magnitude of change in the excess risk of death would differ by age and RRT modality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used time-dependent relative survival models including data from persons with incident ESRD as recorded in the US Renal Data System and age-, sex-, race-, and calendar year-specific general population mortality rates from the Centers for Disease Control and Prevention. We calculated relative excess risks (analogous to hazard ratios) to examine the association between advancing calendar time and the primary outcome of all-cause mortality. RESULTS: We included 1,938,148 children and adults with incident ESRD from 1995 to 2013. Adjusted relative excess risk per 5-year increment in calendar time ranged from 0.73 (95% confidence interval, 0.69 to 0.77) for 0-14 year olds to 0.88 (95% confidence interval, 0.88 to 0.88) for >=65 year olds, meaning that the excess risk of ESRD-related death decreased by 12%-27% over any 5-year interval between 1995 and 2013. Decreases in excess mortality over time were observed for all ages and both during treatment with dialysis and during time with a functioning kidney transplant (year by age and year by renal replacement modality interactions were both P<0.001), with the largest relative improvements observed for the youngest persons with a functioning kidney transplant. Absolute decreases in excess ESRD-related mortality were greatest for the oldest persons. CONCLUSIONS: The excess risk of all-cause mortality among people with ESRD, over and above the risk in the general population, decreased significantly between 1995 and 2013 in the United States. PMID- 29242374 TI - Involvement of Adapter Protein Complex 4 in Hypersensitive Cell Death Induced by Avirulent Bacteria. AB - Plant immunity to avirulent bacterial pathogens is associated with subcellular membrane dynamics including fusion between the vacuolar and plasma membranes, resulting in hypersensitive cell death. Here, we report that ADAPTOR PROTEIN COMPLEX-4 (AP-4) subunits are involved in plant immunity associated with hypersensitive cell death. We isolated a mutant with a defect in resistance to an avirulent strain of Pseudomonas syringae pv. tomato (Pto) DC3000 avrRpm1 from a vacuolar protein sorting mutant library of Arabidopsis (Arabidopsis thaliana). The mutant was identical to gfs4-1, which has a mutation in the gene encoding the AP-4 subunit AP4B. Thus, we focused on AP4B and another subunit, AP4E. All of the mutants (ap4b-3, ap4b-4, ap4e-1, and ap4e-2) were defective in hypersensitive cell death and resistance to Pto DC3000 with the type III effector AvrRpm1 or AvrRpt2, both of which are recognized on the plasma membrane, while they showed slightly enhanced susceptibility to the type-III-secretion-deficient P. syringae strain hrcC On the other hand, both ap4b-3 and ap4b-4 showed no defect in resistance to Pto DC3000 with the type III effector AvrRps4, which is recognized in the cytosol and does not induce hypersensitive cell death. Upon infection with Pto DC3000 avrRpt2, the ap4b-3 and ap4b-4 leaf cells did not show fusion between vacuolar and plasma membranes, whereas the wild-type leaf cells did. These results suggest that AP-4 contributes to cell death-associated immunity, possibly via membrane fusion, after type III effector-recognition on the plasma membrane. PMID- 29242375 TI - Control of Adventitious Root Architecture in Rice by Darkness, Light, and Gravity. AB - Rice (Oryza sativa) is a semiaquatic plant that is well adapted to partial flooding. Rice stems develop adventitious root (AR) primordia at each node that slowly mature but emerge only when the plant gets flooded, leading to the formation of a whole new secondary root system upon flooding. AR growth is induced by ethylene that accumulates in submerged plant tissues due to its lowered diffusion rate in water. Here, we report that the architecture of the secondary root system in flooded rice plants is controlled not only by altered gas diffusion but also by gravity and light. While ethylene promotes the emergence and growth of ARs, gravity and light determine their gravitropic setpoint angle (i.e. the deviation of growth direction relative to vertical). ARs grow upward at about 120 degrees in the dark and downward at 54 degrees in the light. The upward growth direction is conserved in indica and japonica rice varieties, suggestive of a conserved trait in rice. Experiments with a klinostat and with inverted stem orientation revealed that gravity promotes upward growth by about 10 degrees . Red, far-red, and blue light lead to negative phototropism in a dose-dependent manner, with blue light being most effective, indicating that phytochrome and blue light signaling control AR system architecture. The cpt1 (coleoptile phototropism1) mutant, which lacks one of the phototropin-interacting CPT proteins, shows reduced sensitivity to blue light. Hence, the gravitropic setpoint angle of rice ARs is controlled by genetic and environmental factors that likely balance the need for oxygen supply (upward growth) with avoidance of root desiccation (downward growth). PMID- 29242376 TI - Mineral Deposits in Ficus Leaves: Morphologies and Locations in Relation to Function. AB - Ficus trees are adapted to diverse environments and have some of the highest rates of photosynthesis among trees. Ficus leaves can deposit one or more of the three major mineral types found in leaves: amorphous calcium carbonate cystoliths, calcium oxalates, and silica phytoliths. In order to better understand the functions of these minerals and the control that the leaf exerts over mineral deposition, we investigated leaves from 10 Ficus species from vastly different environments (Rehovot, Israel; Bologna, Italy; Issa Valley, Tanzania; and Ngogo, Uganda). We identified the mineral locations in the soft tissues, the relative distributions of the minerals, and mineral volume contents using microcomputed tomography. Each Ficus species is characterized by a unique 3D mineral distribution that is preserved in different environments. The mineral distribution patterns are generally different on the adaxial and abaxial sides of the leaf. All species examined have abundant calcium oxalate deposits around the veins. We used micromodulated fluorimetry to examine the effect of cystoliths on photosynthetic efficiency in two species having cystoliths abaxially and adaxially (Ficusmicrocarpa) or only abaxially (Ficuscarica). In F. microcarpa, both adaxial and abaxial cystoliths efficiently contributed to light redistribution inside the leaf and, hence, increased photosynthetic efficiency, whereas in F. carica, the abaxial cystoliths did not increase photosynthetic efficiency. PMID- 29242377 TI - The Kinase OsCPK4 Regulates a Buffering Mechanism That Fine-Tunes Innate Immunity. AB - The calcium-dependent protein kinase OsCPK4 has been demonstrated to play important roles in salt and drought tolerance, plant growth, and development in rice (Oryza sativa). However, little is known about molecular mechanisms underlying OsCPK4 function in rice immunity. In this study, we demonstrated that the generation of oxidative burst and pathogenesis-related gene expression triggered by microbe-associated molecular patterns were significantly enhanced in the oscpk4 mutants. These mutant lines are more resistant to bacterial blight and fungal blast diseases than the wild-type plants, indicating that OsCPK4 negatively regulates innate immunity in rice. OsCPK4 was further identified to interact with a receptor-like cytoplasmic kinase OsRLCK176. OsRLCK176 accumulation is negatively regulated by OsCPK4. Interestingly, the kinase-dead OsCPK4 promotes OsRLCK176 degradation more strongly than the wild-type protein. OsCPK4 and OsRLCK176 mutually phosphorylate each other and form a feedback loop. Moreover, the kinase activity and phosphorylation of OsCPK4 and OsRLCK176 contribute to the stability of OsRLCK176. These findings indicate that the kinase inactive OsCPK4 promotes OsRLCK176 degradation and restricts plant defenses, whereas the activation of OsCPK4-OsRLCK176 phosphorylation circuit invalidates the OsRLCK176 degradation machinery, thus enhancing plant immunity. Collectively, the study proposes a novel defense buffering mechanism mediated by OsCPK4, which fine-tunes microbe-associated molecular pattern-triggered immunity in rice. PMID- 29242378 TI - Flavodiiron Protein Substitutes for Cyclic Electron Flow without Competing CO2 Assimilation in Rice. AB - Flavodiiron protein (FLV) mediates photoreduction of O2 to H2O. It is conserved from cyanobacteria to gymnosperms but not in angiosperms. The introduction of a moss (Physcomitrella patens) FLV (PpFLV) gene into Arabidopsis (Arabidopsis thaliana) made photosystem I (PSI) resistant to fluctuating light. Here, we used the same strategy with three rice (Oryza sativa) genotypes. PpFLV in the wild type rice background functioned as an efficient PSI electron sink and increased resistance to PSI photodamage under fluctuating light. The introduction of PpFLV into the PGR5-RNAi mutant [defective in PROTON GRADIENT REGULATION5 (PGR5) dependent cyclic electron transport around PSI, CET-PSI], the crr6 mutant [defective in chloroplast NAD(P)H-dehydrogenase-like complex (NDH)-dependent CET PSI], and the PGR5-RNAi crr6 double mutant (double defective in CET-PSI activity) alleviated PSI photodamage under fluctuating light. Furthermore, PpFLV substituted for the function of PGR5- and NDH-dependent CET-PSI without competing for CO2 assimilation under constant light, as there was no difference in CO2 assimilation per Rubisco content and biomass production was recovered to the wild type level. Thus, the exogenous FLV system could act not only as a safety valve under fluctuating light, but also generate a proton motive force for balancing the ATP/NADPH production ratio during steady-state photosynthesis. PMID- 29242379 TI - High-throughput and Sensitive Immunopeptidomics Platform Reveals Profound Interferongamma-Mediated Remodeling of the Human Leukocyte Antigen (HLA) Ligandome. AB - Comprehensive knowledge of the human leukocyte antigen (HLA) class-I and class-II peptides presented to T-cells is crucial for designing innovative therapeutics against cancer and other diseases. However methodologies for their purification for mass-spectrometry analysis have been a major limitation. We designed a novel high-throughput, reproducible and sensitive method for sequential immuno-affinity purification of HLA-I and -II peptides from up to 96 samples in a plate format, suitable for both cell lines and tissues. Our methodology drastically reduces sample-handling and can be completed within five hours. We challenged our methodology by extracting HLA peptides from multiple replicates of tissues (n = 7) and cell lines (n = 21, 108 cells per replicate), which resulted in unprecedented depth, sensitivity and high reproducibility (Pearson correlations up to 0.98 and 0.97 for HLA-I and HLA-II). Because of the method's achieved sensitivity, even single measurements of peptides purified from 107 B-cells resulted in the identification of more than 1700 HLA-I and 2200 HLA-II peptides. We demonstrate the feasibility of performing drug-screening by using ovarian cancer cells treated with interferon gamma (IFNgamma). Our analysis revealed an augmented presentation of chymotryptic-like and longer ligands associated with IFNgamma induced changes of the antigen processing and presentation machinery. This straightforward method is applicable for basic and clinical applications. PMID- 29242382 TI - Correction: The drug ornidazole inhibits photosynthesis in a different mechanism described for protozoa and anaerobic bacteria. PMID- 29242381 TI - Therapeutic targeting of non-coding RNAs in cancer. AB - The majority of the human genome encodes RNAs that do not code for proteins. These non-coding RNAs (ncRNAs) affect normal expression of the genes, including oncogenes and tumour suppressive genes, which make them a new class of targets for drug development in cancer. Although microRNAs (miRNAs) are the most studied regulatory ncRNAs to date, and miRNA-targeted therapeutics have already reached clinical development, including the mimics of the tumour suppressive miRNAs miR 34 and miR-16, which reached phase I clinical trials for the treatment of liver cancer and mesothelioma, the importance of long non-coding RNAs (lncRNAs) is increasingly being recognised. Here, we describe obstacles and advances in the development of ncRNA therapeutics and provide the comprehensive overview of the ncRNA chemistry and delivery technologies. Furthermore, we summarise recent knowledge on the biological functions of miRNAs and their involvement in carcinogenesis, and discuss the strategies of their therapeutic manipulation in cancer. We review also the emerging insights into the role of lncRNAs and their potential as targets for novel treatment paradigms. Finally, we provide the up-to date summary of clinical trials involving miRNAs and future directions in the development of ncRNA therapeutics. PMID- 29242383 TI - Correction: Integration of flux measurements to resolve changes in anabolic and catabolic metabolism in cardiac myocytes. PMID- 29242384 TI - Correction: Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2. PMID- 29242380 TI - Insights into the Proteome of Gastrointestinal Stromal Tumors-Derived Exosomes Reveals New Potential Diagnostic Biomarkers. AB - Developing tumors continuously release nano-sized vesicles that represent circulating "fingerprints" of the tumor's identity. In gastrointestinal stromal tumor (GIST), we have previously reported that these tumors release "oncosomes" carrying the constitutively activated tyrosine kinase (TK) receptor KIT. Despite the clinical utility of TK inhibitors, such as imatinib mesylate (IM), recurrence and metastasis are clinical problems that urge the need to identify new tumor derived molecules. To this aim, we performed the first high quality proteomic study of GIST-derived exosomes (GDEs) and identified 1,060 proteins composing the core GDE proteome (cGDEp). The cGDEp was enriched in diagnostic markers (e.g. KIT, CD34, ANO1, PROM1, PRKCQ, and ENG), as well as proteins encoded by genes previously reported expressed in GIST (e.g. DPP4, FHL1, CDH11, and KCTD12). Many of these proteins were validated using cell lines, patient-derived KIT+ exosomes, and GIST tissues. We further show that in vitro and in vivo-derived GDE, carry proteins associated with IM response, such as Sprouty homolog 4 (SPRY4), surfeit 4 (SURF4), ALIX, and the cGMP-dependent 3',5'-cyclic phosphodiesterase 2A (PDE2A). Additionally, we report that the total exosome levels and exosome associated KIT and SPRY4 protein levels have therapeutic values. In fact, molecular characterization of in vivo-derived KIT+ exosomes indicate significant sorting of p-KITTyr719, total KIT, and SPRY4 after IM-treatment of metastatic patients as compared with the pre-IM levels. Our data suggest that analysis of circulating exosomes levels and molecular markers of IM response in GIST patients with primary and metastatic disease is suitable to develop liquid based biopsies for the diagnosis, prognosis, and monitoring of response to treatment of these tumors. In summary, these findings provide the first insight into the proteome of GIST-derived oncosomes and offers a unique opportunity to further understand their oncogenic elements which contribute to tumorigenesis and drug resistance. Data are available via ProteomeXchange with identifier PXD007997. PMID- 29242385 TI - Differential Regulation of Zfp30 Expression in Murine Airway Epithelia Through Altered Binding of ZFP148 to rs51434084. AB - Neutrophil chemotaxis to the airways is a key aspect of host response to microbes and a feature of multiple pulmonary diseases including asthma. Tight regulation of this recruitment is critical to prevent unwanted host tissue damage and inflammation. Using a mouse (Mus musculus) model of asthma applied to the Collaborative Cross population, we previously identified a lung gene expression quantitative trait locus (eQTL) for Zinc finger protein 30 (Zfp30) that was also a QTL for neutrophil recruitment and the hallmark neutrophil chemokine CXCL1. The Zfp30 eQTL is defined by three functionally distinct haplotypes. In this study, we searched for causal genetic variants that underlie the Zfp30 eQTL to gain a better understanding of this candidate repressor's regulation. First, we identified a putative regulatory region spanning 500 bp upstream of Zfp30, which contains 10 SNPs that form five haplotypes. In reporter gene assays in vitro, these haplotypes recapitulated the three previously identified in vivo expression patterns. Second, using site-directed mutagenesis followed by reporter gene assays, we identified a single variant, rs51434084, which explained the majority of variation in expression between two out of three haplotype groups. Finally, using a combination of in silico predictions and electrophoretic mobility shift assays, we identified ZFP148 as a transcription factor that differentially binds to the Zfp30 promoter region harboring rs51434084. In conclusion, we provide evidence in support of rs51434084 being a causal variant for the Zfp30 eQTL, and have identified a mechanism by which this variant alters Zfp30 expression, namely differential binding of ZFP148. PMID- 29242386 TI - Dosage-Dependent Expression Variation Suppressed on the Drosophila Male X Chromosome. AB - DNA copy number variation is associated with many high phenotypic heterogeneity disorders. We systematically examined the impact of Drosophila melanogaster deletions on gene expression profiles to ask whether increased expression variability owing to reduced gene dose might underlie this phenotypic heterogeneity. Indeed, we found that one-dose genes have higher gene expression variability relative to two-dose genes. We then asked whether this increase in variability could be explained by intrinsic noise within cells due to stochastic biochemical events, or whether expression variability is due to extrinsic noise arising from more complex interactions. Our modeling showed that intrinsic gene expression noise averages at the organism level and thus cannot explain increased variation in one-dose gene expression. Interestingly, expression variability was related to the magnitude of expression compensation, suggesting that regulation, induced by gene dose reduction, is noisy. In a remarkable exception to this rule, the single X chromosome of males showed reduced expression variability, even compared with two-dose genes. Analysis of sex-transformed flies indicates that X expression variability is independent of the male differentiation program. Instead, we uncovered a correlation between occupancy of the chromatin-modifying protein encoded by males absent on the first (mof) and expression variability, linking noise suppression to the specialized X chromosome dosage compensation system. MOF occupancy on autosomes in both sexes also lowered transcriptional noise. Our results demonstrate that gene dose reduction can lead to heterogeneous responses, which are often noisy. This has implications for understanding gene network regulatory interactions and phenotypic heterogeneity. Additionally, chromatin modification appears to play a role in dampening transcriptional noise. PMID- 29242387 TI - Inbred or Outbred? Genetic Diversity in Laboratory Rodent Colonies. AB - Nonmodel rodents are widely used as subjects for both basic and applied biological research, but the genetic diversity of the study individuals is rarely quantified. University-housed colonies tend to be small and subject to founder effects and genetic drift; so they may be highly inbred or show substantial genetic divergence from other colonies, even those derived from the same source. Disregard for the levels of genetic diversity in an animal colony may result in a failure to replicate results if a different colony is used to repeat an experiment, as different colonies may have fixed alternative variants. Here we use high throughput sequencing to demonstrate genetic divergence in three isolated colonies of Mongolian gerbil (Meriones unguiculatus) even though they were all established recently from the same source. We also show that genetic diversity in allegedly "outbred" colonies of nonmodel rodents (gerbils, hamsters, house mice, deer mice, and rats) varies considerably from nearly no segregating diversity to very high levels of polymorphism. We conclude that genetic divergence in isolated colonies may play an important role in the "replication crisis." In a more positive light, divergent rodent colonies represent an opportunity to leverage genetically distinct individuals in genetic crossing experiments. In sum, awareness of the genetic diversity of an animal colony is paramount as it allows researchers to properly replicate experiments and also to capitalize on other genetically distinct individuals to explore the genetic basis of a trait. PMID- 29242388 TI - Letter by Yu et al Regarding Article, "Island Sign: An Imaging Predictor for Early Hematoma Expansion and Poor Outcome in Patients With Intracerebral Hemorrhage". PMID- 29242389 TI - Response by Li to Letter Regarding Article, "Island Sign: An Imaging Predictor for Early Hematoma Expansion and Poor Outcome in Patients With Intracerebral Hemorrhage". PMID- 29242390 TI - Enlightenment and Challenges Offered by DAWN Trial (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo). PMID- 29242391 TI - Method Verification Requirements for an Advanced Imaging System for Microbial Plate Count Enumeration. AB - The Growth DirectTM System that automates the incubation and reading of membrane filtration microbial counts on soybean-casein digest, Sabouraud dextrose, and R2A agar differs only from the traditional method in that micro-colonies on the membrane are counted using an advanced imaging system up to 50% earlier in the incubation. Based on the recommendations in USP <1223> Validation of New Microbiological Testing Methods, the system may be implemented in a microbiology laboratory after simple method verification and not a full method validation.LAY ABSTRACT: The Growth DirectTM System that automates the incubation and reading of microbial counts on membranes on solid agar differs only from the traditional method in that micro-colonies on the membrane are counted using an advanced imaging system up to 50% earlier in the incubation time. Based on the recommendations in USP <1223> Validation of New Microbiological Testing Methods, the system may be implemented in a microbiology laboratory after simple method verification and not a full method validation. PMID- 29242392 TI - Benchmarking of Sterilizing-Grade Filter Membranes with Liposome Filtration. AB - Cytotoxic drugs can be encapsulated in liposomes vesicles, which act as drug delivery vehicles and reduce the risk of exposure of drug to healthy cells. The sterility of such liposome solutions is typically ensured using 0.2 MUm-rated sterilizing-grade membranes, but due to the high viscosity and low surface tension of these formulations, they can cause premature blocking and increased risk of bacterial penetration through a 0.2 MUm sterilizing-grade membrane. The low surface tension of liposome solutions affects the contact angle with membrane and reduces bubble point, leading to bacterial penetration through the membrane. This poses a great challenge to select an appropriate sterilizing-grade membrane for a given process and for filter manufacturers to develop a sterilizing-grade membrane that specifically addresses these needs. In this study, the influence of different variables that could affect the total throughput and bacterial retention performance of different membrane types on processing of liposome solutions was evaluated. Based on the results, we conclude that the membrane properties, for example, surface porosity, surface tension, pore size, symmetry/asymmetry, hydrophilicity and liposome properties (e.g., composition, lipid size, and concentration) affect bacterial retention and total throughput capacity. Process parameters such as temperature, pressure, and flow should also be optimized to improve process efficiency.LAY ABSTRACT: Cytotoxic drugs can be encapsulated in liposomes vesicles, which act as drug delivery vehicles and reduce the risk of exposure of drug to healthy cells. Liposome solution cause premature blocking and increased risk of bacterial penetration through a 0.2 MUm sterilizing-grade membrane due to their high viscosity and low surface tension. In this study, we demonstrated the total throughput and bacterial retention performance of different sterilizing-grade membranes with liposome solution. Based on the results, we conclude that some sterilizing-grade membranes yield less throughput and bacterial retention compared to other membranes. This is due to liposome formulation and membrane properties. Therefore, it is important to identify the product formulation and membrane properties before selection of a suitable sterilizing-grade filter for a given process application to ensure expected throughput and bacterial retention. PMID- 29242393 TI - A Risk Index and Data Display for Process Performance in the Pharmaceutical Industry. AB - We propose a new index and graphical display for quantifying and visualizing process performance in the pharmaceutical industry. These tools can provide management a comprehensive, high level overview of the process performance of a global manufacturing network suitable for risk ranking, by which is meant: identifying those processes at greatest risk of failing to meet specifications, and prioritizing resources to drive continuous process improvement. Our index, like others currently in use, compares the observed variation of CQAs-critical quality attributes-to their specifications. However, instead of relying on traditional data summaries such as means and standard deviations to characterize process results, the proposed index uses sample quantiles. Quantiles are more accurate and reliable when data are skewed or short-tailed as is often observed for pharmaceutical processes. Perhaps just as important, we communicate the results with a new visual display that accurately compares processes and sites. The display identifies instances when the summaries may mislead and the subject matter expert needs to "drill down" into manufacturing data to assure correct understanding.LAY ABSTRACT: The proposed risk index and graphical display enables high-risk processes to be identified, process improvements to be prioritized, resources to be efficiently allocated, and strategic planning for continuous process improvement to be evidence-based. PMID- 29242394 TI - A QRM Discussion of Microbial Contamination of Non-sterile Drug Products, Using FDA and EMA Warning Letters Recorded between 2008 and 2016. AB - Microbial quality control of non-sterile drug products has been a concern to regulatory agencies and the pharmaceutical industry since the 1960s. Despite being an old challenge to companies, microbial contamination still affects a high number of manufacturers of non-sterile products. Consequences go well beyond the obvious direct costs related to batch rejections or product recalls, as human lives and a company's reputation are significantly impacted if such events occur. To better manage risk and establish effective mitigation strategies, it is necessary to understand the microbial hazards involved in non-sterile drug products manufacturing, be able to evaluate their potential impact on final product quality, and apply mitigation actions. Herein we discuss the most likely root causes involved in microbial contaminations referenced in warning letters issued by US health authorities and non-compliance reports issued by European health authorities over a period of several years. The quality risk management tools proposed were applied to the data gathered from those databases, and a generic risk ranking was provided based on a panel of non-sterile drug product manufacturers that was assembled and given the opportunity to perform the risk assessments. That panel identified gaps and defined potential mitigation actions, based on their own experience of potential risks expected for their processes. Major findings clearly indicate that the manufacturers affected by the warning letters should focus their attention on process improvements and microbial control strategies, especially those related to microbial analysis and raw material quality control. Additionally, the WLs considered frequently referred to failures in quality-related issues, which indicates that the quality commitment should be reinforced at most companies to avoid microbiological contaminations.LAY ABSTRACT: Microbial contamination of drug products affects the quality of non-sterile drug products produced by numerous manufacturers, representing a major risk to patients. It is necessary to understand the microbial hazards involved in the manufacturing process and evaluate their impact on final product quality so that effective prevention strategies can be implemented. A risk-based classification of most likely root causes for microbial contamination found in the warning letters issued by the US Food and Drug Administration and the European Medicines Agency is proposed. To validate the likely root causes extracted from the warning letters, a subject matter expert panel made of several manufacturers was formed and consulted. A quality risk management approach to assess microbiological contamination of non-sterile drug products is proposed for the identification of microbial hazards involved in the manufacturing process. To enable ranking of microbial contamination risks, quality risk management metrics related to criticality and overall risk were applied. The results showed that manufacturers of non-sterile drug products should improve their microbial control strategy, with special attention to quality controls of raw materials, primary containers, and closures. Besides that, they should invest in a more robust quality system and culture. As a start, manufacturers may consider investigating their specific microbiological risks, adressing their sites' own microbial ecology, type of manufacturing processes, and dosage form characteristics, as these may lead to increased contamination risks. Authorities should allow and enforce innovative, more comprehensive, and more effective approaches to in-process contamination monitoring and controls. PMID- 29242395 TI - Cross-sectional surveys of the amount of sugar, energy and caffeine in sugar sweetened drinks marketed and consumed as energy drinks in the UK between 2015 and 2017: monitoring reformulation progress. AB - OBJECTIVES: To investigate the sugar, energy and caffeine content of sugar sweetened drinks marketed and consumed as energy drinks available in the UK. STUDY DESIGN: We carried out a cross-sectional survey in 2015 and 2017 of energy drinks available in the main UK retailers. METHODS: The sugar (sugars g/100 mL), energy (kcal/100 mL), caffeine (mg/100 mL) and serving size were collected from product packaging and nutrition information panels of energy drinks available in the nine main UK grocery retailers, three health and beauty retailers and one convenience store. RESULTS: The number of formulations (per 100 mL) and number of products (per serving) have fallen (from 75 to 49 and from 90 to 59) between 2015 and 2017, respectively. Energy drinks surveyed showed a 10% reduction in sugar, from 10.6 to 9.5 g/100 mL (P=0.011) and a 6% reduction in energy content (P=0.005) per 100 mL between 2015 and 2017. The average caffeine content of energy drinks, with a warning label, has remained high at 31.5+/-0.9 in 2015 and 31.3+/-1.0 mg/100 mL in 2017. Despite there being reductions, sugar, energy and caffeine content remain at concerning levels in 2017. CONCLUSIONS: To reduce the harmful impact of energy drinks, further reduction in sugar and a reduction in caffeine by reformulation are urgently needed. Other measures such as ban on the sale of energy drinks to children and smaller product sizes should also be explored, while warning labels should be kept. A reduction in sugar, energy and caffeine content and overall energy drinks consumption could be beneficial in reducing sugar, energy and caffeine intake of consumers of energy drinks. PMID- 29242396 TI - Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC. PMID- 29242397 TI - Whole-Body Voxel-Based Personalized Dosimetry: The Multiple Voxel S-Value Approach for Heterogeneous Media with Nonuniform Activity Distributions. AB - Personalized dosimetry with high accuracy is becoming more important because of the growing interest in personalized medicine and targeted radionuclide therapy. Voxel-based dosimetry using dose point kernel or voxel S-value (VSV) convolution is available. However, these approaches do not consider the heterogeneity of the medium. Here, we propose a new method for whole-body voxel-based personalized dosimetry in heterogeneous media with nonuniform activity distributions-a method we refer to as the multiple VSV approach. Instead of using only a single VSV, as found in water, the method uses multiple numbers (N) of VSVs to cover media of various density ranges, as found in the whole body. Methods: The VSVs were precalculated using GATE Monte Carlo simulation and were convoluted with the time integrated activity to generate density-specific dose maps. CT-based segmentation was performed to generate a binary mask image for each density region. The final dose map was acquired by the summation of N segmented density-specific dose maps. We tested several sets of VSVs with different densities: N = 1 (single water VSV), 4, 6, 8, 10, and 20. To validate the proposed method, phantom and patient studies were conducted and compared with the direct Monte Carlo approach, which was considered the ground truth. Finally, dosimetry on 10 patients was performed using the multiple VSV approach and compared with the single VSV and organ-based approaches. Errors at the voxel and organ levels were reported for 8 organs. Results: In the phantom and patient studies, the multiple VSV approach showed significant decreases in voxel-level errors, especially for the lung and bone regions. As the number of VSVs increased, voxel-level errors decreased, although some overestimations were observed at the lung boundaries. For the multiple VSVs (N = 8), we achieved a voxel-level error of 2.06%. In the dosimetry study, our proposed method showed greatly improved results compared with single VSV and organ-based dosimetry. Errors at the organ level were -6.71%, 2.17%, and 227.46% for single VSV, multiple VSV, and organ-based dosimetry, respectively. Conclusion: The multiple VSV approach for heterogeneous media with nonuniform activity distributions offers fast personalized dosimetry at the whole-body level, yielding results comparable to those of the direct Monte Carlo approach. PMID- 29242398 TI - Impact of 68Ga-PSMA-11 PET/CT on the Management of Prostate Cancer Patients with Biochemical Recurrence. AB - In this prospective survey of referring physicians, we investigated whether and how 68Ga-labeled prostate-specific membrane antigen 11 (68Ga-PSMA-11) PET/CT affects the implemented management of prostate cancer patients with biochemical recurrence (BCR). Methods: We conducted a prospective survey of physicians (NCT02940262) who referred 161 patients with prostate cancer BCR (median prostate specific antigen value, 1.7 ng/mL; range, 0.05-202 ng/mL). Referring physicians completed one questionnaire before the scan to indicate the treatment plan without 68Ga-PSMA-11 PET/CT information (Q1; n = 101), one immediately after the scan to denote intended management changes (Q2; n = 101), and one 3-6 mo later to document the final implemented management (Q3; n = 56). The implemented management was also obtained via electronic chart review or patient contact (n = 45). Results: A complete documented management strategy (Q1 + Q2 + implemented management) was available for 101 of 161 patients (63%). Seventy-six of these (75%) had a positive 68Ga-PSMA-11 PET/CT result. The implemented management differed from the prescan intended management (Q1) in 54 of 101 patients (53%). The postscan intended management (Q2) differed from the prescan intended management (Q1) in 62 of 101 patients (61%); however, these intended changes were not implemented in 29 of 62 patients (47%). Pelvic nodal and extrapelvic metastatic disease on 68Ga-PSMA-11 PET/CT (PSMA T0N1M0 and PSMA T0N1M1 patterns) was significantly associated with implemented management changes (P = 0.001 and 0.05). Conclusion: Information from 68Ga-PSMA-11 PET/CT brings about management changes in more than 50% of prostate cancer patients with BCR (54/101; 53%). However, intended management changes early after 68Ga-PSMA-11 PET/CT frequently differ from implemented management changes. PMID- 29242400 TI - PSMA PET: Transformational Change in Prostate Cancer Management? PMID- 29242399 TI - Functional Renal Imaging with 2-Deoxy-2-18F-Fluorosorbitol PET in Rat Models of Renal Disorders. AB - Precise regional quantitative assessment of renal function is limited with conventional 99mTc-labeled renal radiotracers. A recent study reported that the PET radiotracer 2-deoxy-2-18F-fluorosorbitol (18F-FDS) has ideal pharmacokinetics for functional renal imaging. Furthermore, 18F-FDS is available via simple reduction from routinely used 18F-FDG. We aimed to further investigate the potential of 18F-FDS PET as a functional renal imaging agent using rat models of kidney disease. Methods: Two different rat models of renal impairment were investigated: induction of acute renal failure by intramuscular administration of glycerol in the hind legs, and induction of unilateral ureteral obstruction by ligation of the left ureter. At 24 h after these procedures, dynamic 30-min 18F FDS PET data were acquired using a dedicated small-animal PET system. Urine 18F FDS radioactivity 30 min after radiotracer injection was measured together with coinjected 99mTc-diethylenetriaminepentaacetic acid urine activity. Results: Dynamic PET imaging demonstrated rapid 18F-FDS accumulation in the renal cortex and rapid radiotracer excretion via the kidneys in healthy control rats. On the other hand, significantly delayed renal radiotracer uptake (continuous slow uptake) was observed in acute renal failure rats and unilateral ureteral obstruction kidneys. Measured urine radiotracer concentrations of 18F-FDS and 99mTc-diethylenetriaminepentaacetic acid correlated well with each other (R = 0.84, P < 0.05). Conclusion:18F-FDS PET demonstrated favorable kinetics for functional renal imaging in rat models of kidney diseases. 18F-FDS PET imaging, with its advantages of high spatiotemporal resolution and simple tracer production, could potentially complement or replace conventional renal scintigraphy in select cases and significantly improve the diagnostic performance of renal functional imaging. PMID- 29242401 TI - EBONI: A Tool for Automated Quantification of Bone Metastasis Load in PSMA PET/CT. AB - Prostate-specific membrane antigen (PSMA) PET/CT has a high diagnostic accuracy for lesion detection in metastatic prostate cancer, including bone metastases. Novel therapeutic approaches require valid biomarkers for standardized disease staging and for evaluation of progression and therapy response. Here, we introduce EBONI (Evaluation of Bone Involvement), a software tool to automatically quantify the bone metastasis load in PSMA PET/CT. Lesion quantity, mean and maximum lesional SUV, z score, and percentage of affected bone volume are determined. EBONI is open source and freely available. Methods: To validate EBONI, the results of automated quantification of 38 PSMA PET/CT scans with different levels of bone involvement were compared with visual expert reading. The influence of SUV threshold and Hounsfield unit thresholds was analyzed. Results: A high correlation between bone lesion quantity as determined visually and automatically was found (SUVmax, r2 = 0.97; SUVmean, r2 = 0.88; lesion count, r2 = 0.97). The Hounsfield unit threshold had no significant influence, whereas an SUV threshold of 2.5 proved optimal for automated lesion quantification. The systematic error of false-positive tissue misclassification was low, occurred mainly around the salivary and lacrimal glands, and could easily be corrected. There were no false-negative ratings. Conclusion: EBONI analysis is robust, quick (<3 min per scan), and 100% reproducible. It allows rater-independent quantification of bone metastasis in metastatic prostate cancer. It provides lesion quantification equivalent to that of visual assessment, as well as providing complementary information. It can be easily implemented as an add-on to visual analysis of PSMA PET/CT scans and has the potential to reduce turnaround time. PMID- 29242402 TI - A New Type of Prostate Cancer Imaging: Will 64CuCl2 PET/CT Flourish or Vanish? PMID- 29242403 TI - Does PET Reconstruction Method Affect Deauville Score in Lymphoma Patients? AB - When evaluating 18F-FDG PET images with the Deauville score (DS), the quantification of tumor and reference organs limits the problem of optical misinterpretation. Compared with conventional reconstruction algorithms, point spread function (PSF) modeling increases SUVs significantly in tumors but only moderately in the liver, which could affect the DS. We investigated whether the choice of the reconstruction algorithm affects the DS and whether discordance affects the capability of 18F-FDG PET to stratify lymphoma patients. Methods: Overall, 126 patients with diffuse large B-cell lymphoma were included (56 female and 70 male; median age, 65 y; range, 20-88 y). PET data were reconstructed with the unfiltered PSF method. Additionally, a 6-mm filter was applied to PSF images to meet the requirements of the EANM Research Ltd. (EARL) harmonization program from the European Association of Nuclear Medicine (EANM) (PSFEARL). One hundred interim PET (i-PET) and 95 end-of-treatment PET (EoT-PET) studies were analyzed. SUVmax in the liver and aorta was determined using automatic volumes of interest and compared with SUVmax in the residual mass with the highest 18F-FDG uptake. Results: For i-PET, using PSF and PSFEARL, we classified patients as responders and nonresponders in 60 and 40 cases versus 63 and 37 cases, respectively. Five cases of major discordance (5.0%) occurred (i.e., changes from responder to nonresponder). For Eot-PET, patients were classified using PSF and PSFEARL as responders and nonresponders in 69 and 26 cases versus 72 and 23 cases, respectively. Three cases of major discordance (3.2%) occurred. Concordance (Cohen unweighted kappa) between the PSF and the PSFEARL DS was 0.82 (95% confidence interval, 0.73-0.91) for i-PET and 0.89 (95% confidence interval, 0.81 0.96) for EoT-PET. The median follow-up periods were 28.4 and 27.4 mo for i-PET and EoT-PET, respectively. Kaplan-Meier analysis showed statistically significant differences in progression-free survival and overall survival among responders and nonresponders no matter which reconstruction was used for i-PET and EoT-PET. Conclusion: Neither DS nor risk stratification of diffuse large B-cell lymphoma patients is affected by the choice of PET reconstruction. Specifically, the use of PSF is not an issue in routine clinical processes or in multicenter trials. These findings have to be confirmed in escalation and deescalation procedures based on early i-PET. PMID- 29242404 TI - Comparison of 68Ga-PSMA-11 and 18F-Fluciclovine PET/CT in a Case Series of 10 Patients with Prostate Cancer Recurrence. AB - This was a head-to-head comparison between 68Ga-labeled prostate-specific membrane antigen (PSMA)-11 and 18F-fluciclovine PET/CT in a series of 10 patients with prostate cancer (PCa) recurrence. Methods: In total, 288 patients with PCa recurrence were enrolled in a prospective study of 68Ga-PSMA-11 PET/CT imaging for recurrent disease localization (ClinicalTrials.gov identifier NCT02940262). We retrospectively identified 10 patients who underwent clinically indicated 18F fluciclovine PET/CT prior to enrollment. Results: The median time between the 2 scans was 2.2 mo (range, 0.2-4.2 mo). The median prostate-specific antigen (PSA) value was 1.0 ng/mL (mean, 4.7 ng/mL; range, 0.13-18.1 ng/mL) and 1.1 ng/mL (mean, 6.2 ng/mL; range, 0.24-31.3 ng/mL) at the time of 18F-fluciclovine and 68Ga-PSMA-11 PET/CT, respectively. Five of 10 patients (50%) were negative with 18F-fluciclovine but positive with 68Ga-PSMA-11 PET/CT. Two of 10 patients (20%) were positive with both 18F-fluciclovine and 68Ga-PSMA-11 PET/CT, but 68Ga-PSMA 11 PET/CT showed additional lymph nodes metastasis. Three of 10 patients (30%) were negative with both 18F-fluciclovine and 68Ga-PSMA-11 PET/CT. Conclusion: This case series suggests improved detection rates for 68Ga-PSMA-11 PET/CT when compared with 18F-fluciclovine PET/CT in patients with recurrent PCa. Prospective trials designed to directly compare the two should be initiated. PMID- 29242405 TI - Digitalislike Compounds Restore hNIS Expression and Iodide Uptake Capacity in Anaplastic Thyroid Cancer. AB - Anaplastic thyroid cancer (ATC) is a rare malignancy that accounts for 1%-2% of all thyroid cancers. ATC is one of the most aggressive human cancers, with rapid growth, tumor invasion, and development of distant metastases. The median survival is only 5 mo, and the 1-y survival is less than 20%. Moreover, as a result of severe dedifferentiation, including the loss of human sodium iodide symporter (hNIS) expression, radioactive iodide (RAI) therapy is ineffective. Recently, we have demonstrated beneficial effects of autophagy-activating digitalislike compounds (DLCs) on redifferentiation and concomitant restoration of iodide uptake in RAI-refractory papillary and follicular thyroid cancer cell lines. In the current study, the effects of DLCs on differentiation and proliferation of ATC cell lines were investigated. Methods: Autophagy activity was assessed in ATC patient tissues by immunofluorescent staining for the autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3). In addition, the effect of autophagy-activating DLCs on the proliferation, gene expression profile, and iodide uptake capacity of ATC cell lines was studied. Results: Diminished autophagy activity was observed in ATC tissues, and in vitro treatment of ATC cell lines with DLCs robustly restored hNIS and thyroglobulin expression and iodide uptake capacity. In addition, proliferation was strongly reduced by induction of cell cycle arrest and, to some extent, cell death. Mechanistically, reactivation of functional hNIS expression could be attributed to activation of the transcription factors activating transcription factor 3 and protooncogene c-fosConclusion: DLCs could represent a promising adjunctive therapy for restoring iodide avidity within the full spectrum from RAI-refractory dedifferentiated to ATC. PMID- 29242406 TI - FOXO3 cell resilience gene neighborhood. PMID- 29242408 TI - Energy balance and the sphingosine-1-phosphate/ceramide axis. PMID- 29242409 TI - CDK1: beyond cell cycle regulation. PMID- 29242407 TI - Central role of the p53 pathway in the noncoding-RNA response to oxidative stress. AB - Oxidative stress plays a fundamental role in many conditions. Specifically, redox imbalance inhibits endothelial cell (EC) growth, inducing cell death and senescence. We used global transcriptome profiling to investigate the involvement of noncoding-RNAs in these phenotypes. By RNA-sequencing, transcriptome changes were analyzed in human ECs exposed to H2O2, highlighting a pivotal role of p53 signaling. Bioinformatic analysis and validation in p53-silenced ECs, identified several p53-targets among both mRNAs and long noncoding-RNAs (lncRNAs), including MALAT1 and NEAT1. Among microRNAs (miRNAs), miR-192-5p was the most induced by H2O2 treatment, in a p53-dependent manner. Down-modulated mRNA-targets of miR-192 5p were involved in cell cycle, DNA repair and stress response. Accordingly, miR 192-5p overexpression significantly decreased EC proliferation, inducing cell death. A central role of the p53-pathway was also confirmed by the analysis of differential exon usage: Upon H2O2 treatment, the expression of p53-dependent 5' isoforms of MDM2 and PVT1 increased selectively. The transcriptomic alterations identified in H2O2-treated ECs were also observed in other physiological and pathological conditions where redox control plays a fundamental role, such as ECs undergoing replicative senescence, skeletal muscles of critical limb-ischemia patients and the peripheral-blood mononuclear cells of long-living individuals. Collectively, these findings indicate a prominent role of noncoding-RNAs in oxidative stress response. PMID- 29242410 TI - Adiposity and Cortisol Response to Stress in Indian Adolescents. AB - OBJECTIVE: We examined associations of different adiposity measures with cortisol responses during the Trier Social Stress Test for children (TSST-C). DESIGN: Descriptive study. SETTING: Holdsworth Memorial Hospital, Mysore, India. PARTICIPANTS: Adolescents aged 13.5y from a birth cohort were recruited (N=269, 133 boys). METHODS: The stressor (TSST-C) was 5-minutes each of public speaking and mental arithmetic tasks in front of two unfamiliar 'judges'. Salivary cortisol concentrations were measured at baseline and at regular intervals after TSST-C. Weight, height, sub scapular and triceps skinfold thickness, and waist and hip circumference were measured, and percentage body fat was estimated (fat%; bioimpedance). Body mass index (BMI) and Waist-to-hip ratio (WHR) were calculated. All variables were converted into within-cohort SD scores before analysis. Stress-induced change in cortisol concentrations from baseline (cortisol response) was examined in relation to adiposity. RESULTS: Stress increased cortisol concentrations significantly from baseline (mean (SD): 5.5 (6.4) ng/mL; P<0.001). Higher WHR was associated with lower cortisol response at 20 and 30-minutes after stress (~0.13 SD decrease in cortisol response per SD higher WHR, P<0.05). Higher fat% was also associated with lower cortisol response only in girls 20-minutes post-stress (0.23 SD lower response per SD higher fat%, P=0.004). Sum of skinfold thickness and BMI were not associated with cortisol responses. CONCLUSION: Abdominal adiposity is associated with reduced hypothalamic-pituitary-adrenal axis reactivity to stress in this adolescent population. PMID- 29242411 TI - Mortality in Children with Severe Hand, Foot and Mouth Disease in Guangxi, China. AB - OBJECTIVE: To analyze the clinical features of children with hand foot and mouth disease (HFMD) who died. METHODS: 331 deaths due to HFMD between 2010 and 2014 were included in this retrospective study; 15 autopsies were performed. RESULTS: Most deaths were seen in children aged below 3 y, and with enterovirus 71 infection (91%). The mean (SD) duration of HFMD from onset to death was 3.7(2.9) d. The mean (SD) age of fast progressors (from onset to death less than 4 days) was 17.4 (9.2) mo. Most of them were diagnosed as stage 3 and stage 4 of HFMD. Various pathological changes were observed in brain after autopsy, especially in brain stem and medulla. CONCLUSION: The brain stem encephalitis with the neurotropism of enteroviruses seems to be the main contributor to the death in HFMD. PMID- 29242412 TI - HLA- B*5701 Allele in HIV-infected Indian Children and its Association with Abacavir Hypersensitivity. AB - OBJECTIVE: To determine the prevalence of HLA-B*5701 allele in HIV-infected children, and to find its association with Abacavir hypersensitivity. METHODS: Children (2 to 18 y) already on, or to be initiated on Abacavir were included for PCR sequencing to detect HLA-B*5701. OUTCOME MEASURES WERE: proportion with HLA B*5701 allele and hypersensitivity with Abacavir. Abacavir was stopped if patient tested positive for HLA-B*5701 allele. RESULTS: 100 children (median age 11 y) were enrolled; 10 were already on Abacavir. HLA-B*5701 positivity was observed in 11 (11%) children. Two of these 11 children developed hypersensitivity after initiation of Abacavir. Abacavir was thereafter stopped in all who tested HLA B*5701 positive, irrespective of the development of hypersensitivity reaction. CONCLUSION: HLA-B*5701 allele was present in 11 (11%) of HIV-infected children, of which two developed Abacavir hypersensitivity. None of the patients without the allele developed hypersensitivity. PMID- 29242413 TI - Assisted Physical Exercise for Improving Bone Strength in Preterm Infants Less than 35 Weeks Gestation: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the efficacy of daily assisted physical exercise (starting from one week of postnatal age) on bone strength at 40 weeks of post menstrual age to no intervention in infants born between 27 and 34 weeks of gestation. DESIGN: Open-label randomized controlled trial. SETTING: Tertiary-care teaching hospital in northern India from 16 May, 2013 to 21 November, 2013. PARTICIPANTS: 50 preterm neonates randomized to Exercise group (n=26) or Control group (n=24). INTERVENTION: Neonates in Exercise group underwent one session of physical exercise daily from one week of age, which included range-of-motion exercises with gentle compression, flexion and extension of all the extremities with movements at each joint done five times, for a total of 10-15 min. Infants in Control group underwent routine care and were not subjected to any massage or exercise. MAIN OUTCOME MEASURES: Primary: Bone speed of sound of left tibia measured by quantitative ultrasound at 40 weeks post menstrual age. Secondary: Anthropometry (weight length and head circumference) and biochemical parameters (calcium, phosphorus, alkaline phosphatase) at 40 weeks post menstrual age. RESULTS: The tibial bone speed of sound was comparable between the two groups [2858 (142) m/s vs. 2791 (122) m/s; mean difference 67.6 m/s; 95% CI - 11 to 146 m/s; P=0.38]. There was no difference in anthropometry or biochemical parameters. CONCLUSIONS: Daily assisted physical exercise does not affect the bone strength, anthropometry or biochemical parameters in preterm (27 to 34 weeks) infants. PMID- 29242414 TI - Outcomes of Children with Severe Acute Malnutrition in a Tribal Day-care Setting. AB - OBJECTIVE: To describe the nutritional outcomes of children with severe acute malnutrition (SAM) in a village-level intervention. METHODS: This observational longitudinal study on 179 children aged <3 years was conducted in seven tribal blocks of Central and Eastern India with SAM managed in a comprehensive day care program. RESULTS: 76% children with SAM showed improvement over a 4-6 months period, with 37% shifting to normal anthrometric status. There was a significant shift in Z scores. CONCLUSION: This community-based intervention showed fair results for management of children with SAM at village level. PMID- 29242415 TI - Bronchopulmonary Dysplasia in Preterm Neonates in a Level III Neonatal Unit in India. AB - OBJECTIVE: To find out the incidence and associations of bronchopulmonary dysplasia (BPD) in preterm neonates. DESIGN: Descriptive cohort. Methods: All consecutively born neonates <33 weeks gestation requiring oxygen or respiratory support during first 3 days of life were enrolled from a level III neonatal unit in Chandigarh, India. Those with malformations were excluded. Placenta was examined for histological chorioamnionitis in preterm rupture of membranes and/or preterm spontaneous onset of labour. Serum Malondialdehyde (MDA) and Superoxide dismutase (SOD) and Catalase levels were estimated on day 3 of life. All recruited neonates were followed up till discharge or death. RESULTS: Out of 250 neonates enrolled, 170 (68%) survived till day 28 and BPD developed in 19 (11.2%) infants. The mean gestation and birth weight were significantly lower in infants who developed BPD. Chorioamnionitis (clinical 5.3% vs 1.9%, P=0.375; and histological 37.5% vs 16.7%, P<0.001), patent ductus arteriosus (PDA) (52.6% vs 8.9%, P<0.001), median (IQR) sepsis episodes [2 (2,3) vs 1 (1,2), P<0.001], invasive ventilation (84.2% vs 11.3%, P<0.001), and duration of ventilation [56 (4) d vs 4 (5) d, P=0.001] were significantly higher in infants with BPD. Serum MDA, SOD and Catalase levels were comparable between the two groups. CONCLUSIONS: Chorioamnionitis, PDA and sepsis were significantly associated with BPD. PMID- 29242416 TI - Etiology and Outcome of Cholelithiasis in Turkish Children. AB - OBJECTIVE: The aim of this study was to examine the etiology of gallstones in children and responses to ursodeoxycholic acid (UDCA) treatment. METHODS: 74 children with cholelithiasis were recruited, and underwent ultrasonography to detect gallstones. All relevant clinical information was recorded in a structured proforma. RESULTS: The commonest risk factor was a family history of gallstones. Most children responded to UDCA treatment in the first six months; children with hemolytic diseases showed no response to UDCA. CONCLUSION: UDCA treatment may be useful before surgery in asymptomatic patients of cholelithiasis without hemolytic diseases. PMID- 29242417 TI - Phase Changing Material for Therapeutic Hypothermia in Neonates with Hypoxic Ischemic Encephalopathy - A Multi-centric Study. AB - OBJECTIVE: To assess the feasibility and safety of cooling asphyxiated neonates using phase changing material based device across different neonatal intensive care units in India. DESIGN: Multi-centric uncontrolled clinical trial. SETTING: 11 level 3 neonatal units in India from November 2014 to December 2015. PARTICIPANTS: 103 newborn infants with perinatal asphyxia, satisfying pre-defined criteria for therapeutic hypothermia. INTERVENTION: Therapeutic hypothermia was provided using phase changing material based device to a target temperature of 33.5+/-0.5oC, with a standard protocol. Core body temperature was monitored continuously using a rectal probe during the cooling and rewarming phase and for 12 hours after the rewarming was complete. OUTCOME MEASURES: Feasibility measure Time taken to reach target temperature, fluctuation of the core body temperature during the cooling phase and proportion of temperature recordings outside the target range. Safety measure - adverse events during cooling. RESULTS: The median (IQR) of time taken to reach target temperature was 90 (45, 120) minutes. The mean (SD) deviation of temperature during cooling phase was 33.5 (0.39) oC. Temperature readings were outside the target range in 10.8% (5.1% of the readings were <33oC and 5.7% were >34oC). Mean (SD) of rate of rewarming was 0.28 (0.13)oC per hour. The common adverse events were shock/ hypotension (18%), coagulopathy (21.4%), sepsis/probable sepsis (20.4%) and thrombocytopenia (10.7%). Cooling was discontinued before 72 hours in 18 (17.5%) babies due to reasons such as hemodynamic instability/refractory shock, persistent pulmonary hypertension or bleeding. 7 (6.8%) babies died during hospitalization. CONCLUSIONS: Using phase changing material based cooling device and a standard protocol, it was feasible and safe to provide therapeutic hypothermia to asphyxiated neonates across different neonatal units in India. Maintenance of target temperature was comparable to standard servo-controlled equipment. PMID- 29242418 TI - Subclinical Hypothyroidism: A Prospective Observational Study from Southern India. AB - OBJECTIVE: To assess the natural history and progression of subclinical hypothyroidism and to study factors which help predict evolution of subclinical hypothyroidism into overt hypothyroidism. METHODS: Longitudinal study in 40 children (2-16 yrs) presenting with subclinical hypothyroidism in a tertiary care unit in Chennai, India. Patients showing evidence of overt hypothyroidism or thyroid stimulating hormone >=15 mIU/mL during follow-up were started on thyroxine. Others were followed up with 3-monthly thyroid function tests up to one year. RESULTS: At the end of our study period 3 (7.5%) were overtly hypothyroid, 16 (40%) remained as subclinical hypothyroid, and 21 (52.5%) became euthyroid. Evidence of auto- immunity at baseline was a significant (P<0.05) risk factor for progression to overt hypothyroidism. CONCLUSION: Subclinical hypothyroidism in children, with thyroid stimulating hormone upto 15 mIU/L and irrespective of thyroid autoimmunity, needs only periodic clinical and biochemical follow up. Thyroid autoimmunity may point to an increased probability of progression to overt hypothyroidism. PMID- 29242419 TI - Reduced interleukin-6 immunoexpression and birefringent collagen formation indicate that MTA Plus and MTA Fillapex are biocompatible. AB - Considering that endodontic sealers release some components which may promote delay in the repair process, our purpose was to evaluate the tissue reaction promoted by MTA Plus and MTA Fillapex in comparison with AH Plus (standard control) and Endofill, which has a long clinical track record. One hundred rats were distributed into five groups: MTA Plus (Avalon Biom Inc., Bradenton, FL, USA), MTA Fillapex (Angelus, Londrina, PR, Brazil), AH Plus (Dentsply DeTrey GmbH, Konstanz, Germany), Endofill (Dentsply, Petropolis, RJ, Brazil) and CG (control group, empty polyethylene tubes). The polyethylene tubes filled with sealers or empty (CG) were implanted into subcutaneous. After 7, 15, 30 and 60 days, the tubes surrounded by capsules were paraffin-embedded. In HE-stained sections, the volume density of inflammatory cells (VvIC) was estimated in the capsules. The number of interleukin-6-immunolabelled cells (IL-6), a pro inflammatory cytokine, was also computed in the capsules. The birefringent collagen content was quantified in picrosirius-stained sections. Data were analysed by ANOVA and Tukey tests (p <= 0.05). At 7 days, the capsules showed moderate inflammatory reaction. In all groups, VvIC and IL-6-immunostained cells reduced significantly from 7 to 60 days. At 60 days, IL-6 immunoexpression was reduced significantly in MTA Plus and MTA Fillapex in comparison with AH Plus; no difference was found in the VvIC among MTA Plus, MTA Fillapex, AH Plus and CG whereas Endofill exhibited the highest VvIC. The reduction in VvIC was parallel to an increase in the collagen in all the groups, except Endofill. MTA Plus, MTA Fillapex and AH Plus induce a response that culminates in the regression of inflammation and formation of a fibrous capsule over time. The lower IL-6 immunoexpression in the capsules of MTA Plus and MTA Fillapex than AH Plus suggests that the immune response is suppressed more rapidly in the MTA-based sealers. PMID- 29242420 TI - A versatile fabrication strategy of three-dimensional foams for soft and hard tissue engineering. AB - The fabrication strategies of three-dimensional porous biomaterials have been extensively studied and well established in the past decades, yet the biocompatibility and versatility in preparing porous architecture still lacks. Herewith, we present a novel and green fabrication technique of 3D porous foams for both soft and hard engineering. By utilizing the gelatinization and retrogradation property of starches, stabilized porous constructs made of various building blocks from living cells to ceramic particles were created for the first time. In soft tissue engineering applications, 3D cultured tissue foam (CTF) with controlled release property of cells was developed and the foams constituted by osteoblasts, fibroblasts and vascular endothelial cells all exhibited high mechanical stability and preservation of cell viability or functions. More importantly, the CTF achieved sustained self-release of cells controlled by serum (containing amylase) concentration and the released cells also maintained high viability and functions. In the context of hard tissue engineering applications, ceramic/bioglass (BG) foam scaffolds were developed by the similar starch assisted foaming strategy where the resultant bone scaffolds of hydroxyapatite (HA)/BG and Si3N4/BG possessed>70% porosity with interconnected macropores (sizes 200~400MUm) and fine pores (sizes1~10 MUm) and superior mechanical properties despite the high porosity. Additionally, in vitro and in vivo evaluations on the biological properties revealed that porous HA/BG foam exhibited desired biocompatibility and osteogenesis. The in vivo study indicated new bone ingrowth after 1 week and significant increases in new bone volume after 2 weeks. In conclusion, the presented foaming strategy provides opportunities for biofabricating CTF with different cells for different target soft tissues and preparing porous ceramic/BG foams with different material components and high strengths-showing great versatility in soft and hard tissue engineering. PMID- 29242421 TI - Studies in Mexican Grasshoppers: Three new species of Dactylotini (Acrididae: Melanoplinae) from Mexico and a review of existing conspecifics with comments on their geographical distributions. AB - Three new species of the tribe Dactylotini (Acrididae: Melanoplinae) are described from Central and Southern Mexico. 1) Dasyscirtus monicae sp. nov. Fontana, Marino-Perez, Sanabria-Urban, & Woller is described from the eastern portion of the Balsas River Basin and the outer slope of the Mexican Volcanic Belt; 2) Perixerus obscurus sp. nov. Fontana, Marino-Perez, Sanabria-Urban, & Woller is described from the Sierra Norte de Oaxaca mountain range; and 3), Perixerus triqui sp. nov. Fontana, Marino-Perez, Sanabria-Urban, & Woller is described from the Sierra Madre del Sur mountain range and towards the Pacific Coast of Oaxaca. Taxonomic placement of these species is justified based on distinct morphology and comparisons with congeneric species are provided. Finally, we provide a biogeographical explanation for the distribution of the species in both genera. PMID- 29242422 TI - Remarkable biodiversity of flabelligerids in Japan: seven new species of Diplocirrus (Annelida: Flabelligeridae) from Japanese waters. AB - Seven new species of Diplocirrus are described from Japan: D. asamushiensis sp. nov., D. imajimai sp. nov., D. mamoi sp. nov., D. ohtsukai sp. nov., D. seisuiae sp. nov., D. tohokuensis sp. nov., and D. toyoshioae sp. nov. These species are distinguished from all the known species of Diplocirrus by the following features: length of the cephalic cage, length of lateral papillae, presence of gonopodial lobe, adhering pattern of sediment particles, length of caruncle, length and morphological feature of branchiae, articles and morphological features of neurochaetae, and swollen area along the body. PMID- 29242423 TI - A checklist of the praying mantises of Peru: new records, one new genus (Piscomantis gen. n.) and biogeographic remarks (Insecta, Mantodea). AB - We present a preliminary checklist of the praying mantises (Insecta: Mantodea) of Peru. A total of 67 species are reported, nine of which constitute new records from that country. The following new nomenclatural procedures are introduced: Musoniella margharethae Battiston and Picciau, 2008 is transferred to Musonia as Musonia margharethae (Battiston and Picciau, 2008) (comb. n.), and Phyllovates brevicollis Orofino, Ippolito and Lombardo, 2006 is considered a new synonym (syn. n.) of Pseudovates peruviana (Rehn, 1911). A new genus, Piscomantis gen. n., is established to accommodate Galapagia peruana Beier, 1935, which is now referred to as Piscomantis peruana (Beier, 1935) (comb. n.). Ten species are removed from the Peruvian mantis fauna and two nomina nuda are proposed. An overview of the biogeography and ecology of Peruvian praying mantises is presented. PMID- 29242424 TI - New taxa and notes of katydids from the tribe Meconematini (Orthoptera: Meconematinae) from Brunei Darussalam. AB - Based on the new material collected in Kuala Belalong in Brunei Darussalam, four new taxa of Meconematini katydids (Orthoptera: Tettigoniidae: Meconematinae) are described here. Three new species from three previously known genera are described: Alloteratura (Alloteratura) belalongensis sp. nov., Leptoteratura (Rhinoteratura) chela sp. nov., and Pseudoteratura (Pseudoteratura) kenuan sp. nov. Moreover, one new genus is erected based on the unique type species which is also new to science: Pulchroteratura huiqing gen. et sp. nov. PMID- 29242425 TI - Physoschistura harkishorei, a new species of loach from Arunachal Pradesh, north-eastern India (Teleostei: Nemacheilidae). AB - Physoschistura harkishorei, a new species of nemacheilid loach, is described from the Dibang and Lohit Rivers of Arunachal Pradesh, north-eastern India. The new species can be distinguished from all known congeners by the combination of the following characters: the second branched ray of pectoral fin with a distal filamentous extension; body colour pattern consisting of 9-10 vertically elongated brownish spots or blotches along the flank, and 8-10 brownish saddles on back, the saddles not contiguous with the lateral blotches; lateral line complete; prominent, well-developed pelvic-fin lobe; a well-developed free posterior chamber of the air-bladder; and caudal fin with 7+8 branched rays. The new species occurs sympatrically with Physoschistura dikrongensis and P. elongata in the Brahmaputra basin. PMID- 29242426 TI - First fossil representatives of Pharaxonothinae Crowson (Coleoptera: Erotylidae): indirect evidence for cycads existence in Baltic amber forest. AB - A new species of Erotylidae, Cycadophila (s. str.) mumia sp. nov., the first fossil representative of the subfamily Pharaxo-nothinae, is described and illustrated from Eocene Baltic amber. A second closely related specimen is reported but not described as new due to poor preservation in amber. The occurrence of representatives of the Recent cycad-specialized genus in Baltic amber can indirectly indicate the presence of their host plants (Cycadales: Cycadophyta: Cycadopsida) in the Eocene amber forest. PMID- 29242427 TI - Two new species and the molecular phylogeny of eight species of Macrostomum (Platyhelminthes: Macrostomorpha) from southern China. AB - Two new species of Macrostomum (Platyhelminthes: Macrostomorpha), M. shiyanensis n. sp. and M. lankouensis n. sp. are described from Shiyan Reservoir and Lankou Town. Morphological characteristics of the penis stylets and sperm, as well as the phylogenetic analysis using concatenated sequences of 18S and 28S rDNA genes support the establishment of these two new species and indicate that they are closely related to M. sinensis and M. heyuanensis described from different regions of Guangdong province. Finally, the progress of molecular phylogenetics of Macrostomum worldwide is also discussed. PMID- 29242428 TI - Recognition of a new species of Carmenta from New Mexico supported by morphology and mitochondrial cytochrome oxidase I data (Lepidoptera: Sesiidae: Sesiinae: Synanthedonini). AB - A preliminary phylogeny of 36 species of Carmenta (Lepidoptera: Sesiidae) was reconstructed based on mitochondrial cytochrome oxidase I DNA sequences using parsimony and Bayesian inference in order to assess the placement of a suspected new species. Although the phylogeny was not completely resolved, there were well supported species groups associated with geography. Based on these results and diagnostic morphological characters, Carmenta wildishorum, n. sp., is described and illustrated from the Cimarron Mountain Range in northeastern New Mexico. The new species is sister to C. texana with a 5.2% nucleotide difference between the two, which is similar to the distance between other Carmenta species and exceeds the intraspecific difference observed within C. texana (0.3%). The phylogeny also suggests additional hidden species diversity among Carmenta species that have large geographic distributions. PMID- 29242429 TI - A revision of the subgenus Osmia (Diceratosmia), with descriptions of four new species (Hymenoptera, Megachilidae). AB - The eleven species of the North American subgenus Osmia (Diceratomsia) are revised, four of which are new: Osmia (Diceratosmia) exquisita, n. sp., from Honduras; Osmia (Diceratomia) gonzalezi, n. sp., and Osmia (Diceratomia) spinulifera, n. sp., from Mexico; and Osmia (Diceratomsia) lacunosa, n. sp., from the Bahamas. Diagnoses for the remaining seven species and a key to the males and females of all species are provided. We newly designate a neotype for Osmia botitena Cockerell, junior synonym of Osmia subfasciata Cresson, and remove from synonymy Osmia marilaunidii Cockerell, new status. In addition, we review the known nesting biology, floral hosts, and geographic range of each species. PMID- 29242430 TI - Updates on information about free-living marine nematodes in Brazil: new records and comments on problems in taxonomic studies. AB - New records of nematode species in Brazil, which appeared after or were not mentioned in the last review, are shown in this paper. All environments were considered, including the continental margin. In addition, all studies on marine nematodes in Brazil, including grey literature, ecological papers and book chapters, are listed. Furthermore, information on genera/species richness, dominant genera, and densities is also presented. A total of 11 orders, 72 families, 372 genera, and 450 species of nematodes were recorded in Brazilian marine environments by April 2017. Following problems are discussed: taxonomic lists available only in grey literature, use of outdated identification keys (leading to incorrect identifications), and identifications mostly to putative species or to the genus level. PMID- 29242431 TI - Catalog of taxa introduced by Luitfried Salvini-Plawen (1939-2014). AB - Luitfried Salvini-Plawen was one of the most distinguished researchers for molluscan phylogenetic systematics of the last decades. In his publications he described a total of 193 species: 134 Solenogastres, 34 Caudofoveata, 14 interstitial Gastropoda, one polyplacophoran and the remaining comprising Cnidaria, Priapulida, Kamptozoa, and Echinodermata. In addition, he introduced 47 genus-group names and 54 names for family-level and higher taxa. This catalog comprises lists of all taxon names published by Luitfried Salvini-Plawen. The catalog entries contain taxonomic information, original citations, type localities and type collections. It aims to facilitate further research on these and related taxa. PMID- 29242433 TI - A new species of Paraleptophlebia Lestage, 1917 (Ephemeroptera: Leptophlebiidae) and a re-description of adults for Paraleptophlebia westoni Imanishi, 1937 with the first description of the larva, from the Russian Far East. AB - Male, female imagoes and eggs of Paraleptophlebia kunashirica sp. nov. and the larva, male and female imagoes of Paraleptophlebia westoni are described based on material from the Russian Far East. Comparison of the male imago of Paraleptophlebia kunashirica sp. nov. and the larva and male imago of Paraleptophlebia westoni with other known larvae and imagoes of Paraleptophlebia are given. Paraleptophlebia westoni larvae may be distinguished from congeners by characters associated with the mouthparts, such as the ratio of the length of the maxillary and labial palp segments, shape of hypopharynx, and structure of the claw. Male imagoes of Paraleptophlebia kunashirica sp. nov. and Paraleptophlebia westoni san be distinguished between themselves and other representatives close to them in the form of the ventral appendages and the apex of the penis lobes. PMID- 29242432 TI - Contribution to the morphological description of the marine leech, Ozobranchus margoi (Apathy) (Rhynchobdellida: Ozobranchidae) by using combined histology, micro-CT and SEM. AB - The ozobranchid leech, Ozobranchus margoi (Apathy, 1890), parasite of the loggerhead turtle, Caretta caretta (Linnaeus), was described through a multilevel approach including three different techniques: scanning electronic microscopy, histology and micro-CT. New insights are provided concerning the structure of the sensilla on the body, the eyes with emphasis on the structure of photoreceptors, the digestive system and the reproductive organs. PMID- 29242434 TI - Shallow-water Ascidians from Matua Island (central Kuril Islands, NW Pacific), part 2. AB - The paper reports several ascidians, previously not known from central group of Kurile Islands, including two new species, Synoicum polyzoinum n. sp. and Aplidium matua n. sp. In order to systematize our knowledge on numerous members of these genera, reported from NW Pacific, we provide an overview of all Synoicum and Aplidium species, known from Far Eastern Seas of Russia, including comments on the species erroneously identified in the past. PMID- 29242435 TI - A new genus and species of Pheronematidae (Porifera: Hexactinellida: Amphidiscosida) from the western Pacific Ocean. AB - A new genus and species of glass sponge, belonging to the family Pheronematidae, is described from a single specimen collected from a seamount near Yap Trench in the western Pacific Ocean. Pheronemoides fungosus gen. et sp. nov. is described based on external morphology. In Pheronemoides gen. nov. the basalia are grouped in a broad semicircular tuft attaching to the dermal surface, and marginalia are located on the boundary between the atrial and dermal surfaces. Given the positions of the basalia and the marginalia, we recognize Pheronemoides as a transitional genus between Pheronema and Sericolophus. We also used a partial sequence of the 16S rDNA gene to confirm the validity of the new species designation. PMID- 29242436 TI - A new species of minute beetle (Coleoptera: Clambidae) from Baltic amber (Paleogene, Eocene). AB - A new species of Clambidae, Clambus helheimricus sp. nov., is described and illustrated from Baltic amber. A list of the smallest beetles described from this Lagerstatte is provided. PMID- 29242438 TI - Tegoribatidae of North America, with proposal of Protectoribates gen. nov., and new species (Acari, Oribatida, Tegoribatidae). AB - The oribatid mite family Tegoribatidae has been represented in continental North America by the genera Tegoribates and Tectoribates. Herein, I describe a new genus of Tegoribatidae from North America, Protectoribates, and two new species: Protectoribates occidentalis sp. nov., from forest habitats in western North American, and Tegoribates walteri sp. nov., from forest habitats in California, based on adults and immatures. The descriptions of adults of the type species of Tegoribates, T. subniger Ewing, and other North American species, T. americanus Hammer and T. bryophilus Woolley, are expanded and immatures of T. americanus are described for the first time. Immatures of Protectoribates are apheredermous whereas those of Tegoribates are eupheredermous, though retaining centrodorsal setae. Scutozetes Hammer 1952 is transferred from Tegoribatidae to Ceratozetidae after re-examination of type material. I provide a revised diagnosis for Tegoribates and a key to tegoribatid genera and species for North America. Finally, I provide a revised diagnosis for Tegoribatidae based on world genera. PMID- 29242437 TI - Mimogonellus dreybrodti sp. n., a new cave-inhabiting Osoriinae from Laos (Coleoptera: Staphylinidae). AB - A new osoriine species, Mimogonellus dreybrodti Yin & Steiner, sp. n., collected from a cave in Houaphanh Province, Laos, is described and illustrated. This represents the third Mimogonellus species in Asia, and the first in the genus known to inhabit a cave environment. PMID- 29242439 TI - A new species of Marmara (Lepidoptera: Gracillariidae: Marmarinae), with an Annotated List of Known Hostplants for the Genus. AB - Larvae of the New World gracillariid moth genus Marmara are primarily stem/bark miners, with some species mining in leaves or fruits. We describe a new species, M. viburnella Eiseman & Davis, which feeds on Viburnum, initially mining the leaves but completing development as a stem miner. The type series is from Nantucket Island, Massachusetts, with observations of leaf mines indicating the species is widespread in the eastern USA. Combining previously published data, our own observations, and other sources, we present a list of known Marmara hostplants, many of which represent undescribed species. PMID- 29242440 TI - Bird distributional patterns support biogeographical histories and are associated with bioclimatic units in the Atlantic Forest, Brazil. AB - Rivers as barriers to dispersal and past forest refugia are two of the hypotheses proposed to explain the patterns of biodiversity in the Atlantic Forest. It has recently been shown that possible past refugia correspond to bioclimatically different regions, so we tested whether patterns of shared distribution of bird taxa in the Atlantic Forest are 1) limited by the Doce and Sao Francisco rivers or 2) associated with the bioclimatically different southern and northeastern regions. We catalogued lists of forest birds from 45 locations, 36 in the Atlantic forest and nine in Amazon, and used parsimony analysis of endemicity to identify groups of shared taxa. We also compared differences between these groups by permutational multivariate analysis of variance and identified the species that best supported the resulting groups. The results showed that the distribution of forest birds is divided into two main regions in the Atlantic Forest, the first with more southern localities and the second with northeastern localities. This distributional pattern is not delimited by riverbanks, but it may be associated with bioclimatic units, surrogated by altitude, that maintain current environmental differences between two main regions on Atlantic Forest and may be related to phylogenetic histories of taxa supporting the two groups. PMID- 29242441 TI - Description of the helminth communities of sympatric rodents (Muroidea: Cricetidae) from the Atlantic Forest in northeastern Argentina. AB - Taxonomic and ecological aspects of the helminths found in the assemblage of sigmodontine rodents (Cricetidae-Muroidea) of the Atlantic Forest in Argentina are studied in this paper. The following species Akodon montensis, Brucepattersonius sp. and Thaptomys nigrita (Tribe Akodontini), as well as, Euryoryzomys russatus, Nectomys squamipes, Oligoryzomys nigripes, and Sooretamys angouya (Tribe Oryzomyini) are analyzed. A complete taxonomic list with a total of 25 species of helminths, including Digenea (Dicrocoeliidae), Cestoda (Hymenolepididae) and Nematoda (Trichuridae, Capillariidae, Cooperidae, Helligmonellidae, Oxyuridae, and Onchocercidae) is provided. Twenty new host and locality records for Misiones, Argentina, are reported and the results of the ecological descriptors of component communities are given. The highest value of richness was observed for A. montensis (S=8) and E. russatus (S=7). The diversity index (H') reached values between 1.03 and 1.39 in all rodents, with the exception of N. squamipes that reached 0.75. The equitability indeces with highest value were observed for T. nigrita and E. russatus. The Berger-Parker index of dominance was similar for all host species. The highest prevalence, mean abundance and mean intensity values corresponded to Nippostrongylinae, followed by Syphacinii. This survey constitutes the report with the most diverse parasitic assemblage of rodents described for the Atlantic Forest ecoregion and for Argentina. PMID- 29242442 TI - Two new species of Hyalella (Crustacea, Amphipoda, Hyalellidae) from state of Rio Grande do Sul, Southern Brazil. AB - There are 68 known species of Hyalella worldwide, with 23 occurring in Brazil. The state of Rio Grande do Sul, Southern Brazil, has the largest diversity of the genus in the country, with nine species recorded. The current study aimed to describe two new species of Hyalella from state of Rio Grande do Sul, both of them in the Northwest region of the state, one found in a small spring and another in an artificial pond. Hyalella georginae n. sp. presents several clusters of simple setae on antenna 2, maxilliped very slender, gnathopod 2 dactylus not reaching the lobe of propodus, pleopods rami with short plumose setae and a peculiar pattern of setae on uropods and telson. Hyalella gauchensis n. sp. presents antenna 2 with few setae, maxilliped very slender, gnathopod 2 dactylus reaching the lobe of propodus and pleopods rami with long plumose setae. From this work, the number of Hyalella species found in Brazil increases to 25 and 70 for the genus. PMID- 29242443 TI - DNA barcoding and morphological data reveal a new Hyposoter (Hymenoptera: Ichneumonidae: Porizontinae) reared from a rare zygaenid moth Artona flavipuncta Hampson, 1900 in Taiwan. AB - A new species of Hyposoter Foerster, 1869 is discovered based on morphology of adults and cocoons, biology, and DNA barcoding evidence. It is herein described as Hyposoter distriangulum Chen, Huang & Hsu sp. nov. , which is a common parasitoid of a rare zygaenid moth Artona flavipuncta Hampson, 1900. The differences between similar Hyposoter species in Japan and Taiwan are also presented. PMID- 29242444 TI - The current status of Neocnus Arredondo, 1961 (Mammalia: Edentata: Pilosa: Megalonichidae) and a replacement name for its junior homonym in the sea cucumber family Cucumariidae (Echinodermata :Holothuroidea: Dendrochirotida: Cucumariidae). AB - This short communication addresses the problem associated with the current taxonomic status of the prehistoric edentate genus Neocnus Arredondo, 1961 (with type species Micronocnus gliriformis Matthew, 1931) which has long been considered a senior homonym of the dendrochirotid sea cucumber genus Neocnus Cherbonnier, 1972 (type species Neocnus incubans Cherbonnier, 1972) and replaces the latter (junior homonym) with Incubocnus n.g. The diagnosis of the new genus is the same as the cucumariid Neocnus as amended by O'Loughlin & O'Hara (1992). A brief history of the senior homonym Neocnus (Edentata) is given followed by a short literature survey dealing with its junior homonym. PMID- 29242445 TI - A new species of Sweltsa (Plecoptera: Chloroperlidae) from China, with a key to the Sweltsa males of China. AB - A new species of the alloperline genus Sweltsa, Sweltsa hamula sp. nov. is described and illustrated from Sichuan Province of southwestern China. The male of the new species is distinguished from other known Chinese Sweltsa species by the hook-shaped apex of the epiproct. A provisional key is presented to the known Sweltsa males from China. PMID- 29242446 TI - A new species of Eurypeza Lacroix, 2006 (Coleoptera: Scarabaeidae: Melolonthinae: Tanyproctini) from Kenya. AB - The Afrotropical genus Eurypeza Lacroix, 2006 (Coleoptera: Scarabaeidae: Melolonthinae: Tanyproctini) was established for one species, Eurypeza evansi Lacroix, 2006, from Somalia. The genus belongs to the first group of Afrotropical Tanyproctini sensu Lacroix (2007), and is characterized by protarsomeres 1-4 and mesotarsomeres 1-4 broadened and ventrally macrosetaceous, protarsomere 5 and mesotarsomere 5 simple, and labrum transverse and shallowly bilobed. The genus Eurypeza differs from other genera of Lacroix's (2007) first group by club with five antennomeres, antennomere 3 and 4 of equal length, labial palpi with three palpomeres, clypeus broadly rounded, protibia bidentate with proximal tooth well developed, and metatibial carina incomplete (for details, see also Lacroix 2006, 2007). PMID- 29242447 TI - A new species of Angaeus from Malaysia with possible affinity to related genera within Stephanopinae (Araneae: Thomisidae). AB - The crab spider genus Angaeus Thorell, 1881 currently contains 10 described species (Benjamin 2013; WSC 2017). All species of the genus are restricted to tropical Asia. The aim of this correspondence is to illustrate and describe a new species of the genus characterized by a number of features previously found in the genera Angaeus, Borboropactus Simon, 1884, Epidius Thorell, 1877 and Geraesta Simon, 1889. The most unusual feature is the elongated tibia of the male palp that was previously thought to be diagnostic of Epidius (Figs 1, 2, 8; character 1 in Benjamin 2011; Benjamin 2017). However, the new species lacks tibial macrosetae (Figs 1, 2, 8) and lacks a flexibly attached MA, both also being characteristics of Epidius (characters 2 and 18 in Benjamin 2011). Furthermore, this new species differs considerably in general appearance from all known species of Epidius. PMID- 29242448 TI - New species of Colombian Triplocania Roesler (Psocodea: 'Psocoptera': Ptiloneuridae). AB - Based on a survey of the genus Triplocania (Psocodea: 'Psocoptera') in forests of natural areas and Natural Parks in Colombia, 46 species were found, 42 of which are new to science and are here described and illustrated. Added to T. colombiana Garcia Aldrete, the number of species of Triplocania now known in Colombia is raised to 47. To date, 40 species described in this paper are recorded only in Colombia, and seven species are shared with neighboring countries, three with Brazil, one with Venezuela, two with Ecuador, and one with Ecuador and Brazil. Females of three previously known species are also described. An identification key to the species of Triplocania present in Colombia is included. PMID- 29242449 TI - Review of Dissomphalus Ashmead (Hymenoptera, Bethylidae) from Panama, with key to the Central American species. AB - Sixty-four species of Dissomphalus from Panama are recognized, 31 are described and illustrated as new to science: D. abarus sp. nov., D. afestus sp. nov., D. arbeius sp. nov., D. ardonius sp. nov., D. areius sp. nov., D. aretisus sp. nov., D. arteobius sp. nov., D. arteus sp. nov., D. asfartus sp. nov., D. asitius sp. nov., D. azagus sp. nov., D. borus sp. nov., D. citus sp. nov., D. ettus sp. nov., D. geortus sp. nov., D. ibocius sp. nov., D. ibrastus sp. nov., D. ilarius sp. nov., D. iozus sp. nov., D. isortus sp. nov., D. isteus sp. nov., D. racarus sp. nov., D. raziogus sp. nov., D. sartus sp. nov., D. teobus sp. nov., D. teraus sp. nov., D. terbius sp. nov., D. tisinus sp. nov., D. trisus sp. nov., D. urazius sp. nov. and D. ubracus sp. nov.. Eight species are registered for the first time from Panama: D. angulatus Azevedo, D. galeatus Alencar & Azevedo, D. infissus Evans, D. persontaus Redighieri & Azevedo, D. pilus Alencar & Azevedo, D. politus Ashmead, D. pronus Alencar & Azevedo and D. vallensis Evans. Eighteen species had their known distribution broadened in the country: D. bilobatus Azevedo, D. brasiliensis Kieffer, D. cervoides Azevedo, D. coronatus Alencar & Azevedo, D. culteratus Alencar & Azevedo, D. curvifoveatus Azevedo, D. dilatatus Azevedo, D. geniculatus Azevedo, D. gilvipes Evans, D. guttus Azevedo, D. intradentatus Azevedo, D. piscicercus Azevedo, D. plaumanni Evans, D. punctatus (Kieffer), D. rettenmeyeri Evans, D. rufipalpis Kieffer, D. strepsus Azevedo and D. unitus Azevedo. Seven species previously recorded from Panama were not found in the studied material: D. altivolans Evans, D. apertus Kieffer, Alencar & Azevedo, D. declinatus Alencar & Azevedo, D. latus Azevedo, D. ramosus Alencar & Azevedo, D. strabus Azevedo and D. subdeformis Azevedo. A key to species of Dissomphalus from Central America is provided. PMID- 29242450 TI - A taxonomic monograph of the genus Dodomeira Bello & Baviera, a new genus of Peritelini from Sicily (Coleoptera: Curculionidae: Entiminae). AB - The genus Dodomeira Bello & Baviera gen. n. of the tribe Peritelini Lacordaire (1863) (Curculionidae: Entiminae) which includes 39 species is described. Seven species are transferred from Pseudomeira Stierlin, 1881: Dodomeira confusa (Pierotti, 2012) comb. n., Dodomeira exigua (Stierlin, 1861) comb. n., Dodomeira ficuzzensis (Bello & Baviera, 2011) comb. n., Dodomeira himerensis (Bello & Baviera, 2011) comb. n., Dodomeira petrensis (Bello & Baviera, 2011) comb. n., Dodomeira pfisteri (Stierlin, 1864) comb. n., Dodomeira trinacriae (Bello & Baviera, 2011) comb. n.. Thirty-two species are new for science and here described: Dodomeira adrianae Bello & Baviera sp. n., Dodomeira alta Bello & Baviera sp. n., Dodomeira angelae Bello & Baviera sp. n., Dodomeira asinelliensis Bello & Baviera sp. n., Dodomeira belicensis Bello & Baviera sp. n., Dodomeira bertoni Bello & Baviera sp. n., Dodomeira calatina Bello & Baviera sp. n., Dodomeira caoduroi Bello & Baviera sp. n. n., Dodomeira elima Bello & Baviera sp. n., Dodomeira enzoi Bello & Baviera sp. n., Dodomeira fossor Bello & Baviera sp. n., Dodomeira forbicionii Bello & Baviera sp. n., Dodomeira genistae Bello & Baviera sp. n., Dodomeira giustoi Bello & Baviera sp. n., Dodomeira hiemalis Bello & Baviera sp. n., Dodomeira ibleiensis Bello & Baviera sp. n., Dodomeira illuminatae Bello & Baviera sp. n., Dodomeira juliae Bello & Baviera sp. n., Dodomeira laliaensis Bello & Baviera sp. n., Dodomeira magrinii Bello & Baviera sp. n., Dodomeira montivaga Bello & Baviera sp. n., Dodomeira margheritae Bello & Baviera sp. n., Dodomeira maritimaensis Bello & Baviera sp. n., Dodomeira nobilis Bello & Baviera sp. n., Dodomeira paladinii Bello & Baviera sp. n., Dodomeira sabellai Bello & Baviera sp. n., Dodomeira saccoi Bello & Baviera sp. n., Dodomeira sicana Bello & Baviera sp. n., Dodomeira sicelidis Bello & Baviera sp. n., Dodomeira siderea Bello & Baviera sp. n., Dodomeira silvanae Bello & Baviera sp. n., Dodomeira zingara Bello & Baviera sp. n.. In addition, according to morphological characters, eight informal groups of species are established (the number of species ascribed to the group is in brackets): Dodomeira adrianae species group (13), Dodomeira caoduroi species group (2), Dodomeira exigua species group (5), Dodomeira ficuzzensis species group (2), Dodomeira maritimaensis species group (1), Dodomeira petrensis species group (2), Dodomeira pfisteri species group (13), Dodomeira saccoi species group (1). We present a key for the identification of the new genus among Palaearctic Peritelini, one for single species groups and an other for each species. A checklist of all the species currently known of Dodomeira gen. n. and Pseudomeira Stierlin (1881), with distribution maps and data on ecology and phenology of all the species of Dodomeira gen. n. are also provided. PMID- 29242452 TI - Taxonomic and morphological revision of butterfly rays of the Gymnura micrura (Bloch & Schneider 1801) species complex, with the description of two new species (Myliobatiformes: Gymnuridae). AB - An extensive taxonomic revision of Gymnura micrura based on external and internal morphology, and considering specimens from its entire geographical distribution in the Atlantic Ocean, is presented. Gymnura micrura is redescribed and a neotype is designated; its distributional range is limited to the Southwestern Atlantic. Two new species of butterfly rays are described: Gymnura lessae, sp. nov., occurring in the North and Central Western Atlantic, and Gymnura sereti, sp. nov., found in the Eastern Central Atlantic. The three species are morphologically very similar (with G. micrura most similar to G. lessae, sp. nov.) and cannot be distinguished based on the primary diagnostic characters typically utilized for butterfly rays. The dorsal color, smaller size and eventual presence of a dorsal fin in some males may be helpful to distinguish G. micrura, whereas the size and morphology of the clasper are the main external characters separating G. sereti, sp. nov., from the other two species, although the shape of disc (especially among adult males) and contour of the lower lip are also helpful. Despite the skeleton being conservative among the species, we found consistent variations that support the validity of the new species described. Due to similarity in external morphology these internal characters were fundamental to discriminate the new species. The scapulocoracoid was an important diagnostic skeletal structure, exhibiting a series of variations that separated the three species. Variations in the synarcual, outline of the dorsal cranial fontanelle, number and shape of mesopterygia, and small differences in the mandibular arches and pelvic girdle were useful to diagnose G. sereti, sp. nov. The contour of the hyomandibula was an important diagnostic character distinguishing G. lessae, sp. nov., from the other two species. Meristic data were also useful, with G. sereti, sp. nov., presenting a lower number of radials in the second element of the mesopterygium and a higher number of diplospondylous vertebrae. In contrast, G. lessae, sp. nov., presented a higher number of pectoral-fin radials. Subtle, but consistent differences, were also found in the design of the ventral lateral-line system. A Canonical Discriminant Analysis provides strong statistical support for the validity of the new species, significantly distinguishing the three species groupings (p < 0.00001). External morphology, ventral lateral-line system and skeleton are described and illustrated for all three valid species. PMID- 29242451 TI - World Catalogue of the Druid Flies (Diptera: Schizophora: Clusiidae). AB - Family-, genus- and species-level groups in the family Clusiidae (Diptera: Schizophora) are catalogued, providing reference to occurrences of these taxa in the literature, including all those relevant to nomenclature. Full synonymies are provided, including generic combinations for species, and the collection locality, depository and sex of primary type specimens. Published species distributions are provided, noting country and biogeographic region; specimen data representing new country records for species are listed. The Clusiidae are known from 636 species in 14 genera and three subfamilies, with many additional species expected. Nearly half of all described species are Sobarocephala, with 269 species, followed by the clusiodine genera Heteromeringia (86 species), Allometopon (68), Hendelia (53 species), Czernyola (50 species) and Clusiodes (31 species); the remaining eight genera (seven extant, one fossil) are smaller, consisting of 1 to 16 species. Two other fossil genera, Acartophthalmites Hennig and Xenanthomyza Hennig, are also treated here, but are unlikely to belong to the family. Taxa formerly considered Clusiidae are listed. Tranomeringia scutellata Sasakawa is transferred to Heteromeringia, n. comb. Czernyola is maintained as the replacement name for Craspedochaeta, following Bezzi (1907), McAlpine (1971) and Lonsdale, et al. (2010), resulting in the following new combinations: Czernyola amazonensis (Lonsdale & Marshall) n. comb.; C. apsilutea (Lonsdale & Marshall) n. comb.; C. argoniae (Lonsdale & Marshall) n. comb.; C. biloba (Lonsdale & Marshall) n. comb.; C. brunneivibrissa (Lonsdale & Marshall) n. comb.; C. candida (Lonsdale & Marshall) n. comb.; C. chauliodon (Lonsdale & Marshall) n. comb.; C. chela (Lonsdale & Marshall) n. comb.; C. concinna (Williston) n. comb.; C. feminea (Lonsdale & Marshall) n. comb.; C. loreto (Lonsdale & Marshall) n. comb.; C. maai (Sasakawa) n. comb.; C. melanosoma (Lonsdale & Marshall) n. comb.; C. novaeguinea (Soos) n. comb.; C. pacaraima (Lonsdale & Marshall) n. comb.; C. parva (Sasakawa) n. comb.; C. phaios (Lonsdale & Marshall) n. comb.; C. pilosa (Sasakawa) n. comb.; C. pleuralis (Williston) n. comb.; C. pollostos (Lonsdale & Marshall) n. comb.; C. protomis (Lonsdale & Marshall) n. comb.; C. quinquespinula (Sasakawa) n. comb.; C. sasakawai (Lonsdale & Marshall) n. comb.; C. spinulifera (Sasakawa) n. comb.; C. unguicauda (Sasakawa) n. comb.; C. varicolor (Sueyoshi) n. comb.; C. vietnamensis (Sasakawa) n. comb.; C. weemsi (Lonsdale & Marshall) n. comb.; C. xanthonotum (Lonsdale & Marshall) n. comb.; C. xanthopleura (Sasakawa) n. comb.; C. zongo (Lonsdale & Marshall) n. comb. PMID- 29242453 TI - Revision of the Alycaeidae of China, Laos and Vietnam (Gastropoda: Cyclophoroidea) I: The genera Dicharax and Metalycaeus. AB - This is the first part of the revision of the Alycaeidae of China, Laos and Vietnam. Here we revise the species hitherto classified in Chamalycaeus Mollendorff, 1897 (genera Dicharax and Metalycaeus in this study). We show that no Chamalycaeus live in the region, and the alycaeid species of the investigated region can be classified into five genera: Alycaeus Baird, 1850, Dicharax Kobelt & Mollendorff, 1900, Dioryx Benson, 1859, Metalycaeus Pilsbry, 1900 and Pincerna Preston, 1907. We propose Dioryx dautzenbergi Pall-Gergely nom. nov. as a replacement name for Alycaeus (Dioryx) major Bavay & Dautzenberg, 1900, non Alycaeus (Dioryx) granum var. major Godwin-Austen, 1893. Alycaeus anceyi Mabille, 1887, A. eydouxi Venmans, 1956, A. mouhoti L. Pfeiffer, 1862, A. rolfbrandti Maassen, 2006 and A. vanbuensis Bavay & Dautzenberg, 1900 are retained in Alycaeus. Alycaeus costulosa Bavay & Dautzenberg, 1912 and A. maolanensis Luo, Zhang & Zhuo 2009 were transferred to Pincerna. We examined newly collected specimens and the type specimens of all species with the exception of the following: A. elevatus Heude, 1886, A. expansus Heude, 1890, A. neglectus Heude, 1885, Chamalycaeus libonensis Chen, Li & Luo 2003, C. panshiensis Chen, 1989, C. tangmaiensis Chen & Zhang, 2001, C. zayuensis Zhang, Chen & Zhou, 2008. Fifteen new species are described as follows: Dicharax (?) abdoui Pall-Gergely, n. sp., Dicharax (?) alticola Pall-Gergely & Hunyadi n. sp., Dicharax (?) ellipticus Pall Gergely n. sp., Dicharax (?) immaculatus Pall-Gergely n. sp., Dicharax bison Pall Gergely & Hunyadi n. sp., Dicharax draco Pall-Gergely & Hunyadi n. sp., Dicharax imitator Pall-Gergely & Hunyadi n. sp., Dicharax microcostatus Pall-Gergely n. sp., Dicharax micropolitus Pall-Gergely & Hunyadi n. sp., Dicharax robustus Pall Gergely & Hunyadi, n. sp., Metalycaeus (?) awalycaeoides Pall-Gergely & Hunyadi n. sp., Metalycaeus (?) ibex Pall-Gergely & Hunyadi n. sp., Metalycaeus laosensis Pall-Gergely n. sp., Metalycaeus oharai Pall-Gergely & Hunyadi n. sp., Metalycaeus (?) okuboi Pall-Gergely & Hunyadi, n. sp. A total of twelve names are synonymised with valid species. In this revision we payed special attention to conchological characters hitherto neglected, such as the fine sculpture of the embryonic whorls and the fine structure of the microtunnels along the breathing tube. We described the radula and penis morphology of five Dicharax species. PMID- 29242454 TI - A contribution to the knowledge of the subfamily Panagaeinae Hope, 1838 from Africa. Part 3. Revision of the Craspedophorus strachani and C. brevicollis groups (Coleoptera: Carabidae). AB - Revised are Afrotropical species of the Craspedophorus strachani and C. brevicollis groups. New taxa are C. dicranulothorax n. sp. (Cameroon), C. lemariei n. sp. (Gabon), C. phenacoides n. sp. (Cameroon), C. ruficroides n. sp. (Guinea), C. cuneatus rotundatus n. ssp. (Cameroon, central Africa), C. ruficroides thomsoni n. ssp. (Cameroon, central Africa, Gabon), C. strachani bamendanus n. ssp. (Cameroon), C. tetrastigma morettoi n. ssp. (west Africa) and C. brevicollis beninensis n. ssp. (Benin). C. ruficrus (Laferte-Senectere, 1851) and C. gabonicus (Thomson, 1858) are considered nomina dubia, because their original descriptions do not provide enough information to allow linking the names to any known specimens. To correct the situation, the authorship of C. ruficrus is ascribed to the first reviser, Chaudoir (1861) [as a valid name (sp. resurr.)], who designated a lectotype and provided an adequate redescription; the invalid name C. gabonicus (Thomson) sensu Chaudoir (1861) is synonymized with C. muata (Harold, 1883). The status of the following species is changed to subspecies: C. grossus (Hope, 1842) is demoted to ssp. of C. strachani (Hope, 1842), C. paromius Basilewsky, 1987 is demoted to ssp. of C. cuneatus (Alluaud, 1915) and C. milzi Duvivier, 1891 is demoted to ssp. of C. tetrastigma (Laferte). C. strachani depressus Burgeon, 1930 is synonymized with C. tetrastigma milzi Duvivier, 1891 and C. chevalieri jokoanus Basilewsky, 1987 is synonymized with C. chevalieri (Alluaud, 1915). C. strachani and C. brevicollis groups sensu Chaudoir 1879 are redefined. C. latemaculatus Alluaud, 1930 is removed from C. reflexus group Hackel 2016 and transferred to C. strachani group nov. PMID- 29242455 TI - A review of all Recent species in the genus Novocrania (Craniata, Brachiopoda). AB - The Recent species in the craniid genus Novocrania are reviewed, based on the examination of actual specimens wherever possible, especially for species named from one or a few specimens. The fourteen Recent species currently in the literature are reduced to eight; five species names are synonymized. One species name was given to a specimen that is not a craniid. The wide morphological ranges of the remaining Novocrania species are described and figured and the extended geographical ranges illustrated. Diagnoses of the remaining species are provided. The long-standing debate whether Novocrania anomala and N. turbinata are separate species or synonyms is resolved; they are separate species. New molecular analyses and a relative time-tree are provided by Cohen et al. (Appendix 1), the time-tree is calibrated herein and the results of Cohen et al. (2014; Appendix 1) and the time tree are discussed. The likelihood of craniid long-distance migration based on their geographical ranges is discussed. PMID- 29242456 TI - Taxonomic status of Parotia berlepschi Kleinschmidt, 1897 based on analysis of external appearance, voice and behavior (Aves: Paradisaeidae). AB - Described from trade-skins of unknown origins, Parotia berlepschi Kleinschmidt, 1897 was the subject of a longstanding ornithological mystery that remained unresolved for well over a century. With few specimens and no known wild population, most taxonomic assessments over the last century have treated P. berlepschi as a subspecies of Parotia carolae Meyer, 1894. Following discovery of its geographical home in 2005, most authorities returned to giving P. berlepschi full species status. However, evidence supporting the delineation of P. berlepschi from P. carolae has not yet been fully articulated in the literature. Here, we assess phenotypic differentiation and the taxonomic status of P. berlepschi relative to P. carolae based on specimens and recordings of wild birds. With regard to external appearance and voice, which are important intersexual signals among polygynous birds-of-paradise, our analysis confirms that P. berlepschi is well-differentiated from P. carolae and should be treated as specifically distinct. Evidence for differentiation in courtship behavior is inconclusive and requires further study. PMID- 29242457 TI - The complete mitochondrial genome of the Korean endemic millipede Anaulaciulus koreanus (Verhoeff, 1937), with notes on the gene arrangement of millipede orders. AB - The millipede Anaulaciulus koreanus (Verhoeff, 1937), belonging to the family Julidae, is an endemic species of the Korean fauna. In this study, we sequence and annotate the mitochondrial genome of A. koreanus. The complete mitochondrial genome of this species is 14,916 bp in length and contains 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes (16S and 12S rRNA), and a large non-coding region. The genome has a very high A+T content (71.1%), less than of the species Brachycybe lecontii Wood, 1864 (order Platydesmida; 76.6%) and Sphaerotheriidae sp. (order Sphaerotheriida; 71.2%). In comparison with the mitochondrial gene arrangement of eight other millipede species, the whole mitochondrial gene arrangement of A. koreanus is most similar to the nemasomatid species, Antrokoreana gracilipes Verhoeff, 1938, but differs from those of the other diplopod orders. The absence of tRNACys between the ND2 and COI regions is unique to the order Polydesmida, whereas the translocation of tRNATyr to between ND2 and COI is exclusive to the Sphaerotheriida. It is also shown that the translocation of tRNAThr between ND4L and ND1 may be a synapomorphy to support a close relationship of two orders Spirobolida and Spirostreptida. PMID- 29242458 TI - On four new species of the jumping spider genus Mago O. Pickard-Cambridge, 1882 from South America (Araneae: Salticidae). AB - Four new species of Mago O. Pickard-Cambridge, 1882 are described. Mago furcatus sp. nov. and Mago mimicus sp. nov. are described from Ecuador (Orellana and Napo provinces, respectively), both based only on the male holotypes. Both sexes of Mago pardo sp. nov. and the male of Mago apophysis sp. nov. are also described from the state of Para, Brazil. A map with records of these species is given. PMID- 29242459 TI - New species and new records of Sorolopha Lower, 1901 from China (Lepidoptera, Tortricidae, Olethreutini). AB - Six species of Sorolopha Lower, 1901 are recorded from China. Among them, S. nanlingica, sp. nov., S. latiuscula, sp. nov., and S. singularis, sp. nov., are described as new. Sorolopha brunnorbis Razowski, 2009, S. cyclotoma Lower, 1901, and S. euochropa Diakonoff, 1973 are recorded for the first time from China. Photographs of the adults and genitalia of the new species are provided. PMID- 29242461 TI - Cydninae (Hemiptera, Heteroptera, Cydnidae) in Brazil: updated checklist, new records, and description of Tominotus ondulatus sp. nov. AB - Cydninae is the largest subfamily among burrower bugs all around the world and for Brazil the genera Cyrtomenus, Dallasiellus, Ectinopus, Melanaethus, Onalips, Pangaeus, Prolobodes and Tominotus were reported with a total of 39 species, so far. Basing on the material of nine entomological collections, we updated the list to 47 species including new records and a new species, Tominotus ondulatus sp. nov. described from Restinga, Rio Grande do Sul. Distribution maps and photos of dorsal habits for several species are also provided. PMID- 29242462 TI - The Neotropical sharpshooter genus Ruppeliana Young (Insecta: Hemiptera: Cicadellidae): four new species, key to males, and new synonyms. AB - Four new Brazilian species of Ruppeliana are described and illustrated: R. barbarensis sp. nov., R. grossii sp. nov., R. longiphallus sp. nov., and R. serrana sp. nov., the first from Minas Gerais State and the other three from Rio de Janeiro State. The new taxa can be easily distinguished from other Ruppeliana species by their color pattern and male genitalia morphology. Ruppeliana coronulifera (Stal, 1862) and R. taschenbergi (Berg, 1899) are synonymized with R. signiceps (Stal, 1862). Additionally, a diagnosis of the genus and a key to species are provided. PMID- 29242463 TI - New data on the genus Domene (Coleoptera: Staphylinidae: Paederinae) of mainland China. AB - Material of the genus Domene Fauvel, 1873 from the Chinese provinces Heilongjiang, Anhui, Zhejiang, Fujian, Guizhou, Sichuan, Shaanxi, Yunnan, Guangdong and Guangxi was examined. Twelve species were identified, seven of them described previously, and five are newly described: D. aqiang Peng and Li, sp. n. (Guangdong: Nanling); D. jiangi Peng and Li, sp. n. (Fujian: Tanshan Park); D. jini Peng and Li, sp. n. (Guangxi: Jiuwan Shan); D. nanlingensis Peng and Li, sp. n. (Guangdong: Nanling); D. tui Peng and Li, sp. n. (Guizhou: Sanchahe). The genus is now represented in mainland China by 21 species. A key to the Domene species of mainland China is provided. PMID- 29242464 TI - Data on the scale insect (Hemiptera: Coccomorpha) fauna of Greece, with description of two new species. AB - Surveys of the scale insect (Hemiptera: Coccomorpha) fauna of Greece were carried out in 2013 and 2014. Altogether 93 scale insect species were collected, belonging to 11 families. Thirty-eight species (41%) proved to be new to the Greek fauna, including two species new to science (Anophococcus hellenicus Kaydan & Szita sp. n. (Acanthococcidae) and Iberococcus attikus Szita & Fetyko sp. n. (Pseudococcidae)), and two introduced invasive species (Phenacoccus graminicola Leonardi and Pseudococcus comstocki (Kuwana), both Pseudococcidae). The rest of the species seem to be native to the Greek fauna. The total number of scale insect species recorded from Greece is increased to 253. PMID- 29242465 TI - A new slipper lobster of the genus Petrarctus Holthuis, 2002 (Crustacea, Decapoda, Scyllaridae) from Southwest coast of India. AB - A new species of slipper lobster of the genus Petrarctus Holthuis, 2002 was discovered from southwestern India during a survey of deep sea crustaceans. The new species closely resembles P. veliger Holthuis, 2002 from the Andaman Sea and western Pacific but differs mainly in the color marking on abdominal somite I, having a relatively lower cardiac tooth but with better developed tubercles on the abdomen, as well as a differently shaped anterior part of the thoracic sternum. Molecular genetic analysis also confirms the distinct taxonomic status of the new species. To fix the identity of the type species of the genus, a neotype of P. rugosus (H. Milne Edwards, 1837) was selected from a recently collected Indian specimen with color and genetic information. PMID- 29242466 TI - Two new species of the genus Plusiodonta Guenee, 1852 from Southeast Asia (Lepidoptera, Erebidae: Calpinae). AB - Two new species of the genus Plusiodonta Guenee, 1852, Plusiodonta pasi sp. n. and Plusiodonta stumpfi sp. n. are described from Thailand and Philippines. The distribution of Plusiodonta calcaurea Holloway, 2005 in Southeast Asia is clarified. The adult and genitalia of referred species as well as male and female of Plusiodonta coenolota (Kollar, 1844) are illustrated. The checklist the genus Plusiodonta over the World is presented. PMID- 29242467 TI - First record of Psilacrum Becker 1912 (Chloropidae, Diptera) from Brazil, with the description of a new species. AB - Psilacrum Becker was recorded from the Neotropical Region by Wheeler (2010) based on Oscinoides annulicrus (Duda, 1933) described from Costa Rica with a further five to six species from the Region (Wheeler, 2010). Here we describe a new species from Brazil. PMID- 29242468 TI - A new species of small and highly abbreviated caecilian (Gymnophiona: Indotyphlidae) from the Seychelles island of Praslin, and a recharacterization of Hypogeophis brevis Boulenger, 1911. AB - A new species of indotyphlid caecilian amphibian, Hypogeophis pti sp. nov., is described based on a series of specimens from the Seychelles island of Praslin. The type series was collected in 2013 and 2014, and a referred specimen previously identified as H. brevis Boulenger, 1911 was collected from an unspecified Seychelles locality in 1957. The new species most closely resembles the Seychelles endemic Hypogeophis brevis in being short (maximum known total length in life ca. 120 mm) and long snouted, but differs by having a less anteriorly positioned tentacular aperture and fewer primary annuli and vertebrae. In having only 67-69 vertebrae, H. pti sp. nov. is the most abbreviated extant species of caecilian reported to date. PMID- 29242469 TI - A new diploid species belonging to the Odontophrynus americanus species group (Anura: Odontophrynidae) from the Espinhaco range, Brazil. AB - The Odontophrynus americanus species group is a complex of diploid and tetraploid species hardly distinguished by morphological characters. It currently consists of three allopatric diploid species (i.e. O. cordobae, O. lavillai, and O. maisuma) and one widely distributed tetraploid species (i.e. O. americanus). We herein describe a new diploid allopatric species from campo rupestre, a typical phytophysiognomy of the Espinhaco Range, Brazil. The new species is distinguishable by the diploid complement of 2n = 2x = 22 chromosomes, small to medium-sized dorsal dark brown blotches with low contrast on a light brown background, light mid-dorsal stripe absent or greatly interrupted in most specimens with yellowish coloration as the background of both head and flanks of the body, advertisement call with dominant frequency of 840-1080 Hz, pulse rate of 90.5-106.7 pulses/s, and small tadpoles (TL = 24.30-35.69 mm). PMID- 29242470 TI - Gastropods from the Late Jurassic-Early Cretaceous seep deposits in Spitsbergen, Svalbard. AB - Eleven gastropod species from seven latest Jurassic-earliest Cretaceous hydrocarbon seep deposits from central Spitsbergen, Svalbard are described and illustrated. Six new species and one new genus are introduced. Sassenfjordia gen. nov. is tentatively classified as a naticoid and is characterized by a naticiform gross teleoconch morphology and a large protoconch ornamented with spiral ribs, similar to those present in the subfamily Sininae. The patellogastropod ?Pectinodonta borealis sp. nov. represents the oldest occurrence of pectinodontid limpets in chemosynthesis-based associations. The colloniid Hikidea svalbardensis sp. nov. is the oldest confirmed occurrence of this genus so far. The eucyclid Eucycloidea bitneri sp. nov. is the second report of an occurrence of this genus at hydrocarbon seeps (both of which come from the Paleo-Barents Sea). Abyssomelania sp. is the third known, and the oldest occurrence of this genus. Hudlestoniella hammeri sp. nov. represents another occurrence of this genus at seeps in the Paleo-Barents Sea; its current higher-rank assignment is reviewed herein. It may belong either to the rissoids, as previously suggested, or to the abyssochrysoids (or zygopleurids). A fossil identified as Cretadmete sp. is here classified in the Purpurinidae, a family of stem neogastropods or tonnoideans. The heterobranch Hyalogyrina knorringfjelletensis sp. nov. is the oldest occurrence of hyalogyrinids in chemosynthesis-based associations. Several oldest occurrences of seep taxa in moderately shallow-water seeps in Spitsbergen suggest that the previously questioned onshore-offshore hypothesis of seep and vent colonization should be carefully re-investigated. PMID- 29242471 TI - The spider family Dysderidae in the Balearic Islands. AB - The spider family Dysderidae in the Balearic Islands counts 6 species, which have all been revised. Dysdera arnedoi Lissner n. sp. and Parachtes riberai Bosmans n. sp. are newly described species from Majorca, where they seem to be confined. A neotype is designated for Dysdera balearica Thorell, 1873 and D. mordax L. Koch, 1882 is considered a junior synonym of the former. Dysdera lata Reuss, 1834 is cited for the first time in Majorca. Dysdera crocata C. L. Koch, 1838 and Harpactea dufouri (Thorell, 1873) occur on all the main Balearic Islands. Harpactea corticalis (Simon, 1882) and H. hombergi (Scopoli, 1763) were misidentified in the past and are deleted from the Balearic Islands list. PMID- 29242472 TI - Photophore counts in the deep-sea commercial shrimp Aristeus alcocki Ramadan, 1938 (Crustacea: Decapoda: Aristeidae), with a revised key to the Indo-West Pacific species of the genus. AB - The availability of abundant fresh material of Aristeus alcocki Ramadan, 1938 from India allowed the evaluation of the variation in the numbers of photophores on the pereiopods in this species, as well as other diagnostic characters for species discrimination. Although the pereiopodal photophore counts in A. alcocki largely overlap with those of A. semidentatus Bate, 1888, it is found that A. alcocki is unique in the Indo-West Pacific species of the genus by the lower end of the cervical carina considerably farther away from the branchiostegal carina. Molecular genetic analysis confirmed the distinct taxonomic status of the six currently known species in this genus from the Indo-West Pacific and a revised key is provided for distinguishing them. PMID- 29242473 TI - Morphological variation of the Long-tailed Reed Finch Donacospiza albifrons (Vieillot, 1817) (Aves: Thraupidae). AB - The Long-tailed Reed Finch Donacospiza albifrons of south-central South America is patchily distributed in a variety of open habitats, usually near water. I present a detailed study of morphological variation based on 141 specimens, describing its plumage sequence and presenting notes on its molt and breeding. The Long-tailed Reed Finch shows no sexual dichromatism, but males average longer winged than females. The species shows three distinct age-related plumages, which are redescribed here. It also shows marked individual variation in plumage and size, also showing marked plumage variation due to feather wear. Geographic variation is also marked, with birds from dry grasslands in northern highlands typically being larger, paler, and less streaked than birds from wet grasslands in southern lowlands, but there at some exceptions to this geographic pattern. I conclude that there is no solid basis for splitting the species into two or more taxa, and suggest considering the Long-tailed Reed Finch as a single, highly polymorphic species. PMID- 29242474 TI - Six new species and new records of the spider genus Chrosiothes from Brazil with the description of the female of Chrosiothes venturosus Marques & Buckup, 1997 (Araneae, Theridiidae, Spintharinae). AB - The spider genus Chrosiothes Simon, 1894 currently comprises 21 described species. Spiders of this genus are mainly known from the Neotropical Region, but are poorly studied in Brazil. In this paper six new species of Chrosiothes are described from Brazil: Chrosiothes diabolicus new species; Chrosiothes carajaensis new species; Chrosiothes cicuta new species; Chrosiothes murici new species; Chrosiothes decorus new species and Chrosiothes una new species. The female of Chrosiothes venturosus Marques & Buckup, 1997 is described and illustrated for the first time. Additionally, new records from Brazil are provided for C. perfidus Marques & Buckup, 1997 and C. niteroi Levi, 1964. PMID- 29242475 TI - New species and new records of ground spiders (Araneae: Gnaphosidae) from Cyprus. AB - New taxonomic data on the ground spiders of the family Gnaphosidae from the island of Cyprus are presented. Three species are proposed as new to science (Drassyllus cyprius sp. n., Setaphis mccowani sp. n., Zelotes limnatis sp. n.). The male of Synaphosus shirin Ovtsharenko, Levy & Platnick, 1994 and the female of Zelotes zekharya Levy, 2009 are described for the first time. The transfer of Zelotes helvolus (O.P. Cambridge, 1872) and Z. helvoloides Levy, 1998 (the latter not recorded in Cyprus) to Cryptodrassus is proposed. The mismatching of male and female of C. helvoloides is discussed, and the female originally described as C. helvoloides is transferred to C. helvolus. Micaria pallipes (Lucas, 1846) is here recorded and the synonymy with Castanilla marchesii Caporiacco, 1936 is rejected, while the paralectotype of Castanilla marchesii is here assigned to Leptodrassex algericus Dalmas, 1919. Finally a male Poecilochroa still not attributed to a known or new species is described. PMID- 29242476 TI - A new species of the catfish genus Cordylancistrus (Siluriformes, Loricariidae) from the Sierra Nevada de Santa Marta, Colombia. AB - As a part of an assessment of loricariid catfishes inhabiting the Andes of Colombia, specimens belonging to an interesting new species were identified. The new species is described herein, and it is tentatively included in the genus Cordylancistrus. The new species can be easily distinguished among its congeners by the presence of a unique diagnostic character: a fleshy keel or excrescence, black or dark brown, over the posterior tip of supraoccipital. Specimens of the new species were captured in rivers of the Sierra Nevada de Santa Marta and the Sierra de Perija that drain to the Magdalena River Basin and Caribbean Sea. The occurrence of one species of Cordylancistrus in the Sierra Nevada de Santa Marta could have interesting biogeographic implications for hypotheses related to the geological history of northwestern corner of South America or to the dispersal or vicariance models used to explain biogeographical patterns of related species in Colombia. PMID- 29242477 TI - Two new species of freshwater Macrostomum (Rhabditophora: Macrostomorpha) found in China. AB - There is limited information about the ecology of freshwater flatworms in China, in particular, the members of the genus Macrostomum. Surveying freshwater bodies to explore the species diversity is the first step to obtain more ecological information about those flatworms. We hereby report the discovery of two new species of freshwater flatworms in Macrostomum. Macrostomum chongqingensis Lin and Wang, n. sp. was discovered from stones in the shallow water of Jialing River bed near Chongqing. Macrostomum zhaoqingensis Lin and Wang, n. sp. was discovered in the water of Xing Lake near Zhaoqing city, Guangdong province. Xing Lake is a part of an ancient river that has changed its course. For each species, we describe the morphology of the whole specimen, penis stylet, and sperm, as well as other internal anatomical features based on serial sections. We determined 18S, 28S rDNA and COI sequences from the two new species, and performed a phylogenetic analysis to confirm the status and evolutionary position of the two new species. We discuss the significance of our discoveries in terms of flatworm biodiversity studies in China and the Oriental realm. PMID- 29242478 TI - Taxonomic contribution to the genus Sphaerosyllis (Annelida: Syllidae: Exogoninae) in the Black Sea. AB - During a study of fauna associated with a shallow-water Zostera (Zosterella) noltei bed from the southern part of the Romanian Black Sea coast, among the identified material collected in 2015, a syllid polychaete belonging to the subfamily Exogoninae, Sphaerosyllis taylori Perkins, 1981, represents a new record for the Black Sea. Re-examination of available specimens previously identified as Sphaerosyllis bulbosa Southern, 1914 revealed that they belong to an unknown species, described herein as Sphaerosyllis pontica sp. nov. The new species is characterized by the median antenna inserted more posteriorly than the lateral antennae, dorsal cirri with bulbous bases and very short tips, shorter than the parapodial lobes, dorsal cirri absent on chaetiger 2, parapodial glands with fibrillar material from chaetiger 4 onwards, compound chaetae with short blades and smooth shafts, anterior parapodia with two aciculae each, one straight and one with bent tip. Descriptions of both species are provided together with a key to all Sphaerosyllis species known from the Black Sea. PMID- 29242479 TI - Two new species of the genus Leeonychiurus Sun & Arbea, 2014 (Collembola: Onychiuridae) from Korea. AB - Two new species of the genus Leeonychiurus Sun & Arbea, 2014 from South Korea, i.e. L. koreanus sp. nov. and L. analis sp. nov., are described and illustrated. The former differs from other known congeners by having only 2 distinct pseudocelli on each side of Abd. III (three in all other species). The second species, L. analis sp. nov., being rather similar to L. koreanus sp. nov., can easily be distinguished due to the presence of dorsal pso on Th. I (absent in L. koreanus sp. nov.) and three dorsal pso on Abd. III (only two pso in L. koreanus sp. nov.), chaetotaxy of anal valves is also specific, characterized by the presence of chaetae a1 and the absence of chaeta c0 on upper anal valve. An identification key to all known species of the genus Leeonychiurus species is also provided. PMID- 29242480 TI - Cleonini (Coleoptera: Curculionidae: Lixinae) are monophyletic and flightless: tribe overview, rampant adult homoplasy and illustrated global diversity. AB - We summarize knowledge of the weevil tribe Cleonini worldwide, including its monophyly, relationships, distribution, biology, immature stages, economic significance and paleontology. We score adult morphological characters for 79 of a total of 96 extant genus-group Cleonini taxa considered valid to date. The resulting matrix contains 121 parsimoniously informative characters scored for 145 ingroup (Cleonini) and 29 outgroup terminals. Maximum Parsimony (MP) and Bayesian Inference (BI) analyses consistently recover monophyletic Lixinae and Cleonini. Relationships within the latter remain unresolved with either 47 (BI) or 37 (MP) branches radiating from the tribe's most recent common ancestor. Most of the speciose genera of Cleonini emerge as monophyletic in both BI and MP analyses (generic names followed by the number of terminals, then by BI posterior probability / MP bootstrap): Adosomus (5, 94/77), Asproparthenis (6, 99/98), Chromonotus (6, 98/85), Cleonis (3, 64/76), Coniocleonus (10, 95/41), Conorhynchus (5, 95/51), Cyphoclenus (4, 65/76), Maximus (4, 84/68), Mecaspis (4, 95/91), Scaphomorphus (4, 90/84), Temnorhinus (8, 99/62) and Xanthochelus (6, 84/71). The genera Pseudocleonus (6, -/26) and Stephanocleonus (22, -/23) are not recovered in BI and weakly supported in MP. No genera are here added to, or removed from, Cleonini. We suggest that adult morphology of Cleonini was subject to widespread homoplasy obscuring the phylogenetic signal of morphological characters. Unlike the rest of Lixinae, all extant Cleonini are hypothesised to be flightless, even though often being macropterous. All 145 ingroup terminals are illustrated in three standard views; images of the type species of 15 of the 17 genus-group taxa that are not represented in our analysis are provided. PMID- 29242481 TI - Discovery of another new species of Charadrahyla (Anura, Hylidae) from the cloud forest of northern Oaxaca, Mexico. AB - Charadrahyla esperancensis, a new species of tree frog, is described from the cloud forest of Sierra d Juarez on the northern slopes of Oaxaca. This species is sympatric with C. nephila and is distinguished by the presence of a protuding snout with a distinctive downward slope posterior to the nostril in lateral view, with an evident rostral keel, and the flanks and anterior and posterior surfaces of limbs with yellow spots. With the discovery of this new species, the species number of the genus increases to seven and adds another species of Charadrahyla for the assemblage of anurans from northern Oaxaca. This is the first instance of sympatry of species in the genus Charadrahyla. Additionally, we provide a key to the species of the genus. PMID- 29242482 TI - The larva of Agapetus episkopi Malicky 1972 (Trichoptera: Glossosomatidae), including a key to the larvae of Glossosomatidae of the Hellenic western Balkan region. AB - In this paper, we present a description of the previously unknown larva of Agapetus episkopi Malicky 1972 (Trichoptera: Glossosomatidae). Information on the morphology of the larvae is given and the most important diagnostic features are photographed. As a species of subfamily Agapetinae Martynov 1913, A. episkopi larvae belong to the group of species with sclerites present on the pro-, meso-, and metanota. Because lateral setae on abdominal segment III are lacking and the larval case lacks a sand collar at its base, A. episkopi keys with Agapetus laniger Pictet 1834 and Agapetus delicatulus McLachlan 1884. Within this trio, each of the latter two species can be easily separated from A. episkopi by the coloration pattern of their frontoclypeus, where a pale central area is present, and by the presence of only one lateral seta on each side of abdominal segment I. With respect to distribution, A. episkopi has been recorded from European Ecoregion 6 (= Hellenic western Balkan region) and Asia Minor. In addition, ecological characteristics are briefly discussed, and a key to the known glossosomatid larvae of European Ecoregion 6 is included. PMID- 29242483 TI - A new species and a new form of leafhopper from the Great Smoky Mountains National Park (Hemiptera: Cicadellidae: Typhlocybinae). AB - A new species Erasmoneura tricuspidata sp.n. and a new morphological variant of Erythridula stolata McAtee are described from the Great Smoky Mountains National Park. PMID- 29242484 TI - A new species of the genus Neobubastes Blackburn, 1892 from Western Australia (Coleoptera: Buprestidae: Buprestinae: Pterobothrini). AB - A description of Neobubastes obscura sp. nov. from Western Australia is provided. The new species is illustrated and compared with other species of the genus. A key to and images of all species of the genus Neobubastes Blackburn, 1892 are provided. PMID- 29242485 TI - Pterostichus neilgaimani sp. nov., a new species of ground beetles (Coleoptera: Carabidae) from relict sacred grove in Eastern Georgia. AB - A new species of ground beetles (Coleoptea: Carabidae) belonging to the subgenus Aphaonus Reitter, 1887 (genus Pterostichus Bonelli, 1810) is described, based on two specimens collected from the sacred grove of Khevsha (Eastern Georgia). PMID- 29242486 TI - Entyposis cordipenis new species from Ethiopia (Coleoptera: Scarabaeidae: Melolonthinae: Schizonychini). AB - Entyposis Kolbe, 1895 (Coleoptera: Scarabaeidae: Melolonthinae: Schizonychini) was established for Schizonycha cavicollis Fairmaire, 1887 and newly described Entyposis impressa Kolbe, 1895. Lacroix & Montreuil (2012) revised the genus, designated S. cavicollis Fairmaire, 1887 as the type species and described six new species: Entyposis bidentata, E. martinezi, E. rasplusi, and E. madogolelei from Mozambique; E. excavata from Tanzania; and E. squamulata from Kenya and Tanzania. They also synonymized E. nyukana (Kolbe, 1910) and E. montana (Moser, 1913) with E. mendax Peringuey, 1904. Entyposis differs from other schizonychine genera in having a low occipital carina and with the pronotum in both sexes thickened basally into conspicuous bulges (with medial tubercle) and with deeper medial impression extending anteriorly into a weak or prominent point (Kolbe 1895; Lacroix & Montreuil 2012). Entyposis is very similar to Entypophana Moser, 1913. Both genera are characterized by conspicuous bulges (with lateral tubercle) on the pronotum, but Entypophana differs by having a double vertical frontal carina and occipital carina medially elevated into a simple or double horn or a broad, straight edge. The pronotum of both genera is laterally thickened into conspicuous bulges (with lateral tubercle) and medially bears a shallow, apically narrowing impression (Burgeon 1946; Moser 1913, 1917; Sehnal 2017). PMID- 29242487 TI - A cybertaxonomic revision of the new dung beetle tribe Parachoriini (Coleoptera: Scarabaeidae: Scarabaeinae) and its phylogenetic assessment using molecular and morphological data. AB - Two Oriental dung beetle genera: Parachorius Harold, 1873 and Cassolus Sharp, 1875 have long had an ambiguous tribal position in Scarabaeinae (Coleoptera: Scarabaeidae), but have never been considered as closely related. A recently discovered species representing the morphological link between the two genera gave a hint to their possible close affiliation. To assess phylogenetic and taxonomic placement of these genera, I conducted phylogenetic analyses of global dung beetle samples using morphological (134 taxa, 232 characters) and molecular (551 terminals, 8 gene regions) data. Both morphological and molecular analyses strongly support the monophyly of Parachorius + Cassolus. This leads to the synonymy of Parachorius with Cassolus new synonymy, and resulted in the new generic concept for Parachorius. The isolated phylogenetic position of Parachorius and its morphological distinctiveness from all other known Scarabaeinae tribes suggest recognition of a new tribe, Parachoriini new tribe, to maintain the stability of tribal classification in dung beetles. Investigation of old and recent material of Parachorius revealed a large number of undescribed species and the need for a taxonomic revision of this genus. The revision of Parachorius, powered by the 3i cybertaxonomic tool, is presented in this study. The revised Parachorius is comprised of 19 species from the Oriental and southeastern Palaearctic Regions, of which seven are newly described (P. asymmetricus new species, P. bolavensis new species, P. longipenis new species, P. newthayerae new species, P. pseudojavanus new species, P. schuelkei new species, and P. solodovnikovi new species). Three species names in Parachorius are synonymized, namely, P. fungorum Kryzhanovsky & Medvedev, 1966 = P. krali Utsunomiya & Masumoto, 2001 new synonymy; P. thomsoni Harold, 1873 = P. lannathai Hanboonsong & Masumoto, 2001 new synonymy; and P. peninsularis (Arrow, 1907) = C. pongchaii Masumoto, 2001 new synonymy. Two species originally described in Cassolus (C. sumatranus and C. minutus) are transferred to the genus Panelus Lewis, 1895. The rank of the genus Macropanelus is lowered to a subgenus within Panelus (i.e. Panelus (Macropanelus) new status). PMID- 29242488 TI - A new species of Tenuipalpoides (Acari: Tetranychidae) from Astragalus (Leguminoseae) in Iran. AB - A new species of the genus Tenuipalpoides (Tetranychidae: Tenuipalpoidini), Tenuipalpoides iraniensis sp. nov. is described and illustrated based on females and deutonymphs collected from Astragalus spp. (Leguminoseae) in Southern Iran (Hormozgan Province). This is the fifth report of this genus for the world and the first report of the tribe Tenuipalpoidini from Iran. The deutonymph of this genus is described for the first time and a key to the species of Tenuipalpoidini of the world is also provided. PMID- 29242489 TI - Review of the genus Termioptycha Meyrick, 1889 (Lepidoptera, Pyralidae) from China, with descriptions of four new species. AB - The genus Termioptycha Meyrick, 1889 from China is reviewed. Among the ten species studied, T. longiclavata sp. nov., T. longispina sp. nov., T. nigrimacularis sp. nov. and T. cornutitrifurca sp. nov. are described as new; T. conjuncta (Warren, 1896), comb. rev. is re-allocated in this genus from Salma Walker, 1863; and T. conjuncta and T. eucarta (Felder & Rogenhofer, 1875) are newly recorded in China. Photographs of adults and genitalia are provided. A key to the ten species in China based on male genitalia is provided. PMID- 29242490 TI - An authentic record of Eutropis bibronii (Gray, 1838) (Reptilia: Scincidae) from Sri Lanka. AB - Among the eight species of Eutropis Fitzinger currently known from Sri Lanka, Eutropis bibronii (Gray, 1838) is among the least known. Hence, the occurrence of this species in Sri Lanka has been doubted by some authors since there were no confirmed records from live specimens for the past 70 years. The species has been previously reported mostly from northern regions of Sri Lanka. Here, we report the collection of a live Eutropis bibronii from the Chundikulam National Park in the Northern Province of Sri Lanka confirming its occurrence in the country. PMID- 29242491 TI - Corinnella lourii, a rare new species of Baetidae (Ephemeroptera) from central Brazil. AB - A new species of the rare genus Corinnella is described based on nymphs from the Rio Pindaiba, a river located close to the Cerrado - Amazonian border. The new species is more related to C. eximia than to C. thomasi, but can be distinguished from them by the following combination of characters: 1) distomedial emargination of labrum broad and with very small process; 2) maxillary palp 2.0* length of galea-lacinia; 3) posterior margin of terga I-IX with pointed spaced spines; 4) claws with four denticles. PMID- 29242492 TI - A distinctive new species of biting midge in the subgenus Euprojoannisia Brethes from Mexico with new records of Neotropical species of Forcipomyia Meigen (Diptera: Ceratopogonidae). AB - A new species of biting midge, Forcipomyia (Euprojoannisia) bibaana, is described and illustrated from an adult male collected in the state Oaxaca, Mexico. The first records of Forcipomyia (E.) mortuifolii Saunders, F. (Lasiohelea) cornuta Saunders and F. (L.) stylifer (Lutz) are provided from Mexico as well as the first record of F. (L.) anitae Huerta & Ibanez-Bernal from Guatemala. PMID- 29242493 TI - First finding of the shrimp genus Harperalpheus Felder & Anker, 2007 in the eastern Pacific, with description of a new species from Bahia Malaga, Colombia (Malacostraca: Decapoda: Alpheidae). AB - A new infaunal species of the rare alpheid genus Harperalpheus Felder & Anker, 2007 is described from Bahia Malaga, Pacific coast of Colombia, based on single, incomplete holotype specimen. Harperalpheus leptodactylus sp. nov. may be easily separated from the western Atlantic type species and only other species of the genus, H. pequegnatae Felder & Anker, 2007, by several morphological characters on the first and fifth pereiopod, as well as on the antennular peduncle. PMID- 29242494 TI - Incidental Anatomic Finding of Celiacomesenteric Trunk Associated with 'Nutcracker Phenomenon,' or Compression of the Left Renal Vein. AB - BACKGROUND Celiacomesenteric trunk (CMT) is a very rare anatomic finding in which the celiac artery and the superior mesenteric artery (SMA) originate from the abdominal aorta through a common trunk. Clinical associations with CMT include arterial aneurysm, thrombosis, and celiac artery compression. However, an association between CMT and abdominal venous congestion caused by left renal vein compression, or 'nutcracker phenomenon,' has not been previously reported. CASE REPORT A 91-year-old woman, who died from a cerebrovascular accident (CVA), underwent a cadaveric examination at our medical school. On examination of the abdomen, there was an incidental finding of CMT. The arterial and venous diameters were measured, and vascular histopathology was undertaken. The vascular anatomy was consistent with CMT type 1-b. Nutcracker phenomenon (NCP) (left renal vein compression) was seen anatomically as dilatation and engorgement of the left renal vein, relative to the right renal vein (10.77+/-0.13 mm vs. 4.49+/-0.56 mm, respectively), and dilatation and engorgement of the left ovarian vein, relative to the right ovarian vein (4.37+/-0.15 mm vs. 1.06+/-0.09 mm, respectively) with left ovarian varicocele. The aortoceliac angle (ACA) and the aortomesenteric angle (AMA) approached zero degrees. CONCLUSIONS We have described a rare anatomic finding of CMT that created an acute AMA and NCP. Awareness of this rare association between CMT and NCP by clinicians, vascular surgeons, and radiologists may be of value in the future evaluation and surgical management of patients who present clinically with 'nutcracker syndrome.' PMID- 29242495 TI - The Evolution of Corneal Transplantation. AB - BACKGROUND The aim of this study was to investigate the evolution of surgical methods in and leading indications for corneal transplantation from 2005 to 2016. MATERIAL AND METHODS Data from the corneal graft waiting list and from all keratoplasties carried out between 2005 and 2016 at the University Eye Hospital Tubingen were retrospectively evaluated. RESULTS A total of 1259 keratoplasties were performed between 2005 and 2016 at the University Eye Hospital Tubingen. The most common surgical indications for corneal transplantation were Fuchs endothelial corneal dystrophy (45.5%) and keratoconus (14.2%). The mean rate of corneal transplantations almost doubled from 71 keratoplasties per year in the first 6-year period to 139 keratoplasties per year in the second 6-year period (P=0.005). The number of penetrating keratoplasties remained similar. The number of Descemet membrane endothelial keratoplasties (DMEK) increased significantly from 2008 to 2016 (P<0.0001). One DMEK procedure was performed in 2008 (representing 1.4% of all transplantations), while 75 DMEK procedures were performed in 2016 (representing 60.5% of all transplantations) (P<0.0001). DMEK became the favored surgical method for endothelial disorders, exceeding penetrating keratoplasty in 2013. CONCLUSIONS Our study shows evolutionary changes in preferred corneal transplantation techniques and leading indications for keratoplasty from 2005 to 2016. Since its introduction a decade ago, DMEK is currently the golden standard in the management of corneal endothelial dysfunction. PMID- 29242496 TI - Assessment of Fetal Myocardial Performance Index in Women with Placenta Previa. AB - BACKGROUND This study investigated whether fetuses of placenta previa pregnancies have cardiac dysfunction by use of a modified myocardial performance index (Mod MPI). MATERIAL AND METHODS A prospective cross-sectional study was conducted including 178 fetuses at 28-40 weeks of gestation. Eighty-nine fetuses of mothers with placenta previa and without pregnancy complications were recruited (placenta previa group) and matched with 89 fetuses of mothers with normal pregnancies (control group). Fetal cardiac function parameters and perinatal outcomes as well as the Mod-MPI were compared between the 2 groups. RESULTS The median Mod-MPI was significantly increased in fetuses of mothers with placenta previa compared with controls (0.47+/-0.05 vs. 0.45+/-0.05; P<0.01). Among fetuses of mothers with or without placenta previa, the Mod-MPI was significantly higher in the incomplete placenta previa group compared with the complete placenta previa group and control group (P<0.01). An increased Mod-MPI in placenta previa pregnancies was independently associated with fetal cord pH <7.2 (odds ratio, 4.8; 95% confidence interval, 0.98-23.54; P=0.003). CONCLUSIONS There is impairment of fetal cardiac function in pregnancies with placenta previa. An increased MPI was independently associated with adverse perinatal outcomes to some extent in the placenta previa pregnancies. PMID- 29242497 TI - Silicon CMOS architecture for a spin-based quantum computer. AB - Recent advances in quantum error correction codes for fault-tolerant quantum computing and physical realizations of high-fidelity qubits in multiple platforms give promise for the construction of a quantum computer based on millions of interacting qubits. However, the classical-quantum interface remains a nascent field of exploration. Here, we propose an architecture for a silicon-based quantum computer processor based on complementary metal-oxide-semiconductor (CMOS) technology. We show how a transistor-based control circuit together with charge-storage electrodes can be used to operate a dense and scalable two dimensional qubit system. The qubits are defined by the spin state of a single electron confined in quantum dots, coupled via exchange interactions, controlled using a microwave cavity, and measured via gate-based dispersive readout. We implement a spin qubit surface code, showing the prospects for universal quantum computation. We discuss the challenges and focus areas that need to be addressed, providing a path for large-scale quantum computing. PMID- 29242498 TI - MicroRNA-221-3p, a TWIST2 target, promotes cervical cancer metastasis by directly targeting THBS2. AB - MicroRNAs have implicated in the relapse and metastasis of cervical cancer, which is the leading cause of cervical cancer-related mortality. However, the underlying molecular mechanisms need further elucidation. Our present study revealed that miR-221-3p is transcriptionally promoted in metastatic cervical cancer tissues compared with non-metastatic cervical cancer tissues. Forced overexpression of miR-221-3p facilitated EMT and promoted cell migration and invasion in vitro and lymphatic metastasis in vivo. Twist homolog 2 (TWIST2) was found to be a key transcription factor binding to the promoter of miR-221-3p. Inhibitors of miR-221-3p drastically reduced the induction of EMT and decreased cell migration and invasion mediated by TWIST2. By combined computational and experimental approaches, THBS2 was recognized to be an important downstream target gene of miR-221-3p. In cervical cancer tissues, especially with lymphatic metastasis, miR-221-3p and TWIST2 were increased and THBS2 was decreased, suggesting that TWIST2 induces miR-221-3p expression and consequently suppresses its direct target THBS2 in lymphatic metastasis CC. Our findings uncover a mechanistic role for miR-221-3p in lymph node metastasis, suggesting that miR-221 3p is upregulated by the transcription factor TWIST2 and downregulates its target THBS2, which may potentially promote lymph node metastasis in cervical cancer. PMID- 29242499 TI - High internal noise and poor external noise filtering characterize perception in autism spectrum disorder. AB - An emerging hypothesis postulates that internal noise is a key factor influencing perceptual abilities in autism spectrum disorder (ASD). Given fundamental and inescapable effects of noise on nearly all aspects of neural processing, this could be a critical abnormality with broad implications for perception, behavior, and cognition. However, this proposal has been challenged by both theoretical and empirical studies. A crucial question is whether and how internal noise limits perception in ASD, independently from other sources of perceptual inefficiency, such as the ability to filter out external noise. Here, we separately estimated internal noise and external noise filtering in ASD. In children and adolescents with and without ASD, we computationally modeled individuals' visual orientation discrimination in the presence of varying levels of external noise. The results revealed increased internal noise and worse external noise filtering in individuals with ASD. For both factors, we also observed high inter-individual variability in ASD, with only the internal noise estimates significantly correlating with severity of ASD symptoms. We provide evidence for reduced perceptual efficiency in ASD that is due to both increased internal noise and worse external noise filtering, while highlighting internal noise as a possible contributing factor to variability in ASD symptoms. PMID- 29242500 TI - Comparative analysis of the genomes of Stylophora pistillata and Acropora digitifera provides evidence for extensive differences between species of corals. AB - Stony corals form the foundation of coral reef ecosystems. Their phylogeny is characterized by a deep evolutionary divergence that separates corals into a robust and complex clade dating back to at least 245 mya. However, the genomic consequences and clade-specific evolution remain unexplored. In this study we have produced the genome of a robust coral, Stylophora pistillata, and compared it to the available genome of a complex coral, Acropora digitifera. We conducted a fine-scale gene-based analysis focusing on ortholog groups. Among the core set of conserved proteins, we found an emphasis on processes related to the cnidarian dinoflagellate symbiosis. Genes associated with the algal symbiosis were also independently expanded in both species, but both corals diverged on the identity of ortholog groups expanded, and we found uneven expansions in genes associated with innate immunity and stress response. Our analyses demonstrate that coral genomes can be surprisingly disparate. Future analyses incorporating more genomic data should be able to determine whether the patterns elucidated here are not only characteristic of the differences between S. pistillata and A. digitifera but also representative of corals from the robust and complex clade at large. PMID- 29242501 TI - High-throughput RNA sequencing reveals distinct gene signatures in active IgG4 related disease. AB - We aimed to characterize the molecular differences and effects from prednisone treatment among IgG4-related disease with salivary gland lesions (RD-SG), without SG lesions (RD-nonSG), and IgG4-related retroperitoneal fibrosis (RF). RNA sequencing was conducted on blood from 25 RD-SG, 11 RD-nonSG, 3 RF and 10 control subjects. Among these, 8 RD-nonSG and 12 RD-SG patients were subjected to treatment with prednisone and/or glucocorticoid-sparing agents. Six RD patients had a longitudinal time point. The mRNA levels of IgG4 and IgE, genes specific for Th2 cells, eosinophils, and neutrophils were over-expressed in RD-SG and RD nonSG. A B-cell signature was suppressed in patients group versus controls, while Th1, Th2, Treg, and eosinophil gene signatures were increased in patients without treatment. Interestingly, Tfh genes and B cell signature were decreased at flare disease state. Prednisone treatment led to increased neutrophil, but decreased Treg signatures. Serum IgG4 levels correlated with the eosinophil and neutrophil gene signatures in RD-SG patients, and with a B cell signature in only RD-nonSG patients. IgG4, IgE, and cell-specific signatures are regulated in patients, suggesting the imbalance of immune and inflammatory cells in IgG4-related disease. Prednisone treatment selectively modulates Treg, eosinophil, and neutrophil signatures. PMID- 29242502 TI - Impact of Electrode Position on the Elicitation of Sodium Spikes in Retinal Bipolar Cells. AB - Bipolar cells of the magnocellular pathway in the primate retina can generate action potentials because they have an axonal segment with high sodium channel density, comparable to the sodium channel band in retinal ganglion cells or pyramidal cells. The similarity between the non-human primate and the human retina is of interest for the research on retinal implants for the blind, and especially, the conditions to elicit sodium spikes in bipolar cells using extracellular stimulation. A comparison of excitation characteristics of three model neurons, a bipolar cell, a retinal ganglion cell, and a cortical pyramidal cell, demonstrates the similarities and differences regarding stimulation with microelectrodes. Moving a microelectrode parallel to the axon of a neuron commonly allows to generate spikes for every position - and this rule holds both for cathodic and anodic pulses. However, for the simulated bipolar cell anodic pulses cannot generate sodium spikes directly. Further, there is only a small region for electrode placing where extracellular cathodic stimulation causes direct spike initiation in the sodium channel band. For all other positions, a sodium spike can only be generated by antidromic current flow originating from strongly depolarized terminals. PMID- 29242503 TI - Comparison of intrafascial and non-intrafascial radical prostatectomy for low risk localized prostate cancer. AB - In this meta-analysis study, we compared the oncological and functional outcomes of intrafascial radical prostatectomy (IFRP) with non-intrafascial radical prostatectomy (NIFRP) in the treatment of patients with low risk localized prostate cancer (PCa). Relevant articles were identified by searching PubMed, EMBASE, Cochrane Library, Ovid, and the ISI Web of Knowledge databases. A total of 2096 patients were included from 7 eligible studies. Results of the pooled data showed that the oncological outcomes including gleason score, positive surgical margin and biochemical free survival rates were similar between the two groups. IFRP was superior to NIFRP with lower postoperative complication rates (RR 0.57, 95% CI 0.38, 0.85, p = 0.006), higher continence rates at 3 months post operation (RR: 1.14; 95% CI, 1.04, 1.26; p = 0.006), and higher potency rates at 6 months (RR: 1.53; 95% CI, 1.07, 2.18; p = 0.02) and 12 months post-operation (RR: 1.38; 95% CI, 1.11, 1.73; p = 0.005). Additionally, there was a tendency towards higher potency rate in patients <=65 years old compared with patients >65 years old after IFRP. Overall, these findings suggest that IFRP in young patients with low risk localized PCa had less postoperative complications, shortened time to return to continence and improved potency rate without compromising complete tumor control. PMID- 29242504 TI - Scalable excitatory synaptic circuit design using floating gate based leaky integrators. AB - We propose a scalable synaptic circuit realizing spike timing dependent plasticity (STDP)-compatible with randomly spiking neurons. The feasible working of the circuit was examined by circuit simulation using the BSIM 4.6.0 model. A distinguishable feature of the circuit is the use of floating-gate integrators that provide the compact implementation of biologically plausible relaxation time scale. This relaxation occurs on the basis of charge tunneling that mainly relies upon area-independent tunnel barrier properties (e.g. barrier width and height) rather than capacitance. The circuit simulations feature (i) weight-dependent STDP that spontaneously limits the synaptic weight growth, (ii) competitive synaptic adaptation within both unsupervised and supervised frameworks with randomly spiking neurons. The estimated power consumption is merely 34 pW, perhaps meeting one of the most crucial principles (power-efficiency) of neuromorphic engineering. Finally, a means of fine-tuning the STDP behavior is provided. PMID- 29242505 TI - Memory-less response and violation of the fluctuation-dissipation theorem in colloids suspended in an active bath. AB - We investigate experimentally and numerically the stochastic dynamics and the time-dependent response of colloids subject to a small external perturbation in a dense bath of motile E. coli bacteria. The external field is a magnetic field acting on a superparamagnetic microbead suspended in an active medium. The measured linear response reveals an instantaneous friction kernel despite the complexity of the bacterial bath. By comparing the mean squared displacement and the response function we detect a clear violation of the fluctuation dissipation theorem. PMID- 29242506 TI - MicroRNAs regulate key cell survival pathways and mediate chemosensitivity during progression of diffuse large B-cell lymphoma. AB - Despite better therapeutic options and improved survival of diffuse large B-cell lymphoma (DLBCL), 30-40% of the patients experience relapse or have primary refractory disease with a dismal prognosis. To identify biological correlates for treatment resistance, we profiled microRNAs (miRNAs) of matched primary and relapsed DLBCL by next-generation sequencing. Altogether 492 miRNAs were expressed in the DLBCL samples. Thirteen miRNAs showed significant differential expression between primary and relapse specimen pairs. Integration of the differentially expressed miRNAs with matched mRNA expression profiles identified highly anti-correlated, putative targets, which were significantly enriched in cancer-associated pathways, including phosphatidylinositol (PI)), mitogen activated protein kinase (MAPK), and B-cell receptor (BCR) signaling. Expression data suggested activation of these pathways during disease progression, and functional analyses validated that miR-370-3p, miR-381-3p, and miR-409-3p downregulate genes on the PI, MAPK, and BCR signaling pathways, and enhance chemosensitivity of DLBCL cells in vitro. High expression of selected target genes, that is, PIP5K1 and IMPA1, was found to be associated with poor survival in two independent cohorts of chemoimmunotherapy-treated patients (n = 92 and n = 233). Taken together, our results demonstrate that differentially expressed miRNAs contribute to disease progression by regulating key cell survival pathways and by mediating chemosensitivity, thus representing potential novel therapeutic targets. PMID- 29242507 TI - Investigation of bioaccessibility of Cu, Fe, Mn, and Zn in market vegetables in the colon using PBET combined with SHIME. AB - The in vitro bioaccessibility of trace metals associated with oral ingestion of market vegetables (lettuce, pak choi, cole, and leaf lettuce) of Beijing, China was studied. The physiologically based extraction test (PBET) combined with the Simulator of Human Intestinal Microbial Ecosystem (SHIME) was applied to simulate stomach, small intestine, and colon of human. In the gastro-intestinal phases, the bioaccessibility of Cu, Fe, Mn, and Zn varied within 5.7-75.5%, 17.3-50.4%, 13.3-49.1%, and 19.9-63.7%, respectively. There was no significant difference in the metal bioaccessibility between the gastric and small intestinal phases, except for higher Cu bioaccessibility in the small intestine. Besides, the bioaccessibility of the four trace metals in the colon phase was first ever reported. A significant decline in Cu bioaccessibility (1.8-63.7%) and slight increases in the bioaccessibility of Fe (16.7-56.4%), Mn (21.2-71.6%), and Zn (15.7-69.7%) were revealed, which could mainly be attributed to the effect of colon microbiota. In addition, the estimated daily intakes (EDIs) of Cu, Fe, Mn, and Zn were worked out to be 0.7, 8.8, 2.7, and 4.5 MUg kg-1 body weight d-1, based on which the potential influences of these trace metals in vegetables on the health of the local consumers was demonstrated. PMID- 29242508 TI - Variations in cochlear duct shape revealed on clinical CT images with an automatic tracing method. AB - Cochlear size and morphology vary greatly and may influence the course of a cochlear implant electrode array during insertion and its final intra-cochlear position. Detailed insight into these variations is valuable for characterizing each cochlea and offers the opportunity to study possible correlations with surgical or speech perception outcomes. This study presents an automatic tracing method to assess individual cochlear duct shapes from clinical CT images. On pre operative CT scans of 479 inner ears the cochlear walls were discriminated by interpolating voxel intensities along radial and perpendicular lines within multiplanar reconstructions at 1 degree intervals from the round window. In all 479 cochleas, the outer wall could be traced automatically up to 720 degrees. The inner wall and floor of the scala tympani in 192 cochleas. The shape of the cochlear walls were modelled using a logarithmic spiral function including an offset value. The vertical trajectories of the scala tympani exhibited a non monotonous spiral slope with specific regions at risk for CI-related insertion trauma, and three slope categories could be distinguished. This presented automatic tracing method allows the detailed description of cochlear morphology and can be used for both individual and large cohort evaluation of cochlear implant patients. PMID- 29242509 TI - SHP2 associates with nuclear localization of STAT3: significance in progression and prognosis of colorectal cancer. AB - Tyrosine phosphatase SHP2, encoded by PTPN11, has been implicated in many physiologic and pathologic processes in neoplastic progression. However, controversies are emerging from many studies, indicating SHP2 has a dual role in different types of tumors. We aimed to explore the role of SHP2 in progression and prognosis of colorectal cancer (CRC). SHP2 inhibited CRC cell proliferation and migration, and the phosphorylation of STAT3 was negatively regulated by SHP2 in CRC. SHP2 and nuclear STAT3 were examined in 270 CRC tissues. SHP2 was significantly correlated with nuclear STAT3 (Spearman's rho = -0.408, P <= 0.001). Based on Cox regression analysis, patients with high levels of SHP2 and low levels of nuclear STAT3 had longer disease-specific survival (DSS) (HR, 0.362; 95% CI, 0.165-0.794) and disease-free survival (DFS) (HR, 0.447; 95% CI, 0.227-0.877). Further, low levels of SHP2 and high levels of nuclear STAT3 were independently associated with adverse outcomes in the whole cohort (DFS; HR, 2.353; 95% CI, 1.199-4.619). These results suggest that combination of SHP2 and nuclear STAT3 is a strong prognostic predictor in CRC. PMID- 29242510 TI - Nanofluid based on self-nanoencapsulated metal/metal alloys phase change materials with tuneable crystallisation temperature. AB - Nanofluids using nanoencapsulated Phase Change Materials (nePCM) allow increments in both the thermal conductivity and heat capacity of the base fluid. Incremented heat capacity is produced by the melting enthalpy of the nanoparticles core. In this work two important advances in this nanofluid type are proposed and experimentally tested. It is firstly shown that metal and metal alloy nanoparticles can be used as self-encapsulated nePCM using the metal oxide layer that forms naturally in most commercial synthesis processes as encapsulation. In line with this, Sn/SnOx nanoparticles morphology, size and thermal properties were studied by testing the suitability and performance of encapsulation at high temperatures and thermal cycling using a commercial thermal oil (Therminol 66) as the base fluid. Secondly, a mechanism to control the supercooling effect of this nePCM type based on non-eutectic alloys was developed. PMID- 29242511 TI - Communicative predictions can overrule linguistic priors. AB - Predictions allow for efficient human communication. To be efficient, listeners' predictions need to be adapted to the communicative context. Here we show that during speech processing this adaptation is a highly flexible and selective process that is able to fine-tune itself to individual language styles of specific interlocutors. In a newly developed paradigm, speakers differed in the probabilities by which they used particular sentence structures. Probe trials were applied to infer participants' syntactic expectations for a given speaker and to track changes of these expectations over time. The results show that listeners fine-tune their linguistic expectations according to the individual language style of a speaker. Strikingly, nine months after the initial experiment these highly specific expectations could be rapidly reactivated when confronted with the particular language style of a speaker but not merely on the basis of an association with speaker identity per se. These findings highlight that communicative interaction fine-tunes and consolidates interlocutor specific communicative predictions which can overrule strong linguistic priors. PMID- 29242512 TI - Synthetic integrin-binding immune stimulators target cancer cells and prevent tumor formation. AB - Immuno-oncology approaches mainly utilize monoclonal antibodies or protein-based scaffolds that bind with high affinity to cancer cells and can generate an immune response. Peptides can also bind with high affinity to cancer cells and are intermediate in size between antibodies and small molecules. They are also synthetically accessible and therefore easily modified to optimize their stability, binding affinity and selectivity. Here we describe the design of immune system engagers (ISErs), a novel class of synthetic peptide-based compounds that bind specifically to cancer cells and stimulate the immune system. A prototype, Y9, targets integrin alpha3, which is overexpressed on several cancer cells, and activates the immune system via a formyl methionine-containing effector peptide. Injection of Y9 leads to immune cell infiltration into tissue and prevents tumor formation in a guinea pig model. The anti-tumor activity and synthetic accessibility of Y9 illustrate that ISErs could be applied to a wide variety of targets and diseases. PMID- 29242513 TI - SCARF-1 promotes adhesion of CD4+ T cells to human hepatic sinusoidal endothelium under conditions of shear stress. AB - Liver-resident cells are constantly exposed to gut-derived antigens via portal blood and, as a consequence, they express a unique repertoire of scavenger receptors. Whilst there is increasing evidence that the gut contributes to chronic inflammatory liver disease, the role of scavenger receptors in regulating liver inflammation remains limited. Here, we describe for the first time the expression of scavenger receptor class F, member 1 (SCARF-1) on hepatic sinusoidal endothelial cells (HSEC). We report that SCARF-1 shows a highly localised expression pattern and co-localised with endothelial markers on sinusoidal endothelium. Analysis of chronically inflamed liver tissue demonstrated accumulation of SCARF-1 at sites of CD4+ T cell aggregation. We then studied the regulation and functional role of SCARF-1 in HSEC and showed that SCARF-1 expression by HSEC is regulated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS). Furthermore, SCARF-1 expression by HSEC, induced by proinflammatory and gut-derived factors acts as a novel adhesion molecule, present in adhesive cup structures, that specifically supports CD4+ T cells under conditions of physiological shear stress. In conclusion, we show that SCARF-1 contributes to lymphocyte subset adhesion to primary human HSEC and could play an important role in regulating the inflammatory response during chronic liver disease. PMID- 29242514 TI - DNA damage causes rapid accumulation of phosphoinositides for ATR signaling. AB - Phosphoinositide lipids (PPIs) are enriched in the nucleus and are accumulated at DNA damage sites. Here, we investigate roles of nuclear PPIs in DNA damage response by sequestering specific PPIs with the expression of nuclear-targeted PH domains, which inhibits recruitment of Ataxia telangiectasia and Rad3-related protein (ATR) and reduces activation of Chk1. PPI-binding domains rapidly (< 1 s) accumulate at damage sites with local enrichment of PPIs. Accumulation of PIP3 in complex with the nuclear receptor protein, SF1, at damage sites requires phosphorylation by inositol polyphosphate multikinase (IPMK) and promotes nuclear actin assembly that is required for ATR recruitment. Suppressed ATR recruitment/activation is confirmed with latrunculin A and wortmannin treatment as well as IPMK or SF1 depletion. Other DNA repair pathways involving ATM and DNA PKcs are unaffected by PPI sequestration. Together, these findings reveal that nuclear PPI metabolism mediates an early damage response through the IPMK dependent pathway to specifically recruit ATR. PMID- 29242516 TI - MRONJ risk of adjuvant bisphosphonates in early stage breast cancer. AB - Medication-related osteonecrosis of the jaw (MRONJ) has most commonly been associated with bisphosphonates. The routine uses of these drugs are now well established predominantly in metastatic cancer with bone involvement, multiple myeloma, hypercalcaemia, osteoporosis and Paget's disease. Recently, however, the use of bisphosphonates in early breast cancer has shown a reduction in breast cancer recurrence and breast cancer deaths. This new indication for their use approximates to a further 20,000 women per year in the UK being prescribed bisphosphonates. In this article, we consider the dental impact of this new use of bisphosphonates, report on the rates of MRONJ seen in early breast cancer bisphosphonate trials and discuss strategies aimed at minimising the risk of bisphosphonate-exposed patients developing MRONJ. PMID- 29242517 TI - The Crisis at Christmas Dental Service: a review of an annual volunteer-led dental service for homeless and vulnerably housed people in London. AB - Background The UK charity Crisis originated in 1967 as a response to the increasing numbers of homeless people in London, and the first Crisis at Christmas event for rough sleepers was established in 1971. Since then, Crisis has provided numerous services over the Christmas period to the most vulnerable members of society. One of these is the Crisis at Christmas Dental Service (CCDS) which provides emergency and routine dental care from 23-29 of December each year. The charity is entirely dependent on voluntary staffing and industry donations including materials and facilities. This paper aims to assess the impact of the service over the last six years of clinical activity from 2011 2016.Method Anonymised data were collected from the annual CCDS delivered over the last six consecutive years. Services included: dental consultations; oral hygiene instruction; scale and polishes; permanent fillings; extractions; and fluoride varnish applications. In addition, anonymised patient feedback was collected after each dental attendance.Results On average, 80-85% of the patients were male and the majority were between 21 and 60 years of age. The most common nationality was British (46%). Over the six-year data collection period intervention treatments (restorations and extractions) remained fairly consistent, while the number of fluoride varnish applications and oral hygiene instruction have increased. The majority of patients reported positive satisfaction with their treatment and would have recommended the service to others. Approximately 75% of patients did not regularly attend a dentist outside of Crisis and a similar proportion were given information on where to access year round dental services for homeless people in London. The majority of dental volunteers felt that they enjoyed the experience and would consider volunteering again for Crisis in the future.Conclusion The Crisis at Christmas Dental Service has emerged as a valuable asset to the portfolio of resources accessible to vulnerable, marginalised people over the Christmas period and exposes the high dental need of the homeless population of London. PMID- 29242515 TI - Efficient transgenesis and annotated genome sequence of the regenerative flatworm model Macrostomum lignano. AB - Regeneration-capable flatworms are informative research models to study the mechanisms of stem cell regulation, regeneration, and tissue patterning. However, the lack of transgenesis methods considerably hampers their wider use. Here we report development of a transgenesis method for Macrostomum lignano, a basal flatworm with excellent regeneration capacity. We demonstrate that microinjection of DNA constructs into fertilized one-cell stage eggs, followed by a low dose of irradiation, frequently results in random integration of the transgene in the genome and its stable transmission through the germline. To facilitate selection of promoter regions for transgenic reporters, we assembled and annotated the M. lignano genome, including genome-wide mapping of transcription start regions, and show its utility by generating multiple stable transgenic lines expressing fluorescent proteins under several tissue-specific promoters. The reported transgenesis method and annotated genome sequence will permit sophisticated genetic studies on stem cells and regeneration using M. lignano as a model organism. PMID- 29242518 TI - What is a regional trainee representative? A personal perspective of a pilot role within the East Midlands. AB - Dental trainees have an important role to play in quality assuring training programmes. Local education and training boards (LETBs) actively encourage trainee engagement through structured feedback, which acts as a valuable source of critical appraisal. This is designed to support the structure of training programmes and influences its quality and content. In 2014, East Midlands LETB appointed a regional trainee representative to collate, present and promote dental foundation and core trainee issues to the Dental School Board, as well as highlight their accomplishments and achievements. The pilot brief given was to evolve the post to better support trainees and quality manage the various feedback pathways. This allowed for further research into the existing trainee representative posts across the East Midlands, and highlighted the specific and unique benefits of having regional trainee representation to be the overarching voice on the LETB. This article sets out the framework of responsibilities of a regional trainee representative, contrasts it with established representative posts (regionally and nationally), and advocates why dental schools should appoint to these positions to promote the voices of their trainees. It will also explain the advantages of being a representative, as well as highlight some of the challenges, in the hope that it encourages the next generation to consider applying for these roles. PMID- 29242520 TI - Reproductive endocrinology: Restoring ovarian function. PMID- 29242519 TI - Timing and Amount of Physical Therapy Treatment are Associated with Length of Stay in the Cardiothoracic ICU. AB - Significant variability exists in physical therapy early mobilization practice. The frequency of physical therapy or early mobilization of patients in the cardiothoracic intensive care unit and its effect on length of stay has not been investigated. The goal of our research was to examine variables that influence physical therapy evaluation and treatment in the intensive care unit using a retrospective chart review. Patients (n = 2568) were categorized and compared based on the most common diagnoses or surgical procedures. Multivariate semi logarithmic regression analyses were used to determine correlations. Differences among patient subgroups for all independent variables other than age and for length of stay were found. The regression model determined that time to first physical therapy evaluation, Charlson Comorbidity Index score, mean days of physical therapy treatment and mechanical ventilation were associated with increased hospital length of stay. Time to first physical therapy evaluation in the intensive care unit and the hospital, and mean days of physical therapy treatment associated with hospital length of stay. Further prospective study is required to determine whether shortening time to physical therapy evaluation and treatment in a cardiothoracic intensive care unit could influence length of stay. PMID- 29242521 TI - Surveillance of Live Poultry Markets for Low Pathogenic Avian Influenza Viruses in Guangxi Province, Southern China, from 2012-2015. AB - Infections with low pathogenic avian influenza viruses (LPAIVs) can be mild or asymptomatic in poultry; however, in humans, LPAIVs can cause severe infections and death, as demonstrated by the H7N9 and H10N8 human infection outbreaks in 2013 in China. In this study, we conducted an epidemiological survey of LPAIVs at live poultry markets (LPMs) in Guangxi Province, Southern China, which is near several Southeast Asian countries. From January 2012 to December 2015, we collected 3,813 swab samples from poultry at LPMs in Guangxi. Viral isolation, hemagglutination inhibition assay and viral sequencing were utilized to identify LPAIVs in the collected samples. Among the samples, 622 (16.3%) were positive for LPAIVs. Six subtypes (H1, H3, H4, H6, H9 and H11) were individually isolated and identified. Of these subtypes, H3, H6 and H9 were predominant in ducks, geese and chickens, respectively. Among the 622 positive samples, 160 (25.7%) contained more than one subtype, and H8, H10, H12, H13, and H16 were identified among them, which highlights the continuous need for enhanced surveillance of AIVs. These results provide detailed information regarding the epidemic situation of LPAIVs in the area, which can aid efforts to prevent and control AIV transmission in humans and animals. PMID- 29242523 TI - Migraine: CGRP-targeting antibodies reduce migraine frequency. PMID- 29242524 TI - Clinical implications of the plasma EphA2 receptor level in critically ill patients with septic shock. AB - The Eph/ephrin receptor ligand system is known to play a role in inflammation induced by infection, injury, and inflammatory diseases. The present study aimed to evaluate plasma EphA2 receptor levels in critically ill patients with sepsis. This study was a prospective cohort study evaluating samples and clinical data from the medical intensive care unit (MICU) of a 2000-bed university tertiary referral hospital in South Korea. Positive correlations of the plasma EphA2 receptor level with the acute physiology and chronic health evaluation (APACHE) II score and the sequential organ failure assessment (SOFA) score were observed. The area under the curve (AUC) for the plasma EphA2 receptor level on a receiver operating characteristic curve was 0.690 (95% confidence interval [CI], 0.608 0.764); the AUCs for the APACHE II score and SOFA scores were 0.659 (95% CI, 0.576-0.736) and 0.745 (95% CI, 0.666-0.814), respectively. A Cox proportional hazard model identified an association between an increased plasma EphA2 receptor level (>51.5 pg mL-1) and increased risk of 28-day mortality in the MICU (hazard ratio = 3.22, 95% CI, 1.709-6.049). An increased plasma EphA2 receptor level was associated with sepsis severity and 28-day mortality among sepsis patients. PMID- 29242525 TI - Inhibition of human kynurenine aminotransferase isozymes by estrogen and its derivatives. AB - The kynurenine aminotransferase (KAT) enzymes are pyridoxal 5'-phosphate dependent homodimers that catalyse the irreversible transamination of kynurenine into kynurenic acid (KYNA) in the tryptophan metabolic pathway. Kynurenic acid is implicated in cognitive diseases such as schizophrenia, and several inhibitors have been reported that selectively target KAT-II as it is primarily responsible for kynurenic acid production in the human brain. Not only is schizophrenia a sexually dimorphic condition, but women that have schizophrenia have reduced estrogen levels in their serum. Estrogens are also known to interact in the kynurenine pathway therefore exploring these interactions can yield a better understanding of the condition and improve approaches in ameliorating its effects. Enzyme inhibitory assays and binding studies showed that estradiol disulfate is a strong inhibitor of KAT-I and KAT-II (IC50: 291.5 MUM and 26.3 MUM, respectively), with estradiol, estradiol 3-sulfate and estrone sulfate being much weaker (IC50 > 2 mM). Therefore it is possible that estrogen levels can dictate the balance of kynurenic acid in the brain. Inhibition assay results and modelling suggests that the 17-sulfate moiety in estradiol disulfate is very important in improving its potency as an inhibitor, increasing the inhibition by approximately 10-100 fold compared to estradiol. PMID- 29242526 TI - Percentiles for skeletal muscle index, area and radiation attenuation based on computed tomography imaging in a healthy Caucasian population. AB - BACKGROUND/OBJECTIVES: Muscle mass is a key determinant of nutritional status and associated with outcomes in several patient groups. Computed tomography (CT) analysis is increasingly used to assess skeletal muscle area (SMA), skeletal muscle index (SMI) and muscle radiation attenuation (MRA). However, interpretation of these muscle parameters is difficult since values in a healthy population are lacking. The aim of this study was to provide sex specific percentiles for SMA, SMA and MRA in a healthy Caucasian population and to examine the association with age and BMI in order to define age- and BMI specific percentiles. SUBJECTS/METHODS: In this retrospective cross-sectional study CT scans of potential kidney donors were used to assess SMA, SMI and MRA at the level of the third lumbar vertebra. Sex specific distributions were described and, based on the association between age/BMI and muscle parameters, age, and BMI specific predicted percentiles were computed. The 5th percentile was considered as cut-off. RESULTS: CT scans of 420 Individuals were included (age range 20-82 years and BMI range 17.5-40.7 kg/m2). Sex specific cut-offs of SMA, SMI and MRA were 134.0 cm2, 41.6 cm2/m2 and 29.3 HU in men and 89.2 cm2, 32.0 cm2/m2 and 22.0 HU in women, respectively. Correlations were negative between age and all three muscle parameters, positive between BMI and SMA/SMI and negative between BMI and MRA, resulting in age- and BMI specific percentiles. CONCLUSIONS: This study provides sex specific percentiles for SMA, SMI, and MRA. In addition, age- and BMI specific percentiles have been established. PMID- 29242522 TI - Amyloid-beta and tau complexity - towards improved biomarkers and targeted therapies. AB - Most neurodegenerative diseases are proteinopathies, which are characterized by the aggregation of misfolded proteins. Although many proteins have an intrinsic propensity to aggregate, particularly when cellular clearance systems start to fail in the context of ageing, only a few form fibrillar aggregates. In Alzheimer disease, the peptide amyloid-beta (Abeta) and the protein tau aggregate to form plaques and tangles, respectively, which comprise the histopathological hallmarks of this disease. This Review discusses the complexity of Abeta biogenesis, trafficking, post-translational modifications and aggregation states. Tau and its various isoforms, which are subject to a vast array of post-translational modifications, are also explored. The methodological advances that revealed this complexity are described. Finally, the toxic effects of distinct species of tau and Abeta are discussed, as well as the concept of protein 'strains', and how this knowledge can facilitate the development of early disease biomarkers for stratifying patients and validating new therapies. By targeting distinct species of Abeta and tau for therapeutic intervention, the way might be paved for personalized medicine and more-targeted treatment strategies. PMID- 29242527 TI - Correlates of overall and central obesity in adults from seven European countries: findings from the Food4Me Study. AB - BACKGROUND/OBJECTIVES: To identify predictors of obesity in adults and investigate to what extent these predictors are independent of other major confounding factors. SUBJECTS/METHODS: Data collected at baseline from 1441 participants from the Food4Me study conducted in seven European countries were included in this study. A food frequency questionnaire was used to measure dietary intake. Accelerometers were used to assess physical activity levels (PA), whereas participants self-reported their body weight, height and waist circumference via the internet. RESULTS: The main factors associated (p < 0.05) with higher BMI per 1-SD increase in the exposure were age (beta:1.11 kg/m2), intakes of processed meat (beta:1.04 kg/m2), red meat (beta:1.02 kg/m2), saturated fat (beta:0.84 kg/m2), monounsaturated fat (beta:0.80 kg/m2), protein (beta:0.74 kg/m2), total energy intake (beta:0.50 kg/m2), olive oil (beta:0.36 kg/m2), sugar sweetened carbonated drinks (beta:0.33 kg/m2) and sedentary time (beta:0.73 kg/m2). In contrast, the main factors associated with lower BMI per 1 SD increase in the exposure were PA (beta:-1.36 kg/m2), intakes of wholegrains (beta:-1.05 kg/m2), fibre (beta:-1.02 kg/m2), fruits and vegetables (beta:-0.52 kg/m2), nuts (beta:-0.52 kg/m2), polyunsaturated fat (beta:-0.50 kg/m2), Healthy Eating Index (beta:-0.42 kg/m2), Mediterranean diet score (beta:-0.40 kg/m2), oily fish (beta:-0.31 kg/m2), dairy (beta:-0.31 kg/m2) and fruit juice (beta: 0.25 kg/m2). CONCLUSIONS: These findings are important for public health and suggest that promotion of increased PA, reducing sedentary behaviours and improving the overall quality of dietary patterns are important strategies for addressing the existing obesity epidemic and associated disease burden. PMID- 29242528 TI - Trends in the distribution of body mass index and waist circumference among South Korean adults, 1998-2014. AB - BACKGROUND/OBJECTIVES: An increase in mean body mass index (BMI) or prevalence of obesity may be accompanied by changes in the population BMI distribution. This study aimed to examine how the distributions of BMI and waist circumference (WC) have changed in South Korea over a 16-year interval (1998-2014). SUBJECTS/METHODS: Using the Korea National Health and Nutrition Examination Survey, we analyzed changes in mean, standard deviation (SD), 5th, and 95th percentile values of BMI and WC distributions for 46,343 (BMI) and 46,327 (WC) adults aged 25-64 years. RESULTS: For men, mean BMI increased at an annual rate of 0.060 units (95% CI: 0.047-0.073) with annual increases of 0.029 units in SD (95% CI: 0.019-0.039), 0.121 units in the 95th percentile (95% CI: 0.097-0.145) and 0.042 units in the 5th percentile (95% CI: 0.021-0.062). The 95th percentile and SD of the WC distribution increased, but not mean WC and the 5th percentile. For women, mean BMI decreased at an annual rate of 0.030 units (95% CI: 0.010 0.049) with a 0.030-unit increase in SD (95% CI: 0.012-0.048) and a 0.049-unit decrease in the 5th percentile (95% CI: 0.029-0.070). Mean WC also decreased with an increase in SD and a decrease in the 5th percentile. CONCLUSIONS: These findings suggest increasing dispersion in the distribution of BMI and WC derived from significant shifts in the upper tails for Korean men, but not women. Future research needs to identify the factors that underlie the increasing dispersion of obesity measures. PMID- 29242530 TI - Correlated production and consumption of chloromethane in the Arabidopsis thaliana phyllosphere. AB - Chloromethane (CH3Cl) is a toxic gas mainly produced naturally, in particular by plants, and its emissions contribute to ozone destruction in the stratosphere. Conversely, CH3Cl can be degraded and used as the sole carbon and energy source by specialised methylotrophic bacteria, isolated from a variety of environments including the phyllosphere, i.e. the aerial parts of vegetation. The potential role of phyllospheric CH3Cl-degrading bacteria as a filter for plant emissions of CH3Cl was investigated using variants of Arabidopsis thaliana with low, wild-type and high expression of HOL1 methyltransferase previously shown to be responsible for most of CH3Cl emissions by A. thaliana. Presence and expression of the bacterial chloromethane dehalogenase cmuA gene in the A. thaliana phyllosphere correlated with HOL1 genotype, as shown by qPCR and RT-qPCR. Production of CH3Cl by A. thaliana paralleled HOL1 expression, as assessed by a fluorescence-based bioreporter. The relation between plant production of CH3Cl and relative abundance of CH3Cl-degrading bacteria in the phyllosphere suggests that CH3Cl degrading bacteria co-determine the extent of plant emissions of CH3Cl to the atmosphere. PMID- 29242529 TI - Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer. AB - Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation. Importantly, DAC treatment increases ICN1 expression (the active intracellular domain of NOTCH1) significantly inhibiting cell proliferation and causing changes in cell size inducing morphological alterations reminiscent of senescence. These changes were not associated with beta-galactosidase activity or increased p16 levels, but instead were associated with substantial IL-6 release. Increased IL-6 release was observed in both DAC-treated and ICN1 overexpressing cells as compared to control cells. Exogenous IL-6 expression was associated with a similar enlarged cell morphology that was rescued by the addition of a monoclonal antibody against IL-6. Treatment with DAC, overexpression with ICN1 or addition of exogenous IL-6 showed CK5 reduction, a surrogate marker of differentiation. Overall this study suggests that in MIBC cells, DNA hypomethylation increases NOTCH1 expression and IL-6 release to induce CK5 related differentiation. PMID- 29242532 TI - Jagged1-induced Notch activation contributes to the acquisition of bortezomib resistance in myeloma cells. PMID- 29242531 TI - Long noncoding RNA expression profile reveals lncRNAs signature associated with extracellular matrix degradation in kashin-beck disease. AB - Kashin-Beck disease (KBD) is a deformative, endemic osteochondropathy involving degeneration and necrosis of growth plates and articular cartilage. The pathogenesis of KBD is related to gene expression and regulation mechanisms, but long noncoding RNAs (lncRNAs) in KBD have not been investigated. In this study, we identified 316 up-regulated and 631 down-regulated lncRNAs (>= 2-fold change) in KBD chondrocytes using microarray analysis, of which more than three-quarters were intergenic lncRNAs and antisense lncRNAs. We also identified 232 up regulated and 427 down-regulated mRNAs (>= 2-fold change). A lncRNA-mRNA correlation analysis combined 343 lncRNAs and 292 mRNAs to form 509 coding noncoding gene co-expression networks (CNC networks). Eleven lncRNAs were predicted to have cis-regulated target genes, including NAV2 (neuron navigator 2), TOX (thymocyte selection-associated high mobility group box), LAMA4 (laminin, alpha 4), and DEPTOR (DEP domain containing mTOR-interacting protein). The differentially expressed mRNAs in KBD significantly contribute to biological events associated with the extracellular matrix. Meanwhile, 34 mRNAs and 55 co expressed lncRNAs constituted a network that influences the extracellular matrix. In the network, FBLN1 and LAMA 4 were the core genes with the highest significance. These novel findings indicate that lncRNAs may play a role in extracellular matrix destruction in KBD. PMID- 29242533 TI - Chiral expression from molecular to macroscopic level via pH modulation in terbium coordination polymers. AB - Chiral expression from the molecular to macroscopic level is common in biological systems, but is difficult to realise for coordination polymers (CPs). The assembly of homochiral CPs in both crystalline and helical forms can provide a bridge for understanding the relationship between the molecular and macroscopic scales of chirality. Herein, we report homochiral helices of [Tb(R- or S pempH)3]?2H2O (R - or S -1) (pempH2 = (1-phenylethylamino)methylphosphonic acid) and their crystalline counterparts (R - or S -3), which are formed at different pH of the reaction mixtures under hydrothermal conditions. By combining the experiments and molecular simulations, we propose that the formation of helices of R -1 or S -1 occurs via a hierarchical self-assembly route, which involves twisted packing due to the geometric incompatibility of the different types of chains. The observed chiral transcription from molecules to morphologies is significant for understanding bio-related self-assembly processes on the nano- to macro-scale. PMID- 29242536 TI - Nitrogen fixation in two coastal upwelling regions of the Taiwan Strait. AB - Recent studies have demonstrated that dinitrogen fixation can be important in nutrient-rich coastal upwelling regions. During a cruise to the Taiwan Strait in summer 2015, we found that the nitrogen fixation rate in surface waters ranged from below detection limits to 7.51 nmol N L-1 d-1. Higher rates accompanied by low N:P ratios (1-10.4:1) associated with low temperatures occurred in the surface water where the Pingtan and the Dongshan upwelling regions met (the NE area). In contrast, insignificant rates were observed in the southwest area of the Dongshan upwelling region (the SW area) with sufficient N and deficient P, and therefore high N:P ratios (e.g., >43 at station C2) due largely to the influence of the Pearl River plume. Diatom-associated symbionts (het-1; 104-106 copies L-1) that are efficient in organic matter export were found to dominate the other diazotrophic groups that were surveyed, which may represent a direct relationship between new nitrogen input and export in the upwelling regions. Our results suggest a hydrographical influence on the diazotroph community and N2 fixation in coastal upwelling regions. PMID- 29242534 TI - The celecoxib derivatives AR-12 and AR-14 induce autophagy and clear prion infected cells from prions. AB - Prion diseases are fatal infectious neurodegenerative disorders that affect both humans and animals. The autocatalytic conversion of the cellular prion protein (PrPC) into the pathologic isoform PrPSc is a key feature in prion pathogenesis. AR-12 is an IND-approved derivative of celecoxib that demonstrated preclinical activity against several microbial diseases. Recently, AR-12 has been shown to facilitate clearance of misfolded proteins. The latter proposes AR-12 to be a potential therapeutic agent for neurodegenerative disorders. In this study, we investigated the role of AR-12 and its derivatives in controlling prion infection. We tested AR-12 in prion infected neuronal and non-neuronal cell lines. Immunoblotting and confocal microscopy results showed that AR-12 and its analogue AR-14 reduced PrPSc levels after only 72 hours of treatment. Furthermore, infected cells were cured of PrPSc after exposure of AR-12 or AR-14 for only two weeks. We partially attribute the influence of the AR compounds on prion propagation to autophagy stimulation, in line with our previous findings that drug-induced stimulation of autophagy has anti-prion effects in vitro and in vivo. Taken together, this study demonstrates that AR-12 and the AR-14 analogue are potential new therapeutic agents for prion diseases and possibly protein misfolding disorders involving prion-like mechanisms. PMID- 29242537 TI - Surface enhancement of THz wave by coupling a subwavelength LiNbO3 slab waveguide with a composite antenna structure. AB - Highly intense terahertz electromagnetic field and efficiently surface localized terahertz field in subwavelength volumes are of vital importance for terahertz photonics integration, also will greatly accelerate the development for integrated applications in biochemical sensing, imaging, terahertz spectroscopy, enhancement of nonlinear effects and even quantum research. In this paper, we achieved large terahertz field enhancement and surface field localization through depositing a pair of Au composite antennas on a LiNbO3 subwavelength slab waveguide, which can serve as an excellent on-chip platform for terahertz research and application. The antennas consist of two opposing tip-to-tip triangles separated by a gap, and each triangle combines with a strip antenna. Time-resolved imaging and finite-difference time-domain method were used to resolve the characteristics of the designed antennas experimentally and simulatively. Through these methods, we demonstrated outstanding abilities of the platform: leading to a large electric field enhancement, concentrating almost full terahertz energy on the waveguide's surface when they are resonant with the terahertz waves and tunable resonant frequency. These abilities make the subwavelength waveguide coupling with the composite antennas be able to sever as a good integrated device to identify terahertz-sensitive small objects, or an excellent platform to terahertz spectroscopy and quantum research. PMID- 29242535 TI - Lipid bodies containing oxidatively truncated lipids block antigen cross presentation by dendritic cells in cancer. AB - Cross-presentation is a critical function of dendritic cells (DCs) required for induction of antitumor immune responses and success of cancer immunotherapy. It is established that tumor-associated DCs are defective in their ability to cross present antigens. However, the mechanisms driving these defects are still unknown. We find that impaired cross-presentation in DCs is largely associated with defect in trafficking of peptide-MHC class I (pMHC) complexes to the cell surface. DCs in tumor-bearing hosts accumulate lipid bodies (LB) containing electrophilic oxidatively truncated (ox-tr) lipids. These ox-tr-LB, but not LB present in control DCs, covalently bind to chaperone heat shock protein 70. This interaction prevents the translocation of pMHC to cell surface by causing the accumulation of pMHC inside late endosomes/lysosomes. As a result, tumor associated DCs are no longer able to stimulate adequate CD8 T cells responses. In conclusion, this study demonstrates a mechanism regulating cross-presentation in cancer and suggests potential therapeutic avenues. PMID- 29242538 TI - Nuclear RNF2 inhibits interferon function by promoting K33-linked STAT1 disassociation from DNA. AB - Prolonged activation of interferon-STAT1 signaling is closely related to inflammatory autoimmune disorders, and therefore the identification of negative regulators of these pathways is important. Through high-content screening of 115 mouse RING-domain E3 ligases, we identified the E3 ubiquitin ligase RNF2 as a potent inhibitor of interferon-dependent antiviral responses. RNF2 deficiency substantially enhanced interferon-stimulated gene (ISG) expression and antiviral responses. Mechanistically, nuclear RNF2 directly bound to STAT1 after interferon stimulation and increased K33-linked polyubiquitination of the DNA-binding domain of STAT1 at position K379, in addition to promoting the disassociation of STAT1/STAT2 from DNA and consequently suppressing ISG transcription. Our study provides insight into the regulation of interferon-dependent responses via a previously unrecognized post-translational modification of STAT1 in the nucleus. PMID- 29242540 TI - Microbiota & cancer response. PMID- 29242541 TI - STAT5B in RICD. PMID- 29242542 TI - Scoring presentation. PMID- 29242539 TI - Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells. AB - Although deletion of certain autophagy-related genes has been associated with defects in hematopoiesis, it remains unclear whether hyperactivated mitophagy affects the maintenance and differentiation of hematopoietic stem cells (HSCs) and committed progenitor cells. Here we report that targeted deletion of the gene encoding the AAA+-ATPase Atad3a hyperactivated mitophagy in mouse hematopoietic cells. Affected mice showed reduced survival, severely decreased bone-marrow cellularity, erythroid anemia and B cell lymphopenia. Those phenotypes were associated with skewed differentiation of stem and progenitor cells and an enlarged HSC pool. Mechanistically, Atad3a interacted with the mitochondrial channel components Tom40 and Tim23 and served as a bridging factor to facilitate appropriate transportation and processing of the mitophagy protein Pink1. Loss of Atad3a caused accumulation of Pink1 and activated mitophagy. Notably, deletion of Pink1 in Atad3a-deficient mice significantly 'rescued' the mitophagy defect, which resulted in restoration of the progenitor and HSC pools. Our data indicate that Atad3a suppresses Pink1-dependent mitophagy and thereby serves a key role in hematopoietic homeostasis. PMID- 29242543 TI - The twilight of immunity: emerging concepts in aging of the immune system. AB - Immunosenescence is a series of age-related changes that affect the immune system and, with time, lead to increased vulnerability to infectious diseases. This Review addresses recent developments in the understanding of age-related changes that affect key components of immunity, including the effect of aging on cells of the (mostly adaptive) immune system, on soluble molecules that guide the maintenance and function of the immune system and on lymphoid organs that coordinate both the maintenance of lymphocytes and the initiation of immune responses. I further address the effect of the metagenome and exposome as key modifiers of immune-system aging and discuss a conceptual framework in which age related changes in immunity might also affect the basic rules by which the immune system operates. PMID- 29242544 TI - Self-RNA sentinels signal viral invasion. PMID- 29242545 TI - Hyperactivated mitophagy in hematopoietic stem cells. PMID- 29242546 TI - Another way to not get eaten. PMID- 29242547 TI - Decoding the intestinal epithelium cell by cell. PMID- 29242549 TI - Assaulting the microbiota. PMID- 29242548 TI - Silent clearance. PMID- 29242550 TI - Diversity of vaginal microbiota increases by the time of labor onset. AB - Vaginal microbiota is an important early source of bacterial colonization for newborns. However, only a few small studies have investigated the composition of vaginal microbiota during labor. In this work, we analyzed vaginal swabs collected at 36 weeks gestation and at the onset of labor from 256 women participating in a randomized placebo-controlled study of probiotic supplementation for the prevention of atopic dermatitis in offspring. Although individuals' vaginal microbiota was stable over time, several bacterial families, which are characteristic of mixed community state type (CST) IV, were overrepresented in vaginal swabs sampled at labor. Alpha-diversity also tended to increase by between 36 weeks gestation and the onset of birth. In the majority of women, CST remained the same throughout the study. Among the women who switched their vaginal microbiota from one CST to another, approximately half shifted towards CST IV. Although CST IV is often associated with bacterial vaginosis, which in turn may lead to preterm birth, in our cohort this shift was not associated with self-reported vaginosis, preterm delivery or birthweight. Probiotic consumption did not alter vaginal microbiota. PMID- 29242551 TI - Ezh2 phosphorylation state determines its capacity to maintain CD8+ T memory precursors for antitumor immunity. AB - Memory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity. Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator(s) underpinning this process remains unknown. Herein, we show that the histone methyltransferase Ezh2 controls CD8+ T memory precursor formation and antitumor activity. Ezh2 activates Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies. PMID- 29242552 TI - A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions. AB - Assessment of pharmacodynamic (PD) drug interactions is a cornerstone of the development of combination drug therapies. To guide this venture, we derive a general pharmacodynamic interaction (GPDI) model for >=2 interacting drugs that is compatible with common additivity criteria. We propose a PD interaction to be quantifiable as multidirectional shifts in drug efficacy or potency and explicate the drugs' role as victim, perpetrator or even both at the same time. We evaluate the GPDI model against conventional approaches in a data set of 200 combination experiments in Saccharomyces cerevisiae: 22% interact additively, a minority of the interactions (11%) are bidirectional antagonistic or synergistic, whereas the majority (67%) are monodirectional, i.e., asymmetric with distinct perpetrators and victims, which is not classifiable by conventional methods. The GPDI model excellently reflects the observed interaction data, and hence represents an attractive approach for quantitative assessment of novel combination therapies along the drug development process. PMID- 29242554 TI - Response of pedogenic magnetite to changing vegetation in soils developed under uniform climate, topography, and parent material. AB - Pedogenesis produces fine-grained magnetic minerals that record important information about the ambient climatic conditions present during soil formation. Yet, differentiating the compounding effects of non-climate soil forming factors is a nontrivial challenge that must be overcome to establish soil magnetism as a trusted paleoenvironmental tool. Here, we isolate the influence of vegetation by investigating magnetic properties of soils developing under uniform climate, topography, and parent material but changing vegetation along the forest-prairie ecotone in NW Minnesota. Greater absolute magnetic enhancement in prairie soils is related to some combination of increased production of pedogenic magnetite in prairie soils, increased deposition of detrital magnetite in prairies from eolian processes, or increased dissolution of fine-grained magnetite in forest soils due to increased soil moisture and lower pH. Yet, grain-size specific magnetic properties associated with pedogenesis, for example relative frequency dependence of susceptibility and the ratio of anhysteretic to isothermal remanent magnetization, are insensitive to changing vegetation. Further, quantitative unmixing methods support a fraction of fine-grained pedogenic magnetite that is highly consistent. Together, our findings support climate as a primary control on magnetite production in soils, while demonstrating how careful decomposition of bulk magnetic properties is necessary for proper interpretation of environmental magnetic data. PMID- 29242553 TI - Nuclear lamin A/C harnesses the perinuclear apical actin cables to protect nuclear morphology. AB - The distinct spatial architecture of the apical actin cables (or actin cap) facilitates rapid biophysical signaling between extracellular mechanical stimuli and intracellular responses, including nuclear shaping, cytoskeletal remodeling, and the mechanotransduction of external forces into biochemical signals. These functions are abrogated in lamin A/C-deficient mouse embryonic fibroblasts that recapitulate the defective nuclear organization of laminopathies, featuring disruption of the actin cap. However, how nuclear lamin A/C mediates the ability of the actin cap to regulate nuclear morphology remains unclear. Here, we show that lamin A/C expressing cells can form an actin cap to resist nuclear deformation in response to physiological mechanical stresses. This study reveals how the nuclear lamin A/C-mediated formation of the perinuclear apical actin cables protects the nuclear structural integrity from extracellular physical disturbances. Our findings highlight the role of the physical interactions between the cytoskeletal network and the nucleus in cellular mechanical homeostasis. PMID- 29242555 TI - Intrinsic interactive reinforcement learning - Using error-related potentials for real world human-robot interaction. AB - Reinforcement learning (RL) enables robots to learn its optimal behavioral strategy in dynamic environments based on feedback. Explicit human feedback during robot RL is advantageous, since an explicit reward function can be easily adapted. However, it is very demanding and tiresome for a human to continuously and explicitly generate feedback. Therefore, the development of implicit approaches is of high relevance. In this paper, we used an error-related potential (ErrP), an event-related activity in the human electroencephalogram (EEG), as an intrinsically generated implicit feedback (rewards) for RL. Initially we validated our approach with seven subjects in a simulated robot learning scenario. ErrPs were detected online in single trial with a balanced accuracy (bACC) of 91%, which was sufficient to learn to recognize gestures and the correct mapping between human gestures and robot actions in parallel. Finally, we validated our approach in a real robot scenario, in which seven subjects freely chose gestures and the real robot correctly learned the mapping between gestures and actions (ErrP detection (90% bACC)). In this paper, we demonstrated that intrinsically generated EEG-based human feedback in RL can successfully be used to implicitly improve gesture-based robot control during human-robot interaction. We call our approach intrinsic interactive RL. PMID- 29242556 TI - Functional redundancy and sensitivity of fish assemblages in European rivers, lakes and estuarine ecosystems. AB - The impact of species loss on ecosystems functioning depends on the amount of trait similarity between species, i.e. functional redundancy, but it is also influenced by the order in which species are lost. Here we investigated redundancy and sensitivity patterns across fish assemblages in lakes, rivers and estuaries. Several scenarios of species extinction were simulated to determine whether the loss of vulnerable species (with high propensity of extinction when facing threats) causes a greater functional alteration than random extinction. Our results indicate that the functional redundancy tended to increase with species richness in lakes and rivers, but not in estuaries. We demonstrated that i) in the three systems, some combinations of functional traits are supported by non-redundant species, ii) rare species in rivers and estuaries support singular functions not shared by dominant species, iii) the loss of vulnerable species can induce greater functional alteration in rivers than in lakes and estuaries. Overall, the functional structure of fish assemblages in rivers is weakly buffered against species extinction because vulnerable species support singular functions. More specifically, a hotspot of functional sensitivity was highlighted in the Iberian Peninsula, which emphasizes the usefulness of quantitative criteria to determine conservation priorities. PMID- 29242557 TI - The metabolic syndrome- associated small G protein ARL15 plays a role in adipocyte differentiation and adiponectin secretion. AB - Common genetic variants at the ARL15 locus are associated with plasma adiponectin, insulin and HDL cholesterol concentrations, obesity, and coronary atherosclerosis. The ARL15 gene encodes a small GTP-binding protein whose function is currently unknown. In this study adipocyte-autonomous roles for ARL15 were investigated using conditional knockdown of Arl15 in murine 3T3-L1 (pre)adipocytes. Arl15 knockdown in differentiated adipocytes impaired adiponectin secretion but not adipsin secretion or insulin action, while in preadipocytes it impaired adipogenesis. In differentiated adipocytes GFP-tagged ARL15 localized predominantly to the Golgi with lower levels detected at the plasma membrane and intracellular vesicles, suggesting involvement in intracellular trafficking. Sequencing of ARL15 in 375 severely insulin resistant patients identified four rare heterozygous variants, including an early nonsense mutation in a proband with femorogluteal lipodystrophy and non classical congenital adrenal hyperplasia, and an essential splice site mutation in a proband with partial lipodystrophy and a history of childhood yolk sac tumour. No nonsense or essential splice site mutations were found in 2,479 controls, while five such variants were found in the ExAC database. These findings provide evidence that ARL15 plays a role in adipocyte differentiation and adiponectin secretion, and raise the possibility that human ARL15 haploinsufficiency predisposes to lipodystrophy. PMID- 29242558 TI - The NLR and LMR ratio in newly diagnosed MM patients treated upfront with novel agents. PMID- 29242559 TI - A functional variant in the OAS1 gene is associated with Sjogren's syndrome complicated with HBV infection. AB - Hepatitis B virus (HBV) has been suspected to contribute to several autoimmune diseases, including Sjogren's syndrome (SS), although the exact mechanism is unknown. The 2'-5' oligoadenylate synthetase (OAS1) is one of the most important components of the immune system and has significant antiviral functions. We studied a polymorphism rs10774671 of OAS1 gene in Han Chinese descent. The minor allele G was significantly associated with a decreased risk for SS, anti-SSA positive SS, and anti-SSA-positive SS complicated with HBV infection, which have not been seen in anti-SSA-negative SS and HBcAb-negative SS patients. Gene expression analysis showed that the risk-conferring A allele was correlated with lower expression of p46 and increased expression of p42, p48, and p44. A functional study of enzymatic activities revealed that the p42, p44, and p48 isoforms display a reduced capacity to inhibit HBV replication in HepG2 cells compared to the normal p46 isoform. Our data demonstrated that the functional variant, rs10774671, is associated with HBV infection and anti-SSA antibody positive SS. The SAS variant switches the primary p46 isoform to three alternatives with decreased capacities to inhibit HBV replication. These data indicated that individuals harboring the risk allele might be susceptible to hepatitis B infection and SS development. PMID- 29242560 TI - Characterising the nicotine metabolite ratio and its association with treatment choice: A cross sectional analysis of Stop Smoking Services in England. AB - Pharmacotherapy provision based on Nicotine Metabolite Ratio (NMR) status (slow/normal metabolism) may improve smoking cessation rates. However, it is unclear whether NMR status is consistent across patient characteristics and current treatment choice. Data come from 1,826 participants attending Stop Smoking Services (SSS) across England in 2012/13. Sociodemographic, mental/physical health, smoking and treatment characteristics (nicotine replacement therapy vs. other pharmacotherapy; group vs. one-to-one behavioural support) were assessed. Salivary nicotine metabolites were measured and NMR (3 hydroxycotinine/cotinine) computed, characterising smokers as slow (NMR < 0.31) or normal (NMR >= 0.31) metabolisers. Normal metabolisers were older than slow metabolisers (Odds Ratio (OR) = 1.49, 95% Confidence Interval (CI) = 1.32-1.69) but no other characteristics were associated with NMR status. Overall, predictors accounted for only 7.3% of NMR variance. In adjusted analysis, pharmacotherapy type was not associated with NMR status, but normal metabolisers were less likely to use group support (OR = 0.67, 95% CI = 0.51-0.89). NMR status does not vary substantially across sociodemographic characteristics. Given its impact on pharmacotherapy efficacy, the lack of an association with pharmacotherapy choice suggests there is scope to use NMR status to optimise the selection and efficacy of smoking cessation pharmacotherapy. The unexpected association of NMR status with behavioural support should be explored further. PMID- 29242561 TI - Hepatitis B virus persistence in mice reveals IL-21 and IL-33 as regulators of viral clearance. AB - Hepatitis B virus (HBV) generally causes self-limiting infection in immunocompetent adults, but establishes chronic infection in some adults and in most maternally infected infants. Factors determining clearance versus persistence are not fully understood. Hydrodynamic injection (HDI) of HBV replicon plasmid via tail vein generally results in quick clearance in immunocompetent adult mice. Here, we report the identification of strain-specific persistence of HBV in mice: one genotype B strain, designated BPS, persisted up to 33 weeks in ~50% of HDI mice. BPS persistence requires viral replication and multiple viral features. Compared to quickly cleared strains, BPS fails to induce robust post-exposure serum IL-21/IL-33 responses. Injection of IL-21-expressing or IL-33-expressing plasmids facilitates clearance of pre-established BPS persistence and protects cured mice from BPS re-challenge. IL-21 and IL-33 also induce clearance of pre-established HBV persistence in another mouse model. These data reveal IL-21 and IL-33 as potent regulators of HBV clearance and valid drug candidates. PMID- 29242562 TI - ROS-induced cleavage of NHLRC2 by caspase-8 leads to apoptotic cell death in the HCT116 human colon cancer cell line. AB - Excess production of reactive oxygen species (ROS) is known to cause apoptotic cell death. However, the molecular mechanisms whereby ROS induce apoptosis remain elusive. Here we show that the NHL-repeat-containing protein 2 (NHLRC2) thioredoxin-like domain protein is cleaved by caspase-8 in ROS-induced apoptosis in the HCT116 human colon cancer cell line. Treatment of HCT116 cells with the oxidant tert-butyl hydroperoxide (tBHP) induced apoptosis and reduced NHLRC2 protein levels, whereas pretreatment with the antioxidant N-acetyl-L-cysteine prevented apoptosis and the decrease in NHLRC2 protein levels seen in tBHP treated cells. Furthermore, the ROS-induced decrease in NHLRC2 protein levels was relieved by the caspase inhibitor z-VAD-fmk. We found that the thioredoxin-like domain of NHLRC2 interacted with a proenzyme form of caspase-8, and that caspase 8 cleaved NHLRC2 protein at Asp580 in vitro. Furthermore, siRNA-mediated knockdown of caspase-8 blocked the ROS-induced decrease in NHLRC2 protein levels. Both shRNA and CRISPR-Cas9-mediated loss of NHLRC2 resulted in an increased susceptibility of HCT116 cells to ROS-induced apoptosis. These results suggest that excess ROS production causes a caspase-8-mediated decrease in NHLRC2 protein levels, leading to apoptotic cell death in colon cancer cells, and indicate an important role of NHLRC2 in the regulation of ROS-induced apoptosis. PMID- 29242564 TI - Increased apoptosis of regulatory T cells in patients with active autoimmune hepatitis. PMID- 29242563 TI - CK2 modulates adipocyte insulin-signaling and is up-regulated in human obesity. AB - Insulin plays a major role in glucose metabolism and insulin-signaling defects are present in obesity and diabetes. CK2 is a pleiotropic protein kinase implicated in fundamental cellular pathways and abnormally elevated in tumors. Here we report that in human and murine adipocytes CK2-inhibition decreases the insulin-induced glucose-uptake by counteracting Akt-signaling and GLUT4 translocation to the plasma membrane. In mice CK2 acts on insulin-signaling in adipose tissue, liver and skeletal muscle and its acute inhibition impairs glucose tolerance. Notably, CK2 protein-level and activity are greatly up regulated in white adipose tissue from ob/ob and db/db mice as well as from obese patients, regardless the severity of their insulin-resistance and the presence of pre-diabetes or overt type 2 diabetes. Weight loss obtained by both bariatric surgery or hypocaloric diet reverts CK2 hyper-activation to normal level. Our data suggest a central role of CK2 in insulin-sensitivity, glucose homeostasis and adipose tissue remodeling. CK2 up-regulation is identified as a hallmark of adipose tissue pathological expansion, suggesting a new potential therapeutic target for human obesity. PMID- 29242565 TI - Anti-IL-20 monoclonal antibody inhibited tumor growth in hepatocellular carcinoma. AB - Interleukin (IL)-20 is a proinflammatory cytokine involved in rheumatoid arthritis, atherosclerosis, and osteoporosis. However, the role of IL-20 in hepatocellular carcinoma (HCC) is unclear. We explored the function of IL-20 in HCC. Tumor tissue samples were analyzed the expression of IL-20 and cyclin D1 by using immunohistochemistry staining and quantitative real-time polymerase chain reaction (qRT-PCR) analysis. To examine the role of anti-IL-20 monoclonal antibody (7E) in tumor growth, BALB/c mice was injected with ML-1 cells and treated with 7E. HCC tumor tissue expressed higher levels of IL-20 than did non tumor tissue. High IL-20 expression in HCC was correlated with poor overall survival (relative risk:>3). IL-20 and cyclin D1 expression were also highly correlated in HCC patient specimens and 3 human HCC cell lines. IL-20 also increased cell proliferation and migration, and it regulated matrix metalloproteinase (MMP)-13, tumor necrosis factor (TNF)-alpha, cyclin D1, and p21WAF1 expression in ML-1 cells. 7E attenuated tumor growth in mice inoculated with ML-1 cells. The expression of cyclin D1, TNF-alpha, MMP-9, and vascular endothelial growth factor was significantly inhibited after 7E treatment. The findings of this study suggest that IL-20 plays a role in the tumor progression of HCC. PMID- 29242566 TI - Identifying models of dielectric breakdown strength from high-throughput data via genetic programming. AB - The identification of models capable of rapidly predicting material properties enables rapid screening of large numbers of materials and facilitates the design of new materials. One of the leading challenges for computational researchers is determining the best ways to analyze large material data sets to identify models that can rapidly predict a given property. In this paper, we demonstrate the use of genetic programming to generate simple models of dielectric breakdown based on 82 representative dielectric materials. We identified the band gap Eg and phonon cut-off frequency omegamax as the two most relevant features, and new classes of models featuring functions of Eg and omegamax were uncovered. The genetic programming approach was found to outperform other approaches for generating models, and we discuss some of the advantages of this approach. PMID- 29242568 TI - Automatic multiple zebrafish larvae tracking in unconstrained microscopic video conditions. AB - The accurate tracking of zebrafish larvae movement is fundamental to research in many biomedical, pharmaceutical, and behavioral science applications. However, the locomotive characteristics of zebrafish larvae are significantly different from adult zebrafish, where existing adult zebrafish tracking systems cannot reliably track zebrafish larvae. Further, the far smaller size differentiation between larvae and the container render the detection of water impurities inevitable, which further affects the tracking of zebrafish larvae or require very strict video imaging conditions that typically result in unreliable tracking results for realistic experimental conditions. This paper investigates the adaptation of advanced computer vision segmentation techniques and multiple object tracking algorithms to develop an accurate, efficient and reliable multiple zebrafish larvae tracking system. The proposed system has been tested on a set of single and multiple adult and larvae zebrafish videos in a wide variety of (complex) video conditions, including shadowing, labels, water bubbles and background artifacts. Compared with existing state-of-the-art and commercial multiple organism tracking systems, the proposed system improves the tracking accuracy by up to 31.57% in unconstrained video imaging conditions. To facilitate the evaluation on zebrafish segmentation and tracking research, a dataset with annotated ground truth is also presented. The software is also publicly accessible. PMID- 29242567 TI - A Coxiella mutualist symbiont is essential to the development of Rhipicephalus microplus. AB - The cattle tick Rhipicephalus microplus is a hematophagous ectoparasite that causes important economic losses in livestock. Different species of ticks harbor a symbiont bacterium of the genus Coxiella. It was showed that a Coxiella endosymbiont from R. microplus (CERM) is a vertically transmitted mutualist symbiont, comprising 98% of the 16S rRNA sequences in both eggs and larvae. Sequencing of the bacterial genome revealed genes for biosynthetic pathways for several vitamins and key metabolic cofactors that may provide a nutritional complement to the tick host. The CERM was abundant in ovary and Malpighian tubule of fully engorged female. Tetracycline treatment of either the tick or the vertebrate host reduced levels of bacteria in progeny in 74% for eggs and 90% for larvae without major impact neither on the reproductive fitness of the adult female or on embryo development. However, CERM proved to be essential for the tick to reach the adult life stage, as under antibiotic treatment no tick was able to progress beyond the metanymph stage. Data presented here suggest that interference in the symbiotic CERM-R. microplus relationship may be useful to the development of alternative control methods, highlighting the interdependence between ticks and their endosymbionts. PMID- 29242569 TI - Ecosystem respiration and its components in a rainfed spring maize cropland in the Loess Plateau, China. AB - We estimated ecosystem respiration (Re) and its components in a rainfed spring maize field in the Loess Plateau, China, during the growing seasons of 2012, 2013, and 2014 using measurements of eddy covariance and soil respiration (Rs). The multi-factor equation, which included photosynthetic active radiation, 5-cm soil temperature, 10-cm soil water content, and green leaf area index (GLAI), had goodness-of-fit values of between 0.81 and 0.94 for Re, autotrophic respiration (Ra), and above-ground autotrophic respiration (Raa), and goodness-of-fit values of between 0.50 and 0.67 for Rs, below-ground autotrophic respiration (Rab), and heterotrophic respiration (Rh). The highly significant linear correlations between gross primary production (GPP) and Re and its components indicate that GPP had a strong influence on Re and its components. The growing season Re was dominated by Ra (64-71%), which in turn was dominated by Raa (63-73%). Although Rs was mainly made up of Rh (56-61%), Rs resembled Rab more closely than Rh. The relationships between GLAI and Ra/Re and between GLAI and Rab/Rs were described by logarithmic equations with goodness-of-fit values of between 0.88 and 0.89 and between 0.77 and 0.84, respectively, indicating that GLAI controlled Ra/Re and Rab/Rs. PMID- 29242570 TI - Monitoring cerebral oxygenation of preterm infants using a neonatal specific sensor. AB - INTRODUCTION: Cerebral oxygenation (rcSO2) monitoring in preterm infants may identify periods of cerebral hypoxia or hyperoxia. We hypothesised that there was a relationship between rcSO2 values and short term outcome in infants of GA < 32weeks. METHODS: RcSO2 values were recorded for the first 48 h of life using an INVOS monitor with a neonatal sensor. The association between cranial ultrasound scan measured brain injury and rcSO2 was assessed. RESULTS: 120 infants were included. Sixty-nine percent (83) of infants had a normal outcome (no IVH, no PVL, and survival at 1 month); less than one-quarter, 22% (26), had low grade IVH 1 or 2 (moderate outcome); and 9% (11) of infants had a severe outcome (IVH >= 3, PVL or died before 1 month age). rcSO2 values were lower for infants GA < 28weeks when compared with those GA 28-32, p < 0.001. There was no difference in absolute rcSO2 values between the three outcome groups but a greater degree of cerebral hypoxia was associated with preterm infants who had low grade 1 or 2 IVH. CONCLUSION: Infants of GA < 28 weeks have lower cerebral oxygenation in the first 2 days of life. A greater degree of hypoxia was seen in infants with grade 1 or 2 haemorrhage. Normative ranges need to be gestation specific. PMID- 29242572 TI - Response to Malla et al. PMID- 29242571 TI - Divergent risk factors for cerebellar and intraventricular hemorrhage. AB - OBJECTIVE: To identify whether intraventricular hemorrhage (IVH) and cerebellar hemorrhage (CH) have common or divergent risk factors. STUDY DESIGN: This is a retrospective cross-sectional cohort of infants including all infants born <30 weeks from 2007 to 2016. Comprehensive perinatal and clinical factors were extracted from the medical record. Outborn infants, infants with major congenital anomaly, those transferred prior to discharge, and those with mixed or no brain injury were excluded. The remaining infants were divided into two groups: IVH only and CH only. Continuous variables were evaluated with the Wilcoxon-Mann Whitney test, and categorical variables were evaluated with Fisher's exact test. Multinomial logistic regression was used to identify factors which predispose infants towards injury type more than another, holding other factors constant. RESULTS: In total, 127 infants were included (CH n = 27, IVH n = 100). Compared to those with IVH, infants with CH were of lower EGA (p = 0.03), lower birth weight (p = 0.01), more often of multiple gestation (p = 0.03), more frequently born emergently (p = 0.03), had a greater number of ventilator days (p = 0.03), received postnatal steroids more often (p = 0.02), had a greater incidence of hemodynamically significant patent ductus arteriosus (PDA), and less frequently had pulmonary hemorrhage (p = 0.04). In multinomial regression analysis, three factors were identified which favored CH over IVH: multiple gestation (RR 4.70, 95% CI 1.56-14.21, p < 0.01), chorioamnionitis (RR 3.18, 95% CI 1.13-8.92, p = 0.03), and emergent delivery (RR 4.14, 95% CI 1.48-11.55, p < 0.01). Only advancing gestational favored IVH over CH (RR 0.74, 95% CI 0.65-0.85, p < 0.01). CONCLUSIONS: IVH and CH have unique risk factors. These results highlight the need to tailor neuroimaging surveillance to specific patient risk factors. PMID- 29242573 TI - Extremely premature birth, informed written consent, and the Greek ideal of sophrosyne. AB - Most extremely premature infants die in the intensive care unit or suffer significant neurologic impairment. Many therapies result in unhealthy consequences, and the emotional and financial turmoil for families warrant reappraisal of our motives. Shared decision-making and informed consent in preference-sensitive conditions imply the family: (a) understands the medical problem, (b) grasps the risks and benefits of each therapy, (c) has the opportunity to ask questions and reflect upon options, (d) knows their values and preferences are understood, and (e) accepts or declines therapies without judgment or penalty. Mandatory resuscitation of premature infants or inflexible palliative comfort care policies are inconsistent with the principles of informed consent and shared decision-making. Physicians should emulate the Greek ideal of sophrosyne-virtue inherent to balance, reasoned limits, freedom but restraint, and humility. Informed choice is fundamental to liberty; evidence-based periviability guidelines and decision aids bolstered by structured informed consent ensure process integrity. PMID- 29242574 TI - Anti-corrosion performance of the synergistic properties of benzenecarbonitrile and 5-bromovanillin on 1018 carbon steel in HCl environment. AB - The synergistic properties of the combined admixture of benzenecarbonitrile and 5 bromovanillin (BNV) on the corrosion resistance of 1018 carbon steel in 1 M HCl was analysed with potentiodynamic polarization technique, weight loss method, micro-analytical studies and ATF-FTIR spectroscopy. Results obtained show the admixed organic compound was effective with optimal corrosion inhibition values of 99.33% and 90.34% at 1.25% BNV concentration from both electrochemical methods due to the effective inhibition action and passivation characteristics of the protonated inhibitor molecules in the acid solution. Primary amines, stretch alkyl halides and C-H triple bond functional groups of the molecules were observed to actively adsorb during the corrosion inhibition reaction from ATF FTIR spectroscopic analysis. Calculations from thermodynamic evaluation confirmed cationic adsorption mechanism to be chemisorption obeying the Langmuir and Frumkin adsorption isotherm. Micro-analytical observations of the inhibited carbon steel morphology significantly contrast the unprotected steel due to visible surface deterioration and presence of micro/macro-pits. The organic derivatives showed mixed type inhibition reactions. PMID- 29242576 TI - Can 100 must-read papers also reflect 'who' is ecology? PMID- 29242575 TI - ASXL1 c.1934dup;p.Gly646Trpfs*12-a true somatic alteration requiring a new approach. PMID- 29242577 TI - Editorial board members are a non-random sample of ecological experts. PMID- 29242578 TI - It is time to overcome unconscious bias in ecology. PMID- 29242579 TI - The future of ecology is collaborative, inclusive and deconstructs biases. PMID- 29242580 TI - Author Correction: The energy cost of polypeptide knot formation and its folding consequences. AB - The original version of this article contained an error in the spelling of the author Christian A.M. Wilson, which was incorrectly given as Christian M.A. Wilson. This has now been corrected in both the PDF and HTML versions of the article. PMID- 29242581 TI - IL-33 is induced in undifferentiated, non-dividing esophageal epithelial cells in eosinophilic esophagitis. AB - The molecular and cellular etiology of eosinophilic esophagitis (EoE), an emerging tissue-specific allergic disease, involves dysregulated gene expression in esophageal epithelial cells. Herein, we assessed the esophageal expression of IL-33, an epithelium-derived alarmin cytokine, in patients with EoE. IL-33 protein was markedly overexpressed within the nuclei of a subpopulation of basal layer esophageal epithelial cells in patients with active EoE compared to control individuals. IL-33 exhibited dynamic expression as levels normalized upon EoE remission. IL-33-positive basal epithelial cells expressed E-cadherin and the undifferentiated epithelial cell markers keratin 5 and 14 but not the differentiation marker keratin 4. Moreover, the IL-33-positive epithelial cells expressed the epithelial progenitor markers p75 and p63 and lacked the proliferation markers Ki67 and phospho-histone H3. Additionally, the IL-33 positive cells had low expression of PCNA. IL-33 expression was detected in ex vivo-cultured primary esophageal epithelial cells in a subpopulation of cells lacking expression of proliferation markers. Collectively, we report that IL-33 expression is induced in an undifferentiated, non-dividing esophageal epithelial cell population in patients with active EoE. PMID- 29242582 TI - Outcomes of patients with peripheral T-cell lymphoma in first complete remission: data from three tertiary Asian cancer centers. PMID- 29242583 TI - Hybrid splicing minigene and antisense oligonucleotides as efficient tools to determine functional protein/RNA interactions. AB - Alternative splicing is a complex process that provides a high diversity of proteins from a limited number of protein-coding genes. It is governed by multiple regulatory factors, including RNA-binding proteins (RBPs), that bind to specific RNA sequences embedded in a specific structure. The ability to predict RNA-binding regions recognized by RBPs using whole-transcriptome approaches can deliver a multitude of data, including false-positive hits. Therefore, validation of the global results is indispensable. Here, we report the development of an efficient and rapid approach based on a modular hybrid minigene combined with antisense oligonucleotides to enable verification of functional RBP-binding sites within intronic and exonic sequences of regulated pre-mRNA. This approach also provides valuable information regarding the regulatory properties of pre-mRNA, including the RNA secondary structure context. We also show that the developed approach can be used to effectively identify or better characterize the inhibitory properties of potential therapeutic agents for myotonic dystrophy, which is caused by sequestration of specific RBPs, known as muscleblind-like proteins, by mutated RNA with expanded CUG repeats. PMID- 29242586 TI - Thylacine tales. PMID- 29242585 TI - Risks to pollinators and pollination from invasive alien species. AB - Invasive alien species modify pollinator biodiversity and the services they provide that underpin ecosystem function and human well-being. Building on the Intergovernmental Science-Policy Platform for Biodiversity and Ecosystem Services (IPBES) global assessment of pollinators and pollination, we synthesize current understanding of invasive alien impacts on pollinators and pollination. Invasive alien species create risks and opportunities for pollinator nutrition, re organize species interactions to affect native pollination and community stability, and spread and select for virulent diseases. Risks are complex but substantial, and depend greatly on the ecological function and evolutionary history of both the invader and the recipient ecosystem. We highlight evolutionary implications for pollination from invasive alien species, and identify future research directions, key messages and options for decision making. PMID- 29242587 TI - Our first year by the numbers. PMID- 29242584 TI - Mis-expression of grainyhead-like transcription factors in zebrafish leads to defects in enveloping layer (EVL) integrity, cellular morphogenesis and axial extension. AB - The grainyhead-like (grhl) transcription factors play crucial roles in craniofacial development, epithelial morphogenesis, neural tube closure, and dorso-ventral patterning. By utilising the zebrafish to differentially regulate expression of family members grhl2b and grhl3, we show that both genes regulate epithelial migration, particularly convergence-extension (CE) type movements, during embryogenesis. Genetic deletion of grhl3 via CRISPR/Cas9 results in failure to complete epiboly and pre-gastrulation embryonic rupture, whereas morpholino (MO)-mediated knockdown of grhl3 signalling leads to aberrant neural tube morphogenesis at the midbrain-hindbrain boundary (MHB), a phenotype likely due to a compromised overlying enveloping layer (EVL). Further disruptions of grhl3-dependent pathways (through co-knockdown of grhl3 with target genes spec1 and arhgef19) confirm significant MHB morphogenesis and neural tube closure defects. Concomitant MO-mediated disruption of both grhl2b and grhl3 results in further extensive CE-like defects in body patterning, notochord and somite morphogenesis. Interestingly, over-expression of either grhl2b or grhl3 also leads to numerous phenotypes consistent with disrupted cellular migration during gastrulation, including embryo dorsalisation, axial duplication and impaired neural tube migration leading to cyclopia. Taken together, our study ascribes novel roles to the Grhl family in the context of embryonic development and morphogenesis. PMID- 29242589 TI - CAR T cells - what have we learnt? PMID- 29242590 TI - Lung cancer: First-in-man phase I trial with lorlatinib. PMID- 29242588 TI - In retinitis pigmentosa TrkC.T1-dependent vectorial Erk activity upregulates glial TNF-alpha, causing selective neuronal death. AB - In some diseases the TrkC.T1 isoform is upregulated in glia, associated with glial TNF-alpha production and neuronal death. What remains unknown are the activating signals in glia, and how paracrine signals may be selective for a targeted neuron while sparing other proximate neurons. We studied these questions in the retina, where Muller glia contacts photoreceptors on one side and retinal ganglion cells on the other. In a mutant Rhodopsin mouse model of retinitis pigmentosa (RP) causing progressive photoreceptor death-but sparing retinal ganglion cells-TrkC.T1 and NT-3 ligand are upregulated in Muller glia. TrkC.T1 activity generates p-Erk, which causes increased TNF-alpha. These sequential events take place predominantly in Muller fibers contacting stressed photoreceptors, and culminate in selective death. Each event and photoreceptor death can be prevented by reduction of TrkC.T1 expression, by pharmacological antagonism of TrkC or by pharmacological inhibition Erk. Unmasking the sequence of non-cell autologous events and mechanisms causing selective neuronal death may help rationalize therapies. PMID- 29242591 TI - Colorectal cancer: Defining location effect in nonmetastatic disease. PMID- 29242592 TI - Immunotherapy: No effect of CAR-T-cell infusion on infection risk. PMID- 29242593 TI - Dual repression of endocytic players by ESCC microRNAs and the Polycomb complex regulates mouse embryonic stem cell pluripotency. AB - Cell fate determination in the early mammalian embryo is regulated by multiple mechanisms. Recently, genes involved in vesicular trafficking have been shown to play an important role in cell fate choice, although the regulation of their expression remains poorly understood. Here we demonstrate for the first time that multiple endocytosis associated genes (EAGs) are repressed through a novel, dual mechanism in mouse embryonic stem cells (mESCs). This involves the action of the Polycomb Repressive Complex, PRC2, as well as post-transcriptional regulation by the ESC-specific cell cycle-regulating (ESCC) family of microRNAs. This repression is relieved upon differentiation. Forced expression of EAGs in mESCs results in a decrease in pluripotency, highlighting the importance of dual repression in cell fate regulation. We propose that endocytosis is critical for cell fate choice, and dual repression may function to tightly regulate levels of endocytic genes. PMID- 29242594 TI - Automated tracking to measure behavioural changes in pigs for health and welfare monitoring. AB - Since animals express their internal state through behaviour, changes in said behaviour may be used to detect early signs of problems, such as in animal health. Continuous observation of livestock by farm staff is impractical in a commercial setting to the degree required to detect behavioural changes relevant for early intervention. An automated monitoring system is developed; it automatically tracks pig movement with depth video cameras, and automatically measures standing, feeding, drinking, and locomotor activities from 3D trajectories. Predictions of standing, feeding, and drinking were validated, but not locomotor activities. An artificial, disruptive challenge; i.e., introduction of a novel object, is used to cause reproducible behavioural changes to enable development of a system to detect the changes automatically. Validation of the automated monitoring system with the controlled challenge study provides a reproducible framework for further development of robust early warning systems for pigs. The automated system is practical in commercial settings because it provides continuous monitoring of multiple behaviours, with metrics of behaviours that may be considered more intuitive and have diagnostic validity. The method has the potential to transform how livestock are monitored, directly impact their health and welfare, and address issues in livestock farming, such as antimicrobial use. PMID- 29242595 TI - Germline BRCA mutation in male carriers-ripe for precision oncology? AB - BACKGROUND: Prostate cancer (PC) is one of the known heritable cancers with individual variations attributed to genetic factors. BRCA1 and BRCA2 are tumour suppressor genes with crucial roles in repairing DNA and thereby maintaining genomic integrity. Germline BRCA mutations predispose to multiple familial tumour types including PC. METHODS: We performed a Pubmed database search along with review of reference lists from prominent articles to capture papers exploring the association between BRCA mtuations and prostate cancer risk and prognosis. Articles were retrieved until May 2017 and filtered for relevance, and publication type. RESULTS: We explored familial PC genetics; discussed the discovery and magnitude of the association between BRCA mutations and PC risk and outcome; examined implications of factoring BRCA mutations into PC screening; and discussed the rationale for chemoprevention in this high-risk population. We confirmed that BRCA1/2 mutations confer an up to 4.5-fold and 8.3-fold increased risk of PC, respectively. BRCA2 mutations are associated with an increased risk of high-grade disease, progression to metastatic castration-resistant disease, and 5-year cancer-specific survival rates of 50 to 60%. CONCLUSION: Despite the growing body of research on DNA repair genes, deeper analysis is needed to understand the aetiological role of germline BRCA mutations in the natural history of PC. There is a need for awareness to screen for this marker of PC risk. There is similarly an opportunity for structured PC screening programs for BRCA mutation carriers. Finally, further research is required to identify potential chemopreventive strategies for this high-risk subgroup. PMID- 29242596 TI - Total energy expenditure and vigorous-intensity physical activity are associated with reduced odds of reclassification among men on active surveillance. AB - BACKGROUND: Research examining the association between physical activity (PA) and prostate cancer (PCa) has accumulated; however, few studies have examined this association in the context of active surveillance. The current study examines this among men initially diagnosed with favorable-risk PCa and managed by active surveillance at Sunnybrook Health Sciences Centre in Canada and the Royal Marsden Hospital in the United Kingdom. METHODS: Participants completed a questionnaire on daily participation in non-leisure, transport, and recreational PA. A logistic regression was employed using PA as the independent variable and whether the patient reclassified to higher-risk PCa while on active surveillance as the dependent variable. Demographic and lifestyle covariates were incorporated in the analysis to assess potential confounding and effect modification. RESULTS: Men from both hospitals presented with similar clinical and demographic characteristics. Total PA was inversely associated with odds of reclassification while on active surveillance (p-trend = 0.027). A weaker inverse association was observed with recreational PA (p-trend = 0.30). Men who participated in weekly vigorous PA were less likely to reclassify than those who did not (odds ratio (95% confidence interval): 0.42 (0.20-0.85)). CONCLUSIONS: Total and vigorous PA were inversely associated with odds of reclassification in two active surveillance cohorts. Given the limitations of this study, more robust prospective observational studies involving objective PA measures are warranted to confirm findings. PMID- 29242597 TI - Rheological Droplet Interface Bilayers (rheo-DIBs): Probing the Unstirred Water Layer Effect on Membrane Permeability via Spinning Disk Induced Shear Stress. AB - A new rheological droplet interface bilayer (rheo-DIB) device is presented as a tool to apply shear stress on biological lipid membranes. Despite their exciting potential for affecting high-throughput membrane translocation studies, permeability assays conducted using DIBs have neglected the effect of the unstirred water layer (UWL). However as demonstrated in this study, neglecting this phenomenon can cause significant underestimates in membrane permeability measurements which in turn limits their ability to predict key processes such as drug translocation rates across lipid membranes. With the use of the rheo-DIB chip, the effective bilayer permeability can be modulated by applying shear stress to the droplet interfaces, inducing flow parallel to the DIB membranes. By analysing the relation between the effective membrane permeability and the applied stress, both the intrinsic membrane permeability and UWL thickness can be determined for the first time using this model membrane approach, thereby unlocking the potential of DIBs for undertaking diffusion assays. The results are also validated with numerical simulations. PMID- 29242598 TI - Mismatched unrelated donor allogeneic stem cell transplant for high risk haematological malignancy: A single centre experience. PMID- 29242599 TI - Stochastic gene expression in Arabidopsis thaliana. AB - Although plant development is highly reproducible, some stochasticity exists. This developmental stochasticity may be caused by noisy gene expression. Here we analyze the fluctuation of protein expression in Arabidopsis thaliana. Using the photoconvertible KikGR marker, we show that the protein expressions of individual cells fluctuate over time. A dual reporter system was used to study extrinsic and intrinsic noise of marker gene expression. We report that extrinsic noise is higher than intrinsic noise and that extrinsic noise in stomata is clearly lower in comparison to several other tissues/cell types. Finally, we show that cells are coupled with respect to stochastic protein expression in young leaves, hypocotyls and roots but not in mature leaves. Our data indicate that stochasticity of gene expression can vary between tissues/cell types and that it can be coupled in a non-cell-autonomous manner. PMID- 29242600 TI - Author Correction: Resonant out-of-phase fluorescence microscopy and remote imaging overcome spectral limitations. AB - The Peer Review File associated with this Article was updated shortly after publication to redact from the authors' point-by-point response a description of unpublished work describing how Speed OPIOM may in future be used to facilitate discrimination between FRET and direct excitation. PMID- 29242601 TI - Cell cycle synchronisation of Trypanosoma brucei by centrifugal counter-flow elutriation reveals the timing of nuclear and kinetoplast DNA replication. AB - We report an optimised centrifugal counter-flow elutriation protocol for the rapid and direct isolation of G1 cell cycle synchronised populations of both the procyclic and bloodstream form stages of Trypanosoma brucei that yields viable and proliferative cells. The high quality of the synchronisation achieved can be judged by the uniform DNA content, narrow size distribution, synchronous division, and the maintenance of synchronicity into subsequent cell cycles. We show that early-eluting fractions represent different G1 subpopulations that progress through the cell cycle with distinct temporal profiles post-elutriation, as exemplified by the observation of the maturation of a second flagellar basal body in late G1 phase, DNA replication in S phase, and dimethylation of histone H3 in mitosis/cytokinesis. We use our temporal observations to construct a revised model of the relative timing and duration of the nuclear and kinetoplast cell cycle that differs from the current model. PMID- 29242602 TI - Altered heart rate regulation by the autonomic nervous system in mice lacking natriuretic peptide receptor C (NPR-C). AB - Natriuretic peptides (NPs) play essential roles in the regulation of cardiovascular function. NP effects are mediated by receptors known as NPR-A, NPR B or NPR-C. NPs have potent effects on regulation of heart rate (HR) by the autonomic nervous system (ANS), but the role of NPR-C in these effects has not been investigated. Accordingly, we have used telemetric ECG recordings in awake, freely moving wildtype and NPR-C knockout (NPR-C-/-) mice and performed heart rate variability (HRV) analysis to assess alterations in sympatho-vagal balance on the heart following loss of NPR-C. Our novel data demonstrate that NPR-C-/- mice are characterized by elevations in HR, reductions in circadian changes in HR and enhanced occurrence of sinus pauses, indicating increased arrhythmogenesis and a loss of HRV. Time domain and frequency domain analyses further demonstrate that HRV is reduced in NPR-C-/- mice in association with a reduction in parasympathetic activity. Importantly, the low frequency to high frequency ratio was increased in NPR-C-/- mice indicating that sympathetic activity is also enhanced. These changes in autonomic regulation were confirmed using atropine and propranolol to antagonize the ANS. These findings illustrate that loss of NPR-C reduces HRV due to perturbations in the regulation of the heart by the ANS. PMID- 29242603 TI - Development of expression-based biomarkers of Dasatinib response in hematologic malignancies. PMID- 29242605 TI - DDIAS suppresses TRAIL-mediated apoptosis by inhibiting DISC formation and destabilizing caspase-8 in cancer cells. AB - DNA damage-induced apoptosis suppressor (DDIAS) has an anti-apoptotic function during DNA damage in lung cancer. However, the anti-apoptotic mechanism of DDIAS in cancer cells under other conditions has not been reported. We report here that DDIAS protects cancer cells from tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by two distinct mechanisms in non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC) cells. DDIAS depletion sensitized NSCLC and HCC cells to TRAIL-mediated apoptosis, an effect that was abrogated by pharmacological or genetic inhibition of caspase-8 and was independent of caspase-9, p53, or mitogen-activated protein kinase signaling. Interestingly, we found that the N terminus of DDIAS interacted with the death effector domain of Fas-associated protein death domain (FADD) and prevented its recruitment to the death-inducing signaling complex (DISC), thereby blocking caspase-8 activation. DDIAS knockdown also suppressed epidermal growth factor induced phosphorylation of p90 ribosomal S6 kinase (RSK) 2 and stabilized caspase 8 by preventing its ubiquitination and proteasomal degradation. This effect was abolished by RSK2 overexpression. Taken together, DDIAS has dual functions in inhibiting DISC formation as well as in destabilizing caspase-8, thereby suppressing TRAIL-mediated apoptosis of cancer cells. Thus, we suggest that DDIAS can serve as an effective therapeutic target in the treatment of NSCLC and HCC. PMID- 29242604 TI - Ribosomal protein S15a promotes tumor angiogenesis via enhancing Wnt/beta-catenin induced FGF18 expression in hepatocellular carcinoma. AB - Ribosomal protein s15a (RPS15A) plays a promotive role in the mRNA/ribosome interactions during early translation. Our previous study has found that inhibiting RPS15A expression can decrease proliferation and induce cell cycle arrest in hepatocellular carcinoma (HCC) cell lines. However, the mechanism underlying the involvement of RPS15A in HCC pathogenesis and the clinical significance of RPS15A expression remain unclear. In this study, an evaluation of RPS15A expression in 110 surgically resected HCCs and matched tumor-adjacent normal tissues revealed an overexpression of RPS15A in HCC, which was correlated with worse survival. In addition, tumor tissue with higher RPS15A expression demonstrated a higher microvascular density (MVD). Subsequently, two HCC cell lines, Huh7 (low-level constitutive RPS15A expression) and HepG2 (high RPS15A expression) were used to further evaluate the role of RPS15A in angiogenesis. The co-culture experiment of HCC cells with endothelial cells revealed that the induced overexpression of RPS15A in Huh7 cells increased the angiogenic potential of HUVEC in a paracrine fashion; conversely, knockdown of RPS15A in HepG2 cells showed an opposite effect. Further analysis indicated that RPS15A modulated FGF signaling by enhancing Wnt/beta-catenin-mediated FGF18 expression in HCC cells. FGF18, in turn, through binding to its FGFR3 receptor on endothelial cells, can activate the AKT and ERK pathway and promotes angiogenesis in a tumor microenvironment. Our in vivo experiment further confirmed that inhibition of RPS15A expression in HCC xenografts dramatically hindered tumor growth and inhibited tumor angiogenesis. Together, our findings suggest that RPS15A promotes angiogenesis in HCCs by enhancing Wnt/beta-catenin induced FGF18 expression. The RPS15A/FGF18 pathway may be a rational target for anti-angiogenic therapy of HCC. PMID- 29242606 TI - Murine stroma adopts a human-like metabolic phenotype in the PDX model of colorectal cancer and liver metastases. AB - Cancer research is increasingly dependent of patient-derived xenograft model (PDX). However, a major point of concern regarding the PDX model remains the replacement of the human stroma with murine counterpart. In the present work we aimed at clarifying the significance of the human-to-murine stromal replacement for the fidelity of colorectal cancer (CRC) and liver metastasis (CRC-LM) PDX model. We have conducted a comparative metabolic analysis between 6 patient tumors and corresponding PDX across 4 generations. Metabolic signatures of cancer cells and stroma were measured separately by MALDI-imaging, while metabolite changes in entire tumors were quantified using mass spectrometry approach. Measurement of glucose metabolism was also conducted in vivo using [18F] fluorodeoxyglucose (FDG) and positron emission tomography (PET). In CRC/CRC-LM PDX model, human stroma was entirely replaced at the second generation. Despite this change, MALDI-imaging demonstrated that the metabolic profiles of both stromal and cancer cells remained stable for at least four generations in comparison to the original patient material. On the tumor level, profiles of 86 water-soluble metabolites as well as 93 lipid mediators underlined the functional stability of the PDX model. In vivo PET measurement of glucose uptake (reflecting tumor glucose metabolism) supported the ex vivo observations. Our data show for the first time that CRC/CRC-LM PDX model maintains the functional stability at the metabolic level despite the early replacement of the human stroma by murine cells. The findings demonstrate that human cancer cells actively educate murine stromal cells during PDX development to adopt the human-like phenotype. PMID- 29242607 TI - The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling. AB - Carcinoma-associated fibroblasts (CAFs) influence tumor initiation, progression, and metastasis within the tumor-associated stroma. This suggests that CAFs would be a potential target for tumor therapy. Here we found that Hydrogen peroxide inducible clone-5 (Hic-5), also named transforming growth factor beta-1-induced transcript 1 protein (Tgfb1i1), was strongly induced in CAFs found in human colorectal cancer. To investigate the role of Hic-5 in CAFs, we isolated CAFs and the control counterpart normal fibroblasts (NFs) from human colorectal cancer and non-cancerous regions, respectively. Hic-5 was highly expressed in isolated human CAFs and strongly induced in NFs in culture by the supernatant from cultured colorectal cancer cells as well as cytokines such as TGF-beta, IL-1beta and stromal cell-derived factor 1 (SDF-1/CXCL12). Furthermore, tumor growth was inhibited in a co-culture assay with Hic-5 knockdown fibroblasts compared with control fibroblasts. To clarify the function and significance of Hic-5 in colorectal cancer in vivo, we utilized a mouse model of azoxymethane (AOM) induced colorectal cancer using Hic-5-deficient mice. Lack of Hic-5 in CAFs completely prevented AOM-induced colorectal cancer development in the colon tissues of mice. Mechanistic investigation revealed that Hic-5 promoted the expression of lysyl oxidase and collagen I in human control counterpart fibroblasts. Taken together, these results demonstrate that Hic-5 in CAFs is responsible for orchestrating or generating a tumor-promoting stroma. PMID- 29242610 TI - Cancer: Strategies for mature T cell cancers. PMID- 29242611 TI - Infectious disease: Blocking malaria parasite invasion and egress. PMID- 29242612 TI - Drug discovery effectiveness from the standpoint of therapeutic mechanisms and indications. AB - This corrects the article DOI: 10.1038/nrd.2017.194. PMID- 29242608 TI - Immunotherapies for malignant glioma. AB - Glioblastoma multiforme (GBM) is a highly malignant primary brain cancer with a dreadful overall survival and for which treatment options are limited. Recent breakthroughs in novel immune-related treatment strategies for cancer have spurred interests in usurping the power of the patient's immune system to recognize and eliminate GBM. Here, we discuss the unique properties of GBM's tumor microenvironment, the effects of GBM standard on care therapy on tumor associated immune cells, and review several approaches aimed at therapeutically targeting the immune system for GBM treatment. We believe that a comprehensive understanding of the intricate micro-environmental landscape of GBM will abound into the development of novel immunotherapy strategies for GBM patients. PMID- 29242613 TI - Addressing challenges in the diagnosis and treatment of rare genetic diseases. AB - The past 5 years have seen an unprecedented rate of discovery of genes that cause rare diseases and with it a commensurate increase in the number of diagnosable but nevertheless untreatable disorders. Here, we discuss the increasing opportunity for diagnosis and therapy of rare diseases and how to tackle the associated challenges. PMID- 29242609 TI - Automating drug discovery. AB - Small-molecule drug discovery can be viewed as a challenging multidimensional problem in which various characteristics of compounds - including efficacy, pharmacokinetics and safety - need to be optimized in parallel to provide drug candidates. Recent advances in areas such as microfluidics-assisted chemical synthesis and biological testing, as well as artificial intelligence systems that improve a design hypothesis through feedback analysis, are now providing a basis for the introduction of greater automation into aspects of this process. This could potentially accelerate time frames for compound discovery and optimization and enable more effective searches of chemical space. However, such approaches also raise considerable conceptual, technical and organizational challenges, as well as scepticism about the current hype around them. This article aims to identify the approaches and technologies that could be implemented robustly by medicinal chemists in the near future and to critically analyse the opportunities and challenges for their more widespread application. PMID- 29242614 TI - Cancer Immunotherapy: The right shape. PMID- 29242615 TI - Mechanistic enzymology in drug discovery: a fresh perspective. AB - This corrects the article DOI: 10.1038/nrd.2017.219. PMID- 29242616 TI - Anemia in myelofibrosis-prevalence, the U2AF1 connection, new treatments. PMID- 29242617 TI - Diversity of trion states and substrate effects in the optical properties of an MoS2 monolayer. AB - Almost all experiments and future applications of transition metal dichalcogenide monolayers rely on a substrate for mechanical stability, which can significantly modify the optical spectra of the monolayer. Doping from the substrate might lead to the domination of the spectra by trions. Here we show by ab initio many-body theory that the negative trion (A-) splits into three excitations, with both inter- and intra-valley character, while the positive counterpart (A+) consists of only one inter-valley excitation. Furthermore, the substrate enhances the screening, which renormalizes both band gap and exciton as well as the trion binding energies. We verify that these two effects do not perfectly cancel each other, but lead to red-shifts of the excitation energies for three different substrates ranging from a wide-bandgap semiconductor up to a metal. Our results explain recently found experimental splittings of the lowest trion line as well as excitation red-shifts on substrates. PMID- 29242618 TI - A Simple Platform for the Rapid Development of Antimicrobials. AB - Recent infectious outbreaks highlight the need for platform technologies that can be quickly deployed to develop therapeutics needed to contain the outbreak. We present a simple concept for rapid development of new antimicrobials. The goal was to produce in as little as one week thousands of doses of an intervention for a new pathogen. We tested the feasibility of a system based on antimicrobial synbodies. The system involves creating an array of 100 peptides that have been selected for broad capability to bind and/or kill viruses and bacteria. The peptides are pre-screened for low cell toxicity prior to large scale synthesis. Any pathogen is then assayed on the chip to find peptides that bind or kill it. Peptides are combined in pairs as synbodies and further screened for activity and toxicity. The lead synbody can be quickly produced in large scale, with completion of the entire process in one week. PMID- 29242619 TI - Instagram, Flickr, or Twitter: Assessing the usability of social media data for visitor monitoring in protected areas. AB - Social media data is increasingly used as a proxy for human activity in different environments, including protected areas, where collecting visitor information is often laborious and expensive, but important for management and marketing. Here, we compared data from Instagram, Twitter and Flickr, and assessed systematically how park popularity and temporal visitor counts derived from social media data perform against high-precision visitor statistics in 56 national parks in Finland and South Africa in 2014. We show that social media activity is highly associated with park popularity, and social media-based monthly visitation patterns match relatively well with the official visitor counts. However, there were considerable differences between platforms as Instagram clearly outperformed Twitter and Flickr. Furthermore, we show that social media data tend to perform better in more visited parks, and should always be used with caution. Based on stakeholder discussions we identified potential reasons why social media data and visitor statistics might not match: the geography and profile of the park, the visitor profile, and sudden events. Overall the results are encouraging in broader terms: Over 60% of the national parks globally have Twitter or Instagram activity, which could potentially inform global nature conservation. PMID- 29242620 TI - Protective role of trehalose during radiation and heavy metal stress in Aureobasidium subglaciale F134. AB - An isolated black yeast-like strain was obtained from radiation-polluted soil collected from Xinjiang province in northwest China. On the basis of ITS and LSU rDNA sequence analysis, in combination with the colony morphology and phenotypic properties, the isolated strain was revealed to represent a novel variety of Aureobasidium subglaciale, designated as A. subglaciale F134. Compared to other yeasts and bacteria, this isolate displayed superior resistance to gamma irradiation, UV light, and heavy metal ions. It was discovered that the resistance of the isolate was correlated with the stress protector trehalose. Through the overexpression of the trehalose-6-phosphate synthase gene tps1 and the deletion of acid trehalase gene ath1, the APT?A double mutant exhibited a survival rate of 1% under 20 kGy of gamma-radiation, 2% survival rate at a UV dosage of 250 J/m2, and tolerance towards Pb2+ as high as 1500 mg/L, which was in agreement with the high accumulation of intracellular trehalose compared to the wild-type strain. Finally, the protective effects and the mechanism of trehalose accumulation in A. subglaciale F134 were investigated, revealing a significant activation of the expression of many of the stress tolerance genes, offering new perspectives on the adaptations of radioresistant microorganisms. PMID- 29242621 TI - Fractal analysis of collision cascades in pulsed-ion-beam-irradiated solids. AB - The buildup of radiation damage in ion-irradiated crystals often depends on the spatial distribution of atomic displacements within collision cascades. Although collision cascades have previously been described as fractals, the correlation of their fractal parameters with experimental observations of radiation damage buildup remains elusive. Here, we use a pulsed-ion-beam method to study defect interaction dynamics in 3C-SiC irradiated at 100 degrees C with ions of different masses. These data, together with results of previous studies of SiC and Si, are analyzed with a model of radiation damage formation which accounts for the fractal nature of collision cascades. Our emphasis is on the extraction of the effective defect diffusion length from pulsed beam measurements. Results show that, for both Si and SiC, collision cascades are mass fractals with fractal dimensions in the range of ~1-2, depending on ion mass, energy, and the depth from the sample surface. Within our fractal model, the effective defect diffusion length is ~10 nm for SiC and ~20 nm for Si, and it decreases with increasing cascade density. These results demonstrate a general method by which the fractal nature of collision cascades can be used to explain experimental observations and predict material's response to radiation. PMID- 29242622 TI - Assessment of disturbed glucose metabolism and surrogate measures of insulin sensitivity in obese children and adolescents. AB - BACKGROUND: With the rising prevalence of obesity and type 2 diabetes (T2D) in obese children, it is becoming imperative to detect disturbed glucose metabolism as early as possible in order to prevent T2D development. SUBJECTS/METHODS: Cross sectional study of 92 obese children (median age 11.7 years, 51% female) and 7 lean children (median age 11.4 years, 57% female) who underwent an oral glucose tolerance test (OGTT) in a tertiary pediatric care center. Glucose tolerance was assessed and different indices for beta-cell function, insulin sensitivity and insulin secretion were calculated. RESULTS: Nineteen obese children were identified with prediabetes (PD, 12 impaired glucose tolerance, 4 increased fasting glucose and 3 combined). Compared with the 73 obese children with normal glucose tolerance (nGT), subjects with PD had higher insulin resistance, but lower insulin sensitivity and beta-cell function, although their glycated hemoglobin (HbA1c) levels were comparable. The Whole Body Insulin Sensitivity Index (WBISI) and beta-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) strongly correlated with the OGTT glucose area under the curve 0-120 min (r = 0.392, p < 0.0002; r = 0.547, p < 0.0001, respectively). When testing the relation between early insulin response during OGTT by insulinogenic index and insulin sensitivity assessed by WBISI, a hyperbolic relationship between insulin secretion and insulin sensitivity was found. The calculated disposition index was lower in subjects with PD vs. nGT (median 459 vs. 792, p = 0.004). We identified the OGTT 30-min/120-min insulin ratio as a simple marker, which is significantly lower in obese children with vs. without PD (median 0.87 vs. 1.29, p = 0.021) and which has a better sensitivity and specificity for detecting PD than HbA1c among obese children. CONCLUSIONS: Children with identified PD had changes of several markers for beta-cell function, insulin sensitivity and resistance before changes in HbA1c occurred. The lower disposition index indicates that these children have already inadequate beta-cell compensation for the degree of insulin resistance. PMID- 29242623 TI - Clinical and radiological responses to oral methotrexate alone or in combination with other agents in Erdheim-Chester disease. PMID- 29242624 TI - Plant-derived compounds strigolactone GR24 and pinosylvin activate SIRT1 and enhance glucose uptake in rat skeletal muscle cells. AB - Insulin resistance is a characteristic finding in hyperglycaemia and type 2 diabetes. SIRT1 is a NAD+ dependent deacetylase that plays a central role in glucose homeostasis and energy metabolism. SIRT1 activators, including plant polyphenols such as resveratrol, improve insulin sensitivity in skeletal muscle tissue. We hypothesised that the novel plant-derived compounds, strigolactone and pinosylvin, beneficially enhance SIRT1 function, insulin signalling, glucose uptake, and mitochondrial biogenesis in skeletal muscle cells. Rat L6 skeletal muscle myotubes were treated with strigolactone analogue GR24 and pinosylvin. Resveratrol was included in experiments as a reference compound. We measured the effects of these compounds on SIRT1 function, insulin signalling, glucose uptake, mitochondrial biogenesis and gene expression profiles. Strigolactone GR24 upregulated and activated SIRT1 without activating AMPK, enhanced insulin signalling, glucose uptake, GLUT4 translocation and mitochondrial biogenesis. Pinosylvin activated SIRT1 in vitro and stimulated glucose uptake through the activation of AMPK. The regulation of SIRT1 by strigolactone GR24 and the activation of AMPK by pinosylvin may offer novel therapeutic approaches in the treatment of insulin resistance in skeletal muscle. PMID- 29242625 TI - Regulation of hyperoxia-induced social behaviour in Pristionchus pacificus nematodes requires a novel cilia-mediated environmental input. AB - Social behaviours are frequently utilised for defence and stress avoidance in nature. Both Caenorhabditis elegans and Pristionchus pacificus nematodes display social behaviours including clumping and bordering, to avoid hyperoxic stress conditions. Additionally, both species show natural variation in social behaviours with "social" and "solitary" strains. While the single solitary C. elegans N2 strain has evolved under laboratory domestication due to a gain-of function mutation in the neuropeptide receptor gene npr-1, P. pacificus solitary strains are commonplace and likely ancestral. P. pacificus therefore provides an opportunity to further our understanding of the mechanisms regulating these complex behaviours and how they evolved within an ecologically relevant system. Using CRISPR/Cas9 engineering, we show that Ppa-npr-1 has minimal influence on social behaviours, indicating independent evolutionary pathways compared to C. elegans. Furthermore, solitary P. pacificus strains show an unexpected locomotive response to hyperoxic conditions, suggesting a novel regulatory mechanism counteracting social behaviours. By utilising both forward and reverse genetic approaches we identified 10 genes of the intraflagellar transport machinery in ciliated neurons that are essential for this inhibition. Therefore, a novel cilia mediated environmental input adds an additional level of complexity to the regulation of hyperoxia-induced social behaviours in P. pacificus, a mechanism unknown in C. elegans. PMID- 29242626 TI - Stable transgenerational epigenetic inheritance requires a DNA methylation sensing circuit. AB - Epigenetic states are stably propagated in eukaryotes. In plants, DNA methylation patterns are faithfully inherited over many generations but it is unknown how the dynamic activities of cytosine DNA methyltransferases and 5-methylcytosine DNA glycosylases interact to maintain epigenetic homeostasis. Here we show that a methylation-sensing gene regulatory circuit centered on a 5-methylcytosine DNA glycosylase gene is required for long-term epigenetic fidelity in Arabidopsis. Disrupting this circuit causes widespread methylation losses and abnormal phenotypes that progressively worsen over generations. In heterochromatin, these losses are counteracted such that methylation returns to a normal level over four generations. However, thousands of loci in euchromatin progressively lose DNA methylation between generations and remain unmethylated. We conclude that an actively maintained equilibrium between methylation and demethylation activities is required to ensure long-term stable inheritance of epigenetic information. PMID- 29242627 TI - Adding loci improves phylogeographic resolution in red mangroves despite increased missing data: comparing microsatellites and RAD-Seq and investigating loci filtering. AB - The widespread adoption of RAD-Seq data in phylogeography means genealogical relationships previously evaluated using relatively few genetic markers can now be addressed with thousands of loci. One challenge, however, is that RAD-Seq generates complete genotypes for only a small subset of loci or individuals. Simulations indicate that loci with missing data can produce biased estimates of key population genetic parameters, although the influence of such biases in empirical studies is not well understood. Here we compare microsatellite data (8 loci) and RAD-Seq data (six datasets ranging from 239 to 25,198 loci) from red mangroves (Rhizophora mangle) in Florida to evaluate how different levels of data filtering influence phylogeographic inferences. For all datasets, we calculated population genetic statistics and evaluated population structure, and for RAD-Seq datasets, we additionally examined population structure using coalescence. We found higher F ST using microsatellites, but that RAD-Seq-based estimates approached those based on microsatellites as more loci with more missing data were included. Analyses of RAD-Seq datasets resolved the classic Gulf-Atlantic coastal phylogeographic break, which was not significant in the microsatellite analyses. Applying multiple levels of filtering to RAD-Seq datasets can provide a more complete picture of potential biases in the data and elucidate subtle phylogeographic patterns. PMID- 29242630 TI - Heavy rainfall triggers increased nocturnal flight in desert populations of the Pacific black duck (Anas superciliosa). AB - Understanding of avian nocturnal flight comes mainly from northern hemisphere species in seasonal temperate ecosystems where nocturnal flight is often precisely timed and entrained by annual photoperiod. Here we investigate patterns of nocturnal flight in waterbirds of Australian desert ecosystems that fly considerable distances to find temporary water bodies formed from rainfall which is highly unpredictable seasonally and spatially, and when there is sufficient water, they then breed. How they perform these feats of navigation and physiology remain poorly known. Using GPS tracking of 38 satellite tagged Pacific black ducks (Anas superciliosa) in two contrasting ecosystems, before and after heavy rainfall we revealed a key role for facultative nocturnal flight in the movement ecology of this species. After large rainfall events, birds rapidly increased nocturnal flight activity in the arid aseasonal ecosystem, but not in the mesic seasonal one. Nocturnal flights occurred throughout the night in both ecosystems. Long range flights (>50 km in 2 hours) occurred almost exclusively at night; at night the distance flown was higher than during the day, birds visited more locations, and the locations were more widely dispersed. Our work reveals that heavy rainfall triggers increased nocturnal flight activity in desert populations of waterbirds. PMID- 29242628 TI - Mutant Runx2 regulates amelogenesis and osteogenesis through a miR-185-5p-Dlx2 axis. AB - Regulation of microRNAs (miRNA) has been extensively investigated in diseases; however, little is known about the roles of miRNAs in cleidocranial dysplasia (CCD). The aim of the present study was to investigate the potential involvement of miRNAs in CCD. In vitro site-directed mutagenesis was performed to construct three mutant Runx2 expression vectors, which were then transfected into LS8 cells and MC3T3-E1 cells, to determine the impact on amelogenesis and osteogenesis, respectively. miRCURY LNA miRNA microarray identify miR-185-5p as a miRNA target commonly induced by all three Runx2 mutants. Real-time quantitative PCR was applied to determine the expression of miR-185-5p and Dlx2 in samples. Dual luciferase reporter assays were conducted to confirm Dlx2 as a legitimate target of miR-185-5p. The suppressive effect of miR-185-5p on amelogenesis and osteogenesis of miR-185-5p was evaluated by RT-PCR and western blot examination of Amelx, Enam, Klk4, and Mmp20 gene and protein expression, and by Alizarin Red stain. We found that mutant Runx2 suppressed amelogenesis and osteogenesis. miR 185-5p, induced by Runx2, suppressed amelogenesis and osteogenesis. Furthermore, we identified Dlx2 as direct target of miR-185-5p. Consistently, Dlx2 expression was inversely correlated with miR-185-5p levels. This study highlights the molecular etiology and significance of miR-185-5p in CCD, and suggests that targeting miR-185-5p may represent a new therapeutic strategy in prevention or intervention of CCD. PMID- 29242631 TI - Cumulant expansion for fast estimate of non-Condon effects in vibronic transition profiles. AB - When existing, cumulants can provide valuable information about a given distribution and can in principle be used to either fully reconstruct or approximate the parent distribution function. A previously reported cumulant expansion approach for Franck-Condon profiles [Faraday Discuss., 150, 363 (2011)] is extended to describe also the profiles of vibronic transitions that are weakly allowed or forbidden in the Franck-Condon approximation (non-Condon profiles). In the harmonic approximation the cumulants of the vibronic profile can be evaluated analytically and numerically with a coherent state-based generating function that accounts for the Duschinsky effect. As illustration, the one-photon 1 1Ag -> 1 1B2u UV absorption profile of benzene in the electric dipole and (linear) Herzberg-Teller approximation is presented herein for zero Kelvin and finite temperatures. PMID- 29242629 TI - Immune microenvironment of experimental rat C6 gliomas resembles human glioblastomas. AB - Glioblastoma (GBM) is the most aggressive primary brain tumor, with ineffective anti-tumor responses and a poor prognosis despite aggressive treatments. GBM immune microenvironment is heterogenous and activation of specific immune populations in GBM is not fully characterized. Reliable animal models are critical for defining mechanisms of anti-tumor immunity. First we analyzed the immune subpopulations present in rat C6 gliomas. Using flow cytometry we determined kinetics of infiltration of myeloid cells and T lymphocytes into glioma-bearing brains. We found significant increases of the amoeboid, pro tumorigenic microglia/macrophages, T helper (Th) and T regulatory (Treg) cells in tumor-bearing brains, and rare infiltrating T cytotoxic (Tc) cells. Transcriptomic analyses of glioma-bearing hemispheres revealed overexpression of invasion and immunosuppression-related genes, reflecting the immunosuppressive microenvironment. Microglia, sorted as CD11b+CD45low cells from gliomas, displayed the pro-invasive and immunosuppressive type of activation. Accumulation of Th and Treg cells combined with the reduced presence of Tc lymphocytes in rat gliomas may result in the lack of effective anti-tumor responses. Transcriptional profiles of CD11b+ cells and composition of immune infiltrates in C6 gliomas indicate that rat C6 gliomas employ similar immune system evasion strategies as human GBMs. PMID- 29242632 TI - Quantitative assessment of cell fate decision between autophagy and apoptosis. AB - Autophagy and apoptosis are cellular processes that regulate cell survival and death, the former by eliminating dysfunctional components in the cell, the latter by programmed cell death. Stress signals can induce either process, and it is unclear how cells 'assess' cellular damage and make a 'life' or 'death' decision upon activating autophagy or apoptosis. A computational model of coupled apoptosis and autophagy is built here to analyze the underlying signaling and regulatory network dynamics. The model explains the experimentally observed differential deployment of autophagy and apoptosis in response to various stress signals. Autophagic response dominates at low-to-moderate stress; whereas the response shifts from autophagy (graded activation) to apoptosis (switch-like activation) with increasing stress intensity. The model reveals that cytoplasmic Ca2+ acts as a rheostat that fine-tunes autophagic and apoptotic responses. A G protein signaling-mediated feedback loop maintains cytoplasmic Ca2+ level, which in turn governs autophagic response through an AMP-activated protein kinase (AMPK)-mediated feedforward loop. Ca2+/calmodulin-dependent kinase kinase beta (CaMKKbeta) emerges as a determinant of the competing roles of cytoplasmic Ca2+ in autophagy regulation. The study demonstrates that the proposed model can be advantageously used for interrogating cell regulation events and developing pharmacological strategies for modulating cell decisions. PMID- 29242633 TI - Sexual function in women with polycystic ovary syndrome and their hormonal and clinical correlations. AB - Polycystic ovary syndrome (PCOS) appears to be related to sexual dysfunction, especially if associated with obvious clinical and hormonal signs of hyperandrogenism. The objective of this study was to determine the correlation of PCOS and its hormonal and clinical parameters with sexual function. This prospective, cross-sectional study conducted on 18-45-year-old PCOS women (according to the Rotterdam criteria), who were referred to the Reproductive Endocrinology Research Center, Iran, was invited to participate from January 2012 to December 2015. The Female Sexual Function Index (FSFI) was used to evaluate sexual function, and serum levels of total and free testosterone, androstenedione, and sex hormone-binding globulin (SHBG) were determined and employed to calculate free androgen index (FAI) values. Univariate and multiple logistic regression analyses were performed to examine the association between sexual dysfunction and independent variables. In all, 783 participated in the study and 492 women fully completed the Female Sexual Function Index (FSFI) questionnaire. Of these, 226 (45.75%) women met the criteria for sexual dysfunction. The mean age of women was 24.91 +/- 4.90 years. No significant association between having a low score for any FSFI domain and having a low serum total or free testosterone or androstenedione and SHBG level was demonstrated. There was association between FAI > 4.5 and increased sexual function score but it is not significant. Logistic regression analysis showed that there were significant associations between sexual function score and the literacy, alopecia, and infertility. No evidence of associations between low scores for any of the sexual domains evaluated and low serum total and free testosterone levels, but the low literacy, alopecia, and infertility contributed to low sexual function in women with PCOS. The burden of PCOS and sexual dysfunction suggests the need for further attention to this patient population. PMID- 29242634 TI - Extracellular matrix alterations after blood instillation in tunica albuginea of rats. AB - The cause of Peyronie's disease (PD) is still not completely understood. The objective of this study, therefore, was to analyze the histological and biochemical alterations that occur after the instillation of blood in the tunica albuginea (TA) of rats with an emphasis on the remodeling process of ECM. Thirty male Wistar rats were divided into 4 groups: two control groups with instillation of distilled water in TA followed by penectomy after 15 days or 45 days, respectively and two experimental groups with instillation of blood in TA followed by penectomy after 15 days or 45 days, respectively. Histological, immunofluorescent and immunohistochemical analyses were performed. The higher presence of fibrotic tissue in rats injected with blood demonstrated alterations in TA similar to inflammation found in PD. The increased expression of TGF-beta, MMP9, HPSE, and biglycan associated with the decreased expression of syndecan-1 and aggrecan in the experimental groups suggested an enhancement in the remodeling of ECM. The results contribute to show that blood instillation on TA appears to trigger alterations in the ECM similar to the ones found in inflammatory diseases such as PD. PMID- 29242635 TI - MYD88 mutations predict unfavorable prognosis in Chronic Lymphocytic Leukemia patients with mutated IGHV gene. PMID- 29242636 TI - A Millifluidic System for Analysis of Daphnia magna Locomotory Responses to Water born Toxicants. AB - Aquatic toxicity testing in environmental monitoring and chemical risk assessment is critical to assess water quality for human use as well as predict impact of pollutants on ecosystems. In recent years, studies have increasingly focused on the relevance of sub-lethal effects of environmental contaminants. Sub-lethal toxicity endpoints such as behavioural responses are highly integrative and have distinct benefits for assessing water quality because they occur rapidly and thus can be used to sense the presence of toxicants. Our work describes a Lab-on-a Chip system for the automated analysis of freshwater cladoceran Daphnia magna locomotory responses to water-born toxicants. The design combines a Lab-on-a-Chip system for Daphnia sp. culture under perfusion with time-resolved videomicroscopy and software tracking locomotory activity of multiple specimens. The application of the system to analyse the swimming behaviour of water fleas exposed to different concentrations of water-born toxicants demonstrated that Lab-on-a-Chip devices can become important research tools for behavioural ecotoxicology and water quality biomonitoring. PMID- 29242637 TI - Probing defect dynamics in monolayer MoS2 via noise nanospectroscopy. AB - Monolayer molybdenum disulfide (MoS2) has received intense interest as a strong candidate for next-generation electronics. However, the observed electrical properties of monolayer MoS2 exhibit several anomalies: samples universally exhibit unexpectedly low mobilities, n-type characteristics, and large contact resistances regardless of contact metal work function. These anomalies have been attributed to the presence of defects, but the mechanism behind this link has been elusive. Here we report the ionization dynamics of sulfur monovacancy defects in monolayer MoS2 probed via noise nanospectroscopy, realized by combining noise-current analysis with atomic force microscopy. Due to the nanoscale dimension of the in situ channel defined by the tip size, we probe a few monovacancy defects at a time. Monovacancy defects exhibit switching between three distinct ionization configurations, corresponding to charge states 0, -1, and -2. The most probable charge configurations are 0 and -1, providing a plausible mechanism to explain the observed anomalies of MoS2 monolayers. PMID- 29242638 TI - Re-calibration of coronary risk prediction: an example of the Seven Countries Study. AB - We aimed at performing a calibration and re-calibration process using six standard risk factors from Northern (NE, N = 2360) or Southern European (SE, N = 2789) middle-aged men of the Seven Countries Study, whose parameters and data were fully known, to establish whether re-calibration gave the right answer. Greenwood-Nam-D'Agostino technique as modified by Demler (GNDD) in 2015 produced chi-squared statistics using 10 deciles of observed/expected CHD mortality risk, corresponding to Hosmer-Lemeshaw chi-squared employed for multiple logistic equations whereby binary data are used. Instead of the number of events, the GNDD test uses survival probabilities of observed and predicted events. The exercise applied, in five different ways, the parameters of the NE-predictive model to SE (and vice-versa) and compared the outcome of the simulated re-calibration with the real data. Good re-calibration could be obtained only when risk factor coefficients were substituted, being similar in magnitude and not significantly different between NE-SE. In all other ways, a good re-calibration could not be obtained. This is enough to praise for an overall need of re-evaluation of most investigations that, without GNDD or another proper technique for statistically assessing the potential differences, concluded that re-calibration is a fair method and might therefore be used, with no specific caution. PMID- 29242639 TI - Development of an adenovirus vector vaccine platform for targeting dendritic cells. AB - Adenoviral (Ad) vector vaccines represent one of the most promising modern vaccine platforms, and Ad vector vaccines are currently being investigated in human clinical trials for infectious disease and cancer. Our studies have shown that specific targeting of adenovirus to dendritic cells dramatically enhanced vaccine efficacy. However, this was achieved using a molecular adapter, thereby necessitating a two component vector approach. To address the mandates of clinical translation of our strategy, we here sought to accomplish the goal of DC targeting with a single-component adenovirus vector approach. To redirect the specificity of Ad vector vaccines, we replaced the Ad fiber knob with fiber fibritin chimeras fused to DC1.8, a single-domain antibody (sdAb) specific for murine immature DC. We engineered a fiber-fibritin-sdAb chimeric molecule using the coding sequence for DC1.8, and then replaced the native Ad5 fiber knob sequence by homologous recombination. The resulting Ad5 virus, Ad5FF1.8, expresses the chimeric fiber-fibritin sdAb chimera. Infection with Ad5FF1.8 dramatically enhances transgene expression in DC2.4 dendritic cells compared with infection with native Ad5. Ad5FF1.8 infection of bone marrow-derived DC demonstrates that Ad5FF1.8 selectively infects immature DC consistent with the known specificity of DC1.8. Thus, sdAb can be used to selectively redirect the tropism of Ad5 vector vaccines, providing the opportunity to engineer Ad vector vaccines that are specifically targeted to DC, or specific DC subsets. PMID- 29242640 TI - Effects of maternal obesity on Wharton's Jelly mesenchymal stromal cells. AB - We investigated whether maternal metabolic environment affects mesenchymal stromal/stem cells (MSCs) from umbilical cord's Wharton's Jelly (WJ) on a molecular level, and potentially render them unsuitable for clinical use in multiple recipients. In this pilot study on umbilical cords post partum from healthy non-obese (BMI = 19-25; n = 7) and obese (BMI >= 30; n = 7) donors undergoing elective Cesarean section, we found that WJ MSC from obese donors showed slower population doubling and a stronger immunosuppressive activity. Genome-wide DNA methylation of triple positive (CD73+CD90+CD105+) WJ MSCs found 67 genes with at least one CpG site where the methylation difference was >=0.2 in four or more obese donors. Only one gene, PNPLA7, demonstrated significant difference on methylome, transcriptome and protein level. Although the number of analysed donors is limited, our data suggest that the altered metabolic environment related to excessive body weight might bear consequences on the WJ MSCs. PMID- 29242641 TI - Ubiquitin ligases in oncogenic transformation and cancer therapy. AB - The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including homeostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of the ubiquitin chains dictates the fate of the substrates, marking them for recognition and degradation by the proteasome or altering their subcellular localization or assembly into functional complexes. Both genetic and epigenetic alterations account for the deregulation of E3s in cancer. Consequently, the stability and/or activity of E3 substrates are also altered, in some cases leading to downregulation of tumour-suppressor activities and upregulation of oncogenic activities. A better understanding of the mechanisms underlying E3 regulation and function in tumorigenesis is expected to identify novel prognostic markers and to enable the development of the next generation of anticancer therapies. This Review summarizes the oncogenic and tumour-suppressor roles of selected E3s and highlights novel opportunities for therapeutic intervention. PMID- 29242642 TI - Targeting mutant p53 for efficient cancer therapy. AB - The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression. The high frequency of TP53 mutation in tumours has prompted efforts to restore normal function of mutant p53 and thereby trigger tumour cell death and tumour elimination. Small molecules that can reactivate missense-mutant p53 protein have been identified by different strategies, and two compounds are being tested in clinical trials. Novel approaches for targeting TP53 nonsense mutations are also underway. This Review discusses recent progress in pharmacological reactivation of mutant p53 and highlights problems and promises with these strategies. PMID- 29242644 TI - Parallelogram based approach for in vivo dose estimation of genotoxic metabolites in humans with relevance to reduction of animal experiments. AB - When employing metabolism studies of genotoxic compounds/metabolites and cancer tests for risk estimation, low exposure doses in humans are roughly extrapolated from high exposure doses in animals. An improvement is to measure the in vivo dose, i.e. area under concentration-time curve (AUC), of the causative genotoxic agent. In the present work, we propose and evaluate a parallelogram based approach for estimation of the AUC of genotoxic metabolites that incorporates in vitro metabolic data and existing knowledge from published in vivo data on hemoglobin (Hb) adduct levels, using glycidamide (GA) as a case study compound that is the genotoxic metabolite of acrylamide (AA). The estimated value of AUC of GA per AUC of AA from the parallelogram approach vs. that from Hb adduct levels measured in vivo were in good agreement; 0.087 vs. 0.23 in human and 1.4 vs. 0.53 in rat, respectively. The described parallelogram approach is simple, and can be useful to provide an approximate estimation of the AUC of metabolites in humans at low exposure levels for which sensitive methods for analyzing the metabolites are not available, as well as aid in reduction of animal experiments for metabolism studies that are to be used for cancer risk assessment. PMID- 29242643 TI - RNAs coordinate nuclear envelope assembly and DNA replication through ELYS recruitment to chromatin. AB - Upon fertilisation, the sperm pronucleus acquires the competence to replicate the genome through a cascade of events that link chromatin remodelling to nuclear envelope formation. The factors involved have been partially identified and are poorly characterised. Here, using Xenopus laevis egg extracts we show that RNAs are required for proper nuclear envelope assembly following sperm DNA decondensation. Although chromatin remodelling and pre-replication complex formation occur normally, RNA-depleted extracts show a defect in pre-RC activation. The nuclear processes affected by RNA-depletion included ELYS recruitment, which accounts for the deficiency in nuclear pore complex assembly. This results in failure in chromatin relaxation as well as in the import and proper nuclear concentration of the S-phase kinases necessary for DNA replication activation. Our results highlight a translation-independent RNA function necessary for the parental genome progression towards the early embryonic cell cycle programme. PMID- 29242645 TI - Retinal Angiogenesis Regulates Astrocytic Differentiation in Neonatal Mouse Retinas by Oxygen Dependent Mechanisms. AB - In mice, retinal vascular and astrocyte networks begin to develop at birth, expanding radially from the optic nerve head (ONH) towards the retinal periphery. The retinal vasculature grows towards the periphery ahead of differentiated astrocytes, but behind astrocytic progenitor cells (APCs) and immature astrocytes. Endothelial cell specific Vegfr-2 disruption in newborn mice not only blocked retinal vascular development but also suppressed astrocytic differentiation, reducing the abundance of differentiated astrocytes while causing the accumulation of precursors. By contrast, retinal astrocytic differentiation was accelerated by the exposure of wild-type newborn mice to hyperoxia for 24 hours, or by APC specific deficiency in hypoxia inducible factor (HIF)-2alpha, an oxygen labile transcription factor. These findings reveal a novel function of the retinal vasculature, and imply that in normal neonatal mice, oxygen from the retinal circulation may promote astrocytic differentiation, in part by triggering oxygen dependent HIF-2alpha degradation in astrocytic precursors. PMID- 29242646 TI - Reflective Small Angle Electron Scattering to Characterize Nanostructures on Opaque Substrates. AB - Features sizes in integrated circuits (ICs) are often at the scale of 10 nm and are ever shrinking. ICs appearing in today's computers and hand held devices are perhaps the most prominent examples. These smaller feature sizes demand equivalent advances in fast and accurate dimensional metrology for both development and manufacturing. Techniques in use and continuing to be developed include X-ray based techniques, optical scattering and of course the electron and scanning probe microscopy techniques. Each of these techniques have their advantages and limitations. Here the use of small angle electron beam scattering measurements in a reflection mode (RSAES) to characterize the dimensions and the shape of nanostructures on flat and opaque substrates is demonstrated using both experimental and theoretical evidence. In RSAES, focused electrons are scattered at angles smaller than 1 degrees with the assistance of electron optics typically used in transmission electron microscopy. A proof-of-concept experiment is combined with rigorous electron reflection simulations to demonstrate the efficiency and accuracy of RSAES as a method of non-destructive measurement of shapes of features less than 10 nm in size on flat and opaque substrates. PMID- 29242647 TI - Newer airway assessment techniques: A view on their utility. PMID- 29242648 TI - Enhancing airway assessment of patients with head and neck pathology using virtual endoscopy. AB - Studies have demonstrated that poor assessment and planning contribute to airway complications and that current airway assessment strategies have a poor diagnostic accuracy in predicting difficult intubation in the general population. Patients with head and neck pathology are at higher risk for difficulties during airway management and are more likely to need emergency surgical access. Therefore, thorough assessment of this group of patients is mandatory. The addition of virtual endoscopy (VE) to clinical history and computerised tomography imaging has been shown to improve diagnostic accuracy for supraglottic, glottic and infraglottic lesions and has a positive influence in formulating a more cautious and thorough airway management strategy in this high risk group of patients. This article reviews whether VE can enhance airway assessment in patients with head and neck pathology and help reduce airway complications. PMID- 29242649 TI - Dose-reversal effect relationship of three different doses of neostigmine in obese patients: A randomised clinical trial. AB - Background and Aims: Previous studies suggest that administration of vecuronium based on total body weight rather than ideal body weight (IBW) in obesity results in overdosing with prolonged recovery times. We hypothesised that larger doses of neostigmine could result in faster recovery in obese patients administered vecuronium based on total body weight. Methods: Forty-five obese American Society of Anesthesiologists' II patients undergoing elective surgery under general anaesthesia were randomised into 3 groups to receive neostigmine 30, 40 and 50 MUg/kg. Following induction, patients were paralysed with vecuronium 0.1 mg/kg based on total body weight. Reversal was achieved with neostigmine based on the patient's group, and time to train-of-four (TOF) ratios of 0.5, 0.7 and 0.9 measured. The primary outcome variable was time to achieve TOF ratio >0.9. Results: Neostigmine 50 MUg/kg achieved faster recovery to TOF 0.7 than neostigmine 30 and 40 MUg/kg. There was no significant difference in recovery times to TOF 0.7 in patients receiving either 30 or 40 MUg/kg of neostigmine. However, neostigmine 40 MUg/kg attained TOF ratio 0.9 faster than 30 MUg/kg. We did not note a significant difference between the 40 and 50 MUg/kg dose with regard to recovery of TOF to 0.9. Conclusion: Facilitated recovery from neuromuscular blockade to TOF of 0.7 was faster with neostigmine 50 MUg/kg compared to 40 or 30 MUg/kg. Recovery to TOF ratio of 0.9 was not significantly different with 40 or 50 MUg/kg doses although such time was faster as compared to 30 MUg/kg dose. PMID- 29242650 TI - Infusion dose requirement of rocuronium in patients on phenytoin therapy - A prospective comparative study. AB - Background and Aims: Patients with intracranial tumour are usually on anticonvulsants. Patients on phenytoin therapy demonstrate rapid metabolism of nondepolarising muscle relaxants secondary to enzyme induction. Infusion dose requirement of rocuronium in such patients has been sparingly studied. We studied the continuous infusion dose requirement of rocuronium bromide in patients on phenytoin therapy and its correlation with serum levels of phenytoin. Methods: Seventy-five patients scheduled for supratentorial tumour surgery were included in the study. Patients not on phenytoin were taken as control. The primary outcome variable studied was the infusion dose requirement of rocuronium in patients on phenytoin. Based on pre-operative serum phenytoin levels, study group patients were divided into two groups: sub-therapeutic level group (phenytoin level <10 MUg/mL) and therapeutic level group (phenytoin level >10 MUg/mL). Following anaesthesia induction, rocuronium bromide 0.6 mg/kg was administered to achieve tracheal intubation. Rocuronium infusion was titrated to maintain zero response on the train-of-four response. Results: Demographic data were comparable. Patients receiving phenytoin required higher infusion dose compared to the control group (0.429 +/- 0.2 mg/kg/h vs. 0.265 +/- 0.15 mg/kg/h, P < 0.001). The serum phenytoin level had no correlation to infusion dose requirement of rocuronium (0.429 +/- 0.205 mg/kg/h vs. 0.429 +/- 0.265 mg/kg/h (P = 0.815). The recovery was faster in the phenytoin group compared to the control group. Haowever, it was not clinically significant. Conclusion: The infusion dose requirement of rocuronium bromide in patients on phenytoin is higher and the serum levels of phenytoin does not influence the dose required. PMID- 29242651 TI - Perioperative sildenafil therapy for children with ventricular septal defects and associated pulmonary hypertension undergoing corrective surgery: A randomised clinical trial. AB - Background and Aims: Sildenafil is known to reduce pulmonary artery pressure but its role in the perioperative period has not been well studied. We aimed to evaluate the efficacy of sildenafil in controlling post-operative pulmonary hypertension in children with pulmonary hypertension undergoing surgeries for correction of ventricular septal defect. Methods: The patients were divided randomly into two groups of thirty each. Group 1 (placebo) received pre-operative placebo and post-operative sildenafil (0.5mg/kg every 6 hrs) while Group 2 (sildenafil) received pre- and post-operative sildenafil (0.5mg/kg every 6 hrs). Results: In the Group 1, systolic pulmonary artery pressure reduced from 81.63 (+/-12.1) mmHg preoperatively to 79.26 (+/-11.29) mmHg pre-cardiopulmonary bypass (CPB) and 56.76 (+/-11) mmHg (with 10 minutes post-CPB), whereas in Group 2, it reduced from 83.3 (+/-12.1) before surgery to 68.9 (+/-11.3) mmHg pre-CPB and after CPB, to 42.2 (+/-7.6) mmHg (P = 0.001). The mean pulmonary artery pressure decreased from 60.63 (+/-10.5) mmHg to 42.13 (+/-8.3) mmHg in the Group 1 whereas it reduced from 54.36 (+/-10) mmHg to 31.36 (+/-6.5) mmHg in Group 2 (P = 0.001). The reductions in pulmonary artery/aortic ratio and Intensive Care Unit stay were statistically significant No adverse effects were recorded. Conclusion: The use of perioperative sildenafil has a statistically significant reduction in the mean pulmonary artery pressure without any adverse effects. PMID- 29242652 TI - The effect of intravenous dextrose administration for prevention of post operative nausea and vomiting after laparoscopic cholecystectomy: A double-blind, randomised controlled trial. AB - Background and Aims: Post-operative nausea and vomiting (PONV) is a common and distressing complication after laparoscopic cholecystectomy (LC). The aim of this study was to evaluate the effect of intravenous (IV) dextrose administration for the prophylaxis of PONV after LC. Methods: In a double-blind, randomised controlled trial, a total of 150 female patients who were scheduled for elective LC were randomly assigned into two groups (A and B). Thirty minutes before induction of anaesthesia, patients received an infusion of 500 cc lactated Ringer's solution (Group A) and 5% dextrose in lactated Ringer's solution (Group B) and over a period of 30 min. All patients rated their nausea and vomiting intensity using the verbal rating scale immediately at post-anaesthesia care unit (PACU) arrival; 30, 60, 90 and 120 min after arriving at the PACU and 6, 12 and 24 h after surgery. Results: There was a statistically significant time trend and group effect along with significant differences in time/group interaction effect in both groups for nausea and vomiting scores (P < 0.05). A low negative correlation coefficient was found (r = -0.394, P < 0.001) between blood glucose levels and nausea scores upon PACU arrival. Dextrose administration reduced the odds of vomiting events compared to placebo (estimate: -0.87, odds ratio = 0.42, 95% confidence interval: 0.28-0.64). Conclusion: Administration of IV dextrose before anaesthesia induction may be recommended as an effective, and safe method for the prophylaxis of PONV after LC. PMID- 29242653 TI - Awake orotracheal fibre-optic intubation: Comparison of two different doses of dexmedetomidine on intubation conditions in patients undergoing cervical spine surgery. AB - Background and Aims: Awake fibre-optic intubation (AFOI) is an integral part of anaesthetic management of difficult airways. Conscious sedation is essential to assist AFOI. This study compared two different doses of dexmedetomidine in combination with topical spray and airway blocks for awake orotracheal fibre optic intubation in patients undergoing elective cervical spine surgery with rigid cervical collar in situ. Methods: A randomized, prospective, comparative study design was conducted in sixty patients divided into two groups: Group (L) (n = 30) patients received low dose of dexmedetomidine (0.5 MUg/kg) along with airway blocks and Group (H) (n = 30) patients received standard dose of dexmedetomidine (1 MUg/kg) along with airway blocks. Both the groups received dexmedetomidine infusion over 10 min followed by airway block. Quantitative data were analysed by applying Student's t-test whereas qualitative data were analysed with Chi-square test. The objectives were to compare patients' Observer's Assessment of Alertness/Sedation scale (OAA/S) as primary outcome and other variables such as endoscopy, intubation condition, tolerance and haemodynamic stability among low and standard doses of dexmedetomidine. Results: Group H had more favourable OAA/S score than that of Group L, but endoscopy and intubation time, patient tolerance, vocal cord and limb movement and satisfaction score did not differ significantly between the groups. There were no significant haemodynamic differences between the two groups. Conclusion: The 0.5 MUg/kg dose of dexmedetomidine was found optimal and effective in combination with topical spray and airway blocks for awake orotracheal fibre-optic intubation for patients undergoing elective cervical spine surgery. PMID- 29242654 TI - Comparison of volume control and pressure control ventilation in patients undergoing single level anterior cervical discectomy and fusion surgery. AB - Background and Aims: Pressure control and volume control ventilation are the most preferred modes of ventilator techniques available in the intraoperative period. The study compared the intraoperative ventilator and blood gas variables of volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) in patients undergoing single level anterior cervical discectomy and fusion (ACDF). Methods: After obtaining Institutional Ethical Committee approval and informed consent, sixty patients scheduled for single level ACDF surgery performed in supine position under general anaesthesia were included. Group V (30 patients) received VCV and Group P (30 patients) received PCV. The primary objective was oxygenation variable PaO2/FiO2 at different points of time i.e. T1-20 min after the institution of the ventilation, T2-20 min after placement of the retractors and T3-20 min after removal of the retractors. The secondary objectives include other arterial blood gas parameters, respiratory and haemodynamic parameters. NCSS version 9 statistical software was used for statistics. Two-way repeated measures for analysis of variance with post hoc Tukey Kramer test was used to analyse continuous variables for both intra- and inter-group comparisons, paired sample t-test for overall comparison and Chi-square test for categorical data. Results: The primary variable PaO2/FiO2 was comparable in both groups (P = 0.08). The respiratory variables, PAP and Cdynam were statistically significant in PCV group compared to VCV (P < 0.05), though clinically insignificant. Other secondary variables were comparable. (P > 0.05). Conclusion: Clinically, both PCV and VCV group appear to be-equally suited ventilator techniques for anterior cervical spine surgery patients. PMID- 29242655 TI - Evaluation of the role of dexmedetomidine in improvement of the analgesic profile of thoracic paravertebral block in thoracic surgeries: A randomised prospective clinical trial. AB - Background and Aims: Thoracic paravertebral block (TPB) is one of the effective methods for management of post-operative pain in thoracic surgeries. The aim of the study was to evaluate effectiveness of addition of dexmedetomidine to paravertebral block with bupivacaine in improving the postoperative pain relief and pulmonary functions in patients undergoing thoracic surgeries. Methods: A prospective randomized double-blinded study was performed on forty patients scheduled for thoracic surgery. A paravertebral catheter was secured under ultrasound guidance preoperatively for all patients. Group B (n = 20) received a bolus dose of 0.25% bupivacaine at 0.3 mL/kg followed by continuous infusion of 0.125% bupivacaine 0.1 mL/kg/h. Group (BD) received a bolus dose of 0.25% bupivacaine + dexmedetomidine 1 MUg/kg at 0.3 mL/kg followed by continuous infusion of dexmedetomidine 0.2 MUg/kg/h + 0.125% bupivacaine 0.1 mL/kg/h. Anaesthesia technique was standardized for all patients. Postoperatively, all patients were assessed during first 24 hours for intraoperative fentanyl and post operative morphine requirements, Visual Analogue Scores (VAS) scores at rest and during cough, and postoperative pulmonary functions. Results: Post-operative morphine consumption in the first 24 hours and intraoperative fentanyl requirement were significantly less in group BD (2.95 +/- 1.986 mg, 80.75 +/- 31.551MUg respectively) compared to group B (9.85 +/- 3.468 mg, 186 +/- 39.683 MUg respectively). Group BD showed less VAS scores during cough and better postoperative pulmonary functions (P < 0.05). Conclusion: Addition of dexmedetomidine to paravertebral bupivacaine in patients undergoing thoracic surgeries provides more effective analgesia with improvement in post-operative pulmonary functions. PMID- 29242656 TI - Single bolus dose of epidural magnesium prolongs the duration of analgesia in cardiac patients undergoing vascular surgeries. AB - Background and Aims: Magnesium, a physiological antagonist of calcium and N methyl-d-aspartate, has a role in the prevention of pain in patients undergoing surgery for peripheral vascular diseases with cardiac comorbidities such as ischaemic heart disease and coronary artery disease. The objective of our study was assessment of effects of epidural magnesium in cardiac patients undergoing vascular surgery. Methods: Sixty patients of either sex American Society of Anesthesiologists physical status III undergoing surgeries for peripheral vascular diseases were enrolled. The control group had 30 patients who received levobupivacaine 0.25% 10 ml with fentanyl 50 MUg while 30 patients in study group received levobupivacaine 0.25% 10 ml with fentanyl 50 MUg and magnesium 100 mg. The primary outcome was duration of analgesia. Sedation score, pain assessment using visual analogue scale (VAS), systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate (HR), respiratory rate (RR) and fentanyl consumption were also recorded. Statistical analyses were performed using Minitab 15 statistical software. Results: Both groups were similar demographically and with respect to baseline HR, SBP, DBP and RR. In the study group, compared to the control group, duration of analgesia was 4.17 +/- 1.07 h versus 1.55 +/- 0.47 h (P < 0.01), sedation score were? better (P = 0.003) and the VAS scores was lower (P < 0.01). Conclusion: Epidural magnesium, added to levobupivacaine and fentanyl as a single bolus dose effectively prolongs the duration of analgesia in high risk cardiac patients undergoing peripheral vascular surgery. PMID- 29242657 TI - Acute kidney injury following rhabdomyolysis and sepsis after non-poisonous desert monitor bite. AB - The desert monitor, Varanus griseus, is a species of desert monitor lizard found in North-Western India. They are believed to be non-poisonous. We report a case of Indian desert monitor bite leading to acute renal failure following rhabdomyolysis and severe sepsis. Prompt diagnosis and treatment resulted in the favourable outcome. This is author's intent to highlight the complication that may occur after Indian desert monitor bite. PMID- 29242658 TI - Quadratus lumborum block for post-operative pain relief in patient with Prune belly syndrome. AB - Abdominal field blocks are commonly used as part of multimodal analgesia for post operative pain relief in patients undergoing abdominal surgery. Conventionally, transversus abdominis plane block is used, but has the disadvantage of limited spread only to T10-T12 segments, providing only partial pain relief. The new quadratus lumborum (QL) block has the advantage of providing wider sensory block from T6 to L1 and thus has an evolving role in opioid-free anaesthesia. Opioid induced cough depression, urinary retention, and drowsiness can be problematic in patients with Prune belly syndrome, who have deficient abdominal muscles and myriad of genitourinary problems. We report a case of a young male with Prune belly syndrome, who had a pain-free post-operative period after high inguinal orchidectomy with unilateral QL block. PMID- 29242659 TI - Changes in respiratory mechanics during extraperitoneal insufflation in inguinal hernia surgery. PMID- 29242660 TI - Radiological images through an anaesthesiologists' looking glass: Airway management in cervical lipomatosis in an infant. PMID- 29242661 TI - Newer design, newer problems: Unusual complication with Limb-O anaesthesia circuit. PMID- 29242662 TI - Nil per oral instructions in chronic tobacco chewers: Are they enough? PMID- 29242663 TI - Pectoralis block for breast surgery: A surgical concern? PMID- 29242664 TI - Ultrasound as a point-of-care tool for early detection of potential complications like pneumothorax associated with the pectoralis block. PMID- 29242665 TI - Unfavourable outcome after uneventful anaesthesia and surgery in a child with Hurler syndrome. PMID- 29242666 TI - Recent advances in low temperature sterilization - Moving ahead from CidexTM/ETO to OPA/Ozone: An update. PMID- 29242667 TI - The baffling issues of Brugada electrocardiogram pattern for anaesthesiologist! PMID- 29242668 TI - Reading Digital with Low Vision. AB - Reading difficulty is a major consequence of vision loss for more than four million Americans with low vision. Difficulty in accessing print imposes obstacles to education, employment, social interaction and recreation. In recent years, research in vision science has made major strides in understanding the impact of low vision on reading, and the dependence of reading performance on text properties. The ongoing transition to the production and distribution of digital documents brings about new opportunities for people with visual impairment. Digital documents on computers and mobile devices permit customization of print size, spacing, font style, contrast polarity and page layout to optimize reading displays for people with low vision. As a result, we now have unprecedented opportunities to adapt text format to meet the needs of visually impaired readers. PMID- 29242669 TI - Crustacean zooplankton release copious amounts of dissolved organic matter as taurine in the ocean. AB - Taurine (Tau), an amino acid-like compound, is present in almost all marine metazoans including crustacean zooplankton. It plays an important physiological role in these organisms and is released into the ambient water throughout their life cycle. However, limited information is available on the release rates by marine organisms, the concentrations and turnover of Tau in the ocean. We determined dissolved free Tau concentrations throughout the water column and its release by abundant crustacean mesozooplankton at two open ocean sites (Gulf of Alaska and North Atlantic). At both locations, the concentrations of dissolved free Tau were in the low nM range (up to 15.7 nM) in epipelagic waters, declining sharply in the mesopelagic to about 0.2 nM and remaining fairly stable throughout the bathypelagic waters. Pacific amphipod-copepod assemblages exhibited lower dissolved free Tau release rates per unit biomass (0.8 +/- 0.4 MUmol g-1 C biomass h-1) than Atlantic copepods (ranging between 1.3 +/- 0.4 MUmol g-1 C biomass h-1 and 9.5 +/- 2.1 MUmol g-1 C-biomass h-1), in agreement with the well documented inverse relationship between biomass-normalized excretion rates and body size. Our results indicate that crustacean zooplankton might contribute significantly to the dissolved organic matter flux in marine ecosystems via dissolved free Tau release. Based on the release rates and assuming steady state dissolved free Tau concentrations, turnover times of dissolved free Tau range from 0.05 d to 2.3 d in the upper water column and are therefore similar to those of dissolved free amino acids. This rapid turnover indicates that dissolved free Tau is efficiently consumed in oceanic waters, most likely by heterotrophic bacteria. PMID- 29242670 TI - Reach-scale river metabolism across contrasting sub-catchment geologies: Effect of light and hydrology. AB - We investigated the seasonal dynamics of in-stream metabolism at the reach scale (~ 150 m) of headwaters across contrasting geological sub-catchments: clay, Greensand, and Chalk of the upper River Avon (UK). Benthic metabolic activity was quantified by aquatic eddy co-variance while water column activity was assessed by bottle incubations. Seasonal dynamics across reaches were specific for the three types of geologies. During the spring, all reaches were net autotrophic, with rates of up to 290 mmol C m-2 d-1 in the clay reach. During the remaining seasons, the clay and Greensand reaches were net heterotrophic, with peak oxygen consumption of 206 mmol m-2 d-1 during the autumn, while the Chalk reach was net heterotrophic only in winter. Overall, the water column alone still contributed to ~ 25% of the annual respiration and primary production in all reaches. Net ecosystem metabolism (NEM) across seasons and reaches followed a general linear relationship with increasing stream light availability. Sub-catchment specific NEM proved to be linearly related to the local hydrological connectivity, quantified as the ratio between base flow and stream discharge, and expressed on a timescale of 9 d on average. This timescale apparently represents the average period of hydrological imprint for carbon turnover within the reaches. Combining a general light response and sub-catchment specific base flow ratio provided a robust functional relationship for predicting NEM at the reach scale. The novel approach proposed in this study can help facilitate spatial and temporal upscaling of riverine metabolism that may be applicable to a broader spectrum of catchments. PMID- 29242671 TI - In patients suspected of cognitive decline, what is the most accurate in-office screening instrument to determine if there is dementia needing further evaluation and management? AB - While screening for dementia in patients without symptoms is not recommended by the United States Preventative Services Task Force (USPSTF), screening in those presenting with symptoms may help patients and caregivers prepare for the future. When selecting which screening tool to use in a primary care office, one needs to consider practicality, feasibility, applicability, and psychometric properties. The MIS, MiniCog, PhotoTest, and GPCOG have been found to have short administration times, good accuracy, and applicability for a broad range of patient education and backgrounds. The BAS, MiniCog, PhotoTest and MAT have been found to be the most accurate tests. However, the evidence is limited and more studies need to be done to accurately answer the presented question. PMID- 29242672 TI - Paths towards Family-friendly Working Time Arrangements: Comparing Workplaces in Different Countries and Industries. AB - Although studies have examined the distribution and conditions of employer provided work-family arrangements, we still lack a systematic investigation of how these vary for different countries and industries. Based on the European Working Conditions Survey 2010, this study examines the conditions under which firms provide family-friendly working time arrangements and what the differences are across four countries (Austria, Denmark, Italy and the UK) and four industries. The impact of employee representatives, employee involvement, manager support and female managers varies across countries and industries because of the institutional environment (prevailing family model, industrial relations) and workforce composition (gender). The impact of employee representatives depends on their co-determination rights, and the direction of their effect on the prevailing family model (e.g. negative in conservative countries such as Austria) and the gender composition of the workforce (negative in male-dominated production, but positive in services). Employee involvement in the work organization is significantly positive in Austria and Denmark (both with co operative industrial relations), while manager support has the strongest effect in the UK (liberal regime). At the industry level, female supervisors are positively associated with family-friendly working time arrangements only in the male-dominated production industry. These findings suggest that the effects of agency variables and their direction vary depending on the institutional context. PMID- 29242673 TI - Mexican-origin Adolescents' Educational Expectation Trajectories: Intersection of Nativity, Sex, and Socioeconomic Status. AB - Expectancy value theory and a cultural-ecological framework are integrated in this study to examine the trajectories of 246 Mexican-origin adolescents' (Mage = 12.52, SDage = 0.58; 51% girls, 62% U.S.-born) educational expectations across eight years. Findings from a multilevel growth model revealed that early adolescents expected to complete a post-bachelor's degree, but expectations declined in middle adolescence and improved in late adolescence. This pattern was more pronounced for immigrant, compared to U.S-born, adolescents. Higher socioeconomic status was associated with higher expectations. Boys and girls differed in their trajectories, such that boys showed a curvilinear trajectory and girls showed a stable trajectory. Nativity moderated these sex differences. Immigrant boys showed curvilinear trajectories that dipped in middle adolescence and immigrant girls showed a declining trajectory. In contrast, U.S.-born boys and girls showed linear and stable trajectories. The discussion addresses suggestions for targeted interventions with at-risk subgroups during a sensitive period in adolescence. PMID- 29242674 TI - LONGWOOD - integrating woodland history and ecology in a geodatabase through an interdisciplinary approach. AB - Forests in Europe have been shaped considerably by human activities during most of the Holocene. Changes in forest structure, distribution of tree species and forest biodiversity are partly driven by management history, and many current forest types result from former management. The interdisciplinary project "Long term woodland dynamics in Central Europe: from estimations to a realistic model" (LONGWOOD) aims to reconstruct long-term dynamics of woodland cover, structure and management in the eastern Czech Republic (Moravia, ca. 27,000 km2), compare the historical and present state of forests, and analyze general patterns of changes and stability of woodlands as well as the role of humans in these processes. In the LONGWOOD project, palaeoecological, archaeological, historical and ecological sources of information on woodland cover, species composition, and human activities (management, settlement density) over the past 7500 years are collected and integrated in the form of a geodatabase. Combining data of different origin, scale, degree of spatial precision and detail into a single geodatabase is a challenging task. The level of detail, information content, and spatio-temporal distribution of data varies between layers as well as individual records according to the nature of the data source and the data itself. The limited and incomplete sources of information until ca. 1100 AD provide a coarser view on forest history while the historical period (especially the past ca. 250 years) is covered by large amounts of precisely located ecological and historical data enabling detailed spatial and temporal analyses. Data on forest structure, history and management will be related to environmental factors (soil type, climate, elevation and other topographic variables derived from DEM) and social historical data (settlement distribution, population density, landuse). A spatio temporal forest landscape model will be built to assess the forest changes and the main drivers of change. PMID- 29242675 TI - Charge transport and structure in semimetallic polymers. AB - Owing to changes in their chemistry and structure, polymers can be fabricated to demonstrate vastly different electrical conductivities over many orders of magnitude. At the high end of conductivity is the class of conducting polymers, which are ideal candidates for many applications in low-cost electronics. Here, we report the influence of the nature of the doping anion at high doping levels within the semi-metallic conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) on its electronic transport properties. Hall effect measurements on a variety of PEDOT samples show that the choice of doping anion can lead to an order of magnitude enhancement in the charge carrier mobility > 3 cm2/Vs at conductivities approaching 3000 S/cm under ambient conditions. Grazing Incidence Wide Angle X-ray Scattering, Density Functional Theory calculations, and Molecular Dynamics simulations indicate that the chosen doping anion modifies the way PEDOT chains stack together. This link between structure and specific anion doping at high doping levels has ramifications for the fabrication of conducting polymer-based devices. (c) 2017 The Authors. Journal of Polymer Science Part B: Polymer Physics Published by Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018, 56, 97-104. PMID- 29242676 TI - Program ACTIVE: Cognitive Behavioral Therapy to Treat Depression in Adults With Type 2 Diabetes in Rural Appalachia. AB - High rates of type 2 diabetes (T2DM) and depression exist in rural Appalachia with limited access to psychotherapeutic treatment. No manualized cognitive behavioral therapy (CBT) treatment materials exist that are culturally tailored for individuals in this region with T2DM. We describe the development of the Program ACTIVE CBT intervention for use with adults with T2DM and depression by mental health providers in rural Appalachia. Qualitative and quantitative methods were used to test the feasibility and acceptability of Program ACTIVE. Intervention materials were rated at the 6th-7th grade reading level. Key informant interviews evaluated materials as culturally sensitive and accessible. Participants indicated high levels of satisfaction with therapy (94%), support from their therapist (86%), and usefulness of therapy and depression improvement (80.3%). Program ACTIVE was found to be a feasible and acceptable culturally tailored manualized CBT treatment for adults with T2DM and depression living in rural Appalachia. Implementation of these materials on a regional scale needs to be assessed. PMID- 29242677 TI - Infection reduces anti-predator behaviors in house finches. AB - Infectious diseases can cause host mortality through direct or indirect mechanisms, including altered behavior. Diminished anti-predator behavior is among the most-studied causes of indirect mortality during infection, particularly for systems in which a parasite's life-cycle requires transmission from prey to predator. Significantly less work has examined whether directly transmitted parasites and pathogens also reduce anti-predator behaviors. Here we test whether the directly-transmitted bacterial pathogen, Mycoplasma gallisepticum (MG), reduces responses to predation-related stimuli in house finches (Haemorhous mexicanus). MG causes conjunctivitis and reduces survival among free-living finches, but rarely causes mortality in captivity, suggesting a role for indirect mechanisms. Wild-caught finches were individually housed in captivity and exposed to the following treatments: 1) visual presence of a stuffed, mounted predator (a Cooper's Hawk (Accipiter cooperii)) or control object (a vase or a stuffed, mounted mallard duck (Anas platyrhynchos)), 2) vocalizations of the same predator and non-predator, 3) approach of a researcher to enclosures, and 4) simulated predator attack (capture by hand). MG infection reduced anti-predator responses during visual exposure to a mounted predator and simulated predator attack, even for birds without detectable visual obstruction from conjunctivitis. However, MG infection did not significantly alter responses during human approach or audio playback. These results are consistent with the hypothesis that predation plays a role in MG-induced mortality in the wild, with reduced locomotion, a common form of sickness behavior for many taxa, as a likely mechanism. Our results therefore suggest that additional research on the role of sickness behaviors in predation could prove illuminating. PMID- 29242679 TI - Mn Doped AIZS/ZnS Nanocrystals: Synthesis and Optical Properties. AB - In this work, Mn doped AIZS/ZnS (Mn:AIZS/ZnS) nanocrystals (NCs) have been synthesized in an approach using heat-up and drop-wise addition of precursors. On the basis of the characterization of these doped NCs on their optical properties and materials, it is found that: (1) as more Mn atoms are doped into NCs, the doped NCs present photoluminescence (PL) red-shift and quantum yield quenching; (2) the doped NCs possess a short PL lifetime in tens of microseconds and a long PL lifetime in hundreds of microseconds, and the short lived PL is more dominant than the long lived one; and (3) the doped NCs present a reversible PL thermal quenching in a range from room temperature to 170 degrees C. Possible PL mechanisms of these NCs were discussed by analyzing their time-resolved PL spectra and thermal stability. PMID- 29242681 TI - Last Frontier. PMID- 29242680 TI - What makes an individual patient different from others? PMID- 29242678 TI - KEAP1 and Done? Targeting the NRF2 Pathway with Sulforaphane. AB - Background: Since the re-discovery of sulforaphane in 1992 and the recognition of the bioactivity of this phytochemical, many studies have examined its mode of action in cells, animals and humans. Broccoli, especially as young sprouts, is a rich source of sulforaphane and broccoli-based preparations are now used in clinical studies probing efficacy in health preservation and disease mitigation. Many putative cellular targets are affected by sulforaphane although only one, KEAP1-NRF2 signaling, can be considered a validated target at this time. The transcription factor NRF2 is a master regulator of cell survival responses to endogenous and exogenous stressors. Scope and Approach: This review summarizes the chemical biology of sulforaphane as an inducer of NRF2 signaling and efficacy as an inhibitor of carcinogenesis. It also provides a summary of the current findings from clinical trials using a suite of broccoli sprout preparations on a series of short-term endpoints reflecting a diversity of molecular actions. Key Findings and Conclusions: Sulforaphane, as a pure chemical, protects against chemical-induced skin, oral, stomach, colon, lung and bladder carcinogenesis and in genetic models of colon and prostate carcinogenesis. In many of these settings the antitumorigenic efficacy of sulforaphane is dampened in Nrf2-disrupted animals. Broccoli preparations rich in glucoraphanin or sulforaphane exert demonstrable pharmacodynamic action in over a score of clinical trials. Measures of NRF2 pathway response and function are serving as guideposts for the optimization of dose, schedule and formulation as clinical trials with broccoli based preparations become more commonplace and more rigorous in design and implementation. PMID- 29242682 TI - Forensic dentistry: Adding a perio 'scope' to it! AB - Human identification during mass disasters using the stereotyped techniques such as fingerprint analysis is a cumbersome task. With a view to overcome this predicament, dental evidence of the deceased has gained importance in the recent years. Various branches of dentistry have augmented forensic research through innumerable scientific contributions. The following narrative review of literature aims to summarize the findings of studies that reported periodontal associations or potential associations that could play a role in forensic research. It is designed to inspire the "perio-society" to lend a helping hand to forensic odontology. PMID- 29242683 TI - Probiotics in the treatment of periodontal disease: A systematic review. AB - Over the years, probiotics have been used in the treatment of a variety of diseases. The use of probiotics in the treatment of periodontal disease has caught on over the last decade or so. This review was performed to determine whether administration of probiotics produced a lasting clinical benefit in the treatment of periodontal disease. A MEDLINE, Cochrane database and a hand search was performed on human randomized placebo controlled trials using probiotics in the treatment of periodontal disease. A total of thirteen papers which addressed the question of the use of probiotics in the treatment of periodontal disease were retrieved. Most of the studies reviewed showed only a short term benefit with regards to reduction in gingival inflammation and probing depth reduction. Lasting clinical benefits were not seen in any of the studies. At least four different combinations and strains of probiotics have been used in the studies. There also existed significant heterogeneity in the methodology of the studies reviewed. It was concluded that current regimens of probiotics in the treatment of periodontal disease produce only short-term clinical and microbiologic benefits. PMID- 29242685 TI - Inhibitory effect of cranberry extract on periodontopathogenic biofilm: An integrative review. AB - Background: Combating biofilm-dependent oral infections involves the use of synthetic antibiotics, which are often associated with bacterial resistance and adverse effects. As a result, herbs such as cranberry have emerged as an alternative treatment. The aim of this study was to evaluate, through an integrative literature review, the effectiveness of cranberry extract on cultures and biofilms of periodontopathogenic bacteria. Materials and Methods: In vitro and in vivo studies evaluating the action of cranberry extract on the growth, coaggregation and formation of periodontopathogenic bacteria and periodontal biofilm were identified. Searches were carried out in the "Cochrane Library," "MEDLINE," "Web of Science," "Scopus," "LILACS," "Scielo," and "Google Scholar" databases, using the terms: "vaccinium macrocarpon;" "cranberries;" "cranberry;" "biofilms;" "periodontitis;" "chronic periodontitis;" "aggressive periodontitis;" "periodontal diseases;" and "periodont*." Results: a low number of studies evaluating the effectiveness of cranberry extract on periodontal disease were found, and no human studies were identified. In general, the eight studies included in the revision found that the compounds effectively inhibited the formation of a biofilm of Porphyromonas gingivalis and Fusobacterium nucleatum at concentrations equal or superior to 62.5 MUg/ml, but did not significantly inhibit bacterial growth or promote the breakdown of preformed biofilm. Conclusions: while most of the studies presented certain methodological limitations, they did identify an inhibiting effect of cranberry on periodontal bacteria. These results serve as support for the development of further studies evaluating the most effective vehicle and ideal concentration that can be used without causing adverse effects on oral tissues. PMID- 29242684 TI - Drug-induced gingival overgrowth: A critical insight into case reports from over two decades. AB - Drug-induced gingival overgrowth (DIGO) is a well-recognized adverse effect of certain systemic medications. Calcium channel blockers, anticonvulsants, and immunosuppressants are frequently implicated drugs in the etiology of DIGO. Drug variables, plaque-induced inflammation, and genetic factors are the three important factors in the expression of gingival changes after systemic medication use. Careful clinical examination and thorough history taking form the basis for diagnosis of DIGO. Histopathological examination is often neglected; however, it is an important aid that helps in differential diagnosis. Cessation or change of drug and meticulous plaque control often leads to regression of the lesion, which however might need surgical correction for optimal maintenance of gingival health. The purpose of the present article is to review case reports and case series published in the last two decades and to assimilate and compile the information for clinical applications such as diagnosis and therapeutic management of DIGO. PMID- 29242686 TI - Tumor necrosis factor-alpha, interleukin-4 and -6 in the serum of health, chronic periodontitis, and type 2 diabetes mellitus. AB - Background: Cytokines are significant in the development and progression of chronic periodontitis (ChP) and type 2 diabetes mellitus (DT2). Insufficient information is available regarding the pro- versus anti-inflammatory cytokines in ChP's influence on systemic levels of cytokines on DT2. This study investigated the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-4 and IL 6 in the serum of patients with ChP, DT2, and with both ChP and DT2, as compared to health. Materials and Methods: A total of eighty participants were grouped equally groups as healthy (NH), ChP with, and without DT2 (ChP and ChP + DT2) and only type 2 diabetes (DT2). Plaque and gingival indices, bleeding on probing, pocket probing depths, clinical attachment loss, were evaluated. Serum samples were collected to measure glycated hemoglobin, random blood sugar. TNF-alpha, IL 4 and -6 was assessed by ELISA. Results: The selected cytokines were detected in all the participants. TNF-alpha and IL-6 were highest in ChP + DT2 group, whereas IL-4 was highest in health. Significant differences and correlation were observed between the cytokines, periodontal, and glycemic parameters and among the four groups. Conclusion: TNF-alpha and IL-6 appear to heighten the inflammatory state in patients with both type 2 diabetes and periodontitis, but IL-4, though considered an anti-inflammatory mediator was not convincing in such a role in this study. The cytokine behavior needs to be studied further in larger studies. PMID- 29242687 TI - The antiplaque efficacy of white tea extract mouthrinse. AB - Objective: This study was conducted to assess the antiplaque efficacy of a mouthwash containing white tea. It also assessed the antibacterial properties of white tea against Prevotella intermedia (Pi), Porphyromonas gingivalis (Pg), and Aggregatibacter actinomycetemcomitans (Aa) in vitro. Materials and Methods: Forty five subjects with healthy periodontium were randomly chosen and were divided into three groups and advised to use mouthwashes A, B, and C (Group A, white tea; Group B, distilled water [placebo]; Group C, chlorhexidine) for 4 days. They were advised to refrain from any kind of mechanical oral hygiene techniques. Plaque index (PI) was checked on day 1 and 5. In vitro testing for against Pi, Pg, and Aa against white tea extract was undertaken. Results: PI significantly increased from day 1 to day 5 (P < 0.01) in Groups A, B, and C. In inter-group comparison, there was a statistical significant difference between white tea mouthrinse group and placebo group, chlorhexidine group and placebo group and also chlorhexidine group and white tea mouthrinse group. However, chlohexidine showed superior antiplaque activity. In vitro test, white tea showed effective inhibition against all three bacterial strains Pi, Pg, and Aa at 1% concentration. Conclusion: White tea mouthrinse potently inhibits plaque formation although not as comparable to chlorhexidine mouthrinse. Hence, for those preferring herbal products, white tea mouthrinse is a good option. PMID- 29242688 TI - Evaluation of efficacy of a novel resorbable collagen membrane for root coverage of Miller's Class I and Class II recession in the maxillary anteriors and premolars. AB - Background: There are several surgical techniques in literature that have been used to perform root coverage (RC). Currently, the use of a resorbable collagen membrane (RCM) as a guided tissue regenerative material is one of the highly sought treatment modalities. The present study aimed at evaluating the clinical outcome of RC in the treatment of Miller's Class I and II recession defects in maxillary anteriors and premolars by coronally advanced flap (CAF) with and without RCM. Materials and Methods: This split-mouth study (bilateral buccal recession defects) was randomized to include 15 test (CAF + membrane) and 15 control (CAF alone) sites. Clinical parameters included gingival recession depth (RD), probing pocket depth (PPD), clinical attachment level (CAL), and keratinized tissue height (KTH) measured at baseline and 9 months postoperatively. Results: Both test and control groups showed statistically significant (P < 0.05) reductions in RD (1.54 +/- 0.46 mm and 1.60 +/- 0.07 mm), PPD (0.53 +/- 0.15 mm and 0.94 +/- 0.10 mm), increase in KTH (0.67 +/- 0.90 mm and 0.73 +/- 0.14 mm) and CAL (1.94 +/- 0.27 mm and 2.60 +/- 0.19 mm) when comparing the 9-month data from baseline. The present study showed that mean improvement in RD was 1.60 +/- 0.507 and 1.53 +/- 0.64 mm in both test and control groups, respectively. Mean percent RC was 58.33% +/-12.19% and 56.22% +/ 10.22% for test and control groups, respectively. However, there were no statistically significant differences between groups for RD, PPD, KTH, and CAL. Conclusion: The results of this study suggest that both the groups CAF (control) and CAF and RCM (test) could be successfully used to treat Miller's Class I and II gingival recession defects and also demonstrated an overall significant improvement in all the assessed clinical parameters. However, there was a greater reduction of gingival RD with the use of RCM when compared with the group of CAF alone. PMID- 29242689 TI - Awareness of periodontal disease and its management among medical faculty in Guntur district: A questionnaire-based study. AB - Aim: The aim of this study was to assess the awareness of periodontal disease, its influence on general health, and attitude toward periodontal disease management among medical faculty in Guntur district. Materials and Methods: In this cross-sectional study, 150 medical faculty members from different specialties in Guntur district were included in the study. A self-administered questionnaire was prepared based on knowledge, attitude, and practice surveys to assess the awareness of periodontal disease and its management. Results: Majority of the study participants (82%) had a previous dental visit. Only 31.3% believed that plaque is the major cause for periodontal disease. 56.7% responded that the relation between periodontal disease and systemic diseases is bidirectional. Only 39.3% were aware that periodontal disease is a risk factor for preterm low-birth weight infants. 52.6% of the medical faculty thought that scaling causes loss of enamel. 54.7% were aware that light amplification by stimulated emission of radiation is used in the periodontal treatment. Medical professionals who visited specialist in their previous dental visit obtained mean periodontal score (5.35 +/- 1.686) greater than those who had visited general dentist and the difference is statistically significant (0.024). Conclusion: This study clearly demonstrates that medical practitioners had fair knowledge about various aspects of periodontal disease. This was particularly evident among those who have had a previous visit to a dentist. It was also found that young professionals with limited experience in the profession had better knowledge. PMID- 29242690 TI - A cross-sectional survey to assess the effect of socioeconomic status on the oral hygiene habits. AB - Background: It is widely accepted that there are socioeconomic inequalities in oral health. A socioeconomic gradient is found in a range of clinical and self reported oral health outcomes. Aim: The present study was conducted to assess the differences in oral hygiene practices among patients from different socioeconomic status (SES) visiting the Outpatient Department of the Sudha Rustagi College of Dental Sciences. Materials and Methods: A cross-sectional survey was conducted from June to October 2014 to assess the effect of SES on the oral hygiene habits. The questionnaire included the questions related to the demographic profile and assessment of the oral hygiene habits of the study population. Results: Toothbrush and toothpaste were being used significantly (P < 0.05) more by lower middle class (84.4%) and upper middle class (100.0%). A significantly higher frequency of cleaning teeth (twice a day) was reported among the lower middle class (17.2%) and upper middle class (21.5%). The majority (34.3%) of the study population changed their toothbrush once in 3 months. The cleaning of tongue was reported by patients belonging to the upper middle (62.0%), lower middle (52.1%), and upper lower class (30.0%). The use of tongue cleaner was reported to be significantly (P < 0.05) more among upper middle (10.1%) class patients. A significantly higher number of patients from the lower class (81.3%) never visited a dentist. Conclusion: The oral hygiene practices of the patients from upper and lower middle class was found to be satisfactory whereas it was poor among patients belonging to lower and upper lower class. PMID- 29242691 TI - Evaluation of Nano-Bio Fusion gel as an adjunct to scaling and root planing in chronic periodontitis: A clinico-microbiological study. AB - Background: The oral cavity being a natural moist environment, topical application reduces its potency and effectiveness, but the nanoparticles in the Nano-Bio Fusion (NBF) gel are efficient in rapidly penetrating the cells. The purpose of the study aimed to evaluate clinically and microbiologically the effectiveness of locally delivered NBF technology gel as an adjunctive therapy to scaling and root planing (SRP) in the treatment of chronic periodontitis. Materials and Methods: Six chronic periodontitis patients with 76 sites and probing pocket depth (PD) between 5 and 7 mm were selected in a randomized controlled clinical trial. SRP was performed in both control and test group followed by NBF gel application in 38 sites. The plaque index, gingival index, papillary bleeding index, probing PD, and clinical attachment level (CAL) were recorded at baseline, 6 weeks, and 3 months. Supragingival microbial plaque analysis was done at baseline and 6 weeks interval. The statistical analysis with paired t-test was used to compare the test and control sites. Results: From baseline to a period of 3 months, a statistically significant difference was seen between both groups for PD, CAL, P value being PD (P = 0.001) and CAL (P = 0.01) along with the significant reduction of colony-forming units of aerobic periodontopathogens. Conclusions: Locally delivered NBF gel exhibited a significant improvement compared with SRP alone in chronic periodontitis. PMID- 29242692 TI - To compare the effect of the local delivery of hyaluronan as an adjunct to scaling and root planing versus scaling and root planing alone in the treatment of chronic periodontitis. AB - Background: Hyaluronan is a critical component of the extracellular matrix and contributes significantly to tissue hydrodynamics and cell migration and proliferation. Studies have demonstrated its anti-inflammatory, antibacterial, and regenerative effects. The present study aimed to assess the clinical effects of the subgingival application of 0.8% hyaluronic acid gel as an adjunct to scaling and root planing (SRP) in the treatment of generalized chronic periodontitis. Materials and Methods: Patients with chronic periodontitis were recruited to participate in a study with a split-mouth design and provided informed consent. One hundred sites were included in the study and divided into fifty test sites and fifty control sites. These were assessed for plaque index (PI), gingival index (GI), pocket probing depths, and relative attachment level (RAL) at-pretreatment (baseline), 4, and 12 weeks posttreatment. The patients received full-mouth SRP. A 0.8% hyaluronan gel was administered subgingivally in the test sites at baseline and after 1 week. Significant differences between test and control were evaluated using the t-test, analysis of variance (test) followed by Bonferroni post hoc test. Results: A significant reduction in PI and GI was observed in both groups at 12 weeks (P < 0.05). Significant reduction in the pocket probing depths and gain RAL was observed in both the groups as compared to baseline (P < 0.05). The hyaluronan group compared to control at 12 weeks showed statistically significant reduction in the probing pocket depth and gain in RAL (P < 0.05). Conclusion: The subgingival application of 0.8% hyaluronan gel in conjunction with SRP may have a beneficial effect on periodontal health in patients with chronic periodontitis. PMID- 29242693 TI - Palatal approach of anterior superior alveolar injection technique may not be potentially useful in periodontal procedures. AB - Background: The palatal approach of anterior superior alveolar (P-ASA) using WAND injection was reported to effectively provide a profound bilateral maxillary anesthesia of the soft tissue of anterior one-third of the palate and facial gingivae extending from canine to canine which lasted for more than an hour thus making it ideal for scaling root planing and minor periodontal procedures in the anterior maxilla. Our study suggests that the conventional P-ASA injection is of very short duration and the extent of anesthesia was not profound and consistent. This has not been reported earlier in the literature. Materials and Methods: Thirty-five cases (20 males and 15 females), who underwent scaling, root planing and minor periodontal surgical procedures such as abscess drainage, gingivectomy, and frenectomy in the maxillary anterior region in the age range of 19-45 years was assessed for the efficacy of the P-ASA injection. After the administration of the P-ASA injection, the subjective and the objective symptoms were used to evaluate the extent and duration of the anesthesia at 10, 15, and 20 min. Results: This study suggests that the conventional P-ASA injection technique does not provide anesthesia for more than 20 min. Wilcoxon matched pairs test was used to compare the effect of anesthesia at the different time intervals and the results were found to be statistically significant (P < 0.05). Conclusions: The conventional P-ASA injection technique is of very short duration and does not demonstrate effectiveness in periodontal surgery of the anterior maxilla. PMID- 29242694 TI - Management of phenytoin-induced gingival enlargement in a patient with antiphospholipid antibody syndrome: A rare case report. AB - Antiphospholipid antibody (APLA) syndrome is a noninflammatory autoimmune disease, with innumerable clinical manifestations ranging from recurrent thrombosis and pregnancy morbidity to valvular lesions, transverse myelitis, thrombocytopenia, and hemolytic anemia. APLAs in antiphospholipid syndrome (APS) are well-known risk factors for cerebrovascular accidents. Stroke is the most common manifestation of APS in the central nervous system. Gingival enlargement is a known side effect of phenytoin which is an antiepileptic drug. This can have a significant effect on the quality of life as well as increasing the oral bacterial load by generating plaque retention sites. The management of gingival overgrowth seems to be directed at controlling gingival inflammation through a good oral hygiene regimen. Thus, this case report aims to describe the conservative management of phenytoin-induced gingival enlargement combined with inflammatory enlargement in a patient with APLA syndrome. PMID- 29242695 TI - Desquamative gingivitis mimicking mild gingivitis. AB - The aim of this report is to diagnose the cause for episodic, shifting type of mild inflammation in the isolated areas of gingiva noted by the patient for 1 year. A 33-year-old female patient presented with a chief complaint of mild pain and occasional burning sensation confined to the gingiva to the Department of Periodontology and Oral Implantology. Clinical presentation of the gingiva was seen to mimic mild form of gingivitis for 1 year, with no noted systemic involvement gingival biopsy was performed. The presence of Tzanck cell was noted along with intraepithelial split pointing toward pemphigus. Thus, the study concludes that thorough and meticulous gingival examination can reveal the picture of underlying systemic alterations and is the key for early diagnosis and prompt treatment. PMID- 29242696 TI - An algorithm for the split-feasibility problems with application to the split equality problem. AB - In this paper, we study the split-feasibility problem in Hilbert spaces by using the projected reflected gradient algorithm. As applications, we study the convex linear inverse problem and the split-equality problem in Hilbert spaces, and we give new algorithms for these problems. Finally, numerical results are given for our main results. PMID- 29242697 TI - An inequality for generalized complete elliptic integral. AB - In this paper, we show an elegant inequality involving the ratio of generalized complete elliptic integrals of the first kind and generalize an interesting result of Alzer. PMID- 29242698 TI - Embedding Learning with Events in Heterogeneous Information Networks. AB - In real-world applications, objects of multiple types are interconnected, forming Heterogeneous Information Networks. In such heterogeneous information networks, we make the key observation that many interactions happen due to some event and the objects in each event form a complete semantic unit. By taking advantage of such a property, we propose a generic framework called HyperEdge-BasedEmbedding (Hebe) to learn object embeddings with events in heterogeneous information networks, where a hyperedge encompasses the objects participating in one event. The Hebe framework models the proximity among objects in each event with two methods: (1) predicting a target object given other participating objects in the event, and (2) predicting if the event can be observed given all the participating objects. Since each hyperedge encapsulates more information of a given event, Hebe is robust to data sparseness and noise. In addition, Hebe is scalable when the data size spirals. Extensive experiments on large-scale real world datasets show the efficacy and robustness of the proposed framework. PMID- 29242699 TI - Motivation Precedes Goal Setting in Prediction of Cannabis Treatment Outcomes in Adolescents. AB - Studies have shown that motivation to change is related to better substance use outcomes among treatment-seeking adolescents. Goal setting, which may be related to motivation, also has been shown to be associated with positive treatment outcomes. However, relationships between motivation and goal setting as mediators of change in cannabis use over time among treated youth have not been investigated. This study tested direct and indirect associations of motivation and goal setting with cannabis use frequency over 12 month follow-up among treated adolescents. A longitudinal study of 163 adolescents enrolled in intensive outpatient substance use treatment (mean age = 16.69, 34% female, 87% Caucasian) provided repeated assessment of motivation, goal setting, and cannabis use. Path analysis tested direct and indirect effects of motivation and goal setting on cannabis use. A comparison of two path models that tested motivation and goal setting independently showed that goal setting had better model fit and accounted for more of the variance in 6-month (R2 = .35) and 12-month (R2 = .46) cannabis use frequency than motivation (R2 = .28, .44, respectively). When both mediators were included in the same model, better model fit was found for motivation preceding goal setting in the context of double mediation. Overall, results suggest that goal setting, or the combination of motivation preceding goal setting in a double mediation model, predicted lower cannabis use in treated adolescents. PMID- 29242700 TI - LiDAR-guided Archaeological Survey of a Mediterranean Landscape: Lessons from the Ancient Greek Polis of Kolophon (Ionia, Western Anatolia). AB - In 2013, an airborne laser scan survey was conducted in the territory of the Ionian city of Kolophon near the western coast of modern Turkey as part of an archaeological survey project carried out by the Mimar Sinan University of Istanbul (Turkey) and the University of Vienna (Austria). Several light detection and ranging (LiDAR) studies have been carried out in the temperate climate zones of Europe, but only a few in Mediterranean landscapes. Our study is based on the first LiDAR survey carried out for an archaeological purpose in Turkey and one of the first in the Mediterranean that have been planned, measured and filtered especially for archaeological research questions. The interpretation of LiDAR data combined with ground-observations proved extremely useful for the detection and documentation of archaeological remains below Mediterranean evergreen vegetation and dense maquis. This article deals with the methodological aspects of interpreting LiDAR data, using the Kolophon data as a case study. We offer a discussion of the strengths and limitations of LiDAR as an archaeological remote sensing method and suggest a best practice model for interpreting LiDAR data in a Mediterranean context. (c) 2017 The Authors. Archaeological Prospection published by John Wiley & Sons Ltd. PMID- 29242701 TI - A Software Tool for the Annotation of Embolic Events in Echo Doppler Audio Signals. AB - The use of precordial Doppler monitoring to prevent decompression sickness (DS) is well known by the scientific community as an important instrument for early diagnosis of DS. However, the timely and correct diagnosis of DS without assistance from diving medical specialists is unreliable. Thus, a common protocol for the manual annotation of echo Doppler signals and a tool for their automated recording and annotation are necessary. We have implemented original software for efficient bubble appearance annotation and proposed a unified annotation protocol. The tool auto-sets the response time of human "bubble examiners," performs playback of the Doppler file by rendering it independent of the specific audio player, and enables the annotation of individual bubbles or multiple bubbles known as "showers." The tool provides a report with an optimized data structure and estimates the embolic risk level according to the Extended Spencer Scale. The tool is built in accordance with ISO/IEC 9126 on software quality and has been projected and tested with assistance from the Divers Alert Network (DAN) Europe Foundation, which employs this tool for its diving data acquisition campaigns. PMID- 29242702 TI - Proliferative Synovitis of the Shoulder Bursae is a Key Feature for Discriminating Elderly Onset Rheumatoid Arthritis Mimicking Polymyalgia Rheumatica From Polymyalgia Rheumatica. AB - Semiquantitative scoring for subacromial bursa (SAB), subdeltoid bursa (SDB), and subcoracoid bursa by both gray-scale (GS) and power Doppler (PD) ultrasonography was performed in 15 patients with polymyalgia rheumatica (PMR) (72.6 +/- 7.7 years old) and 15 patients with elderly onset rheumatoid arthritis with PMR-like onset (pm-EORA) (70.7 +/- 7.0 years old) before starting treatment. The GS grades of SAB were significantly higher in the shoulders with pm-EORA than in the shoulders with PMR. The GS and PD scores of SAB and the PD scores of SDB were significantly higher in pm-EORA than in PMR cases. The sums of GS and/or PD scores for the three bursae were significantly higher in pm-EORA than in patients with PMR. The sums of GS and PD scores for SAB were significantly higher in pm EORA than in PMR cases. Moderate to severe proliferative synovitis of the shoulder bursae, especially in SAB, is a key feature for discriminating pm-EORA from PMR. PMID- 29242703 TI - Clinical Characteristics of Patients With Renal Cell Carcinoma and Metastasis to the Thyroid Gland. AB - Introduction: Renal cell carcinoma (RCC) is the most common malignancy to metastasize to the thyroid gland. The aims of this study are as follows: (1) to analyze the clinical characteristics of patients with thyroid involvement of RCC and (2) in patients with RCC thyroid metastasis, to determine whether RCC metastasis to glandular organs only portends a better prognosis compared with other patterns of RCC metastasis. Methods: Patients from Wake Forest Baptist Medical Center (WFBMC) diagnosed with thyroid metastasis from RCC were identified and medical records retrospectively examined. A systematic review of the literature for cases of RCC involving the thyroid gland was also performed. The clinical characteristics of the institutional cohort and the cases from the literature review were compared. Descriptive statistical analysis was performed, and overall survival (OS) was summarized using Kaplan-Meier methods. Results: The median OS for the WFBMC cohort was 56.4 months. In the literature review cohort, OS of patients with RCC thyroid metastasis was 213.6 months, and there was no statistically significant survival difference based on the site of metastasis. Median survival after thyroid metastasis from RCC for the WFBMC and literature cohort was 21.6 and 45.6 months, respectively. Conclusions: Metastatic RCC should be included in the differential of a new thyroid mass. Treatment directed at the thyroid metastasis results in prolonged survival in some cases. Further analysis into the genomic differences and mechanisms of thyroid metastasis is warranted. PMID- 29242704 TI - Effects of Prolonged Treatment With Co-trimoxazole on the Thyroid Gland, Liver, and Epididymal Sperm Reserve in Dogs. AB - Co-trimoxazole is an antimicrobial drug gotten from potentiation of sulfamethoxazole with trimethoprim. It is widely used for the treatment of bacterial and protozoan infections in humans. It is also used in veterinary clinics against susceptible microorganisms, but thyroid dysfunction has raised concern especially in dogs. This study aimed to determine the effects of prolonged treatment with co-trimoxazole in euthyroid dogs. Dogs were given co trimoxazole at 30, 60, and 120 mg/kg body weight at 12-hour intervals for 21 days. Standard procedures were used to assay total T4 and T3, thyrotropin, testosterone, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in serum. The thyroid gland and testes were weighed. In addition, thyroid and liver were examined histologically. Epididymal sperm count was also performed. Co-trimoxazole caused dose-dependent depression of serum thyroxine levels with severe colloid depletion, intrafollicular hemorrhage, hyperplasia, and hypertrophy of the follicular cells. The liver showed vacuolar hepatopathy. Epididymal sperm count was low in the 120 mg/kg-treated group. The study revealed that thyroid hemorrhage and lowered epididymal sperm reserve were new findings in co-trimoxazole toxicity in dogs. PMID- 29242705 TI - Workplace Policies and Mental Health among Working-Class, New Parents. AB - Little research has explored linkages between workplace policies and mental health in working-class, employed parents, creating a gap in our knowledge of work-family issues across social class levels. The current U.S. study addresses this gap by employing hierarchical linear modeling techniques to examine how workplace policies and parental leave benefits predicted parents' depressive symptoms and anxiety in a sample of 125, low-income, dual-earner couples interviewed across the transition to parenthood. Descriptive analyses revealed that, on average, parents had few workplace policies, such as schedule flexibility or child care supports, available to them. Results revealed, however, that, when available, schedule flexibility was related to fewer depressive symptoms and less anxiety for new mothers. Greater child care supports predicted fewer depressive symptoms for fathers. In terms of crossover effects, longer maternal leave predicted declines in fathers' anxiety across the first year. Results are discussed with attention to how certain workplace policies may serve to alleviate new parents' lack of time and resources (minimize scarcity of resources) and, in turn, predict better mental health during the sensitive period of new parenthood. PMID- 29242706 TI - Effects of simulated historical tree litter raking on the understorey vegetation in a central European forest. AB - Question: What is the impact of simulated historical tree litter removal on understorey plants and soil properties in a temperate deciduous forest? What is the role of seasonal timing of tree litter removal on understorey plants? Location: Podyji National Park, Czech Republic. Methods: We conducted an experiment in a randomized complete block design of 45 plots (5 * 5 m). Each block (N = 15) consisted of one plot for each of the three treatments. Treatments consisted of (i) tree litter removal during spring, (ii) tree litter removal during autumn, or (iii) no litter removal as control treatment. These treatments were repeated for a duration of four years. In each plot we recorded the understorey plant species composition and collected soil samples prior to treatment (year 0) and in each subsequent year (years 1-4). Temporal trends in species richness were analysed using repeated measures ANOVAs. The impact of the treatments on vegetation composition over time was analysed using Principal Response Curves. Results: Total species richness per plot significantly changed over time, but this was not related to treatment. Annual species richness increased significantly, but only for the autumn treatment. Annual species also showed the highest inter-annual variation. Endangered species were not affected. When compared to the control treatment, the effect of autumn raking on species composition was stronger than the effect of spring raking. Although the amount of removed nutrients substantially exceeded ambient nitrogen input, no changes in soil conditions were detected. Conclusions: The season in which tree litter removal took place had a small but significant impact on the understorey vegetation, in particular affecting the germination and establishment of annual species. The large inter-annual variation in species richness calls for a long term field experiment. The removal of nutrients via litter raking greatly exceeds atmospheric nutrient deposition, warranting a further investigation of litter raking as a potential tool for forest conservation. PMID- 29242707 TI - The mental health of youth and young adults during the transition to adulthood in Egypt. AB - BACKGROUND: There has been growing interest in the stalled transition to adulthood in the Middle East and North Africa (MENA) and its consequences for young people's socioeconomic outcomes. However, little is known about how important life transitions relate to youth psychosocial well-being in the region. OBJECTIVE: Drawing on a life course framework, we estimate the associations between making transitions in education, employment, and marriage with changes in mental health among young people in Egypt. METHODS: We descriptively analyze mental health scores, measured via the Self-Reporting Questionnaire-20 and disaggregated by gender, for a panel of young people first surveyed in 2009 at ages 13-29 and followed up in late 2013 and early 2014. We regress change in mental health scores against indicators of making different transitions. RESULTS: Young women experience worse mental health than young men overall. Lower school achievement was associated with poorer mental health; being out of the labor force was an additional risk factor for young men. While average mental health scores improved over time, over a quarter of the sample experienced worsening mental health, related to failure to marry and find a job among older men, and failure to finish schooling among younger women. CONCLUSIONS: Mental health is an important but often overlooked component of youth well-being during the transition to adulthood in MENA, and potentially other low- and middle-income countries. CONTRIBUTION: This is the first paper to empirically examine the relationship between psychosocial well-being and achieving important socioeconomic milestones among a nationally representative cohort of young people in MENA. PMID- 29242708 TI - Physical attractiveness and women's HIV risk in rural Malawi. AB - BACKGROUND: Qualitative evidence from sub-Saharan Africa, where a generalized AIDS epidemic exists, suggests that attractiveness may play a role in shaping individual-level HIV risk. Attractive women, who are often blamed for the epidemic and stigmatized, are believed to pose a higher HIV risk because they are viewed as having more and riskier partners. OBJECTIVE: We examine the association between perceived attractiveness and HIV infection and risk in rural Malawi in the midst of the country's severe AIDS epidemic. METHODS: We use interviewers' ratings of respondents' attractiveness, along with HIV test results and women's assessments of their own likelihood of infection, to estimate the association between perceived attractiveness and HIV infection and risk for a random sample of 961 women aged 15-35. RESULTS: Results show that women who are rated by interviewers as 'much less' or 'less' attractive than other women their age are 9% more likely to test positive for HIV. We also find that attractiveness is associated with women's own assessments of their HIV risk: Among women who tested negative, those perceived as 'much less' or 'less' attractive than average report themselves to be at greater risk of HIV infection. CONCLUSIONS: These results suggest that attractiveness is negatively associated with HIV risk in Malawi, countering local beliefs that hold attractive women responsible for perpetuating the epidemic. CONTRIBUTION: This study highlights the need to consider perceived physical attractiveness, and sexual desirability more broadly, as an under examined axis of inequality in HIV risk in high-prevalence settings. PMID- 29242709 TI - Standardized Assessment of Thin-film Vitrification for Aquatic Species. AB - Ultra-rapid cooling under the appropriate conditions will produce vitrification, a glass-like state used to cryopreserve small sample volumes, but there are a number of major technical drawbacks impeding application of vitrification to germplasm of aquatic species. These include a lack of suitable devices, and poor reproducibility and comparability among studies due to a lack of standardization. We used 3-dimensional (3-D) printing to produce a viewing pedestal coupled with a classification system to rapidly assess frozen film quality of vitrification loops. Classification time declined with practice from 2.1 +/- 0.3 sec to 1.5 +/- 0.2 sec (after 200 assessments), and assessments were consistently made in < 2.5 sec. Classifications should be reported with representative images allowing harmonization for quality control. This approach permits rapid classification and can be applied for development of methods including evaluation of vitrification solution components, concentrations of solution and target cells, and configurations and volumes of new devices. Future studies should address the custom fabrication of 3-D printed vitrification devices for use with aquatic species and other applications. PMID- 29242710 TI - Retreatment Options Following HCV Direct Acting Antiviral Failure. AB - Despite the excellent efficacy of direct acting antivirals (DAA) for hepatitis C virus (HCV), treatment failures do occur. Until recently, retreatment decisions after DAA failure were influenced by the number of available agents, concerns about HCV drug resistance, and lack of data regarding retreatment. Recommended treatment approaches previously depended on limited clinical trials and expert opinion. In this article, we review the current state of the evidence for HCV retreatment after DAA failure. Based on recent clinical trial data, most patients who fail HCV treatment with DAA agents now have excellent retreatment options. While some patients may benefit from resistance testing after DAA therapy failure to select the optimal treatment and duration, newly approved salvage therapies are not significantly impacted by common mutations and have been approved by the Food and Drug Administration for HCV retreatment without regard for the presence of resistance associated substitutions. While prior retreatment efforts were limited to longer courses of therapy, the addition of ribavirin, or novel combinations of approved therapies based on expert guidance, current DAA options make HCV retreatment in the DAA era more streamlined and evidence-based. PMID- 29242711 TI - Effect of Point-of-Care Diagnostics on Maternal Outcomes in Human Immunodeficiency Virus-Infected Women: Systematic Review and Meta-analysis. AB - Introduction: The World Health Organization advocates for increased accessibility of HIV-related point-of-care (POC) diagnostics in settings that lack laboratory infrastructure. The aim of this study is to assess the impact of POC diagnostics on maternal health outcomes in HIV-infected women. Methods: A systematic literature review used multiple data sources as follows: Cochrane Infectious Disease Group Specialized Register; Cochrane Central Register of Control Trials, published in The Cochrane Library; PubMed; EBSCOhost and LILACS from January 2000 to October 2015. References of included studies were hand searched. Randomized controlled trials (RCTs) and observational studies examining health outcomes of HIV-infected women were eligible for inclusion in this review. The Cochrane Risk of Bias tool was used for bias assessment of the included studies. PRISMA guidelines were used for reporting. Results: Of the 695 studies identified, six retrievable studies (five cross-sectional studies and one case control study) met the inclusion criteria and were included in this study. These studies examined a total of 167 HIV-infected women in different study settings. No studies reported evidence of CD4 count, viral load and TB, and the syphilis POC test impact on HIV infected women was not found by this study. Included studies reported the impact of various HIV rapid tests across the following five maternal outcomes: timely receipt of results with pooled effect size (ES) = 1.00 (95% confidence interval [CI]: (0.98; 1.02); enabling partner testing, ES = 0.95 (0.85; 1.04); prevention of mother-to-child transmission of HIV, ES = 0.86 (0.79; 0.93); linkage to antiretroviral treatment (ART), ES = 0.76 (0.69; 0.84); and linkage to HIV care, ES = 0.50 (0.18; 0.82). No studies reported evidence of the impact of POC testing on maternal mortality or maternal and child morbidity of HIV-infected women. Conclusions: The review provides an international overview of the impact of HIV POC diagnostics on maternal outcomes in HIV-infected women, showing the evidence that the HIV POC test is significantly associated with decreased mother-to-child transmission of HIV and increased linkage to ART and HIV care for HIV-infected women. It also revealed a gap in the literature aimed at assessing the impact of POC diagnostics on maternal morbidity and mortality in HIV-infected women. PMID- 29242712 TI - Corrigendum: Conditional Knockout of Cav2.1 Disrupts the Accuracy of Spatial Recognition of CA1 Place Cells and Spatial/Contextual Recognition Behavior. AB - [This corrects the article on p. 214 in vol. 10, PMID: 27857685.]. PMID- 29242713 TI - Electrochemical disinfection of repeatedly recycled blackwater in a free standing, additive-free toilet. AB - Decentralized, energy-efficient waste water treatment technologies enabling water reuse are needed to sustainably address sanitation needs in water- and energy scarce environments. Here, we describe the effects of repeated recycling of disinfected blackwater (as flush liquid) on the energy required to achieve full disinfection with an electrochemical process in a prototype toilet system. The recycled liquid rapidly reached a steady state with total solids reliably ranging between 0.50 and 0.65% and conductivity between 20 and 23 mS/cm through many flush cycles over 15 weeks. The increase in accumulated solids was associated with increased energy demand and wide variation in the free chlorine contact time required to achieve complete disinfection. Further studies on the system at steady state revealed that running at higher voltage modestly improves energy efficiency, and established running parameters that reliably achieve disinfection at fixed run times. These results will guide prototype testing in the field. PMID- 29242714 TI - Compressive hyperspectral time-resolved wide-field fluorescence lifetime imaging. AB - Spectrally resolved fluorescence lifetime imaging1-3 and spatial multiplexing1,4,5 have offered information content and collection-efficiency boosts in microscopy, but efficient implementations for macroscopic applications are still lacking. An imaging platform based on time-resolved structured light and hyperspectral single-pixel detection has been developed to perform quantitative macroscopic fluorescence lifetime imaging (MFLI) over a large field of view (FOV) and multiple spectral bands simultaneously. The system makes use of three digital micromirror device (DMD)-based spatial light modulators (SLMs) to generate spatial optical bases and reconstruct N by N images over 16 spectral channels with a time-resolved capability (~40 ps temporal resolution) using fewer than N2 optical measurements. We demonstrate the potential of this new imaging platform by quantitatively imaging near-infrared (NIR) Forster resonance energy transfer (FRET) both in vitro and in vivo. The technique is well suited for quantitative hyperspectral lifetime imaging with a high sensitivity and paves the way for many important biomedical applications. PMID- 29242715 TI - The Promise of Tailoring Incentives for Healthy Behaviors. AB - Purpose: To describe how tailoring financial incentives for healthy behaviors to employees' goals, values, and aspirations might improve the efficacy of incentives. Design/methodology/approach: We integrate insights from self determination theory (SDT) with principles from behavioral economics in the design of financial incentives by linking how incentives could help meet an employee's life goals, values, or aspirations. Findings: Tailored financial incentives could be more effective than standard incentives in promoting autonomous motivation necessary to initiate healthy behaviors and sustain them after incentives are removed. Research implications: Previous efforts to improve the design of financial incentives have tested different incentive designs that vary the size, schedule, timing, and target of incentives. Our strategy for tailoring incentives builds on strong evidence that difficult behavior changes are more successful when integrated with important life goals and values. We outline necessary research to examine the effectiveness of this approach among at risk employees. Practical implications: Instead of offering simple financial rewards for engaging in healthy behaviors, existing programs could leverage incentives to promote employees' autonomous motivation for sustained health improvements. Social implications: Effective application of these concepts could lead to programs more effective at improving health, potentially at lower cost. Originality/value: Our approach for the first time integrates key insights from SDT, behavioral economics, and tailoring to turn an extrinsic reward for behavior change into an internalized, self-sustaining motivator for long-term engagement in risk-reducing behaviors. PMID- 29242716 TI - Dietary Broccoli Impacts Microbial Community Structure and Attenuates Chemically Induced Colitis in Mice in an Ah receptor dependent manner. AB - Consumption of broccoli mediates numerous chemo-protective benefits through the intake of phytochemicals, some of which modulate aryl hydrocarbon receptor (AHR) activity. Whether AHR activation is a critical aspect of the therapeutic potential of dietary broccoli is not known. Here we administered isocaloric diets, with or without supplementation of whole broccoli (15% w/w), to congenic mice expressing the high-affinity Ahrb/b or low-affinity Ahrd/d alleles, for 24 days and examined the effects on AHR activity, intestinal microbial community structure, inflammatory status, and response to chemically induced colitis. Cecal microbial community structure and metabolic potential were segregated according to host dietary and AHR status. Dietary broccoli associated with heightened intestinal AHR activity, decreased microbial abundance of the family Erysipelotrichaceae, and attenuation of colitis. In summary, broccoli consumption elicited an enhanced response in ligand-sensitive Ahrb/b mice, demonstrating that in part the beneficial aspects of dietary broccoli upon intestinal health are associated with heightened AHR activity. PMID- 29242717 TI - Prevalence, treatments and medical cost of multiple sclerosis in Japan based on analysis of a health insurance claims database. AB - Objective: To understand, through an analysis of health insurance claims data, the current treatment status and medical cost of multiple sclerosis (MS) in Japan. Methods: We analyzed claims data (January 2005-January 2016) from the Japan Medical Data Center Co., Ltd., identifying MS patients, except those with neuromyelitis optica, using an algorithm based on diagnosis codes. Prescription drug usage and medical costs for MS patients were analyzed. Results: A total of 713 MS patients were identified in the database. Between 2011 and 2015, the age adjusted prevalence of MS in the database increased from 0.015% to 0.019%, and the female-to-male ratio increased from 1.70 to 2.03. The prescription rate for disease-modifying therapy drugs was higher in larger care settings. Prescriptions for fingolimod increased from 2011, with a concomitant decrease in prescriptions for interferon. The per patient per month cost for MS was Y124 337 (US$1190 or ?1084, as of October 2016). This was higher than the costs for Parkinson's disease (Y84 410), myasthenia gravis (Y82 944) and rheumatoid arthritis (Y53 843). However, the total per member per month cost for MS, which represents the population-based economic impact, was Y25.2, which was lower than the parallel costs for Parkinson's disease (Y123.0) and rheumatoid arthritis (Y311.6) because of the low prevalence of MS in Japan. Conclusions: Using real-world data, we obtained up-to-date prevalence, treatment status and medical cost information for MS in Japan. The present results showed the efficacy of a real-world database to obtain the latest national trends for rare diseases, such as MS; this could have important implications for clinicians and policymakers. PMID- 29242718 TI - A Bayesian Assessment of Real-World Behavior During Multitasking. AB - Multitasking is common in everyday life, but its effect on activities of daily living is not well understood. Critical appraisal of performance for both healthy individuals and patients is required. Motor activities during meal preparation were monitored in healthy individuals with a wearable sensor network during single and multitask conditions. Motor performance was quantified by the median frequencies (fm) of hand trajectories and wrist accelerations. The probability that multitasking occurred based on the obtained motor information was estimated using a Naive Bayes Model, with a specific focus on the single and triple loading conditions. The Bayesian probability estimator showed task distinction for the wrist accelerometer data at the high and low value ranges. The likelihood of encountering a certain motor performance during well-established everyday activities, such as preparing a simple meal, changed when additional (cognitive) tasks were performed. Within a healthy population, the probability of lower acceleration frequency patterns increases when people are asked to multitask. Cognitive decline due to aging or disease might yield even greater differences. PMID- 29242720 TI - A Pilot RCT of a Values-Based Mindfulness Group Intervention with Jail Inmates: Evidence for Reduction in Post-Release Risk Behavior. AB - This study pilot-tested a values and mindfulness-based intervention (Re-Entry Values and Mindfulness Program: REVAMP) in a sample of male jail inmates. REVAMP aimed to reduce post-release risky behavior by targeting dimensions of mindfulness (e.g., willingness/acceptance) and associated proximal outcomes/mechanisms of action (emotion regulation, self-control, shame/guilt). Inmates were randomly assigned to REVAMP (n=21) or treatment as usual (TAU, n=19). Attendance and feedback supported REVAMP's feasibility and acceptability. At post-treatment, ANCOVAs showed that the REVAMP group increased more on willingness/acceptance, self-judgment and shame relative to TAU. Relative increases in willingness/acceptance persisted at 3-month post-release. Criminal activity was assessed by self-report at three months post-release and official criminal records at three years post-release. At both time-points, there was a marginally statistically significant trend of medium effect size for lower criminal recidivism in the REVAMP group compared to TAU. There were no statistically significant differences in self-reported post-release substance misuse. This pilot RCT indicated mindfulness-based interventions may hold promise for reducing inmates' post-release risky behavior and encourages future research in this area. PMID- 29242719 TI - Plasma-Assisted Synthesis of Monodispersed and Robust Ruthenium Ultrafine Nanocatalysts for Organosilane Oxidation and Oxygen Evolution Reactions. AB - We report a facile and general approach for preparing ultrafine ruthenium nanocatalysts by using a plasma-assisted synthesis at <100 degrees C. The resulting Ru nanoparticles are monodispersed (typical size 2 nm) and remain that way upon loading onto carbon and TiO2 supports. This gives robust catalysts with excellent activities in both organosilane oxidation and the oxygen evolution reaction. PMID- 29242721 TI - Message from the President-Elect of the World Federation of Nuclear Medicine and Biology. PMID- 29242723 TI - SPECT/CT in the Treatment of Differentiated Thyroid Cancer. AB - Single-photon emission computed tomography with integrated computed tomography (SPECT/CT) systems has been applied in a wide range of clinical circumstances, and differentiated thyroid cancer (DTC) is one of the most important indications of SPECT/CT imaging. In the treatment of DTC, SPECT/CT images have been reported to have many advantages over conventional planar whole-body scintigraphy based on its precise localization and characterization of abnormal foci of radioactive iodine (RAI) accumulation, influencing the staging, risk stratification, and clinical management as well as reader confidence. On the other hand, SPECT/CT has limitations including additional radiation exposure from the CT component, additional imaging time, and cost-related issues. Each SPECT/CT image acquired at different time points throughout the management of DTC may have a different clinical meaning and significance. This review article addresses the clinical usefulness of RAI SPECT/CT images acquired during the pre-ablation period, post therapy period, and long-term follow-up period, respectively. PMID- 29242722 TI - Recent Progress in the Development of TSPO PET Ligands for Neuroinflammation Imaging in Neurological Diseases. AB - Neuroinflammation is heavily associated with various neurological diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke. It is strongly characterized by the activation of microglia which can be visualized using position emission tomography (PET). Traditionally, translocator protein 18 kDa (TSPO) has been the preferred target for imaging the inflammatory progression of the microglial component. TSPO is expressed in the outer mitochondrial membrane and present in very low concentrations in the healthy human brain, but is markedly upregulated in response to brain injury and inflammation. Due to its value as a marker of microglial activation and subsequent utility for evaluating neuroinflammation in CNS disorders, several classes of TSPO radioligands have been developed and evaluated. However, the application of these second-generation TSPO radiotracers has been subject to several limiting factors, including a polymorphism that affects TSPO binding. This review focuses on recent developments in TSPO imaging, as well as current limitations and suggestions for future directions from a medical imaging perspective. PMID- 29242724 TI - Longitudinal Decline of Striatal Subregional [18F]FP-CIT Uptake in Parkinson's Disease. AB - Purpose: Dopamine transporter imaging is suggested to be a useful imaging biomarker for Parkinson's disease (PD) progression and monitoring drug effects. We investigated the longitudinal decline characteristics of striatal [18F]FP-CIT uptake in PD. Methods: We retrospectively reviewed 35 PD patients and 9 non-PD patients. All patients underwent [18F]FP-CIT PET at the initial diagnosis and follow-up. PET images were spatially normalized and analyzed with eight striatal and one occipital VOI templates. We measured the specific to non-specific binding ratio (SNBR) of the striatal subregions and calculated the absolute annual reduction (AAR) and relative annual reduction (%RAR) of the SNBRs. Results: Total striatal SNBRs in PD patients were significantly lower than those in non-PD patients, with the most significant difference in the posterior putamen. Both AAR (0.26 +/- 0.14 vs. 0.09 +/- 0.19, p < 0.05) and %RAR (6.9 +/- 3.5 vs. 1.2 +/- 2.7, p < 0.001) of total striatal SNBRs were significantly greater in PD than non PD patients. There were no significant differences in the AAR and %RAR of total striatal SNBRs between elderly and young onset PD. The AARs of the posterior putamen were higher in early PD than in advanced PD. Conversely, the %RARs were not significantly different between early and more advanced PD. The disease duration was significantly negatively correlated with the AAR but not with the %RAR of the posterior putamen. Conclusions: The longitudinal decline of striatal [18F]FP-CIT uptake in PD was nonlinear and significantly faster than that in non PD, with a different rate of decline among the striatal subregions. PMID- 29242725 TI - 68Ga-PSMA PET/CT Imaging Predicting Intraprostatic Tumor Extent, Extracapsular Extension and Seminal Vesicle Invasion Prior to Radical Prostatectomy in Patients with Prostate Cancer. AB - Purpose: 68Ga-labeled prostate-specific membrane antigen (PSMA) ligand positron emission tomography/computed tomography (PET/CT) has shown promising results in patients with biochemical recurrence after primary therapy for prostate cancer. In this study, we evaluated the usefulness of PSMA I&T (imaging and therapy) PET/CT prior to radical prostatectomy. Methods: The study population consisted of 21 patients with prostate cancer who underwent 68Ga-PSMA I&T PET/CT before either open or laparoscopic radical prostatectomy. Intraprostatic tumor extent, extracapsular extension (ECE) and seminal vesicle invasion (SVI) were assessed on the PET/CT scans. Tracer uptake was quantified in terms of standardized uptake values (SUVs). Imaging findings were correlated with final whole-gland histopathology. Results: Of the 21 patients, two had T stage 2b disease, nine stage 2c, six stage 3a and four stage 3b. The median Gleason score was 7. The SUVmean of the primary tumors was 9.5 +/- 8.8. SUVmean was higher in tumors with ECE than in organ-confined tumors (13.8 +/- 11.0 vs. 5.6 +/- 3.2, p = 0.029). Peak tracer uptake was significantly positively correlated with Gleason score (rs = 0.49, p = 0.025). Sensitivity, specificity, positive predictive value and negative predictive value were, respectively, 94.7%, 75.0%, 97.3% and 60.0% for tumor infiltration of an individual prostate lobe, 75.0%, 100.0%, 100.0% and 97.4% for SVI, and 90.0%, 90.9%, 90.0% and 90.9% for ECE, using an angulated contour of the prostate as the criterion. Tumor volume derived from 68Ga-PSMA I&T PET/CT was significantly correlated with preoperative prostate-specific antigen value (rp = 0.75, p < 0.001) and tumor volume on histopathology (rp = 0.45, p = 0.039). Conclusions: 68Ga-PSMA I&T PET/CT prior to radical prostatectomy can contribute to presurgical local staging of prostate cancer. In this pilot study, 68Ga-PSMA I&T PET/CT showed promising results for prediction of lobe infiltration, ECE and SVI. PMID- 29242726 TI - Relationship Between Dual Time Point FDG PET/CT and Clinical Prognostic Indexes in Patients with High Grade Lymphoma: a Pilot Study. AB - Purpose: This study investigated the correlative relationship between metabolic parameters estimated from dual time point 2-deoxy-2-[18F] fluoro-D-glucose (18F FDG) positron emission tomography/computerized tomography (PET/CT) and the clinical tools predicting the outcome of a lymphoma. We also measured metabolic and volumetric alterations between early and delayed 18F-FDG PET/CT in patients with high grade lymphoma (HGL). Methods: The samples were 122 lymph nodes and extralymphatic lesions from 26 patients diagnosed with HGL. All patients were applied to the International Prognostic Index (IPI), Ann Arbor stage, and revised IPI as clinical prognostic parameters. 18F-FDG dual time point PET/CT (DTPFP) consisted of an early scan 1 h after 18F-FDG injection and a delayed scan 2 h after the early scan. Based on an analysis of DTPFP, we estimated the standardized uptake value (SUV) of tumors from the early and delayed scans, retention index (RI) representing the percentage change between early and delayed SUV, and metabolic volume different index (MVDI) calculated using metabolic tumor volumes (MTV). Results: RImax showed a multiple positive correlative relationship with stage and IPI in lesion-by-lesion analysis (p < 0.01). In the case of IPI, the high risk group exhibited higher RImax than the low risk group (p = 0.004). In the case of revised IPI, the RImax of the low risk group were significantly lower than the intermediate and high risk groups, respectively (p < 0.01). The MVDIs of the best outcome group were decreased in comparison to the moderate outcome group (p = 0.029). There was a significant negative correlative relationship between RImax and MVDI, and the inclinations for decreased MVDIs were slightly associated with increased RIs. Conclusions: RImax extracted from DTPFP had a significant relationship to extranodal involvement, staging, IPI, and revised IPI. MVDI showed significant negative correlation with RImax. Further large scale studies are warranted to support and extend these preliminary results. PMID- 29242727 TI - Evaluation of Cadmium-Zinc-Telluride Detector-based Single-Photon Emission Computed Tomography for Nuclear Cardiology: a Comparison with Conventional Anger Single-Photon Emission Computed Tomography. AB - Purpose: The differences in performance between the cadmium-zinc-telluride (CZT) camera or collimation systems and conventional Anger single-photon emission computed tomography (A-SPECT) remain insufficient from the viewpoint of the user. We evaluated the performance of the D-SPECT (Spectrum Dynamics, Israel) system to provide more information to the cardiologist or radiological technologist about its use in the clinical field. Materials and Methods: This study evaluated the performance of the D-SPECT system in terms of energy resolution, detector sensitivity, spatial resolution, modulation transfer function (MTF), and collimator resolution in comparison with that of A-SPECT (Bright-View, Philips, Japan). Energy resolution and detector sensitivity were measured for Tc-99m, I 123, and Tl-201. The SPECT images produced by both systems were evaluated visually using the anthropomorphic torso phantom. Results: The energy resolution of D-SPECT with Tc-99m and I-123 was approximately two times higher than that of A-SPECT. The detector sensitivity of D-SPECT was higher than that of A-SPECT (Tc 99m: 4.2 times, I-123: 2.2 times, and Tl-201: 5.9 times). The mean spatial resolution of D-SPECT was two times higher than that of A-SPECT. The MTF of D SPECT was superior to that of the A-SPECT system for all frequencies. The collimator resolution of D-SPECT was lower than that of A-SPECT; however, the D SPECT images clearly indicated better spatial resolution than the A-SPECT images. Conclusion: The energy resolution, detector sensitivity, spatial resolution, and MTF of D-SPECT were superior to those of A-SPECT. Although the collimator resolution was lower than that of A-SPECT, the D-SPECT images were clearly of better quality. PMID- 29242728 TI - Quantitative Single-Photon Emission Computed Tomography/Computed Tomography for Glomerular Filtration Rate Measurement. AB - Purpose: We propose a quantitative Tc-99m diethylenetriaminepentaacetic acid (DTPA) single-photon emission computed tomography/computed tomography (SPECT/CT) for glomerular filtration rate (GFR) measurement. Methods: Quantitative SPECT/CT data obtained at 2-3 min post-Tc-99m DTPA injection (370 MBq) were used to determine % injected doses (%IDs) for individual kidneys. The reproducibility of %ID measurement was tested and compared with planar scintigraphy. Cr-51 ethylenediaminetetraacetic acid (EDTA) GFR was used as reference standard. Nine young volunteers, representing normal GFR, and ten older volunteers, reflecting impaired GFR, were enrolled. The established GFR equation derived from these volunteers was applied to 19 renal tumor patients post-partial nephrectomy. Results: At 2-3 min, %ID was most reproducible with the highest intraclass correlation (ICC) (0.9379) and lowest % coefficient of variation (CV) (6.5259%), which were more reliable than the ICC (0.9368) and %CV (6.7689%) of planar scintigraphy. Cr-51 EDTA GFR (93.16 +/- 24.81 ml/min) correlated significantly with %ID (7.66 +/- 2.15%, r = 0.7906, p = 0.0001), yielding an equation: Cr-51 EDTA GFR (ml/min) = (%ID * 9.1462) + 23.0653. This equation revealed significant decreases in total and nephrectomized kidney GFR (p = 0.0012 and p < 0.0001, respectively) from preoperative to 3-month postoperative measurements. Conclusions: Quantitative Tc-99m DTPA SPECT/CT produces reliable and clinically applicable %ID estimates that translate to the GFR of individual kidneys. PMID- 29242729 TI - Altered Biodistribution of 99mTc-DPD on Bone Scan After Intravenous Iron Supplement. AB - We report a case with altered biodistribution of 99mTc-dicarboxypropane diphosphonate (99mTc-DPD) on whole body bone scan after intravenous iron supplement therapy. A 47-year-old male patient who had recently been detected with a hepatic mass suggestive of hepatocellular carcinoma underwent bone scan as staging work-up before surgery. Bone scan images at 3 h after injection of 99mTc DPD demonstrated unusually increased blood pool activities in the heart, liver, and spleen with usual skeletal uptakes. The patient had been treated for severe anemia from hemorrhoid with two intravenous administration of ferric hydroxide carboxymaltose complex at approximately 22 h and 2 h prior to the 99mTc-DPD injection, which we consider as the most probable cause of altered biodistribution of 99mTc-DPD. PMID- 29242730 TI - Unusual Contralateral Axillary Lymph Node Metastasis in a Second Primary Breast Cancer Detected by FDG PET/CT and Lymphoscintigraphy. AB - Contralateral metastatic axillary lymph nodes in a patient with breast cancer is a rare condition. Here, we present a 55-year-old woman with a second primary breast cancer. The patient underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) for staging work-up. Additionally, preoperative lymphoscintigraphy was performed to detect sentinel lymph nodes. FDG PET/CT demonstrated increased FDG uptake in the left nipple and right axillary lymph nodes. Lymphoscintigraphy identified the right axillary lymph nodes which was consistent with the FDG PET/CT findings. This case emphasizes the usefulness of FDG PET/CT and lymphoscintigraphy for identifying unpredictable contralateral axillary lymph node metastasis from a second primary breast cancer. PMID- 29242731 TI - Recurrent Follicular Dendritic Cell Sarcoma of the Parotid Gland Imaged with 18F FDG PET/CT. AB - Follicular dendritic cell sarcoma (FDCS) is an extremely rare tumor with only 67 cases of head and neck FDCS reported in the literature. A 65-year-old female had a 6-cm follicular dendritic cell sarcoma resected from the left parotid gland with close margins. It recurred 1 year later as a 5-cm mass that was intensely [18F] fluoro-2-deoxy-D-glucose (18F-FDG) avid on positron emission tomography/computed tomography (PET/CT) and was re-excised. A follow-up PET/CT did not show any metastatic disease. The use of 18F-FDG PET/CT in the management of FDCS warrants further research. We present the 18F-FDG PET/CT imaging findings of this rare tumor. PMID- 29242732 TI - Usefulness of Tc-99m Pertechnetate SPECT/CT in the Diagnosis of Testicular Infarction After Inguinal Herniorrhaphy. AB - A 77-year-old male underwent open repair for a right indirect inguinal hernia and complained of right scrotal pain on the third postoperative day. Color Doppler imaging revealed decreased blood flow with heterogeneous hypoechogenicity in the right testis. A Tc-99m pertechnetate testicular scan showed diffuse hyperemia and increased uptake in the right scrotum. Additional SPECT/CT revealed a photon defect in the right testicle with increased uptake in the peri-testicular area. A subsequent operation revealed a large hematoma in the right spermatic cord and consequent right testicular infarction, and right orchiectomy was performed. PMID- 29242733 TI - 68Ga-PSMA PET-CT Imaging of Metastatic Adenoid Cystic Carcinoma. AB - A patient with a history of adenoid cystic carcinoma of the nasal cavity presented himself with bone pain and an elevated PSA level. On suspicion of metastatic prostate cancer a 68Ga-PSMA PET-CT was performed. The PET-CT showed numerous lung and non-sclerotic bone metastasis. Biopsy of a bone metastasis was performed and pathology showed adenoid cystic carcinoma instead of prostate cancer. Immunohistochemical PSMA staining of the primary tumour showed intense PSMA expression in adenoid cystic carcinoma tumour cells. Because of the high PSMA expression of adenoid cystic carcinoma, 68Ga-PSMA PET-CT might be a promising imaging modality for this malignancy. PMID- 29242734 TI - Images from 18F-DOPA Scan in Congenital Hyperinsulinism: Not Always a Clue for Diagnosis. AB - Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in childhood (Horm Res 70:65-72, 2008; J Clin Endocr Metab 93:869 875, 2008). 18-Fluoro-L-dihydroxy-phenylalanine (18F-DOPA) positron emission tomography (PET) can detect areas of increased activity in the pancreas and may differentiate focal from diffuse CHI (J Clin Endocr Metab 93:869-875, 2008; Radiology 253:216-222, 2009). We here report the case of a girl who complained of recurrent episodes of severe hypoglycaemia despite previous partial pancreatectomy. To evaluate the need for additional surgical intervention, we performed 18F-DOPA PET/computed tomography (CT), which showed a focal lesion corresponding to the anatomical region of the pancreatic tail. On the other hand, abdominal magnetic resonance imaging (MRI) clearly demonstrated that the 18F-DOPA uptake was in a loop of bowel occupying the previous surgical bed. Our case highlights that bowel uptake can be a possible pitfall in the interpretation of 18F-DOPA PET/CT in children affected by CHI, suggesting that when 18F-DOPA PET/CT results do not fit the clinical picture, magnetic resonance imaging (MRI) may allow a more accurate correlation of the radiotracer activity with the underlying anatomical or pathological structure. PMID- 29242735 TI - Microcalcified Hepatic Metastases Incidentally Detected on F-18 NaF PET/CT in a Patient with Prostate Cancer. AB - F-18 NaF PET/CT evaluation has gained importance in recent years. Achievements from F-18 NaF PET/CT are: higher sensitivity of positron imaging, higher target background ratio with higher tracer accumulation in bone hydroxyapatite and higher specificity through CT correlation. These properties have also given directions to new research fields based on imaging microcalcifications, very recently. A limited number of cases have reported the F-18 NaF uptake in macrocalcified soft tissue metastases. Although the presence of microcalcification was not proved; accumulation of F-18 NaF in the metastatic brain lesion with no visible calcification on the CT, in a patient with ductal breast carcinoma has also been reported. Herein we present a patient with microcalcified hepatic metastasis of prostate cancer incidentally detected on F 18 NaF PET/CT which was confirmed with histochemical staining. PMID- 29242736 TI - Inguinal Herniation of Urinary Bladder on F-18 Sodium Fluoride (NaF) PET-CT. AB - Inguinal herniation of urinary bladder is uncommon and usually an incidental finding in asymptomatic patients. In some of these patients, residual urine volume and consequently, urinary tracer activity can be higher in the herniated bladder than the native bladder, in which case interpretation can be challenging on conventional planar imaging. We describe an interesting case of physiological activity in a herniated bladder simulating a "tear-drop". This case serves an important reminder that whilst F-18 NaF PET-CT has a similar spectrum of urinary activity to conventional bone scintigraphy; morphological correlation on hybrid imaging is invaluable in ensuring the physiological nature of uptake. PMID- 29242737 TI - Radiation-Induced Giant Cell Granuloma Mimicking Relapsed Hodgkin Lymphoma at FDG PET/CT. AB - A 22-year-old woman was diagnosed with intermediate risk stage II Hodgkin lymphoma and treated with three cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by involved-field radiation therapy. A complete metabolic remission was achieved after two cycles of ABVD, which was maintained until three years after completion of treatment. Follow-up FDG-PET/CT four years after completion of treatment, however, showed a new FDG-avid (Deauville score of 4) lesion in the right scapula, suggesting relapsed disease. Computer tomography (CT)-guided biopsy of this lesion was performed and subsequent histological examination revealed a radiation-induced giant cell granuloma. PMID- 29242738 TI - Social Vision: Functional Forecasting and the Integration of Compound Social Cues. AB - For decades the study of social perception was largely compartmentalized by type of social cue: race, gender, emotion, eye gaze, body language, facial expression etc. This was partly due to good scientific practice (e.g., controlling for extraneous variability), and partly due to assumptions that each type of social cue was functionally distinct from others. Herein, we present a functional forecast approach to understanding compound social cue processing that emphasizes the importance of shared social affordances across various cues (see too Adams, Franklin, Nelson, & Stevenson, 2010; Adams & Nelson, 2011; Weisbuch & Adams, 2012). We review the traditional theories of emotion and face processing that argued for dissociable and noninteracting pathways (e.g., for specific emotional expressions, gaze, identity cues), as well as more recent evidence for combinatorial processing of social cues. We argue here that early, and presumably reflexive, visual integration of such cues is necessary for adaptive behavioral responding to others. In support of this claim, we review contemporary work that reveals a flexible visual system, one that readily incorporates meaningful contextual influences in even nonsocial visual processing, thereby establishing the functional and neuroanatomical bases necessary for compound social cue integration. Finally, we explicate three likely mechanisms driving such integration. Together, this work implicates a role for cognitive penetrability in visual perceptual abilities that have often been (and in some cases still are) ascribed to direct encapsulated perceptual processes. PMID- 29242739 TI - Healthy Food Availability Among Food Sources in Rural Maryland Counties. AB - Most studies examining the association of the food environment and health outcomes have focused on urban settings. However, rural adults and children have high rates of obesity, which may be related to their food environments. This study examines the food environment in 7 rural counties in Maryland. A cross sectional study was conducted at 244 retail food stores from 2012 to 2013. Data on store-level characteristics were collected and a healthy food availability index (HFAI) ranging from 0 to 31 points was calculated for each store. Convenience stores (18.9%) and other nontraditional stores (16.8%) were the most common store types, and box stores were the least (4.9%). Supermarkets had the highest mean HFAI (24.8), whereas gas stations (8.7) had the lowest; convenience stores were also low (11.1). In rural Maryland, the most common food source types have low healthy food availability, and nontraditional food sources are an important part of the food environment. PMID- 29242740 TI - Near-Infrared Irradiation Increases Length of Axial Pattern Flap Survival in Rats. AB - Objective: We previously reported that near-infrared irradiation nonthermally induces long-lasting vasodilation of the subdermal plexus by causing apoptosis of vascular smooth muscle cells. To clarify the possible application of near infrared irradiation to prevent skin flap necrosis, we evaluated the length of axial pattern flap survival in rats by near-infrared irradiation. Methods: A bilaterally symmetric island skin flap was elevated under the panniculus carnosus on the rat dorsum. Half of the flap was subjected to near-infrared irradiation just before flap elevation with a device that simulates solar radiation, which has a specialized contact cooling apparatus to avoid thermal effects. The length of flap survival of the near-infrared irradiated side was measured 7 days after flap elevation and compared with the nonirradiated side. Results: The irradiated side showed elongation of flap survival compared with the nonirradiated side (73.3 +/- 11.7 mm vs 67.3 +/- 14.9 mm, respectively, P = .03). Conclusions: Near infrared irradiation increases the survival length of axial pattern flaps in rats. PMID- 29242741 TI - Bayesian joint models with INLA exploring marine mobile predator-prey and competitor species habitat overlap. AB - Understanding spatial physical habitat selection driven by competition and/or predator-prey interactions of mobile marine species is a fundamental goal of spatial ecology. However, spatial counts or density data for highly mobile animals often (1) include excess zeros, (2) have spatial correlation, and (3) have highly nonlinear relationships with physical habitat variables, which results in the need for complex joint spatial models. In this paper, we test the use of Bayesian hierarchical hurdle and zero-inflated joint models with integrated nested Laplace approximation (INLA), to fit complex joint models to spatial patterns of eight mobile marine species (grey seal, harbor seal, harbor porpoise, common guillemot, black-legged kittiwake, northern gannet, herring, and sandeels). For each joint model, we specified nonlinear smoothed effect of physical habitat covariates and selected either competing species or predator prey interactions. Out of a range of six ecologically important physical and biologic variables that are predicted to change with climate change and large scale energy extraction, we identified the most important habitat variables for each species and present the relationships between these bio/physical variables and species distributions. In particular, we found that net primary production played a significant role in determining habitat preferences of all the selected mobile marine species. We have shown that the INLA method is well-suited for modeling spatially correlated data with excessive zeros and is an efficient approach to fit complex joint spatial models with nonlinear effects of covariates. Our approach has demonstrated its ability to define joint habitat selection for both competing and prey-predator species that can be relevant to numerous issues in the management and conservation of mobile marine species. PMID- 29242742 TI - Highly lipophilic fluorescent dyes in nano-emulsions: towards bright non-leaking nano-droplets. AB - Dye-loaded lipid nano-droplets present an attractive alternative to inorganic nanoparticles, as they are composed of non-toxic biodegradable materials and easy to prepare. However, to achieve high fluorescence brightness, the nano-droplets have to be heavily loaded with the dyes avoiding fluorescence self-quenching and release (leakage) of the encapsulated dyes from the nano-droplets in biological media. In the present work, we have designed highly lipophilic fluorescent derivatives of 3-alkoxyflavone (F888) and Nile Red (NR668) that can be encapsulated in the lipophilic core of stable nano-emulsion droplets at exceptionally high concentrations in the oil core, i.e. up to 170 mM and 17 mM, respectively, corresponding to ~ 830 and 80 dyes per 40-nm droplet. Despite this high loading, these dyes keep high fluorescence quantum yield and thus, provide high nano-droplet brightness, probably due to their bulky structure preventing self-quenching. Moreover, simultaneous encapsulation of both dyes at high concentrations in single nano-droplets allows observation of FRET. FRET and fluorescence correlation spectroscopy (FCS) studies showed that NR668 release in the serum-containing medium is very slow, while the reference hydrophobic dye Nile Red leaks immediately. This drastic difference in the leakage profile between NR668 and Nile Red was confirmed by in vitro cellular studies as well as by in vivo angiography imaging on zebrafish model, where the NR668-loaded nano droplets remained in the blood circulation, while the parent Nile Red leaked rapidly from the droplets distributing all over the animal body. This study suggests new molecular design strategies for obtaining bright nano-droplets without dye leakage and their use as efficient and stable optical contrast agents in vitro and in vivo. PMID- 29242743 TI - Open repair management of a patient with aortic arch saccular aneurysm, penetrating atherosclerotic ulcer, one vessel coronary artery disease and an isolated dissection of the abdominal aorta. AB - Isolated saccular compared to fusiform aneurysm is considered to be a rare entity with challenges of its own. A 62-year-old female was diagnosed with a case of saccular aneurysm and penetrating atherosclerotic ulcer of the aortic arch. Additionally, she also had one vessel coronary artery disease and type B abdominal aortic dissection. She was then managed with open aortic arch repair and coronary artery bypass grafting. If required, elective endovascular repair will be done for the abdominal aorta on a later date. PMID- 29242744 TI - Lung Talaromyces marneffei infection in an Indonesian papillary thyroid carcinoma patient. AB - Talaromycosis, a disseminated and progressive infection caused by Talaromyces marneffei, is highly endemic in the tropical region of Asia. However, accumulated data show very low incidence in Indonesia. Here, we report a case of papillary thyroid carcinoma with pulmonary T. marneffei infection. Screening of T. marneffei in this immunocompromised Indonesian patient is recommended even though the reported incidence of this particular fungal infection in Indonesia is low. PMID- 29242745 TI - The liver and Chilaiditi's syndrome: Significance of hepatic surface grooves. AB - Chilaiditi's syndrome describes a symptomatic patient with radiographic findings of interposed colon between the diaphragm and right lobe of liver. It may mimic a pneumoperitoneum on plain radiographs. We present a case in which Chilaiditis' syndrome was entertained, delaying a decision for laparotomy. This case reinforces the diagnostic difficulty associated with Chilaiditi's syndrome, and it increases awareness of an uncommon variation in the liver surface anatomy. PMID- 29242746 TI - A practical method of I-131 thyroid cancer therapy dose optimization using estimated effective renal clearance. AB - In thyroid cancer patients with renal impairment or other complicating factors, it is important to maximize I-131 therapy efficacy while minimizing bone marrow and lung damage. We developed a web-based calculator based on a modified Benua and Leeper method to calculate the maximum I-131 dose to reduce the risk of these toxicities, based on the effective renal clearance of I-123 as measured from two whole-body I-123 scans, performed at 0 and 24 h post-administration. PMID- 29242747 TI - Usefulness of preoperative echography for detection of lymphatic vessels for lymphaticovenous anastomosis. AB - Case 1: A 63-year-old woman with secondary lower limb lymphedema. As it was difficult to detect the lymphatic vessels in the right thigh in indocyanine green lymphography because of thick fat, we tried echography and observed circular structures beneath the superficial fascia. Intraoperatively, we found a dilated lymphatic vessel just as observed on echography. Case 2: A 45-year-old woman with primary lower limb lymphedema. As she was allergic to iodinated contrast medium, we could not use indocyanine green lymphography preoperatively. In echography, we found vascular architectures and found the dilated lymphatic vessels intraoperatively just as observed on echography. In conclusion, application of echography in detecting the lymphatic vessels was useful as a preoperative examination of lymphaticovenous anastomosis. PMID- 29242748 TI - Optimization of prostate MRI acquisition and post-processing protocol: a pictorial review with access to acquisition protocols. AB - The aim of this review article is to provide insight into the optimization of 1.5 Testla (T) and 3-T prostate magnetic resonance imaging (MRI). An approach for optimization of data quantification, especially diffusion-weighted imaging (DWI), is provided. Benefits and limitations of various pulse sequences are discussed. Importable MRI protocols and access to imaging datasets is provided. Careful optimization of prostate MR acquisition protocol allows the acquisition of high quality prostate MRI using clinical 1.5-T/3-T MR scanners with an overall acquisition time < 15 min. PMID- 29242749 TI - Setting the research and implementation agenda for equitable access to surgical care in South Africa. AB - South Africa is an upper-middle-income country with widespread social and geographical inequality of surgical provision. The National Forum on Surgery and Anaesthesia in South Africa brought together various stakeholders, including government, societies, academic clinicians and the biomedical industry, to define the core strategy for a national surgical plan. During the forum, presentations and breakaway workshops explored and reported the challenges and opportunities these stakeholders may have in sustaining and improving surgical provision in South Africa. We present the recommendations of these reports with a literature review and other recent reports from organisations involved in healthcare systems in South Africa. We acknowledge the importance of access to safe and affordable surgery for all as a core component of healthcare provision for South Africa. The proposed core strategies for a South African National Surgical Plan to achieve these goals are the following. First, research will focus on high-quality interdisciplinary collaborative research and audit, which addresses the Global Surgery indices, adopts internationally consistent data points and focuses particularly on maternal mortality and the 'Bellwether procedures'. Second, workforce and training must be tailored to the country's specific surgical needs, based on a primary healthcare and district hospital model, which is supported by government and academic organisations. Third, the surgical infrastructure and service delivery needs to be strengthened by the district hospital. Finally, strong leadership with appropriate financial support by healthcare managers who partner with clinicians both locally and nationally is needed to achieve these objectives. PMID- 29242750 TI - Global investment targets for malaria control and elimination between 2016 and 2030. AB - Background: Access to malaria control interventions falls short of universal health coverage. The Global Technical Strategy for malaria targets at least 90% reduction in case incidence and mortality rates, and elimination in 35 countries by 2030. The potential to reach these targets will be determined in part by investments in malaria. This study estimates the financing required for malaria control and elimination over the 2016-2030 period. Methods: A mathematical transmission model was used to explore the impact of increasing intervention coverage on burden and costs. The cost analysis took a public provider perspective covering all 97 malaria endemic countries and territories in 2015. All control interventions currently recommended by the WHO were considered. Cost data were sourced from procurement databases, the peer-reviewed literature, national malaria strategic plans, the WHO-CHOICE project and key informant interviews. Results: Annual investments of $6.4 billion (95% uncertainty interval (UI $4.5-$9.0 billion)) by 2020, $7.7 billion (95% UI $5.4-$10.9 billion) by 2025 and $8.7 billion (95% UI $6.0-$12.3 billion) by 2030 will be required to reach the targets set in the Global Technical Strategy. These are equivalent to annual investment per person at risk of malaria of US$3.90 by 2020, US$4.30 by 2025 and US$4.40 by 2030, compared with US$2.30 if interventions were sustained at current coverage levels. The 20 countries with the highest burden in 2015 will require 88% of the total investment. Conclusions: Given the challenges in increasing domestic and international funding, the efficient use of currently available resources should be a priority. PMID- 29242752 TI - Out-of-pocket expenditures for prevention and treatment of cardiovascular disease in general and specialised cardiac hospitals in Addis Ababa, Ethiopia: a cross sectional cohort study. AB - Background: Cardiovascular disease poses a great financial risk on households in countries without universal health coverage like Ethiopia. This paper aims to estimate the magnitude and intensity of catastrophic health expenditure and factors associated with catastrophic health expenditure for prevention and treatment of cardiovascular disease in general and specialised cardiac hospitals in Addis Ababa. Methods and findings: We conducted a cross-sectional cohort study among individuals who sought cardiovascular disease care in selected hospitals in Addis Ababa during February to March 2015 (n=589, response rate 94%). Out-of pocket payments on direct medical costs and direct non-medical costs were accounted for. Descriptive statistics was used to estimate the magnitude and intensity of catastrophic health expenditure within households, while logistic regression models were used to assess the factors associated with it.About 27% (26 .7;95% CI 23.1 to 30.6) of the households experienced catastrophic health expenditure, defined as annual out-of-pocket payments above 10% of a household's annual income. Family support was the the most common coping mechanism. Low income, residence outside Addis Ababa and hospitalisation increased the likelihood of experiencing catastrophic health expenditure. The bottom income quintile was about 60 times more likely to suffer catastrophic health expenditure compared with the top quintile (adjusted OR=58.6 (16.5-208.0), p value=0.00). Of those that experienced catastrophic health expenditure, the poorest and richest quintiles spent on average 34% and 15% of households' annual income, respectively. Drug costs constitute about 50% of the outpatient care cost. Conclusions: Seeking prevention and treatment services for cardiovascular disease in Addis Ababa poses substantial financial burden on households, affecting the poorest and those who reside outside Addis Ababa more. Economic and geographical inequalities should also be considered when setting priorities for expanding coverage of these services. Expanded coverage has to go hand-in-hand with implementation of sound prepayment and risk pooling arrangements to ensure financial risk protection to the most needy. PMID- 29242751 TI - Prevalence of non-communicable disease risk factors in three sites across Papua New Guinea: a cross-sectional study. AB - : Papua New Guinea (PNG) is a culturally, environmentally and ethnically diverse country of 7.3 million people experiencing rapid economic development and social change. Such development is typically associated with an increase in non communicable disease (NCD) risk factors. Aim: To establish the prevalence of NCD risk factors in three different regions across PNG in order to guide appropriate prevention and control measures. Methods: A cross-sectional survey was undertaken with randomly selected adults (15-65 years), stratified by age and sex recruited from the general population of integrated Health and Demographic Surveillance Sites in West Hiri (periurban), Asaro (rural highland) and Karkar Island (rural island), PNG. A modified WHO STEPS risk factor survey was administered along with anthropometric and biochemical measures on study participants. Results: The prevalence of NCD risk factors was markedly different across the three sites. For example, the prevalences of current alcohol consumption at 43% (95% CI 35 to 52), stress at 46% (95% CI 40 to 52), obesity at 22% (95% CI 18 to 28), hypertension at 22% (95% CI 17 to 28), elevated levels of cholesterol at 24% (95% CI 19 to 29) and haemoglobin A1c at 34% (95% CI 29 to 41) were highest in West Hiri relative to the rural areas. However, central obesity at 90% (95% CI 86 to 93) and prehypertension at 55% (95% CI 42 to 62) were most common in Asaro whereas prevalences of smoking, physical inactivity and low high-density lipoprotein cholesterol levels at 52% (95% CI 45 to 59), 34% (95% CI 26 to 42) and 62% (95% CI 56 to 68), respectively, were highest in Karkar Island. Conclusion: Adult residents in the three different communities are at high risk of developing NCDs, especially the West Hiri periurban population. There is an urgent need for appropriate multisectoral preventive interventions and improved health services. Improved monitoring and control of NCD risk factors is also needed in all regions across PNG. PMID- 29242753 TI - Activating transcription factor 3 in immune response and metabolic regulation. AB - Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-response element binding protein (CREB) family of transcription factors. In response to stress stimuli, ATF3 forms dimers to activate or repress gene expression. Further, ATF3 modulates the immune response, atherogenesis, cell cycle, apoptosis, and glucose homeostasis. Recent studies have shown that ATF3 may also be involved in pathogenesis of other diseases. However, more studies are needed to determine the role of ATF3 in metabolic regulation. PMID- 29242754 TI - The Relationship Between Family, Parent, and Child Characteristics and Intimate Partner Violence (IPV) Among Ukrainian Mothers. AB - Objective: To assess the prevalence of intimate partner violence (IPV) in a sample of Ukrainian mothers of schoolchildren, and to examine the relationship between IPV and family, parent, and child characteristics utilizing multilevel models. Method: Mothers of children aged 9-16 (n = 278, 93.5% Ukrainians) answered the Revised Conflict Tactics Scale (CTS2) assessing IPV. We also examined the relationship between IPV and maternal age, education, employment and marital status, family income, and rural or urban residence. Results: Eighty-one percent of women reported psychological violence and 58% reported physical assault. On average, women reported 66 instances of IPV during the last year. Multilevel modeling revealed that lower maternal education, unemployment, not living with the husband or partner, and urban residency were associated with higher IPV victimization. Younger age and family income were not significantly related to IPV. Conclusions: IPV was a significant social problem in the present sample of Ukrainian mothers of school age children. Future policy and violence prevention programming should focus on supporting academic and employment opportunities for women, particularly for those living in urban areas. PMID- 29242755 TI - The Effects of Men's Hostility Toward Women, Acute Alcohol Intoxication, and Women's Condom Request Style on Men's Condom Use Resistance Tactics. AB - Objective: To extend previous research demonstrating that intoxicated men high in hostility toward women report stronger intentions to use coercive condom use resistance (CUR) tactics to have unprotected sex by examining the role of women's condom request style. Methods: Community, non-problem drinking men, ages 21-30 (N = 296) completed standard alcohol administration procedures and read an eroticized story of a casual sexual interaction. Following the woman's request to use a condom, intentions to engage in coercive CUR tactics were assessed. Generalized linear models with gamma distributions assessed the 3-way interaction of men's hostility toward women, beverage condition (alcohol or sober), and the woman's condom request style (indirect, direct, or insistent). Results: The 3-way interaction between hostility toward women, beverage condition, and indirect condom request (vs. direct) significantly predicted men's coercive CUR intentions. Men high in hostility toward women reported stronger CUR intentions after experiencing an indirect condom request, when sober or intoxicated, and after a direct condom request when intoxicated. Men high in hostility toward women reported the weakest CUR intentions when sober following an insistent or direct condom request. Conclusions: Men high in hostility toward women pose a threat to women's sexual safety, particularly when intoxicated or following an indirect condom request. Hostility toward women and alcohol consumption should be addressed in sexual risk prevention programs. Pending further replication, women should be informed of the relative effectiveness of using insistent condom requests. PMID- 29242756 TI - Intersession Test-Retest Variability of Microperimetry in Type 2 Macular Telangiectasia. AB - Purpose: Microperimetry is used as an endpoint in type 2 macular telangiectasia (mactel) trials. The change required for defining disease progression depends on measurement error. We determined the threshold of test-retest variability (TRV) of microperimetry in mactel. Methods: A prospective study was done of 24 patients with stable mactel enrolled in a tertiary eye clinic. Each patient underwent three sessions of microperimetry separated by a median of 28 days. An identical testing protocol was used: 4-2 staircase algorithm at 37 loci radial grid covering central 6 degrees . Microperimetry variables were compared across three visits. TRV was quantified by calculating the coefficients of repeatability (CRs) for mean and median foveal sensitivity and the number of loci with dense scotoma (DS) or normal sensitivity (NS). The 95% confidence intervals (CIs) for CRs were calculated. Results: Mean and median foveal sensitivity increased from first to second testing sessions. Test duration, visual acuity, number of loci with DS, and fixation stability remained stable through the three test sessions. The intersession CRs for mean and median foveal sensitivity were 2.6 (95% CI, 1.8 3.3) and 2.4 (95% CI, 1.7-3.1) dB, respectively. CRs for the number of DS and NS loci were 5 and 12 loci. CR for both logBCEA63 and logBCEA95 was 1.0 (95% CI, 0.8 1.2). Conclusions: The first microperimetry examination should be discarded due to learning effects. TRV in foveal sensitivity may be as high as 3.3 and 3.1 dB (~0.3 log unit; 2* change) for its mean and median. Translational Relevance: Our results have implications for the design of clinical trials in mactel. PMID- 29242758 TI - Comprehensive Review of Preschool Age Anemia in the Pacific Island Jurisdictions. AB - Anemia can be an indicator of poor nutrition and health, and it can have significant consequences. Children are disproportionately affected by anemia. This comprehensive review summarizes the available literature on anemia prevalence in young children in the islands of the Oceania region. The anemia prevalence, the criteria used for diagnosis, the date the data was reported, and the types of samples collected were reviewed. Anemia prevalence estimates were reported for eighteen of the Pacific Island Jurisdictions. From the fifteen data sources that were evaluable, anemia prevalence ranged from 12.3% to over 70%. A major limitation in the data is a lack of representative primary data from many of the jurisdictions in the region. Prevalance estimates reported for those jurisdictions are estimated by regression analysis from the World Health Organization (WHO). Moreover, the primary data available does not use standardized reporting criteria. Nevertheless, this review serves as a new baseline for further investigations on the prevalence of anemia and a baseline for evaluating public health prevention and treatment measures to detect and improve anemia prevalence in the Pacific. PMID- 29242757 TI - Differential Gene Transcription of Extracellular Matrix Components in Response to In Vivo Corneal Crosslinking (CXL) in Rabbit Corneas. AB - Purpose: We studied changes in gene transcription after corneal crosslinking (CXL) in the rabbit cornea in vivo and identified potential molecular signaling pathways. Methods: A total of 15 corneas of eight male New-Zealand-White rabbits were de-epithelialized and equally divided into five groups. Group 1 served as an untreated control. Groups 2 to 5 were soaked with 0.1% riboflavin for 20 minutes, which in Groups 3 to 5 was followed by UV-A irradiation at a fluence of 5.4 J/cm2. Ultraviolet A (UVA) irradiation was delivered at 3 mW/cm2 for 30 minutes (Group 3, standard CXL protocol), 9 mW/cm2 for 10 minutes (Group 4, accelerated), and 18 mW/cm2 for 5 minutes (Group 5, accelerated). At 1 week after treatment, corneal buttons were obtained; mRNA was extracted and subjected to cDNA sequencing (RNA-seq). Results: A total of 297 differentially transcribed genes were identified after CXL treatment. CXL downregulated extracellular matrix components (collagen types 1A1, 1A2, 6A2, 11A1, keratocan, fibromodulin) and upregulated glycan biosynthesis and proteoglycan glycosylation (GALNT 3, 7, and 8, B3GALT2). Also, CXL activated pathways related to protein crosslinking (transglutaminase 2 and 6). In 9.1% of the significantly different genes, CXL at 3 mW/cm2 (Group 1) induced a more distinct change in gene transcription than the accelerated CXL protocols, which induced a lower biomechanical stiffening effect. Conclusions: Several target genes have been identified that might be related to the biomechanical stability and shape of the cornea. Stiffening-dependent differential gene transcription suggests the activation of mechano-sensitive pathways. Translational Relevance: A better understanding of the molecular mechanisms behind CXL will permit an optimization and individualization of the clinical treatment protocol. PMID- 29242760 TI - Medical School Hotline: Four Decades at the University of Hawai'i: An Interview with Dr. Satoru Izutsu. PMID- 29242759 TI - Breast and Cervical Cancer Screening in Palau: Have We Improved Early Detection and Survival? AB - The Breast and Cervical Cancer Early Detection Program (BCCEDP) was first introduced in Palau in 1997. The program's aim is to recruit and screen women for early detection of breast and cervical cancers. An assessment of this screening program was conducted to evaluate its effectiveness, including impact on stage of diagnosis and survival time of patients diagnosed with breast and cervical cancers through both screening and clinical diagnosis. A retrospective cohort study using secondary data from 2004-2013 was conducted. There were 45 women diagnosed with breast or cervical cancer. Due to the small number of cases, a comparison of two time periods was made (2004-2008) and (2009-2013). There were more cancer cases detected through screening (26%) in the earlier time period (2004-2008), as compared to those diagnosed through screening (8%) in the later time period (2009-2013), though this difference was not statistically significant (P=.09). The proportion of breast and cervical cancers diagnosed at an earlier stage (0-3) may have decreased between the two time periods (42% to 23%, P=.3). A greater proportion of women who were diagnosed between 2004-2008 lived longer than 2 years (58%), than women who were diagnosed between 2009-2013 (39%; P=.23). The screening program has not shown improvement over the years despite the measures taken to detect the early onset of breast and cervical cancer, and survival outcomes in Palau remain poor. PMID- 29242761 TI - Insights in Public Health: Reframing Hepatitis C: Lessons in Successful Public Health Collaboration. PMID- 29242763 TI - Optimization of a resazurin-based microplate assay for large-scale compound screenings against Klebsiella pneumoniae. AB - A new resazurin-based assay was evaluated and optimized using a microplate (384 well) format for high-throughput screening of antibacterial molecules against Klebsiella pneumoniae. Growth of the bacteria in 384-well plates was more effectively measured and had a > sixfold higher signal-to-background ratio using the resazurin-based assay compared with absorbance measurements at 600 nm. Determination of minimum inhibitory concentrations of the antibiotics revealed that the optimized assay quantitatively measured antibacterial activity of various antibiotics. An edge effect observed in the initial assay was significantly reduced using a 1-h incubation of the bacteria-containing plates at room temperature. There was an approximately 10% decrease in signal variability between the edge and the middle wells along with improvement in the assay robustness (Z' = 0.99). This optimized resazurin-based assay is an efficient, inexpensive, and robust assay that can quantitatively measure antibacterial activity using a high-throughput screening system to assess a large number of compounds for discovery of new antibiotics against K. pneumoniae. PMID- 29242764 TI - Diversity of intestinal bacterial lactase gene in antibiotics-induced diarrhea mice treated with Chinese herbs compound Qi Wei Bai Zhu San. AB - The current investigation is trying to study the impact of the mixture of Chinese herbs Qi Wei Bai Zhu San (QWBZS) on bacterial lactase gene from antibiotics induced diarrhea (AAD) mice, as the good curative effect of QWBZS on diarrhea. Mice (6 mice per group) were randomly selected as control, model and treatment groups. To induce diarrhea, mice in both model and treatment groups were intragastrically injected with mixture of gentamycin sulfate and cefradine (23.33 mL kg-1 day-1) twice per day and continuously for totally 5 days. After the success of establishing diarrhea model, the mice in treatment group were gavaged with QWBZS for 3 days. Intestinal contents in all three groups were then collected and DNA was extracted in aseptic environment for the following sequencing. The results showed that mice from QWBZS treatment group had obviously detectable levels of intestinal bacteria, such as Actinobacteria, Firmicutes and Proteobacteria, which produce phyla lactase specifically. In comparison with other groups, the mice in treatment group had more abundant expression of lactase gene from Acidovorax sp. KKs102, Stenotrophomonas sp. LMG11000, Pseudomonas oleovorans, Eggerthella and Burkholderia. Interestingly, the Shannon index decreased significantly after the treatment with QWBZS (P < 0.01 or P < 0.05). 63.1% of lactase genes detected in the mice in treatment group were unclassified, and 32.8% of them were non-homologous to any fragments in the gene bank, which means that most of lactase-producing bacteria are novel. Our results indicate that treatment with QWBZS did not increase the diversity of bacterial lactase gene. Its curative effect on diarrhea may be relevant to its role in facilitating the growth of novel or some key lactase-producing strains. PMID- 29242766 TI - Conflict of Interest Disclosures. PMID- 29242765 TI - Global Spine Congress 2017 Abstracts Special Issue. PMID- 29242767 TI - The Myriad Influences of Alcohol Advertising on Adolescent Drinking. AB - Purpose of Review: This review investigates effects of alcohol advertising on adolescent drinking. Prior reviews focused on behavioral outcomes and long-term effects. In contrast, the present review focuses on subgroups with greater exposure to alcohol advertising, research methods to study alcohol advertising, potential mechanisms underlying relationships between adolescent exposure to alcohol advertising and increased drinking and points to prevention/intervention strategies that may reduce effects of alcohol advertising. Recent Findings: Alcohol advertising influences current and future drinking. Further, evidence suggests adolescents may be targeted specifically. Alcohol advertisements may influence behavior by shifting alcohol expectancies, norms regarding alcohol use, and positive attitudes. Media literacy programs may be an effective intervention strategy. Summary: Adolescents are exposed to large quantities of alcohol advertisements, which violates guidelines set by the alcohol industry. However, media literacy programs may be a promising strategy for adolescents to increase critical thinking and create more realistic expectations regarding alcohol. PMID- 29242768 TI - Neural Correlates of Social Influence on Risk Taking and Substance Use in Adolescents. AB - Purpose of Review: Adolescents often engage in elevated levels of risk taking that gives rise to substance use. Family and peers constitute the primary contextual risk factors for adolescent substance use. This report reviews how families and peers influence adolescent neurocognitive development to inform their risk taking and subsequent substance use. Recent Findings: Developmental neuroscience using functional magnetic resonance imaging (fMRI) has identified regions of the brain involved in social cognition, cognitive control, and reward processing that are integrally linked to social influence on adolescent risk taking. These neural mechanisms play a role in how peer and family influence (e.g., physical presence, relationship quality, rejection) translates into adolescent substance use. Summary: Peers and families can independently, and in tandem, contribute to adolescent substance use, for better or for worse. We propose that future work utilize fMRI to investigate the neural mechanisms involved in different aspects of peer and family influence, and how these contexts uniquely and interactively influence adolescent substance use initiation and escalation across development. PMID- 29242769 TI - Vaccines for the Prevention of Melioidosis and Glanders. AB - Purpose of review: Burkholderia pseudomallei's and Burkholderia mallei's high rate of infectivity, limited treatment options, and potential use as biological warfare agents underscore the need for development of effective vaccines against these bacteria. Research efforts focused on vaccines against these bacteria are in pre-clinical stages, with no approved formulations currently on the market. Recent findings: Several live attenuated and subunit vaccine formulations have been evaluated in animal studies, with no reports of significant long term survival after lethal challenge. Summary: This review encompasses the most current vaccine strategies to prevent B. pseudomallei and B. mallei infections while providing insight for successful vaccines moving forward. PMID- 29242770 TI - Route bundling in polygonal domains using Differential Evolution. AB - Route bundling implies compounding multiple routes in a way that anchoring points at intermediate locations minimize a global distance metric to obtain a tree-like structure where the roots of the tree (anchoring points) serve as coordinating locus for the joint transport of information, goods and people. Route bundling is a relevant conceptual construct in a number of path-planning scenarios where the resources and means of transport are scarce/expensive, or where the environments are inherently hard to navigate due to limited space. In this paper we propose a method for searching optimal route bundles based on a self-adaptive class of Differential Evolution using a convex representation. Rigorous computational experiments in scenarios with and without convex obstacles show the feasibility and efficiency of our approach. PMID- 29242772 TI - Fungal nomenclature evolving: changes adopted by the 19th International Botanical Congress in Shenzhen 2017, and procedures for the Fungal Nomenclature Session at the 11th International Mycological Congress in Puerto Rico 2018. AB - This article summarizes the key changes in the rules relating to the nomenclature of fungi made at the XIX International Botanical Congress in Shenzhen, China, in July 2017. Most significant was the decision to transfer decision-making on matters related only to the naming of fungi from International Botanical to International Mycological Congresses (IMCs). The rules relating to fungi are to be grouped together in a separate section of the International Code of Nomenclature for algae, fungi, and plants (ICN). The way in which the Fungal Nomenclature Session will operate at the upcoming IMC in Puerto Rico in 2018 is summarized and the timetable for new proposals is presented. In addition, approval for names included on lists of protected names to be protected against unlisted as well as known competing names were passed, as were some simplifications relating to the naming of pleomorphic fungi. From 1 January 2019, it will also be necessary to deposit details of lecto-, neo-, and epitypifications in one of the recognized repositories of fungal names in order for them to be validly published and to establish their priority. Various aspects relating to typifications were referred to a new Special Committee, with a separate Special Subcommittee charged with addressing the issue of using DNA sequences as types for all groups covered by the ICN. It is anticipated that the Shenzhen Code will be published in the first half of 2018. PMID- 29242771 TI - Sentinels at the frontline: the role of intraepithelial lymphocytes in inflammatory bowel disease. AB - Purpose of review: Intestinal mucosal immunity is tightly regulated to ensure effective host defense against invasive microorganisms while limiting the potential for aberrant damage. In inflammatory bowel disease (IBD), an imbalance between effector and regulatory T cell populations results in an uncontrolled inflammatory response to commensal bacteria. Intraepithelial lymphocytes (IEL) are perfectly positioned within the intestinal epithelium to provide the first line of mucosal defense against luminal microbes or rapidly respond to epithelial injury. This review will highlight how IELs promote protective intestinal immunity and discuss the evidence indicating that altered IEL responses contribute to the pathogenesis of IBD. Recent findings: Although the role of IELs in mucosal homeostasis has been largely underappreciated, many of the same factors that contribute to the dysregulation of host defense in IBD also adversely affect IELs. For example, IL-23 and the endoplasmic reticulum stress response can enhance IEL lytic activity toward enterocytes. Microbial dysbiosis or defective microbial recognition results in the loss of regulatory IELs, further amplifying these pro-inflammatory effects. Migration of T cells into or within the intraepithelial compartment has a profound effect on their differentiation or effector function demonstrating that IELs are exquisitely sensitive to changes in the local intestinal microenvironment. Summary: Enhanced mechanistic insight into the regulation of IEL survival, differentiation and effector function may provide useful tools to modulate IEL surveillance or enhance IEL regulatory function. Elucidation of these processes may result in the development of novel therapeutics to reduce intestinal inflammation and reinforce the mucosal barrier in IBD. PMID- 29242773 TI - Multiple new cryptic pathogenic Phytophthora species from Fagaceae forests in Austria, Italy and Portugal. AB - During surveys of Phytophthora diversity in natural and semi-natural Fagaceae forests in Austria, Italy and Portugal, four new cryptic species were isolated from rhizosphere soil samples. Multigene phylogeny based on nuclear ITS, beta tubulin and HSP90 and mitochondrial cox1 and NADH1 gene sequences demonstrated that two species, P. tyrrhenica and P. vulcanica spp. nov., belong to phylogenetic Clade 7a, while the other two species, P. castanetorum and P. tubulina spp. nov., clustered together with P. quercina forming a new clade, named here as Clade 12. All four new species are homothallic and have low optimum and maximum temperatures for growth and very slow growth rates at their respective optimum temperature. They differed from each other and from related species by a unique combination of morphological characters, cardinal temperatures, and growth rates. Pathogenicity of all Phytophthora species to the root system of their respective host species was demonstrated in soil infestation trials. PMID- 29242774 TI - Multigene phylogeny of Endogonales, an early diverging lineage of fungi associated with plants. AB - Endogonales is a lineage of early diverging fungi within Mucoromycota. Many species in this order produce small sporophores ("sporocarps") containing a large number of zygospores, and many species form symbioses with plants. However, due to limited collections, subtle morphological differentiation, difficulties in growing these organisms in vitro, and idiosyncrasies in their rDNA that make PCR amplification difficult, the systematics and character evolution of these fungi have been challenging to resolve. To overcome these challenges we generated a multigene phylogeny of Endogonales using sporophores collected over the past three decades from four continents. Our results show that Endogonales harbour significant undescribed diversity and form two deeply divergent and well supported phylogenetic clades, which we delimit as the families Endogonaceae and Densosporaceae fam. nov. The family Densosporaceae consists of the genus Densospora,Sphaerocreas pubescens, and many diverse lineages known only from environmental DNA sequences of plant-endosymbiotic fungi. Within Endogonaceae there are two clades. One corresponds to Endogone and includes the type species, E. pisiformis. Species of Endogone are characterized by above- and below-ground sporophores, a hollow and infolded sporophore form, a loose zygosporangial hyphal mantle, homogeneous gametangia, and an enigmatic trophic mode with no evidence of ectomycorrhizal association for most species. For the other clade we introduce a new generic name, Jimgerdemannia gen. nov. Members of that genus (J. flammicorona and J. lactiflua species complexes, and an undescribed species) are characterized by hypogeous sporophores with a solid gleba, a well-developed zygosporangial hyphal mantle, heterogeneous gametangia, and an ectomycorrhizal trophic mode. Future studies on Densosporaceae and Endogonaceae will be important for understanding fungal innovations including evolution of macroscopic sporophores and symbioses with plants. PMID- 29242775 TI - Calonectria species isolated from Eucalyptus plantations and nurseries in South China. AB - Diseases caused by species of Calonectria (Ca.) represent a serious threat to the growth and sustainability of Eucalyptus plantations in China. Symptoms caused by these fungi mainly include leaf blight on trees in plantations and rotting of stems and leaves in nurseries. Extensive surveys have recently been conducted where Calonectria species were collected in Eucalyptus plantations and nurseries in the FuJian, GuangDong, GuangXi, and YunNan Provinces of South China. Additional isolates were baited from soil samples in the Hong Kong Region. The aim of this study was to identify the 115 Calonectria isolates obtained using comparisons of DNA sequence data for the beta-tubulin (tub2), calmodulin (cmdA), histone H3 (his3) and partial translation elongation factor-1alpha (tef1) gene regions as well as their morphological features. Seven known species were identified, including Calonectria arbusta, Ca. asiatica, Ca. chinensis, Ca. eucalypti, Ca. hongkongensis, Ca. mossambicensis and Ca. pentaseptata. In addition, six novel taxa were collected and are described here as Ca. aciculata, Ca. honghensis, Ca. lantauensis, Ca. pseudoturangicola, Ca. pseudoyunnanensis, and Ca. yunnanensis spp. nov. Overall, the results reflect a high diversity of Calonectria species in China. PMID- 29242776 TI - New species of Auritella (Inocybaceae) from Cameroon, with a worldwide key to the known species. AB - Two new species in the genus Auritella (Inocybaceae) are described as new from tropical rainforest in Cameroon. Descriptions, photographs, line drawings, and a worldwide taxonomic key to the described species of Auritella are presented. Phylogenetic analysis of 28S rDNA and rpb2 nucleotide sequence data suggests at least five phylogenetic species that can be ascribed to Auritella occur in the region comprising Cameroon and Gabon and constitute a strongly supported monophyletic subgroup within the genus. Phylogenetic analysis of ITS data supports the conspecificity of numerous collections attributed to the two new species as well as the monophyly of Australian species of Auritella. This work raises the known number of described species of Auritella to thirteen worldwide, four of which occur in tropical Africa, one in tropical India, and eight in temperate and tropical regions of Australia. This is the first study to confirm an ectomycorrhizal status of Auritella using molecular data. PMID- 29242777 TI - A new family and genus in Dothideales for Aureobasidium-like species isolated from house dust. AB - An international survey of house dust collected from eleven countries using a modified dilution-to-extinction method yielded 7904 isolates. Of these, six strains morphologically resembled the asexual morphs of Aureobasidium and Hormonema (sexual morphs ?Sydowia), but were phylogenetically distinct. A 28S rDNA phylogeny resolved strains as a distinct clade in Dothideales with families Aureobasidiaceae and Dothideaceae their closest relatives. Further analyses based on the ITS rDNA region, beta-tubulin, 28S rDNA, and RNA polymerase II second largest subunit confirmed the distinct status of this clade and divided strains among two consistent subclades. As a result, we introduce a new genus and two new species as Zalariaalba and Z. obscura, and a new family to accommodate them in Dothideales. Zalaria is a black yeast-like fungus, grows restrictedly and produces conidiogenous cells with holoblastic synchronous or percurrent conidiation. Zalaria microscopically closely resembles Hormonema by having only one to two loci per conidiogenous cell, but species of our new genus generally has more restricted growth. Comparing the two species, Z. obscura grows faster on lower water activity (aw) media and produces much darker colonies than Z. alba after 7 d. Their sexual states, if extant, are unknown. PMID- 29242778 TI - Emerging citrus diseases in Europe caused by species of Diaporthe. AB - Species of Diaporthe are considered important plant pathogens, saprobes, and endophytes on a wide range of plant hosts. Several species are well-known on citrus, either as agents of pre- or post-harvest infections, such as dieback, melanose and stem-end rot on fruit. In this study we explored the occurrence, diversity and pathogenicity of Diaporthe species associated with Citrus and allied genera in European orchards, nurseries, and gardens. Surveys were carried out during 2015 and 2016 in Greece, Italy, Malta, Portugal, and Spain. A total of 79 Diaporthe strains were isolated from symptomatic twigs, branches and trunks. A multi-locus phylogeny was established based on five genomic loci (ITS, tef1, cal, his3 and tub2), and the morphological characters of the isolates determined. Preliminary pathogenicity tests were performed on lemon, lime, and orange plants with representative isolates. The most commonly isolated species were D. foeniculina and D. baccae, while only four isolates of D. novem were collected. Two new Diaporthe species, described here as D. limonicola and D. melitensis spp. nov. were found associated with a new devastating dieback disease of lemon plants. Furthermore, one cluster of sterile Diaporthe isolates was renamed as D. infertilis. Pathogenicity tests revealed most of the Citrus species as susceptible to D. baccae, D. foeniculina, and D. novem. Moreover, D. limonicola and D. melitensis caused serious cankers affecting all the Citrus species tested. This study is the first report of D. baccae and D. novem on citrus in Europe, and the first detection of a new Diaporthe canker disease of citrus in Europe. However, no isolates of D. citri were found. The study improves our understanding of the species associated with several disease symptoms on citrus plants, and provides useful information for effective disease management. PMID- 29242779 TI - A phylogenetically-based nomenclature for Cordycipitaceae (Hypocreales). AB - The ending of dual nomenclatural systems for pleomorphic fungi in 2011 requires the reconciliation of competing names, ideally linked through culture based or molecular methods. The phylogenetic systematics of Hypocreales and its many genera have received extensive study in the last two decades, however resolution of competing names in Cordycipitaceae has not yet been addressed. Here we present a molecular phylogenetic investigation of Cordycipitaceae that enables identification of competing names in this family, and provides the basis upon which these names can be maintained or suppressed. The taxonomy presented here seeks to harmonize competing names by principles of priority, recognition of monophyletic groups, and the practical usage of affected taxa. In total, we propose maintaining nine generic names, Akanthomyces, Ascopolyporus, Beauveria, Cordyceps, Engyodontium, Gibellula, Hyperdermium, Parengyodontium, and Simplicillium and the rejection of eight generic names, Evlachovaea, Granulomanus, Isaria, Lecanicillium, Microhilum, Phytocordyceps, Synsterigmatocystis, and Torrubiella. Two new generic names, Hevansia and Blackwellomyces, and a new species, Beauveria blattidicola, are described. New combinations are also proposed in the genera Akanthomyces, Beauveria, Blackwellomyces, and Hevansia. PMID- 29242780 TI - An expanded phylogeny for the genus Phytophthora. AB - A comprehensive phylogeny representing 142 described and 43 provisionally named Phytophthora species is reported here for this rapidly expanding genus. This phylogeny features signature sequences of 114 ex-types and numerous authentic isolates that were designated as representative isolates by the originators of the respective species. Multiple new subclades were assigned in clades 2, 6, 7, and 9. A single species P. lilii was placed basal to clades 1 to 5, and 7. Phytophthora stricta was placed basal to other clade 8 species, P. asparagi to clade 6 and P. intercalaris to clade 10. On the basis of this phylogeny and ancestral state reconstructions, new hypotheses were proposed for the evolutionary history of sporangial papillation of Phytophthora species. Non papillate ancestral Phytophthora species were inferred to evolve through separate evolutionary paths to either papillate or semi-papillate species. PMID- 29242781 TI - IMA Genome-F 8: Draft genome of Cercospora zeina, Fusarium pininemorale, Hawksworthiomyces lignivorus, Huntiella decipiens and Ophiostoma ips. AB - The genomes of Cercospora zeina, Fusarium pininemorale, Hawksworthiomyces lignivorus, Huntiella decipiens, and Ophiostoma ips are presented in this genome announcement. Three of these genomes are from plant pathogens and otherwise economically important fungal species. Fusarium pininemorale and H. decipiens are not known to cause significant disease but are closely related to species of economic importance. The genome sizes range from 25.99 Mb in the case of O. ips to 4.82 Mb for H. lignivorus. These genomes include the first reports of a genome from the genus Hawksworthiomyces. The availability of these genome data will allow the resolution of longstanding questions regarding the taxonomy of these species. In addition these genome sequences through comparative studies with closely related organisms will increase our understanding of how these species or close relatives cause disease. PMID- 29242782 TI - Two logics of policy intervention in immigrant integration: an institutionalist framework based on capabilities and aspirations. AB - The effectiveness of immigrant integration policies has gained considerable attention across Western democracies dealing with ethnically and culturally diverse societies. However, the findings on what type of policy produces more favourable integration outcomes remain inconclusive. The conflation of normative and analytical assumptions on integration is a major challenge for causal analysis of integration policies. This article applies actor-centered institutionalism as a new framework for the analysis of immigrant integration outcomes in order to separate two different mechanisms of policy intervention. Conceptualising integration outcomes as a function of capabilities and aspirations allows separating assumptions on the policy intervention in assimilation and multiculturalism as the two main types of policy approaches. The article illustrates that assimilation is an incentive-based policy and primarily designed to increase immigrants' aspirations, whereas multiculturalism is an opportunity-based policy and primarily designed to increase immigrants' capabilities. Conceptualising causal mechanisms of policy intervention clarifies the link between normative concepts of immigrant integration and analytical concepts of policy effectiveness. PMID- 29242783 TI - Mechanical strength of welding zones produced by material extrusion additive manufacturing. AB - As more manufacturing processes and research institutions adopt customized manufacturing as a key element in their design strategies and finished products, the resulting mechanical properties of parts produced through additive manufacturing (AM) must be characterized and understood. In material extrusion (MatEx), the most recently extruded polymer filament must bond to the previously extruded filament via polymer diffusion to form a "weld". The strength of the weld limits the performance of the manufactured part and is controlled through processing conditions. Under-standing the role of processing conditions, specifically extruder velocity and extruder temperature, on the overall strength of the weld will allow optimization of MatEx-AM parts. Here, the fracture toughness of a single weld is determined through a facile "trouser tear" Mode III fracture experiment. The actual weld thickness is observed directly by optical microscopy characterization of cross sections of MatEx-AM samples. Representative data of weld strength as a function of printing parameters on a commercial 3D printer demonstrates the robustness of the method. PMID- 29242784 TI - Why do we lack a Research Culture? Analysing the Indian Medical Landscape. PMID- 29242785 TI - Compressive Femoral Neuropathy Associated with Iliopsoas Hematoma Complicating Hip Hemiarthroplasty: A Case Report. AB - Introduction: Femoral nerve compression caused by iliopsoas hematoma is a rare complication after hip surgery. To the best of our knowledge, this is the first case after hemiarthroplasty. In this case, iliacus hematoma resulted from spontaneous bleeding favored by anticoagulant therapy. Case Report: A 78-year-old female developed left groin pain associated with typical symptoms of femoral nerve palsy about 2weeks after left hip hemiarthroplasty[1, 2, 3]. Computed tomography revealed the presence of a left iliopsoas hematoma that was surgically drained. Inguinal pain was immediately relieved, while nerve palsy recovered only partially, but the quality of life drastically improved and she was able to walk using a walker without pain. Conclusion: Even if it is a rare condition, the formation of a hematoma of iliopsoas muscle should be considered in patients that present symptoms of femoral nerve palsy, especially if treated with heparin or other anticoagulant drugs. Surgical drainage of the hematoma is indicated when symptoms are severe and disabling, and in this way, surgery could improve quality of life. PMID- 29242786 TI - Radius and Ulna Stress Fractures in a Patient with Neuromyelitis Optica: A Case Report. AB - Introduction: Stress fractures are more common in the weight-bearing bones of the lower limb and are particularly prevalent in athletes. Whereas, those of the upper limb are usually reported as unique events in rare circumstances. Case Report: We present a case of a 40-year-old White British female with neuromyelitis optica (NMO) who mobilized in a wheelchair and presented to our center in April 2016 with a week-long history of a hot, swollen, and unstable right forearm. Plain radiographs demonstrated fractures of both the radius and ulna of the dominant right arm. These were managed by open reduction and internal fixation to facilitate mobility and transfer using the forearm. Intra operatively, these were confirmed to be fatigue fractures, and there was evidence that the fracture was several days old. The neurological deficit in this patient had led to a delayed presentation owing to the lack of pain. Unfortunately, this construct failed within 8days, and a refixation was performed 2months later. 1year following the revision, no further problems have been reported, and there has been satisfactory union. Conclusion: This is the first report in the published literature of a stress fracture in a patient with NMO. We recommend screening for stress fractures with a nuclear bone scan in patients who mobilize in atypical ways, particularly if their sensation is compromised. The use of constructs stronger than those routinely applied to the upper limb should also be considered if patients are weight bearing through their arms. PMID- 29242787 TI - Foot Deformities in Hajdu-Cheney Syndrome: A Rare Case Report and Review of the Literature. AB - Introduction: Hajdu-Cheney syndrome (HCS) is a rare autosomal dominant disease characterized by acroosteolysis, wormian skull bones with persistent skull sutures, premature loss of teeth, micrognathia, short stature, hypermobility of the joints, neurologic manifestations such as basilar invagination with subsequent paresthesia, hearing loss, and speech alterations, and osteoporosis with tendency to pathologic fractures of long bones and vertebrae as well as painful hands and feet. Very few cases have been earlier reported in the literature. Case Report: We report a case of a 50-year-old female with bilateral foot deformities as a manifestation of the rare genetic disorder HCS. Surgical management of the left foot consisted of Morton's neuroma excision and Weil osteotomy with proximal interphalangeal joint resection and Kirschner wire fixation of the second and third metatarsophalangeal (MTP) joints. Recurrent subluxation of the left second MTP joint was observed at 5-week follow-up. The right foot was treated similarly 7weeks after the initial operation. The post operative course of the right foot was complicated by bone resorption and nonunion of the second and third metatarsal Weil osteotomies. Conclusion: Management of complex foot deformities associated with HCS can be challenging and have not previously been described in the literature. Underlying bone and connective tissue abnormalities intrinsic to the syndrome may increase the risk of recurrence after surgical correction. Consideration should be given to such post-operative complications when treating foot deformities in a patient with HCS. PMID- 29242788 TI - Obturator Dislocation of Hip with Ipsilateral Fracture Neck Femur-A Case Report. AB - Introduction: Traumatic dislocation of the hip with ipsilateral fracture neck femur is a rare injury because of the different mechanism of both these injuries. The management of such injuries is a challenge as the chances of nonunion and avascular necrosis of femoral head are very high with fixation methods. We report a case of obturator dislocation of the hip with ipsilateral fracture neck of the femur which was treated with uncemented total hip replacement. Case Report: A 32 year-old male sustained obturator dislocation with ipsilateral fracture neck femur following road traffic accident. After initial assessment and treatment, definitive treatment was carried out. Hip was approached through Watson-Jones approach. The head and neck was found to be dislocated and lying close to obturator foramen. A button hole through the anterior capsule and medium-sized chondral defect of the femoral head articular surface was noted. An uncemented total hip arthroplasty was performed. Post-operative period was uneventful and the patient was mobilized weight-bearing as tolerated with walker. He was discharged on the 5th post-operative day. He regained pain-free good range of motion over a period of 6 weeks. Conclusion: Fracture pattern combining obturator dislocation and ipsilateral fracture neck femur is a rare injury. Although both head preservation and replacement methods of treatment are available, the choice of treatment depends on duration of injury, age of the patient, associated chondral injuries of femoral head, and the patient's choice. The antero-lateral or lateral approach helps to deal with the anteriorly lying head in a better way as compared to the postero-lateral approach. PMID- 29242789 TI - Giant-cell Tumor of Metacarpal in the Skeletally Immature Patient and Free Osteoarticular Metatarsal Transfer: Review of Literature with Case Report. AB - Introduction: In the customary wisdom, it is conceded that giant-cell tumor (GCT) is a pathology of fused epiphysis, but there are literatures available to depict that even though rare bit, but it occurs in the skeletally immature patients. Here, we are presenting a rare case of GCT of the fifth metacarpal in the skeletally immature patient. Case Report: It is a case report of a 13-year-old girl with the history of swelling over her right hand for 5 months. X-ray revealed that there was an osteolytic fusiform expansible lesion. The biopsy sent and it conferred the diagnosis of GCT. Dorsal approach used for the enbloc resection of the fifth metacarpals (except at the base) and partial excision of the surrounding muscles done. The capsule and collateral ligament of the fifth metacarpophalangeal joint were left. The fourth metatarsal was harvested from the foot along with its capsule and collateral ligament of the metatarsophalangeal joint and sutured to the counter capsuloligamentous structure at the recipient site. Conclusion: In our case, we are presenting the GCT of metacarpal in a skeletally immature patient, which was managed by osteoarticular graft. Management by autologous metatarsal graft is a nontraditional approach. We bring it to the horizon of knowledge to discuss the clinical and radiological presentation with surgical as well as functional outcome. PMID- 29242790 TI - Surgical Retrieval of an Impaled Tapestry Needle from the True Pelvic Cavity of a Child-An Unusual Case Report. AB - Introduction: Impalement injuries of pelvis have been reported in children but are uncommon. Impalement could be associated with injuries to deep organs, wound contamination, crush injuries, and in certain instances, can even be fatal. Case Report: We present a bizarre case of a 2-year-old female child who presented to us with a tapestry needle embedded in the true pelvic cavity after a history of fall on the buttock while playing at home. The impaled needle was eventually successfully extracted surgically using the modified Stoppa's approach and the post-operative period was uneventful. We also briefly review the literature surrounding such unusual injuries and discuss tips and tricks regarding the surgical technique in such cases. Conclusions: In impalement injuries, adequate analgesia, tetanus prophylaxis, antibiotics, and immobilization must be given initially followed by meticulous pre-operative planning in the form of radiographs and computed tomography(CT) scans. Minimally invasive CT-guided extraction of needle can be attempted by an experienced interventional radiologist when there is no significant risk of damaging neighboring vital organs or neurovascular structures. The surgical approach if an open approachis decided must be chosen wisely; backup may be needed from an abdominal surgeon, urologist, or gynecologist in certain cases. PMID- 29242791 TI - Managing Recurrence in Intraarticular Melorheostosis Involving the Knee Joint: A Case Report. AB - Introduction: Melorheostosis is a rare benign sclerosing dysplasia affecting bone, which causes significant morbidity in the form of pain and restriction of joint movement. Treatment options are varied, and recurrence is common after surgical treatment. Choosing the most appropriate treatment option in the management of a recurrent case is challenging, with very little supporting evidence in literature owing to the rarity of the disease. We hereby present a case of recurrent melorheostosis involving the knee; discuss treatment options and the rationale of our treatment. Case Report: We present the case of a 42-year old female who was operated at our institution previously 7 years ago for melorheostosis of her left knee and had undergone excision of intrarticular hyperostotic masses. However, pain and limitation of motion recurred in the operated knee 4 years later, and radiographs and computed tomography revealed a mineralized mass situated behind the patella in the patellofemoral joint. She was treated with repeat open excision of the mass and put on a regimen of physiotherapy and bisphosphonates. Conclusion: Open excision of symptomatic hyperostotic or mineralized soft tissue masses is perhaps the favored treatment option in such cases, the other options being arthroscopic excision and total knee arthroplasty. Limited knee motion and size of the mass often make arthroscopy an unfeasible option. Total knee arthroplasty should be reserved for cases with significant flexion contractures of the knee, or where multiple excisions have failed. PMID- 29242792 TI - Minimal Invasive Dynamic Hip Screw Fixation Technique in Patient with Cardiac Complications: A Case Scenario. AB - Introduction: Intertrochanteric fracture comprises nearly half of hip fractures occurring in elderly individuals with osteoporosis. Considering the age group of its population, they are often associated with multiple comorbidities which warrant optimum management with less surgical. Case Report: This article reports the case of 56-year-old women with in tertrochanteric fracture associated with the cardiac complication restricting operating duration. Minimal invasive dynamic hip screw (MIDHS) fixation technique with modified instruments was performed which facilitated minimizing the operating time and intraoperative blood loss. Conclusion: MIDHS fixation is an important technique for providing the necessary fixation minimizing soft tissue dissection, operating time, intraoperative blood loss and surgical expense without compromising fixation stability, and rehabilitation protocol. PMID- 29242793 TI - Open Anterior Peri-lunarDislocation of the Carp: A Case Report. AB - Introduction: The anterior perilunate dislocations of the carp (PDC)are exceptional and poorly known lesions, which may go unnoticed in an emergency. They derive their importance from the severity of sequelae, which are dominated by chronic wrist instability and long-term osteoarthritis. Case Report: We report the case of an open anterior PDC with no carpal fracture in a young patient. The injury occurred in a road accident and was treated at once with satisfactory results 1year after. Conclusion: The management of carp dislocations is not well codified in the literature. Surgical treatment is often necessary to restore intracarpal anatomy. The prognosis is often good if diagnosed early. PMID- 29242794 TI - Bilateral Anterior Shoulder Dislocation in the Elderly - A Case Report and Review of the Literature. AB - Introduction: Bilateral shoulder dislocations are rare and a diagnostic as well as a therapeutic challenge. Case Report: We report the case of a 67-year-old male who fell while skiing and suffered a bilateral anterior shoulder dislocation associated with a four-part proximal humerus fracture on the left side and an osseous avulsion of the rotator cuff, a Pulley lesion, and a Hill-Sachs lesion on the right side. In addition, we searched the PubMed database using the terms "bilateral shoulder dislocation" and also "bilateral glenohumeral dislocation". All retrieved matches were browsed for reports of bilateral anterior shoulder dislocations in patients aged 40 years or older. We identified and analyzed 35 case reports, including our own, regarding 20 male and 15 female patients with an average age of 58.9 years (female: 59.2 years, male: 58.6 years). Conclusion: Elderly patients with a bilateral shoulder dislocation are at special risk for late diagnosis (five of 35 cases were not detected on the same day, but up to nine months later), concomitant pathologies (proximal humerus fractures were present in 19 cases; rotator cuff pathologies in seven cases), and insufficient diagnostic soft-tissue imaging (only four cases performed ultrasound/magnetic resonance imaging). Our reported case assembles a variety of possible concomitant pathologies. Through careful and comprehensive diagnostics all accompanying lesions were detected and subsequently addressed. The patient's outcome shows that even in older patients with a combination of various bony, cartilaginous, muscular and ligamentous pathologies, good-to-excellent post-reductive and post operative results are possible if diagnostics are comprehensive and treatment is prompt. PMID- 29242795 TI - Head-on Allograft Transplantation: A Unique Case Report Where a Large Piece of Femoral Bone was Extruded from One Patient's Body and Impaled Another Patient's Tibia. AB - Introduction: Open femoral fractures are relatively uncommon occurrences, with few reports addressing their management. They are caused by high-energy mechanisms, and bone loss is a possible, but infrequent occurrence. We present a case in which two friends, 20- and 21-year-old males, were involved in a motorcycle collision. A large piece of bone was ejected from one patient's femur as a bony projectile and impaled the other patient's tibia, resulting in an open tibial plateau fracture. This is the first case in the English literature, to the best of our knowledge, in which a piece of bone was ejected from one patient, causing a fracture in another. Case Report: Two males, in their mid-twenties, were involved in a head-on motorcycle collision. Both patients sustained open fractures to their lower extremities. A large piece of bone was ejected from one patient's femur and impaled the other patient's tibia, causing an open tibial plateau fracture. The patient who provided the bony projectile underwent retrograde intramedullary nail fixation. The segmental piece of bone was not replanted, and he went on to heal without negative sequelae at 2-year follow-up. Conclusion: To the best of our knowledge, this is the first case documented in the English literature in which an ejected piece of bone from one person caused a fracture in another fracture. Management of extruded bone segments should be considered on a case-by-case basis. PMID- 29242796 TI - Bilateral Femoral Neck Fractures in Cerebrotendinous Xanthomatosis Treated by Hip Arthroplasties: The First Case Report and Literature Review. AB - Introduction: Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive lipid storage disease caused by mutations of the CYP27A1 gene and deficiency of the sterol-27-hydroxylase enzyme in bile acid biosynthesis. It is characterized by the accumulation of cholestanol and bile alcohols in plasma, the formation of xanthomatous lesions in various tissues, and organ degeneration. This disorder is also associated with osteoporosis and increased risk of fracture. To date, only two CTX patients with femoral neck fractures have been reported. Neither was treated by arthroplasties, and the operative outcomes are lacking. Case Report: We report the case of a 46-year-old Thai female who presented with consecutive bilateral femoral neck fractures following minor trauma within a 3-year period and received cementless bipolar hemiarthroplasties. Her phenotypic expression included Achilles tendon masses, childhood-onset cataracts, intellectual disability, and cerebellar ataxia. A brain computed tomography showed non enhancing hypodense lesions in the bilateral cerebellar hemispheres with mild brain atrophy. Histopathology from an Achilles tendon biopsy revealed tendinous xanthoma and molecular analysis confirmed a homozygous nonsense mutation, c.1072C>T (p.Gln358Ter), in exon 6 of the CYP27A1 gene. The intra-operative crack of a calcar femorale was a major complication during both prosthetic insertion surgeries and warranted cerclage wiring. At the 7-month follow-up of the right hip and the 41-month follow-up of the left hip, postoperative radiographs showed well-fixed and well-aligned prostheses. Independent household ambulation could be resumed with Harris hip scores of 81 points equally. Conclusion: CTX is associated with osteoporosis, and middle-aged patients could present with femoral neck fracture following minor trauma. Cementless bipolar hemiarthroplasty for a totally displaced fracture is justified for a patient who has cognitive impairment. Intra-operative fracture is a major complication during prosthetic insertion and warrants cerclage wiring to achieve predictable bone healing and a satisfactory result. PMID- 29242797 TI - Lipoma Arborescens - Eyes See What Mind Knows! AB - Introduction: Lipoma arborescens is a rare lesion, benign in nature and was first described in detail in 1957. <200 cases have been reported in the literature by now. It consists of subsynovial villous proliferation of mature fat cells. Since the incidence of the condition is very rare, definite etiology has not established. Arthroscopic or open synovectomy has been the treatment of choice of the lesion. Case Report: We present you a case of lipomatosis arborescens of the right knee in a 28-year-old male. The magnetic resonance imaging images showed high signal intensity villous or nodular foci on both T1- and T2-weighted images which were indicative of fat globules. They were predominantly found in huge number in suprapatellar pouch. The patient underwent arthroscopic synovectomy showing numerous broad- based polypoid or thin papillary villi composed of fatty tissue. Approximately 40 cc of lobulated globules were removed, and some were sent to histopathology which confirmed the presence of benign synovial tissue and fragments of adipose tissue present beneath the synovial surface. On 1-year follow-up, the patient was free of pain and devoid of any mechanical symptoms. Conclusion: Hence, we conclude that this is a rare entity that needs early intervention to prevent progressive joint degeneration and has excellent patient satisfaction with arthroscopic debridement with very low incidence of recurrence. PMID- 29242798 TI - Anterior Elbow Pain Caused by Compression of the Lateral Antebrachial Cutaneous Nerve. AB - Introduction: The complex anatomy and biomechanics of the elbow joint can lead to diagnostic uncertainty when a clinician is determining the cause of a patient's anterior elbow pain. We present a case of anterior elbow pain with an uncommon and often overlooked etiology. Elbow pain due to compression of the lateral antebrachial nerve (LACN) has an unknown incidence or prevalence. Case Report: A 27-year-old left-hand dominant male presented to our orthopedic elbow clinic complaining of bilateral elbow clicking and discomfort which had been present for several years. His painful symptoms were localized to the anterior aspect of both elbows and had slowly become more painful despite simple analgesia and physiotherapy. Examination revealed the full range of movement of both elbows with no instability or weakness. Plain imaging and magnetic resonance imaging scans of both elbows did not reveal any pathology, and the decision was made to explore the right elbow, as this was the most symptomatic. Under general anesthesia with tourniquet an anterior curvilinear antecubital fossa incision was made. The lateral border of the distal biceps tendon showed evidence of compression of the LACN at the musculotendinous junction. The tendon was partially resected, and the nerve confirmed to move freely without further entrapment. At 4 weeks after surgery, he was completely asymptomatic. The patient was later listed to undergo a similar procedure to the left side; however, he could not go ahead with surgery so far due to work commitment. Conclusion: Entrapment or compression of the LACN is an uncommon and often misdiagnosed differential diagnosis with patients presenting with anterior elbow pain, which can lead to permanent neurological damage if left untreated. A high index of suspicion is required to enable prompt diagnosis and investigation as surgical treatment has a high success rate, often with complete resolution of symptoms. PMID- 29242799 TI - Superior Mesenteric Artery Syndrome after Kyphosis Correction - A Case Report. AB - Introduction: Obstruction of the third part of duodenum by superior mesenteric artery is known as superior mesenteric artery syndrome. Incidence of superior mesenteric artery syndrome following spine deformity correction is 0.5-4.7%. Till now, this syndrome after isolated kyphosis correction with vertebral column resection is rarely reported in literature. Case Report: A 17-year-old male patient with normal body habitus presented with 80 degrees of congenital thoracolumbar kyphosis. He underwent kyphosis correction with vertebral column resection and posterior instrumentation and posterior spinal fusion under neuro monitoring. Deformity correction was excellent; the patient was alright in immediate post-operative period. 2 weeks after surgery presented with repeated vomiting and abdominal pain. Contrast computed tomography was showing decreased aortomesenteric angle and decreased aortomesenteric distance which confirmed the diagnosis of superior mesenteric artery syndrome. Initial management was conservative, but as symptoms were progressive, duodenojejunostomy was done. The patient was completely recovered from obstructive symptoms. Conclusion: Superior mesenteric artery syndrome is a life-threatening complication that can occur after spine deformity correction. Early recognition and appropriate measures are critical to prevent the development of severe complications including death. PMID- 29242800 TI - Subtotal Calcanectomy for the Treatment of Chronic Ulcer Associated with Osteomyelitis: A Case Report. AB - Introduction: Subtotal calcanectomy is a therapeutic option for the treatment of chronic ulcer associated with calcaneal osteomyelitis. Closure of the surgical wound can be difficult due to the lack of local cutaneous coverage. We present the first case of subtotal calcanectomy in which the ankle was positioned in plantar flexion allowing the primary closure of the surgical wound without the need for flap. Case Report: We present a case of 62-year-old female patient with a foot ulcer associated with osteomyelitis. After an initial assessment, a subtotal calcanectomy with primary wound closure was performed. After healing of the surgical wound, the patient started rehabilitation with recovery of dorsiflexion and independent gait without support after 12 weeks. Conclusion: The result shows that subtotal calcanectomy with the ankle in plantar flexion allows primary closure of the operative wound, without causing difficulty for rehabilitation. PMID- 29242801 TI - Spindle Cell Hemangioma of the Midfoot: A Case Report. AB - Introduction: Spindle cell hemangioma (SCH) of the bone (midfoot) is a rare disease, but it can cause symptomatic pain and invade surrounding tissues lead to limb deformities and functional loss. Case Report: We report the case of a 35 year-old woman who experienced a firm mass over the left midfoot for 5 years causing pain and numbness in the foot. Radiographs showed a geographic osteolytic lesion involving calcification of the base of the 2nd and 3rd metatarsals, cuneiforms bones and surrounding soft tissue. Magnetic resonance imaging revealed a lobulated mass in the midfoot containing tangles of tortuous blood vessels and dark foci characteristic of phleboliths. Wide resection of the 2nd and 3rd cuneiforms, metatarsal bones and surrounding tissues with a curved iliac bone graft reconstruction were performed. Histological assessment revealed a lesion composed of a vascular channel containing endothelial cells with smooth muscle but without cellular atypia. The definite diagnosis was spinal cell hemangioma. The pain resolved within 4 months. The foot was stable, and no recurrence was found at the 48 months follow-up. Conclusion: This unusual disease, SCH of the midfoot responded favorably to wide resection and curved iliac bone grafting. It is suggested that this approach will provide a satisfactory functional result. PMID- 29242802 TI - Resistant Non-union of Humerus After Intramedullary Nailing Treated with Locking Compression Plate with Bone Grafting With Nail in Situ and Shoulder Spica: A Case Report. AB - Introduction: Humerus non-union is a challenging situation for the surgeon and devastating and morbid situation for the patient. Surgical approach to the humerus is demanding because of the complex neurovascular anatomy and especially when previous surgeries have been attempted. Case Report: We report a case of a young adult male who sustained a compound fracture of humerus shaft treated with intramedullary nailing followed by subsequent bone grafting and eventually landed up in non-union and was treated at our center by locking compression plate application with nail in situ with iliac crest autogenous bone graft followed by shoulder spica application. Conclusion: Although humerus nailing is a valid therapeutic option for humeral shaft fractures, compression plating is considered the gold standard and non-union secondary to failed interlocking nailing is a challenging situation. PMID- 29242803 TI - As a Definitive Choice of Treatment, Joint and Defect Spanning Multiplanar Tubular External Fixation in the Management of Pediatric Open Defective Supracondylar Humerus Fracture: A Case Report. AB - Introduction: Although supracondylar fractures of the humerus are common in children, open fractures of are extremely rare injuries. Gustilo- Anderson Type III fractures in the upper extremity are primarily associated with considerable bone loss resulting from high energy trauma. In this study, a case of open pediatric supracondylar humerus fracture treated by a joint and defect spanning multiplanar tubular external fixation is presented. Case Report: A boy aged 3 years suffered from a Gustilo-Anderson Type-IIIA supracondylar humerus fractures. There was no neurovascular compromise. Intravenous antibiotic regimen was introduced. A joint and defect spanning multiplanar tubular external fixation was employed within 4 h of the accident. After the operation, the patient was closely followed in the inpatients unit. The external fixator was removed in the 6th week of follow-up, and range of motion exercises was started. With the exception of limited flexion of the elbow in 12th month of follow-up, supination and pronation were full. At the 48th month follow-up, 120 degrees of elbow flexion, full extension, and full forearm rotation were observed. Physical examination showed 15 degrees change in carrying angle to cubitus varus; radiologic examination showed a slight varus angulation of the distal humerus, a decreased Baumann's angle. The Mayo elbow performance score was 100 points. Conclusion: When taking into account the high remodeling capacity, healing potential, and greater resistance to joint stiffness in fractures of children, joint and external fixators appear as a viable definitive treatment in such cases. PMID- 29242804 TI - Isolated Pure Lateral Dislocation of Elbow in a 9-year-old Child: A Rare Case Report. AB - Introduction: Dislocations of elbow constitute about 3-6% of all injuries occurring around elbow in children. Posterior dislocations are the most common type, whereas other types of dislocations, especially lateral dislocation in a child are extremely rare. Case Report: A 9-year-old boy with a history of trauma presented with complaints of pain, swelling, and difficulty to move his left elbow. Radiographs revealed lateral dislocation of elbow associated with avulsion of medial condyle. Closed reduction was done successfully under short general anesthesia. Conclusion: Pure lateral dislocation of the elbow is rare in pediatric age group. Lateral elbow dislocation is mostly managed surgically, but a chance of conservative management should be given before surgery. PMID- 29242805 TI - A Case Report of Primary Synovial Chondromatosis with Bilateral Genu Valgum. AB - Introduction: Synovial chondromatosis is the rare and benign metaplasia of the synovial membrane resulting in the formation of multiple intra-articular cartilaginous loose bodies. Synovial chondromatosis is known by several other names including articular chondrosis and synovial chondrosis. Case Report: An 18 year-old boy presented with complaints of difficulty in walking with growing deformity with restriction and painful movements of knee joints bilaterally. The patient gives a history of swelling which was initially there about 8 years back and was accompanied by fever. The patient has taken some treatment for the same by local medics but has not been relieved of his symptoms. Patient's symptoms are insidious in onset and have gradually progressed in its severity. The patient first noticed swelling over knee right side, which was accompanied by a fever followed by progressive deformity. He gave a history of locking in both knee joints. The patient gives no definitive history regarding any definitive treatment taken for his complaints. Conclusion: Curvilinear or rounded calcified lesions within a soft tissue mass in the close vicinity of the joint should always be further investigated for the possibility of primary synovial osteochondromatosis (PSC). The imaging appearance of PSC appears sufficiently unique to allow its differentiation from other causes of intra-articular pathology. Genu valgum following synovial chondromatosis is not yet reported in the literature. Probably increased vascularity and synovitis may be the cause for valgus deformity. This patient is in follow-up for the past 3 years, and no recurrence of loose bodies has been noted. This case is unique in terms of the age of presentation and developmental deformity which is rare in PSC. PMID- 29242806 TI - Comparison of the Source and Quality of Information on the Internet Between Anterolateral Ligament Reconstruction and Anterior Cruciate Ligament Reconstruction: An Australian Experience. AB - Background: The internet is a valuable tool, but concerns exist regarding the quality and accuracy of medical information available online. Purpose: To evaluate the source and quality of information on the internet relating to anterolateral ligament reconstruction (ALLR) compared with anterior cruciate ligament reconstruction (ACLR). Study Design: Cross-sectional study. Methods: A questionnaire was administered to 50 ACLR patients in Australia to determine their use of the internet to research their operation and their familiarity with the anterolateral ligament (ALL) of the knee. The most common search terms were determined, and the first 70 websites returned by the 5 most popular search engines were used to assess the quality of information about ACLR and ALLR. Each site was categorized by type and was assessed for quality and validity using the DISCERN score, the Journal of the American Medical Association (JAMA) benchmark criteria, and a novel specific content score for each procedure. The presence of the Health on the Net Code (HONcode) seal was also recorded. Results: The majority (84%) of ACLR patients used the internet to research their operation. The quality of information available for ALLR was significantly inferior to that for ACLR according to the DISCERN score (37.3 +/- 3.4 vs 54.4 +/- 4.6; P < .0001) and specific content score (5.3 +/- 1.3 vs 11.0 +/- 1.5; P < .0001). ACLR websites were predominantly physician produced, while the majority of ALLR websites were academic. In contrast to ACLR websites, the majority of ALLR websites did not provide information on the indication for treatment or potential complications. ALLR websites scored better on the JAMA benchmark criteria due to the predominance of academic websites. A greater proportion of ACLR websites (14.6%) versus ALLR websites (2.5%) provided an HONcode seal. Correlation was demonstrated between the DISCERN score and specific content scores for both ACLR and ALLR but not with JAMA benchmark criteria. The specific content score had high reliability for both ACLR and ALLR. Conclusion: The majority of patients undergoing ACLR in Australia used the internet to research the procedure. The quality of information on the internet relating to ALLR was significantly inferior to information about ACLR. Most ALLR websites failed to include crucial information about the indication or options for treatment, prognosis, and potential complications. Surgeons should be aware of the information to which their patients are exposed through the internet and should be proactive in directing patients to appropriate websites. PMID- 29242807 TI - Parents' and Child's Concussion History as Predictors of Parental Attitudes and Knowledge of Concussion Recognition and Response. AB - Background: Parents' knowledge of and attitudes toward concussions are often vital factors that affect care for injured adolescent athletes. It is important to understand the role that parents' personal experiences with concussions play with regard to current concussion knowledge and attitudes so that clinicians may tailor their educational approaches. Purpose/Hypothesis: The purpose of this study was to determine an association between parents' personal experiences and their child's experiences with concussions as well as parental concussion knowledge and attitudes. We hypothesized that parents who have personally experienced symptoms or have a child who has experienced symptoms would have better knowledge and more favorable attitudes toward concussions. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Parents of youth sport athletes (N = 234 [82 male, 144 female, 8 unreported]; mean age, 44.0 +/- 6.3 years) completed a prevalidated survey for concussion knowledge (maximum score possible, 29) and attitudes (maximum score possible, 49). Higher scores indicated better knowledge and more favorable attitudes toward concussive injuries. Parents reported the frequency of concussion diagnoses and/or experiences of concussion related symptoms and whether their child had suffered a diagnosed concussion or experienced concussion symptoms (yes/no). Spearman rank correlation and multivariable regression were used to examine the association between experience of symptom clusters (self or child) and concussion knowledge and attitudes. Results: Knowledge was moderate (mean, 23.3 +/- 2.5 of 29), while attitudes prioritized disclosure (mean, 46.3 +/- 3.7 of 49). Parents' experience of the sleep-arousal symptom cluster was positively associated with concussion attitudes (r = 0.22, P = .002; beta = -3.301, P = .011). Parents with children who experienced sleep-arousal and vestibular-somatic symptom clusters were weakly associated with parental concussion knowledge (sleep-arousal: r = 0.15, P = .041; vestibular-somatic: r = 0.17, P = .020; beta = 0.540, P = .012). Conclusion: Our findings suggest that parents' personal experiences with concussion-related symptoms have little effect on parental knowledge and attitudes as a whole. However, clinicians should consider particular symptom clusters that may provide insight into targets for future concussion education. According to these findings, parents of youth sport participants would benefit from increased concussion education focusing on the types of symptoms as well as the consequences of suffering a concussion. PMID- 29242808 TI - Small peptide substrates and high resolution peptide gels for the analysis of site-specific protein phosphorylation and dephosphorylation. AB - Protein phosphorylation and dephosphorylation reactions play key regulatory roles in many fundamental cellular processes. Due to the large number of kinases and phosphatases in the genome, the identification of the specific enzymes responsible for a given site in a given protein is immensely challenging. However, because protein kinases and phosphatases recognize local specificity determinants within proteins, it is possible to use small peptides to study the characteristics of site-specific phosphorylation. In addition, phosphorylation usually causes retardation in gel mobility, providing an opportunity to investigate peptide phosphorylation and dephosphorylation by monitoring migration on high resolution peptide gels. In this study, we demonstrate the utility of such a technique using small peptides corresponding to cyclin-dependent kinase-1 (Cdk1)/cyclin B1 sites in two important apoptotic regulatory proteins, Bcl-xL and caspase-9. We show that the mobility of the peptides is retarded following Cdk1 mediated phosphorylation, and that peptide dephosphorylation, catalyzed either by purified phosphatase or by crude cell extracts, is readily observable by increased peptide gel mobility. Furthermore, the procedure can be conducted without the use of radioactive adenosine triphosphate (ATP), and does not require any specialized reagents or apparatus. The method can be used to identify and characterize specific kinase and phosphatases responsible for phosphorylation and dephosphorylation of specific sites in any protein of interest. PMID- 29242809 TI - Effect of Levodopa-carbidopa Intestinal Gel on Non-motor Symptoms in Patients with Advanced Parkinson's Disease. AB - Background: Levodopa-carbidopa intestinal gel (LCIG; carbidopa-levodopa enteral suspension in the United States), delivered via percutaneous gastrojejunostomy (PEG-J) and titrated in the inpatient setting, is an established treatment option for advanced Parkinson's disease (PD) patients with motor fluctuations. However, long-term prospective data on the efficacy of LCIG on non-motor symptoms and the safety of outpatient titration are limited. Methods: In this 60-week, open-label phase 3b study, LCIG titration was initiated in an outpatient setting following PEG-J placement in PD patients. The efficacy of LCIG on motor and non-motor symptoms, quality of life, and safety was assessed. Results: Thirty-nine patients were enrolled in the study and 28 patients completed the treatment. A majority of patients (54%) completed outpatient titration within the first week of LCIG infusion. LCIG led to significant reductions from baseline in Non-Motor Symptom Scale (NMSS) total score (least squares mean +/- SE = -17.6 +/- 3.6, P < 0.001) and 6 of the NMSS domain scores (sleep/fatigue, attention/memory, gastrointestinal tract, urinary, sexual function, miscellaneous) at week 12. These reductions were maintained at week 60 with the exception of the urinary domain. "Off" time (-4.9 +/- 0.5 hours/day, P < 0.001) and "On" time without troublesome dyskinesia (-4.3 +/- 0.6 hours/day, P < 0.001) were improved at week 60. Adverse events (AEs) were reported in 37 (95%) patients. Conclusions: LCIG treatment led to reductions in non-motor symptom burden and motor fluctuations in advanced PD patients. The safety profile was consistent with previous studies that used inpatient titration and outpatient titration did not appear to pose additional risk. PMID- 29242810 TI - "Her Life Rests on Your Shoulders": Doing Worry as Emotion Work in the Care of Children With Diabetes. AB - Research on parents' caregiving experiences in the context of diabetes management have consistently shown that parents experience high levels of pediatric parenting stress, anxiety, depression, and general worry. However, how parents understand their worry is largely unexplored and little attention is paid to the work parents are already actively doing to manage their worry. Adopting Arlie Hochschild's concept of "emotion work" and Dorothy Smith's concept of "work," this article examines how parents engage in the emotion work of doing worry. Drawing on the analysis of transcribed data from interviews with seven parents caring for children with diabetes, I show how parents expressed worry as an emotion they experience as well as an embodied way of knowing the presence of potential threats to their child's health. Thus, doing worry is an essential aspect of work done by parents to ensure the safety and well-being of their children with diabetes. PMID- 29242811 TI - Patients with Dementia Are Easily Distracted. AB - : Mild cognitive impairment (MCI) is the middle ground between normal, age appropriate memory impairment, and dementia. Whereas patients with MCI are able to cope with the memory deficit, those with dementia are not: Their memory impairment and other cognitive deficits are of sufficient magnitude to interfere with the patients' ability to cope independently with daily activities. In both MCI and dementia, there is evidence of declining cognitive functions from a previously higher level of functioning. In both the conditions, there is also an evidence of dysfunction in one or more cognitive domains. There are two subtypes of MCI depending on whether memory is predominantly affected: amnestic type and nonamnestic/behavioral type. Not all patients with MCI transition to dementia, some recover. In this case scenario, we present a 68-year-old man with MCI who lives with his wife. They are getting ready to host dinner. His wife asks him to vacuum the dining room while she runs an urgent errand. We describe how this simple task vacuuming a room ended in a catastrophe with the patient spending the night in jail and his wife hospitalized. We discuss what went wrong in the patient/wife interaction and how the catastrophic ending could have been avoided. Objectives: At the end of this case discussion readers will know the following:The differences between mild cognitive impairment (MCI), normal aging, and dementia.MCI is often a precursor of dementia and has an amnestic or nonamnestic/behavioral presentation. However, not all patients with MCI develop dementia, some even recover.MCI is an opportunity to discuss with the patient various issues that may arise, should it progress to dementia such as preparing a will, transitioning from driver to passenger, and addressing various financial and legal issues including end-of-life issues and selecting someone to have power of attorney.Patients with MCI should be regularly followed up to determine whether and when they will transition to dementia as this changes the level of care needed.Patients with MCI are at an increased risk of triggering accidents because of their cognitive impairment and often impaired judgment.It may be hazardous to leave patients with MCI alone, without supervision.The importance of support groups, social media, and cameras when providing care to patients with MCI and dementias. PMID- 29242812 TI - Proceedings From the Symposium on Kidney Disease in Older People: Royal Society of Medicine, London, January 19, 2017. AB - People are living longer. On the whole, they have healthier lives and many of the problems previously seen at a younger age now appear in their later years. Kidneys, like other organs, age, and kidney disease in the aged is a prime example. In the United Kingdom, as in other developed countries, the prevalence of end stage kidney disease is highest in the 70- to 79-year-old age group. There are many older people who require renal replacement and are now considered for dialysis. While older patients with end-stage renal disease invariably aspire for a better quality of life, this needs a specialized approach and management. In January 2017, the Royal Society of Medicine held a seminar in London on "Kidney Disease in Older People" with presentations from a multidisciplinary body of experts speaking on various aspects of kidney problems in this age group and its management. The objectives were to increase awareness and improve the understanding of nephrology in the context of geriatric medicine but also geriatrics in its interface with nephrology, especially in the area of chronic kidney disease. PMID- 29242813 TI - Cobalt-chromium alloys in fixed prosthodontics in Sweden. AB - Aim: The aim of this study was to compile the usage of Co-Cr alloys in fixed prosthodontics (FP) among dental laboratories in Sweden. Methods: From March to October 2015, questionnaires were sent to 542 registered dental laboratories in Sweden. The questionnaires were divided in two parts, one for fixed dental supported prosthodontics (FDP) and one for fixed implant-supported prosthodontics (FIP). Reminders were sent three times. Results: In total of 542 dental laboratories, 55% answered the questionnaires. Most dental laboratories use Co-Cr in FP, 134 (74%) in FDP and 89(66%) in FIP. The laboratories used Co-Cr alloys of various compositions in the prostheses, 35 for FDP and 30 for FIP. The most commonly used Co-Cr alloys for tooth-supported FDPs were (a) Wirobond(r) 280, (b) Cara SLM and (c) Wirobond(r) C. For implant-supported frameworks the frequently used alloys were: (a) Cara SLM, (b) Cara Milled and (c) Wirobond(r) 280. Except for the difference in composition of these alloys, they were also manufactured with various techniques. In tooth-supported prostheses the dominating technique was the cast technique while newer techniques as laser-sintering and milling were more commonly reported for implant-supported constructions. A fourth technique; the 'pre-state' milling was reported in FDP. Conclusion: More than 30 different Co-Cr alloys were reported as being used in FP. Thus, there is a need for studies exploring the mechanical and physical behavior and the biological response to the most commonly used Co-Cr alloys. PMID- 29242814 TI - Release of titanium after insertion of dental implants with different surface characteristics - an ex vivo animal study. AB - In the present study, amount of titanium (Ti) released into the surrounding bone during placement of implants with different surface structure was investigated. Quantification of Ti released during insertion from three different implants was performed in this ex vivo study. Jaw bone from pigs was used as model for installation of the implants and Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES) was used for analysis of the released Ti. Implant surface were examined with scanning electron microscopy (SEM), before and after the placement into the bone. Ti was abraded to the surrounding bone upon insertion of a dental implant and the surface roughness of the implant increased the amount of Ti found. Diameter and total area of the implant were of less importance for the Ti released to the bone. No visible damages to the implant surfaces could be identified in SEM after placement. PMID- 29242815 TI - Fracture strength of veneered translucent zirconium dioxide crowns with different porcelain thicknesses. AB - Objective: To evaluate fracture strength of veneered translucent zirconium dioxide crowns designed with different porcelain layer thicknesses. Materials and Methods: Sixty crowns, divided into six groups of 10, were used in this study. Groups were divided according to different thicknesses of porcelain veneer on translucent zirconium dioxide cores of equal thickness (0.5 mm). Porcelain thicknesses were 2.5, 2.0, 1.0, 0.8, 0.5 and 0.3 mm. Crowns were artificially aged before loaded to fracture. Determination of fracture mode was performed using light microscope. Results: Group 1.0 mm showed significantly (p <= .05) highest fracture loads (mean 1540 N) in comparison with groups 2.5, 2.0 and 0.3 mm (mean 851, 910 and 1202 N). There was no significant difference (p>.05) in fracture loads among groups 1.0, 0.8 and 0.5 mm (mean 1540, 1313 and 1286 N). There were significantly (p <= .05) more complete fractures in group 0.3 mm compared to all other groups which presented mainly cohesive fractures. Conclusions: Translucent zirconium dioxide crowns can be veneered with minimal thickness layer of 0.5 mm porcelain without showing significantly reduced fracture strength compared to traditionally veneered (1.0-2.0 mm) crowns. Fracture strength of micro-veneered crowns with a layer of porcelain (0.3 mm) is lower than that of traditionally veneered crowns but still within range of what may be considered clinically sufficient. Porcelain layers of 2.0 mm or thicker should be used where expected loads are low only. PMID- 29242816 TI - Dimensional stability of two impression materials after a 6-month storage period. AB - Objective: Oral rehabilitation success is enhanced by an accurate and reproducible final impression. The purpose of this study is to evaluate the dimensional changes of a polyether and addition silicone subjected to disinfection and/or sterilization after a long storage period. Material and methods: Ninety samples were obtained from polyether ImpregumTM PentaTM (3M ESPETM, Seefeld, Germany) and 90 of addition silicone ImprintTM 4 PentaTM Putty (3M ESPETM, Seefeld, Germany) according to ISO 4823:2000. The samples of each material were split to form three groups with 30 samples each: a control group, a hypochlorite group (disinfection) and an autoclave group (sterilization). Samples were stored in the Portuguese Institute for Quality for six months at 23 degrees C. Samples were measured by laser interferometry, according to the Michelson technique before calculating dimensional stability according ISO 4823:2000. A statistical analysis via a three-way mixed ANOVA was performed. Results: Significant shrinkage of ImpregumTM PentaTM was 0.77 +/- 0.17% in the control group, 0.42 +/- 0.19% in the hypochlorite group and 0.52 +/- 0.28% in the autoclave group. For ImprintTM 4 PentaTM Putty, the control group had a shrinkage of 0.42 +/- 0.12%, the hypochlorite group 0.36 +/- 0.09% and the autoclave group 0.59 +/- 0.13%. Conclusions: The long-term storage of samples subjected to disinfection with 5.25% hypochlorite or autoclave sterilization can be used in a clinical setting as the dimensional changes are below the maximum permitted by the ISO 4823:2000, since there are no clinically significant changes in the dimension of the samples during the storage period. PMID- 29242817 TI - Vitamin D Deficiency and Association With Body Mass Index and Lipid Levels in Hispanic American Adolescents. AB - In this retrospective study, vitamin D deficiency was examined with body mass index (BMI) and lipid levels in a sample of Hispanic American adolescents. The prevalence of vitamin D deficiency among 234 subjects aged 13 to 19 years was 27.8%. Vitamin D deficiency was significantly associated with a BMI of 85 kg/m2 or higher (odds ratio = 2.02, 95% confidence interval = 1.11-3.69, chi2 = 5.37, P = .021), and 55.6% of the sample were overweight or obese (BMI >= 85%). In the overweight or obese subjects, vitamin D deficiency was significantly associated with higher mean lipid levels compared with those with adequate vitamin D levels: total cholesterol = 165 +/- 28.6 mg/dL versus 145.7 +/- 27.5 mg/dL, P = .0003; low-density lipoprotein = 92.7 +/- 25.7 mg/dL versus 80.8 +/- 21.4 mg/dL, P = .007; and triglycerides = 148.9 +/- 97.1 mg/dL versus 90.6 +/- 40.7 mg/dL, P = .0000. The mean triglyceride level of 148.9 mg/dL in the overweight or obese subjects was in the dyslipidemic range. In the underweight and healthy weight subjects (BMI <= 84), there was no statistically different lipid levels between the vitamin D adequate and vitamin D deficient groups. The effect of vitamin D on lipid levels was confirmed by regression analysis. Elevated lipids and dyslipidemic triglyceride levels, associated with vitamin D deficiency in overweight or obese Hispanic American adolescents, indicates a need for clinical monitoring and appropriate intervention. PMID- 29242818 TI - Exploring Accelerometer Versus Self-Report Sleep Assessment in Youth With Concussion. AB - This study examines accelerometer-based and self-report assessment of sleep disturbance from a larger prospective cohort of youth 5 to 18 years of age with postconcussive injury. Twenty-one participants with self-reported sleep disturbance were evaluated using accelerometers. Participants completed the Pittsburgh Sleep Quality Index (PSQI) every 48 hours and also measured sleep via accelerometry. Correlations were conducted matching PSQI scores to accelerometry assessment. PSQI scores were significantly correlated only with "average number of awakenings" (r = -0.21; P = .049). Accelerometer-measured mean (standard deviation) sleep efficiency was 79.9% (5.20%), with normal sleep defined as >85%. The mean (standard deviation) PSQI global score was 10.5 (3.78) out of 21, where scores of >5 indicate subjective insomnia. Results suggest the PSQI and accelerometers may be measuring different attributes of sleep. Both may be needed as actual sleep is important but so is perception of good sleep. These findings call for further validity testing of objective sleep assessment measures and commonly used self-report tools. PMID- 29242819 TI - Effects of E-cigarette Advertising Messages and Cues on Cessation Outcomes. AB - Objectives: We examined effects of e-cigarette ad messages and visual cues on outcomes related to combustible cigarette smoking cessation: smoking cessation intention, smoking urges, and immediate smoking behavior. Methods: US adult smokers (N = 3293) were recruited through Amazon Mechanical Turk and randomized to condition in a 3 (message: e-cigarette use anywhere, harm reduction, control) * 2 (e-cigarette cue presence or absence) between-subjects experiment. Stimuli were print ads for cigarette-like e-cigarettes ("cigalikes") that were manipulated for the experimental conditions. We conducted ANOVA and logistic regression analyses to investigate effects of the manipulations. Results: Message effects on cessation intention and smoking urges were not statistically significant. There was no evidence of cue effects or message * cue interactions across outcomes. Contrary to expectations, e-cigarette use anywhere and harm reduction messages were associated with lower odds of immediate smoking than the control message (AOREUA = 0.75, 95%CI = 0.58, 0.97, p = .026; AORHR = 0.72, 95%CI = 0.55, 0.93, p = .013). Conclusions: E-cigarette use anywhere and harm reduction messages may encourage smoking cessation, given the observed reduction in immediate smoking. E-cigarette cues may not influence smoking cessation outcomes. Future studies should investigate whether message effects are a result of smokers believing e-cigarettes to be effective cessation aids. PMID- 29242820 TI - ESTABLISHING A LIVE CARTILAGE-ON-CARTILAGE INTERFACE FOR TRIBOLOGICAL TESTING. AB - Mechano-biochemical wear encompasses the tribological interplay between biological and mechanical mechanisms responsible for cartilage wear and degradation. The aim of this study was to develop and start validating a novel tribological testing system, which better resembles the natural joint environment through incorporating a live cartilage-on-cartilage articulating interface, joint specific kinematics, and the application of controlled mechanical stimuli for the measurement of biological responses in order to study the mechano-biochemical wear of cartilage. The study entailed two parts. In Part 1, the novel testing rig was used to compare two bearing systems: (a) cartilage articulating against cartilage (CoC) and (b) metal articulating against cartilage (MoC). The clinically relevant MoC, which is also a common tribological interface for evaluating cartilage wear, should produce more wear to agree with clinical observations. In Part II, the novel testing system was used to determine how wear is affected by tissue viability in live and dead CoC articulations. For both parts, bovine cartilage explants were harvested and tribologically tested for three consecutive days. Wear was defined as release of glycosaminoglycans into the media and as evaluation of the tissue structure. For Part I, we found that the live CoC articulation did not cause damage to the cartilage, to the extent of being comparable to the free swelling controls, whereas the MoC articulation caused decreased cell viability, extracellular matrix disruption, and increased wear when compared to CoC, and consistent with clinical data. These results provided confidence that this novel testing system will be adequate to screen new biomaterials for articulation against cartilage, such as in hemiarthroplasty. For Part II, the live and dead cartilage articulation yielded similar wear as determined by the release of proteoglycans and aggrecan fragments, suggesting that keeping the cartilage alive may not be essential for short term wear tests. However, the biosynthesis of glycosaminoglycans was significantly higher due to live CoC articulation than due to the corresponding live free swelling controls, indicating that articulation stimulated cell activity. Moving forward, the cell response to mechanical stimuli and the underlying mechano-biochemical wear mechanisms need to be further studied for a complete picture of tissue degradation. PMID- 29242821 TI - Regulation of regeneration by Heparan Sulfate Proteoglycans in the Extracellular Matrix. AB - Just as the building of a house requires a blueprint, the rebuilding of lost or damaged body parts through regeneration requires a set of instructions for the assembly of the various tissues into the right places. Much progress has been made in understanding how to control the differentiation of different cell types to provide the building blocks for regeneration, such as bone, muscle, blood vessels and nerves/Schwann cells. These are the cells that follow the blueprint (the pattern-following cells) and end up in the right places relative to each other in order to restore the lost function. Much less is known about the cells that are specialized to generate and regenerate the blueprint (the pattern forming cells) in order to instruct the pattern-following cells as to how and where to rebuild the structures. Recent studies provide evidence that the pattern forming cells synthesize an information-rich extracellular matrix (ECM) that controls the behavior of pattern-following cells leading to the regeneration of limb structures. The ability of the ECM to do this is associated with glycosaminoglycans that have specific spatial and temporal modifications of sulfation patterns. This mechanism for controlling pattern formation appears to be conserved between salamanders and mammals, and thus the next challenge for inducing human regeneration is to identify and understand the biology of these pattern-forming cells and the ECM that they synthesize. PMID- 29242822 TI - Abstinence from Cocaine-Induced Conditioned Place Preference Produces Discrete Changes in Glutamatergic Synapses onto Deep Layer 5/6 Neurons from Prelimbic and Infralimbic Cortices. AB - Glutamatergic signaling in the medial prefrontal cortex (mPFC) plays a critical role in drug addiction and relapse. The mPFC is functionally subdivided into dorsal (prelimbic, PL) and ventral (infralimbic, IL) regions, and evidence suggests a differential role of these two divisions in the control of drug seeking and taking; however, there is a dearth of information on the cocaine induced adaptations in PL- and IL-mPFC synaptic glutamate transmission and their regulation of behavioral responses to cocaine-associated stimuli. We tested male rats in a cocaine-induced conditioned place preference (CPP) paradigm. In vitro whole-cell recordings were performed at different abstinence intervals to investigate the neuroadaptations in synaptic glutamate transmission in PL- and IL mPFC deep layer (5/6) pyramidal neurons. Our results show that in naive animals, PL-mPFC neurons expressed higher frequency of spontaneous events (sEPSCs) than IL mPFC neurons. Following cocaine-CPP and a short abstinence (SA) period (8 d), we observed decreases in the amplitude of sEPSCs in both mPFC regions. Longer abstinence periods (30 d), resulted in a sustained decrease in the frequency of sEPSCs and an increase in AMPA receptor rectification only in PL-mPFC neurons. In addition, PL-mPFC neurons expressed a decrease in the area under the curve of sEPSCs, suggesting altered receptor activation dynamics. Synaptic glutamate transmission was not significantly different between retested and naive rats. These results suggest that retention of cocaine-CPP requires differential modulation of glutamate transmission between PL- and IL-mPFC neurons and that these adaptations are dependent on the abstinence interval and reexposure to the cocaine context. PMID- 29242824 TI - Modular Peptide Amphiphile Micelles Improving an Antibody-Mediated Immune Response to Group A Streptococcus. AB - Inducing a strong and specific immune response is the hallmark of a successful vaccine. Nanoparticles have emerged as promising vaccine delivery devices to discover and elicit immune responses. Fine-tuning a nanoparticle vaccine to create an immune response with specific antibody and other cellular responses is influenced by many factors such as shape, size, and composition. Peptide amphiphile micelles are a unique biomaterials platform that can function as a modular vaccine delivery system, enabling control over many of these important factors and delivering payloads more efficiently to draining lymph nodes. In this study, the modular properties of peptide amphiphile micelles are utilized to improve an immune response against a Group A Streptococcus B cell antigen (J8). The hydrophobic/hydrophilic interface of peptide amphiphile micelles enabled the precise entrapment of amphiphilic adjuvants which were found to not alter micelle formation or shape. These heterogeneous micelles significantly enhanced murine antibody responses when compared to animals vaccinated with nonadjuvanted micelles or soluble J8 peptide supplemented with a classical adjuvant. The heterogeneous micelle induced antibodies also showed cross-reactivity with wild type Group A Streptococcus providing evidence that micelle-induced immune responses are capable of identifying their intended pathogenic targets. PMID- 29242825 TI - Hydraulic fracturing and infant health: New evidence from Pennsylvania. AB - The development of hydraulic fracturing ("fracking") is considered the biggest change to the global energy production system in the last half-century. However, several communities have banned fracking because of unresolved concerns about the impact of this process on human health. To evaluate the potential health impacts of fracking, we analyzed records of more than 1.1 million births in Pennsylvania from 2004 to 2013, comparing infants born to mothers living at different distances from active fracking sites and those born both before and after fracking was initiated at each site. We adjusted for fixed maternal determinants of infant health by comparing siblings who were and were not exposed to fracking sites in utero. We found evidence for negative health effects of in utero exposure to fracking sites within 3 km of a mother's residence, with the largest health impacts seen for in utero exposure within 1 km of fracking sites. Negative health impacts include a greater incidence of low-birth weight babies as well as significant declines in average birth weight and in several other measures of infant health. There is little evidence for health effects at distances beyond 3 km, suggesting that health impacts of fracking are highly local. Informal estimates suggest that about 29,000 of the nearly 4 million annual U.S. births occur within 1 km of an active fracking site and that these births therefore may be at higher risk of poor birth outcomes. PMID- 29242823 TI - Processing of Natural Echolocation Sequences in the Inferior Colliculus of Seba's Fruit Eating Bat, Carollia perspicillata. AB - For the purpose of orientation, echolocating bats emit highly repetitive and spatially directed sonar calls. Echoes arising from call reflections are used to create an acoustic image of the environment. The inferior colliculus (IC) represents an important auditory stage for initial processing of echolocation signals. The present study addresses the following questions: (1) how does the temporal context of an echolocation sequence mimicking an approach flight of an animal affect neuronal processing of distance information to echo delays? (2) how does the IC process complex echolocation sequences containing echo information from multiple objects (multiobject sequence)? Here, we conducted neurophysiological recordings from the IC of ketamine-anaesthetized bats of the species Carollia perspicillata and compared the results from the IC with the ones from the auditory cortex (AC). Neuronal responses to an echolocation sequence was suppressed when compared to the responses to temporally isolated and randomized segments of the sequence. The neuronal suppression was weaker in the IC than in the AC. In contrast to the cortex, the time course of the acoustic events is reflected by IC activity. In the IC, suppression sharpens the neuronal tuning to specific call-echo elements and increases the signal-to-noise ratio in the units' responses. When presenting multiple-object sequences, despite collicular suppression, the neurons responded to each object-specific echo. The latter allows parallel processing of multiple echolocation streams at the IC level. Altogether, our data suggests that temporally-precise neuronal responses in the IC could allow fast and parallel processing of multiple acoustic streams. PMID- 29242827 TI - Abrupt shift in the observed runoff from the southwestern Greenland ice sheet. AB - The recent decades of accelerating mass loss of the Greenland ice sheet have arisen from an increase in both surface meltwater runoff and ice flow discharge from tidewater glaciers. Despite the role of the Greenland ice sheet as the dominant individual cryospheric contributor to sea level rise in recent decades, no observational record of its mass loss spans the 30-year period needed to assess its climatological state. We present for the first time a 40-year (1975 2014) time series of observed meltwater discharge from a >6500-km2 catchment of the southwestern Greenland ice sheet. We find that an abrupt 80% increase in runoff occurring between the 1976-2002 and 2003-2014 periods is due to a shift in atmospheric circulation, with meridional exchange events occurring more frequently over Greenland, establishing the first observation-based connection between ice sheet runoff and climate change. PMID- 29242826 TI - A Triassic plesiosaurian skeleton and bone histology inform on evolution of a unique body plan. AB - Secondary marine adaptation is a major pattern in amniote evolution, accompanied by specific bone histological adaptations. In the aftermath of the end-Permian extinction, diverse marine reptiles evolved early in the Triassic. Plesiosauria is the most diverse and one of the longest-lived clades of marine reptiles, but its bone histology is least known among the major marine amniote clades. Plesiosaurians had a unique and puzzling body plan, sporting four evenly shaped pointed flippers and (in most clades) a small head on a long, stiffened neck. The flippers were used as hydrofoils in underwater flight. A wide temporal, morphological, and morphometric gap separates plesiosaurians from their closest relatives (basal pistosaurs, Bobosaurus). For nearly two centuries, plesiosaurians were thought to appear suddenly in the earliest Jurassic after the end-Triassic extinctions. We describe the first Triassic plesiosaurian, from the Rhaetian of Germany, and compare its long bone histology to that of later plesiosaurians sampled for this study. The new taxon is recovered as a basal member of the Pliosauridae, revealing that diversification of plesiosaurians was a Triassic event and that several lineages must have crossed into the Jurassic. Plesiosaurian histology is strikingly uniform and different from stem sauropterygians. Histology suggests the concurrent evolution of fast growth and an elevated metabolic rate as an adaptation to cruising and efficient foraging in the open sea. The new specimen corroborates the hypothesis that open ocean life of plesiosaurians facilitated their survival of the end-Triassic extinctions. PMID- 29242828 TI - Machine learning unifies the modeling of materials and molecules. AB - Determining the stability of molecules and condensed phases is the cornerstone of atomistic modeling, underpinning our understanding of chemical and materials properties and transformations. We show that a machine-learning model, based on a local description of chemical environments and Bayesian statistical learning, provides a unified framework to predict atomic-scale properties. It captures the quantum mechanical effects governing the complex surface reconstructions of silicon, predicts the stability of different classes of molecules with chemical accuracy, and distinguishes active and inactive protein ligands with more than 99% reliability. The universality and the systematic nature of our framework provide new insight into the potential energy surface of materials and molecules. PMID- 29242829 TI - Molecular Mechanisms for Microbe Recognition and Defense by the Red Seaweed Laurencia dendroidea. AB - The ability to recognize and respond to the presence of microbes is an essential strategy for seaweeds to survive in the marine environment, but understanding of molecular seaweed-microbe interactions is limited. Laurencia dendroidea clones were inoculated with the marine bacterium Vibrio madracius. The seaweed RNA was sequenced, providing an unprecedentedly high coverage of the transcriptome of Laurencia, and the gene expression levels were compared between control and inoculated samples after 24, 48, and 72 h. Transcriptomic changes in L. dendroidea in the presence of V. madracius include the upregulation of genes that participate in signaling pathways described here for the first time as a response of seaweeds to microbes. Genes coding for defense-related transcription activators, reactive oxygen species metabolism, terpene biosynthesis, and energy conversion pathways were upregulated in inoculated samples of L. dendroidea, indicating an integrated defensive system in seaweeds. This report contributes significantly to the current knowledge about the molecular mechanisms involved in the highly dynamic seaweed-bacterium interactions. IMPORTANCE Marine bacteria are part of the healthy microbiota associated with seaweeds, but some species, such as Vibrio spp., are frequently associated with disease outbreaks, especially in economically valuable cultures. In this context, the ability of seaweeds to recognize microbes and, when necessary, activate defense mechanisms is essential for their survival. However, studies dedicated to understanding the molecular components of the immune response in seaweeds are rare and restricted to indirect stimulus. This work provides an unprecedentedly large-scale evaluation of the transcriptional changes involved in microbe recognition, cellular signaling, and defense in the red seaweed Laurencia dendroidea in response to the marine bacterium Vibrio madracius. By expanding knowledge about seaweed-bacterium interactions and about the integrated defensive system in seaweeds, this work offers the basis for the development of tools to increase the resistance of cultured seaweeds to bacterial infections. PMID- 29242830 TI - Interaction of Antibiotics with Innate Host Defense Factors against Salmonella enterica Serotype Newport. AB - This study examines the pharmacodynamics of antimicrobials that are used to treat Salmonella with each other and with key components of the innate immune system. Antimicrobial synergy was assessed using time-kill and checkerboard assays. Antimicrobial interactions with innate immunity were studied by employing cathelicidin LL-37, whole-blood, and neutrophil killing assays. Ceftriaxone and ciprofloxacin were found to be synergistic in vitro against Salmonella enterica serotype Newport. Ceftriaxone, ciprofloxacin, and azithromycin each demonstrated synergy with the human cathelicidin defense peptide LL-37 in killing Salmonella. Exposure of Salmonella to sub-MICs of ceftriaxone resulted in enhanced susceptibility to LL-37, whole blood, and neutrophil killing. The activity of antibiotics in vivo against Salmonella may be underestimated in bacteriologic media lacking components of innate immunity. The pharmacodynamic interactions of antibiotics used to treat Salmonella with each other and with components of innate immunity warrant further study in light of recent findings showing in vivo selection of antimicrobial resistance by single agents in this pathogen. IMPORTANCE It is becoming increasingly understood that the current paradigms of in vitro antimicrobial susceptibility testing may have significant shortcomings in predicting activity in vivo. This study evaluated the activity of several antibiotics alone and in combination against clinical isolates of Salmonella enterica serotype Newport (meningitis case) utilizing both conventional and physiological media. In addition, the interactions of these antibiotics with components of the innate immune system were evaluated. Azithromycin, which has performed quite well clinically despite high MICs in conventional media, was shown to be more active in physiological media and to enhance innate immune system killing. Alternatively, chloramphenicol did not show enhanced immune system killing, paralleling its inferior clinical performance to other antibiotics that have been used to treat Salmonella meningitis. These findings are important additions to the building understanding of current in vitro antimicrobial assay limitations that hopefully will amount to future improvements in these assays to better predict clinical efficacy and activity in vivo. PMID- 29242831 TI - Novel Concepts for HIV Vaccine Vector Design. AB - The unprecedented challenges of developing effective vaccines against intracellular pathogens such as HIV, malaria, and tuberculosis have resulted in more rational approaches to vaccine development. Apart from the recent advances in the design and selection of improved epitopes and adjuvants, there are also ongoing efforts to optimize delivery platforms. Viral vectors are the best characterized delivery tools because of their intrinsic adjuvant capability, unique cellular tropism, and ability to trigger robust adaptive immune responses. However, a known limitation of viral vectors is preexisting immunity, and ongoing efforts are aimed at developing novel vector platforms with lower seroprevalence. It is also becoming increasingly clear that different vectors, even those derived from phylogenetically similar viruses, can elicit substantially distinct immune responses, in terms of quantity, quality, and location, which can ultimately affect immune protection. This review provides a summary of the status of viral vector development for HIV vaccines, with a particular focus on novel viral vectors and the types of adaptive immune responses that they induce. PMID- 29242833 TI - Put3 Positively Regulates Proline Utilization in Candida albicans. AB - The zinc cluster transcription factor Put3 was initially characterized in Saccharomyces cerevisiae as the transcriptional activator of PUT1 and PUT2, two genes acting early in the proline assimilation pathway. We have used phenotypic studies, transcription profiling, and chromatin immunoprecipitation with microarray technology (ChIP-chip) to establish that unlike S. cerevisiae, which only uses proline as a nitrogen source, Candida albicans can use proline as a nitrogen source, a carbon source, or a source of both nitrogen and carbon. However, a C. albicans put3 null mutant cannot grow on proline, suggesting that as in S. cerevisiae, C. albicans Put3 (CaPut3) is required for proline catabolism, and because the C. albicans put3 null mutant grew efficiently on glutamate as the sole carbon or nitrogen source, it appears that CaPut3 also regulates the early genes of the pathway. CaPut3 showed direct binding to the CaPUT1 promoter, and both PUT1 and PUT2 were upregulated in response to proline addition in a Put3-dependent manner, as well as in a C. albicans strain expressing a hyperactive Put3. CaPut3 directs proline degradation even in the presence of a good nitrogen source such as ammonia, which contrasts with S. cerevisiae Put3 (ScPut3)-regulated proline catabolism, which only occurs in the absence of a rich nitrogen source. Thus, while overall proline regulatory circuitry differs between S. cerevisiae and C. albicans, the specific role of Put3 appears fundamentally conserved. IMPORTANCECandida albicans poses a significant threat to the lives of immunocompromised people. Historically, knowledge has been drawn from studies on Saccharomyces cerevisiae to understand the pathogen, and many Candida albicans genes are named after their S. cerevisiae orthologs. Direct studies on the pathogen have, however, revealed differences in the roles of some orthologous proteins in the two yeasts. We show that the Put3 transcription factor allows the pathogen to completely degrade proline to usable nitrogen and carbon by evading regulatory restrictions imposed on its S. cerevisiae ortholog, which mandates conditional use of proline only as a nitrogen source in the baker's yeast. The ability of Candida albicans to freely obtain nutrients from multiple sources may help it thrive as a commensal and opportunistic pathogen. PMID- 29242832 TI - Persistence of Supplemented Bifidobacterium longum subsp. infantis EVC001 in Breastfed Infants. AB - Attempts to alter intestinal dysbiosis via administration of probiotics have consistently shown that colonization with the administered microbes is transient. This study sought to determine whether provision of an initial course of Bifidobacterium longum subsp. infantis (B. infantis) would lead to persistent colonization of the probiotic organism in breastfed infants. Mothers intending to breastfeed were recruited and provided with lactation support. One group of mothers fed B. infantis EVC001 to their infants from day 7 to day 28 of life (n = 34), and the second group did not administer any probiotic (n = 32). Fecal samples were collected during the first 60 postnatal days in both groups. Fecal samples were assessed by 16S rRNA gene sequencing, quantitative PCR, mass spectrometry, and endotoxin measurement. B. infantis-fed infants had significantly higher populations of fecal Bifidobacteriaceae, in particular B. infantis, while EVC001 was fed, and this difference persisted more than 30 days after EVC001 supplementation ceased. Fecal milk oligosaccharides were significantly lower in B. infantis EVC001-fed infants, demonstrating higher consumption of human milk oligosaccharides by B. infantis EVC001. Concentrations of acetate and lactate were significantly higher and fecal pH was significantly lower in infants fed EVC001, demonstrating alterations in intestinal fermentation. Infants colonized by Bifidobacteriaceae at high levels had 4-fold lower fecal endotoxin levels, consistent with observed lower levels of Gram negative Proteobacteria and Bacteroidetes. IMPORTANCE The gut microbiome in early life plays an important role for long-term health and is shaped in large part by diet. Probiotics may contribute to improvements in health, but they have not been shown to alter the community composition of the gut microbiome. Here, we found that breastfed infants could be stably colonized at high levels by provision of B. infantis EVC001, with significant changes to the overall microbiome composition persisting more than a month later, whether the infants were born vaginally or by caesarean section. This observation is consistent with previous studies demonstrating the capacity of this subspecies to utilize human milk glycans as a nutrient and underscores the importance of pairing a probiotic organism with a specific substrate. Colonization by B. infantis EVC001 resulted in significant changes to fecal microbiome composition and was associated with improvements in fecal biochemistry. The combination of human milk and an infant associated Bifidobacterium sp. shows, for the first time, that durable changes to the human gut microbiome are possible and are associated with improved gut function. PMID- 29242834 TI - Novel ITS1 Fungal Primers for Characterization of the Mycobiome. AB - Studies of the human microbiome frequently omit characterization of fungal communities (the mycobiome), which limits our ability to investigate how fungal communities influence human health. The internal transcribed spacer 1 (ITS1) region of the eukaryotic ribosomal cluster has features allowing for wide taxonomic coverage and has been recognized as a suitable barcode region for species-level identification of fungal organisms. We developed custom ITS1 primer sets using iterative alignment refinement. Primer performance was evaluated using in silico testing and experimental testing of fungal cultures and human samples. Using an expanded novel reference database, SIS (18S-ITS1-5.8S), the newly designed primers showed an average in silico taxonomic coverage of 79.9% +/- 7.1% compared to a coverage of 44.6% +/- 13.2% using previously published primers (P = 0.05). The newly described primer sets recovered an average of 21,830 +/- 225 fungal reads from fungal isolate culture samples, whereas the previously published primers had an average of 3,305 +/- 1,621 reads (P = 0.03). Of note was an increase in the taxonomic coverage of the Candida genus, which went from a mean coverage of 59.5% +/- 13% to 100.0% +/- 0.0% (P = 0.0015) comparing the previously described primers to the new primers, respectively. The newly developed ITS1 primer sets significantly improve general taxonomic coverage of fungal communities infecting humans and increased read depth by an order of magnitude over the best-performing published primer set tested. The overall best performing primer pair in terms of taxonomic coverage and read recovery, ITS1 30F/ITS1-217R, will aid in advancing research in the area of the human mycobiome. IMPORTANCE The mycobiome constitutes all the fungal organisms within an environment or biological niche. The fungi are eukaryotes, are extremely heterogeneous, and include yeasts and molds that colonize humans as part of the microbiome. In addition, fungi can also infect humans and cause disease. Characterization of the bacterial component of the microbiome was revolutionized by 16S rRNA gene fragment amplification, next-generation sequencing technologies, and bioinformatics pipelines. Characterization of the mycobiome has often not been included in microbiome studies because of limitations in amplification systems. This report revisited the selection of PCR primers that amplify the fungal ITS1 region. We have identified primers with superior identification of fungi present in the database. We have compared the new primer sets against those previously used in the literature and show a significant improvement in read count and taxon identification. These primers should facilitate the study of fungi in human physiology and disease states. PMID- 29242835 TI - Characterization of the Mechanisms of Daptomycin Resistance among Gram-Positive Bacterial Pathogens by Multidimensional Lipidomics. AB - Previous work suggests that altered lipid metabolism may be associated with daptomycin resistance in Gram-positive pathogens, but lipidomic changes underlying resistance are not fully understood. We performed untargeted lipidomics by using three-dimensional hydrophilic interaction liquid chromatography-ion mobility-mass spectrometry (HILIC-IM-MS) to characterize alterations in the lipidomes of daptomycin-susceptible and -resistant isogenic strain pairs of Enterococcus faecalis, Staphylococcus aureus, and Corynebacterium striatum. We first validated the HILIC-IM-MS method by replicating the expected alterations of phospholipid metabolism in the previously studied E. faecalis strain pairs, such as reduced phosphatidylglycerols (PGs), while also revealing additional changes in cardiolipins (CLs), lysyl-PGs, and glycolipids. Whole genome sequencing of the S. aureus and C. striatum strains found that daptomycin resistance was associated with mutations in pgsA, which encodes phosphatidylglycerophosphate synthase, as well as mutations in genes affecting fatty acid biosynthesis and cell wall metabolism. Lipidomics revealed significantly decreased levels of PGs, CLs, and amino acid-modified PGs, as well as accumulation of lipids upstream of PGs, such as glycolipids and phosphatidic acids, in the resistant strains. Notably, the glycolipids, diglucosyldiacylglycerols, were significantly elevated in a fatty acid-dependent manner in the daptomycin-resistant S. aureus strain. In daptomycin-resistant C. striatum, which has a unique cell envelope architecture, the glycolipids, glucuronosyldiacylglycerols, and phosphatidylinositols were significantly elevated. These results demonstrate that alteration of lipid metabolism via mutations in pgsA is a common mechanism of daptomycin resistance in two distinct species of Gram-positive bacteria and point to the potential contribution of altered glycolipid and fatty acid compositions to daptomycin resistance. IMPORTANCE This work comprehensively characterizes lipidomic changes underlying daptomycin resistance in three Gram-positive bacterial species, E. faecalis, S. aureus, and C. striatum, by using a novel three-dimensional lipidomics methodology based on advanced mass spectrometry. We demonstrated a number of advantages of our method in comparison with other methods commonly used in the field, such as high molecular specificity, sensitivity, and throughput. Whole genome sequencing of the S. aureus and C. striatum strains identified mutations in pgsA, which encodes phosphatidylglycerophosphate synthase, in both resistant strains. Lipidomics revealed significantly decreased levels of lipids downstream of PgsA, as well as accumulation of lipids upstream of PgsA in the resistant strains. Furthermore, we found that changes in individual molecular species of each lipid class depend on the their specific fatty acid compositions. The characteristic changes in individual lipid species could be used as biomarkers for identifying underlying resistance mechanisms and for evaluating potential therapies. PMID- 29242836 TI - Vaccination with a Recombinant H7 Hemagglutinin-Based Influenza Virus Vaccine Induces Broadly Reactive Antibodies in Humans. AB - Human influenza virus infections with avian subtype H7N9 viruses are a major public health concern and have encouraged the development of effective H7 prepandemic vaccines. In this study, baseline and postvaccination serum samples of individuals aged 18 years and older who received a recombinant H7 hemagglutinin vaccine with and without an oil-in-water emulsion (SE) adjuvant were analyzed using a panel of serological assays. While only a small proportion of individuals seroconverted to H7N9 as measured by the conventional hemagglutination inhibition assay, our data show strong induction of anti-H7 hemagglutinin antibodies as measured by an enzyme-linked immunosorbent assay (ELISA). In addition, cross-reactive antibodies against phylogenetically distant group 2 hemagglutinins were induced, presumably targeting the conserved stalk domain of the hemagglutinin. Further analysis confirmed an induction of stalk specific antibodies, suggesting that epitopes outside the classical antigenic sites are targeted by this vaccine in the context of preexisting immunity to related H3 hemagglutinin. Antibodies induced by H7 vaccination also showed functional activity in antibody-dependent cell-mediated cytotoxicity reporter assays and microneutralization assays. Additionally, our data show that sera from hemagglutination inhibition seroconverters conferred protection in a passive serum transfer experiment against lethal H7N9 virus challenge in mice. Interestingly, sera from hemagglutination inhibition nonseroconverters also conferred partial protection in the lethal animal challenge model. In conclusion, while recombinant H7 vaccination fails to induce measurable levels of hemagglutination-inhibiting antibodies in most subjects, this vaccination regime induces homosubtypic and heterosubtypic cross-reactive binding antibodies that are functional and partly protective in a murine passive transfer challenge model. IMPORTANCE Zoonotic infections with high case fatality rates caused by avian H7N9 influenza viruses have been reported since early 2013 in China. Since then, the fifth wave of the H7N9 epidemic emerged in China, resulting in higher numbers of laboratory-confirmed cases than in previous years. Recently, H7N9 has started to antigenically drift and split into two new lineages, the Pearl River Delta and Yangtze River Delta clades, which do not match stockpiled H7 vaccines well. Humans are immunologically naive to these subtypes, and an H7N9 strain that acquires the capability of efficient human-to-human transmission poses a credible pandemic threat. Other characteristics of H7N9 are raising concerns as well, like its ability to bind to receptors in the human upper respiratory tract, the recent emergence of highly pathogenic variants, and the ability to quickly gain resistance to neuraminidase inhibitors. Therefore, developing and testing H7N9 vaccines constitutes a priority for pandemic preparedness. PMID- 29242837 TI - The Human Gut Microbial Metabolome Modulates Fungal Growth via the TOR Signaling Pathway. AB - Candida albicans is well known as a major human fungal pathogen, but it is also a permanent resident of healthy gastrointestinal tracts. Recent studies have shown that the human gut microbial metabolome represents an interesting source of bioactive molecules with a significant degree of chemical diversity. Some of these bioactive molecules may have useful antivirulence activities. For instance, intestinal bacterial species belonging to the Lachnospiraceae family were found to secrete molecules that attenuate Salmonella pathogenicity and repress the expression of virulence genes. Here, we have investigated whether the microbial gut metabolome (GM) contains molecules that might promote the commensal lifestyle and/or inhibit the expression of virulence of C. albicans in the intestine. We found that metabolites from human feces inhibited the growth of C. albicans and other opportunistic yeasts. A genetic screen in C. albicans suggested that TOR is the molecular target of the antifungal molecule(s) of the GM. In addition, we found that the GM metabolites inhibit both C. albicans hyphal growth and the invasion of human enterocytes. The antigrowth and antivirulence activities were partially recapitulated by secretions from Roseburia spp. and Bacteroides ovatus strains, respectively. This study demonstrates that the antimicrobial activity of the GM can be extended to a eukaryotic pathogen, C. albicans, illuminating the antagonistic interkingdom interactions between a fungus and intestinal commensal bacteria. IMPORTANCECandida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections. The human gastrointestinal tract is the main reservoir of C. albicans, from where systemic infections originate as a consequence of the disruption of the intestinal mucosal barrier. Recent studies provided convincing evidence that overgrowth of C. albicans and other related species in the gut is predominantly associated with chronic intestinal inflammatory bowel diseases. Here, we showed, for the first time, the antagonistic interkingdom interactions between C. albicans and common intestinal commensal bacteria. From a therapeutic perspective, administering a defined bacterial community, such as the one described here with anti-Candida activity, could provide potential therapeutic protection against gastrointestinal inflammatory diseases. PMID- 29242838 TI - A Dirichlet-Multinomial Bayes Classifier for Disease Diagnosis with Microbial Compositions. AB - Dysbiosis of microbial communities is associated with various human diseases, raising the possibility of using microbial compositions as biomarkers for disease diagnosis. We have developed a Bayes classifier by modeling microbial compositions with Dirichlet-multinomial distributions, which are widely used to model multicategorical count data with extra variation. The parameters of the Dirichlet-multinomial distributions are estimated from training microbiome data sets based on maximum likelihood. The posterior probability of a microbiome sample belonging to a disease or healthy category is calculated based on Bayes' theorem, using the likelihood values computed from the estimated Dirichlet multinomial distribution, as well as a prior probability estimated from the training microbiome data set or previously published information on disease prevalence. When tested on real-world microbiome data sets, our method, called DMBC (for Dirichlet-multinomial Bayes classifier), shows better classification accuracy than the only existing Bayesian microbiome classifier based on a Dirichlet-multinomial mixture model and the popular random forest method. The advantage of DMBC is its built-in automatic feature selection, capable of identifying a subset of microbial taxa with the best classification accuracy between different classes of samples based on cross-validation. This unique ability enables DMBC to maintain and even improve its accuracy at modeling species-level taxa. The R package for DMBC is freely available at https://github.com/qunfengdong/DMBC. IMPORTANCE By incorporating prior information on disease prevalence, Bayes classifiers have the potential to estimate disease probability better than other common machine-learning methods. Thus, it is important to develop Bayes classifiers specifically tailored for microbiome data. Our method shows higher classification accuracy than the only existing Bayesian classifier and the popular random forest method, and thus provides an alternative option for using microbial compositions for disease diagnosis. PMID- 29242839 TI - Gender differences in systemic sclerosis: relationship to clinical features, serologic status and outcomes. AB - Introduction: There is a strong female preponderance reported in many connective tissue diseases and in almost all systemic sclerosis (SSc) case series. Methods: We compared gender differences in SSc patients in a large single-center cohort, including demographic features, disease subtype, environmental exposures, disease specific serum autoantibodies, organ system involvement (frequency and severity) and survival. Adjustment for cutaneous subset (diffuse cutaneous [dc] and limited cutaneous [lc]) was performed. Results: We identified key characteristics which distinguished female from male SSc patients. Females were more frequently younger at disease onset with a longer disease duration at the time of their first visit. Females more often had lcSSc and, if an overlap syndrome was present, it was most often systemic lupus erythematosus. In contrast, males more frequently had dcSSc and overlap with myositis. Females more frequently had peripheral vascular involvement but in males it was more often severe. Males were more often cigarette smokers and more frequently had environmental exposures. Males more frequently had interstitial lung disease (ILD or pulmonary fibrosis) which was more severe. Females had a significantly increased frequency of anti-centromere antibody and males anti-topoisomerase I and anti-U3RNP antibody. Males had significantly reduced survival (73% at 5 years and 45% at 10 years after onset of SSc). The most frequent causes of death were ILD in males and pulmonary hypertension in females. Conclusions: Gender differences may be important clues to understanding the natural history and pathogenesis of SSc. PMID- 29242840 TI - The mid-childhood and adolescent antecedents of women's external locus of control orientation. AB - Background: External locus of control orientation (ELOC) is a powerful predictor of adverse consequences in regard to health, educational attainment, inter personal relationships and well-being. Although many cross-sectional studies have been carried out, relatively little is known about antecedent factors influencing the development of ELOC. Methods: Over 12,000 pregnant women who enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) in south-west England, had completed a brief version of the Adult Nowicki-Strickland Internal-External LOC scale, together with detailed questions concerning their own parents and childhood. A series of hypothesis-free structured backwards stepwise logistic regression analyses used an exposome approach with ELOC as the outcome. Results: Significant positive associations were found with smoking of the parents of the surveyed women, including prenatal exposure, and their own onset of regular smoking in mid-childhood (6-11 years). Increased odds of ELOC were also found with the absence of their fathers in early childhood, presence of older siblings, and with being born and brought up in the same area as they resided in at the time surveyed. Protective influences in the surveyed women included positive rating of their mother's care, having a relatively educated mother, attending boarding school, their own age (the older they were, the less likely were they to have an external orientation), having a mentally ill parent, a sibling hospitalized or a relative die. Conclusions: There are two conclusions: (i) that not all stressful events contribute to the development of ELOC and it would be essential for models of antecedents of ELOC to take note of this complexity, and (ii) there are consistent (albeit unexpected) findings that highlight associations with cigarette smoke exposure of the woman from fetal life through to when starting to smoke regularly herself in mid-childhood. It is important that these findings are tested in other populations. PMID- 29242841 TI - Unexpected diagnosis in a patient with a left ventricular assist device: rectal cancer. PMID- 29242842 TI - Endoscopic vein harvesting: the growing role in cardiac surgery. PMID- 29242843 TI - Systemic oxidoreductive balance and vascular function in individuals without clinical manifestation of atherosclerosis. AB - Introduction: Endothelial dysfunction is recognized as the earliest disorder in the development of atherosclerosis, in the pathogenesis of which oxidative stress plays a crucial role. The aim of this study was to determine the relationships between non-invasive parameters of vascular dysfunction and oxidative stress. Material and methods: Forty-eight individuals without clinical manifestation of atherosclerosis were studied. The plasma concentrations of the following were determined in all 48 subjects: retinol, ascorbic acid, alpha-tocopherol and uric acid, as well as the products of oxidative DNA damage repair: 8-oxo-7,8-dihydro 2'-deoxyguanosine (8-oxodG) in blood leukocytes and urine, and 8-oxo-7,8 dihydroguanine (8-oxoGua) in urine. The following parameters of vascular dysfunction were also examined: flow- (FMD) and nitroglycerin- (NMD) mediated dilatation of the brachial artery, pulse pressure (PP), distensibility coefficient (DC), pulsation (PI) and resistance (RI) index, carotid intima-media thickness (cIMT), and ankle-brachial index (ABI). Results: Individuals with an FMD value of >= 8.8% had significantly higher blood concentrations of antioxidative vitamins and lower concentrations of 8-oxodG in their urine and blood leukocytes than their counterparts. Blood concentration of alpha-tocopherol or ascorbic acid positively correlated with FMD, PI, RI, DC and ABI and negatively with PP and cIMT. The reverse was the case for 8-oxodG in urine and leukocytes. In multiple regression analysis, markers of oxidative DNA damage positively determined the variance in PP and ABI. Conclusions: In persons without clinical manifestation of atherosclerosis, oxidative stress was an independent factor associated with vascular wall dysfunction, and a better predictor than smoking and blood concentrations of glucose, lipids and creatinine. PMID- 29242844 TI - Effects of increased body weight and short-term weight loss on serum PCSK9 levels - a prospective pilot study. AB - Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with low-density lipoprotein (LDL) catabolism, but its serum concentration is not uniformly associated with cardiovascular disease in clinical studies. Obesity is linked with increased cardiovascular risk, but the effect of increased body weight and short-term weight loss on serum PCSK9 levels is not well studied. Material and methods: The aim of this prospective pilot study was to assess differences in serum PCSK9 levels (determined with a quantitative sandwich enzyme immunoassay) between otherwise healthy drug-naive obese subjects and healthy individuals with normal body weight. Additionally, PCSK9 levels were determined at baseline and after a 3-month weight-loss program with a low-fat diet in a randomly assigned subgroup of the obese subjects (n = 15). Results: Obese subjects (n = 35) were older (age: 43 +/-11 years) and had significantly higher body mass index, total cholesterol, triglycerides, LDL cholesterol (LDL-C), apolipoprotein B and homeostasis model assessment of insulin resistance (HOMA) index levels, as well as significantly lower high-density lipoprotein cholesterol (HDL-C) concentration, compared with normal-weight subjects (n = 20, age: 35 +/-6 years). Serum PCSK9 levels were significantly higher in obese subjects compared with normal-weight individuals, even after adjustment for age, LDL-C, triglycerides, HDL-C, apolipoprotein A1, apolipoprotein B, apolipoprotein E, glucose, insulin and HOMA index levels (p = 0.018). Obese subjects experienced significant weight loss (from 109 +/-22 to 104 +/-23 kg, p < 0.01), but serum PCSK9 levels did not significantly change after the 3-month weight-loss program. Conclusions: Serum PCSK9 levels are higher in obese subjects than in normal weight individuals. Short-term weight loss with a low-fat diet does not significantly affect PCSK9 levels. PMID- 29242846 TI - High prevalence of dyslipidemia among primary care patients with hypertension and diabetes in Jamaica. AB - Introduction: The aim of the study was to determine the prevalence of dyslipidemia among primary care patients with hypertension and diabetes in Jamaica and the proportion of patients who achieve recommended targets. Material and methods: An audit of 500 dockets of adult patients with chronic disease attending public primary care clinics in Jamaica was conducted between October and December 2013. Data were collected on patient characteristics including medical history, medications, anthropometry, and lipid profiles (since January 1, 2011). Lipid targets were based on the Ministry of Health 2007 management guidelines. Stepwise multivariable logistic regression analysis was performed to determine the predictors of achieving lipid targets. Results: Four hundred and thirty-seven patient records had a lipid profile done and 90% of these had at least one abnormal lipid value. 15.3% of the patients achieved the low density lipoprotein cholesterol (LDL-C) target, 63.2% high density lipoprotein cholesterol (HDL-C), 85.1% triglycerides and 57.4% the total cholesterol target. Statins were prescribed for 49% and these patients were less likely to achieve LDL-C (OR = 0.57; 95% CI: 0.33-0.97; p = 0.04) or total cholesterol (OR = 0.21; 95% CI: 0.13-0.33; p < 0.001) targets. Patients over 80 years were more likely to achieve the LDL-C target (OR = 3.21; 95% CI: 1.64-6.28; p = 0.002) than those less than 50 years old. More men than women achieved total cholesterol targets (OR = 2.2; 95% CI: 1.4-3.6; p = 0.001). Conclusions: Dyslipidemia is widespread among primary care patients with hypertension and diabetes. The proportion of patients who achieve the respective lipid targets must be documented and routinely monitored and appropriate medication and lifestyle changes implemented to improve this. PMID- 29242845 TI - No effect of vitamin D supplementation on cardiovascular risk factors in subjects with metabolic syndrome: a pilot randomised study. AB - Introduction: Patients with metabolic syndrome (MetS) may have lower 25 hydroxyvitamin D (25(OH)VitD) serum levels compared with non-MetS individuals. Vitamin D (VitD) deficiency is associated with various cardiovascular disease (CVD) risk factors. Yet, the effect of VitD supplementation on MetS remains uncertain. Our aim was to examine the effect of VitD supplementation on CVD risk factors in MetS subjects. Material and methods: This pilot study had a PROBE (prospective, randomised, open-label, blinded end-point) design. Fifty patients with MetS were included and randomised either to dietary instructions (n = 25) (control group) or dietary instructions plus VitD 2000 IU/day (n = 25) (VitD group) for 3 months. This study is registered in ClinicalTrials.gov (NCT01237769). Results: In both groups a similar small weight reduction was achieved. In the VitD group serum 25(OH)VitD levels significantly increased by 91% (from 16.0 (3.0-35.0) to 30.6 (8.4-67.0) ng/ml, p < 0.001), while in the control group no significant change was observed (from 10.0 (4.0-39.6) to 13.0 (3.5-37.0) ng/ml). In both groups triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting glucose, haemoglobin A1c, homeostasis model assessment index and diastolic blood pressure did not significantly change. Systolic blood pressure decreased by 3.7% (from 134 +/-14 to 129 +/-13 mm Hg, p = 0.05) in the VitD group, while it decreased by 1.5% (from 132 +/-13 to 130 +/-16 mm Hg, p = NS) in the control group (p = NS between groups). In the VitD group serum 25(OH)VitD increase was negatively correlated with SBP decrease (r = -0.398, p = 0.049). Conclusions: VitD supplementation (2000 IU/day) did not affect various CVD risk factors in patients with MetS. PMID- 29242847 TI - Simvastatin intolerance genetic determinants: some features in ethnic Uzbek patients with coronary artery disease. AB - Introduction: The objective is to study the influence of CYP3A5 (6986A>G), CYP2C9 (430C>T), CYP2C9 (1075A>C), SLCO1B1 (521T>C) and BCRP (ABCG2, 421C>A) gene polymorphisms on the development of simvastatin intolerance in ethnic Uzbek patients with coronary artery disease (CAD). Material and methods: The case group contained 50 patients with clinical simvastatin-induced intolerance symptoms; the control group contained 50 patients without side-effects. Genotyping was performed by means of the PCR-RFLP method. Results: Among 37 patients with simvastatin-induced liver symptoms the *3/*3 genotype of the CYP3A5 gene (p = 0.0001) and variant genotype of the CA BCRP gene were observed more frequently than in the control group (p = 0.0001). However, when the 13 patients who had statin-associated muscle symptoms (SAMS) were compared with the control group (n = 50), it was found that in the case group the 3*/3* genotype of the CYP3A5 gene (OR = 8.6; 95% CI: 2.1-34.1; p = 0.003) and C allele carriers of the gene polymorphism SLCO1B1 (OR = 3.54; 95% CI: 1.35-9.27; Chi2 = 5.7; p = 0.017) were predominant. Conclusions: The *3/*3 genotype of the CYP3A5 (6986A>G) gene and CA genotype of the BCRP (ABCG2, 421C>A) gene were associated with simvastatin induced liver symptoms in ethnic Uzbek CAD patients, whereas in patients with simvastatin-associated muscle symptoms (SAMS), the combination of *3/*3 genotype of CYP3A5 (6986A> G) and carriage of the C allele of the SLCO1B1 gene polymorphism was predominant. PMID- 29242848 TI - Effect of combined endurance-resistance training and soy extract supplementation on expression of eNOS gene in ovariectomized rats. AB - Introduction: Menopause is an independent risk factor for cardiovascular disease (CVD). Physical exercise and soybean diets have been suggested to reduce the risk of CVD in postmenopausal women. The purpose of this study was to investigate the effects of combined resistance and endurance (RE) training and soy extract (SOY) supplementation, both known to improve endothelial function, on expression of the eNOS gene in the heart of ovariectomized (OVX) rats. Material and methods: Fifty female Wistar rats were divided into five groups: 1) sham (SHAM); 2) ovariectomy (OVX); 3) ovariectomy with soy extract supplementation (OVX + SOY); 4) OVX with RE training (OVX + RE); 5) and ovariectomy plus RE training with soy extract supplementation (OVX + RE + SOY). RE training and soy extract supplementation were administered alone or in combination for 6 weeks. The effects of these treatments on cardiac eNOS expression were measured using real-time PCR. Results: Ovariectomy down-regulated cardiac eNOS gene expression; however, 6 weeks of SOY treatment or RE training reversed this effect (p <= 0.05). The combination of SOY plus RE was greater than RE or SOY alone in reversing estrogen-deficiency-caused eNOS down-regulation (p <= 0.05). Conclusions: Our data suggest that the combinatory regimen of soy extract supplementation and regular RE training may be more beneficial to cardiovascular disease risk in a menopause rat model than either exercise or soy supplementation alone. PMID- 29242849 TI - Does contrast media volume affect long-term survival in patients with chronic kidney disease? AB - Introduction: The aim of this study was to investigate the relationships between survival and related features in patients with chronic kidney disease undergoing cardiac catheterization and coronary angiography. Material and methods: Three hundred and seven consecutive patients with an estimated glomerular filtration rate (e-GFR) less than 60 ml/min/1.73 m2 undergoing coronary angiography were enrolled in the study. The study population was pursued with a median follow-up duration of 41.5 months. Results: In the Cox proportional hazards regression model, age (HR = 1.047, 95% CI: 1.011-1.084, p = 0.01), contrast media volume (HR = 1.004, 95% CI: 1.001-1.007, p = 0.008), angiotensin II receptor blocker (ARB) use (HR = 0.485, 95% CI: 0.261-0.901, p = 0.02), and e-GFR (HR = 0.978, 95% CI: 0.940-1.016, p = 0.04) were found to be independent predictors of long-term all cause mortality. The survival analysis showed that the long-term all-cause mortality rate was higher in patients using contrast media volume greater than 140 ml compared to patients given less than or equal to 140 ml during the coronary angiography (3.6% vs. 11.6% log-rank, p = 0.001). Conclusions: In patients with chronic kidney disease undergoing cardiac catheterization, age, contrast media volume, e-GFR and low ARB use were found to be independent predictors of long-term all-cause mortality. Contrast media volume used > 140 ml was independently associated with long-term all-cause mortality compared to less than or equal to 140 ml during cardiac catheterization. PMID- 29242850 TI - Developing Neolignans as Proangiogenic Agents: Stereoselective Total Syntheses and Preliminary Biological Evaluations of the Four Guaiacylglycerol 8-O-4' Coniferyl Ethers. AB - Stereoselective total syntheses of the four stereoisomeric forms of guaiacylglycerol 8-O-4'-coniferyl ether, viz., compounds 1, ent-1, 2, and ent-2, have been established. The key step involves an Evans/Seebach auxiliary controlled and syn-selective aldol process followed, in the reaction sequences leading to the anti-compounds, by a Mitsunobu reaction involving a benzylic alcohol residue. The proangiogenic properties of the synthetic materials were evaluated in a human microvascular endothelial cell tubule formation assay, thus revealing that they are all active, with the 8S-configured compounds 1 and 2 being the most potent. PMID- 29242852 TI - Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high dose posttransplantation cyclophosphamide. AB - Allogeneic blood or marrow transplantation (BMT) candidates may lack HLA-matched, related haploidentical, and unrelated umbilical cord options. Barriers to partially HLA-mismatched, unrelated donor (mMUD) BMT include excess graft-versus host disease (GVHD), graft failure, and death. We prospectively studied nonmyeloablative (NMA) mMUD BMT with high-dose posttransplantation cyclophosphamide (PTCy) for patients with hematologic malignancies. Three transplants were performed with busulfan/fludarabine conditioning, with subsequent change to fludarabine/Cy/total body irradiation (flu/Cy/TBI). Twenty mMUD transplants are reported using flu/Cy/TBI, T-cell replete bone marrow grafts, and PTCy, mycophenolate mofetil, and sirolimus or tacrolimus (1 patient) for GVHD prophylaxis. The median patient age was 56. Ofthese unrelated grafts, 45% had >=2 mismatched HLA loci, 25% had >=3 mismatched loci, and 50% had HLA-C mismatches. No graft failure or grades 3-4 acute GVHD occurred. The median times to neutrophil recovery (>=500/MUL) and platelet recovery (>=20 000/MUL) were 19 days and 31 days, respectively. Full-donor chimerism was achieved in 95% of evaluable patients by day 60. The 180-day probability of grades 2-4 acute GVHD (all grade 2) was 25%, and the 1-year probability of any chronic GVHD was 16% (none severe). The 2-year nonrelapse mortality probability was 6%. With 4-year median follow-up, the 1-year progression-free and overall survival probabilities were 65% and 75%, respectively. NMA, T-cell replete mMUD BMT is thus a potentially viable option for patients without other suitable donors. This trial was registered at www.clinicaltrials.gov as #NCT01203722. PMID- 29242854 TI - State Estimation Under Correlated Partial Measurement Losses: Implications for Weight Control Interventions. AB - The growing prevalence of obesity and related health problems warrants immediate need for effective weight control interventions. Quantitative energy balance models serve as powerful tools to assist in these interventions, as a result of their ability to accurately predict individual weight change based on reliable measurements of energy intake and energy expenditure. However, the data collected in most existing weight interventions is self-monitored; these measurements often have significant noise or experience losses resulting from participant non adherence, which in turn, limits accurate model estimation. To address this issue, we develop a Kalman filter-based estimation algorithm for a practical scenario where on-line state estimation for weight, or energy intake/expenditure is still possible despite correlated partial data losses. To account for non linearities in the models, an algorithm based on extended Kalman filtering is also developed for sequential state estimation in the presence of missing data. Simulation studies are presented to illustrate the performance of the algorithms and the potential benefits of these techniques in real-life interventions. PMID- 29242851 TI - In-depth PtdIns(3,4,5)P3 signalosome analysis identifies DAPP1 as a negative regulator of GPVI-driven platelet function. AB - The class I phosphoinositide 3-kinase (PI3K) isoforms play important roles in platelet priming, activation, and stable thrombus formation. Class I PI3Ks predominantly regulate cell function through their catalytic product, the signaling phospholipid phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], which coordinates the localization and/or activity of a diverse range of binding proteins. Notably, the complete repertoire of these class I PI3K effectors in platelets remains unknown, limiting mechanistic understanding of class I PI3K-mediated control of platelet function. We measured robust agonist-driven PtdIns (3,4,5)P3 generation in human platelets by lipidomic mass spectrometry (MS), and then used affinity-capture coupled to high-resolution proteomic MS to identify the targets of PtdIns (3,4,5)P3 in these cells. We reveal for the first time a diverse platelet PtdIns(3,4,5)P3 interactome, including kinases, signaling adaptors, and regulators of small GTPases, many of which are previously uncharacterized in this cell type. Of these, we show dual adaptor for phosphotyrosine and 3-phosphoinositides (DAPP1) to be regulated by Src-family kinases and PI3K, while platelets from DAPP1-deficient mice display enhanced thrombus formation on collagen in vitro. This was associated with enhanced platelet alpha/delta granule secretion and alphaIIbbeta3 integrin activation downstream of the collagen receptor glycoprotein VI. Thus, we present the first comprehensive analysis of the PtdIns(3,4,5)P3 signalosome of human platelets and identify DAPP1 as a novel negative regulator of platelet function. This work provides important new insights into how class I PI3Ks shape platelet function. PMID- 29242855 TI - Development of an MRI-Compatible Needle Driver for In-Bore Prostate Biopsy. AB - Minimally invasive percutaneous approaches routinely employ insertion of needles into soft tissue for diagnostic or therapeutic purposes. Lack of targeting accuracy while inserting needles can significantly mitigate the effectiveness of these methods. Robot-assisted needle steering under magnetic resonance imaging (MRI) guidance is a viable option for reaching the target accurately. In this paper, we report the development of an MRI-compatible needle driver for in-bore prostate biopsy. The device easily mounts onto and works together with our previously developed MRI-compatible prostate interventional robot. It is the first robotic device using a standard biopsy gun, which is easily replaceable/detachable in case of multi-sampling biopsy applications. The mechanism enables rotation, translation, and triggering of the biopsy gun to steer the bevel needle through the tissue and to take samples accurately from the target loci. Using the rotational and translational capabilities, the same system can also assist brachytherapy needle placement. Preliminary experiments have shown that the design meets the requirements set by the clinical workflow. System feasibility was verified by multiple users inserting 2 different types of needles under visual feedback into a phantom made of soft plastic. The average targeting errors were 0.92 mm for 18 gauge biopsy and 1.65 mm for 20 gauge brachytherapy needle. PMID- 29242856 TI - Defect engineering in metal-organic frameworks: a new strategy to develop applicable actinide sorbents. AB - The preliminary results described here show that the adsorbability of uranyl ions by a highly stable MOF UiO-66 can be drastically enhanced by tailoring the missing-linker defects in this MOF. The combination of defect-induced functionality improvement with the acid-resistant nature of UiO-66 substantiates the applicability of this material for actinide capture from acidic media. PMID- 29242853 TI - Differential Effects of 3rd Trimester-Equivalent Binge Ethanol and Tobacco Specific Nitrosamine Ketone Exposures on Brain Insulin Signaling in Adolescence. AB - Background: Fetal alcohol spectrum disorder (FASD) is associated with impairments in insulin and insulin-like growth factor (IGF) signaling through Akt pathways and altered expression of neuro-glial proteins needed for structural and functional integrity of the brain. However, alcohol abuse correlates with smoking, and tobacco smoke contains 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone (NNK), which like other nitrosamines, impairs insulin and IGF signaling. Hypothesis: NNK exposure can serve as a co-factor in mediating long-term neuro developmental abnormalities associated with FASD. Design: Long Evans rat pups were IP administered ethanol (2 g/kg) on postnatal days (P) 2, 4, 6 and/or NNK (2 mg/kg) on P3, P5, and P7, simulating third trimester human exposures. Temporal lobes from P30 rats (young adolescent) were used to measure signaling through the insulin/IGF-1/Akt pathways by multiplex ELISAs, and expression of neuroglial proteins by duplex ELISAs. Results: Ethanol, NNK, and ethanol + NNK exposures significantly inhibited insulin receptor tyrosine phosphorylation, and IRS-1 and myelin-associated glycoprotein expression. However, the major long-term adverse effects on Akt pathway downstream signaling and its targeted proteins including choline acetyltransferase, Tau, pTau, ubiquitin, and aspartate-beta-hydroxylase were due to NNK rather than ethanol. Conclusion: Alcohol and tobacco exposures can both contribute to long-term brain abnormalities currently regarded fetal ethanol effects. However, the findings suggest that many of the adverse effects on brain function are attributable to smoking, including impairments in signaling through survival and metabolic pathways, and altered expression of genes that regulate myelin synthesis, maturation and integrity and synaptic plasticity. Therefore, public health measures should address both substances of abuse to prevent "FASD". PMID- 29242857 TI - Biphasic drug release from electrospun polyblend nanofibers for optimized local cancer treatment. AB - The application of the biphasic release profile furnished by electrospun polyblend nanofibers for local cancer treatment was investigated. By adjusting the weight ratio of the hydrophilic polymer (poly(ethylene oxide), PEO) and hydrophobic polymer (poly(l-lactide), PLA), PEO10-PLA90 fibers with typical biphasic release kinetics were successfully prepared. Due to their unique release profile, PEO10-PLA90 fibers can quickly access the tumor site in vivo at a high drug content within 1 h and keep at a high level for longer than two weeks. In vivo antitumor and safety studies demonstrated that PEO10-PLA90 fibers can achieve optimized local cancer treatment efficacy and avoid undesired adverse reactions. The biphasic drug release profile provided by the polyblend electrospun technology was proven to be a new conception for local chemotherapy. PMID- 29242858 TI - Formic acid: an accelerator and quality promoter for nonseeded growth of CH3NH3PbI3 single crystals. AB - With the aid of formic acid, CH3NH3PbI3 single crystal of 9 mm in length was directly harvested within 3 days via a nonseeded solution temperature-lowering (STL) method. It showed a record-narrow full width at half maximum of 13 arcsec for the high-resolution X-ray rocking curve, a low trap-state density of 3.1 * 109 cm-3, a high carrier mobility of 162 cm2 V-1 s-1 and high moisture stability. The addition of formic acid could suppress the oxidation of iodide ions in a conventional STL process, resulting in rapid growth of high-quality CH3NH3PbI3 single crystals. PMID- 29242859 TI - Experimental evidence of charged domain walls in lead-free ferroelectric ceramics: light-driven nanodomain switching. AB - The control of ferroelectric domain walls at the nanometric level leads to novel interfacial properties and functionalities. In particular, the comprehension of charged domain walls, CDWs, lies at the frontier of future nanoelectronic research. Whereas many of the effects have been demonstrated for ideal archetypes, such as single crystals, and/or thin films, a similar control of CDWs on polycrystalline ferroelectrics has not been achieved. Here, we unambiguously show the presence of charged domain walls on a lead-free (K,Na)NbO3 polycrystalline system. The appearance of CDWs is observed in situ by confocal Raman microscopy and second harmonic generation microscopy. CDWs produce an internal strain gradient within each domain. Specifically, the anisotropic strain develops a crucial piece in the ferroelectric domain switching due to the coupling between the polarization of light and the ferroelectric polarization of the nanodomain in the (K,Na)NbO3 ceramic. This effect leads to the tuning of the ferroelectric domain switching by means of the light polarization angle. Our results will help to understand the relevance of charged domain walls on the ferroelectric domain switching process and may facilitate the development of domain wall nanoelectronics by remote light control utilizing polycrystalline ferroelectrics. PMID- 29242860 TI - Aluminum nanostructures with strong visible-range SERS activity for versatile micropatterning of molecular security labels. AB - The application of aluminum (Al)-based nanostructures for visible-range plasmonics, especially for surface-enhanced Raman scattering (SERS), currently suffers from inconsistent local electromagnetic field distributions and/or inhomogeneous distribution of probe molecules. Herein, we lithographically fabricate structurally uniform Al nanostructures which enable homogeneous adsorption of various probe molecules. Individual Al nanostructures exhibit strong local electromagnetic field enhancements, in turn leading to intense SERS activity. The average SERS enhancement factor (EF) for individual nanostructures exceeds 104 for non-resonant probe molecules in the visible spectrum. These Al nanostructures also retain more than 70% of their original SERS intensities after one-month storage, displaying superb stability under ambient conditions. We further achieve tunable polarization-dependent SERS responses using anisotropic Al nanostructures, facilitating the design of sophisticated SERS-based security labels. Our micron-sized security label comprises two-tier security features, including a machine-readable hybrid quick-response (QR) code overlaid with a set of ciphertexts. Our work demonstrates the versatility of Al-based structures in low-cost modern chemical nano-analytics and forgery protection. PMID- 29242861 TI - Intramolecular nucleophilic addition of carbanions generated from N-benzylamides to cyclopropenes. AB - An unusual reaction is described, involving a formal intramolecular nucleophilic substitution of bromocyclopropanes with nitrogen ylides generated in situ from N benzyl carboxamides. It is shown that this reaction involves cyclopropene intermediates and allows for the facile and expeditious preparation of 3 azabicyclo[3.1.0]hexan-2-one scaffolds. PMID- 29242862 TI - Stochastic pumping of non-equilibrium steady-states: how molecules adapt to a fluctuating environment. AB - In the absence of input energy, a chemical reaction in a closed system ineluctably relaxes toward an equilibrium state governed by a Boltzmann distribution. The addition of a catalyst to the system provides a way for more rapid equilibration toward this distribution, but the catalyst can never, in and of itself, drive the system away from equilibrium. In the presence of external fluctuations, however, a macromolecular catalyst (e.g., an enzyme) can absorb energy and drive the formation of a steady state between reactant and product that is not determined solely by their relative energies. Due to the ubiquity of non-equilibrium steady states in living systems, the development of a theory for the effects of external fluctuations on chemical systems has been a longstanding focus of non-equilibrium thermodynamics. The theory of stochastic pumping has provided insight into how a non-equilibrium steady-state can be formed and maintained in the presence of dissipation and kinetic asymmetry. This effort has been greatly enhanced by a confluence of experimental and theoretical work on synthetic molecular machines designed explicitly to harness external energy to drive non-equilibrium transport and self-assembly. PMID- 29242863 TI - Cyclic amino(carboranyl) silylene: synthesis, structure and reactivity. AB - A carbene-stabilized cyclic amino(carboranyl) silylene has been prepared from the reaction of cyclic amino(carboranyl) chlorosilane with N-heterocyclic carbene via HCl elimination. Its structure has been characterized by single-crystal X-ray analysis and DFT calculations. It is a very strong sigma donor and relatively poor pi acceptor. It can form a Lewis acid-base adduct with borane and undergo cycloaddition reactions with unsaturated molecules such as diphenylacetylene and benzophenone. PMID- 29242864 TI - Three-in-one type fluorescent sensor based on a pyrene pyridoxal cascade for the selective detection of Zn(ii), hydrogen phosphate and cysteine. AB - A novel fluorescent receptor L was synthesized by Schiff base condensation of 1 pyrenemethylamine with the vitamin B6 cofactor pyridoxal. The receptor L is highly selective and sensitive towards Zn2+ ions among other tested metal ions. Upon interaction with Zn2+, the receptor L showed a distinct fluorescence enhancement at 485 nm due to the excimer formation leading to the fluorescent colour change from blue to bluish-green. Subsequently, when the in situ generated ZnL2 complex interacted with various anions and amino acids, the addition of H2PO4- and cysteine reinstated the fluorescence of the receptor L due to the demetalation of Zn2+ from the ZnL2 complex. Accordingly, the receptor L was developed for the highly selective, specific and sensitive detection of three important bioactive analytes, i.e., Zn2+, H2PO4- and cysteine with a detection limit down to 2.3 * 10-6 M, 2.18 * 10-7 M and 1.59 * 10-7 M, respectively. Additionally, the receptor L was applied to the detection of intracellular Zn2+ ions in live HeLa cells. PMID- 29242865 TI - A nickel catalyzed acceptorless dehydrogenative approach to quinolines. AB - A general, efficient and environmentally benign, one-step synthesis of substituted quinoline derivatives was achieved by acceptorless dehydrogenative coupling of o-aminobenzylalcohols with ketones and secondary alcohols catalyzed by a cheap, earth abundant and easy to prepare nickel catalyst [Ni(MeTAA)], featuring a tetraaza macrocyclic ligand (tetramethyltetraaza[14]annulene (MeTAA)). A wide variety of substituted quinolines were synthesized in high yields starting from readily available o-aminobenzylalcohols and ketones or secondary alcohols. A few controlled reactions were carried out to establish the acceptorless dehydrogenative nature of the reactions. PMID- 29242866 TI - The curved kinetic boundary layer of active matter. AB - A body submerged in active matter feels the swim pressure through a kinetic accumulation boundary layer on its surface. The boundary layer results from a balance between translational diffusion and advective swimming and occurs on the microscopic length scale . Here , DT is the Brownian translational diffusivity, tauR is the reorientation time and l = U0tauR is the swimmer's run length, with U0 the swim speed [Yan and Brady, J. Fluid. Mech., 2015, 785, R1]. In this work we analyze the swim pressure on arbitrary shaped bodies by including the effect of local shape curvature in the kinetic boundary layer. When delta ? L and l ? L, where L is the body size, the leading order effects of curvature on the swim pressure are found analytically to scale as JSlambdadelta2/L, where JS is twice the (non-dimensional) mean curvature. Particle-tracking simulations and direct solutions to the Smoluchowski equation governing the probability distribution of the active particles show that lambdadelta2/L is a universal scaling parameter not limited to the regime delta, l ? L. The net force exerted on the body by the swimmers is found to scale as Fnet/(ninfinityksTsL2) = f(lambdadelta2/L), where f(x) is a dimensionless function that is quadratic when x ? 1 and linear when x ~ 1. Here, ksTs= zetaU02tauR/6 defines the 'activity' of the swimmers, with zeta the drag coefficient, and ninfinity is the uniform number density of swimmers far from the body. We discuss the connection of this boundary layer to continuum mechanical descriptions of active matter and briefly present how to include hydrodynamics into this purely kinetic study. PMID- 29242867 TI - Gold catalyzed Heck-coupling of arenediazonium o-benzenedisulfonimides. AB - Diazonium salts, and precisely arenediazonium o-benzenedisulfonimides, have been used for the first time as efficient electrophilic partners in gold catalyzed Heck-coupling reactions. The synthetic protocol was general, easy and gave the target products in satisfactory yields. Mechanistic insights revealed the fundamental roles of the o-benzenedisulfonimide anion as an electron transfer agent thath promotes a radical pathway that does not require the presence of photocatalysts or external oxidants. PMID- 29242868 TI - Synthesis of the natural product descurainolide and cyclic peptides from lignin derived aromatics. AB - Alternative sources of potential feedstock chemicals are of increasing importance as the availability of oil decreases. The biopolymer lignin is viewed as a source of useful mono-aromatic compounds as exemplified by the industrial scale production of vanillin from this biomass. Alternative lignin-derived aromatics are available in pure form but to date examples of the use of these types of compounds are rare. Here we address this issue by reporting the conversion of an aromatic keto-alcohol to the anti- and syn-isomers of Descurainolide A. The key step involves a rhodium-catalyzed allylic substitution reaction. Enantio-enriched allylic alcohols were generated via an isothiourea-catalyzed kinetic resolution enabling access to both the (2R,3R) and (2S,3S) enantiomers of anti Descurainolide A. In addition we show that the lignin-derived keto-alcohols can be converted into unnatural amino acid derivatives of tyrosine. Finally, these amino acids were incorporated into cyclic peptide scaffolds through the use of both chemical and an enzyme-mediated macrocylisation. PMID- 29242869 TI - A model electronic Hamiltonian for the self-assembly of an octahedron-shaped coordination capsule. AB - A model electronic Hamiltonian to describe ligand exchange reactions of palladium(ii) complexes with pyridine (Py) and tridentate (L) ligands was developed. It was shown that the model Hamiltonian can adequately reproduce the structures and potential energies of the reactant/product, intermediate, and transition state of the ligand exchange reaction of [PdPy4]2+ with free Py. The model Hamiltonian was extended to describe reactions of multi-metal complexes and was adequately applied to describe various clusters, [PdaLbPyc]2a+, in the self assembly of an octahedron-shaped coordination capsule, [Pd6L8]12+. The heterogeneity in the energetics of intermediate species [PdaLbPyc]2a+ was strongly suggested by the calculations, and the underlying microscopic interactions were clarified with the geometrical motif. The present framework provides a way to examine the reaction mechanisms of complex metal ligand self assembly, which can be complementary microscopic information to the recently investigated novel experimental results for the real time evolutions. PMID- 29242870 TI - High-throughput double emulsion-based microfluidic production of hydrogel microspheres with tunable chemical functionalities toward biomolecular conjugation. AB - Chemically functional hydrogel microspheres hold significant potential in a range of applications including biosensing, drug delivery, and tissue engineering due to their high degree of flexibility in imparting a range of functions. In this work, we present a simple, efficient, and high-throughput capillary microfluidic approach for controlled fabrication of monodisperse and chemically functional hydrogel microspheres via formation of double emulsion drops with an ultra-thin oil shell as a sacrificial template. This method utilizes spontaneous dewetting of the oil phase upon polymerization and transfer into aqueous solution, resulting in poly(ethylene glycol) (PEG)-based microspheres containing primary amines (chitosan, CS) or carboxylates (acrylic acid, AA) for chemical functionality. Simple fluorescent labelling of the as-prepared microspheres shows the presence of abundant, uniformly distributed and readily tunable functional groups throughout the microspheres. Furthermore, we show the utility of chitosan's primary amine as an efficient conjugation handle at physiological pH due to its low pKa by direct comparison with other primary amines. We also report the utility of these microspheres in biomolecular conjugation using model fluorescent proteins, R-phycoerythrin (R-PE) and green fluorescent protein (GFPuv), via tetrazine-trans-cyclooctene (Tz-TCO) ligation for CS-PEG microspheres and carbodiimide chemistry for AA-PEG microspheres, respectively. The results show rapid coupling of R-PE with the microspheres' functional groups with minimal non-specific adsorption. In-depth protein conjugation kinetics studies with our microspheres highlight the differences in reaction and diffusion of R-PE with CS-PEG and AA-PEG microspheres. Finally, we demonstrate orthogonal one-pot protein conjugation of R-PE and GFPuv with CS-PEG and AA-PEG microspheres via simple size-based encoding. Combined, these results represent a significant advancement in the rapid and reliable fabrication of monodisperse and chemically functional hydrogel microspheres with tunable properties. PMID- 29242871 TI - Alternating ring-opening metathesis polymerization by Grubbs-type catalysts with N-pentiptycenyl, N-alkyl-NHC ligands. AB - A Grubbs-Hoveyda type catalyst with a N-pentiptycenyl, N-cyclohexyl-NHC ligand provides poly(nbe-alt-coe) with an excellent degree of alternation while lacking significant activity in the homopolymerization of cyclooctene. PMID- 29242872 TI - Phenylamino derivatives of tris(2-pyridylmethyl)amine: hydrogen-bonded peroxodicopper complexes. AB - A series of copper complexes bearing new 6-substituted tris(2-pyridylmethyl)amine ligands (LR) appended with NH(p-R-C6H4) groups (R = H, CF3, OMe) were prepared. These ligands are electronically tunable (DeltaE1/2 = 160 mV) and CuI(LR)+ complexes react with oxygen to form hydrogen bonded (trans-1,2-peroxo)dicopper species. PMID- 29242873 TI - The effect of amorphous TiO2 in P25 on dye-sensitized solar cell performance. AB - P25 is one of the most widely used forms of titanium(iv) oxide (TiO2), routinely utilised in dye-sensitised solar cells (DSCs), where it is often employed as a control, in spite of its poorly defined nature and the typically low device efficiency (or possibly because of this). Work by Park in 2000 and later by Lin et al. suggests that the rutile component might not be to blame for this, as has often been claimed. Recently it has been observed that P25 has quite a sizable amorphous content. A method to selectively remove this non-crystalline material has been developed, allowing for scrutiny of the role this amorphous material plays. Here we compare hydrothermally treated P25 (H-P25) with the as-received material, realizing solar-to-electric conversion efficiencies of 5.3% and 3.2% respectively. More importantly, this reveals important information about the detrimental effect of amorphous TiO2 on DSC performance, with broader implications, as most researchers do not actively examine their synthesized materials for the presence of an amorphous component. PMID- 29242874 TI - Aromatic aldehyde-selective aldol addition with aldehyde-derived silyl enol ethers. AB - The aldol reaction using aldehyde-derived silyl enolates as nucleophiles with aromatic aldehydes chemoselectively proceeded in the presence of silyl triflate and 2,2'-bipyridyl to produce beta-siloxy aldehydes, while the aliphatic aldehydes were completely recovered. The unprecedented chemoselectivities depend on the reactivities of the pyridinium-type intermediates derived from the aromatic and aliphatic aldehydes. PMID- 29242875 TI - Square transition-metal carbides MC6 (M = Mo, W) as stable two-dimensional Dirac cone materials. AB - Searching for new two-dimensional (2D) Dirac cone materials has been popular since the exfoliation of graphene. Herein, based on density functional theory, we predict a novel family of 2D Dirac cone materials in square transition-metal carbides MC6 (M = Mo, W) which show inherent stability confirmed by phonon spectrum analysis and ab initio molecular dynamics calculations. The Dirac point, located exactly at the Fermi level, mainly arises from the hybridization of M dz2,x2-y2 and C-pz orbitals which gives rise to an ultrahigh Fermi velocity comparable to that of graphene. Moreover, strong spin-orbit coupling related to M d electrons can generate large band gaps of 35 and 89 meV for MoC6 and WC6 monolayers, respectively, which allows MC6 materials to be operable at room temperature (26 meV), as candidates for nanoelectronics in the upcoming post silicon era. The conceived novel stable metal-carbon framework materials provide a platform for designing 2D Dirac cone materials. PMID- 29242876 TI - Correction: Dietary fucoidan modulates the gut microbiota in mice by increasing the abundance of Lactobacillus and Ruminococcaceae. AB - Correction for 'Dietary fucoidan modulates the gut microbiota in mice by increasing the abundance of Lactobacillus and Ruminococcaceae' by Qingsen Shang et al., Food Funct., 2016, 7, 3224-3232. PMID- 29242877 TI - Unravelling the mechanisms that determine the uptake and metabolism of magnetic single and multicore nanoparticles in a Xenopus laevis model. AB - Multicore superparamagnetic nanoparticles have been proposed as ideal tools for some biomedical applications because of their high magnetic moment per particle, high specific surface area and long term colloidal stability. Through controlled aggregation and packing of magnetic cores it is possible to obtain not only single-core but also multicore and hollow spheres with internal voids. In this work, we compare toxicological properties of single and multicore nanoparticles. Both types of particles showed moderate in vitro toxicity (MTT assay) tested in Hep G2 (human hepatocellular carcinoma) and Caco-2 (human colorectal adenocarcinoma) cells. The influence of surface chemistry in their biological behavior was also studied after functionalization with O,O'-bis(2-aminoethyl) PEG (2000 Da). For the first time, these nanoparticles were evaluated in a Xenopus laevis model studying their whole organism toxicity and their impact upon iron metabolism. The degree of activation of the metabolic pathway depends on the size and surface charge of the nanoparticles which determine their uptake. The results also highlight the potential of Xenopus laevis model bridging the gap between in vitro cell-based assays and rodent models for toxicity assessment to develop effective nanoparticles for biomedical applications. PMID- 29242878 TI - Theoretical study on photo-induced processes of 1-methyl-3-(N-(1,8 naphthalimidyl)ethyl)imidazolium halide species: an application of constrained density functional theory. AB - 1-Methyl-3-(N-(1,8-naphthalimidyl)ethyl)imidazolium (MNEI) has potential as a versatile sensor that can measure the electronegativity of anions based on the fluorescence intensity upon irradiation. To clarify the factors that determine the fluorescence intensity, constrained density functional theory (CDFT) was applied to explore the electron transfer (ET) states of MNEI halide species (MNEI X; X = F, Cl, Br, I). According to the CDFT potential energy surface, intra molecular ET (SM1) states on MNEI are responsible for the intensity of absorption and fluorescence spectra. However, inter-molecular ET (SET) states between MNEI and X are certainly responsible for fluorescence quenching. Hence, the energetic difference between the SM1 state and the SET state (DeltaEM1_ET) is a crucial factor that determines the fluorescence intensity in the spectra of MNEI-X complexes. DeltaEM1_ET decreases as the electronegativity of X decreases (i.e., F > Cl > Br > I). This explains the fluorescence intensity of MNEI-X. PMID- 29242879 TI - Translesion DNA synthesis across double-base lesions derived from cross-links of an antitumor trinuclear platinum compound: primer extension, conformational and thermodynamic studies. AB - Polynuclear platinum complexes represent a unique structural class of DNA-binding agents of biological significance. They contain at least two platinum coordinating units bridged by a linker, which means that the formation of double base lesions (cross-links) in DNA is possible. Here, we show that the lead compound, bifunctional [{trans-PtCl(NH3)2}2MU-trans-Pt(NH3)2{H2N(CH2)6NH2}2]4+ (Triplatin or BBR3464), forms in DNA specific double-base lesions which affect the biophysical and biochemical properties of DNA in a way fundamentally different compared to the analogous double-base lesions formed by two adducts of monofunctional chlorodiethylenetriamineplatinum(ii) chloride (dienPt). We find concomitantly that translesion DNA synthesis by the model A-family polymerase, the exonuclease deficient Klenow fragment, across the double-base lesions derived from the intrastrand CLs of Triplatin was markedly less extensive than that across the two analogous monofunctional adducts of dienPt. Collectively, these data provide convincing support for the hypothesis that the central noncovalent tetraamine platinum linker of Triplatin, capable of hydrogen-bonding and electrostatic interactions with DNA and bridging the two platinum adducts, represents an important factor responsible for the markedly lowered tolerance of DNA double-base adducts of Triplatin by DNA polymerases. PMID- 29242880 TI - Ab initio modeling of MAX phase solid solutions using the special quasirandom structure approach. AB - MAX phases are technologically important materials exhibiting both metallic and ceramic properties. In the present study we propose the use of the special quasirandom structure (SQS) approach as a computationally tractable method to predict the phase stability of disordered MAX phase solid solutions. We have generated 128-atom SQS structures to mimic the 211 MAX phase solid solutions with random distribution of different elements within either the M or the A sublattice. Using DFT-calculated mixing energy and instability energy as predictors, we show that (Zr1-xMx)2AlC (for M = Nb and Ta) and Zr2(Al1-xAx)C (for A = Bi, Pb and Sn) MAX phase solid solutions may be experimentally synthesized. Our predicted results are in agreement with the limited available experimental data and chemical bonding analysis using the crystal-orbital Hamilton population (COHP) technique. The SQS cells reported are transferable and can be employed to model numerous MAX phase solid solutions. PMID- 29242881 TI - Understanding the formation of the metastable ferroelectric phase in hafnia zirconia solid solution thin films. AB - Hf1-xZrxO2 (x ~ 0.5-0.7) has been the leading candidate of ferroelectric materials with a fluorite crystal structure showing highly promising compatibility with complementary metal oxide semiconductor devices. Despite the notable improvement in device performance and processing techniques, the origin of its ferroelectric crystalline phase (space group: Pca21) formation has not been clearly elucidated. Several recent experimental and theoretical studies evidently showed that the interface and grain boundary energies of the higher symmetry phases (orthorhombic and tetragonal) contribute to the stabilization of the metastable non-centrosymmetric orthorhombic phase or tetragonal phase. However, there was a clear quantitative discrepancy between the theoretical expectation and experiment results, suggesting that the thermodynamic model may not provide the full explanation. This work, therefore, focuses on the phase transition kinetics during the cooling step after the crystallization annealing. It was found that the large activation barrier for the transition from the tetragonal/orthorhombic to the monoclinic phase, which is the stable phase at room temperature, suppresses the phase transition, and thus, plays a critical role in the emergence of ferroelectricity. PMID- 29242882 TI - Donor-acceptor type blends composed of black phosphorus and C60 for solid-state optical limiters. AB - Novel donor-acceptor blends composed of black phosphorus (BP) as an electron donor and C60 as an electron acceptor have been prepared and successfully embedded into a non-optically active poly(methylmethacrylate) (PMMA) matrix producing a BP:C60/PMMA film. In contrast to C60, BP and non-annealed BP:C60 blends, annealed BP:C60 blends show a significantly enhanced optical limiting response due to the thermal-induced intermolecular charge transfer effect between BP and C60. PMID- 29242883 TI - The anharmonic quartic force field infrared spectra of hydrogenated and methylated PAHs. AB - Polycyclic aromatic hydrocarbons (PAHs) have been shown to be ubiquitous in a large variety of distinct astrophysical environments and are therefore of great interest to astronomers. The majority of these findings are based on theoretically predicted spectra, which make use of scaled DFT harmonic frequencies for band positions and the double harmonic approximation for intensities. However, these approximations have been shown to fail at predicting high-resolution gas-phase infrared spectra accurately, especially in the CH stretching region (2950-3150 cm-1, 3 MUm). This is particularly worrying for the subset of hydrogenated or methylated PAHs to which astronomers attribute the observed non-aromatic features that appear in the CH-stretching region of spectral observations of the interstellar medium (ISM). In our previous work, we presented the anharmonic theoretical spectra of three linear PAHs and five non linear PAHs, demonstrating the importance of including anharmonicities into theoretical calculations. In this work we extend these techniques to two methylated PAHs (9-methylanthracene, and 9,10-dimethylanthracene) and four hydrogenated PAHs (9,10-dihydroanthracene, 9,10-dihydrophenanthrene, 1,2,3,4 tetrahydronaphthalene, and 1,2,3,6,7,8-hexahydropyrene) in order to better understand the aliphatic IR features of substituted PAHs. The theoretical spectra are compared with the spectra obtained under matrix isolation low-temperature conditions for the full vibrational fundamental range and under high-resolution, low-temperature gas-phase conditions for the CH-stretching region. Excellent agreement is observed between the theoretical and high-resolution experimental spectra with a deviation of 0.00% +/- 0.17%, and changes to the spectra of PAHs upon methylation and hydrogenated are tracked accurately and explained. PMID- 29242884 TI - The effect of Ho3+ doping on 13C dynamic nuclear polarization at 5 T. AB - Dissolution dynamic nuclear polarization was introduced in 2003 as a method for producing hyperpolarized 13C solutions suitable for metabolic imaging. The signal to noise ratio for the imaging experiment depends on the maximum polarization achieved in the solid state. Hence, optimization of the DNP conditions is essential. To acquire maximum polarization many parameters related to sample preparation can be modulated. Recently, it was demonstrated that Ho3+, Dy3+, Tb3+, and Gd3+ complexes enhance the polarization at 1.2 K and 3.35 T when using the trityl radical as the primary paramagnetic center. Here, we have investigated the influence of Ho-DOTA on 13C solid state DNP at 1.2 K and 5 T. We have performed 13C DNP on [1-13C] sodium acetate in 1 : 1 (v/v) water/glycerol with 15 mM trityl OX063 radicals in the presence of a series of Ho-DOTA concentrations (0, 0.5, 1, 2, 3, 5 mM). We have found that adding a small amount of Ho-DOTA in the sample preparation not only enhances the 13C polarization but also decreases the buildup time. The optimum Ho-DOTA concentration was 2 mM. In addition, the microwave sweep spectrum changes character in a manner that suggests both the cross effect and thermal mixing are active mechanisms for trityl radical at 5 T and 1.2 K. PMID- 29242885 TI - An isolable magnesium diphosphaethynolate complex. AB - The reaction of magnesium chloride with two equivalents of sodium phosphaethynolate, Na[OCP].(dioxane)2.5 (1), yields a magnesium diphosphaethynolate complex, [(THF)4Mg(OCP)2] (3). The formation of compound 3 goes through a monosubstituted chloromagnesium phosphaethynolate Mg(OCP)Cl (2). The structure of 3 was determined via a single crystal X-ray diffraction study. For comparison, we also report the structure of a monomeric sodium phosphaethynolate complex, [Na(OCP)(dibenzo-18-crown-6)] (4). PMID- 29242886 TI - Solvent effect on the intermolecular proton transfer of the Watson and Crick guanine-cytosine and adenine-thymine base pairs: a polarizable continuum model study. AB - Herein we present our results on the study of the double proton transfer (DPT) mechanism in the adenine-thymine (AT) and guanine-cytosine (GC) base pairs, both in gas phase and in solution. The latter was modeled using the polarizable continuum method (PCM) in different solvents. According to our DFT calculations, the DPT may occur for both complexes in a stepwise mechanism in condensate phase. In gas phase only the GC base pair exhibits a concerted DPT mechanism. Using the Wigner's tunneling corrections to the transition state theory we demonstrate that such corrections are important for the prediction of the rate constants of both systems in gas and in condensate phase. We also show that (i) as the polarity of the medium decreases the equilibrium constant of the DPT reaction increases in both complexes, and (ii) that the equilibrium constant in the GC complex is four orders of magnitude larger than in AT. This observation suggests that the spontaneous mutations in DNA base pairs are more probable in GC than in AT. PMID- 29242887 TI - Chemical methods for mapping cysteine oxidation. AB - Cysteine residues in proteins are subject to diverse redox chemistry. Oxidation of cysteine to S-nitrosocysteine, cysteine sulfenic and sulfinic acids, disulfides and persulfides are a few prominent examples of these oxidative post translational modifications. In living organisms, these modifications often play key roles in cell signalling and protein function, but a full account of this biochemistry is far from complete. It is therefore an important goal in chemical biology to identify what proteins are subjected to these modifications and understand their physiological function. This review provides an overview of these modifications, how they can be detected and quantified using chemical probes, and how this information provides insight into their role in biology. This survey also highlights future opportunities in the study of cysteine redox chemistry, the challenges that await chemists and biologists in this area of study, and how meeting such challenges might reveal valuable information for biomedical science. PMID- 29242888 TI - Theoretical study of non-Hammett vs. Hammett behaviour in the thermolysis and photolysis of arylchlorodiazirines. AB - Arylchlorodiazirines (ACDA) are thermal and photochemical precursors of carbenes that form these molecules via nitrogen elimination. We have studied this reaction with multireference quantum chemical methods (CASSCF and CASPT2) for a series of ACDA derivatives with different substitution at the aromatic ring. The calculations explain the different reactivity trends found in the ground and excited state, with good correlation between the calculated barriers and the experimental reaction rates. The ground state mechanism can be described as a reverse cycloaddition with small charge transfer from the aromatic ring to the diazirine moiety. This is consistent with the lack of correlation between the Hammett sigma descriptors and the experimental rates. In contrast, the excited state reaction is the cleavage of a single C-N bond mediated by small barriers of 4-6 kcal mol-1. The reaction path goes through a conical intersection with the ground state, which facilitates radiationless decay and explains the disappearance of the transient absorption signal measured experimentally. This leads to a diazomethane intermediate that ultimately yields the carbene. Electronically, excitation to S1 is characterized initially by significant charge transfer from the phenyl ring to the diazirine. The charge transfer is reversed during the C-N cleavage reaction, and this explains the preferential stabilization of the excited-state minimum by polar solvents and electron donating substituents. Therefore, our calculations reproduce and explain the relationship found experimentally between the Hammett sigma+ parameters and the life time of S1 (Y. L. Zhang, et al. J. Am. Chem. Soc., 2009, 131, 16652-16653). PMID- 29242889 TI - Interplay of spectral diffusion and phonon-broadening in individual photo emitters: the case of carbon nanotubes. AB - At cryogenic temperatures, the photoluminescence (PL) spectrum of nano-emitters may still be significantly broadened due to interactions with the environment. The interplay of spectral diffusion (SD) and phonon broadening in this context is still a debated issue. Singlewall carbon nanotubes (SWNTs) are a particularly relevant system to address this topic as they show intense spectral diffusion and undergo a high exciton-phonon coupling due to their one-dimensional geometry. Here, we investigate the correlations between the spectral diffusion of the main line and that of the wings in SWNTs quantitatively and demonstrate that the photoluminescence spectrum undergoes spectral jumps as a whole, without distortions. This behavior suggests that the spectral shape of SWNT PL is defined by exciton-phonon interactions and that spectral diffusion results in an additional flat broadening. The methodology developed here can be used to investigate a broad range of non-Lorentzian emitters undergoing spectral diffusion. PMID- 29242890 TI - Aluminium-mediated carbon-carbon coupling of an isonitrile. AB - Cp*Al reacts with diphenylacetylene to form a Cp*-substituted 1,4 dialuminacyclohexene. The dialuminacyclohexene reacts with four equivalents of an isonitrile to couple the terminal carbon atoms, forming 6 new carbon-carbon bonds and resulting in a zwitterionic diamide ligand which contains a carbocationic backbone. PMID- 29242892 TI - Role of Maternal Race on Algorithms Predicting Retinopathy of Prematurity-Reply. PMID- 29242891 TI - Diagnosis and Treatment of Hypertension in the 2017 ACC/AHA Guidelines and in the Real World. PMID- 29242893 TI - Predicting Response to Treatment in a Tier 2 Supplemental Vocabulary Intervention. AB - Purpose: To effectively implement a response to intervention approach, there is a need for timely and specific information about student learning in response to treatment to ensure that treatment decisions are appropriate. This exploratory study examined responsivity to a supplemental, Tier 2 vocabulary intervention delivered to preschool children with limited language abilities. Method: A secondary analysis of a cluster-randomized trial of a supplemental vocabulary intervention was conducted. Responsivity (e.g., adequate learning) to the intervention was examined, and learning in the 1st few weeks of intervention was evaluated as a possible predictor of response to intervention. Results: Using a criterion of learning of 20% of target vocabulary, nearly one third of participants were identified as poor responders. A 1st unit benchmark was identified that maximized the sensitivity to identification of children who were likely to respond to the intervention. Conclusions: Even for generally effective interventions, there is likely to be a substantial proportion of children who are not responsive. Learning in the 1st few weeks of intervention may be a useful indicator of appropriate response to treatment and could inform instructional decisions. PMID- 29242894 TI - Gated Word Recognition by Postlingually Deafened Adults With Cochlear Implants: Influence of Semantic Context. AB - Purpose: The main goal of this study was to investigate the minimum amount of sensory information required to recognize spoken words (isolation points [IPs]) in listeners with cochlear implants (CIs) and investigate facilitative effects of semantic contexts on the IPs. Method: Listeners with CIs as well as those with normal hearing (NH) participated in the study. In Experiment 1, the CI users listened to unprocessed (full-spectrum) stimuli and individuals with NH listened to full-spectrum or vocoder processed speech. IPs were determined for both groups who listened to gated consonant-nucleus-consonant words that were selected based on lexical properties. In Experiment 2, the role of semantic context on IPs was evaluated. Target stimuli were chosen from the Revised Speech Perception in Noise corpus based on the lexical properties of the final words. Results: The results indicated that spectrotemporal degradations impacted IPs for gated words adversely, and CI users as well as participants with NH listening to vocoded speech had longer IPs than participants with NH who listened to full-spectrum speech. In addition, there was a clear disadvantage due to lack of semantic context in all groups regardless of the spectral composition of the target speech (full spectrum or vocoded). Finally, we showed that CI users (and users with NH with vocoded speech) can overcome such word processing difficulties with the help of semantic context and perform as well as listeners with NH. Conclusion: Word recognition occurs even before the entire word is heard because listeners with NH associate an acoustic input with its mental representation to understand speech. The results of this study provide insight into the role of spectral degradation on the processing of spoken words in isolation and the potential benefits of semantic context. These results may also explain why CI users rely substantially on semantic context. PMID- 29242896 TI - The Oddie Children. PMID- 29242895 TI - Comparison of Laboratory-Developed Tests and FDA-Approved Assays for BRAF, EGFR, and KRAS Testing. AB - Importance: The debate about the role of the Food and Drug Administration (FDA) in the regulation of laboratory-developed tests (LDTs) has focused attention on the analytical performance of all clinical laboratory testing. This study provides data comparing the performance of LDTs and FDA-approved companion diagnostics (FDA-CDs) in proficiency testing (PT) provided by the College of American Pathologists Molecular Oncology Committee. Objective: To compare the analytical performance of LDTs and FDA-CDs on well-characterized PT samples and to compare the practice characteristics of laboratories using these assays. Design, Setting, and Participants: This comparison of PT responses examines the performance of laboratories participating in the College of American Pathologists PT for 3 oncology analytes for which both FDA-CDs and LDTs are used: BRAF, EGFR, and KRAS. A total of 6897 PT responses were included: BRAF (n = 2524; 14 PT samples), EGFR (n = 2216; 11 PT samples), and KRAS (n = 2157, 10 PT samples). US Food and Drug Administration companion diagnostics and LDTs are compared for both accuracy and preanalytic practices of the laboratories. Main Outcomes and Measures: As per the College of American Pathologists PT standards, results were scored and the percentages of acceptable responses for each analyte were compared. These were also broken down by the specific variants tested, by kit manufacturer for laboratories using commercial reagents, and by preanalytic practices. Results: From analysis of 6897 PT responses, this study demonstrates that both LDTs and FDA-CDs have excellent performance overall, with both test types exceeding 97% accuracy for all 3 genes (BRAF, EGFR, and KRAS) combined. Rare variant-specific differences did not consistently favor LDTs or FDA-CDs. Additionally, more than 60% of participants using an FDA-CD reported adapting their assay from the approved procedure to allow for a greater breadth of sample types, minimum tumor content, and instrumentation, changing the classification of their assay from FDA-CD to LDT. Conclusions: This study demonstrates the high degree of accuracy and comparable performance of both LDTs and FDA-CDs for 3 oncology analytes. More significantly, the majority of laboratories using FDA-CDs have modified the scope of their assay to allow for more clinical practice variety, rendering them LDTs. These findings support both the excellent and equivalent performance of both LDTs and FDA-CDs in clinical diagnostic testing. PMID- 29242897 TI - Vijver op Ooidonk. PMID- 29242898 TI - Peter Revson. PMID- 29242899 TI - Can Probability Maps of Swept-Source Optical Coherence Tomography Predict Visual Field Changes in Preperimetric Glaucoma? AB - Purpose: To determine the usefulness of swept-source optical coherence tomography (SS-OCT) probability maps in detecting locations with significant reduction in visual field (VF) sensitivity or predicting future VF changes, in patients with classically defined preperimetric glaucoma (PPG). Methods: Of 43 PPG patients, 43 eyes were followed-up on every 6 months for at least 2 years were analyzed in this longitudinal study. The patients underwent wide-field SS-OCT scanning and standard automated perimetry (SAP) at the time of enrollment. With this wide-scan protocol, probability maps originating from the corresponding thickness map and overlapped with SAP VF test points could be generated. We evaluated the vulnerable VF points with SS-OCT probability maps as well as the prevalence of locations with significant VF reduction or subsequent VF changes observed in the corresponding damaged areas of the probability maps. Results: The vulnerable VF points were shown in superior and inferior arcuate patterns near the central fixation. In 19 of 43 PPG eyes (44.2%), significant reduction in baseline VF was detected within the areas of structural change on the SS-OCT probability maps. In 16 of 43 PPG eyes (37.2%), subsequent VF changes within the areas of SS-OCT probability map change were observed over the course of the follow-up. Conclusions: Structural changes on SS-OCT probability maps could detect or predict VF changes using SAP, in a considerable number of PPG eyes. Careful comparison of probability maps with SAP results could be useful in diagnosing and monitoring PPG patients in the clinical setting. PMID- 29242900 TI - Evaluation of Retinal Nerve Fiber Layer Thinning in Myopic Glaucoma: Impact of Optic Disc Morphology. AB - Purpose: The purpose of this study was to investigate the role of optic disc torsion on the rate of progressive retinal nerve fiber layer (RNFL) thinning in patients with myopic open-angle glaucoma. Methods: We included 102 patients with myopic open-angle glaucoma accompanied by glaucomatous damage confined to a single hemiretina who were followed up over a 5-year period. We divided the subjects into three groups according to the presence or absence of optic disc torsion and the correspondence between the direction of optic disc torsion and the location of glaucomatous damage: torsion with reverse correspondence group (eyes showing inferior optic disc torsion with glaucomatous damage in the superior quadrant or eyes showing superior torsion with damage in the inferior quadrant), no torsion group, and torsion with correspondence group (eyes showing inferior optic disc torsion with glaucomatous damage in the inferior quadrant or eyes showing superior torsion with damage in the superior quadrant). Changes in the peripapillary RNFL thickness (pRNFLT), evaluated using linear mixed model analysis, were compared among the three groups to determine the relationship between optic disc torsion and pRNFLT changes. Results: Among the total of 102 subjects, 13 eyes (12.7%) exhibited optic disc torsion with reverse correspondence, 59 (57.8%) did not exhibit optic disc torsion, and 30 (29.4%) exhibited optic disc torsion with correspondence. pRNFL thinning in the quadrant with glaucomatous damage was significantly faster in the torsion with correspondence group (-1.66 MUm/y) than those in the no torsion (-1.14 MUm/y; P = 0.032) and torsion with reverse correspondence (-0.50 MUm/y; P < 0.001) groups. Conclusions: Our results suggest that the optic disc torsion-glaucomatous damage correspondence is an important prognostic factor for patients with myopic open angle glaucoma. PMID- 29242901 TI - Designed Host Defense Peptides for the Treatment of Bacterial Keratitis. AB - Purpose: To limit corneal damage and potential loss of vision, bacterial keratitis must be treated aggressively. Innovation in antimicrobials is required due to the need for empirical treatment and the rapid emergence of bacterial resistance. Designed host defense peptides (dHDPs) are synthetic analogues of naturally occurring HDPs, which provide defense against invading pathogens. This study investigates the use of novel dHDPs for the treatment of bacterial keratitis. Methods: The minimum inhibitory concentrations (MICs) were determined for dHDPs on both Gram-positive and -negative bacteria. The minimum biofilm eradication concentrations (MBEC) and in vitro time-kill assays were determined. The most active dHDP, RP444, was evaluated for propensity to induce drug resistance and therapeutic benefit in a murine Pseudomonas aeruginosa keratitis model. Results: Designed HDPs were bactericidal with MICs ranging from 2 to >64 MUg/mL and MBEC ranging from 6 to 750 MUg/mL. In time-kill assays, dHDPs were able to rapidly reduce bacterial counts upon contact with as little as 2 MUg/mL. RP444 did not induce resistance after repeated exposure of P. aeruginosa to subinhibitory concentrations. RP444 demonstrated significant efficacy in a murine model of bacterial keratitis as evidenced by a significant dose-dependent decrease in ocular clinical scores, a significantly reduced bacterial load, and substantially decreased inflammatory cell infiltrates. Conclusions: Innovative dHDPs demonstrated potent antimicrobial activity, possess a limited potential for development of resistance, and reduced the severity of murine P. aeruginosa keratitis. These studies demonstrate that a novel dHDP may have potential to treat patients with sight-threatening bacterial keratitis. PMID- 29242902 TI - Effects of Prenatal Alcohol Exposure on the Visual System of Monkeys Measured at Different Stages of Development. AB - Purpose: Fetal alcohol spectrum disorder (FASD) is a developmental disease characterized by behavioral problems and physical defects including malformations of the eye and associated optical defects. How these malformations affect retinal functioning is not well known, although animal models have suggested that scotopic vision is particularly deficient. Age is also known to affect scotopic vision. Here, we determined the combined effects of age and fetal alcohol exposure (FAE) on retinal function using full-field electroretinograms (ERGs) in monkeys (Chlorocebus sabaeus). Methods: ERGs were recorded in monkeys aged 3- to 12-years old, at multiple flash intensities under scotopic and photopic conditions, and functions were fit to the amplitudes of the a- and b-waves. Results: We found that both age and alcohol exposure affected ERGs. In photopic ERGs, amplitudes increased with age, and were higher in FAEs than controls, for data related to the OFF- and ON-pathways. In scotopic ERGs, amplitudes were decreased in young FAE compared with age-matched controls but only for the rod dominated responses, while at brighter flashes, alcohol exposure led to an increase in the amplitude of the a- and b-waves. Conclusions: The ERGs from the FAE animals closely resembled the data from the older sucrose-control monkeys. This suggests that the FAE monkey retina ages more quickly than the control monkeys. This large sample of nonhuman primates, with carefully monitored ethanol exposure, demonstrates the critical interplay between age and alcohol when assessing the integrity of the retina. We suggest that ERGs might be an important adjunct to diagnosing human FASD. PMID- 29242903 TI - Interface Bonding With Corneal Crosslinking (CXL) After LASIK Ex Vivo. AB - Purpose: Interface bonding with corneal crosslinking (CXL) after LASIK using two different photosensitizers was studied ex vivo. Methods: A LASIK flap was created in enucleated rabbit eyes using a femtosecond laser. After the dissection, CXL was performed to seal the interface. In one group interface CXL was performed using rose bengal and green light, whereas in a second group riboflavin and UV-A light was used. In both groups irradiance, radiant exposure, dye concentration, and imbibition time was varied. In a control group, LASIK only was performed. After the procedures, the maximal shear-force required to separate the flap from the stroma was measured. Additionally, corneal transmission spectra were recorded. Results: Optimized parameters for rose bengal/green-light bonding lead to a 2.1-fold increase in shear-force compared with untreated control eyes (P < 0.01). The optimal parameter combination was: irradiance of 180 mW/cm2 for 14 minutes (total radiant exposure 150 J/cm2), rose bengal concentration 0.1%, and an imbibition time of 2 minutes. Optimized riboflavin/UV-A light parameters were 0.5% for 2 minutes with a radiant exposure of 8.1 J/cm2 obtained by an irradiance of 30 mW/cm2 for 4.5 minutes. These optimized parameters lead to a 2-fold increase compared with untreated control eyes (P < 0.01). Optical transmission experiments suggest safety for more posterior structures. Conclusions: Based on ex-vivo results, interface bonding after LASIK using crosslinking with either rose bengal or riboflavin increases the adhesion between flap and stromal bed. In vivo trials are needed to evaluate the temporal evolution of the effect. PMID- 29242904 TI - Platelet-Derived Growth Factor-BB Lessens Light-Induced Rod Photoreceptor Damage in Mice. AB - Purpose: Platelet-derived growth factor (PDGF)-BB is known to have neuroprotective effects against various neurodegenerative disorders. The purpose of this study was to determine whether PDGF-BB can be neuroprotective against light-induced photoreceptor damage in mice. Methods: Mice were exposed to 8000 lux luminance for 3 hours to induce phototoxicity. Two hours before light exposure, the experimental mice were injected with PDGF-BB intravitreally, and the control mice were injected with phosphate-buffered saline. The light-exposed PDGF-BB-injected mice and saline-injected mice were evaluated electroretinographically and histologically. The site and expression levels of PDGFR-beta and PDGF-BB were determined by immunostaining and Western blotting, respectively. The effect of PDGF-BB on light-induced cone and rod photoreceptor damage was also evaluated in vitro in 661W cells, a murine cone photoreceptor cell line, and in primary retinal cell cultures. Results: An intravitreal injection of PDGF-BB significantly reduced the decrease in the amplitudes of the electroretinograms (ERGs) and the thinning of the outer nuclear layer (ONL) induced by the light exposure. It also reduced the number of TUNEL-positive cells in the ONL. PDGFR-beta was expressed in the rod outer segments (OSs) but not the cone OSs. The levels of PDGF-BB and PDGFR-beta were decreased after light irradiation. In addition, PDGF-BB had protective effects against light-induced damage to cells of rod photoreceptors but had no effect on the 661W cells in vitro. Conclusions: These findings indicate that PDGF-BB reduces the degree of light-induced retinal damage by activating PDGFR-beta in rod photoreceptors. These findings suggest that PDGF-BB could play a role in the prevention of degeneration in eyes susceptible to phototoxicity. PMID- 29242905 TI - The Long Noncoding RNA Landscape of the Mouse Eye. AB - Purpose: Long noncoding RNAs (lncRNAs) are important regulators of diverse biological functions. However, an extensive in-depth analysis of their expression profile and function in mammalian eyes is still lacking. Here we describe comprehensive landscapes of stage-dependent and tissue-specific lncRNA expression in the mouse eye. Methods: Affymetrix transcriptome array profiled lncRNA signatures from six different ocular tissue subsets (i.e., cornea, lens, retina, RPE, choroid, and sclera) in newborn and 8-week-old mice. Quantitative RT-PCR analysis validated array findings. Cis analyses and Gene Ontology (GO) annotation of protein-coding genes adjacent to signature lncRNA loci clarified potential lncRNA roles in maintaining tissue identity and regulating eye maturation during the aforementioned phase. Results: In newborn and 8-week-old mice, we identified 47,332 protein-coding and noncoding gene transcripts. LncRNAs comprise 19,313 of these transcripts annotated in public data banks. During this maturation phase of these six different tissue subsets, more than 1000 lncRNAs expression levels underwent >=2-fold changes. qRT-PCR analysis confirmed part of the gene microarray analysis results. K-means clustering identified 910 lncRNAs in the P0 groups and 686 lncRNAs in the postnatal 8-week-old groups, suggesting distinct tissue-specific lncRNA clusters. GO analysis of protein-coding genes proximal to lncRNA signatures resolved close correlations with their tissue-specific functional maturation between P0 and 8 weeks of age in the 6 tissue subsets. Conclusions: Characterizating maturational changes in lncRNA expression patterns as well as tissue-specific lncRNA signatures in six ocular tissues suggest important contributions made by lncRNA to the control of developmental processes in the mouse eye. PMID- 29242906 TI - Reduced Corneal Nerve Fiber Density in Type 2 Diabetes by Wide-Area Mosaic Analysis. AB - Purpose: To determine if corneal subbasal nerve plexus (SBP) parameters derived from wide-area depth-corrected mosaic images are associated with type 2 diabetes. Methods: One hundred sixty-three mosaics were produced from eyes of 82 subjects by laser-scanning in vivo confocal microscopy (IVCM). Subjects were of the same age, without (43 subjects) or with type 2 diabetes (39 subjects). Mosaic corneal nerve fiber length density (mCNFL) and apical whorl corneal nerve fiber length density (wCNFL) were quantified and related to the presence and duration of diabetes (short duration < 10 years and long duration >= 10 years). Results: In mosaics with a mean size of 6 mm2 in subjects aged 69.1 +/- 1.2 years, mCNFL in type 2 diabetes was reduced relative to nondiabetic subjects (13.1 +/- 4.2 vs. 15.0 +/- 3.2 mm/mm2, P = 0.018). Also reduced relative to nondiabetic subjects was mCNFL in both short-duration (14.0 +/- 4.0 mm/mm2, 3.2 +/- 3.9 years since diagnosis) and long-duration diabetes (12.7 +/- 4.2 mm/mm2, 15.4 +/- 4.2 years since diagnosis; ANOVA P = 0.023). Lower mCNFL was associated with presence of diabetes (P = 0.032) and increased hemoglobin A1c (HbA1c) levels (P = 0.047). By contrast, wCNFL was unaffected by diabetes or HbA1c (P > 0.05). Global SBP patterns revealed marked degeneration of secondary nerve fiber branches outside the whorl region in long-duration diabetes. Conclusions: Wide-area mosaic images provide reference values for mCNFL and wCNFL and reveal a progressive degeneration of the SBP with increasing duration of type 2 diabetes. PMID- 29242907 TI - Skin Intrinsic Fluorescence and Age-Related Macular Degeneration: The Beaver Dam Eye Study. AB - Purpose: To determine if skin intrinsic fluorescence (SIF), a noninvasive measure of advanced glycation endproducts and oxidative stress in skin is associated with AMD. Methods: SIF was measured with the SCOUT DS skin fluorescence spectrometer in a cross-sectional cohort study of 969 persons aged 68 to 102 years from the 1181 who participated in the 25-year follow-up examination in the Beaver Dam Eye Study (BDES) in 2014 to 2016. The SCOUT DS skin fluorescence spectrometer uses five light-emitting diodes, centered at 375 nm to 456 nm. AMD was assessed by grading of digital color 45 degrees stereoscopic fundus photographs of the macula using the Wisconsin Age-Related Maculopathy grading scheme. Analyses included logistic regression with generalized estimating equations to account for correlation between the eyes of a person. Results: There were data for 1827 eyes for analyses. Early AMD was present in 22% and late AMD in 4% of the eyes. While adjusting for age, sex, smoking status, and history of cardiovascular disease, there were no significant associations of any SIF measure with any AMD or exudative AMD. SIF01 (odds ratio per 1 SD difference on the log scale, 95% confidence interval) (1.66, 1.00-2.74, P = 0.05) and SIF03 (1.81, 1.16-2.81, P = 0.008) were associated with geographic atrophy. Conclusions: There was a suggestive relationship of two SIF measures, SIF01 and SIF03, using different correction factors from the excitation centered at 375 nm, with the prevalence of geographic atrophy in the BDES. Longitudinal follow-up is indicated to assess a temporal relationship. PMID- 29242909 TI - Patient-Paired Sample Congruence Between 2 Commercial Liquid Biopsy Tests. PMID- 29242908 TI - Changes in Relative Position of Choroidal Versus Retinal Vessels in Preterm Infants. AB - Purpose: The purpose of this study was to characterize a novel finding that relative positions of choroidal and retinal vessels change over time in preterm infants and to identify factors associated with this finding using quantitative analysis. Methods: Fundus images were obtained prospectively through a retinopathy of prematurity (ROP) cohort study. Images were excluded if choroidal vessels could not be identified. Changes in relative position of characteristic choroidal landmarks with respect to retinal vessels between two time points 5 to 7 weeks apart were measured. Univariate and multivariate regression analyses were performed to identify associated factors with the amount of change. Results: The discovery and replication cohorts included 45 and 58 patients, respectively. Ninety-two of them (89%) were non-Hispanic Caucasians. Changes in relative position of choroidal versus retinal vessels were detected in all eyes of the discovery and replication cohorts (mean amount = 0.42 +/- 0.12 and 0.35 +/- 0.12 mm, respectively). On combined multiple regression analysis of the two cohorts, type 1 ROP, higher postmenstral age at the first time point, and shorter distance from optic disc to choroidal landmark were significantly associated with less change in relative position. Conclusions: Choroidal vessels grow anteriorly with respect to retinal vessels at posterior pole in preterm infants, suggesting relatively faster peripheral growth of choroidal versus retinal vessels. Eyes with severe ROP showed less difference in growth, which might represent alterations in choroidal development due to advanced ROP. These findings may contribute to better understanding about the physiology of choroidal development and involvement in ROP. PMID- 29242910 TI - Cerebrospinal Fluid Rhinorrhea and a Lytic-Appearing Lesion of the Posterior Cranial Fossa. PMID- 29242911 TI - Comparison of Airflow Between Spreader Grafts and Butterfly Grafts Using Computational Flow Dynamics in a Cadaveric Model. AB - Importance: Nasal valve compromise is a major cause of nasal obstruction, and multiple methods have been developed to address it. Objective: To compare nasal airflow resistance, airflow partitioning, and mucosal cooling (heat flux) before and after 2 surgical interventions, butterfly and spreader graft placement, used to treat nasal valve compromise. Design, Setting, and Participants: In this cadaveric tissue study, 4 fresh cadaveric heads underwent both spreader graft and butterfly graft surgical procedures in alternating sequence in March 2016. Preoperative and postoperative computed tomographic scans were used to generate 3 dimensional (3-D) models of the nasal airway. These models were then used in steady state computational fluid dynamics simulations of airflow and heat transfer during inspiration. Intervention: Butterfly and spreader graft techniques. Main Outcomes and Measures: Nasal airflow resistance, airflow partitioning, and heat flux. Results: Donors 1, 2, and 3 were white males; donor 4, a white female. Computational fluid dynamics simulations during inspiration in 3-D models generated from preoperative and postoperative computed tomographic scans of the 4 cadaveric heads indicated reductions from preoperative values in nasal airflow resistance associated with both butterfly grafts (range, 20%-51%) and spreader grafts (range, 2%-29%). Butterfly grafts were associated with a greater reduction in nasal airflow resistance in models of all 4 cadaveric heads. Changes from preoperative values for heat flux, a biophysical variable that correlates with the subjective sensation of nasal patency, were more variable, ranging from -11% to 4% following butterfly grafts and -9% to 10% following spreader grafts. The preoperative airflow allocation in the left and right nostrils improved consistently with the butterfly graft. With the spreader graft, there were improvements for donors 1 and 4, but the allocations were worse for donors 2 and 3. Conclusions and Relevance: The results of this study suggest that the more recently developed butterfly graft technique may be associated with a similar level of improved nasal airflow as that observed with the use of a spreader graft in nasal valve compromise. Both interventions were associated with comparable changes in heat flux. Because this study addressed only static internal nasal valve stenosis, even greater differences in air flow and heat flux between the 2 techniques may be anticipated in a dynamic model. Further investigation in patients is warranted. Level of Evidence: NA. PMID- 29242912 TI - Asian Upper Blepharoplasty. PMID- 29242913 TI - Long-term Results of Vermilionectomy in Malignant and Premalignant Lower Lip Lesions. PMID- 29242914 TI - Precision Medicine and Testing for Tumor Biomarkers-Are All Tests Born Equal? PMID- 29242917 TI - A Painful Red Eye. PMID- 29242919 TI - Association of Novel Oral Antithrombotics With the Risk of Intraocular Bleeding. AB - Importance: Novel oral anticoagulation and antiplatelet therapies have become a mainstay of treatment for thromboembolic disease. However, the safety profile of these medications has not been completely characterized. Objective: To determine the risk of developing intraocular hemorrhages with novel oral antithrombotic therapy compared with that of traditional antithrombotic agents. Design, Setting, and Participants: In this retrospective cohort study, a large national insurance claims database was used to generate 2 parallel analyses. All patients with incident use of dabigatran etexilate or rivaroxaban between January 1, 2010, and September 30, 2015, were compared with patients with incident use of warfarin sodium. Similarly, patients with new use of prasugrel hydrochloride were compared with those with new use of clopidogrel bisulfate. Both analyses required the patient to be in the insurance plan for at least 24 months prior to initiation of therapy and excluded patients with any previous diagnosis of intraocular hemorrhages or any prescription for the comparator medications. Furthermore, the antiplatelet analysis required a diagnosis of acute coronary syndrome or a myocardial infarction within 60 days of initiation of pharmacologic therapy. The anticoagulant analysis excluded patients with end-stage renal disease, renal transplants, and those with heart valve disease. Main Outcomes and Measures: Incident intraocular hemorrhages at 90 and 365 days. Multivariate Cox proportional hazards regression models were used to compare the hazard ratio (HR) of developing an intraocular hemorrhage in individuals taking novel agents compared with those taking traditional medications. Results: A total of 146 137 patients taking warfarin (76 714 women and 69 423 men; mean [SD] age, 69.8 [11.8] years) were compared with 64 291 patients taking dabigatran or rivaroxaban (31 576 women and 32 715 men; mean [SD] age, 67.6 [11.7] years). Cox proportional hazards regression revealed a decreased hazard for developing an intraocular hemorrhage with dabigatran or rivaroxaban at 365 days (HR, 0.75; 95% CI, 0.58 0.97; P = .03), but not at 90 days (HR, 0.73; 95% CI, 0.22-2.63; P = .13). A total of 103 796 patients taking clopidogrel (37 578 women and 66 218 men; mean [SD] age, 68.0 [11.3] years) were compared with 8386 patients taking prasugrel (1988 women and 6380 men; mean [SD] age, 61.0 [9.6] years) and no increased hazard for developing an intraocular hemorrhage with prasugrel was seen at 90 days (HR, 0.75; 95% CI, 0.29-1.92; P = .55) or 365 days (HR, 1.19; 95% CI, 0.69 2.04; P = .53). Conclusions and Relevance: These results suggest a decreased risk of intraocular hemorrhage associated with novel direct thrombin inhibitors and direct factor Xa inhibitors, but no difference for P2Y12 inhibitors compared with traditional vitamin K anticoagulation and antiplatelet therapy, respectively. PMID- 29242920 TI - Delivering Bad News: Attitudes, Feelings, and Practice Characteristics Among Speech-Language Pathologists. AB - Purpose: The purpose of this study was to examine the attitudes, feelings, and practice characteristics of speech-language pathologists (SLPs) in Israel regarding the subject of delivering bad news. Method: One hundred and seventy three Israeli SLPs answered an online survey. Respondents represented SLPs in Israel in all stages of vocational experience, with varying academic degrees, from a variety of employment settings. The survey addressed emotions involved in the process of delivering bad news, training on this subject, and background information of the respondents. Frequency distributions of the responses of the participants were determined, and Pearson correlations were computed to determine the relation between years of occupational experience and the following variables: frequency of delivering bad news, opinions regarding training, and emotions experienced during the process of bad news delivery. Results: Our survey showed that bad news delivery is a task that most participants are confronted with from the very beginning of their careers. Participants regarded training in the subject of delivering bad news as important but, at the same time, reported receiving relatively little training on this subject. In addition, our survey showed that negative emotions are involved in the process of delivering bad news. Conclusions: Training SLPs on specific techniques is required for successfully delivering bad news. The emotional burden associated with breaking bad news in the field of speech-language pathology should be noticed and addressed. PMID- 29242918 TI - A Nationwide Cohort Study on the Association Between Past Physical Activity and Neovascular Age-Related Macular Degeneration in an East Asian Population. AB - Importance: It has been suggested that physical activity (PA) is associated with reduced risk for early age-related macular degeneration (AMD). Systematic evaluation has been examining the association between lifestyle and neovascular AMD in an East Asian population, with a particular focus on past vigorous PA. Objective: To investigate the association between neovascular AMD and past PA, particularly a history of vigorous exercise, in the overall study population and among 2 a priori-defined subgroups. Design, Setting, and Participants: In this propensity score-matched cohort study, individuals between ages 45 and 79 years who were included in the South Korean National Health Insurance Service database from 2002 through 2013 were evaluated. Physical activity and incident neovascular AMD were recorded at baseline (2002-2003) and at follow-up (August 1, 2009, to December 31, 2013), respectively. Using a 1:1 propensity score-matched analysis, the incidence of neovascular AMD was compared using hazard ratios (HRs) for neovascular AMD between 105 980 participants who did and 105 980 who did not (no PA) engage in vigorous PA. The data analysis was performed from April 19, 2017, to June 5, 2017. Exposures: Physical activity. Main Outcomes and Measures: Incident cases of neovascular AMD. Results: Of the 211 960 participants (92 036 [43.4%] women; mean [SD] age, 55.1 [7.8] years), neovascular AMD was detected at follow-up in 250 (0.24%) individuals who engaged in past vigorous PA and in 198 (0.19%) of those who did not (HR, 1.23; 95% CI, 1.02-1.49). In subgroup analysis, vigorous PA was associated with a greater HR for neovascular AMD in participants aged 45 to 64 years (HR, 1.30; 95% CI, 1.04-1.63) and in men (HR, 1.36; 95% CI, 1.09-1.69). In the high-PA (>=5 times/wk: HR, 1.54; 95% CI, 1.15-2.06) and moderate-PA (1-4 times/wk: HR, 1.28; 95% CI, 1.01-1.63) groups, there was a greater incidence of neovascular AMD in the vigorous PA than in the no-PA group for men; no association was found for women. Conclusions and Relevance: Self reported past vigorous PA in men aged 45 to 64 years was associated with an increased risk for neovascular AMD. To our knowledge, no previous study has reported such an association; replication of the results would seem warranted to strengthen the likelihood of a cause and effect relationship. PMID- 29242921 TI - Analysis of the Association Between Physical Activity and Age-Related Macular Degeneration. PMID- 29242922 TI - Outcomes Following Cordotomy by Coblation for Bilateral Vocal Fold Immobility. AB - Importance: Bilateral vocal fold immobility (BVFI) can result in considerable voice and airway impairment. Although the carbon dioxide (CO2) laser is commonly used in transverse cordotomy, the coblator, a minimally invasive, low-thermal technology, has been increasingly used in otolaryngology. Objective: To investigate outcomes associated with coblation to treat BVFI. Design, Setting, and Participants: A retrospective case series was conducted between January 2012 and June 2017 including 19 patients with BVFI who underwent cordotomy by coblation in a single tertiary care institution. Main Outcomes and Measures: Clinical, operative, and health status data for all patients were reviewed. Quality of life was measured by the EuroQol 5-Dimensions (EQ-5D), and the Voice Handicap Index (VHI) was used to measure vocal cord function. Results: Nineteen patients were eligible for inclusion, 15 of which underwent cordotomy by coblation for BVFI without stenosis. Mean age was 57 years with 13 (68%) women. The etiology of BVFI included thyroidectomy in 8 (42%) patients and prolonged intubation in 7 (37%). Mean length of surgery for BVFI without stenosis was 17 minutes; mean operating room (OR) time was 63 minutes compared with 88 scheduled OR minutes (effect size, 25 minutes; 95% CI, 9 to 40 minutes). During follow-up, 4 (27%) of these patients developed granulation tissue postoperatively. Following surgery, patient-reported shortness of breath significantly improved, with 10 of 14 (71%; 95% CI, 45% to 88%) patients with some level of preoperative breathing difficulty experiencing improvement in their breathing. Stridor also significantly improved, with 10 of 12 (83%; 95% CI, 55% to 95%) patients with some level of preoperative stridor improved after surgery. The EQ-5D results trended toward improvement postoperatively (0.67 to 0.80; effect size, 0.13; 95% CI, -0.10 to 0.34). The functional (22 to 12; effect size, -10; 95% CI, -19 to 2), emotional (23 to 11; effect size, -12; 95% CI, -23 to -3), and total VHI all significantly improved (68 to 39; effect size, -29; 95% CI, -49 to -8). Conclusions and Relevance: Initial outcomes of cordotomy by coblation revealed that this technique was a safe and efficient approach to treating BVFI. Coblation was associated with significant reduction in OR time compared with scheduled time, and patients experienced significant improvement in shortness of breath, stridor, and vocal cord function. PMID- 29242923 TI - Novel Antithrombotic Drugs and Intraocular Bleeding: The Importance of Observational Data and Future Perspectives. PMID- 29242924 TI - Teaching Low-Income Spanish-Speaking Caregivers to Implement EMT en Espanol With Their Young Children With Language Impairment: A Pilot Study. AB - Purpose: This study examined the effectiveness of teaching low-income Spanish speaking caregivers of young children with language impairment a naturalistic language intervention, EMT en Espanol. Method: A single-case, multiple-baseline, across-behaviors design replicated across 3 caregiver-child dyads was used to examine the effects of teaching core EMT en Espanol strategies. The training program utilized the Teach-Model-Coach-Review instructional approach to teach strategies to support children's language development in Spanish. All sessions were at home and in Spanish. Results: Caregivers increased their use of matched turns, target talk, expansions, and a communication elicitation procedure following training on each specific skill. Additionally, caregivers generalized increased use of matched turns and target talk to an untrained activity during the intervention period and maintained their behavior 1 month after completing intervention. Two of 3 caregivers generalized their use of expansions, and 1 caregiver generalized her use of a communication elicitation procedure. Modest effects on the child's number of different words were observed for 2 of the 3 target children over the course of the intervention sessions. All 3 children demonstrated increases in total spontaneous words. Conclusion: Spanish-speaking caregivers were able to implement naturalistic language teaching strategies with their young children with language impairment in a relatively short-term intervention. PMID- 29242925 TI - Mental Health and Nasal Function. PMID- 29242926 TI - Data-Driven Mammography Screening Practices. PMID- 29242927 TI - Data-Driven Mammography Screening Practices-Reply. PMID- 29242929 TI - Management of the Node-Positive Axilla in Breast Cancer in 2017: Selecting the Right Option. PMID- 29242930 TI - Optical Coherence Tomography Transecting an Omega Retinal Venous Loop en Face in a Patient With Diabetic Retinopathy. PMID- 29242928 TI - Association of Sex With the Global Burden of Cataract. AB - Importance: Eye disease burden could help guide health policy making. Differences in cataract burden by sex is a major concern of reducing avoidable blindness caused by cataract. Objective: To investigate the association of sex with the global burden of cataract by year, age, and socioeconomic status using disability adjusted life-years (DALYs). Design, Setting, and Participants: This international, comparative burden-of-disease study extracted the global, regional, and national sex-specific DALY numbers, crude DALY rates, and age standardized DALY rates caused by cataract by year and age from the Global Burden of Disease Study 2015. The DALY data were collected from January 1, 1990, through December 31, 2015, for ever 5 years. The human development index (HDI) in 2015 was extracted as an indicator of national socioeconomic status from the Human Development Report. Main Outcomes and Measures: Comparisons of sex-specific DALY estimates due to cataract by year, age, and socioeconomic status at the global level. Paired Wilcoxon signed rank test, Pearson correlation, and linear regression analyses were performed to evaluate the socioeconomic-associated sex differences in cataract burden. Results: Differences in rates of cataract by sex were similar between 1990 and 2015, with age-standardized DALY rates of 54.5 among men vs 65.0 among women in 1990 and 52.3 among men vs 67.0 among women in 2015. Women had higher rates than men of the same age, and sexual differences increased with age. Paired Wilcoxon signed rank test revealed that age standardized DALY rates among women were higher than those among men for each HDI based country group (z range, -4.236 to -6.093; P < .001). The difference (female minus male) in age-standardized DALY rates (r = -0.610 [P < .001]; standardized beta = -0.610 [P < .001]) and the female to male age-standardized DALY rate ratios (r = -0.180 [P = .02]; standardized beta = -0.180 [P = .02]) were inversely correlated with HDI. Conclusions and Relevance: Although global cataract health care is progressing, sexual differences in cataract burden showed little improvement in the past few decades. Worldwide, women have a higher cataract burden than men. Older age and lower socioeconomic status are associated with greater differences in rates of cataract by sex. Our findings may enhance public awareness of sexual differences in global cataract burden and emphasize the importance of making sex-sensitive health policy to manage global vision loss caused by cataract. PMID- 29242931 TI - Ultra-Wide-Field Imaging of Spontaneously Dislocated Aphakic Soemmering Ring. PMID- 29242932 TI - Substantial Visual Field Loss Associated With Giant Optic Disc Drusen. PMID- 29242933 TI - Arcuate Retinal Nerve Fiber Layer Defect After Laser Photocoagulation for Diabetic Macular Edema. PMID- 29242936 TI - Role of Maternal Race on Algorithms Predicting Retinopathy of Prematurity. PMID- 29242938 TI - Cardiovascular Guideline Skepticism vs Lifestyle Realism? PMID- 29242939 TI - Mental Health and Nasal Function-Reply. PMID- 29242937 TI - Paclitaxel With and Without Pazopanib for Persistent or Recurrent Ovarian Cancer: A Randomized Clinical Trial. AB - Importance: Ovarian cancer is the leading cause of gynecologic cancer deaths in the United States. Pazopanib is an oral, multitarget kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptors alpha and beta; and proto-oncogene receptor tyrosine kinase (c-KIT). Objective: To estimate the progression-free survival (PFS) hazard ratio (HR) of weekly paclitaxel and pazopanib compared with weekly paclitaxel and placebo in women with recurrent ovarian cancer. Secondary objectives included frequency and severity of adverse events, proportion responding, and overall survival (OS) in each arm. Translational research objectives included exploring the association between possible biomarkers and single-nucleotide polymorphisms in vascular endothelial growth factor A, interleukin 8, and hypoxia-inducible factor 1alpha; and PFS, OS, and proportion responding. Design, Setting, and Participants: A randomized, placebo-controlled, double-blind phase 2 study was conducted at 26 participating institutions. Patients were enrolled between December 12, 2011, and April 22, 2013. Data were frozen on August 11, 2014. Participants were patients with persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with 1 to 3 prior regimens and performance status of 0 to 2. One hundred six patients enrolled; 100 were evaluable for toxic effects. Interventions: All patients received paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 every 28 days and were randomized 1:1 to pazopanib 800 mg orally daily or placebo. Main Outcomes and Measures: The primary end point was PFS. The study was designed to detect a 37.5% reduction in the hazard with 80% power (alpha = 10%). Results: A total of 106 women (median age [range], 61 [35-87] years; 88 [83%] white) were enrolled. Study arms were well balanced for age, performance status, measurable disease, and prior bevacizumab. Proportion responding was 14 of 44 (31.8%) vs 10 of 44 (22.7%) for pazopanib plus paclitaxel vs paclitaxel alone. Median PFS was 7.5 vs 6.2 months for pazopanib plus paclitaxel vs paclitaxel alone, respectively (HR, 0.84; 90% CI, 0.57-1.22; P = .20). Median OS was 20.7 vs 23.3 months for pazopanib plus paclitaxel vs paclitaxel alone (HR, 1.04; 90% CI, 0.60-1.79; P = .90). Severe hypertension was more common on the pazopanib plus paclitaxel arm (relative risk, 12.0; 95% CI, 1.62-88.84). More patients discontinued treatment on the paclitaxel arm for disease progression (34 of 52 [65.4%] vs 17 of 54 [31.5%]), and more on the pazopanib plus paclitaxel arm for adverse events (20 of 54 [37%] vs 5 of 52 [9.6%]). No association was found between single-nucleotide polymorphisms (interleukin 8 and hypoxia-inducible factor 1alpha) and OS and proportion responding. Patients with VEGFA CC genotype may be more resistant to weekly paclitaxel than those with the AC or AA genotype, with 1 of 14 (7%), 3 of 15 (20%), and 4 of 8 (50%) responding, respectively. Conclusions and Relevance: The combination of pazopanib plus paclitaxel is not superior to paclitaxel in women with recurrent ovarian cancer. Trial Registration: clinicaltrials.gov Identifier: NCT01468909. PMID- 29242940 TI - Clinics in diagnostic imaging (182). Acute descending aortic dissection with aortic root retrograde extension. AB - A 77-year-old man presented with acute-onset severe chest pain radiating to the back and elevated blood pressure. Multiphasic computed tomography of the aorta revealed an intimal tear in the descending thoracic aorta which extended both retrograde to the aortic root and antegrade to the infra-renal abdominal aorta. The initial impression, that the images showed a Stanford type B aortic dissection, was because the portion of the false lumen that extended beyond the aortic arch remained unopacified even on delayed phases, making it challenging to assess the extent of the dissection flap. Bedside transthoracic echocardiography revealed a pericardial effusion. Cardiac tamponade ensued and the patient passed away shortly after presentation. This case highlights the need for early and accurate imaging assessment of acute aortic dissection, including accurate identification of the site of intimal tear and the extent of the dissection flap. PMID- 29242942 TI - Erratum: Establishment of a minimally invasive cardiac surgery programme in Singapore. PMID- 29242941 TI - Physical therapy in the management of frozen shoulder. AB - Frozen shoulder, also known as adhesive capsulitis, is a common presentation in the primary care setting and can be significantly painful and disabling. The condition progresses in three stages: freezing (painful), frozen (adhesive) and thawing, and is often self-limiting. Common conservative treatments include nonsteroidal anti-inflammatory drugs, oral glucocorticoids, intra-articular glucocorticoid injections and/or physical therapy. However, many physicians may find themselves limited to prescribing medications for treatment. This article elaborates on physical therapy exercises targeted at adhesive capsulitis, which can be used in combination with common analgesics. PMID- 29242943 TI - Corrigendum: Clinics in diagnostic imaging (180). PMID- 29242944 TI - A laparoscopic revelation: incidental nodule in a patient with bilateral phaeochromocytoma in multiple endocrine neoplasia Type 2A. PMID- 29242945 TI - Degree of Skin Barrier Disruption Affects Lipid Organization in Regenerated Stratum Corneum. AB - Previously, a skin barrier repair model was developed to examine the effect of formulations on the lipid properties of compromised skin. In this model, the lipid organization mimics that of several skin diseases with impaired skin barrier and less dense lateral lipid organization. In addition, parakeratosis was occasionally observed. The present study investigated whether the extent of initial barrier disruption affects lipid organization and parakeratosis in regenerated stratum corneum. After barrier disruption and stratum corneum regeneration the fraction of lipids adopting a less dense lateral organization gradually increased with increasing degree of barrier disruption. Only when 75% of the stratum corneum was removed, were parakeratosis and a change in lamellar organization observed. This demonstrates the possibility of using the skin barrier repair model to study the effects of formulations on compromised skin in which the presence of parakeratosis and lipid organization can be modified by the extent of barrier disruption. PMID- 29242946 TI - Clinical, Viral and Genetic Characteristics of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) in Shanghai, China. AB - DRESS is one of the most severe drug reactions. The aim of this retrospective study was to summarize the clinical presentation, genetic predisposition and prognostic factors of DRESS. A total of 52 patients with DRESS, who were inpatients at a medical referral centre in Shanghai, China, from January 2011 to December 2016, were analysed retrospectively. All the patients had skin eruption, 83% had liver involvement, and <=10% had other organ involvement. Mean cost of hospitalization was US$5,511+/-3,050. The 3 most common causative agents were allopurinol (18/52; 35%), salazosulphapyridine (11/52; 21%) and carbamazepine (5/52; 10%). HLA-B*5801 and HLA-B*1302 were associated with allopurinol-induced DRESS. HLA-B*1301 was related to salazosulphapyridine-induced DRESS. The mortality rate was 6% (3/52). Epstein-Barr virus DNA was found in 10 patients (19%) and indicated a poor prognosis. Human herpes virus 6 DNA was detected in 17 patients (33%) and was associated with autoimmune sequelae. Due to its high medical cost and sometimes poor prognosis, prevention of DRESS should be a high priority. PMID- 29242947 TI - The Position of Targeted Next-generation Sequencing in Epidermolysis Bullosa Diagnosis. AB - The precise classification of epidermolysis bullosa (EB) into 4 main types and more than 30 subtypes is based on the level of skin cleavage, as well as clinical and molecular features, and is crucial for early prognostication, case management, genetic counselling and prenatal or pre-implantation diagnosis. We report here the molecular pathology of 40 consecutive cases of suspected EB, which were investigated by immunofluorescence mapping (IFM) and/or by a targeted next-generation sequencing (NGS) multi-gene panel. IFM correctly established the EB subtype in 76% of cases, while the molecular pathology was completely elucidated in 90% of cases by the targeted NGS multi-gene panel. Thirteen previously unreported mutations in EB genes were identified. In cases with unclear clinical and IFM findings, mutations were found by NGS in previously unexpected genes. IFM was useful in delivering fast results in newborns, and in indicating the consequences of the variants of uncertain significance on protein level. This study underscores the efficacy of the strategy of combining targeted NGS with IFM in resolving unusual EB phenotypes. It also suggests that, despite technological advances, careful clinical evaluation and deep phenotyping remains a crucial factor that dictates successful diagnosis of EB. PMID- 29242948 TI - Light and Laser Modalities in the Treatment of Cutaneous Sarcoidosis: A Systematic Review. AB - Sarcoidosis is a systemic non-caseating granulomatous disease of unknown aetiology. Cutaneous manifestations are present in approximately 10-30% of the patients with the systemic form. Therapy is indicated in case of disabling symptoms, organ dysfunction or cosmetically distressing manifestation. Despite different therapeutic possibilities, cutaneous sarcoidosis remains exceptionally difficult to treat. Light and laser therapy may be a promising alternative. In this systematic review, we summarised the available treatments according to the literature concerning light and laser therapy for cutaneous sarcoidosis. Publications written in English and German, published between January 1990 and July 2016 in the database PubMed, MEDLINE, Embase, and Scopus were analysed. Light therapy with intense pulsed light, photodynamic therapy, and ultraviolet A light therapy, as well as laser therapy with pulsed dye laser, YAG laser, and Q switched ruby laser were described. The results are based on individual case reports and small case series. Randomised controlled studies are lacking. PMID- 29242949 TI - [Rare renal tumors]. PMID- 29242950 TI - Superior canal dehiscence syndrome : Diagnosis with vestibular evoked myogenic potentials and fremitus nystagmus. AB - BACKGROUND: Superior canal dehiscence syndrome (SCDS) is a relatively rare neurotological disorder that is characterized by a heterogeneous clinical picture. Recently, vestibular evoked myogenic potential (VEMP) measurement was established for the diagnosis of SCDS. In the present study, a case series of patients with SCDS were analyzed, with a focus on VEMP. METHODS: Four patients with SCDS were prospectively examined with ocular VEMP (oVEMP) and cervical VEMP (cVEMP). The clinical features and the standard audiovestibular test battery results are summarized and analyzed. The diagnostic accuracy of VEMP testing is evaluated. RESULTS: The increased oVEMP amplitudes had a specificity of 100% in this patient population. All patients had normal caloric function and head impulse testing. The Tullio sign was observed in two patients. Three patients had autophony. The air-bone gap was not greater than 10 dB in any of the patients. Two patients had marked fremitus nystagmus. All patients had a bony dehiscence of the superior semicircular canal on computed tomography imaging. CONCLUSION: The subjective and clinical features in this case series of SCDS patients were heterogeneous. However, objective oVEMP testing had the highest diagnostic value. Furthermore, we describe a new diagnostic clinical sign: fremitus nystagmus. PMID- 29242951 TI - Proposal of a new preliminary scoring tool for early identification of significant blunt bowel and mesenteric injuries in patients at risk after road traffic crashes. AB - PURPOSE: Blunt bowel and mesenteric injuries (BBMI) are regularly missed by abdominal computed tomography (CT) scans. The aim of this study was to develop a risk assessment tool for BBMI to help clinicians in decision-making for blunt trauma after road traffic crashes (RTCs). METHODS: Single-center retrospective study of trauma patients from January 2010 to April 2015. All patients admitted to our hospital after blunt trauma following RTCs and CT scan at admission were assessed. RESULTS: Of the 394 patients included, 78 (19.8%) required surgical exploration and 34 (43.6%) of these had a significant BBMI. A univariate and multivariate analysis were performed comparing patients with BBMI (n = 34) and patients without BBMI (n = 360). A score with a range from 0 to 13 was created. Scores from 8 to 9 were associated with 5-25% BBMI risk. The power of this new score >= 8 to predict a surgically significant BBMI had a sensitivity of 96%, specificity of 86.4%, positive predictive value (PPV) of 48% and negative predictive value (NPV) of 99.4%. CONCLUSION: This score could be a valuable tool for the management of blunt trauma patients after RTA without a clear indication for laparotomy but at risk for BBMI. The outcome of this study suggests selective diagnostic laparoscopy for a score >= 8 in obtunded patients and >= 10 in all other. To assess the value and accuracy of this new score, a prospective validation of these retrospective findings is due. PMID- 29242952 TI - Unicortical self-drilling external fixator pins reduce thermal effects during pin insertion. AB - INTRODUCTION: External fixation is associated with the risk of pin loosening and pin infection potentially associated to thermal bone necrosis during pin insertion. OBJECTIVE: This study aims to investigate if the use of external fixator systems with unicortical pins reduces the heat production during pin insertion compared to fixators with bicortical pins. METHODS: Porcine bone specimens were employed to determine bone temperatures during insertion of fixator pins. Two thermographic cameras were used for a simultaneous temperature measurement on the bone surface (top view) and a bone cross-section (front view). Self-drilling unicortical and bicortical pins were inserted at different rotational speeds: (30-600) rpm. Maximum and mean temperatures of the emerging bone debris, bone surface and bone cross-section were analyzed. RESULTS: Maximum temperatures of up to 77 +/- 26 degrees C were measured during pin insertion in the emerging debris and up to 42 +/- 2 degrees C on the bone surface. Temperatures of the emerging debris increased with increasing rotational speeds. Bicortical pin insertion generated significantly higher temperatures at low insertion speed (30 rpm) CONCLUSION: The insertion of external fixator pins can generate a considerable amount of heat around the pins, primarily emerging from bone debris and at higher insertion speeds. Our findings suggest that unicortical, self-drilling fixator pins have a decreased risk for thermal damage, both to the surrounding tissue and to the bone itself. PMID- 29242953 TI - [Borderline and malignant mesenchymal tumors of the abdomen]. AB - BACKGROUND: Soft tissue sarcomas are most common mesenchymal malignancies in the abdomen. Their radiologic features are often unspecific and establishing a differential diagnosis to other pathologies can be difficult. OBJECTIVES: This review presents a selection of the most common mesenchymal abdominal tumors and their imaging characteristics, as well as the associated differential diagnoses. Knowledge of fundamental pathologic, anatomic and radiologic features of these malignancies is crucial for the differential diagnosis and key in clinical decision making and subsequent selection of an appropriate therapeutic regimen. PMID- 29242954 TI - [Abdominal lymphatic malformations. German version]. AB - BACKGROUND: Abdominal lymphatic malformations (LM) are relatively rare findings in the differential diagnosis of focal abdominal lesions; however, they represent a challenge especially in younger patients. The aim of this review article is to provide up-to-date information about the different kinds of LM manifestations. In addition, related syndromes and typical imaging features to facilitate the diagnosis are discussed. RESULTS: The clinical presentation of abdominal LM is unspecific, whereby most are asymptomatic and comprise incidental findings of thin-walled cystic masses anywhere in the abdomen. The fluid in the cystic masses may be proteinaceous, contain blood, or be infected. Radiological imaging features overlap with other cystic diseases; hallmark in LM is a lack of a solid component and exclusive enhancement of the walls and septae. CONCLUSION: In cystic abdominal masses in early childhood or young adults, abdominal LM must be taken into account by the radiologist. Newly defined entities in this spectrum of diseases are central conducting lymphatic anomaly (CCLA) and generalized lymphatic anomaly (GLA). PMID- 29242955 TI - [An exceptional hematologic case]. PMID- 29242956 TI - [Odontogenic tumours and bone tumours of the jaw : Changes in the new WHO classification]. AB - At the beginning of 2017, the fourth edition of the WHO Classification of Head and Neck Tumours was published, 12 years after the previous version. Notably, various changes introduced in the third edition have been revised so in some aspects the current classification has more similarities to the second edition of 1992 than to the third edition. A central goal of the editors was to create a classification that can be used worldwide. Molecular findings have therefore been included and updated but are not mandatory for establishing a diagnosis. This article discusses and comments on the most important changes implemented in the classification of gnathic lesions. PMID- 29242957 TI - Transvaginal levator myorrhaphy for posthysterectomy vaginal vault prolapse repair. AB - INTRODUCTION AND HYPOTHESIS: Posthysterectomy vaginal vault prolapse repair represents a surgical challenge. Surgical management can be successfully achieved with native-tissue repair through levator myorrhaphy. Despite low morbidity, levator myorrhaphy is not a common procedure. The aim of the video is to provide anatomic views and surgical steps necessary to achieve a successful transvaginal levator myorrhaphy for vaginal vault prolapse repair. METHODS: A 72-year-old woman with symptomatic stage IV vaginal vault prolapse was admitted for transvaginal levator myorrhaphy according to the described technique. RESULTS: Surgical repair was successfully achieved without complications. The final examination revealed good apical support and preservation of vaginal length. This step-by-step video tutorial may represent an important tool to improve surgical know how. CONCLUSIONS: Transvaginal levator myorrhaphy provides an alternative technique for apical support without using prosthetic materials. This technique can be indicated when abdominal approach or synthetic device are not recommended or when peritoneum opening may be challenging. However, due to its possible constricting effect, it should be reserved to sexually inactive patients. PMID- 29242958 TI - Impact of radical hysterectomy on the transobturator sling pathway: a retrospective three-dimensional magnetic resonance imaging study. AB - INTRODUCTION AND HYPOTHESIS: Morphological and functional anomalies of the urethra may cause stress urinary incontinence after radical hysterectomy (RH). We introduce a novel three-dimensional (3D) magnetic resonance imaging (MRI) technique to assess the impact of RH on the transobturator sling pathway. METHODS: 3D-MRI reconstruction models were retrospectively developed for the measurement of various parameters before and after RH, including puncture angle, orientation and distance from the midurethral puncture site to the obturator membrane (DUO), in 31 patients with cervical cancer. Additionally, the correlations between DUO and body height and interspinal diameter were evaluated. RESULTS: No significant differences were noted between the preoperative and postoperative inclination angle (-7.1 +/- 33.5 degrees vs. -0.68 +/- 23.9 degrees , ranges -62.4 to 46.8 degrees vs. -54.1 to 42.2 degrees , respectively) or between the preoperative and postoperative left and right mean rotation angles (left 69.0 +/- 8.0 degrees vs. 67.8 +/- 9.2 degrees ; right 65.1 +/- 8.38 degrees vs. 64.3 +/- 10.5 degrees ). Similarly, there were no statistically or clinically significant differences between the preoperative and postoperative DUO, although slight differences were noted between the two sides before and after RH (P = 0.018 and P = 0.023, respectively). None of the parameters differed significantly between the groups with and without postoperative urodynamic stress incontinence. Further, there was no clinically significant correlation between DUO and height or interspinal diameter. CONCLUSIONS: The sling procedure via the transobturator approach is technically safe from a 3D anatomical standpoint. However, wide variability in the anatomical parameters must be taken into account when planning the procedure. PMID- 29242959 TI - Striking lack of visualization of striatum on 18F-FDG brain PET in chorea acanthocytosis. PMID- 29242960 TI - Incidental identification of osteoid osteoma by 68Ga-PSMA PET/CT. PMID- 29242961 TI - [Important information regarding the guideline for (allergen-)specific immunotherapy (SIT)]. PMID- 29242963 TI - Effect of Strontium Ranelate on the Muscle and Vertebrae of Ovariectomized Rats. AB - Osteoporosis is often accompanied by sarcopenia. The effect of strontium ranelate (SR) on muscle tissue has not been investigated sufficiently. In this study, the effect of different SR treatments on muscle was studied. Additionally, the lumbar vertebrae were analyzed. Three-month-old female rats were divided into five groups (n = 12): Group 1: untreated (NON-OVX); Group 2: ovariectomized and left untreated (OVX); Group 3: SR after OVX until the study ended (13 weeks, SR prophylaxis and therapy = pr+th); Group 4: OVX and SR for 8 weeks (SR prophylaxis = pr); Group 5: SR for 5 weeks from the 8 week after OVX (SR therapy = SR th). SR was applied in food (630 mg/kg body weight). The size of muscle fibers, capillary density, metabolic enzymes, and mRNA expression were assessed in soleus, gastrocnemius, and longissimus muscles. The vertebral bodies underwent micro-CT, biomechanical, and ashing analyses. In general, SR did not alter the muscle histological parameters. The changes in fiber size and capillary ratio were related to the body weight. Myostatin mRNA was decreased in Sr pr+th; protein expression was not changed. SR th led to increase in mRNA expression of vascular endothelial growth factor (Vegf-B). In lumbar spine, SR pr+th enhanced biomechanical properties, bone mineral density, trabecular area, density, and thickness and cortical density. The reduced calcium/phosphate ratio in the SR pr+th group indicates the replacement of calcium by strontium ions. SR has no adverse effects on muscle tissue and it shows a favorable time-dependent effect on vertebrae. A functional analysis of muscles could verify these findings. PMID- 29242962 TI - [Mucous membrane pemphigoid]. AB - Mucous membrane pemphigoid (MMP) is a pemphigoid disease defined by the presence of autoantibodies against the dermal-epidermal junction and predominant involvement of mucous membranes. Diagnosis is made by the clinical presentation and linear deposits of IgG and/or IgA and/or C3 at the dermal-epidermal junction by direct immunofluorescence microscopy of a perilesional biopsy. Circulating autoantibodies can be detected in most patients by indirect immunofluorescence microscopy on salt-split human skin as well as ELISA and immunoblotting with recombinant and cell-derived target antigens. For systemic treatment of MMP, corticosteroids, dapsone, mycophenolates, and azathioprine are applied. In severe cases and in cases with rapid disease progression cyclophosphamide, rituximab, high-dose intravenous immunoglobulins, and immunoadsorption are used. For the successful management of MMP patients, close cooperation with dentists, ophthalmologists, ENT specialists, gynecologists, and gastroenterologists is essential. PMID- 29242964 TI - [Bone substitute materials as local drug carriers : Current status of substitutes of various origins]. AB - BACKGROUND: Autologous bone grafts (autografts) are used in surgery for defect filling and impaction grafting during hip socket and femur reconstruction. Because of their superior osteoinductive capacity, autografts are considered the "gold standard" for these treatments. However, because of a better cost-benefit ratio, allografts are also often used. In the case of limited donor availability for autologous or allogenic bone grafts, bone substitute materials (BSMs) are a reasonable alternative or supplement. BSM are based on or combine different substances. Growth factors of the bone morphogenetic protein family BMP are recombinant proteins that specifically induce the growth of bone and cartilage tissue. CHARACTERISTICS: One advantage of BSM is the option to combine them with several anti-infective agents. The choice of the anti-infective substance should not only be based on the antimicrobial efficacy, but should also take into account possible dose-dependent cellular and pharmacological side effects at the implantation site. Thus, microbiologists, pharmacists and surgeons should decide together which combination is the most appropriate. COMBINATION PRODUCTS: BSM with active agent additives are considered combination products that are characterized by a main effect (bone replacement function) and a secondary effect (prophylaxis of bacterial recolonization of BSM). Both functions must be thoroughly (clinically) evidenced in the course of the registration process as a class III medical device. Drug authorities evaluate the active agents, their function and corresponding indication. Currently, only a few combination products are available on the market. As a consequence of the only limited availability of such commercial combination products, surgeons in clinical practice often manually add the active agent to BSM in the theatre prior to implantation. However, such a customized addition of antibiotics places the surgeon in a situation of a manufacturer where he assumes liability for the product. PMID- 29242965 TI - [Bone banks : The state-of-the-art]. AB - Bone banks are responsible for the collection, production, testing, packaging, storage and delivery of osseous grafts. In compliance with legal and quality requirements, it is their main task to ensure the biological properties and the microbiological safety of the transplants as well. German legal requirements for bone banking are explained and current standards with respect to donor selection, laboratory tests and tissue processing, as well as labeling are discussed. Production and preparation procedures should include a validated microbiological inactivation method that largely preserves the biological properties of the tissue. PMID- 29242966 TI - CYP1A1 genetic polymorphism is a promising predictor to improve chemotherapy effects in patients with metastatic breast cancer treated with docetaxel plus thiotepa vs. docetaxel plus capecitabine. AB - PURPOSE: A prospective study was performed to compare the outcome for metastatic breast cancer (MBC) patients treated with docetaxel plus thiotepa (DT) or docetaxel plus capecitabine (DC), and to explore the value of CYP1A1*2C polymorphisms in predicting clinical efficacy of these chemotherapies. METHODS: MBC patients (n = 130) were randomized to treatment with DT (n = 65) or DC (n = 65). Response rate, disease control rate, progression-free and overall survival were monitored. Genotyping of CYP1A1*2C was performed in all patients. RESULTS: DT and DC produced similar overall disease control rates (76.9 vs 69.2%), median PFS (6.7 vs. 7.5 months) and OS (20.1 vs. 21.0 months) (P > 0.05 for all comparisons); however, DT exhibited a higher rate of control of localized liver metastases (78.6 vs 41.2%, P = 0.023). Among patients homozygous for wild-type CYP1A1*1 genotype (AA), DT treatment was associated with a significantly longer PFS (8.4 vs. 6.4 months, P = 0.019) and OS (33.4 vs. 15.8 months, P = 0.018). Conversely, among patients carrying the variant CYP1A1*2C genotype (AG/GG), DC treatment was associated with a significantly longer PFS (8.4 vs. 5.5 month, P = 0.005), and OS (28.5 vs. 19.6 months, P = 0.010). After adjusting for competing risk factors, CYP1A1*2C genotype was confirmed to be an independent predictor of PFS and OS for each chemotherapy combination. CONCLUSIONS: Overall, DT and DC result in similar clinical efficacy for MBC patients; however, efficacy for each therapy differs depending on CYP1A1*2C genotype. PMID- 29242967 TI - Contrast-associated acute kidney injury is a myth: Yes. PMID- 29242968 TI - Contrast-associated acute kidney injury is a myth: No. PMID- 29242969 TI - Age-associated blood pressure distributions in paediatric intensive care units differ from healthy children. PMID- 29242970 TI - Contrast-associated acute kidney injury is a myth: We are not sure. PMID- 29242971 TI - Effects of hydration on plasma copeptin, glycemia and gluco-regulatory hormones: a water intervention in humans. AB - PURPOSE: High plasma copeptin, a marker of vasopressin, predicts diabetes mellitus. We tested if copeptin could be suppressed by increased water intake in healthy individuals, and if a water-induced change in copeptin was accompanied by altered concentrations of glucose, insulin or glucagon. METHODS: Thirty-nine healthy individuals underwent, in random order, 1 week of high water intake (3 L/day on top of habitual intake) and 1 week of normal (habitual) fluid intake (control). Fasting plasma concentrations of copeptin, glucose, insulin and glucagon were compared between the ends of both periods. Furthermore, acute copeptin kinetics were mapped for 4 h after ingestion of 1 L of water. RESULTS: After acute intake of 1 L water, copeptin was significantly reduced within 30 min, and reached maximum reduction within 90 min with on average 39% reduction (95% confidence interval (95 CI) 34-45) (p < 0.001) and remained low the entire test period (4 h). One week of increased water intake led to a 15% reduction (95 CI 5-25) (p = 0.003) of copeptin compared to control week. The greatest reduction occurred among subjects with habitually high copeptin and concentrated urine ("water-responders"). Water-responders had significant water-induced reduction of glucagon, but glucose and insulin were unaffected. CONCLUSIONS: Both acute and 1 week extra water intake potently reduced copeptin concentration. In those with the greatest decline (water-responders), who are typically low drinkers with high baseline copeptin, water induced a reduction in fasting glucagon. Long-term trials assessing the effect of water on glucometabolic traits should focus on low water drinkers with high copeptin concentration. PMID- 29242973 TI - Re: Estimation of neonatal outcome artery pH value according to CTG interpretation of the last 60 min before delivery: a retrospective study. Can the outcome pH value be predicted? PMID- 29242972 TI - Perioperative pain after robot-assisted versus laparoscopic rectal resection. AB - BACKGROUND: In order to improve the surgical treatment of rectal cancer, robot assisted laparoscopy has been introduced. The robot has gained widespread use; however, the scientific basis for treatment of rectal cancer is still unclear. The aim of this study was to investigate whether robot-assisted laparoscopic rectal resection cause less perioperative pain than standard laparoscopic resection measured by the numerical rating scale (NRS score) as well as morphine consumption. METHODS: Fifty-one patients were randomized to either laparoscopic or robot-assisted rectal resection at the Department of Surgery at Aarhus University Hospital in Denmark. The intra-operative analgetic consumption was recorded prospectively and registered in patient records. Likewise all postoperative medicine administration including analgesia was recorded prospectively at the hospital medical charts. All morphine analogues were converted into equivalent oral morphine by a converter. Postoperative pain where measured by numeric rating scale (NRS) every hour at the postoperative care unit and three times a day at the ward. RESULTS: Opioid consumption during operation was significantly lower during robotic-assisted surgery than during laparoscopic surgery (p=0.0001). However, there were no differences in opioid consumption or NRS in the period of recovery. We found no differences in length of surgery between the two groups; however, ten patients from the laparoscopic group underwent conversion to open surgery compared to one from the robotic group (p=0.005). No significant difference between groups with respect to complications where found. CONCLUSIONS: In the present study, we found that patients who underwent rectal cancer resection by robotic technique needed less analgetics during surgery than patients operated laparoscopically. We did, however, not find any difference in postoperative pain score or morphine consumption postoperatively between the robotic and laparoscopic group. PMID- 29242974 TI - Effect of intramural fibroid on uterine and endometrial vascularity in infertile women scheduled for in-vitro fertilization. AB - PURPOSE: To study the effect of intramural fibroids on uterine and endometrial vascularity in infertile women scheduled for in-vitro fertilization (IVF). METHODS: 3D power Doppler was used to measure the endometrial volume and blood flow indices in 182 women with intramural fibroids not affecting the uterine cavity and compared them to a matched control group without fibroids. RESULTS: There was significantly increased vascularity in the endometrium of the fibroid group as denoted by higher endometrial VI (p = 0.018), FI (p = 0.027) and Endometrial VFI. No significant difference in mean uterine artery RI (p = 0.277) or PI (p = 0.187). Among the fibroid group 62.6% had a fibroid > 4 cm. Women with fibroids > 4 cm had a significantly higher Endometrial FI (p = 0.037), and VFI (p = 0.02). Uterine artery blood flow was not affected, as uterine RI (p = 0.369) and PI (p = 0.321) were not statistically different. Compared with the control group (non fibroid), women with fibroids > 4 cm had significantly higher endometrial VI (p = 0.013), FI (p = 0.004), and VFI (p < 0.001), whereas women with fibroid <= 4 cm had no statistically significant differences in VI (p = 0.292), FI (p = 0.198), and VFI (p = 0.304). CONCLUSION: Intramural fibroids > 4 cm significantly increase endometrial vascularity. This increase in blood flow may be a factor that affects the outcome of IVF. PMID- 29242975 TI - Reinterpretation in visual imagery is possible without visual cues: a validation of previous research. AB - Is visual reinterpretation of bistable figures (e.g., duck/rabbit figure) in visual imagery possible? Current consensus suggests that it is in principle possible because of converging evidence of quasi-pictorial functioning of visual imagery. Yet, studies that have directly tested and found evidence for reinterpretation in visual imagery, allow for the possibility that reinterpretation was already achieved during memorization of the figure(s). One study resolved this issue, providing evidence for reinterpretation in visual imagery (Mast and Kosslyn, Cognition 86:57-70, 2002). However, participants in that study performed reinterpretations with aid of visual cues. Hence, reinterpretation was not performed with mental imagery alone. Therefore, in this study we assessed the possibility of reinterpretation without visual support. We further explored the possible role of haptic cues to assess the multimodal nature of mental imagery. Fifty-three participants were consecutively presented three to be remembered bistable 2-D figures (reinterpretable when rotated 180 degrees ), two of which were visually inspected and one was explored hapticly. After memorization of the figures, a visually bistable exemplar figure was presented to ensure understanding of the concept of visual bistability. During recall, 11 participants (out of 36; 30.6%) who did not spot bistability during memorization successfully performed reinterpretations when instructed to mentally rotate their visual image, but additional haptic cues during mental imagery did not inflate reinterpretation ability. This study validates previous findings that reinterpretation in visual imagery is possible. PMID- 29242976 TI - A rare case of concomitant cervical disc herniation and intradural meningioma treated with one-stage posterior surgery. AB - STUDY DESIGN: Case report. PURPOSE: To present a rare case of cervical disc herniation concomitant with intradural meningioma which was successfully treated using a single one-stage posterior surgery of tumor resection and transdural discectomy. Coexistence of symptomatic disc herniation and intra-spinal tumor in the same cervical segment is extremely rare. Usually, two-stage anterior and posterior surgeries are needed to treat two conditions, respectively. One-stage posterior surgery to treat two pathologies simultaneously has not been reported in the literature. METHODS AND RESULTS: A 76-year-old man presented with leg weakness and numbness for 6 months and left arm pain for 2 months. Contrast MR imaging revealed C3/4 intervertebral disc herniation and a hyperintense intradural lesion at the right portion of C3 canal. A one-stage posterior surgery, including C3/4 laminectomy, intradural tumor resection, transdural C3/4 discectomy, and C3/4 lateral mass instrumentation and fusion, was performed to treat two distinct pathologies together. The patient's arm pain and numbness disappeared right after the surgery and symptoms of myelopathy fully recovered at 6-month follow-up. Histological studies confirmed a herniated disc and a meningioma. CONCLUSION: In rare case, intradural tumor coexists with cervical disc herniation. When suspicious findings were noticed, or clinical symptoms cannot be fully explained, contrast MR imaging is helpful in differential diagnosis. Microscopic transdural discectomy is safe, and could be used as an optional procedure for cervical disc herniation in some cases. PMID- 29242977 TI - The mechanism in junctional failure of thoraco-lumbar fusions. Part I: Biomechanical analysis of mechanisms responsible of vertebral overstress and description of the cervical inclination angle (CIA). AB - PURPOSE: The purpose of the study is to describe the biomechanical theory explaining junctional breakdowns in thoraco-lumbar fusions, by taking the example of vertebral compression fractures. Also, a new angle, the cervical inclination angle (CIA), describing the relative position of the head at each vertebral level, is presented. METHODS: For the CIA, the data were collected from 137 asymptomatic subjects of a prospective database, containing clinical and radiologic informations. All the 137 subjects have an Oswestry score less than 15% and a pain score less than 2/10 and were part of a previously published study describing the Odontoid-hip axis angle (ODHA). For each vertebral level from T1 to T12, the CIA as well as the vertical and horizontal distances was measured in reference to the sella turcica (ST), and a vertical line drawn from the ST. Average values and correlation coefficients were calculated. RESULTS: The CIA is an angle whose average value varies very little between T1 and T5 (74.9 degrees 76.85 degrees ), and then increases progressively from T6 to T12. T1-T5 vertebra are always in line within the thoracic spine for each subject and can be considered as a straight T1-T5 segment. In addition, it was found that the vertical inclination of T1-T5 segment is correlated with the C7 slope (R 2 = 0.6383). CONCLUSION: The T1-T5 segment inclination is correlated with the C7 slope, and because the latter defines the cervical curve as previously shown, the T1-T5 segment can be considered as the base from which the cervical spine originates. Its role is, thus, similar to the pelvis and its sacral slope, which is the base from which the lumbar spine originates. The CIA along with the ODHA, which describes the adequacy of the global balance in young and elderly asymptomatic populations, are two important parameters that could help us to better understand junctional breakdowns in thoraco-lumbar fusion surgeries. PMID- 29242979 TI - Calling phenology of a diverse amphibian assemblage in response to meteorological conditions. AB - The strong association between amphibian activity, breeding and recruitment with local environmental conditions raises concerns regarding how changes in climate may affect the persistence of species populations into the future. Additionally, in a highly diverse assemblage of anurans, competition for breeding sites affects the time and duration of activity, as species compete for limited resources such as water. Meteorological conditions are strong drivers of amphibian activity, so we assessed whether temperature, rainfall, atmospheric pressure and humidity were associated with the calling phenology of an assemblage of anurans in South East Queensland, Australia. We performed calling surveys and collected digital recordings at 45 ponds in an area known for high anuran diversity. We performed detection analyses to investigate the influence of 10 meteorological variables in detection of calling activity in 19 amphibian species. Our results suggest four breeding strategies in the assemblage: explosive summer breeders, prolonged breeders, opportunistic breeders and a winter breeder. Classifying these species into associations provides a framework for understanding how species respond to environmental conditions. Explosive breeders (i.e. species demonstrating short and highly synchronised breeding periods) were particularly responsive to temperature. Our findings help elucidate the breeding phenology of frogs and provide valuable information on their mating systems in native Australian forests. This study highlights the difficulties of surveying even common anurans. We highlight the importance of predictability and stability in climate and the vulnerability of species for which reproduction appears to require highly specific environmental cues. PMID- 29242978 TI - Animal models of L-DOPA-induced dyskinesia: the 6-OHDA-lesioned rat and mouse. AB - Appearance of L-DOPA-induced dyskinesia (LID) represents a major limitation in the pharmacological therapy with the dopamine precursor L-DOPA. Indeed, the vast majority of parkinsonian patients develop dyskinesia within 9-10 years of L-DOPA oral administration. This makes the discovery of new therapeutic strategies an important need. In the last decades, several animal models of Parkinson's disease (PD) have been developed, to both study mechanisms underlying PD pathology and treatment-induced side effects (i.e., LID) and to screen for new potential anti parkinsonian and anti-dyskinetic treatments. Among all the models developed, the 6-OHDA-lesioned rodents represent the models of choice to mimic PD motor symptoms and LID, thanks to their reproducibility and translational value. Under L-DOPA treatment, rodents sustaining 6-OHDA lesions develop abnormal involuntary movements with dystonic and hyperkinetic features, resembling what seen in dyskinetic PD patients. These models have been extensively validated by the evidence that dyskinetic behaviors are alleviated by compounds reducing dyskinesia in patients and non-human primate models of PD. This article will focus on the translational value of the 6-OHDA rodent models of LID, highlighting their main features, advantages and disadvantages in preclinical research. PMID- 29242980 TI - Environmental and biological measurements of isoflurane and sevoflurane in operating room personnel. AB - PURPOSE: The present study aimed to compare the concentration of isoflurane and sevoflurane in the individual's breathing zone and ambient air of operating rooms (ORs), to investigate the correlation between breathing zone levels and urinary concentrations, and to evaluate the ORs pollution in the different working hours and weeks. METHODS: Environmental and biological concentrations of isoflurane and sevoflurane were evaluated at 9ORs. Air samples were collected by active sampling method and urine samples were collected from each subject at the end of the work shift. All samples were analyzed using gas chromatography. RESULTS: The geometric mean +/- GSD concentration of isoflurane and sevoflurane in breathing zone air were 1.41 +/- 2.27 and 0.005 +/- 1.74 ppm, respectively, while in post-shift urine were 2.42 +/- 2.86 and 0.006 +/- 3.83 ug/lurine, respectively. A significant positive correlation was found between the urinary and environmental concentration of isoflurane (r 2 = 0.724, P < 0.0001). The geometric mean +/- GSD values of isoflurane and sevoflurane in ambient air were 2.30 +/- 2.43 and 0.004 +/- 1.56 ppm, respectively. The isoflurane concentration was different for three studied weeks and significantly increased over time in the ambient air of ORs. CONCLUSIONS: The occupational exposure of OR personnel to isoflurane and sevoflurane was lower than national recommended exposure limits. The urinary isoflurane could be a good internal dose biomarker for monitoring of occupational isoflurane exposure. Considering the accumulation of anesthetic waste gases in the studied ORs, real-time air monitoring is better to be done at the end of the work shift. PMID- 29242982 TI - [Iron, a "miralcle cure" for chronic cardiac insufficiency?] AB - Anemia and chronic heart failure are frequent comorbidities in geriatric patients. In approximately one third of older adults the cause of the anemia is an iron, vitamin B12 and/or folate deficiency and in another third a chronic inflammatory process is present. In the case of iron deficiency a differentiation must be made between the absolute and functional forms. Although in functional iron deficiency ferritin, as a parameter of iron metabolism, is within the normal range or can even be higher, an iron-deficient erythropoiesis is present. In cardiac insufficiency a chronic inflammatory process is assumed. According to the recent guidelines of the Deutsche Gesellschaft fur Kardiologie (DGK, German Cardiac Society) and European Society of Cardiology (ESC) a routine contol of the iron status should be performed and, if necessary, initiation of adequate supplementation is recommended. PMID- 29242981 TI - A new look at the heart-novel imaging techniques. AB - The development and successful implementation of cutting-edge imaging technologies to visualise cardiac anatomy and function is a key component of effective diagnostic efforts in cardiology. Here, we describe a number of recent exciting advances in the field of cardiology spanning from macro- to micro- to nano-scales of observation, including magnetic resonance imaging, computed tomography, optical mapping, photoacoustic imaging, and electron tomography. The methodologies discussed are currently making the transition from scientific research to routine clinical use, albeit at different paces. We discuss the most likely trajectory of this transition into clinical research and standard diagnostics, and highlight the key challenges and opportunities associated with each of the methodologies. PMID- 29242983 TI - [Stressed country doctor with acute visual loss : Clear diagnosis?] PMID- 29242984 TI - [Electronic aids for the visually impaired]. PMID- 29242985 TI - Increasing risk of psychiatric morbidity after childhood onset type 1 diabetes: a population-based cohort study. AB - AIMS/HYPOTHESIS: The aim of this study was to investigate psychiatric morbidity following childhood onset of type 1 diabetes. METHODS: In a matched, population based cohort study based on Danish national registers, we identified children and adolescents who had been diagnosed as an in- or outpatient with type 1 diabetes before the age of 18, and afterwards diagnosed with a psychiatric disorder (n = 5084). Control individuals were matched according to sex and date of birth (n = 35,588). The Cox proportional hazards model was used to assess associations between type 1 diabetes and the incidence of psychiatric disorders as well as the effects of age at onset and duration of type 1 diabetes on the risk of subsequently developing psychiatric morbidities. RESULTS: An increased risk of being diagnosed with mood disorders and anxiety, dissociative, eating, stress related and somatoform disorders was observed in both sexes in the years following type 1 diabetes onset, with the highest risk observed five years or more after onset (HR 1.55 [95% CI 1.38, 1.74]). The risk of psychoactive substance-misuse disorders increased significantly only in boys, and the risk of personality disorders increased only in girls. CONCLUSIONS/INTERPRETATION: In the years following type 1 diabetes onset, an increased risk of eating disorders, anxiety and mood disorders, substance misuse, and personality disorders was found. These findings highlight a clinical need to monitor the mental health of children and adolescents in the years following type 1 diabetes onset to identify and treat psychiatric problems associated with type 1 diabetes. PMID- 29242986 TI - Pre- and postconditioning the heart with hydrogen sulfide (H2S) against ischemia/reperfusion injury in vivo: a systematic review and meta-analysis. AB - Conditioning-like infarct limitation by enhanced level of hydrogen sulfide (H2S) has been demonstrated in many animal models of myocardial ischemia/reperfusion injury (MIRI) in vivo. We sought to evaluate the effect of H2S on myocardial infarction across in vivo pre-clinical studies of MIRI using a comprehensive systematic review followed by meta-analysis. Embase, Pubmed and Web of Science were searched for pre-clinical investigation of the effect of H2S on MIRI in vivo. Retained records (6031) were subjected to our pre-defined inclusion criteria then were objectively critiqued. Thirty-two reports were considered eligible to be included in this study and were grouped, based on the time of H2S application, into preconditioning and postconditioning groups. Data were pooled using random effect meta-analysis. We also investigated the possible impact of different experimental variables and the risk of bias on the observed effect size. Preconditioning with H2S (n = 23) caused a significant infarct limitation of - 20.25% (95% CI - 25.02, - 15.47). Similarly, postconditioning with H2S (n = 40) also limited infarct size by - 21.61% (95% CI - 24.17, - 19.05). This cardioprotection was also robust and consistent following sensitivity analyses where none of the pre-defined experimental variables had a significant effect on the observed infarct limitation. H2S shows a significant infarct limitation across in vivo pre-clinical studies of MIRI which include data from 825 animals. This infarct-sparing effect is robust and consistent when H2S is applied before ischemia or at reperfusion, independently on animal size or sulfide source. Validating this infarct limitation using large animals from standard medical therapy background and with co-morbidities should be the way forward. PMID- 29242987 TI - A twin study of cilioretinal arteries, tilted discs and situs inversus. AB - PURPOSE: To establish the prevalence and heritability of cilioretinal arteries (CRAs), tilted discs (TDs) and situs inversus (SI). METHODS: Fundus photos from the Twins UK Adult Twin registry twin database were analyzed: 1812 individuals, 526 complete monozygotic (MZ) twin pairs and 336 complete dizygotic (DZ) pairs. Images were assessed non-stereoscopically on a computer screen by the same ophthalmologist for presence of CRAs, TDs or SI. Prevalence figures, probandwise concordances and heritabilities were calculated. RESULTS: Prevalence of a CRA in subjects' right eyes was 28.6% (26.5-30.8). Prevalence of subjects with a CRA in at least one eye was 45.0% (42.6-47.5), with a TD in at least one eye was 1.2% (0.8-1.9), and with SI at least one eye was 0.5% (0.3-1.0). There was no association between birth weight and presence of CRA. Concordance for CRA in at least one eye (MZ twins) was 60% (95% CI 55-64), and (DZ) was 45% (95% CI 39-51). Heritability for CRAs in at least one eye was 49.4% (95% CI 38.1-59.7) and for both eyes was 32.9% (95% CI 10.4-53.3). We were unable to calculate meaningful heritabilities or concordances for TDs and situs SI, due to insufficient numbers. CONCLUSIONS: The presence of CRAs appears to be moderately heritable, with greater variance explained by individual environmental factors or even stochastic events. They were not associated with low birth weight. Future genetic research and studies of birth/lifecourse cohorts may offer further insights into the etiology of congenital papillovascular abnormalities. PMID- 29242988 TI - Anabolic-androgenic steroids (AAS) increase sensitivity to uncertainty by inhibition of dopamine D1 and D2 receptors. AB - BACKGROUND: Anabolic-androgenic steroid abuse is implicated in maladaptive behaviors such as impaired cognition in humans. In a rat model, our lab has shown that testosterone decreases preference for a large/uncertain reward in probability discounting. Other studies have shown that androgens decrease dopamine D1 and D2 receptors in the nucleus accumbens shell, a region important for decision-making behavior in probability discounting. Thus, we attempted to restore selection of the large/uncertain reward in testosterone-treated rats by administering the D2 receptor agonist quinpirole or the D1 receptor agonist SKF81297 and testing probability discounting. METHODS: Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5 mg/kg) or vehicle (13% cyclodextrin in water), and tested for probability discounting after injections of saline, 0.1 and 0.5 mg/kg of quinpirole or SKF81297. Rats chose between a small/certain reward (1 sugar pellet, 100% probability) and a large/uncertain reward (4 pellets, decreasing probability: 100, 75, 50, 25, 0%). RESULTS: Testosterone-treated rats selected the large/uncertain reward significantly less than vehicle-treated controls after saline injection. However, acute injection with 0.1 mg/kg quinpirole increased large/uncertain reward preference in testosterone-treated rats only, indicated by a testosterone * quinpirole interaction. At 0.5 mg/kg, quinpirole increased large/uncertain reward preference in all rats. Acute injection with SKF81297 at 0.1 or 0.5 mg/kg rescued large/uncertain reward preference in testosterone-treated rats by eliminating the difference between groups. CONCLUSIONS: It appears that altered probability discounting behavior in testosterone-treated rats is due to both decreased D1 and D2 receptor function. PMID- 29242989 TI - Prosthetic supply of facial defects: long-term experience and retrospective analysis on 99 patients. AB - INTRODUCTION: Defects in the head region may be caused by tumour treatments, injuries, as well as congenital malformations. The restoration of these defects that can be performed through reconstructive plastic surgery and/or prosthetic surgery occupies a high priority in the physical and psychological rehabilitation of the patient. The present study reports on long-term experience in supply of facial prosthesis. MATERIALS AND METHODS: The medical records of 99 patients, who had been supplied with custom-made facial prostheses between 2001 and 2011, were evaluated retrospectively. RESULTS: There were 59 male (60%) and 40 (40%) female patients. The reason for prosthetic supplement was a tumour disease in 50 patients, congenital malformation in 39 patients, and trauma in 10 patients. Fifty-three patients were treated with ear prosthesis, twenty-seven patients were treated with eye prosthesis, and nineteen patients with nasal prosthesis. 82.8% of prosthetic supplies were designed as magnetic support prostheses. The most common complication was skin redness around the implants. 10% of patients suffered the loss of the osseointegrated implants. CONCLUSION: The osseointegrated titanium implants with magnet support provide a reliable attachment for prosthesis and constitute a promising alternative to surgical reconstruction of complex facial defects. PMID- 29242990 TI - The influence of cochlear morphology on the final electrode array position. AB - OBJECTIVE: Preoperative information about cochlear morphology and size increasingly seems to be a defining factor of electrode choice in cochlear implant surgery. Different types of electrodes differ in length and diameter to accommodate individual cochlear anatomy. Smaller cochlear size results in increased insertion depth with a higher risk to dislocate and causes cochlear trauma with reduced postoperative outcome. The objective of the current study is to describe the three-dimensional size of the cochlea, to compare interindividual differences, to determine the relationship between cochlear size and insertion angle, and to define risk factors for dislocation during insertion. DESIGN: Four hundred and three patients implanted between 2003 and 2010 inserted via cochleostomy with a perimodiolar electrode array (CochlearTM Contour Advance(r) electrode array) have been compared. CBCT (Cone beam computed tomography) was used to determine electrode array position (scala tympani versus scala vestibuli insertion, intracochlear dislocation, and insertion angle) and cochlear size (diameters and height). The trajectory of the electrode array and the lateral wall have been measured, and the position of the electrode array has been estimated. RESULTS: The mean value of the largest diameter was 9.95 mm and that of the perpendicular distance was 6.54 mm. There was a statistically significant correlation between those values. Mean height was 3.85 mm. The intracochlear relation of the electrode array and the modiolus showed a statistically significant relationship with the cochlear expanse. The electrode array was more likely to dislocate in cochleae with a smaller diameter and a lower height. Cochleae with insertions into scala vestibuli exhibited a smaller height compared to scala tympani insertions with statistical significance. CONCLUSION: Cochlear size and shape is variable, and the measured data of this study confirm the finding of other researchers. This study established two heights by two different planes to achieve a three-dimensional understanding of the cochlea. The electrode array was more likely to dislocate in cochleae with smaller diameter and smaller height. It can be assumed that the height established in this study seems to be a new preoperative parameter to underline the risk of scalar dislocation and not favored scala vestibuli insertion if using a cochleostomy approach. In conclusion, cochlear size, especially the height, is influencing the final position of the electrode array. Using preoperative scans of the cochlear diameters and cochlear height, a next step to custom-sized arrays is available. PMID- 29242991 TI - Mechanisms of Resistance to Targeted Therapies in Chronic Myeloid Leukemia. AB - Patients with newly diagnosed chronic myeloid leukemia (CML) usually received as first-line treatment a first- or second-generation tyrosine kinase inhibitor (TKI). Although initial responses are high, therapy fails in up to 40% of patients and initial response is lost within 2 years in approximately 25% of patients. In the last few years, intensive efforts have been spent to explain treatment failure, and different mechanisms of resistance have been identified, ranging from BCR-ABL1 kinase domain mutations to lack of adherence to therapy. In this review, we briefly summarize the clinical efficacy of approved TKIs and describe the main mechanisms of TKI resistance. PMID- 29242993 TI - Promotion of neuronal regeneration by using self-polymerized dendritic polypeptide scaffold for spinal cord tissue engineering. AB - Tissue engineering technology is applicable for study of nerve regeneration after spinal cord injury. Many natural and artificial scaffold are not applicable because of poor mechanical properties and cell compatibility. Polypeptides with fine three-dimensional structure and cell compatibility and are widely used in tissue engineering research. The purpose of this study was to verify the neuronal differentiation of neural stem cells by using self-polymerize dendritic polypeptide for spinal cord tissue engineering. Neural stem cells were isolated from cerebral cortex of neonatal SD rats.Conventional media was triggered the 1wt% nano peptide solution self polymerizated to formed a nano gel. The gel was tested by scanning electron microscope and transmission electron microscope. Neural stem cells were inoculated onto gel or on Polylysine-coated slides with fetal bovine serum or not. SD rats were randomized divided into four groups. neural stem cells and self-polymerized peptide were transplanted into spinal cord injury models. Then we test the Density of NF-positive axons in the spinal cord injury area at 8 weeks after surgery and MS score of the locomotive function of hind limbs among mice of four groups. Neural stem cells were showed anti Nestin (+), anti NSE (+), anti GFAP (+). The gel tested by scanning electron microscope was showed thick wall structure, another one tested by transmission electron microscope was showed self-polymerized dendritic nanofibers, which contains several spacings. The cells in serum group were differentiate into neurons, but non serum group were not. These results suggest that the self-assembling peptide nanofiber scaffold(SAPNS) were cytocompatible to neural stem cells which were differentiated into neurons. A large number of axonal regeneration and recovery of joint function of hind limb were appeared. The self-polymerized Peptide maybe used as practical tissue engineering materials as future. PMID- 29242992 TI - Dynamic Adaptation in Neurosteroid Networks in Response to Alcohol. AB - The term neurosteroid refers to rapid membrane actions of steroid hormones and their derivatives that can modulate physiological functions and behavior via their interactions with ligand-gated ion channels. This chapter will highlight recent advances pertaining to the modulatory effects of a select group of neurosteroids that are primarily potent positive allosteric modulators of gamma aminobutyric acidA receptors (GABAARs). Nanomolar concentrations of neurosteroids, which occur in vivo, potentiate phasic and tonic forms of GABAAR mediated inhibition, indicating that both synaptic and extrasynaptic GABAARs possess sensitivity to neurosteroids and contribute to the overall ability of neurosteroids to modulate central nervous system excitability. Common effects of alcohol and neurosteroids at GABAARs have stimulated research on the ability of neurosteroids to modulate alcohol's acute and chronic effects. Background on neurosteroid pharmacology and biosynthetic enzymes will be provided as it relates to experimental findings. Data will be summarized on alcohol and neurosteroid interactions across neuroanatomical regions and models of intoxication, consumption, dependence, and withdrawal. Evidence supports independent regulation of neurosteroid synthesis between periphery and brain as well as across brain regions following acute alcohol administration and during withdrawal. Local mechanisms for fine-tuning neuronal excitability via manipulation of neurosteroid synthesis exert predicted behavioral and electrophysiological responses on GABAAR mediated inhibition. Collectively, targeting neurosteroidogenesis may be a beneficial treatment strategy for alcohol use disorders. PMID- 29242995 TI - An assessment of commonly employed satellite-based remote sensors for mapping mangrove species in Mexico using an NDVI-based classification scheme. AB - Optimizing the classification accuracy of a mangrove forest is of utmost importance for conservation practitioners. Mangrove forest mapping using satellite-based remote sensing techniques is by far the most common method of classification currently used given the logistical difficulties of field endeavors in these forested wetlands. However, there is now an abundance of options from which to choose in regards to satellite sensors, which has led to substantially different estimations of mangrove forest location and extent with particular concern for degraded systems. The objective of this study was to assess the accuracy of mangrove forest classification using different remotely sensed data sources (i.e., Landsat-8, SPOT-5, Sentinel-2, and WorldView-2) for a system located along the Pacific coast of Mexico. Specifically, we examined a stressed semiarid mangrove forest which offers a variety of conditions such as dead areas, degraded stands, healthy mangroves, and very dense mangrove island formations. The results indicated that Landsat-8 (30 m per pixel) had the lowest overall accuracy at 64% and that WorldView-2 (1.6 m per pixel) had the highest at 93%. Moreover, the SPOT-5 and the Sentinel-2 classifications (10 m per pixel) were very similar having accuracies of 75 and 78%, respectively. In comparison to WorldView-2, the other sensors overestimated the extent of Laguncularia racemosa and underestimated the extent of Rhizophora mangle. When considering such type of sensors, the higher spatial resolution can be particularly important in mapping small mangrove islands that often occur in degraded mangrove systems. PMID- 29242994 TI - Selective effects of different fatigue protocols on the function of upper body muscles assessed through the force-velocity relationship. AB - PURPOSE: This study explored the feasibility of the force-velocity relationship (F-V) to detect the acute effects of different fatigue protocols on the selective changes of the maximal capacities of upper body muscles to produce force, velocity, and power. METHODS: After determining the bench press one-repetition maximum (1RM), participants' F-V relationships were assessed during the bench press throw exercise on five separate sessions after performing one of the following fatiguing protocols: 60%1RM failure, 60%1RM non-failure, 80%1RM failure, 80%1RM non-failure, and no-fatigue. In the non-failure protocols, participants performed half the maximum number of repetitions than in their respective failure protocols. RESULTS: The main findings revealed that (1) all F V relationships were highly linear (median r = 0.997 and r = 0.982 for averaged across participants and individual data, respectively), (2) the fatiguing protocols were ranked based on the magnitude of power loss as follows: 60%1RM failure > 80%1RM failure > 60%1RM non-failure > 80%1RM non-failure, while (3) the assessed maximum force and velocity outputs showed a particularly prominent reduction in the protocols based on the lowest and highest levels of fatigue (i.e., 80%1RM non-failure and 60%1RM failure), respectively. CONCLUSIONS: The results support the use of F-V to assess the effects of fatigue on the distinctive capacities of the muscles to produce force, velocity, and power output while performing multi-joint tasks, while the assessed maximum force and velocity capacities showed a particularly prominent reduction in the protocols based on the lowest and highest levels of fatigue (i.e., 80%1RM non-failure and 60%1RM failure), respectively. PMID- 29242996 TI - Personalized Health Monitoring System for Managing Well-Being in Rural Areas. AB - Rural India lacks easy access to health practitioners and medical centers, depending instead on community health workers. In these areas, common ailments that are easy to manage with medicines, often lead to medical escalations and even fatalities due to lack of awareness and delayed diagnosis. The introduction of wearable health devices has made it easier to monitor health conditions and to connect doctors and patients in urban areas. However, existing initiatives have not succeeded in providing adequate health monitoring to rural and low-literate patients, as current methods are expensive, require consistent connectivity and expect literate users. Our design considerations address these concerns by providing low-cost medical devices connected to a low-cost health platform, along with personalized guidance based on patient physiological parameters in local languages, and alerts to medical practitioners in case of emergencies. This patient-centric integrated healthcare system is designed to manage the overall health of villagers with real-time health monitoring of patients, to offer guidance on preventive care, and to increase health awareness and self-monitoring at an affordable price. This personalized health monitoring system addresses the health-related needs in remote and rural areas by (1) empowering health workers in monitoring of basic health conditions for rural patients in order to prevent escalations, (2) personalized feedback regarding nutrition, exercise, diet, preventive Ayurveda care and yoga postures based on vital parameters and (3) reporting of patient data to the patient's health center with emergency alerts to doctor and patient. The system supports community health workers in the diagnostic procedure, management, and reporting of rural patients, and functions well even with only intermittent access to Internet. PMID- 29242997 TI - Synergistic production of 20(S)-protopanaxadiol from protopanaxadiol-type ginsenosides by beta-glycosidases from Dictyoglomus turgidum and Caldicellulosiruptor bescii. AB - 20(S)-Protopanaxadiol (APPD) has potential uses in the pharmaceutical, cosmetic, and food industries because of its anti-stress, anti-fatigue, anti-cancer, anti inflammatory, and anti-wrinkle properties. However, APPD production is difficult because beta-glycosidases that convert the protopanaxadiol (PPD)-type ginsenoside compound K to APPD are rare. beta-Glycosidase from Dictyoglomus turgidum (DT-bgl) has the highest specific activity for converting compound K to APPD, but exhibits no activity towards the alpha-L-arabinopyranoside moiety in compound Y. Therefore, beta-glycosidase from Caldicellulosiruptor bescii (CB-bgl), which has a strong alpha-L-arabinopyranosidase activity, was used along with DT-bgl. The volumetric and specific productivities of the two-enzyme system for APPD using ginseng root extract were 38.4- and 38.7-fold higher, respectively, than those of beta-glycosidase from Pyrococcus furiosus, which had the highest volumetric productivity previously reported, at the same enzyme and substrate concentrations. Thus, DT-bgl combined with CB-bgl completely converted PPD-type ginsenosides to APPD with the highest volumetric and specific productivities reported thus far. PMID- 29242998 TI - Contrasting liquid imbibition into uncoated versus pigment coated paper enables a description of imbibition into new-generation surface-filled paper. AB - The transport of print fluids into paper is directly dependent on the imbibition characteristic of the paper including both the z-, x- and y-directions. As the measurement of free liquid imbibition into the paper thickness (z-direction) is difficult experimentally, due to the thin nature of paper, in this paper we resort to imbibition along the y-direction of paper to analyse and explore the possibility of understanding the mechanistic differences between wicking into uncoated unfilled paper versus that of controllable pigment-filled paper and paper coating. Considering the classical imbibition dynamic, the measured imbibition was characterised firstly with respect to [Formula: see text] and secondly with respect to linear t. It is shown that the wicking behaviour of uncoated unfilled paper follows neither the classical viscous drag balance model of Lucas-Washburn ([Formula: see text]) nor the more comprehensive inertia included imbibition described by Bosanquet. However, by increasing the filler load into the surface layer of the paper, the imbibition dynamic is seen to revert to the Bosanquet model. Thus, when using highly filled papers, the imbibition dynamic for printing liquid shows a fast imbibition at the initial stages dominated by inertial plug flow, and then transits to the Lucas-Washburn viscosity-dominated imbibition component over longer time. PMID- 29242999 TI - Color vision as a biological marker able to differentiate two phenotypically similar neurological diseases. PMID- 29243001 TI - Comparing strategies for selection of low-density SNPs for imputation-mediated genomic prediction in U. S. Holsteins. AB - SNP chips are commonly used for genotyping animals in genomic selection but strategies for selecting low-density (LD) SNPs for imputation-mediated genomic selection have not been addressed adequately. The main purpose of the present study was to compare the performance of eight LD (6K) SNP panels, each selected by a different strategy exploiting a combination of three major factors: evenly spaced SNPs, increased minor allele frequencies, and SNP-trait associations either for single traits independently or for all the three traits jointly. The imputation accuracies from 6K to 80K SNP genotypes were between 96.2 and 98.2%. Genomic prediction accuracies obtained using imputed 80K genotypes were between 0.817 and 0.821 for daughter pregnancy rate, between 0.838 and 0.844 for fat yield, and between 0.850 and 0.863 for milk yield. The two SNP panels optimized on the three major factors had the highest genomic prediction accuracy (0.821 0.863), and these accuracies were very close to those obtained using observed 80K genotypes (0.825-0.868). Further exploration of the underlying relationships showed that genomic prediction accuracies did not respond linearly to imputation accuracies, but were significantly affected by genotype (imputation) errors of SNPs in association with the traits to be predicted. SNPs optimal for map coverage and MAF were favorable for obtaining accurate imputation of genotypes whereas trait-associated SNPs improved genomic prediction accuracies. Thus, optimal LD SNP panels were the ones that combined both strengths. The present results have practical implications on the design of LD SNP chips for imputation enabled genomic prediction. PMID- 29243003 TI - Animal cognition: an integrative approach. PMID- 29243002 TI - Comprehending the three-dimensional mandibular morphology of facial asymmetry patients with mandibular prognathism. AB - BACKGROUND: The purpose of this study was to elucidate the factors that cause facial asymmetry by comparing the characteristics of the mandibular morphology in patients with mandibular prognathism with or without facial asymmetry using three dimensional computed tomography (3D-CT). METHODS: We studied 28 mandibular prognathism patients whose menton deviated by >= 4 mm from the midline (FA group, n = 14) and those with a < 4-mm deviation (NA group, n = 14). DICOM data from multislice CT images were reconstructed and analysed using 3D image analysing software. Mandibular structures were assessed via linear, angular, or volumetric measurements and analysed statistically. RESULTS: The lengths of the ramal and body components and condylar volume in the FA group were significantly greater on the nondeviated side than those on the deviated side. The mandibular body length of the nondeviated side in the FA group was significantly longer than that of the NA group. Other components of the FA group did not significantly differ from those of the NA group. CONCLUSIONS: Imbalances in the sizes of the ramal and body components as well as the increased body length of the nondeviated side in the FA group compared with that of the NA group may contribute to facial asymmetry in patients with mandibular prognathism. PMID- 29243000 TI - RNA interference-based therapy and its delivery systems. AB - RNA interference (RNAi) is considered a highly specific approach for gene silencing and holds tremendous potential for treatment of various pathologic conditions such as cardiovascular diseases, viral infections, and cancer. Although gene silencing approaches such as RNAi are widely used in preclinical models, the clinical application of RNAi is challenging primarily because of the difficulty in achieving successful systemic delivery. Effective delivery systems are essential to enable the full therapeutic potential of RNAi. An ideal nanocarrier not only addresses the challenges of delivering naked siRNA/miRNA, including its chemically unstable features, extracellular and intracellular barriers, and innate immune stimulation, but also offers "smart" targeted delivery. Over the past decade, great efforts have been undertaken to develop RNAi delivery systems that overcome these obstacles. This review presents an update on current progress in the therapeutic application of RNAi with a focus on cancer therapy and strategies for optimizing delivery systems, such as lipid based nanoparticles. PMID- 29243004 TI - Altered effective connectivity contributes to micrographia in patients with Parkinson's disease and freezing of gait. AB - Recently, it was shown that patients with Parkinson's disease (PD) and freezing of gait (FOG) can also experience freezing episodes during handwriting and present writing problems outside these episodes. So far, the neural networks underlying increased handwriting problems in subjects with FOG are unclear. This study used dynamic causal modeling of fMRI data to investigate neural network dynamics underlying freezing-related handwriting problems and how these networks changed in response to visual cues. Twenty-seven non-freezers and ten freezers performed a pre-writing task with and without visual cues in the scanner with their right hand. The results showed that freezers and non-freezers were able to recruit networks involved in cued and uncued writing in a similar fashion. Whole group analysis also revealed a trend towards altered visuomotor integration in patients with FOG. Next, we controlled for differences in disease severity between both patient groups using a sensitivity analysis. For this, a subgroup of ten non-freezers matched for disease severity was selected by an independent researcher. This analysis further exposed significantly weaker coupling in mostly left hemispheric visuo-parietal, parietal - supplementary motor area, parietal - premotor, and premotor-M1 pathways in freezers compared to non-freezers, irrespective of cues. Correlation analyses revealed that these impairments in connectivity were related to writing amplitude and quality. Taken together, these findings show that freezers have reduced involvement of the supplementary motor area in the motor network, which explains the impaired writing amplitude regulation in this group. In addition, weaker supportive premotor connectivity may have contributed to micrographia in freezers, a pattern that was independent of cueing. PMID- 29243005 TI - Efficacy and safety outcomes in vitamin D supplement users in the fingolimod phase 3 trials. AB - BACKGROUND: Low serum levels of 25-hydroxyvitamin D have been associated with worse outcomes in multiple sclerosis (MS) patients treated with interferon-beta. Association of vitamin D nutrition on the outcomes of other MS therapies has been studied less. OBJECTIVE: Whether patients in the phase 3 fingolimod trials using vitamin D supplements have better clinical, MRI and safety outcomes than non users. MATERIALS AND METHODS: Pooled data from phase 3 FREEDOMS trials was analyzed post hoc. Vitamin D use was defined as 'non-users' (n = 562), 'casual users' (n = 157) and 'daily users' (usage 100% time in the study, n = 110). RESULTS: Expanded Disability Status Scale change from baseline to month 24, and annual relapse rate and proportion of patients with relapses were similar across the vitamin D user groups. Proportion of patients free of new/enlarging T2 lesions significantly favored vitamin D 'daily users' versus 'non-users'. Mean number of lesions were lower and proportion of patients free of gadolinium enhanced T1-lesions were higher in the 'daily users'. At month 12, percent brain volume change was significantly lower in the 'daily users' versus 'non-users' and remained low at month 24 (non-significant). Incidence of depression was lower for vitamin D 'daily users' (non-significant). CONCLUSIONS: We observed improved MRI outcomes on percent brain volume change and proportion of patients free of new/enlarging T2 lesions, and a trend of less depression in the 'daily users' of vitamin D supplement in patients in the FREEDOMS trials. PMID- 29243006 TI - Ocular ultrasound for monitoring pseudotumor cerebri syndrome. AB - The aim of this study was to evaluate the feasibility of ocular ultrasound in the follow-up of pseudotumor cerebri syndrome and to correlate ultrasound with clinical parameters. In a cohort study of 22 consecutive adult patients, ocular ultrasound was performed measuring optic nerve sheath diameter, optic nerve diameter, and optic disc elevation compared with symptoms referred by the patients. The patients showed increased optic nerve sheath diameter [median, 6.51 mm (interquartile range 6.13-7.10)], optic nerve diameter [3.02 mm (2.86-3.27)], and optic disc elevation [0.90 mm (0.64-1.36)] at the time of admission and had ophthalmologically confirmed the presence of papilledema in all 22 patients. After 6 months all parameters decreased significantly for optic nerve sheath diameter [6.08 mm (5.59-6.73), P = 0.002], optic nerve diameter [2.87 mm (2.70 3.15), P = 0.007], and optic disc elevation [0.48 mm (0.30-0.70), P < 0.001]. In addition, a discrete negative correlation between optic nerve sheath diameter and headache change after 6 months was observed with rho = - 0.477 and P = 0.02. No correlation was found between optic disc elevation and headache. In conclusion, longitudinal follow-up with ocular ultrasound combined with clinical information may provide support for treatment of this condition. PMID- 29243007 TI - Comparison of Telephone and Televideo Modes for Delivery of Genetic Counseling: a Randomized Trial. AB - Telephone and televideo have yielded equivalent patient satisfaction and psychosocial outcomes when compared to in-person genetic counseling, yet little is known about how they compare to one another. In this randomized controlled trial, veterans received genetic counseling via telephone or traveled to a clinic to participate via encrypted televideo. Knowledge and visit satisfaction were assessed 2 weeks later. Travel time, mileage, and out-of-pocket costs were calculated for videoconferencing. Qualitative interviews were conducted with patients and counselors to assess acceptability. Of the 20 male patients randomized to telephone, 90% received counseling and provided outcomes; of the 18 randomized to televideo, 67% received counseling and 50% provided outcomes. Telephone patients answered a mean of 4.4 of eight questions correctly at baseline and 4.7 at follow-up; televideo means were 5.6 and 6.5, respectively. Satisfaction was 25.2 out of 30 for telephone and 26.9 for televideo. Televideo patients incurred a median of 2.8 h of travel time, 40 roundtrip miles, and $67.29 in costs. Patients and counselors found both modes acceptable for providing education and answering questions. Although patients liked the flexibility of telephone, counselors felt patients missed more appointments and were distracted when using telephone. A noted advantage of videoconferencing was reading body language. Further evaluation of alternative delivery modes is needed. PMID- 29243008 TI - Examining the Psychosocial Impact of Genetic Testing for Cardiomyopathies. AB - Inherited cardiomyopathies, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), are the most common monogenic cause of cardiac disease and can rarely lead to sudden cardiac death (SCD). They are characterized by incomplete and age-dependent penetrance and are usually initially symptomatic in adulthood yet can present in childhood as well. Over 20 genes have been identified to cause HCM, and more than 40 genes are known to cause DCM. Genetic testing for these genes has been integrated into medical care; however, the psychological impact of genetic testing and the impact of the uncertainty that comes with receiving these results have not been well studied. This study surveyed 90 adult probands and relatives with a personal or family history of cardiomyopathy from a single hospital-based cardiac genetic program to determine the psychosocial impact of genetic testing for cardiomyopathies. Standardized psychological instruments including an adapted Multidimensional Impact of Cancer Risk Assessment (aMICRA), Impact of Event Scale (IES), and Satisfaction with Decision (SWD) scales were utilized. Patients with positive genetic test results had higher scores for intrusive thoughts, avoidance, and distress when compared to those with negative genetic test results and were also more likely to make or plan to make life changes because of the results of their genetic testing. Satisfaction with the decision to undergo genetic testing was similar regardless of genetic test results. The results of this study provide insight into the patient experience of genetic testing for cardiomyopathies and how these experiences are associated with genetic test results and cardiac history. PMID- 29243010 TI - Simpson grade IV resections of skull base meningiomas: does the postoperative tumor volume impact progression? PMID- 29243011 TI - Public Stigma and the Label of Gambling Disorder: Does it Make a Difference? AB - This study examined public gambling stigma by testing stigmatization of those diagnosed with a gambling disorder, as specified by the DSM-5 (American Psychiatric Association in Diagnostic and statistical manual of mental disorders, 2013. https://doi.org/10.1176/appi.books.9780890425596.dsm16 ). The researchers hypothesized that the magnitude of stigmatization would fall in this order, from most stigmatized to least: (a) the target labelled and described in ways consistent with moderate gambling disorder (b) the target described in ways consistent with moderate gambling disorder, (c) the target described in ways consistent with recreational gambling, (d) and control. Participants were randomly presented with one of the four descriptions, then completed measures of cognitive, affective, and behavioral reactions. Results showed that those labelled with gambling disorder evoked slightly more social distance than those meeting criteria for the disorder with no label. However, both groups meeting criteria were more stigmatized than those who gamble without meeting criteria and those who do not gamble. Those described who gamble without meeting criteria were no more stigmatized than those who do not gamble, giving a more total picture of what gambling stigma is by indicating what it is not. Findings and implications are discussed. PMID- 29243009 TI - Adrenaline induces mitochondrial biogenesis in rat liver. AB - We studied the effects of adrenaline administration and depletion (induced by reserpine) on rat liver oxidative metabolism. We showed that adrenaline increases, and reserpine decreases aerobic capacity (inferred by cytochrome oxidase activity) in tissue modifying the hepatic content of mitochondrial proteins without changing mitochondrial aerobic capacity. The changes in tissue cytochrome oxidase activity, which agreed with the expression levels of factors involved in mitochondrial biogenesis, such as PGC-1, NRF-1, and NRF-2, were associated with similar changes in tissue and mitochondrial State 3 respiration. Adrenaline and reserpine induced extensive lipid and protein oxidative damage in tissue and mitochondria. The increase in H2O2 release by respiring mitochondria and the decrease in the activities of the antioxidant enzymes glutathione peroxidase and reductase contributed to the reserpine effect on oxidative damage. The adrenaline effect is more difficult to explain, since the hormone increased the antioxidant enzyme activities but, in respiring mitochondria, increased ROS release rate in the presence of succinate and decreased it in the presence of pyruvate/malate. These opposite changes were due to the increased content of the autoxidizable electron carrier located at complex III and decreased content of that located at complex I. Our data suggest that adrenaline can be involved in the mitochondrial population adaptation which verify in conditions in which an increased body energy expenditure verify such as cold exposure. PMID- 29243012 TI - Use of a Unique Farmers' Market Program Targeting Lower-Income Community Members. AB - We examined use of a farmers' market that leverages community partnerships to provide free produce to lower-income persons. Participants (n = 422) were asked to complete a questionnaire and given an ID number, which was used to track market use from 2014 to 2015. Chi square tests were used to examine associations between 2014/2015 market use and reasons for market use, financial support received, and how attendees had learned about the market. Ordinal regression was used to identify household characteristics associated with increased market attendance. Although the proportion of lower-income attendees declined over the study period, a substantial proportion of households in 2014 (69.1%) and 2015 (54.6%) were below the poverty threshold. We identified significant differences in attendees' reasons for market use and ways attendees heard about the market from 2014 to 2015. The most frequently reported reason for 2014 market use was retirement/fixed income (P < 0.001) and in 2015 was low-income (P < 0.001). Most attendees heard about the market through flyers (P < 0.001) and word of mouth (P <= 0.001) in 2014 and through local, non-profit services (P < 0.001) in 2015. In the ordinal regression, households with an older person registering the household for the market used the market more times per year (P < 0.001). Impoverished households (P = 0.020) and households receiving more financial support services (P < 0.001) used the market fewer times per year. While a substantial proportion of lower-income persons used the free-produce market, frequency of use was still lowest among this group indicating a need to address barriers beyond produce cost. PMID- 29243013 TI - Exercise Performance in Pediatric Liver Transplant Recipients and Its Related Cardiac Function. AB - The aim of this study was to evaluate an exercise test in pediatric liver transplant recipients and its relation to their cardiac function. This cross sectional study was conducted on 58 children who had successfully undergone orthotopic liver transplantation at least 6 months prior to the study, with the same age and gender-matched control group. M-mode, Doppler, tissue Doppler echocardiography and an exercise test were performed for all the participants. The VO2 values and METS in patients were less than the control (P = 0.001). Left ventricular posterior wall thickness in systole, left ventricular posterior wall thickness in diastole, interventricular septum diameter in diastole, AT, pulmonary acceleration time, ST and EaT, AaM, and SS had a significant difference between patients and the control group (P value < 0.05). Maximal oxygen consumption (Max VO2) and metabolic equivalent task (METs) values had a significant correlation with tricuspid valve S parameter (P = 0.018, r = 0.310). Max VO2 and METs values did not have a significant correlation with the diastolic dysfunction index, such as E/A and E/Ea. In this study, the exercise test showed decreased functional capacity in liver-transplanted children; however, the echocardiographic evaluation did not reveal any definite correlation with systolic or diastolic dysfunction. PMID- 29243014 TI - Prognostic Value of LVEDP in Acute Myocardial Infarction: a Systematic Review and Meta-Analysis. AB - Left ventricular end-diastolic pressure (LVEDP) is an easily obtained, physiologically integrative measure of total LV function. LVEDP may be a useful prognostic measure in patients with acute myocardial infarction and utilised to guide medical therapy and assess risk for post myocardial infarction heart failure. To assess the utility of LVEDP as a prognostic measure in patients presenting with acute myocardial infarction. We performed an unrestricted search of electronic databases (1946 to March 2017) using a predefined search strategy. Publications were included if patients had an acute coronary syndrome and LVEDP was measured by cardiac catheterisation and included outcome data specifying major adverse cardiac events. Two reviewers performed independent study selection, data abstraction and quality assessment by using the Cochrane tool for randomised trials and the ROBINS-I tool for non-randomised studies. Our search identified 8637 patients in seven studies. In patients with elevated LVEDP and STEMI, there was a significantly increased risk of 30-day death (three studies, 5372 participants; RR 1.9; 95% CI 1.4-2.7; p < 0.001; I 2 = 35.3%) and heart failure (two studies, 2574 participants; RR 2.9; 95% CI 1.9-4.5; p = < 0.001; I 2 = 0.0%). There was no significant increase in risk of 30 day reinfarction (RR 1.25; 95% CI 0.77-2.1; p = 0.37; I 2 = 41.3%). Elevated LVEDP measured during cardiac catheterisation for acute myocardial infarction appears to be a predictor of heart failure and mortality. PMID- 29243015 TI - Relational autonomy in the care of the vulnerable: health care professionals' reasoning in Moral Case Deliberation (MCD). AB - In Moral Case Deliberation (MCD), healthcare professionals discuss ethically difficult patient situations in their daily practice. There is a lack of knowledge regarding the content of MCD and there is a need to shed light on this ethical reflection in the midst of clinical practice. Thus, the aim of the study was to describe the content of healthcare professionals' moral reasoning during MCD. The design was qualitative and descriptive, and data consisted of 22 audio recorded inter-professional MCDs, analysed with content analysis. The moral reasoning centred on how to strike the balance between personal convictions about what constitutes good care, and the perceived dissonant care preferences held by the patient. The healthcare professionals deliberated about good care in relation to demands considered to be unrealistic, justifications for influencing the patient, the incapacitated patient's nebulous interests, and coping with the conflict between using coercion to achieve good while protecting human dignity. Furthermore, as a basis for the reasoning, the healthcare professionals reflected on how to establish a responsible relationship with the vulnerable person. This comprised acknowledging the patient as a susceptible human being, protecting dignity and integrity, defining their own moral responsibility, and having patience to give the patient and family time to come to terms with illness and declining health. The profound struggle to respect the patient's autonomy in clinical practice can be understood through the concept of relational autonomy, to try to secure both patients' influence and at the same time take responsibility for their needs as vulnerable humans. PMID- 29243016 TI - Health Status and Experience of the Migrant Workers Returned from Spain to Colombia: A Qualitative Approach. AB - This study aims to understand the migratory experience and the employment, work and health conditions of the returned migrants from Spain to Colombia. A qualitative study was conducted by means of 23 semi-structured interviews with Colombian returned migrant workers. Qualitative narrative content analysis was performed using Atlas.Ti software. Main findings are represented by nine categories emerged from the participants' discourses: (1) impact of the economic crisis on work and employment conditions in Spain, (2) economic crisis and return, (3) characteristics of returnees, (4) perception of the returnees about Colombia, (5) the role of social support networks, (6) employment and working conditions in Colombia, (7) health and wellbeing, (8) future plans and expectations, (9) the experience of being immigrant. Adjustment difficulties in participants are evidenced by the return migration process and the conditions of the social, political and economic system in Colombia. Return migration represents the reconfiguration of personal and working lives of this population. This situation requires the development of global policies and strategies in public health to facilitate the adaptation of these people. PMID- 29243017 TI - Diabetes Self-Care Behaviors Among Marshallese Adults Living in the United States. AB - Marshallese experience high rates of type 2 diabetes. Proper management of diabetes requires multiple self-care behaviors, yet little is known about Marshallese's diabetes-related self-care behaviors. Survey data from 111 Marshallese adults with diabetes were used to examine relationships between self care behaviors and socio-demographic characteristics. The most common self-care behavior was attending annual doctor visits, while the least common was maintaining a normal weight. Age group, education level, and having a regular doctor were significantly associated with engaging in self-care behaviors. Having a regular doctor had the most effect on performing self-care behaviors (p = 0.006); although, only 38.7% reported having a regular doctor. To minimize diabetes-related complications, efforts to improve self-care behaviors among the Marshallese should be developed. Alternatives to traditional healthcare providers, such as community health workers, may be a viable strategy with this population given only one-third reported having a regular doctor. PMID- 29243018 TI - Decreased MicroRNA miR-181c Expression Associated with Gastric Cancer. AB - PURPOSE: This study investigated miRNA-181c expression in control patients (healthy gastric mucosa), patients with gastritis, and patients with gastric cancer. The presence of Helicobacter pylori was determined, and the associations between H. pylori infection, levels of miRNA-181c expression, and gastric disease were also analyzed. METHODS: A total of 158 subjects were included in the study, and the three groups were respectively composed of 53 controls, 86 patients with gastritis, and 19 patients with gastric cancer. miRNA-181c expression and H. pylori infection were determined by quantitative real-time PCR and PCR, respectively. The subsequent target gene analysis was performed using the bioinformatics approach to understand the possible mechanisms of gastric cancer. RESULTS: We determined significantly lower miRNA-181c expression in the gastric cancer group when compared to the control and gastritis groups, regardless of the presence of H. pylori. There was no difference in miRNA-181c expression between the control group and gastritis group, whether the presence of H. pylori was considered or not. The bioinformatics approach identified several genes as possible targets for miRNA-181c, including the X-linked inhibitor of apoptosis (XIAP) gene (which encodes a protein that belongs to a family of apoptotic suppressor proteins), the caspase 9 gene, and the caspase 3 gene. All target genes identified may be involved in gastric cancer and apoptosis pathways. CONCLUSION: The results suggest that the presence of H. pylori has no influence on microRNA expression and that the downregulation of miR-181c may play an important role in gastric cancer progression by controlling important genes associated with apoptosis. Therefore, miRNA-181c may be a potential marker of gastric cancer. PMID- 29243019 TI - Evaluation of bone metastatic burden by bone SPECT/CT in metastatic prostate cancer patients: defining threshold value for total bone uptake and assessment in radium-223 treated patients. AB - OBJECTIVES: To establish a new three-dimensional quantitative evaluation method for bone metastasis, we applied bone single photon emission tomography with computed tomography (SPECT/CT). The total bone uptake (TBU), which measures active bone metastatic burden, was calculated as the sum of [mean uptake obtained as standardized uptake value (SUV) above a cut-off level] * (the volume of the lesion) in the trunk using bone SPECT/CT. We studied the threshold value and utility of TBU in prostate cancer patients treated with radium-223 (Ra-223) therapy. METHODS: To establish the threshold value of TBU, we compared bone metastatic and non-metastatic regions in 61 prostate cancer patients with bone metastasis and 69 without. Five fixed sites in each patient were selected as evaluation points and divided into bone metastatic and non-metastatic sites. Sensitivity and specificity analysis was applied to establish the threshold level. Using the obtained threshold value, we then calculated the TBU in nine prostate cancer patients who received Ra-223 therapy, and compared the results with the bone scan index (BSI) by BONENAVI(r) and visual evaluation of bone scintigraphy. RESULTS: Uptake was significantly lower in non-metastatic sites in patients with bone metastasis than in patients without metastasis. Sensitivity and specificity analysis revealed SUV = 7.0 as the threshold level. There was a discrepancy between TBU and BSI change in two of the nine patients, in whom TBU change correlated with visual judgement, but BSI change did not. In two patients, BSI was nearly 0 throughout the course, but the TBU was positive and changed, although the change was not large. These results suggest that TBU may be more accurate and sensitive than BSI for quantitative evaluation of active bone metastatic burden. CONCLUSION: We established a threshold value (SUV > 7.0) for three-dimensional TBU for evaluating active bone metastatic burden in prostate cancer patients using bone SPECT/CT. Despite the small number of patients, we expect the change in TBU could be more accurate and sensitive than the change in BSI among patients who received Ra-223. PMID- 29243020 TI - Effect of 1064-nm Q-switched Nd:YAG laser on invasiveness and innate immune response in keratinocytes infected with Candida albicans. AB - Candida albicans is an opportunistic pathogen commensal in the oral cavity, vagina, and healthy skin. Common therapeutic options for fungal infections are topical or systemic antifungal drugs. Recently, in cutaneous pathologies, lasers and light-based treatments have emerged showing few contraindications and minimal side effects. The Q-switched (Nd-YAG) laser at a wavelength of 1064 nm has been shown to be useful in dermatology, dentistry, and some other medical specialties. It is used to treat onychomycoses, warts, and wounds and in some other treatments. We analyzed the effect of Q-switched (Nd-YAG) laser 1064 nm on human keratinocytes infected with C. albicans. In particular, we evaluated the effect of laser on invasiveness of C. albicans and on inflammatory and protective response of HaCaT cells infected. The results obtained did not show inhibitory, fungicidal, or fungistatic effects of laser on yeast; in addition, laser did not affect HaCaT vitality. HaCaT cells infected with C. albicans and irradiated with laser showed a reduction of invasiveness of TNF-alpha and IL8 gene expression and an increase of immunomodulatory cytokines such as TGFbeta. Furthermore, laser induces a significant over-expression of HSP70B (heat shock protein) and of HBD-2 (Human beta defensin-2) in HaCaT infected with C. albicans, compared to the untreated control. The use of Q-switched Nd:YAG laser in skin mycosis caused by C. albicans reduces yeast invasiveness in keratinocytes, downregulates inflammatory activities, and facilitates cytoprotection and antimicrobial defense. Our results offer a promising therapeutic strategy in the management of skin candidiasis, also in combination with conventional therapies. PMID- 29243021 TI - Subclavian Artery Pseudoaneurysm Following Lung Abscess in a Child. PMID- 29243022 TI - A Novel Mutation in CD40LG Gene Causing X-Linked Hyper IgM Syndrome. PMID- 29243023 TI - LEF-1 is a Sensitive Marker of Cribriform Morular Variant of Papillary Thyroid Carcinoma. AB - Cribriform morular variant of PTC (CMV-PTC) frequently shows activation of the CTNNB1/Wnt pathway with nuclear accumulation of beta catenin. The utility of LEF 1, also in the CTNNB1/WNT pathway, in the diagnosis of CMV-PTC has not been previously studied. LEF-1 immunohistochemistry was performed on seven CMV-PTC, 52 benign cases and 101 malignant thyroid neoplasms. LEF-1 was scored by stain intensity (0 = no nuclear stain, 1 = weak nuclear stain, less than lymphocyte and 2 = strong nuclear stain, intense as lymphocyte) and percentage of positive cells at each intensity, for a maximum total score of 200. Sensitivity and specificity of LEF-1 stain for all cases and to differentiate between regular PTC and CMV-PTC was also calculated. Six of the seven CMV-PTCs showed >= 30% strong (2+) nuclear LEF-1 staining and a total score over 100. Beta catenin also showed strong and diffuse nuclear staining in these cases. One CMV-PTC was negative for both LEF-1 and beta catenin and did not have a history of FAP. All control PTC cases uniformly lacked LEF-1 staining at 2+ intensity. LEF-1 had a sensitivity of 86% and specificity of 98% for the diagnosis of CMV-PTC. LEF-1 is highly sensitive and specific marker for CMV-PTC, especially when used in the setting of a PTC neoplasm. The pattern of staining is important with >= 30% of cells showing strong 2+ nuclear staining having the highest combined sensitivity and specificity. PMID- 29243024 TI - Adenosquamous Carcinoma of the Tongue. AB - A 51-year-old white female presented with a painful ulcer of the left ventrolateral tongue. An incisional biopsy confirmed a diagnosis of adenosquamous carcinoma. The adenosquamous carcinoma is an uncommon malignant tumor with histopathological features of a squamous carcinoma and an adenocarcinoma. A definitive diagnosis requires histopathological examination of a deep biopsy involving the submucosal tissue. This malignant tumor shows aggressive behavior with early invasive growth and a poor prognosis. The histopathological findings and differential diagnosis of a case of adenosquamous carcinoma of the tongue are discussed. PMID- 29243025 TI - Heroin Use Could Be Also Associated with Ruptured Aortic Aneurysms. PMID- 29243026 TI - Unraveling the Mechanisms of Memory Extinction. PMID- 29243027 TI - Lactobacillus rhamnosus reduces parasite load on Toxocara canis experimental infection in mice, but has no effect on the parasite in vitro. AB - Human toxocariasis is a neglected global parasitic zoonosis. The efficacy of drug treatment for this disease has been hindered by the biological complexity of the main etiological agent, the nematode Toxocara canis. Experimental studies have shown the potential of probiotics to promote a reduction in the parasite load of T. canis larvae. This study aimed to evaluate the effect of probiotic Lactobacillus rhamnosus ATCC 7469 on the parasite load of BALB/c mice with acute toxocariasis and evaluate the direct effect of this probiotic on T. canis larvae in vitro. In vivo administration of probiotics reduced the parasite load of T. canis larvae by 53.3% (p = 0.0018) during the early stage of infection in mice. However, when analyzed in vitro, it was observed that the probiotic did not present a deleterious effect on the larvae, as approximately 90% of these remained viable. These results demonstrate the potential of the probiotic L. rhamnosus in the reduction of T. canis larvae in BALB/c mice and suggest it could be used as an alternative means for the controlling of visceral toxocariasis. However, further studies are required to elucidate the mechanisms of action promoted by this probiotic. PMID- 29243028 TI - Perspectives from the Patient and the Healthcare Professional in Multiple Sclerosis: Social Media and Patient Education. AB - A diagnosis of multiple sclerosis (MS) is life-altering. Because the course of MS is heterogeneous, patients may face uncertainty in terms of long-term physical and cognitive challenges, potential loss of employment, and the risk of social isolation. Patients often turn to the Internet and social media for information about MS and its management, and to seek out fellow patients and support groups. Here, we examine the use of social media and the Internet among patients with MS, considering its impact on patient education. We consider the access that these conduits provide not only to other patients with MS but also to a wealth of disease-related information online. These themes are further illustrated with first-hand experiences of the patient author and her physician. We also explore the impact of the Internet and social media on the education and support of patients with MS from the healthcare professional's (HCP's) perspective, including opportunities for HCPs to promote disease education among their patients, and the advantages that arise from patients being better informed about their disease. The rise of the Internet and social media has changed the patient experience, helping patients to support each other, to educate themselves proactively about their condition, and to participate more actively in decisions relating to disease management than perhaps was the case historically. Funding Novartis Pharmaceuticals Corporation. PMID- 29243029 TI - Vitamin D and Multiple Sclerosis: A Comprehensive Review. AB - Numerous observational studies have suggested that there is a correlation between the level of serum vitamin D and MS risk and disease activity. To explore this hypothesis, a literature search of large, prospective, observation studies, epidemiological studies, and studies using new approaches such as Mendelian randomization was conducted. Available data and ongoing research included in this review suggest that the level of serum vitamin D affects the risk of developing MS and also modifies disease activity in MS patients. Newer Mendelian randomization analyses suggest there is a causal relationship between low vitamin D level and the risk of MS. Post-hoc evaluations from two phase 3 studies, BENEFIT and BEYOND, support the findings of observational trials. Study limitations identified in this review recognize the need for larger controlled clinical trials to establish vitamin D supplementation as the standard of care for MS patients. Though there is increasing evidence indicating that lower vitamin D levels are associated with increased risk of MS and with greater clinical and brain MRI activity in established MS, the impact of vitamin D supplementation on MS activity remains inadequately investigated. PMID- 29243030 TI - Sinapic Acid Inhibits the IL-1beta-Induced Inflammation via MAPK Downregulation in Rat Chondrocytes. AB - Osteoarthritis (OA) is a degenerative joint disease frequently seen in the elderly population. Sinapic acid (SA), a commonly found phenolic acid, has been pharmacologically evaluated for its anti-inflammation effects in various studies. To explore its potential therapeutic role for OA, rat chondrocytes were treated with IL-1beta (10 ng/ml) with different concentrations of SA in vitro. Our study revealed that SA could inhibit the IL-1beta-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2). Consistent with these findings, the increased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (Cox) 2 could also be downregulated by SA. Moreover, SA could also suppress the IL 1beta-induced expression of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) in chondrocytes. Furthermore, our data found that SA could suppress the IL-1beta induced mitogen-activated protein kinase (MAPK) pathway activation. In general, this paper elucidates that sinapic acid inhibits the IL-1beta-induced inflammation via MAPK pathways and may be a good agent for the treatment of OA. PMID- 29243031 TI - Prospective randomization of post-remission therapy comparing autologous peripheral blood stem cell transplantation versus high-dose cytarabine consolidation for acute myelogenous leukemia in first remission. AB - We prospectively compared outcomes of autologous stem cell transplantation (ASCT) versus high-dose cytarabine (HiDAC) consolidation as post-remission therapy for favorable- and intermediate-risk acute myelogenous leukemia (AML) in first complete remission (CR1). Two-hundred-forty patients under 65 years with AML-M1, M2, M4, or M5 subtypes were enrolled. After induction, 153 patients did not undergo randomization, while the remaining 87 who achieved CR1 were prospectively randomized to HiDAC (n = 45) or ASCT arm (n = 42). In the HiDAC arm, 43 patients completed three cycles of HiDAC, whereas in ASCT arm 22 patients completed two cycles of consolidation consisting of intermediate-dose cytarabine plus mitoxantrone or etoposide followed by ASCT. The three-year disease-free survival (DFS) rate was 41% in HiDAC and 55% in ASCT arm (p = 0.25). Three-year overall survival (OS) rates were 77 and 68% (p = 0.67). Incidence of relapse was 54 and 41% (p = 0.22). There was no significant difference in nonrelapse mortality between two arms (p = 0.88). Patients in the ASCT arm tended to have higher DFS rates and lower relapse rates than patients in HiDAC; however, there was no significant improvement in OS in patients with favorable- and intermediate-risk AML in CR1. Patients with AML are not benefited by the intensified chemotherapy represented by ASCT. PMID- 29243033 TI - Incontinence-Associated Dermatitis: Pathogenesis, Contributing Factors, Prevention and Management Options. AB - Incontinence-associated dermatitis (IAD) is a common type of irritant contact dermatitis, seen in patients with urinary or faecal incontinence. Mechanical factors such as traumata and friction may aggravate the lesions. The fragile skin in elderly patients is more prone to developing IAD. The clinical picture of IAD consists of persistent redness on the one hand and skin loss on the other. Both categories may be associated with clinical signs of major colonisation or infection. It is important to distinguish IAD from pressure ulcers and other dermatoses in the genital region. Due to the lack of well-established clinical trials, recommendations about prevention and treatment are based on expert opinion and best practice. Gentle cleansing, use of hydrating topical agents and application of barrier products are the main elements in the prevention and treatment of IAD. It is important to translate these recommendations and general guidelines into ready-to-use protocols that can be implemented for each specific clinical manifestation of IAD. PMID- 29243032 TI - Zinc Transporter Proteins. AB - Zinc, which is involved in the structure of all enzyme classes, is a micro nutrient element and necessary for growth and development. The ability of zinc to function without causing toxic effects is depends on the protection of its homeostasis. Zinc transporter proteins are responsible for keeping zinc at certain concentrations. Based on their predicted membrane topology, Zn transporters are divided into two major families, SLC39s/ZIPs and SLC30s/ZnTs, which transport Zn in opposite directions through cellular and intracellular membranes. ZIPs increases the zinc concentration in the cytosol. For this, the ZIPs carries the zinc from extracellular and intracellular compartments to the cytosol. ZnTs, reduces the concentration of zinc in the cytosol. For this, ZnTs carries the zinc from the cytosol to extracellular and intracellular compartments. After being transported to the cell, 50% of the zinc is found in the cytoplasm, 30-40% in the nucleus, and 10% in the plasma and organelle membranes. The expression of many zinc transporter proteins in the cell is depending on the concentration of zinc and the physiological problems. The aim of this study is to give information about association of zinc transporter proteins with physiological events and health problems. PMID- 29243034 TI - Application of Pyridostigmine in Pediatric Gastrointestinal Motility Disorders: A Case Series. AB - BACKGROUND: Gastrointestinal (GI) motility disorders are common in children. Treatment is challenging with limited medical and surgical options. Pyridostigmine, an acetyl cholinesterase inhibitor, increases acetylcholine at the neuromuscular junction promoting intestinal contractions. Little is known about the role and dosing of pyridostigmine in pediatric GI motility disorders. METHODS: We present a case series of children with GI dysmotility managed with oral pyridostigmine. Patients' diagnoses include chronic intestinal pseudo obstruction, gastroparesis with delayed small bowel transit, chronic constipation with failure to thrive, and prolonged ileus after pelvic surgery with chronic opioid use. RESULTS: Pyridostigmine was effective and safe in all cases. Pyridostigmine decreased abdominal distention, increased bowel movement frequency, and improved enteral feeding tolerance. Effective dosing ranged between 0.25-2.0 mg/kg/day. One patient experienced cramping abdominal pain while on pyridostigmine, but pain resolved after medication was discontinued. CONCLUSION: We found oral pyridostigmine to be helpful in children with different GI motility problems. Pyridostigmine should be considered in such patients when other treatment interventions have not been beneficial. PMID- 29243035 TI - Systemic lupus erythematosus and ocular involvement: an overview. AB - Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of undefined etiology and with remarkably heterogeneous clinical features. Virtually any organ system can be affected, including the eye. SLE-related eye involvement can be diagnosed in approximately one-third of the patients and is usually indicative of disease activity. An early diagnosis and the adoption of suitable therapeutic measures are necessary to prevent sight-threatening consequences, especially in patients with juvenile SLE. Periocular lesions, such as eyelid involvement and orbital inflammation, are relatively rare and, in case of orbital masses, may require a biopsy control. Keratoconjunctivitis sicca or secondary Sjogren's syndrome is the most frequent ophthalmic manifestation of SLE. According to its variable severity, lubricating tear drops may be sufficient in mild cases, whereas cyclosporine-A ophthalmic solution, glucocorticoids (GCs), methotrexate, and/or other immunosuppressive drugs may be required in the more severe cases. Partial occlusion of the lacrimal punctum by thermal cautery is rarely applied. Although uncommon, episcleritis and scleritis can sometimes be detected as an initial finding of SLE and reveal themselves as moderate to intense ocular pain, redness, blurred vision, and lacrimation. Unilateral or more often bilateral retinopathy is responsible for visual loss of variable severity and is ascribed to vasculitis of the retinal capillaries and arterioles. In addition to the combined treatment suitable for all patients with active SLE, intravitreal bevacizumab should be considered in cases of severe vaso-occlusive retinopathy and laser photocoagulation in cases of neovascularization. Purtscher like retinopathy is likely ascribable to the formation of microemboli that results in retinal vascular occlusion and microvascular infarcts. Choroidal disease is characterized by monolateral or bilateral blurred vision. Because of the choroidal effusion, retinal detachment and secondary angle-closure glaucoma may occur. Ischemic optic neuropathy is characterized by acute-onset and progressive binocular visual impairment as a consequence of occlusion of the small vessels of the optic nerves due to immune complex vasculitis. Intravenous GC boluses followed by oral GCs and/or, in case of recurrence, intravenous cyclophosphamide and/or rituximab are commonly employed. Neovascularization can be treated by intravitreal bevacizumab and progression of retinal ischemic areas by retinal laser photocoagulation. Ocular adverse events (AE) have been described following the long-term administration of one or more of the drugs presently used for the treatment of SLE patients. Posterior subcapsular cataracts and secondary open-angle glaucoma are common AE of the prolonged GC administration. The long term administration of hydroxychloroquine (HCQ) sulfate is well known to be associated with AE, such as vortex keratopathy and in particular the often irreversible and sight-threatening maculopathy. Length of administration > 5 years, > 1000 g total HCQ consumption, > 6.5 mg/kg daily dosing, coexistence of renal disease, and preexisting maculopathy are all considered risk factors for HCQ-induced retinopathy. Ocular AE of additional immunosuppressive and biological agents are still poorly known, given the worldwide more limited experience with their long-term use. A thorough ophthalmological control is strongly recommended at closer intervals for all SLE patients, in step with the total length of exposure to the drugs and the cumulative dose administered. PMID- 29243036 TI - Mediators of angiogenesis and fibrosis in IgG4-related disease. AB - IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory condition that can affect almost any organ, characterized by tumefactive lesions and often by eosinophilia and elevated serum IgG4 concentrations. The aim of the study is to analyze in IgG4-RD patients the serum levels of a group of cytokines and growth factors potentially involved in the regulation of fibrotic processes. In the sera of 12 patients affected by IgG4-RD and of 15 normal healthy subjects (NHS), pro fibrogenic mediators (TGF-beta1 and periostin) and pro- (VEGF and angiogenin-1) and anti- (endostatin and thrombospondin-1) angiogenic mediators were measured by sandwich enzyme immunoassay. Among mediators regulating fibrosis and angiogenesis, endostatin levels were significantly higher in IgG4-RD patients compared to NHS (p < 0.0001). No differences in the levels of TGF-beta1, periostin, VEGF, angiogenin-1 and thrombospondin-1 were observed between groups. Our study suggests that among the mediators mainly involved in fibrosis and angiogenesis endostatin might play a role in the pathogenetic processes of IgG4 RD. PMID- 29243037 TI - Expert Opinion vs Patient Perspective in Treatment of Rare Disorders: Tooth Removal in Lesch-Nyhan Disease as an Example. AB - Treatment recommendations for rare disorders often are limited by a lack of data from objective clinical trials. As a result, recommendations are often based on expert opinion. Because expert opinions sometimes conflict, many patients turn to the Internet for guidance from others who may have tried a treatment. The increasing numbers of patients and families who post opinions regarding outcomes allow for systematic data collection regarding specific treatments from the patient perspective. We used social media research methods to determine the opinions of family members or other caregivers regarding permanent removal of teeth for treatment of self-injurious biting (SIB) in patients with Lesch-Nyhan disease (LND), a particularly difficult treatment decision where expert opinion is divided. A content analysis of social media postings was used to systematically interpret caregiver posts about tooth extraction from families and other caregivers of patients with LND who posted comments regarding physical or emotional well-being after tooth extraction. A scale was used to rate all posted opinions. Scores ranged from 1 to 5, with 1 being completely negative and 5 being completely positive. 170 comments from 46 unique individuals were collected and scored by two raters. Inter-rater reliability, determined using a correlation coefficient across all postings, was 0.85, suggesting a high degree of reliability. The overall average caregiver sentiment score was 4.86, which is an overwhelmingly positive endorsement of tooth extraction as a means for controlling SIB. These methods provide a simple strategy for recommending treatment strategies based on real-world experience when objective clinical trials are unviable. PMID- 29243038 TI - What Performance Analysts Need to Know About Research Trends in Association Football (2012-2016): A Systematic Review. AB - BACKGROUND: Evolving patterns of match analysis research need to be systematically reviewed regularly since this area of work is burgeoning rapidly and studies can offer new insights to performance analysts if theoretically and coherently organized. OBJECTIVE: The purpose of this paper was to conduct a systematic review of published articles on match analysis in adult male football, identify and organize common research topics, and synthesize the emerging patterns of work between 2012 and 2016, according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. METHODS: The Web of Science database was searched for relevant published studies using the following keywords: 'football' and 'soccer', each one associated with the terms 'match analysis', 'performance analysis', 'notational analysis', 'game analysis', 'tactical analysis' and 'patterns of play'. RESULTS: Of 483 studies initially identified, 77 were fully reviewed and their outcome measures extracted and analyzed. Results showed that research mainly focused on (1) performance at set pieces, i.e. corner kicks, free kicks, penalty kicks; (2) collective system behaviours, captured by established variables such as team centroid (geometrical centre of a set of players) and team dispersion (quantification of how far players are apart), as well as tendencies for team communication (establishing networks based on passing sequences), sequential patterns (predicting future passing sequences), and group outcomes (relationships between match-related statistics and final match scores); and (3) activity profile of players, i.e. playing roles, effects of fatigue, substitutions during matches, and the effects of environmental constraints on performance, such as heat and altitude. CONCLUSION: From the previous review, novel variables were identified that require new measurement techniques. It is evident that the complexity engendered during performance in competitive soccer requires an integrated approach that considers multiple aspects. A challenge for researchers is to align these new measures with the needs of the coaches through a more integrated relationship between coaches and researchers, to produce practical and usable information that improves player performance and coach activity. PMID- 29243040 TI - Protective effect of acacetin on sepsis-induced acute lung injury via its anti inflammatory and antioxidative activity. AB - Sepsis is a clinical syndrome with no effective protective or therapeutic treatments. Acacetin, a natural flavonoid compound, has anti-oxidative and anti inflammatory effects which can potentially work to reduce sepsis. We investigated the potential protective effect of acacetin on sepsis-induced acute lung injury (ALI) ALI and dissect out the underlying mechanisms. Mice were divided into five groups: a sham group, a sepsis-induced ALI group, and three sepsis groups pre treated with 20, 40, and 80 mg/kg body weight of acacetin. We found that acacetin significantly attenuated sepsis-induced ALI, in histological examinations and lung edema. Additionally, acacetin treatment decreased protein and inflammatory cytokine concentration and the number of infiltrated inflammatory cells in BALF compared with that in the non-treated sepsis mice. Pulmonary myeloperoxidase (MPO) activity was lower in the acacetin-pre-treated sepsis groups than in the sepsis group. The mechanism underlying the protective effect of acacetin on sepsis is related to the regulation of certain antioxidation genes, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), superoxide dismutases (SODs), and heme oxygenase 1 (HO-1).Taken together, our results indicate that acacetin pre-treatment inhibits sepsis-induced ALI through its anti inflammatory and antioxidative activity, suggesting that acacetin may be a potential protective agent for sepsis-induced ALI. PMID- 29243039 TI - Alkaloids from Narcissus poeticus cv. Pink Parasol of various structural types and their biological activity. AB - Fifteen Amaryllidaceae alkaloids (1-15) of various structural types were isolated by standard chromatographic methods from fresh bulbs of Narcissus poeticus cv. Pink Parasol. The chemical structures were elucidated by MS, and 1D and 2D NMR spectroscopic analyses, and by comparison with literature data. Narcipavline (5) and narcikachnine (6) are reported here for the first time. In their structure are combined two basic structural types of Amaryllidaceae alkaloids (galanthamine and galanthindole-structural types), which represent a new structural type of these compounds. Alkaloids isolated in sufficient amounts were evaluated for their human erythrocytic acetylcholinesterase, and human serum butyrylcholinesterase (HuBuChE) inhibition activity using Ellman's method. Z-Gly Pro-p-nitroanilide was used as substrate in the prolyl oligopeptidase (POP) assay. Untested alkaloids were also screened for their cytotoxic activity against a small panel of human cancer cells, which spanned cell lines from different tissue types. In parallel, MRC-5 human fibroblasts were employed to determine overall toxicity against noncancerous cells. Some compounds were evaluated for their antiprotozoal activity. The newly isolated alkaloid narcipavline (5) showed interesting HuBuChE inhibition activity (IC50 = 24.4 +/- 1.2 uM), and norlycoramine (11) demonstrated promising POP inhibition (IC50 = 0.21 +/- 0.01 mM). PMID- 29243041 TI - Cre/loxP-Mediated Multicopy Integration of the Mevalonate Operon into the Genome of Methylobacterium extorquens AM1. AB - Methylobacterium extorquens AM1 is the model strain for methylotrophic bacteria that metabolize methanol as the sole carbon and energy source. Genetically modified M. extorquens AM1 is used as a methylotrophic cell factory (MeCF) for high value-added chemical production. We tested the Cre-loxP recombination system for its ability to mediate multicopy gene integration of the mvt3 operon (mvt3) in M. extorquens AM1. mvt3 controls the expression of the first three enzymes of the mevalonate synthesis pathway. We assayed for Cre-mediated multigene integration by screening for multicopy mutants via their survival in culture with a high kanamycin concentration (600 MUg/mL). We identified mutant strains in which the mevalonate titer was increased by up to 1.9-fold compared with M2 (M. extorquens AM1DeltacelABCDeltaattTn7::mvt3::loxP) and confirmed mvt3 integration at 2-3 copies per genome. This result demonstrates the feasibility of multicopy integration in M. extorquens AM1 mediated by Cre-loxP recombination and its potential for improving the output of M. extorquens AM1 metabolic pathways, e.g., optimization of terpenoid synthesis. PMID- 29243042 TI - CALB-Catalyzed Two-Step Alcoholytic Desymmetrization of 3-Methylglutaric Diazolides in MTBE. AB - Optically pure 3-substituted glutarates can be prepared from the alcoholic ring opening of cyclic anhydride derivatives, esterification of 3-substituted glutaric acid, and hydrolysis, alcoholysis, aminolysis, and ammonolysis of the diester derivatives via hydrolases or organocatalysts. Unfortunately, most of them mainly focus on the first-step desymmetrization, leading to the difficulty on producing optically pure enantiomers. As a general trend in lipase-catalyzed desymmetrization of 3-methylglutarates, poorer enantiomeric excesses with lower chemical yields were found, as the methyl substituent is relatively small to induce a high enzyme stereodiscrimination. The two-step desymmetrization for CALB catalyzed alcoholysis of 3-methylglutaric di-1,2,4-triazolide 1a in anhydrous MTBE is first developed to increase the enzyme activity in each reaction step. The enantioselectivity for the second-step kinetic resolution is furthermore improved by using 3-methylglutaric dipyrazolide 1b as the substrate. The kinetic and thermodynamic analysis is, moreover, addressed for shedding insights into the desymmetrization process. PMID- 29243043 TI - Quality of life in a broader perspective: Does ASCOT reflect the capability approach? AB - PURPOSE: Economic evaluation of services and interventions in care services tends to focus on quality of life(QoL) based on health-related measures such as EQ5D, with a major focus on health and functioning. The Capability Approach (CA) provides an alternative framework for measuring QoL and challenges some of the conventional issues in the current practice of measurement of QoL. The Adult Social Care Outcomes Toolkit (ASCOT) aims to measure social care-related QoL in a broad sense. This article investigates whether and, if so, how the ASCOT addresses issues put on the agenda by the CA. METHODS: Literature analysis concerning theoretical assumptions and arguments of CA and ASCOT. RESULTS: The Capability Approach (CA) puts three issues on the agenda regarding QoL. First, the focus of evaluation should not be on functioning, but on freedom of choice. Second, evaluation should be critical about adaptive preferences, which entail that people lower expectations in situations of limited possibilities. Third, evaluation should not only address health, but also other domains of life. Our analysis shows that freedom of choice is reflected in the response option 'as I want' in the ASCOT questionnaire. The problem of adaptive preferences is countered in the ASCOT by developing a standard based on preferences of the general population. Third, the ASCOT contains several domains of life. CONCLUSIONS: We conclude that the CA and the ASCOT contribute to the discussion on QoL, and that the ASCOT operationalizes core assumptions of the CA, translating the issues raised by the CA in a practical way. PMID- 29243045 TI - Prognostic information on HCM patients via speckle tracking. PMID- 29243044 TI - Conversion of standard retrospective patient-reported outcomes to momentary versions: cognitive interviewing reveals varying degrees of momentary compatibility. AB - PURPOSE: The purpose of this study was to adapt different domains of an existing retrospective questionnaire to momentary versions, to use and assess cognitive interviewing for evaluating the new versions, and to compare momentary compatibility (i.e. an item's potential to be validly converted to a momentary version) across different scales. METHODS: Initial momentary versions of retrospective patient-reported outcomes were produced by converting present perfect tense wording to present tense wording. Cognitive interviews were conducted iteratively with 21 patients to determine which reference period they actually employed, and to identify problems with new, revised versions. A think aloud interview protocol was supplemented with non-specific concurrent and specific retrospective probing. The momentary compatibility of each item was evaluated by calculating the proportion of interviews wherein momentary reference periods were identified; problems were categorized according to cognitive aspects of survey methodology taxonomy. The efficiency of various cognitive interviewing techniques was determined by evaluating whether applied reference periods were identified by think-aloud alone or by supplementary probes. RESULTS: The momentary compatibility varied from 5 to 100% across items. Cognitive interviews revealed potential problems of various severities in the majority of items. Think aloud alone was sufficient at determining the applied reference period in one third of the cases, and the efficiency of additional concurrent and retrospective probing was 50 and 94%, respectively. CONCLUSIONS: Cognitive interviewing techniques proved useful for developing and evaluating momentary items. Researchers should be aware of the applied reference period and of emerging problems when evaluating adapted momentary items, since not all concepts are suitable. We recommend the proposed method in future adaptations of existing instruments. PMID- 29243046 TI - [Stem cell-based cardiac regeneration after myocardial infarction]. AB - Myocardial infarction leads to an irreversible loss of vital myocardial cells. The transplantation of new cardiomyocytes into the heart was first described over 20 years ago and represents a straightforward approach to remuscularize a damaged heart. Due to the lack of human cells a clinical application seemed ambitious; however, dramatic progress in stem cell biology over the last two decades has paved the way towards a clinical application. This is especially important as the prognosis for patients with terminal heart failure is still poor. The transplantation of either cardiomyocytes or engineered heart tissue derived from pluripotent stem cells (either embryonic stem cells or induced pluripotent stem cells) might represent a new regenerative approach. Transplantation of either cells or tissue constructs has now been evaluated in several preclinical models, which have demonstrated that an injured heart can be (partially) remuscularized; however, major hurdles towards a clinical application are the transplantation related occurrence of arrhythmia, the potential tumorigenicity of pluripotent cells and the required immunosuppression. Several groups are working hard to solve these problems and we are optimistic that the first clinical studies will take place within the next few years. PMID- 29243047 TI - Role of beta-catenin in cisplatin resistance, relapse and prognosis of head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of cancer in India with high incidence and rapid recurrence rates. Here, we aimed to investigate the role of beta-catenin, a developmental pathway gene, in HNSCC therapy resistance, DNA damage response, recurrence and prognosis. METHODS: In total 80 HNSCC samples were included. Western blot, immunohistochemistry and qRT-PCR analyses were performed to assess beta-catenin expression in the cut margin and tumor areas of each sample. Kaplan-Meier analyses were performed to correlate beta-catenin expression with the survival and prognosis of HNSCC patients. In addition, chemo-resistance, DNA damage response and DNA repair capacities were evaluated in HNSCC-derived cell lines through LiCl-mediated up-regulation and siRNA-mediated silencing of beta-catenin expression. RESULTS: We observed beta-catenin up-regulation in cut margin areas of recurrent patients compared to their corresponding tumor regions, which subsequently could be associated with poor prognosis. In addition, we found that LiCl-mediated up-regulation of beta-catenin in HNSCC-derived cells led to cisplatin resistance, evasion of apoptosis, enhanced DNA repair and enhanced migration. The effects of beta-catenin silencing correlated with its putative role in chemo-resistance and DNA damage response. CONCLUSION: From our results we conclude that beta-catenin may contribute to HNSCC therapy resistance and disease relapse. As such, beta-catenin may be explored as a therapeutic target along with conventional therapeutics. PMID- 29243048 TI - Spectroscopic Evidence of Phosphorous Heterocycle-DNA Interaction and its Verification by Docking Approach. AB - In the present work, the interaction of phosphorous heterocycle (PH) with calf thymus DNA (CTDNA) has been studied using spectroscopy and verified by molecular modeling which is found to be in consonance with each other. Apparent association constant (Kapp = 4.77 * 103 M- 1), calculated using UV-Vis spectra indicating an adequate complex formation between CTDNA and PH. A dynamic mode of the fluorescence quenching mechanism in case of ethidium bromide (EB) + CTDNA by PH has been observed confirming formation of DNA-PH complex. A moderate binding constants of PH with CTDNA + EB has been observed (2.74 * 104 M- 1 at 293 K) by means of fluorescence data. Calculated values of thermodynamic parameters enthalpy change (DeltaH) and entropy change (DeltaS), suggests weak (van der Walls like) force and hydrogen bonds playing the main role in the binding of PH to CTDNA. Furthermore, the results of circular dichroism (CD) reveal that PH does not disturb native conformation of CTDNA. As observed from absorption and fluorescence spectroscopy the binding mode of PH with DNA was indicative of a non intercalative binding, which was supposed to be a groove binding. The molecular modeling results show that PH is capable of binding DNA having docking binding energy = -7.26 kcal * mol- 1. Above mentioned experimental results are found to be in consonance with molecular docking simulations and supports the CTDNA-PH binding. Graphical Abstract. PMID- 29243049 TI - High PD-L1 expression indicates poor prognosis of HIV-infected patients with non small cell lung cancer. AB - BACKGROUND: The status of antitumor immunity represented by the expression of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) and immune cell (IC) infiltration is unknown in HIV-infected patients with non-small cell lung cancer (NSCLC). METHODS: Fifteen HIV-infected patients with NSCLC were compared with 29 non-HIV-infected patients with NSCLC. Analysis of 13 propensity score-matched patients in the two groups was also compared. The expression of PD 1/PD-L1 and tumor infiltration by CD4+, CD8+, and CD56+ immune cells were examined by immunohistochemistry; score of >= 2 was defined as positive. RESULTS: Although high PD-L1 expression in tumor cells was observed in HIV and non-HIV cohorts, the association of PD-1/PD-L1 was significant only in the HIV cohort. In overall as well as the propensity-matched analyses, HIV-infected patients with high PD-L1 expression showed shorter survival than HIV-infected patients with low PD-L1 expression; no significant difference was observed in this respect in the non-HIV cohort. CONCLUSION: High PD-L1 expression in tumor tissue was associated with poor prognosis in HIV-infected NSCLC patients but not in non-HIV-infected NSCLC patients. These results suggest that antitumor immunity by PD-1/PD-L1 axis might be suppressed more in HIV-infected NSCLC patients as compared to their non HIV-infected counterparts. PMID- 29243050 TI - A single point mutation in precursor protein VI doubles the mechanical strength of human adenovirus. AB - Viruses are extensively studied as vectors for vaccine applications and gene therapies. For these applications, understanding the material properties of viruses is crucial for creating optimal functionality. Using atomic force microscopy (AFM) nanoindentation, we studied the mechanical properties of human adenovirus type 5 with the fiber of type 35 (Ad5F35) and compared it to viral capsids with a single point mutation in the protein VI precursor protein (pVI S28C). Surprisingly, the pVI-S28C mutant turned out to be twice as stiff as the Ad5F35 capsids. We suggest that this major increase in strength is the result of the DNA crosslinking activity of precursor protein VII, as this protein was detected in the pVI-S28C mutant capsids. The infectivity was similar for both capsids, indicating that mutation did not affect the ability of protein VI to lyse the endosomal membrane. This study highlights that it is possible to increase the mechanical stability of a capsid even with a single point mutation while not affecting the viral life cycle. Such insight can help enable the development of more stable vectors for therapeutic applications. PMID- 29243051 TI - Diagnostic outcome and indications for testing in patients with positive ANCA at a Canadian tertiary care centre. AB - INTRODUCTION/OBJECTIVE: With widespread availability of anti-neutrophil cytoplasmic antibody (ANCA) testing, interpreting positive results has become increasingly challenging. Here, we conducted a retrospective study to evaluate indications for testing and diagnosis of patients with positive ANCA. METHODS: Positive ANCA tests (immunofluorescence or immunoassay) performed between April 2014 and March 2015 were identified using the Ottawa Hospital (TOH) laboratory information system. TOH electronic records of subjects with positive ANCA were reviewed. RESULTS: 96 patients had first-time positive ANCA in the study year. The indications for testing were suspicion for: AAV in 22 patients (23%), unspecified vasculitis in 24(25%), an inflammatory condition in 46(48%), and unknown in 4(4%). Twenty-eight patients (29% of first-time positives) were diagnosed with AAV, corresponding to 16(72%), 8(33%), 4(9%), and 0 patients tested for these indications, respectively; 49(51%) of patients had other inflammatory or infectious etiologies, and non-inflammatory diagnoses accounted for the remaining 19(20%). One hundred and forty-four repeat ANCAs were performed with life-time mean of 4.4 re-tests per patient (range 0-44). Routine monitoring accounted for 86(72%) of all repeat tests. Management was changed following 34% of all re-tests performed for changed clinical status and 1% of re-tests conducted routinely. CONCLUSION: Few patients who start with low clinical suspicion for AAV and have positive ANCA are subsequently diagnosed with AAV. Serial ANCA testing is common but is not supported by clear evidence, and rarely leads to change in management. Clarification of guidelines on effective ANCA ordering may reduce hospital laboratory costs. PMID- 29243052 TI - Motivation and emotion predict medical students' attention to computer-based feedback. AB - Students cannot learn from feedback unless they pay attention to it. This study investigated relationships between the personal factors of achievement goal orientations, achievement emotions, and attention to feedback in BioWorld, a computer environment for learning clinical reasoning. Novice medical students (N = 28) completed questionnaires to measure their achievement goal orientations and then thought aloud while solving three endocrinology patient cases and reviewing corresponding expert solutions. Questionnaires administered after each case measured participants' experiences of five feedback emotions: pride, relief, joy, shame, and anger. Attention to individual text segments of the expert solutions was modelled using logistic regression and the method of generalized estimating equations. Participants did not attend to all of the feedback that was available to them. Performance-avoidance goals and shame positively predicted attention to feedback, and performance-approach goals and relief negatively predicted attention to feedback. Aspects of how the feedback was displayed also influenced participants' attention. Findings are discussed in terms of their implications for educational theory as well as the design and use of computer learning environments in medical education. PMID- 29243053 TI - Should biodiversity and nature have to earn their keep? What it really means to bring environmental goods into the marketplace. AB - Pursuit of economic gain has sponsored much of our planet's despoliation. Yet conservation increasingly operates as an economic sector that markets biodiversity, ecosystems, and nature as natural capital, service provider, or option value. This essay first elucidates what basic moral theory says about the principle that the goodness of biodiversity and nature is largely economic. It explains why economic valuations may be morally unimportant, inapt for environmental goods, and subversive of more important ideals. It also shows why neither econometric notions of option value nor Daniel Faith's qualitative one credibly applies. The essay then turns to what an economic conception of goodness implies for conservation practice. It refers to two prominent conservation organizations, whose conservation principles match the market-based ones of the World Business Council on Sustainable Development's. The environmental record of the latter organization's practices according to these principles predicts what their adoption for conservation entails. PMID- 29243054 TI - Strategies for reducing airborne pesticides under tropical conditions. AB - Brazil is currently one of the largest pesticide consumers worldwide. However, a lack of scientific information regarding airborne pollution is still an issue, with tragic consequences to human health and the environment. To reduce pollution of the lower air layers, where pesticide spraying occurs, green barriers that filter the air could be an effective mitigation procedure. Modifying pulverization habits, by pulverizing in the late afternoon instead of in the morning could also reduce pesticide volatilization, while other recommendations with the purpose of lowering the pesticide amounts currently applied are likewise pursued. Data obtained about volatilization have demonstrated that, in order to reduce air pollution risks, one of the most effective preventive strategies is to ban products with high vapor pressure. Global/local stakeholders need to assume the responsibility to find the best way to reduce airborne pesticide pollution, which has increasingly shown disastrous effects as major poisons to human health and the environment. PMID- 29243055 TI - Population-based study suggests an increased risk of Alzheimer'sdisease in Sjogren's syndrome. AB - This population-based study was designed to estimate and compare the risk of Alzheimer's disease (AD) between patients with primary Sjogren's syndrome (SS) and non-SS patients during a 10-year follow-up period. This is a retrospective cohort study. Data were obtained from the Taiwan's National Health Insurance Research Database. We identified 4463 primary SS patients and 22,315 non-SS patients; patients were matched by sex, age, and the year of index use of health care. Each patient was studied to identify the subsequent manifestation of AD. Cox proportional hazard regression was used to study the subsequent manifestation of AD, and Kaplan-Meier survival curves were used to compare survival probability. During the 10-year follow-up period, 7 primary SS and 13 non-SS patients developed AD. During the 10-year follow-up period, the risk of AD was 2.68-fold higher in the primary SS cohort with an overall adjusted hazard ratio (HR) of 2.69 (95% CI 1.07-6.76), after adjusting for demographics and comorbidities. Within the 10-year period, patients with primary SS showed a 2.69 fold increased risk of developing AD. This risk increases with time, and the relative risk of AD is higher in older patients with primary SS. PMID- 29243056 TI - Association between urinary sodium and potassium excretion and blood pressure and inflammation in patients with rheumatoid arthritis. AB - Hypertension is highly prevalent in patients with rheumatoid arthritis (RA). In other populations, high sodium (Na+) and low potassium (K+) intake are associated with an increased risk of hypertension, and in animal models, a high salt intake exacerbated arthritis. Patients with RA have many comorbidities associated with salt sensitivity, but their salt intake and its relationship to blood pressure and inflammation is unknown. Using the Kawasaki formula, Na+ and K+ urinary excretion (reflecting intake) was estimated in 166 patients with RA and 92 controls, frequency matched for age, sex, and race. Inflammatory markers and disease activity were measured in RA patients. We tested the associations between blood pressure and Na+ and K+ excretion. Estimated 24-h Na+ excretion was similarly high in both RA (median [IQR] 5.1 g, [3.9-6.6 g]) and controls (4.9 g, [4.0-6.5 g]), p = 0.9, despite higher rates of hypertension in RA (54 vs. 39%, p = 0.03). The Na+:K+ excretion ratio was significantly higher in RA (2.0 [1.6 2.4]) vs. 1.7 [1.5-2.1]), p = 0.02] compared to controls. In RA, a lower K+ excretion was inversely correlated with diastolic blood pressure (adjusted beta = - 1.79, p = 0.04). There was no significant association between Na+ or K+ excretion and inflammatory markers. Despite a similar Na+ excretion, patients with RA had higher rates of hypertension than controls, a finding compatible with increased salt sensitivity. Patients with RA had a lower Na+:K+ excretion ratio than controls, and lower K+ excretion was associated with higher diastolic blood pressure in RA. PMID- 29243058 TI - Does prophylactic ondansetron reduce norepinephrine consumption in patients undergoing cesarean section with spinal anesthesia? AB - PURPOSE: Spinal anesthesia-induced hypotension (SAIH) during cesarean delivery is not rare and frequently leads to materno-fetal discrepancy and collapse. More recently, norepinephrine has been proposed for the prevention and treatment of SAIH with fewer tendencies to decrease heart rate and cardiac output. Ondansetron has been reported to reduce the incidence of SAIH in patients undergoing cesarean section. The aim of the present study was to assess the effect of prophylactic ondansetron on the incidence of SAIH, norepinephrine consumption, and adverse effects. METHODS: We recruited 108 parturients with uncomplicated pregnancies undergoing elective cesarean delivery under spinal anesthesia. The parturients were divided into two groups randomly. The first group (n = 54) received 8 mg ondansetron IV (group O) and the second group (n = 54) received the same volume (4 ml) of saline (group S), 5 min before spinal anesthesia. The incidence of hypotension, cumulative episodes of hypotension, total norepinephrine consumption, and adverse effects were recorded. RESULTS: There was no significant difference between the two groups in demographic data, parturient characteristics, and duration of surgery. No significant difference was found in the incidence of hypotension in the saline and ondansetron groups (p = 0.767). However, the cumulative episodes of hypotension and norepinephrine consumptions were significantly greater in group S than in group O (p = 0.009) (p = 0.009). There was also no significant difference in the incidence of adverse effects between the two groups. CONCLUSION: Eight milligrams of intravenous ondansetron given 5 min before spinal anesthesia attenuated but did not prevent spinal anesthesia-induced hypotension in parturients undergoing elective cesarean delivery. PMID- 29243057 TI - Decreased muscle mass is independently associated with knee pain in female patients with radiographically mild osteoarthritis: a nationwide cross-sectional study (KNHANES 2010-2011). AB - To evaluate the association between muscle mass and knee pain in relation to radiographic severity of knee osteoarthritis. We consulted nationwide health examination and survey records collected from 2010 to 2011 and extracted data regarding female patients aged > 50 years and diagnosed with knee osteoarthritis. Radiographic severity was assessed on plain radiographs using the Kellgren Lawrence system, whereas appendicular skeletal mass was obtained from dual-energy X-ray absorptiometry data. We performed multivariate logistic regression to evaluate the association between knee pain and muscle mass index (appendicular skeletal muscle mass divided by body weight in percentile) in patient groups stratified by radiographic severity of knee osteoarthritis. Among 17,476 participants of the national survey, 2013 female knee osteoarthritis patients were identified and stratified by radiographic severity (grade <= 1, n = 1136; grade 2, n = 240; grade 3, n = 379; and grade 4, n = 258). For mild osteoarthritis (Kellgren-Lawrence grade 2), muscle mass index was significantly lower in patients with knee pain than in those without knee pain (24.9 +/- 3.9 vs 26.5 +/- 6.3%, P = 0.023), whereas no such difference was noted for severe osteoarthritis (Kellgren-Lawrence grade > 2). After adjusting for clinical variables by multivariate logistic regression, decreased muscle mass index remained significantly associated with knee pain in patients with mild osteoarthritis but not in those with severe osteoarthritis (regression coefficient 0.915, 95% confidence interval 0.854-0.981, P = 0.012). Lower muscle mass may be a risk factor for knee pain in patients with radiographically mild knee osteoarthritis but not in those with radiographically severe osteoarthritis. PMID- 29243059 TI - Standardised pre-operative diagnostics and treatment of peripheral arterial disease reduce wound complications in geriatric ankle fractures. AB - PURPOSE: The aim of this study was to evaluate a standardised algorithm to assess and treat impaired limb perfusion prior to surgical fixation of geriatric ankle fractures and determine the prevalence of peripheral arterial disease (PAD) in geriatric patients presenting with ankle fractures. METHODS: Eighty-four patients >65 years pre-operatively diagnosed and treated according to an algorithm (study group) were compared with 84 patients diagnosed and treated before the algorithm was introduced (control group). RESULTS: In 14 patients of the study group, clinical noninvasive examination revealed signs of relevant PAD, which was confirmed with computed tomographic angiography (CTA) in nine patients, all of whom had successful angioplasty prior to surgical fixation of the ankle fracture. In three of these patients, PAD had previously been diagnosed. After standardised diagnostics and treatment of malperfusion, a significantly reduced overall and, particularly, wound complication rate was found. CONCLUSION: PAD is an underdiagnosed condition in geriatric patients presenting with ankle fractures. This study underlines the relevance of limb perfusion for adequate wound healing in geriatric ankle fractures. Therefore, special attention should be paid to diagnose and-if indicated-optimise limb perfusion prior to surgical fixation of geriatric ankle fractures. PMID- 29243060 TI - Synovial aspiration and serological testing in two-stage revision arthroplasty for prosthetic joint infection: evaluation before reconstruction with a mean follow-up of twenty seven months. AB - INTRODUCTION: The two-stage revision protocol is the gold standard for controlling and treating low-grade prosthetic joint infections of total hip and total knee arthroplasty. The antibiotic pause for diagnostic reasons before reconstruction (stage two) is discussed in relation to the persistence of the infection and the development of resistant bacterial strains. Serological markers and a synovial analysis are commonly used to exclude the persistence of infection. Therefore, we asked (1) is the serological testing of C-reactive protein and leucocytes a valuable tool to predict a persistence of infection? and (2) what is the role of synovial aspiration of Plymethylmethacrylat (PMMA) spacers in hip and knee joints? MATERIALS AND METHODS: One hundred twelve patients who were MSIS criteria-positive for a prosthetic joint infection were studied, including 45 total hip arthroplasties (THA) and 67 total knee artrhoplasties (TKA) patients. All patients were treated with a two-stage protocol using a mobile PMMA spacer after a 14-day antibiotic-free interval, during which we measured serological markers (C-reactive protein and leucocytes) and performed synovial aspiration (white blood cell count, polymorphonuclear cell percentage, and microbiological culture) in these patients and compared the results with those of their long-term-follow-up (mean follow-up 27 months, range 24-36 months). RESULTS: Of the 112 patients, 89 patients (79.5%; 95% CI 72-86.9) exhibited infection control after a two-stage exchange, and we detected most methicillin-resistant, coagulase-negative Staphylococci (CoNS) in cases of a persistent infection. The mean sensitivity of serum C-reactive protein in the patients was 0.43 (range 0.23-0.64), and the mean specificity was 0.73 (range 0.64-0.82). For serum leucocytes, the mean sensitivity was 0.09 (range 0-0.29), and the mean specificity was 0.81 (range 0.7-0.92). The mean sensitivity for the WBC count in the synovial fluid (PMMA spacer aspiration) was 0.1 (range 0-0.29), and the mean specificity was 0.79 (range 0.68-0.92). For the PMN percentage, the mean sensitivity was 0.1 (range 0-0.29), and the mean specificity was 0.79 (range 0.68-0.92). No cut-off values could be established for C-reactive protein, leucocytes, WBC count and PMN percentage due to the low AUC. CONCLUSION: No reliable markers were identified for the long-term persistence of infection. C reactive protein and leucocytes were often elevated, even when the infection was controlled. In addition, normalized serum markers did not exclude the persistence of infection during follow-up. The synovial analysis of the WBC count and PMN percentage did not predict the persistence of infection. However, microbiological synovial fluid analysis is often misleading due to false positive microbiological cultures, which results in overtreatment. PMID- 29243061 TI - Neuroprotective Effect of Curcumin Against Cerebral Ischemia-Reperfusion Via Mediating Autophagy and Inflammation. AB - Curcumin, a polyphenolic compound extracted from Curcuma longa, has drawn attention for its effective bioactivities against ischemia-induced injury. This study aimed to evaluate the neuroprotective effect of curcumin and investigate the underlying mechanism that mediates autophagy and inflammation in an animal model of middle cerebral artery occlusion (MCAO) in rats. Curcumin was delivered to Sprague Dawley male rats at a dose of 200 mg/kg curcumin by intraperitoneal injection 30 min after ischemia-reperfusion (I/R). LY294002, a specific inhibitor of the PI3K/Akt/mTOR pathway, as well as anisomycin, an activator of TLR4/p38/MAPK, was administered by ventricle injection 30 min before MCAO. The same volume of saline was given as a control. Brain infarction and neurological function were determined 24 h post-MCAO. Immunoblotting and immunofluorescence were used to detect alterations in autophagy-relevant proteins Akt, p-Akt, mTOR, p-mTOR, LC3-II, and LC3-I, and inflammation-related proteins TLR4, p-38, p-p38, and IL-1 in the ipsilateral hemisphere. Cerebral I/R injury resulted in significant alterations of LC3-II/LC3-I, IL-1, TLR4, and p-p38. Curcumin in MCAO rats significantly improved brain damage and neurological function by upregulating p-Akt and p-mTOR and downregulating LC3-II/LC3-I, IL-1, TLR4, p-38, and p-p38. However, these protective effects against ischemia could be suppressed when LY294002 or anisomycin was included. Curcumin exerts neuroprotective effects by attenuating autophagic activities through mediating the PI3K/Akt/mTOR pathway, while also suppressing an inflammatory reaction by regulating the TLR4/p38/MAPK pathway. Furthermore, this study indicates that curcumin could be an effective therapy for patients afflicted with ischemia. PMID- 29243062 TI - Pre-clinical study of a TNFR1-targeted 18F probe for PET imaging of breast cancer. AB - Tumor necrosis factor receptor 1 (TNFR1) is overexpressed in several varieties of carcinoma, including breast cancer. WH701 (Ala-Thr-Ala-Gln-Ser-Ala-Tyr-Gly), which was identified by phage display, can specifically bind to TNFR1. In this study, we labeled WH701 with 18F and investigated its tumor diagnostic value. WH701 was synthesized by standard Fmoc-solid phase synthetic protocols and conjugated by NOTA-NHS. NOTA-WH701 was radiolabeled with 18F using NOTA-AlF chelation reaction. The tumor target properties were evaluated in vitro and in vivo using MCF-7 xenografts and inflammation models. [18F]AlF-NOTA-WH701 was labeled in 25 min with a decay-corrected yield of 38.1 +/- 4.8% (n = 5) and a specific activity of 10.4-13.0 GBq/MUmol. WH701 had relatively high affinity for MCF-7 cells in vitro and [18F]AlF-NOTA-WH701 displayed relatively high tumor uptake in vivo. The tumor to muscle ratio was 4.25 +/- 0.56 at 30 min post injection (p.i.); further, there was a significant difference between the tumor/muscle and inflammation/muscle (3.22 +/- 0.56) ratio, which could differentiate the tumor and inflammation. The tumor uptake of [18F]AlF-NOTA-WH701 could be inhibited by 71.1% by unlabeled WH701 at 30 min p.i. We have developed a promising PET tracer [18F]AlF-NOTA-WH701 for the noninvasive detection of breast cancer in vivo. PMID- 29243063 TI - Molecular characterization of the spike gene of the porcine epidemic diarrhea virus in Mexico, 2013-2016. AB - In Mexico, the first outbreaks suggestive of the circulation of the porcine epidemic diarrhea virus (PEDV) were identified at the beginning of July 2013. To identify the molecular characteristics of the PEDV Spike (S) gene in Mexico, 116 samples of the intestine and diarrhea of piglets with clinical signs of porcine epidemic diarrhea (PED) were obtained. Samples were collected from 14 farms located in six states of Mexico (Jalisco, Puebla, Sonora, Veracruz, Guanajuato, and Michoacan) from 2013 to 2016. To identify PEDV, we used real-time RT-PCR to discriminate between non-INDEL and INDEL strains. We chose samples according to state and year to characterize the S gene. After amplification of the S gene, the obtained products were sequenced and assembled. The complete amino acid sequences of the spike protein were used to perform an epitope analysis, which was used to determine null mutations in regions SS2, SS6, and 2C10 compared to the sequences of G2. A phylogenetic analysis determined the circulation of G2b and INDEL strains in Mexico. However, several mutations were recorded in the collagenase equivalent (COE) region that were related to the change in polarity and charge of the amino acid residues. The PEDV strain circulating in Jalisco in 2016 has an insertion of three amino acids (232LGL234) and one change in the antigenic site of the COE region, and strains from the years 2015 and 2016 changed the index of the surface probability, which could be related to the re-emergence of disease outbreaks. PMID- 29243064 TI - Interferon lambda4 polymorphism is not associated with human papillomavirus infection outcome. AB - Interferon (IFN) lambdas are important specific components of the mucosal innate immune response. The IFN lambda 4 (IFNL4) dinucleotide polymorphism (DeltaG/TT) determines the IFN lambdas and related Interferon-stimulated genes activation, in HCV and other chronic infections. Our group first reported that IFN Lambda response was impaired in high-risk Human Papillomavirus (HPV) cervical infections and in precancerous lesions. Accordingly, we sought to evaluate the possible role of the IFNL4 polymorphism in determining HPV infection outcome. The DeltaG/TT alleles were not differently distributed in 221 women with high- or low-risk HPV infection, with HPV infection clearance or persistence, and with abnormal cytology. PMID- 29243065 TI - Long-term effects of grazing and topography on extra-radical hyphae of arbuscular mycorrhizal fungi in semi-arid grasslands. AB - Grazing and topography have drastic effects on plant communities and soil properties. These effects are thought to influence arbuscular mycorrhizal (AM) fungi. However, the simultaneous impacts of grazing pressure (sheep ha-1) and topography on plant and soil factors and their relationship to the production of extra-radical AM hyphae are not well understood. Our 10-year study assessed relationships between grazing, plant species richness, aboveground plant productivity, soil nutrients, edaphic properties, and AM hyphal length density (HLD) in different topographic areas (flat or sloped). We found HLD linearly declined with increasing grazing pressure (1.5-9.0 sheep ha-1) in sloped areas, but HLD was greatest at moderate grazing pressure (4.5 sheep ha-1) in flat areas. Structural equation modeling indicates grazing reduces HLD by altering soil nutrient dynamics in sloped areas, but non-linearly influences HLD through plant community and edaphic changes in flat areas. Our findings highlight how topography influences key plant and soil factors, thus regulating the effects of grazing pressure on extra-radical hyphal production of AM fungi in grasslands. Understanding how grazing and topography influence AM fungi in semi-arid grasslands is vital, as globally, severe human population pressure and increasing demand for food aggravate the grazing intensity in grasslands. PMID- 29243066 TI - Serum-glucocorticoid-regulated kinase 1 contributes to mechanical stretch-induced inflammatory responses in cardiac fibroblasts. AB - Excessive mechanical stretch induces production of proinflammatory mediators in cardiac fibroblasts, which could act as inflammatory supporter cells in heart failure. Accumulation evidence and our previous studies suggest that serum glucocorticoid-regulated kinase 1 (SGK1) contributes to cardiac remodeling and fibrosis, development of heart failure. However, the role and mechanism of SGK1 in mechanical stretch-induced inflammation of cardiac fibroblasts remain unclear. Here, cardiac fibroblasts isolated from wild-type (WT) and SGK1 knockout (SGK1-/ ) mice were stimulated by 18% cyclic stretch, under static condition as the control. The results showed that mechanical stretch increased SGK1 expression and activation in WT cardiac fibroblasts but not its isoform, SGK2 or SGK3 expression. Bio-Plex array revealed hyperstretch could enhance chemokines release in WT cardiac fibroblasts, but SGK1 knockout significantly attenuated chemokines production through blocking activation of nuclear factor-kappa B (NF-kappaB). Moreover, supernatants from WT cardiac fibroblasts subjected to hyperstretch promoted macrophage migration, enhanced expression of macrophage-derived profibrotic mediators, whereas supernatants from SGK1 deficiency suppressed these effects. Although SGK1 did not directly affect mechanical stretch-induced myofibroblast differentiation, SGK1 activation of cardiac fibroblasts facilitated myofibroblast differentiation through the upregulation of the profibrotic mediators secreted by macrophages. These results suggest that SGK1 may play a critical role in the inflammatory cascade of cardiac fibroblasts triggered by mechanical stretch; SGK1 could be used as a potential target for treatment of cardiac fibrosis and heart failure. PMID- 29243069 TI - Identification of a New Uncompetitive Inhibitor of Adenosine Deaminase from Endophyte Aspergillus niger sp. AB - Adenosine deaminase (ADA) is an enzyme widely distributed from bacteria to humans. ADA is known as a potential therapeutic target for the treatment of lymphoproliferative disorders and cancer. Endophytes are endosymbionts, often bacteria or fungi, which live within plant tissues and internal organs or intercellular space. Endophytes have a broad variety of bioactive metabolites that are used for the identification of novel natural compounds. Here, 54 morphologically distinct endophyte strains were isolated from six plants such as Peganum harmala Linn., Rheum officinale Baill., Gentiana macrophylla Pall., Radix stephaniae tetrandrae, Myrrha, and Equisetum hyemale Linn. The isolated strains were used for the search of ADA inhibitors that resulted in the identification of the strain with the highest inhibition activity, Aspergillus niger sp. Four compounds were isolated from this strain using three-step chromatography procedure, and compound 2 was determined as the compound with the highest inhibition activity of ADA. Based on the results of 1H and 13C NMR spectroscopies, compound 2 was identified as 3-(4-nitrophenyl)-5-phenyl isoxazole. We showed that compound 2 was a new uncompetitive inhibitor of ADA with high cytotoxic effect on HepG2 and SMCC-7721 cells (the IC50 values were 0.347 and 0.380 mM, respectively). These results suggest that endophyte strains serve as promising sources for the identification of ADA inhibitors, and compound 2 could be an effective drug in the cancer treatment. PMID- 29243067 TI - Translational regulation in the anoxic turtle, Trachemys scripta elegans. AB - The red-eared slider turtle (Trachemys scripta elegans), has developed remarkable adaptive mechanisms for coping with decreased oxygen availability during winter when lakes and ponds become covered with ice. Strategies for enduring anoxia tolerance include an increase in fermentable fuel reserves to support anaerobic glycolysis, the buffering of end products to minimize acidosis, altered expression in crucial survival genes, and strong metabolic rate suppression to minimize ATP-expensive metabolic processes such as protein synthesis. The mammalian target of rapamycin (mTOR) is at the center of the insulin-signaling pathway that regulates protein translation. The present study analyzed the responses of the mTOR signaling pathway to 5 (5H) or 20 h (20H) of anoxic submergence in liver and skeletal muscle of T. scripta elegans with a particular focus on regulatory changes in the phosphorylation states of targets. The data showed that phosphorylation of multiple mTOR targets was suppressed in skeletal muscle, but activated in the liver. Phosphorylated mTORSer2448 showed no change in skeletal muscle but had increased by approximately 4.5-fold in the liver after 20H of anoxia. The phosphorylation states of upstream positive regulators of mTOR (p-PDK-1Ser241, p-AKTSer473, and protein levels of GbetaL), the relative levels of dephosphorylated active PTEN, as well as phosphorylation state of negative regulators (TSC2Thr1462, p-PRAS40Thr246) were generally found to be differentially regulated in skeletal muscle and in liver. Downstream targets of mTOR (p-p70 S6KThr389, p-S6Ser235, PABP, p-4E-BP1Thr37/46, and p-eIF4ESer209) were generally unchanged in skeletal muscle but upregulated in most targets in liver. These findings indicate that protein synthesis is enhanced in the liver and suggests an increase in the synthesis of crucial proteins required for anoxic survival. PMID- 29243071 TI - Assessment of left ventricular mass by SPECT MPI. PMID- 29243070 TI - Extensive evolution analysis of the global chikungunya virus strains revealed the origination of CHIKV epidemics in Pakistan in 2016. AB - Chikungunya virus (CHIKV) is a mosquito-borne virus that causes epidemics widely in the world especially in the tropical and subtropical regions. Phylogenetic analysis has found that the CHIKV lineages were associated with the spatial and temporal distributions, which were related to the virus adaption to the major mosquito species and their distributions. In this study, we reported the complete genome sequences of eight CHIKV isolates from the outbreak in Pakistan last year. Then we reviewed the evolutionary history using extensive phylogenetic analysis, analyzed lineage-specific substitutions in viral proteins, and characterized the spreading pathway of CHIKV strains including the Pakistani strains. The results showed that the Pakistani stains belonged to the ECSA.IOL sub-lineage and derived from India. The genetic properties of the Pakistani strains including the adaptive substitution to vectors were further characterized, and the potential risks from the occurrence of CHIKV infection in Pakistan were discussed. These results provided better understanding of CHIKV evolution and transmission in the world and revealed the possible origination of the CHIKV outbreak and epidemic in Pakistan, which would promote the disease prevention and control in the identified countries and territories with the history of CHIKV infections as well as new regions with potential risk of CHIKV outbreaks. PMID- 29243072 TI - Volume-based glucose metabolic analysis of FDG PET/CT: The optimum threshold and conditions to suppress physiological myocardial uptake. AB - OBJECTIVE: FDG PET/CT plays a significant role in the diagnosis of inflammatory heart diseases and cardiac tumors. We attempted to determine the optimal FDG uptake threshold for volume-based analyses and to evaluate the relationship between the myocardial physiological uptake volume in FDG PET and several clinical factors. METHODS: A total of 190 patients were retrospectively analyzed. The cardiac metabolic volume (CMV) was defined as a volume within the boundary determined by a threshold (SUVmean of blood pool * 1.5). RESULTS: The SUVmean of the blood pool measured in the descending aorta (DA) (r = 0.86, intraclass correlation coefficient [ICC] = 0.93, P < 0.0001) and that in the left ventricle (LV) cavity (r = 0.87, ICC = 0.90, P < 0.0001) showed high inter-operator reproducibility. However, the SUVmean in the LV cavity showed a significant correlation with the CMV (P = 0.0002, r = 0.26). The CMV in the patients who fasted < 18 hours were significantly higher (49.7 +/- 73.2 vs. 18.0 +/- 53.8 mL, P = 0.0013) compared to the patients with > 18-hour fasting. The multivariate analysis demonstrated that only the fasting period > 18 hours was independently associated with CMV = 0. CONCLUSION: Our findings revealed that the DA is suitable to decide the threshold for the volume-based analysis. The fasting time was significantly associated with the cardiac FDG uptake. PMID- 29243074 TI - Predictive factors and the important role of detectable prostate-specific antigen for detection of clinical recurrence and cancer-specific mortality following robot-assisted radical prostatectomy. AB - PURPOSE: To evaluate predictive factors associated with detectable prostate specific antigen (PSA) and describe clinical recurrence (CR) and cancer-specific mortality (CSM) after robot-assisted radical prostatectomy (RARP). METHODS: The study included 2500 patients who were treated with RARP at a single institution between 2000 and 2016. All patients had clinically localized PCa. Patients were divided into two groups according to PSA value at 6 weeks after surgery: undetectable (n = 2271; PSA < 0.1 ng/dl) and persistently elevated (n = 229; PSA >= 0.1 ng/dl). The association between various covariates and: (1) detectable PSA and (2) CR was evaluated. Kaplan-Meier analyses estimated CR and CSM rates according to PSA persistence. RESULTS: Inside the group of detectable PSA, 146 men (63.75%) received adjuvant treatments, 44 patients (19.21%) salvages therapies and 38 men (16.5%) experienced CR. Factors associated with aggressive disease predicted PSA persistence. Within patients with detectable PSA, pathologic stage >= pT3a (HR 2.71; p < 0.029) and to received adjuvant androgen deprivation therapy (ADT) due to bad prognosis tumors (HR 13.36; p < 0.001) were associated with CR. Overall 14 (0.56%) died of PCa. 5 and 10-year CSM rates were higher for patients with CR (9.6 and 23.7%, p < 0.001), and Gleason >= 8 (5.7 and 6.9%, p = 0.003). CONCLUSIONS: A detectable PSA is affected by factors associated with aggressive prostate cancer. Within men with persistent PSA, those with higher pathologic stage and who received adjuvant ADT are more likely to have CR. Patients with CR, Gleason >= 8, and those who received adjuvant ADT must have a close monitoring due to the high rate of mortality. PMID- 29243076 TI - PTA Stent of Dural Sinuses in Brain DAVF : A Report of 4 Cases. AB - BACKGROUND AND PURPOSE: Type I and IIa dural arteriovenous fistulas (DAVFs) have a low hemorrhagic risk, but are often the cause of debilitating tinnitus that requires treatment. While Onyx(r) and PHILTM (Precipitating hydrophobic injectable liquid) transarterial embolization represent the first endovascular option, there are occasional cases where performing angioplasty and stenting of the affected sinus may lead to satisfactory results. MATERIAL AND METHODS: We retrospectively analyzed four consecutive cases of patients with DAVF-induced pulsatile tinnitus secondary to type I and II DAVFs who were treated with angioplasty and stenting of the sinus only. All the patients had clinical and radiological long-term follow-up. RESULTS: We noticed a significant radiological and clinical improvement in all the cases. Of the patients two were completely cured at follow-up with eradication of the neurological symptoms as well as the fistula, one was retreated with Onyx(r) for a very small residual shunt despite having no more tinnitus, and one showed improvement in venous drainage (from type IIa+b to type I fistula) without resolution of the fistula. CONCLUSION: In cases of type I and II DAVFs associated with sinus stenosis, angioplasty and stenting alone seem to be safe and effective. This treatment probably compresses the venules within the sinus walls, promoting thrombosis of the shunts thus solving the underlying cause of the fistula. PMID- 29243075 TI - The effect of aspirin on circulating tumor cells in metastatic colorectal and breast cancer patients: a phase II trial study. AB - PURPOSE: Aspirin could reduce the risk of cancer metastasis. Circulating tumor cells (CTCs) are a key factor of cancer metastasis, but no evidence has revealed how aspirin affects CTCs and its epithelial-mesenchymal transition (EMT). Here, we conducted a clinical trial to investigate how aspirin affects CTCs in metastatic colorectal cancer (MCC) and breast cancer patients (MBC). METHODS: The trial is retrospective registered at clinicaltrials.gov (NCT02602938). The eligible patients are given 100 mg aspirin q.d. for 8 weeks, and CTCs are evaluated at baseline, 4 and 8 weeks for absolute number, phenotype (epithelial type, E+, mesenchymal type, M+, and biophenotypic type, B+), and vimentin expression. RESULTS: Data on 21 MCC and 19 MBC patients are analyzed, and it revealed that the CTC numbers decreased with aspirin treatment in MCC (p < 0.001) but not MBC (p = 0.0532); besides, ratio of E+ CTCs increased (p = 0.037) and M+ CTCs decreased at 2 months in MCC (p = 0.013), but neither the ratio of E+ or M+ CTCs changes significantly in MBC; vimentin expression of M+ CTCs is higher than E+ and B+ CTCs either in MBC or MCC patients at baseline (p < 0.01); and aspirin suppresses the vimentin expression in M+ (p = 0.002)and B+ (p = 0.006) CTCs of MCC and M+ CTCs of MBC (p = 0.004); besides it find vimentin expression in B+ (p = 0.004) or M+ (p < 0.001), CTCs are markedly decreased in patients with total CTC numbers declined. CONCLUSION: Aspirin could decrease CTCs numbers and block EMT transition in MCC patients and part of MBC patients. PMID- 29243077 TI - Pulmonary embolus as cause of death in an adolescent: demonstration on postmortem CT. AB - Computed tomography (CT) is widely accepted in adult forensic death investigations (determination of cause and manner of death) but is only beginning to play a larger role in the cause of death determination in infants and children. We present a case of an adolescent with nephrotic syndrome who sustained cardiac arrest and died in the emergency department. A postmortem CT was requested by the state Office of the Medical Examiner as part of the medicolegal death investigation. Postmortem CT showed a saddle pulmonary embolus that was confirmed on conventional autopsy, demonstrating a natural manner of death. PMID- 29243073 TI - Clinical Quantification of Myocardial Blood Flow Using PET: Joint Position Paper of the SNMMI Cardiovascular Council and the ASNC. PMID- 29243078 TI - Presence of bisphenol S and surfactants in the sediments of Kongsfjorden: a negative impact of human activities in Arctic? AB - Pollution and fate of pollutants in polar region are important topics of investigation in the last several decades. We have analysed sediment samples from Kongsfjorden and Krossfjorden, two sites from Arctic region, and detected a number of emerging contaminants (ECs) using high-resolution mass spectrometry connected to UPLC (LC-Q-ToF-MS). Out of the seven sampling sites selected, bisphenol S (BPS), an identified pollutant and plasticiser, was detected and quantified in three sediment samples from Kongsfjorden (~ 0.2 ppm). Four major surfactants (decylbenzenesulphonic acid, undecylbenzenesulphonic acid, 2 dodecylbenzenesulphonic acid and tridecylbenzenesulphonic acid) were also identified. A possible metabolite of BPS (sulphur trioxide derivative of BPS) was identified in one of the samples. It is proposed that the presence of ECs is the result of human activities in the region for a long time. To the best our knowledge, this is the first report on the identification of BPS and surfactants in the Arctic region. PMID- 29243080 TI - Innovation in neurosurgery-response to: "IDEAL", the operating microscope, and the parachute. PMID- 29243079 TI - Should Clinicians Split or Lump Psychiatric Symptoms? The Structure of Psychopathology in Two Large Pediatric Clinical Samples from England and Norway. AB - It has been suggested that the structure of psychiatric phenomena can be reduced to a few symptom dimensions. These proposals, mainly based on epidemiological samples, may not apply to clinical populations. We tested the structure of psychiatric symptoms across two pediatric clinical samples from England (N = 8434) and Norway (N = 5866). Confirmatory factor analyses of the parent-reported Strengths and Difficulties Questionnaire (SDQ) evaluated the relative fit of several models, including a first-order model, a second-order model with the widely-established broad symptom dimensions of internalizing-externalizing, and two bi-factor models capturing a general psychopathology factor. Predictive value of the SDQ subscales for psychiatric disorders was examined. A first-order five factor solution better fit the data. The expected SDQ subscale(s) related best to the corresponding psychiatric diagnosis. In pediatric clinical samples, a granular approach to psychiatric symptoms where several dimensions are considered seems to fit the data better than models based on lumping symptoms into internalizing/externalizing dimensions. PMID- 29243081 TI - A novel DMAPP-responding genetic circuit sensor for high-throughput screening and evolving isoprene synthase. AB - High-throughput screening is a popular tool for collating biological data which would otherwise require the use of excessive resources. In this study, an artificial genetic circuit sensor responding to dimethylallyl diphosphate (DMAPP) was constructed based on a modified L-arabinose operon for high-throughput screening and isoprene synthase (ispS) evolution in Escherichia coli (E. coli). As a first step, the DNA sequence of the L-arabinose ligand-binding domain (LBD) was replaced with an ispS gene to enable the AraC operon responding to DMAPP, which is the substrate of the IspS enzyme. Then, an enhanced GFP (eGFP) was also introduced as a reporter for pBAD promoter. The expression level of the reporter was monitored using either of the two tools: flow cytometer (FCM) and microplate reader. Sequentially, we observed that a high DMAPP concentration led to low eGFP fluorescence, and the overexpression of ispS gene, which consumes DMAPP, resulted in a high eGFP expression. These results demonstrated that the artificial genetic circuit sensor responded directly to the intracellular concentration of DMAPP, and the expression of IspS enzyme could be positively correlated to the expression level of eGFP. Finally, we identified two IspS mutants with different activities from an ispS gene library and further validated the screening method. PMID- 29243082 TI - Dihydroquercetin ameliorated acetaminophen-induced hepatic cytotoxicity via activating JAK2/STAT3 pathway and autophagy. AB - Acetaminophen (APAP) overdose is currently the leading cause of acute liver disease, but therapeutic treatment strategies are commonly limited. Although dihydroquercetin (DHQ) is an attractive botanical antioxidant, its protective potential for liver disease remains elusive. The present study investigated the protective effects of DHQ against APAP-induced hepatic cytotoxicity. Primary mouse hepatocytes were treated with different concentrations of DHQ followed by APAP administration. Our data showed that DHQ relieved APAP-induced growth inhibition and lactate dehydrogenase (LDH) release in a dose-dependent manner, as well as inhibited APAP-induced necrosis and extracellular signal regulated kinase c-Jun-N-terminal kinase (ERK-JNK) stress. In addition, reactive oxygen species (ROS) accumulation and mitochondria dysfunction were also reversed by DHQ treatment. Further study revealed that DHQ induced phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) cascade and thus modulated expression of anti-apoptotic Bcl-2 family proteins. Moreover, DHQ induced autophagy which mediated its protective effects in hepatocytes. The protection was abrogated through pharmacological blockage of autophagy by chloroquine (CQ). These studies demonstrated, for the first time, that DHQ possessed hepatocellular protective effects in the context of APAP-induced cytotoxicity and subsequently revealed that the mechanisms comprised activation of JAK2/STAT3 signaling pathway and autophagy. These altogether highlighted the significant therapeutic potential of this agent during acute liver failure and other types of liver diseases. PMID- 29243083 TI - Enhancing the copper-sensing capability of Escherichia coli-based whole-cell bioreporters by genetic engineering. AB - Metals are essential to all organisms; accordingly, cells employ numerous genes to maintain metal homeostasis as high levels can be toxic. In the present study, the gene operons responsive to metal(loid)s were employed to generate bacterial cell-based biosensors to detect target metal(loid)s. The cluster of genes related to copper transport known as the cop-operon is regulated by the interaction between the copA promoter region (copAp) and CueR, turning on and off gene expression upon copper ion binding. Therefore, the detection of copper ions could be achieved by inserting a plasmid harboring the fusion of copAp and reporter genes, such as enzymes and fluorescent genes. However, copAp is not as strong a promoter as other metal-inducible promoters, such as znt-, mer-, and ars-operons; thereby, its sensitivity toward copper ions was not sufficient for quantification. To overcome this problem, we engineered Escherichia coli with a deletion of copA to interfere with copper export from cells. The engineered E. coli whole-cell bioreporter was able to detect copper ions at 0 to 10 MUM in an aqueous solution. Most importantly, it was specific to copper among several tested heavy metal(loid)s. Therefore, it will likely be useful to detect copper in diverse environmental systems. Although additional improvements are still required to optimize the E. coli-based copper-sensing whole-cell bioreporters presented in this study, our results suggest that there is huge potential to generate whole-cell bioreporters for additional targets by molecular engineering. PMID- 29243084 TI - Quantification of Breast Cancer Protein Biomarkers at Different Expression Levels in Human Tumors. AB - Liquid chromatography-selected reaction monitoring (LC-SRM) mass spectrometry has developed into a versatile tool for quantification of proteins with a wide range of applications in basic science, translational research, and clinical patient assessment. This strategy uniquely complements traditional pathology approaches, like hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC). The multiplexing capabilities offered by mass spectrometry are currently unmatched by other techniques. However, quantification of biomarkers in tissue specimens without the other data obtained from H&E-stained slides or IHC, including tumor cellularity or percentage of positively stained cells inter alia, may not provide as much information that is needed to fully understand tumor biology or properly assess the patient. Therefore, additional characterization of the tissue proteome is needed, which in turn requires the ability to assess protein markers across a wide range of expression levels from a single sample. This protocol provides an example of multiplexed analysis in breast tumor tissue quantifying specific biomarkers, specifically estrogen receptor, progesterone receptor, and the HER2 receptor tyrosine kinase, in combination with other proteins that can report on tissue content and other aspects of tumor biology. PMID- 29243085 TI - Patterns in spatial distribution and root trait syndromes for ecto and arbuscular mycorrhizal temperate trees in a mixed broadleaf forest. AB - Functional differences between trees with arbuscular (AM) or ectomycorrhizal (ECM) partnerships influence important ecological processes including nutrient cycling, community assembly, and biomass allocation patterns. Although most broadleaf temperate forests show both mycorrhizal types, relatively few studies have addressed functional difference among coexisting mycorrhizal tree species. The maintenance of ECM associations usually requires higher C investment than AM, leading to (A) lower root biomass and (B) more conservative root trait syndromes in ECM tree species compared to AM species. Here we quantified the representation and trait syndromes of 14 canopy tree species associated with either AM or ECM fungi in a natural forest community. Our results showed that, whereas species root abundance was proportional to basal area, some ECM tree roots were largely under-represented (up to ~ 33%). Most of the under-representation was due to lower than expected root abundance of Quercus rubra and Fagus grandifolia. Functional root traits in tree species were similar, with the exception of higher tissue density in ECM species. Moreover, closely related AM and ECM exhibited similar traits, suggesting inherited trait syndrome from a common ancestor. Thus, we found little evidence of divergent functional root trait syndromes between mycorrhizal types. Cores dominated by ECM species influenced trait distribution at the community level, but not total biomass, suggesting that mycorrhizal affiliation may have a stronger effect on the spatial distribution of traits but not on biomass stocks. Our results present an important step toward relating belowground carbon dynamics to species traits, including mycorrhizal type, in broadleaf temperate forests. PMID- 29243086 TI - Utility of Pulse Oximetry to Detect Aspiration: An Evidence-Based Systematic Review. AB - Pulse oximetry is a commonly used means to measure peripheral capillary oxyhemoglobin saturation (SpO2). Potential use of pulse oximetry to detect aspiration is attractive to clinicians, as it is readily available, quick, and noninvasive. However, research regarding validity has been mixed. This systematic review examining evidence on the use of pulse oximetry to detect a decrease in SpO2 indicating aspiration during swallowing is undertaken to further inform clinical practice in dysphagia assessment. A multi-engine electronic search was conducted on 8/25/16 and updated on 4/8/17 in accordance with standards published by the Preferred Reporting for Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA). Inclusion criteria included use of pulse oximetry to detect aspiration with simultaneous confirmation of aspiration via a gold standard instrumental study. Keywords included dysphagia or aspiration AND pulse oximetry. Articles meeting criteria were reviewed by two blinded co-investigators. The search yielded 294 articles, from which 19 were judged pertinent and reviewed in full. Ten met the inclusion criteria and all were rated at Level III-2 on the Australian Diagnostic Levels of Evidence. Study findings were mixed with sensitivity ranging from 10 to 87%. Potentially confounding variables were observed in all studies reviewed, and commonly involved defining "desaturation" within a standard measurement error range (~ 2%), mixed populations, mixed viscosities/textures observed during swallowing, and lack of comparison group. The majority of studies failed to demonstrate an association between observed aspiration and oxygen desaturation. Current evidence does not support the use of pulse oximetry to detect aspiration. PMID- 29243087 TI - Effect of plasma immersion ion implantation on polycaprolactone with various molecular weights and crystallinity. AB - Polycaprolactone with five different molecular weights was spin-coated on silicon wafers and plasma immersion ion implanted (PIII) with ion fluence in the range 5 * 1014-2 * 1016 ions/cm2. The effects of PIII treatment on the optical properties, chemical structure, crystallinity, morphology, gel fraction formation and wettability were investigated. As in the case of a number of previously studied polymers, oxidation and hydrophobic recovery of the PIII treated PCL follow second order kinetics. CAPA 6250, which has the lowest molecular weight and the highest degree of crystallinity of the untreated PCL films studied, has the highest carbonization of the modified layer after PIII treatment. Untreated medical grade PCL films, mPCL PC12 (Perstorp) and mPCL OsteoporeTM have similar chemical structures and crystallinity. Accordingly, the chemical and structural transformations caused by PIII treatment and post-treatment oxidation are almost identical for these two polymers. In general, PIII treatment destroys the nano scale lamellar structure and results in a reduction of PCL crystallinity. Examination after washing PIII treated PCL films in toluene confirmed our hypothesis that cross-linking due to PIII treatment is significantly higher in semi-crystalline PCL as compared with amorphous polymers. PMID- 29243088 TI - Hierarchical structure assembly model of rice dwarf virus particle formation. AB - Rice dwarf virus (RDV) of the family Reoviridae and genus Phytoreovirus, is the cause of rice dwarf disease, a major negative effector of rice production throughout East Asia, including Japan. RDV has an icosahedral double-layered shell of approximately 70 nm diameter. The structural proteins constituting the capsid can self-assemble into a correct particle without requiring the help of any external factors in vitro. A total of more than 900 components assemble to make the full particle. A series of structural and functional studies of RDV, including X-ray crystallography and cryo-electron microscopy, suggest a hierarchical self-assembly mechanism involving both homologous and heterologous interactions. As such, systems for the recognition of each component should be essential for particle formation. PMID- 29243089 TI - Structural insights on the dynamics of proteasome formation. AB - Molecular organization in biological systems comprises elaborately programmed processes involving metastable complex formation of biomolecules. This is exemplified by the formation of the proteasome, which is one of the largest and most complicated biological supramolecular complexes. This biomolecular machinery comprises approximately 70 subunits, including structurally homologous, but functionally distinct, ones, thereby exerting versatile proteolytic functions. In eukaryotes, proteasome formation is non-autonomous and is assisted by assembly chaperones, which transiently associate with assembly intermediates, operating as molecular matchmakers and checkpoints for the correct assembly of proteasome subunits. Accumulated data also suggest that eukaryotic proteasome formation involves scrap-and-build mechanisms. However, unlike the eukaryotic proteasome subunits, the archaeal subunits show little structural divergence and spontaneously assemble into functional machinery. Nevertheless, the archaeal genomes encode homologs of eukaryotic proteasome assembly chaperones. Recent structural and functional studies of these proteins have advanced our understanding of the evolution of molecular mechanisms involved in proteasome biogenesis. This knowledge, in turn, provides a guiding principle in designing molecular machineries using protein engineering approaches and de novo synthesis of artificial molecular systems. PMID- 29243090 TI - States of phage T3/T7 capsids: buoyant density centrifugation and cryo-EM. AB - Mature double-stranded DNA bacteriophages have capsids with symmetrical shells that typically resist disruption, as they must to survive in the wild. However, flexibility and associated dynamism assist function. We describe biochemistry oriented procedures used to find previously obscure flexibility for capsids of the related phages, T3 and T7. The primary procedures are hydration-based buoyant density ultracentrifugation and purified particle-based cryo-electron microscopy (cryo-EM). We review the buoyant density centrifugation in detail. The mature, stable T3/T7 capsid is a shell flexibility-derived conversion product of an initially assembled procapsid (capsid I). During DNA packaging, capsid I expands and loses a scaffolding protein to form capsid II. The following are observations made with capsid II. (1) The in vivo DNA packaging of wild type T3 generates capsid II that has a slight (1.4%), cryo-EM-detected hyper-expansion relative to the mature phage capsid. (2) DNA packaging in some altered conditions generates more extensive hyper-expansion of capsid II, initially detected by hydration based preparative buoyant density centrifugation in Nycodenz density gradients. (3) Capsid contraction sometimes occurs, e.g., during quantized leakage of DNA from mature T3 capsids without a tail. PMID- 29243091 TI - Sedimentation velocity analytical ultracentrifugation for characterization of therapeutic antibodies. AB - Sedimentation velocity analytical ultracentrifugation (SV-AUC) coupled with direct computational fitting of the observed concentration profiles (sedimentating boundary) have been developed and widely used for the characterization of macromolecules and nanoparticles in solution. In particular, size distribution analysis by SV-AUC has become a reliable and essential approach for the characterization of biopharmaceuticals including therapeutic antibodies. In this review, we describe the importance and advantages of SV-AUC for studying biopharmaceuticals, with an emphasis on strategies for sample preparation, data acquisition, and data analysis. Recent discoveries enabled by AUC with a fluorescence detection system and potential future applications are also discussed. PMID- 29243092 TI - "Multiple partial recognitions in dynamic equilibrium" in the binding sites of proteins form the molecular basis of promiscuous recognition of structurally diverse ligands. AB - Promiscuous recognition of ligands by proteins is as important as strict recognition in numerous biological processes. In living cells, many short, linear amino acid motifs function as targeting signals in proteins to specify the final destination of the protein transport. In general, the target signal is defined by a consensus sequence containing wild-characters, and hence represented by diverse amino acid sequences. The classical lock-and-key or induced-fit/conformational selection mechanism may not cover all aspects of the promiscuous recognition. On the basis of our crystallographic and NMR studies on the mitochondrial Tom20 protein-presequence interaction, we proposed a new hypothetical mechanism based on "a rapid equilibrium of multiple states with partial recognitions". This dynamic, multiple recognition mode enables the Tom20 receptor to recognize diverse mitochondrial presequences with nearly equal affinities. The plant Tom20 is evolutionally unrelated to the animal Tom20 in our study, but is a functional homolog of the animal/fungal Tom20. NMR studies by another research group revealed that the presequence binding by the plant Tom20 was not fully explained by simple interaction modes, suggesting the presence of a similar dynamic, multiple recognition mode. Circumstantial evidence also suggested that similar dynamic mechanisms may be applicable to other promiscuous recognitions of signal peptides by the SRP54/Ffh and SecA proteins. PMID- 29243093 TI - Single-molecule fluorescence-based analysis of protein conformation, interaction, and oligomerization in cellular systems. AB - Single-molecule imaging (SMI) of proteins in operation has a history of intensive investigations over 20 years and is now widely used in various fields of biology and biotechnology. We review the recent advances in SMI of fluorescently-tagged proteins in structural biology, focusing on technical applicability of SMI to the measurements in living cells. Basic technologies and recent applications of SMI in structural biology are introduced. Distinct from other methods in structural biology, SMI directly observes single molecules and single-molecule events one-by one, thus, explicitly analyzing the distribution of protein structures and the history of protein dynamics. It also allows one to detect single events of protein interaction. One unique feature of SMI is that it is applicable in complicated and heterogeneous environments, including living cells. The numbers, location, movements, interaction, oligomerization, and conformation of single protein molecules have been determined using SMI in cellular systems. PMID- 29243096 TI - Miniaturisation of PCNL. AB - Conventional PCNL leads to a high stone-free rate but is associated with a significant treatment morbidity. To decrease the morbidity of PCNL but to achieve an equal stone-free rate, in 2001 a miniaturised version of a conventional PCNL (Mini-PCNL) was introduced. Meanwhile numerous modifications of the Mini-PCNL were reported. The ongoing experience with the Mini-PCNL technique showed that Mini-PCNL is not only a miniaturisation but also a different method to remove the stones, as the stones come out of the calyceal system only by means of the irrigation flow without any further need of forceps or baskets. Due to a limited number of papers in the literature, the guidelines so far do not distinguish between conventional and Mini-PCNL, although the Mini-PCNL already became a frequent treatment modality in daily routine worldwide. From the current point of view, Mini-PCNL can be recommended to treat all kinds of upper urinary tract stones exceeding a diameter of 10 mm. In this context, Mini-PCNL is a treatment alternative to flexible ureterorenoscopy, SWL and conventional PCNL. The available literature shows that the morbidity of Mini-PCNL is less and the stone free rate is equal to that of conventional PCNL. It seems that there is no limitation to Mini-PCNL in the treatment of upper urinary tract stones. The future will show what kind of further miniaturisation of the Mini-PCNL procedure will be appropriate. PMID- 29243098 TI - Bullying and Identity Development: Insights from Autistic and Non-autistic College Students. AB - Reduced cognitive empathy may put autistic people at risk for bullying. We compared interpretations of bullying provided by 22 autistic and 15 non-autistic college students. Autistic (and non-autistic) students reported less severe bullying in college relative to earlier in development. Chronic bullying was associated with improvements in self-descriptions and self-acceptance. Autistic students who were chronically bullied were more likely to self-identify as autistic when asked to explain their disability. Autistic and non-autistic students demonstrated similar levels of cognitive empathy, providing no evidence that a "double empathy problem" contributes to bullying for all autistic individuals. Findings suggest that recovery from bullying can contribute to resilience and that autistic people gain insights about bullying and how to overcome it with development. PMID- 29243097 TI - Validating the Revised Illness Perception Questionnaire as a Measure of Parent Perceptions of Autism Spectrum Disorder. AB - The illness perception questionnaire (IPQ) and its revision (IPQ-R) measure perceptions about health-related diagnoses and the influence of cognitions on coping. In this study, the factor structure of a version revised for use with autism spectrum disorder (ASD) was investigated with a sample of parents (n = 361) whose children have ASD. Subsequently, multidimensional item response theory was used to evaluate item and subscale properties. Results indicated items from five of the seven IPQ-R-ASD scales loaded as expected, though subscales related to control were not distinct. Additionally, parents' response patterns were evaluated and discussed. Use of this measure in ASD-focused research may enhance understanding of how parents' cognitions of their child's ASD impacts treatment selection, treatment implementation, and overall family well-being. PMID- 29243094 TI - Hierarchical design of artificial proteins and complexes toward synthetic structural biology. AB - In multiscale structural biology, synthetic approaches are important to demonstrate biophysical principles and mechanisms underlying the structure, function, and action of bio-nanomachines. A central goal of "synthetic structural biology" is the design and construction of artificial proteins and protein complexes as desired. In this paper, I review recent remarkable progress of an array of approaches for hierarchical design of artificial proteins and complexes that signpost the path forward toward synthetic structural biology as an emerging interdisciplinary field. Topics covered include combinatorial and protein engineering approaches for directed evolution of artificial binding proteins and membrane proteins, binary code strategy for structural and functional de novo proteins, protein nanobuilding block strategy for constructing nano architectures, protein-metal-organic frameworks for 3D protein complex crystals, and rational and computational approaches for design/creation of artificial proteins and complexes, novel protein folds, ideal/optimized protein structures, novel binding proteins for targeted therapeutics, and self-assembling nanomaterials. Protein designers and engineers look toward a bright future in synthetic structural biology for the next generation of biophysics and biotechnology. PMID- 29243095 TI - Ca2+-CaMKKbeta pathway is required for adiponectin-induced secretion in rat submandibular gland. AB - Adiponectin functions as a promoter of saliva secretion in rat submandibular gland via activation of adenosine monophosphate-activated protein kinase (AMPK) and increased paracellular permeability. Ca2+ mobilization is the primary signal for fluid secretion in salivary acinar cells. However, whether intracellular Ca2+ mobilization is involved in adiponectin-induced salivary secretion is unknown. Here, we found that full-length adiponectin (fAd) increased intracellular Ca2+ and saliva secretion in submandibular glands. Pre-perfusion with ethylene glycol bis (2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) combined with thapsigargin (TG), an endoplasmic reticulum Ca2+-ATPase inhibitor, abolished fAd induced salivary secretion, AMPK phosphorylation, and enlarged tight junction (TJ) width. Furthermore, in cultured SMG-C6 cells, co-pretreatment with EGTA and TG suppressed fAd-decreased transepithelial electrical resistance and increased 4 kDa FITC-dextran flux responses. Moreover, fAd increased phosphorylation of calcium/calmodulin-dependent protein kinase (CaMKKbeta), a major kinase that is activated by elevated levels of intracellular Ca2+, but not liver kinase B1 phosphorylation. Pre-perfusion of the isolated gland with STO-609, an inhibitor of CaMKKbeta, abolished fAd-induced salivary secretion, AMPK activation, and enlarged TJ width. CaMKKbeta shRNA suppressed, whereas CaMKKbeta re-expression rescued fAd-increased paracellular permeability. Taken together, these results indicate that adiponectin induced Ca2+ modulation in rat submandibular gland acinar cells. Ca2+-CaMKKbeta pathway is required for adiponectin-induced secretion through mediating AMPK activation and increase in paracellular permeability in rat submandibular glands. PMID- 29243099 TI - Autism and Accommodations in Higher Education: Insights from the Autism Community. AB - This article builds on the growing body of research on higher education for autistic students by soliciting input from autistic adults on their higher education experiences and suggestions on making these experiences more 'autism friendly'. Sixty-six individuals participated in a national exploratory survey and thirty-one participated in follow-up, online focus groups. The article reviews the accommodations individuals received and the accommodations they would have liked to receive. Concrete strategies are provided for institutes of higher education to address the social and sensory needs of autistic students, areas many participants reported being neglected in their academic experience, such as mentors and a neurodiverse space. These suggestions are intended to complement traditional academic accommodations to improve the outcomes of autistic students. PMID- 29243100 TI - Parents' Use of Complementary Health Approaches for Young Children with Autism Spectrum Disorder. AB - Knowledge of why parents use complementary health approaches (CHA) for children with autism spectrum disorder (ASD) is limited. We conducted a mixed methods study to better understand factors influencing parents' decision to use CHA for ASD. Parent-reported data about CHA use were collected on a probability sample of 352 young children with ASD in Denver, Colorado; Los Angeles, California; or Portland, Oregon. Follow-back interviews were conducted with 31 parents. CHA use was negatively associated with older child age and positively associated with parents' belief ASD has major consequences, living in Portland or Denver, and medication use. Nine themes help explain these results. Study findings may have utility for healthcare providers working with children with ASD and their families regarding CHA. PMID- 29243101 TI - Fractures in a nationwide population-based cohort of users of breast cancer hormonal therapy. AB - PURPOSE: Although users of aromatase inhibitors have higher total fracture risk in some randomized trials, little is known about their risk outside of clinical trials or in older higher-risk cohorts. METHODS: In a population-based retrospective cohort study, we identified all older US Medicare D prescription drug insurance plan-enrolled women who had initial breast cancer surgery in 2006 2008 and began hormonal therapy (an aromatase inhibitor (AI) or tamoxifen) within the subsequent year. Total nonvertebral and hip fractures through 2012 were identified using a validated algorithm. The association of fracture outcomes with hormonal therapy type was assessed using competing risk regression models that accounted for differences in measured baseline covariates. Treatment assignment bias was reduced using inverse probability of treatment weighting computed from propensity scores. RESULTS: Among 23,378 women taking hormonal therapy (23.2% aged 80 or over), there were 3000 total and 436 hip fractures. Although AI users were younger and had lower comorbidity, after propensity score weighting, these and other covariates were balanced. Total nonvertebral risk was higher for users of AIs compared with tamoxifen, HR 1.11 (1.02-1.21), but the small increase in risk for hip fracture was not statistically significant, HR 1.04 (0.84-1.30). CONCLUSIONS: Although total nonvertebral fracture risk was higher among AI users, differences in hip fractures were not significant in a large population-based cohort of older women. IMPLICATIONS FOR CANCER SURVIVORS: Use of aromatase inhibitors by older women is associated with high risk for nonvertebral fracture that is increased compared with use of tamoxifen. Fracture risk should be assessed among patients taking these medications. PMID- 29243103 TI - Endoscopic Treatment of Biliary Leaks After Laparoscopic Cholecystectomy: Cut or Plug? PMID- 29243102 TI - Split-Dose Bowel Preparation Reduces the Need for Early Repeat Colonoscopy Without Improving Adenoma Detection Rate. AB - BACKGROUND AND AIMS: Split-dose bowel preparation is associated with improved mucosal visualization and patient tolerance, becoming a standard of care. However, quality measures data associated with this preparation are limited. At our academic tertiary-care facility, we aim to study the effect of changing from single- to split-dose preparation on colonoscopy quality measures. METHODS: A retrospective cohort study with quality indicators was conducted using electronic medical record data. Cases were identified via ICD9 code V76.51, "Special screening for malignant neoplasms of colon." Single-dose preparation data was collected from 9/1/13 to 8/31/14. Split-dose preparation was implemented 11/2014, and data were collected from 1/1/15 to 8/31/15. RESULTS: A total of 1602 colonoscopies in the single-dose group and 1061 colonoscopies in the split-dose group were analyzed. The Boston Bowel Preparation Scale was significantly improved in the split-dose group 8.64 +/- SD 1.25 versus 8.25 +/- SD 1.61, p < 0.001. There was no significant difference in adenoma detection rate 40.7% (95% CI 37.8-43.7%) versus 40.5% (95% CI 38.1-42.9%), p = 0.92; however, the rate for recommending an early repeat examination due to an inadequate bowel preparation was significantly decreased to 3.9% (95% CI 2.7-5.0%) versus 8.9% (95% CI 1.52 2.97%), p < 0.001. CONCLUSION: While split-dose preparation significantly improves overall bowel cleanliness, there is no significant adenoma detection rate improvement with high baseline rate, suggesting a threshold which may not improve with enhanced preparations. Split-dose preparation significantly reduces the frequency with which inadequate preparation prompts an early repeat examination, which has important clinical implications on performance, costs, and patient experience, providing further evidence supporting split-dose preparation use. PMID- 29243104 TI - Skepticism Regarding Vaccine and Gluten-Free Food Safety Among Patients with Celiac Disease and Non-celiac Gluten Sensitivity. AB - BACKGROUND: There has been a marked increase in the adoption of the gluten-free (GF) diet. AIMS: To query individuals with celiac disease (CD) and non-celiac gluten sensitivity (NCGS) on their beliefs toward the health effects of gluten, and safety of vaccines and GF food products. METHODS: We distributed a Web-based survey to individuals with CD and NCGS on a CD center e-mail list. We used univariate and multivariate analysis to compare responses of respondents with CD and NCGS. RESULTS: The overall response rate was 27% (NCGS n = 217, CD n = 1291). Subjects with NCGS were more likely than those with CD to disagree with the statement that "vaccines are safe for people with celiac disease" (NCGS 41.3% vs. CD 26.4% (p < 0.0001), and were more likely to decline vaccination when offered (30.9 vs. 24.2%, p = 0.007). After adjusting for age and gender, NCGS subjects were more likely than CD subjects to avoid genetically modified (GMO) foods (aOR 2.30; 95% CI 1.71-3.10), eat only organic products (aOR 2.87; 95% CI 2.04-4.03), believe that the FDA is an unreliable source of information (aOR 1.82, 95% CI 1.26-2.64), and believe a GF diet improves energy and concentration (aOR 2.52; 95% CI 1.86-3.43). CONCLUSIONS: Subjects with NCGS were more likely than those with CD to have doubts about vaccine safety and believe in the value of non-GMO and organic foods. Our findings suggest that the lack of reliable information on gluten and its content in food and medications may reinforce beliefs that result in a detriment to public health. PMID- 29243105 TI - Comparative Effectiveness of Infliximab Versus Adalimumab in Patients with Biologic-Naive Crohn's Disease. AB - BACKGROUND: Direct head-to-head studies comparing the long-term outcomes of infliximab (IFX) to adalimumab (ADA) in Crohn's disease (CD) are sparse. AIMS: We compared the short-term and long-term efficacy and safety of IFX and ADA in CD. METHODS: We performed a single-center retrospective study including biologic naive adult patients with CD who were started on IFX or ADA at the McGill University Health Center. The primary end points were clinical response and remission at 12 months. Secondary end points included corticosteroid-free remission at 12 months, durable remission, and treatment failure with need for steroids, hospitalization or surgery. Safety was also assessed. RESULTS: Two hundred and twenty patients were included (143 IFX, 77 ADA). Patients on IFX had a higher prevalence of fistulizing or perianal disease and corticosteroid treatment at baseline. Rates of clinical remission and corticosteroid-free remission at 12 months were similar between both groups: 63.8 versus 76.3% (p = 0.139) and 54.1 versus 44.7% (p = 0.354), respectively, for IFX and ADA. Combination therapy led to significantly higher remission rates at 12 months compared to monotherapy for patients on IFX (81.2 vs. 52.1%, p = 0.008), but not for those on ADA. Higher rates of adverse events were reported with IFX compared to ADA (p = 0.006). CONCLUSIONS: Our real-life experience in biologic-naive CD patients demonstrated that patients started on IFX were more likely to have a harder-to-treat phenotype. Despite that, efficacy end points were similar between both groups. Clinical remission was higher in patients with combination therapy for IFX, but not for those on ADA. This warrants further investigation. PMID- 29243106 TI - Quantitative validation of immunofluorescence and lectin staining using reduced CLARITY acrylamide formulations. AB - The CLARITY technique enables three-dimensional visualization of fluorescent labeled biomolecules in clarified intact brain samples, affording a unique view of molecular neuroanatomy and neurocircuitry. It is therefore, essential to find the ideal combination for clearing tissue and detecting the fluorescent-labeled signal. This method requires the formation of a formaldehyde-acrylamide fixative generated hydrogel mesh through which cellular lipid is removed with sodium dodecyl sulfate. Several laboratories have used differential acrylamide and detergent concentrations to achieve better tissue clearing and antibody penetration, but the potential effects upon fluorescent signal retention is largely unknown. In an effort to optimize CLARITY processing procedures we performed quantitative parvalbumin immunofluorescence and lectin-based vasculature staining using either 4 or 8% sodium dodecyl sulfate detergent in combination with different acrylamide formulas in mouse brain slices. Using both confocal and CLARITY-optimized lightsheet microscope-acquired images, we demonstrate that 2% acrylamide monomer combined with 0.0125% bis-acrylamide and cleared with 4% sodium dodecyl sulfate generally provides the most optimal signal visualization amongst various hydrogel monomer concentrations, lipid removal times, and detergent concentrations. PMID- 29243107 TI - Impact of geriatric assessment for the therapeutic decision-making of breast cancer: results of a French survey. AFSOS and SOFOG collaborative work. AB - BACKGROUND: Cancer management in the elderly is often considered as suboptimal, highly variable, and rarely evidence-based. Data are needed to understand decision-making processes in this population. MATERIALS AND METHODS: A survey was performed in France to describe decision-making in gynaecologic patients over 70. It followed a three-step method: (1) 101 representative physicians questioned about treatment decision criteria; (2) simplified individual data were collected; (3) as well as detailed data patients receiving chemotherapy. This analysis refers to breast cancer subgroup of patients. RESULTS: Main decision criteria were performance status, comorbidities, and renal function. In adjuvant setting, the main concern was life expectancy, whereas it was quality of life in metastatic setting. Of the 631 patients entered in the simplified analysis, 41% had been evaluated by a geriatrician, 67% received chemotherapy. In the detailed analysis, patients older than 75 were more likely to receive a monochemotherapy and to be treated with weekly/divided dose. In adjuvant setting, respectively, 19, 55, and 26% of the patients were treated with regimen validated in the elderly, validated in a younger population, and not validated. A G-CSF was prescribed in 48% of the patients, as primary prophylaxis in 78 and in 41% of patients with a risk of febrile neutropenia < 10%. CONCLUSION: Geriatric covariates become an increasing concern in the decision-making process. This survey also suggests an insufficient use of validated chemotherapy regimens. To date, age remains a risk factor for heterogeneity in oncologic practice justifying a persistent effort for elaborating and disclosing specific recommendations. PMID- 29243108 TI - Identification of a Novel High Yielding Source of Multipotent Adult Human Neural Crest-Derived Stem Cells. AB - Due to their extraordinarily broad differentiation potential and persistence during adulthood, adult neural crest-derived stem cells (NCSCs) are highly promising candidates for clinical applications, particularly when facing the challenging treatment of neurodegenerative diseases or complex craniofacial injuries. Successful application of human NCSCs in regenerative medicine and pharmaceutical research mainly relies on the availability of sufficient amounts of tissue for cell isolation procedures. Facing this challenge, we here describe for the first time a novel population of NCSCs within the middle turbinate of the human nasal cavity. From a surgical point of view, high amounts of tissue are routinely and easily removed during nasal biopsies. Investigating the presence of putative stem cells in obtained middle turbinate tissue by immunohistochemistry, we observed Nestin+/p75NTR+/S100+/alpha smooth muscle actin (alphaSMA)- cells, which we successfully isolated and cultivated in vitro. Cultivated middle turbinate stem cells (MTSCs) kept their expression of neural crest and stemness markers Nestin, p75 NTR and S100 and showed the capability of sphere formation and clonal growth, indicating their stem cell character. Application of directed in vitro differentiation assays resulted in successful differentiation of MTSCs into osteogenic and neuronal cell types. Regarding the high amount of tissue obtained during surgery as well as their broad differentiation capability, MTSCs seem to be a highly promising novel neural crest stem cell population for applications in cell replacement therapy and pharmacological research. PMID- 29243109 TI - HIV Pre-exposure Prophylaxis (PrEP) Uptake and Retention Among Men Who Have Sex with Men in a Community-Based Sexual Health Clinic. AB - In a community-based clinic serving men who have sex with men in San Francisco, California, this study characterized key steps of the pre-exposure prophylaxis (PrEP) cascade and identified correlates of retention in care. In total, 344 patients were evaluated for PrEP. Three-fourths (78%) of those who sought PrEP services initiated PrEP. The overall cumulative incidence of discontinuing PrEP at 13 months was 38%. Men with a sexually transmitted infection (STI) were 44% less likely to be retained (adjusted hazard ratio [aHR] 0.56, 95% confidence interval [0.33-0.95]). Comprehensive retention efforts for men with STIs are crucial to optimize the benefits of PrEP. PMID- 29243110 TI - Retrospective analysis of the development of PIRADS 3 lesions over time: when is a follow-up MRI reasonable? AB - PURPOSE: Often PIRADS 3 findings are usually followed up with further MRIs of the prostate. Current guidelines do not state an optimal interval between the initial MRI and the follow-up MRI. The aim of this study was to find out if PIRADS 3 lesions evolve over time and to determine how long the optimal interval between initial MRI and follow-ups should be. METHODS: In this retrospective study, 141 consecutive patients were included who underwent at least one follow-up MRI after an initial PIRADS 3 finding. Changes in PIRADS score and the interval between the first and the follow-up MRI were recorded. An optimal duration was calculated. RESULTS: Of all patients, 76.6% had a change from PIRADS 3 to either 2 or 4 in the first follow-up MRI. Reclassifications to PIRADS 4 happened earlier than reclassifications to PIRADS 2 (after 366.5 +/- 217.9 days and after 534.2 +/- 253.0 days, respectively). An optimal point of time for a follow-up to distinguish between changes to PIRADS 2 versus PIRADS 4 turned out to be 379 days (12.4 months, AUC 0.734, p = 0.0001). Of all patients with a PIRADS 3 lesion 14.8% harboured a prostate carcinoma. CONCLUSION: Performing follow-up mpMRI rather than immediate biopsy may be beneficial for patients with PIRADS 3, as most lesions can be reclassified after a manageable period of time. Upgrades to PIRADS 4 seem to happen earlier and within fewer follow-ups than downgrades to PIRADS 2. The optimal interval for follow-up MRIs seems to be 12.4 months. PMID- 29243112 TI - The role of PSMA PET scans in salvage therapy planning. PMID- 29243111 TI - Retrospective comparison of measured stone size and posterior acoustic shadow width in clinical ultrasound images. AB - PURPOSE: Posterior acoustic shadow width has been proposed as a more accurate measure of kidney stone size compared to direct measurement of stone width on ultrasound (US). Published data in humans to date have been based on a research using US system. Herein, we compared these two measurements in clinical US images. METHODS: Thirty patient image sets where computed tomography (CT) and US images were captured less than 1 day apart were retrospectively reviewed. Five blinded reviewers independently assessed the largest stone in each image set for shadow presence and size. Shadow size was compared to US and CT stone sizes. RESULTS: Eighty percent of included stones demonstrated an acoustic shadow; 83% of stones without a shadow were <= 5 mm on CT. Average stone size was 6.5 +/- 4.0 mm on CT, 10.3 +/- 4.1 mm on US, and 7.5 +/- 4.2 mm by shadow width. On average, US overestimated stone size by 3.8 +/- 2.4 mm based on stone width (p < 0.001) and 1.0 +/- 1.4 mm based on shadow width (p < 0.0098). Shadow measurements decreased misclassification of stones by 25% among three clinically relevant size categories (<= 5, 5.1-10, > 10 mm), and by 50% for stones <= 5 mm. CONCLUSIONS: US overestimates stone size compared to CT. Retrospective measurement of the acoustic shadow from the same clinical US images is a more accurate reflection of true stone size than direct stone measurement. Most stones without a posterior shadow are <= 5 mm. PMID- 29243114 TI - Effect of cytochrome P450 2C19 polymorphism on adverse cardiovascular events after drug-eluting stent implantation in a large Hakka population with acute coronary syndrome receiving clopidogrel in southern China. AB - BACKGROUND AND OBJECTIVES: The objective of this study is to evaluate the effects of cytochrome P450 2C19 (CYP2C19) polymorphism on adverse cardiovascular events (MACE) in Hakka patients with acute coronary syndrome (ACS) receiving clopidogrel who had undergone coronary drug-eluting stent placement after percutaneous coronary intervention (PCI) in southern China. METHODS: Genotyping of CYP2C19 and MACE of 934 ACS patients with PCI on clopidogrel maintenance therapy were analyzed. Patients who carried loss-of-function CYP2C19 were treated with a 150 mg maintenance dose of clopidogrel or 90 mg of ticagrelor antiplatelet therapy, and patients who were non-carriers received clopidogrel therapy daily at a maintenance dose of 75 mg and the patients were followed-up for at least 12 months. The primary efficacy endpoint was a composite of cardiovascular death, myocardial infarction, and target vessel revascularization and stroke. RESULTS: The allelic frequency of CYP2C19*2 and CYP2C19*3 of Hakka patients in the current study was 31.64 and 5.19%, respectively. The CYP2C19 wild-type homozygotes (*1/*1) were the most predominant among the patients (40.36%), followed by the CYP2C19*2 heterozygotes (*1/*2) (40.26%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM; 40.36%), intermediate metabolizers (IM; 45.61%), and poor metabolizers (PM; 14.03%). Based on the genotype-guided antiplatelet therapy, there was no significant association between the carrier status and the clinical outcome at 1, 6, and 12 months. In addition, no significant difference in the rates of bleeding was found among the three groups. After logistic regression analysis, hypertension was the only independent predictor of cardiovascular events (relative risk, 1.501; 95% CI, 1.011 to 2.229; P = 0.044). CONCLUSIONS: Our results shed new light on the important benefit of testing CYP2C19 polymorphisms before prescribing clopidogrel in patients treated with drug-eluting stent implantation after PCI. The testing may help to optimize pharmacotherapy effectiveness by providing individualized treatment to the Chinese population. Our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy in a Hakka population in southern China. PMID- 29243113 TI - Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta analysis. AB - PURPOSE: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Recently, increasing evidence suggested that polymorphisms in UGT2B7 gene were associated with VPA pharmacokinetics, but results remained controversial. Therefore, a meta-analysis was performed to derive a more precise evaluation between C802T, C161T, and G211T polymorphisms and plasma concentration of VPA. METHODS: The PubMed, EMBASE, and the Cochrane library databases were searched for eligible studies. Articles meeting the inclusion criteria were comprehensively reviewed, and the available data were accumulated. The mean difference (MD) and 95% confidence interval (CI) were applied to assess the strength of the relationship. RESULTS: A total of 12 studies involving 1996 related East Asia epilepsy patients were assessed. We found that the UGT2B7 G211T polymorphism was associated with adjusted plasma VPA concentration (GG versus TT: P = 0.01, I 2 = 97%; GG versus GT: P < 0.00001, I 2 = 0%). Additionally, we also observed a significantly association between the C161T polymorphism and adjusted plasma VPA concentration (CC versus CT: P = 0.01, I 2 = 77%). Nevertheless, the pooled analysis showed that the C802T polymorphism had no significant effect on adjusted serum concentration of VPA. CONCLUSIONS: The results of this meta-analysis demonstrated that UGT2B7 G211T and C161T polymorphisms were able to affect the pharmacokinetics in epilepsy patients treated with VPA, which provide further evidence for genetic effects of UGT2B7 gene on pharmacokinetics and pharmacodynamics of VPA. Epilepsy patients with these genotypes may be necessary to increase (or decrease) VPA dose to ensure its therapeutic effect. PMID- 29243115 TI - Activity of taurolidine gels on ex vivo periodontal biofilm. AB - OBJECTIVES: The purpose of this study is to evaluate the activity of two different taurolidine (TAU) gels in comparison with a 0.2% chlorhexidine (CHX) gel on an ex vivo subgingival biofilm. MATERIAL AND METHODS: Subgingival including supragingival biofilm samples from periodontitis patients were cultured for 10 days, before TAU 1% and TAU 3% gels and CHX gel were applied for 10 min and thereafter diluted with nutrient media to 10% for 50 min. One third of the samples were analyzed for bacterial counts, biofilm quantity, and biofilm metabolic activity. In the two other thirds, 90% of the nutrient media were replaced and biofilms were incubated for 23 h. The second third was analyzed in the same way as before. In the third part, patients' microorganisms were added again and incubated for additional 24 h to allow reformation of biofilm before proceeding to analysis. RESULTS: Decrease of bacterial counts in biofilms was highest following application of TAU 3% after 60 min (0.87 log10 cfu, corresponding 86.5%), 24 and 48 h (reformation of biofilms), respectively. All antimicrobials reduced biofilm quantity after 24 h (each p < 0.05) and following reformation of biofilms (each p < 0.01). Metabolic activity in biofilms was decreased at 60 min (each p < 0.05) and at 24 h (each p < 0.01) after application of TAU gels, while the activity of the reformed biofilm was lower after application of all evaluated antimicrobials (each p < 0.01) than in the control group (e.g., without exposure to antimicrobials). CONCLUSION: The antimicrobial activity of taurolidine gels clearly depends on its taurolidine concentration. A high concentrated taurolidine gel is equally active or even superior to 0.2% chlorhexidine gel. However, the activity of antimicrobials is limited in a complex established biofilm and underlines the pivotal role of mechanical biofilm disruption. CLINICAL RELEVANCE: Within their limits, the data suggest that TAU 3% gel might represent a potential alternative to 0.2% chlorhexidine gel. PMID- 29243116 TI - Oral health-related quality of life depending on dental and periodontal health in different patients before and after liver transplantation. AB - BACKGROUND: The aim of this study was to evaluate the oral health-related quality of life (OHRQoL) depending on dental and periodontal health of different patients before and after liver transplantation (pre- and postLTx) compared to a healthy control group (HC). METHODS: OHRQoL was rated using the German short form of Oral Health Impact Profile (OHIP G14). To estimate dental health, the decayed (D-T), missing (M-T), and filled (F-T) teeth index (DMF-T) was used. Periodontal health was classified as healthy/mild, moderate, or severe periodontitis. The following statistics are used: Mann-Whitney U test, Kruskal-Wallis test, chi-square test, and Fisher test (alpha = 5%). RESULTS: A total of 24 preLTx, 47 postLTx, and 75 HC patients were included. Significant differences in DMF-T, D-T, M-T, and F-T scores were detected between groups (p < 0.001). Prevalence of periodontitis was comparable between groups (p = 0.340). OHRQoL was reduced in pre- and postLTx (OHIP G14 preLTx 4.2 [1.5; 0-4.0], postLTx 4.1 [1; 0-5.0], HC 1.4 [0; 0-2.0]; p = 0.003), without associations to their oral status (p > 0.05). CONCLUSIONS: These preliminary findings show a reduced OHRQoL without associations to their oral status, which might indicate an influence of potential disease-related factors on OHRQoL. Further studies with larger groups are necessary to verify this observation. CLINICAL RELEVANCE: A special dental care of patients before and after LTx is needed, including a comprehensive assessment of the individual patient's OHRQoL. PMID- 29243117 TI - Epaphroditidae sensu novo, an Endemic Caribbean Family of Morphologically Divergent Praying Mantises (Insecta, Mantodea). AB - Three endemic Caribbean praying mantis genera with a complex taxonomic history were recently discovered to be part of a lineage that colonized the Caribbean region during the Cretaceous period (Svenson & Rodrigues, Proc R Soc B Biol Sci 284, 2017). In all classification systems proposed up to now, the three genera, Callimantis, Epaphrodita, and Gonatista, were never considered as close relatives, a reflection of their divergent morphology. More recently, the genus Brancsikia was placed with Epaphrodita in a family based on the similarity of camouflage-related morphology. To address recent phylogenetic results that do not track current classification, we compared the morphology of the three Caribbean genera with each other and representative members of traditional or current family groups. Our morphological analysis of external and male genital characters provides strong support for the Caribbean lineage despite the divergent morphological evolution present in the three genera. We raise this Caribbean lineage to family status by employing a precedent family-group name, Epaphroditidae Brunner de Wattenwyl, 1893 sensu novo. We remove Brancsikia from our new concept of Epaphroditidae, rendering the genus incertae sedis. PMID- 29243118 TI - Some Mathematical Properties of the Matrix Decomposition Solution in Factor Analysis. AB - A new factor analysis (FA) procedure has recently been proposed which can be called matrix decomposition FA (MDFA). All FA model parameters (common and unique factors, loadings, and unique variances) are treated as fixed unknown matrices. Then, the MDFA model simply becomes a specific data matrix decomposition. The MDFA parameters are found by minimizing the discrepancy between the data and the MDFA model. Several algorithms have been developed and some properties have been discussed in the literature (notably by Stegeman in Comput Stat Data Anal 99:189 203, 2016), but, as a whole, MDFA has not been studied fully yet. A number of new properties are discovered in this paper, and some existing ones are derived more explicitly. The properties provided concern the uniqueness of results, covariances among common factors, unique factors, and residuals, and assessment of the degree of indeterminacy of common and unique factor scores. The properties are illustrated using a real data example. PMID- 29243119 TI - Action, observation or imitation of virtual hand movement affect differently regions of the mirror neuron system and the default mode network. AB - Virtual reality (VR)-based paradigms use visual stimuli that can modulate visuo motor networks leading to the stimulation of brain circuits. The aims of this study were to compare the changes in blood-oxygenation level dependent (BOLD) signal when watching and imitating moving real (RH) and virtual hands (VH) in 11 healthy participants (HP). No differences were found between the observation of RH or VH making this VR-based experiment a promising tool for rehabilitation protocols. VH-imitation involved more the ventral premotor cortex (vPMC) as part of the mirror neuron system (MNS) compared to execution and VH-observation conditions. The dorsal-anterior Precuneus (da-Pcu) as part of the Precuneus/posterior Cingulate Cortex (Pcu/pCC) complex, a key node of the Default Mode Network (DMN), was also less deactivated and therefore more involved. These results may reflect the dual visuo-motor roles for the vPMC and the implication of the da-Pcu in the reallocation of attentional and neural resources for bimodal task management. The ventral Pcu/pCC was deactivated regardless of the condition confirming its role in self-reference processes. Imitation of VH stimuli can then modulate the activation of specific areas including those belonging to the MNS and the DMN. PMID- 29243120 TI - Validated Alzheimer's Disease Risk Index (ANU-ADRI) is associated with smaller volumes in the default mode network in the early 60s. AB - Strong evidence is available suggesting that effective reduction of exposure to demonstrated modifiable risk factors in mid-life or before could significantly decrease the incidence of Alzheimer's disease (AD) and delay its onset. A key ingredient to achieving this goal is the reliable identification of individuals at risk well before they develop clinical symptoms. The aim of this study was to provide further neuroimaging evidence of the effectiveness of a validated tool, the ANU Alzheimer's Disease Risk Index, for the assessment of future risk of cognitive decline. Participants were 461 (60-64 years, 48% female) community living individuals free of dementia at baseline. Associations between risk estimates obtained with the ANU-ADRI, total and regional brain volumes including in the default mode network (DMN) measured at the same assessment and diagnosis of MCI/dementia over a 12-year follow-up were tested in a large sample of community-living individuals free of dementia at baseline. Higher risk estimates on the ANU-ADRI were associated with lower cortical gray matter and particularly in the DMN. Importantly, difference in participants with high and low risk scores explained 7-9% of the observed difference in gray matter volume. In this sample, every one additional risk point on the ANU-ADRI was associated with an 8% increased risk of developing MCI/dementia over a 12-year follow-up and this association was partly mediated by a sub-region of the DMN. Risk of cognitive decline assessed with a validated instrument is associated with gray matter volume, particularly in the DMN, a region known to be implicated in the pathological process of the disease. PMID- 29243121 TI - Neural processing of food and monetary rewards is modulated by metabolic state. AB - In humans, food is considered a powerful primary reinforcer, whereas money is a secondary reinforcer, as it gains a value through learning experience. Here, we aimed to identify the neural regions supporting the processing of food-related reinforcers, relate it to the neural underpinnings of monetary reinforcers, and explore their modulation by metabolic state (hunger vs satiety). Twenty healthy male participants were tested in two experimental sessions, once hungry and once satiated, using functional magnetic resonance imaging. Participants performed an associative learning task, receiving food or monetary rewards (in the form of images) on separate blocks. Irrespective of incentive type, both food and monetary rewards engaged ventral striatum, medial orbitofrontal cortex and amygdala, regions that have been previously associated with reward processing. Food incentives additionally engaged the opercular part of the inferior frontal gyrus and the insula, collectively known as a primary gustatory cortex. Moreover, in response to negative feedback (here, reward omission), robust activation was observed in anterior insula, supplementary motor area and lateral parts of the prefrontal cortex, including middle and inferior frontal gyrus. Furthermore, the interaction between metabolic state and incentive type resulted in supramarginal gyrus (SMG) activity, among other motor and sensory-related regions. Finally, functional connectivity analysis showed correlation in the hungry state between the SMG and mesolimbic regions, including the hippocampus, midbrain and cingulate areas. Also, the interaction between metabolic state and incentive type revealed coupling between SMG and ventral striatum. Whereas general purpose reward-related regions process incentives of different kinds, the current results suggest that the SMG might play a key role in integrating the information related to current metabolic state and available incentive type. PMID- 29243122 TI - Aberrant baseline brain activity in psychogenic erectile dysfunction patients: a resting state fMRI study. AB - Recent neuroimaging studies have elucidated many interesting and promising findings on sexuality regarding the neural underpinnings of both normal and abnormal sexual processes. Psychogenic erectile dysfunction (pED) consists of a major part of male sexual dysfunction in China, but the understanding of the central mechanism of pED is still in its infancy. It is commonly appreciated that pED is a functional disorder, which can be attributed predominantly or exclusively to psychological factors, such as anxiety, depression, loss of self esteem, and psychosocial stresses. Most previous studies probed the central response in the brain of pED patients using sexual-related stimuli. However, little concern has been given to a more fundamental issue whether the baseline brain activity is altered in pED or not. With rs-fMRI data, the current study aimed to explain the central mechanism behind pED by investigating the alterations in baseline brain activity in patients with pED, as indexed by the amplitude of low-frequency (0.01-0.08 Hz) fluctuation (ALFF). After the psychological screening and urological examination procedure, 26 pED patients and 26 healthy matched controls were enrolled. Our results explicated significantly lower baseline brain activity in the right anterior insula and right orbitofrontal cortex for pED patients (multiple comparison corrected). Additionally, the voxel-wise correlation analysis showed that ALFF of the right anterior insula was correlated with the outcomes of erectile function (multiple comparison corrected). Our results implied there was impaired cognitive and motivational processing of sexual stimuli in pED patients. Our current findings may shed light on the neural pathology underlying pED. We hope that our study has provided a new angle looking into pED research by investigating resting state brain activity. Furthermore, we suggest that the current study may put forward a more subtle conception of insular influence on pED, which may help foster new specific, mechanistic insights. PMID- 29243123 TI - Response assessment in pancreatic ductal adenocarcinoma: role of imaging. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive gastrointestinal (GI) malignancy with poor 5-year survival rate. Advances in surgical techniques and introduction of novel combination chemotherapy and radiation therapy regimens have necessitated the need for biomarkers for assessment of treatment response. Conventional imaging methods such as RECIST have been used for response evaluation in clinical trials particularly in patients with metastatic PDAC. However, the role of these approaches for assessing response to loco-regional and systemic therapies is limited due to complex morphological and histological nature of PDAC. Determination of tumor resectability after neoadjuvant therapy remains a challenge. This review article provides an overview of the challenges and limitations of response assessment in PDAC and reviews the current evidence for the utility of novel morphological and functional imaging tools in this disease. PMID- 29243126 TI - Efficiency of Reovirus Concentration from Water with Positively Charged Filters. AB - This study examined the efficacy of reovirus concentration from large volumes of water using two positively charged filters: Zeta Plus 1MDS and NanoCeram. The results indicated that an average of 61 and 81% of input reoviruses were effectively recovered, respectively, from recycled water and tap water using NanoCeram filtration. PMID- 29243124 TI - Gut microbiome: a new player in gastrointestinal disease. AB - The gastrointestinal (GI) tract harbors a diverse and host-specific gut microbial community. Whereas host-microbe interactions are based on homeostasis and mutualism, the microbiome also contributes to disease development. In this review, we summarize recent findings connecting the GI microbiome with GI disease. Starting with a description of biochemical factors shaping microbial compositions in each gut segment along the longitudinal axis, improved histological techniques enabling high resolution visualization of the spatial microbiome structure are highlighted. Subsequently, inflammatory and neoplastic diseases of the esophagus, stomach, and small and large intestines are discussed and the respective changes in microbiome compositions summarized. Finally, approaches aiming to restore disturbed microbiome compositions thereby promoting health are discussed. PMID- 29243125 TI - Minichromosome maintenance complex component 6 (MCM6) expression correlates with histological grade and survival in endometrioid endometrial adenocarcinoma. AB - Minichromosome maintenance complex component 6 (MCM6) is involved in initiating DNA replication and is upregulated during licensed G0 phase of the cell cycle. This early expression permits its labeling of more proliferating cells than those by Ki-67. Here using a cohort of 89 endometrioid adenocarcinoma, we report findings made on the prognostic value of MCM6 based on immunohistochemical labeling index (LI) of the protein in comparison with that of Ki67 as no such information is currently available. Additionally, we examined the prognostic values of these markers based on their mRNA expression using a cohort of uterine corpus endometrial carcinoma (UCEC, n = 307) taken from The Cancer Genome Atlas (TCGA) database. Our evidence indicated the presence of a positive correlation between the LI of MCM6 and the histological grade of endometrioid endometrial adenocarcinoma (grade I, 66.7%; grade II, 75.3%; grade III, 81.4%; p < 0.001) and an inverse correlation between the LI of MCM6 and the overall and progression free survival (p = 0.02 for both). The LI of Ki-67 correlated with grade (p < 0.001), but not survival. The MCM6 and Ki-67 inter-observer intra-class correlation coefficients were excellent: 0.84 (95% confidence interval, 0.83 0.91) and 0.84 (0.77-0.90), respectively. For in silico analyses of the TCGA cohort, both univariate and multivariate Cox analyses (p = 0.003 and p = 0.03, respectively) revealed high MCM6 mRNA Z-scores associated with reduced overall survival. This association was absent for Ki-67. MCM6 is thus a highly reproducible marker of poor prognosis in endometrial cancer. Evaluation of MCM6 should thus be considered in daily practice for risk stratification. PMID- 29243127 TI - Investigating the roles of loneliness and clinician- and self-rated depressive symptoms in predicting the subjective quality of life among people with psychosis. AB - PURPOSE: To examine the roles of loneliness and clinician- and self-rated depressive symptoms as predictors of the subjective quality of life (QoL) in psychosis. METHODS: This cross-sectional study was conducted on a sample of 207 patients diagnosed with psychotic disorders. They were assessed with self reported measures of QoL, loneliness and depression and with clinician-rated measures of depression and overall psychopathology. Multiple indicators multiple causes (MIMIC) modeling was used to analyze the data. RESULTS: Both loneliness and depression turned out to be independent predictors of impaired QoL. However, once loneliness was accounted for, the effect of depression on QoL was markedly reduced and the effect of loneliness proved to be visibly larger. Self-rated depression was found to be more strongly associated with QoL than clinician-rated depression. Each type of depression measure explained a unique amount of variance in QoL. Depression moderated the relationship between loneliness and QoL in such a way that the negative effect of loneliness on QoL weakened with the increasing intensity of depressive symptoms. CONCLUSIONS: Therapeutic programs aiming to enhance the QoL of people with psychotic disorders should incorporate interventions targeting both loneliness and depression and need to be tailored to the clinical status of patients. The emphasis on alleviating loneliness should be placed first of all in the case of those with low levels of depression, among whom the negative impact of loneliness on QoL is especially strong. Researchers should be aware that the method chosen for assessing depressive symptoms in models predicting QoL in psychosis matters. PMID- 29243128 TI - Measurement of 131I activity in air indoor Polish nuclear medical hospital as a tool for an internal dose assessment. AB - This paper presents results of 131I air activity measurements performed within nuclear medical hospitals as a tool for internal dose assessment. The study was conducted at a place of preparation and administration of 131I ("hot room") and at a nurse station. 131I activity measurements were performed for 5 and 4 consecutive working days, at the "hot room" and nurse station, respectively. Iodine from the air was collected by a mobile HVS-30 aerosol sampler combined with a gas sampler. Both the gaseous and aerosol fractions were measurement. The activities in the gaseous fraction ranged from (28 +/- 1 Bq m-3) to (492 +/- 4) Bq m-3. At both sampling sites, the activity of the gaseous iodine fraction trapped on activated charcoal was significantly higher than that of the aerosol fraction captured on Petrianov filter cloth. Based on these results, an attempt has been made to estimate annual inhalation effective doses, which were found to range from 0.47 mSv (nurse female) to 1.3 mSv (technician male). The highest annual inhalation equivalent doses have been found for thyroid as 32, 27, 13, and 11 mSv, respectively, for technician male, technical female, nurse male, and nurse female. The method presented here allows to fill the gaps in internal doses measurements. Moreover, because method has been successful used for many years in radioactive contamination monitoring of air in cases of serious nuclear accidents, it should also be used in nuclear medicine. PMID- 29243130 TI - Neuroleptic malignant syndrome as a presenting feature of subacute sclerosing panencephalitis. AB - Subacute sclerosing panencephalitis (SSPE) is a slowly progressive degenerative disorder caused by measles virus. It is characterised by typical clinical and electrophysiological features in the form of slow myoclonic jerks, with progressive cognitive impairment, visual symptoms, and periodic complexes on EEG, with raised titres of anti-measles antibodies in CSF and serum. Atypical presentations of SSPE have been reported including brainstem involvement, ADEM like presentation, acute encephalitis, and cerebellar ataxia. Presentation with predominant extrapyramidal features is uncommon. We describe a case of SSPE presenting with extensive rigidity with highly elevated CPK values, mimicking neuroleptic malignant syndrome (NMS) which was most probably due to central dopaminergic blockade induced by the disease process. To our knowledge, this is the first case of SSPE presenting with a NMS-like syndrome. PMID- 29243129 TI - Contrast-enhanced ultrasound for needle biopsy of central lung cancer with atelectasis. AB - PURPOSE: Contrast-enhanced ultrasound (CEUS) can distinguish between central lung cancer and atelectatic lung tissue. The aim of this study was to explore the clinical value of CEUS for biopsy in patients with central lung cancer with obstructive atelectasis. METHODS: One hundred and twelve patients were selected and CEUS was performed to display central lung cancer and atelectatic lung tissue. The front edge of central lung cancer was punctured with a needle, avoiding the necrotic area, under the guidance of CEUS. RESULTS: All of the 112 lesions were diagnosed with a clear central lung cancer mass and atelectatic lung tissue. In 104 cases, the central lung cancer mass presented with a "slow-in and fast-out" pattern compared to atelectatic lung tissue. In eight cases, the central lung cancer mass presented with a "fast-in and fast-out" pattern compared to atelectatic lung tissue. The mean number of punctures was 2.6, and the success rate of puncture biopsy was 98%. Of the 112 patients, six cases had hemoptysis during the procedure and 10 patients had bloody sputum in the postoperative period. No complications were found in the other cases. CONCLUSION: CEUS has important clinical value for needle biopsy of central lung cancer with atelectasis. PMID- 29243131 TI - Analysis of variability of urinary excreted JC virus strains in patients infected with HIV and healthy donors. AB - In immunocompromised individuals, especially in patients with T cell immunodeficiency, reactivation of JCPyV can cause serious life-threatening diseases. Nowadays, HIV infection is one of the most important factor for reactivation of JCPyV and the development of of the progressive multifocal leukoencephalopathy (PML). Mutations in the outer loops of the VP1 region can lead to the selection of the viral variants with changed tropism and increased pathological potential. The aims of this study were to determine sequence variation and amino acid changes within VP1 loops and the structure of non-coding control region (NCCR) of urinary excreted JCPyV isolates among HIV-infected patients and healthy donors. Single urine samples from 114 HIV-infected patients and 120 healthy donors were collected. PCR was performed for amplification of VP1 and NCCR. Amplified fragments were directly sequenced and analyzed by using bioinformatics tools. Nucleotide substitutions were detected within DE and EF loops and in the beta-sheets of both studied groups. In HIV-infected patients group, 70% of mutations were detected within receptor domains. Among healthy donors, one mutation was identified within beta-sheets while the remaining were located within receptor domains. The most prevalent mutation was L157V in both groups. Analysis of NCCR revealed that all isolates had archetype structure with some minor changes. Since single point mutations at specific place within outer loop of VP1 region can cause formation of variants with changed receptor specificity, identification of these mutations in HIV-infected patients can help to single out those with higher risk for development of polyomavirus-associated diseases. PMID- 29243132 TI - HIV-associated opsoclonus-myoclonus-ataxia syndrome: early infection, immune reconstitution syndrome or secondary to other diseases? Case report and literature review. AB - Opsoclonus-myoclonus-ataxia (OMA) syndrome is a debilitating autoimmune neurological disorder. Post-infectious opsoclonus-myoclonus-ataxia syndrome has been described with varying bacterial, spirochetal, and viral infections including several patients with HIV. However, specific immunopathological mechanisms that may lead to opsoclonus-myoclonus in HIV-positive patients are unknown.We report a case of HIV-associated opsoclonus-myoclonus and early HIV infection. A review of published literature shows opsoclonus-myoclonus can occur during early infection, in immune reconstitution syndrome or in association with other infections, especially tuberculosis. PMID- 29243133 TI - Symptomatic cerebrospinal fluid HIV-1 escape with no resistance-associated mutations following low-level plasma viremia. AB - The majority of neurologically symptomatic cerebrospinal fluid HIV-1 escape cases are connected with resistance-associated mutations and potentially explained by low cerebrospinal fluid antiretroviral concentrations. However, there are still significant knowledge gaps regarding the physiopathology and long-term management of neurosymptomatic viral escape. We report a case of Parkinson-like syndrome following cerebrospinal fluid HIV-1 escape in a 40-year-old female patient with an history of persistent low-level plasma viremia under treatment. No resistance associated mutations, high viral diversity (env deep sequencing), adequate pharmacokinetics, atypical CD3-CD14-CD4+CD5-CD2-/+CD7-/+ lymphocytes, low-level Epstein-Barr virus replication, and white matter autoimmune reactivity were observed in the cerebrospinal fluid. Antiretroviral regimen modification led to rapid clinical and radiological improvements. This case may increase the current uncertain knowledge on the origin of cerebrospinal fluid HIV-1 and illustrates the consequences of uncontrolled compartmental viral replication; it also highlights the relevance and persistence of immune activation and the possibility of various detrimental mechanisms underlying neurosymptomatic viral escape. PMID- 29243135 TI - The simplest acquisition protocol is sometimes the best protocol: performing and learning a 1:2 bimanual coordination task. AB - An experiment was conducted to determine if the performance and learning of a multi-frequency (1:2) coordination pattern between the limbs are enhanced when a model is provided prior to each acquisition trial. Research has indicated very effective performance of a wide variety of bimanual coordination tasks when Lissajous plots with goal templates are provided, but this research has also found that participants become dependent on this information and perform quite poorly when it is withdrawn. The present experiment was designed to test three forms of modeling (Lissajous with template, Lissajous without template, and limb model), but in each situations, the model was presented prior to practice and not available during the performance of the task. This was done to decrease dependency on the model and increase the development of an internal reference of correctness that could be applied on test trials. A control condition was also collected, where a metronome was used to guide the movement. Following less than 7 min of practice, participants in the three modeling conditions performed the first test block very effectively; however, performance of the control condition was quite poor. Note that Test 1 was performed under the same conditions as used during acquisition. Test 2 was conducted with no augmented information provided prior to or during the performance of the task. Only participants in the limb model condition were able to maintain performance on Test 2. The findings suggest that a very simple intuitive display can provide the necessary information to form an effective internal representation of the coordination pattern which can be used guide performance when the augmented display is withdrawn. PMID- 29243134 TI - Sensory uncertainty impacts avoidance during spatial decisions. AB - When making risky spatial decisions, humans incorporate estimates of sensorimotor variability and costs on outcomes to bias their spatial selections away from regions that incur feedback penalties. Since selection variability depends on the reliability of sensory signals, increasing the spatial variance of targets during visually guided actions should increase the degree of this avoidance. Healthy adult participants (N = 20) used a computer mouse to indicate their selection of the mean of a target, represented as a 2D Gaussian distribution of dots presented on a computer display. Reward feedback on each trial corresponded to the estimation error of the selection. Either increasing or decreasing the spatial variance of the dots modulated the spatial uncertainty of the target. A non target distractor cue was presented as an adjacent distribution of dots. On a subset of trials, feedback scores were penalized with increased proximity to the distractor mean. As expected, increasing the spatial variance of the target distribution increased selection variability. More importantly, on trials where proximity to the distractor cue incurred a penalty, increasing variance of the target increased selection bias away from the distractor cue and prolonged reaction times. These results confirm predictions that increased sensory uncertainty increases avoidance during risky spatial decisions. PMID- 29243136 TI - Recalibration of hand position sense during unconscious active and passive movement. AB - Precise knowledge of one's limbs' position in space is fundamental for goal directed action. The brain's representation of the body in space is thought to be generated through a process of multisensory integration of visual, tactile and proprioceptive signals. In this study, we devised a setup that allowed us to displace participants' right hand without their subjective awareness. We accomplished this task by instructing the participants to view a live video feed of their hand from the first-person perspective. In the active condition, we used a sensorimotor illusion that caused the participants to actively but unknowingly displace their unseen right hand to a location 8 cm lateral to the image of their hand. In the passive condition, we mechanically displaced the participants' hand at a slow, unnoticeable velocity-to the same location. We found that during active displacement, the participants indicated that the location of their hand was closer to the digital image of the hand rather than the veridical location of the hand, as compared with the passive condition, in which the participants indicated that the locations of their hand were closer to the actual location. These results indicated that, compared with passive displacement, active movements cause greater recalibration of the hand's spatial position and that the boosted spatial recalibration of hand position sense in the active task is driven by error-based sensorimotor corrections. These results have bearing on the perceptual mechanisms of recalibration of perceived limb location. PMID- 29243137 TI - Activation of ankle muscles following rapid displacement of a light touch contact during treadmill walking. AB - The first exposure of a rapid displacement of a light touch reference induces an inappropriate balance corrective response during standing in a proportion of participants that is extinguished with repeated exposures. We hypothesized that if the spatial touch reference was critical to performing of a task the evoked response would be more consistently expressed across participants and observed with repeated exposures to the disturbance. To test this, 20 participants received either forward (N = 10) or backward right-touch displacements at right heel strike during motorized treadmill walking without visual feedback. Electromyographic recordings from four arm, four leg and one neck muscle were sampled along with joint kinematic and step cycle data. Rapid displacement of the touch surface elicited responses in all 20 participants. However, the frequency of first trial responses was not different from what was observed during standing. In contrast, responses were observed in all participants with subsequent trials. None of the participants tripped or stumbled as a result of the touch perturbations; however, the step cycle duration was consistently shorter following the first forward-touch displacement. A post-experiment questionnaire revealed that many participants often perceived the touch plate displacement as a disturbance to the treadmill belt speed, suggesting the disturbance was occasionally misinterpreted. The activation of ankle muscles following the unexpected slip of a touch reference during walking suggests that tactile information from the finger is a relevant sensory cue for the regulation and control of stepping and stability. PMID- 29243138 TI - First molecular detection of porcine bocavirus in Malaysia. AB - Several strains of porcine bocaviruses have been reported worldwide since their first detection in Sweden in 2009. Subsequently, the virus has been reported to be associated with gastrointestinal and respiratory signs in weaner and grower pigs. Although Malaysia is host to a self-sufficient swine livestock industry, there is no study that describes porcine bocavirus in the country. This report is the first to describe porcine bocavirus (PBoV) in Malaysian swine herds. PBoV was identified in various tissues from sick and runt pigs using the conventional PCR method with primers targeting conserved regions encoding for the nonstructural protein (NS1) gene. Out of 103 samples tested from 17 pigs, 32 samples from 15 pigs were positive for porcine bocavirus. In addition, a higher detection rate was identified from mesenteric lymph nodes (52.9%), followed by tonsil (37.0%), and lungs (33.3%). Pairwise comparison and phylogenetic analyses based on a 658 bp fragment of NS1 gene revealed that the Malaysian PBoV strains are highly similar to PBoV3 isolated in Minnesota, USA. The presence of porcine bocavirus in Malaysia and their phylogenetic bond was marked for the first time by this study. Further studies will establish the molecular epidemiology of PBoV in Malaysia and clarify pathogenicity of the local isolates. PMID- 29243139 TI - Prevalence and risk factors of Japanese encephalitis virus (JEV) in livestock and companion animal in high-risk areas in Malaysia. AB - Japanese encephalitis (JE) is vector-borne zoonotic disease which causes encephalitis in humans and horses. Clinical signs for Japanese encephalitis virus (JEV) infection are not clearly evident in the majority of affected animals. In Malaysia, information on the prevalence of JEV infection has not been established. Thus, a cross-sectional study was conducted during two periods, December 2015 to January 2016 and March to August in 2016, to determine the prevalence and risk factors in JEV infections among animals and birds in Peninsular Malaysia. Serum samples were harvested from the 416 samples which were collected from the dogs, cats, water birds, village chicken, jungle fowls, long tailed macaques, domestic pigs, and cattle in the states of Selangor, Perak, Perlis, Kelantan, and Pahang. The serum samples were screened for JEV antibodies by commercial IgG ELISA kits. A questionnaire was also distributed to obtain information on the animals, birds, and the environmental factors of sampling areas. The results showed that dogs had the highest seropositive rate of 80% (95% CI: +/- 11.69) followed by pigs at 44.4% (95% CI: +/- 1.715), cattle at 32.2% (95% CI: +/- 1.058), birds at 28.9% (95% CI: +/- 5.757), cats at 15.6% (95% CI: +/- 7.38), and monkeys at 14.3% (95% CI: +/- 1.882). The study also showed that JEV seropositivity was high in young animals and in areas where mosquito vectors and migrating birds were prevalent. PMID- 29243140 TI - Mutational analysis of IZUMO1R in women with fertilization failure and polyspermy after in vitro fertilization. AB - PURPOSE: The etiology of fertilization failure and polyspermy during assisted reproductive technology (ART) remains elusive. The aim of this study was to determine whether mutations in the IZUMO1 receptor (IZUMO1R) gene, which is essential for mammalian fertilization, contribute to the pathogenesis of fertilization failure or polyspermy in humans. METHODS: We recruited 215 female subjects with fertilization failure/poor fertilization, 330 females with polyspermy, and 300 matched controls. All subjects underwent IVF treatment. Peripheral blood DNA of cases was extracted and screened for mutations in IZUMO1R gene. RESULTS: Four rare single nucleotide polymorphisms (SNPs) of the IZUMO1R were identified among specimens from patients with fertilization failure and polyspermy but were absent in the 300 control subjects. These included a missense SNP (rs76779571 in exon 4), which was found in two fertilization failure patients, and a nonsynonymous SNP (rs61742524 in exon 1) and two synonymous SNPs (rs76781645 in exon 1 and rs377369966 in intron 2), which were found among three polyspermy cases. CONCLUSIONS: The variations in IZUMO1R might play a role in the pathogenesis of fertilization failure and polyspermy, and the putative functions and effects of these rare variants require further studies. PMID- 29243142 TI - Highlights of the 21th Annual Scientific Meeting of the Australasian Musculoskeletal Imaging Group (AMSIG) 2017, Melbourne, Australia. PMID- 29243141 TI - Comparison of the development of human embryos cultured in either an EmbryoScope or benchtop incubator. AB - PURPOSE: In this current study, our main goal was to establish that EmbryoScope incubation environment is comparable to standard incubation. METHODS: The development of sibling human zygotes was compared after culture in either a benchtop incubator (SI) or an EmbryoScope time-lapse incubator (ES). Between May 2015 to April 2016, a total of 581 normally fertilized 2PN, pronuclear-stage embryos, from 47 patients were allocated to culture in either a benchtop incubator (SI) or an EmbryoScope incubator (ES). RESULTS: The development of embryos to cleavage (up to day 3) and blastocyst stages (day 5/6) was compared between the two different incubators. The proportion of good quality embryos was higher in the ES group compared to the SI on day 2 (66.8 vs. 50.5%, P = 0.014) and on day 3 (75.1 vs. 56.0%, P = 0.006). Those differences were statistically significant. A higher proportion of embryos developed to good quality blastocysts when cultured in the EmbryoScope compared to the benchtop (49.4 vs. 42.0%, P = 0.24), but this was not significant. Finally, no significant differences were noted with the proportion of blastocysts chosen for cryopreservation on day 5/6 in the two incubators. CONCLUSIONS: The findings support the view that the EmbryoScope incubator supports at least equivalent in vitro development of human embryos compared to other standard incubation methods and may promote improved development during early cleavage stages. PMID- 29243143 TI - Highlights of the 44th Annual Scientific Congress of the International Skeletal Society (ISS) 2017, New York, New York. AB - This paper summarizes the highlights of the Special Scientific Sessions of the 44th Annual Scientific Meeting of the International Skeletal Society (ISS), which was hosted in New York, NY, in August 2017. PMID- 29243144 TI - Intraarticular calcifying aponeurotic fibroma of the wrist: mimicking gout or calcium pyrophosphate dihydrate deposition disease. AB - Calcifying aponeurotic fibroma is a rare, benign fibroblastic tumor that typically occurs in the palms of the hands and soles of the feet in children and adolescents. We report an unusual case of a calcifying aponeurotic fibroma with diffuse intra-articular involvement of the carpal joints in a 59-year-old female. Radiographs and computed tomography scans revealed a large lobulated soft tissue mass with multiple stippled calcifications around the carpal joints and numerous erosions of the second to fifth carpometacarpal and intercarpal joints. Magnetic resonance imaging showed diffuse multinodular synovial proliferation with inhomogeneous hypo- to isointense signal intensity on T1-weighted images, inhomogeneous hypointense to hyperintense signal intensity on T2-weighted images, and inhomogeneous intense enhancement on fat-suppressed contrast-enhanced T1 weighted images. Radiologic diagnosis included gout, calcium pyrophosphate dihydrate deposition disease, and tenosynovial giant cell tumor. Surgical excision was performed, and the mass was diagnosed on pathologic examination as a calcifying aponeurotic fibroma. There has been no reported case of a calcifying aponeurotic fibroma with diffuse intra-articular involvement of the carpal joints in the literature. PMID- 29243145 TI - The First Consensus Statement on One Anastomosis/Mini Gastric Bypass (OAGB/MGB) Using a Modified Delphi Approach. AB - BACKGROUND: An increasing number of surgeons worldwide are now performing one anastomosis/mini gastric bypass (OAGB/MGB). Lack of a published consensus amongst experts may be hindering progress and affecting outcomes. This paper reports results from the first modified Delphi consensus building exercise on this procedure. METHODS: A committee of 16 recognised opinion-makers in bariatric surgery with special interest in OAGB/MGB was constituted. The committee invited 101 OAGB/MGB experts from 39 countries to vote on 55 statements in areas of controversy or variation associated with this procedure. An agreement amongst >= 70.0% of the experts was considered to indicate a consensus. RESULTS: A consensus was achieved for 48 of the 55 proposed statements after two rounds of voting. There was no consensus for seven statements. Remarkably, 100.0% of the experts felt that OAGB/MGB was an "acceptable mainstream surgical option" and 96.0% felt that it could no longer be regarded as a new or experimental procedure. Approximately 96.0 and 91.0% of the experts felt that OAGB/MGB did not increase the risk of gastric and oesophageal cancers, respectively. Approximately 94.0% of the experts felt that the construction of the gastric pouch should start in the horizontal portion of the lesser curvature. There was a consensus of 82, 84, and 85% for routinely supplementing iron, vitamin B12, and vitamin D, respectively. CONCLUSION: OAGB/MGB experts achieved consensus on a number of aspects concerning this procedure but several areas of disagreements persist emphasising the need for more studies in the future. PMID- 29243146 TI - Correction to: Contraception, Menstruation, and Sexuality after Bariatric Surgery: a Prospective Cohort Study. AB - The spelling of author name Jill Shawe was incorrect in the original article. It is correct here. PMID- 29243147 TI - Seasonal variations in size distribution, water-soluble ions, and carbon content of size-segregated aerosols over New Delhi. AB - Size distribution, water-soluble inorganic ions (WSII), and organic carbon (OC) and elemental carbon (EC) in size-segregated aerosols were investigated during a year-long sampling in 2010 over New Delhi. Among different size fractions of PM10, PM0.95 was the dominant fraction (45%) followed by PM3-7.2 (20%), PM7.2-10 (15%), PM0.95-1.5 (10%), and PM1.5-3 (10%). All size fractions exceeded the ambient air quality standards of India for PM2.5. Annual average mass size distributions of ions were specific to size and ion(s); Ca2+, Mg2+, K+, NO3-, and Cl- followed bimodal distribution while SO42- and NH4+ ions showed one mode in PM0.95. The concentrations of secondary WSII (NO3-, SO42-, and NH4+) increased in winters due to closed and moist atmosphere whereas open atmospheric conditions in summers lead to dispersal of pollutants. NH4+and Ca2+were dominant neutralization ions but in different size fractions. The summer-time dust transport from upwind region by S SW winds resulted in significantly high concentrations of PM0.95 and PM3-7.2 and PM7.2-10. This indicted influence of dust generation in Thar Desert and its transport is size selective in nature in downwind direction. The mixing of different sources (geogenic, coal combustions, biomass burning, plastic burning, incinerators, and vehicular emissions sources) for soluble ions in different size fractions was noticed in principle component analysis. Total carbon (TC = EC + OC) constituted 8-31% of the total PM0.95 mass, and OC dominated over EC. Among EC, char (EC1) dominated over soot (EC2 + EC3). High SOC contribution (82%) to OC and OC/EC ratio of 2.7 suggested possible role of mineral dust and high photochemical activity in SOC production. Mass concentrations of aerosols and WSII and their contributions to each size fraction of PM10 are governed by nature of sources, emission strength of source(s), and seasonality in meteorological parameters. PMID- 29243148 TI - Impaired reproduction and individual growth of the water flea Daphnia magna as consequence of exposure to the non-ester pyrethroid etofenprox. AB - The effect of the pesticide etofenprox (0.76, 0.95, 1.18, 1.48, and 1.85 MUg L-1) on survival, reproduction, and growth of Daphnia magna organisms was monitored using 21-day exposure tests. In order to test pesticide effects on D. magna, survival, length, mean total neonates per female, mean brood size, time to first reproduction, mean number broods per female, cumulative molting, and the population parameter intrinsic rate of natural increase (r) were used. Reproduction was seriously affected by etofenprox. Concentrations of etofenprox higher than 1.18 MUg L-1affected all the reproductive parameters analyzed as well as individual length. However, daphnids' survival after 21 days of pesticide exposure did not exhibited differences among experimental and control groups. The no observed effect concentration (NOEC), the lowest observed effect concentration (LOEC), and the maximum acceptable toxicant concentration (MATC) were calculated for the different parameters. A MATC estimation of 1.32 MUg L-1 was calculated for mean brood size, mean number of broods per female, mean number of neonates per female, and the intrinsic rate of growth population. Etofenprox effect on the algae Nannochloris oculata was also evaluated. The selected etofenprox concentrations did not affect algal growth rate (MU) after 24 h; however, N. oculata exposed during 48 and 72 h to the highest etofenprox concentration showed a decreased in its population rate. PMID- 29243149 TI - Ferulic acid protects against radiation-induced testicular damage in male rats: impact on SIRT1 and PARP1. AB - Ionizing radiation is a major contributor to male infertility by destroying spermatogenesis. Therefore, the need for an effective radio-protective agent is evident. The objective of the present study was to investigate the potential radio-protective effect of ferulic acid (FA) on radiation-induced testicular damage. Mature male Sprague-Dawley rats were either exposed to a single-dose gamma radiation (5 Gy) and/or treated with FA (50 mg/kg), daily for 7 days before irradiation. Sirtuin1 (SIRT1), poly (ADP-ribose) polymerase 1 (PARP1), cytosolic calcium content, and the male reproductive functions (sperm head abnormality) as well as oxidative stress markers were assessed 7 days after irradiation. FA significantly maintained active spermatogenesis. Moreover, it reversed the oxidative stress effects of irradiation. The irradiated group showed marked elevation in both PARP1 expression and activity as well as in cytosolic calcium concentration, whereas SIRT1 activity and expression markedly decreased; in contrast, FA treatment prevented these alterations. Results of histopathological examination of testicular tissues indicated coincidence with those recorded by biochemical analyses. Our data show for the first time that FA had radio protective effect against radiation-induced testicular damage. It improved spermatogenesis through increasing testicular SIRT1 and testosterone levels and decreasing oxidative stress, PARP1, and cytosolic calcium. PMID- 29243150 TI - Characterization of multiple antibiotic resistance of culturable microorganisms and metagenomic analysis of total microbial diversity of marine fish sold in retail shops in Mumbai, India. AB - Marine fish species were analyzed for culturable and total metagenomic microbial diversity, antibiotic resistance (AR) pattern, and horizontal gene transfer in culturable microorganisms. We observed a high AR microbial load of 3 to 4 log CFU g-1. Many fish pathogens like Providencia, Staphylococcus, Klebsiella pneumoniae, Enterobacter, Vagococcus, and Aeromonas veronii were isolated. Photobacterium and Vibrio were two major fish and human pathogens which were identified in the fish metagenome. Other pathogens that were identified were Shewanella, Acinetobacter, Psychrobacter, and Flavobacterium. Most of these pathogens were resistant to multiple antibiotics such as erythromycin, kanamycin, neomycin, streptomycin, penicillin, cefotaxime, bacitracin, rifampicin, trimethoprim, ciprofloxacin, and doxycycline with a high multiple antibiotic resistance index of 0.54-0.77. The fish microflora showed high prevalence of AR genes like bla TEM, Class I integron, tetA, aph(3')-IIIa, ermB, aadA, and sul1. Nineteen of 26 AR isolates harbored Class I integrons showing high co-resistance to trimethoprim, kanamycin, doxycycline, and cefotaxime. Mobile R-plasmids from 6 of the 12 AR pathogens were transferred to recipient E. coli after conjugation. The transconjugants harbored the same R-plasmid carrying bla CTX-M, dfr1, tetA, bla TEM, and cat genes. This study confirms that fish is a potential carrier of AR pathogens which can enter the human gut via food chain. To the best of our knowledge, this is the first study in the Indian subcontinent reporting a direct evidence of spread of AR pathogens to humans from specific marine fish consumption. PMID- 29243151 TI - Improving a compact biofilm reactor to realize efficient nitrogen removal performance: step-feed, intermittent aeration, and immobilization technique. AB - Purifying tank as a compact biofilm reactor has been widely used to remove organic matter in rural sewage, but its potential for nitrogen removal is rare to be discussed. This study developed a lab-scale compact biofilm reactor to realize an efficient nitrogen removal performance by step-feed, intermittent aeration, and immobilization technique. The results show that an efficient simultaneous nitrification and denitrification (SND) process took place by feeding with synthetic wastewater under high C/N ratio of 2 and with real sewage as well, mainly due to the step-feed. The average removal efficiency of total inorganic nitrogen arrived at 72.7 and 63.3% for synthetic wastewater and real sewage, respectively. Besides the step-feed operation, the intermittent aeration was adopted to enhance SND, which allowed hydraulic behavior of compact biofilm reactor following the model of completely stirred tank reactor. The high throughput sequencing analysis indicates that Sphaerotilus became the dominant genera with relative abundance of 30.29% under high C/N ratio, and the nitrifiers were not greatly inhibited. Moreover, the immobilization technique helped restore microbial activity under low temperature, promoting the satisfactory nitrogen removal performance of recovered microorganism to be rebuilt by feeding nutrient solution. Overall, the long-term SND process and maintaining effective biofilm activity can be established in the compact biofilm reactor through several improving alternatives. PMID- 29243152 TI - Transgene escape and persistence in an agroecosystem: the case of glyphosate resistant Brassica rapa L. in central Argentina. AB - Brassica rapa L. is an annual Brassicaceae species cultivated for oil and food production, whose wild form is a weed of crops worldwide. In temperate regions of South America and especially in the Argentine Pampas region, this species is widely distributed. During 2014, wild B. rapa populations that escaped control with glyphosate applications by farmers were found in this area. These plants were characterized by morphology and seed acidic profile, and all the characters agreed with B. rapa description. The dose-response assays showed that the biotypes were highly resistant to glyphosate. It was also shown that they had multiple resistance to AHAS-inhibiting herbicides. The transgenic origin of the glyphosate resistance in B. rapa biotypes was verified by an immunological test which confirmed the presence of the CP4 EPSPS protein and by an event-specific GT73 molecular marker. The persistence of the transgene in nature was confirmed for at least 4 years, in ruderal and agrestal habitats. This finding suggests that glyphosate resistance might come from GM oilseed rape crops illegally cultivated in the country or as a seed contaminant, and it implies gene flow and introgression between feral populations of GM B. napus and wild B. rapa. The persistence and spread of the resistance in agricultural environments was promoted by the high selection pressure imposed by intensive herbicide usage in the prevalent no-till farming systems. PMID- 29243153 TI - Amine-functionalized diatom frustules: a platform for specific and sensitive detection of nitroaromatic explosive derivative. AB - In the present study, an attempt was made to develop a proof of concept for the detection of nitroaromatic explosive derivatives through the photoluminescence (PL) quenching process using functionalized diatom frustules as a sensing platform. The diatom frustules are composed of nanostructured, highly porous biogenic silica material and emit strong, visible blue PL upon UV excitation. PL active biosilica was isolated from the marine diatom Nitzschia sp. and was amine functionalized to develop a sensing platform. Functionalized diatom frustules were further characterized using field emission scanning electron microscope and a series of spectroscopic methods. When nitroaromatic compounds were bound to the functionalized diatom frustules biosilica, the PL intensity from the functionalized biosilica was partially quenched due to the electrophilic nature of the nitro (-NO) groups. The quenching process confirmed the Meisenheimer complex formation and was investigated by using Fourier transform infrared spectroscopy and time-resolved photoluminescence studies. The developed platform was further evaluated for its sensitivity and specificity, and the limit of detection (LOD) of the assay was determined as 1 MUM for a series of nitroaromatic explosive compounds. In conclusion, the developed sensing platform will have great utility in the development of on-site detection platforms for sensitive detection of warfare explosive nitroaromatic compounds from the environment. PMID- 29243154 TI - Nitrate trends in groundwater of the Campania region (southern Italy). AB - The Environmental Protection Agency of the Campania region in Italy (ARPAC) manages a groundwater quality monitoring network. For almost all the polluted waters, the key parameter driving the classification is the concentration of nitrate; hence, the Campania region, in coherence with the EU regulations, outlined the vulnerable areas and undertook remediation policies. The best groundwater quality is recorded for carbonate aquifers of the Apennine chain; on the contrary, the Tyrrhenian coastal plains are affected by severe contamination, with a locally very contaminated groundwater of the shallow and also the deeper aquifers. The study is especially focused on a large coastal plain of Campania region, where nitrate concentration sometimes exceeds 200 mg/L. The study, based on almost 200 sampling points for the whole region during the period 2003-2015 (approx two samples per year), verified the effectiveness of the groundwater monitoring network, the present distribution of nitrate in groundwater, and the evolution of nitrate trends at different scales: regional, groundwater body, and single well, using spatial and time series statistical approaches. Significant variations in contamination evolution within the study area have been observed and the correlation with land use has been highlighted. PMID- 29243156 TI - Comfort Eating and All-Cause Mortality in the US Health and Retirement Study. AB - PURPOSE: Comfort eating is a prevalent behavior. Prior research shows that comfort eating is associated with reduced stress responses and increased metabolic risk across adolescence, young adulthood, and middle adulthood. The purpose of the current research was to test if comfort eating prospectively predicted all-cause mortality in older adulthood. METHOD: The US Health and Retirement Study is an ongoing, nationally representative, longitudinal study of older adults. The final sample for the present study (N = 1445) included participants randomly selected to report how often they comfort ate. Comfort eating data were collected in 2008 and all-cause mortality data were collected in 2014. Participants also reported how often they consumed high-fat/sugar food as well as their height and weight in 2008. RESULTS: For each 1-unit increase in comfort eating, the expected odds of all-cause mortality (n = 255 deceased) decreased by 14%, OR = 0.86, p = 0.048, 95% CI [0.74, 0.99]. This analysis statistically accounted for other predictors of mortality in the sample including age, biological sex, race, highest educational degree attained, moderate and vigorous exercise, smoking, and cumulative illness. High-fat/sugar intake did not mediate (or diminish) the association but body mass index did. CONCLUSION: Comfort eating-irrespective of consuming high-fat/sugar food-may be associated with reduced mortality in older adults because it may promote greater body mass, and greater body mass is associated with lower risk of mortality in nationally representative samples. Interventionists might consider both beneficial and detrimental aspects of comfort eating across the lifespan. PMID- 29243155 TI - Trends in plant research using molecular markers. AB - MAIN CONCLUSION: A deep bibliometric analysis has been carried out, obtaining valuable parameters that facilitate the understanding around the research in plant using molecular markers. The evolution of the improvement in the field of agronomy is fundamental for its adaptation to the new exigencies that the current world context raises. In addition, within these improvements, this article focuses on those related to the biotechnology sector. More specifically, the use of DNA markers that allow the researcher to know the set of genes associated with a particular quantitative trait or QTL. The use of molecular markers is widely extended, including: restriction fragment length polymorphism, random-amplified polymorphic DNA, amplified fragment length polymorphism, microsatellites, and single-nucleotide polymorphisms. In addition to classical methodology, new approaches based on the next generation sequencing are proving to be fundamental. In this article, a historical review of the molecular markers traditionally used in plants, since its birth and how the new molecular tools facilitate the work of plant breeders is carried out. The evolution of the most studied cultures from the point of view of molecular markers is also reviewed and other parameters whose prior knowledge can facilitate the approach of researchers to this field of research are analyzed. The bibliometric analysis of molecular markers in plants shows that top five countries in this research are: US, China, India, France, and Germany, and from 2013, this research is led by China. On the other hand, the basic research using Arabidopsis is deeper in France and Germany, while other countries focused its efforts in their main crops as the US for wheat or maize, while China and India for wheat and rice. PMID- 29243157 TI - Why is a prone sleeping position dangerous for certain infants? AB - The prone (face down) sleeping position is known to be associated with a significantly increased risk of sudden and unexpected death in infancy (sudden infant death syndrome or SIDS), however, the reasons for this are unclear. Suggested mechanisms have involved suffocation from occlusion of the external airways by soft bedding/pillows or from flattening of the nose with backward displacement of the tongue, rebreathing of carbon dioxide, blunting of arousal responses with decreased cardiac responses to auditory stimulation, diaphragmatic splinting or fatigue, lowering of vasomotor tone with tachycardia, nasopharyngeal bacterial overgrowth, overheating, alteration of sleep patterns, compromise of cerebral blood flow and upper airway obstruction from distortion of nasal cartilages. Recent studies have, however, shown a significant reduction in substance P in the inferior portion of the olivo-cerebellar complex in SIDS infants which is crucial for the integration of motor and sensory information for the control of head and neck movement. This deficit may explain why some infants are not able to move their faces away from potentially dangerous sleeping environments. PMID- 29243158 TI - Bilateral native nephrectomy to reduce oxalate stores in children at the time of combined liver-kidney transplantation for primary hyperoxaluria type 1. AB - OBJECTIVE: Primary hyperoxaluria type-1 (PH-1) is a rare genetic disorder in which normal hepatic metabolism of glyoxylate is disrupted resulting in diffuse oxalate deposition and end-stage renal disease (ESRD). While most centers agree that combined liver-kidney transplant (CLKT) is the appropriate treatment for PH 1, perioperative strategies for minimizing recurrent oxalate-related injury to the transplanted kidney remain unclear. We present our management of children with PH-1 and ESRD on hemodialysis (HD) who underwent CLKT at our institution from 2005 to 2015. METHODS: On chart review, three patients (2 girls, 1 boy) met study criteria. Two patients received deceased-donor split-liver grafts, while one patient received a whole liver graft. All patients underwent bilateral native nephrectomy at transplant to minimize the total body oxalate load. Median preoperative serum oxalate was 72 MUmol/L (range 17.8-100). All patients received HD postoperatively until predialysis serum oxalate levels fell <20 MUmol/L. All patients, at a median of 7.5 years of follow-up (range 6.5-8.9), demonstrated stable liver and kidney function. CONCLUSIONS: While CLKT remains the definitive treatment for PH-1, bilateral native nephrectomy at the time of transplant reduces postoperative oxalate stores and may mitigate damage to the renal allograft. PMID- 29243159 TI - Characterization and Identification of Recalcitrant Organic Pollutants (ROPs) in Tannery Wastewater and Its Phytotoxicity Evaluation for Environmental Safety. AB - Tannery wastewater (TWW) is of serious environmental concern to pollution control authorities, because it contains highly toxic, recalcitrant organic and inorganic pollutants. The nature and characteristics of recalcitrant organic pollutants (ROPs) are not fully explored to date. Hence, the purpose of this study was to characterize and identify the ROPs present in the treated TWW. Gas chromatography mass spectrometry data analysis showed the presence of a variety of ROPs in the treated TWW. Results unfolded that benzyl chloride, butyl octyl phthalate, 2,6 dihydroxybenzoic acid 3TMS, dibutyl phthalate, benzyl alcohol, benzyl butyl phthalate, 4-chloro-3-methyl phenol, phthalic acid, 2'6'-dihydroxyacetophenone, diisobutyl phthalate, 4-biphenyltrimethylsiloxane, di-(-2ethy hexyl)phthalate, 1,2-benzenedicarboxylic acid, dibenzyl phthalate, and nonylphenol were present in the treated TWW. Due to endocrine disrupting nature and aquatic toxicity, the U.S. Environmental Protection Agency classified many of these as "priority pollutants" and restricted their use in leather industries. In addition, the physicochemical analysis of the treated TWW also showed very high BOD, COD, and TDS values along with high Cr and Pb content beyond the permissible limits for industrial discharge. Furthermore, phytotoxicity assessment unfolds the inhibitory effects of TWW on the seed germination, seedling growth parameters, and alpha-amylase activity in Phaseolus aureus L. This indicates that the TWW discharged even after secondary treatment into the environment has very high pollution parameters and may cause a variety of serious health threats in living beings upon exposure. Overall, the results reported in this study will be helpful for the proper treatment and management of TWW to combat the environmental threats. PMID- 29243160 TI - Guidelines to the Practice of Anesthesia - Revised Edition 2018. AB - OVERVIEW: The Guidelines to the Practice of Anesthesia Revised Edition 2018 (the Guidelines) were prepared by the Canadian Anesthesiologists' Society (CAS), which reserves the right to determine their publication and distribution. The Guidelines are subject to revision and updated versions are published annually. The Guidelines to the Practice of Anesthesia Revised Edition 2018 supersedes all previously published versions of this document. Although the CAS encourages Canadian anesthesiologists to adhere to its practice guidelines to ensure high quality patient care, the CAS cannot guarantee any specific patient outcome. Anesthesiologists should exercise their own professional judgement in determining the proper course of action for any patient's circumstances. The CAS assumes no responsibility or liability for any error or omission arising from the use of any information contained in its Guidelines to the Practice of Anesthesia. PMID- 29243161 TI - History of the crest and motto of the Canadian Anesthesiologists' Society. PMID- 29243162 TI - Interventions to improve the mechanical ventilation fidelity of the Laerdal SimMan(r) 3G simulation mannequin. PMID- 29243163 TI - Computational Analysis of the Utilisation of the Shape Memory Effect and Balloon Expansion in Fully Polymeric Stent Deployment. AB - The desire to overcome the limitations of cardiovascular metal stents is driven by the global clinical need to improve patient outcomes. The opportunity for fully polymeric stents made from materials like Poly-L-lactide Acid (PLLA) is significant. Unfortunately, this potential has not been fully realised due to pressing concerns regarding the radial strength and recoil associated with material stiffness and recoverability. In an effort to achieve effective and reliable performance, it is conceivable that a certain degree of shape memory effect (SME) could be beneficial in order to improve on high recoil associated with fully polymeric stents. In this paper, a computational model is presented to explore this possibility, using a stent geometry based on that of a commercially available polymeric stent (Abbott Absorb). The model predicts improvements in the recoil behaviour if the stent is subjected to temperature changes (introducing the shape memory effect to the material) prior to implantation compared to balloon inflation alone. The analysis indicates that combination of self expansion and balloon inflation is capable of reducing stent recoil to a desirable level (5%). Additionally, the analysis suggests that the recoil is not strongly related to expansion rate variation. However, the stent expansion rate is critically linked to the maximum stresses in the material, with significantly higher stresses found if the stent was deployed with a higher rate, leading to a significantly higher material failure risk. It is concluded that the model provides new insights that can guide the development of fully polymeric stents towards optimised clinical performance with the potential to improve patient outcomes. PMID- 29243164 TI - Effects of exercise during chemotherapy on chemotherapy-induced peripheral neuropathy: a multicenter, randomized controlled trial. AB - PURPOSE: Over half of all cancer patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy experience chemotherapy-induced peripheral neuropathy (CIPN), which includes numbness, tingling, pain, cold sensitivity, and motor impairment in the hands and feet. CIPN is a dose-limiting toxicity, potentially increasing mortality. There are no FDA-approved drugs to treat CIPN, and behavioral interventions such as exercise are promising yet understudied. This secondary analysis of our nationwide phase III randomized controlled trial of exercise for fatigue examines (1) effects of exercise on CIPN symptoms, (2) factors that predict CIPN symptoms, and (3) factors that moderate effects of exercise on CIPN symptoms. METHODS: Cancer patients (N = 355, 56 +/- 11 years, 93% female, 79% breast cancer) receiving taxane-, platinum-, or vinca alkaloid based chemotherapy were randomized to chemotherapy or chemotherapy plus Exercise for Cancer Patients (EXCAP(c)(r)). EXCAP is a standardized, individualized, moderate-intensity, home-based, six-week progressive walking and resistance exercise program. Patients reported CIPN symptoms of numbness and tingling and hot/coldness in hands/feet (0-10 scales) pre- and post-intervention. We explored baseline neuropathy, sex, age, body mass index, cancer stage, and cancer type as possible factors associated with CIPN symptoms and exercise effectiveness. RESULTS: Exercise reduced CIPN symptoms of hot/coldness in hands/feet (-0.46 units, p = 0.045) and numbness and tingling (- 0.42 units, p = 0.061) compared to the control. Exercise reduced CIPN symptoms more for patients who were older (p = 0.086), male (p = 0.028), or had breast cancer (p = 0.076). CONCLUSIONS: Exercise appears to reduce CIPN symptoms in patients receiving taxane-, platinum-, or vinca alkaloid-based chemotherapy. Clinicians should consider prescribing exercise for these patients. TRIAL REGISTRATION: Clinical Trials.gov , # NCT00924651, http://www.clinicaltrials.gov . PMID- 29243165 TI - Ease of walking associates with greater free-living physical activity and reduced depressive symptomology in breast cancer survivors: pilot randomized trial. AB - PURPOSE: We hypothesized exercise training-induced improvements in ease of walking would associate with favorable changes in objectively measured physical activity (PA) and self-reported depressive symptoms following a PA behavior change intervention in non-metastatic breast cancer survivors (BCS). METHODS: Twenty-seven BCS received random assignment to an intervention (INT) or control group (CON). INT included counseling/group discussions coupled with supervised exercise tapered to unsupervised exercise. PA, depressive symptoms, and ease of walking were evaluated pre-/post-intervention using 10-day accelerometry, HADS depression subscale, and indirect calorimetry during a standardized treadmill test, respectively. PA composite score was calculated by converting weekly minutes of moderate-to-vigorous PA and average steps/day to z-scores then dividing the sum by 2. Cardiac efficiency was determined by dividing steady-state oxygen uptake by heart rate to evaluate the volume of oxygen consumed per heartbeat. RESULTS: ANCOVA revealed a significant time by group interaction showing the INT group exhibited greater positive changes in the PA composite compared to the CON (INT, + 0.14 +/- 0.66 au vs. CON, - 0.48 +/- 0.49 au; p = 0.019; eta p2 = 0.21). Changes occurring from baseline to follow-up, among all participants, revealed improved ease of walking (less oxygen uptake) associated with increased PA composite (r = - 0.52; p = 0.010) and lower depressive symptomology (r = 0.50; p = 0.012) adjusted for age, race, and months since cancer diagnosis. Increased cardiac efficiency during the standardized treadmill test also associated with less daily sedentary time (r = - 0.52; p = 0.021). CONCLUSIONS: These data support the assertion that reducing the physiological difficulty of walking may contribute to greater engagement in free-living PA, less sedentary time, and decreased psychosocial distress among BCS. PMID- 29243166 TI - A hospital and home-based exercise program to address functional decline in people following allogeneic stem cell transplantation. AB - PURPOSE: The aims of this study are to investigate the feasibility of an exercise program commencing 60 days following allogeneic stem cell transplantation (alloSCT), to investigate changes in physical function and health-related quality of life (HRQoL) in patients from pre- to post-alloSCT and to explore changes in patient outcomes before and after the program. METHODS: This study is a single site, prospective case series including 43 adults undergoing alloSCT. The intervention was an 8-week outpatient and home-based exercise and education program. Outcomes included feasibility (consent, attendance, compliance and completion rates), functional exercise capacity (incremental shuttle walk test), muscle strength (hand-held dynamometry), self-efficacy for physical activity (Physical Activity Assessment Inventory) and HRQoL (Functional Assessment of Cancer Therapy-Bone Marrow Transplant). Outcomes were measured pre-alloSCT, 60 days post-alloSCT (pre-intervention) and 100 days post-alloSCT (post intervention). RESULTS: The consent rate was 93%. From baseline to 60 days post alloSCT, there was significant decline in functional exercise capacity (mean difference 224 m, 95% CI 153-295, p < 0.0005), self-efficacy for physical activity (294 points, 95% CI 136-452, p = 0.001) and HRQoL (15 points, 95% CI 8 21, p < 0.0005). Ten participants did not commence the exercise program due to death (n = 5), illness (n = 1) or cancellation of alloSCT (n = 4). The intervention was feasible in those not affected by major medical complications or death. No adverse events occurred. From pre- to post-intervention, there was significant improvement in functional exercise capacity (p = 0.001) and HRQoL (p = 0.001). CONCLUSIONS: AlloSCT results in significant decline in functional exercise capacity, self-efficacy for physical activity and HRQoL, which may be improved through an exercise program. This pilot demonstrated safety, feasibility and high patient interest. Further randomised research is required. PMID- 29243167 TI - Psychological distress among Indigenous Australian cancer survivors. AB - PURPOSE: The purpose of this study is to identify the level of and factors associated with distress in 155 Indigenous Australian cancer survivors approximately 6 months post-diagnosis. METHODS: The distress thermometer (DT) was used to assess clinically significant distress (defined as having a DT score >= 4). Logistic regression was used to identify sociodemographic and clinical factors associated with clinically significant distress. RESULTS: The mean distress score was 2.7 (SD 2.9), with about one in three Indigenous cancer survivors reporting clinically significant distress (35%; n = 54). After adjusting for age and sex, clinically significant distress was more likely among those who were separated/divorced/widowed than those who were married (odds ratio (OR) = 2.99, 95% confidence intervals (95% CI) 1.21-7.35, p = 0.017) and less likely among those residing in remote areas than those in major cities (OR = 0.23, 95% CI 0.08-0.71, p = 0.001) and in those receiving non-surgical treatment only compared with surgery only (OR = 0.24, 95% CI 0.08-0.68, p = 0.008). CONCLUSIONS: Despite increased screening for distress in cancer care, this is, to our knowledge, the first published assessment of distress among Indigenous Australian cancer survivors. The characteristics of Indigenous cancer survivors associated with greater likelihood of clinically significant distress indicate at risk subgroups who would benefit from screening and early intervention. Further research is required to identify the specific aetiologies of distress. Our findings indicate a need to identify psychological distress and for survivorship care to include culturally sensitive and tailored psychological support for Indigenous cancer survivors. PMID- 29243168 TI - The views of patients with metastatic prostate cancer towards physical activity: a qualitative exploration. AB - PURPOSE: Patients with metastatic cancer can experience debilitating symptoms, which may influence attitudes towards and engagement in physical activity. This study aimed to examine the attitudes of patients living with metastatic prostate cancer towards physical activity. MATERIALS AND METHODS: Semi-structured interviews were completed with male patients living with metastatic prostate cancer. Interviews included eight questions related to patients' attitudes towards physical activity. Content analysis was conducted on the transcribed interview data. Twenty men with metastatic prostate cancer (mean age 71 +/- 8.5 years; body mass index 30.19 +/- 5.37 kg/cm2) and associated bone metastases (55% with > 2 regions affected) participated in the study. RESULTS: Men's views towards physical activity were coded into the following major themes: (1) barriers to physical activity, (2) benefits of physical activity, (3) a reduction in physical activity levels post diagnosis and (4) social support for physical activity. Symptoms of metastatic prostate cancer and treatment side effects including pain and fatigue negatively influenced activity participation. In addition, many generic barriers to physical activity were described such as bad weather and a lack of suitable facilities for exercising in rural areas. CONCLUSION: Men living with metastatic prostate cancer have unique needs regarding physical activity related to symptoms of both their cancer and cancer treatment. There is a need to increase prompts that encourage those with metastatic prostate cancer to maintain/increase physical activity levels post diagnosis. Given the individualised needs of this patient group, referral to a cancer exercise specialist should be considered for prescription of tailored physical activity programmes. TRIAL REGISTRATION: Clinicaltrials.gov NLM Identifier: NCT02453139. PMID- 29243169 TI - Efficacy of two types of palliative sedation therapy defined using intervention protocols: proportional vs. deep sedation. AB - PURPOSE: This study investigated the effect of two types of palliative sedation defined using intervention protocols: proportional and deep sedation. METHODS: We retrospectively analyzed prospectively recorded data of consecutive cancer patients who received the continuous infusion of midazolam in a palliative care unit. Attending physicians chose the sedation protocol based on each patient's wish, symptom severity, prognosis, and refractoriness of suffering. The primary endpoint was a treatment goal achievement at 4 h: in proportional sedation, the achievement of symptom relief (Support Team Assessment Schedule (STAS) <= 1) and absence of agitation (modified Richmond Agitation-Sedation Scale (RASS) <= 0) and in deep sedation, the achievement of deep sedation (RASS <= - 4). Secondary endpoints included mean scores of STAS and RASS, deep sedation as a result, and adverse events. RESULTS: Among 398 patients who died during the period, 32 received proportional and 18 received deep sedation. The treatment goal achievement rate was 68.8% (22/32, 95% confidence interval 52.7-84.9) in the proportional sedation group vs. 83.3% (15/18, 66.1-100) in the deep sedation group. STAS decreased from 3.8 to 0.8 with proportional sedation at 4 h vs. 3.7 to 0.3 with deep sedation; RASS decreased from + 1.2 to - 1.7 vs. + 1.4 to - 3.7, respectively. Deep sedation was needed as a result in 31.3% (10/32) of the proportional sedation group. No fatal events that were considered as probably or definitely related to the intervention occurred. CONCLUSION: The two types of intervention protocol well reflected the treatment intention and expected outcomes. Further, large-scale cohort studies are promising. PMID- 29243170 TI - Associations among physical symptoms, fear of cancer recurrence, and emotional well-being among Chinese American breast cancer survivors: a path model. AB - PURPOSE: Most existing studies on fear of cancer recurrence (FCR) are exploratory without theoretical underpinnings and have been conducted among non-Hispanic Whites. Based on theoretical models, we hypothesized that more physical symptoms (pain and fatigue) would be associated with higher FCR, which, in turn would be related to lower emotional well-being among Chinese American breast cancer survivors. METHODS: Participants were 77 Chinese American women who were diagnosed with breast cancer of stages 0-III. A cross-sectional path analysis was conducted with a bootstrapping method. RESULTS: The final model showed that indirect paths from pain interference to emotional well-being and from fatigue to emotional well-being via FCR were significant. That is, higher levels of pain interference and fatigue were associated with higher FCR, which was further related to lower emotional well-being. CONCLUSIONS: To our best knowledge, this is the first theory-driven study that investigates FCR experiences among Chinese American breast cancer survivors. Our study might provide a more comprehensive understanding of FCR as it simultaneously shows predictors and a psychological consequence of FCR. Results need to be replicated in large, racially/ethnically diverse samples and longitudinal studies. PMID- 29243173 TI - Magnetic resonance imaging findings of two cases with multinodular and vacuolating neuronal tumor. AB - Multinodular and vacuolating neuronal tumors (MVNT) are low grade neuronal tumors classified in cerebral tumors based on 2016 WHO central nerve system classification. Previously, MVNTs were probably tumors incidentally determined by imaging methods, but they could not be diagnosed or they were misdiagnosed. Two cases are reported in the present study, for which radiological imaging was carried out for epilepsy in one and for headache in the other. The first case was a twenty seven years old female patient with headache complaint. Brain MRI examination revealed a clustering lesion of multinodular character located in an about 4.0 * 3.5 * 1.5 cm area which had a left precuneal subcortical juxtacortical location. The other case was a male patient with epilepsy. A clustering lesion of multinodular nature was determined in an area of about 2.0 * 2.0 * 1.5 cm in cortical-subcortical area in corona radiata-convexity plane of right middle frontal girus. No changes in size or nature were determined in follow-up examinations. MVNTs are recently defined tumors, and the characteristic feature for diagnosis of these rare tumor entities could be a subcortical white matter lesion with satellite nodules that manifest itself as T2/FLAIRhyperintensity. Increasing number of case reports and studies in the literature could make the radiological and pathological signs of the condition clearer. PMID- 29243172 TI - Therapeutic Delivery of Simvastatin Loaded in PLA-PEG Polymersomes Resulted in Amplification of Anti-inflammatory Effects in Activated Microglia. AB - Simvastatin (Sim), a lipid-lowering drug has been studied in chronic neuroinflammation associated with degenerative brain disorders due to its potential protective properties against inflammatory reaction, oxidative damage, neuronal dysfunction, and death. Meanwhile, potential application of Sim in neuroinflammation will require a suitable delivery system that can overcome notable challenges pertaining to poor blood-brain barrier (BBB) permeability and side/off-target effects. Herein, we engineered and characterized nano-sized polymersomes loaded with Sim (Sim-Ps) using PEG-PdLLA (methoxy polyethylene glycol-poly(D,L) lactic acid) diblock co-polymers. Studies in BV2 microglia indicated that Sim-Ps was superior to Sim alone in suppressing nitric oxide (NO) and proinflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) secretion against LPS activation. The effectiveness of Sim-Ps as compared with Sim alone, in attenuating NO and cytokine production by activated BV2 cells can be attributed to (a) colloidal stability of the delivery platform, (b) protracted release of biologically active Sim, and (c) particulate internalization coupled with enhanced Sim exposure to BV2 cells. Intranasal delivery in BALB/c mice demonstrated enhanced brain distribution with increasing time after administration. Overall data demonstrated suitability of PEG-PdLLA polymersomes in Sim delivery for potential application in treating neuroinflammation. PMID- 29243171 TI - iPSCs-based generation of vascular cells: reprogramming approaches and applications. AB - Recent advances in the field of induced pluripotent stem cells (iPSCs) research have opened a new avenue for stem cell-based generation of vascular cells. Based on their growth and differentiation potential, human iPSCs constitute a well characterized, generally unlimited cell source for the mass generation of lineage and patient-specific vascular cells without any ethical concerns. Human iPSCs derived vascular cells are perfectly suited for vascular disease modeling studies because patient-derived iPSCs possess the disease-causing mutation, which might be decisive for full expression of the disease phenotype. The application of vascular cells for autologous cell replacement therapy or vascular engineering derived from immune-compatible iPSCs possesses huge clinical potential, but the large-scale production of vascular-specific lineages for regenerative cell therapies depends on well-defined, highly reproducible culture and differentiation conditions. This review will focus on the different strategies to derive vascular cells from human iPSCs and their applications in regenerative therapy, disease modeling and drug discovery approaches. PMID- 29243174 TI - Prion propagation and inositol polyphosphates. AB - The [PSI+] prion is a folded in-register parallel beta-sheet amyloid (filamentous polymer) of Sup35p, a subunit of the translation termination factor. Our searches for anti-prion systems led to our finding that certain soluble inositol polyphosphates (IPs) are important for the propagation of the [PSI+] prion. The IPs affect a wide range of processes, including mRNA export, telomere length, phosphate and polyphosphate metabolism, energy regulation, transcription and translation. We found that 5-diphosphoinositol tetra(or penta)kisphosphate or inositol hexakisphosphate could support [PSI+] prion propagation, and 1 diphosphoinositol pentakisphosphate appears to inhibit the process. PMID- 29243175 TI - Survival of the drowsiest: the hibernating 100S ribosome in bacterial stress management. AB - In response to nutrient deprivation and environmental insults, bacteria conjoin two copies of non-translating 70S ribosomes that form the translationally inactive 100S dimer. This widespread phenomenon is believed to prevent ribosome turnover and serves as a reservoir that, when conditions become favorable, allows the hibernating ribosomes to be disassembled and recycled for translation. New structural studies have revealed two distinct mechanisms for dimerizing 70S ribosomes, but the molecular basis of the disassembly process is still in its infancy. Many details regarding the sequence of dimerization-dissociation events with respect to the binding and departure of the hibernation factor and its antagonizing disassembly factor remain unclear. PMID- 29243176 TI - Understanding and reducing complex systems pharmacology models based on a novel input-response index. AB - A growing understanding of complex processes in biology has led to large-scale mechanistic models of pharmacologically relevant processes. These models are increasingly used to study the response of the system to a given input or stimulus, e.g., after drug administration. Understanding the input-response relationship, however, is often a challenging task due to the complexity of the interactions between its constituents as well as the size of the models. An approach that quantifies the importance of the different constituents for a given input-output relationship and allows to reduce the dynamics to its essential features is therefore highly desirable. In this article, we present a novel state and time-dependent quantity called the input-response index that quantifies the importance of state variables for a given input-response relationship at a particular time. It is based on the concept of time-bounded controllability and observability, and defined with respect to a reference dynamics. In application to the brown snake venom-fibrinogen (Fg) network, the input-response indices give insight into the coordinated action of specific coagulation factors and about those factors that contribute only little to the response. We demonstrate how the indices can be used to reduce large-scale models in a two-step procedure: (i) elimination of states whose dynamics have only minor impact on the input-response relationship, and (ii) proper lumping of the remaining (lower order) model. In application to the brown snake venom-fibrinogen network, this resulted in a reduction from 62 to 8 state variables in the first step, and a further reduction to 5 state variables in the second step. We further illustrate that the sequence, in which a recursive algorithm eliminates and/or lumps state variables, has an impact on the final reduced model. The input-response indices are particularly suited to determine an informed sequence, since they are based on the dynamics of the original system. In summary, the novel measure of importance provides a powerful tool for analysing the complex dynamics of large-scale systems and a means for very efficient model order reduction of nonlinear systems. PMID- 29243177 TI - 24-Epibrassinolide-induced alterations in the root cell walls of Cucumis sativus L. under Ca(NO3)2 stress. AB - Brassinosteroids (BRs) can effectively alleviate the oxidative stress caused by Ca(NO3)2 in cucumber seedlings. The root system is an essential organ in plants due to its roles in physical anchorage, water and nutrient uptake, and metabolite synthesis and storage. In this study, 24-epibrassinolide (EBL) was applied to the cucumber seedling roots under Ca(NO3)2 stress, and the resulting chemical and anatomical changes were characterized to investigate the roles of BRs in alleviating salinity stress. Ca(NO3)2 alone significantly induced changes in the components of cell wall, anatomical structure, and expression profiles of several lignin biosynthetic genes. Salt stress damaged several metabolic pathways, leading to cell wall reassemble. However, EBL promoted cell expansion and maintained optimum length of root system, alleviating the oxidative stress caused by Ca(NO3)2. The continuous transduction of EBL signal thickened the secondary cell wall of casparian band cells, thus resisting against ion toxicity and maintaining water transport. PMID- 29243178 TI - Development and validation of a loop-mediated isothermal amplification assay for the detection of Mycoplasma bovis in mastitic milk. AB - Mycoplasma mastitis is often difficult to control due to a lack of rapid and accurate diagnostic tools. The aim of the current study was to develop a loop mediated isothermal amplification (LAMP) assay for the detection of Mycoplasma bovis (M. bovis) in mastitic milk. The assay was developed using primers designed for three different target genes: uvrC, 16S rRNA, and gyrB, and validated using mastitic milk samples previously found positive for the target pathogen. Specificity of the developed assay was determined by testing cross-reactivity of LAMP primers against closely related bovine mastitis bacterial pathogens. The sensitivity was found to be higher compared to conventional polymerase chain reaction (PCR). The LAMP assay was also capable of detecting M. bovis in PCR negative milk samples of cows with clinical mastitis. The uvrC primers were found to be more sensitive, while gyrB primers were more specific; however, 16S rRNA primers were less specific and sensitive compared to either uvrC or gyrB primers. Cohen's kappa values for uvrC, gyrB, and 16S rRNA primers used in the LAMP assays were 0.940, 0.970, and 0.807, respectively. There was a high level of agreement between the test results and the true-disease status as indicated by the receiver operating characteristic (ROC) curve. Our findings suggest that the newly developed LAMP assays targeting the uvrC and gyrB genes could be a useful tool for rapid and accurate diagnosis of mastitis caused by M. bovis. PMID- 29243179 TI - Melanoma risk assessment based on relatives' age at diagnosis. AB - PURPOSE: The aim of this study was to determine risk for melanoma among individuals who have a first- or second-degree relative with a history of melanoma, based on the unaffected individual's age and age at diagnosis of the relative. METHODS: The study employed a case-control design using a statewide database linked with a Surveillance Epidemiology and End Results cancer registry. A population-based sample of individuals who received at least one diagnosis of first primary, malignant melanoma (n = 14,281), as well as their first- and second-degree relatives, was included. Control individuals with no history of melanoma (n = 70,889) were matched to cases on birth year, gender, race/ethnicity, and county at birth. RESULTS: Risk for melanoma among relatives of melanoma patients declined with relative's age and age at diagnosis. Individuals between ages 40 and 49 who are first-degree relatives of melanoma patients diagnosed between ages 40 and 49 had the greatest risk for melanoma compared with individuals without a first-degree relative with a melanoma history (HR 4.89; 95% CI 3.11-7.68). Increased melanoma risk among second-degree relatives of patients was typically lower than that for first-degree relatives. CONCLUSIONS: Risk for melanoma, at earlier ages than expected, is increased among relatives of individuals with a history of melanoma, particularly if the melanoma case was diagnosed at a young age. Further research on the relationship between age at diagnosis and relative's melanoma risk could inform melanoma screening recommendations for individuals with a family history of the disease. PMID- 29243180 TI - Transoral thyroidectomy: a viable surgical option with unprecedented complications-a case series. AB - PURPOSE: To report the clinical implications of an initial experience with transoral endoscopic thyroidectomy vestibular approach (TOETVA). METHODS: From March to November 2017, five cases of TOETVA were performed. Data reported include patient demographics, indication for surgery, extent of surgery, operative time, the need to convert to cervicotomy, the length of hospital stay and post-operative pain and morbidity. Unconventional complications regarded as specific for TOETVA were reported. The burden of surgery on the patient's quality of life was evaluated using the 36-item short form (SF-36) health survey 1 month after surgery. RESULTS: All patients were females with a mean age of 36 years. They all underwent a right-sided hemithyroidectomy for a solitary thyroid nodule measuring on average 3.5 cm in size. The nodule was reported as Bethesda category II (n = 3), III (n = 1), and IV (n = 1) on fine needle aspiration cytology. The mean operative time was 122 min. Conversion to a transverse cervicotomy was required in one case. None of the patients developed post-operative bleeding, and none experienced vocal fold or mental nerve palsy. Surgical site infection did not occur. All patients developed subcutaneous emphysema that resolved within 12 48 h. All patients reported a long-standing bothersome pulling sensation along the surgical track that resulted in a poor outcome in some scales of the SF-36 survey. Flap perforation occurred in one case. The median VAS score was 3. CONCLUSION: Patients strongly motivated to undergo a novel surgical procedure tailored to their needs and desires should be properly counselled particularly regarding unconventional procedure-related complications. PMID- 29243181 TI - Tooth agenesis code (TAC) in complete unilateral and bilateral cleft lip and palate patients. AB - The objective of this study is to characterize and compare tooth agenesis codes and their prevalence in a population of Spanish patients with unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP), and to determine if the extent of the cleft (BCLP or UCLP) was associated with the number of absent teeth. This retrospective cross-sectional human study included 118 patients with complete BCLP (29) or UCLP (89) and permanent dentition from first molar to first molar. Congenitally missing teeth were identified on panoramic radiographs using the tooth agenesis code (TAC) to identify agenesis codes. Agenesis prevalence was 50.6 and 51.7% for UCLP and BCLP patients, respectively. The lateral upper incisor was the most frequently absent tooth, especially in the cleft quadrant. Numbers of absent teeth ranged from 1 to 6. This study represents a different approach from previous agenesis investigations in cleft patients. These Spanish patients showed a high number of ageneses, presenting nineteen different tooth agenesis codes. A total of five TACs were unique, in other words, observed in a single patient in the sample. No statistically significant relationship was found between the extent of the cleft and the number of absent teeth. The TAC system makes it possible to identify agenesis codes with simultaneous absence of teeth not detected in general prevalence studies. PMID- 29243182 TI - The facial nerve: anatomy and associated disorders for oral health professionals. AB - The facial nerve, the seventh cranial nerve, is of great clinical significance to oral health professionals. Most published literature either addresses the central connections of the nerve or its peripheral distribution but few integrate both of these components and also highlight the main disorders affecting the nerve that have clinical implications in dentistry. The aim of the current study is to provide a comprehensive description of the facial nerve. Multiple aspects of the facial nerve are discussed and integrated, including its neuroanatomy, functional anatomy, gross anatomy, clinical problems that may involve the nerve, and the use of detailed anatomical knowledge in the diagnosis of the site of facial nerve lesion in clinical neurology. Examples are provided of disorders that can affect the facial nerve during its intra-cranial, intra-temporal and extra-cranial pathways, and key aspects of clinical management are discussed. The current study is complemented by original detailed dissections and sketches that highlight key anatomical features and emphasise the extent and nature of anatomical variations displayed by the facial nerve. PMID- 29243183 TI - Effects of experimental periodontitis on the metabolic system in rats with diet induced obesity (DIO): an analysis of serum biochemical parameters. AB - Recent studies have shown that periodontitis accelerates the progression of obesity-associated metabolic diseases. Thus, we examined the influence of periodontitis on serum biochemical parameters of metabolic disease in a diet induced obesity (DIO) rat. First, we established the DIO model using ten male rats fed with either basal diet (lean group) or high-fat diet (DIO group) for 12 weeks. Second, to examine the interaction between periodontitis and obesity, we divided 24 DIO rats into the following four groups. (1) Porphyromonas gingivalis (Pg) group was applied with Pg around the maxillary first molar (M1). (2) Ligature group was applied with ligature placement around M1. (3) Ligature/Pg group was treated with both ligature placement and Pg. (4) Control was non treatment group. Serum biochemical parameters and maxillary histopathology were evaluated at 12 weeks. The DIO model demonstrated significant increases in body weight, serum insulin, alanine aminotransaminase (ALT) levels, and insulin resistance (HOMA-IR) compared to the lean group. In the DIO ligature and ligature/Pg groups, alveolar bone resorption and inflammatory cell infiltration were significantly increased compared to the control. Serum levels of fasting glucose, lactate dehydrogenase, and uric acid were also significantly higher, while the liver damage markers ALT and aspartate aminotransferase were only higher in ligature/Pg group. However, we observed no significant differences between the Pg group and Control. The present study suggested a possibility that periodontitis induced by ligature placement changed serum metabolic parameter regarding organs such as the liver in DIO rat. PMID- 29243184 TI - Study of MYB-NFIB chimeric gene expression, tumor angiogenesis, and proliferation in adenoid cystic carcinoma of salivary gland. AB - Adenoid cystic carcinoma (ACC) is one of the common malignant tumors in salivary glands, and the clinical prognosis is poor with frequent distant metastasis which may lead to death. Expression of the MYB-NFIB chimeric gene in ACC has been reported recently. MYB is an oncogene with transcription regulating functions, and NFIB encodes nuclear transcription factor although detailed functions are unknown. This study investigated whether MYB-NFIB chimeric gene expression affects tumor angiogenesis and proliferation in salivary gland ACC. In 26 salivary gland ACC cases, MYB-NFIB chimeric gene expression was analyzed by RT PCR and direct sequencing. Immunohistochemical studies for CD31, vascular endothelial growth factor (VEGF) and Ki-67 were performed. Tumor angiogenesis was evaluated by blood vessel (CD31-positive) density and tumor proliferation by Ki 67 labeling index, and the relationship with MYB-NFIB chimeric gene expression was analyzed. MYB-NFIB chimeric gene expression was detected in nine of 26 ACC cases. Blood vessel density was significantly higher in chimeric gene-expressing cases compared to non-expressing cases. VEGF score tended to be higher in chimeric gene-expressing cases than in non-expressing cases, while Ki-67 labeling index was not significantly different. The number of chimeric gene-expressing cases increased with age, peaking in the sixties age group and declining thereafter, while the number of non-expressing cases increased with age continuously. In ACC, blood vessel density was significantly higher in MYB-NFIB chimeric gene-expressing cases compared to non-expressing cases, which may be due to higher VEGF production capability. MYB-NFIB chimeric gene expression may also be related to the onset age of ACC. PMID- 29243185 TI - Effect of fiber post length and abutment height on fracture resistance of endodontically treated premolars prepared for zirconia crowns. AB - The purpose of this study was to compare the fracture resistance, mode of fracture, and stress distribution of endodontically treated teeth prepared with three different fiber post lengths and two different abutment heights, using both experimental and finite element (FE) approaches. Forty-eight human maxillary premolars with two roots were selected and endodontically treated. The teeth were randomly distributed into six equally sized groups (n = 8) with different combinations of post lengths (7.5, 11, and 15 mm) and abutment heights (3 and 5 mm). All the teeth restored with glass fiber post (Rely X Fiber Post, 3M ESPE, USA) and a full zirconia crown. All the specimens were thermocycled and then loaded to failure at an oblique angle of 135 degrees . Statistical analysis was performed for the effects of post length and abutment height on failure loads using ANOVA and Tukey's honestly significant difference test. In addition, corresponding FE models of a premolar restored with a glass fiber post were developed to examine mechanical responses. The factor of post length (P < 0.01) had a significant effect on failure load. The abutment height (P > 0.05) did not have a significant effect on failure load. The highest mean fracture resistance was recorded for the 15 mm post length and 5 mm abutment height test group, which was significantly more resistant to fracture than the 7.5 mm post and 5 mm abutment height group (P < 0.05). The FE analysis showed the peak compression and tension stress values of 7.5 mm post length were higher than that of 11 and 15 mm post length. The stress value of remaining tooth decreased as the post length was increased. Within the limitations of this experimental and FE analysis study, increasing the post length inside the root of endodontically treated premolar teeth restored with glass-fiber posts increase the fracture resistance to non axial forces. Failure mode is more favorable with reduced abutment heights. PMID- 29243186 TI - Effect of root canal sealers on human periodontal ligament fibroblast viability: ex vivo study. AB - The aim of the study was to compare ex vivo the toxic effects of six root canal sealers immediately after mixing or setting on human periodontal ligament fibroblasts (HPdLF). Freshly mixed (I group) or set (allowed to dry for 24 h) (II group) specimens of AH Plus Jet (AH), Apexit Plus (AP), MTA Fillapex (FL), GuttaFlow (GF), MetaSEAL Soft (META), and Tubli-Seal (TS) were prepared. HPdLF were exposed for 24 h to the specimens. 3-(4,5-dimethylthiazolo-2-yl)-2,5 diphenyltetrazolium bromide assay was used to examine the effect of the root canal sealers on mitochondrial metabolic activity. Fluorescein isothiocyanate (FITC)-annexin V (AnV) and propidium iodide staining followed by flow cytometry was used to identify the effects of the materials on cell apoptosis/necrosis. Statistical analyses were performed by one-way ANOVA followed by post hoc tests, and significance was determined at P < 0.05. Most materials from the two groups reduced the viability of the cultured cells compared with the control group (P < 0.05). Statistical analysis showed significant differences in HPdLF viability between the individual materials in each group (P < 0.001). AH and AP induced a significant increase in the percentage of apoptotic cells, while TS, FL, and META elevated the proportion of necrotic cells compared with other materials and the controls (p < 0.05). The cytotoxic effects of the tested root canal sealers (both fresh and set) on HPdLF varied. Both forms of sealers were able to cause toxic effects by inducing apoptosis and necrosis in HPdLF. The cytotoxicity of FL, META, TS was mainly associated with necrosis, while AH and AP with apoptosis. PMID- 29243187 TI - Bonding performance of self-adhesive flowable composites to enamel, dentin and a nano-hybrid composite. AB - This study aimed to analyze bond strengths of self-adhesive flowable composites on enamel, dentin and nano-hybrid composite. Enamel, dentin and nano-hybrid composite (Venus Diamond, Heraeus Kulzer, Germany) specimens were prepared. Three self-adhesive composites (Constic, DMG, Germany; Fusio Liquid Dentin, Pentron Clinical, USA; Vertise Flow, Kerr Dental, Italy) or a conventional flowable composite (Venus Diamond Flow, Heraeus Kulzer, Germany, etch&rinse technique) were applied to enamel and dentin. Nano-hybrid composite specimens were initially aged by thermal cycling (5000 cycles, 5-55 degrees C). Surfaces were left untreated or pretreated by mechanical roughening, Al2O3 air abrasion or silica coating/silanization. In half of the composite specimens, an adhesive (Optibond FL, Kerr Dental, Italy) was used prior to the application of the flowable composites. Following thermal cycling (5000 cycles, 5-55 degrees C) of all specimens, shear bond strengths (SBS) and failure modes were analyzed (each subgroup n = 16). Statistical analysis was performed by ANOVAs/Bonferroni post hoc tests, Weibull statistics and chi 2-tests (p < 0.05). SBS (MPa) of the self adhesive composites on enamel and dentin were significantly lower (enamel: < 5, dentin: < 3) than those of the conventional flowable composite (enamel: 13.0 +/- 5.1, dentin: 11.2 +/- 6.3), and merely adhesive failures could be observed. On the nano-hybrid composite, SBS were significantly related to the pretreatment. Adhesive application improved SBS of the conventional, but not of the self adhesive composites. The self-adhesive composite groups showed less cohesive failures than the reference group; the occurence of cohesive failures increased after surface pretreatment. Bonding of self-adhesive flowable composites to enamel and dentin is lower than bonding to a nano-hybrid composite. PMID- 29243188 TI - Current management of lipoblastoma. AB - : Lipoblastoma is a rare and benign tumor arising from embryonal fat cells. It is generally diagnosed in children younger than 3 years of age and can occur in the extremities or on the trunk. We present our series of 10 children with lipoblastoma treated at Schneider Children's Medical Center of Israel between 2011 and 2016. Six boys and four girls underwent tumor resection at a median age of 2 years and 3 months (range 5 months to 5.6 years). Locations were trunk (6), groin (2), perineum (1), and omentum (1). Follow up ranges from 1 to 5 years. Two patients had a local recurrence and required a second resection 2 years (perineal) and 6 years (trunk) after the first surgery without further recurrence at 1.9 and 2.9 years, respectively. CONCLUSION: Higher awareness of lipoblastoma enables optimal imaging strategies and resection. Long follow up is required due to local recurrences. The treatment of choice consists of complete, but non mutilating surgical resection. What is Known: * Lipoblastoma is a rare benign tumor of fatty tissue affecting children * Treatment consists of surgical resection What is New: * MRI is the modality of choice for follow up * Ten-year long-term follow up is required due to late recurrence. PMID- 29243189 TI - Congenital portosystemic venous shunt. AB - : Congenital portosystemic venous shunts are rare developmental anomalies resulting in diversion of portal flow to the systemic circulation and have been divided into extra- and intrahepatic shunts. They occur during liver and systemic venous vascular embryogenesis and are associated with other congenital abnormalities. They carry a higher risk of benign and malignant liver tumors and, if left untreated, can result in significant medical complications including systemic encephalopathy and pulmonary hypertension. CONCLUSION: This article reviews the various types of congenital portosystemic shunts and their anatomy, pathogenesis, symptomatology, and timing and options of treatment. What is Known: * The natural history and basic management of this rare congenital anomaly are presented. What is New: * This paper is a comprehensive review; highlights important topics in pathogenesis, clinical symptomatology, and treatment options; and proposes an algorithm in the management of congenital portosystemic shunt disease in order to provide a clear idea to a pediatrician. An effort has been made to emphasize the indications for treatment in the children population and link to the adult group by discussing the consequences of lack of treatment or delayed diagnosis. PMID- 29243190 TI - Faltering growth in the critically ill child: prevalence, risk factors, and impaired outcome. AB - : Low body mass index (BMI) z score is commonly used to define undernutrition, but faltering growth allows for a complementary dynamic assessment of nutritional status. We studied the prevalence of undernutrition and faltering growth at admission in the pediatric intensive care (PICU) setting and their impacts on outcome. All (685) consecutive children (aged 0 to 18 years old) admitted in a single-center PICU over a 1-year period were prospectively enrolled. Nutritional status assessment was based on anthropometric measurements performed at admission and collected from medical files. Undernutrition was considered when z score BMI for age was < - 2SD. Faltering growth was considered when the weight for age curve presented a deceleration of > - 1 z score in the previous 3 months. Undernutrition was diagnosed in 13% of children enrolled, and faltering growth in 13.7% mostly in children with a normal BMI. Faltering growth was significantly associated with a history of underlying chronic disease, and independently with extended length of PICU stay in a multivariate analysis. CONCLUSION: Assessment of nutritional status in critically ill children should include both undernutrition and faltering growth. This study highlights that faltering growth is independently associated with suboptimal outcome in PICU. What is Known: * Malnutrition, defined according to BMI-for-age z score, is correlated with poor outcome in the critically ill child. * In this setting, nutritional assessment should consist not only of a static assessment based on BMI-for-age z score but also of a dynamic assessment to identify recent faltering growth. What is New: * Critically ill children frequently present with faltering growth at admission. * Faltering growth is a newly identified independent associated factor of suboptimal outcome in this setting (extended length of stay). PMID- 29243193 TI - Comparison between two-point and three-point compression ultrasound for the diagnosis of deep vein thrombosis. AB - Lower extremity deep vein thrombosis (DVT) is a frequent cause of admission to the emergency departments (ED). Although the gold standard for diagnosis is the Duplex ultrasound examination, the current study used for diagnosis of DVT in the ED by emergency physicians is the point-of-care compression ultrasound (POCUS). To compare the sensitivity and specificity of the two-point and three-point compression ultrasound (2PCUS and 3PCUS respectively) for diagnosis of lower extremity DVT in an ED management. We prospectively recruited outpatients who were admitted to the ED with suspected lower extremity DVT. Each patient underwent 2PCUS and 3PCUS performed by a trained ED physician. The ED physician recorded the results and then referred the patient to the vascular clinic for the Duplex ultrasound examination. 195 patients recruited to this study between July 2015 and June 2016 in the ED of Rabin Medical Center-Beillinson Hospital, Israel. DVT was diagnosed by Duplex examination in 48 of 195 patients (24.6%). There were significant correlations among the findings regarding the deep veins on both the 2PCUS and 3PCUS tests and on the Duplex examination (p < 0.001). DVT at any vein was correctly diagnosed with the 2PCUS in 38 of48 patients with positive findings on Duplex examination and incorrectly diagnosed (false positive) in 2 of 133 patients without DVT (sensitivity 82.76%, specificity 98.52%). DVT was correctly diagnosed with the 3PCUS in 43 of 48 DVT and incorrectly diagnosed (false positive) in 2 of133 patients without DVT (sensitivity 90.57%, specificity 98.52%). The sensitivity of the 3PCUS was significantly higher than the 2PCUS (p < 0.001), while the specificity was similar. A short training is satisfactory for achieving a good clinical capability to identify DVT by ED physicians. The 3PCUS examination preformed in the ED, is a noninvasive, accurate and quick diagnostic test for evaluation of patients presenting with signs and symptoms suggestive of a DVT. By Using 3PCUS, the ED physicians may decrease time to diagnosis, definitive care and length of stay in the ED. PMID- 29243192 TI - A novel personalized 3D injectable protein scaffold for regenerative medicine. AB - Biomaterials should be designed to closely resemble the characteristics and functions of the native extracellular matrix to provide mechanical support and signals to direct biological events. Here we have developed a novel injectable plasma rich in growth factors (PRGF-Endoret)-based formulation that combines a thermal-denaturation step of plasma with an autologous fibrin crosslinking. Rheological and mechanical properties were evaluated. Additionally, the microstructure and biological capacity of the biomaterial was also characterized. This novel formulation exhibited ideal mechanical properties and a gel-like behavior with the ability to progressively release its growth factor load over time. The results also suggested that the novel injectable formulation is non cytotoxic, biocompatible and suitable for cell ingrowth as it is deduced from the fibroblast proliferation within the scaffold. Finally, stimulation of both cell proliferation and matrix proteins synthesis demonstrated the regenerative potential of this autologous protein based injectable scaffold. PMID- 29243191 TI - Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice. AB - There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause-and-effect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L-NAME, and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns, and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation. PMID- 29243195 TI - Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with Siewert type II/III early gastric cancer. AB - BACKGROUND: Because of the poor prognosis of proximal gastric cancers, there is debate as to whether the conventional indications for endoscopic resection can be used. METHODS: Among subjects who underwent surgery for esophagogastric junction or gastric cardia cancer, 256 patients with T1 type II/III of the Siewert classification were included in this study. The association of lymph node metastasis (LNM) with each variable was analyzed using logistic regression models. A receiver operating characteristic curve was used to determine the discriminatory ability of the model. Propensity score-matched non-cardia cancer patients were selected to compare LNM and long-term survival rates. RESULTS: Of the 256 patients with T1 Siewert II/III gastric cancer, 21 (8.2%) had LNM. Because there was no LNM in T1a cancers, risk factors were analyzed only in patients with T1b. Tumor size (OR 1.42, 95% CI 1.10-1.82, P = 0.007) and lymphovascular invasion (LVI) (OR 5.13, 95% CI 1.88-14.06, P = 0.002) were determined to be predictors of LNM (sensitivity = 66.7% and specificity = 81.6%). Among patients without LVI, the groups with negligible risk for LNM were mucosa confined cancer, or SM1 cancer with a tumor size <=3 cm. No LNM was observed in patients satisfying the absolute or extended criteria for endoscopic resection of early gastric cancers. LNM and long-term survival rates of patients with Siewert II/III did not differ significantly compared with matched non-cardia cancer patients. CONCLUSIONS: Tumor size and LVI were associated with LNM in patients with early Siewert type II/III gastric cancer, and the expanded indication for endoscopic resection may be used. PMID- 29243194 TI - Kallistatin inhibits lymphangiogenesis and lymphatic metastasis of gastric cancer by downregulating VEGF-C expression and secretion. AB - BACKGROUND: Tumor-induced lymphangiogenesis and lymphatic metastasis are predominant during the metastasis of many types of cancers. However, the endogenous inhibitors that counterbalance the lymphangiogenesis and lymphatic metastasis of tumors have not been well evaluated. Kallistatin has been recognized as an endogenous angiogenesis inhibitor. METHODS AND RESULTS: Our recent study showed for the first time that the lymphatic vessel density (LVD) was reduced in lung and stomach sections from kallistatin-overexpressing transgenic mice. Kallistatin expresses anti-lymphangiogenic activity by inhibiting the proliferation, migration, and tube formation of human lymphatic endothelial cells (hLECs). Therefore, the present study focuses on the relationships of changes in kallistatin expression with the lymphangiogenesis and lymphatic metastasis of gastric cancer and its underlying mechanisms. Our results revealed that the expression of kallistatin in cancer tissues, metastatic lymph nodes, and plasma of gastric cancer patients was significantly downregulated and that the plasma level of kallistatin was negatively associated with the phase of lymph node metastasis. Furthermore, treatment with kallistatin recombinant protein decreased LVD and lymph node metastases in the implanted gastric xenograft tumors of nude mice. Mechanically, kallistatin suppressed the lymphangiogenesis and lymphatic metastasis by downregulating VEGF-C expression and secretion through the LRP6/IKK/I?B/NF-?B signaling pathway in gastric cancer cells. CONCLUSIONS: These findings demonstrated that kallistatin functions as an endogenous lymphangiogenesis inhibitor and has an important part in the lymphatic metastasis of gastric cancer. PMID- 29243198 TI - Total eclipse in the heart. PMID- 29243197 TI - Dimensional Latent Structure of Early Disruptive Behavior Disorders: A Taxometric Analysis in Preschoolers. AB - Although disruptive behavior disorders (DBDs) are used as a distinct categorical diagnosis in clinical practice, they have repeatedly been described as having a dimensional structure in taxometric analyses. In the current study the authors analyzed the latent status of disruptive behaviors (DB) in a large sample (N = 2,808) of German preschool children (2-6 years old, mean age 53.7 months, SD = 13.5, 48.4% girls). The Eyberg Child Behavior Inventory (ECBI) as well as the Strengths and Difficulties Questionnaire (SDQ) were used to compile indicators of the DB core dimensions (Temper Loss, Aggression, Noncompliance, and Low Concern for others). Three widely used taxometric methods (a) MAXEIG, (b) MAMBAC, and (c) L-Mode were applied. Simulation data were created to evaluate the Comparison Curve Fit Index values (CCFIs), which were below 0.45, supporting a dimensional solution. Hence, in the current study the latent structure of DB in preschoolers encompassed differences in degree rather than kind. Researchers and practitioners should be mindful of the dimensional latent status of DB in theory building, assessment, classification, and labeling. PMID- 29243196 TI - Chronic Mild Hyperhomocysteinemia Alters Inflammatory and Oxidative/Nitrative Status and Causes Protein/DNA Damage, as well as Ultrastructural Changes in Cerebral Cortex: Is Acetylsalicylic Acid Neuroprotective? AB - Homocysteine is a sulfur-containing amino acid derived from methionine metabolism. When plasma homocysteine levels exceed 10-15 MUM, there is a condition known as hyperhomocysteinemia, which occur as a result of an inborn error of methionine metabolism or by non-genetic causes. Mild hyperhomocysteinemia is considered a risk factor for development of neurodegenerative diseases. The objective of the present study was to evaluate whether acetylsalicylic acid has neuroprotective role on the effect of homocysteine on inflammatory, oxidative/nitrative stress, and morphological parameters in cerebral cortex of rats subjected to chronic mild hyperhomocysteinemia. Wistar male rats received homocysteine (0.03 MUmol/g of body weight) by subcutaneous injections twice a day and acetylsalicylic acid (25 mg/Kg of body weight) by intraperitoneal injections once a day from the 30th to the 60th postpartum day. Control rats received vehicle solution in the same volume. Results showed that rats subjected to chronic mild hyperhomocysteinemia significantly increased IL-1beta, IL-6, and acetylcholinesterase activity and reduced nitrite levels. Homocysteine decreased catalase activity and immunocontent and superoxide dismutase activity, caused protein and DNA damage, and altered neurons ultrastructure. Acetylsalicylic acid totally prevented the effect of homocysteine on acetylcholinesterase activity and catalase activity and immunocontent, as well as the ultrastructural changes, and partially prevented alterations on IL-1beta levels, superoxide dismutase activity, sulfhydryl content, and comet assay. Acetylsalicylic acid per se increased DNA damage index. In summary, our findings showed that chronic chemically induced model of mild hyperhomocysteinemia altered some parameters and acetylsalicylic acid administration seemed to be neuroprotective, at least in part, on neurotoxicity of homocysteine. PMID- 29243199 TI - Total eclipse in the heart. PMID- 29243200 TI - The Cascading Effects of Multiple Dimensions of Implementation on Program Outcomes: a Test of a Theoretical Model. AB - This study tests a theoretical cascade model in which multiple dimensions of facilitator delivery predict indicators of participant responsiveness, which in turn lead to improvements in targeted program outcomes. An effectiveness trial of the 10-session New Beginnings Program for divorcing families was implemented in partnership with four county-level family courts. This study included 366 families assigned to the intervention condition who attended at least one session. Independent observers provided ratings of program delivery (i.e., fidelity to the curriculum and process quality). Facilitators reported on parent attendance and parents' competence in home practice of program skills. At pretest and posttest, children reported on parenting and parents reported child mental health. We hypothesized effects of quality on attendance, fidelity and attendance on home practice, and home practice on improvements in parenting and child mental health. Structural Equation Modeling with mediation and moderation analyses were used to test these associations. Results indicated quality was significantly associated with attendance, and attendance moderated the effect of fidelity on home practice. Home practice was a significant mediator of the links between fidelity and improvements in parent-child relationship quality and child externalizing and internalizing problems. Findings provide support for fidelity to the curriculum, process quality, attendance, and home practice as valid predictors of program outcomes for mothers and fathers. Future directions for assessing implementation in community settings are discussed. PMID- 29243201 TI - Should Fear of Adverse Events Influence the Decision to Administer Preoperative Therapy to Patients with Pancreatic Cancer? PMID- 29243203 TI - Impact of posterior urethral diameter/external urethral sphincter diameter as a new tool to predict detrusor pressure in the voiding phase. AB - PURPOSES: We measured posterior urethra diameter (PUD) and external urethral sphincter diameter (EUSD), which can also be measured by voiding cystourethrography (VCUG) and investigated the relationship between PUD/EUSD and detrusor pressure (Pdet) during voiding by videourodynamics (VUDS). METHODS: Sixty-three children, who were 3 years old or less and underwent VUDS, were enrolled in the present study. We measured PUD and EUSD in addition to detrusor pressure at the time of the widest EUS during voiding (Pdet-voiding) by VUDS, and PUD/EUSD was investigated compared to Pdet-voiding. RESULTS: Seventy-eight VUDS were performed in 63 patients, and the median age at VUDS was 10.2 months. These studies revealed a significant correlation between PUD/EUSD and Pdet-voiding (r = 0.641, p < 0.001). However, a significant correlation was not observed between PUD/EUSD and age (r = 0.180). We defined Pdet-voiding of more than 80 cmH2O as a high voiding pressure, and a PUD/EUSD of 2.4 was a good predictor for the cutoff value for high voiding pressure. Pdet-voiding was significantly higher in children with a PUD/EUSD of >= 2.4 (p < 0.001). In 19 children who had neurological diseases, a significant correlation was found between PUD/EUSD and Pdet-voiding (r = 0.842, p < 0.001), and a PUD/EUSD of 2.4 was a useful cutoff value for high voiding pressure. CONCLUSIONS: PUD/EUSD is a valuable tool to predict high voiding pressure in pediatric patients. A PUD/EUSD of >= 2.4 in VCUG indicates the need to perform more invasive tests, such as VUDS, in pediatric patients aged 3 and under with neuropathic diseases. PMID- 29243204 TI - Genome-Wide Assessment of Polygalacturonases-Like (PGL) Genes of Medicago truncatula, Sorghum bicolor, Vitis vinifera and Oryza sativa Using Comparative Genomics Approach. AB - The polygalacturonases (PG) is one of the important members of pectin-degrading glycoside hydrolases of the family GH28. In plants, PG represents multigene families associated with diverse processes. In the present study, an attempt has been made to investigate the diversity of PG genes among monocots and dicots with respect to phylogeny, gene duplication and subcellular localization to get an insight into the evolutionary and functional attributes. The genome-wide assessment of Medicago truncatula, Vitis vinifera Sorghum bicolor, and Oryza sativa L. ssp. japonica genomes revealed 53, 49, 38 and 35 PG-like (PGL) genes, respectively. The predominance of glyco_hydro_28 domain, hydrophilic nature and genes with multiple introns were uniformly observed. The subcellular localization showed the presence of signal sequences targeting the secretory pathways. The phylogenetic tree constructed marked uniformity with three distinct clusters for each plant irrespective of the variability in the genome sizes. The site-specific selection pressure analysis based on K a/K s values showed predominance of purifying selection pressures among different groups identified in these plants. The functional divergence analysis revealed significant site-specific selective constraints. Results of site-specific selective pressure analysis throw light on the functional diversity of PGs in various plant processes and hence its constitutive nature. These findings are further strengthened by functional divergence analysis which reveals functionally diverse groups in all the four species representing monocots and dicots. The outcome of the present work could be utilized for deciphering the novel functions of PGs in plants. PMID- 29243202 TI - Non-invasive Cerebellar Stimulation: a Promising Approach for Stroke Recovery? AB - Non-invasive brain stimulation (NIBS) combined with behavioral training is a promising strategy to augment recovery after stroke. Current research efforts have been mainly focusing on primary motor cortex (M1) stimulation. However, the translation from proof-of-principle to clinical applications is not yet satisfactory. Possible reasons are the heterogeneous properties of stroke, generalization of the stimulation protocols, and hence the lack of patient stratification. One strategy to overcome these limitations could be the evaluation of alternative stimulation targets, like the cerebellum. In this regard, first studies provided evidence that non-invasive cerebellar stimulation can modulate cerebellar processing and linked behavior in healthy subjects. The cerebellum provides unique plasticity mechanisms and has vast connections to interact with neocortical areas. Moreover, the cerebellum could serve as a non lesioned entry to the motor or cognitive system in supratentorial stroke. In the current article, we review mechanisms of plasticity in the cortico-cerebellar system after stroke, methods for non-invasive cerebellar stimulation, and possible target symptoms in stroke, like fine motor deficits, gait disturbance, or cognitive impairments, and discuss strategies for multi-focal stimulation. PMID- 29243205 TI - Correction to: A Phase II Study Evaluating Combined Neoadjuvant Cetuximab and Chemotherapy Followed by Chemoradiotherapy and Concomitant Cetuximab in Locoregional Oesophageal Cancer Patients. AB - Errors were subsequently identified in the article and the following corrections should be noted. PMID- 29243207 TI - Sparing and impairing: Emotion modulation of the attentional blink and the spread of sparing in a 3-target RSVP task. AB - The performance impairment (attentional blink, AB) on a second target (T2) when it is presented within 200-500 ms after a first target (T1) during rapid serial visual presentation (RSVP) is typically attributed to resource depletion. The AB does not occur when targets appear in immediate sequence (sparing). Recently, this account has been challenged by findings that the lag 1 sparing can spread to later lags when using a 3-target RSVP. Two experiments using the 3-targets RSVP investigated the relative contribution of resource depletion and attentional enhancement and/or inhibition on the AB and the sparing when T1 (Exp. 1) or T3 (Exp. 2) are emotionally salient. Findings showed a greater sparing for neutral T3s when preceded by negative compared with neutral T1s (Exp. 1) and for negative T3s (Exp. 2). In contrast, the AB on neutral T3s was greater after negative than after neutral T1s (Exp. 1), but it was reduced when T3 was negative (Exp. 2). The AB and the sparing also depended on how many targets before T3 were correctly reported. These findings indicate that although there is a cost for processing multiple targets, the emotional modulations of the AB and the sparing are better explained by an interplay between emotion-enhancement and capacity limitations on temporal selective attention. PMID- 29243206 TI - ICaL and Ito mediate rate-dependent repolarization in rabbit atrial myocytes. AB - Rate-dependent repolarization (RDR) of action potential (AP) in cardiomyocyte plays a critical role in the genesis of arrhythmias and RDR in atrium has been linked with atrial fibrillation. However, detailed studies focusing on the role of RDR in rabbit atrium are scant. In this study, atrial cells were isolated from rabbit heart and rate-dependent property was explored in single atrial cell to elucidate the underlying mechanism. Our results indicated that rate-dependent prolongation was evident at the action potential duration at 20% (APD20) and 50% (APD50) repolarization but not at 90% repolarization (APD90) under control condition. Using transient outward potassium current (Ito) inhibitor 4 Aminopyridine (4-AP, 2 mM) effectively eliminated the changes in APD20 and APD50, and unmasked the rate-dependent reduction of APD90 which could be diminished by further adding L-type calcium current (ICaL) inhibitor nifedipine (30 MUM). However, using the selective late sodium current (INaL) inhibitor GS-458967 (GS967, 1 MUM) caused minimal effect on APD90 of atrial cells both in the absence and presence of 4-AP. In consistence with results from APs, Ito and ICaL displayed significant rate-dependent reduction because of their slow reactivation kinetics. In addition, the magnitude of INaL in rabbit atrium was so small that its rate-dependent changes were negligible. In conclusion, our study demonstrated that Ito and ICaL mediate RDR of AP in rabbit atrium, while minimal effect of INaL was seen. PMID- 29243208 TI - Plasma Cholinesterase Activity in Female Green Turtles Chelonia mydas Nesting in Laguna de Terminos, Mexico Related to Organochlorine Pesticides in Their Eggs. AB - The inhibition of cholinesterase (ChE) activity has been used as a biomarker of exposure to organophosphate and carbamate insecticides. ChE of nesting female green turtles (Chelonia mydas) were biochemically characterized using two substrates, acetylthiocholine iodide and butyrylthiocholine iodide, and three ChE inhibitors (eserine sulfate, BW284C51 and iso-OMPA). The results indicated that BChE is the predominant plasma ChE in female C. mydas, but with atypical properties that differ from those found in human BChE. Eggs from green turtles nesting at two sites in Laguna de Terminos contained ug g-1 (wet weight) quantities of organochlorine (OC) pesticides. Drins (aldrin, dieldrin, endrin, endrin ketone, endrin aldehyde) were found at the highest concentrations with no significant differences in the concentrations in eggs collected at the two sampling sites. A negative relationship was found between levels of OC pesticides in eggs and BChE activity in the plasma of female turtles laying the eggs. Since OC pesticides are not cholinesterase inhibitors, we hypothesized that this inverse relationship may be related to an antagonistic effect between OCs and organophosphate pesticides and mobilization of OCs from the fatty tissues of the female turtles into their eggs. However, further study is required to verify the hypothesis. It is also possible that other contaminants, such as petroleum hydrocarbons are responsible for the modulation of cholinesterase activity in female turtles. PMID- 29243209 TI - Differential Metal Tolerance and Accumulation Patterns of Cd, Cu, Pb and Zn in the Liverwort Marchantia polymorpha L. AB - In this study, we investigated the bioaccumulation, tissue distribution and physiological responses to different metal concentration (0.2 and 2 mM) and time of exposure of 1, 2 and 3 weeks with cadmium (Cd), copper (Cu), lead (Pb) and zinc (Zn) using the model liverwort Marchantia polymorpha. Our data showed, on one hand, a significant enrichment and tissue translocation of Cu, Zn, and specially Cd, reaching concentrations of 1800 ug g- 1 in 3 weeks. On the other hand, Pb exhibited the lowest concentration values (50 ug g- 1), and 90% of the total concentration in the rhizoids. We could observe a positive correlation between tissue concentration, metal translocation and an enhanced toxic response. The results obtained in this study might contribute not only in the application of this species in environmental studies with heavy metals but also as a starting point to study the evolution of metal tolerance in land plants. PMID- 29243210 TI - An Embryonic Field of Study: The Aquatic Fate and Toxicity of Diluted Bitumen. AB - Canada has experienced a significant increase in the transport of diluted bitumen (dilbit), a predominant oil sands product that combines bitumen with diluents derived from oil-gas condensates and other proprietary compounds. The proportion of diluent and the chemical composition of dilbit vary to meet seasonal transport requirements. While the toxic effects of a variety of crude and refined oils are well-studied, the toxicity of dilbit to aquatic species is less well known. This focused review summarizes dilbit production, chemistry, and the few data on toxicity to aquatic species. These data suggest that un-weathered dilbit would cause effects on fish equivalent to those of conventional oils, but its toxicity may be lower, depending on interactions among test conditions, the behavior of dilbit added to water and the species tested. PMID- 29243211 TI - Manganese Concentrations in Tissues and Skin of Three Dolphin Species Stranded in the Croatian Waters of the Adriatic Sea from 1995 to 2013. AB - Manganese concentrations were determined in muscle, kidney, liver, spleen, lung and fat tissues and skin of three cetacean species, the bottlenose (Tursiops truncatus), striped (Stenella coeruleoalba) and Risso's (Grampus griseus) dolphins, stranded along the Croatian Adriatic coast between 1995 and 2013. Mean ranges determined in tissues were (mg/kg, ww): muscle 0.23-0.27, liver 2.87-4.00, kidney 0.66-1.26, spleen 0.37-0.79, lung 0.18-0.57, skin 0.11-0.97, fat 0.06 0.42. The highest Mn mean levels in tissues were measured in species (mg/kg, ww): T. truncates lung 0.41, skin 0.97, fat 0.42; S. coeruleoalba muscle 0.26; G. griseus kidney 1.26, liver 4.00, spleen 0.64. Significant differences of Mn concentrations in the liver (p = 0.034), spleen (p = 0.037) and skin (p = 0.013) were found among the three dolphin species. Significant differences in Mn levels were found between young and adult T. truncates in kidney (p = 0.042), lung (p = 0.0040) and skin (p = 0.0034). PMID- 29243213 TI - Accuracy of co-morbidity data in patients undergoing abdominal wall hernia repair: a retrospective study. AB - OBJECTIVES: To determine the baseline accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of routinely collected co-morbidity data in patients undergoing abdominal wall hernia repair. METHODS: All patients aged > 18 who underwent umbilical, para-umbilical, inguinal or incisional hernia repair between 1 January 2015 and 1 November 2016 were identified. All parts of the clinical notes were searched for co-morbidities by two authors independently. The following co-morbidities were considered: hypertension, ischaemic heart disease (IHD), diabetes, asthma, chronic obstructive pulmonary disease (COPD), cerebrovascular disease (CVD), chronic kidney disease (CKD), hypercholesterolemia, obesity and smoking. The co morbidities data from clinical notes were compared with corresponding data in hospital episode statistics (HES) database to calculate accuracy, sensitivity, specificity, PPV and NPV of HES codes for co-morbidities. To assess the agreement between clinical notes and HES data, we also calculated Cohen's Kappa index value as a more robust measure of agreement. RESULTS: Overall, 346 patients comprising 3460 co-morbidity codes were included in the study. The overall accuracy of HES codes for all co-morbidities was 77% (Kappa: 0.13). When calculated separately for each co-morbidity, the accuracy was 72% (Kappa: 0.113) for hypertension, 82% (Kappa: 0.232) for IHD, 85% (Kappa: 0.203) for diabetes, 86% (Kappa: 0.287) for asthma, 91% (Kappa: 0.339) for COPD, 92% (Kappa: 0.374) for CVD, 94% (Kappa: 0.424) for CKD, 74% (Kappa: 0.074) for hypercholesterolemia, 71% (Kappa: 0.66) for obesity and 24% (Kappa: 0.005) for smoking. The overall sensitivity, specificity, PPV and NPV of HES codes were 9, 100, 100, and 77%, respectively. The results were consistent when individual co-morbidities were analyzed separately. CONCLUSIONS: Our results demonstrated that HES co-morbidity codes in patients undergoing abdominal wall hernia repair are specific with good positive predictive value; however, they have substandard accuracy, sensitivity, and negative predictive value. The presence of a relatively large number of false negative or missed cases in HES database explains our findings. Better documentation of co-morbidities in admission clerking proforma may help to improve the quality of source documents for coders, which in turn may improve the accuracy of coding. PMID- 29243214 TI - Does the laparoscopic treatment of paediatric hydroceles represent a better alternative to the traditional open repair technique? A retrospective study of 1332 surgeries performed at two centres in China. AB - PURPOSE: To evaluate the safety, efficacy and merits of laparoscopic repair in children with hydroceles by comparing the outcomes of laparoscopic repair and the traditional open repair (OR) procedure. The outcomes of the following three laparoscopic percutaneous extra-peritoneal closure (LPEC) approaches were also compared: conventional two-port surgery, transumbilical single-site two-port surgery and single-port surgery. METHODS: We retrospectively compared the demographic, perioperative and follow-up data from the consecutive records obtained for 382 boys who underwent OR and 950 boys who underwent LPEC at two children's medical centres in China. In the LPEC group, regardless of the hydrocele form, one of the three approaches with percutaneous aspiration was performed: conventional two-port surgery was performed in 387 cases, single-site two-port surgery was performed in 468 cases and single-port surgery was performed in 95 cases. The clinical data and complications were statistically analysed. RESULTS: Postoperative follow-up data were obtained for all the patients. The mean follow-up time was 36 months (24-48 months) in the OR group and 32.5 months (20-44 months) in the LPEC group. Significant differences in recurrence were not observed between the groups (five in the OR and 10 in the LPEC; P = 0.69). However, the operation time, postoperative hospital stay, incidence of scrotal oedema, incision infection and contralateral metachronous hernia or hydrocele were significantly higher in the OR group than those in the LPEC group (P < 0.01). Eighteen children (4.71%) had a negative exploration of the patent processus vaginalis (PPV) in the OR group. Fourteen children (1.47%) in the LPEC group had a closed internal ring and were converted to a scrotal procedure. Significant differences in the clinical data or complications were not observed between the two centres for the laparoscopic procedure (P > 0.05). Contralateral PPV (cPPV) was found in 18 patients in the single-port group (18.9%). Of the patients affected with cPPV, significant differences were observed between the single-port group and the two-port LPEC group (122 patients, 31.5%, P = 0.016) and the single-site two-port group (the 148 patients, 31.6%, P = 0.013). A contralateral metachronous hernia or hydrocele was found in zero, zero and two cases in these groups, respectively, and significant differences were observed (P < 0.01) between the single-site surgery and the other two laparoscopic approaches. CONCLUSIONS: LPEC is safe, feasible and effective for treating hydroceles in children and has the same recurrence rate as OR. However, LPEC is superior in operation time, hospital stay, occurrence of scrotal oedema, incision infection and occurrence of metachronous hernia or hydrocele. The transumbilical single-site two-port procedure has the same cosmetic effect as the single-port LPEC. According to our experience, the two-port LPEC approach is better for diagnosing cPPV and reducing metachronous hernia or hydrocele than the single port LPEC procedure. PMID- 29243212 TI - Controlling centriole numbers: Geminin family members as master regulators of centriole amplification and multiciliogenesis. AB - To ensure that the genetic material is accurately passed down to daughter cells during mitosis, dividing cells must duplicate their chromosomes and centrosomes once and only once per cell cycle. The same key steps-licensing, duplication, and segregation-control both the chromosome and the centrosome cycle, which must occur in concert to safeguard genome integrity. Aberrations in genome content or centrosome numbers lead to genomic instability and are linked to tumorigenesis. Such aberrations, however, can also be part of the normal life cycle of specific cell types. Multiciliated cells best exemplify the deviation from a normal centrosome cycle. They are post-mitotic cells which massively amplify their centrioles, bypassing the rule for once-per-cell-cycle centriole duplication. Hundreds of centrioles dock to the apical cell surface and generate motile cilia, whose concerted movement ensures fluid flow across epithelia. The early steps that control the generation of multiciliated cells have lately started to be elucidated. Geminin and the vertebrate-specific GemC1 and McIdas are distantly related coiled-coil proteins, initially identified as cell cycle regulators associated with the chromosome cycle. Geminin is required to ensure once-per-cell cycle genome replication, while McIdas and GemC1 bind to Geminin and are implicated in DNA replication control. Recent findings highlight Geminin family members as early regulators of multiciliogenesis. GemC1 and McIdas specify the multiciliate cell fate by forming complexes with the E2F4/5 transcription factors to switch on a gene expression program leading to centriole amplification and cilia formation. Positive and negative interactions among Geminin family members may link cell cycle control to centriole amplification and multiciliogenesis, acting close to the point of transition from proliferation to differentiation. We review key steps of centrosome duplication and amplification, present the role of Geminin family members in the centrosome and chromosome cycle, and discuss links with disease. PMID- 29243215 TI - Identification of Banana Lectin Isoforms and Differential Acetylation Through Mass Spectrometry Approaches. AB - Banana lectin (BanLec) exhibits specificity to glucose/mannose residues present in oligo saccharides or glycoconjugates and has attracted a lot of attention recently as a potent therapeutic agent. Structural studies and molecular cloning methods has revealed the presence of three different BanLec proteins in two species. In our study, initial mass spectrometric analysis of affinity purified native BanLec from banana pulp (Musa paradisiaca) indicated the presence of proteins with different molecular mass. Through the bottom up and top down analysis we identified three major isoforms with acetylation at N terminus. Especially, top down analysis revealed one isoform being present as non acetylated species. The combination of mass spectrometry approaches provided insights on genetic variants and differential modifications in native BanLec. PMID- 29243216 TI - Lipid A adjuvanted Chylomicron Mimicking Solid Fat Nanoemulsions for Immunization Against Hepatitis B. AB - Traditional parenteral recombinant hepatitis B virus (HBV) vaccines have effectively reduced the disease burden despite being able to induce seroprotective antibody titers in 5-10% vaccinated individuals (non-responders). Moreover, an estimated 340 million chronic HBV cases are in need of treatment. Development of safe, stable, and more effective hepatitis B vaccine formulation would address these challenges. Recombinant hepatitis B surface antigen (rHBsAg) entrapped solid fat nanoemulsions (SFNs) containing monophosphoryl lipid A (MPLA) that was prepared and optimized by quality by design (QbD) using response surface methodology (RSM), i.e., central composite design (CCD). Its immune potential was evaluated with preset immunization protocol in a murine model. Dose escalation study revealed that formulation containing 1 MUg of rHBsAg entrapped SFNs with MPLA-induced significant higher humoral, and cellular response compared to the marketed vaccine (Genvac B) administered intramuscularly. SFNs with nanometric morphology and structural similarity with chylomicrons assist in improved uptake and processing to lymphatics. Moreover, the presence of an immunogenic component in its structure further augments delivery of rHBsAg to immune cells with induction of danger signals. This multi-adjuvant based approach explores new prospect for the dose sparing. Improved cellular immune response induced by this vaccine formulation suggests that it could be tested as an immunotherapeutic vaccine as well. PMID- 29243217 TI - Oral health in Lebanon: a pilot pathfinder survey. AB - A pilot pathfinder survey for oral health was conducted in order to identify the level of caries and periodontal diseases in Lebanon and to produce baseline data, to be followed by a national oral health survey. The study involved 320 students, of whom 158 were 12 years old and 162 were 15 years old. The decayed, missing and filled permanent teeth (DMFT) scores for 12 and 15-year-olds were 5.0 and 7.7, respectively. Ninety-two per cent (92%) of the children aged 12 years and 96% of the children aged 15 years were affected by dental caries. The prevalence of periodontal disease among 15-year-olds was shown to be one of the highest (94.5%) in the Eastern Mediterranean Region. PMID- 29243218 TI - No pain, no gain: balancing central versus peripheral benefits of analgesics in the age of the opioid crisis. PMID- 29243220 TI - Cancer mechanobiology: Effects and therapeutic perspectives. PMID- 29243219 TI - PD-1 blockade enhances the antitumor efficacy of GM-CSF surface-modified bladder cancer stem cells vaccine. AB - Eliminating cancer stem cells (CSCs) is a key issue in eradicating tumor. The streptavidin-granulocyte-macrophage-colony stimulating factor (SA-GM-CSF) surface modified bladder CSCs vaccine previously developed using our protein-anchor technology could effectively induce specific immune response for eliminating CSCs. However, program death receptor-1 (PD-1)/program death ligand 1 (PD-L1) signaling in tumor microenvironment results in tumor-adaptive immune resistance. Although the CSCs vaccine could increase the number of CD8+ T cells, a part of these CD8+ T cells expressed PD-1. Moreover, the CSCs vaccine upregulated the PD L1 expression of tumor cells, resulting in immune resistance. Adding PD-1 blockade to the CSCs vaccine therapy increased the population of CD4+ , CD8+ and CD8+ IFN-gamma+ but not CD4+ Foxp3+ T cells and induced the highest production of IFN-gamma. PD-1 blockade could effectively enhance the functions of tumor specific T lymphocytes generated by the CSCs vaccine. This combination therapy improved the cure rate among mice and effectively protected the mice against a second CSCs cell challenge, but not a RM-1 cell challenge. These results indicate that PD-1 blockade combined with the GM-CSF-modified CSCs vaccine effectively induced a strong and specific antitumor immune response against bladder cancer. PMID- 29243221 TI - Nursing interventions for smoking cessation. AB - BACKGROUND: Healthcare professionals, including nurses, frequently advise people to improve their health by stopping smoking. Such advice may be brief, or part of more intensive interventions. OBJECTIVES: To determine the effectiveness of nursing-delivered smoking cessation interventions in adults. To establish whether nursing-delivered smoking cessation interventions are more effective than no intervention; are more effective if the intervention is more intensive; differ in effectiveness with health state and setting of the participants; are more effective if they include follow-ups; are more effective if they include aids that demonstrate the pathophysiological effect of smoking. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialized Register and CINAHL in January 2017. SELECTION CRITERIA: Randomized trials of smoking cessation interventions delivered by nurses or health visitors with follow-up of at least six months. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically-validated rates if available. Where statistically and clinically appropriate, we pooled studies using a Mantel Haenszel fixed-effect model and reported the outcome as a risk ratio (RR) with a 95% confidence interval (CI). MAIN RESULTS: Fifty-eight studies met the inclusion criteria, nine of which are new for this update. Pooling 44 studies (over 20,000 participants) comparing a nursing intervention to a control or to usual care, we found the intervention increased the likelihood of quitting (RR 1.29, 95% CI 1.21 to 1.38); however, statistical heterogeneity was moderate (I2 = 50%) and not explained by subgroup analysis. Because of this, we judged the quality of evidence to be moderate. Despite most studies being at unclear risk of bias in at least one domain, we did not downgrade the quality of evidence further, as restricting the main analysis to only those studies at low risk of bias did not significantly alter the effect estimate. Subgroup analyses found no evidence that high-intensity interventions, interventions with additional follow-up or interventions including aids that demonstrate the pathophysiological effect of smoking are more effective than lower intensity interventions, or interventions without additional follow-up or aids. There was no evidence that the effect of support differed by patient group or across healthcare settings. AUTHORS' CONCLUSIONS: There is moderate quality evidence that behavioural support to motivate and sustain smoking cessation delivered by nurses can lead to a modest increase in the number of people who achieve prolonged abstinence. There is insufficient evidence to assess whether more intensive interventions, those incorporating additional follow-up, or those incorporating pathophysiological feedback are more effective than one-off support. There was no evidence that the effect of support differed by patient group or across healthcare settings. PMID- 29243222 TI - Population Modeling of Tumor Kinetics and Overall Survival to Identify Prognostic and Predictive Biomarkers of Efficacy for Durvalumab in Patients With Urothelial Carcinoma. AB - Durvalumab is an anti-PD-L1 monoclonal antibody approved for patients with locally advanced or metastatic urothelial carcinoma (UC) that has progressed after platinum-containing chemotherapy. A population tumor kinetic model, coupled with dropout and survival models, was developed to describe longitudinal tumor size data and predict overall survival in UC patients treated with durvalumab (NCT01693562) and to identify prognostic and predictive biomarkers of clinical outcomes. Model-based covariate analysis identified liver metastasis as the most influential factor for tumor growth and immune-cell PD-L1 expression and baseline tumor burden as predictive factors for tumor killing. Tumor or immune-cell PD-L1 expression, liver metastasis, baseline hemoglobin, and albumin levels were identified as significant covariates for overall survival. These model simulations provided further insights into the impact of PD-L1 cutoff values on treatment outcomes. The modeling framework can be a useful tool to guide patient selection and enrichment strategies for immunotherapies across various cancer indications. PMID- 29243223 TI - Population Pharmacokinetics of Durvalumab in Cancer Patients and Association With Longitudinal Biomarkers of Disease Status. AB - The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, an anti-PD-L1 antibody, and quantify the impact of baseline and time-varying patient/disease characteristics on PK. Pooled data from two studies (1,409 patients providing 7,407 PK samples) were analyzed with nonlinear mixed effects modeling. Durvalumab PK was best described by a two compartment model with both linear and nonlinear clearances. Three candidate models were evaluated: a time-invariant clearance (CL) model, an empirical time varying CL model, and a semimechanistic time-varying CL model incorporating longitudinal covariates related to disease status (tumor shrinkage and albumin). The data supported a slight decrease in durvalumab clearance with time and suggested that it may be associated with a decrease in nonspecific protein catabolic rate among cancer patients who benefit from therapy. No covariates were clinically relevant, indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following weight-based and flat-dosing regimens. PMID- 29243224 TI - Palbociclib synergizes with BRAF and MEK inhibitors in treatment naive melanoma but not after the development of BRAF inhibitor resistance. AB - Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination was assessed in human BRAF mutant cell lines that were treatment naive, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors. Xenograft studies were then performed to test the in vivo efficacy of the BRAF and CDK4/6 inhibitor combination. Melanoma cells that had developed early reversible tolerance or acquired resistance to BRAF inhibition remained sensitive to palbociclib. In drug-tolerant cells, the efficacy of the combination of palbociclib with BRAF and/or MEK inhibitors was equivalent to single agent palbociclib. Similarly, acquired BRAF inhibitor resistance cells lost efficacy to the palbociclib and BRAF combination. In contrast, upfront treatment of melanoma cells with palbociclib in combination with BRAF and/or MEK inhibitors induced either cell death or senescence and was superior to a BRAF plus MEK inhibitor combination. In vivo palbociclib plus BRAF inhibitor induced rapid and sustained tumor regression without the development of therapy resistance. In summary, upfront dual targeting of CDK4/6 and mutant BRAF signaling enables tumor cells to evade resistance to monotherapy and is required for robust and sustained tumor regression. Melanoma patients whose tumors have acquired resistance to BRAF inhibition are less likely to have favorable responses to subsequent treatment with the triplet combination of BRAF, MEK and CDK4/6 inhibitors. PMID- 29243226 TI - Traction haemostasis. PMID- 29243227 TI - Precision oncology: East meets West. PMID- 29243225 TI - Current priorities in the Zika response. AB - Zika virus (ZIKV), a single-stranded RNA virus of the Flaviviridae family, is an arbovirus (viruses transmitted by arthropods) transmitted to humans and non-human primates through the bites of infected female Aedes sp. mosquitoes. Although first isolated in 1947, it only recently emerged as a global threat, present in several countries resulting in a pandemic scenario. ZIKV infections may have severe outcomes, such as neurological impairment, and with the intrinsic ability of inducing microcephaly in fetuses of infected pregnant women, the virus has become a major public health problem. This review discusses some advances in diagnosis; vaccine development and the problems associated with their administration; the importance of the cross-reactivity with other flaviviruses in protecting or worsening the disease; the implications of the recent outbreak caused by the virus in the world; and future prospects for the complete understanding of this disease. PMID- 29243228 TI - Mitochondria and redox balance in coeliac disease: A case-control study. AB - BACKGROUND: Coeliac disease (CD) is a gluten-sensitive autoimmune disorder. Gluten toxicity encompasses a wide spectrum of target organ functions and pathologies, including the activation of the immune response and triggering of oxidative stress. The aim of this study was to investigate inflammation and the redox balance in patients with active CD, and to evaluate whether alteration of mitochondrial function is involved in the disease status. DESIGN: In this prospective case-control study, blood samples from sixteen adult CD patients and sixteen healthy controls (HC) were investigated for IL-1beta, IL-6 and IL-8 plasma concentrations, for serum PON1 arylesterase, total and MnSOD antioxidant enzyme activities, induced TBARs levels, and for lymphocyte mtDNA content. RESULTS: Patients showed IL-8 and IL-1beta concentrations significantly higher than HC counterparts. Patients had a significantly higher content of induced TBARS compared to HC value, indicating a shift in their serum redox balance towards pro-oxidant species. The assay of antioxidant enzyme activities showed a significant 25% increase in PON1, a higher total SOD, and a significant 21% higher MnSOD in patients compared to HC. Lymphocyte mtDNA content in patients was significantly twofold higher than in HC, supporting the induction of mitochondrial biogenesis. The patients' mitochondrial compensatory response may explain the correlation between MnSOD activity and mtDNA content. The patients' mitochondrial oxidative stress, cooperating to cytokines secretion, may justify the correlation between IL-1beta concentration and mtDNA content. CONCLUSIONS: These results highlight the mitochondrial involvement in CD and suggest the evaluation of the mtDNA content as a potential diagnostic and follow-up parameter. PMID- 29243229 TI - Mirabegron: potential off target effects and uses beyond the bladder. AB - : The beta3 -adrenoceptor was initially an attractive target for several pharmaceutical companies due to its high expression in rodent adipose tissue, where its activation resulted in decreased adiposity and improved metabolic outputs (such as glucose handling) in animal models of obesity and Type 2 diabetes. However, several drugs acting at the beta3 -adrenoceptor failed in clinical trials. This was thought to be due to their lack of efficacy at the human receptor. Recently, mirabegron, a beta3 -adrenoceptor agonist with human efficacy, was approved in North America, Europe, Japan and Australia for the treatment of overactive bladder syndrome. There are indications that mirabegron may act at other receptors/targets, but whether they have any clinical relevance is relatively unknown. Besides overactive bladder syndrome, mirabegron may have other uses such as in the treatment of heart failure or metabolic disease. This review gives an overview of the off-target effects of mirabegron and its potential use in the treatment of other diseases. LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc. PMID- 29243230 TI - Two patients with PNKP mutations presenting with microcephaly, seizure, and oculomotor apraxia. PMID- 29243231 TI - Gaining Mechanistic Insight Into Coproporphyrin I as Endogenous Biomarker for OATP1B-Mediated Drug-Drug Interactions Using Population Pharmacokinetic Modeling and Simulation. AB - This study evaluated coproporphyrin I (CPI) as a selective endogenous biomarker of OATP1B-mediated drug-drug interactions (DDIs) relative to clinical probe rosuvastatin using nonlinear mixed-effect modeling. Plasma and urine CPI data in the presence/absence of rifampicin were modeled to describe CPI synthesis, elimination clearances, and obtain rifampicin in vivo OATP Ki. The biomarker showed stable interoccasion baseline concentrations and low interindividual variability (<25%) in subjects with wildtype SLCO1B1. Biliary excretion was the dominant CPI elimination route (maximal >85%). Estimated rifampicin in vivo unbound OATP Ki (0.13 MUM) using CPI data was 2-fold lower relative to rosuvastatin. Model-based simulations and power calculations confirmed sensitivity of CPI to identify moderate and weak OATP1B inhibitors in an adequately powered clinical study. Current analysis provides the most detailed evaluation of CPI as an endogenous OATP1B biomarker to support optimal DDI study design; further pharmacogenomic and DDI data with a panel of inhibitors are required. PMID- 29243232 TI - A de novo loss-of-function DYNC1H1 mutation in a patient with parkinsonian features and a favourable response to levodopa. AB - Graphical summary of 'A de novo loss-of-function DYNC1H1 mutation in a patient with parkinsonian features and a favourable response to levodopa' by Szczaluba et al.. PMID- 29243234 TI - Equine gestational length and location: is there more that the research could be telling us? AB - Clear definitions of 'normal' equine gestation length (GL) are elusive, with GL being subject to a considerable number of internal and external variables that have confounded interpretation and estimation of GL for over 50 years. Consequently, the mean GL of 340 days first established by Rossdale in 1967 for Thoroughbred horses in northern Europe continues to be the benchmark value referenced by veterinarians, breeders and researchers worldwide. Application of a 95% confidence limit to reported GL range values indicates a possible connection between geographic location and GL. Improved knowledge of this variable may help in assessing the degree of the neonate's prematurity and dysmaturity at or soon after birth, and identification of conditions such as incomplete ossification of the carpal and tarsal bones. Associated pathologies such as bone malformation and fracture, angular limb deformity and degenerative joint disease can cause chronic unsoundness, rendering horses unsuitable for athletic purpose and shortening ridden careers. This review will examine both the factors contributing to GL variation and the published data to determine whether there is potential to refine our understanding of GL by establishing a more accurate and regionally relevant GL range based on a 95% confidence limit. This may benefit both equine industry economics and equine welfare by improving early identification of skeletally immature neonates, so that appropriate intervention may be considered. PMID- 29243236 TI - Isolation of [Actinobacillus] rossii from an aborted piglet. AB - CASE REPORT: This report describes an investigation into the cause of abortions on a commercial pig farm in Victoria in October 2015 in which six sows aborted over a 2-month period. Four of the abortions occurred in the 3 weeks prior to the sows' anticipated farrowing dates and the other two occurred in the second trimester of pregnancy. An analysis of farm data showed that the abortion rate in the previous 12 months (2014-15) was more than twice that of the previous 2 years (1.2% vs 0.5%). Parity appeared not to be a risk factor for abortions. There were no other indicators of reproductive failure on the farm and there were no obvious clinical signs of disease in affected sows. Placenta and aborted fetuses for postmortem analysis were collected while one of the sows was aborting. The only gross abnormality detected in piglets was reddening over the skin. On gross examination the surfaces of the placentas appeared diffusely thickened and 'furry'. Histological examination of fixed placenta from one of two piglets showed a severe, acute, multifocal, necrosuppurative placentitis. Gram staining of a histological section of the placenta revealed abundant Gram-negative short bacilli, consistent with Pasteurella-Actinobacillus spp. A sample of stomach contents from one piglet yielded a profuse predominant growth of bacteria described as Pseudomonas-like. This organism was subsequently identified using 16sRNA sequencing to have 98% homology with [Actinobacillus] rossii. CONCLUSION: This is the first reported case of [A.] rossii isolated from an aborted pig's stomach in Australia. PMID- 29243233 TI - Finding the needle in the haystack: systematic identification of psychobiotics. AB - The brain-gut-microbiota axis is increasingly viewed as a novel paradigm in neuroscience with the capacity to generate innovative therapies for patients with psychiatric illnesses. Psychobiotics, defined as live bacteria, which when ingested in adequate amounts, confer mental health benefits, are increasingly of interest, as preclinical trials continue to show promising results. Particularly in stress-related, anxiety and depressive disorders, there is potential for psychobiotics to deliver new therapies. The question of which microbes may prove to be the most promising psychobiotic in delivering such therapies at a clinical level is of great importance. Here we look at the characteristics of psychobiotics, in an attempt to present an outline from which the identification of potential new psychobiotics may be possible. LINKED ARTICLES: This article is part of a themed section on When Pharmacology Meets the Microbiome: New Targets for Therapeutics? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.24/issuetoc. PMID- 29243237 TI - Beak and feather disease virus carriage by Knemidocoptes pilae in a sulphur crested cockatoo (Cacatua galerita). AB - BACKGROUND: This paper describes the pathology associated with psittacine beak and feather disease in a wild sulphur-crested cockatoo with concurrent knemidocoptic mange, cestodiasis and mycotic encephalitis. METHODS & RESULTS: Large numbers of Knemidocoptes pilae Lavoipierre and Griffiths, 1951 (Acari: Epidermoptidae, Knemidokoptinae) were identified in affected skin associated with enhanced expression of beak and feather disease virus (BFDV) determined by immunohistochemistry. Also, BFDV antigen was demonstrated in high concentration in the gut and faecal sacs of mites, raising the possibility of ectoparasites as fomites and vectors of BFDV transmission. Large numbers of Raillietina spp. cestodes were present in the intestines. Within the brain there was a focally extensive region of necrosis and inflammation associated with branching, septate, pigmented hyphae consistent with zygomycete fungal infection. CONCLUSION: This case highlights the potential immunosuppressive effects of BFDV infection and its potential as a keystone pathogen in the Australian environment. PMID- 29243238 TI - Dorsal surgical stabilisation using tension bands for treatment of traumatic atlanto-occipital instability in a cat. AB - CASE REPORT: An atlanto-occipital instability secondary to a dog bite was diagnosed in a 4-year-old Persian cat. Dorsal stabilisation of the instability was made with two OrthoFiber prostheses (Securos), which were used as tension bands between the nuchal crests of the occipital bone and the spinous process of the axis. Total recovery was achieved 4 days after surgery. Normal alignment of the atlanto-occipital joint was observed on survey radiographs taken 6 weeks post surgery. Although the right loop had failed, the alignment was still normal and no neurological after-effects could be identified. CONCLUSION: Dorsal divergent tension bands between the nuchal crests of the occipital bone and the spinous process of the axis can be used to stabilise traumatic atlanto-occipital instability. PMID- 29243239 TI - Evaluation of Australian surveillance for freedom from bovine tuberculosis. AB - BACKGROUND: Australia declared freedom from bovine tuberculosis (TB) in accordance with international guidelines in 1997 and has since maintained ongoing surveillance for this disease, primarily through abattoir surveillance of cattle carcases (meat inspection) for TB-like granulomas. The objectives of this study were to estimate the sensitivity of Australia's surveillance system and quantify the probability that Australia is free from bovine TB at the specified design prevalence. METHODS: The analysis included approximately 80 million records of individual cattle slaughtered and meat inspected at Australian abattoirs between 2005 and 2015 calendar years. Animals were identified and aggregated by property of birth within year. Herd- and population-level sensitivities and probability of freedom were estimated on an annual basis using a simulation model to account for uncertainty about the unit sensitivity of the meat inspection process. RESULTS: The estimated median population sensitivity of Australia's TB surveillance system varied from a high of 80%, in years when traditional meat inspection was used, to as low as 50% after the introduction of visual-only meat inspection, for a design prevalence of 0.01% (19 herds) of Australian breeding cattle herds and 0.5% of animals within infected herds. The level of confidence in Australia's freedom from bovine TB was >95% after the first year of the analysis and >99.5% from 2007 through to the end of the analysis period in 2015. Reducing the animal-level or herd-level design prevalence, or the estimated sensitivity of meat inspection, reduced system sensitivity but confidence of disease freedom remained high. CONCLUSION: The results demonstrated a very high level of confidence that Australia's cattle herd is truly free from bovine TB. Meat inspection for granulomas in the head and thorax of slaughtered cattle underpins this result by providing surveillance data on an extremely large number of animals each year. PMID- 29243240 TI - Initial steps in defining the environment of the prepuce of the bull by measuring pH and temperature. AB - OBJECTIVE: To determine the baseline pH and temperature of the preputial cavity of bulls. METHODS: We enrolled 55 bulls ranging in age from 15 to 84 months. The preputial temperature and pH were measured by insertion of temperature and pH probes, respectively, into the preputial orifice prior to routine breeding soundness examinations. Information was obtained from owners regarding the diet of each bull and categorised as one of three categories: forage only, grain supplemented or silage supplemented. RESULTS: The average temperature of the prepuce was 37.81 degrees C +/- 1.76 and the median pH of the prepuce was 8.45 (6.35-9.46). Preputial temperatures of the bull weakly correlated with ambient temperatures (rs = -0.29, P = 0.028). The preputial pH of silage-fed bulls was significantly lower than that of bulls fed forage only (P = 0.025) or grain supplemented diets (P = 0.002). The median preputial pH of bulls fed a silage based diet was 7.6 (6.3-8.9) compared with a median pH 8.7 (7.8-9.1) for bulls fed forage-based diets or a median of 8.5 (7.7-9.4) for those given grain supplemented diets. CONCLUSION: Diet and ambient temperature can, respectively, affect pH and the temperature in the prepuce. Further studies to describe and understand the microbiota of the prepuce and penis may assist in developing treatments for diseases of the genital tract in bulls. PMID- 29243242 TI - Cross-sectional survey of health management and prevalence of vector-borne diseases, endoparasites and ectoparasites in Samoan dogs. AB - OBJECTIVE: To determine the prevalence of selected canine vector-borne diseases (Leishmania infantum, Anaplasma spp., Ehrlichia canis, Borrelia burgdorferi and Dirofilaria immitis) and endo- and ectoparasites in Samoan dogs presenting for surgical sterilisation and to report on the general health management of the dogs. METHODS: This study was a prospective serological cross-sectional survey. Management data were obtained for 242 dogs by interview with their owners. Blood samples were collected from 237 dogs and screened for the canine vector-borne diseases using point-of-care qualitative ELISA assays. Anaplasma spp. positive samples were screened by PCR and sequenced for species identification. Rectal faecal samples were collected from 204 dogs for faecal flotation and immunofluorescent antibody tests were performed for Giardia and Cryptosporidium spp. on a subset of 93 faecal samples. The skin and coat of 221 dogs were examined for presence of ectoparasites. RESULTS: The D. immitis antigen was detected in 46.8% (111/237) of dogs. Seroprevalence of Anaplasma spp. was 8.4% (20/237); A. platys was confirmed by PCR. Prevalence of hookworm was 92.6% (185/205) and Giardia was 29.0% (27/93). Ectoparasites were detected on 210/221 (95.0%) of dogs examined and 228/242 dogs (94.2%) had previously never received any preventative medication. CONCLUSIONS: There was a very high prevalence of D. immitis, hookworm and external parasites in Samoan dogs, and prophylactic medication is rarely administered. This is the first report confirming A. platys in Samoa and the South Pacific islands. The public health implications of poor management of the dogs should be considered and investigated further. PMID- 29243244 TI - Clinical diagnosis of crusted scabies: Reverse focal pattern of plantar keratoderma. PMID- 29243243 TI - Shikonin inhibits myeloid differentiation protein 2 to prevent LPS-induced acute lung injury. AB - BACKGROUND AND PURPOSE: Acute lung injury (ALI) is a challenging clinical syndrome, which manifests as an acute inflammatory response. Myeloid differentiation protein 2 (MD2) has an important role in mediating LPS-induced inflammation. Currently, there are no effective molecular-based therapies for ALI or viable biomarkers for predicting the severity of disease. Recent preclinical studies have shown that shikonin, a natural naphthoquinone, prevents LPS-induced inflammation. However, little is known about the underlying mechanisms. EXPERIMENTAL APPROACH: The binding affinity of shikonin to MD2 was analysed using computer docking, surface plasmon resonance analysis and elisa. In vitro, the anti-inflammatory effect and mechanism of shikonin were investigated through elisa, real-time quantitative reverse transcription PCR, Western blotting and immunoprecipitation assay. In vivo, lung injury was induced by intratracheal administration of LPS and assessed by changes in the histopathological and inflammatory markers. The underlying mechanisms were investigated by immunoprecipitation in lung tissue. KEY RESULTS: Shikonin directly bound to MD2 and interfered with the activation of toll-like receptor 4 (TLR4) induced by LPS. In cultured macrophages, shikonin inhibited TLR4 signalling and pro-inflammatory cytokine production. These effects were produced through suppression of key signalling proteins including the NF-kappaB and the MAPK pathway. We also showed that shikonin inhibits MD2-TLR4 complex formation and reduces LPS-induced inflammatory responses in a mouse model of ALI. CONCLUSIONS AND IMPLICATIONS: Our studies have uncovered the mechanism underlying the biological activity of shikonin in ALI and suggest that the targeting of MD2 may prove to be beneficial as a treatment option for this condition. PMID- 29243245 TI - Treatment deintensification in human papillomavirus-positive oropharynx cancer: Outcomes from the National Cancer Data Base. AB - BACKGROUND: The growing epidemic of human papillomavirus-positive (HPV+) oropharyngeal cancer and the favorable prognosis of this disease etiology have led to a call for deintensified treatment for some patients with HPV+ cancers. One of the proposed methods of treatment deintensification is the avoidance of chemotherapy concurrent with definitive/adjuvant radiotherapy. To the authors' knowledge, the safety of this form of treatment de-escalation is unknown and the current literature in this area is sparse. The authors investigated outcomes after various treatment combinations stratified by American Joint Committee on Cancer (AJCC) eighth edition disease stage using patients from the National Cancer Data Base. METHODS: A retrospective study of 4443 patients with HPV+ oropharyngeal cancer in the National Cancer Data Base was conducted. Patients were stratified into AJCC eighth edition disease stage groups. Multivariate Cox regressions as well as univariate Kaplan-Meier analyses were conducted. RESULTS: For patients with stage I disease, treatment with definitive radiotherapy was associated with diminished survival compared with chemoradiotherapy (hazard ratio [HR], 1.798; P = .029), surgery with adjuvant radiotherapy (HR, 2.563; P = .002), or surgery with adjuvant chemoradiotherapy (HR, 2.427; P = .001). For patients with stage II disease, compared with treatment with chemoradiotherapy, patients treated with a single-modality (either surgery [HR, 2.539; P = .009] or radiotherapy [HR, 2.200; P = .030]) were found to have poorer survival. Among patients with stage III disease, triple-modality therapy was associated with improved survival (HR, 0.518; P = .024) compared with treatment with chemoradiotherapy. CONCLUSIONS: Deintensification of treatment from chemoradiotherapy to radiotherapy or surgery alone in cases of HPV+ AJCC eighth edition stage I or stage II disease may compromise patient safety. Treatment intensification to triple-modality therapy for patients with stage III disease may improve survival in this group. Cancer 2018;124:717-26. (c) 2017 American Cancer Society. PMID- 29243247 TI - Randomized cross-over trial comparing the diagnosis of gestational diabetes by oral glucose tolerance test and a designed breakfast glucose profile. AB - OBJECTIVE: To compare a glucose test based on a standardized, designed breakfast to the 75-g oral glucose tolerance test (OGTT), comparing venous and capillary glucose values for the diagnosis of gestational diabetes mellitus (GDM). METHODS: The present prospective, randomized, cross-over trial enrolled patients at high risk of developing GDM who were attending the High-Risk Antenatal Clinic of Tygerberg Hospital, Cape Town, South Africa, between March 1 and December 31, 2015. Patients were randomized to initial testing with either the OGTT or a designed breakfast glucose profile (DBGP) glucose test before the alternate test was performed 1 week later; no dietary or other interventions were applied in the intervening period. Venous and capillary fasting and 2-hour glucose values were measured and were compared between the OGTT and DBGP, and between OGTT and laboratory venous samples. RESULTS: There were 51 patients included in the study. The fasting and 2-hour capillary glucose values from the OGTT correlated significantly with the laboratory venous samples (P<0.001 at both time intervals). The 2-hour capillary glucose values from the DBGP demonstrated a satisfactory correlation with those from the OGTT (P<0.001). CONCLUSIONS: The DBGP provided a sufficiently accurate alternate test for the diagnosis of GDM; it warrants further investigation. PMID- 29243246 TI - Patients not patents: Drug research and development as a public enterprise. PMID- 29243248 TI - Uptake kinetics and storage capacity of dissolved inorganic phosphorus and corresponding N:P dynamics in Ulva lactuca (Chlorophyta). AB - Dissolved inorganic phosphorus (DIP) is an essential macronutrient for maintaining metabolism and growth in autotrophs. Little is known about DIP uptake kinetics and internal P-storage capacity in seaweeds, such as Ulva lactuca (Chlorophyta). Ulva lactuca is a promising candidate for biofiltration purposes and mass commercial cultivation. We exposed U. lactuca to a wide range of DIP concentrations (1-50 MUmol . L-1 ) and a nonlimiting concentration of dissolved inorganic nitrogen (DIN; 5,000 MUmol . L-1 ) under fully controlled laboratory conditions in a "pulse-and-chase" assay over 10 d. Uptake kinetics were standardized per surface area of U. lactuca fronds. Two phases of responses to DIP-pulses were measured: (i) a surge uptake (VS ) of 0.67 +/- 0.10 MUmol . cm-2 . d-1 and (ii) a steady state uptake (VM ) of 0.07 +/- 0.03 MUmol . cm-2 . d-1 . Mean internal storage capacity (ISCP ) of 0.73 +/- 0.13 MUmol . cm-2 was calculated for DIP. DIP uptake did not affect DIN uptake. Parameters of DIN uptake were also calculated: VS = 12.54 +/- 1.90 MUmol . cm-2 . d-1 , VM = 2.26 +/- 0.86 MUmol . cm-2 . d-1 , and ISCN = 22.90 +/- 6.99 MUmol . cm-2 . Combining ISC and VM values of P and N, nutrient storage capacity of U. lactuca was estimated to be sufficient for ~10 d. Both P and N storage capacities were filled within 2 d when exposed to saturating nutrient concentrations, and uptake rates declined thereafter at 90% for DIP and at 80% for DIN. Our results contribute to understanding the ecological aspects of nutrient uptake kinetics in U. lactuca and quantitatively evaluating its potential for bioremediation and/or biomass production for food, feed, and energy. PMID- 29243249 TI - Retrospective observational study of interventions to improve acceptance of long acting reversible contraception following abortion at Lusaka Teaching Hospital, Zambia. AB - OBJECTIVE: To evaluate long-acting reversible contraceptive (LARC) uptake immediately after abortion at Lusaka University Teaching Hospital, Zambia in the period following an intervention to increase the acceptance of LARC. METHODS: The present retrospective, observational study reviewed the clinical records of all patients admitted to the Lusaka University Teaching Hospital for an incomplete abortion or for a legal induced abortion between January 1 and December 31, 2016. The primary outcome measure was the proportion of adult women (aged 20-44 years) and adolescents (aged 10-19 years) who were already using an available contraceptive method at the time of hospital discharge. Contraceptive use was compared with historical data from the same institution before the intervention to increase LARC acceptance was performed. RESULTS: Data from 3858 patients (587 adolescents and 3271 adults) were included. LARC use was recorded among 108 (18.4%) and 409 (12.5%) adolescents and adults, respectively. This compared with rates from 2011 of less than 1% and less than 4%, respectively. CONCLUSION: The rate of LARC use at discharge following incomplete or induced abortion had increased when compared with historical control data from before the intervention program was performed; however, there remains room for improvement. PMID- 29243250 TI - A camera-based method for estimating absolute density in animals displaying home range behaviour. AB - The measurement of animal density may take advantage of recent technological achievements in wildlife video recording. Fostering the theoretical links between the patterns depicted by cameras and absolute density is required to exploit this potential. We explore the applicability of the Hutchinson-Waser's postulate (i.e. when animal density is stationary at a given temporal and spatial scale, the absolute density is given by the average number of animals counted per frame), which is a counter-intuitive statement for most ecologists and managers who are concerned with counting the same individual more than once. We aimed to reconcile such scepticism for animals displaying home range behaviour. The specific objectives of this paper are to generalize the Hutchinson-Waser's postulate for animals displaying home range behaviour and to propose a Bayesian implementation to estimate density from counts per frame using video cameras. Accuracy and precision of the method was evaluated by means of computer simulation experiments. Specifically, six animal archetypes displaying well-contrasted movement features were considered. The simulation results demonstrate that density could be accurately estimated after an affordable sampling effort (i.e. number of cameras and deployment time) for a great number of animals across taxa. The proposed method may complement other conventional methods for estimating animal density. The major advantages are that identifying an animal at the individual level and precise knowledge on how animals move are not needed, and that density can be estimated in a single survey. The method can accommodate conventional camera trapping data. The major limitations are related to some implicit assumptions of the underlying model: the home range centres should be homogeneously distributed, the detection probability within the area surveyed by the camera should be known, and animals should move independently to one another. Further improvements for circumventing these limitations are discussed. PMID- 29243251 TI - Factors affecting estimates of size at age and growth in grey triggerfish Balistes capriscus from the northern Gulf of Mexico. AB - Growth zones in dorsal spines of grey triggerfish Balistes capriscus from the northern Gulf of Mexico were utilized to estimate growth and examine factors that may affect estimates of size at age. Age was estimated from dorsal-spine sections of 4687 individuals sampled from U.S. waters during 2003-2013, including both fishery-independent (n = 1312) and fishery-dependent (n = 3375) samples. Ninety six per cent (n = 4498) of these sections were deemed suitable for ageing; average per cent error between two independent readers was 10.8%. Fork length (LF ) ranged from 65 to 697 mm and age estimates from 0 to 14 years. Both sex and sample source (fishery-independent v. recreational) significantly affected estimated size at age for 2-6 year-old fish. Data were pooled between sources to fit sex-specific von Bertalanffy growth functions. Results for the female model were Linfinity = 387 mm LF , k = 0.52 year-1 and t0 = 0.01 year, while for males Linfinity = 405 mm LF , k = 0.55 year-1 and t0 = 0.02 year. These results were significantly different between sexes and indicate clear sexual dimorphism. Thus, growth should be modelled separately by sex when examining population parameters or conducting stock assessment modelling. The positive bias in estimates of size at age computed for recreational v. fishery-independent samples also has clear implications for stock assessment as growth functions computed with fishery-dependent samples would tend to overestimate stock productivity. PMID- 29243252 TI - Predicting calvarial growth in normal and craniosynostotic mice using a computational approach. AB - During postnatal calvarial growth the brain grows gradually and the overlying bones and sutures accommodate that growth until the later juvenile stages. The whole process is coordinated through a complex series of biological, chemical and perhaps mechanical signals between various elements of the craniofacial system. The aim of this study was to investigate to what extent a computational model can accurately predict the calvarial growth in wild-type (WT) and mutant type (MT) Fgfr2C342Y/+ mice displaying bicoronal suture fusion. A series of morphological studies were carried out to quantify the calvarial growth at P3, P10 and P20 in both mouse types. MicroCT images of a P3 specimen were used to develop a finite element model of skull growth to predict the calvarial shape of WT and MT mice at P10. Sensitivity tests were performed and the results compared with ex vivo P10 data. Although the models were sensitive to the choice of input parameters, they predicted the overall skull growth in the WT and MT mice. The models also captured the difference between the ex vivoWT and MT mice. This modelling approach has the potential to be translated to human skull growth and to enhance our understanding of the different reconstruction methods used to manage clinically the different forms of craniosynostosis, and in the long term possibly reduce the number of re-operations in children displaying this condition and thereby enhance their quality of life. PMID- 29243253 TI - Healthcare provider attitudes regarding the provision of assisted reproductive services for HIV-affected couples in Addis Ababa, Ethiopia. AB - OBJECTIVE: To evaluate the acceptability and feasibility of providing assisted reproductive services as part of routine HIV care and treatment in Ethiopia. METHODS: The present cross-sectional study using semistructured in-depth interviews was conducted at St. Paul Hospital Millennium Medical College (SPHMMC), Addis Ababa, Ethiopia, during July 2014 and July 2015. The interviews assessed the perspectives of healthcare providers (HCPs) regarding the reproductive desires of HIV-affected couples, on assisting them in achieving pregnancy, and on the facilitators and barriers to offering such services as part of routine HIV care. RESULTS: There were 40 HCPs from two SPHMMC clinics interviewed. All HCPs asserted that HIV-affected couples should have equal access to assisted reproductive services and most agreed that couples should have this access to reduce the risk of HIV transmission, even in the absence of underlying infertility. However, the HCPs cited systemic and structural barriers to the implementation and delivery of assisted reproductive services. CONCLUSION: The integration of assisted reproductive services into HIV care and treatment programs is acceptable and feasible to HCPs. Formal training of HCPs may improve the implementation of these services for HIV-affected couples in low-resource settings. PMID- 29243254 TI - Graduating otolaryngology resident preparedness for fellowship as assessed by fellowship faculty. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to evaluate fellowship program directors' perceptions of incoming clinical fellows' preparedness for subspecialty training and to thereby identify strengths and shortcomings in otolaryngology training programs' ability to prepare residents for fellowship. STUDY DESIGN: Validated e-mail survey. METHODS: Two hundred eleven otolaryngology subspecialty fellowship program directors and faculty directly involved with training fellows were contacted. A validated survey by the American College of Surgeons was modified and distributed to otolaryngology fellowship faculty in six otolaryngology subspecialties. The 59-item survey employed a five-response Likert scale tailored to each subspecialty. Responses were collected between November 2016 and January 2017. RESULTS: One hundred ten otolaryngology faculty responded to the survey (52%). Respondents had worked with fellows for a mean of 12 years (standard deviation = 8). Respondents felt fellows were competent in the areas of professionalism, clinical evaluation, and management. Pediatric faculty were more likely to disagree about fellows' independence in the operating room (P = .004) and during call (P = .002) compared to other specialties. Laryngology and facial plastic and reconstructive surgery faculty felt more neutral about anatomy recognition (P = .008), tissue manipulation (P = .002), and use of energy sources (e.g., cautery, lasers) (P < .001). Fellows in all subspecialties were felt to be least prepared in research and academic interest. CONCLUSIONS: Faculty involved in fellowship training feel that fellows are well-prepared overall upon entering fellowship. Residency programs may benefit from providing more experience with facial plastic reconstructive surgery, laryngology, and pediatrics. Regardless of specialty, residents could benefit from increased training in research design, data analysis, and basic statistics. LEVEL OF EVIDENCE: NA Laryngoscope, E280 E286, 2018. PMID- 29243255 TI - Viscoelastic properties of human aryepiglottic fold and ventricular fold tissues at phonatory frequencies. AB - OBJECTIVE: The purpose of this study was to quantify the viscoelastic shear properties of the human ventricular fold (or false vocal fold) mucosa and aryepiglottic fold mucosa at frequencies of phonation. METHODS: Linear viscoelastic shear properties of the mucosa of false vocal fold and aryepiglottic fold specimens from seven cadaveric subjects were determined as functions of frequency (5-250 Hz) and compared to those of the true vocal fold cover. Measurements of elastic shear modulus (G') and dynamic viscosity (eta') were made with a controlled-strain simple-shear rheometer. Linear least-squares regression was conducted to curve-fit log G' and log eta' versus log frequency, and statistical analysis was performed with one-way analysis of variance. RESULTS: All specimens showed similar frequency dependence of the viscoelastic functions G' and eta', with G' gradually increasing with frequency and eta' monotonically decreasing with frequency. The magnitudes of G' and eta' of the false fold mucosa were generally higher than those of the aryepiglottic fold mucosa and true vocal fold cover, but there were no significant differences in G' and eta' among the false fold, aryepiglottic fold, and true vocal fold. CONCLUSION: The false vocal fold and aryepiglottic fold mucosa showed similar frequency dependence and a similar range of tissue viscoelastic behavior as the true vocal fold. These preliminary findings suggested that such tissues could become candidates for the replacement of the true vocal fold lamina propria in patients with significant tissue loss and deficiencies, for those requiring laryngeal reconstruction following partial laryngectomy or airway reconstruction. LEVEL OF EVIDENCE: NA. Laryngoscope, E296-E301, 2018. PMID- 29243256 TI - The effectiveness of platelet-rich plasma in an anosmia-induced mice model. AB - OBJECTIVE: In this study, we aimed to functionally and morphologically demonstrate the effectiveness of platelet-rich plasma (PRP) on anosmia in a mouse model of anosmia. STUDY DESIGN: Animal study. METHODS: A total of 16 male mice were included. When selecting the mice, the food-finding test (FFT) was used to make sure that the animals could smell, and anosmia was induced by administration of intraperitoneal 3-methylindole. The mice were randomly divided into two groups of eight (groups A and B). After 1 week, topical PRP was administered to the mice in group A and topical saline was administered to the mice in group B. The FFT was again administered at 7, 14, and 21 days. The mice were sacrificed on day 21, the olfactory neuroepithelium was histopathologically examined, and the epithelial damage scores and epithelial thickness were measured. RESULTS: After topical administration of PRP and saline, the difference in the average FFT values of the groups was statistically significant at 7, 14, and 21 days (P < 0,005). During the histopathological examination, the epithelial damage score was statistically significantly lower in the PRP group (P = 0.001) than in the saline group, and epithelial thickness was statistically significantly greater in the PRP group compared to the saline group (P = 0.003). CONCLUSION: We showed that PRP administration has a curative effect on olfactory functions in an anosmia induced mice model. However, there is a need for further research before PRP can be considered for use in patients with anosmia in clinical practice. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:E157-E162, 2018. PMID- 29243258 TI - The diagnostic pathway of oropharyngeal squamous cell carcinoma in a large U.S. healthcare system. AB - OBJECTIVE: To examine the current diagnostic pathway of oropharyngeal squamous cell carcinoma (OPSCC) and identify factors associated with time to diagnosis. METHODS: Retrospective cohort study of patients with OPSCC in an integrated healthcare system from January 1, 2013, to December 31, 2013. Patient demographics, tobacco and alcohol use, chief complaint, tumor stage, human papilloma virus (HPV) status, physician factors (diagnosis, antibiotic prescription, performance of endoscopic exam, biopsy), and time intervals were examined. Time variations by patient characteristics and physician practice were assessed. RESULTS: We identified 152 patients with OPSCC. Of those, 90% had stage III to IV disease. The cohort was largely male (85%), white (79%), with HPV positive tumors (84%). Most common chief complaints were neck mass (52%) and sore throat (20%). Among those with neck a mass, 94% had HPV-positive tumors. Prescription of antibiotics was associated with longer time to first otolaryngology evaluation. Median time from symptom onset to first primary care physician (PCP) contact was 3.0 weeks; from PCP to otolaryngologist was 1.1 weeks, and from otolaryngologist to tissue diagnosis was 0.4 weeks. At the first otolaryngology visit, 82% underwent in-office flexible endoscopy and 58% had same day biopsy, resulting in rapid time to tissue diagnosis. Diagnostic time intervals did not differ by HPV status. CONCLUSION: The overall diagnostic process was efficient, although initial antibiotic treatment resulted in longer time to first otolaryngology visit. Tumor HPV status was associated with presenting findings but not time to diagnosis. The variation in diagnostic delay time and impact on survival outcomes is unknown and merits further investigation. LEVEL OF EVIDENCE: 4. Laryngoscope, 1867-1873, 2018. PMID- 29243259 TI - A unique anomaly of the ear: Oculo-auriculo-vertebral spectrum or an isolated disruption? AB - We present a rare case of a neonate with an isolated congenital condition of his right ear involving the outer ear, middle ear, eustachian tube, and the facial nerve, with an external opening into the skull that connects to the oropharynx. Taking this bizarre aspect of the exterior lesion and the oropharyngeal communication into account, we consider the condition presented here, which to our knowledge is the first of its kind to have resulted from a vascular disruption. Laryngoscope, 1927-1931, 2018. PMID- 29243260 TI - Multimodal treatment in difficult sialolithiasis: Role of extracorporeal shock wave lithotripsy and intraductal pneumatic lithotripsy. AB - OBJECTIVES: To assess results after treatment of difficult/complex sialolithiasis with extracorporeal shock-wave lithotripsy (ESWL) and intraductal pneumatic lithotripsy (IPL). STUDY DESIGN: Retrospective study in a tertiary referral center. METHODS: Altogether, 63 stones were diagnosed in 38 patients with difficult/complex sialolithiasis. Forty-nine stones were treated with fragmentation using both ESWL and IPL. Stones accessible with the sialendoscope were treated primarily with IPL in multiple sialolithiasis. RESULTS: Seventy-one ESWL procedures and 57 IPL were performed in our patients. Forty-nine stones were treated by 67 ESWL procedures and 52 IPL. ESWL converted sialoliths from sialendoscopically untreatable into sialendoscopically treatable cases in 94.7%; the treatment then was completed by a total of 52 IPL procedures. ESWL was performed before IPL (81.6%), in combination with IPL (7.9%) and after (10.5%). Complete fragmentation was achieved in 97.9%. Four stones each were treated with ESWL and IPL alone in multiple sialolithiasis. Altogether, 53 stones were treated by 57 IPL procedures. Complete fragmentation was achieved in 98.1% of the 53 stones. ESWL and IPL were the dominant treatment modalities in 84.1% of all 63 stones treated. Of all 38 patients, 92.1% became stone-free and all became symptom-free. All the glands were preserved. Multiple stones were treated in 34.2% of the patients; of these, 92.3% became stone-free. CONCLUSION: These results show that patients with difficult and complex sialolithiasis can be treated with high success rates of > 90% using a multimodal, minimally invasive, and gland-preserving treatment approach. ESWL and IPL played a key role in this multimodal treatment regime in > 80% of stones. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:E332-E338, 2018. PMID- 29243257 TI - Differential impact of tongue exercise on intrinsic lingual muscles. AB - OBJECTIVES/HYPOTHESIS: Aging is associated with muscle fiber hypotrophy and decreased percentages of rapidly contracting myosin heavy chain (MyHC) type IIb muscle fibers. Tongue exercise programs used to treat dysphagia target age related decline in tongue muscle function, but the impact of exercise on the intrinsic tongue muscles is unknown. We hypothesized that exercise would induce muscle fiber hypertrophy and increase the percentage of MyHC IIa fibers in the intrinsic tongue. STUDY DESIGN: Animal model. METHODS: Eight old and eight young adult rats underwent 8 weeks of tongue exercise training, and 8 animals of each age group served as controls. Longitudinal, transverse, and verticalis muscle samples from the anterior, middle, and posterior regions of the tongue were sectioned and stained to determine muscle fiber diameter and MyHC composition. RESULTS: MyHC fiber type distribution was altered by exercise, and the effects differed by muscle and region of the tongue. In the exercise groups, as compared to the control groups, the anterior transverse and middle superior longitudinal muscles had significantly reduced percentages of MyHC IIx positive fibers and higher percentages of rapidly contracting fatigable MyHC IIb positive muscle fibers, whereas the middle transverse and posterior longitudinal muscles had increased percentages of the less rapidly contracting and more fatigue-resistant MyHC IIa fibers. The impact of exercise did not differ with age, as there was no significant interaction between age and exercise. Tongue exercise had no significant effect on muscle fiber diameter. CONCLUSIONS: The impact of exercise varied among the tongue muscles, which may indicate different functional contributions to the tongue exercise task. LEVEL OF EVIDENCE: NA Laryngoscope, 128:2245-2251, 2018. PMID- 29243262 TI - Does intraglandular injection of botulinum toxin improve pediatric sialorrhea? PMID- 29243261 TI - Quality indicators of oropharyngeal cancer care in the elderly. AB - OBJECTIVE: To examine associations between quality of care, survival, and costs in elderly patients treated for oropharyngeal squamous cell cancer (OPSCC). STUDY DESIGN: Retrospective analysis of Surveillance, Epidemiology, and End Results Medicare data. METHODS: We evaluated 666 patients diagnosed with OPSCC from 2004 to 2007 using multivariate regression and survival analysis. Using quality indicators derived from guidelines for recommended care, summary measures of quality were calculated for diagnosis, initial treatment, surveillance, treatment for recurrence, end-of-life care, performance, and an overall summary measure of quality. RESULTS: Higher-quality care was associated with significant differences in survival for initial treatment (hazard ratio [HR] = 0.55 [0.41 to 0.73]), surveillance (HR = 0.32 [0.22 to 0.48]), treatment of recurrence (HR = 2.37 [1.56 to 3.60]), performance measures (HR = 0.50 [0.36 to 0.69]), and the overall summary measure of quality (HR = 0.53 [0.39 to 0.71]). Higher-quality salvage surgery was associated with improved survival (HR = 0.16 [0.04 to 0.54]), whereas higher-quality chemotherapy given for recurrence was associated with worse survival (HR = 5.70 [1.92 to 16.94]). Overall, higher-quality care was not associated with differences in costs. Higher-quality care was associated with significantly lower mean incremental costs for treatment of recurrence and end-of life care, and higher costs for diagnosis and surveillance. CONCLUSION: Higher quality OPSCC care in elderly patients was associated with improved survival; however, higher-quality care was not associated with reduced costs, and higher quality care for treatment of recurrence was associated with poorer survival, primarily due to poorer survival in patients treated with palliative chemotherapy. These data demonstrate a complex relationship between quality and costs in elderly OPSCC patients, which can be used to frame discussions of value and guide disease-specific quality-measure development. LEVEL OF EVIDENCE: 2c. Laryngoscope, 128:2312-2319, 2018. PMID- 29243263 TI - Overcoming the limitations of cutoffs for defining atomic coordination in multicomponent systems. AB - A common way to understand structure in multimolecular systems is the coordination shell which comprises all the neighbors of an atom. Coordination, however, is nontrivial to determine because there is no obvious way to determine when atoms are neighbors. A common solution is to take all atoms within a cutoff at the first minimum of the radial distribution function, g(r). We show that such an approach cannot be consistently applied to model multicomponent systems, namely mixtures of atoms differing in size or charge. Coordination shells using the total g(r) are found to be too restrictive for atoms of different size while those using pairwise g(r)s are excessive for charged mixtures. The recently introduced relative angular distance algorithm, however, which defines coordination instantaneously from atomic positions, is consistently able to define coordination shells containing the expected neighboring atoms for all these systems. This more robust way to determine coordination should in turn make coordination a more robust way to understand structure. (c) 2017 Wiley Periodicals, Inc. PMID- 29243265 TI - What motivates men to donate blood? A systematic review of the evidence. AB - BACKGROUND AND OBJECTIVES: Effective recruitment and retention of male donors are vital for the ongoing provision of blood products. Compared with females, male donors are less likely to be medically deferred or experience vasovagal reactions and are typically preferred for plasmapheresis donation in voluntary non remunerated settings. However, females outnumber males among donors aged under 40 years. This systematic review aimed to synthesize evidence and identify key motivators for blood donation among males to inform targeted recruitment/retention campaigns. MATERIALS AND METHODS: Databases (e.g. EBSCOhost, Web of Science) were searched using terms (dona* OR dono*) AND (blood OR aphaeresis OR apheresis OR plasma* OR platelet* OR platlet*) in title AND (male OR gender OR sex OR female) AND (motivat* OR intention OR attitude OR behavi* OR predictor OR barrier OR deter*) NOT (organ OR sperm OR tissue OR autologous OR oocyte) in text. Two researchers independently systematically scanned quantitative, full-text, English language, peer-reviewed publications from 1990 to 2015 that examined males/females separately with outcomes of blood donation or self-reported intention. Two additional researchers resolved discrepancies. RESULTS: Among 28 identified articles, the most frequently cited motivators for male blood product donation were as follows: altruism; positive attitude towards incentives; health check(s); subjective norms. Altruism was less pronounced among males compared with females and was combined with 'warm glow' in novice males (impure altruism). Perceived health benefits and incentives (e.g. coffee mugs) were stronger motivators of males than females. CONCLUSION: Marketing campaigns for recruitment/retention of male donors should focus on identified motivators rather than take a 'one-size-fits-all' approach. PMID- 29243264 TI - Prolonged platelet storage associated with increased frequency of transfusion related adverse events. AB - BACKGROUND: Platelets (PLTs) have been associated with the highest rate of transfusion-associated adverse events (AEs) among all blood products. Most of PLT associated AEs are considered to have an inflammatory mechanism. However, it is still unclear whether prolonged storage of platelets is associated with an increased rate of transfusion-related AEs, especially in the era of universal prestorage leucoreduction. METHODS/MATERIALS: In this retrospective study, 52 649 PLT products consisting of about 80% apheresis PLTs and 20% whole blood-derived (WBD) PLTs were transfused to 9415 patients from July 2011 to March 2017. All the PLTs were leucoreduced prior to storage. All but 69 units of the apheresis PLTs were irradiated and none of WBD PLTs were irradiated. During this period, a total of 284 AEs that were reported to the transfusion service were analysed. RESULTS: Univariate and multivariate logistic analyses showed that apheresis/irradiated PLTs and PLT age were associated with a significantly increased frequency of inflammation type AEs (OR (95% CI): 2.24 (1.32, 4.15) and 1.30 (1.12, 1.52), respectively). There was a significant increase in the frequency of inflammation AEs associated with prolonged storage of apheresis/irradiated PLTs [OR (95% CI): 1.26 (1.03, 1.53)]. In contrast, there was no association between allergic symptoms and PLT age. Moreover, the frequency of transfusion AEs associated with apheresis/irradiated PLTs (57.2/10 000) was significantly higher than that of WBD/nonirradiated PLTs (26.0/10 000) (P < 0.01). CONCLUSION: Prolonged storage of apheresis/irradiated PLTs was associated with a higher frequency of inflammation AEs. Apheresis/irradiated PLTs caused more AEs than WBD/nonirradiated PLTs. PMID- 29243266 TI - Frontal EEG alpha asymmetry and emotion: From neural underpinnings and methodological considerations to psychopathology and social cognition. PMID- 29243267 TI - Naegleria fowleri immunization modifies lymphocytes and APC of nasal mucosa. AB - We investigated whether intranasal immunization with amoebic lysates plus cholera toxin modified the populations of T and B lymphocytes, macrophages and dendritic cells by flow cytometry from nose-associated lymphoid tissue (NALT), cervical lymph nodes (CN), nasal passages (NP) and spleen (SP). In all immunized groups, the percentage of CD4 was higher than CD8 cells. CD45 was increased in B cells from mice immunized. We observed IgA antibody-forming cell (IgA-AFC) response, mainly in NALT and NP. Macrophages from NP and CN expressed the highest levels of CD80 and CD86 in N. fowleri lysates with either CT or CT alone immunized mice, whereas dendritic cells expressed high levels of CD80 and CD86 in all compartment from immunized mice. These were lower than those expressed by macrophages. Only in SP from CT-immunized mice, these costimulatory molecules were increased. These results suggest that N. fowleri and CT antigens are taking by APCs, and therefore, protective immunity depends on interactions between APCs and T cells from NP and CN. Consequently, CD4 cells stimulate the differentiation from B lymphocytes to AFC IgA-positive; antibody that we previously found interacting with trophozoites in the nasal lumen avoiding the N. fowleri attachment to nasal epithelium. PMID- 29243269 TI - Excitation energy transfer pathways in light-harvesting proteins: Modeling with PyFREC. AB - Excitation energy transfer (EET) determines the fate of sunlight energy absorbed by light-harvesting proteins in natural photosynthetic systems and photovoltaic cells. As previously reported (D. Kosenkov, J. Comput. Chem. 2016, 37(19), 1847), PyFREC software enables computation of electronic couplings between organic molecules with a molecular fragmentation approach. The present work reports implementation of direct fragmentation-based computation of the electronic couplings and EET rates in pigment-protein complexes within the Forster theory in PyFREC. The new feature enables assessment of EET pathways in a wide range of photosynthetic complexes, as well as artificial molecular architectures that include light-harvesting proteins or tagged fluorescent biomolecules. The developed methodology has been tested analyzing EET in the Fenna-Matthews-Olson (FMO) pigment-protein complex. The pathways of excitation energy transfer in FMO have been identified based on the kinetics studies. (c) 2017 Wiley Periodicals, Inc. PMID- 29243270 TI - An experimental examination of alcohol consumption, alcohol expectancy, and self blame on willingness to report a hypothetical rape. AB - This study experimentally examined the role of victim alcohol intoxication, and self-blame in perceiving and reporting rape to the police using a hypothetical interactive rape scenario. Participants (N = 79) were randomly assigned to consume alcohol (mean BAC = 0.07%) or tonic water before they engaged in the scenario. Alcohol expectancy was manipulated, and participant beliefs about the beverage they thought they had consumed and their feelings of intoxication were measured. Alcohol consumption and expectancy did not affect the likelihood that the nonconsensual intercourse depicted in the scenario was perceived and would be reported as rape. Participants with higher levels of self-blame were less likely to say they would report the hypothetical rape. Self-blame levels were higher for participants who believed they had consumed alcohol, and were associated with increased feelings of intoxication. The implications are discussed. PMID- 29243271 TI - Dynamic modelling of limitations on improving leaf CO2 assimilation under fluctuating irradiance. AB - A dynamic model of leaf CO2 assimilation was developed as an extension of the canonical steady-state model, by adding the effects of energy-dependent non photochemical quenching (qE), chloroplast movement, photoinhibition, regulation of enzyme activity in the Calvin cycle, metabolite concentrations, and dynamic CO2 diffusion. The model was calibrated and tested successfully using published measurements of gas exchange and chlorophyll fluorescence on Arabidopsis thaliana ecotype Col-0 and several photosynthetic mutants and transformants affecting the regulation of Rubisco activity (rca-2 and rwt43), non-photochemical quenching (npq4-1 and npq1-2), and sucrose synthesis (spsa1). The potential improvements on CO2 assimilation under fluctuating irradiance that can be achieved by removing the kinetic limitations on the regulation of enzyme activities, electron transport, and stomatal conductance were calculated in silico for different scenarios. The model predicted that the rates of activation of enzymes in the Calvin cycle and stomatal opening were the most limiting (up to 17% improvement) and that effects varied with the frequency of fluctuations. On the other hand, relaxation of qE and chloroplast movement had a strong effect on average low irradiance CO2 assimilation (up to 10% improvement). Strong synergies among processes were found, such that removing all kinetic limitations simultaneously resulted in improvements of up to 32%. PMID- 29243272 TI - Chronic kidney disease and coronary artery calcification in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - BACKGROUND: Chronic kidney disease is a worldwide public health concern due to the increased prevalence the high fatalities related to heart disease in this population. Among novel cardiovascular risk markers, the coronary artery calcification score (CAC) emerged as an independent predictor of cardiovascular events. HYPOTHESIS: We aimed to test if glomerular filtration rate or albuminuria are independently associated with coronary calcification. METHODS: The Brazilian Longitudinal Study of Adult Health is a cohort of men and women aged 35 to 74 years old addressing cardiovascular diseases. We analyzed the association of CAC, estimated glomerular filtration rate (eGFR), albumin-to-creatinine ratio (ACR) according to stages of eGFR (1 = >=90; 2 = 60-89; 3 = <60 mL/min/1.73 m2 ), and ACR (<30; 30 to 300; >300 mg/g). These associations were estimated by logistic regression with a model including age, sex, race, income, and cardiovascular risk factors. RESULTS: Among 4189 persons (median age = 51 years, 54% women), 1183 had CAC. The odds ratio (OR) and the 95% confidence interval (95% CI) in the multivariate model was 0.86 (0.58-1.29) for the category of eGFR <60 mL/min/1.73 m2 compared to people with eGFR >90 mL/min/1.73m2 . On the other hand, the OR (95% CI) for individuals with ACR >300 mg/g was 4.31 (1.27-14.64) compared to people with ACR <30 mg/g. A discrete interaction factor for the association with CAC between eGFR and ACR were analyzed as continuous variable. CONCLUSIONS: Albuminuria was independently associated with coronary calcification, but the reduction of the glomerular filtration rate was not associated with CAC score in this sample of apparently healthy adults. PMID- 29243273 TI - Long-term use of continuous positive airway pressure therapy in coronary artery disease patients with nonsleepy obstructive sleep apnea. AB - BACKGROUND: Excessive daytime sleepiness is a frequent symptom of obstructive sleep apnea (OSA) and has been proposed as a motivator for adherence to continuous positive airway pressure (CPAP) therapy. However, excessive daytime sleepiness is absent in many patients with coronary artery disease (CAD) and concomitant OSA. We evaluated long-term use of CPAP and predictors of CPAP use in nonsleepy and sleepy OSA patients from a CAD cohort. HYPOTHESIS: Long-term CPAP use is lower in CAD patients with nonsleepy OSA vs sleepy OSA. METHODS: Nonsleepy (Epworth Sleepiness Scale [ESS] score < 10) OSA patients randomized to CPAP (n = 122) and sleepy (ESS >=10) OSA patients offered CPAP (n = 155) in the RICCADSA trial in Sweden were included in this substudy. The median follow-up was 4.8 years for the main trial, with a predefined minimum follow-up of 2 years. RESULTS: The probability of remaining on CPAP at 2 years was 60% in nonsleepy patients and 77% in sleepy patients. Multivariate analyses indicated that age and hours of CPAP use per night at 1 month were independently associated with long term CPAP use in nonsleepy patients. In the sleepy phenotype, body mass index, acute myocardial infarction at baseline, and hours of CPAP use per night at 1 month were predictors of long-term CPAP use. CONCLUSIONS: Long-term use of CPAP is likely to be challenging for CAD patients with nonsleepy OSA. Early CPAP use is an important predictor of continued long-term use of CPAP, so optimizing patients' initial experience with CPAP could promote adherence. PMID- 29243275 TI - In vitro toxicity assessment of nanocrystals in tissue-type cells and macrophage cells. AB - Nanocrystals (NCs), a type of innovative material particle, are a potential drug delivery platform that aims to improve the bioavailability of hydrophobic drugs. However, due to the lack of consideration of their toxicity, existing studies have not investigated whether the nanoscale properties of NCs, such as particle sizes, may lead to NC-induced toxicity. Because of the disparity between the rapid development of NCs and the lack of studies regarding NC toxicity, the present study investigated possible NC toxicity and clarified the relationship between particle sizes and NC toxicity. RAW264.7 and HepG2 cells were chosen as representatives of macrophage cells and tissue-type cells, respectively. Monosodium urate NCs were used as a drug model. Different particle sizes of monosodium urate NCs were prepared using precipitation methods. Methyl tetrazolium, lactate dehydrogenase, oxidative stress and apoptosis/necrosis assays were then used to evaluate cell damage and recovery. The results showed that small NC particle sizes produced higher toxicity than larger ones. In immune cells, these cytotoxic effects were greater than in tissue cells. After removal of small NCs, tissue cell damage could be significantly reversed, while immune cells were only slightly restored. However, after removal of large NCs, both cell types had almost no recovery. In summary, despite conventional wisdom, our research confirmed that NCs are not very safe and that NC particle sizes are closely related to the degree of NC toxicity. PMID- 29243274 TI - Target achievement with maximal statin-based lipid-lowering therapy in Korean patients with familial hypercholesterolemia: A study supported by the Korean Society of Lipid and Atherosclerosis. AB - BACKGROUND: Data on treatment results of lipid-lowering therapy (LLT) in familial hypercholesterolemia (FH) are limited, particularly in Asian patients. HYPOTHESIS: We sought to evaluate the target achievement rate and associated variables in Korean patients with FH after maximal statin-based LLT. METHODS: We enrolled 146 patients with heterozygous FH, and 90 patients were finally analyzed. Patients were initially prescribed rosuvastatin 10 mg or atorvastatin 20 mg, and the regimen was adjusted to achieve the low-density lipoprotein cholesterol (LDL-C) target of 100 mg/dL. The primary evaluation point was the achievement rate of the LDL-C targets at 12 months: LDL-C < 100 mg/dL and >=50% LDL-C reduction. The associations between clinical variables and target achievement were also analyzed. RESULTS: At 12 months, 58% of patients were receiving high-intensity regimens, whereas 46% were receiving combination therapy. The mean pre- and post-treatment LDL-C levels were 229 and 118 mg/dL, respectively. Twenty-eight percent of patients achieved LDL-C < 100 mg/dL, and 47% achieved >=50% LDL-C reduction. Pretreatment LDL-C and high-intensity regimens indicated a negative tendency toward the attainment of LDL-C < 100 mg/dL. Conversely, pretreatment LDL-C and diabetes mellitus were positively associated with a higher rate of >=50% LDL-C reduction. CONCLUSIONS: The target achievement of LDL-C < 100 mg/dL was low, and 50% LDL-C reduction was moderately achieved in Korean patients with FH receiving maximal statin-based LLT. Pretreatment LDL-C levels and diabetes mellitus were associated with target achievement. Our results provide rare and informative data on FH treatment in Asian patients. PMID- 29243276 TI - The influence of Shc proteins and high-fat diet on energy metabolism of mice. AB - : The purpose of this study was to determine if Shc proteins influence the metabolic response to acute (7 days) feeding of a high-fat diet (HFD). To this end, whole animal energy expenditure (EE) and substrate oxidation were measured in the Shc knockout (ShcKO) and wild-type (WT) mice fed a control or HFD. The activities of enzymes of glycolysis, the citric acid cycle, electron transport chain (ETC), and beta-oxidation were also investigated in liver and skeletal muscle of ShcKO and WT animals. The study showed that ShcKO increases (P < .05) EE adjusted for either total body weight or lean mass. This change in EE could contribute to decreases in weight gain in ShcKO versus WT mice fed an HFD. Thus, our results indicate that Shc proteins should be considered as potential targets for developing interventions to mitigate weight gain on HFD by stimulating EE. Although decreased levels of Shc proteins influenced the activity of some enzymes in response to high-fat feeding (eg, increasing the activity of acyl-CoA dehydrogenase), it did not produce concerted changes in enzymes of glycolysis, citric acid cycle, or the ETC. The physiological significance of observed changes in select enzyme activities remains to be determined. SIGNIFICANCE OF THE STUDY: We report higher EE in ShcKO versus WT mice when consuming the HFD. Although decreased levels of Shc proteins influenced the activity of a central enzyme of beta-oxidation in response to high-fat feeding, it did not produce concerted changes in enzymes of glycolysis, citric acid cycle, or the ETC. Thus, an increase in EE in response to consumption of an HFD may be a mechanism that leads to decreased weight gain previously reported in ShcKO mice with long-term consumption of an HFD. PMID- 29243277 TI - Purification of angiotensin-converting enzyme from human plasma and investigation of the effect of some active ingredients isolated from Nigella sativa L. extract on the enzyme activity. AB - In the present study, one-step purification of angiotensin-converting enzyme (ACE, peptidyldipeptidase A, EC 3.4.15.1), responsible for regulation of blood pressure, was achieved using affinity chromatography from human plasma. The enzyme was purified 12,860-fold with a specific activtiy of 5080 EU/mg protein. Optimum temperature and pH were determined for the enzyme as 35-40 degrees C and pH 7.4-7.5, respectively. The purity of ACE was determined by SDS-PAGE and the enzyme showed two bands at 60 and 70 kDa on the gel. The native molecular weight of ACE was found to be 260 kDa by gel filtration chromatography, demonstrating that the enzyme has a heterodimeric structure. Natural fatty acids of Nigella sativa (Ranunculaceae) were isolated by means of column chromatography. The structures of these compounds were determined using NMR and GC-MS. The results showed that high concentrations of linoleic, oleic and palmitic acids were isolated from the plant. The effect of six fractions (Fr 1-6) on ACE activity was examined. Fraction 3 increased the ACE activity while the other fractions decreased the enzyme activity. The concentrations of the fractions inhibiting the half-maximum activity of the enzyme were calculated as 1.597 mg/mL for Fr 1, 0.053 mg/mL for Fr 2, 0.527 mg/mL for Fr 4, 0.044 mg/mL for Fr 5 and 0.136 mg/mL for Fr 6 using a Lineweaver-Burk graph. PMID- 29243278 TI - Reasons for non-exclusive breast-feeding in the first 6 months. AB - BACKGROUND: Maternal sociodemographic, delivery- and infant-related factors as well as hospital practice are relevant for breast-feeding practice. The aim of this study was to identify the sociodemographic and delivery-related factors that may affect exclusive breast-feeding (EBF) of infants aged 0-6 months in Poland. METHODS: A total of 446 mothers (18-42 years old) of infants aged 0-6 months were interviewed using the computer-assisted Web interview method. The questionnaire collected information about maternal sociodemographic situation and anthropometrics, delivery-related factors, and infant feeding-related factors. Data were analyzed using the chi-squared test and Mann-Whitney U-test. Predictors of non-exclusive breast-feeding (N-EBF) in the first 6 months of life were assessed on multivariate logistic regression. RESULTS: A total of 43% of mothers did not breast-feed exclusively (n = 191; N-EBF group) and 57% did breast-feed exclusively during the study period (n = 255; EBF group). After adjustment for other potential risk factors, the highest risk factors for N-EBF were maternal age <20 years (OR, 6.12; P <= 0.01), and inadequate breast-feeding knowledge (OR, 3.43; P <= 0.01), whereas the lowest risk was associated with pre-pregnancy intention to breast-feed (OR, 0.35; P <= 0.01), very good knowledge about breast feeding (OR, 0.45; P <= 0.001) and maternal age 26-30 years (OR, 0.48; P <= 0.001). In a multivariate model, maternal education, employment status and preterm delivery were no longer statistically significant. CONCLUSIONS: Breast feeding practice is influenced by a variety of factors, including sociodemographic and psychosocial conditions, maternal obesity and mode of delivery. Further work is needed to establish the role of education and prophylactic programs in modifying the aforementioned risk factors. PMID- 29243280 TI - Mixed histiocytosis: A case report and published work review. AB - Histiocytoses are a group of heterogeneous diseases that encompass Langerhans cell histiocytosis and non-Langerhans cell histiocytosis. Cutaneous plane xanthoma is a non-Langerhans cell histiocytic disorder characterized by the presence of yellow-orange plaques on the face, neck, upper trunk and extremities. It can appear in association with several systemic diseases (including dyslipidemias, paraproteinemias, cardiovascular diseases and lymphoproliferative disorders), but is rarely connected with Langerhans cell histiocytoses. Eosinophilic granuloma is one of the clinical entities of Langerhans cell histiocytoses, characterized by skeletal lesions and occurring prominently in children. Mixed histiocytosis, the concomitant occurrence of Langerhans cell histiocytosis and non-Langerhans cell histiocytosis in a single patient, is exceptional. We herein report a case of eosinophilic granuloma in an adult Chinese man who also developed plane xanthoma on his scalp and face, and we also include a published work review of the comorbid cases of eosinophilic granuloma and non-Langerhans cell histiocytosis. To the best of our knowledge, this is the first report on the mixed histiocytosis of cutaneous plane xanthoma and eosinophilic granuloma in China. PMID- 29243279 TI - The mito::mKate2 mouse: A far-red fluorescent reporter mouse line for tracking mitochondrial dynamics in vivo. AB - Mitochondria are incredibly dynamic organelles that undergo continuous fission and fusion events to control morphology, which profoundly impacts cell physiology including cell cycle progression. This is highlighted by the fact that most major human neurodegenerative diseases are due to specific disruptions in mitochondrial fission or fusion machinery and null alleles of these genes result in embryonic lethality. To gain a better understanding of the pathophysiology of such disorders, tools for the in vivo assessment of mitochondrial dynamics are required. It would be particularly advantageous to simultaneously image mitochondrial fission-fusion coincident with cell cycle progression. To that end, we have generated a new transgenic reporter mouse, called mito::mKate2 that ubiquitously expresses a mitochondria localized far-red mKate2 fluorescent protein. Here we show that mito::mKate2 mice are viable and fertile and that mKate2 fluorescence can be spectrally separated from the previously developed Fucci cell cycle reporters. By crossing mito::mKate2 mice to the ROSA26R-mTmG dual fluorescent Cre reporter line, we also demonstrate the potential utility of mito::mKate2 for genetic mosaic analysis of mitochondrial phenotypes. PMID- 29243281 TI - Type 1 diabetes mellitus effects on dental enamel formation revealed by microscopy and microanalysis. AB - BACKGROUND: Type 1 diabetes mellitus (T1DM) largely affects children, occurring therefore at the same period of deciduous and permanent teeth development. The aim of this work was to investigate birefringence and morphology of the secretory stage enamel organic extracellular matrix (EOECM), and structural and mechanical features of mature enamel from T1DM rats. METHODS: Adult Wistar rats were maintained alive for a period of 56 days after the induction of experimental T1DM with a single dose of streptozotocin (60 mg/kg). After proper euthanasia of the animals, fixed upper incisors were accurately processed, and secretory stage EOECM and mature enamel were analyzed by transmitted polarizing and bright field light microscopies (TPLM and BFLM), energy-dispersive x-ray (EDX) analysis, scanning electron microscopy (SEM), and microhardness testing. RESULTS: Bright field light microscopies and transmitted polarizing light microscopies showed slight morphological changes in the secretory stage EOECM from diabetic rats, which also did not exhibit statistically significant alterations in birefringence brightness when compared to control animals (P > .05). EDX analysis showed that T1DM induced statistically significant little increases in the amount of calcium and phosphorus in outer mature enamel (P < .01) with preservation of calcium/phosphorus ratio in that structure (P > .05). T1DM also caused important ultrastructural alterations in mature enamel as revealed by SEM and induced a statistically significant reduction of about 13.67% in its microhardness at 80 MUm from dentin-enamel junction (P < .01). CONCLUSIONS: This study shows that T1DM may disturb enamel development, leading to alterations in mature enamel ultrastructure and in its mechanical features. PMID- 29243282 TI - Simultaneous quantification of multiple components in rat plasma by UPLC-MS/MS and pharmacokinetic study after oral administration of Huangqi decoction. AB - A rapid, sensitive and accurate UPLC-MS/MS method was developed for the simultaneous quantification of components of Huangqi decoction (HQD), such as calycosin-7-O-beta-d-glucoside, calycosin-glucuronide, liquiritin, formononetin glucuronide, isoliquiritin, liquiritigenin, ononin, calycosin, isoliquiritigenin, formononetin, glycyrrhizic acid, astragaloside IV, cycloastragenol, and glycyrrhetinic acid, in rat plasma. After plasma samples were extracted by protein precipitation, chromatographic separation was performed with a C18 column, using a gradient of methanol and 0.05% acetic acid containing 4mm ammonium acetate as the mobile phase. Multiple reaction monitoring scanning was performed to quantify the analytes, and the electrospray ion source polarity was switched between positive and negative modes in a single run of 10 min. Method validation showed that specificity, linearity, accuracy, precision, extraction recovery, matrix effect and stability for 14 components met the requirements for their quantitation in biological samples. The established method was successfully applied to the pharmacokinetic study of multiple components in rats after intragastric administration of HQD. The results clarified the pharmacokinetic characteristics of multiple components found in HQD. This research provides useful information for understanding the relation between the chemical components of HQD and their therapeutic effects. PMID- 29243283 TI - Intra-articular injection of autologous adipose-derived mesenchymal stem cells in the treatment of knee osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease and is considered to be the fourth leading cause of disability and the second cause of inability to work in men. Recently, adipose-derived mesenchymal stem cells (AD MSCs) came into focus for regenerative medicine as a promising tool for the treatment of OA. The administration of stem cells into impaired joints results in pain relief and improves quality of life, accompanied by restoration of hyaline articular cartilage. METHODS: In the present study, nine patients (including two patients with bilateral symptoms) diagnosed with osteoarthritis (International Knee Documentation grade B in 5 and grade D in six knees) were treated using a single injection of AD-MSCs at a concentration of 0.5-1.0 * 107 cells and were followed up for 18 months. During follow-up, all the cases were evaluated clinically by Knee Society score (KSS), Hospital for Special Surgery knee score (HSS-KS), Tegner-Lysholm (T-L) score and visual analogue scale (VAS) of pain, as well as by plain radiography and by magnetic resonance imaging visualization with 2D Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score assessment. RESULTS: Significant improvement of all four clinical scores was observed within the first 6 months (KSS for 41.4 points, HSS-KS for 33.9 points, T-L score for 44.8 points, VAS of pain from 54.5 to 9.3) and improvement persisted throughout the rest of the follow-up. MOCART score showed significant cartilage restoration (from 43 +/- 7.2 to 63 +/- 17.1), whereas radiography showed neither improvement, nor further joint degeneration. CONCLUSIONS: The results obtained in the present study provide good basis for prospective randomized controlled clinical trials with respect to the use of AD-MSCs in the treatment of osteoarthritis. PMID- 29243284 TI - Professional paradox: identity formation in qualified doctors pursuing further training. AB - CONTEXT: Many newly qualified specialists and subspecialists pursue additional training. Although their motivations are many, the pursuit of further training as an alternative to unemployment is an emerging trend. Paradoxically, doctors continue as trainees with a consultant's credentials, and without the guarantee of eventual employment. This study explores seven doctors' experiences, the effects of further training on their professional identity formation (PIF), and how these effects are reconciled on a personal and professional level. METHODS: This phenomenological study involved interviews with seven qualified Canadian specialists (three were female) who pursued additional training in response to a lack of available positions in their respective specialties. Template analysis generated theoretical constructs of influences on their PIF, and characteristics of their lived experiences. RESULTS: Four themes shaped PIF: setting and context; language and communication; responsibilities and privileges; and participants' visions of their future selves. Professional identity formation (PIF) continued to develop in further training, but was inconsistently affirmed by participants' communities of practice. Four major themes characterised training experiences: prescription; managing multiple masters; limiting access to others and community ties; and constantly questioning the value of extra training. CONCLUSION: Qualified doctors traverse professional paradoxes as they seek further education with no guarantee of employment and provide consultant-level care as 'trainees'. An identity dissonance emerges that may continue until a clear identity is prescribed for them. Although disruptive to these doctors' PIF and personal and professional lives, the long-term effects of additional training are unknown. Its utility and influence on securing employment and future job satisfaction are areas for further research. PMID- 29243285 TI - Cholesterol embolization syndrome: An under-recognized entity in cardiovascular interventions. AB - Cholesterol embolization syndrome (CES) is a multi-systemic disease caused by embolization of atherosclerotic plaque contents from proximal large-caliber artery to distal small to medium arteries, occurring spontaneously or more commonly after vascular intervention. This report is a comprehensive review of the reported cases of CES found in our literature search. We discuss the risk factors, clinical manifestations, management, and prognosis of CES. The major predisposing factors for CES include older age, male sex, atherosclerotic cardiovascular risk factors, anticoagulation, and femoral access route. The composite incidence of atheroembolic renal disease was 92% and mortality 63%. Our review highlights the importance to recognize this disease entity for the cardiologist and nephrologist. PMID- 29243286 TI - Conformational dynamics of human protein kinase CK2alpha and its effect on function and inhibition. AB - Protein kinase, casein kinase II (CK2), is ubiquitously expressed and highly conserved protein kinase that shows constitutive activity. It phosphorylates a diverse set of proteins and plays crucial role in several cellular processes. The catalytic subunit of this enzyme (CK2alpha) shows remarkable flexibility as evidenced in numerous crystal structures determined till now. Here, using analysis of multiple crystal structures and long timescale molecular dynamics simulations, we explore the conformational flexibility of CK2alpha. The enzyme shows considerably higher flexibility in the solution as compared to that observed in crystal structure ensemble. Multiple conformations of hinge region, located near the active site, were observed during the dynamics. We further observed that among these multiple conformations, the most populated conformational state was inadequately represented in the crystal structure ensemble. The catalytic spine, was found to be less dismantled in this state as compared to the "open" hinge/alphaD state crystal structures. The comparison of dynamics in unbound (Apo) state and inhibitor (CX4945) bound state exhibits inhibitor induced suppression in the overall dynamics of the enzyme. This is especially true for functionally important glycine-rich loop above the active site. Together, this work gives novel insights into the dynamics of CK2alpha in solution and relates it to the function. This work also explains the effect of inhibitor on the dynamics of CK2alpha and paves way for development of better inhibitors. PMID- 29243288 TI - Corrigendum. PMID- 29243287 TI - Evaluation of the effect of dabrafenib and metabolites on QTc interval in patients with BRAF V600-mutant tumours. AB - AIMS: The effect of repeat oral supratherapeutic dosing of the BRAF inhibitor dabrafenib on QTc interval was assessed in patients with BRAF V600-mutant tumours. METHODS: Part 1 of this phase 1, multicentre, 2-part study (BRF113773/NCT01738451) assessed safety/tolerability of dabrafenib 225 or 300 mg twice daily (BID) to inform part 2 dosing. Patients in part 2 received dabrafenib matched placebo on day -1, single-dose dabrafenib 300 mg on day 1, 300 mg BID on days 2 to 7, and 300 mg on day 8 (morning), followed by 24-h Holter electrocardiographic monitoring and pharmacokinetics sample collection each dose day. Pharmacokinetics/pharmacodynamics analysis assessed combined dabrafenib and metabolite effects on QTc interval. RESULTS: Part 1 (n = 12) determined supratherapeutic dosing, 300 mg BID, for part 2. Thirty-one patients completed part 2. Mean maximum DeltaDeltaQTcF occurred on day 8, 10 h postdose (2.86 msec; 90% CI, -1.36 to 7.07). Categorical analysis showed no placebo and dabrafenib outliers (increase >60 msec; QTcF >500 msec). Day 1 dabrafenib 300 mg Cmax and AUC(0-infinity) were ~ 2-fold higher than with single-dose 150 mg. Day 8 AUC(0 tau) with 300 mg BID was ~ 2.7-fold higher than with 150 mg BID. Dabrafenib metabolites showed similar trends. Pharmacokinetics/pharmacodynamics modelling/simulation showed that median QTc increase was <5 msec (upper 90% CI, <10 msec). No unexpected toxicities occurred with supratherapeutic dosing. CONCLUSION: Repeat oral supratherapeutic dabrafenib 300 mg BID dosing had no clinically relevant effect on QTc interval, with no new safety signals seen. PMID- 29243289 TI - Examining the content and moderators of women's fears for giving birth: A meta synthesis. AB - AIMS AND OBJECTIVES: This meta-synthesis aimed to identify key elements contributing to FOC derived from women's own reports. BACKGROUND: Fear of childbirth (FOC) encompasses fear or anxiety about giving birth, which can resemble a phobic response. FOC holds implications for women's antenatal and postnatal well-being, and decisions made about the birth but a clear definition of the construct does not exist. METHOD: A meta-synthesis was conducted by searching databases (Web of Knowledge, CINAHL, EBSCO, MEDLINE, PsychInfo and PsychArticles) for qualitative studies describing women's perspectives with respect to fear, anxiety, concerns, phobia or stress about birth. A total of 25 papers, reporting findings from 24 studies, fulfilled eligibility criteria and were included in the synthesis. RESULTS: Six key elements of FOC were identified; fears of the unknown, potential for injury, pain, capacity to give birth, losing control and adequacy of support from care providers. A single overarching theme linking all elements was "the unpredictability of childbirth." Three moderators of FOC were also identified; awareness of negative birthing experiences, information received about birth and support received from care providers. CONCLUSIONS: Findings highlight the role of uncertainty in the birthing process as an overarching theme underpinning women's fears. Enhancing tolerance of uncertainty may be a way to reduce women's FOC. RELEVANCE TO CLINICAL PRACTICE: Identification of the elements and moderators of FOC provide an insight into the potential mechanisms that contribute to women's fears, which can be used to inform methods of identifying women with FOC or a basis upon which to base supportive strategies to reduce women's fears for giving birth. PMID- 29243290 TI - A noncoding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family. AB - Expanded mutation detection and novel gene discovery for isolated polycystic liver disease (PCLD) are necessary as 50% of cases do not have identified mutations in the seven published disease genes. We investigated a family with five affected siblings for which no loss-of-function variants were identified by whole exome sequencing analysis. SNP genotyping and linkage analysis narrowed the candidate regions to ~8% of the genome, which included two published PCLD genes in close proximity to each other, GANAB and LRP5. Based on these findings, we re evaluated the exome sequencing data and identified a novel intronic nine base pair deletion in the vicinity of the GANAB exon 24 splice donor that had initially been discarded by the sequence analysis pipelines. We used a minigene assay to show that this deletion leads to skipping of exon 24 in cell lines and primary human cholangiocytes. These findings prompt genomic evaluation beyond the coding region to enhance mutation detection in PCLD and to avoid premature implication of other genes in linkage disequilibrium. PMID- 29243291 TI - Antiinflammatory properties of betulinic acid and xylopic acid in the carrageenan induced pleurisy model of lung inflammation in mice. AB - This study investigated the antiinflammatory properties of betulinic acid (BA) and xylopic acid (XA) extracted from Margaritaria discoidea and Xylopia aethiopica, respectively. M. discoidea and X. aethiopica are plants native in Ghana and the West-African region and used traditionally to treat different pathologies including inflammatory conditions. The antiinflammatory effect of BA and XA was established by an in vivo assay using the carrageenan-induced pleural inflammation model in mice. Also, the ability of BA and XA to increase catalase, superoxide dismutase, glutathione levels and decrease lipid peroxidation level in reactive oxidative assays was assessed. In addition, the ability of XA and BA to prevent potential lung tissue damage was quantified. Pretreatment with BA and XA reduced significantly, signs of inflammation: neutrophil infiltration, oedema, and alveoli septal thickening in carrageenan-treated lung tissue. Additionally, BA or XA pretreatment lowered the degree of lipid peroxidation in the lung tissue while increasing the levels of catalase, superoxide dismutase, and glutathione in vivo. Comparatively, XA was more efficacious than BA in the prevention of lung tissue damage. BA and XA derived from X. aethiopica and M. discoidea possess antiinflammatory and in vivo antioxidant activities in mice pleurisy model. The effect of these compounds gives credence to the traditional use in the management of inflammatory conditions of the airway. PMID- 29243292 TI - Effects of endovascular cooling on infarct size in ST-segment elevation myocardial infarction: A patient-level pooled analysis from randomized trials. AB - OBJECTIVES: This study sought to examine the relationship between temperature at reperfusion and infarct size. BACKGROUND: Hypothermia consistently reduces infarct size when administered prior to reperfusion in animal studies, however, clinical results have been inconsistent. METHODS: We performed a patient-level pooled analysis from six randomized control trials of endovascular cooling during primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) in 629 patients in which infarct size was assessed within 1 month after randomization by either single-photon emission computed tomography (SPECT) or cardiac magnetic resonance imaging (cMR). RESULTS: In anterior infarct patients, after controlling for variability between studies, mean infarct size in controls was 21.3 (95%CI 17.4-25.3) and in patients with hypothermia <35 degrees C it was 14.8 (95%CI 10.1-19.6), which was a statistically significant absolute reduction of 6.5%, or a 30% relative reduction in infarct size (P = 0.03). There was no significant difference in infarct size in anterior >=35 degrees C, or inferior infarct patients. There was no difference in the incidence of death, ventricular arrhythmias, or re-infarction due to stent thrombosis between hypothermia and control patients. CONCLUSIONS: The present study, drawn from a patient-level pooled analysis of six randomized trials of endovascular cooling during primary PCI in STEMI, showed a significant reduction in infarct size in patients with anterior STEMI who were cooled to <35 degrees C at the time of reperfusion. The results support the need for trials in patients with anterior STEMI using more powerful cooling devices to optimize the delivery of hypothermia prior to reperfusion. PMID- 29243293 TI - The association between coeliac disease and periodontitis: Results from NHANES 2009-2012. AB - AIM: To investigate whether coeliac disease (CD) was associated with periodontitis among a nationally representative sample of US adults. MATERIALS AND METHODS: The National Health and Nutrition Examination Survey (NHANES) 2009 2012 enrolled 6,661 subjects with full-mouth periodontal examination and serological testing for antitissue transglutaminase (tTg) and antiendomysial (EMA) antibodies. CD was defined as (i) self-reported physician diagnosis while on a gluten-free diet; or (ii) tTg levels >10.0 U/ml and positive EMA results. Positive serology without self-reported diagnosis was defined as undiagnosed CD (UdxCD). Periodontitis was defined according to the CDC/AAP definition. Multivariable linear and logistic models were used to regress the mean probing depth (PD) or attachment loss (AL) outcomes across CD categories (none, diagnosed and undiagnosed). RESULTS: The prevalence of moderate/severe periodontitis and diagnosed/undiagnosed CD was 40% and 0.74%, respectively. Mean AL was lower among those with CD although results were not statistically significant (p = .67). The odds of periodontitis among individuals with diagnosed and undiagnosed CD were: 0.5(0.22, 1.16) and 0.62(0.1, 3.75), respectively. Mean PD levels among those without CD or with diagnosed or undiagnosed CD were 1.49 +/- 0.02, 1.36 +/- 0.11 and 1.31 +/- 0.11 (p = .03). CONCLUSION: CD is associated with modestly lower levels of mean PD but was not associated with mean AL or periodontitis. Larger studies are necessary to enhance precision and strengthen conclusions. PMID- 29243294 TI - Hybridization can promote adaptive radiation by means of transgressive segregation. AB - Understanding the mechanisms of rapid adaptive radiation has been a central problem of evolutionary ecology. Recently, there is a growing recognition that hybridization between different evolutionary lineages can facilitate adaptive radiation by creating novel phenotypes. Yet, theoretical plausibility of this hypothesis remains unclear because, for example, hybridization can negate pre existing species richness. Here, we theoretically investigate whether and under what conditions hybridization promotes ecological speciation and adaptive radiation using an individual-based model to simulate genome evolution following hybridization between two allopatrically evolved lineages. The model demonstrated that transgressive segregation through hybridization can facilitate adaptive radiation, most powerfully when novel vacant ecological niches are highly dissimilar, phenotypic effect size of mutations is small and there is moderate genetic differentiation between parental lineages. These results provide a theoretical basis for the effect of hybridization facilitating adaptive radiation. PMID- 29243295 TI - Extended phase graph formalism for systems with magnetization transfer and exchange. AB - PURPOSE: An extended phase graph framework (EPG-X) for modeling systems with exchange or magnetization transfer (MT) is proposed. THEORY: EPG-X models coupled two-compartment systems by describing each compartment with separate phase graphs that exchange during evolution periods. There are two variants: EPG-X(BM) for systems governed by the Bloch-McConnell equations, and EPG-X(MT) for the pulsed MT formalism. For the MT case, the "bound" protons have no transverse components, so their phase graph consists of only longitudinal states. METHODS: The EPG-X model was validated against steady-state solutions and isochromat-based simulation of gradient-echo sequences. Three additional test cases were investigated: (i) MT effects in multislice turbo spin-echo; (ii) variable flip angle gradient-echo imaging of the type used for MR fingerprinting; and (iii) water exchange in multi-echo spin-echo T2 relaxometry. RESULTS: EPG-X was validated successfully against isochromat based transient simulations and known steady-state solutions. EPG-X(MT) simulations matched in-vivo measurements of signal attenuation in white matter in multislice turbo spin-echo images. Magnetic resonance fingerprinting-style experiments with a bovine serum albumin (MT) phantom showed that the data were not consistent with a single-pool model, but EPG-X(MT) could be used to fit the data well. The EPG-X(BM) simulations of multi echo spin-echo T2 relaxometry suggest that exchange could lead to an underestimation of the myelin-water fraction. CONCLUSIONS: The EPG-X framework can be used for modeling both steady-state and transient signal response of systems exhibiting exchange or MT. This may be particularly beneficial for relaxometry approaches that rely on characterizing transient rather than steady state sequences. Magn Reson Med 80:767-779, 2018. (c) 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. PMID- 29243296 TI - Role of conventional immunomarkers, HNF4-alpha and SATB2, in the differential diagnosis of pulmonary and colorectal adenocarcinomas. AB - AIMS: Pulmonary (ADC) and colorectal (CRC) adenocarcinomas are frequent entities in pathological routine diagnostics. Whereas the differential diagnosis is usually straightforward based on histomorphology, it can be challenging in small biopsies. In general, CDX-2, CK20, Napsin-A and TTF-1 are recommended immunohistological markers in this scenario. Hepatocyte nuclear factor 4 alpha (HNF4-alpha) and special AT-rich sequence-binding protein 2 (SATB2) were described recently as promising additional markers, but comprehensive large-scale data are lacking so far. Therefore, we analysed the expression of these six markers in 1021 non-small-cell lung cancers (NSCLC), including 472 ADC as well as in 80 pulmonary metastases of CRC. METHODS AND RESULTS: Tissue microarrays of NSCLC and pulmonary metastases of CRC were stained for CDX-2, CK20, HNF4-alpha, Napsin-A, SATB2 and TTF-1 and staining results were correlated with clinicopathological variables. ADC exhibited expression of CDX-2, CK20, HNF4 alpha, Napsin-A, SATB2 and TTF-1 in nine (2%), 21 (4%), 17 (4%), 345 (73%), 35 (7%) and 408 (86%) samples, while 80 CRC were positive in 79 (99%), 74 (93%), 77 (96%), no (0%), 78 (98%) and five (6%) cases, respectively. CONCLUSIONS: In addition to conventional immunomarkers, HNF4-alpha and particularly SATB2 may be helpful in the differential diagnosis of pulmonary ADC and metastases of CRC. PMID- 29243297 TI - Graphitic Carbon Nitride as a Distinct Solid Stabilizer for Emulsion Polymerization. AB - g-C3 N4 has been found to be highly functional in many fields, such as photocatalysis, electrocatalysis, and chemical analysis. Pickering emulsion polymerization is a fascinating strategy to fabricate a range of nanomaterials, in which the emulsion is stabilized by solid particles, rather than molecular surfactants. Herein, we demonstrate that g-C3 N4 can act as a remarkable stabilizer for Pickering emulsion polymerization. Contrary to normal Pickering systems, monodisperse polystyrene microspheres with tunable size, surface charge, and morphology were achieved using this approach. Importantly, the g-C3 N4 hybridized latex is highly processable and has exhibited multiple functions: manufacture of photonic crystals via self-organization, stabilizing Pickering emulsion owing to proper wettability, and acting as bioimaging agents with enriched fluorescent colors. Considering the easy synthesis and low cost of g-C3 N4 , our approach has a high potential for scale-up synthesis and practical translation. PMID- 29243298 TI - Local anesthesia in pediatric dermatologic surgery: Evaluation of a patient centered approach. AB - BACKGROUND/OBJECTIVES: A few studies have documented the effect of local anesthesia for minor dermatologic surgical procedures on children and their parents. Our objective was to evaluate the psychological effect and global satisfaction of a patient-centered approach to dermatologic surgery under local anesthesia. METHODS: Two self-administered questionnaires were used to evaluate the distress and global satisfaction of 388 children who underwent dermatologic surgery under local anesthesia, accompanied by oral and written therapeutic education measures (structured information and a cartoon brochure illustrating the procedure) addressed to children and parents. Distraction techniques were also used during the procedures. RESULTS: Although 54.5% of patients manifested some degree of fear, all other parameters analyzed (pain, surgery-related distress, surgical team-patient and -family relationship, global satisfaction) indicated that the procedures resulted in limited distress and that the large majority of children and parents tolerated them well. CONCLUSION: Specific measures for therapeutic pediatric patient education may be helpful in limiting discomfort, anxiety, and pain perception linked to procedures performed under local anesthesia. Further controlled studies are required to more precisely assess the benefits of specific therapeutic education measures. PMID- 29243299 TI - Antidepressant use during pregnancy and the risk of attention deficit/hyperactivity disorder in the children: a meta-analysis of cohort studies. AB - BACKGROUND: Evidence for the relationship between antidepressant use during pregnancy and the risk of attention-deficit/hyperactivity disorder (ADHD) in the children is conflicting. OBJECTIVE: To assess the association between fetal exposure to antidepressant drugs and the subsequent development of ADHD. SEARCH STRATEGY: A systematic literature search was conducted in PubMed, EMBASE, PsycINFO, and CINAHL databases to identify relevant cohort studies published from inception until October 2017. SELECTION CRITERIA: Cohort studies, identifying children with ADHD diagnosis and linking antidepressant use during pregnancy in their mothers. DATA COLLECTION: Two reviewers independently abstracted data and assessed study quality. MAIN RESULTS: The literature search identified six relevant cohort studies with association between antidepressant exposure during pregnancy and the risk of ADHD in children [hazard ratio (HR) 1.34; 95% confidence interval (CI) 1.14-1.57]. However, the association was not statistically significant when the reference group was mothers with psychiatric disorders not treated during pregnancy (HR 0.96; 95% CI 0.76-1.2; n = 2 studies). Moreover, preconception exposure to antidepressants was significantly associated with increased risk of ADHD (HR 1.82; 95% CI 1.54-2.15; n = 3 studies). CONCLUSIONS: The significant association between antidepressant exposure during pregnancy and ADHD in the children can be partially explained by confounding by indication. Given the low number of included studies, further studies with prospective designs that use validated measurements and controls for important confounders are needed to verify our findings. TWEETABLE ABSTRACT: Antidepressant use during pregnancy may be not associated with ADHD in the offspring. PMID- 29243300 TI - Antagonists of Wnt/beta-catenin signalling in the periodontitis associated with type 2 diabetes and smoking. AB - AIM: This study evaluated the levels of sclerostin (SOST) and Dickkopf (DKK)-1 in the chronic periodontitis (CP) associated with type 2 diabetes (DM) and/or smoking. Relationships between SOST, DDK1, RANKL, OPG, IL-1beta, IL-6 and TNF alpha, and pathogens were assessed. MATERIAL AND METHODS: The study population included non-diabetic non-smokers (control), non-smokers with DM (DM group), non diabetic smokers (S group) and smokers with DM (SDM group), all with CP. Serum and gingival levels of SOST, DKK1, RANKL, OPG, IL-1beta, IL-6 and TNF-alpha were evaluated by multiplex immunoassay. Gene expressions of these biomarkers and subgingival levels of pathogens were assessed by qPCR. RESULTS: Gingival protein and/or mRNA levels of DKK1 and SOST were higher in subjects with DM and/or smoking than in controls (p < .05). Serum levels of SOST were higher in the DM group than in controls (p < .05). DKK1 positively correlated with SOST in the DM, SDM and control groups (p < .05) at mRNA levels. DKK-1 and SOST correlated with pathogens, especially in both groups with DM. CONCLUSIONS: SOST and DKK1 were upregulated in patients with CP presenting DM and/or smoking. DM, alone or with smoking, particularly influenced the correlations of SOST and DKK1 with each other and with the other biomarkers mostly at mRNA levels, as well as with periodontal pathogens. PMID- 29243302 TI - A sideways look at conservation and consistency in tourism policy. PMID- 29243301 TI - Evaluation of the Live Biotherapeutic Product, Asymptomatic Bacteriuria Escherichia coli 2-12, in Healthy Dogs and Dogs with Clinical Recurrent UTI. AB - BACKGROUND: Antimicrobial resistance is an emerging problem. HYPOTHESIS/OBJECTIVE: To investigate the safety and efficacy of a live biotherapeutic product, ASB E. coli 2-12 for UTI treatment. ANIMALS: Six healthy research dogs; nine client-owned dogs with recurrent UTI. METHODS: Prospective noncontrolled clinical trial. For safety data, research dogs were sedated, a urinary catheter was inserted into the bladder; 1010 CFU/mL of ASB E. coli 2-12 was instilled. Urine was cultured on days 1, 3, and 8 post-instillation and dogs were observed for lower urinary tract signs (LUTS). For client-owned dogs, ASB E. coli 2-12 was instilled similarly and urine cultures analyzed on days 1, 7, and 14 days postinstillation. RESULTS: No LUTS were noted in any of the 6 research dogs after ASB E. coli 2-12 infusion. Pulse field gel electrophoresis (PFGE) studies confirmed the bacterial strains isolated matched that ASB E. coli 2-12 strain. Four of the nine client-owned dogs had complete or nearly complete clinical cures by day 14. Of these four dogs, 3 also had microbiologic cures at day 14; one of these dogs had subclinical bacteriuria (in addition to ASB E. coli 2-12). Three of these four dogs had ASB E. coli 2-12 isolated from their urine at day 14. With the exception of mild, temporary, self-limiting, hyporexia in two dogs on the day of biotherapeutic administration, there were no major adverse effects. CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest ASB E. coli 2 12 is safe and should be investigated in a larger controlled study evaluating clinical UTI in dogs. PMID- 29243304 TI - Holmes heart and tetralogy of Fallot in association with PHACE. AB - PHACE is an association between large infantile hemangiomas and brain, arterial, cardiac, and/or ocular abnormalities. Aortic or subclavian aberrations are the most common cardiovascular anomalies in PHACE, whereas complex congenital heart disease is rare. We report a case of Holmes heart and three cases of tetralogy of Fallot in PHACE association. PMID- 29243303 TI - Genotoxic and mutagenic properties of Ni and NiO nanoparticles investigated by comet assay, gamma-H2AX staining, Hprt mutation assay and ToxTracker reporter cell lines. AB - Nickel (Ni) compounds are classified as carcinogenic to humans but the underlying mechanisms are still poorly understood. Furthermore, effects related to nanoparticles (NPs) of Ni have not been fully elucidated. The aim of this study was to investigate genotoxicity and mutagenicity of Ni and NiO NPs and compare the effect to soluble Ni from NiCl2 . We employed different models; i.e., exposure of (1) human bronchial epithelial cells (HBEC) followed by DNA strand break analysis (comet assay and gamma-H2AX staining); (2) six different mouse embryonic stem (mES) reporter cell lines (ToxTracker) that are constructed to exhibit fluorescence upon the induction of various pathways of relevance for (geno)toxicity and cancer; and (3) mES cells followed by mutagenicity testing (Hprt assay). The results showed increased DNA strand breaks (comet assay) for the NiO NPs and at higher doses also for the Ni NPs whereas no effects were observed for Ni ions/complexes from NiCl2 . By employing the reporter cell lines, oxidative stress was observed as the main toxic mechanism and protein unfolding occurred at cytotoxic doses for all three Ni-containing materials. Oxidative stress was also detected in the HBEC cells following NP-exposure. None of these materials induced the reporter related to direct DNA damage and stalled replication forks. A small but statistically significant increase in Hprt mutations was observed for NiO but only at one dose. We conclude that Ni and NiO NPs show more pronounced (geno)toxic effects compared to Ni ions/complexes, indicating more serious health concerns. Environ. Mol. Mutagen. 59:211-222, 2018. (c) 2017 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. PMID- 29243305 TI - Opioid analgesic dose and the risk of misuse, overdose, and death: A narrative review. AB - PURPOSE: Despite the rise in serious adverse events paralleling increased prescription opioid analgesic use in the United States over the past 2 decades, the association between opioid analgesic dose and the risk of serious adverse health outcomes is incompletely characterized. We sought to synthesize the medical literature for observational studies examining the association between opioid analgesic dose and the risk of serious adverse health outcomes, with particular attention to the outcomes of misuse, abuse, addiction, overdose, and death. METHODS: Searching MEDLINE using PubMed and bibliography review, we identified 22 observational studies published between 2000 and 2015 that assessed the association between opioid analgesic dose and the risk of serious adverse health outcomes. Some of these studies had significant methodological limitations. Twelve reviewed studies examined the outcomes of misuse, overdose, or death; no studies examining the risk of addiction or abuse met our criteria for inclusion. RESULTS: The results of multiple studies clearly indicate an increasing risk of serious adverse health outcomes associated with increasing opioid analgesic dose. In particular, the risk of misuse, overdose, and death increases with increasing opioid analgesic dose. However, there is no opioid dose inflection point beyond which the risk of these adverse health outcomes increases. No opioid analgesic dose is without risk. CONCLUSIONS: The reviewed studies show an increasing risk of serious adverse health outcomes-including misuse, overdose, and death-associated with increasing opioid analgesic dose. Further research is needed to characterize the relationship between opioid analgesic dose and the risk of addiction and abuse. This analysis could inform policy actions for regulators and clinical decision making for providers. PMID- 29243307 TI - Pulmonary nodules and nodular scleritis in a teenager with superficial granulomatous pyoderma gangrenosum. AB - Superficial granulomatous pyoderma gangrenosum, a rare variant of pyoderma gangrenosum, has been considered to be the most benign form of the disease. We present the case of a 15-year-old boy with pulmonary involvement and nodular scleritis associated with this unusual type of pyoderma gangrenosum and discuss its differential diagnosis. PMID- 29243308 TI - Western herbal medicine consultations for common menstrual problems; practitioner experiences and perceptions of treatment. AB - To explore the prevalence with which Australian Western herbalists treat menstrual problems and their related treatment, experiences, perceptions, and interreferral practices with other health practitioners. Members of the Practitioner Research and Collaboration Initiative practice-based research network identifying as Western Herbalists (WHs) completed a specifically developed, online questionnaire. Western Herbalists regularly treat menstrual problems, perceiving high, though differential, levels of effectiveness. For menstrual problems, WHs predominantly prescribe individualised formulas including core herbs, such as Vitex agnus-castus, and problem-specific herbs. Estimated clients' weekly cost (median = $25.00) and treatment duration (median = 4-6 months) covering this Western herbal medicine treatment appears relatively low. Urban-based women are more likely than those rurally based to have used conventional treatment for their menstrual problems before consulting WHs (p = .001). Only 19% of WHs indicated direct contact by conventional medical practitioners regarding treatment of clients' menstrual problems despite 42% indicating clients' conventional practitioners recommended consultation with WH. Western herbal medicine may be a substantially prevalent, cost-effective treatment option amongst women with menstrual problems. A detailed examination of the behaviour of women with menstrual problems who seek and use Western herbal medicine warrants attention to ensure this healthcare option is safe, effective, and appropriately co-ordinated within women's wider healthcare use. PMID- 29243309 TI - Relevance of terrorism for Italian students not directly exposed to it: The affective impact of the 2015 Paris and the 2016 Brussels attacks. AB - Notwithstanding the dramatically increasing frequency of acts of terrorism in Europe and the extent of their media coverage, there is lack of knowledge on people's affective reactions and associated emotion regulation strategies. We explored the affective impact on two cohorts of Italian students (n = 193) possibly exposed vicariously through the mass media to the 2015 Paris or the 2016 Brussels terrorist attacks, respectively. We accessed data from three online questionnaires: one on emotion regulation administered before each attack; one on daily affect administered just before and after each attack; and one on causes of weekly affect and life satisfaction administered at the end of the week in which each attack occurred. The attacks were perceived as relevant for influencing negative affect for 22% of the students. For them, suppression-less frequently used than reappraisal-was associated with an improvement of affect after each attack but negatively related to life satisfaction concerning the week in which the attacks occurred. Our data showed that the recent terrorist attacks occurring in Europe had an affective impact on people at some distance who were vicariously exposed and point to the protective role of emotion regulation as a key resource for individuals' well-being. PMID- 29243310 TI - Coriolus versicolor aqueous extract ameliorates insulin resistance with PI3K/Akt and p38 MAPK signaling pathways involved in diabetic skeletal muscle. AB - Patients with type 2 diabetes mellitus (T2DM) are usually with poor immunity and easier to suffer from cancer and microbial infections. Herein, we report an efficient anti-diabetic medicinal mushroom, Coriolus versicolor (CV). This study aimed to investigate the anti-diabetic and anti-insulin-resistance effects of CV aqueous extract in myoblasts (L6 cells) and skeletal muscle of T2DM rat. Our results showed that CV extract treatment significantly reduced blood glucose levels of T2DM rats, whereas CV extract increased glucose consumption in insulin resistant L6 cells. Besides, the translocation and expression of glucose transporter 4 were enhanced by CV extract, which indicated that CV extract was effective in diabetic skeletal muscle. Moreover, CV extract treatments resulted in remarkable anti-insulin-resistance effects, which was reflected by the change of gene and protein expression levels in PI3K/Akt and p38 MAPK pathways. PI3K inhibitor, LY29004, and p38 MAPK inhibitor, SB203580 confirmed it further. In conclusion, our results demonstrated that the CV extract exhibited anti-diabetic and anti-insulin-resistance effects in diabetic skeletal muscle, and the effects were mediated by PI3K/Akt and p38 MAPK pathways. These findings are remarkable when considering the use of commercially available CV by diabetic patients who also suffer from cancer or microbial infections. PMID- 29243311 TI - Husbandry protocols for the Band-tailed pigeon, Patagioenas fasciata albilinea, at the WCS, Bronx Zoo for future conservation management programs. AB - From 2015 to 2016 we determined the husbandry protocols involved in the captive rearing of the Band-tailed Pigeon (BTPI), Patagioenas fascinate albilinea, for use as a tool in the future management of like extant and extinct avian taxa. Current and historical ex-situ conservation management of BTPIs and the closely related Passenger Pigeon, Ectopistes migratorius, is limited in scope and required further examination. Focus on the BTPI within zoos and private aviculture facilities is currently lacking. New pressures on the wild populations and future examination of the parameters involved in the possible restoration of the Passenger Pigeon may rely on a complete understanding of these conservation management techniques. Here we report on the establishment of a colony of BTPIs, at the Wildlife Conservation Society (WCS), and detail the progress attained. A confiscated group of BTPIs was presented to WCS and allowed us to set up the colony, document the husbandry involved, and monitor neonatal development and the factors that influence that development. The information has provided a better understanding of the BTPI and has implications for the future conservation management of this and like species. PMID- 29243312 TI - Duration of anaemia during the first week of life is an independent risk factor for retinopathy of prematurity. AB - AIM: This study evaluated the correlation between retinopathy of prematurity (ROP), anaemia and blood transfusions in extremely preterm infants. METHODS: We included 227 infants born below 28 weeks of gestation at King Edward Memorial Hospital, Perth, Australia, from 2014-2016. Birth characteristics and risk factors for ROP were retrieved, and anaemia and severe anaemia were defined as a haemoglobins of <110 g/L and <80 g/L, respectively. Logistic regression was used for the analysis. RESULTS: Retinopathy of prematurity treatment was needed in 11% of cases and the mean number of blood transfusions (p < 0.01), and mean number of weeks of anaemia (p < 0.001) and of severe anaemia (p < 0.05), had positive associations with ROP cases warranting treatment. In the multivariate logistic regression analysis, the best-fit model of risk factors included anaemic days during first week of life, with an odds ratio (OR) of 1.46% and 95% confidence interval (CI) of 1.16-1.83 (p < 0.05), sepsis during the first 4 weeks of life (OR 3.14, 95% CI 1.10-9.00, p < 0.05) and days of ventilation (OR 1.03, 95% CI 1.01-1.06, p < 0.05). CONCLUSION: The duration of anaemia during the first week of life was an independent risk factor for ROP warranting treatment and preventing early anaemia may decrease this risk. PMID- 29243313 TI - Nutrients from salmon parents alter selection pressures on their offspring. AB - Organisms can modify their surrounding environment, but whether these changes are large enough to feed back and alter their evolutionary trajectories is not well understood, particularly in wild populations. Here we show that nutrient pulses from decomposing Atlantic salmon (Salmo salar) parents alter selection pressures on their offspring with important consequences for their phenotypic and genetic diversity. We found a strong survival advantage to larger eggs and faster juvenile metabolic rates in streams lacking carcasses but not in streams containing this parental nutrient input. Differences in selection intensities led to significant phenotypic divergence in these two traits among stream types. Stronger selection in streams with low parental nutrient input also decreased the number of surviving families compared to streams with high parental nutrient levels. Observed effects of parent-derived nutrients on selection pressures provide experimental evidence for key components of eco-evolutionary feedbacks in wild populations. PMID- 29243314 TI - A Self-Repairing Cathode Material for Lithium-Selenium Batteries: Se-C Chemically Bonded Selenium-Graphene Composite. AB - Lithium-selenium batteries, employing selenium as a cathode material, exhibit some notable advantages, such as high discharge rates and good cycling performance, due to their high electrical conductivity, high output voltages, and high volumetric capacity density. However, an important problem, termed the "shuttle effect", can lead to capacity decay in Li-Se cells (and in Li-S cells), which arises from aggregation and the loss of Se or S from the cathode into the electrolyte. In this work, in order to solve this problem, a new self-repairing system has been devised, in which some Se atoms are chemically bonded to the carbon atoms of graphene and act as reclaiming points for dissociated Se atoms through the establishment of -Se-Se-Se- chains. Se-decorated graphene (Se-GE) was first constructed through a facile high-energy ball-milling process. Its formation was confirmed by XRD, SEM, HRTEM, XPS, and Raman analyses. As we anticipated, in examining cell properties, the as-prepared Se-GE composite underwent an initial capacity decay in the first 20 cycles (from 1050 mAh g-1 to 750 mAh g-1 , ca. 29 % loss), but the capacity then reverted to 970 mAh g-1 (ca. 92 % of the initial value). Other measurements were also consistent with the recapture of dissociated Se atoms. PMID- 29243315 TI - Synthesis and Dimerization Studies of a Lipophilic Photoresponsive Aryl-Extended Tetraurea-Calix[4]pyrrole. AB - We describe the syntheses of the lipophilic aryl-extended alpha,alpha,alpha,alpha tetraurea-phenyl-calix[4]pyrrole 1, featuring four appended azo-phenyl groups with two tert-butoxy carbonyl meta-substituents and its photo-inactive counterpart 2. In CD2 Cl2 solutions, both tetraurea-calix[4]pyrroles self assemble into dimeric capsules by encapsulating one molecule of a suitable bis-N oxide or two molecules of a mono-N-oxide. The dimeric capsules are mainly stabilized by a cyclic array of sixteen hydrogen bonds established between the eight unidirectionally oriented urea groups. Photoirradiation experiments demonstrated the trans-to-cis isomerization of the azo-phenyl groups and the formation of a plethora of stereo isomeric cis-azo-enriched capsular assemblies. The highly cis-azo enriched capsular assemblies seem to show a reduced stability and their involvement in equilibria with non-capsular counterparts that also bind the N-oxides. The thermally induced cis-to-trans interconversion processes demonstrated the reversibility of the photoisomerization and the photostability of most binding partners. An equimolar mixture of the two tetraureas produced two homodimeric capsules and the heterodimeric counterpart in a ratio close to statistical distribution. PMID- 29243316 TI - Effect of lactic acid bacteria-treated King grass silage on the performance traits and serum metabolites in New Zealand white rabbits (Oryctolagus cuniculus). AB - This study examined the effects of Lactobacillus plantarum and Pediococcus acidilactici-treated silage of King grass (Pennisetum purpureophoides) on the productive traits and blood biochemistry of New Zealand white (NZW) rabbits. King grass was ensiled without or with L. plantarum (T1), P. acidilactici (T2) and P. acidilactici + L. plantarum (T3). A total of 72 male NZW rabbits (6 weeks) of similar weight and appearance were housed in groups in metallic cages in a completely randomized design. The performance traits, daily feed intake, body weight gain and feed convention ratio were not affected by the silage treatment. Triglyceride and alanine aminotransferase (ALT) concentration was increased (p < .05) in T2 (0.92 mmol/L) compared to the other treatments. The superoxide dismutase (SOD), phosphorous (P) and magnesium (Mg) increased (p < .05) in T1 (658.01 nmol/ml, 5.1 mg/kg and 2.43 mg/kg, respectively) compared to the control and other experimental groups. Cu and Mn decreased (p < .05), while Zn increased (p < .05) in the treated groups compared to the control. The CP decreased (p < .05) in the treatment groups compared to the control. Neutral detergent fibre (NDF) increased (p < .05) in T2 (54.40%) compared to the other treatments. The inoculation of lactic acid bacteria-treated King grass silage supplementation positively affected rabbit performance and improved blood cholesterol profile, antioxidant status and improve nutrients digestibility. PMID- 29243318 TI - Effect of maturity and infection on the rate of relaxation of the respiratory muscles in ventilated, newborn infants. AB - AIM: To assess the respiratory muscle time constant of relaxation (tau), an index of respiratory muscle function in ventilated newborns. METHODS: Sixty-two infants (42 born prematurely) with a median gestational age of 29 [interquartile range (IQR) 26-37] weeks were prospectively studied. Measurement of tau was taken during spontaneous breathing on endotracheal continuous positive airway pressure prior to extubation, and tau was calculated from the reciprocal of the slope of the airway pressure decline versus time. Infants were classified as having had systemic or respiratory infection (positive microbiology) if they had any positive bacterial blood or respiratory culture prior to measurement. RESULTS: Measurement of tau was taken at a median post-natal age of 6 (IQR 3-29) days. The median tau was higher in premature infants [17.4 (IQR 7.7-28.3) sec/cmH2 O] compared to term infants [6.8 (IQR 4.4-8.7) sec/cmH2 O, p < 0.001]. The median tau was higher in infants who had had positive microbiology [17.6 (IQR 9.9-29.1) sec/cmH2 O] compared to infants with negative microbiology [8.0 (IQR 6.3-17.9) sec/cmH2 O, p = 0.034]. tau was related to gestational age (r = -0.265, p = 0.003) and weight at measurement (r = -0.269, p = 0.002). CONCLUSION: Respiratory muscle function in ventilated newborns is negatively affected by prematurity and previous systemic or respiratory infection. PMID- 29243320 TI - Re: Genetic variation in the progesterone receptor gene and susceptibility to recurrent pregnancy loss: a case-control study: Progesterone receptor genetic variants as predictors of recurrent pregnancy loss: an epidemiological study. PMID- 29243319 TI - Zebrafish Rfx4 controls dorsal and ventral midline formation in the neural tube. AB - BACKGROUND: Rfx winged-helix transcription factors, best known as key regulators of core ciliogenesis, also play ciliogenesis-independent roles during neural development. Mammalian Rfx4 controls neural tube morphogenesis via both mechanisms. RESULTS: We set out to identify conserved aspects of rfx4 gene function during vertebrate development and to establish a new genetic model in which to analyze these mechanisms further. To this end, we have generated frame shift alleles in the zebrafish rfx4 locus using CRISPR/Cas9 mutagenesis. Using RNAseq-based transcriptome analysis, in situ hybridization and immunostaining we identified a requirement for zebrafish rfx4 in the forming midlines of the caudal neural tube. These functions are mediated, least in part, through transcriptional regulation of several zic genes in the dorsal hindbrain and of foxa2 in the ventral hindbrain and spinal cord (floor plate). CONCLUSIONS: The midline patterning functions of rfx4 are conserved, because rfx4 regulates transcription of foxa2 and zic2 in zebrafish and in mouse. In contrast, zebrafish rfx4 function is dispensable for forebrain morphogenesis, while mouse rfx4 is required for normal formation of forebrain ventricles in a ciliogenesis-dependent manner. Collectively, this report identifies conserved aspects of rfx4 function and establishes a robust new genetic model for in-depth dissection of these mechanisms. Developmental Dynamics 247:650-659, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29243323 TI - Continuous Scientific Growth through an Open-Minded Attitude. AB - "New frontiers in chemistry must be built on a solid foundation because innovation is rooted in a firm understanding of traditional fields. However, researchers must ambitiously navigate unchartered areas. An open-minded attitude to learn traditional research fields will lead to new developments in these fields." The new Editorial Board Chairman Susumu Kitagawa shares his vision for the future of Chemistry-An Asian Journal. PMID- 29243317 TI - IL-17 in neonatal health and disease. AB - Over the last few years, scientific interest in the cytokine IL-17A has intensified as its role in human health and disease has been elucidated. Discovered almost a quarter century ago, IL-17A is known to have poor biologic activity when acting alone, but attains robust actions when working synergistically with potent mediators of proinflammatory immune responses, such as IL-6 and IL-8. IL-17A is produced by specialized innate immune cells that protect host barriers from the outside world. Like sentries, these innate immune cells can "sound the alarm" through increased production of IL-17A, causing activation and recruitment of primed neutrophils and monocytes when pathogens escape initial host defenses. In this way, IL-17A promulgates mechanisms responsible for pathogen death and clearance. However, when IL-17A pathways are triggered during fetal development, due to chorioamnionitis or in utero inflammatory conditions, IL-17A can instigate and/or exacerbate fetal inflammatory responses that increase neonatal morbidities and mortality associated with common neonatal conditions such as sepsis, bronchopulmonary dysplasia (BPD), patent ductus arteriosus (PDA), and necrotizing enterocolitis (NEC). This review details the ontogeny of IL-17A in the fetus and newborn, discusses how derangements in its production can lead to pathology, and describes known and evolving therapies that may attenuate IL-17A-mediated human conditions. PMID- 29243322 TI - Transient Myocardial Thickening in Cats Associated with Heart Failure. AB - BACKGROUND: Cats with hypertrophic cardiomyopathy (HCM) and congestive heart failure (CHF) can have resolution of both left ventricular hypertrophy and CHF. OBJECTIVES: To describe the clinical characteristics of cats with transient myocardial thickening (TMT) and CHF compared with a control population of cats without resolution of HCM. ANIMALS: A total of 21 cats with TMT, 21 cats with HCM. METHODS: Retrospective study. Clinical records at 4 veterinary centers were searched for TMT cases and a control group of cats with HCM and CHF. TMT was defined as initial maximal left ventricular wall thickness (LVWT) >=6 mm with left-sided CHF, with subsequent resolution of CHF, reduction in left atrium/aorta (LA/Ao), and LVWT<5.5 mm. HCM was defined as persistent LVWT >=6 mm. RESULTS: Cats with TMT were younger (2 [0.4-11.4] years) than cats with HCM (8 [1.6-14] years) (P < 0.0001), and antecedent events were more common (15/21 versus 6/21, respectively) (P = 0.01). In cats with TMT, LVWT normalized from 6.8 [6.0-9.7] mm to 4.8 [2.8-5.3] mm and LA/Ao decreased from 1.8 [1.6-2.3] to 1.45 [1.2-1.7] after a mean interval of 3.3 (95% CI: 1.8-4.7) months. CHF recurred in 1 of 21 TMT and 15 of 21 cats with HCM. Cardiac treatment was discontinued in 20 of 21 cats with TMT and 0 of 21 HCM cats. All cats with TMT survived, whereas 8 of 19 cats with HCM died during the study period. CONCLUSIONS AND CLINICAL IMPORTANCE: TMT occurs in younger cats, and antecedent events are common. The prognosis is better in cats with CHF associated with TMT than HCM. PMID- 29243324 TI - Validation of histone deacetylase 3 as a therapeutic target in castration resistant prostate cancer. AB - BACKGROUND: Whereas the androgen receptor (AR) signaling axis remains a therapeutic target in castration-resistant prostate cancer (CRPC), the emergence of AR mutations and splice variants as mechanisms underlying resistance to contemporary inhibitors of this pathway highlights the need for new therapeutic approaches to target this disease. Of significance in this regard is the considerable preclinical data, indicating that histone deacetylase (HDAC) inhibitors may have utility in the treatment of CRPC. However, the results of clinical studies using HDAC inhibitors (directed against HDAC1, 2, 3, and 8) in CRPC are equivocal, a result that some have attributed to their ability to induce an epithelial to mesenchymal transition (EMT) and neuroendocrine differentiation. We posited that it might be possible to uncouple the beneficial effects of HDAC inhibitors on AR signaling from their undesired activities by targeting specific HDACs as opposed to using the pan-inhibitor strategy that has been employed to date. METHODS: The relative abilities of pan- and selective-Class I HDAC inhibitors to attenuate AR-mediated target gene expression and proliferation were assessed in several prostate cancer cell lines. Small interfering RNA (siRNA) mediated knockdown approaches were used to confirm the importance of of HDAC 1, 2, and 3 expression in these processes. Further, the ability of each HDAC inhibitor to induce the expression of EMT markers (RNA and protein) and EMT-like phenotype(s) (migration) were also assessed. The anti-tumor efficacy of a HDAC3 selective inhibitor, RGFP966, was compared to the pan-HDAC inhibitor Suberoylanilide Hydroxamic Acid (SAHA) in the 22Rv1 xenograft model. RESULTS: Using genetic and pharmacological approaches we demonstrated that a useful inhibition of AR transcriptional activity, absent the induction of EMT, could be achieved by specifically inhibiting HDAC3. Significantly, we also determined that HDAC3 inhibitors blocked the activity of the constitutively active AR V7-splice variant and inhibited the growth of xenograft tumors expressing this protein. CONCLUSIONS: Our studies provide strong rationale for the near-term development of specific HDAC3 inhibitors for the treatment of CRPC. PMID- 29243325 TI - Camp-based multi-component intervention for families of young children with type 1 diabetes: A pilot and feasibility study. AB - BACKGROUND: Managing type 1 diabetes mellitus (T1DM) in preschool-aged children has unique challenges that can negatively impact glycemic control and parental coping. OBJECTIVE: To evaluate the impact of a camp-based multi-component intervention on glycated hemoglobin A1c (HbA1c) in young children with T1DM and psychosocial measures for their parents. SUBJECTS AND METHODS: Two separate cohorts of 18 children (ages 3-5 years) and their families participated in a camp based intervention that included didactic and interactive parent education, child centered education and family-based recreational activities. In Camp 1.0, measures of HbA1c, parental fear of hypoglycemia, mealtime behaviors and quality of life (QOL) were compared before and after an initial session (I) and follow-up booster session (II) 6 months later. Based on these results, the intervention was consolidated into 1 session (Camp 2.0) and repeated with additional measures of parental stress and parental self-efficacy with diabetes management tasks. RESULTS: Participants in Camp 2.0 exhibited a significant decrease in mean HbA1c level (-0.5%, P = .002) before and after camp. Mothers exhibited a significant improvement in diabetes-specific QOL (Camp 1.0/Session I and Camp 2.0) and reduction in stress as measured on the Pediatric Inventory for Parent (PIP) assessment (Camp 2.0). The booster session in Camp 1.0 showed no added benefit. CONCLUSIONS: A family centered, camp-based multi-component intervention in young children with T1DM improved HbA1c and perceived QOL and stress in their mothers. PMID- 29243326 TI - Three-dimensional ultrasound cranial imaging and early neurodevelopment in preterm growth-restricted infants. AB - AIM: Fetal growth restriction (FGR) is associated with increased perinatal morbidity, mortality and long-term neurodevelopmental sequelae. The objective of this study was to examine whether information about early neurodevelopmental deficits was evident using three-dimensional head ultrasound and developmental assessments in preterm infants with FGR, compared with appropriate for gestational age (AGA) infants in the early post-natal period. METHODS: Twenty preterm FGR infants weighing <10th centile and born between 28 and 32 weeks were compared with age-matched AGA infants. In the second post-natal week after birth, we used three-dimensional ultrasound to assess cerebral ventricular volumes. Prechtl General Movement Assessments were performed at 4-6 weeks after birth. Test of Infant Motor Performance (TIMP) to measure functional motor behaviour was performed at 4-6 and 12-14 weeks corrected age. RESULTS: There was no statistically significant difference in the combined cerebral ventricular volume between the two groups (FGR, 0.81 +/- 0.42 vs. AGA 0.72 +/- 0.38 cm3 , P = 0.4). The TIMP assessment at 12-14 week term corrected demonstrated lower scores (worse performance) in FGR infants compared with the AGA cohort (regression coefficient: -7.74 (95% CI -16.06, 0.57); P = 0.07). We observed a significant correlation between greater ventricular volume and lower TIMP scores in the cohorts separately and also overall (FGR, r = -0.5, P = 0.06 vs. AGA, r = -0.62, P = 0.007 and overall, r = -0.53, P = 0.001). CONCLUSION: Ultrasound in the early weeks may be useful to detect the neuropathology which could then mediate functional consequences. PMID- 29243327 TI - Fluorine-Containing Silsesquioxane-Based Hybrid Porous Polymers Mediated by Bases and Their Use in Water Remediation. AB - Two different silsesquioxane-based porous polymers (FHPPs), namely FHPP-1 and FHPP-2, have been prepared, respectively, by changing the acid scavenger from sodium bicarbonate to triethylamine in the Heck reaction between octavinylsilsesquioxane (OVS) and 1,4-dibromotetrafluorobenzene. It was observed that defluorination occurred in the case of triethylamine. FHPP-1 possesses a higher surface area of 600 m2 g-1 and a hierarchical porous structure; in contrast, FHPP-2 possesses a SBET value of 325 m2 g-1 and a microporous structure. This work provides a new approach to the preparation and tuning of fluorine-containing porous polymers based on silsesquioxanes. These porous materials were employed to remove dyes and a heavy metal from water, showing good binding efficiencies. PMID- 29243328 TI - Why conservation scientists should re-embrace their ecocentric roots. PMID- 29243330 TI - Direct, Metal-free C(sp2 )-H Chalcogenation of Indoles and Imidazopyridines with Dichalcogenides Catalysed by KIO3. AB - Herein, we report a greener protocol for the synthesis of 3-Se/S-indoles and imidazo[1,2-a]pyridines through direct C(sp2 )-H bond chalcogenation of heteroarenes with half molar equivalents of different dichalcogenides, using KIO3 as a non-toxic, easy-to-handle catalyst and a stoichiometric amount of glycerol. The reaction features are high yields, based on atom economy, easy performance on gram-scale, metal- and solvent-free conditions as well as applicability to different types of N-heteroarenes. PMID- 29243329 TI - Thrombopoietin receptor agonists in patients with persistent or chronic immune thrombocytopenia. AB - OBJECTIVES: To assess long-term treatment patterns and outcomes in patients with persistent or chronic immune thrombocytopenia (ITP), also considering the impact of the treatment with thrombopoietin receptor agonists (TPO-RAs) prior to splenectomy. METHODS: Medical records of all patients with persistent or chronic ITP seen at our institution between January 1985 and December 2016 were reviewed. Data on demographic and clinical characteristics were analyzed using descriptive statistics. Wilcoxon rank-sum test was used to compare medians between groups of patients. RESULTS: Among 80 patients with persistent or chronic ITP, 34 underwent splenectomy and 59 were treated with TPO-RAs. Twenty patients were both splenectomized and treated with TPO-RAs; among them, 9 received TPO-RAs before splenectomy. Median time to splenectomy from diagnosis of ITP was 25 months in the group of patients pretreated with TPO-RAs vs 14.5 months in the group of splenectomized patients. These differences were not statistically significant. CONCLUSIONS: Our study provides some initial data on the potential benefits of the treatment with TPO-RAs that may allow splenectomy to be safely deferred for prolonged periods. More research is needed to evaluate the impact of the treatment with TPO-RAs prior to splenectomy. PMID- 29243331 TI - A 5-year retrospective audit of prescribing by a critical care outreach team. AB - UK prescribing legislation changes made in 2006 and 2012 enabled appropriately qualified nurses to prescribe any licensed medication, and all controlled drugs in schedule 2-5 of the Misuse of Drugs Regulations 2001, for any medical condition within their clinical competence. Critical Care Outreach nurses who are independent nurse prescribers are ideally placed to ensure that acutely ill patients receive treatment without delay. The perceived challenge was how Critical Care Outreach nurses would be able to safely prescribe for a diverse patient group. This study informs this developing area of nurse prescribing in critical care practice. The aims of the audit were to: identify which medications were prescribed; develop a critical care outreach formulary; identify the frequency, timing and number of prescribing decisions being made; identify if prescribing practice changed over the years and provide information for our continuing professional development. This article reports on data collected from a 5-year retrospective audit; of prescribing activity undertaken by nine independent nurse prescribers working in a 24/7 Critical Care Outreach team of a 600-bedded district general hospital in the UK. In total, 8216 medication items were prescribed, with an average of 2.6 prescribed per shift. The most commonly prescribed items were intravenous fluids and analgesia, which were mostly prescribed at night and weekends. The audit has shown that Critical Care Outreach nurse prescribing is feasible in a whole hospital patient population. The majority of prescribing occurred after 16:00 and at night. Further research would be beneficial, particularly looking at patient outcomes following reviews from prescribing critical care outreach nurses. The audit is one of the only long-term studies that describes prescribing practice in Critical Care Outreach teams in the UK. PMID- 29243332 TI - Extrinsic and intrinsic blood supply to the optic chiasm. AB - Although there have been many studies of the arterial cerebral blood supply, only seven have described the optic chiasm (OC) blood supply and their results are contradictory. The aim of this study was to analyze the extrinsic and intrinsic OC blood supply on cadaveric specimens using dissections and microcomputer tomography (Micro-CT). Thirteen human specimens were dissected and the internal or common carotid arteries were injected with red latex, China Ink with gelatin or barium sulfate. Three Micro-CTs were obtained to reveal the intrinsic blood supply to the OC. The superior hypophyseal arteries (SupHypA) (13/13) and posterior communicating artery (PCoA) (12/13) supplied the pial network on the inferior side of the OC. The first segment of the anterior cerebral artery (ACA) (10/10), SupHypA (7/10), the anterior communicating artery (ACoA) (9/10), and PComA (1/10) supplied the pial network of its superior side. The intrinsic OC blood supply was divided into three networks (two lateral and one central). Capillaries entering the OC originated principally from the inferior pial network. The lateral network capillaries had the same orientation as the visual lateral pathways, but the central network was not correlated with the nasal fibers crossing into the OC. There was no anastomosis in the pial or intrinsic networks. Only SupHypA, PCoA, ACoA, and ACA were involved in the OC blood supply. Because there was no extrinsic or intrinsic anastomosis, all arteries should be preserved. Tumor compression of the inferior intrinsic arterial network could contribute to visual defects. Clin. Anat. 31:432-440, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29243334 TI - Effects of a targeted blood management programme on allogeneic blood transfusion in abdominal aortic aneurysm surgery. AB - OBJECTIVES: To investigate the impact of a dedicated cell salvage practitioner team on blood loss and allogeneic transfusion in abdominal aortic aneurysm (AAA) surgery. BACKGROUND: Cell salvage reduces allogeneic transfusion in AAA surgery, but is commonly performed by the anaesthetic nurse. At our hospital, a dedicated patient blood management practitioner is present for all elective open AAA repairs. METHODS/MATERIALS: Data were collected on 171 AAA patients operated on at the John Radcliffe Hospital, Oxford over a 3-year period, looking at the Patient Blood Management processes, including: blood loss, cell salvage, near patient testing (thrombelastography) and transfusion rates of allogeneic blood products. RESULTS: Blood loss ranged from 3-108% of estimated blood volume (EBV) (median 25% = 1500 mL). In seven patients who lost 70-110% of their EBV, none reached the thrombelastography intervention threshold for R time (11 min) or MA (48 mm) despite such massive blood loss. Overall, only 7/171 (4%) patients received intra-operative allogeneic blood, all of whom had a mean baseline haemoglobin concentration < 106 g L-1 (median 98, range 95-105 g L-1 ). In terms of other blood products, only 4/171 (2.3%) received one unit of platelets each intra-operatively. None received FFP or cryoprecipitate. CONCLUSIONS: Such low levels of allogeneic transfusion have not been reported previously. We hypothesise that this is due to the additional blood management contributions of the specialised cell salvage practitioners and collaboration with the rest of the vascular surgical team. These results support the development of pre-operative anaemia clinics. Overall the service runs at a profit to the trust. PMID- 29243333 TI - Psoralea corylifolia L: Ethnobotanical, biological, and chemical aspects: A review. AB - Psoralea corylifolia L. (Leguminosae) is a well-known traditional medicinal plant used from ancient times for treatment of various ailments. It is widely distributed and an important part of therapeutics in Ayurveda and in Chinese medicines. The aim of this review is to present comprehensive and most up to date report on its ethnobotanical, ethnopharmacological, clinical, phytochemical, and side effects. Studies on the ethnobotanical, ethnopharmacological, clinical, phytochemical, and side effects of P. corylifolia were published until year 2017 and were searched using various scientific databases. The scientific literature searched revealed that these plant species has been extensively investigated in vivo and in vitro for various biological and phytochemical studies. It has cardiotonic, vasodilator, pigmentor, antitumor, antibacterial, cytotoxic, and anti-helminthic properties and locally used for alopecia, inflammation, leukoderma, leprosy, psoriasis, and eczema. So far, about a hundred bioactive compounds have been isolated from seeds and fruits, and most important compounds identified belongs to coumarins, flavonoids, and meroterpenes groups. This review article summarized the most updated scientific literature on bioactive phytochemical and biological activities of P. corylifolia. This article will be a useful addition to providing information for future research, and more standard clinical trials are needed for the plant to be used as therapeutic agent. PMID- 29243335 TI - Comparative performance of pharmacogenetics-based warfarin dosing algorithms derived from Caucasian, Asian, and mixed races in Thai population. AB - AIM: This study was conducted to compare predictive accuracy of the available pharmacogenetics (PGx)-guided warfarin dosing algorithms derived from Caucasian, Asian, and mixed population to identify a suitable algorithm for Thai population. METHODS: Ten warfarin dosing algorithms derived from different population including Caucasian, East Asian, South-East Asian, and mixed races were selected and tested with clinical and genetic data of Thai patients. Comparative performances of these algorithms were tested using mean dose error (MDE) between actual warfarin maintenance dose (AWMD) and predicted dose generated by each dosing algorithm, and percentage of ideal dose prediction (IDP). Sensitivity analysis for predictive accuracy was also conducted by stratifying patients into low (AWMD <=21 mg/wk), intermediate (AWMD >21 to <49 mg/wk), and high maintenance dose (AWMD >=49 mg/wk) groups. RESULTS: Data of 165 patients were included for the analyses. Mean actual warfarin dose of the study population was 25.03 +/- 10.53 mg/wk. Large variability of MDE, ranging from -12.11 to 11.24 mg/wk, among algorithms was observed. International Warfarin Pharmacogenetics Consortium, Gage et al, and Ohno et al algorithms had comparable performances to Sangviroon et al algorithm, as observed by MDE of <1 mg/wk with percentage of IDP >=40%. Further sensitivity analyses among patients requiring low and intermediate maintenance doses confirmed such findings with IDP percentage ranging from 37.8% to 59.2%. Among high-dose group, only Ohno et al and Sarapakdi et al algorithms had acceptable performance. CONCLUSIONS: Warfarin PGx-guided dosing algorithms derived from large, mixed population performed comparably to Sangviroon et al algorithm. Certain algorithms should be avoided due to significant dose prediction error. PMID- 29243336 TI - O4 -Alkylated-2-Deoxyuridine Repair by O6 -Alkylguanine DNA Alkyltransferase is Augmented by a C5-Fluorine Modification. AB - Oligonucleotides containing various adducts, including ethyl, benzyl, 4 hydroxybutyl and 7-hydroxyheptyl groups, at the O4 atom of 5-fluoro-O4 -alkyl-2' deoxyuridine were prepared by solid-phase synthesis. UV thermal denaturation studies demonstrated that these modifications destabilised the duplex by approximately 10 degrees C, relative to the control containing 5-fluoro-2' deoxyuridine. Circular dichroism spectroscopy revealed that these modified duplexes all adopted a B-form DNA structure. O6 -Alkylguanine DNA alkyltransferase (AGT) from humans (hAGT) was most efficient at repair of the 5 fluoro-O4 -benzyl-2'-deoxyuridine adduct, whereas the thymidine analogue was refractory to repair. The Escherichia coli AGT variant (OGT) was also efficient at removing O4 -ethyl and benzyl adducts of 5-fluoro-2-deoxyuridine. Computational assessment of N1-methyl analogues of the O4 -alkylated nucleobases revealed that the C5-fluorine modification had an influence on reducing the electron density of the O4 -Calpha bond, relative to thymine (C5-methyl) and uracil (C5-hydrogen). These results reveal the positive influence of the C5 fluorine atom on the repair of larger O4 -alkyl adducts to expand knowledge of the range of substrates able to be repaired by AGT. PMID- 29243337 TI - Actual body weight or perceived body weight? Comment on 'childhood obesity and school absenteeism: a systematic review and meta-analysis'. PMID- 29243338 TI - A partially linear additive model for clustered proportion data. AB - Proportion data with support lying in the interval [0,1] are a commonplace in various domains of medicine and public health. When these data are available as clusters, it is important to correctly incorporate the within-cluster correlation to improve the estimation efficiency while conducting regression-based risk evaluation. Furthermore, covariates may exhibit a nonlinear relationship with the (proportion) responses while quantifying disease status. As an alternative to various existing classical methods for modeling proportion data (such as augmented Beta regression) that uses maximum likelihood, or generalized estimating equations, we develop a partially linear additive model based on the quadratic inference function. Relying on quasi-likelihood estimation techniques and polynomial spline approximation for unknown nonparametric functions, we obtain the estimators for both parametric part and nonparametric part of our model and study their large-sample theoretical properties. We illustrate the advantages and usefulness of our proposition over other alternatives via extensive simulation studies, and application to a real dataset from a clinical periodontal study. PMID- 29243339 TI - Causes and mechanisms of adipocyte enlargement and adipose expansion. AB - Adipose tissue plays a significant role in whole body energy homeostasis. Obesity associated diabetes, fatty liver and metabolic syndrome are closely linked to adipose stress and dysfunction. Genetic predisposition, overeating and physical inactivity influence the expansion of adipose tissues. Under conditions of constant energy surplus, adipocytes become hypertrophic and adipose tissues undergo hyperplasia so as to increase their lipid storage capacity, thereby keeping circulating blood glucose and fatty acids below toxic levels. Nonetheless, adipocytes have a saturation point where they lose capacity to store more lipids. At this stage, when adipocytes are fully lipid-engorged, they express stress signals. Adipose depots (particularly visceral compartments) from obese individuals with a severe metabolic phenotype are characterized by the high proportion of hypertrophic adipocytes. This review focuses on the mechanisms of adipocyte enlargement in relation to adipose fatty acid and cholesterol metabolism, and considers how this may be related to adipose dysfunction. PMID- 29243340 TI - Testicular sperm extraction after laparoscopic orchiectomy for bilateral postpubertal intra-abdominal cryptorchidism: What chance of sperm retrieval? AB - Infertility occurs in up to 54% of men with bilateral undescended testes. Orchiectomy is considered the best therapeutic approach, especially when cryptorchidism is diagnosed in adulthood, due to a high risk of malignancy. A 33 year-old man was referred with a clinical presentation of empty scrotum and an ultrasonography and magnetic resonance imaging evaluation of intra-abdominal bilateral cryptorchidism. Follicle-stimulating hormone was 23.20 IU/L, luteinising hormone was 14.10 IU/L, total testosterone was 12.1 nmol/L, and 17 beta-oestradiol was 0.16 nmol/L. Semen analysis showed absolute azoospermia. Tumour marker levels were in the normal range. Testicular volume was 4.0 ml for right testis and 4.6 ml for left testis. The patient underwent a laparoscopy bilateral orchiectomy and subsequently a testicular sperm extraction (TESE), in the purpose to finding mature spermatozoa. The biological examination revealed the presence of immature sperm cells, not efficient for a cryopreservation. The histologic analyses show a pattern of Sertoli cell-only syndrome and maturation arrest. TESE might be a good option for patients with absolute azoospermia and cryptorchidism, especially if bilateral. The procedure, performed after orchiectomy, is safe and does not have any impact on patient's health, although it is important to clarify the very low potential of sperm recovery. PMID- 29243341 TI - A prospective study of topical carteolol therapy in Chinese infants with superficial infantile hemangioma. AB - BACKGROUND/OBJECTIVE: To report our observations from a trial of the short-term effectiveness and safety of topical carteolol hydrochloride drops to treat infantile hemangiomas (IHs). METHODS: From October 2012 to September 2015, the study recruited 349 children with superficial IHs. Participants were randomized to two groups: treatment (n = 224 who received 2% carteolol hydrochloride drops administered to the lesion surface twice daily) and observation (n = 125 who did not receive treatment). Therapy duration was 6 months. RESULTS: The mean age at the beginning of treatment was 3.2 months. Treatment responses were categorized as class 1 (total regression), class 2 (partial regression or controlled growth), or class 3 (no response). Of infants receiving carteolol treatment, 10.7% (24 patients) were categorized as class 1, 72.3% (162 patients) as class 2, and 17.0% (38 patients) as class 3. Of infants in the observation group, 5.6% (7 patients) were categorized as class 1, 25.6% (32 patients) as class 2, and 68.8% (86 patients) as class 3. No adverse effects were noted during treatment. CONCLUSION: Carteolol is an effective, safe topical treatment for superficial IHs. Carteolol may be used to treat proliferative superficial IHs, particularly in infants younger than 6 months. PMID- 29243342 TI - Achilles' Heel of Lithium-Air Batteries: Lithium Carbonate. AB - The lithium-air battery (LAB) is envisaged as an ultimate energy storage device because of its highest theoretical specific energy among all known batteries. However, parasitic reactions bring about vexing issues on the efficiency and longevity of the LAB, among which the formation and decomposition of lithium carbonate Li2 CO3 is of paramount importance. The discovery of Li2 CO3 as the main discharge product in carbonate-based electrolytes once brought researchers to "the end of the idyll" in the early 2010s. In the past few years, tremendous efforts have been made to understand the formation and decomposition mechanisms of Li2 CO3 , as well as to conceive novel chemical/material strategies to suppress the Li2 CO3 formation and to facilitate the Li2 CO3 decomposition. Moreover, the study on Li2 CO3 in LABs is opening up a new research field in energy technology. Considering the rapid development and innumerous emerging issues, it is timely to recapitulate the current understandings, define the ambiguities and the scientific gaps, and discuss topics of high priority for future research, which is the aim of this Minireview. PMID- 29243343 TI - Health-related quality of life and patient burden in patients with split thickness skin graft donor site wounds. AB - Split-thickness skin grafting is a common procedure to treat different kinds of wounds. This systematic, multicentre, observational, cross-sectional study of adult patients with split-thickness skin graft (STSG) donor site wounds was conducted to evaluate quality of life (QoL) impairments caused by donor site wounds following split-thickness skin grafting. Therefore, 112 patients from 12 wound centres in Germany were examined based on patient and physician questionnaires as well as a physical examination of the donor site wound. Most indications for skin grafting were postsurgical treatment (n = 51; 42.5%) and chronic wounds (n = 47; 39.2%). European QoL visual analoque scale (EQ VAS) averaged 64.7 +/- 23.3, European QoL 5 dimensions (EQ-5D) averaged 77.4 +/- 30.0. Wound-QoL (range: 0-4) was rated 0.8 +/- 0.8 post-surgery and 0.4 +/- 0.6 at the time of survey (on average 21 weeks between the time points). Compared to averaged Wound-QoL scores of chronic wounds donor site-related QoL impairments in split-thickness skin-graft patients were less pronounced. There were significant differences in patient burden immediately after surgery compared to the time of the survey, with medium effect sizes. This supports the hypothesis that faster healing of the donor site wound leads to more favourable patient-reported outcomes. PMID- 29243344 TI - Intensive care survivor-reported symptoms: a longitudinal study of survivors' symptoms. AB - BACKGROUND: There is growing interest in potential long-term outcomes following intensive care, but few researchers have studied the prevalence of multiple symptoms or the association between pain and other symptoms. AIMS: To investigate the prevalence of anxiety, depression, fatigue, sleep disturbance and post traumatic stress symptoms (PTSS) among intensive care survivors 3 months and 1 year after being discharged from an intensive care unit (ICU) and to determine whether pain is associated with higher prevalence of these symptoms 3 months and 1 year after ICU stay. STUDY DESIGN: Exploratory, longitudinal cohort of intensive care survivors from two mixed ICUs in a tertiary referral hospital in Norway. METHODS: Intensive care survivors completed surveys at 3 months (n = 118) and 1 year (n = 89) after ICU discharge. Clinical Trials: NCT02279212. RESULTS: Prevalence rates of intensive care survivors' symptoms were pain 58 (49.2%), anxiety/depression 24/118 (20.8%), fatigue 18/118(15.3%), PTSS 15 (12.8%) and sleep disturbance 58/118 (49.2%) at 3 months after ICU discharge (n = 118). Prevalence rates at 1 year (n = 89) changed only slightly to pain 34 (38.2%), anxiety/depression 17 (20.0%), fatigue 12 (13.8%), PTSS 13 (15.1%) and sleep disturbance 40/89 (46.5%). Associations were strong between pain and presence of sleep disturbance, anxiety/depression, PTSS and fatigue. CONCLUSIONS: Intensive care survivors have multiple symptoms and the prevalence rates of these symptoms remained almost unchanged from 3 months to 1 year after ICU discharge. The presence of pain was associated with high odds for the presence of sleep disturbance, anxiety/depression, PTSS and fatigue, compared to a no-pain group. ICU survivors may benefit from targeted interventions designed to alleviate the symptom burden. RELEVANCE TO CLINICAL PRACTICE: Knowledge about ICU survivor's prevalence and risk for having multiple symptoms may help health care professionals to give better care, if needed, to the ICU survivors. PMID- 29243345 TI - Deoxythymidine-Pterin Fluorescent Adduct Formation through a Photosensitized Process. AB - A new fluorescent compound was isolated from UVA-irradiated aqueous solutions containing pterin (Ptr) and 2'deoxythymidine (dT) in anaerobic conditions. Pterins are widespread in living systems in small amounts, but they are accumulated in some pathological situations. Under UVA radiation, pterins are photochemically active, fluorescent, and photosensitize the generation of singlet oxygen [1 O2 (1 Deltag )]. The isolated compound was structurally characterized by using liquid chromatography coupled to tandem mass spectrometry, and its photophysical properties were studied with the time-correlated single-photon counting technique. The molecular weight and the analysis of the fragmentation correspond to a molecule where the pterinic moiety is attached to the thymine nucleobase. The product exhibits photophysical properties similar to those of Ptr, including relatively high fluorescence and 1 O2 production quantum yields. PMID- 29243346 TI - Hodgkin's variant of Richter's transformation during ibrutinib therapy in a series of CLL patients; the Polish Adult Leukemia Group report (PALG). PMID- 29243348 TI - Mental healthcare staff well-being and burnout: A narrative review of trends, causes, implications, and recommendations for future interventions. AB - Rising levels of burnout and poor well-being in healthcare staff are an international concern for health systems. The need to improve well-being and reduce burnout has long been acknowledged, but few interventions target mental healthcare staff, and minimal improvements have been seen in services. This review aimed to examine the problem of burnout and well-being in mental healthcare staff and to present recommendations for future research and interventions. A discursive review was undertaken examining trends, causes, implications, and interventions in burnout and well-being in healthcare staff working in mental health services. Data were drawn from national surveys, reports, and peer-reviewed journal articles. These show that staff in mental healthcare report poorer well-being than staff in other healthcare sectors. Poorer well-being and higher burnout are associated with poorer quality and safety of patient care, higher absenteeism, and higher turnover rates. Interventions are effective, but effect sizes are small. The review concludes that grounding interventions in the research literature, emphasizing the positive aspects of interventions to staff, building stronger links between healthcare organizations and universities, and designing interventions targeting burnout and improved patient care together may improve the effectiveness and uptake of interventions by staff. PMID- 29243347 TI - Cost-effectiveness of increasing the reach of smoking cessation interventions in Germany: results from the EQUIPTMOD. AB - AIMS: To evaluate costs, effects and cost-effectiveness of increased reach of specific smoking cessation interventions in Germany. DESIGN: A Markov-based state transition return on investment model (EQUIPTMOD) was used to evaluate current smoking cessation interventions as well as two prospective investment scenarios. A health-care perspective (extended to include out-of-pocket payments) with life time horizon was considered. A probabilistic analysis was used to assess uncertainty concerning predicted estimates. SETTING: Germany. PARTICIPANTS: Cohort of current smoking population (18+ years) in Germany. INTERVENTIONS: Interventions included group-based behavioural support, financial incentive programmes and varenicline. For prospective scenario 1 the reach of group-based behavioral support, financial incentive programme and varenicline was increased by 1% of yearly quit attempts (= 57 915 quit attempts), while prospective scenario 2 represented a higher reach, mirroring the levels observed in England. MEASUREMENTS: EQUIPTMOD considered reach, intervention cost, number of quitters, quality-of-life years (QALYs) gained, cost-effectiveness and return on investment. FINDINGS: The highest returns through reduction in smoking-related health-care costs were seen for the financial incentive programme (?2.71 per ?1 invested), followed by that of group-based behavioural support (?1.63 per ?1 invested), compared with no interventions. Varenicline had lower returns (?1.02 per ?1 invested) than the other two interventions. At the population level, prospective scenario 1 led to 15 034 QALYs gained and ?27 million cost-savings, compared with current investment. Intervention effects and reach contributed most to the uncertainty around the return-on-investment estimates. At a hypothetical willingness-to-pay threshold of only ?5000, the probability of being cost effective is approximately 75% for prospective scenario 1. CONCLUSIONS: Increasing the reach of group-based behavioural support, financial incentives and varenicline for smoking cessation by just 1% of current annual quit attempts provides a strategy to German policymakers that improves the population's health outcomes and that may be considered cost-effective. PMID- 29243350 TI - Maternal history of recurrent pregnancy loss is associated with increased risk for long-term pediatric gastrointestinal morbidity in the offspring. AB - PROBLEM: Recurrent pregnancy loss (RPL) potentially involves an abnormal maternal inflammatory response. We investigated whether children of mothers with a history of RPL are at an increased risk for childhood gastrointestinal (GI) morbidity, with a specific focus on inflammatory bowel diseases (IBD). METHOD OF STUDY: A population-based cohort analysis comparing the risk for long-term GI morbidity in children born to mothers with and without a history of RPL. Gastrointestinal (GI) morbidity included hospitalizations involving a pre-defined set of ICD-9 codes. RESULTS: During the study period, 242 186 newborns met the inclusion criteria; 5% of which were offspring to mothers with a history of RPL. Gastrointestinal morbidity was significantly more common in the RPL group (6.6% vs 5.3%). Specifically, offspring to mothers with a history of RPL had significantly higher rates of IBD (2.1% vs 1.7%). CONCLUSION: Maternal history of RPL is associated with an increased risk for pediatric GI morbidity in the offspring. PMID- 29243349 TI - Autosomal recessive primary microcephaly due to ASPM mutations: An update. AB - Autosomal recessive microcephaly or microcephaly primary hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The abnormal spindle-like microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster "abnormal spindle" gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological, and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities. PMID- 29243352 TI - A review on gradient hydrogel/fiber scaffolds for osteochondral regeneration. AB - Osteochondral tissue regeneration is a complicated field due to the distinct properties and healing potential of osseous and chondral phases. In a natural osteochondral region, the composition, mechanics, and structure vary smoothly from bony to cartilaginous phase. Therefore, a homogeneous scaffold cannot satisfy the complexity of the osteochondral matrix. In essence, a natural extracellular matrix is composed of fibrous proteins elongated into a gelatinous background. A hydrogel/fiber scaffold possessing gradient in both phases would be of the utmost interest to imitate tissue arrangement of a native osteochondral interface. However, there are limited research works that exploit hydrogel/fiber scaffolds for osteochondral restoration. In the present review, currently used fibrous or gelatinous scaffolds for osteochondral damages are discussed. Moreover, superiority of using gradient hydrogel/fiber composites for osteochondral regeneration and practical approaches to develop those scaffolds is debated. PMID- 29243351 TI - Is it cost-effective to provide internet-based interventions to complement the current provision of smoking cessation services in the Netherlands? An analysis based on the EQUIPTMOD. AB - BACKGROUND AND AIM: The cost-effectiveness of internet-based smoking cessation interventions is difficult to determine when they are provided as a complement to current smoking cessation services. The aim of this study was to evaluate the cost-effectiveness of such an alternate package compared with existing smoking cessation services alone (current package). METHODS: A literature search was conducted to identify internet-based smoking cessation interventions in the Netherlands. A meta-analysis was then performed to determine the pooled effectiveness of a (web-based) computer-tailored intervention. The mean cost of implementing internet based interventions was calculated using available information, while intervention reach was sourced from an English study. We used EQUIPTMOD, a Markov-based state-transition model, to calculate the incremental cost-effectiveness ratios [expressed as cost per quality-adjusted life years (QALYs) gained] for different time horizons to assess the value of providing internet-based interventions to complement the current package.). Deterministic sensitivity analyses tested the uncertainty around intervention costs per smoker, relative risks, and the intervention reach. RESULTS: Internet-based interventions had an estimated pooled relative risk of 1.40; average costs per smoker of ?2.71; and a reach of 0.41% of all smokers. The alternate package (i.e. provision of internet-based intervention to the current package) was dominant (cost-saving) compared with the current package alone (0.14 QALY gained per 1000 smokers; reduced health-care costs of ?602.91 per 1000 smokers for the life-time horizon). The alternate package remained dominant in all sensitivity analyses. CONCLUSION: Providing internet-based smoking cessation interventions to complement the current provision of smoking cessation services could be a cost-saving policy option in the Netherlands. PMID- 29243353 TI - First in human evaluation of the vascular biocompatibility and biomechanical performance of a novel ultra high molecular weight amorphous PLLA bioresorbable scaffold in the absence of anti-proliferative drugs: Two-year imaging results in humans. AB - OBJECTIVES: In this first-in-human study, we prospectively studied the vascular compatibility and mechanical performance of a novel bare ultra-high molecular weight amorphous PLLA bioresorbable scaffold (BRS, FORTITUDE(r), Amaranth Medical, Mountain View, California) up to two years after implantation using multimodality imaging techniques. BACKGROUND: The vascular biocompatibility of polymers used in BRS has not been fully characterized in the absence of anti proliferative drugs. METHODS: A total of 10 patients undergoing single scaffold implantation were included in the final analysis and were followed up using optical coherence tomography (OCT) at 2-years. All devices were implanted under angiographic and intravascular ultrasound (IVUS) guidance. Angiographic and IVUS follow up was performed at 6 months. Additionally, angiography and OCT imaging were performed at 2-years. RESULTS: At 6 months, mean intra-scaffold angiographic MLD slightly decreased from baseline procedural values. However, at 2 years, mean angiographic MLD increased (post procedure; 2.9 [2.7, 3.1] mm vs. 6 months; 2.1 [1.6, 2.5] vs. 2 years; 2.4 [2.1, 2.6], P = .001). Also, angiographic percent diameter stenosis decreased and late lumen gain increased between 6 months and 2 years follow up. Mean neointimal hyperplasia volume assessed by IVUS at 6 months was 26% [15.2, 29.3]. At 2 years OCT follow up neointimal hyperplasia volume was 24.2% [19.4, 28.9]. No presence of neoatherosclerosis was identified in any of the analyzed cases. CONCLUSION: At 2 years, this novel PLLA-based BRS induced expansive vascular remodeling from 6 to 24 months, a biological phenomenon that appears to be independent of the presence of anti-proliferative drugs. PMID- 29243354 TI - Effectiveness of extended contact interventions for weight management delivered via text messaging: a systematic review and meta-analysis. AB - BACKGROUND: Extended contact interventions provide support for continued weight management (weight loss/prevention of weight regain) following a weight loss intervention. Text messages offer a medium for delivery in a potentially cost effective, broad-reach manner. OBJECTIVES: This study aims to examine (i) the effectiveness of extended contact, text message interventions for adults in supporting weight management, and (ii) which intervention characteristics are common to those that are effective. METHODS: A systematic database search (to 19 September 2016) was conducted. Meta-analyses were performed to quantify the average weight changes (kg) during the extended contact intervention, net of control (if a control group was present) and within-group. RESULTS: Seven studies were eligible for inclusion. The pooled effect of the extended contact intervention compared with control (n = 3 studies) was -0.82 kg (95% confidence interval -1.43, -0.21), while the pooled within-group weight loss (n = 6 studies) during the extended contact interventions was -2.16 kg (95% confidence interval 3.40, -0.91). Interventions considered 'effective' (n = 4) were more likely to be >12 weeks duration, compared with interventions considered 'ineffective' (n = 3). CONCLUSION: Evidence from the small number of studies reviewed suggests that extended contact, text message-delivered interventions are effective. Further research is required to elucidate effective intervention components and the longer-term impact on weight, diet and physical activity behaviour. PMID- 29243355 TI - Practitioners' perspectives on community-based breast cancer survivorship care in Singapore: A focus group study. AB - With the long-term goal of optimising the delivery of breast cancer survivorship care in Singapore, we conducted a qualitative study to gather in-depth descriptions from community practitioners (general practitioners and community pharmacists) about their perceptions of community-based cancer survivorship care in Singapore. Sixteen participants (11 general practitioners and five community pharmacists) participated in four structured focus group discussions between August and November 2016. The focus group discussions were analysed using deductive content analysis. The majority of community practitioners do not encounter breast cancer survivors in their clinical practices. Perceived barriers to community-based survivorship care include patients' lack of confidence in primary care, financial constraints and lack of empanelment. Most community practitioners concur that the success of community-based survivorship care largely depends on the co-operation and participation of survivors. Survivorship management via standardised care pathways is not fully advocated by practitioners. Survivorship care plans are identified as useful, but they should also incorporate a non-cancer-related medical history and medication list. Community practitioners in Singapore are eager to participate in the delivery of cancer survivorship care. Future studies should develop a community-based care model that involves community practitioners and evaluate the cost-effectiveness of such a care model. The current model of cancer survivorship in Singapore is not sustainable. Differences in healthcare ecosystems, cultures and resources available in an Asian context should be taken into consideration before designing a community-based cancer survivorship program in Singapore. PMID- 29243357 TI - BJOG Editor-in-Chief number 8: James Young 1943-1963. PMID- 29243356 TI - Turning frequency in adult bedridden patients to prevent hospital-acquired pressure ulcer: A scoping review. AB - The aim of this study was to identify current research on turning frequencies of adult bed-bound patients and inform future turning practices for hospitals based on evidence-based practice. We undertook a scoping review framework that provided a transparent and systematic methodology using 8 electronic databases (CINAHL, PubMed, Cochrane Library, ScienceDirect, PsycINFO, Scopus, ProQuest, and Web of Science) to identify articles published from 2000 to 2016. Articles were included if they focused on the prevention of hospital-acquired pressure ulcers related to the frequency of turning or repositioning of bed-bound patients. Literature search and data extraction were performed independently by 3 authors. The study followed the PRISMA guidelines. In total, 911 articles were identified, of which 10 were eligible. Of the eligible articles, 8 studies could not reach a conclusion on the effective frequency of turning and duration for repositioning patients to prevent the development of pressure ulcers. Only 2 studies found significant differences among the intervention and control groups. Results regarding turning and repositioning schedules are inconclusive; however, the topic needs further exploration to improve the outdated guidelines surrounding pressure ulcer prevention. This may, in turn, make the work of nurses more efficient and make treatment cost-effective for both the patients and the hospitals. PMID- 29243360 TI - Pelvic endometriosis: will centralisation of services improve patient care? PMID- 29243359 TI - Healthcare professionals should be actively involved in gender violence reduction: political consensus emerges in Spain. PMID- 29243361 TI - Authors' reply re: Immediate versus delayed initiation of the levonorgestrel releasing intrauterine system following medical termination of pregnancy - 1-year continuation rates: a randomised controlled trial. PMID- 29243362 TI - Effect of fructo-oligosaccharides on nutrient digestibility and digesta retention time in adult guinea pigs. AB - A previous study suggested that addition of fructo-oligosaccharides (FOS) to the diet improved nitrogen (N) utilization and decreased acid detergent fiber (ADF) digestibility in guinea pigs. The present study was conducted to clarify the relationship between ADF digestibility and gastrointestinal mean retention time (MRT) in guinea pigs under FOS supplementation. Adult male guinea pigs were fed a commercial diet (50 g/day) with either 5% glucose (glucose group) or 5% FOS (FOS group) for 12 days in individual metabolism cages. Unlike the glucose group, N utilization improved, but ADF digestibility significantly (P < 0.05) decreased in the FOS group. MRT of solid digesta also significantly (P < 0.05) decreased in the FOS group compared with that in the glucose group. We concluded that reduction of MRT of solid digesta containing FOS decreased ADF digestibility in guinea pigs. PMID- 29243363 TI - Surfacing and addressing hospitalized patients' needs: Proactive nurse rounding as a tool. AB - AIMS: This paper reports on rounding interventions employed at high performing hospitals, and provides three case studies on how proactive nurse rounding was successfully implemented to improve patient-centredness. BACKGROUND: Proactive nurse rounding is a popular form of rounding that has shown promise for improving patient outcomes, yet, little evidence exists on how to implement it successfully. METHODS: We identified high-performing hospitals in the domains of staff responsiveness and nurse communications in the Hospital Consumer Assessment of Health Providers and Systems survey nationally, and conducted case studies at three of these hospitals exploring their implementation of proactive nurse rounding. We partnered with leaders from these hospitals to describe the associated challenges and lessons learned. RESULTS: Twenty-six high performing hospitals in the domains of staff responsiveness and/or nurse communication were identified. The majority of nursing units reported proactive nurse rounding as their main rounding intervention (96%). CONCLUSIONS: Proactive rounding interventions are a feasible approach to help surface and address hospitalized patients' needs in a timely manner. IMPLICATIONS FOR NURSING MANAGEMENT: The information and tools provided in this paper build upon the learning from high performing hospitals' experiences and are useful to nurse leaders in their efforts to improve the patient-centeredness in the hospital. PMID- 29243364 TI - Perceived needs of carers of people with psychosis: An Australian longitudinal population-based study of caregivers of people with psychotic disorders. AB - Studies have documented the perceived needs of carers of people with psychosis but most recruitment has utilised convenience sampling resulting in limited understanding of carers' needs. This longitudinal study was conducted within the second Australian prevalence study of psychosis, aiming to obtain generalisable findings regarding perceived needs of carers of people with psychosis. Semi structured interviews were conducted with 98 carers of people with psychosis recruited in the Australian prevalence study of psychosis. Seventy-eight of the carers were reinterviewed 1 year later to measure changes in their perceived needs. Correlational and paired T tests were conducted to identify relationships between perceived needs and carer's health and well-being, and changes in levels of perceived needs over time. Qualitative responses were structurally coded by segmentation according to the Carers' and Users' Expectations of Services-Carer version. Thematic analysis of common words and phrases was undertaken to identify key themes concerning carers' perceived needs. There was minimal improvement in carers' perceived needs over time and their needs were closely related to their perception of their own social connectedness, psychological health and quality of life. Five themes were identified: Greater involvement of carers in the treatment plan, provision of relevant information to carers, multiple biopsychosocial support for carers, well-being and independence interventions for people with psychosis, and choice to care and alternate caring arrangements. Although policy recognises the need to support carers, findings show that focused interventions are required to address carers' perceived needs more holistically in current mental health services. To support carers' recovery, services need to include carers in treatment planning, and consider ways to address their needs and improve their own health and well-being. PMID- 29243365 TI - Vitamin A-coupled liposome system targeting free cholesterol accumulation in hepatic stellate cells offers a beneficial therapeutic strategy for liver fibrosis. AB - AIM: Liver fibrosis is a life-threatening disorder for which no approved therapy is available. Recently, we reported that mouse hepatic stellate cell (HSC) activation increased free cholesterol (FC) accumulation, partly by enhancing signaling through sterol regulatory element-binding protein 2 (SREBP2) and microRNA-33a (miR-33a), which resulted in HSC sensitization to transforming growth factor-beta (TGFbeta)-induced activation in a "vicious cycle" of liver fibrosis. METHODS: Human HSCs were isolated from surgical liver specimens from control patients and patients with liver fibrosis. C57BL/6 mice were treated with carbon tetrachloride for 4 weeks and concurrently given SREBP2-siRNA- or anti-miR 33a-bearing vitamin A-coupled liposomes. RESULTS: In human activated HSCs obtained from patients with liver fibrosis, FC accumulation was enhanced independently of serum cholesterol levels through increased signaling by both SREBP2 and miR-33a. This increased FC accumulation enhanced Toll-like receptor 4 (TLR4) protein levels and lowered the TGFbeta-pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor) mRNA levels in HSCs. Notably, in a mouse liver fibrosis model, reduction of FC accumulation, specifically in activated HSCs by suppression of SREBP2 or miR-33a expression using SREBP2-siRNA- or anti-miR-33a-bearing vitamin A-coupled liposomes, downregulated TLR4 signaling, increased Bambi expression, and consequently ameliorated liver fibrosis. CONCLUSIONS: Our results suggest that FC accumulation in HSCs, as an intracellular mediator promoting HSC activation, contributes to a vicious cycle of HSC activation in human and mouse liver fibrosis independent of serum cholesterol levels. Targeting FC accumulation-related molecules in HSCs through a vitamin A-coupled liposomal system represents a favorable therapeutic strategy for liver fibrosis. PMID- 29243366 TI - ENG mutational mosaicism in a family with hereditary hemorrhagic telangiectasia. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder caused by mutations in ENG, ACVRL1, or SMAD4. Around 90% of HHT patients present with a heterozygous pathogenic genetic variation. Almost all cases of HHT have a family history. Very few cases are de novo or mosaicism. We describe a case with mutational mosaicism that would not be observed in the clinical routine when using Sanger sequencing or a NGS read coverage below app. 100. METHODS: DNA was extracted from peripheral blood leukocytes, and buccal swabs. The coding region, exon-intron boundaries, and the flanking sequences of the genes were sequenced by NGS. RESULTS: The proband had clinical HHT fulfilling the Curacao criteria and genetic testing identified a frameshift mutation in ENG. The mother of the proband, also with clinical HHT, was found negative when analyzing DNA from blood for the familial mutation using Sanger sequencing. Analyzing her DNA by NGS HHT panel sequencing when extracted from both peripheral blood leukocytes, and cheek swabs, identified the familial ENG mutation at low levels. CONCLUSION: We provide evidence of ENG mutational mosaicism in an individual presenting with clinical HHT. These findings illustrate the importance of considering mutational mosaicism. PMID- 29243367 TI - Vaccinations are not associated with inhibitor development in boys with severe haemophilia A. AB - BACKGROUND: Inhibitor development in previously untreated patients (PUPs) with severe haemophilia A is a multifactorial event. It is unknown whether paediatric vaccinations given in close proximity to factor VIII (FVIII) are associated with inhibitor development. OBJECTIVE: To assess whether paediatric vaccinations in close proximity to FVIII within the first 75 exposure days (EDs) are associated with inhibitor development in PUPs with severe haemophilia A. METHODS: We included 375 PUPs with severe haemophilia A (<0.01 IU/mL) from the PedNet Registry who had received vaccinations between the first and 75th ED or inhibitor development. Inhibitor risk was compared between patients who did and who did not receive vaccinations within 24, 72 or 120 hours of FVIII infusion. Unadjusted and adjusted hazard ratios were calculated for any or repeated vaccinations in close proximity to FVIII, using Cox regression. RESULTS: Inhibitor development occurred in 77 of 375 patients (20.5%). Overall inhibitor development appeared similar or lower in patients receiving vaccinations in close proximity to FVIII as compared to patients receiving vaccinations without FVIII: for 24 hours, this was 19.2% and 21.4% (P = .186), for 72 hours, 16.4% and 27.3% (P = .023) and for 120 hours, 18.3% and 25.0% (P = .085), respectively. CONCLUSION: We found no association between vaccinations given in close proximity to FVIII exposure within the first 75 EDs and inhibitor development. Our data do not support avoiding administration of FVIII at time of routine vaccinations. PMID- 29243368 TI - A 2000 patient retrospective assessment of a new strategy for burn wound management in view of infection prevention and treatment. AB - Infections in burn patients are still the principal cause of complications in burn injuries. The aim of this study is to assess a new strategy for burn wound management in view of infection prevention and treatment in the experience of the Burn Treatment Center in Siemianowice Slaskie. The applied methodology involved the analysis of patient records describing the hospital's epidemiological situation between 2014 and 2016. The analysis also included the use and cost of antibiotics, silver-containing dressings, and other antiseptics relative to the number of sepsis cases, including those caused by Pseudomonas aeruginosa, as well as the mortality ratio. The total costs of prevention and treatment of infections were reduced, while the use of silver-containing dressings and antiseptics increased. The number of patients with sepsis decreased, including cases caused by P. aeruginosa, and the mortality ratio was reduced. Introducing a strategy for burn wound-oriented infection prevention and treatment in burn patients provides a number of benefits. It is also cost-effective. Using locally applied active dressings and antiseptics can be a welcome choice for often-unnecessary antibiotic therapy of a suspected or existing burn wound infection. PMID- 29243369 TI - Burden of influenza, respiratory syncytial virus, and other respiratory viruses and the completeness of respiratory viral identification among respiratory inpatients, Canada, 2003-2014. AB - BACKGROUND: A regression-based study design has commonly been used to estimate the influenza burden; however, these estimates are not timely and many countries lack sufficient virological data. Alternative approaches that would permit a timelier assessment of the burden, including a sentinel surveillance approach recommended by the World Health Organization (WHO), have been proposed. We aimed to estimate the hospitalization burden attributable to influenza, respiratory syncytial virus (RSV), and other respiratory viruses (ORV) and to assess both the completeness of viral identification among respiratory inpatients in Canada and the implications of adopting other approaches. METHODS: Respiratory inpatient records were extracted from the Canadian Discharge Abstract Database from 2003 to 2014. A regression model was used to estimate excess respiratory hospitalizations attributable to influenza, RSV, and ORV by age group and diagnostic category and compare these estimates with the number with a respiratory viral identification. RESULTS: An estimated 33 (95% CI: 29, 38), 27 (95% CI: 22, 33), and 27 (95% CI: 18, 36) hospitalizations per 100 000 population per year were attributed to influenza, RSV, and ORV, respectively. An influenza virus was identified in an estimated 78% (95% CI: 75, 81) and 17% (95% CI: 15, 21) of respiratory hospitalizations attributed to influenza for children and adults, respectively, and 75% of influenza-attributed hospitalizations had an ARI diagnosis. CONCLUSIONS: Hospitalization rates with respiratory viral identification still underestimate the burden. Approaches based on acute respiratory case definitions will likely underestimate the burden as well, although each proposed method should be compared with regression-based estimates of influenza-attributed burden as a way of assessing their validity. PMID- 29243371 TI - American Board of Prosthodontics. PMID- 29243370 TI - Neurological, nutritional and alcohol consumption factors underlie cognitive and motor deficits in chronic alcoholism. AB - Variations in pattern and extent of cognitive and motor impairment occur in alcoholism (ALC). Causes of such heterogeneity are elusive and inconsistently accounted for by demographic or alcohol consumption differences. We examined neurological and nutritional factors as possible contributors to heterogeneity in impairment. Participants with ALC (n = 96) and a normal comparison group (n = 41) were examined on six cognitive and motor domains. Signs of historically determined subclinical Wernicke's encephalopathy were detected using the Caine et al. criteria, which were based on postmortem examination and chart review of antemortem data of alcoholic cases with postmortem evidence for Wernicke's encephalopathy. Herein, four Caine criteria provided quantification of dietary deficiency, cerebellar dysfunction, low general cognitive functioning and oculomotor abnormalities in 86 of the 96 ALC participants. Subgroups based on Caine criteria yielded a graded effect, where those meeting more criteria exhibited greater impairment than those meeting no to fewer criteria. These results could not be accounted for by history of drug dependence. Multiple regression indicated that compromised performance on ataxia, indicative of cerebellar dysfunction, predicted non-mnemonic and upper motor deficits, whereas low whole blood thiamine level, consistent with limbic circuit dysfunction, predicted mnemonic deficits. This double dissociation indicates biological markers that contribute to heterogeneity in expression of functional impairment in ALC. That non-mnemonic and mnemonic deficits are subserved by the dissociable neural systems of frontocerebellar and limbic circuitry, both commonly disrupted in ALC, suggests neural mechanisms that can differentially affect selective functions, thereby contributing to heterogeneity in pattern and extent of dysfunction in ALC. PMID- 29243373 TI - How Dentists Read a Technique Article: A Grounded Theory Investigation. AB - PURPOSE: To conduct an empirical investigation using qualitative techniques of the way dentists engage in the process of reading a technique-oriented journal article and what they pay attention to in the process. MATERIALS AND METHODS: Grounded theory was used to identify how dentists read an article describing the fabrication of an interim prosthesis in the esthetic zone. Twenty-one experienced practitioners were videotaped, and their verbatim reflections were coded. The sequence of attending to various features of the paper was noted. RESULTS: Ninety five percent of readers voiced specific, multiple attempts to identify or refine the main purpose of the article as they processed the material. All readers engaged in various activities to navigate through the article, including skipping and backtracking, and none "read" the article straight through. All readers also made repeated observations about the relevance of the technique to their personal practice situation. Eighty percent used some form of "distancing," whereby the content and value of the article were accepted, but the reader reserved the privilege of not being bound by the results because of technical, sponsorship, or methodological issues that "might be present." The quality of photographs was accepted as a proxy for the quality of technical work performed. CONCLUSIONS: Dentists actively customized the reading of a journal article that described a technical procedure. They imposed a non-linear structure for absorbing information and a standard of personal relevance, and, while accepting the results, created reasons for not necessarily having to accept them as applicable. The approach clinicians use in reading a procedural article may be different from the structure writers use in preparing a paper. PMID- 29243374 TI - Molecular classification of autofluorescence excision margins in oral potentially malignant disorders. AB - OBJECTIVE: To define molecular differences between autofluorescence and white light defined excision margins in oral potentially malignant disorders (OPMD) using transcriptome expression profiles. MATERIALS AND METHODS: Excisional biopsy specimens were taken from 11 patients at three different sites for each lesion: centre, white light margin and autofluorescence margin. The lesions were diagnosed histopathologically as oral epithelial dysplasia, oral lichenoid dysplasia, oral lichen planus or other. Transcriptome analysis was performed by RNA sequencing, hierarchical clustering, differential expression and biological pathway analysis. RESULTS: For hierarchical clustering, the samples broadly clustered according to histology rather than the margins with lichenoid samples clustering together. Differential expression analysis showed that independent of histology, there was greater molecular dysregulation between the lesion centre and autofluorescence margin compared to the lesion centre and white light margin. Furthermore, the autofluorescence and white light margins were molecularly distinct, indicating the white light margins harboured abnormality. CONCLUSION: Our results indicate that the molecular profile of OPMD changes with divergence away from the centre of the lesion, and that autofluorescence determined margins are superior to the white light margin in achieving a clear molecular margin when excising an OPMD. PMID- 29243375 TI - Parental experiences and perceptions of infant complementary feeding: a qualitative evidence synthesis. AB - BACKGROUND: Interventions to prevent childhood obesity increasingly focus on infant feeding, but demonstrate inconsistent effects. A comprehensive qualitative evidence synthesis is essential to better understand feeding behaviours and inform intervention development. The aim of this study is to synthesize evidence on perceptions and experiences of infant feeding and complementary feeding recommendations. METHODS: Databases CINAHL, EMBASE, MEDLINE, PsycINFO, Academic Search Complete, SocIndex and Maternity and Infant Care were searched from inception to May 2017. Eligible studies examined parents' experiences of complementary feeding of children (<2 years). Data were synthesized using thematic synthesis. RESULTS: Twenty-five studies met inclusion criteria for review. Four key themes emerged. 'Guidelines and advice' highlights variety and inconsistencies between sources of complementary feeding information. 'Stage of weaning' describes infant feeding as a process involving different stages. 'Knowing and trying' outlines parents' engagement in feeding approaches based on instinct, prior experience or trial and error. 'Daily life' highlights problematic cost and time constraints for parents. DISCUSSION: Parents predominantly understand and want to engage in healthy feeding processes. Consideration of infant feeding as a process that changes over time is necessary to support parents. Provision of clear, consistent information and guidance from trusted sources on when, what and how to feed is also essential. PMID- 29243376 TI - Comparison of the three waves of avian influenza A(H7N9) virus circulation since live poultry markets were permanently closed in the main urban areas in Zhejiang Province, July 2014-June 2017. AB - BACKGROUND: The sudden increase in the number of human cases infected with avian influenza A(H7N9) virus after September 2016 raised global concern. OBJECTIVES: To assess the changes in epidemiological characteristics of H7N9 cases since the massive closure of live poultry markets (LPMs) in the main urban areas in Zhejiang province. METHODS: We used descriptive statistics to compare epidemiological characteristics of the three distinct waves of H7N9 cases in Zhejiang province. The rural or urban cases were defined according to the location where the patients had exposure within 2 weeks before illness onset. RESULTS: Between July 2014 and June 2017, 166 H7N9 cases were reported in Zhejiang province, with 45, 34, and 87 cases reported in the third, fourth, and fifth wave, respectively. Across the three waves, most reported cases were from rural areas. A similar percentage of cases in all three waves reported exposure to LPMs, raising poultry at home or around the house, as well as occupational exposure. Compared to the third (80.00%) and fourth wave (70.59%), a significantly larger proportion of cases from the non-LPMs closure areas were observed in the fifth wave (89.66%) (P = .034). CONCLUSION: Epidemiological characteristics of human cases infected with avian influenza A(H7N9) virus had generally remained unchanged since the massive closure of LPMs in the main urban area of Zhejiang province. The sudden increase in the number of H7N9 cases in the fifth wave was mainly attributed to the excessive cases reported from areas where LPMs were not permanently closed. PMID- 29243377 TI - Mindfulness in nursing students: The five facet mindfulness questionnaire in samples of nursing students in China, the Philippines, and South Africa. AB - Mindfulness as a clinical strategy for helping manage physical and psychological symptoms is gathering an impressive evidence base. It is also being embraced widely for personal and professional development. As a therapeutic intervention for nurses working across a spectrum of settings, it helps expand practice, and integrating mindfulness in nursing undergraduate and graduate curricula is imminent. In the present study, we outline the development and measurement of mindfulness as a personality trait and therapeutic intervention, and advocate the use of a questionnaire alternative to expensive and impractical laboratory measures. The aims of the present study were to examine and compare the use and reliability of the Five Facet Mindfulness Questionnaire (FFMQ) in samples of nursing students from South Africa, China, and the Philippines, and compare the findings in the nursing student samples to other student and non-student samples. Three samples of students of nursing from China (n = 193), the Philippines (n = 243), and South Africa (n = 131) completed the 31-item FFMQ. The internal consistency was acceptable, and the correlations were significant among all facets and the total score. Although the total mean scores between the three samples were not significantly different, there were significant and interesting differences in the facet scores, and these are discussed in the light of likely cultural influences, and comparative data from other samples of students and clinical populations. The instrument shows promise for future use in educational research as a tool for curriculum change, for personal and professional development of nurses, and as a clinical tool for determining mindfulness changes over time. PMID- 29243378 TI - Reading Research and Practice: Indian Perspective. AB - The authors outline the basic structure of akshara, the basic unit of writing in Indic writing systems used widely in South and Southeast Asia; present preliminary studies relating to reading, assessment, and instruction of akshara; and outline recommendations for future studies. PMID- 29243380 TI - Neurolinguistic Studies of Reading in Chinese. AB - Using the Chinese writing system, which is unique with respect to the composition of each character in terms of its graphic shape, as an example, this chapter addresses the neurobiological underpinnings of reading and writing and how these brain circuits are used in different languages. PMID- 29243379 TI - Cultural Adaptation of a Neurobiologically Informed Intervention in Local and International Contexts. AB - The relationship between early adversity and numerous negative outcomes across the lifespan is evident in a wide range of societies and cultures (e.g., Pakulak, Stevens, & Neville, 2018). Among the most affected neural systems are those supporting attention, self-regulation, and stress regulation. As such, these systems represent targets for neurobiologically informed interventions addressing early adversity. In prior work with monolingual native English-speaking families, we showed that a two-generation intervention targeting these systems in families improves outcomes across multiple domains including child brain function for selective attention (for detail, see Neville et al., 2013). Here, we discuss the translation and cultural adaptation (CA) of this intervention in local and international contexts, which required systematic consideration of cultural differences that could affect program acceptability. First, we conducted a translation and CA of our program to serve Latino families in the United States using the Cultural Adaptation Process (CAP), a model that works closely with stakeholders in a systematic, iterative process. Second, to implement the adapted program in Medellin, Colombia, we conducted a subsequent adaptation for Colombian culture using the same CAP. Our experience underscores the importance of consideration of cultural differences and a systematic approach to adaptation before assessing the efficacy of neurobiologically informed interventions in different cultural contexts. PMID- 29243381 TI - State of Early Child Development Research, Practice, and Policy for Most Vulnerable Children: A Global Perspective. AB - Interventions to enhance development of children ages 0-6 have profound benefits for children, families, and societies. The benefits are well documented, recognized internationally, and supportive of policies and programs targeting early child development (ECD). Intervening in the early years is a critical first step toward alleviating poverty, reducing inequality, and ensuring a productive workforce for the global economy. The challenges presented by the almost 250 million at-risk children in low- and middle-income countries and the main obstacles to investing in ECD demand a paradigm shift in social policy and an action agenda integrated with the world's sustainable development goals for 2030. There are four main tasks and three essential building blocks for ECD action. PMID- 29243382 TI - Bringing the Bottom Billion into Basic Literacy: How We Can and Why We Must. AB - Close to one billion people in the world do not have basic literacy skills. A key challenge is reaching children in the midst of circumstances that make a traditional school-based approach impractical. This chapter will describe a cross disciplinary, mobile technology approach to literacy education. The Curious Learning approach distributes research-based, English literacy content on mobile devices to children without access to an adequate school. The software platform is equipped with data collection tools to measure usage patterns and literacy outcomes. Results indicate that regular access resulted in higher early literacy skills. Future efforts will focus on adapting this approach in the languages spoken in the homes of the children. PMID- 29243383 TI - Global Approaches to Early Learning Research and Practice: An Introduction. AB - This chapter introduces the issue, highlighting the importance of early childhood development and learning. PMID- 29243385 TI - Assessing the Impact of Early Learning Programs in Africa. AB - We present results from early learning programs in six African countries: Ethiopia, Kenya, Liberia, Malawi, Tanzania, and Uganda. In partnership with ministries of education, RTI International has worked within government systems to support the design and deployment of locally contextualized materials, training, and assessment tools, with the goal of improving outcomes for early learners in primary schools, and in Kenya and Tanzania preprimary as well. Here we report on the experience and evidence of impact from specific programs in each country, including summary assessment results when available. In several countries with completed impact evaluations, there are significant and important learning gains of between 0.2 and 2.57 SD in effect size; in one case the percentage of students reaching grade-level reading proficiency increased from 12% to 47%. In the context of increased urgency surrounding what UNESCO has called a "global learning crisis," these experiences provide useful lessons for policymakers and practitioners alike. PMID- 29243384 TI - Poverty's Impact on Children's Executive Functions: Global Considerations. AB - Poverty detrimentally affects child executive function (EF), a subset of cognitive abilities implicated in reading and other achievement outcomes. Consequently, research has focused on understanding explanatory and mediating mechanisms in this association. This research, however, has mainly involved populations from Western, high-income countries. Children from low- and middle income countries comprise a significant proportion of the world's population and are at additional risk for poor EF as a result of a more disadvantaged context. The present review examines global work on poverty and EF to highlight important cross-national similarities and differences. Findings suggest a global association between poverty and EF and point to cognitive stimulation and environmental enrichment as common mediating variables that may also be moderators and targets for intervention. However, findings also underscore the need to consider the sociocultural context of countries when examining impacts of parenting, schooling, and other metrics. Research and intervention implications are discussed. PMID- 29243386 TI - Global Approaches to Early Learning Research and Practice: Integrative Commentary. AB - This commentary presents highlights from the seven articles in this volume, along with a synthesis of take-home points that can be used to inform policy and practice. Across each article there is a story of both successes and the challenges of ongoing work that seeks to enhance children's development in diverse and challenging environments across the globe. Although the topics covered in this volume range from development of early self-regulation and executive function to the use of technology to aid literacy acquisition in remote areas, each points to the need for systems-level coordination and sustained commitment to reach children at risk. PMID- 29243387 TI - Investigation of Cryptococcus neoformans magnesium transporters reveals important role of vacuolar magnesium transporter in regulating fungal virulence factors. AB - Cryptococcus neoformans is an important opportunistic fungal pathogen in humans. Recent studies have demonstrated that metals are critical factors for the regulation of fungal virulence in hosts. In this study, we systemically investigated the function of C. neoformans magnesium transporters in controlling the intracellular Mg balance and virulence-associated factors. We identified three Mg transporters in C. neoformans: Mgt1, Mgt2, and Mgt3. While we could not detect a Mg2+ -related growth phenotype in mgt1 and mgt3 knockout strains, a GAL7p-Mgt2 strain showed significant Mg-dependent growth defects in the presence of glucose. Further analysis demonstrated that MGT2 is a homolog of MNR2 in Saccharomyces cerevisiae, which is localized to the vacuolar membrane and participates in intracellular Mg transport. Interestingly, a transcriptome analysis showed that Mgt2 influenced the expression of 19 genes, which were independent of Mg2+ . We showed that melanin synthesis in C. neoformans required Mg2+ and Mgt2, and that capsule production was negatively regulated by Mg2+ and Mgt2. Repressing the expression of MGT2-induced capsule, which resulted in an increased fungal burden in the lungs. Cumulatively, this study sets the stage for further evaluation of the important role of Mg homeostasis in the regulation of melanin and capsule in C. neoformans. PMID- 29243389 TI - Taking Photochromism beyond Visible: Direct One-Photon NIR Photoswitches Operating in the Biological Window. AB - The success of photopharmacology is inevitably tied to the availability of photoswitches, which can be operated within the biological window (lambda=650 1450 nm) to maximize penetration in tissue. A general design strategy has been devised and a dihydropyrene derivative is described here that displays negative T type photochromism, allowing for efficient and nearly quantitative (95 %) switching induced by NIR light lambda>800 nm. The thermal half-life of the decolored ring-open meta-cyclophanediene isomer ranges from minutes to hours, depending on the solvent polarity and hence serves as a probe of the local environment. Due to the rather subtle geometrical differences between the two isomers, suitably modified NIR photoswitches are potential candidates for switching when bound in the pocket of the biological target, in principle allowing for reversible light-induced inhibitor deactivation as an alternative approach to externally regulate biological functions. PMID- 29243388 TI - The treatment outcomes of antiretroviral substitutions in routine clinical settings in Asia; data from the TREAT Asia HIV Observational Database (TAHOD). AB - INTRODUCTION: Although substitutions of antiretroviral regimen are generally safe, most data on substitutions are based on results from clinical trials. The objective of this study was to evaluate the treatment outcomes of substituting antiretroviral regimen in virologically suppressed HIV-infected patients in non clinical trial settings in Asian countries. METHODS: The study population consisted of HIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD). Individuals were included in this analysis if they started combination antiretroviral treatment (cART) after 2002, were being treated at a centre that documented a median rate of viral load monitoring >=0.8 tests/patient/year among TAHOD enrolees, and experienced a minor or major treatment substitution while on virally suppressive cART. The primary endpoint to evaluate outcomes was clinical or virological failure (VF), followed by an ART class change. Clinical failure was defined as death or an AIDS diagnosis. VF was defined as confirmed viral load measurements >=400 copies/mL followed by an ART class change within six months. Minor regimen substitutions were defined as within-class changes and major regimen substitutions were defined as changes to a drug class. The patterns of substitutions and rate of clinical or VF after substitutions were analyzed. RESULTS: Of 3994 adults who started ART after 2002, 3119 (78.1%) had at least one period of virological suppression. Among these, 1170 (37.5%) underwent a minor regimen substitution, and 296 (9.5%) underwent a major regimen substitution during suppression. The rates of clinical or VF were 1.48/100 person years (95% CI 1.14 to 1.91) in the minor substitution group, 2.85/100 person years (95% CI 1.88 to 4.33) in the major substitution group and 2.53/100 person years (95% CI 2.20 to 2.92) among patients that did not undergo a treatment substitution. CONCLUSIONS: The rate of clinical or VF was low in both major and minor substitution groups, showing that regimen substitution is generally effective in non-clinical trial settings in Asian countries. PMID- 29243391 TI - Bayesian molecular dating: opening up the black box. AB - Molecular dating analyses allow evolutionary timescales to be estimated from genetic data, offering an unprecedented capacity for investigating the evolutionary past of all species. These methods require us to make assumptions about the relationship between genetic change and evolutionary time, often referred to as a 'molecular clock'. Although initially regarded with scepticism, molecular dating has now been adopted in many areas of biology. This broad uptake has been due partly to the development of Bayesian methods that allow complex aspects of molecular evolution, such as variation in rates of change across lineages, to be taken into account. But in order to do this, Bayesian dating methods rely on a range of assumptions about the evolutionary process, which vary in their degree of biological realism and empirical support. These assumptions can have substantial impacts on the estimates produced by molecular dating analyses. The aim of this review is to open the 'black box' of Bayesian molecular dating and have a look at the machinery inside. We explain the components of these dating methods, the important decisions that researchers must make in their analyses, and the factors that need to be considered when interpreting results. We illustrate the effects that the choices of different models and priors can have on the outcome of the analysis, and suggest ways to explore these impacts. We describe some major research directions that may improve the reliability of Bayesian dating. The goal of our review is to help researchers to make informed choices when using Bayesian phylogenetic methods to estimate evolutionary rates and timescales. PMID- 29243392 TI - Indoor renovation and diabetes mellitus: Evidence from a cohort study. PMID- 29243390 TI - Aquaporin 4 blockade improves survival of murine heart allografts subjected to prolonged cold ischemia. AB - Prolonged cold ischemia storage (CIS) is a leading risk factor for poor transplant outcome. Existing strategies strive to minimize ischemia-reperfusion injury in transplanted organs, yet there is a need for novel approaches to improve outcomes of marginal allografts and expand the pool of donor organs suitable for transplantation. Aquaporins (AQPs) are a family of water channels that facilitate homeostasis, tissue injury, and inflammation. We tested whether inhibition of AQP4 improves the survival of fully MHC-mismatched murine cardiac allografts subjected to 8 hours of CIS. Administration of a small molecule AQP4 inhibitor during donor heart collection and storage and for a short-time posttransplantation improves the viability of donor graft cells, diminishes donor reactive T cell responses, and extends allograft survival in the absence of other immunosuppression. Furthermore, AQP4 inhibition is synergistic with cytotoxic T lymphocyte-associated antigen 4-Ig in prolonging survival of 8-hour CIS heart allografts. AQP4 blockade markedly reduced T cell proliferation and cytokine production in vitro, suggesting that the improved graft survival is at least in part mediated through direct effects on donor-reactive T cells. These results identify AQPs as a promising target for diminishing donor-specific alloreactivity and improving the survival of high-risk organ transplants. PMID- 29243393 TI - Quality of life in elderly patients with an ostomy - a study from the population based PROFILES registry. AB - AIM: Ostomies are being placed frequently in surgically treated elderly patients with colorectal cancer (CRC). An insight into the (potential) impact of ostomies on quality of life (QoL) could be useful in patient counselling as well as in the challenging shared treatment decision-making. METHOD: Patients with CRC diagnosed between 2000 and 2009 and registered in the population-based Eindhoven Cancer Registry received a QoL questionnaire (EORTC QLQ-C30) in 2010. In addition, QoL was compared with an age- and sex-matched normative population. RESULTS: The study included 2299 CRC patients, of whom 494 had an ostomy. No differences were found in reported ostomy-related problems between patients aged <=65, 66-75 and >=76 years. Ostomy patients aged 66-75 and >=76 years reported significantly lower physical functioning compared with those without an ostomy. In the elderly (those aged >=76 years) ostomates reported a worse physical and social functioning compared with the normative population. All these differences were of small clinical relevance. The impact of an ostomy seems to be more prominent in younger (<=75 years old) ostomates, as they experience more functional limitations and a decrease in global health status compared with younger nonostomy patients and the normative population. CONCLUSION: Although elderly (>=76 years old) patients with an ostomy report significantly more limitations in functioning compared with a normative population and elderly CRC patients without an ostomy, the clinical relevance of this finding is limited. In contrast, the impact of an ostomy is more prominent in younger patients. Thus, age itself is not a reason for withholding an ostomy. PMID- 29243395 TI - Species Comparison of Postnatal Development of the Female Reproductive System. AB - The postnatal development of the female reproductive system in laboratory animals and humans is reviewed. To enable a meaningful species comparison of the developing female reproductive system, common definitions of developmental processes were established with a focus made on aspects that are similar across species. A species comparison of the key endocrine, morphologic, and functional (onset of ovarian cycles and ability to reproduce) features of postnatal development of the female reproductive system is provided for human, nonhuman primate, dog, rat, and also mouse, minipig, and rabbit where possible. Species differences in the timing and control of female sexual maturation are highlighted. Additionally, a species comparison of the type and timing of female reproductive ovarian cycles was compiled. Human development provided the frame of reference, and then other common laboratory species were compared. The comparison has inherent challenges because the processes involved and sequence of events can differ greatly across species. Broad strokes were taken to assign a particular average age to an event and are to be used with caution. Methods of evaluation of postnatal female reproductive development in laboratory animals are discussed. Lastly, control rodent data from one of the author's laboratory on vaginal opening, first estrus, estrous cyclicity, and the histopathology involved with the developing female rat and mouse are presented. The information provided in this review is intended to be a resource for the design and interpretation of juvenile animal toxicity testing and ultimately, the relevance of the data to characterize potential risks for women and girls. Birth Defects Research 110:163 189, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29243394 TI - The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. AB - The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i-IFTA) and its relationship to T cell-mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody-mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i-IFTA is associated with reduced graft survival. Furthermore, these groups presented that i-IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i-IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor-specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next-generation clinical trials. PMID- 29243397 TI - Effect of strong tooth-bleaching with 38% hydrogen peroxide on marginal seal of dental restorations using self-etch and total-etch adhesives. AB - : The purpose of this study was to evaluate the distance and/or thickness of dye penetration at enamel and cementum/dentin margins of restorations before and after vital bleaching. Class V cavities were prepared on extracted human premolars and restored with light-cured resin composite using either AQ-Bond or Single-Bond2 adhesives. Four conditions: no bleaching (control), restored before bleaching (RB), bleached and immediately restored (BIR), bleached and stored in artificial saliva for 7 days then restored (B7R), were used for each adhesive group. After soaking in basic fuchsin dye for 24 hours, all specimens were vertically sectioned through the middle of restorations to measure the distance and/or the thickness of dye penetration. No microleakage was found either on enamel and cementum/dentin margins of control group using AQ-Bond. Whereas leakage was found in the control group using Single-Bond2 and bleached groups. Statistically significant differences in leakage distance and/or thickness were found among groups at the cementum/dentin margin (P < .05). Dye could penetrate into the pulp chamber of BIR (60%) and B7R (15%) specimens. CLINICAL SIGNIFICANCE: The negative control or leakage-free group is very important when discussing the effects of bleaching on marginal seal or microleakage. Bleaching using 38% H2 O2 increases the microleakage distance and dye penetration area of cementum/dentin margin more than that of enamel margin. The bleached tooth is not a good substrate for reliable bonding and complete seal and it is also a channel for external stimuli reaching the pulp. PMID- 29243396 TI - Bariatric Surgery-Induced Cardiac and Lipidomic Changes in Obesity-Related Heart Failure with Preserved Ejection Fraction. AB - OBJECTIVE: To determine the effects of gastric bypass on myocardial lipid deposition and function and the plasma lipidome in women with obesity and heart failure with preserved ejection fraction (HFpEF). METHODS: A primary cohort (N = 12) with HFpEF and obesity underwent echocardiography and magnetic resonance spectroscopy both before and 3 months and 6 months after bariatric surgery. Plasma lipidomic analysis was performed before surgery and 3 months after surgery in the primary cohort and were confirmed in a validation cohort (N = 22). RESULTS: After surgery-induced weight loss, Minnesota Living with Heart Failure questionnaire scores, cardiac mass, and liver fat decreased (P < 0.02, P < 0.001, and P = 0.007, respectively); echo-derived e' increased (P = 0.03), but cardiac fat was unchanged. Although weight loss was associated with decreases in many plasma ceramide and sphingolipid species, plasma lipid and cardiac function changes did not correlate. CONCLUSIONS: Surgery-induced weight loss in women with HFpEF and obesity was associated with improved symptoms, reverse cardiac remodeling, and improved relaxation. Although weight loss was associated with plasma sphingolipidome changes, cardiac function improvement was not associated with lipidomic or myocardial triglyceride changes. The results of this study suggest that gastric bypass ameliorates obesity-related HFpEF and that cardiac fat deposition and lipidomic changes may not be critical to its pathogenesis. PMID- 29243398 TI - Venous leg ulcer management in clinical practice in the UK: costs and outcomes. AB - The aim of this study was to estimate the patterns of care and annual levels of health care resource use attributable to managing venous leg ulcers (VLUs) in clinical practice by the UK's National Health Service (NHS) and the associated costs of patient management. This was a retrospective cohort analysis of the records of 505 patients in The Health Improvement Network (THIN) Database. Patients' characteristics, wound-related health outcomes and health care resource use were quantified, and the total NHS cost of patient management was estimated at 2015/2016 prices. Overall, 53% of all VLUs healed within 12 months, and the mean time to healing was 3.0 months. 13% of patients were never prescribed any recognised compression system, and 78% of their wounds healed. Of the 87% who were prescribed a recognised compression system, 52% of wounds healed. Patients were predominantly managed in the community by nurses with minimal clinical involvement of specialist clinicians. Up to 30% of all the VLUs may have been clinically infected at the time of presentation, and only 22% of patients had an ankle brachial pressure index documented in their records. The mean NHS cost of wound care over 12 months was an estimated L7600 per VLU. However, the cost of managing an unhealed VLU was 4.5 times more than that of managing a healed VLU (L3000 per healed VLU and L13 500 per unhealed VLU). This study provides important insights into a number of aspects of VLU management in clinical practice that have been difficult to ascertain from other studies and provides the best estimate available of NHS resource use and costs with which to inform policy and budgetary decisions. PMID- 29243400 TI - Highly Efficient Gas-Phase Oxidation of Renewable Furfural to Maleic Anhydride over Plate Vanadium Phosphorus Oxide Catalyst. AB - Maleic anhydride (MAnh) and its acids are critical intermediates in chemical industry. The synthesis of maleic anhydride from renewable furfural is one of the most sought after processes in the field of sustainable chemistry. In this study, a plate vanadium phosphorus oxide (VPO) catalyst synthesized by a hydrothermal method with glucose as a green reducing agent catalyzes furfural oxidation to MAnh in the gas phase. The plate catalyst-denoted as VPOHT -has a preferentially exposed (200) crystal plane and exhibited dramatically enhanced activity, selectivity and stability as compared to conventional VPO catalysts and other state-of-the-art catalytic systems. At 360 degrees C reaction temperature with air as an oxidant, about 90 % yield of MAnh was obtained at 10 vol % of furfural in the feed, a furfural concentration value that is much higher than those (<2 vol %) reported for other catalytic systems. The catalyst showed good long-term stability and there was no decrease in activity or selectivity for MAnh during the time-on-stream of 25 h. The high efficiency and catalyst stability indicate the great potential of this system for the synthesis of maleic anhydride from renewable furfural. PMID- 29243399 TI - Diabetic foot ulcer management in clinical practice in the UK: costs and outcomes. AB - The aim of this study was to estimate the patterns of care and annual levels of health care resource use attributable to managing diabetic foot ulcers (DFUs) in clinical practice by the UK's National Health Service (NHS), and the associated costs of patient management. This was a retrospective cohort analysis of the records of 130 patients with a newly diagnosed DFU in The Health Improvement Network (THIN) database. Patients' characteristics, wound-related health outcomes and health care resource use were quantified, and the total NHS cost of patient management was estimated at 2015-2016 prices. Patients were predominantly managed in the community by nurses, with minimal clinical involvement of specialist physicians. 5% of patients saw a podiatrist, and 5% received a pressure offloading device. Additionally, 17% of patients had at least one amputation within the first 12 months from initial presentation of their DFU. 14% of DFUs were documented as being clinically infected at initial presentation, although an additional 31% of patients were prescribed an antimicrobial dressing at the time of presentation. Of all the DFUs, 35% healed within 12 months, and the mean time to healing was 4.4 months. Over the study period, 48% of all patients received at least one prescription for a compression system, but significantly more patients healed if they never received compression (67% versus 16%; P < 0.001). The mean NHS cost of wound care over 12 months was an estimated L7800 per DFU (of which 13% was attributable to amputations), ranging from L2140 to L8800 per healed and unhealed DFU, respectively, and L16 900 per amputated wound. Consolidated medical records from a primary care held database provided 'real-world evidence' highlighting the consequences of inefficient and inadequate management of DFUs in clinical practice in the UK. Clinical and economic benefits to both patients and the NHS could accrue from strategies that focus on (i) wound prevention, (ii) improving wound-healing rates and (iii) reducing infection and amputation rates. PMID- 29243404 TI - Molecular viability testing of viable but non-culturable bacteria induced by antibiotic exposure. AB - Nucleic acid amplification-based methods are limited by their inability to discriminate between viable and dead cells. To overcome this drawback, propidium monoazide (PMA) combined with qPCR has been used to differentiate viable from nonviable cells in environmental samples. However, assessing bacterial physiology using PMA-qPCR remains a challenge due to its incapability of detecting metabolic activities, leading to overestimation of the viable bacteria population under an inactivation condition (e.g. antibiotic treatments). A recent advanced technique to amplify ribosomal RNA precursors (pre-rRNA) has been shown to detect viable cells because pre-rRNAs are intermediates in rRNA synthesis. This study investigated the effect of different types of antibiotics on the bacterial viability or viable but non-culturable (VBNC) state using both PMA-qPCR and pre rRNA analyses with Pseudomonas aeruginosa. This study demonstrated that P. aeruginosa was more sensitive to colistin than it was to carbenicillin, gentamicin and levofloxacin. We could discriminate VBNCP. aeruginosa cells using PMA-qPCR when antibiotic pressure induced the VBNC state. Also, pre-rRNA was able to distinguish viable cells from colistin-inactivated bacteria cells, and it could detect the presence of VBNC and persister cells. Our results showed that these two molecular methods could successfully eliminate false-positive signals derived from antibiotics-inactivated cells. PMID- 29243407 TI - Rheumatic diseases are associated with a higher risk of dementia: A nation-wide, population-based, case-control study. AB - AIM: Previous research demonstrated the possible relevance of dementia and rheumatic diseases. This population-based study aims to investigate the association of rheumatic diseases and dementia. METHODS: The data of this case control study was extracted from the Taiwan National Health Insurance Research Database. Diagnosis of dementia and rheumatic diseases mentioned in this study were retrieved by the International Classification of Diseases-9 code. We recruited cases (n = 10 180) with dementia and controls (n = 61 080) during 2000 2010, by matching on age, gender and index date with a match ratio 1 : 6. The Chi square test was used to calculate the baseline characteristics of the cases and controls for categorical variables such as age and gender. Simple conditional and multivariable conditional logistic regression models were used to estimate crude and adjusted odds ratios. RESULTS: Statistical significance was observed in Sjogren's syndrome (SS), systemic lupus erythematosus (SLE), and osteoarthritis (OA) among females (P < 0.05 for SS and SLE; P < 0.01 for OA), and in SS, psoriatic arthritis (PsA) and OA among males (P < 0.01 for SS; P < 0.05 for PsA and OA). Further, we also demonstrated a significant difference in SLE and OA among the younger group (age = 40-64) (P < 0.01 for SLE and OA), and in SS and OA among the older group (age ? 65) (P < 0.01 for SS and OA). CONCLUSION: In this population-based case-control study, we found that patients with rheumatoid arthritis, SS, SLE, PsA and OA are significantly associated with a higher risk of dementia than those without rheumatic diseases. We hypothesized that inflammation and medications are two possible mechanisms. PMID- 29243405 TI - Bluetongue virus serotype 27: Experimental infection of goats, sheep and cattle with three BTV-27 variants reveal atypical characteristics and likely direct contact transmission BTV-27 between goats. AB - Bluetongue virus (BTV) hitherto consisted of 26 recognized serotypes, of which all except BTV-26 are primarily transmitted by certain species of Culicoides biting midges. Three variants of an additional 27th bluetongue virus serotype (BTV-27v01-v03) were recently detected in asymptomatic goats in Corsica, France, 2014-2015. Molecular characterization revealed genetic differences between the three variants. Therefore, in vivo characteristics were investigated by experimental infection of a total of 15 goats, 11 sheep and 4 cattle with any one of the three variants in separated animal trials. In goat trials, BTV-naive animals of the same species were kept in a facility where direct contact was unhindered. Of the 15 inoculated goats, 13 and 14 animals were found positive for BTV-RNA and antibodies (Ab), respectively, until the end of the experiments. Surprisingly, BTV-Ab levels as measured with ELISA and neutralization test (SNT) were remarkably low in all seropositive goats. Virus isolation from whole-blood was possible at the peak of viremia until 49 dpi. Moreover, detection of BTV 27v02-RNA and Ab in one contact goat indicated that-similar to BTV-26-at least one of three BTV-27 variants may be transmitted by contact between goats. In the field, BTV-27 RNA can be detected up to 6 months in the whole-blood of BTV-27 infected Corsican goats. In contrast, BTV RNA was not detected in the blood of cattle or sheep. In addition, BTV-27 Abs were not detected in cattle and only a transient increase in Ab levels was observed in some sheep. None of the 30 animals showed obvious BT-like clinical signs. In summary, the phenotypes observed for BTV-27v01-v03 phenotypes correspond to a mixture of characteristics known for BTV-25 and 26. PMID- 29243406 TI - The national burden of influenza-associated severe acute respiratory illness hospitalization in Zambia, 2011-2014. AB - BACKGROUND: Estimates of influenza-associated hospitalization are limited in low- and middle-income countries, especially in Africa. OBJECTIVE: To estimate the national number of influenza-associated severe acute respiratory illness (SARI) hospitalization in Zambia. METHODS: We conducted active prospective hospital based surveillance for SARI at the University Teaching Hospital (UTH) situated in Lusaka Province during 2011-2014. Upper respiratory tract samples were tested for influenza virus using a reverse transcriptase polymerase chain reaction assay. We estimated age-specific rates of influenza-associated SARI hospitalizations for the UTH using census and secondary data on respiratory hospitalizations following estimation approaches recommended by the World Health Organization. We used the UTH hospitalization rates as a proxy for Lusaka Province. These rates were adjusted for each of the remaining 9 provinces based on their prevalence of risk factors for pneumonia and healthcare-seeking behavior. Rates were expressed per 100,000 population. RESULTS: SARI cases accounted for 77.1% (13 389/17 354) of respiratory admissions at the UTH; 82.7% (11 859/14 344) and 50.8% (1530/3010) among individuals aged <5 and >=5 years, respectively. Among SARI cases tested, the influenza virus detection rate was 5.5% (152/2734), 4.8% (48/998), and 6.0% (104/1736) among individuals aged <5 and >=5 years, respectively. The mean annual national number of influenza-associated SARI hospitalizations was 6181 (95% CI: 4321-8041-rate: 43.9; 95% CI: 30.7-57.1); 4669 (95% CI: 3287-6051-rate: 187.7; 95% CI: 132.1-243.3) among children aged <5 years; and 1512 (95% CI: 1037-1987 rate: 13.1; 95% CI: 9.0-17.2) among individuals aged >=5 years. CONCLUSIONS: The burden of influenza-associated SARI hospitalizations was substantial and was highest among children aged <5 years. PMID- 29243401 TI - Heterojunction Engineering for High Efficiency Cesium Formamidinium Double-Cation Lead Halide Perovskite Solar Cells. AB - It is essential to minimize the interfacial trap states and improve the carrier collection for high efficiency perovskite solar cells (PSCs). Herein, we present a facile method to construct a p-type graded heterojunction (GHJ) in normal PSCs by deploying a gradient distribution of hole-transporting materials (poly[bis(4 phenyl)(2,4,6-trimethylphenyl)amine], PTAA, in this case) in the shallow perovskite layer. The formation of the GHJ structure facilitates charge transfer and collection, and passivates interfacial trap states, thus delivering a power conversion efficiency (PCE) of 20.05 % along with steady output efficiency of 19.3 %, which is among the highest efficiencies for cesium formamidinium (Cs-FA) lead halide PSCs. Moreover, the unencapsulated devices based on these (Cs-FA) lead halide perovskites show excellent long-term stability; more than 95 % of their initial PCE can be retained after 1440 h storage under ambient conditions. This study may provide an effective strategy to fabricate high-efficiency PSCs with great stability. PMID- 29243402 TI - National burden of hospitalized and non-hospitalized influenza-associated severe acute respiratory illness in Kenya, 2012-2014. AB - BACKGROUND: Influenza-associated respiratory illness was substantial during the emergence of the 2009 influenza pandemic. Estimates of influenza burden in the post-pandemic period are unavailable to guide Kenyan vaccine policy. OBJECTIVES: To update estimates of hospitalized and non-hospitalized influenza-associated severe acute respiratory illness (SARI) during a post-pandemic period (2012-2014) and describe the incidence of disease by narrow age categories. METHODS: We used data from Siaya County Referral Hospital to estimate age-specific base rates of SARI. We extrapolated these base rates to other regions within the country by adjusting for regional risk factors for acute respiratory illness (ARI), regional healthcare utilization for acute respiratory illness, and the proportion of influenza-positive SARI cases in each region, so as to obtain region-specific rates. RESULTS: The mean annual rate of hospitalized influenza-associated SARI among all ages was 21 (95% CI 19-23) per 100 000 persons. Rates of non hospitalized influenza-associated SARI were approximately 4 times higher at 82 (95% CI 74-90) per 100 000 persons. Mean annual rates of influenza-associated SARI were highest in children <2 years of age with annual hospitalization rates of 147 (95% CI of 134-160) per 100 000 persons and non-hospitalization rates of 469 (95% CI 426-517) per 100 000 persons. For the period 2012-2014, there were between 8153 and 9751 cases of hospitalized influenza-associated SARI and 31 785 38 546 cases of non-hospitalized influenza-associated SARI per year. CONCLUSIONS: The highest burden of disease was observed among children <2 years of age. This highlights the need for strategies to prevent influenza infections in this age group. PMID- 29243412 TI - Authors' reply re: Partner smoking infl uences whether mothers quit smoking during pregnancy: a prospective cohort study. PMID- 29243408 TI - Genotoxicity of non-alcoholic mouth rinses: A micronucleus and nuclear abnormalities study with fluorescent microscopy. AB - AIM: The aim of the present study was to evaluate the genotoxicity of non alcoholic mouth rinses on buccal epithelial cells using a micronucleus test. METHODS: A total of 105 patients were selected and randomly divided into five groups. Four different mouth rinses and normal saline were given for 2 weeks' duration, and cytological smears were collected before and after exposure. These smears were subjected to micronucleus (MN) and other nuclear abnormalities (ONA) tests using acridine orange stain, and their frequencies were obtained in 500 buccal epithelial cells. The statistical analysis included mean, chi2 -test, analysis of variance, and post-hoc analysis by Bonferroni test. RESULTS: Micronucleated cells (P < .00) and MN (P < .00) were higher in individuals exposed to chlorhexidine (CHX), followed by chlorine dioxide (ClO2 ), potassium nitrate (KNO3 ), and sodium fluoride (NaF), amine fluoride (AmF), and normal saline. ONA were greater (P < .00) in individuals exposed to CHX, followed by ClO2 , AmF, KNO3 , and NaF and normal saline. Overall, the results showed that genotoxic damage was greater in the case of CHX, followed by ClO2 , KNO3 , and NaF, AmF, and normal saline. CONCLUSION: Chronic exposure to mouth rinses can cause genotoxic damage to buccal epithelial cells. Long-term injudicious and inadvertent use of mouth rinses should be discouraged. PMID- 29243410 TI - Clinical and radiographic peri-implant parameters and proinflammatory cytokine levels among cigarette smokers, smokeless tobacco users, and nontobacco users. AB - BACKGROUND: It is postulated that clinical and radiographic peri-implant parameters are worse and levels of interleukin (IL)-1beta and matrix metalloproteinase (MMP)-9 in the peri-implant sulcular fluid (PISF) are higher in cigarette-smokers (CS) and smokeless-tobacco users (STU) compared with nontobacco user (NTU). PURPOSE: The present study aimed to compare clinical and radiographic peri-implant inflammatory parameters and levels of IL-1beta and MMP-9 levels among CS, STU, and NTU. MATERIALS AND METHODS: Forty-five CS (Group-1), 42 STU (Group-2), and 44 NTU (Group-3) were included. Demographic data was collected using a structured baseline questionnaire. Peri-implant plaque index (PI), bleeding on probing (BOP), and probing depth (PD) were recorded and crestal bone loss (CBL) were assessed using standardized digital radiographs. PISF volume and levels of IL-1beta and MMP-9 in PISF were quantified using enzyme-linked immunosorbent assay. Clinical peri-implant parameters and PISF IL-1beta and MMP-9 concentrations were analyzed with Kruskal-Wallis test. Bonferroni post hoc adjustment test was used for multiple comparisons. P-value was set at .05. RESULTS: Peri-implant PI and PD were significantly worse in group-1 and group-2 patients as compared to group-3 individuals (P < .05). Peri-implant CBL was also significantly higher in group-1 and group-2 compared with group-3 (P < .05). Peri implant BOP was significantly higher in group-2 and group-3 as compared to group 1 individuals (P < .05). The PISF volume (P < .05) collected and levels of IL 1beta and MMP-9 were statistically significantly elevated among individuals in group-1 and group-2 compared with group-3 (P < .01). There was no significant difference in PI, PD, CBL, and PISF levels of IL-1beta and MMP-9 among participants in groups 1 and 2. CONCLUSION: Clinical and radiographic peri implant parameters were compromised among CS and STU as compared to NTU. Increased expression of local proinflammatory cytokines may explain greater susceptibility of CS and STU to peri-implant breakdown. PMID- 29243409 TI - Thermophilic bacterial communities inhabiting the microbial mats of "indifferent" and chalybeate (iron-rich) thermal springs: Diversity and biotechnological analysis. AB - Microbial mats are occasionally reported in thermal springs and information on such mats is very scarce. In this study, microbial mats were collected from two hot springs (Brandvlei (BV) and Calitzdorp (CA)), South Africa and subjected to scanning electron microscopy (SEM) and targeted 16S rRNA gene amplicon analysis using Next Generation Sequencing (NGS). Spring water temperature was 55 degrees C for Brandvlei and 58 degrees C for Calitzdorp while the pH of both springs was slightly acidic, with an almost identical pH range (6.2-6.3). NGS analysis resulted in a total of 4943 reads, 517 and 736 OTUs for BV and CA at, respectively, a combined total of 14 different phyla in both samples, 88 genera in CA compared to 45 in BV and 37.64% unclassified sequences in CA compared to 27.32% recorded in BV. Dominant bacterial genera in CA microbial mat were Proteobacteria (29.19%), Bacteroidetes (9.41%), Firmicutes (9.01%), Cyanobacteria (6.89%), Actinobacteria (2.65%), Deinococcus-Thermus (2.57%), and Planctomycetes (1.94%) while the BV microbial mat was dominated by Bacteroidetes (47.3%), Deinococcus-Thermus (12.35%), Proteobacteria (7.98%), and Planctomycetes (2.97%). Scanning electron microscopy results showed the presence of microbial filaments possibly resembling cyanobacteria, coccids, rod-shaped bacteria and diatoms in both microbial mats. Dominant genera that were detected in this study have been linked to different biotechnological applications including hydrocarbon degradation, glycerol fermentation, anoxic-fermentation, dehalogenation, and biomining processes. Overall, the results of this study exhibited thermophilic bacterial community structures with high diversity in microbial mats, which have a potential for biotechnological exploitation. PMID- 29243403 TI - Microglia: Driving critical periods and sexual differentiation of the brain. AB - The proverbial role of microglia during brain development is shifting from passive members of the brain's immune system to active participants that are able to dictate enduring outcomes. Despite these advances, little attention has been paid to one of the most critical components of early brain development-sexual differentiation. Mounting evidence suggests that the normal developmental functions microglia perform-cell number regulation and synaptic connectivity-may be involved in the sex-specific patterning of the brain during these early sensitive periods, and may have lasting sex-dependent and sex-independent effects on behavior. In this review, we outline the known functions of microglia during developmental sensitive periods, and highlight the role they play in the establishment of sex differences in brain and behavior. We also propose a framework for how researchers can incorporate microglia in their study of sex differences and vice versa. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 580-592, 2018. PMID- 29243414 TI - Biomedical device innovation methodology: applications in biophotonics. AB - The process of medical device innovation involves an iterative method that focuses on designing innovative, device-oriented solutions that address unmet clinical needs. This process has been applied to the field of biophotonics with many notable successes. Device innovation begins with identifying an unmet clinical need and evaluating this need through a variety of lenses, including currently existing solutions for the need, stakeholders who are interested in the need, and the market that will support an innovative solution. Only once the clinical need is understood in detail can the invention process begin. The ideation phase often involves multiple levels of brainstorming and prototyping with the aim of addressing technical and clinical questions early and in a cost efficient manner. Once potential solutions are found, they are tested against a number of known translational factors, including intellectual property, regulatory, and reimbursement landscapes. Only when the solution matches the clinical need, the next phase of building a "to market" strategy should begin. Most aspects of the innovation process can be conducted relatively quickly and without significant capital expense. This white paper focuses on key points of the medical device innovation method and how the field of biophotonics has been applied within this framework to generate clinical and commercial success. PMID- 29243413 TI - Clinical response to apatinib monotherapy in advanced non-small cell lung cancer. AB - AIM: Apatinib, an oral tyrosine kinase inhibitor mainly targeting VEGFR-2, exerts both antiangiogenesis and antiproliferation effects. Apatinib shows clinical benefit in advanced non-small cell lung cancer (NSCLC) at an initial dose of 750 mg qd. We further assessed the efficacy and safety of apatinib at a more frequently used dose of 500 mg qd. The preliminary clinical outcome of apatinib in patients with brain metastases was also reported. METHODS: We retrospectively reviewed the clinical data of 25 patients who received apatinib between August 2015 and May 2016. Progression-free survival (PFS) was calculated by using the Kaplan-Meier method. RESULTS: The objective response rate and disease control rate were 8.0% and 68.0%, respectively. The median PFS was 5.17 (95% confidence interval [CI]: 0.76-9.57) months. In the second-line setting (n = 13), the median PFS was 7.37 (95% CI: 0.01-14.72) months, whereas the median PFS for the 12 patients treated with apatinib as third line or beyond therapy was 5.17 (95% CI: 1.78-8.55) months. Of the seven patients with brain metastases, four patients had stable disease. All patients were well tolerant to apatinib without any grade 3 or 4 adverse events. The most common grade 1 or 2 adverse events included hypertension (72.0%), hand-foot-skin reaction (24.0%), fatigue (24.0%) and abnormal liver function (20.0%). CONCLUSIONS: Apatinib is effective and well tolerated in patients with advanced NSCLC, even at a dosage of 500 mg qd, and might offer a new option for the treatment of such patients with brain metastases. PMID- 29243415 TI - Compact dual-mode diffuse optical system for blood perfusion monitoring in a porcine model of microvascular tissue flaps. AB - In reconstructive surgery, the ability to detect blood flow interruptions to grafted tissue represents a critical step in preventing postsurgical complications. We have developed and pilot tested a compact, fiber-based device that combines two complimentary modalities-diffuse correlation spectroscopy (DCS) and diffuse reflectance spectroscopy-to quantitatively monitor blood perfusion. We present a proof-of-concept study on an in vivo porcine model (n=8). With a controllable arterial blood flow supply, occlusion studies (n=4) were performed on surgically isolated free flaps while the device simultaneously monitored blood flow through the supplying artery as well as flap perfusion from three orientations: the distal side of the flap and two transdermal channels. Further studies featuring long-term monitoring, arterial failure simulations, and venous failure simulations were performed on flaps that had undergone an anastomosis procedure (n=4). Additionally, benchtop verification of the DCS system was performed on liquid flow phantoms. Data revealed relationships between diffuse optical measures and state of occlusion as well as the ability to detect arterial and venous compromise. The compact construction of the device, along with its noninvasive and quantitative nature, would make this technology suitable for clinical translation. PMID- 29243411 TI - Randomized crossover trial comparing EUS-guided fine-needle aspiration with EUS guided fine-needle biopsy for gastric subepithelial tumors. AB - AIM: The purpose of this study is to compare the diagnostic yield of endoscopic ultrasound (EUS)-guided fine-needle aspiration (EUS-FNA) and EUS-guided fine needle biopsy (EUS-FNB) for gastric subepithelial tumors (SET). METHODS: Patients diagnosed SET derived from fourth layer of the stomach were prospectively enrolled and randomly assigned to undergo both EUS-FNA using standard needle and EUS-FNB using a core biopsy needle alternatively to the same lesion a total of four times per session. The specimen was carefully examined for the presence of a macroscopic visible core, appearing as threadlike yellowish or bloody pieces of tissue and blinded histocytologic analyses were conducted. For spindle cell lesions by hematoxylin and eosin staining (H&E) on histologic evaluation, immunohistochemical staining was performed in all cases to confirm the pathological diagnosis. RESULTS: A total of 23 patients were enrolled and underwent paired EUS-FNA and -FNB sampling. The diagnostic rate due to immunohistochemical staining was 73.9% and 91.3%, respectively (P = .120). The rate of obtaining specimens with a macroscopic yellowish core and only a bloody core among the tissue specimens were respectively 43.5% and 52.2% for EUS-FNA and 69.6% and 30.4% for EUS-FNB. The diagnostic rate for a yellowish core (84.6%) and a bloody core (84.2%, P = .971) did not differ significantly. CONCLUSION: Both techniques were equivalently safe and successful in terms of a high diagnostic yield for gastric SET. And the tissue that can be immunohistochemically stained is present even in the specimens that appear to be a macroscopically bloody core. PMID- 29243419 TI - [Advances of mechanism research on procyanidin in prevention and treatment of type 2 diabetes mellitus]. AB - Diabetes mellitus, a chronic disease, is characterized by high blood glucose that could induce various complications. Procyanidin, a kind of polyphenol compounds existing in many plants, have shown to be effective in preventing and treating type 2 diabetes mellitus as they may lower blood glucose, moderate insulin resistance and protect islet beta cells. This review focused on the research advances on the preventive and therapeutic application of procyanidin in promoting glucose absorption, protecting islet beta cells, modulating intestinal microbiota and regulating diabetic complications of type 2 diabetes mellitus, which should provide useful reference for subsequent studies. PMID- 29243416 TI - Partial correlation-based functional connectivity analysis for functional near infrared spectroscopy signals. AB - A theoretical framework, a partial correlation-based functional connectivity (PC FC) analysis to functional near-infrared spectroscopy (fNIRS) data, is proposed. This is based on generating a common background signal from a high passed version of fNIRS data averaged over all channels as the regressor in computing the PC between pairs of channels. This approach has been employed to real data collected during a Stroop task. The results show a strong significance in the global efficiency (GE) metric computed by the PC-FC analysis for neutral, congruent, and incongruent stimuli (NS, CS, IcS; GEN=0.10+/-0.009, GEC=0.11+/-0.01, GEIC=0.13+/ 0.015, p=0.0073). A positive correlation (r=0.729 and p=0.0259) is observed between the interference of reaction times (incongruent-neutral) and interference of GE values (GEIC-GEN) computed from [HbO] signals. PMID- 29243417 TI - [Development in synthesis of andrographolide derivatives]. AB - Andrographolide is one of the major natural active constituents in Andrographis panniculata of Acanthaceae family. Andrographolide and its derivatives are proved to posses a wide range of biological activities, such as anti-inflammatory, antiviral, anti-tumor, anti-human immunodeficiency virus(HIV), hepatoprotective and alpha-glucosidase inhibition activity. In this paper, the development of synthesis of rographolide derivatives and their related pharmacological activities were reviewed. PMID- 29243418 TI - [Research progress of pharmacokinetics and pharmacodynamics of total glucosides of peony in hepatoprotective effects]. AB - Total glucosides of peony (TGP), containing the effective components of paeoniflorin (Pae), albiflorin (Alb) and so on, are effective parts of Radix Paeoniae Alba. And it possesses extensive pharmacological actions, one of which is hepatoprotective effect. In recent years, abundant of pharmacokinetics and pharmacodynamics research of TGP in hepatoprotective effects have been performed. However, the relative medicine of TGP in hepatoprotective effect has not been developed for clinical application. In order to provide reference for the development and rational clinical application of TGP, the research progresses of pharmacokinetics and pharmacodynamics of TGP in hepatoprotective effect were summarized in this paper. Pharmacokinetics research has clarified the process of absorption, distribution, metabolism and excretion of TGP in vivo, and liver injury disease can significantly influence its metabolic processes. Pharmacodynamics studies suggested that TGP can protect against acute liver injury, non-alcoholic fatty liver diseases (NAFLD), chronic liver fibrosis and liver cancer. However, the action mechanism and in vivo process about hepatoprotective effects of TGP have not been clearly revealed. How liver injury influences the metabolism of TGP and its integrated regulation through multiple targets need to be further studied. The combined pharmacokinetics and pharmacodynamics studies should be performed in favour of medicine development and clinical application of TGP in hepatoprotective effects. PMID- 29243420 TI - [Application progress of proteomic in pharmacological study of Chinese medicinal formulae]. AB - Chinese medicinal formulae are the important means of clinical treatment in traditional Chinese medicine. It is urgent to use modern advanced scientific and technological means to reveal the complicated mechanism of Chinese medicinal formulae because they have the function characteristics of multiple components, multiple targets and integrated regulation. The systematic and comprehensive research model of proteomic is in line with the function characteristics of Chinese medicinal formulae, and proteomic has been widely used in the study of pharmacological mechanism of Chinese medicinal formulae. The recent applications of proteomic in pharmacological study of Chinese medicinal formulae in anti cardiovascular and cerebrovascular diseases, anti-liver disease, antidiabetic, anticancer, anti-rheumatoid arthritis and other diseases were reviewed in this paper, and then the future development direction of proteomic in pharmacological study of Chinese medicinal formulae was put forward. This review is to provide the ideas and method for proteomic research on function mechanism of Chinese medicinal formulae. PMID- 29243421 TI - [History evolution of salt production and processing with brine]. AB - Salt is an important excipient for Chinese medicine salt. The standardization of its quality is conducive to ensuring the quality of Chinese medicine pieces. In this paper, the processing with brine and the processing auxiliary salt were studied from three aspects: the history evolution of salt, the history evolution of processing with brine, and the modern research of processing with brine. It has been found that salt plays an important role in the history of China. It has a long history and a wide variety. The salt used in the processing of traditional Chinese medicine mainly includes three categories: common salt, halitum and white salt. The quality of salt is closely related to its origin and processing, mainly based on the color and the place of origin. In ancient times, the varieties of salt used in the production of different Chinese herbal medicines were different, which might be related to the nature of drugs. The primary purpose of processing with brine is to increase the efficacy of drugs. At present, there are many reports on optimizing the preparation technology of processing with brine, but the evaluation indexes are quite different, and its scientific nature is to be discussed. The processing method with brine and its processing auxiliary materials are lacking of relevant evaluation standards and quality standards, which is not conducive to the healthy development of Chinese herbal pieces. In this paper, the relevant literature was studied in order to provide reference for the establishment of standards for salt processing excipient in traditional Chinese medicine. PMID- 29243422 TI - [Effects of light quality on growth and internal quality of Whitmania pigra]. AB - In this study, four light color treatments (red blue, white, natural light) were tested to determine effects of light spectrum on the growth of larval Whitmania pigra (30 days old) at the same intensity. The experiment lasted for 50 days. The specific growth rate (SGR) under blue light condition was significantly higher during 30 days to 40 days. At the end of the experiment, specific growth rate (SGR) and weight gain rate under red light condition were higher (P<0.05) than those under other groups. Meanwhile, the enzymes activities of digestive enzymes (protease, amylase and lipase) were higher under red light condition. However, the enzymes activities of antioxidant enzymes (SOD, CAT, ALP) were lower under white light condition compared with the other treatments(P<0.05). In addition, no significant changes were observed for water content, total ash, acid insoluble ash, pH and antithrombin activity in the all treatments. After 50 days, the digestive enzymes and growth rate were higher under red light condition but antioxidant enzymes were lower under white light condition. Furthermore, light spectrum has no significant effect on the internal quality of Wh. pigra. PMID- 29243423 TI - [Effects of sampling time on polysaccharides of Dendrobium catenatum under temperature-controlled condition]. AB - In order to reveal the accumulation trend of polysaccharides in Dendrobium catenatum and determine the effect of sampling time on polysaccharides, D. Catenatum D21 clone was harvested from January to December after culturing for 2 to 5 months in the growth chamber with constant temperature. Polysaccharides were determined by phenol-sulfuric acid method and the monosaccharide compositions were analyzed by pre-column derivative-UPLC. The results showed that the content of polysaccharide and its key component mannose was positively correlated with the culture time, but the contents of polysaccharides in all kinds of culture peaked from 5 to 6 months, which were consistent with the trend of field planting. The results suggested that the trend of polysaccharide accumulation in the plant could be related to the life rhythm of the sensory seasons of D. catenatum, which was significantly affected by the harvesting season, even under the constant condition of the culture chamber. PMID- 29243424 TI - [Tissue culture of callus and establishment of regeneration system of Tussilago farfara petiole]. AB - Young petiole of Tussilago farfara was used as the material to investigate the plant growth regulators which could influence in vitro culture and plant regeneration and to establish rapid propagation technique. The ideal sterilization method was that young petiole of T. farfara was sterilized with 75% ethanol for 30 s, and then transferred to saturated bleaching power supernatant for 15 min. The suitable medium for callus induction was MS+6-BA 3.0 mg*L-1+2,4-D 2.0 mg*L-1 with 96.2% induction rate. The seedlings had better differentiation with 91% differentiation rate and 8.26 buds on the medium containing MS+ZT 2.0 mg*L-1+NAA 0.3 mg*L-1. The preferred enrichment medium of adventitious bud was MS+KT 1.0 mg*L-1+IBA 0.3 mg*L-1 with 11.81 enrichment times and 4.9 cm seedling height. The rooting medium included 1/2MS+IBA 0.2 mg*L-1 with the average number of rooting was 5.86 and the rooting rate was above 95.22%. The container seedlings can grow well and the survival rate was more than 90% when they were transplanted on the medium added with river sand and organic fertilizer with the ratio of 3?1. The field experiments indicated that significant differences in increment and yield of pollen grains among the tissue-culture, cultivation and wild type of T. farfara under the same cultivation conditions. The cultivated plants were relatively high on the increment and yield of pollen grains. The active ingredient content of the tissue culture and the wild materials was basically the same. PMID- 29243426 TI - [Monitoring method of extraction process for Schisandrae Chinensis Fructus based on near infrared spectroscopy and multivariate statistical process control]. AB - To establish an on-line monitoring method for extraction process of Schisandrae Chinensis Fructus, the formula medicinal material of Yiqi Fumai lyophilized injection by combining near infrared spectroscopy with multi-variable data analysis technology. The multivariate statistical process control (MSPC) model was established based on 5 normal batches in production and 2 test batches were monitored by PC scores, DModX and Hotelling T2 control charts. The results showed that MSPC model had a good monitoring ability for the extraction process. The application of the MSPC model to actual production process could effectively achieve on-line monitoring for extraction process of Schisandrae Chinensis Fructus, and can reflect the change of material properties in the production process in real time. This established process monitoring method could provide reference for the application of process analysis technology in the process quality control of traditional Chinese medicine injections. PMID- 29243425 TI - [Overexpression and isolation of CYP76AH1 in Salvia miltiorrhiza hairy roots]. AB - Protein complexes are involved in the synthesis of multiple secondary metabolites in plants, and their separation is essential to elucidate plant secondary metabolism and improve in vitro catalytic efficiency. In this study, the transgenic hairy roots of CYP76AH1, a key enzyme of tanshinone synthesis pathway, was constructed and the transgenic hairy roots of Danshen overexpressing CYP76AH1 protein were screened by Western blotting and used as a tissue culture material for the subsequent extraction of protein complex in tanshinone synthesis pathway. By optimizing the type and concentration of the detergent in the protein extraction buffer, the buffer containing 0.5% Triton X-100 was selected as the best extraction buffer, and a relatively large amount of soluble CYP76AH1 protein was isolated. This study lays the foundation for the further separation and purification of protein complexes interacting with CYP76AH1, and provides the idea for deep analysis of tanshinone metabolic pathway. PMID- 29243428 TI - [Relative molecular mass and monosaccharide composition of polysaccharide in Dendrobium officinale flowers]. AB - In order to provide new information on polysaccharide in Dendrobium officinale flowers,the monosaccharide composition and relative molecular mass distribution of 11 families of flowers were investigated and analyzed by high performance gel filtration chromatography (HPGFC) and pre-column derivatization ultra performance liquid chromatography (UPLC) in this study. Then cluster analysis was carried out for the monosaccharide peak areas by utilizing SPSS 19.0 software. The results showed that the polysaccharides of all the above 11 hybrid families of D. officinale flower were separated into three fractions (DOP-1, DOP-2 and DOP-3) with the average relative molecular mass of 5.53*105, 3.49*105 and 2.12*105. The polysaccharides in 11 different families were mainly composed of glucose, mannose, galactose, galacturonic acid and arabinose; mannose had the highest proportion among them, with mannose/glucose ratio of 0.302-3.335. Additionally, the relative contents of various monosaccharides in different families varied. 11 families of D. officinale flower could be classified into four categories according to their monosaccharide components and relative contents. In this study, the relative molecular mass distribution and monosaccharide composition of polysaccharides in D. officinale flowers were defined, which can provide foundations for its resource utilization.. PMID- 29243427 TI - [Adsorption characteristics of proteins on membrane surface and effect of protein solution environment on permeation behavior of berberine]. AB - In order to explore the adsorption characteristics of proteins on the membrane surface and the effect of protein solution environment on the permeation behavior of berberine, berberine and proteins were used as the research object to prepare simulated solution. Low field NMR, static adsorption experiment and membrane separation experiment were used to study the interaction between the proteins and ceramic membrane or between the proteins and berberine. The static adsorption capacity of proteins, membrane relative flux, rejection rate of proteins, transmittance rate of berberine and the adsorption rate of proteins and berberine were used as the evaluation index. Meanwhile, the membrane resistance distribution, the particle size distribution and the scanning electron microscope (SEM) were determined to investigate the adsorption characteristics of proteins on ceramic membrane and the effect on membrane separation process of berberine. The results showed that the ceramic membrane could adsorb the proteins and the adsorption model was consistent with Langmuir adsorption model. In simulating the membrane separation process, proteins were the main factor to cause membrane fouling. However, when the concentration of proteins was 1 g*L-1, the proteins had no significant effect on membrane separation process of berberine. PMID- 29243430 TI - [Study on screening antitumor active fractions and chemical components in active fractions from root of Anaycclus pyrethrum]. AB - Components that systematic separated from the root of Anaycclus pyrethrum were identified, in order to lay a foundation for future study of the root of A. pyrethrum. The CCK-8 assay showed that dichloromethane fraction exhibited the highest degree of cytotoxicity than others. Ten monomeric components were obtained from dichloromethane fraction and ethyl acetate fraction extracted from the root of A. pyrethrum, including 7 N-alkylamides, one coumarin and two flavonoid glycosides. They were identified as tetradeca-2E,4E,8E-trienoic acid 4 hydroxyphenylethylamide(1), deca-2E,4E-dienoicacid isobutylamide(2), undeca-2E,4E diene-8,10-diynoic acid phenylethylamide(3), tetradeca-2E,4E-dienoic acid 4 hydroxyphenylethylamide(4), tetradeca-2E,4E-diene-8,10-diynoic acid isobutylamide(5), deca-2E,4E- dienoic acid 4-hydroxyphenylethylamide(6), dodeca 2E,4E-dienoic acid 4-hydroxy -phenyl-ethylamide(7), isoscopoletin(8), quercetin-7 O-beta-D-glucopyranoside(9), isorhamnetin-7-O-beta-D-glucopyranoside(10). Among them, compound 1 was identified as a new compound, Compounds 2-4, 8-10 were isolated from this herb for the first time. PMID- 29243429 TI - [Effects of different drying methods on content of bioactive component and antioxidant activity in Lycium ruthenicum]. AB - To compare the appearances, tastes, contents of bioactive components and antioxidant activity of Lyceum ruthenicum under different drying methods, so as to direct its production practice. The folin-phenol colorimetric method, UV, extinction coefficient method and DPPH, as well as fluorescence recovery after photobleaching (FRAP) method to determine the contents of polyphenols, proanthocyanidins, total anthocyanin and antioxidant activity under different drying methods: vacuum freeze drying, low-temperature oven drying and air drying for L. ruthenicum. The results showed that the drying methods had certain effects on its appearances, tastes, contents of bioactive components and antioxidant activity. The appearances and tastes were best after the L. ruthenicum was dried by vacuum freeze drying, with significantly lower moisture than air drying method. The contents of total polyphenols, anthocyanin and proanthocyanidins were highest by air-drying but lowest by low temperature oven drying in L. ruthenicum. The scavenging ability to DPPH was strongest by freeze-drying and lowest by low temperature oven drying, while the antioxidant activity was strongest by air drying in the FRAT method. In addition, the appearances and tastes were poor in air drying, with higher moisture but highest contents of the three bioactive components. Therefore, the drying methods for L. ruthenicum shall be comprehensively considered. PMID- 29243431 TI - [Sesquiterpenes with anti-metastasis breast cancer activity from Chloranthus henryi]. AB - To study sesquiterpenes with anti-metastasis breast cancer activity from Chloranthus henryi, ten sesquiterpenes ,zedoarofuran (1), chlorajapolide D (2), 4beta, 8beta-dihydroxy-5alpha(H)-eudesm-7(11)-en-8, 12-olide (3), curcolonol (4), lasianthuslactone A (5), chlomultin C (6), (1E,4Z)-8-hydroxy-6-oxogermacra-1(10), 4, 7(11) -trieno-12, 8-lactone (7), shizukanolide E (8) , shizukanolide F (9) , 9alpha-hydroxycurcolonol (10), and five bis-sesquiterpenes, shizukaol B (11), shizukaol C (12) , cycloshizukaol A (13) , sarcandrolide B (14) , henriol A(15), were isolated by using different kinds of column chromatography methods from the ethyl acetate part of Ch.henryi and their structures were identified based on spectroscopic methods. Compounds 2, 8, 9, and 10 were obtained from the genus Chloranthus for the first time. Compounds 2, 5, 8-10, 12,and 14 were obtained from this plant for the first time. Some isolated compounds were subjected to evaluate the anti-metastasis breast cancer activity by using pharmacological methods, and only compounds 4, 11, and 12 were potent active. PMID- 29243433 TI - [Comparative study on specific chromatograms and main nucleosides of cultivated and wild Cordyceps sinensis]. AB - This study is to establish the HPLC specific chromatogram and determine four main nucleosides of wild and cultivated Cordyceps sinensis. Uridine, inosine, guanosine and adenosine were selected as reference substance. HPLC analysis was performed on a Waters XSelect HSS T3 C18 (4.6 mm*250 mm, 5 MUm), with a mobile phase consisting of water(A)-acetonitrile (B) at a flow rate of 0.6 mL*min-1 (0-5 min,0% B;5-15 min,0%-10% B, 15-30 min,10%-20% B, 30-33 min, 20%-50% B, 33-35 min, 50%-0% B, 35-40 min, 0% B). The detection wavelength was 260 nm and the column temperature was controlled at 30 C, and the injection volume was 5 MUL. HPLC specific chromatogram of wild and cultivated C. sinensis was established and four main nucleosides were simultaneously determined by the above method. Specific chromatograms and contents of four main nucleosides showed no significant differences between cultivated and wild C. sinensis. These results can provide scientific evidences for further development and utilization of cultivated C. sinensis. PMID- 29243437 TI - [Intervention effects of Zuoguiwan containing serum on osteoblast through ERK1/2 and Wnt/beta-catenin signaling pathway in models with kidney-Yang-deficiency, kidney-Yin-deficiency osteoporosis syndromes]. AB - To clarify the effects of Zuoguiwan containing serum on osteoblast proliferation and alkaline phosphatase(ALP) expression and its effects on the expression of beta-catenin, ERK1, ERK2 mRNA and protein of osteoblast through ERK1/2, Wnt/beta catenin signaling pathway in models with osteoporosis(OP) kidney-Yang-deficiency, osteoporosis(OP) kidney-Yin-deficiency syndrome. Rat osteoporosis models were established by ovariectomy surgery, and 10 weeks after surgery, hydrocortisone was injected and thyroxine was administered by intragastric administration to establish OP kidney-Yang-deficiency rat model, and OP kidney-Yin-deficiency rat model. Osteoblasts were obtained from 24 h newborn rat skull and were identified by alkaline phosphatase and alizarin red staining. Zuoguiwan containing serum of OP, OP kidney-Yang-deficiency, and OP kidney-Yin-deficiency, as well as the blank serum were used to intervene the osteoblast, and the cells proliferation was detected by MTS. ELISA assay was used to detect ALP expression. RT-PCR assay was used to detect the mRNA expression of ERK1, ERK2, beta-catenin and protein expression levels were detected by Western blot. The results showed that Zuoguiwan containing serum in OP kidney-Yin-deficiency model had stronger effect than OP kidney-Yang-deficiency in promoting osteoblast proliferation, ALP expression, osteoblast ERK1/2, Wnt/beta-catenin signaling pathway related factors beta-catenin, ERK1, ERK2 mRNA and protein expression levels. This was consistent with the TCM theory of "Zuoguiwan nourishes kidney Yin", providing a scientific basis for the clinical and dialectical treatment of osteoporosis. Zuoguiwan could regulate the proliferation and differentiation of bone cells by ERK1/2 and Wnt/beta-catenin signaling pathway, which may be one of the mechanisms of Zuoguiwan for the prevention of osteoporosis. PMID- 29243432 TI - [Qualitative and quantitative analysis of Evodiae Fructus based on the UPLC technology]. AB - An UPLC method was developed for the studies of fingerprint and quantification of multi-components for Evodiae Fructus. The chromatographic separation was performed on a C18 column (2.1 mm*50 mm,1.7 MUm) with mobile phase of 0.2% formic acid-acetonitrile and 0.2% formic acid-water in gradient mode, and the detection wavelength was set at 320 nm.Dehydroevodiamine was used as the reference peak, there were 24 common peaks in the fingerprint of 29 samples were detected, and among them 10 chromatographic peaks were identified with the reference substance and they were neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, hyperin, isorhamnetin-3-O-beta-D-rutinoside, dehydroevodiamine, evodiamine, rutaecarpine, evocarpine and dihydroevocarpine. The fingerprint data was evaluated with similarity evaluation system for chromatographic fingerprint of traditional Chinese medicine (Version 2008A), and the similarity of 19 batches of Evodiae Fructus was greater than 0.9 in the 29 samples. In addition, 9 components including neochlorogenic acid, chlorogenic acid, hyperin, isorhamnetin-3-O-beta-D rutinoside, dehydroevodiamine, evodiamine, rutaecarpine, evocarpine and dihydroevocarpine were simultaneously determined at the same chromatographic conditions, whose peak area integral values showed good linear relationship at the range of 0.000 46-0.138, 0.000 146-0.175, 0.000 412-0.124, 0.000 448-0.134, 0.000 452-0.136, 0.003 38-0.169, 0.000 44-0.132, 0.001 07-0.128, 0.001 71-0.128, respectively. Their average recoveries were 100.3%, 100.4%, 101.6%, 97.51%, 102.9%, 101.4%, 103.8%, 104.0%, 95.99%, and RSD were 2.4%, 2.0%, 3.0%, 0.80%, 1.9%, 2.1%, 1.1%, 2.2%, 2.4%, respectively. The established UPLC method not only realized the full separation of all chemical constituents of Evodiae Fructus within 20 minutes, but also achieved the chromatographic fingerprint determination and simultaneous multi-components determination of Evodiae Fructus at the same chromatographic conditions. Compared with other methods in literatures, the method has the following characteristics of strong specificity, good separation, high purity of chromatographic peaks, simplity and feasibility, which provides better means for the simultaneous qualitative and quantitative analysis of Evodiae Fructus. PMID- 29243438 TI - [Effects of aqueous extracts of gecko on stemness of hepatocellular carcinoma]. AB - To explore the effects and mechanism of aqueous extracts of gecko on cancer stem cells properties of hepatocellular carcinoma. In vitro, MTT assay was used to detect the cells growth in Huh7 and Hep3B. Spheroid-forming assay and flow cytometry were performed to observe the the stemness of Huh7 and Hep3B cells. The protein expressions of beta-catenin, CD44, c-Myc, CCND1, Sox2, Oct4, Nanog and ABCG2 were detected by Western blot. Interacting proteins were detected by co immunoprecipitation; and a subcutaneous xenograft model was used to detect the stemness of hepatoma carcinoma cells. The results indicated that aqueous extracts of gecko induced cell growth inhibition in a dose- and time-dependent manner, with the IC50 of (0.750+/-0.112) g*mL-1 for Huh7 and (0.454+/-0.039) g*mL-1 for Hep3B, respectively. The number and size of tumor spheres formed by hepatoma carcinoma cells were decreased after treatment by aqueous extracts of gecko(P<0.05); the proportions of cells staining with putative markers for cancer stem cells, such as CD133 and CD44, were decreased(P<0.05). After treatment with aqueous extracts of gecko, the expression levels of beta-catenin, CD44, c-Myc, CCND1, Sox2, Oct4, Nanog and ABCG2 were decreased. Co-immunoprecipitation results showed that the aqueous extracts of gecko could inhibit the interaction between LRP6 and Frizzled6, indicating that the aqueous extracts of gecko could inhibit the proliferation of hepatoma cells, the formation of tumor spheres and the proportion of tumor stem cells, and inhibit the Wnt signaling pathway by targeting LRP6 to prevent the formation of LRP6 and Frizzled6 complexes. PMID- 29243434 TI - [Influence of different cultivation measures on the content of three free carbohydrates of Codonopsis Radix]. AB - To provide a scientific evidence for the quality control of Codonopsis Radix, a method was established for determining the content of three free carbohydrates of Codonopsis Radix. The developed method showed good linearity. The calibration curves were linear within the range of 2.312 5-18.500 0 MUg for sucrose, 1.500 0 12.000 0 MUg for glucose, and 2.000 0-16.000 0 MUg for fructose, resgectwely. The recoveries varied between 96.31%-101.8%. The method is simple, accurate and reproducible, and can be used for determining the content of sucrose, glucose and fructose of Codonopsis Radix. The results showed that different cultivation measures had an effect on the content of three free carbohydrates of Codonopsis Radix. According to the content of sucrose, using Zhuanggenling>not using Zhuanggenling. While, not pinching, shelving>not pinching, not shelving>pinching, not shelving>pinching, shelving. According to the content of glucose and fructose, not using Zhuanggenling>using Zhuanggenling. While, pinching, shelving>not pinching, not shelving>not pinching, shelving>pinching, not shelving. In consideration of the differences of sweetness and content of the three free carbohydrates in Codonopsis Radix, we recommend that the content of free carbohydrates could be considered as the marker to evaluate the quality of Codonopsis Radix. PMID- 29243436 TI - [Effect of neoflavonoid latifolin isolated from Dalbergia odorifera on acute myocardial ischemia in rats and its mechanism of Nrf2 signaling pathway]. AB - The present study was designed to evaluate the cardioprotective effect of latifolin on pituitrin(Pit) or isoproterenol(ISO)-induced myocardial injury in rats, and further investigate its underlying mechanisms. Rats were administrated sublingually with pituitrin or subcutaneously with isoproterenol to induce acute myocardial ischemia in rats, and lead II electrocardiograph was recorded. In rats with isoproterenol, ELISA assay or colorimetric method was used to detect the content or activity of myocardial injury markers in serum, and the SOD activity and MDA content in myocardium were detected by colorimetric assay; histopathological examination was conducted by HE staining; the frozen section of myocardial tissues was used for DCFH-DA fluorescent staining to detect the content of ROS in myocardium; Western blot was used to detect the protein expression levels of Nrf2, Keap1, HO-1 and NQO1 in myocardium. Results showed that latifolin significantly inhibited ST-segment changes induced by pituitrin or isoproterenol, and increased heart rate. Further mechanism study showed that latifolin reduced cardiac troponin I(cTnI) level, aspartate transaminase(AST) and lactate dehydrogenase(LDH) activities in serum, increased myocardial superoxide dismutase(SOD) activity and reduced myocardial malondialdehyde(MDA) level, and protected myocardium with less necrosis, infiltration of inflammatory cells and fracture of myocardial fibers. Furthermore, latifolin obviously reduced ROS level in myocardium, inhibited the expression of Kelch-like ECH-associated protein 1(Keap1), increased the nuclear translocation of nuclear factor erythroid 2 related factor 2(Nrf2), and promoted the expression of Heme oxygenase-1(HO-1) and NAD(P)H quinone oxidoreductase-1 (NQO1) in myocardial tissues. Our data suggest that latifolin has a potent protective effect against pituitrin or isoproterenol induced myocardial injury, which may be related to inhibition of oxidative stress by activating Nrf2 signaling pathway. PMID- 29243435 TI - [New qualities control strategy of Scutellaria baicalensis by isothermal titration calorimetry]. AB - It has been focused on that there will be precipitates when decoction of Scutellariat Radix mixed with Coptidis Rhizoma. Precipitation was derived from interaction between acidic and basic compounds. This study was based on the interaction between active ingredients after compatibility, strived to explore whether it was feasible to judge the qualities of different Scutellariat Radix by isothermal titration calorimetry (ITC), build a new method established to characterize the qualities of traditional Chinese medicine by taking a series of active ingredients as index. We selected Scutellariat Radix (including three batches of different Scutellariat Radix bought from market and immature Scutellariat Radix which usually was used as adulterant) in different batches as the samples. First, we used ITC to determine the binding heat of the reactions between berberine and the decoctions of different Scutellariat Radix. The test showed that the binding heat of berberine titrated Scutellariat Radix was Scutellariat Radix A (-317.20 MUJ), Scutellariat Radix B (-292.83 MUJ), Scutellariat Radix C (-208.95 MUJ) and immature Scutellariat Radix (-21.53 MUJ), respectively. We chose deionized water titrated by berberine (2.51 MUJ) as control. The heat change of berberine titrated immature Scutellariat Radix was much less than berberine titrated Scutellariat Radix. Then we determined the absorbance of different decoctions of Scutellariat Radix by UV Spectrophotometry on the maximum absorption wavelength, and the result is: Scutellariat Radix A (0.372), Scutellariat Radix B (0.333), Scutellariat Radix C (0.272), immature Scutellariat Radix (0.124). The absorbance of immature Scutellariat Radix was also less than Scutellariat Radix. The result of ITC assay was corresponded to UV spectrophotometry test. In conclusion, ITC could be used to characterize the quality of Scutellariat Radix. The new method to characterize the qualities of traditional Chinese medicine by taking a kind of active ingredients as index building by ITC was simple, scientific and feasible. PMID- 29243439 TI - [Identification of saponins from Panax notoginseng in metabolites of rats]. AB - UPLC-QTOF-MS/MS was used to identify metabolites in rat blood, urine and feces after the administration of n-butanol extract derived from steamed notoginseng. The metabolic process of saponins came from steamed notoginseng was analyzed. The metabolites were processed by PeakView software, and identified according to the structural characteristics of prototype compounds and the accurate qualitative and quantitative changes of common metabolic pathways. Four saponins metabolites were identified based on MS/MS information of metabolites, namely ginsenoside Rh4, Rk3, Rk1, Rg5,and their 15 metabolites were verified. The metabolic pathways of the four ginsenosides in n-butanol extract included glucuronidation, desugar, sulfation, dehydromethylation, and branch loss. The metabolites of main active saponin components derived from steamed Panax notoginseng were analyzed from the perspective of qualitative analysis. And the material basis for the efficacy of steamed notoginseng was further clarified. PMID- 29243440 TI - [Tissue distribution of araloside A in rats]. AB - Araloside A is one of the main active ingredients of Aralia taibaiensis. In this study, HPLC-MS/MS analysis method of araloside A in the main organs of SD rats was established. At the same time, the content of araloside A in the main organs (heart, liver, spleen, lung, kidney, brain) after oral administration with araloside A (50 mg*kg-1) were determined to explore the tissue distribution characteristics of araloside A in vivo. The results showed that the methodological study of araloside A in the main organs of SD rats met the requirements, araloside A distributed in heart, liver, spleen, lung, kidney and brain tissues reached peak at 1 h or 2 h after oral administration with 50 mg*kg 1.The distributions of araloside A at different time points after administration were distinct as follows: the content of araloside A at 20 min:liver>heart>spleen>lung>kidney>brain; the content of araloside A at 1 h: liver>spleen>kidney>lung>heart>brain; the content of araloside A at 2 h: liver>kidney>heart>spleen>lung>brain; the content of araloside A at 4 h: kidney>liver>spleen>heart>lung>brain; the content of araloside A at 8 h: spleen>heart>liver>kidney>lung>brain. Therefore, araloside A was mainly distributed in liver tissue, which had a certain correlation with the common use of Aralia taibaiensis in the treatment of hepatic disease. In addition, araloside A shows a low content but an obvious distribution in brain tissues, which indicates that the drug can pass through blood-brain barrier, and provides the basis for the study of araloside A in brain tissue. PMID- 29243441 TI - [Efficacy and safety of Kuhuang injection in treating viral hepatitis: systematic review and Meta-analysis of randomized controlled trials]. AB - To systematically evaluate the effectiveness and safety of Kuhuang injection in treating viral hepatitis. Eight electronic databases and clinic trials were searched to collect randomized controlled trials for the effect of Kuhuang injection in the treatment of viral hepatitis. According to the Cochrane Handbook 5.1, two independent reviewers screened out the literatures, extracted data and assessed the quality of thestudies included. RevMan5.3 software was used for the data analysis. A total of 32 articles were included, involving 3 188 patients, including male 1 951 cases (61.2%), female 859 cases (26.9%), and 378 cases of unknown sex (11.9%). All the clinical studies showed a low quality. Due to the complication of diseases and difficulty in intervention measures, most trails were classified by the condition of diseases, and then a descriptive analysis was made. The results showed that the test group was better than the control group in total efficiency of treating severe icteric viral hepatitis, and the test group was advantageous over the control group in jaundice removal and liver function recovery rate in treating icteric hepatitis. In the Meta-analysis on the RCTs for icteric viral hepatitis, the total efficiency of Kuhuang injection + comprehensive treatment group was higher than that of the comprehensive treatment group (RR=1.35, 95%CI=[1.10,1.66], P=0.61). In addition, when Kuhuang injection was dripped too fast, patients had such adverse reactionsas dizziness, palpitation, nausea, vomiting and skin rash, which could be relieved at a lower dripping speed.Based on the existing evidences, Kuhuang injection had a certain effect in treating viral hepatitis. Most clinic trails did not include viral hepatitis etiology, clinical classification and diversified intervention measures, which resulted in a high clinical heterogeneity and poor comparability between trails. Besides, most trials had a low methodological quality, which affected the authenticity of the results. Therefore, more high-quality, multi center, large-sample, randomized double-blind controlled trialsarerequired to prove the evidences. PMID- 29243442 TI - [Regression analysis of serum bone metabolic markers and traditional Chinese medicine syndromes in patients with CKD-MBD]. AB - To analyze the interdependent relationship between serum bone metabolic markers and traditional Chinese medicine (TCM) syndromes in patients with chronic kidney disease (stages 3 and 4)-related mineral and bone disorder (CKD-MBD), in order to provide the objective basis for exploring the rules of TCM syndrome differentiation in patients with CKD-MBD. The retrospective survey was conducted to collect 105 cases with CKD (stages 3 and 4)-MBD. General clinical indexes, frequency of TCM syndromes and distribution of TCM syndrome type were investigated. Furthermore, serum bone metabolic markers, including calcium (Ca2+), phosphonium (P3+), intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), procollagen type 1 amino-N-terminal propeptide (P1NP) and beta crosslaps (beta-CTX) were analyzed, respectively. Meanwhile, bone mineral density (BMD) was assessed. And then, the multivariate regression analysis was performed for serum bone metabolic markers and TCM syndromes. The results showed that the general clinical features of the 105 patients included old age, hypertension, fracture, loss of bone mass and mild abnormalities of serum bone metabolic markers. High-frequency TCM syndromes were related to Yang deficiency in Spleen and Kidney, Qi deficiency in Spleen and Kidney and blood stasis. Moreover, Yang deficiency in Spleen and Kidney and blood stasis were found as the most frequent characteristics of the distribution of TCM syndromes type. The clinical characteristics of patients with the syndrome type of Yang deficiency in Spleen and Kidney were probably old age, increase in TCM syndrome scores and abnormalities in iPTH and P1NP. In addition, the interdependent relationship between abnormality in Ca2+ and syndromes of hair loss, tooth shake and sexual dysfunction, abnormality in P3+ and syndromes of aches in waist and knees, abnormality in iPTH and syndromes of soreness and weakness in waist and knees, lassitude, fatigue and extreme chilliness, abnormality in ALP and syndromes of loose stools, abnormality in P1NP and syndromes of fear of chills, tendency of warmth and loose stools, and abnormality in beta-CTX and syndromes of chills and pain in waist and knees. In general, among the 105 cases with CKD (stages 3 and 4)-MBD were clinically characterized by mild changes in serum bone metabolic markers; And their main TCM syndrome was the deficiency in spleen and kidney. Serum bone metabolic markers with mild changes have an interdependent relationship with main TCM syndromes, and can be considered as an objective syndrome factor of TCM syndrome differentiation. PMID- 29243444 TI - [Analysis of difficult problems on European Union laws and regulations of traditional herbal medicinal products]. AB - Registration of Chinese patent medicine in European Union (EU) is of great significance to the internationalization of traditional Chinese medicine as EU market acts as an important position in the global botanical market. In retrospect, the domestic studies on EU regulations of traditional herbal medicinal products have been conducted for more than 10 years, but there is still some cognitive bias and lack of research. In this paper, a review of the relevant research progress and the main misunderstanding problems about Directive 2004/24/EC, like the centralized and decentralized supervision system of traditional herbal medicinal products in the EU, marketing authorization procedures for traditional herbal medicinal products, Community Herbal Monograph and List Entries, would be systematically analyzed, so as to provide reference for the registration of Chinese patent medicine in EU. PMID- 29243443 TI - [Effect of clomiphene citrate and Dingkun Dan on ovulation induction and clinical pregnancy of polycystic ovary syndrome]. AB - The evaluation is based on clomiphene citrate (CC)+gonadotropin (Gn), clinical study on CC and Dingkun Dan's treatment on ovulation induction and clinical pregnancy effect of PCOS, and to provide ideas and methods for traditional Chinese medicine assisted reproductive treatment. This study selected 60 PCOS infertility patients treated with ovulation induction in reproductive medicine clinic, Jiangsu Province Hospital of traditional Chinese medicine during 2015-10 01-2017-04-23. They were randomly divided into two groups: Group A (CC+Gn+HCG) and Group B (CC+Gn+Dingkun Dan). These results were observed and compared including cycle ovulation rate, cycle cancellation rate, cycle pregnancy rate, cumulative pregnancy rate, endometrial thickness, duration of Gn, total amount of Gn, the occurring rate of luteinized unruptured follicle syndrome and ovarian hyperstimulation syndrome. Group A had lower cycle ovulation rate, cycle pregnancy rate, cumulative pregnancy rate and endometrial thickness, compared with Group B, the difference was statistically significant(P<0.05). However, Group A had higher cycle cancellation rate, duration of Gn and total amount of Gn, compared with Group B, the difference was statistically significant(P<0.05). In this study, no case of LUFS or OHSS was found in all patients. CC and Dingkun Dan had the effect of promoting ovulation on PCOS infertility patients, and CC+Gn+Dingkun Dan could elevate clinical pregnancy rate. PMID- 29243448 TI - Obstructive sleep apnea: are we going overboard? PMID- 29243445 TI - [Relationship between pre-clinical toxicity and efficacy of traditional Chinese medicine]. AB - Based on the different category of syndromes between traditional Chinese medicine(TCM) and Western medicine, the relationship between the efficacy and non clinical toxicity of the TCM was analyzed. If TCM preparations have the same pharmacological targets to treat disease with modern medicine or the Chinese herbal preparations treat the diseases with its toxicity, their toxicity often exhibits the amplification and extension of activity; on the other hand, if TCM preparations have overlapped pharmacological targets but not completely the same with modern medicine, or if they have totally different pharmacological targets, the toxicity of TCM could not be inferred by pharmacological activity. With the great progress in extraction and separation technique for active parts of TCM as well as the application of some novel technique and excipients, some toxicity may be from the reactions unrelated with the pharmacological activity. In conclusion, better design and quality control could be obtained by understanding the relationship between pharmacological and toxicological study for the investigation of new traditional medicine. PMID- 29243462 TI - Editorial. PMID- 29243463 TI - ALL THINGS DIGITAL. AB - Recently I attend the Nursing Informatics Australia annual conference in Melbourne. The theme of the conference was the role of the nurse in digital health innovation for consumers, clinicians, connectivity and community. PMID- 29243464 TI - ALL HANDS ON TECH. HOW DIGITAL TECHNOLOGY IS REDEFINING HEALTHCARE. AB - Digital technology is on the cusp of transforming healthcare. The number of health apps at the fingertips of consumers has surpassed 165,000, giving people around the world more access to information than ever and the tools to take care of themselves. Similarly, the adoption of digital medical records across clinical settings is another catalyst shaping the new landscape. Robert Fedele explores the digital health movement amid its upward spiral. PMID- 29243451 TI - [Gestures facilitate interaction in multicultural primary care consultations]. AB - Using gestures simultaneously with speech prevents and solves problems of understanding in consultations where the doctor and the patient do not share the same cultural and linguistic background. Gestures illustrate what is being said, and highlight the essential information. As gestures are used globally, and can also be interpreted despite limited vocabulary, they make the speech easier to follow. In primary care consultations, the topics are easily expressed by gestures, as they are often related to physical matters such as body parts, symptoms, examinations and treatment. Furthermore, gestural mimicry conveys empathy and willingness to collaborate. PMID- 29243453 TI - [New self-assessment tools for evaluating work ability]. AB - Assessment and support of the work ability and function is an elementary responsibility of health care. The focus of assessment lies in the remaining functional capacity and its sufficiency with respect to occupational demands. Objective and subjective perspectives, personal resources and limitations, and the subject's relationship to the environment are taken into account according to biopsychosocial models of work ability. We recommend three useful self-report measurement tools for work ability and function. Return-to-Work-Readiness Questionnaire (RTW-RQ), Return-to-Work Self-Efficacy (RTW-SE) and Sheehan Disability Scale (SDS). These tools structure an interactive evaluation providing possibilities for follow-up. They provide means to discuss one's personal resources and limitations and to promote return-to-work. PMID- 29243461 TI - [Physicians' working conditions, health and working capacity]. AB - Changes in the working environment will also influence the work of physicians. The greatest of these changes on the Finnish scale, the SOTE reform (the reform in social welfare and public health services), still lies ahead. Labor shortage, on-call duties and patient record systems providing little support to work add to the burden. In surveys related to psychosocial working conditions, physicians' greatest work load factors have been rush, forced working pace and poor communication despite the fact that, on average, they consider their working conditions to be good, frequently better than those of other professional groups, and are committed to carry on with their work until retirement age. Although psychic symptoms and sleep disturbances are common among physicians, there are fewer disability pensions due to e.g. depression among physicians than in other professional groups. Among the municipal professions, physicians have nearly the lowest rate of job absenteeism due to sickness. Challenges brought about by the changes in physician's work can be met with fair management, development of the social capital of the work community, organization of tasks and flexibility of working hours. PMID- 29243447 TI - Evaluation of patients' compliance in different age groups: preventive methodology. AB - BACKGROUND: The aim of this work was to evaluate the effectiveness of the SSRD Department of University of Milan PREVENTION PROGRAM between subjects of different sex and ages. METHODS: Prevention Program is divided into six stages, in which specific and standardized procedures are effected on patient; then checkups are planned after three months. Ninety patients (48 females, 42 males) were included. Subjects were divided into three ages groups: 6-9, 10-12 and over 12 years old. Plaque Index, Bleeding Index, and quantitative and qualitative variations of bacterial plaque were considered. RESULTS: Remarkable results were obtained regarding both the effective reduction of bacterial oral flora and patient's compliance and learning, especially in the group of patients older than 10 years. The new values of parameters recorded at the end of the study showed that all the subjects included in the sample had an improvement of compliance in oral hygiene, in particular: 1) P.I. level 3, 10-12 age, female; 2) B.I. level 4, males over 10, female 6-9 age; 3) quantitative and qualitative variations of bacterial plaque, level 4, all groups. CONCLUSIONS: Patient instruction and motivation allow to obtain optimal results in particular in patients aged more than 10 years. PMID- 29243449 TI - Are we ready for automated optimal cerebral perfusion pressure? PMID- 29243446 TI - Prevalence of dental caries among schoolchildren from North-Eastern Italian population. AB - BACKGROUND: The longitudinal aspect of dental caries has not been previously reported for the Italian population. The primary object of the present study is to collect information of the prevalence of dental decay among the schoolchildren of primary school of Gradisca d'Isonzo (GO) and to analyze the tendency of caries among the students followed since the first year of school. METHODS: Subsequent examinations hold from 2011 to 2015 has been conducted by two calibrated examiners. Oral hygiene instruction and motivation followed the visits. According to WHO principals DMFT and dmft were recorded. The children in the survey were divided into 5 groups according to their ages (6, 7, 8 and 9 years), and these groups were considered separately. Descriptive and statistical analysis of the data was conducted. RESULTS: More than 400 pupils were recruited, resulting in almost 900 examinations during 5 years. Overall, the %dft >=1 children range from 18.9% (10 years, 2013) to 53.5% (8 years, 2011) across the different age groups. Overall, the %DFT>=1 children range from 8.3% (6 years, 2011) to 44.1% (10 years, 2012) across the different age groups. CONCLUSIONS: Within the limits of the present study, the WHO goals are still not met, among the population in exam. Our results show a trend of decay diminution that enhances in the cohort of 10-aged children suggesting the importance of dental education. Furthermore, the lack of pediatric initiatives of oral hygiene may be overcome by a national intensive educational program, supported by further scientific evidence. PMID- 29243458 TI - Prevalence of life-supporting prolonged invasive ventilation support in Finland. AB - BACKGROUND: There is no comprehensive data in our country on the prevalence of life-supporting prolonged invasive ventilation support. The objective of the survey was to clarify in all hospital districts of continental Finland the prevalence of patients who were dependent on invasive ventilation support, and the disease leading to the treatment. PATIENTS AND METHODS: The KOTIVEHNO 2015 survey was carried out as population-based cross-sectional study by sending a questionnaire to all doctors in charge of prolonged invasive ventilation support. The questionnaires were used to collect data on the patients within care on 1st January, 2017. RESULTS: The prevalence of life-supporting prolonged invasive ventilation support in Finland among the population aged over 16 years or more was 2/4 patients/100,000 habitants. Altogether 107 patients were within the care. There was variation in the prevalence among the hospital districts. Of the patients, 24% were affected with a motoneuron disease, in 18% the cause was spinal cord injury, 15% suffered from Duchenne's muscular dystrophy, and the rest had some other rare neurological disease. CONCLUSIONS: Life-supporting prolonged invasive ventilation support is rare in Finland. The treatment is associated with neuromuscular diseases causing respiratory insufficiency, and with spinal cord injuries. PMID- 29243459 TI - Adrenomyeloneuropathy due to mutation in the ABCD1 gene as underlying factor in spastic paraparesis. AB - We present a Finnish family in which adrenomyeloneuropathy (AMN) caused by the mutation in the ABCD1 gene was revealed as the cause of spastic paraparesis. . Two patients had hypoadrenalism, which is in some cases some associated with the disease . AMN is a hereditary disease manifested both in men and women. but owing to the location of the gene in the X chromosome the symptoms are usually more severe in male patients. . Diagnoses was trucked down with gene-panel sequencing and confirmed through detection of an elevated level of very long-chain fatty acids in the serum of the patients. Specific molecular genetic diagnosis is beneficial, because it enables precise genetic counseling as well as recognition and treatment of associated symptoms, such as severe cortisol deficiency. PMID- 29243454 TI - The use of laparoscopy for locally advanced rectal cancer. AB - INTRODUCTION: In the last decades, the use of minimally invasive surgery has dramatically increased for the treatment of rectal cancer. However, no clear evidence exists on the role of laparoscopy for locally advanced rectal cancer, especially for cT4 tumors, after neoadjuvant therapy. EVIDENCE ACQUISITION: A literature search was performed on Embase, Medline, and Cochrane databases to identify relevant studies published up to November 2017 analyzing the outcomes of laparoscopic surgery for locally advanced rectal cancer. EVIDENCE SYNTHESIS: Systematic reviews and meta-analyses showed that laparoscopic proctectomy is associated with faster recovery compared to open approach while oncologic and survival outcomes are equivalent. However, concerns still exist on the quality of laparoscopic mesorectal excision. In the majority of the available studies, cT4 tumors were not included, but based on few retrospective series in tertiary referral centers laparoscopic rectal resection of T4 rectal cancer appeared to be safe and feasible, with faster recovery and adequate oncologic outcomes. Robotics and transanal approaches are promising minimally invasive alternatives. CONCLUSIONS: Locally advanced rectal cancers require multidisciplinary management including neoadjuvant chemo-radiotherapy and surgery. Preoperative re-staging may be useful to plan the best surgical procedure. Minimally invasive surgery, especially laparoscopy, can provide adequate outcomes in selected patients with locally advanced rectal cancer with the advantage of faster recovery compared to open surgery. However, the overall evidence is poor, and further studies are needed to elucidate the role of minimally invasive surgery for cT4 rectal cancer. PMID- 29243456 TI - Robotic versus laparoscopic sleeve gastrectomy: a review of the current evidence. AB - INTRODUCTION: The purpose of the present study was to review the existing evidence on obese patients treated with either robotic or laparoscopic sleeve gastrectomy, in order to compare the clinical and perioperative outcomes of the two methods. EVIDENCE ACQUISITION: A systematic literature search was performed in PubMed, Cochrane library and Scopus databases. EVIDENCE SYNTHESIS: Sixteen studies were included in the present review and incorporated 29,787 patients. RSG technique was associated with significantly increased mean operative time and length of hospital stay. Postoperative incidence of leakage, bleeding, wound infection and excess weight reduction were comparable between the two groups. The majority of the studies assessing cost found higher charges in RSG population. CONCLUSIONS: Newer randomized controlled trials, comparing RSG to LSG, are necessary in order to further assess their clinical outcomes in relation to cost. PMID- 29243450 TI - [Pathogenesis of age-related macular degeneration - dialogue between autophagy and inflammasomes] . AB - Age-related macular degeneration is a condition affecting central vision, and is the leading cause of blindness and visual impairment in the western countries. For a long time, inflammation has been associated with the pathogenesis of the condition, and according to current knowledge, inflammation in the retinal pigment epithelial cells (RPE) results from an impairment of intracellular cleansing systems. In combination with the degeneration of RPE cells, this eventually leads to the destruction of light-sensing cells. By influencing the accumulation or elimination of waste material or the inflammatory reaction following its accumulation we may in the future possibly slow the progression of the disease or, in the best case, even cure it. PMID- 29243466 TI - HAVE YOU HAD THE HPV VACCINE? YOU STILL NEED TO BE SCREENED FOR CERVICAL CANCER. AB - Nearly all cervical cancer is caused by one or more oncogenic strain of Human Papilloma Virus (HPV) (Walboomers et al. 1999). There are about 40 anogenital HPV types and approximately 15 are associated with cancer of the cervix. PMID- 29243452 TI - [Laparoscopic appendectomy]. AB - Laparoscopic appendectomy has practically replaced open surgery. Appendectomy, i.e. surgical excision of the appendix, is one of the most common procedures of a specializing surgeon, and serves to help learn the basics of laparoscopy - first by following and later independently performing the operation. Properative preparation, precise diagnosis, correct surgical technique and follow-up treatment are the cornerstones of successful care. The anatomy of the patient must be considered in the placement of trocars. The appendix is usually easily found, but its position and location may vary. In the operation, the base and the artery of the appendix are ligated, and the appendix removed in a plastic bag. Also a healthy appendix should be removed, but in this case other causes of the symptoms should be searched for. Surgical excision of a perforated appendix is considerably more challenging, and peritonitis should be operated without delay. Surgery of a periappendicular abscess requires experience and should be postponed until daytime. Most patients having undergone an excision of non-perforated appendix can be discharged within 23 hours after the operation. PMID- 29243460 TI - [Update on Current Care Guideline: Neck pain (adults)]. AB - Neck pain is usually non-specific, but serious illness or specific reasons for neck pain need to be ruled out. Patients are encouraged to continue their daily activities. Acute neck pain often disappears without any special treatment. Patient information is important. If pain medication is needed, paracetamol is the primary choice. Multidisciplinary treatment is recommended if disabling pain does not improve during the first two months. Neck-specific exercises are recommended in the chronic phase. PMID- 29243457 TI - Surgical management of obesity. AB - Obesity is a spreading epidemic associated with significant morbidity and mortality with a prevalence of over 36% worldwide. In the face of a growing epidemic, increasing medical costs, and the disappointing limitations of medical and lifestyle modification bariatric surgery was found to consistently lead to significant weight loss and improvement in obesity-associated comorbidities when compared to non-surgical interventions. Bariatric procedures fall within three basic categories: restrictive procedures, malabsorptive procedures, and procedures that combine both restrictive and malabsorptive mechanisms. Four major procedures are currently performed (most often laparoscopically): Roux-en-Y gastric bypass, biliopancreatic diversion with duodenal switch, adjustable gastric banding, and sleeve gastrectomy. Although the laparoscopic Roux-en-Y gastric bypass was the most frequently performed bariatric procedure, the laparoscopic sleeve gastrectomy has since become the most popular. Bariatric surgery currently has similar mortality rates to standard general surgical operations. Morevoer, bariatric surgery reduces mortality by the improvement and remission of obesity-related comorbidities. Newer minimally-invasive weight loss procedures and endoscopic methods continue to evolve as we expand our understanding of the intricacies of obesity and the effects of currently available surgical treatments. PMID- 29243465 TI - Atypical hemolytic-uremic syndrome. AB - Atypical hemolytic-uremic syndrome (aHUS) is a rare form of thrombotic microagiopathy caused dysregulation of the alternative pathway of the complement resulting in tissue. In aHUS, activation of the alternative pathway of the complement is in an aberrant way directed against endothelial cells and blood cells. This is either due to a mutation in a complement factor, most commonly factor H, or an autoantibody against a complement regulator. In some patients the underlying disorder is not identified despite thorough examinations. Typical aHUS patients have acute kidney injury and microangiopathic hemolysis and, to a varying degree, disturbances of other organs. An effective inhibitor of the final product of complement, eculizumab, has revolutionized the treatment of these patients. PMID- 29243467 TI - High-resolution CT of the lungs: Indications and diagnosis. AB - High-resolution computed tomography (HRCT) is a method of examination which is more precise than chest 2-rat in the diagnosis and monitoring of diseases of the lung tissue and the airways. Modern CT equipment enables a volume HRCT scan covering the whole lung tissue. HRCT slices can also be constructed from contrast enhanced CT scans of the chest of the whole body. HRCT of the lungs can be applied to the diagnosis of both acute and more chronic diffuse diseases of the lung tissue and the airways. The best-known indications for HRCT include idiopathic interstitial pneumonias, such as idiopathic pulmonary fibrosis. High resolution computed tomography has also become established in the diagnostics of pneumoconiosis, such as asbestosis. More acute indications for HRCT include various inflammations, drug reactions and diffuse alveolar injury. Medical history plays a central role in the interpretation of lung HRCT, because a finding in imaging examination is often unspecific. A good test requisition is therefore important. PMID- 29243468 TI - DELIRIUM. AB - What is delirium? Delirium is a common but serious complication of hospitalisation. Delirium can occur in patients of all ages, but the highest incidence is in older patients (>65 years) (MacLullich et al. 2008). PMID- 29243469 TI - NURSES -- ARE WE EVER OFF DUTY? AB - Halfway home from a family holiday to Fiji I had just put down my book and closed my eyes, when my husband nudged me and pointed out a man in the opposite row calling for help. Without thinking I jumped up and assessed the situation. PMID- 29243471 TI - INAPPROPRIATE ACCESS TO MEDICAL RECORDS -- A CASE OF PROFESSIONAL MISCONDUCT. AB - Health Professionals' code of ethics and conduct emphasise a duty of confidentiality owed to the patient by their treating health practitioner. While these codes are not laws they are often used in disciplinary tribunal matters in consideration of what is proper professional conduct. PMID- 29243470 TI - Update on Current Care Guideline: Venous insufficiency of the lower limb. AB - Venous insufficiency of the lower limb is a common disease. Diagnosis is based on symptoms, clinical findings and duplex ultrasound. Consideration and planning of invasive treatment cannot be performed without ultrasound. Vast majority of invasive treatments in superficial venous insufficiency can be done by ultrasound guided endovenous methods with local anesthesia. Thermoablation (laser of radiofrequency) is the first-line treatment. There are promisisng endovenous methods for treatment of deep venous obstruction in selected cases. PMID- 29243455 TI - Intrathoracic stomach in hiatal hernia: the role of laparoscopic repair. AB - INTRODUCTION: For decades, intrathoracic stomach has been an indication for surgical repair and over time laparoscopy has become standard treatment. However, there are still many aspects in the treatment of intrathoracic stomach that are subject of debate. We performed a literature review to discuss the role of laparoscopy in intrathoracic stomach repair. EVIDENCE ACQUISITION: We performed an extensive literature search in Pubmed, Embase and Cochrane and reviewed studies from the last 5 years. To provide a complete overview, references from the found studies are also used. All data was compiled into a review format. EVIDENCE SYNTHESIS: Laparoscopic surgery is proven to be superior to open hiatal hernia repair in the treatment of intrathoracic stomach. The role of hernia sac excision, short esophagus, mesh reinforcement, fundoplication, complications and future perspectives are discussed in this review. CONCLUSIONS: Laparoscopy plays a major role in the treatment of intrathoracic stomach and regarding most aspects of the treatment. All available techniques have their advantages and disadvantages, and the decision on how to repair the intrathoracic stomach, remains a tailored based decision. PMID- 29243472 TI - Preliminary ethical appraisal of a trial - what's it all about? AB - Preliminary ethical appraisal of medical trials is often based on the following four principles: respect for autonomy, beneficence, non-maleficence, and justice. Preliminary ethical appraisal should, however, not be understood solely as application of these four principles to practice. Ethical committees will inevitably interpret the principles and make decisions about their reciprocal importance in connection with each trial. Reasoning does not always proceed from above towards practical recommendations of action, but can instead also be based on a moral rule or practice relating to a certain action. A good preliminary ethical appraisal will also take into account everyday standards of morality, law and shared moral values of the society. PMID- 29243473 TI - ELDER ABUSE. AB - The following excerpt is from our Elder Abuse tutorial on the ANMF's Aged Care Training Room (ACTR). Subtopics covered include defining elder abuse, legalities, contributing factors, indicators of elder abuse, organisational issues, characteristics of the abused resident/client and their abuser, worker characteristics, prevention and compulsory reporting to name but a few. PMID- 29243474 TI - REFUGEES IN NAURU. AB - A report alleging appalling abuse and neglect of refugees and asylum seekers living in detention on Nauru has recently been released based on Amnesty International and Human Rights Watch's investigations. The report detailed inhumane conditions, abuse and assault of detainees including neglect by locals and healthcare providers. The Department of Immigration has lashed out strongly refuting many of the claims in the report. Registered Nurse and citizen of Nauru Sue Barker also says the treatment of refugees and asylum seekers is very different to the one painted by the media. Sue has written to the ANMJ asking to give her account about the humane support refugees and asylum seekers are given by the locals on Nauru. PMID- 29243475 TI - Hope for better treatment in participating clinical drug trials. AB - An informed consent is a prerequisite for participating in medical trials, whereby the person asked to take part in the trial shall understand what he is committing himself to, and that the consent is given voluntarily. Voluntariness can be undermined by so-called therapeutic optimism, i.e. belief in personal benefit brought about by the trial, as well as the difficulty of understanding how conventional treatment and the trial differ from each other, i.e. the so called therapeutic misconception. The investigator, especially if he is also the attending physician, may influence the development of therapeutic misconception, because the participant may assume that the physician works as an investigator for the best benefit of the patients. It is important to recognize unrealistic optimism and therapeutic misconception of the trial, because for the participant they may result in disappointment and loss of confidence during the trial. PMID- 29243478 TI - Background-Free Imaging of a Viral Capsid Proteins Coated Anisotropic Nanoparticle on a Living Cell Membrane with Dark-Field Optical Microscopy. AB - Exploring the diffusion dynamics of a viral capsid proteins (VCP)-functionalized nanocarrier on a living cell membrane could provide much kinetic information for the better understanding of their biological functionality. Gold nanoparticles are an excellent core material of nanocarriers because of the good biocompatibility as well as versatile surface chemistry. However, due to the strong scattering background from subcellular organelles, it is a grand challenge to selectively image an individual nanocarrier on a living cell membrane. In this work, we demonstrated a convenient strategy to effectively screen the scattering background from living cells for single-particle imaging with a polarization resolved dual-channel imaging module. By taking advantage of the polarization of anisotropic gold nanoparticles (gold nanorods, GNRs), the signals from cell components could be counteracted after subtracting the sequential images one by one, while those transiently rotating GNRs on the cell membrane still exist in the processed image. In contrast to the previously reported methods, this method does not require a complicated optical setup alignment and sophisticated digital image analysis process. According to the single-particle imaging results, the majority of VCP-GNRs were anchoring on the cell membrane with confined diffusion. Interestingly, on further inspection of the diffusion trajectories, the particles displayed anomalous confined diffusion with randomly distributed large walking steps during the whole track. Non-Gaussian step distribution was noted, indicating heterogeneous binding and desorption processes on the cell membrane. As a consequence of the robust background screening capability, this approach would find broad applications for single-particle imaging under a noisy environment, e.g., living cells. PMID- 29243479 TI - Size-Dependent Catalytic Activity of Monodispersed Nickel Nanoparticles for the Hydrolytic Dehydrogenation of Ammonia Borane. AB - Nickel (Ni) nanoparticles (NPs) with controlled sizes in the range of 4.9-27.4 nm are synthesized by tuning the ratio of the nickel acetylacetonate precursor and trioctylphosphine in the presence of oleylamine. X-ray diffraction and transmission electron microscopy confirm the formation of the metallic Ni crystal phase and their monodispersed nature. These Ni NPs are found to be effective catalysts for the hydrolytic dehydrogenation of ammonia borane, and their catalytic activities are size-dependent. A volcano-type activity trend is observed with 8.9 nm Ni NPs presenting the best catalytic performance. The activation energy and turnover frequency (TOF) of the 8.9 nm NP catalyst are further calculated to be 66.6 kJ.mol-1 and 154.2 molH2.molNi-1.h-1, respectively. Characterization of the spent catalysts indicates that smaller-sized NPs face severe agglomeration, resulting in poor stability and activity. Three carbon support materials are thus used to disperse and stabilize the Ni NPs. It shows that 8.9 nm Ni NPs supported on Ketjenblack (KB) exhibit higher activity than that supported on carbon nanotubes and graphene nanoplatelets. The agglomeration induced activity loss is further illustrated by immobilizing 4.9 nm Ni NPs onto KB, which exhibits significantly enhanced activity with a high TOF of 447.9 molH2.molNi-1.h-1 as well as an excellent reusability in the consecutive dehydrogenation of ammonia borane. The high catalytic performance can be attributed to the intrinsic activity of nanoparticulate Ni and the improved activity and stability due to the strong Ni/KB metal-support interactions. PMID- 29243476 TI - Michael-Addition-Mediated Photonic Crystals Allow Pretreatment-Free and Label Free Sensoring of Ciprofloxacin in Fish Farming Water. AB - Abuse of antibiotics results in a large number of antibiotics residues in the environment and even causes the problem of "super bacteria". Therefore, it is crucial to develop a powerful analytic method to monitor antibiotics quickly and simply. Photonic crystal (PC), as a sensing material, has promising application prospects. Herein, we try to use PC to realize pretreatment-free and label-free detection of Ciprofloxacin (CF) through Michael addition reaction. The recognition process is carried out by the Michael addition reaction between the piperazine group of CF and the o-benzoquinone group on the PC. The monodisperse microspheres with o-benzoquinone groups are prepared by polymerization and oxidation and then stacked to form PC. During the detection, the peak intensity of the PC decreases with the increasing CF concentration, and the linear range is from 2 to 512 MUg/L. The limit of detection (LOD) is 0.76 MUg/L. Furthermore, the PC retains 97% of the initial response after storage in a Petri dish at room temperature for 1 month, which shows that it has good stability. Moreover, CF in fish farming water can be detected directly without any pretreatment and label, and the results are in good accordance with the LC-MS-MS results. This Michael addition-mediated PC is accurate, easily prepared, cost-efficient, and long-term stable. In addition, it is environmentally friendly, because little organic solvent is needed during both the preparation and the detection. PMID- 29243481 TI - Occurrence and Partitioning of Bisphenol Analogues in Adults' Blood from China. AB - Widespread human exposure and associated adverse health effects led to regulations on the usage of bisphenol A (BPA). Several bisphenol analogues (BPs) have been introduced as BPA alternatives in various applications. However, these BPs have been shown to exhibit similar or even stronger endocrine-disrupting activities compared with that of BPA. Currently, information on the human exposure to BPA alternatives remains limited. In this study, nine BPs were quantified in 81 pairs of plasma and red blood cell (RBC) samples from Chinese participants. In human plasma, the predominant BPs was BPA, bisphenol S (BPS), and bisphenol AF (BPAF), with the mean concentrations of 0.40, 0.15, and 0.073 ng/mL, respectively. BPA (accounting for 63% of total BPs) and BPS (18%) were the major BPs in the RBC fraction. Mass fractions in plasma (Fp) were found to be highest for BPS (mean, 0.78), followed by BPAF (0.71) and BPA (0.67), indicating strong partitioning to the plasma fraction. However, bisphenol AP was more frequently detected in the RBC fraction. Estimated total daily intake (EDI) of BPA was in the range of 0.0048-0.75 MUg/kg bw/day for the participants, and adults aged >50 years had comparatively lower EDI. To our knowledge, this is the first study to assess the occurrence and partitioning of BPA alternatives in paired human plasma and RBCs from the Chinese general population. PMID- 29243482 TI - Glycosyl Bunte Salts: A Class of Intermediates for Sugar Chemistry. AB - S-Glycosyl thiosulfates have been discovered as a new class of synthetic intermediates in sugar chemistry, named "glycosyl Bunte salts" after 19th-century German chemist, Hans Bunte. The synthesis was achieved by direct condensation of unprotected sugars and sodium thiosulfate using a formamidine-type dehydrating agent in water-acetonitrile mixed solvent. The application of glycosyl Bunte salts is demonstrated with transformation reactions into other glycosyl compounds such as a 1-thio sugar, a glycosyl disulfide, a 1,6-anhydro sugar, and an O glycoside. PMID- 29243483 TI - Relative Binding Free Energy Calculations in Drug Discovery: Recent Advances and Practical Considerations. AB - Accurate in silico prediction of protein-ligand binding affinities has been a primary objective of structure-based drug design for decades due to the putative value it would bring to the drug discovery process. However, computational methods have historically failed to deliver value in real-world drug discovery applications due to a variety of scientific, technical, and practical challenges. Recently, a family of approaches commonly referred to as relative binding free energy (RBFE) calculations, which rely on physics-based molecular simulations and statistical mechanics, have shown promise in reliably generating accurate predictions in the context of drug discovery projects. This advance arises from accumulating developments in the underlying scientific methods (decades of research on force fields and sampling algorithms) coupled with vast increases in computational resources (graphics processing units and cloud infrastructures). Mounting evidence from retrospective validation studies, blind challenge predictions, and prospective applications suggests that RBFE simulations can now predict the affinity differences for congeneric ligands with sufficient accuracy and throughput to deliver considerable value in hit-to-lead and lead optimization efforts. Here, we present an overview of current RBFE implementations, highlighting recent advances and remaining challenges, along with examples that emphasize practical considerations for obtaining reliable RBFE results. We focus specifically on relative binding free energies because the calculations are less computationally intensive than absolute binding free energy (ABFE) calculations and map directly onto the hit-to-lead and lead optimization processes, where the prediction of relative binding energies between a reference molecule and new ideas (virtual molecules) can be used to prioritize molecules for synthesis. We describe the critical aspects of running RBFE calculations, from both theoretical and applied perspectives, using a combination of retrospective literature examples and prospective studies from drug discovery projects. This work is intended to provide a contemporary overview of the scientific, technical, and practical issues associated with running relative binding free energy simulations, with a focus on real-world drug discovery applications. We offer guidelines for improving the accuracy of RBFE simulations, especially for challenging cases, and emphasize unresolved issues that could be improved by further research in the field. PMID- 29243480 TI - Reshaping the Energy Landscape Transforms the Mechanism and Binding Kinetics of DNA Threading Intercalation. AB - Molecules that bind DNA via threading intercalation show high binding affinity as well as slow dissociation kinetics, properties ideal for the development of anticancer drugs. To this end, it is critical to identify the specific molecular characteristics of threading intercalators that result in optimal DNA interactions. Using single-molecule techniques, we quantify the binding of a small metal-organic ruthenium threading intercalator (Delta,Delta-B) and compare its binding characteristics to a similar molecule with significantly larger threading moieties (Delta,Delta-P). The binding affinities of the two molecules are the same, while comparison of the binding kinetics reveals significantly faster kinetics for Delta,Delta-B. However, the kinetics is still much slower than that observed for conventional intercalators. Comparison of the two threading intercalators shows that the binding affinity is modulated independently by the intercalating section and the binding kinetics is modulated by the threading moiety. In order to thread DNA, Delta,Delta-P requires a "lock mechanism", in which a large length increase of the DNA duplex is required for both association and dissociation. In contrast, measurements of the force dependent binding kinetics show that Delta,Delta-B requires a large DNA length increase for association but no length increase for dissociation from DNA. This contrasts strongly with conventional intercalators, for which almost no DNA length change is required for association but a large DNA length change must occur for dissociation. This result illustrates the fundamentally different mechanism of threading intercalation compared with conventional intercalation and will pave the way for the rational design of therapeutic drugs based on DNA threading intercalation. PMID- 29243477 TI - Electrochemical Selectivity Achieved Using a Double Voltammetric Waveform and Partial Least Squares Regression: Differentiating Endogenous Hydrogen Peroxide Fluctuations from Shifts in pH. AB - Hydrogen peroxide (H2O2) is a reactive oxygen species that serves as an important signaling molecule in normal brain function. At the same time, excessive H2O2 concentrations contribute to myriad pathological consequences resulting from oxidative stress. Studies to elucidate the diverse roles that H2O2 plays in complex biological environments have been hindered by the lack of robust methods for probing dynamic H2O2 fluctuations in living systems with molecular specificity. Background-subtracted fast-scan cyclic voltammetry at carbon-fiber microelectrodes provides a method of detecting rapid H2O2 fluctuations with high temporal and spatial resolution in brain tissue. However, H2O2 fluctuations can be masked by local changes in pH (DeltapH), because the voltammograms for these species can have significant peak overlap, hindering quantification. We present a method for removing DeltapH-related contributions from complex voltammetric data. By employing two distinct potential waveforms per scan, one in which H2O2 is electrochemically silent and a second in which both DeltapH and H2O2 are redox active, a clear distinction between H2O2 and DeltapH signals is established. A partial least-squares regression (PLSR) model is used to predict the DeltapH signal and subtract it from the voltammetric data. The model has been validated both in vitro and in vivo using k-fold cross-validation. The data demonstrate that the double waveform PLSR model is a powerful tool that can be used to disambiguate and evaluate naturally occurring H2O2 fluctuations in vivo. PMID- 29243484 TI - Nanopatterns of Surface-Bound EphrinB1 Produce Multivalent Ligand-Receptor Interactions That Tune EphB2 Receptor Clustering. AB - Here we present a nanostructured surface able to produce multivalent interactions between surface-bound ephrinB1 ligands and membrane EphB2 receptors. We created ephrinB1 nanopatterns of regular size (<30 nm in diameter) by using self assembled diblock copolymers. Next, we used a statistically enhanced version of the Number and Brightness technique, which can discriminate-with molecular sensitivity-the oligomeric states of diffusive species to quantitatively track the EphB2 receptor oligomerization process in real time. The results indicate that a stimulation using randomly distributed surface-bound ligands was not sufficient to fully induce receptor aggregation. Conversely, when nanopatterned onto our substrates, the ligands effectively induced a strong receptor oligomerization. This presentation of ligands improved the clustering efficiency of conventional ligand delivery systems, as it required a 9-fold lower ligand surface coverage and included faster receptor clustering kinetics compared to traditional cross-linked ligands. In conclusion, nanostructured diblock copolymers constitute a novel strategy to induce multivalent ligand-receptor interactions leading to a stronger, faster, and more efficient receptor activation, thus providing a useful strategy to precisely tune and potentiate receptor responses. The efficiency of these materials at inducing cell responses can benefit applications such as the design of new bioactive materials and drug delivery systems. PMID- 29243486 TI - Immunogenicity considerations for antibody-drug conjugates: a focus on neutralizing antibody assays. PMID- 29243487 TI - Assessing a multiplex-targeted proteomics approach for the clinical diagnosis of periodontitis using saliva samples. AB - AIM: The present study focused on the research of new biomarkers based on the liquid chromatography-multiple-reaction monitoring (MRM) proteomic profile in whole saliva of patients with periodontitis compared with periodontal healthy patients. METHODS: A 30-min multiplexed liquid chromatography-MRM method was used for absolute quantification of 35 plasma biomarkers in saliva from control patients and patients with periodontitis. RESULTS: Three proteins namely hemopexin, plasminogen and alpha-fibrinogen were shown to be clearly related to the presence of periodontitis compared with healthy patients. Apolipoprotein H was found to discriminate for the first time chronic and aggressive periodontitis. CONCLUSION: Our results indicate that this innovative MRM method could be used to screen for periodontitis in clinical environment. Furthermore, apolipoprotein H was found to be a discriminant biomarker of aggressive periodontitis. PMID- 29243489 TI - Application of matrix-assisted laser desorption/ionization mass spectrometry imaging in combination with LC-MS in pharmacokinetic study of metformin. AB - AIM: To demonstrate and discuss the pros and cons of various conventional and innovative analytical approaches. Methodology & results: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MSI) of tissue sections as well as the extraction of tissue homogenates, blood plasma and dried blood spots coupled with LC-MS were employed to monitor the pharmacokinetics of metformin in mice. The time profile of metformin measured by matrix-assisted laser desorption/ionization MSI correlated well with the results found by LC-MS. Repeatability of the preparation of tissue sections for MSI was very good. CONCLUSION: MSI provided valuable information on the spatial distribution and relative concentration of the analyte within tissue sections. The analysis of the extracts of tissue homogenates, blood plasma and blood spots provided quantitative data on metformin. The dried blood spot approach is a progressive method of sampling, especially in studies where the amount of available blood is limited. PMID- 29243499 TI - Do not hesitate: Peripheral artery disease is a fatal condition! PMID- 29243493 TI - Quorum-sensing network-associated gene regulation in Gram-positive bacteria. AB - Quorum sensing (QS) is the chemical communication processes between bacteria, which may be inter-genus or intra-genus. In general, several physiological functions, such as nutrient uptake, competence development, biofilm formation, sporulation, and toxin secretion, are accomplished through QS process. The QS (cell density-dependent process) circuit in Gram-positive bacteria consists mainly of two parts: an inducer molecule and a receptor protein. The binding of inducer molecule to receptor activates the target gene, which then performs the necessary function in bacteria. In the past few years, several investigations have been conducted to explore the QS circuit in various bacteria, but still this information is insufficient to fully understand the bacterial gene expression cascade. In the present review, we summarize the QS architecture and their associated gene regulation in four Gram-positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, Bacillus cereus, and Streptococcus pneumoniae. It is well established that S. aureus, B. cereus, and S. pneumoniae are potent human pathogen. A detailed understanding of QS circuit in these bacteria would be useful in preparation of customized medicine in future. Whereas, B. subtilis is an industrially important candidate and has been used in several biotechnology sectors. Understanding of QS circuit in B. subtilis will definitely enrich the antibiotics and enzyme industries. PMID- 29243497 TI - Preventing recurrent events in survivors of acute coronary syndromes in Australia: consensus recommendations using the Delphi process. AB - OBJECTIVE: There remain substantial gaps in implementation of evidence-based care in patients with acute coronary syndromes (ACS) in Australia, which contribute to high recurrent event rates. Improved translation of evidence into effective action is a key health-care priority. We engaged cardiovascular experts from across Australia to develop straightforward, easily actionable recommendations on key medications to use following ACS. METHODS: An eight-person steering committee (SC) reviewed the published evidence and developed an initial set of statements to be developed into consensus recommendations using a modified Delphi technique. A panel of 21 expert cardiologists in the ACS field (including the SC) voted on their level of agreement with the statements using a 6 point Likert scale. Statements that did not reach consensus (>=80% agreement) were reviewed by the SC, modified as appropriate based on input from the panel and circulated for re voting. RESULTS: Twenty-eight statements were developed by the SC across six classes of medication: low-density lipoprotein (LDL) cholesterol lowering agents, aspirin, dual antiplatelet therapy, renin-angiotensin-aldosterone system inhibitors, beta blockers and "other". Twenty-six recommendations were endorsed by the voting panel; two statements did not reach consensus. CONCLUSIONS: Despite the extensive evidence base and detailed guidelines outlining best practice post ACS, there remain considerable gaps in translating these into everyday care. We used an internationally recognized technique to develop practical consensus recommendations on medical treatment following ACS. These simple, up-to-date recommendations aim to improve evidence-based medication use and thereby reduce the risk of future cardiovascular events for Australian patients with ACS. PMID- 29243490 TI - Percutaneous cryoablation of breast tumours in patients with stable metastatic breast cancer: safety, feasibility and efficacy. AB - PURPOSE: To evaluate safety, feasibility and efficacy of percutaneous cryoablation of breast tumours in patients with clinically stable metastatic breast cancer, and to compare the findings with reports on alternative procedures, namely surgery and local radiotherapy. METHODS: 17 female patients (average age of 54.8 years +/- 10.8; range 37-72) with primary breast tumour not surgically treated because of metastatic disease were included. Patients were treated for their primary lesion by percutaneous cryotherapy in period of stable disease. This minimally intervention was performed using ultrasound or CT scan guidance. All patients had clinical and breast-MRI evaluation before and at 1, 3, 6 and 12 months after the procedure. RESULTS: All procedures were performed under local anaesthesia and technically successful. The mean largest diameter of the primary lesions was 16 +/- 12 mm (size range 5-45 mm). In 15 patients, we obtained a complete regression of the primary breast lesion without recurrence during the follow-up period. Two patients with lesions measured at 40 and 45 mm had recurrence in follow up period. A second session of cryotherapy was performed for these 2 patients, not included in this study. Five patients had painful masses before cryotherapy. All were immediately relieved after the intervention and durably during all follow-up. CONCLUSION: These results show that the cryoablation of primary breast lesions seems to be well suited to the palliative care of metastatic patients, particularly because of its good tolerance, low complication rate and ability to provide local or analgesic control. Advances in knowledge: Therapies are limited for these symptomatic patients at metastatic state of primary breast tumour. This study shows that cryoablation in palliative care is achievable in common practice, is effective in local control of the tumour and can provide immediate and long-term analgesic control. PMID- 29243488 TI - Comparison and optimization of imaging techniques in suspected physical abuse paediatric radiography. AB - OBJECTIVE: This study compares protocols in clinical use for paediatric suspected physical abuse (SPA) radiographic imaging across four National Health Service Trusts in the UK. The patient dose delivered from a SPA skeletal survey was compared between two sites using different imaging technology. Additionally, the technique in use for the abdomen anteroposterior (AP) radiographic projection was optimized at one of the participant sites. METHODS: Retrospective data collection was performed to compare SPA protocols. Exposure details and patient dose data for SPA skeletal surveys were collected and compared. SPA skeletal surveys were performed on two anthropomorphic paediatric phantoms using two digital imaging systems. Effective dose (ED) was calculated using a dose calculator software (PCXMC v. 2.0, STUK, Helsinki, Finland) and used as a quantification of the radiation risk. For the optimization study, abdomen AP radiographs of the phantoms were acquired over a range of tube potentials (40-117 kV) for constant ED on a digital radiography (DR) system. The contrast-to-noise ratio (CNR) between "bone" and "soft tissue" in the images was measured and used as an indicator of image quality. RESULTS: This study showed that there is a variation in the protocols and a range of techniques in use for SPA imaging across the four participant sites. The skeletal surveys undertaken on the newborn phantom at two sites resulted in an ED of 57 +/- 3 uSv and 90 +/- 4 uSv, on the DR unit and digital radiography/fluoroscopy (dRF) unit, respectively. Measurements of the abdomen AP projection achieved an improved CNR (4%) at a lower tube potential (55 kV) without increasing ED, compared with the current clinical setting (64 kV). Advances in knowledge: This study showed that an improved CNR can be achieved for newborn and 1-year-old abdomen AP radiographs using 0.1 mm copper filtration and a reduced kV (55 kV) without increasing ED. PMID- 29243491 TI - Immunogenicity of therapeutic protein products: current considerations for anti drug antibody assay in Japan. AB - Immunogenicity assessment is an important issue for ensuring the safety and efficacy of therapeutic protein products. Although the reliability of the anti drug antibody (ADA) assay is one of the key points, there are some difficulties in assessing its validity because the analytes are polyclonal antibodies with variable and unknown characteristics. To elucidate the points to consider for the ADA assay, a Japanese research group was established that discusses the issues raised on the immunogenicity assessment. In this review, we first introduce the current situation regarding the development and immunogenicity assessment of therapeutic protein products in Japan. We then present our current view and recommendations on the ADA assay by considering its unique features. PMID- 29243494 TI - Does subinhibitory concentrations of clinically important antibiotic induce biofilm production of Enterococcus faecium strains? AB - Biofilm structures are the most resistant form of active microorganisms against sanitation, disinfection, and sterilization processes. One of the specific properties of biofilm is the development of antibiotic resistance that can be up to 1,000-fold greater than planktonic cells. Enterococcus faecium is a human pathogen that causes nosocomial bacteremia and at the present time, it is well known that most of the chronic infections are biofilm-based. Recent evidence suggested that subinhibitory concentrations (sub-MICs) of antibiotics have an important role in the evolution of antibiotic resistance and induction on biofilm formation. Based on this information, we aimed to determine the effect of subinhibitory antibiotic concentrations on biofilm formation and the role of the antibiotic concentrations on the enterococcal surface protein gene (esp). To determine the impact of clinically important antibiotics on biofilm production, crystal violet assay was used. Then, the effect of sub-MICs of antibiotics on the expression of the esp gene was investigated by quantitative real-time PCR. Biofilm production assays show that MIC/2 of erythromycin (ERT; 512 MUg/ml), MIC/32 of vancomycin (VAN; 16 MUg/ml), MIC/64 of streptomycin (STR; 32 MUg/ml), and MIC/128 of kanamycin (KAN; 4 MUg/ml) values induce maximum biofilm production compared with the control. According to q-PCR results, sub-MIC values of ERT, VAN, and STR antibiotics were found to enhance esp gene expression. In addition, despite the increasing biofilm production after KAN treatment, the antibiotic was not effective on the esp expression. PMID- 29243485 TI - Molecular imaging of prostate cancer. AB - Prostate cancer is a common malignancy with various treatments from surveillance, surgery, radiation and chemotherapy. The institution of appropriate, effective treatment relies in part on accurate imaging. Molecular imaging techniques offer an opportunity for increased timely detection of prostate cancer, its recurrence, as well as metastatic disease. Advancements within the field of molecular imaging have been complex with some agents targeting receptors and others acting as metabolic intermediaries. In this article, we provide an overview of the most clinically relevant radiotracers to date based on a combination of the five states model and the National Comprehensive Cancer Network Guidelines. PMID- 29243496 TI - Increased expression of CD44 is associated with more aggressive behavior in clear cell renal cell carcinoma. AB - AIM: Although CD44 has been suggested as a prognostic marker in renal cell carcinoma (RCC), the prognostic significance of this marker in three main subtypes of RCC is still unclear. Thus, the present study was conducted to evaluate the expression and prognostic significance of CD44 as a cancer stem cell marker in different histological subtypes of RCC. Methodology & results: CD44 expression was evaluated in 206 well-defined renal tumor samples using immunohistochemistry on tissue microarrays. Higher CD44 expression was associated with more aggressive behavior, tumor progression and worse prognosis in clear cell RCC (ccRCC) but not in papillary and chromophobe RCC subtypes. DISCUSSION & CONCLUSION: Cancer stem cell marker CD44 may be a promising target for cancer treatment only in ccRCC. PMID- 29243492 TI - A label-free platform for dopamine biosensing. AB - AIM: This work presents a label-free platform for dopamine (DA) monitoring based on the spectroscopic properties of laccase. RESULTS: Working in batch mode, DA ranging from 25 to 250 MUM, can be determined without the interference of norepinephrine and epinephrine. Laccase immobilized in a polyacrylamide film is the basis of a platform for the label-free determination of DA. The linear range goes from 100 to 900 MUM with an RSD of 5.3% and a film lifetime of more than 30 measurements. The biosensors also permit the DA + epinephrine + norepinephrine determination. CONCLUSION: The method permits the determination of DA and the total concentration of the three neurotransmitters, and could be used for DA monitoring in urine samples. PMID- 29243498 TI - "cART intensification by the HIV-1 Tat B clade vaccine: progress to phase III efficacy studies". AB - INTRODUCTION: In spite of its success at suppressing HIV replication, combination antiretroviral therapy (cART) only partially reduces immune dysregulation and loss of immune functions. These cART-unmet needs appear to be due to persistent virus replication and cell-to-cell transmission in reservoirs, and are causes of increased patients' morbidity and mortality. Up to now, therapeutic interventions aimed at cART-intensification by attacking the virus reservoir have failed. Areas covered: We briefly review the rationale and clinical development of Tat therapeutic vaccine in cART-treated subjects in Italy and South Africa (SA). Vaccination with clade-B Tat induced cross-clade neutralizing antibodies, immune restoration, including CD4+ T cell increase particularly in low immunological responders, and reduction of proviral DNA. Phase III efficacy trials in SA are planned both in adult and pediatric populations. Expert commentary: We propose the Tat therapeutic vaccine as a pathogenesis-driven intervention that effectively intensifies cART and may lead to a functional cure and provide new perspectives for prevention and virus eradication strategies. PMID- 29243504 TI - Promoting language and social communication development in babies through an early storybook reading intervention. AB - PURPOSE: This study examined the effectiveness of low- and high-intensity early storybook reading (ESR) intervention workshops delivered to parents for promoting their babies language and social communication development. These workshops educated parents on how to provide a stimulating home reading environment and engage in parent-child interactions during ESR. METHOD: Parent-child dyads (n = 32); child age: 3-12 months, were assigned into two intervention conditions: low and high intensity (LI versus HI) groups. Both groups received the same ESR strategies; however, the HI group received additional intervention time, demonstrations and support. Outcome measures were assessed pre-intervention, one and three months post-intervention and when the child turned 2 years of age. RESULT: A significant time-group interaction with increased performance in the HI group was observed for language scores immediately post-intervention (p = 0.007) and at 2-years-of-age (p = 0.022). Significantly higher broader social communication scores were associated with the HI group at each of the time points (p = 0.018, p = 0.001 and p = 0.021, respectively). Simple main effect revealed that both groups demonstrated a significant improvement in language, broader social communication and home reading practices scores. CONCLUSIONS: ESR intervention workshops may promote language and broader social communication skills. The HI ESR intervention workshop was associated with significantly higher language and broader social communication scores. PMID- 29243505 TI - Cardiopulmonary exercise testing and risk stratification in heart failure with reduced, midrange or preserved ejection fraction: When nomenclature may not match with pathophysiology. PMID- 29243495 TI - The recombinant fusion protein CFP10-ESAT6-dIFN has protective effect against tuberculosis in guinea pigs. AB - Development of effective vaccine candidates against tuberculosis (TB) is currently the most important challenge in the prevention of this disease since the BCG vaccine fails to guarantee a lifelong protection, while any other approved vaccine with better efficiency is still absent. The protective effect of the recombinant fusion protein CFP10-ESAT6-dIFN produced in a prokaryotic expression system (Escherichia coli) has been assessed in a guinea pig model of acute TB. The tested antigen comprises the Mycobacterium tuberculosis (Mtb) proteins ESAT6 and CFP10 as well as modified human gamma-interferon (dIFN) for boosting the immune response. Double intradermal immunization of guinea pigs with the tested fusion protein (2 * 0.5 ug) induces a protective effect against subsequent Mtb infection. The immunized guinea pigs do not develop the symptoms of acute TB and their body weight gain was five times more as compared with the non-immunized infected guinea pigs. The animal group immunized with this dose of antigen displays the minimum morphological changes in the internal organs and insignificant inflammatory lesions in the liver tissue, which complies with a decrease in the bacterial load in the spleen and average Mtb counts in macrophages. PMID- 29243506 TI - Macrocognition in the Healthcare Built Environment (mHCBE): A Focused Ethnographic Study of "Neighborhoods" in a Pediatric Intensive Care Unit. AB - OBJECTIVES: The objectives of this research were to describe the interactions (formal and informal), in which macrocognitive functions occur and their location on a pediatric intensive care unit, to describe challenges and facilitators of macrocognition using space syntax constructs (openness, connectivity, and visibility), and to analyze the healthcare built environment (HCBE) using those constructs to explicate influences on macrocognition. BACKGROUND: In high reliability, complex industries, macrocognition is an approach to develop new knowledge among interprofessional team members. Although macrocognitive functions have been analyzed in multiple healthcare settings, the effect of the HCBE on those functions has not been directly studied. The theoretical framework, "macrocognition in the healthcare built environment" (mHCBE) addresses this relationship. METHOD: A focused ethnographic study was conducted including observation and focus groups. Architectural drawing files used to create distance matrices and isovist field view analyses were compared to panoramic photographs and ethnographic data. RESULTS: Neighborhoods comprised of corner configurations with maximized visibility enhanced team interactions as well as observation of patients, offering the greatest opportunity for informal situated macrocognitive interactions (SMIs). CONCLUSIONS: Results from this study support the intricate link between macrocognitive interactions and space syntax constructs within the HCBE. These findings help increase understanding of how use of the framework of Macrocognition in the HCBE can improve design and support adaptation of interprofessional team practices, maximizing macrocognitive interaction opportunities for patient, family, and team safety and quality. PMID- 29243500 TI - Designing medical technology for resilience: integrating health economics and human factors approaches. AB - INTRODUCTION: The slow adoption of innovation into healthcare calls into question the manner of evidence generation for medical technology. This paper identifies potential reasons for this including a lack of attention to human factors, poor evaluation of economic benefits, lack of understanding of the existing healthcare system and a failure to recognise the need to generate resilient products. Areas covered: Recognising a cross-disciplinary need to enhance evidence generation early in a technology's life cycle, the present paper proposes a new approach that integrates human factors and health economic evaluation as part of a wider systems approach to the design of technology. This approach (Human and Economic Resilience Design for Medical Technology or HERD MedTech) supports early stages of product development and is based on the recent experiences of the National Institute for Health Research London Diagnostic Evidence Co-operative in the UK. Expert commentary: HERD MedTech i) proposes a shift from design for usability to design for resilience, ii) aspires to reduce the need for service adaptation to technological constraints iii) ensures value of innovation at the time of product development, and iv) aims to stimulate discussion around the integration of pre- and post-market methods of assessment of medical technology. PMID- 29243507 TI - Hydration measured by doubly labeled water in ALS and its effects on survival. AB - We present a study of hydration in ALS patients and its effects on survival. This was a multicenter study over 48 weeks in 80 ALS patients who underwent 250 individual measurements using doubly labeled water (DLW). Total body water (TBW) and water turnover (a surrogate for water intake) were 3.4% and 8.6% lower, respectively, in patients compared to age- and gender-matched healthy controls, and both significantly decreased over study duration. In 20% of patients, water turnover measured over 10 d was 2 standard deviations below the mean value in healthy controls. In a separate clinic cohort of 208 patients, water intake estimated from a de novo equation created from common clinical endpoints was a prognostic indicator of survival. Regardless of nutritional state assessed by BMI, survival was two-fold longer in the group above the median for estimated water intake, suggesting that hydration may be a more important predictor of survival than malnutrition. Risk factors for poor hydration were identified. Water intake equations recommended by US Centers for Medicare and Medicaid Services in healthy elderly were inaccurate for use in ALS patients. We developed equations to estimate TBW and water intake in ALS patients for use in clinics to accurately estimate hydration and improve clinical care. PMID- 29243503 TI - Women's beliefs about what causes obesity: variation by race/ethnicity and acculturation in a Washington State sample. AB - OBJECTIVE: Individuals' beliefs about the causes of multifactorial health conditions (causal attributions) shape how they conceptualize and respond to health threats and are therefore important for health promotion. Studies of racial/ethnic and cultural variation in obesity causal beliefs, however, are scarce. To address this gap, this study described beliefs about the underlying causes of obesity (genetic inheritance, diet, and physical activity) in Hispanic and non-Hispanic White women participating in a longitudinal cohort study in South King County, Washington State (n = 1,002). DESIGN: Analysis of baseline survey data. Self-reported obesity causal beliefs were compared by race/ethnicity and acculturation indicators (survey language and nativity) using marginal effect estimates generated from multinomial logistic regression models. RESULTS: Hispanic women had a higher probability of not believing 'at all' in inheritance and physical activity as causes of obesity - an absolute increase of 33% and 5% over non-Hispanic White women, respectively. Both acculturation indicators were also associated with a higher probability of not believing 'at all' in inheritance as a cause of obesity, though Hispanic women who completed the survey in English and were born in the United States had genetic causal beliefs similar to non-Hispanic White women. Behavioral attributions did not vary by acculturation indicators in Hispanic women. CONCLUSIONS: Differences in obesity casual beliefs, particularly genetic attributions, exist and may be important for developing and delivering effective obesity-related health promotion interventions. Identifying the determinants and public health consequences of cultural variation in obesity attributions should be the focus of future research. PMID- 29243501 TI - Critical analysis of valuation and strategical orientation of merger and acquisition deals in the pharmaceutical industry. AB - INTRODUCTION: The pharmaceutical industry is undergoing major shifts due to changing macro and micro factors. As the industry is highly capital intensive and patents are expiring, the outlook is on generating inorganic growth, mainly through M&A. Using the income valuation approach, one analyses two completed deals in 2016 above 1bn USD. Thereafter one outlines the main motives behind M&A deals and concluded by discussing whether M&A harms medical innovations. Areas covered: The paper is based on empirical study questioning existing literature in order to critically analyse valuation and the strategical orientation of pharmaceutical companies Expert commentary: Pharmaceutical companies understand the changing market conditions and favour their expertise. The restructuring of the industry moves to small niche companies (I.e. Biopharma or biotech companies) researching key innovations and big companies purchasing them to develop them, create clinical trials and distribute them as this is a costly manner Conclusion: One can expect more M&A deals during the next years focusing on value rather than volume. Pharmaceutical players resilient to the market changes may survive if they change their business model from a traditional vertical one to outsourcing and diversification including external players. PMID- 29243502 TI - Evidence-based management of incidental focal uptake of fluorodeoxyglucose on PET CT. AB - Focal incidental uptake, with or without CT abnormalities, is a common finding on fluorodeoxyglucose PET/CT and evidence-based management for this type of uptake is lacking. This article reviews the evidence on focal incidental uptake including the incidence of malignancy, differential diagnosis and imaging criteria which can be used to further characterize it. The article focusses on PET rather than CT criteria. The strength of the evidence base is highly variable ranging from systematic reviews and meta-analyses to a virtual absence of evidence. Caution needs to be used when using standardized uptake values (SUVs) reported in other studies due to interpatient and institution observed variation in SUVs. There is sufficient evidence to permit specific suggestions on how to interpret the foci and recommend further management in the: pituitary (investigate when SUVmax >4.1), thyroid (investigate all), breast (investigate all), lung parenchyma (if focus of fluorodeoxyglucose without a CT nodule, no further investigations), colon (investigate all foci with SUVmax >5.9, urgently if SUVmax >11.4), adrenals (criteria depend on if patient has cancer) and prostate gland (investigate in males aged >50 years or >40 years if peripheral uptake or patient has other risk factors). There is some evidence to guide further management for the parotid gland, naso-orophaynx, oesophagus, pancreas, uterus and ovaries. There is insufficient evidence to guide management for the liver, spleen, kidneys, gallbladder, testis and bone, for these organs patient characteristics and other guidelines will likely be of more use in determining further management. PMID- 29243508 TI - The effectiveness of hydrokinesiotherapy on postural balance of hemiplegic patients after stroke: a systematic review and meta-analysis. AB - OBJECTIVE: To summarize evidence on the effects of hydrokinesiotherapy (HT) on postural balance in hemiplegic patients after stroke and compare them with conventional land therapy. DATA SOURCES: A literature search until October 2017 was conducted on CINAHL, PubMed, Cochrane EBM Reviews, Cochrane Clinical Trials, DARE, MEDLINE, Physiotherapy Evidence Database (PEDro), PsycInfo and Rehabilitation and Sports Medicine Source. REVIEW METHODS: Only randomized controlled trials with pre-intervention and post-intervention assessment on postural control have been included. Assessment of the quality (by Downs and Black quality assessment tool) of the included studies was performed by two reviewers, and a meta-analysis was undertaken. RESULTS: A total of 11 trials on postural control with 305 stroke patients were included. The majority of studies showed a beneficial effect of HT in postural control of the patients. The meta analysis showed statistically significant improvement ( P < 0.05) in Berg Balance Scale (BBS), mediolateral (ML) and anteroposterior (AP) sway velocity of center of pressure with eyes closed (EC) in both groups, but the mean differences in BBS (3.85 points), ML sway velocity of center of pressure (1.38 points) and AP sway velocity of center of pressure (1.64 points) were statistically improved ( P < 0.05) in HT over land therapy program. CONCLUSION: HT is superior to land therapy program regarding postural balance in terms of BBS, ML and AP sway velocity of center of pressure. PMID- 29243510 TI - Health-related quality of life and risk of composite coronary heart disease and cerebrovascular events in the Moli-sani study cohort. AB - Background To assess the association between health-related quality of life (HRQL) and a composite outcome including incident coronary heart disease (CHD) and cerebrovascular events in a large general population-based cohort. Design Prospective analysis on 17,102 men and women (mean age 53 +/- 11) free from cardiovascular disease at time of enrolment in the Moli-sani cohort (2005-2010). Methods HRQL was assessed by the 36-Item Short Form Health Survey. Hazard ratios with 95% confidence intervals (95% CIs) were calculated using multivariable Cox proportional hazard models. Results At the end of follow-up (median 4.2 years), 237 new events occurred (coronary heart disease n = 197, cerebrovascular disease n = 42). In a multivariable model adjusted for socioeconomic factors, chronic disease and health-related behaviours, both mental and physical HRQL were inversely associated with the risk of the composite outcome (hazard ratio = 0.57; 0.39-0.84 and hazard ratio = 0.62; 0.40-0.94, respectively; highest vs. lowest quartile). Further adjustment for C-reactive protein marginally modified the association with physical HRQL (hazard ratio = 0.67; 0.43-1.02). Similar findings were obtained when only CHD events were analysed (hazard ratio = 0.63; 0.41-0.96 for highest versus lowest mental HRQL) although results with physical HRQL were no longer significant (hazard ratio = 0.65; 0.40-1.04 for highest versus lowest quartile). Associations with incident cerebrovascular disease showed a trend toward protection (hazard ratio = 0.50; 0.22-1.17 and hazard ratio = 0.51; 0.22 1.23 for highest versus lowest tertile of mental and physical HRQL, respectively). Conclusions HRQL is an independent predictor of composite CHD/cerebrovascular outcomes in an adult population. The magnitude of the association was not affected either by socioeconomic factors, health conditions or health-related behaviours. Improvement of quality of life may be a major factor in targeting appropriate prevention strategies for cardiovascular health. PMID- 29243509 TI - Loss of MTAP expression is a negative prognostic marker in Ewing sarcoma family of tumors. AB - AIM: The Ewing sarcoma family of tumors (ESFT) is a group of malignant small round cell neoplasms of bones and soft tissues closely histogenetically related. Methylthioadenosine phosphorylase (MTAP) deficiency has been recently associated with increased tumor aggressiveness and poor outcomes in different types of neoplasms. However, the expression of this biomarker and its biological role in ESFT remain largely unknown. METHODS: Immunohistochemical expression of MTAP was accessed in 112 patients with ESFT in a tissue microarray platform and associated with clinicopathological parameters and overall survival (OS). RESULTS: Loss of MTAP expression was significantly associated with lower OS in both univariate and multivariate analyses. CONCLUSION: Loss of MTAP expression is an independent negative prognostic biomarker in ESFT. PMID- 29243511 TI - Acute stress disorder and C-reactive protein in patients with acute myocardial infarction. AB - Background Myocardial infarction-triggered acute stress disorder (ASD) and subclinical inflammation associate with the development of posttraumatic stress disorder, and worsen the prognosis of myocardial infarction patients. We examined the relationship between ASD severity and C-reactive protein levels in patients with acute myocardial infarction. Methods We assessed 190 patients (median age 59 years; 83% men) with a verified myocardial infarction within 48 h of an acute coronary intervention. Circulating levels of C-reactive protein were categorized according to their prognostic risk for cardiovascular disease: 0 to <5, 5 to <10, 10 to <20, and >= 20 mg/l. Patients completed the ASD-Scale (ASDS) for myocardial infarction-triggered symptoms and questionnaires for demographic factors, health behaviours, cardiac-related variables and psychosocial characteristics. Results The ASDS sum score was positively associated with C-reactive protein categories in the bivariate analysis ( r = 0.20, p < 0.01). Significant relationships with C reactive protein also emerged for dissociation ( r = 0.25, p < 0.001) and avoidance ( r = 0.19, p < 0.01), but not for arousal and re-experiencing. Similarly, C-reactive protein levels >= 20 mg/l versus < 20 mg/l were predicted by the ASDS sum score, and the dissociation, avoidance and arousal subscores (all p-values < 0.05) in the fully adjusted binary regression analyses. C-reactive protein levels >= 20 mg/l were also independently predicted by male gender, body mass index, lower education, and lower left ventricular ejection fraction and higher white blood cell count. Conclusions Higher levels of myocardial infarction triggered ASD symptoms associate with a greater inflammatory response in patients with acute myocardial infarction independently of important covariates. The findings suggest a link between myocardial infarction-triggered ASD symptoms and a heightened acute phase response with a potential impact on cardiovascular disease prognosis. PMID- 29243512 TI - The Relationship Between Hospital Construction and High-Risk Infant Auditory Function at NICU Discharge: A Retrospective Descriptive Cohort Study. AB - PURPOSE: To describe the difference in auditory function at neonatal intensive care unit (NICU) discharge between high-risk infant cases exposed to hospital construction during NICU stay and those not exposed. BACKGROUND: Noise produced by routine NICU caregiving exceeds recommended intensity. As California hospitals undergo construction to meet seismic safety regulations, vulnerable neonates are potentially exposed to even higher levels of noise. Ramifications are unknown. METHODS: Retrospective data-based descriptive cohort design was used to compare high-risk infant auditory function at NICU discharge between hospital construction exposed and unexposed groups. SAMPLE SIZE: N = 540 infant cases (243 construction exposed and 297 unexposed controls). INCLUSION CRITERIA: Infant cases born and discharged from the study site NICU in the year 2010 (unexposed) and year 2015 (exposed) and received a newborn hearing screening by automated auditory brainstem evoked response (ABER) prior to discharge with results reported. Infant cases excluded: hearing screen results by ABER unavailable, potentially confounding characteristics (congenital infection, major anomalies including cleft lip and/or palate), and transferred into or out of the study site. INSTRUMENTATION: ABER. ANALYSIS: descriptive statistics (SPSS Version 24.0), hypothesis testing, correlation, and logistic regression. RESULTS: The difference in auditory function at NICU discharge between high-risk infant cases exposed to hospital construction noise and those unexposed was statistically insignificant, chi2 = 1.666, df = 4, p = .1968, 95% confidence interval [-0.635, 2.570]. CONCLUSIONS: More research is needed to better understand whether hospital construction exposure during NICU admission negatively affects high-risk infant auditory function. Findings may catalyze theory development, future research, and child health policy. PMID- 29243514 TI - Serendipity: How the search for meaning of serum uric acid might lead to the repurposing of an old drug in patients with cardiovascular disease. PMID- 29243513 TI - Evaluation of healthcare costs and utilization for patients with gout: a population-based matched cohort study. AB - OBJECTIVES: To better understand the economic burden of gout patients in Taiwan, a nationwide retrospective study was conducted to compare the healthcare costs and utilization between gout and gout-free patients. METHODS: The Longitudinal Health Insurance Database (LHID) 2010 was used to identify gout cases and matched gout-free controls. Gout cases were defined as having (1) at least three instances of diagnoses of gout on medical claims, or (2) one diagnosis of gout with at least one gout-related pharmacy claim in 2011. A control cohort was matched with cases at a 3:1 ratio by age, gender, residential area, and the Charlson Comorbidity Index. All medical utilization and costs per patient within the 365 days following the index date were compared between cases and controls. RESULTS: Out of 993,332 beneficiaries, a total of 21,376 matched gout patients met the gout inclusion criteria. Compared to controls, gout patients had more outpatient visits (mean = 31.2 vs 22.6), inpatient visits (mean = 1.7 vs 1.5), and ER visits (mean = 1.9 vs 1.7) (all p < .0001), as well as more outpatient costs (median = USD $634 vs $404), inpatient costs (median = USD $1330 vs $1254), and ER costs (median = USD $87 vs $89) (all p < .05). CONCLUSION: Gout patients had higher medical utilization and costs than gout-free patients. In gout patients, all-cause and gout-related utilization were mostly outpatient visits, whereas most of the all-cause and gout-related costs were due to hospitalization. The study findings could be useful for future economic evaluations and healthcare resource allocation. PMID- 29243515 TI - Alkaloids from Juglans Mandshurica maxim induce distinctive cell death in hepatocellular carcinoma cells. AB - The aim of this work was to further investigate the anticancer potential of Juglans mandshurica Maxim, including the separation of active constituents and their anti-proliferative effects with underlying mechanism of action. Five alkaloids (1-5) were isolated from the bark of J. mandshurica. Among them, 1 showed the highest cytotoxic activities against Hep3B and HepG2 cells with an IC50 values of 61.80 and 56.24 MUM, respectively. Therefore, the cellular mechanism involved 1 was subsequently studied. Our results showed that 1 markedly caused apoptosis and autophagy, but without cell cycle arrest in HepG2 cells. Interestingly, only autophagic cell death was induced in 1-treated Hep3B cells. It is concluded that the isolated alkaloids exerted a certain anti-hepatoma potential, and our results may provide a basis for the further investigation of the alkaloids extracted from J. mandshurica. PMID- 29243517 TI - Why yogurt reduces heart disease risks. PMID- 29243518 TI - Synaesthesia is linked to more vivid and detailed content of autobiographical memories and less fading of childhood memories. AB - People with synaesthesia have enhanced memory on a wide range of laboratory tests of episodic memory, but very little is known about their real-world memory. This study used a standard measure of autobiographical remembering (the Autobiographical Memory Questionnaire, AMQ) considering four constructs (Recollection, Belief, Impact and Rehearsal) and two time periods (recent memories from adulthood, remote memories from childhood). Synaesthetes reported more Recollection (e.g., sensory detail) and Belief (e.g., confidence) which interacted with time, such that remote memories are reported to be comparatively better preserved in synaesthetes. This cannot be explained by synaesthetes recalling more salient episodes (the groups did not differ in Impact). It suggests instead that childhood memories have a special status in synaesthesia that reflects the different neurodevelopmental trajectory of this group. With regards to Rehearsal, controls tended to report that more recent memories tend to resurface (i.e., adulthood > childhood), but the synaesthetes showed the opposite dissociation (i.e., childhood > adulthood). PMID- 29243519 TI - Changes in behavioral outcomes among children affected by HIV: Results of a randomized controlled trial in China. AB - This study assessed the effects of a multilevel intervention on HIV-affected children's negative behaviors. A total of 536 children aged 6-18 years from 475 HIV-affected families in Anhui, China, participated in the randomized controlled trial. A significant overall intervention effect on reducing negative behaviors was observed at 18-month follow-up, and the effect remained at 24-month follow up. The intervention showed greater effects for children aged 13-18 years than those aged 6-12 years. Study findings suggest that a multilevel intervention approach could be beneficial for reducing negative behavior in HIV-affected children. Age-specific programs should be considered to maximize the intervention effects. PMID- 29243520 TI - Caveats and pitfalls associated with researching community engagement in the context of HIV vaccine trials. AB - HIV vaccine efficacy trials require the enrolment of large numbers of HIV negative individuals and thus it is necessary to engage with communities where HIV incidence is high. We identify some of the caveats and pitfalls associated with researching community engagement in the context of HIV vaccine trials. These are as follows: the lack of consensus of what community engagement is and how it is practiced, the sometimes paradoxical role of community advisory boards as community representatives and challenges associated with information dissemination in communities. We identify a set of considerations for community engagement practitioners, trial investigators and social scientists when conducting community engagement. PMID- 29243516 TI - Gas6 as a predictor of esophageal varices in patients affected by hepatitis C virus related-chronic liver disease. AB - AIM: Plasma Gas6 was tested as an alternative to Baveno VI criteria (liver stiffness <20 kPa and platelet count >150 * 109/l) in an endoscopy-sparing strategy. METHODS: A total of 160 patients with chronic hepatitis C and advanced fibrosis/cirrhosis underwent, on the same occasion, liver elastography, upper endoscopy, a platelet count and serum Gas6 measurement. RESULTS: A total of 74/160 (46%) patients had esophageal varices, that were small (diameter <5 mm) in 57/160 (34%) and large in 17/160 (11%) cases. A total of 34/160 (21%) patients satisfied Baveno VI criteria, according to which screening for esophageal varices could have been omitted; 1/34 had large varices (sensitivity 94%). A plasma Gas6 value <45 ng/ml, detected in 34/160 (21%) patients, was also 94% sensitive. CONCLUSION: Plasma Gas6 might represent a feasible alternative to Baveno VI criteria when transient elastography is unavailable/unsuccessful. PMID- 29243521 TI - Sexual function and quality-of-life-related problems during the menopausal period. AB - This study aims to evaluate the relationship between the sexual functions and quality of life and the problems during menopausal period. This descriptive, cross-sectional study included a total of 317 women. The mean total Female Sexual Function Index score was 18.8 +/- 8.7, while the mean total Sexual Quality of Life Questionnaire-Female score was 72.7 +/- 13.7. Sexual dysfunction was found in 82 percent. There was a positive significant correlation between the total Female Sexual Function Index scores and total Sexual Quality of Life Questionnaire-Female scores ( p < 0.05). Our study results suggest that women do not often experience serious menopausal symptoms, but have sexual dysfunction with a moderate sexual quality of life. PMID- 29243524 TI - Talking about cancer: Explaining differences in social support among Chinese American and European American breast cancer survivors. AB - Cultural models of emotional disclosure and its impact on seeking support are understudied in the context of cancer diagnosis. We argue that two different cultural norms must be considered: (1) the importance of emotional disclosure and (2) attitudes toward seeking support from loved ones. Our interviews with 37 foreign-born Chinese American and 23 European American breast cancer survivors revealed differences in disclosure of cancer diagnosis and perception of social support. Both Chinese American and European American survivors receive and provide emotional and social support with loved ones, but their manifestations of disclosure and help-seeking behaviors are culturally specific. PMID- 29243523 TI - Causes and consequences of uncertainty about illness risk perceptions. AB - We identified determinants of uncertainty about perceived risk judgments and demonstrated that uncertainty is associated with lower engagement in risk reducing behavior. We found that people likely have metacognitive awareness of when their judgments are overly pessimistic, resulting in uncertainty and that question context (more constraints) and people's time orientation (future orientation) are associated with lower uncertainty. Uncertainty about conditioned risk judgments was associated with lower engagement in exercising and eating a healthy diet in order to reduce risk for heart disease. As a potential determinant of behavior, uncertainty about risk judgments merits further consideration for integration into theories of health behavior. PMID- 29243522 TI - Experiencing the cancer of a loved one influences decision-making for breast cancer prevention. AB - Prior research demonstrates that family history influences breast cancer prevention decisions among healthy women at elevated risk of the disease. Drawing on in-depth interviews with 50 African American and White women, this study reveals an important psychological mechanism of this relationship: exposure to cancer among loved ones. Four distinct categories of cancer exposure (Abstract, Generalized, Practical, and Traumatic), distinguished by the characteristics of women's experiences with cancer among family members and close friends, are associated with differences in knowledge and decisions about breast cancer prevention options. Racial differences and distinct experiences among those with BRCA mutations are also discussed. PMID- 29243527 TI - The Neural Correlates of Negative Symptoms in Schizophrenia: Examples From MRI Literature. AB - Negative symptoms of schizophrenia have a negative impact on psychosocial functioning and disease outcome. It is therefore important to investigate the pathophysiology underlying negative symptoms as this may aid the development of better treatment. In the current article, examples from studies investigating neural correlates of negative symptoms in schizophrenia are given. Investigations using both structural and functional magnetic resonance imaging are presented at different levels of symptomatology descriptions, from the more heterogenous construct of negative symptoms to more single discrete symptoms. Some methods to improve imaging studies of negative symptoms in schizophrenia are also suggested. PMID- 29243525 TI - Galectin-3 and outcomes after anterior-wall myocardial infarction treated by primary percutaneous coronary intervention. AB - AIM: Galectin-3 (Gal-3), a biomarker of inflammation, tissue repair and fibrogenesis, is associated to left ventricular remodeling after ST-elevated myocardial infarction (STEMI), but its relation with long-term outcomes is unclear. METHODS: In 103 consecutive patients with a first anterior STEMI treated by primary angioplasty, we assayed Gal-3 and NT-proBNP. RESULTS: Age was 65 (56 76) years, 28% were women. During 18 +/- 13 months, 20 patients (19.4%) died or were admitted for heart failure. After adjustment for age, gender, renal and ventricular function, troponin, NT-proBNP and Gal-3 independently predicted the combined end point (hazard ratio: 1.11; 95% CI: 1.05-1.17; per 1 ng/ml increase). Event-free survival was 42.3 versus 93.5% for Gal-3>= versus <16.8 ng/ml (p < 0.001). CONCLUSION: Among anterior STEMI patients, early postangioplasty Gal-3 levels may be useful for risk stratification. PMID- 29243526 TI - Relationship Between Persistent Negative Symptoms and Findings of Neurocognition and Neuroimaging in Schizophrenia. AB - Negative symptoms are defined as loss or reduction of otherwise present behaviors or functions in illness situation, and they have constituted an important aspect of schizophrenia. Although negative symptoms have usually been considered as a single entity, neurobiological investigations yielded discrepant results. To overcome challenges that derive from this discrepancy, researchers have proposed several approaches to structure negative symptoms into more homogenous constructs. Concept of persistent negative symptoms (PNS) is one of the proposed approaches, and includes both primary and secondary negative symptoms that persist after adequate treatment. PNS is relatively easy to assess, and by definition, more inclusive; yet it represents an unmet therapeutic need. Therefore, it is a target of several neurobiological and pharmacological studies. There are several structural and functional brain alterations associated with negative symptoms. On the other hand, neurocognitive investigations in patients with schizophrenia have revealed deficits in several domains that showed correlations with negative symptoms. There are several shared features between negative symptoms and neurocognitive deficits in schizophrenia such as prevalence rates, course through the illness, prognostic importance, and impact on social functioning. However, exact mechanisms behind the neurobiology of PNS and how it interacts with neurocognition remain to be explained. Earlier reviews on neuroimaging and neurocognitive correlates of PNS have been focused on studies with broadly defined negative symptoms that were selected by methodological closeness to PNS. In this review, we focus on neural correlates and neurocognitive associations of PNS, and we discuss PNS findings available to date. PMID- 29243528 TI - Electrophysiological and Neuroimaging Research on Negative Symptoms: Future Challenges. PMID- 29243529 TI - Avolition-Apathy and White Matter Connectivity in Schizophrenia: Reduced Fractional Anisotropy Between Amygdala and Insular Cortex. AB - The avolition/apathy domain of negative symptoms includes motivation- and pleasure-related impairments. In people with schizophrenia, structural and functional abnormalities were reported in key regions within the motivational reward system, including ventral-tegmental area (VTA), striatum (especially at the level of the nucleus accumbens, NAcc), orbitofrontal cortex (OFC), as well as amygdala (Amy) and insular cortex (IC). However, the association of the reported abnormalities with avoliton-apathy is still controversial. In the present study, we investigated white matter connectivity patterns within these regions, using a probabilistic analysis of diffusion tensor imaging (DTI) data, in male subjects with schizophrenia. Thirty-five male subjects with schizophrenia (SCZ) and 17 male healthy controls (HC) matched for age, underwent DTI. SCZ were evaluated using the Schedule for Deficit Syndrome (SDS), the Positive and Negative Syndrome Scale (PANSS), and the MATRICS Consensus Cognitive Battery (MCCB). Probabilistic tractography was applied to investigate pathways connecting the Amy and the NAcc with the OFC and IC. Reduced fractional anisotropy (FA) was observed in left Amy ventral anterior IC connections, in SCZ compared with controls. This abnormality was negatively correlated with avolition/apathy but not with expressive deficit scores. SCZ showed also a reduced connectivity index between right NAcc and medial OFC, as compared with controls. Finally, the left NAcc-dorsal anterior IC connectivity index was negatively correlated with working memory scores. Our results indicate that only the avolition/apathy domain of negative symptoms is related to abnormal connectivity in the motivation-related circuits. The findings also demonstrate that distinct alterations underlie cognitive impairment and avolition/apathy. PMID- 29243530 TI - Electrophysiological Markers of Motivation in Psychosis. AB - Motivation is associated with electrophysiological markers, such as awake state delta oscillation and frontal alpha asymmetry, as well as event-related potentials, such as error-related negativity, feedback-related negativity, and prepulse inhibition. These indicators provide an objective measure of motivational deficits in psychiatric conditions, and response to treatment. Also, these modalities of brain activities are drawing attention as a target of neurofeedback training. The aim of this article is to provide a brief overview on electrophysiological findings relevant to the understanding of the mechanisms underlying impaired motivation in psychiatric disorders and clinical practice. PMID- 29243531 TI - Impact of Reward and Loss Anticipation on Cognitive Control: An Event-Related Potential Study in Subjects With Schizophrenia and Healthy Controls. AB - INTRODUCTION: Deficits of cognitive functions and motivation are core aspects of schizophrenia. The interaction of these deficits might contribute to impair the ability to flexibly adjust behavior in accordance with one's intentions and goals. Many studies have focused on the anterior N2 as a correlate of cognitive control based on motivational value. AIMS: Given the key role of motivation impairment in schizophrenia as a predictor of functional outcome, we aimed to study the impact of reward- and avoidance-based motivation on cognitive control using N2. METHOD: Event-related potentials were recorded during the execution of the "Monetary Incentive Delay (MID)" task in 34 patients with schizophrenia (SCZ) stabilized on second-generation antipsychotics and 22 healthy controls (HC). Cognitive domains were assessed using the MATRICS Consensus Cognitive Battery. Negative symptom domains (Avolition/apathy and Expressive deficit), as well as positive and disorganization dimensions were also assessed in SCZ. RESULTS: We did not observe any group difference in N2 amplitude or latency. In HC, N2 amplitude was significantly larger for anticipation of large loss with regard to all reward conditions and for all incentive versus neutral conditions. In SCZ, N2 amplitude did not discriminate between large loss and reward or between incentive and neutral conditions. N2 amplitude was not correlated with psychopathological dimensions or MCCB-assessed cognitive deficits in SCZ. CONCLUSION: Our data in HC are in line with the hypothesis that N2 amplitude reflects the impact of motivational salience on cognitive control. Our results in SCZ indicate a deficit in the discrimination of motivational salience to the service of cognitive control, independently of psychopathology and other cognitive deficits. PMID- 29243532 TI - Use of Transcranial Direct Stimulation in the Treatment of Negative Symptoms of Schizophrenia. AB - Schizophrenia is a debilitating disease that affects approximately 1% of the population. Negative symptoms are among the major determinants of the functional impairment and a significant proportion of patients with negative symptoms will continue to experience these symptoms despite antipsychotic medications. There are promising results in the application of brain stimulation, particularly transcranial direct current stimulation (tDCS), for the reduction of negative symptoms of schizophrenia. However, findings are still controversial. This is a selective review of the literature published between 2011 and 2017 on use of tDCS in treatment of negative symptoms of schizophrenia. We included only randomized controlled trials where schizophrenia and negative symptoms were assessed using any psychometrically validated scale (eg, Positive and Negative Symptoms Scale or Scale for the Assessment of Negative Symptoms). Studies of participants with neurological conditions were excluded, as were those that did not report any symptom outcome variables. Only 5 studies are included. Three studies showed a decrease of negative symptoms. The other studies did not show any therapeutic effects of tDCS in the severity of positive and negative symptoms compared to controls. Our findings suggest that negative symptoms in schizophrenia can be treated with tDCS over the dorsolateral prefrontal cortex, but results are affected by several factors, such as the electrode montage, the concomitant medication, the homogeneity of the sample, the intensity of the tDCS treatment. Further randomized, double-blinded, sham-controlled studies in large samples are still needed to establish the effectiveness of the tDCS in the treatment of negative symptoms in schizophrenia, but there is the potential for tDCS to become a useful complementary treatment option in this population. PMID- 29243533 TI - Assessing Living Donor Priorities Through Nominal Group Technique. AB - The need for kidneys for transplantation continues to far surpass the number of donors. Although studies have shown that most people are aware of and support the idea of living donation, it remains unclear what motivates individuals who are aware, knowledgeable, and in support of donation to actually donate, or conversely, what deters them from donating. Utilizing nominal group technique, 30 individuals participated in 4 groups in which they brainstormed factors that would impact willingness to be a living donor and voted on which factors they deemed most important. Responses were analyzed and categorized into themes. Factors that influence the donation decision, from most to least important as rated by participants, were altruism, relationship to recipient, knowledge, personal risk/impact, convenience/access, cost, support, personal benefit, and religion. Participants reported a significant lack of information about donation as well as lack of knowledge about where and how to obtain information that would motivate them to donate or help make the decision to donate. Findings suggest that public campaign efforts seeking to increase rates of living donation should appeal to altruism and increase knowledge about the impact (or lack thereof) of donation on lifestyle factors and future health, and transplant programs should aim to maximize convenience and minimize donor burden. Future research should examine whether tailoring public campaigns to address factors perceived as most salient by potential donors reduces the significant gap in supply of and demand for kidneys. PMID- 29243534 TI - Eight-and-a-half syndrome caused by a pontine haemorrhage: a case report and review of the literature. AB - BACKGROUND: Eight-and-a-half syndrome is caused by a lesion in the dorsal tegmentum of the caudal pons involving parapontine reticular formation and median longitudinal fasciculus, as well as the nucleus and/or the fasciculus of the facial nerve. It is characterized by one-and-a-half syndrome and an ipsilateral cranial nerve VII palsy. Also, many variants of eight-and-a-half syndrome have been described, including nine syndrome, thirteen-and-a-half syndrome and fifteen and-a-half syndrome. METHODS: We describe a case of a 49-year-old man who presented with eight-and-a-half syndrome combined with contralateral hemiparesis. We reviewed the literature describing the related spectrum of eight-and-a-half syndrome associated with various etiologies. RESULTS: Brain computed tomography scan revealed a hyperdensity located in the left paramedian aspect of the dorsal pons. T2-weighted magnetic resonance imaging at the 11-month follow-up showed hyperintensity and enlargement of the inferior olivary nuclei, which were compatible with a diagnosis of hypertrophic olivary degeneration. In light of our observations and cases reported in the literature, we categorize the spectrum of eight-and-a-half syndrome into three types, namely classic eight-and-a-half syndrome, eight-and-a-half syndrome variants and eight-and-a-half plus syndrome. Besides, the clinical feature and outcome of the three types are discussed in this article. CONCLUSIONS: Recognition of the spectrum of eight-and-a-half syndrome allows precise anatomic localization of the lesion to pontine tegmentum region. PMID- 29243535 TI - Ease-of-learning judgments are based on both processing fluency and beliefs. AB - Processing fluency influences many types of judgments. Some metacognitive research suggests that the influence of processing fluency may be mediated by participants' beliefs. The current study explores the influence of processing fluency and beliefs on ease-of-learning (EOL) judgments. In two experiments (Exp 1: n = 94; Exp 2: n = 146), participants made EOL judgments on 24 six-letter concrete nouns, presented in either a constant condition (high fluency) with upper-case letters (e.g., BUCKET) or an alternating condition (low fluency) with mixed upper- and lower-case letters (e.g., bUcKeT). After judging words individually, participants studied the words and completed a free recall test. Finally, participants indicated what condition they believed made the words more likely to be learned. Results show constant-condition words were judged as more likely to be learned than alternating condition words, but the difference varied with beliefs. Specifically, the difference was biggest when participants believed the constant condition made words more likely to be learned, followed by believing there was no difference, and then believing the alternating condition made words more likely to be learned. Thus, we showed that processing fluency has a direct effect on EOL judgments, but the effect is moderated by beliefs. PMID- 29243536 TI - Variation in Pediatric Organ Donor Management Practices Among US Organ Procurement Organizations. AB - INTRODUCTION: Reports of actual pediatric organ donor management practice among US organ procurement organizations are sparse, and the use of standardized management guidelines is unknown. A recent consensus statement from the Society of Critical Care Medicine, the American College of Chest Physicians, and the Association of Organ Procurement Organizations offers guidelines for the management of the pediatric organ donor. RESEARCH QUESTION: To describe the use of guidelines and routine practices in the management of the pediatric organ donor with respect to hemodynamics, lung and ventilator management, fluid and electrolytes, hormonal replacement therapy, the use of blood products, thermoregulation, and prophylactic antibiotics. DESIGN: Cross-sectional observational study using a survey and follow-up telephone interview with respondents from all 58 US organ procurement organizations. RESULTS: All 58 US Organ Procurement Organizations participated. A majority employed written guidelines for the management of pediatric donor hemodynamics, thermoregulation, fluids, and electrolytes. Management of blood products, the lung, and mechanical ventilation were less commonly committed to written guidelines, but common practices were described. All used various forms of hormonal replacement therapy and the majority administered empiric antibiotic therapy. Wide variation was observed in the management of the lung, mechanical ventilation, and glycemic control. DISCUSSION: Most OPOs used forms of standardized donor management for the pediatric organ donor although variation in the content of that management exists. Barriers to an evidence-based approach to the pediatric donor need to be determined and addressed. PMID- 29243537 TI - Migration and health at older age in rural Malawi. AB - The connection between migration and health has long been established, but relatively little is known about this relationship for older persons, particularly in sub-Saharan Africa (SSA). In this paper, we examine migration selection with regards to health status among older individuals in Malawi, by testing whether older migrants differ from non-migrants in health status before migration. To do so, we use data from the Malawi Longitudinal Study of Families and Health, a longitudinal panel dataset that includes a relatively large number of individuals at older ages. We focus on three measures: mental health, physical health, and HIV status. We find that the relationship between migration and health selection differs by gender. Older women who are HIV-positive are nearly 10 times more likely to migrate compared to their HIV-negative counterparts. For men, those with better mental health are less likely to migrate in the future. These results suggest that, although research in some settings shows that migrants have better health before moving, some older migrants have worse health than their non-migrant peers, and may, therefore, add to the already-heavy burden on rural health centres in Africa. PMID- 29243538 TI - Antineoplastic agents exacerbating Charcot Marie Tooth disease: red flags to avoid permanent disability. AB - BACKGROUND: Charcot Marie Tooth (CMT) disease is the most common form of hereditary neuropathy. Due to the high prevalence of mild and undiagnosed forms, patients with CMT disease may be exposed to severe neurotoxicity following the administration of neurotoxic chemotherapies. The aim of this report is to alert oncologists to the potential to precipitate severe irreversible peripheral neuropathies when administering neurotoxic compounds to undiagnosed CMT patients. MATERIAL AND METHODS: A retrospective research in the OncoNeuroTox database was performed (2010-2016), searching for patients with the diagnosis of chemotherapy induced peripheral neuropathy (CIPN) and CMT disease. A comprehensive literature review for previously published cases was performed using the Pubmed and Cochrane databases (1972-2017). RESULTS: Among 428 patients with CIPN, we identified eight patients with concomitant CMT disease. Seven patients out of the eight had no previous diagnosis of CMT disease, although accurate familial history disclosed mild signs of peripheral neuropathy in five cases. Patients themselves had minor stigmata of long-standing peripheral damage. Patients received chemotherapy regimens based on vinca alkaloids, taxanes or a combination of vinca alkaloids and platinum compounds. In two cases, cumulative doses were below or equal to the expected neurotoxic threshold. Following chemotherapy administration, patients developed severe length-dependent sensory-motor deficits. Despite early drug discontinuation, most patients remained severely disabled. CONCLUSION: A brief checklist to disclose long-standing signs of peripheral neuropathy could be helpful to detect patients with undiagnosed hereditary neuropathies who could be at risk of developing severe irreversible neurotoxicity following the administration of neurotoxic agents. PMID- 29243539 TI - The Influence of Neighbor Effect and Urbanization Toward Organ Donation in Thailand. AB - INTRODUCTION: Toward population wellness, an extreme scarcity of organ supply is proven to be an enormous hindrance. Preferences toward organ donation are vital to raise the organ donation rate. Notably, the area people live in can address the social influence on individual preference toward organ donation. RESEARCH QUESTIONS: This article studies the impact of the neighbor effect on organ donation decisions, addressing the social influence of urbanization on preferences. How neighborhood-specific variables, population density, and socioeconomic status drive the neighbor effect is investigated. The pursuit of organ donor traits is to be answered. DESIGN: The study uses organ donation interview survey data and neighborhood-specific data from Thailand to estimate a series of logistic regression models. RESULTS: Individuals residing in urban areas exhibit a greater likelihood to sign the donor card than those in rural areas. The neighborhood socioeconomic status is the key driver. An individual is more willing to be an organ donor when having neighbors with higher socioeconomic statuses. Results also reveal positive influences of males and education on the organ donation rate. DISCUSSION: This article documents the "neighbor effect" on the organ donation decision via living area type, offering an alternative exposition in raising the organ donation rate. In shifting the society norm toward organ donation consent, policy-makers should acknowledge the benefit of urbanization on organ donation decision derived from resourceful urban areas. Moreover, raising education levels does improve not only citizens' well-being but also their tendency to exhibit an altruistic act toward others. PMID- 29243540 TI - Safety Assessment of Plant-Derived Fatty Acid Oils. AB - The Cosmetic Ingredient Review Expert Panel (Panel) assessed the safety of 244 plant-derived fatty acid oils as used in cosmetics. Oils are used in a wide variety of cosmetic products for their skin conditioning, occlusive, emollient, and moisturizing properties. Since many of these oils are edible, and their systemic toxicity potential is low, the review focused on potential dermal effects. The Panel concluded that the 244 plant-derived fatty acid oils are safe as used in cosmetics. PMID- 29243541 TI - Safety Assessment of Benzyl Alcohol, Benzoic Acid and its Salts, and Benzyl Benzoate. AB - Benzyl alcohol, benzoic acid and its salts, and benzyl benzoate function mostly as fragrance ingredients/preservatives in cosmetic products. The Cosmetic Ingredient Review Expert Panel previously established concentration limits for benzyl alcohol, benzoic acid, and sodium benzoate in cosmetics and determined that the available data were insufficient to support the safety of these ingredients during inhalation exposure. After reviewing newly available data, it was concluded that benzyl alcohol, benzoic acid and its salts, and benzyl benzoate are safe in the present practices of use and concentration described in this safety assessment. PMID- 29243543 TI - A kainate receptor GluK4 deletion, protective against bipolar disorder, is associated with enhanced cognitive performance across diagnoses in the TwinsUK cohort. AB - OBJECTIVES: Cognitive deficits are a common feature of neuropsychiatric disorders. We investigated the relationship between cognitive performance and a deletion allele within GluK4 protective against risk for bipolar disorder, in 1,642 individuals from the TwinsUK study. METHODS: Cognitive performance was assessed using the National Adult Reading Test, four CANTAB tests (Spatial Working Memory, Paired Associates Learning, Pattern Recognition Memory and Reaction Time), and two Principal-Component Analysis-derived factors. Performance in individuals homozygous for the insertion allele was compared to deletion carriers and analysis was adjusted for age of diagnosis, medication and clinical diagnosis. RESULTS: Individuals with the GluK4 protective deletion allele performed significantly better in Spatial Working Memory compared to insertion homozygotes when adjusted for a clinical diagnosis. GluK4 deletion carriers who had a mental health problem (predominately depression) showed better performance in visuo-spatial ability and mental processing speed compared to individuals with mental health problems homozygous for the insertion. CONCLUSIONS: These findings of genotype-dependent cognitive enhancement across clinical groups support the potential clinical use of the GluK4 deletion allele in personalised medicine strategies and provide new insight into the relationship between genetic variation and mood disorders. PMID- 29243542 TI - Safety Assessment of Dimethiconol and Its Esters and Reaction Products as Used in Cosmetics. AB - Dimethiconol and its esters and reaction products are used in cosmetics as either skin-conditioning agents or hair-conditioning agents. The Cosmetic Ingredient Review (CIR) Expert Panel reviewed relevant data and concluded that these ingredients are safe in the present practices of use and concentration described in this safety assessment. While there is an absence of data on reproductive and developmental toxicity and limited tumorigenicity and toxicokinetics data, the Panel reasoned that these ingredients would not be absorbed through the skin, obviating concern over potential reproductive and developmental toxicity or carcinogenicity. PMID- 29243544 TI - Communication is key: the utility of a revised neuropsychological report format. AB - OBJECTIVE: The neuropsychological report is a critical tool for communicating evaluation results to multiple audiences who have varying knowledge about neuropsychology and often have limited ability to review long, complex reports. Considerable time is spent writing these reports and challenges persist related to readability, length/complexity, and billable clinical time (which may be capped by third-party payors or families' ability to pay). METHODS: This quality improvement effort systematically evaluated the redesign of pediatric neuropsychological reports in an outpatient clinic serving primarily medical populations. RESULTS: Revised reports were shorter, with improved readability, structure, and effectiveness in communicating results and recommendations. Improved clinical efficiency was also observed. CONCLUSIONS: We suggest that adaptation to efficient, readable, and effective reports is possible within the practice of neuropsychology. Findings encourage replication in other settings. Through collaboration with key stakeholders, providers can identify their populations' and audience's unique needs and set report targets accordingly. To encourage that practice, we summarize our general process, provide a set of guidelines that can be adapted across multiple settings, and include an appended sample report. PMID- 29243545 TI - The role of macrophages in the differentiation process of ureteral polyps. AB - Objective To evaluate the role of macrophage infiltration in the differentiation process of ureteral polyps and cancers. Methods This retrospective immunohistochemical study analysed archival samples of pathologically-confirmed specimens of low- and high-grade ureteral cancer, ureteral papilloma and ureteral polyps. The samples were immunohistochemically stained for cluster of differentiation (CD)4, CD8, CD16, CD25, CD56 and CD68 using immunofluorescence in order to identify different T-lymphocyte populations and macrophages. Results A total of 70 specimens were included in the analysis: 21 specimens of ureteral cancer, 17 specimens of ureteral papilloma, and 32 specimens of ureteral polyps. The largest proportion of CD4+CD25+ regulatory T cells was observed in the low grade ureteral cancer group and almost none were observed in ureteral papillomas. The largest proportion of CD8+ cytotoxic T-lymphocytes was observed in the ureteral polyps. The largest proportion of CD56+ natural killer cells was detected in the ureteral polyps, with very low levels observed in the other three groups. The largest proportion of CD16+CD68+ macrophages was observed in the high grade ureteral cancer group, which was significantly higher than that observed in the ureteral papillomas. Conclusions This study revealed that CD16+CD68+ macrophages appear to participate in ureteral neoplastic transformation. PMID- 29243547 TI - Posttraumatic Stress Disorder, Quality of Life, and the Subjective Experience in Liver Transplant Recipients. AB - OBJECTIVE: A high prevalence of posttraumatic stress disorder (PTSD) symptoms among transplant recipients has been associated with a low adherence to treatment and poor survival. It is crucial to detect and prevent the development of posttraumatic stress in transplant settings. METHODS: We examined the prevalence of posttraumatic stress symptoms in 3 liver transplant recipients by means of the Essen Trauma Inventory (ETI), a self-report questionnaire. The Short Form-36 was used to assess the perceived health-related quality of life. Patients were asked to indicate the most traumatic events within the context of the liver transplantation procedure. RESULTS: Five patients (4.9%) fulfilled the criteria for PTSD related to liver disease or transplantation (ETI score greater than 27). In these patients, diagnosis was confirmed by a structured clinical interview. Fourteen (13.6%) patients had a partial PTSD with the ETI score less than 27 and greater than 16. Posttraumatic stress symptoms were significantly associated with perceived poor physical and mental health-related quality of life. Patients reported that the physicians' disclosure of diagnosis was experienced as traumatic, followed by treatment in an intensive care unit and the liver transplantation itself. CONCLUSIONS: The ETI resulted in prevalence rates for PTSD comparable to previous studies in liver transplantation settings. Medical professionals requested additional training in how to deliver severe diagnoses to patients. PMID- 29243546 TI - Changes in medication use in a cohort of patients with advanced cancer: The international multicentre prospective European Palliative Care Cancer Symptom study. AB - BACKGROUND: Information on medication use in the last months of life is limited. AIM: To describe which medications are prescribed and deprescribed in advanced cancer patients receiving palliative care in relation to time before death and to explore associations with demographic variables. DESIGN: Prospective study, using case report forms for monthly data collection. Medication included cancer treatment and 19 therapeutic groups, grouped into four categories for: (1) cancer therapy, (2) specific cancer-related symptom relief, (3) other symptom relief and (4) long-term prevention. Data were analysed retrospectively using death as the index date. We compared medication use at 5, 4, 3, 2 and 1 month(s) before death by constructing five cross-sectional subsamples with medication use during that month. Paired analyses were done on a subsample of patients with at least two assessments before death. SETTING/PARTICIPANTS: We studied the medication use of 720 patients (mean age 67, 56% male) in 30 cancer centres representing 12 countries. RESULTS: From 5 to 1 month(s) before death, cancer therapy decreased (55%-24%), most medications for symptom relief increased, for example, opioids (62%-81%) and sedatives (35%-46%), but medication for long-term prevention decreased (38%-27%). The prevalence of chemotherapy was 15.5% in the last month of life, with 9% of new courses started in the last 2 months. With higher age, chemotherapy and opioid use decreased. CONCLUSION: Medications for symptom relief increased in almost all medication groups. Deprescribing was found in heart medication/anti-hypertensives and cancer therapy, although use of the latter remained relatively high. PMID- 29243548 TI - Readability of Human Subjects Training Materials for Research. AB - Institutions are required to ensure that persons involved in human subjects research receive appropriate human subjects protections training and education. Several organizations use the Collaborative Institutional Training Initiative (CITI) program to fulfill training requirements. Most researchers find the CITI program too complex for community members who collaborate with researchers. This study aimed to determine the readability of CITI modules most frequently used in community-based participatory research (CBPR). The mean readability level of the CITI modules is 14.8 grade; CBPR readability levels ranged from 11.6 to 12.0 grade (sixth- to eighth-grade reading level is recommended). With a baseline objective measure, modifications can be made to improve the plain language quality and understandability of human subjects training modules for community members. PMID- 29243549 TI - How primary care reforms influenced health indicators in Manisa district in Turkey: Lessons for general practitioners. AB - BACKGROUND: Turkish health reforms began in 2003 and brought some significant changes in primary care services. Few studies in Turkey compare the shift from health centres (HC) to family physicians (FP) approach, which was initiated by reforms. OBJECTIVES: This study compares health status indicators during the HC period before reforms (2003-2007) and the FP period after reforms (2008-2012) in Turkey. METHODS: This study encompasses time series data consisting of the results of a 10-year assessment (2003-2012) in Manisa district. All the data were obtained electronically and by month. The intersection points of the regression curves of these two periods and the beta coefficients were compared using segmented linear regression analysis. RESULTS: The mean number of follow-up per person/year during the HC period in infants (10.5), pregnant women (6.6) and women (1.8) was significantly higher than the mean number of follow-up during the FP period in infants (6.7), pregnant women (5.6) and women (0.9). Rates of BCG and measles vaccinations were significantly higher during the FP period; however, rates of HBV and DPT were same. The mean number of outpatient services per person/year during the FP period (3.3) was significantly higher than HC period (2.8). Within non-communicable diseases, no difference was detected for hypertension prevalence. Within communicable diseases, there was no difference for rabies suspected bites but acute haemorrhagic gastroenteritis significantly decreased. The infant mortality rate and under five-year child mortality rate significantly increased during the FP period. CONCLUSION: Primary care services should be reorganized and integrated with public health services. PMID- 29243550 TI - Attention-deficit/hyperactivity disorder is associated with reduced levels of serum low-density lipoprotein cholesterol in adolescents. Data from the population-based German KiGGS study. AB - OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a multifactorial, complex and the most common neurodevelopmental disorder in childhood. In this analysis, we tested the hypothesis that altered serum lipid patterns are associated with ADHD. METHODS: Using data from the nationwide, population-based German Health Interview and Examination Survey for Children and Adolescents (KiGGS), we compared serum levels of total cholesterol, high-density (HDL) and low-density lipoprotein (LDL) cholesterol, and also triglycerides, in participants with physician-diagnosed and/or suspected ADHD, as defined by a value of >=7 on the hyperactivity-inattention subscale of the Strengths and Difficulties Questionnaire (SDQ), with non-ADHD controls. RESULTS: Among 6,898 participants aged between 11 and 17 years, 666 (9.7%) had a physician-based diagnosis of ADHD and/or suspected ADHD. We found correlations between the parent rated SDQ scores on the hyperactivity-inattention subscale and concentrations of triglycerides (r = 0.064, p < .001), total cholesterol (r = -0.026, p = .033), HDL cholesterol (r = -0.059, p < .001) and LDL cholesterol (r = -0.027, p = .031). In multivariate models, low serum levels of LDL cholesterol remained a significant predictor of ADHD (Exp(beta) = 0.382, 95% confidence interval = 0.165 0.888, p = .025). CONCLUSIONS: Our findings in a large, nationwide and representative sample of German adolescents demonstrated a small, but significant and inverse link between LDL cholesterol levels and symptoms of ADHD. Further studies are required to decipher the biochemical mechanisms behind this relationship. PMID- 29243551 TI - Donor Leucocytosis Predicts Bacterial and Fungal Contamination of the Preservation Solution in Visceral Organ Transplantation. AB - INTRODUCTION: Contamination of the preservation solution may contribute to septic complications that can occur after transplantation and cause higher morbidity and mortality among recipients. The aim of this study was to determine potential donor-related predictors of positive microbiological findings in the preservation solution. DESIGN: We retrospectively studied 16 donor parameters on data from our center for microbiological findings in the preservation solution used in solid organ recovery. From January 2008 through December 2011, 976 solid organs were transplanted, and in 167, the solution was positive for contaminants. RESULTS: The most frequently detected contaminant was coagulase-negative staphylococci. Only the donor leucocyte count (cutoff at 9.1 * 109/L) predicted positive microbiological findings in the preservation solution ( P = .0024). Multivariable regression analysis found that donor age, donor sex, intensive care unit stay, total number of organs recovered, and leucocyte count differentiated various categories of potentially pathogenic bacteria. CONCLUSION: Donor leucocyte count higher than 9.1 * 109/L predicts contamination of preservation solution. PMID- 29243552 TI - Is it possible to draw firm conclusions from the PLIANT trial? PMID- 29243553 TI - Disease modeling studies using induced pluripotent stem cells: are we using enough controls? AB - The comparison of differentiated induced pluripotent stem cells (iPSCs) derived from patients with disease to differentiated iPSCs derived from healthy patients enables powerful disease modeling. By performing an informal retrospective survey of disease modeling studies published in high impact journals, we found that the median and average number of controls used in these studies were 1 and 1.6, respectively. The bulk of these studies did not control for age, gender and ethnicity. Since a large proportion of phenotypic differences observed between iPSC lines are due to genetic variation or variation between lines, this is an insufficient number of controls to confidently rule out standard variation. Future studies need to include more controls and ensure that these controls are appropriately matched for gender, age and ethnicity. PMID- 29243554 TI - Parametric estimates for the receiver operating characteristic curve generalization for non-monotone relationships. AB - Diagnostic procedures are based on establishing certain conditions and then checking if those conditions are satisfied by a given individual. When the diagnostic procedure is based on a continuous marker, this is equivalent to fix a region or classification subset and then check if the observed value of the marker belongs to that region. Receiver operating characteristic curve is a valuable and popular tool to study and compare the diagnostic ability of a given marker. Besides, the area under the receiver operating characteristic curve is frequently used as an index of the global discrimination ability. This paper revises and widens the scope of the receiver operating characteristic curve definition by setting the classification subsets in which the final decision is based in the spotlight of the analysis. We revise the definition of the receiver operating characteristic curve in terms of particular classes of classification subsets and then focus on a receiver operating characteristic curve generalization for situations in which both low and high values of the marker are associated with more probability of having the studied characteristic. Parametric and non-parametric estimators of the receiver operating characteristic curve generalization are investigated. Monte Carlo studies and real data examples illustrate their practical performance. PMID- 29243555 TI - Philanthropy and the nation-state in global health: The Gates Foundation in India. AB - In recent years, philanthropic actors such as the Gates Foundation have been understood as commanding sweeping influence in global health. They have been associated with the outsourcing of public health services, shifting of policy priorities, and the eventual sidelining of national governments. This article makes a different argument about the impact of global philanthropic actors. It focuses on the work of the Gates Foundation in India over the last decade and a half, tracing how the foundation initially circumvented the national government but then moved on to a discourse of partnership. Ironically, after an early discounting of the role of the government, the foundation later sought to transition its programmes to the state. The foundation's evolving trajectory reflects its experiences on the ground and also the difficulties of realising its original ambitions. While the foundation's work in India is marked by ebbs and flows, the state's institutions remain constant. The article argues that there is not always a straightforward marginalisation of the government vis-a-vis global philanthropic actors. Actors such as the Gates Foundation, perceived as enormously powerful in global health institutions in Geneva and New York, may have a far more qualified impact in large developing countries such as India. PMID- 29243556 TI - Preferences of AAA/AAG codon recognition by modified nucleosides, taum5s2U34 and t6A37 present in tRNALys. AB - Deficiency of 5-taurinomethyl-2-thiouridine, taum5s2U at the 34th 'wobble' position in tRNALys causes MERRF (Myoclonic Epilepsy with Ragged Red Fibers), a neuromuscular disease. This modified nucleoside of mt tRNALys, recognizes AAA/AAG codons during protein biosynthesis process. Its preference to identify cognate codons has not been studied at the atomic level. Hence, multiple MD simulations of various molecular models of anticodon stem loop (ASL) of mt tRNALys in presence and absence of taum5s2U34 and N6-threonylcarbamoyl adenosine (t6A37) along with AAA and AAG codons have been accomplished. Additional four MD simulations of multiple ASL mt tRNALys models in the context of ribosomal A-site residues have also been performed to investigate the role of A-site in recognition of AAA/AAG codons. MD simulation results show that, ASL models in presence of taum5s2U34 and t6A37 with codons AAA/AAG are more stable than the ASL lacking these modified bases. MD trajectories suggest that taum5s2U recognizes the codons initially by 'wobble' hydrogen bonding interactions, and then tRNALys might leave the explicit codon by a novel 'single' hydrogen bonding interaction in order to run the protein biosynthesis process smoothly. We propose this model as the 'Foot-Step Model' for codon recognition, in which the single hydrogen bond plays a crucial role. MD simulation results suggest that, tRNALys with taum5s2U and t6A recognizes AAA codon more preferably than AAG. Thus, these results reveal the consequences of taum5s2U and t6A in recognition of AAA/AAG codons in mitochondrial disease, MERRF. PMID- 29243557 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions 1 July-31 August 2017. PMID- 29243558 TI - Ex vivo and in vivo genome editing: a regulatory scientific framework from early development to clinical implementation. AB - Recent advances in human genome science have paved the way to a new class of human gene therapies based on gene editing, with the potential to provide a long lasting curative strategy for many debilitating and complex disorders, for which there is an unmet medical need. Therapeutic genome editing encompasses both ex vivo and in vivo gene correction modalities, for which similar and also application-specific considerations apply, which dictate the overall strategy to be followed from a scientific, clinical and regulatory perspective. Here, the major regulatory barriers to successful clinical implementation are discussed, together with the key issues to be considered for generating safe (minimizing risks of tumorigenesis and off-target effects) and effective gene editing-based medicines for application in regenerative medicine. PMID- 29243559 TI - Multiplicity and mutuality in the transition of patient and therapist's self states: Comparison of good vs. poor outcome groups. AB - OBJECTIVE: According to the Assimilation Model, the self is consisted of multiple internal voices which are sometimes conflicted, or even dissociated, from one another. Thus, a key therapeutic goal is to create awareness and dialogue between a patient's various internal voices, in order to facilitate positive change. A recent development of this theoretical line suggests that clinically addressing both the patients' and therapists' internal voices, and their mutual influences, contributes significantly to the treatment outcome. Current study aims to examine: (a) Patients' progression throughout treatment in their quality of movement of self-states, from lower levels of dissociation to higher ones of dialectics, and whether this pattern is associated with positive outcomes; (b) temporal congruence in patient-therapist quality of movement of self-states and its association with session outcome. METHOD: Nine good and nine poor-outcome cases of psychodynamic treatment were analyzed (N = 18) for both the patient and the therapist using the TPA, an expansion of the assimilation of problematic experiences scale (APES). Patients completed the Outcome Rating Scale (i.e., ORS), a session-by-session measure that assesses overall functioning, and symptomatic pre-and-post treatment measures (BDI). RESULTS: A quadratic pattern of change was observed on the TPA of patients from the good-outcome cases: Patients showed more conflict in the beginning, avoidance between self-states in the middle phase, and dialectics towards the end. Additionally, the patient therapist TPA temporal congruence was significantly related to session outcome of the good-outcome group. CONCLUSION: These findings emphasize the importance of combining an intra-psychic and inter-psychic set of lenses when inquiring therapeutic processes. PMID- 29243561 TI - Patient Safety Communication Among Differently Educated Nurses: Converging and Diverging Meaning Systems. AB - Studies that suggest an increased number of bachelor's prepared nurses (BSNs) at the bedside improves patient safety do not stratify their samples into traditional bachelor's and associates (ADN) to BSN graduates. This qualitative study investigated potential differences in patient safety meaning among BSNs and ADN to BSN graduates. Guided by the theory of Language Convergence/Meaning Divergence, interview data from eight BSN and eight ADN to BSN graduates were analyzed. Findings indicate there are two meaning levels or systems, the local level and the systemic level. At the local level, the meaning of patient safety is focused at the patient's bedside and regulated by the nurse. The systemic level included the notion that health system factors such as policies and staffing are paramount to keeping patients safe. More frequently, ADN to BSN graduates' meaning of patient safety was at the local level, while BSNs' meaning centered at the systemic level. PMID- 29243560 TI - Factors associated with delayed initiation of breastfeeding: a survey in Northern Uganda. AB - BACKGROUND: Initiation of breastfeeding later than 1 hour after birth is associated with increased neonatal morbidity and mortality. OBJECTIVE: To determine the prevalence and factors associated with delayed initiation of breastfeeding. METHODS: We conducted a survey in 2016 of 930 children under the age of 2 years in Lira district, northern Uganda. Mothers of the children were interviewed and data was collected on mobile phones using Open Data Kit software ( https://opendatakit.org ). Multivariable logistic regression was used to determine factors associated with delayed initiation of breastfeeding. RESULTS: Almost half [48.2%, 95% confidence interval (CI) (44.3-52.1)] of the mothers delayed initiation of breastfeeding. Factors significantly associated with delayed initiation of breastfeeding in multivariable analysis included caesarean delivery [Adjusted Odds Ratio (AOR) 11.10 95% CI (3.73-33.04)], discarding initial breast milk [AOR 2.02 95% CI (1.41-2.88)], home delivery [AOR 1.43 95% CI (1.04-1.97)] and mother being responsible for initiating breastfeeding as compared to a health worker or relative [AOR 1.73 95% CI (1.33-2.26)]. Mothers having a secondary education were less likely [AOR 0.54 95% CI (0.30-0.96)] to delay initiation of breastfeeding as compared to those with no education. CONCLUSION: About half the mothers delayed initiation of breastfeeding until after 1 hour after birth. Programs to promote, protect and support breastfeeding in this post conflict region are urgently needed. PMID- 29243563 TI - Safety Culture, Patient Safety, and Quality of Care Outcomes: A Literature Review. AB - This integrative literature review was conducted to examine the relationships between safety culture and patient safety and quality of care outcomes in hospital settings and to identify directions for future research. Using a search of six electronic databases, 17 studies that met the study criteria were selected for review. This review revealed semantic inconsistencies, infrequent use of a theory or theoretical framework, limited discussions of validity of instruments used, and significant methodological variations. Most notably, this review identified a large array of nonsignificant and inconsistent relationships between safety culture and patient safety and quality of care outcomes. To improve understanding of the relationships, investigators should consider using a theoretical framework and valid measures of the key concepts. Researchers should also give more attention to selecting appropriate sampling and data collection methods, units of analysis, levels of data measurement and aggregation, and statistical analyses. PMID- 29243562 TI - Measurement and Outcomes of the Perceived Risk of Stroke: A Review. AB - Stroke continues to be a public health problem, and risk perceptions are key to understanding people's thoughts about stroke risk and their preventive health behaviors. This review identifies how the perceived risk of stroke has been measured and outcomes in terms of levels, predictors, accuracy, and intervention results. Sixteen studies were included. The perceived risk of stroke has primarily been assessed with single-item measures; no multi-item surveys were found. In general, people tend to perceive a low-moderate risk of stroke; the most common predictors of higher stroke risk perceptions were having risk factors for stroke (hypertension, diabetes) and a higher number of risk factors. However, inaccuracies were common; at least half of respondents underestimated/overestimated their risk. Few studies have examined whether interventions can improve the perceived risk of stroke. Strategies to improve stroke risk perceptions should be explored to determine whether accuracy can promote healthy lifestyles to reduce stroke risk. PMID- 29243564 TI - Deportation of non-citizen military veterans: A critical analysis of implications for the right to health. AB - Military personnel are commonly exposed to health-harming conditions during their service, resulting in higher rates of physical and mental health conditions compared with the general population. In an era of mass deportations, it is notable that non-citizen military veterans are not exempt from deportation. We utilised a human rights framework to conduct a critical analysis of potential health consequences of deportation for U.S. military veterans, identifying three ways in which veterans' rights to health may be constrained through deportation. First, honourably discharged deported veterans may be denied access to free or subsidised Veterans Affairs health services to which they would likely otherwise be entitled. Second, availability of and access to healthcare may be limited for reasons including barriers to enrolling in public insurance schemes, challenges navigating unfamiliar health systems and stigma and discrimination towards deported migrants. Finally, quality of available care may be sub-optimal due to limited expertise in service-related health issues and lack of evidence-based treatment for some health conditions (e.g. substance abuse/dependence). Binational multi-sectoral efforts are necessary to ensure that the rights to health of deported military veterans are adequately protected. PMID- 29243565 TI - Finding the Best Evidence to Support Care of Students With Chronic Conditions: CLUE #2: Acquire. AB - Every day, school nurses make practice decisions that impact the care provided to school children. Our professional standards require that we stay up to date with best practice options, yet there is neither time nor money to attend a continuing education offering for every practice concern we encounter. Learning how to acquire the evidence that leads to best practice can ensure our practice is current and that our students have the best chance to have positive health and academic outcomes. This article explains where to find good evidence and how to access it. PMID- 29243566 TI - For Shawnee: Keeping the Student (and Family) Front and Center. AB - Patient-centered care is a buzzword heard often as part of health care reform efforts. For school nurses patient-centered care means student- and family centered care. Student-centered care can improve student compliance and actually decrease school nurse workload. This article explains what student-centered means and provides examples of how school nurses can provide student and families centered care in their communities. Approaches that center on individual students, as well as community cafes will be included. PMID- 29243568 TI - Diabetes Management in the School Setting: Position Statement. PMID- 29243567 TI - Building Hopeful Leaders. PMID- 29243571 TI - Practice observed. PMID- 29243570 TI - Planning for juvenescence - Winter crisis. PMID- 29243573 TI - Corrigendum to Effects of alteplase for acute stroke according to criteria defining the European Union and United States marketing authorizations: Individual-patient- data meta-analysis of randomized trials. PMID- 29243572 TI - Development, dissemination, and applications of a new terminological resource, the Q-Code taxonomy for professional aspects of general practice/family medicine. AB - BACKGROUND: While documentation of clinical aspects of General Practice/Family Medicine (GP/FM) is assured by the International Classification of Primary Care (ICPC), there is no taxonomy for the professional aspects (context and management) of GP/FM. OBJECTIVES: To present the development, dissemination, applications, and resulting face validity of the Q-Codes taxonomy specifically designed to describe contextual features of GP/FM, proposed as an extension to the ICPC. DEVELOPMENT: The Q-Codes taxonomy was developed from Lamberts' seminal idea for indexing contextual content (1987) by a multi-disciplinary team of knowledge engineers, linguists and general practitioners, through a qualitative and iterative analysis of 1702 abstracts from six GP/FM conferences using Atlas.ti software. A total of 182 concepts, called Q-Codes, representing professional aspects of GP/FM were identified and organized in a taxonomy. Dissemination: The taxonomy is published as an online terminological resource, using semantic web techniques and web ontology language (OWL) ( http://www.hetop.eu/Q ). Each Q-Code is identified with a unique resource identifier (URI), and provided with preferred terms, and scope notes in ten languages (Portuguese, Spanish, English, French, Dutch, Korean, Vietnamese, Turkish, Georgian, German) and search filters for MEDLINE and web searches. APPLICATIONS: This taxonomy has already been used to support queries in bibliographic databases (e.g., MEDLINE), to facilitate indexing of grey literature in GP/FM as congress abstracts, master theses, websites and as an educational tool in vocational teaching, Conclusions: The rapidly growing list of practical applications provides face-validity for the usefulness of this freely available new terminological resource. PMID- 29243574 TI - Stock-outs! Improvisations and processes of infrastructuring in Uganda's HIV/Aids and malaria programmes. AB - This paper examines the stock-outs of medicines and diagnostic devices in Uganda. Our aim is to trace and compare interruptions in the supply of antiretrovirals and Rapid Diagnostic Tests in order to provide an ethnographic account of the complex role that improvisations play within global health infrastructures. We will argue that the fragmented and mobile infrastructures of these key global health technologies require and necessitate improvisations by the different actors involved as well as on almost all levels of the Ugandan health-care system. The extent and abundance of improvisations in itself works to acquire infrastructural capacities, a process that we will call the infrastructuring of care and treatment. We will also show how this process of infrastructuring of care and treatment - here rendered visible through improvisations - produces new dilemmas and uncertainties. Our approach to infrastructure challenges technocratic overtones prevalent in current debates around the much-needed strengthening of health systems. Our study of stock-outs aims to show how the infrastructure of under-resourced health systems is maintained by a complex nexus of socio-material practices and improvisations. PMID- 29243575 TI - Nanomedicine Strategies for Sustained, Controlled and Targeted Treatment of Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) is one of the most devastating diseases worldwide. The current drugs for AD can only ameliorate the symptoms rather than reverse or prevent the progress of AD. On the other hand, blood-brain barrier (BBB), as a natural barrier, significantly impedes drug delivery from the blood circulation into the brain. Nanomedicine can be a safe, effective and promising approach to treat AD. OBJECTIVE: This review summarizes the recent nanomedicine research in this area, including the use of liposomes and nanoparticles (NPs), to provide new approach for targeted treatment of AD. METHOD: Collecting and referring to the related literature in recent 10 years, via searching MeSH Terms "Alzheimer's disease; nanomedicine; nanoparticle; amyloid beta peptide; tau protein; autophagy". RESULTS: Nanomedicines show superiority over conventional anti-AD drugs as a potential weapon against AD by the five proposed mechanisms: many unfavorable pharmaceutical properties of conventional anti-AD drugs maybe greatly overcome by nanomedicine; nanomedicines trigger efficient production of high-titer anti-Abeta antibodies following controlled release of antigens by them; some apolipoprotein- based nanomedicines could preferably bind to Abeta and increase the elimination of Abeta nanomedicine-induced autophagy could be facilitated to increase the elimination of Abeta nanomedicineinduced inhibition of tau aggregation. CONCLUSION: Therefore, nanomedicine-mediated drug therapy is promising in the treatment of AD. PMID- 29243576 TI - A Novel Polymer-Lipid Hybrid Nanoparticle for the Improvement of Topotecan Hydrochloride Physicochemical Properties. AB - BACKGROUND: Topotecan (TPT) is a water-soluble derivate of camptothecin, which undergoes ring-opening hydrolysis in neutral solutions, leading to stability loss and poor cellular uptake. Lipid nanoencapsulation can improve TPT stability, and polymer-lipid hybrid nanoparticles (PLN) are interesting alternatives to improve TPT nanoencapsulation. OBJECTIVE: This study seeks to prepare complexes between the cationic TPT and the negatively charged dextran sulfate (DS) with a view of improving drug loading, chemical stability and release control. METHODS: The optimum ionic molar ratio in DS-TPT complexation was determined, and the selected complex was characterized by FTIR and solid-state 13C NMR. TPT solubility in the free and complexed forms was also assayed. TPT-PLN was then obtained via a microemulsion technique, and particle size, zeta potential, encapsulation efficiency, drug loading and drug recovery were determined. Additionally, the TPT stability and in vitro release were determined from PLN and compared with free TPT, TPT-DS complex and TPT encapsulated in nanostructured lipid carriers (NLC) of similar composition. RESULTS: TPT-DS complexation was confirmed by FTIR and NMR. TPT solubility in the complex was drastically decreased when compared to free TPT. TPT-PLN had high encapsulation efficiency (97%) and drug loading capacity (5.5%). Additionally, TPT-PLN showed a mean diameter, polidispersivity index e zeta potential of 140 nm, 0.2 and -22 mV, respectively. The TPT chemical stability and release from PLN were observed to be superior when compared to NLC. CONCLUSION: PLN has shown to be a more effective nanosystem for TPT nanoencapsulation because TPT loading, stability and release were superior when compared to TPT-NLC. PMID- 29243577 TI - Recent Developments of Coumarin Hybrids as Anti-fungal Agents. AB - Fungi place a huge burden on global healthcare systems attributed to the fact that fungal infections are responsible for the high morbidity and mortality rates in patients who received stem cell transplantation, antineoplastic chemotherapy, organ transplants or suffered Human Immunodeficiency Virus (HIV) infection. Unfortunately, almost none of the representative anti-fungal agents currently used in clinical therapy are ideal in terms of efficacy, anti-fungal spectrum or safety. Moreover, the rapid development of resistance to existing anti-fungal drugs has further aggravated the mortality and spread of fungi, creating an urgent need for novel anti-fungal agents. The broad spectrum of biological activities and successful usage in clinic made coumarins a promising anti-fungal candidate. Furthermore, hybridization of other pharmacophores with coumarin motif may enhance the anti-fungal efficacy, broaden the anti-fungal spectrum and improve the safety profiles. Thus, numerous coumarin hybrids have been assessed for their anti-fungal activities, and some of them showed promising potency and may have a novel mechanism of action. This review aims to outline the recent development of coumarin hybrids as potential anti-fungal agents and summarize their Structure-Activity Relationship (SAR) to provide an insight for rational designs of more active agents. PMID- 29243578 TI - Design, Synthesis and In Vitro Anti-microbial Evaluation of Ethylene/ Propylene 1H-1,2,3-Triazole-4-Methylene-tethered Isatin-coumarin Hybrids. AB - OBJECTIVE: A new class of ethylene/propylene-1H-1,2,3-triazole-4-methylene tethered isatincoumarin hybrids 8a-j, integrating three anti-tuberculosis pharmacophores coumarin, isatin and 1,2,3- triazole was designed and synthesized. METHOD: These hybrids were assessed for their in vitro anti-TB activity against MTB H37Rv and MDRTB, as well as anti-bacterial activity against Gram-positive and Gram-negative strains, and cytotoxicity in VERO cell line. RESULTS: The results showed that all hybrids with acceptable cytotoxicity (CC50: 64-512 ug/mL) exhibited weak to moderate anti-microbial activity. The most active hybrid 8i with MIC of 50 ug/mL against MTB H37Rv and MDR-TB, also has excellent cytotoxicity profile (CC50: 128 ug/mL). CONCLUSION: The resistance index of hybrid 8i was 1, indicating that hybrid 8i has no cross-resistance with the first line anti-TB agent. Thus, hybrid 8i could act as a lead for further optimization. PMID- 29243579 TI - Recent Development of Coumarin Derivatives as Potential Antiplasmodial and Antimalarial Agents. AB - Malaria still remains one of the leading deadliest diseases throughout the world, leading to around 1 million deaths annually. The emergence and spread of growing resistance to the firstline antimalarials are an alarming the serious problem in malaria control, demanding the need for new drugs more potent than earlier with improved Absorption, Distribution, Metabolism, and Excretion (ADME) profiles. Coumarins, which exhibited various biological properties, also displayed potential in vitro antiplasmodial and in vivo antimalarial activities. Moreover, many of coumarin derivatives have already been used in clinical practice for the treatment of several diseases. Therefore, coumarin derivatives play a pivotal role in medicinal chemistry, also making them promising candidates for the treatment of malaria. This review aims to summarize the recent advances made towards the development of coumarin-containing derivatives as antiplasmodial and antimalarial agents and their structure-activity relationship is also discussed. PMID- 29243581 TI - Anticancer Natural Coumarins as Lead Compounds for the Discovery of New Drugs. AB - Cancer is one of the most serious illnesses of our civilization. The International Agency for Research on Cancer estimated that 14.1 million new cancer cases have been diagnosed last year. Therefore, the cure efficiency of cancer chemotherapy depends not only on how the anticancer drug is delivered to its targets but also on the anticancer drug itself. Among the approved drugs, 80% are derived from natural compounds. In this sense, coumarins, natural polyphenols for which anticancer activity has been proved, can be a source or inspire the synthesis of new anticancer agents. Several natural coumarins, such as scopoletin, daphnetin, esculetin and the less known wedelolactone and galbanic acid, appear to have promising anticancer activities. This paper will provide a comprehensive overview of the advances on natural coumarins with potential therapeutic applications as anticancer agents highlighting the ones for which the mechanism of action is well defined and can serve as lead compounds for the design of new more potent molecules. PMID- 29243580 TI - Coumarins as Promising Scaffold for the Treatment of Age-related Diseases - An Overview of the Last Five Years. AB - Degenerative diseases are becoming more common with increasing life expectancy of the human population. The 20th century faced a progressive demographic change in the industrialized world, followed by identical trends in population aging in Asia, Africa, and Middle and South America. A significant increase in chronic age dependent disorders will soon cause important challenges for several countries. Age-related pathologies are commonly seen in elderly patients. More than 40% of adults over 60 years old present a combination of risk factors, described as metabolic syndrome, which significantly increases the tendency for developing degenerative diseases, and some types of cancers. Among these, Parkinson's, Alzheimer's and cardiovascular diseases are on the top of the list. The discovery of effective cardio- and neuroprotective alternative therapeutics that decrease or block disease's progression at early stages, is the main goal of research groups working in the field. A wide range of different substituted coumarins, and the pharmacological properties they may display, are trend topics because of their synthetic accessibility, as well as their abundance in plants and other naturally-occurring products. These heterocyclic compounds play an important role in a variety of areas, but stand out in the field of Medicinal Chemistry. This review provides an overview of the last five years about the potential of coumarins as modulators of several physiological mechanisms involved in age related pathologies. PMID- 29243582 TI - Consensus Validation of SimplerTM: A Tool to Improve Pharmacist Delivery of Quality, Evidence-Based Diabetes Care. AB - BACKGROUND: Studies on a structured method used by pharmacists to provide comprehensive, evidence-based diabetes care are lacking. The aim of this study was to prioritise, rank and construct validate indicators categorised as seven treatment factors utilised in the management of type 2 diabetes namely: Cholesterol, blood pressure and glycaemia control; medication and lifestyle management; cardiovascular risk management and patient education using the Delphi process. METHODS: A Delphi questionnaire consisted of 29 Part 1 and nine Part 2 indicators which were incorporated into a tool called SimplerTM. The indicators were mainly sourced from American, Australian and Malaysian diabetes management guidelines. Diabetes experts were asked to rank indicators in the order of importance in Part 1. In Part 2, indicators had to be chosen for inclusion into SimplerTM using a fivepoint Likert scale. The consensus level was pre-set at 60%. RESULTS: A three round Delphi process was used to validate all 38 indicators by 12 experts from Australia and Malaysia: five pharmacists, four doctors, two endocrinologists and a diabetes nurse. Consensus was reached for 93.1% (27/29) of the Part 1 indicators and all nine Part 2 indicators (100%). Five out of nine indicators in Part 2 questionnaire obtained consensus disagreement for inclusion into the Simpler TM tool. CONCLUSION: The SimplerTM tool is the first structured diabetes multifactorial tool to address all seven evidence-based factors. The tool was refined and validated by multi-disciplinary health professionals from Australia and Malaysia. Pharmacists can use the SimplerTM tool to facilitate evidence-based comprehensive individualised care among type 2 diabetes patients. PMID- 29243583 TI - The GSTM1 and GSTT1 null genotypes increase the risk for Type 2 diabetes mellitus and the subsequent development of diabetic complications: A meta-analysis. AB - BACKGROUND: Studies pertaining to association of GSTM1 and GSTT1 null genotypes with risk of T2DM and its complications were often inconclusive, thus spurring the present study. METHODS: Meta-analysis of 25 studies for evaluating the role of GSTM1/GSTT1 null polymorphisms in determining the risk for T2DM and 17 studies for evaluating the role of GSTM1/GSTT1 null polymorphisms in development of T2DM related complications were conducted. RESULTS: Our study revealed an association between GSTM1 and GSTT1 null polymorphism with T2DM (GSTM1; OR=1.37;95% CI =1.10 1.70 and GSTT1; OR=1.29;95% CI =1.04-1.61) with an amplified risk of 2.02 fold for combined GSTM1-GSTT1 null genotypes. Furthermore, the GSTT1 null (OR=1.56;95%CI=1.38-1.77) and combined GSTM1-GSTT1 null genotypes (OR=1.91;95%CI=1.25-2.94) increased the risk for development of T2DM related complications, but not the GSTM1 null genotype. Stratified analyses based on ethnicity reveals GSTM1 and GSTT1 null genotypes increase the risk for T2DM in both Caucasians and Asians, with Asians showing much higher risk for T2DM complications than Caucasians for the same. DISCUSSION: GSTM1, GSTT1 and combined GSTM1-GSTT1 null polymorphism may be associated with increased risk for T2DM; while GSTT1 and combined GSTM1-GSTT1 null polymorphism may increase risk for subsequent development of T2DM complications with Asian population carrying an amplified risk for the polymorphism. CONCLUSION: Thus GSTM1 and GSTT1 null genotypes increases the risk for Type 2 diabetes mellitus alone, in combination or with regards to ethnicity. PMID- 29243584 TI - Prediction and analysis of three dimensional structure of the p7-transactivated protein1 of hepatitis C virus. AB - BACKGROUND: The p7-transactivated protein of Hepatitis C virus is a small integral membrane protein of 127 amino acids, which is crucial for assembly and release of infectious virions. Ab initio and comparative modelling, is an essential tool to solve the problem of protein structure prediction and to comprehend the physicochemical fundemental of how proteins fold in nature. RESULTS: Only one domain (1-127) of p7 had been predicted using the systematic in silico approach, ThreaDom. I-TASSER was ranked as the best server for full-length 3-D protein structural predictions of p7 where the benchmarked scoring system such as C-score, TM-score, RMSD and Z-score are used to obtain quantitative assessments of the I-TASSER models. Scanning protein motif databases, along with secondary and surface accessibility predictions integrated with post translational modification sites (PTMs) prediction revealed functional and protein binding motifs. Three protein binding motifs (two Asp/Glutamnse, CTNNB1 bd_N) with high sequence conservation and two PTMs prediction: Camp_phospho_site and Myristyl site were predicted using BLOCKS and PROSITE scan. These motifs and PTMs were related to the function of p7 protein in inducing ion channel/pore and release of infectious virions. Using SCOP, only one hit matched protein sequence at 71-120 and was classified as small proteins and FYVE/PHD zinc finger superfamily. CONCLUSION: Integrating this information about the p7 protein with SCOP and CATH annotations of the templates facilitate the assignment of structure function/ evolution relationships to known and newly determined protein structures. PMID- 29243585 TI - Review: The Role of Radiolabeled DOTA-Conjugated Peptides for Imaging and Treatment of Childhood Neuroblastoma. AB - BACKGROUND: Childhood neuroblastoma is a heterogenous disease with varied clinical presentation and biology requiring different approaches to investigation and management. Metaiodobenzylguanidine (MIBG) is an essential component of metastatic staging for neuroblastoma and has been used as a treatment strategy for relapsed and refractory neuroblastoma. However, as 10% of children with neuroblastoma will have 123I-MIBG non-avid imaging and up to 60% with relapsed and refractory neuroblastoma will require further treatment with 131I-MIBG, alternative radioisotopes have been investigated for imaging and treatment. Neuroblastoma tumors express mostly somatostatin receptor- 2 (SSTR2) that can be targeted by somatostatin analogues including DOTA-conjugated peptides e.g. DOTATATE, DOTATOC. OBJECTIVES: This review summarizes the rationale, utility and experience of DOTA-conjugated peptides in imaging and treatment of childhood neuroblastoma. RESULTS AND CONCLUSIONS: Radiolabeled DOTA-peptides are used routinely in adults to image neuroendocrine tumors and have potential to be used to image and treat neuroblastoma. 68Ga-DOTATATE PET/CT has been shown to have better sensitivity, quicker clearance and administration times, reduced radiation exposure and limited toxicity compared to 123I-MIBG. Therapeutic studies of peptide receptor radionuclides e.g. 177Lu-DOTATATE in patients with relapsed neuroblastoma have used 68Ga- DOTATATE PET/CT to determine eligibility for therapy. Further studies would need to investigate appropriate indications, timings, scoring and clinical significance of radiolabeled DOTA-peptide conjugated PET/CT imaging in childhood neuroblastoma. PMID- 29243586 TI - Symptomatic lumbosacral transitional vertebra: a review of the current literature and clinical outcomes following steroid injection or surgical intervention. AB - Bertolotti's syndrome (BS) refers to the possible association between the congenital malformation lumbosacral transitional vertebra (LSTV), and low back pain (LBP). Several treatments have been proposed including steroid injections, resections of the LSTV, laminectomy, and lumbar spinal fusion. The aim of this review was to compare the clinical outcomes in previous trials and case reports for these treatments in patients with LBP and LSTV. A PubMed search was conducted. We included English studies of patients diagnosed with LSTV treated with steroid injection, laminectomy, spinal fusion or resection of the transitional articulation. Of 272 articles reviewed 20 articles met the inclusion criteria. Their level of evidence were graded I-V and the clinical outcomes were evaluated. Only 1 study had high evidence level (II). The remainders were case series (level IV). Only 5 studies used validated clinical outcome measures. A total of 79 patients were reported: 31 received treatment with steroid injections, 33 were treated with surgical resection of the LSTV, 8 received lumbar spinal fusion, and 7 cases were treated with laminectomy. Surgical management seems to improve the patient's symptoms, especially patients diagnosed with "far out syndrome" treated with laminectomy. Clinical outcomes were more heterogenetic for patient's treated with steroid injections. The literature regarding BS is sparse and generally with low evidence. Non-surgical management (e.g., steroid injections) and surgical intervention could not directly be compared due to lack of standardization in clinical outcome. Generally, surgical management seems to improve patient's clinical outcome over time, whereas steroid injection only improves the patient's symptoms temporarily. Further studies with larger sample size and higher evidence are warranted for the clinical guidance in the treatment of BS. PMID- 29243587 TI - Human subthalamic nucleus activity during non-motor decision making. AB - Recent studies have implicated the subthalamic nucleus (STN) in decisions that involve inhibiting movements. Many of the decisions that we make in our daily lives, however, do not involve any motor actions. We studied non-motor decision making by recording intraoperative STN and prefrontal cortex (PFC) electrophysiology as participants perform a novel task that required them to decide whether to encode items into working memory. During all encoding trials, beta band (15-30 Hz) activity decreased in the STN and PFC, and this decrease was progressively enhanced as more items were stored into working memory. Crucially, the STN and lateral PFC beta decrease was significantly attenuated during the trials in which participants were instructed not to encode the presented stimulus. These changes were associated with increase lateral PFC-STN coherence and altered STN neuronal spiking. Our results shed light on why states of altered basal ganglia activity disrupt both motor function and cognition. PMID- 29243590 TI - Optimisation of novel method for the extraction of steviosides from Stevia rebaudiana leaves. AB - Stevioside, a diterpene glycoside, is well known for its intense sweetness and is used as a non-caloric sweetener. Its potential widespread use requires an easy and effective extraction method. Enzymatic extraction of stevioside from Stevia rebaudiana leaves with cellulase, pectinase and hemicellulase, using various parameters, such as concentration of enzyme, incubation time and temperature, was optimised. Hemicellulase was observed to give the highest stevioside yield (369.23+/-0.11MUg) in 1h in comparison to cellulase (359+/-0.30MUg) and pectinases (333+/-0.55MUg). Extraction from leaves under optimised conditions showed a remarkable increase in the yield (35 times) compared with a control experiment. The extraction conditions were further optimised using response surface methodology (RSM). A central composite design (CCD) was used for experimental design and analysis of the results to obtain optimal extraction conditions. Based on RSM analysis, temperature of 51-54 degrees C, time of 36 45min and the cocktail of pectinase, cellulase and hemicellulase, set at 2% each, gave the best results. Under the optimised conditions, the experimental values were in close agreement with the prediction model and resulted in a three times yield enhancement of stevioside. The isolated stevioside was characterised through 1H-NMR spectroscopy, by comparison with a stevioside standard. PMID- 29243591 TI - Stevia rebaudiana Bertoni, source of a high-potency natural sweetener: A comprehensive review on the biochemical, nutritional and functional aspects. AB - Stevia rebaudiana Bertoni, an ancient perennial shrub of South America, produces diterpene glycosides that are low calorie sweeteners, about 300 times sweeter than saccharose. Stevia extracts, besides having therapeutic properties, contain a high level of sweetening compounds, known as steviol glycosides, which are thought to possess antioxidant, antimicrobial and antifungal activity. Stevioside and rebaudioside A are the main sweetening compounds of interest. They are thermostable even at temperatures of up to 200 degrees C, making them suitable for use in cooked foods. S. rebaudiana has a great potential as a new agricultural crop since consumer demand for herbal foods is increasing and proximate analysis has shown that Stevia also contains folic acid, vitamin C and all of the indispensable amino acids with the exception of tryptophan. Stevia cultivation and production would further help those who have to restrict carbohydrate intake in their diet; to enjoy the sweet taste with minimal calories. PMID- 29243592 TI - Phlorotannins of the edible brown seaweed Ecklonia cava Kjellman induce sleep via positive allosteric modulation of gamma-aminobutyric acid type A-benzodiazepine receptor: A novel neurological activity of seaweed polyphenols. AB - The primary objective was to investigate whether seaweeds have hypnotic activity. Methanol extracts of 30 seaweeds were screened for their binding activity at the GABA type A-benzodiazepine (GABAA-BZD) receptor, a well-characterised molecular target for sedative-hypnotics. The most active seaweed was Ecklonia cava Kjellman (ECK). An ethanol extract of ECK (ECK-E) significantly potentiated pentobarbital induced sleep in mice. In four solvent fractions separated from ECK-E, hypnotic activity was proportional to contents of total phenols and total phlorotannins, known as seaweed polyphenols. Major phlorotannins of the ethyl acetate (EtOAc) fraction with the highest activity were eckol, eckstolonol, dieckol, and triphlorethol-A, and their Ki (binding affinity, MUM) values for [3H]-flumazenil binding were 1.070, 1.491, 3.072, and 4.419, respectively. Hypnotic effects of ECK-E and the EtOAc fraction were fully inhibited by flumazenil, a specific GABAA BZD receptor antagonist. These results imply that phlorotannins of ECK induce sleep by positive allosteric modulation of the GABAA-BZD receptor. PMID- 29243588 TI - Dynamic modulation of activity in cerebellar nuclei neurons during pavlovian eyeblink conditioning in mice. AB - While research on the cerebellar cortex is crystallizing our understanding of its function in learning behavior, many questions surrounding its downstream targets remain. Here, we evaluate the dynamics of cerebellar interpositus nucleus (IpN) neurons over the course of Pavlovian eyeblink conditioning. A diverse range of learning-induced neuronal responses was observed, including increases and decreases in activity during the generation of conditioned blinks. Trial-by-trial correlational analysis and optogenetic manipulation demonstrate that facilitation in the IpN drives the eyelid movements. Adaptive facilitatory responses are often preceded by acquired transient inhibition of IpN activity that, based on latency and effect, appear to be driven by complex spikes in cerebellar cortical Purkinje cells. Likewise, during reflexive blinks to periocular stimulation, IpN cells show excitation-suppression patterns that suggest a contribution of climbing fibers and their collaterals. These findings highlight the integrative properties of subcortical neurons at the cerebellar output stage mediating conditioned behavior. PMID- 29243593 TI - Heating of milk alters the binding of curcumin to casein micelles. A fluorescence spectroscopy study. AB - Curcumin, a polyphenolic compound present in turmeric, is a hydrophobic molecule that has been shown to bind to casein micelles. The present work tested the hypothesis that surface changes in the casein micelles caused by heat-induced interactions with the whey proteins would affect the binding of curcumin. Binding was quantified by direct and tryptophan quenching fluorescence spectroscopy. Curcumin binds to the hydrophobic moieties of the casein proteins, with a 10nm blue shift in its fluorescence emission peak, and causes quenching of the intrinsic fluorescence spectra of the proteins. The fluorescence intensity of curcumin increased after heating of milk at 80 degrees C for 10min; a similar trend in the binding constants was also observed with casein micelles separated from the soluble proteins by centrifugation. There was an increase in the non specific interactions with heating milk at 80 degrees C for 10min, both in milk as well as in casein micelles separated from the serum proteins. The increased capacity of milk proteins to bind curcumin after heat treatment can be attributed to whey protein denaturation, as whey proteins bind to the surface of casein micelles with heating. PMID- 29243594 TI - Adaptogenic-active components from Kaempferia parviflora rhizomes. AB - Kaempferia parviflora rhizome extracts obtained by maceration with hexane, chloroform, methanol, and ethanol were screened for their adaptogenic activities using swimming tests of mice. The effective adaptogenic extract dose was 500mg/kg of body weight and was given orally once a day. Crude hexane extract showed significantly shorter mouse immobilisation time than those of the other and control extracts. This crude hexane extract was separated into three fractions by column chromatography. Among these fractions, the fraction rich in terpenoids possessed the highest adaptogenic activity and was comparable to that of the crude ginseng root powder used as a reference control. Therefore, terpenes contained in this fraction could be attributed to the decrease in exhaustion during the swimming of mice. There was no effect on body weight, heart, liver, kidneys, and adrenal glands of the mice. Chemical characterisation of this adaptogenic-active fraction by NMR and GC-MS showed germacene D, beta-elemene, alpha-copaene, and E-caryophyllene as major constituents. Accordingly, these terpenes are considered the adaptogenic agents of K. parviflora rhizomes. PMID- 29243595 TI - Effects of a hydrodynamic process on extraction of carotenoids from tomato. AB - We evaluated the results of using a proprietary hydrodynamic method, which was introduced with the hope of increasing accessibility of beneficial nutrition enhancing fruit and vegetable products. Tomato, a major dietary source of carotenoids, notably lycopene, was tested because of its many health benefits to consumers. Samples before and after treatment were compared for lycopene, phytoene, and phytofluene contents. Extractable lycopene and other carotenoids increased significantly. In nature, lycopene exists almost exclusively as the all trans stereoisomer. Cis-lycopene isomers form during cooking and digestion, resulting in higher percentages in plasma and tissues than ingested. Cis-lycopene isomers are more bioavailable than all-trans lycopene. Extraction using this proprietary method increased extracted cis-lycopene to as high as 43% of the total lycopene, indicating increased isomerisation. This method could therefore contribute significantly to the delivery of health benefits of biologically available lycopene from tomato products for metabolic functions. PMID- 29243589 TI - Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity. AB - Defective Ca2+ handling is a key mechanism underlying hepatic endoplasmic reticulum (ER) dysfunction in obesity. ER Ca2+ level is in part monitored by the store-operated Ca2+ entry (SOCE) system, an adaptive mechanism that senses ER luminal Ca2+ concentrations through the STIM proteins and facilitates import of the ion from the extracellular space. Here, we show that hepatocytes from obese mice displayed significantly diminished SOCE as a result of impaired STIM1 translocation, which was associated with aberrant STIM1 O-GlycNAcylation. Primary hepatocytes deficient in STIM1 exhibited elevated cellular stress as well as impaired insulin action, increased glucose production and lipid droplet accumulation. Additionally, mice with acute liver deletion of STIM1 displayed systemic glucose intolerance. Conversely, over-expression of STIM1 in obese mice led to increased SOCE, which was sufficient to improve systemic glucose tolerance. These findings demonstrate that SOCE is an important mechanism for healthy hepatic Ca2+ balance and systemic metabolic control. PMID- 29243596 TI - Impact of boron, calcium and genetic factors on vitamin C, carotenoids, phenolic acids, anthocyanins and antioxidant capacity of carrots (Daucus carota). AB - Carrots (Daucus carota L.) were used to investigate the effects and interactions of cultivar and mineral supply on the nutritional quality (antioxidant potential, vitamin C, carotenoids and phenolic acids) of the resulting storage roots. The supplement of boron (B) and or calcium (Ca) in the feeding solutions, during plant growth, influenced the accumulation of other minerals, such as P, K, Mg, S and Na, in the storage roots (p<0.05). When no additional B or Ca was supplied (e.g. -B or -Ca treatment), we observed 33-50% increase in the accumulated levels of alpha- and beta-carotenes, and 45-70% increase of vitamin C. Carrots grown with no supplement of B in the nutrient solutions (e.g. -B treatment and -ve control) had significantly higher (p<0.001) levels of total phenolic acids compared to the carrots with the supplement of B (e.g. -Ca treatment and +ve control). A strong positive correlation was observed between the total phenolic contents and ORAC values (r=0.932) in all the cultivars. The results suggest that both cultivar and mineral supply were major determinants of nutritional quality of the carrots. The nutritional value of carrot crops (with an acceptable physical quality) can be enhanced by manipulating mineral nutrient applications. PMID- 29243597 TI - Physico-chemical, amino acid composition, functional and antioxidant properties of roe protein concentrates obtained from Channa striatus and Lates calcarifer. AB - Roe protein concentrates prepared from Channa striatus (CRPC) and Lates calcarifer (LRPC) were investigated for physico-chemical characteristics, amino acid composition, functional properties and antioxidant activity. Channa and Lates roes yielded 20.7% and 22.5% of protein concentrates possessing 90.2% and 82.5% protein, respectively. Major differences were not observed in each of the amino acids except leucine in CRPC and LRPC. The solubility of protein was 3.93 54.6% and 1.6-55.5% over a pH range of 2-12 in CRPC and LRPC, respectively. Water absorption, oil absorption, foam capacity, stability and emulsifying capacity were found to be higher in CRPC than in LRPC. Antioxidant activity determined by the radical scavenging activity and ferric reducing power was higher in CRPC. SDS PAGE of both roe protein concentrates showed protein bands of 170, 95 and 55kDa. Moisture sorption isotherms of protein concentrates indicated their hygroscopic nature. PMID- 29243598 TI - Electroseparation of an antibacterial peptide fraction from snow crab by-products hydrolysate by electrodialysis with ultrafiltration membranes. AB - Recently, a snow crab by-products hydrolysate has demonstrated antibacterial properties due to a peptide with a molecular weight of about 800Da, but only at high concentration. Consequently, peptide hydrolysate has been fractionated to obtain peptides in a more purified form. The aim of this work was to separate a snow crab by-products hydrolysate by electrodialysis with ultrafiltration membranes (EDUF). EDUF, which allows separation of molecules according to their charges and molecular weights, was used to recover and concentrate the active antibacterial fraction. Two different ultrafiltration membranes (20 and 50kDa) and two electrical field strengths (2 and 14V/cm) were used as separation parameters. After EDUF separation, the 300-600Da peptide molecular weight range was the most recovered with an abundance of 94%. Moreover, fractionation at 14V/cm with ultrafiltration membranes of 50kDa allowed the recovery of an anionic fraction which showed antibacterial properties on Escherichia coli ATCC 25922 and Listeria innocua HPB 13. PMID- 29243600 TI - Effects of short-term anoxia treatment on browning of fresh-cut Chinese water chestnut in relation to antioxidant activity. AB - The effects of short-term anoxia pre-treatment on browning of fresh-cut Chinese water chestnut (CWC), stored at 4 degrees C, in relation to antioxidant activity were investigated. CWC slices were exposed to pure N2 for 4h and then stored at 4 degrees C for 18d. Anoxia significantly inhibited browning of CWC slices during storage, accompanied by lower contents of malondialdehyde, H2O2, and lipoxygenase activity. Furthermore, anoxia induced the activities of superoxide dismutase and ascorbate peroxidase, which could benefit scavenging reactive oxygen species and alleviating lipid peroxidation. In addition, better maintenance of reducing power and free-radical-scavenging activities against alpha,alpha-diphenyl-beta picrylhydrazy (DPPH), superoxide anions and hydroxyl was observed in N2-treated CWC slices, with higher phenolic compounds and ascorbic acid contents. Collectively, these finds suggest that N2 pre-treatment enhanced enzymatic and non-enzymatic antioxidant activity in CWC slices, and thereby contributed to alleviating lipid peroxidation and maintenance of storage quality. PMID- 29243599 TI - Determination of biogenic amines in Bokbunja (Rubus coreanus Miq.) wines using a novel ultra-performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry. AB - A rapid and novel ultra-performance liquid chromatography/quadrupole-time of flight mass spectrometry (UPLC/Q-TOFMS) method was developed for the detection of seven biogenic amines in Korean Bokbunja wines. The biogenic amines were pre column derivatised with dansyl chloride and subsequently extracted by a solid phase extraction cartridge. For the analysis, the dansylated amines were separated on an AcquityTM UPLC column and detected with a micrOTOF-Q II mass spectrometer. The method was validated in terms of linearity, sensitivity, precision and recovery. The coefficient of determination (R2) was higher than 0.994 for all calibration curves. The limit of detection was between 3 and 15ng/mL. The intra- and inter-day precisions were below 5.0% and 10.7%, respectively. The proposed method was successfully applied for the biogenic amine analysis of 18 commercially available Bokbunja wines. None of the biogenic amine levels found in Bokbunja wines surpassed the toxic levels reported in the literature. PMID- 29243601 TI - Analysis of the tumoral cytotoxicity of green tea-infusions enriched with broccoli. AB - Broccoli has risen as rich in bioactive phytochemicals (glucosinolates and phenolic compounds) closely linked with the reduction of cancer risk. Green tea infusion is a beverage that also contains anticarcinogenic compounds, mainly represented by flavanols. The compounds present in new broccoli-enriched green tea drinks and their potential antitumoral activity in vitro were evaluated. The distinct compounds present in the prepared beverages were identified by HPLC-PAD ESI-MSn and quantified by HPLC-PAD. Caco-2 and CCD-18Co cell lines were exposed to growing percentages (0.2-5%) of infusions of distinct combinations of plant material. The time-dependent cytotoxicity on the malignant cells was also achieved. Cell death was evaluated by trypan blue dye exclusion and a more efficient specific cytotoxic effect on Caco-2 cells was observed on the cells incubated with the mixture of broccoli and green tea than on cells exposed to control infusions. Broccoli added to green tea resulted in a combination of phytochemicals with antitumoral activity with potential for further developments in mechanistic models and the design of novel foods. PMID- 29243602 TI - Comparison of sterol composition between Tuber fermentation mycelia and natural fruiting bodies. AB - Truffle, belonging to Tuber genera, is a nutritious and sterol-rich edible fungus, and sterol is a potential health beneficial compound. A comparison of Tuber sterol composition indicates that the total sterol contents in the fermentation mycelia (i.e., 10.5mgg-1) (n=3) were approximately 3.2-5.6 times higher than that of the fruiting bodies (p<0.05) with the addition of soybean flour into the basal fermentation media. Moreover, the phytosterol profile of fermentation mycelia could be significantly improved by adding soybean flour into the fermentation media. After the addition of soybean flour, stigmasterol and beta-sitosterol appeared in the fermentation mycelia and the contents of total phytosterols (2279MUgg-1) (n=3), brassicasterol (943MUgg-1) (n=3), and campesterol (418MUgg-1) (n=3) were all increased significantly (p<0.05). Moreover, the total contents of sterols and phytosterols in the fermentation mycelia cultured in the soybean media were much higher than those in the fruiting bodies (i.e., 1883-3240 and 479-1832MUgg-1, respectively) (n=3, p<0.05). This work confirms the potentiality of Tuber fermentation mycelia as the alternative resource for its fruiting bodies from the viewpoint of sterols production. PMID- 29243603 TI - Bioactivity and chemical composition of blackcurrant (Ribes nigrum) cultivars with and without pesticide treatment. AB - Eleven blackcurrant cultivars grown with pesticide (PT) and without pesticide treatment (PF) were evaluated to compare the differences in plant growth and physical condition, total anthocyanin content, ascorbic acid content, total antioxidant capacity, effect on prostaglandin E2 (PGE2) production and anticancer cell proliferation activities. Results showed that the yield and growth of PT blackcurrants were higher. However, PF blackcurrants contained a higher amount of ascorbic acid, and displayed an increased inhibition against cancer cells compared to PT blackcurrants, indicating that PF blackcurrants have an increased potential to deliver health-promoting benefit for consumers. Significant differences were observed between blackcurrant cultivars in relation to plant growth and physical condition, total anthocyanin content and PGE2 assay, highlighting the importance of cultivar selection. PMID- 29243604 TI - Physical and chemical stability of beta-carotene-enriched nanoemulsions: Influence of pH, ionic strength, temperature, and emulsifier type. AB - The enrichment of foods and beverages with carotenoids may reduce the incidences of certain chronic diseases. However, the use of carotenoids in foods is currently limited because of their poor water-solubility, high melting point, low bioavailability, and chemical instability. The potential of utilising oil-in water (O/W) nanoemulsions stabilised by a globular protein (beta-lactoglobulin) for encapsulating and protecting beta-carotene was examined. The influence of temperature, pH, ionic strength, and emulsifier type on the physical and chemical stability of beta-carotene enriched nanoemulsions was investigated. The rate of colour fading due to beta-carotene degradation increased with increasing storage temperature (5-55 degrees C), was faster at pH 3 than pH 4-8, and was largely independent of ionic strength (0-500mM of NaCl). beta-Lactoglobulin-coated lipid droplets were unstable to aggregation at pH values close to the isoelectric point of the protein (pH 4 and 5), at high ionic strengths (NaCl >200mM, pH 7), and at elevated storage temperatures (55 degrees C). beta-Carotene degradation was considerably slower in beta-lactoglobulin-stabilised nanoemulsions than in Tween 20-stabilised ones. These results provide useful information for facilitating the design of delivery systems to encapsulate and stabilise beta-carotene for application within food, beverage, and pharmaceutical products. PMID- 29243605 TI - Isolation and evaluation of the antioxidant activity of phenolic constituents of the Garcinia brasiliensis epicarp. AB - A new glycosylated biflavonone, morelloflavone-4'"-O-beta-d-glycosyl, and the known compounds 1,3,6,7-tetrahydroxyxanthone, morelloflavone (fukugetin) and morelloflavone-7"-O-beta-d-glycosyl (fukugeside) were isolated from the epicarp of Garcinia brasiliensis collected in Brazil. The structures of these compounds were established using 1H and 13C NMR, COSY, gHMQC and gHMBC spectroscopy. The compounds exhibited antioxidant activity. The greatest potency was displayed by morelloflavone (2), with IC50=49.5mM against DPPH and absorbance of 0.583 at 400MUg/mL for the reduction of Fe3+. The weakest potency was displayed by 1,3,6,7 tetrahydroxyxanthone (1), with IC50=148mM against DPPH and absorbance of 0.194 at 400MUg/mL for the reduction of Fe3+. PMID- 29243606 TI - Oxidative properties of lactoferrins of different iron-saturation in an emulsion consisting of metmyoglobin and cod liver oil. AB - Lactoferrins (LFs) at iron-saturation 8 (native) and 100%, respectively, were present in an oil-in-water (O/W) emulsion composed of 5% (w/v) cod liver oil (CLO) and metmyoglobin (metMb) in 50mM phosphate buffer at pH 6.0. Initially both LFs acted as antioxidants and reduced initial peroxide formation, but after 48h holo LF revealed the most peroxides but the least trienes. Native LF (0.8mg/ml) gave the highest (p<0.05) amounts of lipid derived volatiles after 48h incubation at 4 degrees C. Both LFs gave similar increases in adducts to metMb with time. The most extensive aggregation induced by radicals or peroxides was found for native LF. The results pointed at reactions at the O/W interphase as highly influential for lipid and protein oxidation kinetics. Added ascorbic acid (1mM), however, behaved as an antioxidant in the pro-oxidative oil-in-water emulsion system and prevented lipid degradation and protein adductation as well as protein aggregation. PMID- 29243607 TI - Anticholinesterase potential of flavonols from paper mulberry (Broussonetia papyrifera) and their kinetic studies. AB - It is necessary to develop food additives to help treat chronic disorders like neurodegenerative diseases from medicinal plants. Ethanol extracts of paper mulberry were found to display significant inhibition against cholinesterases, enzymes that are strongly linked with Alzheimer's disease (AD). The active components were identified as prenylated flavonols (2-4) that inhibited two related human cholinesterases in a dose-dependent manner, with IC50's ranging between 0.8 and 3.1MUM and between 0.5 and 24.7MUM against human acetylcholinesterase (hAChE) and butylcholinesterase (BChE), respectively. Prenyl groups within these flavonols were found to play a critical role for inhibition because the parent compound 1, quercetin, was inactive (IC50>500MUM) towards the target enzymes. Flavonols (2-4) showed mixed inhibition kinetics as well as slow and time-dependent reversible inhibition toward hAChE. The affinity between protein and inhibitors was investigated using fluorescence quenching. The affinity constants (KSA) of inhibitors increased in proportion to their inhibitory potencies. PMID- 29243608 TI - Hypolipidemic and antihyperlipidemic effects from an aqueous extract of Pachyptera hymenaea (DC.) leaves in rats. AB - Hypolipidemic and antihyperlipidemic effect from an aqueous extract Pachyptera hymenaea were studied and volatile constituents from the extract were analysed by GC-MS. Extract was administered to normal and diet-induced hypercholestrolemic rats for 28days and serum lipid profiles were estimated. An oral dose, at 200mg/kg/day, resulted in significant declines in plasma LDL-cholesterol, triglycerides (TG) and total cholesterol (TC) by 44.0%, 27.9% and 28.1% respectively, compared to normal rats. An extract at 400mg/kg/day, to hypercholestremic rats, resulted in significant declines in plasma TC, LDL cholesterol and TG, by 66.1%, 60.0% and 57.6% respectively, compared to a hypercholestremic control. GC-MS study of the volatile oil revealed the presence of two main organosulphur compounds, diallyldisulphide (65.9%, v/v) and diallyltrisulphide (29.6%, v/v). Evidently the extract possesses pronounced hypolipidemic and antihyperlipidemic effects which are comparable to those of atorvastatin. These effects are due to the presence of organosulphur compounds, flavonoids and polyphenols present in the extract. PMID- 29243609 TI - Optimisation of aqueous extraction of gum from durian (Durio zibethinus) seed: A potential, low cost source of hydrocolloid. AB - The main goal of the present study was to investigate the effect of aqueous extraction conditions on the extraction yield and physicochemical properties of the durian seed gum. The studied aqueous extraction variables were water/seed (W/S) ratio (20:1-60:1, w/w), temperature (25.0-85.0 degrees C), and pH (4.0 10.0). The results indicated that the aqueous extraction variables exhibited the least significant (p<0.05) effect on oil-holding capacity (OHC). Conversely, they had the most significant (p<0.05) effect on the span and extraction yield. The current study revealed that the interaction effect of aqueous extraction variables showed the least significant (p<0.05) effect on the solubility and OHC of durian seed gum. The optimum extraction condition led to the production of durian seed gum with a relatively high extraction yield (56.4%), solubility (27.9%), volume-weighted mean (98.7MUm), span (3.8), water-holding capacity (WHC) (270.6g water/100g gum), and OHC (146.5g oil/100g gum). PMID- 29243610 TI - Azuki bean (Vigna angularis) extract inhibits the development of experimentally induced atopic dermatitis-like skin lesions in NC/Nga mice. AB - The present study investigated the effects of azuki bean (Vigna angularis) extract (VAE) on the progress of atopic dermatitis (AD)-like skin lesions in NC/Nga mice induced by 1-chloro-2,4-dinitrobenzene. The efficacy of VAE in NC/Nga mice was determined by measuring gross and histological skin lesions, serum IgE levels, eosinophil ratio in peripheral leucocytes, and mRNA expression levels of interleukin (IL)-4, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma in splenocytes. Continuous ingestion of VAE inhibited the development of the AD like skin lesions in a dose-dependent manner. In the VAE-treated mice, the numbers of mast cells in the skin, eosinophil ratio in peripheral leucocytes, relative mRNA expression of inflammatory cytokines in the spleen, and serum IgE levels were significantly reduced. Results suggest that VAE can inhibit the development of AD-like skin lesions in NC/Nga mice by regulating immune mediators and cells, and may be an effective alternative therapy for AD. PMID- 29243611 TI - Effects of selected plant extracts on anti-oxidative enzyme activities in rats. AB - The effects of plant extracts on the activity of anti-oxidative enzymes in rats were investigated. Sprague-Dawley rats were fed with the extracts and fractions from Rhus javanica, Malus sieboldii, and Ostrya japonica, and the activities of anti-oxidative enzymes, such as superoxide dismutase (SOD) and catalase (CAT) were investigated. SOD activities in blood serum and liver increased following an injection of 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH), and these increases were not cancelled out by feeding plant extracts. CAT activities in blood serum and liver increased following the AAPH injection, but these increases were reversed by feeding the extracts of R. javanica and O. japonica. This finding was similar to the result that the CAT activity increase induced by feeding alcohol was cancelled out by feeding ascorbic acid. These results suggest that anti-oxidative polyphenolics from these plants may act through the same mechanism as that of the well-known antioxidant ascorbic acid towards hydrogen peroxide. PMID- 29243612 TI - Physicochemical changes in surimi with salt substitute. AB - Protein endothermic transitions (thermal denaturation), rheological properties (protein gelation), and fundamental texture properties (shear stress and strain at mechanical fracture) of Alaska pollock surimi gels made with 0 (control), 1, 2, and 3g/100g of salt (NaCl) were determined and compared with equal molar concentration of salt substitute. Salt and salt substitute shifted the onset of myosin transition to higher temperature and resulted in larger myosin peaks (i.e., transition enthalpy). Endothermic transitions showed similar trends to rheological properties. The elastic modulus (G') increased when salt or salt substitute was added to surimi, except at the highest concentration of salt and salt substitute. Salt and salt substitute also induced the onset of protein gelation (i.e., as measured by significant increase of G') at lower temperature. Surimi gels with salt substitute and salt at equal molar concentrations had similar texture properties (shear stress and strain). Based on the present study, salt substitute can be used in the development of low-sodium surimi seafood products without significant change in gelation and texture. PMID- 29243614 TI - Neriifolin S, a dimeric serine protease from Euphorbia neriifolia Linn.: Purification and biochemical characterisation. AB - A dimeric serine protease Neriifolin S of molecular mass 94kDa with milk clotting activity has been purified from the latex of Euphorbia neriifolia by anion exchange and size-exclusion chromatography. It hydrolyses peptidyl substrates l Ala-pNA with highest affinity (Km of 0.195mM) and physiological efficiency (Kcat/Km of 144.5mMs). Enzyme belongs to the class of neutral proteases with pI value of 6.8, optimal proteolytic activity displayed at pH 9.5 and temperature 45 degrees C. Its proteolytic activity is strongly stimulated in the presence of Ca+2 ions and exclusively inhibited by serine protease inhibitors. Enzyme is fairly stable toward chemical denaturants, pH and temperature. The apparent Tm, was found to be 65 degrees C. Thermal inactivation follow first order kinetics with activation energy (Ea), activation enthalpy (DeltaH*), free energy change (DeltaG*) and entropy (DeltaS*) of 27.54kJmol-1, 24.89kJmol-1, -82.34kJmol-1 and 337.20Jmol-1K-1. PMID- 29243613 TI - Characterisation of trypsin purified from the viscera of Tunisian barbel (Barbus callensis) and its application for recovery of carotenoproteins from shrimp wastes. AB - Trypsin was purified from the viscera of barbel by precipitation using ammonium sulphate (0-80%), Sephadex G-100, and Mono Q-Sepharose ion exchange chromatography. The trypsin was purified 27-fold, with 79U/mg specific activity and 31% recovery. The enzyme had a molecular weight of 24kDa; purified trypsin appeared as a single band on native-PAGE. The optimum pH and temperature for enzyme activity were pH 10.0 and 55 degrees C with BAPNA used as a substrate. The N-terminal amino acid sequence of the first 12 amino acids of the purified trypsin was IVGGYECTPYSQ. The Michaelis-Menten constant (Km) and catalytic constant (kcat) values of the enzyme were 0.018mM and 1.21s-1, respectively. The study also investigated the effects of purified trypsin on the recovery of carotenoproteins from shrimp (Parapenaeus longirostris) shells through hydrolysis using 1.0U barbel trypsin/g shrimp shells for 1h at 30 degrees C. The freeze dried carotenoproteins recovered contained 71.09% protein, 16.47% lipid, 7.78% ash, and 1.79% chitin. PMID- 29243615 TI - Effect of ingestion of dark chocolates with similar lipid composition and different cocoa content on antioxidant and lipid status in healthy humans. AB - The association between in vitro antioxidant capacity of dark chocolates with different cocoa percentage and the in vivo response on antioxidant status was investigated. In a randomized crossover design, 15 healthy volunteer consumed 100g of high antioxidants dark chocolate (HADC) or dark chocolate (DC). In vitro, HADC displayed a higher Total Antioxidant Capacity (TAC) than DC. In vivo, plasma TAC significantly peaked 2h after ingestion of both chocolates. TAC levels went back to zero 5h after DC ingestion whilst levels remained significantly higher for HADC. HADC induced a significantly higher urinary TAC in the 5-12h interval time than DC. No change was detected in urinary excretion of F2-isoprostanes. Plasma thiols and triacylglycerol (TG) levels significantly increased for both chocolate with a peak at 2h remaining significantly higher for DC after 5h respect to HADC. Results provide evidence of a direct association between antioxidant content of chocolate and the extent of in vivo response on plasma antioxidant capacity. PMID- 29243616 TI - Enzymatic lipophilisation of phenolic acids through esterification with fatty alcohols in organic solvents. AB - We investigated and optimised the synthesis of lipophilized esters between selected phenolic acids and fatty alcohols in a binary solvent system, composed of hexane and butanone. The effect of proportions of hexane and butanone was first studied by varying the volume ratio of hexane/butanone from 85:15 to 45:55. It was found that the conversion of phenolic acids strongly depended on the proportions of hexane and butanone. To examine the effect of carbon chain length of fatty alcohols on the reaction rate, the esterifications of C4-C18 straight chain fatty alcohol with dihydrocaffeic acid (DHCA), as a model phenolic acid, were systematically evaluated. The results indicated that the conversion of DHCA was significantly affected by the number of carbon chain of fatty alcohols. Roughly 95% conversion was achieved within 3days when hexanol was used as an acyl acceptor; while only 56% and 44% conversions were achieved when 1-butanol and octadecanol were employed, respectively. However, the conversions of ferulic and caffeic acids under the same conditions were much lower than was that of DHCA. The optimal mixture ratio of hexane to butanone was found to be 65:35. Using the reaction of octanol and DHCA as a model, the reaction parameters, such as temperature, enzyme load, reaction time and substrate molar ratio, were optimised with response surface methodology (RSM). A second polynomial model was generated and optimised reaction conditions were obtained as: temperature 60 degrees C, reaction time 3.9days, enzyme load 238mg, and substrate molar ratio 3.6 (octanol/DHCA). A validation reaction, based on the optimal conditions, was conducted, to yield 94.5% conversion of DHCA, indicating the suitability of the RSM model. PMID- 29243617 TI - Mechanism of formation of sulphur aroma compounds from l-ascorbic acid and l cysteine during the Maillard reaction. AB - The sulphur aroma compounds produced from a phosphate-buffered solution (pH 8) of l-cysteine and l-, l-[1-13C] or l-[4-13C] ascorbic acid, heated at 140+/-2 degrees C for 2h, were examined by headspace SPME in combination with GC-MS. MS data indicated that C-1 of l-ascorbic acid was not involved in the formation of sulphur aroma compounds. The sulphur aroma compounds formed by reaction of l ascorbic acid with l-cysteine mainly contained thiophenes, thiazoles and sulphur containing alicyclic compounds. Among these compounds, 1-butanethiol, diethyl disulphide, 5-ethyl-2-methylthiazole, cis and trans-3,5-dimethyl-1,2,4 trithiolane, thieno[2,3-b]thiophene, thieno[3,2-b]thiophene, cis and trans-3,5 diethyl-1,2,4-trithiolane, 1,2,5,6-tetrathiocane, 2-ethylthieno[2,3-b]thiophene, 2,4,6-trimethyl-1,3,5-trithiane and cyclic octaatomic sulphur (S8) were formed solely by l-cysteine degradation, and the rest by reaction of l-ascorbic acid degradation products, such as hydroxybutanedione, butanedione, acetaldehyde, acetol, pyruvaldehyde and formaldehyde with l-cysteine or its degradation products, such as H2S and NH3. A new reaction pathway from l-ascorbic acid via its degradation products was proposed. PMID- 29243618 TI - Effects of palm oil quality and packaging on the storage stability of dry vegetable bouillon paste. AB - Vegetable bouillon paste, prepared by dry-mixing of pre-produced dry ingredients with addition of semisolid palm oil, was stored at the slightly elevated temperature of 40 degrees C for up to 12weeks for comparing modified atmosphere packaging (MAP; oxygen concentration initially below 0.5%) packaging with free availability of oxygen in order to identify the mechanisms leading to quality degradation. An increased browning and increased formation of volatile compounds related to Maillard reactions and oxidation of secondary lipid oxidation products were observed for the vegetable bouillon paste stored without limiting the oxygen availability. The use of palm oil (kept liquid by heating to 50 degrees C for one week) was further found to promote quality degradation as compared to fresh palm oil when the availability of oxygen was not limited by the packaging of the vegetable bouillon paste. For modified atmosphere packaging, the effect of the quality of the oil on storage stability of the product was less pronounced. PMID- 29243619 TI - Non-covalent binding of proteins to polyphenols correlates with their amino acid sequence. AB - The present paper describes the assessment of non-covalent binding (NCB) between milk proteins and polyphenols and its correlation with the physicochemical parameters of proteins. A method based on ultrafiltration and liquid chromatography-tandem mass spectrometry was used to analyse free and non covalently bound polyphenols (ligands) in mixtures with major milk proteins. Binding strength values of individual polyphenols were normalised to those obtained with quercitrin (quercetin-3-O-rhamnoside), used as a reference compound. NCB data acquired by experiments at pH 6.6 without any preliminary protein denaturation were correlated with the physicochemical parameters of ligands and proteins. Unsupervised multivariate analysis revealed that NCB of proteins clustered according to their family (caseins separated from albumins). Based on this model, a predictive relationship was observed between protein polyphenol binding strength and primary/secondary structure parameters of the proteins e.g. number of charges, proline residues and extended strand. These results confirm that, under the investigated experimental conditions, the NCB between polyphenols and protein mixtures can be predicted and optimised based on the molecular structures. PMID- 29243620 TI - Textural and biochemical properties of cobia (Rachycentron canadum) sashimi tenderised with the ultrasonic water bath. AB - The present study investigated the tenderisation effects ultrasound processing (UT) on farmed cobia sashimi. Age-treated cobia trunk muscles (AT) were used as the control. The pH, total volatile base nitrogen, trimethylamine nitrogen, thiobarbituric acid reactive substances, ATP catabolism components, K1 value, and texture were evaluated. The texture of AT sashimi reached the optimal firmness range with 8.53N at day 7. However, AT samples could not be served raw after day 7 because of their poor freshness indexes, including a TVBN value of 18.53g/100g, a TMAN value of 3.25mg/100g, and a TBARS value 0.983MDAmg/100g. Moreover, the K1 value of AT sashimi was 20.21% at day 5. UT was employed to efficiently tenderise cobia sashimi with an initial firmness of 9.70-7.82N after 90min of treatment. The results of this study indicate that UT accelerates the biochemical reaction rate, as evidenced by the increases in the TVBN, TMAN, and TBARS contents; however, these values were very low. The results of this study could provide basic information for the development of a novel ultrasonic tenderisation technique in raw seafood designed for restaurants and consumers. PMID- 29243621 TI - Bioactive sesquiterpenoids from the solid culture of the edible mushroom Flammulina velutipes growing on cooked rice. AB - The edible mushroom Flammulina velutipes was cultivated on cooked rice. Six new cuparene sesquiterpenes, enokipodins E-J (1-6), and two new sterpurane sesquiterpenes, sterpurols A (10) and B (11), with four known sesquiterpenes, 2,5 cuparadiene-1,4-dione (7), enokipodins B (8) and D (9), and sterpuric acid (12), were isolated from the solid culture of F. velutipes. The structures of new metabolites were elucidated by NMR experiments. The absolute configurations in new compounds were assigned by X-ray crystallographic analysis, the modified Mosher method, and CD data analysis. Bioactivity screening indicated that compounds 5-9 displayed weak antibacterial activity against Bacillus subtilis; 2, 3, and 5 showed weak antifungal activity against Aspergilus fumigatus; 6-9 showed both moderate cytotoxicity against the human tumor cell lines (HepG2, MCF-7, SGC7901, and A549) and antioxidant activity in DPPH scavenging assay. These results suggest that the solid culture of F. velutipes on cooked rice could be a good functional food. PMID- 29243622 TI - Study on decomposition products of norbixin during bleaching with hydrogen peroxide and a peroxidase by means of UPLC-UV and mass spectrometry. AB - The decomposition products of norbixin, a component of the natural colouring agent annatto, have been studied under bleaching conditions in water and in a whey matrix. In water, several unsaturated aldehydes and ketones of carboxylic acids were identified with UPLC-UV/MS and high resolution mass spectrometry techniques. Based on these products a reaction scheme for the decomposition of norbixin is proposed. In whey, the norbixin is also degraded during bleaching, but no decomposition products are detected. Most likely these products react with endogenous compounds from the whey matrix. For one of these compounds, i.e. cysteine, the formation of a reaction product with 3-acetylacrylic acid (decomposition product of norbixin) was shown. PMID- 29243623 TI - Profiling of in vitro neurobiological effects and phenolic acids of selected endemic Salvia species. AB - The ethyl acetate and methanol extracts from 16 Salvia L. species were screened for their inhibitory activity against acetylcholinesterase, butyrylcholinesterase, lipoxygenase, and tyrosinase; the enzymes linked to neurodegeneration. Their antioxidant activity was also tested using DPPH radical scavenging, metal-chelation, and ferric-reducing antioxidant power (FRAP) assays. Total flavonoid content of the extracts was determined by AlCl3 reagent, while HPLC technique was applied for analysis of various phenolic acids in the extracts. The extracts exerted weak cholinesterase and tyrosinase inhibition, and remarkable inhibition against lipoxygenase (13.07+/-2.73-74.21+/-5.61%) at 100MUgml-1. The methanol extracts showed higher antioxidant activity in DPPH radical scavenging and FRAP assays. The extracts were analyzed for their gallic, protocateuchic, p-hydroxy-benzoic, vanillic, caffeic, chlorogenic, syringic, o- and p-coumaric, ferulic, rosmarinic, and tr-cinnamic acid contents and the methanol extract of Salvia ekimiana (153.50mg100g-1) was revealed to be the richest in terms of rosmarinic acid. PMID- 29243624 TI - Evaluation of the potential of FTIR and chemometrics for separation between defective and non-defective coffees. AB - The objective of this work was to evaluate the potential of Fourier transform infrared spectroscopy (FTIR) for the discrimination of defective and non defective coffee beans. Defective (black, immature and sour) and non-defective Arabica coffee beans were submitted to FTIR analysis by transmittance readings employing KBr discs and reflectance readings employing attenuated total reflectance (ATR) and diffuse reflectance (DR) accessories. Multivariate statistical analysis (PCA, clusters) was performed in order to verify the possibility of discrimination between defective and non-defective coffee samples. A clear separation between defective and non-defective coffee beans was observed, based on both PCA and cluster analysis of the reflectance spectra (ATR and DR accessories) and of the first derivatives of the transmittance spectra (KBr discs). Such results indicate that FTIR analysis has the potential for the development of a fast and reliable analytical methodology for the discrimination between defective and non-defective coffee beans. PMID- 29243625 TI - Effects of exogenous abscisic acid on fruit quality, antioxidant capacities, and phytochemical contents of southern high bush blueberries. AB - Abscisic acid (ABA) is a plant growth regulator that has a potential to increase antioxidant capacity and phenolic content of fruits and vegetables. The objective of this study was to examine whether an exogenous ABA application can positively affect fruit quality, antioxidant capacity, and phytochemical content of southern high bush blueberries (Vaccinium darrowii). Two varieties, namely Star and Windsor, were tested with ABA water solutions of three concentrations (0, 200, and 400ppm) using a randomised complete block design. Results showed that ABA significantly increased the firmness of berries in both varieties, suggesting a ripening delay effect. Such effect was more pronounced in Windsor variety as reflected by a lower percentage of ripe berries and smaller sized berries on ABA treated bushes. In conclusion, ABA delayed the ripening of blueberries, but did not affect total phenolic content, antioxidant capacity, or the content of individual phytochemicals in ripe blueberries. PMID- 29243626 TI - Purification of serine protease from mango (Mangifera Indica Cv. Chokanan) peel using an alcohol/salt aqueous two phase system. AB - An alcohol/salt-based aqueous two-phase (ATPS) system, as a novel method of purification, was employed to purify serine proteases from mango (Mangifera Indica Cv. Chokanan) peel. The effectiveness of different parameters, such as type and concentration of alcohol (1-propanol, 2-propanol, and ethanol), type of salt (sodium citrate, potassium phosphate, and ammonium sulphate), pH, and NaCl, on the purification and selective separation of serine protease was investigated. Desirable conditions of partition coefficient (K), selectivity (S), purification factor (P), and yield (Y%) of serine protease, using ATPS, were determined. The highest partition coefficient (64.5) and selectivity (343.2) for serine protease purification value were achieved in an ATPS of 16% (w/w) 2-propanaol, 19% (w/w) potassium phosphate, and 5% (w/v) NaCl at pH 7.5. It was demonstrated that serine protease could be recovered with a yield of 96.7% and a purification factor of 11.6. PMID- 29243627 TI - Relationship between histochemical, structural characteristics and oxidative stability of rhea limb muscles. AB - Histochemical and structural characteristics were investigated in Gastrocnemius pars interna (GN) and Iliofiburalis (IF) limb muscles of Rhea americana. The average myofibre area cross-section was greater in GN than IF muscle (p<0.001), whereas the fibre density per section was higher in IF than GN muscle. The only type of myofibre found in both the rhea limb muscles analysed in this study was fast-twitch oxidative-glycolytic fibres (FOG). Immunolabelling analysis and ultrastructural observation of myofibres confirmed the contractile and metabolic characteristics of rhea myofibres, revealing the absolute fast isoform of myosin heavy chain and the abundance of glycogen and mitochondria inside the cells, mainly in IF muscle. These findings converged with previous results on the biochemical and physicochemical characteristics of rhea meat to provide further evidence that myofibre composition substantially influences the oxidative reactions of the muscle and therefore the meat quality, but more in-depth examination is needed to establish the links between myofibre characteristics, myofibre glycogen concentration and meat stability during storage. PMID- 29243628 TI - The effect of diets supplemented with thyme essential oils and rosemary extract on the deterioration of farmed gilthead seabream (Sparus aurata) during storage on ice. AB - The effect on quality were assessed for gilthead seabream fed five different diets: control (basal diet); BHT (basal diet with 200mgkg-1 of butylated hydroxytoluene); rosemary (basal diet with 600mgkg-1 of rosemary extract Rosmarinus officinalis); carvacrol (basal diet with 500mgkg-1 of essential oil of Thymbra capitata, carvacrol chemotype); and thymol (basal diet with 500mgg-1 of essential oil of Thymus zygis, subspecies gracilis, thymol chemotype). After 18weeks of experimentation, the animals were stored on ice at 4 degrees C for 0, 7, 14, and 21days. Physical-chemical, microbiological and sensory analyses were carried out at each sampling point to determine the degree of deterioration in the gilthead seabream. Lower indices of oxidation were observed in animals who were administered feeds supplemented with BHT, carvacrol and (to a lesser degree) rosemary. Lower bacteria counts were observed for the BHT and thymol groups, in addition to a slower deterioration in terms of sensory perception. Accordingly, the addition of natural antioxidants to the diet may have an added effect on fish quality, delaying post mortem deterioration. PMID- 29243629 TI - Influence of unit operations on the levels of polyacetylenes in minimally processed carrots and parsnips: An industrial trial. AB - Carrots and parsnips are often consumed as minimally processed ready-to-eat convenient foods and contain in minor quantities, bioactive aliphatic C17 polyacetylenes (falcarinol, falcarindiol, falcarindiol-3-acetate). Their retention during minimal processing in an industrial trial was evaluated. Carrot and parsnips were prepared in four different forms (disc cutting, baton cutting, cubing and shredding) and samples were taken in every point of their processing line. The unit operations were: peeling, cutting and washing with chlorinated water and also retention during 7days storage was evaluated. The results showed that the initial unit operations (mainly peeling) influence the polyacetylene retention. This was attributed to the high polyacetylene content of their peels. In most cases, when washing was performed after cutting, less retention was observed possibly due to leakage during tissue damage occurred in the cutting step. The relatively high retention during storage indicates high plant matrix stability. Comparing the behaviour of polyacetylenes in the two vegetables during storage, the results showed that they were slightly more retained in parsnips than in carrots. Unit operations and especially abrasive peeling might need further optimisation to make them gentler and minimise bioactive losses. PMID- 29243630 TI - Comparison of free amino acids and 5'-nucleotides between Tuber fermentation mycelia and natural fruiting bodies. AB - The profiles of free amino acids and 5'-nucleotides were first compared between Tuber fermentation mycelia and natural fruiting bodies. A total of 20 free amino acids and five 5'-nucleotides were identified in the Tuber fermentation mycelia and natural fruiting bodies. Not only the total contents of the free amino acids and 5'-nucleotides, but also the contents of umami amino acids and flavour 5' nucleotides in the fermentation mycelia were higher than those in the fruiting bodies. By the addition of soybean flour in the fermentation media, the flavour 5'-nucleotides content in the fermentation mycelia was significantly increased, and the equivalent umami concentration of the fermentation mycelia (i.e., 608.07g/100g) was approximately 38.1-93.4 times higher than those of the fruiting bodies. From the viewpoint of umami taste, this work confirms the potentiality of Tuber fermentation mycelia as the alternative resource for its fruiting bodies. PMID- 29243631 TI - Absorption and excretion of cranberry-derived phenolics in humans. AB - Absorption and excretion of twenty cranberry-derived phenolics were studied following the consumption of cranberry juice, sauces, and fruits by healthy human volunteers. Plasma and urine samples were collected and analysed by gas chromatography-mass spectrometry (GC-MS). A high performance liquid chromatography (HPLC) method was employed for analysing urinary creatinine, which was used as a normalisation agent. Significant increases in the sum of plasma phenolics were observed with different concentration peaks (between 0.5 and 2h) for individual subjects. Some of the phenolics, such as trans-cinnamic, vanillic, p-coumaric acids, and catechin showed second plasma concentration peaks. All of cranberry-derived phenolics increased significantly in urine samples after the intake of each cranberry product. The high molecular weight quercetin and myricetin, which were abundant in cranberry foodstuffs, were not found in either plasma or urine samples. This study provided the fundamental information for understanding the absorption and excretion of phenolics in the human gastrointestinal system after dietary intake of cranberry products. PMID- 29243632 TI - The use of cyclic voltammetry to study the oxidation of l-5 methyltetrahydrofolate and its preservation by ascorbic acid. AB - A cyclic voltammetry study of 1mM l-5-methyltetrahydrofolate (l-5-MTHF) was performed in pH 5.5 Britton-Robinson buffer at room temperature to study the stability of l-5-MTHF alone and in combination with ascorbic acid (AA). The degradation of l-5-MTHF and AA over a period of 12h both followed first order reaction kinetics. Using this technique, oxidation peaks of l-5-MTHF were identified at +0.17 and +1.18V, and another oxidation peak appeared after 4h under air at +0.89V. Cyclic voltammetry and HPLC quantification enable us to confirm that l-5-MTHF can be highly preserved by the addition of an equimolar concentration of AA. This treatment was equivalent to a purge of nitrogen used to remove oxygen and thus minimise oxidation of l-5-MTHF when present in aqueous solutions. HPLC confirmed the fact that a full regeneration of oxidised l-5-MTHF occurred with the addition of sodium ascorbate, thus denoting that the redox character of l-5-MTHF can be controlled by the presence of reducing agents. Cyclic voltammetry proved to be a sensitive and accurate method for characterising l-5-MTHF oxidation and potential preservation with ascorbic acid. To our knowledge, this is the first study that has demonstrated the number of oxidation sites on l-5-MTHF. PMID- 29243633 TI - Characterisation of odour-active compounds in aged rum. AB - The volatiles of rum matured in oak casks were carefully isolated by solvent extraction followed by solvent-assisted flavour evaporation. Among the 116 volatile compounds identified by GC-MS, seven of them were found for the first time in rum. Application of the aroma extract dilution analysis (AEDA) on the volatile fraction revealed 18 odour-active areas in the flavour dilution factor range of 32-1024. On the basis of the quantitative data and odour thresholds in 35% ethanol (v/v), the odour activity values (OAV; ratio of concentration to odour threshold) were calculated. Nineteen aroma compounds showed OAVs >1, among which ethanol, (E)-beta-damascenone, ethyl butanoate, ethyl hexanoate, vanillin, (Z)-oak lactone, ethyl 2-methylpropanoate, 1,1-diethoxyethane, ethyl 2 methylbutanoate, 3-methylbutyl acetate, ethyl octanoate, ethyl decanoate, 2 phenylethyl acetate, 2-phenylethanol, 2-methoxyphenol, 4-ethyl-2-methoxyphenol, 4 propyl-2-methoxyphenol, gamma-nonalactone, and eugenol showed the highest values and should be considered as the most odour-active compounds. PMID- 29243634 TI - Phenolic composition and nutraceutical properties of organic and conventional cinnamon and peppermint. AB - Conventional and organic cinnamon and peppermint were investigated for their phenolic profile, anti-proliferative, anti-inflammatory, and antioxidant properties. Accelerated solvent extraction with 75% acetone was used to extract samples. Caffeic acid was the most abundant phenolic acid in peppermint. Catechin, (-)-epigallocatechin gallate, syringic acid, gallic acid, vanillic acid, and p-coumaric acid were also detected in both spices. There was no significant difference between conventional and organic spices in the composition of most individual phenolics. All conventional and organic peppermint and cinnamon extracts exhibited strong anti-proliferative and anti-inflammatory properties. Cinnamon was more efficient in inhibiting IL-1beta and COX-2 expression, while peppermint showed better inhibitory effect on IL-6 and MCP-1. This study indicates that cinnamon and peppermint may potentially be used as dietary sources of bioactive phytochemicals for improving health. PMID- 29243635 TI - Waxy fraction containing long-chain aliphatic aldehydes in virgin olive oils. AB - Long-chain aliphatic aldehydes are natural minor components occurring in the cuticle of numerous plant species and also evidenced in virgin olive oils. The fraction containing these compounds can be isolated from the oil samples by using a solid-phase extraction silica-gel cartridge and then directly analysed by GC on a 5% diphenyl-95% dimethylsiloxane capillary column, using an on column-injection system. The proposed methodology showed that extra virgin olive oils contain long chain aliphatic aldehydes, with even carbon-atom numbers from C22 to C30. Quantitative results, using the synthesised aldehyde C21 as internal standard, give concentrations of total long-chain aliphatic aldehydes in a variable range below 116mgkg-1, being hexacosanal (C26-al) the most abundant aldehyde. The different experimental conditions utilised during olive oil extraction processes influence the total aldehydes concentration. Besides contribution to the knowledge of the minor-component composition present in olive oil, their interest and relationship with wax esters, aliphatic alcohols and n-alkanes are discussed. PMID- 29243636 TI - Antioxidant properties and phytochemical composition of China-grown pomegranate seeds. AB - Four cultivars of Shanxi-grown pomegranate seeds were investigated for their phytochemical composition and antioxidant properties. Pomegranate seed oils were extracted and analysed for their fatty acid profiles, and tocopherol and carotenoid contents. The defatted flours were extracted with 50% acetone or 80% methanol, and evaluated for levels of phenolics, flavonoids and proanthocyanidins, and scavenging capacities against DPPH and ABTS+ and their ferric ion reducing abilities. Pomegranate seed oil was rich in punicic acid (73.5-78.8g/100g oil) and total tocopherols (5.3-12.0MUmol/g). The 50% acetone and 80% methanol were appropriate solvents for extraction of total phenolic and total flavonoid, respectively. The four cultivars were significantly different in levels of phenolics, flavonoids, proanthocyanidins and their antioxidant properties (P<0.05), generally flowing an order: Suanshiliu>Tianhongdan>Sanbaitian~Jingpitian. This study will assist in the cultivar selection of the above pomegranate seeds for commercial production to meet the market demand. PMID- 29243637 TI - Urolithins, ellagitannin metabolites produced by colon microbiota, inhibit Quorum Sensing in Yersinia enterocolitica: Phenotypic response and associated molecular changes. AB - The mammalian enteropathogen Yersinia enterocolitica produces two main N acylhomoserine lactones (AHLs) involved in Quorum Sensing (QS)-mediated infection processes, such as virulence, biofilm maturation and motility. Ellagitannin (ET) rich fruits exhibit anti-QS activity but in vivo effects against intestinal pathogens may be associated to the ETs gut microbiota derived metabolites, urolithin-A (Uro-A) and urolithin-B (Uro-B). In this work we show that urolithins, at concentrations achievable in the intestine through the diet, reduce the levels of N-hexanoyl-l-homoserine lactone (C6-HSL) and N-(3-oxo hexanoyl)-l-homoserine lactone (3-oxo-C6-HSL) in Y. enterocolitica and inhibit QS associated biofilm maturation and swimming motility. These inhibitory effects were not associated to downregulation of the expression of some of the genes involved in the synthesis of AHLs (yenI and yenR) or in motility (flhDC, fliA, fleB). Our results suggest that urolithins may exert antipathogenic effects in the gut against Y. enterocolitica and highlight the need to investigate the antipathogenic in vivo properties of plant derived metabolites. PMID- 29243638 TI - Cholesterol-lowering effect of dietary Lupinus angustifolius proteins in adult rats through regulation of genes involved in cholesterol homeostasis. AB - In the absence of a clear indication from previous studies, a rat study was designed to evaluate a possible hypolipidaemic effect of Lupinus angustifolius (blue lupin) proteins. Rats were fed for 28days Nath's hypercholesterolaemic diets containing 20% casein or blue lupin proteins. After 14 and 28days of dietary treatment, blue-lupin-fed rats had markedly lower plasma total cholesterol levels than rats fed casein (-53.0% and -55.3%, respectively, p<0.0005). No significant differences were instead observed for triglyceride and HDL-cholesterol levels between the two groups. Lupin-protein-fed rats displayed higher hepatic mRNA levels of SREBP-2, a major transcriptional regulator of intracellular cholesterol levels, and CYP7A1, the rate-limiting enzyme in bile acid biosynthesis (p<0.05). In conclusion, the present study demonstrates a marked cholesterol-lowering activity of proteins from L. angustifolius in rats. Moreover, blue lupin proteins appear to affect cellular lipid homeostasis by up regulating SREBP-2 and CYP7A1 genes. PMID- 29243639 TI - Speciation analysis and characterisation of arsenic in lavers collected from coastal waters of Fujian, south-eastern China. AB - Laver samples (Porphyra haitanensis) were collected from the coastal waters of Fujian province, south-eastern China and then the speciation characteristics of arsenic in the samples were studied in detail. These laver samples contained five arsenical species, namely arsenobetaine, monomethylarsonic acid, As(V) and two kinds of arsenic-containing ribosides (arsenosugars), with a relatively high concentration of total arsenic in the range of 28.85-63.03MUgAs/g dried weight. DMAsSugarMethoxy was found to be the predominant species of arsenic in lavers, accounting for 90-98% of total arsenic. As3+ was not detected and the level of inorganic arsenic was much lower than the national tolerable average residue level (TARL), suggesting that the lavers are safe for consumption. PMID- 29243640 TI - Intramuscular lipids of Mertolenga-PDO beef, Mertolenga-PDO veal and "Vitela Tradicional do Montado"-PGI veal. AB - Three quality branded meats (n=68), "Vitela Tradicional do Montado"-PGI veal, Mertolenga-PDO veal and Mertolenga-PDO beef were analysed for cholesterol (HPLC UV), alpha-tocopherol (HPLC-FD), fatty acid composition (GC-FID), including conjugated linoleic acid (CLA) isomeric profile (Ag+-HPLC), and nutritional value of lipids. All the meats analysed had similar contents (P>0.05) of cholesterol, alpha-tocopherol and intramuscular fat. In contrast, the percentage of 18:0 was lower for PGI veal, and that of 18:1 c9 was higher in PDO veal, whilst the percentage of 18:2 n-6 was higher in PDO beef, relative to other two meats. The content of total CLA and the percentage of its t11,c13 isomer were higher, and the n-6/n-3 ratio was lower, in PDO veal, relative to the other two meats. The data suggested that PGI veal has higher variability for most fatty acids than the other two types of meat. Finally, a discriminant analysis was conducted and the three meat types were well discriminated using the meat fatty acid profile as variables. PMID- 29243641 TI - Variation of total phenolics, anthocyanins, ellagic acid and radical scavenging capacity in various raspberry (Rubus spp.) cultivars. AB - The aim of this study was to assess the level of some phytochemicals in 19 raspberry cultivars grown in Lithuania. The content of total ellagic acid measured after 20h acidic hydrolysis of investigated raspberry cultivars, varied from 119.8 (cv. 'Pokusa') to 323.5mg/100g (cv. 'Bristol'). The content of total phenolics ranged from 278.6 (cv. 'Pokusa') to 714.7mg/100g (cv. 'Bristol'). The total anthocyanins content varied from 2.1 (yellow cv. 'Beglianka') to 325.5mg/100g (black cv. 'Bristol'). The radical scavenging capacity of the tested raspberry cultivars highly correlating with their total phenolics and total ellagic acid content (r=0.90 and 0.92, respectively). The results of this study expand the knowledge about variation in the content of valuable bioactive compounds in raspberries and may help for the selection and validation of the most productive cultivars. PMID- 29243642 TI - Li, Cr, Mn, Co, Ni, Cu, Zn, Se and Mo levels in foodstuffs from the Second French TDS. AB - In 2006, the French Food Safety Agency (AFSSA) conducted the Second French Total Diet Study (TDS) to estimate dietary exposures to the main minerals and trace elements from 1319 samples of foods typically consumed by the French population. The foodstuffs were analysed by inductively coupled plasma-mass spectrometry (ICP MS) after microwave-assisted digestion. Occurrence data for lithium, chromium, manganese, cobalt, nickel, copper, zinc, selenium and molybdenum were reported and compared with results from the previous French TDS. The results indicate that the food groups presenting the highest levels of these essential trace elements were "tofu" (for Li, Mn, Ni, Cu, Zn and Mo),"fish and fish products" particularly "shellfish" (for Li, Co, Cu, Zn, Se and Mo), "sweeteners, honey and confectionery" particularly dark chocolate (for Cr, Mn, Co, Ni and Cu), "cereals and cereal products" (for Mn, Ni and Mo) and "ice cream" (for Cr, Co and Ni). PMID- 29243643 TI - Physical and oxidative stability of pre-emulsified oil bodies extracted from soybeans. AB - Soybeans contain oil bodies that are coated by a layer of oleosin proteins. In nature, this protein coating protects the oil bodies from environmental stresses and might be utilised by food manufacturers for the same purpose. In this study, an aqueous extraction method was developed to increase the yield of oil bodies extracted from soybean. This method involved a two-step procedure: (i) blending, dispersion, and filtration of soybeans; (ii) homogenisation, suspension, and centrifugation of the filter cake. Using this extraction method about 65% of the oil bodies could be obtained. The mean particle diameter (d43) and sedimentation of the resulting oil bodies increased during storage, suggesting they were prone to aggregation. Heat treatment (90 degrees C, 30min) of the oil body suspensions immediately after extraction improved their storage stability, which was attributed to deactivation of endogenous enzymes such as lipase and lipoxygenase. Heat treatment did not adversely affect the oxidative stability of the oil body suspensions at pH 3 or 7 during storage at 37 degrees C. These results suggest that this aqueous extraction method can be used to prepare oil body suspensions with improved long-term stability. PMID- 29243644 TI - Cholesterol-lowering effect of whole lupin (Lupinus albus) seed and its protein isolate. AB - This study describes the hypocholesterolaemic effect of whole lupin and its protein in hamsters. The diets were: casein (control group HC), lupin protein isolate (group HPI) and whole lupin seed (group HWS). Diets from HPI and HWS promoted a significant reduction of total cholesterol and non-HDL cholesterol in the hamsters' plasma as compared with HC. The true digestibility of HPI and HC groups were similar and differed significantly from the HWS one, which in turn showed a significant difference in total sterol excretion as compared to the former groups. Histological analysis of the liver revealed that animals fed on HPI and HWS diets presented a low level of steatosis (level 1) as compared to the ones fed on HC diet (level 4). Our findings demonstrate that protein isolate from Lupinus albus from Brazil has a metabolic effect on endogenous cholesterol metabolism and a protector effect on development of hepatic steatosis. PMID- 29243645 TI - Structural identification of isomallotusinin and other phenolics in Phyllanthus emblica L. fruit hull. AB - The air-dried fruit hull of Phyllanthus emblica L. was extracted with 95% ethanol, and then the extract was partitioned by diethyl ether and ethyl acetate (EA). The EA fraction was then subjected to separation and purification using silica gel and Sephadex LH-20 column chromatography repeatedly to obtain five hydrolysable tannins. They were identified as mucic acid 1,4-lactone 3-o-gallate (C1), isocorilagin (C2), chebulanin (C3), chebulagic acid (C4) and isomallotusinin (C5) using mass spectrometry and nuclear magnetic resonance (NMR) spectrometry. Isomallotusinin and chebulanin were identified from emblica dried fruit hull for the first time, and isomallotusinin was the first time identified from Phyllanthus. Furthermore, the antioxidant abilities of these hydrolysable tannins were investigated using DPPH and ABTS+ radical scavenging systems. All hydrolysable tannins showed strong DPPH and ABTS+ radical scavenging activities. Isomallotusinin and chebulagic acid exhibited the highest antioxidant activity compared to other purified compounds tested. PMID- 29243647 TI - The quantitative analysis of biologically active compounds in Lithuanian honey. AB - Different sorts of Lithuanian honey were analysed by quantitative determination of eight free phenolic acids and phenylpropanoid vanillin using high performance liquid chromatography (HPLC). Aqueous ethanol 60% was used as a solvent for preparation of honey samples. Amounts of phenolic acids honey solutions were in the range from 7.176 to 125.624mg/ml. Free phenolic acids and vanillin had been detected in all samples of honey, but their composition and amount depended on its botanic origin. p-Coumaric and ferulic acids proved to be the main components in the acacia and buckwheat honey. Raspberry and polyfloral forest honey contained the highest amounts of chlorogenic acid. Gallic acid is a principal phenolic acid in eucalyptus honey. The highest amount of vanillin was identified in buckwheat honey. The results of the analysis revealed that free phenolic acids and vanillin were detected in all honey samples analysed, and their range and amounts varied. PMID- 29243646 TI - Unravelling process-induced pectin changes in the tomato cell wall: An integrated approach. AB - The activity of the pectin-modifying enzymes pectin-methylesterase (PME) and polygalacturonase (PG) in tomato fruit was tailored by processing. Tomatoes were either not pretreated, high-temperature blanched (inactivation of both PME and PG), or high-pressure pretreated (selective inactivation of PG). Subsequently, two types of mechanical disruption, blending or high-pressure homogenisation, were applied to create tomato tissue particle suspensions with varying degrees of tissue disintegration. Process-induced pectin changes and their role in cell-cell adhesion were investigated through in situ pectin visualisation using anti-pectin antibodies. Microscopic results were supported with a (limited) physicochemical analysis of fractionated walls and isolated polymers. It was revealed that in intact tomato fruit pectin de-esterification is endogenously regulated by physical restriction of PME activity in the cell wall matrix. In disintegrated tomato tissue on the other hand, intensive de-esterification of pectin by the activity of PME occurred throughout the entire cell wall. PG was selectively inactivated (i.e. in high-pressure pretreated tomatoes), with de-esterification of pectin by PME, which resulted in a high level of Ca2+-cross-linked pectin and a strong intercellular adhesion. In non-pretreated tomato suspensions on the other hand, combined PME and PG activity presumably led to pectin depolymerisation and, hence, reduced intercellular adhesion. However, because of the high amount of Ca2+-cross-linked pectin in these samples, cell-cell adhesion was still stronger than in the high-temperature blanched tomatoes, in which the absence of PME activity during suspension preparation implied few Ca2+-cross linked pectic polymers and extensive cell separation upon tissue disruption. PMID- 29243648 TI - Recent developments and applications of surface plasmon resonance biosensors for the detection of mycotoxins in foodstuffs. AB - Over the past 10years, great efforts on the development of methods for rapid mycotoxin detection in foodstuffs have been made. As one of the relatively new analytical techniques, surface plasmon resonance (SPR) has been proven particularly advantageous for rapid, label-free, sensitive analyte detection. Using SPR, qualitative and quantitative analysis can be performed in real-time. Mycotoxins are a group of small, toxic products formed as secondary metabolites by a few fungal species. They can contaminate foodstuffs on a large scale and consequently threaten human health through food chain. Thus, rapid, sensitive, and selective determination of mycotoxin is of great significance for the food safety. This contribution addresses the basic principle of SPR, the existing detection methods, and the progress on mycotoxin detection using SPR biosensor. PMID- 29243649 TI - Estimation of uncertainties of the method to determine the concentrations of Cd, Cu, Fe, Pb, Sn and Zn in tomato paste samples analysed by high resolution ICP-MS. AB - Cadmium, copper, iron, lead, tin and zinc were determined in tomato paste samples by using high resolution inductively coupled plasma mass spectrometry. This study was a part of Proficiency Testing scheme conducted by National Metrology Institute (UME) of Turkey. The method was validated. The percentage relative errors obtained for each element ranged between 1.4% and 9.0% for NIST SRM 1573a, tomato leaves. Measurement uncertainties of all elements were calculated by applying bottom-up approach. The calculated percentage relative uncertainties for the elements were between 8.2% and 16.4%. The major contributions to the uncertainty budget came from the calibration curves, repeatability and recovery. Tomato paste samples gathered from the supermarkets in Turkey were analysed by using the validated method. Their levels were compared both with the literature values and European Commission Regulations. PMID- 29243650 TI - Automated flow pH-method for the determination of total free fatty acids content in edible oils. AB - An automated flow pH-method for the determination of titratable acidity (TA) in edible oil without titration is proposed, based on pH measurements on an oil sample emulsion in a suitable reagent. The developed flow pH system involves two constant rate flows: the flow of oils samples and the flow of reagent: triethanolamine+KNO3+H2O+i-PrOH, in which oils is insoluble. The flows are mixed in the mixer forming the emulsion in which the free fatty acids (FFA) extraction is started. Then, the emulsion is passed to the coil for completion of FFA extraction and thermostation and then forwarded to pH-cell for pH measurement. Using pH values and linear dependence of pH vs. log (TA) allows the TA determination. The optimum parameters for the automated flow pH-system have been found, i.e., volumes of the mixer and the coils, the rate of sample and reagent, pH and TA ranges. The results of the TA determination in the edible oils were statistically compared with the standard titration method. PMID- 29243651 TI - A multiplex degenerate PCR analytical approach targeting to eight genes for screening GMOs. AB - Currently, the detection methods with lower cost and higher throughput are the major trend in screening genetically modified (GM) food or feed before specific identification. In this study, we developed a quadruplex degenerate PCR screening approach for more than 90 approved GMO events. This assay is consisted of four PCR systems targeting on nine DNA sequences from eight trait genes widely introduced into GMOs, such as CP4-EPSPS derived from Acetobacterium tumefaciens sp. strain CP4, phosphinothricin acetyltransferase gene derived from Streptomyceshygroscopicus (bar) and Streptomyces viridochromogenes (pat), and Cry1Ab, Cry1Ac, Cry1A(b/c), mCry3A, and Cry3Bb1 derived from Bacillus thuringiensis. The quadruplex degenerate PCR assay offers high specificity and sensitivity with the absolute limit of detection (LOD) of approximate 80targetcopies. Furthermore, the applicability of the quadruplex PCR assay was confirmed by screening either several artificially prepared samples or samples of Grain Inspection, Packers and Stockyards Administration (GIPSA) proficiency program. PMID- 29243652 TI - Quantification of organophosphate insecticides and herbicides in vegetable samples using the "Quick Easy Cheap Effective Rugged and Safe" (QuEChERS) method and a high-performance liquid chromatography-electrospray ionisation-mass spectrometry (LC-MS/MS) technique. AB - A Quick Easy Cheap Effective Rugged and Safe (QuEchERS) extraction was developed and followed by selective analysis using a liquid chromatography-mass spectrometry method for the quantification of eighteen pesticides in vegetable samples. This method was accurate (?99.5%), and it exhibited limits of detection and quantification values in the 0.006-0.091 and 0.020-0.314MUgkg-1 ranges, respectively. Furthermore, the coefficients of variations (?0.9999) were less than 1% at the low MUgkg-1 end of the method. Mean recoveries ranged between 94% and 102%, and relative standard deviations were below 10%. Based on these results, the methodology was proven to be highly efficient, robust, and suitable for monitoring the maximum residue limits (MRL) compliance of a wide range of commodity/pesticide combination. This method was successfully applied to the analysis of vegetable samples that were collected from different government farmers' markets and street shops in urban areas. The presence of target pesticides was found in the range of 0.016 and 50.85MUgkg-1. PMID- 29243653 TI - Quantitative determination of major polyphenol constituents in pomegranate products. AB - The anti-oxidant content and potential health benefits associated with consuming pomegranate and pomegranate-containing products has lead to increased consumer demand for this crop resulting in it becoming a high value crop. The potential health benefits and high anti-oxidant content of this fruit is attributed to the polyphenolic compounds it contains, including the ubiquitous phenolic acids, gallic acid and ellagic acid, and punicalagin A and punicalagin B, two polyphenolics unique to this fruit. A rapid HPLC-UV method targeting these four metabolites requiring minimal sample cleanup and offering runtimes half as long as existing methods was established. Within day and inter-day run-to-run variability for the four metabolites ranged from 1.9% to 6.6% and 5.3% to 11.4%, respectively. Spike recovery percentages for gallic acid, punicalagin A, punicalagin B and ellagic acid were found to be 98.5%, 92.4%, 95.5%, and 96.5%, respectively. This method was applied to the evaluation of various pomegranate products, including commercial drinks, handmade juice, and marc extracts. This method may be readily used to verify the presence of pomegranate metabolites in juices, extracts, and other products. PMID- 29243655 TI - Highly selective optical nitrite sensor for food analysis based on Lauth's violet triacetyl cellulose membrane film. AB - A new sensor has been developed for the determination of nitrite based on the immobilisation of Lauth's violet on triacetyl cellulose membrane using absorption spectrophotometry. The optical sensor signal is based on the reaction of Lauth's violet with bromate as an oxidant in the presence of nitrite to produce a colourless product. Nitrite has a strong catalytic effect on the oxidation of Lauth's violet with bromate in acidic media. The difference in the absorbance of the optode at 617nm between uncatalysed and catalysed reactions (DeltaA) was directly proportional to the concentration of nitrite in sample solution. A linear calibration curve (r2=0.985) was observed in the nitrite concentration range of 10.12-1012ngmL-1 and a detection limit of 8.3ngmL-1 was found. PMID- 29243654 TI - Comparative study of aroma profile and phenolic content of Montepulciano monovarietal red wines from the Marches and Abruzzo regions of Italy using HS SPME-GC-MS and HPLC-MS. AB - Montepulciano is one of the most famous and important red-berried grapes of Italy. This article presents and discusses a comparative study of aroma profile and phenolic content of the Montepulciano wine from the Marches and the Abruzzo regions. The volatile composition of wines was determined by using headspace solid phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS). The PDMS fibre was chosen. The dominating esters in Montepulciano wines were ethyl hexanoate, ethyl decanoate, and ethyl octanoate, whereas phenyl ethanol and 3-methyl-1-butanol were dominating alcohols. Phenolic compounds, namely gallic acid, p-coumaric acid, trans-ferulic acid, caffeic acid, trans-resveratrol, (+)-catechin and (-)-epicatechin, were examined using HPLC-MS with direct injection of wine samples. The total phenolic content of the analysed wines was in the range of 30.4-61.9mgl-1. The presence of high amounts of esters seems to characterise the volatiles of Montepulciano wines from the Marches, whereas a high level of alcohols was found in Montepulciano wines from Abruzzo. Moreover, multivariate chemometric techniques, such as cluster analysis and principal component analysis, supported this thesis. Headspace solid phase microextraction and gas chromatography-mass spectrometry were used to analyse 20 commercial wine samples (Montepulciano monovarietal red wines) from the Marches (10 samples) and Abruzzo (10 samples). PMID- 29243656 TI - Authentication of edible vegetable oils adulterated with used frying oil by Fourier Transform Infrared Spectroscopy. AB - The application of Fourier Transform Infrared (FTIR) Spectroscopy to authenticate edible vegetable oils (corn, peanut, rapeseed and soybean oil) adulterated with used frying oil was introduced in this paper. The FTIR spectrum of oil was divided into 22 regions which corresponded to the constituents and molecular structures of vegetable oils. Samples of calibration set were classified into four categories for corn and peanut oils and five categories for rapeseed and soybean oils by cluster analysis. Qualitative analysis of validation set was obtained by discriminant analysis. Area ratio between absorption band 19 and 20 and wavenumber shift of band 19 were treated by linear regression for quantitative analysis. For four adulteration types, LODs of area ratio were 6.6%, 7.2%, 5.5%, 3.6% and wavenumber shift were 8.1%, 9.0%, 6.9%, 5.6%, respectively. The proposed methodology is a useful tool to authenticate the edible vegetable oils adulterated with used frying oil. PMID- 29243657 TI - The application of near-infrared (NIR) and Raman spectroscopy to detect adulteration of oil used in animal feed production. AB - Basic vegetable blends (BVB's) and soya oils, used in the animal feed industry, are sometimes adulterated with transformer and mineral oil as a means of illegally increasing profit. A set of BVB's and soya oil samples adulterated with transformer oil and mineral oil were characterised using both NIRS and Raman spectroscopy. Applying chemometrics to the NIRS and Raman spectral data, very good calibration and prediction statistics were obtained for transformer and mineral oils. Using NIRS, R2 values greater than 0.99 were obtained with corresponding values for root mean squared error of calibration and prediction (<0.57 and <0.55, respectively). Using Raman, R2 values greater than 0.97 were obtained with the root mean squared error of calibration (<2.01) and prediction (<1.92) calculated. Furthermore, using a qualitative approach it was possible, using PCA, to discriminate between 100% soya and BVB. This study demonstrates that both NIRS and Raman technology can be successfully applied as rapid screening techniques for the detection of oil adulteration and fraud in the food and feed industry. PMID- 29243658 TI - 1H HRMAS-NMR metabolomic to assess quality and traceability of mozzarella cheese from Campania buffalo milk. AB - The production of Mozzarella di Bufala Campana (MBC) is relevant for the agro food economy of the Campania Region of Italy and the mark of Protected Designation of Origin (PDO) has been assigned to MBC in relation to its geographical origin. Advanced analytical methods must be then employed to assess authenticity, traceability, and quality of MBC. 1H HRMAS-NMR (High Resolution Magic Angle Spinning Nuclear Magnetic Resonance) spectroscopy was applied here to directly identify specific metabolites in MBC intact samples without time consuming sample pre-treatments. Overcrowded conventional 1H HRMAS-NMR spectra were selectively simplified with two NMR pulse sequences: eCPMG and eDiff, by modulating spin-spin relaxation times and diffusion of MBC molecular components, respectively. Signal elaboration of edited spectra was combined with multivariate analyses to enable significant metabolic differentiation between MBC samples from two different production sites in Campania. Principal Components Analysis (PCA) for eCPMG spectra explained 97.54% of total variance between the two MBC groups for four metabolites (beta-galactose, beta-lactose, acetic acid, and glycerol). Less efficient was groups distinction by PCA for eDiff spectra, although differences in polyunsaturated acids, such as linoleic and linolenic acids, were highlighted. Similarly, Discriminant Analysis (DA) provided MBC group classification with 100% success in validation tests for eCPMG spectra, while DA prediction ability was reduced to 94.12% for eDiff spectra. Hierarchical Cluster Analysis (HCA) gave a totally correct classification between the two MBC groups only for eCPMG spectra. eCPMG spectra were also used to identify metabolites during MBC aging. As compared to fresh samples, 2 days old MBC samples showed increasing signals for isobutylic alcohol, lactic acid, and acetic acid. This work shows that 1H HRMAS-NMR spectroscopy can rapidly characterise the metabolic profile of intact MBC samples and statistically distinguish the geographical origin of buffalo milk mozzarella and its freshness. PMID- 29243660 TI - Lactate blood measurement in acute cyanide poisoning: effect of preanalytical delay and hydroxocobalamin uses as treatment. AB - We quantify the impact of several variables including site of blood draw, delay in measurement, and use of the cyanide antidote hydroxocobalamin on detection of both normal (<2 mmol/L) and elevated (>6 mmol/L) human plasma lactate. An in vivo study assessed effects of venous or arterial origin of blood samples. Two in vitro studies assessed the effect of a 2 h delay in measuring plasma lactate concentrations, as well as the interference of low (100 MUmol/L) and high (300 MUmmol/L) plasma hydroxocobalamin concentrations on detecting normal and elevated levels of lactate. A relative change of 20% in the measured lactate concentration was considered clinically significant. There was no clinically relevant effect of the site of blood draw on lactate measurements. Plasma lactate concentrations were artificially increased by a delay of 2 h between blood draw and sample measurement. Under conditions where plasma lactate levels were in a normal range, the dose equivalent to 300 MUmol/L hydroxocobalamin concentration caused an artificial increase in lactate measurements that could possibly be misinterpreted clinically as an elevation. Under conditions where plasma lactate levels were elevated, as would occur in cases of acute cyanide poisoning, neither the low nor high concentration of hydroxocobalamin caused a clinically relevant change in lactate measurements. Clinicians should be cautious in interpreting lactate concentrations if there has been a significant delay between blood draw and laboratory analysis, or when blood was collected shortly after the completion of hydroxocobalamin administration. PMID- 29243661 TI - Mechanisms of optical orientation of an individual Mn2+ ion spin in a II-VI quantum dot. AB - We provide a theoretical description of the optical orientation of a single Mn$^{2+}$ ion spin under quasi-resonant excitation demonstrated experimentally by Goryca ?textit{et al.} [Phys. Rev. Lett. ?textbf{103}, 087401 (2009)]. We build and analyze a hierarchy of models by starting with the simplest assumptions (transfer of perfectly spin-polarized excitons from Mn-free dot to the other dot containing a single Mn$^{2+}$ spin, followed by radiative recombination) and subsequently adding more features, such as spin relaxation of electrons and holes. Particular attention is paid to the role of the influx of the dark excitons and the process of biexciton formation, which are shown to contribute significantly to the orientation process in the quasi-resonant excitation case. Analyzed scenarios show how multiple features of the excitonic complexes in magnetically-doped quantum dots, such as the values of exchange integrals, spin relaxation times, etc., lead to a plethora of optical orientation processes, characterized by distinct dependencies on light polarization and laser intensity, and occurring on distinct timescales. Comparison with experimental data shows that the correct description of the optical orientation mechanism requires taking into account Mn$^{2+}$ spin-flip processes occurring not only when the exciton is already in the orbital ground state of the light-emitting dot, but also those that happen during the exciton transfer from high-energy states to the ground state. Inspired by the experimental results on energy relaxation of electrons and holes in nonmagnetic dots, we focus on the process of biexciton creation allowed by mutual spin-flip of an electron and the Mn$^{2+}$ spin, and we show that by including it in the model, we obtain good qualitative and quantitative agreement with the experimental data on quasi-resonantly driven Mn$^{2+}$ spin orientation. PMID- 29243659 TI - Comparative study of the serum measurement of PTH on Roche Cobas e411(r) versus the Abbott Architect ci8200(r). AB - Parathormone (PTH) is the main hormone of phosphocalcic homeostasis. It is synthesized and secreted by the parathyroid glands. PTH has become a routine test in the medical biology laboratory. However, its measurement presents analytical difficulties with the various marketed kits. The aim of this work is to present the results of a comparative study between the PTH measurment on Abbott architect ci8200 and on Roche's Cobas e411 automaton. It is a prospective study carried out for 252 hospitalized patients in the various departments of the University Hospital Center Mohammed VI of Oujda. The "intact" PTH tests were performed on two automata: Abbott Architect ci8200 and Roche Cobas e411. The first uses chemiluminescent microparticle immunoassay. The second uses electrochemiluminiscence sandwich enzyme immunoassay. The agreement of the results between the different techniques was evaluated using the Bland-Altman difference diagram and the Passing-Bablok and Deming regression line (MedCalc software version 14.8.1.0(r)). By analyzing the diagram of Bland-Altman, we note that the average bias between both methods is of the order of 193.9 pg/mL. As for the equation of the right of Passing-Bablok, it is: Y(Architect) = 3.11 X (Cobas) - 12.26. In conclusion, our study shows a great discrepancy between the results of the PTH assay on the Architect ci8200 versus the Cobas e411, hence the biologist's indisputable role in the control and evaluation of the kits marketed through the various validation tests. PMID- 29243662 TI - Long range of indirect exchange interaction on the edges of MoS2 flakes. AB - We study the Ruderman-Kittel-Kasuya-Yosida interaction between two magnetic impurities connected to the edges of zigzag-terminated MoS2 flakes. When the impurities lie on the edges of the flake, the effective exchange interaction exhibits sizable noncollinear Dzyaloshinskii-Moriya character that competes with a strong Ising coupling. We analyze the characteristic decay exponent for doping levels inside the band gap of the infinite layer, corresponding to edge states of the flake at the Fermi level. The characteristic exponents show sub-two-dimensional (sub-2D) behavior for these band fillings, with decays much slower than quadratic. The Ising interaction has effectively one dimensional (1D) long range, while the noncollinear component that grows for short impurity separation becomes comparable in magnitude. The resulting tunable exchange interaction on these systems opens the way for the study of interesting phases of impurity arrays with long-range stable helical order. PMID- 29243663 TI - Characterization of Compton-scatter imaging with an analytical simulation method. AB - By collimating the photons scattered when a megavoltage therapy beam interacts with the patient, a Compton-scatter image may be formed without the delivery of an extra dose. To characterize and assess the potential of the technique, an analytical model for simulating scatter images was developed and validated against Monte Carlo (MC). For three phantoms, the scatter images collected during irradiation with a 6 MV flattening-filter-free therapy beam were simulated. Images, profiles, and spectra were compared for different phantoms and different irradiation angles. The proposed analytical method simulates accurate scatter images up to 1000 times faster than MC. Minor differences between MC and analytical simulated images are attributed to limitations in the isotropic superposition/convolution algorithm used to analytically model multiple-order scattering. For a detector placed at 90 degrees relative to the treatment beam, the simulated scattered photon energy spectrum peaks at 140-220 keV, and 40-50% of the photons are the result of multiple scattering. The high energy photons originate at the beam entrance. Increasing the angle between source and detector increases the average energy of the collected photons and decreases the relative contribution of multiple scattered photons. Multiple scattered photons cause blurring in the image. For an ideal 5 mm diameter pinhole collimator placed 18.5 cm from the isocenter, 10 cGy of deposited dose (2 Hz imaging rate for 1200 MU min-1 treatment delivery) is expected to generate an average 1000 photons per mm2 at the detector. For the considered lung tumor CT phantom, the contrast is high enough to clearly identify the lung tumor in the scatter image. Increasing the treatment beam size perpendicular to the detector plane decreases the contrast, although the scatter subject contrast is expected to be greater than the megavoltage transmission image contrast. With the analytical method, real-time tumor tracking may be possible through comparison of simulated and acquired patient images. PMID- 29243664 TI - Editorial-Focus on inorganic semiconductor nanowires for device applications. PMID- 29243665 TI - Anthropomorphic thorax phantom for cardio-respiratory motion simulation in tomographic imaging. AB - Patient motion during medical imaging using techniques such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), or single emission computed tomography (SPECT) is well known to degrade images, leading to blurring effects or severe artifacts. Motion correction methods try to overcome these degrading effects. However, they need to be validated under realistic conditions. In this work, a sophisticated anthropomorphic thorax phantom is presented that combines several aspects of a simulator for cardio-respiratory motion. The phantom allows us to simulate various types of cardio-respiratory motions inside a human-like thorax, including features such as inflatable lungs, beating left ventricular myocardium, respiration-induced motion of the left ventricle, moving lung lesions, and moving coronary artery plaques. The phantom is constructed to be MR-compatible. This means that we can not only perform studies in PET, SPECT and CT, but also inside an MRI system. The technical features of the anthropomorphic thorax phantom Wilhelm are presented with regard to simulating motion effects in hybrid emission tomography and radiotherapy. This is supplemented by a study on the detectability of small coronary plaque lesions in PET/CT under the influence of cardio respiratory motion, and a study on the accuracy of left ventricular blood volumes. PMID- 29243666 TI - Electric field tuned MoS2/metal interface for hydrogen evolution catalyst from first-principles investigations. AB - Understanding the interfacial properties of catalyst/substrate is crucial for the design of high-performance catalyst for important chemical reactions. Recent years have witnessed a surge of research in utilizing MoS2 as a promising electro catalyst for hydrogen production, and field effect has been employed to enhance the activity (Wang et al 2017 Adv. Mater. 29, 1604464; Yan et al 2017 Nano Lett. 17, 4109-15). However, the underlying atomic mechanism remains unclear. In this paper, by using the prototype MoS2/Au system as a probe, we investigate effects of external electric field on the interfacial electronic structures via density functional theory (DFT) based first-principles calculations. Our results reveal that although there is no covalent interaction between MoS2 overlayer and Au substrate, an applied electric field efficiently adjusts the charge transfer between MoS2 and Au, leading to tunable Schottky barrier type (n-type to p-type) and decrease of barrier height to facilitate charge injection. Furthermore, we predict that the adsorption energy of atomic hydrogen on MoS2/Au to be readily controlled by electric field to a broad range within a modest magnitude of field, which may benefit the performance enhancement of hydrogen evolution reaction. Our DFT results provide valuable insight into the experimental observations and pave the way for future understanding and control of catalysts in practice, such as those with vacancies, defects, edge states or synthesized nanostructures. PMID- 29243667 TI - Graphene-induced band gap renormalization in polythiophene: a many-body perturbation study. AB - Density functional theory and many-body perturbation theory at the G0W0 level are employed to study the electronic properties of polythiophene (PT) adsorbed on the graphene surface. Analysis of the charge density difference shows that substrate adsorbate interaction leads to a strong physisorption and interfacial electric dipole moment formation. The electrostatic potential displays a -0.19 eV shift in the graphene work function from its initial value of 4.53 eV, as the result of the interaction. The LDA band gap of the polymer does not show any change. However, the band structure exhibits weak orbital hybridizations resulting from slight overlapping between the polymer and graphene states wave functions. The interfacial polarization effects on the band gap and levels alignment are investigated at the G0W0 level and show a notable reduction of PT band gap compared to that of the isolated chain. PMID- 29243668 TI - Chemotactic droplet swimmers in complex geometries. AB - Chemotaxis1 and auto-chemotaxis are key mechanisms in the dynamics of micro organisms, e.g. in the acquisition of nutrients and in the communication between individuals, influencing the collective behaviour. However, chemical signalling and the natural environment of biological swimmers are generally complex, making them hard to access analytically. We present a well-controlled, tunable artificial model to study chemotaxis and autochemotaxis in complex geometries, using microfluidic assays of self-propelling oil droplets in an aqueous surfactant solution (Herminghaus et al 2014 Soft Matter 10 7008-22; Kruger et al 2016 Phys. Rev. Lett. 117). Droplets propel via interfacial Marangoni stresses powered by micellar solubilisation. Moreover, filled micelles act as a chemical repellent by diffusive phoretic gradient forces. We have studied these chemotactic effects in a series of microfluidic geometries, as published in Jin et al (2017 Proc. Natl Acad. Sci. 114 5089-94): first, droplets are guided along the shortest path through a maze by surfactant diffusing into the maze from the exit. Second, we let auto-chemotactic droplet swimmers pass through bifurcating microfluidic channels and record anticorrelations between the branch choices of consecutive droplets. We present an analytical Langevin model matching the experimental data. In a previously unpublished experiment, pillar arrays of variable sizes and shapes provide a convex wall interacting with the swimmer and, in the case of attachment, bending its trajectory and forcing it to revert to its own trail. We observe different behaviours based on the interplay of wall curvature and negative autochemotaxis, i.e. no attachment for highly curved interfaces, stable trapping at large pillars, and a narrow transition region where negative autochemotaxis makes the swimmers detach after a single orbit. PMID- 29243669 TI - Simultaneous tumor and surrogate motion tracking with dynamic MRI for radiation therapy planning. AB - Respiration-induced tumor motion is a major obstacle for achieving high-precision radiotherapy of cancers in the thoracic and abdominal regions. Surrogate-based estimation and tracking methods are commonly used in radiotherapy, but with limited understanding of quantified correlation to tumor motion. In this study, we propose a method to simultaneously track the lung tumor and external surrogates to evaluate their spatial correlation in a quantitative way using dynamic MRI, which allows real-time acquisition without ionizing radiation exposure. To capture the lung and whole tumor, four MRI-compatible fiducials are placed on the patient's chest and upper abdomen. Two different types of acquisitions are performed in the sagittal orientation including multi-slice 2D cine MRIs to reconstruct 4D-MRI and two-slice 2D cine MRIs to simultaneously track the tumor and fiducials. A phase-binned 4D-MRI is first reconstructed from multi-slice MR images using body area as a respiratory surrogate and groupwise registration. The 4D-MRI provides 3D template volumes for different breathing phases. 3D tumor position is calculated by 3D-2D template matching in which 3D tumor templates in the 4D-MRI reconstruction and the 2D cine MRIs from the two slice tracking dataset are registered. 3D trajectories of the external surrogates are derived via matching a 3D geometrical model of the fiducials to their segmentations on the 2D cine MRIs. We tested our method on ten lung cancer patients. Using a correlation analysis, the 3D tumor trajectory demonstrates a noticeable phase mismatch and significant cycle-to-cycle motion variation, while the external surrogate was not sensitive enough to capture such variations. Additionally, there was significant phase mismatch between surrogate signals obtained from the fiducials at different locations. PMID- 29243670 TI - High-pressure structural and vibrational properties of monazite-type BiPO4, LaPO4, CePO4, and PrPO4. AB - Monazite-type BiPO4, LaPO4, CePO4, and PrPO4 have been studied under high pressure by ab initio simulations and Raman spectroscopy measurements in the pressure range of stability of the monazite structure. A good agreement between experimental and theoretical Raman-active mode frequencies and pressure coefficients has been found which has allowed us to discuss the nature of the Raman-active modes. Besides, calculations have provided us information on how the crystal structure is modified by pressure. This information has allowed us to determine the equation of state and the isothermal compressibility tensor of the four studied compounds. In addition, the information obtained on the polyhedral compressibility has been used to explain the anisotropic axial compressibility and the bulk compressibility of monazite phosphates. Finally, we have carried out a systematic discussion on the high-pressure behavior of the four studied phosphates in comparison to results of previous studies. PMID- 29243671 TI - Solvent-free nanofluid with three structure models based on the composition of a MWCNT/SiO2 core and its adsorption capacity of CO2. AB - A series of core/shell nanoparticle organic/inorganic hybrid materials (NOHMs) with different weight ratios of two components, consisting of multi-walled carbon nanotubes (MWCNTs) and silicon dioxide (SiO2) as the core were synthesized. The NOHMs display a liquid-like state in the absence of solvent at room temperature. Five NOHMs were categorized into three kinds of structure states based on different weight ratio of two components in the core, named the power strip model, the critical model and the collapse model. The capture capacities of these NOHMs for CO2 were investigated at 298 K and CO2 pressures ranging from 0 to 5 MPa. Compared with NOHMs having a neat MWCNT core, it was revealed that NOHMs with the power strip model show better adsorption capacity toward CO2 due to its lower viscosity and more reactive groups that can react with CO2. In addition, the capture capacities of NOHMs with the critical model were relatively worse than the neat MWCNT-based NOHM. The result is attributed to the aggregation of SiO2 in these samples, which may cause the consumption and hindrance of reactive groups. However, the capture capacity of NOHMs with the collapse model was the worst of all the NOHMs, owing to its lowest content of reactive groups and hollow structure in MWCNTs. In addition, they presented non-interference of MWCNTs and SiO2 without aggregation state. PMID- 29243672 TI - The tricky "trichs" in dermatology! PMID- 29243673 TI - Congenital erosive and vesicular dermatosis healing with reticulated supple scarring: Report of four cases. PMID- 29243674 TI - Turmeric: A condiment, cosmetic and cure. AB - Turmeric (Curcuma longa L.) is an integral part of Asian culture and cuisine. It has been used in traditional medicine since centuries. A myriad of health benefits have been attributed to it. Curcumin, the most biologically active curcuminoid in turmeric, is being investigated in pre-clinical and clinical trials for its role in disease prevention and cure. It has antioxidant, anti inflammatory, antineoplastic, anti-proliferative and antimicrobial effects. We review the chemistry of this plant, its cultural relevance in Indian skin care, and its uses in dermatology. PMID- 29243675 TI - Handheld narrow band ultraviolet B comb as home phototherapy device for localised vitiligo: Dosimetry and calibration. PMID- 29243676 TI - Reinterpreting minimum inhibitory concentration (MIC) data of itraconazole versus terbinafine for dermatophytosis - time to look beyond the MIC data? PMID- 29243678 TI - The relationship between pathological wear of teeth and temporomandibular joint dysfunction. AB - OBJECTIVE: Temporomandibular joint dysfunction (TMJD) is quite frequent pathology in population. In scientific literature pathological tooth wear (PTW) is listed among the predisposing factors of it. MATERIAL AND METHODS: During the survey 189 primary patients of dental department in polyclinic of Panevezys city were examined. According to the tooth wear degree 2 groups have been formed: control group (grade 0-1) withouth TMJ dysfunction; and experimental group (grade 2-4) with presumable TMJD. RESULTS: In experimental group tooth wear of anterior and posterior region increases with age respectively (p<0.05). It was also found that centric occlusion (CO) and relative rest heights difference increases with age in the control group (p<0.05) as well as the experimental group (p=0.001). In patients with diagnosed TMJD the difference between heights in CO and relative rest was bigger than in patients without TMJD (p=0.039). In the experimental group TMJD was diagnosed the most of patients grade-4 in 90%. The most common symptom is joint sounds was observed in 72.2%. CONCLUSIONS: 35-50 and over 50 age groups of patients had a higher first molars degree of wear than the younger ones. In patients with diagnosed TMJD the difference between heights in CO and relative rest was bigger than in patients without TMJD. TMJD symptoms and of posterior teeth pathological wear interface hypothesis confirmed. In the experimental group TMJD was diagnosed the most common in 90% of patients grade-4. The most common symptom is "Nutcracker" of experimental group patients 77.2%. PMID- 29243677 TI - Authors' reply. PMID- 29243679 TI - Surgery-related factors affecting the stability of orthodontic mini implants screwed in alveolar process interdental spaces: a systematic literature review. AB - The ambiguous results of scientific researches on surgical factors affecting the stability of mini implants (MI) impels the physicians to constantly analyze this problem. The objective of this article was to conduct a systematic literature review about surgery related factors affecting the stability of MI screwed in alveolar process buccal surface between the second premolar and first molar roots based on peer reviewed publications of 2009-2015. The Cochrane and PRISMA references were used while searching for scientific literature. Two data bases and scientific publications were browsed in the Lithuanian University of Health Sciences library. Criteria for article selection were: 1) research in which surgical factors affecting MI stability were analyzed, 2) research in which stability of MI screwed in alveolar process between adjacent teeth roots was analyzed, 3) research in which MI stability was analyzed in clinical practice, 4) articles which were published in 2009-2015. Selected articles were evaluated in accordance with methodical quality. 13 articles met the selection criteria of the research. 2652 MI screwed in 1205 people jawbones' alveolar processes were analyzed in selected articles. The MI success rate was 87.7-97%. Root proximity was identified to be the main determinant of all MI success influencing surgical factors (MI and root contact determined a 9-26.7% failure rate). The results of this article confirm the sufficient MI stability rate in clinical practice and specifies root proximity as the main surgical factor affecting the MI stability. PMID- 29243680 TI - A review of PEEK polymer's properties and its use in prosthodontics. AB - OBJECTIVE: The aim of this study is to review polyether ether ketone (PEEK), its characteristics and use in prosthodontics. MATERIAL AND METHODS: Information search for articles about PEEK and it's use in prosthodontics between January 2010 and April 2017 was conducted in Medline via PubMed, Science direct, Wiley online library as well as the Web search Google Scholar sources. Twelve full text articles were selected and used in this review. RESULTS: 143 articles were found in the database using keywords: PEEK, prosthodontics, dentistry. Data on the suitability of PEEK polymer were organized according to mechanical, chemical, physical properties and PEEK surface preparation. CONCLUSIONS: PEEK polymer is suitable to use in prosthodontics. However, there are not enough statements about complications, biofilm formation on PEEK surface and its resistance to compression. More research should be done to find out the results. PMID- 29243681 TI - Conservative management of large mandibular dentigerous cysts with a novel approach for follow up: Two case reports. AB - BACKGROUND: Dentigerous cysts are odontogenic cysts of the jaws accounting for approximately 24% of all epithelium-lined jaw cysts. Rarely, these cysts can become extremely large causing additional symptoms, while challenging treatment. This article represents a novel approach for radiological treatment follow up of large dentigerous cysts. MATERIAL AND METHODS: Dentigerous cysts were treated by marsupialization, using dedicated obturators and enucleation of the cyst afterwards. Teeth vitality in the lesion was regularly assessed by laser doppler flowmetry, follow-up of lesion regression was accomplished using semi-automatic radiographic analysis of bone healing quantification. RESULTS: Cystic marsupialization by means of the obturator resulted in a number of advantages compared to a conventional approach: lower risk of spontaneous fracture of the mandible, anatomical structure preservation, mandibular canal identification and preservation of tooth vitality as measured by intraoral laser doppler flowmetry. Notwithstanding that a 1-year follow-up panoramic image could not visualize a remnant bone defect nor cystic lesion recurrence, 3D-CBCT based semi-automated bone quantification could only demonstrate an increase of 46% of mineralized bone volume one year after surgery. Bone healing typically occurred starting from the periphery of the original lesion towards the inner core. CONCLUSIONS: The presently reported cystic marsupialization was useful as a preliminary treatment for subsequent enucleation. 3-D CBCT based objective quantification of the bone volume and healing can provide new insights in lesion healing in general and more particular in the outcome of specific diagnostic and therapeutic challenges. PMID- 29243682 TI - Orthodontic-surgical treatment: electromyographic and kinesiographic evaluation in follow up period. Experimental study. AB - INTRODUCTION: The aim of this study was to investigate muscular function and mandibular kinesiology of patients undergoing orthodontic-surgical treatment by electromyography and kinesiography. Electromyographic evaluation is essential to estimate masticatory forces in patients undergoing combined surgical-orthodontic treatment. MATERIALS AND METHODS: 60 patients referred for orthodontic surgical treatment were included in the study, 43 patients presented a class III while 17 presented a class II. The patients underwent electromyographic and kinesiographic examinations during all the therapeutic orthodontic-surgical phases. RESULTS: The relationship between fundamental electromyographic values and age, weight, asymmetry and activation was weak. A strong and positive relationship was observed between the relaxation percentage after TENS (transcutaneous electrical neuromuscular stimulation), the steepness of the post-surgery rehabilitation curve, the initial POC (percentage overlapping coefficient), and for the values in microvolts of the right and left temporal and masseters at the beginning of treatment. CONCLUSIONS: Patients with dentofacial deformities corrected by surgical treatment, have a significant positive treatment outcome in respect of masticatory activity and performance electromyographic evaluation on, before, during and follow up period of the analized patients permit to underline that this examination can predict long term stability. PMID- 29243683 TI - The comparison of cement- and screw-retained crowns from technical and biological points of view. AB - OBJECTIVE: The aim of this review was to evaluate the most common complications in implant prosthodontics with porcelain-fused-to-metal crowns, to evaluate the influence of biomechanical properties on fractures and cracks of veneered porcelain, and to compare the effects of crowns with different connections on soft tissues. MATERIAL AND METHODS: A search of literature in the English language between 2009 and 2015 was conducted using the following databases: Medline via PubMed, Science Direct, Wiley online library, Taylor& Francis, and Cochrane library. In total, 10 studies that met the inclusion criteria were found. RESULTS: Four investigations showed that technical complications more often occurred in screw-retained prostheses, although two studies concluded that cement-retained crowns were also susceptible to technical complications. Two investigations showed that the deeper the abutment margin was subgingivally, the more excess cement was left in the peri-implant sulcus. Four studies concluded that cement-retained prostheses were more susceptible to biological complications, but two investigations also showed that biological complications were observed in tissues adjacent to screw-retained crowns. CONCLUSIONS: The research of literature data for the last five years showed that screw-retained crowns demonstrated more failures such as porcelain cracks and fractures or screw loosening, while cement-retained crowns caused more severe biological complications such as peri-implant soft tissue inflammation or pathological bone resorption. PMID- 29243684 TI - Large oral ulcer of tongue related to dental trauma. AB - A 36-year-old Philippine male has a several month-history of burning pain of his tongue with lingual erythema and oral bleeding. Here we describe a classical case of oral chronic ulcer related to mechanical dental trauma. In this case, unilateral crossbite malocclusion was able to produce oral mucosal lesion that was sufficient to cause a large, chronic tongue ulcer and subsequent mild epithelial dysplasia. A specific tongue-retaining device was made. In absence of dental trauma, his chronic ulcer of the tongue resolved within a few weeks. This case suggests evidence on the direct relationship between chronic oral trauma and the potential occurrence of a dysplastic process. PMID- 29243685 TI - The efficacy of short (6 mm) dental implants with a novel thread design. AB - OBJECTIVE: To assess efficacy of short (6 mm) implants with a novel macrostructure and thread design placed in a compromised bone situations of edentulous posterior regions of maxilla (3-4 mm of bone height under sinus floor) as compared to results of clinical situations treated with simultaneous maxillary sinus grafting and placement of long (>=10 mm) implants of the same company. STUDY DESIGN: Clinical cases of conducted clinical study. PATIENTS AND METHODS: Patients with compromised bone height in edentulous posterior regions of maxilla were randomly divided into two groups. Short (6mm length) implant treatment conducted in the test group and simultaneous sinus lift with standard length implant placement treatment in the control group. RESULTS: In general implant stability quotient (ISQ) and marginal bone level (MBL) changes values in both groups were comparable. However, significant negative correlation was found between implant's diameter and MBL changes. CONCLUSIONS: Implant's length has little if none impact on initial implant anchorage, especially in greatly compromised residual bone situations. Results have confirmed that implant initial stability mainly depends on implant's macro-design and further its development on implant's micro-design: namely, implant diameter rather than length, tapered shape and improved thread design determines primarily acquired mechanical anchorage, while bioactive surface treatment ensures development of biological stability. PMID- 29243686 TI - Bone augmentation and simultaneous soft tissue thickening with collagen tissue matrix derivate membrane in an aesthetic area. A case report. AB - Aesthetic implant restoration in the anterior maxilla is a challenge for clinicians. Alveolar ridge and surrounding gingiva deficiencies aggravates implant placement in the aesthetic area. This case report describes a technique for aesthetic single implant placement with simultaneous bone grafting and soft tissue thickening. At the time of implant surgery, allogenic (Maxgraft, Botiss Biomaterials, Germany) and xenogenic bone substitute (Cerabone, Botiss Biomaterials, Germany) was used for bone grafting, soft tissues were augmented simultaneously with collagen tissue matrix derivate membrane (Mucoderm, Botiss Biomaterials, Germany). After 4 months during second stage surgery the implant was exposed. Subsequently healing abutment was replaced with provisional crown for gingival contouring. An individual zirconia abutment was made and a cemented full-ceramic crown was placed for final restoration. The 12-month follow-up check up revealed a pleasing aesthetic treatment outcome, as well as clinically healthy peri-implant soft tissues. Radiological examination showed a stable bone crest with minor bone remodelling around the implant platform. The use of an collagen tissue matrix derivate, simultaneously with GBR, in the aesthetic area can provide excellent results, by establishing and maintaining facial bone wall and thick soft tissue in aesthetic area. PMID- 29243687 TI - Sutureless valves and the quality of perfusion: towards a goal directed aortic valve replacement. AB - BACKGROUND: Aim of this study was to assess the potential differences in respecting the principles of goal-directed perfusion between aortic valve replacement with sutureless vs. conventional stented bioprostheses. METHODS: Data from 94 consecutive patients undergoing aortic valve replacement with Perceval sutureless valve, with or without concomitant coronary artery bypass grafting, were compared to a contemporary cohort of 116 patients receiving conventional stented bioprostheses. Propensity score matching was used to reduce selection bias. Flow-dependent estimate of oxygen delivery and carbon dioxide production were compared in accordance to the principles of goal directed perfusion. Hospital outcomes were assessed as well. RESULTS: Propensity score matching resulted in 39 pairs with similar characteristics and operative risk. Cross clamping time (41.6+/-20.6 vs. 89.6+/-48.2; P<0.001) and cardiopulmonary bypass time (66.9+/-29.4 vs. 121.2+/-56.6, P<0.001) were shorter in Perceval patients. Flow-dependent parameters were significantly better in Perceval patients (peak VCO2i P=0.010; nadir VO2i P=0.035; nadir DO2i/VCO2i P=0.015; peak RQ P=0.020) and therefore goal-directed perfusion principles were met more frequently (all P<0.001). Peak lactates were higher in controls (P=0.001), as well as number of patients receiving transfusions during CPB (P=0.044). QualyP Score was also higher in controls (P<0.001). Perceval patients experienced reduced postoperative bleeding, had a lower incidence of surgical revisions and transfusions. Duration of ventilation was longer in controls. CONCLUSIONS: The use of sutureless valves significantly reduces cardiopulmonary bypass and cross-clamping times and contributes to achieve a goal-directed perfusion. This results in better perfusion quality, with a positive clinical impact. PMID- 29243690 TI - Clinical examination & record-keeping: Part 2: History taking. AB - This article is the second part of a BDJ series of Practice papers on the subject of clinical examination and related record keeping. The series is taken from the Faculty of General Dental Practice UK (FGDP[UK]) 2016 Good Practice Guidelines book on this topic, edited by A. M. Hadden. This particular article discusses history taking, where information may be gathered prior to the patient seeing the clinician or, in some cases, this may be carried out chairside by the individual. The information gathered can include a medical history, socio-behavioural history, and patient anxiety levels. It is important to note that throughout this article (and the BDJ series and associated FGDP[UK] book), the specific guidelines will be marked as follows: A: Aspirational, B: Basic, C: Conditional. Further information about this guideline notation system is provided in Part 1 of this series ( 2017; 223: 765-768). PMID- 29243693 TI - Can poor oral health lead to dementia? AB - Evidence Summary: The relationship between oral health and dementia. PMID- 29243695 TI - Dental notation: A case of the craftsman. PMID- 29243697 TI - Say it right. AB - Patient understanding of commonly used oral medicine terminology. PMID- 29243698 TI - Erratum. PMID- 29243701 TI - Perspectives: 'Patient reassurance is paramount'. PMID- 29243703 TI - Notices: Obituaries. PMID- 29243704 TI - Peter Dyer: 'There is a big challenge in deciding how we fund clinical care'. PMID- 29243705 TI - Author Q&A: Andrew Sturrock. AB - To find out more about work being carried out looking at the feasibility of oral health promotion using community pharmacists, we spoke to Dr Andrew Sturrock from the University of Sunderland about his recent BDJ paper. If you are interested in learning even more why not read Stephen Hancocks' summary of the paper here: http://go.nature.com/2B8mqG8 or the full paper at http://go.nature.com/2BkamTi. PMID- 29243708 TI - Again and again and will it be again? PMID- 29243709 TI - Dental professionals urged to #keepantibioticsworking. PMID- 29243711 TI - JCVI defers decision on HPV. PMID- 29243713 TI - The GDC - a law unto itself? AB - The following two pieces are published here to help highlight the parlous state of affairs between the British Dental Association ([BDA] the dental profession) and its regulator, the General Dental Council (GDC). The first piece by Mick Armstrong details the background to one of the letters he sent to Mr William Moyes, Chair of the GDC and provides a link to rest of the lengthy correspondence. The second piece by BDA Chief Executive Peter Ward questions how autonomous the GDC can actually be under the law and asks whether such a body is in fact acting without the law. PMID- 29243719 TI - Event report: 'A heart-warming and truly humbling experience'. PMID- 29243716 TI - Oral surgery II: Part 5. Chronic orofacial pain. AB - Chronic orofacial pain syndromes represent a diagnostic challenge for any practitioner. Patients are frequently misdiagnosed or attribute their pain to a prior event such as a dental procedure, ENT problem or facial trauma. Psychiatric symptoms of depression and anxiety are prevalent in this population and compound the diagnostic conundrum. Treatment is less effective than in other pain syndromes and thus often requires a multidisciplinary approach to address the many facets of these conditions. PMID- 29243717 TI - Minimal intervention dentistry: Greatly worried. PMID- 29243725 TI - Alternative sugars: Lactose (milk sugar). PMID- 29243727 TI - Stickers are so 2016! AB - What reward does a child prefer for behaving well at the dentist? PMID- 29243729 TI - Special feature: 'Patients should be given the necessary support'. PMID- 29243732 TI - Dentists on film: The Man Who Knew Too Much. PMID- 29243734 TI - Chemically synthesized histone H2A Lys13 di-ubiquitination promotes binding of 53BP1 to nucleosomes. PMID- 29243735 TI - Orbital decompression for thyroid eye disease: methods, outcomes, and complications. AB - PurposeTo determine the safety and effectiveness of orbital decompression for thyroid eye disease (TED) in our unit. To put this in the context of previously published literature.Patients and methodsA retrospective case review of all patients undergoing orbital decompression for TED under the care of one orbital surgeon (SMS) between January 2009 and December 2015. A systematic literature review of orbital decompression for TED.ResultsWithin the reviewed period, 93 orbits of 55 patients underwent decompression surgery for TED. There were 61 lateral (single) wall decompressions, 17 medial one-and-a-half wall, 11 two-and-a half wall, 2 balanced two wall, and 2 orbital fat only decompressions. For the lateral (single) wall decompressions, mean reduction in exophthalmometry (95% confidence interval (CI) was 4.2 mm (3.7-4.8), for the medial one-and-a-half walls it was 2.9 mm (2.1-3.7), and for the two-and-a-half walls it was 7.6 mm (5.8-9.4). The most common complications were temporary postoperative numbness (29% of lateral decompressions, 17% of other bony decompressions, OR 0.50, 95% CI 0.12-2.11) and new postoperative diplopia (9% of lateral decompressions, 39% of other bony decompressions, OR 6.8, 95% CI 1. 5-30.9). Systematic literature searching showed reduction in exophthalmometry for lateral wall surgery of 3.6 4.8 mm, with new diplopia 0-38% and postoperative numbness 12-50%. For other bony decompressions, reduction in exophthalmometry was 2.5-8.0 mm with new diplopia 0 45% and postoperative numbness up to 52%.ConclusionDiffering approaches to orbital decompression exist. If the correct type of surgery is chosen, then safe, adequate surgical outcomes can be achieved. PMID- 29243737 TI - Clinical outcome of Descemet stripping automated endothelial keratoplasty in 18 cases with iridocorneal endothelial syndrome. AB - PurposeTo evaluate the clinical outcome of Descemet stripping automated endothelial keratoplasty (DSAEK) in eyes with iridocorneal endothelial (ICE) syndrome.Patients and methodsA retrospective case series study was conducted. Eighteen consecutive Chinese patients with 20 DSAEK grafts were enrolled. Participants were evaluated by anterior segment optical coherence tomography and confocal microscopy. Postoperative complications, graft survival, endothelial cell counts, corneal thickness, and anterior chamber depth were analysed. A Log rank test in a Kaplan-Meier analysis and a Cox proportional hazard regression were used to analyse potential risk factors of graft failure.ResultsThe mean follow-up duration was 19.0+/-8.6 months. The donors' endothelial cell density (ECD) (cells/mm2) values at 1, 3, 6, 12, 18, and 24 months were 3342.2+/-287.0, 1897.6+/-745.4, 1793.6+/-755.7, 1618.1+/-604.3, 1421.9+/-650.8, 1265.1+/-844.1, and 1148.2+/-1217.8, respectively. Eleven of the 20 grafts exhibited secondary graft failure, with a mean estimated graft survival of 23.4 months. Immediate postoperative complications (air bubble ventilation for elevated intraocular pressure or rebubbling for graft detachment) were more common in eyes exhibiting graft failure (P=0.040). Postkeratoplasty glaucoma surgery emerged as a risk factor of graft failure, with a hazard ratio of 5.174. Eyes with a poor prognosis showed statistically greater central corneal thickness at 1 month, greater graft thickness at 3 months, and a shallower anterior chamber at 6 and 12 months.ConclusionsThe long-term outcome of DSAEK in eyes with ICE syndrome is relatively poor. Immediate postoperative complications, postkeratoplasty glaucoma surgery, thicker corneal parameters, and a shallow anterior chamber were all associated with graft failure. PMID- 29243736 TI - A novel missense mutation in HSF4 causes autosomal-dominant congenital lamellar cataract in a British family. AB - PurposeInherited cataract, opacification of the lens, is the most common worldwide cause of blindness in children. We aimed to identify the genetic cause of isolated autosomal-dominant lamellar cataract in a five-generation British family.MethodsWhole exome sequencing (WES) was performed on two affected individuals of the family and further validated by direct sequencing in family members.ResultsA novel missense mutation NM_001040667.2:c.190A>G;p.K64E was identified in the DNA-binding-domain of heat-shock transcription factor 4 (HSF4) and found to co-segregate with disease.ConclusionWe have identified a novel mutation in HSF4 in a large British pedigree causing dominant congenital lamellar cataract. This is the second mutation in this gene found in the British population. This mutation is likely to be dominant negative and affect the DNA binding affinity of HSF4. PMID- 29243738 TI - Tissue staining for THSD7A in glomeruli correlates with serum antibodies in primary membranous nephropathy: a clinicopathological study. AB - Thrombospondin type-1 domain-containing 7A (THSD7A) is the most recently recognized target antigen in patients with membranous nephropathy. We stained membranous nephropathy biopsies processed in our laboratory for phospholipase A2 receptor and THSD7A over an 18-month period and selected all THSD7A-positive cases for study. Serum samples from most patients were tested by an indirect immunofluorescence assay for the presence of THSD7A antibodies (Euroimmun). A total of 31 patients were diagnosed with THSD7A-associated membranous nephropathy for a prevalence of 2.4% among patients with membranous nephropathy. The patients were most often male (male-to-female ratio of 1.6) with a mean age of 62 years and a mean proteinuria of 9.6 g per day (range 1.1-15.9). Two of the 31 patients had a history of cancer and none were diagnosed with malignancy on follow-up. Serum samples were available at the time of biopsy from 24 patients and all tested positive for antibodies against THSD7A. Conversely, all 20 serum samples from patients with membranous nephropathy who had negative staining for THSD7A were negative for serum reactivity to THSD7A. We conclude that THSD7A tissue staining of kidney biopsies with membranous nephropathy is a sensitive and specific method for the diagnosis of THSD7A-associated membranous nephropathy and it correlates strongly with the serum antibody testing. We also present the clinicopathologic details of the largest cohort to date of THSD7A-associated membranous nephropathy from a single institution. PMID- 29243739 TI - Frozen sections are unreliable for the diagnosis of necrotizing soft tissue infections. AB - Necrotizing soft tissue infections are rare but are associated with high rates of morbidity and mortality. The use of bedside or intraoperative frozen sections has been reported to be associated with faster diagnosis and better outcomes; however, to date no large studies have been published to determine the sensitivity and specificity of frozen sections in this setting. Twenty years of cases suspicious for necrotizing soft tissue infection at a large academic referral center were reviewed, blinded to the final clinical diagnosis (gold standard). Cases were assessed for the number of neutrophils, extent of necrosis, presence of thrombi, bacteria, karyorrhexis, and fibrin, and concordance with permanent sections. A total of 166 cases suspicious for necrotizing soft tissue infection had frozen section slides available for review. Sixty-three cases were clinically determined to be positive and 103 negative. Neutrophils, necrosis, thrombi, bacteria, karyorrhexis, and fibrin were present in both positive and negative cases; however, no histological feature or combination of features was found to be both sensitive and specific for necrotizing soft tissue infection. The combined presence of necrosis and frequent neutrophils was 73% sensitive and 68% specific, with a 58% positive predictive value and 80% negative predictive value. The additional observation of bacteria decreased sensitivity to 32%, whereas raising specificity to 91%, with 69% positive predictive value and 68% negative predictive value. Thirty-two cases (19%) contained findings identified on permanent sections (eg, bacteria) not observed on frozen section slides, highlighting the risk of false negatives owing to technical limitations or sampling errors. Frozen sections in necrotizing soft tissue infections and negative cases may show similar histological findings. Combined with the risk of false negatives, these results suggest that frozen sections are likely to be of limited clinical utility due to lack of sensitivity and specificity, and risk for delayed diagnosis and treatment. PMID- 29243740 TI - Will oncotype DX DCIS testing guide therapy? A single-institution correlation of oncotype DX DCIS results with histopathologic findings and clinical management decisions. AB - Given the increased detection rates of ductal carcinoma in situ (DCIS) and the limited overall survival benefit from adjuvant breast irradiation after breast conserving surgery, there is interest in identifying subsets of patients who have low rates of ipsilateral breast tumor recurrence such that they might safely forgo radiation. The Oncotype DCIS score is a reverse transcription-PCR (RT-PCR) based assay that was validated to predict which DCIS cases are most likely to recur. Clinically, these results may be used to assist in selecting which patients with DCIS might safely forgo radiation therapy after breast-conserving surgery; however, little is currently published on how this test is being used in practice. Our study examines traditional histopathologic features used in predicting DCIS risk with Oncotype DCIS results and how these results affect clinical decision-making at our academic institution. Histopathologic features and management decisions for 37 cases with Oncotype DCIS results over the past 4 years were collected. Necrosis, high nuclear grade, biopsy site change, estrogen receptor and progesterone receptor positivity <90% on immunohistochemistry, and Van Nuys Prognostic Index score of 8 or greater were significant predictors of an intermediate-high recurrence score on multivariate regression analysis (P<0.02). Low Oncotype DCIS scores and low nuclear grade were associated with lower rate of radiation therapy (P<0.008). There were seven cases (19%) with Oncotype DCIS results that we considered unexpected in relation to the histopathologic findings (ie, high nuclear grade with comedonecrosis and a low Oncotype score, or hormone receptor discrepancies). Overall, pathologic features correlate with Oncotype DCIS scores but unexpected results do occur, making individual recommendations sometimes challenging. PMID- 29243741 TI - Impact of copy neutral loss of heterozygosity and total genome aberrations on survival in myelodysplastic syndrome. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases with varying genetic aberrations. Half of MDS patients have normal karyotype, obscuring the underlying condition indicating a need for new markers for improved diagnostics and prognosis. We performed a retrospective review of sequential MDS patients who underwent chromosomal genetic array testing (CGAT) between November 2008 and March 2014. Total Genomic Aberration (TGA) scores, with and without copy neutral loss of heterozygosity (cnLOH), were compared to pathology and clinical data. Of 68 MDS participants, 50 patients (73%) had abnormal CGAT results. 32% showedcnLOH, 41% had no cnLOH but displayed copy number aberration (CNAs). Of 26 patients with normal cytogenetics, 46% had clonal abnormalities by CGAT. Abnormal CGAT results were associated with lower overall survival (P=0.04). Overall survival in patients with TGA above the median (68.6 Mb) was significantly inferior to those below the median (HR=2.9, 95% CI=1.3-6.8, P=0.01). Furthermore, there was an observed association between increased TGA and increased dysplastic lineages (Ptrend=0.003). CGAT studies provide important findings that extend beyond current standard testing. Clinical utility of CGAT includes improved diagnostic yield, correlation of extent of TGA and increased dysplastic features, and survival. PMID- 29243742 TI - Corrigendum: A Comprehensive Infrastructure for Big Data in Cancer Research: Accelerating Cancer Research and Precision Medicine. AB - [This corrects the article on p. 83 in vol. 5, PMID: 28983483.]. PMID- 29243743 TI - Correction: Prognostic and diagnostic significance of lncRNAs expression in cervical cancer: a systematic review and meta-analysis. AB - [This corrects the article DOI: 10.18632/oncotarget.18323.]. PMID- 29243744 TI - Editorial: Antibiotics in dentistry: Be responsible! PMID- 29243745 TI - MBaYB6O12 (M = Rb, Cs): two new rare-earth borates with large birefringence and short ultraviolet cutoff edges. AB - Two new rare-earth borates, MBaYB6O12 (M = Rb, Cs), which are the first reported compounds in M2O-BaO-RE2O3-B2O3 (M = Rb, Cs; RE = rare-earth) quaternary systems, have been discovered through a high-temperature solution method and their structures were determined by single-crystal X-ray diffraction. These two compounds are isostructural with the centrosymmetric space group R3[combining macron] (no. 148) and the fundamental building blocks are the B3O6 groups which are nearly parallel to each other. The spectral measurement shows that the cutoff edges of the two compounds are all down to the deep-ultraviolet (deep-UV) region (below 200 nm). And the experimental birefringence of RbBaYB6O12 and RbBaYB6O12 is about 0.12 at 589 nm. Moreover, first-principles theoretical studies were carried out to gain a better understanding of the structure-property relationships. The calculation results demonstrate that both the compounds have a large birefringence of 0.100 at 589 nm, which corresponds to the experimental value. Both experimental and theoretical studies suggest that MBaYB6O12 (M = Rb, Cs) are potential birefringent materials for UV and deep-UV applications. PMID- 29243746 TI - Supramolecular frameworks based on 5,10,15,20-tetra(4-carboxyphenyl)porphyrins. AB - We have investigated the hydrogen bond-driven assembly of nickel and freebase tetra(carboxyphenyl) and tetra(carboxylatophenyl) porphyrins. When the tetracarboxylates were crystallized with bis(amidinium) species, their crystal structures contained a range of hydrogen bond geometries, and we did not obtain well-ordered networks. Use of a tetrahedral tetra(amidinium) building block yielded a 3D framework material with a PtS topology, which contains only a "paired" hydrogen bonding arrangement. This framework is highly porous, with ~3/4 of the unit cell volume occupied by disordered solvent molecules, although it loses crystallinity upon removal from solvent. Favourable interactions between porphyrin carboxylic acid hydrogen bond donors and bipyridine nitrogen atoms were then used to prepare a stable 2D porphyrin grid-like network. PMID- 29243747 TI - Aggregates of octenylsuccinate oat beta-glucan as novel capsules to stabilize curcumin over food processing, storage and digestive fluids and to enhance its bioavailability. AB - Self-aggregates of octenylsuccinate oat beta-glucan (AOSG) have been verified as nanocapsules to load curcumin, a representative of hydrophobic phytochemicals. This study primarily investigated the stability of curcumin-loaded AOSGs over food processing, storage and digestive fluids. Curcumin in AOSGs showed better stability over storage and thermal treatment than its free form. Curcumin loaded in AOSGs stored at 4 degrees C in the dark exhibited higher stability than that at higher temperatures or exposed to light. Approximately 18% of curcumin was lost after five freeze-thaw cycles. Curcumin in AOSG was more stable than its free form in mimetic intestinal fluids, attesting to the effective protection of AOSG for curcumin over digestive environments. When curcumin-loaded AOSG travelled across mimetic gastric and intestinal fluids, curcumin was tightly accommodated in the capsule, while it rapidly escaped as the capsule reached the colon. Interestingly, the curcumin loaded in AOSG generated higher values of Cmax and area under the curve than did its free counterpart. These observations showed that AOSG is a powerful vehicle for stabilizing hydrophobic phytochemicals in food processing and storage, facilitating their colon-targeted delivery and enhancing their bioavailability. PMID- 29243748 TI - Global minimum profile error (GMPE) - a least-squares-based approach for extracting macroscopic rate coefficients for complex gas-phase chemical reactions. AB - Master equation/Rice-Ramsperger-Kassel-Marcus (ME/RRKM) has shown to be a powerful framework for modeling kinetic and dynamic behaviors of a complex gas phase chemical system on a complicated multiple-species and multiple-channel potential energy surface (PES) for a wide range of temperatures and pressures. Derived from the ME time-resolved species profiles, the macroscopic or phenomenological rate coefficients are essential for many reaction engineering applications including those in combustion and atmospheric chemistry. Therefore, in this study, a least-squares-based approach named Global Minimum Profile Error (GMPE) was proposed and implemented in the MultiSpecies-MultiChannel (MSMC) code (Int. J. Chem. Kinet., 2015, 47, 564) to extract macroscopic rate coefficients for such a complicated system. The capability and limitations of the new approach were discussed in several well-defined test cases. PMID- 29243749 TI - Association between berries intake and cardiovascular diseases risk factors: a systematic review with meta-analysis and trial sequential analysis of randomized controlled trials. AB - The main goal of this work was to clarify the effects of the consumption of berries on cardiovascular disease (CVD) risk factors by performing a systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) statement, followed by a meta-analysis and a trial sequential analysis (TSA) of randomized controlled trials (RCTs). The electronic search was conducted in PubMed, Scopus, SciELO, Web of Science and Cochrane Library between April and June 2016. To be included, RCTs had to report 1 or more of the following outcomes: total cholesterol (TC), HDL-cholesterol (HDL), LDL cholesterol (LDL), triglycerides (TG), blood pressure (BP), C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), vascular cell adhesion molecule-1 (VCAM), intercellular adhesion molecule-1 (ICAM), glucose, insulin, apolipoprotein A-I (Apo A-I) or apolipoprotein B (Apo B). It was observed that the intake of berries reduces TC, LDL, TG, and BP while increasing the level of HDL, suggesting a beneficial effect on the control of CVDs' risk factors. Thus, the intake of berries as nutraceuticals or functional foods could be suggested for the prevention and control of CVDs. PMID- 29243750 TI - Strong up-conversion luminescence of rare-earth doped oxide films enhanced by gap modes on ZnO nanowires. AB - Up-conversion luminescence (UCL) from rare-earth doped oxide (RE) films has great potential for application in fields such as solar cells, bioanalysis, or display technologies. However, the relatively high phonon energy of oxide matrices usually facilitates nonradiative relaxation leading to low UCL efficiency. Herein, we report a three-layer hierarchical structure of Ag/ZnO nanowires (nw ZnO)/RE composite films, which enhances the UCL of rare-earth doped oxide films. An optimization of the geometric structure of the composite films demonstrated an increase of UCL by up to almost two orders of magnitude in Er3+ and Tm3+ doped YbMoO4 films. This UCL enhancement is attributed to the formation of a very strong electric field in the tips of the nw-ZnO creating a highly effective electric field at the composite films, combined with reflection at the silver layer. Furthermore, we use the UCL properties of these novel Ag/nw-ZnO/RE composite films to demonstrate their possible use in ZnO-based photocatalytic processes to enhance the utilization of near-infrared sunlight in these devices. PMID- 29243751 TI - The effect of surfactants on electrohydrodynamic jet printing and the performance of organic field-effect transistors. AB - In this article, we report on the direct writing of multi-walled carbon nanotube (MWCNT) composite inks based on three different surfactants via the electrohydrodynamic (EHD) jet printing technique. All three surfactants, including two types of polymeric surfactants and an ionic surfactant, successfully dispersed the MWCNTs in the ink medium. Although the MWCNT composite with the ionic surfactant could not be printed by the EHD process, the MWCNT composites with polymeric surfactants could be successfully printed using this technique. Furthermore, the printed lines exhibited different electrical and electronic characteristics, depending on the type of surfactant. A large amount of the poly(4-styrenesulfonic acid) (PSS) surfactant was required to disperse the MWCNTs in ethanol, whereas a smaller amount of polymeric Triton X-100 (TX100) was required to obtain a MWCNT composite suspension in distilled water, and therefore, the printed lines of the latter provided higher conductivities. In addition, the surface potential and charge carrier injection properties of the EHD-printed MWCNT lines depended on the type of surfactant in the MWCNT composite. Finally, organic field-effect transistors (OFETs) employing source/drain electrodes based on MWCNT/surfactant composites exhibited opposing electrical characteristics depending on the type of surfactant. The MWCNT/PSS lines showed excellent electrical performance when used as electrodes in p-type OFETs, whereas the MWCNT/TX100 lines exhibited excellent performance when used as electrodes in n-type OFETs. PMID- 29243752 TI - In situ carbon encapsulation of vertical MoS2 arrays with SnO2 for durable high rate lithium storage: dominant pseudocapacitive behavior. AB - Improving the conductivity and charge transfer kinetics is favourable for innovation of sustainable energy devices such as metal oxide/sulfide-based electrodes. Herein, with an intercalation pseudocapacitance effect, an in situ polymerization-carbonization process for novel carbon-sealed vertical MoS2-SnO2 anchored on graphene aerogel (C@MoS2-SnO2@Gr) has enabled excellent rate performance and durability of the anode of lithium ion batteries to be achieved. The integrated carbon layer and graphene matrix provide a bicontinuous conductive network for efficient electron/ion diffusion pathways. The charge transfer kinetics could be enhanced by the synergistic effects between vertical MoS2 nanosheets and well-dispersed SnO2 particles. Based on the crystal surface matching, the ameliorated electric contact between MoS2 and SnO2 can promote the extraction of Li+ from Li2O and restrain the serious aggregation of LixSn. As a result, the improved reversibility leads to a higher initial coulombic efficiency (ICE) of 80% (0.1 A g-1 current density) compared to that of other materials. In particular, with the dominating surface capacitive process, the C@MoS2-SnO2@Gr electrode delivers a stable capacity of 680 mA h g-1 at 2.5 A g-1 for 2000 cycles. Quantitative insight into the origin of the boosted kinetics demonstrated the high pseudocapacitance contribution (above 90%) which leads to the durable high rate Li ion storage. PMID- 29243753 TI - Extracts from the edible seaweed, Ascophyllum nodosum, inhibit lipase activity in vitro: contributions of phenolic and polysaccharide components. AB - A polyphenol-rich extract (PRE) from the edible seaweed, Ascophyllum nodosum, inhibited pancreatic lipase activity in an oil-based turbidimetric assay with an IC50 of 200 MUg gallic acid equivalents (GAE) perassay) [~230 MUg DW] whereas the known inhibitor, Orlistat, gave an IC50 at 0.4 MUg per assay. A phlorotannin enriched fraction (TRF) purified from the PRE was more potent with an IC50 = 60 MUg GAE per assay (~65 MUg DW). When the assay was started by the addition of lipase, both Orlistat and TRF were much less effective which suggests that pre incubation of enzyme and inhibitor improved inhibition. Based on phenol content, water extracts from Ascophyllum were more potent lipase inhibitors than PRE (IC50 ~ 150 MUg GAE per assay). However, this was equivalent to ~580 MUg DW and these extracts contained polysaccharides (e.g. alginate content = 110 MUg mL-1) which may also contribute to inhibition. Indeed, a polysaccharide-enriched fraction obtained by ethanol precipitation gave an IC50 of 1000 MUg DW which was equivalent to 130 MUg GAE and 420 MUg alginate per assay. Therefore a >3 fold increase in alginate content did not markedly improve inhibition. Re precipitation increased alginate content and reduced polyphenol content but lipase inhibition was markedly reduced (i.e. IC50 at ~1100 MUg DW per assay, 700 MUg alginate and 25 MUg GAE). Purifying the polysaccharide fraction by ion exchange removed all phenolics but the IC50 increased to >2500 MUg DW, equivalent to >1970 MUg alginate per assay. In conclusion, polysaccharides and phlorotannins may inhibit lipase in an additive fashion, with phlorotannins apparently more effective in vitro. However, interactions between these components may be important when food products containing this edible seaweed are consumed. PMID- 29243754 TI - Recycling of zincite (ZnO) via uptake of hydrogen halides. AB - Hydrogen halides (HCl/HBr) represent major halogen fragments from the thermal decomposition of halogen laden materials, most notably PVC and brominated flame retardants (BFRs). Co-pyrolysis of halogen-containing solid waste with metal oxides is currently deployed as a mainstream strategy to treat halogen content as well as to recycle the valuable metallic fraction embedded in electric arc furnace dust (EAFD) and e-waste. However, designing an industrial-scale recycling facility necessitates accurate knowledge on mechanistic and thermo-kinetic parameters dictating the interaction between metal oxides and hydrogen halides. In this contribution, we investigate chemical interplay between HCl/HBr and zincite surfaces as a representative model for structures of zinc oxides in EAFD by using different sets of functionals, unit cell size and energy cut-off. In the first elementary step, dissociative adsorption of the HCl/HBr molecules affords oxyhalide structures (Cl/Br-Zn, H-O) via modest activation barriers. Conversion of the oxyhalide structure into zinc halides occurs through two subsequent steps, further dissociative adsorption of HCl/Br over the same surface Zn atom as well as the release of a H2O molecule. Evaporation (or desorption of zinc halide molecules) signifies a bottleneck for the overall halogenation of ZnO. Our simplified kinetic model on the HCl + ZnO system concurs very well with experimentally reported TGA weight loss profiles on two grounds: accumulation of oxyhalides until ~700 K and desorption of ZnCl2 at higher temperatures. The thermo-kinetic and mechanistic aspects reported herein could be useful in the pursuit of a design of a large-scale catalytic upgrading unit that operates to extract valuable zinc loads from EAFD. PMID- 29243755 TI - Efficient skyrmion transport mediated by a voltage controlled magnetic anisotropy gradient. AB - Despite the inefficiencies associated with current-induced spin torques, they remain the predominant mode of skyrmion propulsion. In this work, we demonstrate numerically that skyrmions can be transported much more efficiently with a voltage-controlled magnetic anisotropy (VCMA) gradient. An analytical model was developed to understand the underlying skyrmion dynamics on a track under the VCMA conditions. Our calculations reveal that the repulsive skyrmion-edge interaction not only prevents the skyrmion from annihilating but also generates most of the skyrmion propulsion. A multiplexed array of gate electrodes can be used to create discrete anisotropy gradients over a long distance, leading to the formation of a series of translatable skyrmion potential wells. Due to the strong confining potentials, skyrmions are transported at a 70% higher packing density. Finally, we demonstrated that this form of skyrmion propulsion can also be implemented on almost any 2D geometry, providing improved versatility over current-induced methods. PMID- 29243756 TI - Concise total synthesis of (+)-asperazine A and (+)-pestalazine B. AB - The highly convergent total synthesis of dimeric diketopiperazine alkaloids (+) asperazine A and (+)-pestalazine B is described. A critical aspect of our expedient route was the development of a directed regio- and diastereoselective C3-N1' coupling of complex tetracyclic diketopiperazine components. This late stage heterodimerization reaction was made possible by design of tetracyclic diketopiperazines that allow C3-carbocation coupling of the electrophilic component to the N1' locus of the nucleophilic fragment. The application of this new coupling reaction to the first total synthesis of (+)-asperazine A led to our revision of the sign and magnitude of the optical rotation for the reported structure. PMID- 29243757 TI - Musa paradisiaca inflorescence induces human colon cancer cell death by modulating cascades of transcriptional events. AB - Colorectal cancer (CRC) is one of the leading causes of cancer death, and diet plays an important role in the etiology of CRC. Traditional medical practitioners in many South Asian countries use plantain inflorescence to treat various gastro intestinal ailments. The aim of the present study was to investigate the anticancer effects of extracts of inflorescence of Musa paradisiaca against HT29 human colon cancer cells and elucidate the mechanism of these effects by studying the modulation of cascades of transcriptional events. In vitro assays depicted that methanol extract of Musa paradisiaca inflorescence (PIMET) was cytotoxic to HT29 cells. PIMET induced DNA damage and arrested the cell cycle at the G2/M phase. Expression studies showed that PIMET pretreatment upregulates pro apoptotic Bcl2 and downregulates anti-apoptotic Bax proteins. Different assays showed that the deregulation of pro/antiapoptotic proteins reduces the mitochondrial membrane potential and ATP production; moreover, it enhances cytochrome c release, which triggers the apoptotic pathway, and further cleaves caspase 3 and PARP proteins, resulting in apoptosis. Changes in the protein expression profile of HT29 cells after PIMET treatment were analyzed using mass spectrometry-based proteomics. PIMET treatment significantly altered the expression of HT29 protein; interestingly, X-linked inhibitor of apoptosis protein was also downregulated. Alteration in the expression of this protein has significant effects, leading to HT29 cell death. PMID- 29243758 TI - A convergent synthesis of vinyloxyimidazopyridine via Cu(i)-catalyzed three component coupling. AB - The synthesis of vinyloxyimidazopyridine with complete regio- and stereoselectivity has been achieved by the Cu(i)-catalyzed three-component coupling of 2-aminopyridine, 2-oxoaldehyde and alkyne. This protocol is operationally very simple and has much potential for the synthesis of heteroarylated vinyl ethers from basic chemicals. Steroidal imidazopyridinyl vinyl ether was obtained successfully from ethynylestradiol. PMID- 29243759 TI - An insight into the photodynamic approach versus copper formulations in the control of Pseudomonas syringae pv. actinidiae in kiwi plants. AB - In the last decade, the worldwide production of kiwi fruit has been highly affected by Pseudomonas syringae pv. actinidiae (Psa), a phytopathogenic bacterium; this has led to severe economic losses that are seriously affecting the kiwi fruit trade. The available treatments for this disease are still scarce, with the most common involving frequently spraying the orchards with copper derivatives, in particular cuprous oxide (Cu2O). However, these copper formulations should be avoided due to their high toxicity; therefore, it is essential to search for new approaches for controlling Psa. Antimicrobial photodynamic therapy (aPDT) may be an alternative approach to inactivate Psa. aPDT consists in the use of a photosensitizer molecule (PS) that absorbs light and by transference of the excess of energy or electrons to molecular oxygen forms highly reactive oxygen species (ROS) that can affect different molecular targets, thus being very unlikely to lead to the development of microbe resistance. The aim of the present study was to evaluate the effectiveness of aPDT to photoinactivate Psa, using the porphyrin Tetra-Py+-Me and different light intensities. The degree of inactivation of Psa was assessed using the PS at 5.0 MUM under low irradiance (4.0 mW cm-2). Afterward, ex vivo experiments, using artificially contaminated kiwi leaves, were conducted with a PS at 50 MUM under 150 mW cm-2 and sunlight irradiation. A reduction of 6 log in the in vitro assays after 90 min of irradiation was observed. In the ex vivo tests, the decrease was lower, approximately 1.8 log reduction at an irradiance of 150 mW cm-2, 1.2 log at 4.0 mW cm-2, and 1.5 log under solar radiation. However, after three successive cycles of treatment under 150 mW cm-2, a 4 log inactivation was achieved. No negative effects were observed on leaves after treatment. Assays using Cu2O were also performed at the recommended concentration by law (50 g h L 1) and at concentrations 10 times lower, in which at both concentrations, Psa was efficiently inactivated (5 log inactivation) after a few minutes of treatment, but negative effects were observed on the leaves after treatment. PMID- 29243760 TI - Augmenting static and dynamic mechanical strength of carbon nanotube/epoxy soft nanocomposites via modulation of purification and functionalization routes. AB - A detailed experimental investigation was carried out to establish the relationship between CNT purification and functionalization routes and the average response of CNT/epoxy nanocomposites under static and dynamic loading. It was shown that the relative improvement in the mechanical properties of the epoxy matrix due to the addition of CNTs depends on the choice of purification and functionalization steps. A better dispersion of CNTs was recorded for the functionalized CNTs as compared to the oxidized and CVD grown CNTs. Moreover, tensile, 3-point bending and nanoDMA testing performed on nanocomposites processed with CVD-grown, oxidized and functionalized CNTs revealed that COOH functionalization after the oxidation of CNTs at 350 degrees C is the optimized processing route to harness the excellent properties of CNTs in CNT/epoxy nanocomposites. PMID- 29243761 TI - High-valent nitridorhenium(v) complexes containing PNP ligands: implications of ligand flexibility. AB - The synthesis of (PNP)Re(N)X (PNP = [2-P(CHMe2)2-4-MeC6H3]2N, X = Cl and Me) complexes is described. The methylnitridorhenium complex 3 was found to react differently with CO and isocyanides, leading to the isolation of a Re(v) acyl complex 4 and an isocyanide adduct 6. Two parallel pathways were observed for the reaction of 3 with CO: (1) CO inserts into the Re-Me bond to afford 4, and (2) 3 isomerizes by distortion of the aryl backbone of the PNP ligand to afford the isomer 3'. This is followed by the reaction of 3' with CO to afford the tricarbonyl complex 5, which was fully characterized. The contrasting reaction of 3 with 2,6-dimethylphenyl isocyanide lends further support for the proposed isomerization pathway. DFT (M06) calculations suggest that insertion of CNR into the Re-Me bond (27.2 kcal mol-1) is inaccessible at room temperature. Instead the substrate adds to the metal center via the most accessible face i.e. syn to the rhenium-nitrido bond, to afford 6. The addition of CO to isomer 3' is proposed to proceed with a similar mechanism to 2,6-dimethylphenyl isocyanide. PMID- 29243763 TI - I2 catalyzed access of spiro[indoline-3,4'-pyridine] appended amine dyad: new ON OFF chemosensors for Cu2+ and imaging in living cells. AB - An easy access to an amine-appended spiro[indoline-3,4'-pyridine] ON-OFF chemosensor by a one-pot four-component reaction using commercially available and an environmentally benign catalytic amount of molecular I2 (10 mol%) in aqueous ethanol at ambient temperature is described. The generated system could be utilized for the selective detection of Cu2+ as it demonstrated a colorimetric naked eye change along with an ON-OFF fluorescence response towards Cu2+ at physiological pH. The sensors exhibited high selectivity for Cu2+ over other common cations with detection limit in the range of 10-7 (M). Notably, this is the first report of a spiro[indoline-3,4'-pyridine] moiety acting as a sensor for Cu2+via a on-off fluorescence response. In addition, the probe system was successfully applied for imaging Cu2+ in human hepatocellular liver carcinoma cells (HepG2), demonstrating a new avenue for molecular imaging and biomedical applications. PMID- 29243762 TI - Mono- and dinuclear Ni(i) products formed upon bromide abstraction from the Ni(i) ring-expanded NHC complex [Ni(6-Mes)(PPh3)Br]. AB - Bromide abstraction from the three-coordinate Ni(i) ring-expanded N-heterocyclic carbene complex [Ni(6-Mes)(PPh3)Br] (1; 6-Mes = 1,3-bis(2,4,6-trimethylphenyl) 3,4,5,6-tetrahydropyrimidin-2-ylidene) with TlPF6 in THF yields the T-shaped cationic solvent complex, [Ni(6-Mes)(PPh3)(THF)][PF6] (2), whereas treatment with NaBArF4 in Et2O affords the dimeric Ni(i) product, [{Ni(6-Mes)(PPh3)}2(MU Br)][BArF4] (3). Both 2 and 3 act as latent sources of the cation [Ni(6 Mes)(PPh3)]+, which can be trapped by CO to give [Ni(6-Mes)(PPh3)(CO)]+ (5). Addition of [(Et3Si)2(MU-H)][B(C6F5)4] to 1 followed by work up in toluene results in the elimination of phosphine as well as halide to afford a co crystallised mixture of [Ni(6-Mes)(eta2-C6H5Me)][B(C6F5)4] (4), and [6MesHC6H5Me][B(C6F5)4]. Treatment of 1 with sodium salts of more strongly coordinating anions leads to substitution products. Thus, NaBH4 yields the neutral, diamagnetic dimer [{Ni(6-Mes)}2(BH4)2] (6), whereas NaBH3(CN) gives the paramagnetic monomeric cyanotrihydroborate complex [Ni(6-Mes)(PPh3)(NCBH3)] (7). Treatment of 1 with NaOtBu/NHPh2 affords the three-coordinate Ni(i) amido species, [Ni(6-Mes)(PPh3)(NPh2)] (8). The electronic structures of 2, 5, 7 and 8 have been analysed in comparison to that of previously reported 1 using a combination of EPR spectroscopy and density functional theory. PMID- 29243764 TI - Aqueous dispersions of lipid nanoparticles wet hydrophobic and superhydrophobic surfaces. AB - Efficient delivery of aqueous sprays to hydrophobic surfaces is the key technological challenge in a wide variety of applications, including pesticide delivery to plants. To account for losses due to bouncing of pesticide sprays off hydrophobic leaf surfaces, a large excess of pesticide is typically employed, resulting in environmentally hazardous run-offs that contaminate soil and ground water. We demonstrate that aqueous dispersions of glycerol monooleate nanoparticles, called cubosomes, wet hydrophobic and superhydrophobic surfaces and adhere to them. Cubosomes comprise glycerol monooleate lipid molecules self assembled into a double diamond cubic phase, that form stable aqueous dispersions that are sterically stabilized using amphiphilic block copolymers. We use high speed imaging to monitor the spreading and retraction of aqueous drops impinged on model hydrophobic substrates and on superhydrophobic lotus leaves. We show that cubosomes diffuse to hydrophobic substrates and reorganize to form a thin, ~2 nm adsorbed lipid layer during the millisecond time scales that characterize drop impact. This adsorbed film drastically reduces the water contact angle, transforming the hydrophobic surface to hydrophilic, thus facilitating retention of the aqueous drop on the surface. Aqueous drops of cubosomes impinged at low velocities on inclined natural superhydrophobic lotus leaf surfaces do not roll off, unlike drops of water or surfactant solutions. When sprayed on inclined lotus leaves, corresponding to the case of high velocity drop impingement, cubosome dispersions form a continuous wetting film. Our results have important implications for efficient, environment-friendly delivery of pesticide sprays. PMID- 29243765 TI - Colloidal particles for the delivery of steroid glycosides. AB - Water insoluble bioactive molecules with very high melting temperature and low solubility in water are difficult to formulate in food products. We demonstrate the synthesis of nanoscale particles from steroid glycosides using a facile liquid antisolvent precipitation method in the presence of various food grade stabilizers. Colloidal particles with sizes well below 200 nm are prepared from steroid glycosides containing extracts, as well as mixtures with phytosterol. In the mixtures, the formation of the typical for the phytosterol rod-like particles is suppressed. Particle size and structure are investigated by electron microscopy and dynamic light scattering. Due to the presence of surface charge and steric stabilization, colloidal particles do not display aggregation and are stable for a period of longer than one year. The results of this study are important for the formulation and delivery of steroid glycoside and phytosterol bioactive molecules in the fields of food, nutraceuticals, and medical applications. PMID- 29243766 TI - Crystalline and permanently porous porphyrin-based metal tetraphosphonates. AB - The new porphyrin-based tetraphosphonic acid (Ni-H8TPPP) was employed in the synthesis of four isostructural MOFs of composition [M(Ni-H6TPPP)(H2O)], denoted CAU-29 (M = Mn, Co, Ni, Cd). Ni-CAU-29 was thoroughly characterized regarding its thermal and chemical stability as well as for proton conductivity. PMID- 29243767 TI - A novel bismuth-based anode material with a stable alloying process by the space confinement of an in situ conversion reaction for a rechargeable magnesium ion battery. AB - A novel Bi-based anode material with a stable alloy reaction is prepared by a solvothermal method. The Mg storage mechanism is elucidated for the first time. Owing to the space confinement of in situ conversion, the anode material shows superior magnesium storage performance, especially the cycling stability (capacity retention >96% after 100 cycles). PMID- 29243768 TI - Rapidly Growing Nodule on the Finger of a 20-year-old Woman: A Quiz. PMID- 29243769 TI - Indeterminate Cell Histiocytosis Presenting with Leonine Facies. PMID- 29243770 TI - Adipose-derived stem cells in articular cartilage regeneration: current concepts and optimization strategies. AB - Knee osteoarthritis (KOA) is the most common progressive joint disorder associated with disability in the world. As a chronic disease, KOA has multifactorial etiology. However, the poor self-healing ability of the articular cartilage due to its intrinsic tissue hypovascularity and hypocellularity seems to be directly incriminated in the physio-pathological mechanism of KOA. While conventional therapies result in unfavorable clinical outcomes, regenerative cell therapies have shown great promise in articular cartilage regeneration. Adipose derived stem cells (ASCs) appear to be an ideal alternative to bone-marrow derived stem cells (BMSCs) and autologous chondrocytes, due to their lower immunogenicity, richer source and easier acquisition. Since the first case report in 2011, ASCs have demonstrated safety and efficacy for articular cartilage regeneration in several phase I/II clinical trials. However, different levels of abnormality were found in the regenerated cartilage for most of the patients. A large portion of recent publications investigated different optimization strategies to improve the therapeutic function of ASCs, including cell source selection, preconditioning and co-delivery. Herein, we give an update on the latest research progress on ASCs, with a focus on the most promising optimization strategies for ASC-based therapy. PMID- 29243771 TI - Role of Bcl-2 and Bax in parotid gland atrophy. AB - OBJECTIVE: To investigate the expression and correlation of B-cell lymphoma-2 (Bcl-2) and Bax in the parotid gland after leading duct ligation in rat. MATERIALS AND METHODS: Atrophy of the right parotid was induced by ligating the right Stensen's duct of rats. Immunohistochemical labeling was performed to study the changes in number and distribution of Bcl-2 and Bax in each step of glandular atrophy, and every group at 1, 3, 5, 7, 14, 21, 30, 60, 90, 150, 180 days after ligation. RESULTS: Bcl-2 and Bax showed a low level of expression in normal glandular tissues. At different time points after the ligation of the main duct, Bcl-2 was highly expressed in the duct cells, and the absorbance value reached a peak value at 21-day (3.02+0.10). The 1 D expression of Bax was found in some of the cells in the 3 D, and the expression of Bax reached the peak (1.99+0.10), and the expression of Bcl-2 and Bax were decreased in some cells. Bcl-2/Bax ratio increased at 1 day-21 day, and then decreased and stabilized. CONCLUSIONS: The expression of Bax and Bcl-2 after ligation of the parotid gland is closely related to the process of the parotid gland atrophy. PMID- 29243772 TI - Treating ureteric obstruction secondary to gynecological disease assisted with retrograde ureteroscopic stenting. AB - OBJECTIVE: To analyze the technical experience and clinical efficacy of ureteroscopic treatment of middle and lower ureteral obstruction due to gynecological disease. PATIENTS AND METHODS: From January 2007 to December 2015, 58 cases of ureteral obstruction were collected in 55 patients caused by gynecological factors. 19 cases had the history of gynecological iatrogenic injury and 39 cases were secondary to gynecological tumors. Different situations of luminal stenosis included obliteration, suture penetration, transection and unrecognized ureteral orifice. The ureteral stents were retrogradely placed ureteroscopically assisted by holmium laser or transurethral plasma kinetic resection. RESULTS: A total of 51 cases of operations were completed successfully by one-stage ureteroscopic stenting with the mean operation time of 33.5 min. No severe complications were observed. The serum creatinine two weeks after operation had a significant decline compared with that of preoperation (p<0.05). The mean follow-up time was 5.3 months. 44 cases with successful stent placement showed nice improvement of hydronephrosis by ultrasound. CONCLUSIONS: Ureteroscopic stent placement with the use of holmium laser or plasma kinetic resection device, has good clinical effects, which provides a relatively simple and minimal-invasive treatment option to resolve middle and lower ureteral obstruction caused by complex gynecological factors. PMID- 29243773 TI - Evaluation of maxillary sinus septa: a retrospective clinical study with cone beam computerized tomography (CBCT). AB - OBJECTIVE: To determine the prevalence, height, location, orientation, and type of maxillary sinus septa in atrophic, non-atrophic, and partially atrophic maxillary segments using cone beam computerized tomography (CBCT). PATIENTS AND METHODS: This cross-sectional study was conducted on a retrospective evaluation of CBCT images of 1000 maxillary sinus with 500 subjects from December 2009 to December 2012. The differences among gender, left and right side of maxillary sinus, type of crest and feature of septa were statistically analyzed. RESULTS: A total of 297 septa was recorded in 1000 maxillary sinuses (29.7%) with a mean height was 4.62+/-2.50 mm. Forty-four (8.7%) septa were located in the anterior area, 123 (24.5%) in the middle area, and 131 (26.4%) in the posterior area. Seventy maxillary sinus septa (26.1%) were observed with a mediolateral type orientation. There were no significant differences between all features of maxillary sinus septa and gender or type of crest. The only significant association identified was between type of crest and type of septa. CONCLUSIONS: The maxillary sinus septa exhibited variable characteristics according to orientation and type of crest. CBCT analysis is very important and should be performed before maxillary sinus surgery to prevent possible complications. PMID- 29243774 TI - Clinical significance of long non-coding RNA EWSAT1 as a novel prognostic biomarker in osteosarcoma. AB - OBJECTIVE: Long non-coding RNA EWSAT1 (EWSAT1) has been identified as a tumor promoter in several tumors, but its prognostic values in osteosarcoma have not been reported. The purpose of this study was to explore the association between EWSAT1 expression and prognosis of osteosarcoma patients. PATIENTS AND METHODS: EWSAT1 levels were examined in 176 osteosarcoma tissues and matched normal bone tissues by qRT-PCR analysis. The associations of EWSAT1 expression with clinicopathologic variables were analyzed. The survival curves were calculated by the Kaplan-Meier method. The Cox proportional hazards regression model was used to identify independent prognostic factors with independent prognostic for overall survival (OS) and disease-free survival (DFS). RESULTS: We found that EWSAT1 levels were significantly higher in osteosarcoma tissues compared with matched non-cancerous tissues (p<0.01). The level of EWSAT1 expression was significantly associated with clinical stage (p=0.001) and distant metastasis (p=0.011). Then, Kaplan-Meier analysis showed that high EWSAT1 expression level was associated with poorer OS (p=0.0007) and DFS (p=0.0010). Furthermore, Cox multivariate analyses demonstrated that EWSAT1 expression was an independent prognostic factor for both OS (p<0.001) and DFS (p=0.001) in osteosarcoma patients CONCLUSIONS: Increased EWSAT1 expression was associated with poor outcomes in osteosarcoma patients, and EWSAT1 could serve as a potential unfavorable prognostic biomarker. PMID- 29243775 TI - Independent prognostic Factor of low-expressed LncRNA ZNF667-AS1 for cervical cancer and inhibitory function on the proliferation of cervical cancer. AB - OBJECTIVE: To investigate the expression of long non-coding RNA ZNF667-AS1 in cervical cancer and its effect on the proliferation of cervical cancer cell line, SiHa cells. MATERIALS AND METHODS: The expression level of ZNF667-AS1 from two microarray datasets (GSE63514 and GSE6791) and TCGA (The Cancer Genome Atlas) were selected to analyze the difference between cervical cancer tissues and normal cervical tissues with bioinformatics methods. Then, the prognosis of ZNF667-AS1 was calculated in TCGA. The expression of LncRNA ZNF667-AS1 in 30 normal cervical tissues and 60 cervical cancer tissue samples was explored using qRT-PCR. In addition, analysis of the clinical data found that the expression of LncRNA ZNF667-AS1 was correlated with the total survival, tumor size and International Federation of Gynecology and Obstetrics (FIGO) stage. At last, the proliferative ability was detected by CCK8 and colon formation assay. RESULTS: Search the relevant microarray datasets using the keywords "cervical cancer" and "GPL570" from the Gene Expression Omnibus (GEO) database. Afterwards, two microarray datasets (GSE63514 and GSE6791) were selected to analyze the differentially expressed genes in cervical cancer tissues and normal cervical tissues using bioinformatics methods. The results showed that the expression of LncRNA ZNF667-AS1 in cervical cancer was significantly lower than that in normal cervical tissues. 30 normal cervical tissues and 60 cervical cancer tissue samples were selected to extract total RNA for qRT-PCR experiment, and found that the expression of LncRNA ZNF667-AS1 in cervical cancer tissues was lower than that in normal cervical tissues, which was consistent with that of TCGA. Analysis of the clinical data found that the expression of LncRNA ZNF667-AS1 was correlated with the total survival, tumor size and FIGO stage. Compared with the negative control group, the proliferation ability and cell cloning ability of cells with over-expressed LncRNA ZNF667-AS1 were significantly decreased (p<0.001), indicating that overexpression of ZNF667-AS1 inhibited the proliferation of SiHa cells. CONCLUSIONS: Expression of LncRNA ZNF667-AS1 was significantly lower in cervical cancer tissues, and its expression was negatively correlated with the overall survival, tumor size and FIGO stage. ZNF667-AS1 inhibited the proliferation of cervical cancer cells and was expected to be the biomarker and potential therapeutic target for predicting cervical cancer and determining its prognosis. PMID- 29243776 TI - Hypoxia promotes invasion of retinoblastoma cells in vitro by upregulating HIF 1alpha/MMP9 signaling pathway. AB - OBJECTIVE: The aim of this study is to investigate the effect of hypoxia inducible transcription factors-1alpha (HIF-1alpha)/matrix metalloproteinase 9 (MMP9) signaling pathway on hypoxia triggered invasion in retinoblastoma cell line HXO-RB44. MATERIALS AND METHODS: HXO-RB44 cells were cultured under hypoxia conditions for 24 h. The effect of hypoxia on invasion ability of HXO-RB44 cells was monitored with transwell invasion assay; the mRNA and protein expression levels of HIF-1alpha and MMP9 were detected by Real-time polymerase chain reaction (RT-PCR) and Western blot; luciferase assay was performed to assess the MMP9 regulation by HIF-1alpha, and HIF-1alpha regulation by hypoxia. Furthermore, HIF-1alpha and MMP9 siRNA were used to investigate the effect of HIF-1alpha/MMP9 signaling on hypoxia-induced cell invasion. RESULTS: The results demonstrated that hypoxia could promote HXO-RB44 cells invasion. The mRNA and protein level of HIF-1alpha and MMP9 were upregulated by hypoxia treatment, whereas HIF-1alpha and MMP9 siRNA could reverse these processes. CONCLUSIONS: Hypoxia promotes retinoblastoma cell line HXO-RB44 invasion by activating HIF-1alpha/MMP9 signaling pathway. PMID- 29243777 TI - MiRNA-338-3p regulates cervical cancer cells proliferation by targeting MACC1 through MAPK signaling pathway. AB - OBJECTIVE: Aberrant expression of miR-338-3p has recently involved in the progression and development of various types of malignant tumors, but its role in the progression of cervical cancer remains unknown. This study aims to investigate the role of miR-338-3p/MACC1 axis in the progression of cervical cancer. PATIENTS AND METHODS: MiR-338-3p and metastasis-associated in colon cancer 1 (MACC1) expression was determined in cervical cancer by quantitative real-time PCR (qRT-PCR). We explored the association of miR-338-3p expression with pathology and prognosis in cervical cancer patients. We explored the function of miR-338-3p and MACC1 on cell proliferation. A luciferase reporter assay was conducted to confirm the target gene of miR-338-3p in cervical cancer cells. RESULTS: In the present work, our data showed that the expression of miR 338-3p was substantially decreased in cervical cancer tissues and associated with advanced FIGO stage, lymph node metastasis, depth of cervical invasion and poor overall survival. However, the MACC1 had an opposite expression. Mechanistically, we identified that MACC1 which acted as a functional downstream target for miR 338-3p. Furthermore, overexpression of miR-338-3p decreased expression of MACC1 in cervical cancer cells could significantly inhibit cervical cancer cell proliferation and induce cells apoptosis. Interestingly, miR-338-3p and MACC1 had proven to be involved in the progression of cervical cancer cells by regulating mitogen-activated protein kinase (MAPK) signaling pathway. CONCLUSIONS: Our results suggested miR-338-3p/MACC1/MAPK regulatory pathway play an important role in the progression of cervical cancer. PMID- 29243778 TI - Apatinib resensitizes cisplatin-resistant non-small cell lung carcinoma A549 cell through reversing multidrug resistance and suppressing ERK signaling pathway. AB - OBJECTIVE: To observe the reversal effect of apatinib on the resistance to cisplatin (DDP) of A549/cisplatin (A549/DDP) cells and its relevant mechanism. MATERIALS AND METHODS: A549/DDP cells were treated with the control method, apatinib alone, DDP alone and DDP combined with apatinib. The cell proliferation was detected by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the cell clone formation assay. The cell apoptosis was detected by Hoechst 33258 staining and annexin V and propidium iodide (PI) double labeling. The changes in apoptotic proteins, multidrug resistance protein 1 (MDR1) and extracellular signal-regulated kinase (ERK) signaling pathway proteins in each group after treatment were detected by Western blotting. RESULTS: MTT assay results showed that compared with A549 cells, A549/DDP cells had obvious resistance to DDP. MTT assay and cell clone formation assay revealed that the tumor inhibition rate of the sub-lethal dose of apatinib (10 MUM) combined with DDP was higher than that of DDP alone. The apoptosis detection results indicated that the proportion of apoptotic cells in the apatinib (10 MUM) combined with DDP group was significantly increased. Western blotting results revealed that compared with that in parental A549 cells, the expression level of MDR1 in A549/DDP cells was significantly increased, and the ERK signaling pathway was activated. In the apatinib combined with DDP group, the levels of cleaved caspase 3, cleaved caspase-9 and B-cell lymphoma-2 (Bcl-2)-associated X (BAX) proteins were significantly upregulated, while the level of Bcl-2 proteins was downregulated. Apatinib could inhibit the expression of MDR1 and the activity of the ERK signaling pathway in a dose-dependent manner. CONCLUSIONS: Apatinib can restore the sensitivity of A549/DDP cells to DDP by down-regulating the expression level of MDR1 and inhibiting the activity of the ERK signaling pathway. PMID- 29243779 TI - Effects of NGX6 expression on proliferation and invasion of nasopharyngeal carcinoma cells and survival of patients. AB - OBJECTIVE: To detect the expressions of nasopharyngeal carcinoma-associated gene 6 (NGX6) in nasopharyngeal carcinoma cells and tissues, and to investigate the effects of NGX6 on the proliferation and invasion of nasopharyngeal carcinoma cells and the survival of patients. PATIENTS AND METHODS: The human nasopharyngeal carcinoma cells (HONE1) and immortalized human nasopharyngeal epithelial cells (NP69) were selected and cultured. The mRNA and protein expression levels of NGX6 were detected via quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The expression of NGX6 in HONE1 was up-regulated using the gene transfection technique. Moreover, the effects of NGX6 on the proliferation and invasion capacities of HONE1 were observed via methyl thiazolyl tetrazolium (MTT) assay and Transwell assay. 50 biopsy tissue specimens of nasopharyngeal carcinoma and 20 non-neoplastic nasopharyngeal biopsy tissue specimens were collected, and the immunohistochemical method was used to detect the protein expression of NGX6 in tumor tissues of patients with esophageal carcinoma. Finally, the follow-up data of patients were recorded, Kaplan-Meier method was used for survival analysis, and the difference in survival rates was detected using the Log-rank test. RESULTS: The results of qRT-PCR and Western blot showed that the mRNA and protein expressions of NGX6 in HONE1 were significantly lower than those in nasopharyngeal carcinoma cells (NP69). After the overexpression of NGX6, the protein expression of NGX6 in HONE1 was significantly increased, but the proliferation and invasion capacities of HONE1 were significantly decreased. Besides, the immunohistochemical results revealed that the expression of NGX6 in tumor tissues of patients with nasopharyngeal carcinoma was significantly lower than that in normal tissues; the survival analysis showed that the level of NGX6 was positively correlated with the survival and prognosis of patients with nasopharyngeal carcinoma. CONCLUSIONS: NGX6 is lowly expressed in nasopharyngeal carcinoma, and it can inhibit the proliferation and invasion of nasopharyngeal carcinoma cells, whose expression is positively correlated with the survival and prognosis of patients with nasopharyngeal carcinoma. PMID- 29243780 TI - Long non-coding RNA CRNDE is a novel tumor promoter by modulating PI3K/AKT signal pathways in human gastric cancer. AB - OBJECTIVE: Long non-coding RNA CRNDE (CRNDE) recently emerged as a carcinogenic promoter in various cancers including gastric cancer (GC). However, the functions and molecular mechanisms of CRNDE to GC are still largely unclear. The aim of this study was to investigate the clinical significance and functional mechanisms of CRNDE expression in GC. PATIENTS AND METHODS: The expression of CRNDE was detected by quantitative Real-time PCR (qRT-PCR) in GC specimens and cell lines. The correlation between the CRNDE expression and clinicopathological parameters was investigated. Survival rate was determined with Kaplan-Meier and statistically analyzed with the log-rank method between groups. Subsequently, the significance of survival variables was analyzed using the Cox multivariate proportional hazards model. Then, MTT and Transwell assays were used to assess cell proliferation, migration and invasion capacity. Finally, Western blot analysis was performed to explore the effects of CRNDE knockdown on the PI3K/Akt pathway. RESULTS: We observed that expression of CRNDE was higher in GC tissues and cells compared with the normal gastric tissue and normal gastric cell lines. High expression of CRNDE was correlated with invasion depth (p = 0.006), TNM stage (p = 0.010) and lymph node metastasis (p = 0.005). Furthermore, high CRNDE expression was associated with shorter overall survival (p = 0.0066) of GC patients. Multivariate analysis confirmed that high CRNDE expression was a significant independent predictor of poor survival in GC. In vitro assay indicated that knockdown of CRNDE inhibited cell proliferation, migration and invasion of GC. Finally, the data of Western blot showed that CRNDE exerted its oncogenic role by affecting PI3K/AKT signaling pathways. CONCLUSIONS: Our findings indicate that CRNDE plays an important role in promoting GC progression and may represent a novel prognostic biomarker in GC. PMID- 29243781 TI - A novel screening test for esophageal squamous cell carcinoma: sirtuin-3. AB - OBJECTIVE: Human sirtuin-3, a protein involved in the mediation of tumors, has been shown to be present in malignancies. The goal of this study was to measure serum sirtuin-3 levels in esophageal squamous cancer cells and to determine whether sirtuin-3 may possess predictive value in advanced cases of esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: A total of 130 ESCC patients and 50 healthy control subjects participated to the study. Serum sirtuin 3 levels for all 180 subjects were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Median sirtuin-3 levels were significantly higher in patients with ESCC than in the control subjects. CONCLUSIONS: The presence of considerably elevated levels of sirtuin-3, could be a powerful mediator of advanced ESCC in ESCC patients, suggests that sirtuin-3 may be a useful indicator of the disease. PMID- 29243782 TI - Evaluation of clinical significance of endoglin expression during breast cancer and its correlation with ER and PCNA. AB - OBJECTIVE: The present study is aimed to investigate the expression of Endoglin during breast cancer. Moreover, its clinical pathological significance, as well as correlation with estrogen receptor (ER) and proliferating cell nuclear antigen (PCNA), were also studied. PATIENTS AND METHODS: qRT-PCR and Western blot assays were utilized to study PCNA mRNA, ER, Endoglin and protein expression. Immunohistochemistry analysis was conducted to determine the expression of Endoglin, ER, and PCNA protein in breast cancer tissue and adjacent cancer tissue. The microvascular density (MVD) was indicated by expression of Endoglin protein. The positive cell rate was used to express the protein expression level of ER and PCNA. RESULTS: The mRNA expression levels of Endoglin, ER, and PCNA were significantly elevated in breast cancer tumor tissues in comparison with the cancer-adjacent tissues. The positive expression rates of Endoglin, ER, and PCNA were 69%, 56%, and 73% respectively in breast cancer tumor tissues. Endoglin MVD values in breast cancer tissues and cancer-adjacent tissues were (35.18 +/- 9.57)/mm2 and (7.21 +/- 1.63)/mm2, respectively. The expression of Endoglin protein in breast tumor tissues was positively correlated to lymph node metastasis and TNM stages, but it was not to menopause and tumor size. Endoglin protein was positively correlated to the expression of PCNA protein, but was not correlated to ER expression. CONCLUSIONS: Endoglin protein expression is positively correlated to PCNA protein expression. So, Endoglin MVD in breast cancer tissues has important clinical significance in the assessment of breast cancer prognosis. PMID- 29243783 TI - Research on the nutrition and cognition of high-risk stroke groups in community and the relevant factors. AB - OBJECTIVE: To investigate the prevalence rate of nutritional risk in high-risk stroke groups in community, analyze its influencing factors, and analyze and compare the relationship between nutritional risk or malnutrition assessed by different nutritional evaluation methods and cognitive function, so as to provide the basis and guidance for clinical nutritional assessment and support. PATIENTS AND METHODS: A cross-sectional survey was performed for 1196 cases in high-risk stroke groups in community from December 2015 to January 2017. At the same time, the nutritional status of patients was evaluated using the mini nutritional assessment (MNA) and MNA-short form (MNA-SF), and the cognitive status of patients was evaluated using the mini-mental state examination (MMSE). Moreover, the relevant influencing factors of nutritional risk and MMSE score were analyzed and compared. RESULTS: High-risk stroke groups in community suffered from a high risk of malnutrition. MNA-SF had a higher specificity and lower false positive rate than MNA. Nutritional risk occurred more easily in high-risk stroke groups in community with a history of diabetes mellitus, less physical exercise or light manual labor, daily use of multiple drugs, and higher age. Those with a higher nutritional risk were more prone to cognitive impairment. High-risk stroke groups in community, complicated with hyperhomocysteinemia, daily use of three or more kinds of prescription drugs, and a previous history of stroke, were accompanied by cognitive impairment easily. CONCLUSIONS: MNA-SF can be used for the nutritional screening of high-risk stroke groups in community. For the high-risk stroke groups in community, the rational nutritional diet should be publicized, blood sugar should be controlled in a scientific manner and physical exercise should be moderately increased. PMID- 29243784 TI - Value of immunofluorescence-mediated detection of Ig, C1q, C3, and FRA for the identification and diagnosis of atypical membranous nephropathy. AB - OBJECTIVE: The present study was to investigate the value of immunofluorescence mediated detection of Ig, C1q, C3, and FRA for the identification and diagnosis of atypical membranous nephropathy (AMN). PATIENTS AND METHODS: Fifty-five patients with AMN and 135 patients with idiopathic membranous nephropathy (IMN) diagnosed by renal biopsy in our hospital were consecutively selected. The positive expressions of Ig, C1q, C3, and FRA by immunofluorescence were analyzed. RESULTS: We compared the levels of blood urea nitrogen, creatinine, cystatin C, and 24 h urine protein, and the levels of serum IgA, IgG, IgM, and C3. The differences were not significant (p>0.05). Proportionate increases in glomerular spiky projection formations in patients with AMN were observed by light microscopy, without observation of other pathologic changes. By immunofluorescence, AMN patients showed higher positive rates of deposition of IgA, IgM, C1q, and FRA compared with IMN patients. Comparison of the positive rates of deposition of IgG and C3 showed no differences. By electron microscopy, AMN patients showed higher percentages of mesangial cell and mesangial matrix proliferation. Deposition of electron dense granules was mostly found in subepithelium, inside basement membranes, and in the mesangial area. The comparisons between the two groups showed no differences. CONCLUSIONS: Immunofluorescence-mediated detection of Ig, C1q, C3, and FRA have important application value for the identification and diagnosis of AMN. PMID- 29243785 TI - Induction of proliferation and activation of rat hepatic stellate cells via high glucose and high insulin. AB - OBJECTIVE: To further investigate the occurrence mechanism of diabetic hepatic fibrosis through observing the effects of insulin and glucose in different concentrations on hepatic stellate cell (HSC) proliferation, and mRNA expressions of transforming growth factor-beta1 (TGF-beta1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in rats, so as to provide a theoretical and experimental basis for the occurrence, prevention and treatment of diabetic hepatic fibrosis (HF). MATERIALS AND METHODS: The HSCs in rats were cultured in vitro with high glucose alone and high glucose + high insulin as the stimulating factors and mannitol as the high osmotic pressure control. After the above 10 groups of HSC were cultured for some time, the absorbance value of each group was determined using the Cell Counting Kit-8 (CCK-8) to clarify the number of proliferative HSC. Moreover, the count per minute (Cpm) of DNA in HSC was detected via the 3H-thymidine incorporation (3H-TDR incorporation) to clear the proliferation status of HSC. Finally, the mRNA expressions of TGF-beta1 and TIMP 1 in HSC in each group were detected via Real-time fluorescence quantitative polymerase chain reaction (RT-FQ-PCR). RESULTS: Both HSC proliferation and DNA synthesis were increased in a glucose concentration-dependent manner, while the HSC proliferation and DNA synthesis in glucose groups with insulin were significantly higher than those in glucose groups without insulin (p<0.05). The DNA synthesis in insulin + mannitol group was higher than that in insulin + normal glucose group. The mRNA level in TGF-beta1 in glucose groups with insulin was decreased, but that in TIMP-1 was increased. CONCLUSIONS: Both high glucose and high insulin can induce the HSC proliferation, and high insulin can further activate HSC and promote the progression of hepatic fibrosis course. PMID- 29243786 TI - Spectrum of gastric histopathologies in morbidly obese Turkish patients undergoing laparoscopic sleeve gastrectomy. AB - OBJECTIVE: In this study, we aimed to describe the findings associated with gastric pathology and to identify the prevalence of Helicobacter pylori (H. pylori) in patients undergoing laparoscopic sleeve gastrectomy (LSG). PATIENTS AND METHODS: Gastric specimens of a total of 291 patients (225 females, 66 males; mean age: 42 years; range: 18 to 60 years) who underwent LSG for the treatment of morbid obesity were analyzed. Histopathologic diagnoses and their relation with body mass index (BMI), age and gender were evaluated. RESULTS: In the histopathological examination of sleeve specimens, 58 patients (19.93%) had chronic gastritis, 102 patients (35.05%) had chronic active gastritis, 27 patients (9.27%) had follicular gastritis, 47 patients (16.15%) had active follicular gastritis, one patient (0.34%) had a glomus tumor, and one patient (0.34%) had a gastrointestinal stromal tumor. The gastric mucosa was normal in 55 patients (18.90%). Intestinal metaplasia was detected in eight patients (2.74%). The H. pylori test result was positive in 126 patients (43.29%). There was no statistically significant difference between the pathological diagnoses and age and sex of the patient. CONCLUSIONS: Our study results suggest that the prevalence of chronic active gastritis and H. pylori positivity is high in morbidly obese Turkish patient population. No significant difference was found between the pathological diagnosis in obese patients with LSG operation in terms of age and sex. PMID- 29243787 TI - Atherosclerosis and cardiovascular involvement in celiac disease: the role of autoimmunity and inflammation. AB - OBJECTIVE: The aim of this review is to explore the evidence about the association among celiac disease (CD), atherosclerosis (AS) and cardiovascular (CV) diseases, and the role of inflammation in this connection. MATERIALS AND METHODS: A systematic literature search was conducted using PubMed, EMBASE, and Cochrane Library for the association among CD, AS and CV diseases. RESULTS: Several studies reported the association of CD with accelerated AS, as evidenced by the alterations of a number of parameters indicative of subclinical AS, as increased carotid artery intima-media thickness, endothelial dysfunction and increased arterial stiffness. In addition, recent evidence reported an increase of CV diseases prevalence in CD patients respect to controls, many of which including ischemic diseases as acute myocardial infarction and angina pectoris, as well as death from ischemic heart disease, and, more rarely, stroke for cerebrovascular involvement. Other not-ischemic CV diseases associated with CD are represented by dilated cardiomyopathy, atrial fibrillation, and myocarditis. CONCLUSIONS: On the basis of the reported association among CD, AS and CV diseases, we suggest to perform a more detailed CV risk assessment in all CD patients than what is currently being achieved in clinical practice, in order to scan and treat modifiable CV risk factors in these patients. In particular, we suggest to resort to instrumental techniques to detect AS in the subclinical stage, in order to prevent AS development and CV diseases in CD patients. PMID- 29243788 TI - Evaluation on the impact of spontaneous reperfusion on cardiac muscle of acute myocardial infarction by three-dimensional speckle tracking imaging. AB - OBJECTIVE: To explore the effect of spontaneous reperfusion (SR) on three dimensional myocardial strain in patients with acute anterior myocardial infarction by three-dimensional speckle tracking imaging (3D-STI) technology. PATIENTS AND METHODS: Patients diagnosed with acute anterior myocardial infarction during 2013 to 2016 were consecutively selected and divided into SR group and non-spontaneous reperfusion (Non-SR) group based on whether there was SR. Patients in both groups received direct percutaneous coronary intervention (PCI) in time window. Baseline information, patency rates of culprit vessel, durations of operation, intraoperative non-reflow phenomenon ratios, and thrombolysis in myocardial infarction (TIMI) blood flows after reperfusion of patients in each group were recorded. Hospital stays of patients were compared between the two groups. Before discharge, left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDd) were measured. Global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) of left ventricular (LV) were also detected by 3D-STI, so as to assess movement situations of ventricular wall and cardiac muscle in occlusive blood vessel distribution area. LVEF, LVEDd and various 3D-STI parameters were reexamined and compared one year after discharge. RESULTS: There were no significant differences between the Non-SR group and the SR group regarding the patency rate of culprit vessel, duration of operation, intraoperative non-reflow phenomenon ratio, TIMI blood flow after reperfusion, and LVEDd (p>0.05). Both LVEF before discharge and LV three-dimensional strain indexes of the SR group, were clearly higher than those of the Non-SR group (p<0.05). After one-year follow-up, the SR group had a remarkably lower LVEDd than the Non-SR group (p<0.05). LVEF of the SR group was overtly higher than that of the Non-SR group (p<0.05). LV three-dimensional strain indexes were also distinctly higher in the SR group than in the Non-SR group (p<0.05). There were good correlations between GLS, GRS, GCS and LVEF (r values were -0.620, -0.674 and 0.723, respectively). CONCLUSIONS: SR can improve nosocomial and long-term LV remodeling in patients with acute anterior myocardial infarction, and 3D-STI is able to assess ventricular remodeling after myocardial infarction. PMID- 29243789 TI - Relationship between blood pressure variability and target organ damage in elderly patients. AB - OBJECTIVE: To investigate the relationship between 24 h systolic blood pressure variability (SBPV) and target organ damage in elderly patients with essential hypertension. PATIENTS AND METHODS: 180 elderly patients (>= 80 y) with hypertension admitted to our hospital from January 2015 to January 2017 were selected as hypertension group and divided into high blood pressure variability (BPV) group and low BPV group according to the 50th percentile (P50) of 24 h SBPV, while 90 elderly non-hypertension patients admitted during the same period were enrolled as control group. 24 h ambulatory blood pressure values of patients in the three groups were recorded. The total cholesterol (TC), left ventricular mass index (LVMI), carotid artery intima-media thickness (IMT), 24 h microalbuminuria (MA) and complications with cardiovascular disease in patients of the three groups were compared and analyzed. Logistic analysis was conducted with MA, IMT and LVMI as the dependent variables and the remaining risk factors as the independent variables. RESULTS: 24 h SBPV and daytime SBPV (d SBPV) in patients of the hypertension group were significantly higher than those in the control group (p < 0.01); the incidences of coronary heart disease and atherosclerotic plaque as well as IMT, LVMI and MA were higher in the high BPV group than those in the low BPV group (p < 0.05 or p < 0.01). The multivariate results showed that 24 h SBPV was associated with IMT, LVMI and MA. CONCLUSIONS: BPV can serve as an important indicator to predict target organ damage in elderly patients with essential hypertension. 24 h SBPV can reflect the degree of target organ damage in elderly hypertensive patients. PMID- 29243790 TI - MiR-93 inhibition ameliorates OGD/R induced cardiomyocyte apoptosis by targeting Nrf2. AB - OBJECTIVE: To identify the expression changes of microRNA 93 (miR-93) in oxygen glucose deprivation/reoxygenation (OGD/R) injury in cardiomyocytes and its mechanism of mediating OGD/R and inducing apoptosis. MATERIALS AND METHODS: Primary cardiomyocytes were extracted and OGD/R model in cardiomyocytes was established in vitro. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expressions of miR-93, and Western blot assay was applied to measure the protein levels of nuclear factor erythroid 2 related factor 2 (Nrf2) and caspase-3. Flow cytometry was utilized to examine the cardiomyocyte apoptosis rate. RESULTS: The apoptosis rate was increased after OGD/R in cardiomyocytes, accompanied by remarkable rise of miR-93 expression. After transfection of miR-93 antagomir, the apoptosis rate of cardiomyocyte induced by OGD/R was down-regulated, and the expression of cleaved caspase-3 was decreased. Meanwhile, the results of qRT-PCR and Western blot showed that the levels of Nrf2 mRNA and protein expression were up-regulated after the miR-93 level was inhibited, and luciferase reporter assay affirmed that Nrf2 was a target molecule for OGD/R-induced apoptosis mediated by miR-93. CONCLUSIONS: miR 93 mediates OGD/R-induced hypoxia/reoxygenation injury apoptosis in cells by targeting Nrf2. PMID- 29243791 TI - MiR-181a mediates Ang II-induced myocardial hypertrophy by mediating autophagy. AB - OBJECTIVE: To investigate the relationship between miR-181a and cardiac hypertrophy and autophagy in rats with myocardial hypertrophy, and whether miR 181a regulates the autophagy through ATG5, thereby participating in the occurrence and development of myocardial hypertrophy. MATERIALS AND METHODS: The rat model of myocardial hypertrophy was established via the abdominal aortic coarctation. The expression of miR-181a in cardiac tissues was detected via reverse transcription-polymerase chain reaction (RT-PCR). The expressions of autophagy-related proteins, ATG5 and LC3II/LC3I, in cardiac tissues, were detected via Western blotting (WB). After the primary culture of myocardial cells in rats, they were stimulated via Angiotensin II (Ang II) to observe the effects of autophagy inhibitor 3-methyladenine (3-MA) and overexpression of ATG5 on the expression of hypertrophic genes in myocardial cells, respectively. The expressions of autophagy-related proteins ATG5 and LC3II/LC3I were detected via WB, the autophagic rate was observed via flow cytometry and the changes in autophagic vacuoles of myocardial cells were observed using the transmission electron microscope. The changes in mRNA and protein expressions of ATG in myocardial cells were observed after the overexpression of miR-181a or the inhibition of miR-181a activity. The changes in miR-181a and the expression of hypertrophic genes in myocardial cells after Ang II stimulation were observed via RT-PCR. RESULTS: In rats with myocardial hypertrophy, the cardiac autophagy was increased and the expression of miR-181a in hypertrophic myocardium was downregulated. 3-MA inhibited the ATG5-induced autophagy and improved the Ang II induced myocardial hypertrophy, while the overexpression of ATG5 enhanced the myocardial autophagy and the expression of hypertrophic genes. MiR-181a regulated the ATG5-induced myocardial autophagy, and its downregulation mediated the Ang II induced myocardial hypertrophy. CONCLUSIONS: The enhancement of ATG5-induced myocardial autophagy mediates the Ang II-induced myocardial hypertrophy. ATG5 is the target gene of miR-181a, it can regulate the myocardial autophagy via ATG5, thus mediating the Ang II-induced myocardial hypertrophy. PMID- 29243792 TI - Analysis of correlation between the mild cognitive impairment (MCI) and level of adiponectin in elderly patients with type 2 diabetes mellitus (T2DM). AB - OBJECTIVE: To investigate the correlation between the mild cognitive impairment (MCI) and serum level of adiponectin in elderly patients with Type II diabetes mellitus (T2DM), so as to provide evidence for early diagnosis of MCI and effective evaluation of the impairment of cognitive functions, thereby preventing the impairment of cognitive function as early as possible. PATIENTS AND METHODS: Clinical data were collected from 260 T2DM patients (>= 60 years old) in Endocrine Department and 120 healthy subjects (>= 60 years old) who underwent physical examination in our hospital between June 2015 and June 2017. According to the evaluation results of MCI, these T2DM patients were further divided into the T2DM + MCI group (n = 138) and the T2DM + NMCI group (n = 122). General data, including gender, age, disease history and body mass index (BMI), and the laboratory indexes, including serum adiponectin, fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c) and blood fat, were collected for statistical analysis in T2DM + MCI group, T2DM + NMCI group and healthy control group. RESULTS: Comparisons among T2DM + MCI group, T2DM + NMCI group and healthy control group, showed that the serum level of adiponectin in T2DM + MCI group was significantly lower than those in remaining two groups (p < 0.01). Spearman correlation analysis revealed that score of Montreal Cognitive Assessment (MoCA) was positively correlated with the serum level of adiponectin (r = 0.446, p < 0.01). Multivariate linear regression analysis indicated that education (standard beta = 0.325, p = 0.003), age (standard beta = -0.236, p = 0.016), disease course of hypertension (standard beta = -0.242, p = 0.006), disease course of diabetes mellitus (standard beta = -0.377, p < 0.001) and the level of adiponectin were correlated with the cognitive impairment. The results of itemized assessment in MoCA scale showed that in T2DM + MCI group, the scores in visuospatial and executive abilities, attention, language and orientation were significantly lower than those in other two groups (p < 0.01). As for the delayed recall, the score in T2DM + MCI group was significantly lower than those in other two groups (p < 0.01), while the score in T2DM + NMCI group was lower than that in the healthy control group (p < 0.01); in terms of the naming ability and abstraction, no statistically significant differences were identified among three groups (p > 0.05). CONCLUSIONS: Age, poor education, disease course of hypertension, disease course of diabetes mellitus and a low level of adiponectin in serum are the risk factors in MCI of T2DM patients. Besides, the level of adiponectin in serum of T2DM patients is correlated with the development of MCI; elderly T2DM patients are afflicted by cognitive impairment, mainly in visuospatial and executive abilities, attention, language, delayed recall and orientation. PMID- 29243794 TI - Editorial - Channelopathies: a link between brain and heart: the model of epilepsy. PMID- 29243793 TI - A new antioxidant formulation reduces the apoptotic and damaging effect of cigarette smoke extract on human bronchial epithelial cells. AB - OBJECTIVE: In this study we evaluated the possible protective effect of an antioxidant formulation containing microfiltered milk derived polypeptides, Curcumin, Vitamin B2, Carnitine and N-Acetyl-cysteine (NAC) in an in vitro model of chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Human bronchial epithelial cells (16HBE) were used in this study. Cells were treated for 24 h in the presence or absence of 10% of cigarette smoke extract (CSE) and in the presence or absence of antioxidant formulation. We evaluated cell viability by MTT assay, reactive oxygen species by flow cytometer and quantitative analysis of gene expression by Real-time PCR. RESULTS: The data obtained showed a significant increase of cell viability in CSE-exposed cells and a significant reduction of reactive oxygen species (ROS) production compared to cells treated with only CSE. The antioxidant effects of formulation were confirmed by a decrease of inflammatory cytokines genes IL-1beta, IL-6, TNFalpha, nitric oxide synthase gene (NOS2) and through an induction of antioxidant genes such as heme oxygenase 1 (HO-1), nuclear transcription factor erythroid 2 (NRF2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC 1alpha). CONCLUSIONS: The results suggest that antioxidants combination plays a protective role on oxidative stress and inflammation, in an in vitro model of COPD, activating key genes in response to oxidative stress and decreasing the cytokines responsible for the inflammatory pathways. PMID- 29243795 TI - The effect on clinical results of adding recombinant LH in late phase of ovarian stimulation of patients with repeated implantation failure: a pilot study. AB - OBJECTIVE: To evaluate the efficacy of recombinant LH (r-LH) addition in the late phase of ovarian stimulation in patients with repeated implantation failure (RIF). PATIENTS AND METHODS: 66 infertile couples undergoing ICSI treatment due to male factor were allocated to group A (33) and to group B (33). Group A (29 subjects) received recombinant FSH (r-FSH) supplemented by r-LH in the late follicular phase starting the same day of GnRH-antagonist (GnRH-ant) administration, and group B (32 subjects) received r-FSH alone. All patients were stimulated with a GnRH-ant flexible protocol starting r-FSH on day 2 of a spontaneous or induced cycle. hCG (10000 IU) was administered by intramuscular route when at least 2 follicles reached 18 mm in diameter. RESULTS: Metaphase II (MII) oocytes with cytoplasmic maturation showed a significant difference in the r-LH group (89.02%) compared to the one with FSH alone (81.15%) (p < 0.01). The number of positive pregnancy test, 14 (48.3%) and 8 (25%), was significantly greater in the r-LH group compared to the group treated with r-FSH alone (p < 0.03). The number of gestational sacs was 20 in the r-LH group vs. 9 in the r-FSH group (p < 0.001). The implantation rate was significantly higher in the r-LH group compared to the r-FSH only group (19% vs. 7% respectively; p < 0.01). Also, a lower abortion rate was found in the r-LH group (21% vs. 37.5% respectively - p < 0.01). CONCLUSIONS: Ovarian stimulation should be personalized because it seems that some subgroups of patients, like those with RIF, reach a better clinical outcome with the addition of r-LH in the advanced follicular phase stimulation. PMID- 29243796 TI - Can high levels of D-chiro-inositol in follicular fluid exert detrimental effects on blastocyst quality? AB - OBJECTIVE: It was previously shown that higher concentrations of myo-inositol in human follicular fluid improve oocyte and embryo quality, whereas D-chiro inositol seems to worsen oocyte quality and ovarian response in polycystic ovary syndrome patients. Our study was the first one aiming to test whether different myo-inositol and D-chiro-inositol concentration in follicular fluids correlate with blastocyst quality in healthy young women. PATIENTS AND METHODS: Eight egg donors and eleven couples undergoing in vitro fertilization, were involved in a prospective observational study. Myo-inositol/D-chiro-inositol ratio was calculated in the follicular fluids and associated with different blastocyst grades. Donors were homogeneous and followed the same standard stimulation protocol. RESULTS: The ratio between myo-inositol and D-chiro-inositol was significantly higher in the specimens rated as good quality blastocysts, compared to those rated as poor-quality blastocysts. In this study, almost all the transferred blastocysts were graded as good quality and were correlated to lower D-chiro-inositol content in the follicular fluid; the implantation rate and pregnancy rate were satisfying. Our data suggest that the reduction of such ratio in follicular fluid seems to play a negative role in follicular development. CONCLUSIONS: We found a correlation between myo-inositol/D-chiro-inositol ratio in follicular fluid and blastocyst quality. The value of this ratio may represent a new biomarker for estimating the good features of blastocysts, and a prognostic factor of embryo implantation and pregnancy success. Moreover, the pre-treatment with myo-inositol in women undergoing in vitro fertilization (IVF) may improve oocyte quality and ART outcome. CLINICAL TRIAL REGISTRATION NUMBER: NCT03055442 (ClinicalTrials.gov registry). PMID- 29243797 TI - Rapamycin induces human acute promyelocytic leukemia cell HL-60 autophagic apoptosis. AB - OBJECTIVE: We aimed at investigating the effects of rapamycin on apoptosis and autophagy of human acute promyelocytic leukemia cell line HL-60, and to preliminarily explore the mechanism of extra medullary infiltration of leukemia cells with human acute promyelocytic leukemia cell line HL-60 as the object of study, providing a theoretical basis for the clinical treatment of leukemia. MATERIALS AND METHODS: After HL-60 cells were cultured in vitro, the effect of rapamycin on proliferation ability of HL-60 cells was determined by methyl thiazolyl tetrazolium (MTT) method, the cell apoptosis ratio was detected by flow cytometer, the change of autophagy after HL-60 cells acted by rapamycin was tested by monodansylcadaverine (MDC) fluorescence staining, the mRNA expression of autophagy-related molecule was detected by polymerase chain reaction (PCR), and the expressions of apoptosis-related protein and autophagy-related protein were determined by Western blotting (WB). RESULTS: HL-60 cell proliferation could be significantly inhibited by rapamycin (80 MUg/mL-640 MUg/mL), which was in a dose-dependent manner. HL-60 cell apoptosis ratio and apoptosis-related protein expression were distinctly improved by rapamycin. Cell autophagy level, mRNA expression of autophagy-related molecule and autophagy-related protein expression were remarkably induced by rapamycin. CONCLUSIONS: Rapamycin can induce HL-60 cell apoptosis, which is produced mainly by inducing cell autophagy. PMID- 29243799 TI - Parkinson revealed by a shadow at sunset. PMID- 29243798 TI - Effects of propofol or sevoflurane anesthesia on the perioperative inflammatory response, pulmonary function and cognitive function in patients receiving lung cancer resection. AB - OBJECTIVE: To investigate the effects of propofol and sevoflurane anesthesia on the inflammatory response, pulmonary function and cognitive function of patients undergoing lung cancer resection and their differences. PATIENTS AND METHODS: 62 patients with lung cancer who underwent pulmonary lobectomy from January 2014 to January 2016 in Jining First People's Hospital were selected and randomly divided into two groups: the propofol group (n=31) and the sevoflurane group (n=31). Patients in the propofol group were treated with intravenous injection of propofol for anesthesia maintenance, whereas those in the sevoflurane group inhaled sevoflurane for anesthesia maintenance. All patients underwent surgical resection of the lobes by the same operator. Changes in the inflammatory response and pulmonary function of patients in the perioperative period were recorded before the induced anesthesia (t1), before one-lung ventilation (t2), after sternal closure by operation (t3) and at 24 h after operation (t4), respectively; the extubation time, eye opening time and response time of two groups of patients were recorded; mini-mental state examination (MMSE) was used to evaluate the changes in cognitive function in patients and detect the concentration of S100 calcium-binding protein beta (S100beta) in serum of patients before the induced anesthesia and at 24 h after operation, respectively. RESULTS: The difference of partial pressure of alveolar-arterial oxygen (A-aDO2), respiratory index (RI) and intra-pulmonary shunt fraction (Qs/Qt) of two groups of patients at t2 and t3 were significantly higher than those at t1 (p<0.01); during t2-t3, A-aDO2, RI and Qs/Qt of patients in the propofol group were significantly lower than those of patients in the sevoflurane group (p<0.05); the levels of interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) in serum of patients after the induced anesthesia in the propofol group were significantly higher than those at t1, while the level of interleukin-10 (IL-10) was lower than that at t1 (p<0.01); during t2-t4, the levels of IL-6 and MMP-9 in serum of patients in the propofol group were significantly lower than those in patients in the sevoflurane group, while the level of IL-10 was significantly higher than that in patients in the sevoflurane group (p<0.05). The postoperative extubation time, eye opening time and response time of patients in the propofol group were significantly shorter than those of patients in the sevoflurane group (p<0.05). From intraoperative period to 24 h after operation, the prevalence rate of adverse reactions in patients in the propofol group was significantly lower than that in patients in the sevoflurane group (p<0.05); MMSE scores of two groups of patients at t4 were significantly lower than those at t1, while the concentration of S100beta was significantly higher than that at t1 (p<0.01); at t4, the MMSE score of patients in the propofol group was significantly higher than that in the sevoflurane group, while the concentration of S100beta was lower than that of patients in the sevoflurane group (p<0.05). CONCLUSIONS: Compared with sevoflurane anesthesia, propofol anesthesia can significantly reduce the perioperative inflammatory response in patients receiving lung cancer resection, shorten the recovery time after operation, protect the pulmonary function of patients, improve postoperative cognitive function, and reduce the prevalence rate of intraoperative adverse reactions. PMID- 29243800 TI - Vesicoureteral reflux in infants: what do we know about the gender prevalence by age? AB - OBJECTIVE: Vesicoureteral reflux (VUR) affects up to 1% of Caucasian children. Primary VUR is characterized by failure of the ureterovesicular junction to prevent urine from traveling in a retrograde fashion from the bladder to the ureters and the kidneys. Several reports in the literature describe the prevalence of this condition in pediatric patients; overall, VUR affects more males during infancy and with higher grades. However, a thorough consideration of these articles reveals important contradictions regarding the prevalence by gender and age. We analyzed those contradictions and suggested a possible explanation based on our single center experience with this patient group. In particular, for the age interval 0-2 years: we have found that (1) VUR mostly affects boys; (2) the male/female ratio steadily declines over time; (3) the unequal prevalence between males and females essentially disappears when children reach the age of two years. CONCLUSIONS: The natural history of VUR in infant boys differs from that of infant girls, and therefore requires a gender-specific approach. Available data support the need to redefine the categorization and clinical guidelines for this disease. PMID- 29243801 TI - Adverse reactions to denture resin materials. AB - Irrespective of the new generation of dental materials, acrylates still have a wide indication field. Although they are classified as biomaterials, acrylates can have both local and systemic side effects. The individual components of the acrylic materials may leave the dental restorations and diffuse into saliva. The aim of this study was to point out the potentially toxic components of acrylic dental materials, as well as their possible adverse effects on oral tissues and the organism in general. The paper was based on the assumption that the appropriate selection of the type of acrylic material and the proper method of their preparation reduce their adverse effects to a minimum, which was proven using literature data. PMID- 29243802 TI - Significant difference of neutrophil-lymphocyte ratio between colorectal cancer, adenomatous polyp and healthy people. AB - OBJECTIVE: Tumor was reported to correlate with inflammation and the host's inflammatory response to tumor has been shown to independently predict the outcome. Many measures of the systemic inflammatory response have been studied in recent years. In the present study the full blood count (leukocyte, neutrophil, lymphocyte) of colorectal cancers (CRCs) adenomatous polyps, and healthy people were collected, and the difference of ratios was studied. PATIENTS AND METHODS: A total of 752 individuals (242 colorectal cancers, 248 adenomatous polyps, and 262 healthy people) were randomized enrolled in the present study. The full blood counts (leukocyte, neutrophil, and lymphocyte) of each individual were collected and the NLRs were calculated. RESULTS: The leukocyte count, neutrophil ratio and neutrophil-lymphocyte ratio were the highest in colorectal cancer group, the second in adenomatous polyp group, and the lowest in healthy control (p < 0.001). The lymphocyte ratio was in the reverse order (p < 0.001). The ROC curve analysis showed that sensitivity and specificity levels of NLR were 66.9% and 77.6% for CRCs, 36.7% and 80.9% for adenomatous polyp. The leukocyte count was higher in the advanced adenomatous polyp compared with low-risk group (p = 0.042). Further analyses of the diagnostic value of NLR are warranted in the future. CONCLUSIONS: Difference of leukocyte count, neutrophil ratio and NLR may provide available information in the differential diagnosis of CRC, adenomatous polyp and healthy people. PMID- 29243803 TI - Effect of metformin on fibrosarcoma in hamsters. AB - OBJECTIVE: We investigated the effect of metformin on an in vivo solid tumor model of fibrosarcoma in hamsters. MATERIALS AND METHODS: 33 Syrian golden hamsters of both sexes, weighing approximately 100 g, were randomly allocated to 3 experimental and 2 control groups. 2 x 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals' back in 4 groups. The first experimental group (7 animals) started peroral treatment with metformin 500 mg/kg daily via a gastric probe 7 days before tumor inoculation, the second (8 animals) 3 days before inoculation and the third (6 animals) immediately after inoculation. After 2 weeks, when the tumors were approximately 2-3 cm in the control group with tumors (6 hamsters), all animals were sacrificed. The blood was collected for glucose and other analyses. The tumors were excised and weighed and their diameters were measured. The tumor samples were histologically assessed and the main organs toxicologically analyzed, including 6 control animals that had received metformin without tumor inoculation. Tumor volume was determined using the formula Lx S2/2, where L was the longest and S the shortest diameter. Ki-67-positive cells in the tumor samples were quantified; images were taken and processed by software UTHSCSA Image Tools for Windows Version 3.00. Statistical significances of differences in tumor weight, volume, number of Ki-67-positive cells and other parameters were determined by the Student's t-test. RESULTS: Metformin inhibited fibrosarcoma growth in hamsters without toxicity. The seven day pretreatment was important for the statistically significant effect. CONCLUSIONS: Administration of metformin as an anti-tumor drug might be an effective and safe therapeutic approach in novel non-toxic therapies for human sarcomas. PMID- 29243804 TI - Notalgia paresthetica: a review for dermatologists. AB - Notalgia paresthetica (NP) is an underdiagnosed condition that presents with unilateral pruritus medial to the scapula on the midback with or without an associated hyperpigmented or hypopigmented macule. There is a paucity of recent reviews on this chronic cutaneous neuropathy in peer-reviewed journals. Current theories propose the condition is likely multifactorial, including spinal entrapment and muscular compressive neuropathy. An extensive literature review was performed by searching the MEDLINE database to review all published works on notalgia paresthetica. This review will provide a useful update for clinicians on the pathogenesis, clinical features, biopsy features, risk factors, and management options for this condition including pharmacological and nonpharmacological methods detailing published treatment options to date for this difficult to treat condition. PMID- 29243805 TI - Interactive media as a tool for reducing waiting anxiety at paediatric rehabilitation hospitals: a randomized controlled trial. AB - AIM: To investigate the efficacy of waiting room media for reducing anxiety and increasing satisfaction at a paediatric rehabilitation hospital. METHOD: In this clustered, parallel, randomized controlled trial, 310 young people with disabilities (age range 5-19y) and their parents attending outpatient clinics were assigned to interactive media (n=113), a silent nature video (n=97), or media-free comparison (n=100) groups. Young person and parent anxiety was reported using the State-Trait Anxiety Inventory (STAI) on arrival and after 10 minutes in the waiting space. Questionnaires measured young person, parent, and staff satisfaction. RESULTS: Young people exposed to interactive media reported a postexposure state anxiety that was 1.1 raw points (2.7 standardized points) lower on the STAI than the comparison group (95% confidence interval [CI] -1.9 to -0.22). There was no difference in postexposure state anxiety between the passive media and comparison groups (95% CI -0.64 to 1.1). Parents' state anxiety did not differ between conditions, but interactive media were associated with greater satisfaction (p=0.009). Of 120 staff, 119 reported that interactive media improved the clinic experience for families. INTERPRETATION: Interactive media designed for accessible, hands-free play mitigate waiting anxiety and increases satisfaction. This paper provides evidence to guide design and decision-making around the use of interactive media in health care spaces. WHAT THIS PAPER ADDS: Interactive media reduced preclinic waiting anxiety for young people with disabilities. Interactive media were accessible to young people with a range of mobility. Interactive media increased parental and staff satisfaction in the clinic. Guidelines for the design of hands-free, inclusive interactive media for health care facilities are presented. PMID- 29243806 TI - Excimer light devices: are they really monochromatic? PMID- 29243807 TI - microRNA as a systemic intervention in the specific breast cancer subtypes with C MYC impacts; introducing subtype-based appraisal tool. AB - Breast cancer is indisputably a heterogeneous disease, in which a formidable combination of definitely dis-regulated C-MYC and microRNA (miRNA) profiles along with other factors are responsible to generate a specific type of breast cancer. C-MYC as a master regulator of more than 20,000 genes can modify the expression of genes underlying to perform diverse conflicting functional frameworks. The functional spectra of miRNA in the new areas of the evolution of cell behaviors are identified. Here, we endeavor to summarize some recent advances of miRNA applications that can be recruited as combinatorial targeted therapy for patients with breast cancer. Also, it is important to indicate that some exosomal miRNAs including miR-126, miR-122, miR-92-1, miR-19a, and miR-29c together with circular miRNAs, such as miR-21-5p, miR-96-5p, and miR-125b-5p can provide a promising evaluation route in breast cancer prognosis. Furthermore, miR-342, miR-520 for triple negative and hormone receptor-positive types of breast cancer, respectively in collaboration with two detected distinct cluster of miRNAs for different breast cancer cell lines can be applied for more dedicated miRNA-based individualized targeted therapy. New DNA handling capacity of C-MYC-related oncogenic miRNAs through coordination with exosomal miRNAs and circulatory ones can be a potential appraisal tool in breast cancer management. Given the notion that genomic instability is a hallmark of breast cancer, the different horizons that are provided in this review can be employed for more precise and profound analyses to achieve an evaluation signature for breast cancer subtypes. PMID- 29243808 TI - The Role of the Dynamic Sensory Perception in the Reformulation of Shakes: Use of TDS for Studying the Effect of Milk, Fiber, and Flavor Addition. AB - : Various factors need to be taken into account when reformulating a food or beverage. The food components, not only macronutrients but also minor ingredients such as flavoring agents, could affect the perception of the sensory sensations, importantly their dynamic aspects, as rising and duration, which are not normally considered. The novelty of this approach is the study of the effects of the addition of several ingredients (fiber, extra milk powder, and strawberry flavoring) on the dynamic perception of a food item (strawberry shakes) using the temporal dominance of sensations (TDS) technique. The occurrence and duration of the key sensory sensations (acid, natural strawberry flavor, thick, sweet, candy strawberry flavor, and milk flavor) extracted from the TDS curves were analyzed and linked to the composition factors and liking and expectations of satiety scores. For example, the addition of flavoring increased the liking scores (increments ranging from 0.3 to 1.1) that was linked to the attenuation of acid sensation; and the addition of extra milk powder increased the expectation of satiety scores (increments ranging from 0.5 to 0.7) that was linked to the perception of early thick sensation in the mouth. In general, the more complex sensory profiles the higher liking and expectations of satiety. PRACTICAL APPLICATION: This work is a case study on how temporal sensory methods can contribute important information on the actual perception of food during consumption. Depending on the ingredients added these sensory properties appear at different times and with different dominance during evaluation affecting liking or fullness expectations. In consequence, the temporal sensory properties should be taken into account when designing or reformulating food. PMID- 29243810 TI - Effects of Pro-Oxidants and Antioxidants on the Total Antioxidant Capacity and Lipid Oxidation Products of Milk During Refrigerated Storage. AB - : Oxidized flavor is a major problem that affects the dairy industry because of its adverse effect on milk acceptability. The objectives of this research were to examine the roles of pro-oxidants and antioxidants on the oxidative stability of whole milk. In the 1st experiment, the effect of light (2300 Lux) and/or cupric sulfate (0, 0.5, and 1.0 mg/kg) as pro-oxidants in milk were investigated during an 11-d refrigerated storage period. The effects of added retinyl palmitate (1.16 mg/L; 2113 IU Vitamin A/L) and tocopheryl acetate (100 mg/kg milk fat; 5.02 IU Vitamin E/L) as antioxidants in the presence of light (2300 Lux) and light with cupric sulfate (0.05 mg/kg) during a 7-d study were investigated in the 2nd experiment. The presence of pro-oxidants significantly (P < 0.05) decreased the total antioxidant capacity (TAC) and increased the lipid oxidation products in milk during storage. Light had a greater effect in the decrease of TAC, although cupric sulfate in the presence of light significantly increased the formation of lipid oxidation products. The addition of antioxidants resulted in a significant (P < 0.05) increase in TAC on day 0. However, with exposure to light and light with cupric sulfate, the antioxidants did not result in a higher TAC in comparison to the treatments without added antioxidant. Analysis of lipid oxidation products by instrumental and sensory methods showed that the presence of light and cupric sulfate significantly (P < 0.05) increased the oxidized flavor from the control, but no significant (P > 0.05) difference in oxidized flavor intensity was detected between milk with and without added antioxidants. PRACTICAL APPLICATION: Production and processing variables can affect the content of pro-oxidants and antioxidants in milk, which has an impact on flavor. An understanding of the role of these components in contributing to or minimizing off-flavor formation in milk, will help dairy producers to provide quality products to consumers. PMID- 29243809 TI - Obesity-induced mitochondrial dysfunction in porcine adipose tissue-derived mesenchymal stem cells. AB - Transplantation of autologous mesenchymal stem cells (MSCs) may be a viable option for treatment of several diseases. MSCs efficacy depends on adequate function of their mitochondria, which might be impaired in a noxious milieu. We hypothesized that obesity compromises MSCs mitochondrial structure and function, possibly via micro-RNA (miRNA)-based mechanisms. MSCs were collected from swine abdominal adipose tissue after 16 weeks of Lean or Obese diet (n = 7 each). Mitochondrial structure was assessed by electron microscopy and function by membrane potential and cytochrome-c oxidase (COX)-IV activity. Oxidative stress was assessed by Mito-SOX and dihydroethidium staining. Next-generation sequencing (RNA-seq) was performed to identify miRNAs expression in MSCs, and predicted mitochondrial target genes were then identified (MitoCarta). Compared to Lean MSCs, mitochondria from Obese-MSCs were smaller and showed cristae remodeling and loss. Mitochondrial membrane potential and COX-IV activity decreased in Obese MSCs, associated with increased mitochondrial oxidative stress. RNA-seq generated reads for 413 miRNAs, of which 5 miRNAs were upregulated in Obese-MSCs (fold change >2, p < 0.05) and found to target 43 specific mitochondrial genes. Obesity impairs MSC mitochondrial structure and function, possibly mediated partly through miRNA-induced mitochondrial gene regulation, leading to increased oxidative stress. Importantly, these alterations may limit the therapeutic use of autologous MSCs in subjects with obesity. PMID- 29243811 TI - Decrease of superficial serine and lactate in the stratum corneum due to repetitive frictional trauma. AB - BACKGROUND: Repetitive frictional trauma can be induced in daily and occupational activities, such as daily ablutions with washcloths. The influence of frictional trauma on the skin barrier function, especially in the perspective of the components of stratum corneum (SC), has not yet been studied in detail. Raman spectroscopy is a noninvasive optical technique based on inelastic light scattering that is capable of measuring several components in the skin. In this study, we used Raman spectroscopy to investigate the change in natural moisturizing factor (NMF) components in the SC following repetitive physical friction. METHODS: Six healthy volunteers, who were included in the study after obtaining an informed consent, performed repetitive washing with soap using nylon towels on the forearm twice a day for 2 weeks and used Raman spectroscopy to investigate the change in NMF components in the SC. RESULTS: Compared with the control, which was washed with soap at the same frequency on the opposite forearm, a significant increase in the transepidermal water loss (TEWL) and a decrease in NMF, serine, and total lactate, responsible for maintenance the SC hydration and structuring and maintaining the epidermal barrier function, in the SC were found. CONCLUSIONS: Increased TEWL and decreased NMF are considered as an etiology of atopic dermatitis (AD); therefore, our findings provide evidence that daily activities with repetitive frictional trauma may be related to the predisposition of AD. PMID- 29243812 TI - Dysregulated mitogen-activated protein kinase signalling as an oncogenic basis for clear cell sarcoma of the kidney. AB - The oncogenic mechanisms and tumour biology underpinning clear cell sarcoma of the kidney (CCSK), the second commonest paediatric renal malignancy, are poorly understood and currently, therapy depends heavily on doxorubicin with cardiotoxic side-effects. Previously, we characterized the balanced t(10;17)(q22;p13) chromosomal translocation, identified at that time as the only recurrent genetic aberration in CCSK. This translocation results in an in-frame fusion of the genes YWHAE (encoding 14-3-3epsilon) and NUTM2, with a somatic incidence of 12%. Clinico-pathological features of that cohort suggested that this aberration might be associated with higher stage and grade disease. Since no primary CCSK cell line exists, we generated various stably transfected cell lines containing doxycycline-inducible HA-tagged YWHAE-NUTM2, in order to study the effect of expressing this transcript. 14-3-3epsilon-NUTM2-expressing cells exhibited significantly greater cell migration compared to isogenic controls. Gene and protein expression studies were indicative of dysregulated MAPK/PI3K-AKT signalling, and by blocking these pathways using neutralizing antibodies, the migratory advantage conferred by the transcript was abrogated. Importantly, CCSK tumour samples similarly show up-regulation/activation of these pathways. These results support the oncogenic role of 14-3-3epsilon-NUTM2 in CCSK and provide avenues for the exploration of novel therapeutic approaches. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29243814 TI - A Reaction-Based Novel Fluorescent Probe for Detection of Hydrogen Sulfide and Its Application in Wine. AB - : A new reaction-based fluorescent probe 6-cyanonaphthalen-2-yl-2,4- dinitrobenzenesulfonate (probe 1) was designed and synthesized for detection of hydrogen sulfide (H2 S). The addition of H2 S to a solution of probe 1 resulted in a marked fluorescence increased accompanied by a visual color change from colorless to yellow. Importantly, this distinct color response indicates that probe 1 could be used as a visual tool for detection of H2 S. H2 S can be detected quantitatively in the concentration range 0 to 25 MUM and the detection limit was 30 nM. Moreover, probe 1 was successfully used as a sensor to determine H2 S levels in red wine and beer. PRACTICAL APPLICATION: Fluorescent probe 1 could be employed as a visible sensor for H2 S. Probe 1 could be used to detect H2 S quantitatively in food simple. PMID- 29243813 TI - Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. AB - BACKGROUND: Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first line treatment for partial onset seizures and sodium valproate for generalised onset seizures; however a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices. OBJECTIVES: To compare the time to withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus). SEARCH METHODS: We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016. SELECTION CRITERIA: We included randomised controlled trials of a monotherapy design in adults or children with partial onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types). DATA COLLECTION AND ANALYSIS: This was an individual participant data (IPD) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events. MAIN RESULTS: IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than current first line treatment carbamazepine and other current first-line treatment lamotrigine performed better than all other treatments (aside from levetiracetam); carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders. AUTHORS' CONCLUSIONS: Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity. PMID- 29243815 TI - Effect of Grinding at Modified Atmosphere or Vacuum on Browning, Antioxidant Capacities, and Oxidative Enzyme Activities of Apple. AB - : This study evaluated the effects of grinding at atmospheric pressure (control), under vacuum (~2.67 kPa), or with modified atmosphere (N2 and CO2 ) on the browning, antioxidant activity, phenolics, and oxidative enzyme activity of apples as a function of time. The control group was affected most, showing distinct browning and losing most of the antioxidant activity and concentrations of the main phenolic compounds. The modified atmosphere groups retained color, antioxidant activity, and phenolic compounds better than the control group. Least changes were obtained with vacuum grinding, particularly in terms of preventing enzymatic browning and oxidation of antioxidants apples. At 12 h after grinding, vacuum-ground apples retained total phenolic contents 5.32, 1.54, and 1.49 times higher than control, nitrogen gas, and carbon dioxide gas-ground samples, respectively. The oxidative enzyme activity, including that of polyphenol oxidase and peroxidase, decreased in the control and modified atmosphere group, but they were maintained in the samples ground under the vacuum. PRACTICAL APPLICATION: In this study, we found that grinding with modified atmosphere or vacuum conditions could effectively prevent browning as well as loss of phenolic compounds and antioxidant activity of ground apples. These results can help scientists and engineers build better grinding systems for retaining nutrient and quality factors of ground apples. In addition, these results may be useful to other fruit and vegetable industries that wish to retain fresh-like quality and nutritional value during grinding and storage. PMID- 29243816 TI - Two decades of persisting income-disparities in dental caries among U.S. children and adolescents. AB - OBJECTIVE: To describe trends in income disparities in dental caries among U.S. children and adolescents during two decades of fluctuating economic growth. METHODS: Data were from National Health and Nutrition Examination Surveys conducted in 1988-1994, 1999-2004, and 2011-2014. The number of tooth surfaces with dental caries experience per child was computed for three age groups: 2-5, 6 11, and 12-17 years. Absolute and relative measures of inequality compared caries experience in families below the poverty level with families where income was at least three times the poverty threshold. RESULTS: Conspicuous, inverse income gradients in dental caries were observed at each time period and in each age group. However, there was no consistent trend or statistically significant change in the degree of inequality between survey periods. CONCLUSIONS: Persisting income disparities in dental caries among U.S. children and adolescents challenge public health dentistry to redouble efforts to redress the inequity. PMID- 29243818 TI - The function of two type II metacaspases in woody tissues of Populus trees. AB - Metacaspases (MCs) are cysteine proteases that are implicated in programmed cell death of plants. AtMC9 (Arabidopsis thaliana Metacaspase9) is a member of the Arabidopsis MC family that controls the rapid autolysis of the xylem vessel elements, but its downstream targets in xylem remain uncharacterized. PttMC13 and PttMC14 were identified as AtMC9 homologs in hybrid aspen (Populus tremula * tremuloides). A proteomic analysis was conducted in xylem tissues of transgenic hybrid aspen trees which carried either an overexpression or an RNA interference construct for PttMC13 and PttMC14. The proteomic analysis revealed modulation of levels of both previously known targets of metacaspases, such as Tudor staphylococcal nuclease, heat shock proteins and 14-3-3 proteins, as well as novel proteins, such as homologs of the PUTATIVE ASPARTIC PROTEASE3 (PASPA3) and the cysteine protease RD21 by PttMC13 and PttMC14. We identified here the pathways and processes that are modulated by PttMC13 and PttMC14 in xylem tissues. In particular, the results indicate involvement of PttMC13 and/or PttMC14 in downstream proteolytic processes and cell death of xylem elements. This work provides a valuable reference dataset on xylem-specific metacaspase functions for future functional and biochemical analyses. PMID- 29243817 TI - Association between atopic dermatitis and squamous cell carcinoma: a case-control study. AB - BACKGROUND: Conflicting data have been published on whether an association exists between atopic dermatitis (AD) and nonmelanoma skin cancer. This study aimed to determine whether individuals with AD had an increased risk of squamous cell carcinoma (SCC) development. METHODS: We conducted a retrospective, case-control study of patients residing in Olmsted County, Minnesota. Cases were selected from patients seen at Mayo Clinic (Rochester, Minnesota) who had an initial SCC diagnosis (either invasive SCC or SCC in situ) from January 1, 1996, through December 23, 2010. Age- and sex-matched controls were selected from patients seen at Mayo Clinic with no history of SCC before the case event date. RESULTS: Three hundred ninety-nine individuals with a documented history of SCC were identified and matched with 780 controls who did not have a history of SCC. After adjusting for race, smoking history, ionizing radiation exposure, corticosteroid and cyclosporine use, and non-SCC skin cancers, the odds ratio for SCC development between patients with history of AD versus patients without history of AD was 1.75 (95% CI, 1.05-2.93). CONCLUSIONS: Our findings support an increased risk of SCC development in the setting of AD. PMID- 29243819 TI - Novel dietary supplement association reduces symptoms in endometriosis patients. AB - Endometriosis is characterized by disabling symptoms that afflict young women with severe physical discomfort, difficulty in relationship life, and infertility; however, the currently available therapeutic strategies are unsatisfactory. Goal of this research was to identify a new combination of natural active ingredients that, administered as dietary supplements, could have the effect of reducing inflammatory response in endometriosis patients, decreasing the symptoms the disease produces and its harmful effects on affected organs. A cohort of endometriosis patient was treated for 3 months with a composition including quercitin, curcumin, parthenium, nicotinamide, 5 methyltetrahydrofolate, and omega 3/6. Using a VAS scale, we demonstrated a significant reduction of the symptoms in endometriosis patients treated with the dietary composition respect to the controls. Moreover, we demonstrated also a significant reduction in the serum levels of PGE2 and CA-125. Further study are required to compare the effect of this combination of molecules with standard therapies and to evaluate if the use of these dietary supplements in combination with standard therapies may lead to the improvement of the regular medical treatment for endometriosis. PMID- 29243820 TI - Generalized eruptive histiocytosis diagnosed in light of dermoscopic findings. PMID- 29243821 TI - Improved recovery of ancient DNA from subfossil wood - application to the world's oldest Late Glacial pine forest. AB - Ancient DNA from historical and subfossil wood has a great potential to provide new insights into the history of tree populations. However, its extraction and analysis have not become routine, mainly because contamination of the wood with modern plant material can complicate the verification of genetic information. Here, we used sapwood tissue from 22 subfossil pines that were growing c. 13 000 yr bp in Zurich, Switzerland. We developed and evaluated protocols to eliminate surface contamination, and we tested ancient DNA authenticity based on plastid DNA metabarcoding and the assessment of post-mortem DNA damage. A novel approach using laser irradiation coupled with bleaching and surface removal was most efficient in eliminating contaminating DNA. DNA metabarcoding confirmed which ancient DNA samples repeatedly amplified pine DNA and were free of exogenous plant taxa. Pine DNA sequences of these samples showed a high degree of cytosine to thymine mismatches, typical of post-mortem damage. Stringent decontamination of wood surfaces combined with DNA metabarcoding and assessment of post-mortem DNA damage allowed us to authenticate ancient DNA retrieved from the oldest Late Glacial pine forest. These techniques can be applied to any subfossil wood and are likely to improve the accessibility of relict wood for genome-scale ancient DNA studies. PMID- 29243822 TI - Nrf2 promotes oesophageal cancer cell proliferation via metabolic reprogramming and detoxification of reactive oxygen species. AB - Cancer cells consume a large amount of energy and maintain high levels of anabolism to promote cell proliferation via metabolic reprogramming. Nuclear factor erythroid 2-related factor 2 (Nrf2; NFE2L2) is a master transcription regulator of stress responses and promotes metabolic reprogramming to support cell proliferation in various types of cancer. As oesophageal cancer is one of the most aggressive gastrointestinal cancers, we aimed to clarify the effect of Nrf2 on metabolic reprogramming in oesophageal cancer. The relationship between Nrf2 expression and clinical outcome was evaluated using a database comprising 201 oesophageal cancers. Using in vitro assays and metabolome analysis, we examined the mechanism by which Nrf2 affects malignant phenotype. High-level immunohistochemical expression of Nrf2 was significantly associated with poor recurrence-free survival (HR = 2.67, p = 0.0004) and overall survival (HR = 2.90, p < 0.0001) in oesophageal cancer patients. In an in vitro assay with siRNA in TE 11 cells, which showed high Nrf2 expression, Nrf2 depletion significantly decreased cell growth and enhanced G1 cell cycle arrest and apoptosis. In addition, reactive oxygen species (ROS) were not removed by detoxification via the Nrf2 pathway, with concomitant induction of the p38 mitogen-activated protein kinase pathway. The metabolome analysis showed that Nrf2 strongly promoted metabolic reprogramming to glutathione metabolism, which synthesizes the essential fuels for cancer progression. Furthermore, metabolome analysis using oesophageal cancer specimens confirmed that samples displaying high Nrf2 expression promoted glutathione synthesis. Metabolic reprogramming to glutathione metabolism, and ROS detoxification by activation of Nrf2, enhanced cancer progression and led to a poor clinical outcome in oesophageal cancer patients. Copyright (c) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29243824 TI - ApoplastP: prediction of effectors and plant proteins in the apoplast using machine learning. AB - The plant apoplast is integral to intercellular signalling, transport and plant pathogen interactions. Plant pathogens deliver effectors both into the apoplast and inside host cells, but no computational method currently exists to discriminate between these localizations. We present ApoplastP, the first method for predicting whether an effector or plant protein localizes to the apoplast. ApoplastP uncovers features of apoplastic localization common to both effectors and plant proteins, namely depletion in glutamic acid, acidic amino acids and charged amino acids and enrichment in small amino acids. ApoplastP predicts apoplastic localization in effectors with a sensitivity of 75% and a false positive rate of 5%, improving the accuracy of cysteine-rich classifiers by > 13%. ApoplastP does not depend on the presence of a signal peptide and correctly predicts the localization of unconventionally secreted proteins. The secretomes of fungal saprophytes as well as necrotrophic, hemibiotrophic and extracellular fungal pathogens are enriched for predicted apoplastic proteins. Rust pathogens have low proportions of predicted apoplastic proteins, but these are highly enriched for predicted effectors. ApoplastP pioneers apoplastic localization prediction using machine learning. It will facilitate functional studies and will be valuable for predicting if an effector localizes to the apoplast or if it enters plant cells. PMID- 29243823 TI - Pathways to Medical Home Recognition: A Qualitative Comparative Analysis of the PCMH Transformation Process. AB - OBJECTIVE: To understand the process of practice transformation by identifying pathways for attaining patient-centered medical home (PCMH) recognition. DATA SOURCES/STUDY SETTING: The CMS Federally Qualified Health Center (FQHC) Advanced Primary Care Practice Demonstration was designed to help FQHCs achieve NCQA Level 3 PCMH recognition and improve patient outcomes. We used a stratified random sample of 20 (out of 503) participating sites for this analysis. STUDY DESIGN: We developed a conceptual model of structural, cultural, and implementation factors affecting PCMH transformation based on literature and initial qualitative interview themes. We then used conventional cross-case analysis, followed by qualitative comparative analysis (QCA), a cross-case method based on Boolean logic algorithms, to systematically identify pathways (i.e., combinations of factors) associated with attaining-or not attaining-Level 3 recognition. DATA COLLECTION METHODS: Site-level indicators were derived from semistructured interviews with site leaders at two points in time (mid- and late-implementation) and administrative data collected prior to and during the demonstration period. PRINCIPAL FINDINGS: The QCA results identified five distinct pathways to attaining PCMH recognition and four distinct pathways to not attaining recognition by the end of the demonstration. Across these pathways, one condition (change leader capacity) was common to all pathways for attaining recognition, and another (previous improvement or recognition experience) was absent in all pathways for not attaining recognition. In general, sites could compensate for deficiencies in one factor with capacity in others, but they needed a threshold of strengths in cultural and implementation factors to attain PCMH recognition. CONCLUSIONS: Future efforts at primary care transformation should take into account multiple pathways sites may pursue. Sites should be assessed on key cultural and implementation factors, in addition to structural components, in order to differentiate interventions and technical assistance. PMID- 29243825 TI - Dermatologic manifestations among human immunodeficiency virus patients in Morocco and association with immune status. AB - OBJECTIVE: The objective was to determine if the type and number of skin diseases can be clinical indicators of underlying immune status in HIV1 disease by estimating and correlating with the CD4 count and CDC stage. MATERIALS AND METHODS: This was a retrospective cross-sectional descriptive study. All consecutive patients infected with HIV1 followed at the Dermatology Department of Rabat Military Hospital between January 2008 and January 2017 were studied for dermatological manifestations, CD4 count and CDC clinical stage. RESULTS: A total of 170 patients with 304 dermatological manifestations were included. The most common dermatoses were fold dermatophytic infections (67%), genital warts (43%), herpes zoster (21%), xerosis (21%), and oral candidiasis (12%). The number of dermatologic manifestations was significantly greater in patients with CD4 count less than 200/mm3 or in stage C of the CDC classification. Five types of skin diseases (dermatophyte infections of the folds, genital warts, shingles, oral candidiasis, and seborrheic dermatitis) were significantly associated (P < 0.05) with CD4 count <200/mm3 . Seborrheic dermatitis was the only one skin disease significantly associated with AIDS stage. In multivariate analysis, genital warts (OR = 0.3, 95% CI 0.10-0.92) are independently associated with CD4 count less than 200 CD4/mm3 . CONCLUSIONS: Skin manifestations not only act as markers but also reflect the underlying immune status. Seborrheic dermatitis and genital warts appear to be a marker of immune status, and seborrheic dermatitis appears to be associated with CDC stage C, especially in their chronic and severe forms. PMID- 29243826 TI - GsSLAH3, a Glycine soja slow type anion channel homolog, positively modulates plant bicarbonate stress tolerance. AB - Alkaline stress is a major form of abiotic stress that severely inhibits plant growth and development, thus restricting crop productivity. However, little is known about how plants respond to alkali. In this study, a slow-type anion channel homolog 3 gene, GsSLAH3, was isolated and functionally characterized. Bioinformatics analysis showed that the GsSLAH3 protein contains 10 transmembrane helices. Consistently, GsSLAH3 was found to locate on plasma membrane by transient expression in onion epidermal cells. In wild soybeans, GsSLAH3 expression was induced by NaHCO3 treatment, suggesting its involvement in plant response to alkaline stress. Ectopic expression of GsSLAH3 in yeast increased sensitivity to alkali treatment. Dramatically, overexpression of GsSLAH3 in Arabidopsis thaliana enhanced alkaline tolerance during the germination, seedling and adult stages. More interestingly, we found that transgenic lines also improved plant tolerance to KHCO3 rather than high pH treatment. A nitrate content analysis of Arabidopsis shoots showed that GsSLAH3 overexpressing lines accumulated more NO3- than wild-type. In summary, our data suggest that GsSLAH3 is a positive alkali responsive gene that increases bicarbonate resistance specifically. PMID- 29243827 TI - One-incision versus two-incision techniques for arthroscopically assisted anterior cruciate ligament reconstruction in adults. AB - BACKGROUND: Anterior cruciate ligament (ACL) tears are serious knee injuries that are frequently treated surgically in the form of arthroscopically assisted reconstruction with grafts from the patella or hamstrings tendons. We reviewed the evidence for the choice of arthroscopically assisted ACL reconstruction technique in terms of whether it should involve one incision (femoral tunnel drilled from inside the knee joint under arthroscopic visualisation) or two incisions (femoral tunnel drilled from outside to inside the knee joint). OBJECTIVES: To assess the effects (benefits and harms) of one-incision versus two incision techniques for arthroscopically assisted ACL reconstruction in adults. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Latin American and Caribbean Health Sciences (LILACS), the World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, reference lists, and conference abstracts. The date of the search was 16 August 2017. SELECTION CRITERIA: Randomised and quasi randomised controlled clinical trials evaluating one-incision versus two-incision techniques for arthroscopically assisted ACL reconstruction in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently searched and selected studies, and extracted data and assessed the risk of bias of the eligible studies. We undertook limited pooling of data using the fixed-effect model. MAIN RESULTS: We included five trials (four randomised and one quasi-randomised) evaluating a total of 320 participants who were mainly in their 20s. All participants underwent ACL reconstruction with patella tendon grafts. All five included trials were at a high risk of bias, particularly performance bias. Based on these limitations and the insufficiency of the available data resulting in imprecision of effect estimates, we judged the quality of the evidence as very low for all outcomes. This means that we are uncertain of the findings of the review.We found very low-quality evidence of no clinically important differences between the two techniques in self reported knee function, measured using the Lysholm knee score (scale 0 to 100: best outcome), at short-term (3 months) (mean difference (MD) 2.73 favours one-incision technique, 95% confidence interval (CI) -2.70 to 8.15; 79 participants, 2 studies), intermediate-term (12 months) (MD 3.68 favours two-incision technique, 95% CI -6.61 to -0.75; 79 participants, 2 studies), and long-term follow-up. The data available for long-term follow-up (2 to 5 years) was expressed in terms of the numbers of participants with excellent Lysholm scores (90 points or more); we found no difference between the two groups (42/45 versus 36/40; risk ratio (RR) 1.04, 95% CI 0.91 to 1.18; 1 study). There were no data for quality of life measures or for overall numbers of participants incurring an adverse event. We found very low-quality evidence of little between group differences in individual adverse events such as infection, knee stiffness, reoperation, and graft failure.We found very low-quality evidence from one study (59 participants) of little difference between the two groups in activity levels measured using Tegner scores (scale 0 to 10: highest sport activity) at two years (MD -0.80 favours two-incision technique, 95% CI -1.90 to 0.30). There was very low-quality evidence from four studies of minimal between-group difference in the number of participants with normal or nearly normal objectively measured knee function (International Knee Documentation Committee objective assessment grading) at intermediate follow-up (means 12 to 28 months): 56/78 versus 63/89; RR 1.01, 95% CI 0.85 to 1.21; 167 participants). AUTHORS' CONCLUSIONS: The very low-quality and often absent evidence means that we are uncertain whether one incision arthroscopically assisted ACL reconstruction techniques yield better, worse, or equivalent results compared with two-incision techniques in terms of short-, intermediate-, or long-term subjective function, quality of life, adverse outcomes, activity levels, and objectively rated knee function. The evidence was available only for single-bundle ACL reconstruction using patella tendon grafts.When considering priorities for high-quality randomised trials on techniques for ACL reconstruction, it is important to note the insufficiency of the evidence available to inform this key comparison. PMID- 29243828 TI - Receptor-mediated endocytosis generates nanomechanical force reflective of ligand identity and cellular property. AB - Whether environmental (thermal, chemical, and nutrient) signals generate quantifiable, nanoscale, mechanophysical changes in the cellular plasma membrane has not been well elucidated. Assessment of such mechanophysical properties of plasma membrane may shed lights on fundamental cellular process. Atomic force microscopic (AFM) measurement of the mechanical properties of live cells was hampered by the difficulty in accounting for the effects of the cantilever motion and the associated hydrodynamic force on the mechanical measurement. These challenges have been addressed in our recently developed control-based AFM nanomechanical measurement protocol, which enables a fast, noninvasive, broadband measurement of the real-time changes in plasma membrane elasticity in live cells. Here we show using this newly developed AFM platform that the plasma membrane of live mammalian cells exhibits a constant and quantifiable nanomechanical property, the membrane elasticity. This mechanical property sensitively changes in response to environmental factors, such as the thermal, chemical, and growth factor stimuli. We demonstrate that different chemical inhibitors of endocytosis elicit distinct changes in plasma membrane elastic modulus reflecting their specific molecular actions on the lipid configuration or the endocytic machinery. Interestingly, two different growth factors, EGF and Wnt3a, elicited distinct elastic force profiles revealed by AFM at the plasma membrane during receptor mediated endocytosis. By applying this platform to genetically modified cells, we uncovered a previously unknown contribution of Cdc42, a key component of the cellular trafficking network, to EGF-stimulated endocytosis at plasma membrane. Together, this nanomechanical AFM study establishes an important foundation that is expandable and adaptable for investigation of cellular membrane evolution in response to various key extracellular signals. PMID- 29243829 TI - Poverty and Serious Mental Illness: Toward Action on a Seemingly Intractable Problem. AB - This paper examines the issue of poverty among people with serious mental illness (SMI), positioning it as a key issue to be confronted by community mental health systems and practitioners. The paper reviews three perspectives on poverty, considering how each sheds light on poverty among people with SMI, and their implications for action: (a) monetary resources, (b) basic needs, and (c) capabilities. The paper argues that community mental health programs and systems are currently unable to address poverty as they are overly focused on individual level interventions that, on their own, cannot raise people out of poverty. The paper calls for a social justice value, informed by the concept of citizenship, as a necessary complement to the recovery concept that has informed community mental health practice for almost 25 years. Finally, the paper argues that community psychologists, with their concepts, methods, and values, are well positioned to contribute to this important issue. However, it also contends that addressing poverty requires collaboration from community psychologists with researchers and practitioners from other fields and domains of expertise to begin to make progress. PMID- 29243831 TI - Sexual Intimacy, Mental Illness, and Homelessness. AB - The current article reviews the literature on sexuality among individuals with a severe mental illness (SMI) who have experienced homelessness, a topic that has received little attention in the research literature, particularly from a community psychology perspective. The review begins with a synthesis of the literature on SMI and sexuality, followed by a review of the available literature on SMI, homelessness, and sexuality. It concludes with an interpretation of the findings using community psychology values and principles. The findings highlight the importance of intimate relationships to recovery for many individuals with an SMI who have experienced homelessness. Policy implications for homeless shelters and housing interventions are discussed. PMID- 29243832 TI - Abiotic rather than biotic filtering shapes the arbuscular mycorrhizal fungal communities of European seminatural grasslands. AB - Although it is well known that arbuscular mycorrhizal fungi (AMF) play a key role in the functioning of natural ecosystems, the underlying drivers determining the composition of AMF communities remain unclear. In this study, we established 138 sampling plots at 46 grassland sites, consisting of 26 acidic grasslands and 20 calcareous grasslands spread across eight European countries, to assess the relative importance of abiotic and biotic filtering in driving AMF community composition and structure in both the grassland soils and in the roots of 13 grassland plant species. Soil AMF communities differed significantly between acidic and calcareous grasslands. In root AMF communities, most variance was attributable to soil variables while very little variation was explained by host plant identity. Root AMF communities in host plant species occurring in only one grassland type closely resembled the soil AMF communities of that grassland type and the root AMF communities of other host plant species occurring in the same grassland type. The observed AMF-host plants networks were not modular but nested. Our results indicate that abiotic conditions, rather than biotic filtering through host plant specificity, are the most important drivers in shaping AMF communities in European seminatural grasslands. PMID- 29243830 TI - Proceedings of the Food and Drug Administration's public workshop on new red blood cell product regulatory science 2016. AB - The US Food and Drug Administration (FDA) held a workshop on red blood cell (RBC) product regulatory science on October 6 and 7, 2016, at the Natcher Conference Center on the National Institutes of Health (NIH) Campus in Bethesda, Maryland. The workshop was supported by the National Heart, Lung, and Blood Institute, NIH; the Department of Defense; the Office of the Assistant Secretary for Health, Department of Health and Human Services; and the Center for Biologics Evaluation and Research, FDA. The workshop reviewed the status and scientific basis of the current regulatory framework and the available scientific tools to expand it to evaluate innovative and future RBC transfusion products. A full record of the proceedings is available on the FDA website (http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConference /ucm507890.htm). The contents of the summary are the authors' opinions and do not represent agency policy. PMID- 29243833 TI - Pharmacological interaction of alpha-bisabolol and diclofenac on nociception, inflammation, and gastric integrity in rats. AB - Preclinical Research & Development The combination of nonsteroidal anti inflammatory drugs (NSAIDs) with herbal products having analgesic and anti inflammatory effects may increase their beneficial effects and limit their side effects. In this study, the effects of an interaction between alpha-bisabolol and the NSAID, diclofenac on nociception (formalin test), inflammation (paw inflammation produced by carrageenan) and gastric injury in rat was assessed. Diclofenac, alpha-bisabolol, or diclofenac-alpha-bisabolol combinations produced antinociceptive and anti-inflammatory effects in rat (p < .05). The systemic administration of diclofenac, but not alpha-bisabolol, produced gastric damage while the diclofenac-alpha-bisabolol combinations produced limited gastric damage. Effective dose (ED40 ) values were determined for each individual drug and analyzed isobolographically. The theoretical ED40 values for the antinociceptive (98.89 mg/kg) and the anti-inflammatory (41.2 mg/kg) effects differed from the experimental ED40 values (antinociception: 38.7 mg/kg and anti inflammation: 13.4 mg/kg). We concluded that the interactions between diclofenac and alpha-bisabolol are synergistic. These data suggest that the diclofenac-alpha bisabolol combinations can interact to produce minor gastric damage, thereby offering a safer therapeutic alternative for the clinical management of inflammation and/or inflammatory pain. PMID- 29243834 TI - Outcome of octogenarians with atrial fibrillation undergoing percutaneous coronary intervention: insights from the AFCAS registry. AB - BACKGROUND: More evidence is needed on the optimal antithrombotic regimen in elderly patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). HYPOTHESIS: Octogenarian patients (aged >=80 years) with AF who underwent PCI have worse 12-month clinical outcome, compared with younger patients. METHODS: We performed a post-hoc analysis of data from the prospective, multicenter AFCAS registry, which enrolled consecutive patients with AF who underwent PCI and stenting. Outcome measures included major adverse cardiac/cerebrovascular events (MACCE; all-cause death, myocardial infarction, repeat revascularization, stent thrombosis, or stroke/transient ischemic attack) and bleeding events at 12-month follow-up. RESULTS: Out of 925 AF patients enrolled in AFCAS registry, 195 (21.1%) were >=80 years. Mean age was 82.9 +/- 2.6 years; 41.5% were women; 32.3% had diabetes mellitus. Compared with patients aged <80 years, there were more females among the octogenarians (P < 0.001). Compared with younger patients, octogenarians smoked and had dyslipidemia less often, and presented more frequently with acute coronary syndrome. The frequency and duration of antithrombotic regimens prescribed at discharge were comparable. At 12-month follow-up, overall MACCE rate was higher in octogenarians compared with younger patients (27.7% vs 20.1%, P = 0.02). The rate of acute myocardial infarction was higher in octogenarians (9.2% vs 4.9%, P = 0.02), but the rates of all bleeds and BARC >2 bleeds were similar (P = 0.13, P = 0.29, respectively). CONCLUSIONS: In real-world patients with AF undergoing PCI, patients aged >=80 years had higher incidence of MACCE at 12-month follow-up compared with younger patients, although they received comparable antithrombotic treatment. The rates of bleeding events were similar. PMID- 29243835 TI - Diallyl Trisulfide inhibits breast cancer stem cells via suppression of Wnt/beta catenin pathway. AB - Cancer stem cells (CSCs) play a central role in the development of breast cancer. The canonical Wnt/beta-catenin signal pathway is critical for maintaining CSCs characteristics. Diallyl trisulfide (DATS), a natural organosulfur compound from the garlic, exhibits effective antitumor properties. However, the role of DATS in regulating breast CSCs activity and the underlying molecular mechanisms remain obscure. In the present study, we reported that DATS efficiently inhibited the viability of breast CSCs as evidenced by reducing turmorspheres formation, decreasing the expression of breast CSCs markers (CD44, ALDH1A1, Nanog, and Oct4), as well as inhibiting proliferation and inducing apoptosis. Furthermore, we showed that DATS downregulated the activity of Wnt/beta-catenin pathway, while LiCl-triggered Wnt/beta-catenin activation diminished DATS inhibition on breast CSCs. Taken together, our results illustrated that DATS suppressed breast CSCs through inhibiting Wnt/beta-catenin pathway activation. These novel findings could provide new insights into the molecular mechanisms of breast CSCs regulation as well as its target intervention and might provide new strategies for preventing and treating breast cancers. PMID- 29243836 TI - The long-term prognostic value of highly sensitive cardiac troponin I in patients with acute pulmonary embolism. AB - BACKGROUND: In patients with acute pulmonary embolism (PE), detectable levels of cardiac troponin I (cTnI) using a highly sensitive assay have been associated with increased in-hospital mortality. We sought to investigate the impact of detectable cTnI on long-term survival following acute PE. HYPOTHESIS: Detectable cTnI levels in patients presenting with acute PE predict increased long-term mortality following hospital discharge. METHODS: In a retrospective cohort study, we analyzed consecutive patients with confirmed acute PE and cTnI assay available from the index hospitalization. The detectable cTnI level was >=0.012 ng/mL. Patients were classified into low and high clinical risk groups according to the Pulmonary Embolism Severity Index (PESI) at presentation. Subjects were followed for all-cause mortality subsequent to hospital discharge using chart review and Social Security Death Index. RESULTS: A cohort of 289 acute PE patients (mean age 56 years, 51% men), of whom 152 (53%) had a detectable cTnI, was followed for a mean of 3.1 +/- 1.8 years after hospital discharge. A total of 71 deaths were observed; 44 (29%) and 27 (20%) in the detectable and undetectable cTnI groups, respectively (P = 0.05). Detectable cTnI was predictive of long-term survival among low-risk (P = 0.009) but not high-risk patients (P = 0.78) who had high mortality rates irrespective of cTnI status. CONCLUSIONS: In patients with acute PE, detectable cTnI is predictive of long-term mortality, particularly among patients who were identified as low risk according to PESI score. PMID- 29243838 TI - Evaluation of Umbilical Vein Blood Volume Flow in Preeclampsia by Angle Independent 3D Sonography. AB - OBJECTIVES: To investigate the association between umbilical vein blood volume flow and the condition of preeclampsia in an at-risk maternal patient cohort. Umbilical vein volume flow was quantified by a 3-dimensional (3D) sonographic technique that overcomes several limitations of standard sonographic flow measurement methods. METHODS: A total of 35 patients, each with a singleton pregnancy, were recruited to provide 5 patients with preeclampsia, derived as a subset from a 26-patient at-risk group, and 9 patients with normal pregnancies. An ultrasound system equipped with a 2.0-8.0-MHz transducer was used to acquire multivolume 3D color flow and power mode data sets to compute the mean umbilical vein volume flow in patients with normal pregnancies and preeclampsia. RESULTS: The gestational ages of the pregnancies ranged from 29.7 to 34.3 weeks in the patients with preeclampsia and from 25.9 to 34.7 weeks in the patients with normal pregnancies. Comparisons between patients with normal pregnancies and those with preeclampsia showed weight-normalized flow with a moderately high separation between groups (P = .11) and depth-corrected, weight-normalized flow with a statistically significant difference between groups (P = .035). Umbilical vein volume flow measurements were highly reproducible in the mean estimate, with an intrapatient relative SE of 12.1% +/- 5.9% and an intrameasurement relative SE of 5.6% +/- 1.9 %. In patients who developed pregnancy-induced hypertension or severe pregnancy-induced hypertension, umbilical vein volume flow suggested gestational hypertensive disorder before clinical diagnosis. CONCLUSIONS: Results indicate that mean depth-corrected, weight-normalized umbilical vein volume flow is reduced in pregnancies complicated by preeclampsia and that volume flow may indicate hypertensive disorder earlier in gestation. Volume flow measurements are highly reproducible, and further study in a larger clinical population is encouraged to determine whether 3D volume flow can complement the management of preeclampsia and, in general, at-risk pregnancy. PMID- 29243837 TI - A minireplicon of plasmid pBMB26 represents a new typical replicon in the megaplasmids of Bacillus cereus group. AB - A new minireplicon (rep26 minireplicon) from pBMB26, the 188 kb indigenous plasmid related to spore-crystal association (SCA) phenotype in Bacillus thuringiensis strain YBT-020, was characterized. A 12 kb EcoRI fragment, which encoded 10 putative open reading frames (ORFs), was capable of supporting replication when cloned in a replication probe vector. Deletion and frame shift mutation analysis showed that a 4.1 kb region encompassing two putative ORFs (orf21 and orf22) was essential for the plasmid replication in B. thuringiensis. Gene orf21 encoding a 49.8 kDa protein (named Rep26) with a helix-turn-helix motif showed no homology with known replication proteins and gene orf22 encoding a protein of 82.6 kDa showed homology to bacterial PcrA helicase. The replication origin of rep26 minireplicon was proved to be located in the coding region of orf21. Plasmid stability experiments indicated that the recombinant plasmid containing rep26 minireplicon has excellent segregational stability. BLASTP analysis revealed that amino acid sequences of ORF21 and ORF22 were well conserved among Bacillus cereus group strains. The rep26 minireplicon was widely distributed and could be defined as a new typical replicon in the megaplasmids of B. cereus group. PMID- 29243839 TI - Correlation of vitamin D and vitamin D receptor expression in patients with alopecia areata: a clinical paradigm. AB - BACKGROUND: Vitamin D (Vit.D) deficiency has been reported in alopecia areata (AA). Downregulation of Vitamin D receptor (VDR) on hair follicles is associated with reduced hair growth. OBJECTIVE: To correlate serum Vit.D levels with severity, pattern, and duration of AA, and density of VDR expression over hair follicles in AA patients. METHODS: Prospective study including 30 AA patients and 30 healthy controls. Clinical details and serum Vit.D measurement and scalp biopsy for histopathology and VDR expression was performed in patients and controls at baseline and after 6 months of treatment of AA. RESULTS: Mean age of patients and controls was 28.9 +/- 9.96 and 31.17 +/- 9.43 years, respectively. Mean SALT score in patients was 35.8 +/- 27.5 with a median disease duration of 48 weeks. Mean serum Vit.D levels was 7.65 +/- 4.50 ng/ml and 15.8 +/- 11.47 ng/ml in patients and controls, respectively. Twenty-nine (96.7%) patients were Vit.D deficient (<20 ng/ml), compared to 22 (73.3%) controls (P = 0.001). Serum Vit.D levels inversely correlated with severity of the disease (r = -256), P = 0.17, and duration of disease but did not correlate with pattern of AA and VDR expression in tissue samples. VDR expression was reduced in all patients and was normal in controls. Inverse correlation of VDR was noted with presence of inflammation on histology (P = 0.02). VDR upregulation post treatment was seen only in 13% of patients and demonstrated no correlation with response to treatment. CONCLUSION: Vit.D deficiency in AA correlates inversely with disease severity and duration. VDR expression is reduced in AA and inversely correlate with inflammation histologically but does not correlates with serum Vit.D levels, severity, pattern, or duration of illness. PMID- 29243840 TI - Conjugal intimacy, gender and modernity in contemporary China. AB - The new generation of modernity theorists have forecast the democratization of gender relations within intimate relationships in late-modern times. Chinese society has undergone rapid and dramatic changes in its unique trajectory of political, social and economic reform. Using China as an example of a region which has been largely ignored in contemporary social theory, this article enters the debate to contest the extent to which conjugal relationships are democratized in line with modernity. We further test the assertion that modern marriages are characterized by increased self-disclosure and communication between partners. Data from a national survey on Chinese families is analysed in relation to the level of self-disclosure between husbands and wives; gender division of housework; household decision-making; and home ownership. We highlight the impact of gender, cohort and location (urban, rural or migrant) on experiences of modernity and draw attention to the material, social and cultural factors which continue to shape conjugal relations in contemporary Chinese society. Based on our findings, we contest the argument that disclosing intimacy between intimate partners is a defining characteristic of modern relationships, and suggest that other social factors may condition degrees of self-disclosure in marriage. Similarly, we question the extent to which heterosexual conjugal equality is attained: the cultural practices and values of patrilineal family organization, together with material circumstances, continue to influence marital relations in China. PMID- 29243841 TI - Encapsulation challenges, the substantial issue in solid lipid nanoparticles characterization. AB - Solid lipid nanoparticles (SLNs), as alternative colloidal carriers, have been used for the sustained release of lipophilic drugs with poor water solubility. One of the most important parameters in the characterization of SLNs is entrapment efficiency (EE). Despite the importance of this factor in estimating the drug loading capacity, EE does not always represent the exact percentage of the entrapped drug. Several variables such as the stirring speed and duration, and concentration of surfactant, emulsifier, and drug play important roles in determining the final EE. In addition, EE is mainly affected by the type and concentration of the lipid. There are two major methods for the measurement of EE are in which the encapsulated drug in SLNs is either directly measured (direct method) or the amount of unencapsulated drug in the supernatant is measured (indirect method). Accuracy of drug analysis is the main challenge for EE calculation, and is either performed in the separated aqueous medium or the particles. In this review, we aimed to introduce the available methods for EE determination in SLNs and discuss the advantages and shortcomings of each method. PMID- 29243842 TI - Exosomes secreted by hypoxic cardiosphere-derived cells enhance tube formation and increase pro-angiogenic miRNA. AB - Exosomes are required for the regenerative effects of human cardiosphere-derived cells (CDCs). Studies show that they mimic the cardioprotective benefits of CDCs in rodents and porcine myocardial infarction (MI) models. Hypoxic preconditioning of stem cells increases the cardioprotective effects of exosomes in MI models by enhancing angiogenesis. Several exosomal microRNAs (miRNAs) up-regulate in response to hypoxia and play a role in cardioprotective and pro-angiogenic effects. In this study, we have demonstrated that human CDCs secreted exosomes under hypoxic conditions (1% O2 for 2 days) enhanced tube formation by human umbilical vein endothelial cells (HUVECs) at a concentration of 25 ug/mL. Pro angiogenic exosomal miRNAs including miR-126, miR-130a, and miR-210 showed a substantial increase (>2-, >2-, and >4-fold, respectively) in the hypoxic exosomes compared to normoxic CDC-derived exosomes. Our study suggested a significant benefit of hypoxic CDC exosomes for the treatment of cardiac diseases by induction of angiogenesis via enrichment of pro-angiogenic exosomal miRNAs. PMID- 29243843 TI - Signaling cascades in thyroid cancer: Increasing the armory of archers to hit bullseye. AB - Thyroid cancer is a multifaceted and therapeutically challenging disease and rapidly accumulating experimentally verified findings have considerably improve our understanding of the molecular mechanisms which underlie its development. Substantial fraction of information has been added into existing landscape of molecular oncology and we have started to develop a sharper understanding of the underlying mechanisms of thyroid cancer. Wealth of information demystified different intracellular signaling cascades which are frequently deregulated in thyroid cancer. In vitro assays and xenografted mice based studies have helped us to identify drug targets and different synthetic and natural products are currently being tested to effectively treat thyroid cancer. Cabozantinib and vandetanib have been approved to treat medullary thyroid cancer (MTC) and two agents (lenvatinib and sorafenib) are also being used to treat radioactive-iodine refractory differentiated thyroid cancer. This review comprehensively summarizes most recent advancements in our knowledge related to dysregulated intracellular signaling cascades in thyroid cancer and how different proteins can be therapeutically exploited. (1) We discuss how loss of TRAIL mediated apoptosis occurred in thyroid cancer cells and how different strategies can be used to restore apoptosis in resistant cancer cells; (2) We provide detailed account of seemingly opposite roles of NOTCH signaling in thyroid cancers; (3) TGF/SMAD mediated signaling also needs detailed research because of context dependent role in thyroid cancer. Researchers have only begun to scratch the surface of how TGF signaling works in thyroid cancer and metastasis; and (4) Role of SHH signaling in thyroid cancer stem cells is also well appreciated and targeting of SHH pathway will be an important aspect in treatment of thyroid cancer. Better concepts and improved knowledge will be helpful for clinicians in getting a step closer to individualized medicine. PMID- 29243844 TI - In vitro improvement of quail primordial germ cell expansion through activation of TGF-beta signaling pathway. AB - Avian primordial germ cells (PGCs) have valuable potentials to cell-based approaches for transgenic bird production. In this regard, improvement of avian PGC expansion in vitro is necessary. Among experimental avian species, quail is a good model for transgenic technology, especially due to its short generation time. In the present study, we have examined the proliferative effects of transforming growth factor beta (TGF-beta) on the quail PGCs. After isolation of quail PGCs from blood (Hamburger-Hamilton [HH stages 13-15]) and gonads (HH stages 28-30), these cells were cultured on quail embryonic fibroblasts (QEF). Our results indicated th at cultured gonadal-derived PGCs proliferated 400 times in comparison to 100 times for blood PGCs over 40-50 days. Upon in vitro exposure to TGF-beta inducers by Activin or the inducer of definitive endoderm 1 (IDE1) small molecule, the number of gonad PGCs significantly increased to 26% and 64%, respectively. In contrast, inhibition of the TGF-beta signaling pathway by SB431542 resulted in a significant reduction in the numbers of PGCs (P < 0.001). Moreover, Phosphorylation of SMAD2/3 in the IDE1 group was higher compared to the Activin-treated ones. We confirmed the PGC identification with periodic acid Schiff (PAS) staining, anti-SSEA1, beta-catenin, beta-integrin, and Nanog immunofluorescence staining. Exogenously IDE1 treated-PGCs migrated toward the embryonic gonads after transplantation into the heart of the recipient embryo at HH stages 13-15. Our results suggested that the application of IDE1 small molecule into the culture of quail PGCs represented a step toward achieving efficient expansion of the avian PGCs. PMID- 29243845 TI - FcER1alpha gene polymorphism shows association with high IgE and anti-FcER1alpha in Chronic Rhinosinusitis with Nasal Polyposis. AB - Despite large number of investigations, the etiology of chronic rhinosinusitis (CRS) remains unclear. Several factors are likely involved in its onset. The genetic susceptibility of IgE-responsiveness likely caused by polymorphism(s) in high affinity receptor for IgE (FcER1alpha) gene can help in understanding the pathophysiology of CRS with nasal polyposis (CRSwNP). A population-based case control association analysis was conducted to assess the risk of CRSwNP conferred by single nucleotide polymorphisms (SNPs) in FcER1alpha gene in a North Indian cohort. Two promoter and three exonic regions of FcER1alpha gene were amplified and sequenced to investigate five SNPs: rs2427827, rs2251746, rs2298804, rs2298805, and rs2269718. BLAST analysis and subsequent multiple alignments, with known sequences available in the NCBI database, were performed. Total serum IgE and FcER1alpha antibody levels were estimated. Patient IgE level of 461.22 +/- 436.43 in comparison to 83.62 +/- 58.043 IU/mL in controls (P < 0.0001), and FcER1alpha antibody level of 292.38 +/- 115.27 in comparison to 160.56 +/- 105.9 in controls (P < 0.0001), depicts their highly significant associations with CRSwNP disease. However, no SNP showed evidence of association with CRSwNP; although relatively higher Odds ratios were observed with rs2427827, rs2251746, and rs2298804. Patient stratification revealed a significant association (P < 0.05) of rs2427827 SNP with high IgE level CRSwNP patients. Nonetheless, we found no SNP associated with low serum IgE level patients. SNP (rs2427827) in the FcER1alpha gene region and high IgE levels may confer susceptibility to CRSwNP in north Indian population. However, further studies including larger sample size, gene-gene, and gene-environment interactions are required for its elucidation. PMID- 29243846 TI - AQP2 can modulate the pattern of Ca2+ transients induced by store-operated Ca2+ entry under TRPV4 activation. AB - There is increasing evidence indicating that aquaporins (AQPs) exert an influence in cell signaling by the interplay with the TRPV4 Ca2+ channel. Ca2+ release from intracellular stores and plasma membrane hyperpolarization due to opening of Ca2+ -activated potassium channels (KCa) are events that have been proposed to take place downstream of TRPV4 activation. A major mechanism for Ca2+ entry, activated after depletion of intracellular Ca2+ stores and driven by electrochemical forces, is the store-operated Ca2+ entry (SOCE). The consequences of the interplay between TRPV4 and AQPs on SOCE have not been yet investigated. The aim of our study was to test the hypothesis that AQP2 can modulate SOCE by facilitating the interaction of TRPV4 with KCa channels in renal cells. Using fluorescent probe techniques, we studied intracellular Ca2+ concentration and membrane potential in response to activation of TRPV4 in two rat cortical collecting duct cell lines (RCCD1 ), one not expressing AQPs (WT-RCCD1 ) and the other transfected with AQP2 (AQP2-RCCD1 ). We found that AQP2 co immunoprecipitates with TRPV4 and with the small-conductance potassium channel (SK3). We also showed that AQP2 is crucial for the activation of SK3 by TRPV4, leading to hyperpolarization of the plasma membrane. This seems to be relevant to modulate the magnitude of SOCE and is accompanied by TRPV4 translocation to the plasma membrane only in AQP2 expressing cells. These findings open the perspective to further investigate whether the interplay between different AQPs with TRPV4 and KCa channels can be an important mechanism to modulate SOCE with physiological relevance. PMID- 29243847 TI - Utility of complete blood count parameters to detect premature ovarian insufficiency in cases with oligomenorrhea/amenorrhea. AB - BACKGROUND: There are very few biomarkers available to diagnose cases with premature ovarian failure. Some complete blood count parameters have been introduced to be diagnostic biomarkers for several disorders associated with inflammatory process. Due to the evidence that indicated chronic inflammatory process to be underlying pathophysiology in premature ovarian insufficiency (POI), we aimed to assess the predictive value of complete blood count parameters for POI diagnosis. METHOD: A total of 96 women diagnosed to have premature ovarian failure were compared with 110 otherwise healthy women in terms of some basal hormone levels and complete blood count parameters. RESULTS: Mean age was similar between groups. Neutrophil/lymphocyte and mean platelet volume/lymphocyte ratios were significantly higher in group with POI (P < .001, P < .003, respectively). In group with POI, there were significant correlations between anti-Mullerian hormone and follicle stimulating hormone (r = -.30, P <.05), anti Mullerian hormone and white blood cell count (r = .23, P < .05). Mean platelet volume/lymphocyte ratio significantly predicted cases with POI (AUC = 0.607, %95 CI: 0.529-0.684; P < .001). CONCLUSIONS: Neutrophil/lymphocyte and mean platelet volume/lymphocyte ratios are elevated in POI. There have been some controversies about the value of neutrophil/lymphocyte in POI diagnosis. We suggest mean platelet volume/lymphocyte ratio as a new biomarker in early POI because it is cheap and easily accessible compared to anti-Mullerian hormone. PMID- 29243848 TI - Analgesic efficacy of preoperative dexketoprofen trometamol: A systematic review and meta-analysis. AB - Post-Market Research Clinical evidence supports the use of dexketoprofen trometamol (DEX) to manage acute postoperative pain. However, controversies surround the impact of the use of this drug in preoperative analgesic protocols. The aim of the present meta-analysis was to evaluate the effectiveness of the preoperative administration of DEX under postoperative pain conditions. Electronic and manual searches were conducted through diverse electronic databases. A systematic review and meta-analysis to evaluate the analgesic efficacy of the preoperative administration of DEX was performed including Randomized Clinical Trials (RCTs) published between 2002 and 2017. Suitable individual studies were evaluated through a quality system, and the data were extracted and analyzed. Fourteen RTCs were included (12 parallel trials and 2 cross-over trials), published in the English and Turkish languages. Follow-up periods ranged from 4, 6, 8, 24, and 48 hr. All trials measured the outcome result as Acute Pain Level (APL) (VAS, NRS, VRS), time to requiring a second dose of DEX or analgesic emergency and consumption of opioids via patient-controlled analgesia. When the comparators were other drugs - paracetamol, Lornoxicam or placebo during the preoperative time, preoperative administration of DEX was superior. When the comparison comprised preoperative and postoperative DEX, both alternatives exhibited comparable analgesic effects. The analgesic efficacy of the preoperative administration of DEX when compared to placebo, lornoxicam, and paracetamol on postoperative pain was evident. Preoperative administration of DEX compared to its immediate postoperative administration showed a similar analgesic effect. PMID- 29243849 TI - Therapeutic patient education in children with moderate to severe atopic dermatitis: A multicenter randomized controlled trial in China. AB - BACKGROUND: Therapeutic patient education is a continuous, systematic, patient centered learning process to help patients and their families acquire and maintain the skills they need to manage their lives with a chronic disease. It has been proven effective in increasing treatment adherence and improving quality of life for patients with atopic dermatitis (AD) in Western countries. We introduce the first multicenter, randomized controlled clinical trial of therapeutic patient education in Chinese children with AD. OBJECTIVES: To evaluate the effects of therapeutic patient education on the severity of AD, quality of life, and understanding and successful use of emollients in Chinese children with eczema. METHODS: We recruited 580 children, ages 2-14 years, with moderate to severe AD from six hospitals in China. Participants were randomized (1:1) to an intervention (n = 293) or control (n = 249) group. In addition to the severity of AD, data on quality of life and a questionnaire on family and patient knowledge of emollients were evaluated at the 6-month follow-up. RESULTS: On study completion, we found that the intervention group showed a significantly greater reduction in mean SCORing Atopic Dermatitis (P < .001) and Infant's Dermatology Life Quality Index (P = .030) scores than the control group. In addition, knowledge about the use of emollients improved significantly in the intervention group. There was no significant difference between groups in Children's Dermatology Life Quality Index scores. CONCLUSIONS: The first randomized controlled trial of a therapeutic patient education program in China had positive long-term effects on decreasing eczema severity and improvement of quality of life in children 2-4 years of age with AD, as well as in promoting greater understanding of the use of emollients. PMID- 29243851 TI - Alterations in gene expression in vitamin D-deficiency: Down-regulation of liver Cyp7a1 and renal Oat3 in mice. AB - The vitamin D-deficient model, established in the C57BL/6 mouse after 8 weeks of feeding vitamin D-deficient diets in the absence or presence of added calcium, was found associated with elevated levels of plasma parathyroid hormone (PTH) and plasma and liver cholesterol, and a reduction in cholesterol 7alpha-hydroxylase (Cyp7a1, rate-limiting enzyme for cholesterol metabolism) and renal Oat3 mRNA/protein expression levels. However, there was no change in plasma calcium and phosphate levels. Appraisal of the liver revealed an up-regulation of mRNA expressions of the small heterodimer partner (Shp) and attenuation of Cyp7a1, which contributed to hypercholesterolemia in vitamin D-deficiency. When vitamin D sufficient or D-deficient mice were further rendered hypercholesterolemic with 3 weeks of feeding the respective, high fat/high cholesterol (HF/HC) diets, treatment with 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ], active vitamin D receptor (VDR) ligand, or vitamin D (cholecalciferol) to HF/HC vitamin D deficient mice lowered the cholesterol back to baseline levels. Cholecalciferol treatment partially restored renal Oat3 mRNA/protein expression back to that of vitamin D-sufficient mice. When the protein expression of protein kinase C (PKC), a known, negative regulator of Oat3, was examined in murine kidney, no difference in PKC expression was observed for any of the diets with/without 1,25(OH)2 D3 /cholecalciferol treatment, inferring that VDR regulation of renal Oat3 did not involve PKC in mice. As expected, plasma calcium levels were not elevated by cholecalciferol treatment of vitamin D-deficient mice, while 1,25(OH)2 D3 treatment led to hypercalcemia. In conclusion, vitamin D-deficiency resulted in down-regulation of liver Cyp7a1 and renal Oat3, conditions that are alleviated upon replenishment of cholecalciferol. PMID- 29243852 TI - Functional divergence and comparative in-silico study of Cas4 proteins of DUF83 class. AB - Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated (CRISPR-Cas) systems present in genomes of bacteria and archaea have been the focus of many research studies recently. The Cas4 proteins of these systems are thought to be responsible for the adaptation step in the CRISPR mechanism. Cas4 proteins exhibit low sequence similarity among themselves and are currently classified into 2 main classes: DUF83 and DUF911. The characteristic features of Cas4 proteins belonging to DUF83 class have been elucidated by determining the structures of Cas4 protein from Sulfolobus solfataricus and Pyrobaculum calidifontis. Although, both Cas4 proteins characterized structurally are of same DUF83 class, these 2 proteins do exhibit significant biochemical and functional differences. The aim of the present study was to explore the structural and evolutionary features responsible for these differences. Our study predicts residues which might be responsible for such differences. Functional divergence analysis was used to predict sites exhibiting type I divergence, where certain amino acids are conserved in 1 clade whereas the same site is highly variable in the other clade. Our intra-molecular interaction analysis reinforces the influence of such divergence sites on the other functionally important amino acids. In general, this study identifies some of the divergence hotspots that could be the focus of future experimental studies for better understanding of Cas4 enzymatic activity in CRISPR mechanism. PMID- 29243853 TI - Design and Synthesis of Aza-Bicyclononene Dienophiles for Rapid Fluorogenic Ligations. AB - Fluorogenic bioorthogonal reactions enable visualization of biomolecules under native conditions with excellent signal-to-noise ratio. Here, we present the design and synthesis of conformationally-strained aziridine-fused trans cyclooctene (aza-TCO) dienophiles, which lead to the formation of fluorescent products in tetrazine ligations without the need for attachment of an extra fluorophore moiety. The presented aza-TCOs adopt the highly strained "half-chair" conformation, which was predicted computationally and confirmed by NMR measurements and X-ray crystallography. Kinetic studies revealed that the aza TCOs belong to the most reactive dienophiles known to date. The potential of the newly developed aza-TCO probes for bioimaging applications is demonstrated by protein labeling experiments, imaging of cellular glycoconjugates and peptidoglycan imaging of live bacteria. PMID- 29243850 TI - Serum pepsinogen 1 and anti-Helicobacter pylori IgG antibodies as predictors of gastric cancer risk in Finnish males. AB - BACKGROUND: Serum pepsinogen 1 (SPG1) and anti-Helicobacter pylori serology have been used for gastric risk stratification in Asia. AIM: To assess utility of these markers in a Western population. METHODS: SPG1 measurements were available for 21 895 Finnish male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. We used Cox proportional hazards models adjusted for potential confounders to estimate gastric cancer hazard ratios (HR) and 95% confidence intervals (95% CI) for low SPG1 (<25 MUg/L). In a subset (n = 3555) with anti-H. pylori serology, these markers jointly defined the following: Group A (H. pylori[ ], SPG1[normal]; reference group), Group B (H. pylori[+], SPG1[normal]), Group C (H. pylori[+], SPG1[low]) and Group D (H. pylori[-], SPG1[low]). Odds ratios (ORs) and 95% CI were calculated using multivariate logistic regression. RESULTS: There were 329 gastric cancers diagnosed an average of 13.9 years after baseline. Pre-diagnostic low SPG1 was significantly associated with increased gastric cancer risk (HR 2.68, 95% CI 1.99-3.61). Among subjects with both SPG1 and H. pylori serology, groups B, C and D had increased gastric cancer ORs (95% CI) of 1.79 (1.21-2.64), 3.85 (2.36-6.28) and 6.35 (2.20-18.34), respectively. CagA seropositives had significantly higher ORs than CagA seronegatives within group B (Pheterogeneity = 0.01). For groups B and C, repeat SPG1 level at 3 years did not further stratify gastric cancer risk. CONCLUSIONS: Low SPG1 was associated with increased gastric cancer risk in our large Finnish cohort. A single measurement of SPG1 along with H. pylori whole cell and CagA serology provides potentially useful prediction of gastric cancer risk. PMID- 29243854 TI - A Coordination Chemistry Approach to Fine-Tune the Physicochemical Parameters of Lanthanide Complexes Relevant to Medical Applications. AB - The geometric features of two pyclen-based ligands possessing identical donor atoms but different site organization have a profound impact in their complexation properties toward lanthanide ions. The ligand containing two acetate groups and a picolinate arm arranged in a symmetrical fashion (L1) forms a Gd3+ complex being two orders of magnitude less stable than its dissymmetric analogue GdL2. Besides, GdL1 experiences a much faster dissociation following the acid catalyzed mechanism than GdL2. On the contrary, GdL1 exhibits a lower exchange rate of the coordinated water molecule compared to GdL2. These very different properties are related to different strengths of the Gd-ligand bonds associated to steric effects, which hinder the coordination of a water molecule in GdL2 and the binding of acetate groups in GdL1. PMID- 29243855 TI - Non-invasive placentation in the marsupials Macropus eugenii (Macropodidae) and Trichosurus vulpecula (Phalangeridae) involves redistribution of uterine Desmoglein-2. AB - In mammalian pregnancy, the uterus is remodeled to become receptive to embryonic implantation. Since non-invasive placentation in marsupials is likely derived from invasive placentation, and is underpinned by intra-uterine conflict between mother and embryo, species with non-invasive placentation may employ a variety of molecular mechanisms to maintain an intact uterine epithelium and to prevent embryonic invasion. Identifying such modifications to the uterine epithelium of marsupial species with non-invasive placentation is key to understanding how conflict is mediated during pregnancy in different mammalian groups. Desmoglein 2, involved in maintaining lateral cell-cell adhesion of the uterine epithelium, is redistributed before implantation to facilitate embryo invasion in mammals with invasive placentation. We identified localization patterns of this cell adhesion molecule throughout pregnancy in two marsupial species with non-invasive placentation, the tammar wallaby (Macropus eugenii; Macropodidae), and the brushtail possum (Trichosurus vulpecula; Phalangeridae). Interestingly, Desmoglein-2 redistribution also occurs in both M. eugenii and T. vulpecula, suggesting that cell adhesion, and thus integrity of the uterine epithelium, is reduced during implantation regardless of placental type, and may be an important component of uterine remodeling. Desmoglein-2 also localizes to the mesenchymal stromal cells of M. eugenii and to epithelial cell nuclei in T. vulpecula, suggesting its involvement in cellular processes that are independent of adhesion and may compensate for reduced lateral adhesion in the uterine epithelium. We conclude that non-invasive placentation in marsupials involves diverse and complementary strategies to maintain an intact epithelial barrier. PMID- 29243856 TI - Structural Origin of Metal Specificity in Isatin Hydrolase from Labrenzia aggregata Investigated by Computer Simulations. AB - We performed quantum-chemical calculations, ab initio molecular dynamics, hybrid quantum mechanics/molecular mechanics (QM/MM) and enhanced sampling metadynamics simulations to investigate the origin of metal specificity in isatin hydrolase from Labrenzia aggregata. The peculiar octahedral binding geometry of the Mn2+ ion in the Michaelis complex includes both the isatin substrate and the catalytic water within the first coordination shell of the cation. Our calculations show that the same arrangement of the ligands cannot be efficiently achieved in the presence of other small divalent metal cations such as Zn2+ or Cu2+ . On the contrary, bulkier alkaline-earth cations such as Mg2+ , which allow octahedral coordination, are not able to activate the catalytic water into the stronger OH- nucleophile required to attack the stable N-aryl-amide moiety of isatin. PMID- 29243857 TI - Clinical outcomes according to symptom presentation in patients with acute myocardial infarction: Results from the FAST-MI 2010 registry. AB - BACKGROUND: Atypical clinical presentation in acute myocardial infarction (AMI) patients is not uncommon; most studies suggest that it is associated with unfavorable prognosis. HYPOTHESIS: Long-term clinical impact differs according to predominant symptom presentation (typical chest pain, atypical chest pain, syncope, cardiac arrest, or dyspnea) in AMI patients. METHODS: FAST-MI 2010, a nationwide French registry, included 4169 patients with AMI in 213 centers at the end of 2010 (76% of active centers). Demographics, medical history, hospital management, and outcomes were compared according to predominant symptom presentation. RESULTS: Typical chest pain with no other symptom was reported in 3020 patients (68% in STEMI patients, 76% in NSTEMI patients). Atypical chest pain, dyspnea, syncope, and cardiac arrest were reported in 11%, 11%, 5%, and 1%, respectively. Patients with atypical clinical presentation had a higher cardiovascular risk profile and received fewer medications and a less invasive strategy. Using Cox multivariate analysis, atypical chest pain was not associated with higher death rate at 3 years (HR: 0.96, 95% CI: 0.69-1.33, P = 0.78), whereas cardiac arrest (HR: 2.44, 95% CI: 1.00-5.97, P = 0.05), syncope (HR: 1.70, 95% CI: 1.18-2.46, P = 0.005), and dyspnea (HR: 1.66, 95% CI: 1.31-2.10, P < 0.001) were associated with higher long-term mortality compared with patients with typical isolated chest pain. Similar trends were observed in STEMI and NSTEMI populations. CONCLUSIONS: Atypical clinical presentation is observed in about 20% of AMI patients. Cardiac arrest, dyspnea, and syncope represent independent predictors of long-term mortality in STEMI and NSTEMI populations. PMID- 29243858 TI - Atrial fibrillation and risk of cardiovascular events and mortality in patients with symptomatic peripheral artery disease: A meta-analysis of prospective studies. AB - BACKGROUND: Atrial fibrillation (AF) is associated with adverse outcomes in terms of survival and morbidity. Peripheral artery disease (PAD) and AF share several common risk factors and often coexist. Whether AF has a prognostic role in patients with PAD has not been extensively studied. HYPOTHESIS: AF is associated with major adverse cardiac events (MACE) and mortality in symptomatic PAD patients. METHODS: Using MEDLINE and Scopus, we searched for studies published before December 2016 that evaluated cardiovascular outcomes based on the presence/absence of AF in a prospective manner with a follow-up period of >=12 months. The outcomes were reported using a random-effects model, and heterogeneity was assessed using the I2 statistic. Sensitivity analyses were performed to test the contribution of each study to the overall results. RESULTS: Six prospective studies (Newcastle-Ottawa score range, 7-9) with 14 656 patients were included in the final analysis (age range, 66-70 years; median follow-up, 1.4 years). Our pooled analysis found a significant association between AF and mortality (odds ratio: 2.52, 95% confidence interval: 1.91-3.34, I2 = 32.6%), without evidence of publication bias (P = 0.63). Meta-analysis showed a significant impact of AF on MACE (odds ratio: 2.54, 95% confidence interval: 1.78 3.63, I2 = 74.3%), without detected publication bias (P = 0.08). CONCLUSIONS: AF is associated with increased risk of mortality and MACE in symptomatic PAD. PMID- 29243860 TI - Serum YKL-40 in workers at an indium-tin oxide production facility - Reply. PMID- 29243859 TI - Neuroinflammatory reactions in sickness behavior induced by bacterial infection: Protective effect of minocycline. AB - The neurological changes elicited by bacterial infection are called sickness behavior. Minocycline (MIN) is neuroprotective with a remarkable brain tissue penetration. MIN was orally administered at a dose 90 mg/kg for 3 days, whereas Escherichia coli was given as a single intraperitoneal injection (0.2 mL of 24 h growth) on the third day. After 24 h of bacterial infection, behavioral tests namely open field and forced swimming were carried out, then animals were decapitated. Rats infected with E. coli displayed reduced struggling time in forced swimming test, as well as, exploration and locomotion in open field test with reduction in neurotransmitters (norepinephrine, dopamine, and serotonin) versus elevation in the inflammatory (tumor necrosis factor-alpha, interferon gamma) and oxidative stress (thiobarbituric acid reactive substance, reduced glutathione) biomarkers. Inflammatory infiltrates of nuclear cells were observed in brains of infected rats. MIN administration prevented the deleterious effects of E. coli infection, thus protects against sickness behavior possibly via defending from neuroinflammation. PMID- 29243861 TI - Serum YKL-40 in workers at an indium-tin oxide production facility. PMID- 29243862 TI - Effects of sodium benzoate, a commonly used food preservative, on learning, memory, and oxidative stress in brain of mice. AB - Sodium benzoate (SB) is a widely used preservative and antimicrobial substance in many foods and soft drinks. However, this compound is generally recognized as safe food additives, but evidence has suggested that a high intake of SB may link to attention deficit-hyperactivity disorder in children. Present study investigate the effects of oral administration of different concentrations of SB (0.56, 1.125, and 2.25 mg/mL) for 4 weeks, on the learning and memory performance tests, and also the levels of malondialdehyde (MDA), reduced glutathione (GSH), and acetylcholinesterase activity (AChE) in the mouse brain. The results showed that SB significantly impaired memory and motor coordination. Moreover, SB decreased reduced GSH and increased the MDA level in the brain significantly (P < 0.001). However, nonsignificant alteration was observed in the AChE activity. These findings suggest that short-term consumption of SB can impair memory performance and increased brain oxidative stress in mice. PMID- 29243863 TI - Synthesis and antioxidant, antixanthine oxidase, and antielastase activities of novel N,S-substituted polyhalogenated nitrobutadiene derivatives. AB - In this study, three substituted polyhalogenated nitrobutadiene derivatives were synthesized. Compound 1-[(2,3-dibromopropyl)sulfanyl]-1,3,4,4-tetrachloro-2 nitrobuta-1,3-diene (4) was synthesized before by our group. Compounds 8-{[1 [(2,3-dibromopropyl)sulfany]-3,4,4-trichloro-2-nitrobuta-1,3-butadien-1-yl}-1,4 dioxa-8-azaspiro[4.5]decane (5) and 1-[(2,3-dibromopropyl)sulfanyl]-3,4,4 trichloro-N-(4-methylpiperazin-1-yl)-2-nitrobuta-1,3-diene-1-amine (6) were synthesized in this work as original compounds. Xanthine oxidase, elastase inhibition abilities, and antioxidant activities were investigated in this work for compounds 4, 5, and 6. In this study, compounds 4, 5, and 6 exhibited antixanthine oxidase, antielastase, and antioxidant activities. Among the compounds screened, compound 4 exhibited xanthine oxidase and elastase inhibitor effect similar to the standard compound. Among the three tested compounds, compound 6 showed potent DPPH radical scavenging and reducing power activities. Therefore, these three compounds (4, 5, and 6) may be useful as an antixanthine oxidase, antielastase, and antioxidant agent in pharmaceutical and cosmetic industry. PMID- 29243865 TI - The air around us. PMID- 29243866 TI - The dual role of MamB in magnetosome membrane assembly and magnetite biomineralization. AB - Magnetospirillum gryphiswaldense MSR-1 synthesizes membrane-enclosed magnetite (Fe3 O4 ) nanoparticles, magnetosomes, for magnetotaxis. Formation of these organelles involves a complex process comprising key steps which are governed by specific magnetosome-associated proteins. MamB, a cation diffusion facilitator (CDF) family member has been implicated in magnetosome-directed iron transport. However, deletion mutagenesis studies revealed that MamB is essential for the formation of magnetosome membrane vesicles, but its precise role remains elusive. In this study, we employed a multi-disciplinary approach to define the role of MamB during magnetosome formation. Using site-directed mutagenesis complemented by structural analyses, fluorescence microscopy and cryo-electron tomography, we show that MamB is most likely an active magnetosome-directed transporter serving two distinct, yet essential functions. First, MamB initiates magnetosome vesicle formation in a transport-independent process, probably by serving as a landmark protein. Second, MamB transport activity is required for magnetite nucleation. Furthermore, by determining the crystal structure of the MamB cytosolic C terminal domain, we also provide mechanistic insight into transport regulation. Additionally, we present evidence that magnetosome vesicle growth and chain formation are independent of magnetite nucleation and magnetic interactions respectively. Together, our data provide novel insight into the role of the key bifunctional magnetosome protein MamB, and the early steps of magnetosome formation. PMID- 29243864 TI - Elimination-Fusion Self-Assembly of a Nanometer-Scale 72-Nucleus Silver Cluster Caging a Pair of [EuW10 O36 ]9- Polyoxometalates. AB - The largest known polyoxometalate (POM)-templated silver-alkynyl cluster, [(EuW10 O36 )2 @Ag72 (tBuC=C)48 Cl2 ?4 BF4 ] (SD/Ag20), was isolated under solvothermal conditions and structurally characterized. It was confirmed by single-crystal X ray diffraction (SCXRD) as a {EuW10 }2 -in-{Ag72 } clusters-in-cluster rod-like compound. The high-resolution electrospray ionization mass spectrometry (HR-ESI MS) shows that such a double anion-templated cluster is assembled from a crucial single anion-templated Ag42 intermediate in the solution. The crystallization of Ag42 species (SD/Ag21), followed by SCXRD, gave an important clue about the assembly route of SD/Ag20 in solution: the Ag42 cluster eliminates six silver atoms laterally, then fuses together at the vacant face to form the final Ag72 cluster (elimination-fusion mechanism). The characteristic emission of [EuW10 O36 ]9- is well maintained in SD/Ag20. This work not only provides a new method for the synthesis of larger silver clusters as well as the functional integration of the silver cluster and POMs, but also gives deep insights about the high-nuclear silver cluster assembly mechanism. PMID- 29243867 TI - Factors for incomplete adherence to antiretroviral therapy including drug refill and clinic visits among older adults living with human immunodeficiency virus - cross-sectional study in South Africa. AB - OBJECTIVES: To assess adherence outcomes to antiretroviral therapy (ART) of recipients >=50 years in Soweto, South Africa. METHODS: This was a secondary data analysis for a cross-sectional study at two HIV clinics in Soweto. Data on ART adherence and covariates were gathered through structured interviews with HIV 878 persons living with HIV (PLHIV) receiving ART. Logistic regression analysis was used to assess associations. RESULTS: PLHIV >=50 years (n = 103) were more likely to miss clinic visits during the last six months than PLHIV aged 25-49 (OR 2.15; 95%CI 1.10-4.18). PLHIV >=50 years with no or primary-level education were less likely to have missed a clinic visit during the last six months than PLHIV with secondary- or tertiary-level education in the same age category (OR 0.3; 95%CI 0.1-1.1), as were PLHIV who did not disclose their status (OR 0.2; 95%CI 0-1.1). There was no evidence of increased risk for non-adherence to ART pills and drug refill visits among older PLHIV. CONCLUSION: Missing a clinic visit was more common among older PLHIV who were more financially vulnerable. Further studies are needed to verify these findings and identify new risk factors associated with ART adherence. PMID- 29243868 TI - Genetic diversity of small populations: Not always "doom and gloom"? AB - Is a key theory of evolutionary and conservation biology-that loss of genetic diversity can be predicted from population size-on shaky ground? In the face of increasing human-induced species depletion and habitat fragmentation, this question and the study of genetic diversity in small populations are paramount to understanding the limits of species' responses to environmental change and to providing remedies to endangered species conservation. Few empirical studies have investigated to what degree some small populations might be buffered against losses of genetic diversity. Even fewer studies have experimentally tested the potential underlying mechanisms. The study of Schou, Loeschcke, Bechsgaard, Schlotterer, and Kristensen () in this issue of Molecular Ecology is elegant in combining classic common garden experimentation with population genomics on an iconic experimental model species (Drosophila melanogaster). The authors reveal a slower rate of loss of genetic diversity in small populations under varying thermal regimes than theoretically expected and hence an unexpected retention of genetic diversity. They are further able to hone in on a plausible mechanism: associative overdominance, wherein homozygosity of deleterious recessive alleles is especially disfavoured in genomic regions of low recombination. These results contribute to a budding literature on the varying mechanisms underlying genetic diversity in small populations and encourage further such research towards the effective management and conservation of fragmented or endangered populations. PMID- 29243869 TI - Biobanks and Comprehensive Cancer Center Finland (FICAN) as institutions enabling clinical drug testing. AB - Clinical trials aiming at developing targeted drug therapies require the identification of appropriate patient groups, utilizing both clinical information and the biological profile of the disease. The Finnish healthcare system provides exceptional possibilities for utilizing health data in identifying patient groups, planning of clinical sample studies and recruiting patients. Biobanks established at university hospitals together with the regional cancer centers play a central role in collecting biological specimens and attaching health data to the specimens. Combined with longitudinal health data, the collections of tissue specimens obtained in connection with the diagnosis offer versatile possibilities for the development of companion diagnostics of targeted drugs. Specimens collected on the basis of informed consent in connection with diagnosis and treatment enable the identification of patients suitable for drug trials, and a contact according to the consent. In the development of new functions, national collaboration - both geographical and between research infrastuctures - becomes of paramount importance. Combining the resources of biobanks, the genome strategy and the Comprehensive Cancer Center, an enabling legislation and, above all, patients with a positive attitude towards examinations, offer excellent possibilities for Finland to become the model country of individualized treatment. PMID- 29243870 TI - Mechanistic Studies on NaHCO3 Hydrogenation and HCOOH Dehydrogenation Reactions Catalysed by a FeII Linear Tetraphosphine Complex. AB - We present a theoretical extension of the previously published bicarbonate hydrogenation to formate and formic acid dehydrogenation catalysed by FeII complexes bearing the linear tetraphosphine ligand tetraphos-1. The hydrogenation reaction was found to proceed at the singlet surface with two competing pathways: A) H2 association to the Fe-H species followed by deprotonation to give a Fe(H)2 intermediate, which then reacts with CO2 to give formate. B) CO2 insertion into the Fe-H bond, followed by H2 association and subsequent deprotonation. B was found to be slightly preferred with an activation energy of 22.8 kcal mol-1 , compared to 25.3 for A. Further we have reassigned the Fe-H complex, as a Fe(H)(H2 ), which undergoes extremely rapid hydrogen exchange. PMID- 29243872 TI - Binding affinity and in vitro cytotoxicity of harmaline targeting different motifs of nucleic acids: An ultimate drug designing approach. AB - The work focuses towards interaction of harmaline, with nucleic acids of different motifs by multispectroscopic and calorimetric techniques. Findings of this study suggest that binding constant varied in the order single-stranded (ss) poly(A) > double-stranded calf thymus (CT) DNA > double-stranded poly(G).poly(C) > clover leaf tRNAPhe . Prominent structural changes of ss poly(A), CT DNA, and poly(G). poly(C) with concomitant induction of optical activity in the bound achiral alkaloid molecule was observed, while with tRNAPhe , very weak induced circular dichroism perturbation was seen. The interaction was predominantly exothermic, enthalpy driven, and entropy favored with CT DNA and poly(G).poly(C), while it was entropy driven with poly(A) and tRNAPhe . Intercalated state of harmaline inside poly(A), CT DNA, and poly(G).poly(C) was shown by viscometry, ferrocyanide quenching, and molecular docking. All these findings unequivocally pointed out preference of harmaline towards ss poly(A) inducing self-structure formation. Furthermore, harmaline administration caused a significant decrease in proliferation of HeLa and HepG2 cells with GI50 of 28MUM and 11.2MUM, respectively. Nucleic acid fragmentation, cellular ultramorphological changes, decreased mitochondrial membrane potential, upregulation of p53 and caspase 3, generation of reactive oxygen species, and a significant increase in the G2 /M population made HepG2 more prone to apoptosis than are HeLa cells. PMID- 29243871 TI - Expression of six3 and otx in Solenogastres (Mollusca) supports an ancestral role in bilaterian anterior-posterior axis patterning. AB - The homeodomain transcription factors six3 and otx are involved in patterning the anterior body and parts of the central nervous system (CNS) in bilaterians. Their similar expression patterns have been used as an argument for homology of heads, brains, segmentation, and ciliated larvae. We investigated the developmental expression of six3 and otx in the aplacophoran mollusk Wirenia argentea. Six3 is expressed in subepithelial cells delimiting the apical organ of the solenogaster pericalymma larva. Otx is expressed in cells of the prototroch and adjacent regions as well as in posterior extensions of the prototrochal expression domain. Advanced larvae also show pretrochal otx expression in the developing CNS. Comparative analysis of six3 and otx expression in bilaterians argues for an ancestral function in anterior-posterior body axis patterning but, due to its presence in animals lacking a head and/or a brain, not necessarily for the presence of these morphological structures in the last common ancestor (LCA) of bilaterians. Likewise, the hypothesis that the posterior border of otx expression corresponds to the border between the unsegmented head and the segmented trunk of the LCA of protostomes is not supported, since otx is extensively expressed in the trunk in W. argentea and numerous other protostomes. PMID- 29243873 TI - A comprehensive review of genetic and epigenetic mechanisms that regulate BDNF expression and function with relevance to major depressive disorder. AB - Major depressive disorder (MDD) is a mood disorder that affects behavior and impairs cognition. A gene potentially important to this disorder is the brain derived neurotrophic factor (BDNF) as it is involved in processes controlling neuroplasticity. Various mechanisms exist to regulate BDNF's expression level, subcellular localization, and sorting to appropriate secretory pathways. Alterations to these processes by genetic factors and negative stressors can dysregulate its expression, with possible implications for MDD. Here, we review the mechanisms governing the regulation of BDNF expression, and discuss how disease-associated single nucleotide polymorphisms (SNPs) can alter these mechanisms, and influence MDD. As negative stressors increase the likelihood of MDD, we will also discuss the impact of these stressors on BDNF expression, the cellular effect of such a change, and its impact on behavior in animal models of stress. We will also describe epigenetic processes that mediate this change in BDNF expression. Similarities in BDNF expression between animal models of stress and those in MDD will be highlighted. We will also contrast epigenetic patterns at the BDNF locus between animal models of stress, and MDD patients, and address limitations to current clinical studies. Future work should focus on validating current genetic and epigenetic findings in tightly controlled clinical studies. Regions outside of BDNF promoters should also be explored, as should other epigenetic marks, to improve identification of biomarkers for MDD. PMID- 29243874 TI - Emotional and behavioral problems in children and adolescents with neurofibromatosis type 1. AB - To assess emotional and behavioral problems in children and adolescents with neurofibromatosis type 1,parents of 183 individuals aged 10.8 +/- 3.1 years (range 6-17) completed the Child Behavior Checklist (CBCL). Also, 173 teachers completed the Teacher's Report Form (TRF), and 88 adolescents (children from 11 to 17 years) completed the Youth Self-Report (YSR). According to parental ratings, 32% scored in the clinical range (above the 90th percentile). This percentage was much lower when rated by teachers or adolescents themselves. Scores from all informants on scales for Somatic complaints, Social problems, and Attention problems were significantly different from normative scores. Attentional problems were associated with lower verbal IQ, male gender, younger age, and ADHD-symptoms. Disease-related factors did not predict behavioral problems scores. Substantial emotional and behavioral problems were reported by parents, teachers, and to a lesser extent by adolescents with NF1 themselves. Possibly, a positive illusory bias affects the observation of behavioral problems by adolescents with NF1. PMID- 29243875 TI - Allometric considerations when assessing aortic aneurysms in Turner syndrome: Implications for activity recommendations and medical decision-making. AB - In Turner syndrome, the potential to form thoracic aortic aneurysms requires routine patient monitoring. However, the short stature that typically occurs complicates the assessment of severity and risk because the relationship of body size to aortic dimensions is different in Turner syndrome compared to the general population. Three allometric formula have been proposed to adjust aortic dimensions, all employing body surface area: aortic size index, Turner syndrome specific Z-scores, and Z-scores based on a general pediatric and young adult population. In order to understand the differences between these formula we evaluated the relationship between age and aortic size index and compared Turner syndrome-specific Z-scores and pediatric/young adult based Z-scores in a group of girls and women with Turner syndrome. Our results suggest that the aortic size index is highly age-dependent for those under 15 years; and that Turner-specific Z-scores are significantly lower than Z-scores referenced to the general population. Higher Z-scores derived from the general reference population could result in stigmatization, inappropriate restriction from sports, and increasing the risk of unneeded medical or operative treatments. We propose that when estimating aortic dissection risk clinicians use Turner syndrome-specific Z-score for those under fifteen years of age. PMID- 29243877 TI - Multiple sulfur isotope constraints on microbial sulfate reduction below an Archean seafloor hydrothermal system. AB - Microbial sulfate reduction is among the most ubiquitous metabolic processes on earth. The oldest evidence of microbial sulfate reduction appears in the ca. 3.5 Ga Dresser Formation in the North Pole area of Pilbara Craton in Western Australia. That evidence was found through analysis of quadruple sulfur isotopes of sulfate and sulfide minerals deposited on the seafloor. However, the activity of microbial sulfate reduction below the Archean seafloor remains poorly understood. Here, we report the quadruple sulfur isotopic compositions of sulfide minerals within hydrothermally altered seafloor basalt and less altered basaltic komatiite collected from the North Pole Dome area. The Delta33 S values of the sulfide minerals were nonzero negative, suggesting that sulfate reduction occurred below the Archean seafloor. To constrain the substrate sulfate sources and sulfate reduction processes, we constructed a numerical model. Comparing the modeled and observed sulfur isotopes, we show that the substrate sulfate comprises seawater sulfate with a negative Delta33 S anomaly and 34 S-enriched sulfate with no anomalous Delta33 S. The latter component probably represents sulfate produced by local hydrothermal processes. The maximum sulfur isotopic fractionation between the putative substrate sulfate and the observed sulfide minerals within the altered basalt and basaltic komatiite is 350/00, which is consistent with a microbial origin. Alternatively, thermochemical sulfate reduction may also produce sulfide. However, considering the hydrothermal temperature inferred from the metamorphic grade of the altered basalt, the sulfur isotopic fractionation produced by inorganic sulfate reduction is probably below 200/00. Collectively, larger fractionations imply the involvement of biological sulfate reduction processes, both in the hydrothermal system below the seafloor and in less altered subsurface settings. PMID- 29243876 TI - Familial transmission of externalizing syndromes in extended Swedish families. AB - Risk for criminal behavior (CB), alcohol use disorder (AUD), and drug abuse (DA) are known to be familial. We know less about their transmission across three generations. We examined 844,109 probands born in Sweden 1980-1990, their parents, aunts/uncles, and grandparents for registration in population-based registers for CB, AUD, and DA. Mean tetrachoric relative-proband correlations (95% CIs) were highest for DA (+0.24, 0.24-0.25), followed by CB (+0.23,0.22 0.23) and AUD (+0.17, 0.16-0.17). AUD and CB were relatively stably transmitted across generations, while DA resemblance among relatives was stronger in the younger generations. For all three syndromes, male-male transmission was modestly stronger than female-female. Cross-sex transmission was significantly weaker than same-sex transmission for DA and CB but not AUD. Risk to probands with only an affected grandparent or aunt/uncle were increased 50-60% for CB and AUD, and 70 100% for DA. Parallel figures for affected parents only and parents + grandparent or aunt/uncle were 2-3-fold and 4-5-fold for CB and AUD, and 4-5-fold and 6-7 fold for DA. CB, AUD, and DA are all substantially familial in the Swedish population with the transmission across three generations stable for CB and AUD but not DA. Modest quantitative sex effects are seen in the familial transmission of CB, AUD, and DA, and qualitative sex effects for CB and DA. Risk prediction in offspring is orderly with affection status in grandparental and avuncular relationships adding appreciably to that from the parental generation. PMID- 29243879 TI - The effects of smoking on vascular endothelial growth factor and inflammation markers: A case-control study. AB - BACKGROUND AND AIMS: Chronic obstructive pulmonary disease (COPD) is a type of obstructive lung disease characterized by long-term poor airflow. Tobacco smoking is the most common cause of COPD. In this study, we aimed to assess the vascular endothelial growth factor (VEGF) and inflammation markers on smokers and non smoking individuals. METHODS: Our study was a case-control study and 175 individuals who want to give up smoking constituted the case group. As a control group, 175 individuals who never smoked. RESULTS: The mean age of 350 participants was 35.83 +/- 13.11 years. Educational status of the non-smokers was significantly higher than that of the smoking group (P < .001). When smoking and non-smoking groups were compared in terms of VEGF and interleukin-6 (IL-6), it was found that these values were statistically higher in smokers than non-smokers (P < .001). The levels of IL-10 were found to be higher in non-smokers than in smokers (P < .001). Although a moderate positive correlation was found between VEGF and IL-6 levels (r = .486, P < .001), there was a weak negative correlation between VEGF and IL-10 (r = -.210, P < .001). A weak negative correlation was found between IL-6 and IL-10 (r = -.185, P < .001). CONCLUSIONS: In our study, IL 6 inflammatory marker and VEGF levels were found to be high and IL-10 anti inflammatory marker was discovered to be low in smokers. For this reason, raising awareness in the society about the harms of smoking and encouraging people to give it up have become more challenging to counteract the inflammatory effects of smoking in human body and to prevent many smoking-related diseases. PMID- 29243878 TI - Predictive value of C-reactive protein for tuberculosis, bloodstream infection or death among HIV-infected individuals with chronic, non-specific symptoms and negative sputum smear microscopy. AB - BACKGROUND: C-reactive protein (CRP) is an inflammatory biomarker that may identify patients at risk of infections or death. Mortality among HIV-infected persons commencing antiretroviral therapy (ART) is often attributed to tuberculosis (TB) or bloodstream infections (BSI). METHODS: In two district hospitals in southern Malawi, we recruited HIV-infected adults with one or more unexplained symptoms present for at least one month (weight loss, fever or diarrhoea) and negative expectorated sputum microscopy for TB. CRP determination for 452 of 469 (96%) participants at study enrolment was analysed for associations with TB, BSI or death to 120 days post-enrolment. RESULTS: Baseline CRP was significantly elevated among patients with confirmed or probable TB (52), BSI (50) or death (60) compared to those with no identified infection who survived at least 120 days (269). A CRP value of >10 mg/L was associated with confirmed or probable TB (adjusted odds ratio 5.7; 95% CI 2.6, 14.3; 87% sensitivity) or death by 30 days (adjusted odds ratio 9.2; 95% CI 2.2, 55.1; 88% sensitivity). CRP was independently associated with TB, BSI or death, but the prediction of these endpoints was enhanced by including haemoglobin (all outcomes), CD4 count (BSI, death) and whether ART was started (death) in logistic regression models. CONCLUSION: High CRP at the time of ART initiation is associated with TB, BSI and early mortality and so has potential utility for stratifying patients for intensified clinical and laboratory investigation and follow-up. They may also be considered for empirical treatment of opportunistic infections including TB. PMID- 29243880 TI - Review article: Best practice management of common knee injuries in the emergency department (part 3 of the musculoskeletal injuries rapid review series). AB - Knee injuries are a common presentation to the ED and are often difficult to assess and definitively diagnose due to the patient's acute pain, effusion and guarding. The quality of ED care provided to patients with fractures or soft tissue injuries of the knee is critical to ensure the best possible outcomes for the patient. This rapid review investigated best practice for the assessment and management of common knee injuries in the ED. Databases were searched in 2017, including PubMed, CINAHL, EMBASE, TRIP and the grey literature, including relevant organisational websites. Primary studies, systematic reviews and guidelines were considered for inclusion. English-language articles published in the past 12 years that addressed the acute assessment, management, follow-up plan or prognosis were included. Data extraction of included articles was conducted, followed by quality appraisal to rate the level of evidence where possible. The search revealed 2250 articles, of which 54 were included in the review (n = 8 primary articles, n = 28 systematic reviews, n = 18 guidelines). This rapid review provides clinicians managing fractures and soft tissue injuries of the knee in the ED, a summary of the best available evidence to enhance the quality of care for optimal patient outcomes. There is consistent evidence to support undertaking a thorough history and physical examination, including the application of special tests and clinical decision rules for imaging. In the undifferentiated knee injury, expedited follow up and further imaging is recommended to improve patient outcomes and cost-effectiveness. PMID- 29243881 TI - Identification of the novel HLA-B*13:98 allele in a Chinese individual. AB - HLA-B*13:98 differs from HLA-B*13:02:01 by a single nucleotide substitution at position 193 A>G. PMID- 29243882 TI - Mental Health Nurses as therapists in a rehabilitation setting: A phenomenological study. AB - Mental Health Nurses have a long tradition of delivering talk-based interventions across a range of clinical settings. Despite this, Mental Health Nurses receive limited recognition of this contribution. This paper presents findings from a study that explored Mental Health Nurses' experience of delivering talk-based therapies in an inpatient rehabilitation setting. This study uses semistructured interviews and a phenomenological approach to explore eight Mental Health Nurses' experience. Themes emerging included that: mental health nursing is a talk-based therapy in its own right, talk-based therapy was part of everyday nursing care on the floor and integrated talk-based therapy enhanced recovery opportunities for consumers. However, a further theme was that there were tensions around providing talk-based therapy conflicted with other roles including unit management and the role of nurses in controlling challenging behaviours. This study found that Mental Health Nurses, in this setting, are offering talk-based therapy to the people they care for. The findings of this study have implications for research: there needs to be a larger study investigating nurses' use of talk-based therapy in inpatient settings. If, as the authors expect that, it is found that mental health nurses are offering these therapies generally in inpatient settings, this has serious implications for postgraduate education in Mental Health Nursing policy in terms of recognition that this is happening and finding ways to support nurses to do this well. There also needs to be further research in the best ways to offer talk-based therapy in these settings. PMID- 29243883 TI - Aspects of silver tolerance in bacteria: infrared spectral changes and epigenetic clues. AB - In this study, the molecular profile changes leading to the adaptation of bacteria to survive and grow at inhibitory silver concentration were explored. The profile obtained through infrared (IR)-based measurements indicated extensive changes in all biomolecular components, which were supported by chemometric techniques. The changes in biomolecular profile were prominent, including nucleic acids. The changes in nucleic acid region (1350-950 cm-1 ) were encountered as a clue for conformational change in DNA. Further analysis of DNA by IR spectroscopy revealed changes in the backbone and sugar conformations. Moreover, Enzyme-Linked Immunosorbent Assay-based measurements of DNA methylation levels were performed to see if epigenetic mechanisms are in operation during bacterial adaptation to this environmental challenge. The results indicated a notable demethylation in Escherichia coli and methylation in Staphylococcus aureus likely to be associated with their elaborate adaptation process to sustain survival and growth. PMID- 29243884 TI - Dynamics of bed bug infestations in three low-income housing communities with various bed bug management programs. AB - BACKGROUND: Infestations of the common bed bug, Cimex lectularius L., have become common in low-income communities in the USA over the last 15 years. We evaluated community-based integrated pest management (IPM) programs for reducing bed bug infestations. Two housing authorities (Bayonne and Hackensack) implemented bed bug IPM programs. A third housing authority (Paterson) was used as the control site. Building-wide surveys were conducted in all communities, three times, to evaluate the effectiveness of the IPM programs. RESULTS: From 0 to 24 months, the infestation rate at Bayonne, Hackensack, and Paterson decreased by 49, 64, and 26%, respectively. The two sites that adopted IPM achieved faster bed bug elimination than the control site. The bed bug introduction rate over a 24-month period at Bayonne, Hackensack, and Paterson was 7, 3, and 11%, respectively. The introduction rate was positively associated with the initial infestation rate. Residents from buildings enrolled in IPM programs were more satisfied with the bed bug control services than residents from the control site. CONCLUSION: IPM programs were more effective in reducing bed bug infestations than traditional pest control services, but many factors contributed to the lower than desired level of reduction in infestation rate. (c) 2017 Society of Chemical Industry. PMID- 29243886 TI - Synthesis and Reactivity of the Phosphorus Analogues of Cyclopentadienone, Tricyclopentanone, and Housene. AB - The phosphorus analogues of cyclopentadienone, tricyclopentanone, and housene were accessed from bis(cyclopropenyl)diphosphetanedione 3, which was prepared by mixing 1,2,3-tris-tert-butylcyclopropenium tetrafluoroborate (1) and sodium phosphaethynolate [Na(OCP)(dioxane)n ]. While photolysis of 3 results in decarbonylation, yielding bis(cyclopropenyl)diphosphene 4 and after rearrangement diphosphahousene 5, thermolysis of 3 leads to phosphatricyclo[2.1.0.0]pentanone 7. Metal-mediated valence isomerization of 7 and subsequent demetalation provides access to phosphacyclopentadienone 12. PMID- 29243885 TI - Synthesis and Reactivity of an End-Deck cyclo-P4 Iron Complex. AB - Reduction of the FeII complex [(Ph PP2Cy )FeCl2 ] (2) generated an electron-rich and unsaturated Fe0 species, which was reacted with white phosphorus. The resulting new complex, [(Ph PP2Cy )Fe(eta4 -P4 )] (3), is the first iron cyclo-P4 complex and the only known stable end-deck cyclo-P4 complex outside Group V. Complex 3 features an FeII center, as shown by Mossbauer spectroscopy, associated to a P42- fragment. The distinct reactivity of complex 3 was rationalized by analysis of the molecular orbitals. Reaction of complex 3 with H+ afforded the unstable complex [(Ph PP2Cy )Fe(eta4 -P4 )(H)]+ (4), whereas with CuCl and BCF, the complexes [(Ph PP2Cy )Fe(eta4 :eta1 -P4 )(MU-CuCl)]2 (5) and [(Ph PP2Cy )Fe(eta4 :eta1 -P4 )B(C6 F5 )3 ] (6) were formed. PMID- 29243887 TI - The Mesomeric Effect of Thiazolium on non-Kekule Diradicals in Pichia stipitis Transketolase. AB - It is theoretically plausible that thiazolium mesomerizes to congeners other than carbene in a low effective dielectric binding site; especially given the energetics and uneven electronegativity of carbene groups. However, such a phenomenon has never been reported. Nine crystal structures of transketolase obtained from Pichia stipitis (TKps) are reported with subatomic resolution, where thiazolium displays an extraordinary ring-bending effect. The bent thiazolium congeners correlate with non-Kekule diradicals because there is no gain or loss of electrons. In conjunction with biophysical and biochemical analyses, it is concluded that ring bending is a result of tautomerization of thiazolium with its non- Kekule diradicals, exclusively in the binding site of TKps. The chemophysical properties of these thiazolium mesomers may account for the great variety of reactivities carried out by thiamine-diphosphate-containing (ThDP) enzymes. The stability of ThDP in living systems can be regulated by the levels of substrates, and hydration and dehydration, as well as diradical mediated oxidative degradation. PMID- 29243888 TI - Looking Back, Looking Forward. AB - Taking stock: Editor-in-Chief Theresa Kueckmann reflects on the year 2017 and lays out plans for the new year. PMID- 29243889 TI - Rhizobial strain-dependent restriction of nitrogen fixation in a legume-Rhizobium symbiosis. PMID- 29243891 TI - Upcoming events of interest. PMID- 29243890 TI - The evolution of floral ontogenetic allometry in the Andean genus Caiophora (Loasaceae, subfam. Loasoideae). AB - The astounding variety of angiosperm flower morphologies has evolved in response to many selective forces. Flower development is highly coordinated and involves developmental associations between size and shape, ontogenetic allometry, which in turn affect the morphology of mature flowers. Although ontogenetic allometries can act as a developmental constraint and may influence adaptive evolution, allometries can evolve themselves and may change rapidly in response to selection. We explored the evolution of ontogenetic allometry in the flowers of 11 species of Loasoideae. Seven species belong to Caiophora, which radiated recently in the central Andes, and contains species that are pollinated by bees, hummingbirds, and small rodents. According to a previous study, the diversification of Caiophora involved departures from simple allometric scaling, but the changes to allometry that enabled flower diversification have not been explored yet. We characterized the ontogenetic allometry of each species with the methods of geometric morphometrics. We studied the evolution of allometries by constructing allometric spaces, in which the allometry of each species is represented by a point and the arrangement of points indicates the relations among allometric trajectories. To examine the history of changes of ontogenetic allometries, we projected the phylogeny into the allometric spaces. Inspection of allometric spaces suggests that ontogenetic variation is limited to a few dominant features. The allometries of the two main functional flower parts under study differ in their evolutionary labilities, and patterns of variation reflect pollination systems, differences in structural organization, and abiotic environmental factors. PMID- 29243892 TI - New study designs in clinical drug development. AB - Clinical development of a novel drug has traditionally been seen as a series of four phases, each having its own objectives in establishing the efficacy and safety of the drug. Increasingly individualized medicine and the changing mechanisms of drug action are also changing the designs of clinical drug testing. The borders of development phases become blurred and the traditional large, controlled multicenter studies may in part be replaced by individual and risk based approaches. The indications for drugs are more precisely targeted from biological starting points, and a target-oriented development may guide the designs of clinical testing at all stages of development. Utilization of data from registries along with modeling will become more common in clinical drug testing. PMID- 29243893 TI - Preliminary appraisal of clinical drug trials is changing. AB - The EU Clinical Trials Regulation will change the preliminary appraisal of trials and lighten the bureaucracy. Routines of the member states will be standardized, processing of applications provided with tighter time limits, and the licensing procedure made more flexible by using a common European portal. At the same time, definitions will be provided for low intervention trials subject to more flexible rules of follow-up, requirements of master file content, and traceability of test drugs. Implementation of the regulation depends on the completion of the EU portal, currently estimated to take place in the autumn of 2018. Preparations for execution in Finland are carried out by a working group appointed by the Ministry of Social Affairs and Health. On the national level, preparations are in progress to e.g. reorganize ethical evaluation, because the deadlines of evaluation of applications cannot be met with the current structure. Furthermore, regulations concerning insurances and collaterals, language requirements and possibilities of petitioning relating to the applications will also be decided on a national basis. PMID- 29243894 TI - Indications for and outcomes of liver transplantation in patients with alcohol associated liver disease. AB - The manufacture and consumption of alcohol are ubiquitous and as old as time. Alcohol use disorder (AUD) is defined as a problematic pattern of alcohol use leading to clinically significant impairment. The physical injuries that result from excessive alcohol consumption are varied including end-organ damage to liver (alcohol-associated liver disease [ALD]), pancreas, brain and heart, and systemic consequences including several forms of cancer. Liver transplantation (LT) remains the treatment of last resort for life-threatening liver disease. LT provides a valuable magnifying glass under which to examine the complex interactions between social drinking, AUD, and ALD. ALD is the second most frequent indication for LT in the US (data of 2015). We review the current data on evaluation of patients with AUD and ALD for liver transplantation; on the significance of abstinence from alcohol in patient selection and pre- and post-LT management. We discuss monitoring for relapse prior to and after LT. Finally, we look at outcomes, first from the perspective of impact on the allograft and then the perspective of maintaining the health of the LT patient with AUD, which includes management of addiction. PMID- 29243895 TI - Thoracic outlet syndrome. AB - It is important to remember the possibility of nonspecific thoracic outlet syndrome (TOS) when treating patients with neck and upper extremity symptoms. There are no specific diagnostic criteria for the syndrome. Diagnosis is based on symptoms, clinical examination and the ruling out of other causes. The first-line option of clinical care is conservative treatment, which in most cases is sufficient for the patient to regain normal functioning. However, some of the most difficult TOS patients need surgical treatment, especially when persistent symptoms have already begun in adolescence, and if compression of neural or vascular structures is thought to result from anatomical structures. Conservative treatment options are essential also for surgically treated patients. PMID- 29243896 TI - Diagnostics and current care of myasthenia gravis. AB - Myasthenia gravis (MG) is the most common neuromuscular transmission disorder, causing weakness of skeletal muscles on exertion. The course of the disease is highly variable, symptoms and signs may change rapidly due to infection or pregnancy. MG is classified using serological, electrophysiological and pharmaceutical tools. A precise diagnosis allows for the choice of right treatment, predicts the course of disease and hence helps with the follow-up. In this review we present Finnish guidelines for diagnostics, treatment and follow up of MG patients. PMID- 29243897 TI - When should a drain be left in the abdominal cavity upon surgery? AB - Passive or active drainage can be used after abdominal surgery. Drains aim at eradicating infected or inflammatory tissue fluids and to alarm of undesired events such as bile, pancreatic, or bowel leak. Drains may, however, occlude or be situated away from the postoperative dilemma. Furthermore, drains themselves are susceptible to cause or maintain infection by retrograde contamination, may irritate the peritoneum causing excess ascites formation, and cause pain. Recent scientific evidence suggests that drains are unnecessary after most abdominal operations. Thus, drains should be used only in certain specific operation types such as pancreatic and emergency surgery. In other operations drains can be omitted if no clear risk factors are present. PMID- 29243898 TI - Invasive treatment of superficial veins of the lower extremities. AB - Modern invasive treatment of superficial venous insufficiency of the lower extremities is largely based on the use of intravenous procedures under ultrasound guidance. The first-line treatment is thermoablation, in which the insufficient superficial vein, typically vena saphena magna or parva, is constricted by using laser or radio frequency energy under ultrasound guidance. The procedure is nearly always successful under local anesthesia and can be performed as an outpatient operation. When necessary, visible collateral varices can be treated with foam sclerotherapy or by surgical excision. The need for associated medication or longer follow-up is limited and recovery is fast. The patients can be mobilized immediately, and only a couple of days of sick leave are usually required. PMID- 29243899 TI - Discussing a serious illness with a patient and family. AB - Learning of a serious illness is unique news. Nothing certain can be known about how it will affect the hearer's outlook on the future before a conception is established about the hearer's expectations and how he/she has understood the issue. For example, a person who has been expecting muscle tension to be an explanation for back pain but hearing that a cancer metastasis is the underlying cause, will inevitably be in shock. The healthcare system is not able to influence everything, but is usually given one possibility to make a good first impression when telling about a serious diagnosis. Various lists of issues to be taken into account have been devised to help this. They do not, however, replace effective interaction, which is a matter of skill but can also be practiced. It is possible to anticipate the reactions of the hearers, as long as they remember that feelings are feelings and facts are facts. PMID- 29243900 TI - The new line of genetically modified mice with constitutive knockout of the gene alpha synuclein to study pathogenetic aspects of differential loss of dopaminergic neurons . AB - The purpose: This study investigated the role of alpha-synuclein in the development of dopaminergic neurons. Methods: In this study a new SNCA knockout mouse line has been used to model the deficiency of alpha-synuclein function. In the knockout and control mice the dynamics of the formation of two distinct populations of dopaminergic neurons differently affected in patients with PD was studied by the comparative morphometric analysis. Results: Here, we revealed a prominent modulating effect of alpha-synuclein on the developing DA neurons in substantia nigra (SN) which is the most affected region in PD patients. Yet, alpha-synuclein had no effect on the formation of DA neurons in ventral tegmental area which is much less susceptible to degeneration in PD patients. Conclusion: The new line of knockout mice is a convenient model for studying pathophysiologic aspects of selective impairment of DA neurons. PMID- 29243901 TI - FOUR score in monitoring the level of consciousness of an intensive care patient: first experience of the use of the Finnish language version. AB - BACKGROUND: The goal was to increase the knowledge of Full Outline of UnResponsiveness (FOUR) score in Finland, release its Finnish version and to evaluate its usefulness in Finnish ICU patients. MATERIALS AND METHODS: The highest FOUR and Glasgow Coma Scale (GCS) scores of the adult ICU patients treated in Tampere University Hospital between 1st January and 31st October 2015 were analyzed retrospectively. In-hospital and 1-month mortality were the primary end-points. RESULTS: The Finnish version of FOUR performed comparably to previous studies. The ability of FOUR to predict mortality was equal to GCS. CONCLUSIONS: FOUR is at least equal to GCS in predicting mortality of ICU patients. PMID- 29243903 TI - Update on Current Care Guideline: Psoriasis (skin and joints). AB - Psoriasis is a chronic, immune-mediated, inflammatory disorder of the skin and joints. Moderate-to-server cases are associated with an independent risk of comorbidity (cardiovascular diseases and diabetes) even after adjusting for risk factors, known to be more prevalent in psoriatics compared to normal population. The systemic underlying inflammation, analogous to that observed in rheumatoid arthritis, calls for a long-term effective treatment. Screening and treatment of cardiovascular risk factors is highly recommended. The biologic drug arsenal has new additions. Long term treatment data from clinical study extensions and independent registries are reviewed. PMID- 29243902 TI - Comparison of physical development and rate of formation sensory-motor reflexes offspring of rats with different experimental model of preeclampsia. AB - Summary: A comparative study of the physical development and the rate of formation of sensory-motor reflexes offspring of rats with experimental preeclampsia (EP) was carried out. In the first experimental group EP was modeled intraperitoneal conduct of L-NAME at a dose of 25 mg/kg from 14 to 21 days of gestation, the second experimental group - the replacement of drinking water by 1.8% sodium chloride solution for the entire period of gestation. In the offspring of both groups, there was a delay of physical development, which was reflected in the later timing of the hair coat development, incisor eruption, pinna detachment as compared to the pups in the control group. It also noted the gap in the formation of sensory-motor reflexes and vestibular reactions. This was manifested in the delayed appearance of the olfactory response, auditory sensitivity, later performing tests "righting reflex", "negative geotaxis", "aerial righting reflex", "cliff avoidance", "horizontal wire test", "raising the head and forelegs", "supporting their bodies on hind legs" as compared to the indices of the pups of the female rats with an uncomplicated pregnancy. The most pronounced lag in postnatal development was observed in the offspring of rats with EP, which instead of drinking water was prepared 1.8% sodium chloride during the entire period of gestation. The purpose: To make a comparative study of the impact of ADMA-like preeclampsia (PE) and preeclampsia modeled by the replacement of drinking water consumed by female rats during gestation with 1.8% NaCl solution on the physical development and the rate of the maturation of sensory motor reflexes of their offspring. Methods: The study was performed on three groups of pregnant female rats aged 3-4 months whose original weight was 210-250 g and their pups. They were divided into three groups: 1: Control group including female rats with an uncomplicated pregnancy (n = 6) and their pups (n = 49); 2. Experimental group 1 - pregnant female rats with PE (n = 6) induced by intraabdominal introduction of L-NAME at a dose of 25 mg/kg from 14 to 21 day of gestation (ADMA-like preeclampsia) and their offspring (n = 35); 3. Experimental group 2 - pregnant female rats with PE (n = 6) modeled by the replacement of drinking throughout gestation with 1.8% NaCl solution and their pups. When studying the physical development of the pups we considered the terms of pinna detachment, hair coat development, incisor eruption and the time when they began to open their eyes. To estimate the rate of the maturation of sensory motor reflexes and motor coordination of the pups of the rats with PE we analyzed the time when they started to support their bodies on hind legs, lift their bodies off the floor, crawl, raise their head and forelegs, show the aerial righting reflex and the righting reflex, negative geotaxis, reactions to auditory and olfactory stimuli as well as the time they managed to stay on the horizontal wire. Results: The pups of the female rats with PE of both experimental groups were found to have later pinna detachment, incisor eruption and hair coat development as compared to the indices of the control group. In addition, the offspring of the experimental groups demonstrated a delay in the performance of the following tests: "righting reflex", "negative geotaxis", "aerial righting reflex", "cliff avoidance", "horizontal wire test", "raising the head and forelegs", "supporting their bodies on hind legs", "reaction to an olfactory stimulus" and "reaction to an auditory stimulus" as compared to the indices of the pups of the female rats with an uncomplicated pregnancy. Conclusion: PE induced by the introduction of ADMA to pregnant female rats and by the replacement of drinking water consumed by female rats during gestation with 1.8% NaCl solution causes a delay in physical development, maturation of sensory motor reflexes and vestibular reactions in their offspring. PMID- 29243904 TI - Suppression of Dendritic Lithium Growth by in Situ Formation of a Chemically Stable and Mechanically Strong Solid Electrolyte Interphase. AB - The growth and proliferation of Li dendrites during repeated Li cycling has long been a crucial issue that hinders the development of secondary Li-metal batteries. Building a stable and robust solid state electrolyte interphase (SEI) on the Li-anode surface is regarded as a promising strategy to overcome the dendrite issues. In this work, we report a simple strategy to engineer the interface chemistry of Li-metal anodes by using tiny amounts of dimethyl sulfate (DMS, C2H6SO4) as the SEI-forming additive. With the preferential reduction of DMS, an SEI layer composed of Li2S/Li2O forms on the Li surface. This inorganic SEI layer features high structural modulus and low interfacial resistant, enabling a dense and dendrite-free Li deposition as evidenced by scanning electron microscopy, atomic force microscopy, and in situ optical images. In addition, this SEI layer can prevent the deposited Li from direct contact with corrosive electrolytes, thus rendering an improved cycling stability of Li anodes with an average Coulombic efficiency of 97% for up to 150 cycles. When the DMS additive is introduced into a Li/NCM full cell, the cycle life of Li-metal batteries can be also improved significantly. This work demonstrates a feasible route to suppress Li dendrite growth by designing appropriate film-forming additives to regulate the interfacial properties of the SEI layer, and also the sulfonyl-based derivatives revealed in this work represent a large variety of new film-forming molecules, providing a broad selectivity for constructing high efficiency and cycle-stable Li anodes to address the intrinsic problems of rechargeable Li-metal batteries. PMID- 29243905 TI - Silver Niobate Lead-Free Antiferroelectric Ceramics: Enhancing Energy Storage Density by B-Site Doping. AB - Lead-free dielectric ceramics with high recoverable energy density are highly desired to sustainably meet the future energy demand. AgNbO3-based lead-free antiferroelectric ceramics with double ferroelectric hysteresis loops have been proved to be potential candidates for energy storage applications. Enhanced energy storage performance with recoverable energy density of 3.3 J/cm3 and high thermal stability with minimal energy density variation (<10%) over a temperature range of 20-120 degrees C have been achieved in W-modified AgNbO3 ceramics. It is revealed that the W6+ cations substitute the B-site Nb5+ and reduce the polarizability of B-site cations, leading to the enhanced antiferroelectricity, which is confirmed by the polarization hysteresis and dielectric tunability. It is believed that the polarizability of B-site cations plays a dominant role in stabilizing the antiferroelectricity in AgNbO3 system, in addition to the tolerance factor, which opens up a new design approach to achieve stable antiferroelectric materials. PMID- 29243906 TI - Realizing High Capacitance and Rate Capability in Polyaniline by Enhancing the Electrochemical Surface Area through Induction of Superhydrophilicity. AB - Polyaniline (PANI) as a pseudocapacitive material has very high theoretical capacitance of 2000 F g-1. However, its practical capacitance has been limited by low electrochemical surface area (ESA) and unfavorable wettability toward aqueous electrolytes. This work deals with a strategy wherein the high ESA of PANI has been achieved by the induction of superhydrophilicity together with the alignment of PANI exclusively on the surface of carbon fibers as a thin layer to form a hybrid assembly. Superhydrophilicity is induced by electrochemical functionalization of the Toray carbon paper, which further induces superhydrophilicity to the electrodeposited PANI layer on the paper, thereby ensuring a high electrode-electrolyte interface. The Toray paper is electrochemically functionalized by the anodization method, which generates a highly active electrochemical surface as well as greater wettability (superhydrophilic) of the carbon fibers. Because of the strong interaction of anilinium chloride with the hydrophilic carbon surface, PANI is polymerized exclusively over the surface of the fibers without any appreciable aggregation or agglomeration of the polymer. The PANI-Toray paper assembly in the solid-state prototype supercapacitor can provide a high gravimetric capacitance of 1335 F g-1 as well as a high areal capacitance of 1.3 F cm-2 at a current density of 10 A g 1. The device also exhibits high rate capability, delivering 1217 F g-1 at a current density of 50 A g-1 and a high energy density of 30 W h kg-1 at a power density of 2 kW kg-1. PMID- 29243907 TI - Strategy of Metal-Polymer Composite Stent To Accelerate Biodegradation of Iron Based Biomaterials. AB - The new principle and technique to tune biodegradation rates of biomaterials is one of the keys to the development of regenerative medicine and next-generation biomaterials. Biodegradable stents are new-generation medical devices applied in percutaneous coronary intervention, etc. Recently, both corrodible metals and degradable polymers have drawn much attention in biodegradable stents or scaffolds. It is, however, a dilemma to achieve good mechanical properties and appropriate degradation profiles. Herein, we put forward a metal-polymer composite strategy to achieve both. Iron stents exhibit excellent mechanical properties but low corrosion rate in vivo. We hypothesized that coating of biodegradable aliphatic polyester could accelerate iron corrosion due to the acidic degradation products, etc. To demonstrate the feasibility of this composite material technique, we first conducted in vitro experiments to affirm that iron sheet corroded faster when covered by polylactide (PLA) coating. Then, we fabricated three-dimensional metal-polymer stents (MPS) and implanted the novel stents in the abdominal aorta of New Zealand white rabbits, setting metal based stents (MBS) as a control. A series of in vivo experiments were performed, including measurements of residual mass and radial strength of the stents, histological analysis, micro-computed tomography, and optical coherence tomography imaging at the implantation site. The results showed that MPS could totally corrode in some cases, whereas iron struts of MBS in all cases remained several months after implantation. Corrosion rates of MPS could be easily regulated by adjusting the composition of PLA coatings. PMID- 29243908 TI - Thin-Film Nanocomposite Membrane with the Minimum Amount of MOF by the Langmuir Schaefer Technique for Nanofiltration. AB - An innovative procedure for positioning a monolayer of hydrophilic metal organic framework (MOF) MIL-101(Cr) (MIL, Materials of Institute Lavoisier) nanoparticles (NPs) in thin-film nanocomposite (TFN) membranes has been implemented by transferring a Langmuir-Schaefer (LS) film of the MOF in between the polyamide thin layer at the top and the cross-linked asymmetric polyimide (P84) support at the bottom. The presence and layout of the LS-MIL-101(Cr) monolayer in the TFN membrane was confirmed by scanning transmission electron microscopy imaging with a high-angle annular dark-field detector images and X-ray photoelectron spectroscopy, energy-dispersive X-ray spectroscopy, electron energy loss spectroscopy, and atomic force microscopy analyses. This methodology requires the smallest amount of MOF reported to date, 3.8 MUg cm-2, and promotes the formation of a defect-free ultrathin MOF film. Although conventional TFN membranes tend to show MOF agglomerates that could contribute to the formation of unselective defects, LS-TFN membranes, characterized by a homogeneous and continuous MOF coating, exhibit an optimal membrane performance, without a significant decrease in selectivity. Outstanding methanol permeances, one of the best results reported to date, of 10.1 +/- 0.5 L m-2 h-1 bar-1 when filtering sunset yellow and of 9.5 +/- 2.1 L m-2 h-1 bar-1 when filtering rose bengal have been achieved in LS-TFN membranes with a rejection higher than 90% in all cases. Methanol permeates through the polyamide and the LS-MIL-101(Cr) monolayer, greatly enhanced by the MOF pore system, in comparison to thin-film composite and conventional TFN membranes (7.5 +/- 0.7 and 7.7 +/- 1.1 L m-2 h-1 bar-1 when filtering sunset yellow), respectively, in which polyamide areas free of MOF NPs are present. PMID- 29243909 TI - Optimization of CoaD Inhibitors against Gram-Negative Organisms through Targeted Metabolomics. AB - Drug-resistant Gram-negative bacteria are of increasing concern worldwide. Novel antibiotics are needed, but their development is complicated by the requirement to simultaneously optimize molecules for target affinity and cellular potency, which can result in divergent structure-activity relationships (SARs). These challenges were exemplified during our attempts to optimize inhibitors of the bacterial enzyme CoaD originally identified through a biochemical screen. To facilitate lead optimization, we developed mass spectroscopy assays based on the hypothesis that levels of CoA metabolites would reflect the cellular enzymatic activity of CoaD. Using these methods, we were able to monitor the effects of cellular enzyme inhibition at compound concentrations up to 100-fold below the minimum inhibitory concentration (MIC), a common metric of growth inhibition. Furthermore, we generated a panel of efflux pump mutants to dissect the susceptibility of a representative CoaD inhibitor to efflux. These approaches allowed for a nuanced understanding of the permeability and efflux liabilities of the series and helped guide optimization efforts to achieve measurable MICs against wild-type E. coli. PMID- 29243910 TI - Facile Synthesis of ZnS/N,S Co-doped Carbon Composite from Zinc Metal Complex for High-Performance Sodium-Ion Batteries. AB - ZnS coated on N,S co-doped carbon (ZnS/NSC) composite has been prepared utilizing zinc pyrithione (C10H8N2O2S2Zn) as raw material via calcination. Through activation using Na2CO3 salt, ZnS nanoparticles encapsulated in NSC (denoted as A ZnS/NSC) with mixed-crystal structure has also been obtained, which reveals much larger specific surface area and more bridges between ZnS and NSC. Based on the existence of bridges (C-S-Zn and S-O-Zn bonds) and the modification of carbon from N,S co-doping, the A-ZnS/NSC composite as an anode for sodium-ion batteries (SIBs) displays significantly enhanced electrochemical performances with a high reversible specific capacity of 516.6 mA h g-1 (at 100 mA g-1), outstanding cycling stability (96.9% capacity retention after 100 cycles at 100 mA g-1), and high rate behavior (364.9 mA h g-1 even at 800 mA g-1). PMID- 29243912 TI - Laser-Printed In-Plane Micro-Supercapacitors: From Symmetric to Asymmetric Structure. AB - Here, we propose and demonstrate a complete solution for efficiently fabricating in-plane micro-supercapacitors (MSCs) from a symmetric to asymmetric structure. By using an original laser printing process, symmetric MSC with reduced graphene oxide (rGO)/silver nanowire (Ag-NW) hybrid electrodes was facilely fabricated and a high areal capacitance of 5.5 mF cm-2 was achieved, which reaches the best reports on graphene-based MSCs. More importantly, a "print-and-fold" method has been creatively proposed that enabled the rapid manufacturing of asymmetric in plane MSCs beyond the traditional cumbersome technologies. alpha-Ni(OH)2 particles with high tapping density were successfully synthesized and employed as the pseudocapacitive material. Consequently, an improved supply voltage of 1.5 V was obtained and an areal capacitance as high as 8.6 mF cm-2 has been realized. Moreover, a demonstration of a miniaturized MSC pack was performed by multiply folding the serial Ag-NW-connected MSC units. As a result, a compact MSC pack with a high supply voltage of 3 V was obtained, which can be utilized to power a light-emitting diode light. These presented technologies may pave the way for the efficiently producing high performance in-plane MSCs, meanwhile offering a solution for the achievement of practical power supply packs integrated in limited spaces. PMID- 29243913 TI - Deep-Red Amplified Spontaneous Emission from cis-Configured Squaraine. AB - We report deep-red amplified spontaneous emission (ASE) from cis-configured squaraine (cis-DCSQ1) under optical pumping. Doping of cis-DCSQ1 into a 4,4' bis(9-carbazolyl)-2,2'-biphenyl (CBP) host film at an appropriate concentration (0.5 wt % for this system) led to a marked increase of photoluminescence quantum yield because of efficient CBP-to-cis-DCSQ1 Forster resonance energy transfer and suppression of aggregation-caused quenching. Thus, this doped film showed clear ASE with a threshold of around 10 MUJ cm-2 and peak wavelength of 687 nm. These results proved that cis-configured squaraine derivatives are promising as gain materials for future applications as deep-red organic lasers. PMID- 29243914 TI - Bimetallic Metal-Organic Frameworks as Efficient Cathode Catalysts for Li-O2 Batteries. AB - Metal-organic frameworks (MOFs) have the potential to improve the electrochemical performance of Li-O2 batteries with high O2 accessibility and catalytic activity of the open metal sites. Here, we explored bimetallic MnCo-MOF-74 as a cathode catalyst in Li-O2 batteries. MnCo-MOF-74 was synthesized with the Mn to Co ratio of 1:4 by a simple hydrothermal reaction. Compared to monometallic Mn-MOF-74 and Co-MOF-74 with only single catalytic activity for LiOH formation or oxygen evolution reactions, bimetallic MnCo-MOF-74 demonstrated a capability to facilitate improved reversibility and efficiency during both discharge and charge cycles. Benefitting from the porous structure of the MOF as well as the complementary contribution from both Mn- and Co-metal clusters, MnCo-MOF-74 outperformed Mn-MOF-74 and Co-MOF-74. A high full discharge capacity of 11 150 mAh g-1 at 200 mA g-1 was achieved in MnCo-MOF-74. During the cycling test, MnCo MOF-74 stably delivered a limited discharge capacity of 1000 mAh g-1 for 44 cycles at 200 mA g-1, which is remarkably longer than those of carbon black, Mn MOF-74, and Co-MOF-74 with cycle lives of 8, 22, and 18 cycles, respectively. PMID- 29243915 TI - Magnetic-Patchy Janus Colloid Surfactants for Reversible Recovery of Pickering Emulsions. AB - We present a straightforward and robust method for the synthesis of Janus colloid surfactants with distinct amphiphilicity and magnetic responsiveness. To this end, hydroxyl-functionalized amphiphilic Janus microparticles (JMPs) are synthesized by seeded monomer swelling and subsequent photopolymerization. By incorporating controlled amounts of hydroxyl groups on poly(styrene-co-vinyl alcohol) seed particles, we adjust the interfacial tension between the seed polymer and the poly(tetradecyl acrylate) secondary polymer (gamma13). From theoretical and experimental observations, we verify that when gamma13 is tuned to ~8.5 mN/m in a medium with controlled solvency, which corresponds to a 0.6 volume fraction of ethanol in water, the particles bicompartmentalize to form oval or ellipsoidal JMPs with controllable bulb dimensions. We also show that bulb site-specific patching of magnetic nanoparticles (NPs) can be achieved using the electrostatic interaction between the polyethylenimine-coated bulb surface and the polyvinylpyrrolidone-stabilized Fe2O3 NPs. Finally, we demonstrate that our magnetic-patchy JMPs can assemble at the oil-water interface, enabling magnetic-responsive reversible recovery of Pickering emulsions. PMID- 29243911 TI - Neurodegenerative Disease Proteinopathies Are Connected to Distinct Histone Post translational Modification Landscapes. AB - Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) are devastating neurodegenerative diseases involving the progressive degeneration of neurons. No cure is available for patients diagnosed with these diseases. A prominent feature of both ALS and PD is the accumulation of protein inclusions in the cytoplasm of degenerating neurons; however, the particular proteins constituting these inclusions vary: the RNA-binding proteins TDP-43 and FUS are most notable in ALS, while alpha-synuclein aggregates into Lewy bodies in PD. In both diseases, genetic causes fail to explain the occurrence of a large proportion of cases, and thus, both are considered mostly sporadic. Despite mounting evidence for a possible role of epigenetics in the occurrence and progression of ALS and PD, epigenetic mechanisms in the context of these diseases remain mostly unexplored. Here we comprehensively delineate histone post-translational modification (PTM) profiles in ALS and PD yeast proteinopathy models. Remarkably, we find distinct changes in histone modification profiles for each. We detect the most striking changes in the context of FUS aggregation: changes in several histone marks support a global decrease in gene transcription. We also detect more modest changes in histone modifications in cells overexpressing TDP-43 or alpha synuclein. Our results highlight a great need for the inclusion of epigenetic mechanisms in the study of neurodegeneration. We hope our work will pave the way for the discovery of more effective therapies to treat patients suffering from ALS, PD, and other neurodegenerative diseases. PMID- 29243916 TI - Effective Cathode Design of Three-Layered Configuration for High-Energy Li-S Batteries. AB - A three-layered cathode structure was designed to minimize the shuttle effect of polysulfides and improve active material utilization. The three-layered configuration was fabricated by directly dropping pure sulfur composite slurry into multifunctional dual-barrier layers consisting of a self-standing TiO2/C interlayer and a very thin acetylene black layer (0.35 mg cm-2). In consequence, a decent discharge capacity of 963 mA h g-1 was acquired after 100 cycles at 0.1 C. With cycling at 0.1, 0.2, 0.5, 1, and 2 C, the cells displayed excellent reversible capacities of 1203, 1145, 1035, 934, and 820 mA h g-1, respectively. Furthermore, the cells still delivered a satisfactory discharge capacity of 799 mA h g-1 after 300 cycles at 0.5 C. The light mass of the three-layered configuration guarantees that the energy density is effectively improved, considering the overall mass of the cathode. The energy density (603 W h kg-1 after 100 cycles) was at a high level compared with those of the reported ones. Therefore, it is believed that the synergistic design for the three-layered cathode structure, which combines the mass-produced layer-by-layer structure, provides a novel protocol to the practical application of lithium-sulfur batteries. PMID- 29243917 TI - High Antimicrobial Activity of Metal-Organic Framework-Templated Porphyrin Polymer Thin Films. AB - Development of surface coatings with high antimicrobial activity is urgently required to fight bacteria and other microorganisms on technical and hygiene relevant surfaces. Control over structure and topology of the surface coatings, combined with the ability to include functional molecules within the structure, is crucial for optimizing their performance. Herein, we describe a novel strategy to synthesize structurally well-defined porphyrin polymer thin films via a template approach. In this approach, bisazido-functionalized porphyrin molecules are preorganized within a metal-organic framework (MOF) structure. Afterward, porphyrin units within the MOF are covalently connected via a secondary linker. Removal of the metal ions of the MOF results in water-stable porphyrin polymer thin films that demonstrate high antibacterial activity against pathogens via visible-light-promoted generation of reactive oxygen species. In addition, this approach offers the inherent possibility to incorporate guest molecules within the structures, to functionalize the surface with biomolecules, and to create hierarchically structured materials. PMID- 29243918 TI - Frustrated Lewis Pairs Catalyzed Asymmetric Metal-Free Hydrogenations and Hydrosilylations. AB - The use of frustrated Lewis pairs is an extremely important approach to metal free hydrogenations. In contrast to the rapid growth of catalytic reactions, asymmetric hydrogenations are far less developed due to a severe shortage of readily available chiral frustrated Lewis pair catalysts with high catalytic activities and selectivities. Unlike the stable Lewis base component of frustrated Lewis pairs, the moisture-sensitive boron Lewis acid component is difficult to prepare. The development of convenient methods for the quick construction of chiral boron Lewis acids is therefore of great interest. In this Account, we summarize our recent studies on frustrated Lewis pair-catalyzed, asymmetric metal-free hydrogenations and hydrosilylations. To address the shortage of highly active and selective catalysts, we developed a novel strategy for the in situ preparation of chiral boron Lewis acids by the hydroboration of chiral dienes or diynes with Piers' borane without further purification, which allows chiral dienes or diynes to act like ligands. This strategy ensures the construction of a useful toolbox of catalysts for asymmetric metal-free hydrogenations and hydrosilylations is rapid and operationally simple. Another strategy is using combinations of readily available Lewis acids and bases containing hydridic and acidic hydrogen atoms, respectively, as a novel type of frustrated Lewis pairs. Such systems provide a great opportunity for using simple chiral Lewis bases as the origins of asymmetric induction. With chiral diene derived boron Lewis acids as catalysts, a broad range of unsaturated compounds, such as imines, silyl enol ethers, 2,3-disubstituted quinoxalines, and polysubstituted quinolines, are all viable substrates for asymmetric metal-free hydrogenations and give the corresponding products in good yields with high enantioselectivities and/or stereoselectivities. These chiral catalysts are very effective for bulky substrates, and the substrate scope for these metal-free asymmetric hydrogenations has been dramatically expanded. Chiral alkenylboranes were designed to enhance the rigidity of the framework and modify the Lewis acidity through the resulting double bonds. Frustrated Lewis pairs of chiral alkenylboranes and phosphines are a class of highly effective catalysts for asymmetric Piers-type hydrosilylations of 1,2-dicarbonyl compounds, and they give the desired products in high yields and enantioselectivities. Moreover, asymmetric transfer hydrogenations of imines and quinoxalines with ammonia borane as the hydrogen source have been achieved with frustrated Lewis pair of Piers' borane and (R)-tert-butylsulfinamide as the catalyst. Mechanistic studies have suggested that the hydrogen transfer occurs via an 8-membered ring transition state, and regeneration of the reactive frustrated Lewis pair with ammonia borane occurs through a concerted 6-membered ring transition state. PMID- 29243919 TI - Zinc(II) Metalated Porphyrins as Photothermogenic Photosensitizers for Cancer Photodynamic/Photothermal Synergistic Therapy. AB - Porphyrin derivatives are the first-generation photosensitizers, and to design a strong near-infrared (NIR)-absorbing porphyrin with good water solubility is highly desired for better therapeutic effect to treat tumors. Herein, three new porphyrin derivatives, 5,10,15,20-tetrakis(3,4-dimethoxyphenyl) porphyrin (P1), 5,10,15,20-tetrakis(3,4-dimethoxyphenyl) zinc porphyrin (ZnP1), and 5,15-bis(3,4 dimethoxyphenyl)-10,20-bis((4-methoxyphenyl)ethynyl) zinc porphyrin (ZnP2) have been synthesized. Among them, ZnP2 shows the longest and most intensive Q-bands in the near-infrared (NIR) region, as it endows the strongest light-harvesting capability and deepest tumor tissue penetration. The three porphyrin derivatives were prepared into nanoparticles (NPs) via nanoprecipitation method, and the NPs exhibit good water dispersibility and passive tumor-targeting property through enhanced permeability and retention effect. Furthermore, these NPs demonstrate both photodynamic and photothermal effects. Through a systematic study of the singlet oxygen quantum yield and cytotoxicity of P1, ZnP1, and ZnP2 NPs in vitro on Hela cells, it is found that ZnP2 shows the highest singlet oxygen quantum yield (79%), and its NPs show the best therapeutic efficacy in vitro. In vivo experiments disclosed that ZnP2 NPs present high phototoxicity, low dark toxicity, and excellent biocompatibility, and could be used as promising photothermogenic photosensitizer for cancer treatment. PMID- 29243920 TI - Novel Terminal Bipheny-Based Diapophytoene Desaturases (CrtN) Inhibitors as Anti MRSA/VISR/LRSA Agents with Reduced hERG Activity. AB - CrtN has been identified as an attractive and druggable target for treating pigmented Staphylococcus aureus infections. More than 100 new compounds were synthesized, which target the overwhelming the defects of the CrtN inhibitor 1. Analogues 23a and 23b demonstrated a significant activity against pigmented S. aureus Newman and 13 MRSA strains (IC50 = 0.02-10.5 nM), along with lower hERG inhibition (IC50 > 30 MUM, ~10-fold decrease in comparison with 1). Furthermore, 23a and 23b were confirmed to reduce the staphylococcal load in the kidney and heart in a mouse model with normal treatment deeper than pretreatment ones, comparable even with vancomycin and linezolid. Remarkably, 23a could strongly block the pigment biosynthesis of these nine multidrug-resistant MRSA strains, including excellent activity against LRSA strains and VISA strains in vivo, and all of which demonstrated that 23a has a huge potential against intractable MRSA, VISA, and LRSA issues as a therapeutic drug. PMID- 29243921 TI - Extra Sugar on Vancomycin: New Analogues for Combating Multidrug-Resistant Staphylococcus aureus and Vancomycin-Resistant Enterococci. AB - Lipophilic substitution on vancomycin is an effective strategy for the development of novel vancomycin analogues against drug-resistant bacteria by enhancing bacterial cell wall interactions. However, hydrophobic structures usually lead to long elimination half-life and accumulative toxicity; therefore, hydrophilic fragments were also introduced to the lipo-vancomycin to regulate their pharmacokinetic/pharmacodynamic properties. Here, we synthesized a series of new vancomycin analogues carrying various sugar moieties on the seventh-amino acid phenyl ring and lipophilic substitutions on vancosamine with extensive structure-activity relationship analysis. The optimal analogues indicated 128 1024-fold higher activity against methicillin-susceptible S. aureus, vancomycin intermediate resistant S. aureus (VISA), and vancomycin-resistant Enterococci (VRE) compared with that of vancomycin. In vivo pharmacokinetics studies demonstrated the effective regulation of extra sugar motifs, which shortened the half-life and addressed concerns of accumulative toxicity of lipo-vancomycin. This work presents an effective strategy for lipo-vancomycin derivative design by introducing extra sugars, which leads to better antibiotic-like properties of enhanced efficacy, optimal pharmacokinetics, and lower toxicity. PMID- 29243922 TI - Achieving High Thermoelectric Figure of Merit in Polycrystalline SnSe via Introducing Sn Vacancies. AB - Thermoelectric power generation technology has emerged as a clean "heat engine" that can convert heat to electricity. Recently, the discovery of an ultrahigh thermoelectric figure of merit in SnSe crystals has drawn a great deal of attention. In view of their facile processing and scale-up applications, polycrystalline SnSe materials with ZT values comparable to those of the SnSe crystals are greatly desired. Here we achieve a record high ZT value ~2.1 at 873 K in polycrystalline Sn1-xSe with Sn vacancies. We demonstrate that the carrier concentration increases by artificially introducing Sn vacancies, contributing significantly to the enhancements of electrical conductivity and thermoelectric power factor. The detailed analysis of the data in the light of first-principles calculations results indicates that the increased carrier concentration can be attributed to the Sn-vacancy-induced Fermi level downshift and the interplay between the vacancy states and valence bands. Furthermore, vacancies break translation symmetry and thus enhance phonon scattering, leading to extralow thermal conductivity. Such high ZT value ~2.1 is achieved by synergistically optimizing both electrical- and thermal-transport properties of polycrystalline SnSe. The vast increase in ZT for polycrystalline SnSe may accelerate practical applications of this material in highly effective solid-state thermoelectric devices. PMID- 29243923 TI - Crystalline Superlattices of Nanoscopic CdS Molecular Clusters: An X-ray Crystallography and 111Cd SSNMR Spectroscopy Study. AB - Systematic 111Cd solid-state (SS) NMR experiments were performed to correlate X ray crystallographic data with SSNMR parameters for a set of CdS-based materials, varying from molecular crystals of small complexes [Cd(SPh)4]2- and [Cd4(SPh)10]2 to superlattices of large monodisperse clusters [Cd54S32(SPh)48(dmf)4]4- and 1.9 nm CdS. Methodical data analysis allowed for assigning individual resonances or resonance groups to particular types of cadmium sites residing in different chemical and/or crystallographic environments. For large CdS frameworks, 111Cd resonances were found to form three groups. This result is noteworthy, since for related systems with size polydispersity and variations in composition, such as CdS or CdSe nanoparticles protected with an organic ligand shell, typically only two groups of resonances were observed. The generalized information obtained in this work can be used for the interpretation of 111/113Cd SSNMR data for large CdS clusters and nanoparticles, for which crystal structure analysis remains inaccessible. Comparison of the powder X-ray diffraction patterns for freshly prepared and dried superlattices of large CdS clusters revealed an interesting superstructure rearrangement that was not observed for the smaller frameworks. PMID- 29243924 TI - Exploration of Crystallization Kinetics in Quasi Two-Dimensional Perovskite and High Performance Solar Cells. AB - Halide perovskites with reduced-dimensionality (e.g., quasi-2D, Q-2D) have promising stability while retaining their high performance as compared to their three-dimensional counterpart. Generally, they are obtained in (A1)2(A2)n 1PbnI3n+1 thin films by adjusting A site cations, however, the underlying crystallization kinetics mechanism is less explored. In this manuscript, we employed ternary cations halides perovskite (BA)2(MA,FA)3Pb4I13 Q-2D perovskites as an archetypal model, to understand the principles that link the crystal orientation to the carrier behavior in the polycrystalline film. We reveal that appropriate FA+ incorporation can effectively control the perovskite crystallization kinetics, which reduces nonradiative recombination centers to acquire high-quality films with a limited nonorientated phase. We further developed an in situ photoluminescence technique to observe that the Q-2D phase (n = 2, 3, 4) was formed first followed by the generation of n = infinity perovskite in Q-2D perovskites. These findings substantially benefit the understanding of doping behavior in Q-2D perovskites crystal growth, and ultimately lead to the highest efficiency of 12.81% in (BA)2(MA,FA)3Pb4I13 Q-2D perovskites based photovoltaic devices. PMID- 29243926 TI - Antibacterial Activity of Nitric Oxide-Releasing Hyperbranched Polyamidoamines. AB - Hyperbranched polyamidoamines (h-PAMAM) were prepared using a one-pot reaction to have similar molecular weight to third generation PAMAM (G3-PAMAM) dendrimers, and then functionalized with N-diazeniumdiolate nitric oxide (NO) donors. A wide range of NO storage capacities (~1-2.50 MUmol mg-1) and NO-release kinetics (t1/2 ~30-80 min) were achieved by changing the extent of propylene oxide (PO) modification. The therapeutic potential of these materials was evaluated by studying their antibacterial activities and toxicity against common dental pathogens and human gingival fibroblast cells, respectively. Our results indicate that the combination of NO release and PO modification is necessary to yield h PAMAM materials with efficient bactericidal action without eliciting unwarranted cytotoxicity. Of importance, NO-releasing PO-modified h-PAMAM polymers exhibited comparable biological properties (i.e., antibacterial action and cytotoxicity) to defect-free G3-PAMAM dendrimers, but at a substantially lower synthetic burden. PMID- 29243925 TI - In Vitro Bypass of Thymidine Glycol by DNA Polymerase theta Forms Sequence Dependent Frameshift Mutations. AB - Unrepaired DNA lesions block replication and threaten genomic stability. Several specialized translesion polymerases, including polymerase theta (Pol theta), contribute to replicative bypass of these lesions. The role of Pol theta in double-strand break repair is well-understood, but its contribution to translesion synthesis is much less so. We describe the action of Pol theta on templates containing thymidine glycol (Tg), a major cytotoxic, oxidative DNA lesion that blocks DNA replication. Unrepaired Tg lesions are bypassed in human cells by specialized translesion polymerases by one of two distinct pathways: high-fidelity bypass by the combined action of Pol kappa and Pol zeta or weakly mutagenic bypass by Pol theta. Here we report that in vitro bypass of Tg by Pol theta results in frameshift mutations (deletions) in a sequence-dependent fashion. Steady-state kinetic analysis indicated that one- and two-nucleotide deletions are formed 9- and 6-fold more efficiently, respectively, than correct, full-length bypass products. Sequencing of in vitro bypass products revealed that bypass preference decreased in the following order on a template where all three outcomes were possible: two-nucleotide deletion > correct bypass > one-nucleotide deletion. These results suggest that bypass of Tg by Pol theta results in mutations opposite the lesion, as well as frameshift mutations. PMID- 29243927 TI - Orbitally Matched Edge-Doping in Graphene Nanoribbons. AB - A series of trigonal planar N-, O-, and S-dopant atoms incorporated along the convex protrusion lining the edges of bottom-up synthesized chevron graphene nanoribbons (cGNRs) induce a characteristic shift in the energy of conduction and valence band edge states along with a significant reduction of the band gap of up to 0.3 eV per dopant atom per monomer. A combination of scanning probe spectroscopy and density functional theory calculations reveals that the direction and the magnitude of charge transfer between the dopant atoms and the cGNR backbone are dominated by inductive effects and follow the expected trend in electronegativity. The introduction of heteroatom dopants with trigonal planar geometry ensures an efficient overlap of a p-orbital lone-pair centered on the dopant atom with the extended pi-system of the cGNR backbone effectively extending the conjugation length. Our work demonstrates a widely tunable method for band gap engineering of graphene nanostructures for advanced electronic applications. PMID- 29243928 TI - A Systematic DFT Study of Some Plausible Zn(II) and Al(III) Interaction Sites in N-Terminally Acetylated alpha-Synuclein. AB - The interactions between the protein alpha-synuclein and the Zn(II) and Al(III) cations at different sites were studied at the M06/6-311+G(d,p)/SMD and the omegaB97X-D/6-311+G(d,p)/SMD levels of theory. For Zn(II), previous experimental studies determined the presence of a high affinity site at Asp121 and a lower affinity one at His50. As for Al(III), an in vitro study showed it to be the most effective cation to induce structural changes in alpha-synuclein and to accelerate its aggregation. Besides Zn(II) and Al(III), Cu(II) also binds alpha synuclein (in fact, its complexes are the most studied and the best characterized ones) forming square planar complexes, and several binding sites are known for it, involving Met1-Asp2 (only in nonacetylated alpha-synuclein), His50, and Asp121. Herein, we applied a simple theoretical methodology, which satisfactorily reproduces experimental geometries and energies for complexes of N-terminally acetylated alpha-synuclein with Cu(II), to study Zn(II) and Al(III) complexes at those same sites, as well as at some structurally analogous alternative sites. We found binding geometries for Zn(II) and Al(III) that differ from the ones for Cu(II). These results can help to understand the interactions between alpha synuclein and metals, one of the factors leading to the formation of potentially neurotoxic alpha-synuclein aggregates. PMID- 29243929 TI - The Chemistry of Some Dalodesmidean Millipedes from Tasmania (Diplopoda, Polydesmida). AB - Millipedes (Diplopoda) are well known for their toxic or repellent defensive secretions. As part of a larger investigation, we describe the chemical constituents of 14 species of Tasmanian millipedes in seven genera. Six species in the genus Gasterogramma were found to produce acyclic ketones, including the pungent unsaturated ketones 1, 2, and 6, and the novel (rel-3R,5S,7S)-3,5,7 trimethyl-2,8-decanedione (7b), for which the stereoconfiguration was established by stereoselective syntheses of pairs of isomers. These compounds have not been detected before in millipede defensive secretions. This report is the first on species of the suborder Dalodesmidea (Polydesmida), a dominant component of the soil and litter fauna of the temperate regions of the Southern Hemisphere. PMID- 29243930 TI - Structure-Based Kinase Profiling To Understand the Polypharmacological Behavior of Therapeutic Molecules. AB - Several drugs elicit their therapeutic efficacy by modulating multiple cellular targets and possess varied polypharmacological actions. The identification of the molecular targets of a potent bioactive molecule is essential in determining its overall polypharmacological profile. Experimental procedures are expensive and time-consuming. Therefore, computational approaches are actively implemented in rational drug discovery. Here, we demonstrate a computational pipeline, based on reverse virtual screening technique using several consensus scoring strategies, and perform structure-based kinase profiling of 12 FDA-approved drugs. This target prediction showed an overall good performance, with an average AU-ROC greater than 0.85 for most drugs, and identified the true targets even at the top 2% cutoff. In contrast, 10 non-kinase binder drugs exhibited lower binding efficiency and appeared in the bottom of ranking list. Subsequently, we validated this pipeline on a potent therapeutic molecule, mahanine, whose polypharmacological profile related to targeting kinases is unknown. Our target prediction method identified different kinases. Furthermore, we have experimentally validated that mahanine is able to modulate multiple kinases that are involved in cross-talk with different signaling molecules, which thereby exhibits its polypharmacological action. More importantly, in vitro kinase assay exhibited the inhibitory effect of mahanine on two such predicted kinases' (mTOR and VEGFR2) activity, with IC50 values being ~12 and ~22 MUM, respectively. Next, we generated a comprehensive drug-protein interaction fingerprint that explained the basis of their target selectivity. We observed that it is controlled by variations in kinase conformations followed by significant differences in crucial hydrogen-bond and van der Waals interactions. Such structure-based kinase profiling could provide useful information in revealing the unknown targets of therapeutic molecules from their polypharmacological behavior and would assist in drug discovery. PMID- 29243931 TI - Structure and Liquid Fragility in Sodium Carbonate. AB - The relationship between local structure and dynamics is explored for molten sodium carbonate. A flexible fluctuating-charge model, which allows for changes in the shape and charge distribution of the carbonate molecular anion, is developed. The system shows the evolution of highly temperature-dependent complex low-dimensional structures which control the dynamics (and hence the liquid fragility). By varying the molecular anion charge distribution, the key interactions responsible for the formation of these structures can be identified and rationalized. An increase in the mean charge separation within the carbonate ions increases the connectivity of the emerging structures and leads to an increase in the system fragility. PMID- 29243932 TI - Role of Aromatic Cross-Links in Structure and Dynamics of Model Three-Stranded beta-Sheet Peptides. AB - A series of closely related peptide sequences that form triple-strand structures was designed with a variation of cross-strand aromatic interactions and spectroscopically studied as models for beta-sheet formation and stabilities. Structures of the three-strand models were determined with NMR methods and temperature-dependent equilibrium studies performed using circular dichroism and Fourier transform infrared spectroscopies. Our equilibrium data show that the presence of a direct cross-strand aromatic contact in an otherwise folded peptide does not automatically result in an increased thermal stability and can even distort the structure. The effect on the conformational dynamics was studied with infrared-detected temperature-jump relaxation methods and revealed a high sensitivity to the presence and the location of the aromatic cross-links. Aromatic contacts in the three-stranded peptides slow down the dynamics in a site specific manner, and the impact seems to be related to the distance from the turn. With a Xxx-DPro linkage as a probe with some sensitivity for the turn, small differences were revealed in the relative relaxation of the sheet strands and turn regions. In addition, we analyzed the component hairpins, which showed less uniform dynamics as compared to the parent three-stranded beta-sheet peptides. PMID- 29243933 TI - New Aspects of the Gold Nanorod Formation Mechanism via Seed-Mediated Methods Revealed by Molecular Dynamics Simulations. AB - New aspects of the formation and growth mechanism of gold nanorods (AuNRs) during seed-mediated colloidal synthesis are revealed from the results of molecular dynamics simulation. The model systems consist of cetyltrimethylammonium bromide (CTAB) units adsorbed on low-index [Au(110), Au(100), and Au(111)] and high-index [Au(250)] gold surfaces. The CTAB units are adsorbed as adjacent cylindrical micelles when the relative number of adsorbed bromide ions is small. At later AuNR growth stages, the number of bromide ions increases as the [AuBr2]- species pass through the channels between the adsorbed micelles on the gold surface. Thus, the mature AuNRs have a high concentration of bromide ions at their surface, which appears to change the organization of the CTAB units on the particle surface from adsorbed micelles to a compact CTAB bilayer. PMID- 29243934 TI - Water-like Behavior of Formamide: Jump Reorientation Probed by Extended Depolarized Light Scattering. AB - Water is a strong self-associated liquid with peculiar properties that crucially depend on H-bonding. As regards its molecular dynamics, only recently has water reorientation been successfully described based on a jump mechanism, which is responsible for the overall H-bonding exchange. Here, using high-resolution broad band depolarized light scattering, we have investigated the reorientational dynamics of formamide (FA) as a function of concentration from the neat liquid to diluted aqueous solutions. Our main findings indicate that in the diluted regime the water rearrangement can trigger the motion of FA solute molecules, which are forced to reorient at the same rate as water. This highlights an exceptional behavior of FA, which perfectly substitutes water within its network. Besides other fundamental implications connected with the relevance of FA, its water-like behavior provides rare experimental evidence of a solute whose dynamics is completely slaved to the solvent. PMID- 29243936 TI - Detection of Gallibacterium anatis by TaqMan fluorescent quantitative PCR. AB - To better understand the prevalence of Gallibacterium anatis in different poultry species, a rapid and accurate method was developed to detect G. anatis using a TaqMan fluorescent quantitative polymerase chain reaction (qPCR). Specific primers and a TaqMan probe were designed based on the reference gtxA gene sequence. The qPCR standard curve showed a good linear relationship, and the method showed good reproducibility, sensitivity, and specificity, indicating its suitability for G. anatis identification and quantitative analysis. A comparison of the detection results in 160 clinical swab samples showed that the detection rate (54.4%) of the qPCR for G. anatis was better than that of two conventional methods: gyrB gene-based qPCR for G. anatis (51.9%) and culture-based identification (34.4%). G. anatis was detected in layer chicken (77.3%), Silkie chicken (72.7%), and duck (27.1%) with relatively high detection rates, whereas dove (8.8%) and quail (3.0%) showed lower detection rates, indicating the different prevalence of G. anatis in different fowl species. PMID- 29243937 TI - Long-Term Coarse Particulate Matter Exposure Is Associated with Asthma among Children in Medicaid. AB - RATIONALE: Short- and long-term fine particulate matter (particulate matter <=2.5 MUm in aerodynamic diameter [PM2.5]) pollution is associated with asthma development and morbidity, but there are few data on the effects of long-term exposure to coarse PM (PM10-2.5) on respiratory health. OBJECTIVES: To understand the relationship between long-term fine and coarse PM exposure and asthma prevalence and morbidity among children. METHODS: A semiparametric regression model that incorporated PM2.5 and PM10 monitor data and geographic characteristics was developed to predict 2-year average PM2.5 and PM10-2.5 exposure during the period 2009 to 2010 at the zip-code tabulation area level. Data from 7,810,025 children aged 5 to 20 years enrolled in Medicaid from 2009 to 2010 were used in a log-linear regression model with predicted PM levels to estimate the association between PM exposure and asthma prevalence and morbidity, adjusting for race/ethnicity, sex, age, area-level urbanicity, poverty, education, and unmeasured spatial confounding. MEASUREMENTS AND MAIN RESULTS: Exposure to coarse PM was associated with increased asthma diagnosis prevalence (rate ratio [RR] for 1-MUg/m3 increase in coarse PM level, 1.006; 95% confidence interval [CI], 1.001-1.011), hospitalizations (RR, 1.023; 95% CI, 1.003-1.042), and emergency department visits (RR, 1.017; 95% CI, 1.001-1.033) when adjusting for fine PM. Fine PM exposure was more strongly associated with increased asthma prevalence and morbidity than coarse PM. The estimates remained elevated across different levels of spatial confounding adjustment. CONCLUSIONS: Among children enrolled in Medicaid, exposure to higher average coarse PM levels is associated with increased asthma prevalence and morbidity. These results suggest the need for direct monitoring of coarse PM and reconsideration of limits on long-term average coarse PM pollution levels. PMID- 29243940 TI - Methods and practices to diversify cell-based products. AB - Medicinal signaling cell (MSC)-based products represent emerging treatments in various therapeutic areas including cardiometabolic, inflammation, autoimmunity, orthopedics, wound healing and oncology. Exploring innovation beyond minimally manipulated plastic-adherent ex vivo expanded allogeneic MSCs enables product delineation. Product delineation is on the critical path to maximize clinical benefits and market access. An innovation framework is presented here along various innovation dimensions comprising composition-of-matter by means of positive cell surface markers, formulation varying for example the cell dose or the preservation mode and medium, manufacturing to adapt the secretome of MSCs to the condition of interest, the mode of delivery and corresponding delivery devices, as well as molecular engineering and biomarkers. The rationale of the innovation space thus described applies generally to all cell-based therapies. PMID- 29243938 TI - Iron Deficiency Affects Seizure Susceptibility in a Time- and Sex-Specific Manner. AB - Iron deficiency (ID) affects more than three billion people worldwide making it the most common micronutrient deficiency. ID is most prevalent during gestation and early life, which is of particular concern since its impact on the developing central nervous system is associated with an increased risk of a wide range of different psychiatric disorders later in life. The cause for this association is not known, but many of these same disorders are also associated with an imbalance between excitation and inhibition (E/I) within the brain. Based on this shared impairment, we asked whether ID could contribute to such an imbalance. Disruptions in the E/I balance can be uncovered by the brain's response to seizure inducing insults. We therefore tested the seizure threshold under different nutritional models of ID. We found that mice which were postnatally exposed to ID (and were acutely ID) had a decreased seizure threshold and increased susceptibility to certain seizure types. In contrast, mice that were exposed to ID only during gestation had an increased seizure threshold and low seizure incidence. We suggest that exposure to ID during gestation might alter the cellular components that contribute to the establishment of a proper E/I balance later in life. In addition, our data highlight the importance of considering the window of vulnerability since gestational ID and postnatal ID have significantly different consequences on seizure probability. PMID- 29243942 TI - XVII International Workshop on Chronic Lymphocytic Leukemia 2017 May 12--15, 2017, New York. PMID- 29243941 TI - Critical success factors in implementing an e-rostering system in a healthcare organisation. AB - Effective and efficient staff scheduling has always been a challenging issue, especially in health service organisations. Both the extremes of staff shortage and overage have an adverse impact on the performance of healthcare organisations. In this case, an electronic and systematic staff scheduling (e rostering) system is the often seen as the best solution. Unless an organisation has an effective implementation of such a system, possible cost savings, efficiency, and benefits could be minimal. This study is aimed to research key success factors for the successful effective implementation of an electronic rostering system, especially at healthcare organisations. A case study research method was used to evaluate critical success factors for effectively implementing an e-rostering system. The data were collected through interviews and observations. The findings indicate that technical support, an effective policy, leadership, clear goals and objectives, gradual change, evidence of the advantages of the new system, senior management support, and effective communication are the critical success factors in implementing an e-rostering system in healthcare organisations. Prior to this study, no such factors were grounded in the current context, so this research would help in bridging the gap towards effective implementation of an e-rostering system in the healthcare sector. This research also suggests future studies in different cultures and contexts. PMID- 29243943 TI - Roadmap to clinical translation: insights from a UK regenerative medicine platform workshop on mesenchymal stromal cells. PMID- 29243945 TI - Coordination in gait: Demonstration of a spectral approach. AB - Many important notions in Life Sciences are linked with the idea of cycles, periodicity, fluctuations and transitions. The aim of this paper is to use spectral analysis in a unique way to study and quantify whole body coordination during gait. A participant walked at 3 km/h and ran at 15 km/h on a treadmill for 2 minutes. Position of the approximate center of rotation of the toe, ankle, knee, hip, shoulder, elbow and wrist, heel, PSIS and head were collected (CODAmotion; 100 Hz). Fast Fourier Transform was performed on x-coordinate data of the 1) knee marker; 2) 4 markers attached to the free lower limb (toe, ankle, heel and knee); 3) left and right free lower limbs; 4) whole body (all markers). Gait is described by a largely harmonic and resonant oscillator that operates unilateral free limbs at the stride frequency, and axial regions at the step frequency. Running is described by a more harmonic and resonant oscillating structure than walking, with a 3 times higher Q factor and 47% lower Inharmonicity Index. This method is presented as a way to capture global dynamics of our complex multi-segment system, and presents a novel application of spectral analysis to study coordination. PMID- 29243944 TI - Mitochondrial complex III Rieske Fe-S protein processing and assembly. AB - Regulation of the mitochondrial respiratory chain biogenesis is a matter of great interest because of its implications for mitochondrial disease. One of the mitochondrial disease genes recently discovered associated to encephalopathy and mitochondrial complex III (cIII) deficiency is TTC19. Our study of TTC19 deficient human and mouse models, has led us to propose a post-assembly quality control role or 'husbandry' function for this factor that is linked to Rieske Fe S protein (UQCRFS1). UQCRFS1 is the last incorporated cIII subunit, and its presence is essential for enzymatic activity. During UQCRFS1 assembly, the precursor is cleaved and its N-terminal part remains bound to the complex, between the two core subunits (UQCRC1 and UQCRC2). In the absence of TTC19 there is a prominent accumulation of these UQCRFS1-derived N-terminal fragments that proved to be detrimental for cIII function. In this article we will discuss some ideas around the UQCRFS1 processing and assembly and its importance for the regulation of cIII activity and biogenesis. PMID- 29243946 TI - Ibrutinib and its use in the treatment of chronic lymphocytic leukemia. AB - Ibrutinib represents a revolution in chronic lymphocytic leukemia treatment scenario providing results never seen before and offering an effective therapy even in high-risk patients with really poor outcome after chemoimmunotherapy. Thanks to longer updates, on one hand, ibrutinib has confirmed its efficacy continuing to show clinical benefits over time; on the other hand, resistance mechanisms are slowly emerging. Moreover, clinicians should be aware of ibrutinib related side effects, paying attention to screen patients that could benefit more from the drug and try to prevent adverse events. While ibrutinib approval indication is expanding, high treatment costs will shortly require a selection of those who can really draw advantage from Bruton's tyrosine kinase inhibition and those who could continue to be treated with chemoimmunotherapy. PMID- 29243947 TI - Multiple target-based pharmacophore design from active site structures. AB - Health care systems have benefitted from rational drug discovery processes like vHTS, virtual high throughput screening pharmacophores and quantitative structure activity relationships, and many challenges have been explored using such techniques: decisions on specificity and selectivity are made after screening millions of molecules for multiple targets. Recent challenges in drug research emphasize the design of drugs that bind with more than one target of interest (multi-target) and do not bind with undesirable targets. This work attempts to use a three-dimensional interaction profile of the active site of a class of proteins, identify selective positions for the binding of functional groups, called features, and develop ensembles of multi-targeted pharmacophores that retain specificity and selectivity. The goal of this study is to develop multi target pharmacophores by computational methods using protein structures alone to guide the discovery of novel inhibitors of plasmepsins, displaying selectivity over their human homologs, cathepsin D and pepsin. The development of such novel tools is attempted using a combination of different approaches such as the molecular interaction field, clique graph and inductive logic programming to identify and compare specific and selective complementary features. The identification of selective combinations of features has resulted in the design of multi-featured specific and selective pharmacophores that are validated using antimalarial compounds in ChEMBL that are known for their anti-plasmepsin II activity. This novel method is computationally less intensive and is applicable to any known class of target structures for finding specific and selective binders simultaneously. PMID- 29243948 TI - Shanghai Health Study (2001-2009): What was learned about benzene health effects? AB - The Shanghai Health Study (SHS) was a large epidemiology study conducted as a joint effort between the University of Colorado and Fudan University in Shanghai, China. The study was funded by members of the American Petroleum Institute between 2001 and 2009 and was designed to evaluate the human health effects associated with benzene exposure. Two arms of the SHS included: an occupational based molecular epidemiology study and several hospital-based case control studies. Consistent with historical literature, following sufficient exposure to relatively high airborne concentrations and years of exposure, the SHS concluded that exposure to benzene resulted in an increased risk of various blood and bone marrow abnormalities such as benzene poisoning, aplastic anemia (AA), myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). Non-Hodgkin lymphoma (NHL) was not significantly increased for the exposures examined in this study. Perhaps the most important contribution of the SHS was furthering our understanding of the mechanism of benzene-induced bone marrow toxicity and the importance of identifying the proper subset of MDS relevant to benzene. Investigators found that benzene-exposed workers exhibited bone marrow morphology consistent with an immune-mediated inflammatory response. Contrary to historic reports, no consistent pattern of cytogenetic abnormalities was identified in these workers. Taken together, findings from SHS provided evidence that the mechanism for benzene-induced bone marrow damage was not initiated by chromosome abnormalities. Instead, chronic inflammation, followed by an immune-mediated response, is likely to play a more significant role in benzene-induced disease initiation and progression than previously thought. PMID- 29243949 TI - Twenty Facts About Cystic Fibrosis. PMID- 29243950 TI - Erratum: Fifty Years of Research in ARDS. Gas Exchange in Acute Respiratory Distress Syndrome. PMID- 29243951 TI - Introduction. PMID- 29243952 TI - Discussion. PMID- 29243953 TI - Contraceptive efficacy and tolerability with a novel combined contraceptive vaginal ring, NuvaRing. AB - NuvaRing is a novel combined contraceptive vaginal ring that releases 15 MUg of ethinylestradiol and 120 MUg etonogestrel per day. Each ring is used for one cycle, comprising 3 weeks continuous use of the ring followed by a 1-week ring free period. The contraceptive efficacy and safety of NuvaRing have been studied in a 1-year, open study conducted in 1145 women. Six pregnancies occurred in 12 109 cycles of exposure, giving a Pearl index of 0.65 (95% confidence interval (CI), 0.24-1.41). However, three of the six women violated the NuvaRing regimen in the cycle of conception. Compliance with the prescribed regimen was high, with criteria being fulfilled in 90.8% of cycles. During the 1 year of the study, 41% of the women did not experience any adverse events. The most frequently reported treatment-related adverse events were headache (6.6%), leukorrhea (5.3%) and vaginitis (5.0%). There was a low incidence of estrogen-related adverse events such as nausea (2.8%) and breast tenderness (1.9%). A total of 173 women (15.1%) discontinued due to an adverse event, with device-related events (comprising ring expulsion, foreign body sensation or coital problems) being the most commonly reported (2.6%). There were no clinically relevant changes in blood biochemistry, hematology, blood pressure, heart rate, body weight, physical examination or cervical cytology. In conclusion, NuvaRing is an effective contraceptive that is well tolerated, has a good safety profile and is not associated with unwanted effects on the cervix. PMID- 29243954 TI - Complete and robust ovulation inhibition with NuvaRing. AB - NuvaRing, a novel contraceptive vaginal ring, releases 15 MUg of ethinylestradiol (EE) and 120 MUg etonogestrel (ENG) per day. A randomized pharmacokinetic study compared NuvaRing with a combined oral contraceptive (COC) containing 30 MUg EE and 150 MUg desogestrel. Maximum levels of EE and ENG with NuvaRing were 30% and 40%, respectively, of those seen with the COC. Because ENG bioavailability was higher following vaginal administration, the systemic progestogen exposures were comparable with the two contraceptives. However, the EE bioavailabilities were similar with both routes and so EE exposure with NuvaRing was half that with the COC. Pharmacodynamic studies have examined ovarian function during recommended and altered NuvaRing use. The use of NuvaRing for the recommended 3-week period completely inhibited ovulation. During an additional 2 weeks of use, ovulation continued to be inhibited. Early NuvaRing removal after just 3 days had no effect on the time to ovulation compared with recommended use, thus indicating that 3 days of use seem to be sufficient to suppress ovarian activity. Finally, delayed ring insertion (when the follicles had developed to 13 mm) resulted in inhibition of ovulation in all women. In conclusion, NuvaRing effectively inhibits ovulation during recommended and altered use, showing that it is a robust contraceptive method. PMID- 29243955 TI - High acceptability and satisfaction with NuvaRing use. AB - NuvaRing is a combined contraceptive vaginal ring that releases constant low doses of ethinylestradiol and etonogestrel. One cycle consists of 3 weeks of ring use followed by a 1-week ring-free period and the ring can easily be inserted and removed by the women themselves. Acceptability and satisfaction were determined by a questionnaire in two large, multicenter, open, 1-year studies conducted in a total of 2393 women, of whom 1950 (82%) completed cycle 3 questionnaires. Overall, 53% of participants switched to NuvaRing from other hormonal contraception; the main reason given for deciding to use NuvaRing (47%) was that it appeared to be a new and attractive method of contraception. Nearly all users considered the ring easy to insert and remove. Although 15% of women and 30% of their partners reported feeling the ring at least occasionally during intercourse, very few partners objected to women using the ring and the majority of women felt comfortable with it during intercourse. Reductions in menstrual pain and the length of the menstrual period were reported during ring use. More than 90% of women were satisfied or very satisfied with the ring at each assessment and 97% of those who completed the studies said they would recommend the method to others. At baseline, the preferred contraceptive method was the pill (66% of users). However, more than 80% of women at each assessment said they would use NuvaRing as their first-choice method. High satisfaction at cycle 3 was a good predictor of low subsequent discontinuation risk. In conclusion, this analysis shows that users express good acceptability and a high level of satisfaction with NuvaRing. PMID- 29243956 TI - Lower hormone dosage with improved cycle control. AB - Cycle control is a key factor that influences contraceptive acceptability and compliance. In combined oral contraceptives (COC), reducing the daily dose of ethinylestradiol (EE) can compromise cycle control. As NuvaRing, the novel combined contraceptive vaginal ring, releases only 15 MUg/day EE, it was therefore important to closely assess cycle control. A 1-year, multicenter study examined cycle control during NuvaRing use in 1182 women. Withdrawal bleeding during the 1-week ring-free period occurred in 98.8% of cycles. Early withdrawal bleeding was relatively uncommon (5.6% of cycles); in 24.2% of cycles, withdrawal bleeding, comprising mainly spotting, extended into the next cycle. From cycle 1 onwards, there was a low incidence of irregular bleeding during the 3 weeks of ring use; on average, irregular bleeding occurred in only 4.4% of cycles and consisted mainly of spotting only. In a combined analysis, cycle control achieved using NuvaRing (n = 121) was compared with that of a standard COC containing 30 MUg/day EE and 150 MUg/day levonorgestrel (n = 126) over six cycles. Late withdrawal bleeding was significantly more frequent with the COC in all cycles. Irregular bleeding occurred in < 5% of all cycles with NuvaRing and between 5.4% and 38.8% per cycle with the COC. Significantly more women using NuvaRing experienced an ideal 'intended bleeding pattern' compared with COC users at every cycle. This excellent cycle control with NuvaRing is expected to improve convenience and acceptability and result in a high level of compliance. PMID- 29243957 TI - Do we really need to reconsider coligranulomatosis (Hjarre and Wramby's disease) in poultry? PMID- 29243958 TI - Correction to: Diabetes Technol Ther 2017;19(9):516-526. PMID- 29243959 TI - Application of Glycemic Variability Percentage: Implications for Continuous Glucose Monitor Utilization and Analysis of Artificial Pancreas Data. AB - BACKGROUND: The problem of glycemic variability has been widely acknowledged in patients with diabetes with severe insulin deficiency. In a companion article, we proposed a novel metric, the glycemic variability percentage (GVP), for assessing glycemic variability that accounts for both the amplitude and frequency of glycemic fluctuations. METHOD: We applied the new metric, the GVP, to a previously reported case of a subject using an earlier generation continuous glucose monitoring (CGM) device, in which successive periods of use were associated with an apparent decrease in glycemic variability. Results were compared with histogram distributions for the rate of change of glucose as well. The GVP was also applied to data from a published study of a bihormonal artificial pancreas system comparing results from open loop and closed loop in adolescents and in adults. RESULTS: The GVP was able to quantify the changes in glycemic variability during successive periods of CGM use. Application of the GVP to a published study of a bihormonal artificial pancreas found an increase in glycemic variability compared with other accepted metrics which suggested a decrease in glycemic variability. CONCLUSION: The GVP may be a clinically useful tool in characterizing the change in glycemic variability in subjects using CGM devices. Compared with metrics, such as the standard deviation, that focus solely on the amplitude of oscillations, the GVP, which measures both frequency and amplitude, may also be a more useful tool in assessing the true level of glycemic variability in artificial pancreas studies. PMID- 29243960 TI - What Can Behavioral Healthcare Learn from Digital Medicine? PMID- 29243962 TI - Reconceptualizing the Link Between Screen Time When Gaming with Physical Activity and Sedentary Behavior. AB - With public health concerns surrounding rates of sedentary behavior (SB), there is often speculation on the role of screen time (in which "computer gaming" is commonly encompassed) as a key contributor to this epidemic. We argue that these assertions are based upon a number of problematic assumptions. Particularly, the notion that screen time necessitates inactivity or SB can be refuted based on the empirical literature. In addition, digital gaming as one so-called problematic screen-time behavior consists of a failed assumption that all games proffer equivalent physical affordances. We argue that these assumptions should be revisited, in which a reconceptualization of screen-time activities (with specific reference to gaming) and its link with inactivity and/or SB should be a key agenda. Within this, we introduce a conceptual model of how this may be realized, with the intention that this may offer a practical guide for researchers, and indeed for health professionals in this field. PMID- 29243963 TI - How Did the Information Flow in the #AlphaGo Hashtag Network? A Social Network Analysis of the Large-Scale Information Network on Twitter. AB - As it becomes common for Internet users to use hashtags when posting and searching information on social media, it is important to understand who builds a hashtag network and how information is circulated within the network. This article focused on unlocking the potential of the #AlphaGo hashtag network by addressing the following questions. First, the current study examined whether traditional opinion leadership (i.e., the influentials hypothesis) or grassroot participation by the public (i.e., the interpersonal hypothesis) drove dissemination of information in the hashtag network. Second, several unique patterns of information distribution by key users were identified. Finally, the association between attributes of key users who exerted great influence on information distribution (i.e., the number of followers and follows) and their central status in the network was tested. To answer the proffered research questions, a social network analysis was conducted using a large-scale hashtag network data set from Twitter (n = 21,870). The results showed that the leading actors in the network were actively receiving information from their followers rather than serving as intermediaries between the original information sources and the public. Moreover, the leading actors played several roles (i.e., conversation starters, influencers, and active engagers) in the network. Furthermore, the number of their follows and followers were significantly associated with their central status in the hashtag network. Based on the results, the current research explained how the information was exchanged in the hashtag network by proposing the reciprocal model of information flow. PMID- 29243965 TI - Enasidenib, a targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. AB - Mutations in IDH2 genes (mIDH2) occur in approximately 12% of patients with acute myeloid leukemia. Enasidenib is an oral, small-molecule inhibitor of mIDH2 proteins. Enasidenib is shown to suppress the oncometabolite, 2-hydroxyglutarate, and promote differentiation of leukemic bone marrow blasts. In a Phase I dose escalation and expansion study, 40.3% of patients with relapsed/refractory acute myeloid leukemia responded to enasidenib monotherapy, including 19.3% who achieved complete remission and 11% who proceeded to transplant. Median overall survival was 9.3 months. 2-hydroxyglutarate suppression did not predict response and mIDH2 clearance was possible, but not required for response. Patients with >=6 co-mutations or NRAS co-mutations were less likely to attain a response. Enasidenib was safe and well tolerated with low rates of treatment-related adverse events. [Formula: see text]. PMID- 29243966 TI - Welcome to the 14th volume of Future Oncology. PMID- 29243967 TI - Extracts of Porphyra tenera (Nori Seaweed) Activate the Immune Response in Mouse RAW264.7 Macrophages via NF-kappaB Signaling. AB - Porphyra tenera, also known as nori, is a red algal species of seaweed. It is cultivated in Asia for culinary purposes. We report that P. tenera extract (PTE) enhances the immune response in mouse macrophages. We found that P. tenera extract regulates the NF-kappaB IkappaB kinase (IKK) signaling pathway, and we assessed the expression and translocation of p65, a subunit of NF-kappaB, in RAW264.7 mouse macrophage cells after treatment with PTE. We also investigated the effects of 10% ethanol PTE (PTE10) in RAW264.7 cells. The production of IL 10, IL-6, TNF-alpha, and IFN-gamma was induced by PTE treatment of the macrophages, and PTE also enhanced p-IkappaB and p-AKT. PTE10 showed no cytotoxicity at 10-20 MUg/mL in RAW264.7 cells. PTE10, in fact, increased cell viability at 24 h, stimulated macrophage cells, and induced the phosphorylation of Akt. Akt stimulates IKK activity through the phosphorylation of IKKalpha and enhances immune activity through the activation of NF-kappaB. In this study, NF kappaB activation was induced by increasing p-NF-kappaB and p-IKK. A subunit of NF-kappaB, p65, was located in the nucleus and increased the expression of various cytokines. PTE thus enhanced the immune response through IkappaB-alpha immunostimulation signaling in RAW264.7 cells. PTE10 has potential therefore for development of future treatments requiring immune system stimulation. PMID- 29243968 TI - Chlorogenic Acid-Enriched Extract of Ilex kudingcha C.J. Tseng Inhibits Angiogenesis in Zebrafish. AB - Kudingcha is a particularly bitter tasting tea that has been widely used in China to eliminate fever and itching eyes, and to clear blood toxins. Kudingcha is considered of value for its potential anticancer effects that are attributed to the presence of characteristic bioactive ingredients. The chlorogenic acid (CGA) derivatives 3-0-caffeoylquinic acid, 5-0-caffeoylquinic acid, 3,5-0 dicaffeoylquinic acid, and 4,5-0-dicaffeoylquinic acid were separated from Ilex kudingcha C.J. Tseng extract by high-performance liquid chromatography (HPLC) photodiode array detector (PDA) and HPLC-nuclear magnetic resonance (NMR). In Tg(flk1:EGFP) zebrafish embryos at 52 hours postfertilization (hpf), angiogenesis was significantly inhibited by kudingcha extract (KDCE) at concentrations of 400 and 500 MUg/mL and CGA also showed significant inhibition in embryos treated with 80, 100, and 130 MUg/mL. Endothelial cell apoptosis showed a dose-dependent increase in response to KDCE and CGA. CGA derivatives from KDCE could have potential as anticancer agents against tumor angiogenesis. PMID- 29243969 TI - Low-Molecular-Weight Oligonol, a Polyphenol Derived from Lychee Fruit, Attenuates Experimental Reflux Esophagitis and HCl/Ethanol-Induced Gastric Ulcer. AB - Oligonol, a polyphenol derived from lychee fruit, is produced by an oligomerization process that converts high-molecular-weight polyphenol polymers into low-molecular-weight oligomers. Evidence suggests that oligonol exerts its beneficial effects based on antioxidant and anti-inflammatory properties. This study was the first to investigate the antioxidative and anti-inflammatory effects of oligonol on gastroesophageal inflammatory models: surgically induced acute reflux esophagitis (RE) and gastric ulcer (GU) induced by HCl/ethanol. In the in vitro study, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3 ethylbenzothiazolin-6-sulfonic acid) (ABTS) radical scavenging assays were performed to determine the antioxidant activity of oligonol. The experimental groups were each composed of normal, vehicle, and oligonol groups. RE rats and GU mice were treated orally with oligonol (100 mg/kg bw) or distilled water as a vehicle (n = 8 for each group). Oligonol exhibited potent free radical-scavenging capacities for DPPH and ABTS radicals, activities that were similar to those of ascorbic acid. The in vivo study revealed that oligonol consumption significantly prevented RE and GU formation and decreased the gross mucosal injury from oxidative stress. Oligonol decreased the reactive oxygen species levels and elevated levels of both inflammatory mediators and cytokines (p-IkappaB, NF kappaBp65, COX-2, iNOS, TNF-alpha, and IL-1beta) in the RE and GU models. Oligonol had a protective effect against oxidative stress by regulating antioxidant enzyme (superoxide dismutase, catalase, and GPx-1/2) activities in GU mice. Oligonol has potential as a preventive and therapeutic agent for gastroesophageal inflammatory diseases, including RE and GU. PMID- 29243972 TI - Endoscopic third ventriculostomy and choroid plexus cauterization in infant hydrocephalus: a prospective study by the Hydrocephalus Clinical Research Network. AB - OBJECTIVE High-quality data comparing endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) to shunt and ETV alone in North America are greatly lacking. To address this, the Hydrocephalus Clinical Research Network (HCRN) conducted a prospective study of ETV+CPC in infants. Here, these prospective data are presented and compared to prospectively collected data from a historical cohort of infants treated with shunt or ETV alone. METHODS From June 2014 to September 2015, infants (corrected age <= 24 months) requiring treatment for hydrocephalus with anatomy suitable for ETV+CPC were entered into a prospective study at 9 HCRN centers. The rate of procedural failure (i.e., the need for repeat hydrocephalus surgery, hydrocephalus-related death, or major postoperative neurological deficit) was determined. These data were compared with a cohort of similar infants who were treated with either a shunt (n = 969) or ETV alone (n = 74) by creating matched pairs on the basis of age and etiology. These data were obtained from the existing prospective HCRN Core Data Project. All patients were observed for at least 6 months. RESULTS A total of 118 infants underwent ETV+CPC (median corrected age 1.3 months; common etiologies including myelomeningocele [30.5%], intraventricular hemorrhage of prematurity [22.9%], and aqueductal stenosis [21.2%]). The 6-month success rate was 36%. The most common complications included seizures (5.1%) and CSF leak (3.4%). Important predictors of treatment success in the survival regression model included older age (p = 0.002), smaller preoperative ventricle size (p = 0.009), and greater degree of CPC (p = 0.02). The matching algorithm resulted in 112 matched pairs for ETV+CPC versus shunt alone and 34 matched pairs for ETV+CPC versus ETV alone. ETV+CPC was found to have significantly higher failure rate than shunt placement (p < 0.001). Although ETV+CPC had a similar failure rate compared with ETV alone (p = 0.73), the matched pairs included mostly infants with aqueductal stenosis and miscellaneous other etiologies but very few patients with intraventricular hemorrhage of prematurity. CONCLUSIONS Within a large and broad cohort of North American infants, our data show that overall ETV+CPC appears to have a higher failure rate than shunt alone. Although the ETV+CPC results were similar to ETV alone, this comparison was limited by the small sample size and skewed etiological distribution. Within the ETV+CPC group, greater extent of CPC was associated with treatment success, thereby suggesting that there are subgroups who might benefit from the addition of CPC. Further work will focus on identifying these subgroups. PMID- 29243973 TI - Cervical sagittal alignment in patients with adolescent idiopathic scoliosis: is it corrected by surgery? AB - OBJECTIVE Cervical sagittal alignment (CSA) is related to function and quality of life, but it has not been frequently studied in patients with adolescent idiopathic scoliosis. This study aimed to reveal the change in CSA following corrective surgery, compare the cervical sagittal parameters according to curve types, and assess related factors for postoperative aggravation of CSA. METHODS The authors studied 318 consecutive patients with adolescent idiopathic scoliosis who underwent corrective surgery at a single center. Occiput-C2 and C2-7 lordosis, C2-7 sagittal vertical axis (SVA), T-1 slope, thoracic kyphosis, and lumbar sagittal profiles were measured preoperatively and postoperatively. Scoliosis Research Society Outcomes Questionnaire (SRS-22) scores were used as clinical outcomes. Each radiological parameter was compared preoperatively and postoperatively according to curve types (double major, single thoracic, and double thoracic curves). Patients were grouped based on preoperative CSA: the lordotic group (group L) and the kyphotic group (group K). Each radiological parameter was compared between the groups. Related factors for postoperative aggravation of CSA were assessed using multivariate logistic analysis. RESULTS Of the total number of patients studied, 67.0% (213 of 318) and 54.4% (173 of 318) showed cervical kyphotic alignment preoperatively and postoperatively, respectively. C2-7 lordosis increased (from -5.8 degrees to -1.1 degrees ; p < 0.001) and C2-7 SVA decreased (from 24.2 to 20.0 mm; p < 0.001) postoperatively regardless of curve types. Although group K showed improvement in C2-7 lordosis (from -12.7 degrees to -4.8 degrees ; p < 0.001), group L showed no difference (from 9.0 degrees to 6.9 degrees ; p = 0.115) postoperatively. Clinical outcomes were not related to the degree of cervical kyphosis in this cohort. C2-7 lordosis (p < 0.001) and pelvic tilt (p = 0.019) were related to postoperative aggravation of CSA. CONCLUSIONS Regardless of the trend of improvement in CSA, many patients (54.4%) still showed cervical kyphotic alignment postoperatively. C2-7 lordosis and C2-7 SVA improved postoperatively in all curve types. However, postoperative changes in C2-7 lordosis showed different results based on preoperative CSA, which could be related to T-1 slope and thoracic kyphosis. However, clinical outcomes showed no difference based on CSA in this study cohort. Greater C2-7 lordosis and proximal thoracic curve preoperatively were risk factors for postoperative aggravation of CSA (p < 0.001 and p = 0.019, respectively). PMID- 29243970 TI - Reactive oxygen species damage drives cardiac and mitochondrial dysfunction following acute nano-titanium dioxide inhalation exposure. AB - Nanotechnology offers innovation in products from cosmetics to drug delivery, leading to increased engineered nanomaterial (ENM) exposure. Unfortunately, health impacts of ENM are not fully realized. Titanium dioxide (TiO2) is among the most widely produced ENM due to its use in numerous applications. Extrapulmonary effects following pulmonary exposure have been identified and may involve reactive oxygen species (ROS). The goal of this study was to determine the extent of ROS involvement on cardiac function and the mitochondrion following nano-TiO2 exposure. To address this question, we utilized a transgenic mouse model with overexpression of a novel mitochondrially-targeted antioxidant enzyme (phospholipid hydroperoxide glutathione peroxidase; mPHGPx) which provides protection against oxidative stress to lipid membranes. MPHGPx mice and littermate controls were exposed to nano-TiO2 aerosols (Evonik, P25) to provide a calculated pulmonary deposition of 11 ug/mouse. Twenty-four hours following exposure, we observed diastolic dysfunction as evidenced by E/A ratios greater than 2 and increased radial strain during diastole in wild-type mice (p < 0.05 for both), indicative of restrictive filling. Overexpression of mPHGPx mitigated the contractile deficits resulting from nano-TiO2 exposure. To investigate the cellular mechanisms associated with the observed cardiac dysfunction, we focused our attention on the mitochondrion. We observed a significant increase in ROS production (p < 0.05) and decreased mitochondrial respiratory function (p < 0.05) following nano-TiO2 exposure which were attenuated in mPHGPx transgenic mice. In summary, nano-TiO2 inhalation exposure is associated with cardiac diastolic dysfunction and mitochondrial functional alterations, which can be mitigated by the overexpression of mPHGPx, suggesting ROS contribution in the development of contractile and bioenergetic dysfunction. PMID- 29243974 TI - Pediatric cerebral venous sinus thrombosis or compression in the setting of skull fractures from blunt head trauma. AB - OBJECTIVE Pediatric cerebral venous sinus thrombosis has been previously described in the setting of blunt head trauma; however, the population demographics, risk factors for thrombosis, and the risks and benefits of detection and treatment in this patient population are poorly defined. Furthermore, few reports differentiate between different forms of sinus pathology. A series of pediatric patients with skull fractures who underwent venous imaging and were diagnosed with intrinsic cerebral venous sinus thrombosis or extrinsic sinus compression is presented. METHODS The medical records of patients at 2 pediatric trauma centers were retrospectively reviewed. Patients who were evaluated for blunt head trauma from January 2003 to December 2013, diagnosed with a skull fracture, and underwent venous imaging were included. RESULTS Of 2224 pediatric patients with skull fractures following blunt trauma, 41 patients (2%) underwent venous imaging. Of these, 8 patients (20%) had intrinsic sinus thrombosis and 14 patients (34%) displayed extrinsic compression of a venous sinus. Three patients with intrinsic sinus thrombosis developed venous infarcts, and 2 of these patients were treated with anticoagulation. One patient with extrinsic sinus compression by a depressed skull fracture underwent surgical elevation of the fracture. All patients with sinus pathology were discharged to home or inpatient rehabilitation. Among patients who underwent follow-up imaging, the sinus pathology had resolved by 6 months postinjury in 80% of patients with intrinsic thrombosis as well as 80% of patients with extrinsic compression. All patients with intrinsic thrombosis or extrinsic compression had a Glasgow Outcome Scale score of 4 or 5 at their last follow-up. CONCLUSIONS In this series of pediatric trauma patients who underwent venous imaging for suspected thrombosis, the yield of detecting intrinsic thrombosis and/or extrinsic compression of a venous sinus was high. However, few patients developed venous hypertension or infarction and were subsequently treated with anticoagulation or surgical decompression of the sinus. Most had spontaneous resolution and good neurological outcomes without treatment. Therefore, in the setting of pediatric skull fractures after blunt injury, venous imaging is recommended when venous hypertension or infarction is suspected and anticoagulation is being considered. However, there is little indication for pervasive venous imaging after pediatric skull fractures, especially in light of the potential risks of CT venography or MR venography in the pediatric population and the unclear benefits of anticoagulation. PMID- 29243975 TI - Erratum. PMID- 29243976 TI - Stereotactic EEG via multiple single-path omnidirectional trajectories within a single platform: institutional experience with a novel technique. AB - OBJECTIVE Stereotactic electroencephalography (SEEG) is being used with increasing frequency to interrogate subcortical, cortical, and multifocal epileptic foci. The authors describe a novel technique for SEEG in patients with suspected epileptic foci refractory to medical management. METHODS In the authors' technique, standard epilepsy evaluation and neuroimaging are used to create a hypothesis-driven SEEG plan, which informs the 3D printing of a novel single-path, multiple-trajectory, omnidirectional platform. Following skull anchor platform fixation, electrodes are sequentially inserted according to the preoperative plan. The authors describe their surgical experience and technique based on a review of all cases, adult and pediatric, in which patients underwent invasive epilepsy monitoring via SEEG during an 18-month period at Vanderbilt University Medical Center. Platform and anatomical variables influencing localization error were evaluated using multivariate linear regression. RESULTS Using this novel technology, 137 electrodes were inserted in 15 patients with focal epilepsy with favorable recording results and no clinical complications. The mean entry point localization error was 1.42 mm (SD 0.98 mm), and the mean target point localization error was 3.36 mm (SD 2.68 mm). Platform distance, electrode trajectory angle, and intracranial distance, but not skull thickness, were independently associated with localization error. CONCLUSIONS The multiple trajectory, single-path, omnidirectional platform offers satisfactory accuracy and favorable clinical results, while avoiding cumbersome frames and prohibitive up-front costs associated with other SEEG technologies. PMID- 29243978 TI - Reduction of shunt dependency rates following aneurysmal subarachnoid hemorrhage by tandem fenestration of the lamina terminalis and membrane of Liliequist during microsurgical aneurysm repair. AB - OBJECTIVE Shunt-dependent hydrocephalus is an important cause of morbidity following aneurysmal subarachnoid hemorrhage (aSAH) in excess of 20% of cases. Hydrocephalus leads to prolonged hospital and ICU stays, well as to repeated surgical interventions, readmissions, and complications associated with ventriculoperitoneal (VP) shunts, including shunt failure and infection. Whether variations in surgical technique at the time of aneurysm treatment may modify rates of shunt dependency remains a matter of debate. Here, the authors report on their experience with tandem fenestration of the lamina terminalis (LT) and membrane of Liliequist (MoL) at the time of open microsurgical repair of the ruptured aneurysm. METHODS The authors conducted a retrospective review of 663 consecutive patients with aSAH treated from 2005 to 2015 by open microsurgery via a pterional or orbitozygomatic craniotomy by the senior author (M.T.L.). Data collected from review of the electronic medical record included age, Hunt and Hess grade, Fisher grade, need for an external ventricular drain, and opening pressure. Patients were stratified into those undergoing no fenestration and those undergoing tandem fenestration of the LT and MoL at the time of surgical repair. Outcome variables, including VP shunt placement and timing of shunt placement, were recorded and statistically analyzed. RESULTS In total, shunt dependent hydrocephalus was observed in 15.8% of patients undergoing open surgical repair following aSAH. Tandem microsurgical fenestration of the LT and MoL was associated with a statistically significant reduction in shunt dependency (17.9% vs 3.2%, p < 0.01). This effect was confirmed with multivariate analysis of collected variables (multivariate OR 0.09, 95% CI 0.03-0.30). Number-needed-to treat analysis demonstrated that tandem fenestration was required in approximately 6.8 patients to prevent a single VP shunt placement. A statistically significant prolongation in days to VP shunt surgery was also observed in patients treated with tandem fenestration (26.6 +/- 19.4 days vs 54.0 +/- 36.5 days, p < 0.05). CONCLUSIONS Tandem fenestration of the LT and MoL at the time of open microsurgical clipping and/or bypass to secure ruptured anterior and posterior circulation aneurysms is associated with reductions in shunt dependent hydrocephalus following aSAH. Future prospective randomized multicenter studies are needed to confirm this result. PMID- 29243977 TI - Factors predicting reoperation of chronic subdural hematoma following primary surgical evacuation. AB - OBJECTIVE Chronic subdural hematoma (CSDH) is commonly encountered in neurosurgical practice. However, surgical evacuation remains complicated by a high rate of reoperation. The optimal surgical approach to reduce the reoperation rate has not been determined. In the current study, the authors evaluated the prognostic value of clinical and radiographic factors to predict reoperation in the context of CSDH. METHODS A retrospective review of 325 CSDH patients admitted to an academic medical center in the United States, between 2006 and 2016, was performed. Clinical and radiographic factors predictive of the need for CSDH reoperation were identified on univariable and multivariable analyses. RESULTS Univariable analysis showed that warfarin use, clopidogrel use, mixed hypo- and isointensity on T1-weighted MRI, greater preoperative midline shift, larger hematoma/fluid residual on first postoperative day CT, lesser decrease in hematoma size after surgery, use of monitored anesthesia care (MAC), and lack of intraoperative irrigation correlated with a significantly higher rate of reoperation. Multivariable analysis, however, showed that only the presence of loculation, clopidogrel or warfarin use, and percent of hematoma change after surgery significantly predicted the need for reoperation. Our results showed that 0% (no reduction), 50%, and 100% hematoma maximum thickness change (complete resolution of hematoma after surgery) were associated with a 41%, 6%, and < 1% rate of reoperation, respectively. The use of drains, either large diameter or small caliber, did not have any effect on the likelihood of reoperation. CONCLUSIONS Among many factors, clopidogrel or warfarin use, hematoma loculation on preoperative CT, and the amount of hematoma evacuation on the first postoperative CT were the strongest predictors of reoperation. PMID- 29243979 TI - A multi-institutional analysis of the untreated course of cerebral dural arteriovenous fistulas. AB - OBJECTIVE The rarity of cerebral dural arteriovenous fistulas (dAVFs) has precluded analysis of their natural history across large cohorts. Investigators from a considerable proportion of the few reports that do exist have evaluated heterogeneous groups of untreated and partially treated lesions. In the present study, the authors exclusively evaluated the untreated course of dAVFs across a multi-institutional data set to delineate demographic, angiographic, and natural history data. METHODS A multi-institutional database of dAVFs was queried for demographic and angiographic data as well as untreated disease course. After dAVFs were stratified by Djindjian type, annual nonhemorrhagic neurological deficit (NHND) and hemorrhage rates were derived, as were risk factors for each. A multivariable Cox proportional-hazards regression model was used to calculate hazard ratios. RESULTS Two hundred ninety-five dAVFs had at least 1 month of untreated follow-up. For 126 Type I dAVFs, there were no episodes of NHND or hemorrhage over 177 lesion-years. Respective annualized NHND and hemorrhage rates were 4.5% and 3.4% for Type II, 6.0% and 4.0% for Type III, and 4.5% and 9.1% for Type IV dAVFs. The respective annualized NHND and hemorrhage rates were 2.3% and 2.9% for asymptomatic Type II-IV dAVFs, 23.1% and 3.3% for dAVFs presenting with NHND, and 0% and 46.2% for lesions presenting with hemorrhage. On multivariate analysis, NHND presentation (HR 11.49, 95% CI 3.19-63) and leptomeningeal venous drainage (HR 5.03, 95% CI 0.42-694) were significant risk factors for NHND; hemorrhagic presentation (HR 17.67, 95% CI 2.99-117) and leptomeningeal venous drainage (HR 10.39, 95% CI 1.11-1384) were significant risk factors for hemorrhage. CONCLUSIONS All Type II-IV dAVFs should be considered for treatment. Given the high risk of rebleeding, lesions presenting with NHND and/or hemorrhage should be treated expediently. PMID- 29243980 TI - Letter to the Editor. Outcome prediction in brain tumor surgery. PMID- 29243981 TI - Assessment of intracranial venous blood flow after subarachnoid hemorrhage: a new approach to diagnose vasospasm with transcranial color-coded duplex sonography. AB - OBJECTIVE Transcranial color-coded duplex sonography (TCCS) is a reliable tool that is used to assess vasospasm in the M1 segment of the middle cerebral artery (MCA) after subarachnoid hemorrhage (SAH). A distinct increase in blood flow velocity (BFV) is the principal criterion for vasospasm. The MCA/internal carotid artery (ICA) index (Lindegaard Index) is also widely used to distinguish between vasospasm and cerebral hyperperfusion. However, extracranial ultrasonography assessment of the neck vessels might be difficult in an intensive care unit. Therefore, the authors evaluated whether the relationship of intracranial arterial to venous BFV might indicate vasospasm with similar or even better accuracy. METHODS Patients who presented between 2008 and 2015 with aneurysmal SAH were prospectively enrolled in the study. Digital subtraction angiography (DSA) and TCCS were performed within 24 hours of each other to assess vasospasm 8 10 days after SAH. The following different TCCS parameters were analyzed to assess vasospasm in the MCA and were compared with the gold-standard DSA parameters: 1) mean time-averaged maximum BFV (Vmean) of the MCA, 2) peak systolic velocity (PSV) of the MCA, 3) the Lindegaard Index using Vmean as well as PSV, and 4) a new arteriovenous index (AVI) between the MCA and the basal vein of Rosenthal using Vmean and PSV. The best cutoff values for these parameters to distinguish vasospasm from normal perfusion or hyperperfusion were calculated using receiver operating characteristic curve analysis. Sensitivity, specificity, positive predictive value, and negative predictive value as well as the overall accuracy for each cutoff value were analyzed. RESULTS A total of 102 patients (mean age 52 +/- 12 years) were evaluated. Bilateral MCA assessment by TCCS was successful in all patients. In 6 cases (3%), the BFV of the basal vein of Rosenthal could not be analyzed. The AVI could not be calculated in 50 of 204 cases (25%) because the insonation quality was very low in one of the ICAs. An AVI > 10 for Vmean and an AVI > 12 for systolic velocity provided the highest accuracies of 87% and 86%, respectively. Regarding the Lindegaard Index, the accuracy was highest using a threshold of > 3 for the mean BFV (84%) as well as systolic BFV (80%). BFVs in the MCA of >= 120 cm/sec (Vmean) and >= 200 cm/sec (PSV) predicted vasospasm with accuracies of 84% and 83%, respectively. A combined analysis of the MCA BFV and the AVI led to a slight increase in specificity (Vmean, 94%; PSV, 93%) and positive predictive value (Vmean, 88%; PSV 86%) without further improvement in accuracy (Vmean, 88%; PSV, 84%). CONCLUSIONS The intracranial AVI is a reliable parameter that can be used to assess vasospasm after SAH. Its reliability for differentiating vasospasm and hyperperfusion is slightly higher than that for the established Lindegaard Index, and this method has the additional advantage of a remarkably lower failure rate. PMID- 29243982 TI - Endoscopic transorbital superior eyelid approach: anatomical study from a neurosurgical perspective. AB - OBJECTIVE Recent studies have proposed the superior eyelid endoscopic transorbital approach as a new minimally invasive route to access orbital lesions, mostly in otolaryngology and maxillofacial surgeries. The authors undertook this anatomical study in order to contribute a neurosurgical perspective, exploring the anterior and middle cranial fossa areas through this purely endoscopic transorbital trajectory. METHODS Anatomical dissections were performed in 10 human cadaveric heads (20 sides) using 0 degrees and 30 degrees endoscopes. A step-by-step description of the superior eyelid transorbital endoscopic route and surgically oriented classification are provided. RESULTS The authors' cadaveric prosection of this approach defined 3 modular routes that could be combined. Two corridors using bone removal lateral to the superior and inferior orbital fissures exposed the middle and anterior cranial fossa (lateral orbital corridors to the anterior and middle cranial base) to unveil the temporal pole region, lateral wall of the cavernous sinus, middle cranial fossa floor, and frontobasal area (i.e., orbital and recti gyri of the frontal lobe). Combined, these 2 corridors exposed the lateral aspect of the lesser sphenoid wing with the Sylvian region (combined lateral orbital corridor to the anterior and middle cranial fossa, with lesser sphenoid wing removal). The medial corridor, with extension of bone removal medially to the superior and inferior orbital fissure, afforded exposure of the opticocarotid area (medial orbital corridor to the opticocarotid area). CONCLUSIONS Along with its minimally invasive nature, the superior eyelid transorbital approach allows good visualization and manipulation of anatomical structures mainly located in the anterior and middle cranial fossae (i.e., lateral to the superior and inferior orbital fissures). The visualization and management of the opticocarotid region medial to the superior orbital fissure are more complex. Further studies are needed to prove clinical applications of this relatively novel surgical pathway. PMID- 29243983 TI - 2017 Is the Year We Have Been Waiting For. PMID- 29243984 TI - Gene Therapy Briefs. PMID- 29243986 TI - Hospital Centralization Impacts High-Risk Lung and Bladder Cancer Surgical Patients. AB - We investigated the effects of hospital centralization on the distribution of the individual surgical patient risk in higher versus lower volume hospitals. Lung (n = 28,471) and bladder (n = 8,160) cancer surgical patients were selected from the New York Statewide Planning and Research Cooperative System database, 1997-2011. Estimated patient risk was consistently lower in the highest compared to the lowest hospital volume-quartiles for lung and bladder cancer mortality, complications, and long length of stay. Although centralization has improved outcomes, lower volume hospitals continue to perform surgery on higher surgical risk patients compared to higher volume hospitals. PMID- 29243987 TI - Association Between HACE1 Gene Polymorphisms and Wilms' Tumor Risk in a Chinese Population. AB - Wilms' tumor is one of the most common solid tumors of childhood; however, the genetic basis underlying the majority of cases remains largely unknown. HACE1 is a putative Wilms' tumor susceptibility gene. We investigated the association between five HACE1 gene polymorphisms and Wilms' tumor susceptibility in a Chinese population consisting of 145 patients and 531 controls. We found a significant association between HACE1 rs9404576 polymorphism and decreased Wilms' tumor risk. No significant association was detected for other polymorphisms in the overall analysis. Our results indicated that HACE1 rs9404576 polymorphism may be associated with Wilms' tumor susceptibility in the Chinese population. PMID- 29243988 TI - Prostate Cancer Probability Prediction By Machine Learning Technique. AB - The main goal of the study was to explore possibility of prostate cancer prediction by machine learning techniques. In order to improve the survival probability of the prostate cancer patients it is essential to make suitable prediction models of the prostate cancer. If one make relevant prediction of the prostate cancer it is easy to create suitable treatment based on the prediction results. Machine learning techniques are the most common techniques for the creation of the predictive models. Therefore in this study several machine techniques were applied and compared. The obtained results were analyzed and discussed. It was concluded that the machine learning techniques could be used for the relevant prediction of prostate cancer. PMID- 29243989 TI - Clinical Application of Detecting 21-Gene Recurrence Score in Predicating Prognosis and Therapy Response of Patients with Breast Cancer from Two Medical Centers. AB - To determine the most suitable strategy in treating patients with invasive breast cancer from Northwest China. Lower recurrence score (RS) correlated with lower recurrence ratio. Patients having a medium-high 21-gene RS who received adjuvant therapy presented lower recurrence risk. Younger patients having RS results (?31) tended to accept adjuvant therapy more often, however, those having intermediate RS results were inclined to wait and did not receive chemotherapy. These results suggested that RS-based precision medicine will allow individualized diagnosis and treatment, resulting in better outcomes and preserved medical resources. PMID- 29243990 TI - Quantification of Plasma Cell-Free Circulating DNA at Different Stages of Colorectal Cancer. AB - Cell-free circulating DNAs (cfcDNAs) have been recognized as promising biomarkers for a number of cancers. This study aimed to quantify the cfcDNA in colorectal cancer to assess its potential value as biomarker. Quantification of baseline cfcDNA was determined as the amount of free glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in plasma, using quantitative real-time polymerase chain reaction (PCR). The calculated area under the curve (AUC) of receiver operating characteristic (ROC) for cfcDNA was 0.875 (95% CI, 0.811-0.94), which was indicative of a high discriminatory power (p < 0.001) and significant accuracy in distinguishing cancer patients from healthy individuals. The quantification of cfcDNA could be useful for clinical settings of CRC. PMID- 29243991 TI - Zoonotic Agents in Feral Pigeons (Columba livia) from Costa Rica: Possible Improvements to Diminish Contagion Risks. AB - Most studies on zoonotic agents in pigeons have been conducted in the Palearctic region, but the scarcity of data is notorious in the Neotropical region, where these birds can breed all year around and are in close contact with humans. In this study, we used a combination of culture-dependent and culture-independent methods to identify infectious agents in 141 fecal samples from pigeons collected at four urban parks from Costa Rica. Of these we identified 34 positive samples for Salmonella enterica subsp. enterica serovar Braenderup (24.1%), 13 for Chlamydophila psittaci (9.2%), 9 for enteropathogenic Escherichia coli (6.4% eaeA, 0% stx-1 and 0% stx-2), and 2 for Campylobacter jejuni (1.4%). These populations of pigeons pose low risk for healthy adult humans, however, they may pose a health risk to immunocompromised patients or children. This study provides scientific data, which can be incorporated into educational programs aiming to reverse the public attitude toward pigeon feeding and to rationally justify population control efforts. PMID- 29243992 TI - Erectile dysfunction in the trajectory of cardiovascular disease. PMID- 29243993 TI - Modeling the bioconversion of starch to P(HB-co-HV) optimized by experimental design using Bacillus megaterium BBST4 strain. AB - Poly(hydroxybutyrate-co-hydroxyvalerate) (P(HB-co-HV)) is a prominent biopolymer as a potential candidate for use in the biomedical area. Several Bacillus spp. strains show promising characteristics in the use of several carbon sources and are an interesting alternative for the production of P(HB-co-HV). Sewage from the agricultural and food processing industries can be used to obtain abundantly starch as a carbon source for PHA production. The aim of the present study was to optimize by response surface methodology and desirability, the production of PHA by a Bacillus megaterium strain using starch as the sole carbon source. Two optimal conditions were determined without sporulation and were used to perform new experiments to calibrate and validate a mechanistic model, developed to simulate the dynamics of PHA and biomass production. The developed model successfully represents the kinetics of the microorganism. Employing different characterization techniques, it was determined that the PHA produced by the strain is a copolymer composed of different HB:HV proportions. Using starch as the sole carbon source in a minimal salt medium, this work shows the first reports in the literature of: 1) a mathematical model for predicting growth kinetic and PHA production for B. megaterium strain and 2) a Bacillus spp. producing P(HB-co-HV) copolymer. PMID- 29243994 TI - Ultrasonic characterisation of particle retention by a double porosity medium. AB - A study was undertaken to characterise the evolution of the clogging of various porous media during filtration experiments. Long-term tracer tests were carried out at various flow velocities. To highlight the effects of intraporosity on transport and retention mechanisms, both single porosity and double porosity media (DPM) were used. The presence of matrix porosity in the two investigated DPM provided additional sites, promoting retention of suspended particles (SP). The particle size distribution (PSD) of the recovered particles increased with time. However, and due to the additional retention sites in intraporosity, the changes in PSD with time were slower for tests on DPM. Ultrasonic transmission was used to detect modifications to the properties of the porous media induced by particle retention. The results demonstrate the capacity of ultrasound for detecting the evolution of physical clogging as a consequence of particle deposition. PMID- 29243995 TI - The relationship of erectile dysfunction and subclinical cardiovascular disease: A systematic review and meta-analysis. AB - Erectile dysfunction (ED) is associated with cardiovascular disease (CVD) and CVD mortality. However, the relationship between ED and subclinical CVD is less clear. We synthesized the available data on the association of ED and measures of subclinical CVD. We searched multiple databases for published literature on studies examining the association of ED and measures of subclinical CVD across four domains: endothelial dysfunction measured by flow-mediated dilation (FMD), carotid intima-media thickness (cIMT), coronary artery calcification (CAC), and other measures of vascular function such as the ankle-brachial index, toe brachial index, and pulse wave velocity. We conducted random effects meta analysis and meta-regression on studies that examined an ED relationship with FMD (15 studies; 2025 participants) and cIMT (12 studies; 1264 participants). ED was associated with a 2.64 percentage-point reduction in FMD compared to those without ED (95% CI: -3.12, -2.15). Persons with ED also had a 0.09-mm (95% CI: 0.06, 0.12) higher cIMT than those without ED. In subgroup meta-analyses, the mean age of the study population, study quality, ED assessment questionnaire (IIEF-5 or IIEF-15), or the publication date did not significantly affect the relationship between ED and cIMT or between ED and FMD. The results for the association of ED and CAC were inconclusive. In conclusion, this study confirms an association between ED and subclinical CVD and may shed additional light on the shared mechanisms between ED and CVD, underscoring the importance of aggressive CVD risk assessment and management in persons with ED. PMID- 29243996 TI - Validation of the visual analog scale in the cervical spine. AB - OBJECTIVE The visual analog scale (VAS) is frequently used to measure treatment outcome in patients with cervical spine disorders. The minimum clinically important difference (MCID) is the smallest change in a score that has clinical importance to the patient. Although it has been established for other medical fields, knowledge of the VAS MCID for the cervical spine is sparse, and it has rarely been considered in relation to measurement noise. The goals in this study were as follows: 1) to validate the VAS-neck and VAS-arm instruments for the cervical spine (e.g., repeatability); 2) to investigate the possible influence of predictive factors and the Hospital Anxiety and Depression Scale (HADS) score on repeatability; and 3) to compute the MCID with 5 different methods. METHODS A post hoc analysis of a prospective randomized controlled trial with 151 patients undergoing surgery for cervical radiculopathy due to degenerative disc disease was performed. Information on age, sex, smoking habits, exercise, employment status, HADS score, and VAS-neck and VAS-arm scores was gathered before surgery and after 1 year. The VAS was applied twice on every occasion, with 15 minutes in between. Repeatability and the association with predictors and HADS score were analyzed using the 1-sample t-test, linear regression models, and Spearman correlation. The MCID was calculated with the following methods: average change, change difference, receiver operating characteristic curve, effect size, and minimum detectable change (MDC). RESULTS The repeatability in VAS-neck was 8.1 mm, and in VAS-arm it was 10.4 mm. Less consistent values on the VAS correlated to female sex and higher values on the HADS. For VAS-neck the MCID ranged from 4.6 to 21.4, and for VAS-arm it ranged from 1.1 to 29.1. The highest MCID came from the MDC method, which was the only method that gave values above the measurement noise in both VAS-neck and VAS-arm. CONCLUSIONS Measurement noise in VAS-neck and VAS-arm for the cervical spine was influenced by female sex and HADS score. The only method to compute MCID that consistently gave results above the measurement noise in VAS-neck and VAS-arm was the MDC. Clinical trial registration no.: 44347115 ( www.isrctn.com ). PMID- 29243997 TI - Transdural approach to resection of retro-odontoid cysts in elderly patients: report of 3 cases. AB - Retro-odontoid cysts that arise from the tectorial membrane are uncommon lesions that can occur in elderly patients. They arise secondary to degenerative changes, including calcium pyrophosphate deposition within the ligaments. Surgical treatment is indicated when these lesions result in intractable pain, instability, and/or myelopathy. Several surgical techniques to treat this condition exist, but the optimal approach in elderly patients with comorbidities remains controversial. Here, the authors present a case series of 3 patients who underwent successful resection of a retro-odontoid lesion performed through a transdural approach. The patients were 70, 81, and 74 years old and presented with symptoms of cervical myelopathy. In consideration of their advanced age and the location of their lesion, resection via a posterior approach was considered. A 1- to 2-cm suboccipital craniectomy and C-1 and partial C-2 laminectomy were performed. These lesions could not be accessed via an extradural posterolateral approach, and so a transdural approach was performed. In the first 2 patients, a preexisting deformity prompted an instrumented fusion. In the third patient, only a lesion resection was performed. In each case, the dural opening was made using a paramedian ipsilateral-sided incision, and the lesion was resected through an incision in the anterior dura mater. Only the posterior dura was closed primarily. MR imaging evidence of excellent spinal cord decompression was evident in follow-up examinations. Transdural resection of retro-odontoid cysts is a viable option for treating asymmetrical ventral extradural cysts. Results from this case series suggest that such an approach is safe and feasible and can provide an alternative to open or endoscopic anterior transpharyngeal approaches. PMID- 29243998 TI - Adjacent-segment disease after thoracic pedicle screw fixation. AB - OBJECTIVE Pedicle screw fixation is a technique widely used to treat conditions ranging from spine deformity to fracture stabilization. Pedicle screws have been used traditionally in the lumbar spine; however, they are now being used with increasing frequency in the thoracic spine as a more favorable alternative to hooks, wires, or cables. Although safety concerns, such as the incidence of adjacent-segment disease (ASD) after cervical and lumbar fusions, have been reported, such issues in the thoracic spine have yet to be addressed thoroughly. Here, the authors review the literature on ASD after thoracic pedicle screw fixation and report their own experience specifically involving the use of pedicle screws in the thoracic spine. METHODS Select references from online databases, such as PubMed (provided by the US National Library of Medicine at the National Institutes of Health), were used to survey the literature concerning ASD after thoracic pedicle screw fixation. To include the authors' experience at Rutgers New Jersey Medical School, a retrospective review of a prospectively maintained database was performed to determine the incidence of complications over a 13-year period in 123 consecutive adult patients who underwent thoracic pedicle screw fixation. Children, pregnant or lactating women, and prisoners were excluded from the review. By comparing preoperative and postoperative radiographic images, the occurrence of thoracic ASD and disease within the surgical construct was determined. RESULTS Definitive radiographic fusion was detected in 115 (93.5%) patients. Seven incidences of instrumentation failure and 8 lucencies surrounding the screws were observed. One patient was observed to have ASD of the thoracic spine. The mean follow-up duration was 50 months. CONCLUSIONS This long-term radiographic evaluation revealed the use of pedicle screws for thoracic fixation to be an effective stabilization modality. In particular, ASD seems to be less of a problem in the relatively immobile thoracic spine than in the more mobile cervical and lumbar spines. PMID- 29243999 TI - Efficacy of intraoperative epidural triamcinolone application in lumbar microdiscectomy: a matched-control study. AB - OBJECTIVE The purpose of this study was to investigate whether the intraoperative application of an epidural steroid (ES) on the decompressed nerve root improves short- and midterm subjective and objective clinical outcomes after lumbar microdiscectomy. METHODS This study was a retrospective analysis of a 2-center database including consecutive cases in which patients underwent lumbar microdiscectomy. All patients who received ES application (40 mg triamcinolone, ES group) were matched by age and sex to patients who had not received ES application (control group). Objective functional impairment (OFI) was determined using age- and sex-adjusted T-scores of the Timed Up and Go (TUG) test. Back and leg pain (visual analog scale), functional impairment (Oswestry Disability Index [ODI], Roland-Morris Disability Index [RMDI], and health-related quality of life (hrQoL; 12-Item Short Form Health Survey [SF-12] physical component summary [PSC] score and EuroQol [EQ-5D index]) were measured at baseline, on postoperative day 3, and at postoperative week 6. RESULTS Fifty-three patients who received ES application were matched with 101 controls. There were no baseline demographic or disease-specific differences between the study groups, and preoperative pain, functional impairment, and hrQoL were similar. On postoperative day 3, the ES group had less disability on the RMDI (mean 7.4 vs 10.3, p = 0.003) and higher hrQoL as determined by the SF-12 PCS (36.5 vs 32.7, p = 0.004). At week 6, the ES group had less disability on the RMDI (3.6 vs 5.7, p = 0.050) and on the ODI by trend (17.0 vs 24.4, p = 0.056); better hrQoL, determined by the SF-12 PCS (44.3 vs 39.9, p = 0.018); and lower OFI (TUG test T-score 100.5 vs 110.2, p = 0.005). The week 6 responder status based on the minimum clinically important difference (MCID) was similar in the ES and control groups for each metric. The rates and severity of complications were similar, with a 3.8% and 4.0% reoperation rate in the ES group and control group, respectively (p = 0.272). There was a tendency for shorter hospitalization in the ES group (5.0 vs 5.8 days, p = 0.066). CONCLUSIONS Intraoperative ES application on the decompressed nerve root is an effective adjunct treatment that may lower subjective and objective functional impairment and increase hrQoL in the short and intermediate term after lumbar microdiscectomy. However, group differences were lower than the commonly accepted MCIDs for each metric, indicating that the effect size of the benefit is limited. ? CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: retrospective cohort trial; evidence: Class II. PMID- 29244000 TI - Identification of recent cases of hepatitis C virus infection using physical chemical properties of hypervariable region 1 and a radial basis function neural network classifier. AB - BACKGROUND: Identification of acute or recent hepatitis C virus (HCV) infections is important for detecting outbreaks and devising timely public health interventions for interruption of transmission. Epidemiological investigations and chemistry-based laboratory tests are 2 main approaches that are available for identification of acute HCV infection. However, owing to complexity, both approaches are not efficient. Here, we describe a new sequence alignment-free method to discriminate between recent (R) and chronic (C) HCV infection using next-generation sequencing (NGS) data derived from the HCV hypervariable region 1 (HVR1). RESULTS: Using dinucleotide auto correlation (DAC), we identified physical-chemical (PhyChem) features of HVR1 variants. Significant (p < 9.58 * 10 4) differences in the means and frequency distributions of PhyChem features were found between HVR1 variants sampled from patients with recent vs chronic (R/C) infection. Moreover, the R-associated variants were found to occupy distinct and discrete PhyChem spaces. A radial basis function neural network classifier trained on the PhyChem features of intra-host HVR1 variants accurately classified R/C-HVR1 variants (classification accuracy (CA) = 94.85%; area under the ROC curve, AUROC = 0.979), in 10-fold cross-validation). The classifier was accurate in assigning individual HVR1 variants to R/C-classes in the testing set (CA = 84.15%; AUROC = 0.912) and in detection of infection duration (R/C-class) in patients (CA = 88.45%). Statistical tests and evaluation of the classifier on randomly-labeled datasets indicate that classifiers' CA is robust (p < 0.001) and unlikely due to random correlations (CA = 59.04% and AUROC = 0.50). CONCLUSIONS: The PhyChem features of intra-host HVR1 variants are strongly associated with the duration of HCV infection. Application of the PhyChem biomarkers to models for detection of the R/C-state of HCV infection in patients offers a new opportunity for detection of outbreaks and for molecular surveillance. The method will be available at https://webappx.cdc.gov/GHOST/ to the authenticated users of Global Hepatitis Outbreak and Surveillance Technology (GHOST) for further testing and validation. PMID- 29244002 TI - Higher recall in metagenomic sequence classification exploiting overlapping reads. AB - BACKGROUND: In recent years several different fields, such as ecology, medicine and microbiology, have experienced an unprecedented development due to the possibility of direct sequencing of microbioimic samples. Among problems that researchers in the field have to deal with, taxonomic classification of metagenomic reads is one of the most challenging. State of the art methods classify single reads with almost 100% precision. However, very often, the performance in terms of recall falls at about 50%. As a consequence, state-of-the art methods are indeed capable of correctly classify only half of the reads in the sample. How to achieve better performances in terms of overall quality of classification remains a largely unsolved problem. RESULTS: In this paper we propose a method for metagenomics CLassification Improvement with Overlapping Reads (CLIOR), that exploits the information carried by the overlapping reads graph of the input read dataset to improve recall, f-measure, and the estimated abundance of species. In this work, we applied CLIOR on top of the classification produced by the classifier Clark-l. Experiments on simulated and synthetic metagenomes show that CLIOR can lead to substantial improvement of the recall rate, sometimes doubling it. On average, on simulated datasets, the increase of recall is paired with an higher precision too, while on synthetic datasets it comes at expenses of a small loss of precision. On experiments on real metagenomes CLIOR is able to assign many more reads while keeping the abundance ratios in line with previous studies. CONCLUSIONS: Our results showed that with CLIOR is possible to boost the recall of a state-of-the-art metagenomic classifier by inferring and/or correcting the assignment of reads with missing or erroneous labeling. CLIOR is not restricted to the reads classification algorithm used in our experiments, but it may be applied to other methods too. Finally, CLIOR does not need large computational resources, and it can be run on a laptop. PMID- 29244001 TI - Transmissibility of intra-host hepatitis C virus variants. AB - BACKGROUND: Intra-host hepatitis C virus (HCV) populations are genetically heterogeneous and organized in subpopulations. With the exception of blood transfusions, transmission of HCV occurs via a small number of genetic variants, the effect of which is frequently described as a bottleneck. Stochasticity of transmission associated with the bottleneck is usually used to explain genetic differences among HCV populations identified in the source and recipient cases, which may be further exacerbated by intra-host HCV evolution and differential biological capacity of HCV variants to successfully establish a population in a new host. RESULTS: Transmissibility was formulated as a property that can be measured from experimental Ultra-Deep Sequencing (UDS) data. The UDS data were obtained from one large hepatitis C outbreak involving an epidemiologically defined source and 18 recipient cases. k-Step networks of HCV variants were constructed and used to identify a potential association between transmissibility and network centrality of individual HCV variants from the source. An additional dataset obtained from nine other HCV outbreaks with known directionality of transmission was used for validation. Transmissibility was not found to be dependent on high frequency of variants in the source, supporting the earlier observations of transmission of minority variants. Among all tested measures of centrality, the highest correlation of transmissibility was found with Hamming centrality (r = 0.720; p = 1.57 E-71). Correlation between genetic distances and differences in transmissibility among HCV variants from the source was found to be 0.3276 (Mantel Test, p = 9.99 E-5), indicating association between genetic proximity and transmissibility. A strong correlation ranging from 0.565-0.947 was observed between Hamming centrality and transmissibility in 7 of the 9 additional transmission clusters (p < 0.05). CONCLUSIONS: Transmission is not an exclusively stochastic process. Transmissibility, as formally measured in this study, is associated with certain biological properties that also define location of variants in the genetic space occupied by the HCV strain from the source. The measure may also be applicable to other highly heterogeneous viruses. Besides improving accuracy of outbreak investigations, this finding helps with the understanding of molecular mechanisms contributing to establishment of chronic HCV infection. PMID- 29244003 TI - Single molecule sequencing-guided scaffolding and correction of draft assemblies. AB - BACKGROUND: Although single molecule sequencing is still improving, the lengths of the generated sequences are inevitably an advantage in genome assembly. Prior work that utilizes long reads to conduct genome assembly has mostly focused on correcting sequencing errors and improving contiguity of de novo assemblies. RESULTS: We propose a disassembling-reassembling approach for both correcting structural errors in the draft assembly and scaffolding a target assembly based on error-corrected single molecule sequences. To achieve this goal, we formulate a maximum alternating path cover problem. We prove that this problem is NP-hard, and solve it by a 2-approximation algorithm. CONCLUSIONS: Our experimental results show that our approach can improve the structural correctness of target assemblies in the cost of some contiguity, even with smaller amounts of long reads. In addition, our reassembling process can also serve as a competitive scaffolder relative to well-established assembly benchmarks. PMID- 29244004 TI - Prediction of missing common genes for disease pairs using network based module separation on incomplete human interactome. AB - BACKGROUND: Identification of common genes associated with comorbid diseases can be critical in understanding their pathobiological mechanism. This work presents a novel method to predict missing common genes associated with a disease pair. Searching for missing common genes is formulated as an optimization problem to minimize network based module separation from two subgraphs produced by mapping genes associated with disease onto the interactome. RESULTS: Using cross validation on more than 600 disease pairs, our method achieves significantly higher average receiver operating characteristic ROC Score of 0.95 compared to a baseline ROC score 0.60 using randomized data. CONCLUSION: Missing common genes prediction is aimed to complete gene set associated with comorbid disease for better understanding of biological intervention. It will also be useful for gene targeted therapeutics related to comorbid diseases. This method can be further considered for prediction of missing edges to complete the subgraph associated with disease pair. PMID- 29244005 TI - GHOST: global hepatitis outbreak and surveillance technology. AB - BACKGROUND: Hepatitis C is a major public health problem in the United States and worldwide. Outbreaks of hepatitis C virus (HCV) infections associated with unsafe injection practices, drug diversion, and other exposures to blood are difficult to detect and investigate. Effective HCV outbreak investigation requires comprehensive surveillance and robust case investigation. We previously developed and validated a methodology for the rapid and cost-effective identification of HCV transmission clusters. Global Hepatitis Outbreak and Surveillance Technology (GHOST) is a cloud-based system enabling users, regardless of computational expertise, to analyze and visualize transmission clusters in an independent, accurate and reproducible way. RESULTS: We present and explore performance of several GHOST implemented algorithms using next-generation sequencing data experimentally obtained from hypervariable region 1 of genetically related and unrelated HCV strains. GHOST processes data from an entire MiSeq run in approximately 3 h. A panel of seven specimens was used for preparation of six repeats of MiSeq libraries. Testing sequence data from these libraries by GHOST showed a consistent transmission linkage detection, testifying to high reproducibility of the system. Lack of linkage among genetically unrelated HCV strains and constant detection of genetic linkage between HCV strains from known transmission pairs and from follow-up specimens at different levels of MiSeq-read sampling indicate high specificity and sensitivity of GHOST in accurate detection of HCV transmission. CONCLUSIONS: GHOST enables automatic extraction of timely and relevant public health information suitable for guiding effective intervention measures. It is designed as a virtual diagnostic system intended for use in molecular surveillance and outbreak investigations rather than in research. The system produces accurate and reproducible information on HCV transmission clusters for all users, irrespective of their level of bioinformatics expertise. Improvement in molecular detection capacity will contribute to increasing the rate of transmission detection, thus providing opportunity for rapid, accurate and effective response to outbreaks of hepatitis C. Although GHOST was originally developed for hepatitis C surveillance, its modular structure is readily applicable to other infectious diseases. Worldwide availability of GHOST for the detection of HCV transmissions will foster deeper involvement of public health researchers and practitioners in hepatitis C outbreak investigation. PMID- 29244006 TI - Framework for reanalysis of publicly available Affymetrix(r) GeneChip(r) data sets based on functional regions of interest. AB - BACKGROUND: Since the introduction of microarrays in 1995, researchers world-wide have used both commercial and custom-designed microarrays for understanding differential expression of transcribed genes. Public databases such as ArrayExpress and the Gene Expression Omnibus (GEO) have made millions of samples readily available. One main drawback to microarray data analysis involves the selection of probes to represent a specific transcript of interest, particularly in light of the fact that transcript-specific knowledge (notably alternative splicing) is dynamic in nature. RESULTS: We therefore developed a framework for reannotating and reassigning probe groups for Affymetrix(r) GeneChip(r) technology based on functional regions of interest. This framework addresses three issues of Affymetrix(r) GeneChip(r) data analyses: removing nonspecific probes, updating probe target mapping based on the latest genome knowledge and grouping probes into gene, transcript and region-based (UTR, individual exon, CDS) probe sets. Updated gene and transcript probe sets provide more specific analysis results based on current genomic and transcriptomic knowledge. The framework selects unique probes, aligns them to gene annotations and generates a custom Chip Description File (CDF). The analysis reveals only 87% of the Affymetrix(r) GeneChip(r) HG-U133 Plus 2 probes uniquely align to the current hg38 human assembly without mismatches. We also tested new mappings on the publicly available data series using rat and human data from GSE48611 and GSE72551 obtained from GEO, and illustrate that functional grouping allows for the subtle detection of regions of interest likely to have phenotypical consequences. CONCLUSION: Through reanalysis of the publicly available data series GSE48611 and GSE72551, we profiled the contribution of UTR and CDS regions to the gene expression levels globally. The comparison between region and gene based results indicated that the detected expressed genes by gene-based and region-based CDFs show high consistency and regions based results allows us to detection of changes in transcript formation. PMID- 29244007 TI - Detecting intermediate protein conformations using algebraic topology. AB - BACKGROUND: Understanding protein structure and dynamics is essential for understanding their function. This is a challenging task due to the high complexity of the conformational landscapes of proteins and their rugged energy levels. In particular, it is important to detect highly populated regions which could correspond to intermediate structures or local minima. RESULTS: We present a hierarchical clustering and algebraic topology based method that detects regions of interest in protein conformational space. The method is based on several techniques. We use coarse grained protein conformational search, efficient robust dimensionality reduction and topological analysis via persistent homology as the main tools. We use two dimensionality reduction methods as well, robust Principal Component Analysis (PCA) and Isomap, to generate a reduced representation of the data while preserving most of the variance in the data. CONCLUSIONS: Our hierarchical clustering method was able to produce compact, well separated clusters for all the tested examples. PMID- 29244008 TI - A divide-and-conquer algorithm for large-scale de novo transcriptome assembly through combining small assemblies from existing algorithms. AB - BACKGROUND: While the continued development of high-throughput sequencing has facilitated studies of entire transcriptomes in non-model organisms, the incorporation of an increasing amount of RNA-Seq libraries has made de novo transcriptome assembly difficult. Although algorithms that can assemble a large amount of RNA-Seq data are available, they are generally very memory-intensive and can only be used to construct small assemblies. RESULTS: We develop a divide and-conquer strategy that allows these algorithms to be utilized, by subdividing a large RNA-Seq data set into small libraries. Each individual library is assembled independently by an existing algorithm, and a merging algorithm is developed to combine these assemblies by picking a subset of high quality transcripts to form a large transcriptome. When compared to existing algorithms that return a single assembly directly, this strategy achieves comparable or increased accuracy as memory-efficient algorithms that can be used to process a large amount of RNA-Seq data, and comparable or decreased accuracy as memory intensive algorithms that can only be used to construct small assemblies. CONCLUSIONS: Our divide-and-conquer strategy allows memory-intensive de novo transcriptome assembly algorithms to be utilized to construct large assemblies. PMID- 29244009 TI - Inference of genetic relatedness between viral quasispecies from sequencing data. AB - BACKGROUND: RNA viruses such as HCV and HIV mutate at extremely high rates, and as a result, they exist in infected hosts as populations of genetically related variants. Recent advances in sequencing technologies make possible to identify such populations at great depth. In particular, these technologies provide new opportunities for inference of relatedness between viral samples, identification of transmission clusters and sources of infection, which are crucial tasks for viral outbreaks investigations. RESULTS: We present (i) an evolutionary simulation algorithm Viral Outbreak InferenCE (VOICE) inferring genetic relatedness, (ii) an algorithm MinDistB detecting possible transmission using minimal distances between intra-host viral populations and sizes of their relative borders, and (iii) a non-parametric recursive clustering algorithm Relatedness Depth (ReD) analyzing clusters' structure to infer possible transmissions and their directions. All proposed algorithms were validated using real sequencing data from HCV outbreaks. CONCLUSIONS: All algorithms are applicable to the analysis of outbreaks of highly heterogeneous RNA viruses. Our experimental validation shows that they can successfully identify genetic relatedness between viral populations, as well as infer transmission clusters and outbreak sources. PMID- 29244011 TI - A deep learning method for lincRNA detection using auto-encoder algorithm. AB - BACKGROUND: RNA sequencing technique (RNA-seq) enables scientists to develop novel data-driven methods for discovering more unidentified lincRNAs. Meantime, knowledge-based technologies are experiencing a potential revolution ignited by the new deep learning methods. By scanning the newly found data set from RNA-seq, scientists have found that: (1) the expression of lincRNAs appears to be regulated, that is, the relevance exists along the DNA sequences; (2) lincRNAs contain some conversed patterns/motifs tethered together by non-conserved regions. The two evidences give the reasoning for adopting knowledge-based deep learning methods in lincRNA detection. Similar to coding region transcription, non-coding regions are split at transcriptional sites. However, regulatory RNAs rather than message RNAs are generated. That is, the transcribed RNAs participate the biological process as regulatory units instead of generating proteins. Identifying these transcriptional regions from non-coding regions is the first step towards lincRNA recognition. RESULTS: The auto-encoder method achieves 100% and 92.4% prediction accuracy on transcription sites over the putative data sets. The experimental results also show the excellent performance of predictive deep neural network on the lincRNA data sets compared with support vector machine and traditional neural network. In addition, it is validated through the newly discovered lincRNA data set and one unreported transcription site is found by feeding the whole annotated sequences through the deep learning machine, which indicates that deep learning method has the extensive ability for lincRNA prediction. CONCLUSIONS: The transcriptional sequences of lincRNAs are collected from the annotated human DNA genome data. Subsequently, a two-layer deep neural network is developed for the lincRNA detection, which adopts the auto-encoder algorithm and utilizes different encoding schemes to obtain the best performance over intergenic DNA sequence data. Driven by those newly annotated lincRNA data, deep learning methods based on auto-encoder algorithm can exert their capability in knowledge learning in order to capture the useful features and the information correlation along DNA genome sequences for lincRNA detection. As our knowledge, this is the first application to adopt the deep learning techniques for identifying lincRNA transcription sequences. PMID- 29244010 TI - RocSampler: regularizing overlapping protein complexes in protein-protein interaction networks. AB - BACKGROUND: In recent years, protein-protein interaction (PPI) networks have been well recognized as important resources to elucidate various biological processes and cellular mechanisms. In this paper, we address the problem of predicting protein complexes from a PPI network. This problem has two difficulties. One is related to small complexes, which contains two or three components. It is relatively difficult to identify them due to their simpler internal structure, but unfortunately complexes of such sizes are dominant in major protein complex databases, such as CYC2008. Another difficulty is how to model overlaps between predicted complexes, that is, how to evaluate different predicted complexes sharing common proteins because CYC2008 and other databases include such protein complexes. Thus, it is critical how to model overlaps between predicted complexes to identify them simultaneously. RESULTS: In this paper, we propose a sampling based protein complex prediction method, RocSampler (Regularizing Overlapping Complexes), which exploits, as part of the whole scoring function, a regularization term for the overlaps of predicted complexes and that for the distribution of sizes of predicted complexes. We have implemented RocSampler in MATLAB and its executable file for Windows is available at the site, http://imi.kyushu-u.ac.jp/~om/software/RocSampler/ . CONCLUSIONS: We have applied RocSampler to five yeast PPI networks and shown that it is superior to other existing methods. This implies that the design of scoring functions including regularization terms is an effective approach for protein complex prediction. PMID- 29244012 TI - Utilizing knowledge base of amino acids structural neighborhoods to predict protein-protein interaction sites. AB - BACKGROUND: Protein-protein interactions (PPI) play a key role in an investigation of various biochemical processes, and their identification is thus of great importance. Although computational prediction of which amino acids take part in a PPI has been an active field of research for some time, the quality of in-silico methods is still far from perfect. RESULTS: We have developed a novel prediction method called INSPiRE which benefits from a knowledge base built from data available in Protein Data Bank. All proteins involved in PPIs were converted into labeled graphs with nodes corresponding to amino acids and edges to pairs of neighboring amino acids. A structural neighborhood of each node was then encoded into a bit string and stored in the knowledge base. When predicting PPIs, INSPiRE labels amino acids of unknown proteins as interface or non-interface based on how often their structural neighborhood appears as interface or non-interface in the knowledge base. We evaluated INSPiRE's behavior with respect to different types and sizes of the structural neighborhood. Furthermore, we examined the suitability of several different features for labeling the nodes. Our evaluations showed that INSPiRE clearly outperforms existing methods with respect to Matthews correlation coefficient. CONCLUSION: In this paper we introduce a new knowledge based method for identification of protein-protein interaction sites called INSPiRE. Its knowledge base utilizes structural patterns of known interaction sites in the Protein Data Bank which are then used for PPI prediction. Extensive experiments on several well-established datasets show that INSPiRE significantly surpasses existing PPI approaches. PMID- 29244013 TI - Cache and energy efficient algorithms for Nussinov's RNA Folding. AB - BACKGROUND: An RNA folding/RNA secondary structure prediction algorithm determines the non-nested/pseudoknot-free structure by maximizing the number of complementary base pairs and minimizing the energy. Several implementations of Nussinov's classical RNA folding algorithm have been proposed. Our focus is to obtain run time and energy efficiency by reducing the number of cache misses. RESULTS: Three cache-efficient algorithms, ByRow, ByRowSegment and ByBox, for Nussinov's RNA folding are developed. Using a simple LRU cache model, we show that the Classical algorithm of Nussinov has the highest number of cache misses followed by the algorithms Transpose (Li et al.), ByRow, ByRowSegment, and ByBox (in this order). Extensive experiments conducted on four computational platforms Xeon E5, AMD Athlon 64 X2, Intel I7 and PowerPC A2-using two programming languages-C and Java-show that our cache efficient algorithms are also efficient in terms of run time and energy. CONCLUSION: Our benchmarking shows that, depending on the computational platform and programming language, either ByRow or ByBox give best run time and energy performance. The C version of these algorithms reduce run time by as much as 97.2% and energy consumption by as much as 88.8% relative to Classical and by as much as 56.3% and 57.8% relative to Transpose. The Java versions reduce run time by as much as 98.3% relative to Classical and by as much as 75.2% relative to Transpose. Transpose achieves run time and energy efficiency at the expense of memory as it takes twice the memory required by Classical. The memory required by ByRow, ByRowSegment, and ByBox is the same as that of Classical. As a result, using the same amount of memory, the algorithms proposed by us can solve problems up to 40% larger than those solvable by Transpose. PMID- 29244014 TI - CAMSA: a tool for comparative analysis and merging of scaffold assemblies. AB - BACKGROUND: Despite the recent progress in genome sequencing and assembly, many of the currently available assembled genomes come in a draft form. Such draft genomes consist of a large number of genomic fragments (scaffolds), whose positions and orientations along the genome are unknown. While there exists a number of methods for reconstruction of the genome from its scaffolds, utilizing various computational and wet-lab techniques, they often can produce only partial error-prone scaffold assemblies. It therefore becomes important to compare and merge scaffold assemblies produced by different methods, thus combining their advantages and highlighting present conflicts for further investigation. These tasks may be labor intensive if performed manually. RESULTS: We present CAMSA-a tool for comparative analysis and merging of two or more given scaffold assemblies. The tool (i) creates an extensive report with several comparative quality metrics; (ii) constructs the most confident merged scaffold assembly; and (iii) provides an interactive framework for a visual comparative analysis of the given assemblies. Among the CAMSA features, only scaffold merging can be evaluated in comparison to existing methods. Namely, it resembles the functionality of assembly reconciliation tools, although their primary targets are somewhat different. Our evaluations show that CAMSA produces merged assemblies of comparable or better quality than existing assembly reconciliation tools while being the fastest in terms of the total running time. CONCLUSIONS: CAMSA addresses the current deficiency of tools for automated comparison and analysis of multiple assemblies of the same set scaffolds. Since there exist numerous methods and techniques for scaffold assembly, identifying similarities and dissimilarities across assemblies produced by different methods is beneficial both for the developers of scaffold assembly algorithms and for the researchers focused on improving draft assemblies of specific organisms. PMID- 29244015 TI - Fast algorithms for computing phylogenetic divergence time. AB - BACKGROUND: The inference of species divergence time is a key step in most phylogenetic studies. Methods have been available for the last ten years to perform the inference, but the performance of the methods does not yet scale well to studies with hundreds of taxa and thousands of DNA base pairs. For example a study of 349 primate taxa was estimated to require over 9 months of processing time. In this work, we present a new algorithm, AncestralAge, that significantly improves the performance of the divergence time process. RESULTS: As part of AncestralAge, we demonstrate a new method for the computation of phylogenetic likelihood and our experiments show a 90% improvement in likelihood computation time on the aforementioned dataset of 349 primates taxa with over 60,000 DNA base pairs. Additionally, we show that our new method for the computation of the Bayesian prior on node ages reduces the running time for this computation on the 349 taxa dataset by 99%. CONCLUSION: Through the use of these new algorithms we open up the ability to perform divergence time inference on large phylogenetic studies. PMID- 29244016 TI - Oleic acid in the modulation of oocyte and preimplantation embryo development. AB - Potential reproductive effects are considered as the major aspect of biomolecules functionality in an organism. The recent identification of differential patterns of fatty acids across ovarian follicles and their association with levels of sexual maturity highlights the importance of these biomolecules. It is well known that fatty acids are highly diverse in terms of their functional properties. Oleic acid is chemically classified as an unsaturated omega-9 fatty acid. Besides serving as an important energy source, oleic acid is involved in metabolic and structural roles. Free and esterified oleic acids are compartmentalized into discrete extracellular fluids, cell organelles and found within the cytosol. This review summarizes the current knowledge on the contribution of oleic acid in regulating female fertility, particularly its involvement in female germ cell growth and development. Oleic acid has been identified as a blastomeric and post cryopreservation survival biomarker in bovine. Several related studies have shown the critical role of oleic acid in counteracting the detrimental effects of saturated fatty acids and in paracrine support of oocyte development. Although available data are not ideally detailed, most data suggest that oleic acid can contribute to normal oocyte and preimplantation embryo development via mechanisms involving metabolic partitioning of fatty acids, change in the membrane structural organization, attenuation of oxidative stress and regulation of intracellular signalling. Thus, oleic acid may play a significant role in oocyte and early embryo development, suggesting that future studies should explore in more detail its potential effects on the physiopathology of female reproduction. PMID- 29244018 TI - Detection of novel Betapapillomaviruses and Gammapapillomaviruses in eyebrow hair follicles using a single-tube 'hanging droplet' PCR assay with modified pan-PV CODEHOP primers. AB - A modified pan-PV consensus-degenerate hybrid oligonucleotide primer (CODEHOP) PCR was developed for generic and sensitive detection of a broad-spectrum of human papillomaviruses (HPVs) infecting the cutaneous epithelium. To test the analytical sensitivity of the assay we examined 149 eyebrow hair follicle specimens from immunocompetent male patients. HPV DNA was detected in 60 % (89/149) of analysed eyebrow samples with a total of 48 different HPV sequences, representing 21 previously described HPVs and 27 putative novel HPV types. Evidence for ten novel HPV subtypes and seven viral variants, clustering to three out of five genera containing cutaneous HPVs, was also obtained. Thus, we have shown that the modified pan-PV CODEHOP PCR assay is able to identify multiple HPV types, even from different genera, in the same clinical sample. Overall, these results demonstrate that the pan-PV CODEHOP PCR is an excellent tool for screening and identification of novel cutaneous HPVs, even in samples with low viral loads. PMID- 29244019 TI - Prevalence, healthcare resource utilization and overall burden of fungal meningitis in the United States. AB - PURPOSE: Previous epidemiological and cost studies of fungal meningitis have largely focused on single pathogens, leading to a poor understanding of the disease in general. We studied the largest and most diverse group of fungal meningitis patients to date, over the longest follow-up period, to examine the broad impact on resource utilization within the United States. METHODOLOGY: The Truven Health Analytics MarketScan database was used to identify patients with a fungal meningitis diagnosis in the United States between 2000 and 2012. Patients with a primary diagnosis of cryptococcal, Coccidioides, Histoplasma, or Candida meningitis were included in the analysis. Data concerning healthcare resource utilization, prevalence and length of stay were collected for up to 5 years following the original diagnosis. RESULTS: Cryptococcal meningitis was the most prevalent type of fungal meningitis (70.1 % of cases over the duration of the study), followed by coccidioidomycosis (16.4 %), histoplasmosis (6.0 %) and candidiasis (7.6 %). Cryptococcal meningitis and candidiasis patients accrued the largest average charges ($103 236 and $103 803, respectively) and spent the most time in the hospital on average (70.6 and 79 days). Coccidioidomycosis and histoplasmosis patients also accrued substantial charges and time in the hospital ($82 439, 48.1 days; $78 609, 49.8 days, respectively). CONCLUSION: Our study characterizes the largest longitudinal cohort of fungal meningitis in the United States. Importantly, the health economic impact and long-term morbidity from these infections are quantified and reviewed. The healthcare resource utilization of fungal meningitis patients in the United States is substantial. PMID- 29244017 TI - Implications of segment mismatch for influenza A virus evolution. AB - Influenza A virus (IAV) is an RNA virus with a segmented genome. These viral properties allow for the rapid evolution of IAV under selective pressure, due to mutation occurring from error-prone replication and the exchange of gene segments within a co-infected cell, termed reassortment. Both mutation and reassortment give rise to genetic diversity, but constraints shape their impact on viral evolution: just as most mutations are deleterious, most reassortment events result in genetic incompatibilities. The phenomenon of segment mismatch encompasses both RNA- and protein-based incompatibilities between co-infecting viruses and results in the production of progeny viruses with fitness defects. Segment mismatch is an important determining factor of the outcomes of mixed IAV infections and has been addressed in multiple risk assessment studies undertaken to date. However, due to the complexity of genetic interactions among the eight viral gene segments, our understanding of segment mismatch and its underlying mechanisms remain incomplete. Here, we summarize current knowledge regarding segment mismatch and discuss the implications of this phenomenon for IAV reassortment and diversity. PMID- 29244020 TI - Association between structural and functional brain alterations in drug-free patients with schizophrenia: a multimodal meta-analysis. AB - BACKGROUND: Neuroimaging studies have shown both structural and functional abnormalities in patients with schizophrenia. Recently, studies have begun to explore the association between structural and functional grey matter abnormalities. By conducting a meta-analysis on morphometric and functional imaging studies of grey matter alterations in drug-free patients, the present study aims to examine the degree of overlap between brain regions with anatomic and functional changes in patients with schizophrenia. METHODS: We performed a systematic search of PubMed, Embase, Web of Science and the Cochrane Library to identify relevant publications. A multimodal analysis was then conducted using Seed-based d Mapping software. Exploratory analyses included jackknife, subgroup and meta-regression analyses. RESULTS: We included 15 structural MRI studies comprising 486 drug-free patients and 485 healthy controls, and 16 functional MRI studies comprising 403 drug-free patients and 428 controls in our meta-analysis. Drug-free patients were examined to reduce pharmacological effects on the imaging data. Multimodal analysis showed considerable overlap between anatomic and functional changes, mainly in frontotemporal regions, bilateral medial posterior cingulate/paracingulate gyrus, bilateral insula, basal ganglia and left cerebellum. There were also brain regions showing only anatomic changes in the right superior frontal gyrus, left supramarginal gyrus, right lingual gyrus and functional alternations involving the right angular gyrus. LIMITATIONS: The methodological aspects, patient characteristics and clinical variables of the included studies were heterogeneous, and we cannot exclude medication effects. CONCLUSION: The present study showed overlapping anatomic and functional brain abnormalities mainly in the default mode (DMN) and auditory networks (AN) in drug free patients with schizophrenia. However, the pattern of changes differed in these networks. Decreased grey matter was associated with decreased activation within the DMN, whereas it was associated with increased activation within the AN. These discrete patterns suggest different pathophysiological changes impacting structural and functional associations within different neural networks in patients with schizophrenia. PMID- 29244021 TI - Diverse functions of homologous actin isoforms are defined by their nucleotide, rather than their amino acid sequence. AB - beta- and gamma-cytoplasmic actin are nearly indistinguishable in their amino acid sequence, but are encoded by different genes that play non-redundant biological roles. The key determinants that drive their functional distinction are unknown. Here, we tested the hypothesis that beta- and gamma-actin functions are defined by their nucleotide, rather than their amino acid sequence, using targeted editing of the mouse genome. Although previous studies have shown that disruption of beta-actin gene critically impacts cell migration and mouse embryogenesis, we demonstrate here that generation of a mouse lacking beta-actin protein by editing beta-actin gene to encode gamma-actin protein, and vice versa, does not affect cell migration and/or organism survival. Our data suggest that the essential in vivo function of beta-actin is provided by the gene sequence independent of the encoded protein isoform. We propose that this regulation constitutes a global 'silent code' mechanism that controls the functional diversity of protein isoforms. PMID- 29244022 TI - The structural basis for dynamic DNA binding and bridging interactions which condense the bacterial centromere. AB - The ParB protein forms DNA bridging interactions around parS to condense DNA and earmark the bacterial chromosome for segregation. The molecular mechanism underlying the formation of these ParB networks is unclear. We show here that while the central DNA binding domain is essential for anchoring at parS, this interaction is not required for DNA condensation. Structural analysis of the C terminal domain reveals a dimer with a lysine-rich surface that binds DNA non specifically and is essential for DNA condensation in vitro. Mutation of either the dimerisation or the DNA binding interface eliminates ParB-GFP foci formation in vivo. Moreover, the free C-terminal domain can rapidly decondense ParB networks independently of its ability to bind DNA. Our work reveals a dual role for the C-terminal domain of ParB as both a DNA binding and bridging interface, and highlights the dynamic nature of ParB networks in Bacillus subtilis. PMID- 29244025 TI - [Medical research, trust and professionalism]. PMID- 29244024 TI - Improving 3D Shape Recognition withElectrostatic Friction Display. AB - Electrovibration technology has the potential for seamless integration into ordinary smartphones and tablets to provide programmable haptic feedback. The aim of this work is to seek effective ways to improve 3D perception of visual objects rendered on an electrovibration display. Utilizing a gradient-based algorithm, we first investigated whether rendering only lateral frictional force on an electrovibration display improves 3D shape perception compared to doing the same using a force-feedback interface. We observed that although users do not naturally associate electrovibration patterns to geometrical shapes, they can map patterns to shapes with moderate accuracy if guidance or context is given. Motivated by this finding, we generalized the gradient-based rendering algorithm to estimate the surface gradient for any 3D mesh and added an edge detection algorithm to render sharp edges. Then, we evaluated the advantages of our algorithm in a user study and found that our algorithm can notably improve the performance of 3D shape recognition when visual information is limited. PMID- 29244026 TI - Pimodivir treatment in adult volunteers experimentally inoculated with live influenza virus: a Phase IIa, randomized, double-blind, placebo-controlled study. AB - BACKGROUND: Pimodivir (formerly JNJ-63623872) is a novel, non-nucleoside polymerase complex inhibitor with in vitro activity against influenza A virus, including pandemic 2009 H1N1, H7N9, H5N1 strains as well as neuraminidase- and amantadine-resistant strains. METHODS: Randomized, double-blind, placebo controlled, Phase IIa study. Healthy volunteers (n=104) were inoculated with an influenza A/Wisconsin/67/2005 (H3N2) challenge virus. 72 received pimodivir and 32 placebo. Pimodivir was dosed for 5 days once daily from 24 h after viral inoculation at four dose levels: 100 mg, 400 mg, loading dose 900/600 mg and loading dose 1,200/600 mg. RESULTS: Pimodivir significantly reduced viral shedding (area under the concentration versus time curve [AUC] measured by 50% tissue culture infective dose [TCID50] or qRT-PCR) versus placebo as measured by cell culture assay in the pooled analysis (Jonckheere-Terpstra dose-response trend test [P=0.036]). Reductions were observed in viral shedding (AUC, duration and peak measured by grade), influenza-like symptoms (AUC, duration and peak measured by grade) and clinical symptoms (duration and peak measured by grade) for all pimodivir groups versus placebo, significantly so for the 1,200/600 mg group. In the 1,200/600 mg group viral shedding (AUC) by qRT-PCR was 0.45 versus 18.4 log10 copies/ml*day for pooled placebo (P=0.014). Pimodivir was generally safe and well-tolerated with no serious adverse events or adverse events leading to discontinuation. CONCLUSIONS: Pimodivir has potential to not only reduce viral load but to have a clinical impact on patients as a novel treatment for influenza A virus infection. Further trials are therefore warranted to assess pimodivir. PMID- 29244027 TI - Charge transfer in (PbSe)1+delta (NbSe2)2 and (SnSe)1+delta (NbSe2)2 ferecrystals investigated by photoelectron spectroscopy. AB - Rotationally disordered, layered (PbSe)[Formula: see text](NbSe2)2 and (SnSe)[Formula: see text](NbSe2)2 ferecrystal heterostructures, consisting of stacked two-dimensional bilayers of either PbSe or SnSe alternating with two planes of NbSe2, were synthesized from modulated elemental reactants. The electronic structure of these ternary systems was investigated using x-ray photoelectron spectroscopy and compared to the binary bulk compounds PbSe, SnSe and NbSe2. The Pb and Sn core level spectra show a significant shift towards lower binding energies and the peak shape becomes asymmetric in the ferecrystals, while the electronic structure of the NbSe2 layers does not change compared to the bulk. This is interpreted in terms of an interlayer interaction in the form of a charge transfer of electrons from PbSe or SnSe into the NbSe2 layers, which is supported by valence band spectra and is consistent with prior results from transport measurements. PMID- 29244023 TI - Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling. AB - Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx expressing cells in sheath tissues, and its action is mediated through TGFbeta/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair. PMID- 29244028 TI - Adaptive heart rate-based epileptic seizure detection using real-time user feedback. AB - OBJECTIVE: Automated seizure detection in the home environment has attracted increasing interest in recent decades. Heart rate-based seizure detection is a way to detect temporal lobe epilepsy seizures at home, but patient-independent classifiers have been shown to be insufficiently accurate. This is due to the high patient-dependence of heart rate features, whereas this method does not use patient-specific data. Patient-specific classifiers take into account patient specific data, but often not enough patient data are available for a fully robust patient-specific classifier. Therefore a real-time adaptive seizure detection algorithm is proposed here. APPROACH: The algorithm starts with a patient independent classifier, but gradually adapts to the patient-specific characteristics while they are obtained 'on the go'. This is done by using real time user feedback to annotate previously generated alarms, causing an immediate update to the used support vector machine classifier. Data annotated as seizures are automatically removed from the updating procedure if their detection would lead to too many false alarms. This is done in order to cope with potentially incorrect feedback. MAIN RESULTS: The adaptive classifier resulted in an overall sensitivity of 77.12% and 1.24 false alarms per hour when applied to over 2833 h of heart rate data from 19 patients with 153 clinical seizures. This is around 30% fewer false alarms compared to a patient-independent classifier with a similar sensitivity. SIGNIFICANCE: This low-complexity adaptive algorithm is able to deal well with incorrect feedback, making it ideal for a seizure warning system, and in the future it will also include complementary modalities to improve its performance. PMID- 29244029 TI - Fluorescence goes from strength to strength in MAF. AB - This year we have been greatly cheered by the near 10% rise in impact factor to 2.7, and the inclusion of Methods and Applications in Fluorescence (MAF) by MEDLINE which means that now all articles can be found on PubMed(r). PMID- 29244030 TI - Static response of deformable microchannels: a comparative modelling study. AB - We present a comparative modelling study of fluid-structure interactions in microchannels. Through a mathematical analysis based on plate theory and the lubrication approximation for low-Reynolds-number flow, we derive models for the flow rate-pressure drop relation for long shallow microchannels with both thin and thick deformable top walls. These relations are tested against full three dimensional two-way-coupled fluid-structure interaction simulations. Three types of microchannels, representing different elasticity regimes and having been experimentally characterized previously, are chosen as benchmarks for our theory and simulations. Good agreement is found in most cases for the predicted, simulated and measured flow rate-pressure drop relationships. The numerical simulations performed allow us to also carefully examine the deformation profile of the top wall of the microchannel in any cross section, showing good agreement with the theory. Specifically, the prediction that span-wise displacement in a long shallow microchannel decouples from the flow-wise deformation is confirmed, and the predicted scaling of the maximum displacement with the hydrodynamic pressure and the various material and geometric parameters is validated. PMID- 29244032 TI - Evaluation methods as quality control in the generation of decellularized peripheral nerve allografts. AB - Nowadays, the high incidence of peripheral nerve injuries and the low success ratio of surgical treatments are driving research to the generation of novel alternatives to repair critical nerve defects. In this sense, tissue engineering has emerged as a possible alternative with special attention to decellularization techniques. Tissue decellularization offers the possibility to obtain a cell free, natural extracellular matrix (ECM), characterized by an adequate 3D organization and proper molecular composition to repair different tissues or organs, including peripheral nerves. One major problem, however, is that there are no standard quality control methods to evaluate decellularized tissues. Therefore, in this review, a brief description of current strategies for peripheral nerve repair is given, followed by an overview of different decellularization methods used for peripheral nerves. Furthermore, we extensively discuss the available and currently used methods to demonstrate the success of tissue decellularization in terms of the cell removal, preservation of essential ECM molecules and maintenance or modification of biomechanical properties. Finally, orientative guidelines for the evaluation of decellularized peripheral nerve allografts are proposed. PMID- 29244031 TI - Transition and post-transition metals in exhaled breath condensate. AB - Water vapor in expired air, as well as dispersed non-volatile components, condense onto a cooler surface after exiting the respiratory tract. This exhaled breath condensate (EBC) provides a dilute sampling of the epithelial lining fluid. Accordingly, the collection of EBC imparts a capacity to provide biomarkers of injury preceding clinical disease. Concentrations of transition and post-transition metals in EBC are included among these endpoints. Iron and zinc are the metals with the highest concentration and are measurable in all EBC samples from healthy subjects; other metals are most frequently either at or below the level of detection in this group. Gender, age, and smoking can impact EBC metal concentrations in healthy subjects. EBC metal concentrations among patients diagnosed with particular lung diseases (e.g. asthma, chronic obstructive disease, and interstitial lung disease) have been of research interest but no definite pattern of involvement has been delineated. Studies of occupationally exposed workers confirm significant exposure to specific metals, but such EBC metal measurements frequently provide evidence redundant with environmental sampling. Measurements of metal concentrations in EBC remain a research tool into metal homeostasis in the respiratory tract and participation of metals in disease pathogenesis. The quantification of metal concentrations in EBC is currently not reliable for clinical use in either supporting or determining any diagnosis. Issues that must be addressed prior to the use of EBC metal measurements include the establishment of both standardized collection and measurement techniques. PMID- 29244033 TI - Older Adults With Hip Arthroplasty: An Individualized Transitional Care Program. AB - BACKGROUND: Most older adults with hip fracture surgery experience functional decline (FD), causing devastating outcomes. However, few studies have examined the effects of nursing interventions to reduce FD for them. PURPOSE: The aim of the study was to evaluate an individualized transitional care program (ITCP) to reduce FD for older adults with hip arthroplasty. METHODS: The study was quasiexperimental, with a nonequivalent control group design. A total of 37 participants scheduled for hip arthroplasty were recruited-21 in the experimental and 16 in the control group. FINDINGS: Two weeks following surgery (i.e., just prior to discharge), the ITCP group displayed less fear of falling than the usual care group. Moreover, the experimental group displayed objectively less FD with increased activities of daily living and Timed Up and Go scores, 6 weeks after hip arthroplasty. CONCLUSIONS: This study provides evidence of the effectiveness of nurse-led rehabilitative practices to reduce FD in older adults with hip arthroplasty. CLINICAL RELEVANCE: The ITCP promoted individual physical functioning for older adults with hip arthroplasty. This study results can aid healthy transitions of elderly patients with other various diseases. PMID- 29244034 TI - Rehabilitation Nurses' Knowledge, Attitudes, and Behaviors for Preventing Urinary Tract Infections From Intermittent Catheterization. AB - PURPOSE: The aim of this study was to develop and examine the reliability of a survey to assess knowledge, attitudes, and behaviors (KAB) of rehabilitation nurses for preventing urinary tract infections in persons requiring intermittent catheterization. DESIGN: Cross-sectional survey with principal component analysis. METHODS: Survey development and administration based on national guidelines. FINDINGS: Principal component analysis produced three reliable components of KAB explaining 54.5% of response variance. Results indicate that nurses report adequate knowledge and training. Although the facility had an evidence-based online catheterization procedure, staff reported that the procedure was not helpful nor useable. Twenty-eight percent incorrectly identified the root cause of urinary tract infection, and 45% reported that other nurses always washed their hands. Barriers to using standard intermittent catheterization technique were staff, time, and patient variables. CONCLUSION: The modified survey is a reliable measure of KAB. CLINICAL RELEVANCE: The survey assists with identifying knowledge gaps, customizing education, and changing practice. PMID- 29244035 TI - Interprofessional Collaboration and Peer Mentors for Bowel Education in Spinal Cord Injury: A Case Consultation. AB - BACKGROUND: Evidence shows that having a bowel management program prevents rehospitalization postacute rehabilitation discharge for persons with a spinal cord injury (SCI). Peer mentors have been used to assist patients in managing their care. PURPOSE: The aim of the study was to illustrate how interprofessional collaboration led to utilizing resources of the inpatient rehabilitation facility's peer mentor program and incorporating peer mentors into bowel education for persons with SCI. METHODS: A descriptive case review of a continuous quality improvement (CQI) project, using an eight-item Likert scale evaluation survey with three open-ended questions to assess the utility of incorporating peer mentors into bowel education. FINDINGS AND CONCLUSIONS: Twenty seven of the 28 participants responded to the survey. Results showed that the education program was useful, should be continued, and include the peer mentors. Responses from open-ended questions included themes related to knowledge, adherence, and taking charge of one's own care. Interprofessional collaboration and involvement of peer mentors as copresenters in SCI bowel education were feasible. PMID- 29244036 TI - Implementing Evidence-Informed Practice: Our Ethical Imperative. PMID- 29244037 TI - A Psychometric Evaluation of the Chinese Version of the M.D. Anderson Symptom Inventory-Heart Failure in Chinese Cancer Patients With Concurrent Heart Failure. AB - PURPOSE: The purpose of the study was to translate the M.D. Anderson Symptom Inventory-Heart Failure (MDASI-HF), a specific instrument to assess symptoms in cancer patients with concurrent heart failure (HF), into Mandarin Chinese and to examine its psychometric properties in Chinese cancer patients. DESIGN: A translation and psychometric evaluation design was used. METHODS: The translation of the MDASI-HF into Mandarin Chinese followed Brislin's model with the four steps: translation, monolingual assessment, backward translation, and comparison. The Chinese version MDASI-HF was tested among 135 cancer patients with concurrent HF from a cancer hospital in Tianjin, China. Psychometric properties of content validity, internal consistency, test- retest reliability, concurrent validity, and sensitivity of the instrument were evaluated. FINDINGS: The Cronbach's alpha was .913 for the core items, .835 for the HF items, and .897 for the interference items. The test-retest reliability was satisfactory with intraclass coefficients > .9 and content validity index was .94. The Chinese version MDASI-HF was significantly correlated with the Eastern Cooperative Oncology Group performance grade (correlation coefficients .456-.600) and the New York Heart Association classification (correlation coefficients .477-.631), indicating the established concurrent validity of the translated instrument. CONCLUSIONS: The Chinese version MDASI-HF is a valid and reliable instrument to assess the symptoms of Chinese cancer patients with concurrent HF. CLINICAL RELEVANCE: Symptom assessment and management play important roles in cancer rehabilitation. The Chinese version MDASI-HF can assist appropriate and timely symptom assessment in cancer patients with concurrent HF and can promote communication between healthcare professionals and patients. On the basis of the assessment, the rehabilitation team could provide effective symptom management, evaluate the effectiveness of interventions, and improve patients' quality of life. PMID- 29244043 TI - Climbing to New Heights After Lower Limb Loss: An Interview With Chad Jukes. PMID- 29244042 TI - Feasibility and Effects of a Nursing Intervention for Patients with Peripheral Vestibular Disorders. AB - PURPOSE: To explore the feasibility and possible outcomes of a nursing intervention in patients with peripheral vestibular disorders. DESIGN: A randomized controlled trial (RCT). METHODS: Thirty-six patients participated in the study: the intervention group (n = 18), who received the intervention, and patients in a control group (n = 18), who received standard care. The intervention includes patient education and individualized nursing support during a 6-month rehabilitation period. Outcomes were symptoms, well-being, sense of coherence, and self-care measured at baseline before randomization and at 6 and 9 months later. FINDINGS: At the 9-month follow up, the patients who received the intervention rated significantly fewer vertigo-related symptoms and a higher sense of coherence than the control group. CONCLUSION: The intervention was feasible and seems to support the patients to manage symptoms, but confirmative studies are warranted. CLINICAL RELEVANCE: Patient education in combination with individual support may be beneficial to help patients with peripheral disorders during their rehabilitation. PMID- 29244044 TI - Examining the Factor Structure and Reliability of the Safe Patient Handling Perception Scale: An Initial Validation Study. AB - PURPOSE: Perceiving imminent safe patient handling and movement (SPH&M) dangers may reduce musculoskeletal (MSK) injuries for nurses in the workplace. The purpose of this study is to develop and validate the 17-item Safe Patient Handling Perception Scale (SPHPS) as an evaluation instrument assessing perceptual risk of MSK injury based on SPH&M knowledge, practice, and resource accessibility in the workplace. METHODS: Data were collected from a convenience sample (N = 117) of nursing employees at a Veteran Affairs Medical Center. Factor analysis identified three factors: knowledge, practice, and accessibility. FINDINGS: The SPHPS demonstrated high levels of reliability, supported by acceptable alpha scores (SPHM knowledge [alpha = .866], SPHM practices [alpha = .901], and access to SPHM resources [alpha = .855]), in addition to the relatively low standard error of measurement scores (SEM). CONCLUSION: The study outcomes suggest that the SPHPS is a valid and reliable tool that can measure participants' perceived risk factors for MSK injuries. PMID- 29244045 TI - Where in the World Is Rehabilitation Nursing? PMID- 29244046 TI - Humor-A Rehabilitative Tool in the Post-Intensive Care of Young Adults With Acquired Brain Injury. AB - PURPOSE: The aim of the study was to describe how paid carers use humor in providing compassionate post-intensive rehabilitation care to young adults with acquired brain injury (ABI) who are unable to perform or direct their own care. DESIGN: This is a qualitative study underpinned by symbolic interactionism. METHODS: Paid carers in a residential aged care facility were interviewed. Interview data were analyzed using grounded theory methods of coding, comparative analysis, memoing, and theoretical sampling. FINDINGS: With young adult's assent, paid carers appropriately used humor, at times even crude humor, as a rehabilitative tool to activate and elicit responses from young people with ABI who could not perform or direct their own care. The use of humor while caring for this population demonstrated that compassion still exists within nursing; however, it may not always be reverent. CONCLUSIONS/CLINICAL RELEVANCE: Humor may be an effective way to provide compassionate care and can be used as a rehabilitative tool to elicit responses from young people with ABI who have no means of verbal communication. PMID- 29244049 TI - Changing the Research Landscape. PMID- 29244051 TI - Towards microwave imaging of cells. AB - Integrated detection techniques that can characterize the morphological properties of cells are needed for the widespread use of lab-on-a-chip technology. Herein, we establish a theoretical and experimental framework to use resonant microwave sensors in their higher order modes so that the morphological properties of analytes inside a microfluidic channel can be obtained electronically. We built a phase-locked loop system that can track the first two modes of a microstrip line resonator to detect the size and location of microdroplets and cells passing through embedded microfluidic channels. The attained resolution, expressed in terms of Allan deviation at the response time, is as small as 2 * 10-8 for both modes. Additionally, simulations were performed to show that sensing with higher order modes can yield the geometrical volume, effective permittivity, two-dimensional extent, and the orientation of analytes. The framework presented here makes it possible to develop a novel type of microscope that operates at the microwave band, i.e., a radar for cells. PMID- 29244050 TI - CD52 inhibits Toll-like receptor activation of NF-kappaB and triggers apoptosis to suppress inflammation. AB - Soluble CD52 is a small glycoprotein that suppresses T-cell activation, but its effect on innate immune cell function is unknown. Here we demonstrate that soluble CD52 inhibits Toll-like receptor and tumor necrosis factor receptor signaling to limit activation of NF-kappaB and thereby suppress the production of inflammatory cytokines by macrophages, monocytes and dendritic cells. At higher concentrations, soluble CD52 depletes the short-lived pro-survival protein MCL-1, contributing to activation of the BH3-only proteins BAX and BAK to cause intrinsic apoptotic cell death. In vivo, administration of soluble CD52 suppresses lipopolysaccharide (LPS)-induced cytokine secretion and other features of endotoxic shock, whereas genetic deletion of CD52 exacerbates LPS responses. Thus, soluble CD52 exhibits broad immune suppressive effects that signify its potential as an immunotherapeutic agent. PMID- 29244052 TI - MnAPO-5 as an efficient heterogeneous catalyst for selective liquid phase partial oxidation reactions. AB - Heterogeneous catalysts play a key role in addressing the economic and environmental issues of the chemical industry due to their several advantages, like ease of product separation, work-up and high recycling efficiency. Herein, we report the synthesis of a robust manganese(iv)-containing aluminophosphate material (MnAPO-5), with an AFI framework topology. This material has been characterized thoroughly by powder XRD, XPS, UHR TEM, FE SEM, 31P CP MAS NMR, atomic absorption spectroscopy, UV-visible spectroscopy and TGA. The Mn containing microporous material has been employed as a heterogeneous catalyst for the oxidation of styrene and the synthesis of adipic acid from cyclohexanone in the presence of tert-butyl hydroperoxide (TBHP) as the oxidant in air and it displayed very high recycling efficiency. PMID- 29244053 TI - Correction: Enantioselective synthesis of sulfoxide using an SBA-15 supported vanadia catalyst: a computational elucidation using a QM/MM approach. AB - Correction for 'Enantioselective synthesis of sulfoxide using an SBA-15 supported vanadia catalyst: a computational elucidation using a QM/MM approach' by Navjot Kaur et al., Phys. Chem. Chem. Phys., 2017, 19, 25059-25070. PMID- 29244055 TI - The Data as It Is, and the Nature of Neurocognitive Difficulties in Post Treatment Lyme Disease. PMID- 29244056 TI - CscoreTool: fast Hi-C compartment analysis at high resolution. AB - Summary: The genome-wide chromosome conformation capture (Hi-C) has revealed that the eukaryotic genome can be partitioned into A and B compartments that have distinctive chromatin and transcription features. Current Principle Component Analyses (PCA)-based method for the A/B compartment prediction based on Hi-C data requires substantial CPU time and memory. We report the development of a method, CscoreTool, which enables fast and memory-efficient determination of A/B compartments at high resolution even in datasets with low sequencing depth. Availability and implementation: https://github.com/scoutzxb/CscoreTool. Contact: xzheng@carnegiescience.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29244054 TI - A Systematic Review for Functional Neuroimaging Studies of Cognitive Reserve Across the Cognitive Aging Spectrum. AB - Objective: Cognitive reserve has been proposed to explain the discrepancy between clinical symptoms and the effects of aging or Alzheimer's pathology. Functional magnetic resonance imaging (fMRI) may help elucidate how neural reserve and compensation delay cognitive decline and identify brain regions associated with cognitive reserve. This systematic review evaluated neural correlates of cognitive reserve via fMRI (resting-state and task-related) studies across the cognitive aging spectrum (i.e., normal cognition, mild cognitive impairment, and Alzheimer's disease). Method: This review examined published articles up to March 2017. There were 13 cross-sectional observational studies that met the inclusion criteria, including relevance to cognitive reserve, subjects 60 years or older with normal cognition, mild cognitive impairment, and/or Alzheimer's disease, at least one quantitative measure of cognitive reserve, and fMRI as the imaging modality. Quality assessment of included studies was conducted using the Newcastle-Ottawa Scale adapted for cross-sectional studies. Results: Across the cognitive aging spectrum, medial temporal regions and an anterior or posterior cingulate cortex-seeded default mode network were associated with neural reserve. Frontal regions and the dorsal attentional network were related to neural compensation. Compared to neural reserve, neural compensation was more common in mild cognitive impairment and Alzheimer's disease. Conclusions: Neural reserve and compensation both support cognitive reserve, with compensation more common in later stages of the cognitive aging spectrum. Longitudinal and intervention studies are needed to investigate changes between neural reserve and compensation during the transition between clinical stages, and to explore the causal relationship between cognitive reserve and potential neural substrates. PMID- 29244057 TI - Measuring Frailty in Medicare Data: Development and Validation of a Claims-Based Frailty Index. AB - Background: Frailty is a key determinant of health status and outcomes of health care interventions in older adults that is not readily measured in Medicare data. This study aimed to develop and validate a claims-based frailty index (CFI). Methods: We used data from Medicare Current Beneficiary Survey 2006 (development sample: n = 5,593) and 2011 (validation sample: n = 4,424). A CFI was developed using the 2006 claims data to approximate a survey-based frailty index (SFI) calculated from the 2006 survey data as a reference standard. We compared CFI to combined comorbidity index (CCI) in the ability to predict death, disability, recurrent falls, and health care utilization in 2007. As validation, we calculated a CFI using the 2011 claims data to predict these outcomes in 2012. Results: The CFI was correlated with SFI (correlation coefficient: 0.60). In the development sample, CFI was similar to CCI in predicting mortality (C statistic: 0.77 vs. 0.78), but better than CCI for disability, mobility impairment, and recurrent falls (C statistic: 0.62-0.66 vs. 0.56-0.60). Although both indices similarly explained the variation in hospital days, CFI outperformed CCI in explaining the variation in skilled nursing facility days. Adding CFI to age, sex, and CCI improved prediction. In the validation sample, CFI and CCI performed similarly for mortality (C statistic: 0.71 vs. 0.72). Other results were comparable to those from the development sample. Conclusion: A novel frailty index can measure the risk for adverse health outcomes that is not otherwise quantified using demographic characteristics and traditional comorbidity measures in Medicare data. PMID- 29244059 TI - Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms. AB - Consuming a Mediterranean diet rich in minimally processed plant foods has been associated with a reduced risk of developing multiple chronic diseases and increased life expectancy. Data from several randomized clinic trials have demonstrated a beneficial effect in the primary and secondary prevention of cardiovascular disease, type 2 diabetes, atrial fibrillation, and breast cancer. The exact mechanism by which an increased adherence to the traditional Mediterranean diet exerts its favorable effects is not known. However, accumulating evidence indicates that the five most important adaptations induced by the Mediterranean dietary pattern are: (a) lipid-lowering effect, (b) protection against oxidative stress, inflammation and platelet aggregation, (c) modification of hormones and growth factors involved in the pathogenesis of cancer, (d) inhibition of nutrient sensing pathways by specific amino acid restriction, and (e) gut microbiota-mediated production of metabolites influencing metabolic health. More studies are needed to understand how single modifications of nutrients typical of the Mediterranean diet interact with energy intake, energy expenditure, and the microbiome in modulating the key mechanisms that promote cellular, tissue, and organ health during aging. PMID- 29244058 TI - Antidepressant Use and Cognitive Outcomes in Very Old Women. AB - Background: Antidepressant use is very common in the elderly, but the effects of antidepressants on cognition in the elderly are controversial with some studies suggesting harm and others protection. We aimed to investigate the association between different antidepressant use and change in cognition and risk of mild cognitive impairment (MCI) or dementia in very old women. Methods: We examined 1,234 community-dwelling women (mean age 83.2 years) from the Study of Osteoporotic Fractures. Baseline antidepressant use was reported and verified by medication containers, and medications were coded with computerized dictionary. Cognitive status (normal, MCI, or dementia) was adjudicated by an expert clinical panel 5 years later. Change in a short-form Mini-Mental State Examination and Trails B were evaluated over 5 years. Results: Eleven per cent of the women were taking antidepressants. Users of selective serotonin reuptake inhibitors (SSRIs) had the greatest cognitive decline over 5 years, after adjustment for demographics, medical comorbidities, benzodiazepine use, and baseline cognition. Multivariable logistic regression shows that the users of SSRIs were more than twice (OR = 2.69, 95% CI = 1.64-4.41) and trazodone users more than three times (3.48, 1.12-10.81) as likely to develop MCI or dementia compared with the nonusers. Further adjustment for baseline cognition or depressive symptoms did not appreciably alter the results, and the association remained after excluding women with high depressive symptoms. The use of tricyclic antidepressants or other antidepressants was not significantly associated with cognitive outcomes. Conclusions: The use of antidepressants, especially SSRIs and trazodone, was associated with an increased risk of cognitive impairment 5 years later among the oldest old women. PMID- 29244060 TI - The Residual Medium and Long-term Cognitive Effects of Benzodiazepine Use: An Updated Meta-analysis. AB - Objective: This study presents an updated meta-analysis of the effects of benzodiazepines on cognitive functioning in long-term, current users of these agents, those who have recently withdrawn and on those who have successfully abstained following withdrawal. The study represents an update of the previous meta-analyses published by our group. Method: A comprehensive search of the computerized databases Medline and PsycINFO was undertaken to identify studies that assessed the cognitive effects of benzodiazepines published up to 28 November 2016 (the date of the last update). Nineteen studies (eight studies published since the previous meta-analyses and 11 studies included in the previous studies) were included. Results: The results of the analysis for current users revealed statistically significant, negative effects for the cognitive domains of working memory, processing speed, divided attention, visuoconstruction, recent memory, and expressive language. For those who had withdrawn and successfully abstained following withdrawal, deficits were observed for the domains of recent memory, processing speed, visuoconstruction, divided attention, working memory, and sustained attention. Conclusions: The results of the study are important in that they corroborate the mounting evidence that a range of neuropsychological functions are impaired as a result of long-term benzodiazepine use, and that these are likely to persist even following withdrawal. The findings highlight the residual neurocognitive compromise associated with long-term benzodiazepine therapy as well as the important clinical implications of these results. PMID- 29244062 TI - Longitudinal Course and Predictors of Apathetic Symptoms after Severe Traumatic Brain Injury. AB - Objectives: Apathy is one of the most common behavioral symptoms encountered after traumatic brain injury (TBI). However, very little is known about the longitudinal course and predictors of apathetic manifestations. The aims of the present study were to examine how apathy changes and the predictive value of cognitive factors (memory, attention/executive mechanisms, and multitasking) and personal identity factors (self-esteem and self-efficacy beliefs) for apathy over a period of 10 months. Method: To this end, 68 participants (32 patients with severe TBI matched with 36 control participants) living in the community were enrolled. At Time 1, participants were given three questionnaires to assess self esteem, self-efficacy beliefs, anxiety and depression symptoms, and five tasks to assess cognitive processes. Simultaneously, a close relative of each participant completed a questionnaire that assessed lack of initiative/initiative. At Time 2, all questionnaires were re-administered to each patient and their relatives. Results: Patients displayed a significant lack of initiative/interest at all post injury assessments. At the individual level, the results revealed that a majority of patients had no change in their apathetic symptoms over the 10-month follow up, whereas in the others, apathetic symptoms mostly increased. Furthermore, impaired memory was the only mechanism that significantly predicted later apathetic manifestations. Complementary profile analyses indicated that patients with worsening symptoms over the follow-up period showed higher inaccurate memory at Time 1 than patients with stable symptoms. Conclusions: These results provide valuable insight into the longitudinal evolution and predictors of apathy after TBI, which opens interesting prospects for psychological interventions. PMID- 29244061 TI - Association Between Sustained Poverty and Changes in Body Mass Index, 1990-2015: The Coronary Artery Risk Development in Young Adults Study. AB - We sought to determine whether sustained poverty is associated with change in body mass index (BMI, calculated as weight (kg)/height (m)2) among 4,762 black and white adults from the Coronary Artery Risk Development in Young Adults study. Household income in the prior year and current BMI were measured at 7 visits between 1990 and 2015. Sustained poverty was the proportion of visits during which household income was below 200% of the federal poverty level (range, 0% 100%). Sustained poverty and BMI were time-updated. Mean age in 1990 was 30 years. In adjusted linear mixed-effects models, every 10% increase in sustained poverty was significantly associated with faster BMI growth among white men (0.004/year, 95% CI: 0.001, 0.008) and white women (0.003/year, 95% CI: 0.000, 0.006), and slower BMI growth among black men (-0.008/year, 95% CI: -0.010, 0.005) and black women (-0.003/year, 95% CI: -0.006, 0.000). In other words, being always versus never in poverty from 1990 to 2015 was predicted to result in greater BMI gain by 1.00 unit and 0.75 units among white men and women and less BMI gain by 2.0 units and 0.75 units among black men and women, respectively. Sustained poverty was a predictor of changes in BMI with differential associations according to race. PMID- 29244063 TI - Association of Maternal Psychosocial Stress With Increased Risk of Asthma Development in Offspring. AB - Prenatal maternal psychosocial stress might influence the development of childhood asthma. Evaluating paternal psychosocial stress and conducting a sibling comparison could provide further insight into the role of unmeasured confounding. We examined the associations of parental psychosocial stress during and after pregnancy with asthma at age 7 years in the Norwegian Mother and Child Cohort Study (n = 63,626; children born in 2000-2007). Measures of psychosocial stress included lifetime major depressive symptoms, current anxiety/depression symptoms, use of antidepressants, anxiolytics, and/or hypnotics, life satisfaction, relationship satisfaction, work stress, and social support. Childhood asthma was associated with maternal lifetime major depressive symptoms (adjusted relative risk (aRR) = 1.19, 95% confidence interval (CI): 1.09, 1.30), in addition to symptoms of anxiety/depression during pregnancy (aRR = 1.17, 95% CI: 1.06, 1.29) and 6 months after delivery (aRR = 1.17, 95% CI: 1.07, 1.28). Maternal negative life events during pregnancy (aRR = 1.10, 95% CI: 1.06, 1.13) and 6 months after delivery (aRR = 1.14, 95% CI: 1.11, 1.18) were also associated with asthma. These associations were not replicated when evaluated within sibling groups. There were no associations with paternal psychosocial stress. In conclusion, maternal anxiety/depression and negative life events were associated with offspring asthma, but this might be explained by unmeasured maternal background characteristics that remain stable across deliveries. PMID- 29244065 TI - A COMPASS to REACH the right patients with thrombocardiology: benefits, risks, and future of the new concept. PMID- 29244064 TI - beta-Cell Control of Insulin Production During Starvation-Refeeding in Male Rats. AB - Mammalian metabolism has evolved to adapt to changes in nutrient status. Insulin, the key anabolic hormone, facilitates intracellular storage of nutrient fuels and plays a pivotal role in the transition away from catabolism upon refeeding. Although circulating insulin relative to nutrient levels has been well characterized during fasting and refeeding, how pancreatic beta-cell biology caters to acute changes in insulin demand has not been sufficiently addressed. Here, we examined the dynamics of (pro)insulin production and associated changes in beta-cell ultrastructure during refeeding after a 72-hour fast in male rats. We found that fasted beta-cells had marked degranulation, which inversely coordinated with the upregulation of autophagolysomal and lysosomal organelles. There was also expanded Golgi that correlated with enhanced (pro)insulin biosynthetic capacity but, conversely, blunted in vivo insulin secretion. Within 4 to 6 hours of refeeding, proinsulin biosynthesis, cellular ultrastructure, in vivo insulin secretion, and glucose tolerance normalized to levels near those of fed control animals, indicating a rapid replenishment of normal insulin secretory capacity. Thus, during a prolonged fast, the beta-cell protects against hypoglycemia by markedly reducing insulin secretory capacity in vivo but is simultaneously poised to efficiently increase (pro)insulin production upon refeeding to effectively return normal insulin secretory capacity within hours. PMID- 29244066 TI - Electrocardiographic and electrophysiologic differentiation between atriofascicular, long atrioventricular, and short atrioventricular decrementally conducting accessory pathways. AB - Aims: We aimed to examine the electrocardiographic and electrophysiologic characteristics of anterograde-conducting decremental accessory pathways (DAP) and to identify surrogate criteria to distinguish short atrioventricular (SAV) DAP from atriofascicular (AF) AP and long atrioventricular (LAV) DAP. Methods and results: We identified all patients with DAPs and analysed electrocardiographic and electrophysiologic characteristics. Distal insertion sites were examined using existing criteria, including V-H interval, ventricular activation at the right ventricular apex, and around tricuspid annulus during antidromic atrioventricular re-entrant tachycardia (A-AVRT) or complete pre-excitation and evaluated the AV node-like properties according to the response to adenosine and radiofrequency ablation. Out of 45 patients with DAPs, 28 (62.2%) had SAV-DAP (13 with definite AF-AP, 2 with definite LAV-DAP, 2 indeterminate). In all, 50% of SAV-DAPs and 53.3% of AF-AP/LAV-DAPs had 'rS' pattern in lead III. Longer QRS duration (159.9 +/- 17.4 ms vs. 139.2 +/- 14.3 ms, P < 0.0001) during full pre excitation or A-AVRT differentiated SAV-DAP from AF-AP. The QRS-V(His) interval was longer for those with SAV-DAP compared vs. AF-AP/LAV-DAP (45.3 +/- 2.4 ms vs. 22.9 +/- 2.5 ms, P < 0.0001) and a cut-off value of 33.0 ms differentiated the two (sensitivity 81.3%, specificity 87.5%). Conclusion: The majority of the SAV DAPs are located at the TA free wall. An 'rS' pattern in lead III is frequently seen in SAV-DAP as well as AF-AP/LAV-DAPs. Measuring the QRS-V(His) interval would be helpful to distinguish SAV-DAP from AF-AP/LAV-DAP. PMID- 29244067 TI - The use of vascular detachable coil for percutaneous closure of iatrogenic aorto right atrial fistula. PMID- 29244068 TI - Short courses of penicillin for streptococcal pharyngitis are not supported by the evidence. PMID- 29244070 TI - Traumatic injury: another unjustified reason to stop oral anticoagulation for atrial fibrillation. PMID- 29244069 TI - Impact of Comprehensive, Minimally Invasive, Multimodal Aesthetic Treatment on Satisfaction With Facial Appearance: The HARMONY Study. AB - Background: Individuals seeking aesthetic treatment have concerns regarding multiple facial areas. Objectives: Assess the aesthetic impact and satisfaction achieved with a multimodal approach to aesthetic treatment using a combination of minimally invasive treatments. Methods: Prospective, multicenter, rater-blinded, 4-month HARMONY study evaluated patient satisfaction and aesthetic impact of a combination of fillers (VYC-20L, HYC-24L, and HYC-24L+), onabotulinumtoxinA, and bimatoprost. Males and females aged 35 to 65 years received on-label, staged treatment with fillers, as needed per investigator assessment, on day 1, with touch ups allowed on day 14. Bimatoprost was self-administered once daily for 17 weeks. OnabotulinumtoxinA was injected into glabellar lines, crow's feet lines, or both at month 3. Primary effectiveness measure was mean change from baseline on the FACE-Q 10-item Satisfaction with Facial Appearance Overall Scale. Results: Of 100 patients treated, 93 underwent at least the 4-month posttreatment assessment and were assessed for efficacy. The FACE-Q Satisfaction with Facial Appearance Overall Scale total score increased from baseline (41.2) to month 4 (72.9; P < 0.00001; effect size, 2.7). Improvement following multimodal treatment was observed on FACE-Q individual items. Self-perceived age decreased from 0.2 years older than actual age at baseline to 4.6 years younger at month 4. Nearly all patients (99%) rated themselves as improved or much improved on the Global Aesthetic Improvement Scale. Investigator assessments also demonstrated improvement. Mild to moderate adverse events occurred in 42 patients. Conclusions: Minimally invasive, multimodal treatment resulted in improvements in FACE-Q scores and perceived age, indicating a high degree of patient satisfaction and a younger facial appearance. Level of Evidence 4: PMID- 29244071 TI - The Glycosyltransferase EOGT Regulates Adropin Expression in Decidualizing Human Endometrium. AB - In pregnancy, resistance of endometrial decidual cells to stress signals is critical for the integrity of the fetomaternal interface and, by extension, survival of the conceptus. O-GlcNAcylation is an essential posttranslational modification that links glucose sensing to cellular stress resistance. Unexpectedly, decidualization of primary endometrial stromal cells (EnSCs) was associated with a 60% reduction in O-linked beta-N-acetylglucosamine (O-GlcNAc) modified proteins, reflecting downregulation of the enzyme that adds O-GlcNAc to substrates (O-GlcNAc transferase; OGT) but not the enzyme that removes the modification (O-GlcNAcase). Notably, epidermal growth factor domain-specific O linked GlcNAc transferase (EOGT), an endoplasmic reticulum-specific OGT that modifies a limited number of secreted and membrane proteins, was markedly induced in differentiating EnSCs. Knockdown of EOGT perturbed a network of decidual genes involved in multiple cellular functions. The most downregulated gene upon EOGT knockdown in decidualizing cells was the energy homeostasis-associated gene (ENHO), which encodes adropin, a metabolic hormone involved in energy homeostasis and glucose and fatty acid metabolism. Analysis of midluteal endometrial biopsies revealed an inverse correlation between endometrial EOGT and ENHO expression and body mass index. Taken together, our findings revealed that obesity impairs the EOGT-adropin axis in decidual cells, which in turn points toward a mechanistic link between metabolic disorders and adverse pregnancy outcome. PMID- 29244073 TI - Incidence of infective endocarditis among patients considered at high risk. AB - Aims: Patients with prior infective endocarditis (IE), a prosthetic heart valve, or a cyanotic congenital heart disease (CHD) are considered to be at high risk of IE by guidelines. However, knowledge is sparse on the relative risk of IE between these three groups and compared controls. Methods and results: Using Danish nationwide registries (1996-2015), we identified all patients with prior IE, a prosthetic heart valve, or a complex CHD (defined as tetralogy of Fallot, truncus arteriosus, and transposition of great arteries) as well as matched control populations. Patients were followed up until death, end of study period, IE hospitalization, emigration, or a maximum of 10 years of follow-up, whichever came first. Multivariable adjusted Cox proportional hazard analysis was used to compare the risk of IE between the study groups and the matched controls. We included 25 945 patients: 5096 had prior IE, 19 478 had a prosthetic heart valve, and 1371 had complex CHD. The cumulative risk of IE at 10 years of follow-up was 8.8%, 6.0%, and 1.3% for patients with prior IE, a prosthetic valve, and complex CHD, respectively. Patients with prior IE and a prosthetic valve had a significant increased associated risk of IE compared with the matched controls [hazard ratio (HR) 65.4, 95% confidence interval (CI) 43.1-99.1 and HR 19.1, 95% CI 15.0-24.4), respectively]. No events occurred among the matched controls for the complex CHD group and an HR could not be calculated. Conclusion: All IE high risk groups carried a higher risk of IE than the matched controls from the general population. These results justify the European and American guidelines in considering these groups at high risk of IE. PMID- 29244072 TI - Impact of prediagnostic smoking and smoking cessation on colorectal cancer prognosis: a meta-analysis of individual patient data from cohorts within the CHANCES consortium. AB - Background: Smoking has been associated with colorectal cancer (CRC) incidence and mortality in previous studies and might also be associated with prognosis after CRC diagnosis. However, current evidence on smoking in association with CRC prognosis is limited. Patients and methods: For this individual patient data meta analysis, sociodemographic and smoking behavior information of 12 414 incident CRC patients (median age at diagnosis: 64.3 years), recruited within 14 prospective cohort studies among previously cancer-free adults, was collected at baseline and harmonized across studies. Vital status and causes of death were collected for a mean follow-up time of 5.1 years following cancer diagnosis. Associations of smoking behavior with overall and CRC-specific survival were evaluated using Cox regression and standard meta-analysis methodology. Results: A total of 5229 participants died, 3194 from CRC. Cox regression revealed significant associations between former [hazard ratio (HR) = 1.12; 95 % confidence interval (CI) = 1.04-1.20] and current smoking (HR = 1.29; 95% CI = 1.04-1.60) and poorer overall survival compared with never smoking. Compared with current smoking, smoking cessation was associated with improved overall (HR<10 years = 0.78; 95% CI = 0.69-0.88; HR>=10 years = 0.78; 95% CI = 0.63-0.97) and CRC-specific survival (HR>=10 years = 0.76; 95% CI = 0.67-0.85). Conclusion: In this large meta-analysis including primary data of incident CRC patients from 14 prospective cohort studies on the association between smoking and CRC prognosis, former and current smoking were associated with poorer CRC prognosis compared with never smoking. Smoking cessation was associated with improved survival when compared with current smokers. Future studies should further quantify the benefits of nonsmoking, both for cancer prevention and for improving survival among CRC patients, in particular also in terms of treatment response. PMID- 29244075 TI - The athlete's heart is a proarrhythmic heart, and what that means for clinical decision making. AB - Recurring questions when dealing with arrhythmias in athletes are about the cause of the arrhythmia and, more importantly, about the eligibility of the athlete to continue sports activities. In essence, the relation between sports and arrhythmias can be understood along three lines: sports as arrhythmia trigger on top of an underlying problem, sports as arrhythmic substrate promotor, or sports as substrate inducer. Often, there is no sharp divider line between these entities. The athlete's heart, a heart that adapts so magically to cope with the demands of exercise, harbours many structural and functional changes that by themselves predispose to arrhythmia development, at the atrial, nodal and ventricular levels. In essence, the athlete's heart is a proarrhythmic heart. This review describes the changes in the athlete's heart that are related to arrhythmic expression and focuses on what this concept means for clinical decision making. The concept of the athlete's heart as a proarrhythmic heart creates a framework for evaluation and counselling of athletes, yet also highlights the difficulty in predicting the magnitude of associated risk. The management uncertainties are discussed for specific conditions like extreme bradycardic remodelling, atrioventricular nodal reentrant tachycardia, atrial fibrillation and flutter, and ventricular arrhythmias. PMID- 29244074 TI - The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin. AB - Aims: Heart failure (HF) is accompanied by major neuroendocrine changes including the activation of the natriuretic peptide (NP) pathway. Using the unique model of patients undergoing implantation of the CARMAT total artificial heart and investigating regional differences in soluble neprilysin (sNEP) in patients with reduced or preserved systolic function, we studied the regulation of the NP pathway in HF. Methods and results: Venous blood samples from two patients undergoing replacement of the failing ventricles with a total artificial heart were collected before implantation and weekly thereafter until post-operative week 6. The ventricular removal was associated with an immediate drop in circulating NPs, a nearly total disappearance of circulating glycosylated proBNP and furin activity and a marked decrease in sNEP. From post-operative week 1 onwards, NP concentrations remained overall unchanged. In contrast, partial recoveries in glycosylated proBNP, furin activity, and sNEP were observed. Furthermore, while in patients with preserved systolic function (n = 6), sNEP concentrations in the coronary sinus and systemic vessels were similar (all P > 0.05), in patients with reduced left-ventricular systolic function, sNEP concentration, and activity were ~three-fold higher in coronary sinus compared to systemic vessels (n = 21, all P < 0.0001), while the trans-pulmonary gradient was neutral (n = 5, P = 1.0). Conclusion: The heart plays a pivotal role as a regulator of the endocrine response in systolic dysfunction, not only by directly releasing NPs but also by contributing to circulating sNEP, which in turn determines the bioavailability of other numerous vasoactive peptides. PMID- 29244076 TI - Reference Brain/Blood Concentrations of Citalopram, Duloxetine, Mirtazapine and Sertraline. AB - Postmortem blood samples may not accurately reflect antemortem drug concentrations, as the levels of some drugs increase due to postmortem redistribution (PMR). The brain has been suggested as an alternative sampling site. The anatomically secluded site of the brain limits redistribution and prolongs the detection window, thereby enabling sampling from deceased individuals where blood is no longer suitable for analysis. We report concentrations in brain tissue and blood from 91 cases for the four antidepressants citalopram, duloxetine, mirtazapine and sertraline. The cases were classified according to their role in the cause of death, as follows: (A) concentrations where the drug was the sole cause of fatal intoxication; (B) concentrations where the drug contributed to a fatal outcome; and (C) concentrations where the drug was not related to the cause of death. The analytical method was successfully validated in brain tissue in terms of linearity, process efficiency, precision and accuracy. Quantification of analytes was performed by ultra-performance liquid chromatography with tandem mass spectrometry. Correlations between blood and brain concentrations were achieved with R2-values between 0.67 and 0.91. The following median brain-blood ratios were obtained: 3.71 for citalopram (range: 1.4-5.9), 11.0 for duloxetine (range: 5.0-21.6), 1.53 for mirtazapine (range: 1.02-4.71) and 7.38 for sertraline (range: 3.2-14.2). The S/R ratio of racemic citalopram was the same in brain (0.80) and blood (0.85), whereas the median citalopram/N-desmethylcitalopram ratio was higher in brain (9.1) than blood (4.1). The results of this study may serve as reference concentrations in brain for forensic cases. PMID- 29244077 TI - Population pharmacokinetics and probability of target attainment of ertapenem administered by subcutaneous or intravenous route in patients with bone and joint infection. AB - Background: Ertapenem is a therapeutic option in patients with Gram-negative bone and joint infection (BJI). The subcutaneous (sc) route of administration is convenient in the outpatient setting and has shown favourable pharmacokinetics (PK), but available data on ertapenem are limited. Objectives: To perform population PK analysis and pharmacokinetic/pharmacodynamic (PK/PD) simulation of ertapenem administered by the intravenous (iv) or sc route to patients with BJI. Patients and methods: This was a retrospective analysis of PK data collected in patients with BJI who received iv or sc ertapenem. Measured ertapenem concentrations were analysed with a non-parametric population approach. Then, simulations were performed based on the final model to investigate the influence of ertapenem route of administration, dosage and renal function on the probability of achieving a pharmacodynamic (PD) target, defined as the percentage of time for which free plasma concentrations of ertapenem remained above the MIC (fT>MIC) of 40%. Results: Forty-six PK profiles (13 with iv and 33 with sc ertapenem) with a total of 133 concentrations from 31 subjects were available for the analysis. A two-compartment model with linear sc absorption and linear elimination best fitted the data. Creatinine clearance was found to significantly influence ertapenem plasma clearance. Simulations showed that twice daily dosing, sc administration and renal impairment were associated with an increase in fT>MIC and target attainment. Conclusions: Our results indicate that 1 g of ertapenem administered twice daily, by the iv or sc route, may optimize ertapenem exposure and achievement of PK/PD targets in patients with BJI. PMID- 29244078 TI - Patterns of Plasma Glucagon Dynamics Do Not Match Metabolic Phenotypes in Young Women. AB - Context: The role of hyperglucagonemia in type 2 diabetes is still debated. Objective: We analyzed glucagon dynamics during oral glucose tolerance tests (oGTTs) in young women with one out of three metabolic phenotypes: healthy control (normoglycemic after a normoglycemic pregnancy), normoglycemic high-risk (normoglycemic after a pregnancy complicated by gestational diabetes), and prediabetes/screening-diagnosed type 2 diabetes. We asked if glucagon patterns were homogeneous within the metabolic phenotypes. Design and Setting: Five-point oGTT, sandwich enzyme-linked immunosorbent assay for glucagon, and functional data analysis with unsupervised clustering. Participants: Cross-sectional analysis of 285 women from the monocenter observational study Prediction, Prevention, and Subclassification of gestational and type 2 Diabetes, recruited between November 2011 and May 2016. Results: We found four patterns of glucagon dynamics that did not match the metabolic phenotypes. Elevated fasting glucagon and delayed glucagon suppression was overrepresented with prediabetes/diabetes, but this was only detected in 21% of this group. It also occurred in 8% of the control group. Conclusions: We conclude that hyperglucagonemia may contribute to type 2 diabetes in a subgroup of affected individuals but that it is not a sine qua non for the disease. This should be considered in future pathophysiological studies and when testing pharmacotherapies addressing glucagon signaling. PMID- 29244079 TI - A Nonhemolytic Group B Streptococcus Strain Exhibits Hypervirulence. AB - Group B streptococci (GBS) are Gram-positive bacteria that are a leading cause of neonatal infections. Most invasive isolates are beta-hemolytic, and hemolytic activity is critical for GBS virulence. Although nonhemolytic GBS strains are occasionally isolated, they are often thought to be virulence attenuated. In this study, we show that a nonhemolytic GBS strain (GB37) isolated from a septic neonate exhibits hypervirulence. Substitution of tryptophan to leucine (W297L) in the sensor histidine kinase CovS results in constitutive kinase signaling, leading to decreased hemolysis and increased activity of the GBS hyaluronidase, HylB. These results describe how nonpigmented and nonhemolytic GBS strains can exhibit hypervirulence. PMID- 29244081 TI - Atrial fibrillation type matters: greater infarct volume and worse neurological defects seen in acute cardiogenic cerebral embolism due to persistent or permanent rather than paroxysmal atrial fibrillation. AB - Aims: Some studies have shown that the type of atrial fibrillation (AF), whether paroxysmal AF (PAF) or persistent or permanent AF (PeAF), affects the incidence of ischaemic stroke. This study sought to determine the relationship between the AF pattern and the severity and brain volume of infarction in an AF population including transient ischaemic attack (TIA) patients. Methods and results: This was a retrospective observational study. We studied 161 consecutive patients who were admitted to our stroke care unit with cardiogenic embolism or TIA related to non-valvular AF (age 79 +/- 9.5, 78 females, and 87 PAF patients). We evaluated the differences in severity and infarct volume between the types of AF. Additionally, we divided the patients into three groups according to severe stroke (n = 38), TIA (n = 28), and those who were neither (stroke, n = 95) for the assessment of the predictors of severe stroke and TIA. Persistent or permanent atrial fibrillation patients with acute cardiogenic stroke or TIA had worse peak National Institute of Health Stroke Scale (NIHSS) scores [PAF median 4 (range 3-14), PeAF 17 (5.8-25); P < 0.0001] and worse NIHSS scores at discharge [PAF 2.0 (1-7), PeAF 11 (3-22); P < 0.0001]. Their infarct brain volume assessed by computed tomography or magnetic resonance imaging was also larger [PAF 4.4 (1.1-32) mL, PeAF 64 (6.9-170) mL; P < 0.0001]. Multivariate analysis of severe stroke vs. non-severe stroke patients showed that having PeAF was the only independent predictor of severe stroke [odds ratio (OR) 4.27, 95% confidence interval (CI) 1.91-10.2; P = 0.0003]. Comparison of TIA vs. non-TIA patients showed that PeAF (OR 0.120, 95% CI 0.0230-0.444; P = 0.0008) and anticoagulant use (OR 8.24, 95% CI 2.15-40.8; P = 0.0018) were independent predictors of TIA. Conclusion: Cardiogenic emboli due to non-valvular PeAF are associated with a worse acute clinical course and greater volume of infarction than those due to PAF. PMID- 29244080 TI - Quantification of Methadone and Main Metabolites in Nails. AB - The quantification of drugs of abuse in keratinized matrices is becoming of special relevance for monitoring consumption and for post-mortem investigations. We aimed to implement an analytical method for the simultaneous detection of morphine (MORF), 6-monoacetylmorphine (6-MAM), methadone (MET), 2-ethylidene-1,5 dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3 diphenylpyrrolidine (EMDP) in nails. After decontamination, the nail samples (30 mg) were submitted to an alkaline digestion followed by a two-step liquid-liquid and SPE extraction using mixed-mode cation exchange cartridges. The analytes were eluted with 5% NH4OH/methanol. After derivatization with N-methyl-N (trimethylsilyl) trifluoroacetamide, the analytes were quantified by gas chromatography-mass spectrometry. The method was optimized and fully validated only for MET, EDDP and EMDP, since for MOR and 6-MAM it was not possible to obtain adequate recovery rates after extraction, although detection of MOR was still possible. The method was selective, accurate and precise. Regression analysis demonstrated linearity over a concentration range of 20.8-333.3 ng/mg for MET and 10.4-166.7 ng/mg for EDDP and EMDP. Limits of detection and quantification values ranged from 3.3 to 6.0 ng/mg and 10.4 to 20.8 ng/mg, respectively, and recovery rates ranged from 82% to 98%. The applicability of the method was demonstrated by analyzing nail and urine samples obtained from heroin consumers under substitution therapy with MET. PMID- 29244082 TI - Quantitation of Cocaine and Metabolites, Phencyclidine, Butalbital and Phenobarbital in Meconium by Liquid Chromatography-Tandem Mass Spectrometry. AB - In this study, a quantitative polarity switching liquid chromatography coupled with a tandem mass spectrometer (LC-MS/MS) method was developed to detect and quantify cocaine and metabolites (cocaethylene, benzoylecgonine and meta hydroxybenzoylecgonine), phencyclidine (PCP) and barbiturates (phenobarbital and butalbital) in meconium. Accuracy and precision samples at 0.0125% and 75% of the upper limit of quantitation (ULOQ) were analyzed in triplicate over 5 days with accuracy above 84% and average %CV values below 11%. Within-run (n = 15) and between-run (n = 15) %CV values were <=5%. Analytical measurement ranges were reproducible and linear (R >= 0.995) for cocaine and metabolites (20-2,000 ng/g), PCP (10-1,000 ng/g) and barbiturates (50-5,000 ng/g). Accuracy of 100 +/- 20% was observed at (the limits of detection) 10 ng/g for cocaine and metabolites, 2.5 ng/g for PCP and 25 ng/g for barbiturates. No carryover was observed at 2X ULOQ and no interfering substances were identified. Sample preparation recoveries were 53-83%. Fifty-one authentic patient samples previously characterized correlated with the newly developed test having R2 values >=0.996. This combined method allows accurate quantitation of the targeted drugs in a complex matrix while decreasing sample preparation and analysis time with reduced sample volume. Clinical data and positivity rates were similar to previously published positivity rates. Validation data and positivity rate agreement signifies a reliable and robust assay. PMID- 29244083 TI - Nucleomethylin deficiency impairs embryonic erythropoiesis. AB - Nucleomethylin (NML) has been shown to contribute to ribosome formation through regulating transcription and post-transcriptional modification of rRNA. Based on the observation that NML-/- mice are frequently embryonic lethal, we analyzed NML /- embryos to clarify the role of NML in embryogenesis. We found that NML deficiency leads to lethality at the time point between E10.5 and E12.5. Most of E10.5 NML-/- embryos exhibited growth retardation and/or malformation with marked impairment of erythropoiesis. Consistent with a previous study, the m1A in 28S rRNA was dramatically reduced in NML-/- foetal liver (FL) cells. Because the previous study demonstrated p53-dependent apoptosis of NML-knockdown cells, and because we observed upregulation of p21, one of the p53 target genes, in NML-/- FL cells, we tested whether p53 disruption cancelled the NML-deficient phenotypes. Contrary to our expectation, suppression of p53 did not rescue the lethality or impaired erythropoiesis of NML-/- embryos, suggesting that p53 independent mechanisms underlie the NML-deficient phenotypes. These results clarify an essential role of NML during embryogenesis, particularly in erythropoiesis. We surmise that embryonic erythropoiesis is particularly sensitive to impaired protein synthesis, which is caused by the defective methylation of rRNA and consequent failure of ribosome formation. PMID- 29244084 TI - The Value of Perioperative Levels of ACTH, DHEA, and DHEA-S and Tumor Size in Predicting Recurrence of Cushing Disease. AB - Context and Objectives: Despite the development of hypocortisolemia after corticotroph surgical adenomectomy, 15% to 20% patients have recurrence of Cushing disease (CD). In this study, we investigated the effect of tumor size and the value of perioperative assessment of corticotropin (ACTH) and adrenal steroid levels in predicting recurrence. Design: Perioperatively, no glucocorticoids were administered until the serum cortisol was <=3 MUg/dL. Blood samples were obtained before and repeatedly after adenomectomy in 79 patients with CD. Of these, 66 had a nadir serum cortisol of <=3.0 MUg/dL and clinical and biochemical remissions. During a median follow-up of 131 months, 11 of 66 had disease recurrence (REC), whereas 55 of 66 did not (NO-REC). Results: Preoperative hormone levels in the REC and NO-REC groups were similar. After adenomectomy, a brief and similar increase in ACTH, cortisol, and dehydroepiandrosterone (DHEA) levels was observed in both groups followed by gradual decline in those levels. Although REC and NO REC patients had similar cortisol levels (3.4 +/- 1.7 MUg/dL vs 2.9 +/- 2.2 MUg/dL) at the 36th postoperative hour, their respective ACTH (33 +/- 7.1 ng/L vs 12.1 +/- 5.4 ng/L; P < 0.0001), DHEA (3.8 +/- 1.7 ng/mL vs 1.2 +/- 1.1 ng/mL; P = 0.005), and dehydroepiandrosterone sulphate (DHEA-S) (143.9 +/- 45.2 MUg/dL vs 48.9 +/- 38.2 MUg/dL; P < 0.0001) were higher. At nadir hypocortisolemia, perioperative ACTH levels were >20 in all REC patients and <20 ng/L in the NO-REC group. Patients with REC had larger tumors than those with NO-REC. Conclusion: Recurrent CD is characterized by persistent perioperative ACTH secretion after adenomectomy. Higher perioperative levels of ACTH, DHEA, and DHEA-S are highly predictive of future disease recurrence, particularly in those with profound hypocortisolemia. PMID- 29244085 TI - Effects of cold exposure on physiology, meat quality, and behavior of turkey hens and toms crated at transport density. AB - The impact of cold exposure while crated at a density characteristic of transport (83 kg/m2) was assessed in 12-wk-old turkey hens and 16-wk-old toms. Turkeys (72 toms, 72 hens) were randomly divided into 3 male and 3 female groups: 2 moderate 20 degrees C groups with either 30% or 80% RH and a cold group exposed to -18 degrees C, with uncontrolled, high RH. Groups of 8 birds (one replicate unit) were observed in a climate-controlled chamber for 8 h prior to slaughter. Core body temperature (CBT), live shrink, heterophil-lymphocyte ratio (HLR), and change in blood glucose levels were assessed; meat quality measures included thigh and breast muscle pH and L*, a*, and b* color values. Significance was declared at P <= 0.05. Live shrink in hens exposed to -18 degrees C (2.8%) was greater (P = 0.001) than those in the 20 degrees C treatments (1.5%). CBT in hens had a tendency to decrease (P = 0.070); no differences in Delta blood glucose or HLR were detected. Thigh pH was higher in the -18 degrees C treatment (hens: 6.39; toms: 6.08) than in both 20 degrees C groups. Color values (L*, a*, and b*) were measured 27 h postmortem. In the -18 degrees C exposed hens, breast L* values were lower, and thigh a* and breast b* values were higher than in both 20 degrees C treatments. No differences were detected in live shrink, CBT, HLR, or color values among toms. Behavior differences were noted between treatments; more time was spent huddling, shivering, preening, and with feathers ptiloerected in cold-exposed turkeys. Generally, cold exposure resulted in higher live shrink, darker meat with greater redness, and a tendency for CBT and blood glucose to decrease, with larger male turkeys experiencing fewer changes. PMID- 29244087 TI - Reply to Redondo et al. PMID- 29244086 TI - Cerebral blood flow changes after radiation therapy identifies pseudoprogression in diffuse intrinsic pontine gliomas. AB - Background: The interval between progression and death in diffuse intrinsic pontine glioma (DIPG) is usually <6 months. However, reports of longer patient survival following radiotherapy, in the presence of radiological signs of progression, suggest that these cases may be comparable to pseudoprogression observed in adult glioblastoma. Our aim was to identify such cases and compare their multimodal MRI features with those of patients who did not present the same evolution. Methods: Multimodal MRIs of 43 children treated for DIPG were retrospectively selected at 4 timepoints: baseline, after radiotherapy, during true progression, and at the last visit. The patients were divided into 2 groups depending on whether they presented conventional MRI changes that mimicked progression. The apparent diffusion coefficient, arterial spin labeling cerebral blood flow (ASL-CBF), and dynamic susceptibility contrast perfusion relative cerebral blood volume (DSCrCBV) and flow (DSCrCBF) values were recorded for each tumor voxel, avoiding necrotic areas. Results: After radiotherapy, 19 patients (44%) showed radiological signs that mimicked progression: 16 survived >6 months following so-called pseudoprogression, with a median of 8.9 months and a maximum of 35.6 months. All 43 patients exhibited increased blood volume and flow after radiotherapy, but the 90th percentile of those with signs of pseudoprogression had a greater increase of ASL-CBF (P < 0.001). Survival between the 2 groups did not differ significantly. During true progression, DSCrCBF and DSCrCBV values increased only in patients who had not experienced pseudoprogression. Conclusions: Pseudoprogression is a frequent phenomenon in DIPG patients. This condition needs to be recognized before considering treatment discontinuation. In this study, the larger increase of the ASL-CBF ratio after radiotherapy accurately distinguished pseudoprogression from true progression. PMID- 29244088 TI - Application of calcium oxide (CaO, heated scallop-shell powder) for the reduction of Listeria monocytogenes biofilms on eggshell surfaces. AB - This study investigated bactericidal activity of 0.05 to 0.50% calcium oxide (CaO) against planktonic cells in tryptic soy broth (TSB) and biofilms of Listeria monocytogenes on eggshell surfaces. The bactericidal activity of CaO against planktonic cells and biofilms of L. monocytogens significantly (P < 0.05) increased log reductions with increasing concentrations of CaO. Exposure to 0.05 to 0.50% CaO for one min reduced planktonic cells in TSB cell suspensions by 0.47 to 3.86 log10CFU/mL and biofilm cells on the shell surfaces by 0.14 to 2.32 log10CFU/cm2. The Hunter colors of eggshells ("L" for lightness, "a" for redness, and "b" for yellowness), shell thickness (puncture force), and sensory quality (egg taste and yolk color) were not changed by 0.05 to 0.50% CaO treatment. The nonlinear Weibull model was used to calculate CR = 3 values as the CaO concentration of 3 log (99.9%) reduction for planktonic cells (R2 = 0.96, RMSE = 0.26) and biofilms (R2 = 0.95, RMSE = 0.18) of L. monocytogens. The CR = 3 value, 0.31% CaO for planktonic cells, was significantly (P < 0.05) lower than 0.57% CaO for biofilms. CaO could be an alternative disinfectant to reduce planktonic cells and biofilms L. monocytogenes on eggshell surface in egg processing plants. PMID- 29244089 TI - The Historical Progression From ADL Scrutiny to IADL to Advanced ADL: Assessing Functional Status in the Earliest Stages of Dementia. AB - Background: Decrements in instrumental activities (IADL) have been observed in the prodromal phase of dementia. Given the long predementia stage in neurodegenerative diseases, it has been proposed that subtle functional changes may precede clinical IADL impairment. Incorporating more challenging advanced ADLs (eg, volunteer work) into the assessment process may increase the sensitivity of functional measures, thus expanding the window for monitoring or interventions. Methods: Longitudinal cohort study was used (follow-ups, 18-24 month), with subjects aged 60 and older (n = 3,635). To elucidate the relationship between cognitive ability and functional status we employed an IADL scale with an extended range (ADL-extended; includes IADL but also more challenging advanced ADLs) that meets item response theory properties of dimensionality, monotonicity, and item hierarchy. Procedures involved (a) a dynamic change model employed to inspect the temporal relationship between ADL extended and cognitive status and (b) Cox proportional hazards to assess the risk of incident dementia based on ADL-extended scores. Results: Growth curve modeling: baseline ADL-extended was significantly associated with all four cognitive domains investigated. Worse baseline ADL-extended was associated with more rapid declines in speed/executive function, and worse baseline memory was associated with more rapid declines in ADL-extended; a concurrent association was found for language and ADL-extended. Cox model: the risk of dementia was decreased for each additional ADL-extended item endorsed (hazard ratio [HR], 0.85; 95% confidence interval = 0.81-0.90). Conclusions: An increased risk of dementia could be observed in the ADL-extended items, which reflects an area of the functional continuum beyond IADL competencies. PMID- 29244091 TI - ASJ Expands to Monthly Publication. PMID- 29244090 TI - Prevalence and Risk of Severe Cognitive Impairment in Advanced Chronic Kidney Disease. AB - Background: Our primary goal is to describe the prevalence, severity, and risk of cognitive impairment (CI) by estimated glomerular filtration rate (eGFR, in mL/min/1.73 m2) in a cohort enriched for advanced chronic kidney disease (CKD; eGFR < 45), adjusting for albuminuria, as measured by urine albumin-to-creatinine ratio (UACR, in mg/g). As both eGFR and albuminuria are associated with CI risk in CKD, we also seek to determine the extent that eGFR remains a useful biomarker for risk of CI in those with CKD and concomitant albuminuria. Methods: Chi-square tests measured the prevalence of severe CI and mild cognitive impairment (MCI) by eGFR level. Logistic regression models and generalized linear models measured risk of CI by eGFR, adjusted for UACR. Results: Participants were 574 adults with a mean age of 69; 433 with CKD (eGFR < 60, nondialysis) and 141 controls (eGFR >= 60). Forty-eight percent of participants with CKD had severe CI or MCI. The prevalence of severe CI was highest (25%) in those with eGFR < 30. eGFR < 30 was only associated with severe CI in those without albuminuria (UACR < 30; OR = 3.3; p = .02) and was not associated with MCI in similar models. Conclusions: One quarter of those with eGFR < 30 had severe CI. eGFR < 30 was associated with over threefold increased odds of severe CI in those with UACR < 30, but not with UACR > 30, suggesting that eGFR < 30 is a valid biomarker for increased risk of severe CI in those without concomitant albuminuria. PMID- 29244092 TI - Scholarship and Pragmatism Help ASJ Achieve Monthly Publication. PMID- 29244093 TI - Commentary on: Efficacy of Retrobulbar Hyaluronidase Injection for Vision Loss Resulting from Hyaluronic Acid Filler Embolization. PMID- 29244094 TI - A Game Changer for the Aesthetic Surgery Journal. PMID- 29244095 TI - CORRIGENDUM FOR "Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline". PMID- 29244096 TI - Treatment of pulmonary tuberculosis: past and present. AB - OBJECTIVES: Surgical interventional has been key in the treatment of tuberculosis (TB) for a long time. Its importance diminished after the emergence of chemotherapy. However, the spread of rapid multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has led us to return to surgery to treat TB. Today, every second patient in Russia with destructive TB has either MDR or XDR TB, which is the reason for the low efficacy of conservative treatment. In 2015, treatment with drugs resulted in clinical recovery in only 29.8% of new cases of destructive TB acid-fast bacilli (AFB)+. METHODS: The author's data from 1999 to 2016 have been analysed. The author performed 5599 surgeries on patients with pulmonary TB aged from 1 to 87 years (mean age 34.6 years). The most common reasons for surgical treatment were fibrotic cavitary and cavitary pulmonary TB, tuberculoma with destruction, tuberculous pleural empyema, caseous pneumonia and intrathoracic lymph nodes. The strategy of early collapse therapy and the use of surgery to treat TB was proposed in the Penza region of Russia; the results were analysed to estimate the long-term outcomes of treatment. RESULTS: In 5599 surgeries, the full clinical effect was achieved in 93% of operated patients with MDR TB, in 92.1% of those with XDR TB and in 98% of patients without MDR or XDR resistance. According to the data from the Penza region, 3 years after surgery, 93.9% (149 of 159 cases) of the operated patients exhibited clinical recovery. CONCLUSIONS: Taking into account the data from the World Health Organization on the insufficient level of therapeutic success in the treatment of MDR and XDR pulmonary TB, surgical treatment is necessary in regions with a high frequency of drug-resistant cases. PMID- 29244097 TI - Reply: A case of CLIPPERS challenging the new diagnostic criteria. PMID- 29244099 TI - The role of vitamin D in adipogenesis. AB - Vitamin D, a secosteroid predominately obtained by endogenous production, has in recent years been linked to obesity and its comorbidities. The purpose of this review is to draw conclusions from animal and human studies on the effects of vitamin D on adipogenesis to identify the molecular links between vitamin D and obesity. The information presented herein was obtained from 4 databases (PubMed, CINAHL, Cochrane Library, Scopus) using predefined search terms, as well as research literature and other reviews. The effects of vitamin D on adipogenesis have been researched in several animal models, and the majority of these studies suggest vitamin D plays an inhibitory role in adipogenesis. Studies into vitamin D status and obesity in humans are limited, with the majority being observational epidemiological studies that provide no conclusions on cause and effect or clear links on the molecular mechanisms. The few cell culture and supplementation studies that have investigated adipogenesis in human cells indicate that, in contrast to findings from rodent studies, vitamin D is proadipogenic. There is insufficient evidence to determine whether 1) vitamin D deficiency is associated with a lean or obese phenotype, 2) vitamin D deficiency is a consequence of obesity, or (3) the effects of vitamin D on fat tissue are due to interactions with calcium. PMID- 29244098 TI - Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. AB - Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia. We report a case of an adult patient who developed the rare condition DPHL and made a nearly complete recovery in the setting of treatment with clemastine, a widely available antihistamine that in preclinical models promotes oligodendrocyte precursor cell differentiation. This suggested possible therapeutic benefit in the more clinically prevalent hypoxic injury of newborns, and we demonstrate in murine neonatal hypoxic injury that clemastine dramatically promotes oligodendrocyte precursor cell differentiation, myelination, and improves functional recovery. We show that its effect in hypoxia is oligodendroglial specific via an effect on the M1 muscarinic receptor on oligodendrocyte precursor cells. We propose clemastine as a potential therapy for hypoxic brain injuries associated with white matter injury and oligodendrocyte precursor cell maturation arrest. PMID- 29244100 TI - Invasive Insular Sampling in Pediatric Epilepsy: A Single-Institution Experience. AB - BACKGROUND: It has been increasingly recognized that the insular cortex plays an important role in frontotemporal-parietal epilepsy in children. The insula, however, cannot be properly interrogated with conventional subdural grids, and its anatomy makes it difficult to implicate the insula with semiology or noninvasive modalities. Frame-based, stereotactic placement of insular depth electrodes for direct extraoperative monitoring is a relatively low-risk maneuver that allows for conclusive interrogation of this region, and, in select cases, can easily be replaced with a laser applicator for minimally invasive treatment via thermoablation. OBJECTIVE: To describe the largest reported series of pediatric patients with refractory epilepsy undergoing insular depth electrode placement. METHODS: We used current procedural terminology billing records to identify cases of depth electrode insertion performed at our institution. Clinical information from patients undergoing invasive insular sampling was then retrospectively collected. RESULTS: Seventy-four insular depth electrodes were placed in 49 patients for extraoperative, inpatient monitoring. The decision to place insular depth electrodes was determined by a multidisciplinary epilepsy team. In 65.3% of cases, direct invasive sampling implicated the insula in seizure onset and prompted either thermoablation or surgical resection of some portion of the insula. There were no serious adverse effects or complications associated with the placement of insular depth electrodes. CONCLUSION: Given the low morbidity of insular depth electrode insertion and the high proportion of patients who exhibited insular involvement, it is worth considering whether insular depth electrodes should be part of the standard presurgical evaluation in children with treatment-refractory frontotemporal-parietal epilepsy. PMID- 29244101 TI - 18F-FDG positron emission tomography/computed tomography for diagnosis of pump housing infections in patients on left ventricular assist devices: should we contain our initial enthusiasm? PMID- 29244102 TI - Association of Opioid Usage with Spinal Cord Stimulation Outcomes. AB - Study Design: Observational study using insurance claims. Objective: To quantify opioid usage leading up to spinal cord stimulation (SCS) and the potential impact on outcomes of SCS. Setting: SCS is an interventional therapy that often follows opioid usage in the care continuum for chronic pain. Methods: This study identified SCS patients using the Truven Health MarketScan databases from January 2010 to December 2014. The index event was the first occurrence of a permanent SCS implant. Indicators of opioid usage at implant were daily morphine equivalent dose (MED), number of unique pain drug classes, and diagnosis code for opioid abuse. System explant was used as a measure of ineffective SCS therapy. Multivariate logistic regression was used to analyze the effect of pre-implant medications on explants. Results: A total of 5,476 patients (56 +/- 14 years; 60% female) were included. SCS system removal occurred in 390 patients (7.1%) in the year after implant. Number of drug classes (odds ratio [OR] = 1.11, P = 0.007) and MED level (5-90 vs < 5 mg/d: OR = 1.32, P = 0.043; >=90 vs < 5 mg/d: OR = 1.57, P = 0.005) were independently predictive of system explant. Over the year before implant, MED increased in 54% (stayed the same in 21%, decreased in 25%) of patients who continued with SCS and increased in 53% (stayed the same in 20%, decreased in 27%) of explant patients (P = 0.772). Over the year after implant, significantly more patients with continued SCS had an MED decrease (47%) or stayed the same (23%) than before (P < 0.001). Conclusions: Chronic pain patients receive escalating opioid dosage prior to SCS implant, and high-dose opioid usage is associated with an increased risk of explant. Neuromodulation can stabilize or decrease opioid usage. Earlier consideration of SCS before escalated opioid usage has the potential to improve outcomes in complex chronic pain. PMID- 29244103 TI - Gender dynamics affecting maternal health and health care access and use in Uganda. AB - Despite its reduction over the last decade, the maternal mortality rate in Uganda remains high, due to in part a lack of access to maternal health care. In an effort to increase access to care, a quasi-experimental trial using vouchers was implemented in Eastern Uganda between 2009 and 2011. Findings from the trial reported a dramatic increase in pregnant women's access to institutional delivery. Sustainability of such interventions, however, is an important challenge. While such interventions are able to successfully address immediate access barriers, such as lack of financial resources and transportation, they are reliant on external resources to sustain them and are not designed to address the underlying causes contributing to women's lack of access, including those related to gender. In an effort to examine ways to sustain the intervention beyond external financial resources, project implementers conducted a follow-up qualitative study to explore the root causes of women's lack of maternal health care access and utilization. Based on emergent findings, a gender analysis of the data was conducted to identify key gender dynamics affecting maternal health and maternal health care. This paper reports the key gender dynamics identified during the analysis, by detailing how gender power relations affect maternal health care access and utilization in relation to: access to resources; division of labour, including women's workload during and after pregnancy and lack of male involvement at health facilities; social norms, including perceptions of women's attitudes and behaviour during pregnancy, men's attitudes towards fatherhood, attitudes towards domestic violence, and health worker attitudes and behaviour; and decision-making. It concludes by discussing the need for integrating gender into maternal health care interventions if they are to address the root causes of barriers to maternal health access and utilization and improve access to and use of maternal health care in the long term. PMID- 29244104 TI - "If it's issues to do with nutrition...I can decide...": gendered decision-making in joining community-based child nutrition interventions within rural coastal Kenya. AB - Gender roles and relations play an important role in child health and nutritional status. While there is increasing recognition of the need to incorporate gender analysis in health planning and programme development, there has been relatively little attention paid to the gendered nature of child nutrition interventions. This qualitative study undertaken in rural Coastal Kenya aimed to explore the interaction between household gender relations and a community-based child nutrition programme, with a focus on household decision-making dynamics related to joining the intervention. Fifteen households whose children were enrolled in the programme were followed up over a period of 12 months. Over a total of 60 household visits, group and individual in-depth interviews were conducted with a range of respondents, supplemented by non-participant observations. Data were analysed using a framework analysis approach. Engagement with the intervention was highly gendered with women being the primary decision-makers and engagers. Women were responsible for managing child feeding and minor child illnesses in households. As such, involvement in community-based nutrition interventions and particularly one that targeted a condition perceived as non-serious, fell within women's domain. Despite this, the nutrition programme of interest could be categorized as gender-blind. Gender was not explicitly considered in the design and implementation of the intervention, and the gender roles and norms in the community with regards to child nutrition were not critically examined or challenged. In fact, the intervention might have inadvertently reinforced existing gender divisions and practices in relation to child nutrition, by (unintentionally) excluding men from the nutrition discussions and activities, and thereby supporting the notion of child feeding and nutrition as "women's business". To improve outcomes, community-based nutrition interventions need to understand and take into account gendered household dynamics, and incorporate strategies that promote behaviour change and attitude shifts in relation to gendered norms and child nutrition. PMID- 29244105 TI - The gendered health workforce: mixed methods analysis from four fragile and post conflict contexts. AB - It is well known that the health workforce composition is influenced by gender relations. However, little research has been done which examines the experiences of health workers through a gender lens, especially in fragile and post-conflict states. In these contexts, there may not only be opportunities to (re)shape occupational norms and responsibilities in the light of challenges in the health workforce, but also threats that put pressure on resources and undermine gender balance, diversity and gender responsive human resources for health (HRH). We present mixed method research on HRH in four fragile and post-conflict contexts (Sierra Leone, Zimbabwe, northern Uganda and Cambodia) with different histories to understand how gender influences the health workforce. We apply a gender analysis framework to explore access to resources, occupations, values, decision making and power. We draw largely on life histories with male and female health workers to explore their lived experiences, but complement the analysis with evidence from surveys, document reviews, key informant interviews, human resource data and stakeholder mapping. Our findings shed light on patterns of employment: in all contexts women predominate in nursing and midwifery cadres, are under represented in management positions and are clustered in lower paying positions. Gendered power relations shaped by caring responsibilities at the household level, affect attitudes to rural deployment and women in all contexts face challenges in accessing both pre- and in-service training. Coping strategies within conflict emerged as a key theme, with experiences here shaped by gender, poverty and household structure. Most HRH regulatory frameworks did not sufficiently address gender concerns. Unless these are proactively addressed post crisis, health workforces will remain too few, poorly distributed and unable to meet the health needs of vulnerable populations. Practical steps need to be taken to identify gender barriers proactively and engage staff and communities on best approaches for change. PMID- 29244106 TI - Psychosocial support for adolescent girls in post-conflict settings: beyond a health systems approach. AB - Adaptive and adequately resourced health systems are necessary to achieve good health outcomes in post-conflict settings, however domains beyond the health system are also critical to ensure broader wellbeing. This paper focuses on the importance of psychosocial support services for adolescent girls in fragile contexts. Its starting point is that adolescence is a pivotal time in the life course but given the physical, cognitive and emotional changes triggered by the onset of puberty, it can also be a period of heightened sensitivity and vulnerability to trauma, social isolation, bullying by peers, a lack of supportive adults and gender-based and sexual violence. Our findings highlight why humanitarian and biomedical approaches in their current form are inadequate to address these complexities. Drawing on qualitative fieldwork (consisting of in depth and key informant interviews as well as group discussions in Gaza, Liberia and Sri Lanka involving a total of 386 respondents across the three countries), we argue that going beyond biomedical approaches and considering the social determinants of health, including approaches to tackle discriminatory gendered norms and barriers to service access, are critical for achieving broader health and wellbeing. While all three case study countries are classified as post conflict, the political economy dynamics vary with associated implications for experiences of psychosocial vulnerabilities and the service environment. The study concludes by reflecting on actions to address psychosocial vulnerabilities facing adolescent girls. These include: tailoring services to ensure gender and age-sensitivity; investing in capacity building of service providers to promote service uptake; and enhancing strategies to regulate and coordinate actors providing mental health and psychosocial support services. PMID- 29244107 TI - The importance of gender analysis in research for health systems strengthening. AB - This editorial discusses a collection of papers examining gender across a range of health policy and systems contexts, from access to services, governance, health financing, and human resources for health. The papers interrogate differing health issues and core health systems functions using a gender lens. Together they produce new knowledge on the multiple impacts of gender on health experiences and demonstrate the importance of gender analyses and gender sensitive interventions for promoting well-being and health systems strengthening. The findings from these papers collectively show how gender intersects with other axes of inequity within specific contexts to shape experiences of health and health seeking within households, communities and health systems; illustrate how gender power relations affect access to important resources; and demonstrate that gender norms, poverty and patriarchy interplay to limit women's choices and chances both within household interactions and within the health sector. Health systems researchers have a responsibility to promote the incorporation of gender analyses into their studies in order to inform more strategic, effective and equitable health systems interventions, programmes, and policies. Responding to gender inequitable systems, institutions, and services in this sector requires an 'all hands-on deck' approach. We cannot claim to take a 'people-centred approach' to health systems if the status quo continues. PMID- 29244108 TI - Optimal doses of rifampicin in the standard drug regimen to shorten tuberculosis treatment duration and reduce relapse by eradicating persistent bacteria. AB - Objectives: Although high-dose rifampicin holds promise for improving tuberculosis disease control by eradication of persistent bacteria, the optimal dose of rifampicin that kills persistent bacteria and shortens the treatment duration is unknown. Methods: The Cornell mouse model was used to test the efficacy of rifampicin at elevated doses combined with isoniazid and pyrazinamide to kill actively growing and persistent bacilli and to measure relapse rate. Persistent bacteria were evaluated using Mycobacterium tuberculosis culture supernatant containing resuscitation-promoting factors. Pharmacokinetic parameters and dose-dependent activity for cultivable and persistent bacilli were determined. Results: Increasing doses of rifampicin in combination with isoniazid and pyrazinamide resulted in dose-dependent faster bacterial clearance. Evaluated both on solid media and in culture filtrate containing resuscitation-promoting factors, a regimen containing a standard dose of rifampicin at 10 mg/kg over 14 weeks failed to achieve organ sterility. In contrast, higher doses of rifampicin achieved organ sterility in a much shorter time of 8-11 weeks. Disease relapse, which occurred in 86% of mice treated with the standard regimen for 14 weeks, was completely prevented by rifampicin doses of >= 30 mg/kg. Conclusions: In the treatment of murine tuberculosis, a rifampicin dose of 30 mg/kg was sufficient to eradicate persistent M. tuberculosis, allowing shorter treatment duration without disease relapse. PMID- 29244109 TI - GADD45a Promotes Active DNA Demethylation of the MMP-9 Promoter via Base Excision Repair Pathway in AGEs-Treated Keratinocytes and in Diabetic Male Rat Skin. AB - Diabetes elevates matrix metalloproteinase (MMP)-9 levels in the skin and its keratinocytes, and activated MMP-9 impairs skin wound healing. Epigenetic regulation of the DNA methylation status within the MMP-9 promoter plays an important role in the alteration of MMP-9 expression. Our aim was to investigate the role and mechanism of growth arrest and DNA damage-inducible 45a (GADD45a), a well-known DNA demethylation regulatory protein that mediates DNA methylation, in the regulation of MMP-9 expression. In this study, we showed that GADD45a was markedly upregulated in skin tissues from patients with diabetic foot ulcers, in diabetic rats, and in human keratinocyte (HaCaT) cells exposed to advanced glycation end products. We observed a substantial positive correlation between the levels of GADD45a and MMP-9 expression. Knockdown of GADD45a ameliorated the increase in MMP-9 transcription induced by a diabetic condition by inhibiting demethylation in the MMP-9 promoter and promoted diabetic HaCaT cell migration, but GADD45a knockdown did not affect HaCaT cell proliferation or apoptosis. Additionally, we demonstrated that overexpression of GADD45a activated MMP-9 expression by inducing promoter demethylation. Moreover, we found that GADD45a binds to the promoter of MMP-9 and recruits thymine-DNA glycosylase for base excision repair-mediated demethylation in diabetic HaCaT cells and diabetic rat skin. Our results reveal a mechanism in which GADD45a is required for demethylation of the MMP-9 promoter and the induction of diabetic wound healing. The inhibition of GADD45a might be a therapeutic strategy for diabetic foot ulcers. PMID- 29244110 TI - Proteomic Profiling of Human Uterine Fibroids Reveals Upregulation of the Extracellular Matrix Protein Periostin. AB - The central characteristic of uterine fibroids is excessive deposition of extracellular matrix (ECM), which contributes to fibroid growth and bulk-type symptoms. Despite this, very little is known about patterns of ECM protein expression in fibroids and whether these are influenced by the most common genetic anomalies, which relate to MED12. We performed extensive genetic and proteomic analyses of clinically annotated fibroids and adjacent normal myometrium to identify the composition and expression patterns of ECM proteins in MED12 mutation-positive and mutation-negative uterine fibroids. Genetic sequencing of tissue samples revealed MED12 alterations in 39 of 65 fibroids (60%) from 14 patients. Using isobaric tagged-based quantitative mass spectrometry on three selected patients (n = 9 fibroids), we observed a common set of upregulated (>1.5-fold) and downregulated (<0.66-fold) proteins in small, medium, and large fibroid samples of annotated MED12 status. These two sets of upregulated and downregulated proteins were the same in all patients, regardless of variations in fibroid size and MED12 status. We then focused on one of the significant upregulated ECM proteins and confirmed the differential expression of periostin using western blotting and immunohistochemical analysis. Our study defined the proteome of uterine fibroids and identified that increased ECM protein expression, in particular periostin, is a hallmark of uterine fibroids regardless of MED12 mutation status. This study sets the foundation for further investigations to analyze the mechanisms regulating ECM overexpression and the functional role of upregulated ECM proteins in leiomyogenesis. PMID- 29244112 TI - The effect of descriptive age norms on the motivation to exercise among older adults. AB - Based on the principles of the Social Identity Approach (SIA), the present experiment aimed to examine the impact of communicating descriptive age norms on older adults' autonomous motivation to exercise. Under the cover of a marketing study, older adults (n = 120; age = 65-70 years) participated in a newly created exercise activity, 'Pattern Stepping'. This activity was framed as an activity that was descriptively normative either for older adults, for younger adults, for both groups, or for none. Repeated measures ANOVAs revealed that participants felt greater satisfaction of their basic psychological needs and were more autonomously motivated to exercise if Pattern Stepping was framed as an activity popular among the young, rather than among older adults. These findings suggest that framing an exercise as descriptively normative for the elderly can thwart older adults' autonomous motivation if they do not identify as an older adult. PMID- 29244111 TI - Serum Albumin as a Prognostic Marker for Serious Non-AIDS Endpoints in the Strategic Timing of Antiretroviral Treatment (START) Study. AB - Background: Serum albumin may be used to stratify human immunodeficiency virus (HIV)-infected persons with high CD4 count according to their risk of serious non AIDS endpoints. Methods: Cox proportional hazards models were used to analyze the risk of serious non-AIDS events in the Strategic Timing of Antiretroviral Treatment (START) study (NCT00867048) with serum albumin as a fixed and time updated predictor. Models with exclusion of events during initial follow-up years were built to assess the ability of serum albumin to predict beyond shorter periods of time. Secondarily, we considered hospitalizations and AIDS events. Results: Among 4576 participants, 71 developed a serious non-AIDS event, 788 were hospitalized, and 63 experienced an AIDS event. After adjusting for a range of variables associated with hypoalbuminemia, higher baseline serum albumin (per 1 g/dL) was associated with a decreased risk of serious non-AIDS events (hazard ratio, 0.37 [95% confidence interval, .20-.71]; P = .002). Similar results were obtained in a time-updated model, after controlling for interleukin 6, and after excluding initial follow-up years. Serum albumin was independently associated with hospitalization but not with risk of AIDS. Conclusions: A low serum albumin level is a predictor for short- and long-term serious non-AIDS events, and may be a useful marker of risk of noncommunicable diseases, particularly in resource limited settings. PMID- 29244113 TI - T1N0 oesophageal cancer: patterns of care and outcomes over 25 years. AB - OBJECTIVES: Historically, surgical resection has been the mainstay of treatment for T1N0 oesophageal cancer (OC). More recently, oesophageal sparing endoscopic techniques have shown value for local control in a large institutional series. However, the effect of their utilization upon survival rates in large population series is largely unknown. METHODS: The surveillance, epidemiology, and end results (SEER) database was queried for T1N0M0-OC patients (1988-2013). Patients with multiple treatment types were excluded. Time periods were divided by 5-year increments. Overall survival and cancer-specific survival (CSS) were compared in the group as a whole and in propensity-matched subgroups. Independent predictors of cancer-specific mortality were studied by the Cox proportional hazard models. RESULTS: We identified 5497 patients with cT1N0M0 OC. Treatment modalities used were changed significantly over time. The ratio of oesophagectomy when compared with local therapy decreased from 15:1 in 1998-92 to 1.4:1 in 2008-13. The proportion of patients treated with radiation slightly increased (35% vs 41%) between 1988-92 and 2008-13. In the propensity-matched groups, 5-year CSS was similar in patients treated with oesophagectomy and local therapy (81% vs 89%; P = 0.257) (n = 216 in each group), whereas oesophagectomy had superior 5-year CSS compared with radiation alone (73% vs 38%; P < 0.001) (n = 497 in each group). In multivariable analysis, significant predictors of cancer-specific mortality included age [hazard ratio (HR) 1.022], tumour size (HR 1.005), radiation therapy (HR 3.67), tumour Grade III/IV (HR 1.25) and early time period of diagnosis (HR 1.75). CONCLUSIONS: Oesophageal sparing endoscopic techniques have been increasingly utilized in the treatment of cT1N0-OC but without compromising CSS. Local therapy, either endoscopic techniques or surgery, remains superior to radiation therapy. PMID- 29244114 TI - Propranolol for gastrointestinal bleeding in two patients with continuous flow left ventricle assist device. AB - Patients with continuous-flow left ventricle assist devices are at risk for gastrointestinal bleeding from angiodysplastic bowel lesions. Neoangiogenesis secondary to von Willebrand factor degradation and increased vascular endothelial growth factor (VEGF) signalling is likely related to their pathophysiology. We speculated that propranolol, known to downregulate VEGF signalling, could be beneficial in patients with recurrent bleeding episodes and anaemia. In this case report, we present a short-term outcome of 2 patients treated with propranolol. PMID- 29244116 TI - The new European regulatory framework for medical devices: opportunities for engagement by electrophysiologists. PMID- 29244117 TI - Quality of Life, Self-Esteem, and Future Expectations of Adolescent and Young Adult Cancer Survivors. AB - Significant advancements in treatment modalities over the past few decades have significantly improved the survival rates of many types of childhood cancer, directing attention to the psychosocial consequences of successful treatment and subsequent survival. This study assesses quality of life (QoL) among survivors of childhood cancer. Data were collected by means of a survey questionnaire. Participants were assured of confidentiality and of the voluntary nature of participation. Participants ranged in age from 12 to 24 years (mean age = 17.2); 62 percent were male; 45.6 percent were in secondary grades (middle school or high school). Results showed that among the QoL domains, spiritual subscale ranked highest, and physical domain showed the lowest mean score. Self-esteem emerged as an important predictor for social domain of QoL. Cancer-specific worry emerged as a significant predictor for overall QoL. The findings suggest that survivors rated high on positive life changes and sense of purpose, which are associated with positive QoL. However, this was tempered by worries and uncertainty. This study provides seminal information on the psychosocial needs of childhood cancer survivors in an Asian context that can be used by health care professionals and providers to further promote support and health care following treatment. PMID- 29244118 TI - Lower dolutegravir plasma concentrations in HIV-positive patients receiving valproic acid. PMID- 29244119 TI - Is Social Work Prepared for Diversity in Hospice and Palliative Care? AB - The purpose of this article is to assess current and future trends in hospice and palliative care with the objective of informing culturally appropriate best practice for social work. Concern for the intersectionality of racial, ethnic, social, and other differences in end-of-life (EOL) care is imperative given the ever growing range of diversity characteristics among the increasing aging populations in the United States. A review of literature from the current decade that is pertinent to the profession contributes to the ability of social work to consider evidence and build agreement germane to EOL practice settings. Administrative reports, government data, academic literature, professional standards, and assessment tools contribute to the profession's ability to work toward cultural competence and develop practice strategies for EOL care. The varied roles held by social workers across health care arenas provide a unique opportunity to promote cultural competence and advance best practice on all levels of work. PMID- 29244115 TI - Atazanavir and darunavir in pregnant women with HIV: evaluation of laboratory and clinical outcomes from an observational national study. AB - Background: Atazanavir and darunavir represent the main HIV PIs recommended in pregnancy, but comparative data in pregnant women are limited. We assessed the safety and activity profile of these two drugs in pregnancy using data from a national observational study. Methods: Women with atazanavir or darunavir exposure in pregnancy were evaluated for laboratory measures and main pregnancy outcomes (e.g. preterm delivery, low birthweight, non-elective caesarean section and neonatal gestational age-adjusted birthweight Z-score). Results: Final analysis included 500 pregnancies with either atazanavir (n = 409) or darunavir (n = 91) exposure. No differences in pregnancy outcomes, weight gain in pregnancy, drug discontinuations, undetectable HIV-RNA, haemoglobin, ALT, total cholesterol, HDL cholesterol and LDL cholesterol were observed between the two groups. At third trimester, exposure to darunavir was associated with higher levels of plasma triglycerides (median 235.5 versus 179 mg/dL; P = 0.032) and a higher total cholesterol/HDL cholesterol ratio (median 4.03 versus 3.27; P = 0.028) and exposure to atazanavir was associated with higher levels of plasma bilirubin (1.54 versus 0.32 mg/dL; P < 0.001). Conclusions: In this observational study, the two main HIV PIs currently recommended by perinatal guidelines showed similar safety and activity in pregnancy, with no evidence of differences between the two drugs in terms of main pregnancy outcomes. Based on the minor differences observed in laboratory measures, prescribing physicians might prefer either drug in some particular situations where the different impacts of treatment on lipid profile and bilirubin may have clinical relevance. PMID- 29244120 TI - All About the Albumin? Prognostic Capacity of Serum Albumin in Patients With Treated HIV Infection. PMID- 29244121 TI - In vitro activity of ceftolozane/tazobactam versus antimicrobial non-susceptible Pseudomonas aeruginosa clinical isolates including MDR and XDR isolates obtained from across Canada as part of the CANWARD study, 2008-16. AB - Objectives: Ceftolozane/tazobactam is a novel beta-lactam beta-lactamase inhibitor combination with a broad spectrum of activity that includes Pseudomonas aeruginosa. The purpose of this study was to evaluate the in vitro activity of ceftolozane/tazobactam and relevant comparators versus a large collection of antimicrobial non-susceptible P. aeruginosa clinical isolates recovered from patients across Canada (CANWARD, 2008-16). Methods: Susceptibility testing was performed on P. aeruginosa clinical isolates obtained from sentinel hospitals across Canada between January 2008 and December 2016 using broth microdilution, as described by the CLSI. MDR P. aeruginosa were defined as isolates that tested non-susceptible to at least one antimicrobial from >=3 classes. XDR P. aeruginosa were defined as isolates that tested non-susceptible to at least one antimicrobial from >=5 classes. Results: In total, 3229 P. aeruginosa isolates were obtained as a part of CANWARD. Ceftolozane/tazobactam was the most active antimicrobial evaluated, with 98.3% of isolates testing susceptible. The percentage of antimicrobial non-susceptible isolates that remained susceptible to ceftolozane/tazobactam ranged from 85.3% (amikacin non-susceptible subset) to 95.0% (ciprofloxacin non-susceptible subset). Four-hundred and sixty-two P. aeruginosa isolates were MDR (14.3% of all isolates tested) and 84 were XDR (2.6% of all isolates tested). Ceftolozane/tazobactam demonstrated excellent in vitro activity versus the MDR and XDR isolates, with 90.5% and 78.6% remaining susceptible, respectively. Conclusions: Ceftolozane/tazobactam demonstrated excellent in vitro activity against antimicrobial non-susceptible P. aeruginosa clinical isolates, including MDR and XDR subsets. It may prove useful in the treatment of infections caused by these organisms. PMID- 29244122 TI - La-related protein 1 (LARP1) repression of TOP mRNA translation is mediated through its cap-binding domain and controlled by an adjacent regulatory region. AB - Cell growth is a complex process shaped by extensive and coordinated changes in gene expression. Among these is the tightly regulated translation of a family of growth-related mRNAs defined by a 5' terminal oligopyrimidine (TOP) motif. TOP mRNA translation is partly controlled via the eukaryotic initiation factor 4F (eIF4F), a translation factor that recognizes the mRNA 5' cap structure. Recent studies have also implicated La-related protein 1 (LARP1), which competes with eIF4F for binding to mRNA 5' ends. However, it has remained controversial whether LARP1 represses TOP mRNA translation directly and, if so, what features define its mRNA targets. Here, we show that the C-terminal half of LARP1 is necessary and sufficient to control TOP mRNA translation in cells. This fragment contains the DM15 cap-binding domain as well as an adjacent regulatory region that we identified. We further demonstrate that purified LARP1 represses TOP mRNA translation in vitro through the combined recognition of both the TOP sequence and cap structure, and that its intrinsic repressive activity and affinity for these features are subject to regulation. These results support a model whereby the translation of TOP mRNAs is controlled by a growth-regulated competition between eIF4F and LARP1 for their 5' ends. PMID- 29244124 TI - A challenging case of aortic valve commissure detachment with fibrous strand ruptures mimicking infective endocarditis. PMID- 29244123 TI - Emergence and genomic analysis of MDR Laribacter hongkongensis strain HLGZ1 from Guangzhou, China. AB - Background: Laribacter hongkongensis is a facultative anaerobic, non fermentative, Gram-negative bacillus associated with community-acquired gastroenteritis and traveller's diarrhoea. No clinical MDR L. hongkongensis isolate has been reported yet. Methods: We performed WGS (PacBio and Illumina) on a clinical L. hongkongensis strain HLGZ1 with an MDR phenotype. Results: HLGZ1 was resistant to eight classes of commonly used antibiotics. Its complete genome was a single circular chromosome of 3 424 272 bp with a G + C content of 62.29%. In comparison with the reference strain HLHK9, HLGZ1 had a higher abundance of genes associated with DNA metabolism and recombination. Several inserts including two acquired resistance gene clusters (RC1 and RC2) were also identified. RC1 carried two resistance gene cassette arrays, aac(6')-Ib-cr-aadA2-Deltaqac Deltasul1-floR-tetR-tetG and arr-3-dfrA32-ereA2-Deltaqac-sul1, which shared significant nucleotide sequence identities with the MDR region of Salmonella Genomic Island 1 from Salmonella enterica serovar Typhimurium DT104. There was also an integron-like structure, intl1-arr3-dfrA27-Deltaqac-sul1-aph(3')-Ic, and a tetR-tetA operon located on RC2. MLST analysis identified HLGZ1 as ST167, a novel ST clustered with two strains previously isolated from frogs. Conclusions: This study provides insight into the genomic characteristics of MDR L. hongkongensis and highlights the possibilities of horizontal resistance gene transfer in this bacterium with other pathogens. PMID- 29244125 TI - Discourse Features Among Providers, Patients, and Companions and Their Effect on Outcomes of Dementia Diagnosis Disclosure. AB - Objectives: Receiving a diagnosis of dementia has major implications. Although protocols for disclosing difficult information have been developed for other health conditions, no such evidence-based method exists for dementia. As a step toward that goal, this study analyzed the discourse within dementia diagnosis disclosure sessions to identify conversational features associated with psychological outcomes. Method: The Roter Interaction Analysis System (RIAS) was used to code the discourse among patients, their companions, and providers during 84 dementia diagnosis disclosure sessions following an initial evaluation at an Alzheimer's Disease Research Center. Results: Providers dominated the conversation in terms of overall time spent talking. With more severe dementia, patients spoke less and companions spoke more. Provider-positive rapport building was associated with lower patient depression and anxiety following the disclosure session. Patient-positive rapport building was associated with higher companion anxiety, but only when the patient was not suspected to have dementia. No associations were found between other types of discourse and patient or companion psychological outcomes. Discussion: A relatively small amount of positive rapport building by providers can lead to reduced distress following dementia disclosure. Dementia disclosure best practices should emphasize patient-centered communication techniques in order to minimize psychological distress following diagnosis. PMID- 29244127 TI - Comparison of Efficiency of Purification (from Human Plasma) of a Nerve Agent Adduct of Butyrylcholinesterase Between the Affinity Gel Method and Immunomagnetic Separation. AB - O-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate (VX) is a highly toxic chemical warfare agent because it inhibits cholinesterase (ChE) activity in the nervous system. Inhibition of butyrylcholinesterase (BChE) activity by VX is due to formation of a phosphorylated BChE adduct; this adduct in human plasma can serve as a biomarker of exposure to nerve agents. We compared purification efficiency between the procainamide affinity gel method and immunomagnetic separation (IMS) for the nerve agent adduct of BChE in plasma and then optimized the sample preparation by purifying BChE to measure biomarkers of human exposure to organophosphorus nerve agents. The purification efficiency of IMS was 5-fold greater than that of the procainamide affinity gel method because the antibody conjugate with protein G magnetic beads ensured highly selective capture and high recovery of VX-inhibited BChE from plasma. Protein isolation and extraction of the adduct of VX-inhibited BChE from plasma were made more specific by IMS. A 50 uL of the IMS solution was enough to bind VX-inhibited BChE in up to 0.5 mL of plasma. Nonetheless, the IMS method has a limitation in terms of reutilization of the complexes antibody-magnetic beads. We expect that this approach can be used to quantify other types of organophosphorus adducts in human plasma, thus serving as a possible general assay for biomarkers of exposure to nerve agents. PMID- 29244128 TI - Transperisosteal "Inside Out" Occipital Artery Harvest and Occipital Artery Anterior Inferior Cerebellar Artery Bypass for Vertebrobasilar Ischemia: 3 Dimensional Operative Video. PMID- 29244126 TI - Silent Cerebral Small-Vessel Disease Is Twice as Prevalent in Middle-Aged Individuals With Well-Controlled, Combination Antiretroviral Therapy-Treated Human Immunodeficiency Virus (HIV) Than in HIV-Uninfected Individuals. AB - Background: Silent cerebral small-vessel disease (CSVD) is defined as white matter hyperintensities, silent brain infarction, or microbleeds. CSVD is responsible for future vascular events, cognitive impairment, frailty, and shorter survival. CSVD prevalence among middle-aged people living with well controlled human immunodeficiency virus (HIV) infection (PLHIV) is unknown. Methods: The French National Agency for Research on AIDS and Viral Hepatitis (ANRS) EP51 Microvascular Brain Retina and Kidney Study (MicroBREAK; NCT02082574) is a cross-sectional study with prospective enrollment of treated PLHIV, >=50 years old with viral load controlled for >=12 months, and frequency age- and sex matched HIV-uninfected controls (HUCs). It was designed to estimate CSVD prevalence on 3T magnetic resonance imaging (3D fluid-attenuated inversion recovery, transversal T2-weighted gradient-echo imaging and diffusion-weighted imaging), as diagnosed by 2 blinded neuroradiologists. A logistic regression model was used to assess the impact of HIV on CSVD after adjustment for traditional risk factors. Results: Between June 2013 and May 2016, 456 PLHIV and 154 HUCs were recruited. Median age was 56 and 58 years, respectively (P = .001), among whom 84.9% and 77.3%, respectively (P = .030), were men. CSVD was detected in 51.5% of PLHIV and 36.4% of HUCs with an adjusted odds ratio (aOR) of 2.3. The HIV impact differed according to age, with aOR values of 5.3, 3.7, and 1.0 for age groups <54, 54-60, and >60 years, respectively (P = .022). Older age, hypertension, and lower CD4 cell count nadir were independently associated with a higher risk of CSVD among PLHIV. Conclusions: HIV is an independent risk factor for CSVD. Despite sustained immunovirological control, the CSVD prevalence was twice as high among middle-aged PLHIV than HUCs. Clinical Trials Registration: NCT02082574. PMID- 29244129 TI - Dolutegravir reshapes the genetic diversity of HIV-1 reservoirs. AB - Objectives: Better understanding of the dynamics of HIV reservoirs under ART is a critical step to achieve a functional HIV cure. Our objective was to assess the genetic diversity of archived HIV-1 DNA over 48 weeks in blood cells of individuals starting treatment with a dolutegravir-based regimen. Methods: Eighty blood samples were prospectively and longitudinally collected from 20 individuals (NCT02557997) including: acutely (n = 5) and chronically (n = 5) infected treatment-naive individuals, as well as treatment-experienced individuals who switched to a dolutegravir-based regimen and were either virologically suppressed (n = 5) or had experienced treatment failure (n = 5). The integrase and V3 loop regions of HIV-1 DNA isolated from PBMCs were analysed by pyrosequencing at baseline and weeks 4, 24 and 48. HIV-1 genetic diversity was calculated using Shannon entropy. Results: All individuals achieved or maintained viral suppression throughout the study. A low and stable genetic diversity of archived HIV quasispecies was observed in individuals starting treatment during acute infection. A dramatic reduction of the genetic diversity was observed at week 4 of treatment in the other individuals. In these patients and despite virological suppression, a recovery of the genetic diversity of the reservoirs was observed up to 48 weeks. Viral variants bearing dolutegravir resistance-associated substitutions at integrase position 50, 124, 230 or 263 were detected in five individuals (n = 5/20, 25%) from all groups except those who were ART-failing at baseline. None of these substitutions led to virological failure. Conclusions: These data demonstrate that the genetic diversity of the HIV-1 reservoir is reshaped following the initiation of a dolutegravir-based regimen and strongly suggest that HIV-1 can continue to replicate despite successful treatment. PMID- 29244130 TI - Effects of neonicotinoid imidacloprid exposure on bumble bee (Hymenoptera: Apidae) queen survival and nest initiation. AB - Neonicotinoids are highly toxic to insects and may systemically translocate to nectar and pollen of plants where foraging bees may become exposed. Exposure to neonicotinoids can induce detrimental sublethal effects on individual and colonies of bees and may have long-term impacts, such as impaired foraging, reduced longevity, and reduced brood care or production. Less well-studied are the potential effects on queen bumble bees that may become exposed while foraging in the spring during colony initiation. This study assessed queen survival and nest founding in caged bumble bees [Bombus impatiens (Cresson) (Hymenoptera: Apidae)] after chronic (18-d) dietary exposure of imidacloprid in syrup (1, 5, 10, and 25 ppb) and pollen (0.3, 1.7, 3.3, and 8.3 ppb), paired respectively. Here we show some mortality in queens exposed at all doses even as low as 1 ppb, and, compared with untreated queens, significantly reduced survival of treated queens at the two highest doses. Queens that survived initial imidacloprid exposure commenced nest initiation; however, they exhibited dose-dependent delay in egg-laying and emergence of worker brood. Furthermore, imidacloprid treatment affected other parameters such as nest and queen weight. This study is the first to show direct impacts of imidacloprid at field-relevant levels on individual B. impatiens queen survival and nest founding, indicating that bumble bee queens are particularly sensitive to neonicotinoids when directly exposed. This study also helps focus pesticide risk mitigation efforts and highlights the importance of reducing exposure rates in the early spring when bumble bee queens, and other wild bees are foraging and initiating nests. PMID- 29244133 TI - Contact Aspiration or Stent Retrieval Thrombectomy for Acute Ischemic Stroke due to Large Vessel Occlusion. PMID- 29244132 TI - Mitochondrial Transfer Into the Cerebrospinal Fluid in the Setting of Subarachnoid Hemorrhage. PMID- 29244134 TI - Consensus Guidelines for the Treatment of Osteoporosis. PMID- 29244135 TI - Neutrophil-Guided Drug Delivery for Targeting Residual Glioma Cells. PMID- 29244131 TI - Reporting antimicrobial susceptibilities and resistance phenotypes in Acinetobacter spp: a nationwide proficiency study. AB - Objectives: To evaluate the proficiency of Spanish microbiology laboratories with respect to the antimicrobial susceptibility testing (AST) of Acinetobacter spp. Methods: Eight Acinetobacter spp. with different resistance mechanisms were sent to 48 Spanish centres which were asked to report: (i) the AST system used; (ii) MICs; (iii) breakpoints used (CLSI versus EUCAST); (iv) clinical category; and (v) resistance mechanisms inferred. Minor, major and very major errors (mE, ME and VME, respectively) were determined. Results: The greatest percentages of discrepancies were: (i) by AST method: 18.5% Etest, 14.3% Vitek 2 and Sensititre; (ii) by breakpoints: 20.5% (CLSI) and 10.8% (EUCAST); and (iii) by antimicrobial agent: ampicillin/sulbactam (56.2% CLSI), minocycline (40.7% CLSI), tobramycin (38.7% CLSI, 16.8% EUCAST), imipenem (27.8% CLSI, 30.0% EUCAST) and meropenem (25.4% CLSI, 20.8% EUCAST). Categorical error rates: (i) by AST method ranged from 30.0% (Phoenix) to 100% (Sensititre and disc diffusion) for mE, 0.0% (Etest, Sensititre, disc diffusion) to 40% (Phoenix) for ME, and 0.0% (Sensititre and disc diffusion) to 30% (Phoenix) for VME; (ii) by breakpoints: mE (80.1% CLSI, 58.4% EUCAST), ME (3.5% CLSI, 12.4% EUCAST) and VME (16.4% CLSI, 29.2% EUCAST); and (iii) by antimicrobial agent: mE (100% levofloxacin/CLSI, 100% levofloxacin and meropenem/EUCAST), ME (35.3% colistin/CLSI, 25.0% colistin/EUCAST) and VME (64.7% colistin/CLSI, 86.7% gentamicin/EUCAST). Conclusions: Clinical microbiology laboratories must improve their ability to determine antimicrobial susceptibilities of Acinetobacter spp. isolates. Higher discrepancies using CLSI when compared with EUCAST are mainly due to mE and to a much lesser extent to ME or VME. PMID- 29244136 TI - Order in Chaos: Understanding Intratumoral Heterogeneity in Gliomas by Tracking Tumor Cell Fate. PMID- 29244137 TI - Severe Traumatic Brain Injury. PMID- 29244139 TI - Anatomic Features of Paraclinoid Aneurysms: Computed Tomography Angiography Study of 144 Aneurysms in 136 Consecutive Patients. PMID- 29244138 TI - Long-Term Results of Responsive Neurostimulation in Different Seizure Onset Locations. PMID- 29244140 TI - The distress and benefit to bereaved family members of participating in a post bereavement survey. AB - Background: Few studies have simultaneously collected quantitative data regarding the positive and negative effects of participating in post-bereavement surveys. Methods: We conducted a cross-sectional postal questionnaire survey in October 2013. Potential participants were caregivers for family members who had died in four inpatient palliative care units, two home hospices, and a general hospital. We collected opinions regarding the distress and benefit of completing a post bereavement survey. After collecting data, we provided feedback to participating institutions in the form of study results and de-identified open-ended comments. Results: Of 692 potential participants, 596 were sent questionnaires; 393 returned questionnaires were valid and analyzed. Of the respondents, 62% reported being distressed by completing the questionnaire. Female participants and those who were mentally ill during the caregiving period reported more distress. However, 86% of respondents reported they found the questionnaire beneficial. Better quality of end-of-life care and respondent depression were associated with more benefit. Major benefits were: contributing to the development of end-of-life care as a family (63%); expressing gratitude to the hospital and medical staff (60%); and looking back and reflecting on the end-of-life period (40%). Feeling benefit was not correlated with feeling distressed (P = -0.02). Conclusion: In this large-scale study on the effects of post-bereavement surveys in Japan, many bereaved family members reported that completing the survey was beneficial. In addition to possibly having feelings of distress, post-bereavement surveys might also be beneficial to end-of-life care facilities. PMID- 29244141 TI - Telavancin for refractory MRSA bacteraemia in intermittent haemodialysis recipients. AB - Background: Patients with end-stage renal disease (ESRD) requiring intermittent haemodialysis (IHD) are at high risk of MRSA bacteraemia (MRSA-B) and often fail first-line therapy. The safety, effectiveness and optimal dosing of telavancin for MRSA-B in this patient population are unclear. Objectives: We aimed to describe clinical outcomes of telavancin in the treatment of refractory MRSA-B in patients with ESRD requiring IHD. Patients and methods: This was a retrospective study of hospitalized patients at two tertiary care academic medical centres with recurrent or persistent (>=3 days) MRSA-B treated with telavancin monotherapy. Outcomes included duration of MRSA-B (pre-telavancin versus post-telavancin) and microbiological failure (duration of MRSA-B >=3 days after initiation of telavancin). Results: Telavancin dosed 10 mg/kg three times weekly post-IHD or 10 mg/kg every 48 h resulted in microbiological cure in 7/8 (87.5%) refractory MRSA B cases. Telavancin monotherapy was associated with a significant reduction in median duration of bacteraemia [16 days pre-telavancin (IQR 8-19 days) versus 1 day post-telavancin (IQR 0-2 days); P = 0.018]. Telavancin was well tolerated by all patients and no adverse events were reported. Conclusions: Telavancin was very safe and highly effective in the treatment of refractory MRSA-B in a cohort of patients with ESRD requiring IHD. These data support the utility of telavancin in the armamentarium against refractory MRSA-B, particularly in the high-risk IHD dependent population. PMID- 29244142 TI - An autofluorescence-based method for the isolation of highly purified ventricular cardiomyocytes. AB - Aims: The aim of our study was to set up a simple and reliable isolation method of living ventricular cardiomyocytes (vCMs) for molecular and biological studies. Methods and results: A standard technique for the retrograde perfusion of an enzymatic solution was used to isolate cardiac cells from adult mouse heart. Fluorescence-activated cell sorting (FACS) on adult murine cardiac ventricle cells was performed, comparing the intrinsic autofluorescence in the FITC channel and the forward scatter (FSC) parameter in order to isolate highly fluorescent cells. The expression of cell-specific mRNAs was assessed with real-time PCR in cells sorted on the basis of their FITC and FSC characteristics. We identified two distinct subpopulations of cells harvested after retrograde perfusion of wild type heart: FITChigh/FSCdim and FITCdim/FSChigh. Immunophenotyping and mRNA analysis (qPCR and RNA sequencing) revealed that only FITChigh/FSCdim cells were highly enriched in CM markers. Genes with high expression in endothelial cells and fibroblasts were enriched in the FITCdim/FSChigh subpopulation. With the use of tdTomatofl/fl-alpha-myosin heavy chain MerCreMer+/-mouse heart, we found that tdTomato-positive vCMs were present in the FITChigh/FSCdim region but were only rare in the FITCdim/FSChigh fraction. Conclusion: We have developed a simple and reliable method for the isolation of highly purified vCMs from the adult murine myocardium, avoiding fixation and permeabilization steps. These isolated vCMs can be used in particular for detailed molecular studies, avoiding contamination with other myocardial cell types. PMID- 29244144 TI - Species Composition of Sand Flies (Diptera: Psychodidae) and Modeling the Spatial Distribution of Main Vectors of Cutaneous Leishmaniasis in Hormozgan Province, Southern Iran. AB - Cutaneous Leishmaniasis (CL) is one of the main neglected vector-borne diseases in the Middle East, including Iran. This study aimed to map the spatial distribution and species composition of sand flies in Hormozgan Province and to predict the best ecological niches for main CL vectors in this area. A database that included all earlier studies on sand flies in Hormozgan Province was established. Sand flies were also collected from some localities across the province. Prediction maps for main vectors were developed using MaxEnt model. A total of 27 sand fly species were reported from the study area. Phlebotomus papatasi Scopoli, Phlebotomus sergenti s.l. Parrot, Phlebotomus alexandri Sinton, Sergentomyia sintoni Pringle, Sergentomyia clydei Sinton, Sergentomyia tiberiadis Adler, and Sergentomyia baghdadis Adler (Diptera: Psychodidae) had the widest distribution range. The probability of their presence as the main vectors of CL was calculated to be 0.0003-0.9410 and 0.0031-0.8880 for P. papatasi and P. sergenti s.l., respectively. The best ecological niches for P. papatasi were found in the central south, southeast, and a narrow area in southwest, whereas central south to northern area had better niches for P. sergenti s.l. The endemic areas are in Bandar-e Jask, where transmission occurs, whereas in Bastak, the cases were imported from endemic foci of Fars province. In conclusion, proven and suspected vectors of CL and VL were recorded in this study. Due to the existence of endemic foci of CL, and favorite ecological niches for its vectors, there is potential risk of emerging CL in new areas. PMID- 29244145 TI - Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastoma. AB - Background: Diagnostic workflows for glioblastoma (GBM) patients increasingly include DNA sequencing-based analysis of a single tumor site following biopsy or resection. We hypothesized that sequencing of multiple sectors within a given tumor would provide a more comprehensive representation of the molecular landscape and potentially inform therapeutic strategies. Methods: Ten newly diagnosed, isocitrate dehydrogenase 1 (IDH1) wildtype GBM tumor samples were obtained from 2 (n = 9) or 4 (n = 1) spatially distinct tumor regions. Tumor and matched blood DNA samples underwent whole-exome sequencing. Results: Across all 10 tumors, 51% of mutations were clonal and 3% were subclonal and shared in different sectors, whereas 46% of mutations were subclonal and private. Two of the 10 tumors exhibited a regional hypermutator state despite being treatment naive, and remarkably, the high mutational load was predominantly limited to one sector in each tumor. Among the canonical cancer-associated genes, only telomerase reverse transcriptase (TERT) promoter mutations were observed in the founding clone in all tumors. Reconstruction of the clonal architecture in different sectors revealed regionally divergent evolution, and integration of data from 2 sectors increased the resolution of inferred clonal architecture in a given tumor. Predicted therapeutic mutations differed in presence and frequency between tumor regions. Similarly, different sectors exhibited significant divergence in the predicted neoantigen landscape. Conclusions: The substantial spatial heterogeneity observed in different GBM tumor sectors, especially in spatially restricted hypermutator cases, raises important caveats to our current dependence on single-sector molecular information to guide either targeted or immune-based treatments. PMID- 29244143 TI - Impact of Human Immunodeficiency Virus Type 1 Minority Variants on the Virus Response to a Rilpivirine-Based First-line Regimen. AB - Background: Minority resistant variants of human immunodeficiency virus type 1 (HIV-1) could influence the virological response to treatment based on nonnucleoside reverse transcriptase inhibitors (NNRTIs). Data on minority rilpivirine-resistant variants are scarce. This study used next-generation sequencing (NGS) to identify patients harboring minority resistant variants to nucleos(t)ide reverse transcriptase inhibitors and NNRTIs and to assess their influence on the virological response (VR). Methods: All the subjects, 541 HIV-1 infected patients started a first-line regimen containing rilpivirine. VR was defined as a HIV-1 RNA load <50 copies/mL at month 6 with continued suppression at month 12. NGS was performed at baseline (retrospectively) on the 454 GS-FLX platform (Roche). Results: NGS revealed resistance-associated mutations accounting for 1% to <5% of variants in 17.2% of samples, for 5%-20% in 5.7% of samples, and for >20% in 29% of samples. We identified 43 (8.8%) and 36 (7.4%) patients who harbored rilpivirine-resistant variants with a 1% sensitivity threshold according to the French National Agency for Research on AIDS and Viral Hepatitis and Stanford algorithms, respectively. The VR was 96.9% at month 12. Detection of minority rilpivirine resistant variants was not associated with virological failure (VF). Multivariate analysis indicated that VF at month 12 was associated with a CD4 count <250 cells/uL at baseline, a slower decrease in viral load at month 3, and rilpivirine resistance at baseline using the Stanford algorithm with a 20% threshold. Conclusions: Minority resistant variants had no impact on the VR of treatment-naive patients to a rilpivirine-based regimen. PMID- 29244147 TI - When not to perform isolated tricuspid valve surgery? Our long-term experience in tricuspid valve replacement in highly symptomatic patients. PMID- 29244146 TI - Ezh2 Mutations Found in the Weaver Overgrowth Syndrome Cause a Partial Loss of H3K27 Histone Methyltransferase Activity. AB - Context: Weaver syndrome is characterized by tall stature, advanced bone age, characteristic facies, and variable intellectual disability. It is caused by heterozygous mutations in enhancer of zeste homolog 2 (EZH2), a histone methyltransferase responsible for histone H3 at lysine 27 (H3K27) trimethylation. However, no early truncating mutations have been identified, suggesting that null mutations do not cause Weaver syndrome. Objective: To test alternative hypotheses that EZH2 variants found in Weaver syndrome cause either a gain of function or a partial loss of function. Design: Exome sequencing was performed in a boy with tall stature, advanced bone age, and mild dysmorphic features. Mutant or wild type EZH2 protein was expressed in mouse growth plate chondrocytes with or without endogenous EZH2, and enzymatic activity was measured. A mouse model was generated, and histone methylation was assessed in heterozygous and homozygous embryos. Results: A de novo missense EZH2 mutation [c.1876G>A (p.Val626Met)] was identified in the proband. When expressed in growth plate chondrocytes, the mutant protein showed decreased histone methyltransferase activity. A mouse model carrying this EZH2 mutation was generated using CRISPR/Cas9. Homozygotes showed perinatal lethality, whereas heterozygotes were viable, fertile, and showed mild overgrowth. Both homozygous and heterozygous embryos showed decreased H3K27 methylation. Conclusion: We generated a mouse model with the same mutation as our patient, found that it recapitulates the Weaver overgrowth phenotype, and demonstrated that EZH2 mutations found in Weaver syndrome cause a partial loss of function. PMID- 29244148 TI - Analysis of Major Components of Bacitracin, Colistin and Virginiamycin in Feed Using Matrix Solid-phase Dispersion Extraction by Liquid Chromatography electrospray Ionization Tandem Mass Spectrometry. AB - A quantitative LC-MS/MS method has been developed for simultaneous determination of bacitracin A, bacitracin B, colistin A, colistin B and virginiamycin M1 in feed. This rapid simple and effective extraction method was based on matrix solid phase dispersion. Qualitative and quantitative analyses were performed by LC-ESI MS/MS. CCbeta of polypeptide antibiotics upon the method ranged from 9.6 to 15.8 MUg kg-1 and 19.4 to 27.5 MUg kg-1, respectively. The limit of quantification of polypeptide antibiotics was 25 MUg kg-1 in feed samples. The recoveries of polypeptide antibiotics spiked in feed samples at a concentration range of 25-100 MUg kg-1 were found above 75.9-87.9% with relative standard deviations within days less than 15.7% and between days less than 20.6%. This rapid and reliable method can be used to efficiently separate, characterize and quantify the residues of polypeptide antibiotics in feed with advantages of simple pretreatment and environmental friendly. PMID- 29244149 TI - Subcutaneous tocilizumab in rheumatoid arthritis: findings from the common framework phase 4 study programme TOZURA conducted in 22 countries. AB - Objectives: The aim of this pooled analysis of the TOZURA study programme was to evaluate the efficacy and safety of subcutaneous tocilizumab (TCZ-SC) as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) in patients with moderate to severe RA who had an inadequate response to csDMARD or anti-TNF agent therapy or who were MTX naive. Methods: TOZURA is a multinational, open-label, single-arm, common-framework, phase 4 study programme (11 protocols, 22 countries). Patients received TCZ-SC 162 mg each week for ?24 weeks, administered at the investigator's discretion, as monotherapy or in combination with a csDMARD. Efficacy, safety and immunogenicity were evaluated; propensity score-based matching was used for between-group comparisons. Results: Of 1804 patients, 353 (19.6%) received monotherapy and 1451 (80.4%) received combination therapy. The 28-joint DAS using ESR (DAS28-ESR) in both groups decreased significantly from baseline to week 24 (mean change: monotherapy -3.40, combination therapy -3.46), with no significant difference between groups (P = 0.46). The proportion of patients who achieved DAS28-ESR or Clinical Disease Activity Index remission or ACR 20/50/70/90 responses was similar between groups. Overall, 13.9% of patients withdrew-6.2% for safety reasons and 1.6% for insufficient therapeutic response; 5.8% of patients experienced one or more serious adverse events [14.6/100 patient-years (PY)]; six deaths occurred (0.64/100 PY). Conclusion: In a common framework of 11 studies in 22 countries, this phase 4 study programme confirmed TCZ-SC's known efficacy and safety profile with comparable effects as monotherapy and in combination with csDMARDs. Trial registration: ClinicalTrials.gov (http://www.clinicaltrials.gov) NCT01941940, NCT01941095, NCT01951170, NCT01987479, NCT01988012, NCT01995201, NCT02001987, NCT02011334, NCT02031471, NCT02046603 and NCT02046616. PMID- 29244151 TI - Diffusion-weighted imaging detects early brain injury after hypothermic circulatory arrest in pigs. AB - OBJECTIVES: Cerebral injury is a complication of surgery with deep hypothermic circulatory arrest (DHCA). This study aimed to evaluate diffusion-weighted imaging (DWI) for the early detection of brain injury after DHCA in an animal model. METHODS: Twelve healthy, adult, male miniature pigs were randomly divided into the DHCA (to receive DHCA; n = 6) and the control (sham surgery under anaesthesia; n = 6) groups. All animals received DWI, T1-weighted imaging (T1WI) and T2WI the day before surgery, 7 h postoperatively and 24 h postoperatively. Histopathological evaluation of the brain tissues was performed in the DHCA group using the Fluoro-Jade C staining to detect neuronal degeneration, the Nissl staining to show neuronal morphology and the TUNEL assay for apoptosis. The Cohen's kappa coefficient was used to compare the results of DWI with those of the histopathological evaluation. RESULTS: All animals survived surgery. In the control group, no new focal brain lesions were detected by postoperative DWI, T1WI or T2WI. In the DHCA group, new focal brain lesions were detected as early as 7 h postoperatively by DWI but not T1WI or T2WI. All three imaging sequences revealed abnormalities 24 h after surgery. In sections from areas showing abnormalities on DWI, the Fluoro-Jade C staining detected neuronal degeneration, the Nissl staining showed morphological abnormalities and the TUNEL assay demonstrated apoptotic cells. The Cohen's kappa statistics showed agreement between DWI findings and the results of all 3 histopathological examinations (TUNEL: kappa = 0.553; Nissl: kappa = 0.652; Fluoro-Jade C: kappa = 0.778; all P < 0.001). CONCLUSIONS: DWI is superior to T1WI or T2WI for the early detection of neurological lesions after DHCA in pigs. PMID- 29244150 TI - Risk and prognostic factors for multiple primary carcinomas in patients with head and neck cancer. AB - Background: Unexpected multiple primary carcinomas (MPCs) that develop in patients with head and neck carcinomas complicate approaches to their management. We therefore investigated the clinical factors associated with survival outcomes after the treatment of MPCs. Methods: We performed a retrospective review of records of 1104 patients who underwent treatment for primary head and neck carcinoma at Hamamatsu University Hospital. We evaluated clinical staging, age, sex, smoking, alcohol consumption, the primary tumor site (particularly the involvement of the mucosal epithelial lining of the aerodigestive tract), and overall survival (OS) as determined by Kaplan-Meier analysis. Information on patients' survival status was obtained after a mean follow-up period of 43.8 months (range, 1-144 months). Results: Among 566 patients with mucosa-associated carcinoma arising in the epithelial lining, the 5- and 10-year OS rates (68.49% and 58.96%, respectively) were significantly shorter than those of patients with mucosa non-associated carcinoma (74.22%, and 66.76%, respectively) (log-rank P = 0.0219). Older age (P = 0.016) and male sex (P < 0.001) were likely independent risk factors for developing MPCs; smoking (P < 0.001) and alcohol consumption (P < 0.001) were also significant risk factors. Conclusion: Mucosa-associated carcinomas arising in the epithelial lining of the aerodigestive tract in the head and neck are a significant risk factor for developing MPC and are a poor prognostic factor. Careful follow-up and more frequent examinations of the aerodigestive tracts of these patients are recommended. PMID- 29244152 TI - Regulation of T cell proliferation with drug-responsive microRNA switches. AB - As molecular and cellular therapies advance in the clinic, the role of genetic regulation is becoming increasingly important for controlling therapeutic potency and safety. The emerging field of mammalian synthetic biology provides promising tools for the construction of regulatory platforms that can intervene with endogenous pathways and control cell behavior. Recent work has highlighted the development of synthetic biological systems that integrate sensing of molecular signals to regulated therapeutic function in various disease settings. However, the toxicity and limited dosing of currently available molecular inducers have largely inhibited translation to clinical settings. In this work, we developed synthetic microRNA-based genetic systems that are controlled by the pharmaceutical drug leucovorin, which is readily available and safe for prolonged administration in clinical settings. We designed microRNA switches to target endogenous cytokine receptor subunits (IL-2Rbeta and gammac) that mediate various signaling pathways in T cells. We demonstrate the function of these control systems by effectively regulating T cell proliferation with the drug input. Each control system produced unique functional responses, and combinatorial targeting of multiple receptor subunits exhibited greater repression of cell growth. This work highlights the potential use of drug-responsive genetic control systems to improve the management and safety of cellular therapeutics. PMID- 29244153 TI - Cohort Profile: The Hoorn Studies. PMID- 29244154 TI - Ventricular arrhythmia solved by surgical correction of pectus excavatum. AB - Pectus excavatum is generally considered a benign problem with a wide spectrum of impact in body image. Some articles had highlighted that this deformity can be associated with important clinical problems. We report a case of a 14-year-old boy with a severe pectus excavatum associated with palpitations who was diagnosed with polymorphic ventricular arrhythmia. The arrhythmia was resolved after minimally invasive surgical correction of the pectus excavatum. PMID- 29244155 TI - Differential RPA-1 and RAD-51 recruitment in vivo throughout the C. elegans germline, as revealed by laser microirradiation. AB - Studies of the repair pathways associated with DNA double strand breaks (DSBs) are numerous, and provide evidence for cell-cycle specific regulation of homologous recombination (HR) by the regulation of its associated proteins. Laser microirradiation is a well-established method to examine in vitro kinetics of repair and allows for live-imaging of DSB repair from the moment of induction. Here we apply this method to whole, live organisms, introducing an effective system to analyze exogenous, microirradiation-induced breaks in the Caenorhabditis elegans germline. Through this method we observed the sequential kinetics of the recruitment of ssDNA binding proteins RPA-1 and RAD-51 in vivo. We analyze these kinetics throughout different regions of the germline, and thus throughout a range of developmental stages of mitotic and meiotic nuclei. Our analysis demonstrates a largely conserved timing of recruitment of ssDNA binding proteins to DSBs throughout the germline, with a delay of RAD-51 recruitment at mid-pachytene nuclei. Microirradiated nuclei are viable and undergo a slow kinetics of resolution. We observe RPA-1 and RAD-51 colocalization for hours post microirradiation throughout the germline, suggesting that there are mixed RPA 1/RAD-51 filaments. Finally, through live imaging analysis we observed RAD-51 foci movement with low frequency of coalescence. PMID- 29244156 TI - Percutaneous increase of mitral leaflet coaptation length after mitral valve repair: results from a preclinical study. AB - OBJECTIVES: The failure of mitral repairs can be the result of inadequate leaflet coaptation length (CL< 8 mm at the A2-P2 level). A new annuloplasty ring conceived by the authors enables post-surgical CL increase using percutaneous balloon catheter technology. We conducted preclinical studies to assess the in vivo feasibility of the procedure and the safety of the postimplant deformable mitral ring. METHODS: The new annuloplasty ring allows the percutaneous and progressive displacement of each of the 3 anatomical regions of the posterior mitral annulus towards the anterior. Displacement is permanent and induced by an angioplasty balloon catheter inserted in a line connecting the ring to the subcutaneous tissue. Under general anaesthesia and cardiopulmonary bypass, healthy adult sheep had mitral annuloplasty. The device was implanted using the interrupted suture technique. The connection line exited the left atrium and reached the skin. Epicardial echocardiography allowed assessment of valve competence, leaflet CL, the mitral valve area and the mitral valve gradient. The mandrel was removed, and the dedicated catheter balloon was inserted into the connection line. The balloon was inflated in the P2 position under fluoroscopic control, and epicardial echocardiography was used to assess the functional parameters of the valve. One month later, the balloon was inserted again through the connection line; the P1 and P3 areas were deformed to increase CL. Valve parameters were measured again using transthoracic echocardiography. After 6 months, transthoracic echocardiography was used to assess the functional parameters of the valve. The sheep were sacrificed and autopsied. RESULTS: Ten adult sheep survived the procedure. A 30-mm ring was implanted in all the sheep, and the 6-month follow-up was uneventful for all of them. The CL increased by 100% (4.2 +/- 2 mm-8.5 +/- 2 mm, P < 0.001); the transmitral gradient increased from 2 +/- 0.5 mmHg to 4 +/- 0.5 mmHg (P < 0.001) and the effective orifice area decreased from 4.5 +/- 0.6 cm2 to 3.5 +/- 0.6 cm2 (30% reduction, P < 0.001). CONCLUSIONS: The device safely enabled a significant improvement of leaflet CL after mitral annuloplasty with an angioplasty-like technique, and the improvement was stable over time. The reshaping of the mitral annulus provided by this technology should benefit all patients having mitral repairs. The future of mitral regurgitation treatment is towards surgical correction followed by late, iterative, percutaneous adjustments of mitral leaflets coaptation. PMID- 29244157 TI - Evaluation of Lambda-Cyhalothrin and Pyriproxyfen Barrier Treatments for Aedes albopictus (Diptera: Culicidae) Management in Urbanized Areas of New Jersey. AB - Mosquito control programs in the United States are still searching for best management practices to control the Asian tiger mosquito, Aedes albopictus (Skuse; Diptera: Culicidae). Most intervention methods for this species are either labor intensive (e.g., source reduction) or short-term (e.g., ultra-low volume adulticiding). We investigated the effectiveness of barrier spray pesticide applications within urban and suburban residential yards in New Jersey as a control strategy using a before-after-control-impact (BACI) approach. Applications of Demand CSR pyrethroid (9.7% AI lambda-cyhalothrin) only or combined Demand CSR and Archer IGR insect growth regulator (1.3% AI pyriproxyfen) applications resulted in significant and similar decreases in adult mosquito abundance post-treatment ranging from 78 to 74% respectively, compared with the untreated control. Both insecticides exceeded the 70% reduction threshold considered as effective for Ae. albopictus control for 2 to 4 wk. However, applications of Archer IGR alone did not reduce adult mosquito abundance. The field study results were supported by laboratory no-choice bioassays using treated leaf foliage. Our study is the first data driven evidence of the residual efficacy of barrier pesticide applications in New Jersey with lambda-cyhalothrin that provided significant reductions in adult Ae. albopictus populations for an extended duration. PMID- 29244158 TI - ZNF830 mediates cancer chemoresistance through promoting homologous-recombination repair. AB - Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites. Moreover, the recruitment of ZNF830 at DNA damage sites is dependent on its phosphorylation at serine 362 by ATR. ZNF830 directly and preferentially binds to double-strand DNA with its 3' or 5' overhang through the Zinc finger (Znf) domain, facilitating HR repair and maintaining genome stability. Thus, our study identified a novel function of ZNF830 as a HR repair regulator in DNA end resection, conferring the chemoresistance to genotoxic therapy for cancers those that overexpress ZNF830. PMID- 29244159 TI - Pre-clinical model of severe glutathione peroxidase-3 deficiency and chronic kidney disease results in coronary artery thrombosis and depressed left ventricular function. AB - Background: Chronic kidney disease (CKD) patients have deficient levels of glutathione peroxidase-3 (GPx3). We hypothesized that GPx3 deficiency may lead to cardiovascular disease in the presence of chronic kidney disease due to an accumulation of reactive oxygen species and decreased microvascular perfusion of the myocardium. Methods. To isolate the exclusive effect of GPx3 deficiency in kidney disease-induced cardiac disease, we studied the GPx3 knockout mouse strain (GPx3-/-) in the setting of surgery-induced CKD. Results. Ribonucleic acid (RNA) microarray screening of non-stimulated GPx3-/- heart tissue show increased expression of genes associated with cardiomyopathy including myh7, plac9, serpine1 and cd74 compared with wild-type (WT) controls. GPx3-/- mice underwent surgically induced renal mass reduction to generate a model of CKD. GPx3-/- + CKD mice underwent echocardiography 4 weeks after injury. Fractional shortening (FS) was decreased to 32.9 +/- 5.8% in GPx3-/- + CKD compared to 62.0% +/- 10.3 in WT + CKD (P < 0.001). Platelet aggregates were increased in the myocardium of GPx3-/ + CKD. Asymmetric dimethylarginine (ADMA) levels were increased in both GPx3-/- + CKD and WT+ CKD. ADMA stimulated spontaneous platelet aggregation more quickly in washed platelets from GPx3-/-. In vitro platelet aggregation was enhanced in samples from GPx3-/- + CKD. Platelet aggregation in GPx3-/- + CKD samples was mitigated after in vivo administration of ebselen, a glutathione peroxidase mimetic. FS improved in GPx3-/- + CKD mice after ebselen treatment. Conclusion: These results suggest GPx3 deficiency is a substantive contributing factor to the development of kidney disease-induced cardiac disease. PMID- 29244161 TI - The impact of coronary anomalies on the outcome in aortic valve surgery: comparison of bicuspid aortic valve versus tricuspid aortic valve morphotype. AB - OBJECTIVES: The association of anomalous anatomy of coronary arteries and bicuspid aortic valve (BAV) has been sporadically reported. Our aim was to evaluate the prevalence of coronary anomalies between BAV and tricuspid aortic valve (TAV) and to analyse their impact on major adverse cardiac events during and after aortic valve surgery. METHODS: A total of 1099 consecutive patients who received preoperative coronary evaluation and elective aortic valve replacement/repair between January 2013 and July 2016 at our institution were involved. Based on surgical inspection at the open-heart surgery, a total of 345 (32%) patients were diagnosed with BAV, whereas the remaining 754 (68%) patients had TAV. Coronary anatomy was evaluated by preoperative coronary angiography (n = 1084) or multislice computed tomography (n = 15). The primary end-point was the prevalence of coronary anomalies in BAV versus TAV cohort. Secondary end-points included postoperative cardiac ischaemia markers, postoperative coronary artery imaging or interventions and hospital mortality. RESULTS: A total of 46 (4%) coronary anomalies were detected and were significantly more frequent in the BAV group (7% vs 3%, P = 0.001). Postoperative markers of myocardial injury (creatine kinase/creatine kinase-MB and troponin) were increased and the need for postoperative coronary angiography/percutaneous coronary intervention was significantly higher in patients with coronary anomalies (12% vs 1%, P < 0.001). CONCLUSIONS: Our study revealed significantly increased prevalence of coronary anomalies in BAV patients when compared with their tricuspid counterparts. Patients with diagnosed coronary anomalies had more postoperative ischaemic cardiac events that resulted in increased morbidity of this cohort. PMID- 29244160 TI - Interplay between the catabolite repression control protein Crc, Hfq and RNA in Hfq-dependent translational regulation in Pseudomonas aeruginosa. AB - In Pseudomonas aeruginosa the RNA chaperone Hfq and the catabolite repression control protein (Crc) act as post-transcriptional regulators during carbon catabolite repression (CCR). In this regard Crc is required for full-fledged Hfq mediated translational repression of catabolic genes. RNAseq based transcriptome analyses revealed a significant overlap between the Crc and Hfq regulons, which in conjunction with genetic data supported a concerted action of both proteins. Biochemical and biophysical approaches further suggest that Crc and Hfq form an assembly in the presence of RNAs containing A-rich motifs, and that Crc interacts with both, Hfq and RNA. Through these interactions, Crc enhances the stability of Hfq/Crc/RNA complexes, which can explain its facilitating role in Hfq-mediated translational repression. Hence, these studies revealed for the first time insights into how an interacting protein can modulate Hfq function. Moreover, Crc is shown to interfere with binding of a regulatory RNA to Hfq, which bears implications for riboregulation. These results are discussed in terms of a working model, wherein Crc prioritizes the function of Hfq toward utilization of favored carbon sources. PMID- 29244162 TI - Efficacy and safety of biologics targeting interleukin-6, -12/23 and -17 pathways for peripheral psoriatic arthritis: a network meta-analysis. AB - Objective: To investigate the comparative efficacy, safety and tolerability of IL 6, IL-12/23 and IL-17 inhibitors for patients with active PsA. Methods: Randomized controlled trials evaluating the efficacy, safety and tolerability of IL-6, IL-12/23 and IL-17 inhibitors were identified by a comprehensive systematic literature review. Pairwise meta-analyses and Bayesian network meta-analyses using the random effects model were performed to estimate pooled odds ratios (ORs) and 95% credible intervals of attaining a 20% or 50% improvement in ACR criteria (ACR20 and ACR50, respectively) across trials. Results: Six trials were identified that included 2411 participants and 11 treatments. Pairwise meta analysis showed that secukinumab, ustekinumab and ixekizumab demonstrated superior efficacy over placebo in achieving an ACR20 and ACR50 response. However, ixekizumab has a higher incidence of adverse events (AEs) than placebo. In contrast, ustekinumab has a higher tolerability (less likely to be discontinued due to AEs) than placebo. Network meta-analysis showed that secukinumab (300 mg monthly) had the highest efficacy in achieving ACR20 and ACR50, whereas clazakizumab (200 mg monthly), ustekinumab (45 mg 12 weekly) and secukinumab (150 mg monthly) had the lowest probability of having AEs, serious AEs and intolerability, respectively. Considering the overall risk-benefit profile, secukinumab (150 mg monthly) may offer an optimal balance for peripheral PsA patients. Conclusion: Secukinumab may be the safest and most efficacious short term treatment for peripheral PsA among all the new biologics targeting IL-6, IL 12/23 and IL-17 pathways. PMID- 29244163 TI - Regulation of chromosome segregation in oocytes and the cellular basis for female meiotic errors. AB - BACKGROUND: Meiotic chromosome segregation in human oocytes is notoriously error prone, especially with ageing. Such errors markedly reduce the reproductive chances of increasing numbers of women embarking on pregnancy later in life. However, understanding the basis for these errors is hampered by limited access to human oocytes. OBJECTIVE AND RATIONALE: Important new discoveries have arisen from molecular analyses of human female recombination and aneuploidy along with high-resolution analyses of human oocyte maturation and mouse models. Here, we review these findings to provide a contemporary picture of the key players choreographing chromosome segregation in mammalian oocytes and the cellular basis for errors. SEARCH METHODS: A search of PubMed was conducted using keywords including meiosis, oocytes, recombination, cohesion, cohesin complex, chromosome segregation, kinetochores, spindle, aneuploidy, meiotic cell cycle, spindle assembly checkpoint, anaphase-promoting complex, DNA damage, telomeres, mitochondria, female ageing and female fertility. We extracted papers focusing on mouse and human oocytes that best aligned with the themes of this review and that reported transformative and novel discoveries. OUTCOMES: Meiosis incorporates two sequential rounds of chromosome segregation executed by a spindle whose component microtubules bind chromosomes via kinetochores. Cohesion mediated by the cohesin complex holds chromosomes together and should be resolved at the appropriate time, in a specific step-wise manner and in conjunction with meiotically programmed kinetochore behaviour. In women, the stage is set for meiotic error even before birth when female-specific crossover maturation inefficiency leads to the formation of at-risk recombination patterns. In adult life, multiple co conspiring factors interact with at-risk crossovers to increase the likelihood of mis-segregation. Available evidence support that these factors include, but are not limited to, cohesion deterioration, uncoordinated sister kinetochore behaviour, erroneous microtubule attachments, spindle instability and structural chromosomal defects that impact centromeres and telomeres. Data from mice indicate that cohesin and centromere-specific histones are long-lived proteins in oocytes. Since these proteins are pivotal for chromosome segregation, but lack any obvious renewal pathway, their deterioration with age provides an appealing explanation for at least some of the problems in older oocytes. WIDER IMPLICATIONS: Research in the mouse model has identified a number of candidate genes and pathways that are important for chromosome segregation in this species. However, many of these have not yet been investigated in human oocytes so it is uncertain at this stage to what extent they apply to women. The challenge for the future involves applying emerging knowledge of female meiotic molecular regulation towards improving clinical fertility management. PMID- 29244164 TI - Cortical and Subcortical Brain Changes in Children and Adolescents With Narcolepsy Type 1. AB - Study Objectives: Neuroimaging studies on structural alterations in patients with type 1 narcolepsy (NT1) have shown controversial and heterogeneous results. The purpose of this study was to investigate microstructural brain changes in patients with NT1 close to disease onset. Methods: We examined cortical and subcortical grey matter volumes in 20 drug-naive children and adolescents with NT1 compared with 19 healthy controls; whole-brain voxel-based morphometry, shape and volumetric analyses, and cortical thickness analysis were used. Results: When compared with controls, NT1 patients revealed reduced grey matter volume in cerebellum and medial prefrontal cortex and increased volume in right hippocampus. Cortical thickness in frontal lobe was also reduced in patients compared with controls. Increased volume and shape expansion in right hippocampus in patients compared with controls were also confirmed by both vertex and volumetric analyses. Conclusions: Our results indicate that subtle structural brain changes involving attentional and limbic circuits are detectable in children and adolescents with NT1. Cerebellum involvement might be related to the childhood NT1 clinical phenotype. PMID- 29244165 TI - Processing conditions and endpoint temperature effects on development of pink defect without pink-generating ligands in cooked ground turkey breast. AB - This study was conducted to characterize the pink pigments associated with storing presalted (2%) and ground turkey breast trim at different processing conditions. Four treatments included: treatment (no NaCl, stored for 7 d before being cooked), treatment 2 (NaCl added and stored for 7 d before being cooked), treatment 3 (NaCl added and immediately cooked), and treatment 4 (stored for 7 d before NaCl added and cooked). All treatments were cooked to 4 endpoint temperatures (71.1, 73.9, 76.7, and 79.4 degrees C). Processing conditions affected the pink defect in cooked ground turkey breast. Undenatured myoglobin in salted meat (treatment 2, 3, 4) still remained (17 to 19%) after cooking. Salted and stored ground turkey (treatment 2) produced a cooked product with the most reducing condition (lowest oxidation-reduction potential, ORP) and one of the most red coloration (CIE a* values). Final internal temperature had limited effects on pigment properties. ORP was similar across cooking temperatures but CIE a* values decreased with temperature. Even at 79.4 degrees C, 15% undenatured myoglobin remained. Cooking yield decreased with temperature as expected (92.8 to 89.5%). Results indicate that to limit the degree of the pink color development processors should avoid storage of ground turkey, particularly when mixed with salt, as it favors the formation of nicotinamide-denatured globin hemochrome. PMID- 29244166 TI - CALCULATIONS OF SHUTDOWN DOSE RATE FOR THE TPR SPECTROMETER OF THE HIGH RESOLUTION NEUTRON SPECTROMETER FOR ITER. AB - This work presents results of the calculations performed in order to predict the neutron-induced activity in structural materials that are considered to be using at the TPR spectrometer-one of the detection system of the High-Resolution Neutron Spectrometer for ITER. An attempt has been made to estimate the shutdown dose rates in a Cuboid #1 and to check if they satisfy ICRP regulatory requirements for occupational exposure to radiation and ITER nuclear safety regulations for areas with personal access. The results were obtained by the MCNP and FISPACT-II calculations. PMID- 29244167 TI - Tracheal surgery in children: outcome of a 12-year survey. AB - OBJECTIVES: Despite the fact that team management has improved the results in recent years, perioperative deaths and complications remain high in paediatric tracheal surgery. We reviewed our institutional experience by comparing our results with those in the literature. METHODS: Between 2005 and 2017, 30 children underwent surgery for tracheal disease. Fifteen were boys and fifteen were girls (50% vs 50%). The median age at operation was 7 months (15 days-9.6 years), and the median weight was 5.2 kg (2.8-34 kg). Congenital tracheal stenosis was diagnosed in 25 children (83.3%), and 5 (16.7%) had acquired lesions. The mean internal diameter in congenital tracheal stenosis was 1.5 mm, with complete tracheal rings present in all patients. Associated malformations were bronchopulmonary in 11 cases (36.7%) and cardiovascular in 16 (53.3%). RESULTS: No in-hospital deaths occurred in our data set. Overall mortality was 4 of 30 cases (13.3%). Twenty-four endoscopic reinterventions were required in 19 children (63%) and consisted of stent positioning in 13 (43.3%), balloon dilatation in 5 (16.7%), granulation removal in 4 (13.3%) and tracheostomy in 2 (6.7%). Of the survivors (26 of 30, 86.7%), 11 children (42.3%) did not require further examination on adequate tracheal diameter for age and absence of symptoms after a median follow-up period of 3.5 years. CONCLUSIONS: The result of paediatric tracheal surgery depends on several factors. The number of cases treated at a particular centre is an important one, but our experience, although limited, can be compared with that at centres with a higher volume of cases. We emphasize the need for applying a multidisciplinary approach to master the surgical command of different reconstructive tracheal procedures, to manage associated defects, particularly cardiovascular defects, and to manage complications under endoscopic guidance. These can be considered the mainstays of building a successful tracheal programme. PMID- 29244168 TI - Factors to consider in the introduction of huddles on clinical wards: perceptions of staff on the SAFE programme. AB - Objectives: To explore paediatric hospital staff members' perceptions of the emerging benefits and challenges of the huddle, a new safety improvement initiative, as well as the barriers and facilitators to its implementation. Design: A qualitative study was conducted using semi-structured interviews to explore staff perspectives and experiences. Setting: Situation Awareness For Everyone (SAFE), a safety improvement programme, was implemented on a sample of National Health Service (NHS) paediatric wards from September 2014 to June 2016. Previously untested in England, the huddle was a central component of the programme. Participants: Semi-structured interviews were conducted with 76 staff members on four wards ~4 months after the start of the programme. Results: A thematic analysis showed that staff perceived the huddle as helping to increase their awareness of important issues, improve communication, facilitate teamwork, and encourage a culture of increased efficiency, anticipation and planning on the ward. Challenges of the huddle included added pressure on staff time and workload, and the potential for junior nurses to be excluded from involvement, thus perhaps inadvertently reinforcing medical hierarchies. Staff also identified several barriers and facilitators to the huddle process, including the importance of senior nursing and medical staff leadership and managing staff time and capacity issues. Conclusions: The findings point towards the potential efficacy of the huddle as a way of improving hospital staff members' working environments and clinical practice, with important implications for other sites seeking to implement such safety improvement initiatives. PMID- 29244169 TI - Circular dichroism spectroscopic study on structural alterations of histones induced by post-translational modifications in DNA damage responses: lysine-9 methylation of H3. AB - We report the global structural alterations in histone H3 proteins induced by lysine-9 mono-, di- and trimethylation, which are part of the critical post translational modifications for DNA damage responses, identified using synchrotron radiation circular dichroism (CD) spectroscopy. Compared with unmodified H3, mono- and dimethylation increases the number of alpha-helices and decreases the numbers of beta-strands, while trimethylation decreases the alpha helix content and increases the beta-strand content. Comparison of the secondary structure contents of these histone H3 proteins suggests that the methylation induced structural alterations occur at residues not only close to but also distant from the methylated sites. Such global structural alterations may regulate the interactions of methylated histones with other molecules, such as histone-binding proteins in DNA damage repair processes. PMID- 29244170 TI - Sleep deprivation triggers cognitive control impairments in task-goal switching. AB - Study objectives: This study investigates the impact of sleep deprivation (SD) on task-goal switching, a key component of cognitive flexibility. Methods: Task-goal switching performance was tested after one night of regular sleep (n = 17 participants) or of total SD (n = 18). To understand the relationships between task-switching performance and other cognitive processes following SD, participants were tested for other key attentional (alertness and vigilance) and executive (inhibition and working memory) functions. Spontaneous eye blink rate (EBR) was also measured as an indirect marker of striatal dopaminergic function. Results: SD negatively impacts task-goal switching as well as attentional and inhibition measures, but not working memory. Changes in task-goal switching performance were not significantly correlated with changes in objective and subjective markers of fatigue and sleepiness, response inhibition, or spontaneous EBR. Conclusions: Altogether, our results show differentiated effects of SD on key executive functions such as working memory, inhibition and task-goal switching. PMID- 29244172 TI - Human in vitro spermatogenesis from pluripotent stem cells: in need of a stepwise differentiation protocol? AB - Recently, complete in vitro generation of male gametes starting from pluripotent stem cells was obtained in a mouse model with live offspring as a result. This breakthrough was probably due to the use of a stepwise differentiation protocol taking the tightly regulated in vivo situation into account. As shown previously, factors of the TGFbeta superfamily, metabolites of vitamin A, growth hormones, sex steroids and, most importantly, somatic cell support are major regulators of the development, survival, proliferation and differentiation of male gametes. However, up till now, all differentiation protocols starting from human pluripotent stem cells only focused on one or two of these substantive factors, not taking any timeframe into account, leading to promising but unsatisfying results with low efficiency. Therefore, progress might be achieved by including a stepwise differentiation protocol, including all proven contributing regulators, and therefore mimicking more closely human in vivo spermatogenesis and its temporo-spatial organization. In this review, the indispensable regulators of in vivo spermatogenesis and the outcomes of related human in vitro studies are discussed with the aim of unravelling the most successful combinations of medium factors to be used in future differentiation protocols. PMID- 29244173 TI - Magnitude of Clinical Benefit of Cancer Drugs Approved by the US Food and Drug Administration. AB - Background: It is uncertain whether drugs approved by the US Food and Drug Administration (FDA) have clinically meaningful benefit as determined by validated scales such as the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods: We searched the Drugs@FDA website for applications of anticancer drugs from January 2006 to December 2016. Study characteristics, outcomes, and regulatory pathways were collected from drug labels and reports of registration trials. For randomized controlled trials (RCTs), ESMO-MCBS grades were applied. Meaningful benefit was defined as a grade of A or B for (neo)adjuvant intent and 4 or 5 for palliative intent. All statistical tests were two-sided. Results: We identified 63 individual drugs for 118 indications. These were supported by 135 studies, among which were 105 RCTs for which ESMO-MCBS could be applied. Only 46 (43.8%) met the ESMO-MCBS meaningful benefit threshold (100% of (neo)adjuvant trials and 38.8% of palliative trials). In palliative therapy trials, meaningful ESMO-MCBS grades were associated with phase III trials (compared with phase II; odds ratio [OR] = 38.45, 95% confidence interval [CI] = 3.27 to 452.00, P = .004), those with overall survival as their primary end point (compared with intermediate end points; OR = 8.28, 95% CI = 2.49 to 27.50, P = .001) and trials of targeted drugs with companion diagnostics (OR = 11.62, 95% CI = 2.95 to 45.78, P < .001). Over time, there has been an increase in the number of trials meeting the ESMO-MCBS threshold (Ptrend = .04). There were insufficient (neo)adjuvant studies to perform statistical analysis. Conclusions: The number of trials meeting the ESMO MCBS threshold for clinical benefit has improved over time. However, fewer than half of RCTs supporting FDA approval meet the threshold for clinically meaningful benefit. PMID- 29244174 TI - The Attractiveness of the Gravid Aedes Trap to Dengue Vectors in Fiji. AB - The Gravid Aedes Trap (GAT) is a passive trap that relies on visual and olfactory cues to lure and capture gravid mosquitoes. The GAT was designed as a dengue vector surveillance tool for use in conditions where power sources are not readily available. Experiments were conducted over a 10-d period in Fiji to determine which species of mosquitoes the GAT would collect, how different infusion types affect the attractiveness of the trap, how long each infusion type took to begin attracting mosquitoes, and how long the infusion was attractive to container breeding Aedes mosquitoes. Infusions were created by adding 10 g of organic material to 2 liters of water. Infusions were made using chicken feed pellets, dried mango leaves (Mangifera indica), and dried lawn grasses (primarily Axonopus spp.). The GAT collected four different vectors Aedes aegypti (Linnaeus) (Diptera: Culicidae), Aedes albopictus (Skuse) (Diptera: Culicidae), Aedes polynesiensis Mark (Diptera: Culicidae), and Culex quinquefasciatus Say (Diptera: Culicidae). As observed in previous studies, using some type of organic infusion improved the attractiveness of the trap. Of the three different infusion components tested, chicken feed was most attractive followed by lawn grasses and mango leaves. All infusions performed better than plain water. Chicken feed was found to be most attractive for Ae. aegypti and Ae. albopictus during the first 6 d after placing the traps and for Cx. quinquifasciatus in days 7-9. The mango and grass infusions took longer to attract mosquitoes but were most attractive during days 7-10 for all species. PMID- 29244171 TI - Arabidopsis MKK10-MPK6 mediates red-light-regulated opening of seedling cotyledons through phosphorylation of PIF3. AB - Photomorphogenesis is an important process in which seedlings emerge from soil and begin autotrophic growth. Mechanisms of photomorphogenesis include light signal perception, signal transduction, and the modulation of expression of light responsive genes, ultimately leading to cellular and developmental changes. Phytochrome-interacting factors (PIFs) play negative regulatory roles in photomorphogenesis. Light-induced activation of phytochromes triggers rapid phosphorylation and degradation of PIFs, but the kinases responsible for the phosphorylation of PIFs are largely unknown. Here, we show that Arabidopsis MPK6 is a kinase involved in phosphorylating PIF3 and regulating red light-induced cotyledon opening, a crucial process during seedling photomorphogenesis. MPK6 was activated by red light, and the cotyledon opening angle in red light was reduced in mpk6 seedlings. MKK10, a MAPKK whose function is currently unclear, appears to act as a kinase upstream of MPK6 in regulating cotyledon opening. Activation of MPK6 by MKK10 led to the phosphorylation of PIF3 and accelerated its turnover in transgenic seedlings. Accordingly, the overexpression of PIF3 suppressed MKK10 induced cotyledon opening. MKK10 and MPK6 function downstream of phyB in regulating seedling cotyledon opening in red light. Therefore, the MKK10-MPK6 cascade appears to mediate the regulation of red-light-controlled seedling photomorphogenesis via a mechanism that might involve the phosphorylation of PIF3. PMID- 29244175 TI - Hans Christian Andersen and the Value of New Cancer Treatments. PMID- 29244176 TI - Parvovirus B19 Is Associated with a Significant Decrease in Hemoglobin Level among Children <5 Years of Age with Anemia in Northwestern Tanzania. AB - Parvovirus B19 (B19) can cause transient aplastic crisis and lead to acute severe anemia. This study investigated the relationship between B19 and anemia among children <5 years old in the city of Mwanza, Tanzania. An enzyme immunoassay was used to detect B19 IgM- and IgG-specific antibodies among children with various categories of anemia according to the World Health Organization (WHO) guidelines. A total of 265 children with median age of 28.5 months (interquartile range 18 39.5) were investigated. Eighty-six children (32.5%) had severe anemia. B19 specific IgM and IgG antibodies were detected in 24 (9%) and 46 (17.4%) children, respectively. Low hemoglobin (Hb) level (p = 0.031), Plasmodium falciparum infection (p = 0.001) and residing in rural areas (p = 0.025) independently predicted B19 IgM seropositivity. Acute B19 infection decreased Hb level by 1.1 g/dl (p = 0.003). In malaria endemic areas, acute B19 infections should be considered among children with severe anemia from rural areas. PMID- 29244178 TI - Manipulating the microbiota to improve human health throughout life. PMID- 29244177 TI - Online Bayesian Phylogenetic Inference: Theoretical Foundations via Sequential Monte Carlo. AB - Phylogenetics, the inference of evolutionary trees from molecular sequence data such as DNA, is an enterprise that yields valuable evolutionary understanding of many biological systems. Bayesian phylogenetic algorithms, which approximate a posterior distribution on trees, have become a popular if computationally expensive means of doing phylogenetics. Modern data collection technologies are quickly adding new sequences to already substantial databases. With all current techniques for Bayesian phylogenetics, computation must start anew each time a sequence becomes available, making it costly to maintain an up-to-date estimate of a phylogenetic posterior. These considerations highlight the need for an online Bayesian phylogenetic method which can update an existing posterior with new sequences. Here, we provide theoretical results on the consistency and stability of methods for online Bayesian phylogenetic inference based on Sequential Monte Carlo (SMC) and Markov chain Monte Carlo. We first show a consistency result, demonstrating that the method samples from the correct distribution in the limit of a large number of particles. Next, we derive the first reported set of bounds on how phylogenetic likelihood surfaces change when new sequences are added. These bounds enable us to characterize the theoretical performance of sampling algorithms by bounding the effective sample size (ESS) with a given number of particles from below. We show that the ESS is guaranteed to grow linearly as the number of particles in an SMC sampler grows. Surprisingly, this result holds even though the dimensions of the phylogenetic model grow with each new added sequence. PMID- 29244179 TI - Sedaxane-Use of Nuclear Receptor Transactivation Assays, Toxicogenomics, and Toxicokinetics as Part of a Mode of Action Framework for Rodent Liver Tumors. AB - Experimental data demonstrate a mode of action (MOA) for liver tumors in male rats and mice treated with sedaxane that starts with activation of CAR, followed by altered expression of CAR-responsive genes, increased cell proliferation, and eventually clonal expansion of preneoplastic cells, leading to the development of altered foci and tumors. This MOA is nonrelevant to human risk assessments. Methods and results in the MOA work for sedaxane illustrate promising directions that future MOA studies may be able to employ, in the spirit of "Tox21" and reduction of in vivo animal use: (1) currently available in vitro CAR and PXR reporter assays demonstrated that sedaxane is a direct CAR activator in mice and rats, and a weak PXR activator in rats; (2) mouse liver microarray results compared with a published CAR biomarker signature (based on 83 genes) showed a clear, statistical match, and a lack of correlation to similar biomarker signatures for AhR, PPARalpha, and STAT5B; (3) Ki67 immunohistochemistry and zonal image analysis showed significant increases in this marker of cell proliferation in mouse liver, without the need to dose a DNA labeling agent; and (4) toxicokinetic analysis of Cmax levels of sedaxane in blood showed a marked species difference between mice and rats that helps to explain differences in sensitivity to sedaxane. Incorporating these tools into the study plan for a new agrochemical or drug during development offers a promising alternative to the traditional need to conduct later, specialized MOA studies after the results of chronic bioassays are known. PMID- 29244180 TI - Seasonal Variation of Allergenic Acarofauna From the Homes of Allergic Rhinitis and Asthmatic Patients. AB - House dust mites (HDMs) play positive role in causing various kinds of allergenic manifestations such as allergic rhinitis (AR), asthma, dermatitis, and urticaria. HDMs are prevalent in temperate regions but various studies have shown the prevalence of HDMs in tropical and subtropical countries. The present study was conducted from March 2015 to February 2016. During the study period, a total of 500 dust samples were collected from 125 homes of 125 patients suffering from AR and asthma. From these 500 dust samples, 466 samples were found to be positive for mites. The year was divided into three climatic classes, i.e., CCL I (March, April, May, June), CCL II (July, August, September, October), and CCL III (November, December, January, February) A total of 7,710 mites were collected, from which 2,902 (37.63%) mites were found in samples collected during summer season, i.e., CCL-I, 3,728 (48.35%) mites were found in samples collected during rainy season, i.e., CCL-II and only 1,080 (14.01%) mites were found in samples collected during winter season, i.e., CCL-III. Total 7,710 mite specimens were isolated with 7,404, i.e., 96.03% were only from the hypoorder Astigmata, 240, i.e., 3.11% from suborder Prostigmata, 46, i.e., 0.60% from order Mesostigmata, and 20, i.e., 0.26% from suborder Oribatida. The present study indicates that Dermatophagoides pteronyssinus (Trouessart 1897) (Astigmata) was most abundant and frequently found allergenic mite species followed by D. farinae (Hughes 1961), D. microceras (Griffiths and Cunnington 1971), Acarus siro (Linnaeus 1758), Tyrophagus putrescentiae (Schrank 1781), Lepidoglyphus destructor (Schrank 1781), Euroglyphus maynei (Cooreman 1950), Cheyletus, Mesostigmatic, and Oribatida mites. PMID- 29244181 TI - Post-veraison irreversible stem shrinkage in grapevine (Vitis vinifera) is caused by periderm formation. AB - Grapevines are characterized by a period of irreversible stem shrinkage around the onset of ripening of the grape berries. Since this shrinkage is unrelated to meteorological conditions or drought, it is often suggested that it is caused by the increased sink strength of the grape berries during this period. However, no studies so far have experimentally investigated the mechanisms underlying this irreversible stem shrinkage. We therefore combined continuous measurements of stem diameter variations and histology of potted 2-year-old grapevines (Vitis vinifera L. 'Boskoop Glory'). Sink strength was altered by pruning all grape clusters (treatment P), while non-pruned grapevines served as control (treatment C). Unexpectedly, our results showed irreversible post-veraison stem shrinkage in both treatments, suggesting that the shrinkage is not linked to grape berry sink strength. Anatomical analysis indicated that the shrinkage is the result of the formation of successive concentric periderm layers, and the subsequent dehydration and compression of the older bark tissues, an anatomical feature that is characteristic of Vitis stems. Stem shrinkage is hence unrelated to grape berry development, in contrast to what has been previously suggested. PMID- 29244182 TI - Poor performance of two rapid immunochromatographic assays for anti-Japanese encephalitis virus immunoglobulin M detection in cerebrospinal fluid and serum from patients with suspected Japanese encephalitis virus infection in Laos. AB - Background: Japanese encephalitis virus (JEV) is a leading identified cause of encephalitis in Asia, often occurring in rural areas with poor access to laboratory diagnostics. We evaluated two rapid diagnostic tests (RDTs) for anti JEV immunoglobulin M (IgM) detection. Methods: Consecutive cerebrospinal fluid and serum from 388 patients (704 samples) with suspected JEV infections admitted to six hospitals in Laos were tested with one of two SD-Bioline anti-JEV IgM RDTs and the World Health Organization standard anti-JEV IgM enzyme-linked immunosorbent assay (ELISA; Panbio Japanese Encephalitis-Dengue IgM Combo ELISA. Results and Conclusions: The performance of both RDTs showed strikingly low sensitivity in comparison to anti-JEV IgM antibody capture ELISA (2.1-51.4%), suggesting low sensitivity of the RDTs. We highlight the fundamental prerequisite to validate RDTs prior to use to ensure that they meet standards for testing. PMID- 29244183 TI - DNA damage and epigenetic alteration in soybean farmers exposed to complex mixture of pesticides. AB - Exposure to pesticides can trigger genotoxic and mutagenic processes through different pathways. However, epidemiological studies are scarce, and further work is needed to find biomarkers sensitive to the health of exposed populations. Considering that there are few evaluations of soybean farmers, the aim of this study was to assess the effects of human exposure to complex mixtures of pesticides. The alkaline comet assay modified with restriction enzyme (hOGG1: human 8-oxoguanine DNA glycosylase) was used to detect oxidised guanine, and compared with the buccal micronucleus cytome assay, global methylation, haematological parameters, biochemical analyses (serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, gamma-glutamyl-transferase and butyrylcholinesterase), and particle-induced X-ray emission (PIXE) for the analysis of inorganic elements. Farm workers (n = 137) exposed to different types of pesticides were compared with a non-exposed reference group (control; n = 83). Results of the enzyme-modified comet assay suggest oxidation of guanine in DNA generated by pesticides exposure. It was observed that DNA damage (comet assay and micronucleus test) was significantly increased in exposed individuals compared to the unexposed group. The micronucleus test demonstrated elimination of nuclear material by budding, defective cytokinesis and dead cells. Occupationally exposed individuals also showed genomic hypermethylation of DNA, which correlated with micronucleus frequency. No differences were detected regarding the haematological and biochemical parameters. Finally, significantly higher concentrations of Al and P were observed in the urine of the soybean farmers. DNA damage could be a consequence of the ability of the complex mixture, including Al and P, to cause oxidative damage. These data indicate that persistent genetic instability associated with hypermethylation of DNA in soybean workers after long-term exposure to a low-level to pesticides mixtures may be critical for the development of adverse health effects such as cancer. PMID- 29244184 TI - Accumulation of long-term transcriptionally active integrated retroviral vectors in active promoters and enhancers. AB - Most retroviruses preferentially integrate into certain genomic locations and, as a result, their genome-wide integration patterns are non-random. We investigate the epigenetic landscape of integrated retroviral vectors and correlate it with the long-term stability of proviral transcription. Retroviral vectors derived from the avian sarcoma/leukosis virus expressing the GFP reporter were used to transduce the human myeloid lymphoblastoma cell line K562. Because of efficient silencing of avian retrovirus in mammalian cells, only ~3% of established clones displayed stable proviral expression. We analyzed the vector integration sites in non-selected cells and in clones selected for the GFP expression. This selection led to overrepresentation of proviruses integrated in active transcription units, with particular accumulation in promoter-proximal areas. In parallel, we investigated the integration of vectors equipped with an anti-silencing CpG island core sequence. Such modification increased the frequency of stably expressing proviruses by one order. The modified vectors are also overrepresented in active transcription units, but stably expressed in distal parts of transcriptional units further away from promoters with marked accumulation in enhancers. These results suggest that integrated retroviruses subject to gradual epigenetic silencing during long-term cultivation. Among most genomic compartments, however, active promoters and enhancers protect the adjacent retroviruses from transcriptional silencing. PMID- 29244185 TI - Loss of imprinting mutations define both distinct and overlapping roles for misexpression of IGF2 and of H19 lncRNA. AB - Imprinted genes occur in discrete clusters that are coordinately regulated by shared DNA elements called Imprinting Control Regions. H19 and Igf2 are linked imprinted genes that play critical roles in development. Loss of imprinting (LOI) at the IGF2/H19 locus on the maternal chromosome is associated with the developmental disorder Beckwith Wiedemann Syndrome (BWS) and with several cancers. Here we use comprehensive genetic and genomic analyses to follow muscle development in a mouse model of BWS to dissect the separate and shared roles for misexpression of Igf2 and H19 in the disease phenotype. We show that LOI results in defects in muscle differentiation and hypertrophy and identify primary downstream targets: Igf2 overexpression results in over-activation of MAPK signaling while loss of H19 lncRNA prevents normal down regulation of p53 activity and therefore results in reduced AKT/mTOR signaling. Moreover, we demonstrate instances where H19 and Igf2 misexpression work separately, cooperatively, and antagonistically to establish the developmental phenotype. This study thus identifies new biochemical roles for the H19 lncRNA and underscores that LOI phenotypes are multigenic so that complex interactions will contribute to disease outcomes. PMID- 29244188 TI - 'The Lights of the Electric Octopus Have Been Switched Off': Visual and Political Culture in Edwardian London. AB - This article reconstructs the visual culture of politics in Edwardian London through a study of the 1907 London County Council election. It moves beyond the memorable account given in Graham Wallas's Human Nature in Politics to examine the actors, especially associations and newspapers, that participated in the election. Drawing upon newspapers, election addresses, cartoon, leaflets, and posters, the article argues that Edwardian London was a prime site in the application of new media for political communication. It shows, however, that new modes of communication could co-exist with, and intensify, established forms of public politics. It reveals a highly knowing visual culture of politics through which issues of authenticity and identity were contested, and recasts understanding of a controversial and critical election. PMID- 29244189 TI - Molecular diagnosis of human microsporidian infections. AB - With the transformation of HIV infection from an acutely life-threatening disease into a chronic condition (as a consequence of the development of effective antiretroviral medication), the perceived clinical importance of diagnosing and treating microsporidian infections diminished, at least in industrialized countries. In locales where effective antiretroviral therapy is not available, as well as in patients with immunodeficiency for reasons other than HIV infection (e.g., following organ transplantation), and in individuals with suspected ocular microsporidiosis, diagnosing microsporidian infections remains a clinical priority. Molecular techniques can readily distinguish different species of microsporidia. At least one molecular diagnostic platform that can detect the intestinal parasites Encephalitozoon intestinalis and Enterocytozoon bieneusi is commercially available. PMID- 29244187 TI - Polycytidylation of mitochondrial mRNAs in Chlamydomonas reinhardtii. AB - The unicellular photosynthetic organism, Chlamydomonas reinhardtii, represents a powerful model to study mitochondrial gene expression. Here, we show that the 5'- and 3'-extremities of the eight Chlamydomonas mitochondrial mRNAs present two unusual characteristics. First, all mRNAs start primarily at the AUG initiation codon of the coding sequence which is often marked by a cluster of small RNAs. Second, unusual tails are added post-transcriptionally at the 3'-extremity of all mRNAs. The nucleotide composition of the tails is distinct from that described in any other systems and can be partitioned between A/U-rich tails, predominantly composed of Adenosine and Uridine, and C-rich tails composed mostly of Cytidine. Based on 3' RACE experiments, 22% of mRNAs present C-rich tails, some of them composed of up to 20 consecutive Cs. Polycytidylation is specific to mitochondria and occurs primarily on mRNAs. This unprecedented post-transcriptional modification seems to be a specific feature of the Chlorophyceae class of green algae and points out the existence of novel strategies in mitochondrial gene expression. PMID- 29244186 TI - Independence between pre-mRNA splicing and DNA methylation in an isogenic minigene resource. AB - Actively transcribed genes adopt a unique chromatin environment with characteristic patterns of enrichment. Within gene bodies, H3K36me3 and cytosine DNA methylation are elevated at exons of spliced genes and have been implicated in the regulation of pre-mRNA splicing. H3K36me3 is further responsive to splicing, wherein splicing inhibition led to a redistribution and general reduction over gene bodies. In contrast, little is known of the mechanisms supporting elevated DNA methylation at actively spliced genic locations. Recent evidence associating the de novo DNA methyltransferase Dnmt3b with H3K36me3-rich chromatin raises the possibility that genic DNA methylation is influenced by splicing-associated H3K36me3. Here, we report the generation of an isogenic resource to test the direct impact of splicing on chromatin. A panel of minigenes of varying splicing potential were integrated into a single FRT site for inducible expression. Profiling of H3K36me3 confirmed the established relationship to splicing, wherein levels were directly correlated with splicing efficiency. In contrast, DNA methylation was equivalently detected across the minigene panel, irrespective of splicing and H3K36me3 status. In addition to revealing a degree of independence between genic H3K36me3 and DNA methylation, these findings highlight the generated minigene panel as a flexible platform for the query of splicing-dependent chromatin modifications. PMID- 29244190 TI - Self-other agreement in personality traits and profiles across cultures: A multirater, multiscale study in Blacks and Whites in South Africa. AB - OBJECTIVE: Despite the importance of self-other agreement for the validity of trait models, few studies have assessed cultural differences systematically. We examined self-other agreement in traits and profiles in the more collectivistic Black group and the more individualistic White group in South Africa. METHOD: Participants were 172 Black and 198 White students, and one relative and one friend of each student. Participants completed a behavior-based and a trait adjective-based inventory. RESULTS: Aggregated across traits and raters, there were no cultural differences in trait agreement. However, agreement was stronger for social-relational concepts in Blacks and for personal growth concepts in Whites, providing moderate support for the hypothesis of stronger agreement on culturally more salient traits. Trait agreement was stronger in Blacks' relatives and Whites' friends, but there was no such interaction in profile agreement. The differences in profile agreement (higher in Whites than in Blacks) involved normative agreement and were mediated by dialecticism (higher in Blacks) and social desirability (higher in Whites). Results with the two inventories were similar. CONCLUSIONS: In the framework of trait consistency research, cultural differences in self-other agreement may be limited compared to differences in perceived trait consistency, although sizable compared to differences in actual behavior consistency. PMID- 29244192 TI - Daily hassles score associates with the somatic and psychological health of patients with Crohn's disease. AB - OBJECTIVE: To examine the associations of daily hassles with the somatic and psychological health of Crohn's disease (CD) patients. METHOD: A cross-sectional study of 400 self-selected adult CD patients was performed with completion of demographic, medical, and psychosocial questionnaires: economic status; Patient Harvey-Bradshaw Index of disease activity; Daily Hassles Scale (DHS); Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and Short-Form Health Survey (SF 36 Physical and Mental Health) quality of life measures; Brief Symptom Inventory of psychological stress with summary Global Severity Index (GSI); Family Assessment Device; and List of Threatening Life Experiences. Analyses included correlations, regressions, and Sobel test statistic. RESULTS: The patients were aged 38.7 +/- 14.1 years, 61% female and 67% working. The Patient Harvey-Bradshaw Index was 5.52 +/- 4.87. The DHS was 88.0 +/- 23.2, similar in men and women, higher in smokers, and increased with greater disease activity (p < .001). The most commonly reported hassles were time, social, and work. DHS had significant negative correlations with age, disease duration, and economic status and positive correlations with GSI, SF-36, and SIBDQ. An increased Daily Hassles score was associated with reduced SIBDQ (p < .001) and SF-36 Mental Health (p < .001) and increased GSI (p < .001) and Patient Harvey-Bradshaw Index (p < .001). This effect of DHS on Patient Harvey-Bradshaw Index was mediated by GSI (Sobel t = 6.09, p < 0.001). CONCLUSION: Daily hassles in CD patients are shown for the first time to be associated with increased psychological stress and disease activity and reduced quality of life and lower economic status. This has psychotherapeutic implications. PMID- 29244191 TI - The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes. AB - The present study was conducted to characterise the transporter(s) responsible for the uptake of cyclic nucleotides to human erythrocytes. Western blotting showed that hRBC expressed OAT2 (SLC22A7), but detection of OAT1 (SLC22A6), or OAT3 (SLC22A8) was not possible. Intact hRBC were employed to clarify the simultaneous cyclic nucleotide egression and uptake. Both these opposing processes were studied. The Km -values for high affinity efflux was 3.5 +/- 0.1 and 39.4 +/- 5.7 MUM for cGMP and cAMP, respectively. The respective values for low affinity efflux were 212 +/- 11 and 339 +/- 42 MUM. The uptake was characterised with apparently low affinity and similar Km -values for cGMP (2.2 mM) and cAMP (0.89 mM). Using an iterative approach in order to balance uptake with efflux, the predicted real Km -values for uptake were 100-200 MUM for cGMP and 50-150 MUM for cAMP. The established OAT2-substrate indomethacin showed a competitive interaction with cyclic nucleotide uptake. Creatinine, also an OAT2 substrate, showed saturable uptake with a Km of 854 +/- 98 MUM. Unexpectedly, co incubation with cyclic nucleotides showed an uncompetitive inhibition. The observed Km -values were 399 +/- 44 and 259 +/- 30 MUM for creatinine, in the presence of cGMP and cAMP, respectively. Finally, the OAT1-substrate para aminohippurate (PAH) showed some uptake (Km -value of 2.0 +/- 0.4 mM) but did not interact with cyclic nucleotide or indomethacin transport. PMID- 29244193 TI - Comparative peptidomic profile between human hypertrophic scar tissue and matched normal skin for identification of endogenous peptides involved in scar pathology. AB - Endogenous peptides recently attract increasing attention for their participation in various biological processes. Their roles in the pathogenesis of human hypertrophic scar remains poorly understood. In this study, we used liquid chromatography-tandem mass spectrometry to construct a comparative peptidomic profiling between human hypertrophic scar tissue and matched normal skin. A total of 179 peptides were significantly differentially expressed in human hypertrophic scar tissue, with 95 upregulated and 84 downregulated peptides between hypertrophic scar tissue and matched normal skin. Further bioinformatics analysis (Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis) indicated that precursor proteins of these differentially expressed peptides correlate with cellular process, biological regulation, cell part, binding and structural molecule activity ribosome, and PPAR signaling pathway occurring during pathological changes of hypertrophic scar. Based on prediction database, we found that 78 differentially expressed peptides shared homology with antimicrobial peptides and five matched known immunomodulatory peptides. In conclusion, our results show significantly altered expression profiles of peptides in human hypertrophic scar tissue. These peptides may participate in the etiology of hypertrophic scar and provide beneficial scheme for scar evaluation and treatments. PMID- 29244194 TI - Arid5a stabilizes OX40 mRNA in murine CD4+ T cells by recognizing a stem-loop structure in its 3'UTR. AB - AT-rich interactive domain-containing protein 5a (Arid5a) is an RNA-binding protein (RBP) required for autoimmunity via stabilization of interleukin-6 (Il6) and signal transducer and activator of transcription 3 (STAT3) mRNAs. However, the roles of Arid5a in Th17 cells and its association with autoimmunity remain unknown. Here, we show that the levels of Arid5a and OX40 are correlated in CD4+ T cells under Th17 conditions in an IL-6-dependent manner. Lack of Arid5a in T cells reduced OX40 expression levels and repressed IL-17 production in response to OX40 ligation. Arid5a stabilized OX40 mRNA by recognizing the alternative decay element (ADE)-like stem-loop (SL) in the 3' untranslated region (3'UTR). Interestingly, Arid5a impaired the RNA-destabilizing functions of Regnase-1 and Roquin-1 on OX40 ADE-like SL. In EAE, Arid5a-deficient mice exhibited resistance to EAE, with reduced OX40 expression in CD4+ T cells, and the number of CD4+ CD45+ T cells was decreased in CNS. Furthermore, ameliorated EAE was induced by adoptive transfer of Arid5a-/- encephalitogenic CD4+ T cells expressing less OX40 mRNA and producing less IL-17. In conclusion, our findings indicate that the Arid5a/OX40 axis in CD4+ T cells may have important implications in pathogenesis of autoimmune diseases such as EAE. PMID- 29244195 TI - Decellularized colorectal cancer matrix as bioactive microenvironment for in vitro 3D cancer research. AB - Three-dimensional (3D) cancer models are overlooking the scientific landscape with the primary goal of bridging the gaps between two-dimensional (2D) cell lines, animal models and clinical research. Here, we describe an innovative tissue engineering approach applied to colorectal cancer (CRC) starting from decellularized human biopsies in order to generate an organotypic 3D-bioactive model. This in vitro 3D system recapitulates the ultrastructural environment of native tissue as demonstrated by histology, immunohistochemistry, immunofluorescence and scanning electron microscopy analyses. Mass spectrometry of proteome and secretome confirmed a different stromal composition between decellularized healthy mucosa and CRC in terms of structural and secreted proteins. Importantly, we proved that our 3D acellular matrices retained their biological properties: using CAM assay, we observed a decreased angiogenic potential in decellularized CRC compared with healthy tissue, caused by direct effect of DEFA3. We demonstrated that following a 5 days of recellularization with HT-29 cell line, the 3D tumor matrices induced an over-expression of IL-8, a DEFA3-mediated pathway and a mandatory chemokine in cancer growth and proliferation. Given the biological activity maintained by the scaffolds after decellularization, we believe this approach is a powerful tool for future pre clinical research and screenings. PMID- 29244196 TI - Iron overload induces G1 phase arrest and autophagy in murine preosteoblast cells. AB - This study aimed to investigate the cell cycle arrest and autophagy induced by iron overload in MC3T3-E1 cells. MC3T3-E1 cells were cultured in different concentrations of ferric ammonium citrate (FAC), and Perls' Prussian blue reaction was used to detect the iron levels of the cells. CCK-8 assays were used to detect the growth of MC3T3-E1. The level of reactive oxygen species (ROS) within cells was investigated with DCFH-DA. PI staining was used to analyze the cell cycle distribution of MC3T3-E1 cells. Finally, the expression levels of cell cycle related proteins, autophagy related proteins, AKT, p38 MAPK, Stat3, and their downstream proteins were detected with Western blot assays. The results showed that the iron levels of MC3T3-E1 cells increased with increasing concentrations of FAC. High levels of ferric ion inhibited proliferation of MC3T3 E1 cells and increased their ROS levels. Additionally, iron overload induced G1arrest in MC3T3-E1 cells and down-regulated the expression of Cyclin D1 , Cyclin D3 , CDK2, CDK4 and CDK6, but up-regulated p27 Kip1. In addition, the expression levels of Beclin-1 and LC3 II increased, but that of p62 decreased. Further experiments showed that the phosphorylation of AKT and its downstream proteins p-GSK-3beta(Ser9) and p-mTOR (Ser2448) were decreased. The levels of p p38 and p53 were up-regulated while those of cdc25A and p-ERK 1/2 were down regulated. Phosphorylation of Stat3 and its downstream proteins was all decreased. These results show that iron overload generates ROS, blocks the PI3K/AKT and Jak/Stat3 signal pathways, and activates p38 MAPK, subsequently inducing G1 arrest and autophagy in MC3T3-E1 cells. PMID- 29244197 TI - Evaluation of an online self-help version of the REACH forgiveness program: Outcomes and predictors of persistence in a community sample. AB - OBJECTIVE: We evaluated outcomes of an online, self-directed REACH forgiveness intervention for community-based adults. Because many participants dropped out before program completion, predictors of program persistence were also examined. METHOD: Participants (N = 130 adults, 122 female; mean age 48) completed pretreatment assessment and were randomized to immediate treatment (IT) or delayed treatment (DT). Twenty-three IT and 13 DT participants completed the 7 hour REACH forgiveness modules and postintervention assessment; 32 participants completed 3-month follow-up. RESULTS: The IT group reported greater postintervention improvements in overall forgiveness and emotional forgiveness, as well as reductions in avoidance motivations with large effect sizes and, marginally, state empathy; but revenge motivations, decisional forgiveness, and well-being indicators did not change. Most postintervention improvements were maintained at 3-month follow-up. In this online intervention, persistence was predicted by perspective taking, willingness to forgive the offender, and conscientiousness. Three-month follow-up supported maintenance of gains, particularly in overall and emotional forgiveness, and increases in trait forgiveness compared to pretreatment. CONCLUSION: An online self-directed version of REACH forgiveness applied in a community sample has potential for improving forgiveness-related responses, particularly those involving emotional forgiveness. However, methods to increase program persistence and target suitable recipients need development. PMID- 29244198 TI - Rethinking the origins of autism: Ida Frye and the unraveling of children's inner world in the Netherlands in the late 1930s. AB - Historiographies on the phenomenon of "autism" display Leo Kanner and Hans Asperger as the great pioneers. The recent controversy on who was first in "discovering" autism urges research into the question of how scientific discoveries relate to processes of academic reflection and social intervention. The Netherlands provide an interesting case in pioneering work in autism, since Dutch experts described autism in children already in the late 1930s, preceding the first publications on autism in children by Kanner and Asperger. This paper examines the Dutch origins of autism by focusing on Ida Frye's contribution to the teamwork at the Paedological Institute in Nijmegen, which resulted in descriptions of children with autism. The theoretical aim of this paper is to underline the importance of the productive interplay between social interventions and scientific efforts concerning the complex inner world of special children. PMID- 29244200 TI - From Hohenschonhausen to Guantanamo Bay: Psychology's role in the secret services of the GDR and the United States. AB - This paper presents a historical analysis of the genesis, context, and function of "Operative Psychology," a little-known branch of applied psychology developed by employees of the Ministry of State Security in the German Democratic Republic. For 25 years, theories and practices of Operative Psychology were taught to elite agents at the Juridical Academy in Potsdam, introducing them to various "silent" psychological techniques of persuasion, interrogation, and repression. After highlighting the economic and political context that increased the need for "silent" techniques of observation and repression, an overview of the topics that were taught and researched at the chair for Operative Psychology is given. Examples of how these techniques were put into practice are provided and the consequences for the victims of Operative Psychology are discussed. Furthermore, commonalities and differences between Operative Psychology and the use of psychological torture by the CIA during the "war on terror" are discussed and questions regarding the relation between methodological and moral strategies of justification are addressed. PMID- 29244199 TI - Secondary prevention of recurrent venous thromboembolism after initial oral anticoagulation therapy in patients with unprovoked venous thromboembolism. AB - BACKGROUND: Currently, little evidence is available on the length and type of anticoagulation used for extended treatment for prevention of recurrent venous thromboembolism (VTE) in patients with unprovoked VTE who have completed initial oral anticoagulation therapy. OBJECTIVES: To compare the efficacy and safety of available oral therapeutic options (aspirin, warfarin, direct oral anticoagulants (DOACs)) for extended thromboprophylaxis in adults with a first unprovoked VTE, to prevent VTE recurrence after completion of an acceptable initial oral anticoagulant treatment period, as defined in individual studies. SEARCH METHODS: For this review, the Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (March 2017) as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2). We also searched trials registries (March 2017) and reference lists of relevant articles. SELECTION CRITERIA: We included randomised controlled trials in which patients with a first, symptomatic, objectively confirmed, unprovoked VTE, who had been initially treated with anticoagulants, were randomised to extended prophylaxis (vitamin K antagonists (VKAs), antiplatelet agents, or DOACs) versus no prophylaxis or placebo. We also included trials that compared one type of extended prophylaxis versus another type of extended prophylaxis. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed quality, and extracted data. We resolved disagreements by discussion. MAIN RESULTS: Six studies with a combined total of 3436 participants met the inclusion criteria. Five studies compared extended prophylaxis versus placebo: three compared warfarin versus placebo, and two compared aspirin versus placebo. One study compared one type of extended prophylaxis (rivaroxaban) versus another type of extended prophylaxis (aspirin). For extended prophylaxis versus placebo, we downgraded the quality of the evidence for recurrent VTE and all-cause mortality to moderate owing to concerns arising from risks of selection and performance bias in individual studies. For all other outcomes in this review, we downgraded the quality of the evidence to low owing to concerns arising from risk of bias for the studies stated above, combined with concerns over imprecision. For extended prophylaxis versus other extended prophylaxis, we downgraded the quality of the evidence for recurrent VTE and major bleeding to moderate owing to concerns over imprecision. Risk of bias in the individual study was low.Meta-analysis showed that extended prophylaxis was no more effective than placebo in preventing VTE-related mortality (odds ratio (OR) 0.98, 95% confidence interval (CI) 0.14 to 6.98; 1862 participants; 4 studies; P = 0.98; low-quality evidence), recurrent VTE (OR 0.63, 95% CI 0.38 to 1.03; 2043 participants; 5 studies; P = 0.07; moderate-quality evidence), major bleeding (OR 1.84, 95% CI 0.87 to 3.85; 2043 participants; 5 studies; P = 0.86; low-quality evidence), all-cause mortality (OR 1.00, 95% CI 0.63 to 1.57; 2043 participants; 5 studies; P = 0.99; moderate-quality evidence), clinically relevant non-major bleeding (OR 1.78, 95% CI 0.59 to 5.33; 1672 participants; 4 studies; P = 0.30; low-quality evidence), stroke (OR 1.15, 95% CI 0.39 to 3.46; 1224 participants; 2 studies; P = 0.80; low-quality evidence), or myocardial infarction (OR 1.00, 95% CI 0.35 to 2.87; 1495 participants; 3 studies; P = 1.00; low-quality evidence).One study showed that the novel oral anticoagulant rivaroxaban was associated with fewer recurrent VTEs than aspirin (OR 0.28, 95% CI 0.15 to 0.54; 1389 participants; P = 0.0001; moderate-quality evidence). Data show no clear differences in the incidence of major bleeding between rivaroxaban and aspirin (OR 3.06, 95% CI 0.37 to 25.51; 1389 participants; P = 0.30; moderate-quality evidence) nor in the incidence of clinically relevant non-major bleeding (OR 0.84, 95% CI 0.37 to 1.94; 1389 participants; 1 study; P = 0.69; moderate-quality evidence). Data on VTE-related mortality, all-cause mortality, stroke, and myocardial infarction were not yet available for participants with unprovoked VTE and will be incorporated in future versions of the review. AUTHORS' CONCLUSIONS: Evidence is currently insufficient to permit definitive conclusions concerning the effectiveness and safety of extended thromboprophylaxis in prevention of recurrent VTE after initial oral anticoagulation therapy among participants with unprovoked VTE. Additional good quality large-scale randomised controlled trials are required before firm conclusions can be reached. PMID- 29244201 TI - Sleep disturbances in treatment-seeking OCD-patients: Changes after concentrated exposure treatment. AB - Research indicates that patients with Obsessive Compulsive Disorder (OCD) frequently suffer from comorbid sleep difficulties, and that these difficulties often are not clinically recognized and diagnosed. There has been limited research investigating if comorbid sleep difficulties impair treatment outcome for OCD and if the sleep difficulties change following OCD-treatment. Thirty-six patients with obsessive compulsive disorder underwent concentrated exposure treatment delivered in a group over four consecutive days and were assessed with measures of OCD, depressive symptoms and sleep disturbance at three different time points (pre, post and 6 months follow-up). The sample was characterized by a high degree of comorbidity with other psychiatric disorders. At pre-treatment nearly 70% of the patients reported sleep difficulties indicative of primary insomnia. The results showed that patients had large reductions of OCD-symptoms as well as significant improvements in sleep disturbance assessed after treatment, and that these improvements were maintained at follow-up. Sleep disturbance did not impair treatment outcome, on the contrary patients with higher degree of sleep disturbance at pre-treatment had better outcome on OCD symptoms after treatment. The results indicated that the majority of the OCD sample suffered from sleep disturbances and that these sleep disturbances were significantly reduced following adequate treatment of OCD without specific sleep interventions. However, a proportion of the patients suffered from residual symptoms of insomnia after treatment. PMID- 29244202 TI - Mental Health Risk Adjustment with Clinical Categories and Machine Learning. AB - OBJECTIVE: To propose nonparametric ensemble machine learning for mental health and substance use disorders (MHSUD) spending risk adjustment formulas, including considering Clinical Classification Software (CCS) categories as diagnostic covariates over the commonly used Hierarchical Condition Category (HCC) system. DATA SOURCES: 2012-2013 Truven MarketScan database. STUDY DESIGN: We implement 21 algorithms to predict MHSUD spending, as well as a weighted combination of these algorithms called super learning. The algorithm collection included seven unique algorithms that were supplied with three differing sets of MHSUD-related predictors alongside demographic covariates: HCC, CCS, and HCC + CCS diagnostic variables. Performance was evaluated based on cross-validated R2 and predictive ratios. PRINCIPAL FINDINGS: Results show that super learning had the best performance based on both metrics. The top single algorithm was random forests, which improved on ordinary least squares regression by 10 percent with respect to relative efficiency. CCS categories-based formulas were generally more predictive of MHSUD spending compared to HCC-based formulas. CONCLUSIONS: Literature supports the potential benefit of implementing a separate MHSUD spending risk adjustment formula. Our results suggest there is an incentive to explore machine learning for MHSUD-specific risk adjustment, as well as considering CCS categories over HCCs. PMID- 29244203 TI - Pediatric tolerogenic DCs expressing CD4 and immunoglobulin-like transcript receptor (ILT)-4 secrete IL-10 in response to Fc and adenosine. AB - We characterized a novel population of tolerogenic myeloid dendritic cells (tmDCs) defined as CD11c+ CD11b+ CD14+ CD4+ and immunoglobulin-like transcript receptor (ILT)-4+ that are significantly more abundant in the circulation of infants and young children than in adults. TmDCs secrete the immunosuppressive lymphokine interleukin (IL)-10 when stimulated with the heavy constant region of immunoglobulins (Fc) and express high levels of the adenosine A2A receptor (A2A R), which, when activated by adenosine, inhibits the release of pro-inflammatory cytokines from most immune cells. Here we show that stimulation of the A2A R on tmDCs by regadenoson or N-ethylcarboxamidoadenosine (NECA) rapidly increases cyclic AMP accumulation and enhances IL-10 production under Fc stimulatory conditions. In co-culture experiments, tmDCs inhibit the differentiation of naive T cells to a pro-inflammatory phenotype. In conclusion, although DCs are classically viewed as antigen presenting cells that activate T cells, we show an independent role of tmDCs in pediatric immune regulation that may be important for suppressing T cell responses to neoantigens in infants and young children. PMID- 29244205 TI - Adding "Circle of Security - Parenting" to treatment as usual in three Swedish infant mental health clinics. Effects on parents' internal representations and quality of parent-infant interaction. AB - This study presents effects of adding Circle of Security-Parenting (COS-P) to an already established comprehensive therapeutic model for early parent-child intervention in three Swedish infant mental health (IMH) clinics. Parents' internal representations and quality of parent-infant interaction were studied in a clinical sample comprised of 52 parent-infant dyads randomly allocated to two comparable groups. One group consisted of 28 dyads receiving treatment as usual (TAU) supplemented with COS-P in a small group format, and another group of 24 dyads receiving TAU only. Assessments were made at baseline (T1), 6 months after inclusion (T2) and 12 months after inclusion (T3). Changes over time were explored in 42 dyads. In the COS-P group, the proportion of balanced representations, as assessed with Working Model of the Child Interview (WMCI), significantly increased between T1 and T3. Further, the proportion of emotionally available interactions, as assessed with Emotional Availability scales (EA), significantly increased over time in the COS-P group. Improvements in the TAU group were close to significant. Limitations of the study are mainly related to the small sample size. Strength is the real world character of the study, where COS-P was implemented in a clinical context not otherwise adapted to research. We conclude by discussing the value of supplementing TAU with COS-P in IMH treatment. PMID- 29244204 TI - Respiratory viral infections and atopic development: From possible mechanisms to advances in treatment. AB - Atopic sensitization and allergic diseases are increasing in modernized countries. These diseases affect millions of individuals, but the mechanisms behind their development are not fully understood. One hypothesis relates to early life respiratory viral infections driving the development of atopic disease including asthma. This review presents the current state of the field, focusing on epidemiologic data supporting a role for early life respiratory viruses in the development of specific IgE, both against aeroallergens and the respiratory virus. Our own work using the Sendai mouse model is then summarized to provide a potential mechanistic explanation for how a respiratory viral infection could drive development of atopic sensitization and disease. We then discuss the components of this mechanistic pathway that have and have not been validated in humans. Finally, we discuss areas ripe for research, as well as potential and current therapeutics that might disrupt the link between respiratory viral infections in early life and atopic sensitization/disease. PMID- 29244206 TI - Deficits in general emotion regulation skills-Evidence of a transdiagnostic factor. AB - OBJECTIVE: Deficits in emotion regulation (ER) skills are discussed as a transdiagnostic factor contributing to the development and maintenance of various mental disorders. However, systematic comparisons of a broad range of ER skills across diagnostic groups that are based on comparable definitions and measures of ER are still rare. METHOD: Therefore, we conducted two studies assessing a broad range of ER skills with the Emotion Regulation Skills Questionnaire in individuals meeting criteria for mental disorders (N1 = 1448; N2 = 137) and in a general population sample (N = 214). RESULTS: Consistent across the two studies, participants in the clinical samples reported lower general and lower specific ER skills than participants in the general population sample. Also consistent across the two studies, diagnostic subgroups of the clinical samples differed significantly with regard to general and specific ER skills. CONCLUSION: The studies provide evidence that deficits in ER are associated with various forms of psychopathology. However, mental disorders seem to differ with regard to how strongly they are linked to ER skills. PMID- 29244207 TI - Information about expert decision and post-decision distortion of facts of own decision. AB - Cognitive representations of decision problems are dynamic. During and after a decision, evaluations and representations of facts change to support the decision made by a decision maker her- or himself (Svenson, 2003). We investigated post decision distortion of facts (consolidation). Participants were given vignettes with facts about two terminally ill patients, only one of whom could be given lifesaving surgery. In Study 1, contrary to the prediction, the results showed that facts were distorted after a decision both by participants who were responsible for the decisions themselves and when doctors had made the decision. In Study 2 we investigated the influence of knowledge about expert decisions on a participant's own decision and post-decisional distortion of facts. Facts were significantly more distorted when the participant's decision agreed with an expert's decision than when the participant and expert decisions disagreed. The findings imply that knowledge about experts' decisions can distort memories of facts and therefore may obstruct rational analyses of earlier decisions. This is particularly important when a decision made by a person, who is assumed to be an expert, makes a decision that is biased or wrong. PMID- 29244209 TI - Generation of a KSHV K13 deletion mutant for vFLIP function study. AB - Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded viral Fas-associated death domain-like IL-1-converting enzyme inhibitory protein (vFLIP) is one of the latently expressed genes and plays a key role in cell survival and maintenance of latent infection by activating the NF-kappaB pathway. To obtain a genetic system for studying KSHV vFLIP mutation in the context of the viral genome, we generated recombinant viruses lacking the coding sequence (CDS) of vFLIP gene (K13/ORF71) by bacterial artificial chromosome (BAC) technology and the Escherichia coli Red recombination system. After a series of verification with PCR, restriction digestion and sequencing, the K13 deletion bacmids was transfected into a stable viral producer cell line based on iSLK cells to create vFLIP-knockout mutant. Importantly, human umbilical vein endothelial cells (HUVECs) could be de novo infected by vFLIP mutant virus, which are now available for studying the roles of vFLIP in regulation of other KSHV genes and viral pathogenesis. PMID- 29244208 TI - Parent-child interactions during traditional and interactive media settings: A pilot randomized control study. AB - Parent-child interactions are pivotal for children's socioemotional development, yet might suffer with increased attention to screen media, as research has suggested. In response, we hypothesized that parent-child play on a tablet computer, as representative of interactive media, would generate higher-quality parent-child interactions than toy play or watching TV. We examined the emotional availability of mothers and their 2-year-old child during the previous three contexts using a randomized crossover design (n = 22) in a laboratory room. Among other results, mothers were more sensitive and structuring during joint gaming on a tablet than when engaged in toy play or watching TV. In addition, mothers were more hostile toward their children during play with traditional toys than during joint tablet gaming and television co-viewing. Such findings provide new insights into the impact of new media on parent-child interactions, chiefly by demonstrating that interactive media devices such as tablets can afford growth enhancing parent-child interactions. PMID- 29244210 TI - Full genomic analysis of G1P[8] rotavirus strains recovered from rotavirus vaccinated and non-vaccinated children hospitalized for acute gastroenteritis in Pune, western India. AB - G1P[8] rotaviruses are predominant in causing diarrheal infections in humans all over the world. This study reports the analysis of complete genomes of G1P[8] strains, two each recovered from RotarixTM vaccine recipients and non-recipients hospitalized for acute gastroenteritis in Pune, western India. All four strains showed a genogroup-1 backbone with intra-genotypic diversity in the VP7 and VP4 gene segments and a homogeneous constellation of the internal gene segments. A divergence in the range of 1.4-17.3% from RotarixTM vaccine strain was revealed by structural and non-structural genes of the strains at nucleotide and amino acid level. These data reflect ability of such G1P[8] strains to cause rotavirus infections in humans. PMID- 29244211 TI - Individuation in relation to parents as a predictor of career goals and career optimism in emerging adults. AB - The aim of this study was to examine the associations of Slovenian emerging adults' individuation characteristics (in relation to mother and father) with career goals and career optimism. We were interested in contributions of age, gender, certainty of study choice, and individuation dimensions when predicting intrinsic/extrinsic career goals and career optimism. The participants provided self-reports on the Individuation Test for Emerging Adults, the Career Goals Scale and the Career Futures Inventory. The results showed that age did not relate to emerging adults' career goals; however, older students reported lower career optimism than their younger counterparts. Furthermore, certainty of study choice was the most important predictor of career optimism, and, along with gender, of intrinsic career goals. Emerging adults who reported higher connectedness with both parents and self-reliance in relation to mother had higher intrinsic career goals, while self-reliance in relation to mother was positively associated with stronger optimism about an individual's future career. Fear of disappointing both parents significantly contributed to the prediction of extrinsic career goals and optimism, while parental intrusiveness did not add significantly to the prediction of the two measured career outcomes. The study confirmed the correlational effects of positive and negative aspects of individuation on career outcomes in emerging adulthood. PMID- 29244212 TI - Detection of enteric- and non-enteric adenoviruses in gastroenteritis patients, Bangladesh, 2012-2015. AB - Human adenoviruses (HAdVs) are common cause of nonbacterial acute gastroenteritis worldwide. Limited data exist on HAdVs molecular epidemiology associated with acute gastroenteritis in Bangladesh. We describe the genetic diversity and epidemiology of HAdVs among hospitalized diarrhea patients, including HAdV genotypes, clinical symptoms, and co-infecting enteric pathogens. Stool samples were collected from ongoing diarrhea surveillance during 2012-2015. HAdV was detected using PCR and genotyped by sequencing and phylogenetic analysis. Detailed socio-demographic and clinical information regarding each individual was recorded such as duration of diarrhea, dehydration status, vomiting, abdominal pain, fever, and severity. Of 871 fecal specimens, HAdV DNA was detected in 93 (10.7%). Among them 56% were co-infected with other known enteric viral and bacterial pathogens and 31.6% had severe gastroenteritis. The majority (55%) of HAdV positives were children <5 years of age. Two main clinical symptoms in HAdV infected patients were diarrhea and vomiting. HAdVs were detected throughout the year with low prevalence in winter (November-January). Five HAdV species (A, B, C, D, and F) including 17 different genotypes were identified during the study period, with enteric HAdV species F (HAdV-40/41) being the most dominant. However, non-enteric HAdV were also detected in substantial proportion of specimens (15% species C, 15% species D, 10.8% species A, and 4.3% species B). Our study demonstrates high genetic diversity of HAdVs including enteric and non enteric HAdVs among diarrhea patients and provides a foundation for further clarification of the role of non-enteric HAdVs in diarrheal diseases. PMID- 29244213 TI - Trajectories of impairment in amyotrophic lateral sclerosis: Insights from the Pooled Resource Open-Access ALS Clinical Trials cohort. AB - INTRODUCTION: Rate of decline of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score is a common outcome measure and a powerful predictor of mortality in ALS. METHODS: Observed rate of decline (postslope) of ALSFRS-R, its linearity, and its relationship to decline at first visit (preslope) were examined in the Pooled Resource Open-Access ALS Clinical Trials cohort by using longitudinal mixed effects models. RESULTS: Mean ALSFRS-R postslope in 3,367 patients was -0.99 points/month. Preslope and postslope were correlated and had powerful effects on survival. ALSFRS-R trajectories were slightly accelerated overall, but slope and direction/degree of curvature varied. Subscore decline was sequential by site of onset. Respiratory subscore decline was the least steep. DISCUSSION: Variable curvilinearity of ALSFRS-R trajectories confounds interpretation in clinical studies that assume linear decline. Subscore trajectories recapitulate phenotypic diversity and topographical progression of ALS. ALSFRS-R is better used as a multidimensional measure. Muscle Nerve 57: 937 945, 2018. PMID- 29244214 TI - Mixed viral infections of the respiratory tract; an epidemiological study during consecutive winter seasons. AB - The current study aimed to describe the molecular epidemiology of mixed respiratory viral infections during consecutive winter seasons in a tertiary care hospital. Patients with symptoms of respiratory tract infection were evaluated during the 2009-2011 and 2013-15 winter seasons. A clinical microarray technique was used for viral detection. Clinical and epidemiological data were correlated with mixed viral detection and the need for hospitalization. In 332 out of 604 (54.4%) evaluated patients (17.6% children) a respiratory virus was identified. Mixed viral infections were diagnosed in 68/332 (20.5%) patients with virus detection (66.2% mixed Influenza-RSV infections). Mixed viral infections were more commonly detected in children (OR 3.7; 95%CI 1.9-5.6, P < 0.01) and patients with comorbidities. In logistic regression analyses, mixed viral infections were associated with younger age (mean age 30.4 years vs. 41.8 years, P <= 0.001) and increased rates of fever (OR: 2.7; 95%CI 1.04-7.2, P < 0.05) but no adverse outcomes or increased rates of hospitalization. High rates of mixed viral infections were noted during all winter seasons (especially Influenza and RSV) and were more common in younger patients. The clinical significance of mixed respiratory viral infection needs further elucidation. PMID- 29244215 TI - Development of a validated liquid chromatographic method for quantification of sorafenib tosylate in the presence of stress-induced degradation products and in biological matrix employing analytical quality by design approach. AB - The current research work envisages an analytical quality by design-enabled development of a simple, rapid, sensitive, specific, robust and cost-effective stability-indicating reversed-phase high-performance liquid chromatographic method for determining stress-induced forced-degradation products of sorafenib tosylate (SFN). An Ishikawa fishbone diagram was constructed to embark upon analytical target profile and critical analytical attributes, i.e. peak area, theoretical plates, retention time and peak tailing. Factor screening using Taguchi orthogonal arrays and quality risk assessment studies carried out using failure mode effect analysis aided the selection of critical method parameters, i.e. mobile phase ratio and flow rate potentially affecting the chosen critical analytical attributes. Systematic optimization using response surface methodology of the chosen critical method parameters was carried out employing a two-factor three-level-13-run, face-centered cubic design. A method operable design region was earmarked providing optimum method performance using numerical and graphical optimization. The optimum method employed a mobile phase composition consisting of acetonitrile and water (containing orthophosphoric acid, pH 4.1) at 65:35 v/v at a flow rate of 0.8 mL/min with UV detection at 265 nm using a C18 column. Response surface methodology validation studies confirmed good efficiency and sensitivity of the developed method for analysis of SFN in mobile phase as well as in human plasma matrix. The forced degradation studies were conducted under different recommended stress conditions as per ICH Q1A (R2). Mass spectroscopy studies showed that SFN degrades in strongly acidic, alkaline and oxidative hydrolytic conditions at elevated temperature, while the drug was per se found to be photostable. Oxidative hydrolysis using 30% H2 O2 showed maximum degradation with products at retention times of 3.35, 3.65, 4.20 and 5.67 min. The absence of any significant change in the retention time of SFN and degradation products, formed under different stress conditions, ratified selectivity and specificity of the systematically developed method. PMID- 29244216 TI - Relationship between glenoid deformity and gait characteristics in a rat model of neonatal brachial plexus injury. AB - : Neonatal brachial plexus injury (NBPI) results in substantial postural and functional impairments associated with underlying muscular and osseous deformities. We examined the relationship between glenoid deformity severity and gait in a rat model of NBPI, an established model for studying the in vivo pathomechanics of NBPI. At 8 weeks post-operatively, we monitored the gait of 24 rat pups who exhibited varying degrees of glenoid deformity following unilateral brachial plexus neurectomy and chemodenervation interventions administered 5 days postnatal. Five basic stride and stance metrics were calculated for the impaired forelimbs over four consecutive gait cycles. Bilateral differences in glenoid version (DeltaGAv ) and inclination (DeltaGAi ) angles were computed from data for the same rats as reported in a previous study. A linear regression model was generated for each deformity-gait pair to identify significant relationships between the two. DeltaGAv was not significantly correlated with any gait measurements, while DeltaGAi significantly correlated with all five gait measurements. Specifically, DeltaGAi was significantly positively correlated with stride length (R2 = 0.38, p = 0.001) and stance factor (R2 = 0.45, p < 0.001), and significantly negatively correlated with stance width (R2 = 0.24, p = 0.016), swing/stance ratio (R2 = 0.17, p = 0.046), and stride frequency (R2 = 0.33, p = 0.003). Rats with declined glenoids exhibited the most altered gait. CLINICAL SIGNIFICANCE: Our findings link musculoskeletal changes and functional outcomes in an NBPI rat model. Thus, gait analysis is a potentially useful, non invasive, quantitative way to investigate the effects of injury and deformity on limb function in the NBPI rat model. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1991-1997, 2018. PMID- 29244217 TI - The follow-up of progressive hypertrophic cardiomyopathy using magnetic resonance rotating frame relaxation times. AB - Magnetic resonance rotating frame relaxation times are an alternative non contrast agent choice for the diagnosis of chronic myocardial infarct. Fibrosis typically occurs in progressive hypertrophic cardiomyopathy. Fibrosis has been imaged in myocardial infarcted tissue using rotating frame relaxation times, which provides the possibility to follow up progressive cardiomyopathy without contrast agents. Mild and severe left ventricular hypertrophy were induced in mice by transverse aortic constriction, and the longitudinal rotating frame relaxation times (T1rho ) and relaxation along the fictitious field (TRAFF2 , TRAFF3 ) were measured at 5, 10, 24, 62 and 89 days after transverse aortic constriction in vivo. Myocardial fibrosis was verified using Masson's trichrome staining. Increases in the relative relaxation time differences of T1rho , together with TRAFF2 and TRAFF3 , between fibrotic and remote tissues over time were observed. Furthermore, TRAFF2 and TRAFF3 showed higher relaxation times overall in fibrotic tissue than T1rho . Relaxation time differences were highly correlated with an excess of histologically verified fibrosis. We found that TRAFF2 and TRAFF3 are more sensitive than T1rho to hypertrophic cardiomyopathy related tissue changes and can serve as non-invasive diagnostic magnetic resonance imaging markers to follow up the mouse model of progressive hypertrophic cardiomyopathy. PMID- 29244218 TI - Person-specific contribution of neuropathologies to cognitive loss in old age. AB - OBJECTIVE: Mixed neuropathologies are the most common cause of dementia at the population level, but how different neuropathologies contribute to cognitive decline at the individual level remains unknown. We quantified the contribution of 9 neuropathologies to cognitive loss at an individual level. METHODS: Participants (n = 1,079) came from 2 longitudinal clinical-pathologic studies of aging. All completed 2 + cognitive evaluations (maximum = 22), died, and underwent neuropathologic examinations to identify Alzheimer disease (AD), other neurodegenerative diseases, and vascular pathologies. Linear mixed models examined associations of neuropathologies with cognitive decline and estimated the proportion of cognitive loss accounted for by each neuropathology at a person specific level. RESULTS: Neuropathology was ubiquitous, with 94% of participants having 1+, 78% having 2+, 58% having 3+, and 35% having 4+. AD was most frequent (65%) but rarely occurred in isolation (9%). Remarkably, >230 different neuropathologic combinations were observed, each of which occurred in <6% of the cohort. The relative contributions of specific neuropathologies to cognitive loss varied widely across individuals. Although AD accounted for an average of about 50% of the observed cognitive loss, the proportion accounted for at the individual level ranged widely from 22% to 100%. Lewy bodies and hippocampal sclerosis also had potent effects, but again their impacts varied at the person specific level. INTERPRETATION: There is much greater heterogeneity in the comorbidity and cognitive impact of age-related neuropathologies than currently appreciated, suggesting an urgent need for novel therapeutic approaches that embrace the complexity of disease to combat cognitive decline in old age. Ann Neurol 2018;83:74-83. PMID- 29244219 TI - Bis(dioxaborine) Dyes with Variable pi-Bridges: Towards Two-Photon Absorbing Fluorophores with Very High Brightness. AB - Bis(dioxaborine) dyes of the A-pi-A format (A: acceptor, pi: conjugated bridge) were prepared and photophysically characterized. The best performing dyes feature (a) visible-light absorption (>400 nm), (b) high molar absorption coefficients (up to 70000 m-1 cm-1 ), (c) Stokes shifts in the range of ca. 2500-5800 cm-1 , and (d) strong fluorescence emission with quantum yields of up to 0.74. This yields very bright-emitting dyes for one-photon excitation. However, the most intriguing feature of the dyes is their strong two-photon absorption. This was achieved by means of increased pi-conjugation in the phenylene or phenylene thiophene bridges through the variation of the conjugation length and rigidity. This provided two-photon absorption cross sections of up to 2800 GM (1 Goeppert Mayer (GM)=10-50 cm4 s photon-1 ). Considering the mentioned high fluorescence quantum yields, exceptionally bright-emitting A-pi-A two-photon absorbing dyes with low molecular mass are obtained. Time-dependent density-functional theory calculations corroborated the experimental results. PMID- 29244220 TI - Closing the Gap: Structural Evidence for the Missing Hexabromide Dianion [Br6 ]2. AB - The formation and experimental characterization of the first hexabromide dianion is presented. This dianion fills the last remaining gap in the series of polybromides from the tribromide [Br3 ]- to the undecabromide [Br11 ]- . The experimental results are compared to quantum-chemical calculations. These calculations predict-based on electrostatic interactions-a T-structure for the hexabromide dianion, while halogen-halogen bonding favors the hockey-stick-like structure experimentally found in the crystal structure. The hexabromide is built of two tribromide moieties, one of which is highly asymmetric. The classification of this unique anion as hexabromide dianion is discussed. The counter ion [C5 H10 N2 Br]+ stabilizes the hexabromide dianion by additional sigma-hole interactions. The compound is fully characterized by mass spectrometry, NMR-, IR and single crystal Raman spectroscopies as well as single-crystal X-ray diffraction. PMID- 29244221 TI - Routes of transmission of influenza A H1N1, SARS CoV, and norovirus in air cabin: Comparative analyses. AB - Identifying the exact transmission route(s) of infectious diseases in indoor environments is a crucial step in developing effective intervention strategies. In this study, we proposed a comparative analysis approach and built a model to simulate outbreaks of 3 different in-flight infections in a similar cabin environment, that is, influenza A H1N1, severe acute respiratory syndrome (SARS) coronavirus (CoV), and norovirus. The simulation results seemed to suggest that the close contact route was probably the most significant route (contributes 70%, 95% confidence interval [CI]: 67%-72%) in the in-flight transmission of influenza A H1N1 transmission; as a result, passengers within 2 rows of the index case had a significantly higher infection risk than others in the outbreak (relative risk [RR]: 13.4, 95% CI: 1.5-121.2, P = .019). For SARS CoV, the airborne, close contact, and fomite routes contributed 21% (95% CI: 19%-23%), 29% (95% CI: 27% 31%), and 50% (95% CI: 48%-53%), respectively. For norovirus, the simulation results suggested that the fomite route played the dominant role (contributes 85%, 95% CI: 83%-87%) in most cases; as a result, passengers in aisle seats had a significantly higher infection risk than others (RR: 9.5, 95% CI: 1.2-77.4, P = .022). This work highlighted a method for using observed outbreak data to analyze the roles of different infection transmission routes. PMID- 29244222 TI - Diffusion-weighted imaging features of breast tumours and the surrounding stroma reflect intrinsic heterogeneous characteristics of molecular subtypes in breast cancer. AB - Breast cancer heterogeneity is the main obstacle preventing the identification of patients with breast cancer with poor prognoses and treatment responses; however, such heterogeneity has not been well characterized. The purpose of this retrospective study was to reveal heterogeneous patterns in the apparent diffusion coefficient (ADC) signals in tumours and the surrounding stroma to predict molecular subtypes of breast cancer. A dataset of 126 patients with breast cancer, who underwent preoperative diffusion-weighted imaging (DWI) on a 3.0-T image system, was collected. Breast images were segmented into regions comprising the tumour and surrounding stromal shells in which features that reflect heterogeneous ADC signal distribution were extracted. For each region, imaging features were computed, including the mean, minimum, variance, interquartile range (IQR), range, skewness, kurtosis and entropy of ADC values. Univariate and stepwise multivariate logistic regression modelling was performed to identify the magnetic resonance imaging features that optimally discriminate luminal A, luminal B, human epidermal growth factor 2 (HER2)-enriched and basal like molecular subtypes. The performance of the predictive models was evaluated using the area under the receiver operating characteristic curve (AUC). Univariate logistic regression analysis showed that the skewness in the tumour boundary achieved an AUC of 0.718 for discrimination between luminal A and non luminal A tumours, whereas the IQR of the ADC value in the tumour boundary had an AUC of 0.703 for classification of the HER2-enriched subtype. Imaging features in the tumour boundary and the proximal peritumoral stroma corresponded to a higher overall prediction performance than those in other regions. A multivariate logistic regression model combining features in all the regions achieved an overall AUC of 0.800 for the classification of the four tumour subtypes. These findings suggest that features in the tumour boundary and stroma around the tumour may be further assessed as potential predictors of molecular subtypes of breast cancer. PMID- 29244223 TI - Fixed-bearing medial unicompartmental knee arthroplasty restores neither the medial pivoting behavior nor the ligament forces of the intact knee in passive flexion. AB - Medial unicompartmental knee arthroplasty (UKA) is an accepted treatment for isolated medial osteoarthritis. However, using an improper thickness for the tibial component may contribute to early failure of the prosthesis or disease progression in the unreplaced lateral compartment. Little is known of the effect of insert thickness on both knee kinematics and ligament forces. Therefore, a computational model of the tibiofemoral joint was used to determine how non conforming, fixed bearing medial UKA affects tibiofemoral kinematics, and tension in the medial collateral ligament (MCL) and the anterior cruciate ligament (ACL) during passive knee flexion. Fixed bearing medial UKA could not maintain the medial pivoting that occurred in the intact knee from 0 degrees to 30 degrees of passive flexion. Abnormal anterior-posterior (AP) translations of the femoral condyles relative to the tibia delayed coupled internal tibial rotation, which occurred in the intact knee from 0 degrees to 30 degrees of flexion, but occurred from 30 degrees to 90 degrees of flexion following UKA. Increasing or decreasing tibial insert thickness following medial UKA also failed to restore the medial pivoting behavior of the intact knee despite modulating MCL and ACL forces. Reduced AP constraint in non-conforming medial UKA relative to the intact knee leads to abnormal condylar translations regardless of insert thickness even with intact cruciate and collateral ligaments. This finding suggests that the conformity of the medial compartment as driven by the medial meniscus and articular morphology plays an important role in controlling AP condylar translations in the intact tibiofemoral joint during passive flexion. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1868-1875, 2018. PMID- 29244224 TI - Osteochondral repair using an acellular dermal matrix-pilot in vivo study in a rabbit osteochondral defect model. AB - : The aim of this pilot project was to introduce a novel use of acellular dermal matrix (ADM) in combination with infrapatellar fat pad mesenchymal stromal cells (IPFP-MSCs) to effect repair in a rabbit osteochondral defect model. ADM, in a range of surgical procedures, has been shown to promote remodelling of tissue at the site of implantation. Rabbit-derived ADM (rabADM) was prepared from the skin of donor rabbits. Autologous IPFP-MSCs were obtained at the time of knee surgery. Osteochondral defects (4 mm cartilage outer/2 mm central bone defect) were drilled into distal femoral condyles of 12 New Zealand White rabbits. Treatments groups: (i) defect only; (ii) rabADM alone; (iii) IPFP-MSCs alone; and (iv) rabADM with IPFP-MSCs. Condyles were harvested at 12 weeks, and analyzed using histology, immunohistochemistry (types I and II collagen) and histomorphometry to evaluate osteochondral repair. The rabADM only group achieved the highest ratio of type II to non-type II collagen (77.3%) using areal measures (similar to normal cartilage), which indicated a higher quality of cartilage repair. The addition of IPFP-MSCs, with or without rabADM, formed a fibrous collagen cap above the lesion site not seen with rabADM alone. Macroscopically, there was no joint erosion, inflammation, swelling or deformity, and all animals maintained full range of motion. CONCLUSIONS: RabADM alone resulted in neocartilage formation similar to native cartilage. IPFP-MSCs limited osteochondral repair and contributed to fibrosis, even in combination with the rabADM. Further studies using ADM for osteochondral repair are warranted in a more appropriate pre clinical model of osteochondral repair. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1919-1928, 2018. PMID- 29244225 TI - Combination of surface and 'vertical' loop elements improves receive performance of a human head transceiver array at 9.4 T. AB - Ultra-high-field (UHF, >=7 T) human magnetic resonance imaging (MRI) provides undisputed advantages over low-field MRI (<=3 T), but its development remains challenging because of numerous technical issues, including the low efficiency of transmit (Tx) radiofrequency (RF) coils caused by the increase in tissue power deposition with frequency. Tight-fit human head transceiver (TxRx) arrays improve Tx efficiency in comparison with Tx-only arrays, which are larger in order to fit multi-channel receive (Rx)-only arrays inside. A drawback of the TxRx design is that the number of elements in an array is limited by the number of available high-power RF Tx channels (commonly 8 or 16), which is not sufficient for optimal Rx performance. In this work, as a proof of concept, we developed a method for increasing the number of Rx elements in a human head TxRx surface loop array without the need to move the loops away from a sample, which compromises the array Tx performance. We designed and constructed a prototype 16-channel tight fit array, which consists of eight TxRx surface loops placed on a cylindrical holder circumscribing a head, and eight Rx-only vertical loops positioned along the central axis (parallel to the magnetic field B0 ) of each TxRx loop, perpendicular to its surface. We demonstrated both experimentally and numerically that the addition of the vertical loops has no measurable effect on the Tx efficiency of the array. An increase in the maximum local specific absorption rate (SAR), evaluated using two human head voxel models (Duke and Ella), measured 3.4% or less. At the same time, the 16-element array provided 30% improvement of central signal-to-noise ratio (SNR) in vivo relative to a surface loop eight element array. The novel array design also demonstrated an improvement in the parallel Rx performance in the transversal plane. Thus, using this method, both the Rx and Tx performance of the human head array can be optimized simultaneously. PMID- 29244226 TI - High-frequency oscillations are not better biomarkers of epileptogenic tissues than spikes. AB - OBJECTIVE: High-frequency oscillations (HFOs) in intracerebral EEG (stereoelectroencephalography; SEEG) are considered as better biomarkers of epileptogenic tissues than spikes. How this can be applied at the patient level remains poorly understood. We investigated how well HFOs and spikes can predict epileptogenic regions with a large spatial sampling at the patient level. METHODS: We analyzed non-REM sleep SEEG recordings sampled at 2,048Hz of 30 patients. Ripples (Rs; 80-250Hz), fast ripples (FRs; 250-500Hz), and spikes were automatically detected. Rates of these markers and several combinations-spikes co occurring with HFOs or FRs and cross-rate (Spk?HFO)-were compared to a quantified measure of the seizure onset zone (SOZ) by performing a receiver operating characteristic analysis for each patient individually. We used a Wilcoxon signed rank test corrected for false-discovery rate to assess whether a marker was better than the others for predicting the SOZ. RESULTS: A total of 2,930 channels was analyzed (median of 100 channels per patient). The HFOs or any of its variants were not statistically better than spikes. Only one feature, the cross rate, was better than all the other markers. Moreover, fast ripples, even though very specific, were not delineating all epileptogenic tissues. INTERPRETATION: At the patient level, the performance of HFOs is weakened by the presence of strong physiological HFO generators. Fast ripples are not sensitive enough to be the unique biomarker of epileptogenicity. Nevertheless, combining HFOs and spikes using our proposed measure-the cross-rate-is a better strategy than using only one marker. Ann Neurol 2018;83:84-97. PMID- 29244228 TI - High-resolution hyperpolarized metabolic imaging of the rat heart using k-t PCA and k-t SPARSE. PMID- 29244227 TI - Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis. AB - : Primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCa). Surveillance for GBCa is recommended, but the clinical utility of surveillance for other hepatobiliary cancers (HBCa) in PSC, namely CCA and hepatocellular carcinoma (HCC), remains unclear. We aimed to determine whether surveillance is associated with better survival after diagnosis of HBCa in patients with PSC. Medical records of PSC patients seen at the Mayo Clinic Rochester from 1995 to 2015 were reviewed. Patients were included if they had >=1 year of follow-up and developed HBCa. Patients were categorized according to their surveillance status (abdominal imaging, carbohydrate antigen 19-9, and alpha-fetoprotein). The primary endpoints were HBCa recurrence, HBCa-related death, and all-cause mortality. Overall survival was assessed by the Kaplan-Meier survival method; HBCa-related survival was assessed using competing risk regression. Tests of significance were two-tailed, and a P value <0.05 was considered statistically significant. From 1995 to 2015, a total of 79 of 830 PSC patients were diagnosed with HBCa. Cumulative follow-up was 712 and 283 person years pre- and post-HBCa diagnosis, respectively. Seventy-eight percent of patients (54/79) developed CCA, 21% (17/79) HCC, 6% (5/79) GBCa, 3% (2/79) both CCA and HCC, and 1% (1/79) both HCC and GBCa. Fifty-one percent (40/79) were under HBCa surveillance, and 49% (39/79) were not. Patients in the surveillance group had significantly higher 5-year overall survival (68% versus 20%, respectively; P < 0.001) and significantly lower 5-year probability of experiencing an HBCa-related adverse event (32% versus 75%, respectively; P < 0.001) compared with the no-surveillance group. CONCLUSION: This study demonstrates that HBCa surveillance significantly improves outcomes, including survival, in patients with PSC. (Hepatology 2018;67:2338-2351). PMID- 29244229 TI - Transoral robotic surgery for residual and recurrent oropharyngeal cancers: Exploratory study of surgical innovation using the IDEAL framework for early phase surgical studies. AB - BACKGROUND: The purpose of this study was to identify the role of transoral robotic surgery (TORS) in the management of residual and recurrent oropharyngeal cancer. METHODS: IDEAL (Idea, Development, Exploration, Assessment, Long-term Follow-up) 2a framework. RESULTS: Of 26 patients assessed for TORS, 21 underwent the procedure, 5 underwent open resection (4 due to unsuitable anatomy/tumor extent and 1 on the basis of patient choice). Three patients underwent intraoperative ultrasound-assisted robotic resection, and 3 received robotic assisted free flap inset. A technical refinement for TORS of residual and recurrent oropharyngeal cancer of the tongue base is described. Actuarial plots showed estimated overall survival of 48.2%, local control of 76.6%, and disease specific survival of 77.1% at 42.6 months. CONCLUSION: TORS is a valid management option for residual and recurrent oropharyngeal cancer. Oncologic outcomes are comparable to open surgery and transoral laser microsurgery, with the added advantages of en bloc resections, facility for intraoperative ultrasound imaging, and inset of free flaps without mandibular split. PMID- 29244230 TI - An extremely rare case of Epstein-Barr virus-associated gastric carcinoma with differentiation to neuroendocrine carcinoma. AB - Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVGC) is defined as a neoplasm comprising monoclonal proliferation of EBV-infected gastric epithelial cells. Although the typical histology is gastric carcinoma with lymphoid stroma (GCLS), the histologic features of the tumor vary. We report herein the case of a 78-year-old man with multiple simultaneous EBVGCs revealing different histopathologic morphologies; one was mixed adenoneuroendocrine carcinoma (MANEC), and the other was GCLS. Both tumor types exhibited positive results for EBV in situ hybridization. To the best of our knowledge, this represents the first report of EBVGC showing neuroendocrine differentiation. Immunohistochemistry also revealed a loss of gastrointestinal features, including CDX2, MUC5AC, and MUC6 expression, among tumor cells from the neuroendocrine component of the MANEC. We describe the pathologic features of this rare neoplasm and discuss the mechanisms underlying the neuroendocrine differentiation of EBVGC cells, along with providing a brief review of the literature. PMID- 29244231 TI - Differences in regional grey matter volumes in currently ill patients with anorexia nervosa. AB - Neurobiological findings in anorexia nervosa (AN) are inconsistent, including differences in regional grey matter volumes. Methodological limitations often contribute to the inconsistencies reported. The aim of this study was to improve on these methodologies by utilising voxel-based morphometry (VBM) analysis with the use of diffeomorphic anatomic registration through an exponentiated lie algebra algorithm (DARTEL), in a relatively large group of individuals with AN. Twenty-six individuals with AN and 27 healthy controls underwent a T1-weighted magnetic resonance imaging (MRI) scan. AN participants were found to have reduced grey matter volumes in a number of areas including regions of the basal ganglia (including the ventral striatum), and parietal and temporal cortices. Body mass index (BMI) and global scores on the Eating Disorder Examination Questionnaire (EDE-Q) were also found to correlate with grey matter volumes in a region of the brainstem (including the substantia nigra and ventral tegmental area) in AN, and predicted 56% of the variance in grey matter volumes in this area. The brain regions associated with grey matter reductions in AN are consistent with regions responsible for cognitive deficits associated with the illness including anhedonia, deficits in affect perception and saccadic eye movement abnormalities. Overall, the findings suggest reduced grey matter volumes in AN that are associated with eating disorder symptomatology. PMID- 29244232 TI - Synthesis of Phenols: Organophotoredox/Nickel Dual Catalytic Hydroxylation of Aryl Halides with Water. AB - A highly effective hydroxylation reaction of aryl halides with water under synergistic organophotoredox and nickel catalysis is reported. The OH group of the resulting phenols originates from water, following deprotonation facilitated by an intramolecular base group on the ligand. Significantly, aryl bromides as well as less reactive aryl chlorides served as effective substrates to afford phenols with a wide range of functional groups. Without the need for a strong inorganic base or an expensive noble-metal catalyst, this process can be applied to the efficient preparation of diverse phenols and enables the hydroxylation of multifunctional pharmaceutically relevant aryl halides. PMID- 29244233 TI - Inadequate brain glycogen or sleep increases spreading depression susceptibility. AB - OBJECTIVE: Glycogen in astrocyte processes contributes to maintenance of low extracellular glutamate and K+ concentrations around excitatory synapses. Sleep deprivation (SD), a common migraine trigger, induces transcriptional changes in astrocytes, reducing glycogen breakdown. We hypothesize that when glycogen utilization cannot match synaptic energy demand, extracellular K+ can rise to levels that activate neuronal pannexin-1 channels and downstream inflammatory pathway, which might be one of the mechanisms initiating migraine headaches. METHODS: We suppressed glycogen breakdown by inhibiting glycogen phosphorylation with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and by SD. RESULTS: DAB caused neuronal pannexin-1 large pore opening and activation of the downstream inflammatory pathway as shown by procaspase-1 cleavage and HMGB1 release from neurons. Six-hour SD induced pannexin-1 mRNA. DAB and SD also lowered the cortical spreading depression (CSD) induction threshold, which was reversed by glucose or lactate supplement, suggesting that glycogen-derived energy substrates are needed to prevent CSD generation. Supporting this, knocking down the neuronal lactate transporter MCT2 with an antisense oligonucleotide or inhibiting glucose transport from vessels to astrocytes with intracerebroventricularly delivered phloretin reduced the CSD threshold. In vivo recordings with a K+ sensitive/selective fluoroprobe, Asante Potassium Green-4, revealed that DAB treatment or SD caused a significant rise in extracellular K+ during whisker stimulation, illustrating the critical role of glycogen in extracellular K+ clearance. INTERPRETATION: Synaptic metabolic stress caused by insufficient glycogen-derived energy substrate supply can activate neuronal pannexin-1 channels as well as lower the CSD threshold. Therefore, conditions that limit energy supply to synapses (eg, SD) may predispose to migraine attacks, as suggested by genetic studies associating glucose or lactate transporter deficiency with migraine. Ann Neurol 2018;83:61-73. PMID- 29244234 TI - Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia. AB - OBJECTIVE: To determine the pathogenic mechanisms of autoantibodies to the cell adhesion molecule Caspr2 in acquired neuromyotonia and autoimmune encephalitis. METHODS: Caspr2-positive samples were confirmed using a cell-based assay, and their IgG subtypes were determined by enzyme-linked immunosorbent assay and cell based assay. A solid phase binding assay quantified the binding of Caspr2 to contactin-2 in the presence of Caspr2 autoantibodies. Living cultures of primary rat hippocampal neurons were incubated with Caspr2-positive or control sera, and the distribution of Caspr2-positive immunofluorescent puncta and total surface Caspr2 was quantified. HEK cells transfected to express Caspr2 were incubated with Caspr2-positive or control samples, and cell-surface biotinylation and Western blot were used to assess total, internalized, and surface levels of Caspr2. RESULTS: We confirmed 6 samples with strong Caspr2 reactivity. IgG4 Caspr2 antibodies were present in all 6 cases. Caspr2 interacted with another cell adhesion molecule, contactin-2, with nanomolar affinity in the solid phase assay, and Caspr2 autoantibodies inhibited this interaction. Caspr2 autoantibodies did not affect the surface expression of Caspr2 in rat primary hippocampal neurons or transfected HEK cells. INTERPRETATION: Caspr2 autoantibodies inhibit the interaction of Caspr2 with contactin-2 but do not cause internalization of Caspr2. Functional blocking of cell adhesion molecule interactions represents a potential mechanism with therapeutic implications for IgG4 autoantibodies to cell adhesion molecules in neurological diseases. Ann Neurol 2018;83:40-51. PMID- 29244236 TI - Pyro-Phyllobilins: Elusive Chlorophyll Catabolites Lacking a Critical Carboxylate Function of the Natural Chlorophylls. AB - A beta-keto ester grouping is a characteristic of ring E of the chlorophylls (Chls). Its presence has also reinforced the original identification of nonfluorescent Chl catabolites (NCCs) as colorless, amphiphilic phyllobilins (PBs). Polar NCCs were also detected in higher plants, in which a free carboxyl group replaced the ring E ester group. Such NCCs are surprisingly resistant to loss of this carboxyl unit, and NCCs lacking the latter, that is, pyro-NCCs (pyNCCs), have not been reported. Intrigued by the question of the natural occurrence of pyro-phyllobilins (pyPBs), we have prepared a representative pyNCC by decarboxylation of a natural NCC. We also converted the pyNCC into its yellow oxidation product, a pyro-YCC (pyYCC). The solution structures of pyNCC and of pyYCC, and a crystal structure of the pyYCC methyl ester (pyYCC-Me) were obtained. pyYCC-Me features the same remarkable H-bonded and pi-stacked dimer structure as the corresponding natural yellow Chl catabolite (YCC) with the ring E methyl ester group. Indeed, the latter substituent has little effect on the structure, as well as on the unique self-assembly and photoswitch behavior of yellow PBs. PMID- 29244235 TI - New Therapy for Refractory Chronic Mechanical Low Back Pain-Restorative Neurostimulation to Activate the Lumbar Multifidus: One Year Results of a Prospective Multicenter Clinical Trial. AB - OBJECTIVES: The purpose of the international multicenter prospective single arm clinical trial was to evaluate restorative neurostimulation eliciting episodic contraction of the lumbar multifidus for treatment of chronic mechanical low back pain (CMLBP) in patients who have failed conventional therapy and are not candidates for surgery or spinal cord stimulation (SCS). MATERIALS AND METHODS: Fifty-three subjects were implanted with a neurostimulator (ReActiv8, Mainstay Medical Limited, Dublin, Ireland). Leads were positioned bilaterally with electrodes close to the medial branch of the L2 dorsal ramus nerve. The primary outcome measure was low back pain evaluated on a 10-Point Numerical Rating Scale (NRS). Responders were defined as subjects with an improvement of at least the Minimal Clinically Important Difference (MCID) of >=2-point in low back pain NRS without a clinically meaningful increase in LBP medications at 90 days. Secondary outcome measures included Oswestry Disability Index (ODI) and Quality of Life (QoL; EQ-5D). RESULTS: For 53 subjects with an average duration of CLBP of 14 years and average NRS of 7 and for whom no other therapies had provided satisfactory pain relief, the responder rate was 58%. The percentage of subjects at 90 days, six months, and one year with >=MCID improvement in single day NRS was 63%, 61%, and 57%, respectively. Percentage of subjects with >=MCID improvement in ODI was 52%, 57%, and 60% while those with >=MCID improvement in EQ-5D was 88%, 82%, and 81%. There were no unanticipated adverse events (AEs) or serious AEs related to the device, procedure, or therapy. The initial surgical approach led to a risk of lead fracture, which was mitigated by a modification to the surgical approach. CONCLUSIONS: Electrical stimulation to elicit episodic lumbar multifidus contraction is a new treatment option for CMLBP. Results demonstrate clinically important, statistically significant, and lasting improvement in pain, disability, and QoL. PMID- 29244237 TI - Regional Susceptibility in VCD Spectra to Dynamic Molecular Motions: The Case of a Benzyl alpha-Hydroxysilane. AB - Experimental and theoretical studies of the vibrational circular dichroism (VCD) spectrum of 3-methyl-1-(methyldiphenlsilyl)-1-phenylbutan-1-ol, whose absolute configuration is key to elucidating the Brook rearrangement of tertiary benzylic alpha-hydroxylsilanes, are presented. It is found that the entire OH-bending region in this spectrum-a region that provides important marker bands-cannot be reproduced at all by standard theoretical approaches even though other regions are well described. Using a novel approach to disentangle contributions to the rotational strength of these bands, internal coordinates are identified that critically influence the appearance of this part of the spectrum. We show that the agreement between experiment and theory is greatly improved when structural dynamics along these coordinates are explicitly taken into account. The general applicability of the approach underlines its usefulness for structurally flexible chiral systems, a situation that is more the rule rather than the exception. PMID- 29244238 TI - Transoral robotic surgery for oropharyngeal squamous cell carcinoma in the era of human papillomavirus. AB - BACKGROUND: The emergence of transoral robotic surgery (TORS) ignited the debate between surgical and nonsurgical strategies on oropharyngeal squamous cell carcinoma (SCC) management; a question further complicated by human papillomavirus (HPV). We evaluated the survival by treatment strategy independently in HPV-related and HPV-nonrelated oropharyngeal SCC. METHODS: The National Cancer Database was queried for patients with oropharyngeal SCC with known HPV status who underwent primary TORS or primary radiotherapy. The overall survival (OS) was compared by treatment strategy, including propensity matching to control for confounders. RESULTS: Of 1873 patients, 73% were HPV-positive and 30% were treated with TORS. The propensity-matched patients with HPV-positive disease displayed no significant difference in 3-year survival; 95% versus 91% (P = .116) for the TORS versus primary radiotherapy. In the HPV-negative cohort, TORS was associated with superior survival; 84% versus 66% (P = .01). CONCLUSION: The TORS-based approach was associated with superior survival in patients with HPV-negative oropharyngeal SCC; similar difference was not observed in patients with HPV-positive disease. PMID- 29244239 TI - Motor sequence awareness is impaired in dystonia despite normal performance. AB - OBJECTIVE: Dystonia is a movement disorder that has been associated with impaired motor learning and sequence recognition. However, despite evidence that patients with dystonia have a reduced sense of agency, it is unclear whether dystonia is specifically associated with impaired recognition of a movement sequence. We have shown previously that performance consistency in the temporal and kinematic domains predicts awareness of underlying motor patterns in a finger-tapping task. Since movements in dystonia are characterized by high variability, we predicted that subjects with dystonia would have decreased motor sequence awareness. METHODS: Subjects with dystonia (n = 20) and healthy control adults (n = 30) performed finger-tapping sequences with a common motor pattern and changing stimulus-to-response mappings. Subjects were said to be "aware" of the motor pattern if they recognized that their fingers moved in the same order during each stimulus-to-response remapping. RESULTS: Subjects with dystonia had decreased motor pattern awareness, but those differences were not due to greater performance variability. Subjects with dystonia tapped sequences as series of discrete movements, rather than as a combined series. INTERPRETATION: Dystonia is associated with impaired recognition of a repeating movement pattern. This difference may result from a strategy of separating sequential elements and attending to them individually. Ann Neurol 2018;83:52-60. PMID- 29244241 TI - Vitamin D and gestational diabetes mellitus: a systematic review based on data free of Hawthorne effect. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is an increasingly prevalent disorder, associated with low blood vitamin D level. OBJECTIVES: To evaluate the relationship between vitamin D and GDM. SEARCH STRATEGY: EMBASE, MEDLINE, Cochrane Library and China Biology Medicine disc were searched up to May 2017. The references of previous studies were screened. SELECTION CRITERIA: Observational studies on the relationship between vitamin D and GDM free from Hawthorne effect and randomised controlled trials of vitamin D supplementation during pregnancy for preventing or treating GDM were included. DATA COLLECTION AND ANALYSIS: Data and information of included articles were extracted by duplicate using piloted tables. Newcastle-Ottawa Scale and Cochrane Handbook were used for quality assessment. Random-effects models were used for meta-analyses. Heterogeneity tests, sensitivity analysis and analysis of publication bias were conducted. MAIN RESULTS: Eighty-seven observational studies and 25 randomised controlled trials involving 55 859 and 2445 women, respectively, were included. Low blood vitamin D level during pregnancy was associated with a higher risk of GDM (OR 1.850, 95% CI 1.471-2.328). Blood vitamin D level for women with GDM were lower than in the control women. Blood vitamin D level was associated with fasting plasma glucose (FPG) and homeostasis model of assessment for insulin resistance index (HOMA-IR) (r = -0.100 and r = -0.351), whereas the correlation between blood vitamin D level and fasting insulin (FINS) might be concealed by publication bias. Vitamin D intervention during pregnancy could change the blood levels of vitamin D, FINS, FPG, HOMA-IR, glutathione, C-reactive protein and lipid. CONCLUSIONS: Low blood vitamin D level could increase the risk of GDM, and vitamin D supplementation during pregnancy could ameliorate the condition of GDM. TWEETABLE ABSTRACT: Low blood vitamin D increases gestational diabetes mellitus (GDM) risk. Vitamin D supplementation ameliorates GDM condition. PMID- 29244242 TI - Erratum. PMID- 29244240 TI - B-cell Therapy for Multiple Sclerosis: Entering an era. AB - Monoclonal antibodies that target CD20 expressing B cells represent an important new treatment option for patients with multiple sclerosis (MS). B-cell-depleting therapy is highly effective against relapsing forms of the disease and is also the first treatment approach proven to protect against disability worsening in primary progressive MS. Moreover, evolving clinical experience with B-cell therapy, combined with a more sophisticated understanding of humoral immunity in preclinical models and in patients with MS, has led to major progress in deciphering the immune pathogenesis of MS. Here, we review the nuanced roles of B cells in MS autoimmunity, the clinical data supporting use of ocrelizumab and other anti-CD20 therapies in the treatment of MS, as well as safety and practical considerations for prescribing. Last, we summarize remaining unanswered questions regarding the proper role of anti-CD20 therapy in MS, its limitations, and the future landscape of B-cell-based approaches to treatment. Ann Neurol 2018;83:13 26. PMID- 29244243 TI - Metabolic interaction between urea cycle and citric acid cycle shunt: A guided approach. AB - This article is a guided pedagogical approach, devoted to postgraduate students specializing in biochemistry, aimed at presenting all single reactions and overall equations leading to the metabolic interaction between ureagenesis and citric acid cycle to be incorporated into a two-three lecture series about the interaction of urea cycle with other metabolic pathways. We emphasize that citrate synthetase, aconitase, and isocitrate dehydrogenase, three enzymes of the citric acid cycle are not involved, thus creating a shunt in citric acid cycle. In contrast, the glutamic-oxaloacetate transaminase, which does not belong to citric acid cycle, has a paramount importance in the metabolic interaction of the two cycles, because it generates aspartate, one of the two fuel molecules of urea cycle, and a-ketoglutarate, an intermediate of the citric acid cycle. Finally, students should appreciate that balancing equations for all atoms and charges is not only a stoichiometric task, but strongly facilitates the discussion of the physiological roles of metabolic pathways. Indeed, this exercise has been used in the classroom, to encourage a deeper level of understanding of an important biochemical issue. (c) 2017 by The International Union of Biochemistry and Molecular Biology, 46(2):182-185, 2018. PMID- 29244244 TI - Mineral Apposition Rates in Coronal Dentine of Mandibular First Molars in Soay Sheep: Results of a Fluorochrome Labeling Study. AB - We studied the spatio-temporal variation of mineral apposition rate (MAR) in postnatally formed coronal dentine of mandibular first molars from Soay sheep repeatedly injected with different fluorochromes. MAR declined along the cuspal to cervical crown axis, and from early to late formed dentine, that is, from the dentine at the enamel-dentine-junction (EDJ) to the dentine adjacent to the dentine-pulp-interface (DPI). Highest mean MARs (about 21 um/day) were recorded in cuspal dentine formed in the period of 28-42 days after birth. Lowest values (<2 um/day) were recorded in late-formed (secondary) dentine close to the DPI. The high MARs recorded in the dentine of the cuspal crown portions enable the formation of a large tooth crown within a relatively short period of less than one year. The established MARs in the dentine of the different crown portions of sheep molars will allow a precise determination of the timing of stress events affecting dentine formation. They are also helpful for devising sampling protocols in studies of trace element or stable isotope distributions in sheep dentine aimed at assessing temporal variation of incorporation into forming dentine. Such data are useful in a variety of contexts, including, for example, the exposure to pollutants and the reconstruction of husbandry practices or feeding regimes. Anat Rec, 301:902-912, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29244245 TI - Substance P in Dorsal Root Ganglion Neurons in Young and Adult Rats, after Nociceptive Stimulation during the Neonatal Period. AB - The nervous system is highly plastic during the neonatal period, being sensitive to noxious stimuli, which may cause short- and long-term pain responsivity changes. Understanding plasticity in peripheral pain pathways is crucial, particularly when the nervous system is still under development and remodeling process. Substance P (SP) is widely used as a marker for peripheral neurons with unmyelinated and small myelinated fibers. We investigated the number of SP immunoreactive neurons in the dorsal root ganglion (DRG) of male and female Wistar rats, 15 and 180 days after nociceptive stimulation during the neonatal period. Right and left 5th lumbar (L5) DRG were incubated in rabbit polyclonal anti-substance P primary followed by biotinylated donkey anti-rabbit secondary antibodies. Reaction was revealed with a nickel-diaminobenzidine solution. Labeled neurons were counted and compared between ages, genders and groups. Gender differences were present in both ages, with the number of SP-positive DRG neurons being larger in 15-days-old males on both sides. After 180 days, males showed a larger number of SP-positive neurons than females only on the nociceptive stimulated side. An increased number of SP-positive neurons in the DRG on the stimulated side was present in females, immediately after nociceptive stimulation, but not after 180 days. In conclusion, neonatal noxious stimulation caused a permanent increase in SP-positive DRG neurons in males that was not observed in females, suggesting that differences in pain processing/responsivity between genders could be related to morphological alterations of the nervous system. Anat Rec, 301:849-861, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29244248 TI - Detection of Fetomaternal Hemorrhage and ABO incompatibility. PMID- 29244247 TI - 2D or Not 2D? Testing the Utility of 2D Vs. 3D Landmark Data in Geometric Morphometrics of the Sculpin Subfamily Oligocottinae (Pisces; Cottoidea). AB - We contrast 2D vs. 3D landmark-based geometric morphometrics in the fish subfamily Oligocottinae by using 3D landmarks from CT-generated models and comparing the morphospace of the 3D landmarks to one based on 2D landmarks from images. The 2D and 3D shape variables capture common patterns across taxa, such that the pairwise Procrustes distances among taxa correspond and the trends captured by principal component analysis are similar in the xy plane. We use the two sets of landmarks to test several ecomorphological hypotheses from the literature. Both 2D and 3D data reject the hypothesis that head shape correlates significantly with the depth at which a species is commonly found. However, in taxa where shape variation in the z-axis is high, the 2D shape variables show sufficiently strong distortion to influence the outcome of the hypothesis tests regarding the relationship between mouth size and feeding ecology. Only the 3D data support previous studies which showed that large mouth sizes correlate positively with high percentages of elusive prey in the diet. When used to test for morphological divergence, 3D data show no evidence of divergence, while 2D data show that one clade of oligocottines has diverged from all others. This clade shows the greatest degree of z-axis body depth within Oligocottinae, and we conclude that the inability of the 2D approach to capture this lateral body depth causes the incongruence between 2D and 3D analyses. Anat Rec, 301:806-818, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29244249 TI - Flow cytometric false myeloperoxidase-positive childhood B-lineage acute lymphoblastic leukemia. AB - BACKGROUND: Flow cytometric intracellular myeloperoxidase (MPO) staining of leukemic blasts is a useful tool in diagnosis of leukemia subtype. Interpretation of high MPO-positivity can be a diagnostic challenge in B-lineage acute lymphoblastic leukemia (B-ALL). While very few such cases have been reported, high MPO positive B-ALL cases without additional myeloid antigen positivity are suspect and require further investigation. METHODS: Three pediatric cases of B ALL with strong MPO staining (clone 8E6; Invitrogen) at diagnosis and three others with negative MPO staining were studied by flow cytometry and immunohistochemistry. In-vitro drug cytotoxicity, oxidative stress generation, and immunophenotyping using other MPO clones were performed to further investigate MPO presence. RESULTS: Expectedly, normal myeloid cells in all six samples were positive and mature lymphocytes negative for MPO staining. However, MPO monoclonal antibody (mAb) obtained from clones other than Invitrogen and other myeloid-specific mAbs gave negative results suggesting false positivity of the initial MPO staining. Immunohistochemistry for MPO was also negative on all six cases tested. Furthermore, in-vitro vincristine cytotoxicity was greater in leukemic cells from MPO false-positive cases compared with MPO-negative B-ALL samples, demonstrating indirect lack of MPO activity. Moreover, drug treatment did not lead to generation of reactive oxidative species, also reflective of lack of significant MPO presence. CONCLUSIONS: The cause of false-positive MPO staining remains unknown in these three cases; a cross reactivity could be the culprit. Caution should be given to similar phenomena and detailed investigation may contribute to the understanding of altered protein expression in such outlier cases. (c) 2017 International Clinical Cytometry Society. PMID- 29244250 TI - Human innate lymphoid cells (ILCs): Toward a uniform immune-phenotyping. AB - Helper innate lymphoid cells (ILCs), the most recently identified population of the ILC family, play a fundamental role in the restoration of tissue integrity, in the protection against infiltrating pathogens as well as in tumor immune surveillance. ILCs have been divided into three main subsets, ILC1, ILC2, and ILC3, that can be specifically activated by different signals coming either indirectly from pathogens or from other cell populations, including cancer cells. Following activation, ILCs are in turn able to promptly secrete a wide range of soluble mediators that modulate effector cell functions. The discovery and the study of these immune cells is now offering important opportunities for innovative therapies of allergic airway diseases, inflammatory disorders and might be crucial for the discovery of new targets for the therapy of cancer. It is therefore fundamental that the scientific community establishes harmonized guidelines to obtain a consensus in the identification and phenotypical and functional characterization of ILCs. (c) 2018 International Clinical Cytometry Society. PMID- 29244246 TI - Role of RNA modifications in brain and behavior. AB - Much progress in our understanding of RNA metabolism has been made since the first RNA nucleoside modification was identified in 1957. Many of these modifications are found in noncoding RNAs but recent interest has focused on coding RNAs. Here, we summarize current knowledge of cellular consequences of RNA modifications, with a special emphasis on neuropsychiatric disorders. We present evidence for the existence of an "RNA code," similar to the histone code, that fine-tunes gene expression in the nervous system by using combinations of different RNA modifications. Unlike the relatively stable genetic code, this combinatorial RNA epigenetic code, or epitranscriptome, may be dynamically reprogrammed as a cause or consequence of psychiatric disorders. We discuss potential mechanisms linking disregulation of the epitranscriptome with brain disorders and identify potential new avenues of research. PMID- 29244252 TI - Issue Information-Declaration of Helsinki. PMID- 29244254 TI - Effect of Deconditioning on Cortical and Cancellous Bone Growth in the Exercise Trained Young Rats. PMID- 29244251 TI - Effect of Combination Folic Acid, Vitamin B6 , and Vitamin B12 Supplementation on Fracture Risk in Women: A Randomized, Controlled Trial. AB - Epidemiologic studies have demonstrated an association of elevated plasma homocysteine levels with greater bone resorption and fracture risk. Vitamins B12 , B6 , and folic acid are cofactors in homocysteine metabolism, and supplementation with B vitamins is effective in lowering homocysteine levels in humans. However, randomized trials of supplemental B vitamins for reduction of fracture risk have been limited. Therefore, we performed an ancillary study to the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS), a large randomized trial of women with preexisting cardiovascular disease or three or more coronary risk factors, to test whether a daily B vitamin intervention including folic acid (2.5 mg/day), vitamin B6 (50 mg/day), and vitamin B12 (1 mg/day) reduces nonspine fracture risk over 7.3 years of treatment and follow-up. Among 4810 women, we confirmed 349 nonspine fracture cases by centralized review of medical records. In a substudy of 300 women (150 in treatment group and 150 controls) with paired plasma samples at randomization and follow-up (7.3 years later), we measured two bone turnover markers, including C-terminal cross-linking telopeptide of type I collagen (CTX) and intact type I procollagen N-propeptide (P1NP). In Cox proportional hazards models based on intention-to-treat, we found no significant effects of B vitamin supplementation on nonspine fracture risk (relative hazard = 1.08; 95% confidence interval, 0.88 to 1.34). In a nested case cohort analysis, there were no significant effects of B vitamins on fracture risk among women with elevated plasma homocysteine levels, or low levels of vitamins B12 or B6 , or folate at baseline. Furthermore, treatment with B vitamins had no effect on change in markers of bone turnover. We found no evidence that daily supplementation with B vitamins reduces fracture risk or rates of bone metabolism in middle-aged and older women at high risk of cardiovascular disease. (c) 2017 American Society for Bone and Mineral Research. PMID- 29244255 TI - The 'values journey' of nursing and midwifery students selected using multiple mini interviews; Year One findings. AB - AIM: To explore how adult, child and mental health nursing and midwifery students, selected using multiple mini interviews, describe their 'values journey' following exposure to the clinical practice environment. BACKGROUND: Values based recruitment (VBR) incorporates assessment of healthcare students' personal values using approaches like multiple mini interviews. Students' experience of adjustment to their values during their programme is conceptualized as a 'values journey'. The impact of VBR in alleviating erosion of personal values remains unclear. DESIGN: A cross-professional longitudinal cohort study was commenced at one university in England in 2016 with data collection points at the end of years one, two and three. Non-probability consecutive sampling resulted in 42 healthcare students (8 adult, 8 child and 9 mental health nursing and 17 midwifery students) taking part. METHODS: Six semi-structured focus groups were conducted at the end of participants' Year One (DC1). Data analysis incorporated inductive and deductive approaches in a hybrid synthesis. FINDINGS: Participants described a 'values journey' where their values, particularly communication, courage and wanting to make a difference, were both challenged and retained. Participants personal journeys also acknowledged the: 'courage it takes to use values'; 'reality of values in practice' and 'need for self-reflection on values'. CONCLUSION: A 'values journey' may begin early in a healthcare student's education programme. This is important to recognize so that appropriate interventions designed to support students in higher education and clinical practice can be implemented. The values incorporated in VBR should be continually evaluated for fitness for purpose. PMID- 29244256 TI - Myricetin Induces Protective Autophagy by Inhibiting the Phosphorylation of mTOR in HepG2 Cells. AB - Myricetin, a natural flavonoid present in a variety of fruits and vegetables, has been studied as a promising cancer chemopreventive agent in many cancer models. It has been reported that myricetin could inhibit tumor promotion by inducing cell cycle arrest and promoting apoptotic cell death. At present, autophagy is considered to be closely associated with cancer, functioning as either an anti cancer or pro-cancer mechanism depending on the cancer stage. Till date, the role of myricetin in regulating autophagy has not been reported. In this study, we found that myricetin can induce autophagy by inhibiting mTOR activation in HepG2 cells. Our findings thus provide evidence for further research and application of myricetin as a potential cancer therapeutic agent. Anat Rec, 301:786-795, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29244257 TI - Normal reference intervals and the effects of sample handling on dynamic viscoelastic coagulometry (Sonoclot) in healthy adult horses. AB - OBJECTIVE: To determine reference intervals and the effect of sample agitation and rest time on Sonoclot analysis in healthy adult horses. DESIGN: Original prospective study. SETTING: University veterinary medical teaching hospital. ANIMALS: Sixty healthy adult horses. INTERVENTIONS: Blood was collected for assessment of complete blood count, serum biochemical analysis, and Sonoclot analysis. MEASUREMENTS AND MAIN RESULTS: Horses were determined to be healthy based upon physical examination, CBC, and serum biochemistry analysis. Blood was analyzed in a glass bead-containing cuvette using the Sienco Sonoclot analyzer following 2 rest periods (30 mins and 240 min) and with 2 sample handling interventions (agitated and nonagitated), to obtain values for clot rate, time-to peak, activated clotting time, and platelet function. This study failed to detect a significant difference when a rest time of 30 minutes was compared with 240 minutes, but based on wide limits of agreement the 2 rest times were not considered interchangeable. Agitation at both rest times significantly affected all Sonoclot analyses leading to changes indicative of hypercoagulability. CONCLUSIONS: Sample agitation and rest time should be taken into consideration when developing preanalytical guidelines for Sonoclot analysis in horses. Calculated reference intervals were relatively wide. Further research is needed to evaluate the clinical utility of Sonoclot analysis in horses. PMID- 29244258 TI - Stillbirth: understand, standardise, educate - time to end preventable harm. PMID- 29244259 TI - Stillbirth prevention 1921 and 2016: the call for 'adequate antenatal supervision'. PMID- 29244260 TI - Stillbirth: improving access to evidence based literature - research isn't just for health professionals. PMID- 29244262 TI - When religion opens the door: Despite the challenges, partnerships with religious and spiritual communities can address medical disparities and improve patients' wellbeing. PMID- 29244263 TI - Intentional Insulin Overdose for Euphoric Experience. PMID- 29244264 TI - Personality Traits and Anxiety and Depressive Disorders in Patients With Medication-Overuse Headache Versus Episodic Migraine. AB - Objective: An episodic migraine (EM) may lead to medication-overuse headache (MOH), an abnormal behavioral pattern of noncompliance. Anxiety disorders, mood disorders, and disorders caused by psychoactive substances other than analgesics all have been reported with MOH at higher rates than with EM. The objective of this study was to evaluate the relationships between personality traits and anxiety and depressive disorders and headache type. Methods: In this cross sectional study, 55 patients with EM and 50 patients with MOH were recruited from were recruited from 2 university hospital clinics in Tehran, Iran, from January 2013 to November 2015. Personality traits were assessed with the Temperament and Character Inventory (TCI-125). Patients were assessed for depression with the 9 item Patient Health Questionnaire (PHQ-9) and anxiety with the 7-item Generalized Anxiety Disorder scale (GAD-7). Results: There was no significant difference between the 2 groups regarding sex, age, or educational level. The TCI-125 analysis between the 2 groups showed a significant mean +/- SD difference in reward dependence (EM: 9.77 +/- 2.06, MOH: 8.69 +/- 2.15, P = .01) and self transcendence (EM: 8.42 +/- 2.45, MOH: 6.83 +/- 3.90, P = .03). The GAD-7 and PHQ 9 analyses demonstrated no significant difference between the 2 groups. Conclusions: Reward-dependence and self-transcendence scores were significantly lower in patients with MOH than in those with EM. These results suggest that people with lower reward-dependence and self-transcendence scores may not adequately respond to prescribed medications, leading them to the frequent use of multiple drugs at higher doses. A multidisciplinary approach to management may be suggested for migraine patients, and it is reasonable to consider behavioral therapy in conjunction with pharmacotherapy to ameliorate comorbid conditions. PMID- 29244265 TI - Herpes Zoster and Dementia: A Nationwide Population-Based Cohort Study. AB - OBJECTIVE: Some infectious diseases have been found to be associated with cognitive impairment and dementia. However, the relationship between herpes zoster and dementia has received little attention. This study aimed to investigate this association as well as associations of antiviral treatments for herpes zoster and incident dementia using a large national sample. METHODS: Cases were identified from the Taiwan National Health Insurance Research Database with a new diagnosis of herpes zoster (ICD-9-CM code: 053) between 1997 and 2013. Each identified individual with a case of herpes zoster was compared with 1 sex-, age , and residence-matched control subject. Both groups were followed until the first diagnosis of dementia (ICD-9-CM codes: 290.0 to 290.4, 294.1, 331.0 to 331.2, and 331.82), withdrawal from the registry, or the end of 2013. Cox regression analyses and competing risk model were applied, adjusting for sex, age, residence, depression, autoimmune disease, ischemic stroke, traumatic brain injury, alcohol use disorder, and antiviral treatments for herpes zoster to evaluate the risk of interest. RESULTS: A total of 39,205 cases with herpes zoster were identified. Of the 78,410 study and comparison subjects, 4,204 were diagnosed as having dementia during a mean (SD) follow-up period of 6.22 (4.05) years. Herpes zoster was associated with a slightly increased risk of dementia in the fully adjusted model (hazard ratio [HR] = 1.11; 95% CI, 1.04-1.17). Prescriptions of antiviral therapy were associated with a reduced risk of developing dementia following the diagnosis of herpes zoster (HR = 0.55; 95% CI, 0.40-0.77). CONCLUSIONS: Herpes zoster was associated with an increased risk of dementia, independent of potential confounding factors. Antiviral treatment might be protective in preventing dementia in patients with herpes zoster. PMID- 29244266 TI - Patients With Alcohol Use Disorder Co-Occurring With Depression and Anxiety Symptoms: Diagnostic and Treatment Initiation Recommendations. PMID- 29244267 TI - Re: An unanswered question in pediatric urology: the post pubertal persistence of prepubertal congenital penile curvature correction by tunical plication. PMID- 29244268 TI - REPLY BY THE AUTHORS: Re: An unanswered question in pediatric urology: the post pubertal persistence of prepubertal congenital penile curvature correction by tunical plication. PMID- 29244269 TI - Current trends of percutaneous nephrolithotomy in a developing country. AB - INTRODUCTION: To present the current practice patterns on percutaneous nephrolithotomy (PCNL) in a developing country. MATERIALS AND METHODS: A survey was offered to Brazilian urologists during the II International Endourology Symposium held in Sao Paulo, in 2015. The first seven questions were related to demographic data while the 20 remaining were directed to urologists who performed PCNL. RESULTS: From 250 participants, 100 replied to the survey, 81% performed PCNL and 60.4% of performers had been in practice for less than 15 years. Eighty one percent were trained in the prone position and 64% in supine. PCNL was learned during the residency in 66.7% and 2.5% had fellowship training. Prone position was the preferred decubitus for simple or complex calculi, though for obese patients there was no difference. Younger surgeons prefer supine while older surgeons prefer prone. The access was obtained by the surgeon in all cases, 96.3% use fluoroscopy and 3.7% prefer ultrasonography. Forty-seven percent use ultrasonic lithotripters and 4.1% laser. For kidney drainage, 71.6% place a nephrostomy tube. Double J stent is left in 77%. The postoperative image method was CT for 50%. Colonic injury was reported by 25%, predominantly in the senior group without statistically difference between positions. CONCLUSIONS: From a selected group of urologists, we observe that Brazilian urologists usually gain their own access for PCNL guided by fluoroscopy. They predominantly prefer the prone position, use fascial dilators, ultrasonic lithotripters and place a nephrostomy tube when exiting the kidney. Fellowship programs, ultrasonography, flexible nephoscopy and tubeless procedures could be encouraged. PMID- 29244271 TI - Laparoscopic dismembered pyeloplasty combined with port entrance flexible renoscopic lithotripsy. AB - INTRODUCTION: Ureteropelvic junction obstruction and concomitant calculus disease may coexist. We demonstrate our use of flexible renoscopy during laparoscopic pyeloplasty for caliceal stone removal. PATIENT AND METHODS: A 28-year-old female patient presented with recurrent attacks of flank pain of two years duration. When noncontrast-CT and DTPA were performed, the patient was diagnosed with ureteropelvic junction stenosis and 3 stones with a total burden of 14mm in the lower pole of right kidney. After pneumoperitoneum was established in right flank position, three 10mm trocars were placed including one camera port. 5mm trocar was placed for convenience to retraction and dissection. The surgery was uneventful, with no operative complications or evidence of intra-abdominal bleeding. RESULTS: The duration of the surgery was 110 minutes. The amount of bleeding was 30ml. On the postoperative 2nd day, the urethral catheter was removed and the patient was discharged on the fourth day postoperatively. Stent removal was done on the 3rd postoperative week and retrograde pyelogram showed normal ureter. Post-operative follow-up with ultrasound showed that hydronephrosis had regressed. Conclusions: Laparoscopic pyeloplasty and concomitant flexible renoscopy through lowermost trocar with basket extraction is a simple, attractive alternative for the simultaneous treatment of ureteropelvic junction obstruction presenting with coexisting nephrolithiasis. This method is useful and feasible, with minimal invasiveness and an early post-operative recovery. PMID- 29244270 TI - Vaginal cuff recurrence after radical cystectomy: an under - studied site of bladder cancer relapse. AB - INTRODUCTION: Vaginal cuff recurrence of tumor following radical cystectomy is a rare site of disease recurrence, however it has never been specifically studied. The aim of the study is to evaluate incidence, risk factors, and long-term oncologic outcomes of vaginal cuff recurrence in a cohort of female patients treated with radical cystectomy for invasive urothelial carcinoma of the bladder. MATERIALS AND METHODS: From 1985 to 2012, a prospectively maintained institutional bladder cancer registry was queried for vaginal cuff recurrence post radical cystectomy. Overall mortality and cancer-specific mortality were reported using the Kaplan-Meier method for patients with vaginal cuff recurrence, recurrence at another local or distant site, and those without evidence of recurrence. Comparisons were performed using the log-rank test. Cox proportional hazards regression model was performed to assess predictors of vaginal cuff recurrence. RESULTS: From 469 women treated with radical cystectomy for bladder cancer, 34 patients (7.3%) developed vaginal cuff recurrence, 130 patients (27.7%) had recurrence involving either a local or distant site, and 305 patients (65%) had no evidence of recurrence. The 5-year overall mortality-free survival rate was 32.4% for vaginal cuff recurrence, but 25.0% for other sites of recurrence. Cancer-specific mortality-free survival rate was 32.4% for vaginal cuff recurrence, and 30.3% for the other sites of recurrence. Multivariate Cox proportional hazards regression analysis demonstrated that the presence of tumor in posterior location at radical cystectomy (Hazard Ratio [HR], 0.353 [95% CI, 0.159-0.783]) and anterior vaginectomy, compared to no vaginectomy (HR, 2.595 [95% CI, 1.077-6.249]) were independently associated with vaginal cuff recurrence. CONCLUSION: Anterior vaginectomy, despite our best attempts, is perhaps not sufficient to prevent vaginal cuff recurrence. Therefore, follow-up evaluation is essential, and further studies are necessary to address the optimal approach for initial management. Patient Summary: Although vaginal cuff recurrence is an unusual site of recurrence, careful evaluation is needed before cystectomy and during follow-up to identify patients at risk. PMID- 29244273 TI - Ecologic Perspective of Dermatologic Problems in India. PMID- 29244274 TI - Two Types of Allergy (to Quinine) Occurring Simultaneously in Two Patients. PMID- 29244272 TI - Comparison of perioperative outcomes with or without renorrhaphy during open partial nephrectomy: A propensity score-matched analysis. AB - PURPOSE: Renorrhaphy in partial nephrectomy may damage intraparenchymal vessels and compress the renal parenchyma, which may lead to the formation of renal artery pseudoaneurysms or vascularized parenchymal volume reduction. Using propensity score matching, we compared surgical outcomes following non renorrhaphy and renorrhaphy techniques for open partial nephrectomy (OPN) for T1a renal tumors. MATERIALS AND METHODS: We retrospectively analyzed data from 159 patients with normal contralateral kidneys who underwent OPN for T1a renal tumors and pre- and postoperative enhanced computed tomography between 2012 and 2015. Patient variables were adjusted using 1:1 propensity score matching between the two Groups: renorrhaphy (inner and outer layer sutures) and non-renorrhaphy (inner layer sutures only). Postoperative complications and renal function were compared between the two groups. RESULTS: We matched 43 patients per Group. Operative time, estimated blood loss, cold ischemic time, and postoperative hospital stay were not significantly different between the two Groups. Urine leakage (Clavien-Dindo grade >=3) occurred in 0 renorrhaphy cases and 2 non renorrhaphy cases (0% versus 4.6%, P=0.49). Renal artery pseudoaneurysm (RAP) occurred in 6 renorrhaphy cases and in 0 non-renorrhaphy cases (13% versus 0%, P=0.02). CONCLUSIONS: The non-renorrhaphy technique may result in a lower risk of RAP but a greater risk of urine leakage. This technique needs further refinement to become a standard procedure for OPN. PMID- 29244275 TI - Psoriasis. PMID- 29244276 TI - Sex Education. PMID- 29244277 TI - Preventive Aspects of Moral and Social Hygiene. PMID- 29244278 TI - Diagnosis of Leprosy. PMID- 29244279 TI - Control of Venereal Diseases - My lmpression. PMID- 29244280 TI - A note on observations on the Maintenance of Nichol's Train of Treponema Pollida in Rabbits. PMID- 29244281 TI - A short Synopsis of Salient Features of Aim and Results of the inquiry on study of Incidence and Relationship of the Prenatal and Neonatal Syphilis and results of the Treatment Penicillin at various stages. PMID- 29244283 TI - Yaws in Trivandrum. PMID- 29244282 TI - Practical Problem of Perspiration. PMID- 29244285 TI - Clinical Cytodiagnosis as an aid to Dermatology. PMID- 29244284 TI - Plant Dermatitis, The Significance of Variety - Specific Sensitization. PMID- 29244286 TI - Prophylactic Therapy Against Leprosy. PMID- 29244287 TI - Gonorrhoea - a growing problem. PMID- 29244288 TI - The 4th All India Conference of Dermatologists and Venereologists of India. PMID- 29244292 TI - Association Notes. PMID- 29244290 TI - Knowledge From World Contemporaries. PMID- 29244289 TI - Announcement of the 4th All India Conference of Dermatologists and Venereologists. PMID- 29244293 TI - Correspondence. PMID- 29244294 TI - Syphilis and Infancy. PMID- 29244295 TI - Vasectomy. PMID- 29244296 TI - Medical Ethics in Ancient India. PMID- 29244297 TI - Knowledge From World Contemporaries. PMID- 29244298 TI - iv th All India Conference of Dermatologists and Venereologists. PMID- 29244300 TI - The Visiting Client. PMID- 29244299 TI - The effect of Ultraviolet- Irradiation and 8-Melhoxypsoralen on copper and glutathione levels in tissues of Albino Rats. PMID- 29244302 TI - IV th All India Conference of Dermatologist and Vencreologists. PMID- 29244301 TI - Bowen's Disease. PMID- 29244304 TI - Control of Venereal Diseases. PMID- 29244303 TI - The Pattern of Venereal Diseases. PMID- 29244306 TI - Follow up of Treatment of Neurosyphilis. PMID- 29244307 TI - Evaluation of R. M . T. & V. D. R. L. Tests Carried out Simultaneously in 1594 Cases. PMID- 29244305 TI - Pattern of Venereal Diseases. PMID- 29244308 TI - Dermatology and Sociology. PMID- 29244309 TI - The Fourth All India Conference of Dermatologists and Venereologits. PMID- 29244310 TI - Systemic Lupus Erythematosus. PMID- 29244311 TI - Bacteriology of Pyodermas. PMID- 29244312 TI - Pattern of Skin Diseases in India. PMID- 29244313 TI - Remarks on the Statistics from the Christian Medical College Hospital, Vellore at the "Seminar on the Pattern of Skin Disease in lndia". PMID- 29244314 TI - Pattern of Skin Diseases in Karachi-Pakistan. PMID- 29244315 TI - Skin Diseases Incidence in All India Institute of Medical Sciences. PMID- 29244316 TI - Abstract of Presentation in the Seminar on Pattern of Skin Disease in India. PMID- 29244317 TI - Disease of Out-Patient Department of Skin & V. I. D., V. J. Hospital, Amritsar of the 1959. PMID- 29244318 TI - Epidemiological Survey of Leprosy in Maharashtra State (india). PMID- 29244319 TI - Role and Organisation of Leprosy Section. PMID- 29244320 TI - Followup of Contacts of Leprosy Patients and Early Leprosy. PMID- 29244321 TI - Ten Years Follow up of Treatment of Leprosy Cases. PMID- 29244322 TI - A Social Worker's Experience of Leprosy. PMID- 29244324 TI - Granuloma Venereum a Retrospective Study. PMID- 29244323 TI - Surgical Procedures in Leprosy. PMID- 29244326 TI - Medical Statistics in Dermato Venereology. PMID- 29244325 TI - Tuberculous Ulcer on Glans Penis - A Case Note. PMID- 29244327 TI - Allergy. PMID- 29244328 TI - The Role and Organisation of an Allergy Department. PMID- 29244329 TI - Allergy in General Practice and As a Speciality in Dermatology. PMID- 29244331 TI - Griseofulvin Therapy Gf Dermatomycoses. PMID- 29244330 TI - Role and Organisation of Mycology Section. PMID- 29244333 TI - "Tuberculoderma" a Brief Review Together" with Statistical Analysis and Observations. PMID- 29244332 TI - Developments of the Approaches in the Therapy of Vitiligo. PMID- 29244334 TI - Histochemical and Electron Microscopic Study of Epidermal Neoplasms. PMID- 29244335 TI - Plastic Surgery in Dermatology. PMID- 29244336 TI - Bacterial Flora of Normal Skin. PMID- 29244337 TI - The Role and Organisation of V. D. Clinics. PMID- 29244339 TI - 5th All India Conference of Dermatologists and Venereologists. PMID- 29244338 TI - Sulphadimethoxine in Some Pyogenic Dermatological Disorders. PMID- 29244340 TI - Serologic Tests For Syphilis in Leprosy. PMID- 29244341 TI - Serological Tests For Syphilis. PMID- 29244342 TI - Penicillin Resistance in Gonorrhoea. PMID- 29244343 TI - Actinomycosis - A Review - with A Case Report. PMID- 29244344 TI - Onychomadesis, Keratosis Pilaris Like Eruptions Symblepheron and Pseudo conjunctival Cysts As Late Sequelae of Penicillin Allergy. PMID- 29244345 TI - Epidermolysis Bullosa. PMID- 29244346 TI - Diagnosis and Management of Reactions in Leprosy. PMID- 29244347 TI - Study of Serum Copper Levels in Patients with Pigmentary Disorders. PMID- 29244348 TI - Incidence of Framboesia Tropica Within a Mongoloid Tribe of Indo-bhutan Border. PMID- 29244349 TI - Yaws in Bengal. PMID- 29244350 TI - The Mystery and Miracle That Is Urine. PMID- 29244352 TI - Calcinosis Cutis. PMID- 29244351 TI - Tuberculous Ulcer Glans Penis - A Case Note. PMID- 29244353 TI - Cornu Cutaneum Genitalis. PMID- 29244355 TI - Recent Assessments in the Aetiology and Therapy of Skin Carcinomas. PMID- 29244354 TI - Evaluation of Local Measures in Allergic Dermatoses Antihistamines and Corticosteroids. PMID- 29244356 TI - A Clinical Trial of Cyprohep- Tadine ('Periactin'). PMID- 29244357 TI - Non-gonococcal Urethritis. PMID- 29244358 TI - Keratosis Palmaris Et Plantaris (tylosis) with Carcinoma Oesophagus. PMID- 29244360 TI - VI All India Conference. PMID- 29244359 TI - Indications and Dosages in Long Range Therapy of Cortisteroids in Dermatology. PMID- 29244361 TI - Personalities. PMID- 29244362 TI - Tropenema Pallidum Immune Ad-herence (tpia) Test For Syphilis. PMID- 29244363 TI - Transaminases and Ascorbic Acid Leveis in Blood in. PMID- 29244364 TI - A Survey on the Prevalence of Syphilis in a Railway Colony, Lucknow. PMID- 29244365 TI - Adventures in Dermato-Venereology. PMID- 29244366 TI - VI Joint Annual Conference of Indian Association of Dermatologists and Venereologists. PMID- 29244367 TI - Malignant Neoplasms of the Skin. PMID- 29244368 TI - Treatment of Lupus Vulgaris with Diethyl Dithio-Lisophthalate ('Etisul' ). PMID- 29244369 TI - Spiramycin in Acute Gonococcal Urethritis in Males. PMID- 29244370 TI - Venereal Diseases in Relation To the National Emergency. PMID- 29244371 TI - Bilateral Zoster. PMID- 29244372 TI - Physical and Physiological Disorders of Skin. PMID- 29244373 TI - Association Activities. PMID- 29244374 TI - Correspondences. PMID- 29244375 TI - Therapy Resistant Pyogenic Folliculitis on Legs in the Adult Males with Hypergammaglobulinemia. PMID- 29244376 TI - Some Serum Enzymes in Vitiligo. PMID- 29244377 TI - Hemospermia. PMID- 29244378 TI - Venereology Dying But Not Venereal Diseases. PMID- 29244379 TI - Epidermolysis Bullosa Hereditaria. PMID- 29244380 TI - Physiological Disorders of the Skin. PMID- 29244382 TI - Infra-red Rays in the Treatment of Weeping (exudative) Eczema. PMID- 29244381 TI - Amoebic Ulcer of Skin. PMID- 29244383 TI - Jawaharlal Nehru. PMID- 29244384 TI - Neoplasms of the Sweat Glands. PMID- 29244385 TI - Dermatofibroma. PMID- 29244387 TI - Relationships Between Dermatologist Employee Employer and Insurance Carrier. PMID- 29244386 TI - Value of Flagyl in the Treatment of Trichomoniasis. PMID- 29244388 TI - Seborrhoea. PMID- 29244389 TI - Neurological Patterns of Leprosy. PMID- 29244390 TI - A Case of Chloramphenicol Resistant Primary Syphilis Treated with Penicillin. AB - A primary syphilis patient was treated with oral chloromycetin therapy at a dose of 2 capsules 4 hourly for 16 days ie. total 192 capsules or 48 gms. His original serological titre was VDRL 1:64 and W R 1:160 dil. MKR Positive Kahn + + +, DG,Tp + +.After therapy his titre declined to VDRL 1:8 dil within 11 weeks but then it was at this level for 28 weeks. He had no history of reinfection during follow up period. Then he was given penicillin at a rate of 1lac 4 hourly for 15 days i.e. total 90 lacs. After penicillin therapy within 12weeks his serum was negative of all serological tests done. PMID- 29244391 TI - Indian Association of Dermatologists and Venereologists. PMID- 29244392 TI - Some Comments on "The Survey on the Prevalence of Syphilis in a Railway Colony, Lucknow". PMID- 29244393 TI - Reply to Some Comments on The Survey of The Prevalence of Syphilis in A Railway, Lucknow. PMID- 29244394 TI - Post Lumbar Puncture Reactions in Syphilitic Patients From a V. D. Clinic. PMID- 29244395 TI - Psoriasis - A Clinical Study. PMID- 29244396 TI - Study of Dermato- Venereology in Medical Institutions of India. PMID- 29244397 TI - Pigment Formation. PMID- 29244398 TI - Lederkyn in the Treatment of Leprosy. PMID- 29244399 TI - Triphysol in Chronic Superficial Dermatomycoses. PMID- 29244400 TI - Penicillin Resistant Gonorrhoea. PMID- 29244401 TI - Griseofulvin-fine Particle For the Systemic Treatment of Superficial Dermatomycoses. PMID- 29244403 TI - The Physician and Traffic Safety. PMID- 29244402 TI - Serum Leucine Amino Peptidase Activity in Vitiligo. PMID- 29244404 TI - Lederkyn in Chancroid. PMID- 29244405 TI - Pigmentary Function. PMID- 29244406 TI - Tuberous Sclerosis. PMID- 29244408 TI - Indian Association of Dermatolog ists and Venereologists at Scientific Programme of Conference, 1965. PMID- 29244407 TI - An Unusual Case of Urethritis Due to Foreign Body. AB - A case of urethritis due to an unusual foreign body (half burnt bidi) in urethra is reported. PMID- 29244410 TI - Editorial Homage. PMID- 29244409 TI - Clinical Meeting. PMID- 29244411 TI - Tinea Capitis. PMID- 29244413 TI - The Management of Pyodermas and Eczematous Dermatoses with Varied Combinations of Neomycin, Bacitracin, Sulphacetamide and Hydrocortisone in an Ointment Base. PMID- 29244412 TI - Progressive Pigmentary Der- Matosis of Schamberg. PMID- 29244414 TI - Case Report of Dermatofibrosarcoma Protuberans. PMID- 29244415 TI - Presidential Address. PMID- 29244416 TI - Presidetial Address. PMID- 29244418 TI - Letter to the Editor. PMID- 29244417 TI - The Seventh All India Conference of Dermatologists and Venereologists. PMID- 29244420 TI - Pemphigus in Northern India-Clinical Studies in 34 Patients. PMID- 29244419 TI - Lupus Erythematosus- An Auto- Immune Disease. PMID- 29244421 TI - Supronal in Acute and Chronic Urethritis. PMID- 29244422 TI - 4 Cases of Pseudoxanthoma Elasticum. PMID- 29244423 TI - Dr. V. Govindan Nair. PMID- 29244425 TI - The Role of Skin Chemistry in the Understanding of Disease Mechanisms. PMID- 29244424 TI - Immunologic Function. PMID- 29244426 TI - The Nature of Allergic and Eczematous Dermatoses in a Skin Department in Bombay. PMID- 29244427 TI - Taurine and Psoriasis. PMID- 29244428 TI - Skeletal Manifestations in Early Acquired Syphilis. PMID- 29244430 TI - Lupus Vulgaris of Thigh and Vulva. PMID- 29244429 TI - Skeletal Manifestations of Late Syphilis. PMID- 29244431 TI - Studies of Skin Colonisation by Staphylococcus Aureus. PMID- 29244432 TI - A Study of Serum Proteins in Primary Pyodermas. PMID- 29244433 TI - The Natural History of Progressive Systemic Sclerosis (difuse Scleroderma). PMID- 29244434 TI - Case Report of Granuloma Inguinale From Punjab. PMID- 29244436 TI - Pemphigus Vegetans. PMID- 29244435 TI - Weber Christian Syndrome in a Child. PMID- 29244438 TI - V. D. Section :- Recommendation of 1965 joint statement on venereal disease. PMID- 29244439 TI - Management of Trophic Ulcers in Leprosy. PMID- 29244437 TI - Iontophoresis Study on 20 Cases of Chronic Nonspecific Eczema in Industrial Workers. PMID- 29244441 TI - Prof. Alfred Marchionini, Munich. PMID- 29244440 TI - Preventiva Medicine in Ancient India. PMID- 29244442 TI - Reiter Protein Complement Fixation (R.P.C.F.) Test For Syphilis. PMID- 29244443 TI - The 'in Vitro' Effect of Griseofulvin on Ringworm and Other Fungi. PMID- 29244444 TI - Lincomycin in Acute Gonococcal Urethritis. PMID- 29244446 TI - Histopathology of Psoriasis At Various Stages. PMID- 29244445 TI - Non-Specific Urethritis. PMID- 29244447 TI - News & Views. PMID- 29244448 TI - Correspondence. PMID- 29244449 TI - Investigations on Some Inedigenous Drugs in the Treatment of Leprosy. PMID- 29244450 TI - Pemphigus. PMID- 29244451 TI - Further Experiences with Patch Testing in Suspected Cases of Contact Dermatitis. PMID- 29244452 TI - Evaluation of Tolbutamide Treatment in Vitiligo. PMID- 29244453 TI - A Clinical Experience with R 2040-Creme. PMID- 29244454 TI - Some Aspects of Skin Diseases and Diabetes Mellitus. PMID- 29244455 TI - A New Entity - Pingranliquosis. PMID- 29244456 TI - Presidential Address: 5th All India Conference of Dermatologists & Venereologists. PMID- 29244457 TI - Water balance of lung and nitrogen oxide in blood at experimental autoimmune encephalomyelitis after capsaicin blockade of vagus nerve. AB - The purpose of the research: To study the water balance of lung and NO level in blood in experimental autoimmune encephalomyelitis combined with capsaicin blockade of vagus nerve. Methods: Experiments were conducted on 47 adult (16-week old) male rats weighing 220-280 g. To simulate the experimental autoimmune encephalomyelitis (EAE) rats were subcutaneously injected with encephalitogenic mixture in complete Freund's adjuvant (0.2 ml; the content of inactivated Mycobacterium tuberculosis was 5 mg/ml) at the rate of 100 mg of homologous spinal cord homogenate per animal. Sapsaicin blockade was performed by bilateral application of 50 uM capsaicin ("Sigma") on the neck portions of vagus nerves. The animals were divided into 4 groups: intact rats - control group1; rats with EAE; rats with capsaicin application on vagus nerve + EAE; sham operated rats subjected to vagus nerves allocation without the subsequent capsaicin application + EAE - control group 2. The next parameters were detected: the content of nitric oxide in blood plasma; protein content in broncho-alveolar lavage fluid; lung water balance indices including the amount of total, extra- and intravascular fluid and blood supply of lungs, which were calculated based on wet and dry lung mass and the hemoglobin content in blood and lung tissue determined by hemiglobincyanide method. Results: It was found that EAE is accompanied by an increase of total fluid, extravascular fluid (EVF) and blood supply of lungs on the background of increasing content of nitric oxide in arterial (art) and venous (ven) blood. In EAE and its combination with bilateral capsaicin blockade of vagus nerve a strong negative correlation between the NOart / NOven coefficient and EVF amount was found out. The blockade of capsaicin-sensitive vagal afferents normalized lung water balance impaired in EAE and restored the levels of nitric oxide in blood plasma. Conclusion: The obtained results suggest that capsaicin sensitive vagal afferents with NO-ergic mechanisms involvment take part in the development of pulmonary hyperhydration during experimental autoimmune encephalomyelitis. PMID- 29244458 TI - Heat shock protein HSP40 family chaperone DNAJB6/MRJ expression analysis in blood cells obtained from patients with atopic dermatitis in different phases. AB - : Heat shock protein HSP40 family molecular chaperone DNAJB6/MRJ expression has been analyzed in blood cells of patients with atopic dermatitis compared with healthy donors. Severity of disease was estimated according index SCORAD. Methods: Peripheral blood cells were separated using Percoll density gradient. Purified neutrophils and lymphocytes have been stained with antibodies to the heat shock protein DNAJB6/MRJ. Cells were analyzed using flow cytometry. Real time PCR method has been used to verify the bacterial contamination of the skin of patients with atopic dermatitis. Statistical analysis was performed by ANOVA. Results: Expression of DNAJB6/MRJ protein has been found to be elevated in all samples of cells obtained from patients with atopic dermatitis. The highest level of the DNAJB6/MRJ protein expression was shown in neutrophils at the acute phase of severe atopic dermatitis. DNAJB6/MRJ protein expression in lymphocytes of patients with atopic patients was less extensive compared with neutrophil level and was shown to be higher at subacute phase of disease. The DNAJB6/MRJ protein expression was found to be statistically significant higher in lymphocytes from atopic patients compared with healthy donors. The bacterial contamination of skin (verified by PCR) was shown to influence the DNAJB6/MRJ protein level in lymphocytes of atopic dermatitis patients. Conclusion: Expression of the heat shock protein DNAJB6/MRJ was elevated in neutrophils and lymphocytes of patients with atopic dermatitis compared with healthy donors. The highest level of the DNAJB6/MRJ protein was found to be in neutrophils at acute phase of severe atopic dermatitis and gradually decline as continue to the disease. PMID- 29244459 TI - HEALTH HISTORY TAKING WITH VOLUNTEER PATIENTS. AB - Monash University aims to produce dynamic graduate nurses and midwives recognized for their excellent, innovative practice and positive impact on people's lives. PMID- 29244460 TI - COUNCIL OF DEANS FOR NURSING AND MIDWIFERY. AB - Established in 1993, the Council of Deans for Nursing and Midwifery (Australia & New Zealand) (CDNM) is the peak organization that represents the Deans, Leaders and Heads of Higher Education providers offering courses for nursing and midwifery throughout Australia and New Zealand. PMID- 29244461 TI - LOCATIONS OF CLINICAL PLACEMENTS CRUCIAL FOR LEARNING AND WORK READINESS. AB - The value of clinical placements in the Bachelor of Nursing program cannot be over emphasised. Students undertake a variety of clinical experiences during the three-year program in order to develop and hone an effective range of competencies for a beginning Registered Nurse. PMID- 29244462 TI - CREATING SIMULATION ACTIVITIES FOR UNDERGRADUATE NURSING CURRICULA. AB - Simulation is considered a valuable educational strategy to prepare nursing students for clinical practice and bridge the gap between theory and clinical experience (Unsworth et al. 2012) with Milkins et al. (2014) advocating for the use of simulation in student education to support the National Safety and Quality Health Service Standards (NSQHSS) (Australian Commission on Safety and Quality in Health Care (ACSQHC), 2012). PMID- 29244463 TI - ACTIVE LEARNING: WHAT DO WE KNOW ABOUT IT? AB - It's critical for nurse educators to have a solid understanding of the principles underpinning active learning, to mediate some of the pitfalls which include: inadequate student preparedness for active learning, poorly designed learning activities and an unprepared or unsafe learning environment (White et al. 2014). PMID- 29244464 TI - DIVERSITY: RESEARCHERS AND NURSE EDUCATORS COLLABORATE. AB - Inter-professional collaboration between the RDNS Education and Learning Centre and RDNS Institute has resulted in the design and development of a diversity training workshop for community aged care staff. PMID- 29244465 TI - PEER REVIEWED BASED ASSESSMENT IN POST GRADUATE EDUCATION. AB - Students have a propensity to focus their learning aligned to the assessment items established within the units of study, rather than acknowledging the broader need to learn and apply the content taught. This approach to education stifles students' learning and their ability to apply knowledge, and as a result, essential content can be poorly retained. PMID- 29244466 TI - Surfactant system and water balance of the lungs in modeling of neurodegeneration and focus of pathological activity in the substantia nigra. AB - : The comparative analysis of surfactant metabolism and water balance of the lungs in modeling the formation and neurodegeneration focus of pathological activity in the substantia nigra of the brain. Methods: Experiments were performed on male rats - nonlinear, including the control, sham operated with unilateral stereotaxic administration of the neurotoxin 6-hydroxydopamine (Sigma) in the substantia nigra compact part and the implantation of cobalt metal nanopowder (Berlin) in the reticular part of the structure. Complex investigations included determination of surfactant phospholipid fractions by thin layer chromatography, total phospholipids and cholesterol in the bronchoalveolar lavage and surface-active properties by the Wilhelmy method, phospholipase activity, lipid peroxidation intensity on the content of TBA-active products in the lung tissue, evaluation of water balance using the gravimetric method. Results: It has been established that the introduction of intranigral neurotoxin and implantation of cobalt in the structure of the brain called the deterioration of the surface activity of the alveolar lining set against the backdrop of an imbalance of fractional composition of surfactant lipids with multidirectional changes in the amount of phospholipids and the degree of hydration of the lung. Induction focus of pathological activity in the substantia nigra was accompanied by an increase in alveolar phospholipids by lysophosphatidylcholine, sphingomyelin, phosphatidylethanolamine, intensification of lipid peroxidation of the lung tissue and organ hyperhydration. Modeling neurodegeneration - reduction of total phospholipids, phosphatidylcholine and lysophosphatidylcholine accumulation in terms of activation of phospholipase hydrolysis, increasing blood supply to the lungs. Conclusion: Metabolism of surfactant lipids and water balance in the lung, along with changes of rhythmogenesis and mode of ventilation, may lead to the development of disregulation of pneumopathy with dysfunction of the substantia nigra of the brain. PMID- 29244468 TI - INDUSTRY SPECIFIC EDUCATION. AB - All nurses registered with AHPRA are aware of the requirements to maintain regulation standards. Including continuing professional development (CPD). So too are numerous healthcare organisations and peak bodies, all offering a range of conferences, clinical courses and workshops along with many other practical and theoretical opportunities for learning. PMID- 29244467 TI - Features purine metabolism in patients with pulmonary tuberculosis. AB - : The purpose - comprehensive study of the purine metabolic enzymes in serum and immune cells in patients with pulmonary tuberculosis for the understanding of the pathogenesis of a specific lung disease. Methods: The enzymes of purine metabolism (adenosine deaminase (ADA) and its isoenzymes (ADA-1 and ADA-2), dipeptidylpeptidase IV (DPPIV - CD26), ecto-5'-nucleotidase (5'-NC) in the blood and immune cells was studied in 29 and 76 patients with fibro-cavernous (FCPT) and infiltrative (IPT) pulmonary tuberculosis correspondingly. Results: In patients found changes in purine metabolism, the severity and pathophysiological significance of which depend of clinical forms of tuberculosis, that is, from the gravity specific of the process. Reduced activity of ADA mononuclear cells was accompanied by a decrease in the expression of CD26 in patients with FCPT and the growth of the IPT ectopeptidase patients, that is, the concentration of CD26 mononuclear cells and neutrophils are associated with form of pulmonary tuberculosis. The increased levels of another enzyme purine metabolism - 5'-NC registered in both forms of pulmonary tuberculosis. Conclusion: In the context of the ADA and CD26 association with the IPT can assume increased participation of each of them in the activation of cell proliferation and cytokine production. Low levels of CD26 immune cells in the absence of their connection with the activity of ADA is typical for patients with FCPT and reflects their inherent failure of cellular immunity. We can assume that the formation of complexes with the ADA ectopeptidases (CD26 and 5'-NC) for newly diagnosed IPT provides a balance CD26_ADA extracellular / intracellular adenosine and 5'-NC / adenosine and thereby adequate metabolism of immunocompetent cells. PMID- 29244469 TI - USEFUL TIPS FOR TEACHING INTERNATIONAL NURSING STUDENTS. AB - International students studying nursing in Australia has increased (Glew, 2013). For most of these students, English may not be their first language. The style of teaching and learning international students had previously experienced differ vastly from the Western style of teaching. PMID- 29244470 TI - UNDERGRADUATE NURSING EDUCATION RELATED TO EUTHANASIA. AB - Euthanasia is a subject that has been debated in health ethics courses for many years. With the increase in quality palliative care and emphasis on 'dying well', in response to the increased number of people living with life limiting conditions (Swerissen & Duckett, 2014), it has not been so prevalent in public forum discussions of late. PMID- 29244471 TI - Endothelial dysfunction in experimental hyperhomocysteinemia. AB - : To investigate the consequences of the endothelium dysfunction caused by the experimental hyperhomocysteinemia. Methods: The experiment included the similar aged 42 white non-pedigree male rats with average weight of 150 grams. The rats were divided in two groups each of these having 21 species. Hyperhomocysteinemia was induced in experimental rats by intraperitoneal injection of 0,1 mmol homocysteine per 1 gr of weight once a day during 14 days. The equal intraperiotenal dose of the physiological solution was injected to the rats of the control group. The level of homocysteine was determined in the blood serum with high-yield liquid chromatography (HYLC), the content of IFNg, TNFa, IL-17A s was measured with the system of multiplex analysis FlowCytomix 5 plex (BMS826FF) combined with Simplex Kit (BMS8635FF) of appropriate analyts for "Bender Medsystems" rats (Austria). Coagulation indices were determined in the blood plasm of subclavian vein. TF expression of tissue factor was estimated with immune histochemical method. Results: Fivefold increase of endothelin level and decrease of nitrates and nitrites levels were found in rats with hyperhomocysteinemia. Expression of tissue factor, shortening of activated partial thromboplastin and thrombin times, increase of soluble fibrin monomeric complex level, significant increase of tumor necrosis factor and interferon gamma levels were identified in endothelial cells of myocardial vessels. Conclusion: Thus, experimental hyperhomocysteinemia (HHC) proved to be accompanied by expressed endothelium dysfunction which is marked by thrombogenic activity of blood as well as endothelium and cytokine level increasing. PMID- 29244472 TI - ENHANCING FERTILITY LITERACY FOR NURSES AND MIDWIVES IN PRIMARY CARE. AB - Prevention in healthcare through improved health literacy is at the very heart of change in Australia's health system to improve overall population health, ensure health equity, and make Australia's health system sustainable into the future (Australian government Department of Health and Ageing, 2010). PMID- 29244473 TI - Destabilase-lysozyme-2 - original recombinant thrombolytic preparation of medicinal leech inhibits horse platelets aggregation. AB - : The purpose. Identifying the capacity of the medicinal leech novel original recombinant thrombolytic preparation Destabilase-Lysozyme-2 to inhibit the blood platelet aggregation. Methods: Gene of destabilase-lysozyme. ds2 (mlDL-Ds2 ), was cloned in E.coli cells. Recombinant protein was isolated in denaturing conditions using metal-chelate chromatography followed by denaturation of the polypeptide by rapid dilution in exact accordance with the procedure described by Kurdyumov A.S. et al. ( 2016, Russian Journal of Bioorganic Chemistry, v.42, s. 42-52). Blood was collected from the jugular vein of 18 horses. The functional status of platelets in the presence of different destabilase-lysozyme concentrations were evaluated for their aggregation in Platelet Rich Plasma ( PRP) and in Washed Platelet suspension (WP) using aggregometers Chrono-Log-700 and Shrono-Log-560, USA560, SSHA. As used aggregation inducers of ADP, collagen type III and human thrombin. Results: First demonstrated the ability of newly synthesized (Kurdyumov A.S. et al. 2016, Russian Journal of Bioorganic Chemistry, v42, s. 42-52) thrombolytic recombinant enzyme destabilase-lyzosyme to inhibit more than 40% of ADP-stimulated PRP aggregation and ADP- stimulated aggregation of horse blood washed platelets. Conclusion: The ability of destabilase-lyzosyme -2 to inhibit platelets aggregation extends biological properties of recombinant thrombolytic enzyme, pre-clinical trials which resulted in the end of 2015. PMID- 29244474 TI - Lymphocyte-platelet interactions in patients with deep frostbites with various nutritional statuses. AB - : The purpose of the study was to determine the relative number and degree of lymphocyte-platelet adhesion in patients with frostbites of III-IV degree of extremities with malnutrition and eutrophia. Methods: Non-randomized prospective controlled study was performed in 49 patients of both sexes, aged from 16 to 60 years, with frostbites of III-IV degree of extremities. The object of the study was the blood plasma. Test subjects were divided into two groups according to the trophic status on the scale of Luft V.M and Kostyuchenko A.L. By the original method of the Professor Vitkovsky Yu.A. (1999) number of lymphocyte-platelet coaggregations was counted in 100 cells (percentage), which is relative number of the lymphocyte-platelet adhesion (LTA). In this case lymphocyte which adhered to its surface one or more platelets was named the coaggregation. Lymphocyte platelet index (LTI) or the degree of LTA was determined as the arithmetic mean of the number of platelets which have adhered to a single lymphocyte. Results: The relative number of LTA greater in patients with eutrophia (n = 19) vs. (p<0.001) the control group (n = 20) and vs. (p = 0.008) patients with malnutrition (n = 20). The relative number of LTA is not different in patients with malnutrition vs. (p = 0.085) the control group. LTI greater in patients with eutrophia vs. the control group (p<0.001), and vs. patients with malnutrition (p = 0.020). LTI greater in patients with malnutrition vs. the control group (p = 0.006). Conclusion: It was established that LTI increased irrespective of premorbid trophic status, and LTA percentage increased only in patients with eutrophia. In patients with malnutrition LTA degree and LTA percentage were detected less than in patients with normal nutritional status. PMID- 29244475 TI - ONBOARDING AT MIDLAND. AB - The onboarding of 1,200 people for the opening of the 307-bed St John of God Midland Public Hospital (Midland) was a massive undertaking. From the onset we wanted to ensure that the onboarding effectively provided cultural alignment, technical expertise and a safe opening. PMID- 29244476 TI - COLLABORATIVE CLUSTERS EDUCATION MODEL -- AN EVOLUTION OF THE DEDICATED EDUCATION UNIT. AB - Clinical experience is critical for the development of practice knowledge that can support patients and their families. How opportunities for students to learn from experience, particularly workplace experiences, are structured is an important aspect of curriculum design in nursing. From a sociocultural viewpoint of learning, the learner should be totally engaged in the culture of the workplace (Billet, 2014). PMID- 29244477 TI - Cytokine mediated changes of pain sensitivity in predisposition to substance dependence. AB - : The purpose of study was evaluation of extra and intracellular cytokine production in blood cultures and cytokine-pain relationship at different stages od addiction. Methods: Classic and multiplex enzyme immunoassay, flow, cytometry, algometry, visual analogue scale were used in 34 abusers, 12 users and 20 control subjects. Results: Cytokine profile correlated with clinical parameters and pain sensitivity in abusers (mostly IL-6 and IL-1beta). IL-10 production is increased in episodic and systematic users. Activation of intracellular IL-6 synthesis was found in users. Both parameters are expected to affect the emotional evaluation of pain. Conclusion: To assess the predisposition to substance dependence most informative are balance of extra and intracellular production of IL-6 and IL-10 and algometry. PMID- 29244478 TI - Another One (of the "Undruggable" Targets) Bites the Dust: Discovery of a Potent and Selective Inhibitor of the Histone Acetyl Transferase p300/CBP. PMID- 29244479 TI - Discovery of Intermetallic Compounds from Traditional to Machine-Learning Approaches. AB - Intermetallic compounds are bestowed by diverse compositions, complex structures, and useful properties for many materials applications. How metallic elements react to form these compounds and what structures they adopt remain challenging questions that defy predictability. Traditional approaches offer some rational strategies to prepare specific classes of intermetallics, such as targeting members within a modular homologous series, manipulating building blocks to assemble new structures, and filling interstitial sites to create stuffed variants. Because these strategies rely on precedent, they cannot foresee surprising results, by definition. Exploratory synthesis, whether through systematic phase diagram investigations or serendipity, is still essential for expanding our knowledge base. Eventually, the relationships may become too complex for the pattern recognition skills to be reliably or practically performed by humans. Complementing these traditional approaches, new machine learning approaches may be a viable alternative for materials discovery, not only among intermetallics but also more generally to other chemical compounds. In this Account, we survey our own efforts to discover new intermetallic compounds, encompassing gallides, germanides, phosphides, arsenides, and others. We apply various machine-learning methods (such as support vector machine and random forest algorithms) to confront two significant questions in solid state chemistry. First, what crystal structures are adopted by a compound given an arbitrary composition? Initial efforts have focused on binary equiatomic phases AB, ternary equiatomic phases ABC, and full Heusler phases AB2C. Our analysis emphasizes the use of real experimental data and places special value on confirming predictions through experiment. Chemical descriptors are carefully chosen through a rigorous procedure called cluster resolution feature selection. Predictions for crystal structures are quantified by evaluating probabilities. Major results include the discovery of RhCd, the first new binary AB compound to be found in over 15 years, with a CsCl-type structure; the connection between "ambiguous" prediction probabilities and the phenomenon of polymorphism, as illustrated in the case of TiFeP (with TiNiSi- and ZrNiAl-type structures); and the preparation of new predicted Heusler phases MRu2Ga and RuM2Ga (M = first-row transition metal) that are not obvious candidates. Second, how can the search for materials with desired properties be accelerated? One particular application of strong current interest is thermoelectric materials, which present a particular challenge because their optimum performance depends on achieving a balance of many interrelated physical properties. Making use of a recommendation engine developed by Citrine Informatics, we have identified new candidates for thermoelectric materials, including previously unknown compounds (e.g., TiRu2Ga with Heusler structure; Mn(Ru0.4Ge0.6) with CsCl-type structure) and previously reported compounds but counterintuitive candidates (e.g., Gd12Co5Bi). An important lesson in these investigations is that the machine-learning models are only as good as the experimental data used to develop them. Thus, experimental work will continue to be necessary to improve the predictions made by machine learning. PMID- 29244480 TI - Correction to Layer Control of Tubular Graphene for Corrosion Inhibition of Nickel Wires. PMID- 29244481 TI - Nanostructured Na2Ti9O19 for Hybrid Sodium-Ion Capacitors with Excellent Rate Capability. AB - Herein, we report a new Na-insertion electrode material, Na2Ti9O19, as a potential candidate for Na-ion hybrid capacitors. We study the structural properties of nanostructured Na2Ti9O19, synthesized by a hydrothermal technique, upon electrochemical cycling vs Na. Average and local structures of Na2Ti9O19 are elucidated from neutron Rietveld refinement and pair distribution function (PDF), respectively, to investigate the initial discharge and charge events. Rietveld refinement reveals electrochemical cycling of Na2Ti9O19 is driven by single-phase solid solution reaction during (de)sodiation without any major structural deterioration, keeping the average structure intact. Unit cell volume and lattice evolution on discharge process is inherently related to TiO6 distortion and Na ion perturbations, while the PDF reveals the deviation in the local structure after sodiation. Raman spectroscopy and X-ray photoelectron spectroscopy studies further corroborate the average and local structural behavior derived from neutron diffraction measurements. Also, Na2Ti9O19 shows excellent Na-ion kinetics with a capacitve nature of 86% at 1.0 mV s-1, indicating that the material is a good anode candidate for a sodium-ion hybrid capacitor. A full cell hybrid Na-ion capacitor is fabricated by using Na2Ti9O19 as anode and activated porous carbon as cathode, which exhibits excellent electrochemical properties, with a maximum energy density of 54 Wh kg-1 and a maximum power density of 5 kW kg-1. Both structural insights and electrochemical investigation suggest that Na2Ti9O19 is a promising negative electrode for sodium-ion batteries and hybrid capacitors. PMID- 29244482 TI - Two-Dimensional Polymer Synthesized via Solid-State Polymerization for High Performance Supercapacitors. AB - Two-dimensional (2-D) polymer has properties that are attractive for energy storage applications because of its combination of heteroatoms, porosities and layered structure, which provides redox chemistry and ion diffusion routes through the 2-D planes and 1-D channels. Here, conjugated aromatic polymers (CAPs) were synthesized in quantitative yield via solid-state polymerization of phenazine-based precursor crystals. By choosing flat molecules (2-TBTBP and 3 TBQP) with different positions of bromine substituents on a phenazine-derived scaffold, C-C cross coupling was induced following thermal debromination. CAP-2 is polymerized from monomers that have been prepacked into layered structure (3 TBQP). It can be mechanically exfoliated into micrometer-sized ultrathin sheets that show sharp Raman peaks which reflect conformational ordering. CAP-2 has a dominant pore size of ~0.8 nm; when applied as an asymmetric supercapacitor, it delivers a specific capacitance of 233 F g-1 at a current density of 1.0 A g-1, and shows outstanding cycle performance. PMID- 29244483 TI - Biomembrane Permeabilization: Statistics of Individual Leakage Events Harmonize the Interpretation of Vesicle Leakage. AB - The mode of action of membrane-active molecules, such as antimicrobial, anticancer, cell penetrating, and fusion peptides and their synthetic mimics, transfection agents, drug permeation enhancers, and biological signaling molecules (e.g., quorum sensing), involves either the general or local destabilization of the target membrane or the formation of defined, rather stable pores. Some effects aim at killing the cell, while others need to be limited in space and time to avoid serious damage. Biological tests reveal translocation of compounds and cell death but do not provide a detailed, mechanistic, and quantitative understanding of the modes of action and their molecular basis. Model membrane studies of membrane leakage have been used for decades to tackle this issue, but their interpretation in terms of biology has remained challenging and often quite limited. Here we compare two recent, powerful protocols to study model membrane leakage: the microscopic detection of dye influx into giant liposomes and time-correlated single photon counting experiments to characterize dye efflux from large unilamellar vesicles. A statistical treatment of both data sets does not only harmonize apparent discrepancies but also makes us aware of principal issues that have been confusing the interpretation of model membrane leakage data so far. Moreover, our study reveals a fundamental difference between nano- and microscale systems that needs to be taken into account when conclusions about microscale objects, such as cells, are drawn from nanoscale models. PMID- 29244484 TI - Charge-Switchable Nanozymes for Bioorthogonal Imaging of Biofilm-Associated Infections. AB - Early detection of biofilms is crucial for limiting infection-based damage. Imaging these biofilms is challenging: conventional imaging agents are unable to penetrate the dense matrix of the biofilm, and many imaging agents are susceptible to false positive/negative responses due to phenotypical mutations of the constituent microbes. We report the creation of pH-responsive nanoparticles with embedded transition metal catalysts (nanozymes) that effectively target the acidic microenvironment of biofilms. These pH-switchable nanozymes generate imaging agents through bioorthogonal activation of profluorophores inside biofilms. The specificity of these nanozymes for imaging biofilms in complex biosystems was demonstrated using coculture experiments. PMID- 29244486 TI - Going Vertical To Improve the Accuracy of Atomic Force Microscopy Based Single Molecule Force Spectroscopy. AB - Single-molecule force spectroscopy (SMFS) is a powerful technique to characterize the energy landscape of individual proteins, the mechanical properties of nucleic acids, and the strength of receptor-ligand interactions. Atomic force microscopy (AFM)-based SMFS benefits from ongoing progress in improving the precision and stability of cantilevers and the AFM itself. Underappreciated is that the accuracy of such AFM studies remains hindered by inadvertently stretching molecules at an angle while measuring only the vertical component of the force and extension, degrading both measurements. This inaccuracy is particularly problematic in AFM studies using double-stranded DNA and RNA due to their large persistence length (p ~ 50 nm), often limiting such studies to other SMFS platforms (e.g., custom-built optical and magnetic tweezers). Here, we developed an automated algorithm that aligns the AFM tip above the DNA's attachment point to a coverslip. Importantly, this algorithm was performed at low force (10-20 pN) and relatively fast (15-25 s), preserving the connection between the tip and the target molecule. Our data revealed large uncorrected lateral offsets for 100 and 650 nm DNA molecules [24 +/- 18 nm (mean +/- standard deviation) and 180 +/- 110 nm, respectively]. Correcting this offset yielded a 3-fold improvement in accuracy and precision when characterizing DNA's overstretching transition. We also demonstrated high throughput by acquiring 88 geometrically corrected force extension curves of a single individual 100 nm DNA molecule in ~40 min and versatility by aligning polyprotein- and PEG-based protein-ligand assays. Importantly, our software-based algorithm was implemented on a commercial AFM, so it can be broadly adopted. More generally, this work illustrates how to enhance AFM-based SMFS by developing more sophisticated data-acquisition protocols. PMID- 29244487 TI - Synergistic Inhibitory Effect of GQDs-Tramiprosate Covalent Binding on Amyloid Aggregation. AB - Inhibiting the amyloid aggregation is considered to be an effective strategy to explore possible treatment of amyloid-related diseases including Alzheimer's disease, Parkinson's disease, and type II diabetes. Herein, a new high-efficiency and low-cytotoxicity Abeta aggregation inhibitors, GQD-T, was designed through the combination of two Abeta aggregation inhibitors, graphene quantum dots (GQDs) and tramiprosate. GQD-T showed the capability of efficiently inhibiting the aggregation of Abeta peptides and rescuing Abeta-induced cytotoxicity due to the synergistic effect of the GQDs and tramiprosate. In addition, the GQD-T has the characteristics of low toxicity and great biocompatibility. It is believed that GQD-T may be a potential candidate for an Alzheimer's drug and this work provides a new strategy for exploring Abeta peptide aggregation inhibitors. PMID- 29244488 TI - Mechanistic Insights into Solvent and Ligand Dependency in Cu(I)-Catalyzed Allylic Alkylation with gem-Diborylalkanes. AB - The recent Cu-catalyzed allylic substitution reaction between gem-diboryalkane and allyl electrophiles shows intriguing solvent and ligand-controlled regioselectivity. The alpha-alkylation product was obtained in DMF solvent, while gamma-alkylation product was obtained in dioxane solvent and the dioxane and NHC ligand situation. In the present study, density functional theory calculations have been used to investigate the reaction mechanism and origin of the regioselectivity. For both dioxane and DMF, gamma-alkylation undergoes successive oxidative addition (CH2Bpin trans to leaving group) and direct Cgamma-C reductive elimination. The alpha-alkylation is found to undergo oxidative addition (CH2Bpin trans to leaving group), isomerization, and Calpha-C reductive elimination rather than the previously proposed oxidative addition (-CH2Bpin cis to the leaving group) and Calpha-C reductive elimination. The gamma-alkylation and alpha alkylation is, respectively, favorable for dioxane and DMF solvent, which is consistent with the gamma- and alpha-selectivity in experiment. The solvent interferes the isomerization step, thereby affects the relative facility of the alpha- and gamma-alkylation. Further investigation shows that eta1-intermediate formation promoted by solvent is the rate-determining step of the isomerization. The stronger electron-donating ability of DMF than dioxane facilitates the eta1 intermediate formation and finally results in the easier isomerization in DMF. For dioxane and NHC situation, in the presence of neutral NHC ligand, the -PO4Et2 group tightly coordinates with the Cu center after the oxidative addition, preventing the isomerization process. The regioselectivity is determined by the relative facility of the oxidative addition step. Therefore, the favorable oxidative addition (in which -CH2Bpin trans to the leaving group) results in the facility of gamma-alkylation. PMID- 29244485 TI - Critical Role of Trp-588 of Presynaptic Munc13-1 for Ligand Binding and Membrane Translocation. AB - Munc13-1 is a presynaptic active-zone protein essential for neurotransmitter release and presynaptic plasticity in the brain. This multidomain scaffold protein contains a C1 domain that binds to the activator diacylglycerol/phorbol ester. Although the C1 domain bears close structural homology with the C1 domains of protein kinase C (PKC), the tryptophan residue at position 22 (588 in the full length Munc13-1) occludes the activator binding pocket, which is not the case for PKC. To elucidate the role of this tryptophan, we generated W22A, W22K, W22D, W22Y, and W22F substitutions in the full-length Munc13-1, expressed the GFP tagged constructs in Neuro-2a cells, and measured their membrane translocation in response to phorbol ester treatment by imaging of the live cells using confocal microscopy. The extent of membrane translocation followed the order, wild-type > W22K > W22F > W22Y > W22A > W22D. The phorbol ester binding affinity of the wild type Munc13-1C1 domain and its mutants was phosphatidylserine (PS)-dependent following the order, wild-type > W22K > W22A ? W22D in both 20% and 100% PS. Phorbol ester affinity was higher for Munc13-1 than the C1 domain. While Munc13-1 translocated to the plasma membrane, the C1 domain translocated to internal membranes in response to phorbol ester. Molecular dynamics (80 ns) studies reveal that Trp-22 is relatively less flexible than the homologous Trp-22 of PKCdelta and PKCtheta. Results are discussed in terms of the overall negative charge state of the Munc13-1C1 domain and its possible interaction with the PS-rich plasma membrane. This study shows that Trp-588 is an important structural element for ligand binding and membrane translocation in Munc13-1. PMID- 29244489 TI - Environmentally Friendly in Situ Regeneration of Graphene Aerogel as a Model Conductive Adsorbent. AB - Adsorption is a classical process widely used in industry and environmental protection, and the regeneration of exhausted adsorbents, as the reverse process of adsorption, is vital to achieving a sustainable adsorption process. Chemical and thermal regeneration, which feature high costs and environmental side effects, are classical but not environmentally friendly methods. Herein, a new regeneration method based on an electrochemical process using graphene aerogel (GA) as a model conductive adsorbent was proposed. First, 3D GA was prepared to adsorb organic and inorganic pollutants, avoiding the inconvenience of using powdered graphene. Then, the exhausted GA was cleaned by the electrochemical desorption and degradation of adsorbed organic pollutants if undesired and the electrorepulsion of adsorbed metal ions in the absence of any additional chemicals, showing a high processing capability of 1.21 L g-1 GA h-1 and low energy consumption (~0.2 kWh m-3 solution). The mechanisms involved in the electrochemistry-induced desorption process cover a decline in the GA adsorption performance depended on the electrochemically adjustable surface charge conditions, and the further repulsion and migration of adsorbates is subject to the strong in situ electric field. This work has important implications for the development of environmentally friendly regeneration processes and qualified adsorbents as well as the application of a green and efficient regeneration concept for traditional adsorption processes. PMID- 29244491 TI - Surface Single-Cluster Catalyst for N2-to-NH3 Thermal Conversion. AB - The ammonia synthesis from N2 is of vital importance, with imitating biological nitrogen fixation attracted much interest. Herein, we investigate the catalytic mechanisms of N2-to-NH3 thermal conversion on the singly dispersed bimetallic catalyst Rh1Co3/CoO(011), and find that the preferred pathway is an associative mechanism analogous to the biological process, in which alternating hydrogenations of the N2 occur, with H2 activation on both metal sites. We propose that the singly dispersed bimetallic M1An catalyst, in which the doped metal atom M substitutes an oxygen atom on the oxide surface of metal A, serves as a new surface single-cluster catalyst (SCC) design platform for the biomimetic N2-to-NH3 thermal conversion. The catalytic ability of M1An catalyst is attributed to both the charge buffer capacity of doped metal M and the complementary role of synergic metal A in catalysis. Our work provides insights and guidelines for further optimizing the M1An catalyst. PMID- 29244490 TI - Discovery of Potent and Selective Allosteric Inhibitors of Protein Arginine Methyltransferase 3 (PRMT3). AB - PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is crucial for maturation of ribosomes and has been implicated in several diseases. We recently disclosed a highly potent, selective, and cell active allosteric inhibitor of PRMT3, compound 4. Here, we report comprehensive structure-activity relationship studies that target the allosteric binding site of PRMT3. We conducted design, synthesis, and evaluation of novel compounds in biochemical, selectivity, and cellular assays that culminated in the discovery of 4 and other highly potent (IC50 values: ~10-36 nM), selective, and cell-active allosteric inhibitors of PRMT3 (compounds 29, 30, 36, and 37). In addition, we generated compounds that are very close analogs of these potent inhibitors but displayed drastically reduced potency as negative controls (compounds 49-51). These inhibitors and negative controls are valuable chemical tools for the biomedical community to further investigate biological functions and disease associations of PRMT3. PMID- 29244492 TI - New Insights into the Photochemical Degradation of the Insensitive Munition Formulation IMX-101 in Water. AB - This study describes photolysis of the insensitive munition formulation IMX-101 [2,4-dinitroanisole (DNAN), NQ (nitroguanidine), and 3-nitro-1,2,4-triazol-5-one (NTO)] in aqueous solutions using a solar simulating photoreactor. Due to a large variance in the water solubility of the three constituents DNAN (276 mg L-1), NQ (5,000 mg L-1), and NTO (16,642 mg L-1), two solutions of IMX-101 were prepared: one with low concentration (109.3 mg L-1) and another with high concentration (2831 mg L-1). The degradation rate constants of DNAN, NQ, and NTO (0.137, 0.075, and 0.202 d-1, respectively) in the low concentration solution were lower than those of the individually photolyzed components (0.262, 1.181, and 0.349 d-1, respectively). In the high concentration solution, the molar loss of NTO was 4.3 times higher than that of NQ after 7 days of irradiation, although NQ was two times more concentrated and that NQ alone degraded faster than NTO. In addition to the known degradation products, DNAN removal in IMX-101 was accompanied by multiple productions of methoxydinitrophenols, which were not observed during photolysis of DNAN alone. One route for the formation of methoxydinitrophenols was suggested to involve photonitration of the DNAN photoproduct methoxynitrophenol during simultaneous photodenitration of NQ and NTO in IMX-101. Indeed, when DNAN was photolyzed in the presence of 15NO2-labeled explosive CL 20, we detected methoxydinitrophenols with an increase of 1 mass unit, indicating that denitration of DNAN and renitration of products simultaneously occurred. As was the case with DNAN, we found that guanidine, a primary degradation product of NQ, also underwent renitration in the presence of NTO and the photocatalyst TiO2. We concluded that the three constituents of IMX-101 can be photodegraded in surface water and that fate and primary degradation products of IMX-101 can be influenced by the interactions between the formulation ingredients and their degradation products. PMID- 29244493 TI - pH-Controlled One Pot Syntheses of Giant Mo2O2S2-Containing Seleno-Tungstate Architectures. AB - Self-assembly reactions of Na2WO4, SeO2/SeO32-, and [Mo2O2(MU-S)2(H2O)6]2+ give, depending on the pH value, two new large polyoxometalate complexes: i.e., [(gamma Se2W14O52)3(Mo2O2(MU-S)2(H2O)2)6]24- (1) isolated at pH 3.5 and [(gamma Se2W14O52)4(WO3(H2O))8(W2O5)2(W4O12)2(Mo2O2(MU-S)2(H2O)2)4(Mo2O2(MU S)2(SeO3))4]36- (2) isolated at pH 2. Both compounds were characterized in the solid state by single-crystal X-ray diffraction, EDX, elemental analysis, TGA, and FT-IR and in solution by ESI-MS and NMR. PMID- 29244494 TI - Matrix-Infrared Spectra and Structures of HM-SiH3 (M = Ge, Sn, Pb, Sb, Bi, Te Atoms). AB - The reactions of Ge, Sn, Pb, Sb, Bi, and Te atoms with silane molecules were studied using matrix-isolation Fourier transform infrared spectroscopy and density functional theoretical (DFT) calculations. All metals generate the inserted complexes HM-SiH3, which were stabilized in an argon matrix, while H2M?SiH2 and H3M=SiH were not observed. DFT and CCSD(T) calculations show the insertion complex HM-SiH3 is the most stable isomer with a near right angle H-M Si moiety. However, silydene complexes H2M?SiH2 (M = C, Si) were calculated and identified as the most stable complexes with the lighter elements. The bonding difference is mainly due to relativistic effects, which is that for heavier metal atoms valence s and p orbitals have a lower tendency to form hybrid orbitals. PMID- 29244495 TI - Antiprotozoal Sesquiterpene Lactones and Other Constituents from Tarchonanthus camphoratus and Schkuhria pinnata. AB - In continuation of a search for new antiprotozoal agents from plants of the family Asteraceae, Tarchonanthus camphoratus and Schkuhria pinnata have been investigated. By following the promising in vitro activity of the dichloromethane extracts from their aerial parts, bioassay-guided chromatographic isolation yielded two known sesquiterpene lactones (1 and 2) from T. camphoratus and 20 known compounds of this type from S. pinnata. From the latter, a new eudesmanolide, (1R*,5S*,6R*,7R*,8R*,10R*)-1-hydroxy-8-[5"-hydroxy-4'-(2" hydroxyisovaleroyloxy)tigloyloxy]-3-oxoeudesma-11(13)-en-6,12-olide (3), and two new germacranolides, 3beta-(2"-hydroxyisovaleroyloxy)-8beta-(3 furoyloxy)costunolide (14) and 1(10)-epoxy-3beta-hydroxy-8beta-[5'-hydroxy-4'-(2" hydroxyisovaleroyloxy)tigloyloxy]costunolide (16), were obtained. Additionally, the flavonoid pectolinarigenin (24) and 3-hydroxy-4,5-dimethoxybenzenepropanol (25) were also isolated from S. pinnata. The compounds were characterized by analysis of 1D and 2D NMR spectroscopic and HR/MS data. In vitro antitrypanosomal activity and cytotoxicity against mammalian cells (L6 cell line) were evaluated for all the compounds. Santhemoidin A (13) and 3beta-(2"-hydroxyisovaleroyloxy) 8beta-(3-furoyloxy)costunolide (14) were the most active compounds found in this study, with IC50 values of 0.10 and 0.13 MUM against Trypanosoma brucei rhodesiense trypomastigotes and selectivity indices of 20.5 and 29.7, respectively. PMID- 29244496 TI - Quantitating Volatile Phenols in Cabernet Franc Berries and Wine after On-Vine Exposure to Smoke from a Simulated Forest Fire. AB - Smoke-taint is a wine defect linked to organoleptic volatile phenols (VPs) in Vitis vinifera L. berries that have been exposed to smoke from wildland fires. Herein, the levels of smoke-taint-associated VPs are reported in Cabernet Franc berries from veraison to commercial maturity and in wine after primary fermentation following on-vine exposure to simulated wildland fire smoke. VPs increased after smoke exposure were rapidly stored as acid-labile conjugates, and the levels of both free VPs and conjugated forms remained constant through ripening to commercial maturity. An increase in total VPs after primary fermentation suggested the existence of VP-conjugates other than the acid-labile VP-glycosides already reported. This conclusion was supported with base hydrolysis on the same samples. Relative to published results, the data suggested a multifactorial regional identity for smoke-taint and they inform efforts to produce a predictive model for perceptible smoke-taint in wine based on the chemical composition of smoke-exposed berries. PMID- 29244497 TI - Semiclassical Path Integral Calculation of Nonlinear Optical Spectroscopy. AB - Computation of nonlinear optical response functions allows for an in-depth connection between theory and experiment. Experimentally recorded spectra provide a high density of information, but to objectively disentangle overlapping signals and to reach a detailed and reliable understanding of the system dynamics, measurements must be integrated with theoretical approaches. Here, we present a new, highly accurate and efficient trajectory-based semiclassical path integral method for computing higher order nonlinear optical response functions for non Markovian open quantum systems. The approach is, in principle, applicable to general Hamiltonians and does not require any restrictions on the form of the intrasystem or system-bath couplings. This method is systematically improvable and is shown to be valid in parameter regimes where perturbation theory-based methods qualitatively breakdown. As a test of the methodology presented here, we study a system-bath model for a coupled dimer for which we compare against numerically exact results and standard approximate perturbation theory-based calculations. Additionally, we study a monomer with discrete vibronic states that serves as the starting point for future investigation of vibronic signatures in nonlinear electronic spectroscopy. PMID- 29244498 TI - Labile Low-Valent Tin Azides: Syntheses, Structural Characterization, and Thermal Properties. AB - The first two examples of the class of tetracoordinate low-valent, mixed-ligand tin azido complexes, Sn(N3)2(L)2, are shown to form upon reaction of SnCl2 with NaN3 and SnF2 with Me3SiN3 in either pyridine or 4-picoline (2, L = py; 3, L = pic). These adducts of Sn(N3)2 are shock- and friction-insensitive and stable at r.t. under an atmosphere of pyridine or picoline, respectively. A new, fast, and efficient method for the preparation of Sn(N3)2 (1) directly from SnF2, and by the stepwise de-coordination of py from 2 at r.t., is reported that yields 1 in microcrystalline form, permitting powder X-ray diffraction studies. Reaction of 1 with a nonbulky cationic H-bond donor forms the salt-like compound {C(NH2)3}Sn(N3)3 (4) which is comparably stable despite its high nitrogen content (55%) and the absence of bulky weakly coordinating cations that are conventionally deemed essential in related systems of homoleptic azido metallates. The spectroscopic and crystallographic characterization of the polyazides 1-4 provides insight into azide-based H-bonded networks and unravels the previously unknown structure of 1 as an important lighter binary azide homologue of Pb(N3)2. The atomic coordinates for 1 and 2-4 were derived from powder and single crystal XRD data, respectively; those for 1 are consistent with predictions made by DFT-D calculations under periodic boundary conditions. PMID- 29244499 TI - Lanthanides as Catalysts: Guided Ion Beam and Theoretical Studies of Sm+ + COS. AB - Reactions of samarium cations with carbonyl sulfide are examined using a guided ion beam tandem mass spectrometer and a variable temperature selected ion flow tube apparatus. Formation of SmS+ + CO is observed in both instruments with a kinetic energy and temperature dependence demonstrating a barrierless reaction occurring with an efficiency of 26 +/- 9%. Formation of SmO+ + CS is also observed at high kinetic energies and exhibits a threshold determined as 2.81 +/- 0.32 eV, substantially higher than expected from known thermochemistry. The potential energy surfaces for these reactions along sextet and octet spin surfaces are also examined theoretically at the MP2 and CCSD(T) levels. The observed barrier for oxidation is shown to likely correspond to the energy of the crossing between surfaces corresponding to the ground state electronic configuration of Sm+ (8F,4f66s1) and an excited surface having two electrons in the valence space (excluding 4f), which are needed to form the strong SmO+ bond. In contrast, the S-CO bond is activated much more readily because this crossing occurs at much lower energies. This result is attributed to the much weaker S-CO bond energy as well as the ability of sulfur to bind effectively at different angles. Although both reactions are spin-forbidden, evidence for a more efficient spin-allowed process is also observed in the SmS+ + CO cross section. PMID- 29244500 TI - Corrected Polarizable Embedding: Improving the Induction Contribution to Perichromism for Linear Response Theory. AB - An extension of the polarizable embedding (PE) approach for the computation of perichromatic shifts within linear response theory, termed corrected PE, is presented. It covers the change in induction effects in addition to contributions from electrostatics and nonresonant excitonic coupling and thereby presents a combination of the corrected linear response and the PE method. Using this method, we analyzed the individual contributions for six different excitations from four molecules in different solvents to clarify the question, which effects should be accounted for by a polarizable solvation model? The (vertical) reference excitation energies are evaluated by the means of full quantum mechanical computations of large solute-solvent clusters. Excellent agreement is achieved when both the shift due to the change in induction and nonresonant excitonic coupling in addition to the shift due to electrostatics are accounted for. PMID- 29244502 TI - Half-Sandwich Complexes of an Extremely Electron-Donating, Redox-Active eta6 Diborabenzene Ligand. AB - The heteroarene 1,4-bis(CAAC)-1,4-diborabenzene (1; CAAC = cyclic (alkyl)(amino)carbene) reacts with [(MeCN)3M(CO)3] (M = Cr, Mo, W) to yield half sandwich complexes of the form [(eta6-diborabenzene)M(CO)3] (M = Cr (2), Mo (3), W (4)). Investigation of the new complexes with a combination of X-ray diffraction, spectroscopic methods and DFT calculations shows that ligand 1 is a remarkably strong electron donor. In particular, [(eta6-arene)M(CO)3] complexes of this ligand display the lowest CO stretching frequencies yet observed for this class of complex. Cyclic voltammetry on complexes 2-4 revealed one reversible oxidation and two reversible reduction events in each case, with no evidence of ring-slippage of the arene to the eta4 binding mode. Treatment of 4 with lithium metal in THF led to identification of the paramagnetic complex [(1)W(CO)3]Li.2THF (5). Compound 1 can also be reduced in the absence of a transition metal to its dianion 12-, which possesses a quinoid-type structure. PMID- 29244503 TI - Zerovalent Nickel Compounds Supported by 1,2-Bis(diphenylphosphino)benzene: Synthesis, Structures, and Catalytic Properties. AB - Zerovalent nickel compounds which feature 1,2-bis(diphenylphosphino)benzene (dppbz) were obtained via the reactivity of dppbz towards Ni(PMe3)4, which affords sequentially (dppbz)Ni(PMe3)2 and Ni(dppbz)2. Furthermore, the carbonyl derivatives (dppbz)Ni(PMe3)(CO) and (dppbz)Ni(CO)2 may be obtained via the reaction of CO with (dppbz)Ni(PMe3)2. Other methods for the synthesis of these carbonyl compounds include (i) the formation of (dppbz)Ni(CO)2 by the reaction of Ni(PPh3)2(CO)2 with dppbz and (ii) the formation of (dppbz)Ni(PMe3)(CO) by the reaction of (dppbz)Ni(CO)2 with PMe3. Comparison of the nu(CO) IR spectroscopic data for (dppbz)Ni(CO)2 with other (diphosphine)Ni(CO)2 compounds provides a means to evaluate the electronic nature of dppbz. Specifically, comparison with (dppe)Ni(CO)2 indicates that the o-phenylene linker creates a slightly less electron donating ligand than does an ethylene linker. The steric impact of the dppbz ligand in relation to other diphosphine ligands has also been evaluated in terms of its buried volume (%Vbur) and steric maps. The nickel center of (dppbz)Ni(PMe3)2 may be protonated by formic acid at room temperature to afford [(dppbz)Ni(PMe3)2H]+, but at elevated temperatures, effects catalytic release of H2 from formic acid. Analogous studies with Ni(dppbz)2 and Ni(PMe3)4 indicate that the ability to protonate the nickel centers in these compounds increases in the sequence Ni(dppbz)2 < (dppbz)Ni(PMe3)2 < Ni(PMe3)4; correspondingly, the pKa values of the protonated derivatives increase in the sequence [Ni(dppbz)2H]+ < [(dppbz)Ni(PMe3)2H]+ < [Ni(PMe3)4H]+. (dppbz)Ni(PMe3)2 and Ni(PMe3)4 also serve as catalysts for the formation of alkoxysilanes by (i) hydrosilylation of PhCHO by PhSiH3 and Ph2SiH2 and (ii) dehydrocoupling of PhCH2OH with PhSiH3 and Ph2SiH2. PMID- 29244504 TI - Mode-Selective Laser Control of Palladium Catalyst Decomposition. AB - It is generally assumed that molecules behave ergodically during chemical reactions, that is, reactivities depend only on the total energy content and not on the initial state of the molecule. While there are a few examples of nonergodic behavior in small (usually electronically excited) species, to date there have been no reports of such behavior in larger covalently bound species composed of several tens of atoms. Here, we demonstrate vibrational mode selective behavior in a series of palladium catalysts. When we excite solvent tagged gas-phase Pd catalysts with an infrared laser that is tuned to be resonant with specific molecular vibrations, depending on which vibration we excite, we can select different reaction pathways. We also demonstrate that this behavior can be "turned off" via chemical substitution. PMID- 29244505 TI - Drainage from a Fluid-Handling Component Because of Inclination. AB - The onset of drainage of liquids from fluid-handling components with a single, circular orifice was evaluated. A component was filled with water, ethylene glycol, or ethyl alcohol and then oriented vertically with its orifice facing downward. The lower end of the component was slowly tilted toward the horizon. No flow occurred until a critical angle of inclination was reached. The onset of drainage was successfully modeled as a balance between the hydrostatic pressure in the bulk liquid and the Laplace pressure of the air-liquid interface within the orifice. If the Laplace pressure was greater than the hydrostatic pressure, then the flow from the component was impeded. With further inclination, a critical angle was exceeded that allowed the liquid to flow from the component. The theoretical model gave reasonable estimates of the measured values. PMID- 29244501 TI - Origins of Enzyme Catalysis: Experimental Findings for C-H Activation, New Models, and Their Relevance to Prevailing Theoretical Constructs. AB - The physical basis for enzymatic rate accelerations is a subject of great fundamental interest and of direct relevance to areas that include the de novo design of green catalysts and the pursuit of new drug regimens. Extensive investigations of C-H activating systems have provided considerable insight into the relationship between an enzyme's overall structure and the catalytic chemistry at its active site. This Perspective highlights recent experimental data for two members of distinct, yet iconic C-H activation enzyme classes, lipoxygenases and prokaryotic alcohol dehydrogenases. The data necessitate a reformulation of the dominant textbook definition of biological catalysis. A multidimensional model emerges that incorporates a range of protein motions that can be parsed into a combination of global stochastic conformational thermal fluctuations and local donor-acceptor distance sampling. These motions are needed to achieve a high degree of precision with regard to internuclear distances, geometries, and charges within the active site. The available model also suggests a physical framework for understanding the empirical enthalpic barrier in enzyme catalyzed processes. We conclude by addressing the often conflicting interface between computational and experimental chemists, emphasizing the need for computation to predict experimental results in advance of their measurement. PMID- 29244506 TI - Synthesis of Double-Bond-Substituted Hemithioindigo Photoswitches. AB - A very short, high yielding, and convergent synthesis with broad substrate scope, enabling access to a very diverse range of hemithioindigos with 4-fold substituted double-bonds, is presented. With this method, carbon as well as nitrogen, oxygen, or sulfur based substituents can easily be introduced, delivering a wide array of novel structural motifs. Irradiation studies with visible light demonstrate proficient photoswitching properties of these chromophores at wavelengths up to 625 nm. PMID- 29244507 TI - Nanoscale Generation of White Light for Ultrabroadband Nanospectroscopy. AB - Achieving efficient localization of white light at the nanoscale is a major challenge due to the diffraction limit, and nanoscale emitters generating light with a broadband spectrum require complicated engineering. Here we suggest a simple, yet highly efficient, nanoscale white-light source based on a hybrid Si/Au nanoparticle with ultrabroadband (1.3-3.4 eV) spectral characteristics. We incorporate this novel source into a scanning-probe microscope and observe broadband spectrum of photoluminescence that allows fast mapping of local optical response of advanced nanophotonic structures with submicron resolution, thus realizing ultrabroadband near-field nanospectroscopy. PMID- 29244508 TI - Diffusion of Supercritical Fluids through Single-Layer Nanoporous Solids: Theory and Molecular Simulations. AB - With the advent of graphene material, membranes based on single-layer nanoporous solids appear as promising devices for fluid separation, be it liquid or gaseous mixtures. The design of such architectured porous materials would greatly benefit from accurate models that can predict their transport and separation properties. More specifically, there is no universal understanding of how parameters such as temperature, fluid loading conditions, or the ratio of the pore size to the fluid molecular diameter influence the permeation process. In this study, we address the problem of pure supercritical fluids diffusing through simplified models of single-layer porous materials. Basically, we investigate a toy model that consists of a single-layer lattice of Lennard-Jones interaction sites with a slit gap of controllable width. We performed extensive equilibrium and biased molecular dynamics simulations to document the physical mechanisms involved at the molecular scale. We propose a general constitutive equation for the diffusional transport coefficient derived from classical statistical mechanics and kinetic theory, which can be further simplified in the ideal gas limit. This transport coefficient relates the molecular flux to the fluid density jump across the single-layer membrane. It is found to be proportional to the accessible surface porosity of the single-layer porous solid and to a thermodynamic factor accounting for the inhomogeneity of the fluid close to the pore entrance. Both quantities directly depend on the potential of mean force that results from molecular interactions between solid and fluid atoms. Comparisons with the simulations data show that the kinetic model captures how narrowing the pore size below the fluid molecular diameter lowers dramatically the value of the transport coefficient. Furthermore, we demonstrate that our general constitutive equation allows for a consistent interpretation of the intricate effects of temperature and fluid loading conditions on the permeation process. PMID- 29244509 TI - Fabrication of Supramolecular Chirality from Achiral Molecules at the Liquid/Liquid Interface Studied by Second Harmonic Generation. AB - We present the investigation into the supramolecular chirality of 5-octadecyloxy 2-(2-pyridylazo)phenol (PARC18) at water/1,2-dichloroethane interface by second harmonic generation (SHG). We observe that PARC18 molecules form supramolecular chirality through self-assembly at the liquid/liquid interface although they are achiral molecules. The bulk concentration of PARC18 in the organic phase has profound effects on the supramolecular chirality. By increasing bulk concentration, the enantiomeric excess at the interface first grows and then decreases until it eventually vanishes. Further analysis reveals that the enantiomeric excess is determined by the twist angle of PARC18 molecules at the interface rather than their orientational angle. At lower and higher bulk concentrations, the average twist angle of PARC18 molecules approaches zero, and the assemblies are achiral; whereas at medium bulk concentrations, the average twist angle is nonzero, so that the assemblies show supramolecular chirality. We also estimate the coverage of PARC18 molecules at the interface versus the bulk concentration and fit it to Langmuir adsorption model. The result indicates that PARC18 assemblies show strongest supramolecular chirality in a half-full monolayer. These findings highlight the opportunities for precise control of supramolecular chirality at liquid/liquid interfaces by manipulating the bulk concentration. PMID- 29244510 TI - Intramolecular Capture of HDDA-Derived Benzynes: (i) 6- to 12-Membered Ring Formation, (ii) Internally (vis-a-vis Remotely) Tethered Traps, and (iii) Role of the Rate of Trapping by the Benzynophile. AB - Reported here are studies that have established novel features of the hexadehydro Diels-Alder reaction of substrates containing tethered trapping moieties. Products having new structural motifs can be created. (i) Medium-sized fused rings can be produced by varying the length of the tether. (ii) The tether can emanate from an atom within the linker unit that joins the 1,3-diyne and diynophile. (iii) The importance of the rate of trapping by the benzynophile is established. PMID- 29244511 TI - Molecular Rotors for Universal Quantitation of Nanoscale Hydrophobic Interfaces in Microplate Format. AB - Hydrophobic self-assembly pairs diverse chemical precursors and simple formulation processes to access a vast array of functional colloids. Exploration of this design space, however, is stymied by lack of broadly general, high throughput colloid characterization tools. Here, we show that a narrow structural subset of fluorescent, zwitterionic molecular rotors, dialkylaminostilbazolium sulfonates [DASS] with intermediate-length alkyl tails, fills this major analytical void by quantitatively sensing hydrophobic interfaces in microplate format. DASS dyes supersede existing interfacial probes by avoiding off-target fluorogenic interactions and dye aggregation while preserving hydrophobic partitioning strength. To illustrate the generality of this approach, we demonstrate (i) a microplate-based technique for measuring mass concentration of small (20-200 nm), dilute (submicrogram sensitivity) drug delivery nanoparticles; (ii) elimination of particle size, surfactant chemistry, and throughput constraints on quantifying the complex surfactant/metal oxide adsorption isotherms critical for environmental remediation and enhanced oil recovery; and (iii) more reliable self-assembly onset quantitation for chemically and structurally distinct amphiphiles. These methods could streamline the development of nanotechnologies for a broad range of applications. PMID- 29244512 TI - CuH-Catalyzed Asymmetric Intramolecular Reductive Coupling of Allenes to Enones. AB - The CuH-catalyzed asymmetric intramolecular reductive coupling of allenes to enones is successfully realized, providing cis-hydrobenzofurans with promising yields and excellent enantioselectivities. Such brilliant enantioselectivities are partially contributed by CuH-catalyzed favorable kinetic resolution of the cyclization products. This protocol tolerates a broad range of functional groups, allowing for further construction of tricyclic and bridged-ring structures. Moreover, the meta-chiral functionalization of 4-substituted phenol and asymmetric dearomatization modification of phenol-contained bioactive molecules are also described. PMID- 29244513 TI - Scission Free Energies for Wormlike Surfactant Micelles: Development of a Simulation Protocol, Application, and Validation for Personal Care Formulations. AB - We present a scheme to calculate wormlike micelle scission free energies from a potential of mean force (PMF) derived from a weighted histogram analysis method (WHAM) applied to coarse grained dissipative particle dynamics (DPD) simulations. In contrast to previous related work, we use a specially chosen external potential based on a reaction coordinate that reversibly drives surfactants out of the nascent scission location. For the application to a model body wash formulation, we predict how addition of NaCl and small molecules such as perfume raw materials (PRMs) affect scission energies. The results show qualitative agreement and correct trends compared to recently determined scission energies for the same system; however, a more rigorous parametrization of the underlying DPD potential is required for quantitative agreement. PMID- 29244514 TI - Diastereoselective Synthesis of C-Vinyl Glycosides via Gold(I)-Catalyzed Tandem 1,3-Acyloxy Migration/Ferrier Rearrangement. AB - A novel gold-catalyzed C-glycosylation has been developed to gain access to alpha,(Z)-selective C-vinyl glycosides, starting from readily available glycals and propargylic carboxylate. This reaction involves a tandem intermolecular gold catalyzed 1,3-acyloxy migration/Ferrier rearrangement with the involvement of allenic ester as the glycosyl acceptor. A wide range of substrate scope with good to excellent yields was achieved with complete diastereoselectivity. PMID- 29244515 TI - Millisecond Self-Assembly of Stable Nanodispersed Drug Formulations. AB - We report the development of a new spray-drying and nanoparticle assembly process (SNAP) that enables the formation of stable, yet rapidly dissolving, sub-200 nm nanocrystalline particles within a high Tg glassy matrix. SNAP expands the class of drugs that spray-dried dispersion (SDD) processing can address to encompass highly crystalline, but modestly hydrophobic, drugs that are difficult to process by conventional SDD. The process integrates rapid precipitation and spray-drying within a custom designed nozzle to produce high supersaturations and precipitation of the drug and high Tg glassy polymer. Keeping the time between precipitation and drying to tens of milliseconds allows for kinetic trapping of drug nanocrystals in the polymer matrix. Powder X-ray diffraction, solid state 2D NMR, and SEM imaging shows that adding an amphiphilic block copolymer (BCP) to the solvent gives essentially complete crystallization of the active pharmaceutical ingredient (API) with sub-200 nm domains. In contrast, the absence of the block copolymer results in the API being partially dispersed in the matrix as an amorphous phase, which can be sensitive to changes in bioavailability over time. Quantification of the API-excipient interactions by 2D 13C-1H NMR correlation spectroscopy shows that the mechanism of enhanced nanocrystal formation is not due to interactions between the drug and the BCP, but rather the BCP masks interactions between the drug and hydrophobic regions of the matrix polymers. BCP-facilitated SNAP samples show improved stability during aging studies and rapid dissolution and release of API in vitro. PMID- 29244516 TI - Defect Mitigation of Solution-Processed 2D WSe2 Nanoflakes for Solar-to-Hydrogen Conversion. AB - Few-atomic-layer nanoflakes of liquid-phase exfoliated semiconducting transition metal dichalcogenides (TMDs) hold promise for large-area, high-performance, low cost solar energy conversion, but their performance is limited by recombination at defect sites. Herein, we examine the role of defects on the performance of WSe2 thin film photocathodes for solar H2 production by applying two separate treatments, a pre-exfoliation annealing and a post-deposition surfactant attachment, designed to target intraflake and edge defects, respectively. Analysis by TEM, XRD, XPS, photoluminescence, and impedance spectroscopy are used to characterize the effects of the treatments and photoelectrochemical (PEC) measurements using an optimized Pt-Cu cocatalyst (found to offer improved robustness compared to Pt) are used to quantify the performance of photocathodes (ca. 11 nm thick) consisting of 100-1000 nm nanoflakes. Surfactant treatment results in an increased photocurrent attributed to edge site passivation. The pre annealing treatment alone, while clearly altering the crystallinity of pre exfoliated powders, does not significantly affect the photocurrent. However, applying both defect treatments affords a considerable improvement that represents a new benchmark for the performance of solution-processed WSe2: solar photocurrents for H2 evolution up to 4.0 mA cm-2 and internal quantum efficiency over 60% (740 nm illumination). These results also show that charge recombination at flake edges dominates performance in bare TMD nanoflakes, but when the edge defects are passivated, internal defects become important and can be reduced by pre-annealing. PMID- 29244517 TI - Pyridinium Salt Forming Rh(III)-Catalyzed Annulation Reaction of Secondary Allylamines with Internal Alkynes and Its Application to Surface Modification of a Mesoporous Material. AB - A Rh(III)-catalyzed C-H activation reaction has been developed for the preparation of pyridinium salts from secondary allylamines and internal alkynes. The pyridinium salts formed by this N-annulation reaction have interesting fluorescence properties. This protocol has been applied to the surface modification of mesoporous silica materials to generate functionalized silica that can be used for the detection of nitrobenzene. PMID- 29244518 TI - Differential Wavevector Distribution of Surface-Enhanced Raman Scattering and Fluorescence in a Film-Coupled Plasmonic Nanowire Cavity. AB - We report on the experimental observation of differential wavevector distribution of surface-enhanced Raman scattering (SERS) and fluorescence from dye molecules confined to a gap between plasmonic silver nanowire and a thin, gold mirror. The fluorescence was mainly confined to higher values of in-plane wavevectors, whereas SERS signal was uniformly distributed along all the wavevectors. The optical energy-momentum spectra from the distal end of the nanowire revealed strong polarization dependence of this differentiation. All these observations were corroborated by full-wave three-dimensional numerical simulations, which further revealed an interesting connection between out-coupled wavevectors and parameters such as hybridized modes in the gap-plasmon cavity, and orientation and location of molecular dipoles in the geometry. Our results reveal a new prospect of discriminating electronic and vibrational transitions in resonant dye molecules using a subwavelength gap plasmonic cavity in the continuous-wave excitation limit, and can be further harnessed to engineer molecular radiative relaxation processes in momentum space. PMID- 29244519 TI - Synthetic Marine Sponge Collagen by Late-Stage Dihydroxylation. AB - Based on the observation that an increased substrate size is paralleled by an enhanced diastereoselectivity, a late-stage dihydroxylation protocol toward the 21mer CMP (collagen model peptide) Ac-(Pro-Hyp-Gly)3-Pro-Dyp-Gly-(Pro-Hyp-Gly)3 NH2 is presented. C3 and C4 hydroxylation have a converse effect on the triple helical stability of collagen. Their combined influence on the melting temperature was studied by NMR spectroscopy. PMID- 29244520 TI - Enantioselective Total Synthesis of Cannogenol-3-O-alpha-l-rhamnoside via Sequential Cu(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions. AB - A concise and scalable enantioselective total synthesis of the natural cardenolides cannogenol and cannogenol-3-O-alpha-l-rhamnoside has been achieved in 18 linear steps. The synthesis features a Cu(II)-catalyzed enantioselective and diastereoselective Michael reaction/tandem aldol cyclization and a one-pot reduction/transposition, which resulted in a rapid (6 linear steps) assembly of a functionalized intermediate containing C19 oxygenation that could be elaborated to cardenolide cannogenol. In addition, a strategy for achieving regio- and stereoselective glycosylation at the C3 position of synthetic cannogenol was developed and applied to the preparation of cannogenol-3-O-alpha-l-rhamnoside. PMID- 29244521 TI - Reply to Wijmans et al.: Optical Coherence Tomography: A Valuable Novel Tool for Assessing the Alveolar Compartment in Interstitial Lung Disease? PMID- 29244522 TI - Pulmonary Vasodilator Therapy in Shock-associated Cardiac Arrest. AB - RATIONALE: Many in-hospital cardiac arrests are precipitated by hypotension, often associated with systemic inflammation. These patients are less likely to be successfully resuscitated, and novel approaches to their treatment are needed. OBJECTIVES: To determine if the addition of inhaled nitric oxide (iNO) to hemodynamic-directed cardiopulmonary resuscitation (HD-CPR) would improve short term survival from cardiac arrest associated with shock and systemic inflammation. METHODS: In 3-month-old swine (n = 21), LPS was intravenously infused, inducing systemic hypotension. Ventricular fibrillation was induced, and animals were randomized to blinded treatment with either: 1) HD-CPR with iNO, or 2) HD-CPR without iNO. During HD-CPR, chest compression depth was titrated to peak aortic compression pressure of 100 mm Hg, and vasopressor administration was titrated to coronary perfusion pressure greater than or equal to 20 mm Hg. Defibrillation attempts began after 10 minutes of resuscitation. The primary outcome was 45-minute survival. MEASUREMENTS AND MAIN RESULTS: The iNO group had higher rates of 45-minute survival (10 of 10 vs. 3 of 11; P = 0.001). During cardiopulmonary resuscitation, the iNO group had lower pulmonary artery relaxation pressure (mean +/- SEM, 10.9 +/- 2.4 vs. 18.4 +/- 2.4 mm Hg; P = 0.03), higher coronary perfusion pressure (21.1 +/- 1.5 vs. 16.9 +/- 1.0 mm Hg; P = 0.005), and higher aortic relaxation pressure (36.6 +/- 1.6 vs. 30.4 +/- 1.1 mm Hg; P < 0.001) despite shallower chest compressions (5.88 +/- 0.25 vs. 6.46 +/- 0.40 cm; P = 0.02) and fewer vasopressor doses in the first 10 minutes (median, 4 [interquartile range, 3-4] vs. 5 [interquartile range, 5-6], P = 0.03). CONCLUSIONS: The addition of iNO to HD-CPR in LPS-induced shock-associated cardiac arrest improved short-term survival and intraarrest hemodynamics. PMID- 29244523 TI - Hip Distraction Without a Perineal Post: A Prospective Study of 1000 Hip Arthroscopy Cases. AB - BACKGROUND: Hip arthroscopy has traditionally been performed with a perineal post, resulting in various groin-related complications, including pudendal nerve neurapraxias, vaginal tears, and scrotal necrosis. PURPOSE: To assess the safety of a technique for hip distraction without the use of a perineal post. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We prospectively analyzed a consecutive cohort of 1000 hips presenting to a dedicated hip preservation clinic; all patients had hip pain and were subsequently treated with hip arthroscopy. Demographic variables, hip pathology, and lateral center edge angle were recorded for each case. In the operating room, the patient's feet were placed in traction boots in a specifically designed distraction setup, and the operative table was placed in varying degrees of Trendelenburg. With this technique, enough resistance is created by gravity and friction between the patient's body and the bed to allow for successful hip distraction without the need for a perineal post. In a subset of 309 hips (n = 281 patients), the degrees of Trendelenburg as well as the distraction force were analyzed. RESULTS: The mean +/- SD Trendelenburg angle used among the subset of 309 hips was 11 degrees +/- 2 degrees . The mean initial distraction force necessary was 90 +/- 28 lb, which decreased to 65 +/- 24 lb by 30 minutes after traction initiation ( P < .0001). The most important variables in determining initial force for this cohort of patients were, in order of magnitude, sex ( P < .0001), weight ( P < .0001), and lateral center edge angle ( P < .01). No groin-related complications occurred among the entire cohort of patients, including soft tissue or nerve-related complications. The rate of deep venous thrombosis was 2 in 1000. CONCLUSION: The use of the Trendelenburg position and a specially designed distraction setup during hip arthroscopy allows for safe hip distraction without a perineal post, thereby eliminating groin-related soft tissue and nerve complications. Certain patient variables can be used to estimate the required distraction force and inclination angle with this method. PMID- 29244524 TI - Inhaled Diesel Exhaust Decreases the Antimicrobial Peptides alpha-Defensin and S100A7 in Human Bronchial Secretions. PMID- 29244525 TI - 20-Year Outcomes of Anterior Cruciate Ligament Reconstruction With Hamstring Tendon Autograft: The Catastrophic Effect of Age and Posterior Tibial Slope. AB - BACKGROUND: No well-controlled studies have compared the long-term outcome of anterior cruciate ligament (ACL) reconstruction with hamstring tendon autograft between adolescents and adults. Increased posterior tibial slopes (PTSs) have been reported in the ACL-injured versus controls, but the effect of PTS on the outcome after reconstruction is relatively unexplored. PURPOSE: To compare the prospective longitudinal outcome of "isolated" ACL ruptures treated with anatomic endoscopic ACL reconstruction using hamstring tendon autograft over 20 years in adolescent and adult cohorts and to examine factors for repeat ACL injury. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A single-surgeon series of 200 consecutive patients undergoing isolated primary ACL reconstruction with hamstring tendon autograft were prospectively studied. Subjects were assessed preoperatively and at 2, 7, 15, and 20 years postoperatively. Outcomes included International Knee Documentation Committee (IKDC) Knee Evaluation, IKDC subjective scores, KT-1000 instrumented laxity testing, and radiological evaluation of degenerative change and medial tibial slope. Twenty-year outcomes were compared between those who underwent surgery at the age of 18 years or younger (adolescent group, n = 39) and those who underwent surgery when older than 18 years (adult group, n = 161). RESULTS: At 20 years, 179 of 200 subjects were reviewed (89.5%). ACL graft rupture occurred in 37 subjects and contralateral ACL injury in 22 subjects. Of those with intact ACL grafts at 20 years, outcomes were not statistically different between adolescents and adults for the variables of IKDC subjective score ( P = .29), return to preinjury activity level ( P = .84), current activity level ( P = .69), or degree of radiological degenerative change at 20 years ( P = .51). The adolescent group had a higher proportion of grade 1 ligamentous laxity testing compared with the adult group ( P = .003). Overall, ACL graft survival at 20 years was 86% for adults and 61% for adolescents (hazard ration, 3.3; P = .001). The hazard for ACL graft rupture was increased by 4.8 in adolescent males and 2.5 in adolescent females compared with adults. At 20 years, the ACL survival for adolescents with a PTS of >=12 degrees was 22%. The hazard for ACL graft rupture was increased by 11 in adolescents with a PTS of >=12 degrees ( P = .001) compared with adults with a PTS <12 degrees . CONCLUSION: Repeat ACL injury after isolated ACL reconstruction is common, occurring in 1 in 3 over 20 years. In the absence of further injury, isolated ACL reconstruction using this technique was associated with good long term outcomes with respect to patient-reported outcomes and return to sports, regardless of age. However, mild ligament laxity and ACL graft rupture after ACL reconstruction are significantly more common in adolescents, especially adolescent males, compared with adults. PTS of 12 degrees or more is the strongest predictor of repeat ACL injury, and its negative effect is most pronounced in adolescents. PMID- 29244526 TI - Optical Coherence Tomography: A Valuable Novel Tool for Assessing the Alveolar Compartment in Interstitial Lung Disease? PMID- 29244527 TI - Motivations for Extradyadic Infidelity Revisited. AB - Relationship infidelities are motivated by many distinct factors, with previous research indicating motivations of dissatisfaction, neglect, anger, and sexual desire (Barta & Kiene, 2005). We expand on this by demonstrating additional, empirically distinct motivations for infidelity. Using an Internet-based questionnaire, participants (N = 495), most of whom were young adults, self reported their infidelities. In addition to evidence for previously studied motivations, our data demonstrate additional factors, including lack of love ("I had 'fallen out of love with' my primary partner"), low commitment ("I was not very committed to my primary partner"), esteem ("I wanted to enhance my popularity"), gaining sexual variety ("I wanted a greater variety of sexual partners"), and situational factors ("I was drunk and not thinking clearly"). Our results also show personality correlates with infidelity motivations. Consistent with predictions, attachment insecurity was associated with motivations of anger, lack of love, neglect, low commitment, and esteem, while unrestricted sociosexual orientation was associated with sexual variety. Implicit beliefs (e.g., growth, destiny, romanticism) were differentially associated with sexual desire, low commitment, lack of love, and neglect. These findings highlight multifaceted motivations underlying infidelity, moving beyond relationship deficit models of infidelity, with implications for research and psychotherapy involving people's romantic and sexual relationships. PMID- 29244529 TI - What Is the Role of Symptom Management and Patient-Reported Outcomes in Adherence to Aromatase Inhibitors? PMID- 29244528 TI - Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE. AB - Purpose Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR) positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. Methods Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) + TRAS + AI, TRAS + AI, or LAP + AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP + TRAS + AI versus TRAS + AI. Secondary end points were PFS (comparison of other arms), overall survival, overall response rate, clinical benefit rate, and safety. Results Three hundred fifty-five patients were included in this analysis: LAP + TRAS + AI (n = 120), TRAS + AI (n = 117), and LAP + AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP + TRAS + AI versus TRAS + AI (median PFS, 11 v 5.7 months; hazard ratio, 0.62; 95% CI, 0.45 to 0.88; P = .0064). Consistent PFS benefit was observed in predefined subgroups. Overall response rate, clinical benefit rate, and overall survival also favored LAP + TRAS + AI. The median PFS with LAP + AI versus TRAS + AI was 8.3 versus 5.7 months (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P = .0361). Common adverse events (AEs; >= 15%) with LAP + TRAS + AI, TRAS + AI, and LAP + AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the three groups, and AEs leading to discontinuation were lower with LAP + TRAS + AI. Conclusion Dual HER2 blockade with LAP + TRAS + AI showed superior PFS benefit versus TRAS + AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population. PMID- 29244530 TI - Establishing Measurement Equivalence Across Computer- and Paper-Based Tests of Spatial Cognition. AB - Objective The purpose of the present research is to establish measurement equivalence and test differences in reliability between computerized and pencil and-paper-based tests of spatial cognition. Background Researchers have increasingly adopted computerized test formats, but few attempt to establish equivalence for computer-based and paper-based tests. The mixed results in the literature on the test mode effect, which occurs when performance differs as a function of test medium, highlight the need to test for, instead of assume, measurement equivalence. One domain that has been increasingly computerized and is thus in need of tests of measurement equivalence across test mode is spatial cognition. Method In the present study, 244 undergraduate students completed two measures of spatial ability (i.e., spatial visualization and cross-sectioning) in either computer- or paper-and-pencil-based format. Results Measurement equivalence was not supported across computer-based and paper-based formats for either spatial test. The results also indicated that test administration type affected the types of errors made on the spatial visualization task, which further highlights the conceptual differences between test mediums. Paper-based tests also demonstrated increased reliability when compared with computerized versions of the tests. Conclusion The results of the measurement equivalence tests caution against treating computer- and paper-based versions of spatial measures as equivalent. We encourage subsequent work to demonstrate test mode equivalence prior to the utilization of spatial measures because current evidence suggests they may not reliably capture the same construct. Application The assessment of test type differences may influence the medium in which spatial cognition tests are administered. PMID- 29244531 TI - Effects of natural peptides from food proteins on angiotensin converting enzyme activity and hypertension. AB - Cardiovascular diseases are the leading cause of death. The underlying pathophysiology is largely contributed by an overactivation of the renin angiotensin-aldosterone-system (RAAS). Herein, angiotensin II (AngII) is a key mediator not only in blood pressure control and vascular tone regulation, but also involved in inflammation, endothelial dysfunction, atherosclerosis, hypertension and congestive heart failure. Since more than three decades suppression of AngII generation by inhibition of the angiotensin-converting enzyme (ACE) or blockade of the AngII-receptor has shown clinical benefit by reducing hypertension, atherosclerosis and other inflammation-associated cardiovascular diseases. Besides pharmaceutical ACE-inhibitors some natural peptides derived from food proteins reduce in vitro ACE activity. Several animal studies and a few human clinical trials have shown antihypertensive effects of such peptides, which might be attractive as food additives to prevent age-related RAAS activation. However, their inhibitory potency on in vitro ACE activity does not always correlate with an antihypertensive impact. While some peptides with high inhibitory activity on ACE-activity in vitro show no antihypertensive effect in vivo, other peptides with only a moderate ACE inhibitory activity in vitro cause such effects. The explanation for this conflicting phenomenon between inhibitory activity and antihypertensive effect remains unclear to date. This review shall critically address the effects of natural peptides derived from different food proteins on the cardiovascular system and the possible underlying mechanisms. A central aspect will be to point to conceptual gaps in the current understanding of the action of these peptides with respect to in vivo blood pressure lowering effects. PMID- 29244533 TI - Systematic overview of neuroanatomical differences in ADHD: Definitive evidence. AB - OBJECTIVES: This article seeks to identify neuroanatomical differences in ADHD through an overview of systematic reviews that report encephalic differences compared to a control group in volume, area, activation likelihood or chemical composition. METHODS: We conducted a systematic search using Cochrane guidelines and PRISMA criteria in PubMed, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects. RESULTS: Results revealed broad encephalic involvement that includes a functional frontal and cingulate hypoactivation and structural differences in corpus callosum, cerebellum and basal nuclei. CONCLUSIONS: ADHD symptoms might be due to a multi network unbalanced functioning hypothesis. PMID- 29244534 TI - Assessing Infant Carriage Systems: Ground Reaction Force Implications for Gait of the Caregiver. AB - Objective To assess the acute alterations of anterior infant carriage systems on the ground reaction force experienced during over-ground walking. Background Previous research has identified the alterations in posture and gait associated with an increased anterior load (external or internal); however, the forces applied to the system due to the altered posture during over-ground walking have not been established. Method Thirteen mixed gender participants completed 45 over ground walking trials at a self-selected pace under three loaded conditions (unloaded, semi-structured carrier 9.9 kg, and structured carrier 9.9 kg). Each trial consisted of a 15-m walkway, centered around a piezoelectric force platform sampling at 1,200 Hz. Differences were assessed between loaded and unloaded conditions and across carriers using paired samples t tests and repeated measures ANOVA. Results Additional load increased all ground reaction force parameters; however, the magnitude of force changes was influenced by carrier structure. The structured carrier displayed increased force magnitudes, a reduction in the time to vertical maximum heel contact, and an increased duration of the flat foot phase in walking gait. Conclusion Evidence suggests that the acute application of anterior infant carriers alters both kinetic and temporal measures of walking gait. Importantly, these changes appear to be governed not solely by the additional mass but also by the structure of the carrier. Application These findings indicate carrier structure should be considered by the wearer and may be used to inform policy in the recommendation of anterior infant carriage systems use by caregivers. PMID- 29244535 TI - Whether Flexible Flatfoot Needs the Treatment? An Observation of Plantar Pressure Effects on Adults with Flexible Flatfoot by Wearing over the Counter Insoles When Walking on Level Surface, Upstairs and Downstairs. AB - BACKGROUND: Orthotic insole is one popular physiotherapy for flatfoot. However, the effects and if flexible flatfoot needs the treatment are not clear and how the plantar pressure change while walking upstairs and downstairs had not been studied. This study observed the plantar pressure of different walking condition to find out the answers. METHODS: Fifteen adults with flexible flatfoot and fifteen adults with normal foot were examined while walking on a level surface, walking up and down 10 cm and 20 cm stairs before treatment. The max force and the arch index were acquired using the RSscan system. Then the subjects with flexible flatfoot were instructed to wear the orthotic insoles for 3 months and the plantar pressure were measured again after treatment. The repeated measure was performed to analyze the data. RESULTS: Both max force and arch index of flatfoot after treatment were significantly decreased under different walking conditions (p<0.01). When walking down 10 cm and 20 cm stairs, the plantar data of both normal foot and flatfoot were significantly increased (p<0.05). CONCLUSIONS: Orthotic insoles could effectively improve the plantar pressure of flatfoot under different walking conditions. In addition, the arches of both normal foot and flatfoot were obviously influenced when walking downstairs. It is therefore necessary to wear orthotic insoles for flexible flatfoot to prevent further deformation. PMID- 29244536 TI - Dietary intake of fish, n-3 polyunsaturated fatty acids and risk of hip fracture: A systematic review and meta-analysis on observational studies. AB - Previous studies have shown that fish consumption and dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs) are associated with hip fracture; however, findings were conflicting. The present review aimed to summarize the current evidence on the association of fish consumption and dietary intake of n-3 PUFAs with hip fracture. The online databases of PubMed, ISI Web of Science, Scopus, ProQuest, Science Direct and Embase were searched until August 2017 for related publications using relevant keywords. To pool data, either a fixed effects model or random-effects models were used. Cochran's Q tests were used to assess heterogeneity between studies. In total, 10 studies (7 prospective and 3 case-control studies) were included in this systematic review, and 9 studies with total sample size of 292657 participants were included in the meta-analysis. The age of participants was 20 years or older. Combining 8 effect sizes from 4 prospective studies and 2 case-control studies revealed a significant inverse association between fish consumption and risk of hip fracture (pooled effect size: 0.88, 95% CI: 0.79-0.98, P = 0.02). Although this relationship became non significant in prospective studies, a significant inverse association was found in prospective studies with sample size of 10000 individuals or more, and studies that considered body mass index as a covariate. Furthermore, dietary intake of n 3 PUFAs was inversely associated with risk of hip fracture (pooled effect size: 0.89, 95% CI: 0.80-0.99, P = 0.02). Also, such relationship was seen after excluding one case-control study and combining effect sizes only from prospective studies (pooled effect size: 0.88, 95% CI: 0.80-0.98, P = 0.02). In conclusion, we found that fish consumption and dietary intake of n-3 PUFAs might have protective effects on bone health and decline the risk of hip fracture. PMID- 29244532 TI - Risk Factors and Predictors of Significant Chondral Surface Change From Primary to Revision Anterior Cruciate Ligament Reconstruction: A MOON and MARS Cohort Study. AB - BACKGROUND: Articular cartilage health is an important issue following anterior cruciate ligament (ACL) injury and primary ACL reconstruction. Factors present at the time of primary ACL reconstruction may influence the subsequent progression of articular cartilage damage. HYPOTHESIS: Larger meniscus resection at primary ACL reconstruction, increased patient age, and increased body mass index (BMI) are associated with increased odds of worsened articular cartilage damage at the time of revision ACL reconstruction. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Subjects who had primary and revision data in the databases of the Multicenter Orthopaedics Outcomes Network (MOON) and Multicenter ACL Revision Study (MARS) were included. Reviewed data included chondral surface status at the time of primary and revision surgery, meniscus status at the time of primary reconstruction, primary reconstruction graft type, time from primary to revision ACL surgery, as well as demographics and Marx activity score at the time of revision. Significant progression of articular cartilage damage was defined in each compartment according to progression on the modified Outerbridge scale (increase >=1 grade) or >25% enlargement in any area of damage. Logistic regression identified predictors of significant chondral surface change in each compartment from primary to revision surgery. RESULTS: A total of 134 patients were included, with a median age of 19.5 years at revision surgery. Progression of articular cartilage damage was noted in 34 patients (25.4%) in the lateral compartment, 32 (23.9%) in the medial compartment, and 31 (23.1%) in the patellofemoral compartment. For the lateral compartment, patients who had >33% of the lateral meniscus excised at primary reconstruction had 16.9-times greater odds of progression of articular cartilage injury than those with an intact lateral meniscus ( P < .001). For the medial compartment, patients who had <33% of the medial meniscus excised at the time of the primary reconstruction had 4.8 times greater odds of progression of articular cartilage injury than those with an intact medial meniscus ( P = .02). Odds of significant chondral surface change increased by 5% in the lateral compartment and 6% in the medial compartment for each increased year of age ( P <= .02). For the patellofemoral compartment, the use of allograft in primary reconstruction was associated with a 15-fold increased odds of progression of articular cartilage damage relative to a patellar tendon autograft ( P < .001). Each 1-unit increase in BMI at the time of revision surgery was associated with a 10% increase in the odds of progression of articular cartilage damage ( P = .046) in the patellofemoral compartment. CONCLUSION: Excision of the medial and lateral meniscus at primary ACL reconstruction increases the odds of articular cartilage damage in the corresponding compartment at the time of revision ACL reconstruction. Increased age is a risk factor for deterioration of articular cartilage in both tibiofemoral compartments, while increased BMI and the use of allograft for primary ACL reconstruction are associated with an increased risk of progression in the patellofemoral compartment. PMID- 29244537 TI - Role of renin-angiotensin aldosterone system on short-term blood pressure variability in hypertensive patients. AB - The relationship between the renin-angiotensin aldosterone system and short-term blood pressure variability has not been well elucidated. Here, we investigated whether blood pressure variability determined by ambulatory blood pressure monitoring differed among patients with primary aldosteronism (PA), renovascular hypertension (RVHT), and essential hypertension (EHT). We examined 25 patients with PA, 28 patients with RVHT, and 18 patients with EHT. Ambulatory blood pressure monitoring was conducted in all patients. Short-term blood pressure variability was evaluated by calculating the standard deviation (SD), coefficient of variation (CV), and average real variability (ARV) of 24-h, daytime, and nighttime blood pressure values. Day-night differences in blood pressure were also determined. The mean 24-h systolic blood pressure (SBP) and the mean diastolic blood pressure (DBP) in the PA and RVHT groups were found to be comparable to those in the EHT group. The SD, the CV, nor the ARV of the 24-h, daytime, and nighttime blood pressures showed any significant differences among the three groups. The day-night differences in blood pressure were comparable among the three groups. The short-term blood pressure variabilities evaluated by ambulatory blood pressure monitoring were comparable among the patients with EHT, RVHT, and PA. The results suggest that the renin-angiotensin aldosterone system may contribute little to short-term blood pressure variability in individuals with hypertension. PMID- 29244539 TI - Genotype-phenotype variability of retinal manifestation in primary hyperoxaluria type 1. AB - BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare congenital metabolic disorder of the glyoxylate pathway, which manifests with nephrocalcinosis, urolithiasis, and end-stage renal failure (ESRD) as well as deposition of oxalate crystals within ocular tissues. This report demonstrates classical ocular features of PH1 of the posterior pole and furthermore highlights the ocular genotype-phenotype variability among siblings with identical compound heterozygous alanine-glyoxylate aminotransferase (AGXT) mutations. MATERIALS AND METHODS: Two siblings, an 8-year-old boy and an 18-year-old girl, with genetically confirmed AGXT mutation (c.364C>T (p.R122X) and c.33dupC), but different renal phenotype underwent an ophthalmic examination, including slit lamp examination and funduscopy as well as optical coherence tomography (OCT), near-infrared autofluorescence (NIA), and microperimetry examination. RESULTS: The 8-year-old boy presented with a best-corrected visual acuity (BCVA) of 20/630. Fundus examination revealed bilateral, whitish oxalate deposits and prominent fibrotic macular scars. OCT imaging illustrated hyperdense deposits in all retinal layers and the choroid and the vitreous body along with a prominent dome-shaped macular fibrosis. NIA imaging outlined macular retinal pigment epithelium (RPE) atrophy with panretinal hyperreflective material. Bilateral symptomatic epiphora was putatively due to bilateral depositions of palpable nodular oxalate deposits at the level of the lacrimal sac. In contrary, the 18 year-old sister presented without any signs of ocular oxalate deposition and a BCVA of 20/20. CONCLUSIONS: PH1 is potentially accompanied with a considerable decline in visual acuity due to macular scaring and fibrosis, whereas a profound variability of ocular manifestations can be observed in PH1 patients with identical genotypes. PMID- 29244538 TI - Associations Between Dietary Patterns and Longitudinal Quality of Life Changes in Colorectal Cancer Patients: The ColoCare Study. AB - Quality of life (QoL) is an important clinical outcome in cancer patients. We investigated associations between dietary patterns and QoL changes in colorectal cancer (CRC) patients. The study included 192 CRC patients with available EORTC QLQ-C30 data before and 12 months post-surgery and food frequency questionnaire data at 12 months post-surgery. Principal component analysis was used to identify dietary patterns. Multivariate regression models assessed associations between dietary patterns and QoL changes over time. We identified four major dietary patterns: "Western" dietary pattern characterized by high consumption of potatoes, red and processed meat, poultry, and cakes, "fruit&vegetable" pattern: high intake of vegetables, fruits, vegetable oils, and soy products, "bread&butter" pattern: high intake of bread, butter and margarine, and "high carb" pattern: high consumption of pasta, grains, nonalcoholic beverages, sauces and condiments. Patients following a "Western" diet had lower chances to improve in physical functioning (OR = 0.45 [0.21-0.99]), constipation (OR = 0.30 [0.13 0.72]) and diarrhea (OR: 0.44 [0.20-0.98]) over time. Patients following a "fruit&vegetable" diet showed improving diarrhea scores (OR: 2.52 [1.21-5.34]. A "Western" dietary pattern after surgery is inversely associated with QoL in CRC patients, whereas a diet rich in fruits and vegetables may be beneficial for patients' QoL over time. PMID- 29244540 TI - Overcoming Impediments to OTP Expansion in the United States and Abroad. AB - By all published accounts and federal government reports, the United States is experiencing a serious opioid use epidemic. Additional treatment resources are needed in order to provide access to evidence based medical care for untreated individuals with substance use disorders. The focus of this commentary is increasing access to more opioid treatment programs and overcoming the significant impediments, which block such efforts. PMID- 29244541 TI - Race and Trends in Pornography Viewership, 1973-2016: Examining the Moderating Roles of Gender and Religion. AB - While some research has uncovered racial differences in patterns of pornography viewership, no studies to date have considered how these patterns may be changing over time or how these trends may be moderated by other key predictors of pornography viewership-specifically, gender and religion. Using nationally representative data from the 1973-2016 General Social Survey (GSS; N = 20,620), and taking into account different ethnoreligious histories with pornography as a moral issue, we examined how race, gender, and religion intersect to influence trends in pornography viewership over 43 years. Analyses revealed that Black Americans in general were more likely to view pornography than Whites, and they were increasing in their pornography viewership at a higher rate than Whites. Moreover, Black men were more likely to consume pornography than all other race/gender combinations, but differed only from White women in their increasing rate of pornography viewership. Lastly, frequent worship attendance moderated trends in pornography viewership only for White men. By contrast, regardless of attendance frequency, Black men and women showed increasing rates of pornography use, while White women showed flat rates. We conclude by discussing the implications of these findings for research on the intersections of race, gender, religion, and sexuality. PMID- 29244542 TI - Differential long-term medication impact on executive function and delay aversion in ADHD. AB - The objective was to compare long-term effects of methylphenidate (MPH) and atomoxetine (ATX) on executive functions (EF) and delay aversion (DAv) in ADHD. A randomized controlled trial was conducted. A comprehensive neuropsychological battery was administered at three moments (Naive, Post-1, Post-2). ADHD participants who showed deficits in the naive evaluation (n = 26) were randomized to receive either MPH (n = 13; Mage = 11 +/- 1, MIQ 96 +/- 8) or ATX (n = 13; Mage = 10 +/- 1, MIQ 106 +/- 16.5) optimal dosages. Parallel test forms were administered after three (Post-1) and six months (Post-2) of treatment. A control group (n = 19; Mage = 11 +/- 1; MIQ = 106 +/- 16.5) performed the neuropsychological battery similarly. Both MPH and ATX significantly improved scores in verbal working memory (vWM) (Naive: p < 0.0001, d = 0.75; Post-1: p = 0.71, d = 0.12), spatial working memory (sWM) (Naive p < 0.0001, d = 0.63; Post-2 p = 0.44; d = 0.03), planning (Naive p < 0.0001, d = 0.54; Post-2 p = 0.6, d = 0.18), decision making (Naive p < 0.001 d = 0.28; Post-1 = 0.06 d = 0.12) and inhibition (Naive <0.0001, d = 0.66; Post-2 p = 0.08, d = 0.00), reaching an improved treatment response after three months of treatment in vWM and after six months in sWM, planning, and inhibition. No beneficial effect on DAv and risk taking was found with MPH and neither with ATX. Long-term treatment in range of optimal clinical dosages with either MPH or ATX improves EF, but not DAv in children with ADHD. PMID- 29244543 TI - In situ Rates of Fertilization Among Broadcast Spawning Gorgonian Corals. AB - Fertilization rates among marine benthic taxa have implicitly been assumed to be uniformly high in most analyses of life history evolution, but in situ fertilization rates during natural spawning events are rarely measured. Fertilization rates of the Caribbean gorgonians Plexaura kuna and Pseudoplexaura porosa were measured at a site in the San Blas Islands, Panama, by collecting eggs downstream of colonies during synchronous spawning events during the summer months in the years 1988-1994. Eggs collected by divers were incubated, and the proportion of eggs that developed was determined. Proportions of eggs developing suggest fertilization rates that vary from 0% to 100%. Monthly means ranged from 0% to 60.4%. Failure of gametes to develop can be attributed to sperm limitation, as eggs collected during spawning had higher fertilization rates if incubated with an excess of sperm. Plexaura kuna fertilization rates were highest during the July spawning events. Fertilization of Plexaura kuna eggs was usually lower during the first two nights of the 4-6 night spawning event. The proportion of eggs being fertilized when collected from a given place and time was highly variable, with one peak in the frequency distribution at or below 20% fertilization, and a second group of samples with greater fertilization rates. High variance in fertilization rates is evident at all levels of analysis: between replicate samples, times within nights, and among nights and months. This variance can be attributed to a combination of the effects of heterogeneity in the water column as gametes are diluted, spawning behavior of the gorgonians, and the current regime. Fertilization rates are often low and may represent a limiting step in recruitment during some years. Low fertilization rates may also be an important component of the life history evolution of these species. PMID- 29244544 TI - Completely Direct Development of Abatus cordatus, a Brooding Schizasterid (Echinodermata: Echinoidea) from Kerguelen, With Description of Perigastrulation, a Hypothetical New Mode of Gastrulation. AB - Development of the brooding schizasterid Abatus cordatus, a subantarctic echinoid endemic to Kerguelen, is described. Females spawn nonbuoyant eggs 1300 MUm in diameter, which are fertilized by elongated sperm (head 1 MUm wide and 15 MUm long). The main characteristics of this development are (1) incomplete cleavage beginning at the animal pole that becomes holoblastic, giving a filled wrinkled blastula 26 days after fertilization; (2) apparent (fate-mapping studies have not been done) external migration of mesenchyme cells, in the perivitelline space, from the animal to the vegetal pole during gastrulation while the archenteron invaginates; (3) hatching occurring at the end of the gastrulation (65 days after fertilization); (4) differentiation of the vestibule from a thickening of the oral epidermis as soon as the end of gastrulation is attained; and (5) production of a juvenile directly from the gastrula without any larval stage. The juvenile that leaves the brood chamber is 2 mm in diameter and about 250 days old. A. cordatus is a true completely direct developer (no larva and no metamorphosis). We propose to use (1) the term perigastrulation, as a tentative one until more definitive studies are available, to describe the hypothetical peculiar movement of cells during gastrulation and (2) the terms of direct development only for completely direct developing species and abbreviated development for species that have more or less transformed plutei. PMID- 29244545 TI - Gastrovascular Flow and Colony Development in Two Colonial Hydroids. AB - Using field-collected Podocoryne carnea and Hydractinia symbiolongicarpus, ten colonies of each species were produced by sexual crosses and grown from primary polyps to sexual maturity. At comparable stages in the life history, each colony's morphology was measured using digital image analysis, and each colony's gastrovascular flow to three peripheral stolon tips was recorded using video microscopy. Gastrovascular flow to peripheral stolon tips shows very different patterns in the two species. H. symbiolongicarpus exhibits maximal flow as a primary polyp. Both the mean and the variance of the flow rate decline by the time of stolonal mat formation. When covering the substratum, gastrovascular flow is low and somewhat more variable than at the time of stolonal mat formation. On the other hand, P. carnea exhibits minimal flow as a primary polyp. At subsequent stages, flow increases monotonically. Thus at the primary polyp stage, H. symbiolongicarpus exhibits a greater rate of flow to peripheral stolon tips than P. carnea. The reverse is true at subsequent stages. In general, these results support the hypothesis that higher rates of gastrovascular flow produce runner like colonies, while lower rates of flow produce sheet-like colonies. PMID- 29244546 TI - The Relationship Between Predator Activity State and Sensitivity to Prey Odor. AB - Predators searching for prey commonly alternate periods of endogenous locomotory activity with rest. We examined the effects of activity state on behavioral responses to prey odor by predatory blue crabs (Callinectes sapidus) and spiny lobsters (Panulirus interruptus). All animals to be tested were placed individually in large seawater tanks (1.5-m diameter) outdoors, where they were assayed for their responses. Initial experiments were conducted at night, the period of greatest normal endogenous activity, in either moonlight or dim, far red illumination. Prey odor was presented to crabs and lobsters as they either spontaneously walked or rested (for 15-30 min) between locomotory bouts. Only walking animals significantly responded; they either turned towards the site of odor delivery or probed the substratum with chelae and legs. An additional experiment was conducted by presenting a purified prey attractant (ATP) to spiny lobsters. Remarkably, ATP was 498 times more potent in evoking response from walking animals than from resting ones. Neither the duration (15-30 min compared with 4-8 h) nor the timing (night compared with day) of the rest period influenced the sensitivity of the behavioral response. On the basis of our current results, chemical stimuli appear principally to modulate searching by predators already aroused rather than to initiate foraging or feeding from the quiescent state. Significantly, whenever experiments restrict the activity of freely ranging animals, determinations of chemosensory-stimulated behavior may substantially overestimate the concentrations needed to evoke responses. PMID- 29244547 TI - Convergence in the Feeding Apparatuses of Lophophorates and Pterobranch Hemichordates Revealed by 18S rDNA: An Interpretation. AB - Homology of the feeding apparatus of pterobranch hemichordates and the lophophore of bryozoans, brachiopods, and phoronids has been postulated but never rigorously tested. I employ Patterson's (1, 2) three criteria of conjunction, similarity, and congruence to test this putative homology. Although the conjunction and similarity criteria are satisfied, congruence is not. The congruence test is based on a phylogeny derived from 18s rDNA sequence data which show that pterobranchs and lophophorates are in diRerent metazoan subkingdoms and are not closely related. This finding indicates that a lophophore-like apparatus has evolved at least twice in metazoans even though the gross morphology, feeding mechanics, ultrastructure, and ciliary patterns of these organisms are very similar. The high degree of morphological convergence presumably results from similar selective regimes acting on these taxa. These findings indicate that major clades of organisms can evolve in a correspondingfashion despite independent origins. PMID- 29244548 TI - Efferent Mechanisms of Discharging Cnidae: I. Measurements of Intrinsic Adherence of Cnidae Discharged From Tentacles of the Sea Anemone, Aiptasia pallida. AB - Two kinds of cnida predominate in the tentacles of the acontiate sea anemones: spirocysts and microbasic mastigophore nematocysts. These cnidae discharge in response to appropriate mechanical and chemical stimulation. In this paper, we calculate the strengths of attachment between the tentacle and the capsules (= "tentacle adherence") of discharged spirocysts and mastigophores by measuring adhesive force and by determining the numbers of spirocysts and mastigophores discharged onto targets under conditions where the attachment of everted cnida tubules to the target (= "cnida adhesion") exceeds tentacle adherence. Under these conditions, the average contribution of individual cnidae to adhesive force is called the intrinsic adherence. The intrinsic adherence is a measure of the average frictional force required to dislodge the capsule of individual discharged cnidae from the tentacle. The intrinsic adherence of discharged mastigophores varies inversely, from 0.45 to 0.15 mgf (4.41 to 1.47 MUN), with the number of discharged mastigophores. The larger values characterize mastigophores discharged by mechanically triggering nonchemosensitized tentacles, whereas the lower values characterize the intrinsic adherence of mastigophores discharged from chemosensitized tentacles. In contrast, the intrinsic adherence of discharged spirocysts is very low to insignificant. Thus, by comparison to mastigophores, spirocysts contribute little, if any, to adhesive force, and, by inference, do not directly secure captured prey to the tentacle. Our measurements indicate that penetrable prey are primarily secured to the tentacle by discharged mastigophores and by the inherent stickiness of the tentacle surface. PMID- 29244549 TI - Karyotype of the Sea Anemone Aiptasiomorpha sp. (Anthozoa, Actiniaria) From Japan. AB - In the Anthozoa, only one karyological study has been performed, namely, a study of the coral Goniopora lobata (2n = 28) by a "squash" method (1) and no information about the chromosomes of a sea anemone has been presented apart from a recent preliminary report of the diploid chromosome number and the complement of chromosomes of Haliplanella lineata (= H. luciae) (2n = 32), which were examined by an air-drying method (2). Morphological details of the chromosomes were not provided. The present study is the first attempt at karyotypic analysis in Actiniaria, a poorly studied order of Coelenterata (3-6). The karyotype of Aiptasiomorpha sp. was determined by conventional Giemsa-stained preparations of early embryos. This species has 2n = 32 chromosomes, consisting of 14pairs of biarmed chromosomes and 2 pairs of chromosomes having one arm or with the second arm extremely small. The presence of two large metacentric pairs characterizes the karyotype of Aiptasiomorpha species. PMID- 29244550 TI - Classification of Nerve Cells Dissociated From Tentacles of the Sea Anemone Calliactis parasitica. AB - Nerve cells from tentacles of the sea anemone Calliactis parasitica were dissociated in 1000 units/ml of collagenase for scanning electron microscopic studies and in 0.125% elastase followed by 12 units/ml of ficin for cell counts using light microscopy. The studies revealed 33 distinguishable neuronal shapes, which were categorized as either sensory cells having an apical cilium or ganglion cells with or without a perikaryal cilium and further subdivided into unipolar, bipolar and multipolar neurons based on the number of processes that extended from the perikaryon. Unipolar sensory cells were characterized by an apical cilium adjacent to the perikaryon and a long, simple or terminally branched axon. Unipolar ganglion cells lacked an apical cilium. Bipolar sensory cells had a neck between the cilium and perikaryon and an oppositely directed axon. Bipolar ganglion cells had isopolar processes or asymmetrical processes, which were simple or complexly branched. One type of bipolar ganglion cell with isopolar processes had a perikaryal cilium. Multipolar sensory cells had a distinct neck between the perikaryon and the cilium and two or more simple or complexly branched processes extending from the triangularly shaped cell body. Multipolar ganglion cells had variously shaped perikarya from which extended three or more short or long processes that were simple or complexly branched. One type of tripolar ganglion cell had a perikaryal cilium. The different types of nerve cells were quantified, and statistical comparisons were made. PMID- 29244551 TI - Intersex Red Claw Crayfish, Cherax quadricarinatus (von Martens): Functional Males with Pre-vitellogenic Ovaries. AB - Intersex individuals, possessing both male and female genital openings, were assessed in two groups-7 and 19 months old-of Australian red claw crayfish (Cherax quadricarinatus). All intersex individuals investigated were functional males, as suggested by their malelike morphology and the presence of testes, sperm ducts, androgenic glands, and viable spermatozoa. When an ovary was present in an intersex individual from either group, the gonadosomatic index, the diameter of the oocytes, and the ovarian cytosolic polypeptide profile were similar to those of immature, pre-vitellogenic females. We conclude that intersexuality in C. quadricarinatus does not indicate a case of protandric sequential hermaphroditism, as previously suggested. The case of intersexuality described here presents a unique model for the study of the role of the androgenic gland in the regulation of sex differentiation in crustaceans. PMID- 29244552 TI - Acid-Base Status of the Oyster Crassostrea virginica in Response to Air Exposure and to Infections by Perkinsus marinus. AB - Hemolymph acid-base variables were investigated in the Eastern oyster, Crassostrea virginica, to determine its responses to air exposure and to infections by the parasite Perkinsus marinus. Infected and uninfected oysters were subjected to two treatments of temperature (21 degrees and 30 degrees C) and air exposure (5 and 24 h). Upon exposure to air, oysters underwent a respiratory acidosis that remained uncompensated in uninfected oysters but was partially compensated in highly infected oysters at both 21 degrees and 30 degrees C. The acidosis was significantly greater in oysters with high infections. Hemolymph in uninfected oysters had a greater buffering capacity ( 6.80 +/- 0.76 SEM slykes) than hemolymph in highly infected oysters (-3.30 +/- 0.50 SEM slykes). Calcium ion concentrations in hemolymph increase when the hemolymph becomes acidic, suggesting that shell decalcification plays a role in buffering the acid. During air exposure, although oysters do not visibly gape, they access air and are apparently not completely anaerobic. PMID- 29244553 TI - Embryos at the Edge of Tolerance: Effects of Environment and Structure of Egg Masses on Supply of Oxygen to Embryos. AB - Oxygen concentrations in gelatinous egg masses of two species of opisthobranch gastropods were examined with microelectrodes. Embryos in central positions are near the limit of the oxygen supply required for development. This limit is approached despite a diffusion constant for oxygen in masses that is close to that in water. Closed-chamber respirometry shows that oxygen is consumed by masses in the dark but generated in the light. Internal oxygen concentrations were greater in bright than in dim light. Thus photosynthesis and respiration of microorganisms associated with the masses affects the supply of oxygen to embryos within the mass. This effect of light was confirmed for egg masses of a polychaete. These observations, together with other published observations on the effects of hypoxia on development, indicate that the developmental rates of embryos in egg masses may depend on algal photosynthesis and metabolism. Flow around the masses also affects delivery of oxygen to embryos, but masses in dim light are at the limit of adequate supply even in a strong flow with a very thin boundary layer. Because the central embryos are near the limit for adequate supply of oxygen by diffusion, their development rate thus depends on light, abundance of photosynthetic and heterotrophic microorganisms, flow, and oxygen concentration in the surrounding water. PMID- 29244554 TI - Letter from the Editor. PMID- 29244555 TI - Theoretical Approaches in Evolutionary Ecology: Environmental Feedback as a Unifying Perspective. AB - Evolutionary biology and ecology have a strong theoretical underpinning, and this has fostered a variety of modeling approaches. A major challenge of this theoretical work has been to unravel the tangled feedback loop between ecology and evolution. This has prompted the development of two main classes of models. While quantitative genetics models jointly consider the ecological and evolutionary dynamics of a focal population, a separation of timescales between ecology and evolution is assumed by evolutionary game theory, adaptive dynamics, and inclusive fitness theory. As a result, theoretical evolutionary ecology tends to be divided among different schools of thought, with different toolboxes and motivations. My aim in this synthesis is to highlight the connections between these different approaches and clarify the current state of theory in evolutionary ecology. Central to this approach is to make explicit the dependence on environmental dynamics of the population and evolutionary dynamics, thereby materializing the eco-evolutionary feedback loop. This perspective sheds light on the interplay between environmental feedback and the timescales of ecological and evolutionary processes. I conclude by discussing some potential extensions and challenges to our current theoretical understanding of eco-evolutionary dynamics. PMID- 29244556 TI - Seasonal Food Scarcity Prompts Long-Distance Foraging by a Wild Social Bee. AB - Foraging is an essential process for mobile animals, and its optimization serves as a foundational theory in ecology and evolution; however, drivers of foraging are rarely investigated across landscapes and seasons. Using a common bumblebee species from the western United States (Bombus vosnesenskii), we ask whether seasonal decreases in food resources prompt changes in foraging behavior and space use. We employ a unique integration of population genetic tools and spatially explicit foraging models to estimate foraging distances and rates of patch visitation for wild bumblebee colonies across three study regions and two seasons. By mapping the locations of 669 wild-caught individual foragers, we find substantial variation in colony-level foraging distances, often exhibiting a 60 fold difference within a study region. Our analysis of visitation rates indicates that foragers display a preference for destination patches with high floral cover and forage significantly farther for these patches, but only in the summer, when landscape-level resources are low. Overall, these results indicate that an increasing proportion of long-distance foraging bouts take place in the summer. Because wild bees are pollinators, their foraging dynamics are of urgent concern, given the potential impacts of global change on their movement and services. The behavioral shift toward long-distance foraging with seasonal declines in food resources suggests a novel, phenologically directed approach to landscape-level pollinator conservation and greater consideration of late-season floral resources in pollinator habitat management. PMID- 29244557 TI - Rising Variability, Not Slowing Down, as a Leading Indicator of a Stochastically Driven Abrupt Transition in a Dryland Ecosystem. AB - Complex systems can undergo abrupt state transitions near critical points. Theory and controlled experimental studies suggest that the approach to critical points can be anticipated by critical slowing down (CSD), that is, a characteristic slowdown in the dynamics. The validity of this indicator in field ecosystems, where stochasticity is important in driving transitions, remains unclear. We analyze long-term data from a dryland ecosystem in the Shapotou region of China and show that the ecosystem underwent an abrupt transition from a nearly bare to a moderate grass cover state. Prior to the transition, the system showed no (or weak) signatures of CSD but exhibited expected increasing trends in the variability of the grass cover, quantified by variance and skewness. These surprising results are consistent with the theoretical expectation of stochastically driven abrupt transitions that occur away from critical points; indeed, a driver of vegetation-annual rainfall-showed rising variance prior to the transition. Our study suggests that rising variability can potentially serve as a leading indicator of stochastically driven transitions in real-world ecosystems. PMID- 29244558 TI - Loss of Color Pigmentation Is Maintained at High Frequency in a Monkey Flower Population. AB - Color polymorphisms have long been of evolutionary interest for their diverse roles, including mate choice, predator avoidance, and pollinator attraction. While color variation is often under strong selection, some taxa demonstrate unexpectedly high frequencies of presumed deleterious color forms. Here we show that a genetic variant underlying complete loss of anthocyanin pigmentation has risen to an unexpectedly high frequency of >0.2 in a natural population of the plant Mimulus guttatus. Decreased expression of MYB5 transcription factor is associated with unpigmented morphs. While the allele was found only in heterozygote adults in the wild, suggesting negative selection, experiments were unable to demonstrate a fitness cost for unpigmented plants, suggesting a cryptic selection pressure in the wild. However, life-history differences among morphs suggests that unpigmented individuals benefit from later flowering and clonal growth. Overall, our study highlights the complex interplay of factors maintaining variation in nature, even for genes of major effect. PMID- 29244559 TI - Thermoregulatory Behavior Simultaneously Promotes and Forestalls Evolution in a Tropical Lizard. AB - The role of behavior in evolution has long been discussed, with some arguing that behavior promotes evolution by exposing organisms to selection (behavioral drive) and others proposing that it inhibits evolution by shielding organisms from environmental variation (behavioral inertia). However, this discussion has generally focused on the effects of behavior along a single axis without considering that behavior simultaneously influences selection in various niche dimensions. By examining evolutionary change along two distinct niche axes structural and thermal-we propose that behavior simultaneously drives and impedes evolution in a group of Anolis lizards from the Caribbean island of Hispaniola. Specifically, a behavioral shift in microhabitat to boulders at high altitude enables thermoregulation, thus forestalling physiological evolution in spite of colder environments. This same behavioral shift drives skull and limb evolution to boulder use. Our results emphasize the multidimensional effects of behavior in evolution. These findings reveal how, rather than being diametrically opposed, niche conservatism and niche lability can occur simultaneously. Furthermore, patterns of niche evolution may vary at different geographic scales: because of thermoregulatory behavior, lizards at high and low elevation share similar microclimatic niches (consistent with niche conservatism) while inhabiting distinct macroclimatic environments (consistent with niche divergence). Together, our results suggest that behavior can connect patterns of niche divergence and conservatism at different geographic scales and among traits. PMID- 29244560 TI - Sex-Specific Heterogeneity in Fixed Morphological Traits Influences Individual Fitness in a Monogamous Bird Population. AB - Theoretical work has emphasized the important role of individual traits on population dynamics, but empirical models are often based on average or stage dependent demographic rates. In this study on a monogamous bird, the Eurasian hoopoe (Upupa epops), we show how the interactions between male and female fixed and dynamic heterogeneity influence demographic rates and population dynamics. We built an integral projection model including individual sex, age, condition (reflecting dynamic heterogeneity), and fixed morphology (reflecting fixed heterogeneity). Fixed morphology was derived from a principal component analysis of six morphological traits. Our results revealed that reproductive success and survival were linked to fixed heterogeneity, whereas dynamic heterogeneity influenced mainly the timing of reproduction. Fixed heterogeneity had major consequences for the population growth rate, but interestingly, its effect on population dynamics differed between the sexes. Female fixed morphology was directly linked to annual reproductive success, whereas male fixed morphology also influenced annual survival, being twice higher in large than in small males. Even in a monogamous bird with shared parental care, large males can reach 10% higher fitness than females. Including the dynamics of male and female individual traits in population models refines our understanding of the individual mechanisms that influence demographic rates and population dynamics and can help in identifying differences in sex-specific strategies. PMID- 29244561 TI - Mechanisms of Assortative Mating in Speciation with Gene Flow: Connecting Theory and Empirical Research. AB - The large body of theory on speciation with gene flow has brought to light fundamental differences in the effects of two types of mating rules on speciation: preference/trait rules, in which divergence in both (female) preferences and (male) mating traits is necessary for assortment, and matching rules, in which individuals mate with like individuals on the basis of the presence of traits or alleles that they have in common. These rules can emerge from a variety of behavioral or other mechanisms in ways that are not always obvious. We discuss the theoretical properties of both types of rules and explain why speciation is generally thought to be more likely under matching rather than preference/trait rules. We furthermore discuss whether specific assortative mating mechanisms fall under a preference/trait or matching rule, present empirical evidence for these mechanisms, and propose empirical tests that could distinguish between them. The synthesis of the theoretical literature on these assortative mating rules with empirical studies of the mechanisms by which they act can provide important insights into the occurrence of speciation with gene flow. Finally, by providing a clear framework we hope to inspire greater alignment in the ways that both theoreticians and empiricists study mating rules and how these rules affect speciation through maintaining or eroding barriers to gene flow among closely related species or populations. PMID- 29244562 TI - Learning to Cooperate: The Evolution of Social Rewards in Repeated Interactions. AB - Understanding the behavioral and psychological mechanisms underlying social behaviors is one of the major goals of social evolutionary theory. In particular, a persistent question about animal cooperation is to what extent it is supported by other-regarding preferences-the motivation to increase the welfare of others. In many situations, animals adjust their behaviors through learning by responding to the rewards they experience as a consequence of their actions. Therefore, we may ask whether learning in social situations can be driven by evolved other regarding rewards. Here we develop a mathematical model in order to ask whether the mere act of cooperating with a social partner will evolve to be inherently rewarding. Individuals interact repeatedly in pairs and adjust their behaviors through reinforcement learning. We assume that individuals associate with each game outcome an internal reward value. These perceived rewards are genetically evolving traits. We find that conditionally cooperative rewards that value mutual cooperation positively but the sucker's outcome negatively tend to be evolutionarily stable. Purely other-regarding rewards can evolve only under special parameter combinations. On the other hand, selfish rewards that always lead to pure defection are also evolutionarily successful. These findings are consistent with empirical observations showing that humans tend to display conditionally cooperative behavior and also exhibit a diversity of preferences. Our model also demonstrates the need to further integrate multiple levels of biological causation of behavior. PMID- 29244564 TI - 2017 American Society of Naturalists Awards. PMID- 29244563 TI - Offspring Size and Reproductive Allocation in Harvester Ants. AB - A fundamental decision that an organism must make is how to allocate resources to offspring, with respect to both size and number. The two major theoretical approaches to this problem, optimal offspring size and optimistic brood size models, make different predictions that may be reconciled by including how offspring fitness is related to size. We extended the reasoning of Trivers and Willard (1973) to derive a general model of how parents should allocate additional resources with respect to the number of males and females produced, and among individuals of each sex, based on the fitness payoffs of each. We then predicted how harvester ant colonies should invest additional resources and tested three hypotheses derived from our model, using data from 3 years of food supplementation bracketed by 6 years without food addition. All major results were predicted by our model: food supplementation increased the number of reproductives produced. Male, but not female, size increased with food addition; the greatest increases in male size occurred in colonies that made small females. We discuss how use of a fitness landscape improves quantitative predictions about allocation decisions. When parents can invest differentially in offspring of different types, the best strategy will depend on parental state as well as the effect of investment on offspring fitness. PMID- 29244565 TI - Do Sperm Really Compete and Do Eggs Ever Have a Choice? Adult Distribution and Gamete Mixing Influence Sexual Selection, Sexual Conflict, and the Evolution of Gamete Recognition Proteins in the Sea. AB - The evolution of gametic compatibility and the effectiveness of compatibility, within and across species, depend on whether sperm from different males directly compete for an egg and whether eggs ever have a choice. Direct sperm competition and egg choice depend on whether sperm from different males arrive at an egg in the brief interval between first sperm contact and fertilization. Although this process may be relevant for all sexually reproducing organisms, it is most easily examined in aquatic external fertilizers. When sperm are released into the sea, packets of seawater at the spatial scale relevant to single eggs might contain sperm from only one male, eliminating the potential for direct sperm competition and egg choice. Field experiments and a simple heuristic model examining the degree of sperm mixing for the sea urchin Strongylocentrotus franciscanus indicate that degree of competitive fertilization depends on density and distribution of competing males and that the nature of this competition influences whether males with high- or low-affinity gamete recognition protein genotypes have higher reproductive success. These results provide a potential explanation for the generation and maintenance of variation in gamete recognition proteins and why effectiveness of conspecific sperm precedence can be density dependent. PMID- 29244566 TI - The Price Equation, Gradient Dynamics, and Continuous Trait Game Theory. AB - A recent article convincingly nominated the Price equation as the fundamental theorem of evolution and used it as a foundation to derive several other theorems. A major section of evolutionary theory that was not addressed is that of game theory and gradient dynamics of continuous traits with frequency dependent fitness. Deriving fundamental results in these fields under the unifying framework of the Price equation illuminates similarities and differences between approaches and allows a simple, unified view of game-theoretical and dynamic concepts. Using Taylor polynomials and the Price equation, I derive a dynamic measure of evolutionary change, a condition for singular points, the convergence stability criterion, and an alternative interpretation of evolutionary stability. Furthermore, by applying the Price equation to a multivariable Taylor polynomial, the direct fitness approach to kin selection emerges. Finally, I compare these results to the mean gradient equation of quantitative genetics and the canonical equation of adaptive dynamics. PMID- 29244567 TI - Temporal Variation in Predation Risk May Explain Daily Rhythms of Foraging Behavior in an Orb-Weaving Spider. AB - Daily rhythms occur in numerous physiological and behavioral processes across an immense diversity of taxa, but there remain few cases in which mechanistic links between rhythms of trait expression and organismal fitness have been established. We construct a dynamic optimization model to determine whether risk allocation provides an adaptive explanation for the daily foraging rhythm observed in many species using the orb-weaving spider Cyclosa turbinata as a case study. Our model predicts that female C. turbinata should generally start foraging at lower levels of energy reserves (i.e., should be less bold) during midday when predators are most abundant. We also find that individuals' foraging efficacy determines whether daily rates of encounters with predators or prey more strongly influences boldness under high risk. The qualitative model predictions are robust to variation in our parameter estimates and likely apply to a wide range of taxa. The predictions are also consistent with observed patterns of foraging behavior under both laboratory and field conditions. We discuss the implications of our study for understanding the evolution of daily rhythms and the importance of model predictions for interpreting empirical studies and generating additional hypotheses regarding behavioral evolution. PMID- 29244568 TI - Ultrastructural Localization of Antho-RWamides I and II at Neuromuscular Synapses in the Gastrodermis and Oral Sphincter Muscle of the Sea Anemone Calliactis parasitica. AB - Light microscopic studies have shown that the sea anemone neuropeptides Antho RWamides I (= 0.5 cm) that had received >= 1 intralesional treatment with triamcinolone, regardless of prior, concurrent, or adjuvant treatments, were eligible for inclusion. Data collected included patient characteristics, results of cytologic and histologic testing and tumor staging, triamcinolone dosage, treatment response, and adverse events. RESULTS 23 dogs with 24 tumors were included. Tumors were treated by means of intralesional triamcinolone administration alone (n = 5), intralesional triamcinolone administration with concurrent oral administration of glucocorticoids (6), and intralesional triamcinolone administration with concurrent cytotoxic chemotherapy, with or without oral administration of corticosteroids and radiation therapy (13). Of 5 dogs treated with intralesional triamcinolone administration alone, 1 achieved a complete response, 3 achieved a partial response, and 1 maintained stable disease. The response rate for all 24 tumors (23 dogs) was 67% (16/24), including 4 with a complete response and 12 with a partial response. The median time to progression was 63 days (range, 6 to 447 days). Three dogs experienced adverse events (local hemorrhage [n = 1]; suspected gastrointestinal ulceration [2]). CONCLUSIONS AND CLINICAL RELEVANCE Intralesional triamcinolone administration may be well tolerated and effective for treatment of nonresectable mast cell tumors in dogs. PMID- 29244609 TI - Outcomes in dogs with uroabdomen: 43 cases (2006-2015). AB - OBJECTIVE To determine the rate of and factors associated with survival to hospital discharge in dogs with uroabdomen. DESIGN Retrospective case series. ANIMALS 43 dogs with uroabdomen confirmed at 2 veterinary teaching hospitals from 2006 through 2015. PROCEDURES Medical records were reviewed and data extracted regarding cause and location of urinary tract rupture, serum creatinine concentration and other variables at hospital admission, and outcomes. Variables were tested for associations with survival to hospital discharge. RESULTS Urinary tract rupture occurred in the urinary bladder (n = 24 [56%]), urethra (11 [26%]), kidney (2 [5%]), ureter (1 [2%]), both the urinary bladder and kidney (1 [2%]), and undetermined sites (4 [9%]). Rupture causes included traumatic (20 [47%]), obstructive (9 [21%]), and iatrogenic (7 [16%]) or were unknown (7 [16%]). Surgery was performed for 37 (86%) dogs; the defect was identified and surgically corrected in 34 (92%) of these dogs. Hypotension was the most common intraoperative complication. Nineteen dogs had information recorded on postoperative complications, of which 10 (53%) had complications that most often included death (n = 3) and regurgitation (3). Thirty-four (79%) dogs survived to hospital discharge. Dogs with intraoperative or postoperative complications were significantly less likely to survive than dogs without complications. Serum creatinine concentration at admission was not associated with survival to discharge. CONCLUSIONS AND CLINICAL RELEVANCE A high proportion of dogs with uroabdomen survived to hospital discharge. No preoperative risk factors for nonsurvival were identified. Treatment should be recommended to owners of dogs with uroabdomen. PMID- 29244610 TI - Inhibition of exosome release by ketotifen enhances sensitivity of cancer cells to doxorubicin. AB - Exosomes released from cancer cells support metastasis and growth of recipient cells and increase their resistance to chemotherapy. Therapeutic targeting of exosomes is a promising area in cancer research. Our aim is to test the effect of the mast cell stabilizer ketotifen on exosomes release from cancer cells and how this can modify their response to doxorubicin. Exosomes release from three cancer cell lines (MCF7, HeLa and BT549) was assessed by scan electron microscope and exosomes quantification kit. Doxorubicin export within exosomes was monitored flurometrically and cellular sensitivity to doxorubicin +/- ketotifen was measured by sulphorhodamine-B and colony formation assays. The three cell lines release different amounts of exosomes with the highest quantity released from BT549 followed by MCF7 and then HeLa. Ketotifen (10 umol L-1) reduced exosomes release in all three cell lines with different efficiency (HeLa>MCF7>BT549). Doxorubicin export via exosomes was highest in BT549, lower in HeLa and lowest in MCF7 cells. Pretreatment with ketotifen sensitized the cells to doxorubicin (HeLa>MCF7>BT549) with a sensitization factor of 27, 8 and 1.25 respectively. Increased sensitivity of cells to doxorubicin by ketotifen was proportional to its effect on exosomes release. Our data is the first report of ketotifen modulating exosomes release from cancer cells and opens the avenue for exosomes targeting cancer therapy. The differential effects of ketotifen on doxorubicin exosomal export in the cell lines studied, suggests an opportunity of pharmacological enhancement of doxorubicin anti-tumor activity in some but not all cancer types. PMID- 29244611 TI - Learning New Letter-like Writing Patterns Explicitly and Implicitly in Children and Adults. AB - A handwriting task was used to test the assumption that explicit learning is dependent on age and working memory, while implicit learning is not. The effect of age was examined by testing both, typically developing children (5-12 years old, n = 81) and adults (n = 27) in a counterbalanced within-subjects design. Participants were asked to repeatedly write letter-like patterns on a digitizer with a non-inking pen. Reproduction of the pattern was better after explicit learning compared to implicit learning. Age had positive effects on both explicit and implicit learning; working memory did not affect learning in either conditions. These results show that it may be more effective to learn writing new letter-like patterns explicitly and that an explicit teaching method is preferred in mainstream primary education. PMID- 29244612 TI - Letter to the editor regarding "The role of age-sex interaction in the development of post-herpetic neuralgia". AB - The objective of the study was to evaluate the role of age and sex and their combined effect in the development of post-herpetic neuralgia (PHN) in a large population-based study, in order to confirm the results published previously by Amicizia et al. Data were extracted from population and healthcare databases from the Valencia Region (2009-2014). Logistic regressions were implemented to estimate the effect of increasing age on the probability of developing PHN stratified by sex. From a cohort of 2,289,485 subjects >= 50 years, 87,086 cases of HZ were registered and 13,658 (15.7%) of them developed PHN. In our population, PHN cases were more common in women and rose with increasing age independently of the sex. PMID- 29244613 TI - Kinetics study on recombinant alkaline phosphatase and correlation with the generated fluorescent signal. AB - : Alkaline phosphatase (AP) (EC 3.1.3.1) is one of the most commonly used enzymes in immunoassays. In VIDAS(r) assays (bioMerieux, Marcy l'Etoile, France), AP catalyzes the hydrolysis of 4-methylumbelliferyl phosphate (4-MUP) in 4 methylumbelliferone (4-MU) producing a fluorescent signal. This work introduces an original method of characterization of the kinetic parameters Km, Vmax, and Kcat of AP embedded in VIDAS(r) assays. Assessment of such constants allows us to predict the fluorescent signal generated for given amounts of enzyme and its associated substrate; in the particular case of VIDAS(r), it has been estimated that 0.06 nmol/L of AP produces 3144 Relative Fluorescent Values (RFV). ABBREVIATIONS: 4-MUP, 4-Methylumbelliferyl phosphate; 4-MU, 4 Methylumbelliferone; RFV, Relative Fluorescent Values; RFU, Relative Fluorescent Units; QDs, Quantum Dots; LoD, Limit of Detection. PMID- 29244615 TI - Risk assessment for Japanese encephalitis vaccination. AB - Japanese encephalitis (JE) is the most commonly diagnosed viral encephalitis in Asia. JE is caused by a virus called JE virus (JEV), a member of the genus Flavivirus, family Flaviviridae, and is transmitted by Culex mosquitoes. Neutralising antibody to JEV protects against JE, and can be induced by vaccination. JE is a potential threat to travellers to endemic areas, which are most of South and Southeast Asia and some Pacific Islands. The risk of JE can be expected to increase with increasing mosquito exposure and time spent in regions and seasons of active transmission. JE is very rare in travellers, but mortality is high, around 1 in 3, and there is a high rate of lasting neurological damage. JE can therefore be a profoundly life changing event for a traveller. Travellers and their healthcare providers need to balance the low risk of disease against the very high severity of disease if it does occur. In order to make an informed decision, the severity of JE disease should be carefully explained to travellers to Asia. PMID- 29244616 TI - Application of passive sorbent tube and canister samplers for volatile organic compounds at refinery fenceline locations in Whiting, Indiana. AB - : Select volatile organic compounds (VOCs) in ambient air were measured at four fenceline sites at a petroleum refinery in Whiting, IN, using modified EPA Method 325 A/B with passive tubes and EPA Compendium Method TO-15 with canister samplers. One-week, time-integrated samplers were deployed for 8 weeks with tubes and canister samplers deployed in duplicate. Good precision was obtained from the duplicate tubes (<7%) and duplicate canisters (<=10%) for BTEX, perchloroethylene, and styrene. The tubes yielded statistically significantly higher concentrations than canisters for benzene, toluene, ethylbenzene, and m,p xylene. However, all differences were estimated to be <0.1 ppbv. No concentration differences among the four Whiting sites were found for any of the VOCs. IMPLICATIONS: Recently enacted EPA Methods 325A/B use passive-diffusive tube samplers to measure benzene at refinery fenceline locations. This pilot study presents VOC data applying a modified version of EPA Method 325 A/B and its comparison to EPA Compendium Method TO-15 canister samplers at four refinery fenceline sites. The findings from this study provide additional confidence in application of the tube method at refineries to ascertain VOC source influence since tube and canister samplers were comparable and good precision was obtained from duplicate sampling for both methods. No overall difference in these reported VOC concentrations was found between Whiting sites for tubes or canisters. PMID- 29244618 TI - Guest Editors' Introduction. PMID- 29244617 TI - Differentiation of High-Grade from Low-Grade Astrocytoma: Improvement in Diagnostic Accuracy and Reliability of Pharmacokinetic Parameters from DCE MR Imaging by Using Arterial Input Functions Obtained from DSC MR Imaging. AB - Purpose To evaluate whether arterial input functions (AIFs) derived from dynamic susceptibility-contrast (DSC) magnetic resonance (MR) imaging, or AIFDSC values, improve diagnostic accuracy and reliability of the pharmacokinetic (PK) parameters of dynamic contrast material-enhanced (DCE) MR imaging for differentiating high-grade from low-grade astrocytomas, compared with AIFs obtained from DCE MR imaging (AIFDCE). Materials and Methods This retrospective study included 226 patients (138 men, 88 women; mean age, 52.27 years +/- 15.17; range, 24-84 years) with pathologically confirmed astrocytomas (World Health Organization grade II = 21, III = 53, IV = 152; isocitrate dehydrogenase mutant, 11.95% [27 of 226]; 1p19q codeletion 0% [0 of 226]). All patients underwent both DSC and DCE MR imaging before surgery, and AIFDSC and AIFDCE were obtained from each image. Volume transfer constant (Ktrans), volume of vascular plasma space (vp), and volume of extravascular extracellular space (ve) were processed by using postprocessing software with two AIFs. The diagnostic accuracies of individual parameters were compared by using receiver operating characteristic curve (ROC) analysis. Intraclass correlation coefficients (ICCs) and the Bland Altman method were used to assess reliability. Results The AIFDSC-driven mean Ktrans and ve were more accurate for differentiating high-grade from low-grade astrocytoma than those derived by using AIFDCE (area under the ROC curve: mean Ktrans, 0.796 vs 0.645, P = .038; mean ve, 0.794 vs 0.658, P = .020). All three parameters had better ICCs with AIFDSC than with AIFDCE (Ktrans, 0.737 vs 0.095; vp, 0.848 vs 0.728; ve, 0.875 vs 0.581, respectively). In AIF analysis, maximal signal intensity (0.837 vs 0.524) and wash-in slope (0.800 vs 0.432) demonstrated better ICCs with AIFDSC than AIFDCE. Conclusion AIFDSC-driven DCE MR imaging PK parameters showed better diagnostic accuracy and reliability for differentiating high-grade from low-grade astrocytoma than those derived from AIFDCE. (c) RSNA, 2017 Online supplemental material is available for this article. PMID- 29244620 TI - Calming Cycle Theory and the Co-Regulation of Oxytocin. AB - The biological functions of oxytocin in attachment and bonding between mother and infant in parturition and breastfeeding and between adults have been studied extensively. However, most current authors have proposed that infant attachment to the mother is learned through operant conditioning mechanisms via the infant's brain and central nervous system. We propose that oxytocin levels in the mother and infant are co-regulated by emotional connection or disconnection, and that the autonomic co-conditioning learning mechanism can be exploited to change a negative physiological and behavioral response between mother and infant into a positive one. Lack of efficacy and scalability of child development therapies that have come out of the attachment theoretical framework have prompted calls for new ideas. Here, we review calming cycle theory, which takes a new view of the emotional relationship of mother and infant, and predicts ways to positively intervene when problems arise. The theory builds upon the research and ideas of Pavlov and his followers and proposes that subcortical Pavlovian co-conditioning of the autonomic nervous systems of mother and infant is the key to maintaining emotional connection between the two and to shaping emotional behavior of the infant into adulthood. We review evidence in support of calming cycle theory from a randomized controlled trial of Family Nurture Intervention (FNI), which is designed to overcome adverse emotional, behavioral, and developmental outcomes in prematurely born infants. Finally, we discuss the role of visceral oxytocin and emotional behavior, and that the conditional mother-infant relationship may affect behavioral changes through anti-inflammatory gut-brain stem vagal signaling. PMID- 29244621 TI - On Mourning and Recovery: Integrating Stages of Grief and Change Toward a Neuroscience-Based Model of Attachment Adaptation in Addiction Treatment. AB - Interpersonal attachment and drug addiction share many attributes across their behavioral and neurobiological domains. Understanding the overlapping brain circuitry of attachment formation and addiction illuminates a deeper understanding of the pathogenesis of trauma-related mental illnesses and comorbid substance use disorders, and the extent to which ending an addiction is complicated by being a sort of mourning process. Attention to the process of addiction recovery-as a form of grieving-in which Kubler-Ross's stages of grief and Prochaska's stages of change are ultimately describing complementary viewpoints on a general process of neural network and attachment remodeling, could lead to more effective and integrative psychotherapy and medication strategies. PMID- 29244622 TI - Growing Up with Attachment Theory-A Personal View. PMID- 29244623 TI - Attachment Figure's Regulation of Infant Brain and Behavior. AB - Altricial infants (i.e., requiring parental care for survival), such as humans and rats, form an attachment to their caregiver and receive the nurturing and protections needed for survival. Learning has a strong role in attachment, as is illustrated by strong attachment formed to non-biological caregivers of either sex. Here we summarize and integrate results from animal and human infant attachment research that highlights the important role of social buffering (social presence) of the stress response by the attachment figure and its effect on infant processing of threat and fear through modulation of the amygdala. Indeed, this work suggests the caregiver switches off amygdala function in rodents, although recent human research suggests a similar process in humans and nonhuman primates. This cross-species analysis helps provide insight and unique understanding of attachment and its role in the neurobiology of infant behavior within attachment. PMID- 29244624 TI - The Effects of Psychosocial Deprivation on Attachment: Lessons from the Bucharest Early Intervention Project. AB - The absence of typical caregiving, including warm and responsive parenting, has been suggested to significantly affect the young child's ability to form adaptive relationships with adults and peers. The Bucharest Early Intervention Project (BEIP), a randomized controlled trial of foster/family care for young children with a history of institutionalization has provided the context to assess these relationships. Here we review data from the BEIP with specific focus on attachment. The findings clearly show the importance of early family care on the emergence of attachment, on the prevention of psychopathology, and on links between brain and social behavior. PMID- 29244625 TI - The Role of Oxytocin and Vasopressin in Attachment. AB - Selective relationships and attachments are central to human health and well being, both in current societies and during the course of evolution. The presence or absence of social bonds has consequences across the lifespan. The neurobiology of attachment is grounded in neuroendocrine substrates that are shared with reproduction and survival. Experimental studies of species, such as sheep or prairie voles, capable of showing selective social behaviors toward offspring or partners, have provided empirical evidence for the role of oxytocin and vasopressin in the formation of selective attachments. Developmental exposure to social experiences and to peptides, including oxytocin and vasopressin, also can "retune" the nervous system, altering thresholds for sociality, emotion regulation, and aggression. Without oxytocin and without the ability to form attachments the human brain as we know it could not exist. Knowledge of the neurobiology of attachment, and especially the role of oxytocin, also has implications for understanding both healthy behavior and treating mental disorders. PMID- 29244627 TI - Attachment in the Psychiatric Curriculum. AB - Psychiatric trainees are expected to learn the fundamental concepts of psychodynamic psychotherapy, but they often struggle to understand and appreciate the relevance of this work. An introduction to attachment theory can go a long way toward assisting our trainees in understanding the relevance of psychodynamic psychiatry. To help programs develop this component of their curriculum, we summarize the history of the development of the attachment paradigm including the Strange Situation and Adult Attachment Interview (AAI), useful tools to teach these concepts, as well as ramifications of this work. We provide a summary of information regarding the evidence base connected to this paradigm, potential clinical relevance, health implications, work from neuroscience, and infant intervention models to assist in bringing psychodynamic concepts to life. Exposure to the attachment paradigm provides a model of intervention, prevention, and hope for our trainees as they transition from learning phenomenologic models of psychiatric diagnostics to other paradigms of human development and intervention. PMID- 29244628 TI - The Neurobiology of Attachment: From Infancy to Clinical Outcomes. AB - Attachment theory was developed by John Bowlby in the 1950s. He defined attachment as a specific neurobiological system that resulted in the infant connecting to the primary caretaker in such a way to create an inner working model of relationships that continues throughout life and affects the future mental health and physical health of the infant. Given the significance of this inner working model, there has been a tremendous amount of research done in animals as well as humans to better understand the neurobiology. In this article the neurobiology of early development will be outlined with respect to the formation of attachment. This article will review what we have begun to understand as the neurobiology of attachment and will describe how the relationship with the primary caretaker affects the infant in a way leading to neurobiological changes that later in life affect emotional responses, reward, and perception difficulties that we recognize as psychiatric illness and medical morbidity. PMID- 29244629 TI - Evolution, Shame, and Psychotherapy. AB - Medea, the title character in Euripides' play, murdered her two sons in response to her husband Jason's abandonment. If her behavior can be understood, it is best understood in the context of shame. In an evolutionary context, shame is the affective response to the loss of one's place in the group. This response is related to the neurobiology of pain-not the acute pain experienced through the post-central gyrus, but the chronic, lingering pain that is experienced through the insular and cingulate cortices where homeostasis is regulated "from above." Shame is thus a fall in self-esteem, but shame is also a crisis of homeostasis, a crisis that can lead to drastic and, as in the case of Medea, violent attempts to "repair" the imbalance. Shame is a primitive, evolutionarily preserved response to the loss of one's place in the group. PMID- 29244630 TI - Epidemiology and Outcomes of Bloodstream Infections in Patients With Solid Tumors in a Central American Population at Mexico Hospital, San Jose, Costa Rica. AB - PURPOSE: Bloodstream infections (BSIs) are an important cause of mortality in patients with solid tumors. We conducted a retrospective study to evaluate the epidemiologic profile and mortality of patients with solid tumors who have BSIs and were admitted to Mexico Hospital. This is the first study in Costa Rica and Central America describing the current epidemiologic situation. METHODS: We analyzed the infectious disease database for BSIs in patients with solid tumors admitted to Mexico Hospital from January 2012 to December 2014. Epidemiology and mortality were obtained according to microorganism, antibiotic sensitivity, tumor type, and presence of central venous catheter (CVC). Descriptive statistics were used. RESULTS: A total of 164 BSIs were recorded, the median age was 58 years, 103 patients (63%) were males, and 128 cases of infection (78%) were the result of gram-negative bacilli (GNB). Klebsiella pneumoniae (21%), Escherichia coli (21%), and Pseudomonas aeruginosa (15%) were the most common microorganisms isolated. Gram-positive cocci (GPC) were found in 36 patients, with the most frequent microorganisms being Staphylococcus aureus (10%) and Staphyloccocus epidermidis (6%). With respect to tumor type, BSIs were more frequent in the GI tract (57%) followed by head and neck (9%) and genitourinary tract (8%). Regarding antibiotic susceptibility, only 17% (GNB) expressed extended-spectrum beta-lactamase and 12% (GPC) had methicillin resistance. Patients with CVCs (n = 59) were colonized mainly by GNB (78%). Overall the mortality rate at 30 days was about 30%. CONCLUSION: GNB are the most frequent cause of BSIs in solid tumors and in patients with CVCs. GI cancers had more BSIs than other sites. Mortality and antibiotic sensitivity remained stable and acceptable during this observational period in this Latin American population. PMID- 29244631 TI - Initial Results of Peripheral-Blood Stem-Cell Mobilization, Collection, Cryopreservation, and Engraftment After Autologous Transplantation Confirm That the Capacity-Building Approach Offers Good Chances of Success in Critical Contexts: A Kurdish-Italian Cooperative Project at the Hiwa Cancer Hospital, Sulaymaniyah. AB - INTRODUCTION: At Hiwa Cancer Hospital (Sulaymaniyah, Iraqi Kurdistan) after the center was started by a cooperative project in June 2016, autologous transplantation was developed. PATIENTS AND METHODS: To develop the project, the capacity-building approach was adopted, with on-site training and coaching of personnel, educational meetings, lectures, on-the-job training, and the implementation of quality management planning. RESULTS: Here, we report initial results of peripheral-blood stem-cell mobilization and collection of the first 27 patients (age 12 to 61 years; 19 males and 8 females; multiple myeloma, n = 10; plasma cell leukemia, n = 1; Hodgkin lymphoma, n = 12; non-Hodgkin lymphoma, n = 3; and acute myeloid leukemia, n = 1). Only three (11.5%) of 26 patients experienced a failure of mobilization. A median of 6.1 * 106/kg CD34-positive cells per patient were collected (range, 2.4 to 20.8), with two apheretic runs. Twenty-four patients underwent autologous transplantation. All but one transplantation engrafted fully and steadily, with 0.5 and 1.0 * 109/L polymorphonucleates on day 10.5 (range, 8 to 12) and day 11 (range, 9 to 15), respectively, and with 20 and 50 * 109/L platelets on day 13 (range, 10 to 17) and day 17 (range, 2 to 44), respectively. More than 95% of patients are projected to survive 1 year after autograft. CONCLUSION: These data are the result of an Italian effort to establish in Iraqi Kurdistan a leading center for hemopoietic stem-cell transplantation. The capacity building approach was used, with on-site training and coaching as instruments for the development of provider ability and problem solving. With future limitations for immigration, this method will be helpful, especially in the field of high-technology medicine. PMID- 29244632 TI - Delivery of Global Cancer Care: An International Study of Medical Oncology Workload. AB - BACKGROUND: To our knowledge, there is no literature that has described medical oncology (MO) workload in the global context. Here, we report results of an international study of global MO workload. METHODS: An online survey was distributed through a snowball method via national oncology societies to chemotherapy-prescribing physicians in 65 countries. Countries were classified into low- or low-middle-income countries (LMICs), upper-middle-income countries (UMICs), and high-income countries (HICs) on the basis of World Bank criteria. Workload was measured as the annual number of new consultations provided to patients with cancer per oncologist. RESULTS: A total of 1,115 physicians completed the survey: 13% (147 of 1,115) from LMICs, 17% (186 of 1,115) from UMICs, and 70% (782 of 1,115) from HICs. Eighty percent (897 of 1,115) of respondents were medical oncologists, 10% (109 of 1,115) were clinical oncologists, and 10% (109 of 1,115) were other. The median number of annual consults per oncologist was 175 (interquartile range, 75 to 275); 13% (140 of 1,103) saw >= 500 new patients in a year. Annual case volume in LMICs (median consults, 425; 40% of respondents seeing > 500 consults) was substantially higher than in UMICs (median consults, 175; 14% > 500) and HICs (median consults, 175; 7% > 500; P < .001). Among LMICs, UMICs, and HICs, median working days per week were 6, 5, and 5, respectively ( P < .001). The highest annual case volumes per oncologist were in Pakistan (median consults, 950; 73% > 500 consults), India (median consults, 475; 43% > 500), and Turkey (median consults, 475; 27% > 500). CONCLUSION: There is substantial global variation in medical oncology case volumes and clinical workload; this is most striking among LMICs, where huge deficits exist. Additional work is needed, particularly detailed country-level mapping, to quantify activity-based global MO practice and workload to inform training needs and the design of new pathways and models of care. PMID- 29244633 TI - Leveraging the Global Health Service Partnership Model for Workforce Development in Global Radiation Oncology. AB - A major contributor to the disparity in cancer outcome across the globe is the limited health care access in low- and middle-income countries that results from the shortfall in human resources for health (HRH), fomented by the limited training and leadership capacity of low-resource countries. In 2012, Seed Global Health teamed up with the Peace Corps to create the Global Health Service Partnership, an initiative that has introduced a novel model for tackling the HRH crises in developing regions of the world. The Global Health Service Partnership has made global health impacts in leveraging partnerships for HRH development, faculty activities and output, scholarship engagement, adding value to the learning environment, health workforce empowerment, and infrastructure development. PMID- 29244635 TI - An Interview with Joe Randolph, President and CEO, Innovation Institute, La Palma, California, USA. PMID- 29244637 TI - U-shaped Relation between Prestimulus Alpha-band and Poststimulus Gamma-band Power in Temporal Tactile Perception in the Human Somatosensory Cortex. AB - Neuronal oscillations are a ubiquitous phenomenon in the human nervous system. Alpha-band oscillations (8-12 Hz) have been shown to correlate negatively with attention and performance, whereas gamma-band oscillations (40-150 Hz) correlate positively. Here, we studied the relation between prestimulus alpha-band power and poststimulus gamma-band power in a suprathreshold tactile discrimination task. Participants received two electrical stimuli to their left index finger with different SOAs (0 msec, 100 msec, intermediate SOA, intermediate SOA +/- 10 msec). The intermediate SOA was individually determined so that stimulation was bistable, and participants perceived one stimulus in half of the trials and two stimuli in the other half. We measured neuronal activity with magnetoencephalography (MEG). In trials with intermediate SOAs, behavioral performance correlated inversely with prestimulus alpha-band power but did not correlate with poststimulus gamma-band power. Poststimulus gamma-band power was high in trials with low and high prestimulus alpha-band power and low for intermediate prestimulus alpha-band power (i.e., U-shaped). We suggest that prestimulus alpha activity modulates poststimulus gamma activity and subsequent perception: (1) low prestimulus alpha-band power leads to high poststimulus gamma band power, biasing perception such that two stimuli were perceived; (2) intermediate prestimulus alpha-band power leads to low gamma-band power (interpreted as inefficient stimulus processing), consequently, perception was not biased in either direction; and (3) high prestimulus alpha-band power leads to high poststimulus gamma-band power, biasing perception such that only one stimulus was perceived. PMID- 29244636 TI - Event-related Electroencephalographic Lateralizations Mark Individual Differences in Spatial and Nonspatial Visual Selection. AB - Selective attention controls the distribution of our visual system's limited processing resources to stimuli in the visual field. Two independent parameters of visual selection can be quantified by modeling an individual's performance in a partial-report task based on the computational theory of visual attention (TVA): (i) top-down control alpha, the relative attentional weighting of relevant over irrelevant stimuli, and (ii) spatial bias wlambda, the relative attentional weighting of stimuli in the left versus right hemifield. In this study, we found that visual event-related electroencephalographic lateralizations marked interindividual differences in these two functions. First, individuals with better top-down control showed higher amplitudes of the posterior contralateral negativity than individuals with poorer top-down control. Second, differences in spatial bias were reflected in asymmetries in earlier visual event-related lateralizations depending on the hemifield position of targets; specifically, individuals showed a positivity contralateral to targets presented in their prioritized hemifield and a negativity contralateral to targets presented in their nonprioritized hemifield. Thus, our findings demonstrate that two functionally different aspects of attentional weighting quantified in the respective TVA parameters are reflected in two different neurophysiological measures: The observer-dependent spatial bias influences selection by a bottom-up processing advantage of stimuli appearing in the prioritized hemifield. By contrast, task-related target selection governed by top-down control involves active enhancement of target, and/or suppression of distractor, processing. These results confirm basic assumptions of the TVA framework, complement the functional interpretation of event-related lateralization components in selective attention studies, and are of relevance for the development of neurocognitive attentional assessment procedures. PMID- 29244638 TI - Memory Contextualization: The Role of Prefrontal Cortex in Functional Integration across Item and Context Representational Regions. AB - Memory recall is facilitated when retrieval occurs in the original encoding context. This context dependency effect likely results from the automatic binding of central elements of an experience with contextual features (i.e., memory "contextualization") during encoding. However, despite a vast body of research investigating the neural correlates of explicit associative memory, the neural interactions during encoding that predict implicit context-dependent memory remain unknown. Twenty-six participants underwent fMRI during encoding of salient stimuli (faces), which were overlaid onto unique background images (contexts). To index subsequent context-dependent memory, face recognition was tested either in intact or rearranged contexts, after scanning. Enhanced face recognition in intact relative to rearranged contexts evidenced successful memory contextualization. Overall subsequent memory effects (brain activity predicting whether items were later remembered vs. forgotten) were found in the left inferior frontal gyrus (IFG) and right amygdala. Effective connectivity analyses showed that stronger context-dependent memory was associated with stronger coupling of the left IFG with face- and place-responsive areas, both within and between participants. Our findings indicate an important role for the IFG in integrating information across widespread regions involved in the representation of salient items and contextual features. PMID- 29244640 TI - Cross-frequency Phase-Amplitude Coupling as a Mechanism for Temporal Orienting of Attention in Childhood. AB - Temporal orienting of attention operates by biasing the allocation of cognitive and motor resources in specific moments in time, resulting in the improved processing of information from expected compared with unexpected targets. Recent findings have shown that temporal orienting operates relatively early across development, suggesting that this attentional mechanism plays a core role for human cognition. However, the exact neurophysiological mechanisms allowing children to attune their attention over time are not well understood. In this study, we presented 8- to 12-year-old children with a temporal cueing task designed to test (1) whether anticipatory oscillatory dynamics predict children's behavioral performance on a trial-by-trial basis and (2) whether anticipatory oscillatory neural activity may be supported by cross-frequency phase-amplitude coupling as previously shown in adults. Crucially, we found that, similar to what has been reported in adults, children's ongoing beta rhythm was strongly coupled with their theta rhythm and that the strength of this coupling distinguished validly cued temporal intervals, relative to neutral cued trials. In addition, in long trials, there was an inverse correlation between oscillatory beta power and children's trial-by-trial reaction, consistent with oscillatory beta power reflecting better response preparation. These findings provide the first experimental evidence that temporal attention in children operates by exploiting oscillatory mechanism. PMID- 29244639 TI - Oscillatory Mechanisms of Response Conflict Elicited by Color and Motion Direction: An Individual Differences Approach. AB - Goal-directed behavior requires control over automatic behavior, for example, when goal-irrelevant information from the environment captures an inappropriate response and conflicts with the correct, goal-relevant action. Neural oscillations in the theta band (~6 Hz) measured at midfrontal electrodes are thought to form an important substrate of the detection and subsequent resolution of response conflict. Here, we examined the extent to which response conflict and associated theta-band activity depend on the visual stimulus feature dimension that triggers the conflict. We used a feature-based Simon task to manipulate conflict by motion direction and stimulus color. Analyses were focused on individual differences in behavioral response conflict elicited across different stimulus dimensions and their relationship to conflict-related midfrontal theta. We first confirmed the presence of response conflict elicited by task-irrelevant motion and stimulus color, demonstrating the usefulness of our modified version of the Simon task to assess different sensory origins of response conflict. Despite titrating overall task performance, we observed large individual differences in the behavioral manifestations of response conflict elicited by the different visual dimensions. These behavioral conflict effects were mirrored in a dimension-specific relationship with conflict-related midfrontal theta power, such that, for each dimension, individual midfrontal theta power was generally higher when experienced response conflict was high. Finally, exploratory analyses of interregional functional connectivity suggested a role for phase synchronization between frontal and parietal scalp sites in modulating experienced conflict when color was the task-relevant visual dimension. Highlighting the importance of an individual differences approach in cognitive neuroscience, these results reveal large individual differences in experienced response conflict depending on the source of visual interference, which are predicted by conflict-related midfrontal theta power. PMID- 29244641 TI - Pavlovian Control of Escape and Avoidance. AB - To survive in complex environments, animals need to have mechanisms to select effective actions quickly, with minimal computational costs. As perhaps the computationally most parsimonious of these systems, Pavlovian control accomplishes this by hardwiring specific stereotyped responses to certain classes of stimuli. It is well documented that appetitive cues initiate a Pavlovian bias toward vigorous approach; however, Pavlovian responses to aversive stimuli are less well understood. Gaining a deeper understanding of aversive Pavlovian responses, such as active avoidance, is important given the critical role these behaviors play in several psychiatric conditions. The goal of the current study was to establish a behavioral and computational framework to examine aversive Pavlovian responses (activation vs. inhibition) depending on the proximity of an aversive state (escape vs. avoidance). We introduce a novel task in which participants are exposed to primary aversive (noise) stimuli and characterized behavior using a novel generative computational model. This model combines reinforcement learning and drift-diffusion models so as to capture effects of invigoration/inhibition in both explicit choice behavior as well as changes in RT. Choice and RT results both suggest that escape is associated with a bias for vigorous action, whereas avoidance is associated with behavioral inhibition. These results lay a foundation for future work seeking insights into typical and atypical aversive Pavlovian responses involved in psychiatric disorders, allowing us to quantify both implicit and explicit indices of vigorous choice behavior in the context of aversion. PMID- 29244643 TI - Editorial Board: EOV. PMID- 29244644 TI - To have not and then to have: A challenging immune paradox. PMID- 29244645 TI - It's time to consider pharmacotherapy for obesity. PMID- 29244642 TI - Sex, Sleep Deprivation, and the Anxious Brain. AB - Insufficient sleep is a known trigger of anxiety. Nevertheless, not everyone experiences these effects to the same extent. One determining factor is sex, wherein women experience a greater anxiogenic impact in response to sleep loss than men. However, the underlying brain mechanism(s) governing this sleep-loss induced anxiety increase, including the markedly different reaction in women and men, is unclear. Here, we tested the hypothesis that structural brain morphology in a discrete network of emotion-relevant regions represents one such explanatory factor. Healthy participants were assessed across sleep-rested and sleep-deprived conditions, with brain structure quantified using gray matter volume measures. Sleep loss triggered greater levels of anxiety in women compared with men. Reduced gray matter volume in the anterior insula and lateral orbitofrontal cortex predicted the anxiogenic impact of sleep loss in women, yet predicted resilience in men, and did so with high discrimination accuracy. In contrast, gray matter volume in ventromedial prefrontal cortex predicted the anxiogenic impact of sleep loss in both men and women. Structural human brain morphology therefore appears to represent one mechanistic pathway (and possible biomarker) determining anxiety vulnerability to sleep loss-a discovery that may help explain the higher prevalence of sleep disruption and anxiety in women. PMID- 29244646 TI - Is it time to abandon fasting for routine lipid testing? PMID- 29244647 TI - Diagnosis and treatment of hyperkalemia. AB - Hyperkalemia results either from the shift of potassium out of cells or from abnormal renal potassium excretion. Cell shift leads to transient increases in the plasma potassium concentration, whereas decreased renal excretion of potassium leads to sustained hyperkalemia. Impairments in renal potassium excretion can be the result of reduced sodium delivery to the distal nephron, decreased mineralocorticoid level or activity, or abnormalities in the cortical collecting duct. In some instances, all 3 of these perturbations are present. Excessive intake of potassium can cause hyperkalemia but usually in the setting of impaired renal function. We discuss the clinical manifestations of hyperkalemia and outline an approach to its diagnosis and treatment. PMID- 29244649 TI - Big heart, small ring. PMID- 29244648 TI - Diagnostic value of the physical examination in patients with dyspnea. AB - We reviewed the evidence for the diagnostic accuracy of the physical examination in diagnosing pneumonia, pleural effusion, chronic obstructive pulmonary disease, and congestive heart failure in patients with dyspnea and found that the physical examination has reliable diagnostic accuracy for these common conditions. PMID- 29244650 TI - Pharmacotherapy for obesity: What you need to know. AB - Weight-loss drugs are being evaluated for their role in obesity management. This article reviews the available weight-loss drugs, their efficacy and side effects, and their best clinical use. PMID- 29244651 TI - Drug reaction or metastatic lung cancer? PMID- 29244652 TI - The Leser-Trelat sign. PMID- 29244653 TI - High capacity lithium ion batteries composed of cobalt oxide nanoparticle anodes and Raman spectroscopic analysis of nanoparticle strain dynamics in batteries. AB - Cobalt nanoparticle thin films were electrophoretically deposited on copper current collectors and were annealed into thin films of hollow Co3O4 nanoparticles. These thin films were directly used as the anodes of lithium ion batteries (LIBs) without the addition of conducting carbons and bonding agents. LIBs thus fabricated show high gravimetric capacities and long cycle lives. For ~1.0 MUm thick Co3O4 nanoparticle films the gravimetric capacities of the batteries were more than 800 mAh g-1 at a current rate of C/15, which is about 90% of the theoretical maximum. Additionally, the batteries were able to undergo 200 charge/discharge cycles at a relatively fast rate of C/5 and maintain 50% of the initial capacity. In order to understand the electrochemistry of lithiation in the context of nanoparticles, Raman spectra were collected at different stages of the electrode cycles to determine the chemical and structural changes in the nanomaterials. Our results indicate that initially the electrode nanoparticles were under significant strain and as the battery underwent many cycles of charging/discharging the nanoparticles experienced progressive strain relaxation. PMID- 29244654 TI - Novel nanostructured electron transport compact layer for efficient and large area perovskite solar cells using acidic treatment of titanium layer. AB - A new method for the deposition of a pinhole-free compact layer of TiO2 is introduced for the development of efficient perovskite solar cells. Acidic treatment of titanium layer (ATTL), deposited by rotational magnetron sputtering, presents a compact pinhole-free TiO2 thin film. Deposition of a compact TiO2 thin film on fluorine-doped tin oxide layers by ATTL did not change the surface roughness. To compare the introduced method, perovskite solar cell devices were fabricated and studied using different methods for the deposition of the TiO2 compact layers, which were used as common compact layer deposition methods. The ATTL method proposed considerable photovoltaic enhancement of perovskite solar cell performance (at least 22% enhancement in this work) by reducing the pinholes and sheet resistance of the TiO2 thin film. The improvement in the open-circuit voltage and the fill factor of the prepared devices using the ATTL method strongly confirmed the nature of the deposited pinhole-free TiO2 thin film. This method is shown to be an appropriate route for the reliable large-scale deposition of TiO2 compact layers. PMID- 29244655 TI - Duplex-imprinted nano well arrays for promising nanoparticle assembly. AB - A large area nano-duplex-imprint technique is presented in this contribution using natural cicada wings as stamps. The glassy wings of the cicada, which are abundant in nature, exhibit strikingly interesting nanopillar structures over their membrane. This technique, with excellent performance despite the nonplanar surface of the wings, combines both top-down and bottom-up nanofabrication techniques. It transitions micro-nanofabrication from a cleanroom environment to the bench. Two different materials, dicing tape with an acrylic layer and a UV optical adhesive, are used to make replications at the same time, thus achieving duplex imprinting. The promise of a large volume of commercial manufacturing of these nanostructure elements can be envisaged through this contribution to speeding up the fabrication process and achieving a higher throughput. The contact angle of the replicated nanowell arrays before and after oxygen plasma was measured. Gold nanoparticles (50 nm) were used to test how the nanoparticles behaved on the untreated and plasma-treated replica surface. The experiments show that promising nanoparticle self-assembly can be obtained. PMID- 29244656 TI - Characterization of gelatin and chitosan scaffolds cross-linked by addition of dialdehyde starch. AB - In this study the influence of the addition of dialdehyde starch on the properties of scaffolds based on gelatin and chitosan obtained by the freeze drying method was investigated. In addition, the adhesion and proliferation of human osteosarcoma SaOS-2 cells on the obtained scaffolds was examined. Chitosan and gelatin were mixed in different weight ratios (75/25, 50/50, 25/75) with 1, 2 and 5 wt% addition of dialdehyde starch. The obtained scaffolds were subjected to mechanical testing, infrared spectroscopy, swelling measurements, low-pressure porosimetry and zeta potential measurement. Internal material structures were observed by scanning electron microscopy. The results showed that the cross linking process occurred after the addition of dialdehyde starch and resulted in increased mechanical strength, swelling properties, zeta potential and porosity of studied materials. The attachment of SaOS-2 cells to all modified materials was better compared to an unmodified control and the proliferation of these cells was markedly increased on modified scaffolds. PMID- 29244657 TI - An Unusual Case of an Intra-Articular Osseous Fragment Associated with a Medial Collateral Ligament Femoral Avulsion Fracture in an Adult: A Case Report. AB - CASE: The medial collateral ligament (MCL) is the most commonly injured ligament of the knee; however, to our knowledge, avulsion fractures of the MCL resulting in an intra-articular fragment have not been reported. We present the case of a 55-year-old woman with a posterior cruciate ligament avulsion fracture and an MCL avulsion fracture with an intra-articular bony fragment. CONCLUSION: Patients who sustain trauma to the knee should be carefully evaluated for ligamentous avulsion injuries. Avulsion fractures in adults represent substantial traumatic injuries, and associated injuries should be suspected. While the MCL is an extracapsular structure, this case report demonstrates that the MCL femoral-sided osseous attachment can displace intra-articularly. PMID- 29244658 TI - A Distally Based Sartorius Muscle Flap for a Gustilo Grade-III Open Fracture of the Lateral Femoral Condyle and the Head of the Fibula with a Complex Soft-Tissue Defect: A Case Report and Review of the Literature. AB - CASE: We present a case of lower-limb trauma associated with an extensive soft tissue defect around the knee joint, which led to the exposure of bone and the metalwork that was used for the management of the associated fractures. Coverage was performed with a distally based sartorius muscle flap in a single-stage procedure, allowing good recovery with a nice aesthetic and functional outcome at the 1-year follow-up. Additionally, we discuss alternative options for the coverage of severe soft-tissue defects based on the clinical context. CONCLUSION: A distally based sartorius muscle flap may be a suitable alternative for coverage of complex soft-tissue defects around the knee joint. PMID- 29244659 TI - Intra-Articular Patellar Dislocation: A Technique for Closed Reduction: A Case Report and Review of the Literature. AB - CASE: An 87-year-old man fell onto a flexed knee and sustained a closed intra articular patellar dislocation. A closed reduction was performed under intravenous sedation by flexing the knee to 90 degrees , applying an anterior drawer force to the tibia, and applying pressure to the inferior pole of the patella. The day after reduction, weight-bearing was begun in a hinged brace set at 0 degrees to 90 degrees . Full function was regained by 6 weeks postreduction. CONCLUSION: Intra-articular patellar dislocation may present as an unusual cause of a locked knee. Our experience confirms that it can be managed successfully with closed reduction under light sedation in an emergency department. PMID- 29244660 TI - Adverse Local-Tissue Reactions in the Upper Extremity. PMID- 29244661 TI - Systemic and Cutaneous Immune Reactions Following Orthopaedic Procedures. PMID- 29244662 TI - A Rare Case of Congenital Tibiofemoral Fusion with Bilateral Proximal Femoral Focal Deficiency: A Case Report. AB - CASE: We report a unique combination of neonatal bilateral proximal femoral focal deficiency with a congenital tibiofemoral fusion of the right leg. CONCLUSION: To the best of our knowledge, the combination of proximal femoral focal deficiency and the congenital absence of the knee joint in a child has not previously been reported. PMID- 29244663 TI - Scapular Winging Caused by Combined Palsy of the Spinal Accessory Nerve and the Long Thoracic Nerve: A Case Report. AB - CASE: A 37-year-old man with scapular winging, caused by combined palsy of the spinal accessory nerve and the long thoracic nerve, was successfully treated with a pectoralis major transfer to substitute for the serratus anterior muscle, and with levator scapulae and rhomboid muscle transfers to substitute for the trapezius muscle. CONCLUSION: The serratus anterior paralysis was thought to have occurred secondary to traction of the long thoracic nerve by the unsupported scapula following the spinal accessory nerve palsy. Even with combined paralyses of the serratus anterior and trapezius muscles, combined muscle transfers that substitute for the paralyzed muscles can improve shoulder function. PMID- 29244664 TI - Glenoid Erosion Leading to Contact with Retained Metallic Suture Anchors: Bilateral Metallosis After Bilateral Shoulder Hemiarthroplasty: A Case Report. AB - CASE: Hemiarthroplasty of the shoulder is commonly indicated for younger patients with osteoarthritis who desire to continue recreational and employment activities. In patients who have undergone prior shoulder surgery, metallic suture anchors may be present in the glenoid. We present a case of bilateral shoulder metallosis following bilateral resurfacing hemiarthroplasty for arthropathy in the setting of previous shoulder instability; the prostheses caused eventual glenoid erosion, leading to contact with the retained metal anchors. CONCLUSION: Because glenoid erosion is a common complication after shoulder hemiarthroplasty, patients with retained metal anchors are at risk for secondary metallosis due to medial protrusion of the prosthesis in the glenoid, with subsequent erosion of the metal anchors. PMID- 29244665 TI - Osseous Myopericytoma Simulating a Giant Cell Tumor of Bone: A Case Report. AB - CASE: Myopericytoma is a benign perivascular myoid neoplasm that typically presents in the dermal and subcutaneous soft tissues of the distal aspect of the extremities. These types of tumor form a clinicopathological spectrum with myofibromas, angiopericytomas, angioleiomyomas, and glomus tumors. Intraosseous myopericytomas are exceptionally rare, and to our knowledge, no cases of myopericytoma involving long bones previously have been described. We present a case of myopericytoma occurring in the distal aspect of the femur of a 36-year old man. CONCLUSION: This case report describes a unique location of this tumor, which demonstrates that myopericytomas have a more diverse tropism than previously indicated. PMID- 29244667 TI - Periosteal Ewing Sarcoma in a 65-Year-Old Man: A Case Report. AB - CASE: Ewing sarcoma is predominantly a pediatric bone malignancy involving the medullary canal. Periosteal Ewing sarcoma, a subtype arising from the periosteum, is exceedingly rare, with approximately 30 reported cases in the literature. We describe a case of periosteal Ewing sarcoma in the tibia of a 65-year-old man. Magnetic resonance imaging revealed a heterogeneous mass in the proximal tibial diaphysis without medullary involvement. The diagnosis was confirmed histologically after biopsy. The patient was treated with neoadjuvant chemotherapy, radical resection, and adjuvant chemotherapy. CONCLUSION: To the best of our knowledge, this case report describes the oldest documented patient with periosteal Ewing sarcoma. PMID- 29244666 TI - Natural Correction and Adaptation of a Severely Deformed Sacral Dome in an Adolescent with Isthmic Spondylolisthesis: A Case Report. AB - CASE: A spinal deformity with wedging of L5 and rounding of the surface of the sacral dome is very common in pediatric patients with spondylolisthesis at the L5 vertebral level, and it has been well documented that severe spondylolisthesis is a good indication for spinal arthrodesis. We report the natural correction and adaptation of a severely deformed sacral dome with slippage (40.8%) in a pediatric patient with nonoperative treatment. CONCLUSION: Vertebral deformity in children can be reversible. Orthopaedic surgeons should be aware that pediatric patients with a severe deformity of the sacral dome and vertebral slippage can be managed nonoperatively. PMID- 29244668 TI - Diaphyseal Tibial Soft-Tissue Mass After Total Knee Arthroplasty: A Case Report. AB - CASE: A 64-year-old woman had undergone bilateral total knee arthroplasty in 1998. In 2010, she presented with a large, painless, diaphyseal soft-tissue mass of the lower leg. She indicated that she had no history of knee pain, trauma, or infection. Ultimately, the mass was found to be a synovial fluid-filled cyst that communicated with the knee joint, which was a result of severe osteolysis. CONCLUSION: Large diaphyseal tibial masses in the presence of total knee arthroplasty should raise a high index of suspicion not only for tumors and infections, but also for severe osteolysis. Knowledge of the various ways that osteolysis can present as well as an appropriate workup will help to guide diagnosis and management. PMID- 29244669 TI - Operative Fixation of an Anterior Inferior Iliac Spine Apophyseal Avulsion Fracture Nonunion in an Adolescent Soccer Player: A Case Report. AB - CASE: A 14-year-old male competitive soccer player presented with a history of recurrent right hip pain for 18 months. He was diagnosed with an anterior inferior iliac spine (AIIS) apophyseal avulsion fracture nonunion with subspinal impingement, which was confirmed by radiographs, computed tomography, and magnetic resonance imaging. The patient underwent surgical fixation and subspinal decompression. He returned to competitive soccer 5 months postoperatively. CONCLUSION: AIIS apophyseal avulsion fractures occur in adolescent athletes and generally respond to nonoperative treatment. When such management is unsuccessful, surgical fixation can lead to resolution of pain with return of full function. PMID- 29244670 TI - Kienbock Disease in a Patient with Congenital Synostosis of the Lunate and the Triquetrum: A Case Report. AB - CASE: We describe the case of a 40-year-old man with Minnaar type-III congenital synostosis of the lunate and the triquetrum who presented with Lichtman stage-I Kienbock disease. Surgical treatment consisted of capitate shortening with a capitate-hamate fusion. CONCLUSION: This case demonstrates the tenuous regional nature of the vascularity to the lunate, even in the setting of a complete lunotriquetral synostosis. PMID- 29244671 TI - Sterile Abscess with Subsequent Iatrogenic Draining Sinus Tract Formation 3 Years After FiberWire and ENDOBUTTON Distal Biceps Brachii Tendon Repair: A Case Report. AB - CASE: We report a case of a sterile abscess with subsequent sinus tract formation mimicking infection 3 years after uncomplicated distal biceps brachii tendon repair with FiberWire suture in a 42-year-old man. The preoperative workup for infection was unremarkable. Intraoperative culture specimens confirmed the absence of infection. Excision of the sinus tract and FiberWire-ENDOBUTTON construct was curative. At the 1-year follow-up, there had been no recurrence of symptoms. CONCLUSION: Foreign-body inflammatory reactions should be considered in the differential diagnosis of patients with apparent infection with a history of FiberWire suture fixation and negative serologic workup. PMID- 29244672 TI - A Short Femoral Stem in Revision Total Hip Replacement: An Alternative Solution for Prosthetic Fracture: A Case Report. AB - CASE: A 65-year-old farmer re-presented 5 years after sustaining a midshaft prosthetic fracture of a previous long-stem revision hip replacement. He was treated with a proximal-loading short femoral stem, and did not require an extended trochanteric osteotomy for removal of the well-fixed distal implant. He was able to fully bear weight immediately postoperatively, and he remained pain free without functional loss at the 42-month follow-up. CONCLUSION: This use of a modern short-stem prosthesis is a treatment option for a potentially complex prosthetic fracture in highly active patients, and it reduces intraoperative complexity. PMID- 29244673 TI - Using Double-Contrast CT Arthrography to Confirm Suspected Dissociation of a Cemented Polyethylene Liner in the Setting of Revision Total Hip Arthroplasty: A Case Report. AB - CASE: A 67-year-old woman who underwent a re-revision of a total hip arthroplasty with a cemented polyethylene liner fell 14 months after surgery. The patient had symptoms of pain and weakness; however, clinical, laboratory, and radiographic evaluation did not disclose fracture, infection, osteolysis, or component migration. Liner dissociation was suspected, and a double-contrast computed tomography (CT) arthrogram confirmed failure at the cement-liner interface. She underwent additional revision surgery and was doing well at the 3-year follow-up. CONCLUSION: Double-contrast CT arthrography confirmed failure at the cement-liner interface and is an effective diagnostic tool in identifying suspected dissociations of cemented polyethylene liners. PMID- 29244674 TI - Thrower's Fracture of the Humerus: An Investigation of Risk Factors Following an Unlikely Scenario: A Case Report. AB - CASE: A 26-year-old amateur baseball player without prodromal arm pain sustained a thrower's fracture of the humerus on a warm-up throw performed with submaximal effort. The fracture occurred during the first throwing session following a 6 week layoff. The patient was treated nonoperatively and made a full recovery, but he elected to not return to throwing sports. CONCLUSION: Because of the lack of risk factors in this case, we suggest that time off or irregularity in throwing may play a greater role in a thrower's fracture than previously established. Recreational throwers should undergo appropriate preseason training before returning to throwing. PMID- 29244675 TI - High-Pressure Injection Injury Caused by Electronic Cigarette Explosion: A Case Report. AB - CASE: Electronic cigarettes are an increasingly popular and poorly regulated alternative to traditional cigarettes that deliver nicotine and other aerosolized substances to the user via a battery-powered atomizer. We report a case in which an electronic cigarette explosion resulted in a high-pressure injection injury of the finger. CONCLUSION: Explosions involving electronic cigarettes and similar handheld products should be treated as high-pressure injection injuries until proven otherwise. Radiographs are indispensable in the workup of these injuries. Because the true content of injected material cannot be determined with certainty, we recommend immediate surgical debridement, intravenous antibiotics, and close follow-up to observe the evolution of the injury. PMID- 29244676 TI - Severe Metal Hypersensitivity Following Internal Fixation of an Ankle Fracture: A Case Report. AB - CASE: A 67-year-old woman underwent internal fixation of an ankle fracture. Ten days postoperatively, the patient developed systemic hives, difficulty breathing, and oral swelling. At 8 weeks postoperatively, the hardware was removed because of a suspected metal hypersensitivity. Despite experiencing perioral edema and difficulty breathing after the hardware removal, she had complete resolution of the symptoms at the 2-week, 6-week, and 12-month follow-up appointments. CONCLUSION: Hypersensitivities to metal-based implants can develop and cause local and systemic reactions. Orthopaedic surgeons should inquire about a history of metal allergies, and possibly perform allergy testing for patients with a history suggestive of metal hypersensitivities. Consideration should be given for hospital admission following hardware removal for patient monitoring. PMID- 29244677 TI - Allergic Dermatitis After Total Knee Arthroplasty Using the Prineo Wound-Closure Device: A Report of Three Cases. AB - CASE: Three patients who underwent uncomplicated total knee arthroplasty with use of the Prineo (Ethicon) wound-closure system had development of allergic contact dermatitis. All patients were started on Keflex (cephalexin), and two were started on topical corticosteroid. In all patients, the reaction resolved within weeks. CONCLUSION: To our knowledge, the present report describes the first case series of patients in whom allergic contact dermatitis developed in association with the use of the Prineo wound-closure system during orthopaedic procedures. The presentation can range from blistering to erythematous papules and vesicles to crusted plaques that resolve with Keflex and topical corticosteroid cream. PMID- 29244678 TI - Oncogenic Osteomalacia Secondary to a Metastatic Phosphaturic Mesenchymal Tumor in the Talus: A Case Report and Review of the Literature. AB - CASE: We report the case of a 50-year-old woman with oncogenic osteomalacia secondary to a metastatic phosphaturic mesenchymal tumor (PMT) that presented, to our knowledge, with the first reported lesion in the talus. CONCLUSION: Oncogenic osteomalacia is a rare condition with a unique serum biochemical profile that requires a high index of suspicion for diagnosis. A PMT is a rare neoplasm that can lead to oncogenic osteomalacia through secretion of fibroblast growth factor 23. Symptoms can be debilitating, and diagnostic delays are extremely common. This case report emphasizes the importance of comprehensive anatomic assessment and the need for fastidious postoperative monitoring. PMID- 29244679 TI - Rice Bodies and a Partial Flexor Tendon Rupture in a Patient with Juvenile Idiopathic Arthritis: A Case Report and Review of the Literature. AB - CASE: We present a case of rice-body formation and partial flexor tendon rupture in a 3-year-old child with seronegative juvenile idiopathic arthritis (JIA), which presented as a painless soft-tissue mass of the volar aspect of the hand. The diagnosis was not confirmed until histologic examination. The patient was managed with a tenosynovectomy and oral medication; he made a full recovery. CONCLUSION: JIA is one of the most common rheumatologic conditions of childhood. Establishing the diagnosis can be challenging in very young children, particularly when clinical presentation is atypical and serology is negative. Surgical intervention may be warranted in the appropriately selected patient with JIA. PMID- 29244681 TI - Preventing and Managing Post-THA Hip Dislocations. PMID- 29244680 TI - Irreducible Ankle Fracture from an Interposed Chaput Fragment: A Case Report. AB - CASE: A 23-year-old active-duty military service member sustained an unusual irreducible fracture-dislocation of the ankle joint. Preoperative computed tomography showed an anterolateral tibial (Chaput) fragment entrapped within the distal syndesmosis, preventing adequate reduction. An open reduction of the fragment was performed in the operating room, which allowed near-anatomic reduction and internal fixation of the tibiotalar joint. At the 21-month follow up visit, the patient remained on active duty in the Navy without limitations. CONCLUSION: To our knowledge, this rare injury pattern, an interposed Chaput fragment preventing closed reduction of the syndesmosis in a skeletally mature patient, has not previously been described in the literature. An open reduction and internal fixation of the Chaput fragment allowed near-anatomic reduction of the tibiotalar joint. PMID- 29244682 TI - Spinal Epidural Hematoma: Rare, But Potentially Devastating. PMID- 29244683 TI - Insufficiency Fracture Occurring 3 Years After Union of an Intertrochanteric Hip Fracture: A Case Report. AB - CASE: We present a rare case of insufficiency fracture at the level of the distal interlocking screw following union of an intertrochanteric hip fracture. A 74 year-old woman reported chronic thigh pain for 1 month. She had a history of an osteoporotic stable intertrochanteric fracture that was successfully treated with a short intramedullary nail 3.5 years prior. However, after union, the neck-shaft angle of the femur changed from 125 degrees to 117 degrees . She had been on alendronic acid therapy to prevent a secondary osteoporotic fracture. A recent radiograph and bone scan suggested an insufficiency fracture around the level of the distal interlocking screw. Revision surgery with a long intramedullary nail was performed, and complete union was observed 1 year postoperatively. CONCLUSION: This case suggests that subsequent insufficiency fracture can occur after complete union of an intertrochanteric hip fracture. Physicians should be aware of the possibility of a stress fracture when a patient has thigh pain after an intertrochanteric fracture has healed following repair with a short intramedullary nail. PMID- 29244684 TI - Open Hip Dislocation Through the Scrotum without Osseous Injury: A Case Report. AB - CASE: A 36-year-old bicyclist sustained an open anterior hip dislocation through the scrotum after being struck by 2 motor vehicles. There was no osseous injury present. The hip was irreducible by closed means and required open reduction via a Smith-Petersen approach. Postoperatively, the patient did not develop osteonecrosis of the femoral head but did have signs of mild osteoarthritis and heterotopic ossification. CONCLUSION: Open anterior hip dislocation into the scrotum is an exceedingly rare injury. Closed reduction can be attempted, but open intervention is often required. A Smith-Petersen approach allows visualization for reduction and does not violate the vascularity to the femoral head. PMID- 29244685 TI - Mycobacterium cosmeticum Infection After Total Knee Arthroplasty: A Case Report. AB - CASE: A 67-year-old immunocompetent man presented with a periprosthetic infection 4 months after a left total knee arthroplasty. Repeated aspirations failed to show any organism growth. After irrigation and debridement with polyethylene exchange, there was minimal clinical improvement. Subsequently, the patient developed an arthrocutaneous fistula, which prompted a 2-stage revision arthroplasty. Mycobacterium cosmeticum grew on the culture specimens taken during this procedure, and the patient was treated with 6 months of antibiotics. CONCLUSION: To our knowledge, this is the first reported case of an M. cosmeticum prosthesis-related infection. The patient recovered well following a 2-stage revision arthroplasty and treatment with a Mycobacterium species-specific antibiotic. PMID- 29244686 TI - High Thoracic Disc Herniation Causing Horner Syndrome with the Intraoperative Finding of Conjoined Nerve Root Compression: A Case Report. AB - CASE: A 29-year-old man presented with right medial arm pain with paresthesia, as well as right-sided ptosis, miosis, and anhidrosis. Magnetic resonance imaging revealed a right paracentral disc herniation at the T1-T2 level. The patient underwent a hemilaminectomy with a medial facetectomy through a posterolateral approach to the T1-T2 disc space, followed by a discectomy. Intraoperative findings were notable for a conjoined nerve root. CONCLUSION: Although high thoracic disc herniation is rare, its diagnosis should be considered when patients present with radicular arm pain and Horner syndrome. A high index of suspicion should be maintained for nerve root anomalies to limit iatrogenic injury and to ensure successful decompression. PMID- 29244687 TI - Pilon Fractures of the Base of the Proximal Phalanx: Direct Intraosseous Joint Reduction with Bone-Grafting and Mini-Screws: A Case Report. AB - CASE: A 31-year-old woman sustained a closed pilon fracture of the base of the second proximal phalanx. Computed tomography showed comminution, central depression, and splaying of the articular surface. We used a method of direct intraosseous joint reduction in combination with bone-grafting and mini-screws to treat the fracture. For reduction, a golf-club-shaped instrument was inserted into the medullary cavity through a drill-hole in the phalanx. CONCLUSION: The advantage of this technique is that it leaves the joint capsular complex and the extensor hood intact. A stable joint was achieved, and early rehabilitation was possible. The clinical outcome and radiographic results were very good. PMID- 29244688 TI - Arthrofibrosis Associated with the Surgical Treatment of Chronic Lyme Arthritis and a Concomitant Medial Meniscal Tear: A Case Report. AB - CASE: We describe a case of refractory Lyme arthritis in an adolescent patient with a concomitant medial meniscal tear. The patient underwent arthroscopic synovectomy and meniscal repair, and required additional surgery for subsequent decreased range of motion. We describe the presentation, the intraoperative findings, the course of recovery, and the literature regarding Lyme arthritis and meniscal tears. CONCLUSION: Refractory Lyme arthritis commonly is treated successfully with arthroscopic synovectomy. We describe a patient who presented with a concomitant medial meniscal tear; he underwent initial medial meniscal repair and a partial meniscectomy. He required additional surgery before full recovery was achieved. PMID- 29244689 TI - Trochanteric Femoral Fracture Around a Birmingham Hip Resurfacing Prosthesis: A Case Report and Review of the Literature. AB - CASE: A traumatic nondisplaced periprosthetic trochanteric fracture around a well fixed and functioning Birmingham Hip Resurfacing prosthesis was managed with a reconstruction intramedullary nail. The surgical procedure provided excellent pain relief, and the patient was able to mobilize with crutches the day after surgery. Follow-up at 1 year confirmed excellent clinical and radiographic results. CONCLUSION: In a patient with a previously well-functioning hip resurfacing prosthesis, internal fixation rather than revision hip arthroplasty can offer good clinical and radiographic outcomes. The use of a reconstruction intramedullary nail may be a good option for fixing a periprosthetic trochanteric fracture around a Birmingham Hip Resurfacing implant. PMID- 29244690 TI - Aseptic Lymphocyte-Dominated Vasculitis-Associated Lesion as Early as Six Weeks After Total Hip Replacement: A Case Report. AB - CASE: A 40-year-old man who underwent total hip replacement on the left side with a metal-on-metal (MOM) implant reported swelling at the operative site within 6 weeks of the arthroplasty. Tissue sampled during the revision arthroplasty showed an aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL). CONCLUSION: ALVAL is a widely recognized complication of MOM hip implants and needs to be considered early, even in completely asymptomatic patients with normal metal ion levels and normal radiographs. PMID- 29244691 TI - Delayed-Onset Sciatic Nerve Palsy After Periacetabular Osteotomy: A Case Report. AB - CASE: A large surgical correction was required for severe hip dysplasia, which was associated with a delayed-onset sciatic nerve injury in an adolescent patient. A cortical bone spur on the outside of the acetabular fragment produced an indirect injury that became symptomatic during mobilization of the patient. CONCLUSION: The risk of direct injury to the sciatic nerve during a periacetabular osteotomy is quite low when the osteotomy is executed in extension with abduction of the hip and flexion of the knee to reduce tension on the sciatic nerve. Reported injuries have been attributed to direct damage from excessive soft-tissue retraction or during osseous ischial, supra-acetabular, and/or retroacetabular osteotomies. PMID- 29244692 TI - Reconstruction of Extended Bone Defects Using Massive Allografts Combined with Surgical Angiogenesis: A Case Report. AB - CASE: A 20-year-old patient presented with an extended composite knee defect with destruction of the medial femoral condyle, including the medial collateral ligament. Treatment included using an anterolateral thigh flap for soft-tissue reconstruction, tensor fasciae latae muscle for ligament repair, and a massive allogenic bone graft of the medial femoral condyle that was revascularized with an osteocutaneous composite free flap from the contralateral femur. At 17 months postoperatively, the outcome was evaluated with scores on several established scales and radiographic assessment. CONCLUSION: The combination of vascularized soft-tissue reconstruction and osseous reconstruction using allogenic bone along with surgical angiogenesis proved to be effective. Complex extremity reconstruction should be discussed with interdisciplinary specialists. PMID- 29244693 TI - Bilateral Simultaneous Femoral Neck Stress Fracture Despite Clinical Recovery from Anorexia Nervosa: A Case Report. AB - CASE: A 38-year-old woman who had returned to sports activity (running) after having clinically recovered from anorexia nervosa presented with a bilateral femoral neck stress fracture that was treated with bilateral hip osteosynthesis. CONCLUSION: Although exercise is usually considered to be beneficial for health, heavy exercise (such as running) after recovery from anorexia nervosa may be associated with an increased risk of fracture. PMID- 29244694 TI - Failure of Patellar Plating with Mini-Fragment Implants: A Case Report. AB - CASE: A 40-year-old woman presented to the emergency department with a comminuted fracture of the patella with separation of the bone fragments. The patient underwent an open reduction and osteosynthesis using medial and lateral 2.0-mm nonlocking plates, which subsequently led to pain in the anterior and posterior aspects of the knee. CONCLUSION: In this patient, bicolumnar nonlocking plating was unable to adequately resist the tensile forces of the extensor mechanism. We believe that the probable cause of failure was an insufficient neutralization of the tensile forces exerted by the extensor mechanism. Because of the substantial forces acting on the patella, a method of converting these tensile forces into compressive forces is very beneficial, as seen with anterior tension-band wiring. Although we used nonlocking plates in our patient, we believe that locking-plate fixation placed along the medial and lateral columns also would have had a biomechanical disadvantage in dispersing the tensile forces exerted by the extensor mechanism. PMID- 29244695 TI - Recurrent Hip Dislocation Following Total Hip Arthroplasty: Treatment with Sagittal Spinal Deformity Correction: A Case Report. AB - CASE: A 63-year-old woman with lumbar degenerative kyphosis who had undergone total hip arthroplasty 34 months previously presented after having multiple episodes of anterior hip dislocation; evaluation also revealed progressive osteoarthritis in the contralateral hip joint. The patient was managed with sagittal correction with pedicle subtraction osteotomy, which resulted in optimal positioning of the acetabular component and an upright posture. The patient had had no additional dislocation events in the involved hip and had reduced pain in the contralateral hip at the time of the 2-year follow-up. CONCLUSION: It is important to evaluate and address preexisting sagittal imbalance before performing total hip arthroplasty. However, for patients with neglected sagittal imbalance resulting in recurrent hip dislocation after total hip arthroplasty, sagittal deformity correction may be beneficial. PMID- 29244696 TI - Selective Spinal Fusion for Neuromuscular Scoliosis in a Patient with Pompe Disease: A Case Report and Review of the Literature. AB - CASE: A 16-year-old girl with Pompe disease underwent surgery for scoliosis. She had been able to walk without any assistance, and kept her balance by swinging her waist. Therefore, we performed posterior selective spinal correction and fusion to avoid any adverse effects on walking ability that could occur with immobilization of the lumbosacral spine. After surgery, she was highly satisfied with her ability to perform the activities of daily living. CONCLUSION: For nonambulatory patients with scoliosis and Pompe disease, long fusion from the upper thoracic spine to the pelvis is generally required. However, in ambulatory patients, in order to maintain the ability to walk, selective spinal fusion is an alternative. PMID- 29244697 TI - Occipitocervical Fusion for Severe Atlantoaxial Dislocation in an Underdeveloped Child with Chondrodysplasia Punctata: A Case Report. AB - CASE: We present a case of brachytelephalangic chondrodysplasia punctata with a severe atlantoaxial dislocation in an underdeveloped child. The patient underwent halo jacket application using 10 halo pins with <1 lb/in of torque, followed by posterior occipitocervical fusion with onlay rib and iliac autografts. After bone grafts and replacement of the halo ring multiple times, successful osseous fusion had been achieved by the 2-year follow-up. CONCLUSION: Although simple bone grafting with a halo jacket is useful in underdeveloped patients with skeletal dysplasia, the complications related to halo fixation, including cranial bone perforation, and the patient's neurological status must be carefully monitored. PMID- 29244698 TI - Restoration of Humeral Bone Stock Two Years After Internal Fixation of a Periprosthetic Fracture with a Loose Stem: A Report of Two Cases. AB - CASE: We describe 2 patients who sustained a periprosthetic humeral fracture with a loosened long-stemmed Coonrad-Morrey total elbow prosthesis. As noted in the literature, the success rate for a major revision with use of strut grafts is around 70%; therefore, both cases were managed without revision of the prosthesis. A submuscular locking plate was placed following typical fracture fixation principles. Screws that interfered with the humeral stem and the distal flange stabilized both the distal fragment and the humeral stem. CONCLUSION: At 2 years postoperatively, both fractures had healed, with increased endosteal bone stock. In each case, the prosthesis was successfully salvaged, and radiographic reconstitution of the implant-bone interface was noted after 2 years. PMID- 29244699 TI - Acute and Rapid Development of Spontaneous Spinal Epidural Hematoma Associated with Combined Aspirin-Dipyridamole Therapy: A Case Report. AB - CASE: Spontaneous spinal epidural hematoma (SSEH) is a known, although rare, clinical entity that may be challenging to diagnose. This case report describes the rapid development of a large SSEH in an elderly patient on aspirin dipyridamole combination therapy after she shifted her position in bed. Magnetic resonance imaging obtained 4 hours after the onset of symptoms demonstrated a large spinal epidural hematoma that extended from T4 to L1. CONCLUSION: With early diagnosis, the patient was successfully treated with a laminectomy and evacuation of the hematoma, and there was full neurological recovery. PMID- 29244700 TI - Conversion of Glenohumeral Fusion to Reverse Total Shoulder Arthroplasty: A Case Report. AB - CASE: A 41-year-old woman presented 5 years after glenohumeral arthrodesis. She experienced symptomatic relief following conversion to reverse total shoulder arthroplasty, regaining nearly full passive range of motion and >50% of normal active forward flexion, abduction, internal rotation, and external rotation. CONCLUSION: Conversion from glenohumeral arthrodesis to reverse total shoulder arthroplasty in a patient with a functioning deltoid and adequate bone stock may provide symptomatic relief and improved function in the setting of symptomatic glenohumeral arthrodesis refractory to conservative measures. PMID- 29244701 TI - Reconstruction of a Neglected Tibial Plateau Fracture Malunion with an Open-Book Osteotomy: A Case Report. AB - CASE: Surgical management of tibial plateau fractures can be challenging, and complications can be devastating. We report the case of a lateral tibial plateau fracture malunion with an associated intra-articular depression, which we treated with an open-book osteotomy, obviating the need for an early corrective osteotomy or knee arthroplasty. CONCLUSION: A tibial plateau fracture malunion can be reconstructed. The surgical team should give priority to salvage options, which can obviate or delay the need for and the implications of an early total knee arthroplasty, especially in a young and active patient. PMID- 29244702 TI - Challenging Lower-Extremity Fractures in Newborns and Infants. PMID- 29244703 TI - The Risk of Assuming Abuse in an Infant with an Isolated Metaphyseal Lesion: A Case Report. AB - CASE: The classic metaphyseal lesion, or corner fracture, is considered a strong indicator of nonaccidental trauma. In the present case, the parents brought their 8-month-old boy to a community hospital after he stopped crawling on the right leg. A knee radiograph demonstrated an isolated metaphyseal lesion, which prompted concern for child abuse. The patient was transferred to the nearest academic medical center; the pediatric radiology expert in child abuse determined that the lesion was a normal variant and not the result of abuse. CONCLUSION: An isolated metaphyseal lesion is not pathognomonic for child abuse, and a thoughtful differential diagnosis should be considered. PMID- 29244704 TI - Nonunion of a Nondisplaced Radial Neck Fracture: A Case Report. AB - CASE: We describe the case of a 66-year-old man who sustained a nondisplaced radial neck fracture and subsequently developed a symptomatic nonunion. After a period of unsuccessful conservative treatment, a radial head resection was performed. CONCLUSION: Radial neck fractures, unlike their radial head counterparts, have a low rate of nonunion. Our patient's only positive risk factor was age, but he developed a nonunion. At the 2-year follow-up after excision of the radial head, there was a lack of proximal migration of the radius during axial loading, demonstrating a positive outcome without the need for replacement of the radial head. PMID- 29244705 TI - Arthroscopic Repair of Recurrent Posterior Shoulder Subluxation After Total Shoulder Arthroplasty: A Case Report. AB - CASE: A 53-year-old man presented with osteoarthritis (Walch biconcave [B2] glenoid retroversion, 22 degrees ; glenohumeral subluxation index, 65%) and a partial rupture of the supraspinatus tendon in the left shoulder. Following anatomic total joint replacement, he developed disabling recurrent posterior subluxation despite a stable prosthesis and a correctly centered glenoid head, as observed with postoperative radiography and computed tomography. In order to avoid bone loss and the complications associated with revision arthroplasty, we performed arthroscopic reefing of the posterior capsule as an experimental minimally invasive treatment. The reduction in capsular volume successfully stabilized the shoulder for approximately 9 years; thereafter, the recurrence of instability ultimately required the conversion to a reverse prosthesis. CONCLUSION: Arthroscopic capsular reefing proved to be an effective treatment for posterior shoulder subluxations after total shoulder arthroplasty, and can be considered to avoid revision arthroplasty in young patients with a stable and correctly centered prosthesis. PMID- 29244706 TI - Streptococcus pneumoniae Osteomyelitis in a 25-Year-Old Man as the Initial Presentation of Multiple Myeloma: A Case Report. AB - CASE: We report the case of a 25-year-old man with femoral Streptococcus pneumoniae pyomyositis as well as hypercalcemia, mild anemia, and elevated inflammatory markers; he subsequently was diagnosed with immunoglobulin G (IgG) kappa multiple myeloma. CONCLUSION: Multiple myeloma most commonly affects patients who are >60 years of age, and causes clinical symptoms from anemia, lytic bone lesions, hypercalcemia, and renal failure. These findings and a monoclonal protein spike serve as initial diagnostic and treatment criteria. Multiple myeloma is associated with susceptibility to bacterial infections, especially encapsulated organisms; however, this is rarely the initial presentation. Additionally, it is unusual for myeloma to be diagnosed in a young person (<40 years of age). PMID- 29244707 TI - Complicated Total Knee Arthroplasty in a Patient with Klippel-Trenaunay-Weber Syndrome: A Case Report. AB - CASE: A 66-year-old Caucasian man with Klippel-Trenaunay-Weber syndrome (KTWS) presented with chronic changes related to the KTWS, along with worsening pain and motion associated with residual damage from an episode of spontaneous septic arthritis that occurred 1 year prior. He underwent total joint arthroplasty with a rotating hinged knee implant. CONCLUSION: Arthroplasty is a treatment option for patients with KTWS; however, there are risks that must be considered. This case report outlines the management of a patient with KTWS and a history of septic arthritis. PMID- 29244708 TI - Quality of Life and Sexual Function 2 Years After Vaginal Surgery for Prolapse: Correction. PMID- 29244709 TI - Breastfeeding Initiation Associated With Reduced Incidence of Diabetes in Mothers and Offspring: Correction. PMID- 29244710 TI - Physicochemical and Antimicrobial Characterization of Beeswax-Starch Food-Grade Nanoemulsions Incorporating Natural Antimicrobials. AB - Nanoemulsions are feasible delivery systems of lipophilic compounds, showing potential as edible coatings with enhanced functional properties. The aim of this work was to study the effect of emulsifier type (stearic acid (SA), Tween 80 (T80) or Tween 80/Span 60 (T80/S60)) and emulsification process (homogenization, ultrasound or microfluidization) on nanoemulsion formation based on oxidized corn starch, beeswax (BW) and natural antimicrobials (lauric arginate and natamycin). The response variables were physicochemical properties, rheological behavior, wettability and antimicrobial activity of BW-starch nanoemulsions (BW-SN). The BW SN emulsified using T80 and microfluidized showed the lowest droplet size (77.6 +/- 6.2 nm), a polydispersion index of 0.4 +/- 0.0 and whiteness index (WI) of 31.8 +/- 0.8. This BW-SN exhibited a more negative zeta-potential: -36 +/- 4 mV, and Newtonian flow behavior, indicating great stability. BW-SN antimicrobial activity was not affected by microfluidization nor the presence of T80, showing inhibition of the deteriorative fungi R. stolonifer, C. gloeosporioides and B. cinerea, and the pathogenic bacterium S. Saintpaul. In addition, regardless of emulsifier type and emulsification process, BW-SN applied on the tomato surface exhibited low contact angles (38.5 degrees to 48.6 degrees ), resulting in efficient wettability (-7.0 mN/m to -8.9 mN/m). These nanoemulsions may be useful to produce edible coatings to preserve fresh-produce quality and safety. PMID- 29244712 TI - Performance Analysis of a Novel Hybrid S-ALOHA/TDMA Protocol for Beta Distributed Massive MTC Access. AB - Simultaneous random access of massive machine type communications (MTC) devices are expected to cause congestion in the radio access network. Not only the performance of MTC, but the coexisting human to human (H2H) communications would also degrade dramatically without an appropriate medium access control (MAC) protocol. However, most existing solutions focus on the random access procedure without dealing with the sunsequent data transmission procedure. In this paper, we firstly derive a packet size threshold based on the capacity analysis of slotted ALOHA (S-ALOHA) and time division multiple access (TDMA) protocols. Then a novel hybrid S-ALOHA/TDMA MAC protocol (HSTMAC) is presented for massive MTC access, in which the resources are separated for beta distributed machine to machine (M2M) traffic with small size packets and high priority H2H traffic with large size packets. Considering access class barring (ACB) scheme as an overload control method, the system equilibrium under arbitrary retransmission limit is analyzed rigorously, which can provide insights on quality of service (QoS) guarantee. Finally, a dynamic pre-backoff (DPBO) algorithm is designed for load balance by adaptively scattering the highly synchronized M2M traffic over the transmission interval. Numerical and simulation results validate our analysis and show that the HSTMAC protocol is superior to pure S-ALOHA protocol and pure TDMA protocol. The proposed DPBO algorithm can achieve a higher success probability and resource utilization ratio with a much reduced average delay than that of uniform pre-backoff (UPBO) scheme. PMID- 29244713 TI - Nanoengineered Interfaces, Coatings, and Structures by Plasma Techniques. AB - Nanoparticles, nanotubes, nanobelts, nanoneedles, nanosheets, nanowires, nanopillars: the variety of nanostructured interfaces that can be created and modified using plasma processes is virtually endless.[...]. PMID- 29244711 TI - Flavonoids and Ellagitannins Characterization, Antioxidant and Cytotoxic Activities of Phyllanthus acuminatus Vahl. AB - The phenolic composition of leaves from Phyllanthus acuminatus L., a plant commonly used in Costa Rica as traditional medicine, was studied using UPLC-ESI MS on an enriched phenolic extract. A total of 20 phenolic compounds were identified, comprising eight flavonoids (two flavanones-pinocembrin isomers and six derivatives from apigenin, chrysin, quercetin, and kaempferol); seven ellagitannins, two flavan-3-ols (prodelphinidin B dimer and (epi)gallocatechin); and three phenolic acids (ellagic acid, trimethylellagic acid, and ferulic acid). All of these compounds are reported for the first time in P. acuminatus, while previously reported in the genus Phyllanthus. Antioxidant evaluation was performed for P. acuminatus phenolic extract obtaining DPPH results with a remarkably low IC50 value of 0.15 MUg/mL. Also, cytotoxicity on gastric AGS and colon SW20 adenocarcinoma cell lines was evaluated, and highly promising results were obtained, with IC50 values of 11.3 MUg/mL and 10.5 MUg/mL, respectively. Furthermore, selectivity index values obtained when comparing cytotoxicity on normal Vero cells was SI > 20 for both cancer cell lines, indicating a particularly high selectivity. Additionally, Justicidin B, a metabolite extensively studied for its antitumoral activity, was isolated from a non-polar extract of P. acuminatus, and comparatively evaluated for both bioactivities. The DPPH value obtained for Justicidin B was moderate (IC50 = 14.28 MUg/mL), while cytotoxicity values for both AGS (IC50 = 19.5 MUg/mL) and SW620 (IC50 = 24.8 MUg/mL) cell lines, as well as selectivity when compared with normal Vero cells (SI = 5.4 and 4.2 respectively), was good, but lower than P. acuminatus extract. These preliminary results suggest that P. acuminatus enriched phenolic extract containing flavonoids, ellagitannins, flavan-3-ols, and phenolic acids, reported for the first time in this plant, could be of interest for further cancer cytotoxicity studies to elucidate structure-bioactivity relationships, and the molecular mechanisms and pathways. PMID- 29244714 TI - Identification of Novel Human NK Cell Progenitor Subsets. AB - Understanding the pathways and regulation of human haematopoiesis, in particular, lymphopoiesis, is vital to manipulation of these processes for therapeutic purposes. However, although haematopoiesis has been extensively characterised in mice, translation of these findings to human biology remains rudimentary. Here, we describe the isolation of three progenitor subsets from human foetal bone marrow that represent differential stages of commitment to the natural killer (NK) cell lineage based on IL-15 responsiveness. We identify CD7 as a marker of IL-15 responsive progenitors in human bone marrow and find that this expression is maintained throughout commitment and maturation. Within the CD7+ fraction, we focussed on the lineage potential of three subsets based on CD127 and CD117 expression and observed restricted lymphoid and biased NK cell potential amongst subsets. We further demonstrate the presence of subsets similar in both phenotype and function in umbilical cord blood and the bone marrow of humanised mice, validating these as appropriate sources of progenitors for the investigation of human haematopoiesis. Overall, we describe several stages in the process of lymphopoiesis that will form the basis of investigating the regulators of this process in humans. PMID- 29244715 TI - Response Characterization of an Inexpensive Aerosol Sensor. AB - Inexpensive aerosol sensors have been considered as a complementary option to address the issue of expensive but low spatial coverage air quality monitoring networks. However, the accuracy and response characteristics of these sensors is poorly documented. In this study, inexpensive Shinyei PPD42NS and PPD60PV sensors were evaluated using a novel laboratory evaluation method. A continuously changing monodisperse size distribution of particles was generated using a Vibrating Orifice Aerosol Generator. Furthermore, the laboratory results were validated in a field experiment. The laboratory tests showed that both of the sensors responded to particulate mass (PM) concentration stimulus, rather than number concentration. The highest detection efficiency for the PPD42NS was within particle size range of 2.5-4 um, and the respective optimal size range for the PPD60PV was 0.7-1 um. The field test yielded high PM correlations (R2 = 0.962 and R2 = 0.986) for viable detection ranges of 1.6-5 and 0.3-1.6 um, when compared to a medium cost optical dust monitor. As the size distribution of atmospheric particles tends to be bimodal, it is likely that indicatively valid results could be obtained for the PM10-2.5 size fraction (particulate mass in size range 2.5-10 um) with the PPD42NS sensor. Respectively, the PPD60PV could possibly be used to measure the PM2.5 size fraction (particulate mass in size below 2.5 um). PMID- 29244716 TI - Two-Dimensional Fluorescence Difference Spectroscopy of ZnO and Mg Composites in the Detection of Physiological Protein and RNA Interactions. AB - Two-dimensional fluorescence difference spectroscopy (2-D FDS) was used to determine the unique spectral signatures of zinc oxide (ZnO), magnesium oxide (MgO), and 5% magnesium zinc oxide nanocomposite (5% Mg/ZnO) and was then used to demonstrate the change in spectral signature that occurs when physiologically important proteins, such as angiotensin-converting enzyme (ACE) and ribonuclease A (RNase A), interact with ZnO nanoparticles (NPs). When RNase A is bound to 5% Mg/ZnO, the intensity is quenched, while the intensity is magnified and a significant shift is seen when torula yeast RNA (TYRNA) is bound to RNase A and 5% Mg/ZnO. The intensity of 5% Mg/ZnO is quenched also when thrombin and thrombin aptamer are bound to the nanocomposite. These data indicate that RNA-protein interaction can occur unimpeded on the surface of NPs, which was confirmed by gel electrophoresis, and importantly that the change in fluorescence excitation, emission, and intensity shown by 2-D FDS may indicate specificity of biomolecular interactions. PMID- 29244717 TI - Femtograms of Interferon-gamma Suffice to Modulate the Behavior of Jurkat Cells: A New Light in Immunomodulation. AB - Since interferon-gamma (IFN-gamma) tunes both innate and adaptive immune systems, it was expected to enter clinical practice as an immunomodulatory drug. However, the use of IFN-gamma has been limited by its dose-dependent side effects. Low dose medicine, which is emerging as a novel strategy to treat diseases, might circumvent this restriction. Several clinical studies have proved the efficacy of therapies with a low dose of cytokines subjected to kinetic activation, while no in vitro data are available. To fill this gap, we investigated whether low concentrations, in the femtogram range, of kinetically activated IFN-gamma modulate the behavior of Jurkat cells, a widely used experimental model that has importantly contributed to the present knowledge about T cell signaling. In parallel, IFN-gamma in the nanogram range was used and shown to activate Signal transducer and activator of transcription (STAT)-1 and then to induce suppressor of cytokine signaling-1 (SOCS-1), which inhibits downstream signaling. When added together, femtograms of IFN-gamma interfere with the transduction cascade activated by nanograms of IFN-gamma by prolonging the activation of STAT-1 through the downregulation of SOCS-1. We conclude that femtograms of IFN-gamma exert an immunomodulatory action in Jurkat cells. PMID- 29244719 TI - Synthesis and Biological Activity of 2',3'-iso-Aryl-abscisic Acid Analogs. AB - 2',3'-iso-Benzoabscisic acid (iso-PhABA), an excellent selective abscisic acid (ABA) analog, was developed in our previous work. In order to find its more structure-activity information, some structural modifications were completed in this paper, including the substitution of phenyl ring and replacing the ring with heterocycles. Thus, 16 novel analogs of iso-PhABA were synthesized and screened with three bioassays, Arabidopsis and lettuce seed germination and rice seedling elongation. Some of them, i.e., 2',3'-iso-pyridoabscisic acid (iso-PyABA) and 2',3'-iso-franoabscisic acid (iso-FrABA), displayed good bioactivities that closed to iso-PhABA and natural (+)-ABA. Some others, for instance, substituted iso-PhABA, exhibited certain selectivity to different physiological process when compared to iso-PhABA or (+)-ABA. These analogs not only provided new candidates of ABA-like synthetic plant growth regulators (PGRs) for practical application, but also new potential selective agonist/antagonist for probing the specific function of ABA receptors. PMID- 29244718 TI - Prebiotic Dietary Fiber and Gut Health: Comparing the in Vitro Fermentations of Beta-Glucan, Inulin and Xylooligosaccharide. AB - Prebiotic dietary fiber supplements are commonly consumed to help meet fiber recommendations and improve gastrointestinal health by stimulating beneficial bacteria and the production of short-chain fatty acids (SCFAs), molecules beneficial to host health. The objective of this research project was to compare potential prebiotic effects and fermentability of five commonly consumed fibers using an in vitro fermentation system measuring changes in fecal microbiota, total gas production and formation of common SCFAs. Fecal donations were collected from three healthy volunteers. Materials analyzed included: pure beta glucan, Oatwell (commercially available oat-bran containing 22% oat beta-glucan), xylooligosaccharides (XOS), WholeFiber (dried chicory root containing inulin, pectin, and hemi/celluloses), and pure inulin. Oatwell had the highest production of propionate at 12 h (4.76 MUmol/mL) compared to inulin, WholeFiber and XOS samples (p < 0.03). Oatwell's effect was similar to those of the pure beta-glucan samples, both samples promoted the highest mean propionate production at 24 h. XOS resulted in a significant increase in the genus Bifidobacterium after 24 h of fermentation (0 h:0.67 OTUs (operational taxonomic unit); 24 h:5.22 OTUs; p = 0.038). Inulin and WholeFiber increased the beneficial genus Collinsella, consistent with findings in clinical studies. All analyzed compounds were fermentable and promoted the formation of beneficial SCFAs. PMID- 29244720 TI - Functional Imaging with 18F-FDG PET/CT and Diffusion Weighted Imaging (DWI) in Early Response Evaluation of Combination Therapy of Elotuzumab, Lenalidomide, and Dexamethasone in a Relapsed Multiple Myeloma Patient. AB - Elotuzumab is the first monoclonal antibody approved for the treatment of relapsed-refractory multiple myeloma (MM) in combination with lenalidomide, an immunodulatory drug, and dexamethasone. We report on a multiply pre-treated MM patient with disease progression due to appearance of new focal lesions on imaging modalities, who was started on a combination treatment of elotuzumab, lenalidomide, and dexamethasone. After completion of three cycles of the new therapy the patient responded very well with a major decline of serological myeloma activity parameters serum monoclonal protein, kappa light chains, free light chains (FLC) ratio. The patient was also monitored with the functional imaging modalities 18F-FDG PET/CT and diffusion weighted imaging (DWI), which exhibited a mismatch of almost complete metabolic remission on positron emission tomography/computed tomography (PET/CT) with 18F-fluoro-2-deoxy-d-glucose (18F FDG) (consistent with the serological response), and signal elevation persistence on DWI. This case demonstrates the potentially superior performance of 18F-FDG PET/CT over DWI in early response evaluation of combined treatment with a monoclonal antibody, an immunomodulatory drug, and dexamethasone in MM. PMID- 29244721 TI - Constructing Sheet-On-Sheet Structured Graphitic Carbon Nitride/Reduced Graphene Oxide/Layered MnO2 Ternary Nanocomposite with Outstanding Catalytic Properties on Thermal Decomposition of Ammonium Perchlorate. AB - We unprecedentedly report that layered MnO2 nanosheets were in situ formed onto the surface of covalently bonded graphitic carbon nitride/reduced graphene oxide nanocomposite (g-C3N4/rGO), forming sheet-on-sheet structured two dimension (2D) graphitic carbon nitride/reduced graphene oxide/layered MnO2 ternary nanocomposite (g-C3N4/rGO/MnO2) with outstanding catalytic properties on thermal decomposition of ammonium perchlorate (AP). The covalently bonded g-C3N4/rGO was firstly prepared by the calcination of graphene oxide-guanidine hydrochloride precursor (GO-GndCl), following by its dispersion into the KMnO4 aqueous solution to construct the g-C3N4/rGO/MnO2 ternary nanocomposite. FT-IR, XRD, Raman as well as the XPS results clearly demonstrated the chemical interaction between g-C3N4, rGO and MnO2. TEM and element mapping indicated that layered g-C3N4/rGO was covered with thin MnO2 nanosheets. Furthermore, the obtained g-C3N4/rGO/MnO2 nanocomposite exhibited promising catalytic capacity on thermal decomposition of AP. Upon addition of 2 wt % g-C3N4/rGO/MnO2 ternary nanocomposite as catalyst, the thermal decomposition temperature of AP was largely decreased up by 142.5 degrees C, which was higher than that of pure g-C3N4, g-C3N4/rGO and MnO2, respectively, demonstrating the synergistic catalysis of the as-prepared nanocomposite. PMID- 29244722 TI - Fault Diagnosis of Internal Combustion Engine Valve Clearance Using the Impact Commencement Detection Method. AB - Internal combustion engines (ICEs) are widely used in many important fields. The valve train clearance of an ICE usually exceeds the normal value due to wear or faulty adjustment. This work aims at diagnosing the valve clearance fault based on the vibration signals measured on the engine cylinder heads. The non stationarity of the ICE operating condition makes it difficult to obtain the nominal baseline, which is always an awkward problem for fault diagnosis. This paper overcomes the problem by inspecting the timing of valve closing impacts, of which the referenced baseline can be obtained by referencing design parameters rather than extraction during healthy conditions. To accurately detect the timing of valve closing impact from vibration signals, we carry out a new method to detect and extract the commencement of the impacts. The results of experiments conducted on a twelve-cylinder ICE test rig show that the approach is capable of extracting the commencement of valve closing impact accurately and using only one feature can give a superior monitoring of valve clearance. With the help of this technique, the valve clearance fault becomes detectable even without the comparison to the baseline, and the changing trend of the clearance could be trackable. PMID- 29244723 TI - An Online MFL Sensing Method for Steel Pipe Based on the Magnetic Guiding Effect. AB - In order to improve the sensitivity of online magnetic flux leakage (MFL) testing for steel pipe, a sensing method based on the magnetic guiding effect is proposed and investigated in this paper. Compared to the conventional contact sensing method using a non-ferromagnetic support, the proposed method creatively utilizes a ferromagnetic one to guide more magnetic flux to leak out. Based on Hopkinson's law, the principle of the magnetic guiding effect of the ferromagnetic support is theoretically illustrated. Then, numerical simulations are conducted to investigate the MFL changes influenced by the ferromagnetic support. Finally, the probe based on the proposed method is designed and developed, and online MFL experiments are performed to validate the feasibility of the proposed method. Online tests show that the proposed sensing method can greatly improve the MFL sensitivity. PMID- 29244724 TI - rLj-RGD3 Suppresses the Growth of HeyA8 Cells in Nude Mice. AB - In the previous study, rLj-RGD3, a recombinant toxin protein which contains three RGD motifs, was reported to not only inhibit the proliferation of an ovarian cancer cell line, HeyA8 cells, by inducing apoptosis, but also block their adhesion, migration and invasion processes. However, whether rLj-RGD3 could also suppress the tumor growth in HeyA8 xenografted mice has not been reported yet. In the present study, rLj-RGD3 was intraperitoneally injected in the nude mice bearing HeyA8 tumors. Compared with the control group (normal saline), rLj-RGD3 inhibited the tumor growth significantly in the HeyA8 xenografted mice in a dose dependent manner without affecting their body weights. Based on the H&E, Hoechst 33258 and TUNEL staining assays, as well as western blot analysis, rLj-RGD3 reduced the weight and volume of the solid tumors, probably by disturbing the tissue structure, inducing apoptosis and suppressing the FAK/PI3K/AKT pathway. Most importantly, rLj-RGD3 was found to prolong the survival days of the ovarian tumor xenografted mice, which suggested rLj-RGD3 might act as an effective and safe drug to treat ovarian cancer patients. PMID- 29244725 TI - Exploring the Glycans of Euglena gracilis. AB - Euglena gracilis is an alga of great biotechnological interest and extensive metabolic capacity, able to make high levels of bioactive compounds, such as polyunsaturated fatty acids, vitamins and beta-glucan. Previous work has shown that Euglena expresses a wide range of carbohydrate-active enzymes, suggesting an unexpectedly high capacity for the synthesis of complex carbohydrates for a single-celled organism. Here, we present an analysis of some of the carbohydrates synthesised by Euglena gracilis. Analysis of the sugar nucleotide pool showed that there are the substrates necessary for synthesis of complex polysaccharides, including the unusual sugar galactofuranose. Lectin- and antibody-based profiling of whole cells and extracted carbohydrates revealed a complex galactan, xylan and aminosugar based surface. Protein N-glycan profiling, however, indicated that just simple high mannose-type glycans are present and that they are partially modified with putative aminoethylphosphonate moieties. Together, these data indicate that Euglena possesses a complex glycan surface, unrelated to plant cell walls, while its protein glycosylation is simple. Taken together, these findings suggest that Euglena gracilis may lend itself to the production of pharmaceutical glycoproteins. PMID- 29244726 TI - Potential of Bioactive Glasses for Cardiac and Pulmonary Tissue Engineering. AB - Repair and regeneration of disorders affecting cardiac and pulmonary tissues through tissue-engineering-based approaches is currently of particular interest. On this matter, different families of bioactive glasses (BGs) have recently been given much consideration with respect to treating refractory diseases of these tissues, such as myocardial infarction. The inherent properties of BGs, including their ability to bond to hard and soft tissues, to stimulate angiogenesis, and to elicit antimicrobial effects, along with their excellent biocompatibility, support these newly proposed strategies. Moreover, BGs can also act as a bioactive reinforcing phase to finely tune the mechanical properties of polymer based constructs used to repair the damaged cardiac and pulmonary tissues. In the present study, we evaluated the potential of different forms of BGs, alone or in combination with other materials (e.g., polymers), in regards to repair and regenerate injured tissues of cardiac and pulmonary systems. PMID- 29244727 TI - An Efficient Estimator for Moving Target Localization Using Multi-Station Dual Frequency Radars. AB - Localization of a moving target in a dual-frequency radars system has now gained considerable attention. The noncoherent localization approach based on a least squares (LS) estimator has been addressed in the literature. Compared with the LS method, a novel localization method based on a two-step weighted least squares estimator is proposed to increase positioning accuracy for a multi-station dual frequency radars system in this paper. The effects of signal noise ratio and the number of samples on the performance of range estimation are also analyzed in the paper. Furthermore, both the theoretical variance and Cramer-Rao lower bound (CRLB) are derived. The simulation results verified the proposed method. PMID- 29244728 TI - Transcriptome Analysis of Paraburkholderia phymatum under Nitrogen Starvation and during Symbiosis with Phaseolus Vulgaris. AB - Paraburkholderia phymatum belongs to the beta-subclass of proteobacteria. It has recently been shown to be able to nodulate and fix nitrogen in symbiosis with several mimosoid and papilionoid legumes. In contrast to the symbiosis of legumes with alpha-proteobacteria, very little is known about the molecular determinants underlying the successful establishment of this mutualistic relationship with beta-proteobacteria. In this study, we performed an RNA-sequencing (RNA-seq) analysis of free-living P. phymatum growing under nitrogen-replete and -limited conditions, the latter partially mimicking the situation in nitrogen-deprived soils. Among the genes upregulated under nitrogen limitation, we found genes involved in exopolysaccharides production and in motility, two traits relevant for plant root infection. Next, RNA-seq data of P. phymatum grown under free living conditions and from symbiotic root nodules of Phaseolus vulgaris (common bean) were generated and compared. Among the genes highly upregulated during symbiosis, we identified-besides the nif gene cluster-an operon encoding a potential cytochrome o ubiquinol oxidase (Bphy_3646-49). Bean root nodules induced by a cyoB mutant strain showed reduced nitrogenase and nitrogen fixation abilities, suggesting an important role of the cytochrome for respiration inside the nodule. The analysis of mutant strains for the RNA polymerase transcription factor RpoN (sigma54) and its activator NifA indicated that-similar to the situation in alpha-rhizobia-P. phymatum RpoN and NifA are key regulators during symbiosis with P. vulgaris. PMID- 29244729 TI - Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: In Vitro Cellular Uptake. AB - Iron deficiency anemia is a common clinical consequence for people who suffer from chronic kidney disease, especially those requiring dialysis. Intravenous (IV) iron therapy is a widely accepted safe and efficacious treatment for iron deficiency anemia. Numerous IV iron drugs have been approved by U.S. Food and Drug Administration (FDA), including a single generic product, sodium ferric gluconate complex in sucrose. In this study, we compared the cellular iron uptake profiles of the brand (Ferrlecit(r)) and generic sodium ferric gluconate (SFG) products. We used a colorimetric assay to examine the amount of iron uptake by three human macrophage cell lines. This is the first published study to provide a parallel evaluation of the cellular uptake of a brand and a generic IV iron drug in a mononuclear phagocyte system. The results showed no difference in iron uptake across all cell lines, tested doses, and time points. The matching iron uptake profiles of Ferrlecit(r) and its generic product support the FDA's present position detailed in the draft guidance on development of SFG complex products that bioequivalence can be based on qualitative (Q1) and quantitative (Q2) formulation sameness, similar physiochemical characterization, and pharmacokinetic bioequivalence studies. PMID- 29244730 TI - Isolation and Characterization of Ftsz Genes in Cassava. AB - The filamenting temperature-sensitive Z proteins (FtsZs) play an important role in plastid division. In this study, three FtsZ genes were isolated from the cassava genome, and named MeFtsZ1, MeFtsZ2-1, and MeFtsZ2-2, respectively. Based on phylogeny, the MeFtsZs were classified into two groups (FtsZ1 and FtsZ2). MeFtsZ1 with a putative signal peptide at N-terminal, has six exons, and is classed to FtsZ1 clade. MeFtsZ2-1 and MeFtsZ2-2 without a putative signal peptide, have seven exons, and are classed to FtsZ2 clade. Subcellular localization found that all the three MeFtsZs could locate in chloroplasts and form a ring in chloroplastids. Structure analysis found that all MeFtsZ proteins contain a conserved guanosine triphosphatase (GTPase) domain in favor of generate contractile force for cassava plastid division. The expression profiles of MeFtsZ genes by quantitative reverse transcription-PCR (qRT-PCR) analysis in photosynthetic and non-photosynthetic tissues found that all of the MeFtsZ genes had higher expression levels in photosynthetic tissues, especially in younger leaves, and lower expression levels in the non-photosynthetic tissues. During cassava storage root development, the expressions of MeFtsZ2-1 and MeFtsZ2-2 were comparatively higher than MeFtsZ1. The transformed Arabidopsis of MeFtsZ2-1 and MeFtsZ2-2 contained abnormally shape, fewer number, and larger volume chloroplasts. Phytohormones were involved in regulating the expressions of MeFtsZ genes. Therefore, we deduced that all of the MeFtsZs play an important role in chloroplast division, and that MeFtsZ2 (2-1, 2-2) might be involved in amyloplast division and regulated by phytohormones during cassava storage root development. PMID- 29244732 TI - Middleware for Plug and Play Integration of Heterogeneous Sensor Resources into the Sensor Web. AB - The study of global phenomena requires the combination of a considerable amount of data coming from different sources, acquired by different observation platforms and managed by institutions working in different scientific fields. Merging this data to provide extensive and complete data sets to monitor the long term, global changes of our oceans is a major challenge. The data acquisition and data archival procedures usually vary significantly depending on the acquisition platform. This lack of standardization ultimately leads to information silos, preventing the data to be effectively shared across different scientific communities. In the past years, important steps have been taken in order to improve both standardization and interoperability, such as the Open Geospatial Consortium's Sensor Web Enablement (SWE) framework. Within this framework, standardized models and interfaces to archive, access and visualize the data from heterogeneous sensor resources have been proposed. However, due to the wide variety of software and hardware architectures presented by marine sensors and marine observation platforms, there is still a lack of uniform procedures to integrate sensors into existing SWE-based data infrastructures. In this work, a framework aimed to enable sensor plug and play integration into existing SWE based data infrastructures is presented. First, an analysis of the operations required to automatically identify, configure and operate a sensor are analysed. Then, the metadata required for these operations is structured in a standard way. Afterwards, a modular, plug and play, SWE-based acquisition chain is proposed. Finally different use cases for this framework are presented. PMID- 29244733 TI - The Association of Triiodothyronine-to-Thyroxine Ratio with Body Mass Index in Obese Nigerian Children and Adolescents. AB - The interest in the relationship between thyroid dysfunction and obesity is on the increase. This study compares the triiodothyronine-to-thyroxine (T3/T4) ratio in obese and lean children and adolescents, and correlates thyroid hormones with body mass index (BMI) in obese Nigerian children. It is a retrospective study of records of 76 obese children and adolescents with a BMI of 31.7 +/- 0.1 kg/m2 (26 males aged 10.9 +/- 0.35 years, and 50 females aged 10.8 +/- 0.4 years) that were referred to the laboratory for thyroid hormone evaluation because of their obese status. The controls were 20 age-matched non-obese apparently healthy subjects, with a mean age of 11.0 +/- 0.47 years and a BMI of 20.2 +/- 0.2 kg/m2. Serum T3, T4, and thyroid stimulating hormone (TSH) were determined using ELECSYS 1010 auto analyzer (Roche Diagnostics, Penzberg, Germany). The BMI (p < 0.001), T3 (p < 0.01), TSH (p < 0.001) and T3/T4 ratio (p < 0.001) were significantly higher in obese than non-obese children and adolescents. Triiodothyronine (r = 0.230; p < 0.05), TSH (r = 0.272; p < 0.02), and T3/T4 ratio (r = 0.232; p < 0.05) correlated positively with BMI in obese children and adolescents. The T3/T4 ratio (p < 0.005) was significantly higher in obese boys than obese girls. Serum T3, TSH, and T3/T4 ratio correlated positive with BMI in obese Nigerian children and adolescents. Since thyroid dysfunction represents a continuum from asymptomatic to clinical symptomatic disease, it is suggested that obese children be counseled on the need to maintain ideal BMI in order to avoid the risks associated with obesity. PMID- 29244731 TI - Comparative Therapeutic Effects of Plant-Extract Synthesized and Traditionally Synthesized Gold Nanoparticles on Alcohol-Induced Inflammatory Activity in SH SY5Y Cells In Vitro. AB - The present study describes potential beneficial and adverse effects of plant extract synthesized gold nanoparticles (AuNPs) on ethanol toxicity in SH-SY5Y cells. Although kudzu root extract (K), edible-gum extract (G), alone or in combination (KG), reduced Au3+ into AuNPs, the extract's composition and the reaction temperature determined their size (AuNPKG(90<50<37) << AuNPK(90,50<37) < AuNPG(90<50); the subscript KG, K, or G is extract identification and numerical vales are reaction temperature in Celsius) and biological properties (AuNPKG(90,50>37) << AuNPK(90,50>37) < AuNPG(90,50)). The surface of each AuNP contained the extract's active ingredients, that were analyzed and confirmed using laser desorption ionization (LDI)) and low-matrix laser desorption ionization (LMALDI). AuNPKG-50 was (i) least toxic to SH-SY5Y cells, but most effective in suppressing the adverse effects of ethanol on SH-SY5Y cells, and (ii) more effective than a combination of free kudzu and gum extracts. The beneficial and adverse effects of AuNPs may have been modified by the formation of proteins corona. This study provides a proof of concept for possible application of plant-extract synthesized AuNPs in mitigating ethanol toxicity. PMID- 29244734 TI - "I Learned to Let Go of My Pain". The Effects of Mindfulness Meditation on Adolescents with Chronic Pain: An Analysis of Participants' Treatment Experience. AB - Chronic pain can lead to significant negative outcomes across many areas of life. Recently, mindfulness-based interventions (MBIs) have been identified as potentially effective tools for improved pain management among adolescents living with pain. This study aimed to explore the experience of adolescents who participated in an eight-week mindfulness group adapted for adolescents with chronic pain (MBI-A), and obtain their feedback and suggestions on group structure and content. A mixed method design was used employing qualitative data from focus groups and data from a satisfaction questionnaire. Focus group data were transcribed and analyzed using inductive simple descriptive content analysis. Of the total participants (n = 21), 90% (n = 19) provided feedback by completing satisfaction questionnaires and seventeen (n = 17) of those also participated across two focus groups. Analysis of the focus group transcripts uncovered six themes: mindfulness skills, supportive environment, group exercises (likes and dislikes), empowerment, program expectations, and logistics. Participants reported positive experiences in the MBI-A program, including support received from peers and mindfulness skills, including present moment awareness, pain acceptance, and emotion regulation. Group members suggested increasing the number of sessions and being clearer at outset regarding a focus on reduction of emotional suffering rather than physical pain. PMID- 29244735 TI - Development of the Precision Link Biobank at Boston Children's Hospital: Challenges and Opportunities. AB - Increasingly, biobanks are being developed to support organized collections of biological specimens and associated clinical information on broadly consented, diverse patient populations. We describe the implementation of a pediatric biobank, comprised of a fully-informed patient cohort linking specimens to phenotypic data derived from electronic health records (EHR). The Biobank was launched after multiple stakeholders' input and implemented initially in a pilot phase before hospital-wide expansion in 2016. In-person informed consent is obtained from all participants enrolling in the Biobank and provides permission to: (1) access EHR data for research; (2) collect and use residual specimens produced as by-products of routine care; and (3) share de-identified data and specimens outside of the institution. Participants are recruited throughout the hospital, across diverse clinical settings. We have enrolled 4900 patients to date, and 41% of these have an associated blood sample for DNA processing. Current efforts are focused on aligning the Biobank with other ongoing research efforts at our institution and extending our electronic consenting system to support remote enrollment. A number of pediatric-specific challenges and opportunities is reviewed, including the need to re-consent patients when they reach 18 years of age, the ability to enroll family members accompanying patients and alignment with disease-specific research efforts at our institution and other pediatric centers to increase cohort sizes, particularly for rare diseases. PMID- 29244737 TI - Investigation of Flat Clinching Process Combined with Material Forming Technology for Aluminum Alloy. AB - In recent years, the use of aluminum alloy has tended to increase for building lightweight automobiles to reduce their automotive weight, which is helpful to save energy and protect the environment. In order to join aluminum alloy, a flat clinching process combined with material forming technology was investigated to join aluminum alloy sheets using an experimental and a numerical method. Al1060 was chosen as the material of the sheet, and DEFORM-2D software was used to build the numerical model. After the numerical model was validated by the experimental results, the influences of punch diameter and holder force on the materials deforming behavior of the clinched joint were analyzed using the numerical model. Then, the material flow, joining ability, and joining quality were investigated to assess the clinched joint. The results showed that an increase in punch diameter could give rise to an increase in neck thickness and interlocking length, while an increase in blank holder force induced a decrease in interlocking length and an increase in neck thickness. The joining quality could be increased by increasing the forming force. It can be concluded that a clinched joint has better joining quality for joining light-weight sheets onto automotive structures. PMID- 29244736 TI - Frequency of Fruit and Vegetable Consumption and the Oral Health-Related Quality of Life among Japanese Elderly: A Cross-Sectional Study from the Kyoto-Kameoka Study. AB - OBJECTIVE: Many previous studies have reported that fruit and vegetable consumption is associated with a reduced risk of various disease, but whether or not their consumption is associated with the oral health-related quality of life (OHRQoL) is unclear. The objective of this study was to examine the association between the frequency of fruit and vegetable consumption and the OHRQoL in elderly subjects by sex. METHODS: We analyzed cross-sectional data from a population-based Kyoto-Kameoka Study in 2012 of 3112 men and 3439 women (age >= 65 years). The frequencies of fruit and vegetable consumption were assessed using a validated food frequency questionnaire. We evaluated the OHRQoL using the General Oral Health Assessment Index (GOHAI), a self-reported measure designed to assess the oral health problems in old adults. RESULTS: After adjusting for age, body mass index, alcohol, smoking, education, socioeconomic status, history of disease, medication use, mobility disability, and total energy intake, a higher frequency of combined fruit and vegetable consumption showed a significant positive association with the GOHAI score in both men and women (p-trend < 0.001 in both sexes). These associations remained significant after adjustment for poor mastication and denture use (p-trend all < 0.05 in both sexes). We observed a significant positive association even when the frequencies of fruit or vegetable consumption were analyzed separately (all p-trend < 0.05 in both sexes). CONCLUSIONS: A higher frequency of fruit and/or vegetable consumption independently showed a strong positive association with the OHRQoL in both men and women. Further prospective studies are needed to confirm these findings. PMID- 29244738 TI - Design of an Air Pollution Monitoring Campaign in Beijing for Application to Cohort Health Studies. AB - No cohort studies in China on the health effects of long-term air pollution exposure have employed exposure estimates at the fine spatial scales desirable for cohort studies with individual-level health outcome data. Here we assess an array of modern air pollution exposure estimation approaches for assigning within city exposure estimates in Beijing for individual pollutants and pollutant sources to individual members of a cohort. Issues considered in selecting specific monitoring data or new monitoring campaigns include: needed spatial resolution, exposure measurement error and its impact on health effect estimates, spatial alignment and compatibility with the cohort, and feasibility and expense. Sources of existing data largely include administrative monitoring data, predictions from air dispersion or chemical transport models and remote sensing (specifically satellite) data. New air monitoring campaigns include additional fixed site monitoring, snapshot monitoring, passive badge or micro-sensor saturation monitoring and mobile monitoring, as well as combinations of these. Each of these has relative advantages and disadvantages. It is concluded that a campaign in Beijing that at least includes a mobile monitoring component, when coupled with currently available spatio-temporal modeling methods, should be strongly considered. Such a campaign is economical and capable of providing the desired fine-scale spatial resolution for pollutants and sources. PMID- 29244739 TI - Metabolic Characterization of the Anthocyanidin Reductase Pathway Involved in the Biosynthesis of Flavan-3-ols in Elite Shuchazao Tea (Camellia sinensis) Cultivar in the Field. AB - Anthocyanidin reductase (ANR) is a key enzyme in the ANR biosynthetic pathway of flavan-3-ols and proanthocyanidins (PAs) in plants. Herein, we report characterization of the ANR pathway of flavan-3-ols in Shuchazao tea (Camellia sinesis), which is an elite and widely grown cultivar in China and is rich in flavan-3-ols providing with high nutritional value to human health. In our study, metabolic profiling was preformed to identify two conjugates and four aglycones of flavan-3-ols: (-)-epigallocatechin-gallate [(-)-EGCG], (-)-epicatechin-gallate [(-)-ECG], (-)-epigallocatechin [(-)-EGC], (-)-epicatechin [(-)-EC], (+)-catechin [(+)-Ca], and (+)-gallocatechin [(+)-GC], of which (-)-EGCG, (-)-ECG, (-)-EGC, and (-)-EC accounted for 70-85% of total flavan-3-ols in different tissues. Crude ANR enzyme was extracted from young leaves. Enzymatic assays showed that crude ANR extracts catalyzed cyanidin and delphinidin to (-)-EC and (-)-Ca and (-)-EGC and (-)-GC, respectively, in which (-)-EC and (-)-EGC were major products. Moreover, two ANR cDNAs were cloned from leaves, namely CssANRa and CssANRb. His Tag fused recombinant CssANRa and CssANRb converted cyanidin and delphinidin to ( )-EC and (-)-Ca and (-)-EGC and (-)-GC, respectively. In addition, (+)-EC was observed from the catalysis of recombinant CssANRa and CssANRb. Further overexpression of the two genes in tobacco led to the formation of PAs in flowers and the reduction of anthocyanins. Taken together, these data indicate that the majority of leaf flavan-3-ols in Shuchazao's leaves were produced from the ANR pathway. PMID- 29244740 TI - Chirality-Dependent Interaction of d- and l-Menthol with Biomembrane Models. AB - Chirality plays a vital role in biological membranes and has a significant effect depending on the type and arrangement of the isomer. Menthol has two typical chiral forms, d- and l-, which exhibit different behaviours. l-Menthol is known for its physiological effect on sensitivity (i.e. a cooling effect), whereas d menthol causes skin irritation. Menthol molecules may affect not only the thermoreceptors on biomembranes, but also the membrane itself. Membrane heterogeneity (lipid rafts, phase separation) depends on lipid packing and acyl chain ordering. Our interest is to elaborate the chirality dependence of d- and l menthol on membrane heterogeneity. We revealed physical differences between the two optical isomers of menthol on membrane heterogeneity by studying model membranes using nuclear magnetic resonance and microscopic observation. PMID- 29244741 TI - Fluorescent and Colorimetric Electrospun Nanofibers for Heavy-Metal Sensing. AB - The accumulation of heavy metals in the human body and/or in the environment can be highly deleterious for mankind, and currently, considerable efforts have been made to develop reliable and sensitive techniques for their detection. Among the detection methods, chemical sensors appear as a promising technology, with emphasis on systems employing optically active nanofibers. Such nanofibers can be obtained by the electrospinning technique, and further functionalized with optically active chromophores such as dyes, conjugated polymers, carbon-based nanomaterials and nanoparticles, in order to produce fluorescent and colorimetric nanofibers. In this review we survey recent investigations reporting the use of optically active electrospun nanofibers in sensors aiming at the specific detection of heavy metals using colorimetry and fluorescence methods. The examples given in this review article provide sufficient evidence of the potential of optically electrospun nanofibers as a valid approach to fabricate highly selective and sensitive optical sensors for fast and low-cost detection of heavy metals. PMID- 29244742 TI - Fibrinogen Gamma Chain Mutations Provoke Fibrinogen and Apolipoprotein B Plasma Deficiency and Liver Storage. AB - p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen gamma. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the "end-to-end" interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon. PMID- 29244744 TI - A Carbon Dioxide Limitation-Inducible Protein, ColA, Supports the Growth of Synechococcus sp. PCC 7002. AB - A limitation in carbon dioxide (CO2), which occurs as a result of natural environmental variation, suppresses photosynthesis and has the potential to cause photo-oxidative damage to photosynthetic cells. Oxygenic phototrophs have strategies to alleviate photo-oxidative damage to allow life in present atmospheric CO2 conditions. However, the mechanisms for CO2 limitation acclimation are diverse among the various oxygenic phototrophs, and many mechanisms remain to be discovered. In this study, we found that the gene encoding a CO2 limitation-inducible protein, ColA, is required for the cyanobacterium Synechococcus sp. PCC 7002 (S. 7002) to acclimate to limited CO2 conditions. An S. 7002 mutant deficient in ColA (DeltacolA) showed lower chlorophyll content, based on the amount of nitrogen, than that in S. 7002 wild type (WT) under ambient air but not high CO2 conditions. Both thermoluminescence and protein carbonylation detected in the ambient air grown cells indicated that the lack of ColA promotes oxidative stress in S. 7002. Alterations in the photosynthetic O2 evolution rate and relative electron transport rate in the short-term response, within an hour, to CO2 limitation were the same between the WT and DeltacolA. Conversely, these photosynthetic parameters were mostly lower in the long-term response of a few days in DeltacolA than in the WT. These data suggest that ColA is required to sustain photosynthetic activity for living under ambient air in S. 7002. The unique phylogeny of ColA revealed diverse strategies to acclimate to CO2 limitation among cyanobacteria. PMID- 29244743 TI - Hematological and Hemodynamic Responses to Acute and Short-Term Creatine Nitrate Supplementation. AB - In a double-blind, crossover, randomized and placebo-controlled trial; 28 men and women ingested a placebo (PLA), 3 g of creatine nitrate (CNL), and 6 g of creatine nitrate (CNH) for 6 days. Participants repeated the experiment with the alternate supplements after a 7-day washout. Hemodynamic responses to a postural challenge, fasting blood samples, and bench press, leg press, and cycling time trial performance and recovery were assessed. Data were analyzed by univariate, multivariate, and repeated measures general linear models (GLM). No significant differences were found among treatments for hemodynamic responses, clinical blood markers or self-reported side effects. After 5 days of supplementation, one repetition maximum (1RM) bench press improved significantly for CNH (mean change, 95% CI; 6.1 [3.5, 8.7] kg) but not PLA (0.7 [-1.6, 3.0] kg or CNL (2.0 [-0.9, 4.9] kg, CNH, p = 0.01). CNH participants also tended to experience an attenuated loss in 1RM strength during the recovery performance tests following supplementation on day 5 (PLA: -9.3 [-13.5, -5.0], CNL: -9.3 [-13.5, -5.1], CNH: 3.9 [-6.6, -1.2] kg, p = 0.07). After 5 days, pre-supplementation 1RM leg press values increased significantly, only with CNH (24.7 [8.8, 40.6] kg, but not PLA (13.9 [-15.7, 43.5] or CNL (14.6 [-0.5, 29.7]). Further, post-supplementation 1RM leg press recovery did not decrease significantly for CNH (-13.3 [-31.9, 5.3], but did for PLA (-30.5 [-53.4, -7.7] and CNL (-29.0 [-49.5, -8.4]). CNL treatment promoted an increase in bench press repetitions at 70% of 1RM during recovery on day 5 (PLA: 0.4 [-0.8, 1.6], CNL: 0.9 [0.35, 1.5], CNH: 0.5 [-0.2, 0.3], p = 0.56), greater leg press endurance prior to supplementation on day 5 (PLA: -0.2 [ 1.6, 1.2], CNL: 0.9 [0.2, 1.6], CNH: 0.2 [-0.5, 0.9], p = 0.25) and greater leg press endurance during recovery on day 5 (PLA: -0.03 [-1.2, 1.1], CNL: 1.1 [0.3, 1.9], CNH: 0.4 [-0.4, 1.2], p = 0.23). Cycling time trial performance (4 km) was not affected. Results indicate that creatine nitrate supplementation, up to a 6 g dose, for 6 days, appears to be safe and provide some ergogenic benefit. PMID- 29244745 TI - Immunotherapeutic Potential of Oncolytic H-1 Parvovirus: Hints of Glioblastoma Microenvironment Conversion towards Immunogenicity. AB - Glioblastoma, one of the most aggressive primary brain tumors, is characterized by highly immunosuppressive microenvironment. This contributes to glioblastoma resistance to standard treatment modalities and allows tumor growth and recurrence. Several immune-targeted approaches have been recently developed and are currently under preclinical and clinical investigation. Oncolytic viruses, including the autonomous protoparvovirus H-1 (H-1PV), show great promise as novel immunotherapeutic tools. In a first phase I/IIa clinical trial (ParvOryx01), H 1PV was safe and well tolerated when locally or systemically administered to recurrent glioblastoma patients. The virus was able to cross the blood-brain (tumor) barrier after intravenous infusion. Importantly, H-1PV treatment of glioblastoma patients was associated with immunogenic changes in the tumor microenvironment. Tumor infiltration with activated cytotoxic T cells, induction of cathepsin B and inducible nitric oxide (NO) synthase (iNOS) expression in tumor-associated microglia/macrophages (TAM), and accumulation of activated TAM in cluster of differentiation (CD) 40 ligand (CD40L)-positive glioblastoma regions was detected. These are the first-in-human observations of H-1PV capacity to switch the immunosuppressed tumor microenvironment towards immunogenicity. Based on this pilot study, we present a tentative model of H-1PV-mediated modulation of glioblastoma microenvironment and propose a combinatorial therapeutic approach taking advantage of H-1PV-induced microglia/macrophage activation for further (pre)clinical testing. PMID- 29244746 TI - Effects of Beetroot Juice Supplementation on a 30-s High-Intensity Inertial Cycle Ergometer Test. AB - Background: Beetroot juice (BJ) is rich in inorganic nitrates and has proved effective at increasing blood nitric oxide (NO) levels. When used as a supplement BJ has shown an ergogenic effect on cardiorespiratory resistance exercise modalities, yet few studies have examined its impact on high intensity efforts. Objective: To assess the effects of BJ intake on anaerobic performance in a Wingate test. Methods: Fifteen trained men (age 21.46 +/- 1.72 years, height 1.78 +/- 0.07 cm and weight 76.90 +/- 8.67 kg) undertook a 30-s maximum intensity test on an inertial cycle ergometer after drinking 70 mL of BJ (5.6 mmol NO3-) or placebo. Results: Despite no impacts of BJ on the mean power recorded during the test, improvements were produced in peak power (6%) (p = 0.034), average power 0 15 s (6.7%) (p = 0.048) and final blood lactate levels (82.6%) (p < 0.001), and there was a trend towards a shorter time taken to attain peak power (-8.4%) (p = 0.055). Conclusions: Supplementation with BJ has an ergonomic effect on maximum power output and on average power during the first 15 s of a 30-s maximum intensity inertial cycle ergometer test. PMID- 29244748 TI - Design of New-Generation Usable Forms of Topical Haemostatic Agents Containing Chitosan. AB - Designing usable forms of topical haemostatic agents is the most important activity during the design process, resulting in strengthened functional properties of the final medical devices. This study aimed to propose indications for a research programme based on risk management supporting the development of two usable forms of a topical haemostatic agent: chitosan/alginate lyophilized foam and chitosan/alginate impregnated gauze. Both of the usable forms of the topical haemostatic agent, being the main part of the modified combat gauze, were fabricated using the chitosan/alginate complex. Risk analysis is helpful in developing an appropriate research programme, significantly reducing the risk to an acceptable level. PMID- 29244747 TI - Ophthalmic Formulation Containing Nilvadipine Nanoparticles Prevents Retinal Dysfunction in Rats Injected with Streptozotocin. AB - Retinopathy leads to irreparable vision loss via capillary closure and areas of nonperfusion. However, the current instillation systems do not allow a sufficient amount of drug required to treat retinopathy to reach the posterior segment (retina); therefore, a new formulation targeting the posterior segment is expected as therapy for retinopathy. We prepared ophthalmic formulations containing nilvadipine nanoparticles (NILnano), and demonstrated whether the instillation of NILnano can prevent retinal dysfunction in rats injected with excessive streptozotocin (STZ rats) in this study. NILnano (mean particle size, 77 nm) was prepared by wet bead mill treatment, with the inclusion of various additives (2-hydroxypropyl-beta-cyclodextrin, benzalkonium chloride, d-mannitol, and methylcellulose). Retinal dysfunction was observable two weeks after rats received intraperitoneal injections of streptozotocin (100 mg/kg * 2, consecutive days, STZ rat). Changes in retinal function were evaluated by electroretinogram (ERG) and immunological methods. The retinal thickness, measured as the distance between the ganglion cell layer and the distal border of the outer nuclear layer, increased two weeks after the injection of streptozotocin, resulting in decreases in the levels of a-waves, b-waves, and oscillatory potential amplitudes in ERG of rats. The instillation of NILnano allowed the topical supplement of nilvadipine into the retina, and repeated instillation of NILnano (2 times/day) attenuated the retinal disorders led by the excessive streptozotocin. In conclusion, we found that retinal dysfunction in rats injected with streptozotocin can be prevented by the NILnano instillation. These results are useful in further studies aimed at the therapeutic treatment of retinopathy. PMID- 29244749 TI - Serum Levels of S100b and NSE Proteins in Patients with Non-Transfusion-Dependent Thalassemia as Biomarkers of Brain Ischemia and Cerebral Vasculopathy. AB - Patients with non-transfusion-dependent thalassemia (NTDT) are at risk of developing brain ischemia. Transcranial Doppler (TCD) has been established as a useful screening tool of cerebrovascular disease in patients with sickle cell disease. Proteins neuron specific enolase (NSE) and S100B are biomarkers that reflect CNS injury. The purpose of this study is to evaluate cerebral vessel vasculopathy and brain damage in NTDT patients using non-invasive methods as TCD and measurement serum levels of NSE and S100B. We included in our study 30 patients with NTDT, aged between 8 and 62 years old (mean: 29.4, median: 32) who presented in our Unit for regular follow-up. We performed in all patients a non imaging TCD examination and have measured serum S100, NSE and lactate dehydrogenase (LDH) levels. We investigated the possible correlation between TCD results and S100B, NSE and LDH levels as well as between NSE-LDH and S100B-LDH levels by regression analysis. We found a statistically significant relationship for both NSE, S100B with LDH. We also found a statistically significant relationship for S100B and time-averaged mean velocity (TAMV)/peak velocity of left middle cerebral artery (MCA), NSE and pulsatility index (PI)/resistive index (RI) of the left posterior cerebral artery (PCA). TCD results correlated with biomarkers for brain ischemia. This finding enhances the role of TCD as a screening tool for brain ischemia in patients with NTDT. PMID- 29244750 TI - HIGA: A Running History Information Guided Genetic Algorithm for Protein-Ligand Docking. AB - Protein-ligand docking is an essential part of computer-aided drug design, and it identifies the binding patterns of proteins and ligands by computer simulation. Though Lamarckian genetic algorithm (LGA) has demonstrated excellent performance in terms of protein-ligand docking problems, it can not memorize the history information that it has accessed, rendering it effort-consuming to discover some promising solutions. This article illustrates a novel optimization algorithm (HIGA), which is based on LGA for solving the protein-ligand docking problems with an aim to overcome the drawback mentioned above. A running history information guided model, which includes CE crossover, ED mutation, and BSP tree, is applied in the method. The novel algorithm is more efficient to find the lowest energy of protein-ligand docking. We evaluate the performance of HIGA in comparison with GA, LGA, EDGA, CEPGA, SODOCK, and ABC, the results of which indicate that HIGA outperforms other search algorithms. PMID- 29244751 TI - Spirulina Extract Enhanced a Protective Effect in Type 1 Diabetes by Anti Apoptosis and Anti-ROS Production. AB - Interest in the nutritional value and pharmacological activities of blue-green algae has gradually increased. Spirulina extracts show protective effects against apoptosis and inflammatory damage in various cell types. Here, we investigated the protective effects of extracts from Spirulina maxima in a cytokine-mediated type 1 diabetes model in vitro and in streptozotocin-induced diabetic Wistar rats in vivo. Interleukin-1beta and interferon-gamma induced substantial cytotoxicity to RINm5F rat insulinoma cells, increasing nitric oxide (NO) production, nuclear factor-kappa B (NF-kappaB) activity, the expression of endoplasmic reticulum (ER) stress genes, and activation of mitogen-activated protein kinases and key genes related apoptosis. However, the cytotoxicity of cytokines was significantly attenuated by Spirulina extract, which effectively prevented NO production by inhibiting the synthesis of cytokine-activated NO synthase (iNOS), and apoptosis was suppressed. These results suggest that Spirulina extract might be effective to preserve the viability and function of pancreatic beta-cells against cytotoxic conditions. Moreover, diabetic mice orally administered Spirulina extract showed decreased glucose levels, increased insulin, and improvement in liver enzyme markers. The antioxidant effect of Spirulina extract may be helpful in treating type 1 diabetes by enhancing the survival, and reducing or delaying cytokine mediated beta-cells destruction. PMID- 29244753 TI - Identification of a Multicomponent Traditional Herbal Medicine by HPLC-MS and Electron and Light Microscopy. AB - BACKGROUND: Commercial pharmaceutical herbal products have enabled people to take traditional Chinese medicine (TCM) in a convenient and accessible form. However, the quantity and quality should be additionally inspected. To address the issue, a combination of chemical and physical inspection methods were developed to evaluate the amount of an herbal formula, Xiang-Sha-Liu-Jun-Zi-Tang (XSLJZT), in clinical TCM practice. METHODS: A high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) method with electrospray ionization was developed to measure the herbal biomarkers of guanosine, atractylenolide III, glycyrrhizic acid, dehydrocostus lactone, hesperidin, and oleanolic acid from XSLJZT. Scanning electron microscopy (SEM) photographs and light microscopy photographs with Congo red and iodine-KI staining were used to identify the cellulose fibers and starch content. Furthermore, solubility analysis, swelling power test, and crude fiber analysis were contributed to measure the starch additive in pharmaceutical products. RESULTS: The results demonstrated large variations in the chemical components of different pharmaceutical brands. The SEM photographs revealed that the starch was oval, smooth, and granular, and that the raw herbal powder appears stripy, stretched, and filiform. The stained light microscopy photographs of all of the pharmaceutical products showed added starch and raw herbal powder as extenders. CONCLUSION: The developed chemical and physical methods provide a standard operating procedure for the quantity control of the herbal pharmaceutical products of XSLJZT. PMID- 29244752 TI - Proteomic Analysis Reveals Coordinated Regulation of Anthocyanin Biosynthesis through Signal Transduction and Sugar Metabolism in Black Rice Leaf. AB - Black rice (Oryza sativa L.) is considered to be a healthy food due to its high content of anthocyanins in the pericarp. The synthetic pathway of anthocyanins in black rice grains has been identified, however, the proteomic profile of leaves during grain development is still unclear. Here, isobaric Tags Relative and Absolute Quantification (iTRAQ) MS/MS was carried out to identify statistically significant changes of leaf proteome in the black rice during grain development. Throughout three sequential developmental stages, a total of 3562 proteins were detected and 24 functional proteins were differentially expressed 3-10 days after flowering (DAF). The detected proteins are known to be involved in various biological processes and most of these proteins were related to gene expression regulatory (33.3%), signal transduction (16.7%) and developmental regulation and hormone-like proteins (12.5%). The coordinated changes were consistent with changes in regulatory proteins playing a leading role in leaves during black rice grain development. This indicated that signal transduction between leaves and grains may have an important role in anthocyanin biosynthesis and accumulation during grain development of black rice. In addition, four identified up-regulated proteins associated with starch metabolism suggested that the remobilization of nutrients for starch synthesis plays a potential role in anthocyanin biosynthesis of grain. The mRNA transcription for eight selected proteins was validated with quantitative real-time PCR. Our results explored the proteomics of the coordination between leaf and grain in anthocyanins biosynthesis of grain, which might be regulated by signal transduction and sugar metabolism in black rice leaf. PMID- 29244754 TI - Evaluation of Traffic Density Parameters as an Indicator of Vehicle Emission Related Near-Road Air Pollution: A Case Study with NEXUS Measurement Data on Black Carbon. AB - An important factor in evaluating health risk of near-road air pollution is to accurately estimate the traffic-related vehicle emission of air pollutants. Inclusion of traffic parameters such as road length/area, distance to roads, and traffic volume/intensity into models such as land use regression (LUR) models has improved exposure estimation. To better understand the relationship between vehicle emissions and near-road air pollution, we evaluated three traffic density based indices: Major-Road Density (MRD), All-Traffic Density (ATD) and Heavy Traffic Density (HTD) which represent the proportions of major roads, major road with annual average daily traffic (AADT), and major road with commercial annual average daily traffic (CAADT) in a buffered area, respectively. We evaluated the potential of these indices as vehicle emission-specific near-road air pollutant indicators by analyzing their correlation with black carbon (BC), a marker for mobile source air pollutants, using measurement data obtained from the Near-road Exposures and Effects of Urban Air Pollutants Study (NEXUS). The average BC concentrations during a day showed variations consistent with changes in traffic volume which were classified into high, medium, and low for the morning rush hours, the evening rush hours, and the rest of the day, respectively. The average correlation coefficients between BC concentrations and MRD, ATD, and HTD, were 0.26, 0.18, and 0.48, respectively, as compared with -0.31 and 0.25 for two commonly used traffic indicators: nearest distance to a major road and total length of the major road. HTD, which includes only heavy-duty diesel vehicles in its traffic count, gives statistically significant correlation coefficients for all near-road distances (50, 100, 150, 200, 250, and 300 m) that were analyzed. Generalized linear model (GLM) analyses show that season, traffic volume, HTD, and distance from major roads are highly related to BC measurements. Our analyses indicate that traffic density parameters may be more specific indicators of near road BC concentrations for health risk studies. HTD is the best index for reflecting near-road BC concentrations which are influenced mainly by the emissions of heavy-duty diesel engines. PMID- 29244755 TI - Doped Halloysite Nanotubes for Use in the 3D Printing of Medical Devices. AB - Previous studies have established halloysite nanotubes (HNTs) as viable nanocontainers capable of sustained release of a variety of antibiotics, corrosion agents, chemotherapeutics and growth factors either from their lumen or in outer surface coatings. Accordingly, halloysite nanotubes (HNTs) hold great promise as drug delivery carriers in the fields of pharmaceutical science and regenerative medicine. This study explored the potential of 3D printing drug doped HNT constructs. We used a model drug, gentamicin (GS) and polylactic acid (PLA) to fabricate GS releasing disks, beads, and pellets. Gentamicin was released from 3D printed constructs in a sustained manner and had a superior anti bacterial growth inhibition effect that was dependent on GS doping concentration. While this study focused on a model drug, gentamicin, combination therapy is possible through the fabrication of medical devices containing HNTs doped with a suite of antibiotics or antifungals. Furthermore, tailored dosage levels, suites of antimicrobials, delivered locally would reduce the toxicity of individual agents, prevent the emergence of resistant strains, and enable the treatment of mixed infections. PMID- 29244756 TI - Recent Progress in Biosensors for Environmental Monitoring: A Review. AB - The environmental monitoring has been one of the priorities at the European and global scale due to the close relationship between the environmental pollution and the human health/socioeconomic development. In this field, the biosensors have been widely employed as cost-effective, fast, in situ, and real-time analytical techniques. The need of portable, rapid, and smart biosensing devices explains the recent development of biosensors with new transduction materials, obtained from nanotechnology, and for multiplexed pollutant detection, involving multidisciplinary experts. This review article provides an update on recent progress in biosensors for the monitoring of air, water, and soil pollutants in real conditions such as pesticides, potentially toxic elements, and small organic molecules including toxins and endocrine disrupting chemicals. PMID- 29244758 TI - Protein Subcellular Localization with Gaussian Kernel Discriminant Analysis and Its Kernel Parameter Selection. AB - Kernel discriminant analysis (KDA) is a dimension reduction and classification algorithm based on nonlinear kernel trick, which can be novelly used to treat high-dimensional and complex biological data before undergoing classification processes such as protein subcellular localization. Kernel parameters make a great impact on the performance of the KDA model. Specifically, for KDA with the popular Gaussian kernel, to select the scale parameter is still a challenging problem. Thus, this paper introduces the KDA method and proposes a new method for Gaussian kernel parameter selection depending on the fact that the differences between reconstruction errors of edge normal samples and those of interior normal samples should be maximized for certain suitable kernel parameters. Experiments with various standard data sets of protein subcellular localization show that the overall accuracy of protein classification prediction with KDA is much higher than that without KDA. Meanwhile, the kernel parameter of KDA has a great impact on the efficiency, and the proposed method can produce an optimum parameter, which makes the new algorithm not only perform as effectively as the traditional ones, but also reduce the computational time and thus improve efficiency. PMID- 29244757 TI - Expression of Staphylococcal Enterotoxins under Stress Encountered during Food Production and Preservation. AB - Staphylococcal food poisoning (SFP) is the most prevalent cause of food-borne intoxications worldwide. Consumption of enterotoxins preformed in food causes violent vomiting and can be fatal in children and the elderly. While being repressed by competing bacteria in most matrices, Staphylococcus aureus benefits from crucial competitive advantages in foods with high osmolarity or low pH. During recent years, the long-standing belief in the feasibility of assessing SFP risk based on colony-forming units of S. aureus present in food products has been disproven. Instead, researchers and food business operators are acutely aware of the imminent threat arising from unforeseeable enterotoxin production under stress conditions. This paradigm shift led to a variety of new publications enabling an improved understanding of enterotoxin expression under stress conditions encountered in food. The wealth of data provided by these studies is extremely diverse, as it is based on different methodological approaches, staphylococcal strains, stressors, and enterotoxins. Therefore, in this review, we aggregated and critically evaluated the complex findings of these studies, to provide readers with a current overview of the state of research in the field. PMID- 29244759 TI - Requirements for Efficient Thiosulfate Oxidation in Bradyrhizobium diazoefficiens. AB - One of the many disparate lifestyles of Bradyrhizobium diazoefficiens is chemolithotrophic growth with thiosulfate as an electron donor for respiration. The employed carbon source may be CO2 (autotrophy) or an organic compound such as succinate (mixotrophy). Here, we discovered three new facets of this capacity: (i) When thiosulfate and succinate were consumed concomitantly in conditions of mixotrophy, even a high molar excess of succinate did not exert efficient catabolite repression over the use of thiosulfate. (ii) Using appropriate cytochrome mutants, we found that electrons derived from thiosulfate during chemolithoautotrophic growth are preferentially channeled via cytochrome c550 to the aa3-type heme-copper cytochrome oxidase. (iii) Three genetic regulators were identified to act at least partially in the expression control of genes for chemolithoautotrophic thiosulfate oxidation: RegR and CbbR as activators, and SoxR as a repressor. PMID- 29244761 TI - Study of Separation and Fouling of Reverse Osmosis Membranes during Model Hydrolysate Solution Filtration. AB - Prehydrolysate, a dilute solution consisting mainly of pentoses, hexoses, and lesser quantities of organic acids, furfural and phenolics, is generated in the Kraft dissolving pulp process. An obstacle facing the valorization of the solution in hemicellulose biorefineries, by conversion of the sugars into bioproducts such as furfural, is the low sugar concentration. Membrane filtration is typically proposed in several hemicellulose based biorefineries for concentrating the solution, although they are usually generated using different wood species, pretreatment methods, and operating conditions. However, the chemical composition of the solutions is generally not considered. Also, the combined effect of composition and operating conditions is rarely investigated for biorefinery applications. The purpose of this work was to determine the impact of the prehydrolysate composition and operating parameters on the component separation and permeate flux during membrane filtration. Using model prehydrolysate solutions, two commercial reverse osmosis (RO) membranes were screened, and one was selected for use, based on its higher sugar and acetic acid retention. A Taguchi L18 experimental design array was then applied to determine the dominant parameters and limiting factors. Results showed that the feed pressure and temperature have the highest impact on permeate flux, but the least effect on sugar retention. Further experiments to quantify flux decline, due to fouling and osmotic pressure, showed that furfural has the highest membrane fouling tendency, and can limit the lifetime of the membrane. Regeneration of the membrane by cleaning with a sodium hydroxide solution is also effective for reversing fouling. It has been demonstrated that RO can efficiently and sustainably concentrate wood prehydrolysate. PMID- 29244760 TI - Impact of Methods on the Measurement of mRNA Turnover. AB - The turnover of the RNA molecules is determined by the rates of transcription and RNA degradation. Several methods have been developed to study RNA turnover since the beginnings of molecular biology. Here we summarize the main methods to measure RNA half-life: transcription inhibition, gene control, and metabolic labelling. These methods were used to detect the cellular activity of the mRNAs degradation machinery, including the exo-ribonuclease Xrn1 and the exosome. On the other hand, the study of the differential stability of mature RNAs has been hampered by the fact that different methods have often yielded inconsistent results. Recent advances in the systematic comparison of different method variants in yeast have permitted the identification of the least invasive methodologies that reflect half-lives the most faithfully, which is expected to open the way for a consistent quantitative analysis of the determinants of mRNA stability. PMID- 29244762 TI - Towards Realistic Urban Traffic Experiments Using DFROUTER: Heuristic, Validation and Extensions. AB - Traffic congestion is an important problem faced by Intelligent Transportation Systems (ITS), requiring models that allow predicting the impact of different solutions on urban traffic flow. Such an approach typically requires the use of simulations, which should be as realistic as possible. However, achieving high degrees of realism can be complex when the actual traffic patterns, defined through an Origin/Destination (O-D) matrix for the vehicles in a city, remain unknown. Thus, the main contribution of this paper is a heuristic for improving traffic congestion modeling. In particular, we propose a procedure that, starting from real induction loop measurements made available by traffic authorities, iteratively refines the output of DFROUTER, which is a module provided by the SUMO (Simulation of Urban MObility) tool. This way, it is able to generate an O-D matrix for traffic that resembles the real traffic distribution and that can be directly imported by SUMO. We apply our technique to the city of Valencia, and we then compare the obtained results against other existing traffic mobility data for the cities of Cologne (Germany) and Bologna (Italy), thereby validating our approach. We also use our technique to determine what degree of congestion is expectable if certain conditions cause additional traffic to circulate in the city, adopting both a uniform pattern and a hotspot-based pattern for traffic injection to demonstrate how to regulate the overall number of vehicles in the city. This study allows evaluating the impact of vehicle flow changes on the overall traffic congestion levels. PMID- 29244763 TI - Bisphenol A Causes Liver Damage and Selectively Alters the Neurochemical Coding of Intrahepatic Parasympathetic Nerves in Juvenile Porcine Models under Physiological Conditions. AB - Bisphenol A (BPA) is an extremely common polymer that is used in typical everyday products throughout the world, especially in food and beverage containers. Within the last ten years, it has been found that the BPA monomer tends to leach into foodstuffs, and nanogram concentrations of it may cause a variety of deleterious health effects. These health problems are very evident in developing children and in young adults. The aim of this study was to expose developing pigs to dietary BPA at both legally acceptable and ten-fold higher levels. Livers that had been exposed to BPA showed vacuolar degeneration, sinusoidal dilatation, vascular congestion and glycogen depletion that increased with exposure levels. Furthermore, the livers of these models were then examined for irregularities and double-labeled immunofluorescence was used to check the innervated hepatic samples for varying neuronal expression of selected neuronal markers in the parasympathetic nervous system (PSNS). It was found that both the PSNS and all of the neuronal markers showed increased expression, with some of them being significant even at recommended safe exposure levels. The implications are quite serious since these effects have been observed at recommended safe levels with expression increasing in-line with exposure levels. The increased neuronal markers studied here have been previously correlated with behavioral/psychological disorders of children and young adults, as well as with childhood obesity and diabetes. However, further research must be performed in order to develop a mechanism for the above-mentioned correlations. PMID- 29244764 TI - The Seagrass Holobiont and Its Microbiome. AB - Seagrass meadows are ecologically and economically important components of many coastal areas worldwide. Ecosystem services provided by seagrasses include reducing the number of microbial pathogens in the water, providing food, shelter and nurseries for many species, and decreasing the impact of waves on the shorelines. A global assessment reported that 29% of the known areal extent of seagrasses has disappeared since seagrass areas were initially recorded in 1879. Several factors such as direct and indirect human activity contribute to the demise of seagrasses. One of the main reasons for seagrass die-offs all over the world is increased sulfide concentrations in the sediment that result from the activity of sulfate-reducing prokaryotes, which perform the last step of the anaerobic food chain in marine sediments and reduce sulfate to H2S. Recent seagrass die-offs, e.g., in the Florida and Biscayne Bays, were caused by an increase in pore-water sulfide concentrations in the sediment, which were the combined result of unfavorable environmental conditions and the activities of various groups of heterotrophic bacteria in the sulfate-rich water-column and sediment that are stimulated through increased nutrient concentrations. Under normal circumstances, seagrasses are able to withstand low levels of sulfide, probably partly due to microbial symbionts, which detoxify sulfide by oxidizing it to sulfur or sulfate. Novel studies are beginning to give greater insights into the interactions of microbes and seagrasses, not only in the sulfur cycle. Here, we review the literature on the basic ecology and biology of seagrasses and focus on studies describing their microbiome. PMID- 29244765 TI - New Insights into Solid Form Stability and Hydrate Formation: o-Phenanthroline HCl and Neocuproine HCl. AB - The moisture- and temperature dependent stabilities and interrelation pathways of the practically relevant solid forms of o-phenanthroline HCl (1) and neocuproine HCl (2) were investigated using thermal analytical techniques (HSM, DSC and TGA) and gravimetric moisture sorption/desorption studies. The experimental stability data were correlated with the structural changes observed upon dehydration and the pairwise interaction and lattice energies calculated. For 1 the monohydrate was identified as the only stable form under conditions of RH typically found during production and storage, but at RH values >80% deliquescence occurs. The second compound, 2, forms an anhydrate and two different hydrates, mono- (2-Hy1) and trihydrate (2-Hy3). The 2-Hy1 structure was solved from SCXRD data and the anhydrate structure derived from a combination of PXRD and CSP. Depending on the environmental conditions (moisture) either 2-Hy1 or 2-Hy3 is the most sable solid form of 2 at RT. The monohydrates 1-Hy1 and 2-Hy1 show a high enthalpic stabilization (>=20 kJ mol-1) relative to the anhydrates. The anhydrates are unstable at ambient conditions and readily transform to the monohydrates even in the presence of traces of moisture. This study demonstrates how the right combination of experiment and theory can unravel the properties and interconversion pathways of solid forms. PMID- 29244766 TI - Antifungal Activity of Ramulus cinnamomi Explored by 1H-NMR Based Metabolomics Approach. AB - A 1H nuclear magnetic resonance (NMR)-based approach to metabolomics combined bioassay was used to elucidate the antifungal activity of cinnamaldehyde (the main active compound of Ramulus cinnamomi) isolated from Ramulus cinnamomi (RC). Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS DA) of NMR data was constructed to analyze all the P. italicum data acquired from the control and treatment groups at 4, 8, and 12 h. Metabolic profiles disclosed metabolic changes that were related to the antifungal effects of cinnamaldehyde against P. italicum including oxidative stress, disorder of energy metabolism, amino acids, and nucleic acids metabolism in treatment group. This integrated metabolomics approach provided an effective way to detect the antifungal effects of cinnamaldehyde against P. italicum dynamically. PMID- 29244767 TI - Regulatory Elements Located in the Upstream Region of the Rhizobium leguminosarum rosR Global Regulator Are Essential for Its Transcription and mRNA Stability. AB - Rhizobium leguminosarum bv. trifolii is a soil bacterium capable of establishing a symbiotic relationship with clover (Trifolium spp.). Previously, the rosR gene, encoding a global regulatory protein involved in motility, synthesis of cell surface components, and other cellular processes was identified and characterized in this bacterium. This gene possesses a long upstream region that contains several regulatory motifs, including inverted repeats (IRs) of different lengths. So far, the role of these motifs in the regulation of rosR transcription has not been elucidated in detail. In this study, we performed a functional analysis of these motifs using a set of transcriptional rosR-lacZ fusions that contain mutations in these regions. The levels of rosR transcription for different mutant variants were evaluated in R. leguminosarum using both quantitative real-time PCR and beta-galactosidase activity assays. Moreover, the stability of wild type rosR transcripts and those with mutations in the regulatory motifs was determined using an RNA decay assay and plasmids with mutations in different IRs located in the 5'-untranslated region of the gene. The results show that transcription of rosR undergoes complex regulation, in which several regulatory elements located in the upstream region and some regulatory proteins are engaged. These include an upstream regulatory element, an extension of the -10 element containing three nucleotides TGn (TGn-extended -10 element), several IRs, and PraR repressor related to quorum sensing. PMID- 29244769 TI - Effects of UV-Ozone Treatment on Sensing Behaviours of EGFETs with Al2O3 Sensing Film. AB - The effects of UV-ozone (UVO) treatment on the sensing behaviours of extended gate field-effect transistors (EGFETs) that use Al2O3 as the sensing film have been investigated. The Al2O3 sensing films are UVO-treated with various duration times and the corresponding EGFET sensing behaviours, such as sensitivity, hysteresis, and long-term stability, are electrically evaluated under various measurement conditions. Physical analysis is also performed to characterize the surface conditions of the UVO-treated sensing films using X-ray photoelectron spectroscopy and atomic force microscopy. It is found that UVO treatment effectively reduces the buried sites in the Al2O3 sensing film and subsequently results in reduced hysteresis and improved long-term stability of EGFET. Meanwhile, the observed slightly smoother Al2O3 film surface post UVO treatment corresponds to decreased surface sites and slightly reduced pH sensitivity of the Al2O3 film. The sensitivity degradation is found to be monotonically correlated with the UVO treatment time. A treatment time of 10 min is found to yield an excellent performance trade-off: clearly improved long-term stability and reduced hysteresis at the cost of negligible sensitivity reduction. These results suggest that UVO treatment is a simple and facile method to improve the overall sensing performance of the EGFETs with an Al2O3 sensing film. PMID- 29244770 TI - A Highly Sensitive Two-Dimensional Inclinometer Based on Two Etched Chirped-Fiber Grating Arrays. AB - We present a novel two-dimensional fiber-optic inclinometer with high sensitivity by crisscrossing two etched chirped fiber Bragg gratings (CFBG) arrays. Each array is composed of two symmetrically-arranged CFBGs. By etching away most of the claddings of the CFBGs to expose the evanescent wave, the reflection spectra are highly sensitive to the surrounding index change. When we immerse only part of the CFBG in liquid, the effective index difference induces a superposition peak in the refection spectrum. By interrogating the peak wavelengths of the CFBGs, we can deduce the tilt angle and direction simultaneously. The inclinometer has a resolution of 0.003 degrees in tilt angle measurement and 0.00187 rad in tilt direction measurement. Due to the unique sensing mechanism, the sensor is temperature insensitive. This sensor can be useful in long term continuous monitoring of inclination or in real-time feedback control of tilt angles, especially in harsh environments with violent temperature variation. PMID- 29244768 TI - Identification and Expression Profiling of the Auxin Response Factors in Capsicum annuum L. under Abiotic Stress and Hormone Treatments. AB - Auxin response factors (ARFs) play important roles in regulating plant growth and development and response to environmental stress. An exhaustive analysis of the CaARF family was performed using the latest publicly available genome for pepper (Capsicum annuum L.). In total, 22 non-redundant CaARF gene family members in six classes were analyzed, including chromosome locations, gene structures, conserved motifs of proteins, phylogenetic relationships and Subcellular localization. Phylogenetic analysis of the ARFs from pepper (Capsicum annuum L.), tomato (Solanum lycopersicum L.), Arabidopsis and rice (Oryza sativa L.) revealed both similarity and divergence between the four ARF families, and aided in predicting biological functions of the CaARFs. Furthermore, expression profiling of CaARFs was obtained in various organs and tissues using quantitative real-time RT-PCR (qRT-PCR). Expression analysis of these genes was also conducted with various hormones and abiotic treatments using qRT-PCR. Most CaARF genes were regulated by exogenous hormone treatments at the transcriptional level, and many CaARF genes were altered by abiotic stress. Systematic analysis of CaARF genes is imperative to elucidate the roles of CaARF family members in mediating auxin signaling in the adaptation of pepper to a challenging environment. PMID- 29244771 TI - How Can We Achieve Healthy Aging? AB - Population aging affects all countries, and all income groups.[...]. PMID- 29244773 TI - Nanoscale Phase Evolution during Continuum Decomposition of Fe-Cr Alloys. AB - The continuum decomposition of the Fe-Cr alloys from initial phase separation to steady-state coarsening with concentrations varying from 25 at % Cr and 30 at % Cr to 33 at % Cr aged at 750 K was studied by utilizing three-dimensional phase field simulations. The dynamic stages of separation of nanoscale Cr-enriched alpha' phase were distinguished by the evolution of the volume fraction, particle number density and the average particle radius of the alpha' phase. The stage of steady-state coarsening was characterized with an equilibrium volume fraction and decreasing particle number density. The coarsening rate constant by linear fitting of the cube of average radius and aging time shows an increase with the increasing Cr concentration. The time exponents decrease from the growth and coarsening stage to the steady-state coarsening stage and show a dependence on the particles number density at different concentrations. The quantitative evolutions of alpha' phase via nucleation growth and spinodal decomposition are theoretically helpful for understanding the microstructure evolution with aging time in Fe-Cr alloys. PMID- 29244772 TI - Sphingosine-1-Phosphate Receptor 1, Expressed in Myeloid Cells, Slows Diet Induced Atherosclerosis and Protects against Macrophage Apoptosis in Ldlr KO Mice. AB - We generated myeloid specific sphingosine-1-phosphate receptor 1 (S1pr1) deficient mice by crossing mice that had myeloid specific expression of Cre recombinase (lyzMCre) with mice having the S1pr1 gene flanked by loxP recombination sites. We transplanted bone marrow from these mice and control lyzMCre mice with intact macrophage S1pr1 gene expression into low-density lipoprotein (LDL) receptor gene (Ldlr) deficient mice. The resulting chimeras were fed a high fat atherogenic diet for nine or twelve weeks and evaluated for atherosclerosis development in the aortic sinus. Selective S1pr1 deficiency in bone marrow-derived myeloid cells resulted in accelerated development of atherosclerosis, necrotic core formation and the appearance of apoptotic cells within atherosclerotic plaques of Ldlr knockout mice in response to a high fat diet. Examination of macrophages in culture revealed that the sphingosine-1 phosphate receptor 1 selective agonist, SEW2871 or high density lipoprotein (HDL), protected macrophages against apoptosis induced by endoplasmic reticulum (ER) stress or oxidized LDL, through activation of phosphatidylinositol-3 kinase/Akt signaling. Targeted S1pr1-deletion prevented Akt activation and protection against apoptosis by either SEW2871 or HDL. Our data suggests that sphingosine-1-phosphate receptor 1 in macrophages plays an important role in protecting them against apoptosis in vitro and in atherosclerotic plaques in vivo, and delays diet induced atherosclerosis development in Ldlr deficient mice. PMID- 29244774 TI - 3DCONS-DB: A Database of Position-Specific Scoring Matrices in Protein Structures. AB - Many studies have used position-specific scoring matrices (PSSM) profiles to characterize residues in protein structures and to predict a broad range of protein features. Moreover, PSSM profiles of Protein Data Bank (PDB) entries have been recalculated in many works for different purposes. Although the computational cost of calculating a single PSSM profile is affordable, many statistical studies or machine learning-based methods used thousands of profiles to achieve their goals, thereby leading to a substantial increase of the computational cost. In this work we present a new database compiling PSSM profiles for the proteins of the PDB. Currently, the database contains 333,532 protein chain profiles involving 123,135 different PDB entries. PMID- 29244776 TI - Internet of Things (IoT) Based Design of a Secure and Lightweight Body Area Network (BAN) Healthcare System. AB - As sensor networks and cloud computation technologies have rapidly developed over recent years, many services and applications integrating these technologies into daily life have come together as an Internet of Things (IoT). At the same time, aging populations have increased the need for expanded and more efficient elderly care services. Fortunately, elderly people can now wear sensing devices which relay data to a personal wireless device, forming a body area network (BAN). These personal wireless devices collect and integrate patients' personal physiological data, and then transmit the data to the backend of the network for related diagnostics. However, a great deal of the information transmitted by such systems is sensitive data, and must therefore be subject to stringent security protocols. Protecting this data from unauthorized access is thus an important issue in IoT-related research. In regard to a cloud healthcare environment, scholars have proposed a secure mechanism to protect sensitive patient information. Their schemes provide a general architecture; however, these previous schemes still have some vulnerability, and thus cannot guarantee complete security. This paper proposes a secure and lightweight body-sensor network based on the Internet of Things for cloud healthcare environments, in order to address the vulnerabilities discovered in previous schemes. The proposed authentication mechanism is applied to a medical reader to provide a more comprehensive architecture while also providing mutual authentication, and guaranteeing data integrity, user untraceability, and forward and backward secrecy, in addition to being resistant to replay attack. PMID- 29244775 TI - Spatial, Temporal, and Dietary Variables Associated with Elevated Mercury Exposure in Peruvian Riverine Communities Upstream and Downstream of Artisanal and Small-Scale Gold Mining. AB - Artisanal and small-scale gold mining (ASGM) is a primary contributor to global mercury and its rapid expansion raises concern for human exposure. Non occupational exposure risks are presumed to be strongly tied to environmental contamination; however, the relationship between environmental and human mercury exposure, how exposure has changed over time, and risk factors beyond fish consumption are not well understood in ASGM settings. In Peruvian riverine communities (n = 12), where ASGM has increased 4-6 fold over the past decade, we provide a large-scale assessment of the connection between environmental and human mercury exposure by comparing total mercury contents in human hair (2-cm segment, n = 231) to locally caught fish tissue, analyzing temporal exposure in women of child bearing age (WCBA, 15-49 years, n = 46) over one year, and evaluating general mercury exposure risks including fish and non-fish dietary items through household surveys and linear mixed models. Calculations of an individual's oral reference dose using the total mercury content in locally sourced fish underestimated the observed mercury exposure for individuals in many communities. This discrepancy was particularly evident in communities upstream of ASGM, where mercury levels in river fish, water, and sediment measurements from a previous study were low, yet hair mercury was chronically elevated. Hair from 86% of individuals and 77% of children exceeded a USEPA (U.S. Environmental Protection Agency) provisional level (1.2 ug/g) that could result in child developmental impairment. Chronically elevated mercury exposure was observed in the temporal analysis in WCBA. If the most recent exposure exceeded the USEPA level, there was a 97% probability that the individual exceeded that level 8-10 months of the previous year. Frequent household consumption of some fruits (tomato, banana) and grains (quinoa) was significantly associated with 29-75% reductions in hair mercury. Collectively, these data demonstrate that communities located hundreds of kilometers from ASGM are vulnerable to chronically elevated mercury exposure. Furthermore, unexpected associations with fish mercury contents and non-fish dietary intake highlight the need for more in-depth analyses of exposure regimes to identify the most vulnerable populations and to establish potential interventions. PMID- 29244777 TI - Sparse Adaptive Iteratively-Weighted Thresholding Algorithm (SAITA) for Lp Regularization Using the Multiple Sub-Dictionary Representation. AB - Both L1/2 and L2/3 are two typical non-convex regularizations of Lp (0150 g. PMID- 29244783 TI - Using a Commonly Down-Regulated Cytomegalovirus (CMV) Promoter for High-Level Expression of Ectopic Gene in a Human B Lymphoma Cell Line. AB - BACKGROUND Vectors are widely used to drive gene expression using a promoter. However, not all promoters are able to drive ectopic gene expression efficiently, including CMV promoter. Here, we report our data using CMV promoter for high level gene expression in a B lymphoma cell line DG75. MATERIAL AND METHODS A plasmid (pcDNA3.1(+)) containing the CD21 gene driven under CMV promoter was constructed. The plasmid was stably transfected into a human B lymphoma cell line DG75 for cellular surface CD21 expression, and flow cytometry was used to monitor CD21 expression. CD21+ cells in the stable cell line were purified using anti CD21 antibody-coupled Dynabeads for CD21-mediated antigen presentation experiment. RESULTS The percentage of CD21+ cells in newly generated stable DG75 pcDNA3.1(+)-CD21 cells was only 6.5% as determined by flow cytometry, which was unexpected and did not fit the requirements for further experiments. However, CD21+ cells could be purified to 100% using anti-CD21 antibody-coupled beads. The percentage of CD21+ cells in purified cells can be kept at 95%, 82%, 42%, 15%, and 42% at 7 d, 14 d, 34 d, and 42 d after purification, respectively. Specific T cell response against CD21-mediated antigen presentation can be activated successfully only when surface CD21 expression remains high. CONCLUSIONS A commonly down-regulated CMV promoter can be used to drive ectopic gene expression at a high-level in stable cell lines. Our results should facilitate future experimental design using other down-regulated promoters containing vectors such as SV40 and PGK1. PMID- 29244784 TI - Factors associated to inpatient mortality rates in type-2-diabetic patients: a cross-sectional analytical study in three Peruvian hospitals. AB - INTRODUCTION: Diabetes mortality has increased in recent years. In Peru, there are few studies on in-hospital mortality due to type 2 diabetes in the provinces. OBJECTIVE: To determine factors associated to hospital mortality in patients with diabetes mellitus type 2 in three hospitals from Cusco-Peru. METHODS: An analytical cross-sectional study was performed. All patients with diabetes mellitus type 2 hospitalized in the city of Cusco during the 2016 were included. Socio-educational and clinical characteristics were evaluated, with "death" as the variable of interest. The crude (cPR) and adjusted (aPR) prevalence ratios were estimated using generalized linear models with Poisson family and log link function, with their respective 95% confidence intervals (95% CI). The values p <0.05 were considered significant. RESULTS: A total of 153 patients were studied; 33.3% (51) died in the hospital. The mortality rate increased when the following factors were associated: age of the patients increased the mortality rate by one year increments (aPR: 1.02; CI95%: 1.01-1.03; p<0.001); to have been admitted by the emergency service (aPR: 1.93; CI95%: 1.34-2.77; p<0.001); being a patient who is readmitted to the hospital (aPR: 2.01; CI95%: 1.36-2.98; p<0.001); and patients who have had a metabolic in-hospital complication (aPR: 1.61; CI95%: 1.07-2.43; p=0.024) or renal in-hospital complications (aPR: 1.47; CI95%: 1.30 1.67; p<0.001). Conversely, the mortality rate was reduced when admission was due to a urinary tract infection (aPR: 0.50; CI95%: 0.35-0.72; p<0.001); adjusted by seven variables. CONCLUSIONS: A third of hospitalized diabetes mellitus type 2 patients died during the study period. Mortality was increased as age rises, patients admitted through emergency rooms, patients who were readmitted to the hospital, and patients who had metabolic or renal complications. Patients admitted for a urinary tract infection had a lower mortality rate. PMID- 29244785 TI - Co-authorship and scientific collaboration networks in Medwave. AB - Scientific collaboration between researchers is one of the most important aspects in the evolution of science helping promote the quality of the studies that are carried out. In turn, it determines an increase in citations when research results are published in scholarly journals. It is interesting to explore the dynamics of scientific collaboration networks regarding co-authorship of scientific articles published in Medwave from January 2014 to September of 2017 and indexed in PubMed/MEDLINE. The largest collaboration networks occurred among authors Rada G, Corsi O and Pena J; and, at universities and healthcare centers level, in the Faculty of Medicine belonging to the Pontificia Universidad Catolica de Chile located in Santiago, Chile. PMID- 29244786 TI - Functional assessment as a predictor of cognitive impairment: a retrospective cohort study. AB - INTRODUCTION: It is estimated that major neurocognitive disorders will affect 115.4 million people by 2050, representing a significant financial burden for society. Likewise, functional dependence for basic or instrumental activities of daily life is usually a consequence of the greater prevalence of disabling pathologies, and of the progressive decrease of the physiological reserve due to aging. OBJECTIVES: To determine the ratio between the functional test and prediction of deterioration of cognitive function in geriatric patients. To determine which factors are associated with decreased cognitive functions in elderly patients. METHODS: This is a retrospective cohort study. We included participants who attended the Geriatrics Outpatient Services of the Naval Medical Center of Peru from 2010 to 2014. Two groups were formed, the first comprised those who presented physiological loss of cognitive functions, defined as the decrease less than 4.1 points in the score of the Mini Mental State Examination during follow-up and a second group who had a pathological loss of cognitive functions, defined as a decrease of 4.2 points in average or more in the Mini Mental State Examination score during follow-up. Patients were followed for four years, performing functional evaluations, as well as collecting data on comorbidities and sociodemographic factors. RESULTS: We included 368 patients, whose mean age was 75.8 years and 50.91% male. Female gender (53.72%), poor education (62.81%), and comorbidities were statistically more frequent in the pathological cognitive decline group. Functional assessment variables had a worse disease progress through follow-up in the group with pathological disease progress of the Mini Mental State Examination score, including Timed Up and Go Test. CONCLUSIONS: Score values of Timed Up and Go Test manage to predict the risk of a pathological decrease in Mini Mental State Examination regardless of sociodemographic factors, comorbidities, and functional assessment. PMID- 29244787 TI - Loss of podocalyxin causes a novel syndromic type of congenital nephrotic syndrome. AB - Many cellular structures directly imply specific biological functions. For example, normal slit diaphragm structures that extend from podocyte foot processes ensure the filtering function of renal glomeruli. These slits are covered by a number of surface proteins, such as nephrin, podocin, podocalyxin and CD2AP. Here we report a human patient presenting with congenital nephrotic syndrome, omphalocele and microcoria due to two loss-of-function mutations in PODXL, which encodes podocalyxin, inherited from each parent. This set of symptoms strikingly mimics previously reported mouse Podxl-/- embryos, emphasizing the essential function of PODXL in mammalian kidney development and highlighting this patient as a human PODXL-null model. The results underscore the utility of current genomics approaches to provide insights into the genetic mechanisms of human disease traits through molecular diagnosis. PMID- 29244788 TI - Dual modulation of human hepatic zonation via canonical and non-canonical Wnt pathways. AB - The hepatic lobule is divided into three zones along the portal-central vein axis. Hepatocytes within each zone exhibit a distinctive gene expression profile that coordinates their metabolic compartmentalization. The zone-dependent heterogeneity of hepatocytes has been hypothesized to result from the differential degree of exposure to oxygen, nutrition and gut-derived toxins. In addition, the gradient of Wnt signaling that increases towards the central vein seen in rodent models is believed to play a critical role in shaping zonation. Furthermore, hepatic zonation is coupled to the site of the homeostatic renewal of hepatocytes. Despite its critical role, the regulatory mechanisms that determine the distinctive features of zonation and its relevance to humans are not well understood. The present study first conducted a comprehensive zone dependent transcriptome analysis of normal human liver using laser capture microdissection. Upstream pathway analysis revealed the signatures of host responses to gut-derived toxins in the periportal zone, while both the canonical Wnt pathway and the xenobiotic response pathway govern the perivenular zone. Furthermore, we found that the hypoxic environment of the perivenular zone promotes Wnt11 expression in hepatocytes, which then regulates unique gene expression via activation of the non-canonical Wnt pathway. In summary, our study reports the comprehensive zonation-dependent transcriptome of the normal human liver. Our analysis revealed that the LPS response pathway shapes the characteristics of periportal hepatocytes. By contrast, the perivenular zone is regulated by a combination of three distinct pathways: the xenobiotic response pathway, canonical Wnt signaling, and hypoxia-induced noncanonical Wnt signaling. PMID- 29244789 TI - Pigment epithelium-derived factor from ARPE19 promotes proliferation and inhibits apoptosis of human umbilical mesenchymal stem cells in serum-free medium. AB - Clinical expansion of mesenchymal stem cells (MSCs) is hampered by the lack of knowledge regarding how to prevent MSC apoptosis and promote their proliferation in serum-free medium. Our in vitro studies demonstrated that human umbilical cord MSCs (HUCMSCs) underwent apoptosis in the serum-free medium. When HUCMSCs were co cultured with retinal pigment epithelial cells (ARPE19), however, HUCMSCs exhibited normal growth and morphology in serum-free medium. Their colony formation was promoted by the conditioned medium (CM) of ARPE19 cells on Matrigel. Proteomics analysis showed that pigment epithelium-derived factor (PEDF) was one of the most abundant extracellular proteins in the ARPE19 CM, whereas enzyme-linked immunosorbent assay confirmed that large amounts of PEDF was secreted from ARPE19 cells. Adding anti-PEDF-blocking antibodies to the co culture of HUCMSCs with ARPE19 cells increased apoptosis of HUCMSCs. Conversely, treatment with PEDF significantly reduced apoptosis and increased proliferation of HUCMSCs in serum-free medium. PEDF was further demonstrated to exert this anti apoptotic effect by inhibiting P53 expression to suppress caspase activation. In vivo studies demonstrated that co-injection of HUCMSCs with ARPE19 cells in immunocompromised NOD-SCID mice also increased survival and decreased apoptosis of HUCMSCs. PEDF also showed no negative effect on the mesoderm differentiation capability of HUCMSCs. In conclusion, this study is the first to demonstrate that PEDF promotes HUCMSC proliferation and protects them from apoptosis by reducing p53 expression in the serum-free medium. This study provides crucial information for clinical-scale expansion of HUCMSCs. PMID- 29244791 TI - Management and outcomes of childhood Goodpasture's disease. AB - BackgroundIn an attempt to improve knowledge about childhood Goodpasture's disease, we performed a retrospective analysis of patients with Goodpasture's disease from several pediatric nephrology centers.MethodsWe analyzed the responses to 27 questions that elicited information about the following: incidence, demographics, patient history and clinical presentation, diagnostics performed, acute and chronic therapy, course of disease, and outcome.ResultsGoodpasture's disease, which is extremely rare in this age group, may manifest in 2-year-old toddlers and does not typically present with pulmonary findings before puberty. Goodpasture's disease has a poor outcome with more than 50% of patients progressing to end-stage renal disease. No deaths were reported in this cohort, and renal improvement was observed in children with severe biopsy findings who required renal replacement therapy during the acute phase.ConclusionThe present investigation gives detailed information about childhood Goodpasture's disease under real-life conditions and reveals that very few pediatric cases have been reported. Nearly 50% of children progressed to end stage renal disease. However, long-term outcome in children might be better than in adults. Aggressive immunosuppressive therapy might be necessary for all affected children, even in patients who require renal replacement therapy or have severe biopsy findings. PMID- 29244792 TI - Tight glycemic control in critically ill pediatric patients: a meta-analysis and systematic review of randomized controlled trials. AB - BackgroundThere still are controversies in the impact of tight glycemic control (TGC) in critically ill children. The aim of this study was to assess the benefits and risks of TGC compared with conventional glycemic control (CGC) in critically ill pediatric patients admitted to the pediatric intensive care unit (PICU) by using the data retrieved from randomized controlled trials (RCTs).MethodsEMBASE, CNKI, PubMed, and the Cochrane Database were searched for RCTs comparing TGC with CGC in critically ill children in PICU.ResultsThe meta analysis included 5 RCTs representing 3,933 patients that compared TGC with CGC. Our result revealed that TGC did not reduce 30-day mortality rates (odds ratio (OR) 0.99, 95% confidence interval (CI) 0.74-1.32, P=0.95) and was not associated with decreasing health care-associated infections (OR 0.80, 95% CI 0.64-1.00, P=0.05) compared with CGC, but significantly increased the incidence of hypoglycemia (OR 6.37, 95% CI 4.41-9.21, P<0.001).ConclusionTight glycemic control was not associated with reducing 30-day mortality rates and acquired infections compared with CGC in critically ill children. Significant increase of incidence of hypoglycemia was revealed in TGC group. The conclusion should be interpreted with caution for the methodological heterogeneity among trials. PMID- 29244793 TI - Effects of epinephrine on hemodynamic changes during cardiopulmonary resuscitation in a neonatal piglet model. AB - BackgroundAsphyxia is the most common reason for newborns to fail to make a successful fetal-to-neonatal transition. There is currently a lack of data evaluating hemodynamic effects of epinephrine during neonatal cardiopulmonary resuscitation.MethodsTwenty-four newborn piglets were exposed to asphyxia. Thereafter, positive pressure ventilation was commenced for 30 s, followed by chest compressions (CC). Piglets were randomized into three experimental groups: 3:1 compression:ventilation ratio; CC during sustained inflation (SI) at a rate of 90 CC per minute, or CC during SI at a rate of 120 CC per minute. Epinephrine (0.01 mg/kg per dose) was administered to a maximum of four doses. Hemodynamic parameters were measured throughout the experiment.ResultsAnimals were divided into survivors and nonsurvivors. End-diastolic and developed pressures declined after epinephrine administration in the survivor group. dp/dt min was significantly higher in the survivor group whereas dp/dt max showed no significant differences. Epinephrine had no effect on either heart rate or cardiac output in both groups. Ejection fraction increased after epinephrine with no significant difference between groups.ConclusionEpinephrine did not affect survival rates or return of spontaneous circulation in our postnatal porcine model of neonatal asphyxia. PMID- 29244790 TI - Lentivirus-mediated silencing of the PTC1 and PTC2 genes promotes recovery from spinal cord injury by activating the Hedgehog signaling pathway in a rat model. AB - This study aimed to investigate the effect of Patched-1 (PTC1) and PTC2 silencing in a rat model, on Hedgehog (Hh) pathway-mediated recovery from spinal cord injury (SCI). An analytical emphasis on the relationship between the sonic hedgehog (Shh) pathway and nerve regeneration was explored. A total of 126 rats were divided into normal, sham, SCI, negative control (NC), PTC1-RNAi, PTC2-RNAi and PTC1/PTC2-RNAi groups. The Basso, Beattie and Bresnahan (BBB) scale was employed to assess hind limb motor function. Quantitative real-time polymerase chain reaction and western blotting were performed to examine the mRNA and protein levels of PTC1, PTC2, Shh, glioma-associated oncogene homolog 1 (Gli-1), Smo and Nestin. Tissue morphology was analyzed using immunohistochemistry, and immunofluorescent staining was conducted to detect neurofilament protein 200 (NF 200) and glial fibrillary acidic protein (GFAP). The PTC1/PTC2-RNAi group displayed higher BBB scores than the SCI and NC groups. Shh, Gli-1, Smo and Nestin expression levels were elevated in the PTC1/PTC2-RNAi group. PTC1 and PTC2 mRNA and protein expression was lower in the PTC1/PTC2-RNAi group than in the normal, sham and SCI groups. Among the seven groups, the PTC1/PTC2-RNAi group had the largest positive area of NF-200 staining, whereas the SCI group exhibited a larger GFAP-positive area than both the normal and the sham groups. The Shh pathway may provide new insights into therapeutic indications and regenerative recovery tools for the treatment of SCI. Activation of the Hh signaling pathway by silencing PTC1 and PTC2 may reduce inflammation and may ultimately promote SCI recovery. PMID- 29244794 TI - Health implications of dietary habits in transition countries-a life course perspective. PMID- 29244795 TI - Jack Widness: the importance of connections. PMID- 29244796 TI - RSV vs. rhinovirus bronchiolitis: difference in nasal airway microRNA profiles and NFkappaB signaling. AB - BackgroundAlthough rhinovirus infection is associated with increased risks of acute and chronic respiratory outcomes during childhood compared with respiratory syncytial virus (RSV), the underlying mechanisms remain unclear. We aimed to determine the differences in nasal airway microRNA profiles and their downstream effects between infants with rhinovirus and RSV bronchiolitis.MethodsAs part of a multicenter cohort study of infants hospitalized for bronchiolitis, we examined nasal samples obtained from 16 infants with rhinovirus and 16 infants with RSV. We tested nasal airway samples using microarrays to profile global microRNA expression and determine the predicted regulation of targeted transcripts. We also measured gene expression and cytokines for NFkappaB pathway components.ResultsBetween the virus groups, 386 microRNAs were differentially expressed (false discovery rate (FDR)<0.05). In infants with rhinovirus, the NFkappaB pathway was highly ranked as a predicted target for these differentially expressed microRNAs compared with RSV. Pathway analysis using measured mRNA expression data validated that rhinovirus infection had upregulation of NFkappaB family (RelA and NFkappaB2) and downregulation of inhibitor kappaB family. Infants with rhinovirus had higher levels of NFkappaB-induced type-2 cytokines (IL-10 and IL-13; FDR<0.01).ConclusionIn infants with bronchiolitis, rhinovirus and RSV infections had different nasal airway microRNA profiles associated with NFkappaB signaling. PMID- 29244797 TI - Association between maternal hypothyroidism and autism spectrum disorders in children. AB - BackgroundTo determine whether hypothyroidism is associated with autism spectrum disorders (ASD) and how this association is influenced by race-ethnicity, sex, and timing of exposure.MethodsA retrospective cohort study was conducted using records from 397,201 children who were delivered from 1991 to 2011 and remained health plan members from 1993 to 2014.ResultsChildren of hypothyroid women had higher ASD rates than children of women without the diagnosis (2.14 vs. 1.62/1,000 person-years; adjusted hazard ratios (adj.HR), 1.31; 95% confidence interval (CI), 1.13-1.53). This occurred in women diagnosed before as well as during pregnancy. Maternal hypothyroidism was associated with ASD for both boys (3.93 vs. 2.62/1,000 person-years; adj.HR, 1.27; 95% CI, 1.07-1.50) and girls (1.10 vs. 0.61/1,000 person-years; adj.HR, 1.51; 95% CI, 1.10-2.08). Of women with a diagnosis of hypothyroidism during pregnancy, normal thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels were not associated with an increased risk of ASD in children. Compared with white children, prenatal hypothyroidism was associated with an increased risk of ASD in children of Hispanics (adj.HR, 1.09; 95% CI, 1.01-1.17) and women of other/mixed race ethnicity (adj.HR, 1.08; 95% CI, 1.00-1.16).ConclusionMaternal hypothyroidism is associated with ASD in children in a manner dependent on race-ethnicity. Management of maternal hypothyroidism may ameliorate the risk of ASD. PMID- 29244798 TI - Amplitude-integrated electroencephalography during the first 72 h after birth in neonates diagnosed prenatally with congenital heart disease. AB - BackgroundLittle is known on amplitude-integrated electroencephalography (aEEG) during the first few days after birth in neonates with congenital heart disease (CHD). Our aim was, therefore, to assess electrocortical activity using aEEG within the first 72 h after birth in neonates diagnosed prenatally with CHD, and to define independent prenatal and postnatal predictors for abnormal aEEG.MethodsNeonates with CHD who were admitted to the neonatal intensive care unit between 2010 and 2017 were retrospectively included. We assessed aEEG background patterns, sleep-wake cycling, and epileptic activity during the first 72 h after birth and defined prenatal and postnatal clinical parameters associated with aEEG patterns.ResultsSeventy-two neonates were included. Twenty six (36%) had mildly abnormal and six (8%) had severely abnormal aEEG background patterns at some point during the study period. Sleep-wake cycling was present in 97% of the neonates. Subclinical seizures were common (15%), whereas none of the neonates had clinical seizures. Only treatment with sedatives was a significant predictor for abnormal aEEG background patterns, explaining 56% of the variance.ConclusionAbnormal aEEG background patterns are common and are strongly associated with treatment with sedatives in neonates with prenatally diagnosed CHD. Future studies should assess the association between early postnatal aEEG abnormalities and neurodevelopmental outcome. PMID- 29244799 TI - Prenatal and early postnatal measures of brain development and childhood sleep patterns. AB - BackgroundBrain development underlies maturation of sleep patterns throughout childhood. Intrauterine head growth-marker of early neurodevelopment-has not been associated with childhood sleep characteristics. We explored associations between ultrasonographic measures of prenatal and early postnatal neurodevelopment and childhood sleep.MethodsA total of 6,808 children from a population-based birth cohort (Generation R) were included. Head circumference (HC) and lateral ventricles size were assessed with mid- and late-pregnancy fetal ultrasounds, and with cranial ultrasound 3-20 weeks postnatally. Mothers reported children's sleep duration at 2 and 3 years, and sleep problems at 1.5, 3, and 6 years.ResultsLarger ventricular size, but not HC, was related to longer sleep duration at 3 years (beta=0.06 h, 95% confidence interval (CI): 0.02; 0.10 in late-pregnancy and beta=0.11 h, 95% CI: 0.02; 0.20 in early infancy, mid pregnancy parameters were unrelated to sleep duration). Larger HC in mid pregnancy was associated with a reduced risk for being a "problematic sleeper" up to the age of 6 years (odds ratio (OR): 0.94, 95% CI: 0.89; 0.99). Consistently, children with larger HC in early infancy were less likely to be "problematic sleepers" at 3 and 6 years.ConclusionsThis study shows that variations in fetal and neonatal brain size may underlie behavioral expression of sleep in childhood. Albeit small effect estimates, these associations provide evidence for neurodevelopmental origins of sleep. PMID- 29244801 TI - Hope vs. caution: ethical and regulatory considerations for neonatal stem cell therapies. PMID- 29244800 TI - HLA-DQ genetics in children with celiac disease: a meta-analysis suggesting a two step genetic screening procedure starting with HLA-DQ beta chains. AB - BackgroundSpecific HLA-DQ genes have been recognized as necessary - but not sufficient - factors for the occurrence of Celiac Disease (CD). Through a meta analysis, evaluating the distribution of CD-related HLA genotypes in children, we aimed at providing insights for a potential widened screening strategy.MethodsAfter a systematic search on the association between class II HLA genes and CD in children, 46 publications were obtained and assessed for eligibility. A total of 13 eligible studies were submitted to data extraction and analysis (10 case-control studies and 3 cohort studies). Case-control studies collectively enrolled 740 CD patients and 943 controls.ResultsIn the population stratified analysis, the following alleles conferred a significantly increased risk for CD: HLA-DQB1*02 (odds ratio [OR]=10.28) and HLA-DQB1*03:02 (OR=2.24). By drafting a risk gradient to develop CD according to HLA genetic background, the highest risk is confirmed to exist for DQ2/DQ2 homozygous subjects, regardless of the ethnicities (OR=5.4). Actually, the genotype DQ2/beta2 showed basically the same risk (OR=5.3). Indeed, no differences have been found in CD risk between DQ2/beta2 and DQ2/DQ2, as well as between DQ8/beta2 and DQ2/DQ8, and between beta2/DQX and DQ2/X.ConclusionThe HLA-DQB1*02:01 allele is present in more than 90% CD children. In the perspective of a widened pediatric population screening for CD, a double-step process might be suggested: HLA-DQB1*02:01 might be investigated first and, only if this result is positive, children might be candidate for a prospective serologic screening, as a second step. PMID- 29244802 TI - Elevations of inflammatory proteins in neonatal blood are associated with obesity and overweight among 2-year-old children born extremely premature. AB - BackgroundChildhood obesity is associated with elevated blood concentrations of inflammation markers. It is not known to what extent inflammation precedes the development of obesity.MethodsIn a cohort of 882 infants born before 28 weeks of gestation, we examined relationships between concentrations of 25 inflammation related proteins in blood obtained during the first two postnatal weeks and body mass index at 2 years of age.ResultsAmong children delivered for spontaneous indications (n=734), obesity was associated with elevated concentrations of four proteins (IL-1beta, IL-6, TNF-R1, and MCP-1) on the first postnatal day; one protein (IL-6) on postnatal day 7; and two proteins (ICAM-3 and VEGF-R1) on postnatal day 14. Among children delivered for maternal or fetal indications (n=148), obesity was associated with elevated concentrations of seven proteins on the 14th postnatal day. In multivariable models in the spontaneous indications subsample, elevated IL-6 on day 1 predicted obesity (odds ratio: 2.9; 95% confidence limits: 1.2, 6.8), whereas elevated VCAM-1 on day 14 predicted overweight at 2 years of age (odds ratio: 2.3; 95% confidence limits: 1.2, 4.3).ConclusionsIn this cohort, neonatal systemic inflammation preceded the onset of obesity, suggesting that inflammation might contribute to the development of obesity. PMID- 29244803 TI - Changes in brain morphology and microstructure in relation to early brain activity in extremely preterm infants. AB - Background and ObjectiveTo investigate the relation of early brain activity with structural (growth of the cortex and cerebellum) and white matter microstructural brain development.MethodsA total of 33 preterm neonates (gestational age 26+/-1 weeks) without major brain abnormalities were continuously monitored with electroencephalography during the first 48 h of life. Rate of spontaneous activity transients per minute (SAT rate) and inter-SAT interval (ISI) in seconds per minute were calculated. Infants underwent brain magnetic resonance imaging ~30 (mean 30.5; min: 29.3-max: 32.0) and 40 (41.1; 40.0-41.8) weeks of postmenstrual age. Increase in cerebellar volume, cortical gray matter volume, gyrification index, fractional anisotropy (FA) of posterior limb of the internal capsule, and corpus callosum (CC) were measured.ResultsSAT rate was positively associated with cerebellar growth (P=0.01), volumetric growth of the cortex (P=0.027), increase in gyrification (P=0.043), and increase in FA of the CC (P=0.037). ISI was negatively associated with cerebellar growth (P=0.002).ConclusionsIncreased early brain activity is associated with cerebellar and cortical growth structures with rapid development during preterm life. Higher brain activity is related to FA microstructural changes in the CC, a region responsible for interhemispheric connections. This study underlines the importance of brain activity for microstructural brain development. PMID- 29244805 TI - Tongue-driven sonar beam steering by a lingual-echolocating fruit bat. AB - Animals enhance sensory acquisition from a specific direction by movements of head, ears, or eyes. As active sensing animals, echolocating bats also aim their directional sonar beam to selectively "illuminate" a confined volume of space, facilitating efficient information processing by reducing echo interference and clutter. Such sonar beam control is generally achieved by head movements or shape changes of the sound-emitting mouth or nose. However, lingual-echolocating Egyptian fruit bats, Rousettus aegyptiacus, which produce sound by clicking their tongue, can dramatically change beam direction at very short temporal intervals without visible morphological changes. The mechanism supporting this capability has remained a mystery. Here, we measured signals from free-flying Egyptian fruit bats and discovered a systematic angular sweep of beam focus across increasing frequency. This unusual signal structure has not been observed in other animals and cannot be explained by the conventional and widely-used "piston model" that describes the emission pattern of other bat species. Through modeling, we show that the observed beam features can be captured by an array of tongue-driven sound sources located along the side of the mouth, and that the sonar beam direction can be steered parsimoniously by inducing changes to the pattern of phase differences through moving tongue location. The effects are broadly similar to those found in a phased array-an engineering design widely found in human-made sonar systems that enables beam direction changes without changes in the physical transducer assembly. Our study reveals an intriguing parallel between biology and human engineering in solving problems in fundamentally similar ways. PMID- 29244804 TI - Conditional knockout mice for the distal appendage protein CEP164 reveal its essential roles in airway multiciliated cell differentiation. AB - Multiciliated cells of the airways, brain ventricles, and female reproductive tract provide the motive force for mucociliary clearance, cerebrospinal fluid circulation, and ovum transport. Despite their clear importance to human biology and health, the molecular mechanisms underlying multiciliated cell differentiation are poorly understood. Prior studies implicate the distal appendage/transition fiber protein CEP164 as a central regulator of primary ciliogenesis; however, its role in multiciliogenesis remains unknown. In this study, we have generated a novel conditional mouse model that lacks CEP164 in multiciliated tissues and the testis. These mice show a profound loss of airway, ependymal, and oviduct multicilia and develop hydrocephalus and male infertility. Using primary cultures of tracheal multiciliated cells as a model system, we found that CEP164 is critical for multiciliogenesis, at least in part, via its regulation of small vesicle recruitment, ciliary vesicle formation, and basal body docking. In addition, CEP164 is necessary for the proper recruitment of another distal appendage/transition fiber protein Chibby1 (Cby1) and its binding partners FAM92A and FAM92B to the ciliary base in multiciliated cells. In contrast to primary ciliogenesis, CEP164 is dispensable for the recruitment of intraflagellar transport (IFT) components to multicilia. Finally, we provide evidence that CEP164 differentially controls the ciliary targeting of membrane associated proteins, including the small GTPases Rab8, Rab11, and Arl13b, in multiciliated cells. Altogether, our studies unravel unique requirements for CEP164 in primary versus multiciliogenesis and suggest that CEP164 modulates the selective transport of membrane vesicles and their cargoes into the ciliary compartment in multiciliated cells. Furthermore, our mouse model provides a useful tool to gain physiological insight into diseases associated with defective multicilia. PMID- 29244806 TI - Cellular selectivity of AAV serotypes for gene delivery in neurons and astrocytes by neonatal intracerebroventricular injection. AB - The non-pathogenic parvovirus, adeno-associated virus (AAV), is an efficient vector for transgene expression in vivo and shows promise for treatment of brain disorders in clinical trials. Currently, there are more than 100 AAV serotypes identified that differ in the binding capacity of capsid proteins to specific cell surface receptors that can transduce different cell types and brain regions in the CNS. In the current study, multiple AAV serotypes expressing a GFP reporter (AAV1, AAV2/1, AAVDJ, AAV8, AAVDJ8, AAV9, AAVDJ9) were screened for their infectivity in both primary murine astrocyte and neuronal cell cultures. AAV2/1, AAVDJ8 and AAV9 were selected for further investigation of their tropism throughout different brain regions and cell types. Each AAV was administered to P0-neonatal mice via intracerebroventricular injections (ICV). Brains were then systematically analyzed for GFP expression at 3 or 6 weeks post-infection in various regions, including the olfactory bulb, striatum, cortex, hippocampus, substantia nigra (SN) and cerebellum. Cell counting data revealed that AAV2/1 infections were more prevalent in the cortical layers but penetrated to the midbrain less than AAVDJ8 and AAV9. Additionally, there were differences in the persistence of viral transgene expression amongst the three serotypes examined in vivo at 3 and 6 weeks post-infection. Because AAV-mediated transgene expression is of interest in neurodegenerative diseases such as Parkinson's Disease, we examined the SN with microscopy techniques, such as CLARITY tissue transmutation, to identify AAV serotypes that resulted in optimal transgene expression in either astrocytes or dopaminergic neurons. AAVDJ8 displayed more tropism in astrocytes compared to AAV9 in the SN region. We conclude that ICV injection results in lasting expression of virally encoded transgene when using AAV vectors and that specific AAV serotypes are required to selectively deliver transgenes of interest to different brain regions in both astrocytes and neurons. PMID- 29244807 TI - Socioeconomic position and ten-year survival and virologic outcomes in a Ugandan HIV cohort receiving antiretroviral therapy. AB - Lifelong ART is essential to reducing HIV mortality and ending the epidemic, however the interplay between socioeconomic position and long-term outcomes of HIV-infected persons receiving antiretroviral therapy (ART) in sub-Saharan Africa is unknown. Furthering the understanding of factors related to long-term ART outcomes in this important region will aid the successful scale-up of ART programs. We enrolled 559 HIV-infected Ugandan adults starting ART in 2004-2005 at the Infectious Diseases Institute in Kampala, Uganda and followed them for 10 years. We documented baseline employment status, regular household income, education level, housing description, physical ability, and CD4 count. Viral load was measured every six months. Proportional hazard regression tested for associations between baseline characteristics and 1) mortality, 2) virologic failure, and 3) mortality or virologic failure as a composite outcome. Over ten years 23% (n = 127) of participants died, 6% (n = 31) were lost-to-follow-up and 23% (107/472) experienced virologic treatment failure. In Kaplan-Meier analysis we observed an association between employment and mortality, with the highest cumulative probability of death occurring in unemployed individuals. In univariate analysis unemployment and disease severity were associated with mortality, but in multivariable analysis the only association with mortality was disease severity. We observed an association between higher household income and an increased incidence of both virologic failure and the combined outcome, and an association between self-employment and lower incidence of virologic failure and the combined outcome when compared to unemployment. Formal education level and housing status were unrelated to outcomes. It is feasible to achieve good ten year survival, retention-in-care, and viral suppression in a socioeconomically diverse population in a resource-limited setting. Unemployment appears to be related to adverse 10-year ART outcomes. A low level of formal education does not appear to be a barrier to successful long-term ART. PMID- 29244808 TI - FGMD: A novel approach for functional gene module detection in cancer. AB - With the increasing availability of multi-dimensional biological datasets for the same samples (i.e., gene expression, microRNAs, copy numbers, mutations, methylations), it has now become possible to systematically understand the regulatory mechanisms operating in a cancer cell. For this task, it is important to discover a set of co-expressed genes with functions, representing a so-called functional gene module, because co-expressed genes tend to be co-regulated by the same regulators, including transcription factors, microRNAs, and copy number aberrations. Several algorithms have been used to identify such gene modules, including hierarchical clustering and non-negative matrix factorization. Although these algorithms have been applied to many microarray datasets, only a few systematic analyses of these algorithms have been performed for RNA-sequencing (RNA-Seq) data to date. Although gene expression levels determined based on microarray and RNA-Seq datasets tend to be highly correlated, the expression levels of some genes differ depending on the platforms used for analysis, which may result in the construction of different gene modules for the same samples. Here, we compare several module detection algorithms applied to both microarray and RNA-seq datasets. We further propose a new functional gene module detection algorithm (FGMD), which is based on a hierarchical clustering algorithm that was modified to reflect actual biological observations, including the fact that a single gene may be involved in multiple biological pathways. Application of existing algorithms and the new FGMD algorithm to breast cancer and ovarian cancer datasets from The Cancer Genome Atlas showed that the FGMD algorithm had the best performance for most of the functional pathway enrichment tests and in the transcription factor enrichment test. We expect that the FGMD algorithm will contribute to improving the identification of functional gene modules related to cancer. PMID- 29244809 TI - HIV-1 viraemia and drug resistance amongst female sex workers in Soweto, South Africa: A cross sectional study. AB - BACKGROUND: HIV drug resistance (HIVDR) poses a threat to future antiretroviral therapy success. Monitoring HIVDR patterns is of particular importance in populations such as sex workers (SWs), where documented HIV prevalence is between 34-89%, and in countries with limited therapeutic options. Currently in South Africa, there is a dearth in evidence and no ongoing surveillance of HIVDR amongst sex work populations. This study aims to describe the prevalence of HIVDR amongst a sample of female sex workers (FSWs) from Soweto, South Africa. METHODOLOGY: A cross-sectional, respondent driven sampling (RDS) recruitment methodology was used to enrol FSWs based in Soweto. Participants were tested for HIV and undertook a survey that included HIV knowledge and treatment status. Whole blood specimens were collected from HIV positive FSWs to measure for CD4 counts, viral load (VL) and perform HIVDR genotyping. Frequencies were determined for categorical variables and medians and interquartile ranges (IQR) for the continuous. RESULTS: Of the 508 enrolled participants, 55% (n = 280) were HIV positive and of median age 32 (IQR: 20-51) years. Among the HIV positive, 51.8% (132/269) were defined as virologically suppressed (VL < 400 copies/ml). Of the 119 individuals with unsuppressed viral loads who were successfully genotyped for resistance testing 37.8% (45/119) had detectable drug resistance. In this group, HIVDR mutations were found amongst 73.7% (14/19) of individuals on treatment, 27.4% (26/95) of individuals who were treatment naive, and 100% (5/5) of defaulters. One phylogenetic cluster was found amongst treatment naive FSWs. The K103N mutation was detected most commonly in 68.9% (31/45) individuals with HIVDR mutations, with 20/26 (76.9%) of treatment naive FSW with detectable resistance having this mutation. The M184V mutation was found in both FSWs on treatment (12/14, 85.7%) and those defaulting (1/5, 20.0%). DISCUSSION: More than one third (45/119) of the genotyped sample had HIVDR, with resistance to the NNRTI class being the most common. Almost half of HIV positive FSWs had unsuppressed viral loads, increasing the likelihood for onward transmission of HIV. Disturbingly, more than 1:4 treatment naive women with unsuppressed viral loads had HIVDR suggesting that possible sexual transmission of drug resistance is occurring in this high-risk population. Given the high burden of HIVDR in a population with a high background prevalence of HIV, it is imperative that routine monitoring of HIVDR be implemented. Understanding transmission dynamics of HIVDR in FSW and its impact on treatment success should be urgently elucidated. PMID- 29244810 TI - Synaptic augmentation in a cortical circuit model reproduces serial dependence in visual working memory. AB - Recent work has established that visual working memory is subject to serial dependence: current information in memory blends with that from the recent past as a function of their similarity. This tuned temporal smoothing likely promotes the stability of memory in the face of noise and occlusion. Serial dependence accumulates over several seconds in memory and deteriorates with increased separation between trials. While this phenomenon has been extensively characterized in behavior, its neural mechanism is unknown. In the present study, we investigate the circuit-level origins of serial dependence in a biophysical model of cortex. We explore two distinct kinds of mechanisms: stable persistent activity during the memory delay period and dynamic "activity-silent" synaptic plasticity. We find that networks endowed with both strong reverberation to support persistent activity and dynamic synapses can closely reproduce behavioral serial dependence. Specifically, elevated activity drives synaptic augmentation, which biases activity on the subsequent trial, giving rise to a spatiotemporally tuned shift in the population response. Our hybrid neural model is a theoretical advance beyond abstract mathematical characterizations, offers testable hypotheses for physiological research, and demonstrates the power of biological insights to provide a quantitative explanation of human behavior. PMID- 29244811 TI - Impact of increased influenza vaccination in 2-3-year-old children on disease burden within the general population: A Bayesian model-based approach. AB - INTRODUCTION: During the 2013-2014 influenza season, Public Health England extended routine influenza vaccination to all 2- and 3-year-old children in England. To estimate the impact of this change in policy on influenza-related morbidity and mortality, we developed a disease transmission and surveillance model informed by real-world data. METHODS: We combined real-world and literature data sources to construct a model of influenza transmission and surveillance in England. Data were obtained for four influenza seasons, starting with the 2010 2011 season. Bayesian inference was used to estimate model parameters on a season by-season basis to assess the impact of targeting 2- and 3-year-old children for influenza vaccination. This provided the basis for the construction of counterfactual scenarios comparing vaccination rates of ~2% and ~35% in the 2- and 3- year-old population to estimate reductions in general practitioner (GP) influenza-like-illness (ILI) consultations, respiratory hospitalizations and deaths in the overall population. RESULTS: Our model was able to replicate the main patterns of influenza across the four seasons as observed through laboratory surveillance data. Targeting 2- and 3-year-old children for influenza vaccination resulted in reductions in the general population of between 6.2-9.9% in influenza attributable GP ILI consultations, 6.1-10.7% in influenza-attributable respiratory hospitalizations, and 5.7-9.4% in influenza-attributable deaths. The decrease in influenza-attributable ILI consultations represents a reduction of between 4.5% and 7.3% across all ILI consultations. The reduction in influenza attributable respiratory hospitalizations represents a reduction of between 1.2% and 2.3% across all respiratory hospitalizations. Reductions in influenza attributable respiratory deaths represent a reduction of between 0.9% and 2.4% in overall respiratory deaths. CONCLUSION: This study has provided evidence that extending routine influenza vaccination to all healthy children aged 2 and 3 years old leads to benefits in terms of reduced utilization of healthcare resources and fewer respiratory health outcomes and deaths. PMID- 29244812 TI - Optimal occlusion uniformly partitions red blood cells fluxes within a microvascular network. AB - In animals, gas exchange between blood and tissues occurs in narrow vessels, whose diameter is comparable to that of a red blood cell. Red blood cells must deform to squeeze through these narrow vessels, transiently blocking or occluding the vessels they pass through. Although the dynamics of vessel occlusion have been studied extensively, it remains an open question why microvessels need to be so narrow. We study occlusive dynamics within a model microvascular network: the embryonic zebrafish trunk. We show that pressure feedbacks created when red blood cells enter the finest vessels of the trunk act together to uniformly partition red blood cells through the microvasculature. Using mathematical models as well as direct observation, we show that these occlusive feedbacks are tuned throughout the trunk network to prevent the vessels closest to the heart from short-circuiting the network. Thus occlusion is linked with another open question of microvascular function: how are red blood cells delivered at the same rate to each micro-vessel? Our analysis shows that tuning of occlusive feedbacks increase the total dissipation within the network by a factor of 11, showing that uniformity of flows rather than minimization of transport costs may be prioritized by the microvascular network. PMID- 29244813 TI - A different view on the Necker cube-Differences in multistable perception dynamics between Asperger and non-Asperger observers. AB - BACKGROUND: During observation of the Necker cube perception becomes unstable and alternates repeatedly between a from-above-perspective ("fap") and a from-below perspective ("fbp") interpretation. Both interpretations are physically equally plausible, however, observers usually show an a priori top-down bias in favor of the fap interpretation. Patients with Autism spectrum disorder are known to show an altered pattern of perception with a focus on sensory details. In the present study we tested whether this altered perceptual processing affects their reversal dynamics and reduces the perceptual bias during Necker cube observation. METHODS: 19 participants with Asperger syndrome and 16 healthy controls observed a Necker cube stimulus continuously for 5 minutes and indicated perceptual reversals by key press. We compared reversal rates (number of reversals per minute) and the distributions of dwell times for the two interpretations between observer groups. RESULTS: Asperger participants showed less perceptual reversal than controls. Six Asperger participants did not perceive any reversal at all, whereas all observers from the control group perceived at least five reversals within the five minutes observation time. Further, control participants showed the typical perceptual bias with significant longer median dwell times for the fap compared to the fbp interpretation. No such perceptual bias was found in the Asperger group. DISCUSSION: The perceptual system weights the incomplete and ambiguous sensory input with memorized concepts in order to construct stable and reliable percepts. In the case of the Necker cube stimulus, two perceptual interpretations are equally compatible with the sensory information and internal fluctuations may cause perceptual alternations between them-with a slightly larger probability value for the fap interpretation (perceptual bias). Smaller reversal rates in Asperger observers may result from the dominance of bottom-up sensory input over endogenous top-down factors. The latter may also explain the absence of a fap bias. PMID- 29244814 TI - Forecasting influenza-like illness dynamics for military populations using neural networks and social media. AB - This work is the first to take advantage of recurrent neural networks to predict influenza-like illness (ILI) dynamics from various linguistic signals extracted from social media data. Unlike other approaches that rely on timeseries analysis of historical ILI data and the state-of-the-art machine learning models, we build and evaluate the predictive power of neural network architectures based on Long Short Term Memory (LSTMs) units capable of nowcasting (predicting in "real-time") and forecasting (predicting the future) ILI dynamics in the 2011 - 2014 influenza seasons. To build our models we integrate information people post in social media e.g., topics, embeddings, word ngrams, stylistic patterns, and communication behavior using hashtags and mentions. We then quantitatively evaluate the predictive power of different social media signals and contrast the performance of the-state-of-the-art regression models with neural networks using a diverse set of evaluation metrics. Finally, we combine ILI and social media signals to build a joint neural network model for ILI dynamics prediction. Unlike the majority of the existing work, we specifically focus on developing models for local rather than national ILI surveillance, specifically for military rather than general populations in 26 U.S. and six international locations., and analyze how model performance depends on the amount of social media data available per location. Our approach demonstrates several advantages: (a) Neural network architectures that rely on LSTM units trained on social media data yield the best performance compared to previously used regression models. (b) Previously under explored language and communication behavior features are more predictive of ILI dynamics than stylistic and topic signals expressed in social media. (c) Neural network models learned exclusively from social media signals yield comparable or better performance to the models learned from ILI historical data, thus, signals from social media can be potentially used to accurately forecast ILI dynamics for the regions where ILI historical data is not available. (d) Neural network models learned from combined ILI and social media signals significantly outperform models that rely solely on ILI historical data, which adds to a great potential of alternative public sources for ILI dynamics prediction. (e) Location-specific models outperform previously used location-independent models e.g., U.S. only. (f) Prediction results significantly vary across geolocations depending on the amount of social media data available and ILI activity patterns. (g) Model performance improves with more tweets available per geo-location e.g., the error gets lower and the Pearson score gets higher for locations with more tweets. PMID- 29244815 TI - Analysis of the efficacy of Taiwanese freeze-dried neurotoxic antivenom against Naja kaouthia, Naja siamensis and Ophiophagus hannah through proteomics and animal model approaches. AB - In Southeast Asia, envenoming resulting from cobra snakebites is an important public health issue in many regions, and antivenom therapy is the standard treatment for the snakebite. Because these cobras share a close evolutionary history, the amino acid sequences of major venom components in different snakes are very similar. Therefore, either monovalent or polyvalent antivenoms may offer paraspecific protection against envenomation of humans by several different snakes. In Taiwan, a bivalent antivenom-freeze-dried neurotoxic antivenom (FNAV) against Bungarus multicinctus and Naja atra is available. However, whether this antivenom is also capable of neutralizing the venom of other species of snakes is not known. Here, to expand the clinical application of Taiwanese FNAV, we used an animal model to evaluate the neutralizing ability of FNAV against the venoms of three common snakes in Southeast Asia, including two 'true' cobras Naja kaouthia (Thailand) and Naja siamensis (Thailand), and the king cobra Ophiophagus hannah (Indonesia). We further applied mass spectrometry (MS)-based proteomic techniques to characterize venom proteomes and identify FNAV-recognizable antigens in the venoms of these Asian snakes. Neutralization assays in a mouse model showed that FNAV effectively neutralized the lethality of N. kaouthia and N. siamensis venoms, but not O. hannah venom. MS-based venom protein identification results further revealed that FNAV strongly recognized three-finger toxin and phospholipase A2, the major protein components of N. kaouthia and N. siamensis venoms. The characterization of venom proteomes and identification of FNAV recognizable venom antigens may help researchers to further develop more effective antivenom designed to block the toxicity of dominant toxic proteins, with the ultimate goal of achieving broadly therapeutic effects against these cobra snakebites. PMID- 29244816 TI - Treatment with albumin-hydroxyoleic acid complex restores sensorimotor function in rats with spinal cord injury: Efficacy and gene expression regulation. AB - Sensorimotor dysfunction following incomplete spinal cord injury (SCI) is often characterized by paralysis, spasticity and pain. Previously, we showed that intrathecal (i.t.) administration of the albumin-oleic acid (A-OA) complex in rats with SCI produced partial improvement of these symptoms and that oral 2 hydroxyoleic acid (HOA, a non-hydrolyzable OA analogue), was efficacious in the modulation and treatment of nociception and pain-related anxiety, respectively. Here we observed that intrathecal treatment with the complex albumin-HOA (A-HOA) every 3 days following T9 spinal contusion injury improved locomotor function assessed with the Rotarod and inhibited TA noxious reflex activity in Wistar rats. To investigate the mechanism of action of A-HOA, microarray analysis was carried out in the spinal cord lesion area. Representative genes involved in pain and neuroregeneration were selected to validate the changes observed in the microarray analysis by quantitative real-time RT-PCR. Comparison of the expression between healthy rats, SCI rats, and SCI treated with A-HOA rats revealed relevant changes in the expression of genes associated with neuronal morphogenesis and growth, neuronal survival, pain and inflammation. Thus, treatment with A-HOA not only induced a significant overexpression of growth and differentiation factor 10 (GDF10), tenascin C (TNC), aspirin (ASPN) and sushi repeat-containing X-linked 2 (SRPX2), but also a significant reduction in the expression of prostaglandin E synthase (PTGES) and phospholipases A1 and A2 (PLA1/2). Currently, SCI has very important unmet clinical needs. A-HOA downregulated genes involved with inflammation and upregulated genes involved in neuronal growth, and may serve to promote recovery of function after experimental SCI. PMID- 29244817 TI - Curcumin inhibits activation induced by urban particulate material or titanium dioxide nanoparticles in primary human endothelial cells. AB - Curcumin has protective effects against toxic agents and shows preventive properties for various diseases. Particulate material with an aerodynamic diameter of <=10 MUm (PM10) and titanium dioxide nanoparticles (TiO2-NPs) induce endothelial dysfunction and activation. We explored whether curcumin is able to attenuate different events related to endothelial activation. This includes adhesion, expression of adhesion molecules and oxidative stress induced by PM10 and TiO2-NPs. Human umbilical vein endothelial cells (HUVEC) were treated with 1, 10 and 100 MUM curcumin for 1 h and then exposed to PM10 at 3 MUg/cm2 or TiO2-NPs at 10 MUg/cm2. Cell adhesion was evaluated by co-culture with U937 human myelomonocytic cells. Adhesion molecules expression was measured by flow cytometry after 3 or 24 h of exposure. Oxidative stress was determined by 2,7 dichlorodihydrofluorescein (H2DCF) oxidation. PM10 and TiO2-NPs induced the adhesion of U937 cells and the expression of E- and P-selectins, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1). The expression of E- and P-selectins matched the adhesion of monocytes to HUVEC after 3 h. In HUVEC treated with 1 or 10 MUM curcumin, the expression of adhesion molecules and monocytes adhesion was significantly diminished. Curcumin also partially reduced the H2DCF oxidation induced by PM10 and TiO2-NPs. Our results suggest an anti inflammatory and antioxidant role by curcumin attenuating the activation caused on endothelial cells by exposure to particles. Therefore, curcumin could be useful in the treatment of diseases where an inflammatory process and endothelial activation are involved. PMID- 29244818 TI - Postural control during quiet bipedal standing in rats. AB - The control of bipedal posture in humans is subject to non-ideal conditions such as delayed sensation and heartbeat noise. However, the controller achieves a high level of functionality by utilizing body dynamics dexterously. In order to elucidate the neural mechanism responsible for postural control, the present study made use of an experimental setup involving rats because they have more accessible neural structures. The experimental design requires rats to stand bipedally in order to obtain a water reward placed in a water supplier above them. Their motions can be measured in detail using a motion capture system and a force plate. Rats have the ability to stand bipedally for long durations (over 200 s), allowing for the construction of an experimental environment in which the steady standing motion of rats could be measured. The characteristics of the measured motion were evaluated based on aspects of the rats' intersegmental coordination and power spectrum density (PSD). These characteristics were compared with those of the human bipedal posture. The intersegmental coordination of the standing rats included two components that were similar to that of standing humans: center of mass and trunk motion. The rats' PSD showed a peak at approximately 1.8 Hz and the pattern of the PSD under the peak frequency was similar to that of the human PSD. However, the frequencies were five times higher in rats than in humans. Based on the analysis of the rats' bipedal standing motion, there were some common characteristics between rat and human standing motions. Thus, using standing rats is expected to be a powerful tool to reveal the neural basis of postural control. PMID- 29244819 TI - Climbing ability of teneral and sclerotized adult bed bugs and assessment of adhesive properties of the exoskeletal fluid using atomic force microscopy. AB - We observed that teneral adults (<1 h post-molt) of Cimex lectularius L. appeared more adept at climbing a smooth surface compared to sclerotized adults. Differences in climbing ability on a smooth surface based on sclerotization status were quantified by measuring the height to which bed bugs climbed when confined within a glass vial. The average maximum height climbed by teneral (T) bed bugs (n = 30, height climbed = 4.69 cm) differed significantly (P< 0.01) from recently sclerotized (RS) bed bugs (n = 30, height climbed = 1.73 cm at ~48 h post molt), sclerotized group 1 (S1) bed bugs (n = 30, S1 = 2.42 cm at >72 h), and sclerotized group 2 (S2) bed bugs (n = 30, height climbed = 2.64 cm at >72 h post molt). When heights from all climbing events were summed, teneral bed bugs (650.8 cm climbed) differed significantly (P< 0.01) from recently sclerotized (82 cm climbed) and sclerotized (group 1 = 104.6 cm climbed, group 2 = 107.8 cm climbed) bed bugs. These findings suggested that the external surface of teneral bed bug exoskeletons possess an adhesive property. Using atomic force microscopy (AFM), we found that adhesion force of an exoskeletal (presumably molting) fluid decreased almost five-fold from 88 to 17 nN within an hour of molting. Our findings may have implications for laboratory safety and the effectiveness of bed bug traps, barriers, and biomimetic-based adhesives. PMID- 29244820 TI - Probiotics reduce repeated water avoidance stress-induced colonic microinflammation in Wistar rats in a sex-specific manner. AB - The colonic response to stress is greater in female rats than in male rats. The aim of this study was to evaluate the effect of probiotics in the repeated water avoidance stress (rWAS)-induced colonic microinflammation model of Wistar rats in a sex-specific manner. The three groups (no-stress, WAS, and WAS with probiotics) were exposed to r-WAS for 1 h daily for 10 days, and Lactobacillus farciminis was administered by oral gavage for 10 days to animals in the probiotics group. The visceromotor response (VMR) to colorectal distension (CRD) was assessed using a barostat and noninvasive manometry before and after WAS exposure. Immunohistochemistry for mast cells and real-time polymerase chain reaction (RT PCR) for detection of mucosal cytokines were performed using distal colon tissue after the animals were sacrificed. Significant reduction of VMR to CRD (visceral analgesia) was observed at 60 mmHg in the female WAS group (P = 0.045), but not in males. In addition, the female WAS with probiotics group showed a significantly lower colonic mucosal mast cell count in comparison to the female WAS group (P = 0.013), but this phenomenon was not observed in the male group. The colonic mucosal mRNA levels of interferon-gamma (IFNR), tumor necrosis factor alpha (TNFA), interleukin (IL) 6, and IL17 were higher in the female WAS group than in the male WAS group. The mRNA levels of IFNR, TNFA, and IL6 were significantly decreased in WAS females who received probiotics (all P < 0.050). In conclusion, rWAS is induced in a sex-specific manner. A 10-day-long treatment with L. farciminis is an effective therapy for rWAS-induced colonic microinflammation in female rates, but not in male rats. PMID- 29244822 TI - Alcohol consumption and breast cancer-specific and all-cause mortality in women diagnosed with breast cancer at the New York site of the Breast Cancer Family Registry. AB - PURPOSE: Alcohol consumption is an established and important risk factor for breast cancer incidence in the general population. However, the relationship between alcohol and mortality among women with breast cancer is less clear. This study examines the effect of alcohol consumption on mortality in women affected with breast cancer at baseline from a high-risk family breast and ovarian cancer registry. METHODS: We studied 1116 women affected with breast cancer at baseline from the Metropolitan New York Registry. The examined reported alcohol consumption (total of beer, wine, liquor) was defined as the average number of drinks per week reported from age 12 to age at baseline. We assessed vital status of each participant using participant or family reported data and we used the National Death Index to supplement deaths reported through family updates. We used Cox proportional hazards models to estimate the association between alcohol intake and overall mortality (HRO), breast cancer-specific mortality (HRBC), and non-breast cancer mortality (HRNBC), adjusted for confounders. RESULTS: After a mean follow-up of 9.1 years, we observed 211 total deaths and 58 breast cancer deaths. Compared to non-drinkers, we found that both low and moderate to heavy levels of alcohol intake were not associated with greater overall mortality (<=3 drinks/week: HRO: 0.66, 95% CI: 0.38-1.14); > 3 drinks/week: HRO: 1.16, 95% CI: 0.85-1.58), breast cancer-specific mortality (<= 3 drinks/week: HRBC:0.62, 95% CI: 0.19-2.03; >3 drinks/week: HR BC: 0.96, 95% CI: 0.49-1.89), or non-breast cancer-specific mortality (<=3 drinks/week: HR NBC: 0.73, 95% CI: 0.32-1.6; >3 drinks/week: HRNBC: 1.18, 95% CI: 0.75-1.86). CONCLUSIONS: Alcohol intake reported from age 12 to age at baseline was not associated with overall or breast cancer-specific mortality in this cohort of affected women with a family history of breast cancer. PMID- 29244821 TI - Genotyping of Mycobacterium leprae for better understanding of leprosy transmission in Fortaleza, Northeastern Brazil. AB - Leprosy is endemic in large part of Brazil with 28,761 new patients in 2015, the second largest number worldwide and reaches 9/10.000 in highly endemic regions and 2.7/10.000 in the city of Fortaleza, Ceara, Northeast Brazil. For better understanding of risk factors for leprosy transmission, we conducted an epidemiologic study supplemented by 17 locus VNTR and SNP 1-4 typing of Mycobacterium leprae in skin biopsy samples from new multibacillary (MB) patients diagnosed at a reference center in 2009 and 2010. Among the 1,519 new patients detected during the study period, 998 (65.7%) were MB and we performed DNA extraction and genotyping on 160 skin biopsy samples, resulting in 159 (16%) good multilocus VNTR types. Thirty-eight of these patients also provided VNTR types from M. leprae in nasal swabs. The SNP-Type was obtained for 157 patients and 87% were of type 4. Upon consideration all VNTR markers, 156 different genotypes and three pairs with identical genotypes were observed; no epidemiologic relation could be observed between individuals in these pairs. Considerable variability in differentiating index (DI) was observed between the different markers and the four with highest DI [(AT)15, (TA)18, (AT)17 and (GAA)21] frequently demonstrated differences in copy number when comparing genotypes from both type of samples. Excluding these markers from analysis resulted in 83 genotypes, 20 of which included 96 of the patients (60.3%). These clusters were composed of two (n = 8), three (n = 6), four (n = 1), five (n = 2), six (n = 1), 19 (n = 1) and 23 (n = 23) individuals and suggests that recent transmission is contributing to the maintenance of leprosy in Fortaleza. When comparing epidemiological and clinical variables among patients within clustered or with unique M. leprae genotypes, a positive bacterial index in skin biopsies and knowledge of working with someone with the disease were significantly associated with clustering. A tendency to belong to a cluster was observed with later notification of disease (mean value of 3.4 months) and having disability grade 2. A tendency for lack of clustering was observed for patients who reported to have lived with another leprosy case but this might be due to lack of inclusion of household contacts in the study. Although clusters were spread over the city, kernel analysis revealed that some of the patients belonging to the two major clusters were spatially related to some neighborhoods that report poverty and high disease incidence in children. Finally, inclusion of genotypes from nasal swabs might be warranted. A major limitation of the study is that sample size of 160 patients from a two year period represents only 15% of the new patients and this could have weakened statistical outcomes. This is the first molecular epidemiology study of leprosy in Brazil and although the high clustering level suggests that recent transmission is the major cause of disease in Fortaleza; the existence of two large clusters needs further investigation. PMID- 29244823 TI - Cost-effectiveness of national health insurance programs in high-income countries: A systematic review. AB - OBJECTIVES: National health insurance is now common in most developed countries. This study reviews the evidence and synthesizes the cost-effectiveness information for national health insurance or disability insurance programs across high-income countries. DATA SOURCES: A literature search using health, economics and systematic review electronic databases (PubMed, Embase, Medline, Econlit, RepEc, Cochrane library and Campbell library), was conducted from April to October 2015. STUDY SELECTION: Two reviewers independently selected relevant studies by applying screening criteria to the title and keywords fields, followed by a detailed examination of abstracts. DATA EXTRACTION: Studies were selected for data extraction using a quality assessment form consisting of five questions. Only studies with positive answers to all five screening questions were selected for data extraction. Data were entered into a data extraction form by one reviewer and verified by another. EVIDENCE SYNTHESIS: Data on costs and quality of life in control and treatment groups were used to draw distributions for synthesis. We chose the log-normal distribution for both cost and quality-of-life data to reflect non-negative value and high skew. The results were synthesized using a Monte Carlo simulation, with 10,000 repetitions, to estimate the overall cost-effectiveness of national health insurance programs. RESULTS: Four studies from the United States that examined the cost-effectiveness of national health insurance were included in the review. One study examined the effects of medical expenditure, and the remaining studies examined the cost-effectiveness of health insurance reforms. The incremental cost-effectiveness ratio (ICER) ranged from US$23,000 to US$64,000 per QALY. The combined results showed that national health insurance is associated with an average incremental cost-effectiveness ratio of US$51,300 per quality-adjusted life year (QALY). Based on the standard threshold for cost-effectiveness, national insurance programs are cost-effective interventions. CONCLUSIONS: Although national health insurance programs have been introduced in most developed countries, only a few studies have examined their cost-effectiveness. All the selected studies revealed strong evidence to support health insurance programs or health reforms in the United States. The average ICER in this study is below the standard threshold for cost-effectiveness used in the US. The small number of relevant studies is the main limitation of this study. PMID- 29244824 TI - A backwards glance at words: Using reversed-interior masked primes to test models of visual word identification. AB - The experiments reported here used "Reversed-Interior" (RI) primes (e.g., cetupmor-COMPUTER) in three different masked priming paradigms in order to test between different models of orthographic coding/visual word recognition. The results of Experiment 1, using a standard masked priming methodology, showed no evidence of priming from RI primes, in contrast to the predictions of the Bayesian Reader and LTRS models. By contrast, Experiment 2, using a sandwich priming methodology, showed significant priming from RI primes, in contrast to the predictions of open bigram models, which predict that there should be no orthographic similarity between these primes and their targets. Similar results were obtained in Experiment 3, using a masked prime same-different task. The results of all three experiments are most consistent with the predictions derived from simulations of the Spatial-coding model. PMID- 29244826 TI - MAGPIE: Simplifying access and execution of computational models in the life sciences. AB - Over the past decades, quantitative methods linking theory and observation became increasingly important in many areas of life science. Subsequently, a large number of mathematical and computational models has been developed. The BioModels database alone lists more than 140,000 Systems Biology Markup Language (SBML) models. However, while the exchange within specific model classes has been supported by standardisation and database efforts, the generic application and especially the re-use of models is still limited by practical issues such as easy and straight forward model execution. MAGPIE, a Modeling and Analysis Generic Platform with Integrated Evaluation, closes this gap by providing a software platform for both, publishing and executing computational models without restrictions on the programming language, thereby combining a maximum on flexibility for programmers with easy handling for non-technical users. MAGPIE goes beyond classical SBML platforms by including all models, independent of the underlying programming language, ranging from simple script models to complex data integration and computations. We demonstrate the versatility of MAGPIE using four prototypic example cases. We also outline the potential of MAGPIE to improve transparency and reproducibility of computational models in life sciences. A demo server is available at magpie.imb.medizin.tu-dresden.de. PMID- 29244825 TI - Associations of sodium intake with obesity, metabolic disorder, and albuminuria according to age. AB - Sodium intake is associated with obesity and metabolic disorder in the general population. However, sodium intake is significantly reduced according to the decrease of energy intake in older adults although the prevalence of obesity is higher than younger adults. We evaluate the association of sodium excretion (UNa) with blood pressure, obesity, metabolic disorders, and albuminuria according to age. An observational study using data from the Korean National Health and Nutrition Examination Survey IV-V (2008-2011) was performed (N = 18,146). The 24 hour UNa was estimated from a single fasting urine sample.Participants aged>=75 years showed the highest risk for hypertension (HTN) in the highest quartile of UNa (1.769, 95% CI, 1.174-2.665), and the risks for HTN increased with advancing age. Obesity was not associated with UNa in participants aged>=75 years, and hypertriglyceridemia and body fat were not related to UNa in participants aged>=65 years, although these values were significantly associated with UNa in participants aged<65 years. Impaired fasting glucose (IFG) and insulin resistance (IR) were associated with UNa only in participants aged 20-39 years. The highest quartile of UNa showed a 3.777 fold increased risk for albuminuria in those aged 20-39 years (95% CI, 1.130-12.630), and a 1.885 fold increased risk (95% CI, 1.156-3.075) among participants aged 40-64 years. In participants aged>=65 years, albuminuria was not associated with UNa. In contrast with HTN, UNa was not associated with albuminuria, obesity, hypertriglyceridemia, IFG, and IR in older adults despite a strong association in younger adults. PMID- 29244827 TI - Neuroligin 4X overexpression in human breast cancer is associated with poor relapse-free survival. AB - The molecular mechanisms involved in breast cancer progression and metastasis still remain unclear to date. It is a heterogeneous disease featuring several different phenotypes with consistently different biological characteristics. Neuroligins are neural cell adhesion molecules that have been implicated in heterotopic cell adhesion. In humans, alterations in neuroligin genes are implicated in autism and other cognitive diseases. Until recently, neuroligins have been shown to be abundantly expressed in blood vessels and also play a role implicated in the growth of glioma cells. Here we report increased expression of neuroligin 4X (NLGN4X) in breast cancer. We found NLGN4X was abundantly expressed in breast cancer tissues. NLGN4X expression data for all breast cancer cell lines in the Cancer Cell Line Encyclopedia (CCLE) was analyzed. Correlation between NLGN4X levels and clinicopathologic parameters were analyzed within Oncomine datasets. Evaluation of these bioinfomatic datasets results revealed that NLGN4X expression was higher in triple negative breast cancer cells, particularly the basal subtype and tissues versus non-triple-negative sets. Its level was also observed to be higher in metastatic tissues. RT-PCR, flow cytometry and immunofluorescence study of MDA-MB-231 and MCF-7 breast cancer cells validated that NLGN4X was increased in MDA-MB-231. Knockdown of NLGN4X expression by siRNA decreased cell proliferation and migration significantly in MDA-MB-231 breast cancer cells. NLGN4X knockdown in MDA-MB-231 cells resulted in induction of apoptosis as determined by annexin staining, elevated caspase 3/7 and cleaved PARP by flow cytometry. High NLGN4X expression highly correlated with decrease in relapse free-survival in TNBC. NLGN4X might represent novel biomarkers and therapeutic targets for breast cancer. Inhibition of NLGN4X may be a new target for the prevention and treatment of breast cancer. PMID- 29244828 TI - Involvement of phenoloxidase in browning during grinding of Tenebrio molitor larvae. AB - Insects are investigated as alternative protein source to meet the increasing demand for proteins in the future. Enzymatic browning occurring during grinding of insect and subsequent extraction of proteins can influence the proteins' properties, but it is unclear which enzymes are responsible for this phenomenon. This study was performed on larvae of three commonly used insect species, namely Tenebrio molitor, Alphitobius diaperinus and Hermetia illucens. Oxygen consumption measurements on protein extracts showed activity on L-tyrosine, L-3,4 di-hydroxy-phenylalanine (L-DOPA) and L-dopamine, indicating phenoloxidase as a key player in browning. Furthermore, no reaction on 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulphonic acid) was observed, ruling out an important contribution of laccase to browning. The browning reaction was most prominent at pH 6 for T. molitor and A. diaperinus, and 7 for H. illucens. As the enzyme activity of H. illucens was the lowest with the darkest color formation, this was likely caused by another factor. The activity of phenoloxidase was confirmed for T. molitor and A. diaperinus by activity measurements after fractionation by anion-exchange chromatography. Color measurements showed the presence of activity on both L-DOPA and L-tyrosine in the same fractions. Both substrates were converted into dopachrome after incubation with enzyme-enriched fractions. No DOPA-decarboxylase, tyrosine hydroxylase and peroxidase activities were observed. By using native PAGE with L-DOPA as staining-solution, active T. molitor protein bands were resolved and characterized, identifying a tyrosinase/phenoloxidase as the active enzyme species. All together, these data confirmed that tyrosinase is an important enzyme in causing enzymatic browning in T. molitor and likely in A. diaperinus. PMID- 29244829 TI - Cost-effectiveness analysis of introducing malaria diagnostic testing in drug shops: A cluster-randomised trial in Uganda. AB - BACKGROUND: Private sector drug shops are an important source of malaria treatment in Africa, yet diagnosis without parasitological testing is common among these providers. Accurate rapid diagnostic tests for malaria (mRDTs) require limited training and present an opportunity to increase access to correct diagnosis. The present study was a cost-effectiveness analysis of the introduction of mRDTs in Ugandan drug shops. METHODS: Drug shop vendors were trained to perform and sell subsidised mRDTs and artemisinin-based combination therapies (ACTs) in the intervention arm while vendors offered ACTs following presumptive diagnosis of malaria in the control arm. The effect on the proportion of customers with fever 'appropriately treated of malaria with ACT' was captured during a randomised trial in drug shops in Mukono District, Uganda. Health sector costs included: training of drug shop vendors, community sensitisation, supervision and provision of mRDTs and ACTs to drug shops. Household costs of treatment-seeking were captured in a representative sample of drug shop customers. FINDINGS: The introduction of mRDTs in drug shops was associated with a large improvement of diagnosis and treatment of malaria, resulting in low incremental costs for the health sector at US$0.55 per patient appropriately treated of malaria. High expenditure on non-ACT drugs by households contributed to higher incremental societal costs of US$3.83. Sensitivity analysis showed that mRDTs would become less cost-effective compared to presumptive diagnosis with increasing malaria prevalence and lower adherence to negative mRDT results. CONCLUSION: mRDTs in drug shops improved the targeting of ACTs to malaria patients and are likely to be considered cost-effective compared to presumptive diagnosis, although the increased costs borne by households when the test result is negative are a concern. PMID- 29244830 TI - Transcriptome profiling identifies regulators of pathogenesis in collagen VI related muscular dystrophy. AB - OBJECTIVES: The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies and are characterized by distal joint laxity and a combination of distal and proximal joint contractures. Inheritance can be dominant negative (DN) or recessive depending on the type and location of the mutation. DN mutations allow incorporation of abnormal chains into secreted tetramers and are the most commonly identified mutation type in COL6-RD. Null alleles (nonsense, frameshift, and large deletions) do not allow incorporation of abnormal chains and act recessively. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD individuals from controls. METHODS: RNA-Seq allows precise detection of all expressed transcripts in a sample and provides a tool for quantification of expression data on a genomic scale. We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD individuals (8 dominant negative and 5 null) and 6 controls. To better assess the transcriptional changes induced by abnormal collagen VI in the extracellular matrix (ECM); we compared transcriptional profiles from subjects with DN mutations and subjects with null mutations to transcriptional profiles from controls. RESULTS: Differentially expressed transcripts between COL6-RD and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples. CONCLUSIONS: Differentially expressed genes identified here may help identify new targets for development of therapies and biomarkers to assess the efficacy of treatments. PMID- 29244831 TI - Antimicrobial susceptibility and molecular epidemiology of clinical Enterobacter cloacae bloodstream isolates in Shanghai, China. AB - BACKGROUND: Enterobacter cloacae is a major nosocomial pathogen causing bloodstream infections. We retrospectively conducted a study to assess antimicrobial susceptibility and phylogenetic relationships of E. cloacae bloodstream isolates in two tertiary university-affiliated hospitals in Shanghai, in order to facilitate managements of E. cloacae bloodstream infections and highlight some unknowns for future prevention. METHODS: Fifty-three non-duplicate E. cloacae bloodstream isolates were consecutively collected from 2013 to 2016. Antimicrobial susceptibility was determined by disk diffusion. PCR was performed to detect extended-spectrum beta-lactamase (ESBL), carbapenemase and colistin resistance (MCR-1) gene. Plasmid-mediated AmpC beta-lactamase (pAmpC) genes were detected using a multiplex PCR assay targeting MIR/ACT gene (closely related to chromosomal EBC family gene) and other plasmid-mediated genes, including DHA, MOX, CMY, ACC, and FOX. eBURST was applied to analyze multi-locus sequence typing (MLST). RESULTS: The rates of resistance to all tested antibiotics were <40%. Among 53 E. cloacae isolates, 8(15.1%) were ESBL producers, 3(5.7%) were carbapenemase producers and 18(34.0%) were pAmpC producers. ESBL producers bear significantly higher resistance to cefotaxime (100.0%), ceftazidime (100.0%), aztreonam (100.0%), piperacillin (87.5%), tetracycline (75.0%), and trimethoprim sulfamethoxazole (62.5%) than non-producers (p<0.05). PAmpC- and non-producers both presented low resistance rates (<40%) to all antibiotics (p>0.05). SHV (6/8, 75.0%) and MIR/ACT (15/18, 83.3%) predominated in ESBL and pAmpC producers respectively. Moreover, 2 isolates co-carried TEM-1, SHV-12, IMP-26 and DHA-1. MLST analysis distinguished the 53 isolates into 51 STs and only ST414 and ST520 were assigned two isolates of each (2/53). CONCLUSION: The antimicrobial resistance rates were low among 53 E. cloacae bloodstream isolates in the two hospitals. Multiclonality disclosed no evidence on spread of these isolates in Shanghai. The simultaneous presence of ESBL, carbapenemase and pAmpC detected in 2 isolates was firstly reported in Shanghai, which necessitated active ongoing surveillances and consistent prevention and control of E. cloacae. PMID- 29244832 TI - Productivity, impact, and collaboration differences between transdisciplinary and traditionally trained doctoral students: A comparison of publication patterns. AB - Transdisciplinary (TD) approaches are increasingly used to address complex public health problems such as childhood obesity. Compared to traditional grant-funded scientific projects among established scientists, those designed around a TD, team-based approach yielded greater publication output after three to five years. However, little is known about how a TD focus throughout graduate school training may affect students' publication-related productivity, impact, and collaboration. The objective of this study was to compare the publication patterns of students in traditional versus TD doctoral training programs. Productivity, impact, and collaboration of peer-reviewed publications were compared between traditional (n = 25) and TD (n = 11) students during the first five years of the TD program. Statistical differences were determined by t-test or chi square test at p < 0.05. The publication rate for TD students was 5.2 +/- 10.1 (n = 56) compared to 3.6 +/ 4.5 per traditional student (n = 82). Publication impact indicators were significantly higher for TD students vs. traditional students: 5.7 times more citations in Google Scholar, 6.1 times more citations in Scopus, 1.3 times higher journal impact factors, and a 1.4 times higher journal h-index. Collaboration indicators showed that publications by TD students had significantly more co authors (1.3 times), and significantly more disciplines represented among co authors (1.3 times), but not significantly more organizations represented per publication compared to traditional students. In conclusion, compared to doctoral students in traditional programs, TD students published works that were accepted into higher impact journals, were more frequently cited, and had more cross disciplinary collaborations. PMID- 29244833 TI - Genomic characterization and molecular evolution analysis of subtype B and BF recombinant HIV-1 strains among Argentinean men who have sex with men reveal a complex scenario. AB - Currently, data on HIV-1 circulating strains among men who have sex with men (MSM) in Argentina is scarce. In South America, the distribution and the prevalence of BF recombinants are dissimilar and exhibit an underappreciated heterogeneity of recombinant structures. Here, we studied for the first time the genetic diversity of HIV-1 BF recombinants and their evolution over time through in-depth phylogenetic analysis and multiple recombination detection methods involving 337 HIV-1 nucleotide sequences (25 near full-length (NFL) and 312 partial pol gene) obtained from Argentinean MSM. The recombination profiles were studied using multiple in silico tools to characterize the genetic mosaicism, and phylogenetic approaches to infer their relationships. The evolutionary history of BF recombinants and subtype B sequences was reconstructed by a Bayesian coalescent-based method. By phylogenetic inference, 81/312 pol sequences clustered within BF clade. Of them, 46 sequences showed a genetic mosaic with CRF12_BF-like patterns, including plausible second-generation recombinants. Other CRFs_BF like (CRF17, 28, 29, 39, 42, 44, 47) and probable URFs_BF were less frequently found. Phylogenetic and recombination analyses on NFL sequences allowed a meticulous definition of new BF mosaics of genomic patterns. The Bayesian analyses pointed out quite consistent onset dates for the CRFs_BF clade based on B and F gene datasets (~1986 and ~1991 respectively). These results indicate that the CRFs_BF variants have been circulating among Argentinean MSM for about 30 years. This study reveals, through growing evidence showing the importance of MSM in the dynamics of the HIV-1 epidemic in Argentina, the coexistence of CRF12_BF-like and high diversity of strains exhibiting several BF mosaic patterns, including non-reported URFs that may reflect active clusters as potential intervention targets to hinder HIV-1 transmission. PMID- 29244835 TI - Tumor suppressor protein p53-mediated repression of human mitotic centromere associated kinesin gene expression is exerted via down-regulation of Sp1 level. AB - The repressive role of p53 on the human mitotic centromere-associated kinesin (MCAK) core promoter from -266 to +54, relative to the transcription start site, has been determined. The MCAK mRNA and protein levels were 2.1- and 3.0-fold higher, respectively, in HCT116 (p53-/-) than in HCT116 (p53+/+) cells. Enforced down-regulation of p53 levels either in HCT116 (p53+/+) cells by p53 RNAi treatment or in MCF-7 cells using shRNA for p53 (shp53) resulted in a remarkable increase in the MCAK protein level. Site-directed mutagenesis and ChIP analyses showed that p53-mediated repression of the MCAK core promoter activity was not directly exerted by p53-binding to putative p53-response elements (p53-RE1 at 173/-166 and p53-RE2 at -245/-238), but indirectly by attenuating Sp1 binding to GC-motifs (GC1 at -93/-84 and GC2 at -119/-110). Treatment of HEK-293 cells bearing the MCAK core promoter-reporter (pGL2-320-Luc) with mithramycin A, which down-regulates Sp1 gene expression, reduced the promoter activity as well as endogenous MCAK levels. Exposure of HCT116 (p53+/+) cells to nutlin-3a, a validated activator of p53, caused a simultaneous reduction in Sp1 and MCAK protein levels, but not in HCT116 (p53-/-) cells. In contrast to wild-type (wt) p53, tumor-derived p53 mutants (p53V143A, p53R248W, and p53R273H) failed to repress the Sp1-dependent activation of the MCAK promoter and to down-regulate endogenous levels of Sp1 and MCAK proteins. Collectively, these findings demonstrate that p53 can repress MCAK promoter activity indirectly via down regulation of Sp1 expression level, and suggest that MCAK elevation in human tumor cells might be due to p53 mutation. PMID- 29244834 TI - Factors influencing psychological well-being in patients with Parkinson's disease. AB - BACKGROUND: Both motor and non-motor symptoms could contribute to significant deterioration of psychological well-being in patients with Parkinson's disease (PD). However, its assessment has been only indirectly evaluated using tools based on health-related quality of life (HRQoL), such as the PDQ-39 scale. OBJECTIVES: To evaluate psychological well-being in PD using a specific tool of assessment, the Psychological Well-being Scale (PWS), and its clinical correlates. METHODS: This article reports data of patients' perception of health state, as measured by means of the PWS, from an epidemiological, cross-sectional study conducted in Italian PD patients (FORTE Study). We tested possible relationship between well-being and clinical characteristics including fatigue, depression, sleep disruption and HRQoL. RESULTS: 272 patients completed the PWS questionnaire. Significant and clinically-relevant correlations were found between PWS total score and Parkinson's Fatigue Scale, Beck Depression Inventory, UPDRS Section I, PD Sleep Scale and PDQ-39 for HRQoL scores. Only clinically negligible correlations were found between PWS and motor scores. CONCLUSIONS: Non motor symptoms have a significant impact on psychological well-being in PD patients. PMID- 29244836 TI - Energy compensation after sprint- and high-intensity interval training. AB - BACKGROUND: Many individuals lose less weight than expected in response to exercise interventions when considering the increased energy expenditure of exercise (ExEE). This is due to energy compensation in response to ExEE, which may include increases in energy intake (EI) and decreases in non-exercise physical activity (NEPA). We examined the degree of energy compensation in healthy young men and women in response to interval training. METHODS: Data were examined from a prior study in which 24 participants (mean age, BMI, & VO2max = 28 yrs, 27.7 kg*m-2, and 32 mL?kg-1?min-1) completed either 4 weeks of sprint interval training or high-intensity interval training. Energy compensation was calculated from changes in body composition (air displacement plethysmography) and exercise energy expenditure was calculated from mean heart rate based on the heart rate-VO2 relationship. Differences between high (>= 100%) and low (< 100%) levels of energy compensation were assessed. Linear regressions were utilized to determine associations between energy compensation and DeltaVO2max, DeltaEI, DeltaNEPA, and Deltaresting metabolic rate. RESULTS: Very large individual differences in energy compensation were noted. In comparison to individuals with low levels of compensation, individuals with high levels of energy compensation gained fat mass, lost fat-free mass, and had lower change scores for VO2max and NEPA. Linear regression results indicated that lower levels of energy compensation were associated with increases in DeltaVO2max (p < 0.001) and DeltaNEPA (p < 0.001). CONCLUSIONS: Considerable variation exists in response to short-term, low dose interval training. In agreement with prior work, increases in DeltaVO2max and DeltaNEPA were associated with lower energy compensation. Future studies should focus on identifying if a dose-response relationship for energy compensation exists in response to interval training, and what underlying mechanisms and participant traits contribute to the large variation between individuals. PMID- 29244837 TI - Frailty and quality of life among older people with and without a cancer diagnosis: Findings from TOPICS-MDS. AB - BACKGROUND: The number of older cancer patients is rising. Especially in older people, treatment considerations should balance the impact of disease and treatment on quality of life (QOL) and survival. How a cancer diagnosis in older people interacts with concomitant frailty to impact on QOL is largely unknown. We aimed to determine the association between frailty and QOL among community dwelling older people aged 65 years or above with and without a cancer diagnosis cross-sectionally and at 12 months follow-up. METHODS: Data were derived from the TOPICS-MDS database. Frailty was quantified by a frailty index (FI). QOL was measured with the subjective Cantril's Self Anchoring Ladder (CSAL, range: 0-10) and the health-related EuroQol-5D (EQ-5D, range:-0.33-1.00) at baseline and after 12 months. To determine associations, linear mixed models were used. RESULTS: 7493 older people (78.6+/-6.4 years, 58.4% female) were included. Dealing with a cancer diagnosis (n = 751) was associated with worse QOL both at baseline (CSAL: 0.25 (95%-CI:-0.36;-0.14), EQ-5D:-0.03 (95%-CI:-0.05;-0.02)) and at follow-up (CSAL:-0.13 (95%-CI:-0.24;-0.02), EQ-5D:-0.02 (95%-CI:-0.03;-0.00)). A ten percent increase in frailty was also associated with a decrease in QOL at baseline (CSAL:-0.35 (95%-CI:-0.38;-0.32), EQ-5D:-0.12 (95%-CI:-0.12;-0.11)) and follow-up (CSAL:-0.27 (95%-CI:-0.30;-0.24), EQ-5D:-0.07 (95%-CI:-0.07;-0.06)). When mutually adjusting for frailty and a cancer diagnosis, associations between a cancer diagnosis and QOL only remained significant for CSAL at baseline (-0.14 (95%-CI:-0.25;-0.03)), whereas associations between frailty and QOL remained significant for all QOL outcomes at baseline and follow-up. No statistical interactions between cancer and frailty in their combined impact on QOL were found. CONCLUSIONS: Cancer diagnosis and frailty were associated with worse health-related and self-perceived QOL both at baseline and at follow-up. Differences in QOL between older people with and without a cancer diagnosis were explained to a large extent by differences in frailty levels. This stresses the importance to take into account frailty in routine oncologic care. PMID- 29244838 TI - Muscle function in glenohumeral joint stability during lifting task. AB - Ensuring glenohumeral stability during repetitive lifting tasks is a key factor to reduce the risk of shoulder injuries. Nevertheless, the literature reveals some lack concerning the assessment of the muscles that ensure glenohumeral stability during specific lifting tasks. Therefore, the purpose of this study was to assess the stabilization function of shoulder muscles during a lifting task. Kinematics and muscle electromyograms (n = 9) were recorded from 13 healthy adults during a bi-manual lifting task performed from the hip to the shoulder level. A generic upper-limb OpenSim model was implemented to simulate glenohumeral stability and instability by performing static optimizations with and without glenohumeral stability constraints. This procedure enabled to compute the level of shoulder muscle activity and forces in the two conditions. Without the stability constraint, the simulated movement was unstable during 74%+/-16% of the time. The force of the supraspinatus was significantly increased of 107% (p<0.002) when the glenohumeral stability constraint was implemented. The increased supraspinatus force led to greater compressive force (p<0.001) and smaller shear force (p<0.001), which contributed to improved glenohumeral stability. It was concluded that the supraspinatus may be the main contributor to glenohumeral stability during lifting task. PMID- 29244839 TI - Direct and indirect climate controls predict heterogeneous early-mid 21st century wildfire burned area across western and boreal North America. AB - Predicting wildfire under future conditions is complicated by complex interrelated drivers operating across large spatial scales. Annual area burned (AAB) is a useful index of global wildfire activity. Current and antecedent seasonal climatic conditions, and the timing of snowpack melt, have been suggested as important drivers of AAB. As climate warms, seasonal climate and snowpack co-vary in intricate ways, influencing fire at continental and sub continental scales. We used independent records of seasonal climate and snow cover duration (last date of permanent snowpack, LDPS) and cell-based Structural Equation Models (SEM) to separate direct (climatic) and indirect (snow cover) effects on relative changes in AAB under future climatic scenarios across western and boreal North America. To isolate seasonal climate variables with the greatest effect on AAB, we ran multiple regression models of log-transformed AAB on seasonal climate variables and LDPS. We used the results of multiple regressions to project future AAB using GCM ensemble climate variables and LDPS, and validated model predictions with recent AAB trends. Direct influences of spring and winter temperatures on AAB are larger and more widespread than the indirect effect mediated by changes in LDPS in most areas. Despite significant warming trends and reductions in snow cover duration, projected responses of AAB to early mid 21st century are heterogeneous across the continent. Changes in AAB range from strongly increasing (one order of magnitude increases in AAB) to moderately decreasing (more than halving of baseline AAB). Annual wildfire area burned in coming decades is likely to be highly geographically heterogeneous, reflecting interacting regional and seasonal climate drivers of fire occurrence and spread. PMID- 29244840 TI - High expression of lncRNA PVT1 independently predicts poor overall survival in patients with primary uveal melanoma. AB - The plasmacytoma variant translocation 1 gene (PVT1) plays an oncogenic role in the initiation and progression of multiple cancers. In this study, by using deep sequencing data and follow-up data in the Cancer Genome Atlas-Uveal melanomas (TCGA-UVM), we assessed the association between the expression of PVT1 and clinicopathological characteristics of patients with uveal melanoma, the mechanism of its dysregulation and its prognostic value. Results showed that high PVT1 expression group had a higher proportion of epithelioid cell dominant disease (a more malignant histological subtype than spindle cell dominant disease) and more cases of extrascleral extension (a risk factor for metastasis) compared with the low PVT1 expression group. 61 out of 80 cases (76.3%) of primary uveal melanoma had PVT1 amplification in TCGA-UVM. In addition, PVT1 expression was strongly and negatively correlated with its methylation status (Pearson's r = -0.712, Spearman's r = -0.806). By performing univariate and multivariate analysis, we found that high PVT1 expression was an independent predictor of poor OS in patients with uveal melanoma (HR: 12.015, 95%CI: 1.854 77.876, p = 0.009). Based on these findings, we infer that PVT1 expression is modulated by both DNA amplification and methylation and its expression might serve as a valuable and specific prognostic biomarker in terms of OS in uveal melanoma. PMID- 29244841 TI - Individual preferences for physical exercise as secondary prevention for non specific low back pain: A discrete choice experiment. AB - BACKGROUND: Exercise is effective in improving non-specific low back pain (LBP). Certain components of physical exercise, such as the type, intensity and frequency of exercise, are likely to influence participation among working adults with non-specific LBP, but the value and relative importance of these components remain unknown. The study's aim was to examine such specific components and their influence on individual preferences for exercise for secondary prevention of non specific LBP among working adults. METHODS: In a discrete choice experiment, working individuals with non-specific LBP answered a web-based questionnaire. Each respondent was given ten pairs of hypothetical exercise programs and asked to choose one option from each pair. The choices comprised six attributes of exercise (i.e., type of training, design, intensity, frequency, proximity and incentives), each with either three or four levels. A conditional logit regression that reflected the random utility model was used to analyze the responses. RESULTS: The final study population consisted of 112 participants. The participants' preferred exercise option was aerobic (i.e., cardiovascular) rather than strength training, group exercise with trainer supervision, rather than individual or unsupervised exercise. They also preferred high intensity exercise performed at least once or twice per week. The most popular types of incentive were exercise during working hours and a wellness allowance rather than coupons for sports goods. The results show that the relative value of some attribute levels differed between young adults (age <= 44 years) and older adults (age >= 45 years) in terms of the level of trainer supervision required, exercise intensity, travel time to exercise location and financial incentives. For active study participants, exercise frequency (i.e., twice per week, 1.15; CI: 0.25; 2.06) influenced choice of exercise. For individuals with more than one child, travel time (i.e., 20 minutes, -0.55; CI: 0.65; 3.26) was also an influential attribute for choice of exercise, showing that people with children at home preferred to exercise close to home. CONCLUSIONS: This study adds to our knowledge about what types of exercise working adults with back pain are most likely to participate in. The exercise should be a cardiovascular type of training carried out in a group with trainer supervision. It should also be of high intensity and preferably performed twice per week during working hours. Coupons for sports goods do not appear to motivate physical activity among workers with LBP. The findings of the study could have a substantial impact on the planning and development of exercise provision and promotion strategies to improve non-specific LBP. Providers and employers may be able to improve participation in exercise programs for adults with non-specific LBP by focusing on the exercise components which are the most attractive. This in turn would improve satisfaction and adherence to exercise interventions aimed at preventing recurrent non-specific LBP. PMID- 29244842 TI - Intensive care treatments associated with favorable discharge outcomes in Argentine children with severe traumatic brain injury: For the South American Guideline Adherence Group. AB - OBJECTIVE: Little is known about the critical care management of children with traumatic brain injury (TBI) in low middle income countries. We aimed to identify indicators of intensive care unit (ICU) treatments associated with favorable outcomes in Argentine children with severe TBI. METHODS: We conducted a secondary analysis of data from patients previously enrolled in a prospective seven center study of children with severe TBI who were admitted to an ICU in one of the seven study centers. Severe TBI was defined by head AIS >= 3, head CT with traumatic lesion, and admission GCS < 9. Seven indicators of best practice TBI care were examined. The primary outcome was discharge Pediatric Cerebral Performance Category Scale [PCPC] and Pediatric Overall Performance category Scale [POPC]. We also examined variation in ICU care and in-patient mortality. RESULTS: Of the 117 children, 67% were male and 7.5 (4.3) years on average, 92% had isolated TBI. Hypotension (54%) was more common than hypoxia (28%) and clinical or radiographic signs of high intracranial pressure (ICP) were observed in 92%. Yet, ICP monitoring occurred in 60% and hyperosmolar therapy was used in only 36%. Adherence to indicators of best TBI practice ranged from 55.6% to 83.7% across the seven centers and adherence was associated with favorable discharge PCPC (aRR 0.98; 95% CI [0.96, 0.99]), and POPC (aRR 0.98; 95% CI [0.96, 0.99]). Compared to patients whose adherence rates were below 65%, patients whose adherence rates were higher between 75%-100% had better discharge PCPC (aRR 0.28; 95% CI [0.10, 0.83]) and POPC (aRR 0.32; 95% CI [0.15, 0.73]. Two indicators were associated with favorable discharge PCPC: Avoidance of hypoxia (aRR 0.46; 95% CI [0.23, 0.93]), and Nutrition started in 72 hours (aRR 0.45; 95% CI [0.21, 0.99]). Avoiding hypoxia was also associated with favorable discharge POPC (aRR 0.47; 95% CI [0.22, 0.99]). CONCLUSION: There is variation in Argentine ICU practice in the care of children with severe TBI. Second insults are common and hyperosmolar therapy use is uncommon. Adherence to best practice TBI care by avoiding hypoxia and providing timely nutrition were associated with significantly favorable discharge outcomes. Implementing strategies that prevent hypoxia and facilitate early nutrition in the ICUs are urgently needed to improve pediatric TBI outcomes. PMID- 29244843 TI - Pathology in repeated transurethral resection of a bladder tumor as a risk factor for prognosis of high-risk non-muscle-invasive bladder cancer. AB - The prognostic value of repeat transurethral resection of bladder tumor (TURBT) in patients with diagnosed high-risk, non-muscle-invasive bladder cancer (NMIBC) was investigated. We retrospectively reviewed the medical records of patients treated from October 2004 to December 2013 at Seoul National University who underwent repeated TURBT within 2-6 weeks after an initial resection. The study enrolled patients who had been diagnosed with NMIBC at both the initial and repeat TURBT; patients with muscle-invasive tumors on repeat TURBT were excluded. We used stepwise multivariate Cox regression models stratified by study to assess the independent effects of the predictive factors and estimated hazard ratios (HRs) from the Cox models. We investigated a total of 198 patients who were diagnosed with high-risk NMIBC. In logistic regression analyses, number of bladder tumors (2-7: OR, 2.319; 8<=: OR, 3.353; p<0.05), initially high tumor grade (OR, 2.435; p = 0.040), and presence of carcinoma in situ lesion (OR, 3.639; p = 0.017) correlated with residual tumor in the repeated-TURBT specimen. T1 stage in repeated-TURBT significantly correlated with recurrence (HR, 1.837; p = 0.010) and progression (HR, 2.806; p = 0.029) in multivariate analysis. The high grades of tumors in repeated-TURBT also significantly correlated with progression but not recurrence in the multivariate analysis (HR 2.152; p = 0.008). In this study, the pathologic findings in repeated-TURBT correlated with recurrence and progression in high-risk NMIBC. Repeated-TURBT is valuable because it can predict the recurrence and progression of high-risk NMIBC in addition to obtaining accurate pathologic findings. PMID- 29244844 TI - Diagnostic markers for the detection of ovarian cancer in BRCA1 mutation carriers. AB - BACKGROUND: Screening for ovarian cancer (OC) in women at high risk consists of a combination of carbohydrate antigen 125 (CA125) and transvaginal ultrasound, despite their low sensitivity and specificity. This could be improved by the combination of several biomarkers, which has been shown in average risk patients but has not been investigated until now in female BRCA mutation carriers. METHODS: Using a multiplex, bead-based, immunoassay system, we analyzed the concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, CA125 and human epididymis antigen 4 in 26 healthy wild type women, 26 healthy BRCA1 mutation carriers, 28 wildtype OC patients and 26 OC patients with BRCA1 mutation. RESULTS: Using the ROC analysis, we found a high overall sensitivity of 94.3% in differentiating healthy controls from OC patients with comparable results in the wildtype subgroup (sensitivity 92.8%, AUC = 0.988; p = 5.2e-14) as well as in BRCA1 mutation carriers (sensitivity 95.2%, AUC = 0.978; p = 1.7e-15) at an overall specificity of 92.3%. The used algorithm also allowed to identify healthy BRCA1 mutation carriers when compared to healthy wildtype women (sensitivity 88.4%, specificity 80.7%, AUC = 0.895; p = 6e-08), while this was less pronounced in patients with OC (sensitivity 66.7%, specificity 67.8%, AUC = 0.724; p = 0.00065). CONCLUSION: We have developed an algorithm, which can differentiate between healthy women and OC patients and have for the first time shown, that such an algorithm can also be used in BRCA mutation carriers. To clarify a suggested benefit to the existing early detection program, large prospective trials with mainly early stage OC cases are warranted. PMID- 29244845 TI - Diet and stable isotope analyses reveal the feeding ecology of the orangeback squid Sthenoteuthis pteropus (Steenstrup 1855) (Mollusca, Ommastrephidae) in the eastern tropical Atlantic. AB - In the eastern tropical Atlantic, the orangeback flying squid Sthenoteuthis pteropus (Steenstrup 1855) (Cephalopoda, Ommastrephidae) is a dominant species of the epipelagic nekton community. This carnivore squid has a short lifespan and is one of the fastest-growing squids. In this study, we characterise the role of S. pteropus in the pelagic food web of the eastern tropical Atlantic by investigating its diet and the dynamics of its feeding habits throughout its ontogeny and migration. During three expeditions in the eastern tropical Atlantic in 2015, 129 specimens were caught by hand jigging. Stomach content analyses (via visual identification and DNA barcoding) were combined with stable isotope data (?15N and ?13C) of muscle tissue to describe diet, feeding habits and trophic ecology of S. pteropus. Additionally, stable isotope analyses of incremental samples along the squid's gladius-the chitinous spiniform structure supporting the muscles and organs-were carried out to explore possible diet shifts through ontogeny and migration. Our results show that S. pteropus preys mainly on myctophid fishes (e.g. Myctophum asperum, Myctophum nitidulum, Vinciguerria spp.), but also on other teleost species, cephalopods (e.g. Enoploteuthidae, Bolitinidae, Ommastrephidae), crustaceans and possibly on gelatinous zooplankton as well. The squid shows a highly opportunistic feeding behaviour that includes cannibalism. Our study indicates that the trophic position of S. pteropus may increase by approximately one trophic level from a mantle length of 15 cm to 47 cm. The reconstructed isotope-based feeding chronologies of the gladii revealed high intra- and inter-individual variability in the squid's trophic position and foraging area. These findings are not revealed by diet or muscle tissue stable isotope analysis. This suggests a variable and complex life history involving individual variation and migration. The role of S. pteropus in transferring energy and nutrients from lower to higher trophic levels may be underestimated and important for understanding how a changing ocean impacts food webs in the eastern Atlantic. PMID- 29244846 TI - Characterization of a not so new potexvirus from babaco (Vasconcellea x heilbornii). AB - A new member of the genus Potexvirus was fully sequenced and characterized. The virus was isolated from babaco (Vasconcellea x heilbornii), a natural hybrid native to Ecuador. The virus contains a 6,692 nt long genome organized in five open reading frames in an arrangement typical of other potexviruses. Sequence comparisons revealed close relatedness with Papaya mosaic virus (PapMV), Alternathera mosaic virus (AltMV) and Senna mosaic virus (SenMV), exhibiting nucleotide identities up to 67% for the polymerase (Pol) and 68% for the coat protein (CP), with deduced amino acid identities of 70% and 72% for the Pol and CP, respectively. The presence of an AlkB domain, in the polymerase region, was observed. Terminal nucleotide sequences were conserved across potexviruses with characteristic motifs and predicted secondary structures at the 3' UTR. Although serologically undistinguishable from PapMV and AltMV, the new virus showed differences in host range and symptom induction. The name babaco mosaic virus is proposed for this newly characterized Potexvirus. The complete genome sequence of the new virus has been deposited in NCBI GenBank under accession number MF978248. PMID- 29244847 TI - Cognitive failures in late adulthood: The role of age, social context and depressive symptoms. AB - The incidence of self-reported cognitive failures among older adults may be an index of successful cognitive aging. However, self-reported cognitive failures are biased by variation in depressive symptomatology. This study examined age related and socio-cultural context effects on cognitive failures while controlling for depressive symptoms. Both overall and specific factors of cognitive failures were determined. A further goal was to investigate the relationship between working memory and cognitive efficiency measures and cognitive failures. One hundred and thirty-nine cognitively healthy adults were recruited from two populations known to differ in their dispositions toward cognitive failures and depressive symptoms (Sardinia and northern Italy). The participants were assigned to Young Old (65-74 years old), Old (75-84 years of age) or Oldest Old (>=85 years of age) groups, and individually presented with a test battery including the Cognitive Failures Questionnaire, the Centre for Epidemiological Studies of Depression Scale, and Forward and Backward Digit Span tests. Specific factors of cognitive failures were differentially associated with measures of depression and working memory. While age had no impact on any aspect of cognitive failures, overall and specific dispositions varied between the two populations. The overall liability to cognitive failure was lower in participants from Sardinia, however, this group also had a higher liability to lapses of action (Blunders factor). Overall, these findings highlight that richer information about cognitive failures may be revealed through the investigation of specific factors of cognitive failures. They also confirm that the absence of changes in cognitive failures across old age is independent of variation in depressive symptoms, at least among cognitively healthy elders. PMID- 29244848 TI - Surface-modified nanoparticles as anti-biofilm filler for dental polymers. AB - The objective of the study was to synthesis silica nanoparticles modified with (i) a tertiary amine bearing two t-cinnamaldehyde substituents or (ii) dimethyl octyl ammonium, alongside the well-studied quaternary ammonium polyethyleneimine nanoparticles. These were to be evaluated for their chemical and mechanical properties, as well for antibacterial and antibiofilm activity. Samples were incorporated in commercial dental resin material and the degree of monomer conversion, mechanical strength, and water contact angle were tested to characterize the effect of the nanoparticles on resin material. Antibacterial activity was evaluated with the direct contact test and the biofilm inhibition test against Streptococcus mutans. Addition of cinnamaldehyde-modified particles preserved the degree of conversion and compressive strength of the base material and increased surface hydrophobicity. Quaternary ammonium functional groups led to a decrease in the degree of conversion and to low compressive strength, without altering the hydrophilic nature of the base material. In the direct contact test and the anti-biofilm test, the polyethyleneimine particles exhibited the strongest antibacterial effect. The cinnamaldehyde-modified particles displayed antibiofilm activity, silica particles with quaternary ammonium were ineffective. Immobilization of t-cinnamaldehyde onto a solid surface via amine linkers provided a better alternative to the well-known quaternary ammonium bactericides. PMID- 29244849 TI - Nutrients resorption and stoichiometry characteristics of different-aged plantations of Larix kaempferi in the Qinling Mountains, central China. AB - Elucidating the stoichiometry and resorption patterns of multiple nutrients is of essential importance to holistically understanding plant nutrition and biogeochemical cycling. Although many studies on ecological stoichiometry have been carried out, surprisingly few of them were simultaneously done on the investigation of both nutrient resorption efficiency and stoichiometry for different-aged plantations of a perennial tree. Here, both green and senesced leaf samples were collected from four Larix kaempfer plantations aged of 8, 15, 22, and 32 years in the Qinling Mountains to examine nutrients resorption efficiency and stoichiometry characteristics. The results suggested that the nutrient concentrations of N, P, K, Ca, Mg, Al, and Fe in both green and senesced leaves of L. kaempferi (a deciduous conifer tree) did not show a regular change trends along the plantation ages in the Qinling Mountains. The concentrations of the most nutrients examined, except for Fe, in the green leaves were relatively lower than or close to the required physiological concentrations, suggesting a relative limitation of multiple nutrients exists in L. kaempferi for its above ground biomass growth. The rank order of resorption efficiencies of four key nutrients (N, P, K, and Mg) was K (80.89%) > N (67.42%) > P (65.34%) > Mg (41.16%), whereas the nutrient Ca and Fe tended to accumulate in senesced leaves. Overall, the nutrient resorption efficiency of all examined elements did not exhibit a regular trend corresponding to the change of the plantation ages in L. kaempferi, but it was positively related to the nutrient concentrations in green leaves. The mean C:N and C:P ratios in the green and senesced leaves were significantly higher than those reported globally (on average). By contrast, the N:P ratio, at <14, was not only much lower than that reported for both China's flora and globally (on average), but it did suggest that the N nutrient limits growth of L. kaempferi in these plantations. Taken together, the results of this study are of substantial interest and value to forest managers and for the sustainable development of the Qinling forest ecosystems. PMID- 29244850 TI - Intensity matters: Therapist-dependent dose of spinal transcutaneous electrical nerve stimulation. AB - The intensity used during transcutaneous electrical nerve stimulation (TENS) in both, clinical practice and research studies, is often based on subjective commands such as "strong but comfortable sensation". There is no consensus regarding the effectiveness dose of TENS. The objective was to determine the difference in the effect of spinal TENS on soleus H-reflex modulation when applied by two therapists instructed to apply the stimulation at a "strong but comfortable" intensity. Twenty healthy volunteers divided into two groups: Therapist 1 (n = 10) and Therapist 2 (n = 10). Both therapist applied spinal TENS and sham stimulation at the T10-12 spinal level for 40min in random order to each subject, at an intensity designed to produce a "strong but comfortable" sensation. To avoid habituation, the intensity was adjusted every 2min. Soleus H reflex was recorded before, during, and 10min after TENS by an observer blinded to the stimulus applied. Despite the instruction to apply TENS at a "strong comfortable" level, a significant difference in current density was identified: Therapist 1 (0.67mA/cm2, SD 0.54) applied more than Therapist 2 (0.53mA/cm2, SD 0.57; p<0.001) at the onset of the intervention. Maximal peak-to-peak H-reflex amplitude was inhibited significantly more 10min following TENS applied by Therapist 1 (-0.15mV, SD 0.16) compared with Therapist 2 (0.04mV, SD 0.16; p = 0.03). Furthermore, current density significantly correlated with the inhibitory effect on peak-to-peak Soleus H-reflex amplitude 10 min after stimulation (Rho = 0.38; p = 0.04). TENS intensity dosage by the therapist based on the subjective perception of the participants alone is unreliable and requires objective standardization. In addition, higher current density TENS produced greater inhibition of the Soleus H-reflex. PMID- 29244852 TI - Proteometabolomic response of Deinococcus radiodurans exposed to UVC and vacuum conditions: Initial studies prior to the Tanpopo space mission. AB - The multiple extremes resistant bacterium Deinococcus radiodurans is able to withstand harsh conditions of simulated outer space environment. The Tanpopo orbital mission performs a long-term space exposure of D. radiodurans aiming to investigate the possibility of interplanetary transfer of life. The revealing of molecular machinery responsible for survivability of D. radiodurans in the outer space environment can improve our understanding of underlying stress response mechanisms. In this paper, we have evaluated the molecular response of D. radiodurans after the exposure to space-related conditions of UVC irradiation and vacuum. Notably, scanning electron microscopy investigations showed that neither morphology nor cellular integrity of irradiated cells was affected, while integrated proteomic and metabolomic analysis revealed numerous molecular alterations in metabolic and stress response pathways. Several molecular key mechanisms of D. radiodurans, including the tricarboxylic acid cycle, the DNA damage response systems, ROS scavenging systems and transcriptional regulators responded in order to cope with the stressful situation caused by UVC irradiation under vacuum conditions. These results reveal the effectiveness of the integrative proteometabolomic approach as a tool in molecular analysis of microbial stress response caused by space-related factors. PMID- 29244851 TI - Inhibition of merozoite invasion and transient de-sequestration by sevuparin in humans with Plasmodium falciparum malaria. AB - SEVERE MALARIA: Even with the best available treatment, the mortality from severe Plasmodium falciparum malaria remains high. Typical features at death are high parasite loads and obstructed micro- vasculature. Infected erythrocytes (IE) containing mature parasites bind to the host receptor heparan sulfate, which is also an important receptor for merozoite invasion. To block merozoite invasion has not previously been proposed as an adjunctive therapeutic approach but it may preclude the early expansion of an infection that else leads to exacerbated sequestration and death. SEVUPARIN IN PHASE I STUDY: The drug sevuparin was developed from heparin because heparan sulfate and heparin are nearly identical, so the rationale was that sevuparin would act as a decoy receptor during malaria infection. A phase I study was performed in healthy male volunteers and sevuparin was found safe and well tolerated. SEVUPARIN IN PHASE I/II CLINICAL STUDY: A phase I/II clinical study was performed in which sevuparin was administered via short intravenous infusions to malaria patients with uncomplicated malaria who were also receiving atovaquone/proguanil treatment. This was a Phase I/II, randomized, open label, active control, parallel assignment study. Sevuparin was safe and well tolerated in the malaria patients. The mean relative numbers of ring-stage IEs decreased after a single sevuparin infusion and mature parasite IEs appeared transiently in the circulation. The effects observed on numbers of merozoites and throphozoites in the circulation, were detected already one hour after the first sevuparin injection. Here we report the development of a candidate drug named sevuparin that both blocks merozoite invasion and transiently de-sequesters IE in humans with P. falciparum malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT01442168. PMID- 29244853 TI - Limited detection of small (<= 10 mm) colorectal liver metastasis at preoperative CT in patients undergoing liver resection. AB - OBJECTIVE: To retrospectively determine the sensitivity of preoperative CT in the detection of small (<= 10 mm) colorectal liver metastasis (CRLM) nodules in patients undergoing liver resection. METHODS: The institutional review board approved the study and waived informed consent. We included 461 pathologically confirmed CRLM nodules in 211 patients (including 71 women; mean age, 66.4 years) who underwent 229 liver resections following abdominal CT. Prior to 163 resections, gadoxetic acid-enhanced liver MR imaging was also performed. Nodules were matched between pathology reports and prospective CT reports following a predefined algorithm. Per-nodule sensitivity of CT was calculated by nodule-size category. Generalized estimating equations were used to adjust for within-case correlation. RESULTS: Fourteen nodule sizes were missing in the pathology report. Nodules of 1-5 mm and 6-10 mm accounted for 8.1% (n = 36) and 23.5% (n = 105) of the remaining 447 nodules, and the number of nodules gradually decreased as nodule size increased beyond 10 mm. The overall sensitivity of CT was 81.2% (95% confidence interval, 77.1%, 85.2%; 365/461). The sensitivity was 8% (0%, 17%; 3/36), 55% (45%, 65%; 59/105), 91%, 95%, and 100% for nodules of 1-5 mm, 6-10 mm, 11-15 mm, 16-20 mm, and >20 mm, respectively. The nodule-size distribution was similar between resections undergoing gadoxetic acid-enhanced MR imaging and those not undergoing the MR imaging. CONCLUSION: CT has limited sensitivity for nodules of <= 10 mm and particularly of <= 5 mm. PMID- 29244854 TI - Morphological switch to a resistant subpopulation in response to viral infection in the bloom-forming coccolithophore Emiliania huxleyi. AB - Recognizing the life cycle of an organism is key to understanding its biology and ecological impact. Emiliania huxleyi is a cosmopolitan marine microalga, which displays a poorly understood biphasic sexual life cycle comprised of a calcified diploid phase and a morphologically distinct biflagellate haploid phase. Diploid cells (2N) form large-scale blooms in the oceans, which are routinely terminated by specific lytic viruses (EhV). In contrast, haploid cells (1N) are resistant to EhV. Further evidence indicates that 1N cells may be produced during viral infection. A shift in morphology, driven by meiosis, could therefore constitute a mechanism for E. huxleyi cells to escape from EhV during blooms. This process has been metaphorically coined the 'Cheshire Cat' (CC) strategy. We tested this model in two E. huxleyi strains using a detailed assessment of morphological and ploidy level variations as well as expression of gene markers for meiosis and the flagellate phenotype. We showed that following the CC model, production of resistant cells was triggered during infection. This led to the rise of a new subpopulation of cells in the two strains that morphologically resembled haploid cells and were resistant to EhV. However, ploidy-level analyses indicated that the new resistant cells were diploid or aneuploid. Thus, the CC strategy in E. huxleyi appears to be a life-phase switch mechanism involving morphological remodeling that is decoupled from meiosis. Our results highlight the adaptive significance of morphological plasticity mediating complex host-virus interactions in marine phytoplankton. PMID- 29244855 TI - Vitreous hyper-reflective dots in pseudophakic cystoid macular edema assessed with optical coherence tomography. AB - PURPOSE: This study compares the presence of vitreous hyper-reflective dots (VHDs) detected with optical coherence tomography (OCT) between eyes with pseudophakic cystoid macular edema (CME) and those with no CME after cataract surgery. In addition, we evaluated the impact of VHDs on the responsiveness of pseudophakic CME to cortisone treatment. SETTING: Department of Ophthalmology, Medical University of Graz, Austria. DESIGN: Retrospective, monocenter case controlled study. METHODS: Inclusion criteria for the study group and the control group were CME and no CME within 12 weeks following uneventful phacoemulsification in otherwise healthy eyes, respectively. VHDs (number and size) and the macular thickness were assessed with OCT. Furthermore, the number of peribulbar or intravitreal steroid injections was assessed. RESULTS: A total of 284 eyes from 267 patients were analyzed, among which 119 met the inclusion criteria for the study (n = 63) and the control group (n = 56). VHDs were observed in 54 (85.7%) study eyes and 21 (37.5%, p = 0.013) control eyes. The number of VHDs was 3.9+/-3.4 in the study group and 0.7+/-1 in the control group (p<0.001). The size of the VHDs was 33.5+/-9.1 MUm and 36.6+/-17.9 MUm in the study and control groups, respectively (p = 0.978). Overall, the number of VHDs correlated with central subfield thickness (r = 0.584, p<0.001), cube volume (r = 0.525, p<0.001), and postoperative best-corrected visual acuity (BCVA) (r = 0.563, p<0.001). The number of VHDs did not correlate with the frequency of peribulbar or intravitreal steroid injections. CONCLUSION: VHDs occurred more often in eyes with CME than in eyes without CME following cataract surgery. In addition, the number of VHDs had an impact on the extent of macular thickening and subsequently postoperative BCVA. No correlation was found between the number of VHDs and the frequency of required peribulbar or intravitreal steroid injections. PMID- 29244856 TI - In vitro anthelmintic effects of Spigelia anthelmia protein fractions against Haemonchus contortus. AB - Gastrointestinal nematodes are a significant concern for animal health and well being, and anthelmintic treatment is mainly performed through the use of chemical products. However, bioactive compounds produced by plants have shown promise for development as novel anthelmintics. The aim of this study is to assess the anthelmintic activity of protein fractions from Spigelia anthelmia on the gastrointestinal nematode Haemonchus contortus. Plant parts were separated into leaves, stems and roots, washed with distilled water, freeze-dried and ground into a fine powder. Protein extraction was performed with sodium phosphate buffer (75 mM, pH 7.0). The extract was fractionated using ammonium sulfate (0-90%) and extensively dialyzed. The resulting fractions were named LPF (leaf protein fraction), SPF (stem protein fraction) and RPF (root protein fraction), and the protein contents and activities of the fractions were analyzed. H. contortus egg hatching (EHA), larval exsheathment inhibition (LEIA) and larval migration inhibition (LMIA) assays were performed. Proteomic analysis was conducted, and high-performance liquid chromatography (HPLC) chromatographic profiles of the fractions were established to identify proteins and possible secondary metabolites. S. anthelmia fractions inhibited H. contortus egg hatching, with LPF having the most potent effects (EC50 0.17 mg mL-1). During LEIA, SPF presented greater efficiency than the other fractions (EC50 0.25 mg mL-1). According to LMIA, the fractions from roots, stems and leaves also reduced the number of larvae, with EC50 values of 0.11, 0.14 and 0.21 mg mL-1, respectively. Protein analysis indicated the presence of plant defense proteins in the S. anthelmia fractions, including protease, protease inhibitor, chitinase and others. Conversely, secondary metabolites were absent in the S. anthemia fractions. These results suggest that S. anthelmia proteins are promising for the control of the gastrointestinal nematode H. contortus. PMID- 29244857 TI - Maternal plasma angiogenic and inflammatory factor profiling in foetal Down syndrome. AB - OBJECTIVE AND DESIGN: Angiogenic factors are proteins that are related to certain foetal chromosomal abnormalities. The aim of this study was to determine the concentration of 60 angiogenic factors in the plasma of women with offspring possessing trisomy 21/Down syndrome (DS). METHOD: After analysing karyotyping results, we selected 20 patients with foetuses possessing DS, and for the control group, we selected 28 healthy patients with uncomplicated pregnancies who delivered healthy newborns at term (i.e., 15-18 weeks of gestation). To assess the concentration of proteins in the blood plasma, we used a protein macroarray which enabled simultaneous determination of 60 angiogenic factors per sample. RESULTS: We observed a statistically significant increase in the concentration of these five angiogenic and inflammatory factors: TGFb1 (p = 0.039), angiostatin (p = 0.0142), I-309 (p = 0.0476), TGFb3 (p = 0.0395), and VEGF-D (p = 0.0173) compared to concentrations in patients with healthy foetuses. CONCLUSION: Our findings suggest that angiogenic factors may play role in DS pathogenesis. PMID- 29244858 TI - Correction: Protocols for the delivery of small molecules to the two-spotted spider mite, Tetranychus urticae. AB - [This corrects the article DOI: 10.1371/journal.pone.0180658.]. PMID- 29244859 TI - The second molecular epidemiological study of HIV infection in Mongolia between 2010 and 2016. AB - OBJECTIVE: Our previous 2005-2009 molecular epidemiological study in Mongolia identified a hot spot of HIV-1 transmission in men who have sex with men (MSM). To control the infection, we collaborated with NGOs to promote safer sex and HIV testing since mid-2010. In this study, we carried out the second molecular epidemiological survey between 2010 and 2016 to determine the status of HIV-1 infection in Mongolia. METHODS: The study included 143 new cases of HIV-1 infection. Viral RNA was extracted from stocked plasma samples and sequenced for the pol and the env regions using the Sanger method. Near-full length sequencing using MiSeq was performed in 3 patients who were suspected to be infected with recombinant HIV-1. Phylogenetic analysis was performed using the neighbor-joining method and Bayesian Markov chain Monte Carlo method. RESULTS: MSM was the main transmission route in the previous and current studies. However, heterosexual route showed a significant increase in recent years. Phylogenetic analysis documented three taxa; Mongolian B, Korean B, and CRF51_01B, though the former two were also observed in the previous study. CRF51_01B, which originated from Singapore and Malaysia, was confirmed by near-full length sequencing. Although these strains were mainly detected in MSM, they were also found in increasing numbers of heterosexual males and females. Bayesian phylogenetic analysis estimated transmission of CRF51_01B into Mongolia around early 2000s. An extended Bayesian skyline plot showed a rapid increase in the effective population size of Mongolian B cluster around 2004 and that of CRF51_01B cluster around 2011. CONCLUSIONS: HIV-1 infection might expand to the general population in Mongolia. Our study documented a new cluster of HIV-1 transmission, enhancing our understanding of the epidemiological status of HIV-1 in Mongolia. PMID- 29244860 TI - Lithium reduces blood glucose levels, but aggravates albuminuria in BTBR-ob/ob mice. AB - Glycogen synthase kinase 3 (GSK3) plays an important role in the development of diabetes mellitus and renal injury. GSK3 inhibition increases glucose uptake in insulin-insensitive muscle and adipose tissue, while it reduces albuminuria and glomerulosclerosis in acute kidney injury. The effect of chronic GSK3 inhibition in diabetic nephropathy is not known. We tested the effect of lithium, the only clinical GSK3 inhibitor, on the development of diabetes mellitus and kidney injury in a mouse model of diabetic nephropathy. Twelve-week old female BTBR ob/ob mice were treated for 12 weeks with 0, 10 and 40 mmol LiCl/kg after which the development of diabetes and diabetic nephropathy were analysed. In comparison to BTBR-WT mice, ob/ob mice demonstrated elevated bodyweight, increased blood glucose/insulin levels, urinary albumin and immunoglobulin G levels, glomerulosclerosis, reduced nephrin abundance and a damaged proximal tubule brush border. The lithium-10 and -40 diets did not affect body weight and resulted in blood lithium levels of respectively <0.25 mM and 0.48 mM. The Li-40 diet fully rescued the elevated non-fasting blood glucose levels. Importantly, glomerular filtration rate was not affected by lithium, while urine albumin and immunoglobulin G content were further elevated. While lithium did not worsen the glomerulosclerosis, proximal tubule function seemed affected by lithium, as urinary NGAL levels were significantly increased. These results demonstrate that lithium attenuates non-fasting blood glucose levels in diabetic mice, but aggravates urinary albumin and immunoglobulin G content, possibly resulting from proximal tubule dysfunction. PMID- 29244861 TI - Reliability of the parameters of the power-duration relationship using maximal effort time-trials under laboratory conditions. AB - The purpose of this study was to assess the reliability of critical power (CP) and the total amount of work accomplished above CP (W') across repeated tests using ecologically valid maximal effort time-trials (TT) under laboratory conditions. After an initial incremental exercise test, ten well-trained male triathletes (age: 28.5 +/- 4.7 years; body mass: 73.3 +/- 7.9 kg; height: 1.80 +/ 0.07 m; maximal aerobic power [MAP]: 329 +/- 41 W) performed three testing sessions (Familiarization, Test I and Test II) each comprising three TT (12, 7, and 3 min with a passive recovery of 60 min between trials). CP and W' were determined using a linear regression of power vs. the inverse of time (1/t) (P = W' ? 1/t + CP). A repeated-measures ANOVA was used to detect differences in CP and W' and reliability was assessed using the intra-class correlation coefficient (ICC) and the coefficient of variation (CoV). CP and W' values were not significantly different between repeated tests (P = 0.171 and P = 0.078 for CP and W', respectively). The ICC between Familiarization and Test I was r = 0.86 (CP) and r = 0.58 (W') and between Tests I and II it was r = 0.94 (CP) and r = 0.95 (W'). The CoV notably decreased from 4.1% to 2.6% and from 25.3% to 8.2% for CP and W', respectively. Despite the non-significant differences for both parameter estimates between Familiarization, Test I, and Test II, ICC and CoV values improved notably after the familiarization trial. Our novel findings indicate that for both, CP and W' a familiarization trial increased reliability. It is therefore advisable to familiarize well-trained athletes when determining the power-duration relationship using TT under laboratory conditions. PMID- 29244862 TI - Application of system dynamics and participatory spatial group model building in animal health: A case study of East Coast Fever interventions in Lundazi and Monze districts of Zambia. AB - East Coast Fever (ECF) is the most economically important production disease among traditional beef cattle farmers in Zambia. Despite the disease control efforts by the government, donors, and farmers, ECF cases are increasing. Why does ECF oscillate over time? Can alternative approaches such as systems thinking contribute solutions to the complex ECF problem, avoid unintended consequences, and achieve sustainable results? To answer these research questions and inform the design and implementation of ECF interventions, we qualitatively investigated the influence of dynamic socio-economic, cultural, and ecological factors. We used system dynamics modelling to specify these dynamics qualitatively, and an innovative participatory framework called spatial group model building (SGMB). SGMB uses participatory geographical information system (GIS) concepts and techniques to capture the role of spatial phenomenon in the context of complex systems, allowing stakeholders to identify spatial phenomenon directly on physical maps and integrate such information in model development. Our SGMB process convened focus groups of beef value chain stakeholders in two distinct production systems. The focus groups helped to jointly construct a series of interrelated system dynamics models that described ECF in a broader systems context. Thus, a complementary objective of this study was to demonstrate the applicability of system dynamics modelling and SGMB in animal health. The SGMB process revealed policy leverage points in the beef cattle value chain that could be targeted to improve ECF control. For example, policies that develop sustainable and stable cattle markets and improve household income availability may have positive feedback effects on investment in animal health. The results obtained from a SGMB process also demonstrated that a "one-size-fits-all" approach may not be equally effective in policing ECF in different agro ecological zones due to the complex interactions of socio-ecological context with important, and often ignored, spatial patterns. PMID- 29244863 TI - A parapoxviral virion protein targets the retinoblastoma protein to inhibit NF kappaB signaling. AB - Poxviruses have evolved multiple strategies to subvert signaling by Nuclear Factor kappaB (NF-kappaB), a crucial regulator of host innate immune responses. Here, we describe an orf virus (ORFV) virion-associated protein, ORFV119, which inhibits NF-kappaB signaling very early in infection (<= 30 min post infection). ORFV119 NF-kappaB inhibitory activity was found unimpaired upon translation inhibition, suggesting that virion ORFV119 alone is responsible for early interference in signaling. A C-terminal LxCxE motif in ORFV119 enabled the protein to interact with the retinoblastoma protein (pRb) a multifunctional protein best known for its tumor suppressor activity. Notably, experiments using a recombinant virus containing an ORFV119 mutation which abrogates its interaction with pRb together with experiments performed in cells lacking or with reduced pRb levels indicate that ORFV119 mediated inhibition of NF-kappaB signaling is largely pRb dependent. ORFV119 was shown to inhibit IKK complex activation early in infection. Consistent with IKK inhibition, ORFV119 also interacted with TNF receptor associated factor 2 (TRAF2), an adaptor protein recruited to signaling complexes upstream of IKK in infected cells. ORFV119-TRAF2 interaction was enhanced in the presence of pRb, suggesting that ORFV119-pRb complex is required for efficient interaction with TRAF2. Additionally, transient expression of ORFV119 in uninfected cells was sufficient to inhibit TNFalpha induced IKK activation and NF-kappaB signaling, indicating that no other viral proteins are required for the effect. Infection of sheep with ORFV lacking the ORFV119 gene led to attenuated disease phenotype, indicating that ORFV119 contributes to virulence in the natural host. ORFV119 represents the first poxviral protein to interfere with NF-kappaB signaling through interaction with pRb. PMID- 29244864 TI - Resistant and susceptible responses in alfalfa (Medicago sativa) to bacterial stem blight caused by Pseudomonas syringae pv. syringae. AB - Bacterial stem blight caused by Pseudomonas syringae pv. syringae is a common disease of alfalfa (Medicago sativa L). Little is known about host-pathogen interactions and host defense mechanisms. Here, individual resistant and susceptible plants were selected from cultivars Maverick and ZG9830 and used for transcript profiling at 24 and 72 hours after inoculation (hai) with the isolate PssALF3. Bioinformatic analysis revealed a number of differentially expressed genes (DEGs) in resistant and susceptible genotypes. Although resistant plants from each cultivar produced a hypersensitive response, transcriptome analyses indicated that they respond differently at the molecular level. The number of DEGs was higher in resistant plants of ZG9830 at 24 hai than in Maverick, suggesting that ZG9830 plants had a more rapid effector triggered immune response. Unique up-regulated genes in resistant ZG9830 plants included genes encoding putative nematode resistance HSPRO2-like proteins, orthologs for the rice Xa21 and soybean Rpg1-b resistance genes, and TIR-containing R genes lacking both NBS and LRR domains. The suite of R genes up-regulated in resistant Maverick plants had an over-representation of R genes in the CC-NBS-LRR family including two genes for atypical CCR domains and a putative ortholog of the Arabidopsis RPM1 gene. Resistance in both cultivars appears to be mediated primarily by WRKY family transcription factors and expression of genes involved in protein phosphorylation, regulation of transcription, defense response including synthesis of isoflavonoids, and oxidation-reduction processes. These results will further the identification of mechanisms involved in resistance to facilitate selection of parent populations and development of commercial varieties. PMID- 29244866 TI - Molecular dynamics simulations of the glucocorticoid receptor DNA-binding domain suggest a role of the lever-arm mobility in transcriptional output. AB - One of the first and essential steps in gene expression regulation involves the recruitment of transcription factors (TFs) to specific response elements located at enhancers and/or promoters of targeted genes. These DNA elements have a certain variability in both sequence and length, which may affect the final transcriptional output. The molecular mechanisms in which TFs integrate the subtle differences within specific recognition sequences to offer different transcriptional responses is still largely unknown. Here we used molecular dynamics simulations to study the DNA binding behavior of the glucocorticoid receptor (GR), a ligand-regulated TF with pleiotropic effects in almost all cells. By comparing the behavior of the wild type receptor and a well characterized Ala477Thr substitution within the rat GR DNA binding domain, we found that the region that connects the two-zinc fingers (i.e. the lever arm) would likely play a key role in GR transcriptional output. PMID- 29244865 TI - The Arabidopsis thaliana F-box gene HAWAIIAN SKIRT is a new player in the microRNA pathway. AB - In Arabidopsis, the F-box HAWAIIAN SKIRT (HWS) protein is important for organ growth. Loss of function of HWS exhibits pleiotropic phenotypes including sepal fusion. To dissect the HWS role, we EMS-mutagenized hws-1 seeds and screened for mutations that suppress hws-1 associated phenotypes. We identified shs-2 and shs 3 (suppressor of hws-2 and 3) mutants in which the sepal fusion phenotype of hws 1 was suppressed. shs-2 and shs-3 (renamed hst-23/hws-1 and hst-24/hws-1) carry transition mutations that result in premature terminations in the plant homolog of Exportin-5 HASTY (HST), known to be important in miRNA biogenesis, function and transport. Genetic crosses between hws-1 and mutant lines for genes in the miRNA pathway also suppress the phenotypes associated with HWS loss of function, corroborating epistatic relations between the miRNA pathway genes and HWS. In agreement with these data, accumulation of miRNA is modified in HWS loss or gain of function mutants. Our data propose HWS as a new player in the miRNA pathway, important for plant growth. PMID- 29244867 TI - Dietary sources and intakes of folates and vitamin B12 in the Spanish population: Findings from the ANIBES study. AB - BACKGROUND: Folates and vitamin B12 are key nutrients in one-carbon metabolism and related diseases. Updated and plausible information on population intakes and their major dietary sources is scarce and urgently needed in Spain in order to increase the knowledge that can lead as previous step to prevention by fortification and supplementation policies. AIMS: The present study aims to evaluate main dietary folate and vitamin B12 sources and intakes in the Spanish population. MATERIALS AND METHODS: Results were derived from the ANIBES cross sectional study using a nationally representative sample of the Spanish population (9-75 years, n = 2,009). RESULTS: Food groups with the highest mean proportional contribution to total folate intakes in both males and females were vegetables (21.7-24.9%) and cereals (10.7-11.2%), while meat and meat products (26.4%) and milk and dairy products (27.3%) were for B12. Total median folate and B12 intakes amongst women were 156.3 MUg/d and 4.0 MUg/d while for men were 163.6 MUg/d and 4.5 MUg/d, respectively. In all age groups, vitamin intakes were significantly higher in plausible than in non-plausible energy reporters. CONCLUSION: A limited number of participants had adequate folate intakes, whereas vitamin B12 intakes were adequate for practically the entire population. There is a clear need for improving folates intake in the Spanish population. PMID- 29244869 TI - LSPR-mediated high axial-resolution fluorescence imaging on a silver nanoparticle sheet. AB - This paper reports our original technique for visualizing cell-attached nanointerfaces with extremely high axial resolution using homogeneously excited localized surface plasmon resonance (LSPR) on self-assembled silver nanoparticle sheets. The LSPR sheet can confine and enhance the fluorescence at the nanointerface, which provides high signal-to-noise ratio images of focal adhesion at the cell-attached interface. The advantage of this LSPR-assisted technique is its usability, which provides comparable or higher-quality nanointerfacial images than TIRF microscopy, even under epifluorescence microscopy. We also report the cytotoxicity of silver nanoparticles, as determined via morphological analysis of adherent cells on the sheet. PMID- 29244868 TI - Cyclodextrin-containing hydrogels as an intraocular lens for sustained drug release. AB - To improve the efficacy of anti-inflammatory factors in patients who undergo cataract surgery, poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (p(HEMA-co-MMA)) hydrogels containing beta-cyclodextrin (beta-CD) (pHEMA/MMA/beta CD) were designed and prepared as intraocular lens (IOLs) biomaterials that could be loaded with and achieve the sustained release of dexamethasone. A series of pHEMA/MMA/beta-CD copolymers containing different ratios of beta-CD (range, 2.77 to 10.24 wt.%) were obtained using thermal polymerization. The polymers had high transmittance at visible wavelengths and good biocompatibility with mouse connective tissue fibroblasts. Drug loading and release studies demonstrated that introducing beta-CD into hydrogels increased loading efficiency and achieved the sustained release of the drug. Administering beta-CD via hydrogels increased the equilibrium swelling ratio, elastic modulus and tensile strength. In addition, beta-CD increased the hydrophilicity of the hydrogels, resulting in a lower water contact angle and higher cellular adhesion to the hydrogels. In summary, pHEMA/MMA/beta-CD hydrogels show great potential as IOL biomaterials that are capable of maintaining the sustained release of anti-inflammatory drugs after cataract surgery. PMID- 29244870 TI - Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake. AB - Human hepatic lipase (hHL) is mainly localized on the hepatocyte cell surface where it hydrolyzes lipids from remnant lipoproteins and high density lipoproteins and promotes their hepatic selective uptake. Furthermore, hepatic lipase (HL) is closely associated with obesity in multiple studies. Therefore, HL may play a key role on lipid homeostasis in liver and white adipose tissue (WAT). In the present study, we aimed to evaluate the effects of hHL expression on hepatic and white adipose triglyceride metabolism in vivo. Experiments were carried out in hHL transgenic and wild-type mice fed a Western-type diet. Triglyceride metabolism studies included beta-oxidation and de novo lipogenesis in liver and WAT, hepatic triglyceride secretion, and adipose lipoprotein lipase (LPL)-mediated free fatty acid (FFA) lipolysis and influx. The expression of hHL promoted hepatic triglyceride accumulation and de novo lipogenesis without affecting triglyceride secretion, and this was associated with an upregulation of Srebf1 as well as the main genes controlling the synthesis of fatty acids. Transgenic mice also exhibited more adiposity and an increased LPL-mediated FFA influx into the WAT without affecting glucose tolerance. Our results demonstrate that hHL promoted hepatic steatosis in mice mainly by upregulating de novo lipogenesis. HL also upregulated WAT LPL and promoted triglyceride-rich lipoprotein hydrolysis and adipose FFA uptake. These data support the important role of hHL in regulating hepatic lipid homeostasis and confirm the broad cardiometabolic role of HL. PMID- 29244872 TI - The ubiquitin-proteasome system is required for African swine fever replication. AB - Several viruses manipulate the ubiquitin-proteasome system (UPS) to initiate a productive infection. Determined viral proteins are able to change the host's ubiquitin machinery and some viruses even encode their own ubiquitinating or deubiquitinating enzymes. African swine fever virus (ASFV) encodes a gene homologous to the E2 ubiquitin conjugating (UBC) enzyme. The viral ubiquitin conjugating enzyme (UBCv1) is expressed throughout ASFV infection and accumulates at late times post infection. UBCv is also present in the viral particle suggesting that the ubiquitin-proteasome pathway could play an important role at early ASFV infection. We determined that inhibition of the final stage of the ubiquitin-proteasome pathway blocked a post-internalization step in ASFV replication in Vero cells. Under proteasome inhibition, ASF viral genome replication, late gene expression and viral production were severely reduced. Also, ASFV enhanced proteasome activity at late times and the accumulation of polyubiquitinated proteins surrounding viral factories. Core-associated and/or viral proteins involved in DNA replication may be targets for the ubiquitin proteasome pathway that could possibly assist virus uncoating at final core breakdown and viral DNA release. At later steps, polyubiquitinated proteins at viral factories could exert regulatory roles in cell signaling. PMID- 29244871 TI - Inflammatory monocytes mediate control of acute alphavirus infection in mice. AB - Chikungunya virus (CHIKV) and Ross River virus (RRV) are mosquito-transmitted alphaviruses that cause debilitating acute and chronic musculoskeletal disease. Monocytes are implicated in the pathogenesis of these infections; however, their specific roles are not well defined. To investigate the role of inflammatory Ly6ChiCCR2+ monocytes in alphavirus pathogenesis, we used CCR2-DTR transgenic mice, enabling depletion of these cells by administration of diptheria toxin (DT). DT-treated CCR2-DTR mice displayed more severe disease following CHIKV and RRV infection and had fewer Ly6Chi monocytes and NK cells in circulation and muscle tissue compared with DT-treated WT mice. Furthermore, depletion of CCR2+ or Gr1+ cells, but not NK cells or neutrophils alone, restored virulence and increased viral loads in mice infected with an RRV strain encoding attenuating mutations in nsP1 to levels detected in monocyte-depleted mice infected with fully virulent RRV. Disease severity and viral loads also were increased in DT treated CCR2-DTR+;Rag1-/- mice infected with the nsP1 mutant virus, confirming that these effects are independent of adaptive immunity. Monocytes and macrophages sorted from muscle tissue of RRV-infected mice were viral RNA positive and had elevated expression of Irf7, and co-culture of Ly6Chi monocytes with RRV-infected cells resulted in induction of type I IFN gene expression in monocytes that was Irf3;Irf7 and Mavs-dependent. Consistent with these data, viral loads of the attenuated nsP1 mutant virus were equivalent to those of WT RRV in Mavs-/- mice. Finally, reconstitution of Irf3-/-;Irf7-/- mice with CCR2 DTR bone marrow rescued mice from severe infection, and this effect was reversed by depletion of CCR2+ cells, indicating that CCR2+ hematopoietic cells are capable of inducing an antiviral response. Collectively, these data suggest that MAVS-dependent production of type I IFN by monocytes is critical for control of acute alphavirus infection and that determinants in nsP1, the viral RNA capping protein, counteract this response. PMID- 29244874 TI - Maximum walking speed in multiple sclerosis assessed with visual perceptive computing. AB - BACKGROUND: Gait is often impaired in people with multiple sclerosis (PwMS), but detailed assessment of gait impairment in research and care remains challenging. In a previous pilot study we reported the feasibility of visual perceptive computing (VPC) for gait assessment in PwMS using the Short Maximum Speed Walk (SMSW), which assesses gait on recording distances confined to less than 4 meters. OBJECTIVE: To investigate the equivalence of SMSW to rater-based timed 25ft. walk (T25FW) in a large cohort of PwMS, and to investigate the association of SMSW-derived gait parameters with clinical disability, as well as subjective and objective gait impairment, in order to validate the SMSW as a quick and objective measure of clinical relevance possibly superior to T25FW. METHODS: 95 PwMS and 60 healthy controls (HC) performed the SMSW using a VPC system with Microsoft Kinect. All participants received two immediate retests to establish test-retest-reliability. Both PwMS and HC performed the T25FW. PwMS were rated according to the Expanded Disability Status Scale (EDSS) and answered the 12-item Multiple Sclerosis Walking Scale (MSWS-12) as a measure of self-perceived walking impairment. RESULTS: PwMS showed reduced average speed (p<0.001) and higher mediolateral deviation (p = 0.002) during SMSW than HC. Average speed was the most reliable SMSW parameter in PwMS and HC (intra-class correlation coefficient (ICC) in PwMS = 0.985, and in HC = 0.977). Average speed declined with age in PwMS and HC (r in PwMS = -0.648, and in HC = -0.452, both p<0.001). Correlation of SMSW average speed and T25FW speed was high in both groups (r in PwMS = 0.783, and in HC = 0.747, both p<0.001) and mean difference (0.0013 m/s) between methods was below smallest detectable change. Average speed correlated well with both clinical disability based on EDSS (r = -0.586, p<0.001) and self-perceived walking impairment based on MSWS-12 (r = -0.546, p<0.001). CONCLUSION: VPC assessed walking parameters during SMSW can reliably detect gait disturbance in PwMS over very short distance. Specifically, maximum gait speed can be obtained with high accuracy in this simple test set-up. Cross-sectional associations with disability and self-perceived walking impairment support clinical relevance. Given its objectivity in a simple test set-up, SMSW is superior to T25FW. PMID- 29244873 TI - Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD) NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel [15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI] predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity [AUROC = 0.92]. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn't affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment. PMID- 29244875 TI - Effect of age and stereopsis on a multiple-object tracking task. AB - 3D vision develops during childhood and tends to diminish after 65 years of age. It is still relatively unknown how stereopsis is used in more complex/ecological contexts such as when walking about in crowds where objects are in motion and occlusions occur. One task that shares characteristics with the requirements for processing dynamic crowds is the multiple object-tracking task (MOT). In the present study we evaluated the impact of stereopsis on a MOT task as a function of age. A total of 60 observers consisting of three groups of 20 subjects (7-12 years old, 18-40 years old and 65 years and older) completed the task in both conditions (with and without stereoscopic effects). The adult group obtained the better scores, followed by the children and the older adult group. The performance difference between the stereoscopic and non-stereoscopic conditions was significant and similar for the adults and the children but was non significant for the older observers. These results show that stereopsis helps children and adults accomplish a MOT task, but has no impact on older adults' performances. The present results have implications as to how populations differ in their efficiency of using stereoscopic cues for disambiguating complex dynamic scenes. PMID- 29244876 TI - Water quality assessment of Australian ports using water quality evaluation indices. AB - Australian ports serve diverse and extensive activities, such as shipping, tourism and fisheries, which may all impact the quality of port water. In this work water quality monitoring at different ports using a range of water quality evaluation indices was applied to assess the port water quality. Seawater samples at 30 stations in the year 2016-2017 from six ports in NSW, Australia, namely Port Jackson, Botany, Kembla, Newcastle, Yamba and Eden, were investigated to determine the physicochemical and biological variables that affect the port water quality. The large datasets obtained were designed to determine the Water Quality Index, Heavy metal Evaluation Index, Contamination Index and newly developed Environmental Water Quality Index. The study revealed medium water quality index and high and medium heavy metal evaluation index at three of the study ports and high contamination index in almost all study ports. Low level dissolved oxygen and higher level of total dissolved solids, turbidity, fecal coliforms, copper, iron, lead, zinc, manganese, cadmium and cobalt are mainly responsible for the poor water qualities of the port areas. Good water quality at the background samples indicated that various port activities are the likely cause for poor water quality inside the port area. PMID- 29244877 TI - Identification and characterization of the three members of the CLC family of anion transport proteins in Trypanosoma brucei. AB - CLC type anion transport proteins are homo-dimeric or hetero-dimeric with an integrated transport function in each subunit. We have identified and partially characterized three members of this family named TbVCL1, TbVCL2 and TbVCL3 in Trypanosoma brucei. Among the human CLC family members, the T. brucei proteins display highest similarity to CLC-6 and CLC-7. TbVCL1, but not TbVCL2 and TbVCL3 is able to complement growth of a CLC-deficient Saccharomyces cerevisiae mutant. All TbVCL-HA fusion proteins localize intracellulary in procyclic form trypanosomes. TbVCL1 localizes close to the Golgi apparatus and TbVCL2 and TbVCL3 to the endoplasmic reticulum. Upon expression in Xenopus oocytes, all three proteins induce similar outward rectifying chloride ion currents. Currents are sensitive to low concentrations of DIDS, insensitive to the pH in the range 5.4 to 8.4 and larger in nitrate than in chloride medium. PMID- 29244878 TI - Isolation and functional analysis of fatty acid desaturase genes from peanut (Arachis hypogaea L.). AB - BACKGROUND: Fatty acid desaturases are enzymes that introduce double bonds into fatty acyl chains. Extensive studies of fatty acid desaturases have been done in many plants. However, less is known about the diversity of this gene family in peanut (Arachis hypogaea L.), an important oilseed crop that is cultivated worldwide. RESULTS: In this study, twelve novel AhFADs genes were identified and isolated from peanut. Quantitative real-time PCR analysis indicated that the transcript abundances of AhFAB2-2 and AhFAD3-1 were higher in seeds than in other tissues examined, whereas the AhADS and AhFAD7-1 transcripts were more abundant in leaves. AhFAB2-3, AhFAD3-2, AhFAD4, AhSLD-4, and AhDES genes were highly expressed in flowers, whereas AhFAD7-2, AhSLD-2, and AhSLD-3 were expressed most strongly in stems. During seed development, the expressions of AhFAB2-2, AhFAD3 1, AhFAD7-1, and AhSLD-3 gradually increased in abundance, reached a maximum expression level, and then decreased. The AhFAB2-3, AhFAD3-2, AhFAD4, AhADS, and AhDES transcript levels remained relatively high at the initial stage of seed development, but decreased thereafter. The AhSLD-4 transcript level remained relatively low at the initial stage of seed development, but showed a dramatic increase in abundance at the final stage. The AhFAD7-2 and AhSLD-2 transcript levels remained relatively high at the initial stage of seed development, but then decreased, and finally increased again. The AhFAD transcripts were differentially expressed following exposure to abiotic stresses or abscisic acid. Moreover, the functions of one AhFAD6 and four AhSLD genes were confirmed by heterologous expression in Synechococcus elongates or Saccharomyces cerevisiae. CONCLUSIONS: The present study provides valuable information that improves understanding of the biological roles of FAD genes in fatty acid synthesis, and will help peanut breeders improve the quality of peanut oil via molecular design breeding. PMID- 29244879 TI - Characterization of Toxoplasma DegP, a rhoptry serine protease crucial for lethal infection in mice. AB - During the infection process, Apicomplexa discharge their secretory organelles called micronemes, rhoptries and dense granules to sustain host cell invasion, intracellular replication and to modulate host cell pathways and immune responses. Herein, we describe the Toxoplasma gondii Deg-like serine protein (TgDegP), a rhoptry protein homologous to High temperature requirement A (HtrA) or Deg-like family of serine proteases. TgDegP undergoes processing in both types I and II strains as most of the rhoptries proteins. We show that genetic disruption of the degP gene does not impact the parasite lytic cycle in vitro but affects virulence in mice. While in a type I strain DegPI appears dispensable for the establishment of an infection, removal of DegPII in a type II strain dramatically impairs the virulence. Finally, we show that KO-DegPII parasites kill immunodeficient mice as efficiently as the wild-type strain indicating that the protease might be involved in the complex crosstalk that the parasite engaged with the host immune response. Thus, this study unravels a novel rhoptry protein in T. gondii important for the establishment of lethal infection. PMID- 29244880 TI - Comparative study of qualitative and quantitative methods to determine toxicity level of Aspergillus flavus isolates in maize. AB - An attempt was made to compare between easy and inexpensive qualitative method (ammonia vapour test) and analytical methods (thin layer chromatography and enzyme-linked immunosorbent assay) for identification of aflatoxigenic isolates of Aspergillus flavus in maize. In this comparative study the toxicity level of A. flavus isolates exhibited 100% agreement among ammonia vapour test, ELISA and TLC for highly toxigenic (>2000 ppb) and toxigenic (501-2000 ppb) isolates while 88.5% agreement observed for least toxic (<20 ppb) isolates. In ammonia vapour test 51% of A. flavus isolates showed creamish or no colour change corresponding to least toxic/atoxic (<20ppb) category estimated by ELISA. Similarly 22% highly toxic isolates exhibited plum red colour, 12% moderately toxic indicated pink colour and 10% toxic isolates showed red colour. However, 11.5% isolates were found to be false positive in cream colour category (least toxic) and 28.5% false negatives in pink colour (moderately toxic) category. The isolates from different agroclimatic zones of maize in India showed high variability for aflatoxin B1 (AFB1) production potential ranging from 0.214-8116.61 ppb. Toxigenic potential of Aspergillus flavus isolates in culture was further validated by inoculating maize grain sample with four different isolates with varied toxin producing ability. With good agreement percentage between cultural and analytical methods the study concludes the ammonia vapour test to be easy, inexpensive, reliable and time saving method that can be used for segregating or pre-screening of contaminated samples from bulk food/feed stock. PMID- 29244881 TI - Treating iron deficiency in patients with gastrointestinal disease: Risk of re attendance in secondary care. AB - BACKGROUND: Patients with gastrointestinal disease may have comorbid iron deficiency anaemia (IDA) and an increased risk of hospitalisation and re attendance in hospital. The purpose of this study was to determine if oral and intravenous (IV) treatment of IDA in patients with gastrointestinal disease attending hospital were associated with differential rates of subsequent re attendance. METHODS AND FINDINGS: Data from the Clinical Practice Research Datalink (primary care) and Hospital Treatment Insights (secondary care) databases in England were used to conduct this retrospective cohort study. Patients with a coded gastrointestinal disease and IDA who attended hospital (inpatient or outpatient) and were dispensed oral or IV iron between 01/01/2010 31/10/2013 were included. Elective and emergency re-attendances in secondary care within 30 days of the initial attendance were determined. Demographics, medical diagnoses and treatments were extracted. Re-attendance rates following oral or IV iron were compared using chi-square tests and a step-wise logistic regression model to adjust for confounders. 2,844 patients contributed 6,294 initial attendances; 80% of patients received oral iron, 14% received intravenous iron, and 6% received both. Of initial attendances recording oral iron, 77% resulted in re-attendance in hospital, compared to 34% of those recording IV iron (unadjusted odds ratio [OR]: 0.16; adjusted OR: 0.52 [95% CI: 0.44-0.61]). Initial attendances using IV treatment were more likely to result in elective re attendance (84%) than those recording oral treatment (43%) (p<0.001). Median length of stay in hospital tended to be shorter for patients using IV iron (1.4 days; interquartile range 0.5-3.6 days; oral iron: 5.1 days; interquartile range: 2.2-9.6 days). CONCLUSIONS: Patients with gastrointestinal disease and IDA who received IV iron were less likely to re-attend hospital, more likely to re-attend electively, and tended to have a shorter length of stay in hospital. The mode of IDA treatment could have a real-world impact on healthcare utilisation. PMID- 29244884 TI - About an energy functioning by fusion, independently. AB - An innovative biological energy has been observed related to the eye sight and fusing with another energy over tap water through a small metallic chain. The fused energy has been repeatedly described under standard conditions and it is characteristics vary according to the condition of the eye sight and the water content. This energy may be called: "EFI" (energy functioning, by fusion, independently). PMID- 29244882 TI - alphaII-spectrin in T cells is involved in the regulation of cell-cell contact leading to immunological synapse formation? AB - T-lymphocyte activation after antigen presentation to the T-Cell Receptor (TCR) is a critical step in the development of proper immune responses to infection and inflammation. This dynamic process involves reorganization of the actin cytoskeleton and signaling molecules at the cell membrane, leading to the formation of the Immunological Synapse (IS). The mechanisms regulating the formation of the IS are not completely understood. Nonerythroid spectrin is a membrane skeletal protein involved in the regulation of many cellular processes, including cell adhesion, signaling and actin cytoskeleton remodeling. However, the role of spectrin in IS formation has not been explored. We used molecular, imaging and cellular approaches to show that nonerythroid alphaII-spectrin redistributes to the IS during T-cell activation. The redistribution of spectrin coincides with the relocation of CD45 and LFA-1, two components essential for IS formation and stability. We assessed the role of spectrin by shRNA-mediated depletion from Jurkat T cells and show that spectrin-depleted cells exhibit decreased adhesion and are defective in forming lamellipodia and filopodia. Importantly, IS formation is impaired in spectrin-depleted cells. Thus, spectrin may be engaged in regulation of distinct events necessary for the establishment and maturity of the IS: besides the involvement of spectrin in the control of CD45 and LFA-1 surface display, spectrin acts in the establishment of cell-cell contact and adhesion processes during the formation of the IS. PMID- 29244883 TI - Effects of mechanical repetitive load on bone quality around implants in rat maxillae. AB - Greater understanding and acceptance of the new concept "bone quality", which was proposed by the National Institutes of Health and is based on bone cells and collagen fibers, are required. The novel protein Semaphorin3A (Sema3A) is associated with osteoprotection by regulating bone cells. The aims of this study were to investigate the effects of mechanical loads on Sema3A production and bone quality based on bone cells and collagen fibers around implants in rat maxillae. Grade IV-titanium threaded implants were placed at 4 weeks post-extraction in maxillary first molars. Implants received mechanical loads (10 N, 3 Hz for 1800 cycles, 2 days/week) for 5 weeks from 3 weeks post-implant placement to minimize the effects of wound healing processes by implant placement. Bone structures, bone mineral density (BMD), Sema3A production and bone quality based on bone cells and collagen fibers were analyzed using microcomputed tomography, histomorphometry, immunohistomorphometry, polarized light microscopy and birefringence measurement system inside of the first and second thread (designated as thread A and B, respectively), as mechanical stresses are concentrated and differently distributed on the first two threads from the implant neck. Mechanical load significantly increased BMD, but not bone volume around implants. Inside thread B, but not thread A, mechanical load significantly accelerated Sema3A production with increased number of osteoblasts and osteocytes, and enhanced production of both type I and III collagen. Moreover, mechanical load also significantly induced preferential alignment of collagen fibers in the lower flank of thread B. These data demonstrate that mechanical load has different effects on Sema3A production and bone quality based on bone cells and collagen fibers between the inside threads of A and B. Mechanical load induced Sema3A production may be differentially regulated by the type of bone structure or distinct stress distribution, resulting in control of bone quality around implants in jaw bones. PMID- 29244885 TI - Effect of Fiber Post Cementation Timing on the Bond Strength of Resin Cements in Epoxy Resin-Obturated Canals. AB - This study evaluated the influence of timing after endodontic treatment and type of resin cement used on the bond strength of fiber posts to epoxy resin-obturated canals. A total of 80 bovine incisor roots were divided into four groups (n = 20). Glass fiber posts were cemented at two different times, immediately or 7 days after endodontic treatment, using either a dual-curing resin cement (RelyX ARC, 3M ESPE) or a self-adhesive resin cement (RelyX U200, 3M ESPE). Following post cementation, the samples were cross-sectioned into slices containing root dentin, cement, and fiber post at the cervical, mid, and apical root thirds. The push-out test was performed on a universal testing machine. Three-way analysis of variance for randomized blocks showed no significant effect within the triple interaction (P = .394) or between the double interactions cement-timing (P = .395), cement-root thirds (P = .996), and timing-root thirds (P = .331). The main factor cement revealed a significant effect, showing that regardless of the timing and root third, RelyX ARC provided significantly higher bond strength values than U200. Regardless of root third and timing, the dual-curing resin cement showed higher bond strength to root dentin when the canals were filled with epoxy resin-based cement. PMID- 29244886 TI - The Modified Apically Repositioned Flap Technique: A Long-Term (4 to 16 Years) Retrospective Study. AB - Attached gingiva is desirable for the maintenance of gingival health. Although many methods are used to increase the zone of attached gingiva, the modified apically repositioned flap (MARF) technique has the advantages of simplicity and predictability. The short-term follow-up of the MARF technique demonstrated an increase in keratinized tissue and attached gingiva. This study evaluated long term results of the MARF technique as used to increase the apicocoronal dimensions of keratinized tissue and attached gingiva in 28 sites (25 patients; average follow-up of 9 years). There was a statistically significant increase in keratinized tissue and attached gingiva with no increase in probing depths or gingival recession. These results suggest that the MARF procedure predictably generates keratinized tissue and attached gingiva with long-term stability. PMID- 29244887 TI - Carbon-Fiber Framework for Full-Arch Implant-Supported Fixed Dental Prostheses Supporting Resin-Based Composite and Lithium Disilicate Ceramic Crowns: Case Report and Description of Features. AB - This case report presents a new approach for shock-absorbing carbon-fiber composite frameworks for full-arch implant-supported fixed dental prostheses supporting resin-based and lithium disilicate ceramic crowns. It describes the characteristics of the materials used, the procedures for implementing the framework, and the requirements to achieve the best mechanical and clinical properties. The result is a full-arch prosthesis with masticatory load shock absorption capacities, chemical bonding between materials, good esthetics, and wear similar to natural enamel. A 24-month follow-up full-arch bimaxillary implant-supported rehabilitation, performed with computer-guided surgery, is described. PMID- 29244888 TI - Evaluation of the Periodontal Status of Abutment Teeth in Removable Partial Dentures. AB - The purpose of this study was to evaluate whether the use of removable partial dentures affects the periodontal status of abutment teeth. An observational cross sectional study was done on a sample of patients rehabilitated with removable partial dentures (2010 to 2013). At a recall appointment, a clinical examination was done to collect data related to the rehabilitation and periodontal status of the abutment teeth. Of 145 invited patients, 54 attended the requested follow-up appointment (37.2%). Mean patient age was 59.1 years, and the study population was 42.6% male and 57.4% female. The mean follow-up time for the prosthesis was 26 months. Abutment teeth had higher values in all periodontal variables (P < .001). Occlusal clasps had the worst results in relation to clasps with a gingival approach (P < .005). Significant differences were also found in mandibular abutment teeth of Kennedy Class I and II compared to Class III (P < .048). The periodontal status of the abutment teeth of removable partial dentures is affected by these rehabilitations. A recall program for these patients involving removable prosthodontics and periodontology appointments is mandatory. PMID- 29244889 TI - Elderly Patients with Ongoing Migraine Show Reduced Gray Matter Volume in Second Somatosensory Cortex. AB - AIMS: To identify structural changes in gray matter in suspected migraine generators (the hypothalamus and/or brainstem nuclei) and pain pathways and to evaluate whether structural changes in migraine are definitive or resolve with age. METHODS: Voxel-based morphometry (VBM) was used to assess differences in gray matter between 39 healthy controls (HC), 25 episodic migraine (EM) subjects, and 37 subjects with a history of migraine (HM). In addition, morphometric changes were specifically investigated in suspected migraine generators and/or pain pathways. For statistical analyses, t tests between the groups were performed, and a correction for multiple comparisons was used. RESULTS: Whole brain analysis did not reveal any gray or white matter changes. However, when the analysis was limited to the pain matrix, a lower gray matter volume was observed in the left second somatosensory (SII) cortex in EM subjects compared to HC subjects. This volume was significantly reduced in the EM group compared to the HC group and to the HM group, but not in the HM group compared to the HC group. CONCLUSION: Morphometric abnormalities in the SII in subjects with ongoing migraine but not in subjects with a resolved migrainous disease are likely to characterize a migrainous state rather than be a marker of brain susceptibility to migraine. PMID- 29244890 TI - Prevalence and Predictors of Sjogren's Syndrome in Patients with Burning Mouth Symptoms. AB - AIMS: To investigate the prevalence and predictive factors of Sjogren's syndrome (SS) in a cohort of patients with burning mouth symptoms. METHODS: A total of 125 patients with burning mouth symptoms were enrolled in a prospective study and assessed for the presence of SS. The severity of oral symptoms was evaluated by using questionnaires. Salivary flow rates and salivary scintigraphy were used to evaluate salivary function. Patient laboratory work-ups were reviewed, and SS was diagnosed by a rheumatologist based on the American-European Consensus Group criteria. The differences between the SS patient group and the non-SS patient group were analyzed with chi-square test or t test. RESULTS: A total of 12 of the 125 enrolled patients (9.5%) had a positive autoimmune antibody test, and 6 (4.8% of the entire cohort) had SS (4 [3.2%] primary and 2 [1.6%] secondary). Patients with SS exhibited significantly decreased hemoglobin levels, an increased erythrocyte sedimentation rate, and an increased prevalence of autoantibody positive results compared to non-SS patients. Salivary scintigraphy showed that the uptake ratio of the submandibular gland in SS patients was decreased significantly. CONCLUSION: The prevalence of SS in patients with burning mouth symptoms was 4.8%. Therefore, clinicians who treat patients with burning mouth symptoms should evaluate laboratory findings and salivary functions to identify patients with SS. PMID- 29244891 TI - The Effects of Experimental Temporalis Muscle Pain on Jaw Muscle Electromyographic Activity During Jaw Movements and Relationships with Some Psychological Variables. AB - AIMS: To determine if the effects of experimental temporalis muscle pain on jaw muscle activity vary with the jaw task performed, jaw displacement magnitude, participant being studied, and with psychological measures. METHODS: Jaw movement was tracked, and electromyographic (EMG) activity was recorded from the masseter and anterior temporalis and digastric muscles in 14 asymptomatic participants during standardized opening/closing jaw movement, free chewing, and standardized chewing tasks. Tasks were repeated in three blocks: Block 1 (baseline), Block 2 (during 5% hypertonic or 0.9% isotonic saline infusion into the anterior temporalis), and Block 3 (during infusion of the opposite solution). Participants also completed the Depression, Anxiety, and Stress Scales 21 (DASS 21), the Fear of Pain Questionnaire (FPQ III), the Pain Self-Efficacy Questionnaire (PSEQ), and the Pain Catastrophizing Scale (PCS). Analyses involved linear mixed-model analysis and Pearson correlations. P < .05 was considered statistically significant. RESULTS: The presence of a significant difference in jaw muscle EMG activity between hypertonic and isotonic saline infusions varied between tasks and between jaw muscle agonists and antagonists, but not in displacement magnitude. There were qualitative differences between participants in the effects of infusion on EMG activity. During hypertonic saline infusion, significant positive correlations were noted between jaw-closing EMG activity and anxiety, fear of medical pain, and PCS scores. CONCLUSION: Noxious stimulation of the temporalis muscle results in changes in jaw muscle activity, which can vary with the task, the muscle, the participant, and some psychological variables. PMID- 29244892 TI - Alterations in the Masticatory System in Patients with Amyotrophic Lateral Sclerosis. AB - AIMS: To determine the effect of amyotrophic lateral sclerosis (ALS) on aspects of masticatory function and to assess the relationship between ALS and the prevalence of traumatic mucosal lesions caused by oral self-injury. METHODS: A total of 153 ALS patients and 23 control subjects participated in this cross sectional study. Clinical characteristics including site of onset, medication, type of feeding, and use of noninvasive mechanical ventilation were recorded. The Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) protocol and a specific questionnaire to assess aspects of masticatory dysfunction and frequency of self-injury of the oral mucosa were applied to all participants. Maximum mandibular range of motion, maximum bite force, and maximum finger-thumb grip force were determined and tested with Mann Whitney, Kruskal-Wallis, or chi-square tests. P < .05 was considered significant. RESULTS: Maximum unassisted and assisted mouth opening, protrusion, left laterotrusion, and finger-thumb grip force were significantly reduced in both spinal- (n = 102) and bulbar-onset (n = 40) patients compared to the control group; however, bite force was reduced only in bulbar-onset patients. ALS patients with tube feeding (n = 16) had the greatest reduction in maximum bite force and mandibular opening. There was no relationship between TMD and ALS. Oral self-injury due to biting was more frequent in the ALS group (29.9%) than in the control group (8.7%) and in the bulbar-onset group (55.0%) compared to the spinal- (20.8%) and respiratory-onset (18.2%) groups. Of the ALS patients in the study, 10% sought dental treatment related to the condition. CONCLUSION: The ALS patients in this study had a reduction in finger-thumb grip force that was twice as great as the reduction in bite force. The maximum range of mandibular movement was also reduced, especially in bulbar-onset patients. ALS patients did not have a higher prevalence of TMD but did have more traumatic mucosal injury than controls. The dentist should be an integral part of the multidisciplinary team to manage ALS patients. PMID- 29244893 TI - Effectiveness of Intra-Articular Injections of Sodium Hyaluronate or Corticosteroids for Intracapsular Temporomandibular Disorders: A Systematic Review and Meta-Analysis. AB - AIMS: To assess the effectiveness of intra-articular injections of sodium hyaluronate (NaH) or corticosteroids (CS) for treatment of intracapsular temporomandibular disorders (TMD). METHODS: Single- or double-blinded randomized controlled trials (RCTs) on the effectiveness of NaH or CS injections, compared to each other or to placebo, for the treatment of intracapsular TMD due to osteoarthritis and/or internal joint derangement were analyzed in this systematic review and meta-analysis. Electronic searches of MEDLINE through the PubMed, Web of Science, and Cochrane Library databases were conducted on March 17, 2015, and an updated search was conducted on June 7, 2017. Three reviewers independently extracted the data and assessed the risk of bias of included studies. RESULTS: An initial search yielded 245 studies, and 5 additional studies were identified through cross referencing. A total of 22 studies were identified as relevant based on the abstracts, but only 7 RCTs met the inclusion criteria. Six of the included studies had unclear risk of bias, and one had high risk of bias. Four studies were eligible for meta-analysis. Pooled results showed no significant difference in short- or long-term pain improvement with NaH compared to CS. The number of responders to NaH was significantly more than placebo in one study, but not significantly higher than CS in another study. CONCLUSION: Although there was no significant difference between the effectiveness of NaH and CS intra-articular injections, there was some evidence that NaH was better than placebo. Further research is needed to determine the minimum effective dose and long-term side effects of both injections. PMID- 29244894 TI - The Concealed Information Test is Susceptible to Misleading Information. AB - An approach toward detecting hidden knowledge is the Concealed Information Test (CIT). It relies on the memory of crime-relevant information. This study investigated whether its validity is susceptible to memory distortion by misleading information. A misleading information paradigm was employed to distort memory prior to an interrogation with a CIT. Forty-one participants watched a video with specific crime-related information. After a 1-week retention interval, misleading information was introduced. Afterward, a CIT was performed, followed by a threefold memory test. When misleading information was presented, memory performance was reduced, and no physiological response differences between crime relevant and crime-irrelevant information were found. Without presenting misleading information, physiological responses differed between responses to crime-relevant and crime-irrelevant information. However, responses in all physiological measures also differed between misleading and irrelevant information. The results indicate that the CIT is susceptible to misleading information, which reduces its validity in specific constellations. PMID- 29244895 TI - Forensic Use of the Piracatinga Fish (Callophysius macropterus) to Locate and Identify Human Remains Retrieved From the Amazon River. AB - Piracatinga (Callophysius macropterus) are a type of bottom feeder catfish encountered in the Amazon River and its tributaries. We report two cases in which human remains were first located based on a characteristic circular distortion of the surface of the river that the Piracatinga make while they feed. Human skin samples of one of the victims recovered from the Piracatinga digestive tract were subjected to mitochondrial DNA analysis that allowed identification of the body of Case 1; the family recognized body parts of Case 2. Importantly, the location of human body parts and their identification based on DNA analysis enabled the respective families to obtain a death certificate expeditiously in the absence of identifiable remains-a process that normally requires 5 years under current Brazilian law, and in the absence of closure, imposes severe emotional stress on the family of the deceased. PMID- 29244896 TI - Total Synthesis of Sarpagine-Related Bioactive Indole Alkaloids. AB - Extension of the asymmetric Pictet-Spengler reaction to bulkier Nb -alkylated tryptophan derivatives resulted in an improved stereospecific access to the key bicyclo[3.3.1]nonane core of bioactive C-19 methyl substituted sarpagine/macroline/ajmaline indole alkaloids with excellent diastereoselectivity by internal asymmetric induction. Complete stereocontrol of the C-19 methyl function in either the alpha- or beta-configuration was achieved, which enables the total synthesis of any member from this group of thirty alkaloids. We report herein, the total synthesis of macrocarpines (A-C) 1-3, talcarpine 4, N(4)-methyl N(4),21-secotalpinine 5, dihydroperaksine 8 and deoxyperaksine 9. PMID- 29244897 TI - New Electrode and Electrolyte Configurations for Lithium-Oxygen Battery. AB - Cathode configurations reported herein are alternative to the most diffused ones for application in lithium-oxygen batteries, using an ionic liquid-based electrolyte. The electrodes employ high surface area conductive carbon as the reaction host, and polytetrafluoroethylene as the binding agent to enhance the oxygen reduction reaction (ORR)/oxygen evolution reaction (OER) reversibility. Roll-pressed, self-standing electrodes (SSEs) and thinner, spray deposited electrodes (SDEs) are characterized in lithium-oxygen cells using an ionic liquid (IL) based electrolyte formed by mixing lithium bis(trifluoromethanesulfonyl)imide (LiTFSI) salt and N,N-diethyl-N-(2 methoxyethyl)-N-methylammonium bis(trifluoromethanesulfonyl)imide (DEMETFSI). The electrochemical results reveal reversible reactions for both electrode configurations, but improved electrochemical performance for the self-standing electrodes in lithium-oxygen cells. These electrodes show charge/discharge polarizations at 60 degrees C limited to 0.4 V, with capacity up to 1 mAh cm-2 and energy efficiency of about 88 %, while the spray deposited electrodes reveal, under the same conditions, a polarization of 0.6 V and energy efficiency of 80 %. The roll pressed electrode combined with the DEMETFSI-LiTFSI electrolyte and a composite Lix Sn-C alloy anode forms a full Li-ion oxygen cell showing extremely limited polarization, and remarkable energy efficiency. PMID- 29244898 TI - Climate-driven diversity change in annual grasslands: Drought plus deluge does not equal normal. AB - Climate forecasts agree that increased variability and extremes will tend to reduce the availability of water in many terrestrial ecosystems. Increasingly severe droughts may be exacerbated both by warmer temperatures and by the relative unavailability of water that arrives in more sporadic and intense rainfall events. Using long-term data and an experimental water manipulation, we examined the resilience of a heterogeneous annual grassland community to a prolonged series of dry winters that led to a decline in plant species richness (2000-2014), followed by a near-record wet winter (2016-2017), a climatic sequence that broadly resembles the predicted future in its high variability. In our 80, 5-m2 observational plots, species richness did not recover in response to the wet winter, and the positive relationship of richness to annual winter rainfall thus showed a significant weakening trend over the 18-year time period. In experiments on 100, 1-m2 plots, wintertime water supplementation increased and drought shelters decreased the seedling survival and final individual biomass of native annual forbs, the main functional group contributing to the observed long term decline in richness. Water supplementation also increased the total cover of native annual forbs, but only increased richness within nested subplots to which seeds were also added. We conclude that prolonged dry winters, by increasing seedling mortality and reducing growth of native forbs, may have diminished the seedbank and thus the recovery potential of diversity in this community. However, the wet winter and the watering treatment did cause recovery of the community mean values of a key functional trait (specific leaf area, an indicator of drought intolerance), suggesting that some aggregate community properties may be stabilized by functional redundancy among species. PMID- 29244899 TI - Spatial response of synthetic microDiamond and diode detectors measured with kilovoltage synchrotron radiation. AB - PURPOSE: To map the spatial response of four solid-state radiation detectors of types commonly used for radiotherapy dosimetry. METHODS: PTW model 60016 Diode P, 60017 Diode E, 60018 Diode SRS, and 60019 microDiamond detectors were radiographed using a high resolution conventional X-ray system. Their spatial response was then investigated using a 0.1 mm diameter beam of 95 keV average energy photons generated by a synchrotron. The detectors were scanned through the beam while their signal was recorded as a function of position, to map the response. These 2D response maps were created in both the end-on and side-on orientations. RESULTS: The results show the location and size of the active region. End-on, the active area was determined to be centrally located and within 0.2 mm of the manufacturer's specified diameter. The active areas of the 60016 Diode P, 60017 Diode E, 60018 Diode SRS detectors are uniform to within approximately 5%. The 60019 microDiamond showed local variations up to 30%. The extra-cameral signal in the microDiamond was calculated from the side-on scan to be approximately 8% of the signal from the active element. CONCLUSIONS: The spatial response of four solid-state detectors has been measured. The technique yielded information about the location and uniformity of the active area, and the extra-cameral signal, for the beam quality used. PMID- 29244900 TI - The bidirectional relationship between anxiety disorders and circulating levels of inflammatory markers: Results from a large longitudinal population-based study. AB - BACKGROUND: Although there has been abundant research on chronic low-grade inflammation as a potential mechanism underlying the link between mood disorders and cardiovascular risk, less is known about the role of inflammatory factors and anxiety disorders. The aim of this paper is to evaluate the bi-directional associations between inflammatory markers including interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and high sensitivity C-reactive protein (hsCRP) with anxiety disorders and its subgroups. METHODS: The sample consisted of 3,113 participants (53.7% women; mean age: 51.0, S.D. 8.8 years), randomly selected from the general population, who underwent comprehensive somatic and psychiatric evaluations at baseline and follow-up (mean follow-up duration = 5.5 years, S.D. 0.6). Anxiety disorders were assessed with semistructured diagnostic interviews. Inflammatory biomarkers were analyzed in fasting blood samples. RESULTS: After adjustment for potential confounders, current anxiety disorders (beta = 0.09, 95% CI 0.00-0.17) and agoraphobia (beta = 0.25, 95% CI: 0.07-0.43) at baseline were associated with a steeper increase of hsCRP levels over the follow-up period. Current posttraumatic stress disorder (PTSD) was associated with a lower increase of IL-6 levels over the follow-up period (beta = -0.52, 95% CI: -1.00/-0.04). There was no evidence for an association between inflammation markers at baseline and anxiety disorders at follow-up. CONCLUSIONS: The prospective association between agoraphobia at baseline and hsCRP levels over the follow-up period suggests that chronic low-grade inflammation may be a consequence of this condition. The decrease in IL-6 in PTSD also requires further investigation. No evidence was found for chronic low-grade inflammation as a predictor of future anxiety disorders. PMID- 29244901 TI - Trauma exposure and undetected posttraumatic stress disorder among adults with a mental disorder. AB - BACKGROUND: Trauma exposure and posttraumatic stress disorder (PTSD) are common among individuals with a mental disorder, but symptoms often go undetected and untreated. METHODS: The aim of this study was to determine the prevalence of PTSD among a large sample of adults with psychiatric diagnoses and to establish factors associated with symptoms going undetected. Participants were 1,946 adults recruited by the National Centre for Mental Health. Structured interviews and validated self-report questionnaires were used to ascertain clinical and demographic information for analysis. RESULTS: The prevalence of participants screening positive for PTSD that had not been detected by clinical services was 13.9% [12.4-15.5%, 95% confidence interval]). Factors associated with undetected PTSD were female gender, younger age of first contact with psychiatric services, and lower household income. Especially, poor rates of detection were observed after traumatic events, such as child abuse and sexual assault. CONCLUSIONS: Our findings demonstrate the need for routine assessment of trauma histories and symptoms of PTSD among individuals with anymental disorder. PMID- 29244902 TI - Feasibility of predicting tumor motion using online data acquired during treatment and a generalized neural network optimized with offline patient tumor trajectories. AB - PURPOSE: The accurate prediction of intrafraction lung tumor motion is required to compensate for system latency in image-guided adaptive radiotherapy systems. The goal of this study was to identify an optimal prediction model that has a short learning period so that prediction and adaptation can commence soon after treatment begins, and requires minimal reoptimization for individual patients. Specifically, the feasibility of predicting tumor position using a combination of a generalized (i.e., averaged) neural network, optimized using historical patient data (i.e., tumor trajectories) obtained offline, coupled with the use of real time online tumor positions (obtained during treatment delivery) was examined. METHODS: A 3-layer perceptron neural network was implemented to predict tumor motion for a prediction horizon of 650 ms. A backpropagation algorithm and batch gradient descent approach were used to train the model. Twenty-seven 1-min lung tumor motion samples (selected from a CyberKnife patient dataset) were sampled at a rate of 7.5 Hz (0.133 s) to emulate the frame rate of an electronic portal imaging device (EPID). A sliding temporal window was used to sample the data for learning. The sliding window length was set to be equivalent to the first breathing cycle detected from each trajectory. Performing a parametric sweep, an averaged error surface of mean square errors (MSE) was obtained from the prediction responses of seven trajectories used for the training of the model (Group 1). An optimal input data size and number of hidden neurons were selected to represent the generalized model. To evaluate the prediction performance of the generalized model on unseen data, twenty tumor traces (Group 2) that were not involved in the training of the model were used for the leave-one-out cross validation purposes. RESULTS: An input data size of 35 samples (4.6 s) and 20 hidden neurons were selected for the generalized neural network. An average sliding window length of 28 data samples was used. The average initial learning period prior to the availability of the first predicted tumor position was 8.53 +/- 1.03 s. Average mean absolute error (MAE) of 0.59 +/- 0.13 mm and 0.56 +/- 0.18 mm were obtained from Groups 1 and 2, respectively, giving an overall MAE of 0.57 +/- 0.17 mm. Average root-mean-square-error (RMSE) of 0.67 +/- 0.36 for all the traces (0.76 +/- 0.34 mm, Group 1 and 0.63 +/- 0.36 mm, Group 2), is comparable to previously published results. Prediction errors are mainly due to the irregular periodicities between cycles. Since the errors from Groups 1 and 2 are within the same range, it demonstrates that this model can generalize and predict on unseen data. CONCLUSIONS: This is a first attempt to use an averaged MSE error surface (obtained from the prediction of different patients' tumor trajectories) to determine the parameters of a generalized neural network. This network could be deployed as a plug-and-play predictor for tumor trajectory during treatment delivery, eliminating the need for optimizing individual networks with pretreatment patient data. PMID- 29244904 TI - Pharmacokinetics of the cannabinoid receptor ligand [18 F]MK-9470 in the rat brain - Evaluation of models using microPET. AB - PURPOSE: The positron emission tomography ligand [18 F]MK-9470 is an inverse agonist that binds reversibly and with high affinity to the cannabinoid type 1 receptor. Due to its slow brain kinetics, care is required in the definition of its dissociation rates from the receptor. The goal of this study was to investigate pharmacokinetic analysis methods using an arterial input function. METHODS: Five Sprague-Dawley rats received injections of 13 to 25 MBq of [18 F]MK 9470 and were scanned over a period of 90 min. Arterial blood samples were collected throughout the scan. Data were analyzed using four different compartmental models: a reversible one-tissue model, reversible two tissue models with and without parameter constraints and an irreversible two-tissue model. The outcome values were goodness of fit measures (Akaike information criterion; standard error), pharmacokinetic modeling parameters (volume of distribution; irreversible uptake constant) and intersubject variability. RESULTS: Goodness of fit measures indicated that the experimental data are more adequately described by a two-tissue model than a one-tissue model. Differences in mean Akaike information criterion values between all two-tissue models were < 5%. Mean standard errors of model parameters were lowest for the irreversible model (range: 1% to 6%). The irreversible model delivered plausible results for all animals that were less variable compared to results of the other two-tissue models. CONCLUSIONS: A reversible two-tissue model may not deliver stable results for all animals and regions within a 90-min microPET study protocol. Stable parameters for all animals and regions are obtained when an irreversible model is used. If the acquisition time of the experiment is limited, an irreversible model provides a consistent distribution of composite outcome parameters, suggesting its suitability for use in future studies. PMID- 29244905 TI - Posttraumatic Stress Symptoms and Posttraumatic Growth in Children and Adolescents Following an Earthquake: A Latent Transition Analysis. AB - This study examined the transitions in classes of posttraumatic stress symptoms and posttraumatic growth in a sample of children and adolescents (N = 757), between 8 and 20 months after the 2013 Ya'an earthquake in China. Using latent profile analysis, three classes of symptoms (resilient, thriving, and struggling) were identified at 8 and 20 months after the earthquake. Latent transition analysis indicated that the majority of survivors remained in the same class during the period, while others showed a transition between different classes over time. The transition was mainly characterized by three paths: from struggling to resilient, and from thriving to either resilient or struggling. Of the survivors who were classified as thriving at 8 months, those transitioning to the struggling class at 20 months were more likely to experience higher levels of loss and injury compared with those transitioning to the resilient class (Cohen's d = 0.72) or remaining in the thriving class (Cohen's d = 0.36) at 20 months postearthquake. Survivors who remained stable in the struggling class were older than those who remained stable in the thriving class (Cohen's d = 0.41) or those who moved from thriving at 8 months to resilient at 20 months after the earthquake (Cohen's d = 0.39). It is recommended that clinicians consider the classes of posttraumatic stress symptoms and posttraumatic growth, and the potential development paths and associated factors, when implementing interventions for children and adolescents after a natural disaster. PMID- 29244903 TI - Dermal fibroblast in cutaneous development and healing. AB - The skin is the largest organ of the body and is composed of two layers: the overlying epidermis and the underlying dermis. The dermal fibroblasts originate from distinct locations of the embryo and contain the positional identity and patterning information in the skin. The dermal fibroblast progenitors differentiate into various cell types that are fated to perform specific functions such as hair follicle initiation and scar formation during wound healing. Recent studies have revealed the heterogeneity and plasticity of dermal fibroblasts within skin, which has implications for skin disease and tissue engineering. The objective of this review is to frame our current understanding and provide new insights on the origin and differentiation of dermal fibroblasts and their function during cutaneous development and healing. WIREs Dev Biol 2018, 7:e307. doi: 10.1002/wdev.307 This article is categorized under: Birth Defects > Organ Anomalies Signaling Pathways > Cell Fate Signaling Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Nervous System Development > Vertebrates: Regional Development. PMID- 29244906 TI - Finding treatment-resistant depression in real-world data: How a data-driven approach compares with expert-based heuristics. AB - BACKGROUND: Depression that does not respond to antidepressants is treatment resistant depression (TRD). TRD definitions include assessments of treatment response, dose and duration, and implementing these definitions in claims databases can be challenging. We built a data-driven TRD definition and evaluated its performance. METHODS: We included adults with depression, >=1 antidepressant, and no diagnosis of mania, dementia, or psychosis. Subjects were stratified into those with and without proxy for TRD. Proxies for TRD were electroconvulsive therapy, deep brain, or vagus nerve stimulation. The index date for subjects with proxy for TRD was the procedure date, and for subjects without, the date of a randomly selected visit. We used three databases. We fit decision tree predictive models. We included number of distinct antidepressants, with and without adequate doses and duration, number of antipsychotics and psychotherapies, and expert based definitions, 3, 6, and 12 months before index date. To assess performance, we calculated area under the curve (AUC) and transportability. RESULTS: We analyzed 33,336 subjects with no proxy for TRD, and 3,566 with the proxy. Number of antidepressants and antipsychotics were selected in all periods. The best model was at 12 months with an AUC = 0.81. The rule transported well and states that a subject with >=1 antipsychotic or >=3 antidepressants in the last year has TRD. Applying this rule, 15.8% of subjects treated for depression had TRD. CONCLUSION: The definition that best discriminates between subjects with and without TRD considers number of distinct antidepressants (>=3) or antipsychotics (>=1) in the last year. PMID- 29244907 TI - Pleading for a Dual Molecular-Orbital/Valence-Bond Culture. AB - Electron pairs through the looking glass might well discover that they can show two faces, one delocalized or the other localized, and that both are perfectly correct. Going back and forth between these two representations, according to which one is the most relevant and insightful for the case at hand, is easy and essential to get a complete understanding of electronic structure. PMID- 29244908 TI - Changes in coping and social motives for drinking and alcohol consumption across the menstrual cycle. AB - BACKGROUND: Alcohol use has been reported to fluctuate over women's menstrual cycles (MCs), with increased intake occurring premenstrually/menstrually (phases characterized by heightened negative affect) and during the ovulatory phase (a phase characterized by positive affect). This suggests women may drink for particular emotion-focused reasons at specific points in their cycles. However, no research had yet examined MC variability in drinking motives, or links between cycle-related changes in drinking motives and alcohol consumption. METHODS: Ninety-four normally cycling women (Mage = 22.9 years old, SDage = 4.7) completed daily diary measures (via Smartphone surveys), with questions pertaining to state drinking motives and quantity of alcohol consumed for the course of a full MC. RESULTS: Drinking motives differed by cycle phase. Women reported a slight increase in drinking to self-medicate for negative affect premenstrually, with drinking to cope peaking in the menstrual phase and declining mid-cycle. Women reported a slight increasing trend across the cycle in social motives for drinking, while enhancement motives remained relatively stable across the cycle. Cycle-related changes in drinking motives predicted increases in the quantity of alcohol consumed. Drinking to cope with negative affect predicted a greater number of drinks menstrually (days 1-5). While social motives predicted a greater number of drinks during the follicular and ovulatory phases (days 5-16), enhancement motives were unrelated to drinking quantity across cycle phase. CONCLUSIONS: Clinicians should be attentive to cycle phase when treating reproductive-aged women with alcohol disorders (e.g., encouraging the use of healthier means of coping with negative affect during menses). PMID- 29244909 TI - Changes of humoral anti-endotoxin immunity and low-intensity inflammation in diabetes mellitus type 1 and 2. AB - The purpose: The purpose. Investigate the levels of different classes serum anti endotoxin antibodies in patients with diabetes mellitus type 1 and 2 and to hold the cluster analysis of the relationship between the individual levels of such antibodies and the concentration of C-reactive protein in the blood. Methods: We examined 51 patients with diabetes mellitus type 1 and 60 patients with diabetes mellitus type 2. The diagnosis of diabetes mellitus type 1 or type 2 has been delivered in accordance with the criteria of the World Health Organization. The control group included 49 healthy people who have not a history of any chronic disease, and the clinical manifestations of acute diseases were absent at the time of the survey. By sex and age, the control group of healthy people matched to a group of patients with diabetes type 1 and type 2. The concentration of C reactive protein in the blood and the levels of serum anti-endotoxin antibodies of different classes (A, M and G) was determined by ELISA. Results: Using cluster analysis revealed that 40.8% of patients with type 1 diabetes increased concentration of C-reactive protein in the blood is associated with a significant reduction of levels of serum anti-endotoxin antibodies classes A, M and G. In 56.7% of patients with type 2 diabetes the high concentration of C-reactive protein in the blood levels of serum anti-endotoxin antibody classes A and M were not significantly different from the normal values, but the levels of serum anti endotoxin antibodies of class G were significantly increased. The activation of inflammation with a further increase of C-reactive protein in the blood of patients with type 2 diabetes mellitus accompanied by a significant increase in levels of serum anti-endotoxin antibodies classes A and G, and also a tendency to reduce of levels anti-endotoxin antibodies class M. Conclusion: The results suggest about the relationship between low-intensity inflammation and immune response to enterobacterial endotoxins in patients with diabetes mellitus type 1 and 2. PMID- 29244910 TI - Lymph cytokines as markers oncogenesis and effective treatment of experimental breast cancer Wistar rat. AB - : The purpose of this paper is to examine the levels of cytokines in the lymph involved in the pathogenesis of breast cancer. Methods: Breast cancer was induced by introducing n-methyl-N-nitrosourea rats Wistar breed. Some of the animals subjected to surgery alone or chemotherapy alone (cyclophosphamide, methotrexate, 5-fluorouracil). Some animals combine both types of therapy, as well as a separate group to the administration of chemotherapy added Panagene drag presenting a fragmented DNA. To investigate the concentration of cytokines used in lymph test system Bio-Plex Pro Rat Cytokoness 24-Plex Assay (Bio-Rad, USA). Results: In rats with breast cancer content of most studied cytokines such as, IL 1b, IL-2, IL-4, IL-6, IL-7, IL-12, IL-13, IL-17A, MIP-1a, MIP-3a, RANTES, TNF-a, MCP-1 was significantly higher than in intact animals. Surgical removal of the tumor resulted in a significant decrease in the content in the lymph as a pro inflammatory cytokine. Comparative performance study cytokine content in the lymph after tumor removal from intact animals showed that the content of cytokines such as IL-10, IL-18, GRO / KC, RANTES were significantly higher in the control animals group. Conducting chemotherapy has led to a significant decrease in the content of IL-1b, IL-4, IL-6, IL-7, IL-10, MIP-1a, MIP-3a, RANTES in rat breast cancer lymph. Comparative study of cytokine content in the lymph operated animals after the administration of chemotherapy and Panagene revealed that most of the content indicators cytokines such as IL-5, IL-6, IL-7, IL-10, IL-13, IL 17A, IL- 18, GRO / KC, IFNg, MIP-3a in the lymph was higher after administration of the drug Panagene. Conclusion: In a comparative study cytokine profile lymph Wistar rats found that cytokine content depended on the therapy in animals with induced breast cancer. Lymph cytokine levels may serve as a diagnostic criterion for tumor growth, as well as the predictor of the effectiveness of the therapy and the risk of metastasis of breast cancer. PMID- 29244911 TI - The role of circulating cytokines and thyroid hormones in the development of the nephrotic variant of glomerulonephritis. AB - : The purpose of the research - studying the features of the production of pro- and anti-inflammatory cytokines, as well as indicators of thyroid status in patients with nephrotic variant of glomerulonephritis (GN). Research methods. Methods: The examination involved 78 patients with primary GN, including 30 patients with nephrotic syndrome (NS) and 48 GN patients who had no NS symptoms. Laboratory researches included the determination of the concentration of the main cytokines circulating in the blood - IL-1b, IL-2, IL-4, IL-10, IFN-g and the receptor antagonist of IL-1b - Ra-IL-1b by the method of solid-phase enzyme linked immunosorbent assay enzyme immunoassay (ELISA) in the system of the bideterminant definition of antigen with the use of peroxidase as indicator enzyme using standard sets ("Cytokine", St.-Petersburg) according to the technique attached to a set. The investigation of the basic indicators of thyroid status - free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), anti-thyroid peroxydase antibodies (TPOAb) is carried out by the ELISA using standard sets and NGO techniques "Diagnostic systems" (N-Novgorod). The researches were conducted twice - before the hospitalization (1-2 days) and after the end of a stationary stage of treatment (12-14 days). Results: In 90% of patients with nephrotic option of GN there have been identified laboratory signs of hypothyroidism of different degrees of severity accompanied by increasing of production levels of proinflammatory cytokine IL-1b and IL-4, related to the activity of a humoral link of adaptive immunity. The reduction of glomerular, erythropoietic, concentration kidney functions, as well as proteinuria in patients with nephrotic option GN are associated with the decrease of T4 levels in the blood and increased levels of the cytokines circulating in the blood - IL 1b and IL-4. Conclusion: The obtained data demonstrate that the high level of production of IL-1b and IL-4 in GN patients causes hypothyroidism resulting in the formation of NS. PMID- 29244912 TI - Influence hypervitaminosis D3 on hemodynamic presentation of experimental copper intoxication. AB - : As a component of various enzymes, it refers to copper essential trace elements, but the excessive consumption of the metal leads to the development of the pathogenic effects of xenobiotics on the functional condition of the cardiovascular system. However, the works devoted to the study of the effectiveness of prophylactic calcium in a copper toxicity, is not in the current literature. The purpose: study the effect of long-term toxicity of copper on the functional state of the cardiovascular system and its reactivity in experimental hypercalcemia. Methods: Experimental hypercalcemia model was created by forming a pilot hypervitaminosis D, by introducing "Akvadetrim" atraumatic preparation through a probe into the stomach in the dose 3000 IU (0.2 ml) / 100 g of body weight for 30 days. Chronic copper poisoning model created by intragastric administration of copper sulfate solution at a dosage of 20 mg/kg (in terms of metal) for 30 days, daily one time a day. The study of the functional state of the cardiovascular system is to determine the mean arterial pressure, specific peripheral vascular resistance, stroke index, cardiac index, the reactivity of the renin-angiotensin system and adrenoreactivity cardiovascular system. Results: The experimental study revealed that long-term copper poisoning leads to the development of hypertension due to an increase in total peripheral vascular resistance, along with the marked decline in the pumping function of the heart. Experimental hypercalcemia simulated by intragastric administration of vitamin D promotes more pronounced toxic effects of copper sulfate on the cardiovascular system. Conclusion: Copper poisoning of the body is characterized by the development of hypertension and the condition of artificial hypercalcemia potentiates the cardiotoxic effects of copper. PMID- 29244913 TI - Modern state of problem of delivery of medicines with use of erythrocytes as cell carriers. AB - Erythrocytes are prospective carriers of wide range of medicines and other biologically active agents. Main peculiarity and advantage of erythrocytes as carriers of medicines is their absolute bio-compatibility and ability for long circulation in an organism. While growing old these cells undergo natural process of biodegradation. Relatively inactive endocellular environment protects carried medicine from being inactivated by different endogenous factors. At the present time different methods of loading medicines in erythrocytes are used: electroporation, induced endocytosis, osmotic pulse hematolysis, hypotonic hematolysis. Most of these methods are based on the ability of these cells for reversible deformation of the surface without changing area of surface. Introduction of medicines in erythrocytes can be conducted in natural way as a result of their sorption on cell membrane. Different medicines can be used as the objects for targeted transport: antibiotics, antineoplastic drugs, corticosteroids, peptides, enzymes etc. extracorporeal pharmacotherapy with use of erythrocytes as carriers can be applied in the treatment of different diseases. Range of used medicines and provided possibilities is quite wide at a present time, but further development of this direction is very prospective. The aim of the authors was to outline a common concept of the potential of erythrocytes as universal transportation means of medicines for therapy of different pathological conditions. PMID- 29244914 TI - Novel liquid chromatography-mass spectrometrymethod to analyze hdl lipidome. AB - Subject: High-density lipoprotein (HDL) is highly heterogeneous in function, structure, and composition. Components of HDL can be assayed using various techniques, including LC/MC approaches. The purpose of this study was to develop a novel method for the analysis of the HDL lipidome. Since phospholipids represent a major bioactive lipid component of HDL, the phosphosphingolipidome of major normolipidemic HDL subpopulations was characterized in this study. Methods and Results: The article describes the methodology used for the analysis of the HDL lipidome. Based on existing methods of lipidomic analysis, an original method of analyzing lipidome of HDL by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI/MS/MS) was developed. This technique was used to analyze the lipidome of five normolipidemic HDL subpopulations. Conclusion: The developed method allowed to identify and quantify 162 individual molecular lipid species in five normolipidemic HDL subpopulations across nine lipid subclasses, including 23 phosphatidylcholine, 22 sphingomyelin, 9lysophosphatidylcholine, 25 phosphatidylethanolamine, 17 phosphatidylinositol, 11 phosphatidylglycerol, 24 ceramide, 18 phosphatidylserine, and 13 phosphatidic acid species. PMID- 29244915 TI - SHF radiation from albumin solution upon external excitation. AB - : The purpose of the research consisted in the measurement of nonequilibrium radiation in superhigh frequency (SHF) range from aqueous solution of albumin upon its mechanical stimulation. Methods: the monitoring of change in the ratio between brightness temperatures TSHF and TIR values after the mechanical stimulation of aqueous solution of albumin in the measuring cell at 35-39 degrees S. The measurements of brightness temperatures were carried out with use of radiothermometer. SHF frequency range corresponded to 3.4-4.2 GHz, SHF frequency range corresponded to 8-13 mm. Results: It was found that mechanical stimulation of aqueous solution of albumin at the temperature ~39 degrees S, the change in the ratio between TSHF and TIR occurs. This corresponds to emergence of nonequilibrium SHF radiation from the solution near the phase transition with ~39 degrees S temperature. Conclusion: The effect of emergence of nonequilibrium SHF radiation from protein solution near its temperature 39 degrees S was found. This temperature corresponds to the temperature of human organism upon a number of pathological states connected with inflammatory processes. The discovered effect can be used in the development of novel non-invasive methods of disease diagnostics. PMID- 29244916 TI - Structure changes of human brain gray matter neurons and astrocytes in acute local ischemic injury. AB - : The purpose to identify key morphological features of the Astrocytes and Neurons in the acute local cerebral ischemia human cortex. Subjects and Methods: Left middle cerebral artery ischemic stroke died persons (n = 9) brain tissue samples from 3 zones: 1st - contiguous to the tissue necrotic damage site zone, 2nd - 5-10 cm distant from the previous one, 3rd - the damage site symmetrical zone of the contralateral hemisphere. For GFAP, MAP-2, NSE, p53 detection indirect immunoperoxidase immunohistochemical staining method has been used. Also, the samples were Nissl and Hematoxylin-Eosin stained. Results: The most pronounced changes in the quantity and morphological structure of astrocytes and neurons are found in directly adjacent to the necrotic core region of theleft middle cerebral artery ischemic stroke brain. This indicates the prevalence of the inflammation processes around the area of nerve tissueischemic destruction. Morphological changes of neurons and astrocytes, apoptosis, enhanced neuron astrocyte interaction found in the area bordering on necrotic core (5-10 cm from it), as well as ischemic hearth symmetrical sites of the contralateral hemisphere. This interaction is essential for the neuroplasticityrealization in the local ischemic brain injury. Conclusion: The results obtained were shown the nerve tissue morphological characteristics changes occur in local cerebral cortex ischemic injury not only in the lesion, but also in the contralateral hemisphere. These changes are probably related to the implementation of neuroplasticity. PMID- 29244917 TI - Omega-3 polyunsaturated fatty acids when administered to lactating rats modify the development of experimental anxiety-depressive state in the rat pups exposed to the dipeptidyl peptidase-IV inhibitor diprotin A on the second - third weeks after the birth. AB - : Omega-3 polyunsaturated fatty acids (PUFAs) belong to the hypolipidemic drugs, exhibit antioxidant properties and are used in the clinic for secondary prevention of several diseases. The effects of omega-3 PUFAs on the course of the stress-induced and endogenous depression are under investigation. We have previously demonstrated that synthetic inhibitors of prolyl endopeptidase (PEP; EC 3.4.21.26) exhibit antidepressant-like properties in different experimental models of emotional and motivational disorders. It is known that omega-3 PUFAs show PEP inhibitory activity. The purpose of this work was to study the effects of the drug Omacor (Abbot, Germany) containing omega-3 PUFAs, when administered to the lactating Wistar rats, on the emotional and motivational behavior of the offspring with the experimental anxiety-depressive disorder caused by the inhibitor of dipeptidyl peptidase IV (DPP- IV; CD 26; EC 3.4.14.5) diprotin A on postnatal day (PND) 5-18 (second - third weeks of postnatal development). Methods: We used conventional methods of assessing the emotional and motivational behavior and sensorimotor reactivity in animals. Omega-3 PUFAs were administered to lactating rats at a dose 0.3 g / kg, per os, for 28 days starting from the next day after the birthing. Diprotin A was administered systemically at a dose of 2 mg/kg. Results: Omega-3 PUFAs when administered to the lactating females, prevented the development of depressive-like behavior in adolescent rats neonatally exposed to DPP-IV inhibitor diprotin A, and contributed to the formation of antidepressive phenotype in control rats. However, under these circumstances, the omega-3 PUFAs increased anxiety and did not prevent an increase in aggression in rats with the experimental anxiety-depressive disorder and increased anxiety and stress-provoked aggression in the controls. Conclusion: The results support the hypothesis on the involvement of proline-specific peptidases DPP-IV and PEP in the mechanisms of emotional and motivational disturbances and expand the spectrum of omega-3 PUFAs action. PMID- 29244918 TI - Anticonvulsant effects of citicoline and diazepam at their combined application on model of the acute generalized convulsions induced by pentylenetetrazole in Wistar rats. AB - The purpose: Studying of efficiency of the combined application of the citicoline possessing nootropic and anticonvulsive action and antiepileptic drug of diazepam on the acute generalized convulsions (AGC) caused by a convulsant pentylentetrazole (PTZ). Methods: Experiments are executed on the male Wistar rats (n = 68) weighing 160-190 g on the AGS model caused by of PTZ in a dose of 80 mg/kg, intraperitoneally (i.p.). For studying of efficiency of the combined use of drugs determined the minimum anticonvulsive action of a citicoline (Tserakson, "Nicomed Ferrer Internacional, S.A.") and diazepam (Relanium, Warsaw pharmaceutical plant of Polf AO, Warsaw, Poland). For this citicoline were administered i.p. in doses 500 and 300 mg/kg 1 hour before the PTZ and diazepam - in doses of 0,5 and 0,25 mg/kg 30 min before administration of PTZ. Control animals were injected with saline to the same extent and under the same experimental conditions. Results: It is shown that the combined administration of a citicoline and diazepam in minimum active doses (300 and 0.25 mg/kg respectively), increases anticonvulsive properties of both drugs. Conclusion: The combined administration of citicoline with diazepam in minimally active doses enhances anticonvulsant properties of both drugs, thereby reducing the risk of development of side effects. In addition, the research may serve as experimental justification for the use of drugs in case of convulsions for the purpose beneficial effect on cognitive function and delays of progressing of neurodegenerative processes. PMID- 29244919 TI - System of KISS-KISS1R: focus on peripheral signaling in androgen-dependent tissues in the experimentally induced model hypogonadotropic hypogonadism. AB - : Kisspeptins, ligands of G protein-coupled receptor 54 (GPR54) encoded by the KiSS-1 gene, have recently emerged as key gatekeepers of the gonadotropic axis. Unlike its role at the hypothalamus on GnRH secretion, the effects of kisspeptins on gonadal and other peripheral tissues need to be clarified. The purpose: To investigate the impact of experimentally induced hypogonadism in male rats on kisspeptins signaling in androgen-dependent tissues and blood. Methods: Wistar male rats (total number 31) were used. Rats were divided into four groups. Group 1 (control, prepubertal rats aged 2 months, n = 7). Group 2 (control, pubertal rats aged 4 months, n = 6). Group 3 (unilaterally gonadectomized (ULG) in neonatal period). Group 4 (ULG testosterone-treated with testosterone (T) propionate 5 mg/kg/d during 10 days). In all the four groups density of GPR54 in testes and muscle and serum kisspeptin levels and T levels were estimated. The data was expressed as median values (Me) that were compared by Wilkokson criterion. Results: Density of GPR54 in gonads in group 3 was lower than in group 2 (Me 0,88 ng/mg vs 1,13 ng/mg, p<0,05) and similar to group 1(Me 0,92 ng/mg). Unlike above, density of GPR54 in muscle in all groups 1,2,3 was not any differences (Me 0,1; 0,12; 0,13 ng/mg, p>0,05).Generally, density of GPR54 in group 2 in gonads was significantly higher than in the same group in muscle (Me 0,784 ng/mg vs 0.114 ng/mg, p<0,01). In the group 3 a significant decrease in serum levels of T (Me 15,39 ng/mg) in comparison with group 2 (Me 20,02 ng/mg, p<0,01) was invented. However, serum levels of kisspeptins in both groups had not any differences (0,27 ng/mg and 0,26 ng/mg, p>0,05). Treatment with testosterone propionate of the rats of group 4 lead to increase of serum level of T (from 15,39 ng/mg to 26,26 ng/mg, p<0,01), but didn't modify the density of GPR54 in gonads (Me 0,79 ng/mg). Conclusions: Hypogonadism lead to decrease of kisspeptins signaling in peripheral androgen-dependent tissues. Serum level of kisspeptins is physiologically low and, probably, it can not be used as a marker of activity of kisspeptins system. Efficacy of treatment with testosterone is not enough that is required a novel therapeutic resources. PMID- 29244920 TI - Neuroprotective and antiamnestic effects of mutant molecules of erythropoietin on model of photochemical thrombosis of rat brain prefrontal cortex. AB - Mutant EPO molecules, deprived of erythropoietic activity, but possessing cytoprotective action, were created by the method of genetic engineering. The assessment of the therapeutic effectiveness of the received mutant proteins was carried out by the retention of the conditioned reflex of passive avoidance (PA), developed before the ischemic injury of rat brain prefrontal cortex, and by the MRI-analysis of ischemic damage volume. Antiamnestic and neuroprotective action of mutant molecules - MERO-Fc and MEPO-TR is investigated on model of photothrombosis of rat brain prefrontal cortex at single intranasal introduction in 1 h after cortex ischemic damage. The neuroprotective (MRI) and antiamnestic (PA) effects of mutant molecules of erythropoietin derivatives are shown. PMID- 29244921 TI - Influence of iatrogenic hypercorticoidism induced by long-term application of dexamethasone on power of muscular contraction of white rats. AB - : Research objective consisted in detection of nature of the changes of the myothermis and the ergometric parameters of the contraction of the forward tibial muscle of rats in the course of performing of the tiring work at the saturation of an organism by therapeutic doses of dexamethasone. Method: The experiments were performed on sexually mature rats-females (200-220 g), divided into control (n = 10) and experimental (n = 60) groups. The animals of experimental group received dexamethasone (D, KRKA, Slovenia) in a dose of 0,25 mg/kg (intraperitoneal, 1 time in 2 days) during from 10 to 60 days. On anesthetized animals (sodium thiopental, 100 mg/kg) with the use of myothermia and ergographia the nature of change of power of the muscle's contraction in the course of the performance of the tiring work (3 six-second tetanus with external loading of 80 g) was studied. Restults: At the initial stage of the development of iatrogenic hypercorticoidism (after 5-20 injections of D) the initial value of the external work of the muscle in comparison with the control is significantly lower (for 30 52%) and the temperature cost of the unit of the work (TCMW), on the contrary, - is higher (for 26-82%). On the end of the 2-month period of application of D the initial values of the power parameters of the muscle came back to control level. During the performance of the tiring tetanus in animal experimental groups the decline of the external work of the muscle is greater (69-73%) compared with the control (55%). This effect does not depend of the number of injections of D, which indicates about a high pathophysiological activity of glucocorticoid concerning working capacity of the muscle. At expressed fatigue the TCMW always increases from 104% (5 injections of D) to 230% (20 injections); at control animals the effect of the tiring work on TCMW is significantly weaker (28%). At long-term application of D (2 months) the described effect of the preparation is weakened, though remains accurately expressed. Conclusion: The obtained data are considered from the point of view of formation at the hypercorticoidizm of the pathophysiological mechanism - the increase of power cost of muscular work. The revealed effect of D can be the cornerstone of the formation of the number of the pathophysiological mechanisms in neuromuscular system including causing the development of the myopathy at the hypercorticoidizm. PMID- 29244922 TI - The Effect of Kinesitherapy Exercises on the Level of Irisin among Females with Cardio-vascular diseases depending on the body mass and hormonal status. AB - The observation was conducted on 41 female subjects age 32 to 69 with compensated cardio-vascular diseases. 23 of the subjects had an increased body mass index (BMI). It was established that the older the females the less of the irisin muscle hormone is found in the blood. In the subjects with a higher BMI the level of irisin in the blood is also higher. Direct correlations were found between the level of irisin and the level of female sex hormones - estrogen and progesterone. Under the effect of kinesitherapy exercises the level of irisin in females with normal BMI increases; whereas in the females with a higher BMI it generally stays the same or is decreased. The characteristics of irisin's response to the kinesitherapy exercises depends on its original level, the intensity of physical exercise and the subject's physique. PMID- 29244924 TI - Organized structure of ventricular fibrillation in dogs with myocardial ischaemia. AB - The purpose of the investigation: To reveal and study the organized activity of ventricular fibrillation (VF) in dogs with myocardial ischaemia before VF using the spectral analysis of electrocardiogram (ECG) in VF by the method of Fast Fourie Transform (FFT). Methods: Four experiments was carried on dogs with myocardial ischaemia before VF. The ECG in dogs was recorded during 2 minutes before VF and within the first 10 minutes of VF, which was caused under stimulation the chest of the dog by alternating current (50 Hz; 30 V) within 2-3 seconds. The spectral analysis of ECG in VF was carried using the method of FFT in 5 frequency bands: very low frequencies (1-3 Hz), low (4-7 Hz), medium (8-12 Hz), high (13-17 Hz) and very high frequencies (18-40 Hz). The spectral power (mV) and proportion (%) of oscillations was determined in five-second intervals of ECG during VF in the range of the very low frequencies, low, medium, high and the very high frequencies. Results: The low frequency oscillations of 4-7 Hz dominated during the first minute of VF in dogs with myocardial ischaemia before VF. Domination of the low frequency oscillations was replaced by domination of the low and medium frequency oscillations of 4-12 Hz during the second and third minutes of VF. The low and medium frequency oscillations dominated at 4-10-th minutes of VF Conclusion: The first 10 minutes of VF in dogs with myocardial ischaemia before VF are characterized by an organized activity that confirmed by dominant frequency structure of the ECG oscillations. Organized structure of VF is resistant to ischaemia: an organized structure persisted under the influence of 10 minutes of myocardiual ischaemia during VF. PMID- 29244923 TI - Sodium-L-arginine succinate - a new vasodilating medicine for the treatment and prophylaxis of doxorubicin-induced cardiotoxicity. AB - The purpose: to ascertain possible cardioprotective effect of Sodium-L-arginine Succinate in case of myocardial lesions caused by Doxorubicin in rats. Methods. The effectiveness of the drug was assessed by morphometric and biochemical changes reflecting peroxidation intensity and structural and functional changes in myocardium. Results. Sodium-L-arginine Succinate used for the treatment and prophylaxis of antracyclic cardiomyopathy was demonstrated to decrease Doxorubicin effects lessening cardiomyocytal destruction and the left ventricular dysfunction with myocardial hypertrophy. PMID- 29244925 TI - Cardio and cytoprotective effect of cytoflavin in terms of experimental perinatal hemic hypoxia. AB - The purpose: The purpose of research is to study cardiocytoprotective effect of cytoflavin in terms of aperinatal hypoxia in experiment. Methods: During research the offspring (22 pups) of 15 females of white Wistar line rats aged 3-4 months were involved. The hypoxia was recreated by daily intraperitoneal introduction of sodium nitrite (NaNO2) in a dose of 5 mg/100 g of the body weight causing a moderately severe hypoxia. To females of the first group, and also their posterity medicamental correction wasn't carried out. To females of the second group (8 females) after administration of sodium nitrite Cytoflavin was injected intraperitoneally. For an assessment of consequences of a perinatal hypoxia pups aged 7 days were slaughtered by means of a fast decapitation under ethereal anesthesia. Results: It is taped that the hypoxia induced by nitrobonds has the expressed damaging effect on cardiomyocytes of newborn infant rats which is shown in the form of the hypoxemic and ischemic changes caused, first of all, by disturbance of integrity of cellular and mitochondrial membranes causes formation of hypoxemic type of a metabolism in a cardiac muscle, disturbance of energy balance in it found reflection in disturbance of automatism of a myocardium of experimental animals. Cytoflavin at pregnant females in experiment allows to lower a damage rate of cardiomyocytes at newborn animals, first of all, at the expense of his protective properties. Conclusion: Membrane-protective properties of the drug along with its anti-hypoxic and antioxidant effects can put Cytoflavin in a number of promising drugs with cardiological and cytological protective action, leading to the optimization of energy metabolism in ischemic myocardium and allows it to take its rightful place among the modern drugs which are used to correct disorders of energy metabolism in the ischemic myocardium including pathologies in the neonatal period. PMID- 29244926 TI - Interrelation secretory activity of stomach and immunes changes of peripheral blood when ulcerogenesis stomach. AB - : Incidence of gastric ulcer is high in almost all countries of the world. On the development and course of the disease affect the state acid- and enzymes production stomach, immune status. The purpose was to determine the presence and power of correlative links secretory activity of the stomach and immune changes in the peripheral blood during exacerbation of ulcer disease stomach. Methods: Surveyed in obtaining informed consent 42 patients with gastric ulcer in the acute phase prior to the eradication and antisecretory therapy and 40 healthy volunteers. On the state of function acid- and enzymes production of the gastric mucosa judged by the results of a 2-hour intragastric pH-metry and serum concentration pepsinogen, gastrin before the start of active treatment. Immunophenotype lymphocytes on CD-antigens (CD3, CD4, CD8, CD16, CD19, CD45, CD56) was measured by immunofluorescence, levels immunoglobulin isotype M, G, A, E - ELISA method. Results: When short-term intragastric pH-metry of the stomach hyperacidity patients recorded 6.7 times more likely than healthy, normacidity - 12.3 times less. Reduction of acid production was observed up to 8.6 times more, indicating the development of mucosal atrophy. Basal pH in the antrum was lower by 54.5% than in the control group, with stimulation increased by 33.6%, but remained lower than the values of healthy individuals by 48.7%. When ELISA amount pepsinogen patients showed significant increase in serum levels of PG-I relative to the control group at 33.4%, PG-II - 52%. In assessing the immune status of patients were identified changes in system phagocytes, cellular and humoral links, most pronounced for severe current peptic ulcer disease. Conclusion: The results indicate the presence of positive and negative correlative links mild to moderate force between indicators of secretory activity of gastric mucosal innate and adaptive immunity in patients with acute exacerbation of peptic ulcer disease. The presence and nature of these relationships should be taken into account when appointing antisecretory drugs. PMID- 29244927 TI - The impact of adipogenic diet on rats' tissue trace elements content. AB - The purpose: The influence of high-fat diet (HFD) on trace elements status, adipokine level, and markers of carbohydrate and lipid metabolism in weanling Wistar rats was investigated. Methods: A total of 20 male 1-months-old Wistar rats divided into two equal groups were used in the present study. The first group of animals obtained a standard diet (STD), whereas animals from the second group (NAFLD) were maintained on high-fat diet containing 10 and 31.6% of total calories from fat, respectively, during 1 month. Fat diet (HFD). Trace element status (using inductively coupled plasma mass spectrometry), serum levels of insulin, adiponectin, and leptin (using enzyme-linked immunosorbent assay), total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL C), high-density lipoprotein cholesterol (HDL-C), glucose (spectrophotometrically), apolipoprotein A1 (ApoA1) and B (ApoB) (using immunoturbidimetric method) were assessed. Results: It was shown that 1-month HFD feeding resulted in significant increase of EDAT, RPAT, total adipose tissue mass, and adipocyte area. HFD-fed animals were also characterized by a significant increase in circulating leptin levels and leptin-to-adiponectin ratio as compared to the control ones. No significant HFD-related difference in serum lipid spectrum, adiponectin, apolipoproteins, glucose, insulin, and HOMA-IR were revealed. Liver Cu, I, Mn, Se, Zn; EDAT Cr, V, Co, Cu, Fe,I, and RPAT Co, Cu, I, Cr, V, Fe, and Zn were significantly decreased in HFD-fed rats in comparison with the control group levels. Hair Co, Mn, Si, and V levels significantly exceeded the respective control values, whereas Se and I content were decreased in studied animals. At the same time, only serum Cu was significantly decreased in HFD-fed rats. Conclusion: The interplay between the impaired trace elements metabolism of HFD-fed weanling Wistar rats and disorder of adipokine balance was demonstrated. It is supposed that the altered trace elements status is primary and precedes other metabolic obesity-related disturbances. PMID- 29244928 TI - Effects of CAR-regimen autohemochemotherapy on redox-dependent processes in erythrocytes of tumor-bearing organism in experimental ovarian cancer. AB - The purpose: The purpose of the study was to investigate the effect of the scheme autohemochemotherapy ATS on redox-dependent processes in red blood cells of tumor bearing organism at an experimental ovarian cancer. Methods: We studied the dynamics of redox-dependent processes in red blood cells of rats with experimental ascitic ovarian tumor during CAP-regimen autohemochemotherapy (cyclophosphamide, doxorubicin and cisplatin). We assessed the indicators of oxidative modification of proteins in erythrocytes - carbonyl derivatives at l = 346 nm, 370 nm, 430 nm and 530 nm, the parameters of lipid peroxidation - malondialdehyde, ketodienes, diene conjugates, Schiff bases; the enzymatic part of antioxidant system - the activity of catalase, glutathione transferase and superoxide dismutase biochemically. Results: The red blood cells of tumor-bearing animals were found having increased the products of lipid peroxidation and oxidative modification of proteins while reducing the activity of antioxidant enzymes, suggesting a state of oxidative and carbonyl stress. Conclusion: We showed that extracorporeal incubation of cytotoxic drugs used in the CAP scheme with autoblood prior to infusion - the method of autohemochemotherapy - either in monochemotherapy, or in CAP-regimen, decreases the levels of lipid peroxidation, oxidative modification of proteins and increases activity of first line antioxidant defense enzymes - catalase and superoxide dismutase in circulating red blood cells. Such dynamics of redox-dependent processes suggests a stabilizing effect of autohemochemotherapy on circulating erythrocytes in a tumor bearing organism. PMID- 29244929 TI - Relationship between the change of ethological status and concentration of certain cytokines in blood in experimental desynchronosis under led lighting. AB - : Changing the natural rhythm of day and night leads to the development of DS, disruption of coordinated muscular activity, adequate behavioral activity, a decrease of attention in the performance of night work by experts in various fields. Changes ethological status may potentiate or weaken the changes in the indices of immune status, contribute to the formation of allostatic load at desynchronosis. The purpose: To investigate the relationship between changes ethological status and concentration of certain cytokines in peripheral blood in experimental desynchronosis under LED lighting. Methods: The study was performed on 158 adult guinea pigs, which were randomly assigned into 2 groups: 1 group- animals in the conditions of standard fixed (12 h light / 12 h dark) LED lighting (SFSDO); 2 group- animals with jet lag in terms of LED lighting (DESSDO). Light desynchronosis created by keeping animals at clock coverage for 30 days. Behavioral activity was studied in the test "open field" cognitive function was assessed using aqueous "labyrinth" Morris. By ELISA was determined on the apparatus in the peripheral blood concentration of interleukin - 4 (IL-4), interferon-gamma (IFN-g), melatonin, cortisol via specific for guinea pig test systems. Results: It was found that in animals of DS in terms of LED lighting in the dynamics of 10-30 days of observation show signs of anxiety, depression orienting-exploratory behavior, reduce the long-term memory and learning ability, spatial orientation disorders. It found that when a jet lag LED lighting conditions for 10 days, 20 days and 30 days in peripheral blood melatonin concentration decreases, the concentration of cortisol rises. In peripheral blood decreased IL-4 concentrations of 20 and 30 days, reducing the concentration of IFN-g at 30 days. Based on the results of correlation analysis, ethological change status and progress of cognitive function with a decrease in the blood concentration of IL-4 and IFN-g, the concentration of melatonin increase cortisol levels. Conclusion: The results indicate that in experimental conditions in desynchronosis LED lighting changes ethological status are associated with the progression of immune status changes. PMID- 29244930 TI - Reactive oxygen species and high-nitrogen compound in the mechanism of protection and damage in white blood cells in pulmonary tuberculosis. AB - The purpose: The aim of the study was to determine changes in the level of reactive oxygen species (ROS) and high-nitrogen compounds (HNC) of white blood cells of patients with various forms of pulmonary tuberculosis, and attempt to identify the pathogenic importance marked disturbances in protection mechanisms and damaged by the disease. Methods: A prospective study of 92 people, who were divided into 4 groups: I - 25 patients with newly diagnosed infiltrative tuberculosis and localization process within the same lobe of the lung, II - 42 patients with newly diagnosed pulmonary tuberculosis with a limited process (tuberculoma), III - 15 patients with fibrosis - cavernosis pulmonary tuberculosis with disease duration of less than 2 years old and group IV - healthy people - 10. Results: It has been found that chronic TB infection suppresses the phagocytes activity of leukocytes in any form of study of its development. However, in more severe forms of tuberculosis with a predominance of exudative tissue reactions (infiltrative) levels of these metabolites in the white blood cells increases and they become damaging significance. With limited forms of pulmonary tuberculosis - tuberculoma - levels of these metabolites (especially ICA) in white blood cells is reduced, which may have a protective value. Conclusion: The obtained results allow to claim that in the diagnosis and assessment of the nature of the tuberculosis process may be used definition of functional and metabolic characteristics of blood leukocytes and plasma (phagocytosis, peroxide, total lipid, BURST TEST, AFC, ICA and their derivatives), as well as the number of amino acids, taurine and arginine in plasma and leukocytes. PMID- 29244931 TI - Binuclear Purkinje neurons. AB - Until the end of the XX century binuclear neurons of Purkinje in rodents and the humans were a subject of casual finds. However already then it was noticed that such cells are in old and sick mammals more often. It is therefore assumed that the appearance of the second nucleus has a regenerative value - compensation age related or pathogenic loss of Purkinje cells. In 2003, in research on stem cell transplantation was made the first observations related to the mechanism of the appearance of the second nucleus in Purkinje neurons. The transgender studies in humans and in transgenic experiments on mice have shown that bone marrow derived donor cells can fuse with Purkinje neurons of the recipient, thus transfer to neuron its nucleus. It is very important that the binuclear neurons can appear in old and sick people and rodents without transplantation. But in that case neither the donor cell, nor the mechanism of origin of the second nucleus remain not clear. Relevance of clarification of this question increases of the fact that literature of the last years proves: emergence of the second nucleus is a form of physiological and reparative regeneration of neurons of Purkinje. PMID- 29244932 TI - Mitochondria and inflammation. AB - Endosymbiotic theory of mitochondrial origin contributed to research the role of mitochondria in the immune system activation, inflammation and the pathogenesis of inflammatory diseases. Factors that are referred to as mitochondrial damage associated molecular patterns (mtDAMPs) are one of a number of DAMPs, which are an endogenous molecules that activates an inflammatory response in case of cell damage or death. Activation of the immune system cells via mtDAMPS is caused by mitochondrial N-formyl peptides, mitochondrial cardiolipnin, ATP, mitochondrial DNA (mtDNA) and reactive oxygen species (mROS). In mitochondrial dysfunction, mtDAMPs release within the cell contributes to the recognition of the cell by pattern recognition receptors (PRRs) of innate immunity. Mitochondria are able to perceive signals of inflammation initiating danger by activating and managing the innate immune system. This review provides the information on the relationship of the immune signaling receptors (Toll-like receptors (TLR); RIG-1-like receptors (RLR); NOD-like receptors (NLR)) with mitochondrial functions and describes the role of mitochondria in the initiation and development of inflammation. PMID- 29244933 TI - Chronic obstructive pulmonary disease and diabetes: a look at the epidemiology, pathogenetic mechanisms, treatment. AB - Lately, increasingly studied the negative impact of diabetes type 2 on chronic obstructive pulmonary disease (COPD). According to literary data diabetes type 2 is more often diagnosed in patients with COPD in comparison with the general population: diabetes type 2 occur among patients with COPD in 18.7%, in comparison with patients without COPD - in 10,5%. The complexity of this association is primarily that chronic obstructive lung disease is regarded as a risk factor for diabetes type 2. The results of some researches show existence of close connection between the glycemic status and spirometric indicators - forced expiratory volume 1-second, forced vital capacity. Obstructive, restrictive, mixed ventilatory lung dysfunction observed in the states prior to the beginning of diabetes, such as impaired glucose tolerance and / or in patients with metabolic syndrome. The associations between lungs function and diabetes type 2 is explained by biochemical changes in airways, in lungs tissue. In patients with diabetes type 2 the decrease of lungs function is considered as a result of diabetes type 2 and as risk of development and progressing of COPD. Communication between the two complex nosologies - COPD and diabetes type 2 is confirmed by epidemiological data, common pathogenetic mechanisms - chronic systemic inflammation, oxidative stress, hypoxia, chronic hyperglycemia, side effects of drugs used in the treatment of two diseases - inhaled and / or systemic corticosteroids, inhaled bronchodilators, oral hypoglycemic agents. However, the pathogenetic mechanisms underlying the high prevalence of diabetes type 2 in patients with COPD is still unclear and requires a detailed study. Thus, it is actually and reasonable to conduct scientific and clinical work on identifying and better understanding of the exact mechanisms of the association between COPD and diabetes type 2 to develop methods for their correction, prevention and selection of adequate combination regimens in patients with these comorbid pathologies. PMID- 29244934 TI - Pathophysiological and molecular mechanisms of extracellular matrix protein resorption during skin aging, and the ways to their restoration. AB - The article is a short review of the most studied molecular mechanisms leading to skin aging. It considers mechanisms of cellular aging, oxidative stress, development of chronic inflammation, as well as synthesis and degradation of extracellular matrix proteins. The review also contains examples of extracellular matrix restoration using cell and pharmacological technologies. PMID- 29244935 TI - Endothelial dysfunction and Protein kinase C activity development interrelation at ischemic injury of a brain. AB - The ischemic stroke is the reason of high mortality and population disability worldwide and it is closely connected with endothelium dysfunction (ED). The endothelium carries out regulation of specific functions, generally the universal modulator - nitrogen oxide. A number of enzymes participates in a production of nitric oxide, but specific for an endothelium is endothelial NO synthase (eNOS), which violation of regulation is observed at an ischemic stroke. Significant role in activity of eNOS regulation plays protein kinase C (PKC). In this review the following processes were investigated: ED and nitric oxide interrelation at an ischemic stroke; some features of biological activity of nitric oxide depending on a place of synthesis and on time of ischemic damage; eNOS activity regulation by means of PKC; interrelation between ED and PKC activity at oxidative stress; the main alarm ways including activation of eNOS and PKC which regulate microvascular permeability and a tone of vessels of a brain. Being guided by the carried-out analysis of theoretical data, it should be noted that at development of ED the PKC hyperactivity is observed, therefore, the search of the substances possessing inhibiting influence on activity of PKC for treatment of the majority of cardiovascular diseases and an ischemic stroke has become particularly important and perspective. PMID- 29244936 TI - Vaccine manufacturing and technology: from biotechnological platforms to syntethic epitopes, current viepoint. AB - The Purposes: The Purposes: the review take into account short history of vaccination practice and development of vaccine technology. Methods: In the review we include data from several monographs about manufacturing of vaccines published by authors from such companies as Merck & Co; Sanofi Pasteur; Dynavax Europe/Rhein Biotech GmbH; Latham Biopharm Group; Aridis Pharmaceuticals LLC; Genentech; Amgen; Shamir Biologics LLC; Biopharm Services US; Novartis Pharma AG, and several research centers: Laboratory of Bacterial Polysaccharides, Center for Biologics Evaluation and Research; Purdue University, West Lafayette, IN, US; Department of Pharmaceutical Chemistry, Univ. Of Kansas; Max Planck Institute for dynamics of Complex Technical Systems; Fraunhofer USA Center for Molecular Biotechnology; US Dep. of Agriculture Animal and Plant Health Inspection Service, etc. Results: In historic literature there are data about inoculation practices in antique China, Persia, India, Byzantium, native Americans, some African population. In modern immunology since the end of XIX century the vaccines were produced at the in vivo platforms - in animals (rabbits, mice, cows). Since 1931 due to E. Goodpasture' elaboration most virus vaccines were and are produced at the in ovo platform. In 1949 J.F. Enders elaborated large-scale polio virus production in the primary culture of monkey kidney cells in vitro. Up to day primary culture of chiken embrio fibroblasts are used to large-scale production of vaccine viruses of measles, mumps, rabies. Since 2000-th in Western countries most part of virus vaccines were began to produced via a cultivation in continuous tumor cell lines. The last technology is the most low cost for large scale production of vaccines. We review several new biotechnological platforms for the production of the recombinant protein or virus-like particles as subunit vaccines: plant system, algae, mushrooms, insect cells, etc. Conclusion: Beside of good purpose of vaccination - prophylactic of several infectious deseases, doctors must take into account possibility of inter-species transmission of unknown pathogens (retroviruses, prions, etc) from biotechnological platforms - animals, cell cultures - into human population, and don't ignore L.A. Zilber' theory of virus' etiology of cancer diseases. PMID- 29244937 TI - Cytogenetic recapitulation, induced by medical preparations, as the universal stage of formation of urgent protection against damage at organ transplantation. AB - In this article modern representations about cellular mechanisms of formation by pharmacological preparations of urgent protection of organs against damage are given at transplantation. On an example of ischemic damage of kidneys it is shown, that at use of preparations of different pharmacological groups by the most expressed protective effect those from them which operating within the limits of a nonspecific adaptive syndrome of cellular systems, clearly induce in organs the evolutional developed signs of cytogenetic recapitulation possess: support a cellular homeostasis at the lowered level at the expense of activation of a glycolysis and conformational reorganizations of macromolecules, and also change in cells of water contain- decrease of free and increase of bound. PMID- 29244938 TI - Problems and prospects of investigating monocyte subsets during the development of inflammation-associated diseases. AB - In this review, we present information about a heterogeneity of monocyte subsets based on their unique functional and phenotypic properties. Here we also discuss the search of an optimal technique for the isolation of monocyte subsets as well as the origin of monocyte subsets and their role in inflammation. PMID- 29244939 TI - The technology of obtaining multipotent spheroids from limbal mesenchymal stromal cells for reparation of injured eye tissues. AB - It is known that stem and progenitor cells open new possibilities for restoring injured eye tissues. Limbal eye zone, formed mainly by derivatives of neural crest, is the main source of stem cells for regeneration. The current study considers development of innovative technology for obtaining 3D spheroids from L MMSC. It was shown that under 3D conditions L-MMSC due to compactization and mesenchymal-epithelial transition self-organize into cellular reparative modules. Formed L-MMSC spheroids retain and promote undifferentiated population of stem and progenitor limbal cells, as supported by expression of pluripotency markers - Oct4, Sox2, Nanog. Extracellular matrix synthetized by cells in spheroids allows retaining the functional potential of L-MMSC that are involved in regeneration of both anterior and, probably, posterior eye segment. PMID- 29244940 TI - Blood serum structures integrated assessment of pathophysiological changes in experimental cerebral ischemia. AB - The purpose: The purpose. To reveal solid-phase structures of blood serum during and after experimental cerebral ischemia. Methods: Integrated estimation pathophysiological changes at brain ischemia received on solid-phase structures of blood serum (BS) at 27 rats-male Vistar in weight of 300-390 g. Reversible brain ischemia of moderate severity was reproduced imposing surgical clips on both common carotids for 15 minutes then clips removed and provided bloodstream restoration on carotids. Blood took away in Eppendorf's test tube in volume on 1 ml before imposing clips, directly ahead of their removal and in 30 minutes after bloodstream restoration. By the Method cuneiform dehydration received BS facia (dry a film) which structures analyzed by means of stereomicroscope MZ12 firm "Leica". Results of researches fixed on structural parameters BS before imposing clips, after removal clips and in 30 minutes after bloodstream restoration. Results: Before ischemia the integrated picture facias BS rats had the harmonious system organisation: the radial or partially-radial arrangement of the cracks, accurately generated konkrecias that testified to normal physiological condition of experimental animals. During the period occlusions carotids there were markers of a ischemia, activation of a capillary blood-groove, inflammatory reaction and stress. Partially these signs remained at reperfusion. Conclusion: The conducted researches of structures BS on experimental animals have allowed to reveal marker structures BS similar revealed at inspection of people with an ischemia of a brain. PMID- 29244941 TI - Monitoring of brightness temperature of suspension of follicular thyroid carcinoma cells in SHF range by radiothermometry. AB - The purpose: The purpose of this research consisted in monitoring of brightness temperature of the suspension of follicular thyroid carcinoma cells during the necrosis of these cells in superhigh frequency (SHF) range. Methods: The monitoring of the change in the ratio between brightness temperatures TSHF and TIR values during the necrosis of these cells. The object of study was follicular thyroid carcinoma cells suspension prepared with use of Versene solution and 0.25% trypsin solution. The cells were precipitated by centrifugation and re suspended in culture medium. The measurements of brightness temperatures were carried out with use of radiothermoimeter. SHF range was 3.4-4.2 GHz, and infrared (IR) range was 8-13 mm. The temperature of the suspension was maintained at 37.5 degrees S. Results: It was found that upon the necrosis in the suspension of cells, an increase in brightness temperature in 3.4-4.2 GHz range (SHF range) occurs, while brightness temperature of the medium in the IR range does not change. Conclusion: The monitoring of necrosis of follicular thyroid carcinoma cells was carried out by SHF-radiothermometry. It was shown that during the necrosis the change of non-equilibrium state of cell medium occurs, that results in the change in the ratio between TSHF and TIR. During the necrosis, the brightness temperature in SHF range (TSHF) increases. PMID- 29244942 TI - Application of the capillary electrophoresis method for the study of plasma proteins homocysteinylation. AB - Purpose: Purpose. This article describes the use of capillary electrophoresis with UV detection to determine the ratio of protein-bound homocysteine and cysteine concentrations in human plasma. Methods: Plasma samples were reduced with dithiothreitol and derivatized by thiocarbonyldiimidazole before being filtered again for purification of proteins. The pre-concentration of analytes was carried out directly in the capillary (48.5 cm in length and an inner diameter of 50 mkm) by NaOH post-injection. The eletrophoretic separation of analytes was carried out using 0.2 M ammonium acetate with 25 mM hexadecyltrimethylammonium bromide. Results: Limit of quantitation for homocysteine was 0.8 mkM, reproducible ratio of cysteine/homocysteine <5%, full analysis time 15 min. Conclusion: The ratio of bound cysteine to homocysteine is characterized by the same regularity as the ratio of their total content. It has a fairly high degree of correlation with the level of bound homocysteine and it is characterized by less variability than the level of total homocysteine. This has the advantage of use the bound cysteine/homocysteine ratio for assessing the risk of cardiovascular disease complications. PMID- 29244943 TI - Electrical Programming of Soft Matter: Using Temporally Varying Electrical Inputs To Spatially Control Self Assembly. AB - The growing importance of hydrogels in translational medicine has stimulated the development of top-down fabrication methods, yet often these methods lack the capabilities to generate the complex matrix architectures observed in biology. Here we show that temporally varying electrical signals can cue a self-assembling polysaccharide to controllably form a hydrogel with complex internal patterns. Evidence from theory and experiment indicate that internal structure emerges through a subtle interplay between the electrical current that triggers self assembly and the electrical potential (or electric field) that recruits and appears to orient the polysaccharide chains at the growing gel front. These studies demonstrate that short sequences (minutes) of low-power (~1 V) electrical inputs can provide the program to guide self-assembly that yields hydrogels with stable, complex, and spatially varying structure and properties. PMID- 29244944 TI - Evaluating the Performance of Household Liquefied Petroleum Gas Cookstoves. AB - Liquefied petroleum gas (LPG) cookstoves are considered to be an important solution for mitigating household air pollution; however, their performance has rarely been evaluated. To fill the data and knowledge gaps in this important area, 89 laboratory tests were conducted to quantify efficiencies and pollutant emissions from five commercially available household LPG stoves under different burning conditions. The mean thermal efficiency (+/-standard deviation) for the tested LPG cookstoves was 51 +/- 6%, meeting guidelines for the highest tier level (Tier 4) under the International Organization for Standardization, International Workshop Agreement 11. Emission factors of CO2, CO, THC, CH4, and NOx on the basis of useful energy delivered (MJd) were 142 +/- 17, 0.77 +/- 0.55, 130 +/- 196, 5.6 +/- 8.2, and 46 +/- 9 mg/MJd, respectively. Approximately 90% of the PM2.5 data were below the detection limit, corresponding to an emission rate below 0.11 mg/min. For those data above the detection limit, the average emission factor was 2.4 +/- 1.6 mg/MJd, with a mean emission rate of 0.20 +/- 0.16 mg/min. Under the specified gas pressure (2.8 kPa), but with the burner control set to minimum air flow rate, less complete combustion resulted in a visually yellow flame, and CO, PM2.5, EC, and BC emissions all increased. LPG cookstoves met guidelines for Tier 4 for both CO and PM2.5 emissions and mostly met the World Health Organization Emission Rate Targets set to protect human health. PMID- 29244946 TI - In Situ Synthetic Functionalization of a Transmembrane Protein Nanopore. AB - Monitoring current flow through a single nanopore has proved to be a powerful technique for the in situ detection of molecular structure, binding, and reactivity. Transmembrane proteins, such as alpha-hemolysin, provide particularly attractive platforms for nanopore sensing applications due to their atomically precise structures. However, many nanopore applications require the introduction of functional groups to tune selectivity. To date, such modifications have required genetic modification of the protein prior to functionalization. Here we demonstrate the in situ synthetic modification of a wild-type alpha-hemolysin nanopore embedded in a membrane. We show that reversible dynamic covalent iminoboronate formation and the resulting changes in the ion current flowing through an individual nanopore can be used to map the reactive behavior of lysine residues within the nanopore channel. Crucially, the modification of lysine residues located outside the nanopore channel was found not to affect the stability or utility of the nanopore. Finally, knowledge of the reactivity patterns enabled the irreversible functionalization of a single, assignable lysine residue within the nanopore channel. The approach constitutes a simple, generic tool for the rapid, in situ synthetic modification of protein nanopores that circumvents the need for prior genetic modification. PMID- 29244945 TI - Pd-Catalyzed Aerobic Oxidation Reactions: Strategies To Increase Catalyst Lifetimes. AB - The palladium complex [(neocuproine)Pd(MU-OAc)]2[OTf]2 (1, neocuproine = 2,9 dimethyl-1,10-phenanthroline) is an effective catalyst precursor for the selective oxidation of primary and secondary alcohols, vicinal diols, polyols, and carbohydrates. Both air and benzoquinone can be used as terminal oxidants, but aerobic oxidations are accompanied by oxidative degradation of the neocuproine ligand, thus necessitating high Pd loadings. Several strategies to improve aerobic catalyst lifetimes were devised, guided by mechanistic studies of catalyst deactivation. These studies implicate a radical autoxidation mechanism initiated by H atom abstraction from the neocuproine ligand. Ligand modifications designed to retard H atom abstractions as well as the addition of sacrificial H atom donors increase catalyst lifetimes and lead to higher turnover numbers (TON) under aerobic conditions. Additional investigations revealed that the addition of benzylic hydroperoxides or styrene leads to significant increases in TON as well. Mechanistic studies suggest that benzylic hydroperoxides function as H atom donors and that styrene is effective at intercepting Pd hydrides. These strategies enabled the selective aerobic oxidation of polyols on preparative scales using as little as 0.25 mol % of Pd, a major improvement over previous work. PMID- 29244947 TI - New Strategy for in Vitro Determination of Carbonic Anhydrase Activity from Analysis of Oxygen-18 Isotopes of CO2. AB - The oxygen-18 isotopic (18O) composition in CO2 provides an important insight into the variation of rate in isotopic fractionation reaction regulated by carbonic anydrase (CA) metalloenzyme. This work aims to employ an 18O-isotope ratio-based analytical method for quantitative estimation of CA activity in erythrocytes for clinical testing purposes. Here, a new method has been developed that contains the measurements of 18O/16O isotope ratios during oxygen-18 isotopic exchange between 12C16O16O and H218O of an in vitro biochemical reaction controlled by erythrocytes CA and estimation of enzymatic activity of CA from the isotopic composition of CO2. We studied the enrichments of 18O-isotope of CO2 with increments of CA activities during isotopic fractionation reaction. To check the influence of subject-specific body temperature, pH, H218O, and cellular produced CO2 on this reaction, we performed the in vitro experiments in closed containers with variations of those parameters. Finally, we mimicked the exchange reaction at 5% [CO2], 50/00 [H218O], pH of 7.4, and temperature of 37 degrees C to create the physiological environment equivalent to that of the human body and monitored the exchange kinetics with variations of CA activities, and subsequently, we derived the quantitative relation between the 18O-isotope of CO2 and CA activity in erythrocytes. This assay may be applicable for rapid and simple quantification of carbonic anhydrase activity which is very important to prevent the carbonic-anhydrase-associated disorders in human. PMID- 29244948 TI - Residential Coal Combustion as a Source of Levoglucosan in China. AB - Levoglucosan (LG) has been widely identified as a specific marker for biomass burning (BB) sources and frequently utilized in estimating the BB contribution to atmospheric fine particles all over the world. However, this study provides direct evidence to show that coal combustion (CC) is also a source of LG, especially in the wintertime in Northern China, based on both source testing and ambient measurement. Our results show that low-temperature residential CC could emit LG with emission factors (EF) ranging from 0.3 to 15.9 mg kg-1. Ratios of LG to its isomers, mannosan and galactosan, differ between CC and BB emissions, and the wintertime ratios in Beijing ambient PM2.5 and source-specific tracers including carbon isotopic signatures all indicated a significant contribution from CC to ambient levoglucosan in winter in Beijing. The results suggest that LG cannot be used as a distinct source marker for biomass burning in special cases such as some cities in the northern China, where coal is still widely used in the residential and industrial sectors. Biomass burning sources could be overestimated, although such an over-estimation could vary spatially and temporally. PMID- 29244949 TI - Growth Kinetics and Size Distribution Dynamics of Viscous Secondary Organic Aerosol. AB - Low bulk diffusivity inside viscous semisolid atmospheric secondary organic aerosol (SOA) can prolong equilibration time scale, but its broader impacts on aerosol growth and size distribution dynamics are poorly understood. Here, we present quantitative insights into the effects of bulk diffusivity on the growth and evaporation kinetics of SOA formed under dry conditions from photooxidation of isoprene in the presence of a bimodal aerosol consisting of Aitken (ammonium sulfate) and accumulation (isoprene or alpha-pinene SOA) mode particles. Aerosol composition measurements and evaporation kinetics indicate that isoprene SOA is composed of several semivolatile organic compounds (SVOCs), with some reversibly reacting to form oligomers. Model analysis shows that liquid-like bulk diffusivities can be used to fit the observed evaporation kinetics of accumulation mode particles but fail to explain the growth kinetics of bimodal aerosol by significantly under-predicting the evolution of the Aitken mode. In contrast, the semisolid scenario successfully reproduces both evaporation and growth kinetics, with the interpretation that hindered partitioning of SVOCs into large viscous particles effectively promotes the growth of smaller particles that have shorter diffusion time scales. This effect has important implications for the growth of atmospheric ultrafine particles to climatically active sizes. PMID- 29244950 TI - Bioinspired Assembly of Carbon Nanotube into Graphene Aerogel with "Cabbagelike" Hierarchical Porous Structure for Highly Efficient Organic Pollutants Cleanup. AB - Nowadays, physical absorption has become a feasible method offering an efficient and green route to remove organic pollutants from the industrial wastewater. Inspired by polydopamine (PDA) chemistry, one-dimensional PDA-functionalized multiwalled carbon nanotubes (MWCNT-PDA) were creatively introduced into graphene aerogel framework to synthesize a robust graphene/MWCNT-PDA composite aerogel (GCPCA). The whole forming process needed no additional reducing agents, significantly reducing the contamination emissions to the environment. The GCPCA exhibited outstanding repeatable compressibility, ultralight weight, as well as hydrophobic nature, which were crucial for highly efficient organic pollution absorption. The MWCNTs in moderate amounts can provide the composite aerogels with desirable structure stability and extra specific surface area. Meanwhile, the eventual absorption performance of GCPCAs can be improved by optimizing the microporous structure. In particular, a novel "cabbagelike" hierarchical porous structure was obtained as the prefreezing temperature was decreased to -80 degrees C. The miniaturization of pore size around the periphery of GCPCA enhanced the capillary flow in aerogel channels, and the super-absorption capacity for organic solvents was up to 501 times (chloroform) its own mass. Besides, the GCPCAs exhibited excellent reusable performance in absorption squeezing, absorption-combustion, and absorption-distillation cycles according to the characteristic of different organic solvents. Because of the viable synthesis method, the resulting GCPCAs with unique performance possess broad and important application prospects, such as oil pollution cleanup and treatment of chemical industrial wastewater. PMID- 29244951 TI - Interfacial Adsorption of Neutral and Ionic Solutes in a Water Droplet. AB - Direct (solute-water) and indirect (water-water) contributions to adsorption at an air-water interface are identified using the Widom potential distribution theorem and quantified using molecular dynamics simulations of a liquid water droplet containing either neopentane or iodide-like solutes with charges of 0 or +/-1. The results are used to quantitatively compare direct and indirect energetic and entropic contributions to adsorption, as well as to critically test surface capillary wave, linear response (LR), and mean field (MF) predictions. The negative signs of the total adsorption energies and entropies of both the anionic and cationic solutes are found to result from indirect adsorption induced changes in water-water interactions, rather than from surface capillary wave perturbations, which are found to be asymmetric with respect to solute charge. The LR and MF approximations both accurately describe the adsorption of neutral (hydrophobic) solutes, while for ionic solutes the MF approximation is entirely inappropriate and LR predictions are qualitatively (but not quantitatively) accurate. PMID- 29244952 TI - Metabolic Responses of Mytilus galloprovincialis to Fullerenes in Mesocosm Exposure Experiments. AB - In this study, Mediterranean mussels (Mytilus galloprovincialis) were exposed through the diet to fullerene soot at three concentrations in parallel to a control group. Their metabolomics response was assessed by high-performance liquid chromatography coupled to high-resolution mass spectrometry (HPLC-HRMS). The experiments were conducted in marine mesocosms, during 35 days (7 days of acclimatization, 21 days of exposure, and 7 days of depuration). Real conditions were emulated in terms of physicochemical conditions of the habitat. Results confirmed the bioaccumulation of fullerenes, and the metabolome of the exposed organisms revealed significant differences in the concentrations of seven free amino acids in comparison to the control group. An increase in small nonpolar amino acids (e.g., alanine) and branched chain amino acids (leucine and isoleucine) were observed. Also, glutamine concentrations decreased significantly, suggesting the activation of facultative anaerobic energy metabolism. Branched chain amino acids, such as leucine and isoleucine, followed the opposite trend after the highest level of exposure, which can imply hormesis effects. Other significant differences were observed on lipids content, such as the general increase of free fatty acids, i.e., long-chain fatty acids (lauric, myristic, and palmitic acids) when the concentration of exposure was increased. These results were consistent with hypoxia and oxidative stress. PMID- 29244953 TI - MetaQSAR: An Integrated Database Engine to Manage and Analyze Metabolic Data. AB - The study describes the MetaQSAR tool, a new database engine specifically tailored to collect and analyze metabolic data. This is a plug-in embedded in the VEGA suite of programs (freely downloadable at www.vegazz.net ) and takes advantage from all cheminformatics features implemented in the software with additional tools aimed to perform statistical analyses, similarity searches, and physicochemical profiling of the stored molecules. MetaQSAR also implements a novel metabolism classification, which groups the metabolic reactions in 101 classes and can find numerous applications in metabolic analyses. The potentials of MetaQSAR are here assessed by using it to store and analyze an extended database focused on metabolism of xenobiotics, which was collected by manually curated meta-analysis of the recent literature. The database includes 1890 substrates taken from about 1500 original papers in the years 2004-2015. The database was utilized in both physicochemical analyses and similarity searches, so evidencing the notable potentialities of MetaQSAR, which can find particularly fruitful applications in developing targeted predictive approaches. PMID- 29244955 TI - Dose and Diet - Sources of Arsenic Intake in Mouse in Utero Exposure Scenarios. AB - In humans, early life exposure to inorganic arsenic is associated with adverse health effects. Inorganic arsenic in utero or in early postnatal life also produces adverse health effects in offspring of pregnant mice that consumed drinking water containing low part per billion levels of inorganic arsenic. Because aggregate exposure of pregnant mice to inorganic arsenic from both drinking water and food has not been fully evaluated in experimental studies, quantifying arsenic exposure of the developing mouse is problematic. Here, we determined levels of total arsenic and arsenic species in natural ingredient rodent diets that are composed of many plant and animal-derived foodstuffs and in a purified ingredient rodent diet that is composed of a more restricted mixture of foodstuffs. In natural ingredient diets, total arsenic levels ranged from ~60 to ~400 parts per billion, and in the purified ingredient diet, total arsenic level was 13 parts per billion. Inorganic arsenic was the predominant arsenic species in trifluoroacetic acid extracts of each diet. Various exposure scenarios were evaluated using information on inorganic arsenic levels in diet and drinking water and on daily food and water consumption of pregnant mice. In a scenario in which pregnant mice consumed drinking water with 10 parts per billion of inorganic arsenic and a natural ingredient diet containing 89 parts per billion of inorganic arsenic, drinking water contributed only ~20% of inorganic arsenic intake. Quantitation of arsenic species in diets used in studies in which drinking water is the nominal source of arsenic exposure provides more accurate dosimetry and improves understanding of dose-response relations. Use of purified ingredient diets will minimize the discrepancy between the target dosage level and the actual dosage level attained in utero exposure studies designed to evaluate effects of low level exposure to inorganic arsenic. PMID- 29244954 TI - Single Atomic Layer Ferroelectric on Silicon. AB - A single atomic layer of ZrO2 exhibits ferroelectric switching behavior when grown with an atomically abrupt interface on silicon. Hysteresis in capacitance voltage measurements of a ZrO2 gate stack demonstrate that a reversible polarization of the ZrO2 interface structure couples to the carriers in the silicon. First-principles computations confirm the existence of multiple stable polarization states and the energy shift in the semiconductor electron states that result from switching between these states. This monolayer ferroelectric represents a new class of materials for achieving devices that transcend conventional complementary metal oxide semiconductor (CMOS) technology. Significantly, a single atomic layer ferroelectric allows for more aggressively scaled devices than bulk ferroelectrics, which currently need to be thicker than 5-10 nm to exhibit significant hysteretic behavior (Park, et al. Adv. Mater. 2015, 27, 1811). PMID- 29244956 TI - Effects of carbohydrate and branched-chain amino acid beverage ingestion during acute upper body resistance exercise on performance and postexercise hormone response. AB - The purpose of this investigation was to examine the individual and combined effects of ingesting carbohydrates (CHO) and branched-chain amino acids (BCAA) during high-volume upper body resistance exercise (RE) on markers of catabolism and performance. Thirteen resistance-trained males completed 4 experimental trials with supplementation, ingesting beverages containing CHO, BCAA, CHO+BCAA, or placebo (PLA) in a randomized, double-blind design. The beverages were ingested in 118-mL servings 6 times during an ~60-min RE session consisting of bench press, bent-over row, incline press, and close-grip row. Each RE was performed with 5 sets of repetitions at 65% 1-repetition maximum until volitional fatigue. Blood samples were collected at baseline, immediately postexercise, and 60 min postexercise to assess glucose and insulin. Cortisol was assessed immediately and at 60 min postexercise. No significant performance benefits were observed for any RE. CHO+BCAA (152.4 +/- 71.4 ng/mL) resulted in the lowest cortisol levels, which was lower than BCAA and PLA (193.7 +/- 88.5, 182.8 +/- 67.5 ng/mL, p < 0.05), but not different from CHO (165 +/- 76.5 ng/mL, p = 0.342). Postexercise insulin concentrations were significantly higher with CHO (4.79 +/- 3.4 mU/L) compared with BCAA and PLA (3.7 +/- 2.0, 3.5 +/- 1.8 mU/L, p < 0.05), but not different from CHO+BCAA (4.3 +/- 2.5 mU/L, p = 0.339). There was no treatment effect for glucose, but glucose significantly increased from baseline to immediately postexercise and significantly decreased at 60 min postexercise. Ingesting beverages containing CHO with or without BCAA during upper body resistance exercise may promote a more favorable postexercise less catabolic environment. PMID- 29244958 TI - Does Pronounced Birth Weight Loss Indicate Breastfeeding Failure? PMID- 29244959 TI - Wound Curriculum for Nurses. AB - The European Wound Management Association (EWMA) has just finalised the first curriculum in a series of several curricula intended for use in levels 5-7 of the European Qualifications Framework (EQF)1. The aim of these is to support a common approach to post-registration qualification in wound management for nurses across Europe. EWMA hopes and will work towards a close collaboration with European nurse organisations as well as educational institutions to implement these common curricula. PMID- 29244960 TI - Reply to "Does Pronounced Birth Weight Loss Indicate Breastfeeding Failure?" PMID- 29244957 TI - Hypercementosis Associated with ENPP1 Mutations and GACI. AB - Mineralization of bones and teeth is tightly regulated by levels of extracellular inorganic phosphate (Pi) and pyrophosphate (PPi). Three regulators that control pericellular concentrations of Pi and PPi include tissue-nonspecific alkaline phosphatase (TNAP), progressive ankylosis protein (ANK), and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Inactivation of these factors results in mineralization disorders affecting teeth and their supporting structures. This study for the first time analyzed the effect of decreased PPi on dental development in individuals with generalized arterial calcification of infancy (GACI) due to loss-of-function mutations in the ENPP1 gene. Four of the 5 subjects reported a history of infraocclusion, overretained primary teeth, ankylosis, and/or slow orthodontic tooth movement, suggesting altered mineral metabolism contributing to disrupted tooth movement and exfoliation. All subjects had radiographic evidence of unusually protruding cervical root morphology in primary and/or secondary dentitions. High-resolution micro-computed tomography (micro-CT) analyses of extracted primary teeth from 3 GACI subjects revealed 4 fold increased cervical cementum thickness ( P = 0.00007) and a 23% increase in cementum density ( P = 0.009) compared to age-matched healthy control teeth. There were no differences in enamel and dentin densities between GACI and control teeth. Histology revealed dramatically expanded cervical cementum in GACI teeth, including cementocyte-like cells and unusual patterns of cementum resorption and repair. Micro-CT analysis of Enpp1 mutant mouse molars revealed 4-fold increased acellular cementum thickness ( P = 0.002) and 5-fold increased cementum volume ( P = 0.002), with no changes in enamel or dentin. Immunohistochemistry identified elevated ENPP1 expression in cementoblasts of human and mouse control teeth. Collectively, these findings reveal a novel dental phenotype in GACI and identify ENPP1 genetic mutations associated with hypercementosis. The sensitivity of cementum to reduced PPi levels in both human and mouse teeth establishes this as a well-conserved and fundamental biological process directing cementogenesis across species (ClinicalTrials.gov NCT00369421). PMID- 29244961 TI - Time-dependent therapeutic roles of nitazoxanide on high-fat diet/streptozotocin induced diabetes in rats: effects on hepatic peroxisome proliferator-activated receptor-gamma receptors. AB - Targeting peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-gamma modulators display improvements in the insulin-sensitizing and adverse effects of the traditional thiazolidinediones. Nitazoxanide (NTZ) is proposed as a PPAR-gamma receptor ligand with agonistic post-transcriptional effects. Currently, NTZ antidiabetic activities versus pioglitazone (PIO) in a high-fat diet/streptozotocin rat model of type 2 diabetes was explored. Diabetic adult male Wistar rats were treated orally with either PIO (2.7 mg.kg-1.day-1) or NTZ (200 mg.kg-1.day-1) for 14, 21, and 28 days. Body masses, fasting blood glucose, IR, lipid profiles, and liver and kidney functions of rats were assayed. Hepatic glucose metabolism and PPAR-gamma protein expression levels as well as hepatic, pancreatic, muscular, and renal histopathology were evaluated. Significant time-dependent euglycemic and insulin-sensitizing effects with preservation of liver and kidney functions were offered by NTZ. Higher hepatic levels of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase enzymes and PPAR-gamma protein expressions were acquired by NTZ and PIO, respectively. NTZ could be considered an oral therapeutic strategy for DM type 2. Further systematic NTZ/PPAR-gamma receptor subtype molecular activations are recommended. Simultaneous use of NTZ with other approved antidiabetics should be explored. PMID- 29244963 TI - A response to editorial 'a holistic approach to examining the evidence', JWC 2017; 26(11):609. PMID- 29244962 TI - Expression of the Frizzled receptors and their co-receptors in calcified human aortic valves. AB - The cellular mechanisms that induce calcific aortic stenosis are yet to be unraveled. Wnt signaling is increasingly being considered as a major player in the disease process. However, the presence of Wnt Frizzled (Fzd) receptors and co receptors LRP5 and 6 in normal and diseased human aortic valves remains to be elucidated. Immunohistochemistry and quantitative polymerase chain reaction were used to determine Fzd receptor expression in normal and calcified human aortic valve tissue, as well as human aortic valve interstitial cells (HAVICs) isolated from calcified and normal human aortic valves. There was significantly higher mRNA expression of 4 out of the 10 Fzd receptors in calcified aortic valve tissues and 8 out of the 10 in HAVICs, and both LRP5/6 co-receptors in calcified aortic valves (P < 0.05). These results were confirmed by immunohistochemistry, which revealed abundant increase in immunoreactivity for Fzd3, 7, and 8, mainly in areas of lipid core and calcified nodules of diseased aortic valves. The findings of abundant expression of Fzd and LRP5/6 receptors in diseased aortic valves suggests a potential role for both canonical and noncanonical Wnt signaling in the pathogenesis of human aortic valve calcification. Future investigations aimed at targeting these molecules may provide potential therapies for aortic valve stenosis. PMID- 29244964 TI - Outpatient negative pressure dressing therapy for pretibial lacerations in a patient with high anaesthetic risk: a case study. AB - Pretibial lacerations are a common cause of presentation to accident and emergency departments. The management of these wounds is contentious with a variation in practise between individual institutions. We present the case of a 49-year-old female with a background of pulmonary atresia and associated pulmonary hypertension, who underwent successful outpatient negative pressure wound therapy (NPWT) for three pretibial lacerations. We would propose that this therapy is an effective option for the management of these wounds in independently mobile patients who are at high-risk when under anaesthetic. PMID- 29244965 TI - Management of chronic diabetic foot ulcers using platelet-rich plasma. AB - OBJECTIVE: Platelet-rich plasma (PRP) has been proposed as an adjunct for the treatment of foot ulcers in patients with diabetes, as well as a treatment for chronic and acute wounds. This study examined the application of PRP in the treatment of diabetic foot ulcers (DFUs) in patients. METHODS: This prospective study was conducted between 2011 and 2014. We used PRP, produced by a kit, for the treatment of DFUs. Patients were allocated to one of three groups, according to size of ulcer. The significance of changes in time for wound healing were statistically assessed. RESULTS: The study was completed by 150 patients, and a total of 150 foot ulcers were assessed. Wound size reduction was detected in patients after four weeks of treatment. In DFUs with a 2-5.5 cm2 surface area, complete closure happened after 7.2 weeks, 5.5-8.5cm2 DFUs completely closed after 7.5 weeks, and 8.5-12.5cm2 DFUs healed completely after 8.8 weeks. None of the wounds reopened after eight months of monitoring. CONCLUSIONS: This study will provide more evidence for the use of autologous PRP for DFUs in patients. PMID- 29244966 TI - Lords-a-leaping put wound care centre stage. PMID- 29244967 TI - Diagnosis and treatment of chronic wounds: current standards of Germany's Initiative for Chronic Wounds e. V. AB - The diagnosis and treatment of patients with chronic wounds is an enormous challenge in various disciplines of medicine. These very complex processes usually involve several experts of different medical specialties with varying educational backgrounds. A necessary basis for consistent communication and documentation is the use of unambiguous nomenclature. Therefore, the board of the German wound association, Initiative for Chronic Wounds (ICW) e.V., has started to define various terms and procedures. An easy to remember algorithm, in the form of the ABCDE rule, has been developed for the structured diagnosis of chronic wounds. The successful therapy of chronic wounds is then based on the causal treatment of the underlying, pathophysiological relevant diseases. M.O.I.S.T. a concept which helps health professionals in the systematic approach to the local treatment of patients with chronic wounds, in conforming to the most up-to-date scientific knowledge. By using consistent definitions and standards in wound care, it is possible to optimise current diagnostic and treatment strategies as well as to make them more easily understandable. PMID- 29244968 TI - The House of Lords debates wound care strategy. AB - On Tuesday 22 November, the House of Lords (London, UK) held a short debate 'Improving the standard of wound care in the NHS.' It consisted of nine questions from the floor and a response from Lord O'Shaughnessy, The Parliamentary Under Secretary of State for Health (Conservative). Here, Paul Browning, (Doctoral Research Student, University of Worcester, employed by 3M UK plc) summarises the key points from the evening and explains why it is so important we keep wound care on the Government's agenda. PMID- 29244969 TI - Treatment of open upper limb injuries with infection prevention and negative pressure wound therapy: a systematic review. AB - OBJECTIVE: Open upper limb injuries requiring soft reconstruction can pose a dilemma for trauma surgeons when considering the treatment options. The British Orthopaedic Association and British Association of Plastic, Reconstructive and Aesthetic Surgeons Standard for Trauma (BOAST) have addressed the management of severe open lower limb fractures with the creation of the BOAST 4 guidelines. However, no such gold standard exists for the treatment of open injuries of the upper limb. Furthermore, treatment of these injuries is often more difficult and requires complicated strategies. Since the advent of negative pressure wound therapy (NPWT), there has been an improvement in wound care, though a focused review of its use in wound closure and infection prevention in the upper limb has not been published. We examine wound care management for open upper limb injuries with regard to the dressings applied, NPWT, wound closure and infection prevention. METHOD: A systematic search of Medline, Cochrane and Google Scholar was performed using the key words. The key word searches were performed by two independent reviewers and 8,792 papers were found. Manuscripts between 1990 and 2010 were included, with the addition of key manuscripts before this date. Each manuscript was assessed by the two authors independently for methodology and validity Results: Approximately 120 manuscripts fulfilled selection criteria examining the influence of NPWT on open upper and lower limb injuries, and those examining infection risk in the same injuries. Of these 120 manuscripts, 28 were suitable for inclusion in the review. The systematic review is presented, allied to the BOAST 4 principles, examining the use of NPWT and the tools available for infection prevention for wounds of the upper and lower limb. The use of NPWT in conjunction with antibiotic-bead therapy improved the way in which open fractures of both the upper and lower limb are treated. CONCLUSION: Production of guidelines is warranted for the treatment of upper limb injuries. The treatment options available for wound closure and infection prevention that are used in the treatment of open injuries of the lower limb could be adopted to open injuries of the upper limb. PMID- 29244970 TI - Maggot debridement therapy for an electrical burn injury with instructions for the use of Lucilia sericata larvae. AB - OBJECTIVE: Maggot debridement therapy (MDT) has proved an efficient and reliable approach for wound healing. We explain the use of maggots with a stepwise procedure for conducting MDT in a patient with severe and large electrical wounds. METHOD: We captured the flies of Lucilia sericata from the natural environment, Alborz, Iran, and reared them in netted cages. The eggs obtained from the flies were disinfected with chloramine, and then were incubated on culture medium. RESULTS: The young larvae, in open ended pouches, were applied to the wound of a 29-year-old man who suffered from extensive fourth degree electrical burns. The patient's wounds were fully debrided, while adequate granulation tissue grew on the wounds in just 16 days of treatment. MDT prepared the wound bed to receive skin autograft, successfully, without any interaction, allergy, or inflammation. CONCLUSION: Our case study indicated that MDT can be a suitable pre-grafting measure for electrical wounds. Implementing the stated procedures in the present study can help health professionals to employ MDT for similar cases. PMID- 29244971 TI - Developing antimicrobial calcium alginate fibres from neem and papaya leaves extract. AB - OBJECTIVE: The aim of this study was to evaluate an alternative approach to developing antimicrobial alginate fibres using plant extracts, such as those from neem and papaya leaves. METHOD: Aqueous leaves extract from neem, papaya and their hybrid combinations were used as solvent to develop sodium alginate fibres. Sodium alginate polymer containing these extracts was extruded in a calcium chloride (CaCl2) bath to develop neem (NE), papaya (PE) and their hybrid combinations-based calcium alginate fibres (H-1 to H-5). The surface morphology, spectra, liquid absorption, tensile strength and antimicrobial activity of these developed fibres were measured. RESULTS: NE fibre showed greater tensile strength than PE. The liquid absorption property of all developed fibres decreased, but showed antibacterial properties against Staphylococcus aureus and reduced bacterial growth up to 85% when compared with pure calcium alginate fibre. CONCLUSION: Neem, papaya and hybrid extract-based calcium alginate fibres have the potential to be used as wound dressings. PMID- 29244972 TI - Evaluating an iPad app in measuring wound dimension: a pilot study. AB - OBJECTIVE: This pilot study tested the reliability, validity and sensitivity of an innovative prototype iPad app, WoundAide, developed to measure wound dimension (length, width and surface area) using image analysis. METHOD: A prospective evaluation was conducted comparing WoundAide (WA) with two gold standard instruments, Wound Zoom (WZ) and Visitrak (VT). The study was conducted in a tertiary hospital in Singapore. Patients were recruited after obtaining local ethics approval. RESULTS: We recruited six patients with 10 venous wounds. Images were captured by two researchers. Generally, 7/10 (70%) of the wounds had surface areas of less than 16cm2. The intraclass correlation coefficient was greater than 0.95 for length, width and surface area for all measuring devices. The mean differences for length, width and surface area were not statistically significant. The average percentage of coefficient of variation for WA ranged from 3% to 33.3%, WZ 1.3% to 19.3%, and VT 2.1% to 43.4%. Length, width and surface area fell within the 95% limit of agreement. The capturing sensitivity was, on average, 75% for WA, 99.4% for VT, and 100% for WZ. CONCLUSION: WA has similar reliability and validity as WZ and VT. However, WA has the least sensitivity in image captures. Nonetheless, with enhancements made to its user interface and system algorithm, this limitation can be addressed. PMID- 29244973 TI - Cooperativity between antibiotics and antiseptics: testing the bactericidal effect. AB - OBJECTIVE: Treatment with antibiotics together with local application of antiseptics is common in wound care. We investigated the effectiveness of an antiseptic in two variations: octenidine (Oct) and octenidine+ (Oct+ with isotonic glucose addition). METHOD: Using the agar diffusion test with cultures of pathogenic Staphylococcus aureus and the non-pathogenic Bordetella petrii, we compared the effectiveness of octenidine to the classical antiseptics beta isodona (povidone-iodine; PI), chlorhexidine (Chl) and taurolin (Tau) alone, and in combination with various common antibiotics to uncover cooperativity between antiseptics and antibiotics. RESULTS: We detected strong interactions between antibiotics and antiseptics, that either enhanced or reduced the bactericidal efficiency. Effectiveness was dependent on the type of organism tested. Oct applied together with ineffective antibiotics frequently led to effective growth inhibition of Bordetella petrii. With Staphylococcus aureus we did not find such an effect. To this end, we reason that positively charged Oct may associate with antibiotic compounds via electrostatic interactions and guide it more efficiently to the bacterial cell wall. Interaction with antibiotics sometimes led to sequestration and reduced availability of some antiseptic/antibiotic combinations, but never with Oct. CONCLUSION: These data provide new arguments for decision planning concerning the choice of agent in the treatment of wound infections. PMID- 29244974 TI - The use of an antioxidant dressing on hard-to-heal wounds: a multicentre, prospective case series. AB - OBJECTIVE: Oxidative stress can contribute to impaired wound healing and chronic wounds. Our objective was to test the results of a new antioxidant dressing that could help stop the oxidative stress of cells in the wound bed. METHOD: A multicentre, prospective case study series was conducted in three Spanish hospitals. The RESVECH 2.0 index was used for healing assessment. Data from each patient was collected by the attending clinical researchers. Data analysis was performed using the statistical concept intention-to-treat (ITT). Descriptive results were presented as frequency and percentages for qualitative variables and mean, standard deviation (SD), range and median for quantitative variables. For analytical-inferential analyses, incidence of healing was calculated for chronic and acute wounds. Relative risk (RR) was used to establish the differences of healing between both types of wounds. Healing was represented by Kaplan-Meier survival curves, and these were compared using the log-rank test. RESULTS: A total of 31 patients with hard-to-heal wounds were recruited. During the 8-week follow-up period, nine wounds (29%) completely healed, of which seven (77.8%) were acute and two (22.2%) chronic. The remaining wounds (22) showed a significant improvement after treatment with the antioxidant dressing. RESVECH 2.0 scores decreased an average of 10.16 points over the 8-week period. CONCLUSION: The antioxidant dressing could represent an alternative in the dressing landscape for many types of acute and chronic wounds. PMID- 29244975 TI - Review of the molecular mechanisms in wound healing: new therapeutic targets? AB - The restoration of the skin barrier in acute and chronic wounds is controlled by several molecular mechanisms that synergistically regulate cell kinetics, enzymatic functions, and neurovascular activation. These pathways include genetic and epigenetic activation, which modulate physiological wound healing. Our review describes the genetic background of skin repair, namely transcription-independent diffusible damage signals, individual variability, epigenetic mechanism, controlled qualitative traits, post-translational mechanisms, antioxidants, nutrients, DNA modifications, bacteria activation, mitochondrial activity, and oxidative stress. The DNA background modulating skin restoration could be used to plan new diagnostics and therapeutics. PMID- 29244976 TI - Response to editorial 'food for thought: innovation and debate' JWC; 2017; 26(7):359 and to Swanson et al. letter JWC;26(9):570-571 in response to above. PMID- 29244977 TI - Errata. PMID- 29244979 TI - Errata. PMID- 29244978 TI - Errata. PMID- 29244980 TI - End-of-Life Care and Opioid Use in India: Challenges and Opportunities. PMID- 29244981 TI - Treatment, Not Terror: Time for Unique Problem-Solving Partnerships for Cancer Care in Resource-Challenged Environments. PMID- 29244982 TI - Diagnostic Dilemma: Primary Peritoneal Mesothelioma With Para-Occupational Asbestos Exposure. PMID- 29244983 TI - Allogeneic Stem Cell Transplant for Acute Myeloid Leukemia: Evolution of an Effective Strategy in India. AB - Purpose There are limited data from developing countries on the role and cost effectiveness of allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML). Patients and Methods We undertook a retrospective descriptive study of all patients with AML who underwent allo-SCT from 1994 to 2013 at our center to evaluate the clinical outcomes and cost effectiveness of this therapeutic modality. Results Two hundred fifty-four consecutive patients, median age 34 years, who underwent allo-SCT at our center were included in this study. There were 161 males (63.4%). The 5-year overall survival (OS) and event-free survival for the entire cohort was 40.1 +/- 3.5% and 38.7 +/- 3.4%, respectively. The 5-year OS for patients in first (CR1), second, and third complete remission and with disease/refractory AML was 53.1 +/- 5.2%, 48.2 +/- 8.3%, 31.2 +/- 17.8%, and 16.0 +/- 4.4%, respectively ( P < .001). From 2007, reduced intensity conditioning (RIC) with fludarabine and melphalan (Flu/Mel) was used in a majority of patients in CR1 (n = 67). Clinical outcomes were compared with historical conventional myeloablative conditioning regimens (n = 38). Use of Flu/Mel was associated with lower treatment-related mortality at 1 year, higher incidence of chronic graft-versus-host-disease, and comparable relapse rates. The 5-year OS and event-free survival for Flu/Mel and myeloablative conditioning group was 67.2 +/- 6.6% versus 38.1 +/- 8.1% ( P = .003) and 63.8 +/- 6.4% versus 32.3 +/- 7.9% ( P = .002), respectively. Preliminary cost analysis suggests that in our medical cost payment system, RIC allo-SCT in CR1 was likely the most cost-effective strategy in the management of AML. Conclusion In a resource-constrained environment, Flu/Mel RIC allo-SCT for AML CR1 is likely the most efficacious and cost-effective approach in a subset of newly diagnosed young adult patients. PMID- 29244984 TI - Cancer Pathology Turnaround Time at Queen Elizabeth Central Hospital, the Largest Referral Center in Malawi for Oncology Patients. AB - Purpose In all settings, a need exists for expedited pathology processing for patients with a suspected cancer diagnosis. In low- and middle-income countries (LMICs) with limited resources, processing pathology samples is particularly challenging, so the measurement of turnaround times (TATs) for pathology results is an important quality metric. We explored the pathology TAT for suspected cancer patients at Queen Elizabeth Central Hospital in Malawi to determine whether a difference exists when patients paid an out-of-pocket fee (paid for [PF] v nonpaid for [NPF]) to facilitate sample processing. Methods and Population This retrospective descriptive study included all patients with suspected cancer (N = 544) who underwent incisional and excisional biopsy in 2010 at Queen Elizabeth Central Hospital, a teaching hospital in Malawi. Data were abstracted from patient charts and administrative forms to build a database and determine the TAT for PF and NPF samples. Results The median TAT for the 544 patients was 71 days (interquartile range [IQR], 31 to 118 days). The median pathology processing time was 31 days (IQR, 15 to 52 days) and was shorter for PF versus NPF samples. The median TAT was 43 days for PF samples (IQR, 27 to 69 days) versus 101 days for NPF samples (IQR, 31 to 118 days), which was significantly different by the Wilcoxon rank sum test ( P < .01). Conclusion The TAT for pathology samples among patients with suspected cancer was longer than reported for other African countries during the study period, was longer than considered acceptable in high-income countries, and differed between PF and NPF samples. PMID- 29244985 TI - Malignancy-Related Hypercalcemia in Advanced Solid Tumors: Survival Outcomes. AB - Purpose Malignancy-related hypercalcemia (MRH) is associated with a dismal prognosis. The widespread use of bisphosphonates (BPs), availability of more effective drugs in cancer treatment, and improvement in supportive care might have attenuated its impact. Patients and Methods To assess overall survival (OS) of patients with MRH in a contemporary setting, we conducted a retrospective analysis of 306 patients with solid cancer hospitalized for symptomatic hypercalcemia. A multivariable Cox proportional hazards regression model was performed to evaluate possible prognostic factors associated with MRH. Results All patients had serum ionized calcium > 5.5 mg/dL or total Ca > 10.5 mg/dL. Median age was 57 years, and the majority had squamous cell carcinoma (62%) and Eastern Cooperative Oncology Group performance status > 1 (96%). Head and neck was the most frequent primary site (28%). Forty-five percent had no previous chemotherapy (CT), and subsequent CT was administered to 32%. Eighty-three percent received BP with no survival gain. Median OS was 40 (95% CI, 33 to 47) days. Patients with a performance status > 2, altered mental status, C-reactive protein > 30 mg/L, albumin < 2.5 g/dL, or body mass index < 18 kg/m2 had significantly poorer survival in a univariable analysis, and longer OS was related to treatment-naive patients, subsequent CT, and breast primary site. In the multivariable analysis, subsequent CT led to a median OS improvement of 144 versus 25 days (hazard ratio, 0.24; 95% CI, 0.14 to 0.40; P < .001). Conclusion In a contemporary setting, MRH remains a marker of poor prognosis. Patients treated with CT had better survival, which suggests that appropriate treatment of selected patients might alter the course of this syndrome. PMID- 29244986 TI - Breast Cancer in Ghana: Demonstrating the Need for Population-Based Cancer Registries in Low- and Middle-Income Countries. AB - Purpose Breast cancer, the most common cancer worldwide, is the leading cause of cancer mortality in Ghanaian women. Previous studies find Ghanaian women are diagnosed at a younger age and at more advanced stages (III and IV), and have tumors with characteristics similar to African American women. We sought to remedy gaps in knowledge about breast cancer survival in Ghana and its relation to demographic and biologic factors of the tumors at diagnosis to assist in cancer control and registration planning. Methods Individuals with a breast cancer diagnosis who sought care at Komfo Anokye Teaching Hospital from 2009 to 2014 were identified via medical records. Follow-up telephone interviews were held to assess survival. Kaplan-Meier plots and Cox proportional hazards models assessed survival associated with clinical and demographic characteristics. Results A total of 223 patients completed follow-up and were analyzed. The median survival was 3.8 years. Approximately 50% of patients were diagnosed with grade 3 tumors, which significantly increased the risk of recurrence or death (hazard ratio [HR] for grade 2 versus 1, 2.98; 95% CI, 1.26 to 7.02; HR grade 3 v 1, 2.56; 95% CI, 1.08 to 6.07; P = .04). No other variables were significantly associated with survival. Conclusion Higher tumor grade was significantly associated with shorter survival, indicating impact of aggressive biology at diagnosis on higher risk of cancer spread and recurrence. Contrary to prevailing notions, telephone numbers were not reliable for follow-up. Collecting additional contact information will likely contribute to improvements in patient care and tracking. A region-wide population-based active registry is important to implement cancer control programs and improve survival in sub-Saharan Africa. PMID- 29244987 TI - Gnathic Osteosarcoma: Clinical, Radiologic, and Pathologic Review of Bone Beard Tumor. PMID- 29244988 TI - Chemotherapy Use at the End of Life in Uganda. AB - Purpose Avoiding chemotherapy during the last 30 days of life has become a goal of cancer care in the United States and Europe, yet end-of-life chemotherapy administration remains a common practice worldwide. The purpose of this study was to determine the frequency of and factors predicting end-of-life chemotherapy administration in Uganda. Methods Retrospective chart review and surveys and interviews of providers were performed at the Uganda Cancer Institute (UCI), the only comprehensive cancer center in the area, which serves a catchment area of greater than 100 million people. All adult patients at the UCI with reported cancer deaths between January 1, 2014, and August 31, 2015 were included. All UCI physicians were offered a survey, and a subset of physicians were also individually interviewed. Results Three hundred ninety-two patients (65.9%) received chemotherapy. Age less than 55 years (odds ratio [OR], 2.30; P = .004), a cancer diagnosis greater than 60 days before death (OR, 9.13; P < .001), and a presenting Eastern Cooperative Oncology Group performance status of 0 to 2 (OR, 2.47; P = .001) were associated with the administration of chemotherapy. More than 45% of patients received chemotherapy in the last 30 days of life. No clinical factors were predictive of chemotherapy use in the last 30 days of life, although doctors reported using performance status, cancer stage, and tumor chemotherapy sensitivity to determine when to administer chemotherapy. Patient expectations and a lack of outcomes data were important nonclinical factors influencing chemotherapy administration. Conclusion Chemotherapy is administered to a high proportion of patients with terminal cancer in Uganda, raising concern about efficacy. Late presentation of cancer in Uganda complicates end-of-life chemotherapy recommendations, necessitating guidelines specific to sub-Saharan Africa. PMID- 29244990 TI - Clinical and Epidemiological Profile of Breast Cancer in Mexico: Results of the Seguro Popular. AB - Purpose One half of the Mexican population lacks comprehensive health care coverage. In 2003, a reform to the General Health Law was approved that led to the creation of the System of Social Protection in Health and made universal health coverage mandatory. The main innovation of this reform was Seguro Popular, which provided coverage for breast cancer. Here we report the outcomes of women with breast cancer treated at a cancer center in Mexico under Seguro Popular. Materials and Methods This was a retrospective cohort study that included all patients with breast cancer treated in the Instituto Nacional de Cancerologia in Mexico City between January 2007 and December 2013 with Seguro Popular coverage. Demographic and clinical information were collected and survival outcomes were analyzed. Results A total of 4,300 women with breast cancer were included in this analysis. Most patients had locally advanced disease at diagnosis (53%, n = 2,293), and 13% (n = 558) presented with stage IV disease. Neoadjuvant chemotherapy was administered to 1,834 patients (52%), with a pathologic complete response in 25.1% (n = 460). Median follow-up was 40.5 months. Five-year survival for the entire cohort was 82% (95% CI, 81% to 84%). Five-year survival was 97% for early-stage disease (95% CI, 95% to 98%), 82% for locally advanced disease (95% CI, 80% to 84%), and 36% for metastatic disease (95% CI, 30% to 42%). Conclusion This represents the first description of a cohort of patients with breast cancer treated in Mexico under Seguro Popular. Seguro Popular has allowed our institution, and other Mexican centers, to establish efficient standardized mechanisms to treat patients with breast cancer. PMID- 29244991 TI - Cancer Trends in Mexico: Essential Data for the Creation and Follow-Up of Public Policies. AB - Purpose Cancer in a country like Mexico is a challenge for the current health system and for public health. However, the statistics about cancer in Mexico are scarce, so epidemiologic surveillance needs to be improved. The objectives of this article were to describe the extent of cancer and to estimate the national burden of cancer through 2020. Materials and Methods To meet this objective, an analysis of secondary official sources was performed. The cancer cases through 2020 were estimated on the basis of trends in mortality and the projection of incident cases reported by GLOBOCAN. Results In 2013, cancer was the cause of 12.84% of all deaths in Mexico. It is projected that the prevalence of cancer will be 904,581 by 2017 and will reach 1,262,861 by early in the next decade (ie, 2020). Conclusion Available data for cancer are incomplete. The development and implementation of population-based cancer registries in Mexico are essential. Assessment of the future outlook of cancer in Mexico will provide awareness of future challenges and can help health systems prepare to face them. PMID- 29244989 TI - Global Use of Traditional and Complementary Medicine in Childhood Cancer: A Systematic Review. AB - Purpose Traditional and complementary medicine (T&CM) strategies are commonly used in pediatric oncology. Patterns may vary based on country income. We systematically reviewed published studies describing T&CM use among pediatric oncology patients in low-income countries (LIC/LMIC), middle-income countries (UMIC), and high-income countries (HIC). Objectives included describing estimated prevalence of use, reasons for use, perceived effectiveness, modalities used, rates of disclosure, and reporting of delayed or abandoned treatment. Methods MEDLINE, EMBASE, Global Health, CINAHL, PsycINFO, Allied and Complementary Medicine Database, Cochrane Database of Systematic Reviews, and ProceedingsFirst were searched. Inclusion criteria were primary studies involving children younger than the age of 18 years, undergoing active treatment of cancer, and any T&CM use. Exclusion criteria included no pediatric oncology-specific outcomes and studies involving only children off active treatment. Data were extracted by two reviewers using a systematic data extraction form determined a priori. Results Sixty-five studies published between 1977 and 2015 were included, representing 61 unique data sets and 7,219 children from 34 countries. The prevalence of T&CM use ranged from 6% to 100%. Median rates of use were significantly different in LIC/LMIC (66.7% +/- 19%), UMIC (60% +/- 26%), and HIC (47.2% +/- 20%; P = .02). Rates of disclosure differed significantly by country income, with higher median rates in HIC. Seven studies reported on treatment abandonment or delays. Conclusion The use of T&CM in pediatric oncology is common worldwide, with higher median prevalence of use reported in LIC/LMIC. Further research is warranted to examine the impact on treatment abandonment and delay. PMID- 29244992 TI - Oral Morphine Use in South India: A Population-Based Study. AB - Purpose Access to opioids for pain control is recognized as an urgent issue in low- and middle-income countries. Here we report temporal and regional trends in morphine use in Kerala, India. Methods Oral morphine use data for the State of Kerala (2012 to 2015) was used to describe temporal trends, regional variation, and provider characteristics. Total morphine use was calculated for each district of Kerala to derive an annual per capita use rate (milligrams per capita). Each provider was classified as government, private, nongovernment organization (NGO), or NGO partnership. Results Oral morphine use for Kerala was 1.32 mg/capita and increased over the study period 27% (from 1.23 mg/capita to 1.56 mg/capita). There was substantial variation in morphine use across districts (range, 0.49 mg/capita to 2.97 mg/capita; six-fold difference). This variation increased over time (19-fold difference in 2015). In 2015, 31% of morphine providers (51 of 167) were government institutions; they delivered 48% of total morphine in Kerala. Corresponding data for other providers are private institutions, 23% of centers and 13% of morphine; NGOs, 41% of centers and 34% of morphine; and NGO partnerships, 5% of centers and 4% of morphine. From 2012 to 2015, the total number of centers increased by 35%, from 124 to 167. Conclusion Oral morphine use has increased over time in Kerala but remains substantially lower than estimated need. There is significant geographic variation of use. Efforts are needed to improve palliative care in Kerala and to reduce regional disparities in access to opioids. PMID- 29244993 TI - Cervical Cancer in the Greater Accra and Ashanti Regions of Ghana. AB - Purpose Cervical cancer is a common cancer among women worldwide. An estimated 528,000 new cases and 266,000 deaths occurred in 2012. More than 85% of invasive cervical cancer cases occur in low- and middle-income countries. Cervical cancer ranks as the most common cancer among women in Ghana. We conducted a retrospective study to assess the descriptive epidemiology of cervical cancer in Ghana. We describe cervical cancer incidence and mortality rates for the regions served by two large hospitals in Ghana. Patients and Methods Information for women diagnosed with invasive cervical cancer between 2010 and 2013 was collected from the Komfo Anokye and Korle Bu Teaching Hospitals through review of medical, computer, and pathology records at the oncology units and the obstetrics and gynecology departments. Telephone interviews were also conducted with patients and relatives. Data were analyzed using summary statistics. Results A total of 1,725 women with cervical cancer were included in the study. Their ages ranged from 11 to 100 years (mean, 56.9 years). The histology of the primary tumor was the basis of diagnosis in 77.5% of women and a clinical diagnosis was made in 22.5% of women. For the 1,336 women for whom tumor grade was available, 34.3% were moderately differentiated tumors. Late stage at presentation was common. The incidence and mortality rates of cervical cancer increased with age up until the 75 to 79-year age group and began to decrease at older ages. The Greater Accra region had higher overall incidence and mortality rates than the Ashanti region. Conclusion Our study suggests that improvements in the application of preventive strategies could considerably reduce the burden of cervical cancer in Ghana and other low- and middle-income countries. The study provides important information to inform policy on cancer prevention and control in Ghana. PMID- 29244994 TI - Do Perceived Needs Affect Willingness to Use Traditional Chinese Medicine for Survivorship Care Among Chinese Cancer Survivors? A Cross-Sectional Survey. AB - Purpose We aimed to quantify Chinese cancer survivors' perceived needs for survivorship care and to evaluate whether these needs could impact their willingness to use traditional Chinese medicine (TCM). Methods We conducted a cross-sectional survey with members of the Beijing Anti-Cancer Association in China. We measured perceived needs with the seven-item Brief Chinese Cancer Survivorship Needs Scale that assesses psychological, functional, nutritional, social, body image, pain, and symptom needs. The outcome variable was willingness to use TCM for survivorship care. We performed multivariable logistic regression analyses to evaluate whether perceived needs are associated with willingness. Results A total of 600 patients were invited, with a response rate of 81%. The mean (standard deviation) score of the perceived needs scale (0 to 10) was 4.4 (2.2), with the majority of participants endorsing nutritional (72%), symptom (65%), and psychological (54%) needs. Among survivors, 387 (80%; 95% CI, 76% to 83%) were willing to use TCM for survivorship care. In multivariable analysis, a higher perceived needs score (adjusted odds ratio [OR], 1.33; 95% CI, 1.14 to 1.56; P < .001) was associated with greater willingness to use TCM. Specifically, nutritional (OR, 3.17; 95% CI, 1.79 to 5.62; P < .001) and symptom needs (OR, 3.15; 95% CI, 1.79 to 5.55; P < .001) had the strongest relationship. Conclusion A higher level of perceived needs, especially in the areas of nutrition and symptoms, was associated with greater willingness to use TCM for survivorship care. PMID- 29244995 TI - Proceedings of the Strategy Meeting for the Development of an International Consortium for Chinese Medicine and Cancer. AB - On November 3, 2014, in Bethesda, MD, the Office of Cancer Complementary and Alternative Medicine of the National Cancer Institute held a meeting to examine the potential utility and feasibility of establishing an international consortium for Chinese medicine and cancer. There is significant interest in the West in using components of Chinese medicine (CM) -such as botanicals and herbal medicines, acupuncture and acupressure, and qigong-in the field of oncology, as potential anticancer agents, for symptom management, and to improve quality of life. The proposal for a consortium on CM came from the Chinese Academy of Chinese Medical Sciences, with the aims of improving scientific communications and collaborations and modernizing the studies of CM for cancer. The US National Cancer Institute's Office of Cancer Complementary and Alternative Medicine agreed to work with Chinese Academy of Chinese Medical Sciences to explore the feasibility of establishing an international consortium for Chinese medicine and cancer. At the meeting, participants from the United States, China, Canada, Australia, and Korea discussed issues in CM and cancer research, treatment, and management, including potential mechanisms of action, proof of efficacy, adverse effects, regulatory issues, and the need for improving the quality of randomized clinical trials of CM treatments and supportive care interventions. Presented in these proceedings are some of the main issues and opportunities discussed by workshop participants. PMID- 29244996 TI - Health-Seeking Behavior and Barriers to Care in Patients With Rectal Bleeding in Nigeria. AB - Purpose Colorectal cancer (CRC) incidence rates are steadily increasing in Nigeria. Organized screening is still largely unused because of financial and logistical barriers; most CRCs are detected by symptoms. One symptom of CRC is rectal bleeding. This study sought to determine health-seeking behavior and barriers to care in patients with rectal bleeding in Nigeria. This study also surveyed physicians to determine major breakdowns in access to care. Methods The recruitment process for this study involved patients referred for colonoscopy because of rectal bleeding as well as response to a media advertisement for a free colonoscopy. Physicians were recruited at the African Research Group for Oncology meeting. Patient responses were scored on the basis of knowledge of rectal bleeding. The physician questionnaire was supporting information and mainly descriptive in nature. Results A total of 82 patients and 45 physicians participated in this study. Less than 40% of patients knew that rectal bleeding could be caused by cancer. Major barriers to care were resolution of the symptom (42%), no consideration of the bleeding as problematic (40%), and financial constraint (22%). Education was strongly correlated with knowledge of rectal bleeding and health-seeking behavior. Although physicians regularly saw patients with rectal bleeding, most of them provided a differential diagnosis of hemorrhoids and few referred patients for colonoscopy. Conclusion General awareness about the signs of colorectal cancer is lacking. This demonstrates the strong need for patient education programs about this issue. Physicians should also receive additional training on differentiation of a potential cancer diagnosis from something more benign, such as hemorrhoids. PMID- 29244997 TI - Beliefs and Determinants of Use of Traditional Complementary/Alternative Medicine in Pediatric Patients Who Undergo Treatment for Cancer in South America. AB - Purpose The use of traditional complementary/alternative medicine (TCAM) among children with cancer has been well documented. South America has a rich history of traditional healers and medicinal resources; however, little is known about the use of TCAM among children with cancer. We sought to investigate patterns, beliefs, and determinants of TCAM use among South American children with cancer. Methods A cross-sectional survey was administered to 199 children treated for cancer at institutions located in Buenos Aires, Argentina, and Montevideo, Uruguay. Participants were queried about the type of TCAM and strength of beliefs associated with its use. Logistic regression analysis was used to estimate the odds ratios with 95% CIs. Results We found that the use of TCAM was common in both Argentina (47%) and Uruguay (76%). Variations in the forms of TCAM used were observed between the countries; however, both countries used TCAM primarily for supportive care. Mother's education, wealth index, and TCAM belief system were significant predictors of TCAM. Conclusion To our knowledge, this study is the first to report on the use of TCAM in pediatric oncology in South America. The study identifies several predictors of TCAM use, which may serve as target variables for educational and research initiatives. The finding that most families use TCAM for supportive care suggests that future efforts could evaluate the role of TCAM to enhance existing supportive care regimens, particularly in settings where access to conventional medications are limited. PMID- 29244998 TI - Applicability of the National Comprehensive Cancer Network/Multinational Association of Supportive Care in Cancer Guidelines for Prevention and Management of Chemotherapy-Induced Nausea and Vomiting in Southeast Asia: A Consensus Statement. AB - A meeting of regional experts was convened in Manila, Philippines, to develop a resource-stratified chemotherapy-induced nausea and vomiting (CINV) management guideline. In patients treated with highly emetogenic chemotherapy in general clinical settings, triple therapy with a serotonin (5-hydroxytryptamine-3 [5 HT3]) antagonist (preferably palonosetron), dexamethasone, and aprepitant is recommended for acute CINV prevention. In resource-restricted settings, triple therapy is still recommended, although a 5-HT3 antagonist other than palonosetron may be used. In both general and resource-restricted settings, dual therapy with dexamethasone (days 2 to 4) and aprepitant (days 2 to 3) is recommended to prevent delayed CINV. In patients treated with moderately emetogenic chemotherapy, dual therapy with a 5-HT3 antagonist, preferably palonosetron, and dexamethasone is recommended for acute CINV prevention in general settings; any 5 HT3 antagonist can be combined with dexamethasone in resource-restricted environments. In general settings, for the prevention of delayed CINV associated with moderately emetogenic chemotherapy, corticosteroid monotherapy on days 2 and 3 is recommended. If aprepitant is used on day 1, it should be continued on days 2 and 3. Prevention of delayed CINV with corticosteroids is preferred in resource restricted settings. The expert panel also developed CINV management guidelines for anthracycline plus cyclophosphamide combination schedules, multiday cisplatin, and chemotherapy with low or minimal emetogenic potential, and its recommendations are detailed in this review. Overall, these regional guidelines provide definitive guidance for CINV management in general and resource restricted settings. These consensus recommendations are anticipated to contribute to collaborative efforts to improve CINV management in Southeast Asia. PMID- 29244999 TI - Mechanical stress increases brain amyloid beta, tau, and alpha-synuclein concentrations in wild-type mice. AB - INTRODUCTION: Exposure to traumatic brain injury is a core risk factor that predisposes an individual to sporadic neurodegenerative diseases. We provide evidence that mechanical stress increases brain levels of hallmark proteins associated with neurodegeneration. METHODS: Wild-type mice were exposed to multiple regimens of repetitive mild traumatic brain injury, generating a range of combinations of impact energies, frequencies, and durations of exposure. Brain concentrations of amyloid beta 1-42 (Abeta1-42), total tau, and alpha-synuclein were measured by sandwich enzyme-linked immunosorbent assay. RESULTS: There was a highly significant main effect of impact energy, frequency, and duration of exposure on Abeta1-42, tau, and alpha-synuclein levels (P < .001), and a significant interaction between impact energy and duration of exposure for Abeta1 42 and tau (P < .001), but not for alpha-synuclein. DISCUSSION: Dose-dependent and cumulative influence of repetitive mild traumatic brain injury-induced mechanical stress may trigger and/or accelerate neurodegeneration by pushing protein concentration over the disease threshold. PMID- 29245001 TI - Management of the Maxillary Diastema by Various Dental Specialties. AB - PURPOSE: There is considerable controversy in the literature concerning the indications for frenectomy for treating a maxillary diastema and for timing of the procedure. The purpose of this study was to survey pediatric dentists, orthodontists, and oral and maxillofacial surgeons on their opinion of this matter to develop a consensus. MATERIALS AND METHODS: An anonymous 7-item electronic questionnaire was sent to members of the American Academy of Pediatric Dentists, the American Association of Orthodontists, and the American Association of Oral and Maxillofacial Surgeons asking about the etiology of the maxillary diastema, its diagnosis, and treatment. RESULTS: Although there was no agreement among the oral and maxillofacial surgeons for the timing of frenectomy and when the diastema should be closed, the pediatric dentists and orthodontists generally agreed that frenectomy should not be performed before the permanent canines are erupted and that the operation should follow orthodontic closure of the space. CONCLUSION: Although there was no complete consensus among the 3 groups, a logical treatment approach for the maxillary diastema is proposed. PMID- 29245002 TI - Regarding "Is It Time to Reexamine Reexamination?" PMID- 29245000 TI - Does traumatic brain injury hold the key to the Alzheimer's disease puzzle? AB - INTRODUCTION: Neurodegenerative disorders have been a graveyard for hundreds of well-intentioned efforts at drug discovery and development. Concussion and other traumatic brain injuries (TBIs) and Alzheimer's disease (AD) share many overlapping pathologies and possible clinical links. METHODS: We searched the literature since 1995 using MEDLINE and Google Scholar for the terms concussion, AD, and shared neuropathologies. We also studied a TBI animal model as a supplement to transgenic (Tg) mouse AD models for evaluating AD drug efficacy by preventing neuronal losses. To evaluate TBI/AD pathologies and neuronal self induced cell death (apoptosis), we are studying brain extracellular vesicles in plasma and (-)-phenserine pharmacology to probe, in animal models of AD and humans, apoptosis and pathways common to concussion and AD. RESULTS: Neuronal cell death and a diverse and significant pathological cascade follow TBIs. Many of the developing pathologies are present in early AD. The use of an animal model of concussion as a supplement to Tg mice provides an indication of an AD drug candidate's potential for preventing apoptosis and resulting progression toward dementia in AD. This weight drop supplementation to Tg mouse models, the experimental drug (-)-phenserine, and plasma-derived extracellular vesicles enriched for neuronal origin to follow biomarkers of neurodegenerative processes, each and in combination, show promise as tools useful for probing the progression of disease in AD, TBI/AD pathologies, apoptosis, and drug effects on rates of apoptosis both preclinically and in humans. (-)-Phenserine both countered many subacute post-TBI pathologies that could initiate clinical AD and, in the concussion and other animal models, showed evidence consistent with direct inhibition of neuronal preprogrammed cell death in the presence of TBI/AD pathologies. DISCUSSION: These findings may provide support for expanding preclinical Tg mouse studies in AD with a TBI weight drop model, insights into the progression of pathological targets, their relations to apoptosis, and timing of interventions against these targets and apoptosis. Such studies may demonstrate the potential for drugs to effectively and safely inhibit preprogrammed cell death as a new drug development strategy for use in the fight to defeat AD. PMID- 29245003 TI - A Quantitative Assessment of Lip Movements in Different Facial Expressions Through 3-Dimensional on 3-Dimensional Superimposition: A Cross-Sectional Study. AB - PURPOSE: The quantitative assessment of facial modifications from mimicry is of relevant interest for the rehabilitation of patients who can no longer produce facial expressions. This study investigated a novel application of 3-dimensional on 3-dimensional superimposition for facial mimicry. MATERIALS AND METHODS: This cross-sectional study was based on 10 men 30 to 40 years old who underwent stereophotogrammetry for neutral, happy, sad, and angry expressions. Registration of facial expressions on the neutral expression was performed. Root mean square (RMS) point-to-point distance in the labial area was calculated between each facial expression and the neutral one and was considered the main parameter for assessing facial modifications. In addition, effect size (Cohen d) was calculated to assess the effects of labial movements in relation to facial modifications. RESULTS: All participants were free from possible facial deformities, pathologies, or trauma that could affect facial mimicry. RMS values of facial areas differed significantly among facial expressions (P = .0004 by Friedman test). The widest modifications of the lips were observed in happy expressions (RMS, 4.06 mm; standard deviation [SD], 1.14 mm), with a statistically relevant difference compared with the sad (RMS, 1.42 mm; SD, 1.15 mm) and angry (RMS, 0.76 mm; SD, 0.45 mm) expressions. The effect size of labial versus total face movements was limited for happy and sad expressions and large for the angry expression. CONCLUSION: This study found that a happy expression provides wider modifications of the lips than the other facial expressions and suggests a novel procedure for assessing regional changes from mimicry. PMID- 29245004 TI - A Standardized Preoperative Group Intervention Is Feasible and Acceptable to Orthognathic Surgery Patients. AB - PURPOSE: Nearly 10% of patients remain dissatisfied after orthognathic surgery, largely because of psychoeducational or psychosocial factors. The purpose of this study was to evaluate the feasibility and acceptability of a psychoeducationally based group intervention to improve preoperative preparation of orthognathic surgical patients and their caregivers. MATERIALS AND METHODS: The intervention consisted of 2 group sessions, with each session lasting 2 hours. The sessions provided realistic expectations of the surgery, offered teaching strategies for coping with pre- and postoperative symptoms of psychopathology, and highlighted the importance of social support. Feasibility was based on attendance, homework completion, and data collection rates, and acceptability was based on post treatment participant satisfaction scores on the Client Satisfaction Questionnaire-8 (CSQ-8) and credibility and expectancy scores on 2 subscales of the Credibility/Expectancy Questionnaire-Modified (CEQ-M). RESULTS: Twenty-six orthognathic surgical patients were recruited from an outpatient oral and maxillofacial surgery clinic to attend the group-based intervention. Seventy percent of patients who attended at least 1 session completed the 2 sessions, and 64% of those who attended the 2 sessions completed at least 1 homework assignment. The authors successfully collected 84% of the total measures given to patients and their caregivers. The mean satisfaction rating of the patients was 30.12 of 32 (CSQ-8; n = 13; standard deviation [SD], 2.33), the mean credibility rating of the patients and their caregivers was 25.2 of 27 (CEQ-M; n = 20; SD, 1.85), and the mean expectancy rating of the patients and their caregivers was 20.54 of 27 (CEQ-M; n = 20; SD, 4.39). CONCLUSION: The psychoeducationally based group intervention was feasible and acceptable for participants and their caregivers. This article offers suggestions to further improve the feasibility and acceptability of the intervention, including optimizing standardization of data collection procedures, decreasing barriers to access, and increasing participant engagement. PMID- 29245005 TI - CD19 CAR T Cells. AB - CARs are synthetic receptors that reprogram immune cells for therapeutic purposes. They comprise three canonical domains for antigen recognition, T cell activation, and costimulation. The CAR cDNA is genetically integrated in the T cell genome. Autologous CAR T cells are generated from the patient's peripheral blood T cells and expand in the recipient to eliminate the targeted tumor. To view this Bench to Bedside, open or download the PDF. PMID- 29245006 TI - Big Role for a Tiny Genome. AB - In this issue of Cell, Salem et al. demonstrate a remarkable instance of herbivory dependent on a co-evolved mutualism with specialized bacteria. Despite having a tiny genome and limited metabolic repertoire, the bacteria in Cassida beetles produce pectinases predicted to mediate degradation of plant cell walls in the insect diet. PMID- 29245007 TI - Less Lipid, More Commitment. AB - Sexual differentiation of the malaria parasite is a pre-requisite for transmission from humans to the mosquito vector and has emerged as a target for intervention in eradication efforts. In this issue of Cell, a study from Marti, Clardy, and colleagues (Brancucci et al., 2017) describes a host-derived lipid lysophosphatidylcholine (LysoPC) that regulates sexual commitment. PMID- 29245008 TI - On the Design of Combination Cancer Therapy. AB - Combination therapy programs are the hallmark of the successful treatment of all forms of human malignancies. In this issue of Cell, Palmer and Sorger present data suggesting that cell culture results indicative of synergistic anticancer drug interactions rarely translate clinically and that the results of combination therapies in mouse models or human clinical trials, even if successful, are best explained by the independent activities of the individually administered drugs. PMID- 29245009 TI - FIX It in One Go: Enhanced Factor IX Gene Therapy for Hemophilia B. AB - A phase 1/2 clinical trial of AAV-mediated gene therapy in patients with hemophilia B using an enhanced specific activity factor IX (FIX) transgene reports sustained levels of FIX levels, leading to the near elimination of bleeding for more than a year and without serious adverse side effects. These results are the best outcome to date for hemophilia gene therapy. PMID- 29245010 TI - Our Gut Microbiome: The Evolving Inner Self. AB - The "holobiont" concept, defined as the collective contribution of the eukaryotic and prokaryotic counterparts to the multicellular organism, introduces a complex definition of individuality enabling a new comprehensive view of human evolution and personalized characteristics. Here, we provide snapshots of the evolving microbial-host associations and relations during distinct milestones across the lifespan of a human being. We discuss the current knowledge of biological symbiosis between the microbiome and its host and portray the challenges in understanding these interactions and their potential effects on human physiology, including microbiome-nervous system inter-relationship and its relevance to human variation and individuality. PMID- 29245014 TI - Perinatal Licensing of Thermogenesis by IL-33 and ST2. PMID- 29245013 TI - Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy. AB - Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies. PMID- 29245012 TI - Visualizing the Assembly Pathway of Nucleolar Pre-60S Ribosomes. AB - Eukaryotic 60S ribosomal subunits are comprised of three rRNAs and ~50 ribosomal proteins. The initial steps of their formation take place in the nucleolus, but, owing to a lack of structural information, this process is poorly understood. Using cryo-EM, we solved structures of early 60S biogenesis intermediates at 3.3 A to 4.5 A resolution, thereby providing insights into their sequential folding and assembly pathway. Besides revealing distinct immature rRNA conformations, we map 25 assembly factors in six different assembly states. Notably, the Nsa1-Rrp1 Rpf1-Mak16 module stabilizes the solvent side of the 60S subunit, and the Erb1 Ytm1-Nop7 complex organizes and connects through Erb1's meandering N-terminal extension, eight assembly factors, three ribosomal proteins, and three 25S rRNA domains. Our structural snapshots reveal the order of integration and compaction of the six major 60S domains within early nucleolar 60S particles developing stepwise from the solvent side around the exit tunnel to the central protuberance. PMID- 29245015 TI - SnapShot: Abscisic Acid Signaling. AB - Abscisic acid is a key phytohormone produced in response to abiotic stress conditions and is an activator of abiotic stress resistance mechanisms and a regulator during diverse developmental stages in plants. This SnapShot explores how ABA signaling operates and coordinates resistance during stress responses and modulates plant development. PMID- 29245011 TI - Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA. AB - Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection. PMID- 29245017 TI - Investigating the predictors of happiness, life satisfaction and success in schizophrenia. AB - BACKGROUND: Previous studies have suggested that, despite marked functional impairments, remitted first episode patients with schizophrenia report levels of well-being that are comparable to healthy controls. The aim of the current study was to specifically evaluate self-reported happiness, life satisfaction and success in individuals with schizophrenia beyond their first-episode of psychosis, and to investigate the impact of symptoms and functioning on these subjective experiences. METHODS: Fifty-one schizophrenia patients and 56 matched healthy controls participated in the study. Factor scores were computed to compare happiness and life satisfaction and success (LSS) between groups. Hierarchical multiple regression analyses were conducted to investigate the predictive value of symptoms and functional impairments on patients' subjective reports of happiness and LSS. RESULTS: Schizophrenia participants endorsed lower levels of LSS compared to healthy controls, with no significant group differences in self-reported happiness. For patients with schizophrenia, motivation deficits and depressive symptoms predicted reductions in both happiness and LSS. CONCLUSIONS: Patients with schizophrenia do not report significant reductions in their subjective experience of happiness, but do endorse lower levels of life satisfaction and success. Further, the absence of a robust link between poor functioning and lower happiness or LSS serves to reaffirm the notion that functional status does not dictate whether an individual with schizophrenia experiences a sense of happiness, satisfaction or success in life. PMID- 29245016 TI - Preferential myofibroblast differentiation of cardiac mesenchymal progenitor cells in the presence of atrial fibrillation. AB - Atrial fibrillation (AF) is characterized by electrical, contractile, and structural remodeling mediated by interstitial fibrosis. It has been shown that human cardiac mesenchymal progenitor cells (CMPCs) can be differentiated into endothelial, smooth muscle, and fibroblast cells. Here, we have investigated, for the first time, the contribution of CMPCs in the fibrotic process occurring in AF. As expected, right auricolae samples displayed significantly higher fibrosis in AF vs control (CTR) patients. In tissue samples of AF patients only, double staining for c-kit and the myofibroblast marker alpha-smooth muscle actin (alpha SMA) was detected. The number of c-kit-positive CMPC was higher in atrial subepicardial regions of CTR than AF cells. AF-derived CMPC (AF-CMPC) and CTR derived CMPC (Ctr-CMPC) were phenotypically similar, except for CD90 and c-kit, which were significantly more present in AF and CTR cells, respectively. Moreover, AF showed a lower rate of population doubling and fold enrichment vs Ctr-CMPC. When exogenously challenged with the profibrotic transforming growth factor-beta1 (TGF-beta1), AF-CMPC showed a significantly higher nuclear translocation of SMAD2 than Ctr-CMPC. In addition, TGF-beta1 treatment induced the upregulation of COL1A1 and COL1A2 in AF-CMPC only. Further, both a marked production of soluble collagen and alpha-SMA upregulation have been observed in AF-CMPC only. Finally, electrophysiological studies showed that the inwardly rectifying potassium current (IK1) was evenly present in AF- and Ctr-CMPC in basal conditions and similarly disappeared after TGF-beta1 exposure. All together, these data suggest that AF steers the resident atrial CMPC compartment toward an electrically inert profibrotic phenotype. PMID- 29245018 TI - Regulation of MAVS activation through post-translational modifications. AB - RLRs (including RIG-I and MDA5) are the main receptors that recognize cytoplasmic viral RNA. Upon binding of viral RNA, RIG-I and MDA5 recruit mitochondria localized MAVS to activate the downstream antiviral signaling. MAVS forms prion like aggregates on the mitochondria after virus infection. The regulatory mechanisms for MAVS activation have been defined in various studies. Here, we summarize the recent advances about MAVS roles in antiviral immunity, discuss the regulation of MAVS activation, and suggest interesting areas for future research. PMID- 29245019 TI - Genetic polymorphism of 21 non-CODIS STR loci in Chengdu Han population and its interpopulation analysis between 25 populations in China. AB - AGCU 21+1 STR kit contains 21 non-combined DNA index system (non-CODIS) short tandem repeats (STR) loci and a sex-determining locus amelogenin. In this study, we evaluated the genetic diversity and forensically relevant population statistics of 21 non-CODIS loci in 210 Chinese Han individuals from Chengdu city, Sichuan province, Southwest China. No significant deviations from Hardy-Weinberg equilibrium were observed within the 21 non-CODIS STR loci. The combined power of discrimination (CPD) and combined power of exclusion (CPE) were 0.99999999999999999994278, 0.999999355 respectively. To reveal interpopulation differentiations of mainland population of China, a neighbor-joining (N-J) phylogenetic tree was constructed based on Nei's genetic distances among Chengdu Han and 25 published populations. The phylogenetic analyses indicated that Chengdu Han population keeps a close genetic relationship with other Han populations. PMID- 29245020 TI - Killing two birds with one stone? Association between tobacco and alcohol consumption. AB - OBJECTIVES: Tobacco and excessive alcohol consumption are addictive behaviours, listed among the 10 leading risk factors that cause death and disability in the world, and health consequences are greater if their consumption is combined. There is sparse empirical evidence on the variables that influence the simultaneous consumption of tobacco and alcohol. This study aims to identify the variables that influence the joint decision to consume alcohol and tobacco, and that encourage drinkers to smoke. STUDY DESIGN: The sample includes Portuguese adults, mainly aged 50 years and over, extracted from the Survey of Health, Ageing and Retirement in Europe, covering the year 2011. METHODS: We propose a bivariate probit model, which allows us to model simultaneously the two goods, accounting for potential correlation between smoking and drinking decisions. RESULTS: We identified the variables that influence joint consumption, and tobacco consumption among drinkers, which could be used as policy instruments to develop concerted policies. Prevention policies should focus on males, younger and more educated individuals, as well as on individuals with unhealthy eating habits, because these variables were statistically significant and increased joint consumption. In addition, these characteristics also should be regarded if we want to control tobacco consumption among alcohol consumers. CONCLUSIONS: The analysis of the interdependence between alcohol and tobacco use presented in this article may allow reducing their consumption with a common intervention, enabling policymakers to 'kill two birds with one stone' and to achieve extended health and economic gains. PMID- 29245021 TI - Google and suicides: what can we learn about the use of internet to prevent suicides? AB - OBJECTIVES: This article studies the statistical relationship between the search propensity of suicide-related terms on Google and the number of suicides. STUDY DESIGN: Suicide mortality data from all American states from January 2006 to November 2014 (n = 5372) and data on Google search intensity for the same period was collected. METHODS: Regression analysis with dynamic components was performed to determine the relationship between search intensity and the number of suicides. RESULTS: First, this article finds a positive simultaneous correlation between search intensity and the number of suicides. The magnitude of this relationship has grown from 2006 to 2014 suggesting an increased reliance on the internet for suicide-related information. Second, search propensity is a significant predictor for the number of suicides for youth and for males. CONCLUSIONS: Suicide prevention websites should therefore be designed knowing that at-risk individuals in both groups are probably more prone to look for suicide-related information online. PMID- 29245022 TI - Cost-effective way to reduce stimulant-abuse among gay/bisexual men and transgender women: a randomized clinical trial with a cost comparison. AB - OBJECTIVES: A randomized controlled study was conducted with 422 homeless, stimulant-using gay/bisexual (G/B) men and 29 transgender women (n = 451) to assess two community-based interventions to reduce substance abuse and improve health: (a) a nurse case-managed program combined with contingency management (NCM + CM) versus (b) standard education plus contingency management (SE + CM). STUDY DESIGN: Hypotheses tested included: a) completion of hepatitis A/B vaccination series; b) reduction in stimulant use; and c) reduction in number of sexual partners. METHODS: A deconstructive cost analysis approach was utilized to capture direct costs associated with the delivery of both interventions. Based on an analysis of activity logs and staff interviews, specific activities and the time required to complete each were analyzed as follows: a) NCM + CM only; b) SE + CM only; c) time to administer/record vaccines; and d) time to receive and record CM visits. Cost comparison of the interventions included only staffing costs and direct cash expenditures. RESULTS: The study outcomes showed significant over time reductions in all measures of drug use and multiple sex partners, compared to baseline, although no significant between-group differences were detected. Cost analysis favored the simpler SE + CM intervention over the more labor-intensive NCM + CM approach. Because of the high levels of staffing required for the NCM relative to SE, costs associated with it were significantly higher. CONCLUSIONS: Findings suggest that while both intervention strategies were equally effective in achieving desired health outcomes, the brief SE + CM appeared less expensive to deliver. PMID- 29245023 TI - Mild cognitive impairment: what does the general public know about this health condition? PMID- 29245024 TI - Early-onset tobacco use and suicide-related behavior - A prospective study from adolescence to young adulthood. AB - BACKGROUND: Developmental relationships between tobacco use and suicide-related behaviors (SRB) remain unclear. Our objective was to investigate the longitudinal associations of tobacco use in adolescence and SRB in adulthood. METHODS: Using a prospective design, we examined whether tobacco use in adolescence is associated with SRB (intentional self-injury, suicide ideation) in young adulthood in a population-based sample of 1330 twins (626 males, 704 females). The baseline and follow-up data were collected by professionally administered semi-structured poly diagnostic interviews at ages 14 and 22, respectively. RESULTS: After adjusting for multiple potential confounders, those who reported early-onset of regular tobacco use had a significantly increased risk for intentional self-injury, such as cutting or burning, at age 22 (adjusted odds ratio [AOR] 4.57, 95% CI 1.93 10.8) in comparison to those who had not at all initiated tobacco use. Also, daily cigarette smoking at baseline was associated with future intentional self injury (AOR 4.45, 95% CI 2.04-9.70). Early-onset tobacco use was associated with suicidal ideation in females (AOR 3.69, 95% CI 1.56-8.72) but not in males. Considering any SRB, baseline daily smokers (AOR 2.13, 95% CI 1.12-4.07) and females with early onset of regular tobacco use (AOR 3.97, 95% CI 1.73-9.13) had an increased likelihood. Within-family analyses among twin pairs discordant for exposure and outcome controlling for familial confounds showed similar, albeit statistically non-significant, associations. CONCLUSION: Early-onset tobacco use in adolescence is longitudinally associated with SRB (intentional self-injury and/or suicide ideation) in young adulthood, particularly among females. Further investigation may reveal whether this association has implications for prevention of SRB in adolescence and young adulthood. PMID- 29245025 TI - Social and substance use correlates of adult hookah use, 2016. PMID- 29245026 TI - Ketogenic diet-induced extension of longevity in epileptic Kcna1-null mice is influenced by gender and age at treatment onset. AB - Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature mortality in patients with epilepsy, and has been linked to multiple risk factors, including gender and early age at seizure onset. Despite the lack of a targeted therapy for SUDEP, it has recently been shown that a high-fat, low carbohydrate ketogenic diet (KD) enhances longevity in the epileptic Kcna1-null (KO) mouse, a validated model of SUDEP. Here, we asked whether the KD-driven prolongation of lifespan in KO mice is dependent on sex and/or age at treatment onset. We found that as KO mice aged, their daily seizure frequency steadily increased, but had early demise by postnatal day (PD) 46.9+/-0.8. In KO mice started on the KD at PD30, longevity was extended to a mean of PD69.8+/-1.7, accompanied with improved seizure control. Interestingly, while seizure control on the KD was similar between male and female mice, KD-fed female KO mice survived longer than their male counterparts. Further, epileptic mice initiated on the KD at PD25 had longer lifespans compared to those placed on the KD starting at PD35. Collectively, these data further support the notion that the KD can retard disease progression and sudden death in KO mice, but that this beneficial action is influenced by gender and age at the start of treatment. PMID- 29245027 TI - Multidimensional impact of low-Dye taping on low-load hopping in individuals with and without plantar fasciitis. AB - OBJECTIVES: Evaluate the acute effect of low-Dye, placebo and no tape on motor behaviour in individuals with plantar fasciitis (PF). DESIGN: Prospective, experimental. SETTING: Motion analysis laboratory. PARTICIPANTS: Ten participants with PF and ten matched controls. MAIN OUTCOME MEASURES: Hopping behaviour (lower limb stiffness and ankle angle at peak loading) were evaluated during low-load sleigh hopping, during three taping conditions. Stiffness and ankle angle were determined using three-dimensional motion analysis. Pain during submaximal loading was assessed with a numeric pain rating scale. RESULTS: The lower-limb stiffness response to therapeutic taping was modulated by the presence of PF (interaction, F = 4.48, p = 0.018). Matched controls demonstrated a significant increase in stiffness post application of low-Dye taping (p = 0.001), stiffness was unchanged in the PF group. In the PF group, low-Dye taping decreased hopping pain in comparison to placebo (p = 0.037) and no-tape (p = 0.024). There was no difference in ankle angle at peak loading between the groups or across taping conditions. CONCLUSIONS: Low-Dye taping reduces nociceptive inputs more than placebo in the presence of PF pain. Low-Dye tape alters stiffness in the control group but not the PF group. The motor behavioural outputs such as stiffness, during low-load hopping is modulated by both pathology and therapeutic taping. PMID- 29245028 TI - On-site evaluation of Wagyu beef carcasses based on the monounsaturated, oleic, and saturated fatty acid composition using a handheld fiber-optic near-infrared spectrometer. AB - The fat quality is an important aspect, especially for Wagyu beef. A handheld fiber-optic near-infrared spectrometer for on-site evaluation of beef fat quality was developed, and the interactance spectra of the intermuscular fat from 833 Wagyu carcasses at 12 markets were measured. The calibration model was transferred to five slave instruments using twenty-six block samples. The performance of one slave instrument was verified at five meat markets (n=360). The coefficients of determination of the slave instrument for monounsaturated, oleic, and saturated fatty acid compositions determined by gas chromatography and near-infrared measurements were 0.69, 0.64, and 0.67, respectively. The standard error of prediction for the slave instrument was approximately 2%. The fiber optic near-infrared spectrometers were highly accurate in the fat quality evaluation of Wagyu carcasses based on monounsaturated, oleic, and saturated fatty acid composition with easy calibration model transfer. PMID- 29245029 TI - Nursing students' learning dynamics and influencing factors in clinical contexts. AB - Clinical placements are essential for students to develop clinical skills to qualify as nurses. However, various difficulties encountered by nursing students during their clinical education detract from developing clinical competencies. This constructivist grounded theory study aims to explore nursing students' experiences in clinical nursing education, and to identify the factors that influence the clinical education students receive. Twenty-one individual and six group semi-structured interviews were conducted with sixteen fourth year nursing students and four registered nurses. This research identified six factors that influence nursing students' clinical education: interpersonal, socio-cultural, instructional, environmental, emotional and physical factors. The research has developed a dynamic model of learning in clinical contexts, which offers opportunities to understand how students' learning is influenced multifactorially during clinical placements. The understanding and application of the model can improve nursing instructional design, and subsequently, nursing students' learning in clinical contexts. PMID- 29245030 TI - Osmotin: A plant defense tool against biotic and abiotic stresses. AB - Plants are prone to a number of pathogens and abiotic stresses that cause various disorders. However, plants possess a defense mechanism to cope with these stresses. The osmotin protein belongs to the PR-5 family of Pathogenesis-related (PR) proteins, which are produced in response to diseases caused by various biotic and abiotic stresses. Osmotin uses a signal transduction pathway to inhibit the activity of defensive cell wall barriers and increases its own cytotoxic efficiency. However, in response to cytotoxic effects, this pathway stimulates a mitogen-activated protein kinase (MAPK) cascade that triggers changes in the cell wall and enables osmotin's entrance into the plasma membrane. This mechanism involves cell wall binding and membrane perturbation, although the complete mechanism of osmotin activity has not been fully elucidated. Osmotin possesses an acidic cleft that is responsible for communication with its receptor in the plasma membrane of fungi. Osmotin is also involved in the initiation of apoptosis and programmed cell death, whereas its overexpression causes the accumulation of proline in transgenic plants. A higher concentration of osmotin can cause the lysis of hyphae tips. This review highlights the role of osmotin protein in the plant defense mechanism and its mode of action against numerous pathogens in wild and transgenic plants. PMID- 29245031 TI - Nanometer-precise optical length measurement using near-field scanning optical microscopy with sharpened single carbon nanotube probe. AB - We have developed and characterized a plasmon-excitation scattering-type near field scanning optical microscope with sharpened single carbon nanotube probe. The developed microscope can optically capture differences in the refractive index of single-nanometer surface structures. Statistical analysis enabled us to estimate the precision of the optical length measurement to 1.8 nm. PMID- 29245032 TI - Atomic force microscopy capable of vibration isolation with low-stiffness Z-axis actuation. AB - For high-resolution imaging without bulky external vibration isolation, this paper presents an atomic force microscope (AFM) capable of vibration isolation with its internal Z-axis (vertical) actuators moving the AFM probe. Lorentz actuators (voice coil actuators) are used for the Z-axis actuation, and flexures guiding the motion are designed to have a low stiffness between the mover and the base. The low stiffness enables a large Z-axis actuation of more than 700 um and mechanically isolates the probe from floor vibrations at high frequencies. To reject the residual vibrations, the probe tracks the sample by using a displacement sensor for feedback control. Unlike conventional AFMs, the Z-axis actuation attains a closed-loop control bandwidth that is 35 times higher than the first mechanical resonant frequency. The closed-loop AFM system has robustness against the flexures' nonlinearity and uses the first resonance for better sample tracking. For further improvement, feedforward control with a vibration sensor is combined, and the resulting system rejects 98.4% of vibrations by turning on the controllers. The AFM system is demonstrated by successful AFM imaging in a vibrational environment. PMID- 29245033 TI - Response of detoxification system genes on Chironomus riparius aquatic larvae after antibacterial agent triclosan exposures. AB - Triclosan (TCS) is an antimicrobial agent used in a range of personal care and consumer products and is commonly detected in aquatic ecosystems. In the present study, the effects of TCS at the molecular level on the detoxification system of Chironomus riparius aquatic larvae, a test organism widely used for the assessment of aquatic toxicology, were evaluated. The obtained results show that this xenobiotic was able to induce significant changes in transcripts from different cytochrome P450s and glutathione s-transferases genes, involved in phase I and phase II of detoxification system, respectively. In contrast, TCS did not affect the glutathione S-transferase enzyme activity nor the expression pattern of multidrug resistance-associated protein 1, which belongs to phase III of detoxification system. These results provide information about the effects of TCS on the detoxification mechanism of C. riparius and offers different biomarker genes that could be useful in ecotoxicological studies, risk assessment and bioremediation. PMID- 29245034 TI - Impact of magnetite nanoparticles on the syntrophic dechlorination of 1,2 dichloroethane. PMID- 29245035 TI - Multiple long-term trends and trend reversals dominate environmental conditions in a man-made freshwater reservoir. AB - Man-made reservoirs are common across the world and provide a wide range of ecological services. Environmental conditions in riverine reservoirs are affected by the changing climate, catchment-wide processes and manipulations with the water level, and water abstraction from the reservoir. Long-term trends of environmental conditions in reservoirs thus reflect a wider range of drivers in comparison to lakes, which makes the understanding of reservoir dynamics more challenging. We analysed a 32-year time series of 36 environmental variables characterising weather, land use in the catchment, reservoir hydrochemistry, hydrology and light availability in the small, canyon-shaped Rimov Reservoir in the Czech Republic to detect underlying trends, trend reversals and regime shifts. To do so, we fitted linear and piecewise linear regression and a regime shift model to the time series of mean annual values of each variable and to principal components produced by Principal Component Analysis. Models were weighted and ranked using Akaike information criterion and the model selection approach. Most environmental variables exhibited temporal changes that included time-varying trends and trend reversals. For instance, dissolved organic carbon showed a linear increasing trend while nitrate concentration or conductivity exemplified trend reversal. All trend reversals and cessations of temporal trends in reservoir hydrochemistry (except total phosphorus concentrations) occurred in the late 1980s and during 1990s as a consequence of dramatic socioeconomic changes. After a series of heavy rains in the late 1990s, an administrative decision to increase the flood-retention volume of the reservoir resulted in a significant regime shift in reservoir hydraulic conditions in 1999. Our analyses also highlight the utility of the model selection framework, based on relatively simple extensions of linear regression, to describe temporal trends in reservoir characteristics. This approach can provide a solid basis for a better understanding of processes in freshwater reservoirs. PMID- 29245036 TI - Inhibition of microbial fuel cell operation for municipal wastewater treatment by impact loads of free ammonia in bench- and 45L-scale. AB - A 45-liter microbial fuel cell (MFC) system was integrated into a full-scale wastewater treatment plant (WWTP). The system was operated under practical conditions with supernatant of a pre-thickener for 50days in order to identify, whether higher power output and energy recovery is possible compared to the use of primary clarifier effluent, as used in a previous study. The higher COD (chemical oxygen demand) loading rates of supernatant neither increased power densities, nor energy recovery, but impact loads of total ammonia nitrogen (TAN) in concentrations >800mg/L (free ammonia nitrogen (FAN)>40mg/L) led to an instant collapse of power output and nutrient removal, which was reversed when ammonia concentrations decreased. Investigations in lab-scale under defined conditions verified that the inhibition of the exoelectrogenic biofilm is in fact caused by high levels of FAN. Here, COD removal, power output and energy recovery constantly decreased, when FAN-concentrations were increased above 64mg/L. PMID- 29245037 TI - Production of bio-fertilizer from microwave vacuum pyrolysis of palm kernel shell for cultivation of Oyster mushroom (Pleurotus ostreatus). AB - Microwave vacuum pyrolysis of palm kernel shell (PKS) was performed to produce biochar, which was then tested as bio-fertilizer in growing Oyster mushroom (Pleurotus ostreatus). The pyrolysis approach produced biochar containing a highly porous structure with a high BET surface area of up to 270m2/g and low moisture content (<=10wt%), exhibiting desirable adsorption properties to be used as bio-fertilizer since it can act as a housing that provides many sites on which living microorganisms (mycelium or plant-growth promoting bacteria) and organic nutrients can be attached or adsorbed onto. This could in turn stimulate plant growth by increasing the availability and supply of nutrients to the targeted host plant. The results from growing Oyster mushroom using the biochar recorded an impressive growth rate and a monthly production of up to about 550g of mushroom. A shorter time for mycelium growth on one whole baglog (21days) and the highest yield of Oyster mushroom (550g) were obtained from cultivation medium added with 20g of biochar. Our results demonstrate that the biochar-based bio fertilizer produced from microwave vacuum pyrolysis of PKS shows exceptional promise as growth promoting material for mushroom cultivation. PMID- 29245038 TI - Spatiotemporal influence of temperature, air quality, and urban environment on cause-specific mortality during hazy days. AB - Haze is an extreme weather event that can severely increase air pollution exposure, resulting in higher burdens on human health. Few studies have explored the health effects of haze, and none have investigated the spatiotemporal interaction between temperature, air quality and urban environment that may exacerbate the adverse health effects of haze. We investigated the spatiotemporal pattern of haze effects and explored the additional effects of temperature, air pollution and urban environment on the short-term mortality risk during hazy days. We applied a Poisson regression model to daily mortality data from 2007 through 2014, to analyze the short-term mortality risk during haze events in Hong Kong. We evaluated the adverse effect on five types of cause-specific mortality after four types of haze event. We also analyzed the additional effect contributed by the spatial variability of urban environment on each type of cause specific mortality during a specific haze event. A regular hazy day (lag 0) has higher all-cause mortality risk than a day without haze (odds ratio: 1.029 [1.009, 1.049]). We have also observed high mortality risks associated with mental disorders and diseases of the nervous system during hazy days. In addition, extreme weather and air quality contributed to haze-related mortality, while cold weather and higher ground-level ozone had stronger influences on mortality risk. Areas with a high-density environment, lower vegetation, higher anthropogenic heat, and higher PM2.5 featured stronger effects of haze on mortality than the others. A combined influence of haze, extreme weather/air quality, and urban environment can result in extremely high mortality due to mental/behavioral disorders or diseases of the nervous system. In conclusion, we developed a data-driven technique to analyze the effects of haze on mortality. Our results target the specific dates and areas with higher mortality during haze events, which can be used for development of health warning protocols/systems. PMID- 29245039 TI - Prenatal arsenic exposure, child marriage, and pregnancy weight gain: Associations with preterm birth in Bangladesh. AB - BACKGROUND: Preterm birth is a disease of multifactorial etiologies that has environmental, social, and maternal health components. Individual studies have shown that exposure to arsenic contaminated drinking water, child marriage, and low maternal weight gain during pregnancy contribute to preterm birth. These factors are highly prevalent and often co-exist in Bangladesh, a country in South Asia with one of the world's highest prevalences of preterm birth. OBJECTIVE: To evaluate the individual and interactive effects of prenatal arsenic exposure, child marriage, and pregnancy weight gain on preterm birth in a prospective birth cohort in Bangladesh. METHODS: During 2008-2011, we recruited 1613 pregnant women aged >=18years at <=16weeks of gestation and followed them until 1-month post partum. We measured total arsenic in drinking water (n=1184) and in maternal toenails (n=1115) collected at enrollment and <=1-month post-partum, respectively using inductively coupled plasma mass spectrometry. Child marriage (<18years old) was defined using self-report, and 2nd and 3rd trimester pregnancy weight gain was calculated using monthly records. Gestational age was determined at enrollment by ultrasound. RESULTS: In multivariate adjusted Poisson regression models, the risk ratios (RR) for preterm birth were 1.12 (95% CI: 1.07-1.18) for a unit change in natural log water arsenic exposure, 2.28 (95% CI: 1.76-2.95) for child marriage, and 0.64 (95% CI: 0.42-0.97) for a pound per week increase in maternal weight during the 2nd and 3rd trimesters. In stratified analysis by child marriage, pregnancy weight gain was inversely associated with preterm birth among women with a history of child marriage (RR=0.58; 95% CI: 0.37-0.92), but not among women with no history of child marriage (RR=86; 95% CI: 0.37-2.01). Mediation analysis revealed that both arsenic exposure and child marriage had small but significant associations with preterm birth via lowering pregnancy weight gain. Similar associations were observed when arsenic exposure was assessed using maternal toenail arsenic concentrations. CONCLUSIONS: Reducing arsenic exposure and ending child marriage could reduce the risk of preterm birth in Bangladesh. Furthermore, enhancing nutritional support to ensure adequate weight gain during pregnancy may provide additional benefits especially for women with a history of child marriage. PMID- 29245040 TI - Characterising the online weapons trafficking on cryptomarkets. AB - Weapons related webpages from nine cryptomarkets were manually duplicated in February 2016. Information about the listings (i.e. sales proposals) and vendors' profiles were extracted to draw an overview of the actual online trafficking of weapons. Relationships between vendors were also inferred through the analysis of online digital traces and content similarities. Weapons trafficking is mainly concentrated on two major cryptomarkets. Besides, it accounts for a very small proportion of the illicit trafficking on cryptomarkets compared to the illicit drugs trafficking. Among all weapon related listings (n=386), firearms only account for approximately 25% of sales proposal since the proportion of non lethal and melee weapons is important (around 46%). Based on the recorded pseudonyms, a total of 96 vendor profiles were highlighted. Some pseudonyms were encountered on several cryptomarkets, suggesting that some vendors may manage accounts on different markets. This hypothesis was strengthened by comparing pseudonyms to online traces such as PGP keys, images and profiles descriptions. Such a method allowed to estimate more accurately the number of vendors offering weapons across cryptomarkets. Finally, according to the gathered data, the extent of the weapons trafficking on the cryptomarkets appear to be limited compared to other illicit goods. PMID- 29245041 TI - Stability of postmortem methemoglobin: Artifactual changes caused by storage conditions. AB - Hemoglobin is the protein in red blood cells that carries and distributes oxygen to the body. Methemoglobinemia is a blood disorder in which an abnormal amount of methemoglobin (MetHb), a form of hemoglobin (Hb), is produced from either inadequate MetHb reductase activity or too much MetHb production or by exposure to oxidizing agents. This could lead to anoxia and death if it is not treated. However, this parameter has not been investigated as a valid post-mortem indicator because random MetHb levels have been observed in various studies: MetHb increases can be observed due to autoxidation during storage, and MetHb decreases can be observed due to MetHb reductase or microbial activity in post mortem samples. MetHb variations can also come from the blood state and can interfere in the optical measurements of MetHb. We have studied the post-mortem MetHb concentrations according to various storage conditions. Based on our results, both the post-mortem delay and the delay before analysis should be reduced whenever possible to avoid changes in MetHb. If the analysis is delayed for a short period of time (two weeks), the blood sample taken at autopsy should not be frozen but collected in EDTA preservative and stored under refrigeration (4-6 degrees C) until analysis. If the analysis is delayed for a longer period (more than two weeks), the blood sample should be frozen with cryoprotectant at 80 degrees C or -196 degrees C. PMID- 29245042 TI - Is the diagnostic threshold for bulimia nervosa clinically meaningful? AB - The DSM-5 differentiates full- and sub-threshold bulimia nervosa (BN) according to average weekly frequencies of binge eating and inappropriate compensatory behaviors. This study was the first to evaluate the modified frequency criterion for BN published in the DSM-5. The purpose of this study was to test whether community-recruited adults (N=125; 83.2% women) with current full-threshold (n=77) or sub-threshold BN (n=48) differed in comorbid psychopathology and eating disorder (ED) illness duration, symptom severity, and clinical impairment. Participants completed the Clinical Impairment Assessment and participated in semi-structured clinical interviews of ED- and non-ED psychopathology. Differences between the sub- and full-threshold BN groups were assessed using MANOVA and Chi-square analyses. ED illness duration, age-of-onset, body mass index (BMI), alcohol and drug misuse, and the presence of current and lifetime mood or anxiety disorders did not differ between participants with sub- and full threshold BN. Participants with full-threshold BN had higher levels of clinical impairment and weight concern than those with sub-threshold BN. However, minimal clinically important difference analyses suggested that statistically significant differences between participants with sub- and full-threshold BN on clinical impairment and weight concern were not clinically significant. In conclusion, sub threshold BN did not differ from full-threshold BN in clinically meaningful ways. Future studies are needed to identify an improved frequency criterion for BN that better distinguishes individuals in ways that will more validly inform prognosis and effective treatment planning for BN. PMID- 29245043 TI - Participation and needs of children with developmental coordination disorder at home and in the community: Perceptions of children and parents. AB - BACKGROUND: The existing literature provides only a partial understanding of the viewpoints of elementary school-aged children with developmental coordination disorder (DCD) regarding their participation and needs. In order to plan and develop health and social services driven by a personalized approach, it is essential to further document their perceptions with those of their parents. AIMS: The aim of the study was to explore the participation and needs of school aged children with DCD at home and in the community, as perceived by children and parents. METHODS: Participants were ten school-aged children with DCD, from 6 to 13 years old, and their parents, including one couple (n=11). Individual semi structured interviews were conducted with each participant, except the couple who were interviewed together. RESULTS: Most children and all parents perceived some difficulties at home but few in the community. However, participation and needs varied for each child. Children rarely expressed the same expectations as their parents. While most children did not want more support, parents requested training on DCD. CONCLUSIONS: When planning health and social services for children with DCD, it is recommended to consult all stakeholders, including children, as well as offer indirect interventions, such as training and coaching for parents. PMID- 29245044 TI - Changes in lower extremity strength may be related to the walking speed improvements in children with cerebral palsy after gait training. AB - BACKGROUND: Cerebral palsy (CP) has a high probability of resulting in lower extremity strength and walking deficits. Numerous studies have shown that gait training has the potential to improve the walking abilities of these children; however, the factors governing these improvements are unknown. AIMS: This study aimed to evaluate the relationship between change in lower extremity strength, walking speed and endurance of children with CP following gait training. METHODS AND PROCEDURES: Eleven children with CP (GMFCS levels=II-III) completed a gait training protocol three days a week for six weeks. Outcome measures included a 10m fast-as-possible walk test, 6min walking endurance test and lower extremity strength. OUTCOMES AND RESULTS: The group results indicated there were improvements in walking speed, walking endurance and lower extremity strength. In addition, there was a positive correlation between percent change in lower extremity strength and walking speed and a negative correlation between the percent change in lower extremity strength and the child's age. CONCLUSIONS: Our results imply that changes in lower extremity strength might be related to the degree of the walking speed changes seen after gait training. Younger children may be more likely to show improvements in lower extremity strength after gait training. PMID- 29245045 TI - Relations between problem behaviors, perceived symptom severity and parenting in adolescents and emerging adults with ASD: The mediating role of parental psychological need frustration. AB - Research in parents of youngsters with Autism Spectrum Disorder (ASD) increasingly documents associations between children's problem behaviors and symptom severity and more dysfunctional and less adaptive parenting behaviors. However, the mechanisms underlying these associations have not been examined thoroughly. This study examines the mediating role of parental need frustration in the relation between child maladjustment (i.e., problem behavior and autism severity) and parenting behavior (i.e., controlling and autonomy-supportive parenting). The sample included 95 parents of adolescents/emerging adults with ASD (Mage=18.8years, SD=2.3). Parents completed questionnaires assessing their parenting strategies and psychological need frustration as well as the internalizing and externalizing problem behaviors and autism severity of their child. Results indicate that the association between externalizing problems and controlling parenting was partially mediated by need frustration. This suggests that externalizing problems go together with lower feelings of parent-child closeness, lower parental competence, and a decreased sense of volitional functioning, feelings that, in turn, relate to more controlling strategies. Symptom severity has a direct negative association with autonomy support, suggesting that parents lower their autonomy support when their child has high levels of autism symptoms, without experiencing these symptoms as a threat to their own psychological needs. PMID- 29245046 TI - Physiological and self-report responses of parents of children with autism spectrum disorder to children crying. AB - Little is known about the physiological response of parents of children with Autism Spectrum Disorder (ASD) to crying of children who have already received the diagnosis of ASD. This study aimed to compare cardiac dynamics via Inter-Beat Interval (IBI) and self-reported emotional states of parents of children with ASD and of parents with typically developing (TD) children while listening to crying of children with ASD (ASD cry) and of typically developing children (TD cry). Analyses revealed higher IBI in parents of children with ASD than IBI in parents of TD children while listening to both cry groups; however no differences on self reported emotional states were observed. Parents of children with ASD were calmer (higher IBI) than parents of TD children while listening to crying. However, ASD cry did not elicit different IBI compared to TD cry. ASD cry and TD cry were differentiated based on parents' self-responses about what they felt during the listening of crying, their physiological responses showed no differences. These results highlight the similarities and differences between self-reported emotional states and physiological responses of parents of children with ASD, and also point to the importance of monitoring parents' physiological responses in addition to their subjective responses. PMID- 29245047 TI - Polyriboinosinic-polyribocytidylic acid facilitates interleukin-6, and interleukin-8 secretion in human dermal fibroblasts via the JAK/STAT3 and p38 MAPK signal transduction pathways. AB - Polyriboinosinic-polyribocytidylic acid (polyI:C) is a viral dsRNA analoguethat promotes wounds healing, accelerates re-epithelialization, granulation and neovascularization, and induces pro-inflammatory cytokine release. Little is known about polyI:C mediated induction of inflammatory mediators in human dermal fibroblast (HDFs), which form the primary scaffold for epithelial cells covering the wound. Here, we found that polyI:C enhances IL-6 and IL-8 mRNA expression and induces of IL-6 and IL-8 production in a concentration-dependent and time dependent manner in HDFs. PolyI:C treatment rapidly increased phosphorylation level of both STAT3 and p38 mitogen-activated protein kinase (MAPK). Moreover, pretreatment with AG490, a Janus kinase (JAK) inhibitor, inhibited polyI:C induced STAT3 phosphorylation and subsequent IL-6 and IL-8 release. Conversely, pretreatment with SB203580, a selective inhibitor of p38 MAPK, blocked p38 MAPK phosphorylation and IL-6 and IL-8 expression. In conclusion, polyI:C induces IL-6 and IL-8 production in HDFs via the JAK/STAT3 and p38 MAPK signaling pathways. PMID- 29245048 TI - The time-dependent prognostic value of intratumoral cytokine expression profiles in a natural course of primary breast cancer with a long-term follow-up. AB - Despite the increasing evidence for the importance of immunity in breast cancer, the contradictory role of inflammation has not been thoroughly researched. In this study, we investigate the prognostic value of intratumoral inflammation as evaluated by cytokine mRNA levels. Intratumoral mRNA was measured for IL1beta, IL6, IL8, IL10 and IL17A, using Taqman quantitative PCR. By the AUC criteria, none of the cytokines associated with metastasis outcome over the entire follow up period. However, separation of the follow-up period has revealed a time dependent and robust prognostic association of IL beta. It discriminated between patients with and without metastasis relapse by AUCs of 0.21 and 0.82 during the early and late follow-up of 0-7 and 7-14 years, respectively. Interestingly, the prognostic effect by IL1beta shifted during follow-up from good prognosis in the first seven years to bad prognosis thereafter. By the less stringent criteria of Cox regression analysis, other cytokines also significantly associated positively or negatively with metastasis outcome. IL17A associated with good prognosis in the first 7 years of follow up while IL6 associated with poor and IL10 with good prognosis from 7 to 14 years. The revealed time-dependent prognostic effects of cytokine mRNA levels are intriguing and may reflect valuable biological information which should be considered in breast cancer immunotherapy research. PMID- 29245049 TI - Effects of priming with cytokines on intracellular survival and replication of Rhodococcus equi in equine macrophages. AB - Rhodococcus equi is a common cause of pneumonia in foals and an opportunistic pathogen in immunosuppressed people. The ability of R. equi to survive and replicate in macrophages is the basis of its pathogenicity. Limited knowledge about the role of cytokines in host defense against R. equi comes from studies in mice and the role of cytokines in intracellular survival of R. equi in equine macrophages is unknown. The objectives of this study were to determine the effect of priming with interferon (IFN)-gamma, interleukin (IL)-1beta, IL-4, IL-6, IL 10, or tumor necrosis factor (TNF)-alpha at various concentrations on intracellular survival of virulent R. equi in equine monocyte-derived macrophages (MDM), and to determine the effects of various combinations of the same cytokines on intracellular survival of R. equi. MDM from 10 adult horses were primed with recombinant equine cytokines at doubling concentrations ranging from 25 to 200 ng/mL prior to infection with virulent R. equi. Priming with IFN-gamma, TNF alpha, or IL-6 significantly decreased intracellular replication of R. equi compared to unprimed monolayers. In contrast, priming with IL-10 or IL-1beta significantly increased intracellular replication of R. equi. Pairwise combinations of the cytokines listed above did not results in synergism or antagonism. This study demonstrated that IFN-gamma, TNF-alpha, or IL-6 improved equine MDM function against R. equi whereas IL-1beta or IL-10 were detrimental. PMID- 29245050 TI - NANOG restores the impaired myogenic differentiation potential of skeletal myoblasts after multiple population doublings. AB - Adult skeletal muscle regeneration relies on the activity of satellite cells residing in the skeletal muscle niche. However, systemic and intrinsic factors decrease the myogenic differentiation potential of satellite cells thereby impairing muscle regeneration. Here we present data showing that late passage C2C12 myoblasts exhibited significantly impaired myogenic differentiation potential that was accompanied by impaired expression of myogenic regulatory factors (Myf5, MyoD, Myogenin, and MRF4) and members of myocyte enhancer factor 2 family. Notably, ectopic expression of NANOG preserved the morphology and restored the myogenic differentiation capacity of late passage myoblasts, possibly by restoring the expression level of these myogenic factors. Muscle regeneration was effective in 2D cultures and in 3D skeletal microtissues mimicking the skeletal muscle niche. The presence of NANOG was required for at least 15days to reverse the impaired differentiation potential of myoblasts. However, it was critical to remove NANOG during the process of maturation, as it inhibited myotube formation. Finally, myoblasts that were primed by NANOG maintained their differentiation capacity for 20days after NANOG withdrawal, suggesting potential epigenetic changes. In conclusion, these results shed light on the potential of NANOG to restore the myogenic differentiation potential of myoblasts, which is impaired after multiple rounds of cellular division, and to reverse the loss of muscle regeneration. PMID- 29245052 TI - Optical molecular imaging for tumor detection and image-guided surgery. AB - We have witnessed rapid development of fluorescence molecular imaging of solid tumors for cancer diagnosis and image-guided surgery in the past decade. Many biomarkers unique to cancer cells or tumor microenvironment, such as cell surface receptors, hypoxia, secreted proteases and extracellular acidosis have been characterized, and can be used to distinguish cancer from normal tissue. A variety of optical imaging probes have been developed to target these biomarkers to improve tumor contrast over the background tissue. Unlike conventional anatomical and molecular imaging technologies, fluorescent imaging method benefits from its safety, high-spatial resolution and real-time capability, and therefore, has become a highly adoptable imaging method for tumor detection and image-guided surgery in clinics. In this review, we summarize recent progress in 'always-ON' and stimuli-activatable fluorescent imaging probes, and discuss their potentials in tumor detection and image-guided surgery. PMID- 29245051 TI - Magnesium phosphate ceramics incorporating a novel indene compound promote osteoblast differentiation in vitro and bone regeneration in vivo. AB - Incorporating bioactive molecules into synthetic ceramic scaffolds is challenging. In this study, to enhance bone regeneration, a magnesium phosphate (MgP) ceramic scaffold was incorporated with a novel indene compound, KR-34893. KR-34893 induced the deposition of minerals and expression of osteoblast marker genes in primary human bone marrow mesenchymal stem cells (BMSCs) and a mouse osteoblastic MC3T3-E1 cell line. Analysis of the mode of action showed that KR 34893 induced the phosphorylation of MAPK/extracellular signal-regulated kinase and extracellular signal-regulated kinase, and subsequently the expression of bone morphogenetic protein 7, accompanied by SMAD1/5/8 phosphorylation. Accordingly, KR-34893 was incorporated into an MgP scaffold prepared by 3D printing at room temperature, followed by cement reaction. KR-34893-incorporated MgP (KR-MgP) induced the expression of osteoblast differentiation marker genes in vitro. In a rat calvaria defect model, KR-MgP scaffolds enhanced bone regeneration and increased bone volume compared with MgP scaffolds, as assessed by micro-computed tomography and histological analyses. In conclusion, we developed a method for producing osteoinductive MgP scaffolds incorporating a bioactive organic compound, without high temperature sintering. The KR-MgP scaffolds enhanced osteoblast activation in vitro and bone regeneration in vivo. PMID- 29245054 TI - Understanding the transmission of foot-and-mouth disease virus at different scales. AB - Foot-and-mouth disease (FMD) is highly infectious, but despite the large quantities of FMD virus released into the environment and the extreme susceptibility of host species to infection, transmission is not always predictable. Whereas virus spread in endemic settings is characterised by frequent direct and indirect animal contacts, incursions into FMD-free countries may be seeded by low-probability events such as fomite or wind-borne aerosol routes. There remains a void between data generated from small-scale experimental studies and our ability to reliably reconstruct transmission routes at different scales between farms, countries and regions. This review outlines recent transmission studies in susceptible host species, and considers new approaches that integrate virus genomics and epidemiological data to recreate and understand the spread of FMD. PMID- 29245053 TI - Influence of diabetes on the foreign body response to nitric oxide-releasing implants. AB - The foreign body response (FBR) to nitric oxide (NO)-releasing subcutaneous implants was compared between healthy and streptozotocin-induced diabetic swine by evaluating inflammation, collagen capsule formation, and angiogenesis. Steel wire substrates were first modified with polyurethane membranes capable of diverse NO-release kinetics (NO fluxes and release durations of 0.8-630.0 pmol cm 2 s-1 and 2-13 d, respectively). The NO-releasing materials were implanted in the subcutis for 3, 10, or 25 d for histological and immunohistochemical evaluation of the FBR. A delayed, more severe inflammatory response to control (i.e., non-NO releasing) implants was observed in diabetic pigs relative to healthy swine. Regardless of the animal disease state, each NO-releasing implant tested elicited reduced inflammation compared to controls at both 3 and 10 d. However, only the NO-release materials capable of releasing low NO fluxes (0.8-3.3 pmol cm-2 s-1) for 7-13 d durations mitigated the inflammatory response at 25 d. Using immunohistochemical staining for the endothelial cell surface marker CD-31, we also observed poor blood vessel development at non-NO-releasing implants in diabetic swine. Relative to controls, NO-releasing implants with the longest NO release duration (13 d) increased blood vessel densities by 47.1 and 70.4% in the healthy and diabetic pigs, respectively. In the healthy model, tissues surrounding the long NO-release materials contained sparse amounts of collagen, whereas implants with shorter NO-release durations (2, 3, and 7 d) were characterized with a dense collagen encapsulation layer, similar to controls. Collagen deposition in diabetic swine was inhibited, and unaffected by NO. These results emphasize several key differences in the FBR in the setting of acute onset diabetes. The observation that NO release counteracts the more severe FBR in diabetic swine while simultaneously promoting tissue integration may help guide the design of medical implants (e.g., glucose sensors) with improved performance for diabetes management. PMID- 29245055 TI - High proportion of abnormal pap smear tests and cervical dysplasia in women with cystic fibrosis. AB - OBJECTIVES: Insufficient gynecological follow-up and cervical screening has been reported in women with cystic fibrosis (CF). Some of these patients will require a pulmonary transplantation, known to be associated with a higher risk of cervical dysplasia. The aim of this study was to explore the results of cervical screening in adult women with CF, and to report the prevalence of abnormal pap smear tests in this population. STUDY DESIGN: We retrospectively analyzed medical records of sexually active women with CF who attended a gynecological consultation in Lyon University CF referral center between June 2014 and December 2015. The primary outcome was the result of the pap smear test. RESULTS: Forty seven women (32 non-transplanted and 15 transplanted) were included in the study. The median age of the patients was 28 (range 18-53). The clinical examination revealed that 20 (42.5%) women presented an abnormality (inflammatory cervix, cervical or vulvovaginal condyloma). An abnormal pap smear was found in 8/32 (25%) non transplanted women and in 5/15 (33.3%) transplanted women, with no significant difference between the two groups (p=0.75): seven atypical squamous cells of undetermined significance (ASC-US), five low grade squamous intraepithelial lesion (LSIL), one atypical glandular cells (AGC). Six (12.8%) (four non transplanted, and two transplanted) women had an histologically proven dysplasia (four Cervical Intraepithelial Neoplasia (CIN)1, one CIN2, and one endocervical adenocarcinoma in situ). Overall, ten (21.3%) women had a Human Papilloma Virus (HPV) related disease (cervical and/or vulvovaginal). CONCLUSION: A high proportion of transplanted and non-transplanted women with CF had abnormal pap smear tests and cervical dysplasia. A regular gynaecological follow-up, periodic cervical screening, and routine HPV vaccination are strongly recommended in this population. PMID- 29245056 TI - Subcutaneous trastuzumab (Herceptin) versus intravenous trastuzumab for the treatment of patients with HER2-positive breast cancer: A time, motion and cost assessment study in a lean operating day care oncology unit. AB - OBJECTIVE: The subcutaneous (SC) formulation of trastuzumab represents an alternative to the intravenous (IV) infusion in the treatment of patients with HER2-positive metastatic and early breast cancer. We compared the two formulations in terms of time and cost differential. STUDY DESING: We conducted a time, motion and cost assessment study in a lean operating day care oncology unit to determine and compare the time and costs of trastuzumab SC versus IV administration in patients with HER2-positive breast cancer. Outcomes were the mean costs and the mean dedicated time of the health care professional (HCP) and patient chair time. Direct observation methodology was applied to collect data and statistical analysis was performed. RESULTS: The total preparation and administration time for trastuzumab IV was 4.07 times longer than the total time required for the trastuzumab SC administration. The total patient time spent in the day care oncology unit (in minutes) was 71% shorter with using SC administration. IV administration costs ? 50.4 ($54,89) more in HCP time and consumable supplies and ?162.53 ($177.00) of drug wastage. SC administration was associated with a total time saving of 53.7min for the HCPs and 122.5min for the patients. The administration of trastuzumab SC was translated in a cost saving of ?212.93 ($231.73) per patient episode compared to trastuzumab IV, which could lead to a total potential saving of ?3,832.74 ($4,171.06) over a full course of treatment (18 cycles) CONCLUSION: SC administration of trastuzumab was associated with a substantial reduction in active HCP time, patient chair time, unit time, and overall cost. These time and cost could be used to increase capacity within existing resources in a lean operating day dare oncology unit. PMID- 29245057 TI - A new randomized Kaczmarz based kernel canonical correlation analysis algorithm with applications to information retrieval. AB - Canonical correlation analysis (CCA) is a powerful statistical tool for detecting the linear relationship between two sets of multivariate variables. Kernel generalization of it, namely, kernel CCA is proposed to describe nonlinear relationship between two variables. Although kernel CCA can achieve dimensionality reduction results for high-dimensional data feature selection problem, it also yields the so called over-fitting phenomenon. In this paper, we consider a new kernel CCA algorithm via randomized Kaczmarz method. The main contributions of the paper are: (1) A new kernel CCA algorithm is developed, (2) theoretical convergence of the proposed algorithm is addressed by means of scaled condition number, (3) a lower bound which addresses the minimum number of iterations is presented. We test on both synthetic dataset and several real-world datasets in cross-language document retrieval and content-based image retrieval to demonstrate the effectiveness of the proposed algorithm. Numerical results imply the performance and efficiency of the new algorithm, which is competitive with several state-of-the-art kernel CCA methods. PMID- 29245058 TI - Quantitative EEG power and synchronization correlate with Alzheimer's disease CSF biomarkers. AB - Synaptic dysfunction is the best anatomical correlate of early cognitive impairment in Alzheimer's disease (AD). Electroencephalography (EEG) directly reflects brain electrical activity at the level of synapses. The aim of the present study was to investigate correlations of quantitative EEG measures, global field power (GFP) and global field synchronization (GFS), with conventional cerebrospinal fluid (CSF) biomarkers of neurodegeneration in patients diagnosed with subjective cognitive decline (n = 210), mild cognitive impairment (n = 230), and AD (n = 197). Decreased CSF amyloid beta42 significantly correlated with increased theta and delta GFP, whereas increased p- and t-tau with decreased alpha and beta GFP. Decreased CSF amyloid beta42 and increased p- and t-tau were significantly associated with decreased GFS alpha and beta. Subanalysis of the separate diagnostic groups demonstrated significant correlations between CSF biomarkers and generalized power and synchronization already in the subjective cognitive decline and mild cognitive impairment group. These results provide evidence that quantitative EEG measures are associated and possibly sensitive to distinct AD-like CSF biomarker profiles in cognitively impaired patients and are therefore promising early noninvasive markers of AD. PMID- 29245060 TI - Activation of human eosinophils with palladium nanoparticles (Pd NPs): importance of the actin cytoskeleton in Pd NPs-induced cellular adhesion. AB - Palladium (Pd) is known to be released into the environment in the fine and ultrafine (at the nanoscale) airborne particle fractions mainly from automobile catalytic converters leading to an increase human exposure to this noble metal. It was reported that Pd can induce allergic reactions in individuals exposed to it via different ways. Some studies reported an increased number of eosinophils into airways following NP exposure in vivo in rodent models of allergies and inflammation. Knowing the importance of eosinophils in allergies, asthma and other lung diseases, it is surprising to observe that the direct effect of Pd at the nanoscale in eosinophils has been poorly documented. The aim of this study was to determine how Pd NPs will affect the biology of human eosinophils. Characterization of Pd NPs by dynamic light scattering indicates the presence of some aggregates when suspended in diverse solutions used here for the different experiments. Pd NPs did not significantly induce cell necrosis and apoptosis in eosinophils (0.5-150MUg/ml) as assessed by trypan blue exclusion assay, flow cytometry after staining with FITC-annexin V and propidium iodide and by morphological observations by optical microscopy. PD NPs, unlike the positive controls, did not induce reactive oxygen species (ROS) but were found to target the actin cytoskeleton, since actin was differently re-located intracellularly when compared to untreated cells as determined by fluorescence microscopy. Clearly, Pd NPs were found to increase adhesion of eosinophils onto human endothelial EA.hy926 cells. Using cytochalasin D, a cell-permeable and potent inhibitor of actin polymerization, this ability to increase adhesion was drastically reversed. Our results indicate that Pd NPs can target the cytoskeleton and increase the adhesion of human eosinophils by an actin-dependent mechanism. These findings show that human eosinophils can be activated by Pd NPs emphasizing the importance of fully investigating how these NPs could alter the biology of human cells involved in allergies, asthma and other lung diseases as well as in various other inflammatory disorders. PMID- 29245061 TI - Risk and prognosis of cancer after upper-extremity deep venous thrombosis: A population-based cohort study. AB - INTRODUCTION: The association between lower-extremity venous thrombosis and cancer is well-established. However, the extent to which upper-extremity deep venous thrombosis (U-DVT) is a marker of cancer and a prognostic factor for all cause mortality remains poorly understood. We examined the risk of cancer after a diagnosis of U-DVT compared with cancer risk in the general population. MATERIALS AND METHODS: Using Danish nationwide population-based medical registries, we identified all patients with first-time U-DVT during 1980-1993 and 2000-2013. Cancer incidence was ascertained using data from the Danish Cancer Registry. We computed standardized incidence ratios (SIRs) calculated as the observed number of cancers relative to the expected number based on national incidence rates by sex, age, and calendar year. We created a matched comparison cohort of cancer patients without U-DVT, to assess the impact of U-DVT on all-cause mortality. RESULTS: Among 1087 patients with U-DVT, 232 patients subsequently were diagnosed with cancer, corresponding to an overall SIR of 1.69 (95% confidence interval, 1.48-1.92). During the first 6months following U-DVT, the absolute risk of any cancer was 5.4%, corresponding to a 13-fold elevated SIR. During the subsequent 6 12months and >12months, the SIR remained 2-fold and 1.3-fold elevated, respectively. U-DVT was a prognostic factor for all-cause mortality in patients with lung, prostate, and colorectal cancer during the first 6months of follow-up. CONCLUSION: U-DVT was a marker of cancer. The clinical utility of searching for occult cancer in patients with U-DVT remains unknown. PMID- 29245062 TI - Comparative studies on DNA-binding and in vitro antitumor activity of enantiomeric ruthenium(II) complexes. AB - A pair of ruthenium(II) complex enantiomers, Delta- and Lambda-[Ru(bpy)2PBIP]2+ {bpy=2,2'-bipyridine, PBIP=2-(4-bromophenyl)imidazo[4,5-f]1,10-phenanthroline} have been synthesized and characterized. The systematic comparative studies between two enantiomers on their DNA binding-behaviors with calf thymus DNA (CT DNA) were carried out by viscosity measurements, spectrophotometric methods and molecular simulation technology. Additional assays were performed to explore the cytotoxicity of the ruthenium(II) enantiomers against tumor cell lines. DNA binding studies show that both the enantiomers can bind to CT DNA via intercalative mode, and the Delta form binds to CT DNA more strongly than the Lambda form does. Molecular simulation further shows that both the two enantiomers intercalate between base pairs of DNA in minor groove, and that the Delta form intercalates into DNA more deeply than the Lambda form does. In addition, the cell proliferation assays show that the Delta form induces a greater cytotoxicity than the Lambda form on human cervical cancer HeLa cells, which is positive correlated with the results in DNA binding studies and molecular docking, and implies that the DNA binding affinities of ruthenium(II) polypyridyl complexes might be constitute to the part of their anticancer mechanisms. PMID- 29245059 TI - Proteomic analysis of six- and twelve-month hippocampus and cerebellum in a murine Down syndrome model. AB - This study was designed to investigate the brain proteome of the Ts65Dn mouse model of Down syndrome. We profiled the cerebellum and hippocampus proteomes of 6 and 12-month-old trisomic and disomic mice by difference gel electrophoresis. We quantified levels of 2082 protein spots and identified 272 (170 unique UniProt accessions) by mass spectrometry. Four identified proteins are encoded by genes trisomic in the Ts65Dn mouse. Three of these (CRYZL11, EZR, and SOD1) were elevated with p-value <0.05, and 2 proteins encoded by disomic genes (MAPRE3 and PHB) were reduced. Intergel comparisons based on age (6 vs. 12 months) and brain region (cerebellum vs. hippocampus) revealed numerous differences. Specifically, 132 identified proteins were different between age groups, and 141 identified proteins were different between the 2 brain regions. Our results suggest that compensatory mechanisms exist, which ameliorate the effect of trisomy in the Ts65Dn mice. Differences observed during aging may play a role in the accelerated deterioration of learning and memory seen in Ts65Dn mice. PMID- 29245063 TI - Background levels of male DNA in the vaginal cavity. AB - In alleged sexual assault investigations, the detection of male DNA on female intimate swabs can be established through Y-STR profiling. However, in cases where the defendant lives in the same dwelling as the complainant, the defendant may argue that his DNA was transferred through normal social contact, and dispute that intimate contact occurred. This study aimed to determine whether or not male DNA could be detected in samples collected from the vaginal cavity after everyday activities. A total of 300 samples from eight individuals were subjected to DNA quantification and Y-STR amplification. Three donors reported sexual contact during the time of sampling, hence the detection of male-specific DNA in post coital samples was concomitantly evaluated. The majority of samples (n=237, 79%) were undetermined for male DNA by real-time PCR quantification. No Y-STR profiles having three or more alleles were obtained in these samples, with the exception of three samples which displayed three alleles each. One sample was collected six days post-coital, one sample likely presented artefacts, and one exhibited two alleles at the same locus. Male-specific quantification values were obtained for the remaining 63 samples (21%), however only 31 samples displayed alleles at three or more loci. Twenty-three of the 63 samples showed inhibition during real time PCR quantification, and the majority of these exhibited no Y-STRs. A further three samples were excluded from the dataset due to possible contamination. The maximum confirmed time frame for obtaining a full Y-STR profile was six days post coital, but may be longer in some donors. Overall concordance between DNA quantification and Y-STR amplification was 85.8%. This study demonstrates that obtaining a Y-STR profile comprising three or more alleles from a vaginal swab collected from a woman who has not participated in recent intimate sexual activities is not indicated. This suggests that there is unlikely to be detectable adventitious transfer of DNA from male individuals living in the same household as a female donor. However, approximately one in seven samples may display 1-2 unexpected allelic peaks (<400 RFU). These are unlikely to originate from the male partner or cohabitant of the donor and should be interpreted with extreme caution, and with every effort attempted to replicate results before a conclusion is derived about their relevance. These findings support the significance of male DNA profiles consisting of more than three alleles obtained from female intimate samples during investigations of alleged sexual assault. PMID- 29245064 TI - circRNAs in Cancer. AB - Exonic circular RNAs (circRNAs) are mostly generated from exons of protein-coding genes and, in many cases, are more abundant that the linear product from their hosting gene. Certain circRNAs are very abundant in the brain and in non-dividing cells; and many also show physiological-specific and tissue-specific expression. Moreover, recent work has demonstrated that some circRNAs are functional. Lately an important number of research articles have pointed a relation between cancer and certain circRNAs. In this review, we describe general advances in the field regarding circRNA biogenesis and functions in relationship with cancer. Also, we summarize some necessary precautions to work with circRNA that are particularly relevant to cancer-related studies. PMID- 29245065 TI - Diclofenac-induced renal toxicity in female Wistar albino rats is protected by the pre-treatment of aqueous leaves extract of Madhuca longifolia through suppression of inflammation, oxidative stress and cytokine formation. AB - CONTEXT: Kidney has a vital role in renal clearance, maintenance of blood pressure, elimination of toxic products and formation of prostaglandins. Certain medications are known to cause renal injury on its frequent usage and high dosage. Diclofenac is a non-steroidal anti-inflammatory drug which is used in the treatment of pain and arthritis. Madhuca longifolia is a deciduous tree which is known to the have anti-microbial, anti-ulcer, hepatoprotective, anti-diabetic, anti-inflammatory and analgesic activity. The aim of the present study is to evaluate the beneficial effect of aqueous leaf extract of Madhuca longifolia against DFC-induced renal toxicity in female Wistar albino rats. METHODS: Thirty female Wistar albino rats were divided into five groups and the drugs were administrated specifically on each group. After the treatment period, the rats were sacrificed to evaluate the significant changes in renal enzyme markers, antioxidant activities in kidney tissue homogenate and plasma, renal histopathology and protein expression levels. The cytokines like TNF-alpha, IL-6 and IL-1beta were measured through ELISA techniques and the levels of Caspase-3, COX-2 and NF-kappaB were measured through western blotting techniques. DiscussionMadhuca longifolia was observed to show a better result in normalizing the toxicity caused by diclofenac. CONCLUSION: The significant result of the aqueous leaf extract ofMadhuca longifolia was due to its ability in restoring renal function by restoring antioxidants and preventing cellular damages. PMID- 29245066 TI - Immuno-biological comparison of hepatic stellate cells in a reverted and activated state. AB - Human hepatic stellate cells (HSCs) demonstrated great immunological plasticity with important consequences for liver cell therapy. Activated HSCs (aHSCs) are in vitro reverted (rHSCs) to a quiescent-like phenotype with potential benefit to reduce liver fibrosis. The goal of this study is to establish and compare the immunological profile of activated and in vitro reverted HSCs and to investigate the impact of inflammatory priming on the immunobiology of both HSCs populations. The distribution of inflammatory primed activated and reverted HSCs across the different phases of the cell cycle is assessed by flow cytometry. In addition, Flow analysis was done to assess the expression level of neuronal, endothelial and stromal markers, cell adhesion molecules, human leucocyte antigens, co stimulatory molecules, immunoregulatory molecules and natural killer ligands. Our results showed that the cell cycle distribution of both HSCs populations is significantly modulated by inflammation. Accordingly, activated HSC that were in G1 phase switch to S- and G2 phases when exposed to inflammation, while reverted HSCs mostly redistribute into sub-G0 phase. In a HSC state dependent manner, inflammatory priming modulated the expression of the stromal marker CD90, biological receptors (CD95 and CD200R), cell adhesion molecules (CD29, CD54, CD58, CD106 and CD166), human leucocyte antigen HLA-G, co-stimulatory molecules (CD40 and CD252), as well as the immunoregulatory molecules (CD200 and CD274). In conclusion, the immunologic profile of HSCs is significantly modulated by their activation state and inflammation and is important for the development of novel HSC liver cell-based therapy. PMID- 29245067 TI - Lin28a functionally modulates bupivacaine-induced dorsal root ganglion neuron apoptosis through TrkA activation. AB - PURPOSE: Lin-28 Homolog A gene (Lin28a) is an important regulator in nerve system. In this study, we investigated the functional mechanism of Lin28a during the process of bupivacaine (BUP)-induced neuronal apoptosis of spinal cord dorsal root ganglion neurons (DRGNs). METHODS: Young mouse DRGNs were cultured in vitro and treated with series concentrations of BUP. Apoptosis was evaluated by TUNEL assay. Corresponding Lin28a mRNA and protein expressions were evaluated by qRT PCR and western blot (WB) assays. Lin28a was downregulated by siRNA and its effect on BUP (5 mM)-induced DRGN apoptosis was measured by qRT-PCR, WB and TUNEL assays, respectively. Alternatively, Lin28a was upregulated in DRGNs. It's effect on BUP (0.1 mM)-induced DRGN apoptosis was also measured. Finally, WB was used to examine Caspase-3/9 and TrkA protein expressions in Lin28a-downregualted and BUP injured DRGN to explore Lin28a-associated signaling pathways. RESULTS: In DRGN in vitro culture, 0.1 mM BUP induced moderate neuronal apoptosis while 5 mM BUP induced significant apoptosis. Lin28a mRNA and protein were both upregulated by BUP, in concentration-dependent manner. Functional assays showed that Lin28a downregulation rescued 5 mM BUP-induced neuronal apoptosis, whereas Lin28a upregulation aggravated 0.1 mM BUP-induced neuronal apoptosis in DRGNs. WB showed that Lin28a downregulation reduced Caspase-3/9 proteins and activated TrkA through phosphorylation in BUP-injured DRGNs. CONCLUSION: Lin28a is a potent regulator in BUP-induced neuronal apoptosis in DRGNs. The apoptotic protection by Lin28a inhibition is likely through the activation of TrkA signaling pathway. PMID- 29245068 TI - Overexpression of microRNA-375 impedes platelet-derived growth factor-induced proliferation and migration of human fetal airway smooth muscle cells by targeting Janus kinase 2. AB - The abnormal proliferation and migration of airway smooth muscle (ASM) cells play a critical role in airway remodeling during the development of asthma. MicroRNAs (miRNAs) have emerged as critical regulators of ASM cell proliferation and migration in airway remodeling. In this study, we aimed to investigate the potential role of miR-375 in the regulation of platelet-derived growth factor (PDGF)-induced fetal ASM cell proliferation and migration. Our results showed that miR-375 expression was significantly decreased in fetal ASM cells that were treated with PDGF. Functional data showed that overexpression of miR-375 inhibited the proliferation and migration of fetal ASM cells, whereas inhibition of miR-375 enhanced the proliferation and migration of fetal ASM cells. The results of bioinformatics analysis and a dual-luciferase reporter assay showed that miR-375 binds directly to the 3'-untranslated region of Janus kinase 2 (JAK2). Further data confirmed that miR-375 negatively regulates the expression of JAK2 in fetal ASM cells. Moreover, miR-375 also impeded the PDGF-induced activation of signal transducer and activator of transcription 3 (STAT3) in fetal ASM cells. However, restoration of JAK2 expression partially reversed the inhibitory effect of miR-375 on fetal ASM cell proliferation and migration. Overall, our results demonstrate that miR-375 inhibits fetal ASM cell proliferation and migration by targeting JAK2/STAT3 signaling. Our study provides a potential therapeutic target for the development of novel treatment strategies for pediatric asthma. PMID- 29245069 TI - Aqueous extract of Triphala inhibits cancer cell proliferation through perturbation of microtubule assembly dynamics. AB - Triphala (Trl) is an ayurvedic formulation used for treating disorders of the digestive, respiratory, and nervous systems. Its anticancer properties have also been documented. We studied effects of Trl on tubulin, a target protein for several anticancer drugs, and systematically elucidated a possible antiproliferative mechanism of action of Trl. Trl inhibited proliferation of HeLa (cervical adenocarcinoma), PANC-1 (pancreatic adenocarcinoma), and MDA-MB-231 (triple-negative breast carcinoma) cells in microgram quantities and strongly suppressed the clonogenicity of HeLa cells. The formulation disrupted secondary conformation of tubulin and inhibited anilino naphthalene sulfonate binding to tubulin. In cells, Trl-tubulin interactions were manifested as a perturbed microtubule network. Acetylation pattern of Trl-treated cellular microtubules indicated persistent stabilization of microtubule dynamics. In addition, Trl interfered with reassembly of the microtubules. Cells treated with Trl eventually underwent programmed cell death as evidenced by annexin-V staining. Our study shows that the effect of aqueous extract of Trl is potent enough to interfere with the assembly dynamics of microtubules, and that Trl can be investigated further for its antitumor potential. PMID- 29245070 TI - Blood-brain barrier permeability and neuroprotective effects of three main alkaloids from the fruits of Euodia rutaecarpa with MDCK-pHaMDR cell monolayer and PC12 cell line. AB - The fruits of Euodia rutaecarpa (Euodiae Fructus, EF), the widely used traditional Chinese medicine, have various central nervous system effects. Alkaloids following as evodiamine (EDM), rutaecarpine (RCP) and dehydroevodiamine (DEDM) are the major substances in EF. The MDCK-pHaMDR cell monolayer model was utilized as a blood-brain barrier (BBB) surrogate model to study their BBB permeability. The transport samples were analyzed by high performance liquid chromatography and the apparent permeability coefficients (Papp) were calculated. EDM and RCP showed high permeability through BBB by passive diffusion, while DEDM showed moderate permeability with efflux mechanism related to P-glycoprotein (P gp). EDM and RCP could also reduce the efflux of DEDM probably by inhibiting P gp. The neuroprotective effects of the three alkaloids were then studied on the PC12 cell line injured by 1-methyl-4-phenylpyridinium ion (MPP+) or hydrogen peroxide (H2O2). EDM could significantly reduce MPP+ or H2O2-induced cell injury dose-dependently. RCP could increase the cell viability in MPP+ treated group while DEDM showed a protective effect against H2O2 injury. This study predicted the permeability of EDM, RCP and DEDM through BBB and discovered the neuroprotective substance basis of EF as a potential encephalopathy drug. PMID- 29245071 TI - Dual-task training in older adults: The effect of additional motor tasks on mobility performance. AB - OBJECTIVES: Dual-task (DT) performance is common to most activities of daily living and difficulties in DT activities may reduce quality of life in older adults. This study investigated the effect of DT training in a sample of older adults. METHODS: Sixty older adults (mean=74.4+/-3.1years) participated in the study. Twenty-two older adults were included in the control (CG), 19 in the single-task (ST) training and 19 in DT training group. ST group received balance and walking training twice a week for16 weeks, while DT training group performed the same training with additional motor tasks. Data were gathered on 6m timed walk (6MTW), timed up and go test (TUG) and four square step test (FSST). DT conditions required participants to complete 6MTW, TUG and FSST, either (i) while carrying a glass of water or (ii) while carrying a ball on a round tray. RESULTS: A significant Group x Time interaction was found in TUG (F [2,57]=29.5; p<0.01; partial eta2=0.51) and in FSST (F [2,57]=23.2; p<0.01; partial eta2=0.44). After intervention DT showed better scores in overall TUG (mean difference=1.21s [95% CI, 0.82-1.60]; p<0.05) and FSST (mean difference=2.51s [95% CI, 1.67-3.35]; p<0.01), whereas CG and ST did not exhibit significant changes. CONCLUSION: Our results suggested that 16 weeks of motor DT training, using motor additional tasks as manipulation of common objects of everyday life, could improve mobility in older age. PMID- 29245072 TI - Phloretin attenuates mucus hypersecretion and airway inflammation induced by cigarette smoke. AB - BACKGROUNDS: Cigarette smoke (CS)-induced airway mucus hypersecretion and inflammation are the prominent features of chronic obstructive pulmonary disease (COPD). As an anti-inflammatory flavonoid, phloretin was found to be involved in various inflammatory disorders such as sepsis. In this study, the effects of phloretin on CS-induced airway mucin secretion and inflammation were investigated in vivo and in vitro. METHODS: Phloretin dissolved in 1% DMSO was daily injected intraperitoneally to mice, which were then exposed to CS for four weeks. Mouse lung histologic changes were evaluated, the expression of mucin 5ac (MUC5AC) was measured, bronchoalveolar lavage fluid (BALF) total cells, neutrophils, and macrophages were counted. BALF and lung levels of tumor necrosis factor-alpha and interleukin-1 beta (IL-1beta) were quantified. Moreover, the effects of phloretin on cigarette smoke extract (CSE)-induced expression of MUC5AC and IL-1beta were investigated in NCI-H292 cells. Then, to explore the potential mechanisms, the signaling molecules including epidermal growth factor receptor (EGFR), extracellular signal-regulated kinase (ERK) and P38 were evaluated. RESULTS: Phloretin pretreatment dramatically suppressed the mucins secretion, inflammatory cell infiltration and inflammatory cytokine release in mouse lungs induced by CS, and it also suppressed CSE-induced expression of MUC5AC and IL-1beta in NCI-H292 bronchial epithelial cells. Furthermore, western blot showed that phloretin attenuated the activation of EGFR, ERK and P38 both in vivo and in vitro. CONCLUSIONS: This study highlights the protective effect of phloretin on CS related airway mucus hypersecretion and inflammation, where EGFR, ERK and P38 might be involved. These findings suggest that phloretin could be a potential therapeutic drug for COPD. PMID- 29245073 TI - Synthesis and application of bismuth ferrite nanosheets supported functionalized carbon nanofiber for enhanced electrochemical detection of toxic organic compound in water samples. AB - Recently, the multiferroic material has fabulous attention in numerous applications owing to its excellent electronic conductivity, unique mechanical property, and higher electrocatalytic activity, etc. In this paper, we reported that the synthesis of bismuth ferrite (BiFeO3) nanosheets integrated functionalized carbon nanofiber (BiFeO3 NS/F-CNF) nanocomposite using a simple hydrothermal technique. Herein, the structural changes and crystalline property of prepared BiFeO3 NS/F-CNF nanocomposite were characterized using Scanning electron microscopy (SEM), Transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy and X-ray photoelectron spectroscopy (XPS). From this detailed structural evolution, the formation of nanosheets like BiFeO3 and its nanocomposite with F-CNF were scrutinized and reported. Furthermore, the as prepared BiFeO3 NS/F-CNF nanocomposite modified glassy carbon electrode (GCE) was applied for electrochemical detection of catechol (CC). As expected, BiFeO3 NS/F CNF/GCE shows excellent electrocatalytic activity as well as 3.44 (F-CNF/GCE) and 7.92 (BiFeO3 NS/GCE) fold higher electrochemical redox response for CC sensing. Moreover, the proposed sensor displays a wide linear range from 0.003 to 78.02 uM with a very low detection limit of 0.0015 uM. In addition, we have validated the real-time application of our developed CC sensor in different water samples. PMID- 29245074 TI - Fabrication, characterization and photoelectrochemical activity of tungsten copper co-sensitized TiO2 nanotube composite photoanodes. AB - Tungsten-copper co-sensitized TiO2 nanotube films on titanium substrate, used as photoanodes in photoelectrochemical (PEC) water splitting to produce hydrogen, have been synthesized via anodization and chemical bath deposition (CBD) methods. Field emission scanning electron microscopy (FE-SEM), energy dispersive X-ray spectroscopy (EDX) and X-ray diffraction (XRD) were used to study the morphology and elemental composition of the synthetic samples. UV-Vis diffuse reflection spectroscopy (UV-Vis DRS) was sued to investigate the optical features of the samples. The impact of copper and tungsten ratio on the photocatalytic behavior of co-sensitized TiO2 nanotube photoelectrodes in PEC water splitting has been investigated. High photocatalytic activity has been exhibited by the co sensitized TiO2 nanotube samples due to the synergistic effects of the copper and tungsten. Sample T4 had the highest photoelectrochemical activity compared with other samples. In addition, this sample exhibited outstanding photochemical stability even after four runs in the photocatalytic test. A simple method for the synthesis of high performance co-sensitized TiO2 nanotube photocatalysts for application in solar energy conversion has thus been proposed in this work. The advantages of these new photoanodes for practical applications are low cost, ease of synthesis, high activity in visible light and excellent stability. PMID- 29245075 TI - Evidence of coexisting microemulsion droplets in oil-in-water emulsions revealed by 2D DOSY 1H NMR. AB - Optimizing the macroscopic properties, shelf-life and stability of emulsion products requires a better understanding of the microstructural characteristics such as the type (nano, micro and macro) and the relative distribution of components (i.e., oil and surfactant) within the emulsion droplets. We used Diffusion-Ordered NMR Spectroscopy (DOSY NMR) to evaluate these characteristics in model oil-in-water emulsion containing Tween 80 and medium chain triglycerides (MCT). At low MCT concentrations, the solutions were transparent but from 1 to 5 wt% MCT, they became translucent then opaque. 1 wt% MCT was the upper boundary for the appearance of nanoemulsion phase. From the decays of the chemical shift signals of MCT and Tween 80, the DOSY results clearly demonstrate that the self diffusion coefficients (D) are dependent on oil concentration. Small microemulsion droplets of almost uniform size (d = 12-22 nm) coexist with two sets of large nanoemulsion (d < 200 nm) and emulsion (d > 200 nm) droplets. The large droplets increase significantly in size with increasing MCT. The most striking result is the clear evidence for the presence of microemulsion droplets of nearly uniform size in the aqueous phase from below to above the nanoemulsion transition concentration at 1 wt% MCT. PMID- 29245076 TI - Dentritic platinum-palladium/palladium core-shell nanocrystals/reduced graphene oxide: One-pot synthesis and excellent electrocatalytic performances. AB - Herein, we developed a facile one-pot co-reduction method to fabricate highly dentritic platinum-palladium/palladium core-shell nanocrystals on reduced graphene oxide (PtPd@Pd NCs/rGO), where poly-l-lysine (PLL) worked as the eco friendly structure director and stabilizer. The nanocomposite was mainly characterized by microscopic analysis, X-ray photoelectron spectroscopy (XPS), X ray diffraction (XRD), and thermogravimetric analysis (TGA), along with the discussion of the formation mechanism. The synthesized PtPd@Pd NCs/rGO have the enlarged electrochemically active surface area (ECSA) of 51.65 m2 g-1, showing 1.3 folds enhancement in the peak current density relative to commercial Pt/C (50 wt%) for glycerol oxidation reaction (GOR), coupled with the small Tafel slope of 28 mV dec-1 for hydrogen evolution reaction (HER). PMID- 29245077 TI - No overdiagnosis in the Norwegian Breast Cancer Screening Program estimated by combining record linkage and questionnaire information in the Norwegian Women and Cancer study. AB - BACKGROUND: The Norwegian Breast Cancer Screening Program (NBCSP) was implemented across the country in 2005 and has been criticised for potential 'overdiagnosis', i.e. a breast cancer diagnosis that otherwise would not have been detected or treated in a woman's lifetime. We aimed to estimate overdiagnosis in the NBCSP based on the Norwegian Women and Cancer (NOWAC) study using both questionnaire information and record linkage information from NBCSP. METHOD: For 124,978 women aged 49-79 years from the NOWAC study, information on screened women could be cross-validated from the NBCSP database. Based on information from the NOWAC questionnaire, unscreened women were further divided into those who had mammograms taken only outside the NBCSP and those who had never had taken a mammogram. Breast cancers diagnosed in 2005-2013 were identified through linkage to the Cancer Registry of Norway; in situ or DCIS 417; invasive 2845; combined 3262. Cumulative incidence rates (CIRs) for ages 49-79 years of breast cancer were compared using the log-rank test. RESULTS: After exclusion of women with a family history of breast cancer, screened women had a CIR of 9.7% for combined breast cancer, non-significantly lower compared with unscreened women. Screened women had a 1.1% increased CIR or 13.0% increased relative risk of breast cancer diagnosis (significant) compared with women who had never had a mammogram, but for invasive breast cancer alone the difference was reduced to -0.2% (95% CI: 9.1; 8.8). Invasive breast cancers were significantly smaller (<2.5 cm) in screened versus unscreened women. There was a borderline significant decrease in lymph node positive cancer among screened (p = 0.06). CONCLUSION: The findings of no significant overdiagnosis combined with smaller tumours and less lymph node metastases suggest that the prevailing view of overdiagnosis in the NBCSP should be challenged. PMID- 29245078 TI - Analysis of NRAS gain in 657 patients with melanoma and evaluation of its sensitivity to a MEK inhibitor. AB - BACKGROUND: Neuroblastoma rat-sarcoma (NRAS) mutations have been described in Chinese patients with melanoma. However, the status and the clinical significance of NRAS gain have not been investigated on a large scale. METHODS: A total of 657 melanoma samples were included in the study. NRAS copy number was examined using the QuantiGene Plex DNA assay. The sensitivities of cell lines and patient derived xenograft (PDX) models containing NRAS gain to a MAP/ERK kinase (MEK) inhibitor (binimetinib) were also evaluated. RESULTS: The overall incidence of NRAS gain was 14.0% (92 of 657). Incidence of NRAS gain in acral, mucosal, chronic sun-induced damage (CSD) and non-CSD melanomas was 12.2%, 15.8%, 9.5% and 19.4%, respectively. NRAS gain was mutually exclusive to NRAS mutations (P = 0.036). The median survival time for melanoma patients with NRAS gain was significantly shorter than that for patients with normal NRAS copy number (P = 0.006). For patients containing NRAS gain, the median survival time for higher copy number (>4 copies) was significantly shorter than those with lower copy number (2-4 copies; P = 0.002). The MEK inhibitor (binimetinib) inhibited the proliferation of melanoma cells and the tumour growth of PDX models with NRAS gain. CONCLUSIONS: NRAS gain is frequent in patients with melanoma and may predict a poor prognosis of melanoma. The melanoma cells and PDX models containing NRAS gain are sensitive to MEK inhibitor (binimetinib), indicating that NRAS gain might be a new therapeutic target for melanoma. PMID- 29245080 TI - Broadband 19F TOCSY using BURBOP-based spin lock. AB - A train of BURBOP universal rotation pulses has been used to generate a spin lock sufficient to observe TOCSY correlations over a 46 kHz 19F spectral window (i.e. 122 ppm on a 9.4 T spectrometer). This spin lock requires lower RF field (gammaB1 = 15 kHz), and was employed over a wider spectral window, than previously reported DIPSI-2 spin locks. The BURBOP-based spin lock was effected for 80-160 ms periods with a 2% duty cycle without evidence of harm to the RF coil of the probehead. Spectral separation and full set of correlations were obtained for a mixture of perfluorocarbons. PMID- 29245079 TI - What technologies do people engage with while driving and why? AB - This paper presents the findings of a semi-structured interview study that was conducted to identify drivers' self-reported likelihood of engaging with technologies that are now commonly found in modern automobiles. Previous research has focused on the effect these technological tasks have on driving performance, but there has been less focus on how, why and when drivers choose to engage with them. As distraction remains a significant contributor to road accidents, an understanding of why it occurs will give important insights into how it can be prevented. A semi-structured interview schedule was developed to allow drivers to discuss the factors that influence their decision to engage with a variety of different technologies. The methodology facilitated both quantitative ratings of the drivers' likelihood of engaging in a variety of tasks and qualitative insights into why. Age and gender had some influence on the propensity to engage, in line with other findings in the literature, as did road type and task type. The reasons drivers gave for why they engage with potentially distracting tasks inform recommendations for preventing distraction related accidents from the increasingly prevalent sources of technologies available to drivers. PMID- 29245081 TI - Safety in stigmatizing? Instrumental stigma beliefs and protective sexual behavior in Sub-Saharan Africa. AB - How are people's expression of HIV stigma beliefs connected to their own personal decisions concerning safe sexual practices? Does this relationship vary across countries and by the national context in which people reside? To answer these questions, we develop and test individual, contextual, and cross-level interactional hypotheses of the impact of instrumental HIV stigma attitudes on several measures of protective sexual behavior. Using Demographic and Health Survey data from 467,656 unpartnered individuals across 34 sub-Saharan African countries, we first find that counterintuitively, conservative HIV stigma attitudes are associated with lower likelihoods of participating in all types of protective sexual behaviors. Second, this negative relationship is most pronounced in the Southern and Eastern regions of Africa, where HIV prevalence is highest. Together, these findings suggest that stigma beliefs can shape private behaviors in counterintuitive yet important ways that have profound implications for current epidemiological and public health approaches to slowing the spread of HIV. PMID- 29245082 TI - Adolescent mental health and behavioural problems, and intergenerational social mobility: A decomposition of health selection effects. AB - According to the health selection hypothesis, poor mental health and behavioural problems in adolescence limit socioeconomic attainment. But to what extent is health selection driven by prior social causation? This paper quantifies the extent to which health selection - here, restricted or downward intergenerational social class mobility due to poor mental health or behavioural problems - can be attributed to the influence of modifiable childhood risk factors. The UK National Child Development Study provides measures of socioeconomic deprivation and childhood adversities, as well as multiple-informant ratings of adolescents' mental health and behavioural problems, for which confirmatory factor analysis supports a three-factor model. Decomposition analysis is used to robustly assess the extent of attenuation of selection effects when conditioning on the childhood environment. Conduct problems, hyperactivity, and to a lesser extent emotional symptoms at age 16 are associated with individuals' chances of achieving (un)desirable mobility outcomes. When prior childhood risk factors are taken into account, the association of conduct problems with mobility is attenuated by around 50%, indicating a substantial role for confounding and earlier processes of social causation in the generation of this health selection effect. Further analyses indicate that this attenuation is greater for those from the most disadvantaged backgrounds and is mostly driven by the inclusion of indicators of generalised disadvantage such as crowded housing and low income. On the other hand, the effects of emotional symptoms and hyperactivity on mobility outcomes are not significantly accounted for by childhood risk factors. This study adds to the health inequalities literature by interrogating the empirical validity of the usual interpretation of health selection effects as indicating the causal priority of the onset of poor mental health. PMID- 29245083 TI - Concordance between the Wada test and neuroimaging lateralization: Influence of imaging modality (fMRI and MEG) and patient experience. AB - The Wada test remains the traditional test for lateralizing language and memory function prior to epilepsy surgery. Functional imaging, particularly functional MRI (fMRI), has made progress in the language domain, but less so in the memory domain. Magnetoencephalography (MEG) has received less research attention, but shows promise, particularly for language lateralization. We recruited a consecutive sample of 19 patients with epilepsy who had completed presurgical work-up, including the Wada test, and compared fMRI (memory) and MEG (language and memory) with Wada test results. The main research question was the concordance between Wada and these two imaging techniques as preepilepsy surgery investigations. We were also interested in the acceptability of the three techniques to patients. Concordance rates (N=16) were nonsignificant (Cohen's Kappa) between fMRI and Wada test (memory) and between MEG and Wada test (memory and language). The Wada test was a well-established protocol used at several epilepsy surgery centers in the UK. Patients generally found the Wada test an odd, but not aversive procedure. Sixteen (84%) patients who were scanned reported some level of obtundation in MEG. We present these discordant findings in support of the position that functional imaging and the Wada test are distinctive procedures, with little in the way of overlapping mechanisms, and that patient's experience should be taken into account when procedures are selected and offered to them. PMID- 29245084 TI - Application of analytical quality by design principles for the determination of alkyl p-toluenesulfonates impurities in Aprepitant by HPLC. Validation using total-error concept. AB - In the research presented we report the development of a simple and robust liquid chromatographic method for the quantification of two genotoxic alkyl sulphonate impurities (namely methyl p-toluenesulfonate and isopropyl p-toluenesulfonate) in Aprepitant API substances using the Analytical Quality by Design (AQbD) approach. Following the steps of AQbD protocol, the selected critical method attributes (CMAs) were the separation criterions between the critical peak pairs, the analysis time and the peak efficiencies of the analytes. The critical method parameters (CMPs) included the flow rate, the gradient slope and the acetonitrile content at the first step of the gradient elution program. Multivariate experimental designs namely Plackett-Burman and Box-Behnken designs were conducted sequentially for factor screening and optimization of the method parameters. The optimal separation conditions were estimated using the desirability function. The method was fully validated in the range of 10-200% of the target concentration limit of the analytes using the "total error" approach. Accuracy profiles - a graphical decision making tool - were constructed using the results of the validation procedures. The beta-expectation tolerance intervals did not exceed the acceptance criteria of+/-10%, meaning that 95% of future results will be included in the defined bias limits. The relative bias ranged between - 1.3-3.8% for both analytes, while the RSD values for repeatability and intermediate precision were less than 1.9% in all cases. The achieved limit of detection (LOD) and the limit of quantification (LOQ) were adequate for the specific purpose and found to be 0.02% (corresponding to 48MUgg-1 in sample) for both methyl and isopropyl p-toluenesulfonate. As proof-of-concept, the validated method was successfully applied in the analysis of several Aprepitant batches indicating that this methodology could be used for routine quality control analyses. PMID- 29245085 TI - Excretion of metabolites of the synthetic cannabinoid JWH-018 in urine after controlled inhalation. AB - Each year, synthetic cannabinoids are occurring in high numbers on the illicit drug market but data obtained after controlled application are rare. The present study on pharmacokinetics in urine is part of a pilot study on adverse effects of JWH-018, which is one of the oldest and best known synthetic cannabinoids. Six subjects inhaled smoke from 2 and 3mg JWH-018. The drug and ten potential metabolites were analyzed in urine samples collected during 12h after inhalation by liquid chromatography-mass spectrometry (LC-MS/MS) without and with conjugate cleavage. The parent compound was not detectable, but 13 of its metabolites, all of which were conjugated. Concentrations of the predominant metabolite, JWH-018 pentanoic acid, were less than 5ng/ml, but in two subjects it was still detected up to 4 weeks after ingestion. Other major metabolites were 5- and 4-HOpentyl-JWH 018, JWH-073 butanoic acid and a hypothetically dihydroxylated and dehydrogenated metabolite of JWH-018. Occasionally, further hydroxylated metabolites were found. Generally, hydroxylated metabolites were detected in concentrations lower than 1ng/ml already 10h after inhalation. All concentrations were much lower than reported for urine samples of authentic JWH-018 users. The formation of the metabolite JWH-018 pentanoic acid was found to be slightly delayed, but its rather high concentrations and detection over several weeks after single dosing makes it a useful target for urine analysis. The different excretion of carboxylic acid and hydroxylated metabolites may aid in evaluation of time of use. PMID- 29245086 TI - Liquid chromatography-tandem mass spectrometric assay for the quantitation of the novel radiation protective agent and radiation mitigator JP4-039 in murine plasma. AB - JP4-039 radio-protects prior to, and radio-mitigates after ionizing radiation by neutralizing reactive oxygen species. We developed and validated an LC-MS/MS assay for the quantitation of JP4-039 in murine plasma. Methanol protein precipitation of 50MUL plasma was followed by isocratic reverse phase chromatography for a 6min run time, and electrospray positive mode ionization mass spectrometric detection. The plasma assay was linear from 1 to 1000ng/mL with appropriate accuracy (97.1-107.6%) and precision (3.7-12.5%CV), and fulfilled FDA guidance criteria. Recovery was 77.2-136.1% with moderate ionization enhancement (10.9-39.5%). Plasma freeze-thaw stability (98.8-104.2%), stability for 13.5 months at -80 degrees C (93.1-105.6%), and stability for 4h at room temperature (94.2-97.6%) were all acceptable. Limited cross-validation to tissue homogenates suggested that these could also be analyzed for JP4-039 accurately. This assay has been directly applied to determine the pharmacokinetics of JP4-039 in C57BL/6 male mice after IV administration of 20mg/kg JP4-039 and will be extended to other studies of this agent. PMID- 29245087 TI - Genotyping of common EGFR mutations in lung cancer patients by electrochemical biosensor. AB - In this study, we constructed a sandwich-type biosensor to identify six common types of mutations in exon 19 of the epidermal growth factor receptor (EGFR) gene, and tested them using tissue samples from patients with non-small cell lung carcinomas. Considering the characteristics that different locations of non complementary in DNA probes resulting in different hybridization efficiency, we investigated the design of DNA capture probes with varying non-complementary sequence locations in an effort to optimize the selectivity of the biosensor. Our results revealed that non-complementary sequences located in the middle of a capture probe allow excellent hybridization specificity and achieve the strongest discrimination between mutations that differ by a single nucleotide. Based on this finding, we designed capture probes to identify six common types of EGFR mutations (del1-del6) successfully. Further, we proposed a grouped testing approach to reduce workload and rapidly identify mutation types. Subsequently, EGFR exon 19 hotspot deletion types in real samples were discriminated by this method. RT-PCR products from lung cancer patients were digested with lambda-Exo and analyzed using electrochemical biosensors. The results of our grouped testing approach with optimized biosensors were consistent with that of direct sequencing, suggesting that our proposed protocol can be excellent candidate for genotyping of EGFR mutations in lung cancer patients. PMID- 29245088 TI - "Ghost peak" of clofazimine: A solution degradation product of clofazimine via nucleophilic substitution by nitrite leaching from certain glass HPLC vials. AB - Analytical solutions of clofazimine drug substance stored in glass HPLC vials were found to undergo degradation at room temperature occasionally. At the time of each sample preparation, it was unpredictable if a particular solution would undergo such solution degradation. Once the degradation peak was observed in a particular vial, typically within 24h, it would keep growing until reaching a total yield of approximately 2%. By using a strategy that combines LC-PDA/UV-MSn with mechanism-based stress studies, followed by preparative HPLC separation and subsequent structure characterization by 1D and 2D NMR, the unknown peak was identified as a clofazimine nitrite ester. It apparently results from nucleophilic substitution of clofazimine by residual nitrite leaching out of the inner surface of the glass HPLC vials used in the sample preparation. Overall, the percentage of the sample solutions that underwent solution degradation is approximately ~10% to 15%, when the sample solutions were stored in glass HPLC vials at room temperature. Over the period of the analytical method development, it was found that the occurrence of the degradation can be suppressed when the solutions were stored under refrigerated condition (2 - 8 degrees C) or when the samples were prepared in less acidic diluents. PMID- 29245089 TI - Metabolic analysis of Panax notoginseng saponins with gut microbiota-mediated biotransformation by HPLC-DAD-Q-TOF-MS/MS. AB - Saponins such as notoginsenosides and ginsenosides from Panax notoginseng are responsible for the herb's clinical applications. Unfortunately, there is poor oral bioavailability of saponins. However, gut microbiota can transform saponins to yield the metabolites that are potential bioactive substances. In this study, we aimed to characterize the metabolic profiles of P. notoginseng saponins (PNS) by incubating them with human gut microbiota. The notoginsenosides, ginsenosides and related metabolites were separated and identified using a highly sensitive and selective high-performance liquid chromatography coupled with diode array detection/quadrupole tandem time-of-flight mass spectrometry (HPLC-DAD-Q-TOF MS/MS). The results showed that the most abundant metabolites, ginsenoside F1, protopanaxatriol (PPT), ginsenoside Rh2, ginsenoside compound K (GCK) and protopanaxadiol (PPD), were reported to possess stronger related pharmacological activities when compared with parent ginsenosides. These metabolites were identified among a total of 45 other metabolites. Furthermore, it was elucidated that deglycosylation is the main metabolic pathway which saponins are split off from glycosyl moieties by the enzymes secreted from gut microbiota. The gut microbiota may play a significant role in mediating the bioactivities of PNS. PMID- 29245090 TI - Psychological distress and risk for suicidal behavior among university students in contemporary China. AB - BACKGROUND: Psychological distress and suicidal behavior are important mental health problems among university students and warrant research to inform strategies for effective prevention in this young population. The present study aimed to assess psychological distress and suicidal behavior and to unravel their associations among university students. METHODS: A total of 5972 undergraduate students, randomly selected from six universities in central China, comprised the sample. The Chinese version of the Symptom Checklist-90-revised (SCL-90-R) was used to assess various psychological symptoms. Logistic regression analysis was used to examine the relationship between psychological distress and risk for suicidal behavior. RESULTS: 40.7% of the university students reported positive in a least one of the 9 psychological symptom dimensions assessed by the SCL-90-R. 7.6% of the students reported suicidal behavior in the previous twelve months. The risk of suicidal behavior was significantly associated with psychological symptoms of all types, but there were notable differences by sex. For male students, depression and phobic anxiety increased the risk of suicidal behavior. Meanwhile, depression and obsessive-compulsiveness were positively associated with suicidal behavior in female students. Furthermore, increasing risk of suicidal behavior was associated with increasing positive symptom total (PST) score and a statistically significant trend was observed. LIMITATIONS: Data collected from a cross-sectional survey does not allow any examination of causal inference. CONCLUSIONS: Psychological distress and suicidal behavior were both common among university students; and psychological distress was highly associated with suicidal behavior. The findings underscore the importance of mental health care for university students. PMID- 29245091 TI - Specificity in mediated pathways by anxiety symptoms linking adolescent stress profiles to depressive symptoms: Results of a moderated mediation approach. AB - BACKGROUND: We investigated the specificity in mediated pathways that separately link specific stress dimensions through anxiety to depressive symptoms and the protective utility of resilience. Thus, this study goes beyond lumping together potential mediating and moderating processes that can explain the relations between stress and (symptoms of) psychopathology and the buffering effect of resilience. METHODS: Ghanaian adolescents between 13 and 17 years (female = 285; male = 244) completed the Adolescent Stress Questionnaire (ASQ), Spielberger State Anxiety Inventory (STAI), Short Mood Feeling Questionnaire (SMFQ) and the Resilience Scale for Adolescents (READ). Independent samples t-test, multivariate analysis of covariance with follow-up tests and moderated mediation analyses were performed. RESULTS: Evidences were found for specificity in the associations between dimensions of adolescent stressors and depressive symptoms independent of transient anxiety. Transient anxiety partly accounted for the indirect effects of eight stress dimensions on depressive symptoms. Except stress of school attendance and school/leisure conflict, resilience moderated the indirect effects of specific stress dimensions on depressive symptoms. Results suggested differences in how Ghanaian adolescents view the various stress dimensions, and mediated pathways associated with anxiety and depressive symptoms. LIMITATIONS: Use of cross-sectional data does not show causal process and temporal changes over time. CONCLUSIONS: Findings support and clarify the specificity in the interrelations and mediated pathways among dimensions of adolescent stress, transient anxiety, and depressive symptoms. Conditional process analyses shows that resilience does not only buffer direct, but also indirect psychological adversities. Interventions for good mental health may focus on low resilience subgroups in specific stress dimensions while minimizing transient anxiety. PMID- 29245092 TI - Predictors of hospitalization length of stay among re-admitted treatment resistant Bipolar Disorder inpatients. AB - BACKGROUND: Hospitalization accounts for significant health care resource utilization for treatment-resistant Bipolar Disorder (BD), especially among frequent users of acute inpatient psychiatric units. Appraisal of the clinical features and predictive role of selected variables is therefore crucial in such population, representing the aim of the present research. METHODS: A hundred and nineteen BD inpatients with an established history of pharmacological treatment resistance for either mania or bipolar depression were classified as long hospitalization cases (LOS+) and their controls and compared against each other for a number of demographic, clinical, and psychopathological features. RESULTS: Overall, female sex, current second-generation atypical antipsychotic (SGA)/mood stabilizer other than lithium as well as antidepressant treatment at the admission occurred statistically more frequently among LOS+ cases, concordant with higher scores at the Hamilton scales for depression and anxiety. Lithium utilization at the time of hospitalization did not differ between cases and controls (LOS-, n = 81/119), as predominant affective temperament and other psychopathological rating did not. Overall, the time of admission, use of SGA, anticonvulsant (other than lithium), antidepressant, lifetime alcohol dependence, and BD Type (-I or -II), but not current mood polarity at the time of hospitalization, correctly predicted LOS+ grouping 68.2% of the times: Exp(B) = 3.151, p042. LIMITATIONS: Post-hoc, cross-sectional study, relatively small sample size, recall and selection bias on some diagnoses. CONCLUSIONS: Overall, LOS+ treatment-resistant BD inpatients characterize for higher severity and greater pharmaco-utilization use, which warrants replication studies to include additional predictors to shed further light on the matter. PMID- 29245093 TI - Neurocognitive functioning in first-episode Bipolar Disorder: Relationship with functional status. AB - BACKGROUND: The aim of this study was to assess if an association between neurocognitive deficits and psychosocial functioning exists in first-episode BD patients. METHODS: Twenty-five euthymic first-episode BD patients and thirty seven healthy controls were recruited. History of suicide attempts, psychiatric comorbidities, pharmacological exposure, and previous depressive episodes were investigated. Performances on neurocognitive domains (verbal memory, attention, processing speed, and executive functions) as well as a measure of psychosocial functioning were used as outcomes. RESULTS: First-episode BD patients showed medium-to-large size deficits on measures of attention, processing speed, and executive functions. A significant association between verbal memory and psychosocial functioning at the moment of BD diagnosis was detected (beta coefficient -3.9, IC 95% -6.7 to -1.2, p < 0.01). CONCLUSIONS: A relationship between cognitive performance at the moment of BD diagnosis and psychosocial functioning was detected. Possible therapeutic implications of this finding are discussed. PMID- 29245094 TI - Concomitant rhomboid-shaped tibiae and fibulae, finger-like projections, and orthopedic management in a new variant of nievergelt syndrome: A case report. AB - INTRODUCTION: The rare Nievergelt syndrome (NS) is the most severe form of mesomelic dysplasia and is characterized by disproportionate shortness of the limbs. The aim of this case report was to describe the clinical and radiological features of a rare case of NS. PRESENTATION OF CASE: Here we describe a female patient originally presenting with bilateral hand, lower leg, and foot deformities at the age of 10 years old. In addition to the characteristic features of NS, this patient presented with finger-like projections on her heels, bilateral hand anomalies, and atypical facial features. She underwent concomitant bilateral tibial lengthening and deformity correction using external fixators due to severe bilateral lower leg deformities with shortness. At 10 years of age, this patient was able to walk independently with significant improvement in her ambulation. DISCUSSION: There is a clear gap in the literature regarding the orthopedic management of mesomelic limb deformities due to NS. No studies have been designed to illustrate surgical planning in the management of orthopedic deformities in this rare syndrome. CONCLUSION: Limb lengthening and deformity correction using an external fixator can be considered as a salvage method or alternative to amputation for patients with severe mesomelic limb deformities due to NS. PMID- 29245095 TI - A synchronous incidence of eccrine porocarcinoma of the forearm and facial squamous cell carcinoma: A case report. AB - INTRODUCTION: Cutaneous appendageal tumor can differentiate towards or arise from either pilosebaceous apparatus or the eccrine sweat glands. Appendageal tumors are relatively rare, their clinical appearance is non-specific, and the vast majority are not diagnosed until after excision. Eccrine porocarcinoma (EP), also known as malignant eccrine poroma is a rare adnexal tumor arising from the intraepithelial ductal parts of the sweat gland. CASE PRESENTATION: We presented a 65-year-old, Asian, female with medical co-morbids, who came with both a facial squamous cell carcinoma and a long-standing lesion over her left forearm. Histopathological finding of the left forearm demonstrated eccrine porocarcinoma. CONCLUSION: Mohs micrographic surgery is the mainstay treatment of cutaneous carcinoma. It is important to rule out associated syndromes in patient who present with multiple cutaneous appendageal tumors. PMID- 29245096 TI - Pre- and post-operative evaluation of pincer-type femoroacetabular impingement during squat using image-matching techniques: A case report. AB - INTRODUCTION: Although combined evaluation of hip joint kinematics and bone morphology is necessary for accurate assessment of femoroacetabular impingement (FAI), there are no report which evaluated hip kinematics of pincer-type FAI. PRESENTATION OF CASE: The pre- and postoperative hip kinematics of a 46-year-old man, with a pincer-type FAI during squat were evaluated using image-matching techniques and the rim-neck distance was measured. Preoperative simulation of squatting was also performed using patient's bone models and healthy subject's kinematics data to detect the overlapping lesion between the acetabulum and the femur. Post-acetabuloplasty, right coxalgia during squat disappeared, and the Harris Hip Score improved from 79 to 92 at one year after surgery. Posterior pelvic tilt, femoral and hip flexion angle changed from 24.0 degrees , 101.1 degrees , and 70.8 degrees to 23.3 degrees , 92.6 degrees , and 63.3 degrees , respectively. The minimum rim-neck distance at maximum hip flexion improved from 1.8mm to 7.3mm. DISCUSSION: We could evaluate both of hip kinematics and morphology with image-matching techniques, and could visualize the clearance between the femoral head-neck junction and the acetabular rim. CONCLUSION: Image matching techniques were clinically useful to assist surgeons in detecting the location of the impingement and confirming resection of the pincer lesion post operatively. PMID- 29245097 TI - Inverted V-shaped high tibial osteotomy for severe tibia vara associated with Turner syndrome: A case report and review of literature. AB - INTRODUCTION: Severe cases of genu varum represent a major challenge in obtaining normal configuration of the proximal tibia and overall limb alignment. PRESENTATION OF CASE: We performed inverted V-shaped high tibial osteotomy (HTO) by using a locking plate for recurrent severe bilateral tibia vara in a 15-year old female patient with Turner syndrome. Preoperative medial proximal tibial angle (MPTA) and standing femorotibial angle (FTA) of the right/left legs were 67 degrees /69 degrees and 197 degrees /203 degrees , respectively. In order to obtain overall neutral alignment, the correction angle in the right/left knees was required to be 23 degrees /32 degrees . Preoperative planning demonstrated that inverted V-shaped HTO could provide sufficient correction angle with large bone stock and wide bony contact. A postoperative full-standing radiograph showed that the mechanical axes passed through the center of right/left knees with 87 degrees /88 degrees of MPTA. DISCUSSION: Inverted V-shaped HTO has advantages, as it requires a smaller amount of bone resection and smaller opening gap compared to the closing-wedge and opening-wedge osteotomies. CONCLUSION: Inverted V-shaped HTO can be a useful surgical method to treat severe tibia vara in order to obtain adequate configuration of the proximal tibia and overall limb alignment. PMID- 29245098 TI - Pit Bull attack causing limb threatening vascular trauma -A case series. AB - INTRODUCTION: Non-fatal human dog bites are commonplace amongst animal attacks on human beings and these present with mainly skin and soft tissue injuries. However, they can also present with life threatening head and neck injuries, massive soft tissue trauma, as well as combined orthopedic and vascular extremity injuries where a high possibility of limb loss exists. PRESENTATION OF CASES: We present two adult dog bite victims with multiple bites inflicted by large canines identified as Pit-Bull Terriers. They were presented with deep lacerations to the axillary area resulting in limb ischemia and loss of upper limb pulses. The right axillary artery was crushed in both patients whilst the axillary vein was lacerated in one. The vessels were repaired; the wounds debrided and both limbs were salvaged. DISCUSSION: Canine attacks by Pit Bull Terriers and Rottweiler's can occur at any age and in any anatomical area of the body particularly the limbs. Injuries involving the extremities presenting with no pulses or pulsatile bleeding demand an urgent exploration as any undue delay is intolerable especially if there are bony injuries like fractures or fracture/dislocation. All patients with complex neurovascular injuries should be managed by a multidisciplinary team for an optimal outcome. CONCLUSION: Attacks by Pit Bull Terriers are more likely to cause severe morbidity than other breeds of dogs. Immediate surgical exploration is required to prevent catastrophic outcomes, especially limb loss. Stronger animal control laws, public education and responsible dog ownership may reduce deaths from these canines. PMID- 29245099 TI - Total bilateral TMJ reconstruction for pain and dysfunction: Case report. AB - INTRODUCTION: Temporomandibular disorders encompass a set of clinical conditions that affect the temporomandibular joint, the masticatory muscles and the associated tissues. Many therapeutic alternatives can be considered, being divided into non-invasive, minimally invasive and invasive interventions. This work aims to report a case of inflammatory joint pain and dysfunction treated with bilateral TMJ full reconstruction with alloplastic prosthesis stock. CASE REPORT: Patient D.J.S.S., female, 41 years old, hypertensive, for six years had constant pain in TMJ bilaterally, with limitation of mouth opening, with a clinical signs of joint disc displacement without reduction. Initially treated only by conservative approaches. Without improvement, arthrocentesis of the TMJ was performed. The symptoms do not regress, leading the patient to bilateral discopexy procedure. We opted for the alloplastic substitution of the temporomandibular joint with prostheses of stock in both joints through an established protocol. DISCUSSION: The main objective of the reconstruction of the temporomandibular joint in cases of joint bone degeneration is the restoration of form and function, considering the reduction of pain as a secondary result. Alloplastic replacement of TMJ can be considered as an alternative therapy to improve the quality of life of a small group of patients showing signs and symptoms of TMD as a reduction of maximum mouth opening, pain, etc. CONCLUSION: The use of total joint prostheses has been configured as a good therapeutic alternative for severe conditions of TMJ that do not respond to conservative treatments. However, further studies are needed to demonstrate whether these results are long term. PMID- 29245100 TI - Student motivation, stressors, and intent to leave nursing doctoral study: A national study using path analysis. AB - BACKGROUND: The demand for doctorally prepared nurses worldwide is higher than ever. Universities have responded with increased numbers of DNP and Ph.D. in Nursing programs. There are more doctoral nursing students than ever before yet they remain one of the least studied student populations. This is concerning given the high attrition rates reported in doctoral programs. The few studies that do exist are typically qualitative and exploratory in nature. OBJECTIVES: The aim of this national study of Ph.D. and DNP students was to examine how the effects of environmental stressors predict the students' intent to leave their current program of doctoral study. DESIGN: A descriptive survey design was utilized for the study. SETTINGS: Participation requests were sent by email to deans/directors of all Ph.D. and DNP programs across the United States, with the request to forward to all currently enrolled students. PARTICIPANTS: Eight hundred and thirty-five (n=835) Ph.D. and DNP participants responded to this survey. METHODS: The survey was analyzed utilizing path analysis. RESULTS: Findings of the path analysis indicate that two types of stress significantly predicted students' intention to leave. First, stressors related to program issues, primarily relationships between student and faculty/advisor, significantly predict intent to leave. As program stressors rise, so does intent to leave. The other significant factor was related to support issues, specifically support from family/friends. This inverse relationship indicated as family support declines, intent to leave rises. CONCLUSIONS: It is impossible to remove all stressors from students' lives during their doctoral studies. A better understanding of the environmental stressors that affect them offers the potential for nursing programs looking to incorporate adequate resources and support which will help minimize attrition and promote persistence of their doctoral students. Specific recommendations are provided that may assist programs looking to decrease doctoral nursing student attrition. PMID- 29245101 TI - Nursing's role in leading palliative care: A call to action. AB - Palliative care aims to alleviate the suffering of patients with life-limiting illness while promoting their quality of life. In this call to action commentary, we review the ways in which nursing care and palliative care align, describe barriers to nurses engaging in palliative care, and provide specific recommendations for nurses involved in education, training, and administration to assist nurses at all levels of practice to engage in palliative care for their patients. PMID- 29245102 TI - Random responses inflate statistical estimates in heavily skewed addictions data. AB - BACKGROUND: Some respondents may respond at random to self-report surveys, rather than responding conscientiously (Meade and Craig, 2012), and this has only recently come to the attention of researchers in the addictions field (Godinho et al., 2016). Almost no research in the published addictions literature has reported screening for random responses. We illustrate how random responses can bias statistical estimates using simulated and real data, and how this is especially problematic in skewed data, as is common with substance use outcomes. METHOD: We first tested the effects of varying amounts and types of random responses on covariance-based statistical estimates in distributions with varying amounts of skew. We replicated these findings in correlations from a real dataset (Add Health) by replacing varying amounts of real data with simulated random responses. RESULTS: Skew and the proportion of random responses influenced the amount and direction of bias. When the data were not skewed, uniformly random responses deflated estimates, while long-string random responses inflated estimates. As the distributions became more skewed, all types of random responses began to inflate estimates, even at very small proportions. We observed similar effects in the Add Health data. CONCLUSIONS: Failing to screen for random responses in survey data produces biased statistical estimates, and data with only 2.5% random responses can inflate covariance-based estimates (i.e., correlations, Cronbach's alpha, regression coefficients, factor loadings, etc.) when data are heavily skewed. Screening for random responses can substantially improve data quality, reliability and validity. PMID- 29245104 TI - Who goes first? Understanding hepatitis C risk among injecting networks in the prison setting. AB - BACKGROUND: Hepatitis C (HCV) is a blood-borne virus that is most commonly transmitted through shared injecting equipment. Due to the criminalisation of injecting drug use, HCV is highly prevalent among those incarcerated. Using a risk environment framework, this qualitative study sought to understand the role of HCV risk within injecting networks in the prison setting. METHODS: Thirty-two adult prisoners (n=24 men; n=8 women) with a history of injecting drug use participated in this qualitative sub-study. Participants were recruited across four correctional centres. RESULTS: Social, economic, and environmental risk factors contributed to injecting practices within prison. Commonly, the person supplying the drugs injected first, with the person who owns the injecting equipment going next. HCV did not regularly factor into determining order of injection within networks (i.e., first, second, third), although it was reported that some prisoners claimed not to have HCV in efforts to "jump the queue". CONCLUSION: Social, economic, and environmental risk factors contribute to negotiation of injecting order among people who inject drugs in prison. Risk of HCV exposure rarely influenced the injecting order. Harm reduction strategies should consider the social factors influencing injecting drug use in the prison setting especially to optimise the population benefits of the roll-out of highly effective HCV treatments. PMID- 29245103 TI - Long-acting intramuscular naltrexone for opioid use disorder: Utilization and association with multi-morbidity nationally in the Veterans Health Administration. AB - BACKGROUND: Long acting intramuscular (IM) naltrexone is an effective treatment for opioid use disorder (OUD), but rates and correlates of its use have not been studied. METHODS: National administrative from the Veterans Health Administration (VHA) from Fiscal Year 2012 identified only 16 VHA facilities that prescribed IM naltrexone to 5 or more veterans diagnosed with OUD. Data from these facilities were used to identify sociodemographic, diagnostic, and service use characteristics, including use of psychotropic medication, that were characteristic of veterans who filled prescriptions for IM naltrexone. This was in comparison to users of opiate agonist treatments (methadone or buprenorphine) or veterans with no pharmacologic treatment for OUD. Comparisons were made using both bi-variate analyses and multivariable logistic regression. RESULTS: Only 179 of 16,402 veterans with OUD (1%) at these 16 facilities filled a prescription for IM naltrexone and only 256 of 99,394 (0.26%) nationally. These veterans were characterized by past homelessness, co-morbid alcohol use disorder, multiple psychiatric disorders, and a greater likelihood of psychiatric hospitalization, as well as mental health outpatient and antidepressant medication use. CONCLUSIONS: IM naltrexone is rarely used for OUD and is primarily used for patients with multiple co-morbidities, especially alcohol use disorder and serious mental illness. The use of this treatment illustrates many of the principles identified by the emerging focus on multi-morbidity as a critical feature of clinical practice. PMID- 29245105 TI - Autoimmune encephalitis with GABAA receptor antibodies in a 10-year-old girl. AB - Recent studies have indicated that some cases of nonparaneoplastic autoimmune encephalitis in children can be caused by a systemic autoimmune disorder that generates autoantibodies to cell membrane proteins. We describe the clinical features of a 10-year-old girl with autoimmune encephalitis with autoantibodies against the GABAA receptor in whom type 1 diabetes mellitus developed during the course of the disease. The diagnosis was based on the progressive course of disease, pleocytosis in the cerebrospinal fluid (CSF), inflammatory changes in the brain and autoantibodies against the GABAA receptor detected in serum (absent in CSF). The treatment of encephalitis included intravenous immunoglobulins, intravenous methylprednisolone, oral prednisolone, cycles of plasmapheresis; this led to temporary remission. Finally, rituximab was applied as a second-line therapy with positive results. PMID- 29245106 TI - Cerebral arterio-venous malformations in the paediatric population: Angiographic characteristics, multimodal treatment strategies and outcome. AB - OBJECTIVES: Cerebral arterio-venous malformations (AVM) are considered congenital lesions, emerging as an important cause of haemorrhagic stroke in children. The potential influence of age on clinical presentation and angio-architecture have been analysed extensively in the last years. Yet, comparative studies comprising ascending age groups may be limited in their conclusions, especially when comparing young children and adults. It is the aim of this study to evaluate characteristic clinical and angiographic features of AVM within a paediatric subgroup and their correlation to age at presentation. PATIENTS AND METHODS: Between 1990-2015, 46 children harbouring AVMs were treated at our institution. Clinical presentation, radiological data, treatment strategies and outcome were evaluated retrospectively. RESULTS: Of 46 consecutive patients, 18 were male and 28 female patients. Mean age was 11.6+/-4.3years, ranging from 2 to 17 years. 35 patients (76%) presented with haemorrhage. Seizures were found in 6 patients (13%) and progressive or transient focal neurological deficits in 4 individuals (9%). There was one incidental patient, only. Mean age of children presenting with haemorrhage was significantly lower as compared to those without a history of intracranial bleeding (p=0.1). The size of the AVM was small (n=27, 59%), corresponding a grade I AVM in the majority of patients (N=28, 61%). 41 patients (89%) underwent treatment of their AVM by an interdisciplinary approach achieving complete elimination of the lesion in 34 patients (83%). 34 patients (83%) showed at least a favourable outcome (mRS<=2) at last follow-up. An excellent recovery (mRS 0-1) was noted in 28 patients (68%). CONCLUSION: From our data we suggest that patients' age impacts the clinical presentation. Particularly young children seem to bear a higher risk for haemorrhage from their AVM. Treatment of paediatric AVMs can be achieved safely in experienced hands with a high rate of complete elimination and good clinical outcome. PMID- 29245107 TI - Impacts on the seagrass, Zostera nigricaulis, from the herbicide Fusilade Forte(r) used in the management of Spartina anglica infestations. AB - The herbicide Fusilade Forte(r) (FF) is widely applied in agricultural weed management and in the management of the invasive saltmarsh grass, Spartina anglica (ricegrass or cordgrass). FF (active ingredient fluazifop-P acid, FPA) is selective for poaceous grasses. Its primary mode of action is inhibition of the acetyl coenzyme-A carboxylase (ACCase) specific to this taxonomic group, and its secondary mode is by promotion of oxidative stress. FF is applied to S. anglica infestations in the intertidal zone, in proximity to seagrass meadows. Despite the potential for vital seagrass ecosystems to be exposed to FF, there is limited knowledge of any potential impacts. We investigated impacts of FPA on the endemic Australian seagrass, Zostera nigricaulis, measuring ACCase activity and parameters that reflect oxidative stress: photosynthetic performance, lipid peroxidation and photosynthetic pigment content. Seagrass was exposed to FF (0.01 10mgL-1 FPA and a control) for 7d, followed by a 7-d recovery in uncontaminated seawater. An enzyme assay demonstrated that FPA <=10mgL-1 did not inhibit the activity of ACCase isolated from Z. nigricaulis, demonstrating that this seagrass is resistant to FF's primary mode of action. However, physiological impacts occurred following 7 days exposure to >=0.1mgL-1 FPA, including up to a 72% reduction in photosynthetic pigment concentration. After 7-d recovery, photosynthetic pigment content improved in treatment plants; however, treated plants exhibited higher levels of lipid peroxidation. This study demonstrates that while Z. nigricaulis is resistant to FF's primary mode of action, significant physiological impacts occur following 7 days exposure to >=0.1mgL-1 FPA. This study provides valuable information on the effects of FF on a non target species that can better inform approaches to Spartina management in coastal seagrass ecosystems. PMID- 29245108 TI - Learning and transfer of working memory gating policies. AB - knowledge about the tasks we encounter enables us to rapidly and flexibly adapt to novel task contexts. Previous research has focused primarily on abstract rules that leverage shared structure in stimulus-response (S-R) mappings as the basis of such task knowledge. Here we provide evidence that working memory (WM) gating policies - a type of control policy required for internal control of WM during a task - constitute a form of abstract task knowledge that can be transferred across contexts. In two experiments, we report specific evidence for the transfer of selective WM gating policies across changes of task context. We show that this transfer is not tied to shared structure in S-R mappings, but instead in the dynamic structure of the task. Collectively, our results highlight the importance of WM gating policies in particular, and control policies in general, as a key component of the task knowledge that supports flexible behavior and task generalization. PMID- 29245109 TI - Autosomal recessive hypercholesterolemia in Spain. AB - BACKGROUND AND AIMS: Autosomal recessive hypercholesterolemia (ARH) is a very rare disease, caused by mutations in LDL protein receptor adaptor 1 (LDLRAP1). It is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature cardiovascular disease. We aimed to characterize ARH in Spain. METHODS: Data were collected from the Dyslipidemia Registry of the Spanish Atherosclerosis Society. A literature search was performed up to June 2017, and all diagnostic genetic studies for familial hypercholesterolemia of Spain were reviewed. RESULTS: Seven patients with ARH were identified, 6 true homozygous and one compound heterozygous with a novel mutation: c.[863C>T];p.[Ser288Leu]. High genetic heterogeneity was found in this cohort. True homozygous subjects for LDLRAP1 have more severe phenotypes than the compound heterozygous patient, but similar to patients with homozygous familial hypercholesterolemia (HoFH). Cardiovascular disease was present in 14% of the ARH patients. LDL-C under treatment was above 185 mg/dl and the response to PCSK9 inhibitors was heterogeneous. Finally, the estimated prevalence in Spain is very low, with just 1 case per 6.5 million people. CONCLUSIONS: ARH is a very rare disease in Spain, showing high genetic heterogeneity, similarly high LDL-C concentrations, but lower incidence of ASCVD than HoFH. PMID- 29245110 TI - Uncovering the mysteries of inclusion: Empirical and methodological possibilities in participatory evaluation in an international context. AB - The inclusion of stakeholders in participatory evaluation in highly diverse, culturally complex settings remains a challenge, given issues of inequity, power, voice, capacity and skill. These challenges are well documented, but there is a relative absence of papers devoted to addressing them based on examples and evidence. In this paper, we report our review of 51 empirical studies of participatory evaluations conducted in the international domain, focusing on the methods of inclusion used in the evaluations. Our findings address "the who" (which stakeholders are included and which excluded), "the why" (rationales for participation) and "the how" (by what means and in what manner) of inclusion. We were struck by the scale of some development programs, geographically and in terms of the number of diverse program sponsors and stakeholders, and how this necessitated highly creative, innovative participatory techniques to ensure that anyone (and in some cases everyone) could have a voice in the process, regardless of location, language ability, privilege, power, gender, age or culture. PMID- 29245111 TI - Community-based rehabilitation offers cost-effective epilepsy treatment in rural Guinea-Bissau. AB - Treatment of epilepsy in low-income countries is a challenge considering the lack of resources, availability of antiepileptic drugs, and cultural beliefs. We used a community-based rehabilitation (CBR) service for the detection, monitoring, and treatment of epilepsy. A local network of trained community volunteers provided education, good quality antiepileptic drugs, and clinical follow-up for people with epilepsy (PWE). In a period of 2years, approximately 22,500 people were screened in central Guinea-Bissau, and 112 PWE were identified and registered. Monthly check-ups were offered to monitor treatment effect and increase compliance. Retrospective analysis on 81 records of patients under treatment in June 2016 showed a decrease of seizure frequency in 88.8% after treatment initiation and was maintained throughout the clinical follow-up of 15months. A conservative estimation of the treatment and monitoring of a single person with epilepsy revealed a daily cost of $0.73. Despite acknowledging epilepsy as a neglected condition by the World Health Organization (WHO), most PWE still lack appropriate treatment. Although CBR service has been suggested as efficient strategy to reduce the treatment gap, little information is available on the efficacy of the programs. Our experiences show that CBR service is a cost effective approach to monitor treatment and increase compliance in PWE. This experience may be of value for other resource-poor settings. PMID- 29245112 TI - Spectroscopic parameters, vibrational levels, transition dipole moments and transition probabilities of the 9 low-lying states of the NCl+ cation. AB - This work calculates the potential energy curves of 9 Lambda-S and 28Omega states of the NCl+ cation. The technique employed is the complete active space self consistent field method, which is followed by the internally contracted multireference configuration interaction approach with the Davidson correction. The Lambda-S states are X2Pi, 12Sigma+, 14Pi, 14Sigma+, 14Sigma-, 24Pi, 14Delta, 16Sigma+, and 16Pi, which are yielded from the first two dissociation channels of NCl+ cation. The Omega states are generated from these Lambda-S states. The 14Pi, 14Delta, 16Sigma+, and 16Pi states are inverted with the spin-orbit coupling effect included. The 14Sigma+, 16Sigma+, and 16Pi states are very weakly bound, whose well depths are only several-hundredcm-1. One avoided crossing of PECs occurs between the 12Sigma+ and 22Sigma+ states. To improve the quality of potential energy curves, core-valence correlation and scalar relativistic corrections are included. The potential energies are extrapolated to the complete basis set limit. The spectroscopic parameters and vibrational levels are calculated. The transition dipole moments are computed. The Franck-Condon factors, Einstein coefficients, and radiative lifetimes of many transitions are determined. The spectroscopic approaches are proposed for observing these states according to the transition probabilities. The spin-orbit coupling effect on the spectroscopic and vibrational properties is evaluated. The spectroscopic parameters, vibrational levels, transition dipole moments, as well as transition probabilities reported in this paper could be considered to be very reliable. PMID- 29245113 TI - The temporal relationship between activity of the pelvic floor muscles and motion of selected urogenital landmarks in healthy nulliparous women. AB - AIMS: The purpose of this study was to investigate the relationship between pelvic floor muscle (PFM) electromyographic (EMG) activation and urogenital landmark motion measured using 2D transperineal ultrasound (US) imaging. METHODS: Eight healthy, nulliparous women performed maximum voluntary PFM contractions while EMG and transperineal US images were acquired simultaneously. Changes in the levator plate length (LPL), bladder neck (BN) position and urethral position were determined by visual inspection. The relative timing of EMG onset and the onset of landmark motion, and the correlation coefficients between EMG activation and landmark motion were computed. Comparisons between the correlation coefficients and onset latencies of each landmark motion were made using one-way analysis of variance models. RESULTS: Despite generally good reliability metrics for the onset of EMG and the onset of landmark motion, the relative timing of EMG onset and the onset of landmark motion demonstrated no systematic patterns of activation onset. That said, the overall motion of the different urogenital landmarks throughout the MVC task was highly correlated with the PFM EMG data; correlation coefficients were generally good (>0.90) and highly significant (p < .001). The correlation between PFM EMG and LPL motion was significantly better than the correlation between PFM EMG and motion of the other landmarks. The relevance of one outlier is discussed. CONCLUSIONS: The motion of all urogenital landmarks seen on US imaging is highly correlated with PFM EMG activation during maximum voluntary PFM contractions and may therefore be of value in the context of biofeedback training to infer that PFM activation has occurred. The motion of the BN, however, may require more cautious interpretation than the reduction of LPL. The timing of the onset of urogenital landmark motion on transperineal US imaging does not precede nor follow the timing of PFM activation, while the high variance of relative onset timing makes the onset of landmark motion of questionable value when training or evaluating co-ordination or motor control. PMID- 29245114 TI - Subacromial impingement syndrome: An electromyographic study of shoulder girdle muscle fatigue. AB - Muscle fatigue affecting glenohumeral and/or scapular muscles is suggested as one of the contributing factors to the development of subacromial impingement syndrome (SAIS). Nonetheless, the fatigability of shoulder girdle muscles in association with the pathomechanics of SAIS has not been reported. This study aimed to measure and compare fatigue progression within the shoulder girdle musculature of patients and healthy controls. 75 participants including 39 patients (20 females; 19 males) and 36 healthy controls (15 females; 21 males) participated in the study. Study evaluated the progression of muscle fatigue in 15 shoulder girdle muscles by means of surface and fine-wire EMG during submaximal contraction of four distinct movements (abduction, flexion, internal and external rotation). Shoulder strength, subjective pain experience (McGill Pain Questionnaire), and psychological status (Hospital Anxiety and Depression Scale) were also assessed. The results were compared between patient and control groups according to the gender. Despite marked fatigue observed in the majority of muscles particularly during flexion and abduction at 90 degrees , overall results indicated a lower tendency of fatigue progression in the impingement group across the tests (p < 0.05 - p < 0.001). Shoulder Strength, pain experience, and psychological status were significantly different between the two groups (P < .05). Lower tendency to fatigue progression in the impingement group can be attributed to the presence of fear avoidance and pain-related muscle inhibition, which in turn lead to adaptations in motor programme to reduce muscle recruitment and activation. The significantly higher levels of pain experience and anxiety/depression in the impingement group further support this proposition. PMID- 29245115 TI - Effects of grain size on the microstructures and mechanical properties of 304 austenitic steel processed by torsional deformation. AB - In this paper, two grain sized 304 austenitic steel rods (coarse-grained steel with an average grain size of ~20MUm and ultra-coarse-grained steel with an average grain size of ~1mm) were treated by pre-torsional deformation. Gradient microstructures with "dislocations->stacking faults->nanotwins" along the radial direction were formed in the ultra-coarse-grained specimen, and this type of gradient microstructures is beneficial to the mechanical properties. The results also showed that grain size affects the onset of twinning. Under the same strain the onset of twinning in the ultra-coarse-grained specimen was postponed compared to the coarse-grained specimen, and the postponed onset of twinning further affected the martensite transformation. This work showed that applying pre torsional treatment on large grain sized structural materials is beneficial to the overall mechanical properties. PMID- 29245116 TI - Human lung epithelial cells A549 epithelial-mesenchymal transition induced by PVA/Collagen nanofiber. AB - Epithelial-mesenchymal transition (EMT) is a process by which epithelial cells lose their cell-cell contact to become mesenchymal stem cells, which is important on development and embryogenesis, wound healing, and cancer metastasis. This research aims to investigate the effect of topological cue as modulating factor on the EMT by tuning the diameter of electrospinning nanofiber. The cell nanofiber interaction between human lung epithelial cell A549 and electrospinning nanofibers composed of polyvinyl alcohol (PVA) and type I collagen were investigated. The electrospinning of regenerated PVA/Collagen nanofibers were performed with water/acetic acid as a spinning solvent and glutaraldehyde as a chemical cross-linker. Parameterization on concentration, applied voltage and feeding rate was finalized to generate smooth nanofibers with good homogeneity. The scanning electron microscopy result demonstrated that A549 cell appropriately achieved extended morphology by the filopodia attaching to the surface of the nanofibrous mats. When the diameter changed from 90nm to 240nm, the A549 cell was correspondingly express varied EMT related genes. Gene expression analysis was conducted by qPCR using three typical markers for detecting EMT: N-cadherin (NCad), Vimentin (Vim), and Fibronectin (Fib). An increasing expression pattern was observed on cell culturing on 170nm sample with respect to cell cultured on 90nm and 240nm. This result indicated the 170nm PVA/Collagen nanofibers induce A549 cells to process epithelial-mesenchymal transition more seriously than those on 90nm or 240nm. PMID- 29245117 TI - Gold nanoflowers synthesized using Acanthopanacis cortex extract inhibit inflammatory mediators in LPS-induced RAW264.7 macrophages via NF-kappaB and AP-1 pathways. AB - We reported the rapid synthesis (<8s) of gold nanoparticles at room temperature using Acanthopanacis cortex extract (A-AuNPs). We characterized the A-AuNPs using several analytical techniques and found that nano-flower type A-AuNPs, which are known to possess a coarse surface with a high surface to volume ratio, conferring these particles with high binding capacity for various biological molecules. After confirming the stability of the nanoparticles, we investigated the anti inflammatory effect of A-AuNPs in LPS-stimulated RAW264.7 cells. These nanoparticles inhibited LPS-induced iNOS and COX-2 protein as well as gene expression level, along with reduction of NO and PGE2 production. Furthermore, we observed that the A-AuNPs inhibited translocation of NF-kappaB and AP-1 through phosphorylation of MAPK signaling by western blot analysis. In summary, we synthesized gold nanoflowers in an economical and eco-friendly way using Acanthopanacis cortex extract and the resultant flower-like A-AuNPs had anti inflammatory activity, highlighting their potential as therapeutic candidates for suppression of inflammatory-mediated diseases. PMID- 29245118 TI - Higher order longitudinal guided wave modes in axially stressed seven-wire strands. AB - This paper investigates the effect of axial stress on higher order longitudinal guided modes propagating in individual wires of seven-wire strands. Specifically, an acoustoelastic theory for a rod is used to predict the effect of stress on the phase velocity of guided modes in a strand. To this end, the exact acoustoelastic theory for an axially stressed rod is adapted for small deformations. Aside from the exact theory, approximate phase velocity changes (derived from both theory and experiment) are proposed, without the need to solve for dispersion curves. To validate the use of rod theories for strands, a custom-built prestressing bed was designed to apply axial load (up to 50% of yield) to a strand while conducting guided wave measurements. Higher order modes were excited in individual wires, and their phase velocity change under stress is compared to the exact acoustoelastic theory. Furthermore, it is shown that the proposed approximate phase velocity changes derived from theory and experiment only differ by roughly 2% from their exact counterparts. Higher order modes are shown to have stable stress dependence near their peak group velocity, which is beneficial for stress measurement. Additionally, linear stress dependence is observed, which is predicted by rod theories. Due to the unavailability of third order elastic constants for the steel strand, constants for a steel with similar Carbon content (0.6% C Hecla 17) were used as representative values in the theory. Using the Hecla 17 constants, roughly 15% mismatch in the slope of the linear stress dependence was observed when compared to the measurements on a steel strand. PMID- 29245119 TI - DCEUS-based focal parametric perfusion imaging of microvessel with single-pixel resolution and high contrast. AB - This study aimed to develop a focal microvascular contrast-enhanced ultrasonic parametric perfusion imaging (PPI) scheme to overcome the tradeoff between the resolution, contrast, and accuracy of focal PPI in the tumor. Its resolution was limited by the low signal-to-clutter ratio (SCR) of time-intensity-curves (TICs) induced by multiple limitations, which deteriorated the accuracy and contrast of focal PPI. The scheme was verified by the in-vivo perfusion experiments. Single pixel TICs were first extracted to ensure PPI with the highest resolution. The SCR of focal TICs in the tumor was improved using respiratory motion compensation combined with detrended fluctuation analysis. The entire and focal PPIs of six perfusion parameters were then accurately created after filtrating the valid TICs and targeted perfusion parameters. Compared with those of the conventional PPIs, the axial and lateral resolutions of focal PPIs were improved by 30.29% (p < .05) and 32.77% (p < .05), respectively; the average contrast and accuracy evaluated by SCR improved by 7.24 +/- 4.90 dB (p < .05) and 5.18 +/- 1.28 dB (p < .05), respectively. The edge, morphostructure, inhomogeneous hyper-enhanced distribution, and ring-like perfusion features in intratumoral microvessel were accurately distinguished and highlighted by the focal PPIs. The developed focal PPI can assist clinicians in making confirmed diagnoses and in providing appropriate therapeutic strategies for liver tumor. PMID- 29245120 TI - Bioactive polyoxygenated seco-cyclohexenes from Artabotrys hongkongensis. AB - Six new polyoxygenated seco-cyclohexenes, artahongkongenes A-F (1-6), together with six known analogues (7-12) were isolated from the stems and leaves of Artabotrys hongkongensis. Their structures were elucidated by extensive spectroscopic methods. All new compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. New seco-cyclohexenes 1-6 showed significant inhibitory effects against various human cancer cell lines with IC50 values ranging from 0.26 to 16.58 MUM. PMID- 29245121 TI - Co-doped TiO2 nanostructures as a strong antibacterial agent and self-cleaning cover: Synthesis, characterization and investigation of photocatalytic activity under UV irradiation. AB - The aim of this work was synthesis and investigation of various properties of Co doped titanium dioxide nanostructures. However, dopant has no effect on XRD pattern of the host but it can influence on the various characteristics of host such as optical and electrical properties. The results of optical properties showed that absorption energy of TiO2 decreases in presence of cobalt as dopant. Red-shift in absorption spectrum that may be due to the excitation of 3d electrons of Co ions to the conduction band of TiO2 can be considered as a strong evidence to confirm the presence of Co as dopant in TiO2 lattice. Photocatalytic activity of products was examined by degradation of three dyes including: Acid Red 1 (A.R.1.), Reactive Blue 21 (R.A.21.) and Acid Blue 74 (A.B.74.) under UV irradiation and antibacterial activity of this product was tested by inhibition of the growth of three bacteria: Pseudomonas aeruginosa, S. aureus and E. coli. High percent of dye degradation and decreasing the contact angle of surfaces in the presence of this product as a cover confirm that Co-doped TiO2 can be used as a self-cleaning cover on various surfaces. The antibacterial activity is another property of this product as an antibacterial agent. PMID- 29245122 TI - Reduction of cancer cell viability by synergistic combination of photodynamic treatment with the inhibition of the Id protein family. AB - The inhibitor of DNA binding and cell differentiation (Id) proteins are dominant negative regulators of the helix-loop-helix transcription factor family and play a key role during development as well as in vascular disorders and cancer. In fact, impairing the Id-protein activity in cancer cells reduces cell growth and even chemoresistance. Recently, we have shown that a synthetic Id-protein ligand (1Y) consisting of a cyclic nonapeptide can reduce the viability of the two breast cancer cell lines MCF-7 and T47D and of the bladder cancer cells T24 to about 50% at concentrations >=100MUM. Moreover, the cyclopeptide displays both proapoptotic and antiproliferative effects on MCF-7 cells. Herein, we show that the cyclopeptide does not induce cell death at the dose of 5MUMU, but it still inhibits MCF-7 and T24 cell proliferation, which correlates with an increased protein level of the cell-cycle regulator p27Kip1. Furthermore, 1Y-pretreated MCF 7, T47D, and T24 cells are more susceptible than untreated cells to the phototoxic effects of the three photosensitizers meta tetra(hydroxyphenyl)chlorin, porfimer sodium, and hypericin, which are applied in photodynamic therapy (PDT). The combination of the Id-protein ligand with each of the light-activated photosensitizers shows synergistic effects on the reduction of cell viability. In conclusion, an Id-protein ligand with moderate cancer cell killing activity at concentrations >=100MUM can be applied at a 20-fold lower and barely toxic dose to raise the sensitivity of cancer cells towards phototoxicity associated with photodynamic treatment. This suggests the potential benefit of targeting the Id proteins in combined drug approaches for cancer therapy. PMID- 29245125 TI - Delayed-type hypersensitivity to metals in connective tissue diseases and fibromyalgia. AB - Rheumatic diseases include a group of autoimmune disorders with environmental and genetic etiology that are characterized as a subgroup of connective tissue diseases (CTD). Rheumatoid arthritis (RA) often involves the small joints of the hands in a symmetrical fashion that can lead to loss of joint function, and RA, as well as Sjogren's syndrome (SS) and other rheumatic diseases, are often accompanied by sensitivity to metals. Numerous investigations on metal sensitivity were evaluated in this review. A detailed metal exposure history was collected by different evaluation of studies. In all subjects, the main source of metal exposure was nickel, mercury, gold, palladium, titanium, and chromium. All of SLE (systemic lupus erythematosus), RA and SS patients appeared to have an increased frequency of metal delayed-type hypersensitivity (DTH) (Type IV allergy). As dental restorative materials release minor amounts of their metals (including mercury, gold, and nickel), many adults are commonly exposed to these metal ions by vapor or corrosion into saliva. Metal-related DTH in these patients will induce an inflammatory response. Such inflammations are important factors in CTD progress. It is hypothesized that metal-specific T cell reactivity can act as an etiological agent in the propagation and chronification of rheumatic inflammation. The key responses of metal delayed-type hypersensitivity in autoimmunity are precipitating as an appealing challenge for further investigations. PMID- 29245124 TI - Bisphenol and phthalate concentrations and its determinants among pregnant women in a population-based cohort in the Netherlands, 2004-5. AB - BACKGROUND: Exposure to bisphenols and phthalates in pregnancy may lead to adverse health effects in women themselves and their offspring. OBJECTIVE: To describe first trimester bisphenol and phthalate urine concentrations, including bisphenol and phthalate replacements, and determine nutritional, socio demographic and lifestyle related determinants. METHODS: In a population-based prospective cohort of 1396 mothers, we measured first trimester bisphenol, phthalate and creatinine urine concentrations (samples collected in 2004-2005, median gestational age 12.9 weeks [inter-quartile range (IQR) 12.1-14.4]). We examined associations of potential determinants with log-transformed bisphenol and phthalate concentrations. Outcomes were back-transformed. Nutritional analyses were performed in a subgroup of 642 Dutch participants only, as the Food Frequency Questionnaire was aimed at Dutch food patterns. RESULTS: Bisphenol A, bisphenol S, and bisphenol F were detected in 79.2%, 67.8% and 40.2% of the population, respectively. Mono-n-butylphthalate, mono-(2-ethyl-5 hydroxyhexyl)phthalate and monobenzylphthalate were detected in > 90% of the population. Nutritional intake was not associated with bisphenol and phthalate concentrations after correction for multiple testing was applied. Obesity was associated with higher high-molecular-weight phthalate concentrations and the lack of folic acid supplement use with higher di-n-octylphthalate concentrations (respective mean differences were 46.73nmol/l [95% CI 14.56-93.72] and 1.03nmol/l [0.31-2.06]). CONCLUSION: Bisphenol S and F exposure was highly prevalent in pregnant women in the Netherlands as early as 2004-5. Although associations of dietary and other key factors with bisphenol and phthalate concentrations were limited, adverse lifestyle factors including obesity and the lack of folic acid supplement use seem to be associated with higher phthalate concentrations in pregnant women. The major limitation was the availability of only one urine sample per participant. However, since phthalates are reported to be quite stable over time, results concerning determinants of phthalate concentrations are expected to be robust. PMID- 29245126 TI - Geographic and social disparities in exposure to air neurotoxicants at U.S. public schools. AB - Children are especially vulnerable to the health and developmental impacts of environmental hazards and they spend significant portions of their days at school. Yet there are no national-level studies examining school-level environmental inequalities and few have examined disparate exposure to neurological air toxicants, even though chronic exposure to air pollution impacts children's brain functioning. We paired information about the geographic locations and demographics of each public school in the US with air neurotoxicant exposure estimates pertaining to 24 known neurotoxicants included in the US Environmental Protection Agency's National Air Toxics Assessment. Using bivariate and multivariate statistics, we tested for environmental injustices in air neurotoxicant exposure at 84,969 US public schools. Metropolitan New York City (EPA Region 2) is the geographic region most burdened by air neurotoxicant exposures at schools since one-third of all schools in that region are in the top 10% (at "high risk") for ambient neurotoxicant exposure among all schools nationwide. Students attending "high risk" public schools nationwide are significantly more likely to be eligible for free/reduced price meals, and to be Hispanic, black, or Asian/Pacific Islander (API). They are significantly less likely to be white or of another race. In a multivariate generalized estimating equation controlling for school district effects, schools with greater proportions of Hispanic, black, and API students, schools with higher enrollment, and schools located in more urban (vs. rural) counties face greater risks. Schools serving the youngest students (e.g., pre-kindergarten) have greater levels of risk than schools serving older students. Across all analyses, this study shows that racial/ethnic minority children are bearing the brunt of air neurotoxicant exposures at school, which may be unequally impacting their school performance and future potential. PMID- 29245128 TI - Anaerobic accumulation of short-chain fatty acids from algae enhanced by damaging cell structure and promoting hydrolase activity. AB - Short-chain fatty acid (SCFAs) produced from harvested algae by anaerobic fermentation with uncontrolled pH was limited due to the solid cell structure of algae. This study, therefore, was undertaken to enhance the generation of SCFAs from algae by controlling the fermentation pH. pH influenced not only the total SCFAs production, but the percentage of individual SCFA. The maximal yield of SCFAs occurred at pH 10.0 and fermentation time of 6 d (3161 mg COD/L), which mainly contained acetic and iso-valeric acids and was nearly eight times that at uncontrolled pH (392 mg COD/L). Mechanism exploration revealed at alkaline pH, especially at pH 10.0, not only the cell structure of algae was damaged effectively, but also activities and relative quantification of hydrolases as well as the abundance of microorganisms responsible for organics hydrolysis and SCFAs production were improved. Also, the released microcystins from algae were removed efficiently during alkaline anaerobic fermentation. PMID- 29245127 TI - Exogenous allantoin increases Arabidopsis seedlings tolerance to NaCl stress and regulates expression of oxidative stress response genes. AB - Allantoin is a nitrogenous compound derived from purine catabolism that contributes to nitrogen recycling in plants. Accumulation of allantoin in plant tissues and a potential role in protection of plants from abiotic stress conditions has been identified. The present work shows that application of exogenous allantoin increased stress tolerance of Arabidopsis seedlings when germinated on, or subjected to the media containing NaCl. Allantoin-induced tolerance to NaCl stress was associated with decreased production of superoxide and hydrogen peroxide in seedlings. To understand the molecular mechanism, the effect of exogenous allantoin treatment on expression of several stress-related genes was investigated. Exogenous allantoin altered the expression of several antioxidant encoding genes and upregulated the expression of two genes involved in oxidative stress tolerance, SOS1 and RCD1, in the presence or absence of NaCl. Allantoin increased the NaCl tolerance of abscisic acid insensitive mutants, suggesting that it can function independently of abscisic acid signaling. These results provide additional evidence for the role of allantoin in enhancing plants tolerance to oxidative stress. PMID- 29245129 TI - A novel approach of modeling continuous dark hydrogen fermentation. AB - In this study a novel modeling approach for describing fermentative hydrogen production in a continuous stirred tank reactor (CSTR) was developed, using the Aquasim modeling platform. This model accounts for the key metabolic reactions taking place in a fermentative hydrogen producing reactor, using fixed stoichiometry but different reaction rates. Biomass yields are determined based on bioenergetics. The model is capable of describing very well the variation in the distribution of metabolic products for a wide range of hydraulic retention times (HRT). The modeling approach is demonstrated using the experimental data obtained from a CSTR, fed with food industry waste (FIW), operating at different HRTs. The kinetic parameters were estimated through fitting to the experimental results. Hydrogen and total biogas production rates were predicted very well by the model, validating the basic assumptions regarding the implicated stoichiometric biochemical reactions and their kinetic rates. PMID- 29245123 TI - The GDNF Family: A Role in Cancer? AB - The glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs) comprising of GDNF, neurturin, artemin, and persephin plays an important role in the development and maintenance of the central and peripheral nervous system, renal morphogenesis, and spermatogenesis. Here we review our current understanding of GFL biology, and supported by recent progress in the area, we examine their emerging role in endocrine-related and other non-hormone-dependent solid neoplasms. The ability of GFLs to elicit actions that resemble those perturbed in an oncogenic phenotype, alongside mounting evidence of GFL involvement in tumor progression, presents novel opportunities for therapeutic intervention. PMID- 29245130 TI - Biodiesel production from castor oil using heterogeneous Ni doped ZnO nanocatalyst. AB - In the present study, castor oil with high free fatty acid was used for biodiesel production using heterogeneous Ni doped ZnO nanocatalyst. Ni doped ZnO nanocomposite calcinated at 800 degrees C has shown better catalytic activity. Process parameters on heterogeneous catalysis of castor oil into biodiesel were optimized using conventional and Response Surface Methodology (RSM). RSM was found more accurate in estimating the optimum conditions with higher biodiesel yield (95.20%). The optimum conditions for transesterification was found to be oil to methanol molar ratio of 1:8, catalyst loading 11% (w/w), reaction temperature of 55 degrees C for 60 min of reaction time by response surface method. The reusability studies showed that the nanocatalyst can be reused efficiently for 3 cycles. PMID- 29245131 TI - Premagnetization enhancing the reactivity of Fe0/(passivated Fe0) system for high concentration p-nitrophenol removal in aqueous solution. AB - In order to strengthen the treatment efficiency of Fe0 based system for high concentration wastewater treatment, Fe0 particles were passivated by concentrated nitric acid, and a premagnetization Fe0/(passivated Fe0) system was setup for high concentration p-nitrophenol (PNP) removal in this study. The significant parameters of this system were optimized. Under the optimal conditions, the premagnetization Fe0/(passivated Fe0) system could obtain high kobs value for PNP removal (0.100 min-1) and COD removal (15.0% after 60 min) for high concentration PNP (500 mg/L) treatment. In addition, five control experiments were set up to confirm the advantage of the premagnetization Fe0/(passivated Fe0) system. The results suggest that passivated Fe0 particles could be stimulated better than Fe0 particles by premagnetization process, and the premagnetization Fe0/(passivated Fe0) systems is much superior to the other five control systems. Furthermore, the pathway for PNP destruction treated by 6 different systems was also proposed according to intermediates determination by High Performance Liquid Chromatography (HPLC) and UV-vis spectrum, and the carbon mass balance was demonstrated according to the COD and HPLC analyses. Finally, the characteristics of (premagnetization) Fe0 and passivated Fe0 was detected by scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS) and vibrating sample magnetometer (VSM), and the mechanism of premagnetization effectively enhancing the reactivity of Fe0/(passivated Fe0) system (better than that of Fe0 system) was proposed. Consequently, the premagnetization for reactivity improvement of Fe0/(passivated Fe0) system is a promising technology to enhance the efficiency of this system for high concentration wastewater treatment. PMID- 29245132 TI - Transcriptome analysis reveals novel insights into the response to Pb exposure in Phanerochaete chrysosporium. AB - Metals released into the environment continue to be of concern for human health. Using white-rot fungi as biosorbents for heavy metals removal is an attractive alternative owing to its good performance and low cost. However, the molecular mechanism underlying heavy metal tolerance in white-rot fungi has not yet been fully elucidated. This study identified and analyzed the lead (Pb)-induced transcriptional changes in Phanerochaete chrysosporium, a well-known heavy metal hyperaccumulating white-rot fungus. The results confirmed its outstanding ability in Pb tolerance and effective defense system. By comparative analysis of gene expression profiles obtained from cDNA-amplified fragment length polymorphism (cDNA-AFLP), we isolated 43 transcript-derived fragments (TDFs) differentially regulated by Pb exposure in P. chrysosporium, and 23 TDFs presented significant similarities to genes encoding known or putative proteins which belong to different functional categories involving ion binding, energy and carbohydrate metabolism, and signal transduction. The detailed characterization of these Pb responsive genes was presented and the expression patterns of some interesting genes were validated by quantitative RT-PCR. This work provides the first evidence of Pb-responsive genes along with their putatively functional annotations in P. chrysosporium, which may help to understand the mechanism underlying heavy metal accumulation and tolerance in P. chrysosporium. PMID- 29245133 TI - Source identification and ecological impact evaluation of PAHs in urban river sediments: A case study in Taiwan. AB - The Love River and Ho-Jin River, two major urban rivers in Kaohsiung City, Taiwan, are moderately to heavily polluted because different types of improperly treated wastewaters are discharged into the rivers. In this study, sediment and river water samples were collected from two rivers to investigate the river water quality and accumulation of polycyclic aromatic hydrocarbons (PAHs) in sediments. The spatial distribution, composition, and source appointment of PAHs of the sediments were examined. The impacts of PAHs on ecological system were assessed using toxic equivalence quotient (TEQ) of potentially carcinogenic PAHs (TEQcarc) and sediment quality guidelines. The average PAHs concentrations ranged from 2161 ng/g in Love River sediment to 160 ng/g in Ho-Jin River sediment. This could be due to the fact that Love River Basin had much higher population density and pyrolytic activities. High-ring PAHs (4-6 rings) contributed to 59-90% of the total PAHs concentrations. Benzo(a)pyrene (BaP) had the highest toxic equivalence quotient (up to 188 ng TEQ/g). Moreover, the downstream sediments contained higher TEQ of total TPHs than midstream and upstream sediment samples. The PAHs were adsorbed onto the fine particles with high organic content. Results from diagnostic ratio analyses indicate that the PAHs in two urban river sediments might originate from oil/coal combustion, traffic-related emissions, and waste combustion (pyrogenic activities). Future pollution prevention and management should target the various industries, incinerators, and transportation emission in this region to reduce the PAHs pollution. PMID- 29245134 TI - Phosphorus recovery and reuse by pyrolysis: Applications for agriculture and environment. AB - Phosphorus ore extraction for soil fertilization supports the demand of modern agriculture, but extractable resource limitations, due to scarcity, impose a P reuse and recycling research agenda. Here we propose to integrate biochar production (pyrogenic carbon) with municipal and agricultural waste management systems, to recover and reuse phosphorous that would otherwise be lost from the ecological food web. A meta-analysis and available data on total P in biochar indicated that P-enriched feedstocks include animal manure, human excreta, and plant-biomass collected from P-polluted sites. Phosphorus in biochar could participate in P equilibriums in soils and is expected to supply P. The release, sorption and desorption of P by biochar will codetermine the potential of P replenishment by biochar and P loss from biochar-amended soils. Abiotic and biotic factors are expected to affect sorption/desorption of P between biochar and soil aggregates, and P acquisition by plants. Chemical extraction, using acid or alkaline solutions, is considered as a means for P retrieval from high P biochar, especially for biochar with high heavy metal contents. To bridge the gap between academia and practice, this paper proposes future development for phosphorus acclamation by pyrolysis: 1) identification of high-P bio-waste for pyrolysis; 2) retrieval of P by using biochar as soil amendment or by chemical leaching; 3) biochar modification by inorganic nutrients, P solubilizing microorganisms and other organic matter; and 4) compatible pyrolysis equipment fit to the current waste management context, such as households, and waste water treatment plants. PMID- 29245135 TI - Acidogenic fermentation of iron-enhanced primary sedimentation sludge under different pH conditions for production of volatile fatty acids. AB - Iron-based chemically enhanced primary sedimentation (CEPS) is increasingly adopted for wastewater treatment in mega cities, producing a large amount of sludge (Fe-sludge) with a high content of organics for potential organic resource recovery. In this experimental study, acidogenic fermentation was applied treat FeCl3-based CEPS sludge for production of volatile fatty acids (VFAs) at different pHs. Batch fermentation tests on the Fe-sludge with an organic content of 10 g-COD/L showed that the maximum VFAs production reached 2782.2 mg-COD/L in the reactor without pH control, and it reached 688.4, 3095.3, and 2603.7 mg-COD/L in reactors with pHs kept at 5.0, 6.0 and 8.0, respectively. Analysis of the acidogenesis kinetics and enzymatic activity indicated that the alkaline pH could accelerate the rate of organic hydrolysis but inhibited the further organic conversion to VFAs. In semi-continuous sludge fermentation tests, the VFAs yield in the pH6 reactor was 20% higher than that in the control reactor without pH regulation, while the VFAs yield in the pH8 reactor was 10% lower than the control. Illumina MiSeq sequencing revealed that key functional microorganisms known for effective sludge fermentation, including Bacteroidia and Erysipelotrichi, were enriched in the pH6 reactor with an enhanced VFAs production, while Clostridia became more abundant in the pH8 reactor to stand the unfavorable pH condition. The research presented acidogenic fermentation as an effective process for CEPS sludge treatment and organic resource recovery and provided the first insight into the related microbial community dynamics. PMID- 29245137 TI - Synthesis of the repeating unit of O-specific polysaccharide isolated from the water-borne bacteria Aeromonas bestiarum 207. AB - Aeromonas bestiarum 207 is a bacterial pathogen with severe impact on aquaculture. In a recent study, the structure of OPS antigens from Aeromonas bestiarum was identified as pentasaccharide repeating units. Synthesis of the pentasaccharide repeating unit and its derivative are reported. Stereo- and regio specific synthesis was achieved under Schmidt glycosylation conditions employing appropriately protected L-rhamopyranosyl and D-glucopyranosylamine building blocks. The pentasaccharide synthesis was achieved using a [3 + 2] strategy with an overall yield of 5.2% through 11 linear steps from the monosaccharide building blocks 10 and 14. PMID- 29245136 TI - Small Maf functions in the maintenance of germline stem cells in the Drosophila testis. AB - Reactive oxygen species (ROS) are byproducts generated during normal cellular metabolism, and redox states have been shown to influence stem cell self-renewal and lineage commitment across phyla. However, the downstream effectors of ROS signaling that control stem cell behavior remain largely unexplored. Here, we used the Drosophila testis as an in vivo model to identify ROS-induced effectors that are involved in the differentiation process of germline stem cells (GSCs). In the Affymetrix microarray analysis, 152 genes were either upregulated or downregulated during GSC differentiation induced by elevated levels of ROS, and a follow-up validation of the gene expression by qRT-PCR showed a Spearman's rho of 0.9173 (P<0.0001). Notably, 47 (31%) of the identified genes had no predicted molecular function or recognizable protein domain. These suggest the robustness of this microarray analysis, which identified many uncharacterized genes, possibly with an essential role in ROS-induced GSC differentiation. We also showed that maf-S is transcriptionally downregulated by oxidative stress, and that maf-S knockdown promotes GSC differentiation but Maf-S overexpression conversely results in an over-growth of GSC-like cells by promoting the mitotic activity of germ cell lineage. Together with the facts that Maf-S regulates ROS levels and genetically interacts with Keap1/Nrf2 in GSC maintenance, our study suggests that Maf-S plays an important role in the Drosophila testis GSC maintenance by participating in the regulation of redox homeostasis. PMID- 29245139 TI - Scapular-focused exercise treatment protocol for shoulder impingement symptoms: Three-dimensional scapular kinematics analysis. AB - BACKGROUND: The present study aimed to describe the effects of a periscapular strengthening and neuromuscular training protocol in three-dimensional scapular kinematics and resting positioning in participants with shoulder impingement symptoms. Self-reported function was also evaluated. METHOD: The study group comprised 50 subjects with shoulder impingement syndrome (control group, n=25; treatment group, n=25). The treatment group underwent 8weeks of neuromuscular training and periscapular strengthening. Scapular kinematics was measured using an electromagnetic tracking device, and the Brazilian version of the Shoulder Pain and Disability Index (SPADI-Br) questionnaire was carried out before and after the treatment. FINDINGS: In the resting position, treated subjects had lower (p<0.01) internal rotation of the scapula compared to the control group, with a large effect size (2.4). On the coronal plane, the treated group had less scapular upward rotation (p<0.01) and less internal rotation (p<0.05), with a medium effect size. On the sagittal plane, the treated group had less internal rotation (p<0.01), less upward rotation (p<0.05), and less scapular anterior tilt (p<0.01), with a medium effect size. On the scapular plane, a reduction in upward rotation (p<0.01) after the intervention was observed, with a large effect size. Moreover, a reduction in the total SPADI-Br score was found, with a mean difference of 32.4 [24.4; 40.4] points (p<0.01) after the implementation of the protocol and a large effect size (2.0). INTERPRETATION: The results provide biomechanical support for the clinical rationale for indicating therapeutic exercises focused on the periscapular muscles to improve scapular dynamics. PMID- 29245138 TI - Cardiac sarcoidosis presenting as arrhythmogenic right ventricular cardiomyopathy/dysplasia with ventricular aneurysms: a case report. AB - A 70-year old Caucasian man with recurrent ventricular tachycardia and progressive biventricular failure attributed to arrhythmogenic right ventricular cardiomyopathy/dysplasia was evaluated for heart transplantation. Cardiac ventriculography revealed an abnormal left ventricle with five saccular aneurysms. Heart transplantation was performed. Pathology of the explanted heart showed multifocal sarcoid granulomas. Replacement fibrosis was widespread in both ventricles and associated with saccular aneurysms. No genetic basis was identified. Thus, the evidence suggested progressive cardiac sarcoidosis caused this patient's unusual condition. PMID- 29245140 TI - School readiness of maltreated children: Associations of timing, type, and chronicity of maltreatment. AB - Children who have been maltreated during early childhood may experience a difficult transition into fulltime schooling, due to maladaptive development of the skills and abilities that are important for positive school adaptation. An understanding of how different dimensions of maltreatment relate to children's school readiness is important for informing appropriate supports for maltreated children. In this study, the Australian Early Development Census scores of 19,203 children were linked to information on child maltreatment allegations (substantiated and unsubstantiated), including the type of alleged maltreatment, the timing of the allegation (infancy-toddlerhood or preschool), and the total number of allegations (chronicity). Children with a maltreatment allegation had increased odds of poor school readiness in cognitive and non-cognitive domains. Substantiated maltreatment was associated with poor social and emotional development in children, regardless of maltreatment type, timing, or chronicity. For children with unsubstantiated maltreatment allegations, developmental outcomes according to the type of alleged maltreatment were more heterogeneous; however, these children were also at risk of poor school readiness irrespective of the timing and/or chronicity of the alleged maltreatment. The findings suggest that all children with maltreatment allegations are at risk for poor school readiness; hence, these children may need additional support to increase the chance of a successful school transition. Interventions should commence prior to the start of school to mitigate early developmental difficulties that children with a history of maltreatment allegations may be experiencing, with the aim of reducing the incidence of continuing difficulties in the first year of school and beyond. PMID- 29245141 TI - A systematic review of the state of the literature on sexually exploited boys internationally. AB - This systematic review assessed the current state of the literature on sexually exploited boys internationally. We aimed to describe what is known about sexual exploitation of boys, identify gaps in the literature, provide implications for practice, and make recommendations for future research. Multiple database searches were conducted using a combination of controlled vocabulary and keywords to capture child and adolescent sexual exploitation. Our search identified 11,099 unique references and excluded studies that did not include male participants less than 18 years old or disaggregate results by relevant age groups and/or by sex. This review identified 42 studies from 23 countries, providing evidence that sexual exploitation of boys is an issue in both high- and low-income countries. Seventeen articles had sexual exploitation as their primary variable of interest, the majority of which sampled boys who accessed services (i.e., shelters, health care, social, and justice services). Boys' experiences of sexual exploitation varied in terms of venue, exploiters, and compensation. Compared to their non sexually exploited peers, sexually exploited boys more commonly reported experiences of child abuse, substance use, conduct problems, and mental health problems such as anxiety, depression, and self-harm. Despite increasing evidence that boys are sexually exploited around the world, the current literature provides limited data about the antecedents, sequelae, and the specific features of sexual exploitation experiences among boys. Further research is needed to inform, policy, social services and health care delivery specific to the needs of sexually exploited boys. PMID- 29245142 TI - The chest radiologist's role in invasive breast cancer detection. AB - PURPOSE: To assess the ability of chest CT to identify patients needing further evaluation of the breasts. METHODS: IRB approval was obtained with a waiver of consent. Women with chest CT and mammogram within 12months formed the cohort. A breast assessment and recommendation CT score (BARCS) analogous to mammographic BI-RADS was created and compared to the mammogram BI-RADS. RESULTS: BARCS and mammographic BI-RADS management recommendations were concordant for 77.1%. 11 invasive cancers were detected; all by mammogram while CT missed 2. CONCLUSION: BARCS score should be studied in prospective trials. Chest CT might be the earliest opportunity to detect breast cancer. PMID- 29245143 TI - Functionalization of protein crystals with metal ions, complexes and nanoparticles. AB - Self-assembled proteins have specific functions in biology. With inspiration provided by natural protein systems, several artificial protein assemblies have been constructed via site-specific mutations or metal coordination, which have important applications in catalysis, material and bio-supramolecular chemistry. Similar to natural protein assemblies, protein crystals have been recognized as protein assemblies formed of densely-packed monomeric proteins. Protein crystals can be functionalized with metal ions, metal complexes or nanoparticles via soaking, co-crystallization, creating new metal binding sites by site-specific mutations. The field of protein crystal engineering with metal coordination is relatively new and has gained considerable attention for developing solid biomaterials as well as structural investigations of enzymatic reactions, growth of nanoparticles and catalysis. This review highlights recent and significant research on functionalization of protein crystals with metal coordination and future prospects. PMID- 29245144 TI - The MyoRobot: A novel automated biomechatronics system to assess voltage/Ca2+ biosensors and active/passive biomechanics in muscle and biomaterials. AB - We engineered an automated biomechatronics system, MyoRobot, for robust objective and versatile assessment of muscle or polymer materials (bio-)mechanics. It covers multiple levels of muscle biosensor assessment, e.g. membrane voltage or contractile apparatus Ca2+ ion responses (force resolution 1uN, 0-10mN for the given sensor; [Ca2+] range ~ 100nM-25uM). It replaces previously tedious manual protocols to obtain exhaustive information on active/passive biomechanical properties across various morphological tissue levels. Deciphering mechanisms of muscle weakness requires sophisticated force protocols, dissecting contributions from altered Ca2+ homeostasis, electro-chemical, chemico-mechanical biosensors or visco-elastic components. From whole organ to single fibre levels, experimental demands and hardware requirements increase, limiting biomechanics research potential, as reflected by only few commercial biomechatronics systems that can address resolution, experimental versatility and mostly, automation of force recordings. Our MyoRobot combines optical force transducer technology with high precision 3D actuation (e.g. voice coil, 1um encoder resolution; stepper motors, 4um feed motion), and customized control software, enabling modular experimentation packages and automated data pre-analysis. In small bundles and single muscle fibres, we demonstrate automated recordings of (i) caffeine-induced , (ii) electrical field stimulation (EFS)-induced force, (iii) pCa-force, (iv) slack-tests and (v) passive length-tension curves. The system easily reproduces results from manual systems (two times larger stiffness in slow over fast muscle) and provides novel insights into unloaded shortening velocities (declining with increasing slack lengths). The MyoRobot enables automated complex biomechanics assessment in muscle research. Applications also extend to material sciences, exemplarily shown here for spider silk and collagen biopolymers. PMID- 29245145 TI - Comparative leaching of six toxic metals from raw and chemically stabilized MSWI fly ash using citric acid. AB - The leaching behavior of six typical toxic metals (Pb, Zn, Cr, Cd, Cu and Ni) from raw and chemically stabilized (phosphate and chelating agent) municipal solid waste incineration (MSWI) fly ash were investigated using citric acid. Leaching tests indicated that phosphate stabilization can effectively decrease the leaching of Zn, Cd and Cr; whereas chelating agent stabilization shows a strong ability to lower the release of Pb, Cd and Cu, but instead increases the solubility of Zn and Cr at low pH conditions. Sequential extraction results suggested that the leaching of Pb, Zn and Cd in both the stabilized MSWI fly ash samples led to the decrease in Fe/Mn oxide fraction and the increase in exchangeable and carbonate fractions. The leaching of Cr was due to the decrease in exchangeable, carbonate and Fe/Mn oxide fractions in phosphate-stabilized and chelating agent-stabilized MSWI fly ash. The leaching of Cu in both stabilized MSWI fly ash was greatly ascribed to the decrease in Fe/Mn oxide and oxidisable fractions. Moreover, predicted curves by geochemical model indicated that both stabilized MSWI fly ash have the risk of releasing toxic metals under strong acid environment. PMID- 29245146 TI - Effects of elevated O3 on physiological and biochemical responses in three kinds of trees native to subtropical forest in China during non-growing period. AB - Numerous studies have documented the negative effects of ozone (O3) on tree species in growing season, however, little is done in non-growing season. Three evergreen tree species, Phoebe bournei (Hemsl.) Yang (P. bournei), Machilus pauhoi Kanehira (M. pauhoi) and Taxus chinensis (Pilger) Rehd (T. chinensis), were exposed to non-filtered air, 100 nmol mol-1 O3 air (E1) and 150 nmol mol-1 O3 air (E2) in open-top chambers in subtropical China. In the entire period of experiment, O3 fumigation decreased net photosynthesis rate (Pn) through stomatal limitation during the transition period from growing to non-growing season (TGN), and through non-stomatal limitation during the period of non-growing season (NGS) in all species tested. Meanwhile, O3 fumigation reduced and delayed the resilience of Pn in all species tested during the transition period from non growing to growing season (TNG). O3 fumigation significantly decreased chlorophyll contents during NGS, whereas no obvious injury symptoms were observed till the end of experiment. O3 fumigation induced increases in levels of malondialdehyde, superoxide dismutase, total phenolics and reduced ascorbic acid, and changes in four plant endogenous hormones as well in all species tested during NGS. During NGS, E1 and E2 reduced Pn by an average of 80.11% in P. bournei, 94.56% in M. pauhoi and 12.57% in T. chinensis, indicating that the O3 sensitivity was in an order of M. pauhoi > P. bournei > T. chinensis. Overall, O3 fumigation inhibited carbon fixation in all species tested during NGS. Furthermore, O3-induced physiological activities also consumed the dry matter. All these suggested that elevated O3, which is likely to come true during NGS in the future, will adversely affect the accumulation of dry matter and the resilience of Pn during TNG in evergreen tree species, and further inhibit their growth and development in the upcoming growing season. PMID- 29245148 TI - Hydrological and pollution processes in mining area of Fenhe River Basin in China. AB - The hydrological and pollution processes are an important science problem for aquatic ecosystem. In this study, the samples of river water, reservoir water, shallow groundwater, deep groundwater, and precipitation in mining area are collected and analyzed. deltaD and delta18O are used to identify hydrological process. delta15N-NO3- and delta18O-NO3- are used to identify the sources and pollution process of NO3-. The results show that the various water bodies in Fenhe River Basin are slightly alkaline water. The ions in the water mainly come from rock weathering. The concentration of SO42- is high due to the impact of coal mining activity. Deep groundwater is significantly less affected by evaporation and human activity, which is recharged by archaic groundwater. There are recharge and discharge between reservoir water, river water, soil water, and shallow groundwater. NO3- is the main N species in the study area, and forty-six percent of NO3--N concentrations exceed the drinking water standard of China (NO3 -N <= 10 mg/L content). Nitrification is the main forming process of NO3-. Denitrification is also found in river water of some river branches. The sources of NO3- are mainly controlled by land use type along the riverbank. NO3- of river water in the upper reaches are come from nitrogen in precipitation and soil organic N. River water in the lower reaches is polluted by a mixture of soil organic N and fertilizers. PMID- 29245147 TI - Levels of trace elements, methylmercury and polybrominated diphenyl ethers in foraging green turtles in the South China region and their conservation implications. AB - Sea turtles are globally endangered and face daily anthropogenic threats, including pollution. However, there is a lack of ecotoxicological information on sea turtles, especially in the Asia-Pacific region. This study aims to determine pollutant levels of foraging green turtles (Chelonia mydas) in South China, including Hong Kong, Guangdong and Taiwan, as a basis for their conservation. Scute, liver and muscle tissues of stranded green turtles were analysed for levels of 17 trace elements and methylmercury (MeHg) (n = 86 for scute and n = 14 for liver) and polybrominated diphenyl ethers (PBDEs) (n = 11 for muscle and n = 13 for liver). Ten-fold higher levels of Pb, Ba, V and Tl and 40-fold greater Cd levels were measured in green turtle livers in South China relative to other studies conducted over 10 years ago. Measured PBDE levels were also 27-fold and 50-fold greater than those reported in Australia and Japan. These results warrant further investigation of potential toxicological risks to green turtles in South China and their source rookeries in Malaysia, Micronesia, Indonesia, Marshall Islands, Japan and Taiwan. Research should target monitoring pollutant levels in sea turtles within the West Pacific/Southeast Asia regional management unit spanning East Asia to Southeast Asia to fill in knowledge gaps, in particular in areas such as Thailand, Vietnam, Indonesia, Malaysia and the Philippines where less or no data is available and where foraging grounds of sea turtles have been identified. PMID- 29245149 TI - OrganoRelease - A framework for modeling the release of organic chemicals from the use and post-use of consumer products. AB - Chemicals in consumer products have become the focus of recent regulatory developments including California's Safer Consumer Products Act. However, quantifying the amount of chemicals released during the use and post-use phases of consumer products is challenging, limiting the ability to understand their impacts. Here we present a comprehensive framework, OrganoRelease, for estimating the release of organic chemicals from the use and post-use of consumer products given limited information. First, a novel Chemical Functional Use Classifier estimates functional uses based on chemical structure. Second, the quantity of chemicals entering different product streams is estimated based on market share data of the chemical functional uses. Third, chemical releases are estimated based on either chemical product categories or functional uses by using the Specific Environmental Release Categories and EU Technological Guidance Documents. OrganoRelease connects 19 unique functional uses and 14 product categories across 4 data sources and provides multiple pathways for chemical release estimation. Available user information can be incorporated in the framework at various stages. The Chemical Functional Use Classifier achieved an average accuracy above 84% for nine functional uses, which enables the OrganoRelease to provide release estimates for the chemical, mostly using only the molecular structure. The results can be can be used as input for methods estimating environmental fate and exposure. PMID- 29245150 TI - Mobilization of arsenic on nano-TiO2 in soil columns with sulfate reducing bacteria. AB - Arsenic (As) remediation in contaminated water using nanoparticles is promising. However, the fate and transport of As associated with nano-adsorbents in natural environment is poorly understood. To investigate the fate of adsorbed As on nano TiO2 in changed redox condition from oxic to anoxic, we added the As(V)-TiO2 suspension in groundwater to an autoclaved soil column which inoculated a sulfate reducing bacterium, Desulfovibrio vulgaris DP4. The dissolved As(V) in effluent increased to 798 MUg/L for the biotic column and to 1510 MUg/L for the abiotic control, and dissolved As(III) was observed only in biotic column. The total As (dissolved plus particulate) in the biotic column effluent (high to 2.5 mg/L) was substantially higher than the abiotic control (1.5 mg/L). Therefore SRB restrained the release of dissolved As, and facilitated the transport of particulate As. Micro-XRF analysis suggested that the nano-TiO2 with As was mainly retained in the influent front and that its transport was negligible. Our pe-pH calculation and XANES analysis demonstrated that generated secondary iron minerals containing magnetite and mackinawite mainly were responsible for dissolved As retention, and then transported with As as particulate As. The results shed light on the mobilization of adsorbed As on a nano-adsorbent in an anoxic environment. PMID- 29245151 TI - Substantial enhancement of anaerobic pyridine bio-mineralization by electrical stimulation. AB - Due to highly recalcitrant and toxicological nature of pyridine, the conventional anaerobic bioprocess is often limited by low removal rate and poor process stability. In this study, an electricity-assisted anaerobic system was developed in order to enhance biodegradation of pyridine from wastewater. The results showed that the performance and stability of the anaerobic reactor was remarkably improved for pyridine biodegradation with the applied direct current of 0.3 mA, where the efficiencies of pyridine and total organic carbon removal as well as NH4+-N formation were as high as 100.0%, 96.1 +/- 1.2% and 60.1 +/- 2.1% respectively. The compact biofilm due to electrical stimulation as well as the microaerobic environment in the bioanode might promote pyridine bio mineralization in the anaerobic reactor. Moreover, the species related to pyridine biodegradation (Desulfovibrio, Dokdonella, Hydrogenophaga, and Paracoccus) were enriched in the anodic biofilm, which would be another reason for better reactor performance. This study demonstrated that electrical stimulation would be a potential alternative for the enhancement of pyridine removal from wastewater in anaerobic systems. PMID- 29245152 TI - Operator Pelvic Radiation Exposure During Percutaneous Coronary Procedures. AB - OBJECTIVES: To evaluate operator pelvic radiation exposure during percutaneous coronary procedures. BACKGROUND: During percutaneous coronary procedures, the operator's pelvic region is close to the x-ray source and is probably exposed to more radiation than the operator's thorax. However, no data are available on the pelvic radiation exposure of interventional cardiologists. METHODS: The RADIANT study (NCT01974453) is a prospective, single-center, observational study evaluating operator radiation exposure during percutaneous coronary procedures using electronic dosimeters placed at thorax level. In the last period of the study enrollment, a single operator was also equipped with an adjunctive electronic dedicated dosimeter to evaluate pelvic radiation exposure. RESULTS: From a total of 2028 procedures included in the RADIANT study, operator pelvic doses were available for 138 procedures (68 right radial, 55 left radial, and 15 transfemoral). Median fluoroscopy time was 226 sec (interquartile range [IQR], 117-407 sec) and the dose-area product (DAP) was 15.3 Gy*cm2 (IQR, 9.3-27.8 Gy*cm2). Radiation dose at pelvic region was significantly higher (40.1 MUSv; IQR, 22.7-76.3 MUSv) compared to thorax dose (5.6 MUSv; IQR, 1.5-12 MUSv; P<.001) even after normalization by DAP (2.98 MUSv/Gy*cm2 [IQR, 1.6-4.6 MUSv/Gy*cm2] at pelvic vs 0.33 MUSv/Gy*cm2 [IQR, 0.11-0.81 MUSv/Gy*cm2] at thorax level; P<.001). No significant differences were observed comparing pelvic dose in right radial (42 MUSv), left radial (39 MUSv), or femoral access (40 MUSv; P=.43). CONCLUSIONS: Operator radiation exposure to the pelvic region during percutaneous coronary procedures is significantly higher compared to thorax radiation dose independently of the vascular access site employed. PMID- 29245153 TI - Catheter Ablation of Focal Atrial Tachycardia Using Remote Magnetic Navigation. AB - OBJECTIVES: The outcomes of catheter ablation in focal atrial tachycardia (AT) using remote magnetic navigation (RMN) are still controversial. The objectives of this study were to assess the acute and long-term outcomes of catheter ablation in focal AT using RMN. BACKGROUND: A total of 53 patients with focal AT who underwent catheter ablation using RMN were included. Thirty-six patients had structural heart disease, including previous atrial fibrillation ablation and heart surgery (abnormal group), and the remaining 17 patients had no structural heart disease (normal group). METHODS: In 53 patients, a total of 56 atrial foci were found. Acute success of the primary ablation was obtained in 52 patients (98%). Mean procedure duration was 109 +/- 35 min, ablation duration was 401 sec (interquartile range [IQR], 332 sec), and fluoroscopy time was 5.0 min (IQR, 3.0 min). After a mean follow-up of 31 +/- 18 months, 47 patients (89%) were free from focal AT. No major complications were observed. In the abnormal group, age and target atrium volume were higher and the left ventricular ejection fraction was lower when compared to the normal group. However, there were no significant differences in procedure duration (normal group 106 +/- 31 min vs abnormal group 111 +/- 37 min); ablation duration (normal group 457 sec [IQR, 412 sec] vs abnormal group 378 sec [IQR, 217 sec]); fluoroscopy time (normal group 4.2 min [IQR, 3.0 min] vs abnormal group 5.4 min [IQR, 3.3 min]); acute success rate (normal group 100% vs abnormal group 97%); and long-term success rate (normal group 88% vs abnormal group 89%) between the two groups (P>.05). CONCLUSION: Our study has demonstrated that catheter ablation of focal AT using RMN is safe and effective, with low fluoroscopy exposure. PMID- 29245154 TI - Acute Procedural Outcomes of Orbital Atherectomy for the Treatment of Profunda Femoris Artery Disease: Subanalysis of the CONFIRM Registries. AB - OBJECTIVES: We compared the angiographic outcomes of patients treated with orbital atherectomy for profunda femoris artery (PFA) and superficial femoral artery (SFA) disease from the CONFIRM I-III registries. BACKGROUND: Endovascular revascularization of the PFA is considered a high-risk procedure given that it is an important collateral vessel when the SFA becomes occluded. Data on outcomes of endovascular revascularization of calcified PFA disease are limited. METHODS: The treatment of PFA disease with orbital atherectomy has not been previously reported. Patient demographics, lesion characteristics, and procedure data for all CONFIRM patients with at least one PFA lesion location (n = 33 patients; n = 33 lesions) were compared to patients with at least one SFA lesion location (n = 1574 patients; n = 1811 lesions). The primary endpoint was angiographic complication, defined as the composite of flow-limiting dissection, perforation, slow flow, vessel closure, spasm, embolism, or thrombosis. RESULTS: The PFA group had a shorter lesion length, larger residual stenosis, shorter total run time, and shorter inflation time. Adjunctive stenting was only performed in the SFA group (10%); no patient in the PFA group underwent stenting. The primary endpoint was low in the PFA group and compared favorably with the SFA group (3% vs 11%; P=.15). One patient in the PFA group had vessel spasm, while no patients had flow limiting dissection, perforation, slow flow, vessel closure, embolism, or thrombus. CONCLUSIONS: Orbital atherectomy of the PFA was feasible and safe. A randomized trial is needed to determine the ideal treatment strategy for calcified PFA disease. PMID- 29245155 TI - Occupational Hazards in the Cath Lab - Physician, Protect Thyself! PMID- 29245156 TI - Selection and targeting of EpCAM protein by ssDNA aptamer. AB - Aptamers are molecules that reveal highly complex and refined molecular recognition properties. These molecules are capable of binding with high affinity and selectivity to targets, ranging from small molecules to whole living cells. Several aptamers have been selected for targeting cellular proteins and they have also used in developing therapeutics and diagnostic strategies. Epithelial cell adhesion molecule (EpCAM) is considered as a cancer stem cell (CSC) biomarker and one of the most promising targets for aptamer selection against CSCs. In this study, we have developed a ssDNA aptamer with high affinity and selectivity of targeting the EpCAM protein extracellular domain. The SELEX technique was applied and the resulted sequences were tested on EpCAM-positive human gastric cancer cell line, KATO III, and the EpCAM-negative mouse embryonic fibroblast, NIH/3T3 cells. Ep1 aptamer was successfully isolated and showed selective binding on EpCAM-positive KATO III cells when compared to EpCAM-negative NIH/3T3 cells, as observed by the flow cytometry and the confocal imaging results. Additionally, the binding of Ep1 to EpCAM protein was assessed using mobility shifting assay and aptamers-protein docking. Furthermore, the binding affinity of Ep1 was measured against EpCAM protein using EpCAM-immobilized on magnetic beads and showed apparent affinity of 118 nM. The results of this study could suggest that Ep1 aptamer can bind specifically to the cellular EpCAM protein, making it an attractive ligand for targeted drug delivery and as an imaging agent for the identification of cancer cells. PMID- 29245158 TI - [Intrapartum Translabial Ultrasound: A Systematic Analysis of The Fetal Head Station in The First Stage of Labor]. AB - INTRODUCTION: This prospective study aimed to define the angle of progression (AOP) in relation to the height position of the fetal head during the first stage of labour. It was investigated if it is possible to predict the mode of delivery or the duration of labour by AOP. METHODS: Influencing factors on delivery were head circumference, birth-weight, administration of oxytocin, epidural anaesthesia (EA) and parity, and their impact on AOP was analysed. AOP was calculated using three different formulas. Inclusion criteria were vaginal delivery of singletons in cephalic, occipito-anterior presentation. RESULTS: 30/80 recruited women met the study criteria. 90% delivered spontaneously vaginally, 10% had instrument-assisted vaginal delivery. The average AOP in spontaneous vaginal deliveries was 100.9 degrees at cervical dilation less than 5 cm, and 125.3 degrees at cervical dilatation more than 5 cm. The average AOP in instrument-assisted births was 93 degrees and 113.9 degrees when the cervical os was less than 5 cm and more than 5 cm, respectively. Analysis identified a predictive trend towards the duration of labour only by use of the first AOP formula but not regarding the mode of delivery. CONCLUSION: Sonographically assessed AOP during first stage of labour indicates trends regarding the duration of labour. PMID- 29245157 TI - Dynamic cellular complexity of anoxygenic phototrophic sulfur bacteria in the chemocline of meromictic Lake Cadagno. AB - The meromictic Lake Cadagno is characterized by a compact chemocline with high concentrations of anoxygenic phototrophic purple sulfur bacteria (PSB) and green sulfur bacteria (GSB). The co-occurrence of phylogenetically distant bacterial groups such as PSB and GSB in the same ecological niche, makes the chemocline of Lake Cadagno an ideal system for studying the conditions and consequences of coexistence of photosynthetic bacteria populations. In this study, we applied flow cytometry (FCM) as a fast tool to identify metabolic changes due to the production and consumption of inclusion bodies such as sulfur globules (SGBs), and follow population dynamics of closely related anoxygenic photosynthetic sulfur bacteria in their natural environment. Large-celled PSB Chromatium okenii and GSB Chlorobium populations were reliably separated and identified due to differences in auto-fluorescence and cell size. Moreover, we showed that these dominant taxa share the same ecological niche over seasonal periods. Taking advantage of FCM detection of dynamic cellular complexity variation during phases of photosynthetic activity, we identified an unexpected alternation in PSB versus GSB metabolic activity, indicating dynamic interspecific interactions between these two populations. PMID- 29245160 TI - Endoscopic ultrasound-guided gastroenterostomy for the treatment of gastroduodenal obstruction in severe chronic pancreatitis. PMID- 29245159 TI - Serum Sex Hormone Binding Globulin (SHBG) Relation with Different Components of Metabolic Syndrome in Men with Type 2 Diabetes. AB - Sex hormone binding globulin (SHBG) is demonstrated to be decreased in subjects with metabolic syndrome (MetS). The aim of the present study was to investigate the association of SHBG in relation to MetS components among men with type 2 diabetes (T2D). This cross-sectional study was carried out among 429 Saudi T2D male patients aged >30 years. Metabolic syndrome was defined using International Diabetes Federation (IDF) criteria. Fasting blood glucose (FBG), HbA1c, albumin, and lipid parameter were measured. Gonadal hormones, namely total testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and SHBG were determined using ELISA. The SHBG levels of the MetS group was significantly lower than non-MetS group 47.25+/-31.03 nmol/l vs. 56.55+/-37.84 nmol/l; p=0.013. As the MetS score increases, SHBG and HDL levels decrease while weight, BMI, waist circumference, SBP, DBP, FBG, HbA1c, TC, and TG levels increase. SHBG correlated with age, BMI, TG, HDL, TT, free testosterone, and bio-available testosterone. This is the first study that provides detailed analyses of SHBG with MetS components in male diabetic subjects. The mean serum SHBG levels gradually declined with the addition of MetS components in T2D men. TT, free testosterone, and bio-available testosterone remained independently associated with SHBG by multivariable regression analysis. PMID- 29245161 TI - Successful endoscopic treatment of a "windsock" diverticulum: a rare case of duodenal subocclusion. PMID- 29245162 TI - Successful guidewire placement across hilar malignant biliary stricture after deceased donor liver transplantation using new digital cholangioscopy. PMID- 29245163 TI - Long esophageal inlet patch as a rare cause of laryngopharyngeal symptoms. PMID- 29245164 TI - Lumen-apposing metal stent for pediatric use: report of a challenging case. PMID- 29245165 TI - Video capsule endoscopy diagnosis of Takayasu's arteritis. PMID- 29245166 TI - Submucosal tunneling endoscopic resection for seven esophageal leiomyomas. PMID- 29245167 TI - [Are We Really as Happy as We Think We are? A Critical Examination of Work Satisfaction in a University Pediatric Hospital]. AB - Goals Despite numerous reported deficits and an increasingly tense working environment in German hospitals, employees themselves often assess their job satisfaction as being high to very high. Hence, the board of directors does not have important arguments for sustainable improvement of working conditions. This discrepancy between working conditions and subjective satisfaction was the motivation for this work. Methods Data were acquired via an attitude survey at the University Hospital for Children and Adolescents Leipzig, with employees sub divided into medical, nursing and administrative/technical staff. The subjective satisfaction was examined by means of classical global ratings almost exclusively used by companies vs. the much more modern cognitive-emotional concept of the 'Schweizer Modell' describing qualitative job satisfaction. In addition, working hours, work-related effects on mental health, willingness to quit the job and actual dropout rate were compared. Results A rather high level of job satisfaction was revealed while interpreting the classical global ratings. In contrast, the qualitative analysis showed that only 1 in 4 employees was really satisfied with his or her job, amongst doctors even only 1 in 10. Altogether there are four categories of satisfaction. Significant differences between occupational categories were seen when stratifying the data according to age profiles and the evaluation of the consequences of psychological job strain. These differences were not seen in willingness to quit the job. Discussion Reports of high job satisfaction in hospitals in numerous publications can be mostly explained by employees who are resignedly satisfied. This is the psychodynamic outcome of strain compensating. This is not measurable with the concept of classical global ratings. Furthermore, the constructively dissatisfied employees, who are an often-underestimated resource for companies, are neglected. The reduction of strain in these people then mostly results in job changes. PMID- 29245168 TI - [School Entrance Examination for Lateral Entrants - What Can and What Should They be Able to Do? A Discussion Contribution Based on the Data from the Health Authority Frankfurt am Main 2006-2016]. AB - QUESTION: The medical investigation of school beginners is one of the essential tasks of the child and youth services of the health authorities. While in all federal states in Germany, the examination of all school beginners is legally clearly stipulated, the situation for "lateral entry", that is, children of school age, who are moving from a foreign country to a local German community and attending school there, is not clearly regulated in the respective school laws. This article presents the experiences of the lateral entry investigations in Frankfurt am Main. METHOD: All children of school age who moved to Frankfurt from abroad undergo a health check. This encompasses a standardized questionnaire based history with the help of interpreters, including a review of the available vaccination document (case history sheets are available in different languages), an eye examination, hearing test and a physical examination. Children over the age of 15 who came from countries with a high prevalence for tuberculosis had chest x-ray. RESULTS: Between 2006 and June 2016, a total of 8245 children and adolescents were examined, in 4% of the children abnormalities in hearing, and in 22% in visual screening showed noticeable problems, with an increasing trend in recent years. The vaccination status was unknown in two-thirds of the children, one quarter of the children were sufficiently vaccinated against tetanus, diphtheria, polio and pertussis, and 19.5% were immunized against measles (vaccine or disease). Diseases of the respiratory tract, the heart and the circulation were predominant with a total of 4%, followed by musculoskeletal disorders with 3%. Lice infestation was found in 1.7% of children. In 0,7% of 2171 children with chest-X-rays, a conspicuous pulmonary lesion was diagnosed, but no tuberculosis. CONCLUSION: The focus of the lateral entrance examination is a school-related health status. On the basis of experience gained in Frankfurt am Main, it should be pointed out that investigations by the lateral entrants from other countries seem necessary, in particular visual and hearing screening, physical examination and checking the vaccination status, possibly in combination with vaccination. On the other hand, a detailed developmental screening does not appear to be urgent in the case of pupils who will be starting compulsory school, in whom there is no chance for additional encouragement before the start of school. PMID- 29245170 TI - [Consequences of a Failed Project: Introduction and Management of a Hospitalization-Substituting Treatment Model]. AB - This article is a report on a psychiatric project introducing services that substitute in-patient treatment and a new control and management system. The implementation of the project was a failure. Nevertheless, the project has made a contribution to further development of community-based psychiatry. Design, organization and course of the project are described and analyzed from the point of view of the communal actors involved. Effects going beyond the time course of the project have been taken into consideration. The results show that the contracting authority, project developer and local actors involved had differing ideas on the weight attached to different parts of the project as well as on the project goal and resources for carrying out the project. PMID- 29245169 TI - [Mistakes and Drawbacks in German Newspaper Articles on Epidemiologic Studies: "Meat Consumption and Colorectal Cancer" as an Example]. AB - Background Results of epidemiologic studies are often reported in the media because they are of vital interest for many people. Using the example of meat consumption and colorectal cancer, we investigated whether results of epidemiologic studies are reported in an understandable and correct manner in German newspapers and magazines. Methods We gathered all articles published in 13 selected German newspapers and magazines that referred to a press release on meat consumption and colorectal cancer issued by the International Agency for Research on Cancer (IARC) on October 26th 2015. We analyzed these articles with regard to comprehensibility and correctness, and assessed the criteria used by the newspapers and magazines to judge the credibility of the research results. Results In the IARC press release, relative risks were used ("The experts concluded that each 50 gram portion of processed meat eaten daily increases the risk of colorectal cancer by 18%"), which 11 of 13 print media adopted. However, this wording may be misinterpreted by many readers as an increase of 18 percentage points, indicating that absolute risks should be preferred to relative risks in the newspapers and magazines. Only 6 print media reported absolute risks. 5 print media misleadingly reported thresholds for safe meat consumption. Other mistakes were vague descriptions of the index group (e.g. "excessive meat consumption" without specifying the exact amount (g/day)) and the reference group, and lack of time periods for which risks were estimated. To judge the credibility of the research on meat consumption and cancer risk, criteria for the quality of epidemiologic studies such as confounding and precision in the assessment of meat consumption were hardly taken into account. Conclusion Scientific institutions should attach more importance to an understandable presentation of measures of occurrence, measures of effects and important sources of bias in press releases. In the case of meat consumption and colorectal cancer, a higher quality of the press release by the IARC - in particular, reporting absolute instead of relative risks - would probably have led to less misleading publications in the print media. PMID- 29245172 TI - Comment on how foetal growth restriction and preterm birth affects cardiac morphology and function during infancy. PMID- 29245171 TI - Effects of atorvastatin on autophagy in skeletal muscles of diabetic rats. AB - AIMS/INTRODUCTION: Atorvastatin is usually used to decrease the amount of fatty substances in individuals with type 2 diabetes mellitus. However, it can cause side-effects, such as breakdown of skeletal muscle tissue. The present study focused on the effects of atorvastatin on autophagy of the skeletal muscles in diabetic rats. MATERIALS AND METHODS: Diabetes in rats in the diabetic (D) and atorvastatin (T) groups was induced using streptozotocin (65 mg/kg, intraperitoneal injection). Next, rats in the T group were treated with atorvastatin (10 mg/kg/day, intragastric administration), whereas rats in the control and D groups were given water. Additionally, the rats in T and D groups were fed a high-fat and high-sugar diet for 10 weeks. Subsequently, the histopathological changes, and expression levels of microtubule-associated protein 1 light chain 3 (LC3)-I/-II and p62 in the skeletal muscle specimens in the three groups were analyzed. RESULTS: Rats in the T group had reduced lipid droplets, cholesterol and low-density lipoprotein (P < 0.05) levels than those in the D group. Disordered atrophic myocytes, incrassated vascular walls and decreased cross-sectional area of type I fibers were found using hematoxylin eosin and adenosine triphosphatase staining in the D and T groups. The messenger ribonucleic acid and protein levels of LC3-II and the LC3-II/LC3-I ratio were increased in the T group compared with those in the other groups (P < 0.05), whereas the protein level of p62 showed the opposite trend. CONCLUSIONS: Atorvastatin enhanced the autophagy level of skeletal muscles to decrease lipid deposition, which possibly exacerbated myopathy. PMID- 29245173 TI - Patient Perception of Disease-Related Symptoms and Complications in Relapsing Polychondritis. AB - OBJECTIVE: To assess patient-reported symptoms and burden of disease in relapsing polychondritis (RP). METHODS: Patients with RP completed a disease-specific online survey to identify symptoms attributed to illness. Patients were divided into subgroups based upon presence or absence of ear/nose, airway, or joint involvement. Pathway to diagnosis, treatment, and disease-related complications were assessed within each subgroup. RESULTS: Data from 304 respondents were included in this analysis. Prior to diagnosis, most patients with RP went to the emergency room (54%), saw > 3 physicians (54%), and had symptoms for >5 years (64%). A concomitant diagnosis of fibromyalgia and absence of ear/nose or joint involvement was associated with diagnostic delay >1 year. Common diagnoses prior to RP diagnosis included asthma in patients with airway involvement (35% versus 22%; P = 0.03) and ear infection in patients with ear/nose involvement (51% versus 6%; P < 0.01). Patients with joint involvement were more likely to receive a glucocorticoid-sparing agent (85% versus 13%; P < 0.01). Most patients reported a major complication, including disability (25%), tracheomalacia (16%), or hearing loss (34%). Patients with airway involvement reported more tracheomalacia (20% versus 4%; P < 0.01). Disability (24% versus 7%; P < 0.01) and hearing loss (39% versus 11%; P < 0.01) were prevalent in the joint involvement subgroup. CONCLUSION: Patient-reported data in RP highlight a significant burden of disease. Patterns of organ involvement may lead to diagnostic delay and influence treatment decisions, ultimately impacting the development of disease-related complications. Timely diagnosis, standardization of treatment approaches, and prevention of disease-related complications are major unmet needs in RP. PMID- 29245174 TI - Larger temperature response of autumn leaf senescence than spring leaf-out phenology. AB - Climate warming is substantially shifting the leaf phenological events of plants, and thereby impacting on their individual fitness and also on the structure and functioning of ecosystems. Previous studies have largely focused on the climate impact on spring phenology, and to date the processes underlying leaf senescence and their associated environmental drivers remain poorly understood. In this study, experiments with temperature gradients imposed during the summer and autumn were conducted on saplings of European beech to explore the temperature responses of leaf senescence. An additional warming experiment during winter enabled us to assess the differences in temperature responses of spring leaf-out and autumn leaf senescence. We found that warming significantly delayed the dates of leaf senescence both during summer and autumn warming, with similar temperature sensitivities (6-8 days delay per degrees C warming), suggesting that, in the absence of water and nutrient limitation, temperature may be a dominant factor controlling the leaf senescence in European beech. Interestingly, we found a significantly larger temperature response of autumn leaf senescence than of spring leaf-out. This suggests a possible larger contribution of delays in autumn senescence, than of the advancement in spring leaf-out, to extending the growing season under future warmer conditions. PMID- 29245175 TI - Development and Testing of a Hybrid Measure of Muscle Strength in Juvenile Dermatomyositis for Use in Routine Care. AB - OBJECTIVE: To develop and test a hybrid measure of muscle strength for juvenile dermatomyositis (JDM), which is based on the combination of the Manual Muscle Testing in 8 muscles (MMT-8) and the Childhood Myositis Assessment Scale (CMAS) but is more comprehensive than the former and more feasible than the latter. METHODS: The hybrid MMT-8/CMAS (hMC) is composed of all 8 items of the MMT-8 and 3 items of the CMAS: time of head lift, assessment of abdominal muscles, and floor rise. The score ranges 0-100, with 100 indicating normal muscle strength. Validation procedures were conducted using 3 large multinational patient samples, including a total of 810 JDM patients. RESULTS: The hMC revealed face and content validity, good construct validity, excellent test-retest reliability (intraclass correlation coefficient = 0.99), and internal consistency (Cronbach's alpha = 0.94), strong responsiveness to clinical change over time (standardized response mean = 0.8 among patients judged as improved by the caring physician), and satisfactory capacity to discriminate patients judged as being in the states of inactive disease or low, moderate, or high disease activity by the physician (P < 0.001) or patients whose parents were satisfied or not satisfied with the illness course (P < 0.001). CONCLUSION: The hMC was found to possess good measurement properties in a large population of patients with a wide range of disease activity and severity. The new tool, which is primarily intended for use in routine clinical care, should be further tested in other populations of patients evaluated prospectively. PMID- 29245176 TI - High risk of hypogonadism in young male cancer survivors. AB - OBJECTIVE: Cancer and its treatment in childhood and young adulthood can cause hypogonadism, leading to increased risk of long-term morbidity and mortality. The aim of this study was to evaluate the risk of presenting with biochemical signs of hypogonadism in testicular cancer survivors (TCS) and male childhood cancer survivors (CCS) in relation to the type of treatment given. DESIGN: Case-control study. PATIENTS: Ninety-two TCS, 125 CCS (mean age 40 and median age 34 years, respectively; mean follow-up time 9.2 and 24 years, respectively) and a corresponding number of age-matched controls. MEASUREMENTS: Fasting morning blood samples were analysed for total testosterone (TT), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The odds ratios (OR) for hypogonadism, defined as primary, secondary, compensated or ongoing androgen replacement, were calculated for TCS and CCS and for subgroups defined by diagnosis and treatment. RESULTS: Hypogonadism was found in 26% of CCS and 36% of TCS, respectively (OR: 2.1, P = .025 and OR = 2.3, P = .021). Among CCS, the OR was further increased in those given testicular irradiation (OR = 28, P = .004). Radiotherapy other than cranial or testicular irradiation plus chemotherapy, or cranial irradiation without chemotherapy, associated also with increased ORs (OR = 3.7, P = .013, and OR = 4.4, P = .038, respectively). Among TCS, those receiving >4 cycles of cisplatin-based chemotherapy had OR = 17, P = .015. CONCLUSIONS: Biochemical signs of testosterone deficiency are recognized as markers of decreased life expectancy. Thus, the risk of hypogonadism in TCS and CCS should be recognized and emphasizes the need of long-term follow-up for these men. PMID- 29245177 TI - Microplastics as an emerging threat to terrestrial ecosystems. AB - Microplastics (plastics <5 mm, including nanoplastics which are <0.1 MUm) originate from the fragmentation of large plastic litter or from direct environmental emission. Their potential impacts in terrestrial ecosystems remain largely unexplored despite numerous reported effects on marine organisms. Most plastics arriving in the oceans were produced, used, and often disposed on land. Hence, it is within terrestrial systems that microplastics might first interact with biota eliciting ecologically relevant impacts. This article introduces the pervasive microplastic contamination as a potential agent of global change in terrestrial systems, highlights the physical and chemical nature of the respective observed effects, and discusses the broad toxicity of nanoplastics derived from plastic breakdown. Making relevant links to the fate of microplastics in aquatic continental systems, we here present new insights into the mechanisms of impacts on terrestrial geochemistry, the biophysical environment, and ecotoxicology. Broad changes in continental environments are possible even in particle-rich habitats such as soils. Furthermore, there is a growing body of evidence indicating that microplastics interact with terrestrial organisms that mediate essential ecosystem services and functions, such as soil dwelling invertebrates, terrestrial fungi, and plant-pollinators. Therefore, research is needed to clarify the terrestrial fate and effects of microplastics. We suggest that due to the widespread presence, environmental persistence, and various interactions with continental biota, microplastic pollution might represent an emerging global change threat to terrestrial ecosystems. PMID- 29245179 TI - Hot Off the Press: SGEM#196: Gastroparesis-I Feel Like Throwing Up. AB - This randomized controlled trial compared haloperidol along with conventional therapy to placebo along with conventional therapy for gastroparesis in the emergency department. The primary outcomes of pain and nausea scores at 1 hour were significantly improved in the haloperidol group, but not in the placebo group. In this summary, we discuss a quality assessment of the article and summarized the social media commentary from the blog post/podcast. PMID- 29245180 TI - Factors Influencing Cane Use for the Management of Knee Osteoarthritis: A Cross Sectional Survey. AB - OBJECTIVE: To investigate demographic, symptom-related, and cognitive determinants of cane use for knee osteoarthritis (OA) and prioritize the factors that could facilitate cane use in people with no previous cane use. METHODS: A survey of people ages >=45 years with a clinical diagnosis of knee OA was conducted. The survey consisted of the following two sections: 1) demographic and cognitive determinants of cane use assessed via subscales of the Cane Cognitive Mediator Scale, and 2) 19 statements, underpinned by the Behaviour Change Wheel theoretical framework, relating to factors that could facilitate regular cane use. Logistic regression was used to examine determinants of cane use, while a priority pairwise ranking activity (1000minds software) determined the rank order of the 19 statements that could facilitate cane use. RESULTS: A total of 529 people completed Part 1 (80% females; 35% cane users) and 231 people completed Part 2. Age (odds ratio [OR] 1.06, 95% confidence interval [95% CI] 1.03- 1.09), body mass index (BMI) (OR 1.03, 95% CI 1.01-1.06), knee pain >=3 years (OR 2.62, 95% CI 1.63-4.21) and numeric rating scale pain level while walking (OR 1.19, 95% CI 1.09-1.30) were significant independent determinants of cane use. In people who had never used a cane, statements relating to cane-use technique, fitting, knowledge of benefits, and motivation were ranked highest overall. CONCLUSION: Independent determinants of cane use include older age, higher BMI, greater pain duration, and greater severity of knee pain. Strategies targeting an individual's capability and motivation to use a cane may increase cane use among people with knee OA. PMID- 29245178 TI - Review: Transcriptional Regulation of CD4+ T Cell Differentiation in Experimentally Induced Arthritis and Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disorder characterized by chronic inflammation of the joint synovium and infiltration by activated inflammatory cells. CD4+ T cells form a large proportion of the inflammatory cells invading the synovial tissue, and are involved in the RA pathologic process. In general, CD4+ T cells differentiate into various T helper cell subsets and acquire the functional properties to respond to specific pathogens, and also mediate some autoimmune disorders such as RA. Because the differentiation of T helper cell subsets is determined by the expression of specific transcription factors in response to the cytokine environment, these transcription factors are considered to have a role in the pathology of RA. Treg cells control an excess of T cell mediated immune response, and the transcription factor FoxP3 is critical for the differentiation and function of Treg cells. Treg cell dysfunction can result in the development of systemic autoimmunity. In this review, we summarize how the expression of transcription factors modulates T helper cell immune responses and the development of autoimmune diseases, especially in RA. Understanding the role of transcription factors in the pathogenesis of autoimmunity may lead to novel therapeutic strategies to control the differentiation and function of both T helper cells and Treg cells. PMID- 29245181 TI - Revealing a new mode of sensitization induced by mechanical circulatory support devices: Impact of anti-AT1 R antibodies. AB - BACKGROUND: Increased levels of angiotensin II type 1 receptor (AT1 R) antibody have been shown to be associated with allograft rejection. This study aims to determine the rate of development of antibody to AT1 R after mechanical circulatory support device (MCS) implantation, and if the development of strong binding AT1 R antibodies is associated with survival. METHODS: Eighty-eight patients who had one MCS implantation were accessed based on serum availability. Mechanical circulatory support devices in this cohort included pneumatic bilateral paracorporeal ventricular assist device, continuous flow left ventricular assist device, and total artificial heart. RESULTS: Of 88 patients, seven patients had AT1 R antibodies >=40 U/mL preimplantation. For 81 patients who had AT1 R antibodies <40 U/mL, the median value was 8 U/mL. Of these 81 patients, AT1 R antibody levels in 55 (68%) patients reached the saturated concentration (>=40 U/mL) postimplantation (P < .0001), with the highest percentage of patients with the saturated level of AT1 R antibody observed in the pneumatic bilateral paracorporeal ventricular assist device group. Compared to patients without the saturated level of AT1 R antibodies, patients with the saturated AT1 R antibody level had lower 18-month survival (P = .040). CONCLUSION: Mechanical circulatory support devices implantation significantly increases AT1 R antibody levels. The saturated level of AT1 R antibodies is associated with lower patient survival postimplantation. PMID- 29245182 TI - An efficient parallel simulation of unsteady blood flows in patient-specific pulmonary artery. AB - Simulation of blood flows in the pulmonary artery provides some insight into certain diseases by examining the relationship between some continuum metrics, eg, the wall shear stress acting on the vascular endothelium, which responds to flow-induced mechanical forces by releasing vasodilators/constrictors. V. Kheyfets, in his previous work, studies numerically a patient-specific pulmonary circulation to show that decreasing wall shear stress is correlated with increasing pulmonary vascular impedance. In this paper, we develop a scalable parallel algorithm based on domain decomposition methods to investigate an unsteady model with patient-specific pulsatile waveforms as the inlet boundary condition. The unsteady model offers tremendously more information about the dynamic behavior of the flow field, but computationally speaking, the simulation is a lot more expensive since a problem which is similar to the steady-state problem has to be solved many times, and therefore, the traditional sequential approach is not suitable anymore. We show computationally that simulations using the proposed parallel approach with up to 10 000 processor cores can be obtained with much reduced compute time. This makes the technology potentially usable for the routine study of the dynamic behavior of blood flows in the pulmonary artery, in particular, the changes of the blood flows and the wall shear stress in the spatial and temporal dimensions. PMID- 29245184 TI - Evaluation of the Use of Novel Biomarkers to Augment Antimicrobial Stewardship Program Activities. AB - As antimicrobial stewardship increasingly receives worldwide attention for improving patient care by optimizing antimicrobial therapy, programs are evaluating new tools that may augment antimicrobial stewardship activities. Biomarkers are objective, accurate, and reproducible measures that provide information about medical conditions. A systematic literature search using PubMed/MEDLINE databases was performed to evaluate the use of novel biomarkers as additions to the antimicrobial stewardship armamentarium. Procalcitonin may help clinicians discriminate between bacterial and viral infections, help with antimicrobial discontinuation decisions, and predict mortality. beta-d-glucan, Candida albicans germ tube antibody, and galactomannan are useful in suspected fungal infections and may reduce inappropriate antifungal use. Adrenomedullin and soluble triggering receptor on myeloid cells-1 may be useful for mortality prediction and the determination of a need for empiric antibacterials. Although studies evaluating these biomarkers are promising, these biomarkers are not without limitations and should be used in combination with clinical signs, symptoms, or other biomarkers. For successful implementation of biomarker use, stewardship programs should consider the populations most likely to benefit, without using them indiscriminately in all patients. Antimicrobial stewardship programs should facilitate education of clinicians through institutional guidelines to ensure the appropriate use and interpretation of these biomarkers. PMID- 29245183 TI - Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD-1, TIGIT, and TIM-3 in Lymphocytes From Patients With Systemic Sclerosis. AB - OBJECTIVE: Immune dysfunction is an important component of the disease process underlying systemic sclerosis (SSc), but the mechanisms contributing to altered immune cell function in SSc remain poorly defined. This study was undertaken to measure the expression and function of the coinhibitory receptors (co-IRs) programmed cell death 1 (PD-1), T cell immunoglobulin and ITIM domain (TIGIT), T cell immunoglobulin and mucin domain 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3) in lymphocyte subsets from the peripheral blood of patients with SSc. METHODS: Co-IR expression levels on subsets of immune cells were analyzed using a 16-color flow cytometry panel. The functional role of co-IRs was determined by measuring cytokine production after in vitro stimulation of SSc and healthy control peripheral blood mononuclear cells (PBMCs) in the presence of co-IR blocking antibodies. Supernatants from cultures of stimulated PBMCs were added to SSc fibroblasts, and their impact on fibroblast gene expression was measured. Mathematical modeling was used to reveal differences between co-IR functions in SSc patients and healthy controls. RESULTS: Levels of the co-IRs PD-1 and TIGIT were increased, and each was coexpressed, in distinct T cell subsets from SSc patients compared to healthy controls. Levels of TIM-3 were increased in SSc natural killer cells. PD-1, TIGIT, and TIM-3 antibody blockade revealed patient specific roles of each of these co-IRs in modulating activation-induced T cell cytokine production. In contrast to healthy subjects, blockade of TIGIT and TIM 3, but not PD-1, failed to reverse inhibited cytokine production in SSc patients, indicating that enhanced T cell exhaustion is present in SSc. Finally, cytokines secreted in anti-TIM-3-treated PBMC cultures distinctly changed the gene expression profile in SSc fibroblasts. CONCLUSION: The altered expression and regulatory capacity of co-IRs in SSc lymphocytes may contribute to disease pathophysiology by modulating the cytokine-mediated cross-talk of immune cells and fibroblasts at sites of inflammation and/or fibrosis. PMID- 29245186 TI - Endothelial Dysfunction in Early Systemic Lupus Erythematosus Patients and Controls Without Previous Cardiovascular Events. AB - OBJECTIVE: To assess the prevalence and risk factors for endothelial dysfunction detected by peripheral artery tonometry in systemic lupus erythematosus patients with early disease without cardiovascular disease and risk factors. METHODS: All the consecutive adult lupus patients, with a disease duration <5 years, seen in our hospital from December 2014 to March 2016 were considered. We excluded patients with any history of cardiovascular disease or risk factors possibly affecting peripheral artery tonometry. Enrolled patients were matched for sex, age, body mass index, and blood pressure with healthy controls with the same exclusion criteria. Patients and controls received a transthoracic Doppler echocardiogram and an evaluation of endothelial function by peripheral artery tonometry. RESULTS: Twenty patients (100% female) with a median disease duration of 14 months (range 1-58 months), a mean +/- SD age of 42 +/- 15 years, and a mean +/- SD age at diagnosis of 40 +/- 16 years were enrolled and matched with 20 controls. Peripheral artery tonometry showed a significantly higher prevalence of endothelial dysfunction (P = 0.003) and vascular stiffness (P = 0.02), while echocardiography detected a significantly higher prevalence of left ventricular concentric remodeling (P = 0.003), grade I diastolic dysfunction (P = 0.047), and subclinical increase of filling pressures (P = 0.039) in lupus patients compared to controls. Among lupus patients, no features were associated with endothelial dysfunction. CONCLUSION: A high rate of endothelial dysfunction and vascular stiffness occurs in early lupus patients without cardiovascular risk factors and disease. Larger studies are needed to confirm our results and to look for patients' characteristics possibly associated with these abnormalities. PMID- 29245187 TI - News on Relapsing Polychondritis: The Patient's Experience. PMID- 29245185 TI - Contribution of crop model structure, parameters and climate projections to uncertainty in climate change impact assessments. AB - Climate change impact assessments are plagued with uncertainties from many sources, such as climate projections or the inadequacies in structure and parameters of the impact model. Previous studies tried to account for the uncertainty from one or two of these. Here, we developed a triple-ensemble probabilistic assessment using seven crop models, multiple sets of model parameters and eight contrasting climate projections together to comprehensively account for uncertainties from these three important sources. We demonstrated the approach in assessing climate change impact on barley growth and yield at Jokioinen, Finland in the Boreal climatic zone and Lleida, Spain in the Mediterranean climatic zone, for the 2050s. We further quantified and compared the contribution of crop model structure, crop model parameters and climate projections to the total variance of ensemble output using Analysis of Variance (ANOVA). Based on the triple-ensemble probabilistic assessment, the median of simulated yield change was -4% and +16%, and the probability of decreasing yield was 63% and 31% in the 2050s, at Jokioinen and Lleida, respectively, relative to 1981-2010. The contribution of crop model structure to the total variance of ensemble output was larger than that from downscaled climate projections and model parameters. The relative contribution of crop model parameters and downscaled climate projections to the total variance of ensemble output varied greatly among the seven crop models and between the two sites. The contribution of downscaled climate projections was on average larger than that of crop model parameters. This information on the uncertainty from different sources can be quite useful for model users to decide where to put the most effort when preparing or choosing models or parameters for impact analyses. We concluded that the triple-ensemble probabilistic approach that accounts for the uncertainties from multiple important sources provide more comprehensive information for quantifying uncertainties in climate change impact assessments as compared to the conventional approaches that are deterministic or only account for the uncertainties from one or two of the uncertainty sources. PMID- 29245188 TI - Unmet Needs of Aboriginal Australians With Musculoskeletal Pain: A Mixed-Method Systematic Review. AB - OBJECTIVE: Musculoskeletal pain (MSP) conditions are the biggest cause of disability, and internationally, indigenous peoples experience a higher burden. There are conflicting reports about Aboriginal Australians and MSP. We conducted a systematic review to describe the prevalence, associated factors, impacts, care access, health care experiences, and factors associated with MSP among Aboriginal Australians. METHODS: We used a systematic search of quantitative and qualitative scientific and grey literature (PROSPERO# CRD42016038342). Articles were appraised using the Mixed Methods Appraisal Tool. Due to study heterogeneity, a narrative synthesis was conducted. RESULTS: Of 536 articles identified, 18 were included (14 quantitative, 4 qualitative), of high (n = 11), medium (n = 2), and low (n = 5) quality. Prevalence of MSP in Aboriginal populations was similar to or slightly higher than the non-Aboriginal population (prevalence rate ratio 1.1 for back pain, 1.2-1.5 for osteoarthritis [OA], and 1.0-2.0 for rheumatoid arthritis). Aboriginal people accessed primary care for knee or hip OA at approximately half the rate of non-Aboriginal people, and were less than half as likely to have knee or hip replacement surgery. Communication difficulties with health practitioners were the main reason why Aboriginal people with MSP choose not to access care. No articles reported interventions. CONCLUSION: Findings provide preliminary evidence of an increased MSP burden among Aboriginal Australians, and particularly for OA, a mismatch between the disease burden and access to health care. To increase accessibility, health services should initially focus on improving Aboriginal patients' experiences of care, in particular by improving patient-practitioner communication. Implications for care and research are outlined. PMID- 29245189 TI - Right internal thoracic artery or saphenous vein for grafting the right coronary artery? PMID- 29245190 TI - To skeletonize the internal thoracic artery or not to skeletonize? To be or not to be! PMID- 29245191 TI - Left-right choice in coronary artery bypass grafting surgery. PMID- 29245192 TI - Topographic mapping of regional contractile injury in ischemic mitral regurgitation: Are regional shape deformation indices answer enough? PMID- 29245194 TI - High-risk surgery as an alternative to heart transplant or ventricular assist device. PMID- 29245193 TI - High-risk cardiac surgery as an alternative to transplant or mechanical support in patients with end-stage heart failure: A seemingly viable option. PMID- 29245195 TI - High-risk cardiac surgery, transplant, or mechanical support? The answer can be "all of the above". PMID- 29245196 TI - Patient selection is the key issue in the surgical treatment of patients with end stage heart failure. PMID- 29245197 TI - Pulmonary hypertension arising from left heart disease causes intrapulmonary venous arterialization in rats. PMID- 29245198 TI - Not a Cinderella story. PMID- 29245199 TI - Elusive mechanisms responsible for pulmonary hypertension. PMID- 29245200 TI - "Cui periculum"-Who is at risk? PMID- 29245201 TI - Effect of administration of allopurinol on postoperative outcomes in patients undergoing intracardiac repair of tetralogy of Fallot. AB - OBJECTIVE: To determine effects of allopurinol administration on outcomes following intracardiac repair of tetralogy of Fallot (TOF). MATERIALS AND METHODS: Fifty patients undergoing TOF repair were randomized to 2 groups of 25 each: the allopurinol group (n = 25) and the placebo group (n = 25). Postoperatively, inotropic score, rhythm, duration of mechanical ventilation, cardiac output, intensive care unit (ICU) stay, and hospital stay were assessed. Plasma troponin-I, superoxide dismutase (SOD), interleukin (IL) 1-beta, IL-6, and malondialdehyde were measured serially. RESULTS: Inotropic score was lower in the allopurinol compared with placebo group (11.04 +/- 5.70 vs 17.50 +/- 7.83; P = .02). Duration of ICU and hospital stay was lower in the allopurinol group. Plasma levels of SOD preoperative were (2.87 +/- 1.21 U/mL vs 4.5 +/- 2.08 U/mL; P = .012), immediately following release of crossclamp (2.32 +/- 0.98 U/mL vs 5.32 +/- 2.81 U/mL; P < .001), and after termination of CPB (2.18 +/- 1.0.78 U/mL vs 3.44 +/- 1.99 U/mL; P = .003) between the placebo versus allopurinol group, respectively. Postoperative levels of IL1-beta and IL-6 were lower in the allopurinol group. Malondialdehyde levels following CPB were lower in the allopurinol group (11.80 +/- 2.94 pg/mL in the placebo vs 9.16 +/- 3.02 g/mL in the allopurinol group; P < .001). CONCLUSIONS: Allopurinol administration in patients undergoing intracardiac repair of TOF is associated with reduced inotropic scores, duration of mechanical ventilation, ICU stay, and hospital stay and favorable biochemical markers of inflammation. Further studies in multiple setups are needed before recommending it as a routine practice. PMID- 29245202 TI - Zika virus in perspective. PMID- 29245203 TI - The importance of R0. PMID- 29245204 TI - Results in patients undergoing reoperative resection? PMID- 29245205 TI - The value of collaboration between thoracic surgeons and radiation oncologists while awaiting evidence in operable stage i non-small cell lung cancer. PMID- 29245206 TI - The burden of proof. PMID- 29245207 TI - Proposal for building an infrastructure for international randomized, control trials and a comprehensive registry of infective endocarditis. PMID- 29245208 TI - Randomized clinical trials of surgery for infective endocarditis: Reality versus expectations! PMID- 29245209 TI - keep fumbling around in the dark when it comes to infective endocarditis, or produce new, reliable data to redesign the guidelines? PMID- 29245210 TI - Obesity as a confounding factor in a study evaluating the role of M1 polarization in aortic valve calcification. PMID- 29245211 TI - Valve choice: Do data from the past misinform us as technology advances? PMID- 29245212 TI - Case report: A first case of flaxseed-induced anaphylaxis in Korea. AB - RATIONALE: Anaphylaxis is a serious, generalized allergic reaction typically triggered by drugs, food, and bee venom, which can be life-threatening. Seeds are one of the major food allergens and can cause anaphylaxis as well as systemic hypersensitivity reactions. Flaxseed has been widely used crop for numerous purposes, such as in alternative medicine and as a dietary supplement, hypersensitivity to it has rarely been reported. PATIENT CONCERNS: A 42-year-old female presenting with facial edema, dyspnea and urticaria after ingested half teaspoon of flaxseed flour 30 minutes previously. DIAGNOSES: A skin prick test for heated flaxseed flour extract showed negative responses, but intradermal test showed positivity which suggested an Immunoglobulin E-mediated reaction. INTERVENTIONS: The patient was instructed to avoid future ingestion of flaxseed. OUTCOMES: The patient had no recurrence of symptoms at 1-year follow-up. LESSONS: This is the first case of flaxseed-induced anaphylaxis in Korea, confirmed by an intradermal skin test. PMID- 29245213 TI - A case report of atypical nodular cutaneous lupus mucinosis. AB - RATIONAL: Nodular cutaneous lupus mucinosis is regarded as a distinctive cutaneous mucinosis deposition with systemic lupus erythematosus(SLE). All typical cases occurred as asymptomatic cutaneous papules, nodules, or plaques on the trunk, upper and lower extremities, and face. Histopathology is mainly revealed abundant mucin deposits among splayed collagen bundles in the dermis. At the same time we can find A the typical clinical manifestations and biological evidence of SLE. Here, we report the first case of nodular cutaneous lupus mucinosis that did not present with any prior symptoms or history of SLE. PATIENT CONCERNS: We report the first case of nodular cutaneous lupus mucinosis that did not present with any prior symptoms or history of SLE. The patient was 34 years old. One year before admission, nodules began to appear on the elbows, chest, and back, and 2 months before admission erythema occurred on the face. Other notable clinical symptoms were not observed and had no prior history of SLE. DIAGNOSES: Initially, this patient was misdiagnosed by other clinics as having eczema. After histopathological assessment of skin biopsy and examination of antinuclear antibody signals, the patient was correctly diagnosed with nodular cutaneous lupus mucinosis. INTERVENTIONS: Followed administration of systemic steroids and hydroxychloroquine. OUTCOMES: the eruptions quickly disappeared and laboratory indicators improved. LESSONS: This case highlights the need for diagnostic vigilance in cases involving papules and nodules initially developing on the chest and elbows in the absence of obvious lupoid symptoms. We recommend a lower threshold for performing histopathological analysis and examination of antinuclear antibody signals in view of the rare but serious possibility of nodular cutaneous lupus mucinosis. PMID- 29245214 TI - The efficiency and safety of local liposomal bupivacaine infiltration for pain control in total hip arthroplasty: A systematic review and meta-analysis. AB - OBJECTIVE: This meta-analysis aimed to compare the efficiency and safety of local liposomal bupivacaine infiltration and traditional cocktail analgesia for pain management in total hip arthroplasty (THA). METHODS: PubMed, Embase, Web of science, Medline, and Cochrane library databases were systematically searched. INCLUSION CRITERIA: Participants: patients planned for a THA with a diagnosis of hip osteoarthritis. INTERVENTIONS: liposomal bupivacaine was administrated in the experimental groups for pain control. Comparisons: the control groups received local infiltration of traditional analgesics. OUTCOMES: pain scores, opioids consumption, and postoperative complications among the patients. STUDY DESIGN: randomized control trials (RCTs) and non-RCTs. Methodological Index for Non Randomized Studies scale was used to assess the methodological quality of the included studies. Meta-analysis was conducted by Stata 11.0 software. Systematic review registration number is CRD42017120981. RESULTS: Four articles involving 308 participants were included. Current meta-analysis revealed that there were significant differences regarding postoperative pain score at 12 hours (standard mean difference [SMD] = -0.496, 95% CI: -0.717 to -0.275, P = .000), 24 hours (SMD = -0.537, 95% CI: -0.760 to -0.313, P = .000), and 48 hours (SMD = -0.802, 95% CI: -1.029 to -0.576, P = .000). Liposomal bupivacaine intervention was found to significantly decrease opioid consumption at 12 hours (SMD = -0.544, 95% CI: 0.766 to -0.323, P = .000), 24 hours (SMD = -0.357, 95% CI: -0.577 to -0.138, P = .001), and 48 hours (SMD = -0.370, 95% CI: -0.589 to -0.151, P = .001). CONCLUSION: Local liposomal bupivacaine infiltration could significantly reduce visual analogue scale (VAS) scores and opioid consumption within the first 48 hours following THA surgery. In addition, there was a decreased risk of nausea and vomiting in liposomal bupivacaine groups. The overall evidence level was low, which means that further research is likely to significantly alter confidence levels in the effect, as well as potentially changing the estimates. In any subsequent research, further studies should focus on the optimal dose of local anesthetics and the potential adverse side effects. In addition, surgeries that can improve pain relief and enable faster rehabilitation and earlier discharges should also be explored. Several potential limitations of this study should be noted. Four articles are included and the sample size in each trial is small. Some important outcome parameters such as range of motion were not fully described and could not be included in the meta-analysis. All included studies were retrospectives which may decrease evidence levels for the meta-analysis. The evidence quality for each outcome was low which may influence the results of the meta-analysis. Short-term follow-ups may lead to the underestimation of complications, such as neurotoxicity and cardiotoxicity. Publication bias is an inherent weakness that exists in all meta-analyses. PMID- 29245215 TI - A giant and extensive solitary Peutz-Jeghers-type polyp in the antrum of stomach: Case report. AB - RATIONALE: A solitary Peutz-Jeghers-type polyp is a hamartomatous polyp which without either mucocutaneous pigmentation or a family history of Peutz-Jeghers syndrome (PJS). It can occur in all of the gastrointestinal tract, but it is extremely rare in the stomach. PATIENT CONCERNS: A 53-year-old man was admitted to the local hospital with left upper abdominal pain lasting 2 weeks. A gastroscopy showed a giant and extensive bulging lesion on the greater curvature and posterior and anterior walls of the gastric antrum, involving three-quarters of the gastric wall. Endoscopic ultrasonography showed a muscularis mucosa lesion. DIAGNOSES: A solitary Peutz-Jeghers-type polyp in the antrum of stomach. INTERVENTIONS: The patient underwent an endoscopic submucosal dissection (ESD). OUTCOMES: The patient recovered quickly, without any complications. LESSONS: This is the second largest gastric solitary Peutz-Jeghers-polyp reported until now, and the largest gastric solitary Peutz-Jeghers type-polyp treated by endoscope. PMID- 29245216 TI - Magnetic resonance imaging of the spinal cord in the evaluation of 3 patients with sensory neuronopathies: Diagnostic assessment, indications of treatment response, and impact of autoimmunity: A case report. AB - RATIONALE: Sensory neuronopathy can be a devastating peripheral nervous system disorder. Profound loss in joint position is associated with sensory ataxia, and reflects degeneration of large-sized dorsal root ganglia. Prompt recognition of sensory neuronopathies may constitute a therapeutic window to intervene before there are irreversible deficits. However, nerve-conduction studies may be unrevealing early in the disease course. In such cases, the appearance of dorsal column lesions on spinal-cord MRI can help in the diagnosis. However, most studies have not defined whether such dorsal column lesions may occur within earlier as well as chronic stages of sensory neuronopathies, and whether serial MRI studies can be used to help assess treatment efficacy. In this case-series of three sensory neuronopathy patients, we report clinical characteristics, immunological markers, nerve-conduction and skin-biopsy studies, and neuroimaging features. PATIENT CONCERNS: All three patients presented with characteristic features of sensory neuronopathy with abnormal spinal-cord MRI studies. Radiographic findings included non-enhancing lesions in the dorsal columns that were longitudinally extensive (spanning >= 3 vertebral segments). DIAGNOSES: All patients had anti-Ro/SS-A and/or anti-La/SS-B antibodies, with patients one and two having Sjogren's syndrome. MRI findings were similar when performed in the earlier stages of a sensory neuronopathy (patient one, after four months) and chronic stages (patients two and three, after five and three years, respectively). INTERVENTIONS: Patient one was treated with rituximab combined with intravenous immunoglobulin therapy. OUTCOMES: Patient one was initially wheelchair-bound and had improved ambulation after treatment. In this patient, serial MRI studies revealed partial resolution of dorsal column lesions, associated with decreased sensory ataxia and improved nerve-conduction studies. LESSONS: In addition to vitamin B12 and copper deficiency, it is important to include sensory neuronopathies in the differential diagnosis of dorsal column lesions. MRI spinal-cord lesions have similar appearances in the earlier as well as chronic phases of a sensory neuronopathy, and therefore suggest that such dorsal column lesions may reflect inflammatory as well as a gliotic burden of injury. MRI may also be a useful longitudinal indicator of treatment response. PMID- 29245217 TI - Efficacy and safety of Mobi-C cervical artificial disc versus anterior discectomy and fusion in patients with symptomatic degenerative disc disease: A meta analysis. AB - BACKGROUND: Total disc replacement (TDR) using Mobi-C cervical artificial disc might be promising to treat symptomatic degenerative disc disease. However, the results remained controversial. We conducted a systematic review and meta analysis to compare the efficacy and safety of Mobi-C cervical artificial disc and anterior cervical discectomy and fusion (ACDF) in patients with symptomatic degenerative disc disease. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of Mobi-C versus ACDF on the treatment of symptomatic degenerative disc disease were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. The primary outcomes were neck disability index (NDI) score, patient satisfaction, and subsequent surgical intervention. Meta-analysis was performed using the random-effect model. RESULTS: Four RCTs were included in the meta-analysis. Overall, compared with ACDF surgery for symptomatic degenerative disc disease, TDR using Mobi-C was associated with a significantly increased NDI score (Std. mean difference = 0.32; 95% CI = 0.10-0.53; P = .004), patient satisfaction (odds risk [OR] = 2.75; 95% confidence interval [CI] = 1.43-5.27; P = .002), and reduced subsequent surgical intervention (OR = 0.20; 95% CI = 0.11 0.37; P < .001). Mobi-C was found to produce comparable neurological deterioration (OR = 0.77; 95% CI = 0.35-1.72; P = .53), radiographic success (OR = 1.18; 95% CI = 0.39-3.59; P = .77), and overall success (OR = 2.13; 95% CI = 0.80-5.70; P = .13) compared with ACDF treatment. CONCLUSION: Among the 4 included RCTs, 3 articles were studying patients with 1 surgical level, and 1 article reported 2 surgical levels. When compared with ACDF surgery in symptomatic degenerative disc disease, TDR using Mobi-C cervical artificial disc resulted in a significantly improved NDI score, patient satisfaction, and reduced subsequent surgical intervention. There was no significant difference of neurological deterioration, radiographic success, and overall success between TDR using Mobi-C cervical artificial disc versus ACDF surgery. TDR using Mobi-C cervical artificial disc should be recommended for the treatment of symptomatic degenerative disc disease. PMID- 29245218 TI - Bilateral anterior shoulder dislocation as a result of manipulation: A case report. AB - RATIONALE: Bilateral anterior shoulder dislocation is clinically rare and has been reported to be related to high-speed sports. PATIENT CONCERNS: A 76-year-old woman presented with bilateral shoulders pain after traditional Chinese manipulation. DIAGNOSES: She was diagnosed with bilateral anterior dislocations, and a closed reduction was immediately performed. INTERVENTION: The patient was referred for rehabilitation 3 days later, and bilateral rotator cuff injuries were identified from musculoskeletal ultrasound. After 4 weeks of physical therapy, the patient's shoulder pain had reduced and the passive ROM was nearly full. OUTCOMES: At 1-year follow-up, only mild intermittent shoulder pain was noted, and there was no limitation of shoulder ROM. LESSONS: This case illustrates that patients with acute shoulder injuries who receive proper diagnosis and treatment can achieve good outcomes. Therefore, patients with musculoskeletal disorders should seek qualified specialists for accurate diagnosis and appropriate management. PMID- 29245219 TI - A novel germline mutation (c.A527G) in STK11 gene causes Peutz-Jeghers syndrome in a Chinese girl: A case report. AB - RATIONALE: Peutz-Jeghers syndrome (PJS) is a Mendelian autosomal dominant disease caused by mutations in the tumor suppressor gene, serine/threonine kinase 11 (STK11). The features of this syndrome include gastrointestinal (GI) hamartomas, melanin spots on the lips and the extremities, and an increased risk of developing cancer. Early onset of disease is often characterized by mucocutaneous pigmentation and intussusception due to GI polyps in childhood. PATIENT CONCERNS: A girl with a positive family history grew oral pigmentation at 1 and got intussusception by small bowel hamartomas at 5. DIAGNOSES: She was diagnosed with PJS based on oral pigmentation and a positive family history of PJS. INTERVENTIONS: Enteroscopy was employed to treat the GI polyps. Sanger sequencing was used to investigate STK11 mutation in this family. OUTCOMES: A large jejunal polyp together with other smaller ones was resected, and the girl recovered uneventfully. We discovered a heterozygous substitution in STK11, c.A527G in exon 4, in the girl and her father who was also a PJS patient, and the amine acid change was an aspartic acid-glycine substitution in codon 176. This mutation was not found in other healthy family members and 50 unrelated non-PJS controls, and it is not recorded in databases, which prove it a novel mutation. Evolutionary conservation analysis of amino acid residues showed this aspartic acid is a conserved one between species, and protein structure prediction by SWISS-MODEL indicated an obvious change in local structure. In addition, PolyPhen-2 score for this mutation is 1, which indicates it probably damaging. LESSONS: PJS can cause severe complication like intussusception in young children, and early screening for small bowel may be beneficial for these patients. The mutation of STK11 found in this girl is a novel one, which enlarges the spectrum of STK11. Our analysis supported it a causative one in PJS. PMID- 29245220 TI - Case report of intestinal non-rotation, heterotaxy, and polysplenia in a patient with pancreatic cancer. AB - RATIONALE: Heterotaxy with polysplenia is an extremely rare congenital condition resulting from abnormal arrangement of organs in the abdominal and thoracic cavities during embryologic development. When a malignancy such as pancreatic cancer develops under these conditions, surgical resection becomes particularly complex. This case report demonstrates successful pancreatic cancer resection despite the patient's complicated anatomy. PATIENT CONCERNS: An 82-year-old female presented to our institution with complaints of mild right upper quadrant pain radiating to the mid-epigastric region. DIAGNOSES: Physical examination revealed jaundice with scleral icterus consistent with obstructive jaundice. Radiographic imaging revealed hepatic duct dilation with several anatomic anomalies including small bowel location in the right upper abdomen, cecum, and appendix in the left lower quadrant, reversed superior mesenteric artery and superior mesenteric vein positions, and right-sided duodenal-jejunal flexture as well as an entirely right-sided pancreas, and left lower pelvis with >=6 separate splenules. These findings resulted in a diagnosis of heterotaxy syndrome with polysplenia. INTERVENTIONS: Careful preoperative planning and total pancreatectomy was performed without complication. OUTCOMES: The patient recovered well. Pathologic examination of the pancreatic mass revealed moderately/poorly differentiated invasive pancreatic duct adenocarcinoma. The patient remains alive and well without signs of recurrent disease at the 2-year follow-up. LESSONS: Given the wide range of anatomical variants observed in patients with heterotaxy syndrome, a thorough radiologic assessment is necessary before engaging in any surgical procedure. In our case, preoperative identification of the various anatomic anomalies, such as the short and vertically oriented pancreas, the porta hepatis position anterior to the duodenum, the nonrotation of the intestines and the anomalous origin of the right hepatic artery allowed us to perform a safe and uncomplicated total pancreatectomy. PMID- 29245221 TI - Deceleration capacity as a risk predictor in patients presenting to the emergency department with syncope: A prospective exploratory pilot study. AB - Syncope is a common cause for admission to the emergency department (ED). Due to limited clinical resources there is great interest in developing risk stratification tools that allow identifying patients with syncope who are at low risk and can be safely discharged. Deceleration capacity (DC) is a strong risk predictor in postinfarction and heart failure patients. The aim of this study was to evaluate whether DC provides prognostic information in patients presenting to ED with syncope.We prospectively enrolled 395 patients presenting to the ED due to syncope. Patient's electrocardiogram (ECG) for the calculation of DC was recorded by monitoring devices which were started after admission. Both the modified early warning score (MEWS) and the San Francisco syncope score (SFSS) were determined in every patient. Primary endpoint was mortality after 180 days.Eight patients (2%) died after 180 days. DC was significantly lower in the group of nonsurvivors as compared with survivors (3.1 +/- 2.5 ms vs 6.7 +/- 2.4 ms; P < .001), whereas the MEWS was comparable in both was comparable in both groups. (2.1 +/- 0.8 vs 2.1 +/- 1.0; P = .84). The SFSS failed at identifying 4 of 8 nonsurvivors (50%) as high risk patients. No patient with a favorable DC (>=7 ms) died (0.0% vs 3.7%; P = .01, OR 0.55 (95% CI 0.40-0.76), P < .001). In the receiver operating characteristic (ROC) analysis DC yielded an area under the curve of 0.85 (95% CI 0.71-0.98).Our study demonstrates that DC is a predictor of 180-days-mortality in patients admitted to the ED due to syncope. Syncope patients at low risk can be identified by DC and may be discharged safely. PMID- 29245222 TI - Specific demographic factors could predict deceased potential cornea donors: A retrospective study from Beijing Tongren Hospital Eye Bank. AB - Compared with evident cornea donors (ECDs), deceased potential cornea donors (DPCDs) have no obvious donor identifications to reference, which causes many eligible cornea tissues to be wasted. The demographic characteristics of DPCDs might be different from those of ECDs owing to the following different features: donation consent provided by relatives and willingness to donate before death. Thus, the aim of this study is to reveal the demographic characteristics of DPCDs by comparing DPCDs and ECDs.The demographic factors of 138 donors (both DPCDs and ECDs) were collected from the Beijing Tongren Hospital Eye Bank database and analyzed. To differentiate DPCDs from ECDs using the above-mentioned features, we interviewed the relatives of the donors by telephone. The relatives' attitudes toward cornea donation and their suggestions for our donation service were also acquired during the interview. Two logistic regressions were performed to reveal the demographic factors influencing the 2 features and indicate DPCDs.The donors had certain demographic characteristics (elderly, secondary, or tertiary education level, central district resident), and the most frequent cause of death for the donors was a malignant tumor (n = 56, 43.1%). All the relatives had positive attitudes toward cornea donations, and they hoped to increase publicity efforts to encourage more people to donate and establish more convenient and efficient access for cornea donation. In univariate regressions, age (P = .004, >50 years: odds ratio [OR] = 6.89, 95% confidence interval [CI]: 1.82-26.05), marital status (P = .043, divorced: OR = 9.00,95% CI: 1.33-60.80) significantly influenced relative consent, whereas age (P = .001, >50 years: OR = 15.00, 95% CI: 3.00-74.98), and family address (P = .001, central district: OR = 1) were significant factors influencing the willingness to donate before death. In multivariate regression, age (P = .021, >50 years: OR = 8.14, 95% CI: 1.37-48.41) was the only significant factor influencing relative consent. Similarly, age (P = .02, >50 years: OR = 7.55, 95% CI: 1.21-47.25) was the only factor influencing willingness to donate before death.In conclusion, specific demographic factors could indicate DPCDs and might reveal directions and methods for cornea donation coordination in the future. PMID- 29245223 TI - Effect of preoperative pregabalin as an adjunct to a multimodal analgesic regimen in video-assisted thoracoscopic surgery: A randomized controlled trial. AB - BACKGROUND: Depending on the type of injury, the pain mechanisms are multifactorial. Preoperative pregabalin administrations as an adjunct to a multimodal postoperative pain management strategy have been tested in various surgical settings. The purpose of current study was to evaluate the effects of preoperative pregabalin administration on postoperative pain intensity and rescue analgesic requirement following video-assisted thoracoscopic surgery (VATS). METHODS: Sixty adult patients undergoing VATS were randomly assigned either to receive pregabalin 150 mg (Pregabalin group) or placebo (Control group) 1 hour before anesthesia. Primary efficacy variable was pain intensity. Secondary efficacy variables were the requirement of rescue analgesics, total volume of intravenous patient-controlled analgesia (IV-PCA), and adverse effects induced by pregabalin or IV-PCA. RESULTS: Pain intensity scores at post-anesthesia care unit (PACU), 6 and 24 hours were lower significantly in the Pregabalin group compared with the Control group (mean [SD]; 5.6 [2.0] vs 6.8 [1.8]; mean difference: 1.2, 95% CI of difference: 0.2166-2.1835, P = .018, mean [SD]; 3.8 [1.9] vs 5.6 [1.4]; mean difference: 1.8, 95% CI of difference: 1.0074-2.7260, P = .001 and mean [SD]; 2.6 [1.6] vs 3.5 [1.5]; mean difference: 0.9, 95% CI of difference: 0.0946 1.7054, P = .029, respectively]. Also, the frequency of additional rescue drug administered at PACU (median [interquartile range]; 2 [2-3] vs 1 [1-2], P = .027) was significantly less in the Pregabalin group. The incidences of adverse effects related to pregabalin or IV-PCA were not different between the groups. CONCLUSION: A single administration of pregabalin 150 mg before VATS decreased postoperative pain scores and incidence of additional rescue analgesics in the immediate postoperative period without increased risk of adverse effects. PMID- 29245224 TI - A primary cavernous hemangioma of the thyroid gland: A case report and literature review. AB - RATIONALE: Thyroid hemangioma is benign and associated with fine-needle aspiration (FNA) biopsy or trauma in most cases. Its differential diagnosis is very difficult. PATIENT CONCERNS: We presented the case of a 48-year-old man complained of slowly progressed swelling in the anterior neck for 20 years. DIAGNOSES: Ultrasound and CT scan revealed a hypoechogenic and heterogeneous mass measuring 4 * 3.5 cm located in the right lobe of thyroid gland. Postoperative pathological and immunohistochemical examinations of the surgical specimen revealed a primary hemangioma of the thyroid gland. INTERVENTIONS: The patient received a right lobectomy of the thyroid. OUTCOMES: The patient had been followed up for 10 months after surgery without complications and remained asymptomatic. LESSONS: Primary thyroid hemangioma should be considered when there is a well-circumscribed capsule mass on medical imaging without history of FNA or any other cervical procedures or trauma. PMID- 29245225 TI - Efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis: A systematic review and meta-analysis. AB - INTRODUCTION: Bazedoxifene may be promising to treat osteoporosis of postmenopausal women. We conducted a systematic review and meta-analysis to explore the efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of bazedoxifene on osteoporosis of postmenopausal women were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. The primary outcomes were vertebral fracture and spine BMD at 3 and 7 years. RESULTS: Four RCTs are included in the meta-analysis. Overall, compared with placebo intervention in postmenopausal women with osteoporosis, bazedoxifene intervention can significantly reduce the risk of vertebral fracture [risk risks (RRs) = 0.69; 95% confidence interval (95% CI) = 0.52-0.93; P = .01], and increase spine BMD at 3 years (Std. mean difference = 1.71; 95% CI = 1.55-1.87; P < .005) and 7 years (Std. mean difference = 8.31; 95% CI = 8.07-8.55; P < .005). Bazedoxifene intervention results in no increase in adverse events (RR = 1.00; 95% CI = 0.99 1.00; P = .34), serious adverse events (RR = 1.04; 95% CI = 0.97-1.12; P = .31), myocardial infarction (RR = 0.88; 95% CI = 0.51-1.52; P = .64), stroke (RR = 0.97; 95% CI = 0.64-1.46; P = .87), venous thromboembolic event (RR = 1.56; 95% CI = 0.92-2.64; P = .10), and breast carcinoma (RR = 1.03; 95% CI = 0.59-1.79; P = .92). CONCLUSIONS: Compared with placebo intervention for the osteoporosis of postmenopausal women, bazedoxifene intervention is found to significantly reduce the incidence of vertebral fracture and increase spine BMD at 3 and 7 years, and results in no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic event, and breast carcinoma. PMID- 29245226 TI - Clinical analysis of the impact of sublobectomy on pulmonary function. AB - The present study investigated and analyzed the clinical impact of sublobectomy on pulmonary functions.Changes in pulmonary function before and after sublobectomy were compared to the changes after lobectomy.Changes in the pulmonary function before and after sublobectomy and lobectomy did not exhibit remarkable differences in long-term effects. Surgery-related indexes of the sublobectomy group were significantly lower than those of the lobectomy group (P < .05). The indexes of pulmonary function both before and after surgery in the sublobectomy group were not associated with a significant decrease in the quality of survival based on pulmonary function as the main index (P > .05).Compared with lobectomy, sublobectomy maximally retained the normal healthy pulmonary tissue, with similar local recurrence rate, 5-year recurrence-free survival rate, and 5 year survival rate. Sublobectomy decreased the impact on respiratory functions to the minimum. After the operation, the quality of survival with pulmonary functions as the main index did not decrease significantly. Therefore, sublobectomy could be an appropriate choice for elderly patients with poor cardiopulmonary function or with chronic diseases. PMID- 29245227 TI - Spinal intramedullary tuberculoma following pulmonary tuberculosis: A case report and literature review. AB - RATIONALE: Spinal intramedullary tuberculoma (IMTB) is a rare disease that accounts for 1 to 2/100,000 patients with tuberculosis. We presented a case with pulmonary tuberculosis and concurrent IMTB at C3 to C5 level and reviewed the recent case series and discussed the diagnosis, treatment, and outcome. PATIENT CONCERNS: A 33-year-old male had concurrent pulmonary TB and IMTB at the C3 to C5 level. He had quadriplegia (muscle power 0 at 4 limbs) and sensory loss below C5 level. He also had incontinence, anal tone loss, and paradoxical respiratory pattern. DIAGNOSIS: Spinal magnetic resonance imaging (MRI) showed a 25 11mm intramedullary lesion at C3/C4 level. Under the impression of IMTB, he underwent surgery. INTERVENTION: We performed C3 to C5 laminectomy and en bloc removal of the tumor. The patient kept receiving anti-TB medications after the surgery. OUTCOME: His 4 limbs muscle power had improved but could not be liberated from the endotracheal tube, so tracheostomy was performed. Muscle power gradually increased to 3 points in his upper limbs and to 2 points in his lower limbs. Sensation in his 4 limbs gradually improved as well. LESSONS: IMTB is a rare disease that should be treated with a combination of medication and surgery. For patients with prominent spinal cord compression and neurological symptoms, early operation to remove the tumor is necessary. PMID- 29245228 TI - Use of concomitant variceal embolization and prophylactic antiplatelet/anticoagulative in transjugular intrahepatic portosystemic shunting: A retrospective study of 182 cirrhotic portal hypertension patients. AB - Transjugular intrahepatic portosystemic shunting (TIPS) is an effective treatment modality for refractory variceal bleeding and ascites in patients with cirrhotic portal hypertension (CPH). Variceal rebleeding and shunt dysfunction are major post-TIPS morbidities. This study aimed to retrospectively evaluate the effectiveness and safety of use of concomitant variceal embolization and prophylactic antiplatelet/anticoagulative in patients with CPH undergoing TIPS. Between October 2006 and October 2011, 182 patients with CPH were retrospectively and consecutively hospitalized for elective TIPS with Fluency stenting. Concomitant variceal embolization was given after establishing the shunt. Subcutaneous heparin was given after TIPS and replaced by oral clopidogrel, aspirin, or warfarin for at least 6 months. Main outcome measures included shunt patency rate, recurrence of CPH (rebleeding and/or refractory ascites), hepatic encephalopathy (HE) frequency, and post-TIPS survival. The cumulative primary patency rate was 96%, 94%, 90%, 88%, and 88% at 6, 12, 24, 36, and 48 months, respectively. Shunt stenosis occurred in 16 (9%) patients, gastrointestinal (GI) rebleeding in 32 (17.5%) patients, recurrence of refractory ascites 44 (48%) patients, HE in 42 (23%) patients, and death in 36 (20%) patients during the follow-up period. Use of concomitant variceal embolization and prophylactic antiplatelet/anticoagulative was associated with a favorable shunt patency and a low risk of GI rebleeding. PMID- 29245229 TI - Novel chromosomal microduplications associated with dolichocephaly craniosynostosis: A case report. AB - INSTRUCTION: Craniosynostosis is a human disorder characterized by the premature fusing of the cranial sutures in infants. Point mutations in hotspot genes such as FGFRs are the well-recognized causes of syndromic craniosynostosis, but chromosomal abbreviations may also play an important role in developing this disease. Here, we report the case in China of a 2-year-boy dolichocephaly craniosynostosis. Karyotyping by both G-bind staining and array-based DNA hybridization identified microduplications on Chromosomes 8p11.22 q12.1 and 16q11.2 q21, but none of the known pathogenic mutations was detected. CONCLUSIONS: This finding not only expands knowledge on the genetic mechanism of craniosynostosis but also provides a new target for the early diagnosis of this rare disease. PMID- 29245230 TI - Injury of the cortico-ponto-cerebellar tract in a patient with mild traumatic brain injury: A case report. AB - RATIONALE: We report on a patient with injury of the cortico-ponto-cerebellar tract (CPCT) following mild traumatic brain injury (TBI), diagnosed by diffusion tensor tractography (DTT). PATIENT CONCERNS: A 53-year-old female patient was injured in a car crash. While under treatment at a local medical center for headache, mild motor weakness, and cognitive impairment that developed following the car crash, she fell, hitting her head on the ground, about six weeks after the car crash. DIAGNOSES: Approximately three months after the car crash, she began to show tremor on both hands and mild truncal ataxia. Twenty months after the car crash, when she underwent neurological evaluation at the rehabilitation department of a university hospital, she presented with mild resting and intentional tremor on both hands, and mild truncal ataxia. INTERVENTIONS: N/A. OUTCOMES: On 20-month DTT, the left CPCT showed tearing at the level of the subcortical white matter and pons, and discontinuation at the cerebellar portion. However, the integrity of the DRTT was well-preserved in both hemispheres. LESSONS: Using DTT, injury of the CPCT was demonstrated in a patient with ataxia and tremor following mild TBI. PMID- 29245231 TI - Higher efficacy of direct hemoperfusion using coated activated-charcoal column for disopyramide poisoning: A case report. AB - RATIONALE: Cases of severe disopyramide poisoning are rare and few have been reported. We report a case in which activated-charcoal column hemoperfusion was dramatically effective for life-threatening disopyramide poisoning. PATIENT CONCERNS: A teenage girl who had overdosed on disopyramide (total dose, 4950 mg) was brought to our hospital. She was resuscitated from short period cardiopulmonary arrest and subsequently showed severe cardiogenic shock and ventricular arrhythmia. DIAGNOSES: Disopyramide poisoning (self-evident). INTERVENTIONS: As hemodynamics remained unstable after providing percutaneous cardiopulmonary support and intra-aortic balloon pumping, we attempted direct hemoperfusion using a coated activated-charcoal hemoperfusion column. OUTCOMES: Hemodynamics including electrocardiography and serum disopyramide concentration were dramatically improved, and the patient was ambulatory by hospital day 14. LESSONS: Because disopyramide has low molecular weight and a small distribution volume, blood purification is considered to be the most effective therapy. We selected direct hemoperfusion for relatively high protein-binding rate. In fact, clinical status was dramatically improved, and the calculated half-life of the direct hemoperfusion phase was the shortest of all phases. In cases of severe or life-threatening disopyramide poisoning, blood purification therapy including direct hemoperfusion using a coated activated-charcoal column should be performed. PMID- 29245232 TI - Analysis of blood glucose distribution characteristics in a health examination population in Chengdu (2007-2015). AB - With socioeconomic growth and cultural changes in China, the level of blood glucose may have changed in recent years. This study aims to detect the blood glucose distribution characteristics with a large size of health examination population.A total of 641,311 cases (360,259 males and 281,052 females) more than 18 years old during 2007 to 2015 were recruited from the Health Examination Center at West China hospital, Sichuan University.The percentage of cases with abnormal glucose level and the mean level of glucose were significantly increased since 2007 to 2015 overall. The percentage of cases with abnormal glucose level in males was significantly higher than that in females every year, and the percentage of cases with abnormal glucose level in aged population was higher than the young population. In addition, the mean level of glucose was higher in aged population with normal level of glucose than the young population with normal level of glucose, and the mean level of glucose was higher in males with normal level of glucose than the females with normal level of glucose.The population showed an increased level of blood glucose. Some preventive action may be adopted early and more attention can be paid to them. PMID- 29245233 TI - Clinical outcome and surgical strategies for late post-traumatic kyphosis after failed thoracolumbar fracture operation: Case report and literature review. AB - RATIONALE: Thoracic-lumbar vertebral fracture is very common in clinic, and late post-traumatic kyphosis is the main cause closely related to the patients' life quality, which has evocated extensive concern for the surgical treatment of the disease. This study aimed to analyze the clinical outcomes and surgical strategies for late post-traumatic kyphosis after failed thoracolumbar fracture operation. PATIENT CONCERNS: All patients presented back pain with kyphotic apex vertebrae between T12 and L3. According to Frankel classification grading system, among them, 3 patients were classified as grade D, with the ability to live independently. DIAGNOSES: A systematic review of 12 case series of post-traumatic kyphosis after failed thoracolumbar fracture operation was involved. INTERVENTIONS: Wedge osteotomy was performed as indicated-posterior closing osteotomy correction in 5 patients and anterior open-posterior close correction in 7 patients.Postoperatively, thoracolumbar x-rays were obtained to evaluate the correction of kyphotic deformity, visual analog scales (VAS) and Frankel grading system were used for access the clinical outcomes. OUTCOMES: All the patients were followed up, with the average period of 38.5 months (range 24-56 months). The Kyphotic Cobb angle was improved from preoperative (28.65 +/- 11.41) to postoperative (1.14 +/- 2.79), with the correction rate of 96.02%. There was 1 case of intraoperative dural tear, without complications such as death, neurological injury, and wound infection. According to Frankel grading system, no patient suffered deteriorated neurological symptoms after surgery, and 2 patients (2/3) experienced significant relief after surgery. The main VAS score of back pain was improved from preoperative (4.41 +/- 1.08) to postoperative (1.5 +/- 0.91) at final follow-up, with an improvement rate of 65.89%. LESSONS: Surgical treatment of late post-traumatic kyphosis after failed thoracolumbar fracture operation can obtain good radiologic and clinical outcomes by kyphosis correction, decompression, and posterior stability. PMID- 29245234 TI - Hemorrhagic cardiac tamponade complicated by acute type A aortic dissection: A case report with critical care ultrasound findings. AB - RATIONALE: Acute type A aortic dissection (AAAD) is a potentially fatal clinical crisis. Hemorrhagic cardiac tamponade due to the rupture of an ascending aortic root dissection is extremely dangerous and often lacks timely clinical evidence. We report sudden death in a patient diagnosed with AAAD and in whom critical care ultrasound highly indicated hemorrhagic cardiac tamponade. PRESENTING CONCERNS: A 75-year-old man was admitted to our emergency department with a complaint of chest pain for 8 hours. Computed tomography angiography findings indicated AAAD with a wide range of lesions. During the preoperative preparation process, he suddenly lost consciousness with a pulseless femoral artery.Diagnoses: Cardiopulmonary resuscitation was initiated and critical care ultrasound revealed hemorrhagic cardiac tamponade, strongly indicating the rupture of an ascending aortic root dissection. INTERVENTIONS: However, family members refused further surgical interventions. OUTCOMES: The etiology could not be reversed and the patient died. LESSONS: Critical care ultrasound is an important skill that intensivists should master for fast screening of life-threatening complications in patients with AAAD. PMID- 29245235 TI - Impact and outcomes of nutritional support team intervention in patients with gastrointestinal disease in the intensive care unit. AB - Nutritional support has become an important intervention for critically ill patients. Many studies have reported on the effects of nutritional support for the patients within the intensive care unit (ICU); however, no studies have specifically assessed patients with gastrointestinal diseases who may have difficulty absorbing enteral nutrition (EN) in the ICU.Sixty-two patients with gastrointestinal disease were admitted to the ICU between August 2014 and August 2016 at a single tertiary university hospital. We analyzed 2 different patient groups in a retrospective cohort study: those who received nutritional support team (NST) intervention and those who did not.Forty-four (71.0%) patients received nutritional support in ICU and 18 (29.0%) did not. Variables including male sex, high albumin or prealbumin level at the time of ICU admission, and short transition period into EN showed statistically significant association with lower mortality on the univariate analysis (all P < .05). Multivariate analysis revealed that longer length of hospital stay (P = .013; hazard ratio [HR], 0.972; 95% confidence interval [CI], 0.951-0.994), shorter transition into EN (P = .014; HR, 1.040; 95% CI, 1.008-1.072), higher prealbumin level (P = .049; HR, 0.988; 95% CI, 0.976-1.000), and NST intervention (P = .022; HR, 0.356; 95% CI, 0.147 0.862) were independent prognostic factors for lower mortality.In conclusion, NST intervention related to early initiated EN, and high prealbumin levels are beneficial to decrease mortality in the acutely ill patients with GI disease. PMID- 29245236 TI - A unique tripartite collision tumor of the esophagus: A case report. AB - RATIONALE: We report a unique case of a tripartite esophageal collision tumor consisting of three separate histologic types. PATIENTS CONCERNS: Therapeutic dilemmas on the proper treatment of those rare neoplasms remain unanswered considering both proper surgical therapy and adjuvant therapy. DIAGNOSE: In this paper, we report a unique case of a patient with a tripartite esophageal collision tumor consisting of a small cell carcinoma, an adenocarcinoma of medium differentiation and a signet ring cell carcinoma. Diagnosis is difficult as clinical presentation of the patient was undistinguishable from other, commoner tumor types. INTERVENTIONS: The patient's diagnostic and therapeutic course along with available data on the collisions tumor's biological behavior and treatment are briefly discussed. OUTCOMES: Esophagectomy is the best treatment options for these patients. Unique nature of this tumor demands aggresive oncologic treatment. LESSONS: Collision tumors are rare neoplasms consisting of distinct cell populations developing in juxtaposition to one another without any areas of intermingling. Various cell types can be found. However, collision neoplasms of the esophagus combining adenomatous and neuroendocrine components are exceedingly rare, with only 5 cases described to date in the literature. Given their rarity, limited information is available on their tumorigenesis, biological behavior and clinical course. In general, these tumors are aggressive neoplasms and significantly affect patient treatment and prognosis. PMID- 29245237 TI - A rare case of angiosarcoma with skull masses and erythropenia and thrombocytopenia: A case report and review of literature. AB - RATIONALE: Primary splenic angiosarcoma (PSA) is a rare, fatal neoplasm originating from sinusoidal vascular endothelial cells, and usually metastasizes and almost always has a poor prognosis. Surgical excision is the main treatment of this highly malignant disease. PATIENT CONCERNS: We reported a special case of a 68-year-old female who had a 6-month history of scalp masses. DIAGNOSIS: The patient was found to have 2 skull masses on computed tomography (CT). Laboratory findings revealed erythropenia and thrombocytopenia. Enhanced abdomen magnetic resonance imaging (MRI) showed multiple masses in liver and spleen. The pathological result of the skull masses was revealed to be metastatic angiosarcoma. INTERVENTIONS: The patient underwent surgical excision of skull masses, and no subsequent radiotherapy or chemotherapy was done. OUTCOMES: The patient died due to dyscrasia at August 12, 2015, with a survival of nearly 1 month. LESSONS: We highlight the importance for clinicians to be aware of this rare neoplasm, and to consider it in the differential diagnosis when encountering a skull mass. Early confirmation and treatment may improve the prognosis. PMID- 29245238 TI - Autopsy relevance determining hemochromatosis: Case report. AB - RATIONALE: Hemochromatosis is a disorder, associated with an abnormal accumulation of iron leading to toxic organ damage. Clinical symptoms develop during a long period of time, thus, determining accidental or late diagnosis, usually when complications are evident. PATIENT CONCERNS: A 53-year-old man was brought to the emergency unit with symptoms of hypovolemic shock without any apparent cause, which ultimately led to multiple organ failure, severe metabolic acidosis. DIAGNOSES: The final diagnosis of hemochromatosis was determined after the autopsy. INTERVENTIONS: Abnormal findings included a black-grayish pancreas, without any surrounding tissue reaction, and a dilated congestive cardiomyopathy. Histological findings revealed significant hemosiderin deposits in the internal organs, which were more distinct in the pancreas, liver, and kidneys. OUTCOMES: Patient death in less than 12 hours. LESSONS: The necessity of a genetic examination after the autopsy, regarding this case was undeniable, especially focusing on the first-degree relatives, helping to diagnose and prescribe an adequate and early treatment. PMID- 29245239 TI - Predictors of ultimate postoperative cervical sagittal alignment in main thoracic adolescent idiopathic scoliosis: A long-term follow-up study. AB - This is a retrospective study. The aim of this study was to access sagittal compensatory mechanism of the cervical spine in thoracic adolescent idiopathic scoliosis (T-AIS) before and after posterior spinal fusion and to identify preoperative or immediate postoperative radiographic parameters that can predict the ultimate cervical sagittal alignment (CSA) after long-term follow-up.A retrospective study was performed on 44 T-AIS patients treated with posterior spinal fusion and with at least 5 years of follow-up. Preoperative, immediate postoperative and latest follow-up radiographs were reviewed measuring cervical lordosis (CL), cervical sagittal vertical axis (CSVA), upper thoracic kyphosis (UTK), main thoracic kyphosis (MTK), global thoracic kyphosis (GTK), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), and sacral slope (SS). Pearson correlation analysis, stepwise multilinear regression analysis, and receiver operator characteristic (ROC) curve were performed to define the relationship between ultimate CL and preoperative or immediate postoperative radiographic parameters.CL significantly improved from 6.6 +/- 8.8 degree kyphosis preoperatively to 3.8 +/- 8.7 degree kyphosis immediate postoperatively and to 0.5 +/- 7.3 degree lordosis at the latest follow-up. Pre- and postoperative CSVA showed no significant difference. Pearson correlation coefficient test showed that CL was only correlated to T1 slope and UTK before surgery, whereas it was correlated to T1 slope, UTK, and GTK after surgery. The following equation was developed to estimate the ultimate CL: ultimate CL = 2.792 + 0.510 * Preop CL + 0.531 * Postop T1 slope. Furthermore, ROC curve showed that preoperative CL >=-4.5 degree was strongly predictive and postoperative T1 slope >=11.3 degree was moderately predictive of lordotic cervical spine after long-term follow-up.For T-AIS patients, CL significantly increased after surgery with the restoration of the global and regional sagittal profile. The sagittal compensatory mechanism of the cervical spine before surgery is different from that after surgery. In these patients, preoperative CL and immediate postoperative T1 slope could be predictors of the ultimate CSA after long-term follow-up. PMID- 29245240 TI - Excision of sebaceous cyst by intraoral approach: A case report. AB - RATIONALE: Surgical removal of a sebaceous cyst is usually accomplished through an external incision, which inevitably results in a scar. Herein, we described an intraoral approach for excising sebaceous cysts located in the lip or cheek near lip commissure, to avoid a skin scar. PATIENT CONCERNS: Removal of the cyst but without leaving a scar on the face. DIAGNOSES: Six patients were diagnosed with a subcutaneous cyst located in the lip or cheek near lip commissure. INTERVENTIONS: We implemented an intraoral approach to excise the cyst, wherein an intraoral incision was made and blunt dissection was performed through the buccinator muscle or orbicularis oris muscle until the cyst wall was seen. The cyst was then dissected from the surrounding subcutaneous tissue by careful blunt dissection with a hemostat and completely removed through the intraoral incision. OUTCOMES: All patients had complete recovery, with no recurrence or complaints for at least 6 months after the surgery. LESSONS: A sebaceous cyst located in the lip or cheek near lip commissure can be excised by an intraoral approach through the mouth, which avoids a visible scar on the skin. PMID- 29245241 TI - Inflammatory myofibroblastic tumor of kidney together with ipsilateral perinephric and periureteric fibrosis: A case report and literature review. AB - RATIONALE: Both inflammatory myofibroblastic tumor (IMT) and retroperitoneal fibrosis are rare lesions, but kidney involvement is more rare. It is the first study about IMT of the kidney in a patient with perinephric and periureteric fibrosis and we hold that fibroblast proliferation may be an intermediate status in oncogenesis of IMT. But further investigation is necessary in order to better clarify the relationship between fibroblast proliferation and IMT. PATIENT CONCERNS: A 54-year-old female presented no positive signs except dull back pain after overwork. DIAGNOSES: On the basis of the urinary ultrasonography and computed tomography (CT) scan, we strongly suspected a renal cell carcinoma. INTERVENTIONS: Considering the little remaining function of the right kidney and the possibility of malignancy, we performed a laparoscopic right radical nephrectomy. OUTCOMES: According to the analysis of the postoperative paraffin section and immunohistochemistry assay, a final diagnosis of IMT and retroperitoneal fibrosis nodules was made. LESSONS: Both IMTs are rare lesions and its etiology and pathogeny are unclear. It is the first study about IMT of the kidney in a patient with perinephric and periureteric fibrosis. This report suggested that fibroblast proliferation may be an intermediate status in oncogenesis of IMT, but further investigation is necessary in order to better clarify the relationship between fibroblast proliferation and IMT. The preoperative diagnosis of renal IMT remains difficult. Preoperative fine-needle aspiration or percutaneous biopsy and intraoperative frozen section were applied to confirm the diagnosis to avoid unnecessary nephrectomy, especially in patients with renal insufficiency, bilateral masses, or a solitary kidney. PMID- 29245242 TI - Different evolution in the treatment of a severe persistent asthma in 2 twins: Case report and review of the literature. AB - RATIONALE: Asthma is a multifactorial disease with complex genetic inheritance. In children under the age of 5 years, the diagnosis of asthma is a challenge. PATIENT CONCERN: We present the case of twin sisters under the same treatment for persistent asthma, but with different evolution over the time. DIAGNOSES: One of the sister is diagnosed with severe persistent bronchial asthma associated with bronchiectasis and dyslipidemia and the other one only with mild persistent asthma. INTERVENTIONS: At each admission the treatment for the exacerbations and the underlying respiratory infections was represented by antibiotics, short acting beta2 agonists, and, sometimes, oxygen and systemic corticosteroids. As chronic treatment, they received in the last period inhaled corticosteroids associated with long-acting beta2 agonist. OUTCOMES: Until the age of 6.5 years, they had similar diagnoses and treatment; from this point one was asymptomatic, with normal pulmonary function tests. The other one had a more complicated evolution which led to a severe crisis by the age of 10 years old. LESSONS: Although asthma is a multifactorial disease with complex genetic inheritance, the genetics has its limits. Our twins had a similar onset with the same genetic inheritance, with the same risk factors, with the same comorbidities and with the same treatment. In this context, different evolutions of severe persistent asthma require more extensive genetic investigations. PATIENT CONCERN: We present the case of twin sisters under the same treatment for persistent asthma, but with different evolution over the time. PMID- 29245243 TI - Inflammatory foreign body reaction caused by resorbable materials used for orbital fractures repair: A case report. AB - RATIONALE: Resorbable materials have been recommended for orbital fractures repair. Many literatures reported the advantages of resorbable materials in clinical applications, but few reports about complications. PATIENT CONCERNS: In this study, we encountered a 14-year-old boy treated for the orbital fracture by using resorbable plate, in whom inflammatory foreign body reaction was detected. In addition, this patient had repeated history of skin allergy and upper respiratory tract infection. DIAGNOSES: Intraoperative observation showed that the resorbable material near the orbital rim was covered by granulation and inflammatory tissues, without purulent secretions. The histological examination revealed inflammatory foreign body reaction to the resorbable plate. INTERVENTIONS: Debridement was taken to remove the mass on the left lower eyelid. At the outpatient examination, a small amount of granulation tissue was found at the incision. Then, secondary surgery for exploration and removal of the resorbable material was carried, 9 months after the first surgery. OUTCOMES: One month after the surgery, the skin retraction, ectropion, and edema gradually improved. LESSONS: Inadequate degradation of resorbable materials and patient's medical history of allergies may cause an inflammatory foreign body reaction. Therefore, it is prudent to choose resorbable materials for patients. PMID- 29245244 TI - Effect of joint mobilization techniques for primary total knee arthroplasty: Study protocol for a randomized controlled trial. AB - BACKGROUND: Total knee arthroplasty (TKA) has become the most preferred procedure by patients for the relief of pain caused by knee osteoarthritis. TKA patients aim a speedy recovery after the surgery. Joint mobilization techniques for rehabilitation have been widely used to relieve pain and improve joint mobility. However, relevant randomized controlled trials showing the curative effect of these techniques remain lacking to date. Accordingly, this study aims to investigate whether joint mobilization techniques are valid for primary TKA. METHODS/DESIGN: We will manage a single-blind, prospective, randomized, controlled trial of 120 patients with unilateral TKA. Patients will be randomized into an intervention group, a physical modality therapy group, and a usual care group. The intervention group will undergo joint mobilization manipulation treatment once a day and regular training twice a day for a month. The physical modality therapy group will undergo physical therapy once a day and regular training twice a day for a month. The usual care group will perform regular training twice a day for a month. Primary outcome measures will be based on the visual analog scale, the knee joint Hospital for Special Surgery score, range of motion, surrounded degree, and adverse effect. Secondary indicators will include manual muscle testing, 36-Item Short Form Health Survey, Berg Balance Scale function evaluation, Pittsburgh Sleep Quality Index, proprioception, and muscle morphology. We will direct intention-to-treat analysis if a subject withdraws from the trial. DISCUSSION: The important features of this trial for joint mobilization techniques in primary TKA are randomization procedures, single blind, large sample size, and standardized protocol. This study aims to investigate whether joint mobilization techniques are effective for early TKA patients. The result of this study may serve as a guide for TKA patients, medical personnel, and healthcare decision makers. TRIAL REGISTRATION: It has been registered at http://www.chictr.org.cn/showproj.aspx?proj=15262 (Identifier:ChiCTR-IOR-16009192), Registered 11 September 2016. We also could provide the correct URL of the online registry in the WHO Trial Registration. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR-IOR-16009192. PMID- 29245245 TI - Therapeutic effect of Chinese herbal medicines for post stroke recovery: A traditional and network meta-analysis. AB - BACKGROUND: Stroke is a condition with high morbidity and mortality, and 75% of stroke survivors lose their ability to work. Stroke is a burden to the family and society. The purpose of this study was to evaluate the effectiveness of Chinese herbal patent medicines in the treatment of patients after the acute phase of a stroke. METHODS: We searched the following databases through August 2016: PubMed, Embase, Cochrane library, China Knowledge Resource Integrated Database (CNKI), China Science Periodical Database (CSPD), and China Biology Medicine disc (CBMdisc) for studies that evaluated Chinese herbal patent medicines for post stroke recovery. A random-effect model was used to pool therapeutic effects of Chinese herbal patent medicines on stroke recovery. Network meta-analysis was used to rank the treatment for each Chinese herbal patent medicine. RESULTS: In our meta-analysis, we evaluated 28 trials that included 2780 patients. Chinese herbal patent medicines were effective in promoting recovery after stroke (OR, 3.03; 95% CI: 2.53-3.64; P < .001). Chinese herbal patent medicines significantly improved neurological function defect scores when compared with the controls (standard mean difference [SMD], -0.89; 95% CI, -1.44 to -0.35; P = .001). Chinese herbal patent medicines significantly improved the Barthel index (SMD, 0.73; 95% CI, 0.53-0.94; P < .001) and the Fugl-Meyer assessment scores (SMD, 0.60; 95% CI, 0.34-0.86; P < .001). In the network analysis, MLC601, Shuxuetong, and BuchangNaoxintong were most likely to improve stroke recovery in patients without acupuncture. Additionally, Mailuoning, Xuesaitong, BuchangNaoxintong were the patented Chinese herbal medicines most likely to improve stroke recovery when combined with acupuncture. CONCLUSIONS: Our research suggests that the Chinese herbal patent medicines were effective for stroke recovery. The most effective treatments for stroke recovery were MLC601, Shuxuetong, and BuchangNaoxintong. However, to clarify the specific effective ingredients of Chinese herbal medicines, a well-designed study is warranted. PMID- 29245247 TI - Accuracy of intrapartum fetal blood gas analysis by scalp sampling: A retrospective cohort study. AB - Fetal blood gas analysis (FBGA) using scalp blood is commonly used to identify serious fetal distress. However, there is a lack of data regarding its accuracy and reliability. The aim of this study was to determine the positive predictive value (PPV) and negative predictive value (NPV) of FBGA for predicting postpartum acidosis in case of nonreassuring fetal heart rate tracings (NRFHRT). To this end, we conducted a retrospective cohort study of singleton term deliveries with NRFHRT according to Federation Internationale de Gynecologie et d'Obstetrique and Fisher cardiotocography scores undergoing FBGA in a university hospital. The PPV and NPV of FBGA regarding neonatal acidosis (defined as a pH value <= 7.15 in arterial or venous umbilical cord blood) and Apgar scores indicating neonatal depression (defined as a 5-min Apgar score <=5) were evaluated. Multivariate analysis was used to determine the influence of cardiotocography variations and the time delay between FBGA and delivery on the accuracy of FBGA. We analyzed 343 deliveries with NRFHRT. In 32 (9%) of these cases, fetal acidosis was confirmed by a postpartum umbilical cord blood pH value <= 7.15. In 308/343 (90%) cases, FBGA identified NRFHRT as false positive (as confirmed by nonacidotic postpartum pH values) and thus avoided unnecessary interventions such as operative delivery. The overall test accuracy of FBGA was 91%. FBGA accurately predicted postpartum cord blood pH values with a margin of +/-0.2 in 319/343 (93%) cases. On the other hand, the false negative rate of FBGA was 8% (29/343). The PPV and NPV of FBGA for predicting postpartum acidosis were 50% and 91%, respectively. The sensitivity was 9% and the specificity was 99%. In a multivariate logistic regression analysis, maternal body mass index (odds ratio [OR] 1.1; 95% confidence interval [CI] 1.01-1.17; P = .029) and cardiotocography variations (OR 0.80; 95% CI 0.66-0.98; P = .029) independently affected the predictive value of FBGA. The PPV of FBGA regarding neonatal depression according to Apgar scores was low with only 17%. We conclude that FBGA may be used in clinical practice to rule out, but not to rule in, neonatal acidosis in parturients with NRFHRT. It can avoid unnecessary interventions such as cesarean section or operative vaginal delivery in up to 90% of cases, but cannot reliably detect fetal acidosis. PMID- 29245246 TI - Clinical analysis of 23 cases of steroid-associated osteonecrosis of the femoral head with normal initial magnetic resonance imaging presentation. AB - To explore the clinical characteristics of steroid-associated osteonecrosis of the femoral head (ONFH) presenting initially normal magnetic resonance imaging (MRI) results.This retrospective study examined data from 23 cases that suffered from ONFH but presented a normal image at the first MRI examination after corticosteroid therapy from June 2005 to December 2013. Data on protopathy, age, sex, time of pain onset, MRI examination, and initial diagnosis were collected and analyzed.Average time from steroid therapy to first MRI examination was 45.7 +/- 25.5 days (range, 10-94 days). Average time to final diagnosis was 199.9 +/- 165.8 days (range, 32-762 days). Of the 23 cases, 21 cases complained of discomfort and were misdiagnosed because of a normal initial MRI scan. Twelve hips progressed to collapse and 1 hip received lumbar discectomy when got the final diagnosis. Cases with continuous pain (9/21) presented with pain at a later time than those with intermittent pain (12/21), although the continuous pain cases were diagnosed earlier.MRI performed 2 to 3 months after steroid therapy may present normal images. Another MRI examination is necessary to make a definite diagnosis. PMID- 29245248 TI - Association between serum cytokines and progression of breast cancer in Chinese population. AB - The aim of this study was to investigate the roles of serum interleukin-6 (IL-6), IL-8, IL-10, squamous cell cancer antigen (SCC-Ag), and cytokeratin 21-1 fragment (CYFRA 21-1) in the metastasis and prognosis of breast cancer.A total of 534 breast cancer patients admitted to our department between January 2011 and December 2014 were enrolled in this study. Besides, 452 matched healthy individuals received physical examination at the same period served as the normal control. Serum IL-6, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-alpha) were determined using an immunoradiometric assay. SCC-Ag level was evaluated using chemiluminescent microparticle immunoassay. CYFRA 21-1 was determined using the chemiluminescence assay.Compared with the control group, a significant increase was noticed in the serum IL-6, IL-8, and IL-10 in breast cancer patients, especially those with severe conditions (P < .01). Serum IL-6, IL-8, and IL-10 showed a significant increase in the patients with severe breast cancer compared with those with mild conditions (P < .05). For the patients with response after radiotherapy, the serum IL-6, IL-8, and IL-10 were significantly decreased compared with the baseline levels (P < .05). The median survival duration for the patients of SCC-Ag negative patients was 25 months, while that for the SCC-Ag positive group was 16 months. Significant difference was noticed in the survival of SCC-Ag negative group compared with that of SCC-Ag positive group (P < .05).Serum IL-6, IL-8, IL-10, SCC-Ag, and CYFRA 21-1 were considered as potential markers in the metastasis and prognosis of breast cancer. PMID- 29245249 TI - Characteristics of culture-positive invasive pulmonary aspergillosis in patients with hematologic diseases: Comparison between Aspergillus fumigatus and non fumigatus Aspergillus species. AB - While the epidemiology and clinical differences of various Candida spp. has been relatively well-identified, data regarding invasive aspergillosis (IA) caused by different Aspergillus spp. are insufficient.We aimed to determine the epidemiology of culture-positive invasive pulmonary aspergillosis (IPA) and to compare the characteristics and outcomes of Aspergillus fumigatus IPA with those of non-fumigatus IPA in patients with hematologic diseases. All consecutive cases of IPA from 2011 to 2015 were reviewed retrospectively.There were 430 proven/probable IPA and 76 culture-positive proven/probable IPA. Excluding cases of multiple species of fungi or cases having difficulties in species-level identification, 41 A fumigatus and 22 non-fumigatus IPA (Aspergillus flavus [n = 11], Aspergillus niger [n = 6], and Aspergillus terreus [n = 5]) were compared. There were no significant differences in baseline characteristics between the 2 groups. However, disseminated IA was more common in non-fumigatus IPA (2.4% vs 18.2%; P = .046). Paranasal sinus (PNS) involvement was more common in non fumigatus IPA. There was a trend towards higher peak serum galactomannan values in non-fumigatus IPA than in A fumigatus IPA group (median 1.33 [interquartile 0.98-3.29] vs 0.97 [0.66-1.97]; P = .084). Clinical response and mortality did not differ between groups.The culture-positive rate of proven/probable IPA was 17.7%, of which non-fumigatus Aspergillus accounted for about one-third. Disseminated IA, especially involving the PNS, was more frequent in non-fumigatus IPA than in A fumigatus IPA. PMID- 29245250 TI - Inositol supplement improves clinical pregnancy rate in infertile women undergoing ovulation induction for ICSI or IVF-ET. AB - OBJECTIVE: Pretreatment of myoinositol is a very new method that was evaluated in multiple small studies to manage poor ovarian response in assisted reproduction. This study was to determine the efficacy of myoinositol supplement in infertile women undergoing ovulation induction for intracytoplasmic sperm injection (ICSI) or in vitro fertilization embryo transfer (IVF-ET). METHODS: A meta-analysis and systematic review of published articles evaluating the efficacy of myo-inositol in patients undergoing ovulation induction for ICSI or IVF-ET was performed. RESULTS: Seven trials with 935 women were included. Myoinositol supplement was associated with significantly improved clinical pregnancy rate [95% confidence interval (CI), 1.04-1.96; P = .03] and abortion rate (95% CI, 0.08-0.50; P = .0006). Meanwhile, Grade 1 embryos proportion (95% CI, 1.10-2.74; P = .02), germinal vescicle and degenerated oocytes retrieved (95% CI, 0.11-0.86; P = .02), and total amount of ovulation drugs (95% CI, -591.69 to -210.39; P = .001) were also improved in favor of myo-inositol. There were no significant difference in total oocytes retrieved, MII stage oocytes retrieved, stimulation days, and E2 peak level. CONCLUSIONS: Myoinositol supplement increase clinical pregnancy rate in infertile women undergoing ovulation induction for ICSI or IVF-ET. It may improve the quality of embryos, and reduce the unsuitable oocytes and required amount of stimulation drugs. PMID- 29245251 TI - Severe infections in sarcoidosis: Incidence, predictors and long-term outcome in a cohort of 585 patients. AB - Sarcoidosis is associated with cell-mediated immunodeficiency and treatment of symptomatic sarcoidosis usually includes systemic immunosuppressants. Data relative to incidence, prognosis factors, and outcome of infections are scarce.Retrospective cohort study of 585 patients with biopsy proven sarcoidosis in a tertiary referral specialist clinic, with a nested case-control analysis. Twenty nine patients (4.9%) with severe infections were compared to 116 controls subjects with sarcoidosis, matched according to their gender, ethnicity, age at diagnosis, and treatment with corticosteroids.After a median follow-up of 8 years [range; 1-46], 38 severe infections [mycobacterial infections (n = 14), fungal infections (n = 10), bacterial (n = 8), viral (n = 3) and parasitic (n = 1)] were observed in 30 patients. The incidence of severe infections was 0.71% persons year (CI 95% 0.5-0.98) and 0.43% persons-year (CI 95% 0.27-0.66). Patients with severe infection were more frequently of male gender (60% vs 46%) and were more likely treated by >= 3 immunosuppressive agents (OR = 3.8, IC 95% [1.5-9.64], P = .005) and by cyclophosphamide (OR = 5.55, IC 95% [1.9-16.1], P = .002), and with neurological (OR = 3.36 CI 95% [1.37-8.25], P = .008), or cardiac (OR = 2.65 CI 95% [1.09-6.43], P = .031) involvement of the sarcoidosis, compared to the controls. Two patients died within the 6 months following infection, due to progressive multifocal leucoencephalopathy (n = 1), and of peritonitis (n = 1).Severe infections are observed in 5.1% of our patients with sarcoidosis after a median follow-up of 8 years. Risk factors for severe infections included neurological or cardiac involvement of sarcoidosis, the use of immunosuppressive agents and mainly cyclophosphamide. PMID- 29245252 TI - Graft-versus-host disease-like erythroderma: a sign of recurrent thymoma: A case report. AB - RATIONALE: Thymomas are associated with numerous autoimmune disorders, such as myasthenia gravis (MG), pure red cell aplasia (PRCA), and systemic lupus erythematosus (SLE). However, graft-versus-host disease (GVHD)-like erythroderma is a relatively uncommon paraneoplastic disorder associated with thymomas and signifies a poor prognosis. PATIENT CONCERNS: A 35-year-old woman with medical history significant for stage IVa type AB thymoma presented with patchy erythema over face, trunk, and extremities that failed to respond to topical steroids. DIAGNOSIS: A contrast-enhanced computerized tomography (CECT) scan of the chest demonstrated tumors in the right mediastinum and right pleura. Percutaneous right mediastinal pleural biopsy confirmed recurrent thymoma (WHO type B3, Masaoka stage IVb). Histopathologic examination of her skin lesions revealed GVHD-like erythroderma. INTERVENTIONS: The patient received chemotherapy and local thoracic radiotherapy, as well as corticosteroids. OUTCOMES: The eruptions gradually subsided with hyperpigmentation; however the patient eventually died of multiple organ failure. LESSONS: GVHD-like erythroderma is an uncommon paraneoplastic disorder associated with thymomas. Though its pathogenesis still needs further research, prompt diagnosis and appropriate treatment can improve survival rate in patients. PMID- 29245253 TI - The impact of human leukocyte antigen mismatching on graft survival and mortality in adult renal transplantation: A protocol for a systematic review and meta analysis. AB - BACKGROUND: Human leukocyte antigen (HLA) was important biological barrier to a successful transplantation. Quantitative evaluations of the effect of HLA mismatching on heart, liver, umbilical cord blood, and hematopoietic stem cell transplantation, have previously been reported. In new era of immunosuppression, the reported magnitude effect of HLA mismatching on survival outcomes of kidney transplantation was controversial. In addition, the current kidney allocation guideline recommendations in different countries were inconsistent in term of HLA mismatching. We undertake this study to conduct a systematic review and meta analysis to assess the magnitude effect of HLA mismatching in adult kidney transplantation, with a particular focus on graft survival and mortality. METHODS: The present systematic review and meta-analysis protocol was conducted following the Meta-analysis of Observational Studies in Epidemiology protocol (MOOSE-P) and the Preferred Reporting Items for Systematic Reviews and Meta Analysis protocol (PRISMA-P). PubMed, EMBASE, Cochrane library Database will be searched without language restriction. Studies fulfill the following criteria will be eligible: included study cohorts comprising adult recipients; reported the association between HLA mismatching (per mismatches or HLA-A, -B, -DR mismatches) and posttransplant survival outcomes; provided effect estimates of hazard ratios (HRs) with 95% confidence interval (CIs). The incidence of measured outcomes was defined according to the European Renal Best Practice Transplantation Guidelines and Kidney Disease: Improving Global Outcomes Guidelines. RESULTS: This study will quantitatively assess the association of HLA per mismatches, DR-antigen mismatches, A-antigen mismatches, and B-antigen mismatches with survival outcomes of overall graft failure, death-censored graft failure, all-cause mortality, and mortality with a functioning graft. CONCLUSION: This study will determine the issues on what extent HLA compatibility influenced recipient and graft survival and which HLA antigen plays a more important role in kidney transplantation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017071894. PMID- 29245254 TI - A primary gastric synovial sarcoma: A case report and literature review. AB - RATIONALE: When a gastric spindle cell tumor is observed, the possibility of synovial carcinoma, besides common mesenchymal tumor, should also be considered. PRESENTING CONCERNS OF THE PATIENT: The patient is a 51-year-old American woman who underwent medical check-up at a general hospital. Upper endoscopy showed a 2 cm sized mass covered with intact mucosa, and a central depression located on the posterior wall of the mid body. Biopsy of the mass showed focal atypical cells proliferation in mucosa on hematoxylin & eosin (H&E) staining. Endoscopic ultrasound showed a 17-mm homogenously hypoechoic mass within the submucosal layer. INTERVENTIONS: After diagnostic endoscopic submucosal dissection was performed, H&E and immunohistochemical staining showed synovial sarcoma (SS). To confirm the diagnosis, reverse transcriptase-polymerase chain reaction was performed, revealing a chimeric transcript of the SYT-SSX1 fusion gene. The diagnosis of primary gastric SS was confirmed because no evidence of possible primary lesions or metastatic lesions was observed. Therefore, the patient underwent distal gastrectomy. OUTCOMES: After surgery, the surgical specimen demonstrated no residual tumor cells. The patient received no adjuvant therapy, and there has been no evidence of local recurrence or distant metastasis for 2 months after the operation. LESSONS: When gastric subepithelial tumor is suspicious, we should also consider gastric SS. PMID- 29245255 TI - A case report of an emergency in the scrotum of a 4-month-old boy: A hair in the spermatic cord. AB - RATIONALE: Retained foreign body (FB) in soft tissues of children is commonly encountered in the emergency room. The FBs include different kinds of material and associate with some nonspecific symptoms. They usually penetrate the skin or other soft tissues and show some entry holes. PATIENT: A 4-month-old male infant was admitted to our department due to the edema on the right of scrotum, higher skin temperature, and a funicular lump with serious haphalgesia in the right groin and scrotum. DIAGNOSES: Imaging studies revealed a foreign body in right spermatic cord. A surgical exploration was performed, and a hair was dislodged. The pathological diagnosis was hyperplastic fibrous connective tissue and inflammatory reaction. INTERVENTIONS: A surgical exploration was performed to dislodge the foreign body. OUTCOMES: The boy had an uneventful course after the surgery and was discharged from the hospital one week later. The incision healed well when the boy came back for follow-up one week later. LESSONS: We still have no idea that how this FB got to the soft tissue. Few previous studies can be retrieved to help us. But we can learn that foreign body should be one of consideration for the origin of inflammation or infection of soft tissues even there is not any laceration and penetration injuries. PMID- 29245256 TI - Primary pulmonary extranodal NK/T-cell lymphoma of nasal type misdiagnosed as pneumonia: A case report and literature review. AB - RATIONALE: Primary pulmonary NK/T cell lymphoma is extremely rare, and only a few cases have reported so far. Its diagnosis is mainly dependent on open-lung biopsy. PATIENT CONCERNS: Here, we report a 44-year-old male who was initially misdiagnosed as having pneumonia according to the clinical characteristics and computed tomography (CT) findings. DIAGNOSIS: The first lung biopsy indicated a large number of coagulative necrotic lesions, and definite diagnosis was made after the second lung biopsy following non-response to 6-day wide spectrum antibiotic therapy. The second lung biopsy showed the tumor cells were positive for LCA, CD3epsilon, CD30, TIA-1, Ki67 and negative for CD20, CD56, CD1a, MPO, CK, S-100, desmin, and CD34. INTERVENTIONS: This patient refused to receive further therapy and died 1 month after confirmed diagnosis. OUTCOMES: Clinically, it is difficult to differentiate pneumonia from NK/T cell lymphoma in pathology due to the presence of plenty of focal necrosis in primary pulmonary NK/T cell lymphoma. LESSONS: The diagnosis of primary pulmonary NK/T cell lymphoma should be based on lung biopsy (usually multiple lung biopsies are required), immunohistochemistry and clinical and imaging findings. PMID- 29245257 TI - Endometrial stromal sarcoma in combination with mixed type endometrial carcinomas: A case report and literature review. AB - RATIONALE: Endometrial stromal sarcoma (ESS) is rare, representing only approximately 0.2% of all uterine malignancies. Mixed type endometrial carcinomas (MT-ECs) are rare tumors with both type I and II features, and are difficult to diagnose. Cases of ESS and MT-ECs coexisting in the same patient are extremely rare. This study aimed to describe a case of ESS in combination with MT-ECs in a 47-year-old premenopausal woman. PATIENT CONCERNS: A woman presented to the hospital complaining of occasional abdominal pain and had high tumor markers: cancer antigen (CA) 19-9 (263.6 U/mL) and CA 125 (428.0 U/mL). Transvaginal ultrasound examination revealed a complex mass (12.3 * 9.1 * 6.3 cm) with solid and cystic components on the right rear wall of the uterus. Abdominopelvic computed tomography images showed a pelvic cystic-solid mixed mass. The patient underwent an exploratory midline laparotomy. The mass was hypothesized to be malignant on the uterine posterior wall. Tumor deposits were found on bilateral parametrium. On peritoneal implantation, multiple metastases were seen on the serosal surface of the bowel and greater omentum. A frozen section revealed a spindle cell sarcoma. DIAGNOSES: Pathological reports following surgery revealed concurrent ESS and MT-ECs. INTERVENTIONS: The patient underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, total omentectomy, and macroscopic clearance of the tumor. Adjuvant chemotherapy was given. OUTCOMES: The patient was still alive when this report was written. LESSONS: Considering the rarity of ESS in combination with MT-ECs, this study presented an overview of the literature and discussed a number of histological and clinical issues. Nevertheless, etiology and pathogenesis of these tumors need further investigation. PMID- 29245258 TI - Primary atrial fibromyxosarcoma with multiple-system metastases: A case report. AB - RATIONALE: Fibromyxosarcoma is common in head and neck, vessel, omentum, and reproductive system, with low-grade malignant behavior. However, primary atrial fibromyxosarcoma with highly malignant behavior is extremely rare. PATIENT CONCERNS: A 34-year-old female presented with oppression in the chest, short breath, and onset of headache as initial symptoms. The preoperative echocardiogram showed a medium-size echogenic mass close to the posterior leaflet of the mitral valve in the left atrium. DIAGNOSIS: Primary atrial fibromyxosarcoma with multiple-system metastases. INTERVENTIONS: The patient underwent surgery, and the tumor was removed completely. The diagnosis of left atrium fibromyxosarcoma was confirmed through postoperative histopathological examination. Positron emission tomography/computed tomography scan was performed, which revealed multiple metastases to left adnexa, bilateral adrenal glands, left iliacus, right lateral ventricle, and skeletal system. OUTCOMES: The patient died of cerebral hernia caused by hemorrhage from the metastatic brain tumor, 30 days after the surgery, without receiving chemotherapy or radiotherapy. LESSONS: Cardiac fibromyxosarcoma is a rare primary malignant cardiac neoplasm, probably with systemic metastases. The possibility of malignancy should be considered as differential diagnosis for cardiac mass. PMID- 29245259 TI - Efficacy of pudendal nerve block for alleviation of catheter-related bladder discomfort in male patients undergoing lower urinary tract surgeries: A randomized, controlled, double-blind trial. AB - BACKGROUND: Catheter-related bladder discomfort (CRBD) to an indwelling urinary catheter is defined as a painful urethral discomfort, resistant to conventional opioid therapy, decreasing the quality of postoperative recovery. According to anatomy, the branches of sacral somatic nerves form the afferent nerves of the urethra and bladder triangle, which deriving from the ventral rami of the second to fourth sacral spinal nerves, innervating the urethral muscles and sphincter of the perineum and pelvic floor; as well as providing sensation to the penis and clitoris in males and females, which including the urethra and bladder triangle. Based on this theoretical knowledge, we formed a hypothesis that CRBD could be prevented by pudendal nerve block. OBJECTIVE: To evaluate if bilateral nerve stimulator-guided pudendal nerve block could relieve CRBD through urethra discomfort alleviation. DESIGN AND SETTING: Single-center randomized parallel controlled, double blind trial conducted at West China Hospital, Sichuan University, China. PARTICIPANTS: One hundred and eighty 2 male adult patients under general anesthesia undergoing elective trans-urethral resection of prostate (TURP) or trans-urethral resection of bladder tumor (TURBT). Around 4 out of 182 were excluded, 178 patients were randomly allocated into pudendal and control groups, using computer-generated randomized numbers in a sealed envelope method. A total of 175 patients completed the study. INTERVENTION: Pudendal group received general anesthesia along with nerve-stimulator-guided bilateral pudendal nerve block and control group received general anesthesia only. MAIN OUTCOME MEASURES: Incidence and severity of CRBD; and postoperative VAS score of pain. RESULTS: CRBD incidences were significantly lower in pudendal group at 30 minutes (63% vs 82%, P = .004), 2 hours (64% vs 90%, P < .000), 8 hours (58% vs 79%, P = .003) and 12 hours (52% vs 69%, P = .028) also significantly lower incidence of moderate to severe CRBD in pudendal group at 30 minutes (29% vs 57%, P < .001), 2 hours (22% vs 55%, P < .000), 8 hours (8% vs 27%, P = .001) and 12 hours (6% vs 16%, P = .035) postoperatively. The postoperative pain score in pudendal group was lower at 30 minutes (P = .003), 2 hours (P < .001), 8 hours (P < .001), and 12 hours (P < .001), with lower heart rate and mean blood pressure. One patient complained about weakness in levator ani muscle. CONCLUSION: General anesthesia along with bilateral pudendal nerve block decreased the incidence and severity of CRBD for the first 12 hours postoperatively. PMID- 29245260 TI - Risk factors for death in children with critical and severe hand-foot-and-mouth disease in Chongqing, China: An observational study. AB - Hand-foot-and-mouth disease (HFMD) is a common childhood infection that may lead to serious complications and even death. Globally, epidemics of HFMD are increasing each year, especially in China. This study aimed to identify risk factors for death in children with critical and severe HFMD in Chongqing, China.We performed an observational study involving patients with critical and severe HFMD admitted to the Children's Hospital of Chongqing Medical University from January 2009 to December 2016. Overall, 179 patients aged 2 months to 16 years, were included; 127 died (non-survival group) and 52 survived (survival group); the case-fatality rate was 70.94%. Data comprising demographic characteristics, clinical symptoms and signs, and laboratory findings were collected. Non-conditional logistic regression analysis was performed to determine the risk factors for death.Univariate analysis showed that sex, coma, light-reflex insensitivity, pulmonary rales, pulmonary edema or hemorrhage, cold extremities, tachycardia, hypotension, white blood cell count, blood glucose concentration, serum lactate level, creatine kinase-MB isoenzyme level, and acidosis were associated with death (P < .05). Logistic regression analysis identified female sex (odds ratio [OR] 9.6, 95% confidence interval [CI] 3.0 30.2), light-reflex insensitivity (OR 4.4, 95% CI 1.4-13.1), tachycardia (OR 1.05, 95% CI 1.03-1.07), and higher serum lactate levels (OR 1.14, 95% CI 1.19 1.69) as independent risk factors; and longer onset-to-hospitalization time (OR 0.43, 95% CI 0.28-0.66) as an independent protective factor for death in children with critical and severe HFMD.Female sex, light-reflex insensitivity, tachycardia, and higher serum lactate level are potential independent risk factors; and longer onset-to-hospitalization time is possibly an independent protective factor for death in patients with critical and severe HFMD. PMID- 29245261 TI - Extraperitoneal robot-assisted laparoscopic retroperitoneal lymph node dissection for early-stage testicular nonseminomatous germ cell tumors: A case report and literature review. AB - RATIONALE: Typically robot-assisted laparoscopic retroperitoneal lymph node dissection (R-RPLND) has been performed via a transperitoneal approach. Herein we report the first case of a novel R-RPLND using an extraperitoneal approach. PATIENT CONCERNS: A 38-year-old man presented with an enlarging right scrotal mass. DIAGNOSES: Scrotal ultrasonography demonstrated a 5.5-cm solid mass of the right testis. The patient underwent right radical inguinal orchiectomy. Pathologic examination demonstrated a mixed germ cell tumor, predominately embryonal carcinoma with yolk sac tumor. INTERVENTIONS: Extraperitoneal R-PRLND was performed 3 weeks after the radical orchiectomy. OUTCOME: The final pathologic examination showed a count of 19 lymph nodes, all of them negative. Normal antegrade ejaculation returned within 4 weeks postoperatively. No retroperitoneal recurrence or elevation of tumor marker levels were seen via surveillance imaging. LESSONS: Our study shows that extraperitoneal R-RPLND is a safe and feasible procedure using an extraperitoneal approach that provides minimal invasion and rapid recovery of patients. PMID- 29245262 TI - Acute postcataract endophthalmitis at a referral center in northern Taiwan: Causative organisms, clinical features, and visual acuity outcomes after treatment: A retrospective cohort study. AB - Acute-onset endophthalmitis after cataract surgery is a rare but serious complication. In this study, we identified the clinical profile of acute-onset endophthalmitis after cataract surgery using a retrospective review between January 1, 2009 and December 31, 2015 at a referral center in northern Taiwan. Twenty-five eyes of 25 patients with endophthalmitis were included; 60% were male. The mean age at diagnosis was 70.44 +/- 1.66 years. The right eye was affected in 44% of patients. The mean time of cataract surgery to hospital was 12.76 +/- 1.88 days. The mean time from the onset of endophthalmitis to hospital was 3.72 +/- 0.78 days. Furthermore, 56% of patients received the immediate treatment of an intracameral or intravitreal injection of antibiotics at a clinic before referral. The mean initial visual acuity was 1.97 +/- 0.15 logarithm of the minimum angle of resolution. The initial examination found corneal edema in 84% of patients, hypopyon in 48%, and vitritis in 88%. A total of 76% of patients underwent an initial treatment of pars plana vitrectomy and intraocular antibiotic injection (IOAI); 24% received an IOAI. The culture results of 52% (13/25) of patients were positive; 4 isolates were gram-positive, 8 were nontuberculosis Mycobacterium abscessus, and 1 was fungal. Thirteen of 25 patients had hypertension; 2 of 25 had diabetes mellitus. The mean follow-up time was 61.64 +/- 8.27 days. Multiple factors influenced the final visual outcome of acute-onset endophthalmitis after cataract surgery. This study found that early referral for treatment could improve the final outcome. In addition, postcataract endophthalmitis caused by M abscessus recurs easily and has a worse visual outcome despite appropriate treatment. PMID- 29245263 TI - Chronic penetrating renal trauma due to iron wire ingestion: An unusual case report. AB - Foreign body ingestion is a common presentation in the emergency room. However, the complication such as penetrating renal trauma due to sharp objects ingestion is relatively rare. We herein describe an unusual case of penetrating renal trauma in the absence of any other urinary symptoms. A 53-year-old man who had a history of iron wire ingestion went to our hospital, on examination, he only had slight abdominal tenderness due to swallowing a ball pen and 1 cap nut 1 day before, radiological imaging showed penetrating renal trauma, the blood test showed his renal function is normal. Surgical strategies were recommended to remove the pen and the iron wire simultaneously, nonetheless the patient eventually agreed to only receive surgical removal of the swallowed ball pen and cap nut, meanwhile leave the kidney untreated. During 30 months follow-up by phone and regular outpatient examination, he recovered unevenly and had no special complaint. Such cases remind us that chronic penetrating renal trauma due to foreign object ingestion may have no obvious symptoms. It is easily to be neglected. We should try to minimize the possibility of missed lesions by adhering to a meticulous examination technique. PMID- 29245264 TI - Repeated recurrent epidermoid cyst with atypical hyperplasia: A case report and literature review. AB - RATIONALE: Epidermoid cysts are slow-growing, benign tumor which account for less than 1% of all intraspinal tumors and epidermoid cyst with Atypical Hyperplasia is very rare. Surgical resection is the standard treatment of the tumor, but recurrence is not uncommon after incomplete resection. Inappropriate treatment can lead to repeated recurrent. Here, we reported a case of repeated recurrent epidermoid cyst with atypical hyperplasia treated with radiotherapy after surgery. PRESENTING CONCERNS: A 40-year-old female presenting with intraspinal epidermoid cyst showed incomplete paraplegia in lower limbs. DIAGNOSIS: Back pain reappeared 19 months later after surgical treatment. The patient suffered marked weakness in both limbs, along with obvious muscle atrophy and sensation deficiency of warmth and pain in left lower limb. MRI demonstrated a cystic mass with solid content and peripheral strengthen in enhanced scan. INTERVENTIONS: Extended excision with intraoperative local chemotherapy and postoperative radiotherapy was performed and a dramatic reversal of symptoms was gained 4 weeks after surgery, with a total dose of 46 Gy. Postoperative pathological examination revealed epidermoid cyst with mild to moderate atypical hyperplasia. OUTCOMES: No acute side effects of the treatment were reported. Back pain obviously alleviated within 48 hours after surgery, while weakness and numbness of the lower limbs gradually improved and nearly disappeared in the 3-monthly follow-up visit. Until now, no recurrence is found during the 5-years follow-up. LESSONS: Our study highlights that incomplete excision has led to repeated recurrent epidermoid cyst, but its complete removal with adjuvant radiotherapy has achieved remission of symptoms. Atypical hyperplasia discovered by pathological examination reminds us the possibility of malignant transformation and ensures the necessity of adequate treatment. PMID- 29245265 TI - Agrypnia excitata and obstructive apnea in a patient with fatal familial insomnia from China: A case report. AB - RATIONALE: Fatal familial insomnia (FFI) linked to a D178N/129M haplotype mutation in the PRNP gene is the most common genetic prion disease in the Han Chinese population. Here, we describe a Han Chinese patient with FFI who exhibited agrypnia excitata and obstructive apnea. PATIENT CONCERNS: A 46-year old man displayed involuntary movements during sleep time, snoring, autonomic nervous system dysfunction, cognitive deficit, brainstem symptoms, myoclonus and ataxia in order within 8 months. The electroencephalogram (EEG) and Magnetic Resonance Imaging (MRI) revealed abnormal changes but without the typical prion disease signs. DIAGNOSES: After the conduction of Polysomnogram (PSG) and gene detection of PRNP, the patient was diagnosed as FFI. Three others exhibiting the same clinical manifestations were observed in the large family. INTERVENTIONS: The patient responded temporally well to drugs that strengthening the function of mitochondria. OUTCOMES: Sudden death occurred after 3 month ever since the diagnoses. The total disease course was 11 months. LESSONS: The insomnia in FFI is complex, agrypnia excitata and obstructive apnea can also be indicators for FFI. Polysomnogram is necessary for recognizing the sleep loss when the symptom of insomia is not typical. Improving energy metabolism may be a potential treatment for it. PMID- 29245266 TI - Gastric Burkitt lymphoma: A case report and literature review. AB - RATIONALE: Burkitt lymphoma (BL) is an endemic tumor in Africa but rare sporadic cases are diagnosed in Europe. PATIENT CONCERNS: A 60-year-old woman was hospitalized with fulminant hematemesis and a history of recurring melena. DIAGNOSES: The upper gastrointestinal endoscopy revealed a tumor of the antrum. INTERVENTIONS: Emergency gastrectomy was performed. OUTCOMES: Gross findings revealed an ulcerated tumor with elevated margins and several perigastric and extragastric lymph nodes. Histological examination showed proliferation of atypical lymphocytes with a Ki67 index of 100%; they were marked by CD20, CD79a, bcl-6, and CD10 and were negative for CD3, CD5, CD23, TdT, bcl-2, and Cyclin D1. The tumor cells crossed the serosa and presented invasion of the lymph nodes. The patient died 10 days after surgery due to bronchopneumonia and acute renal failure. LESSONS: In our department, only one gastric BL was diagnosed in a 61 consecutive lymphomas of the gastrointestinal tract (1.64%). Less than 200 reports about gastric-BL have been published to date. This case highlights the difficulty of diagnosis of rare variants of aggressive gastric lymphomas in medium-income countries without screening programmes. PMID- 29245267 TI - Refracture of osteoporotic vertebral body after treatment by balloon kyphoplasty: Three cases report. AB - RATIONALE: Balloon kyphoplasty is a widely accepted treatment of osteoporotic vertebral compression fractures (OVCFs) with good results and a low risk for complications. A refracture of previously treated vertebra is a relatively rare condition. PATIENT CONCERNS: We reported our 3 cases and reviewed all relevant literatures of 11 cases with refracture of osteoporotic vertebral body after kyphoplasty. DIAGNOSES: Follow-up radiographs or magnetic resonance imaging examination confirmed refractures of previously treated vertebrae after kyphoplasty. INTERVENTIONS: One patient with 1 refracture of osteoporotic vertebral body after kyphoplasty was treated conservatively, but the other 2 patients were treated surgically because of multiple vertebral fractures or neurological deficits. OUTCOMES: The average age of the patients was 76.8 years (range, 63-86 years). All the patients had severe osteoporosis with a mean T score of -3.46 (range -5.0 to -3.0). The sites of refractures are in the lumbar and thoracolumbar regions. Severe osteoporosis, the presence of intravertebral cleft, and a solid lump injection pattern of polymethylmethacrylate would result in insufficient strengthening effects of cement augmentation and therefore increased the likelihood of refractures of the kyphoplasty vertibrae. LESSONS: Patients with OVCFs and intravertebral cleft who did not obtain complete pain relief at the treated vertebral level after kyphoplasty should be strictly followed up. Early finding of this condition and rapid intervention might contribute to avoiding the occurrence of the cemented vertebral refracture after kyphoplasty. Conservative treatments such as back brace and antiosteoporotic medications were strongly recommended. PMID- 29245268 TI - Posterior reversible encephalopathy syndrome after postpartum hemorrhage and uterine artery embolization: A case report. AB - RATIONALE: Posterior reversible encephalopathy syndrome (PRES) is characterized by clinical and radiological features, including headache, disturbed consciousness, seizures, and cortical blindness associated with findings indicating posterior leukoencephalopathy on imaging studies. Ours is the first case of PRES developing after postpartum hemorrhage and uterine artery embolization. PATIENT CONCERNS: An 18-year-old patient had postpartum hemorrhage after a normal delivery. She required uterine artery embolization to stop the bleeding; however, she developed PRES 2 hours after the surgery. DIAGNOSES: Brain computed tomography suggested subarachnoid hemorrhage or cerebral venous sinus thrombosis. However, findings on magnetic resonance imaging were highly indicative of PRES. INTERVENTIONS: The patient received diazepam and midazolam to prevent seizures. OUTCOMES: Seizures were controlled on the first day. The patient's visual acuity returned to normal on the fourth day of admission. Thirteen days after admission, her neurological signs and symptoms were completely managed. LESSONS: PRES may be related to postpartum hemorrhage, blood pressure fluctuation, inflammation, and contrast agents. Collectively, they cause a breakage in the blood-brain barrier and endothelial cell damage, eventually leading to PRES. We also found PRES had many features similar with contrast induced encephalopathy. PMID- 29245269 TI - Volatile sedation in the intensive care unit: A systematic review and meta analysis. AB - BACKGROUND: Volatile sedation in the intensive care unit (ICU) may reduce the number of adverse events and improve patient outcomes compared with intravenous (IV) sedation. We performed a systematic review and meta-analysis comparing the effects of volatile and IV sedation in adult ICU patients. METHODS: We searched the PubMed, Embase, Cochrane Central Register, and Web of Science databases for all randomized trials comparing volatile sedation using an anesthetic-conserving device (ACD) with IV sedation in terms of awakening and extubation times, lengths of ICU and hospital stay, and pharmacologic end-organ effects. RESULTS: Thirteen trials with a total of 1027 patients were included. Volatile sedation (sevoflurane or isoflurane) administered through an ACD shortened the awakening time [mean difference (MD), -80.0 minutes; 95% confidence intervals (95% CIs), 134.5 to -25.6; P = .004] and extubation time (MD, -196.0 minutes; 95% CIs, 305.2 to -86.8; P < .001) compared with IV sedation (midazolam or propofol). No differences in the lengths of ICU and hospital stay were noted between the 2 groups. In the analysis of cardiac effects of sedation from 5 studies, patients who received volatile sedation showed lower serum troponin levels 6 hours after ICU admission than patients who received IV sedation (P < .05). The effect size of troponin was largest between 12 and 24 hours after ICU admission (MD, -0.27 MUg/L; 95% CIs, -0.44 to -0.09; P = .003). CONCLUSION: Compared with IV sedation, volatile sedation administered through an ACD in the ICU shortened the awakening and extubation times. Considering the difference in serum troponin levels between both arms, volatile anesthetics might have a myocardial protective effect after cardiac surgery even at a subanesthetic dose. Because the included studies used small sample sizes with high heterogeneity, further large, high-quality prospective clinical trials are needed to confirm our findings. PMID- 29245270 TI - Spondylectomy and lateral lumbar interbody fusion for thoracolumbar kyphosis in an adult with achondroplasia: A case report. AB - RATIONALE: Fixed thoracolumbar kyphosis with spinal stenosis in adult patients with achondroplasia presents a challenging issue. We describe the first case in which spondylectomy and minimally invasive lateral access interbody arthrodesis were used for the treatment of fixed severe thoracolumbar kyphosis and lumbar spinal canal stenosis in an adult with achondroplasia. PATIENT CONCERNS: A 61 year-old man with a history of achondroplastic dwarfism presented with low back pain and radiculopathy and neurogenic claudication. DIAGNOSES: Plain radiographs revealed a high-grade thoracolumbar kyphotic deformity with diffuse degenerative changes in the lumbar spine. The apex was located at L2, the local kyphotic angle from L1 to L3 was 105 degrees , and the anterior area was fused from the L1 to L3 vertebrae. MRI revealed significant canal and lateral recess stenosis secondary to facet hypertrophy. INTERVENTIONS: We planned a front-back correction of the anterior and posterior spinal elements. We first performed anterior release at the fused part from L1 to L3 and XLIF at L3/4 and L4/5. Next, the patient was placed in the prone position. Spondylectomy at the L2 vertebra and posterior fusion from T10 to L5 were performed. Postoperative radiographs revealed L1 to L3 kyphosis of 32 degrees . OUTCOMES: No complications occurred during or after surgery. Postoperatively, the patient's low back pain and neurological claudication were resolved. No worsening of kyphosis was observed 24 months postoperatively. LESSONS: Circumferential decompression of the spinal cord at the apical vertebral level and decompression of lumbar canal stenosis were necessary. Front-back correction of the anterior and posterior spinal elements via spondylectomy and lateral lumbar interbody fusion is a reasonable surgical option for thoracolumbar kyphosis and developmental canal stenosis in patients with achondroplasia. PMID- 29245271 TI - Metastatic esophageal cancer presenting as shock by injury of vagus nerve mimicking baroreceptor reflex: A case report. AB - RATIONALE: Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata. PATIENT CONCERNS: A 43-year-old woman with dysphagia presented to our hospital. Computed tomography showed a primary tumor adjacent to and surrounding half the circumference of the descending aorta, and multiple cervical lymph node metastases, including a 55 * 35-mm lymph node overlapping the root of the left vagus nerve. Squamous esophageal cancer (T4bN3M1, stage IV) was diagnosed. Whereas shock status initially appeared soon after left cervical pain, suggesting pain-induced neutrally-mediated syncope, sustained bradycardia and hypotension occurred even after alleviation of pain by opioids. DIAGNOSIS: Disturbance of the left vagus nerve associated with the aortic arch baroreceptor by a large left cervical lymph node metastasis was considered as the cause of shock, pathologically mimicking the baroreceptor reflex. INTERVENTIONS: Systemic steroid administration was performed, and radiotherapy for both the primary site and lymph node metastasis was started 2 days after initiating steroid treatment. OUTCOMES: Four days after initiating steroid administration, hypotension and bradycardia were improved and stable. LESSONS: Disturbance of the vagus nerve controlling the aortic arch baroreceptor should be kept in mind as a potential cause of neurogenic shock in cancer patients, through a pathological reflex mimicking the baroreceptor reflex. PMID- 29245272 TI - Epithelial-myoepithelial carcinoma with high-grade transformation of parotid gland: A case report and literature review. AB - RATIONALE: Epithelial-myoepithelial carcinoma (EMC) is regarded as a rare low grade malignant tumor of the salivary gland, accounting for 0.4% to 1% of all salivary gland tumors. However, epithelial-myoepithelial carcinoma with high grade transformation (EMC with HGT) is extremely rare, therefore it is easily to be inappropriately diagnosed and treated. Herein, we report an unusual case of EMC with HGT involving the parotid gland and discuss the clinical features and histological characteristic of EMC with HGT, in order to remind the doctors to take appropriate diagnosis and treatment. PATIENT CONCERNS: A 77-year-old female sought for treatment in our hospital due to pain mass in the left parotid gland for 6 months with rapid growth recently. DIAGNOSES: EMC with HGT was confirmed by final pathology, and then the result showed there were 2 distinctly different areas in the tumor, including the typical EMC component and intensive spindle cells component. INTERVENTIONS: The extensive resection surgery was performed. OUTCOMES: The patient was uneventful after surgery and no recurrence or metastasis has been observed after follow-up of 4 years. LESSONS: A review of literature suggested that EMC with HGT patients trend to be more aged, more aggressive and poorer prognosis than typical EMC patients. In order to avoid misdiagnosis and inappropriate treatment, it is necessary to accurately recognize the differences between the EMC with HGT and typical EMC. PMID- 29245273 TI - A delayed diagnosis of X-linked hyper IgM syndrome complicated with toxoplasmic encephalitis in a child: A case report and literature review. AB - INTRODUCTION: The X-linked hyper-immunoglobulin M syndrome (XHIGM) is an uncommon primary combined immunodeficiency disease caused by CD40L gene mutations. A delayed or missed diagnosis of XHIGM is common and concerning, owing to atypical immunoglobulin profile and phenotype of some patients, low recognition, and limited knowledge of clinicians on XHIGM in some underdeveloped areas. Opportunistic infections are a prominent clinical feature of XHIGM. However, toxoplasma encephalitis occurs sporadically and is extremely rare in patients with XHIGM. DIAGNOSTIC AND THERAPEUTIC PROCEDURE: A 2 years and 10 months' old male suffered from 3 times of serious infection since 1 year and 4 months of age. Although with history of recurrent respiratory infections, protracted diarrhea, persistent or intermittent neutropenia companioned with oral ulcer, and a typical immunoglobulin profile during his second disease attack, the consideration of XHIGM was still completely ignored because of our low recognition and limited knowledge of this disorder. The diagnosis of XHIGM was ultimately confirmed by detection of elevated serum IgM concentration, decreased serum IgG and IgE concentration, and identification of a mutation c.654C>A (p.C218X) in CD40L gene. Given clinical manifestation of lethargy, uncontrollable somnolence and ataxia, a cat/dog exposure history, positive serum Toxoplasma gondii (T gondii) IgM, positive cerebrospinal fluid T gondii PCR results, and typical characteristics of brain magnetic resonance imaging as multiple rings liked nodules lesions in bilateral cerebral hemisphere cortex, bilateral basal ganglia, and dorsal thalamus, the diagnosis of toxoplasmic encephalitis was considered during his third disease attack. Thereafter, oral administration of sulfadiazine and azithromycin, intravenous immunoglobulin, and subcutaneous injection of G-CSF were initiated. Regrettably, the patient abandoned the treatment because of economic factor and died 3 months after discharge. CONCLUSIONS: A more thorough clinical history and some features like recurrent respiratory infections, protracted diarrhea, and persistent or intermittent neutropenia companioned with oral ulcer could increase clinical suspicion of XHIGM. Cerebral toxoplasmosis is rare in patients with XHIGM, but still should be considered. The present study firstly reported a delayed diagnosed case of XHIGM with CD40L gene c.654C>A (p.C218X) mutant complicated with toxoplasma encephalitis in Chinese population, which highlighted the importance of CD40-CD40L interaction in cell-mediated immunity against T gondii. PMID- 29245274 TI - RAD52 gene polymorphisms are associated with risk of colorectal cancer in a Chinese Han population. AB - Upward trends in the incidence and mortality rates of colorectal cancer (CRC) in China over the past decade mean that it is critical to improve survival outcomes for patients with this malignancy. Analysis of genetic variants may identify biomarkers that have a role in CRC susceptibility and clinical outcomes in Chinese patients with CRC. RAD52 is a key mediator during DNA strand exchange and homologous recombination within mammalian cells. In this study, we explored the effects of RAD52 single nucleotide polymorphisms (SNPs) in the susceptibility and clinicopathological characteristics of Chinese Han patients with CRC. Five RAD52 SNPs (rs1051669, rs10774474, rs11571378, rs6489769, and rs7963551) were analyzed using TaqMan SNP genotyping in 281 patients with CRC and 309 healthy controls. Among those aged over 60 years in the total population, carriers of the variant C allele or at least one T allele of the rs1051669 SNP were at a lower risk of CRC than carriers of the wild-type CC variant of rs1051669, while in those carrying the rs7963551 SNP, the GT or GT+GG alleles were associated with an increased risk of CRC compared with patients carrying TT alleles. We indicated a significant correlation between RAD52 rs7963551 polymorphism and lymph node metastasis in CRC patients. In all patients, the T-T-T-T-T, C-T-T-T-T, and C-T-A-C-T haplotypes were associated with an increasing risk of CRC. Our findings suggest that 4 RAD52 SNPs (rs1051669, rs10774474, rs11571378, and rs6489769) might contribute to the prediction of CRC susceptibility. In conclusion, our study demonstrated that RAD52 polymorphisms were associated with CRC in a Chinese Han cohort. PMID- 29245275 TI - S-1 versus S-1 plus cisplatin concurrent intensity modulated radiation therapy in the treatment of esophageal squamous cell carcinoma: Study protocol for a randomized controlled phase II trial. AB - INTRODUCTION: Chemotherapy regimens are often a 2-drug regimen in concurrent chemotherapy and radiotherapy for esophageal cancer (EC). However, some retrospective studies have suggested that for patients with EC receiving radiotherapy combined with 2-drug chemotherapy have the severe toxicity. And S-1 alone with the combination of radiotherapy treatment effect is good, and achieved good clinical remission rate. The purpose of this trial is compare the efficacy and toxicity of combining S-1 or S-1 plus cisplatin with radiotherapy for esophageal squamous cell carcinoma. METHODS/DESIGN: The study is a randomized, controlled, multicenter trial, comparing S-1 versus S-1 plus cisplatin concurrent radiotherapy for patients with esophageal squamous cell carcinoma. Eighty-eight patients with unresectable or medically unfit for surgery esophageal squamous cell carcinoma (clinical stage I to III), will randomly assigned to receive four cycles (2 concomitant and 2 postradiotherapy) S-1 or S-1 plus cisplatin along with radiotherapy 60-66 Gy/30 to 33 fractions. The primary outcome is complete response rate of primary tumor which will be measured by endoscopy and computer screen at 3 months after the completion of treatment. Secondary outcomes include survival and toxicity. DISCUSSION: To our knowledge, this study protocol is the first to test the effect between S-1 versus S-1 plus cisplatin concurrent intensity modulated radiation therapy in the treatment of esophageal squamous cell carcinoma. If the result will be the same effect and fewer side effects and less costly in S-1 plus radiotherapy. It will supply more treatment selection for esophageal squamous cell carcinoma. PMID- 29245276 TI - Clinical and microbiological characteristics of vancomycin-resistant Enterococcus faecium bloodstream infection in Central Taiwan. AB - Bloodstream infections (BSIs) due to vancomycin-resistant Enterococcus faecium (VREfae) remain a therapeutic challenge. This study aimed to evaluate mortality from BSIs due to VREfae in Central Taiwan.We retrospectively analyzed patients with significant VREfae BSIs in the Changhua Christian Hospital System between January 1, 2010 and December 31, 2014.Of the 152 patients with Enterococcal BSI, 56 patients (36.8%) were admitted to intensive care units (ICUs) at the onset of BSI and 20 (13.2%) patients were associated with polymicrobial bacteremia. VREfae BSI was observed in 36 (23.7%) patients. Van A (100%) is the prevalence genotype, and ST 17 (41.7%) is the predominant ST type among 36 VREfae isolates during the study period. The 30-day mortality rate was 13.2% (20/152). The multivariate logistic regression analysis showed that the onset of VREfae BSI in the ICU (odds ratio [OR] = 4.2, 95% confidence interval [CI] = 1.7-10.0, P = .002) was a significant risk factor for 30-day mortality, whereas an appropriate antimicrobial therapy was a protective factor for 30-day mortality (OR = 0.33, 95% CI = 0.14-0.79, P = .013).Our results underscore the need to assist patients who are admitted to ICUs with VREfae BSIs. We emphasize the use of an appropriate antimicrobial therapy for VREfae BSI with the aim to treat more patients with these infections. PMID- 29245277 TI - Primary intramedullary primitive neuroectodermal tumor: A case report and review of the literature. AB - RATIONALE: Primary spinal primitive neuroectodermal tumors (PNETs) are highly malignant tumors, which are extremely rare entities and primary intramedullary PNETs are extremely rare. Till now, only 24 cases of primary intramedullary PNET have been reported. PATIENT CONCERNS: A 26-year-old male presented with progressive low back and lower limb pain for 1 month. DIAGNOSES: Based on MRI and histopathological findings, he was diagnosed with primary intramedullary PNET. INTERVENTIONS: The patient was treated two times with microsurgical resections. OUTCOMES: Follow-up visit at 14 months after the first surgery showed that the patient is neurologically intact and free of disease. LESSONS: PNETs should be considered in the differential diagnosis of an intramedullary spinal cord tumor manifesting as progressive neurological deterioration. PMID- 29245278 TI - Tonsillar metastasis of nonsmall cell lung cancer with G719S mutation in exon 18: A case report. AB - RATIONALE: Lung cancer has the highest mortality of all malignant tumors and is becoming the leading cause of death in China. Surgical resection is the best treatment for early non-small-cell lung carcinoma. But postoperative tumor recurrence is very common. Brain, bone and liver are the most common metastatic sites of lung cancer. PATIENT CONCERNS: A 59-year-old woman was admitted to our hospital finding a lung nodule in physical examination. No other obvious symptoms were obsessed in this patient. No remarkable abnormality was detected in preoperative laboratory tests and physical examination. DIAGNOSES: A ground-glass nodule was detected on the left inferior lobe in the imaging examination. No metastases were detected before the surgery and early-stage lung cancer was supposed. INTERVENTION: This patient underwent a radical resection of lung cancer successfully and enjoyed a peaceful postoperative rehabilitation. OUTCOMES: Although pathological diagnosed confirmed early stage lung adenocarcinoma (T1N0M0). The patient had tumor recurrence 7 months after operation. Gene sequencing confirmed the G719S mutation in exon 18 of the EGFR gene and target therapy, chemotherapy and radiotherapy were all given to this patient successively, but they were all unresponsive. The patient died 26 months after surgery. LESSONS: We herein first report G719S mutation in lung adenocarcinoma with tonsillar metastasis. Generally, the tumor responded poorly to treatment and progressed quickly, which didn't achieve the desired effect. G719S mutant is supposed to be the cause of poor responsive to treatment. PMID- 29245279 TI - Mitral regurgitation after anthracycline-based chemotherapy in an adult patient with breast cancer: A case report. AB - RATIONALE: Anthracyclines cardiotoxicity characterized by dilated myocardiopathy has been well described in the literature. However, anthracyclines-induced valvular diseases have been seldom reported. PATIENT CONCERNS: In this study, we present the case of a 62-year-old Chinese female patient with breast cancer developing severe mitral regurgitation after anthracycline exposure. DIAGNOSES: The patient was diagnosed with mitral regurgitation with preserved left ventricular ejection fraction and normal cardiac chamber dimensions in the sixth month after the last course of anthracycline-containing chemotherapy. However, continued decrease in LVEF with normal left ventricular wall thickness, and serial increases in left atrial and ventricular dimensions were observed in the follow-up echocardiography. INTERVENTIONS: Treatments with oral itraconazole at a dose of 75 mg/day and local wound care with ciclopirox olamine ointment were administered. OUTCOMES: The patient responded well to the treatment with perindopril, metoprolol succinate, spirolactone, and furosemide, and symptoms associated with heart failure were dramatically relieved. LESSONS: The incipient mitral regurgitation may serve as an early sign of myocardial dysfunction that can facilitate a timely recognition of cardiotoxicity, which is crucial to a timely change of chemotherapy regimen and an appropriate initiation of antiremodeling therapy that could limit anthracycline cardiotoxicity and improve overall outcome. PMID- 29245280 TI - Straight sinus dural arteriovenous fistula presenting with reversible parkinsonism: A case report and literature review. AB - RATIONALE: A dural arteriovenous fistula (DAVF) refers to an abnormal direct connection between an intracranial artery and a dural venous sinus. A DAVF presenting with parkinsonism is rare, and is therefore easily misdiagnosed. Therefore, early consideration of DAVF in the differential diagnosis of reversible parkinsonism is necessary. PATIENT CONCERNS: We present the case of a 51-year-old male with progressive parkinsonism. DIAGNOSES: He was diagnosed as straight sinus occlusion. Imaging studies revealed a DAVF associated with cerebral hypoperfusion of the lenticular nuclei and frontal lobe white matter. INTERVENTIONS: Endovascular embolization was performed through his left occipital artery. OUTCOMES: Treatment resulted in marked clinical improvement that a major improvement of parkinsonism was observed concomitant with no evidence of early venous drainage of this patient. LESSONS: DAVF should always be considered as a potential cause of progressive parkinsonism on account of its potential reversibility. Our case suggests a concomitant role of basal ganglia degeneration and frontal white matter hypoperfusion in the pathology of parkinsonism due to DAVF. However, the precise pathophysiology remains to be investigated. PMID- 29245281 TI - Spontaneous spinal epidural hematoma mimicking transient ischemic attack: A case report. AB - RATIONALE: Spontaneous spinal epidural hematoma (SSEH) is a rare but highly disabling neurological emergency. The initial presentations are variable. Most patients of SSEH present with paraplegia or tetraplegia clinically, but recurrent hemiparesis with complete spontaneous recovery, mimicking transient ischemic attack (TIA), is a very rare initial presentation of SSEH. PATIENT CONCERNS: A 71 year-old female presented to the emergency department with 2 episodes of transient right hemiparesis in 5 hours. Two days later, above symptom reappeared and progressed to quadriplegia, dyspnea, and uroschesis quickly. The neurological examination showed tetraplegia and hypalgesia below the C2 level, but neither facial palsy nor aphasia was found. DIAGNOSIS: The patient was initially misdiagnosed as TIA and treated with antiplatelet therapy. But during the hospital day, the cervical magnetic resonance imaging showed a dorsal epidural hematoma extending from C2 to C6 level and she was diagnosed as SSEH. INTERVENTIONS: She underwent surgical decompression and hematoma removal 1 week later. OUTCOMES: One week after operation, the sensory deficit above C6 level improved, but there was no improvement in her muscle strength and dyspnea. Unfortunately, she died 1 month later. LESSONS: Our case highlights recurrent hemiparesis with complete spontaneous recovery mimicking TIA is a rare initial presentation of SSEH. It is important to perform careful clinical assessments and neuroimaging investigations for correct diagnosis. Neck pain and hemiparesis sparing cranial nerve are important signs for distinction of SSEH from acute ischemic cerebrovascular diseases. PMID- 29245282 TI - Gastroenteropancreatic-origin neuroendocrine carcinomas: Three case reports with favorable responses following localized radiotherapy and a review of literature. AB - RATIONALE: The radiotherapy (RT) responses of gastroenteropancreatic (GEP)-origin neuroendocrine tumors remain unclear. We report cases of favorable response after localized RT of GEP-origin neuroendocrine carcinomas (GEP-NECs). PATIENT CONCERNS: 1. An 82-year-old male presented with a lower esophageal mass. Positron emission tomography computed tomography (PET-CT) scan showed a lower esophageal mass and gastrohepatic lymph nodes. 2. A 52-year-old female presented with abdominal discomfort. CT scan showed a 9.8 cm-sized enhancing mass in the lesser sac abutting the stomach, pancreas and liver. 3. A 54-year-old male patient presented with anal pain and bleeding. CT scan showed a remnant mass in the perirectal area after trans-anal excision. DIAGNOSES: The diagnoses of GEP-NECs were pathologically confirmed by biopsy or excision, and immunohistochemical stainings of Ki-67, CD56, synaptophysin and chromogranin-A. INTERVENTIONS: 1. The patient was treated with definitive RT. 2. The patient was treated with RT after two cycles of etoposide-cisplatin chemotherapy. 3. The patient was treated with adjuvant RT. OUTCOMES: 1. Complete remission was achieved based on CT scan four months after RT. 2. CT scan showed partial regression of the mass with a 5 cm diameter at six months after RT. Adjuvant chemotherapy was administered after RT. 3. The residual mass was almost completely regressed at CT scan four months after RT. LESSONS: In cases of GEP-NECs, RT can be a useful treatment modality with favorable tumor response for patients with inoperable conditions or those suffering from bulky tumor masses. PMID- 29245283 TI - Successful treatment of erythema induratum with topical application of antituberculous drugs: A case report. AB - RATIONALE: Erythema induratum, a chronic recurrent lobular panniculitis with vasculitis, is strongly associated with Mycobacterium tuberculosis infection. The recommended drugs include isoniazid, rifampicin, and pyrazinamide, which are typically administered in combination (orally or intravenously). Till date, there are no reports about topical application of anti-tuberculous (anti-TB) drugs for treatment of erythema induratum. PATIENT CONCERNS: Herein, we present the case of a 73-year-old woman with recurrent ulceration, scarring and obvious pain in her lower legs. DIAGNOSES: She was diagnosed of erythema induratum. INTERVENTIONS: Topical anti-TB treatment (3.75% isoniazid twice a day) was necessitated by the development of severe gastrointestinal upset and significant reduction in platelets after oral treatment with isoniazid and rifampicin. OUTCOMES: The skin lesions showed improvement at one month and remitted mostly at two months. After 6 months, the skin lesions have subsided and no obvious side effects were observed. LESSONS: Our experience may help expand the therapeutic regimens for cutaneous tuberculosis, and provide physicians with alternative options for management of tuberculosis. PMID- 29245284 TI - Multiple cardiac arrests induced by pulmonary embolism in a traumatically injured patient: A case report and review of the literature. AB - RATIONALE: Pulmonary embolism-induced cardiac arrest should not be given up arbitrarily, knowing that the etiology of pulmonary embolism is reversible in most cases. PATIENT CONCERNS: We present a case of continuous resuscitation lasting approximately 4 hours, during which 21 episodes of cardiac arrest occurred in a 46-year-old man who sustained high-level paraplegia after a road traffic accident. DIAGNOSES: Multiple cardiac arrests induced by pulmonary embolism. INTERVENTIONS: The patient received cardiopulmonary resuscitation and thrombolytic therapy. OUTCOMES: The patient was discharged in 2 weeks when his condition turned for the better. LESSONS: Cardiopulmonary resuscitation of patients with pulmonary embolism-induced cardiac arrest should not be given up arbitrarily, knowing that the etiology of pulmonary embolism is reversible in most cases. Effective external cardiac compression can not only save the patient's life but also attenuate neurological sequelae. Thrombolytic therapy is the key to the final success of resuscitation. PMID- 29245285 TI - Perioperative transfusion in pancreatoduodenectomy: The double-edged sword of pancreatic surgeons. AB - We designed the study to clarify the prognostic significance of perioperative (preoperative, intraoperative, and postoperative) red blood cell (RBC) transfusion following pancreaticoduodenectomy (PD) for periampullary cancers.This study retrospectively analyzed 244 periampullary cancer patients (pancreatic cancer, 124 patients; bile duct cancer, 63 patients; and ampullary cancer, 57 patients) treated by PD from June 2001 to June 2010 at the National Cancer Center, Korea (NCC2017-0106).A total of 112 (46%) of 244 patients had received transfusion (preoperative, 5%; intraoperative, 17%; and postoperative, 37%). The 5-year survival rate of patients without perioperative transfusion was 36%, whereas that of patients with a transfusion was 25% (P = .04). Perioperative transfusion and intraoperative transfusion were found to be independent poor prognostic factors [relative risk (RR): 1.52 and 1.95, respectively]. The independent factors associated with perioperative transfusion were being female, operation time >420 minutes, portal vein (PV) resection, and preoperative serum hemoglobin (Hb) < 12 mg/dL. As the amount of perioperative transfusion increased, overall survival (OS) decreased.Perioperative transfusion, especially intraoperative transfusion was an independent prognostic factor for survival after PD. Therefore, for patients with periampullary cancer, intraoperative bleeding and operation time should be minimized and preoperative anemia corrected. PMID- 29245286 TI - Case report for recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy: Characteristics of peripheral TCR beta chain CDR3 repertoires. AB - RATIONALE: High-dose glucocorticoid therapy has been widely applied in clinical practice in systemic lupus erythematosus (SLE)patients, but less is known about the changes of T cells, especially the T cell receptor (TCR) repertoires, during the treatment. The aim of this paper is to describe the changes of TCR that recurrent and new-onset SLE patients treated by high-dose glucocorticoid therapy. PATIENT CONCERNS: Drugs of clinical treatment of SLE mainly include glucocorticoid, immunosuppressive agents, nonsteroidal anti-inflammatory drugs and B cell targeted drugs, etc, but the clinical symptoms were in remission and recurrent of onset patients with SLE. DIAGNOSES: Refer to the diagnostic criteria for SLE in 2011 by the American society of rheumatology. INTERVENTIONS: All patients were treated with High-dose glucocorticoid therapy and surveyed the TCR repertoires at 3 monitoring moments (before treatment, one month after treatment, and 3 months after treatment) to analyze the relationship between the characteristics of TCR repertoire and the highdose glucocorticoid therapy. OUTCOMES: We found that high-dose glucocorticoid therapy resulted in clinical symptom remission, as well as change of diversity, highly expanded clones (HEC), usage of TCR beta chain variable gene (TRBV)/TCR beta chain joining gene (TRBJ), and overlapped sequences of TCR beta chain complementarity determining region 3 (CDR3) repertoires. This suggests that the effect of high-dose glucocorticoids on TCR repertoires is closely related to individual autoimmune T cells. LESSONS: In this study, we have shown that we could evaluate the effect of therapy, the pathogenesis, and the prognosis for the patients with SLE by monitoring the TCR CDR3 repertoires. It could afford a new method to find the therapeutic target of SLE. PMID- 29245287 TI - An inflammatory myofibroblastic tumor in the transplanted liver displaying quick wash-in and wash-out on contrast-enhanced ultrasound: A case report. AB - RATIONALE: Inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal neoplasm, and its presence in a grafted liver is exceedingly rare. PATIENT CONCERNS: A 54-year-old woman was admitted to our hospital with a half-month history of intermittent melena. She had undergone deceased-donor liver transplantation (LT) for hepatitis B virus related liver cirrhosis without hepatocellular carcinoma 5 months previously. DIAGNOSIS: Laboratory examination showed impaired liver and renal functions and Epstein-Barr virus (EBV) infection, but tumor markers within normal ranges. Gastroscopy showed esophageal varices. Ultrasound and computed tomography angiography revealed an ill-defined and irregular solitary lesion in the porta hepatis, encasing both the portal vein and the hepatic artery. The lesion was characterized by arterial hyper-enhancement and hypo-enhancement in the remaining phases with contrast-enhanced ultrasound (CEUS). The lesion was finally confirmed as an IMT by ultrasound-guided biopsy. INTERVENTION: The patient received conservative treatment, including immunosuppression, endoscopic variceal ligation, antibiotics, steroids, and antiviral agents. OUTCOME: The patient's gastrointestinal bleeding was controlled, but the symptoms associated with portal hypertension worsened. Attempts to perform a transjugular intrahepatic portosystemic shunt were unsuccessful, and she unfortunately died soon after. LESSONS: A differential diagnosis of IMT should be considered in LT recipients presenting with EBV infection, normal tumor markers, and a de novo hepatic lesion with quick wash-in and wash-out on CEUS. Ultrasound is associated with the advantages of convenience and nonionizing radiation, and should thus be the priority approach for monitoring transplanted liver. PMID- 29245288 TI - Elevated serum lipoprotein(a) as a risk factor for combined intracranial and extracranial artery stenosis in a child with arterial ischemic stroke: A case report. AB - RATIONALE: Stroke is an uncommon disease in childhood with an estimated incidence of 1 to 6 per 100,000 and stenoocclusive arteriopathy is the main risk factor of recurrent pediatric arterial ischemic stroke (AIS). Dyslipidemia may influence strongly before puberty and in late adolescence when plasma levels are naturally highest. PATIENT CONCERNS: An 11-year-old male presented with acute onset seizure, a drowsy mentality, and right hemiplegia. DIAGNOSES: Magnetic resonance (MR) angiogram demonstrated occlusion of distal basilar artery and left vertebral arteries. Serum Lp(a) was significantly increased as 269 nmol/L (normal<75 nmol/L) only. Thus, he was diagnosed as pediatric AIS. INTERVENTIONS: He was started on aspirin (100 mg/day) for secondary stroke prevention and received nicotinic acid (2 g/day) as a Lp(a)-lowering agent. OUTCOMES: Consciousness gradually improved and the patient regained a normal orientation after 2 weeks. The Lp(a) level was reduced to 48 nmol/L after nicotinic acid administration. LESSONS: High Lp(a) level may be considered in the risk profile assessment of pediatric AIS. Niacin and certain inhibitors of cholesteryl ester transfer protein can be considered to reduce Lp(a). PMID- 29245289 TI - Perioperative management of a patient with Coffin-Lowry syndrome complicated by severe obesity: A case report and literature review. AB - RATIONALE: Coffin-Lowry syndrome (CLS) is a rare inherited disease with specific clinical features, such as mental retardation, facial dysmorphism, and cardiac abnormality. In particular, the characteristic facial features of CLS, including retrognathia and large tongue, are associated with difficult ventilation and/or intubation, which is a serious problem of anesthesia management. However, case reports on anesthesia management of CLS are very limited as there are only two published English reports till date. In this case report, we discuss anesthetic and postoperative considerations in patients with CLS, focusing on difficult airway management, and summarize past reports including some Japanese articles. PATIENT CONCERNS: A 25-year-old man with CLS was planning to undergo laminectomy because of progressive quadriplegia caused by calcification of the yellow ligament. We suspected difficulty in airway management because of several factors in his facial features, short thyromental and sternomental distances in computed tomography, severe obesity, and sleep apnea syndrome. DIAGNOSES: Difficult airway was suspected. However, because of mental retardation, awake intubation was considered difficult. INTERVENTIONS: We selected bronchofiberscope-guided nasotracheal intubation, maintaining spontaneous breathing under moderate sedation with a propofol target-controlled infusion. OUTCOMES: Airway management was safely performed during anesthesia induction. LESSONS: In many patients with CLS, difficult intubation was reported, and sedation or slow induction maintaining spontaneous breathing was mainly selected for anesthesia induction. Spontaneous breathing should be maintained during anesthesia induction in case of CLS patients. PMID- 29245290 TI - Operative versus nonoperative treatment of displaced intra-articular calcaneal fractures: A meta-analysis of current evidence base. AB - BACKGROUND: The relative efficacy of operative and nonoperative treatments for the displaced intra-articular calcaneal fractures (DIACF) remains uncertain. OBJECT: We conducted a meta-analysis to compare the effectiveness of operative and nonoperative treatments in treating patients with DIACF. METHODS: Databases including Cochrane Library, Medline, Embase, CBM, CNKI, and Google Scholar were searched. After independent study selection by 2 authors, data were extracted and collected independently. Comparisons were performed between operative treatment group and nonoperative treatment group. The quality of included studies was assessed using the Newcastle-Ottawa Scale. RevMan 5.3 was used for data analysis. The primary outcome measures were anatomical measures (changes in Bohler angle and calcaneal height and width), functional measures (shoe problems, resuming preinjury work, and residual pain), and complications (including superficial and deep wound infection, skin flap necrosis, neurovascular injury, secondary arthrodesis, reflex sympathetic dystrophy, osteotomy, thromboembolism, and compartment syndromes). RESULTS: Eighteen trials (8 randomized controlled trials and 10 controlled clinical trials) including 1467 patients were considered. For anatomical measurements, the overall mean differences (MDs) for the mean Bohler angle, calcaneal height and width were 15.39 (95% confidence interval [CI] 9.12 21.67), 6.55 (95% CI 2.67-10.43), and 7.05 (95% CI -7.83 to -6.27), respectively. In functional measures, the overall effect MD of American Orthopedic Foot and Ankle Society was 6.23 (95% CI 5.22-17.67) and 0.38 (95% CI 0.22-0.67). The overall relative risks (RRs) of wearing shoes, resuming preinjury work, and having residual pain were 0.32 (95% CI 0.32-1.00), 0.56 (95% CI 0.40-0.77), and 0.90 (95% CI 0.68-1.20), respectively. The overall RR of the incidence of complications was 2.00 (95% CI 1.51-2.64). CONCLUSION: Operative treatment of DIACF may lead to a higher incidence of complications but has better anatomical recovery when compared with nonoperative treatment. PMID- 29245291 TI - Delayed diagnosis of abdominal pain in patient with situs inversus totalis in emergency department: A case report. AB - RATIONALE: Abdominal pain is one of the most common complaints for patients in emergency department. It's difficult to make an accurate diagnosis by emergency physician in time, especially in patients with situs inversus totalis. PATIENT CONCERNS: A patient with acute exacerbation of chronic left upper quadrant abdominal pain.DIAGNOSES:: cholangiolithiasis with situs inversus totalis. INTERVENTIONS: laparoscopic cholecystectomy and laparoscopic exploration of common bile duct. OUTCOMES: The patient had an uneventful recovery. LESSONS: High suspicion and adequate evaluation are important for diagnosis in patients with abdominal pain and situs inversus totalis in emergency department, and physical examination, electrocardiogrphy and radiological investigations are necessary. PMID- 29245292 TI - Long-term result of transcatheter arterial embolization for liver hemangioma. AB - Transcatheter arterial embolization (TAE) is a method for the treatment of liver hemangioma, but fewer studies reported the long-term result.Retrospective study was conducted to liver hemangioma patients who received TAE. The inclusion criteria included the following: the period of follow-up was more than 5 years; and patients were followed up for less than 5 years, but received surgical treatment due to the enlargement of tumor or severe complications of TAE. The collected data included sex, age, size of the tumor, times of TAE, complications, period of follow-up, long-term result, and whether or not surgery was finally performed.Fifty-five patients were included, and the average age was 43.1 +/- 8.6 years. The average size of liver hemangioma was 9.0 +/- 4.3 cm. Four patients (7.3%) had severe complications after TAE, including 2 cases of biloma which were cured by surgery. The tumor size was smaller or the same in 19 patients after 5 years follow-up, and the long-term effective rate was 35.8%. The size of tumor became larger in the other 34 patients (64.2%), and 29 patients (54.7%) received surgery finally. The long-term effective rate for patients with >=10 cm tumor and <10 cm tumor were 12.5% and 45.9%, respectively, and the difference was significant (P = .019).The long-term result of TAE for liver hemangioma was not satisfying, and the treatment had the risk of severe complication. For patients with asymptomatic liver hemangioma, TAE should not be conducted. PMID- 29245293 TI - Association of tourniquet utilization with blood loss, rehabilitation, and complications in Chinese obese patients undergoing total knee arthroplasty: A retrospective study. AB - Obesity not only gives rise to more blood loss volume but also correlates with postoperative rehabilitation and complications in surgical patients. It is not clear at present whether tourniquet utilization is associated with blood loss, rehabilitation, and complications, and it is imperative to ascertain the tactics of utilizing tourniquet in obese patients undergoing total knee arthroplasty (TKA). The present study was designed to explore the association of tourniquet utilization with blood loss, rehabilitation, and complications, and ascertain the tactics of utilizing tourniquet in obese patients undergoing TKA.A total of 130 patients from January 2014 to December 2014 were categorized into tourniquet group (n = 94) and non-tourniquet group (n = 36) based on whether the tourniquet was utilized or not during operation. Recorded data were as follows: total blood loss volume, intraoperative blood loss volume, hidden blood loss volume, blood transfusion volume, drainage volume, difference between hemoglobin value before operation and that on the fifth day after operation (5d Hb D-value), thigh swelling rate and visual analogue scale (VAS) score of motion pain, and Knee Society Score (KSS) score.Mean age was 65.27 +/- 7.43 (49-82) years, and 15 patients (11.5%) were men. No significant difference in total blood loss volume, drainage volume, blood transfusion volume, and 5d Hb D-value was noted between the 2 groups (P > .05 for all). Tourniquet group had significantly less intraoperative blood loss volume and significantly more hidden blood loss volume than the non-tourniquet group (P < .05 for all). Tourniquet group had significantly higher thigh swelling rate and VAS score of motion pain on the third day after operation, and significantly lower KSS function score in the third week after operation than non-tourniquet group (P < .05). No significant difference in KSS function score in the first year after operation was found between the 2 groups (P > .05). No difference in postoperative complications was observed between the groups (P > .05).The current study demonstrated that the tourniquet is not associated with reduced blood loss and increased postoperative complications in obese patients undergoing TKA. Step-down postoperative rehabilitation related to tourniquet is short-term rather than long-term in obese patients undergoing TKA. PMID- 29245294 TI - Gastrointestinal stromal tumor of unusual phenotype after imatinib treatment: A case report and diagnostic utility of ETV1 mRNA in situ hybridization. AB - RATIONALE: Gastrointestinal stromal tumor (GIST) is the most common tumor of mesenchymal origin in gastrointestinal tract. Immunohistochemical (IHC) staining combined with a typical morphology is used for the diagnosis of GIST. Typically, IHC staining for v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene (KIT) and discovered on GIST-1(DOG1) is positive in almost all GISTs. However, imatinib mesylate, a specific inhibitor of KIT tyrosine kinase, frequently involves changes in the morphology and IHC staining of GIST, impeding the diagnosis. Recently, in situ hybridization (ISH) for E26 transformation-specific sequence variant 1 (ETV1) mRNA was introduced as a useful marker to diagnose GIST. PATIENT CONCERNS: We report 2 cases of gastric GIST, which expressed unusual phenotypes after imatinib therapy. DIAGNOSES: The first patient was found to have a gastric subepithelial tumor in gastroduodenoscopy done for regular checkup. In biopsy of the tumor, it showed homogenous spindle cells that were positive to standard IHC markers for GIST. The second patient visited our hospital because of a palpable mass in the abdomen. In abdominal computed tomography (CT), a tumor arising from the stomach was found. A needle biopsy was done and the patient was diagnosed of gastric GIST because the biopsy showed spindle cells positive to typical IHC markers for GIST. After imatinib treatment, in both patients, the resected tumors were composed of heterogeneous spindle cells negative to KIT, DOG1, and CD34 IHC staining, which was unusual for GIST. However, ISH for ETV1 mRNA done for both biopsied and resected tumors was positive, even after imatinib treatment. A molecular analysis found a mutation in exon 11 of KIT gene before and after imatinib therapy in both patients, confirming the diagnosis of GIST. INTERVENTIONS: Both patients took neoadjuvant imatinib treatment, and afterwards, underwent a surgical resection. OUTCOMES: The patients remain on imatinib treatment and no progression or recurrence has been detected to date. LESSONS: ISH for ETV1 mRNA is a useful technique in diagnosing GIST when IHC with KIT, DOG1, or CD34 fail to stain positive after imatinib therapy. PMID- 29245295 TI - Lymphangiomatosis involving the pulmonary and extrapulmonary lymph nodes and surrounding soft tissue: A rare case report. AB - BACKGROUND: Diffuse pulmonary lymphangiomatosis (DPL) mainly affects the lung and pleura. There are very few pathological reports of lung damage accompanied by diffuse involvement of the extrapulmonary lymph nodes and surrounding soft tissue. The clinicopathological significance of coexistence of pulmonary and extrapulmonary lesions is unknown. METHODS: Here, we report a 16-year-old male patient. The pathological specimens of the supraclavicular lymph node and soft tissue together with the lung biopsy were analyzed by pathological observation and immunohistochemical staining. Literatures were reviewed and clinical and imaging findings were discussed. RESULTS: The patient presented with coughing and expectoration for 1 year and intermittent hemoptysis for 4 months. Ultrasound revealed swollen lymph nodes in bilateral neck, left armpit, and pubic symphysis. Chest CT scan showed diffuse grid and linear shadows, bilateral pleural thickening, and nodule formation. Multiple enlarged lymph nodes were mainly investigated in bilateral hilar, mediastinal, para-aortic, lesser curvature, and retroperitoneal. Supraclavicular lymph node biopsy confirmed the lymphatic hyperplasia and expansion in the capsule and surrounding soft tissue. The thoracoscopic examination found bloody chylothorax on the left chest. And lung biopsy showed the lymphatic vessel hyperplasia and expansion on the pleura and adjacent lung tissue. Immunohistochemical stains showed that the lymphatic endothelial cells were positive for D2-40 and CD31. Lymphangiomatosis involving the pulmonary and extrapulmonary lymph nodes and surrounding soft tissue was diagnosed based on the aforementioned histological findings. CONCLUSION: Lymphangiomatosis of superficial lymph node mainly involves the capsule of lymph nodes and its surrounding soft tissue. The information obtained from the lymph node biopsy can prompt and assist the diagnosis of DPL. PMID- 29245296 TI - The clinical surrogate definition of the trigeminocardiac reflex: Development of an optimized model according to a PRISMA-compliant systematic review. AB - BACKGROUND: The trigeminocardiac reflex (TCR) is defined as sudden onset of parasympathetic dysrhythmias including hemodynamic irregularities, apnea, and gastric hypermotility during stimulation of sensory branches of the trigeminal nerve. Since the first description of the TCR 1999, there is an ongoing discussion about a more flexible than the existing clinical definition. Aim of this work was to create a clinical surrogate definition through a systematic review of the literature. METHODS: In this meta-analysis study, literature about TCR occurrences was, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement, systematically identified through various search engines including PubMed (Medline), Embase (Ovid SP), and ISI Web of Sciences databases from January 2005 to August 2015. TCR was defined as a drop of heart rate (HR) below 60 bpm or 20% to the baseline. We extracted detailed data about hemodynamic changes and searched for connections between arterial blood pressure (BP) and HR changes during such episodes. RESULTS: Overall 45 studies harboring 57 patients were included in the study but only 32 patients showed sufficient data for final analyze. HR showed a nonlinear behavior with a "tipping point" phenomena that differs in variance from the central/peripheral (20-30% drop) to ganglion (40-49% drop). BP showed a linear behavior with a "central limit" phenomena not differing in variance in the whole subgroup (30-39% drop). An analyzation of the correlation between BP and HR showed a trend to a linear correlation. CONCLUSIONS: We can show for the first time that HR is the dominant variable in the TCR and present a new surrogate definition model. This model and the role of BP must be better investigated in further studies. PMID- 29245297 TI - Association between tea consumption and osteoporosis: A meta-analysis. AB - BACKGROUND: Previous reports have suggested a potential association of tea consumption with the risk of osteoporosis. As such association is controversial, we conducted a meta-analysis to assess the relationship between tea consumption and osteoporosis. METHODS AND FINDINGS: We systematically searched PubMed, EMBASE and WanFang databases until March 30, 2016, using the keywords "tea and osteoporosis," without limits of language. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were derived by using random-effects models throughout the analyses. We conducted the analysis of the statistical heterogeneity using Cochrane I. The funnel plot was used to speculate the publication bias, while the subgroup analysis and multiround elimination method were employed. RESULTS: Our study was based on 17 journal articles, including 2 prospective cohort studies, 4 case-control studies, and 11 cross-sectional studies. In the present study, the total OR of osteoporosis for the highest versus the lowest categories of tea consumption was 0.62 (95% CI, 0.46-0.83), with significant heterogeneity among studies (I = 94%, P < .01). There was, however, no publication bias of the meta analysis about tea consumption and osteoporosis. Subgroup analysis showed that tea consumption could reduce the risk of osteoporosis in all examined subgroups. CONCLUSION: In the present study, it can be concluded from the results that tea consumption can reduce the risk of osteoporosis. PMID- 29245298 TI - Metachronous double primary cancer of epithelial and mesenchymal origins: A case report of a rare clinical phenomenon. AB - RATIONALE: Metachronous double primary cancers from the same origin have previously been reported in several studies; however, the occurrence of double primary cancers from different tissue origins has not been reported earlier. PATIENT CONCERNS: We analyzed 10 patients with requirement surgical treatment. DIAGNOSES: After over 6 months of the surgery, histopathological examination confirmed the presence of at least two neoplastic lesions with distinct histopathology at different locations. INTERVENTIONS: These patients underwent surgery and the hematoxylin and eosin staining was performed according to standard protocol in all cases. OUTCOMES: Since the occurrence of multiple primary cancers is an extremely rare event, it is difficult to find a large sample size of patients with double primary cancers at one study center. All patients included in this study received surgical therapy twice and had a final tissue histopathologic diagnosis. LESSONS: Based on our findings, it is concluded that a prolonged follow-up examination for cancer patients should be taken into consideration to provide early detection of secondary tumors and improve overall life expectancy of these patients. Furthermore, clinicians should be well aware of the possibility of cancer patients developing a second primary cancer of a different tissue origin. PMID- 29245299 TI - The introspection on the diagnosis and treatment process of a case of Guillain Barre syndrome (GBS) attributed to systemic lupus erythematosus (SLE): A case report. AB - RATIONALE: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory connective tissue disorder. It may cause neurologic damage which is mainly characterized by central and mental system, while peripheral sexual damage is relatively rare in which Guillain-Barre Syndrome (GBS) as the first performance is more rare . GBS is an autoimmune peripheral neuropathy usually triggered by an antecedent bacterial or viral infection, with SLE being a rare cause. PATIENT CONCERNS: A 65-year-old male presented to the hospital with progressive numbness and adynamia in extremities. His vital signs were stable. 5 days later, his condition aggravated and mechanical ventilation was necessitated owing to severe dyspnea. DIAGNOSES: Based on the clinical symptoms and results of the lumbar puncture and electromyography, he was first diagnosed as GBS, however, after treatment his condition was deteriorate and the blood test showed abnormal immune indices, then renal biopsy was performed, which confirmed the diagnosis of peripheral nervous system in patients with systemic lupus erythematosus (PNS SLE). INTERVENTIONS: Firstly he was treated with intravenous immunoglobulin (IVIG) for 5 days. After his condition deterioration, he was conducted endotracheal intubation and, finally, a tracheostomy was performed. Later on he was treated with steroid therapy for several weeks. OUTCOMES: The patient showed remarkable recovery and was able to walk on his own by the time of discharge. LESSONS: PNS-SLE can, by itself, be one of the main causes of morbidity and mortality. Electromyography and renal biopsy should be considered when relevant. Peripheral neuropathy in SLE should be given greater recognition, and rarer forms of presentation should be taken seriously in the differential diagnosis when the clinical picture is atypical. Glucocorticoids may play an important role in the treatment of PNS-SLE. PMID- 29245300 TI - Treatment of the superior sagittal sinus and transverse sinus thrombosis associated with intracranial hemorrhage with the mechanical thrombectomy and thrombolytics: Case report. AB - RATIONALE: The superior sagittal sinus (SSS) and transverse sinus are the major dural sinuses that receive a considerable amount of venous drainage. The occlusion of them has been suggested to cause intracranial hypertension, hemorrhage, and lead to potentially fatal consequences. PATIENT CONCERNS: We reported a 35-year-old woman with headache presented to our emergency department with a decreased level of consciousness and epileptic seizures. The examination of speech, higher mental function, and cranial nerve were normal. Computed tomography (CT) demonstrated both subarachnoid and intraparenchymal hemorrhage and brain edema at the right temporal lobe accompanied by high density shadow in the right transverse sinus. Digital subtraction angiography (DSA) revealed extensive thrombosis of the SSS and bilateral transverse sinus. DIAGNOSES: The SSS and transverse sinus thrombosis, accompanied by right temporal lobe hemorrhage, subarachnoid hemorrhage (SAH). INTERVENTIONS: An emergent mechanical thrombectomy by placed Solitair AB stent in the SSS, respectively, passed left and right sigmoid sinus-transverse sinus route. We removed the most clots, DSA revealed recanalization of the SSS and left transverse sinus was seen with normalization of the venous outflow, the occlusion of right transverse sinus was still present. There were 4 hours after patient back to neurosurgical intensive care unit (NICU), patient appeared anisocoria (R/L:4.0/2.5 mm), bilateral light reflexes disappeared, then we took a CT reexamination revealed intraparenchymal hemorrhage increased, brain edema was aggravated at the left temporal lobe, and mild midline shift. Subsequently, we performed decompressive hemicraniectomy and puncture the hematoma supplemented by B ultrasonic. Anticoagulation treatment was initiated 24 hours after surgery, and follow-up DSA showed gradually improved patency in the SSS and bilateral transverse sinus. OUTCOMES: Despite occlusion of the SSS and bilateral transverse sinus, patient's symptoms resolved after the operations and he was discharged without complications. LESSONS: The favorable clinical outcome after complete occlusion of the SSS and transverse sinus, accompanied by right temporal lobe hemorrhage, SAH has rarely been reported and it might be explained by our timely surgical intervention and development of compensatory cerebral collateral circulation. PMID- 29245301 TI - Copper-associated hepatitis in a patient with chronic myeloid leukemia following hematopoietic stem cell transplantation: A case report. AB - RATIONALE: We report a complicated case of cholestatic hepatitis with suspected autoimmune hemolytic anemia (AIHA) and copper toxicity syndrome after HSCT and donor lymphocyte infusion (DLI). PATIENT CONCERNS: A 19-year-1-month-old girl presented with a history of CML. She underwent matched unrelated donor HSCT and donor lymphocyte infusion subsequently. Three months later, yellowish discoloration of the skin was found, which was accompanied by progressive itchy skin, easy fatigability, insomnia, and dark urine output. After admission, liver function disorders were observed. INTERVENTION: Methylprednisolone was administered for suspected hepatic GVHD. Although abdominal sonography revealed no evidence of biliary tract obstruction and the viral hepatitis survey disclosed unremarkable findings; silymarin and ursodeoxycholic acid were administered to preserve the liver function. In addition, rituximab was prescribed for suspected AIHA. Because hyperbilirubinemia was progressive, mycophenolate and high-dose intravenous immunoglobulin were accordingly administered. As drug-induced liver injury cannot be excluded, all potential unconfirmed causes of drug-related hepatoxicity were discontinued. DIAGNOSIS: In this case, the patient's history of shrimps and chocolate consumption led us to strongly suspect cholestatic hepatitis associated with copper toxicity syndrome. High 24-hour urine copper excretion and low serum zinc levels were also confirmed. Accordingly, D penicillamine and zinc gluconate were administered. OUTCOMES: She succumbed to progressive hepatic failure and eventual multisystem organ failure 14 months after HSCT. No autopsy was performed. LESSONS: This report described the combined effects of hepatic GVHD, AIHA, drugs, and copper toxicity on liver damage, and demonstrated the potential diagnostic challenges and treatment dilemmas associated with this disease. PMID- 29245302 TI - MTHFR C677T gene polymorphism and the severity of coronary lesions in acute coronary syndrome. AB - The association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, circulating levels of homocysteine (Hcy), and the severity of coronary lesion in patients with acute coronary syndrome (ACS) remains unknown.Consecutive ACS patients were included. MTHFR C677T polymorphisms were determined via amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Gensini scores were used to evaluate the severity of coronary lesions.Three hundred ten ACS patients were included, and grouped according to the MTHFR C677T polymorphism variant: CC (n = 78, 25.2%), CT (n = 137, 44.2%), and TT (n = 95, 30.6%) groups. No significant differences were detected with respect to baseline characteristics. Patients in TT group had significantly higher Hcy, and significantly lower folic acid (FA) levels as compared with those in the other 2 groups (P < .05 for both). More importantly, patients with TT had more severe coronary lesions as compared with those from the other 2 groups, as evidenced by higher Gensini scores (P < .05 for both); however, no significant differences were observed with respect to the numbers of affected coronary arteries, or the number, length, and diameter of stents implanted in each group (P > .05 for all). On multivariate logistic regression analysis, presence of a T allele in MTHFR C677T was found to be independently associated with higher circulating Hcy (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.01-1.12, P = .024), and higher Gensini scores (OR: 1.01, 95% CI: 1.00-1.02, P = .046).MTHFR C677T TT polymorphism was associated with higher Hcy levels and more severe coronary lesions in patients with ACS. PMID- 29245303 TI - Viable placental allograft as a biological dressing in the clinical management of full-thickness thermal occupational burns: Two case reports. AB - RATIONALE: Occupational burn injuries can be detrimental and difficult to manage. The majority of complex cases are referred and managed at regional burn centers where access to specialized care is available. As an alternative to hospitalization with staged surgical procedures, placental products may be used for outpatient medical management of these common burn injuries, especially if access to a regional burn center is limited or restricted.Fresh amnion has been a treatment of choice in burns for more than 100 years. As a biological covering with a broad scope of potential uses, human placental membranes represent a dressing that is particularly advantageous for burn therapy. Recent advances in tissue-preservation technology have allowed for the commercialization of placental amnion products. PATIENT CONCERNS: To address several complications associated with burn injuries-contractures, scar formation, and pain-a viable cryopreserved placental membrane (vCPM) (Grafix-PRIME, Osiris Therapeutics, Inc., MD) retaining the anti-inflammatory, anti-fibrotic, and antimicrobial properties of fresh placental tissues was chosen for clinical use in the 2 cases reported, where both patients had restricted access to the regional burn center. DIAGNOSES: Two cases of work-related extremity burns presented to a local rural hospital for immediate post-injury assessment. The 1 case was of a man who sustained a 55.4 cm full-thickness 3 degree thermal burn with exposed bone and tendon, to the left dorsal forefoot after having an industrial pressure washer caught on his work boot. The 2 case was of a female who sustained a 4.7 cm full-thickness 3 degree crush burn to the dorsum extensor surface of her dominant hand's index finger after applying 80-pounds per square inch of heated pressure from a hydraulic press. INTERVENTIONS: Both burn patients elected to continue their care at the outpatient-based wound and hyperbaric center, receiving a combination of weekly ad libitum debridement, applications of vCPM, and occupational therapy. OUTCOMES: Both burns reached timely wound closure, and patients regained full range of motion of the affected limb, allowing for early return to work. The average number of allograft applications was 7.5, allowing both patients to return to work in an average of 63.5 days without adverse events or post-treatment complications. LESSONS: The incorporation of this product in the treatment of these complex burns prevented amputation in one patient, and skin autografting and potential index finger contracture-formation in the second patient. The incorporation of vCPM in burn management may offer a new approach to outpatient burn management and may mitigate several of the complications seen post burn injury, leading to favorable patient outcomes. PMID- 29245304 TI - Computed tomography imaging features of hepatic perivascular epithelioid cell tumor: A case report and literature review. AB - RATIONALE: Perivascular epithelioid cell tumor (PEComa) is a rare tumor which is most frequently found in uterus. The tumor arising from liver is extremely uncommon. PATIENT CONCERNS: A 36-year-old female with abdominal distention, cramps, and low-grade fever for over 15 days. The patient had a history of gastric adenocarcinoma with ovarian, celiac lymph nodes, and retroperitoneal lymph nodes metastases. DIAGNOSES: Computed tomography (CT) imaging demonstrated an ill-defined heterogeneous hypo-dense mass in segment 8 (S8) of the liver. Contrast-enhanced CT imaging showed marked enhancement in arterial phase, mild-to moderate enhancement in portal and equilibrium phases. Tumor-feeding artery was demonstrated from the right hepatic artery by the three-dimensional reconstruction images. Biopsy was performed, and a diagnosis of PEComa was rendered. INTERVENTIONS: No intervention for this tumor before liver biopsy. LESSONS: We present a rare case of hepatic PEComa. The information we provided is useful for summarizing the CT features of this kind of tumors. It should be included in differential diagnoses from common hypervascular neoplasms of liver. The final diagnosis is established on histopathological and immunohistochemical studies that are the "gold standard." PMID- 29245305 TI - A melanotic malignant melanoma presenting as a keloid: A case report. AB - RATIONALE: Amelanotic malignant melanoma (AMM) is a rare subtype of malignant melanoma (MM) that manifests atypically and is easily misdiagnosed or missed altogether. The keloid type of AMM has rarely been reported. Herein, we provide information to improve the clinical diagnosis of AMM types and raise awareness to ensure early diagnosis and timely treatment. PATIENT CONCERNS: A 20-year old woman presented with a mass on her left shoulder of 1 year's duration that had been treated surgically. The lesion recurred 1 month before the present case, along with lymph node enlargement on the left supraclavicular fossa. DIAGNOSES: Histopathology and immunohistochemistry findings suggested AMM. INTERVENTIONS: The original tumor recurred 1 month later after chemotherapy, and an extended resection and a second round of chemotherapy were performed. However, the patient exhibited suspected epileptic symptoms during chemotherapy and was required to return to the local hospital for treatment. OUTCOMES: No tumor recurrence occurred within a 6-month follow-up period. LESSONS: Early AMM diagnosis has a very significant effect on prognosis. For some persistent and growing proliferative lesions, obliterative treatments should be avoided before a definitive histopathological diagnosis has been made. PMID- 29245306 TI - Unusual synchronous liver and brain abscesses infected by rare Aerococcus viridians in a patient with pulmonary arteriovenous malformations on FDG PET/CT: A case report and literature review. AB - RATIONALE: Pulmonary arteriovenous malformations (PAVMs) complicated with multiple organ abscesses is an uncommon manifestation. Because of the low incidence of the disease, F-18 fluorodeoxyglucose positron emission tomography with computed tomography (F-FDG PET/CT) imaging studies for PAVMs complicated with multiple organ abscesses are scarce. PATIENT CONCERNS: We report a case of a 54-year-old man presenting with PAVMs complicated with synchronous multiple organ abscesses founded by F-FDG PET/CT. F-FDG PET/CT revealed tortuous stripes and mass opacities with no significant FDG uptake in the left upper lung lobe. However, hypermetabolic lesions located in the anterior inferior segment of right hepatic lobe [with maximum standardized uptake value (SUVmax) of 10.7], and in the right basal ganglia with SUVmax of 14.1 were found by F-FDG PET/CT. DIAGNOSES: A diagnosis of synchronous liver and brain abscesses infected by rare Aerococcus viridans was determined by tissue culture. INTERVENTIONS: Vancomycin was provided intravenously, and oral linezolidate tablets were prescribed for anti-inflammatory treatment for 1 month. Liver and head magnetic resonance imaging was performed during the follow-up. OUTCOMES: The lesion in the right basal ganglia was reduced, and the lesion in the right liver had disappeared, indicating the lesions were abscesses. LESSONS: The present case indicated that the possibility of abscesses should be considered with patients with PAVMs, and whole-body F-FDG PET/CT is suggested to identify possible accompanying abscesses in multiple organs for PAVMs patients. PMID- 29245307 TI - Radiological presentation of chondromyxoid fibroma in the sellar region: A CARE compliant article and literature review. AB - RATIONALE: Chondromyxoid fibroma (CMF) is a rare benign bone neoplasm which often occurs in the lower extremities. Little is known about the radiological and histological presentation of CMF in the sellar region. PATIENT CONCERNS: A 16 year-old Asian male presented to the hospital 12 months ago with bilateral diplopia involving right visual fields, intermittent headaches, and dizziness. INTERVENTIONS: After the patient underwent enough examinations, the lesion was surgically removed by curettage. DIAGNOSIS: Postoperatively, the lesion was pathologically confirmed to be CMF. OUTCOMES: There was no recurrence at the 12 month follow-up. LESSONS: To the best of our knowledge, this is the second reported case of CMF in the sellar region which was clinically suspected to be a pituitary macroadenoma, craniopharyngioma, or schwannoma due to its location and radiographic features. We reviewed the morbidity, symptoms, radiographic features, pathological findings, and differential diagnosis of CMF. Because of its rarity, attention should be paid to avoid misdiagnosis of this lesion. PMID- 29245308 TI - Total parathyroidectomy with forearm auto-transplantation improves the quality of life and reduces the recurrence of secondary hyperparathyroidism in chronic kidney disease patients. AB - BACKGROUND: Our study aims to explore the effect of total parathyroidectomy (PTX) with forearm autotransplantation (FAT) on the quality of life and recurrence of secondary hyperparathyroidism (SHPT) in chronic kidney disease patients. METHODS: A total of 104 chronic kidney disease patients with SHPT were enrolled and divided into the PTX (n = 62) and PTX + FAT (n = 42) groups. The operation efficacy was evaluated by analyzing preoperative and postoperative values, including levels of intact parathyroid hormone (iPTH), serum phosphorus, serum calcium, alkaline phosphatase (ALP), calcium-phosphorus product, signs and symptoms, and MOS 36-item short-form health survey (SF-36) scores. Moreover, complications and recurrences were followed up for 12 months after the operation. Binary logistic regression was to present the risk factors for the recurrence of chronic kidney disease patients with SHPT. RESULTS: Compared with the preoperative values, the PTX and PTX + FAT groups showed decrease postoperative levels of iPTH, serum phosphorus, serum calcium, calcium-phosphorus product, bone pain, and skin pruritus at all time periods. The PTX and PTX + FAT groups demonstrated decreased ALP, fracture or deformity, and coronary artery calcification at 1 month, decreased short stature at 3 months after the operation but increased SF-36 score after operation. Compared with the PTX group, the level of iPTH decreased and the levels of serum calcium, calcium-phosphorus product increased at 3, 6, and 12 months after the operation in the PTX + FAT group. The levels of ALP, fracture or deformity, short stature, and SF-36 decreased separately at 1 week and 6 and 12 months after the operation, along with the decrease of coronary artery calcification and the recurrence rate, respectively, at 6 and 12 months after the operation in the PTX + FAT group when compared with those in the PTX group. Logistic regression analysis evidenced that the preoperative iPTH level, SF-36 score, and operation type were the risk factors for the recurrence of chronic kidney disease with SHPT. CONCLUSION: Total PTX combined with FAT is more effective in improving the quality of life and reducing the recurrence of chronic kidney disease with SHPT than PTX alone. PMID- 29245309 TI - Value of preoperative ultrasound-guided fine-needle aspiration for localization in Tc-99m MIBI-negative primary hyperparathyroidism patients. AB - To evaluate the value of preoperative ultrasound-guided fine-needle aspiration (UG-FNA) of ultrasound-detected suspicious parathyroid nodules for localization in Tc-99m MIBI-negative primary hyperparathyroidism patients.From May 2008 to December 2016, Tc-99m MIBI-negative primary hyperparathyroidism patients with ultrasound-detected suspicious cervical nodules underwent UG-FNA. The sample obtained from the solid component of the nodule was subjected to cytological evaluation and immunohistochemical staining. The sample obtained from the cystic component of the nodule or solid nodules was subjected to parathyroid hormone determination. After aspiration, the nodules underwent surgical resection or follow-up.Fifteen nodules (5 cystic, 5 cystic and solid, and 5 solid) from 15 patients were subjected to UG-FNA. Aspirate samples were obtained from 12 of the nodules, and the parathyroid hormone (PTH) levels of these samples were markedly elevated (range: 302- >2500 pg/mL). The samples obtained from the solid components of the 4 cystic and solid and 4 solid nodules were subjected to cytological evaluation, and parathyroid cells were identified in 5 of them. Of these 5 cases, 4 were subjected to immunohistochemical staining, which revealed PTH positivity in the cell block. The UG-FNA results suggested that the suspicious nodules were all parathyroid lesions. The surgical pathology results of 13 cases confirmed the UG-FNA results; the follow-up of 2 cases did not reveal any significant change.The cytological evaluation, immunohistochemical staining, and aspirate fluid PTH determination of UG-FNA were helpful for preoperative localization in Tc-99m MIBI-negative primary hyperparathyroidism patients with ultrasound-detected suspicious parathyroid nodules and can be applied selectively or in combination. Aspirate sample PTH determination should be preferred for nodules with cystic components. Further prospective study with large population is needed to confirm our conclusions. PMID- 29245310 TI - A pilot clinical study of apatinib plus irinotecan in patients with recurrent high-grade glioma: Clinical Trial/Experimental Study. AB - BACKGROUND: Malignant glioma is the most common primary malignant brain tumor that displays high vascularity, making vascular endothelial growth factor receptors become promising targets. This study was conducted to evaluate the efficacy and safety of apatinib, a new potent oral small-molecule tyrosine kinase inhibitor targeted vascular endothelial growth factor receptor 2, combined with irinotecan, in patients with recurrent malignant glioma. METHODS: Ten patients with recurrent malignant glioma who were experiencing relapse after treatment of temozolomide were enrolled in this study. They received oral apatinib (500 mg qd) in conjunction with irinotecan (340 mg/m or 125 mg/m depending on use of enzyme inducing antiepileptic drugs) for 6 cycles. After that the patients continued to take apatinib as maintenance. Dosage adjustment occurred in only 3 (30.0%) patients. RESULTS: Among the 10 patients, 9 were available for the efficacy evaluation. There were 5 with partial response, 2 with stable disease and 2 with progressive disease. The objective response rate and the disease control rate (DCR) were 55% (5/9) and 78% (7/9), respectively. The median progress free survival time was 8.3 months. As for safety analysis, the most 3 common adverse events were gastrointestinal reaction (31.8%), hypertension (22.7%), and myelosuppression (18.0%). CONCLUSION: Apatinib combined with irinotecan seems to be a promising therapeutic option for recurrent malignant glioma patients. Perspective clinical studies with adequate sample size are required to validate our results. TRIAL REGISTRATION: NCT02848794 /Ahead-BG306. PMID- 29245311 TI - Role of enteral nutrition in pancreaticocolonic fistulas secondary to severe acute pancreatitis: A case report. AB - RATIONALE: Pancreaticocolonic fistula (PCF) is an exceedingly rare complication of severe acute pancreatitis (SAP) and has primarily been treated surgically, but a few reported cases are successfully treated with nonsurgical methods. PATIENT CONCERNS: A 32-year-old male presented to our hospital with chief complaints of sharp and persistent left upper quadrant abdominal pain radiating to the back. DIAGNOSES: Computed tomography showed a pancreatic pseudocyst replacing a majority of the pancreatic parenchyma and PCF that formed between the pancreas and the colon. However, the final diagnosis of PCF was confirmed by drainage tube radiograph, which revealed extravasation of contrast from the tail of the pancreas into the colon. INTERVENTIONS: A therapeutic strategy of enteral nutrition (EN) was applied. OUTCOMES: The patient responded well to the treatment. No complication and recurrence were reported during 2-year follow-up. LESSONS: This case highlights the role of EN in the treatment of PCF secondary to SAP. To the best of our knowledge, this is the first case of PCF that treated successfully with EN, rather than surgical or endoscopic intervention. PMID- 29245312 TI - Detection of programmed death ligand 1 protein and CD8+ lymphocyte infiltration in plurihormonal pituitary adenomas: A case report and review of the literatures. AB - RATIONALE: Pituitary adenomas secreting two or more hormones were referred to the plurihormonal tumors. The management of this type of the tumor was tumor resection and amelioration of the unbalanced hormones. However, it washard to cure the plurihormonal adenomas, as they were usually refractory to the traditional treatment. New therapeutic methods were needed in dealing this tumor. PATIENT CONCERNS: In this report, we described a patient who suffered from plurihormonal pituitary adenomas, with concomitant prolactin (PRL) and growth hormone (GH) secretion. The adenomas showed aggressive behaviors, which was giant, invasive, and refractory to bromocriptine treatments. INTERVENTIONS: The patient underwent a surgical treatment. DIAGNOSIS: The pathology together with clinical presentation and blood hormone test confirmed that it was PRL-GH secreting tumors. OUTCOMES: Although a gross resection was achieved, the postoperative hormones were not normalized. There were also abundant programmed death ligand-1 proteins and CD8 lymphocyte infiltration in the tumor tissues. LESSONS: Our results indicated immunotherapy as a promising treatment for this tumor. More studies were needed to investigate the possibility of the immunotherapy in pituitary adenomas. PMID- 29245313 TI - CT diagnosis and differentiation of benign and malignant varieties of solitary fibrous tumor of the pleura. AB - To investigate computed tomography (CT) characteristics of benign and malignant solitary fibrous tumors of the pleura (SFTPs).Preoperative CTs for 60 SFTP cases (49 benign and 11 malignant) with subsequently confirmed diagnoses were retrospectively analyzed.Tumor morphologies included mounded or mushroom umbrella shape (19 cases, 31.7%), quasi-circular or oval-shape (30 cases, 50%), and growth resembling a casting mould (12 cases, 20%). Maximum tumor diameters were 1.1 to 18.9 cm (average: 6.4 +/- 4.8 cm). Fifty-seven cases had clear boundaries, and 3 had partially coarse boundaries. Twenty-seven cases showed homogeneous density; 33, "geographic"-patterned inhomogeneous density; 6, calcifications; 12, intratumor blood vessels; and 3, thick nourishing peritumoral blood vessels. Pleural thickening (regular and irregular) was found adjacent to tumors in 4, compression of adjacent ribs with absorption and cortical sclerosis in 2, and location adjacent to ribs with bony destruction in 1. Four cases had a small amount of lung tissue enfolded along the boundary, 2 had multiple peritumoral pulmonary bullae, and 9 had small ipsilateral pleural effusions. Compared with benign and malignant SFTPs were larger (P < .001), had inhomogeneous density, and were more commonly associated with intratumor blood vessels and pleural effusions (P < .01).CT revealed characteristic patterns in SFTPs, including casting mould like growth, rich blood supply, and "geographic"-patterned enhancement. In addition, larger tumor size, inhomogeneous intensities, abundant intratumor blood vessels, and pleural effusions were more common with malignancy. Lastly, multislice CT angiography can reveal feeding arteries and help guide surgical management. PMID- 29245314 TI - The therapeutic effect of silymarin in the treatment of nonalcoholic fatty disease: A meta-analysis (PRISMA) of randomized control trials. AB - BACKGROUND: Silymarin (SIL) is an active extraction of the silybum marianum, milk thistle, which is an ancient medicinal plant for treatment of various liver diseases for centuries. This study is to assess the therapeutic effect of SIL in the treatment of nonalcoholic fatty liver disease through meta-analysis. METHODS: Published randomized controlled trials (RCTs) were included from electronic databases (PubMed, Embase, Cochrane library, Web of Science, and so forth). Cochrane handbook was applied to evaluate the methodological quality. All statistical analyses were directed by Revman 5.3 software, and statistical significance was defined as P < .05. RESULTS: Eight RCTs involved 587 patients were included in this study. The results showed that SIL reduced the AST and ALT levels more significantly than the control group (AST UI/L: MD = -6.57; 95% CI, 10.03 to -3.12; P = .0002; ALT UI/L: MD = -9.16; 95% CI, -16.24 to -2.08; P = .01). Compared with other interventions, there were significant differences decreasing AST and ALT levels when SIL was used alone (AST UI/L: MD = -5.44; 95% CI, -8.80 to -2.08; P = .002; ALT UI/L: MD = -5.08; 95% CI, -7.85 to -2.32; P = .0003). CONCLUSION: SIL has positive efficacy to reduce transaminases levels in NAFLD patients. SIL can be an encouraging and considerable phytotherapy for NAFLD patients. PMID- 29245315 TI - ST segment change and T wave amplitude ratio in lead aVR associated with coronary artery disease severity in patients with non-ST elevation myocardial infarction: A retrospective study. AB - Non-ST elevation myocardial infarction (NSTEMI) severity is difficult only with electrocardiogram (ECG). In most cases, NSTEMI patients are followed with cardiac enzymes without early invasive intervention if no severe chest pain exists in the emergency department (ED) or coronary intensive care unit (CICU).Our aim was to evaluate association between CAD severity and ST segment change in lead aVR (STaVR)/T wave amplitude in lead aVR (TAaVR) ratio in patients with NSTEMI.We included 306 patients with NSTEMI in the ED between 2015 and 2016. STaVR and TAaVR values were measured from 12-derivation ECG underwent on admission to the ED. The absolute values of STaVR and TAaVR were calculated and the following were obtained; ratio 1:|STaVR|/|TAaVR|, ratio 2:|TAaVR|/|STaVR|, and ratio 3: by dividing the variable with larger absolute value to other variable with smaller absolute value (|larger value|/|smaller value|). The SYNTAX score (SS) was calculated from coronary angiography in all patients.In analysis of the bivariate correlation between SS and ratios; significantly positive, strongly with ratio 3 (r = 0.692, P < .001), and only ratio 3 was determined to be an independent predictor for SS in linear regression analysis (OR: 0.642, 95% CI: 0.432-0.853, P = .001).Severity of CAD may be estimated by evaluating STaVR and TAaVR ratio in patients with NSTEMI. PMID- 29245316 TI - Primary malignant myopericytoma with cancer cachexia: Report of the first case and review of literature. AB - RATIONALE: Malignant myopericytoma is extremely rare, with a few cases described in the English literature. PATIENT CONCERNS: This novel study aimed to report a case of malignant myopericytoma with cancer cachexia arising in the left armpit. Also, it presented a review of the English literature regarding primary malignant myopericytoma, aiming to clarify the clinical features and potentially curative treatment. A 56-year-old male presented with an ulcerated and smelly mass involving her left armpit. The patient had obvious symptoms of cancer cachexia, including emaciation, anemia, and lower extremity edema. DIAGNOSES: Computer tomography (CT) scan demonstrated a mass in the left armpit, with no evidence of metastasis according to the chest CT, abdominal ultrasound, and emission CT. The patient underwent a core biopsy of the mass, and a diagnosis of malignant myopericytoma was rendered. INTERVENTIONS: He received 2 standard courses of theprubicin combined with ifosfamide chemotherapy regimen with no tumor response. Then, he subsequently underwent complete excision of the tumor. OUTCOMES: The symptoms of cancer cachexia disappeared gradually after operation. Recurrence and metastasis were not shown during follow-up for 5 years. LESSONS: Myopericytoma are generally considered benign with an indolent clinical course, and a few reports have described malignant myopericytoma in the literature. No standard treatment is available, and complete surgical excision of the lesion may be the only potentially curative treatment. The efficacy of chemotherapy and radiation is uncertain. PMID- 29245317 TI - Bone marrow necrosis secondary to metastatic adenocarcinoma revealed by 18F-FDG PET/CT: A clinical case report. AB - RATIONALE: Bone marrow necrosis (BMN) is a rare malignancy-associated hematologic disorder characterized by necrosis of myeloid and stromal marrow elements with preservation of cortical bone. PATIENT CONCERNS: A 43-year-old female complaining of dizziness and vaginal bleeding for more than 2 months was presented to our department. DIAGNOSIS: Due to the laboratory test results, radiographic findings, especially F-fluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography/computed tomography (PET/CT) which revealed that bone marrow was characterized by diffuse F-FDG uptake with extensive central photopenia, and pathologic results, she was diagnosed with metastatic adenocarcinoma accompanied with BMN. And the cancer most likely originated from reproductive system or breast. INTERVENTIONS: There was no effective interventions for her before knowing the accurate origin of adenocarcinoma. OUTCOMES: Two weeks later, unfortunately, she died. LESSONS: F-FDG PET/CT is a useful diagnostic modality in patients with BMN. Malignant tumor should always be considered in patients with extensive BMN, even in young people. PMID- 29245318 TI - Recurrent malignant phyllodes tumor of the breast: A case report. AB - RATIONALE: Phyllodes tumor is a rare fibro epithelial neoplasm of the breast. They resemble fibroadenomas clinically and can be mistakenly ignored sometimes. PATIENT CONCERNS: We report the case of a young woman with her first presentation to hospital due to a hypoglycemia and she underwent 2 excised fibroadenomas in the same breast before diagnosed of malignant phyllodes tumor. She was complaining about 2 masses presented in her right breast 4 months after mastectomy. DIAGNOSES: Recurrent phyllodes tumor of the breast. INTERVENTIONS: We conducted an immediate autologous myocutaneous flap transplantation after a wide excision. Postoperative radiotherapy was recommended. OUTCOMES: She was in good general condition without tumor relapses during 8 months of follow-up. LESSONS: Recurrent fibroadenomas in the same breast, especially those of large size with rapid growth rate, suggesting a high transformation possibility from fibroadenoma to phyllodes tumor. We recommend an extended tumor resection and immediate or delayed reconstruction of the breast for the recurrent phyllodes tumor with separately multiple relapses. PMID- 29245319 TI - Beverage consumption and risk of ulcerative colitis: Systematic review and meta analysis of epidemiological studies. AB - Epidemiological studies have provided controversial evidence between beverage consumption and the risk of ulcerative colitis (UC). This study aimed to determine the role of beverage consumption in the development of UC. A systematic search was conducted in public databases to identify all relevant studies, and study-specific relative risks (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model. Sixteen studies were identified with a total of 3689 cases and 335,339 controls. Alcohol consumption showed no significant association with UC risk (RR for the highest vs the lowest consumption level: 0.95, 95% CI: 0.65-1.39). Coffee consumption tended to be inversely associated with UC risk (RR: 0.58, 95% CI: 0.33-1.05), but it was not significant and confounded by smoking adjustment. Soft drinks consumption was associated with UC risk (RR: 1.69, 95% CI: 1.24-2.30), and tea consumption was inversely associated with UC risk (RR: 0.69, 95% CI: 0.58-0.83). In conclusion, high consumption of soft drinks might increase the risk of UC, while tea consumption might decrease the risk. PMID- 29245320 TI - QTc prolongation and torsades de pointes due to a coadministration of fluoxetine and amiodarone in a patient with implantable cardioverter-defibrillator: Case report and review of the literature. AB - RATIONALE: Drug-induced prolongation of the corrected QT interval (QTc) may lead to serious and potentially life-threatening ventricular tachyarrhythmia, such as torsades de pointes (Tdp), which is worthy of clinical attention. Here, we report 1 case of Tdp after a coadministration of fluoxetine and amiodarone. PATIENT CONCERNS: A 62-year-old Chinese male who placed with the implanted cardioverter defibrillator (ICD) appeared the QTc prolongation and Tdp after the concurrent administration of fluoxetine and amiodarone. DIAGNOSES: Torsades de pointes (Tdp). INTERVENTIONS: The patient was treated with magnesium and potassium immediately. Her ICD-brady pacing mode was reprogrammed to 90 bpm. Meanwhile, both of fluoxetine and amiodarone were discontinued. OUTCOMES: The further episodes of Tdp were prevented. After a few days, the QTc gradually decreased without clinically significant arrhythmias. LESSONS: The present case demonstrates that a potential drug-drug interaction (DDI) may lead to a life threatening drug adverse reaction (ADR) especially in special subjects. Therefore, clinicians should closely monitor the electrocardiogram (ECG) when QTc prolonging agents are given to patients with cardiac abnormalities, and avoid combining 2 QTc-prolonging drugs. PMID- 29245321 TI - The therapeutic effect of modified Huangqi Guizhi Wuwu Tang for multiple myeloma: An 18-year follow-up case report. AB - RATIONALE: Multiple myeloma (MM) is a hematologic malignancy characterized by proliferation of clonal plasma cells in the bone marrow. The median survival has increased to 6 years in recent years. But MM remains incurable. Some studies about the effects of Chinese herb medicine on MM have been carried out. Long survival in MM patients through Traditional Chinese Medicine (TCM) therapies has been reported rarely before. PATIENT CONCERNS: We report a case of a female patient who was diagnosed with MM in 2000 at the age of 49. She received 9 cycles of multiple chemotherapeutic regimens mainly based on melphalan from September 2000 to May 2001. Though her condition was under control in some degree, she discontinued treatment due to significant side effects such as fatigue, hyperhidrosis, fever, chill, larynx mucosa ulcers, pharynx mucosa ulcers, and poor appetite. Instead, she sought treatment with TCM alone. DIAGNOSES: Based on the TCM theory, the patient's condition was categorized as Xue Bi. INTERVENTIONS: Up to the present, the patient has been using modified Huangqi Guizhi Wuwu Tang (HGWT) continuously for 18 years. In this prescription, Radix Astragali is an important herb. When the patient's condition worsened, its dosage was increased from 30 to 120g. Besides, she has been eating Radix Astragali porridge or drinking Radix Astragali tea for almost 18 years at the same time. OUTCOMES: Throughout the period, no obvious side effects have been observed and her health condition remains stable. LESSONS: Polysaccharides isolated from Astragalus membranaceus (Radix Astragali) and Polyporus umbellatus could promote maturation of dendritic cells. Polysaccharides and flavonoids isolated from Astragalus membranaceus could regulate bone marrow microenvironment by inhibiting secretion of interleukin (IL)-6, IL-12 p40 and bidirectionally regulating the osteogenic capacity of osteoblasts. Besides, Rhizoma Atractylodis Macrocephalae, another important component of the prescription, has inhibitory effects on osteolytic bone lesions. This case suggests TCM treatment may have a positive therapeutic effect on MM. Modified HGWT, especially the Chinese herb medicine Radix Astragali could potentially be an alternative option for the treatment of MM. Both pharmacological studies and randomized clinical trials are needed in the future. PMID- 29245322 TI - Primary rhabdomyosarcoma of the breast in a 17-year-old girl: Case report. AB - RATIONALE: Primary rhabdomyosarcoma of the breast is very rare disease with poor prognosis and no definitive treatment has yet been established. PATIENT CONCERNS: A 17-year-old girl presented with right breast mass without distant metastasis in image study. DIAGNOSIS: The result of core needle biopsy was intraductal carcinoma; however, histopathologic finding after mastectomy was primary rhabdomyosarcoma of breast. INTERVENTIONS: Adjuvant chemotherapy was recommended because resection margin was involved by tumor cells, but she did not visit the clinic anymore. Five months later, tumor recurred with local invasion and chemotherapy of vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VAC/IE) was done. OUTCOMES: In the course of chemotherapy and sequential follow-up, there was no tumor growth until now. LESSONS: Primary breast rhabdomyosarcoma is an uncommon disease, as a result diagnosis is often delayed. For the same reason, there is little information about treatment. This report may be helpful for managing the disease. PMID- 29245323 TI - Lung adenocarcinoma and pulmonary metastases coexist in a patient with papillary thyroid carcinoma: A case report. AB - RATIONALE: Multiple primary malignant tumors (MPMTs) are defined as 2 or more independent primary malignancies of different histologies/origins in the same individual. Although the incidence of MPMTs is being increasing, second primary cancer (SPC) is still rare and difficult to distinguish from metastasis. Here, we present a case of thyroid carcinoma with lung metastasis and primary lung cancer. PATIENTS CONCERNS: The patient was a 66-year-old man diagnosed of papillary thyroid carcinoma (PTC) with lymph nodes, lung, and skeletons metastases. One of the pulmonary nodules had contrary manifestations, such as, noniodine avid, high uptake of F-fluorodexyglucose (F-FDG) and progress after iodine-131 radioiodine therapy. INTERVENTIONS: CT guided biopsy and I-125 seed brachytherapy of nodule in right upper lobe were performed. DIAGNOSIS: The patient was diagnosed of PTC with lymph nodes, lung, and skeletons metastases, accompanied by primary lung adenocarcinoma. OUTCOMES: After 2 years of follow-up, nodules of inferior lobes almost disappeared and the nodule of right upper lobe shrank to only 0.7 cm. LESSONS: Physicians should be aware of SPC in clinical work, and improve the early diagnosis rate with a variety of examination methods and select the best treatment to improve the prognosis of patients. PMID- 29245324 TI - Clinical efficacy of transjugular intrahepatic portosystemic shunt in the treatment of hepatopulmonary syndrome. AB - Transjugular intrahepatic portosystemic shunt (TIPS) reduces the portal venous pressure of patients with hepatopulmonary syndrome (HPS).To describe the patients who underwent TIPS for the treatment of HPS.A retrospective study was performed on 81 patients with HPS and gastrointestinal hemorrhage treated with TIPS. Thirty patients underwent TIPS through the main portal vein (group A), 24 through the left branch of the portal vein (group B), and 27 through the right branch of the portal vein (group C). The partial pressure of arterial oxygen (PaO2), alveolar to-arterial oxygen partial pressure gradient (A-aPO2), oxygen saturation (SO2), and complications were recorded and compared. The survival rate for each group was calculated.The technical success rate was 100% in the 3 groups. Preoperative portal vein pressure showed no significant differences between the 3 groups, which was decreased post-TIPS operation. In group A, PaO2 and SO2 were higher in 15 days and 3 months postoperative than preoperative (P < .05), whereas A-aPO2 was lower (P < .05). No difference occurred between 12 months post- and preoperative group. In group C, PaO2 and SO2 did not alter significantly at each time point after operation (P > .05), whereas A-aPO2 decreased at 3 months (P = .041) than preoperative. In group B, all indicators at each follow-up time point after TIPS were improved significantly as compared with the preoperative group (P < .05), which showed an excellent effect on hypoxemia treatment. Although the 1 year survival rate of 3 groups of patients was 92.85%, 90.90%, and 91.67%, respectively, the rate of hepatic encephalopathy and hepatic myelopathy was 33.33% (10/30), 16.67% (4/24), and 33.33% (9/27) after TIPS.TIPS reduced the pressure of the portal vein effectively and alleviated hypoxemia in most HPS patients successfully. Thus, the left branch of the portal vein is optimal for TIPS owing to fewer complications and efficacy in improving PaO2 as compared with the main portal vein and right branch. PMID- 29245325 TI - Suspected accelerated disease progression after discontinuation of nintedanib in patients with idiopathic pulmonary fibrosis: Two case reports. AB - RATIONAL: The efficacy of nintedanib, a multitarget receptor tyrosine kinase inhibitor, has been demonstrated in recent randomized controlled trials involving patients with idiopathic pulmonary fibrosis (IPF). However, accelerated disease progression after nintedanib discontinuation has never been reported. PATIENT CONCERNS: We report 2 cases involving patients with a history of IPF who presented with respiratory deterioration at 3 weeks after the discontinuation of nintedanib therapy for IPF. Neither patient fulfilled the definition of "acute exacerbation of IPF" on unilateral computed tomography. DIAGNOSES: Accelerated disease progression after the discontinuation of nintedanib therapy for IPF. INTERVENTIONS: One patient received steroid therapy. The other patient refused to undergo steroid therapy. OUTCOMES: The first patient showed that the affected lobe exhibited volume loss with traction bronchiectasis after receiving steroid therapy, and succumbed to pneumothorax after 3 months. The other patient was transferred to another hospital because of a decline in his general condition. LESSONS: To our knowledge, this report is the first to document accelerated disease progression after the discontinuation of nintedanib therapy for IPF. Although the accurate mechanism remains unclear, the effects of nintedanib against vascular endothelial growth factor and platelet-derived growth factor receptor may play a role. Our findings suggest that physicians should carefully monitor patients with IPF after nintedanib discontinuation. PMID- 29245326 TI - Mediastinal masses-transthoracic ultrasonography aspects. AB - Mediastinal masses are usually assessed by computer tomography (CT) and magnetic resonance imaging (MRI). Transthoracic ultrasonography (TUS) can also provide useful information concerning prevascular and posterior mediastinal masses abutting the thoracic wall, but is underused for mediastinal pathology. Moreover, it provides a valuable and safe method for guiding interventional procedures in those areas, even in cases when other approaches are difficult or impossible. Considering TUS a very useful imagistic method for diagnosing mediastinal masses, we present a pictorial essay of various mediastinal diseases which can be assessed by this method. PMID- 29245327 TI - Locked plating as an external fixator in treating tibial fractures: A PRISMA compliant systematic review. AB - OBJECTIVES: This article is a systematic review of the published literature about the biomechanics, functional outcomes, and complications of a locked plate as an external fixator in treating tibial fractures. METHODS: We searched the PubMed, Ovid Medline, Embase, ScienceDirect, and Cochrane Library databases to retrieve the relevant studies. Studies published in English and Chinese which assessed adult patients and more than 4 cases who had sustained any type of fresh tibial fracture treated with the external locking plate, provided that they reported functional outcomes, range of motion (ROM), union or complication rates, and the biomechanical studies of external locked plating are also included. RESULTS: The electronic search strategy revealed 248 studies, and 2 studies were identified as relevant through manual search of references. Finally, 12 studies were included in this systematic review. These consist of 3 pure biomechanical studies, 8 case series, and 1 study including both of biomechanics and case series. Due to the heterogeneity of biomechanical studies, we can only conclude that external locked plate shows inferior structural stiffness than internal locked plate. The clinical studies reported that external locked plating gave a satisfactory ROM of the knee and ankle, functional outcomes, union rate, and low complication rate. CONCLUSIONS: We can only conclude that external locked plate shows inferior structural stiffness than internal locked plate because of the heterogeneity of biomechanical studies. The clinical studies showed locked plating as an external fixator in treating tibial fractures can be considered as a safe and successful procedure. However, as yet, there is unconvincing evidence that it is superior to standard techniques with regards to clinical and functional outcomes. More and well-designed studies about this technique should be carried out. PMID- 29245328 TI - Endobronchial hamartoma mimicking malignant lung tumor contralateral endobronchial metastasis: A case report. AB - RATIONALE: Endobronchial hamartoma, the most common benign lung tumor, is located in the bronchus, and it easily mimics lung cancer or bronchial metastasis. Endobronchial hamartoma can cause coughing, hemoptysis, and pulmonary infection; thus, it should be treated right away by surgery or fiberoptic bronchoscopy. PATIENT CONCERNS: We report a rare case of endobronchial hamartoma in which the clinical symptoms and imaging overlapped strongly with malignant lung tumor contralateral endobronchial metastasis. DIAGNOSES: Endobronchial hamartoma coexisting with a malignant lung tumor. INTERVENTIONS: Fiberoptic bronchoscopy was conducted, and the pathologic diagnosis was hamartoma. A second fiberoptic bronchoscopy was conducted, and fine-needle aspiration cytology of the enlarged lymph nodes indicated squamous cell carcinoma. OUTCOMES: The clinical symptoms were relieved, and the treatment options were docetaxel, cis dichlorodiamineplatinum, and endostatin. LESSONS: Fiberoptic bronchoscopy needs to be guided by imaging and can be considered an effective method for the diagnosis of endobronchial hamartoma. PMID- 29245329 TI - Dural sac area is a more sensitive parameter for evaluating lumbar spinal stenosis than spinal canal area: A retrospective study. AB - Narrowing of the dural sac cross-sectional area (DSCSA) and spinal canal cross sectional area (SCCSA) have been considered major causes of lumbar central canal spinal stenosis (LCCSS). DSCSA and SCCSA were previously correlated with subjective walking distance before claudication occurs, aging, and disc degeneration. DSCSA and SCCSA have been ideal morphological parameters for evaluating LCCSS. However, the comparative value of these parameters is unknown and no studies have evaluated the clinical optimal cut-off values of DSCSA and SCCSA. This study assessed which parameter is more sensitive.Both DSCSA and SCCSA samples were collected from 135 patients with LCCSS, and from 130 control subjects who underwent lumbar magnetic resonance imaging (MRI) as part of a medical examination. Axial T2-weighted MRI scans were acquired at the level of facet joint from each subject. DSCSA and SCCSA were measured at the L4-L5 intervertebral level on MRI using a picture archiving and communications system.The average DSCSA value was 151.67 +/- 53.59 mm in the control group and 80.04 +/- 35.36 mm in the LCCSS group. The corresponding average SCCSA values were 199.95 +/- 60.96 and 119.17 +/- 49.41 mm. LCCSS patients had significantly lower DSCSA and SCCSA (both P < .001). Regarding the validity of both DSCSA and SCCSA as predictors of LCCSS, Receiver operating characteristic curve analysis revealed an optimal cut-off value for DSCSA of 111.09 mm, with 80.0% sensitivity, 80.8% specificity, and an area under the curve (AUC) of 0.87 (95% confidence interval, 0.83-0.92). The best cut off-point of SCCSA was 147.12 mm, with 74.8% sensitivity, 78.5% specificity, and AUC of 0.85 (95% confidence interval, 0.81 0.89).DSCSA and SCCSA were both significantly associated with LCCSS, with DSCSA being a more sensitive measurement parameter. Thus, to evaluate LCCSS patients, pain specialists should more carefully investigate the DSCSA than SCCSA. PMID- 29245330 TI - A first case report of pulmonary hyalinizing granuloma associated with immunoglobulin A nephropathy. AB - RATIONALE: Pulmonary hyalinizing granuloma (PHG) is a rare benign disease that has been shown to be associated with the deposition of immune complexes in the lung parenchyma caused by infection or autoimmune diseases. There have been no reports of PHG in association with immunoglobulin A nephropathy (IgAN). PATIENT CONCERNS: A 30-year-old woman visited with a 12-month history of dyspnea on exertion and cough that had worsened 1 month before her visit. DIAGNOSIS: PHG associated with IgAN. INTERVENTIONS: Steroid pulse therapy was performed. OUTCOMES: The patient was discharged uneventfully. LESSONS: We present a case of PHG presenting as multiple pulmonary nodules mimicking metastatic lung cancer, which was diagnosed using wedge resection of the right middle lobe through video assisted thoracoscopic surgery. PMID- 29245331 TI - When omeprazole met with asymptomatic Clostridium difficile colonization in a postoperative colon cancer patient: A case report. AB - RATIONALE: Clostridium difficile infection (CDI) is a symptomatic infection due to the spore-forming bacterium, C. difficile. Asymptomatic C. difficile colonization is the stage in absence of symptoms, with a prevalence of 1.4% to 21% on hospital admission. Proton-pump inhibitors (PPIs) was implicated as a novel potential contributor to CDI. PPIs injection could make asymptomatic C. difficile colonization progress to C. difficile associated diarrhea (CDAD). PATIENT CONCERNS: A postoperative colon cancer patient, who had been taking omeprazole for 4 years after operation, got asymptomatic C. difficile colonization. When he developed clinical symptoms of digestive tract, tumor recurrence was first suspected and intravenous omeprazole was prescribed, which ultimately led to progression to symptomatic CDI. In this report, we tell the confusing differential diagnosis of cancer-associated diseases and CDAD, and discuss the possibility of solving the PPIs overuse problem by making clinical pathway of PPIs use in Chinese hospitals. DIAGNOSES: CDAD, incomplete intestinal obstruction, postoperation of colon cancer. INTERVENTION: Electrolyte replacement and rehydration. Parenteral nutrition support. Omeprazole was prescribed but withdrawn later, and oral vancomycin was given at a dose of 0.25 g 4 times per day for 10 days. OUTCOMES: Diarrhea was resolved, so long as the acid reflux and vomiting. LESSONS: We have 2 lessons here: Be aware of PPIs induced CDI, especially the asymptomatic C. difficile colonization. Making clinical pathway specified on PPIs use by pharmacists could be a practical way to solve the problem of PPIs overuse. PMID- 29245332 TI - Elevated 18F-NaF uptake in cricoid cartilage in a patient with laryngeal carcinoma: A case report and literature review. AB - RATIONALE: Laryngeal cancer is aggressive tumor that arises from the tissues of the larynx. Although any bone can be affected, involvement of cricoid cartilage was reported very rarely, and there has been no report of 18F-sodium fluoride positron emission tomography-computed tomography (F-NaF PET-CT) and 3D PET-CT for the evaluation of cricoid cartilage invasion. PATIENT CONCERNS: A 54-year-old male discovered a protruding mass in the right anterior neck, which had rapidly increased in size over a period of 2 months. Subsequently, hoarseness, dysphagia, and dyspnea were gradually developed. DIAGNOSES: F-FDG PET-CT demonstrated that the abnormal activity was located in a soft tissue mass, which was about 4.2 cm * 3.8 cm * 3.6 cm in largest dimension in the laryngeal cavity of supraglottic portion (SUVmax: 23.6). A swollen lymph node was revealed in the right submandibular region, which had intense FDG activity with a SUVmax of 18.4. However, there is a high uptake of F-FDG in the region near the bone, which is uncertain whether there is any skeletal invasion. NaF PET-CT and 3D PET-CT demonstrated increased uptake in the right side of cricoid cartilage (SUVmax: 13.2). The histopathologic examination confirmed squamous cell carcinoma of larynx. INTERVENTIONS: The patient underwent tracheotomy and received anti infective treatment to relieve symptoms of dyspnea and prevent asphyxia. OUTCOMES: Clinical follow up of the patient revealed that dyspnea was significantly relieved. LESSONS: The case report shows the imaging features of cricoid cartilage invasion, including F-FDG PET/CT, 18F-sodium fluoride positron emission tomography-computed tomography (F-NaF PET-CT), and 3D PET-CT. Precise understanding of the invasion scope, accurately staging of laryngeal carcinoma, and choosing of the most suitable surgical scheme are the factors that lead to the optimal treatment of laryngeal neoplasms. PMID- 29245333 TI - A rare case of methimazole-induced cholestatic jaundice in an elderly man of Asian ethnicity with hyperthyroidism: A case report. AB - BACKGROUND: Methimazole is an antithyroid drug that is widely used for the treatment of hyperthyroidism. As an inhibitor of the enzyme thyroperoxidase, methimazole is generally well-tolerated. However, there have been increasing reports of methimazole-induced liver damage, although this effect of methimazole has been limited by the absence of objective diagnosis of the liver condition or the inappropriate use of the Naranjo scale. We present the case of an elderly man with hyperthyroidism, gastritis, and epilepsy who developed liver damage after administration of multiple drugs. KEY POINTS FROM THE CASE: Considering the low sensitivity of the Naranjo scale in detecting rare reactions associated with liver damage, we used the Roussel-Uclaf Causality Assessment Method scale, with a finding of cholestatic jaundice hepatitis induced by methimazole. The patient's liver enzyme levels improved after discontinuation of methimazole. MAIN LESSONS LEARNED: Our case underlines the possible hepatoxicity associated with the use of methimazole. A review of the literature confirmed a selective hepatoxicity risk in individuals of Asian ethnicity, which has not been identified in Caucasian or Black populations. Physicians should be aware of the risk of hepatoxicity when prescribing oral methimazole to patients of Asian ethnicity. PMID- 29245334 TI - Fatty acid components in Asian female patients with irritable bowel syndrome. AB - Abdominal pain is one of the key symptoms of irritable bowel syndrome (IBS). Studies have indicated an increase in the incidence of IBS in Asia. However, yet the pathophysiology of this disease remains unknown. Women are more likely to develop the condition than men, especially the constipation-predominant type. Essential fatty acid (EFA) malnutrition is one of several theories discussing the mechanism of IBS.The authors hypothesized that significant EFA deficiency may cause abdominal pain in patients with IBS. However, because patterns in the oral intake of EFAs differ between cultures, the authors narrowed this study to examine the nutritional status of Asian female patients with IBSThe authors investigated Asian female patients with IBS and compared them with a group of healthy controls. Thirty patients with IBS and 39 healthy individuals were included in this study. The participants' age, height, weight, and waist size were recorded. The 24-item Hamilton Depression Rating Scale was documented. Both erythrocyte and plasma fatty acid content were analyzed through gas-liquid chromatography.The authors found that patients with IBS exhibited significantly higher scores for depression, higher proportions of plasma saturated fatty acids and monounsaturated fatty acids, and lower proportions of docosahexaenoic acid and total omega-3 polyunsaturated fatty acids in plasma are associated with IBS in Asian female patients. Further study is indicated to confirm the causality of this association. PMID- 29245335 TI - Spontaneous corneal perforation in Terrien's marginal degeneration in childhood: A case report. AB - RATIONALE: Terrien's marginal corneal degeneration (TMD) is characterized by progressive peripheral corneal thinning. It appears primarily above the age of 40 years and is rare at younger ages. Spontaneous corneal perforation in TMD is a rare, but serious complication that may occur in childhood. PATIENT CONCERNS: This review presents the case of a 16-year-old girl presented with blurred vision in the right eye on awakening in the morning. Slit-lamp examination revealed superior corneal thinning with a corneal perforation. DIAGNOSES: The best corrected visual acuity (BCVA) was 20/50 in the right eye and 20/20 in the left eye. Intraocular pressures were 5 and 18 mm Hg in the right and left eyes, respectively, measured using a noncontact tonometer. Slit-lamp examination revealed superior corneal thinning with superficial pannus. A 1-mm corneal perforation was observed at the 11 o'clock position. The anterior chamber of the right eye was flat and the Seidel test result was positive. The left eye showed no apparent abnormality on slit-lamp examination. Corneal topography showed 4.3 D of against-the-rule astigmatism, and anterior segment optical coherence tomography revealed superior corneal thinning. We diagnosed it as childhood onset TMD. INTERVENTIONS: Multilayered amniotic membrane transplantation was performed over the perforation site and a bandage contact lens was placed. OUTCOMES: At 1 week postoperatively, the BCVA of the right eye improved to 20/32, the amniotic membrane graft was well-attached, and the anterior chamber remained deep. At 2 months postoperatively, the BCVA was 20/25 and the anterior chamber depth was maintained. LESSONS: Spontaneous corneal perforation due to TMD is rare, but may occur in childhood. The possibility of corneal perforation should be considered even in childhood and good surgical results can be obtained with amniotic membrane transplantation. PMID- 29245336 TI - Amelioration of acute orbital compartment syndrome following transvenous embolization for an indirect carotid-cavernous fistula: A case report. AB - RATIONALE: Orbital compartment syndrome (OCS) is a rare occurrence after transvenous embolization of indirect carotid-cavernous fistula (CCF). A lateral canthotomy and cantholysis are the most commonly performed surgical interventions. In our case, as the acute OCS occurred immediately after an uneventful transvenous embolization, an orbital floor orbitectomy was performed. PATIENT CONCERNS: Here, we present a rare case of a 59-year-old patient who required a transvenous embolization of an indirect CCF and subsequently immediately developed an acute OCS. DIAGNOSES: An indirect CCF was revealed using brain magnetic resonance angiography and a transvenous embolization of the fistula was performed using coils. Post-embolization angiograms revealed an occlusion of the CCF. INTERVENTIONS: After the development of a relative afferent pupillary defect and acute OCS, we performed a lateral canthotomy, superior and inferior cantholysis, and an orbital floor orbitectomy. Subsequently, visual acuity and intraocular pressure improved. LESSONS: Our case is the first report of acute OCS occurring after transvenous embolization of a CCF that required further orbital floor decompression to prevent permanent visual loss. Moreover, our case demonstrates that acute OCS may rapidly develop after transvenous embolization due to superior ophthalmic venous (SOV) thrombosis and that an early intervention may reduce the risk of visual impairment. PMID- 29245337 TI - Assessment of pulmonary arterial enhancement on CT pulmonary angiography using a leg vein for contrast media administration. AB - The purpose of our study was to compare pulmonary artery (PA) enhancement according to venous routes of contrast media (CM) administration in patients who underwent CT pulmonary angiography (CTPA) in the emergency department (ED).This retrospective study reviewed the CTPAs of 24 patients who administered CM via leg veins (group A) and 72 patients via arm veins (group B) with age and gender matching at a ratio of 1:3. Clinical data, aorta attenuation (Aoatten), and PA attenuation (PAatten) were compared between group A and B. Each group was subcategorized into diagnostic and nondiagnostic CTPA subgroups, with a threshold of 250 HU at the PA. Then, clinical data, rates of pulmonary embolism (PE), and right ventricle (RV) strain were compared. In group A, the relationship between the narrowest suprahepatic IVC area (IVCarea) and the attenuation ratio of the RV to the intrahepatic IVC (RV/IVCatten) was evaluated.Aoatten (236.6 HU vs 293.1 HU, P < .001) and PAatten (266.7 HU vs 321.4 HU, P = .026) were significantly lower in group A than in group B. The proportion of nondiagnostic CTPA was significantly higher in group A than in group B (58.3% vs 19.4%, P = .001). In the subgroup analysis in of group A, patients with a nondiagnostic CTPA were significantly younger (55.3 years vs 68.6 years, P = .026) and showed a significantly lower incidence rate of PE (14% vs 70%, P = .01) than patients with a diagnostic CTPA. However, the radiological diagnostic rate of RV strain was comparable between patients with nondiagnostic and diagnostic CTPA. In group A, IVCarea and RV/IVCatten were positively correlated, with a correlation coefficient of 0.430 (P < .036).In conclusion, administration of CM through the leg veins increases the nondiagnostic CTPA rate, reducing the detection rate of PE. When CM is injected via the leg veins, the degree of PA enhancement is related with to the diameter of the suprahepatic IVC; therefore, adjustment of respiratory maneuvers may be needed to promote IVC flow into the right cardiac chamber, and to improve PA enhancement. PMID- 29245338 TI - Multifaceted spiral suture: A hemostatic technique in managing placenta praevia or accrete: A retrospective study. AB - Patients with total placenta previa and past history of cesarean delivery often experience overwhelming hemorrhage during childbirth. In order to control intraoperative and postoperative bleeding, we propose a novel multifaceted spiral suture of the lower uterine segment which directly sutures the bleeding site.To evaluate the efficacy and safety of multifaceted spiral suture, a retrospective study was conducted using data from 33 patients with total placenta praevia and caesarean history.All participants underwent multifaceted spiral suture and no patient experienced uncontrollable bleeding or underwent hysterectomy.The average blood loss of all patients involved was 1327.3 +/- 1244.1 mL. Five patients reported blood loss exceeding 3000 mL (15.15%), and the highest reached to 4000 mL. No complications such as fever, pyometra, synechiae, or uterine necrosis were observed. Three cases (3/33, 9.09%) reported hematuria in the first 3 days following surgery and spontaneous resolution were observed within 3 to 7 days following insertion of indwelling catheters. No complaints were received during 6 month follow-up visits.These findings suggest that multifaceted spiral suture is a practical, feasible, and promising technique in potentially minimizing postpartum bleeding and avoiding hysterectomy for patients with placenta praevia or accrete. PMID- 29245339 TI - Ten-year progress of coronary artery lesions prior to Behcet disease diagnosis: A case report and care-compliant article. AB - INTRODUCTION: Behcet disease is a multisystemic chronic inflammatory disorder characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. However, particularly part of patients would present cardiovascular involvements and vascular lesions could be the presenting sign of Behcet disease preceding classical symptoms. We presented a middle aged male patient, in whom abdominal aorta pseudoaneurysm was as the first leading sign to reveal Behcet disease, and with his coronary artery lesions progress through a 10-year period before Behcet disease was diagnosed. CONCLUSIONS: Coronary artery involvement of Behcet disease warrants more attention and investigation; repeated in-stent stenosis, aggressive progress, and elevated inflammation markers should be regard with more care earlier in clinical practice. PMID- 29245340 TI - Successful salvage for the intractable massive chylous leakage in a cirrhotic patient: A case report and literature review. AB - RATIONALE: Iatrogenic chylous leakage (CL) is a rare but potentially life threatening complication after neck surgery. In cirrhotic patient, the massive CL is even more intractable and extremely dangerous due to portal hypertension. PATIENTS CONCERNS: A 54-year-old liver cirrhotic patient had milky fluid leakage from left neck drainage tube after neck dissection surgery and hypopharyngeal cancer ablation. Electrolyte imbalance and shock status were reported when conservative managements and exploratory surgical repair failed to terminate the leakage. DIAGNOSIS: Massive CL up to >5 L/day was recorded on the post-operative day (POD) 9. INTERVENTIONS: A triangular-shaped pectoralis major (PM) muscle was designed to repair the lymph nodes dissected defect over left neck. OUTCOMES: After surgery, CL dramatically reduced to less than 300 mL/day in the coming day without relapses and terminated on the 8th days. After 3 months, the wound completely healed and the food conduit passage was patent without fistula. LESSONS: This report demonstrated the superiority of pectoralis major myocutaneous flap (PMMF) than the conservative treatment, local muscle flap, and radiologic or thoracoscopic duct ligation in cirrhotic patient with massive CL. PMID- 29245341 TI - Case report on the role of radiofrequency-assisted spleen-preserving surgery for splenic metastasis in the era of check-point inhibitors. AB - RATIONALE: An isolated splenic metastasis is a rare phenomenon noted in advanced stage melanoma. We report the role of radiofrequency (RF) -based splenic preserving splenectomy in a patient with a solitary splenic metastasis from advanced stage melanoma that was managed with checkpoint inhibitors. PATIENT CONCERNS: We report a case of a 60-year-old man who presented with multiple lung metastases and a solitary splenic metastasis with advanced stage melanoma following excision of primary from his trunk 2.3 years back. DIAGNOSIS: Considering the diagnosis of advanced stage melanoma with multiple lung metastases and a solitary splenic metastasis, and its ongoing progressive nature. This case was discussed in the tumour board meeting. INTERVENTIONS: A decision was made to commence treatment with immunotherapy in the form of PD-1 inhibitor (programmed cell death 1 receptor) pembrolizumab. Follow-up restaging computer tomography (CT) scan of the abdomen and chest showed a significant reduction in the lung and chest wall lesions, but the splenic lesion remained unchanged. Given the lack of response to treatment in the splenic metastasis and the significant decrease in lung metastases, the multidisciplinary team decided that a partial splenectomy combined with continued immunotherapy treatment would be appropriate as the success of immunotherapy was imminent within the splenic preservation. OUTCOMES: The postoperative recovery was smooth and the patient was discharged from hospital on the sixth postoperative day with normal platelets and white blood cells. The histopathological analysis of the resected specimen showed a metastatic melanoma with negative margins.At 10-month follow-up after the splenic resection the patient had not experienced further tumour recurrences. LESSONS: Spleen-preserving resection for an isolated, solitary splenic metastasis of melanoma is a feasible approach as it not only preserves the ongoing efficacy of checkpoint inhibitors by preserving the physiological T cell milieu, but the immunomodulation properties of RF can produce potentially additional therapeutic benefit. PMID- 29245342 TI - Intravascular epithelioid hemangioendothelioma of the femoral vein diagnosed by contrast-enhanced ultrasonography: A care-compliant case report. AB - RATIONALE: Intravascular epithelioid hemangioendothelioma (EHE) is a rare endothelial tumor with an intermediate grade of malignancy. We present a case of one woman affected by EHE of the femoral vein. Contrast-enhanced ultrasonography played a role in diagnosing EHE and helped differentiate it from thrombosis. To our knowledge, this is the first reported contrast-enhanced ultrasonography of intravascular EHE in the imaging literature. PATIENT CONCERNS: A 46-year-old woman presented to our hospital due to pain and swelling in her right lower limb since 5 years prior to her presentation. DIAGNOSES: The patient was misdiagnosed as having thrombosis by ultrasound. Contrast-enhanced ultrasonography showed solid lesions with visible blood supply, suggesting angiogenic tumors. INTERVENTIONS: The patient was treated by complete surgical removal of the mass and postoperative radiotherapy. Pathological examination confirmed the diagnosis of EHE. OUTCOMES: During follow-up, there were no signs of local or distant relapse. LESSONS: Intravenous EHE may be misdiagnosed as thrombosis by ultrasound and contrast-enhanced ultrasonography can help make the differential diagnosis. PMID- 29245343 TI - Altered Expression of TXNIP in the peripheral leukocytes of patients with coronary atherosclerotic heart disease. AB - BACKGROUND: Coronary atherosclerotic heart disease (CAD) is mainly caused by atherosclerosis, an inflammatory disease characterized by plaque formation in arteries. Reactive oxygen species caused structural damage and dysfunction of arterial endothelial cells. Thioredoxin-interacting protein (TXNIP) is the endogenous inhibitor and regulator of thioredoxin, a major cellular antioxidant and antiapoptotic system. In order to explore the role of TXNIP in the occurrence and development of CAD, we detected the TXNIP expression and discussed its molecular mechanisms in CAD. METHODS: The mRNA levels of TXNIP gene in peripheral leucocytes were detected in CAD and healthy controls (CTR) by quantitative real time polymerase chain reaction. And TXNIP proteins were detected by western blotting. RESULTS: TXNIP gene expression levels in patients with unstable angina pectoris (UAP, n = 96) were significantly increased compared with those of CTR (n = 192, P < .05). However, the situation is different in acute myocardial infarction (n = 96, P > .05). Logistic regression analysis showed that TXNIP levels were significantly positive correlated with UAP (OR = 1.728, P < .05). CONCLUSIONS: TXNIP gene expression in the peripheral leucocytes was increased in patients with UAP, indicating that TXNIP in circulating leucocytes may be involved in the pathogenesis of UAP. PMID- 29245344 TI - Electroacupuncture for women with stress urinary incontinence: Protocol for a systematic review and meta-analysis. AB - BACKGROUND: Stress urinary incontinence (SUI) is a widespread complaint in the adult women. Electroacupuncture has been widely applied in the treatment of SUI. But its efficacy has not been evaluated scientifically and systematically. Therefore, we provide a protocol of systematic evaluation to assess the effectiveness and safety of electroacupuncture treatment on women with SUI. METHODS: The retrieved databases include 3 English literature databases, namely PubMed, Embase, and Cochrane Library, and 3 Chinese literature databases, namely Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang Database. The randomized controlled trials (RCTs) of the electroacupuncture treatment on women with SUI will be searched in the above-mentioned databases from the time when the respective databases were established to December 2017. The change from baseline in the amount of urine leakage measured by the 1-hour pad test will be accepted as the primary outcomes. We will use RevMan V.5.3 software as well to compute the data synthesis carefully when a meta-analysis is allowed. RESULTS: This study will provide a high-quality synthesis to assess the effectiveness and safety of electroacupuncture treatment on women with SUI. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether electroacupuncture is an effective intervention for women with SUI. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42017070947. PMID- 29245345 TI - Incidence of malignant hyperthermia in patients undergoing general anesthesia: Protocol for a systematic review and meta-analysis. AB - BACKGROUND: Malignant hyperthermia (MH) continues to be of potential concern for clinicians whenever inhalational anesthetic agents or succinylcholine are used, because MH is a potentially fatal metabolic disorder. METHODS: A systematic and comprehensive search will be performed using MEDLINE, EMBASE, and Google Scholar, for studies published up to November 2017. Peer-reviewed prospective cohort studies, retrospective cohort studies, and cross-sectional studies or reports issued by government organizations reporting the incidence or prevalence of MH will be eligible for inclusion. The quality of included studies will be assessed using the Newcastle-Ottawa scale and the modified risk of bias tool. Heterogeneity of estimates across studies as well as publication bias will be assessed. This systematic review and meta-analysis will be performed according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. All statistical analyses will be conducted using the Stata SE version 15.0. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: To our knowledge, this systematic review and meta-analysis will be the first to evaluate existing research on the incidence of MH. Our study will provide an overall estimate of the incidence of MH. Subgroup analysis will assess the incidence of MH according to age, gender, geographical region, race, and the provoking agent if possible. The review will benefit patients, healthcare providers, and policymakers. ETHICS AND DISSEMINATION: Ethical approval and informed consent are not required, as the study will be a literature review and will not involve direct contact with patients or alterations to patient care. TRIAL REGISTRATION NUMBER: The protocol for this review has been registered in the PROSPERO network (registration number: CRD42017076628). PMID- 29245346 TI - Two independent incidences of skin metastases in the umbilicus and abdominal wall in ovarian serous adenocarcinoma: A case report and review of the literature. AB - RATIONALE: Advanced ovarian cancer is usually associated with intra-abdominal metastases and while it commonly spreads directly to the omentum, intestine, liver, or other organs, it can also metastasize through the lymphatic channels and the hematogenous pathway. With an increasing number of invasive operations being performed with chemoradiotherapy, the incidence of extra-abdominal metastases has risen. Nevertheless, ovarian cancer with skin metastases is quite rare. PATIENT CONCERNS: We report a case of ovarian cancer with two independent incidences of skin metastases in the umbilicus and abdominal wall. DIAGNOSES: The patient was a 67-year-old woman who was diagnosed with ovarian cancer stage IIIC and underwent cytoreductive surgery. A solitary brown cauliflower-like metastatic lesion, approximately 6 * 5 * 4 cm was identified in the umbilicus area two years after primary surgery. During tumorectomy, intraoperative exploration revealed that while the tumor was located close to the peritoneum, there was no penetration. INTERVENTIONS: The patient recovered well and received multiple rounds of chemotherapy. Ten months later, the patient presented with skin lesions located on the abdominal wall that grew rapidly and spread from the lower abdomen wall to the bilateral waist and femoral skin. These lesions were multiple, ulcerated, rough heliotrope plaques that produced a foul-smelling faint yellow liquid. Biopsy analysis revealed skin metastasis of poorly differentiated serous adenocarcinoma. OUTCOMES: The patient was treated with chemotherapy but died 3 months after the skin metastasis occurred for the second time. LESSONS: Ovarian cancer with skin metastasis is a rare condition with poor prognosis. Pathological diagnosis of early skin lesions is essential for ovarian cancer patients and that systemic and local disease should be treated with surgery or palliative therapy in order to provide patients with the best chances of survival. Tumorectomy is appropriate when lesions are isolated and when the patient's performance status is good. However, systemic therapy including chemotherapy and radiotherapy should be considered when skin lesions are associated with severe intro-abdominal disease. PMID- 29245348 TI - The timing of open surgical release of post-traumatic elbow stiffness: A systematic review. AB - BACKGROUND: Open release of post-traumatic elbow stiffness is effective in restoring elbow function, but there is no guideline on the optimal time point of surgical release so far. The purpose of this article was to summarize the current available literature reporting on the timing of open release of post-traumatic elbow stiffness. METHODS: The PubMed, Cochrane Library, and EMBASE were searched with a set of predefined inclusion and exclusion criteria. Manual searches for references were performed to find potential relevant studies. Two authors separately extracted data from all the articles selected. RESULTS: 27 articles published between 1989 and 2017 were included with an overall enrollment of 836 patients. We divided all included studies into 3 groups according to the timing of surgical release: group 1 (6-10 months after injury), group 2 (11-20 months after injury), and group 3(>20 months after injury). The mean postoperative Mayo Elbow Performance Score (MEPS) and recurrence rate were similar among the 3 groups; however, the mean gain in arc of motion in group 1 was the highest with the lowest complication rate among the 3 groups. CONCLUSION: There was a trend toward a shorter waiting time from injury to open arthrolysis from 12 months to 6 months. The shorter waiting period of 6 to 10 months yielded better results. Therefore, early surgical release of stiff elbows is recommended for a shorter rehabilitation time and earlier return to work. LEVEL OF EVIDENCE: Level IV, Systematic Review. PMID- 29245347 TI - Systematic review and meta-analysis to compare success rates of retrograde intrarenal surgery versus percutaneous nephrolithotomy for renal stones >2 cm: An update. AB - BACKGROUND: We performed a systematic review and meta-analysis comparing stone free rates between retrograde intrarenal surgery (RIRS) and percutaneous nephrolithotomy (PCNL), using updated, more reliable evidence. MATERIALS AND METHODS: Randomized controlled trials comparing RIRS and PCNL for >2 cm stones were identified from electronic databases. Stone-free rates for the procedures were compared by qualitative and quantitative syntheses (meta-analyses). Outcome variables are shown as risk ratios (RRs) with 95% confidence intervals (CIs). RESULTS: Eleven articles were included in this study. Most recently published studies exhibited relatively low quality during quality assessment. For the meta analysis comparing success (stone-free) rates between PCNL and RIRS, the forest plot using the random-effects model showed an RR of 1.11 (95% CI 1.02-1.21, P < .014) favoring PCNL. After determining the among-study heterogeneity, subgroup analysis was performed of 9 studies with less heterogeneity: the stone-free rate of PCNL was superior to that of RIRS using a fixed-effect model (RR 1.07, 95% CI 1.01-1.14, P < .019) for these studies. CONCLUSIONS: RIRS can be a safe and effective procedure for selected patients with large renal stones. However, in this meta-analysis, the postoperative stone-free rate of PCNL was higher than that of RIRS in patients with >2 cm renal stones. PMID- 29245349 TI - Secondary hypertension due to isolated interrupted aortic arch in a 45-year-old person: A case report. AB - RATIONALE: Though it is rare, isolated interrupted aortic arch (IAA) could lead to hypertension. Surgical repair is the only effective curative method to treat IAA conditions and patients with IAA can hardly survive to adulthood with medication alone. We report an IAA case that of a 45-year-old male patient who survived for 45 years without surgical treatment. PATIENT CONCERNS: A 45-year-old man was referred to the hospital presenting with abnormal blood pressure level. Both computed tomography angiogram (CTA) and angiography revealed IAA. DIAGNOSES: The patient was diagnosed as IAA based on computed tomography angiogram (CTA) and angiography. INTERVENTIONS: The patient's blood pressure was severely high and refractory. He refused surgical treatment and accepted antihypertensive medication for 10 days. OUTCOMES: The patient's office blood pressure level was abnormal, fluctuating between 140/90 and 160/100 mm Hg, but 24-hour ambulatory blood pressure monitoring showed normal level. LESSONS: Hypertension due to IAA could be controlled with medications, even surgery is not performed. The discrepancy between ambulatory and office blood pressure levels may be due to the white coat effect. PMID- 29245350 TI - A case report of patient with severe acute cholangitis with tigecycline treatment causing coagulopathy and hypofibrinogenemia. AB - RATIONALE: Tigecycline is the first member of the glycylcycline family. There are rarely reports of tigecycline causing coagulopathy and hypofibrinogenemia until now. We report a case on tigecycline-associated coagulopathy and hypofibrinogenemia and discuss the characteristics of the adverse reaction. PATIENT CONCERNS: A 47-year-old male patient with severe acute cholangitis who developed sepsis was treated with a high dosage (100 mg twice daily) of tigecycline. He experienced coagulopathy and hypofibrinogenemia as substantiated by increased levels of prolonged prothrombin time (PT), the international normalized ratio (INR) and activated partial thromboplastin time (APTT), and in particular, the fibrinogen (FIB) levels obviously decreased. DIAGNOSES: Coagulopathy and hypofibrinogenemia. INTERVENTIONS: We discontinued tigecycline and gave the patient several blood products to prevent spontaneous bleeding. OUTCOMES: The adverse reaction disappeared after the withdrawal of tigecycline. After 30 days of hospitalization, the patient discharged with symptom free. LESSONS: We suggest that coagulation parameters should be closely monitored in patients treated with tigecycline, specifically in patients who may be renal insufficiency, female or use the high-dose. PMID- 29245351 TI - Fixed-flexion view X-ray of the knee superior in detection and follow-up of knee osteoarthritis. AB - A fixed flexion view (FFV) is useful for evaluating joint space when assessing the severity of osteoarthritis (OA) of the knee. We analyzed changes in joint space revealed by standing extended view (SEV) and FFV over a mean 4 years, to compare both views on their capacity to measure joint space width accurately at particular time points during follow-up.SEV and FFV images were acquired in patients with knee OA. The 81 patients (157 knees) followed up for >=24 months were selected as study subjects. Medial joint space widths (MJSW), Kellgren Lawrence (KL) grades, and reductions in MJSW on SEV (DeltaSEV) and FFV (DeltaFFV) were compared in knees evaluated by SEV and FFV.At both time-points, mean MJSW was significantly lower by FFV than by SEV. Mean MJSW was significantly lower at follow-up than at first examination by both SEV and FFV. At both time-points, the KL grade was higher by FFV than by SEV group. The DeltaFFV was significantly greater than the DeltaSEV. DeltaSEV did not differ significantly among KL grades, but DeltaFFV was significantly greater in patients with KL grade II than in patients with other KL grades.FFV is not only useful for evaluating joint space in knees with OA, but also for accurately evaluating the progression of OA. The risk of rapid progression of knee OA may be higher in patients with KL grade II, as determined by FFV. FFV may be superior to SEV in determining appropriate treatment strategies for knee OA. PMID- 29245352 TI - Effect of multiple intra-articular injections of polynucleotides on treatment of intractable knee osteoarthritis: A case report. AB - RATIONALE: Knee osteoarthritis (KOA) is a chronic joint degenerative disease. Intra-articular injection (IAI) of hyaluronic acid (HA) is widely used to treat KOA. However, some HA injections have no effect at all. Polynucleotides (PN) are recently noted as a valid substitute for HA. PATIENT CONCERNS: A 61-year-old female was admitted to the pain center with symptoms of pain over the knee and warmth feeling with stiffness in the left knee. The patient reported chronic severe pain in the left knee area despite 6 times IAI of HA. She had past medical history of breast cancer and thyroid cancer. DIAGNOSES: She was diagnosed as having KOA. INTERVENTIONS: Ultrasound-guided IAI of PN was carried out 3 times in 3 weeks. OUTCOMES: She was followed-up for more than 5 months with good improvement in intractable knee pain without any adverse event. LESSONS: IAI of PN is an efficient therapeutic option for KOA treatment if HA injection is unsuccessful. PMID- 29245353 TI - Multiple aneurysms and gastrointestinal involvement in Behcet's disease: A case report. AB - RATIONALE: Behcet's disease (BD) is a rare systemic vasculitis disorder that can involve vessels of any size. PATIENT CONCERNS: A 60-year-old female had recurrent painful mouth ulcers about 30 years ago and recently presented with abdominal distension, conjunctival congestion, and chest pain in sequence. DIAGNOSES: The patient was diagnosed with BD according to the International Criteria for Behcet's Disease (ICBD). INTERVENTIONS: A therapy of glucocorticoids and cyclophosphamide was administered. OUTCOMES: After a 3-month treatment, follow-up examination showed a depression of the inflammation and a slight decrease of the arterial aneurysms. LESSONS: BD patients may get a delayed diagnosis because of the long duration between the first and subsequent manifestations. Suspect patients should be followed-up and the diagnosis of BD should be considered when multiple tissues or organs are involved. PMID- 29245354 TI - Anesthesia for a parturient with intraneural perineurioma: A case report. AB - RATIONALE: Intraneural perineurioma is an extremely rare form of peripheral nerve sheath tumor; and the anesthetic management of a parturient with intraneural perineurioma, especially affecting spinal roots and nerves of extremities, is very rare. PATIENT CONCERNS: A 28-year-old woman was referred to the hospital at 37+5 weeks' gestation, presenting with a 10-year history of paroxysmal acroanesthesia and aching with distal limbs. DIAGNOSES: Based on the biopsy results, including immunohistochemical and electron microscopic findings, and molecular studies, her condition was diagnosed as intraneural perineurioma. INTERVENTIONS: The size of pelvic nervous masses gradually increased with pregnancy. A scheduled elective cesarean section under general anesthesia was concluded for the patient under preoperative multidisciplinary consultation with anesthesiologist, neonatologist, and neurologist. OUTCOMES: The patient and the neonate were discharged smoothly on the fourth postoperative day. During a 6 month follow-up period, no new neurologic complication was observed. LESSONS: To our knowledge, this is the first case report that documented the anesthetic management for a parturient with intraneural perineuroma. Careful preconception care and multidisciplinary assessment are essential to achieve optimal reproductive outcomes. PMID- 29245356 TI - A case report: Does the ulcer belong to esophageal carcinoma or HIV? AB - RATIONALE: The deep-rooted pathogenesis of the human papilloma virus (HPV) infection is still uncertain and argumentative. As we know, a lot of cases of esophageal infections, such as esophageal squamous cell carcinoma (ESCC) and esophageal squamous papilloma (ESP), associated with HPV are reported. However, primary esophageal ulcer infection associated with HPV is unusual. PATIENT CONCERNS: This case is different from the other reports associated with HPV due to the patient's favorable prognosis. DIAGNOSES: We present a case of a man diagnosed in the Gastroenterology Department of Tianjin Hospital of Integrated Traditional Chinese and Western Medicine, which presented a deep and big esophageal ulcer with irregular borders caused by type 16 HPV infection. INTERVENTIONS: The esophageal ulcer was treated with vidarabine monophosphate treatment. OUTCOME: The esophageal ulcer was cured. LESSONS: We could put forward the diagnostic criteria available for diagnostic guidelines and 2 hypotheses that could possibly prevent esophageal carcinoma from happening. PMID- 29245357 TI - IgG4-related lung disease presenting as interstitial lung disease with bronchiolitis: A case report. AB - RATIONALE: IgG4-related disease is a rare and novel disease entity that tends to involve multiple organs. The pulmonary manifestation of this disease is highly variable and may mimic lung cancer, pneumonia, interstitial lung disease (ILD), sarcoidosis, and so forth. Small airway disease is rarely reported in IgG4 related lung disease (IgG4-RLD). In the current study, we describe a rare case of IgG4-RLD with patterns of ILD and bronchiolitis. PATIENT CONCERN: A 43-year-old man had chronic cough and dyspnea on exertion for 4 years. Initial chest radiography showed diffuse interstitial infiltration. Follow-up chest computed tomography 4 years later revealed bilateral diffuse centrilobular nodules with tree-in-bud pattern, bronchial wall thickening, and mediastinal lymph nodes. Bilateral diffuse multifocal ground-glass opacities and mosaic attenuation were also observed. Pulmonary function test revealed mixed restrictive and obstructive ventilatory impairment. DIAGNOSES: Video-assisted thoracoscopic surgery (VATS) lung biopsy showed interstitial fibrosis with lymphoplasmacytic infiltration rich in IgG4-positive plasma cells. Serum IgG4 level also showed remarkable elevation. Therefore, IgG4-RLD is confirmed. INTERVENTION: VATS wedge resection of right upper lobe and mediastinal lymph node. OUTCOMES: The patient responded well to steroid and immunosuppression therapy, and was regular followed-up in outpatient clinic. LESSONS: IgG4-RLD should be considered not only in ILD, but also in small airway disease. Serum IgG4 level may be a useful tool for screening. PMID- 29245355 TI - Endometriosis-associated malignant transformation in abdominal surgical scar: A PRISMA-compliant systematic review. AB - BACKGROUND: Endometriosis-associated malignant transformation in abdominal surgical scar (EAMTAS) is a very rare and aggressive phenomenon. Our current article aims to provide a clinical overview, focusing on risk factors affecting survival. METHODS: We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review based on prior reviews and case reports regarding the phenomenon published as abstracts in English, from January 1980 to November 2016. Overall, we identified 47 cases, and we included another case from our institution. We further contacted previous investigators to receive updated follow-up regarding their patients. We analyzed the data, focusing on risk factors that might affect overall survival. RESULTS: All the patients reported in the literature had a uterine surgery, mainly caesarean section. The median time-lag from first surgery to the diagnosis of cancer was about 19 years. Clear-cell carcinoma (CCC) was the most prevalent histology (67%), followed by endometrioid adenocarcinoma (15%). Most of the patients were treated by extensive surgery and chemotherapy and/or radiation. Overall 5 years survival was about 40%. Median overall survival was 42 months (95% confidence interval of [18.7, 65.3]). Although our review is currently the largest in the literature, we cannot draw any statistical significant results due to the limited number of patients reported. According to univariate Cox-regression models, a tendency toward worse prognosis was shown for 3-year disease-free survival clear cell histologic-type (P = .169), and tumor diameter >=8 cm in nonclear-cell histology, 18 months postdiagnosis (P = .06). CONCLUSION: EAMTAS is a rare and aggressive disease. It is mostly related to cesarean section scars and is diagnosed many years postsurgery. Clear-cell histology tends to endure from the worse prognosis. The treatment is mainly extensive surgery and adjuvant chemotherapy and/or radiotherapy. PMID- 29245358 TI - Evaluation of the accuracy of renal depth estimation formulas in horseshoe kidney. AB - Estimation formulas are usually used to calculate renal depth when glomerular filtration rate (GFR) is measured by the Gates method. Horseshoe kidney (HSK) anatomical structure is different from the normal form of the kidney. The existing formulas are based on the normal form. It is unknown whether the existing formulas are valid in HSK patients. This study was performed to estimate the accuracy of the existing 6 renal depth estimation formulas in HSK.Renal depth and total thickness (T, cm) of the body at the level of the kidneys were measured by CT in 94 HSK patients. Their sex, age, height (H, cm), and weight (W, kg) were recorded. The existing 6 estimation formulas were used to obtain estimated renal depth. Correlation coefficients, Bland-Altman analysis, and paired t test were performed between estimated and the CT measured renal depth.Estimated renal depths were all lower than the CT measured renal depths and there was significant difference between estimated and CT measured renal depth. The CT measured renal depth and estimated renal depth derived from Ma GY formula correlated best (right: r = 0.80, P < .01; left: r = 0.77, P < .01). The renal depth derived from Tonnesen formula was significantly lower than the CT measured renal depth. The agreement between the estimated renal depth derived from Tonnesen formula and the CT measured renal depth was the worst, with the mean difference of (right: -3.11 +/- 1.13 cm; left: -2.79 +/- 1.07 cm). The agreement between the estimated renal depth derived from Li Q formula and Ma GY formula and the CT measured renal depth was the best, with the mean difference of right: -1.68 +/- 1.09 cm; left: -1.32 +/- 1.06 cm and right: -1.59 +/- 1.01 cm; left: -1.59 +/- 0.99 cm, respectively. But the greatest error of the difference between Li Q formula and Ma GY formula estimated depth and the CT measured depth was up to -4.83 cm, and the estimated deviation is unacceptable.All the existing formulas do not fully apply to HSK. To provide reliable and accurate estimates of renal depth, we should develop a new formula to estimate the renal depth in HSK patients. PMID- 29245359 TI - Potential killer in the ICU-severe tuberculosis combined with hemophagocytic syndrome: A case series and literature review. AB - Hemophagocytic syndrome (HPS) is a life-threatening clinical syndrome that has various presentations, shows rapid progression and is associated with a high mortality. Clinical reports about pulmonary tuberculosis combined with respiratory failure accompanied by HPS are rare.HPS has no special clinical manifestations, and the main presentations include persistent fever, hepatosplenomegaly, hematocytopenia, and rash. In the Intensive Care Unit (ICU), the clinical manifestations of severe infection and secondary HPS overlap, thus there is often a delay in the diagnosis and treatment of HPS.HPS is not an independent disease but represents an excessive inflammatory response due to immune dysfunction induced by various causes such as infection and tumor.The 2 cases in this report show that tuberculosis-associated hemophagocytic syndrome is not easy to find, especially in ICU. There are few clinical reports of pulmonary tuberculosis combined with respiratory failure and HPS. Here, we describe 2 such clinical cases and review the relevant literature in order to deepen our understanding of this disease. PMID- 29245360 TI - Does increased serum d-lactate mean subclinical hyperpermeability of intestinal barrier in middle-aged nonobese males with OSA? AB - Few attention has been directed to the potential effects of intermittent hypoxia experienced in obstructive sleep apnea on the integrity and permeability of intestinal barrier, particularly in adults. Therefore, we evaluated alteration in serum d-lactate concentration in middle-aged males with obstructive sleep apnea to value permeability of intestinal barrier. In this current cross-sectional study, consecutive 159 males were studied. Obstructive sleep apnea was determined by polysomnography and apnea hypopnea index >=15 event/h was defined as obstructive sleep apnea. D-lactate, lipopolysaccharide binding protein, interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha by ELISA method. Nonobese obstructive sleep apnea (OSA) males showed significantly higher serum d LA than did nonobese [1374.35 (816-1735) MUg/L vs 1166.43 (730-1815) MUg/L, P = .018], and obese non-OSA ones [1374.35 (816-1735) MUg/L vs 1188.75 (736-1557) MUg/L, P = .045], whereas serum LBP levels showed no differences within groups. Serum IL-1beta was also slightly higher in nonobese OSA males, but with statistical significance, than in nonobese (19.39 +/- 4.67 ng/L vs 17.25 +/- 3.66 ng/L, P = .041), and obese non-OSA ones (19.39 +/- 4.67 ng/L vs 17.42 +/- 3.79 ng/L, P = .047), whereas other biomarkers, IL-6 and TNF-a did not show significant differences among groups. In stepwise multiple linear regression analysis, serum d-LA was independently positively associated with AHI (B = 5.577, P = .022), and ODI3 (B = 4.550, P = .024) and negatively with LSaO2 (B = -12.234, P = .019). Finally, we arrived at a conclusion that serum d-lactate was increased in nonobese middle-aged males with obstrutive sleep apnea, possibly suggesting existence of subclinical disruption of intestinal barrier, and showed significant associations with inflammatory mediators, possibly being involved in systemic inflammation of obstructive sleep apnea. PMID- 29245361 TI - Effects of remifentanil with or without midazolam pretreatment on the 95% effective dose of propofol for loss of consciousness during induction: A randomized, clinical trial. AB - BACKGROUND: Propofol is a rapid, efficient hypnotic agent with antiemetic effects. However, a high dosage is related to hemodynamic abnormalities such as hypotension and bradycardia. Pretreatment with remifentanil can decrease injection pain and stabilize hemodynamics during the induction period. Remifentanil or midazolam in combination with propofol can provide synergistic or additive effects during anesthesia induction. However, the hypnotic doses of propofol required in patients who receive pretreatment with remifentanil or midazolam remain unclear. METHODS: Patients aged 20 to 50 years who were scheduled to undergo surgery under general anesthesia were enrolled in this study. The patients were randomized into 3 groups using a computer-generated randomization table. Patients in Group P (Propofol) received only propofol for loss of consciousness, those in Group PR (Propofol-Remifentanil) received remifentanil prior to propofol, and those in Group PMR (Propofol-Midazolam Remifentanil) received remifentanil and midazolam prior to propofol. After propofol administration, loss of both the eyelash reflex and verbal response represented success. The 95% effective dose of propofol for loss of consciousness in each group, which was the primary outcome, was determined using a modified biased coin up-and-down method. RESULTS: A total of 124 patients were initially enrolled. Of these, 4 were excluded, and the remaining 120 patients were randomized to each (n = 40) of the 3 groups. The 95% effective dose of propofol for loss of consciousness was 1.74 , 1.38, and 0.92 mg/kg in Groups P, PR, and PMR, respectively. Blood pressure decreased at 2 minutes after propofol administration in all the groups. However, compared with Group P, Groups PR and PMR exhibited a significant decrease in blood pressure. CONCLUSIONS: The effective dose of propofol for loss of consciousness could be decreased by 21% and 47% when remifentanil pretreatment was used without and with midazolam, respectively. However, the decrease in blood pressure was greater with pretreatment than sole propofol use. These findings suggest that the combination of remifentanil with or without midazolam may have no benefit on hemodynamic stability during induction using propofol. TRIAL REGISTRATION: NCT02536690 (clinicaltrials.gov). PMID- 29245363 TI - Nasopharyngeal carcinoma with central nervous system metastases: Two case reports and a review of the literature. AB - RATIONALE: Central nervous system (CNS) metastases are rarely seen in patients with nasopharyngeal carcinoma (NPC). PATIENT CONCERNS: Two NPC patients developed CNS metastases were collected in Fudan University Shanghai Cancer Center. The medical records were reviewed to document patients' characteristics, treatment, and outcomes. In addition, we also provide an overview of the literature concerning this scenario. DIAGNOSES: Both patients were staged T4N1M0 with pathologically confirmed CNS metastases from nasopharyngeal carcinoma. INTERVENTIONS: After the completion of initial chemoradiotherapy, metastases to CNS including brain and/or spine occurred during follow-up. Surgical resection combined with palliative chemoradiation was offered to alleviate the symptoms. OUTCOMES: Although multiple treatment modalities were given, both patients succumbed to disease progression. LESSONS: The mechanism for CNS metastases is postulated through hematogenous route or cerebral spinal fluid spread. Good symptoms amelioration can be achieved with aggressive treatments such as surgery followed by palliative chemoradiation, but prognoses are ominous due to systematic disease dissemination. PMID- 29245362 TI - Characteristics of computed tomography in hemodynamically unstable blunt trauma patients: Experience at a tertiary care center. AB - Emergent exploratory laparotomy is recommended for hemodynamically unstable blunt trauma patients suspected of having hemoperitoneum. However, given the unreliability of ultrasonography and rapid scan speed of computed tomography (CT), CT might help clinicians provide accurate information even in hemodynamically unstable trauma patients. This observational study aimed to describe the bleeding site and hospital course of severe blunt trauma patients with hemoperitoneum diagnosed by CT scan.We enrolled all consecutive adult blunt trauma patients (>=18 years old) who underwent whole-body CT before operation between February 2012 and October 2016. Patients with hemoperitoneum on CT images were included and categorized into hemodynamically stable and unstable (persistent hypotension despite fluid resuscitation) groups.Among 1723 severe blunt trauma patients, 136 patients with hemoperitoneum were included. Of these, 98 (72.1%) patients had documented intraperitoneal injury, and the liver (60.2%) was most frequently damaged site, followed by spleen (23.5%) and mesentery (23.5%). The rate of intraperitoneal organ injury did not differ between hemodynamically stable (n = 107) and unstable (n = 29) groups (69.2% vs 82.8%, P = .15), while the documented active internal bleeding was high in the unstable group (29.9% vs 69.0%, P < .001). In the unstable group, 14 (48.3%) patients underwent emergent operation, while 3 patients underwent embolization, and the others were treated in a conservative manner.Even in hemodynamically unstable hemoperitoneum patients, 17.2% had no documented intraperitoneal injury and over half of the patients were treated without emergent operation. PMID- 29245364 TI - X-linked Charcot-Marie-Tooth disease with GJB1 mutation presenting as acute disseminated encephalomyelitis-like illness: A case report. AB - RATIONALE: Charcot-Marie-Tooth disease (CMT) is typically an autosomal dominant, inherited neuropathy, although there is a rare male X-linked CMT. Such patients show central nervous system (CNS) involvement in addition to peripheral neuropathy. Recently, we encountered a patient who presented with acute disseminated encephalomyelitis (ADEM)-like symptoms, but was later diagnosed as having X-linked CMT (CMTX) due to a mutation. PATIENT CONCERNS: A previously healthy 11-year-old boy was admitted for a sudden transient weakness of his left side extremities. DIAGNOSES: The patient was diagnosed with left side hemiparesis. Brain magnetic resonance imaging (MRI) showed ADEM-like demyelinating lesions on both centrum semiovale. A diagnosis of probable ADEM was made, and the patient soon recovered. After 4 months, a second MRI showed complete resolution of the brain lesions. However, the symptoms recurred 2 years later. A third MRI revealed white matter abnormalities, and a physical examination demonstrated pes cavus deformities and peripheral muscle wasting of both lower extremities. INTERVENTIONS: On the basis of the brain MRI lesions and physical findings, we suspected CMTX. Genotyping confirmed a mutation in the GJB1 gene. OUTCOMES: When the symptoms recurred 2 years later, dysarthria and demyelinating MRI lesions were present. We could not identify any triggering factors. LESSONS: Differential diagnosis of recurrent ADEM-like lesions in the cerebral white matter and peripheral neuropathy should include the possibility of CMTX disease. PMID- 29245365 TI - Teratoma-associated anti-NMDAR encephalitis: Two cases report and literature review. AB - OBJECTIVE: This study aimed to discuss the pathogenesis, clinical manifestation, diagnosis, and treatment of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. CASE REPORT: The diagnosis and treatment of 2 cases with teratoma associated anti-NMDAR encephalitis were summarized and the clinical data of patients reported by domestic and international studies were reviewed in this study. The 2 cases were both adolescent females who showed mental abnormalities as their main clinical manifestation. The patients were positive for anti-NMDAR antibody in their serum and cerebrospinal fluid, and gynecologic ultrasound detected ovarian teratoma. After diagnosis, the patients underwent teratoma resection, followed by pulse therapy of hormones and gamma globulin. Chemotherapy was performed to prevent tumor recurrence, and patients were in a stable condition. CONCLUSIONS: Teratoma-associated anti-NMDAR encephalitis is commonly seen in young women. The clinical manifestation of this disease is nonspecific, and the patients mainly have fever, psychosis, and seizure. Tumor resection and immune therapy are effective treatment strategies, and standardized chemotherapy should also be performed to prevent recurrence. PMID- 29245367 TI - A revision of Eastern Palaearctic Anthobium Leach, 1819 (Coleoptera: Staphylinidae: Omaliinae: Anthophagini). I. Gracilipalpe, morchella and nigrum groups. AB - Three new species-groups are established for eastern Palaearctic species of the genus Anthobium Leach, 1819: Gracilipalpe-group containing A. gracilipalpe (Champion, 1920) (Uttaranchal, Nepal), A. daliense sp.n. (China: Yunnan, Diancang Shan) and A. nivale sp.n. (China: Yunnan, Gaoligong Shan). Morchella-group containing A. morchella sp.n. (China: Yunnan, Baima Shan), A. hydraenoides sp.n. (China: Yunnan, Meili Xue Shan) and A. puetzi sp.n. (China: Sichuan, Daxue Shan, Qionglai Shan). Nigrum-Group containing A. nigrum (Cameron, 1924) (Himalaya), A. anishchenkoi sp.n. (China: Gansu, Dalijia Shan), A. conjunctum sp.n. (China: Yunnan, Diancang Shan), A. densepunctatum sp.n. (China: Yunnan, Meili Xue Shan) and A. ivani sp.n. (Nepal: Bagmati; Bhutan). The species groups are defined, briefly discussed and a key to the species included in each group is given. Lectotypes are designated for Eudeliphrum gracilipalpe Champion, 1920 and Lathrimaeum nigrum Cameron, 1924. Species in each species-group are described/redescribed, illustrated and their geographical distribution is mapped. Members of the genus Anthobium are recorded for the first time from China and Bhutan, and Anthobium gracilipalpe is recorded for the first time from Nepal. PMID- 29245366 TI - Catheter ablation versus rate control in patients with atrial fibrillation and heart failure: A multicenter study. AB - Many trials have shown improvements in left ventricular function, exercise capacity, and quality of life after catheter ablation (CA) of atrial fibrillation (AF) in patients with heart failure (HF). We sought to evaluate the impact of CA on hard outcomes in a retrospective cohort study. AF patients with symptomatic HF from 3 hospitals were included. Our primary endpoint was major adverse cardiac events (MACEs), a composite of all-cause mortality, stroke, and unplanned hospitalization. In total, 90 patients underwent CA and 304 ones received rate control (RaC) were included. After a mean follow-up of 13.5 +/- 5.3 months, 82.2% of patients in CA group got freedom from AF; all patients in RaC group remained in AF. CA group had a significant decreased risk of MACEs compared with RaC group (13.3% vs 29.3%, hazard ratio [HR] 0.51, 95% confidence interval [CI]: 0.32-0.82, P = .005). After propensity score matched for confounding factors, difference in MACEs remained significant between groups (13.3% vs 25.6%, HR 0.50, 95% CI: 0.26 0.98, P = .044). Multivariate regression analysis also indicated that CA was significantly associated with a lower risk of MACEs in overall cohort (HR 0.486, 95% CI: 0.253-0.933, P = .030) and in propensity-matched cohort (HR 0.482, 95% CI: 0.235-0.985, P = .045). Besides, age and NYHA class were associated with an increased risk of MACEs. In conclusion, the present study demonstrated that CA for AF in HF patients could reduce the risk of MACEs in a mid-term follow-up. Thus, CA may be a reasonable option for this population. PMID- 29245368 TI - New species of Brachiacantha Dejean, 1837 (Coleoptera: Coccinellidae) from Mexico and Central America. AB - Five new species of the genus Brachiacantha Dejean (Coccinellidae) from Mexico and Central America are described and illustrated. The species B. angulata sp. nov., B. truncata sp. nov., B. brevicuspidata sp. nov. and B. robustihamata sp. nov. are consistent with the dentipes group. The species B. brevihamata sp. nov. is consistent with the fifth group of Leng (1911); the species shares some characteristics with South American species. PMID- 29245369 TI - Chironomus alchichica sp. n. (Diptera: Chironomidae) from Lake Alchichica, Mexico. AB - Morphological analysis of all developmental stages (except female), mitochondrial DNA sequences from cytochrome c oxidase subunit I (cox1) and cytological analysis of the polytene chromosomes were used to describe a new species of Chironomus found in the littoral and profundal zones of an endorheic, warm-monomictic lake in Mexico. Male imago is distinguished by the shape of superior volsella and by an antennal and bristle ratio lower than two. The pupa is characterized by the spur morphology of abdominal segment VIII. There is also a continuous row of hooklets on abdominal segment II. The larva is distinguished by a combination of antenna, mentum, mandible, and pecten epipharyngis characteristics, and abdominal ventral tubules. Molecular and cytological analysis supported the morphological differences found. The maximum likelihood tree obtained shows that Chironomus alchichica sp. n. clusters together with Chironomus decorus-group sp. 2 Butler et al. (1995) (bootstrap support = 92%), but genetic p-distances within C. alchichica sp. n. (0.004) were lower than the p-distances between other species of the decorus-group (C. decorus-group sp. 2, Chironomus bifurcatus Wulker et al., 2009 and Chironomus maturus Johannsen, 1908) confirming that it is a different species. The new species belongs to thummi cytocomplex, (decorus group), with chromosome set- 2n = 8 and chromosome arm combinations: AB CD EF G. Karyologically, the species is closest to Chironomus riihimaekiensis Wulker (1973). This species has very compact salivary gland chromosomes with well heterochromatinized centromere regions in chromosomes AB CD G. Several fixed homozygous inversions distinguish arm A of the species from that of C. riihimaekiensis. Arm E differs from that of C. riihimaekiensis by simple fixed homozygous inversion. Some similarities in band sequences of this arm were found with species from the decorus-group as Chironomus blaylocki Wulker et al., 2009 and C. bifurcatus (decorus-group). The position of the key constrictions in chromosome G: Nucleolar organizer (NOR) and Balbiani rings (BRs) is similar to the species of decorus-group. C. alchichica sp. n. has been found in soft sediments rich in organic matter in well mineralized waters (where conductivity >10 mS cm-1) and with a high pH (>=9). The profundal zone is inhabited only during the mixing period, when dissolved oxygen is present. PMID- 29245370 TI - Two new species of the genus Nemognathomimus (Coleoptera: Cerambycidae) from Mexico and Guatemala. AB - Two new species of the genus Nemognathomimus Chemsak & Linsley are described and illustrated, Nemognathomimus wappesi sp. nov. from the Mexican states of Chiapas and Oaxaca and from Guatemala, and N. angelicae sp. nov. from the Mexican state of Hidalgo. A key to separate the species of Nemognathomimus is included. PMID- 29245371 TI - The genus Antonia Loew in Egypt: A. gabalensis El-Hawagry, a new synonym of A. fedtschenkoi Loew (Antoniinae, Bombyliidae, Diptera). AB - Antonia gabalensis El-Hawagry, 2009 is hereby synonymized with Antonia fedtschenkoi Loew, 1873. Two homeotypes of A. fedtschenkoi and the primary types of A. gabalensis have been examined and found conspecific. Synonyms, diagnoses and photographs of dorsal habitus and male genitalia of the Egyptian species of Antonia are presented. PMID- 29245372 TI - Three new species of Peruvian Nelidina (Hemiptera: Cicadellidae: Neocoelidiinae) with key to males. AB - Three new species of Nelidina DeLong, 1953 are described and illustrated, N. bifida sp. nov., N. coronata sp. nov. and N. platypenis sp. nov., all from Peru. A key to males of the six known species of Nelidina is presented and a new record for Nelidina sportula Kramer, 1967 is added. PMID- 29245373 TI - Nomenclatural changes in the family Membracidae (Hemiptera, Auchenorrhyncha, Membracoidea). AB - Nomenclatural changes are provided for names in the family Membracidae. The following replacement names are proposed: Gargara (Gargara) discoidea nom.nov. for Gargara (Gargara) discoidalis Ananthasubramanian, 1980; Tricentrus substitutus nom.nov. for Tricentrus yunnanensis (Yuan & Li, 2002); Indicopleustes esakii nom.nov. for Indicopleustes typicus Esaki, 1932; Neoproterpia nom.nov. for Proterpia Stal, 1867; Membracis expansa Walker, 1851 status revised is reinstated as valid on taxonomic grounds. The correct original spelling is fixed for Leptocentrus florifacialis Yuan in Yuan & Chou, 2002, and seven incorrect original spellings are documented for five additional species in which a correct spelling was later adopted by one or more of the original authors. The name Micrutalis minutus Buckton, 1902 is emended to Micrutalis minuta Buckton, 1902 and Brachytalis punctulatus Ramos is emended to Brachytalis punctulata Ramos in both cases to agree with the feminine gender of Micrutalis Fowler, 1895 and Brachytalis Metcalf & Bruner, 1925. PMID- 29245374 TI - Additions to Idiostolidae in Coscaron (2017) "A catalogue of the Heteroptera (Hemiptera) or true bugs from Argentina". AB - Several references missing in the Idiostolidae chapter of the recently published Catalogue of the Heteroptera (Hemiptera) or true bugs from Argentina are provided. Annotations to the bibliography are provided to clarify some records of the family in the country. PMID- 29245375 TI - Taxonomic revision of the species of Colletes Latreille, 1802 (Hymenoptera: Colletidae: Colletinae) found in Chile. AB - A taxonomic revision of Colletes Latreille species with known geographic distribution in Chile is presented. In addition to the traditional morphological approach to taxonomy, DNA barcoding was employed to facilitate sexual association and cryptic species recognition. I provide diagnoses, synonymies, geographic and floral records, and a fully-illustrated key for 31 recognized species, 23 of them previously described: C. alocochila Moure, C. atacamensis Janvier, C. atripes Smith, C. bicolor Smith, C. chusmiza Rojas & Toro, C. cognatus Spinola, C. cyanescens (Haliday), C. cyaniventris Spinola n. stat., C. flaminii Moure, C. fulvipes Spinola, C. gilvus Vachal, C. guanta Rojas & Toro, C. longiceps Friese, C. lucens Vachal, C. mastochila Moure, C. murinus Friese, C. musculus Friese, C. nigritulus Friese, C. patagonicus Schrottky, C. quelu Rojas & Toro, C. rutilans Vachal, C. sulcatus Vachal, and C. vicugnensis Rojas & Toro. In addition, eight new species are described: C. arthuri n. sp., C. coquimbensis n. sp., C. flavipilosus n. sp., C. kuhlmanni n. sp., C. nigropilosus n. sp., C. simulatus n. sp., C. toroi n. sp., and C. ventricarinatus n. sp. Lectotypes for the following species are designated: Andrena cyanescens, Colletes bicolor, C. campoi Herbst, C. chubutensis Cockerell, C. gilvus, C. lucens, C. patagonicus, C. rufosignatus Cockerell, and C. viridans Vachal. Colletes seminitidus Spinola and C. viridans are both proposed as junior synonyms of C. cyanescens, and C. araucariae Friese is considered a junior synonym of C. sulcatus. Colletes cyaniventris n. stat. is resurrected from synonymy. PMID- 29245376 TI - The genus Diphasia L. Agassiz, 1862 (Cnidaria, Hydrozoa) in Northwest Africa. AB - This paper is the result of the study of large collections of Sertulariidae Lamouroux, 1812 (Cnidaria, Hydrozoa, Hydroidolina) obtained from continental margins of Northwest Africa by several Spanish and Norwegian surveys between 2004 and 2012. Material collected from Lusitanian seamounts by the French Seamount 1 expedition and from the Great Meteor Bank by the German survey Meteor 42/3 were also examined. A total of 12 species belonging to the genus Diphasia were studied and illustrated, and four new species were described: Diphasia leonisae n. sp., Diphasia saharica n. sp., Diphasia africana n. sp., and Diphasia anaramosae n. sp. Diphasia attenuata, Diphasia fallax and Diphasia tropica were not represented in the collections. However, they have been discussed here because they had been previously reported in the study area or in the eastern North Atlantic. One species was only identified to the genus level. The syntype material of Diphasia attenuata var. robusta Billard, 1924, neotype of Diphasia delagei Billard, 1912, and comparison material for the other species that have been preserved in several zoological collections were also examined. Besides, an identification key for these species is provided. PMID- 29245377 TI - A new species of Microkayla (Anura: Craugastoridae: Holoadeninae) from Department La Paz, Bolivia. AB - We describe a new species of direct-developing frog of the genus Microkayla from the Cordillera Real of the Bolivian Andes, in the Department of La Paz. The new species, Microkayla huayna sp. nov., is closely related to M. teqta and can be distinguished from other species of the genus by its brown dorsal skin and the presence of a large dark brown vocal sac in males. This is the second species of Microkayla known from the Zongo Valley, and the ninth in the Cordillera Real, contributing to a total of 22 described species in Bolivia. Given its small distribution range, we recommend to considering it as Vulnerable according to IUCN criteria. PMID- 29245378 TI - Review of the genus Promalactis (Lepidoptera: Oecophoridae) Meyrick, 1908 (II). The suzukiella group, with descriptions of eight new species. AB - Fifty-five species of the genus Promalactis Meyrick, 1908 are placed in the suzukiella group based on the forewing patterns. Among them, eight species are described as new: P. foliprocessa Wang, sp. nov., P. similiclavata Wang, sp. nov., P. aliformis Wang, sp. nov., P. dorsiseparata Wang, sp. nov., P. albitriangula Wang, sp. nov., P. sichuanensis Wang, sp. nov., P. huemeri Wang, sp. nov., and P. grandacantha Wang, sp. nov.; the females of P. subclavata Du, Wang et Li, 2014 and P. undulata Wang, Du et Li, 2013 are described for the first time. Photographs of adults and genitalia of the new species are provided; a map showing the type localities of the 55 species in the suzukiella group is given. Species belonging to the suzukiella group are listed. PMID- 29245379 TI - A new species of Hemidactylus (Squamata: Gekkota: Gekkonidae) from Qara Dagh Mountains, Kurdistan Region, with a key to the genus in Iraq. AB - We describe a new species of gecko of the genus Hemidactylus from the oak woodlands of Zagros Forest Steppe of Qara Dagh Mountains, Sulaimani, northeastern Iraq, based on morphological and molecular characteristics. Hemidactylus kurdicus sp. nov. is distinguished from all other related Arid clade Hemidactylus species in the Middle East by having a single pair of postmental scales; it differs H. turcicus, H. robustus, H. ulii, H. sinaitus, H. shihraensis and H. yerburii based on the number of lamellae under the first and fourth toes of pes. Mitochondrial DNA including CytB and 12S identify a consistent divergence between H. kurdicus and H. persicus. An identification key to the genus Hemidactylus in Iraq is presented. PMID- 29245380 TI - Review of the fish genus Epinnula Poey (Perciformes: Gempylidae), with description of a new species from the Pacific Ocean. AB - The gempylid fish genus Epinnula is reviewed and two species are recognized. The type species E. magistralis is considered restricted to the western Atlantic Ocean and a new species from the Pacific Ocean is described. The new species, Epinnula pacifica sp. nov., can be distinguished from E. magistralis by 17 or 18 dorsal-fin rays (vs. 15 or 16 in E. magistralis), 15 or 16 anal-fin rays (vs. 13 or 14), 247-268 total scales on lower lateral line (vs. 285-330), a deeper body, relatively high dorsal fin as reflected by the relatively long fin spines and rays, longer dorsal-fin and anal-fin bases, longer pectoral fin, and longer pelvic fin and pelvic spine. PMID- 29245381 TI - Two new species of Afrodacarellus (Acari: Mesostigmata: Rhodacaridae) from Brazil and a key to the world species of the genus. AB - Within a project to determine the edaphic predatory mites from the Brazilian Alagoas state, two new species of Afrodacarellus Hurlbutt (Rhodacaridae) were found, namely Afrodacarellus alagoensis Santos & Castilho n. sp. and Afrodacarellus xucurukariri Santos & Castilho n. sp.. These are here described based on the morphology of adult females. A key for the separation of females of the 31 recognisable world species of Afrodacarellus is provided, including the newly described species. PMID- 29245382 TI - Resurgence of a forgotten Southern Brazil endemic species: taxonomic position, redescription, and spatio-temporal distribution of Porosagrotis carolia Schaus, 1929 (Lepidoptera: Noctuidae: Noctuinae). AB - The taxonomy of the hitherto unplaced taxon Porosagrotis carolia Schaus, 1929 is evaluated and the name is taken out of taxonomic limbo and combined with Feltia Walker, 1856. Feltia carolia comb. nov., described from a single female specimen, is redescribed, including the first description of the male. Head, thorax and its appendages, and male and female genitalia are illustrated through photographs and line drawings; photographs of the holotype and a distribution map for the species is provided. Additionally, the spatio-temporal occurrence of the species in Rio Grande do Sul was assessed by monthly standardized samplings with light traps from January of 1998 to December of 1999 in ten different physiographical zones of the state. Our results suggest that F. carolia comb. nov. is univoltine and goes through prepupal and pupal estival diapauses. The assessment of the distribution of the species, based on the standardized samplings and specimens deposited in entomological collections, suggests that F. carolia comb. nov. is restricted to the southern Brazilian Campos, a mostly neglected environment discontinuously distributed in mountainous plateaus of the southern Mata Atlantica biome. PMID- 29245383 TI - Re-characterization of Gymelloxes with a re-description of Gymelloxes terea from Central America (Lepidoptera: Hepialidae). AB - The hepialid genus Gymelloxes Viette, 1952 is characterized by, and differs from all other genera, by the male genitalia and a combination of characters. G. terea is redescribed due to the brevity of the original description. The male genitalia of Gymelloxes terea (Schaus, 1892) include two features that are unique within the Hepialidae - a posteriorly angled and digitiform tergal lobe, and two shallow, peg-like processes on the posterior margin of the saccus. The male phallus also exhibits minute sclerotized spicules or spots on the apex of an otherwise membranous tube. The external genitalia of the female includes a sclerotized antevaginalis with a broad, dorsally projecting, flat central margin. The species is included within the cibyrine clade of Hepialidae by the structure of the tergosternal connection and narrow spacing between Sc and R on the hindwing. The potential systematic significance of specialized similarities shared with other cibyrine Hepialidae is discussed. A lectotype of Dalaca terea Schaus, 1892 is here designated. PMID- 29245384 TI - Anaxibia folia spec. nov.-a new litter-dwelling dictynid spider from India (Araneae: Dictynidae: Dictyninae). AB - The dictynid genus Anaxibia Thorell, 1898 currently has six nominal species distributed in the Oriental and Ethiopian regions (World Spider Catalog 2017). The genus represents tiny to small spiders characterised by a reduced cribellum, long, cylindrical anterior and posterior spinnerets, cymbium with caudal modification, palpal patella with dorsal horn, sub-apically arising embolus, conductor with wide lamellar apex and simple female genitalia (Lehtinen 1967). The genus has one representative in India: Anaxibia rebai (Tikader, 1966), originally described under Dictyna Sundevall, 1833 (Tikader 1966; Lehtinen 1967). In this paper, we describe and illustrate a new litter-dwelling Anaxibia species collected from the Kerala state of southern India. PMID- 29245385 TI - A new species of Mycomya Rondani (Diptera, Mycetophilidae, Mycomyinae) from Argentinean Patagonia. AB - Mycomya bowiei n. sp. is described based on male and female specimens from Argentinean Patagonia. Additionally, we provide a redescription of Mycomya bifida Freman (1951) and new records of three species of Mycomya previously unrecorded from either Chubut Province or Argentina. PMID- 29245386 TI - Revisionary systematics of the endemic soft coral fauna (Octocorallia: Alcyonacea: Alcyoniina) of the Agulhas Bioregion, South Africa. AB - The Agulhas Bioregion of southern South Africa supports a unique octocoral fauna that is entirely endemic to the region. Recent molecular phylogenetic studies indicate that this endemism extends to deeper taxonomic levels than had previously been recognized, and that most of these endemic species belong to genera and families that are also endemic to South Africa. Here we revise the taxonomy of soft corals (subordinal group Alcyoniina) that were previously assigned to the cosmopolitan families Alcyoniidae, Nephtheidae and Nidaliidae, describing three new families endemic to South Africa, along with four new genera and four new species. We reassign the endemic genera Acrophytum, Pieterfaurea and Lampophyton to Acrophytidae n. fam, and describe a new species of Lampophyton, L. spinatum n. sp. The endemic species Protodendron bruuni is reassigned to a new, monotypic genus, Corymbophyton bruuni n. comb., and family, Corymbophytidae n. fam. The endemic genus Leptophyton is placed in a third new family, Leptophytidae n. fam., along with three new genera that are established for species previously assigned to Alcyonium: Circularius wilsoni n. comb., Porphyrophyton distinctum n. comb., and Tenerodus fallax n. comb. In addition, we describe new species of Leptophyton, L. fustis n. sp.; Tenerodus, T. pollex n. gen. n. sp.; and Alcyonium, A. dolium n. sp.; reassign Protodendron verseveldti to Tenerodus verseveldti n. comb.; and reassign the endemic genus Dimorphophyton to family Paralcyoniidae. Although molecular phylogenetic analyses unite Acrophytidae, Corymbophytidae and Leptophytidae within a well-supported monophyletic group, both morphological and molecular distinctions support maintaining them as three separate families. These revisions increase the number of endemic species of shallow-water soft corals known from the Agulhas Bioregion to 40, and the number of endemic genera to 13. PMID- 29245387 TI - A new terrestrial species of Chiropterotriton (Caudata: Plethodontidae) from central Mexico. AB - Chiropterotriton is a relatively small genus that comprises 15 species with great morphological and ecological diversity. In previous studies, molecular data provided evidence for a considerable number of species that remain undescribed. In this study, we describe one new species, Chiropterotriton chico sp. nov. based on molecular and morphological characters. We present mtDNA phylogenetic analyses using Bayesian inference and maximum likelihood that include all described and several undescribed species. Morphometric data from eight recognized species provide evidence for the distinctiveness of the new taxon. Description of this new species adds to the already high salamander diversity of the state of Hidalgo, which is an important area for the diversification of the genus. PMID- 29245388 TI - The complete mitochondrial genome of the jumping grasshopper Sinopodisma pieli (Orthoptera: Acrididae) and the phylogenetic analysis of Melanoplinae. AB - In this study, we reported the complete mitochondrial genome (mitogenome) of Sinopodisma pieli by polymerase chain reaction method for the first time, the type species of the genus Sinopodisma. Its mitogenome was a circular DNA molecule of 15,625 bp in length, with 76.0% A+T, and contained 13 protein-coding genes, 22 transfer RNA genes and two ribosomal RNA genes and one A+T control region. The overall base composition of the S. pieli mitogenome was 42.8% for A, 33.2% for T, 13.5% for C, and 10.5% for G, respectively. All 13 mitochondrial PCGs shared the start codon ATN. Twelve of the PCGs ended with termination codon TAA and TAG, while cytochrome coxidase subunit 1 (COI) utilized an incomplete T as terminator codon. All tRNA genes could be folded into the typical cloverleaf secondary structure, except trnS(AGN) lacking of dihydrouridine arm. The sizes of the large and small ribosomal RNA genes were 1379 bp and 794 bp, respectively. The A+T rich region was 798 bp in length and contained 88.5% AT content. A phylogenetic analysis based on 13 PCGs by using Bayesian inference (BI) and maximum likelihood (ML) revealed that Sinopodisma is not monophyletic group. We think that the name and taxonomic status of S. tsinlingensis are right, and it should not be moved into the genus Pedopodisma. These data will provide important information for a better understanding of the population genetics and species identification for Sinopodisma. PMID- 29245389 TI - A new Neotropical genus of bee flies (Diptera, Bombyliidae, Phthiriinae). AB - A new genus of Phthiriinae, Hirsutophallus gen. nov. is described, based on the examination of male and female specimens from the Andean region of Bolivia and Argentina. Hirsutophallus gen. nov. contains several characters that distinguish it from other Phthiriinae genera, such as: prominent tip on the lateral margin of the scape; lower lobes on epiphallus; prominent lateral lobes on epiphallus, with dorsal macrosetae; penial guide of distiphallus with long and dense macrosetae on dorsal surface; gonocoxite with medial process large basally and acute apex in lateral view, with short apical and ventral spines and posterior process with ventral spines; gonostylus with row of spines on apical third of dorsal and ventral surface and furca with V-shaped sclerites, with very long and curved parallel arms. The new genus, endemic to the Neotropical Region, is described to accommodate Hirsutophallus andinus gen. nov. et sp. nov. An identification key to the genera of Phthiriinae is also provided. The species is described and illustrated in detail, including the male and female terminalia. PMID- 29245390 TI - Coelioxoides piscicauda sp. nov., a new cuckoo bee from southeastern Brazil with a key to the species of Coelioxoides Cresson (Hymenoptera: Apidae). AB - A new species of Coelioxoides Cresson (Apidae), Coelioxoides piscicauda sp. nov. Rocha-Filho from Sao Paulo State, Brazil, is described. A key to the four recognized species of the genus, C. exulans (Holmberg), C. piscicauda sp. nov., C. punctipennis Cresson, and C. waltheriae Ducke, is provided. In addition, new host records of Coelioxoides are presented as well as a compilation of published data on species of Tetrapedia Klug associated with this cleptoparasitic genus. PMID- 29245391 TI - The marbled crayfish (Decapoda: Cambaridae) represents an independent new species. AB - Marbled crayfish are a globally expanding population of parthenogenetically reproducing freshwater decapods. They are closely related to the sexually reproducing slough crayfish, Procambarus fallax, which is native to the southeastern United States. Previous studies have shown that marbled crayfish are morphologically very similar to P. fallax. However, different fitness traits, reproductive incompatibility and substantial genetic differences suggest that the marbled crayfish should be considered an independent species. This article provides its formal description and scientific name, Procambarus virginalis sp. nov. PMID- 29245392 TI - Identification of Neoceratitis asiatica (Becker) (Diptera: Tephritidae) based on morphological characteristics and DNA barcode. AB - Neoceratitis asiatica (Becker), which especially infests wolfberry (Lycium barbarum L.), could cause serious economic losses every year in China, especially to organic wolfberry production. In some important wolfberry plantings, it is difficult and time-consuming to rear the larvae or pupae to adults for morphological identification. Molecular identification based on DNA barcode is a solution to the problem. In this study, 15 samples were collected from Ningxia, China. Among them, five adults were identified according to their morphological characteristics. The utility of mitochondrial DNA (mtDNA) cytochrome c oxidase I (COI) gene sequence as DNA barcode in distinguishing N. asiatica was evaluated by analysing Kimura 2-parameter distances and phylogenetic trees. There were significant differences between intra-specific and inter-specific genetic distances according to the barcoding gap analysis. The uncertain larval and pupal samples were within the same cluster as N. asiatica adults and formed sister cluster to N. cyanescens. A combination of morphological and molecular methods enabled accurate identification of N. asiatica. This is the first study using DNA barcode to identify N. asiatica and the obtained DNA sequences will be added to the DNA barcode database. PMID- 29245393 TI - A cave-dwelling Iberian palpigrade (Arachnida: Palpigradi) of the Eukoenenia mirabilis group. AB - A new species Eukoenenia amatei sp. nov. is described on the basis of a female captured in a cave in south-eastern Spain. It is characterized by the presence of a single blade on the lateral organ and the absence of a glandular complex on sternites IV and VI. Some of these characters are shared with five other species distributed in Europe, Asia, Africa and South and Central America. The new species is remarkable for the elongation of basitarsus of leg IV which is the second longest in the E. mirabilis group. Only one other species in this group, E. indalica, has similar troglomorphic characters. In addition, formulas of palp and leg chaetotaxy are provided to facilitate species comparison. PMID- 29245394 TI - A new bamboo-feeding species of Kaochiaoja Tao (Hemiptera: Aphididae) from India. AB - A new species of the genus Kaochiaoja Tao 1963, K. sikkimensis sp. n., was collected on Phyllostachys sp. (Poaceae) from Upper Tadong area of Gangtok, East Sikkim, India. Apterous and alate viviparae of this species are described, illustrated and discussed in comparison with the only other nominal species in this genus. PMID- 29245395 TI - A new species of Lysmata Risso, 1816 (Crustacea, Decapoda, Lysmatidae) from the Gulf of Mexico. AB - A new species of peppermint shrimp, Lysmata baueri n. sp., is described based on a single specimen from the eastern Gulf of Mexico. The new species can be distinguished from other morphologically similar species of Lysmata Risso, 1816 by the number of teeth, length and shape of the rostrum, the length of the antennular peduncle relative to the scaphocerite, the number of meral and ischial articles in the second pereiopods, and the number of spines on the flexor margin of the dactyli from the third to fifth pereiopods. Morphological characters demonstrate that L. baueri n. sp., is most closely related to the eastern Pacific L. californica (Stimpson, 1866), L. nayaritensis Wicksten, 2000 and L. porteri (Rathbun, 1907). PMID- 29245396 TI - A new species of Chrysanthrax Osten Sacken (Diptera: Bombyliidae) from Costa Rica parasitic on an ant lion (Neuroptera: Myrmeleontidae). AB - A new species of bee fly of the genus Chrysanthrax Osten Sacken, C. pennyi, n. sp., is described and illustrated. It was reared from the larva of a myrmeleontid, which marks the first record of parasitism by the genus of that family. The pupal exuvium is described and illustrated and a key to species known from Central America is given. PMID- 29245397 TI - Dicharax (?) candrakirana n. sp. (Gastropoda: Cyclophoridae) from Sempu Island, Indonesia. AB - The Alycaeinae Blanford, 1864 (Gastropoda: Cyclophoridae) is a species-rich group of caenogastropod land snails distributed mainly in Southeast Asia (Kobelt 1902). The Madagascan endemic Boucardicus Fischer-Piette & Bedoucha, 1965 has also been classified in the Alycaeinae (Emberton 2002). The Asian species of Alycaeinae are characterized by a sutural tube on the last whorl that is closed at its posterior end, but is connected to the outside by radial microtunnels opening near the umbilicus. This device is hypothesized to allow gas exchange when the animal is retracted and the operculum seals the shell aperture (Pall-Gergely et al. 2016). PMID- 29245398 TI - First columbellid species (Gastropoda: Buccinoidea) from deep-sea hydrothermal vents, discovered in Okinawa Trough, Japan. AB - The molluscan diversity of deep-sea chemosynthetic ecosystems in Japan has been in general well documented with about 80 described species, of which over half are gastropods (Sasaki et al. 2005; Fujikura et al. 2012; Sasaki et al. 2016). Recently, however, a number of novel hydrothermal vent sites were discovered in the area using multibeam echo-sounding (Nakamura et al. 2015), providing opportunities for new discoveries. As a part of ongoing studies documenting the biodiversity of such sites, we present the first record of Columbellidae from hydrothermal vents, with a new species recovered from Natsu and Aki sites, in the Iheya North hydrothermal field (for map and background on the vent field see Nakamura et al. 2015). PMID- 29245399 TI - Description of male of the rarest European Carpenter-moth Stygioides persephone (Reisser, 1962) (Lepidoptera: Cossidae). AB - Despite the generally good knowledge of the European fauna of Cossidae, several new species (Lepidoptera) have been described in recent years: Dyspessa kostyuki Yakovlev, 2005 (type locality Ukraine, [Lugansk region], "Proval'skaya Stepp" Naturschutsgebiete), D. aphrodite Yakovlev & Witt, 2007 (type locality Greece, Peloponnes, Mega Spileon), and Stygia nilssoni Saldaitis & Yakovlev, 2008 (type locality Islas Canarias, Gran Canaria, Puerto de Mogan) (Yakovlev 2005; Yakovlev & Witt 2007; Saldaitis & Yakovlev 2008). However, a number of European cossids are still poorly known. PMID- 29245400 TI - Description of five new coral associated Barnacles of the genus Trevathana (Balanomorpha: Pyrgomatidae) in Pacific Waters. AB - Five new species of coral inhabiting barnacles of the genus Trevathana (Balanomorpha: Pyrgomatidae), T. dongshaensis sp. nov., T. conica sp. nov., T. doni sp. nov., T. longidonta sp. nov. and T. taiwanus sp. nov., are described. These species are found in West Pacific waters including Japan, Taiwan (mainland and adjacent outlying islands including Dongsha Atoll) and Papua New Guinea. The species exhibit morphological differences in the scutum, the tergum, and cirri II and III, and form distinct clades in a phylogenetic tree based on DNA sequences of two genes, 12S rDNA and cytochrome C oxidase subunit I. Three of the five species, T. dongshaensis sp. nov., T. conica sp. nov. and T. taiwanus sp. nov., have relatively narrow distribution ranges and were recorded from the Dongsha Atoll (T. dongshaensis sp. nov. and T. conica sp. nov.) and the Taiwanese mainland (T. taiwanus sp. nov.). Trevathana longidonta sp. nov. and T. doni sp. nov. have wider distributions. Trevathana longidonta sp. nov. was collected from Japan, Taiwan and Dongsha Atoll and T. doni sp. nov. was collected from Taiwan, Dongsha Atoll and Papua New Guinea. In the waters of Japan, Taiwan and Dongsha Atoll, all the recorded Trevathana species inhabit corals of the family Merulinidae. However, in Papua New Guinea, T. doni sp. nov. is also recorded in the coral Oxypora, belonging to the family Lobophylliidae, and individuals living on Lobophyllidae and Merulinidae did not exhibit great variation in the divergence of the COI and 12S genes. PMID- 29245401 TI - Taxonomy of calcareous sponges (Porifera, Calcarea) sampled on artificial substrates of a recreational marina in the Tropical Northeastern Brazilian coast. AB - Several specimens of calcareous sponges were sampled on artificial substrates of a recreational marina in Salvador, Bahia state, on the northeastern coast of Brazil. They belong to four species, two of which are new: Leucandra serrata, Paraleucilla incomposita, Sycon bellum sp. nov., and S. avus sp. nov. Leucandra serrata is recorded for the first time at the coast of Bahia, filling a large gap in the geographical distribution of this species, while the description of the specimens of P. incomposita revealed new characters that had previously been overlooked. Finally, the new species of Sycon described here differ from all the previously known species of the genus due to their skeletal organisation and spicule size. Our results increase the number of species known in Bahia from 13 to 17 and emphasise that areas with a large amount of artificial hard substrates can potentially harbour an interesting and unknown diversity of calcareous sponges. PMID- 29245402 TI - A new species of freshwater crab of the genus Oziotelphusa Muller, 1887 (Crustacea: Decapoda: Brachyura: Gecarcinucidae) from Tamil Nadu, southern India. AB - A new species of gecarcinucid freshwater crab of the genus Oziotelphusa Muller, 1887, is described from stationary or slow-flowing bodies of water in Keeriparai near Nagercoil, in the state of Tamil Nadu in southern India. Oziotelphusa ravi, new species, is distinguished from its congeners by several distinct characters: the median tooth of the posterior margin of epistome forms a distinct bilobed tip in frontal view, the male pleonal somite 6 is narrowly trapezoidal and slightly wider than long with the lateral margins concave, the terminal segment of the male first gonopod is distinctly bent laterally (along the longitudinal axis) at an angle of about 45 degrees , and the proximal part of the outer margin of the subterminal segment of the male first gonopod has a prominent deep concavity. PMID- 29245403 TI - Spiders of the Sao Paulo state islands, Brazil: redescription of Stenoterommata rassimana (Mello-Leitao, 1923) n. comb. (Araneae, Nemesiidae). AB - Spiders of the islands on the coast of the state of Sao Paulo, Brazil are poorly known. Herein, we redescribe and discuss the taxonomic position of Psalistops crassimanus Mello-Leitao, 1923, described from Alcatrazes Island and formerly included in the Barychelidae. This species is, herein, transferred to the genus Stenoterommata Holmberg, 1881, Nemesiidae, and the new combination Stenoterommata crassimana (Mello-Leitao, 1923) n. comb. is established. Stenoterommata crassimana males are diagnosed by the very slender and long apical portion of embolus having a strong curvature close to its apex. The females have the spermathecae with single elongate lobe bearing two receptacles. This species is probably endemic to the Alcatrazes Archipelago and Queimada Grande and Queimada Pequena Islands, on the coast of the state of Sao Paulo, Brazil. PMID- 29245404 TI - Revision of the Agrilus humilis species-group (Coleoptera: Buprestidae: Agrilini) with description of thirteen new species from Southeastern Asia. AB - The newly defined Agrilus humilis species-group comprising twenty taxa of Indo Malayan and Australasian region is revised based on the examination of type specimens. The taxonomic concept and distribution of all known species is critically revised for the first time since they were described. The complete commented bibliographic data are given for each name. The key to species is provided and complemented with illustration of habitus and genitalia. Images of all primary types are also included. The following thirteen new species are described: Agrilus aruensis sp. nov.; A. ateles sp. nov.; A. bicoloripennis sp. nov.; A. chloros sp. nov.; A. duffelsorum sp. nov.; A. ecalcaratus sp. nov.; A. incrassatus sp. nov.; A. korbicola sp. nov.; A. oidema sp. nov.; A. sphenopterus sp. nov.; A. suturistriatus sp. nov.; A. thailandicus sp. nov. and A. vogti sp. nov. PMID- 29245405 TI - Description of the larva and pupa of Phileurus truncatus (Palisot de Beauvois, 1806) (Coleoptera: Scarabaeidae: Dynastinae: Phileurini) with a key to described third instars of New World Phileurini. AB - The third instar and pupa of Phileurus truncatus (Palisot de Beauvois, 1806) (Coleoptera: Scarabaeidae: Dynastinae: Phileurini) is described for the first time based on specimens from Florida, United States of America. An identification key to the third instars of New World Phileurini is also provided. PMID- 29245406 TI - Periclimenoides tyrannodentatus, a new species of symbiotic shrimps (Crustacea: Decapoda: Palaemonidae) from Taiwan. AB - A new species of sponge-endosymbiotic shrimps, Periclimenoides tyrannodentatus, is described and illustrated. The species is remarkable for its stout subspatulate first pereiopods chelae with lateral fan-shaped pectination on their dactyli. Due to this character and simple ambulatory dactyli, the new species is similar to the type species of the genus, P. odontodactylus. Another remarkable character is in the unique shape of the minor chela of the second pereiopods; the distal cutting edges of its compressed fingers are distinctly expanded and armed with quite impressive dentitions. An identification key to the three currently recognised species of the genus Periclimenoides is provided. The new species represents the first record of the genus Periclimenoides from Taiwan. PMID- 29245407 TI - Description of a new species, Setaleyrodes machili Dubey, sp. nov. (Hemiptera: Aleyrodidae) infesting Machilus odoratissima Nees (Lauraceae) in Western Himalaya, India. AB - A new species of whitefly, Setaleyrodes machili Dubey sp. nov. found infesting Machilus odoratissima Nees (Lauraceae) is described from Kufri in Himachal Pradesh and Dhanaulti and Nainital in Uttarakhand, India. The diagnostic characteristics of puparia and habitus, are illustrated with line drawings and scanning electron microphotographs. Sexual dimorphism and variation in pigmentation during the transformation of instars are noted. An identification key to puparia of Setaleyrodes species so far described is presented. PMID- 29245408 TI - Where are primary type specimens of new mite species deposited? AB - A list of type depositories of new mite species published in two journals (Systematic & Applied Acarology and Zootaxa) during the last five years (2012 2016) is presented in this paper. The 1370 new species are deposited unevenly among 134 collections. The top collection is the Zoological Institute of the Russian Academy of Sciences, St. Petersburg, Russia (145 species), which alone accounts for 10% of the total new species, and the top ten collections accounted for 48% of the total. The average number of new species per collection is 10 and over three quarters of the collections are below the average. Just over half (51%) of the collections are in Europe. However, overall there were still more new species deposited in collections in developing counties (741) than developed countries (629). The top country for type depositories of new mite species for each continent is: Russia (199 species) for Europe, Brazil (134 species) for South America, Iran (133 species) for Asia, Australia (87 species) for Oceania, USA (80 species) for North America and South Africa (36 species) for Africa. The top European collections hold type specimens mostly of foreign origin, whereas those of South America, Asia, Africa and Australasia hold type specimens mostly originating from their own countries. PMID- 29245409 TI - New species of Andiorrhinus Cognetti, 1908 (Oligochaeta: Rhinodrilidae) from Venezuela and Brazil. AB - Findings pertinent to 11 earthworm species from Venezuela and Brazil are reported. Six of these species are described as new to science, one is re described and relocated in the genus Andiorrhinus, and new sites of occurrence are reported for four other species. Eight species of oligochaetes were found in the Andes in the state of Merida, Venezuela: Andiorrhinus (Turedrilus) duranti sp. nov., Andiorrhinus (Meridrilus) timotocuica sp. nov., Andiorrhinus (Meridrilus) torondoy sp. nov., Andiorrhinus (Meridrilus) sp. 1, Andiorrhinus (Quibario) tatuy sp. nov., Andiorrhinus (Meridrilus) kuika (Righi, 1993), Andiorrhinus (Meridrilus) mukuci (Righi, 1993), and Andiorrhinus (Meridrilus) rimeda (Righi & Araujo, 2000). Andiorrhinus (Meridrilus) sp. 1, represented by one specimen only, is possibly a new species. Three other species were collected in Brazil: Andiorrhinus (Amazonidrilus) karinae sp. nov. in the Cerrado bioregion of Mato Grosso state; Andiorrhinus (Amazonidrilus) rodriguezi sp. nov. in the Amazon region in compost, and Andiorrhinus (Amazonidrilus) duseni (Michaelsen, 1918) in the Atlantic Forest, in the states of Sao Paulo and Parana, the last species characterized by broad geographical and land use occurrences. The new subgenus Quibario was distinguished by the presence of three pairs of hearts in segments 10, 11, and 12. Keys are also included to differentiate species of subgenera Amazonidrilus and Meridrilus. The implications of these results in the context of ecological interactions, and dispersion of Andiorrhinus species in South America are discussed. PMID- 29245410 TI - A description of Macrobiotus horningi sp. nov. and redescriptions of M. maculatus comb. nov. Iharos, 1973 and M. rawsoni Horning et al., 1978 (Tardigrada: Eutardigrada: Macrobiotidae: hufelandi group). AB - We examined microscope slides from Horning and Iharos tardigrade collections from Museum of New Zealand Te Papa Tongarewa in Wellington and Hungarian Natural History Museum in Budapest with species of the Macrobiotus hufelandi group. Based on this material we describe one new species, Macrobiotus horningi sp. nov., and re-describe two others, M. maculatus comb. nov. Iharos, 1973 and M. rawsoni Horning et al., 1978. With the oral cavity armature of the patagonicus type and chorion of the hufelandi type, Macrobiotus horningi sp. nov. is most similar to: M. personatus Biserov, 1990, M. sandrae Bertolani & Rebecchi, 1993, M. serratus Bertolani et al., 1996, M. sottilei Pilato et al., 2012, M. terminalis Bertolani & Rebecchi, 1993 and M. vladimiri Bertolani et al., 2011, but it differs from them in morphological and morphometric traits. With eggs of the maculatus type, M. maculatus comb. nov. is most similar to: M. biserovi Bertolani et al., 1996, M. denticulatus Dastych, 2002, M. macrocalix Bertolani & Rebecchi, 1993 and M. ramoli Dastych, 2005, but differs from them in morphological and morphometric characters. PMID- 29245411 TI - The Macrobiotus hufelandi group (Tardigrada) revisited. AB - Species of the Macrobiotus hufelandi group are one of the most often recorded tardigrades throughout the globe. For over a century M. hufelandi has been considered cosmopolitan but in recent decades numerous species of similar morphologies have been described from various continents, which suggests that what was originally defined as a single taxon is, in fact, a complex of species. The definition of the hufelandi group is subject to a long-standing discussion and in this paper we propose a refined set of characters that are hoped to elucidate the taxonomic status of the group. In order to aid interspecific comparisons, we also propose a unified nomenclature for the crucial morphological traits and clar. PMID- 29245412 TI - A new species of Paratrigonidium Brunner von Wattenwyl, 1893 from Hainan, China (Orthoptera: Trigonidiidae; Trigonidiinae). AB - One new species, Paratrigonidium chloropodum sp. nov., is described from Hainan, China. The type specimens are deposited in East China Normal University, Biology of History Museum (ECNU). S. venustula is moved to genus Paratrigonidium as P. venustulum comb. nov. P. vittatum Brunner von Wattenwyl, 1893 syn. is the junior synonym of P. venustulum. PMID- 29245413 TI - A new Setacheres (Copepoda, Siphonostomatoida, Asterocheridae) associated with Ircinia felix (Duchassaing & Michelotti) (Porifera) from Brazil. AB - Recent surveys of the copepod fauna associated with the sponge Ircinia felix (Porifera, Dictyoceratida) in Brazil resulted in the discovery of a new siphonostomatoid species belonging to a recently erected genus of Asterocheridae. Setacheres portobarrensis sp. nov. possesses a 21-segmented antennule, with 3 free distal segments, after the aesthetasc. The third exopodal segment of leg 3 shows a distal seta instead of a spine as in some other congeners. The new species shows several unique features on the third endopodal segment of the antenna, the mandibular stylet, the inner lobe of the maxillule, and setules and spinules located in specific regions of legs 1 to 4. Setacheres portobarrensis sp. nov. follows the same distributional pattern as its congeners, and this is the first record of a siphonostomatoid copepod associated with Ircinia felix. PMID- 29245414 TI - Cherax acherontis (Decapoda: Parastacidae), the first cave crayfish from the Southern Hemisphere (Papua Province, Indonesia). AB - Cherax acherontis n. sp., is a crayfish endemic to the submerged river Yumugima in Hagepma/Jugurama cave in the New Guinea Highlands, Jayawijaya Regency, Papua Province, Indonesia. This species is the first cave crayfish from the Southern Hemisphere. The new species is most similar to Cherax monticola. Both species can be easily distinguished by certain morphological characteristics, which easily demonstrate C. acherontis n. sp. is a valid species. PMID- 29245415 TI - A new species of Trichromothrips (Thysanoptera) from India with four new records. AB - Globally 6100 species of the Order Thysanoptera are reported, of which 739 are known from India (Tyagi & Kumar 2016). The purpose here is to describe from India one new species and record for the first time from this country four other species, representing three different families, and full nomenclatural details are available at ThripsWiki (2017). From three of the species, including the holotype of the new species, DNA was isolated and amplification of partial fragment of mtCOI gene was performed (Tyagi et al. 2017) with the sequences submitted to the Barcode of Life Database. Photographs and illustrations were taken through a Leica Trinocular Microscope (Leica DM-1000) using Leica software application suite (LAS EZ 2.1.0). Voucher specimens, also the new holotype, are deposited in the National Zoological Collections (NZC), Zoological Survey of India, Kolkata, India. PMID- 29245416 TI - Review of the African genera Arantia Stal and Goetia Karsch (Orthoptera: Tettigoniidae: Phaneropterinae). AB - The genus Arantia is reviewed, the distribution and distinguishing characters given. The three species of Goetia are assigned as subgenus to Arantia. Arantia gestri Griffini is transferred to this new subgenus and synonymized with G. dimidiata Bolivar. Other species synonymized are: A. accrana Karsch with A. rectifolia Brunner von Wattenwyl; A. gabunensis Brunner von Wattenwyl with A. regina Karsch; A. mammisignum Karsch and A. tigrina Bolivar with A. excelsior Karsch; A. ugandana Rehn is synonymized with A. fasciata (Walker). 6 species from Tropical Africa are newly described: A. (Arantia) quinquemaculata n. sp., A. (Arantia) ivoriana n. sp., A. (Euarantia) tanzanica n. sp., A. (Euarantia) tibiaspinosa n. sp., A. (Euarantia) bispinosa n. sp. and A. (Euarantia) griffinii n. sp. A key to the subgenera and species of Arantia is provided. The tribe Arantiini is synonymized with Holochlorini. PMID- 29245417 TI - Species diversity of ostracods (Crustacea: Ostracoda) from rice fields in Northeast Thailand, with the description of a new Tanycypris species. AB - The species diversity of ostracods in rice fields from Northeast Thailand was studied. Fifty-two samples were collected from 43 rice fields during 2010-2016. This investigation revealed 23 genera and 52 species, including one new to science (Tanycypris eugenkempfi n. sp.) and 21 endemic species: endemic to the Oriental region (14 species), Southeast Asia (two species) and Thailand (five species). In addition, two species that were restricted to rice fields in this study were recognized: Bradleytriebella tuberculata (Hartmann, 1964) and Notodromas sinensis Neale & Zhao, 1991. The most diverse genus was Pseudostrandesia, followed by Strandesia with eight and five species, respectively. The most widely distributed species were Pseudocypretta maculata Klie, 1932 and Strandesia kraepelini (G.W. Muller, 1906) occurring in 48.8 % of the total of surveyed rice fields. The number of species in individual rice fields ranged from none to 18. Most of the samples contained three species, but one rice field showed very high species richness (18 species). Most of the species recorded in this study were also found in several types of water bodies and reported from several zoogeographical regions. The main distinguishing characters between Tanycypris eugenkempfi n. sp. and other Tanycypris species are the more tumid carapace in dorsal view, the distinctly arched dorsal margin of the carapace in lateral view, the presence of a subapical dorsal seta on the first segment of the first antenna, the smooth large bristles on the third endite of the maxillula, the absence of c-seta on the first thoracopod, and the long proximal claw (Gp) of the caudal ramus. PMID- 29245418 TI - Inpauema, a new genus of Odiniidae (Diptera) from Brazil, with description of five new species. AB - A new genus and five new species of odiniids (Odiniidae: Traginopinae) are described from the Brazilian Amazon and Cerrado biomes: Inpauema mirador gen. nov. et sp. nov. (type species), I. catarinae sp. nov., I. gaimarii sp. nov., I. raimundoluizi sp. nov., and I. xavieri sp. nov. The genus is being characterized by a unique combination of diagnostic characters: body predominantly dark brown to black, with silvery-gray pruinose spots on inner margin of eyes, longitudinally along middle of lunule and face, on notopleuron and mesopleuron; postcranium concave from dorsal view; one pair of stout proclinate ocellar setae; postocellar setae absent; lunule shorter than frons; gena lacking upturned seta; antennae separated by a maximum distance of 2X the diameter of a single antennal socket and gonocoxal apodemes directed upward, forming an arch. A key to separate Helgreelia Gaimari, 2007 from Inpauema gen. nov. and for the new species is provided. PMID- 29245419 TI - New species of Liolaemus (Reptilia, Squamata, Liolaemini) of the Liolaemus donosobarrosi clade from northwestern Patagonia, Neuquen province, Argentina. AB - Two new species of the Liolaemus donosobarrosi clade are described. Liolaemus tirantii sp. nov. and Liolaemus calliston sp. nov. differ from other members of their clade by a combination of coloration characters, morphometric and molecular traits. Liolaemus tirantii sp. nov. is known from three localities separated only a few kilometers from each other and Liolaemus calliston sp. nov. is known only from the type locality. Both species inhabit a region strongly impacted by oil and gas extraction but their conservation status is unknown. PMID- 29245420 TI - A new species of Brachychalcinus (Characiformes: Characidae) from the rio Xingu basin, Serra do Cachimbo, Brazil. AB - Brachychalcinus reisi, a new species of characid fish, is described from the rio Curua, tributary of rio Iriri, rio Xingu basin, Serra do Cachimbo, Para State, Brazil. The new species can be distinguished from its congeners by the presence of a series of longitudinal black wavy stripes on the entire body and by a lower number of longitudinal scale rows between dorsal-fin origin and lateral line (7-8 vs. 8-12). Additionally, the new species differs from B. copei, B. parnaibae, and B. retrospina by the lower number of branched dorsal-fin rays (9 vs.10). This is the first description of a new species of the subfamily since the revisionary study of Stethaprioninae, published almost 30 years ago. PMID- 29245421 TI - Four new species of Phyllophaga Harris (Coleoptera: Scarabaeidae: Melolonthinae) from western Cuba. AB - Four new species in the genus Phyllophaga Harris 1827, subgenus Cnemarachis Saylor 1942 (Coleoptera: Scarabaeidae: Melolonthinae) from Cuba are described: Phyllophaga barroi new species, Phyllophaga guanahacabibensis new species, Phyllophaga pauli new species, and Phyllophaga sabanalamarensis new species. Each species is illustrated using photographs of the habitus, diagnostic features, and male aedeagi. A map is provided showing the geographical distributions of the new species. PMID- 29245422 TI - Taxonomic corrections on Cronion (Hemiptera: Heteroptera: Plataspidae). AB - Vollenhoven (1864) presented a preliminary report and subsequently (Vollenhoven 1865) a detailed description of a new genus of pentatomoid true bugs (Hemiptera: Heteroptera), Poseidon Vollenhoven, 1864, with a single included species, P. malayanus Vollenhoven, 1864; the species is therefore the type species of the genus by monotypy. The genus was placed into Scutelleridae by Vollenhoven (1864, 1865), but the latter taxon was defined broadly, in a way much different from the current concept of this family (see e.g. Rider et al. 2017); Stal (1876) transferred it into Plataspidae defined in the present sense. Bergroth (1891) showed that Poseidon was preoccupied by Poseidon Girard, 1825, a valid genus of ribbon worms (Nemertea), and therefore he proposed a replacement name, Cronion Bergroth, 1891, for it. Miller (1955) described another new plataspid genus, Triodocoris Miller, 1955, and designated the newly described T. cinctus Miller, 1955, as its type species. Both of these genera have remained monotypic, and no author have presented new data on them since their original descriptions. PMID- 29245423 TI - First record of the genus Soliperla (Plecoptera: Peltoperlidae) from China with description of a new species. AB - The genus Soliperla Ricker, 1952 has been considered endemic to western North America, is now reported from Sichuan Province of southwestern China. In this paper, we describe a new species, S. wanglanga Huo & Du, sp. nov. The new species is characterized by a large inverted trapezoid sclerite on tergum 10, a bilobed aedeagal apex, and large dark areas on the frontoclypeus in the adult male. The nymph has conspicuous pale areas on terga 4-7. PMID- 29245424 TI - Revision of Afrotropical Silky Lacewings (Neuroptera: Psychopsidae). AB - Afrotropical Psychopsidae Handlirsch are revised based on morphology. Molecular data from a previous study enables updated taxonomy in this revision, and morphology corroborates phylogenetic divergences. The genus Silveira was found to form a lineage separate from Zygophlebiinae based on molecular data and six morphological synapomorphies. In this revision, Silveira is moved to a new subfamily, leaving only Cabralis and Zygophlebius in Zygophlebiinae. Two new species of Cabralis are described. Afrotropical Psychopsidae now comprise ten species, three genera and two subfamilies. A dichotomous key to these taxa is provided, along with a web link to a fully-illustrated and interactive multi access LUCID v3 key. High resolution images and distribution maps are provided for all species. PMID- 29245425 TI - Revision of the Australian species of Agrotera Schrank (Lepidoptera: Pyraloidea: Crambidae: Spilomelinae). AB - The genus Agrotera Schrank, 1802 is revised for Australia and the generic definition is refined based on the male genitalia. The genera Leucinodella Strand, 1918 stat. rev. with L. leucostola (Hampson, 1896) comb. nov., Nistra Walker, 1859 stat. rev. with N. coelatalis Walker, 1859 comb. rev., Sagariphora Meyrick, 1894 stat. rev. with S. magnificalis (Hampson, 1893) comb. nov., and Tetracona Meyrick, 1884 stat. rev. with T. amathealis (Walker, 1859) comb. rev. and T. pictalis Warren, 1896 comb. rev. are removed from synonymy with Agrotera, as they lack the synapomorphies of Agrotera. Two new species, Agrotera genuflexa sp. nov. from Northern Territory, Queensland and New South Wales, and A. longitabulata sp. nov. from Queensland, are described. The taxonomic status of the Australian species of Agrotera is discussed, and a key to all species, based on males, is provided. The adults and genitalia of the new species and some related species are figured. PMID- 29245426 TI - New Siberian "spineless" species of Thalassaphorura Bagnall, 1949 (Collembola, Onychiuridae), with a key to world species of the genus. AB - Six new species of Thalassaphorura from South Siberia are described and illustrated: T. aspinata sp. nov., T. sayana sp. nov., T. sibirica sp. nov., T. stebaevae sp. nov., T. stepensis sp. nov. and T. weineri sp. nov. Their affinity with related species is discussed and a comparison of all species without anal spines is presented. The key to the world species of Thalassaphorura and their geographic distribution are also provided. PMID- 29245427 TI - Species of Macrostomum (Macrostomorpha: Macrostomidae) from the coastal region of Lima, Peru, with comments on M. rostratum Papi, 1951. AB - Species of Macrostomum are present in almost all regions of the world. These flatworms occur in different kinds of environments, from freshwater to marine ecosystems. Although Peru is considered one of the megadiverse countries in South America, little is known about freshwater microturbellarians in this country. Here we report the presence of M. rostratum Papi, 1951 for the first time in Peru, in a coastal brackish water wetland, and that of M. quiritium Beklemischev, 1951 and M. tuba Graff, 1882 in an inland portion of a river near the city of Lima. All the species were studied alive. Comments on the habitat and associated fauna are given. Detailed information on the copulatory system is provided for M. rostratum; the male system has a bilobed seminal vesicle with thick walls and full of spindle-shaped sperm cells, and a stylet in the form of a solid curved inverted cone with a subterminal opening located on the concave side of the stylet. These findings led us to suggest that M. rostratum may exhibit a hypodermic mating syndrome. The three species of Macrostomum reported here are widespread and, although the diagnostic characters of the species are present, some morphological differences in the copulatory stylet suggest they are cryptic species. PMID- 29245428 TI - Two replacement names of the genus group of Micronoctuini and a new species of the genus Tentaxus Han & Kononenko from Sabah, East Malaysia (Lepidoptera, Erebidae, Hypenodinae). Taxonomic study of Micronoctuini. Contribution I. AB - Two replacement names of the genus group in Micronoctuini (Lepidoptera, Erebidae, Hypenodinae), Tentaxus nom. nov. pro Tentax Fibiger 2011 (unavailable name) and Flaxus nom. nov. pro Flax Fibiger 2011 (unavailable name) are proposed; 43 new conbinations (comb. nov.) are stated. A new species T. zhangweiweii Han & Kononenko, sp. nov. is described from Borneo (Sabah, East Malaysia). PMID- 29245429 TI - Macrobiotus nebrodensis and Adropion vexatum, two new species of Eutardigrada (Tardigrada, Parachela) from Sicily. AB - Two new species of Eutardigrada are described from Sicily: Macrobiotus nebrodensis sp. nov. and Adropion vexatum sp. nov. The former species, belongs to the Macrobiotus hufelandi group, and is characterised by having a small, faint, microplacoid, and variable egg processes (most processes are shaped in the form of an inverted goblet with jagged terminal disc, but others are long, or very long, with a very small terminal disc). Adropion vexatum sp. nov. is characterised by having smooth cuticle, steep, vertical front to the head, pharyngeal tube longer than the pharyngeal bulb, which has small apophyses and three rod-shaped macroplacoids (microplacoid and septulum absent); long placoid row, about half the length of the pharyngeal bulb; main branches of claws with accessory points; lunules and other cuticular thickenings absent on the legs (small dots excluded). PMID- 29245430 TI - Ubristes rex sp. n., a new microdontine hoverfly from northern Brazil (Diptera: Syrphidae: Microdontinae). AB - Ubristes rex sp. n., a hoverfly of the subfamily Microdontinae (Diptera: Syrphidae) is described from northern Brazil (Roraima). A diagnosis and a key are provided for distinguishing this species from the other three known species of Ubristes, which are all Neotropical. Information on distribution and habitat of all known Ubristes species is summarized. A brief comment is made on the decision to describe this species based on a single female specimen. PMID- 29245431 TI - Description of Neoperla yingshana sp. nov. (Plecoptera: Perlidae) from Hubei Province of China. AB - A new species of the genus Neoperla (Plecoptera, Perlidae), N. yingshana Chen & Du sp. nov. from the Wujiashan National Forest Park, Hubei Province of central China is described, illustrated and compared with similar taxa. The new species is characterized by the aedeagal tube long with an upcurved, finger-like spinulose lobe subapically, and by the aedeagal sac plump, gradually tapering to a blunt tip with dense spinules on ventral surface and granules surrounding sac apex. PMID- 29245432 TI - Three new species of Ceraclea Stephens 1829 (Trichoptera: Leptoceridae) from Southeast Asia. AB - Three new species of Ceraclea (Leptoceridae) from Southeast Asia are described and illustrated: Ceraclea (Athripsodina) trisdikooni n. sp. from Myanmar, C. (A.) thongnooi n. sp. from Thailand and Myanmar and C. (A.) thongpongi n. sp. from Laos. Ceraclea trisdikooni n. sp. is distinguished from other species by its inferior appendages recurved ventrad nearly 180 degrees apically. The apex of the basal segment of each inferior appendage is more pointed. In ventral view, each inferior appendage of the new species has an obvious basoventral lobe with numerous long setae. Ceraclea thongnooi n. sp. is distinguished from those by inferior appendages that are each shaped like a seahorse head both in lateral view and ventral view. Ceraclea thongpongi n. sp. is distinguished from other species by the rectangular preanal appendages. In dorsal view, the apical end of segment X is oval and notched apically; in ventral view, the subapicodorsal lobe of each inferior appendage is rounded and straight. PMID- 29245433 TI - Systematics of Thiodinini (Araneae: Salticidae: Salticinae), with description of a new genus and twelve new species. AB - The jumping spider tribe Thiodinini is revised at generic level: diagnoses are proposed for all valid genera, based on the type species of each genus, and in some cases, on new species herein described. The tribe contains seven genera: Thiodina Simon, 1900; Cyllodania Simon, 1902; Hyetussa Simon, 1902; Atomosphyrus Simon, 1902; Arachnomura Mello-Leitao, 1917, Titanattus Peckham & Peckham, 1885 and the new genus Tartamura gen. nov. The following genera are synonymized: Micalula Strand, 1932 and Bredana Gertsch, 1936 with Hyetussa Simon, 1902; Agelista Simon, 1900 with Titanattus Peckham & Peckham, 1885. With this, the following new combinations are established: Hyetussa longithorax (Petrunkevitch, 1925) comb. nov. (this species with a neotype designation), from Micalula, and Hyetussa complicata (Gertsch, 1936) comb. nov. and Hyetussa alternata (Gertsch, 1936) comb. nov., both from Bredana. A transfer is proposed: Thiodina minuta comb. nov. (from Cyllodania). Twelve new species are described: Arachnomura querandi sp. nov.; Cyllodania trinidad sp. nov.; Cyllodania zoobotanica sp. nov.; Hyetussa sergipe sp. nov.; Hyetussa tremembe sp. nov.; Tartamura agatelin sp. nov.; Tartamura huao sp. nov.; Tartamura metzneri sp. nov.; Thiodina firme sp. nov.; Thiodina perian sp. nov.; Titanattus acanjuba sp. nov. and Titanattus euryphaessa sp. nov. Morphological traits and aspects of the phylogeny are discussed. PMID- 29245434 TI - Review of the sulcacitus group of Euschistus (Pentatomidae: Pentatominae: Carpocorini) with description of the internal female genitalia and a new species. AB - Euschistus Dallas is comprised of 66 species in three subgenera. Species of the nominate subgenus occur mainly in Central and North America. Some groups of species have been proposed to Euschistus (Euschistus) based on general external and male genitalic morphologies. Here, we review the sulcacitus group providing illustrations and descriptions of the internal and external genitalia of both sexes, illustrating females for the first time. A new species, Euschistus (Euschistus) tacitus sp. nov. Bianchi & Grazia, from Mexico and Costa Rica is described. We also provide an identification key to species of the group. PMID- 29245435 TI - Electrogena brulini sp. nov. and E. vipavensis Zurwerra & Tomka, 1986 syn. nov. revealed by integrative taxonomy of E. gridellii (Grandi, 1953) (Ephemeroptera: Heptageniidae). AB - A new species belonging to the speciose genus Electrogena Zurwerra & Tomka, 1985 is described based on all stages from material collected in Switzerland, northern Italy and Slovenia. Electrogena brulini Wagner sp. nov. is closely related to E. gridellii (Grandi, 1953). A genetic analysis based on the mitochondrial gene CO1, including 9 specimens from 5 populations, reveals a K2P distance of 22% between both species. Our investigations demonstrate that the description of the nymph of E. gridellii sensu Belfiore (1996) refers in fact to both species. Therefore, E. gridellii is redescribed in all stages. The number of bristles on each mandibular prostheca in the nymphs, the shape of titillators in male genitalia and the shape of the subanal plate in female imagines are the main characters allowing discrimination of these two species. This study also shows that in this case it is possible and helpful to use colour patterns to separate two closely related species. The re-examination of the type material of Electrogena vipavensis Zurwerra & Tomka, 1986 described from western Slovenia indicates that this species is a junior subjective synonym of E. gridellii. PMID- 29245436 TI - A new species of the Cyrtodactylus irregularis complex (Squamata: Gekkonidae) from Gia Lai Province, Central Highlands of Vietnam. AB - We describe a new species of the genus Cyrtodactylus from Gia Lai Province, Central Highlands of Vietnam based on morphological and molecular differences. Cyrtodactylus gialaiensis sp. nov. is differentiated from other congeners by a unique combination of the following characters: Size small, maximum known SVL reaching 62.8 mm; dorsal pattern consisting of six or seven dark transverse bands between limb insertions; intersupranasals two or three; dorsal tubercles at midbody in 16-21 irregular rows, strongly developed on flanks; lateral folds poorly defined with interspersed tubercles; ventral scales between ventrolateral folds 38-45; precloacal pores nine or 10 in males, eight pitted scales in the adult female, in a continuous row; femoral pores absent; enlarged femoral scales present; postcloacal tubercles two or three; dorsal tubercles present to half of tail; subcaudal scales not enlarged. In molecular analyses, the new species is weakly supported as a member of the Cyrtodactylus irregularis species group with a minimum pairwise genetic distance of 13.7% from others within the group. PMID- 29245437 TI - Studies on Dendrothripinae (Thysanoptera, Thripidae) from Japan, with new records and one new species. AB - Pseudodendrothrips maculatus sp.n. is described from Morus leaves in Japan, and the following five species of Dendrothripinae are newly recorded from Japan: Leucothrips furcatus Hood, L. nigripennis Reuter, L. piercei (Morgan), Pseudodendrothrips darci (Girault) and P. lateralis Wang. Moreover, P. bhattii is newly recorded from Taiwan. An identification key to Pseudodendrothrips species from Japan and Taiwan is provided, and the metathoracic pleural area is compared between several Dendrothripinae genera. PMID- 29245438 TI - A preliminary account of the fruit fly fauna of Timor-Leste (Diptera: Tephritidae: Dacinae). AB - Opportunistic monitoring using baited fruit fly traps throughout Timor-Leste revealed the presence of 16 species of Bactrocera and one species of Dacus, all of which are previously reported from the region. Sampling of a range of commercial fruit species detected an additional species, B. latifrons, and revealed that nine species are attacking commercial fruits and vegetables. A key for separating these species is provided. New host records were found for B. minuscula, B. floresiae and B. bellisi. Variation in the morphology of B. minuscula, B. floresiae and an undescribed species and within B. albistrigata confounded attempts at accurate identification of some specimens. PMID- 29245439 TI - Three new species of tube-dwelling spider genus Ariadna Audouin, 1826 (Araneae: Segestriidae) from India. AB - The tube-dwelling spider family Segestriidae is represented in India by only two species, Ariadna nebulosa Simon, 1906 and Segestria inda Simon, 1906. Both species are known only from their type localities. For about 96 years, there has been no report of these spiders from the Indian subcontinent. Here, we describe three new species based on female specimens from India. Ariadna vansda sp. nov. from Gujarat; A. molur sp. nov., and A. chhotae sp. nov. from Karnataka. PMID- 29245440 TI - The genus Tyrinthia Bates, 1866 in Ecuador (Coleoptera, Cerambycidae, Lamiinae, Hemilophini). AB - Tyrinthia frontalis (Guerin-Meneville, 1855) is redescribed, formally recorded from Ecuador, and its type locality is questioned. Tyrinthia napoensis sp. nov. is described from Ecuador. Tyrinthia paraba Martins & Galileo, 1991, and T. turuna Martins & Galileo, 1993 are new country records for Ecuador. A key to species of Tyrinthia from Ecuador is provided. PMID- 29245441 TI - The vespid fauna of Pakistan. AB - This study provides the first annotated check list of the Vespidae of Pakistan. It is based on the National Insect Museum collection and various studies in Pakistan. Among 105 identified taxa, 77 species and 28 subspecies are recorded in the four subfamilies Eumeninae, Masarinae, Polistinae and Vespinae. Three new records for the fauna of Pakistan are added, namely Anterhynchium mellyi, Antepipona ovalis and Eumenes coronatus coronatus. Among the total, 12 species/subspecies are endemic to Pakistan, namely Ancistrocerus pakistanus, Antepipona luteipes, Antodynerus flavescens karachiensis, Celonites nursei, Cyrtolabulus karachiensis, Eustenancistrocerus (Parastenancistrocerus) baluchistanensis, Katamenes dimidiatus watsoni, Knemodynerus lahorensis, Leptochilus (Neoleptochilus) hina, Leptochilus (Neoleptochilus) mirificus, Leptochilus (Neoleptochilus) umerolatus and Tachyancistrocerus pakistanus. Antepipona varentzowi (Morawitz, 1896) and Polistes rothneyi quatei van der Vecht, 1968 were incorrectly reported from Pakistan. PMID- 29245442 TI - New records of tardigrades from Colombia with the description of Paramacrobiotus sagani sp. nov. and Doryphoribius rosanae sp. nov. AB - By examining material collected in the Sierra Nevada de Santa Marta (Department of Magdalena, Colombia), the authors report a new record for the entire South America, Doryphoribius gibber Beasley & Pilato, 1987, and two species new to science, Paramacrobiotus sagani sp. nov., and Doryphoribius rosane sp. nov., are described. Paramacrobiotus sagani sp. nov. belongs to the richtersi group, vanescens subgroup (by having sculptured egg areolae) and is characterized by a peculiar cuticular granulation, trunco-conical egg processes with cylindrical indented apices, and other more detailed cha-racters both qualitative and metric; by the unique combination of characters, it differs from all the other known species of the genus. Doryphoribius rosanae sp. nov. is characterized by reticulated dorsal cuticle with gibbosities (formula IX:4-6-2-6-2-6-4-2-2), two macroplacoids in the pharynx without microplacoid or septulum, and large, stout claws without "free" accessory points but with lunules. It differs from all the other Doryphoribius species with gibbosities by having a unique formula, as well as other more detailed characters. Thanks to this contribution, the number of tardigrade species known for Colombia increases from 52 to 55. PMID- 29245443 TI - Cleaning old cabinets: revealing the taxonomy of Sri Lankan wolf spiders (Araneae, Udubidae and Zoropsidae). AB - The fauna of Udubidae and Zoropsidae of Sri Lanka is reviewed, the families are diagnosed and a distribution map is provided. The udubid genus Campostichomma Karsch, 1892 is diagnosed and redescribed, C. manicatum Karsch, 1892 is redescribed, and we propose three new species, based on females: C. harasbedda sp. nov., C. mudduk sp. nov. and C. alawala sp. nov. The zoropsid genus Devendra Lehtinen, 1967 is diagnosed and redescribed, D. seriatus (Simon, 1898), D. pumilus (Simon, 1898) and D. pardalis (Simon, 1898), are redescribed, and two new species are proposed: D. saama sp. nov. and D. amaiti sp. nov. PMID- 29245444 TI - Systematics of the east Palaearctic pear psyllids (Hemiptera: Psylloidea) with particular focus on the Japanese and Korean fauna. AB - The confused taxonomy of the east Palaearctic pear psyllids, serious pests on cultivated pear, is reviewed. Fifty-six nominal species have been reported from Pyrus, 25 of which we consider valid and ten as not being associated with Pyrus. Our taxonomic revision suggests that, in Korea, four Cacopsylla species develop on pear: the univoltine C. burckhardti Luo et al. previously misidentified as C. pyrisuga (Foerster), the polyvoltine, seasonally dimorphic C. jukyungi (Kwon) (winter form 'cinereosignata' Luo et al., summer form 'jukyungi'), commonly found in Korean pear orchards, and C. maculatili Li (winter form 'maculatili', summer form 'qiuzili' Li) previously misidentified as C. pyricola (Foerster) by some authors, as well as the probably polyvoltine but not dimorphic C. sandolbaea (Park & Lee). The former three species (C. burckhardti, C. jukyungi, misidentified as C. chinensis (Yang & Li), and C. maculatili) occur also in Japan. Keys to the adult and fifth instar immatures as well as short biological notes are provided, and C. jukyungi and C. sandolbaea are redescribed. Following nomenclatorial changes are proposed: Cacopsylla betulaefoliae (Yang & Li, 1981) = Psylla heterobetulaefoliae Yang & Li, 1981, syn. nov.; Cacopsylla bidens (Sulc, 1907) = Psylla jiangli Yang & Li, 1981, syn. nov.; Cacopsylla jukyungi (Kwon) = C. cinereosignata Luo et al., syn. nov.; Cacopsylla maculatili Li = C. qiuzili Li, syn. nov.; Cacopsylla nigella (Konovalova), comb. nov. from Psylla. The synonymy of P. obongsana Kwon with C. sandolbaea is confirmed. PMID- 29245445 TI - Increasing diversity of land planarians (Platyhelminthes: Geoplanidae) in the Interior Atlantic Forest with the description of two new species and new records from Argentina. AB - Here, we describe two new species of land planarians of the genera Pasipha and Imbira from the Atlantic Forest of Argentina: Pasipha quirogai sp. nov. and Imbira negrita sp. nov. Their external features and internal anatomy distinguish them from their congeners. Pasipha quirogai sp. nov. is about 40mm long, characterized by brown beige dorsal pigmentation with a golden yellow median band and thin graphite black para-median stripes, cylindrical pharynx, extrabulbar prostatic vesicle with paired proximal portion, male atrium with small folds in its proximal part, and female canal opening into the dorso-caudal wall of the female atrium. Imbira negrita sp. nov. is about 110mm long, with jet black dorsal pigmentation, pharynx collar-type, short female canal opening in the postero dorsal portion of the female atrium, and epithelial lining of female atrium with stratified appearance. We also provide exhaustive descriptions of Geoplana quagga, Obama ladislavii, and Paraba multicolor, all recorded for the first time in Argentina, by analysing anatomical features of taxonomic relevance. In addition, we improve the description of G. quagga, mainly regarding the musculature, secretory cells, and the copulatory apparatus. PMID- 29245446 TI - A new species of Pangrapta Hubner, 1818 from China (Lepidoptera, Erebidae, Pangraptinae). AB - Pangrapta is a large and morphologically rather diverse genus, which is widely distributed in the New and the Old Worlds. This genus usually has a dark brown ground color on wing and wing margin is often slightly angled; a majority of species have the triangle patch on the forewing costa between subterminal and postmedial lines; uncus is generally slender and tapering apex; valva tends to be long and narrow; harpe is often spine-shaped; vesica typically has one or more cornuti on the diverticula. As currently, Pangrapta is consisted of about 100 species in the world (Hu & Wang, 2013), which is called for a general revision. PMID- 29245447 TI - A new genus of the tribe Praini Mackauer (Hymenoptera: Braconidae: Aphidiinae) from China. AB - A new genus of the tribe Praini Mackauer, 1961 (Braconidae: Aphidiinae) from China is described in this paper, Astigmapraon Tian et Chen, gen. nov. (Type species: A. hei Tian et Chen, sp. nov. from Shaanxi and Sichuan). An identification key to the genera of Praini is added. PMID- 29245448 TI - Observation of a mixed-sex, mixed-species aggregation of velvet ants, genus Timulla Ashmead, 1899 (Hymenoptera: Mutillidae) in the Brazilian Amazon, Roraima, with a new synonymy. AB - An aggregation of two males of Timulla bitaeniata (Spinola, 1841), three single males T. rufogastra (Lepeletier, 1845) and another two males T. rufogastra (Lepeletier, 1845) in copula with two females of T. eriphyla Mickel, 1938 is documented, described and discussed. A new synonymy is proposed for Mutilla rufogastra Lepeletier de Saint-Fargeau, 1845 [=Timulla (Timulla) eriphyla Mickel, 1938, syn. nov.] based on the mating pairs. PMID- 29245449 TI - Description of a new species of Bothynus Hope from Argentina and Bolivia (Coleoptera: Scarabaeidae: Dynastinae). AB - A new species of Bothynus Hope, 1837 (Coleoptera: Scarabaeidae: Dynastinae: Pentodontini) is described from the eastern Andes in South America. The new species is unique in the genus for having the elytra and part of the pronotum covered with small setae. PMID- 29245450 TI - Physoderinae Miller, 1954 (Hemiptera: Heteroptera: Reduviidae): a junior synonym of Epiroderinae Distant, 1904, and a junior homonym of Physoderina Chaudoir, 1877 (Coleoptera: Carabidae). AB - The purpose of the present paper is to review and resolve nomenclatural problems with the family-group name Physoderinae Miller, 1954 (type genus: Physoderes Westwood, 1846), a name being in prevailing usage for a subfamily of assassin bugs (Hemiptera: Heteroptera: Reduviidae). It is demonstrated that this name is a junior synonym of Epiroderinae Distant, 1904 (type genus: Epirodera Westwood, 1847, a junior objective synonym of Physoderes) and permanently invalid as a junior homonym of the family-group name Physoderina Chaudoir, 1877 (type genus: Physodera Eschscholtz, 1829) (Coleoptera: Carabidae: Harpalinae: Lebiini), therefore it is replaced by its senior synonym, Epiroderinae. PMID- 29245451 TI - A synopsis of the Neotropical genus Protoneura (Odonata: Coenagrionidae). AB - A synopsis of the Neotropical genus Protoneura is presented, including an identification key to its 22 species accompanied by illustrations of diagnostic characters, and characterizations, diagnoses, and distribution maps for all species. A lectotype is designated for P. peramans Calvert in Skinner, 1902. PMID- 29245452 TI - Five new species of the genus Nannopus (Copepoda: Harpacticoida: Nannopodidae) from intertidal mudflats of the Korean West Coast (Yellow Sea). AB - Five Nannopus Brady, 1880 species that are new to science are described from the intertidal mudflats of the Korean West Coast, Yellow Sea (South Korea). Nannopus minutus sp. nov. and N. dimorphicus sp. nov. belong to a group of species defined by seven elements on P4 exp-3, and these two species are unique by the pinnate caudal seta III. These species differ in the number of dorsal integumental windows on the cephalothorax (three in N. minutus, one in N. dimorphicus), shape of the distal small seta on the P4 endopod (naked in N. minutus, pinnate in N. dimorphicus), shape of the caudal seta IV (inflated and leaf-shaped in N. minutus, with a globular expansion at its insertion and slender in N. dimorphicus), and shape of the caudal seta V (anterior part cylindrical in N. minutus, inflated and bulbous in N. dimorphicus). The males of N. minutus and N. dimorphicus differ in the number of dorsal integumental windows on the cephalothorax (without any in N. minutus, with one integumental window in N. dimorphicus), number of outer spines on P2-P3 exp-3 (three in N. minutus, four in N. dimorphicus), shape of the inner seta on P3 enp-2 (naked in N. minutus, pinnate in N. dimorphicus), and shape of the outer medial and outermost setae on the P5 endopod (pinnate in N. minutus, naked in N. dimorphicus). Nannopus serratus sp. nov. and N. unisegmentatus Shen & Tai, 1964 share the presence of two setae on P2 enp-2 but differ in ornamentation and position of the setae on the mandibular palp, shape of the inner seta on P3 enp-2, and shape of distal seta on P4 enp-2. Nannopus parvus sp. nov. and N. bulbiseta sp. nov. belong to the group of species with the female P5 exopod fused, but these two species can be separated from the others by the presence of two bulbiform pinnate setae on the second segment of the antennule, as well as by the relative length and shape of the inner subdistal pectinate seta of P4 exp-3 (pectinate and 0.5 to 0.7 times as long as those in other congeners), and the shape of outer medial and outermost setae on the P5 endopod (naked only in female). However, they both display unique characters among all congeners. The caudal ramus of N. parvus is trapezoidal or square-shaped, and 0.4 to 0.5 times as long as those in other congeners, and the caudal seta V is very short and spine-like. Nannopus bulbiseta has four and five setae on P2 and P4 exp-3 respectively, the caudal ramus is sub-cylindrical or sub rectangular, and the proximal part of the female caudal seta V is bulbous and very slender distally. A key to 14 valid species of Nannopus is provided. PMID- 29245453 TI - Astonishing diversity revealed: an annotated and illustrated inventory of Nudipleura (Gastropoda: Heterobranchia) from Mozambique. AB - This paper provides the first comprehensive annotated and illustrated inventory of Nudipleura from Mozambique. A total of 267 species are recorded, including 61 putative new species, documented over a period of seven years from several localities along the coast. At least 20 species need further investigation through molecular and taxomic analysis. Of the 186 confirmed described species, 118 are new records for the Mozambican fauna. Sampling was carried in tidal reefs and depths up to 60m on the subtropical and tropical coast of Mozambique. The most representative families were Chromodorididae (69 species), Discodorididae (30 species), Facelinidae (23 species) and Phyllididae (16 species). Nevertheless, a vast area of Mozambique remains unexplored, thus it is likely that the species documented here represent only a fraction of the true Nudipleura diversity of the country. PMID- 29245454 TI - New genera, species and records of Afrotropical Phaneropterinae (Orthoptera, Tettigoniidae) preserved at the Royal Belgian Institute of Natural Sciences, Bruxelles. AB - The results of the study of the rich material of Orthoptera Phaneropterinae at the Royal Belgian Institute of Natural Sciences, Bruxelles, are reported. The following new taxa are described: Dithela longicaudata n. sp. from the Democratic Republic of Congo, Terpnistriella bredoi n. gen. n. sp. from the Democratic Republic of Congo, Mimoscudderia paulyi n. sp. from the Madagascar, Pseudogoetia constanti n. gen. n. sp. from the Democratic Republic of Congo (including a table listing differences with related genera), and Materuana abyssinica n. sp. from the Ethiopia. Some taxonomic and distributional data about the following species are also reported: Melidia claudiae Massa, 2015, Symmetrokarschia africana (Brunner von Wattenwyl, 1878), Eurycorypha ndokiensis Massa, 2016, Eurycorypha prasinata Stal, 1874, Eurycorypha spinulosa Karsch, 1889, two unidentified species of Eurycorypha recorded by Griffini in 1908, Tylopsis irregularis Karsch, 1893, Pardalota asymmetrica Karsch, 1896, Pardalota haasi Griffini, 1908, Pardalota karschiana Enderlein, 1907, Pardalota versicolor Brunner von Wattenwyl, 1878, Poecilogramma cloetensi (Griffini, 1908), Poecilogramma annulifemur Karsch, 1887, Morgenia spathulifera Griffini, 1908, Mimoscudderia picta Carl, 1914 and Angustithorax spiniger Massa, 2015. The following synonymy is established: Plangiopsis shoutedeni Griffini, 1908 = Plangiopsis adeps Karsch, 1896; the latter species, recently moved to the genus Plangiola Bolivar, 1906 is again transferred to the original genus. PMID- 29245455 TI - Description of the larva and pupa of Neocorvicoana reticulata (Kirby, 1819) (Coleoptera: Scarabaeidae: Cetoniinae: Gymnetini). AB - The third instar and pupa of Neocorvicoana reticulata (Kirby, 1819) (Coleoptera: Scarabaeidae: Cetoniinae: Gymnetini) from Argentina, are described and illustrated. This is the first description of immatures in this genus. A key to the known third-stage larvae of New World Gymnetini species is provided, which now includes 19 species in 10 genera. PMID- 29245456 TI - Revision of the Barsine cardinalis-anomala 'species-complex' (Lepidoptera, Erebidae, Arctiinae). AB - The Barsine cardinalis-anomala 'species-complex' is revised. Five new species (B. pseudocardinalis Volynkin & Cerny, sp. nov. from Indochina, B. fansipana Volynkin & Cerny, sp. nov. from North Vietnam, B. nangkwak Volynkin & Cerny, sp. nov. from North Thailand, B. incompletostriga Volynkin & Cerny, sp. nov. from North-East India and B. rawanga Volynkin & Cerny, sp. nov. from North Burma) and one new subspecies (B. cardinalis gemina Volynkin & Cerny, ssp. nov. from North Thailand) are described. A new combination (Barsine anomala (Elwes, 1890), comb. nov. ), new synonymy (Barsine cardinalis cardinalis (Hampson, 1900) = Miltochrista erubescens Rothschild, 1936, syn. nov.), and six new species-groups are established. Adults, male and female genitalia of all species are illustrated. PMID- 29245457 TI - Description of Stegelletina lingulata sp. n. (Nematoda, Rhabditida, Cephalobidae) from xeric environments in Iran. AB - A new species belonging to the genus Stegelletina, S. lingulata sp. n., is described from xeric natural areas from Iran. It is characterized by having small body (0.51-0.69 mm in females and 0.45-0.64 mm in males), cuticle slightly tessellated especially at anterior end, lateral field with three longitudinal incisures, lips with long acute process at primary axils and three more dentate processes at secondary axils, primary axils with one triangular axillar guard process and secondary axils lacking axillar processes, labial probolae long (9-11 um) with slender peduncle lacking adaxial expansion and with convergent smooth prongs, stoma, pharynx and reproductive systems cephaloboid, excretory pore at isthmus level, spermatheca 1.1-1.4 times, and post-vulval sac 0.9-1.2 times the corresponding body diameters in length, female rectum 0.6-0.8 times anal body diameter long, female tail conoid (35-47 um long, c = 14.0-15.6, c' = 2.1-2.7) with fine rounded terminus, male tail conoid, curved ventrad (53-59 um long, c = 11.0-12.0, c' = 1.9-2.5) with rounded terminus, spicules 31-33 um long with ventrally straight manubrium and gubernaculum 14-17 um long. Measurements and illustrations (line drawings, LM and SEM) are provided for this species. In addition, comments on the morphology of the lip region of the species of the genus Stegelletina are included. PMID- 29245458 TI - New Eurycorypha species (Orthoptera: Tettigonoidea: Phaneropteridae; Phaneropterinae from East Africa. AB - Eight Eurycorypha species are newly described for Tanzania. These are E. binasuta n. sp. from the Nguru and Udzungwa Mountains, E. curviflava n. sp. from the eastern slopes of Mt Kilimanjaro, E. divertata n. sp., E. elongata n. sp. and E. flexata n. sp. from the East Usambara Mountains, E. pseudomeruensis n. sp. from Central-west Tanzania and western Kenya, E. pseudovaria n. sp. from the West and East Usambara Mountains and E. victoriae n. sp. from the shores of Lake Victoria. Further the hitherto unknown females of two Eurycorypha, E. combretoides Hemp and E. ligata Hemp are described. A key to the males of Tanzania and Kenya is provided. PMID- 29245459 TI - Taxonomic review of the genus Euboeus s. str. Boieldieu, 1865 (= Probaticus s. str. Seidlitz, 1896, syn. n.) (Coleoptera, Tenebrionidae). AB - The taxonomic history and position of the genera Euboeus and Probaticus within the tribe Helopini are discussed. A new synonymy, based on morphological characters is established: Euboeus Boieldieu, 1865 = Probaticus (s. str.) Seidlitz, 1896, syn. n. As a result, 67 new combinations (from Probaticus to Euboeus) are estabished for all species formerly placed in Probaticus. A review of Euboeus s. str. with four species (Balkanian-Anatolian E. mimonti Boieldieu, 1865 and E. tentyrioides (Kuster, 1851), Greek E. mori (Brulle, 1832), and Anatolian E. parvostriatus sp. n.) is given. Three new synonyms are established for Euboeus tentyrioides (= Micispa bysantica Motschulsky, 1858, syn. n.; = Micispa pyraei Motschulsky, 1858, syn. nov.; = Micispa graeca Motschulsky, 1858, syn. n.). The forgotten name Helops (Euboeus) parvicollis Baudi di Selve, 1876, nomen oblitum (junior synonym of E. tentyrioides) is discussed. A lectotype is designated for Helops tentyrioides. A key to the four species within the revised Euboeus sensu stricto, along with distributions and images, is provided. PMID- 29245460 TI - New species of Neohybos Ale-Rocha & Carvalho (Diptera, Hybotidae, Hybotinae) from South America. AB - Eleven new species of Neohybos Ale-Rocha & Carvalho from South America are described: N. aberrans sp. nov. (Brazil); N. adustus sp. nov. (Brazil, Peru); N. annulatus sp. nov. (Brazil); N. arcuatus sp. nov. (Brazil); N. elongatus sp. nov. (Brazil); N. hirsutus sp. nov. (Brazil); N. izabelensis sp. nov. (Brazil); N. lautus sp. nov. (Brazil); N. neblinensis sp. nov. (Brazil); N. pectinatus sp. nov. (Colombia, Peru); and N. ramosus sp. nov. (Brazil). Neohybos luridus (Bezzi) is recorded for the first time from Colombia. A key to the South American species is given. PMID- 29245461 TI - Status of Nearctic subgenera of Microscydmus revisited (Coleoptera, Staphylinidae, Scydmaeninae). AB - Nearctic Microscydmus Saulcy & Croissandeau includes species placed in Microscydmus s. str. and subgenera Delius Casey and Neladius Casey. The two latter taxa were originally described as genera, and all Nearctic species of Microscydmus s. str. were placed in a genus Opresus Casey, currently treated as a junior synonym. Detailed examination of the type species of Opresus, Delius and Neladius leads to the following conclusions and changes: Opresus is removed from synonymy with Microscydmus s. str. and placed as a subgenus of Microscydmus; Delius and Neladius are restored as genera. The two latter taxa belong to a group of glandulariine genera characterized by the submentum with lateral sutures, whereas Microscydmus does not have such structures. The type species of the studied genera and subgenera are redescribed: Microscydmus (Opresus) misellus (LeConte), comb. rest., Delius robustulus Casey, comb. rest., and Neladius tenuis Casey, comb. rest. Lectotypes are designated for Scydmaenus misellus LeConte, Delius robustulus Casey and Neladius tenuis Casey. PMID- 29245462 TI - Dolichocephala Macquart of Thailand (Diptera: Empididae: Clinocerinae). AB - Seven new species of Dolichocephala Macquart from Thailand are described (D. bicolor sp. nov., D. curvata sp. nov., D. immaculata sp. nov., D. incus sp. nov., D. longicerca sp. nov., D. srisukai sp. nov., D. thailandensis sp. nov.). A key to species is provided, distributions mapped and phenology and biogeography discussed. PMID- 29245463 TI - A new species of the Chinese endemic genus Sinhomidia (Collembola: Entomobryinae) described and the first description of amale of Sinhomidia bicolor. AB - We describe the male of Sinhomidia bicolor for the first time noting a morphological difference from the female. A new species, Sinhomidia guangxiensis sp. nov. is described and illustrated. The new species differs from S. bicolor by the appendages lacking scales, the mucronal basal spine reaching the apex of subapical tooth, the number of chaetae on the trochanteral organ and the distribution of macrochaetae on Th. II, Abd I and Abd II. A key to Sinhomidia species and a diagnostic table to separate male and female S. bicolor and the new species are provided. PMID- 29245464 TI - Notes on distribution and ecology of Philonthus spinipes Sharp (Coleoptera: Staphylinidae) in the Polish Carpathians. AB - Philonthus spinipes Sharp for the first time was described from East Asia (Sharp 1874). Presently the species occurs in the whole Palaearctic region. Original distribution of this species is difficult to define because it has obviously extended its distribution range westwards (Schillhammer 1999). PMID- 29245465 TI - A new species of Rock Gecko of the genus Cnemaspis Strauch, 1887 (Squamata: Gekkonidae) from Belitung Island, Indonesia. AB - A new species of rock gecko of the genus Cnemaspis Strauch is described from Belitung Island, Indonesia. The new species is differentiated from all other species in the Southern Sunda clade (sensu Grismer et al. 2014a) by having a unique combination of characters including: (1) a maximum SVL of 54.1 mm, (2) five or six postmental scales, (3) enlarged submetacarpal scales on the first finger, (4) enlarged submetatarsal scales on the first toe, (5) keeled ventral scales, (6) absence of precloacal pores, (7) absence of enlarged femoral scales, (8) absence of shield-like subtibial scales, (9) caudal tubercles encircling the tail, (10) an interrupted median row of enlarged keeled subcaudals, (11) presence of a distinct furrow on the lateral surface of the tail (12) 22-24 lamellae beneath fourth toe, and (13) two postcloacal tubercles on each side of the tail base. PMID- 29245466 TI - The change of depository of a collection of scale insects by Ryoichi Takahashi (Hemiptera: Sternorrhyncha: Coccomorpha). AB - Ryoichi Takahashi (1898-1963) was a Japanese entomologist with considerable expertise on the Sternorrhyncha of the Far East and southern Asia. Most of his early articles were in Japanese, the first being published in 1916; but later he also wrote many articles in English. At first he published mainly on aphids (Aphidomorpha) and whiteflies (Aleyrodomorpha). His first article on scale insects did not appear until 1928, describing species from Formosa (Taiwan), where he worked at the Government Agricultural Research Institute. He produced a further 73 articles on scale insects (Garcia et al. 2017). In total, he published almost 420 articles according to Ito and Sorin (1963). PMID- 29245467 TI - Revision of the Genus Leptogomphus Selys in Borneo, including gene trees and a two marker molecular phylogeny (Odonata: Anisoptera: Gomphidae). AB - The Bornean members of the genus Leptogomphus Selys are revised. Two new species are described: Leptogomphus schieli sp. nov. (holotype ?, Gunung Penrissen, Kuching Division, Sarawak, Malaysia, to be deposited in BMNH) and Leptogomphus sii sp. nov. (holotype ?, Sungai Sii, upper Baram, Miri Division, Sarawak, Malaysia, in RMNH). Leptogomphus mariae Lieftinck, 1948 is considered to be a junior synonym of L. coomansi Laidlaw, 1936. The true male of L. pasia van Tol, 1990 is described for the first time; male specimens previously treated as L. pasia or L. cf pasia actually belong to a taxon closely allied to, and possibly merely a form of, L. coomansi. A description is given of the female of another new species, but the species is not named in the absence of the male. Female specimens from south-western Sarawak, similar to L. williamsoni Laidlaw, 1912, are considered likely to also represent a distinct species. The female of L. pendleburyi Laidlaw, 1934 is described for the first time and fresh descriptions of the males of L. coomansi, L. pendleburyi and L. williamsoni, and the female of L. coomansi are given. Keys to both sexes, and distribution maps are given. A molecular analysis of the Bornean species (except L. schieli) using the COI and ITS markers is presented. PMID- 29245468 TI - On the systematic position of the genera Paraplastis Hampson, Migoplastis Felder and Dondera Moore (Lepidoptera, Erebidae, Arctiinae). AB - Type species of three poorly known Arctiinae genera, Paraplastis Hampson, 1901, Migoplastis Felder, 1868 and Dondera Moore, 1877 are examined. All three taxa are transferred here from the subtribe Arctiina to the subtribe Nyctemerina of the tribe Arctiini. Paraplastis and Migoplastis (= Pachyphilonia Butler) are synonymized with the subgenus Deilemera Hubner, [1820] of the genus Nyctemera Hubner, [1820]. Dondera is synonymized with the subgenus Arctata Roepke, 1949 of the genus Nyctemera, and recognized as the older name for the subgenus. Three new combinations are established: Nyctemera (Deilemera) hampsoni (Swinhoe, 1889), comb. nov., Nyctemera (Deilemera) correcta (Walker, [1865]), comb. nov. and Nyctemera (Dondera) alba (Moore, 1877), comb. nov. The check-list of the subgenus Dondera is presented. Male and female genitalia of N. correcta and N. alba and female genitalia of N. hampsoni are described and illustrated for the first time. PMID- 29245469 TI - Diversity and distribution of Phanaeini (Coleoptera: Scarabaeidae: Scarabaeinae) in Mexico. AB - In this study, we systematized available distribution data, obtained from biological databases and relevant literature, for Mexican species belonging to the tribe Phanaeini. The main objectives were to provide an overall description of the distribution records in biological collections, to detect potential sampling biases, to describe the seasonality of collections and to obtain species distribution models using the Desktop GARP algorithm. A total of 5,562 records, corresponding to 32 species in Mexico, were compiled, including the recently described Phanaeus zoque Moctezuma & Halffter, 2017. This compilation includes 784 unique collection records at 325 localities. These records were mainly distributed along the Trans-Mexican Volcanic Belt, the Sierra Madre Oriental and Sierra Madre Occidental mountain ranges and throughout the states of Chiapas and Veracruz. The Mexican High Plateau, the state of Tlaxcala and the Yucatan Peninsula are lacking in records. Distribution maps were created for species of three genera (Phanaeus MacLeay, 1819, Coprophanaeus Olsoufieff, 1924, and Sulcophanaeus Olsoufieff, 1924) and for 29 species present in Mexico. These species distributions are largely delimited by geomorphological features and vegetation types and coincide with expert descriptions of this tribe; some species show expanded distribution ranges. These maps provide a starting point for further analyses, the planning of future field studies, and the verification of possible new species in the Mexican territory. PMID- 29245470 TI - A new species of Marsipococcus Cockerell & Bueker (Hemiptera: Coccomorpha: Coccidae) from Malaysia. AB - The adult female, first-instar nymph, second-instar male, third-instar female, pupa and adult male of a new species of Marsipococcus Cockerell & Bueker (Hemiptera: Coccomorpha: Coccidae) from Malaysia, M. ulubendulensis Lagowska & Martin sp. n., are described and illustrated, while the second-instar female is only described. Marsipococcus is rediagnosed and a key to the adult females of the four species now placed in this genus is included. PMID- 29245471 TI - Contribution to the knowledge of the oribatid mite family Nesozetidae (Acari, Oribatida). AB - A new oribatid mite species of the genus Nesozetes (Oribatida, Nesozetidae) is described from moss (Sphagnum sp.) on the seepage area below a permanent spring in South Africa. Nesozetes membranus sp. nov. differs from its only congener, Nesozetes rostropterus, described from Fiji, by the presence of a second pair of membranes located in the podosomal region, setiform bothridial setae and striate subcapitular mentum. A revised diagnosis of Nesozetidae, discussion on its taxonomic status, and information on distribution and ecology of Nesozetes species are given. PMID- 29245472 TI - Taxonomy of 'Euconnus complex'. Part XVI. Alloconophron Franz transferred to Anhoraeomorphus Franz as subgenus, with notes on systematic position of Noctophus Casey (Coleoptera, Staphylinidae, Scydmaeninae). AB - Based on examination of type species, Alloconophron, previously a subgenus of Euconnus, is placed as a subgenus of Anhoraeomorphus, resulting in Anhoraeomorphus (Alloconophron) grucheti (Franz) comb. n. and Anhoraeomorphus (Alloconophron) impressifrons (Franz) comb. n. All species of Anhoraeomorphus are known to occur in Madagascar. Noctophus stat. rest., a North American taxon originally described as a genus and later placed as a subgenus of Euconnus, is restituted as genus and redefined. Noctophus is morphologically surprisingly similar to Anhoraeomorphus, it also shares many structures with the Australo Pacific Sciacharis. As Noctophus is known from one species represented by a single female holotype only, and the maxillary palps of this specimen are missing, the proposed placement of Noctophus is tentative and requires further study based on complete male specimens. PMID- 29245473 TI - Parasphaerolaimus magdolnae sp. n. (Nematoda, Sphaerolaimidae) with intra uterine development of its offspring from a Brazilian estuarine system. AB - One new species of Parasphaerolaimus is described from a Brazilian estuarine system with intra-uterine development of its offspring. Parasphaerolaimus magdolnae sp. n. is distinguished from other species of the genus by the presence of only one anterior testis, spicules morphology and size and a gubernaculum without dorsal apophysis. The cuticle of the new species is striated and the position of the vulva is far posterior on the body, almost reaching the anus. The taxonomy of Parasphaerolaimus was also re-examined and two other species were transferred from Sphaerolaimus to Parasphaerolaimus after the last revision: P. pentasetus (Pastor de Ward, 1984) comb. n. and P. striatus (Allgen, 1935) comb. n. An updated identification key for all valid species of Parasphaerolaimus is included. PMID- 29245474 TI - Osmiine bees of the genus Haetosmia (Megachilidae, Osmiini): biology, taxonomy and key to species. AB - Haetosmia is a species-poor genus of osmiine bees (Megachilidae) containing six species, which inhabit deserts and semideserts from the Canary Islands to Central Asia. Formerly considered to be restricted to the southern Palaearctic region, the genus is shown here to occur also in the northern Afrotropical region. The females of all six Haetosmia species collect pollen from the narrow-tubed flowers of Heliotropium (Boraginaceae) with the aid of specialized pollen-harvesting bristles on the proboscis. Current knowledge suggests that Haetosmia species are restricted to sandy habitats, excavate their nests in the ground and use chewed leaves to construct their urn-shaped brood cells, which are placed side by side in an enlarged chamber at the end of the nesting burrow. The taxonomic revision of Haetosmia revealed the existence of two undescribed species, H. ethiopiensis spec. nov. from eastern Africa and H. pakistaniensis spec. nov. from Pakistan. Due to clear morphological gaps and overlapping distribution area with the nominotypical subspecies, H. brachyura altera (Peters 1974) is elevated to species rank. Keys for the identification of the six Haetosmia species are provided. PMID- 29245475 TI - A new subspecies of Short-toed Snake-eagle from Wallacea determined from morphological and DNA comparison. AB - The taxonomic status of the geographically isolated population of Short-toed Snake-eagle Circaetus gallicus on the Lesser Sundas (=Nusa Tenggara) has been controversial. In the past they have been regarded as either a migrant population or a recently arrived resident population. Here we obtained DNA sequences from the mitochondrial cytochrome-b gene and combined genetic data with assessments of published and novel morphological data to clarify the taxonomic status of the Lesser Sundas population of C. gallicus. The cytochrome-b distance between the Lesser Sundas and Palearctic populations of C. gallicus is consistent with subspecific differentiation, indicating a possible divergence during one of the most recent Pleistocene glaciations. Although some of the morphological distinctions show overlap, the new subspecies can generally be diagnosed from nominate C. gallicus gallicus by being smaller and paler, and exhibiting less spotting and barring. Unlike nominate populations from mainland Eurasia, the new subspecies seems to lack pronounced sexual dimorphism. We here describe this new subspecies to science and discuss its biology and conservation status. PMID- 29245476 TI - The immature stages of Smicridea (Rhyacophylax) gladiator Flint 1978 (Trichoptera: Hydropsychidae), with notes on distribution and bionomics. AB - Immature stages of many Brazilian Smicridea species remains unknown, and efforts to describe all life stages are required. In this paper, the larva and pupa of Smicridea (Rhyacophylax) gladiator Flint 1978, associated with adults through the metamorphotype method, are described and illustrated. In addition, the known distribution of this species is extended in the Brazilian Amazon Basin with new records from Amazonas state and the first record in Para state. Information about its bionomics is also provided. PMID- 29245477 TI - A new species of Macrosaccus (Lepidoptera: Gracillariidae: Lithocolletinae) from Arizona, USA. AB - A sixth species of Macrosaccus (Gracillariidae), M. coursetiae sp. nov., is described. The larvae are leafminers of Coursetia glandulosa (Fabaceae). The parasitoid Chrysocharis walleyi (Eulophidae) has been reared from the leaf mines; a table summarizing the host records for this wasp is presented. PMID- 29245478 TI - First record of the genus Doliopteryx Hesse, 1956 (Diptera: Mythicomyiidae: Glabellulinae) from Iran, with description of two new species. AB - Two new species of Doliopteryx Hesse, D. nodahaki, sp. nov. and D. fratris, sp. nov. are described and illustrated. This marks the first record of the genus in Iran. PMID- 29245479 TI - Revision of the Megaperidae Manter, 1934 n. comb. (Syn. Apocreadiidae Skrjabin, 1942) including a reorganization of the Schistorchiinae Yamaguti, 1942. AB - Modified and/or new keys to the four subfamilies now recognized within the Megaperidae Manter, 1934 n. comb. (Syn. Apocreadiidae Skrjabin, 1942) as well as the genera within each subfamily are presented. Two new genera, Paraschistorchis n. gen. and Plesioschistorchis n. gen., both within the Schistorchiinae Yamaguti, 1942, are erected and keys are provided to the species considered in both new genera-distinguished by possessing caeca that end either in separate ani or blindly. Plesioschistorchis callyodontis (Yamaguti, 1942) n. comb. and Plesioschistorchis haridis (Nagaty, 1957) n. comb. are re-described from new material collected from the common parrotfish, Scarus psittacus Forsskal (Perciformes: Scaridae), inhabiting the Red Sea off Egypt; S. psittacus represents a new host record for both species. The taxonomic status of Schistorchis sensu stricto Luhe, 1906 is examined and revised, a key to the four species we consider in this genus offered, and the monotypic genus Megacreadium Nagaty, 1956 declared a junior synonym of Schistorchis. Members of Schistorchis sensu stricto possess a unique "complex" (i.e. highly cellular/glandular) instead of "simple" (i.e. entirely muscular) type of oral sucker that is quite large in relation to body size; an elongate, somewhat sub-rectangular-shaped body; 5+ testes arranged in at least two rows; caeca that open via separate ani; a long post-testicular region; a median genital pore either at the anterior margin of or just anterior to the ventral sucker; and species of Schistorchis sensu stricto parasitize the intestine of marine fish within the Order Tetraodontiformes Berg. With the revision of this genus, we re-describe Schistorchis carneus Luhe, 1906 from the lower and mid-intestine of the white-spotted puffer, Arothron hispidus (Linnaeus) (Tetraodontiformes: Tetraodontidae), collected in the Red Sea off Egypt. Finally, a plea is made for further study of the Megaperidae n. comb. focusing, in particular, on the following: (1) obtaining new type/voucher materials of Plesioschistorchis manteri (Gupta & Tandon, 1984) n. comb. and Schistorchis paruchini Kurochkin, 1974; (2) elucidating the life histories (i.e. intermediate hosts) of members of the Postporinae Yamaguti, 1958 and Schistorchiinae; and (3) generating DNA sequence data for more species of megaperids to help future workers produce increasingly accurate taxonomic classifications that better reflect phylogenetic relationships within this ecologically diverse group of digeneans. PMID- 29245480 TI - Monopelopia Fittkau, 1962 (Diptera: Chironomidae) from the Neotropical region: five new species, new records and updated keys. AB - Five new species of Monopelopia from Brazil are described and illustrated, four of which are based on all life stages and one on adult male and pupa. The immature stages of Monopelopia edentata sp. nov. were collected in bromeliad phytotelmata, while the other species were collected associated with aquatic vegetation. New records for M. boliekae Beck & Beck and M. caraguata Mendes, Marcondes & Pinho are provided, as well as updated identification keys for males and immatures of the Nearctic and Neotropical Monopelopia species. PMID- 29245481 TI - The Catocala naganoi species group (Lepidoptera: Noctuidae), with a new species from Vietnam. AB - The Asian Catocala naganoi species group is delimited and reviewed, with a diagnosis of the constituent species based on genitalic, wing pattern, and COI 5' mtDNA characters. The included species are Catocala naganoi Sugi, 1982, C. solntsevi Sviridov, 1997, C. naumanni Sviridov, 1996, and C. katsumii sp. n. which is described here as new. PMID- 29245482 TI - New taxa and new records of butterflies (Lepidoptera: Pieridae, Lycaenidae, Nymphalidae) from Afghanistan. AB - Three new species Karanasa naumanni sp. nov., K. pardesi sp. nov. and K. pseudopamira sp. nov. (Nymphalidae), two new subspecies Karanasa pamira biocellata subsp. nov. (Nymphalidae) and Plebejus (Afarsia) sieversii albolunulatus subsp. nov. (Lycaenidae) are described from Afghanistan. First occurrence records for this country are presented for 26 species: one species of Pieridae (Colias thisoa), fifteen species of Lycaenidae (Deudoryx epijarbas, Everes dipora, Glaucopsyche charybdis, Hyrcanana evansii, Iolana gigantea, Lycaena kasyapa, Plebejus ferganus, Polyommatus amandus, P. dagmara, P. farazi, P. kogistanus, P. lehanus armatheus, P. miris, P. selma, and Turanana panaegides,) and ten species of Nymphalidae (Argynnis jainadeva, Coenonympha nolckeni, Hyponephele maureri, Melitaea balbina, Karanasa grumi, K. incerta, K. leechi, K. maureri, Satyrus alaica, and S. ferula). PMID- 29245483 TI - First report on the Olethreutini (Lepidoptera: Tortricidae: Olethreutinae) of Lao PDR with descriptions of two new species. AB - We present the results of the first study of the tortricid moths of Lao PDR (Laos), with this report focusing on the tribe Oleuthreutini. We report 27 species from Laos for the first time, including two that are described as new: Diakonoffiana laosensis Phewphanh and Pinkaew, n.sp., and Lobesia acicula Phewphanh and Pinkaew, n.sp. As is typical of many inventories, over half of the species (i.e., 15) were documented by a single specimen. PMID- 29245484 TI - New species and new records of Monohelea Kieffer from eastern Amazon, Brazil (Diptera: Ceratopogonidae). AB - Seven new species of Monohelea Kieffer are described and illustrated and new records from M. affinis Felippe-Bauer & Spinelli, M. guaimiesi Lane & Wirth and M. maculipennis (Coquillett) are given based on specimens collected in Para State, eastern Brazilian Amazon. The new species are compared with their similar congeners and the distributional records of both new and previously described species are presented in Figure 1. A key for identification of the Brazilian Amazonian species of Monohelea is also provided. PMID- 29245485 TI - Pseudoliparis swirei sp. nov.: A newly-discovered hadal snailfish (Scorpaeniformes: Liparidae) from the Mariana Trench. AB - Pseudoliparis swirei sp. nov. is described from 37 individuals collected in the Mariana Trench at depths 6898-7966 m. The collection of this new species is the deepest benthic capture of a vertebrate with corroborated depth data. Here, we describe P. swirei sp. nov. and discuss aspects of its morphology, biology, distribution, and phylogenetic relationships to other hadal liparids based on analysis of three mitochondrial genes. Pseudoliparis swirei sp. nov. is almost certainly endemic to the Mariana Trench, as other hadal liparids appear isolated to a single trench/ trench system in the Kermadec, Macquarie, South Sandwich, South Orkney, Peru-Chile, Kurile-Kamchatka and Japan trenches. The discovery of another hadal liparid species, apparently abundant at depths where other fish species are few and only found in low numbers, provides further evidence for the dominance of this family among the hadal fish fauna. PMID- 29245486 TI - A new Palearctic species of the genus Gonempeda Alexander, 1924 (Diptera: Limoniidae). AB - A new species of Gonempeda from Caucasus is described and illustrated. Gonempeda flava (Schummel, 1829) is recorded from Russia for the first time. An identification key of all Palearctic Gonempeda is presented. PMID- 29245487 TI - After 228 years of being ignored or unplaced, Bibio lugens Thunberg, 1789 has its identity fixed (Diptera: Tabanidae: Pangoniinae). AB - In preparing our world catalog of Bombyliidae (Evenhuis & Greathead 1999), we attempted to find any and all names that were or could possibly be attributed to the family. One of these in the latter category, Bibio lugens Thunberg, 1789, collected from the Cape of Good Hope in South Africa, was treated at the end of the catalog as Unplaced Species in Bombyliidae (Evenhuis & Greathead 1999: 528) since access to the type specimen was not feasible at the time and no images existed. All we could go on was its vague original description and placement of the name in Thunberg's paper (1789: 89) in close association with other Bombyliidae. PMID- 29245488 TI - Two new species of Xestia Hubner, 1818 (Lepidoptera, Noctuidae) from Bhutan and China. AB - Xestia Hubner, 1818 is a diverse and widespread Noctuinae genus, most of the known species occur in the Holarctic and the rest in Africa. Due to the expeditions to the hardly explored area of Asia, new species of Xestia have been recognized and described during the last years (Gyulai et al. 2011, 2013; Gyulai & Ronkay 2016). A German expedition (Ratzel, Hauenstein, M. Falkenberg & Trusch) led to the high altitude region of western Bhutan, collected a series of a rather small Perissandria Warren, 1909-like species, of which the genitalia show, surprisingly, the typical features of Xestia, displaying conspicuous external and genitalia differences, comparing with the Tibetan Xestia lithoplana Hreblay, Ronkay & Plante, 1998. The second new species described here below, has already been under discussion for a long time. The genitalia slide was provided by the late Marton Hreblay, from the author's material and suspected by him as Paramathes Boursin, 1954. After the revision of the genus Paramathes (Varga et al 2015), the detailed study led to the recognition that it cannot be a Paramathes, but a hitherto unknown Xestia. Thus, the description of the two new species appears to be reliable and is presented below. PMID- 29245489 TI - Female polymorphism in Chilothrips strobilus (Thysanoptera: Thripidae), with the first description of the male. AB - Polymorphism and sexual dimorphism are common in insects. Thrips have been reported to exhibit intraspecific variation in body size, color and wing length (Mound 2005), also sexual dimorphism in abdominal pore plates, antennal sensoria and fore leg armature (Tyagi et al. 2008). Chilothrips Hood is a small genus that currently comprises seven species (ThripsWiki 2017), three from USA, one from Japan, and three from China. No male has been reported in the three species from China, C. strobilus, C. jiuxiensis and C. hangzhouensis (Hu & Feng 2015), and C. strobilus was described on three female specimens from cones of Pinus in Liaoning Province, northeastern China (Tong & Zhang, 1994). Recently, we have surveyed different parts of northeastern China and collected many male individuals of C. strobilus. We have observed that this species shows sexual dimorphism in mouth cone length, and remarkable variation in form of abdominal segment X among females. PMID- 29245490 TI - Notes on the genus Epsilon de Saussure, 1855 (Hymenoptera: Vespidae: Eumeninae) with description of a new species. AB - The genus Epsilon de Saussure, 1855, is newly recorded from the Moluccas. New distributional records on Epsilon grandipunctatum Gusenleitner, 1996 are provided. Epsilon rufipes Selis, sp. nov. (Moluccas, Aru islands) is described and figured. PMID- 29245491 TI - Generic revision of the large-winged mite superfamily Galumnoidea (Acari, Oribatida) of the world. AB - Genus-level taxa in the oribatid mite superfamily Galumnoidea (Acari, Oribatida) are revised based on morphology of adults and a previously published phylogenetic analysis. We give a concise overview of the general morphology of Galumnoidea, diagnoses and a key for families, genera, and subgenera, and a taxonomic list with two families, 39 genera, 9 non-nominal subgenera, and 590 species. The following nomenclatorial changes to genus-group taxa resulted from our revision: Allogalumna (Allogalumna) Grandjean, 1936 (=Xenogalumna Balogh, 1960(b) syn. nov.), Flagellozetes (Cosmogalumna) Aoki, 1988 comb. nov. (from Galumna (Cosmogalumna)), Flagellozetes (Variogalumna) Mahunka, 1995 stat. nov., Galumna (Galumna) Heyden, 1826 (=Rostrogalumna Engelbrecht, 1973 syn. nov.), Pilogalumna Grandjean, 1956(a) (=Disparagalumna Hammer, 1973 syn. nov.), Trichogalumna (Tanzanycha) Kocak & Kemal, 2008 stat. nov., Galumnella Berlese, 1916(a) (=Monogalumnella Mahunka, 1986 syn. nov. =Trichogalumnella Mahunka, 1992 syn. nov., =Bigalumnella Mahunka, 1994 syn. nov.). The following changes are made to species-group nomenclature: Angulogalumna areolata (Stary, 2005) comb. nov. (from Cuspidogalumna) et stat. ressur. (=Galumna (Angulogalumna) staryi Subias, 2010 syn. nov. replacement name for secondary homonym Galumna (Angulogalumna) areolata (Stary, 2005)), Allogalumna (Allogalumna) longula (Balogh, 1960(b)) comb. nov. (from Xenogalumna), Flagellozetes (Cosmogalumna) areticulata (Ermilov, Sandmann, Klarner, Widyastuti & Scheu, 2015(d)) comb. nov. (from Galumna (Cosmogalumna)), F. (C.) dongnaiensis (Ermilov & Anichkin, 2013) comb. nov. (from Galumna (Cosmogalumna)), F. (C.) ekaterinae (Ermilov & Friedrich, 2016(b)) comb. nov. (from Galumna (Cosmogalumna)), F. (C.) hiroyoshii (Nakamura & Fujikawa, 2004) comb. nov. (from Galumna (Cosmogalumna)), F. (C.) ornata (Aoki, 1988) comb. nov. (from Galumna (Cosmogalumna)), F. (C.) imperfectus (Aoki & Hu, 1993) comb. nov. (from Galumna (Cosmogalumna)) and stat. ressur., (=Galumna (Cosmogalumna) praeoccupata Subias, 2004 syn. nov. replacement name for secondary homonym Galumna (Cosmogalumna) imperfecta (Aoki & Hu, 1993)), F. (C.) sumatrensis (Ermilov, Sandmann, Klarner, Widyastuti & Scheu, 2015(d)) comb. nov. (from Galumna (Cosmogalumna)), F. (C.) tenensis (Ermilov, Vu & Nguyen, 2011) comb. nov. (from Galumna (Cosmogalumna)), F. (C.) vladopesici (Ermilov & Corpuz-Raros, 2015(c)) comb. nov. (from Galumna (Cosmogalumna)), F. (C.) yonaguniensis (Aoki, 2009) comb. nov. (from Galumna (Cosmogalumna)), Flagellozetes (Variogalumna) singularis (Mahunka, 1995) comb. nov. (from Variogalumna), Galumna (Galumna) chrisengelbrechti Ermilov & Klimov, 2017 nom. nov. (=Rostrogalumna rostrata Engelbrecht, 1973, preoccupied by Sellnick (1922)), Galumna (Galumna) teuri Ermilov & Klimov, 2017 nom. nov. for Galumna imperfecta Hammer, 1972 (preoc. Banks, 1906), Pilogalumna tongaensis (Hammer, 1973) comb. nov. (from Disparagalumna), P. rostrata (Fujikawa, 2008) comb. nov. (from Disparagalumna), Setogalumna ambigua (Wallwork, 1977) comb. nov. (from Galumna (Galumna)), Trichogalumna (Tanzanycha) hesperis (Mahunka, 1984) comb. nov. (from Tanzanycha), Galumnella pulchella (Aoki & Hu, 1993) comb. nov. (from Porogalumnella), G. csavasorum (Mahunka, 1994) comb. nov. (from Bigalumnella), G. hauseri (Mahunka, 1992) comb. nov. (from Trichogalumnella), G. neotricha (Mahunka, 1986) comb. nov. (from Monogalumnella). In addition, Galumna pyramidalis Tseng, 1984 was removed from Galumnoidea and transferred to Neoribates (Oripodoidea, Parakalummidae): N. (Neoribates) pyramidalis (Tseng, 1984) comb. nov. (from Galumna). PMID- 29245492 TI - European species of the aphid genus Eulachnus Del Guercio, 1909 (Hemiptera: Aphididae: Lachninae): revision and molecular phylogeny. AB - The aphid genus Eulachnus in Europe is revised to include 12 species, using an integrative taxonomy approach, based on morphometric, molecular and biological traits. Fundatrix, apterous and alate viviparous female of a new species Eulachnus stekolshchikovi Kanturski sp. nov. are described. Neotypes are designated for E. agilis, E. brevipilosus and E. nigricola. Lectotypes are designated for E. alticola, E. cembrae, E. rileyi and E. tuberculostemmatus. New synonyms are proposed: E. abameleki syn. nov. (= Cinara pini), E. cretaceus syn. nov. (= E. agilis), E. tauricus syn. nov. (= E. rileyi), E. pallidus syn. nov. (= E. tuberculostemmatus). Eulachnus mingazzinii (near Cinara piniphila) and E. nigrofasciatus (near C. brauni) are regarded as incertae sedis. Full species status is given for E. garganicus stat. nov. and E. ibericus stat. nov. Apterous viviparous female of E. cembrae; apterous and alate viviparous females of remaining species are redescribed. Sexual morphs of E. agilis, E. alticola, E. cembrae, E. intermedius, E. nigricola, E. rileyi and oviparous female of E. tuberculostemmatus are fully redescribed and figured for the first time. Fundatrices of E. agilis, E. brevipilosus, E. cembrae, E. rileyi and E. tuberculostemmatus, sexuales of E. brevipilosus and the alate male of E. tuberculostemmatus are described and figured. A new host plant-Pinus cembra for E. brevipilosus is reported, and this species is recorded for the first time from Czech Republic. Eulachnus tuberculostemmatus is reported for the first time from Croatia. Phylogenetic studies, based on the COI and ITS2 molecular markers, are provided to visualize and discuss the relationships within the European species. COI barcodes are provided for seven species. PMID- 29245493 TI - Taxonomic review of the Craniophora s. l. (Lepidoptera, Noctuidae, Acronictinae) generic complex with description of 8 new genera and 13 new species. AB - Present paper contains the description of 8 new genera, separated from Craniophora (Harmandicrania, Graesericrania, Eurypterocrania, Turnerinycta, Fascionycta, Berionycta, Draudtinycta and Sinonycta gen. n.) and 13 new species (Harmandicrania barnandi, H. tathabayandi, H. brunneocinerea, H. sinoandi, H. peninsularis, H. nipponica, Berionycta limbata, B. ponticamima, B. nigra, B. orbicularis, B. behouneki, B. berioi and B. beckroberti spp. n.). Based on external and genital morphology and characters of the abdominal segments the taxonomic context of the genus Craniophora was reduced, the genus Megalonycta was extended. 22 new combinations and 11 new states were introduced. 8 lectotypes and 4 neotypes were designated. With 6 plates of morphological characters and 231 figures in 33 plates. The male and female last abdominal segments of most of the species are figured for the first time. PMID- 29245494 TI - An updated checklist of Echinoderms from Indian waters. AB - Species checklists enlist the species available within the defined geographical region and thus serve as essential input for developing conservation and management strategies. The fields of conservation biology and ecology confront the challenge of inflated biodiversity, attributed to non-recognition of taxonomic inconsistencies such as synonyms, alternate representation, emendations etc. Critical review of the checklists and distributional records of Phylum Echinodermata from Indian waters and subsequent validation of species names with World Register of Marine Species (WoRMS) database, revealed that the current literature included 236 incorrect entries comprising of 162 synonyms, 15 emendations, 5 nomina dubia, 1 nomen nudum, 40 species under alternate representation, 9 species with author misnomer, 1 subspecies and 1 unaccepted. The 226 species found to be mixed with valid names and a revised checklist was prepared. The revised and updated checklist holds 741 species of echinoderms comprising of 182 asteroids (24.56%), 70 crinoids (9.45%), 138 echinoids (18.62%), 179 holothuroids (24.16%) and 172 ophiuroids (23.21%), placed under 28 orders and 107 families. This paper discusses the cause for taxonomic inflation and argues that such taxonomic inconsistencies alter our interpretations of a species including its inaccurate distribution and, could possibly impede the country's conservation and management efforts. PMID- 29245495 TI - The generic classification of the Trochilini (Aves: Trochilidae): Reconciling taxonomy with phylogeny. AB - The generic nomenclature of the hummingbirds is unusually complicated. McGuire et al.'s (2014) recent phylogeny of the Trochilidae based on DNA sequence data has greatly clarified relationships within the family but conflicts strongly with the traditional classification of the family at the genus level, especially that of the largest and most recently derived clade, the Trochilini or "emeralds". We recently presented a historical review of this classification and the generic modifications required by the Code of the International Commission on Zoological Nomenclature. Herein we present a revised generic classification of the Trochilini based upon McGuire et al.'s genetic data, while producing diagnosable generic groupings and preserving nomenclatural stability insofar as possible. However, this generic rearrangement has necessitated the resurrection of nine generic names currently considered synonyms, the synonymization of seven currently recognized genera and the creation of one new genus. The generic changes we recommend to the classification are drastic, and we summarize these in tabular form in comparison with the three most recent classifications of the Trochilini. Where appropriate, we outline alternatives to our proposed arrangement. The classification treats 110 species in 35 genera, including two species that remain unplaced for lack of genetic samples. PMID- 29245496 TI - Morphotaxonomic revision of species-groups of Simulium (Simulium) (Diptera: Simuliidae) in the Oriental Region. AB - Species of eight species-groups (seven named and one unnamed) of Simulium (Simulium) Latreille are revised chiefly based on the adult female and male genitalia. Four species-groups are each divided into more than two groups. Thus, the S. christophersi species-group is divided into two (S. christophersi and S. nebulicola species-groups), the S. griseifrons species-group into six (S. griseifrons, S. grossifilum, S. chungi, S. crocinum, S. indicum and S. yadongense species-groups), the S. malyschevi species-group into two (S. malyschevi and S. pavlovskii species-groups), and the S. melanopus species-group into three (S. melanopus, S. dumogaense and S. iridescens species-groups). The S. crassifilum species-group is merged with the S. variegatum species-group. Simulium fulvipes (Ono) of the former S. malyschevi species-group and S. dentastylum Yang, Chen & Luo of Simulium s. str. species unplaced to species-group are removed from the subgenus Simulium because their male styles are subequal in length to the coxites. A revised classification of species of the 15 species-groups including eight new species-groups of Simulium (Simulium) is presented. Keys to 20 species groups of Simulium (Simulium) in the Oriental Region are provided for adult females and males. PMID- 29245497 TI - A new species of direct-developing frog of the genus Pristimantis (Anura: Terrarana: Craugastoridae) from Cordillera del Condor, Ecuador, with comments on threats to the anuran fauna of the region. AB - A new frog in the genus Pristimantis is described from a cloud forest on the western flanks of the Cordillera del Condor and eastern Andean slopes in the province of Zamora Chinchipe, southeastern of Ecuador. We inferred its phylogenetic position using DNA sequences of mitochondrial and nuclear genes. The new species is strongly supported as part of a clade that includes P. ardalonychus, P. cajamarcensis, P. ceuthospilus, P. chalceus, P. minutulus, P. luteolateralis, P. parvillus, P. ockendeni, P. unistrigatus, and P. walkeri. It can be distinguished from all other species from Cordillera del Condor and congeneric species by the unique combination of the following characters: (1) iris light blue with black reticulations; (2) skin of dorsum finely shagreen with scattered pustular tubercles and absence of dorsal folds; (3) tympanic membrane and tympanic annulus visible; (4) snout rounded in dorsal and lateral view; (5) upper eyelid bearing two or three enlarged subconical tubercles; (6) cranial crest absent; (7) males lacking vocal sac and slits; and (8) venter uniformly bright red, light red, salmon or orange. The new species is most closely related to P. ardalonychus, P. cajamarcensis, P. ceuthospilus, P. ockendeni and P. unistrigatus. We consider the new species to be Endangered following IUCN criteria because it has been severely affected by large scale open-pit mining in some localities. Currently, the amphibian fauna of the Cordillera del Condor and nearby protected areas are threatened by large-scale copper and gold mining projects with devastating effects on ~20 species, including several undescribed ones. PMID- 29245498 TI - Description of two new species closely related to Doryctobracon areolatus (Szepligeti, 1911) (Hymenoptera, Braconidae), based on morphometric and molecular analyses. AB - This study clarifies the identity of two morphs that appear similar but not identical to the braconid wasp Doryctobracon areolatus (Szepligeti), by analyses of fore wing morphometry and the ITS2 and D2 region of 28S ribosomal DNA. Wing measurements of D. areolatus and the two morphs, one with a yellow stigma and one with a brown stigma, from several Brazilian localities, were taken and subjected to geometric morphometry. Evaluation of 20 anatomical points on the fore wing by means of multivariate analysis revealed that these morphs consistently differ from D. areolatus. Intraspecific size variation in both molecular markers (ITS2 and 28S-D2 rDNA) was also detected among populations of D. areolatus from the states of Amapa, Sao Paulo, Goias, and Tocantins, but no such difference was observed among samples of the two morphs. However, high sequence variability was observed for both markers among D. areolatus and these morphs. Morphometric analysis yielded similar results and produced dendrogram congruent with those based on the molecular markers, also indicating that D. areolatus corresponds to a complex of cryptic species. Therefore, our morphometric and molecular data, in addition to revealing that D. areolatus includes cryptic species, showed that the unidentified morphs actually represent two distinct, previously undescribed species of Doryctobracon. These new taxa are formally described herein, as D. whartoni sp. nov. and D. adaimei sp. nov. PMID- 29245499 TI - New species and new records of the family Laelapidae (Acari: Mesostigmata) from Republic of Korea. AB - This paper reports on nine species of mites of the family Laelapidae associated with insects and soil in Republic of Korea: Cosmolaelaps hortensis Ishikawa from Allomyrina dichotoma (Coleoptera: Scarabaeidae), and C. chianensis (Gu), C. hrdyi (Samsinak), Cosmolaelaps sejongi sp. nov., Gymnolaelaps laevis (Michael), Holostaspis mooni sp. nov., Hypoaspis longicaudus sp. nov., Laelaspis mandibularis (Ewing) and Ololaelaps wangi Bai et. al. from soil. This is the first record of Gymnolaelaps, Holostaspis and Laelaspis from Republic of Korea. The new species are described and illustrated from adult females and additional morphological characters that complement the description of Ololaelaps wangi Bai et. al. are presented. PMID- 29245500 TI - A new species of Sextonia Chevreux, 1920 (Crustacea: Amphipoda: Liljeborgiidae) from the Okhotsk Sea. AB - A new amphipod species, Sextonia caecus sp. nov., from the shelf of northern Sakhalin Island (Russian Far East) is described. A key to the amphipod species of the genus Sextonia is given. PMID- 29245502 TI - Early ontogeny of Tatia neivai (Ihering, 1930) (Osteichthyes, Auchenipteridae), a small catfish from Neotropical region. AB - The early development of Tatia neivai (Ihering 1930) was analyzed (i) to characterize its morphological, morphometric and meristic development; and (ii) to examine its possible ontogenic variation as a result of the development of structures and organs necessary for survival. Samples were collected in the Baia River, basin Parana River, Mato Grosso do Sul State, Brazil, between February 1999 and April 2000. After identification, the specimens were separated according to notochord development, and the morphometric and meristic characters were measured and counted. Forty-seven larvae and one juvenile with standard length ranging from 6.10 to 23.10 mm were analyzed. Larvae exhibit a cylindrical and highly pigmented body, small eyes, short intestine, terminal mouth, one pair of maxillary barbels and two pairs of mentonian barbels (relatively short). The juveniles presented a body shape similar to their adults. The total number of myomeres (33-35, 12 to 14 pre-anal and 20 to 23 postanal). Number of fin rays: dorsal I+4, anal I+9; pectoral I+5 and ventral six. During ontogeny, morphological changes observed in T. neivai have important ecological consequences, especially between flexion and postflexion stages (metamorphosis) when the larvae develop all necessary structures for its survival, such as locomotion and feeding. PMID- 29245501 TI - Exogoninae (Annelida: Syllidae) from Chilean Patagonia. AB - The subfamily Exogoninae was studied from samples collected in shallow waters of the fjords and channels of the Patagonian region of Chile. Two new species are described: Exogone yagan n. sp. and Erinaceusyllis carrascoi n. sp. The species Exogone heterosetoides, Erinaceusyllis bidentata and Erinaceusyllis perspicax are newly reported to Chile, as well as the genus Erinaceusyllis San Martin, 2005. Parapionosyllis brevicirra, Sphaerosyllis hirsuta and Salvatoria rhopalophora, n. comb., are also reported, with the latter redescribed. Finally, we redescribe Exogone anomalochaeta from Antarctica. Most of the species were found inside tubes of Chaetopterus cf. variopedatus; this habitat is new for Exogoninae. This research is a new taxonomic account of Syllidae in Chile and improves the knowledge of Exogoninae of the Patagonian region. PMID- 29245503 TI - Nephrotoma Meigen (Diptera, Tipulidae) from Xinjiang, China. AB - Only four species of the genus Nephrotoma were previously known to occur in Xinjiang. Here six species are added to the fauna of Xinjiang. Among them Nephrotoma kanasensis sp. nov., is described and illustrated as new, and the following three species are recorded from China for the first time: N. analis (Schummel, 1833), N. lundbecki lundbecki (Nielsen, 1907) and N. tenuipes (Riedel, 1910). A key to the species of Nephrotoma from Xinjiang is presented. PMID- 29245504 TI - A new species of Eupariini from Eocene Baltic amber (Coleoptera: Scarabaeidae: Aphodiinae). AB - Based on 10 specimens from Late Eocene Baltic amber, an extinct species of Eupariini (Coleoptera: Scarabaeidae: Aphodiinae), Airapus lithuanicus Tamutis, Alekseev, & Bukejs new species, is described and illustrated. The new species is compared with two known fossil representatives of Aphodiinae from Baltic amber. The generic placement of these two species, Saprosites succini (Zang, 1905) and Ataenius europaeus Quiel, 1910, is discussed, as are details of paleoecology for the new species. PMID- 29245505 TI - Two new tiger-moth species from Afrotropics with reviews of genera Pericaliella and Monstruncusarctia (Lepidoptera, Noctuoidea: Erebidae, Arctiinae). AB - Two new species, Pericaliella popoudinae Dubatolov, sp. nov. from Rwanda, and Monstruncusarctia anikini Dubatolov, sp. nov. from Uganda are described in comparison with related species, Pericaliella melanodisca (Hampson, 1907) from Uganda, and Monstruncusarctia aurantiaca (Holland, 1893) from Gabon and West Africa. Habitus and male genitalia are illustrated. PMID- 29245506 TI - Description of a new species of Saliocleta Walker, 1862 (Lepidoptera, Notodontidae, Spatalinae, Ceirini) and description of S. notia Schintlmeister, 1997 female from Thailand. AB - One new Saliocleta (type-species nonagrioides Walker, 1862), S. puyak sp. n., and the female of S. notia Schintlmeister, 1997 are described from Northern Thailand. The male genitalia structure of Saliocleta is examined in detail. PMID- 29245507 TI - First record of the genus Parasitorhabditis Fuchs, 1937 (Rhabditida, Nematoda) from Iran with notes on morphological and molecular characters of the Iranian population of P. obtusa (Fuchs, 1915) Chitwood & Chitwood, 1950. AB - Parasitorhabditis obtusa is reported from Iran for the first time. The studied population is characterised with its morphological and molecular data. Morphological characters of the recovered population is in agreement with the currently available data of the species. In molecular phylogenetic studies using partial sequences of 28S rDNA D2/D3 fragment, the species formed a clade with two other isolates of the species with maximal Bayesian posterior probability (1.00) and maximum likelihood bootstrap values (100). The species was in association with bark samples of dead coniferous trees having galleries of bark beetles. It was also recovered from inside of the body of the Mediterranean pine beetle, Orthotomicus erosus, representing a new insect host for this nematode species. PMID- 29245508 TI - Biodiversity and notes on carabid beetles from Angola with description of new taxa (Coleoptera: Carabidae). AB - An annotated list of species of carabids sampled in Angola during three entomological trips is presented. A total of 111 species/subspecies were identified and some ecological remarks as well as its known distribution in this country are provided. Perigona liboloensis sp. n., Lasiocera schuelei sp. n. and Galerita procera capelai ssp. n., are described. New records of some genera and species previously unknown from Angola are given. Further, two dichotomic keys are made available for the identification of Perigona (s. str.) species of Africa and Lasiocera species of southern Africa, respectively. PMID- 29245509 TI - Deep-water scleractinian corals (Cnidaria: Anthozoa) from 2010-2011 INDEMARES expeditions to the Galicia Bank (Spain, northeast Atlantic). AB - During surveys in the Galicia Bank (northeastern Atlantic) in the years 2010-2011 (INDEMARES project), 25 species of scleractinian corals corals were collected in a depth interval of 744-1764 m. Most interesting species are described and depicted. Additionally, species list and remarks are given for the 23 species dredged in the bank during the 1987 SEAMOUNT 1 expedition at 675-1125 m depth.From a literature review and new records from Galicia Bank given herein, 31 species of scleractinian corals are known from this seamount in a depth interval of 614-1764 m depth. Six are colonial and 25 solitary, with 17 occurring on hard bottoms and 14 on soft bottoms. Desmophyllum dianthus, Lophelia pertusa and Madrepora oculata are the most widely distributed species in both number of stations and depth range of specimens collected alive. Some species were recorded outside their previously known bathymetric ranges in the northeastern Atlantic. Javania pseudoalabastra is first documented for the Iberian Peninsula and Spanish faunas. Thrypticotrochus sp. is first collected from the Atlantic Ocean. PMID- 29245510 TI - On the genus Tylorida Simon, 1894 with the first record of the genus Atelidea Simon, 1895 from India (Araneae: Tetragnathidae, Leucauginae). AB - The tetragnathid spider genus Tylorida Simon, 1894 is reviewed in India. The relationship of Tylorida with Orsinome Thorell, 1890 is discussed and illustrated. The taxonomic significance of male chelicerae of Tylorida spp. is discussed and an identification key based on the features of male chelicerae to separate Indian Tylorida spp. is provided. A new species, Tylorida flava sp. nov. is described and illustrated. Two new transfers and four new synonyms are proposed: Orsinome marmorea Pocock, 1901 and Tylorida culta (O. Pickard Cambridge, 1869) are transferred to Tylorida and Mesida Kulczyn'ski, 1911 respectively, Tylorida cylindrata (Wang, 1991) and Tylorida sataraensis Kulkarni, 2014 are synonymised with Tylorida marmorea (Pocock, 1901) comb. nov., Tylorida nicobarensis (Tikader, 1977) is synonymised with Tylorida striata (Thorell, 1877) and Leucauge pondae Tikader, 1970 is synonymised with Tylorida ventralis (Thorell, 1877). The biology, natural history and intraspecific variations of T. marmorea comb. nov. are noted. The occurrence of intraspecific variations and colour polymorphism in T. ventralis is discussed and two colour morphs (Silver and Yellow morphs) and three varieties (varieties I, II & III) for the species are recognised. Additionally, the genus Atelidea Simon, 1895 is recorded for the first time from India and provided the description and illustration of Atelidea nona sp. nov.. The current distribution of Atelidea is mapped. PMID- 29245511 TI - Southern high latitude squat lobsters II: description of Uroptychus macquariae sp. nov. from Macquarie Ridge. AB - Squat lobsters have only recently been recorded from the Macquarie Ridge, which extends south between New Zealand and Antarctica. Among these, Uroptychus insignis (Henderson, 1885) was recorded for the first time outside the western Indian Ocean, exhibiting only subtle morphological differences. Reexamination of the Macquarie Ridge and Indian Ocean specimens attributed to U. insignis using morphological and molecular data revealed the Macquarie Ridge form to represent a separate species. Subtle but consistent morphological differences are evident and partial CO1 sequence data indicates that the specimens collected on Macquarie Ridge differ from those collected in the Indian Ocean by more than 7%. The Macquarie Ridge species is described herein as Uroptychus macquariae n.sp. Subtle morphological differences between the new species and U. insignis are discussed. PMID- 29245512 TI - Review of Nilodosis Kieffer (Diptera: Chironomidae: Chironominae), with description of a new species from South China. AB - The male, female and pupa of Nilodosis austrosinensis Tang & Cranston, sp. n., reared from 2 reservoirs of south China, are described. The male can be separated from congeners by the presence of few squamal setae, a relatively long spur on the mid- and hind legs, a characteristic superior volsella and distinctive pattern of all legs. The female can be separated by features of genitalia, namely the absence of a ventrolateral lobe and the dorsomesal lobe with the apex usually curved. The pupa is separable by a bare tergite VIII and by characteristic spinulation of the sternites. The generic diagnosis is emended and some problems alluded to. This is the first formal record of Nilodosis from the Oriental region, indeed the first outside the Afrotropical region. PMID- 29245513 TI - Descriptions of new species of the genera Camptochaeta Hippa & Vilkamaa and Corynoptera Winnertz (Diptera, Sciaridae) from the Holarctic. AB - Six species of the genus Camptochaeta Hippa & Vilkamaa, 1994 and four of the genus Corynoptera Winnertz, 1867 from the Holarctic region are newly described and illustrated: Camptochaeta chilkatensis sp. n. (USA: Alaska), C. curtipilosa sp. n. (USA: Colorado), C. exquisita sp. n. (USA: Oregon), C. fitzgeraldi sp. n. (USA: Oregon), C. fulvistylata sp. n. (Canada: British Columbia), C. pertenuis sp. n. (Russia: Krasnodarsk region), Corynoptera bocheri sp. n. (Greenland; Canada: Quebec), C. hyperborea sp. n. (Russia: Krasnodarsk region), C. hystricina sp. n. (RUSSIA: Krasnodarsk region) and C. tenuichaeta sp. n. (Russia: Krasnodarsk region). PMID- 29245514 TI - Review of Chinese species of the leafhopper genus Amrasca Ghauri (Hemiptera, Cicadellidae, Typhlocybinae), with description of a new species, species checklist and notes on the identity of the Indian cotton leafhopper. AB - The leafhopper genus Amrasca Ghauri from China is reviewed. Six species are included, of which three are reported for the first time from China. A new species, A. (Amrasca) complana Qin, Wang & Xu, sp. nov. is described based on specimens from south China. A complete checklist of the genus and an identification key to species in the Chinese fauna are provided. Jacobiasca curvata (Ahmed & Samad) comb. nov. is removed from Amrasca and A. (A.) singularis Einyu & Ahmed is treated as a species incertae sedis. Habitus photos of all Chinese Amrasca species and illustrations of male genitalia of the new species are also given. The male holotype specimen of Chlorita bimaculata Matsumura is here designated as the neotype of Empoasca biguttula Ishida to fix the identity of this economically important species and Sundapteryx Dworakowska is reinstated from synonymy as a subgenus of Amrasca. Thus, the correct scientific name of the Indian cotton leafhopper is Amrasca (Sundapteryx) biguttula (Ishida). PMID- 29245515 TI - Two new species of Mycterothrips (Thysanoptera: Thripidae) from Southwestern China. AB - Mycterothrips gongshanensis sp.n. and M. yelangi sp.n. are described from Southwestern China. Both species have been collected from tea (Camellia sinensis), and M. gongshanensis sp.n. is a potential pest in tea gardens. An identification key is provided to the Mycterothrips species recorded from China. PMID- 29245516 TI - Isometopus anlasi sp. nov. (Heteroptera: Miridae) from Turkey. AB - A new species of the genus Isometopus, Isometopus anlasi sp. nov. (Heteroptera: Miridae) is described based on both male and female specimens. Habitus of male, female and last instar nymph, and parameres are illustrated. Data on biology and plant associations of the new species are also recorded. Additionally, an updated key for the European and Middle Eastern species of Isometopus is provided. PMID- 29245517 TI - A new species of Palaeugoa Durante, 2012 from Sierra Leone (Lepidoptera, Erebidae, Arctiinae). AB - The Asura / Miltochrista generic complex (family Erebidae, subfamily Arctiinae, tribe Lithosiini) is one of the largest and taxonomically most difficult Lithosiini groups widely distributed in Afrotropical, Palaearctic, Oriental, and Indo-Australian regions. In Africa, the generic complex is represented by the genera Tumicla Wallengren, 1863 (= Asuroides Durante, 2008, syn. rev.), Afrasura Durante, 2009, Parafrasura Durante, 2012 and Palaeugoa Durante, 2012. The genus Palaeugoa was erected as monobasic for Xanthetis spurrelli Hampson, 1914 described from Ghana (Durante 2012). During the studies of West African Lithosiini materials deposited in the collection of the African Natural History Research Trust, I found a second, yet undescribed species of Palaeugoa collected in Sierra Leone. The description of the new species is given below. PMID- 29245518 TI - A new species of the Chaleponcus dabagaensis-group from Mount Rungwe, Tanzania-support for an extended concept of the Eastern Arc Mountains (Diplopoda, Spirostreptida, Odontopygidae). AB - Chaleponcus altirungwensis sp. nov. is described from Mount Rungwe, Tanzania. The new species belongs to the Chaleponcus dabagaensis group which is otherwise restricted to the Udzungwa Mountains and joins a growing set of taxa indicating close biogeographical connections between Mount Rungwe and the Eastern Arc Mountains in a strict sense. PMID- 29245519 TI - A new genus of Noctuidae (Lepidoptera) from China with the description of two new species. AB - Descriptions and diagnoses of a new genus Gracilisinensis gen. nov. and two new species G. vaiva sp. nov. and G. moha sp. nov. are provided. The new genus is placed into the subfamily Psaphidinae, tribe Psaphidini. It is most closely related to the genus Diphtherocome Warren. PMID- 29245520 TI - New substitute name for Sobara Oman, 1949 and recognization on Chinese Orientus species (Hemiptera: Cicadellidae: Deltocephalinae). AB - Oman (1949) established the leafhopper genus Sobara with Eutettix palliolata Ball, 1902 as its type species. This genus belongs to the tribe Athysanini Van Duzee, 1892 of subfamily Deltocephalinae (Hemiptera: Cicadellidae). Until now, there have been no further reports on this genus, and only one species is recorded from southwest USA. PMID- 29245521 TI - The genus Clubiona Latreille, 1904 (Araneae: Clubionidae) in the Maghreb, with notes on the genevensis group and new records from the Mediterranean Region. AB - A survey of the members of the genus Clubiona Latreille, 1904 in the Maghreb is presented. The presence of Clubiona comta C. L. Koch, 1839, C. dinienis Simon, 1878, C. leucaspis Simon, 1932, C. phragmitis C. L. Koch 1843 and C. vegeta Simon, 1918 is confirmed. Clubiona pseudosimilis Mikhailov, 1990, from the eastern Mediterranean is new to Africa and Portugal. A specimen of C. neglecta O. Pickard-Cambridge, 1862, cited from Morocco in the past, was misidentified and appears to be C. pseudoneglecta Wunderlich, 1994. The species is new to Algeria and Spain. Two new synonyms are revealed: Clubiona baborensis Denis, 1937 from Algeria = C. diniensis Simon, 1878 N. Syn. and Clubiona venusta Pavesi, 1880 from Tunisia = Selamia reticulata (Simon, 1870) N. Syn. Clubiona mandibularis Lucas, 1846 is considered a Nomen dubium. The comta group is redefined and the "genevensis subgroup" is elevated to species group, including two subgroups. A key and illustrations to the species of the genevensis group are presented and all the species occurring in the Maghreb are illustrated. PMID- 29245522 TI - Fixation, description and DNA barcode of a neotype for Botryllus schlosseri (Pallas, 1766) (Tunicata, Ascidiacea). AB - Botryllus schlosseri is a widespread colonial ascidian commonly considered cosmopolitan and amply used as model for researches ranging from developmental biology to immunobiology. Recently, molecular data lead to hypothesize that the species named B. schlosseri may consist of more than a single taxon. Indeed, five highly divergent clades, named A-E, have been genetically identified and are referred as cryptic species. In this context, and lacking both a type and a detailed morphological description, we believe that it is necessary, as a taxonomic reference point, to designate a neotype and re-describe the species. Therefore, a sample from the Lagoon of Venice (Adriatic Sea, Italy) was deposited as neotype in the Natural History Museum of Venice (Italy), preserved both in formalin and in 90% ethanol. Here we provide a morphological description of the suggested neotype of B. schlosseri that takes into account several developmental stages (oozooid, zooid of first blastogenic generations, and mature zooid) and is carefully compared with the previous descriptions of samples coming from other European and non-European localities. Finally, we associate our morphological description to a "DNA barcode", consisting in a long fragment of the mitochondrial COI gene. Our description is associated to clade A, although at now we cannot guarantee that this association is univocal. PMID- 29245523 TI - A new species of Raricirrus (Annelida: Cirratuliformia) from deep-water sunken wood off California. AB - The genus Raricirrus is characterized by the absence of feeding palps, presence of filamentous branchiae, posterior segments shorter and wider than preceding ones, and by having diverse types of chaetae, including serrate capillaries, long natatory capillaries, falcate and finely pectinate, coarsely serrate chaetae and simple curved spines. A new species of Raricirrus is proposed based on morphological and mitochondrial DNA data. The K2P distance comparison of 16S and COI sequences from Raricirrus specimens collected from sunken wood in the deep sea (3100 m) off Monterey, California, differed in less than 0.02 in both loci from those of another undescribed Raricirrus species collected at deep-sea hydrothermal vents in the East Scotia Ridge, Southern Ocean, and they are considered conspecific. This species is unique among its congeners by the lack of serrate chaetae, presence of acicular spines and neuropodial capillaries. Raricirrus jennae sp. nov. has only long capillaries on anterior notopodia, straight acicular spines with companion capillaries on posterior notopodia (from chaetigers 15-20), and similar acicular spines and companion capillaries throughout neuropodia. Raricirrus jennae sp. nov. appears to be an opportunistic and widely distributed species. The genus Raricirrus is emended to include the presence of acicular spines and keys to all cirratulid and ctenodrilid genera and Raricirrus species are presented. PMID- 29245524 TI - Sinorhodeus microlepis, a new genus and species of bitterling from China (Teleostei: Cyprinidae: Acheilognathinae). AB - A new genus and species, Sinorhodeus microlepis gen. et sp. nov., is described from a tributary of the Yangtze River, in Chongqing City, China. Sinorhodeus gen. nov. can be distinguished from four closely related genera, Paratanakia, Pseudorhodeus, Rhodeus, and Tanakia, by the following combination of characters: pharyngeal teeth 0,0,4-4,0,0, longitudinal scales 41-46, white spots on dorsal fin rays absent, a black blotch on dorsal fin in juvenile absent, and less developed wing-like yolk sac projections in larvae. Phylogenetic analysis of one mitochondrial gene and six nuclear genes supports the establishment of the new genus. PMID- 29245525 TI - Schistura larketensis, a new cavernicolous fish (Teleostei: Nemacheilidae) from Meghalaya, Northeast India. AB - Schistura larketensis, a new species of cavernicolous loach, is described from Khung, a limestone cave in Meghalaya, India. The species differs from Schistura papulifera, its only troglomorphic congener from northeast India, in having a smooth ventral surface of the head, the presence of a small cylindrical axillary pelvic lobe, and the presence of three pores in the supratemporal canal of the cephalic lateral-line system. Apart from these differences, the species can be immediately distinguished from all other species of Schistura from the Brahmaputra River and neighboring basins by the complete absence (or only vestigial presence) of eyes. PMID- 29245526 TI - Checklist of the echinoderm fauna of the Adriatic Sea. AB - This paper presents a checklist of echinoderm species in the Adriatic Sea. The checklist is based on the review of the available literature data, with temporal coverage from the end of the 18th century to the present day, including the most recent investigations of benthic communities. A total of 108 species have been recorded: 2 species from class Crinoidea, 23 species from class Asteroidea, 22 species from class Ophiuroidea, 22 species from class Echinoidea and 39 species from class Holothuroidea. Non-indigenous echinoderm species have not been observed. PMID- 29245527 TI - Annotated checklist of aquatic beetles (Coleoptera) and true bugs (Heteroptera) in the Azores Islands: new records and corrections of colonization status. AB - In comparison with other Macaronesian archipelagos, Azorean freshwater macroinvertebrates are characterized by a smaller list of species at the archipelago regional scale. Although knowledge of the freshwater fauna of the Azores has improved in recent years through the implementation of the "Water Framework Directive", we are still far from having a complete inventory and even further from knowing the precise distribution and biology of each species. The lack of knowledge about Azorean freshwater species is coupled with the vulnerability of their habitats to anthropogenic disturbances and the introduction of non-native species. In contributing to overcome Wallacean and Hutchinsonian biodiversity shortfalls, we here provide expanded knowledge on the distribution and biology of the freshwater species of Coleoptera and Heteroptera in the Azores. We compile data from various fieldwork performed between 2006 and 2014, encompassing four islands in the archipelago. We detected new records of two aquatic Heteroptera species (belonging to the families Corixidae and Notonectidae) and six of aquatic Coleoptera (belonging to the families Dytiscidae, Gyrinidae, Hydrophilidae and Hydraenidae) in these islands, and also a new record (Enochrus fuscipennis) for the Azorean archipelago. We also suggest that the introduced colonization status of three Coleoptera species of the family Hydrophilidae should be reformulated as possibly native, with implications for conservation. PMID- 29245528 TI - Tobrilus saprophagus sp. n. and Epitobrilus interstitialis sp. n. (Nematoda, Triplonchida) from Lake Baikal, Russia. AB - Two new nematode species found in Lake Baikal (Russia) are described and illustrated. Tobrilus saprophagus sp. n. is morphologically close to T. bekmanae Tsalolikhin, 1975 and T. securus Gagarin & Naumova, 2011. The new species differs from T. bekmanae by the less slender tail (? c' = 2.9-3.9, ? c' = 3.5-6.8 vs ? c' = 6, ? c' = 9 in T. bekmanae), narrower labial region (24-30 um vs 35-38 um in T. bekmanae), shorter outer labial setae (10-12 um vs 13-18 um in T. bekmanae) and shorter stoma (25-32 um vs 40-56 um in T. bekmanae). T. saprophagus sp. n. differs from T. securus by the shorter and less slender tail (? c = 11.5-16.1, c' = 2.9-3.9, ? c = 8.8-13.1, c' = 3.5-6.8 vs ? c = 6.7-8.4, c' = 6.3-9.3, ? c = 7.1 8.4, c' = 6.6-7.7 in T. securus), longer outer labial setae (10-12 um vs 6.5-9.0 um in T. securus) and shorter spicules (45-48 um vs 52-58 um in T. securus). Epitobrilus interstitialis sp. n. is close to E. steineri (Micoletzky, 1925), but differs by the longer body (3.88-5.97 mm vs 2.14-3.35 mm), longer tail (250-335 um vs 160-199 um for males), longer outer labial setae (27-40 um vs 22-25 um) and longer spicules (73-78 um vs 51-71 um). Diagnostic morphological characters of males of valid species of the genus Epitobrilus Tsalolikhin, 1981 are given. Tobrilus (Epitobrilus) medius G. Schneider, 1916 (apud Tsalolikhin, 1980) is synonymized with the species Eutobrilus peregrinator Tsalolikhin, 1983. PMID- 29245529 TI - Hexapleomera urashima sp. nov. (Crustacea: Tanaidacea), a tanaidid epibiotic on loggerhead sea turtles at Yakushima Island, Japan. AB - We describe Hexapleomera urashima sp. nov. from the carapaces of loggerhead sea turtles (Caretta caretta) on Yakushi-ma Island, southwestern Japan, the primary nesting site for the North Pacific population of this turtle. Hexapleomera urashima closely resembles H. edgari Bamber collected from Australian loggerheads (South Pacific population), sharing a uropod with four articles and maxillipedal endites with distal spiniform setae, but differs in having the maxillipedal coxa with two simple setae, the maxillipedal endite with two tiny dorsosubdistal and two distal spiniform setae, the labial palp fused to the outer lobe of the labium, and the basal article of pleopod 3 without inner setae. Several characters (e.g., size or presence/absence of a dorsal triangular process on the male fixed finger; number of inner setae on the pleopodal endopod), assumed to be diagnostic for species in Hexapleomera, actually vary within H. urashima, indicating that reassessment of species diagnoses is warranted. Hexapleomera urashima showed two COI haplotypes differing by one substitution, but separated from representatives of four other genera by 32.2-48.4% K2P distance. Indices of saturation substitution indicated that COI is not useful for phylogeny reconstruction within Tanaididae. PMID- 29245530 TI - Morphological, histopathological and molecular characterization of Thelohanellus pathankotensis n. sp. (Cnidaria: Myxosporea: Myxozoa) infecting an Indian minor carp, Labeo dero Hamilton, 1822 from a cold water wetland in Punjab (India). AB - A new myxobolid, Thelohanellus pathankotensis parasitizing gill lamellae and caudal fins of the Indian minor carp Labeo dero has been described using light microscopy, histopathology and molecular analyses. The fish host was collected from a cold water wetland, Ranjit Sagar Wetland, Punjab, India located 32 26 30 N Latitude and 75 43 30 E Longitude. The prevalence of infection was 30%. The plasmodia were located in the gill lamellae and the caudal fins were cylindrical and whitish, 0.8-1.0 mm in size containing about 150-300 myxospores. The myxospores had a mean length of 9.70 +/- 0.50 um, width 3.85 +/- 0.27 um, mean length of polar capsule 3.0 +/- 0.15 um, width 2.68 +/- 0.08 um. The 18S rDNA nucleotide with 1098 bp of Thelohanellus pathankotensis n. sp. (accession number KU516661) clustered phylogenetically with other myxozoan parasites, with the species most closely related was T. sp. PBS- 2015 with 92% homogeneity and T. boggoti with 98% homogeneity. The intensity of infection or the mean abundance was determined by the gill plasmodial index (GPI) based on the number of countable plasmodia. The myxospores of the present species differed from others previously described infecting the hosts of family Cyprinidae, same tissue location and geographical location. PMID- 29245531 TI - Contributions to the taxonomy of Vilga Stal (Hemiptera, Coreidae, Pseudophloeinae) with the description of a new species from southern Brazil. AB - A new species belonging to the subgenus Laevivilga is described, as well as the female of Vilga (L.) sanctipauli and male of V. (L.) brasiliensis that were unknown until now. We complement original descriptions, update the distribution records and include the new species in the Dolling's identification key to species of Vilga. PMID- 29245532 TI - Four new earthworm species of Kazimierzus Plisko, 2006 (Clitellata, Kazimierzidae). AB - Four new species of Kazimierzus are described from the Western Cape and Northern Cape, South Africa: K. kleinoodi sp. n., K. nietvoorbiji sp. n., K. nieuwoudtvillensis sp. n., and K. phumlani sp. n. Kazimierzus kleinoodi is distinguished from the other species of this genus by the position of the calciferous glands in 9 and paired spermathecae in five segments. The position of the spermathecae in 11/12-15/16 as well as the position of the calciferous glands in 11 separates K. nietvoorbiji from the other new species. Kazimierzus nieuwoudtvillensis is distinguished from the others by the position of the clitellum (12-25) and spermathecae in four rows. The combination of the position of the clitellum, three rows of spermathecae and the position of the calciferous glands in 10 distinguish K. phumlani from the other species. PMID- 29245533 TI - Oligoaeschna sirindhornae sp. nov., a new dragonfly species from Thailand (Odonata: Anisoptera: Aeshnidae). AB - Oligoaeschna sirindhornae sp. nov. is described from a male from Sakaerat Silvicultural Research Station, Nakhon Ratchasima Province in Thailand. It is the only known Oligoaeschna species recorded from Thailand since Oligoaeschna pramoti (Yeh, 2000) and Oligoaeschna minuta (Hamalainen & Pinratana, 1999) were transferred to the genus Sarasaeschna. PMID- 29245534 TI - The bees of Michigan (Hymenoptera: Apoidea: Anthophila), with notes on distribution, taxonomy, pollination, and natural history. AB - The state of Michigan occupies an area between the Great Plains and the northeastern United States, bordering four Great Lakes, with diverse biogeographical regions. Michigan also has the second most diverse agriculture in the country, with many crops that depend on bees for pollination. This unique combination provides a wide range of opportunities for bees to persist, yet there is no current published checklist of these important insects. This study was conducted to provide the first annotated checklist of the bee (Apoidea: Anthophila) fauna of Michigan, summarizing aspects of their taxonomy and behavior and to provide provisional conservation assessment. The list was compiled from a critical review of published literature, museum specimens, and database records, supplemented by new collections. In total, 465 species are included in the checklist, including 38 new records, however evidence for 13 species is poor, several more species require taxonomic revision, and the presence of additional species is expected. The exotic megachilid species Megachile apicalis Spinola, M. pusilla Perez (=concinna Smith, auct.) and Osmia taurus Smith are reported from Michigan for the first time. New state records of native species include Anthidium tenuiflorae Cockerell and Nomada alpha alpha Cockerell, both previously undocumented from eastern North America, and Nomada sphaerogaster Cockerell, which has rarely been recognized. The taxonomy of some bee species is clarified by the formal publication of 11 new synonymies (some previously reported online or in manuscripts). The following list cites junior synonyms first followed by the valid name: Andrena chippewaensis Mitchell 1960 = A. (Simandrena) wheeleri Graenicher 1904; Osmia hendersoni Cockerell 1907 = O. (Melanosmia) tarsata Provancher 1888; Osmia michiganensis Mitchell 1962 = O. (M.) subarctica Cockerell 1912 (new status, removed from synonymy with O. (M.) tersula Cockerell 1912); Sphecodes persimilis Lovell and Cockerell 1907 = S. davisii Robertson 1897; Sphecodes knetschi Cockerell 1898 = S. dichrous Smith 1853; Sphecodes carolinus Mitchell 1956 = S. coronus Mitchell 1956; Sphecodes stygius Robertson 1893 = S. mandibularis Cresson 1872; Sphecodes prostygius Mitchell 1960 = S. fattigi Mitchell 1956; Stelis vernalis Mitchell 1962 = S. coarctatus Crawford 1916; and Stelis michiganensis Mitchell 1962 = S. foederalis Smith 1854. Poorly known Andrena (Cnemidandrena) are discussed, including A. parnassiae Cockerell, a new state record, A. robervalensis Mitchell, and the extralimital A. runcinatae Cockerell. Of these, only A. robervalensis was considered in the subgeneric revision, but we recognize all three as valid species pending further study. Nomada binotata (Robertson 1903) and N. quadrimaculata (Robertson 1903) are removed from synonymy with N. ovata (Robertson 1903), based on examination of the lectotypes. A new species, Triepeolus eliseae Rightmyer, the eastern representative of the verbesinae species group, is described. A putative undescribed species, Osmia aff. trevoris, is documented, but requires additional study for its status to be fully resolved. A rich bee fauna is documented that includes geographically-restricted species, rare and regionally-declining species, and economically-important species, providing information for ongoing conservation planning and future analysis of trends in bee populations. PMID- 29245535 TI - Revision of the Anotylus sculpturatus group (Coleoptera: Staphylinidae: Oxytelinae) with descriptions of seven new species from China. AB - The Anotylus sculpturatus species group is one of the relatively well-defined assemblages within the very large genus Anotylus Thomson, 1859 of the subfamily Oxytelinae (Coleoptera: Staphylinidae). This paper briefly examines the species group classification of the genus Anotylus and concentrates mainly on the taxonomy of Anotylus sculpturatus group. The paper reviews the Chinese fauna of 13 species, with seven new species described here: Anotylus benisculptilis sp. nov., A. nigelisculptilis sp. nov. and A. brevisculptilis sp. nov. from Sichuan, A. varisculptilis sp. nov. from Yunnan and Sichuan, A. nitelisculptilis sp. nov. from Sichuan, Ningxia, Gansu and Shaanxi, A. rectisculptilis sp. nov. from Zhejiang, and A. extrasculptilis sp. nov. from Yunnan. Lectotypes are designated for Anotylus chinkiangensis (Bernhauer, 1938) and A. subsericeus (Bernhauer, 1938). Color figures and line-drawings are provided for all the new species and most of the earlier known species from China. A preliminary key to the species groups of Anotylus and a key to the species of Anotylus sculpturatus group, mainly focused on Chinese fauna, are also included in the paper, so as to benefit the classification and identification in the future. PMID- 29245536 TI - Redescription of the Afrotropical genus Crassabwa Lugo-Ortiz & McCafferty 1996 (Ephemeroptera: Baetidae: Protopatellata). AB - Larvae, subimagoes, imagoes of both sexes and eggs of Crassabwa flava (Crass 1947) are described based on reared material from South Africa, Zambia and Tanzania. Larvae, subimagoes, imagoes of both sexes and eggs of a new species Crassabwa ludmilae sp. n. are described based on reared material from Zambia, Guinea and Mali. Larvae and details of a male subimago extracted from a mature larva of a new species, Crassabwa ameliae sp. n., are described from Zambia, Guinea and Mali. Diagnosis of the genus Crassabwa Lugo-Ortiz & McCafferty 1996 is corrected. Among species formerly attributed to Crassabwa, the species originally described as Centroptilum loweae Kimmins 1949 is moved to Cheleocloeon Wuillot & Gillies 1993 and synonymized with Ch. excisum (Barnard 1932): Cheleocloeon excisum (Barnard 1932) = Cheleocloeon loweae (Kimmins 1949) comb. n., syn. n. The species formerly attributed to Crassabwa and originally described as Centroptilum badium Kopelke 1979 belongs to a new genus, which will be described in a separate paper by N. Kluge. Crassabwa is closely related to Susua Lugo-Ortiz & McCafferty 1998; the species originally described as Cheleocloeon sigiense Gillies 2001 is treated here as Susua sigiense comb. n.; redescription of Susua and argumentation of this new combination will be given in a separate paper. PMID- 29245537 TI - Generic synopsis of the jumping plant-lice (Hemiptera: Sternorrhyncha: Psylloidea) from Colombia. AB - Jumping plant-lice (Hemiptera: Sternorrhyncha: Psylloidea) are a group of phloem feeding insects with nearly 4000 described species. Previous records from Colombia comprise 19 genera of all eight known families. The revision of material deposited in six Colombian and three foreign museums yielded another nine genera that constitute new country records. Material from 16 departments was examined. Each genus is diagnosed and information is provided on biology, damage and host plants. Local distribution maps and a generic key for the identification of adults are provided. PMID- 29245538 TI - Eleven new species of the spider genus Althepus Thorell, 1898 (Araneae, Ochyroceratidae) from Thailand. AB - Eleven new Althepus species of the spider family Ochyroceratidae are reported from Thailand: A. duan sp. nov., A. duoji sp. nov. (male only), A. huoyan sp. nov., A. jiandan sp. nov., A. kuan sp. nov., A. lakmueangensis sp. nov., A. languensis sp. nov., A. muangensis sp. nov., A. qiqiu sp. nov. (female only), A. tuqi sp. nov., A. xianxi sp. nov. All types are deposited in the Institute of Zoology, Chinese Academy of Sciences in Beijing, China (IZCAS). PMID- 29245539 TI - On the taxonomy of the genus Sidonis Mulsant, stat. nov. (Coleoptera: Coccinellidae: Chnoodini) with descriptions of new species from Brazil. AB - The subgenus Sidonis Mulsant, 1850 is elevated to generic status and two new species from Brazil are described and illustrated: Sidonis bira sp. nov. and Sidonis biguttata sp. nov. New geographic distribution records are provided. In addition, lectotypes of Sidonis consanguinea (Mulsant, 1850) and S. guttata (Sicard, 1912) are designated. Illustrations of diagnostic characters from five of six species of the genus, comments on the differences from similar species and a key to all recognized taxa are included. PMID- 29245540 TI - Taxonomic review of the Oriental flower beetle Coilodera penicillata species complex (Coleoptera: Scarabaeidae: Cetoniinae). AB - The taxonomy of the Coilodera penicillata Hope, 1831 (Coleoptera: Scarabaeidae: Cetoniinae) species complex, which is recognized by the black body and elytra with larger tomentose maculae, is revised. Six Indochinese species assigned to this complex, including C. grandimaculata new species from Tibet, China. Coilodera nigroscutellaris Moser, 1902 revised status and C. formosana Moser, 1910 revised status formerly treated as two subspecies of C. penicillata Hope, 1831 are elevated to species rank. The distribution of C. penicillata in China is confirmed based on examination of specimens from Yunnan and Tibet, and almost all previous Chinese literature records should be referred to C. nigroscutellaris. Coilodera dives (Gory & Percheron, 1833) revised status previously synonymized with C. penicillata is herein considered as a valid species based on the examination of types and additional specimens, and C. miksici Antoine, 1986 new synonymy is regarded as a junior synonym of C. dives. A lectotype is designated for Coilodera dives (Gory & Percheron, 1833). The record of C. mearesii (Westwood, 1842) in southeastern China is attributed to a misidentification of C. nigroscutellaris, and it is here newly recoreded from Tibet near the Nepal-China border. Diagnosis characters and intraspecific variations are illustrated for all six species, new distribution records and a key to species are also presented. Ecological information is provided for all species. PMID- 29245541 TI - Description of two smallest field crickets from South America, Laureopsis nauta Jaiswara gen. nov., sp. nov. and Perugryllus estiron Jaiswara gen. nov., sp. nov. (Orthoptera, Grylloidea, Gryllidae, Gryllinae). AB - Gryllinae are one of the most diverse and widely distributed cricket groups. However, in South America they are known only from 10 genera. We update this list by describing two new genera and species of field crickets i.e. Laureopsis nauta Jaiswara gen. nov., sp. nov. and Perugryllus estiron Jaiswara gen. nov., sp. nov. from Peru. PMID- 29245542 TI - A new endemic species of Willowsia from Florida (USA) and descriptive notes on all New World Willowsia (Collembola: Entomobryidae). AB - Four species of Willowsia have been reported from the Americas (W. buski, W. jacobsoni, W. mexicana, and W. nigromaculata), and to date, W. mexicana is the only member of the genus endemic to the New World. Here, Willowsia pyrrhopygia sp. nov. from Florida is described. Like W. mexicana, this new species has a native New World distribution and uninterrupted rib scale type, but can be separated by color pattern and chaetotaxy. Dorsal head chaetotaxy and other descriptive notes are provided to compliment to descriptions for W. buski, W. jacobsoni, W. mexicana, and W. nigromaculata. Comparative morphological analysis also reveals two unique character states among Entomobryinae-the outer maxillary lobe with two (not three) sublobal hairs and the absence of labial triangle seta r-shared only by endemic New World Willowsia and Americabrya, providing preliminary support for their independent evolution from a common New World ancestor. PMID- 29245543 TI - Relocation of Alona manueli Sinev & Zawisza 2013 and a new closely related species from the Ecuadorian Andes to the new genus Alpinalona (Cladocera, Chydoridae, Aloninae). AB - Alpinalona gen. nov. is described for two species found in high altitude localities of continental North America and South America: Alona manueli (Sinev & Zawisza, 2013) from the Neovolcanic Mexican Axis and Alpinalona cajasi gen. et sp. nov from El Cajas National Park (Ecuador). The new genus is separated from Hexalona and allies by the absence of limb VI and filter plate V; from Anthalona, Coronatella and the elegans-group by having seven setae on exopodite III, and by the presence of a well-developed seta 1 on the IDL of limb III; from Alona s. str. (quadrangularis-group) and Ovalona, by two main head pores, lateral head pores located close to main pores, and by a bilobed exopodite V; from Ovalona by the presence of seta (i) and inner setae 2-3 on limb I, and setae 4-5 of exopodite III being of same size; and from Alona s. lato by weakly developed marginal denticles of postabdomen, clusters of thin setulae on ventral surface of limb I, and by plumose setae 5-6 of exopodite IV. Alpinalona cajasi sp. nov. can be easily distinguished from A. manueli by the following characteristics: prominent posterodorsal angle of carapace; broader headshield; longer PP distance; and postanal marginal denticles organized into groups. PMID- 29245544 TI - Fauna of Plume Moths (Lepidoptera: Pterophoridae) of Garden Route National Park, South Africa. AB - Fourteen species of Pterophoridae are reported for the Garden Route National Park in South Africa. Four of them are described as new to science: Pselnophorus boldyrevae Kovtunovich & Ustjuzhanin sp. nov., Crassuncus kenzo Kovtunovich & Ustjuzhanin sp. nov., Crassuncus ermakovae Kovtunovich & Ustjuzhanin sp. nov., and Hellinsia birichevskayae Kovtunovich & Ustjuzhanin sp. nov. PMID- 29245545 TI - On the synonymy of some taxa of the genus Xylena Hubner (Lepidoptera, Noctuidae). AB - Xylena czernilai Volynkin, 2011 was described on the base of a single male from the Russian Altai Mts. (Volynkin 2011). Later, two externally similar taxa, Xylena alexander Benedek, Babics & Saldaitis, 2013 and Xylena andreas Benedek, Babics & Saldaitis, 2013 were described from Sichuan province, China each on the base of a single female (Benedek et al. 2013). In the same year, a female of X. czernilai was described by Volynkin & Knyazev (2013). The female genitalia of X. czernilai are surprisingly similar to those of the both Chinese species therefore we decided to use a DNA analysis to clarify the status of these three taxa. For the analysis we sampled a female of X. czernilai from the Russian Altai, a male of X. czernilai from the Russian Far East and the holotypes of X. alexander and X. andreas. The analysis of COI barcodes of the sampled specimens has shown that X. alexander and X. andreas are conspecific (the difference is 0.15 %), and their COI sequences differ from those of X. czernilai in 0.93 % only. Such difference is too small to treat Chinese populations as a distinct species (for example, the difference between X. czernilai and its closest relative X. vetusta (Hubner, [1813]) is 4.61% . The detailed morphological comparison of czernilai and vetusta has been given by Volynkin (2011) (Fig. 1) therefore here we synonymize X. alexander and X. andreas with X. czernilai. PMID- 29245546 TI - Is the taxonomy of Brachycephalus (Anura: Brachycephalidae) in need of rescue? A reply to Condez et al. (2017). AB - Brachycephalus is a fascinating genus of miniaturized frogs endemic to the Brazilian Atlantic Forest (Bornschein et al. 2016a). Given the many new species that have been recently discovered (20 species over the past 10 years [Frost 2017]) and their often microendemic distribution (see Bornschein et al. 2016a), there has been an increasing awareness about the need for more extensive field work to locate additional new species, to describe their geographical distributions, and to devise comprehensive efforts to ensure their conservation. In a recent correspondence in Zootaxa, Condez et al. (2017) singled out nine of those new species that have been described by our research group (Ribeiro et al. 2015; Pie & Ribeiro 2015; Bornschein et al. 2016b); two additional species (Ribeiro et al. 2017) were described after their paper was published. According to Condez et al. (2017), our species descriptions included "inadequate diagnoses, which lacked indispensable information for any further comparisons among species" (p. 395). Herein, we explore the extent to which their arguments would undermine the validity of those species. PMID- 29245547 TI - Taxonomic status of Chrysophanus phoenicurus transcaucasicus Miller, 1923 (Lepidoptera, Lycaenidae), with the designation of a neotype. AB - The taxonomic status is clarified for the lycaenine taxon Chrysophanus phoenicurus transcaucasicus Miller, 1923 described from one male collected in eastern Turkey and currently treated within the genus Athamanthia Zhdanko, 1983. Based on the appearance and morphology of the male genitalia compared with A. phoenicurus (Lederer, 1870), it is recognized here as a separate species, A. transcaucasica (Miller, 1923), stat. nov. (= Lycaena melicertes Nekrutenko, 1985). Its holotype is lost, and a neotype is designated herein from recent material collected near the type locality to retain nomenclatural stability. A key to the species of the A. phoenicurus group based on wings pattern and male genitalia is presented. PMID- 29245548 TI - On identification errors in Scytalopus speluncae (Menetries) and S. pachecoi Mauricio from southern Brazil with new data on distribution and biogeography of these taxa (Aves: Rhinocryptidae). AB - The Brazilian tapaculo Scytalopus speluncae species-group has been the subject of intense taxonomic work in the past 18 years, with six new species being named in that time lapse and other taxonomic problems having been highlighted (Bornschein et al. 1998, 2007; Mauricio 2005; Raposo et al. 2006, 2012; Mata et al. 2009; Whitney et al. 2010; Mauricio et al. 2010, 2014; Pulido-Santacruz et al. 2016). One of the most persistent of these problems involves the oldest name in this group, S. speluncae (Menetries), and the taxa it may represent. Historically, this name has been applied to the dark gray populations (whose adult males have plain gray flanks) occurring along coastal mountains between Espirito Santo and Sao Paulo states in Brazil (Raposo et al. 2006; Mauricio et al. 2010). Subsequently, dark gray populations from the Brazilian states of Parana, Santa Catarina, and Rio Grande do Sul, as well as paler gray birds with black-barred brown flanks from northeastern Argentina (Misiones Province) and adjacent southern Brazilian states were also subsumed under S. speluncae (Bornschein et al. 1998; Mauricio 2005; Mauricio et al. 2010). However, the paler gray, barred populations from Argentina and some parts of Santa Catarina and Rio Grande do Sul have proved to be a distinct and partially sympatric species named S. pachecoi Mauricio, which was shown to be not closely related to S. speluncae, but rather pertains to the very divergent clade of S. novacapitalis Sick and related forms (Mauricio 2005; Mata et al. 2009). On the other hand, the dark-gray populations coming from Espirito Santo south to Rio Grande do Sul continued to be identified as S. speluncae. PMID- 29245550 TI - The genus Stactobia McLachlan (Trichoptera, Hydroptilidae) in Japan. AB - The caddisfly genus Stactobia McLachlan (Hydroptilidae) is revised for Japan. Males are redescribed for 6 known species, Stactobia japonica Iwata, S. makartschenkoi Botosaneanu & Levanidova, S. inexpectata Botosaneanu & Nozaki, S. hattorii Botosaneanu & Nozaki, S. nishimotoi Botosaneanu & Nozaki, and S. distinguenda Botosaneanu & Nozaki. Six new species are described, also based on males: S. kanagawa, S. gunma, S. chichibu, S. yona, S. urauchi, and S. campire. A Taiwanese species, S. semele Malicky & Chantaramongkol, is recorded from Japan for the first time. Final instar larvae and their cases of 8 species and early instar larvae of 2 species are also described. PMID- 29245551 TI - Descriptions of three new species of the genus Symmorphus Wesmael, 1836 (Hymenoptera: Vespidae: Eumeninae) from South Korea, with an updated revised key to Far Eastern species. AB - Three new species of the genus Symmorphus Wesmael, 1836 are described with materials from South Korea and Far eastern Russia: Symmorphus kurzenkoi Kim sp. nov., S. truncatoclypeus Kim sp. nov., S. yamanei Kim sp. nov. All are members of the subgenus Symmorphus Wesmael 1836. S. kurzenkoi Kim sp. nov. is likely to be closely related to Symmorphus fuscipes in having well developed and completely closed propodeal submedian carina, but is clearly different from the latter in the shape of metasomal tergum 1 that is not markedly narrowed toward base. Within the S. murarius group proposed by Cumming 1989, Symmorphus truncatoclypeus Kim sp. nov. is unique in having a clypeus with apical margin completely truncated. S. yamanei Kim sp. nov. is separated from congeners by following combination of characteristics: uniformly lengthened mesosomal setae; vestigial epicnemial carina; areolate mesepimeron; propodeal submedian carina that is somewhat strongly developed though doubled and not clearly closed dorsally; weakly raised basal transverse carina on metasomal tergum 1; faintly foveate-reticulate dorsomedian portion of metasomal tergum 1. Re-description of S. tsushimanus Yamane 1990, which is the most poorly known species in the Far East, is presented based on the holotype. Finally, an updated revised determination key to Far Eastern species, supplemented by digital images and line drawings, is given. PMID- 29245552 TI - Morphological and molecular analyses of epikarstic Parastenocarididae (Copepoda: Harpacticoida) from two Sicilian caves, with description of a new Stammericaris. AB - We describe Stammericaris destillans sp. nov., and re-describe Stammericaris trinacriae (Pesce, Galassi and Cottarelli 1988) based on new material. The two species were collected from epikarstic drips and pools on the floor of two different caves: a karstic (Molara Cave) and a gypsum (Entella Cave) cave, respectively, both located in Sicily, Italy. We also report the presence of previously undescribed structures for Stammericaris amyclaea (Cottarelli 1969) and Stammericaris orcina (Chappuis 1938). Phylogenetic analyses of the mitochondrial COI and ribosomal 18S genes attributed the new species to Stammericaris Jakobi 1972, therefore the structure of the male P4 endopod of S. destillans is interpreted as an autapomorphy; other morphological features (structure of male antennule and P3, of female P3; inner ornamentation of P1 basis, armature of caudal rami and shape and armature of P5 of both sexes) correspond to those typical of the genus. Hence, we slithgly amended the generic diagnosis. [zoobank.org:pub:4CC84A0C-C511-4388-9728-41647E58097A]. PMID- 29245553 TI - Gobio baliki, a new gudgeon from Turkey (Teleostei: Cyprinidae). AB - Gobio baliki, new species, is described from the stream Buyuk Melen in the northwestern Anatolian Black Sea basin. The new species is distinguished from other gudgeons in Anatolia by the breast being completely covered by scales, scales extending slightly behind the isthmus; 5-6 scales between the posterior extremity of the pelvic-fin base and the anus; the distance between the anus and the anal-fin origin 7-10% SL; the postorbital distance equal to or greater than the snout length; the depth of the anal-fin approximately equal to the length of the pelvic-fin; 8-9 midlateral black blotches, usually separated from each-other. PMID- 29245554 TI - Three new species of Synagelides Strand, 1906 from China (Araneae: Salticidae). AB - The new species Synagelides jinggangshanensis sp. nov. (?), S. tangi sp. nov. (? and ?) and S. yinae sp. nov. (?) from China are described. Distribution data, detailed morphological characteristics, illustrations of body and copulatory organs are presented. PMID- 29245555 TI - A new species of arboreal microteiid lizard of the genus Euspondylus (Gymnophtalmidae: Cercosaurinae) from the Andean slopes of central Peru with comments on Peruvian Euspondylus. AB - We describe a new species of arboreal gymnophtalmid lizard from the eastern Andean slopes in central Peru. Euspondylus excelsum sp. nov. is assigned tentatively to this genus for the presence of a transparent and divided lower palpebral disc, a pair of prefrontals, striated, subimbricated and homogeneous dorsal scales, lateral scales reduced in proximity to ventrals, and a discontinuous series of femoral pores in males and females. We include a revision of the type material of E. maculatus and clarify morphological differences with the new species. Finally, we discuss the taxonomic status of Peruvian species of Euspondylus. PMID- 29245556 TI - Revision of Hindumanes Logunov, 2004 (Araneae: Salticidae: Lyssomaninae), with description of a new species from the Western Ghats of Kerala, India. AB - The monotypic genus Hindumanes Logunov, 2004 is revised. We present fresh specimens of Hindumanes karnatakaensis (Tikader & Biswas, 1978), the type species, and describe Hindumanes wayanadensis sp. nov. from the Wayanad Wildlife Sanctuary, a part of the Western Ghats, Kerala, India. This paper provides the first description of the male of H. karnatakaensis and a redescription of its female. We also transfer the genus from Asemoneinae Maddison, 2015 to Lyssomaninae Blackwall, 1877. The relationship between Hindumanes and Lyssomanes Hentz, 1845 and the zoogeography of the subfamily are discussed. The distribution records of the genus are mapped. PMID- 29245557 TI - First report on Paratischeria from Asia (Lepidoptera: Tischeriidae). AB - We provide the first report on the leaf-mining Tischeriidae genus Paratischeria Diskus & Stonis from Asia. We describe Paratischeria jingdongensis Xu & Dai, sp. nov., a new species discovered in Yunnan, China, feeding on Dalbergia assamica Benth., Fabaceae and redescribe P. hestias (Meyrick, 1915), comb. nov., a hitherto very little known species from India, which has been recently discovered in northern Vietnam, feeding on Helicteres viscida Blume, Malvaceae. We also report on the Fabaceae family as a novel host-plant family of Tischeriidae. The described and redescribed Paratischeria species are illustrated with photographs of the leaf-mines, adults, genitalia, and habitats. We also provide maps of new Paratischeria findings, and, along with a diagnostic scheme to the genus, present some data on global distribution of Paratischeria occurring in tropical and subtropical regions on both sides of the Equator. In addition, we designate a new Paratischeria neotropicana species group and provide two more new taxonomic combinations: Paratischeria heteroterae (Frey & Boll, 1878) comb. nov. and P. capnota (Meyrick, 1915) comb. nov. PMID- 29245558 TI - Living and fossil Steginoporellidae (Bryozoa: Cheilostomata) from New Zealand. AB - The cheilostome bryozoan family Steginoporellidae in New Zealand comprises seven living species of Steginoporella. Three of these are new to science Steginoporella discors n. sp., Steginoporella lineata n. sp. and Steginoporella modesta n. sp.-and one (Steginoporella magnifica) additionally occurs as a Plio Pleistocene fossil. A new Early Pleistocene fossil species, Steginoporella tiara n. sp., is also recognised. The living species exhibit the full range of colonial morphologies known for the genus, and two of the new deep-shelf taxa described herein have the smallest known colonies, both linear, not exceeding 5 mm in width and 22 mm in length. One species has a recorded depth range down to 615 m, apparently the deepest known for the genus. Zooidal proportions vary, with a length:width ratio in the seven living species ranging from 1.31 to 1.81, exceeded only by that in the new fossil taxon, which has very elongate zooids. Notwithstanding the conspicuous differences in colonial and zooidal morphology, four of the living species appear to be closely related, sharing distinctive reticulation of opercular sclerites, a similar morphology of the median process and no B-zooid morphs. Only one New Zealand taxon has B-zooids. Biogeographically, all the species except S. magnifica (also known from Tonga) are nominally endemic, but it is possible that some of the deeper-water taxa may eventually be found outside the boundary of the New Zealand Exclusive Economic Zone. The operculum in Steginoporella species is initially a single thin layer continuous with the membranous frontal wall, becoming two-layered when fully functioning in feeding zooids and mandibulate B-zooids. PMID- 29245559 TI - New taxa and new records of Deltocephalini leafhoppers from Thailand (Hemiptera: Cicadellidae: Deltocephalinae). AB - Two new genera and three new species of the leafhopper tribe Deltocephalini are described from Thailand, viz., Loeia Duan gen. n. with L. tamtipi Duan sp. n. as type species, Phetchabunia Duan gen. n. with P. janteabi Duan sp. n. as type species, and Maiestas subsirii Duan sp. n.. Five new country records for Thailand are also given, viz. Deltocephalus vulgaris Dash & Viraktamath, Maiestas dinghuensis Zhang & Duan, Maiestas scripta (Distant), Paramesodes sp., and Polyamia acicularis Dai, Xing & Li. PMID- 29245560 TI - New species of Xiphoniscus and new record of Androdeloscia escalonai (Isopoda, Scutocoxifera, Oniscidea, Philosciidae) from Brazilian Amazon. AB - A new species in the previously monotypic genus Xiphoniscus Vandel, 1968, X. adisi sp. nov. is described. Both X. mirabilis Vandel, 1968 from Ecuador and X. adisi sp. nov. from Brazil occur in the Amazon rainforest. The new species shows a prolonged coxal plate II drawn out caudally, an autapomorphy of Xiphoniscus. Xiphoniscus adisi sp. nov. differs from X. mirabilis mainly in the characteristics of buccal appendages and male pleopods. A diagnosis of the genus Xiphoniscus is provided. The species Androdeloscia escalonai is reported from the Brazilian Amazon for the first time. PMID- 29245561 TI - Two new Isotomidae species (Collembola: Entomobryomorpha) from Rio de Janeiro State, Brazil. AB - In the present paper, two new species of Isotomidae belonging to the genera Isotomiella Bagnall, 1939 and Paracerura Deharveng & Oliveira, 1994 are described and illustrated. Isotomiella denticulata sp. nov. is distinguished from all known species specially by a single tooth in the inner edge of the unguis, a unique feature among the members of the genus. Paracerura bella sp. nov., differs from other congeners with respect to overall coloration, the sensillary pattern on tergite abd. IV-V and type of chaetae on both lateral margins of dens. Both species are described from Rio de Janeiro, Brazil. PMID- 29245562 TI - New records of Iranian bark beetles (Coleoptera: Curculionidae, Scolytinae) and their host plants. AB - Bark and ambrosia beetles from the subfamily Scolytinae are among the most important pests in forests of Northern Iran. During investigations conducted in 2013-2016 in different parts of northern forests, the species Crypturgus cribrellus Reitter, Liparthrum bartschti Muhl, Scolytus varshalovitchi Michalski, Scolytus sulcifrons Rey, Scolytus triarmatus (Eggers) and Trypophloeus granulatus (Ratzeburg) were recorded for the first time in Iran; Trypophloeus and Liparthrum were new genera for Iran. As new host plants we found Zelkova sp. for Scolytus varshalovitchi, Michalski, Populus sp. for Liparthrum bartschti, Muhl, Alnus sp. and Pterocarya fraxinifolia for Taphrorychus lenkoranus Reitter, Pterocarya fraxinifolia for Ernoporicus caucasicus (Lindemann), Carpinus sp. for Pteleobius vittatus (Fabricius), Parrotia persica for Scolytus intricatus (Ratzeburg), Alnus sp. and Pterocarya fraxinifolia for Hypothenemus eruditus (Westwood). PMID- 29245563 TI - A checklist of the millipedes (Diplopoda) of Myanmar, with an updated list of Leonardo Fea's collecting localities. AB - At present, the millipede fauna of Myanmar comprises 92 species from 34 genera, 13 families and 8 orders, mostly described in 1889-1896. All literature records are cited with updates on species identities, as well as numerous taxonomic problems which make the number of species and even genera still imprecise. The Myanmar millipede fauna contains 70 endemic and five widespread synanthropic species. One species is found to have erroneously been recorded from Myanmar, and is ejected from the list of Myanmar millipedes also because of its uncertain taxonomic status. A complete bibliography on the millipedes of Myanmar, an updated list of the collecting localities and a map of the journeys of Leonardo Fea, the principal collector of Diplopoda in Burma, are also presented. PMID- 29245564 TI - Two new Cyphoderus (Collembola: Paronellidae) of "tridenticulati" and "bidenticulati" groups from Brazilian Amazon. AB - Two new species of Cyphoderus Nicolet are described from northern Brazil: C. mucrominimus sp. nov. from Curionopolis, Para; and C. mucrostrimenus sp. nov. from Parauapebas, Para. These species belong to tridenticulati and bidenticulati groups respectively. The chaetotaxy of head and whole body are described and an identification key for the species with recorded distribution in Brazil is provided. PMID- 29245565 TI - The South Asian millipede genus Chondromorpha Silvestri, 1897 (Diplopoda, Polydesmida, Paradoxosomatidae, Sulciferini): redescriptions and synonymies. AB - The South Asian millipede genus Chondromorpha Silvestri, 1897 is diagnosed and its relationship with Parchondromorpha Jeekel, 1980 is established. The species C. atopus (Chamberlin, 1920) and C. indus (Chamberlin, 1920), as well as the subspecies C. kelaarti kelaarti (Humbert, 1865), C. kelaarti longipes (Verhoeff, 1936) and C. kelaarti valparaiensis (Carl, 1932) are recognised as junior synonyms of C. kelaarti (Humbert, 1865), thereby reducing the total number of Chondromorpha spp. in India to four: C. kaimura Turk, 1947, C. kelaarti, C. mammifera Attems, 1936 and C. severini Silvestri, 1897 (the type-species). Two species, C. kelaarti and C. mammifera, are redescribed and illustrated in detail. All four Indian Chondromorpha spp. are keyed, and the known distribution records of C. kelaarti and C. mammifera are mapped. PMID- 29245566 TI - A new species of Thalerosphyrus Eaton 1881 (Ephemeroptera: Heptageniidae: Ecdyonurinae) from India. AB - A new species of Thalerosphyrus Eaton 1881 is described based on larvae collected from East Khasi Hills district and East Jaintia Hills district of Meghalaya. Thalerosphyrus meghalayensis Selvakumar & Chandra n. sp. can be distinguished from other known species of the genus by the following combination of characters: (i) posterolateral expansions of segment VIII always shorter than those of segment VII; (ii) pronotum moderately enlarged laterally; (iii) bristles on the dorsal face of hind femora truncate or round at apex; (iv) hind tibia with a row of thin setae; (v) outer margin of superlinguae evenly covered with long setae ending at apex by minute setae and (vi) posterior margin of tergites with regularly pointed teeth, and numerous microdenticles. A modified larval key is provided for known species of this genus. PMID- 29245567 TI - A new species of Lepidodactylus (Reptilia: Squamata: Gekkonidae) from the Kei Islands, Maluku, Indonesia. AB - Lepidodactylus pantai is a new species of gecko from the Kei Islands, Maluku, Indonesia that is closely associated with intertidal habitats. This species does not fit cleanly into any of the three species groups described for the genus because it possesses the unique combination of both divided terminal scansors on all toes and a nearly completely cylindrical tail without fringes or evidence of dorsoventral compression. A phylogenetic analysis including this species demonstrates that it is the sister taxon of a population from Palau, and that this clade is sister to the clade containing Group III species for which we have molecular data. PMID- 29245568 TI - Five new species of Cymatodera Gray, 1832 (Coleoptera: Cleridae: Tillinae) from Mexico and Central America. AB - Five new species of Cymatodera from Mexico, Guatemala, Honduras, Costa Rica and Panama are described here based on adult male and female specimens: Cymatodera humeralis sp. n; Cymatodera lorenae sp. n.; Cymatodera crassa sp. n.; Cymatodera depressa sp. n; and Cymatodera nigrofasciata sp. n. Male genitalia and other characters of taxonomic value are used for diagnostic purposes. PMID- 29245569 TI - A taxonomic revision of the genus Apostichopus (Holothuroidea: Stichopodidae) from Japan. AB - Complete redescriptions of sea cucumbers in the genus Apostichopus Liao, 1980 are provided using the type specimens and specimens deposited in the National Museum of Nature and Science, Tsukuba, Japan. The genus consists of A. armatus (Selenka, 1867) and A. japonicus (Selenka, 1867), which can be distinguished by some spicules in the dorsal body wall; the rim of reduced table spicules in A. armatus is spinous, while that in A. japonicus is smooth. Spicules from the tentacles, papillae, tube feet, and cloaca are similar for both species. PMID- 29245570 TI - Desutterella n. gen., a new genus of Luzarinae (Orthoptera: Grylloidea: Phalangopsidae) and the first report of the Aracambiae group Souza-Dias & Desutter-Grandcolas, 2014 in the Amazon. AB - A new genus and two new species of Luzarinae cricket (Grylloidea, Phalangopsidae) are described from the Amazon Rainforest of Brazil and Colombia. Desutterella manauara n. gen. n. sp. and D. colombiana n. gen. n. sp. are described based in characters of external morphology and genitalia. The new genus is characterized by the presence of reduced and pubescent male forewings, with stridulatory vein visible but other areas for sound production and propagation absent, and file teeth very reduced, vestigial. Regarding the male genitalia, Desutterella n. gen. presents an extra projection in the pseudepiphallic paramere 2, a condition not observed in the Aracambiae until now. Besides the description, we provide morphological evidence for the glandular nature of the metanotum of males through scanning electron microscopy analysis, a discussion about the morphological and genital features of this new genus, and a distribution map of the Aracambiae group. PMID- 29245571 TI - A new species of Phrynobatrachus (Anura: Phrynobatrachidae) from the Eastern Arc Mountians of Tanzania. AB - Phrynobatrachus discogularis sp. nov. (Anura, Phrynobatrachidae) is described from the Eastern Arc Mountains in Tanzania. It occupies upland grasslands and while it morphologically most resembles West and Central African P. gutturosus (Chabanaud, 1921), P. rungwensis (Loveridge, 1932), and P. anotis Schmidt and Inger, 1959, preliminary analysis of mitochondrial 16S rRNA indicates that the new species differs from all other species with published sequence data by a minimum distance of 4.1% and has affinities with P. rungwensis, P. uzungwensis Grandison and Howell, 1983 and P. keniensis Barbour and Loveridge, 1928-all diminutive upland eastern African taxa. The shape and colour of the male's external gular apparatus distinguish this species from all other described Phrynobatrachus species. Although geographically either sympatric or closely allopatric with P. uzungwensis, the lack of overlapping morphological characters indicates the two forms are distinct species. The new taxon is compared with other species from the region. PMID- 29245572 TI - A new bee species of the genus Dasypoda Latreille (Hymenoptera, Apoidea) from Portugal with comparative remarks on the subgenus Heterodasypoda Michez. AB - A new bee species of the genus Dasypoda Latreille (Hymenoptera, Apoidea, Melittidae), D. michezi Radchenko sp. nov., is described from south-western Portugal. This species belongs to the subgenus Heterodasypoda and appears very similar to D. albimana Perez 1905, which occurs in the west Mediterranean Basin. A detailed comparative diagnosis of D. michezi with the other 3 species of the subgenus Heterodasypoda, is provided. The new species is most easily distinguishable by the widened protrusion at the apex of the 6th sternum, which is deeply emarginated apically in the form of a wide triangle. In addition, the new species differs from other described species of the subgenus by the structure of the 7th and 8th sterna, male genitalia, and relative dimensions of antennal flagellomeres. PMID- 29245573 TI - A new species of Ferneiella from the Eocene French amber (Diptera: Scatopsidae). AB - We describe the first fossil representative of the genus Ferneiella, F. gallica sp. nov., in the earliest Eocene Oise amber. PMID- 29245574 TI - A new troglobiotic Protaphorura (Collembola, Hexapoda) from the Siberia, Russia. AB - A new species of Protaphorura Absolon, 1901 (Collembola, Onychiuridae), P. cykini sp.nov., is described from a cold karst cave in the Irkutsk region, Siberia, Russia. It is an obligate cave species with the largest body size (4.3-5.6 mm) of all congeners. The species is further characteristic by the pseudocellar formula as 3(2)2/022/33343, high number of vesicles in postantennal organ (65-71) and subapical organite protected with two papillae. A partial sequence of cytochrome oxidase I (COI DNA barcoding marker) gene is used to verify the taxonomic status of the new species and the barcode sequence is compared with other congeners available in GenBank database. Distribution and diversity of cave Collembola of Siberia is discussed. PMID- 29245575 TI - A new species of Raspy cricket genus Gryllacris (Orthoptera: Gryllacrididae) from Central India. AB - Gryllacris durgensis sp. nov. is described from the Durg district, Chhattisgarh, India. The detailed morphological characters of adult male, female and nymph are provided. PMID- 29245576 TI - Ant-like stone beetles on the roof of the world. Cephenniini of Nepal and Bhutan (Coleoptera, Staphylinidae, Scydmaeninae). AB - The tribe Cephenniini is for the first time reported to occur in the Himalaya Mountains, and 58 species are described: Cephennomicrus arunensis sp. n., Cm. acupunctatus sp. n., Cm. taplejungensis sp. n., Hlavaciellus primitivus sp. n., Cephennodes (s. str.) cavifrons sp. n., C. (s. str.) pampinosus sp. n., C. (s. str.) bagmatianus sp. n., C. (s. str.) popeye sp. n., C. (s. str.) clavodentatus sp. n., C. (s. str.) meredaranus sp. n., C. (s. str.) yangrianus sp. n., C. (s. str.) suturalis sp. n., C. (s. str.) karnaliensis sp. n., C. (s. str.) churtanus sp. n., C. (s. str.) sermathangensis sp. n., C. (s. str.) tipulipes sp. n., C. (s. str.) yeti sp. n., C. (s. str.) inflaticornis sp. n., C. (s. str.) dolakhanus sp. n., C. (s. str.) manangensis sp. n., C. (s. str.) martensi sp. n., C. (s. str.) paramartensi sp. n., C. (s. str.) monolaminatus sp. n., C. (s. str.) thakanus sp. n., C. (s. str.) annapurnaensis sp. n., C. (s. str.) parbatensis sp. n., C. (s. str.) letheanus sp. n., C. (s. str.) myagdiensis sp. n., C. (s. str.) malla sp. n., C. (s. str.) gorkha sp. n., C. (s. str.) tharepatianus sp. n., C. (s. str.) minisulcatus sp. n., C. (s. str.) mustangensis sp. n., C. (s. str.) lalitpuranus sp. n., C. (s. str.) paralalitpuranus sp. n., C. (s. str.) bahrabisensis sp. n., C. (s. str.) bilaminatus sp. n., C. (s. str.) ghorepanianus sp. n., C. (s. str.) cordilaminatus sp. n., C. (s. str.) mangmayanus sp. n. C. (s. str.) bilobatus sp. n., C. (s. str.) gokarnaensis sp. n., C. (s. str.) pseudogokarnaensis sp. n., C. (s. str.) mahisapala sp. n., C. (s. str.) licchavi sp. n., C. (s. str.) gopala sp. n., C. (s. str.) paniporuanus sp. n., C. (s. str.) brachyclavatus sp. n., C. (s. str.) phulchokianus sp. n., C. (s. str.) pokharensis sp. n., C. (s. str.) newar sp. n., C. (s. str.) kusunda sp. n., C. (s. str.) sindhupalchowk sp. n., C. (s. str.) furcatus sp. n., C. (s. str.) penicillipes sp. n., C. (s. str.) sulcatus sp. n., C. (s. str.) kalopanianus sp. n., and C. (s. str.) poonensis sp. n. Cephennodes popeye occurs in Bhutan; all remaining species inhabit Nepal. Four new species groups are established in Cephennodes, and a checklist of all Cephennodes species placed in species groups is given. The presumably plesiomorphic morphological structures of H. primitivus are discussed, and comparative notes on the Himalayan Cephenniini fauna are presented. PMID- 29245577 TI - Deep-water bony fishes collected by the B/O Miguel Oliver on the shelf edge of Pacific Central America: an annotated, illustrated and DNA-barcoded checklist. AB - An annotated and photographically illustrated checklist with DNA barcodes of the species of bony fishes collected during a month-long research cruise of the Spanish Research vessel B/O Miguel Oliver is presented. The vessel made trawls on the continental shelf of the Pacific coast of Central America, in November December 2010, at depths of 108-1625 m. This list, based on 707 specimens (of a total of 876 specimens collected during the whole expedition), includes 129 species belonging to 15 orders, 61 families, and 97 genera. New information is presented on the geographical distributions of more than a third of those species, with 29 species (22.4%) representing new records from Central American waters and 17 species (13.2%) having expanded latitudinal ranges. Data on capture depths demonstrate increased depth ranges due to new minimum and/or maximum known depths for 31 species, i.e. 24% of those captured. Tissue samples from frozen specimens were used to obtain DNA barcodes of 682 (96.5%) individuals belonging to 118 species (91.4% of those recorded here), which have been made publically available in Genbank. Those data include barcodes for 84 species (65.1% of the total collected, and 77.1% of those for which barcodes were obtained) and 30 genera (30.9% of those collected) for which no species barcodes have been previously published. Barcodes of 54 species represent the first genetic sequences of any type published for those species. The abundance of new data indicate that there is still much to learn about the composition and geographical and depth distributions of the fish fauna of the shelf edge and continental slope of this region. PMID- 29245578 TI - Comparative exploration of antennae in Pseudopontia, and antennal clubs of the tribes Leptideini and Dismorphiini (Lepidoptera: Pieridae). AB - We examined antennal ultrastructure in species of Dismorphiinae and Pseudopontiinae (Pieridae) using scanning electron microscopy (SEM). We examined two species of Pseudopontia (Pseudopontiinae) and more than 30 species in seven genera of two tribes in the subfamily Dismorphiinae: Leptidea, Enantia, Pseudopieris, Lieinix, Moschoneura, Dismorphia, and Patia. We focused on the scaleless terminal area of the antenna where there are many types of sensilla, some of which are clustered together and constitute specialized organs. We measured, described, and illustrate at different magnifications structures including the antennal club, antennomeres, sulci, pseudosulci, and chaetic, trichoid, coeloconic, basiconic, and auriculate sensilla, as well as other previously unnamed sensilla. From these antennal features, we created a matrix of characters that allowed us to recognize divergence between the tribes Leptideini and Dismorphiini. The antennae of Leptideini have fewer scaleless antennomeres in the antennal club than those of Dismorphiini, a greater number of pseudosulci disaggregated or dispersed (in Leptidea), and fewer types of sensilla and microtrichia (a more homogeneous antennal morphology), as well as a reduction in the density of sensilla. In Leptidea the antennal form is more specialized: it is shorter in comparison to genera of other Papilionoidea families. We also created a matrix of general morphological characters of Dismorphiinae and Pieridae from the taxonomic literature. This matrix confirms the marked character divergence between the tribes and allows for a more meaningful discussion regarding the relationships between Dismorphiinae and the other subfamilies of Pieridae (i.e., Pseudopontiinae, Coliadinae, and Pierinae). We argue that Pseudopontiinae cannot be considered the least derived subfamily among Pieridae because pupal features, wing venation, and antennal characters exhibit a combination of primitive and specialized states. In addition, we discuss our results from the perspective of patterns of food plant usage in pierid subfamilies, specifically the diversification of several Dismorphiinae genera on Hologalegina and Ingeae (Fabaceae). PMID- 29245579 TI - Two new species of leaf-tailed geckos (Uroplatus) from the Tsaratanana mountain massif in northern Madagascar. AB - The Tsaratanana Massif is the highest mountain massif of Madagascar and is characterized by a high species-level endemism of its biota. Here we describe two new small-sized species of leaf-tailed geckos of the Uroplatus ebenaui group from this region. Named in a preliminary way as confirmed candidate species Uroplatus ebenaui [Ca1] and [Ca2] in previous studies, we here provide detailed data on their molecular and morphological differentiation and describe them as Uroplatus fotsivava sp. nov. and Uroplatus kelirambo sp. nov. Their closest relatives are U. fiera and U. finiavana, respectively, as revealed by a phylogeny based on DNA sequences of four mitochondrial genes. However, integration of various lines of evidence confirms that the new species are independent evolutionary lineages, differing from other Uroplatus by high mitochondrial divergences, lack of haplotype sharing in the nuclear CMOS gene, and shape and relative size of the tail. While U. fotsivava is known from multiple sites at elevations between 1100 1538 m above sea level, U. kelirambo was found only at high elevations between 2000-2200 m a.s.l.; it therefore is the only known forest-dwelling nocturnal gecko reaching such high elevations in Madagascar, and might be narrowly endemic to montane forests of the Tsaratanana Massif. PMID- 29245580 TI - Annotated Checklist of Tingidae (Hemiptera: Heteroptera) in Turkey with new records for the faunas of Europe and Turkish Thrace. AB - In this study, all the so far manuscripts on Tingidae fauna in Turkey has been revised and adults samples from the family Tingidae (Hemiptera: Heteroptera) were collected from different localities in Anatolia and Thrace of Turkey and an annotated checklist of Tingidae occurring is presented. As a results of this study, of Tingidae fauna from Turkey stated that it consists of 78 species has revealed that the number of species is 88 species and 1 subspecies. Nine species and subspecies, Catoplatus horvathi (Puton, 1878), Copium clavicorne clavicorne (Linnaeus, 1758), Derephysia foliacea foliacea (Fallen, 1807), Dictyla nassata (Puton, 1874), Dictyla rotundata (Herrich-Schaeffer, 1835), Dictyonota strichnocera Fieber, 1844, Lasiacantha capucina capucina (Germar, 1837) Stephanitis oschanini Vasiliev, 1935 and Tingis geniculata (Fieber, 1844) are new records for the fauna of Turkish Thrace (European part of Turkey) and of those, S. oschanini is recorded for the first time from Europe. The specimen Dictyonata astragali Stusak & Onder, 1982 type locality in Turkey has been mentioned second locality from Merzifon (Amasya). PMID- 29245581 TI - A new genus and species of Haplobainosomatidae (Diplopoda: Chordeumatida) from the MSS of the Sierra de Guadarrama National Park, central Spain. AB - The chordeumatidan fauna of the Iberian Peninsula is far from being well known, but recent efforts are improving that knowledge. Samplings carried out in the Milieu Souterrain Superficiel (also known as the Mesovoid Shallow Substratum) on several screes of the Sierra de Guadarrama National Park (central Spain) have led to the discovery of a new species of chordeumatidan millipede. This new species belongs to the family Haplobainosomatidae, which is mainly known from the northern Iberian Peninsula, and thus this is the first record of the family in central Spain. However, the extremely simple gonopods of this species are so different from all other known species of the family that it must be placed in a new genus. In this work, a complete description of the species, named as Guadarramasoma ramosae gen. & sp. nov., with a detailed iconography based on scanning electron microscopy images is provided together with a distribution map and a brief discussion of the implications of this new finding. PMID- 29245582 TI - Review of Australian Scirtes Illiger, Ora Clark and Exochomoscirtes Pic Coleoptera: Scirtidae) including descriptions of new species, new groups and a multi-gene molecular phylogeny of Australian and non-Australian species. AB - The phylogenetic relationships of 26 Australian species of Scirtes Illiger, Ora Clark and Exochomoscirtes Pic (Scirtidae) were investigated using adult morphology, particularly male and female genitalia, larval morphology and molecular data from the mitochondrial cytochrome c oxidase subunit I (COI) gene and the nuclear genes elongation factor 1-alpha (EF1- a) and topoisomerase I (TOP1). Four species of Scirtes and one of Ora from Europe, Southeast Asia and Japan were included. The genus Scirtes is shown to be paraphyletic with respect to the genera Ora and Exochomoscirtes. Australian Scirtes were shown to belong to four species groups: Scirtes elegans group (Yoshitomi 2009); S. helmsi group (Watts 2004); S. japonicus group (Nyholm 2002); and S. haemisphaericus group (Yoshitomi 2005). The prehensor and bursal sclerite of 15 species are illustrated as well as habitus illustrations of S. zwicki sp. nov. and S. albamaculatus Watts. Three new species from Australia are described: Scirtes lynnae, S. zwicki and S. serratus spp. nov. Scirtes nehouensis Ruta & Yoshitomi 2010 is synonymised with S. emmaae Watts 2004. Scirtes pygmaeus Watts, 2004 is synonymised with S. pinjarraensis Watts, 2006. Scirtes rutai nom. nov. is proposed as a replacement name for S. beccus Ruta, Kialka & Yoshitomi, 2014 from Sabah as it is preoccupied by S. beccus Watts, 2004 from Australia. PMID- 29245583 TI - Review of the genus Trichiotes Casey (Coleoptera: Tenebrionidae: Pimeliinae: Edrotini), with the description of a new species and a preliminary checklist of the Tenebrionidae from Cuatrocienegas, Mexico. AB - The rarely collected, previously monotypic, darkling beetle genus Trichiotes is reviewed, including new state and country records for T. seriatus Casey, 1907 and a new species, Trichiotes lightfooti Wirth & Smith, n. sp., is described from the Cuatrocienegas Protected Area in Coahuila, Mexico. Differences in stridulatory structures between the species are discussed and the occurrence of a waxy, extracuticular pruinescence is reported for Trichiotes. A species key to the genus is provided and a checklist of the known Tenebrionidae from the Cuatrocienegas region is presented. PMID- 29245584 TI - The taxonomic status of Aphis rostellum (Zhang, Chen, Zhong & Li, 1999) and description of the fundatrix and sexual morphs of Aphis umbrella (Borner, 1950) (Hemiptera: Aphidoidea). AB - Aphis rostellum (Zhang, Chen, Zhong & Li, 1999) is placed as a new subjective synonym of A. umbrella (Borner, 1950). Detailed descriptions are provided of the fundatrix, oviparous female and male of this species. PMID- 29245585 TI - The genus Heteragrion (Odonata: Zygoptera) in Northwestern Colombia, with the description of Heteragrion tatama sp. nov. AB - The Neotropical forest specialist genus Heteragrion counts with 54 species and one subspecies described to date, eight of which have been recorded from Colombia. Here, information on Heteragrion species resulting from ten years of exploration of northwestern Colombia and examination of museum collections, including types and species from Central America, is presented. A new species endemic to the Tatama National Park in the western Andes, Heteragrion tatama sp. nov. is described, as well as the female of Heteragrion aequatoriale Selys, 1886. Heteragrion calendulum Williamson, 1919 was rediscovered, a century after its first collection, which allowed us to compare it with Heteragrion atrolineatum Donnelly, 1992, and to conclude that the latter species is its junior synonym. We present pictures of female prothoracic intersternite, which offer valuable taxonomic information. The variation in coloration patterns for H. aequatoriale and Heteragrion mitratum Williamson, 1919 is discussed, and maps with new distributional data, a taxonomic key, natural history notes and photographs of the Heteragrion species distributed west of the Magdalena valley in Colombia, are also provided. PMID- 29245586 TI - Yet another small brown frog from high altitude on the Marojejy Massif, northeastern Madagascar (Anura: Mantellidae). AB - Madagascar hosts a high diversity of small brown frogs. In this paper, we add another one by describing Gephyromantis (Duboimantis) tohatra sp. nov. The new species is a small brown mantellid frog discovered on a recent expedition to Marojejy National Park in northeastern Madagascar. It is characterised, among other things, by its small size (snout-vent length ~33 mm), an orange to yellowish belly, two dorsolateral ridges, and a distinctive call composed of 7-10 pulsed notes. The new species occurs sympatrically with other members of the subgenus Duboimantis at high altitude (~1700 m above sea level), including its sister species G. schilfi from which it radically differs by advertisement call and by a substantial genetic divergence of 4.3% uncorrected pairwise distance in the mitochondrial 16S rRNA gene. It thus joins the diverse assemblage of Gephyromantis species known from high altitudes on the mountain massifs of northern Madagascar. PMID- 29245587 TI - The first record of the genus Desertoniscus Verhoeff, 1930 (Isopoda, Oniscidea, Agnaridae) from Europe, with the description of a new species. AB - A new woodlouse species, Desertoniscus zaitsevi sp. nov., is described from Kalmykia, Cis-Caspian region of Russia. The diagnostic features of the new species, as well as its affinities within the genus are provided and discussed. The new species is the northwesternmost in Eurasia, expanding the known distribution of this genus into Europe. PMID- 29245588 TI - Validation of Tethya samaaii Ribeiro & Muricy, 2011, replacement name for the sponge Tethya rubra Samaai & Gibbons, 2005 (Demospongiae, Tethyida, Tethyidae). AB - Tethya samaaii Ribeiro & Muricy, 2011 is a massive, irregularly globular or sub spherical sponge with basal rooting processes or a disc-like attachment (Figure 1A). It was described from Oudekraal, on the west coast of South Africa as Tethya rubra Samaai & Gibbons, 2005 based on specimens collected during two surveys in 1996 (Samaai & Gibbons 2005). This species was later reported from Algoa Bay, on the southeast coast of South Africa by Waterworth et al. (2017). PMID- 29245589 TI - The importance of correct labelling of types: an example in Tortricidae (Lepidoptera) and its rectification. AB - Taxonomy is the basic discipline in biology. The taxonomist defines each taxon and provides a unique name for it. Of the systematic categories, the species level is crucial. When a species is described and named, great care should be taken to ensure that all information related to the name is correct. Information on ecology, biology, distribution, etc. is linked to the name, and may be added and repeated in subsequent literature. Great confusion may arise from ambiguous descriptions and/or mislabelled figures. Therefore editors should take special care to ensure that taxonomic papers containing descriptions of new taxa receive careful refereeing and editing. Here we present a case where descriptions of new species became misleading when the labels of the type specimens were switched. If the manuscript had been more thoroughly refereed, the mistake could have been discovered and avoided. PMID- 29245590 TI - Description of the female of Catocala becheri (Lepidoptera: Erebidae). AB - Catocala becheri Borth, Kons & Saldaitis, 2017 was recently described from Central Vietnam. It is a member of a morphologically well-defined group including Catocala intacta Leech, 1889 and Catocala hoferi Ishizuka & Ohshima, 2003 which both differ from C. becheri in wing pattern and male genitalia. (Borth et al. 2017). Recent collecting has provided additional specimens, including the first female C. becheri, described below. PMID- 29245591 TI - New species of Lachesilla (Psocodea: Psocomorpha: Lachesillidae), in species group corona, from southern Mexico and Central America. AB - Sixteen species of Lachesilla in species group corona are here described and illustrated. Five of them are endemic to Guatemala, one each are endemic to Costa Rica and Panama, four and three species respectively are endemic to the Mexican states of Chiapas and Oaxaca, and two species are shared by Chiapas and Guatemala. PMID- 29245592 TI - Checklist of the Free-Living Marine Nematodes of the Iberian Peninsula (north east Atlantic). AB - A Checklist of the Free-Living Marine Nematodes of the Iberian Peninsula, based on the literature published to date, is presented in this paper. The localities where the taxa were collected, as well as the habitats and depths where they were found, are also mentioned. All references to date provide a total of 236 species, 142 genera and 37 unidentified families. Also, the preparation of the present Checklist allowed us to clarify some errors that have been dragging on for some time and make a few clarifications, all of them based on a review of the original papers. PMID- 29245593 TI - Reevaluation of the type species and redescription of five species of Edessa (Heteroptera: Pentatomidae: Edessinae). AB - In accordance with the rules in the International Code of Zoological Nomenclature, the type species for the genus Edessa Fabricius, 1803 is now recognized to be Cimex antilope Fabricius, 1798 rather than the previously recognized Cimex cervus Fabricius, 1787. Edessa antilope is redescribed, as well as the following four species that have in the past been related or compared to E. antilope: E. arabs (Linnaeus, 1758) from French Guiana, Costa Rica and Panama (new record), E. helix Erichson, 1848 from Costa Rica, Panama, Venezuela, Suriname (new record), Guyana, Brazil (new record), Bolivia (new record) and Argentina (new record), E. ibex Breddin, 1903 from Costa Rica, Panama (new record), Ecuador, Brazil (new record), Peru and Bolivia (new record), and E. taurina Stal, 1862 from Mexico, Guatemala, Belize (new record), Honduras (new record). The distribution of Edessa antilope is expanded to Venezuela. The female of E. antilope and the male of E. taurina are described for the first time. Edessa antilope is removed from the synonymy of E. arabs and reinstated as valid species; additionally, E. costalis Stal, 1872 is removed from the synonym of E. helix and is placed as a junior synonym of E. antilope. Edessa saiga Breddin, 1903 is considered a junior synonym of E. ibex. Lectotypes are designated for all species. A key is provided for the identification of the species. PMID- 29245594 TI - A new species of Aspidura Wagler, 1830 (Squamata: Colubridae: Natricinae) from Sri Pada sanctuary (Peak Wilderness), Sri Lanka. AB - We describe a new species, Aspidura ravanai sp. nov., representing the eighth species of the genus known from Sri Lanka. The new species is readily distinguished from all other congeners by its colour pattern, scalation, and genetic distinctiveness. Our molecular results indicated that Aspidura began diversifying in the Miocene approximately 18 Ma, and A. ravanai sp. nov. diverged from its likely sister lineage A. trachyprocta at least 6.2 Ma. The species is currently known only from the type locality, on the western slopes of Sri Pada Peak in the central highlands of Sri Lanka. PMID- 29245595 TI - A new species of the genus Ceratagallia (Cicadellidae: Megophthalminae) from Central Mexico. AB - Ceratagallia (Ceratagallia) brailovskyi sp. nov., is here described and illustrated from Central Mexico. The new species appears to be closely related to the C. bigeloviae species group, which includes previously described Mexican species. A key, species list, and distributional map for Ceratagallia in Mexico are provided. PMID- 29245596 TI - Troublesome Trimes: Potential cryptic speciation of the Trimeresurus (Popeia) popeiorum complex (Serpentes: Crotalidae) around the Isthmus of Kra (Myanmar and Thailand). AB - The taxonomic identity of the Trimeresurus (Popeia) popeiorum complex from the Isthmus of Kra and to the north was investigated. Several studies over the last decade have produced several specimens and associated mtDNA sequence data for a variety of individuals of the T. popeiorum and "T. sabahi" complexes. Here, we combine four mitochondrial genes (12S, 16S, ND4, and CytB) from all available specimens in GenBank with the addition of five new specimens collected from the mainland, Tanintharyi Region of Myanmar. Maximum Likelihood and Bayesian analyses identified that T. popeiorum sensu lato is paraphyletic with two geographically distinct clades: a northern clade representing populations from northern Myanmar, Laos and northern Thailand and a southern clade representing samples from the Tanintharyi Region and adjacent west Thailand. While the two clades have considerable genetic distance, they appear to be morphologically identical, leading to the hypothesis that the southern clade represents a cryptic, undescribed species. Because they appear to be cryptic species and the limitation of only five specimens from the southern lineage, this does not permit us to formally describe the new species. In accordance to past molecular studies, we uncovered paraphyly and lack of genetic support for the validity of taxa within the T. sabahi complex. However, we suggest recognizing these populations as subspecies within T. sabahi. PMID- 29245597 TI - A new species of gecko (Squamata: Diplodactylidae: Strophurus) from central Queensland, Australia. AB - A new species of diplodactylid gecko in the genus Strophurus Fitzinger, from central Queensland, Australia, is described herein as Strophurus trux sp. nov. It is similar to the recently described Strophurus congoo Vanderduys from north Queensland and apparently shares a habitat preference for Triodia hummock open woodlands. It is notably different from the latter in possessing a vivid yellow to golden eye. It is only known from one small area of the Brigalow Belt Bioregion, although it is expected to occur more widely than the one area in which it has been found. It is likely that it is endemic to the Brigalow Belt Bioregion. PMID- 29245598 TI - A new species of large-bodied, tuberculate Hemidactylus Oken (Squamata: Gekkonidae) from the Eastern Ghats, India. AB - A distinct new gecko of the genus Hemidactylus is described from Andhra Pradesh, India. This large-sized (snout to vent length up to at least 105 mm), scansorial Hemidactylus is characterized by dorsal scalation of small granules intermixed with large, pointed, trihedral tubercles that form 16-17 fairly regularly arranged longitudinal rows at midbody; 9-11 subdigital lamellae below the first and 11-13 below the fourth digit; 6-8 strongly pointed and keeled enlarged tubercles on the original tail; 20-23 femoral pores separated by 4 poreless scales in males; 11-13 supralabials and 9-11 infralabials. This is the third vertebrate endemic to the Mahendragiri Range, highlighting the significance of this topographically complex region. PMID- 29245599 TI - New species and new records of Uropodina from Virginia, USA (Acari: Mesostigmata). AB - Jedediella hoffmani sp. nov. and Trachytes virginiana sp. nov. are described on the basis of specimens from Virginia USA. This paper also presents the first published records of Trachytes balazyi Wisniewski & Hirschmann, 1994, Discourella gaitlinburgiana Wisniewski & Hirschmann, 1994 and Discourella modestasimilis Hiramatsu & Hirschmann 1979 from Virginia, and the first record of Discourella modestasimilis from USA. PMID- 29245600 TI - On the identity of Photophilus Folkmanova, 1928: A new generic synonymy (Chilopoda: Geophilomorpha: Geophilidae). AB - The enigmatic monotypic genus Photophilus Folkmanova, 1928 and its type species, Photophilus griseus Folkmanova, 1928, were described almost 90 years ago from the Czech Republic. The new genus was erected not only based on some morphological characters, but also on behavioural features rather peculiar among Central European geophilomorphs. Although the patria of these taxa is among the best studied regions regarding Chilopoda, and focussed effort has been made to collect further representatives of these taxa, none have been found since the original description As the type material is lost and we failed to collect new specimens from the type locality, we tried to elucidate the true identity of these genus and species by analysing the characters given in the original description in comparison to all other geophilomorphs known from Europe. The structure of the mouth-parts, the shape of the ventral pore-fields and the arrangement of the coxal pores indicate Photophilus to be in the closest relation with the genus Geophilus Leach, 1814 from which it is separated by characters which are shown here as artefacts or misinterpretations according to the judgement of the original descriptions illustrations. Considering the remaining characters of Photophilus and its type species-including the behavioural features-they actually fit only to the widespread European species Geophilus carpophagus Leach, 1815, which is formerly proposed here to be the subjective senior synonym of Photophilus griseus Folkmanova, 1928 (syn. nov.). Photophilus is formerly proposed here as subjective junior synonym of Geophilus (syn. nov.). PMID- 29245601 TI - Navigobius kaguya, new species of ptereleotrine goby (Teleostei: Gobiidae) from the West Pacific. AB - Navigobius kaguya is described on the basis of two specimens from the Ryukyu Islands, Japan, and Luzon, Philippines. It differs from other described species of the genus in live coloration, and in having: second dorsal-fin rays I,16; anal fin rays I,16; pectoral-fin rays 21-22; gill rakers 5-6 + 17; and first dorsal fin weakly to moderately incised between spines, taller than second dorsal. It closely resembles an undescribed species from Bali and the Maldives, but differs in lacking an orange-red mid-lateral stripe. The possible placement of Navigobius khanhoa in Oxymetapon is discussed. PMID- 29245602 TI - A new species of Wallacea Baly (Coleoptera: Chrysomelidae: Cassidinae: Bothryonopini) infesting coconut palm in the Indian Ocean Islands of Andaman & Nicobar. AB - Wallacea jarawa n. sp. infesting coconut palm (Cocos nucifera L., Arecaceae) in the Indian Ocean Islands of Andaman & Nicobar is described and illustrated. The structure of the endophallic sclerites is illustrated and used in species recognition. Borassus flabellifer L. (Arecaceae) and an unidentified rattan cane (? Calamus sp., Arecaceae) are reported as additional host plants. PMID- 29245603 TI - Acrosternum heegeri Fieber, 1861 (Hemiptera: Heteroptera: Pentatomidae), another Mediterranean bug expanding to the north. AB - Acrosternum heegeri Fieber, 1861 (Hemiptera: Heteropera: Pentatomidae: Pentatominae: Pentatomini), a Holomediterranean-Turanian shield bug species, is recorded for the first time from Hungary, representing the first known occurrence of the species in Central Europe. The species is illustrated, its geographic distribution is reviewed. The occurrence of A. heegeri in two localities in Budapest, regular records from one of the localities in the years 2015 and 2016, and the finding of an overwintering individual indicate the presence of a stable population in the city; the species is probably already established and it is locally abundant. Its further spread in Europe is expected. PMID- 29245604 TI - Benthic hydroids (Cnidaria, Hydrozoa) from bathyal and abyssal depths of the Northeast Atlantic held in the modern Discovery Collections. AB - The deep-sea benthic hydroid fauna remains poorly known, in part because of less frequent sampling than the shelf fauna, in part owing to the immense study area, and partly also because available samples have been little studied by experts. In order to correct this, deep-sea benthic hydroid material from the modern Discovery Collections has been studied. Samples come from localities in the North East Atlantic including the Porcupine Seabight, Porcupine Abyssal Plain, Rockall Trough, Rockall Bank, and the Mid-Atlantic Ridge. Sixteen species belonging to 12 families and 16 genera were found. Leptothecata are clearly dominant, being represented by 14 species; the remaining species belong to Anthoathecata. Lafoeidae and Tiarannidae are the most diverse families with three species each; the remaining families being represented by a single species. The low species diversity is remarkable at the generic level, with each genus being represented by a single species. Hydroid occurrence is low: twelve species were found in <= 9% of stations; Amphinema biscayana has the highest occurrence (27% of stations). Fifteen species were recorded in the Porcupine Seabight, two in the Rockall Trough, one at Rockall Bank, one on the Porcupine Abyssal Plain, and two at the Mid-Atlantic Ridge. The known bathymetric range for a third of the species is extended; the increase is particularly noteworthy in Amphinema biscayana, Acryptolaria crassicaulis, Clytia gigantea and Schizotricha profunda. Two distinct bathymetric groups are recognized: strictly deep-sea inhabitants and eurybathic species. Most species are globally distributed, some are widely distributed in the Atlantic, and others are limited to the North Atlantic or the Northeast Atlantic. PMID- 29245605 TI - Revision of Ephemerythus Gillies 1960 (Ephemeroptera: Tricorythidae). AB - Four species of Ephemerythus Gillies 1960 are described here. Larvae, subimagoes, imagoes of both sexes and eggs of Ephemerythus niger Gillies 1960 (= E. niger ugandanus Kluge 2010 syn. n.) and Ephemerythus pictus Gillies 1960 (= E. kiboensis Gillies 1960 syn. n.) are redescribed based on reared material from their type localities (Amani in Usambara Mountains and Marangu in Kilimandjaro respectively) and from other places in Tanzania. Larvae, subimagoes, imagoes of both sexes and eggs of a new species Ephemerythus nigricolor sp. n. are described based on reared material from Zambia. The species formerly reported as "Ephemerythus sp. C" (Kluge 2010a) is described here as Ephemerythus gilliesi sp. n., based on one larva with eggs, collected by M.T. Gillies in Cameroon. PMID- 29245606 TI - Morphological redescription of Culex (Microculex) davisi and Cx. (Mcx.) imitator (Diptera: Culicidae) including structures and stages not previously described. AB - The adults, male genitalia and fourth-instar larva of Culex (Microculex) imitator Theobald and Culex (Microculex) davisi Kumm, and the pupa of the latter species, are re-described. The female genitalia of both species and the pupa of Culex (Microculex) imitator are described for the first time. Information on distribution, bionomics and taxonomy is also included. PMID- 29245607 TI - Afrotropical Melambiina: revision of the genus Tragardhus Koch, 1956 and redescription of Pseudemmallus Koch, 1956 (Tenebrionidae: Pedinini). AB - The genus Tragardhus Koch, 1956 (Pedinini: Melambiina) is revised to include nine Afrotropical species, five of which are new. A taxonomic treatment of the genus is provided including a morphological study, new species descriptions, keys, illustrations, and notes on species distributions. The following species are included: Tragardhus (Mitragardhus) nodosus Koch, 1956, T. (M.) ewae sp. nov., T. (M.) ryszardi sp. nov., T. (M.) zuzannae sp. nov., Tragardhus (Tragardhus) biapicalis Koch, 1956, T. (T.) glandipleurum Koch, 1956, T. (T.) jani sp. nov., T. (T.) majae sp. nov. and T. (T.) stigmaticus Koch, 1956. Additionally, a monotypic genus Pseudemmallus Koch, 1956, previously known from a single specimen representing P. aspericollis Koch, 1956, is redescribed based on newly available material. PMID- 29245608 TI - An interesting sexually dimorphic species, Neoribates isabelaensis sp. nov. (Acari, Oribatida, Parakalummidae) with remarks on sexual dimorphism in Oripodoidea. AB - A new species Neoribates isabelaensis sp. nov. showing an interesting sexual dimorphism is described from bamboo litter on Luzon Island in the Philippines. This species is unique among other species of Neoribates in the structure of the posterior part of notogaster in males, which has a large round concavity bearing a pair of large sacculi S3. The specific function of this structure is not yet known, but the found sexual dimorphism is presumably involved in pheromonal communication allowing rapid sperm transfer. This is the fourth Neoribates species displaying sexually dimorphic characters. Additionally, Neoribates isabelaensis sp. nov. differs from the morphologically most similar species, Neoribates barbatus Hammer, 1968, by its smaller body size, pointed rostrum, long and setiform bothridial setae and the localization of notogastral setae h1 and h2, which insert close to each other. Further, we discussed all cases of sexual dimorphism in the family Parakalummidae as well as other related groups of Oripodoidea, and the possible function of these modifications. PMID- 29245609 TI - Taxonomic and nomenclatorial revision within the Neotropical genera of the subtribe Odontocheilina W. Horn in a new sense-19. Odontocheila microptera nom. nov., a new replacement name for O. euryoides W. Horn, 1922, and lectotype designation of O. nitidicollis (Dejean, 1825) (Coleoptera: Cicindelidae). AB - A new replacement name Odontocheila microptera nom. nov. for Odontocheila euryoides W. Horn, 1922 that is a junior primary homonym of Odontocheila bennigseni euryoides W. Horn, 1906 (currently Euryarthron bennigseni euryoides), is introduced. It has been confirmed that O. microptera, due to its atrophic thoracic wings, is the only flightless species of the genus and of the whole subtribe Odontocheilina W. Horn, 1899 sensu Moravec (2012). Redescription and illustrations of the habitus, diagnostic characters and biotope of this hitherto little know species, as well as of the similar O. nitidicollis (Dejean, 1825), along with the lectotype designation of the latter, are presented. Distributions and habitat of both species are treated and discussed. PMID- 29245610 TI - Discovery of the Dinoponera lucida male (Hymenoptera, Formicidae), a threatened giant ant from the Atlantic rain forest. AB - The male of the endangered ant Dinoponera lucida Emery is described, providing morphometric measurements, high-resolution images, and a distribution map of the species. This ant inhabits the Brazilian Atlantic forest, an ecosystem strongly impacted by fragmentation. The males show clear morphological differences from the known males of other species of Dinoponera. We briefly discuss the relevance of the male description for the conservation strategies of this ant. PMID- 29245611 TI - Cirrophorus species (Annelida: Polychaeta: Paraonidae) in the Sea of Marmara, with description of a new species. AB - This paper deals with specimens of Cirrophorus collected from the depths ranging from 3 to 500 m in 2012 and 2013 in the Sea of Marmara, Turkey. Among the material, one new species and two already known species were found. The new species is mainly characterized by having long and clavate notopodial postchaetal lobes in the branchial region; red speckles near nuchal organs; and a very long branch of lyrate chaetae (4 times longer than the shorter one). A recently described species, Cirrophorus nikebianchii, was found at the majority of soft bottom stations. All species found in the area were described and discussed. PMID- 29245612 TI - Description of two new species of Lithoxus (Hypostominae: Loricariidae) from rio Jari and rio Amapa basins, Brazilian Guiana Shield. AB - Two new species of Lithoxus, a genus diagnosed by possessing a dorsoventrally depressed body, a large round oral disk, and small tooth cusps with few teeth, are described from two drainages of the Guiana Shield: Lithoxus jariensis from the rio Jari basin and L. raso from the rio Raso, rio Amapa basin. The new species, L. jariensis, is distinguished from congeners by having an adipose fin, by the number of branched anal-fin and caudal-fin rays, by color pattern of the body, number of teeth, adipose-fin length, dorsal adipose-caudal distance, caudal peduncle depth, cleithral width, and dorsal-anal distance. Lithoxus raso can be diagnosed from congeners by coloration pattern, by having an adipose fin, by the number of branched anal-fin rays, number of teeth, adipose-fin length, dorsal adipose-caudal distance, caudal peduncle depth, and cleithral width. Greater genetic divergence in mitochondrial cytochrome oxidase subunit I (COI) confirms L. jariensis and L. raso as two new species. PMID- 29245613 TI - Micropygomyia (Coquillettimyia) nahua sp. nov., a new Phlebotominae sand fly from Mexico (Diptera, Psychodidae). AB - Micropygomyia (Coquillettimyia) nahua sp. nov., is described and illustrated based on male and female characteristics. Specimens were collected in the Municipality of Naolinco, state of Veracruz, Mexico. This new species of phlebotomine sand fly has characteristics corresponding to the series vexator Fairchild of Galati, with male similar to Micropygomyia (Coquillettimyia) apache (Young & Perkins), Mi. (Coq.) oppidana (Dampf) and Mi. (Coq.) vexator (Coquillett), but recognized by the male paramere structure and simple apex of aedeagal ducts in the male, the later exception for this species series. Female can be confused with Mi. (Coq.) vexator, Mi. (Coq.) oppidana and Mi. (Coq.) apache, but is distinguishable by the cibarial armature combined with the long and very slender individual spermathecal ducts. Keys for male and female species of Micropygomyia (Coquillettimyia) are provided. PMID- 29245614 TI - New species of the Genus Haliclona (Haplosclerida: Chalinidae) from Korea. AB - Two new marine sponges, Haliclona ieoensis sp. nov. and Haliclona sumenyoensis sp. nov. from the south Korea are described. Morphologically distinct from each other, both species are assigned to the genus Haliclona subgenus Haliclona. Haliclona ieoensis sp. nov. individuals are thickly encrusting to massive, beige colour and have small oscules flush on surface. Haliclona sumenyoesis sp. nov. individuals have a cylindrical tube with flexible stalk morphology, ivory colour, and large oscules. The description of these two new species brings the species of Haliclona (Haliclona) in Korea to five. PMID- 29245615 TI - A new species of Xenylla Tullberg, 1869 (Collembola: Hypogastruridae) from Central Amazon, Brazil. AB - A new species of the cosmopolitan genus Xenylla Tullberg, 1869 is herein described and illustrated. The new species, Xenylla hodori sp. nov., from the Amazon Forest of Northern Brazil, resembles X. capixaba Fernandes & Mendonca, 2010 and X. welchi Folsom, 1916 due, the number of eyes, chaetotaxy head and shape of furca. X. hodori sp. nov. is the second species recorded for the Brazilian Amazon Region. PMID- 29245616 TI - A new species of Menestho Moller, 1842 from the Arctic with remarks on Menestho albula (Fabricius, 1780)(Gastropoda: Heterobranchia: Pyramidellidae). AB - North Atlantic and Arctic representatives of the family Pyramidellidae had been intensively studied during the last decades. A valuable contribution was made by Waren (1989; 1991; 1993), who partially revised several genera from the Scandinavian waters. Norwegian representatives of the family were reviewed by Hoisaeter (2014). Distribution and diagnostic of many species had been specified by Schander (1995) and Nekhaev (2011; 2014; 2017). However, in the Eurasian Arctic Seas (except for the SW Barents Sea) only five species of Pyramidellidae had been recorded (Golikov et al. 2001; Kantor & Sysoev 2006; Nekhaev 2017): Liostomia eburnea (Stimpson, 1851), Chrysallida sublustris (Friele, 1886), Amaura candida (Moller, 1842), Amaura arctica (Dall et Bartsch, 1909) and Menestho truncatula Odhner, 1915. PMID- 29245617 TI - Revision of the Palaearctic and Oriental species of the genus Oides Weber, 1801 (Coleoptera: Chrysomelidae: Galerucinae). AB - Forty species of the genus Oides Weber, 1801 are considered as valid in the Palaearctic and Oriental regions. Six new species are described: O. bezdeki sp. nov., O. hsui sp. nov., O. takizawai sp. nov., and O. wangi sp. nov. from Sulawesi (Indonesia); O. boreri sp. nov. from Laos; and O. geiseri sp. nov. from India, Nepal, and Myanmar. The following synonymies are proposed: O. maculicollis Jacoby, 1886 as a junior synonym of O. apicalis Jacoby, 1883; O. niasensis Bowditch, 1925 as a junior synonym of O. duodecimpunctata (Clark, 1865); A. sumatrensis Blanchard, 1853, A. philippinensis Boheman, 1859, O. flavipes Duvivier, 1884, O. abdominalis Duvivier, 1884, O. subtilissima Duvivier, 1884, O. flavida Duvivier, 1884, O. elliptica Duvivier, 1884, O. marcida Duvivier, 1884, O. rhabodscelis Weise, 1922, O. bakeri Laboissiere, 1925, and O. ovalis Laboissiere, 1925 as junior synonyms of O. flava (Olivier, 1807); O. bengalensis Maulik, 1936 as a junior synonym of O. innocua Gahan, 1891; O. violaceipennis Duvivier, 1884 as a junior synonym of O. metallica Jacoby, 1884; O. indosinensis Laboissiere, 1927 as a junior synonym of O. palleata (Fabricius, 1801); O. sternalis Weise, 1913 as a junior synonym of O. quadriguttata Duvivier, 1884; O. gyironga Chen & Jaing, 1981 as a junior synonym of O. scutellata (Hope, 1830); O. indica Baly, 1879 and O. chinensis Weise, 1922 as junior synonyms of O. tarsata (Baly, 1865); O. tibialis Duvivier, 1884 as a junior synonym of O. vixilla Duvivier, 1884. Oides epipleuralis Laboissiere is removed from synonymy with O. laticlava (Fairmaire, 1889); O. laticlava (Fairmaire, 1889) removed from synonymy with O. maculata (Olivier, 1807); O. thibettana Jacoby, 1900 and O. tibiella Wilcox, 1971 removed from synonymies with O. tarsata (Baly, 1865). Neotypes are designated for Adorium maculatum Olivier, 1807; A. subhemisphaericum Guerin Meneville, 1830; A. diardi Guerin-Meneville, 1830; O. chinensis Weise, 1922; and O. leucomelaena Weise, 1922. Host plant information is provided when known. PMID- 29245618 TI - The checklist of longhorn beetles (Coleoptera: Cerambycidae) from India. AB - A checklist of longhorn beetles (Coleoptera: Cerambycidae) within the present geographical frontier of Indian subcontinent up to 2016 is provided. As per the current checklist prepared, there are 1536 species, classified under 440 genera, 72 tribes, and seven subfamilies of Cerambycidae (Parandrinae is not present in India). The report is accounted for 4.2 per cent of species, 7.94 per cent of genera and 28.24 per cent of tribes from India as compared to global record. For each species, accepted nomenclature followed by all relevant works reporting systematics, distribution and ecology of Indian longhorn beetles is provided along with synonyms, type locality and distribution within and outside India. PMID- 29245619 TI - Taxonomy of 'Euconnus complex'. Part XV. Disentangling the Euconnus Sciacharis knot (Coleoptera, Staphylinidae, Scydmaeninae). AB - Many species currently placed in Sciacharis Broun were once included in Euconnus Thomson, and their taxonomic history is complicated due to diffuse and overlapping diagnoses of both genera applied by previous authors, numerous virtually unjustified transfers of species between them, and hundreds of species not assigned to any subgenus. Based on comparative morphological studies of respective type species, we clarify the status of Allomaoria Franz, Austroconophron Franz, Magellanoconnus Franz, Neuraphoconnus Franz and Valdivioconnus Franz. All of them, except for Neuraphoconnus, were originally described as subgenera of Euconnus, later transferred to Sciacharis. Austroconophron is removed from synonymy with Sciacharis s. str. and resurrected as subgenus of Euconnus (resulting in Euconnus (Austroconophron Franz, status rest.); Allomaoria is retained as a junior synonym of Sciacharis s. str.; Magellanoconnus is removed from Sciacharis and restituted as genus (resulting in Magellanoconnus Franz, status rest.); Anthicimimus Franz, previously removed from subgenus of Sciacharis and elevated to genus rank, is reduced to subgenus of Magellanoconnus (resulting in Magellanoconnus (Anthicimimus stat. rev.); Neuraphoconnus is removed from synonymy with Magellanoconnus and resurrected as genus (resulting in Neuraphoconnus Franz, status rest.); and Valdivioconnus is transferred from subgenus of Sciacharis to subgenus of Microscydmus Saulcy & Croissandeau (resulting in Microscydmus (Valdivioconnus Franz, status rev.). The only Australian species of Magellanoconnus is transferred to Kangarooconnus Jaloszynski, gen. n. (resulting in Kangarooconnus carinifrons (Franz), comb. n.). A complete checklist of 302 species and subspecies previously or currently placed in Sciacharis (including 102 restituted and 50 new combinations) is given. Three replacement names are proposed for secondary homonyms resulted from new combinations: Euconnus (Austroconophron) caledonensides Newton, nom. n. (for Euconnus caledonensis Franz, 1986, not Euconnus caledonensis Franz, 1979); Magellanoconnus (s. str.) castrianus Jaloszynski & Newton, nom. n. (for Magellanoconnus castrii (Franz, 1967: 636), not Magellanoconnus castrii (Franz, 1967: 614)); and Sciacharis (Sciacharis) bryantides Newton, nom. n. (for Euconnus bryanti Franz, 1975, not Euconnus bryanti Lhoste, 1939). Lectotypes are designated (des. Jaloszynski) for Euconnus tindoui Franz, 1971, Phagonophana lanosa Broun, 1885, and Neuraphoconnus caledonicus Franz, 1971. PMID- 29245620 TI - Review of the comb-tailed spider genus Hahnia C.L. Koch 1841 (Hahniidae) from Gaoligong Mountains in Yunnan, China. AB - Gaoligong Mountains in Yunnan, China are famous for the biodiversity and are part of Indo-Burmese hotspot. We present a review on the comb-tailed spider genus Hahnia C.L. Koch 1841 based on newly collected specimens. Four new species of Hahnia are described: H. biapophysis sp. nov. (male), H. dongi sp. nov. (male), H. subsaccata sp. nov. (male, female) and H. wangi sp. nov. (male, female). Two additional known species are redescribed: H. himalayaensis Hu & Zhang, 1990 and H. musica Brignoli, 1978. Hahnia musica previously known from Bhutan is recorded from China for the first time. Photos of habitus and genitalia of all species and additionally illustrations of new species are given. PMID- 29245621 TI - The Vietnamese population of Megophrys kuatunensis (Amphibia: Megophryidae) represents a new species of Asian horned frog from Vietnam and southern China. AB - The Asian frog genus Megophrys is a diverse group of morphologically conserved, forest-dwelling frogs. The genus harbours highly localised species diversification and new species continue to be described on a regular basis. We examined the taxonomic status of a population of Megophrys frogs from the Hoang Lien Range in northern Vietnam and southern China previously identified as M. kuatunensis (subgenus Panophrys). Preliminary phylogenetic analyses using a fragment of 16S rDNA places the species in question within the Megophrys (subgenus Panophrys) species group, a primarily Chinese radiation within the genus. On the basis of morphological, molecular and bioacoustic data, we conclude that this population does not represent M. kuatunensis, or any known species in the genus. We herein describe this species of Megophrys as new. Known only from Sa Pa District, Lao Cai Province in Vietnam and Jinping County, Yunnan Province in China, the new species is likely to be threatened by ongoing deforestation in the region. We provide an updated species description of M. kuatunensis based on type specimens, and suggest that M. kuatunensis is likely to be restricted to eastern China. PMID- 29245622 TI - Review of the genus Eburodacrys White, 1853 (Coleoptera: Cerambycidae: Cerambycinae). AB - The genus Eburodacrys White, 1853 is redescribed. Four new species are proposed: Eburodacrys yolandae, from Colombia; E. eduardoi and E. bezarki, from Brazil, and E. santossilvai, from Venezuela. Eburodacrys curialis Gounelle, 1909; and Eburodacrys hesperidis Chemsak & Linsley, 1970 are proposed as synonyms of Eburodacrys nemorivaga Gounelle, 1909; and Eburodacrys amabilis Galileo & Martins, 2009 as synonym of Eburodacrys sulfurifera Gounelle, 1909. The genus is now composed of 89 species. The geographical distribution of 26 species is expanded and the specific locality in Colombia for E. ayri Galileo & Martins, 2006 and in Argentina for E. seabrai Zajciw 1958 are provided. Photographs of Eburodacrys species are included and a key to differentiate them is provided. PMID- 29245623 TI - Systematic position of the Afrotropical species described in Trachyphloeini (Coleoptera: Curculionidae: Entiminae). AB - The Afrotropical species described as Trachyphloeini Lacordaire, 1863 were examined and their taxonomic status is revised. Atrachyphloeus Voss, 1962 is proposed as a junior synonym of Phaylomerinthus Schoenherr, 1842, Cathormiocerus africanus Hoffmann, 1965 as a junior synonym of Tapinomorphus sylvicola Voss, 1962 and Trachyphloeus pustulifer Voss, 1959 as a junior synonym of Platycopes tuberculatus Marshall, 1906. Atrachyphloeus convergens Voss, 1962 is transferred to the genus Phaylomerinthus Schoenherr, 1842, Trachyphloeus hardenbergi Marshall, 1923 and T. notulatus Boheman, 1842 to Glyptosomus Schoenherr, 1847, Trachyphloeus nanus Fahraeus, 1871 to Pentatrachyphloeus Voss, 1974, Trachyphloeus pustulifer Voss, 1959 to Platycopes Schoenherr, 1823 and Trachyphloeus setiger Fahraeus, 1871 to Phaylomerinthus Schoenherr, 1842. "Trachyphloeosoma" brevicolle Voss, 1974, "Trachyphloeus" brevis Boheman, 1842, "T". nodifrons Hoffmann, 1968 and "T". squalidus Boheman, 1842 are provisionally left in their current genera, but new genera for them will be described in future papers. The genus Phaylomerinthus Schoenherr, 1842 has been redefined and redescribed. Lectotypes for the following species are designated (current names added in brackets where different): Cathormiocerus africanus Hoffmann, 1965 (Tapinomorphus sylvicola Voss, 1962), Trachyphloeus hardenbergi Marshall, 1923 (Glyptosomus hardenbergi (Marshall, 1923)), Trachyphloeus nanus Fahraeus, 1871 (Pentatrachyphloeus nanus (Fahraeus, 1871)), Trachyphloeus notulatus Boheman, 1842 (Glyptosomus notulatus (Boheman, 1842)), Trachyphloeus pustulifer Voss, 1959 (Platycopes tuberculatus (Marshall, 1906)), Trachyphloeus setiger Fahraeus, 1871 (Phaylomerinthus setiger (Fahraeus, 1871)), "Trachyphloeus" brevis Boheman in Schoenherr, 1842 and "Trachyphloeus" squalidus Boheman in Schoenherr, 1842. Two paralectotypes of Cathormiocerus africanus Hoffmann, 1965 from Tanzania are described as a new species, Tapinomorphus franzi sp. n. All type specimens are illustrated. PMID- 29245624 TI - Redescription and new records of Jansen's goatfish, Parupeneus jansenii (Mullidae), from the Western Pacific and Eastern Indian Ocean. AB - For Jansen's goatfish, Parupeneus jansenii (Mullidae), taxonomic knowledge has been rather poor and occurrence information restricted to a few localities only, with verified records from northern Sulawesi and Sunda Street (Indonesia), and Luzon (Philippines). This species is here included in the so-called "heptacanthus" group together with the Indo-Pacific cinnabar goatfish, P. heptacanthus, and five Indian Ocean congenerics, based on an evenly, symmetrically rounded posterior maxilla margin and similarities in meristic characters and preserved colour. In total 29 P. jansenii and 53 P. heptacanthus consisting of types, recently collected material from south-central Vietnam, southern Indonesia, and NE Australia, and geographically related reference material were studied along with single types of the other five heptacanthus group species and P. angulatus, a morphologically similar Western Indian Ocean species. In total 62 quantitative meristic and morphometric characters including standard length (SL) were analysed after splitting the data into two size classes (small-sized fish, < 110 mm SL, vs. large-sized fish > 110 mm SL) to account for size-related differences due to allometry. Diagnoses for P. jansenii and P. heptacanthus and a redescription for P. jansenii were prepared. Fresh-fish colour descriptions for both large- and small-sized voucher specimens of P. jansenii are provided and the effects of freshness status on colour patterns is documented. New records for P. jansenii for Vietnam, southern Indonesia and NE Australia (= first verified record for Australia) are reported and depth information (24-100 m depth range) is given for the first time. P. jansenii differs from the co occurring P. heptacanthus - independently of size - in shallower body and caudal peduncle, smaller maximum head depth, shorter barbels, caudal and pelvic fins, shallower first dorsal fin, shallower first ray of second dorsal fin, and lack of small dark red or reddish-brown spot on or just below the eighth lateral-line scale. The populations of P. jansenii from Vietnam and Australia differ from each other in a single character, the height of the eighth dorsal-fin ray, but both overlap with the intermediate population from Indonesia. This comprehensive alpha taxonomic approach provides a useful tool for uncovering the diversity of Parupeneus goatfishes. PMID- 29245625 TI - Hypostomus velhochico, a new keeled Hypostomus Lacepede, 1803 (Siluriformes: Loricariidae) from the rio Sao Francisco basin in Brazil. AB - Hypostomus velhochico sp. n., is described from the rio Sao Francisco basin, in the states of Minas Gerais and Bahia, Brazil. The new species is mainly distinguished from its congeners by a combination of characters such as slender bicuspid teeth, dentaries angled more than 90 degrees, conspicuous keels along lateral series of plates, small roundish dark spots, one plate bordering supraoccipital, spots aligned along lateral series of plates, and by attaining small to medium size. Hypostomus velhochico is widespread in the rio Sao Francisco basin and has a more similar general pattern of external morphology to species from the Northeastern Brazilian Coastal drainages than to species of the rio Sao Francisco basin. Aspects about its ecology and its putative relationship are discussed. PMID- 29245626 TI - The first record of Ia io Thomas, 1902 (Mammalia: Chiroptera: Vespertilionidae) from the Sundaic Subregion, with a description of a new subspecies from peninsular Thailand. AB - The Great evening bat Ia io Thomas, 1902, previously considered as an endemic to the Indochinese subregion, is reported from the Sundaic subregion for the first time based on specimens collected from three localities in Surat Thani Province and Phang Nga Province, peninsular Thailand. It is described herein as a new subspecies based on its substantially larger body and skull size. The mitochondrial COI and cytochrome b genes reveal that the new subspecies has a genetic distance of 1.89% and 1.65%, respectively, from the nominate subspecies. Echolocation calls comprise four harmonics, with the maximum energy in the first harmonic (fmaxe) of 23.6-27.4 kHz. Notes on the population size as well as roosting and foraging behaviour are also provided. PMID- 29245627 TI - First description of the male of the type species Meotipa picturata Simon, 1895 and description of a new Meotipa species (Araneae, Theridiidae) from India. AB - The present paper reports the first description of the type species of the theridid genus Meotipa, Meotipa picturata Simon, 1895 and redescribe the female of the same species with one new species Meotipa multuma sp.nov. from India. The two species are described in detail and we provide digital images and illustrations. Chrysso makiling, Barrion-Dupo & Barrion is transferred to Meotipa Simon, 1895 based on the presence of the generic characters of the last genus. PMID- 29245628 TI - Ressurrection of Curimatus albula Lutken (Characiformes: Curimatidae), a senior synonym of Cyphocharax lundi Dutra, Penido, Mello & Pessali. AB - Curimatus albula Lutken 1874 was described from the Ribeirao da Mata at Lagoa Santa, a tributary of Rio das Velhas, Rio Sao Francisco basin. The species validity was questioned by Lutken (1875) himself, who suggested that the species could be a synonym of Curimatus gilbert Quoy & Gaimard, a species described from the Rio Macacu, a coastal river tributary of Guanabara bay, Rio de Janeiro. That synonymy was only formally proposed by Eigenmann (1910), and followed by most subsequent authors (e. g. Nielsen, 1974; Vari, 1992), except for Fowler (1975), who erroneously listed C. albula as the senior synonym of C. gilbert. Vari (1989) posteriorly removed both nominal species from Curimatus Oken (= Curimata Bosch) reallocating them in Cyphocharax Fowler, based on the lack of synapomorphic conditions present in other valid curimatid genera. Vari (1989) considered that those nominal species belonged to a major group within Cyphocharax also including C. grandocule Fernandez-Yepez, C. modestus Fernandez-Yepez, C. santacatarinae Fernandez-Yepez, and C. voga Hensel, based on the presence of a rhomboidal caudal pigmentation and "random body spotting". Later, Vari (1992) included C. grandocule along with C. albula in the synonymy of C. gilbert, and listed several characters allowing further distinction of that species from the remaining species of the group (i.e., number of vertebrae, scales in transverse series, and pigmentation characters). Among the characters involving the pigmentation pattern, Vari (1992) stressed the lack of randomly arranged dark spots on the lateral and dorsolateral surfaces of the body in C. gilbert (versus present in C. voga). PMID- 29245630 TI - Three new species of Aponuphis (Annelida: Onuphidae) from eastern Australia. AB - The genus Aponuphis, previously known from the eastern North Atlantic and the Mediterranean, is newly reported from Australia. Three new species are described from off Sydney to Wollongong, New South Wales in sandy sediments, in depths of 25-70 m, bringing the number of recognized Aponuphis species to ten. Aponuphis annae n. sp. and A. bellani n. sp. are abranchiate, whilst A. danicae n. sp. has branchiae over a short region of its body. The tubes of A. annae and A. danicae have a fragile mucous consistency with attached sand grains and that of A. bellani is transparent, tight-fitting and smooth. Two specimens of A. annae were collected with developing juveniles in their tubes demonstrating their direct development but the reproductive mode of the other two species is not known. The distinguishing characteristics of all recognized species are tabled and a key to the three Australian species is presented. PMID- 29245629 TI - New feather mites of the genus Amerodectes Valim and Hernandes (Acariformes: Proctophyllodidae) from passerines (Aves: Passeriformes) in Georgia, USA. AB - Eight new species of the feather mite genus Amerodectes Valim and Hernandes, 2010 (Proctophyllodidae: Pterodectinae) are described from passerines (Aves: Passeriformes) in Georgia, USA: Amerodectes cathari sp. n. from Catharus ustulatus (Nuttall) (Turdidae), A. haemorhous sp. n. from Haemorhous mexicanus (Muller, PLS) (Fringillidae), A. helmitheros sp. n. from Helmitheros vermivorum (Gmelin) (Parulidae), A. hribari sp. n. from Geothlypis trichas (Linnaeus) (Parulidae), A. hylocichlae sp. n. from Hylocichla mustelina (Gmelin) (Turdidae), A. passerinae sp. n. from Passerina ciris (Linnaeus) (Cardinalidae), A. seiurus sp. n. from Seiurus aurocapilla (Linnaeus) (Parulidae), and A. spizellae sp. n. from Spizella passerina (Bechstein) (Emberizidae). An updated world checklist of Amerodectes species and a key to species recorded and potentially expected in North America (USA and Canada) are proposed. PMID- 29245631 TI - A new species of Tyrannomyrmex Fernandez 2003 (Formicidae, Myrmicinae, Solenopsidini) from Western Ghats, Kerala, India. AB - A new species of Tyrannomyrmex (Hymenoptera, Formicidae), T. alii sp. nov., is described from the Western Ghats of Kerala State in southern India. This new species can be distinguished from other Tyrannomyrmex species using morphological characters, from T.dux by the petiolar shape, and from T. legatus and T.rex by surface sculpture and pilosity. The gyne of the genus is described for the first time. We provide detailed morphological descriptions of the gyne and worker castes, images from scanning electron microscopy, a key to all four known species of Tyrannomyrmex, and a note on the ecology of this rare genus. PMID- 29245632 TI - Scolionema sanshin sp. n., a new species (Hydrozoa, Limnomedusae, Olindiidae) from the Ryukyu Archipelago, southern Japan. AB - A new species of hydrozoan jellyfish belonging to the order Limnomedusae is reported from the Ryukyu Archipelago, Southern Japan. The species belongs to the genus Scolionema, which prior to this study includes just a single valid species, S. suvaense. This name, however, has several junior synonyms and considerable diversity has been reported for different populations from Mediterranean, Indian ocean and Pacific ocean localities, including Central Japan. The species described in this paper, Scolionema sanshin sp. n., can be differentiated from all other described populations of Scolionema based on shape of gonad, number of tentacles of its medusa stage, and/or genetic sequences. A discussion of the diversity presently united under the name S. suvaense suggests that additional work is necessary to clarify the true number of Scolionema species. PMID- 29245633 TI - Redescription and designation of a neotype for Ophiothrix angulata (Say, 1825 (Echinodermata: Ophiuroidea: Ophiotrichidae). AB - Ophiotrichidae Ljungman, 1867 comprises brittle stars diagnosed by the absence of oral papillae and presence of a cluster of dental papillae covering at least half the height of the dental plate. Ophiothrix Muller & Troschel, 1840 is the largest genus in the family and is composed of many species with a highly variable morphology. Ophiothrix angulata is one species with descriptions showing morphological variation in many of the diagnostic characters stated by Say (1825) in the original description. Say's (1825) type material and specimens studied by him could be located. Thus, in order to elucidate the taxonomic identity of O. angulata and following Article 75 of the International Code for Zoological Nomenclature, here we propose the neotype designation of O. angulata based on topotype specimens from South Carolina, United States. A discussion of the records of O. angulata from the Atlantic Ocean is included. Taxonomic comments on the genus Ophiothrix are also provided. PMID- 29245634 TI - Two new species of Paramphimonhystrella (Nematoda, Monhysterida, Xyalidae) from the deep-sea sediments in the Western Pacific Ocean and adjacent shelf seafloor. AB - Two new species of marine nematodes, Paramphimonhystrella longispicula sp. n. in the deep-sea sediments from the Philippine Sea in the tropical Western Pacific Ocean with the water depth of 3920-5176 m and P. eurystoma sp. n. in the shelf seafloor from the East China Sea with the water depth of 55-64 m, are described. Both species possess long and slender spicules, which are present only in the congener P. barbula, a species discovered from the continental slope of New Zealand. Paramphimonhystrella longispicula sp. n. can be easily distinguished from P. barbula by the relatively broader buccal cavity, the unequally long cervical setae and a higher number of terminal setae. Paramphimonhystrella eurystoma sp. n. is unique in having a peculiar gubernaculum with two proximal capitula and a peculiar hammer-shaped cuticularized piece posterior to vulva, by which it can be distinguished from P. longispicula sp. n. and P. barbula as well as other congeners. Paramphimonhystrella longispicula sp. n. differs from P. eurystoma sp. n. also by the number of terminal setae (4 vs. 2). A dichotomous key to nine valid species of Paramphimonhystrella is provided. PMID- 29245636 TI - Additions to the description of Paroplocephalus atriceps (Serpentes: Elapidae) with a discussion on pupil shape in it and other Australian snakes. AB - Morphometric data on an additional twelve individuals of Paroplocephalus atriceps Storr are included enlarging Keogh et al.'s 2000 description of the genus and further verifying its affinities with Hoplocephalus. Included are comments on its venom and observations confirming arboreality and although primarily nocturnal, it includes some diurnal activity. Various authors have erroneously suggested it has vertically elliptic pupils but they are round. During an examination of snake's eyes, it was found that several additional species have pupils that require re-describing, especially Suta fasciata Rosen, S. punctata Boulenger and Echiopsis curta Schlegel, all of which include individuals with round pupils. A standardised description is suggested for each of the three common pupil shapes in snakes as narrow elliptic where dilation and constriction is lateral or vertical only, wide elliptic where dilation and constriction is both lateral and vertical, and round where any dilation and constriction is equidistant from the centre around the pupil's circumference. PMID- 29245635 TI - Updated information on genus Gomphidictinus (Odonata: Gomphidae) in China with description of Gomphidictinus tongi sp. nov. AB - A new gomphid species, named as Gomphidictinus tongi sp. nov. (Holotype male, Mt. Diaoluoshan, altitude 930m a.s.l., Lingshui County, Hainan Province, China) is described here. It is regarded as the third species of Gomphidictinus based on the presence of the basal spine on median segment of the penis organ. Gomphidia interruptistria Zha, Zhang & Zheng, 2005 is regarded as a junior synonym of Gomphidictinus perakensis (Laidlaw, 1902), which is recorded from Yunnan, China. PMID- 29245637 TI - Doryphoribius chetumalensis sp. nov. (Eutardigrada: Isohypsibiidae) a new tardigrade species discovered in an unusual habitat of urban areas of Mexico. AB - A new species, Doryphoribius chetumalensis, is described from specimens collected in the city of Chetumal (Quintana Roo state, Mexico). The species was found in a new and unusual habitat for urban tardigrades, i.e. the soil sediment accumulated on the border of streets. This discovery shows that tardigrades can live in this habitat, demonstrating once again the wide capacity of this taxon to tolerate adverse habitats, and to survive in environments with high anthropogenic impact. Doryphoribius chetumalensis sp. nov. differs from all the other species of the genus in having enlarged and wide bulbous base of the claws. Within Doryphoribius, it belongs to the zappalai group, and differs from the species in this group, not only in the claw shape, but also by the orange body colour, the smooth cuticle, the absence of a tooth in the wall of the buccal ring, and the absence of lunules under the claws. This is the first record of tardigrades, identified to species level, in Quintana Roo state. A taxonomic key of the Doryphoribius genus is also presented. PMID- 29245638 TI - Austrosciara Schmitz & Mjoberg, 1924, a senior synonym of Ctenosciara Tuomikoski, 1960 (Diptera: Sciaridae) and the description of a new brachypterous species in the genus. AB - Three species of wing-reduced Sciaridae, obtained from pitfall trap material collected from Nothofagus forests in Victoria, Australia, were examined. The females, which were all very similar, do not belong to any of the wing-reduced sciarid genera known to us so far. They instead appear to be females of the genus Austrosciara Schmitz & Mjoberg, 1924, according to the original description and illustration, and one of the species appears to be conspecific with Austrosciara termitophila Schmitz & Mjoberg. The shape of the male hypopygium, as well as the tibial organ of this species in both sexes show typical features of species previously classified as Ctenosciara Tuomikoski, 1960. The genus Ctenosciara Tuomikoski, 1960 n. syn. has therefore to be considered a junior synonym of Austrosciara Schmitz & Mjoberg. A further species described as Austrosciara pedibusa sp. n., based on female specimens, is typically characterized by a deep sensory pit on the basal segment of the palpus. The female of a third species, listed as Austrosciara sp., is illustrated as well. PMID- 29245639 TI - The black coral fauna (Cnidaria: Antipatharia) of Bermuda with new records. AB - The black coral fauna of Bermudan waters is poorly known, in large part due to the logistical challenges of surveying deep-water (>50 m) environments where most species occur. In 2016, the Nekton Expedition sought to survey the deep-water biodiversity around Bermuda using manned submersibles and mixed-gas technical SCUBA. A total of 28 black coral specimens were collected, and these were examined based on skeletal spine morphology, polyp morphology, colony branching pattern and in situ photographs. The specimens were assigned to seven species in three families and four genera, including (1) Antipathes atlantica Gray, 1857, (2) Antipathes furcata Gray, 1857, (3) Stichopathes pourtalesi Brook, 1889, (4) Stichopathes sp., (5) Distichopathes filix (Pourtales, 1867), (6) Tanacetipathes hirta (Gray, 1857), and (7) Tanacetipathes tanacetum (Pourtales, 1867). Of these, three species (Stichopathes sp., S. pourtalesi, and D. filix), one genus (Distichopathes) and one family (Aphanipathidae) are reported from Bermudan waters for the first time, thereby increasing the known black coral diversity of Bermuda to twelve species, five genera and four families. The diagnostic characters of the taxa identified as part of this study are illustrated and described. PMID- 29245640 TI - New species of Selasia Laporte, 1838 (Elateridae: Agrypninae: Drilini) from Nepal and Pakistan. AB - The neotenic click-beetle genus Selasia Laporte, 1838 is distributed mainly in the tropical Africa, and only a few species are known from the Palaearctic and Oriental regions. Herein, I describe and figure two new Palaearctic species: Selasia nigrobrunnea sp. nov. from the western Nepal, and Selasia sabatinellii sp. nov. from Pakistan. Both species are compared with their Palaearctic congeners, and an updated identification key to Selasia species from the Palaearctic region is provided. PMID- 29245641 TI - Two new species of free-living nematodes genera Microlaimus de Man, 1880 and Aponema Jensen, 1978 (Nematoda: Microlaimidae) from the Black Sea. AB - Two new species of the family Microlaimidae Micoletzky, 1922 are described and illustrated from the Black Sea. Aponema pontica sp. n. is morphologically closest to A. torosum in the shape of the body and spicules, size of amphids, but differs in having small and triangular cardia, absence of constriction in head region, shape of gubernaculum apophyses, rounded and weakly sclerotised lumen of pharyngeal bulb and longer spicules. Microlaimus paraglobiceps sp. n. morphologically resembles M. globiceps de Man, 1880 in the shape of the body, structure of the male sexual organs and presence of precloacal pore, but the main difference is a shorter body, cuticle finely annulated all over the body and absence of sexual dimorphism in the size of amphideal fovea. PMID- 29245642 TI - A new species of Laccobius Erichson and additional faunistic records of the genus from China, with a key to subgenus Glyptolaccobius Gentili (Coleoptera: Hydrophilidae). AB - A new species of water scavenger beetle, Laccobius (Glyptolaccobius) yinziweii sp. nov. is described from Yunnan, China. Diagnostic characters are illustrated. Laccobius (Cyclolaccobius) nitidus Gentili, 1984 is reported from Guizhou, Laccobius (Microlaccobius) hammondi Gentili, 1984 from Hubei, and Laccobius (s. str.) inopinus Gentili, 1980 from Guizhou for the first time. Additionally, an identification key to Laccobius (Glyptolaccobius) of the world is updated. PMID- 29245643 TI - An updated checklist of Iranian Encyrtidae (Hymenoptera, Chalcidoidea). AB - An updated checklist of Iranian Encyrtidae (Hymenoptera, Chalcidoidea) is presented based on literature records from 1947-2016. The current list includes 159 species representing 48 genera. Parasitoid-host associations in Iran and distributional data are also provided. Twelve encyrtid species (7.55%) are known only from Iran but a high number of species (68 species, 42.77%) are widely distributed in the Palaearctic region. Four species previously listed from Iran, Metaphycus angustifrons Compere, 1957, Homalotylus ephippium (Ruschka, 1923), H. sinensis Xu & He, 1997, and Ooencyrtus kuvanae (Howard, 1910) are no longer considered present. Hosts of Iranian encyrtid species are tabulated by order and family, with the majority being Hemiptera (66.98%), followed by Lepidoptera and Coleoptera (each 9.44%), Diptera (6.60%), Hymenoptera (4.71%) and Neuroptera (2.83%). The majority of Encyrtidae known in Iran are parasitoids of the superfamily Coccoidea (46.22%). Host-plant associations of Iranian Encyrtidae are also tabulated, by plant family. PMID- 29245644 TI - Ptyctimous mites (Acari, Oribatida) of Victoria (Australia). AB - A list of 37 species of ptyctimous mites from the State of Victoria, Australia, is provided. Seven species new for science are described and further seven are recorded for the first time in Victoria. The genus Arphthicarus has been discovered in Victoria and is represented by two new species. Zoogeographical distribution of each species is provided. Analysis of the ptyctimous fauna from four Victorian areas (Otway Ranges, Yarra Ranges, Errinundra Plateau and Strzelecki Ranges) has revealed that four species occur in a large number of specimens in one of the areas. Similarity analyses indicate that the faunas of Errinundra Plateau and Yarra Ranges are the most similar. An overview of state of knowledge on the ptyctimous mites from State of Victoria, Australia and Australasian Region is presented. PMID- 29245645 TI - Revision of the genus Centrophorus (Squaliformes: Centrophoridae): Part 2 Description of two new species of Centrophorus and clarification of the status of Centrophorus lusitanicus Barbosa du Bocage & de Brito Capello, 1864. AB - Centrophorus specimens with a distinctive long-based first dorsal fin (long finned species) have previously been considered to be Centrophorus lusitanicus first described from Portugal. Critical examination of the original description and illustration reveal that C. lusitanicus should be considered a junior synonym of C. granulosus. However, the specimen considered to be the syntype of C. lusitanicus in the Natural History Museum in London is clearly a long-finned species and not conspecific with C. granulosus. A more detailed investigation revealed that this specimen should not be considered a syntype and was likely not originally collected off the coast of Portugal. Investigation of long-finned specimens of Centrophorus from the Indo-West Pacific and Eastern Atlantic revealed that two undescribed species exist and are herein formally described as C. lesliei and C. longipinnis. The two species are similar morphologically and belong to the long-snout Centrophorus group (e.g. C. isodon and C. harrissoni) but are clearly separable based on their very long first dorsal fins. The two species differ in relative length of the first dorsal fin and several other characters. They also differ genetically. Nonmetric multidimensional ordination based on morphometric data reveals both species level and ontogenetic differences. A short erratum is also provided for Part 1 of this revision of the Centrophorus due to two figure related errors which may cause some confusion. PMID- 29245646 TI - Study of Laemostenus species across Zagros and Central zone of Iran, with the description of seven new cavernicolous species and notes on subgenus Iranosphodrus (Coleoptera: Carabidae: Sphodrini). AB - The species belonging to the Sphodrine genus Laemostenus Bonelli, 1810 from central and southern Zagros Mts. and central zones of Iran were studied. Two new species-groups of the subgenus Antisphodrus Schaufuss, 1865 are proposed, and seven new species belonging to subgenera Antisphodrus Schaufuss, 1865 and Iranosphodrus Lohaj & Casale, 2011 are described. Morphological characters of the habitus and shape of male genitalia were used to delimit the species. New species of subgenus Antisphodrus are: L. (A.) zagrosensis sp. nov. and L. (A.) speleophilus sp. nov. from Chaharmahal and Bakhtiari province, and L. (A.) farsicus sp. nov. from Fars province (zagrosensis species-group); Laemostenus (A) zakariyiensis sp. nov. from Fars province (aequalis species-group), and L. (A.) shirazensis sp. nov. from Fars province (glasunowi species-group). Based on the newly collected material, the subgenus Iranosphodrus is redefined and two new species from Yazd province are described: L.(I.) yazdensis sp. nov. and L.(I.) troglophilus sp. nov. An identification key for the Laemostenus species of the studied area is provided, and a check list for Iranian representatives of subgenera Antisphodrus and Iranosphodrus are given. PMID- 29245647 TI - Thayeria tapajonica (Characiformes: Characidae), a new species from rio Tapajos basin, Brazil. AB - A new species of penguin tetra, Thayeria tapajonica, is described from the rio Tapajos basin. It is most similar to T. boehlkei by presenting a straight midlateral stripe running anteriorly to immediately posterior to the head, while in T. ifati and T. obliqua the midlateral stripe is restricted to the caudal peduncle, merging with an anterodorsal oblique stripe. The new species is restricted to the rio Tapajos basin downriver of the confluence of the rio Juruena and rio Teles Pires, and lower rio Teles Pires, where its distribution overlaps with T. boehlkei. PMID- 29245648 TI - A new species of Hyalella (Crustacea: Amphipoda: Hyalellidae) from Itatiaia National Park, Brazil: an epigean freshwater amphipod with troglobiotic traits at 2,200 meters of altitude. AB - A new species of the freshwater amphipod Hyalella Smith, 1874 is described for the plateau of the Itatiaia National Park, located between the states of Minas Gerais and Rio de Janeiro, southeastern Brazil. This is the first Brazilian species of Hyalella found at more than 2,200 meters of altitude. The specimens were found in a small stream, buried under rocks, in the higher area of the Park. The main morphological characteristics that differentiate the new species are the extreme reduction of the size of the uropod 3, absence of apical setae on telson, absence of comb-scales on gnatopods 1 and 2, absence of curved seta on inner ramus of uropod 1 and sternal gills tubular on pereonites 3 to 7. The new species presents similarities with some cave species of the genus, apparently being troglophile and that is the process of adaptation to the hypogean habitat. The importance of creating new protected areas for the conservation of Hyalella in Brazil is discussed. PMID- 29245649 TI - Rediscovery of Atelopus subornatus Werner, 1899 (Anura: Bufonidae), with a redescription of the tadpole. AB - The Neotropical toads of the genus Atelopus are among the most imperiled of all amphibians (La Marca et al. 2005; Gonzalez-Maya et al. 2013; McCaffery et al. 2015). Nowadays, at least 90% of the 93 listed species are threatened and more than 77% are Critically Endangered (McCaffery et al. 2015; IUCN 2016). Colombia has 44 described species of Atelopus (Frost 2017), two of these are categorized as extinct (EX) by the IUCN (2016): A. ignescens and A. longirostris, although they were recently re-discovered in Ecuador (Tapia et al. 2017), 34 as critical endangered (CR), four as endangered (EN), two as vulnerable (VU), one species has data deficient (DD) and another one has not been evaluated. Atelopus subornatus Werner, 1899, is an endemic Colombian harlequin toad described from 2300 to 2800 m.a.s.l in the municipalities of Sibate (Alto de Sibate and Agua Bonita) and Fusagasuga (above Fusagasuga and Tierra Negra), in Cundinamarca (Fig. 1A), on the western flank from Cordillera Oriental of Colombia (Werner 1899; Lynch 1986; Lotters 1989, 1992). The last record of this species was in 1993 (Lotters 2005), and it currently is listed as Critically Endangered by the IUCN (2016). Herein, we report the rediscovery of A. subornatus at a new locality from Tolima, Colombia (Fig. 1A), and redescribe its tadpole. The determination of the species was based on comparisons with material deposited in the amphibian collection of the Instituto de Ciencias Naturales, Universidad Nacional de Colombia (ICN-UNAL) for all species of Atelopus reported from the same general area in Cundinamarca and relatively similar to A. subornatus. The specimens are housed in the Herpetological collection of the Tolima University (CZUT-A) and amphibian collection of ICN-UNAL. PMID- 29245650 TI - On the identity and status of Darala lineosa (Lepidoptera: Eupterotidae). AB - In 1862, F. Walker described Darala lineosa in the family Liparidae (now Erebidae, subfamily Lymantriinae) on a single female (he stated that it is a male but see Swinhoe 1892: 209) from Australia (Walker 1862: 269). The genus Darala is now considered a synonym of the large genus Anthela which belongs to the Anthelidae, a family entirely confined to the Australian region with representatives in Australia and New Guinea (Edwards & Fairey 1996: 258). These authors mention 61 Anthela species with about the same amount of synonymic species-group names, but they do not cite Darala lineosa, already indicating that this species does not belong to the Australian fauna and hence that the indication of "Australia" in the original description, and repeated in Walker (1865: 369), is erroneous. PMID- 29245651 TI - A new genus of Trichogrammatidae (Hymenoptera: Chalcidoidea) from India. AB - A new genus and species, Ayaanella globugaster M.T. Khan & Anis gen. nov. and sp. nov. (Hymenoptera: Trichogrammatidae) is described from two females collected in Uttar Pradesh State of India. PMID- 29245652 TI - Two new species of the genus Laena Dejean (Coleoptera: Tenebrionidae: Lagriinae) from Hong Kong. AB - Two new species of the genus Laena Dejean, 1821 (Coleoptera: Tenebrionidae: Lagriinae) are described from Hong Kong: Laena hongkongica sp. n. and Laena walkeri sp. n. These constitute the first record of the genus from Hong Kong, as a species previously described from nearby area Laena ovipennis Schuster, 1926, in fact originated from Zhejiang province nearby Shanghai. Both species from Hong Kong possess a wide variation in body length, which is quite unusual for this genus. PMID- 29245653 TI - Discovery of the genus Lebioderus (Coleoptera, Carabidae, Paussinae) from China, with description of two new species. AB - The rare paussine genus Lebioderus Westwood, 1838 is reported from China for the first time, based on two new species, L. sinicus Song & Maruyama sp. nov. and L. maolanus Song & Maruyama sp. nov. The type series of L. sinicus was collected from nests of Carebara Westwood, 1840 ants, which is also a first host record for Lebioderus. PMID- 29245654 TI - Contributions to the palaeofauna of Ptinidae (Coleptera) known from Baltic amber. AB - Hemicoelus favonii sp. nov. is described and illustrated from Eocene Baltic amber. This new fossil species differs from extant congeners in having 11 segmented antennae; a metathoracic ventrite with large impression in its anterior portion; a pronotum distinctly narrower than the elytral base region; the posterior suture of abdominal ventrite 1 weakly arcuate medially; sharp lateral pronotal margins that are incomplete and distinct in their basal half only; elytral striae that are not grouped in pairs; posterior pronotal angles that are rounded; elytral intestriae 3, 5, 7 and 9 that are distinctly convex; and a comparatively small total body size. The presence of Hemicoelus in Baltic amber suggests that moist, rotting wood was available as a microhabitat in the ancient forest. Beyond the new species description, the systematic placement of Anobium jacquelinae Hawkeswood, Makhan & Turner is discussed. A new fossil record for Microbregma waldwico Bukejs & Alekseev, and the first report of the genus Trichodesma LeConte from Eocene Baltic amber are also presented. PMID- 29245655 TI - On the taxonomy of the genus Acronicta (Lepidoptera, Noctuidae). IV. Acronicta digna species-complex. AB - The present paper is the fourth in a series of articles on the genus Acronicta Ochsenheimer (Volynkin et al. 2015; Volynkin 2015; Volynkin et al. 2016). In here, we revive A. metaxantha (Hampson 1909) stat. n., which was synonymized with A. digna (Butler, 1881) by Han & Kononenko (2010) to the species level, designate the neotype for Acronycta agnata Draudt, 1937 and revise the synonymy of A. digna and A. agnata. PMID- 29245656 TI - A new species of the genus Euhemicera (Tenebrionidae: Cnodalonini) from South East Asia, with an updated catalogue of all known species. AB - The genus Euhemicera Ando, 1996 (Tenebrionidae: Cnodalonini) is recorded from Myanmar for the first time. The newly identified representatives of this genus are described herein as Euhemicera amicorum sp. n.. An updated species catalogue of Euhemicera with distributional data is provided. Currently, one hundred species are known to represent this genus. Available data reveals that Euhemicera is widely distributed throughout the oriental region, with the highest diversity in South East Asia. PMID- 29245657 TI - Revision of Brada Stimpson, 1853, and Bradabyssa Hartman, 1967 (Annelida, Flabelligeridae). AB - Among flabelligerid genera Brada Stimpson, 1853 includes several species whose bodies are fusiform or club-shaped, often with a reduced number of chaetigers, and their members are found in temperate and polar waters. In contrast, Bradabyssa Hartman, 1967 is regarded as a monotypic genus with a single Antarctic species with a cylindrical body and a variable number of chaetigers. After examination of all type and non-type material available of both genera, two distinct body patterns were distinguished: one includes the type species for Brada, B. granosa Stimpson, 1853, has only 8 branchial filaments and the neurochaetae are thick, blunt, often falcate, whereas the other includes the type species of Bradabyssa, B. papillata Hartman, 1967, usually has many branchial filaments and neurochaetae are straighter and mucronate. Consequently, Brada is herein restricted to include only 5 species, one of which is new, Brada kudenovi n. sp. Bradabyssa is herein emended to include many species formerly regarded as belonging in Brada, as new combinations, and species can be separated into four groups according to the development of the tunic and its sediment load. Thirteen new species of Bradabyssa are also described: B. indica n. sp., B. mexicana n. sp., B. alaskensis n. sp., B. elinae n. sp., B. grangieri n. sp., B. levensteinae n. sp., B. harrisae n. sp., B. hartmanae n. sp., B. jirkovi n. sp., B. kirkegaardi n. sp., B. monnioti n. sp., B. mezianei n. sp. and B. willeyi n. sp. The species belonging to Brada are B. granosa, B. granulosa Hansen, 1880, B. incrustata Stop-Bowitz, 1948, B. inhabilis (Rathke, 1843), and B. kudenovi n. sp. The species belonging to Bradabyssa are separated into four groups according to the development of their tunic and its sediment load. Group crustosa includes B. indica n. sp., B. mexicana n. sp., B. minuta (Amoureux, 1986) n. comb., and B. sachalina (Annenkova-Chlopina, 1922) n. comb. Group nuda includes B. alaskensis n. sp., B. antarctica (Hartman, 1978) n. comb., B. bransfieldia (Hartman, 1966) n. comb., B. nuda (Annenkova-Chlopina, 1922) n. comb., B. rugosa (Hansen, 1880) n. comb., and B. strelzovi (Jirkov & Filippova in Jirkov, 2001) n. comb. Group verrucosa contains B. abyssalis (Fauchald, 1972) n. comb., B. annenkovae (Buzhinskaja, 2001) n. comb., B. elinae n. sp., B. grangieri n. sp., B. irenaia (Chamberlin, 1919) n. comb., B. levensteinae n. sp., B. mammillata (Grube, 1877) n. comb., B. ochotensis (Annenkova-Chlopina, 1922) n. comb., B. papillata Hartman, 1967, B. tenebricosa (Berkeley, 1966) n. comb., n. status, and B. verrucosa (Chamberlin, 1919) n. comb. Group villosa contains B. capensis (Day, 1961) n. comb., n. status, B. harrisae n. sp., B. hartmanae n. sp., B. ilyvestis (Hartman, 1960) n. comb., B. intoshi (Caullery, 1944) n. comb., B. jirkovi n. sp., B. kirkegaardi n. sp., B. monnioti n. sp., B. parthenopeia (Lo Bianco, 1893) n. comb., B. pilosa (Moore, 1906) n. comb., B. pluribranchiata (Moore, 1923) n. comb., B. setosa (Verrill, 1873) n. comb., B. mezianei n. sp., B. tzetlini (Jirkov & Filippova in Jirkov, 2001) n. comb, B. villosa (Rathke, 1843) n. comb., B. whiteavesi (McIntosh, 1885) n. comb and B. willeyi n. sp. Keys to aid identification of all genera in Flabelligeridae, to species in Brada, and for the species belonging in the four species groups of Bradabyssa are included. PMID- 29245658 TI - Hydraenidae of Madagascar (Insecta: Coleoptera). AB - The Madagascar fauna of the beetle family Hydraenidae is comprehensively revised, based on the study and databasing of 6,949 specimens. New collection records are provided for 11 previously described species, and 95 new species are described. Three new subgenera of Hydraena, viz. H. (Micromadraena), H. (Monomadraena), and H. (Dnahydnaedna) are described, and several new species groups of Hydraena are diagnosed. Two new genera in the tribe Madagastrini are described: Menomadraena and Trinomadraena. The Malagasy hydraenid fauna now comprises 106 species arrayed in the following nine genera: Aulacochthebius (2), Hydraena (65), Limnebius (10), Madagaster (8), Menomadraena (6), Ochthebius (1), Protozantaena (5), Sicilicula (8), and Trinomadraena (1). Lectotypes are designated for the following species: Aulacochthebius plicicollis (Fairmaire), 1898 (Ochthebius); Hydraena dilutipes Fairmaire, 1898; Hydraena impressicollis Fairmaire, 1898; Hydraena marginicollis Regimbart, 1903 (= Hydraena regimbarti Zaitzev 1908; nomen novum); and Ochthebius alluaudi Regimbart, 1903. Hydraena discicollis Fairmaire, 1898, is considered a nomen dubium: no type specimens were found, and the description appears to be that of a species of Aulacochthebius or Ochthebius, not Hydraena. High resolution digital images of lectotypes and holotypes of new species are presented (online versions in color). Male genitalia, representative antennae, maxillary palpi, and female terminal abdominal segments and spermathecae are illustrated. Geographic distributions of all species are mapped. Possible colonization and vicariance events are discussed at the tribal, generic and species group levels. The tribe Madagastrini, found only in Madagascar and southern India, is hygropetric, indicating that this microhabitat type has been continuously present in both Madagascar and India at least since the two separated, currently estimated to be 88 million years ago. Contrastingly, some lowland lentic species of other genera appear to be closely related to species in southern Africa, suggesting rather recent colonization events. New species of Aulacochthebius: A. perlaevis (Mahajanga, Boeny: Mahavavy Kinkony RS). New species of Hydraena (Micromadraena): H. breviceps (Fianarantsoa, 29 km SSW Ambositra, Ankazomivady); H. fortipes (Antsiranana, Foret d' Antsahabe); H. genuvela (Antsiranana, Foret de Binara); H. parvipalpis (Antananarivo, Reserve Speciale d'Ambohitantely); H. rubridentata ((Mahajanga, Parc National de Namoroka); H. serripennis (Antsiranana, Foret d' Antsahabe). New species of Hydraena (Monomadraena): H. acicula (Antsiranana, Antsaba, Galoko Mountains); H. ambohitantely (Antananarivo, Ambohitantely Spec. Res.); H. amplexa (Fianarantsoa, Andringitra NP); H. amplipunctata (Fianarantsoa, 7 km W Ranomafana); H. antsahabe (Antsiranana, Foret d' Antsahabe); H. bergsteni (Antsiranana, Diana: Beraty); H. bisinuata (Toamasina, Tamatave 6.3 km S Ambanizona); H. bisinuloba (Toliara, Menabe: Kirindy RS.); H. bispica (Toamasina, Alaotra Mangoro: Analamazoatra SR); H. casacolumna (Fianarantsoa, Andringitra NP); H. compacta (Antananarivo, Ankaratra, Reserve Manjakatompo); H. contracolorata (Antsiranana, Montagne des Francais); H. epipleurata (Antsiranana, Foret de Binara); H. furcula (Toliara, 40km N of Fort Dauphin, Managotry); H. gereckei (Antananarivo, Ankaratra, Reserve Manjakatompo); H. goldschmidti (Antananarivo, Anjozorobe, Ravoandrina); H. inseriata (Antananarivo, Anjozorobe, Ravoandrina); H. jubata (Antsiranana, Sava Marojejy NP); H. levifurcata (Fianarantsoa, Namarona River, 7 km SW Ranomafana); H. lubrica (Antananarivo, Ambohitantely Spec. Res.); H. mahavavona (Fianarantsoa, Ionilahy, Mahavavona); H. manjakatompo (Antananarivo, Ankaratra, Reserve Manjakatompo); H. marojejy (Antsiranana, Parc National de Marojejy); H. multiarcuata (Fianarantsoa, Ranomafana); H. oscillata (Toamasina, Alaotra Mangoro Andasibe-Mantadia NP); H. parvispinosa (Toamasina, Andasibe NP); H. pentarubra (Antsiranana, Montagne d'Ambre); H. quatriloba (Toliara, Andohahela NP, Tsimelahy); H. ranomafana (Fianarantsoa, Ranomafana); H. ravoandrina (Antananarivo, Anjozorobe, Ravoandrina); H. rubrifurcata (Antsiranana, Sava, Marojejy NP); H. sculponea (Antsiranana, Befingotra (9.2 km WSW), Res. Anjanaharibe-Sud); H. simplicata (Antsiranana, Montagne d'Ambre); H. tibiodentipes (Fianarantsoa, Andringitra NP); H. triaequalis (Fianarantsoa, Ranohira); H. tripartita (Fianarantsoa, Ranomena); H. upsilonica (Toamasina, Zahamena NP); New species of Hydraena (Hydraenopsis): H. andranomena (Toliara, Andranomena); H. arta (Antsiranana, Parc National de Marojejy); H. bucollis (Toamasina, Tamatave, Andranobe Field Station); H. clavulata (Fianarantsoa, Ranomafana); H. contorta (Antananarivo, Anjozorobe forest reserve); H. dilutipoides (Mahajanga, Parc National Tsingy de Bemaraha); H. divisa (Antsiranana, Antsaba,Galoko Mountains); H. elementaria (Antananarivo, Tamatave, Coastal lagoon); H. fulgidicollis (Antananarivo, Parc de Tsimbazaza); H. longiloba (Fianarantsoa, Madiorano); H. nanula (Antsiranana, Ankarana, Ampositelo); H. orchisa (Toamasina, Alaotra Mangoro Andasibe-Mantadia NP); H. pilobova (Antsiranana, Sava, Marojejy NP); H. pilotumida (Fianarantsoa, 7 km W Ranomafana); H. ranarilalatiani (Toamasina, Alaotra Mangoro: Analamazoatra SR); H. randriamihajai (Antsiranana, Diana: Montagne d'Ambre NP); H. renalisa (Antsiranana, Sambava: Marojejy NP); H. sinuatipes (Antsiranana, Ankarana); H. torquata (Fianarantsoa, Andringitra NP). New species of Limnebius: L. angulatus (Fianarantsoa, Namarona River, 7 km W Ranomafana); L. balkei (Antsiranana, Montagne d'Ambre); L. bergsteni (Fianarantsoa, Namarona River, 7 km W Ranomafana); L. clandestinus (Mahajanga, Boeny:Mahavavy Kinkony RSc); L. labratus (Toamasina, Maroantsetra); L. lacrimosus (Toamasina, 18.7911S 48.4259E Alaotra Mangoro Andasibe-Mantadia NP); L. lobatus (Toliara, Manakaravavy); L. maximadus (Toamasina, Alaotra Mangoro: Analamazoatra SR); L. nanostillus (Antsiranana, Ankarana); L. steineri (Fianarantsoa, 7 km W Ranomafana). New species of Madagaster: M. barbata (Fianarantsoa, Andringitra NP); M. bergsteni (Antananarivo, 18.8704S 47.6708E Analamanga); M. cataracta (Antsiranana, Sava, Marojejy NP); M. procarina (Fianarantsoa, 32 km S Ambositra); M. quadricurvipes (Fianarantsoa, Andringitra NP); M. simplissima (Fianarantsoa, 32 km S Ambositra). New species of Menomadraena: M. andringitra (Fianarantsoa, Res. Andringitra); M. concava (Fianarantsoa, R.S. Ivohibe); M. fisheri (Toliara, Enakara (11 km NW), Res. Andohahela); M. ivohibe (Fianarantsoa, R.S. Ivohibe); M. nitedula (Fianarantsoa, Res. Andringitra); M. sembella (Fianarantsoa, Amparihibe). New species of Protozantaena: P. duplicata (Antananarivo, Vakinankaratra: Manjakatompo Stn. Forestiere); P. elongata (Antananarivo, Vakinankaratra: Manjakatompo Stn. Forestiere). New species of Sicilicula: S. ampla (Antananarivo, Onive River near Ilempona); S. bergsteni (Fianarantsoa, 21.2263S 47.3694E, Matsiara Ambony, Ranomafana NP); S. conjugalis (Fianarantsoa, Namarona River, 7 km SW Ranomafana); S. cordicollis (Fianarantsoa, Namarona River, 7 km SW Ranomafana); S. hygropetrica (Fianarantsoa, Matsiara Ambony, Ranomafana NP); S. malagasica (Fianarantsoa, Abohimahasoa); S. sexplanata (Antsiranana, Mt. Tsaratanana). New species of Trinomadraena: T. clusa (Antsiranana, Mt. d'Ambre). PMID- 29245659 TI - Taxonomic revision of Neotropical Phyllocnistis Zeller, 1848 (Lepidoptera: Gracillariidae), with descriptions of seven new species and host plant associations. AB - Until now, 20 species of leaf-mining micromoths of the genus Phyllocnistis Zeller (Lepidoptera, Gracillariidae) have been known to occur in the Neotropical region. Here we revise the previously known species and describe seven new species: four from French Guiana, P. kawakitai Brito & Lopez-Vaamonde, sp. nov., P. norak Brito & Lopez-Vaamonde, sp. nov., P. ohshimai Brito & Lopez-Vaamonde, sp. nov., P. petronellii Brito & Lopez-Vaamonde, sp. nov.; and, three from Brazil, P. helios Brito & Moreira, sp. nov., P. jupiter Brito & Moreira, sp. nov. and P. xylopiella Brito & Becker, sp. nov. Lectotypes are designated for P. aurilinea Zeller, 1877; P. citrella Stainton, 1856; P. rotans and P. sexangula Meyrick, 1915. Detailed descriptions of the pattern of forewing fasciae are provided for all species. Host plant associations, photographs of adults and illustrations of genitalia, when available, are provided for the described species of Neotropical Phyllocnistis. In addition, DNA barcodes were used for the delimitation of some species. PMID- 29245660 TI - Mayflies of the genus Epeorus Eaton, 1881 s.l. (Ephemeroptera: Heptageniidae) from the Caucasus Mountains: a new species of Caucasiron Kluge, 1997 from Georgia and Turkey. AB - The new species Epeorus (Caucasiron) bicolliculatus sp. nov. is described based on larvae and adults. Diagnostic characters are given with regard to the related species. The most pronounced difference is represented by protuberances on larval abdominal terga II-IX, present exclusively in E. (C.) bicolliculatus sp. nov. Primary data on the biology and distribution of the new species are also provided. Delimitation of the new species is verified by the analysis of COI (barcode) sequences. Barcode data for all Caucasian species of the subgenus Caucasiron are provided for the first time and compared with E. (C.) bicolliculatus sp. nov. PMID- 29245661 TI - On some minuscule spiders (Araneae: Theridiosomatidae, Symphytognathidae) from the Choco region of Ecuador with the description of ten new species. AB - The spider families Theridiosomatidae and Symphytognathidae found in the Choco region of Ecuador are examined, a total of 16 and 69 adult specimens were collected respectively in a series of expeditions. In the family Theridiosomatidae, eight new species are described in four different genera; Chthonos kuyllur n. sp.; Naatlo mayzana n. sp.; Ogulnius laranka n. sp., O. paku n. sp.; Theridiosoma ankas n. sp., T. esmeraldas n. sp., T. kullki n. sp., and T. sacha n. sp. We present the first record of the family Symphytognathidae for Ecuador with the description of two new species in two different genera: Anapistula equatoriana n. sp. and Symphytognatha cabezota n. sp. PMID- 29245662 TI - A systematic revision of Charissa, subgenus Pterygnophos Wehrli, 1951, with description of a new species (Lepidoptera: Geometridae). AB - The subgenus Pterygnophos Wehrli, 1951 within the genus Charissa Curtis, 1826 nomen protectum (= Hyposcotis Hubner, [1825] nomen oblitum) is taxonomically revised based on morphology and DNA barcoding. The subgenus comprises four species in total which are presented in detail. Diagnostic characters are depicted and keys to the species based on the morphology of male and female genitalia are provided. Males and females of each species and their genitalia are illustrated. The distribution of all species is described and figured on a map, and a neighbor joining tree based on DNA barcoding of 17 specimens is presented. Charissa (Pterygnophos) beljaevi spec. nov. from Mongolia is described as new. A neotype for Gnophos creperaria Erschoff, 1877, and lectotypes for Gnophos deliciaria shantungensis Wehrli, 1953, Gnophos dorkadiaria Wehrli, 1922, Gnophos ochrofasciata Staudinger, 1895, and Gnophos finitimaria Fuchs, 1899 are designated. The following synonyms are recognized: Gnophos finitimaria Fuchs, 1899 syn. nov. is a synonym of Gnophos ochrofasciata Staudinger, 1895 and Gnophos deliciaria shantungensis Wehrli, 1953 syn. nov. is a synonym of Gnophos agnitaria Staudinger, 1897. PMID- 29245663 TI - Zelotes wunderlichi, a replacement name for the preoccupied ground spider Zelotes turcicus Wunderlich, 2011 (Araneae, Gnaphosidae). AB - In the World Spider Catalog (WSC 2017) the formerly overlooked species Zelotes turcicus Seyyar, Demir & Aktas, 2010 was recently added. Thus Zelotes turcicus Wunderlich, 2011 is a primary homonym and requires a new name. The author informed Jorg Wunderlich who approved the present author to carry out this formal renaming (without suggesting a new name): for Zelotes turcicus Wunderlich, 2011 the replacement name Zelotes wunderlichi nomen novum is herewith proposed. PMID- 29245665 TI - Agrilus (Nigritius) scottoi n. sp. from Cameroun (Coleoptera, Buprestidae). AB - Agrilus scottoi n. sp. from Cameroun is described. The presence of a long tip at the apex of the last visible tergite, places this species in the subgenus Nigritius Curletti, 1998, although the presence of elytral spots and the apical spines makes it very similar to species placed in the subgenus Pantherina Curletti, 1998. PMID- 29245664 TI - Map and shapefile of the biogeographic provinces of Argentina. AB - We provide a map of the 15 biogeographic provinces of Argentina based on the ecoregions recognized for the country, combining climatic, geological and biotic criteria. Argentinean provinces belong to the Neotropical region (Yungas, Parana Forest, Araucaria Forest, Chaco and Pampean provinces), the South American transition zone (Puna, Monte, Comechingones and Cuyan High Andean provinces) and the Andean region (Patagonian, Maule, Valdivian Forest, Magellanic Forest, Falkland Islands and Magellanic Moorland provinces). In order to facilitate future biogeographic analyses, we provide a file of this biogeographical regionalisation in vector format using the World Geodetic Survey 1984. PMID- 29245666 TI - Substitution of some species-level names in the tribe Hygrotini Portevin, 1929 (Coleoptera: Dytiscidae: Hydroporinae). AB - Recently, Villastrigo et al. (2017b) published a new classification of the species of the tribe Hygrotini (subfamily Hydroporinae) based on a thorough phylogenetic investigation using molecular as well as morphological data (Villastrigo et al. 2017a). PMID- 29245667 TI - Rullierinereis imajimai nom. nov., a replacement name for R. profunda Imajima, 2009, secondary homonym to R. profunda (Hartman, 1965), formerly Namalycastis profundus. AB - Hartman (1965) described a nereidid species, Namalycastis profundus[sic], based on a deep-sea specimen collected from off Bermuda (1000 m deep) in the NW Atlantic. Although Hartman (1965) did not mention its etymology, the specific name is believed to be derived from the Latin adjective "profund-" meaning "deep." Because Namalycastis is feminine in gender (Glasby et al. 2016), the original specific name as masculine was incorrect and must be corrected to N. profunda for mandatory gender agreement under Articles 31.2 and 34.2 of the International Code of Zoological Nomenclature (hereafter, "the Code") (International Commission of Zoological Nomenclature 1999). PMID- 29245668 TI - Description of a new species of Dascillus Latreille from Yunnan, China (Coleoptera: Dascillidae). AB - Dascillidae are a small and rarely studied family that includes nine currently recognized genera (Lawrence 2016; Ivie & Barclay 2011; Jin et al. 2013) and about 80 described species divided into two poorly defined subfamilies-Dascillinae and Karumiinae. In recent years, Jin et al. (2013, 2016, 2017) studied the species of Dascillinae and described 13 new species of Dascillus Latreille, 1797. At present, 33 species are included in this genus. Of these, 27 have been reported from China (Jin et al. 2016, 2017; Lobl & Lobl 2016; Terzani et al. 2017). Consequently, the Chinese fauna of Dascillus is extraordinarily rich. PMID- 29245669 TI - First record and a new species of Cylindroxystus Bierig (Coleoptera, Staphylinidae, Paederinae) in Colombia. AB - Cylindroxystus janualis sp. nov., of the Paederinae, subtribe Cylindroxystina, from Choco, northwest Colombia is described, illustrated and distinguished from the other species mainly using aedeagal characters. This is the first record of Cylindroxystus Bierig 1943 from Colombia. PMID- 29245670 TI - On the distribution and natural history of a rarely encountered species: Goliathus (Fornasinius) klingbeili Zoller, Fiebig, & Schulze, 1995 (Coleoptera: Scarabaeidae: Cetoniinae). AB - Mudge et al. (2012) surveyed the Cetoniinae (Coleoptera: Scarabaeidae) of Ghana and recorded Goliathus (Fornasinius) higginsi Westwood, 1874, but no other species from this subgenus. We add the rare species Goliathus (Fornasinius) klingbeili Zoller, Fiebig, & Schulze, 1995 as a new country record for Ghana from the dense forests of the Volta and Eastern Regions. The species was previously reported as very rare in Togo (Zoller et al. 1995) in the northern dry part of the Bafilo Region. We record that the larvae develop in hyrax (Dendrohyrax dorsalis (Fraser, 1855) (Mammalia: Procaviidae) middens and can be locally common in this microhabitat. The purpose of this note is to record the new distributional and natural history data, discuss the taxonomy and bionomy of the subgenus Goliathus (Fornasinius) Bertoloni, 1852, and provide a key to species. PMID- 29245671 TI - Konothrips polychaeta sp.n. from Delaware, North America, with a key to the three species of this genus. AB - The genus Konothrips was erected by Bhatti (1990) for a single species, tuttlei, that was described from Arizona in the genus Chirothrips by zur Strassen (1967). The new genus was distinguished by the longitudinally orientated sculpture on the abdominal terga and sterna, the fore wing costa with only a single seta, and the ovipositor lacking teeth (Bhatti 1990). Subsequently, Nakahara and Foottit (2012) described in Konothrips a second species, colei, from Texas. However, those authors indicated that there is variation in these characters, with colei intermediate in structure between tuttlei and members of Arorathrips. In the new species described below, the abdominal tergal and sternal sculpture is weakly developed, transverse medially with some reticles in the pleurotergites slightly orientated longitudinally, the ovipositor is reduced and smooth, and costal setae are present on the fore wing. This new species is described in Konothrips because antennal segment I is enlarged (more than 3 times wider than base of segment II), antennal segment II is strongly produced laterally, and the mesosternal furcal invaginations are widely separated. These characters are also shared with the species of Arorathrips, and distinguish this pair of genera from Chirothrips. However, the new species, together with tuttlei and colei, is distinguished from species placed in Arorathrips by the presence of more than 6 stout conical setae on the median area of the mesonotum, and the anterior abdominal tergites with D1 and D2 setae spine-like (conical and stout). PMID- 29245672 TI - A new blind groundwater-dwelling genus of the Cladocera (Crustacea: Branchiopoda) from the Korean Peninsula. AB - Groundwater-dwelling Cladocera are to date known only from the caves and hyporheic zones of the rivers in Europe (Belgium, England, France, Bosnia and Herzegovina, Macedonia, Slovenia, Spain), Turkey (European part) and Arabian Peninsula (Yemen). All these animals belong to the subfamily Aloninae Dybowski & Grochowski of the family Chydoridae Dybowski & Grochowski (Cladocera: Anomopoda). Examination of some samples collected by our colleagues - experts in Copepoda, Bathynellidae and Amphipoda-in South Korea led us to discovery of a new stygobiotic alonine genus, which is also the first record of a groundwater dwelling cladoceran in Asia. Aims of this paper are: (1) to describe Korealona gen. nov., represented by two species, Korealona karanovici gen. nov., sp. nov. found in three different localities, and K. choi sp. nov., also found in three different localities; and (2) to discuss its differences from other genera of this subfamily and possible phylogenetic position of this genus among the aloninse. Distribution ranges of two species of Korealona gen. nov. are not unequivocally associated with present-day main river basins in Korea, but more sampling efforts are needed for final conclusions on their distribution ranges in Korea and closest countries and understanding of the genus evolutionary history. PMID- 29245673 TI - An update on the spider genus Loxosceles (Araneae: Sicariidae) in the Afrotropical region, with description of seven new species. AB - In this paper the present state of knowledge of the genus Loxosceles Heineken & Lowe, 1832 from the Afrotropical region is discussed. The distribution of nine of the 16 described Afrotropical species of Loxosceles is updated and the status of the types of L. bergeri Strand, 1906b and L. pilosa Purcell, 1908 are discussed. A further four new species from South Africa: L. cederbergensis sp. nov.; L. dejagerae sp. nov.; L. haddadi sp. nov.; L. makapanensis sp. nov.; and three from Namibia: L. griffinae sp. nov.; L. irishi sp. nov.; and L. maraisi sp. nov., are described. The female of L. smithi Simon, 1897 is described for the first time. A new taxonomic key to all the Afrotropical species is given. PMID- 29245674 TI - Revision of the Venezuelan spider genus Stenosfemuraia Gonzalez-Sponga, with new generic and specific synonymies (Araneae, Pholcidae). AB - The Venezuelan genus Stenosfemuraia Gonzalez-Sponga, 1998 is revised, with redescriptions of its three named species: S. parva Gonzalez-Sponga, 1998 (type species); S. cuadrata Gonzalez-Sponga, 2005; and S. pilosa (Gonzalez-Sponga, 2005) n. comb. The latter species was originally described as Codazziella pilosa, and six years later again as Chichiriviche costanero Gonzalez-Sponga, 2011 (n. syn.). The monotypic genera Codazziella Gonzalez-Sponga, 2005 and Chichiriviche Gonzalez-Sponga, 2011 are thus newly synonymized with Stenosfemuraia. The genus appears restricted to the Cordillera de la Costa region where the spiders occupy near-ground microhabitats in medium to high elevation forests. PMID- 29245675 TI - Coeliccia rolandorum sp. nov. from eastern Cambodia and southern Vietnam, the eastern relative of C. kazukoae Asahina, 1984 (Odonata: Platycnemididae). AB - Coeliccia rolandorum sp. nov. is described from the eastern Cambodia (holotype: Cambodia, Mondulkiri Province, Buu Sraa Waterfall environs, 12 degrees 34' N 107 degrees 24' E, ~780 m a.s.l., 16 June 2014, RMNH) and southern and central Vietnam. It is related to C. kazukoae, which is known from the Cardamom and Sankamphaeng Mts., and replaces it in eastern Indochina. New distributional data on C. kazukoae are presented and its characters are discussed with respect to their change with age. PMID- 29245676 TI - Zyras (Diaulaconia) artemis sp. n., a new termitophilous species from Taiwan (Coleoptera: Staphylinidae: Aleocharinae: Lomechusini). AB - The staphylinid tribe Lomechusini is known for the diverse associations with ants or termites. A new species of rove beetle belonging to Zyras (Diaulaconia) is found to be associated with the fungus-growing termite, Odontotermes formosanus (Shiraki, 1909), and is showing meticulous predatory behavior. In the present study, this species is described as Zyras (Diaulaconia) artemis Liang, Maruyama & Li, sp. n. Its assignment to the subgenus Diaulaconia is based on the comparison of female spermatheca, male aedeagus, and male secondary characters. The habitus photographs and the line drawings of diagnostic characters and their variations are provided. The current knowledge about the taxonomy, phylogeny, and ecology of Diaulaconia is discussed. The checklist of Diaulaconia species of Taiwan is updated. PMID- 29245677 TI - Descriptions of pupae of two Hydropsyche species from China (Insecta, Trichoptera, Hydropsychidae). AB - Pupae of two Hydropsyche species collected from Zhe-jiang Province, China, were examined and their barcode sequences were generated and analyzed. The pupae of H. simulata and H. homunculus were associated with their adult males by mtCOI gene sequences, described, illustrated, and diagnosed. PMID- 29245678 TI - Tricorythodes tragoedia sp. nov. (Ephemeroptera: Leptohyphidae), a new species from Rio Doce and surrounding areas, southeastern Brazil. AB - A new species of Tricorythodes Ulmer (Ephemeroptera: Leptohyphidae) is described and illustrated based on nymphs and adults from the Doce River and surrounding areas in southeastern Brazil. Tricorythodes tragoedia sp. nov. is related to T. arequita Traver, T. mirca Molineri and T. sallesi Dias, Cabette & De Sousa, but its nymphs can be distinguished from these species by having a three-segmented maxillary palp with apical seta and one pair of submarginal denticles on the tarsal claws. Nymphs were collected from small to large rivers at altitudes of less than 100 m where they inhabit submersed substrates in areas with slow current. Nymphs and adults were found throughout the year. PMID- 29245679 TI - A new species of the sandperch genus Parapercis from the Philippines Perciformes: Pinguipedidae). AB - A new species sandperch, Parapercis altipinnis, is described based on the holotype collected from Cebu, the Philippines at 55-65 m by SCUBA. The new species belongs to the P. cylindrica complex and can be distinguished by an extremely high first dorsal fin, the first spine slightly longer than the head; 3 predorsal scales; 42 or 43 lateral-line scales; teeth present on vomer and palatines. The body is reddish dorsally and blackish ventrally, with 5 large brownish saddles alternating with white bands on dorsal surface; scattered dots on top of head, first dorsal fin and dorsal surface; first dorsal fin milky white with 5 black marks on anterior margin; a black broad band below eye; cheek and throat blackish red surrounding by white color; row of 10 short white bars along the lateral side of body axis; row of 9 deep red to blackish bars on lower half of lateral side of body; base of pelvic fin and lower margin of caudal fin blackish; rows of black spots on soft dorsal fin. A key to the species of the complex is provided. PMID- 29245680 TI - A new skipper from China: Notocrypta ariannae n. sp. (Lepidoptera, Hesperiidae). AB - A new skipper species, Notocrypta ariannae n. sp., is described from C Sichuan, illustrated with its male genitalia and compared with the four other Notocrypta species found in China. PMID- 29245681 TI - Philometrid nematodes (Philometridae) of marine teleosts from Balinese waters, Indonesia, including the description of Philometra damriyasai sp. nov. AB - Based on light and scanning electron microscopy, one new species of philometrid nematodes, Philometra damriyasai sp. nov. (Nematoda: Dracunculoidea: Philometridae) from the body cavity of Tylerius spinosissimus (Regan, 1908) (Tetraodontiformes, Tetraodontidae), and five known species are reported in different marine teleosts from South Bali, Indonesia. The new species can be distinguished from the most closely related P. javensis Moravec, Walter & Juniar, 2012 by the absence of sclerotized denticles on the cuticle of the anterior oesophageal lobes of the mouth and smaller larvae. Philometra nemipteri Luo, 2001 of Nemipterus japonicus (Bloch, 1791), P. otolithi Moravec & Manoharan, 2013 of Otolithes ruber (Bloch & Schneider, 1801) (both from gonads) and Philometroides marinus Moravec & Buron, 2009 from the body cavity of Rachycentron canadum (Linnaeus, 1766) are reported for the first time from Indonesian waters, thus extending their range of distribution into the tropical Indo-Pacific Ocean. Philometra lobotidis Moravec, Walter & Yuniar, 2012 from the body cavity of Lobotes surinamensis (Bloch, 1790) and P. ocularis Moravec, Ogawa, Suzuki, Miyaki & Donai, 2002 from the eye cavity of Variola louti (Forsskal, 1775) represent new geographical records, and Philometra sp. was recorded for the first time from Cephalopholis sexmaculata (Ruppell, 1830). A total of 14 philometrids have been so far identified from marine fishes in Indonesia. PMID- 29245682 TI - A new Schistura from an upper Mekong affluent in Yunnan (Teleostei: Nemacheilidae). AB - Schistura stala, new species, is described from the Mekong drainage in Dali, Yunnan Province, China. The new species is readily distinguished from congeners in the upper Mekong and adjacent drainages by having the caudal-fin bar reduced, stretching over the median 1/3 of the fin base. The species can be further diagnosed by a deep body; a short caudal fin, head and pelvic fin; 38 vertebrae modally; 9-12 faint irregular flank bars, that are often anastomotic or dissolved; and few scales scattered on the anterior part of the body. PMID- 29245683 TI - Molecular evidence supporting the expansion of the geographical distribution of the Brazilian cownose ray Rhinoptera brasiliensis (Myliobatiformes: Rhinopteridae) in the western Atlantic. AB - The genus Rhinoptera is composed of eight species widely distributed in tropical, subtropical and temperate coastal waters, which inhabit bays, estuaries and river mouths. Cownose ray Rhinoptera bonasus has been reported to inhabit the Western Atlantic including the Gulf of Mexico and the Caribbean, whereas the Brazilian cownose ray R. brasiliensis has been considered endemic to the coast of Brazil. Recent reports of R. brasiliensis in the Gulf of Mexico bring about the question of whether the species has a wider range than previously reported. Here, the mitochondrial genes COI, Cytb, NADH2 and the nuclear gene RAG1 were used to distinguish among species and to confirm the presence of R. brasiliensis in the Gulf of Mexico. R. brasiliensis specimens collected along the southern Gulf of Mexico showed a remarkable genetic and morphological affinity when compared with R. brasiliensis specimens from Brazil, supporting the presence of the species in Mexico (from Veracruz through Campeche) and providing evidence that its distribution ranges from Brazil to the Caribbean Sea and the Gulf of Mexico. Both species overlap geographically to a large degree, leading to a reassessment of their conservation status. Our results also show that R. bonasus distribution in the Gulf of Mexico may be restricted to the northern portion, in US waters. PMID- 29245684 TI - Revision of the horseface loaches (Cobitidae, Acantopsis), with descriptions of three new species from Southeast Asia. AB - Acantopsis (Cobitidae) is revised based on analysis of morphological and molecular data. Four of the six available names, A. dialuzona, A. spectabilis, A. octoactinotos, and A. thiemmedhi, are valid, and three new species, A. rungthipae, A. dinema, and A. ioa, are described. All species are described morphologically, distributions are mapped, and relationships are discussed for those for which molecular data (CO1, RAG1) are available. Labial barbels, color pattern, and meristic counts are the most diagnostic features. Although the long snout of Acantopsis is perhaps the most emblematic attribute of the genus, its relative length increases with growth, reducing its taxonomic value. Species can be difficult to identify on the basis of color pattern alone, as habitat and preservation methods appear to strongly influence the color pattern. Despite interspecific overlap of some highly variable traits, each species has a unique set of morphological characteristics that remain observable even when the color pattern is obscured, and some species are restricted to single drainages, greatly simplifying identification. The phylogenetic analyses revealed high molecular divergence between even the most morphologically similar species, with mean uncorrected CO1 p-distances between species ranging from 12.1-15.4%. Species of Acantopsis exhibit significant genetic structuring consistent with recognized freshwater ecoregions. Acanthopsis lachnostoma Rutter 1897, from Swatow, China, is not assignable to Acantopsis. PMID- 29245685 TI - Revision of the Madagascan genera Oncodopus Brongniart and Colossopus Saussure (Orthoptera: Tettigoniidae: Conocephalinae; Euconchophorini), with description of Malagasopus gen. nov. AB - The endemic Madagascan genera Oncodopus Brongniart and Colossopus Saussure are revised using museum specimens, including the types, and recently collected material. A new genus, Malagasopus gen. nov., and seven new species, Malagasopus desutterae sp. nov., Malagasopus meridianus sp. nov., Oncodopus janetae sp. nov., Oncodopus brongniarti sp. nov., Oncodopus saussurei sp. nov., Oncodopus soalalaensis sp. nov. and Colossopus parvicavus sp. nov. are described. Lectotypes are designated for Oncodopus zonatus Brongniart, 1897 and Colossopus redtenbacheri (Brongniart, 1897). A new term, mesothoracic auricle, is proposed for a structure on the episternum of the mesothorax. A tabulated key to the genera and keys to the species are presented. All species are described and diagnosed, and their phylogenetic relationships, geographical distributions, habitat preferences and phenologies are documented. The life history of Colossopus grandidieri is described, and the unusual possible mate-guarding behaviour of several species is discussed. Maps showing the distribution of the species are presented, as too are 57 photographs of museum specimens, 51 drawings of morphological characters, 17 photographs of living specimens and one habitat photograph. PMID- 29245686 TI - A new Caryophyllaceae-feeding species of Macrosiphum (Hemiptera: Aphididae) in Republic of Georgia, and a redescription of Macrosiphum hartigi Hille Ris Lambers. AB - Apterous and alate viviparous females and the alate males of Macrosiphum eastopi Barjadze & Blackman sp. n. living on Oberna multifida Ikonn. (=Silene multifida Rohrb.) (Caryophyllaceae) are described from the Republic of Georgia (Caucasus). Type specimens are deposited at the Institute of Zoology, Ilia State University (IZISU), Tbilisi, Georgia; the Natural History Museum (BMNH), London, U.K.; and the University of Catania (UCI), Sicily, Italy. Apterous and alate viviparous females of its close relative M. hartigi Hille Ris Lambers, 1947, living on Silene vulgaris (Moench) Garcke and Stellaria holostea L. (Caryophyllaceae) are redescribed, based on co-types and other material from Austria, France, Italy and Switzerland. The hitherto unknown fundatrix, oviparous females and alate males of M. hartigi are described from Italy and Switzerland. Macrosiphum eastopi sp. n. is differentiated from the morphologically similar M. hartigi and compared with other Macrosiphum species living on Caryophyllaceae. A key is provided to apterous viviparous females of all aphid species recorded on Oberna multifida. PMID- 29245687 TI - A new species of Chiridota (Echinodermata: Holothuroidea: Apodida: Chiridotidae) from Japan, and First record of C. rigida from Japan. AB - A new apodid sea cucumber, Chiridota impatiens sp. nov., is described from the intertidal zone of Okinawa, Japan, and C. rigida Semper, 1867 is also described from the intertidal zone of Wakayama, as new to Japan. C. impatiens sp. nov. is approximately 60-70 mm, with 12 tentacles and 4-7 pairs of digits per tentacle, red or reddish brown in living specimens. The tentacles contain curved rod ossicles, with spinous processes and many branches in C. rigida, however, in C. impatiens sp. nov., the curved rod ossicles are crescent-shaped, sometimes distally, with spinous processes and rarely a few branches on the circumference. In both species, the body wall contains flattened rod ossicles, mostly present along the longitudinal muscle and mesentery, curved rod ossicles primarily in the body wall, and wheel ossicles only in the wheel-papillae. In C. rigida, the contents of the wheel-papillae form a hemispherical sack-shaped structures, in which the teeth-side of the wheel ossicles mostly faces towards the outside of the body. In C. impatiens sp. nov., the contents of the wheel-papillae form a cord-shaped structure (present in both preserved and living specimens), in which the teeth-side of the wheel ossicles faces various directions, and that can be induced to break through the skin of the papillae if stimulated in living specimens. PMID- 29245688 TI - Two new species of Curculionichthys (Siluriformes: Loricariidae) from the rio Amazonas basin, Brazil. AB - In the present study, we describe two new species of Curculionichthys from rio Tapajos and rio Tocantins basins in Brazil. Both species present all diagnostic features of Curculionichthys. Furthermore, both species C. tukana and C. itaim are distinguished from congeners by the combination of seven characters: (1) a higher number of plates in abdominal lateral plates series; (2) the absence of large conspicuous odontodes forming rows on head and trunk; (3) the anterior profile of the head pointed; (4) a higher number of dentary teeth; (5) the lack of contrasting dark spots at the anterodorsal region of body; (6) the absence of an irregular concentration of chromatophores that entirely cover the anal-fin origin and adjacent region, and distal portion of the first unbranched anal-fin ray; and (7) the presence of odontodes forming aligned rows, more evident in the dorsal portion of head and in the lateral portion of caudal peduncle. Furthermore, C. tukana can be further distinguished from congeners by three characters: (1) the papillae aligned in series that extends from the distal portion of lower lip to dentary; (2) the absence of dark-brown spots scattered over the body; and (3) a higher number of maxillary teeth. The species C. itaim also can be further distinguished from congeners by five characters: (1) the papillae randomly distributed throughout the lower lip; (2) a smaller number of medial plates series on lateral portion of the body following the lateral line; (3) a smaller number of median plates series in abdomen; (4) the absence of dark brown spots scattered over the body; and (5) the absence of one unpaired platelet on the dorsal portion of the caudal peduncle. PMID- 29245689 TI - New replacement name for Tricella Catalano & Dietrich, 2017 (Hemiptera: Cicadellidae: Typhlocybinae). AB - We recently established the leafhopper genus Tricella with the type species Tricella antonellae from Ecuador (Catalano & Dietrich 2017). Unfortunately, Tricella n.gen is junior homonym of Tricella Daniels, 1975 (Diptera). Therefore, we propose a new replacement name Carpaneura nom. nov. for Tricella Catalano & Dietrich, 2017 as required by Article 60 of the International Code of Zoological Nomenclature. The genus is named in honor of the first author's husband, Pablo Carpane. The name combines his family name with the suffix of the type genus of the tribe and is treated as a feminine noun. Replacement of the junior homonym also requires the following new combination for the originally designated type species: Carpaneura antonellae (Catalano & Dietrich), comb. nov. PMID- 29245690 TI - A new species of the genus Madecorphnus (Coleoptera: Scarabaeidae: Orphninae) from Madagascar. AB - Madagascar has a unique and diverse Orphninae (Coleoptera: Scarabaeidae) fauna with four genera and 39 described species (Paulian 1977, Frolov et al. 2016). Half of these species belong to the genus Madecorphnus Paulian, 1992 (Paulian 1992, Frolov 2010a,b, 2012, 2014). The purpose of this paper is to describe a new species of Madecorphnus and provide a new record for M. dentatus Frolov, 2010. PMID- 29245692 TI - Description of Coeliccia bhriulieci sp. nov. (Odonata: Zygoptera: Platycnemididae) from central Vietnam. AB - Coeliccia bhriulieci sp. nov. (holotype male from Tay Giang district, Quang Nam province, central Vietnam, deposited in the Zoological collection of the Southern Institute of Ecology, Vietnam Academy of Science and Technology, Ho Chi Minh City, Vietnam) is described based on male specimens. The new species is easily distinguished from other Coeliccia species in the Southeast Asian region by the combination of its blue abdominal tip, black anal appendages and structure of genital ligula with two long flagella extending from lateral corners of apical segment. PMID- 29245691 TI - Racekiela andina sp. nov. (Spongillida: Spongillidae): first report of a freshwater sponge from the Venezuelan Andes. AB - The genus Racekiela Bass & Volkmer-Ribeiro, 1998 comprises six species of freshwater sponges distributed along the Palaearctic, Nearctic and Neotropical regions (Van Soest et al. 2017). They are characterized by an isodictyal skeleton solely of acanthoxeas, sparse spongin fibers, and tri-layered gemmules with radially embedded gemmoscleres of two types, short birotules and long pseudobirotules (Manconi & Pronzato 2002; Volkmer-Ribeiro & Machado 2007). Four species occur in the Northern Hemisphere: R. biceps (Lindenschmidt, 1950) from Michigan (Lindenschmidt 1950), R. pictouensis (Potts, 1885) from eastern Canada to New York (Penney & Racek 1968), R. ryderii (Potts, 1882) which ranges from eastern North America to the British Isles, Faroes and Norway (Manconi & Pronzato 2002), and the recently described R. montemflumina Carballo, Cruz-Barraza, Yanez & Gomez, 2017 from Northwestern Mexico (Carballo et al. 2017). It is worthy to note that R. pictouensis is considered to be an ecomorph of R. ryderii by several authors (Porrier 1977; Ricciardi & Reiswig 1993). The other two species, R. cavernicola (Volkmer-Ribeiro, Bichuette & Machado, 2010) and R. sheilae (Volkmer Ribeiro, De Rosa-Barbosa & Tavares, 1988), are both known only from Brazil (Volkmer-Ribeiro & Machado 2007; Volkmer-Ribeiro et al. 2010). Here we describe a new member of the genus, found in lakes of high-mountain ecosystems, or paramos, in the Cordillera de Merida. This constitutes the first record of specimens belonging to Racekiela for the Andes and Venezuela. PMID- 29245693 TI - Organothrips stongensis sp. n. and Watanabeothrips yasuakii Okajima: new records from Peninsular Malaysia of Thysanoptera: Thripidae. AB - Organothrips stongensis sp. n. is described from Malaysia based on two males. These are sharply bicolored in contrast to other males in this genus, and a key is provided to males of the four known species of this genus. Organothrips was not previously known in Malaysia. Watanabeothrips yasuakii Okajima is also a first record from Malaysia, and differences between these females and the holotype decription are discussed. PMID- 29245694 TI - First records of adult feeding in Megaloptera (Corydalidae, Corydalinae) from Mexico and their possible relationship with the increase in life span. AB - Knowledge of the natural history of the order Megaloptera is incomplete. Immatures are long-lived and widely known for their role as aquatic predators (Contreras-Ramos 1998; Azevedo & Hamada 2007), yet information on habits of the winged terrestrial adults is limited. Previously, it was thought that adults do not feed (Table 1), perhaps because of the relatively short life span of about one week to a month (Contreras-Ramos 1998, 1999; Hayashi 1993), as well as the inability of males of Corydalus Latreille, 1802 to feed due to their large mandibles. Tierno de Figueroa & Palomino (2002) analyzed the digestive tract of Sialis nigripes Pictet, 1865 in Spain, and found debris and a spermatophore in a female. Also, Contreras-Ramos (1999) recorded the acceptance of sugar water by adults of Platyneuromus soror (Hagen, 1861). However, consumption of solid organic matter in adult Megaloptera has not previously been recorded. PMID- 29245695 TI - Five new replacement names in Reduviidae (Heteroptera). AB - The following five new replacement names are proposed for homonymous genus- and species-level names in four different subfamilies of Reduviidae: Dithectocoris nom. nov. for Echinocoris Livingstone & Ravichandran, 1992 nec Echinocoris Miller, 1949 (Ectrichodiinae); Sphedanolestes picturellus tordoi nom. nov. for Sphedanolestes picturellus annulipes Tordo, 1969 nec Sphedanolestes annulipes Distant, 1903 (Harpactorinae); Acanthaspis celidota nom. nov. for Acanthaspis maculata Sucheta & Chopra, 1989 nec Acanthaspis maculata (Distant, 1903); Reduvius lasius nom. nov. for Reduvius villosus Fabricius, 1794 nec (Thunberg, 1783) (Reduviinae); and Oncocephalus enallus nom. nov. for Oncocephalus bipunctatus Livingstone & Ravichandran, 1990 nec Oncocephalus bipunctatus Villiers, 1952. The genus-level replacement also results in Dithectocoris coromandelensis (Livingstone & Ravichandran, 1992) comb. nov. PMID- 29245696 TI - New records of Solenocera barunajaya Crosnier, 1994 and Solenocera rathbuni Ramadan, 1938 (Crustacea: Decapoda: Penaeoidea) from the southwest coast of India. AB - The genus Solenocera Lucas, 1849 consist of 43 species, most with commercial importance and occurring in offshore, deeper waters (Perez Farfante & Kensley 1997; De Grave & Fransen 2011). Twelve species in the genus Solenocera were reported from India, with a few contributing to the regular fishery (S. crassicornis, S. choprai, and S. hextii), and others seldom captured (S.alfonso, S.alticarinata, S.annectens, S.halli, S.koelbeli, S.melantho, S.pectinata, S.pectinulata and S.waltairensis). Members of the Solenoceridae are identified based on the key taxonomic characters of the genitalia and the cephalothorax. Major taxonomic references on solenocerids include Crosnier (1978, 1989), Perez Farfante (1977), and Dall (1999). Specimens are deposited in the Marine Biodiversity Museum at the Central Marine Fisheries Research Institute, Kerala (CMFRI). PMID- 29245697 TI - Rediscovery of the type series of the Sacred Shrew, Sorex religiosus I. Geoffroy Saint-Hilaire, 1826, with additional notes on mummified shrews of ancient Egypt (Mammalia: Soricidae). AB - In 1826, Isidore Geoffroy Saint-Hilaire described the Sacred Shrew, Sorex religiosus [= Crocidura religiosa] from a series of 22 embalmed individuals that comprised a portion of the Italian archeologist Joseph Passalacqua's collection of Egyptian antiquities from an ancient necropolis near Thebes, central Egypt. Living members of the species were not discovered until the beginning of the 20th century and are currently restricted to the Nile Delta region, well north of the type locality. In 1968, the type series of S. religiosus was reported lost, and in 1978, a neotype was designated from among a small collection of modern specimens in the Natural History Museum, London. Our investigations have revealed, however, that the type series is still extant. Most of the specimens used by I. Geoffroy Saint-Hilaire to describe S. religiosus still form part of the Passalacqua Collection in the Agyptisches Museum, Berlin, Germany. We summarize the taxonomic history of S. religiosus, review the history of the Passalacqua collection, and explain why the type series was thought to have been lost. We designate an appropriate lectotype from among the original syntypes of S. religiosus in the Agyptisches Museum. Our examination of the shrew mummies in the Passalacqua collection also yielded a species previously unrecorded from either ancient or modern Egypt: Crocidura pasha Dollman, 1915. Its presence increases the number of soricid species embalmed in ancient Egypt to seven and provides additional evidence for a more diverse Egyptian shrew fauna in the archeological past. Finally, we provide details that will assist in better understanding the variety of mummification procedures used to preserve animals in ancient Egypt. PMID- 29245698 TI - A new species of Cyrtodactylus (Squamata: Gekkonidae) and the first record of C. otai from Son La Province, Vietnam. AB - We describe a new species of Cyrtodactylus on the basis of four specimens collected from the limestone karst forest of Phu Yen District, Son La Province, Vietnam. Cyrtodactylus sonlaensis sp. nov. is distinguished from the remaining Indochinese bent-toed geckos by a combination of the following characters: maximum SVL of 83.2 mm; dorsal tubercles in 13-15 irregular rows; ventral scales in 34-42 rows; ventrolateral folds prominent without interspersed tubercles; enlarged femoral scales 15-17 on each thigh; femoral pores 14-15 on each thigh in males, absent in females; precloacal pores 8, in a continuous row in males, absent in females; postcloacal tubercles 2 or 3; lamellae under toe IV 18-21; dorsal head with dark brown markings, in oval and arched shapes; nuchal loop discontinuous; dorsum with five brown bands between limb insertions, third and fourth bands discontinuous; subcaudal scales distinctly enlarged. In phylogenetic analyses, the new species is nested in a clade consisting of C. huongsonensis and C. soni from northern Vietnam and C. cf. pulchellus from Malaysia based on maximum likelihood and Bayesian analyses. In addition, we record Cyrtodactylus otai Nguyen, Le, Pham, Ngo, Hoang, Pham & Ziegler for the first time from Son La Province based on specimens collected from Van Ho District. PMID- 29245699 TI - Kiwisaldula waiho and K. hurunui, two new species of Saldidae (Hemiptera: Heteroptera) from the South Island of New Zealand, with redescriptions of K. butleri (White) and K. laelaps (White). AB - Kiwisaldula waiho new species and K. hurunui new species, are described from the South Island of New Zealand. Kiwisaldula butleri (White, 1878) and K. laelaps (White, 1878), two taxonomically little-known taxa, are redescribed. Morphological descriptions are provided together with illustrations emphasising the most important diagnostic features of external morphology and male genitalia. Information is given on synonymy, type specimens, material examined, geographic distribution and biology. PMID- 29245700 TI - Description of a new Synergus species from China and comments on other inquiline species (Hymenoptera: Cynipidae: Synergini). AB - A new species, Synergus mongolicus Pujade-Villar & Wang n. sp., is described from galls collected on twigs of Quercus mongolica. The morphological characters useful for differentiating the new species are also discussed. Three inquilines species are recorded from China for the first time: Saphonecrus shirakashii, Synergus belizinellus and S. symbioticus. Saphonecrus tianmushanus is considered a n. syn. of S. shirakashii based on comparison of the types. Saphonecrus taiwanensis Pujade-Villar new name is proposed for Saphonecrus lithocarpii Schweger & Melika, 2015 by homonymy with S. lithocarpi Pujade-Villar, Guo, Wang & Chen, 2015 and finally Saphonecrus chinensis Tang & Schweger, 2015 is considered a n. syn. of S. lithocarpi Pujade-Villar, Guo, Wang & Chen, 2015. PMID- 29245701 TI - Pseudanthias tequila, a new species of anthiadine serranid from the Ogasawara and Mariana Islands. AB - Pseudanthias tequila is described on the basis of two specimens from the Ogasawara Islands. It also is recorded from the Mariana Islands on the basis of colour photographs. The species belongs to a complex that includes P. randalli (Lubbock & Allen), P. pulcherrimus Heemstra & Randall, P. flavicauda Randall & Pyle, P. oumati Williams, Delrieu-Trottin & Planes, and a potentially new species from the Line Islands. Species within the complex are distinguished on the basis of male live colouration, morphometric details and gill-raker and scale counts. Colour photos of all five species are provided. PMID- 29245702 TI - Cirrhilabrus shutmani, a new species of fairy wrasse from the Babuyan Islands, northern Philippines (Teleostei: Labridae). AB - Cirrhilabrus shutmani, new species, is described on the basis of four specimens from Didicas Volcano, Babuyan Islands, Cagayan province, northern Philippines. The holotype and three paratypes were collected at a depth of 50-70 m, along denuded rubble slopes. The new species belong to a complex consisting of C. blatteus, C. claire, C. earlei, C. jordani, C. lanceolatus, C. roseafascia, C. rubrisquamis and C. sanguineus. Aside from similar nuptial male colouration, the nine species share the following character combination: relatively short pelvic fins (not or barely reaching anal-fin origin, except for C. claire with relatively long pelvic fins); a pair of stripes on head (in both sexes); and, dorsal and anal fins without obvious stripes or spots. It differs from the other members of its group in lacking any stripes on the upper and lower body, and in having the following live colouration details: upper part of nape dusky red; dorsal and anal fin bright red with dusky markings; pelvic fins bright red, dusky anteriorly; caudal fin bright yellow basally with distal half bright red. We also present new distribution records for C. claire, C. earlei and C. lanceolatus, as well as a brief mention of a possibly new, related species from the Ogasawara Islands. PMID- 29245703 TI - A new species of Charissa Curtis, 1826 from Europe (Lepidoptera: Geometridae). AB - Charissa is a species-rich genus within the geometrid subfamily Ennominae, and is widely distributed in the Palaearctic and the Oriental regions; one species also occurs in the Nearctic. Their perfect adaptation to rocks on which they rest during daytime makes them sometimes difficult to tell apart on habitus. For that it is often necessary to analyze their genitalia. Since Sauter (1990), about 30 species, almost all European ones, have been newly combined from Gnophos Treitschke, 1825 to Charissa (Parsons et al. 1999). Currently, the genus is under revision by the authors of the present paper, and the genus name is under protection according to S 23.9.3. ICZN (Erlacher & Erlacher 2017). PMID- 29245704 TI - The discovery of the spider genus Putaoa (Araneae, Pimoidae) in Taiwan with the description of a new species, including its web architecture. AB - We report for the first time the occurrence of pimoids (Araneoidea, Pimoidae) in Taiwan, describe Putaoa seediq new species, revise the genus diagnosis accordingly, and illustrate for the first time the web architecture of Putaoa based on field photographs. Males of Putaoa species differ from other pimoids in having distinctively large macrosetae on the pedipalpal tibia and/or cymbium and by the absence of typical cuspules, such as those found in Pimoa and Weintrauboa. In addition, Putaoa species lack a median apophysis and have a relatively short and non-filiform embolus. In Putaoa the metatarsus I is unmodified, while sinuous in the males of most Weintrauboa species. Females of Putaoa are diagnosed by their relatively flat epigynum with lateral openings, relatively short copulatory ducts and medial fertilization ducts. PMID- 29245705 TI - The new sponge species Amphoriscus pedunculatus (Porifera, Calcarea). AB - Amphoriscus is a widespread genus with 17 species. A new species was found in SE Brazil and it represents the second species of this genus in Brazilian waters. Amphoriscus pedunculatus sp. nov. has a special structure, a peduncle, to attach to the substrate. Special attachment structures are not very common in the class Calcarea but this is the third species of the genus with a peduncle. Besides peduncle, another attachment structure found in some species of Amphoriscus is the root-tuft, an attachment structure composed of diactines and anchor-like triactines or tetractines. The evolution of these attachment structures in Amphoriscus is not known but they have also been found out of this genus, suggesting that these structures appeared several times during the evolution of Calcarea or that species currently classified in different genera are in fact congeneric. PMID- 29245706 TI - The Brachyura (Crustacea: Decapoda) of the Deutschen Tiefsee-Expedition auf dem Dampfer 'Valdivia' 1898-1899: dates of publications and authorship. AB - The consequences for the nomenclature of the Brachyura as a result of the inadvertent publication of new names in the two editions of the narrative of the Deutschen Tiefsee-Expedition auf dem Dampfer 'Valdivia' 1898-1899 that were published before their formal descriptions by Doflein in the scientific reports to the expedition are discussed. Both editions of the narrative are shown to have been issued in parts (Lieferungen). Accurate dates of publication for the parts of the narrative and for Doflein's work are presented. A list of new taxon names in other groups of animals that may also have been inadvertently made available in the narrative is included. PMID- 29245707 TI - Taxonomy of the zodiac loaches, Mesonoemacheilus triangularis, M. tambaraparniensis and M. periyarensis, endemic to the Western Ghats of India (Teleostei: Nemacheilidae). AB - The Nemacheilid loaches, Noemacheilus triangularis tambaraparniensis and Nemacheilus periyarensis have been widely considered to be synonyms of the zodiac loach, Mesonoemacheilus triangularis. An integrative taxonomic investigation based on topotypic material, involving molecular analysis of two mitochondrial genes (cytochrome oxidase subunit 1 and cytochrome b), multivariate morphometric analysis based on non-metric multidimensional scaling and non-parametric multivariate analysis of variance suggests that the three species are in fact distinct. PMID- 29245709 TI - A new species and two new records of the leafhopper genus Iassus Fabricius (Hemiptera: Auchenorrhyncha: Cicadellidae) from Korea, with a key to the Korean Iassus species. AB - A new species, Iassus psudoulmi sp. nov. Kwon et Jung, and two new records, Iassus lateralis (Matsumura, 1905) and I. iziaslavi (Anufriev, 1977) from Korea are presented. Descriptions, illustrations of the species and a key to the Korean Iassus species are provided. PMID- 29245708 TI - New species of Poecilocloeus Bruner, 1910 (Orthoptera: Acrididae: Proctolabinae) from Parana State, Brazil. AB - In this study, we describe a new species of the genus Poecilocloeus from Renascenca municipality, Parana State, Brazil. Poecilocloeus renascensis n. sp. inhabits the Atlantic Semideciduous Forest edges of Renascenca and adjacent areas, and our study is the first record of this genus from southern Brazil. The species belongs to the group bullatus (Rehn, 1908), and the descriptions are based on morphological characters, mainly from male genitalia. Morphological descriptions are provided together with illustrations emphasizing the most significant diagnostic features of external morphology and male genitalia. Information is given about type specimens, examined material and geographic distribution. PMID- 29245710 TI - Taxonomic revision of the Andean harvestman genus Rhaucus Simon, 1879 (Arachnida, Opiliones, Cosmetidae). AB - The Andean genus Rhaucus Simon 1879 is revised. Five valid species are recognized, including Rhaucus florezi sp. nov. The following nomenclatural acts are proposed. At genus level: Megarhaucus Mello-Leitao, 1941, Neorhaucus Pickard Cambridge, 1905 and Pararhaucus Pickard-Cambridge, 1905 are considered junior subjective synonyms of Rhaucus. At species level: Neorhaucus aurolineatus Pickard Cambridge, 1905 is considered a junior subjective synonym of Rhaucus vulneratus Simon, 1879; Rhaucus (Rhaucus) tristis Sorensen, 1932, Rhaucus (Rhaucus) muticus Sorensen, 1932 and Pararhaucus obscurus Pickard-Cambridge, 1905 are considered junior subjective synonyms of Rhaucus quinquelineatus Simon, 1879 (the latter combination is restored from current combination Flirtea quinquelineata); Flirtea paucimaculata Roewer, 1963, Rhaucus (Rhaucus) geographicus Sorensen, 1932, Metarhaucus reticulatus Roewer, 1912 and Metarhaucus fuscus Pickard-Cambridge, 1905 are considered junior subjective synonyms of Erginus serripes Simon, 1879 (that is here combined as Rhaucus serripes comb. rest.). Megarhaucus robustus Mello-Leitao, 1941 is newly combined as Rhaucus robustus (Mello-Leitao, 1941) comb. nov. Distribution maps of the species are provided. The new term multicapitate apophysis (mca) is introduced here for a special type of apophysis on coxa IV of males. PMID- 29245711 TI - A new species of the genus Takydromus (Squamata: Lacertidae) from Tianjingshan Forestry Station, northern Guangdong, China. AB - Many early descriptions of species of the genus Takydromus were based on limited diagnostic characteristics. This has caused considerable challenges in accurate species identification, meaning that a number of cryptic species have been erroneously identified as known species, resulting in substantially underestimated species diversity. We have integrated evidence from morphology and DNA sequence data to describe a new species of the Asian Grass Lizard, Takydromus albomaculosus sp. nov., based on two specimens from Tianjingshan Forestry Station, Ruyuan County, Guangdong Province, China. The new species can be distinguished from other known Takydromus species by distinctive morphological differences and significant genetic divergence in the mitochondrial COI gene. Morphologically, the new species differs from the known 22 congeners in the following combination of characters: relatively large body size, SVL 70.9 mm in female, 65.5 mm in male; presence of three or four pairs of femoral pores and four pairs of chin-shields; supraoculars three, rarely four, the posterior loreal either in contact with the anteriormost supraocular or not; the presence of supraciliary granules; the presence of six rows of ventral scales, strongly keeled in the male, and smooth but with the outermost row keeled in the female; the presence of enlarged and keeled lateral scales in a row above the ventrals, but shorter than the ventrals; subdigital lamellae 23-24 under the fourth finger and 29-30 under the fourth toe; dorsal surface brown, ventral surface green, flank dark brown or brown black with several prominent white round spots; the presence of a pair of white longitudinal dorsolateral stripes and a pair of white longitudinal ventrolateral stripes. Takydromus albomaculosus sp. nov. represents the twenty-third species of this genus, of which six species occur in northern Guangdong, where the biodiversity level of Takydromus is the second highest in the world, just below that of Taiwan. PMID- 29245712 TI - A novel symbiotic relationship between mites and recluse spiders (Sicariidae: Loxosceles), with a description of a new Callidosoma species (Trombidiformes: Erythraeidae). AB - This study reports a symbiotic association between an unknown species of Loxosceles (Araneae: Sicariidae) and the adults of a new species of parasitengone mite that lives on their web in Brazilian caves. This mite is described as Callidosoma cassiculophylla sp. nov. (Parasitengona: Erythraeidae). The symbiotic association is clearly beneficial for the mite, which lives with the spider, and feeds on prey captured by their webs, without any aggressive behavior or expulsion of the mites by the spiders. PMID- 29245713 TI - Checklist and new species of caddisfly (Insecta: Trichoptera) from Roraima state, Brazil. AB - We conducted an inventory of the Trichoptera fauna of Serra do Tepequem, Amajari municipality (county), Roraima state, Brazil. Adult caddisflies were collected with Pennsylvania and Malaise traps operated beside three 2nd-order streams near the summit of Serra do Tepequem. We identified 27 Trichoptera species (including two new species), all representing new records for the state of Roraima, five of these species are recorded for the first time in Brazil. In this study, two new species are described: Marilia mahedae sp. nov. differs from all other species of the genus by the following combination of characters: Segment X subquadrate in dorsal view, bipartite, membranous mesally, with short apical V-shaped incision; preanal appendages wide at base in lateral view; endotheca with an acute subapicoventral projection, directed anterad in lateral view; phallotheca very short. Polyplectropus tepequemensis sp. nov. differs from all other species of the genus by the following combination of characters: Posterior margin of sternum IX nearly straight; slightly sclerotized intermediate appendages broad in the basal 2/3 and abruptly slender apically; two phallic ducts, each with an endothecal spine. With this inventory the number of Trichoptera species for Roraima state increased from 37 to 65. PMID- 29245714 TI - The American species of the genus Glaucolepis Braun, 1917 (Neotrifurcula van Nieukerken, syn. nov.) (Lepidoptera: Nepticulidae). AB - We provide diagnostic characters for the genus Glaucolepis Braun, re-examine the type series of the type species of the North American G. saccharella Braun, describe two new species from Chile and Argentina (G. flagellata Remeikis & Stonis, sp. nov. and G. pseudoflagellata Remeikis & Stonis, sp. nov.), and provide the first photographic documentation of the central Andean G. aerifica (Meyrick). We synonymize Neotrifurcula van Nieukerken, 2016, syn. nov. with Glaucolepis and provide one new combination for the south Andean G. gielisorum (van Nieukerken, 2016), comb. nov. All species treated in the paper are illustrated with drawings and (or) photographs of the adults and genitalia. PMID- 29245715 TI - Annotated catalogue of South American Dalodesmidae (Diplopoda, Polydesmida). AB - All published names for genera and species of South American Dalodesmidae are presented with annotated synonymies. Semnosoma chilense (Silvestri, 1903) comb. nov. is introduced for the "orphan" species Iulidesmus chilensis Silvestri, 1903. PMID- 29245716 TI - A second species of the genus Martensolasma (Opiliones, Dyspnoi, Nemastomatidae) from Mexico. AB - A second species of the previously monotypic genus Martensolasma Shear, 2006 is described: Martensolasma catrina sp. n., based on specimens collected in Metztitlan, Hidalgo, Mexico. The taxonomy the genus is briefly discussed. PMID- 29245717 TI - A review of North American Elonus species, with description of E. gruberi n. sp. (Coleoptera: Tenebrionoidea: Aderidae). AB - This work provides a taxonomic survey of the North American species of the genus Elonus Casey, 1895 (Coleoptera: Tenebrionoidea: Aderidae). It includes the description of a new species, Elonus gruberi n. sp. from the United States, related to E. hesperus Werner, 1990 and to E. basalis (LeConte, 1855). A review and key to the North American species is provided. PMID- 29245718 TI - Two new species of Suberitida (Porifera, Heteroscleromorpha) from the Bering Sea. AB - Two new species, Plicatellopsis borealis and Spongosorites beringensis, from the Bering Sea are described; both belong to genera previously not reported from the area. The genus Plicatellopsis, Burton, 1932 (Porifera, Suberitida, Suberitidae) contains five valid species, all recorded from the southern hemisphere. The record of P. borealis n. sp. from the Bering Sea is consequently the first record of the genus from the northern hemisphere. The genus Spongosorites Topsent, 1896 (Porifera, Suberitida, Halichondriidae) contains 22 valid species but none reported from the North Pacific Ocean, Bering Sea or the Arctic Ocean. The geographically closest records are six species occurring in the North Atlantic Ocean. So the description of Spongosorites beringensis n.sp. is the first record of the genus in the region. PMID- 29245719 TI - Aphanius kruppi, a new killifish from Oman with comments on the A. dispar species group (Cyprinodontiformes: Aphaniidae). AB - Eight species are recognised in the Aphanius dispar group. Aphanius dispar from the Red and Mediterranean Sea basins, A. stoliczkanus from coastal areas of the Arabian/Persian Gulf, the northern Arabian Sea east to Gujarat in India, the Gulf of Oman and some endorheic basins in Iran and Pakistan, A. richardsoni from springs in the Dead Sea basin in Jordan and Israel, A. sirhani from the Azraq Oasis in Jordan, A. ginaonis from one spring in Iran, A. furcatus from few streams and springs in Iran and A. stiassnyae from one lake in Ethiopia. Aphanius kruppi, new species, from the Wadi al Batha drainage in northern Oman, is distinguished from adjacent A. stoliczkanus by having 9-14 brown or grey lateral bars on the flank in the male, a roundish, diamond-shaped or somewhat vertically elongate blotch centred on the caudal-fin base in the female and 2-3 scale rows on the caudal-fin base. The available molecular genetic data for A. dispar reject the hypothesis of the presence of a single widespread coastal species in the Middle East and make it likely that two additional unidentified species occur in the Red Sea basin. PMID- 29245720 TI - New species and new records of Calycomyza Hendel (Diptera: Agromyzidae) in Brazil. AB - Two new species and a new record of Calycomyza Hendel are described for the Brazilian Amazon: Calycomyza rolandrae sp. nov. and Calycomyza dryas sp. nov. This is the first time we recorded Calycomyza hyptisicola Spencer and Calycomyza richardsi (Spencer) in Brazil. These species can be distinguished by the structure of the male terminalia, but the female terminalia can be an important taxonomic character, especially the ninth abdominal sternite, ninth abdominal tergite and the marginal seta. PMID- 29245721 TI - Description of Rhamma dawkinsi (Lepidoptera: Lycaenidae) a new mountain butterfly from Colombia. AB - A preliminary assessment of barcode data for the genus Rhamma suggests the presence of several cryptic species in Colombia. Based on morphology and barcodes, we were able to diagnose one of these lineages as a new species that is described herein as Rhamma dawkinsi, sp. nov. Adult specimens and the genitalia of both sexes are illustrated and compared with R. adunca (Draudt, 1919) and R. comstocki (Johnson, 1992), the most closely related species based on phenotypic appearance. PMID- 29245722 TI - Jelinekius prisniyi sp. nov., new species of genus Jelinekius Majer, 1990 (Coleoptera: Dasytidae: Rhadalinae) from Tajikistan. AB - The genus Jelinekius Majer, 1990, previously known only from Iran, is reported from Tajikistan for the first time. A new species, J. prisniyi sp. nov., is described as new to science. PMID- 29245723 TI - A revision of the Myopsalta crucifera (Ashton) species group (Hemiptera: Cicadidae: Cicadettini) with 14 new species from mainland Australia. AB - The genus Myopsalta Moulds is distributed throughout much of Australia. Previous studies have associated several undescribed species with the Myopsalta crucifera (Ashton) species complex. The present study informally divides the cicadas in the genus Myopsalta into two species groups. It provides a revision of the M. crucifera species group, which includes redescriptions of M. crucifera s. str. and M. mackinlayi (Distant). The identity of the latter species is further refined and attributed to material formerly presented under the name Myopsalta atrata (Goding & Froggatt). In addition to the redescriptions, 14 new species belonging to the M. crucifera species group are described, including M. albiventris n. sp., M. bassiana n. sp., M. chrysopedia n. sp., M. gordoni n. sp., M. leona n. sp., M. longicauda n. sp., M. majurae n. sp., M. melanobasis n. sp., M. parvula n. sp., M. platyptera n. sp., M. riverina n. sp., M. septa n. sp., M. umbra n. sp. and M. xerograsidia n. sp. A key to species in the genus Myopsalta is provided. Standard morphological descriptions and descriptions of calling songs unique to each species are included along with a discussion on different song types in the M. crucifera species group. PMID- 29245724 TI - Taxonomy of the subgenus Pseudocypus Mulsant & Rey (Coleoptera: Staphylinidae: Staphylinini) and eight new species from China. AB - Eight new species of the subgenus Pseudocypus Mulsant & Rey, 1876 of the genus Ocypus Leach, 1819 (Coleoptera, Staphylinidae, Staphylinini) are described from China: O. (Pseudocypus) pileaticulminis sp. nov., O. (Pseudocypus) denticulminis sp. nov., O. (Pseudocypus) anguliculminis sp. nov., O. (Pseudocypus) digiticulminis sp. nov., O. (Pseudocypus) alticulminis sp. nov., O. (Pseudocypus) fusciculminis sp. nov., O. (Pseudocypus) nigriculminis sp. nov. and O. (Pseudocypus) recticulminis sp. nov. Line drawings and color illustrations of adult structures and genitalia are given for all new species and the following species recorded in China: O. (Pseudocypus) aenescens Eppelsheim, 1889, O. (Pseudocypus) ballio Smetana, 2007, O. (Pseudocypus) calamis Smetana, 2007, O. (Pseudocypus) densissimus (Bernhauer, 1933), O. (Pseudocypus) dolon Smetana, 2007, O. (Pseudocypus) graeseri Eppelsheim, 1887, O. (Pseudocypus) hecato Smetana, 2007, O. (Pseudocypus) inexspectatus Eppelsheim, 1887 (new record in China), O. (Pseudocypus) menander Smetana, 2007, O. (Pseudocypus) neocles Smetana, 2007, O. (Pseudocypus) orodes Smetana, 2007, O. (Pseudocypus) pelias Smetana, 2007, O. (Pseudocypus) puer (Smetana, 2005a), O. (Pseudocypus) picipennis (Fabricius, 1793), O. (Pseudocypus) rhinton Smetana, 2007, and O. (Pseudocypus) semenowi Reitter, 1887. A key to Chinese species of the subgenus Pseudocypus Mulsant & Rey, 1876 is also provided in the text. PMID- 29245725 TI - Revision of the Hybobathus arx and Pelecinobaccha summa species groups (Diptera: Syrphidae). AB - The morphologically similar Hybobathus arx and Pelecinobaccha summa species groups are revised and distinguished from each other. Four new species are described (H. avittatus sp. nov., H. luciane sp. nov., P. alia sp. nov. and P. impostor sp. nov.), and three new combinations (H. obsoletus comb. nov., H. persimilis comb. nov., and P. cubensis comb. nov.) and several synonimies are proposed: Baccha bivittata Curran = H. arx (Fluke), B. myrtella Hull and B. nectarina Hull = H. obsoletus (Curran), B. druida Hull = H. phaeopterus (Schiner), B. pandora Hull = P. cubensis (Macquart), and B. susio Hull = P. summa (Fluke). The lectotype and paralectotypes of B. phaeoptera Schiner are also designated. The female genitalia are described for all species, and the puparium of H. luciane sp. nov. is described too. New prey records for H. luciane sp. nov. and H. phaeopterus are presented. Picture multi-optional keys were produced and links to these keys, as well as traditional dichotomous keys, are presented in this paper to identify the groups and their species. PMID- 29245726 TI - Drepanosticta rahmani sp. nov., from Kedah, Malaysia (Odonata: Zygoptera: Platystictidae). AB - Drepanosticta rahmani sp. nov. (holotype ?, steep tributary to stream in hills between Baling and Gulai, north west Kedah, Malaysia, 15 xi 2016, leg. R.A. Dow, to be deposited in the Natural History Museum, London) is described from both sexes. PMID- 29245727 TI - Systematics of the family Carditidae (Bivalvia: Archiheterodonta) in the Cenozoic of Argentina. AB - The systematics of the Family Carditidae is currently poorly elucidated. This paper reviews the Eocene to Pleistocene carditids from Patagonia and Entre Rios Province (Argentina). Twelve species are described and illustrated and the presence of the genera Cyclocardia Conrad, Pleuromeris Conrad, Scalaricardita Sacco, Fasciculicardia Maxwell and Purpurocardia Maxwell in southern South America is discussed. The genus Scalaricardita is documented for the first time in South America. Two new genera, Darwinicardia gen. nov. and Kolmeris n. gen. are proposed for the species 'Venericardia' patagonica (Sowerby) and 'V.' tehuelchana (Ihering), respectively, and one new species, Cyclocardia dalek sp. nov., is described. PMID- 29245728 TI - A new species of Pimelodella (Siluriformes: Heptapteridae) from the Guiana Shield, Brazil. AB - A new species of Pimelodella is described from the Rio Ipitinga, Rio Jari basin, a left bank tributary of the Rio Amazonas in Brazil. The new species is diagnosed from all congeners by having a dark oval mark on the humeral region. It also differs from all congeners by a unique set of characters, including the presence of 47 to 49 total vertebrae, unpigmented areas dorsally and ventrally adjacent to the dark midlateral stripe, and maxillary barbels reaching at least to vertical through caudal fin insertion. Faunal similarities between the southern part of the eastern Guiana Shield and coastal drainages in the Guianas and Suriname are discussed. PMID- 29245729 TI - The sharpshooter genus Apogonalia Evans (Hemiptera: Cicadellidae: Cicadellini): description of females and key to species. AB - The Cicadellinae genus Apogonalia Evans, 1947 currently has 22 species and occurs from Arizona (USA) to Panama and the Antilles. Color pattern and female genital structures of 21 species of Apogonalia are here described and illustrated (the female of A. nielsoni Felix & Mejdalani, 2006 is unknown). Comparative morphological notes are included. The female of A. angusta Freytag, 2004 is described for the first time. A key to males and females of all known species of the genus is provided. PMID- 29245730 TI - A report on Lamiaceae-feeding Nepticulidae (Lepidoptera) from South America. AB - We provide a report on Nepticulidae feeding on Lamiaceae plants in South America and describe two new species from the Andes: Stigmella lamiacifoliae Remeikis & Stonis, sp. nov., feeding on Salvia palifolia in Colombia, and S. scutellariae Remeikis & Stonis, sp. nov., feeding on Scutellaria volubilis in Ecuador. The leaf mines, adults, genitalia, and habitats of the new species are illustrated. PMID- 29245731 TI - A new annual fish of the genus Austrolebias (Cyprinodontiformes: Rivulidae) from Rio Camaqua basin, Laguna dos Patos system, Brazilian Pampa. AB - A new species of Austrolebias is described from the middle course of the Rio Camaqua, Laguna dos Patos system, Rio Grande do Sul, Brazil. The new species belongs to the Austrolebias alexandri species group, which is distinguished from the remaining congeners by the presence of a dark gray pectoral fin with bright blue iridescence in males. The new species is distinguished from all remaining species of the A. alexandri species group by the following combination of characters: presence of well-defined bright blue bars on the flank in males, shorter caudal fin length in males and females, contact organs in the first three rays of the pectoral fin in males, one to two post-optic neuromasts (rarely three), basihyal width of 50% of the length, and basihyal cartilage about 50-60% of the basihyal length. The recognition of this new species belonging to the A. alexandri group endemic of the middle course of Rio Camaqua and the recent discovery of Austrolebias bagual in the same general region reinforces the claim of the middle Rio Camaqua basin as an area of endemism for annual fishes and as such, a priority area for conservation in southern Brazil. PMID- 29245732 TI - A new species in the genus Styracaster (Echinodermata: Asteroidea: Porcellanasteridae) from hadal depth of the Yap Trench in the western Pacific. AB - Styracaster yapensis sp. nov. is reported from the Yap Trench in the western Pacific from hadal depths between 6377-6575 m, which is among the deepest known occurrence of a species in this genus. It is distinguished from other Styracaster species by its abactinal surface armature and rudimentary cribriform organs. This paper provides a description of the new species along with detailed photos. The intraspecific differences between the holotype and paratype of the new species are examined with molecular and morphological approaches. PMID- 29245733 TI - Foranotum perforatum gen. et sp. nov.-a new troglobitic darkling beetle (Coleoptera: Tenebrionidae: Kuhitangiinae: Foranotini trib. nov.) from a cave in Southern Zagros, Iran. AB - The troglobitic darkling beetle Foranotum perforatum gen. et sp. nov. from a cave in Southern Zagros Mountains (Iran) is described. This new taxon belongs to the family Tenebrionidae based on the following combination of characters: tarsal formula 5-5-4, antennal insertions concealed from above, antennae 11-segmented, mesocoxal cavities laterally closed by meso- and metaventrite. It is close to Kuhitangia kryzhanovskii Medvedev, 1962 by sharing a similar structure of procoxa (open cavities), labrum (reduced tormal arms) and prothorax (perforating holes on lateral sides of disc). Based on a comprehensive character analysis the subfamily Kuhitangiinae (type genus Kuhitangia Medvedev, 1962) is reestablished. Kuhitangiinae belongs to the pimelioid branch of the family Tenebrionidae based on open mouthparts (mentum small, exposing most of maxillae), mesocoxae externally closed by meso- and metaventrite, metacoxae externally narrowly closed by metaventrite and first abdominal ventrite, tentyrioid structure of abdominal ventrites (absence of membranes between abdominal ventrites 3-5) and absence of defensive glands. The subfamily Kuhitangiinae is divided into following two tribes: Kuhitangiini with a single species Kuhitangia kryzhanovskii Medvedev, 1962 and Foranotini trib. n. with Foranotum perforatum sp. nov. The new tribe differs from Kuhitangiini by the presence of trochanters and epipleura, structure of pronotum, abdominal ventrites and sculpture of meso- and metaventrites. PMID- 29245734 TI - A new species and new country records for the genus Leptobium Casey in the Palaearctic Region (Coleoptera: Staphylinidae: Paederinae). AB - Leptobium yagmuri Anlas, sp. n., from central Anatolia, Turkey, is described, illustrated and distinguished from related congeners. New and additional country records of 19 Leptobium species in the Palaearctic Region are also reported; among them four species are first country records: Iraq (2), Italy (1) and Kazakhstan (1). A key to Turkish Leptobium is presented. Distributions of endemic Leptobium species in Anatolia are mapped. PMID- 29245735 TI - Description of the female of Labena madoricola Gonzalez-Moreno & Bordera, 2015 (Hymenoptera, Ichneumonidae, Labeninae), with new records of Labena species from Mexico. AB - The female of Labena madoricola Gonzalez-Moreno & Bordera, 2015 is described and illustrated for the first time from material collected with Malaise traps in 2016 in the Biocultural Reserve Kaxil Kiuic, Yucatan, Mexico. Diagnostic characters to distinguish females of New World Labena are provided. New distribution records of Labena species in Yucatan Peninsula, are also reported. PMID- 29245736 TI - Rediscovery of the Endangered frog Phrynopus montium (Shreve, 1938) Amphibia, Anura, Craugastoridae) in the cloud forest of central Peru. AB - Phrynopus montium (Shreve, 1938) was described from Cascas, Junin Department, Peru, at an undetermined elevation between 3000 and 4000 m a.s.l. in the Cordillera Central. With the exception of the type specimens used in the original description, no additional sightings of P. montium had been reported for 76 years. Additionally, its coloration in life, microhabitat use, and precise elevational distribution remained unknown. During a field expedition conducted in 2014, two individuals of P. montium were found at an upper cloud forest site in central Peru, 8.7 km south from Hacienda Cascas. Here, I describe the coloration in life, microhabitat use, and elevation of these individuals. PMID- 29245737 TI - A new species of Choroterpes Eaton, 1881 (Ephemeroptera: Leptophlebiidae) from India. AB - A new species of Choroterpes Eaton, 1881 is described based on the larvae from India. Choroterpes (Choroterpes) kaegies sp. n. can be distinguished from other known species of the subgenus by the following combination of characters: (i) anteromedian emargination of labrum broad; (ii) each femur with a dark brown spot at middle and near apex; (iii) gill 1 single and slender and (iv) upper and lower lamellae of gills 2-7 with 3 apical processes, median process relatively slender and longer than laterals. A key to the known species of Choroterpes Eaton, 1881 in India is also provided. PMID- 29245738 TI - A new species of Dohrnemesa and a new species of Polauchenia from Brazil (Hemiptera: Heteroptera: Reduviidae: Emesinae). AB - Dohrnemesa kuarajucassaba sp. nov. and Polauchenia paraprotentor sp. nov. (Hemiptera: Heteroptera: Reduviidae: Emesinae: Emesini) are described respectively from states of Minas Gerais and Para, Brazil. Both species described here were collected from caves. Updated keys to the species of Dohrnemesa Wygodzinsky, 1945 and Polauchenia McAtee & Malloch, 1925 are presented. PMID- 29245739 TI - The Elachistidae (Lepidoptera: Gelechioidea) of Caucasus, with description of three new species. AB - The Elachistidae fauna of the Caucasus is outlined. A total of 47 species are listed, three of which remain unidentified to species level. Three species are described as new: Perittia prolixa sp. nov., Elachista candidella sp. nov. and E. suffusca sp. nov. The new species are diagnosed and illustrated with photographs of the adults and genitalia. Twenty-seven species and the genus Perittia Stainton are reported for the first time from Caucasus. PMID- 29245740 TI - Description of Almafuerte, a new genus of ground spiders from South America (Araneae, Gnaphosidae). AB - A new genus of gnaphosid spiders, Almafuerte, gen. nov., is described for seven species from Southern South America. The new genus is diagnosed by a conspicuous retrolateral tegular projection on the male palp, and by having three teeth on the cheliceral retromargin. It comprises six species from Argentina, A. peripampasica sp. nov. (type species), from Central Argentina, also present in Uruguay, A. kuru sp. nov., from Santiago del Estero, A. vigorosa sp. nov., from Corrientes, A. goloboffi sp. nov., from Salta and Jujuy, A. remota sp. nov., from Santiago del Estero and Mendoza, and A. giaii (Gerschman & Schiapelli) comb. nov., here transferred from Echemus, from Santa Fe (the female is here described by the first time); and one species from Bolivia, A. facon sp. nov., from Cochabamba. Hypotheses of relationships of the new taxa are briefly discussed, in the context of the previously proposed groupings: the subfamilies Echeminae and Drassodinae (sensu Platnick 1990) and the "Echemus group" (sensu Murphy 2007). PMID- 29245741 TI - First description of the last instar larva and pupa of the aquatic crane fly Limnorimarga limonioides (Alexander, 1945) (Diptera: Limoniidae). AB - Descriptions, illustrations and habitat characteristics are given for the previously unknown larvae and pupae of the East Palaearctic monotypic aquatic crane fly genus Limnorimarga Alexander, 1945 collected from Korea in hygropetric habitats. Diagnostic features and phylogenetic relationships are discussed. PMID- 29245742 TI - A review of the Mexican species of Alloeorhynchus Fieber (Hemiptera: Heteroptera: Nabidae: Prostemmatinae) with description of six new species, new distributional records, and key to the species. AB - The genus Alloeorhynchus Fieber (Nabidae) from Mexico is revised. Three species A. moritzii, A. nigrofasciatus and A. nigrolobus are recorded for the first time from Mexico. Six new species are described: A. aureus (from Chiapas and Veracuz), A. bellatulus (from Chiapas and Oaxaca), A. convolutus (from Oaxaca and Veracruz), A. epigaeus (from Guerrero, Michoacan and Oaxaca), A. macer (from Colima, Jalisco and Sonora), and A. vergrandis (from Chiapas and Veracruz). New distributional records for A. trimacula (Stein), the only previously known Mexican species, are added. A key to the species recorded from Mexico is included. Notes on the biology of some species are given. Pictures of the dorsal habitus and parameres are provided. PMID- 29245743 TI - Two new species of the genus Thalassaphorura Bagnall, 1949 (Collembola: Onychiuridae) from south China, with an updated key to world species of the genus. AB - Two new onychiurid species, Thalassaphorura microspinata sp. nov. and T. guangxiensis sp. nov., are reported from the karsts of south China (Guangxi). T. microspinata sp. nov. is similar to T. grandis Sun, Chen & Deharveng, 2010 in having the same dorsal and ventral pso formula, number of pseudocelli on subcoxae 1, number of chaetae in the distal whorl of tibiotarsi and number of p-chaetae between inner posterior pso on head; but it can be recognized by the smaller body size, shorter AS, 5 chaetae on baso-lateral part of labium, distinguishable S chaetae and absence of chaetae on Th. I sternum. T. guangxiensis sp. nov. possesses the same dorsal pso formula as Chinese species T. reducta Sun, Chen & Deharveng, 2010, T. bapen Sun, Chen & Deharveng, 2010 and T. guangdongensis Sun & Li, 2015a, but they could be separated easily by ventral pso formula, number of pseudocelli on subcoxae 1 and other combined characters. An updated key of world species of the genus Thalassaphorura is provided. The species Thalassaphorura saccardyi (Denis, 1935) is transferred to the genus Protaphorura Absolon, 1901 on examination of the type material. In addition to those listed in Sun et al. (2010), two additional species placed in Thalassaphorura by Parimuchova & Kovac 2016 are considered here as incertae sedis because of insufficient descriptions: Thalassaphorura boskovae (Lucic, Dimitrijevic & Mihajlova, 2003), and T. tamdaona (Nguyen, 1995). PMID- 29245744 TI - Pseudochromis stellatus, a new species of dottyback from Indonesia (Teleostei: Pseudochromidae). AB - The Pseudochromis reticulatus complex is diagnosed to include species of Pseudochromis with the combination of a pointed caudal fin (rounded with middle rays produced), a reticulated colour pattern on the upper part of the body, dorsal-fin rays modally III,26, anal-fin rays modally III,15, and pectoral-fin rays modally 18. Members of the complex include P. reticulatus Gill & Woodland, P. pictus Gill & Randall, P. tonozukai Gill & Allen, P. jace Allen, Gill & Erdmann and P. stellatus new species. The last-named is herein described from six specimens from Batanta and Batu Hitam in the Raja Ampat Islands, West Papua, Indonesia. It is distinguished from other members of the complex in live coloration, and in having higher mean numbers of scales in lateral series and of anterior lateral-line scales (36-38 and 29-32, respectively), and a deeper body as measured from the dorsal-fin origin to pelvic-fin origin (31.8-33.5 % SL). PMID- 29245745 TI - An annotated catalogue of Iranian Aulacidae, Evaniidae and Gasteruptiidae (Hymenoptera: Evanioidea). AB - Currently 36 species of the superfamily Evanioidea are recorded from Iran. The family Aulacidae is represented by four species belonging to the genus Pristaulacus Kieffer, 1900), Evaniidae by five species belonging to three genera, Brachygaster Leach, 1815 (one species), Evania Fabricius, 1775 (three species), Prosevania Kieffer, 1911 (one species), and Gasteruptiidae by 27 species belonging to the genus Gasteruption Latreille, 1796. PMID- 29245746 TI - New species and records of Awas Lobl (Coleoptera: Staphylinidae: Pselaphinae) from China, with notes on the biology of the genus. AB - A new species of the arnylliine ant-loving beetle genus Awas Lobl, A. helii Yin, sp. n., collected with Ectomomyrmex ants in Sichuan, SW China, is described and illustrated. The new taxon externally resembles A. kayan Yin & Li from Hunan, central China, but can be readily separated by the different forms of the pronotum and elytra, and details of the aedeagal structures. New collecting data for Awas loebli Yin & Li in eastern China, as well as some notes on the biology of the genus are provided. PMID- 29245747 TI - Zanna robusticephalica sp. nov. (Hemiptera: Fulgoromorpha: Fulgoridae) from China, with comments on some ultrastructural characters of the new species. AB - Zanna robusticephalica sp. nov. (Hemiptera: Fulgoromorpha: Fulgoridae: Zanninae: Zannini), representing the third species of the planthopper genus Zanna Kirkaldy, 1902 from China, is described and illustrated from Yunnan in southwestern China. Scanning electron micrographs of the antennal sensilla, rostral apex, hind tarsal segments, gonoplac and wax glands of the new species are provided. The generic diagnostic characters of Zanna are redefined and the autapomorphies are proposed to support the monophyly of the genus. A check-list of the Oriental Zanna species is included. PMID- 29245748 TI - Seasonal and geographical adaption of two field crickets in China (Orthoptera: Grylloidea: Gryllidae: Gryllinae: Teleogryllus). AB - Crickets of the genus Teleogryllus belong to Gryllidae, Orthoptera. Teleogryllus emma (Ohmachi and Matsumura) and T. occipitalis (Serville) are widely distributed in east Asia, but their distribution and life history have not been reported from China. We studied the seasonal and geographical adaptation by rearing these crickets and measuring specimens. The main results are as follows: T. emma belongs to short-day type, which means nymphs grow rapidly in short day conditions (LD 12:12); T. occipitalis belongs to long-day type, which means nymphs grow rapidly in long day conditions (LD 16:8). The nymphal growth rate accelerates with the increase of temperature by comparing their nymph developmental period at 25 and 30OC. T. emma is mainly distributed in the north of the Yangtze River, while T. occipitalis in the south of it. The body size decreases with the increase of latitude in both species, while the relative length of their ovipositor increases. PMID- 29245749 TI - Two new species of the family Noctuidae from China (Lepidoptera, Noctuidae). AB - Two new species of the subfamilies Bryophilinae (Victrix acronictoides sp. n.) and Noctuinae, tribe Hadenini (Lacanobia chayu sp. n.) are described from China. Adults and male genitalia are illustrated. The checklists of the genera Victrix Staudinger, 1879 in China and Lacanobia Billberg, 1820 are presented. PMID- 29245750 TI - Designation of a neotype for Parastacus nicoleti (Philippi, 1882) (Crustacea: Decapoda: Parastacidae). AB - The type specimen of Parastacus nicoleti (Philippi, 1882) was not designated and the material used for the description has never been found. We designate herein the neotype of P. nicoleti based on the examination of specimens from the type locality deposited in the Museo Nacional de Historia Natural of Chile previously analyzed by Bahamonde (1958), who confirmed the identity and validated the species. To improve the species description we included new drawings and provide additional morphological characters. A synonym list and updated distribution map of this species are also provided. PMID- 29245751 TI - Taxonomic revision of Paraustrosimulium Wygodzinsky & Coscaron: reassignment of Austrosimulium colboi and description of P. obcidens n. sp. from Western Australia. AB - The hitherto monotypic South American genus Paraustrosimulium Wygodzinsky & Coscaron is revised to accommodate two Australian species: Austrosimulium colboi Davies & Gyorkos and Paraustrosimulium obcidens n. sp. The generic diagnosis is updated and the eastern Australian species Paraustrosimulium colboi (Davies & Gyorkos) n. stat. is re-described, including the male for the first time. The Western, Australian sister species of P. colbo, namely P. obcidens Craig, Moulton Currie n. sp. is also fully described. The relationship of Paraustrosimulium to other simuliid genera is discussed, as are aspects of historical biogeography. PMID- 29245752 TI - A new species of Neopronematus and a re-description of Pronematus rykei Meyer & Rodrigues (Acari: Iolinidae) from Iran. AB - Neopronematus iranensis sp. nov. is described and illustrated and the female and male of Pronematus rykei (Meyer & Rodrigues, 1966) are re-described and reported for the first time from Iran. These species were collected from walnut leaves infested by leaf blister mite, Aceria tristriatus, (Nalepa, 1890), in Hamedan and Lorestan provinces, Iran. Furthermore, a key to all known species of Neopronematus is provided. PMID- 29245753 TI - Tropiorhynchus annandalei (Coleoptera: Scarabaeidae: Rutelinae), a new species from Maharashtra, India. AB - Tropiorhynchus annandalei new species (Coleoptera: Scarabaeidae: Rutelinae: Anomalini: Anisopliina) from Bhimshankar Wildlife Sanctuary, Pune district, Maharashtra State, India is described, diagnosed, and illustrated. The new species is compared with all its congeners: Tropiorhynchus orientis (Newman, 1838), T. podagricus (Burmeister, 1844), and T. umbrinus Machatschke, 1954. The newly described species differs from all its congeners by the unique structure of aedeagus, sculpturing of pronotum, medially smooth pygidial surface, and elytral markings. An illustrated key to the species of the genus Tropiorhynchus Blanchard, 1851 is also provided. PMID- 29245754 TI - The genus Acellomyia Gonzalez, a new taxonomic arrangement of its species and descriptions of a new genus and two new species from southern South America (Diptera: Tabanidae: Diachlorini). AB - The tabanid tribe Diachlorini (Diptera) is the most genus-rich tribe in the Tabanidae; the tribe is cosmopolitan, but the greatest species richness and morphological diversity are found in the Australasian and Neotropical Regions. A new arrangement for the species of Acellomyia Gonzalez is given; Acellomyia lauta (Hine) is transferred to a new genus, Montismyia gen.n., based on its morphological differences from Acellomyia and geographical distribution. The morphological differences between Acellomyia and Montismyia gen. n. are discussed. Two new species, Acellomyia casablanca sp.n. and Acellomyia puyehue sp.n., are described from specimens collected in southern Chile. Comparison of the morphology of Acellomyia paulseni mapuche (Coscaron & Philip) stat.nov. indicate that they should be elevated to species rank. A key to species of Acellomyia is provided and diagnostic characters are illustrated. PMID- 29245755 TI - Oldest new genus of Myrmeleontidae (Neuroptera) from the Eocene Green River Formation. AB - Epignopholeon sophiae gen. et sp. nov. (Neuroptera: Myrmeleontidae) is described from the early Eocene of the Green River Formation (Colorado, U.S.A.). It represents the oldest confident record of the family. The new genus is remarkable in that tergite 7 of the female is much shorter than its long sternite 7. The preserved wing venation shows that the genus belongs to the subfamily Myrmeleontinae, and most probably to the tribe Gnopholeontini. The discovery of this species is consistent with estimations of relatively dry and warm conditions during deposition of the upper Parachute Creek Member of the Green River Formation. PMID- 29245756 TI - Presence of Foraminifera of Superfamily Komokioidea (Order Astrorhizida) in Colombian deep Caribbean waters. AB - Research regarding deep-sea benthic foraminifera in the Colombian Caribbean requires further development given the complete lack of information related to the different groups that constitute associations and the ecological functions they fulfill. For this purpose, a taxonomic description of Superfamily Komokioidea was composed from macrofauna samples from between 1,215 m and 3,179 m depth, obtained during the research cruise ANH-COL 4 and COL 5 carried out in 2014. Results showed foraminifera belonging to the three families: Komokiidae, Baculellidae, and Normaninidae, inclu-ding five genera (Lana, Komokia, Ipoa, Normaninam, and Catena) and five species (Lana neglecta, Komokia multiramosa, Normanina conferta, Ipoa fragila, and Catena piriformis). This study presents knowledge regarding deep-sea Colombian Caribbean benthic foraminifera, which to date have not been recorded from this region. Their depth distribution when compared with other studies from the Atlantic and Pacific, allows the expansion of taxonomic inventories and the characterization of biodiversity within poorly explored regions. PMID- 29245757 TI - Scoliorhapis stepanovi-new species of sea cucumber from the North West Pacific (Holothuroidea: Synaptida: Chiridotidae: Taeniogyrinae) and some remarks on the genus Scoliorhapis. AB - New species Scoliorhapis stepanovi has been collected from depths of 10-23 m on the sandy bottom of Avacha Bay (east coast of Kamchatka), Paramushir Island (North Kuril Islands), and Matua Island (Middle Kuril Islands). It is unique in having sigmoid ossicles in the body wall with points at both ends (without an open-eye, and with the two points lying in a perpendicular plane). Such sigmoids do not occur in any other taeniogyrinid species. The two-pointed sigmoids are 80 115 um in length, and are scattered in the body wall and not clustered. Probably the two-pointed sigmoids are underdeveloped typical sigmoid with open-eye. In the tentacles there are straight and C-shaped rods, sometimes branched at the ends, 70-90 um in length. It is assumed that atypical two-pointed sigmoid ossicles may have been originated due to deviating from the usual course of sigmoid development in the middle stages. Scoliorhapis stepanovi resembles S. lindbergi. A key for species of Scoliorhapis is provided. PMID- 29245758 TI - Two new species of Kalyptorhynchia (Koinocystididae and Gnathorhynchidae) from China. AB - Two new species of Kalyptorhynchia (Rhabdocoela), namely Itaipusa sinensis n. sp. (Koinocystididae) and Prognathorhynchus sinensis n. sp. (Gnathorhynchidae) were described from brackish water near Shenzhen Bay, representing the first records of Koinocystididae and Gnathorhynchidae in China. For I. sinensis n. sp., the U shaped cirrus contains 50 triangular lamellar spines, with two cuticular (pseudocuticular) hooks situated at both sides of its anterior part. The hook I (right side) is funnel-shaped, while the hook II (left side) is triangular lamellar in shape. For P. sinensis n. sp., the proboscis hook has two hooks situated in an anterior to posterior sequence. The semicircular tubular stylet has a hollow spherical dead end posteriorly to the distal opening. Both the morphological and phylogenetic (18S rDNA and 28S rDNA) analyses support the establishment of these two new species. PMID- 29245759 TI - A new species of Phyllodytes (Anura: Hylidae) from the Atlantic Rainforest of southern Bahia, Brazil. AB - We describe Phyllodytes amadoi sp. nov., a species of treefrog from the Atlantic Rainforest of southern Bahia, Brazil. The new species can be diagnosed by its small body size (SVL 15.6-23.0 mm) and advertisement call with high dominant frequency (3.789-4.306 Hz). It is known from one locality in the Private Reserve of Natural Heritage Ararauna, in the municipality of Una (15 degrees 18' 38.3" S, 39 degrees 9' 55.9" W, 96 m a.s.l.). PMID- 29245760 TI - The identity of Azara's No. 315 "Ibiyau de cola extrana" and No. 316 "Ibiyau anonimo" (Aves: Caprimulgidae). AB - The identities of Azara's No. 315 "Ibiyau de cola extrana" and No. 316 "Ibiyau anonimo", and those of Caprimulgus sphenurus Vieillot, 1817 and C. epicurus Vieillot, 1817 which were based upon Azara's descriptions, are elucidated. All are found to refer to the taxon currently known as Little Nightjar Setopagis parvula (Gould, 1837). A hitherto overlooked 20th Century usage of the name C. sphenurus by Bertoni (1900) validates this name, and hence, according to the ICZN code it could be correctly applied to this taxon. However, it is recommended that this name be suppressed in the interests of maintaining stability. New synonymies for this species are also clarified. PMID- 29245762 TI - Tunable third harmonic generation of vortex beams in an optical superlattice. AB - We report generation of tunable vortex beams in the blue spectral range, with a 3.3 nm spectral tuning range, by frequency tripling of the near-infrared (IR) wave at around 1.34 um in a LiTaO3 optical superlattice. The nonlinear crystal used in this work has a chirped dual-periodical structure which can provide two expanded reciprocal vectors for tunable performance of the cascaded third harmonic generation (THG). The maximum THG efficiency reaches about 1.4%. PMID- 29245763 TI - Bright off-axis directional emission with plasmonic corrugations. AB - In this work, a new plasmonic bulls-eye structure is introduced to efficiently harvest the emitted light from diamond nitrogen vacancy (NV) centers. We show that the presence of a simple metal sub-layer underneath of a conventional bulls eye antenna, separated by a dielectric layer, results in the spontaneous emission enhancement and increment in out-coupled light intensity. High Purcell factor is accessible in such a structure, which consequently boosts efficiency of the radiated light intensity from the structure. The structure shows considerable enhancement in far-field intensity, about three times higher than that of a one side corrugated (conventional) optimized structure. In addition, we study for the first time asymmetric structures to steer emitted beams in two-axis. Our results show that spatial off-axial steering over a cone is approachable by introducing optimal asymmetries to grooves and ridges of the structure. The steered light retains a level of intensity even higher than conventional symmetric structures. A high value of directivity of 16 for off-axis steering is reported. PMID- 29245764 TI - Ultraviolet photodetector using pn junction formed by transferrable hollow n-TiO2 nano-spheres monolayer. AB - We report an ultraviolet (UV) photodetector with a universally transferable monolayer film with ordered hollow TiO2 spheres on p-GaN. After forming a TiO2 monolayer film by unidirectional rubbing of hollow TiO2 spheres on a polydimethylsiloxane (PDMS) supporting plate, we used a 5% polyvinyl alcohol (PVA) aqueous solution to transfer the film onto the target substrate. The PVA/TiO2 monolayer film was detached from the PDMS film and transferred to the p GaN/Al2O3 substrate. To investigate the effects of crystallized phases of the TiO2 hollow spheres, anatase and rutile TiO2 sphere monolayers prepared by combining template synthesis and thermal treatment. The responsiveness of the UV photodetectors using anatase and rutile hollow n-TiO2 monolayer/p-GaN was 0.203 A/W at 312 nm and 0.093 A/W at 327 nm, respectively. PMID- 29245765 TI - Quantitative birefringence distribution measurement using mixed-state ptychography. AB - Determining the complete optical behavior of anisotropic samples using ptychography is always a difficult problem. We propose a novel birefringence measurement method based on mixed-state ptychography that can simultaneously obtain the azimuth angle and retardation of anisotropic samples in a single scan. By using a reference system transformation, the two mutually orthogonal object states are unambiguously retrieved, and their errors are greatly reduced. The normalized root mean square errors of the obtained azimuth angle and retardation are 0.0011 and 0.0041, respectively. This method offers more rapid data acquisition; compared to interferometric based methods, it has the advantages of unlimited field of view and a simpler, more stable setup. Further, it opens a new possibility for investigating anisotropic samples by means of mixed-state ptychography. PMID- 29245766 TI - Tri-layer silicon nitride-on-silicon photonic platform for ultra-low-loss crossings and interlayer transitions. AB - We present a three-layer silicon nitride on silicon platform for constructing very large photonic integrated circuits. Efficient interlayer transitions are enabled by the close spacing between adjacent layers, while ultra-low-loss crossings are enabled by the large spacing between the topmost and bottommost layers. We demonstrate interlayer taper transitions with losses < 0.15 dB for wavelengths spanning from 1480 nm to 1620 nm. Our overpass waveguide crossings exhibit insertion loss < 2.1 mdB and crosstalk below -56 dB in the wavelength range between 1480 nm and 1620 nm with losses as low as 0.28 mdB. Our platform architecture is suited to meet the demands of large-scale photonic circuits which contain hundreds of crossings. PMID- 29245767 TI - Optical forces in silicon subwavelength-grating waveguides. AB - A theoretical analysis is given for the optical forces induced by the Bloch mode propagating along a silicon subwavelength-grating (SWG) waveguide for the first time. As a periodical structure, an SWG waveguide supports periodical light field distribution along the waveguide. This makes it possible to trap many nano particles stably periodically, which is very different from the case with a conventional optical waveguide. The separation of the trapped nano-particles can be designed easily by modifying the grating period of an SWG waveguide. Furthermore, an SWG waveguide has larger working distance in the lateral direction to trap nano-particles around the waveguide than a conventional optical waveguide. PMID- 29245768 TI - Non-bleaching fluorescence emission difference microscopy using single 808-nm laser excited red upconversion emission. AB - Optical super-resolution microscopy has become a powerful technique to help scientists to monitor the sample of interest at nanoscale. Fluorescence emission difference (FED) microscopy, a very facile super-resolution method, does not require high depleting laser intensity and is independent on the species of agents, which makes FED microscopy possess great potential. However, to date, the biomarkers applied in FED microscopy usually suffer from a photo-bleaching problem. In this work, by introducing Er3+ activated upconverting nanoparticles with red-color emission and non-photobleaching properties, we demonstrate nonbleaching super-resolution imaging with FED microscopy. The dopant neodymium ions (Nd3+) can work as highly efficient sensitizing ions and enable near infrared 808-nm CW laser excitation of relatively low power, which would potentially reduce high intensity/short-wavelength light induced tissue damage. Both simulations and experiments on monodispersed NaYF4:Nd3+/Yb3+/Er3+@NaYF4:Nd3+ UCNPs also indicate that the easy saturation of the multiphoton properties of these UCNPs is beneficial to resolution enhancement in FED microscopy. PMID- 29245769 TI - Blind modulation format identification using nonlinear power transformation. AB - This paper proposes and experimentally demonstrates a blind modulation format identification (MFI) method delivering high accuracy (> 99%) even in a low OSNR regime (< 10 dB). By using nonlinear power transformation and peak detection, the proposed MFI can recognize whether the signal modulation format is BPSK, QPSK, 8 PSK or 16-QAM. Experimental results demonstrate that the proposed MFI can achieve a successful identification rate as high as 99% when the incoming signal OSNR is 7 dB. Key parameters, such as FFT length and laser phase noise tolerance of the proposed method, have been characterized. PMID- 29245770 TI - Fast non-interferometric iterative phase retrieval for holographic data storage. AB - Fast non-interferometric phase retrieval is a very important technique for phase encoded holographic data storage and other phase based applications due to its advantage of easy implementation, simple system setup, and robust noise tolerance. Here we present an iterative non-interferometric phase retrieval for 4 level phase encoded holographic data storage based on an iterative Fourier transform algorithm and known portion of the encoded data, which increases the storage code rate to two-times that of an amplitude based method. Only a single image at the Fourier plane of the beam is captured for the iterative reconstruction. Since beam intensity at the Fourier plane of the reconstructed beam is more concentrated than the reconstructed beam itself, the requirement of diffractive efficiency of the recording media is reduced, which will improve the dynamic range of recording media significantly. The phase retrieval only requires 10 iterations to achieve a less than 5% phase data error rate, which is successfully demonstrated by recording and reconstructing a test image data experimentally. We believe our method will further advance the holographic data storage technique in the era of big data. PMID- 29245771 TI - Demonstration of a mid-infrared NO molecular Faraday optical filter. AB - A molecular Faraday optical filter (MFOF) working in the mid-infrared region is realized for the first time. NO molecule was used as the working material of the MFOF for potential applications in atmospheric remote sensing and combustion diagnosis. We develop a complete theory to describe the performance of MFOF by taking both Zeeman absorption and Faraday rotation into account. We also record the Faraday rotation transmission (FRT) signal using a quantum cascade laser over the range of 1,820 cm-1 to 1,922 cm-1 and calibrate it by using a 101.6 mm long solid germanium etalon with a free spectral range of 0.012 cm-1. Good agreement between the simulation results and experimental data is achieved. The NO-MFOF's transmission characteristics as a function of magnetic field and pressure are studied in detail. Both Comb-like FRT spectrum and single branch transmission spectrum are obtained by changing the magnetic field. The diversity of FRT spectrum expands the range of potential applications in infrared optical remote sensing. This filtering method can also be extended to the lines of other paramagnetic molecules. PMID- 29245772 TI - Illusion optics via one-dimensional ultratransparent photonic crystals with shifted spatial dispersions. AB - In this work, we propose that one-dimensional ultratransparent dielectric photonic crystals with wide-angle impedance matching and shifted elliptical equal frequency contours are promising candidate materials for illusion optics. The shift of the equal frequency contour does not affect the refractive behaviors, but enables a new degree of freedom in phase modulation. With such ultratransparent photonic crystals, we demonstrate some applications in illusion optics, including creating illusions of a different-sized scatterer and a shifted source with opposite phase. Such ultratransparent dielectric photonic crystals may establish a feasible platform for illusion optics devices at optical frequencies. PMID- 29245773 TI - Strong forces in optomechanically actuated resonant mass sensor. AB - As resonance mass sensors shrink in order to improve the sensitivity, traditional methods of transduction and readout struggle to keep up with increasing resonance frequencies and decreasing feature sizes. In this work we demonstrate an all photonically transduced resonant mass sensor that manages to deal with these problems. The strong optomechanical force in slot waveguides is used to drive the mechanical resonanator giving a good signal to noise ratio at low optical powers. Using 120 uW of modulated optical power we measure a frequency noise equivalent to being able to resolve 500 kDa. PMID- 29245774 TI - Fiber ring laser based on MMF-PMFBG-MMF filter for three parameters sensing. AB - A dual-wavelength fiber ring laser based on multimode fiber-polarization maintaining fiber Bragg grating-multimode fiber (MMF-PMFBG-MMF) filter for simultaneously axial strain, temperature and refractive index (RI) sensing is proposed and experimentally demonstrated. In the ring laser, stable dual wavelength lasing is determined by the MMF-PMFBG-MMF filter with two polarization states. The fiber birefringence affected by axial strain is far less than the effect of the temperature. Through monitoring the variations of each wavelength shift and output power, the simultaneous measurement for the axial strain, temperature and RI is realized. In our experiment, the proposed fiber laser sensor exhibits an axial strain sensitivity of 1.16 * 10-3nm/MUepsilon and an RI sensitivity of 81.2dB/RIU. Meanwhile, the temperature sensitivities of two wavelengths are experimentally measured to be 9.74 * 10-3nm/ degrees C and 9.2 * 10-3nm / degrees C, respectively. PMID- 29245775 TI - Single-axis rotation/azimuth-motion insulation inertial navigation control system with FOGs. AB - Rotation modulation technology could effectively improve the accuracy of the inertial navigation system (INS) by compensating for the biases of the inertial sensors automatically. However, the carrier angular motion and rotation control error could reduce the rotation modulation effect and then decrease the navigation accuracy. To address this problem, for the single-axis rotation INS, a novel rotation control scheme is presented. The control scheme employs the fiber optic gyros to control the inertial measurement unit (IMU) rotation angular velocity so that the INS with both rotation modulation and azimuth motion insulation functions. Furthermore, in order to reduce the control error, this study adopts two ways: optimizing the control strategy and shortening the delay time. The former way is to control the IMU rotating about the z-axis of the platform frame with respect to the navigation frame, rather than the up-axis of the navigation frame. The latter way is to apply interrupt mode rather than inquiry mode to complete the data transfer between the navigation and the control processors. The simulation and experimental results demonstrate that: the proposed method would not only realize the rotation modulation of the biases of the inertial sensors, but also achieve the insulation of the azimuth motion. The steady-state control error of the control system is less than 10" and the overshoot control error is less than 50". Compared to the traditional SRINS, the navigation position error in the single-axis rotation/azimuth-motion insulation INS could reduce 50% in some navigation application. PMID- 29245776 TI - pH sensing through a single optical fibre using SERS and CMOS SPAD line arrays. AB - Full exploitation of fibre Raman probes has been limited by the obstruction of weak Raman signals by background fluorescence of the sample and the intrinsic Raman signal of the delivery fibre. Here we utilised functionalised gold nanoshells (NS) to take advantage of the surface-enhanced Raman spectroscopy (SERS) effect to enhance the pH responsive spectrum of 4-mercaptobenzoic acid (MBA). However, the fibre background is still dominant. Using the photon arrival time-resolving capability of a CMOS single-photon avalanche diode (SPAD) based line sensor, we recover the SERS spectrum without a fibre background in a 10 s measurement. In this manner, pH sensing through a multimode fibre at a low excitation power that is safe for future in vivo applications, with short acquisition times (10 or 60 s), is demonstrated. A measurement precision of +/- 0.07 pH units is thus achieved. PMID- 29245777 TI - Generation of largely elliptically polarized terahertz radiation from laser induced plasma. AB - A novel all-optical control scheme is proposed to continuously tune the THz radiation polarization, where the driving laser is based on a three-pulse configuration with adjustable time delays or intensity ratio. With this scheme, not only is the circularly polarized THz radiation realized, the continuous tuning from circular polarization to linear polarization can also be obtained conveniently just by adjusting time delays or intensity ratio. Moreover, the left or the right chirality of THz radiation can be transformed between each other with suitable time delays. PMID- 29245778 TI - Accurate beacon positioning method for satellite-to-ground optical communication. AB - In satellite laser communication systems, accurate positioning of the beacon is essential for establishing a steady laser communication link. For satellite-to ground optical communication, the main influencing factors on the acquisition of the beacon are background noise and atmospheric turbulence. In this paper, we consider the influence of background noise and atmospheric turbulence on the beacon in satellite-to-ground optical communication, and propose a new locating algorithm for the beacon, which takes the correlation coefficient obtained by curve fitting for image data as weights. By performing a long distance laser communication experiment (11.16 km), we verified the feasibility of this method. Both simulation and experiment showed that the new algorithm can accurately obtain the position of the centroid of beacon. Furthermore, for the distortion of the light spot through atmospheric turbulence, the locating accuracy of the new algorithm was 50% higher than that of the conventional gray centroid algorithm. This new approach will be beneficial for the design of satellite-to ground optical communication systems. PMID- 29245779 TI - Optimum thickness of epsilon negative tri-metal layer electrodes for maximizing OLED outcoupling efficiency. AB - A transparent electrode is an essential component that has a strong influence on the extraction of light from organic light-emitting diodes (OLEDs) due to its effect on both electrical and optical performance. In this work, we present theoretical studies, full wave simulations, and experimental results to evaluate the influence of the thickness of epsilon negative tri-metal layer (TML) electrodes on the performance of red phosphorescent OLEDs (PHOLEDs) via an optical microcavity effect. The results show that the external quantum efficiency of the optimized TML-based red PHOLED of 17.6% is significantly improved, and it is approximately 40% higher than that of the conventional indium tin oxide (ITO) based red PHOLED of 12.5%. PMID- 29245780 TI - Intensity-independent wavelength locking of diode lasers to a spectral slope of a fiber-optic sensor for ultrasonic detection. AB - We propose and demonstrate a simple and low-cost method to lock the wavelength of a diode laser to a point with a particular normalized slope on the spectrum of a fiber-optic sensor. The wavelength locking point is independent of the laser intensity variations. The locking involves simultaneously and independently modulating both the laser wavelength and the laser intensity. On the spectral slope, the wavelength modulation is also converted to intensity modulation that is superimposed to the direct intensity modulation. The error signal is the amplitude of the overall intensity modulation. We demonstrate a potential application of the locking method in a fiber-optic ultrasonic detection system using a distributed feedback diode laser and a phase-shifted fiber Bragg grating sensor. PMID- 29245781 TI - Versatile and scalable micropatterns on graphene oxide films based on laser induced fluorescence quenching effect. AB - Here we report on the preparation of quasi-homogeneous fluorescence emission from graphene oxide (GO) film by modifying the local optical properties through the laser-induced fluorescence quenching effect, and the fabrication of single and multilayer micropatterns on quasi-homogeneous GO films. The modification is stemming from the photoreduction of GO, where the reduction degree and fluorescence intensity can be precisely tuned by changing the laser power and irradiation duration. This versatile approach with a mask-free feature can be readily used to fabricate various complex microstructures on quasi-homogeneous GO film from single layer to multilayer in vertical scale, as well as micrometers to centimeters in lateral scale. The micropatterns with varied optical properties are promising for applications in information storage, display technology, and optoelectronic devices. PMID- 29245782 TI - All-organic electro-optic waveguide modulator comprising SU-8 and nonlinear optical polymer. AB - In this paper we describe the principles of operation as well as the fabrication and testing steps of an all-organic waveguide modulator. The modulator comprises an SU-8 core and an electro-optic host-guest polymer cladding. The polymer properties are tuned in order to achieve single mode operation. We used direct write laser lithography in two steps for the preparation of the devices. The electro-optic coefficient of the polymer is estimated from observing the modulation of the device operated in push-pull mode. PMID- 29245783 TI - Analysis and magnetic modulation of chiro-optical properties in anisotropic chiral and magneto-chiral plasmonic systems. AB - We present a systematic study to separate the different contributions to the dichroic response of complex plasmonic split-ring/ring magneto-chiral systems. For this, we first construct metastructures with plasmonic, chiral and magneto optical functionalities by specific arrangements of different building blocks, each of them responsible for one of the functionalities. Then, by the use of Mueller matrices in forward/backward spectroscopic measurements under magnetic field, we separate optical anisotropy from pure chiral contributions to the overall dichroic response of the system. This allows determining the pure chiral response of the structures and the corresponding magnetic field modulation mediated by the magneto-optical effect present in the corresponding building block, which reaches values of 25% at 740 nm. This fabrication and characterization procedure, assigning the different optical functionalities to different building blocks, and decomposing the different contributions to the global optical response, allows an easy and rational identification of the different phenomena exhibited by the magneto-chiral system. PMID- 29245784 TI - Directional optical switching and transistor functionality using optical parametric oscillation in a spinor polariton fluid. AB - Over the past decade, spontaneously emerging patterns in the density of polaritons in semiconductor microcavities were found to be a promising candidate for all-optical switching. But recent approaches were mostly restricted to scalar fields, did not benefit from the polariton's unique spin-dependent properties, and utilized switching based on hexagon far-field patterns with 60 degrees beam switching (i.e. in the far field the beam propagation direction is switched by 60 degrees ). Since hexagon far-field patterns are challenging, we present here an approach for a linearly polarized spinor field, that allows for a transistor-like (e.g., crucial for cascadability) orthogonal beam switching, i.e. in the far field the beam is switched by 90 degrees . We show that switching specifications such as amplification and speed can be adjusted using only optical means. PMID- 29245785 TI - Third order nonlinear optics in Ag nanocubes: local and nonlocal optical responses as a function of excitation wavelength and particle size. AB - Colloidal silver nanocubes in solution were analyzed by the Z-scan technique in the resonant and non-resonant regimes. Three different systems with particle sizes of 56, 99 and 215 nm, and concentrations of 0.378, 0.831 and 0.715 mg/mL, respectively, were obtained by the polyol method. Nonlinear excitation of the samples was performed with laser pulses of 26 ps, at a repetition rate of 10 Hz, and using three different wavelenghts (355, 532 and 1064 nm), exciting only the electronic part of the optical nonlinearity, and avoiding induced thermal loading of the samples. Whenever observable, samples showed saturable absorption for all wavelengths, which was dependent, in general, on concentration and incident intensity. For samples featuring sizes of 55 and 99 nm, saturable absorption could be observed for wavelengths close to their dipolar surface plasmon resonances; while, for samples with sizes of 99 and 215 nm, saturable absorption and positive nonlinear optical refraction (only for size of 215 nm) could be observed at 1064 nm. Besides, for some samples, nonlinear optical response followed the incident intensity profile at wavelengths close to resonance. On the contrary, for wavelengths out of resonance, the nonlinear optical behavior showed to be nonlocal, ie, its profile was narrower than the incident one. PMID- 29245786 TI - Material anisotropy as a degree of freedom in optical design. AB - We present an approach for the design of refractive optical elements using materials degrees of freedom that are accessible via engineered materials. Starting from first principles and an unconstrained general material, we specify homogeneous refractive lenses that focus light with diffraction-limited resolution resulting from a tailored anisotropic refractive index. We analyze the performance, physical feasibility, and advantages over isotropic lenses. Materials degrees of freedom enable new flexibility for imaging system designs with lower complexity expanding the existing aspheric and graded index paradigms. PMID- 29245787 TI - CS-ToF: High-resolution compressive time-of-flight imaging. AB - Three-dimensional imaging using Time-of-flight (ToF) sensors is rapidly gaining widespread adoption in many applications due to their cost effectiveness, simplicity, and compact size. However, the current generation of ToF cameras suffers from low spatial resolution due to physical fabrication limitations. In this paper, we propose CS-ToF, an imaging architecture to achieve high spatial resolution ToF imaging via optical multiplexing and compressive sensing. Our approach is based on the observation that, while depth is non-linearly related to ToF pixel measurements, a phasor representation of captured images results in a linear image formation model. We utilize this property to develop a CS-based technique that is used to recover high resolution 3D images. Based on the proposed architecture, we developed a prototype 1-megapixel compressive ToF camera that achieves as much as 4* improvement in spatial resolution and 3* improvement for natural scenes. We believe that our proposed CS-ToF architecture provides a simple and low-cost solution to improve the spatial resolution of ToF and related sensors. PMID- 29245788 TI - Broad-band difference interferometer as a refractive index sensor. AB - Integrated Optical Broad-Band Difference Interferometer (IO BB DI) is introduced as an alternative and economical measurement method to integrated optical label free affinity sensors. A detailed theoretical analysis of the method is presented and the effects of the waveguide layer on the operation of the system are shown. A very short operating distance of less than 0.5 mm allows miniaturization of the interferometer. The analysis was performed for Si3N4/SiO2 layers that can be obtained in standard microelectronics technological processes. PMID- 29245789 TI - Triggered high-purity telecom-wavelength single-photon generation from p-shell driven InGaAs/GaAs quantum dot. AB - We report on the experimental demonstration of triggered single-photon emission at the telecom O-band from In(Ga)As/GaAs quantum dots (QDs) grown by metal organic vapor-phase epitaxy. Micro-photoluminescence excitation experiments allowed us to identify the p-shell excitonic states in agreement with high excitation photoluminescence on the ensemble of QDs. Hereby we drive an O-band emitting GaAs-based QD into the p-shell states to get a triggered single photon source of high purity. Applying pulsed p-shell resonant excitation results in strong suppression of multiphoton events evidenced by the as measured value of the second-order correlation function at zero delay of 0.03 (and ~0.005 after background correction). PMID- 29245790 TI - Compact and flexible harmonic generator and three-color synthesizer for femtosecond coherent control and time-resolved studies. AB - Intense, multi-color laser fields permit the control of the ionization of atoms and the steering of electron dynamics. Here, we present the efficient collinear creation of the second and third harmonic of a 790 nm femtosecond laser followed by a versatile field synthesizer for the three color fields' composition. Using the device, we investigate the strong-field ionization of neon by fields composed of the fundamental, and the second or third harmonic. The three-color device offers sufficient flexibility for the coherent control of strong-field processes and for time-resolved pump-probe studies. PMID- 29245791 TI - Observation of gain spiking of optical frequency comb in a microcavity. AB - Optical frequency combs are crucial for both fundamental science and applications that demand a wide frequency range and ultra-high resolution. Recent advances in optical frequency combs based on the nonlinear Kerr effect in microcavities have opened up new opportunities with such compact platforms. Although optical frequency combs have previously been well studied in the steady state, some fundamental perspectives such as nonlinear phase modulation during comb generations are yet explored. Here we demonstrate transient nonlinear dynamics during the formation of optical frequency combs inside a Kerr microcavity. We show that gain spiking forms due to nonlinear phase modulation causing comb lines' self-detuning from nearby cavity resonances, which provides one key mechanism to stabilize optical frequency combs. Moreover, we have observed nonlinear beating by injecting an external probe to examine nonlinear cross-phase modulation between comb lines. These nonlinear dynamics reveal the hidden features of self-stabilization and cross modulation during transient comb generations, which may enable new applications in mode-locking comb and tunable comb generation in microcavities. PMID- 29245792 TI - Raman-Kerr frequency combs in microresonators with normal dispersion. AB - We generalize the coupled mode formalism to study the generation of frequency combs in microresonators with simultaneous Raman and Kerr nonlinearities and investigate an impact of the former on the formation of frequency combs and dynamics of platicons in the regime of the normal group velocity dispersion. We demonstrate that the Raman effect initiates generation of sidebands, which cascade further in four-wave mixing and reshape into the Raman-Kerr frequency combs. We reveal that the Raman scattering induces a strong instability of the platicon pulses associated with the Kerr effect and normal dispersion. This instability results in branching of platicons and complex spatiotemporal dynamics. PMID- 29245794 TI - Photonic jets for highly efficient mid-IR focal plane arrays with large angle-of view. AB - One of the trends in design of mid-wave infrared (MWIR) focal plane arrays (FPAs) consists in reduction of the pixel sizes which allows increasing the resolution and decreasing the dark currents of FPAs. To keep high light collection efficiency and to combine it with large angle-of-view (AOV) of FPAs, in this work we propose to use photonic jets produced by the dielectric microspheres for focusing and highly efficient coupling light into individual photodetector mesas. In this approach, each pixel of FPA is integrated with the appropriately designed, fixed and properly aligned microsphere. The tasks consist in developing technology of integration of microspheres with pixels on a massive scale and in developing designs of corresponding structures. We propose to use air suction through a microhole array for assembling ordered arrays of microspheres. We demonstrate that this technology allows obtaining large-scale arrays containing thousands of microspheres with ~1% defect rate which represents a clear advantage over the best results obtained by the techniques of directed self-assembly. We optimized the designs of such FPAs integrated with microspheres for achieving maximal angle of view (AOV) as a function of the index of refraction and diameter of the microspheres. Using simplified two-dimensional finite difference time domain (FDTD) modeling we designed structures where the microspheres are partly immersed in a layer of photoresist or slightly truncated by using controllable temperature melting effects. Compared to the standard microlens arrays, our designs provide up to an order of magnitude higher AOVs reaching ~8 degrees for back-illuminated and ~20 degrees for front-illuminated structures. PMID- 29245795 TI - Thin terahertz-wave phase shifter by flexible film metamaterial with high transmission. AB - Thin terahertz (THz)-wave optical components are fundamentally important for integrated THz-wave spectroscopy and imaging systems, especially for phase manipulation devices. As described herein, a thin THz-wave phase shifter was developed using a flexible film metamaterial with high transmission and polarization independent properties. The metamaterial unit structure employs double-layer un-split ring resonators (USRRs) with a designed distance between the two layers to obtain phase retardance of pi/2, thus constituting a THz-wave phase shifter. The metamaterial design keeps the transmission coefficient as high as 0.91. The phase shifter also has polarization independence due to the four fold symmetry of the USRR structure. Because of the subwavelength feature size of the USRR, this shifter can offer benefits for manipulating the spatial profile for the THz-wave phase through design of a binary optics phase plate by arranging a USRR array. The thickness of 48 MUm has benefits for developing integrated THz optics and other applications that demand compactness and flexibility. The developed film size of 5 cm * 5 cm from the device fabrication process is suitable for THz lenses or gratings of large optical components. PMID- 29245793 TI - Three-dimensional live multi-label light-sheet imaging with synchronous excitation-multiplexed structured illumination. AB - Multiplexed imaging is a powerful tool for studying complex interactions inside biological systems. Spectral imaging methods that capture multiple fluorescent markers synchronously without sacrificing the imaging speed or resolution are most suitable for live imaging. We describe spectral-encoded structured illumination (spectral-SIM) light-sheet microscopy, which enables parallel multi excitation-channel imaging in 3D. Spectral-SIM encodes the excitation wavelength as the phase of the illumination pattern, and allows synchronous image capture over multiple excitation channels at the same speed and spatial resolution as mono-channel structured light-sheet imaging. The technique retains structured light-sheet microscopy's ability in removing out-of-focus and scattered emission background, and generates clear 3D multiplexed images in thick tissue. The capability of this technique was demonstrated by the imaging of live triple labeled transgenic zebrafish to over 300 MUm deep with 0.5MUm-by-2MUm (lateral-by axial) resolution. PMID- 29245796 TI - Thin-core fiber structures with overlays for sensing applications. AB - We investigate thin-core fiber-optic structures with film overlays that can be used for sensing applications. The structures are formed by a section of thin core fibers (SM630 or SM450) spliced between standard SMF-28 fibers. The fibers are coated with overlays using the layer-by-layer assembly technology based on sequential alternating adsorption of polymer monolayers via electrostatic attraction. Transmission spectrum of the structures exhibits resonance dips caused by interaction between cladding modes. We measure the shifts of spectra with increasing thickness of the overlay and with pH value of the external medium. We calculate the shift of resonance wavelengths, which we compare with the experiment. PMID- 29245797 TI - Manipulating discrete solitons and routing the light-transmitting paths in the silicon waveguide array by a d.c. electric-field. AB - Discrete solitons (DS), which could propagate without diffraction in the waveguide array (WA), have attracted great attention. However, its applications are limited to incident light with high power. Here, based on the d.c. Kerr effect in the silicon, we propose and demonstrate theoretically an electrically reconfigurable ridge waveguide array. By applying sech-function bias voltages on the WA, a Kerr-type DS could be mimicked by a low-power incident light. The transmitting paths of DS and low-power light in the WA can be rerouted with great flexibility by changing the local bias voltages applied on the waveguide. Our proposed silicon WA provides new opportunities for electric-controlled optical devices, which may open a gateway towards rerouting light on-chip and designing integrated optics devices. PMID- 29245798 TI - Support vector machine assisted BOTDA utilizing combined Brillouin gain and phase information for enhanced sensing accuracy. AB - Benefiting from both Brillouin amplitude and phase spectral responses during Brillouin scattering, a support vector machine (SVM) assisted Brillouin optical time domain analyzer (BOTDA) enabling the improvement of sensing accuracy with only a slight sacrifice of processing speed has been proposed and demonstrated. Only one SVM model, i.e. SVM-(g + p), is required to effectively combine the Brillouin gain and phase information in the training and testing phases, which avoids separate Brillouin gain spectrum (BGS) and Brillouin phase spectrum (BPS) fitting, and hence saves the processing time. Both simulation and experiments using different parameters were conducted to evaluate the improved performance of SVM-(g + p). Compared with the case of using BGS only or BPS only, SVM assisted BOTDA using combined BGS and BPS enhances the accuracy of temperature extraction by about 30% over a wide range of simulation and experiment parameters, only at a slight expense of the processing speed. Although the processing of both gain and phase information takes extra time, SVM-(g + p) assisted BOTDA still has a processing speed 80 times faster than that of using a conventional curve fitting method like Lorentzian curve fitting (LCF). The improved accuracy, together with fast processing speed, is crucial for future high-speed and accurate BOTDA sensors based on both Brillouin gain and phase detection. PMID- 29245799 TI - Microfiber-coupled superconducting nanowire single-photon detector for near infrared wavelengths. AB - High-performance superconducting nanowire single-photon detectors (SNSPDs) have facilitated numerous experiments and applications, particularly in the fields of modern quantum optics and quantum communication. Two kinds of optical coupling methods have thus far been developed for SNSPDs: one produces standard fiber coupled SNSPDs in which the fibers vertically illuminate the meandered nanowires; the other produces waveguide-coupled SNSPDs in which nanowires are fabricated on the surface of a waveguide that guides photons, and the fibers are coupled to the waveguide. In this paper, we report on first experimental demonstration of a new type of SNSPD that is coupled with a microfiber (MF). Photons are guided by the MF and are evanescently absorbed by the nanowires of the SNSPD when the MF is placed on top of superconducting NbN nanowires. Room-temperature optical experiments indicated that this device has a coupling efficiency of up to 90% when a 1.3 MUm-diameter MF is used for light with wavelength of 1550 nm. We were also able to demonstrate that our MF-coupled detector achieved system detection efficiencies of 50% and 20% at incident wavelengths of 1064 and 1550 nm, respectively, for a 2 MUm-diameter MF at 2.2K. We expect that MF-coupled SNSPDs may show both high efficiency and broadband characteristics upon optimization and will be used for various novel applications, such as micro/nano-fiber optics. PMID- 29245800 TI - Nonclassical photon pairs from warm atomic vapor using a single driving laser. AB - Generation of nonclassical light is an essential tool for quantum optics research and applications in quantum information technology. We present realization of the source of nonclassically correlated photon pairs based on the process of spontaneous four-wave-mixing in warm atomic vapor. Atoms are excited only by a single laser beam in retro-reflected configuration and narrowband frequency filtering is employed for selection of correlated photon pairs. Nonclassicality of generated light fields is proved by analysis of their statistical properties. Measured parameters of the presented source promise further applicability for efficient interaction with atomic ensembles. PMID- 29245801 TI - Effects of finite and discrete sampling and blur on microrheology experiments. AB - The frequency-dependent viscous and elastic properties of fluids can be determined from measurements of the thermal fluctuations of a micron-sized particle trapped by optical tweezers. Finite bandwidth and other instrument limitations lead to systematic errors in measurement of the fluctuations. In this work, we numerically represented power spectra of bead position measurements as if collected by two different measurement devices: a quadrant photodiode, which measures the deflection of the trapping laser; and a high-speed camera, which images the trapped bead directly. We explored the effects of aliasing, camera blur, sampling frequency, and measurement time. By comparing the power spectrum, complex response function, and the complex shear modulus with the ideal values, we found that the viscous and elastic properties inferred from the data are affected by the instrument limitations of each device. We discuss how these systematic effects might affect experimental results from microrheology measurements and suggest approaches to reduce discrepancies. PMID- 29245802 TI - Visible laser-assisted reduction of plasmonic Ag nanoparticles with narrow-band optical absorption for colored holographic reconstruction. AB - Noble metal plasmonic resonance has been utilized in optical data storage widely for its excellent photo-transformation efficiency. TiO2 nanoporous films deposited with Ag nanoparticles present outstanding polarization-response and color-modulation ability. However, the low exposure-sensitivity at single wavelength inhibits their application in optical information processing, which is urgent to be improved by innovative methods. Here, we report that Ag nanoparticles were deposited efficiently via continuous laser irradiation in the TiO2 nanoporous film treated by tannic acid, presenting high-efficient monochromic absorption property. As a result, two sets of holograms were recorded sequentially at the same point of the film with orthogonal circular polarization configurations. The colored reconstruction of the mixed holograms was achieved by utilizing laser polarization state as chrominance segmentation channel. Our method provides a distinctive route for enhancing the photo-energy conversion efficiency of plasmonic nanoparticles, and paves a way to develop advanced display device. PMID- 29245803 TI - Intensity and temporal noise characteristics in femtosecond optical parametric amplifiers. AB - We characterize the relative intensity noise (RIN) and relative timing jitter (RTJ) between the signal and pump pulses of optical parametric amplifiers (OPAs) seeded by three different seed sources. Compared to a white-light continuum (WLC) seeded- and an optical parametric generator (OPG) seeded OPA, the narrowband CW seeded OPA exhibits the lowest root-mean-square (RMS) RIN and RTJ of 0.79% and 0.32 fs, respectively, integrated from 1 kHz to the Nyquist frequency of 1.25 MHz. An improved numerical model based on a forward Maxwell equation (FME) is built to investigate the transfers of the pump and seed's noise to the resulting OPAs' intensity and temporal fluctuation. Both the experimental and numerical study indicate that the low level of noise from the narrowband CW seeded OPA is attributed to the elimination of the RIN and RTJ coupled from the noise of seed source, being one of the important contributions to RIN and timing jitter in the other two OPAs. The approach to achieve lower level of noise from this CW seeded OPA by driving it close to saturation is also discussed with the same numerical model. PMID- 29245804 TI - Extension of the Swanepoel method for obtaining the refractive index of chalcogenide thin films accurately at an arbitrary wavenumber. AB - The well-known Swanepoel method was often used to obtain the refractive index (RI) of thin films at the wavenumber values corresponding to the extremes of the transmission interference fringes. But it is difficult to accurately obtain the RI of chalcogenide thin films, especially at an arbitrary wavenumber. So a regional approach method (RAM) was presented here to extend the Swanepoel method to an arbitrary wavenumber. In the RAM the RI at the arbitrary wavenumber was determined through dynamic matching. The calculated values were used to match the experimental transmittance. The accuracy of the RI is better than 0.5%. The RI of a well-known film was obtained by the RAM. And the results are in great agreement with the true values of the RI of the film which indicates the correctness and effectiveness of the RAM. Moreover, the transmission spectrum of Ge-Sb-Se film was measured in the ultra-broadband range of 2000-18000 cm-1 (555-5000 nm), and finally the RI of the film was obtained at the 22 wavenumbers of the spacer 600 cm-1 by the RAM. PMID- 29245805 TI - Parametric study of high-performance 1.55 MUm InAs quantum dot microdisk lasers on Si. AB - In this paper, we present a parametric study of high performance microdisk lasers at 1.55 MUm telecom wavelength, monolithically grown on on-axis (001) Si substrates incorporating quantum dots (QDs) as gain elements. In the optimized structure, seven layers of QDs were adopted to provide a high gain as well as a suppressed inhomogeneous broadening. The same laser structure employing quantum wells (QWs) on Si was concurrently evaluated, showing a higher threshold and more dispersive quantum efficiency than the QDs. Finally, a statistical comparison of these Si-based QD microdisk lasers with those grown on InP native substrates was conducted, revealing somewhat higher thresholds but of the same order. The monolithically grown QD microlasers on Si also demonstrated excellent temperature stability, with a record high characteristic temperature of 277 K. This work thus offers helpful insight towards the optimization of reliable Si-based QD lasers at 1550 nm. PMID- 29245806 TI - Protein analysis by Mach-Zehnder interferometers with a hybrid plasmonic waveguide with nano-slots. AB - Optical biosensing devices for the affinity analysis of molecular binding events could offer significant advantages over current analytical methods. However, most of those excited with a single optical mode are "blind" to the conformational change of bound molecules. We succeeded in designing Mach-Zehnder interferometers (MZI) with a hybrid plasmonic (HP) waveguide with nano-slots. By addressing the structure with dual polarizations, the optogeometrical properties (density and thickness) of protein layers have been determined without ambiguity. Differences in the hybrid mode dispersion between the transverse electric (TE) and transverse magnetic (TM) modes separately allow the determination of the thickness and the density at all stages during the molecular interaction. Moreover, nano-slots can be equated with an effective optical capacitance resulting in strong field confinement and low propagation loss. A proof of concept is conducted by analyzing the conformational change of HepV, a recombinant fragment of collagen V, during complicated molecular interaction. Instead of wavelength interrogation, a cost-effective method with output intensity variation at particular wavelengths due to "resonance phenomena" was employed to monitor the biological event. PMID- 29245807 TI - Single-fluorophore orientation determination with multiview polarized illumination: modeling and microscope design. AB - We investigate the use of polarized illumination in multiview microscopes for determining the orientation of single-molecule fluorescence transition dipoles. First, we relate the orientation of single dipoles to measurable intensities in multiview microscopes and develop an information-theoretic metric-the solid-angle uncertainty-to compare the ability of multiview microscopes to estimate the orientation of single dipoles. Next, we compare a broad class of microscopes using this metric-single- and dual-view microscopes with varying illumination polarization, illumination numerical aperture (NA), detection NA, obliquity, asymmetry, and exposure. We find that multi-view microscopes can measure all dipole orientations, while the orientations measurable with single-view microscopes is halved because of symmetries in the detection process. We also find that choosing a small illumination NA and a large detection NA are good design choices, that multiview microscopes can benefit from oblique illumination and detection, and that asymmetric NA microscopes can benefit from exposure asymmetry. PMID- 29245808 TI - Generation of extreme pulses on demand in semiconductor lasers with optical injection. AB - The generation of extreme intensity pulses in an optically injected semiconductor laser is studied numerically by using a well-known rate equation model. We show that step-up perturbations of the laser pump current can trigger extreme pulses. We study the perturbation parameters (amplitude, duration) that are more likely to trigger a extreme pulse, and compare the properties of the generated extreme pulses with those spontaneous emitted, which are due to the intrinsic deterministic dynamics of the laser. We study how the phase of the optical field evolves during the pulses and compare both types of pulses (generated by external perturbations and generated by intrinsic nonlinear dynamics). We find that in both cases the phase dynamics is similar with an abrupt rise and fall: as an extreme pulse begins, the phase grows abruptly and reaches a local maximum at the peak of the pulse, then, when the pulse is over, the phase falls down to a value which is similar to the one before the pulse started. PMID- 29245809 TI - Field redistribution inside an X-ray cavity-QED setup. AB - The field redistribution inside an X-ray cavity-QED setup with an embedded 57Fe layer is calculated and studied in detail. The destructive interference between two transitions from the ground state to the two upper dressed states causes that the cavity mode can not be driven. So the field intensity is very weak when the nuclear ensemble is resonant. Moreover, It is found that the resonant nuclear layer can play a role of reflective layer like a mirror and cut the size of the cavity, which will destroy the guided mode. To support this idea, we employ the 57Fe film as the bottom mirror layer of the cavity where a guided mode can only be formed at the resonant energy. Following this perspective, the electromagnetically induced transparency structure based on X-ray cavity-QED setup with nuclear ensemble is reviewed and a phenomenologically self-consistent analysis for the field redistribution is presented. PMID- 29245810 TI - Efficient anchor loss suppression in coupled near-field optomechanical resonators. AB - Elastic dissipation through radiation towards the substrate is a major loss channel in micro- and nanomechanical resonators. Engineering the coupling of these resonators with optical cavities further complicates and constrains the design of low-loss optomechanical devices. In this work we rely on the coherent cancellation of mechanical radiation to demonstrate material and surface absorption limited silicon near-field optomechanical resonators oscillating at tens of MHz. The effectiveness of our dissipation suppression scheme is investigated at room and cryogenic temperatures. While at room temperature we can reach a maximum quality factor of 7.61k (fQ-product of the order of 1011 Hz), at 22 K the quality factor increases to 37k, resulting in a fQ-product of 2 * 1012 Hz. PMID- 29245811 TI - Coherence-length-gated distributed optical fiber sensing based on microwave photonic interferometry. AB - This paper presents a new optical fiber distributed sensing concept based on coherent microwave-photonics interferometry (CMPI), which uses a microwave modulated coherent light source to interrogate cascaded interferometers for distributed measurement. By scanning the microwave frequencies, the complex microwave spectrum is obtained and converted to time domain signals at known locations by complex Fourier transform. The amplitudes of these time domain pulses are a function of the optical path differences (OPDs) of the distributed interferometers. Cascaded fiber Fabry-Perot interferometers (FPIs) fabricated by femtosecond laser micromachining were used to demonstrate the concept. The experimental results indicated that the strain measurement resolution can be better than 0.6 uepsilon using a FPI with a cavity length of 1.5 cm. Further improvement of the strain resolution to the nepsilon level is achievable by increasing the cavity length of the FPI to over 1m. The tradeoff between the sensitivity and dynamic range was also analyzed in detail. To minimize the optical power instability (either from the light source or the fiber loss) induced errors, a single reflector was added in front of an individual FPI as an optical power reference for the purpose of compensation. PMID- 29245812 TI - 1.4 um continuous-wave diamond Raman laser. AB - The longest wavelength (~1.4 um) emitted by a diamond Raman laser pumped by a semiconductor disk laser (SDL) is reported. The output power of the intracavity pumped Raman laser reached a maximum of 2.3 W with an optical conversion efficiency of 3.4% with respect to the absorbed diode pump power. Narrow Stokes emission (FWHM <0.1 nm) was attained using etalons to limit the fundamental spectrum to a single etalon peak. Tuning of the Raman laser over >40 nm was achieved via rotation of an intracavity birefringent filter that tuned the SDL oscillation wavelength. PMID- 29245813 TI - Spatially separated heterodyne grating interferometer for eliminating periodic nonlinear errors. AB - Periodic nonlinear errors caused by frequency mixing are serious obstacles for increasing the resolution of heterodyne grating interferometers. To eliminate the periodic nonlinear errors, a spatially separated heterodyne grating interferometer is proposed in this study. Two modulated beams with different frequencies are transferred respectively by two fibers, which form a spatially separated construction. A couple of comparison experiments in both time domain and frequency domain are designed and conducted. The results of the frequency spectrum analysis experiment showed that the periodic nonlinear errors were no larger than 0.086 nm, which proved that the proposed system was effectual in eliminating periodic nonlinear errors. PMID- 29245814 TI - Micro-displacement reconstruction using a laser self-mixing grating interferometer with multiple-diffraction. AB - In this paper, we demonstrated an improved laser self-mixing grating interferometer (SMGI) with auto-collimation design which can avoid the disturbance from the light feedback of the zero-order diffraction beam. In order to obtain higher optical subdivision, SMGI with multiple-diffraction is implemented. Both theoretical analysis and experimental work show that the proposed system for displacement measurement can achieve high sensitivity and low measurement uncertainty. Using the proposed system, different forms of micro displacement signals applied on the target (grating) have been reconstructed with accuracy of a few nanometers. The work presented in this paper provides a good way to achieve robust and high precision measurement with compact system configuration. PMID- 29245815 TI - High-efficiency strip-loaded waveguide based silicon Mach-Zehnder modulator with vertical p-n junction phase shifter. AB - We demonstrate a silicon Mach-Zehnder modulator (MZM) based on hydrogenated amorphous silicon (a-Si:H) strip-loaded waveguides on a silicon on insulator (SOI) platform, which can be fabricated by using a complementary metal-oxide semiconductor (CMOS) compatible process without half etching of the SOI layer. Constructing a vertical p-n junction in a flat etchless SOI layer provides superior controllability and uniformity of carrier profiles. Moreover, the waveguide structure based on a thin a-Si:H strip line can be fabricated easily and precisely. Thanks to a large overlap between the depletion region and optical field in the SOI layer with a vertical p-n junction, the MZM provides 0.80- to 1.86-Vcm modulation efficiency and a 12.1- to 16.9-dBV loss-efficiency product, besides guaranteeing a 3-dB bandwidth of about 17 GHz and 28-Gbps high-speed operation. The alphaVpiL is considerably lower than that of conventional high speed modulators. PMID- 29245816 TI - Integrated wavelength conversion for adaptively modulated WDM-OFDM signals in a silicon waveguide. AB - All-optical wavelength conversion for 2*11.64 GBaud adaptively-modulated orthogonal frequency division multiplexing (AM-OFDM) signals with QPSK/16QAM formats is experimentally demonstrated in a silicon waveguide. The AM-OFDM signal with partly higher- (and lower-) order formats on lower- (and higher-) frequency subcarriers has better overall conversion performance in receiving optical signal to-noise ratio and power penalty. In comparison with the OFDM-QPSK signal, at the BER of 3.8*10-3, the bit rate increases 11.64 Gbit/s per channel almost without conversion power penalty increased by replacing the QPSK sequence with the 16QAM sequence on half subcarriers. PMID- 29245817 TI - Three-dimensional wide-field pump-probe structured illumination microscopy: erratum. AB - We found errors in Eqs. (5), (6), (7), (8), (23), (25), Figs. 2, 3, 4, 5, 10, and Discussion of our article "Three-dimensional wide-field pump-probe structured illumination microscopy." Here we publish the revised equations, figures, and discussion. In general, the corrections do not affect the essential conclusion and image reconstruction quality improves with these corrections. PMID- 29245818 TI - Nanoscale material redistribution induced by spatially modulated femtosecond laser pulses for flexible high-efficiency surface patterning. AB - In this paper, we investigated the material redistribution phenomenon controlled by spatially modulated femtosecond laser pulses on a silicon surface. The intensity distribution was shaped by using a spatial light modulator. The material was first selectively melted and then redistributed by the laser-induced plasma. Thus, complex surface patterns were formed conformal to the laser intensity distribution. Sub-diffraction-limit size can be achieved due to the nanoscale material redistribution. Only one pulse was needed in the surface patterning process, thus greatly favoring the efficiency improvement. Combined with multibeam interference, a large-scale nanostructure array can be fabricated with high efficiency of 1600 MUm2/pulse. This method offers a simple, flexible and efficient alternative approach for nanoscale surface patterning applications. PMID- 29245819 TI - Formation of optical vortices with all-glass nanostructured gradient index masks. AB - We report the development of microscopic size gradient index vortex masks using the modified stack-and-draw technique. The vortex mask has a form of flat surface all-glass plate. Its functionality is determined by an internal nanostructure composed of two types of soft glass nanorods. The generation of optical vortices with charges 1 and 2 is demonstrated. PMID- 29245821 TI - Enhanced violations of Leggett-Garg inequalities in an experimental three-level system. AB - Leggett-Garg inequalities are tests of macroscopic realism that can be violated by quantum mechanics. In this letter, we realise photonic Leggett-Garg tests on a three-level system and implement measurements that admit three distinct measurement outcomes, rather than the usual two. In this way we obtain violations of three- and four-time Leggett-Garg inequalities that are significantly in excess of those obtainable in standard Leggett-Garg tests. We also report violations the quantum-witness equality up to the maximum permitted for a three outcome measurement. Our results highlight differences between spatial and temporal correlations in quantum mechanics. PMID- 29245822 TI - Nanoapertures with ordered rotations: symmetry transformation and wide-angle flat lensing. AB - We report the experimental demonstration of a two-dimensional (2D) metasurface with ordered rotation of elements and show that it can be used to control the symmetry of light-matter interaction. A 2D lens is demonstrated in the visible region by transforming the rotational symmetry associated with the off-axis incident light to the translational symmetry, allowing an extraordinarily large field of view (FOV) as well as optical Fourier transformation. Furthermore, such a planar lens has a long focal depth, with polarization selectivity and subwavelength resolution. The scheme presented here may provide many new perspectives on the design of novel 2D optical devices. PMID- 29245820 TI - Numerical analysis of wavefront aberration correction using multielectrode electrowetting-based devices. AB - We present numerical simulations of multielectrode electrowetting devices used in a novel optical design to correct wavefront aberration. Our optical system consists of two multielectrode devices, preceded by a single fixed lens. The multielectrode elements function as adaptive optical devices that can be used to correct aberrations inherent in many imaging setups, biological samples, and the atmosphere. We are able to accurately simulate the liquid-liquid interface shape using computational fluid dynamics. Ray tracing analysis of these surfaces shows clear evidence of aberration correction. To demonstrate the strength of our design, we studied three different input aberrations mixtures that include astigmatism, coma, trefoil, and additional higher order aberration terms, with amplitudes as large as one wave at 633 nm. PMID- 29245823 TI - Confined surface plasmon of fundamental wave and second harmonic waves in graphene nanoribbon arrays. AB - The confined surface plasmon of fundamental wave and second harmonic wave (SHW) are investigated in graphene grating structure. The linear-optical absorption spectra with various fermi energy and carrier mobility are investigated with the finite difference time domain (FDTD) simulations and coupled mode theory (CMT). Based on the CMT, a theoretical model for the graphene grating is established to study the spectrum features of fundamental wave. The lifetimes of linear-optical resonant modes in theoretical model are investigated through the theoretical fitting of exact values in simulation, which are tunable with both the fermi energy and carrier mobility. We also have investigated the second-order nonlinearity of graphene grating by introducing the second-order nonlinear source. The proposed configuration and method are useful for research of the absorption, local field enhancement factor, lifetime of light, and nonlinear optical processes in highly integrated graphene photoelectric devices. PMID- 29245824 TI - Calibration method for projector-camera-based telecentric fringe projection profilometry system. AB - By combining a fringe projection setup with a telecentric lens, a fringe pattern could be projected and imaged within a small area, making it possible to measure the three-dimensional (3D) surfaces of micro-components. This paper focuses on the flexible calibration of the fringe projection profilometry (FPP) system using a telecentric lens. An analytical telecentric projector-camera calibration model is introduced, in which the rig structure parameters remain invariant for all views, and the 3D calibration target can be located on the projector image plane with sub-pixel precision. Based on the presented calibration model, a two-step calibration procedure is proposed. First, the initial parameters, e.g., the projector-camera rig, projector intrinsic matrix, and coordinates of the control points of a 3D calibration target, are estimated using the affine camera factorization calibration method. Second, a bundle adjustment algorithm with various simultaneous views is applied to refine the calibrated parameters, especially the rig structure parameters and coordinates of the control points forth 3D target. Because the control points are determined during the calibration, there is no need for an accurate 3D reference target, whose is costly and extremely difficult to fabricate, particularly for tiny objects used to calibrate the telecentric FPP system. Real experiments were performed to validate the performance of the proposed calibration method. The test results showed that the proposed approach is very accurate and reliable. PMID- 29245825 TI - Precise displacement measurement in single-beam interferometry employing photonic metamaterial with effective zero-index. AB - As interferometry is the highest precision distance measuring technique, we proposed a mechanism of single-beam interferometry employing all-dielectric photonic metamaterial with effective zero-index as a means of precise displacement measurement. This mechanism offers a straightforward method for performing optical range-finding over multi-wavelength and sub-wavelength displacements in a compact uniaxial reflection configuration. The higher sensitivity and resolution can be achieved in this mechanism with the intrinsic accuracy of lambda/4. The predesignated measuring device based on the proposed strategy could be directly scaled in dimensions to work at different frequency regions without the need for reconfiguration. Both numerical simulations and experiment have demonstrated its feasibilities and reliability. We believe it will have significant potential applications in the future optical measurement. PMID- 29245826 TI - Optical encryption via monospectral integral imaging. AB - Optical integral imaging (II) uses a lenslet array and CCD sensor as the 3D acquisition device, in which the multispectral information is acquired by a color filter array (CFA). However, color crosstalk exists in CFA that diminishes color gamut, resulting in the reduced resolution. In this paper, we present a monospectral II encryption approach with a monospectral camera array (MCA). The monospectral II system captures images with the MCA that can eliminate color crosstalk among the adjacent spectral channels. It is noteworthy that the captured elemental images (EIs) from the colored scene belong to grayscale; the colored image encryption is converted to grayscale encryption. Consequently, this study will significantly save the calculation load in image encoding and decoding (nearly reduced 2/3) compared with the similar works. Afterwards, an optimized super-resolution reconstruction algorithm is introduced to improve the viewing resolution. PMID- 29245827 TI - Fabrication of photon sieves by laser ablation and optical properties. AB - In this work, we demonstrate the feasibility and performance of photon sieve diffractive optical elements fabricated via a direct laser ablation process. Pulses of 50 ns width and wavelength 1064 nm from an ytterbium fiber laser were focused to a spot diameter of approximately 35 um. Using a galvanometric scan head writing at 100 mm/s, a 30.22 mm2 photon sieve operating at 633 nm wavelength with a focal length of 400 mm was fabricated. The optical performance of the sieve was characterized and is in strong agreement with numerical simulations, producing a focal spot size full-width at half-maximum (FWHM) of 45.12 +/- 0.74 um with a photon sieve minimum pinhole diameter of 62.2 um. The total time to write the photon sieve pattern was 28 seconds as compared to many hours using photolithography methods. We also present, for the first time to our knowledge in the literature, thorough characterization of the influence of angle of incidence, temperature, and illumination wavelength on photon sieve performance. Thus, this work demonstrates the potential for a high speed, low cost fabrication method of photon sieves that is highly customizable and capable of producing sieves with low or high numerical apertures. PMID- 29245828 TI - Direct laser writing for micro-optical devices using a negative photoresist. AB - Direct laser writing (DLW) via two-photon absorption (TPA) has attracted much attention as a new microfabrication technique because it can be applied to fabricate complex, three-dimensional (3D) microstructures. In this study, 3D microstructures and micro-optical devices of micro-lens array on the micrometer scale are fabricated using the negative photoresist SU-8 through TPA with a femtosecond laser pulse under a microscope. The effects of the irradiation conditions on linewidths, such as laser power, writing speed, and writing cycles (a number of times a line is overwritten), are investigated before the fabrication of the 3D microstructures. Various microstructures such as woodpiles, hemisphere and microstructures, 3D micro-lens and micro-lens array for micro optical devices are fabricated. The shape of the micro-lens is evaluated using the shape analysis mode of a laser microscope to calculate the working distance of the fabricated micro-lenses. The calculated working distance corresponds well to the experimentally measured value. The focusing performance of the fabricated micro-lens is confirmed by the TPA fluorescence of an isopropyl thioxanthone (ITX) ethanol solution excited by a Ti:sapphire femtosecond laser at 800 nm. Micro-lens array (assembled 9 micro-lenses) are fabricated. Nine independent woodpile structures are simultaneously manufactured by DLW via TPA to confirm the multi-focusing ability using the fabricated micro-lens array. PMID- 29245829 TI - Sensitive detection of voltage transients using differential intensity surface plasmon resonance system. AB - This paper describes theoretical and experimental study of the fundamentals of using surface plasmon resonance (SPR) for label-free detection of voltage. Plasmonic voltage sensing relies on the capacitive properties of metal electrolyte interface that are governed by electrostatic interactions between charge carriers in both phases. Externally-applied voltage leads to changes in the free electron density in the surface of the metal, shifting the SPR position. The study shows the effects of the applied voltage on the shape of the SPR curve. It also provides a comparison between the theoretical and experimental response to the applied voltage. The response is presented in a universal term that can be used to assess the voltage sensitivity of different SPR instruments. Finally, it demonstrates the capacity of the SPR system in resolving dynamic voltage signals; a detection limit of 10mV with a temporal resolution of 5ms is achievable. These findings pave the way for the use of SPR systems in the detection of electrical activity of biological cells. PMID- 29245830 TI - Distributed gas sensing with optical fibre photothermal interferometry. AB - We report the first distributed optical fibre trace-gas detection system based on photothermal interferometry (PTI) in a hollow-core photonic bandgap fibre (HC PBF). Absorption of a modulated pump propagating in the gas-filled HC-PBF generates distributed phase modulation along the fibre, which is detected by a dual-pulse heterodyne phase-sensitive optical time-domain reflectometry (OTDR) system. Quasi-distributed sensing experiment with two 28-meter-long HC-PBF sensing sections connected by single-mode transmission fibres demonstrated a limit of detection (LOD) of ~10 ppb acetylene with a pump power level of 55 mW and an effective noise bandwidth (ENBW) of 0.01 Hz, corresponding to a normalized detection limit of 5.5ppb?W/Hz. Distributed sensing experiment over a 200-meter long sensing cable made of serially connected HC-PBFs demonstrated a LOD of ~ 5 ppm with 62.5 mW peak pump power and 11.8 Hz ENBW, or a normalized detection limit of 312ppb?W/Hz. The spatial resolution of the current distributed detection system is limited to ~ 30 m, but it is possible to reduce down to 1 meter or smaller by optimizing the phase detection system. PMID- 29245831 TI - Fabrication of monolithic diamond photodetector with microlenses. AB - A monolithic diamond photodetector with microlenses is fabricated by etching microlens arrays (MLAs) on single crystal diamond surface and patterning tungsten electrode strips on the edge of these arrays. Firstly, compact MLAs are etched on half of diamond sample surface by thermal reflow method. Secondly, via magnetron sputtering technique, two sets of interdigitated tungsten electrodes are patterned on the sample surface, one set is on the edge of MLAs, the other set is on the planar area. The optoelectronic performances of photodetectors have been investigated and indicated that the photocurrent of microlens photodetector increases by 74.8 percent at 10 V under 220 nm UV light illumination by comparing with that in planar case. Simulations of photodetectors' electrical and optical properties have been carried out, illustrating an improvement of charge collection ability and light absorption efficiency in microlens case. Furthermore, the present device structure can be extended to other semiconductor photodetectors. PMID- 29245832 TI - Numerical study of ultrashort-optical-feedback-enhanced photonic microwave generation using optically injected semiconductor lasers at period-one nonlinear dynamics. AB - This study numerically investigates the enhancement of photonic microwave generation using an optically injected semiconductor laser operating at period one (P1) nonlinear dynamics through ultrashort optical feedback. For the purpose of practical applications where system miniaturization is generally preferred, a feedback delay time that is one to two orders of magnitude shorter than the relaxation resonance period of a typical laser is emphasized. Various dynamical states that are more complicated than the P1 dynamics can be excited under a number of ultrashort optical feedback conditions. Within the range of the P1 dynamics, on one hand, the frequency of the P1 microwave oscillation can be greatly enhanced by up to more than three folds. Generally speaking, the microwave frequency enhances with the optical feedback power and phase, while it varies saw-wise with the optical feedback delay time. On the other hand, the purity of the P1 microwave oscillation can be highly improved by up to more than three orders of magnitude. In general, the microwave purity improves with the optical feedback power and delay time, while it only varies within an order of magnitude with the optical feedback phase. These results suggest that the ultrashort optical feedback provides the optically injected laser system with an extra degree of freedom to manipulate/improve the characteristics of the P1 microwave oscillation without changing the optical injection condition. PMID- 29245833 TI - Total absorption of light in monolayer transition-metal dichalcogenides by critical coupling. AB - Transition-metal dichalcogenides with exceptional electrical and optical properties have emerged as a new platform for atomic-scale optoelectronic devices. However, the poor optical absorption resists their potential applications. The novel method of critical coupling with guided resonances is proposed to realize total absorption of light in monolayer MoS2 both theoretically and numerically. Simulated results illustrate that the perfect absorption with critical coupling is achieved by choosing suitably the ration of the hole radius to the period of the photonic crystal slab, and that the tunability of absorption peaks is obtained by a small change in the period and the thickness of the slab. Intriguingly, such device manifests the unusual polarization-insensitive feature and the good absorption stability over a wide angle range of incidence. The total absorption in monolayer MoSe2, WS2, and WSe2 is realized handily by the same principle. Hence, our results may open up new possibilities for improving the light-matter interaction in monolayer transition metal dichalcogenides and find utility in wavelength-selective photoluminescence and photodetection. PMID- 29245834 TI - Interrogation of a ring-resonator ultrasound sensor using a fiber Mach-Zehnder interferometer. AB - We experimentally demonstrate an interrogation procedure of a ring-resonator ultrasound sensor using a fiber Mach-Zehnder interferometer (MZI). The sensor comprises a silicon ring resonator (RR) located on a silicon-oxide membrane, designed to have its lowest vibrational mode in the MHz range, which is the range of intravascular ultrasound (IVUS) imaging. Ultrasound incident on the membrane excites its vibrational mode and as a result induces a modulation of the resonance wavelength of the RR, which is a measure of the amplitude of the ultrasound waves. The interrogation procedure developed is based on the mathematical description of the interrogator operation presented in Appendix A, where we identify the amplitude of the angular deflection Phi0 on the circle arc periodically traced in the plane of the two orthogonal interrogator voltages, as the principal sensor signal. Interrogation is demonstrated for two sensors with membrane vibrational modes at 1.3 and 0.77 MHz, by applying continuous wave ultrasound in a wide pressure range. Ultrasound is detected at a pressure as low as 1.2 Pa. Two optical path differences (OPDs) of the MZI are used. Thus, different interference conditions of the optical signals are defined, leading to a higher apparent sensitivity for the larger OPD, which is accompanied by a weaker signal, however. Independent measurements using the modulation method yield a resonance modulation per unit of pressure of 21.4 fm/Pa (sensor #1) and 103.8 fm/Pa (sensor #2). PMID- 29245835 TI - Ptychographic analysis of the photorefractive effect in LiNbO3:Fe. AB - We present light induced refractive index changes in iron doped lithium niobate detected with a novel microscopy technique called ptychography. This method determines the change of the refractive index together with the intensity distribution of the writing beam from a single scan with a reconstructed spatial resolution of 3 MUm and a sensitivity of the refractive index change of 10-5. We show that the light induced refractive index change is strongly connected to the intensity shape of the writing beam and that it shows the expected nonlocal behaviour. Applying the novel method to the investigation of the photorefractive effect offers an excellent opportunity to study this nonlocal response to the spatial distribution of the writing beam. PMID- 29245836 TI - Experimental study of the sensitivity of a porous silicon ring resonator sensor using continuous in-flow measurements. AB - A highly sensitive photonic sensor based on a porous silicon ring resonator was developed and experimentally characterized. The photonic sensing structure was fabricated by exploiting a porous silicon double layer, where the top layer of a low porosity was used to form photonic elements by e-beam lithography and the bottom layer of a high porosity was used to confine light in the vertical direction. The sensing performance of the ring resonator sensor based on porous silicon was compared for the different resonances within the analyzed wavelength range both for transverse-electric and transverse-magnetic polarizations. We determined that a sensitivity up to 439 nm/RIU for low refractive index changes can be achieved depending on the optical field distribution given by each resonance/polarization. PMID- 29245837 TI - Graphene based on-chip variable optical attenuator operating at 855 nm wavelength. AB - This work reports on the fabrication and characterization of a graphene based variable optical attenuator integrated on a photonic Si3N4 waveguide and operating at 855 nm wavelength. The variable optical attenuator utilizes the gate voltage dependent optical absorption of a graphene layer, located in the evanescent field of the waveguide. A maximum attenuation of 17 dB is obtained at 3 V gate voltages for a device length of 700 um. The measured voltage dependent absorption was found to be in good agreement with theoretical simulations, taking into account inter- and intra-band optical conductivity of graphene. An outlook is given on possible margins for increasing the operation speed and reducing the insertion loss of the device, using an optimized layout and improved fabrication processes. PMID- 29245838 TI - Dynamic high pressure induced strong and weak hydrogen bonds enhanced by pre resonance stimulated Raman scattering in liquid water. AB - 355 nm pulsed laser is employed to excite pre-resonance forward stimulated Raman scattering (FSRS) of liquid water at ambient temperature. Due to the shockwave induced dynamic high pressure, the obtained Raman spectra begin to exhibit double peaks distribution at 3318 and 3373 cm-1 with the input energy of 17 mJ,which correspond with OH stretching vibration with strong and weak hydrogen (H) bonds. With laser energy rising from 17 to 27 mJ, the Stokes line at 3318 cm-1 shifts to 3255 and 3230 cm-1 because of the high pressure being enlarged. When the energy is up to 32 mJ, only 3373 cm-1 peak exists. The strong and weak H bond exhibit quite different energy dependent behaviors. PMID- 29245839 TI - Two-dimensional atom localization based on coherent field controlling in a five level M-type atomic system. AB - We study two-dimensional sub-wavelength atom localization based on the microwave coupling field controlling and spontaneously generated coherence (SGC) effect. For a five-level M-type atom, introducing a microwave coupling field between two upper levels and considering the quantum interference between two transitions from two upper levels to lower levels, the analytical expression of conditional position probability (CPP) distribution is obtained using the iterative method. The influence of the detuning of a spontaneously emitted photon, Rabi frequency of the microwave field, and the SGC effect on the CPP are discussed. The two dimensional sub-half-wavelength atom localization with high-precision and high spatial resolution is achieved by adjusting the detuning and the Rabi frequency, where the atom can be localized in a region smaller thanlambda/10*lambda/10. The spatial resolution is improved significantly compared with the case without the microwave field. PMID- 29245840 TI - Tunable electromagnetically induced transparency in integrated silicon photonics circuit. AB - We comprehensively simulate and experimentally demonstrate a novel approach to generate tunable electromagnetically induced transparency (EIT) in a fully integrated silicon photonics circuit. It can also generate tunable fast and slow light. The circuit is a single ring resonator with two integrated tunable reflectors inside, which form an embedded Fabry-Perot (FP) cavity inside the ring cavity. The mode of the FP cavity can be controlled by tuning the reflections using integrated thermo-optic tuners. Under correct tuning conditions, the interaction of the FP mode and the ring resonance mode will generate a Fano resonance and an EIT response. The extinction ratio and bandwidth of the EIT can be tuned by controlling the reflectors. Measured group delay proves that both fast light and slow light can be generated under different tuning conditions. A maximum group delay of 1100 ps is observed because of EIT. Pulse advance around 1200 ps is also demonstrated. PMID- 29245841 TI - Extending the depth of field with chromatic aberration for dual-wavelength iris imaging. AB - We propose a method of extending the depth of field to twice that achievable by conventional lenses for the purpose of a low cost iris recognition front-facing camera in mobile phones. By introducing intrinsic primary chromatic aberration in the lens, the depth of field is doubled by means of dual wavelength illumination. The lens parameters (radius of curvature, optical power) can be found analytically by using paraxial raytracing. The effective range of distances covered increases with dispersion of the glass chosen and with larger distance for the near object point. PMID- 29245842 TI - Dielectric-elastomer-based fabrication method for varifocal microlens array. AB - We report on a method to fabricate a varifocal microlens array that employs a dielectric elastomer (DE) sandwiched between two electrodes as the lens material. The microlens array is patterned on the electrode plates, and when the electrodes are subjected to a controllable operating voltage, the DE material is "squeezed" by the Maxwell force to deform the lens array pattern, thus resulting in curvature deformation yielding a tunable lens profile. The tunable focal length performance ranges from 950 mm to infinity. When compared with liquid-filled lenses, solid-based varifocal lenses are more robust to thermal expansion, gravity, and vibrational motion. Our approach can be utilized in applications such as machine vision systems. PMID- 29245843 TI - Single-photon-induced two qubits excitation without breaking parity symmetry. AB - We investigate theoretically the model of two "qubits" system (one qubit having an auxiliary level) interacting with a single-mode resonator in the ultrastrong coupling regime. We show that a single photon could simultaneously excite two qubits without breaking the parity symmetry of system by properly encoding the excited states of qubits. The optimal parameter regime for achieving high probability approaching one is identified in the case of ignoring the system dissipation. Moreover, using experimentally feasible parameters, we also analyze the dissipation dynamics of the system, and present the realization of two-qubit excitation induced by single-photon. This work offers an alternative approach to realize the single-photon-induced two qubits excitation, which should advance the development of single-photon quantum technologies and have potential applications in quantum information science. PMID- 29245844 TI - Sensitivity improvement of dual-comb spectroscopy using mode-filtering technique. AB - In this study, we demonstrated an improvement in the detection sensitivity of dual-comb spectroscopy using the repetition rate multiplication of optical frequency combs. We compared the dual-comb signals in three dual-comb setups consisting of combinations of two combs with and without mode-filtering, and investigated how the repetition rate influences the signal-to-noise ratio (SNR) of dual-comb measurements. The dual-comb setups using high-repetition-rate combs enabled the absorption lines of HCN gas to be measured with a high SNR in a short averaging time, and real-time spectral data acquisition was realized using a low sensitivity and low-resolution RF spectrum analyzer. PMID- 29245845 TI - High sensitivity visible light refractive index sensor based on high order mode Si3N4 photonic crystal nanobeam cavity. AB - We design and demonstrate a suspended high sensitivity silicon nitride (Si3N4) photonic crystal (PhC) nanobeam cavity sensor. By utilizing the higher order mode, the optical field distribution in the analytes increases dramatically and the light matter interaction between the optical mode and the analytes has been enhanced. A high sensitivity of 321 nm/refractive index unit (nm/RIU) has been experimentally achieved at the wavelength ~700 nm which is the highest value reported so far for a resonator based sensor at such a short wavelength. PMID- 29245846 TI - Low loss GaN waveguides at the visible spectral wavelengths for integrated photonics applications. AB - We perform comprehensive studies on the fundamental loss mechanisms in III nitride waveguides in the visible spectral region. Theoretical analysis shows that free carrier loss dominates for GaN under low photon power injection. When optical power increases, the two photon absorption loss becomes important and eventually dominates when photon energy above half-bandgap of GaN. When the dimensions of the waveguides reduce, the sidewall scattering loss will start to dominate. To verify the theoretical results, a high performance GaN-on-sapphire waveguide was fabricated and characterized. Experimental results are consistent with the theoretical findings, showing that under high power injection the optical loss changed significantly for GaN waveguides. A low optical loss ~2 dB/cm was achieved on the GaN waveguide, which is the lowest value ever reported for the visible spectral range. The results and fabrication processes developed in this work pave the way for the development of III-nitride integrated photonics in the visible and potentially ultraviolet spectral range for nonlinear optics and quantum photonics applications. PMID- 29245847 TI - Attosecond sublevel beating and nonlinear dressing on the 3d-to-5p and 3p-to-5s core-transitions at 91.3 eV and 210.4 eV in krypton. AB - Applying extreme ultraviolet (XUV) transient absorption spectroscopy, the dynamics of the two laser dressed transitions 3d5/2-to-5p3/2 and 3p3/2-to-5s1/2 at photon energies of 91.3 eV and 210.4 eV were examined with attosecond temporal resolution. The dressing process was modeled with density matrix equations which are found to describe very accurately both the experimentally observed transmission dynamics and the linear and nonlinear dressing oscillations at 0.75 PHz and 1.5 PHz frequencies. Furthermore, using Fourier transform XUV spectroscopy, quantum beats from the 3d5/2-3d3/2 and 3p3/2-3p1/2 sublevels at 0.3 PHz and 2.0 PHz were experimentally identified and resolved. PMID- 29245848 TI - Linear laser fast scanning thermography NDT for artificial disbond defects in thermal barrier coatings. AB - Interface disbond in thermal barrier coatings (TBCs) is one of the key issues that cause their premature failure. In general, blind hole defects are often used as substitutes in transient thermography. The linear laser fast scanning thermography (LLFST) method was developed in this study and combined with several post-processing algorithms to accurately detect blind hole defects in TBCs. Through numerical simulation and experimental verification, a unique thermal response characteristic of blind holes in the cooling phase, namely a distinct "tailing" phenomenon, was summarized and utilized to recognize small defects. Validation tests indicated that blind holes with diameters of 1, 2, and 3 mm and artificial disbonds with diameters of 2 and 3 mm in TBCs are detected with high efficiency. PMID- 29245849 TI - Effects of imperfect angular adjustment on plasmonic force. AB - The attractive plasmonic force between two metallic walls due to electromagnetic wave in the slit has been studied earlier for parallel plates and normal incidence. In present paper the effects of imperfectly adjusted plates and laser beam are analyzed. The change of force for non-parallel plates is shown to be of the first order in angle when the wedge is oriented along wave propagation and of the second order for the transverse case. Beam inclination decreases the force due to an antisymmetric mode excited in the slit. PMID- 29245850 TI - Design methodology for moire magnifier based on micro-focusing elements. AB - Moire effect is a well-known interference phenomenon occurred between repetitive structures. Conventional moire fringes are produced by superposing gratings or dots arrays. However, when the micro-image array as base layer and the corresponding micro-focusing elements as revealing layer overlap each other, a special kind of moire effect, so-called moire magnifier, can be observed. Micro image units in the base layer are enlarged and projected to moire space. To our knowledge, there has no complete design methodology for the realization of the moire magnifier. With the combination of the Fourier transform and spectral approach, a new algorithm based on transfer matrix is investigated, which is capable of predicting the location of any arbitrary point in the base layer mapping to the moire space, thus it provides a simple way to explore the physical insight into the field of moire imaging. The magnification factor and the orientation of the synthetically enlarged image are determined not only by the scaling ratio but also by the interrelation between the primitive vectors in the base and revealing layers. Experimental results are in good agreement with theoretical predictions. By using the proposed method, the moire magnifier can extend appealing applications in esthetic security devices, highly accurate measurements and precise color printing. PMID- 29245851 TI - Widely tunable and narrow-bandwidth pulsed mid-IR PPMgLN-OPO by self-seeding dual etalon-coupled cavities. AB - Integrating narrow-bandwidth and wavelength tunability together is crucially important in upgrading the applications of optical parametric oscillators (OPO). Here, we have demonstrated a widely tunable, narrow-bandwidth and efficient mid IR OPO pumped by a single-longitudinal-mode pulsed Yb-fiber laser. By restricting the bandwidth of the oscillated signal via self-seeding dual etalon-coupled cavities, the bandwidth of the idler can be suppressed to about 0.35 nm, with a wide tunable range of 2.85-3.05 MUm, which can be achieved by synergistically adjusting the temperatures of PPMgLN crystal and one of the etalons. The maximum idler power at 3.031 MUm is 2.67 W with an optical-to-optical conversion efficiency of 17.4%. PMID- 29245852 TI - Giant enhancement of reflectance due to the interplay between surface confined wave modes and nonlinear gain in dielectric media. AB - We study theoretically the interplay between the surface confined wave modes and the linear and nonlinear gain of the dielectric layer in the Otto configuration. The surface confined wave modes, such as surface plasmons or waveguide modes, are excited in the dielectric-metal bilayer by obliquely incident p waves. In the purely linear case, we find that the interplay between linear gain and surface confined wave modes can generate a large reflectance peak with its value much greater than 1. As the linear gain parameter increases, the peak appears at smaller incident angles, and the associated modes also change from surface plasmons to waveguide modes. When the nonlinear gain is turned on, the reflectance shows very strong multistability near the incident angles associated with surface confined wave modes. As the nonlinear gain parameter is varied, the reflectance curve undergoes complicated topological changes and sometimes displays separated closed curves. When the nonlinear gain parameter takes an optimally small value, a giant amplification of the reflectance by three orders of magnitude occurs near the incident angle associated with a waveguide mode. We also find that there exists a range of the incident angle where the wave is dissipated rather than amplified even in the presence of gain. We suggest that this can provide the basis for a possible new technology for thermal control in the subwavelength scale. PMID- 29245853 TI - Quantum non-demolition measurement of photon number with atom-light interferometers. AB - When atoms are illuminated by an off-resonant field, the AC Stark effect will lead to phase shifts in atomic states. The phase shifts are proportional to the photon number of the off-resonant illuminating field. By measuring the atomic phase with newly developed atom-light hybrid interferometers, we can achieve quantum non-demolition measurement of the photon number of the optical field. In this paper, we analyze theoretically the performance of this QND measurement scheme by using the QND measurement criteria established by Holland et al [Phys. Rev. A 42, 2995 (1990)]. We find the quality of the QND measurement depends on the phase resolution of the atom-light hybrid interferometers. We apply this QND measurement scheme to a twin-photon state from parametric amplifier to verify the photon correlation in the twin beams. Furthermore, a sequential QND measurement procedure is analyzed for verifying the projection property of quantum measurement and for the quantum information tapping. Finally, we discuss the possibility for single-photon-number-resolving detection via QND measurement. PMID- 29245854 TI - Polycapillary-boosted instrument performance in the extreme ultraviolet regime for inverse photoemission spectroscopy. AB - A collimating polycapillary half lens, traditionally used in the medium and hard X-ray band, is operated at a photon energy of 36 eV for the first time. While the transmission still exceeds 50%, the measured and simulated spatial resolution and angular divergence approach 0.4 mm or less and at most 20 mrad, respectively. This unexpected, superior performance of the polycapillary optic in the extreme Ultraviolet could enable the design of an efficient, versatile and compact spectrometer for inverse photoemission spectroscopy (IPES): Its wavelength dispersive component, a customized reflection zone plate, can maintain an energy resolution of 0.3 eV, whereas the sensitivity may be enhanced by more than one order of magnitude, compared to conventional spectrometers. Furthermore, the overall length of 0.9 m would allow for an eased alignment and evacuation. We see a significant potential for numerous polycapillary-based XUV / soft X-ray instruments in the future, in particular after further optimization for this long wavelength regime. PMID- 29245855 TI - Integration of InGaAs MOSFETs and GaAs/ AlGaAs lasers on Si Substrate for advanced opto-electronic integrated circuits (OEICs). AB - Lasers monolithically integrated with high speed MOSFETs on the silicon (Si) substrate could be a key to realize low cost, low power, and high speed opto electronic integrated circuits (OEICs). In this paper, we report the monolithic integration of InGaAs channel transistors with electrically pumped GaAs/AlGaAs lasers on the Si substrate for future advanced OEICs. The laser and transistor layers were grown on the Si substrate by molecular beam epitaxy (MBE) using direct epitaxial growth. InGaAs n-FETs with an ION/IOFF ratio of more than 106 with very low off-state leakage and a low subthreshold swing with a minimum of 82 mV/decade were realized. Electrically pumped GaAs/AlGaAs quantum well (QW) lasers with a lasing wavelength of 795 nm at room temperature were demonstrated. The overall fabrication process has a low thermal budget of no more than 400 degrees C. PMID- 29245856 TI - Bending-induced inter-core group delays in multicore fibers. AB - We examine the impact of fiber bends on ultrashort pulse propagation in a 169 core multicore fiber (MCF) by numerical simulations and experimental measurements. We show that an L-shaped bend (where only one end of the MCF is fixed) induces significant changes in group delays that are a function of core position but linear along the bending axis with a slope directly proportional to the bending angle. For U- and S-shaped bends (where both ends of the MCF are fixed) the induced refractive index and group delay changes are much smaller than the residual, intrinsic inter-core group delay differences of the unbent MCF. We further show that when used for point-scanning lensless endoscopy with ultrashort pulse excitation, bend-induced group delays in the MCF degrade the point-spread function due to spatiotemporal coupling. Our results show that bend-induced effects in MCFs can be parametrized with only two parameters: the angle of the bend axis and the amplitude of the bend. This remains valid for bend amplitudes up to at least 200 degrees. PMID- 29245857 TI - Interband cascade laser based mid-infrared methane sensor system using a novel electrical-domain self-adaptive direct laser absorption spectroscopy (SA-DLAS). AB - To suppress sensor noise with unknown statistical properties, a novel self adaptive direct laser absorption spectroscopy (SA-DLAS) technique was proposed by incorporating a recursive, least square (RLS) self-adaptive denoising (SAD) algorithm and a 3291 nm interband cascade laser (ICL) for methane (CH4) detection. Background noise was suppressed by introducing an electrical-domain noise-channel and an expectation-known-based RLS SAD algorithm. Numerical simulations and measurements were carried out to validate the function of the SA DLAS technique by imposing low-frequency, high-frequency, White-Gaussian and hybrid noise on the ICL scan signal. Sensor calibration, stability test and dynamic response measurement were performed for the SA-DLAS sensor using standard or diluted CH4 samples. With the intrinsic sensor noise considered only, an Allan deviation of ~43.9 ppbv with a ~6 s averaging time was obtained and it was further decreased to 6.3 ppbv with a ~240 s averaging time, through the use of self-adaptive filtering (SAF). The reported SA-DLAS technique shows enhanced sensitivity compared to a DLAS sensor using a traditional sensing architecture and filtering method. Indoor and outdoor atmospheric CH4 measurements were conducted to validate the normal operation of the reported SA-DLAS technique. PMID- 29245858 TI - High power cryogenic Ho:YAG laser. AB - We have improved significantly the brightness of cryogenic Ho:YAG, reporting up to 65 W output power with a beam quality of M2 <1.3 and a slope efficiency of 71%. The laser emission was ~2 nm wide and centered at 2097.5 nm. This result demonstrates the scalability of both the narrow-line thulium fibre pump laser and the cryogenic laser head. PMID- 29245860 TI - Demonstration of the CDMA-mode CAOS smart camera. AB - Demonstrated is the code division multiple access (CDMA)-mode coded access optical sensor (CAOS) smart camera suited for bright target scenarios. Deploying a silicon CMOS sensor and a silicon point detector within a digital micro-mirror device (DMD)-based spatially isolating hybrid camera design, this smart imager first engages the DMD starring mode with a controlled factor of 200 high optical attenuation of the scene irradiance to provide a classic unsaturated CMOS sensor based image for target intelligence gathering. Next, this CMOS sensor provided image data is used to acquire a focused zone more robust un-attenuated true target image using the time-modulated CDMA-mode of the CAOS camera. Using four different bright light test target scenes, successfully demonstrated is a proof of-concept visible band CAOS smart camera operating in the CDMA-mode using up-to 4096 bits length Walsh design CAOS pixel codes with a maximum 10 KHz code bit rate giving a 0.4096 seconds CAOS frame acquisition time. A 16-bit analog-to digital converter (ADC) with time domain correlation digital signal processing (DSP) generates the CDMA-mode images with a 3600 CAOS pixel count and a best spatial resolution of one micro-mirror square pixel size of 13.68 MUm side. The CDMA-mode of the CAOS smart camera is suited for applications where robust high dynamic range (DR) imaging is needed for un-attenuated un-spoiled bright light spectrally diverse targets. PMID- 29245859 TI - Polarization dependent Brillouin frequency shift fluctuation induced by low birefringence in single mode fiber. AB - The polarization dependent fluctuation of Brillouin frequency shift (BFS) of stimulated Brillouin scattering (SBS) in practical single mode fibers (SMFs) is reported. The phenomenon is actually caused by the interference of the low birefringence in SMF with the SBS spectral polarization spreading of the signal light. The performance of the polarization dependent BFS fluctuation is studied by simulation and confirmed with agreeable experimental results. PMID- 29245861 TI - Digital mobile fronthaul employing differential pulse code modulation with suppressed quantization noise. AB - A differential pulse code modulation (DPCM) based digital mobile fronthaul architecture is proposed and experimentally demonstrated. By using a linear predictor in the DPCM encoding process, the quantization noise can be effectively suppressed and a prediction gain of 7~8 dB can be obtained. Experimental validation is carried out with a 20 km 15-Gbaud/lambda 4-level pulse amplitude modulation (PAM4) intensity modulation and direct detection system. The results verify the feasibility of supporting 163, 122, 98, 81 20-MHz 4, 16, 64, 256 QAM based antenna-carrier (AxC) containers with only 3, 4, 5, 6 quantization bits at a sampling rate of 30.72MSa/s in LTE-A environment. Further increasing the number of quantization bits to 8 and 9, 1024 quadrature amplitude modulation (1024 QAM) and 4096 QAM transmission can be realized with error vector magnitude (EVM) lower than 1% and 0.5%, respectively. The supported number of AxCs in the proposed DPCM based fronthaul is increased and the EVM is greatly reduced compared to the common public radio interface (CPRI) based fronthaul that uses pulse code modulation. Besides, the DPCM-based fronthaul is also experimentally demonstrated to support universal filtered multicarrier signal that is one candidate waveform for the 5th generation mobile systems. PMID- 29245862 TI - Non-destructive residual pressure self-measurement method for the sensing chip of optical Fabry-Perot pressure sensor. AB - We introduce a simple residual pressure self-measurement method for the Fabry Perot (F-P) cavity of optical MEMS pressure sensor. No extra installation is required and the structure of the sensor is unchanged. In the method, the relationship between residual pressure and external pressure under the same diaphragm deflection condition at different temperatures is analyzed by using the deflection formula of the circular plate with clamped edges and the ideal gas law. Based on this, the residual pressure under the flat condition can be obtained by pressure scanning process and calculation process. We carried out the experiment to compare the residual pressures of two batches MEMS sensors fabricated by two kinds of bonding process. The measurement result indicates that our approach is reliable enough for the measurement. PMID- 29245863 TI - Enhancement of the damage resistance of ultra-fast optics by novel design approaches. AB - Dielectric components are essential for laser applications. Chirped mirrors are applied to compress the temporal pulse broadening crucial in the femtosecond regime. However, the design sensitivity and the electric field distribution of chirped mirrors is complex often resulting in low laser induced damage resistances. An approach is presented to increase the damage resistance of pulse compressing mirrors up to 190% in the NIR spectral range. Layers with critical high field intensity of a binary mirror design are substituted by ternary composites and quantized nanolaminates, respectively. The deposition process is improved by an in situ technique monitoring the phase of reflectance. PMID- 29245864 TI - Computational reconfigurable imaging spectrometer. AB - We demonstrate a novel hyperspectral imaging spectrometer based on computational imaging that enables sensitive measurements from smaller, noisier, and less expensive components (e.g. uncooled microbolometers), making it useful for applications such as small space and air platforms with strict size, weight, and power requirements. The computational reconfigurable imaging spectrometer (CRISP) system exploits platform motion and a spectrally coded focal-plane mask to temporally modulate the optical spectrum, enabling simultaneous measurement of multiple spectral bins. Demodulation of this coded pattern returns an optical spectrum in each pixel. PMID- 29245865 TI - Nearly perfect resonant absorption and coherent thermal emission by hBN-based photonic crystals. AB - In this paper, we numerically demonstrate mid-IR nearly perfect resonant absorption and coherent thermal emission for both polarizations and wide angular region using multilayer designs of unpatterned films of hexagonal boron nitride (hBN). In these optimized structures, the films of hBN are transferred onto a Ge spacer layer on top of a one-dimensional photonic crystal (1D PC) composed of alternating layers of KBr and Ge. According to the perfect agreements between our analytical and numerical results, we discover that the mentioned optical characteristic of the hBN-based 1D PCs is due to a strong coupling between localized photonic modes supported by the PC and the phononic modes of hBN films. These coupled modes are referred as Tamm phonons. Moreover, our findings prove that the resonant absorptions can be red- or blue-shifted by changing the thickness of hBN and the spacer layer. The obtained results in this paper are beneficial for designing coherent thermal sources, light absorbers, and sensors operating within 6.2 MUm to 7.3 MUm in a wide angular range and both polarizations. The planar and lithography free nature of this multilayer design is a prominent factor that makes it a large scale compatible design. PMID- 29245866 TI - Compact and stable high-repetition-rate terahertz generation based on an efficient coaxially pumped dual-wavelength laser. AB - A compact and stable terahertz (THz) source is demonstrated based on difference frequency generation (DFG) pumped by an efficient dual-wavelength acousto-optic (AO) Q-switched solid-state Nd:YLF laser with composite gain media (a-cut and c cut) in the coaxial pumping configuration. Optimal power ratio and pulse synchronization of the orthogonal polarized 1047/1053 nm dual-wavelength laser could be realized by varying the pump focusing depth and/or pump wavelength. The total power of 2.92 W was obtained at 5 kHz pumped by 10-W laser-diode power at 803 nm. Such an efficient dual-wavelength laser demonstrated good stability and inconspicuous timing jitter benefiting from the suppressed gain competition between two resonating wavelengths. An 8-mm-long GaSe crystal was employed to generate THz waves at 1.64 THz by DFG and the maximum THz average output power was about 0.93 MUW. This compact coaxial pumping method can be extended to all kinds of neodymium (Nd) doped laser crystals to produce different dual-wavelength lasers for various THz wavelength generation, which have good prospects for portable and costless applications like imaging, non-destructive inspection, etc. PMID- 29245867 TI - Measurement of deep-subwavelength emitter separation in a waveguide-QED system. AB - In the waveguide quantum electrodynamics (QED) system, emitter separation plays an important role for its functionality. Here, we present a method to measure the deep-subwavelength emitter separation in a waveguide-QED system. In this method, we can also determine the number of emitters within one diffraction-limited spot. In addition, we also show that ultrasmall emitter separation change can be detected in this system which may then be used as a waveguide-QED-based sensor to measure tiny local temperature/strain variation. PMID- 29245868 TI - Analysis of distributed optical fibre acoustic sensors through numerical modelling. AB - A distributed optical fibre acoustic sensor is numerically modelled. To increase the flexibility of the model, the building blocks of the sensing system are modelled separately and later combined to form the numerical model. This approach is adopted to facilitate the evaluation of each of the individual building blocks and their effects on the output of the sensor. The numerical model is used to assess the effect of parameters such as the linewidth of the laser source, the width of the probe pulse, and the frequency and amplitude of perturbation on the response of the sensing system. It is shown that the precision and accuracy of the sensing system are affected by the frequency and amplitude of perturbation as well as the pulse width and linewidth of the probe pulse. PMID- 29245869 TI - Contrast and resolution enhanced optical sectioning in scattering tissue using line-scanning two-photon structured illumination microscopy. AB - Optical sectioning imaging with high spatial resolution deep inside scattering samples such as mammalian brain is of great interest in biological study. Conventional two-photon microscopy deteriorates in focus when light scattering increases. Here we develop an optical sectioning enhanced two-photon technique which incorporates structured illumination into line-scanning spatial-temporal focusing microscopy (LTSIM), and generate patterned illumination via laser intensity modulation synchronized with scanning. LTSIM brings scattering background elimination and in-focus contrast enhancement, and realizes nearly 2 fold increase in spatial resolution to ~208 nm laterally and ~0.94 um axially. In addition, the intensity modulated line-scanning implementation of LTSIM enables fast and flexible generation of structured illumination, permitting adjustable spatial frequency profiles to optimize image contrast. The highly qualified optical sectioning ability of our system is demonstrated on samples including tissue phantom, C. elegans and mouse brain at depths over hundreds of microns. PMID- 29245870 TI - Compressed channeled spectropolarimetry. AB - Channeled spectropolarimetry measures the spectrally resolved Stokes parameters. A key aspect of this technique is to accurately reconstruct the Stokes parameters from a modulated measurement of the channeled spectropolarimeter. The state-of the-art reconstruction algorithm uses the Fourier transform to extract the Stokes parameters from channels in the Fourier domain. While this approach is straightforward, it can be sensitive to noise and channel cross-talk, and it imposes bandwidth limitations that cut off high frequency details. To overcome these drawbacks, we present a reconstruction method called compressed channeled spectropolarimetry. In our proposed framework, reconstruction in channeled spectropolarimetry is an underdetermined problem, where we take N measurements and solve for 3N unknown Stokes parameters. We formulate an optimization problem by creating a mathematical model of the channeled spectropolarimeter with inspiration from compressed sensing. We show that our approach offers greater noise robustness and reconstruction accuracy compared with the Fourier transform technique in simulations and experimental measurements. By demonstrating more accurate reconstructions, we push performance to the native resolution of the sensor, allowing more information to be recovered from a single measurement of a channeled spectropolarimeter. PMID- 29245871 TI - Two-photon interferences of nondegenerate photon pairs from Doppler-broadened atomic ensemble. AB - We report two-photon interference experiments performed with correlated photon pairs generated via spontaneous four-wave mixing in a Doppler-broadened atomic ensemble involving the 5S1/2-5P3/2-5D5/2 transition of 87Rb atoms. When two photons with different wavelengths are incident on a polarization-based Michelson interferometer, two kinds of two-photon superposition states, the frequency entangled state and dichromatic path-entangled state depending on whether the two photons are in different paths or in the same path, are probabilistically generated within the interferometer arms. Hong-Ou-Mandel-type interference fringes resulting from the frequency-entangled state are observed over the range of the single-photon coherence length, following introduction of a coarse path length difference between the two interferometer arms and employing phase randomization. When the interferometer is highly phase-sensitive without phase randomization, a phase super-resolved fringe arising from the dichromatic path entangled state is observed, both with and without the accompanying one-photon interference fringes. PMID- 29245872 TI - Development of an all-optical framing camera and its application on the Z-pinch. AB - An all-optical framing camera has been developed which measures the spatial profile of photons flux by utilizing a laser beam to probe the refractive index change in an indium phosphide semiconductor. This framing camera acquires two frames with the time resolution of about 1.5 ns and the inter frame separation time of about 13 ns by angularly multiplexing the probe beam on to the semiconductor. The spatial resolution of this camera has been estimated to be about 140 MUm and the spectral response of this camera has also been theoretically investigated in 5 eV-100 KeV range. This camera has been applied in investigating the imploding dynamics of the molybdenum planar wire array Z-pinch on the 1-MA "QiangGuang-1" facility. This framing camera can provide an alternative scheme for high energy density physics experiments. PMID- 29245873 TI - Graphene-based tunable ultra-narrowband mid-infrared TE-polarization absorber. AB - A graphene-based tunable ultra-narrowband mid-infrared TE-polarization absorber is proposed. The simulation results show that, the absorption peak can be tuned from 5.43896um to 5.41418um, by tuning the Fermi level of graphene from 0.2eV to 1.0eV. The simulation results also show that the absorption bandwidth is less than 1.0nm and the absorption rate is more than 0.99 for TE-polarization (electric field is parallel to grating grooves) in the tuning wavelength range. The ultra-narrowband absorption mechanism is originated from the low power loss in the guided-mode resonance. The tuning function is mainly attributed to the change of the real part of the graphene's permittivity. This tunable ultra narrowband mid-infrared absorber has potential applications in the tunable filtering and tunable coherent emission of thermal source. PMID- 29245874 TI - Finite difference methods for stationary and time-dependent X-ray propagation. AB - We have generalized finite-difference (FD) simulations for time-dependent field propagation problems, in particular in view of ultra-short x-ray pulse propagation and dispersion. To this end, we first derive the stationary paraxial (parabolic) wave equation for the scalar field envelope in a more general manner than typically found in the literature. We then present an efficient FD implementation of propagators for different dimensionality for stationary field propagation, before we treat time-dependent problems by spectral decomposition, and suitable numerical sampling. We prove the validity of the numerical approach by comparison to analytical theory, using simple tractable propagation problems. Finally, we apply the framework to the problem of modal dispersion in X-ray waveguide. We show that X-ray waveguides can be considered as non-dispersive optical elements down to sub-femtosecond pulse width. Only when considering resonant absorption close to an X-ray absorption edge, we observe pronounced dispersion effects for experimentally achievable pulse widths. All code used for the work is made available as supplemental material. PMID- 29245875 TI - Metal-germanium-metal photodetector grown on silicon using low temperature RF PECVD. AB - In this paper, germanium metal-semiconductor-metal photodetectors (MSM PDs) are fabricated on Si using a low-temperature two-step deposition technique by RF PECVD. The photodetectors are optimized to effectively suppress the dark current through the insertion of n-type a-Si:H interlayer between the metal/Ge interface. Tuning the Schottky Barrier Height (SBH) by inserting different thickness of the interlayer is investigated. Results revealed that SBH for electrons and holes can effectively be enhanced by 0.3eV and 0.54eV, respectively. Furthermore, the dark current (IDark) is suppressed significantly by more than four orders of magnitude. The measured IDark is ~76 nA for an applied reverse bias of 1.0 V. Additionally, the Ge MSMs structure exhibited a photo responsivity of 0.8A/W at that bias. The proposed low-temperature (<550 degrees C) Ge-on-Si MSM PD demonstrates a great potential for high-performance Ge-based photodetectors in monolithically integrated CMOS platform. PMID- 29245876 TI - Automated approach for the surface profile measurement of moving objects based on PSP. AB - Phase shifting profilometry can achieve high accuracy for the 3D shape measurement of static object. Errors will be introduced when the object is moved during the movement. The fundamental reason causing the above issue is: PSP requires multiple fringe patterns but the reconstruction model does not include the object movement information. This paper proposes a new method to automatically measure the 3D shape of the rigid object with arbitrary 2D movement. Firstly, the object movement is tracked by the SIFT algorithm and the rotation matrix and translation vector describing the movement are estimated. Then, with the reconstruction model including movement information, a least square algorithm is applied to retrieve the correct phase value. The proposed method can significantly reduce the errors caused by the object movement. The whole reconstruction process does not need human intervention and the proposed method has high potential to be applied in industrial applications. Experiments are presented to verify the effectiveness. PMID- 29245877 TI - Effect of incidence/observation angles and angular diversity on speckle reduction by wavelength diversity in laser projection systems. AB - The speckle reduction for laser projectors has been vigorously studied because speckle causes a serious deterioration in image quality. Most speckle reduction methods can be categorized into wavelength diversity, angular diversity and polarization diversity, which are usually treated independently. In this paper, it is shown that the effect of wavelength diversity and angular diversity on speckle reduction is not independent, and that the effect of wavelength also depends on incidence and observation angles on screen. The speckle reduction effect by wavelength diversity is smaller when the angular diversity is larger. Also, the speckle reduction effect is investigated on various screens including matte and silver screens, and it is shown that the effect of wavelength diversity is larger on matte screen than on silver screen. PMID- 29245878 TI - Strongly coupled exciton-surface plasmon polariton from excited-subband transitions of single-walled carbon nanotubes. AB - We report experimental observation of strong coupling between surface plasmon polariton (SPP) propagating on a thin silver film and excitons from excited subband transtitions of single-walled carbon nanotubes (SWNTs). Clear anti crossing behaviors were observed from attenuated total reflection measurements when the SPP energy approaches the 2nd subband transition of (6,5) SWNTs. The maximum Rabi splitting of the plasmon-exciton mixed states was extracted to be up to ~166.2 meV. Moreover, the splitting was found to be dependent linearly on the square root of the SWNTs concentration, in good agreement with theoretical prediction. PMID- 29245880 TI - Simple optoelectronic frequency-offset estimator for coherent optical OFDM. AB - We propose a carrier frequency-offset estimator for optical OFDM systems using off-the-shelf optical components and simple digital processing as a replacement for the purely digital signal processing using the cyclostationarity property of optical OFDM signals with cyclic prefix. Simulations show the system accuracy of <4% estimate error within the range [-1250 + 1250] MHz offsets for a single polarization 28-Gbaud OFDM signal with 15% cyclic prefix. The effects of the system parameters on the performance are investigated. PMID- 29245879 TI - Radially polarized plasmonic vector vortex generated by a metasurface spiral in gold film. AB - Vector vortices with spatially varying polarization are interesting phenomena and have motivated many recent studies. A vector vortex in the wavefield of a surface plasmon polariton (SPP) may be extended to the sub-wavelength scale, which would be more significant. However, the formation of vector vortices requires the polarization state to possess components parallel to the surface of metal films. In this study, we generated radially polarized vector plasmonic vortices using the metasurface spiral of orthogonal nanoslit pairs. We theoretically derived the x and y component expressions in the central point area of the spiral and obtained a doughnut-shaped intensity distribution with radial polarization. The Jones matrix of the metasurface spiral was generated to describe the polarization characteristics. The results were validated by performing finite-difference time domain simulations. In addition, we used a Mach-Zehnder interferometer system to extract the intensity and phase distributions of different components of the SPP field. The experimental doughnut-shaped radially polarized vector vortex was consistent with the theoretical and simulated results. PMID- 29245881 TI - Multiplex CARS imaging with spectral notch shaped laser pulses delivered by optical fibers. AB - We present an experimental demonstration of single-pulse coherent anti-Stokes Raman spectroscopy (CARS) using a spectrally shaped broadband laser that is delivered by an optical fiber to a sample at its distal end. The optical fiber consists of a fiber Bragg grating component to serve as a narrowband notch filter and a combined large-mode-area fiber to transmit such shaped ultrashort laser pulses without spectral distortion in a long distance. Experimentally, our implementation showed a capability to measure CARS spectra of various samples with molecular vibrations in the fingerprint region. Furthermore, CARS imaging of poly(methyl methacrylate) bead samples was carried out successfully under epi CARS geometry in which backward-scattered CARS signals were collected into a multimode optical fiber. A compatibility of single-pulse CARS scheme with fiber optics, verified in this study, implies a potential for future realization of compact all-fiber CARS spectroscopic imaging systems. PMID- 29245882 TI - Extended depth of field for single biomolecule optical imaging-force spectroscopy. AB - Real-time optical imaging combined with single-molecule manipulation broadens the horizons for acquiring information about the spatiotemporal localization and the mechanical details of target molecules. To obtain an optical signal outside the focal plane without unintended interruption of the force signal in single molecule optical imaging-force spectroscopy, we developed an optical method to extend the depth of field in a high numerical aperture objective (>= 1.2), required to visualize a single fluorophore. By axial scanning, using an electrically tunable lens with a fixed sample, we were successfully able to visualize the epidermal growth factor receptor (EGFR) moving along the three dimensionally elongated filamentous actin bundles connecting cells (intercellular nanotube), while another EGFR on the intercellular nanotube was trapped by optical tweezers in living cells. Our approach is simple, fast and inexpensive, but it is powerful for imaging target molecules axially in single-molecule optical imaging-force spectroscopy. PMID- 29245883 TI - Three-dimensional cut wire pair behavior and controllable bianisotropic response in vertically oriented meta-atoms. AB - This paper investigates three-dimensional cut wire pair (CWP) behavior in vertically oriented meta-atoms. We first analyze CWP metamaterial inclusions using full-wave electromagnetic simulations. The scattering behavior of the vertical CWP differs substantially from that of the planar version of the same structure. In particular, we show that the vertical CWP supports a magnetic resonance that is solely excited by the incident magnetic field. This is in stark contrast to the bianisotropic resonant excitation of in-plane CWPs. We further show that this CWP behavior can occur in other vertical metamaterial resonators, such as back-to-back linear dipoles and back-to-back split ring resonators (SRRs), due to the strong coupling between the closely spaced metallic elements in the back-to-back configuration. In the case of SRRs, the vertical CWP mode (unexplored in previous literature) can be excited with a magnetic field that is parallel to both SRR loops, and exists in addition to the familiar fundamental resonances of the individual SRRs. In order to fully describe the scattering behavior from such dense arrays of three-dimensional structures, coupling effects between the close-packed inclusions must be included. The new flexibility afforded by using vertical resonators allows us to controllably create purely electric inclusions, purely magnetic inclusions, as well as bianisotropic inclusions, and vastly increases the degrees of freedom for the design of metafilms. PMID- 29245884 TI - Transparent electrode design for AlGaN deep-ultraviolet light-emitting diodes. AB - Zinc gallate (ZnGa2O4; ZGO) thin films were employed as the p-type transparent contact layer in deep-ultraviolet AlGaN-based light-emitting diodes (LEDs) to increase light output power. The transmittance of 200-nm-thick ZGO in deep ultraviolet wavelength (280 nm) was as high as 92.3%. Two different ohmic contact structures, a dot-LED (D-LED; ZGO/dot-ITO/LED) and whole-LED (W-LED; ZGO/ITO/LED), exhibited improved light output power and current spreading compared to a conventional ITO-LED (C-LED). At an injection current of 20 mA, the D-LED and W-LED exhibited 33.7% and 12.3% enhancements in light output power, respectively, compared to the C-LED. The enhanced light output power of the D-LED can be attributed to an improvement in current spreading and enhanced light extracting efficiency achieved by introducing ZGO/dot-ITO. PMID- 29245885 TI - Simple method for efficient reconfigurable optical vortex beam splitting: erratum. AB - We found an error in the affiliation list of our article "Simple method for efficient reconfigurable optical vortex beam splitting" [Opt. Express25(16), 18722 (2017)]. We corrected the affiliation list by adding the following organization: Institute for Automation and Control Processes FEB RAS, 5 Radio Str., Vladivostok 690041, Russia. All our results and conclusions have remained unchanged. PMID- 29245886 TI - Liraglutide: another reason to target prediabetes? PMID- 29245887 TI - TGFbeta activates PI3K-AKT signaling via TRAF6. PMID- 29245888 TI - Therapeutic induction of high endothelial venules (HEVs) to enhance T-cell infiltration in tumors. PMID- 29245889 TI - T cells in chronic lymphocytic leukemia: can they fight? PMID- 29245890 TI - SNPs for breast cancer risk assessment. PMID- 29245891 TI - Linking dental pathologies and cancer via Wnt signalling. PMID- 29245892 TI - MEK/ERK addiction in CNL/aCML. PMID- 29245893 TI - The ascorbate transporter SVCT2 to target microglia-dependent inflammation. PMID- 29245894 TI - Elagolix: a promising oral GnRH antagonist for endometriosis-associated pain. PMID- 29245895 TI - Progress and criticalities in the management of acute promyelocytic leukemia. PMID- 29245897 TI - Comparative analysis of primary versus relapse/refractory DLBCL identifies shifts in mutation spectrum. AB - Current understanding of the mutation spectrum of relapsed/refractory (RR) tumors is limited. We performed whole exome sequencing (WES) on 47 diffuse large B cell lymphoma (DLBCL) tumors that persisted after R-CHOP treatment, 8 matched to primary biopsies. We compared genomic alterations from the RR cohort against two treatment-naive DLBCL cohorts (n=112). While the overall number and types of mutations did not differ significantly, we identified frequency changes in DLBCL driver genes. The overall frequency of MYD88 mutant samples increased (12% to 19%), but we noted a decrease in p.L265P (8% to 4%) and increase in p.S219C mutations (2% to 6%). CARD11 p.D230N, PIM1 p.K115N and CD79B p.Y196C mutations were not observed in the RR cohort, although these mutations were prominent in the primary DLBCL samples. We observed an increase in BCL2 mutations (21% to 38% of samples), BCL2 amplifications (3% to 6% of samples) and CREBBP mutations (31% to 42% of samples) in the RR cohort, supported by acquisition of mutations in these genes in relapsed compared to diagnostic biopsies from the same patient. These increases may reflect the genetic characteristics of R-CHOP RR tumors expected to be enriched for during clinical trial enrollment. These findings hold significance for a number of emerging targeted therapies aligned to genetic targets and biomarkers in DLBCL, reinforcing the importance of time-of-treatment biomarker screening during DLBCL therapy selection. PMID- 29245898 TI - A novel small-molecule arylsulfonamide causes energetic stress and suppresses breast and lung tumor growth and metastasis. AB - Neoplastic cells display reprogrammed metabolism due to the heightened energetic demands and the need for biomass synthesis of a growing tumor. Targeting metabolic vulnerabilities is thus an important goal for cancer therapy. Here, we describe a novel small-molecule arylsulfonamide (N-cyclobutyl-N-((2,2-dimethyl-2H pyrano[3,2-b]pyridin-6-yl)methyl)-3,4-dimethoxybenzenesulfonamide) that exerts potent cytotoxicity and energetic stress on tumor cells while largely sparing non cancerous human cells. In tumor cells, it stimulates glycolysis and accelerates glucose consumption. Consequently, intracellular ATP levels plummet, triggering activation of AMP-activated protein kinase (AMPK), and diminishing the mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor 1 (HIF-1) signaling. In orthotopic triple-negative breast cancer and subcutaneous lung cancer mouse models, this arylsulfonamide robustly suppresses primary tumor growth, inhibits the formation of distant metastases to the lung, and extends mouse survival while being very well tolerated. These therapeutic effects are further potentiated by co-administration of 2-deoxy-D-glucose (2-DG), a glucose analog and glycolysis inhibitor. Collectively, our findings provide preclinical proof of concept for the further development of this arylsulfonamide in combination with 2-DG towards cancer treatment. PMID- 29245896 TI - Metabolomic mapping of cancer stem cells for reducing and exploiting tumor heterogeneity. AB - Personalized cancer medicine based on the analysis of tumors en masse is limited by tumor heterogeneity, which has become a major obstacle to effective cancer treatment. Cancer stem cells (CSC) are emerging as key drivers of inter- and intratumoral heterogeneity. CSC have unique metabolic dependencies that are required not only for specific bioenergetic/biosynthetic demands but also for sustaining their operational epigenetic traits, i.e. self-renewal, tumor initiation, and plasticity. Given that the metabolome is the final downstream product of all the -omic layers and, therefore, most representative of the biological phenotype, we here propose that a novel approach to better understand the complexity of tumor heterogeneity is by mapping and cataloging small numbers of CSC metabolomic phenotypes. The narrower metabolomic diversity of CSC states could be employed to reduce multidimensional tumor heterogeneity into dynamic models of fewer actionable sub-phenotypes. The identification of the driver nodes that are used differentially by CSC states to metabolically regulate self-renewal and tumor initation and escape chemotherapy might open new preventive and therapeutic avenues. The mapping of CSC metabolomic states could become a pioneering strategy to reduce the dimensionality of tumor heterogeneity and improve our ability to examine changes in tumor cell populations for cancer detection, prognosis, prediction/monitoring of therapy response, and detection of therapy resistance and recurrent disease. The identification of driver metabolites and metabolic nodes accounting for a large amount of variance within the CSC metabolomic sub-phenotypes might offer new unforeseen opportunities for reducing and exploiting tumor heterogeneity via metabolic targeting of CSC. PMID- 29245899 TI - Constitutive Cyclin O deficiency results in penetrant hydrocephalus, impaired growth and infertility. AB - Cyclin O (encoded by CCNO) is a member of the cyclin family with regulatory functions in ciliogenesis and apoptosis. Homozygous CCNO mutations have been identified in human patients with Reduced Generation of Multiple Motile Cilia (RGMC) and conditional inactivation of Ccno in the mouse recapitulates some of the pathologies associated with the human disease. These include defects in the development of motile cilia and hydrocephalus. To further investigate the functions of Ccno in vivo, we have generated a new mouse model characterized by the constitutive loss of Ccno in all tissues and followed a cohort during ageing. Ccno-/- mice were growth impaired and developed hydrocephalus with high penetrance. In addition, some Ccno+/- mice also developed hydrocephalus and affected Ccno-/- and Ccno+/- mice exhibited additional CNS defects including cortical thinning and hippocampal abnormalities. In addition to the CNS defects, both male and female Ccno-/- mice were infertile and female mice exhibited few motile cilia in the oviduct. Our results further establish CCNO as an important gene for normal development and suggest that heterozygous CCNO mutations could underlie hydrocephalus or diminished fertility in some human patients. PMID- 29245900 TI - GULP1/CED-6 ameliorates amyloid-beta toxicity in a Drosophila model of Alzheimer's disease. AB - Amyloidogenic processing of APP by beta- and gamma-secretases leads to the generation of amyloid-beta peptide (Abeta), and the accumulation of Abeta in senile plaques is a hallmark of Alzheimer's disease (AD). Understanding the mechanisms of APP processing is therefore paramount. Increasing evidence suggests that APP intracellular domain (AICD) interacting proteins influence APP processing. In this study, we characterized the overexpression of AICD interactor GULP1 in a Drosophila AD model expressing human BACE and APP695. Transgenic GULP1 significantly lowered the levels of both Abeta1-40 and Abeta1-42 without decreasing the BACE and APP695 levels. Overexpression of GULP1 also reduced APP/BACE-mediated retinal degeneration, rescued motor dysfunction and extended longevity of the flies. Our results indicate that GULP1 regulate APP processing and reduce neurotoxicity in a Drosophila AD model. PMID- 29245901 TI - Navbeta2 knockdown improves cognition in APP/PS1 mice by partially inhibiting seizures and APP amyloid processing. AB - Voltage-gated sodium channels beta 2 (Navbeta2, encoded by SCN2B) is a substrate of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and regulates cell surface expression of channels in neurons. Previous studies reported enhanced Navbeta2 processing by BACE1 in Alzheimer's disease (AD) model and patients. We investigated whether changes in Navbeta2 expression affect neuronal seizure and amyloid precursor protein (APP) processing in an AD mouse model. Our study used eight-month-old APP/presenilin 1 (PS1) mice and transgenic Navbeta2 knockdown [by 61% vs. wild type (WT)] APP/PS1 mice (APP/PS1/Navbeta2-kd), with age-matched WT and Navbeta2 knockdown (Navbeta2-kd) mice as controls. We found that Navbeta2 knockdown in APP/PS1 mice partially reversed the abnormal Navbeta2 cleavage and the changes in intracellular and total Nav1.1alpha expression. It also restored sodium currents density in hippocampal neurons and neuronal activity, as indicated by EEG tracing; improved Morris water maze performance; and shifted APP amyloidogenic metabolism towards non-amyloidogenic processing. There were no differences in these indicators between WT and Navbeta2-kd mice. These results suggest Navbeta2 knockdown may be a promising strategy for treating AD. PMID- 29245902 TI - COX-2 metabolic products, the prostaglandin I2 and F2alpha, mediate the effects of TNF-alpha and Zn2+ in stimulating the phosphorylation of Tau. AB - Although the roles of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) in regulating amyloid precursor protein (APP) cleavage and beta-amyloid protein (Abeta) production have been the subjects of numerous investigations, their effects on tau phosphorylation have been largely overlooked. Using human TauP301S transgenic (Tg) mice as in vivo model, our results demonstrated that PGI2 and PGF2alpha mediated the effects of tumor necrosis factor alpha (TNF-alpha) and Zinc ions (Zn2+) on upregulating the phosphorylation of tau via the PI3-K/AKT, ERK1/2 and JNK/c-Jun signaling pathways. Specifically, we initially found that high level of Zn2+ upregulates the expression of COX-2 via stimulating the activity of TNF-alpha in a zinc transporter 3 (ZnT3)-dependent mechanism. COX-2 upregulation then stimulates the phosphorylation of tau at both Ser 202 and Ser 400/Thr 403/Ser 404 via PGI2 and F2alpha treatment either in i.c.v.-injected mice or in n2a cells. Using n2a cells as in vitro model, we further revealed critical roles for the PI3-K/AKT, ERK1/2 and JNK/c-Jun pathways in mediating the effects of PGI2 and F2alpha in the phosphorylation of tau. Finally, NS398 treatment delayed the onset of cognitive decline in TauP301S Tg mice according to the nest construction or limb clasping test. PMID- 29245903 TI - Deep sequencing of the T cell receptor beta repertoire reveals signature patterns and clonal drift in atherosclerotic plaques and patients. AB - The T cell receptor (TCR) beta repertoire directly reflects the status of T cell function. Meanwhile, the immune/inflammatory responses regulated by T cells are the critical determinants of atherosclerosis development. However, due to technical limitations, the composition and molecular characteristics of the TCR repertoire in atherosclerotic patients have not been fully elucidated. In the present study, we use powerful immune repertoire sequencing technology to study this issue. Results show that the utilization of V and/or J genes and the diversity of TCRbeta repertoire in atherosclerotic plaques are significantly reduced compared to those in the peripheral blood of normal subjects and atherosclerotic patients. The frequencies of the common T cell clones with certain lengths of the complement determining region 3 regions are notably different among all groups. The high-frequency common clones are also increased in the atherosclerotic plaques compared to that in the other two groups. The expansion of several T cell clonotypes (V29-1J2-1, V20-1J1-6, V6-3J2-7 and V11 2J2-2) is validated in atherosclerotic patients. In short, this study reveals that the diversity of TCR beta repertoire significantly decreases in atherosclerotic plaques, probably because of the reduced utilization of VJ genes and marked expansion of some T cell subclones. It provides the basis for understanding the roles of T lymphocytes in the pathogenesis of atherosclerosis. PMID- 29245904 TI - Functional characterization of a short peptidoglycan recognition protein from Chinese giant salamander (Andrias davidianus). AB - Peptidoglycan (PGN) recognition proteins (PGRPs) are important pattern recognition receptors (PRRs) involved in immune defense against bacterial infections. In this study, a short PGRP (termed AdPGRP-S1) was cloned and functionally characterized from Chinese giant salamander (Andrias davidianus), the largest extant urodela amphibian species. AdPGRP-S1 was 184 aa in length and shared 38.7%-54.9% sequence identities with other vertebrates' short PGRPs. It contained one typical PGRP domain at the C-terminal region and several conserved amino acid (aa) residues involved in amidase and PGN binding. AdPGRP-S1 was constitutively expressed in all tissues examined, with the highest expression level seen in spleen and intestine. It has been shown that AdPGRP-S1 could bind and degrade Lys-PGN and Dap-PGN. Further, AdPGRP-S1 had antibacterial activity against the Gram-negative bacteria, Edwardsiella tarda, and was able to trigger the activation of NF-kappaB signaling. These results demonstrated that AdPGRP-S1 possesses multiple functions in pathogen recognition, mediating ceullular signaling, and initiating antibacterial response. This is the first functional study of a salamander PGRP, providing insight to further understand the functional evolution of verterbates' PGRPs. PMID- 29245906 TI - Effects of nicorandil on PI3K/Akt signaling pathway and its anti-apoptotic mechanisms in coronary microembolization in rats. AB - Coronary microembolization (CME) is a common complication of percutaneous coronary intervention (PCI) for acute coronary syndrome. It leads to myocardial apoptosis and cardiac dysfunction. Nicorandil pretreatment can prevent PCI related myocardial injury and reduce the incidence of no- or slow-reflow phenomena. This cardioprotective effect is probably attributable to the suppression of CME-induced cardiomyocyte apoptosis, but the specific mechanisms have not been clarified. We aimed to investigate the protective effects of nicorandil pretreatment on CME-induced myocardial injury and clarify the underlying mechanisms. In vivo studies, we used echocardiography, cardiac-enzymes measurement, hematoxylin-basic fuchsin-picric acid staining, TUNEL assay, and western blot, and found that CME significantly increased apoptotic cardiomyocytes in the infarct and peri-infarct areas in rats. The PI3K/Akt signaling pathway was involved in cardiomyocyte apoptosis. Nicorandil pretreatment given 7 days before CME effectively reduced cardiomyocyte apoptosis and myocardial injuries in rats, mainly through the activation of PI3K/Akt signaling. In vitro studies further showed that nicorandil reduced hypoxia-induced cardiomyocyte apoptosis and improved cardiomyocyte-survival rate. The PI3K-specific inhibitor LY294002 reduced these cardioprotective effects, indicating that they were attributable to the activation of the PI3K/Akt signaling pathway. In conclusion, nicorandil has significant cardioprotective effects in CME mainly through the activation of the PI3K/Akt signaling pathway and reduction of CME-induced cardiomyocyte apoptosis. Our findings may provide important support for the pre-PCI use of nicorandil to reduce post-PCI myocardial injuries. PMID- 29245905 TI - The sexist behaviour of immune checkpoint inhibitors in cancer therapy? AB - Background: Immune checkpoint inhibitors, targeting the molecules CTLA-4, PD-1 and PD-L1, showed efficacy against several type of cancers and are currently used in clinical practice. An important biological variable that influences innate and adaptive immunity is the sex, acting through genetic, hormonal and environmental factors. The overall differences between sexes could be crucial to evaluate the response to ICIs. Materials and methods: We performed a meta-analysis of Phase II III Clinical Trials published up to June 2017 in which anti-CTLA-4, anti-PD-1 and anti-PD-L1 were studied. We extracted the OS and PFS HR differentiated by sex from subgroups analysis of each trial. We analyzed the three classes of drugs separately. Results: We selected 36 Phase II-III Clinical Trials, 9 of which reported results for OS and 6 for PFS. We analyzed 2 Clinical Trials for OS with anti-CTLA-4, including 1178 patients, observing a benefit for males vs females (HR 0.65, 95% CI 0.55-0.77 vs HR 0.79, 95% CI 0.65-0.96, p 0.078).Not statistically significant results were observed with anti-PD-1 neither for OS (males vs females: HR 0.72, 95% CI 0.64-0.83 vs HR 0.81, 95% CI 0.70-0.94, p 0.285) neither for PFS (males vs females: HR 0.66, 95% CI 0.52-0.82 vs HR 0.85, 95% CI 0.66-1.09, p 0.158). We cannot perform a meta-analysis for anti-PD-L1 due to the lack of data. Conclusions: Different mechanisms could be involved in sex differences with regard to immunotherapy. These differences could be relevant to identify immunological targets in order to draw studies exploring novel combinations of immunotherapy agents. PMID- 29245907 TI - Increased expression of stemness markers and altered tumor stroma in hepatocellular carcinoma under TACE-induced hypoxia: A biopsy and resection matched study. AB - Background: Hepatocellular carcinomas (HCCs) expressing stemness markers are characterized by an aggressive behavior, which might be promoted by an altered tumor stroma. Transarterial chemoembolization (TACE) induces severe hypoxia, and its effect on stemness and tumor stroma of HCCs remains unclear. The purpose of this study was to evaluate the sequential changes of stemness and tumor stroma under TACE-induced hypoxia using biopsy and resection-matched HCCs. Methods: Forty-six biopsy and resection matched HCCs including 10 cases with and 36 cases without preoperative TACE were selected. Immunohistochemistry for stemness (keratin 19 [K19], epithelial cell adhesion molecule [EpCAM], and CD133), hypoxia (carbonic anhydrase IX [CAIX] and vascular endothelial growth factor [VEGF]), and tumor stromal (alpha-smooth muscle actin [alpha-SMA] and fibroblast activation protein [FAP]) markers were performed and compared in matched biopsied and resected HCCs with and without TACE. Results: The accuracy of K19, EpCAM, CD133, CAIX, VEGF, alpha-SMA and FAP detected on biopsied HCCs was 64% ~ 86%, using the expression status in resected HCCs as a reference standard in non-TACE group. The sequential change of hypoxia, stemness and stromal marker expression in matched biopsied and resected HCC was greater in TACE group than in non-TACE group (P < 0.05 for all). The degree of stemness marker expression was well correlated with those of tumor stromal markers, and the degree of CAIX expression was well correlated with that of K19 (P < 0.05). Conclusions: Stemness marker expression is considered to be increased along with tumor stromal alteration under TACE induced hypoxia, which might promote the aggressive biology of HCC. PMID- 29245908 TI - Predictive relevance of PD-L1 expression with pre-existing TILs in gastric cancer. AB - Expression of programmed cell death receptor ligand 1 (PD-L1) has been shown to be up-regulated in some gastric cancer patients and to correlate with the density of tumour infiltrating lymphocytes (TILs). However, conflicting results have been reported regarding TILs and the expression of PD-L1 as a prognostic marker for gastric cancer. We investigated the correlation of PD-L1 and TILs expression with clinicpathological characteristics in 105 well characterized gastric cancer patients. PD-L1 expression and CD3+ and CD8+ TILs were evaluated by fluorescent multiplex immunohistochemistry (mIHC) analysis. PD-L1 positive staining on tumour cells was observed in 35% cases and 48% cases showed PD-L1 expression on immune cells. Up-regulated PD-L1 expression on tumour cells and immune cells was associated with high density of pre-existing tumour infiltrating CD3+ and CD8+. In additional, more than 70% tumor infiltrating CD3+ cells were CD3+CD8+ cells. More than 60% PD-L1+ immune cells were PD-L1+CD3+CD8+ cells. PD-L1 expression in tumour cells was associated with poor prognosis and high density CD3+ and CD8+ TILs indicated improved overall survival in gastric cancer patients. Increased PD L1 expression with low density CD3+ and CD8+ TILs had the shortest overall survival. In accordingly, PD-L1 absence with high density CD3+ and CD8+ TILs indicated the best prognosis. Combination of PD-L1 with pre-existing TILs may be more precise than PD-L1 alone for predicting survival in gastric cancer. PMID- 29245909 TI - Inhibition of aldehyde dehydrogenase 1 enhances the cytotoxic effect of retinaldehyde on A549 cancer cells. AB - We hypothesized that aldehyde dehydrogenase1 (ALDH1) protects cancer cells from retinaldehyde-induced cytotoxicity, and that targeting this enzyme would enhance the therapeutic effect of retinaldehyde. ALDEFLUORTM assays showed high ALDH activity in A549 and H522 cancer cells and low activity in H1666 and T47D cancer cells. Immunoblots showed that expression of ALDH1A1 and ALDH1A3 was high in A549 and H522 cells, but low in H1666 cells. HPLC confirmed that N, N diethylaminobenzaldehyde (DEAB) inhibits ALDH-mediated disposal of retinaldehyde in A549 cells and lysates. Treatment of A549 cells with retinaldehyde in the presence of DEAB augmented reactive oxygen species production and decreased glucose uptake and oxygen consumption. Importantly, DEAB substantially potentiated the ability of retinaldehyde to dose-dependently suppress the survival of A549 and H522 cells, whereas the added effect of DEAB was minor in H1666 and T47D cells. Gene silencing with specific siRNA revealed that ALDH1A1 contributed to protection of A549 cells against retinaldehyde toxicity. These results demonstrate that ALDH1 confers protection against retinaldehyde toxicity in cancer cells. PMID- 29245910 TI - The prognostic value of over-expressed TrkB in solid tumors: a systematic review and meta-analysis. AB - It is reported recently Tropomyosin-related receptor Kinase B (TrkB) plays key roles in the anoikis resistance during the processes of tumorigenesis and metastasis. However, its prognostic significance for clinical patients remains inconclusive. In order to establish a correct and practicable link between increased TrkB and prognostication of human solid tumors, a meta-analysis was performed in this article. A systematic literature research in the electronic databases PubMed, Embase and Web of Science was performed to identify eligible studies. A fixed-effects meta-analytical model was employed to correlate TrkB expression with OS, DFS and clinicopathological features. A total of 11 studies covering 1516 patients with various solid tumors were recruited in this meta analysis. TrkB over-expression was associated with poorer OS and poorer DFS in multivariate analysis. Additionally, the pooled odds ratios (ORs) indicated that TrkB over-expression was associated with large tumor size, lymph node metastasis, distant metastasis and a higher clinical stage. Overall, these results indicated that TrkB over-expression in patients with solid tumors might be related to poor prognosis and serve as a potential predictive marker of poor clinicopathological prognosis factor. PMID- 29245912 TI - Combination of AQP1 and beta-catenin expression is an independent prognosis factor in astrocytoma patients. AB - Previous research usually focused on single protein or gene in tumor development, actually highly heterogeneous nature and different signaling pathways largely contribute to tumor progression and tumor patients' outcomes. Therefore, using combinatorial biomarkers to evaluate the prognostic features and guide management is gradually accepted and urgently needed. beta-catenin is a well-known crucial factor in astrocytoma progression and it is involved in aquaporin1 (AQP1) mediated cell migration. In this study, we revealed the function of AQP1 in astrocytoma progression and provided the first clinical evidence that AQP1 expression was positively correlated with beta-catenin. Furthermore, we proved the functional role of AQP1/beta-catenin pathway in astrocytoma progression. More importantly, we discovered that combination of AQP1 and beta-catenin expression was an independent prognosis factor for astrocytoma patients and it was a better survival predictor than either AQP1 or beta-catenin alone. In conclusion, our study provided a novel more precise prognostication for predicting astrocytoma prognosis based on combinatorial analysis of AQP1 and beta-catenin expression. PMID- 29245911 TI - Down-regulation of HDAC3 inhibits growth of cholangiocarcinoma by inducing apoptosis. AB - Class I histone deacetylases (HDACs) inhibit expression of tumor suppressor genes by removing acetyl groups from histone lysine residues, thereby increasing cancer cell survival and proliferation. We evaluated the expression of class I HDACs in cholangiocarcinoma (CCA). HDAC3 expression was specifically increased in CCA tissues and correlated with reduced patient survival. HDAC3 overexpression inhibited apoptosis and promoted CCA cell proliferation. Conversely, HDAC3 knockdown or pharmacological inhibition decreased CCA cell growth and increased caspase-dependent apoptosis. Inhibition of class I HDACs blocked HDAC3-catalyzed deacetylation and increased expression of downstream pro-apoptotic targets in vitro and in vivo. These results demonstrate for the first time that down regulation of HDAC3 induces apoptosis in human CCA cells, indicating that inhibiting HDAC3 may be an effective therapeutic strategy for treating CCA . PMID- 29245913 TI - Epidermal growth factor receptor T790M mutation as a prognostic factor in EGFR mutant non-small cell lung cancer patients that acquired resistance to EGFR tyrosine kinase inhibitors. AB - Epidermal growth factor receptor (EGFR) T790M mutation accounted for over half of drug resistance cases in EGFR-mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) and led to different outcomes. This study aimed to assess the prognostic role of T790M in NSCLC patients treated with EGFR-TKIs that developed drug resistance. Eligible literatures were reviewed from various databases and a meta-analysis was performed to evaluate the prognostic role of T790M mutation in EGFR-TKIs treated patients that went progression. Three studies containing 192 patients were included in the meta-analysis. The pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were 0.66 (95% CI 0.49-0.89, P = 0.007) and 0.53 (95% CI 0.35-0.79, P = 0.002) respectively. Subgroups analyses were also performed on OS and PFS according to patients' districts, gender and histological type. In conclusion, T790M as a common mutation to cause drug resistance in EGFR-TKIs treated NSCLC patients may be a favorable prognostic factor on OS and PFS both. Further studies are necessary to demonstrate the prognostic role of secondary T790M in NSCLC patients. PMID- 29245914 TI - Radiotherapy for stage IIA rectal cancer may not benefit all. AB - This study sought to determine whether additional radiotherapy is necessary in patients after optimal surgery for stage IIA rectal cancer and how the different covariates influence the efficacy of radiotherapy. The first primary rectal cancer was identified from the 1988-December 2013 Surveillance, Epidemiology and End Results database. We identified 13647 patients with IIA rectal cancer, in which 39.6% received neo-adjuvant radiotherapy and in another 14.96% patients the adjuvant radiotherapy were performed. Neo-adjuvant or adjuvant radiotherapy group had better survival with 10-Year cancer-specific survival estimates as 75.1% and 73.8% compared to 68.4% of no radiotherapy group (P < 0.01). Adjusted hazard ratio (HR) demonstrated neo-adjuvant and adjuvant radiotherapy (HR: 0.814 and 0.848) were all associated with significantly decreased risk for cancer death. However, radiotherapy did not seem to yield the same survival benefit in selected population. Adjusted stratified analysis demonstrated patients with increasing age, relative large tumor size, and more retrieved regional lymph nodes had no additional benefit for cancer specific survival based on radiation use. In conclusions, unselected patients with stage IIA rectal cancer receiving radiotherapy experienced better survival in comparison to patients without radiation. However, additional radiotherapy is not beneficial for all. PMID- 29245915 TI - Curcumin interacts with sildenafil to kill GI tumor cells via endoplasmic reticulum stress and reactive oxygen/ nitrogen species. AB - The present studies focused on the ability of the phosphodiesterase 5 (PDE5) inhibitor sildenafil to enhance the anti-cancer properties of clinically relevant concentrations of the dietary diarylheptanoid curcumin. In gastrointestinal tumor cells, sildenafil and curcumin interacted in a greater than additive fashion to kill. Inhibition of the extrinsic apoptotic pathway suppressed killing by ~50%, as did blockade of the intrinsic apoptotic pathway. Sildenafil and curcumin reduced mTORC1 and mTORC2 activity and increased Beclin1 levels and the numbers of autophagosomes and autolysosomes in cells in a PERK-eIF2alpha-dependent fashion. Knock down of Beclin1 or ATG5 partially suppressed killing. In contrast, stable knock out of ATG16-L1 unexpectedly enhanced killing, an effect not altered by Beclin1/ATG5 knock down. Curcumin and sildenafil exposure reduced the expression of MCL-1, BCL-XL, thioredoxin and superoxide dismutase 2 (SOD2) in an eIF2alpha-dependent fashion. Curcumin and sildenafil interacted in a greater than additive fashion to increase the levels of reactive oxygen species; knock down of thioredoxin or SOD2 enhanced killing and over-expression of thioredoxin or SOD2 suppressed killing. In vivo, curcumin and sildenafil interacted to suppress the growth of colon cancer tumors. Multiplex analyses of plasma taken after drug exposure at animal nadir indicated that the levels of M-CSF, CXCL-9, PDGF and G CSF were significantly increased by [curcumin + sildenafil] and that expression of CXCL1 and CCL5 were significantly reduced. Cells isolated from in vivo treated [curcumin + sildenafil] tumors were resistant to in vitro [curcumin + sildenafil] exposure, a phenotype that was blocked by the colon cancer therapeutic regorafenib. PMID- 29245917 TI - Inhibition of ZEB1 leads to inversion of metastatic characteristics and restoration of paclitaxel sensitivity of chronic chemoresistant ovarian carcinoma cells. AB - ZEB1, a member of the zinc-finger E-box binding homeobox family, is considered to play a crucial role in cancer progression and metastasis. In the current study, we investigated the role of ZEB1 in metastasis and chronic chemoresistance of epithelial ovarian carcinoma (EOC) cells. Using several EOC and acquired paclitaxel (PTX)-resistant EOC cell lines, we investigated whether silencing ZEB1 led to a reversal of the chemoresistance and metastatic potential in vitro and in vivo. Subsequently, the expression of ZEB1 in EOC tissues and its association with the oncologic outcome were investigated. According to the immunohistochemical staining of EOC tissues, as the positivity of ZEB1 expression was increased, the overall survival of EOC patients became poorer (P = 0.0022 for trend). Additionally, cell migration and invasion were significantly decreased by ZEB1 silencing in both PTX-sensitive and PTX- resistant cells. Although PTX sensitivity was not changed by silencing ZEB1 in parental EOC cells, the depletion of ZEB1 made the PTX-resistant EOC cells more sensitive to PTX treatment. In an animal model, mice injected with ZEB1-silencing PTX-resistant cells survived for longer than the control cell-injected mice. Although the intravenous injection of PTX did not affect the tumor weight of shCtrl cells, the tumor weight of shZEB1 cells was significantly reduced by PTX treatment. The current data indicate the possible involvement of ZEB1 in the metastasis and paclitaxel resistance of EOC, and suggest that targeting this molecule may reverse the malignant potential and improve the oncologic outcome for EOC patients. PMID- 29245918 TI - Interleukin-13 reduces cardiac injury and prevents heart dysfunction in viral myocarditis via enhanced M2 macrophage polarization. AB - Viral myocarditis is one of the major causes of congestive heart failure and dilated cardiomyopathy. Recent reports have demonstrated an essential role of cytokines, like interleukin-13 (IL-13), in the pathogenesis of viral myocarditis, while the underlying mechanisms remain poorly defined. Here, using a coxsackie virus B3 (CVB3)-infection model in BALB/C mice, we showed that IL-13 protected mouse heart function in viral myocarditis, seemingly through reduction in T lymphocyte immunity and induction of M2 macrophage polarization. Adoptive transfer to M2 macrophages mimicked the effects of IL-13 on protection from myocarditis, suggesting that the effects of IL-13 may be primarily through regulation of macrophage polarization. Together, our data suggest that application of IL-13 treatment may reduce cardiac Injury and protect heart function in viral myocarditis via enhanced M2 macrophage polarization. PMID- 29245916 TI - Laminarin counteracts diet-induced obesity associated with glucagon-like peptide 1 secretion. AB - Laminarin, a type of beta-glucan isolated from brown seaweeds, exhibits verity of physiological activities, which include immunology modulation and antitumor function. To investigate the effect of laminarin on energy homeostasis, mice were orally administrated with laminarin to test food intake, fat deposition, and glucose homeostasis. Chronically, laminarin treatment significantly decreases high-fat-diet-induced body weight gain and fat deposition and reduces blood glucose level and glucose tolerance. Acutely, laminarin enhances serum glucagon like peptide-1 (GLP-1) content and the mRNA expression level of proglucagon and prohormone convertase 1 in ileum. Subsequently, laminarin suppresses the food intake of mice, the hypothalamic AgRP neuron activity, and AgRP expression but activates pancreatic function. Furthermore, laminarin-induced appetite reduction was totally blocked by Exendin (9-39), a specific competitive inhibitor of GLP-1 receptor. Then, STC-1 cells were adopted to address the underlying mechanism, by which laminarin promoted GLP-1 secretion in vitro. Results showed that laminarin dose-dependently promoted GLP-1 secretion and c-Fos protein expression in STC-1 cells, which were independent of Dectin-1 and CD18. Interestingly, BAPTA-AM, a calcium-chelating agent, potently attenuated laminarin-induced [Ca2+]i elevation, c-Fos expression, and GLP-1 secretion. In summary, our data support that laminarin counteracts diet-induced obesity and stimulates GLP-1 secretion via [Ca2+]i; this finding provides an experimental basis for laminarin application to treat obesity and maintain glucose homeostasis. PMID- 29245919 TI - Icariin induces cell differentiation and cell cycle arrest in mouse melanoma B16 cells via Erk1/2-p38-JNK-dependent pathway. AB - Icariin (ICA) is a major component isolated from Epimedium brevicornum. Emerging evidence shows that ICA can inhibit tumor cell proliferation, invasion and migration. However, the anti-cancer effect of ICA on B16 cells has not been fully investigated. Here we found that the proliferation of B16 cells was inhibited by ICA in a concentration- and time-dependent manner, and the colony formation of B16 cells was also inhibited by ICA in a concentration-dependent manner. Further study showed that the melanin content was increased and the tyrosinase (Tyr) activity was enhanced after ICA treatment in B16 cells. Furthermore, compared with the control group, the mRNA levels of Tyr, Trp1 and Trp2 and the protein level of MITF were increased in ICA-treated B16 cells. In addition, the percentage of G0/G1 phase cells was increased and the protein levels of Cyclin A, CDK2 and p21 were decreased in ICA-treated B16 cells. Finally, we found that ICA increased down-regulated the Erk1/2, p-Erk1/2, p38, p-p38, and p-JNK protein levels in B16 cells when compared with the control group. Taken together, these results indicated that ICA could induce B16 cell differentiation and cell cycle arrest at G0/G1 phase through inhibiting Erk1/2-p38-JNK-dependent signaling molecules. PMID- 29245920 TI - NAMPT overexpression induces cancer stemness and defines a novel tumor signature for glioma prognosis. AB - Gliomas are the most prevalent primary malignant brain tumors associated with poor prognosis. NAMPT, a rate-limiting enzyme that boosts the nicotinamide adenine dinucleotide (NAD) regeneration in the salvage pathway, is commonly expressed in these tumors. NAD metabolism is required to maintain tissue homeostasis. To maintain metabolism, cancer cells require a stable NAD regeneration circuit. However, high levels of NAD confer resistance to therapy to these tumors, usually treated with Temozolomide (TMZ). We report that NAMPT overexpression in glioma cell lines increases tumorigenic properties controlling stem cell pathways and enriching the cancer-initiating cell (CIC) population. Furthermore, NAMPT expression correlated with high levels of Nanog, CD133 and CIC like cells in glioblastoma directly extracted from patients. Meta-analysis reveals that NAMPT is also a key factor inducing cancer stem pathways in glioma cells. Furthermore, we report a novel NAMPT-driven signature which stratify prognosis within tumor staging. NAMPT signature also correlates directly with EGFR positive and IDH negative tumors. Finally, NAMPT inhibition increases sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres. Therefore, NAMPT represents a novel therapeutic target in Glioma progression and relapse. PMID- 29245921 TI - Aflatoxin B1 affects apoptosis and expression of death receptor and endoplasmic reticulum molecules in chicken spleen. AB - Aflatoxin B1 (AFB1) is a natural product of the Aspergillus genus of molds, which grow on several foodstuffs stored in hot moist conditions, and is among the most potent hepatocarcinogens and immunosuppression presently known. The latter was related to the up-regulated apoptosis of immune organs. However, the effect of expression of death receptor and endoplasmic reticulum molecules in AFB1-induced apoptosis of chicken splenocytes was largely unknown. The objective of this study was to investigate this unknown field. One hundred and forty four one-day-old chickens were randomly divided into control group (0 mg/kg AFB1) and AFB1 group (0.6 mg/kg AFB1), respectively and fed with AFB1 for 21 days. Histological observation demonstrated that AFB1 caused slight congestion and lymphocytic depletion in the spleen. TUNEL and flow cytometry assays showed the excessive apoptosis of splenocytes provoked by AFB1. Moreover, quantitative real-time PCR analysis revealed that AFB1 induced the elevated mRNA expression of Fas, FasL, TNF-alpha, TNF-R1, Caspase-3, Caspase-8, Caspase-10, Grp78 and Grp94 in the spleen. These findings suggested that AFB1 could lead the excessive apoptosis and alter the expression of death receptor and endoplasmic reticulum molecules in chicken spleen. PMID- 29245922 TI - Regional lymph node involvement and outcomes in appendiceal neuroendocrine tumors: a SEER database analysis. AB - Background: Appendiceal neuroendocrine neoplasms are most often diagnosed incidentally during appendectomy. The need for subsequent right hemicolectomy (RHC) is determined based on the risk of regional lymph node (LN) involvement. Tumor size has historically been used as an indicator of this risk, but controversy remains regarding its cut off. Furthermore, the impact of RHC on survival is unclear. Methods: We used the SEER database to identify patients diagnosed with appendiceal neuroendocrine tumors. Results: Of 1731 patients, 38.0% had well-differentiated neuroendocrine tumors (WDNETs), 60.8% had mixed histology tumors (MHTs), and 1.2% had poorly differentiated neuroendocrine carcinomas (PDNECs). In patients with WDNETs and MHTs who had adequate lymphadenectomy, higher rates of LN involvement were noted for tumors size 11-20 mm than <=10 mm (56.8% vs. 11.6%, p <0.001; 32.9% vs. 10.4%, p=0.004, respectively). The type of surgery did not affect OS in cases with MHTs with LN involvement (HR 1.00; 95% CI, 0.53-1.89; p =0.99). Patients with regionally advanced WDNET showed excellent survival and only 3 patients (out of 118) died from cancer within 10 years. Conclusions: 10 mm appears to be a more appropriate cutoff than 20 mm for predicting LN metastasis in appendiceal NETs. Cases with WDNETs and nodal involvement demonstrate overall excellent prognosis irrespective of type of surgery (i.e. RHC may not improve outcome). In MHTs with LN metastases, survival is markedly worse in spite of RHC. The role of adjuvant therapy should be evaluated in this subset. PMID- 29245923 TI - EVI1 modulates oncogenic role of GPC1 in pancreatic carcinogenesis. AB - Glypican-1 (GPC1) protein in exosomes was recently identified as a biomarker for the early detection of pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analyses and in vitro assays were conducted to assess the usefulness of GPC1 as a PDAC biomarker, to reveal the biological role of GPC1 in pancreatic carcinogenesis, and to ascertain the regulation mechanism of GPC1. An aberrant overexpression of GPC1 protein which is usually absent in normal pancreatic duct, was a widespread marker across the full spectrum of human PDAC precursors, PDAC, and pancreatic cancerous stroma. In intraductal papillary mucinous neoplasms (IPMNs), GPC1 tended to be positive in gastric-type IPMN. KRAS mutations were found in all GPC1-positive IPMN cases and in one-third of GPC1 negative IPMN cases. In pancreatic cell lines, GPC1 depletion caused remarkable inhibition of cell growth and migration, suggesting its oncogenic roles. GPC1 depletion upregulated the molecules associated with cell cycle arrest in pancreatic cell lines. Furthermore, KRAS and ecotropic viral integration site 1 (EVI1) oncoprotein upregulated GPC1 expression. In a clinical cohort, GPC1 overexpression was not correlated with pancreatic cancer prognosis. Taken together, these findings suggest the necessity of establishing a threshold of GPC1 value for detecting pancreatic malignancy because GPC1 is overexpressed even in low-grade PDAC precursors which do not always become malignant. Our study also reveals a new aspect of pancreatic carcinogenesis: KRAS and EVI1, two important molecules in early phases of pancreatic carcinogenesis, positively regulate GPC1 expression and likely promote pancreatic carcinogenesis. PMID- 29245924 TI - RUNX1 promote invasiveness in pancreatic ductal adenocarcinoma through regulating miR-93. AB - Runt-related transcription factor 1(RUNX1), a key factor in hematopoiesis that mediates specification and homeostasis of hematopoietic stem and progenitor cells (HSPCs), is also overexpressed in several solid human cancers, and correlated with tumor progression. However, the expression and function of RUNX1 in pancreatic ductal adenocarcinoma were still unclear. Here, we show that RUNX1 is highly expressed in pancreatic adenocarcinoma tissues and knocking down of RUNX1 attenuated aggressiveness in pancreatic cell lines. Moreover, we found that RUNX1 could negatively regulate the expression of miR-93. Bioinformatics method showed that there are two binding sites in the the promotor region of miR-93 precursor and through ChIP-qPCR and firefly luciferase reporter assay, we vertified that these two binding sites each have transcriptive activity in one pancreatic cell lines. This result supported our presumption that RUNX1 regulate miR-93 through binding to the promotor region of miR-93. Besides, the expression and function of miR-93 is quite the opposite, miR-93 overexpression suppresses migration and invasiveness in pancreatic cell lines supporting that RUNX1 negatively regulated miR-93. Our findings provided evidence regarding the role of RUNX1 as an oncogene through the inhibition of miR-93. Targeting RUNX1 can be a potential therapeutic strategy in pancreatic cancer. PMID- 29245925 TI - Histopathological expression analysis of intercellular adhesion molecule 1 (ICAM 1) along development and progression of human melanoma. AB - Intercellular adhesion molecule 1 (ICAM-1) protein is an important adhesion molecule that facilitates metastasis on one hand, and on the other hand supports the immunological synapse necessary for T-cell mediated elimination. The expression pattern of ICAM-1 in melanoma was studied more than two decades ago, mainly in cell lines or in unmatched melanoma specimens. By using real time PCR we could not demonstrate a clear difference in ICAM-1 mRNA levels between primary melanocytes and primary cultures of metastatic melanoma. However, immunohistochemistry staining of progression tissue microarray comprised of samples of different disease stages derived from different patients, demonstrated a dramatic ICAM-1 upregulation particularly upon the transition from primary tumor to lymph node metastasis. There was no significant difference between lymph node and distant metastases. Importantly, these results were confirmed in an independent tissue microarray comprised of patient-paired specimens from progressive stages of the patient's disease. These data indicate that ICAM-1 upregulation is required to initiate the lymphatic spread of melanoma (Stage III) but no further increase is associated with progression to remote organs (Stage IV). PMID- 29245926 TI - Prognostic significance of total metabolic tumor volume on 18F-fluorodeoxyglucose positron emission tomography/ computed tomography in patients with diffuse large B-cell lymphoma receiving rituximab-containing chemotherapy. AB - Purpose: The purpose of this study was to determine the prognostic significance of metabolic parameters on pre-treatment 18F-fluorodeoxyglucose positron emission tomography/ computed tomography (FDG PET/CT), in patients with diffuse large B cell lymphoma (DLBCL) receiving rituximab-containing therapy. Materials and Methods: From September 2009 to December 2014, DLBCL patients who had received FDG PET/CT scans for staging were enrolled. The maximal standardized uptake value of tumor (SUVt) was recorded. The metabolic tumor volume (MTV) was the volume of lesion with an elevated SUV greater than 2.5. The total lesion glycolysis (TLG) was the sum of the products of MTV and mean SUV in all measured lesions. Univariate and multivariate analyses were used to assess the prognostic significance of maximal SUVt, total MTV, TLG and other clinical parameters. Results: There were 118 patients enrolled in this study. The median follow-up time was 28.7 months. The 5-year progression-free survival (PFS) for patients with higher and lower total MTV was 32.3% and 66.0% respectively (p = 0.0001). The 5-year overall survival (OS) for patients with higher and lower total MTV was 34.3% and 69.9% respectively (p < 0.0001). Multivariate analysis revealed, besides IPI, that total MTV was independently predictive for PFS (HR: 2.31, 95% CI: 1.16 - 4.60, p = 0.0180) and OS (HR: 2.38, 95% CI: 1.12 - 5.04, p = 0.024). TLG and maximal SUV of tumor were not independent prognostic factors. Conclusions: An elevated total MTV was a predictor for shorter PFS and OS in patients with DLBCL receiving rituximab-containing therapy, independent of IPI. PMID- 29245927 TI - A bioinformatics-to-clinic sequential approach to analysis of prostate cancer biomarkers using TCGA datasets and clinical samples: a new method for precision oncology? AB - Biomarker-driven cancer therapy has met with significant clinical success. Identification of a biomarker implicated in a malignant phenotype and linked to poor clinical outcome is required if we are to develop these types of therapies. A subset of prostate adenocarcinoma (PACa) cases are treatment-resistant, making them an attractive target for such an approach. To identify target molecules implicated in shorter survival of patients with PACa, we established a bioinformatics-to-clinic sequential analysis approach, beginning with 2-step in silico analysis of a TCGA dataset for localized PACa. The effect of candidate genes identified by in silico analysis on survival was then assessed using biopsy specimens taken at the time of initial diagnosis of localized and metastatic PACa. We identified PEG10 as a candidate biomarker. Data from clinical samples suggested that increased expression of PEG10 at the time of initial diagnosis was linked to shorter survival time. Interestingly, PEG10 overexpression also correlated with expression of chromogranin A and synaptophysin, markers for neuroendocrine prostate cancer, a type of treatment-resistant prostate cancer. These results indicate that PEG10 is a novel biomarker for shorter survival of patients with PACa. Also, PEG10 expression at the time of initial diagnosis may predict focal neuroendocrine differentiation of PACa. Thus, PEG10 may be an attractive target for biomarker-driven cancer therapy. Thus, bioinformatics-to clinic sequential analysis is a valid tool for identifying targets for precision oncology. PMID- 29245928 TI - Myocardin and Stat3 act synergistically to inhibit cardiomyocyte apoptosis. AB - Signal transducer and activator of transcription 3 (Stat3) and Myocardin regulate cardiomyocyte differentiation, proliferation, and apoptosis. We report a novel aspect of the cellular function of Myocardin and Stat3 in the regulation of cardiomyocyte apoptosis. Myocardin and Stat3 showed anti-apoptotic function by increasing the expression of Bcl-2 while reducing expression of the pro-apoptotic genes Bax, Apaf-1, caspase-9, and caspase-3. Moreover, myocardin/Stat3-mediated activation of Bcl-2 and Mcl-1 transcription is contingent on the CArG box. Myocardin and Stat3 synergistically inhibited staurosporine-induced cardiomyocyte apoptosis by up-regulating expression of anti-apoptotic Bcl-2 and Mcl-1 in neonatal rat cardiomyocytes. These results describe a novel anti-apoptotic Myocardin/Stat3 signaling pathway operating during cardiomyocyte apoptosis. This provides a molecular explanation for cardiomyocyte apoptosis inhibition as a critical component of myocardial protection. PMID- 29245929 TI - Harnessing the heart's resistance to malignant tumors: cardiac-derived extracellular vesicles decrease fibrosarcoma growth and leukemia-related mortality in rodents. AB - The heart is known for its resistance to cancer. Although different conjectures have been proposed to explain this phenomenon, none has been tested. We propose that the heart microenvironment may exert anti-cancer properties. So, our objective was to test the anti-oncogenic potential of cardiac-derived extracellular vesicles (EVs). For that EVs secreted by cardiosphere-derived cells (CDCs, heart progenitor cells) were tested in vitro on fibrosarcoma HT1080. In vivo models comprised the xenograft HT1080 fibrosarcoma in athymic mice (n=35), and spontaneous acute lymphocyte leukemia in old rats (n=44). CDC-EVs were compared with two control groups: EVs secreted by bone-marrow derived mesenchymal stem cells (MSC-EVs) and phosphate-buffered saline (PBS). Injection of CDC-EVs led to a 2.5-fold decrease of fibrosarcoma growth in mice (p<0.01 and p<0.05 for human and rat EVs, respectively) vs PBS group. The effect was associated with 2 fold decrease of tumor cells proliferation (p<0.001) and 1.5-fold increase of apoptosis (p<0.05) in CDC-EV vs PBS mice. Salutary changes in tumor gene and protein expression were observed in CDC-EV animals. CDC-EVs reduced tumor vascularization compared with PBS (p<0.05) and MSC-EVs (p<0.01). Moreover, CDC EVs increased leukemia-free survival (p<0.05) in old rats vs PBS. MiR-146, highly enriched in CDC-EVs, may be implicated in part of the observed effects. In conclusion, this study presents the first evidence that ties together the long recognized enigma of the "heart immunity to cancer" with an antioncogenic effect of heart-derived EVs. These findings open up cancer as a new therapeutic target for CDC-EVs. PMID- 29245930 TI - The quinone-based derivative, HMNQ induces apoptotic and autophagic cell death by modulating reactive oxygen species in cancer cells. AB - 8-Hydroxy-2-methoxy-1,4-naphthoquinone (HMNQ), a natural compound isolated from the bark of Juglans sinensis Dode, displays cytotoxic activity against various human cancer cells. However, the molecular mechanism of the anticancer effect is unclear. In this study, we examined the cytotoxic mechanism of HMNQ at the molecular level in human cancer cells. Cells were treated with HMNQ in a dose- or time-dependent manner. HMNQ treatment inhibited cell viability, colony formation and cell migration, indicating that HMNQ induced cancer cell death. HMNQ-treated cells resulted in apoptotic cell death through PARP-1 cleavage, Bax upregulation and Bcl-2 downregulation. HMNQ was also observed to induce autophagy by upregulating Beclin-1 and LC3. Furthermore, HMNQ induced reactive oxygen species (ROS) production, which was attenuated by the ROS scavengers, NAC and GSH. Finally, HMNQ increased expression of JNK phosphorylation and the JNK inhibitor SP600125 rescued HMNQ-induced cell death, suggesting that the cytotoxicity of HMNQ is mediated by the JNK signaling pathway. Taken together, our findings show that HMNQ exhibits anticancer activity through induction of ROS-mediated apoptosis and autophagy in human cancer cells. These data suggest the potential value of HMNQ as a natural anticancer drug. PMID- 29245931 TI - Silibinin protects against osteoarthritis through inhibiting the inflammatory response and cartilage matrix degradation in vitro and in vivo. AB - Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and inflammation. Silibinin, a polyphenolic flavonoid derived from fruits and seeds of Silybum marianum, has been reported to possess various potent beneficial biological effects, such as antioxidant, anti-cancer, hepatoprotective and anti-inflammatory activities. However, the anti-inflammatory effects of silibinin on OA have not been reported. This study aimed to assess the effects of silibinin on OA both in vitro and in vivo. In this study, we found that silibinin significantly inhibited the nterleukin-1beta (IL-1beta)-induced production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF alpha) and IL-6, expression of cyclooxygenase2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-1 (MMP-1), MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5, degradation of aggrecan and collagen-II in human OA chondrocytes. Furthermore, silibinin dramatically suppressed IL-1beta-stimulated phosphatidylinositol 3 kinase/ protein kinase B (PI3K/Akt) phosphorylation and nuclear factor-kappa B (NF-kB) activation in human OA chondrocytes. In addition, treatment of silibinin not only prevented the destruction of cartilage and the thickening of subchondral bone but also relieved synovitis in mice OA models. Also, the immunohistochemistry results showed that silibinin significantly decreased the expression of MMP-13 and ADAMTS-5 and increased the expression of collagen-II and aggrecan in mice OA. Taken together, these results suggest that silibinin may be a potential agent in the treatment of OA. PMID- 29245932 TI - Synthesis of methylprednisolone loaded ibuprofen modified dextran based nanoparticles and their application for drug delivery in acute spinal cord injury. AB - To improve the therapeutic efficacy of spinal cord injury (SCI), the methylprednisolone was incorporated into nanoparticles based on the ibuprofen modified dextran. The ibuprofen modified dextran was synthesized using a direct esterification linkage between the carboxylic acids of hydrophobic drug and the hydroxyl groups of the polymer backbone. The morphology of methylprednisolone loaded nanoparticles was evaluated by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The therapeutic efficacy of the prepared nanoparticles on the acute SCI model rats was assessed. It is demonstrated that methylprednisolone loaded ibuprofen modified dextran based nanoparticles (MP loaded NPs) could promote the recovery of neurological deficits, enhance growth of neurons, decrease degeneration of injuried neurons and reduce the tissue tumor necrosis factor alpha (TNF-alpha) levels significantly in the SCI rats. Subsequently, the study indicates that synthesis of methylprednisolone loaded ibuprofen modified dextran based nanoparticles has a great potential in the synergetic effect treatment for spinal cord injury and nanoparticles based drug delivery system will become a powerful weapon of human conquest of disease. PMID- 29245933 TI - mir-193 targets ALDH2 and contributes to toxic aldehyde accumulation and tyrosine hydroxylase dysfunction in cerebral ischemia/reperfusion injury. AB - MicroRNAs (miRNAs, miR) play a fundamental role in cerebral ischemia/reperfusion (I/R) injury. However, the role of miRNAs in toxic aldehyde and tyrosine accumulation is not fully elucidated. We constructed a cerebral I/R rat model and found that overexpression of miR-193 was associated with the accumulation of 4 Hydroxynonenal (4-HNE), Malondialdehyde (MDA), and tyrosine, and with the decrease of aldehyde dehydrogenase (ALDH2), tyrosine hydroxylase (TH), and dopamine. To unveil the molecular mechanism of the miR-193-mediated phenotype in I/R injury as described above, we performed bioinformatic analysis and found that ALDH2 was a potential target of miR-193. Through in vitro experiments (such as miR-193 mimic/inhibitor transfection, luciferase reporter gene plasmid transfection, and 4-HNE exposure) and in vivo infusion of miR-193 agomir, we demonstrated that miR-193 directly suppressed the expression of ALDH2 and led to toxic aldehyde accumulation, resulting in dysfunction of tyrosine hydroxylase. The present study suggests that the overexpression of miR-193 in a rat model exacerbated brain injury due to the following sequential process: targeted suppression of ALDH2, aldehyde accumulation, and tyrosine hydroxylase dysfunction, leading to tyrosine accumulation and insufficiency of dopamine synthesis. PMID- 29245934 TI - Apolipoprotein A-I mimetic peptide 4F suppresses tumor-associated macrophages and pancreatic cancer progression. AB - Pancreatic cancer is an aggressive malignancy that is unresponsive to conventional radiation and chemotherapy. Therefore, development of novel immune therapeutic strategies is urgently needed. L-4F, an Apolipoprotein A-I (ApoA-I) mimetic peptide, is engineered to mimic the anti-inflammatory and anti-oxidative functionalities of ApoA-I. In this work, H7 cells were orthotopically implanted in C57BL/6 mice and treated with L-4F. Then, pancreatic cancer progression and the inflammatory microenvironment were investigated in vivo. The cytotoxicity of L-4F toward H7 cells was assessed in vitro. Furthermore, we investigated the effects of L-4F on macrophage polarization by analyzing the polarization and genes of mouse bone marrow-derived macrophages in vitro. The results show that L 4F substantially reduced the tumorigenicity of H7 cells. L-4F inhibited inflammation by reducing the accumulation of inflammatory cells, such as IL-17A-, IL-4-, GM-CSF-, IL-1beta-, and IL-6-producing cells and Th1 and Th17. Notably, L 4F also decreased the percentage of macrophages in tumor tissues, especially M2 macrophages (CD11b+F4/80+CD206+), which was also confirmed in vitro. Additionally, the expression of the M2 marker genes Arg1, MRC1, and CCL22 and the inflammatory genes IL-6, iNOS, and IL-12 was decreased by L-4F, indicating that L 4F prevents M2 type macrophage polarization. However, L-4F could not directly attenuate H7 cell invasion or proliferation and did not induce apoptosis. In addition, L-4F potently down-regulated STAT3, JNK and ERK signaling pathways but not affects the phosphorylation of p38 in RAW 264.7 cells. These results suggest that L-4F exhibits an effective therapeutic effect on pancreatic cancer progression by inhibiting tumor-associated macrophages and inflammation. PMID- 29245935 TI - Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients. AB - Background: We previously reported an accurate urine-based bladder cancer (BCa) associated diagnostic signature that can be used to non-invasively detect BCa. In this study, we investigated whether a component of this signature could risk stratify patients with BCa. Methods: Utilizing immunohistochemistry, we investigated angiogenin, MMP-2, p53, RB and PAI-1 expression from 939 patients with BCa. The expression levels were scored by assigning a proportion score and an intensity score to yield a total staining score for each protein. The expressions of each protein individually and as an aggregate were then correlated with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results: Differential expressions of these markers were noted in BCa. With multivariate analysis in non-muscle invasive bladder cancer (NMIBC) age, tumor grade portended a worse PFS, while age, tumor grade, nodal status, MMP2, RB and PAI-1 expression portended a worse OS. As for multivariate analysis in muscle invasive bladder cancer (MIBC), age MMP-2 and RB were associated with a worse PFS, while age, nodal status, MMP-2, RB and PAI-1 were associated with a worse OS. Using Kaplan-Meier survival analysis, we noted a significant reduction in OS as more of the five biomarkers were expressed in a tumor. Thus, overall, high expressions of MMP-2, RB and/or PAI-1 in bladder tumors were markers of poor prognosis. Conclusion: Individually, MMP-2, RB and PAI-1, as well as in aggregate correlated with poor survival in patients with BCa. Thus, patients whose bladder tumors express these biomarkers may benefit from early radical treatment and/or neoadjuvant or adjuvant therapies. PMID- 29245936 TI - Podocalyxin promotes proliferation and survival in mature B-cell non-Hodgkin lymphoma cells. AB - Podocalyxin (PCLP1) is a CD34-related sialomucin expressed by some normal cells and a variety of malignant tumors, including leukemia, and associated with the most aggressive cancers and poor clinical outcome. PCLP1 increases breast tumor growth, migration and invasion; however, its role in hematologic malignancies still remains undetermined. The purpose of this study was to investigate the expression and function of PCLP1 in mature B-cell lymphoma cells. We found that overexpression of PCLP1 significantly increases proliferation, cell-to-cell interaction, clonogenicity, and migration of B-cell lymphoma cells. Furthermore, PCLP1 overexpression results in higher resistance to death induced by dexamethasone, reactive oxygen species and type II anti-CD20 monoclonal antibody obinutuzumab. Strikingly, enforced expression of PCLP1 enhances lipid droplet formation as well as pentose phosphate pathway and glutamine dependence, indicative of metabolic reprogramming necessary to support the abnormal proliferation rate of tumor cells. Flow cytometry analysis revealed augmented levels of PCLP1 in malignant cells from some patients with mature B-cell lymphoma compared to their normal B-cell counterparts. In summary, our results demonstrate that PCLP1 contributes to proliferation and survival of mature B-cell lymphoma cells, suggesting that PCLP1 may promote lymphomagenesis and represents a therapeutic target for the treatment of B-cell lymphomas. PMID- 29245938 TI - MiR-195 suppresses the metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by inhibiting YAP. AB - MiR-195, a novel cancer-related microRNA, was previously reported to play an important role in many malignancies. This study aimed to investigate the role of miR-195 mediated epithelial-mesenchymal transition (EMT) and the progression of hepatocellular carcinoma (HCC) as well as the underlying mechanisms. Our result demonstrated that miR-195 were significantly down regulated in HCC and its decreased expression is associated with poor clinical features of HCC patients. Oppositely, expression level of YAP was significantly higher in HCC tissues, and the level of YAP in metastatic tissues was significantly higher. We also found that a strong inversely association between low level expression of miR-195 and high level of YAP in HCC tissues. Notably, this study confirmed that miR-195, YAP and their combination were valuable predictors for the prognosis of HCC patients. We also explored that miR-195 inhibits HCC growth and metastatic capacity. Mechanistically, we confirm that miR-195 inhibits the migration, invasion and EMT of HCC cells by suppressing YAP. Lastly, we revealed YAP was not only the downstream of miR-195 in HCC, but also mediated the promoting effects of miR-195 on the metastasis and EMT of HCC cells. Taken together, miR-195 inhibits the metastasis and EMT in HCC by targeting YAP. MiR-195/YAP pathway may potentially act as novel biomarker and attractive therapeutic target in HCC. PMID- 29245937 TI - NLRP3-inflammasome inhibition prevents high fat and high sugar diets-induced heart damage through autophagy induction. AB - The NLRP3-inflammasome complex has emerged as an important component of inflammatory processes in metabolic dysfunction induced by high-caloric diets. In this study, we investigate the molecular mechanisms by which NLRP3 inhibition may attenuate diet-induced cardiac injury. Here we show the cardiac damage induced by high sugar diet (HSD), high fat diet (HFD) or high sugar/fat diet (HSFD) over 15 weeks. Genetic ablation of NLRP3 protected against this damage by autophagy induction and apoptotic control. Furthermore, NLRP3 inhibition by the selective small molecule MCC950 resulted in similar autophagy induction and apoptotic control in hearts after diets. These data were reproduced in THP-1 cells treated with MCC950 and cultured in media supplemented with serum from mice dosed with MCC950 and fed with diets. NLRP3 inhibition exerted beneficial metabolic, and autophagic adaptations in hearts from obesogenic diets. The inhibition of NLRP3 activation may hold promise in the treatment of metabolic and cardiovascular diseases. PMID- 29245939 TI - Identification of hub genes related to silicone-induced immune response in rats. AB - Silicone implants are used widely in the field of plastic surgery and are used in a large population. However, their safety profile, especially the silicone induced immune response, has been a major concern for plastic surgeons for decades. It has been hypothesized that there is a cause and effect relation between silicone and immunity, but this is controversial. The objective of the present study was to determine the hub genes and key pathways related to silicone implant-induced immune responses in a rat model. In addition to cluster and enrichment analyses, we used weighted gene co-expression network analysis (WGCNA) to examine the gene expression profiles in a systematic context. A total five genes (Fes, Aif1, Gata3, Tlr6, Tlr2) were identified as hub genes that are most likely related to the silicone-induced immune response, four of which (Aif1, Gata3, Tlr6, Tlr2) have been associated with autoimmunity as target genes or disease markers. The Toll-like receptor signaling pathway (p < 0.01, fold enrichment: 7.01) and systemic lupus erythematosus signaling pathway (p < 0.05, fold enrichment: 5.01), which are considered strongly associated with autoimmunity, were significantly enriched in the silicone-implanted skin samples. The results indicate that silicone implants might trigger the localized immune response, as various immune reaction genes were detected after silicone implantation. The identified five hub genes will hopefully serve as novel therapeutic targets for silicone-related complications and the associated autoimmune diseases. PMID- 29245940 TI - Mesenchymal stem cells inhibit T cell activation by releasing TGF-beta1 from TGF beta1/GARP complex. AB - Intervention with mesenchymal stem cells (MSCs) reveals a promising therapeutic tool to treat transplantation and autoimmune disease due to their immunoregulation capability. But the mechanisms of action are not fully investigated yet. Transforming growth factor-beta1 (TGF-beta1) exhibit multiple effects in migration, differentiation, and immunomodulation of MSCs. Glycoprotein A repetitions predominant (GARP) is an important marker of activated Treg (regulatory T cells). GARP binds latent TGF-beta1 to regulate its activation, which is the indispensable step in Treg suppressing effector T cells. So far we don't know whether GARP present on MSCs and its association with MSCs function. Our study show that MSCs express GARP which binds latent TGF-beta1 on their cell surface. We also found that TGF-beta1+/- MSCs produce less TGF-beta1 and exhibit reduced capacity in inhibiting T cells. When TGF-beta1 signaling pathway was blocked, MSCs show decreased activity in inhibiting T cells. Importantly, silencing GARP expression distinctively damaged the capacity of MSCs to inhibit IFN-gamma production. These findings indicated the expression of GARP on MSCs and its functionality in activating LAP, thus demonstrating GARP as a novel biomarker and new target to improve the therapeutic efficacy of MSCs. PMID- 29245941 TI - Tumor-associated macrophages promote tumor metastasis via the TGF-beta/SOX9 axis in non-small cell lung cancer. AB - Tumor-associated macrophages (TAMs), most of which display the immunosuppressive M2 phenotype, affect the tumor microenvironment and promote progression and metastasis in lung carcinoma. In this study, we analyzed clinical non-small cell lung cancer (NSCLC) samples and found that high densities of TAMs were associated with a poor prognosis in NSCLC patients. Moreover, the number of TAMs present correlated positively with expression of sex determining region Y (SRY)-related high mobility group box 9 (SOX9) in NSCLC tissues. TAMs secreted TGF-beta, which increased SOX9 expression and promoted epithelial-to-mesenchymal transition (EMT) in lung cancer cells, thereby promoting tumor proliferation, migration, and invasion. SOX9 knockdown inhibited EMT, indicating that TGF-beta-mediated EMT is SOX9-dependent. TGF-beta induced SOX9 expression by upregulating the C-jun/SMAD3 pathway. These results indicate that TGF-beta secreted by TAMs promotes SOX9 expression via the C-jun/SMAD3 pathway, thereby promoting tumor metastasis. The TGF-beta/SOX9 axis may therefore be an effective target for the treatment of lung cancer. PMID- 29245942 TI - R383C mutation of human CDC20 results in idiopathic non-obstructive azoospermia. AB - Idiopathic azoospermia (IA) is a severe form of male infertility due to unknown causes. To investigate relative gene expression in human idiopathic non obstructive azoospermia, we sequenced all the exons of cell division cycle 20 (CDC20) in 766 patients diagnosed with IA, as well as in 521 normally fertile men. Three novel missense mutations (S72G, R322Q, R383C) of CDC20 were detected and further confirmed by Sanger sequencing. The mRNA levels of securin, cyclin B, cyclin dependent kinase 1 (CDK1), and cyclin dependent kinase 2 (CDK2), which are all targeted for destruction via the anaphase-promoting complex/cyclosomeCDC20 (APC/CCDC20) pathway, were detected at relatively high levels using real-time quantitative polymerase chain reaction analysis. This demonstrated that the CDC20 R383C mutation led to dysfunction during the transition from metaphase to anaphase and facilitation of mitotic exit in vitro, and caused prolonged mitotic arrest during the cell cycle. This study suggests that a CDC20 R383C mutation may result in the pathogenesis of human IA. PMID- 29245943 TI - Saikosaponin-d, a calcium mobilizing agent, sensitizes chemoresistant ovarian cancer cells to cisplatin-induced apoptosis by facilitating mitochondrial fission and G2/M arrest. AB - Cisplatin (CDDP) and its derivatives are first line anti-cancer drugs for ovarian cancer (OVCA). However, chemoresistance due to high incidence of p53 mutations leads to poor clinical prognosis. Saikosaponin-d (Ssd), a saponin from a herbal plant extract, has been shown to induce cell death and sensitize chemoresistant cells to chemotherapeutic agents. Here, we demonstrated that Ssd sensitized chemoresistant OVCA cells with either p53-wt, -mutant and -null to CDDP. The action of Ssd appears to be through induction of mitochondrial fragmentation and G2/M arrest. Ssd is mediated via calcium signaling, up-regulation of the mitochondrial fission proteins Dynamin-related protein 1 (Drp1) and optic atrophy 1 (Opa1), and loss in mitochondrial membrane potential (MMP). Moreover, in the presence of CDDP, Ssd also down-regulates protein phosphatase magnesium-dependent 1 D (PPM1D) and increases the phosphorylation of checkpoint protein kinases (Chk) 1, cell division cycle 25c (Cdc25c) and Cyclin dependent kinase 1 (Cdk1). Our findings suggest that Ssd could sensitize OVCA to CDDP independent of the p53 status through multiple signaling pathways. They support the notion that Ssd may be a novel adjuvant for the treatment of chemoresistant OVCA. PMID- 29245945 TI - High-sensitivity modified Glasgow prognostic score (HS-mGPS) Is superior to the mGPS in esophageal cancer patients treated with chemoradiotherapy. AB - The present study compared the prognostic value of the modified Glasgow prognostic score (mGPS) and high-sensitivity mGPS (HS-mGPS) in unresectable locally advanced esophageal squamous cell carcimona (LAESCC) patients treated with concurrent chemoradiotherapy (CCRT). The baseline data of 163 eligible patients were retrospectively collected. Patients with a C-reactive protein (CRP) <= 10 mg/l and albumin >= 35 g/l were allocated to mGPS-0 group. Patients with only elevated CRP (> 10 mg/l) were assigned to mGPS-1 group. Patients who had both elevated CRP (> 10 mg/l) and hypoalbuminurea (< 35 g/l) were assigned to mGPS-2 group. The HS-mGPS was calculated based on cutoff values of 3mg/l for CRP and the same value (35 g/l) for albumin. Prognostic significance for both tumor response and overall survival (OS) was analyzed by univariate and multivariate analysis. The mGPS was 0 in 95 patients, 1 in 28 patient and 2 in 40 patients. In contrast, the HS-mGPS was 0 in 66 patients, 1 in 47 patients and 2 in 50 patients. In multivariate analysis, the HS-mGPS was the only positive factor for tumor response (P = 0.015). Both the mGPS (P < 0.001) and HS-mGPS (P < 0.001) were good prognostic predictors for OS. However, the HS-mGPS was found to be a superior prognostic predictor compared to the mGPS in a multivariate analysis (P = 0.006). In conclusion, the pretreatment HS-mGPS is a strong prognosticator superior to the mGPS for both tumor response and OS in LAESCC patients who received CCRT. PMID- 29245944 TI - Extracellular vesicles from KSHV-infected endothelial cells activate the complement system. AB - Extracellular vesicles (EVs), released by cells, are associated with cell-to-cell communication and regulate various cellular processes. EVs draw parallels with viruses for their similar structures and functions. Increasing evidences from recent studies indicate that cells infected with viruses release a variety of EVs. Delineating the functions and mechanisms of EVs released during virus infection is essential for understanding the molecular basis of viral infection and replication as well as associated pathogenesis. The most challenging obstacle for these studies is the separation of EVs from viruses. In this study, we successfully isolated the EVs from de novo Kaposi's sarcoma-associated herpesvirus (KSHV) infected-human endothelial cells during the period between virus entry and production. Intriguingly, a proteomics analysis of these EVs has revealed alterations of the complement system. Additionally, we have discovered that the EVs from KSHV-infected endothelial cells are potent activators of an alternative pathway of the complement system via exploitation of the endogenous C3 complement protein and properdin. Furthermore, we have found that complement activation promotes KSHV persistent latent infection by activating the NF-kappaB pathway, which enhances the survival of KSHV-infected cells and inhibits viral lytic replication. Our work identifies a novel role of EVs induced by KSHV during de novo infection and the underlying mechanism of complement activation by EVs. PMID- 29245946 TI - MiR-483-5p promotes IGF-II transcription and is associated with poor prognosis of hepatocellular carcinoma. AB - The human insulin-like growth factor-II (IGF-II) gene transcribes four mRNAs (P1 mRNA-P4 mRNA), and P3 mRNA overexpression contributes to hepatocarcinogenesis. IGF-II-derived miR-483-5p is implicated in the development of cancers. Here, we investigated the involvement of miR-483-5p in P3 mRNA overexpression regulation and its role in hepatocellular carcinoma. Our results showed that miR-483-5p up regulated P3 mRNA transcription by targeting the 5'-untranslated region (5'UTR) of P3 mRNA in hepatocellular carcinoma. The mechanism was involved in recruiting of an argonaute 1(Ago1)-argonaute 2 (Ago2) complex to the P3 mRNA 5'UTR and the P3 promoter of IGF-II gene by miR-483-5p, accompanied by increased enrichment of RNA polymerase II and activating histone marks histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 27 acetylation (H3K27ac), and histone 4 lysine 5/8/12/16 acetylation (H4Kac) at the P3 promoter. High miR-483-5p expression was an independent predictor for shorter survival of HCC patients. The findings suggest that miR-483-5p promotes P3 mRNA transcription by recruiting the Ago1 Ago2 complex to the P3 mRNA 5'UTR and is associated with poor prognosis of HCC. Our results display a potential new model for miRNAs to up-regulate gene expression. PMID- 29245947 TI - ALV-J infection induces chicken monocyte death accompanied with the production of IL-1beta and IL-18. AB - Immunosuppression induced by avian leukosis virus subgroup J (ALV-J) causes serious reproduction problems and secondary infections in chickens. Given that monocytes are important precursors of immune cells including macrophages and dendritic cells, we investigated the fate of chicken monocytes after ALV-J infection. Our results indicated that most monocytes infected with ALV-J including field or laboratory strains could not successfully differentiate into macrophages due to cells death. And cells death was dependent upon viral titer and accompanied with increased IL-1beta and IL-18 mRNA levels. In addition, ALV-J infection up-regulated caspase-1 and caspase-3 activity in monocytes. Collectively, we found that ALV-J could cause cell death in chicken monocytes, especially pyroptosis, which may be a significant reason for ALV-J induced immunosuppression. PMID- 29245948 TI - PD-1/PD-L1 interaction up-regulates MDR1/P-gp expression in breast cancer cells via PI3K/AKT and MAPK/ERK pathways. AB - Programmed cell death ligand 1 (PD-L1) is an immunosuppressive molecule expressed on tumor cells. By interacting with programmed cell death-1 (PD-1) on T cells, it inhibits immune responses. Because PD-L1 expression on cancer cells increases their chemoresistance, we investigated the correlation between PD-L1 and multidrug resistance 1/ P-glycoprotein (MDR1/P-gp) expression in breast cancer cells. Analysis of breast cancer tissues using tissue microarrays revealed a significant correlation between PD-L1 and MDR1/P-gp protein levels. Increased expression of PD-L1 was associated with lymph node metastasis and histological tumor grade. In addition, interaction of PD-L1 with PD-1 induced phosphorylation of AKT and ERK, resulting in the activation of PI3K/AKT and MAPK/ERK pathways and increased MDR1/P-gp expression in breast cancer cells. The PD-1/PD-L1 interaction also increased survival of breast cancer cells incubated with doxorubicin. These findings suggest that the PD-1/PD-L1 inhibition may increase chemotherapy efficacy by inhibiting the MDR1/P-gp expression in breast cancer cells. PMID- 29245949 TI - Functional profiling of microtumors to identify cancer associated fibroblast derived drug targets. AB - Recent advances in chemotherapeutics highlight the importance of molecularly targeted perturbagens. Although these therapies typically address dysregulated cancer cell proteins, there are increasing therapeutic modalities that take into consideration cancer cell-extrinsic factors. Targeting components of tumor stroma such as vascular or immune cells has been shown to represent an efficacious approach in cancer treatment. Cancer-associated fibroblasts (CAFs) exemplify an important stromal component that can be exploited in targeted therapeutics, though their employment in drug discovery campaigns has been relatively minimal due to technical logistics in assaying for CAF-tumor interactions. Here we report a 3-dimensional multi-culture tumor:CAF spheroid phenotypic screening platform that can be applied to high-content drug discovery initiatives. Using a functional genomics approach we systematically profiled 1,024 candidate genes for CAF-intrinsic anti-spheroid activity; identifying several CAF genes important for development and maintenance of tumor:CAF co-culture spheroids. Along with previously reported genes such as WNT, we identify CAF-derived targets such as ARAF and COL3A1 upon which the tumor compartment depends for spheroid development. Specifically, we highlight the G-protein-coupled receptor OGR1 as a unique CAF-specific protein that may represent an attractive drug target for treating colorectal cancer. In vivo, murine colon tumor implants in OGR1 knockout mice displayed delayed tumor growth compared to tumors implanted in wild type littermate controls. These findings demonstrate a robust microphysiological screening approach for identifying new CAF targets that may be applied to drug discovery efforts. PMID- 29245951 TI - Construction of a model predicting the risk of tube feeding intolerance after gastrectomy for gastric cancer based on 225 cases from a single Chinese center. AB - Identifying patients at high risk of tube feeding intolerance (TFI) after gastric cancer surgery may prevent the occurrence of TFI; however, a predictive model is lacking. We therefore analyzed the incidence of TFI and its associated risk factors after gastric cancer surgery in 225 gastric cancer patients divided into without-TFI (n = 114) and with-TFI (n = 111) groups. A total of 49.3% of patients experienced TFI after gastric cancer. Multivariate analysis identified a history of functional constipation (FC), a preoperative American Society of Anesthesiologists (ASA) score of III, a high pain score at 6-hour postoperation, and a high white blood cell (WBC) count on the first day after surgery as independent risk factors for TFI. The area under the curve (AUC) was 0.756, with an optimal cut-off value of 0.5410. In order to identify patients at high risk of TFI after gastric cancer surgery, we constructed a predictive nomogram model based on the selected independent risk factors to indicate the probability of developing TFI. Use of our predictive nomogram model in screening, if a probability > 0.5410, indicated a high-risk patients would with a 70.1% likelihood of developing TFI. These high-risk individuals should take measures to prevent TFI before feeding with enteral nutrition. PMID- 29245950 TI - Antioxidant MMCC ameliorates catch-up growth related metabolic dysfunction. AB - Postnatal catch-up growth may be related to reduce mitochondrial content and oxidation capacity in skeletal muscle. The aim of this study is to explore the effect and mechanism of antioxidant MitoQuinone mesylate beta cyclodextrin complex (MMCC) ameliorates catch-up growth related metabolic disorders. Catch-up growth mice were created by restricting maternal food intake during the last week of gestation and providing high fat diet after weaning. Low birthweight mice and normal birthweight controls were randomly subjected to normal fat diet, high fat diet and high fat diet with MMCC drinking from the 4th week. MMCC treatment for 21 weeks slowed down the catch up growth and ameliorated catch-up growth related obesity, glucose intolerance and insulin resistance. MMCC administration significantly inhibited the peroxidation of the membrane lipid and up-regulated the antioxidant enzymes Catalase and MnSOD. In addition, MMCC treatment effectively enhanced mitochondrial functions in skeletal muscle through the up regulation of the ATP generation, and the promotion of mitochondrial replication and remodeling. To conclude, this study demonstrates that antioxidant MMCC effectively ameliorates catch-up growth related metabolic dysfunctions by increasing mitochondrial functions in skeletal muscle. PMID- 29245953 TI - Distinctive DNA mismatch repair and APC rare variants in African Americans with colorectal neoplasia. AB - Purpose: African Americans have a higher incidence and mortality from colorectal cancer. This disparity might be due, in part, to the type of mutations in driver genes. In this study, we examined alterations specific to APC, MSH3, and MSH6 genes using targeted exome sequencing to determine distinctive variants in the course of neoplastic transformation. Experimental Design: A total of 140 African American colon samples (30 normal, 21 adenomas, 33 advanced adenomas and 56 cancers) were used as our discovery set on an Ion Torrent platform. A 36 samples subset was resequenced on an Illumina platform for variants' validation. Bioinformatics analyses were performed and novel validated variants are reported. Results: Two novel MSH6 variants were validated and mapped to the MutS-V region near the MSH2 binding site. For MSH3, 4 known variants were validated and were located in exon 10 (3 non-synonymous) and exon 18 (1 synonymous). As for APC, 20 variants were validated with 4 novel variants: 3 stopgain and 1 non-synonymous. These variants mapped prior to and on the Armadillo repeats region, to the 15 amino acid repeat region, and to the 20-amino acid repeats region, respectively. Conclusion: We defined novel variants that target DNA mismatch repair and APC genes in African Americans with colorectal lesions. A greater frequency of variants in genes encoding DNA mismatch repair functions and APC likely plays major roles in colorectal cancer initiation and higher incidence of the disease in African Americans. PMID- 29245952 TI - The humanized anti-human AMHRII mAb 3C23K exerts an anti-tumor activity against human ovarian cancer through tumor-associated macrophages. AB - Mullerian inhibiting substance, also called anti-Mullerian hormone (AMH), inhibits proliferation and induces apoptosis of AMH type II receptor-positive tumor cells, such as human ovarian cancers (OCs). On this basis, a humanized glyco-engineered monoclonal antibody (3C23K) has been developed. The aim of this study was therefore to experimentally confirm the therapeutic potential of 3C23K in human OCs. We first determined by immunofluorescence, immunohistochemistry and cytofluorometry analyses the expression of AMHRII in patient's tumors and found that a majority (60 to 80% depending on the detection technique) of OCs were positive for this marker. We then provided evidence that the tumor stroma of OC is enriched in tumor-associated macrophages and that these cells are responsible for 3C23K-induced killing of tumor cells through ADCP and ADCC mechanisms. In addition, we showed that 3C23K reduced macrophages induced-T cells immunosuppression. Finally, we evaluated the therapeutic efficacy of 3C23K alone and in combination with a carboplatin-paclitaxel chemotherapy in a panel of OC Patient-Derived Xenografts. In those experiments, we showed that 3C23K significantly increased the proportion and the quality of chemotherapy-based in vivo responses. Altogether, our data support the potential interest of AMHRII targeting in human ovarian cancers and the evaluation of 3C23K in further clinical trials. PMID- 29245954 TI - Tamoxifen sensitivity-related microRNA-342 is a useful biomarker for breast cancer survival. AB - MicroRNAs (miRNAs) have emerged as one of the crucial regulators of cancer progression. Some miRNAs are reported to be related to the response of breast cancer to tamoxifen (TAM). In this study, we investigated whether the levels of TAM response-related miRNAs translate to patient survival. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used and Gene Set Enrichment Analysis (GSEA) was performed. Four TAM response-related miRNAs, miR 221, miR-222, miR-342, and miR-451, were identified by literature search. Patients with high expression of miR-342, related to TAM sensitivity, were associated with better survival in TCGA cohort (Overall Survival (OS), p=0.02; Disease Free Survival (DFS), p=0.03, respectively), and in two other independent GEO cohorts (OS, p=0.02 and p=0.0007, respectively). High expression of miR-342 was associated with significantly better survival in ER-positive patients (p=0.04), but not in ER-negative or triple-negative patients. Surprisingly, high expression of miR-451, reported to increase the sensitivity to TAM, was associated with worse survival (p=0.002). MiR-221 and miR-222 did not show any significance in survival. Lastly, GSEA demonstrated that lower miR-342 expression was significantly associated with the enrichment of TAM resistance-related gene expression, and higher miR-342 expression with TAM sensitivity-related gene expression, but miR-221, miR-222 and miR-451 were not. For the first time, we used "big data" from TCGA and GEO cohorts to analyze multiple miRNAs with respect to survival impact and TAM sensitivities. We demonstrated that TAM sensitivity related miR-342 could be a promising biomarker, especially in luminal type breast cancer patients. PMID- 29245955 TI - Salivary miRNA panel to detect HPV-positive and HPV-negative head and neck cancer patients. AB - Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of tumours that originate predominantly from the oral cavity, pharynx and larynx. Our aim was to determine whether salivary miRNA expression levels can diagnose these cancer subtypes. Saliva samples were collected from healthy controls (n=113, smoker and non-smokers), HPV-positive (n=54) and HPV-negative (n=47) HNSCC patients. The miRNA expression levels in saliva was quantified using qPCR. The potential of salivary miRNAs to discriminate these groups of patients was evaluated using multiple logistic regression with ROC analysis and a 10-fold cross-validation analysis. Salivary miRNA-9, -127, -134, -191, -222 and -455 were shown to discriminate a control group from a HPV-negative HNSCC patient group with a sensitivity of 60% and a specificity of 94%; whilst salivary miRNA-9,-134, -196b, -210, and -455 were the most parsimonious subset discriminating a control group from a HPV-positive HNSCC group, with a sensitivity of 65% and a specificity of 95%. Furthermore, miRNA-9, -134, -196b, -210 and -455 as a panel, was the most parsimonious subset to discriminate HPV-positive HNSCC patients from HPV-negative HNSCC patients. In addition, the expression levels of miRNA-9, -127, -196a, -196b, -210, -222 and -455 were significantly increased in the saliva collected from early stage HNSCC patients compared to controls. A future multi centre confirmatory study is warranted to test the diagnostic performance of these salivary miRNA prior to clinical implementation. PMID- 29245956 TI - Combination therapy of exendin-4 and allogenic adipose-derived mesenchymal stem cell preserved renal function in a chronic kidney disease and sepsis syndrome setting in rats. AB - Combined therapy with exendin-4 (Ex4) and allogenic adipose-derived mesenchymal stem cells (ADMSC) was tested against either therapy alone for protecting kidney function against chronic kidney disease (CKD) complicated by sepsis syndrome (SS) [i.e., by intraperitoneal injection of cecal-derived bacteria (1.0 * 104) cells/milliliter/total 5.0 cc].Adult-male-Sprague Dawley rats (n=36) were equally divided into group 1 (sham-control), group 2 (CKD), group 3 (CKD-SS), group 4 (CKD-SS-Ex4), group 5 (CKD-SS-ADMSC) and group 6 (CKD-SS-Ex4-ADMSC). At day 42 after CKD induction SS was induced. Thirty-minutes after SS induction, ADMSCs (2.0 *106 cells) were intravenously administered to groups 5 and 6. Ex4 (10 MUg/kg) was intraperitoneally administered groups 4 and 6 at 30 min and days 1 to 5 after SS induction. Animals were euthanized at day 47 after CKD induction. Kidney-injury score, collagen-deposition area, and creatinine/BUN levels were lowest in group 1, highest in group 3 and significantly higher in group 2 than in groups 4 to 6 in a progressively increasing manner (all P<0.0001). Protein expressions of inflammatory (MMP-9/TNF-alpha/NF-kappaB/IL-1beta/ICAM-1), oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (mitochondrial Bax/cleaved-caspase-3/cleaved-PARP) and fibrotic/DNA-damaged (Smad3/TGF beta/gamma-H2AX) biomarkers showed an identical pattern, whereas anti-fibrotic (BMP-2/Smad1/5), anti-apoptotic/endothelial-integrity (Bcl-2/eNOS) and podocyte integrity (ZO-1/p-cadherin) biomarkers exhibited an opposite pattern of kidney injury score among the six groups (all P>0.0001). Cellular expressions of inflammatory (CD14/CD68) and glomerulus/tubular-injury (WT-1/KIM-1) biomarkers displayed an identical pattern, whereas glomerulus/podocyte-component (dystroglycan/nephrin/ZO-1/fibronectin/p-cadherin) biomarkers showed an opposite kidney-injury score among the six groups (all P<0.0001). In conclusion, Ex4-ADMSC therapy effectively preserved renal function in the CKD-SS setting. PMID- 29245957 TI - Glipizide sensitizes lung cancer cells to TRAIL-induced apoptosis via Akt/mTOR/autophagy pathways. AB - The combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with subsidiary agents is a promising anticancer strategy to conquer TRAIL resistance in malignant cells. Glipizide is a second-generation oral hypoglycemic medicine for the cure of type II diabetes because of its capability to selectively stimulate insulin secretion from beta-cells. In this study, we revealed that glipizide could trigger TRAIL-mediated apoptotic cell death in human lung adenocarcinoma cells. Pretreatment with glipizide downregulation of p Akt and p-mTOR in different concentrations. In addition, LC3-II and p-Akt was suppressed in the presence of LY294002, a well-known inhibitor of P13K. Treatment with glipizide commenced in a slight increase in conversion rate of LC3-I to LC3 II and significantly decreased p62 expression levels in a dose-dependent manner. This indicates that glipizide encouraged autophagy flux activation in human lung cancer cells. Inhibition of autophagy flux applying a specific inhibitor and genetically modified ATG5 siRNA enclosed glipizide-mediated enhancing effect of TRAIL. These data demonstrate that inhibition of Akt/mTOR by glipizide sensitizes TRAIL-induced tumor cell death through activating autophagy flux and also suggest that glipizide may be a combination therapeutic target with TRAIL protein in TRAIL-resistant cancer cells. PMID- 29245958 TI - Apelin protects against myocardial ischemic injury by inhibiting dynamin-related protein 1. AB - It is known that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays an important role in ischemic injury of myocardial infarction (MI). Apelin, an endogenous ligand for Apelin receptor, acts as a key modulator of cardiovascular diseases. Here, we examined the effects of Apelin on MI injury and underlying mechanisms. Adult male C57BL/6J mice were treated with Apelin for 4 weeks and then subjected coronary artery ligation (LAD) to induce MI and the protective effects of Apelin on MI injury were evaluated at 6 h post LAD. Mitochondrial fission was significantly increased in MI as evidenced by enhanced expression of phosphorylated Drp1 (p-Drp1ser 616) without affecting total Drp-1 level and degenerative transformation of mitochondria into short rods as typical fission. Apelin markedly inhibited p-Drp1ser 616 and preserved mitochondrial morphology in MI. Similar effects of Apelin were consistently observed in primary cultured cardiomyocytes under hypoxia. Apelin decreased hypoxia-induced cardiomyocyte apoptosis as evidenced by decreased TUNEL-positive cells and preserved mitochondrial membrane potential (MMP). Apelin decreased Bax/Bcl-2 ratio and limited the release of cytochrome C and activation of caspase-9 and caspase-3 both in vivo and in vitro. Finally, Apelin diminished the infarct size and normalized the impaired cardiac function as indicated by rescuing of the decreased ejection faction and fractional shortening in MI mice. In conclusion, Apelin prevented mitochondrial fission by inhibiting p-Drp1Ser616, which prevents loss of MMP and inhibits the mitochondria-mediated apoptosis. These results indicate that the inhibition of Drp-1 activation by Apelin is a novel mechanism of cardioprotection against MI injury. PMID- 29245959 TI - Low concentration of formononetin promotes proliferation of estrogen receptor positive cells through an ERalpha-miR-375-PTEN-ERK1/2-bcl-2 pathway. AB - A low dose of formononetin accelerates the proliferation of nasopharyngeal carcinoma cells in vitro; however, the underlying mechanism remains unknown. Here, we investigated the molecular mechanism of formononetin in CNE2 cell proliferation. CNE2 cells were treated with 0 to 1 MUM formononetin. To inhibit mitogen activated protein kinase / extracellular regulate kinase (MAPK/ERK) kinase (MEK) and microRNA (miR)-375, cells were pretreated with either PD98059 or a miR-375 inhibitor, respectively, followed by co-treatment with formononetin (0.3 MUM) plus an inhibitor. Female rats were ovariectomized (OVX), and some OVX rats received formononetin or estrogen (E2) injections. Sham operated animals were used as controls. Compared to control, 0.3 MUM formononetin accelerated proliferation and decreased late apoptosis of CNE2 cells. However, formononetin induced pro-growth and anti-apoptosis activity was abolished by PD98059 and the miR-375 inhibitor. In addition, 0.1 and 0.3 MUM formononetin significantly increased estrogen receptor-alpha (ERalpha) and bcl-2, but decreased protein phosphatase and tensin homologue (PTEN) protein expression, all of which was reversed by the miR-375 inhibitor. Additionally, formononetin treatment resulted in a transient upregulation of phosphorylated (p)-ERK1/2. In vivo studies indicated that formononetin significantly increased endometrium thickness and down-regulated ERalpha expression in OVX rats. Taken together, our study demonstrates that a low concentration of formononetin can promote growth of CNE2 cells and uterine tissues, possibly through regulating the ERalpha-miR-375-PTEN ERK1/2-bcl-2 signaling pathway. PMID- 29245960 TI - Survival outcomes of double- and triple-sequential targeted therapy in patients with metastatic renal cell carcinoma: a retrospective comparison. AB - Objective: To evaluate the progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) treated with double- and triple-sequence targeted therapy (TT) using tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors (mTORi). Materials and Methods: Records of 292 patients with mRCC, treated with TT between January 2005 and July 2015, were analyzed retrospectively. Kaplan-Meier and log-rank analyses were used to calculate and compare the total PFS (tPFS) and OS when patients underwent double- or triple-TT using TKIs or mTORi. Results: Eighty-one (27.7%) patients who underwent second-line TT were enrolled; 30 (10.3%) of whom underwent third line TT. The tPFS and OS of double-TT using TKI-mTORi (5.4 and 30 months, respectively) were significantly better compared with TKI-TKI (0.3 and 2 months) or mTORi-TKI (2 and 6 months) (p <0.001). For triple-TT, the tPFS and OS of TKI mTORi-TKI (22.8 and 25 months, respectively) were significantly superior compared with those for TKI-TKI-mTORi (4 and 9 months) (p <0.05).For patients with intermediate-risk according to the Heng or Memorial Sloan-Kettering Cancer Center risk models, TKI-mTORi was associated with a significantly longer tPFS and OS compared with TKI-TKI [expect for OS in the Heng group (p = 0.086)]. For the triple TT group, TKI-mTORi-TKI resulted in improved tPFS and OS compared with TKI TKI-TKI or TKI-TKI-mTORi (p <0.05). Conclusion: In patients with mRCC, sequential administration of TKI-mTORi led to a significantly superior tPFS compared with any other TT sequence. By contrast, OS did not differ significantly according to TT sequence. PMID- 29245962 TI - Associations between HVEM/LIGHT/BTLA/CD160 polymorphisms and the occurrence of antibody-mediate rejection in renal transplant recipients. AB - Antibody-mediated rejection (ABMR) is a serious complications that can occur following renal transplantation. The production of donor-specific antibodies by the humoral immune response can trigger costimulatory signals, which are crucial in activating immune cells, and therefore, playing a potential role in ABMR. To investigate the role of HVEM/LIGHT/BTLA/CD160 polymorphisms in ABMR, we retrospectively analyzed 200 renal transplant recipients. We adopted next generation sequencing (NGS) to identify HVEM/LIGHT/BTLA/CD160 single-nucleotide polymorphisms (SNPs) in the genotypes of these patients. We divided the patients into two groups: those with ABMR and those who were stable. We adopted multiple models and performed regression analysis after adjusting for multiple confounding variables, to determine the correlation between the SNPs and ABMR. We obtained 41 high-quality SNPs readouts. However, we did not observe any significant association between these polymorphisms and the pathogenesis of ABMR in any of the models.Nevertheless, since there is evidence suggesting the involvement of costimulatory signals in graft rejection, further research should be conducted to better understand how genetic polymorphisms may be involved in ABMR. PMID- 29245961 TI - Proteome profiling of clear cell renal cell carcinoma in von Hippel-Lindau patients highlights upregulation of Xaa-Pro aminopeptidase-1, an anti proliferative and anti-migratory exoprotease. AB - Patients of the von Hippel-Lindau (VHL) disease frequently develop clear cell renal cell carcinoma (ccRCC). Using archived, formalin-fixed, paraffin-embedded (FFPE) samples, we sought to determine global proteome alterations that distinguish ccRCC tissue from adjacent, non-malignant kidney tissue in VHL patients. Our quantitative proteomic analysis clearly discriminated tumor and non malignant tissue. Significantly dysregulated proteins were distinguished using the linear models for microarray data algorithm. In the ccRCC tissue, we noticed a predominant under-representation of proteins involved in the tricarboxylic acid cycle and an increase in proteins involved in glycolysis. This profile possibly represents a proteomic fingerprint of the "Warburg effect", which is a molecular hallmark of ccRCC. Furthermore, we observed an increase in proteins involved in extracellular matrix organization. We also noticed differential expression of many exoproteases in the ccRCC tissue. Of particular note were opposing alterations of Xaa-Pro Aminopeptidases-1 and -2 (XPNPEP-1 and -2): a strong decrease of XPNPEP-2 in ccRCC was accompanied by abundant presence of the related protease XPNPEP-1. In both cases, we corroborated the proteomic results by immunohistochemical analysis of ccRCC and adjacent, non-malignant kidney tissue of VHL patients. To functionally investigate the role of XPNPEP-1 in ccRCC, we performed small-hairpin RNA mediated XPNPEP-1 expression silencing in 786-O ccRCC cells harboring a mutated VHL gene. We found that XPNPEP-1 expression dampens cellular proliferation and migration. These results suggest that XPNPEP-1 is likely an anti-target in ccRCC. Methodologically, our work further validates the robustness of using FFPE material for quantitative proteomics. PMID- 29245963 TI - Identification of potential metabolic biomarkers of cerebrospinal fluids that differentiate tuberculous meningitis from other types of meningitis by a metabolomics study. AB - Tuberculous meningitis (TBM) is caused by tuberculosis infection of of the meninges, which are the membrane systems that encircle the brain, with a high morbidity and mortality rate. It is challenging to diagnose TBM among other types of meningitis, such as viral meningitis, bacterial meningitis and cryptococcal meningitis. We aimed to identify metabolites that are differentially expressed between TBM and the other types of meningitis by a global metabolomics analysis. The cerebrospinal fluids (CSF) from 50 patients with TBM, 17 with viral meningitis, 17 with bacterial meningitis, and 16 with cryptococcal meningitis were analyzed using ultra high performance liquid chromatography coupled with quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). A total of 1161 and 512 features were determined in positive and negative electrospray ionization mode, respectively. A clear separation between TBM and viral, bacterial or cryptococcal meningitis was achieved by orthogonal projections to latent structures-discriminate analysis (OPLS-DA) analysis. Potential metabolic markers and related pathways were identified, which were mainly involved in the metabolism of amino acid, lipids and nucleosides. In summary, differential metabolic profiles of the CSF exist between TBM and other types of meningitis, and potential metabolic biomarkers were identified to differentiate TBM from other types of meningitis. PMID- 29245964 TI - Phenformin has anti-tumorigenic effects in human ovarian cancer cells and in an orthotopic mouse model of serous ovarian cancer. AB - Obesity and diabetes have been associated with increased risk and worse outcomes in ovarian cancer (OC). The biguanide metformin is used in the treatment of type 2 diabetes and is also believed to have anti-tumorigenic benefits. Metformin is highly hydrophilic and requires organic cation transporters (OCTs) for entry into human cells. Phenformin, another biguanide, was taken off the market due to an increased risk of lactic acidosis over metformin. However, phenformin is not reliant on transporters for cell entry; and thus, may have increased potency as both an anti-diabetic and anti-tumorigenic agent than metformin. Thus, our goal was to evaluate the effect of phenformin on established OC cell lines, primary cultures of human OC cells and in an orthotopic mouse model of high grade serous OC. In three OC cell lines, phenformin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, caused cellular stress, inhibited adhesion and invasion, and activation of AMPK and inhibition of the mTOR pathway. Phenformin also exerted anti-proliferative effects in seven primary cell cultures of human OC. Lastly, phenformin inhibited tumor growth in an orthotopic mouse model of serous OC, coincident with decreased Ki-67 staining and phosphorylated-S6 expression and increased expression of caspase 3 and phosphorylated-AMPK. Our findings demonstrate that phenformin has anti tumorigenic effects in OC as previously demonstrated by metformin but it is yet to be determined if it is superior to metformin for the potential treatment of this disease. PMID- 29245965 TI - The aldehyde group of gossypol induces mitochondrial apoptosis via ROS-SIRT1-p53 PUMA pathway in male germline stem cell. AB - As a widely grown economic crop, cotton is the major oil and protein resource for human and livestock. But the highly toxic of gossypol in cottonseed severely restricts its effective utilization, consequently creating huge resource waste. Previous studies have shown the male germline stem cells were the most vulnerable cells in gossypol damages, but the mechanism was still unclear. We found gossypol induced cell viability decline resulted from apoptosis. And the increase of Caspase-9 activity in gossypol treatment hinted the mitochondrial apoptosis. So the mitochondrial dysfunction was confirmed by the decreased mitochondrial membrane potential and ATP concentration. We found the higher intracellular H2O2 level did not accompany with the O2.- associated increase in gossypol-treated, which indicated that gossypol obstructed the intracellular reactive oxygen species (ROS) elimination. Manipulated gossypol-induced H2O2 level by H2O2 and alpha-lipoic acid, we demonstrated that the mitochondrial dysfunction resulted from the excessive intracellular H2O2. Treated with Apogossypolone (ApoG2), an aldehyde group removed derivative of gossypol, the GSH/GSSG ratio and H2O2 did not decrease. ApoG2 also did not cause the mitochondrial apoptosis. So the aldehyde group is key factor in gossypol cytotoxicity. We respectively detected the NAD+/NADH ratio, SIRT1 activity, the relative protein level and apoptosis. Comparing with the specific inhibitors groups, the data illustrated that gossypol induced apoptosis through SIRT1-P53-PUMA pathway. This study helped to overcome barriers of gossypol cytotoxicity, which is crucial in feed and food use of cottonseed. This also provides a reference for the gossypol derivatives using in male contraception and anticancer. PMID- 29245966 TI - Digenic mutations on SCAP and AGXT2 predispose to premature myocardial infarction. AB - Genetic factors play a vital role in the pathogenesis of premature myocardial infarction (PMI). However, current studies explained only small amounts of genetic risk in MI. In this study, we started from a PMI pedigree with three MI patients occurred at the age of 43, 45 and 53 respectively. Sanger sequencing revealed 6 LDLR mutation carriers in the family, but only one was diagnosed with PMI, indicating that the LDLR mutation may not be the reason for PMI. Upon exome sequencing and bioinformatics analysis, two variants in SCAP and AGXT2 were identified as potential causative mutation for PMI. Further observation revealed that only patients that meet the diagnosis of PMI harbored two variants meantime, while other MI patients or members with no MI carried no more than one of the variants. Screening of the two genes in an independent PMI population identified another variant on SCAP (c.1403 T>C, p.Val468Ala), which was absent in 28, 000 east-Asian population. Further, the two variants on SCAP and AGXT2 were introduced into H293T and EA. hy926 cell lines respectively utilizing CRISPR Cas9. Functional study revealed that the SCAP mutation impaired SCAP-SREBP feedback mechanism which may lead to a "constitutive activation" effect of cholesterol synthesis related genes, while the AGXT2 mutation reduced its aminotransferase activity leading to a down-regulation of NO production by ADMA accumulation. This study indicates that SCAP and AGXT2 are potential causative genes for PMI. Digenic mutation carriers may manifest a more severe phenotype, namely premature MI. PMID- 29245967 TI - Genetic predisposition to ischaemic stroke by RAGE and HMGB1 gene variants in Chinese Han population. AB - Emerging evidence suggests that the multiligand receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 protein (HMGB1) contribute to the pathophysiology of ischaemic stroke (IS). The present study aimed to investigate the association of RAGE and HMGB1 variants with the risk of IS. A total of 1,034 patients and 1,015 age- and sex-matched healthy controls were genotyped to detect five genetic variants of the RAGE gene and four genetic variants of the HMGB1 gene using the Multiplex SNaPshot assay. We found that the rs2070600 variant of RAGE was associated with an increased risk of IS (OR = 1.19, 95% CI: 1.02-1.38, P = 0.043), whereas the rs2249825 variant of HMGB1 was associated with a decreased risk of IS (OR = 0.83, 95% CI: 0.71-0.98, P = 0.041). Further stratification by IS subtypes revealed that the presence of the TT genotype of the RAGE rs2070600 variant confers a higher risk of the large artery atherosclerosis subtype of IS (P = 0.036). Moreover, patients with the variant T allele of the RAGE rs2070600 variant presented with reduced serum soluble RAGE production. Patients carrying the variant G allele of the HMGB1 rs2249825 variant exhibited significantly lower infarct volumes than those with the major CC genotype. These clues may help in the development of optimal personalized therapeutic approaches for IS patients. PMID- 29245968 TI - Associations of tumor regression grade with outcomes in patients with locally advanced rectal cancer treated with preoperative two-week course of radiotherapy. AB - Purpose: Studies concerning tumor regression grade (TRG) after two-week course of radiotherapy (RT) are limited. We tried to assess associations of TRG and outcomes in patients with locally advanced rectal cancer (LARC) treated with preoperative two-week course of RT. Methods: 356 consecutive LARC patients were retrospectively assessed. Patients with complete/intermediate (TRG1-3) and poor (TRG4-5) regressions were compared for overall survival (OS), disease-free survival (DFS) and metastasis-free survival (MFS). Results: By univariate analysis, pretreatment and postoperative factors including TNM stages, ypT, ypN, surgical procedure, pathological grade, and TRG impacted survival outcomes. Complete/intermediate regressions (TRG1-3) had significantly improved survival outcomes compared with poor ones (TRG4-5) (5y-OS, 85.8% vs. 65.8%, P=0.001; 5y DFS, 76.0% vs. 53.7%, P<0.001; 5y-MFS, 84.2% vs. 66.7%, P<0.001). Multivariate analysis showed that ypN (P<0.001) and pathological grade (P=0.018) were the most important independent prognostic factors for DFS. ypT (P=0.014) and ypN (P=0.001) were the independent prognostic factors for MFS. Meanwhile, ypT (P=0.009), ypN (P=0.001), surgical procedure (p=0.001), and TRG (p=0.019) were the independent prognostic factors for OS. Conclusions: Complete/intermediate TRG regressions had a more favorable prognosis than the poor group. When treated with preoperative two-week course of RT; ypT, ypN, surgical procedure, and TRG seem to affect OS. PMID- 29245969 TI - Decreased expression of interferon-induced protein 2 (IFIT2) by Wnt/beta-catenin signaling confers anti-apoptotic properties to colorectal cancer cells. AB - Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through activation of the beta-catenin/TCF7L2 complex. Although genes up-regulated by Wnt/beta-catenin signaling have been intensively studied, the roles of down-regulated genes are poorly understood. In this study, we explored a global gene expression of colorectal cancer cells transfected with beta-catenin siRNAs or a dominant negative form of TCF7L2 (dnTCF7L2), and identified a set of genes down-regulated by Wnt/beta-catenin signaling. Among the genes, we focused here on IFIT2, a gene encoding interferon-induced protein with tetratricopeptide repeats. A reporter assay using plasmids containing a 5' flanking region of the gene showed that the reporter activity was enhanced by either transduction of beta-catenin siRNA or dnTCF7L2, suggesting that the region is involved in the transcriptional regulation as a downstream of the beta catenin/TCF7L2 complex. Consistent with this result, expression of IFIT2 was significantly lower in colorectal cancer tissues than that in normal tissues. Exogenous IFIT2 expression decreased cell proliferation and increased apoptosis of colorectal cancer cells. These data suggested that the down-regulation of IFIT2 by Wnt/beta-catenin signaling may play a vital role in human colorectal carcinogenesis through the suppression of apoptosis. PMID- 29245970 TI - Calcitriol induces cell senescence of kidney cancer through JMJD3 mediated histone demethylation. AB - Calcitriol, also known as 1,25-dihydroxyvitamin D3 (1,25(OH)2VD3), is a biologically active form of vitamin D and has a wide range of anticancer activity against various cancer cell lines. However, the mechanism of calcitriol remains to be further studied. In this study, the biological effect and epigenetic regulation of calcitriol on kidney cancer cells were investigated. Calcitriol can significantly inhibit cell proliferation of kidney cancer cell lines 786-O (P<0.05). Calcitriol also induced cell apoptosis and senescence of 786-O and ACHN (P<0.05). Calcitriol can increase the expression of histone demethylase JMJD3 and cell senescence marker p16INK4A (P<0.05). Knockdown of JMJD3 decreased p16INK4A upregulation after calcitriol treatment (P<0.05), and also reduced calcitriol induced cell senescence (P<0.05). This study reveals a new mechanism of anticancer activity of calcitriol by showing that histone demethylase JMJD3 induced by calcitriol increases p16INK4A expression and cell senescence. Therefore, these results provide new strategy for treatment and prevention of kidney cancer. PMID- 29245971 TI - Systematic analysis of the expression profile of non-coding RNAs involved in ischemia/reperfusion-induced acute kidney injury in mice using RNA sequencing. AB - Acute kidney injury (AKI) is a common and serious disease characterized by a rapid decline in renal function and has an unacceptably high mortality rate with no effective treatment beyond supportive care. AKI can be induced by many factors such as ischemia/reperfusion (IR), sepsis, and drug-induced nephrotoxicity. However, the molecular mechanisms of AKI are poorly understood. A non-coding RNA (ncRNA) is a RNA molecule that is not translated into a protein. NcRNAs play multiple roles in cellular processes, and mutations or imbalances of these molecules within the body can cause a variety of diseases. Although growing evidence has supported the key role of ncRNAs in AKI, the specific mechanism remains largely unknown. In this study, the second-generation gene sequencing was performed to investigate the expression patterns of ncRNAs, including microRNA (miRNA), long non-coding RNAs, and circular RNAs, in the kidneys of mice subjected to IR-induced AKI. This information will contribute to future research of the mechanism of ncRNAs in the pathogenesis of AKI and facilitate the identification of novel therapeutic targets of ncRNAs. PMID- 29245972 TI - Apigenin inhibits colonic inflammation and tumorigenesis by suppressing STAT3-NF kappaB signaling. AB - Apigenin is a naturally occurring compound with anti-inflammatory, antioxidant, and anticancer properties. Here, we investigated the effects of apigeninin inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Apigenin effectively inhibited ulcerative colitis, a type of IBD, and CAC. Apigenin decreased myeloperoxidase (MPO), inflammatory cytokine and COX-2 levels, and it attenuated inflammatory cell infiltration in treated colon tissues as compared to untreated model colon tissues. Apigenin also reduced NF-kappaB and STAT3 activity in vitro and in vivo, thereby inhibiting inflammation and inflammation-induced carcinogenesis. Thus apigenin appears to inhibit inflammation and inflammation induced carcinogenesisin IBD and CAC by suppressing STAT3-NF-kappaB signaling. PMID- 29245974 TI - Chondroitin sulfatases differentially regulate Wnt signaling in prostate stem cells through effects on SHP2, phospho-ERK1/2, and Dickkopf Wnt signaling pathway inhibitor (DKK3). AB - The chondroitin sulfatases N-acetylgalactosamine-4-sulfatase (ARSB) and galactosamine-N-acetyl-6-sulfatase (GALNS) remove either the 4-sulfate group at the non-reducing end of chondroitin 4-sulfate (C4S) and dermatan sulfate, or the 6-sulfate group of chondroitin 6-sulfate, chondroitin 4,6-disulfate (chondroitin sulfate E), or keratan sulfate. In human prostate cancer tissues, the ARSB activity was reduced and the GALNS activity was increased, compared to normal prostate tissue. In human prostate stem cells, when ARSB was reduced by silencing or GALNS was increased by overexpression, activity of SHP2, the ubiquitous non receptor tyrosine phosphatase, declined, attributable to increased binding of SHP2 with C4S. This led to increases in phospho-ERK1/2, Myc/Max nuclear DNA binding, DNA methyltransferase (DNMT) activity and expression, and methylation of the Dickkopf Wnt signaling pathway inhibitor (DKK)3 promoter and to reduced DKK3 expression. Since DKK3 negatively regulates Wnt/beta-catenin signaling, silencing of ARSB or overexpression of GALNS disinhibited (increased) Wnt/beta-catenin signaling. These findings indicate that the chondroitin sulfatases can exert profound effects on Wnt-mediated processes, due to epigenetic effects that modulate Wnt signaling. PMID- 29245973 TI - MicroRNA-433 inhibits oral squamous cell carcinoma cells by targeting FAK. AB - We investigated the involvement of microRNA-433 (miR-433) in the proliferation, migration, and invasiveness of oral squamous cell carcinoma (OSCC). Totally 108 OSCC tissues and adjacent normal tissues from patients with OSCC were collected. Also, transplanted tumor formation experiment in nude mice was conducted to verify the effect of miR-433 and FAK on subcutaneous transplanted tumor. The CD44+ stem cell from SCC-9 were collected and assigned into the blank, miR-433 mimics, mimics control, miR-433 inhibitors, inhibitors control, siFAK and miR-433 inhibitors + siFAK groups. The qRT-PCR and western blotting were used to detect miR-433, FAK, ERK, MEK, pERK and pMEK after transfection. Flow cytometry, MTT assay, scratch test and Transwell assay were performed to determine the cell proportion, growth, migration and invasion of SCC-9 cells. In cell line SCC-9, expression of CD133, Oct-4, and BIM-1 was greater in CD44+ cells than CD44- cells, indicating that CD44+ cells had characteristics of tumor stem cells. Expression of FAK, ERK, MEK, p-ERK and p-MEK was decreased in tumor tissues from the CD44-, miR-433, and siFAK groups. Expression of MiR-433 mRNA was elevated, while levels of FAK, ERK, MEK, p-ERK, and p-MEK mRNA were all decreased in the miR-433 mimics group. In the miR-433 mimics and siFAK groups, cell proliferation, migration, and invasion were all decreased, while the opposite trends were seen in the miR-433 inhibitor group. These results indicate that miR-433 downregulates FAK through the ERK/MAPK signaling pathway to inhibit the proliferation, migration, and invasiveness of SCC-9 OSCC cells. PMID- 29245975 TI - MAPK and ERK polymorphisms are associated with PCOS risk in Chinese women. AB - In this case-control study, we analyzed the association between eight RegulomeDB annotated single nucleotide polymorphisms (SNPs) in the MEK1, MEK2, ERK1 and ERK2 genes and polycystic ovarian syndrome (PCOS). Logistic regression analysis demonstrated that MEK1 rs12050732 (OR = 1.29 [95%CI: 1.06-1.58], P = 0.012), ERK2 rs2266966 (OR = 0.81 [95%CI: 0.67-0.99], P = 0.040) and ERK2 rs5999521 (OR = 0.66 [95%CI: 0.51-0.86], P = 0.002) were associated with PCOS risk without adjusting for age and body mass index. Moreover, PCOS risk increased with allele dosage when these three polymorphisms were combined (Ptrend = 0.001). These findings suggest that genetic variants in key MAPK and ERK genes contribute to PCOS risk in Chinese women. PMID- 29245976 TI - Gsdma3 regulates hair follicle differentiation via Wnt5a-mediated non-canonical Wnt signaling pathway. AB - Hair follicle is a mini-organ that consists of complex but well-organized structures, which are differentiated from hair follicle progenitor or stem cells. How non-canonical Wnt signaling pathway is involved in regulating hair follicle differentiation remains elusive. Here we showed that Wnt5a regulates hair follicle differentiation through an epithelial-mesenchymal interaction mechanism in mice. We first observed that Wnt5a is expressed in the epithelial and dermal papilla cells during hair follicle development and growth. For the upstream of Wnt5a, RT-PCR and immunohistochemistry staining showed that Wnt5a expression is significantly decreased in the Gsdma3-mutant mice in vivo. Overexpression of Gsdma3 results in a significantly increased expression of Wnt5a in the cultured epidermal cells in vitro. We also checked the downstream factors of Wnt5a by adenovirus-mediated overexpression of Wnt5a to the dermal papilla cells isolated from the mouse whisker. We found that overexpression of Wnt5a suppresses canonical Wnt signaling pathway effectors such as beta-catenin and Lef1. In addition, genes involved in maintaining cell quiescent state are also significantly decreased in their expression to the DP cells which were treated by Wnt5a. Our study indicates that Wnt5a mediates epithelia-expressed Gsdma3 to influence DP cell behaviors, which in turn regulate hair follicle epithelia differentiation in mice. PMID- 29245977 TI - The cancer-testis antigen, sperm protein 17, a new biomarker and immunological target in head and neck squamous cell carcinoma. AB - Head and Neck Squamous Cell Carcinoma is a deadly and locally aggressive malignancy that frequently portends a poor prognosis. Since current treatment modalities including surgery, chemotherapy and radiation are heavily debilitating and often result in recurrence intense efforts have been put into the development of novel less toxic and more lasting treatment strategies. Recently, immunotherapy has been proposed as a promising alternative that could potentially meet these requirements. SP17 is a validated cancer-testis antigen in multiple myeloma, ovarian cancer and non-small cell lung cancer. We aim at studying SP17 expression in HNSCC and its immunogenicity as a possible future target for HNSCC therapeutic vaccines. SP17 expression was evaluated in tissue specimens of HNSCC patients and controls. Moreover, SP17 immunogenicity was studied by generating autologous dendritic cells in vitro from the peripheral blood mononucleated cells of HNSCC patients and testing their ability to induce SP17 specific cytotoxic lymphocytes capable of killing autologous tumor cells in vitro. SP17specific immune responses were also evaluated in HNSCC patients as circulating anti-SP17 autoantibodies. SP17 was expressed in HNSCC tissues of HNSCC patients. Autologous dendritic cells pulsed with SP17 antigen induced powerful SP17 MHC class-I restricted, perforin-dependent, cytotoxic T-cells capable of efficiently killing autologous tumor cells in vitro. SP17-specific autoantibodies were detectable in the serum of HNSCC patients irrespective of tumor site or TNM stage. In conclusion, SP17 is an ideal immunotherapeutic target for HNSCC and a potential serological biomarker of the disease. PMID- 29245978 TI - Chronic kidney disease is associated with a risk of higher mortality following total knee arthroplasty in diabetic patients: a nationwide population-based study. AB - Diabetes and chronic kidney disease (CKD) are associated with a higher rate of complications in patients undergoing total knee arthroplasty (TKA). The purpose of this study was to determine the effects of CKD and diabetes in patients after TKA. Diabetic patients who received unilateral primary TKA between January 2008 and December 2011 were enrolled. The follow-up period was more than 6 months. The primary outcome was a TKA-related infection and the secondary outcome was all cause mortality. The study cohort included 13844 patients who were followed for a mean period of 2 years, of whom 1459 (10.5%) had CKD. The patients with CKD were older than those without CKD (71.6 versus 70.3 years, P<0.0001) and had higher rates of hypertension, gouty arthritis, ischemic heart disease, chronic pulmonary obstructive disease, pulmonary embolism and deep vein thrombosis (all P<0.0001). After adjustment of comorbidities, the CKD group had a higher incidence of urinary tract infections (OR: 1.61, 95% CI: 1.19-2.17). There were no significant differences in wound infections, pneumonia, pulmonary embolism or in-hospital death between the two groups. After adjustment of confounders, the CKD group had higher rates of myocardial infarction (HR: 2.06, 95% CI: 1.26-3.39) and mortality (HR: 1.99, 95% CI: 1.59-2.48). The risk of TKA-related infection during follow-up was comparable between the two groups (HR: 1.31, 95% CI: 0.94-1.82). In conclusion, CKD is associated with increased risks of urinary tract infections, myocardial infarction and all-cause mortality after TKA. Surgeons should be aware of this when evaluating TKA patients with renal disease. PMID- 29245979 TI - Variations in plasma concentrations of tamoxifen metabolites and the effects of genetic polymorphisms on tamoxifen metabolism in Korean patients with breast cancer. AB - Inter-individual variation in tamoxifen metabolism in breast cancer patients is caused by various genetic and clinical factors. We measured the plasma concentrations of tamoxifen and its metabolites and investigated genetic polymorphisms influencing those concentrations. We measured the concentrations of tamoxifen, endoxifen, N-desmethyltamoxifen (NDM), and 4-hydroxytamoxifen (4-OH tamoxifen) in 550 plasma specimens from 281 breast cancer patients treated with tamoxifen. Duplicate or triplicate specimens were obtained from 179 patients at 3 month intervals. In 80 patients, genotyping for tamoxifen metabolizing enzymes was performed using the DMET Plus array and long-range PCR. Plasma concentrations of tamoxifen and its metabolites showed wide variations among patients. The following genetic polymorphisms were associated with the plasma concentrations when body mass index and tamoxifen concentrations were considered as co variables: CYP1A2 -2467delT, CYP2B6 genotype, CYP2D6 activity score (AS), and FMO3 441C>T. CYP2D6 AS and three variants in the SULT1E1 gene showed correlation with ratios of tamoxifen metabolites. CYP2D6 AS was the only variable that showed associations with both metabolite concentration and ratio: endoxifen (P < 0.001), NDM (P < 0.001), endoxifen/NDM (P < 0.001), NDM/tamoxifen (P < 0.001), and 4-OH tamoxifen/tamoxifen (P = 0.005). Serial measurements of 448 plasma concentrations in 179 patients at 3-month intervals showed wide intra-individual variation. Our study showed that genetic polymorphisms can in part determine the baseline concentrations of tamoxifen and its metabolites. However, marked intra-individual variations during follow-up monitoring were observed, and this could not be explained by genotype. Therefore, serial measurements of tamoxifen and its metabolites would be helpful in monitoring in vivo tamoxifen metabolic status. PMID- 29245980 TI - An anti-CAPN5 intracellular antibody acts as an inhibitor of CAPN5-mediated neuronal degeneration. AB - CAPN5 has been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). Activation of CAPN5 may increase proteolysis and degradation of a wide range of substrates to induce degeneration in the retina and the nerve system. Thus, we developed an inhibitory intracellular single chain variable fragment (scFv) against CAPN5 as a potential way to rescue degeneration in ADNIV disease or in neuronal degeneration. We report that overexpression CAPN5 increases the levels of the auto-inflammatory factors toll like receptor 4 (TLR4), interleukin 1 alpha (IL1alpha), tumor necrosis factor alpha (TNFalpha) and activated caspase 3 in 661W photoreceptor-like cells and SHSY5Y neuronal-like cells. Both C4 and C8 scFvs specifically recognize human/mouse CAPN5 in 661W cells and SHSY5Y cells, moreover, both the C4 and C8 scFvs protected cells from CAPN5-induced apoptosis by reducing the levels of activated caspase 3 and caspase 9. The cellular expression C4 scFv reduced levels of the pro-inflammatory factor IL1-alpha activated caspase 3 in cells after CAPN5 overexpression. We suggest that CAPN5 expression has important functional consequences in auto-inflammatory processes, and apoptosis in photoreceptor like cells and neural-like cells. Importantly, the specific intracellular targeting of antibody fragments blocking activation of CAPN5 act as inhibitors of CAPN5 functions in neural like cells, thus, our data provides a novel potential tool for therapy in CAPN5-mediated ADNIV or neurodegenerative diseases. PMID- 29245981 TI - Co-targeting aurora kinase with PD-L1 and PI3K abrogates immune checkpoint mediated proliferation in peripheral T-cell lymphoma: a novel therapeutic strategy. AB - Peripheral T-cell non-Hodgkin lymphoma (PTCL) are heterogeneous, rare, and aggressive diseases mostly incurable with current cell cycle therapies. Aurora kinases (AKs) are key regulators of mitosis that drive PTCL proliferation. Alisertib (AK inhibitor) has a response rate ~30% in relapsed and refractory PTCL (SWOG1108). Since PTCL are derived from CD4+/CD8+ cells, we hypothesized that Program Death Ligand-1 (PD-L1) expression is essential for uncontrolled proliferation. Combination of alisertib with PI3Kalpha (MLN1117) or pan-PI3K inhibition (PF-04691502) or vincristine (VCR) was highly synergistic in PTCL cells. Expression of PD-L1 relative to PD-1 is high in PTCL biopsies (~9-fold higher) and cell lines. Combination of alisertib with pan-PI3K inhibition or VCR significantly reduced PD-L1, NF-kappaB expression and inhibited phosphorylation of AKT, ERK1/2 and AK with enhanced apoptosis. In a SCID PTCL xenograft mouse model, alisertib displayed high synergism with MLN1117. In a syngeneic PTCL mouse xenograft model alisertib demonstrated tumor growth inhibition (TGI) ~30%, whilst anti-PD-L1 therapy alone was ineffective. Alisertib + anti-PD-L1 resulted in TGI >90% indicative of a synthetic lethal interaction. PF-04691502 + alisertib + anti PD-L1 + VCR resulted in TGI 100%. Overall, mice tolerated the treatments well. Co targeting AK, PI3K and PD-L1 is a rational and novel therapeutic strategy for PTCL. PMID- 29245982 TI - Endothelial-derived interleukin-6 induces cancer stem cell motility by generating a chemotactic gradient towards blood vessels. AB - Recent evidence suggests that the metastatic spread of head and neck squamous cell carcinomas (HNSCC) requires the function of cancer stem cells endowed with multipotency, self-renewal, and high tumorigenic potential. We demonstrated that cancer stem cells reside in perivascular niches and are characterized by high aldehyde dehydrogenase (ALDH) activity and high CD44 expression (ALDHhighCD44high) in HNSCC. Here, we hypothesize that endothelial cell-secreted interleukin-6 (IL-6) contributes to tumor progression by enhancing the migratory phenotype and survival of cancer stem cells. Analysis of tissue microarrays generated from the invasive fronts of 77 HNSCC patients followed-up for up to 11 years revealed that high expression of IL-6 receptor (IL-6R) (p=0.0217) or co receptor gp130 (p=0.0422) correlates with low HNSCC patient survival. We observed that endothelial cell-secreted factors induce epithelial to mesenchymal transition (EMT) and enhance invasive capacity of HNSCC cancer stem cells. Conditioned medium from CRISPR/Cas9-mediated IL-6 knockout primary human endothelial cells is less chemotactic for cancer stem cells in a microfluidics based system than medium from control endothelial cells (p<0.05). Blockade of the IL-6 pathway with a humanized anti-IL-6R antibody (tocilizumab) inhibited endothelial cell-induced motility in vitro and decreased the fraction of cancer stem cells in vivo. Notably, xenograft HNSCC tumors vascularized with IL-6 knockout endothelial cells exhibited slower tumor growth and smaller cancer stem cell fraction. These findings demonstrate that endothelial cell-secreted IL-6 enhances the motility and survival of highly tumorigenic cancer stem cells, suggesting that endothelial cells can create a chemotactic gradient that enables the movement of carcinoma cells towards blood vessels. PMID- 29245983 TI - Serum corin is associated with the risk of chronic heart failure. AB - It has been well documented that corin is a critical protease involved in the regulation of blood pressure and cardiac function. We performed a case-control study to determine whether serum corin is associated with the risk of chronic heart failure (CHF). We included 484 consecutive CHF patients and 484 control subjects to investigate the potential relationship between serum corin and CHF using logistic regression analysis. Compared with healthy controls, the CHF patients were more likely to have histories of hypertension and diabetes, and had higher levels of N-terminal pro-brain natriuretic peptide and lower levels of corin. The odds ratios of ischemic and non-ischemic HF were significantly reduced with the growing levels of serum corin after multivariate adjustment. Moreover, the decrease in serum corin levels seemed to be associated with the severity of CHF. In conclusion, our study suggested that serum corin levels were reduced in CHF patients and inversely correlated with the incidence of ischemic and non ischemic HF. PMID- 29245984 TI - Kruppel-like factor 2 suppresses human gastric tumorigenesis through inhibiting PTEN/AKT signaling. AB - Kruppel-like factors (KLFs) are a large family of DNA-binding transcriptional regulators that affect basic cellular processes such as growth, survival, migration and differentiation and serve a complicated function in cancers. KLF2, one member of the KLF family, is dysregulated in many tumors. However, the specific role of KLF2 in human gastric tumorigenesis is unknown. Here we show that the expression of KLF2 protein was lower in gastric tumors when compared with adjacent normal tissue. Moreover, downregulated KLF2 expression in primary gastric tumor was closely correlated with patients' survival. Various cell experiments showed that ectopic KLF2 expression suppressed the proliferation, migration and invasion of gastric cancer cells. Moreover, KLF2 overexpression remarkably enhanced cell apoptosis and induced cell cycle arrest. Impaired expression of KLF2 markedly promoted cell growth in vitro and significantly expanded tumor size in vivo. Mechanically, the mRNA and protein level of PTEN was reduced in KLF2 deficient cells and xenograft tumors, suggesting that PTEN/AKT signaling was involved in the gastric tumor inhibitory effect of KLF2. Administration of AKT inhibitor AZD5363 or Insulin-like growth factor-1 (IGF-1) in KLF2 knockdown or ectopic expression cell lines, respectively, substantially reversed the proliferation phenotype. Collectively, our findings provide clinical evidence and a potential mechanism supporting that KLF2 suppresses human gastric tumorigenesis through inhibiting the PTEN/AKT axis. PMID- 29245985 TI - Effect of dexmedetomidine infusion for intravenous patient-controlled analgesia on the quality of recovery after laparotomy surgery. AB - Background: The Quality of Recovery-15 (QoR-15) is a patient-centered questionnaire to evaluate the recovery after surgery and anesthesia. Dexmedetomidine has sedative, analgesic, antiinflammatory and inhibitory sympathetic effects, which may contribute to early recovery. We hypothesized dexmedetomidine added to intravenous patient-controlled analgesia (PCA) could enhance the quality of recovery (QoR) in patients undergoing laparotomy surgery. Methods: In this randomized, double-blind, controlled study, 100 patients undergoing laparotomy surgery were randomly allocated into two groups: Dexmedetomidine (group D) and control (group S). Patients in the group D (n = 46) received dexmedetomidine 0.04 ug/(kg.h) plus sufentanil 0.02 ug/(kg.h) for 48 h after laparotomy surgery, and in the group S (n = 47) received sufentanil 0.04 ug/(kg.h) only. The QoR-15 scores, postoperative pain, rescue analgesia, recovery of gastrointestinal function, patient satisfaction and adverse effects were recorded. Results: The QoR-15 scores were significantly higher in the group D than in the group S on postoperative day (POD) 1, 2, 3 and 5 (P < 0.05). The visual analog scale (VAS) scores were significantly lower in the group D compared with group S within 48 h after surgery (P < 0.05). The pressing times of analgesic pump and rescue tramadol were not significantly different between the two groups (P > 0.05). The incidence of nausea was significantly lower in the Group D. No hypotension, bradycardia, or respiratory depression was observed. Conclusions: The addition of dexmedetomidine to PCA enhanced patient-centered recovery, reduced pain and adverse effect, and improved patient satisfaction after laparotomy surgery. PMID- 29245986 TI - Plasma proteomics reveals coagulation, inflammation, and metabolic shifts in H type hypertension patients with and without acute ischemic stroke. AB - Systematic profiling of a larger portion of circulating plasma proteome provide opportunities for unbiased discovery of novel markers to improve diagnostic, therapeutic, or predictive accuracy. This study aimed to identify differentially expressed proteins (DEPs) in plasma that could provide overall insight into the molecular changes of both H- type hypertension (HH) and HH-related acute ischemic stroke (AIS). This study used an iTRAQ-based LC-MS/MS proteomics approach to screen for plasma DEPs in HH patients with and without AIS, and controls. After excluding highly abundant plasma proteins, more than 600 proteins, and their relative levels, were identified. Of these, 26 DEPs, each showing > 1.2-fold change, were identified in HH and HH-related AIS patients compared with controls. Bioinformatics analysis revealed that these DEPs were enriched in 21 functional gene ontology items; "blood coagulation" was the most predominant pathway showing enrichment. Of these, eight DEPs were located in the hub position of networks involved with protein-protein interactions. AT-3, CRP, ApoB, and AHSG were further validated in each group by enzyme-linked immune sorbent assays. Comparing HH-related AIS with HH, the areas under the curve for AT-3, CRP, ApoB, and AHSG were 0.698, 0.892, 0.626, and 0.847, respectively. This proteomic profiling study provided enhanced pathophysiological understanding of the regulatory processes involved in coagulation, inflammation, and metabolism, and identified a panel of novel biomarkers for detecting HH-related AIS during its pre-stroke stage. PMID- 29245987 TI - Hydrogen sulfide attenuates chronic restrain stress-induced cognitive impairment by upreglulation of Sirt1 in hippocampus. AB - Chronic restraint stress (CRS) has detrimental effects on cognitive function. Hydrogen sulfide (H2S), as a neuromodulator, regulates learning and memory. Hippocampus is a key structure in learning and memory. Sirt1 (silence signal regulating factor 1) plays an important role in modulating cognitive function. Therefore, our present work was to investigate whether H2S meliorates CRS-induced damage in hippocampus and impairment in cognition, and further to explore whether the underlying mechanism is via upreglulating Sirt1. In our present work, the behavior experiments [Y-maze test, Novel object recognition (NOR) test, Morris water maze (MWM) test] showed that sodium hydrosulfide (NaHS, a donor of H2S) blocked CRS-induced cognitive impairments in rats. NaHS inhibited CRS-induced hippocampal oxidative stress as evidenced by decrease in MDA level as well as increases in GSH content and SOD activity. NaHS rescued CRS-generated ER stress as evidenced by downregulations of CPR78, CHOP, and cleaved caspase-12. NaHS reduced CRS-exerted apoptosis as evidenced by decreases in the number of TUNEL positive cells and Bax expression as well as increase in Bcl-2 expression. NaHS upregulated the expression of Sirt1 in the hippocampus of CRS-exposed rats. Furthermore, inhibited Sirt1 by Sirtinol reversed the protective effects of NaHS against CRS-produced cognitive dysfunction and oxidative stress, ER stress as well as apoptosis in hippocampus. Together, these results suggest that H2S meliorates CRS-induced hippocampal damage and cognitive impairment by upregulation of hippocampal Sirt1. PMID- 29245988 TI - Alcohol intake aggravates adipose browning and muscle atrophy in cancer associated cachexia. AB - Cancer is commonly associated with cachexia, a paraneoplastic syndrome characterized by body weight loss, muscle wasting, adipose tissue atrophy and inflammation. Chronic alcohol consumption increases the risk of multiple types of cancer, and enhances cancer-associated cachexia (CAC), but the underlying mechanisms remain poorly defined. To test, C57BL/6 mice were fed with 0% or 20% (w/v) alcohol for 3 months, then inoculated with B16BL6 melanoma cells subcutaneously in the right side of the hip and continued to feed with/without alcohol for 3 or 4 weeks. Alcohol intake upregulated ALDH1A1 expression and elevated retinoic acid (RA) content in inguinal white adipose tissue (iWAT), which led to enhanced iWAT browning and brown adipose tissue (BAT) activation, accelerating fat loss. Moreover, alcohol increased muscle loss through augmenting muscle protein degradation, cell apoptosis and inflammation. In addition, alcohol reduced satellite cell density and impaired myogenesis in skeletal muscle. Taken together, alcohol aggravates cancer-associated cachexia at least partially through elevating adipose browning and muscle atrophy. PMID- 29245989 TI - CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease. AB - Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro, apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo, esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days. Pre and post treatment MRIs, histopathology, and qRT-PCR were utilized to determine response. Our results demonstrated treatment with abemaciclib lead to increased apoptosis, and decreased proliferation in OE19 (p=0.185), OE33 (p=0.048), and FLO1 (p=0.043) with anticipated downstream molecular inhibition. In vivo, 78.9% of treatment animals demonstrated >20% tumor volume decrease (placebo 0%). Mean tumor volume changed in the treatment arm by -65.5% (placebo +133.5%) (p<0.01), and prevalence changed by -37.5% (placebo +16.7%) (p<0.01). Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates. Overall our findings suggest potent antitumor efficacy of abemaciclib against EAC with evident molecular pathway inhibition and reasonable safety, establishing the rationale for future clinical development. PMID- 29245990 TI - Caspase-4 is essential for saikosaponin a-induced apoptosis acting upstream of caspase-2 and gamma-H2AX in colon cancer cells. AB - Saikosaponin a (SSa), a bioactive phytochemical from Bupleurum, triggers sequential caspase-2 and caspase-8 activation, and thereby induces caspase mediated apoptosis in human colon carcinoma (HCC) cells. However, the upstream mechanism of caspase-2 activation remains unknown. Therefore, we investigated the signaling mechanisms underlying SSa-induced caspase activation and apoptosis in HCC cells. SSa treatment triggered marked antitumor effects, especially in HCC cells, in a cell culture model and a mouse xenograft model. SSa also induced the activation of several endoplasmic reticulum (ER) stress signals. Specifically, caspase-4, a critical regulator of ER stress-induced apoptosis, was activated significantly after SSa treatment. Mechanistically, selective inhibition of caspase-4 suppressed SSa-induced apoptosis, colony inhibition, and the activation of caspase-3, -8, and -2, but not vice versa. Consistent with the important role of caspase-2 in the DNA damage response, SSa induced DNA damage, as evidenced by a cytokinesis-block micronucleus assay, single-cell gel electrophoresis, and an increase in the levels of gamma-H2AX, a DNA damage marker. Moreover, inhibition of caspase-4 activation inhibited SSa-induced histone H2AX phosphorylation. Taken together, these results suggest that caspase-4 is an upstream regulator of SSa induced DNA damage and caspase activation in HCC cells. Given that SSa-induced apoptosis appeared to be specific to certain cell types including HCC cells, SSa may be a promising cancer therapy agent in certain types of cancer. PMID- 29245991 TI - The impact of metformin use on survival in prostate cancer: a systematic review and meta-analysis. AB - Background: Metformin has been implicated to reduce the risk of prostate cancer (PCa) beyond its glucose-lowering effect. However, the influence of metformin on prognosis of PCa is often controversial. Results: A total of 13 cohort studies encompassing 177,490 individuals were included in the meta-analysis. Data on overall survival (OS) and cancer-specific survival (CSS) was extracted from 8 and six studies, respectively. Comparing metformin users with non-metformin users, the pooled hazard ratios (HRs) for OS and CSS were 0.79 (95% confidence interval [CI] 0.63-0.98) and 0.76 (95% CI 0.57-1.02), respectively. Subgroup analyses stratified by baseline charcteristics indicated significant CSS benefits were noted in studies conducted in USA/Canada with prospective, large sample size, multiple-centered study design. Five studies reported the PCa prognosis for recurrence-free survival (RFS) and metformin use was significantly associated with patient RFS (HR 0.74, 95% CI, 0.58-0.95). Methods: Relevant studies were searched and identified using PubMed, Embase and Cochrane databases from inception through January 2017, which investigated associations between the use of metformin and PCa prognosis. Combined HRs with 95% CI were pooled using a random-effects model. The primary outcomes of interest were OS and CSS. Conclusions: Our findings provide indication that metformin therapy has a trend to improve survival for patients with PCa. Further prospective, multi-centered, large sample size cohort studies are warranted to determine the true relationship. PMID- 29245992 TI - HTR3A and HTR3E gene polymorphisms and diarrhea predominant irritable bowel syndrome risk: evidence from a meta-analysis. AB - Several studies have reported an association between serotonin receptor type 3 (5 HT3) subunit genes HTR3A (rs1062613) and HTR3E (rs62625044) and diarrhea predominant irritable bowel syndrome (IBS-D). However, the results remain inconclusive and controversial, particularly for the data derived from different ethnicities and genders. Therefore, we performed a meta-analysis to evaluate this association. All eligible case-control studies that met the search criteria were retrieved from multiple databases, and five case-control studies were included for detailed evaluation. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to assess the strengths of the associations of HTR3A (rs1062613) and HTR3E (rs62625044) polymorphisms with IBS-D risk. Our results revealed statistically significant associations of the HTR3A (rs1062613, C/T) polymorphism with a decreased risk of IBS-D in all genetic models. Additionally, the HTR3E (rs62625044, G/A) polymorphism was also found to be significantly associated with a decreased risk of IBS-D in the allele and recessive models. Subgroup analysis revealed that these associations held true especially for Asians and female. In conclusion, this meta-analysis suggested that the C allele of HTR3A (rs1062613) and the G allele of HTR3E (rs62625044) are associated with a decreased risk of IBS-D. PMID- 29245993 TI - Comparison of efficacy between brachytherapy and penectomy in patients with penile cancer: a meta-analysis. AB - We conducted a meta-analysis to compare the efficacy of brachytherapy and penectomy in patients with penile cancer. We searched the published articles in the PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang databases up to March 20, 2017. Twenty-two studies entered the final analyses. We used five-year overall survival rate, five-year local control rate, disease-free progression and lymph node positive rate to assess the efficacy. The meta analysis found that patients who received penectomy had higher five-year local control rate (85% vs 80%, odds ratio = 0.72, 95% confidence interval: 0.58-0.90), five-year disease-free progression rate (77% vs 72%, odds ratio = 0.77, 95% confidence interval: 0.63-0.93) and lymph node positive rates (24% vs 20%, odds ratio = 0.79, 95% confidence interval: 0.64-0.98) than brachytherapy. No significant difference was observed for two group in five-year overall survival rate (76% vs 74%, odds ratios = 1.11 with the 95% confidence interval: 0.91 1.36). Both of penectomy and brachytherapy can improve the survival status. Penectomy provided better control efficacy, and not improved the survival status compared with brachytherapy solely. However, further research was required because of retrospective nature and potential bias of the data. PMID- 29245994 TI - Clinicopathological and prognostic significance of HMGA2 overexpression in gastric cancer: a meta-analysis. AB - Background: High mobility group protein A2 (HMGA2) overexpression has been reported to be closely related to tumor progression [1-4] and indicate significantly worse overall survival in gastric cancer [5-8]. However, a final consensus regarding this issue has not yet been reached. Thus, we conducted a meta-analysis to evaluate the association between HMGA2 expression and prognosis of gastric cancer patients. Methods: The Cochrane Library, Embase, PubMed, Web of Science and China Biology Medicine databases were searched to identify eligible literature published prior to September 2016. In the included studies, the level of HMGA2 amplification was evaluated by immunohistochemistry. We performed a meta analysis, and pooled relative risk (RRs), hazard ratio (HRs), and 95% confidence intervals (CIs) were analyzed using Review Manager 5.3. Results: Six studies [5 7, 9-11] involving 712 gastric cancer patients were included and stratified by HMGA2 amplification magnitude. The results of the analysis indicated that higher HMGA2 levels were associated with several clinicopathological parameters and predicted poor prognosis in terms of overall survival (OS). Conclusions: The results of the present study indicate that higher HMGA2 levels were significantly associated with TNM stage, lymph node status, vascular invasion, and poor OS in patients with gastric cancer. In conclusion, HMGA2 may serve as a promising prognostic biomarker in gastric cancer. PMID- 29245995 TI - Prognostic role of long noncoding RNA ZFAS1 in cancer patients: a systematic review and meta-analysis. AB - Long noncoding RNA ZFAS1 has been identified as a crucial role in the tumorigenesis of malignant tumors. Numerous studies reported that the expression levels of ZFAS1 in tumor tissues were dramatically higher than that in adjacent normal tissues. We conducted a meta-analysis to investigate the correlation between ZFAS1 expression and clinical outcomes of cancer patients. The databases of PubMed, EMBASE, Web of Science, Cochrane Library, CNKI and WanFang were retrieved for eligible studies. A total of 841 patients from 9 studies were eventually included. Our results demonstrated that increased ZFAS1 expression was significantly associated with poor OS in cancer patients (HR = 2.13, 95% CI = 1.71-2.65, P < 0.001). Patients with high ZFAS1 expression presented shorter RFS than those with low ZFAS1 expression (HR = 2.00, 95% CI = 1.45-2.77, P < 0.001). The clinicopathological parameters analysis demonstrated that increased ZFAS1 expression was significantly associated with vascular invasion (OR = 2.26, 95% CI = 1.36-3.78, P = 0.002), lymph node metastasis (OR = 2.98, 95% CI = 2.12-4.19, P < 0.001) and advanced TNM stage (OR = 3.00, 95% CI = 2.18-4.12, P < 0.001). In conclusion, lncRNA ZFAS1 might serve as a prognostic biomarker for cancer patients and increased ZFAS1 expression may be closely related to advanced characteristics of cancer. PMID- 29245996 TI - Prognostic role of long non-coding RNA TUG1 expression in various cancers: a meta analysis. AB - Several studies were conducted to explore the prognostic role of long non-coding RNA taurine upregulated gene 1 (lncRNA TUG1) expression in various cancers, with contradictory. This study aims to summarize the prognostic role of lncRNA TUG1 expression in various cancers. Embase, PubMed and Cochrane Library were completely retrieved. The cohort studies focusing on the prognostic role of lncRNA TUG1 expression in various cancers were eligible. The endpoints were overall survival (OS) and clinicopathological parameters. 9 studies involving a total of 1,078 patients were identified. The results showed that high lncRNA TUG1 expression was obviously associated with worse OS when compared to the low lncRNA TUG1 expression (HR = 1.37, 95% CI = 1.07-1.76, P = 0.01; I2 = 85%). However, No distinct relationship was observed between the lncRNA TUG1 expression and age (OR = 0.99, 95% CI = 0.76-1.28, P = 0.92; I2 = 4%), gender (OR = 0.92, 95% CI = 0.70 1.22, P = 0.57; I2 = 0%), diameter (OR = 0.83, 95% CI = 0.34-2.01, P = 0.67; I2 = 85%), smoking (OR = 1.09, 95% CI = 0.37-3.21, P = 0.87; I2 = 73%), TNM stage (OR = 0.60, 95% CI = 0.25-1.43, P = 0.25; I2 = 86%) and lymph node metastasis (OR = 1.07, 95% CI = 0.47-2.45, P = 0.87; I2 = 86%). In conclusion, it was revealed that high lncRNA TUG1 expression is an unfavorable predictor of OS in patients with cancers, and lncRNA TUG1 expression is a promising prognostic biomarker for various cancers. PMID- 29245997 TI - What is the best combination treatment with transarterial chemoembolization of unresectable hepatocellular carcinoma? a systematic review and network meta analysis. AB - Objective: To assess the comparative efficacy and safety of combination treatment with transarterial chemoembolization (TACE) for patients with unresectable hepatocellular carcinoma (HCC) through a systematic review and network meta analysis and to identify what is the best combination treatment with TACE. Materials and Methods: A network meta-analysis was used to identify evidence from relevant randomized controlled trials. We searched databases for publications up to June 2017. The prespecified primary efficacy outcomes were treatment response and 6-month to 3-year overall survival (OS), while the secondary efficacy outcomes were 1- and 2-year disease-free survival (DFS); safety outcomes were advance effects of combination treatment. We conducted pairwise meta-analyses using a random-effects model and then performed random-effects network meta analyses. Results: A total of 48 trials were eligible (50 analyses), involving 5627 patients and 19 treatment arms. In comparison with other types of combination therapy arms, network meta-analysis disclosed that TACE + three dimensional conformal radiotherapy, TACE + percutaneous ethanol injection, TACE + percutaneous microwave coagulation therapy, TACE + percutaneous acetic acid injection, and TACE + sorafenib were the more effective methods in treatment response, 6-month to 3-year OS, and 1-2 year DFS; the adverse effects of TACE + sorafenib were serious. The study was registered with PROSPERO, number CRD42017071102. Conclusions: When considering the efficacy, combination therapy with TACE seemed to offer clear advantages for patients with unresectable HCC. TACE + Three-dimensional conformal radiotherapy, TACE + Percutaneous ethanol injection, TACE + Percutaneous microwave coagulation therapy, and TACE + Percutaneous acetic acid injection are likely the best options to consider in the application of combination treatment. PMID- 29245998 TI - Effects of levosimendan on mortality in patients with septic shock: systematic review with meta-analysis and trial sequential analysis. AB - Object: Several studies have investigated a survival benefit for levosimendan treatment in patients with septic shock. However, data are conflicting. We conducted a meta-analysis to evaluate the effect of levosimendan treatment on mortality in patients with septic shock. Materials and Methods: We searched PubMed, EMBASE and Cochrane Library Databases up to March 27, 2017, without language restrictions. We searched for terms related to septic shock, levosimendan, randomized clinical trial. Randomized controlled trials reported the effect of levosimendan on mortality were included. Moreover, we constructed the trial sequential analysis (TSA) to determine the reliability of the outcomes. Furthermore, secondary outcomes were cardiac index(CI), mean arterial pressure (MAP), blood lactate, norepinephrine dose and length of ICU stay. Results: Ten studies with a total of 816 patients were included in this meta-analysis. There was no significant difference in the mortality between the levosimendan group and the standard inotropic therapy group [RR = 0.96, 95% CI (0.81-1.12), I2 = 0]. However, methods adapted from formal interim monitoring boundaries applied to TSA indicated that the cumulative evidence was unreliable and inconclusive. Blood lactate was significantly reduced in the levosimendan group while there was no difference in MAP, CI, norepinephrine dose and length of ICU stay. Conclusions: Findings from this meta-analysis demonstrated that levosimendan treatment may not reduce mortality in patients with septic shock. The result remains inclusive and further randomized controlled trials were needed to confirm these conclusions. PMID- 29245999 TI - Long non-coding RNAs for osteosarcoma in the mouse: a meta-analysis. AB - Osteosarcoma, one of the most common primary bone malignances, is a leading cause of cancer death among children and adolescents. Recently, growing studies have found that long non-coding RNAs (lncRNAs) can interfere with the expression of various genes, and participate in the occurrence and development of malignancies. The purpose of this study is to evaluate the potential functions of lncRNAs as diagnostic biomarkers and therapeutic targets for osteosarcoma in mice, thus to direct the strict design for the future preclinical experiments and clinical trials. We systematically searched PubMed, Web of Science, Embase, China Knowledge Resource Integrated Database, VIP, Chinese BioMedical and Wan Fang Database from their initiation date to June 20, 2017. Two researchers independently screened the literatures and withdrew the data, which used the tumor volume and tumor weight as the outcome measures. A total of 10 studies were included, and the results of this meta-analysis revealed that lncRNAs could serve as the diagnostic biomarkers and therapeutic targets for osteosarcoma; and progression of osteosarcoma in mice could be inhibited via rescuing the abnormally expressed lncRNAs. It is necessary to carry out more rigorous basic experiments before lncRNAs can be further investigated in the clinical trials and used in future clinical practices. PMID- 29246000 TI - Increased DCLK1 correlates with the malignant status and poor outcome in malignant tumors: a meta-analysis. AB - Doublecortin-like kinase 1 (DCLK1) has been found to be involved in malignant biological behavior of cancers and poor prognosis of cancer patients. The aim of this meta-analysis was to systematically clarify the relationships between expression level of DCLK1 and clinicopathological characteristics in tumors and assess its clinical value in cancer diagnosis and prognosis. 18 eligible studies with a total of 2660 patients were identified by searching the electronic bibliographic databases. Pooled results showed that DCLK1 was highly expressed in tissues from cancer patients compared to normal tissues (OR, 10.00), and overexpression of DCLK1 was significantly correlated with advanced clinical stage (OR, 2.48), positive lymph node metastasis (OR, 2.18), poorly differentiated cancers (OR, 1.83) and poor overall survival (HR, 2.15). The overall combined sensitivity and specificity for DCLK1 in distinguishing malignant tumors were 0.58 and 0.90, respectively. The mean diagnostic odds ratio was 12.70, and the corresponding area under the summary receiver operating characteristic curve was 0.78. In summary, our study indicated that DCLK1 could be a risk factor for development of malignant tumors and may serve as a promising diagnostic and prognostic biomarker for malignant tumors. PMID- 29246001 TI - Association of PPARG rs 1801282 C>G polymorphism with risk of colorectal cancer: from a case-control study to a meta-analysis. AB - The functional single nucleotide polymorphisms in peroxisome proliferator activated receptor gamma (PPARG) gene were predicted to be correlated with the susceptibility of colorectal cancer (CRC). The aim of the present study was to explore the relationship between PPARG rs1801282 C>G polymorphism and the risk of CRC. First, we conducted a case-control study with 387 CRC cases and 1,536 controls. We used the SNPscan method to determine the genotypes of PPARG rs1801282 C>G polymorphism. We found PPARG rs1801282 C>G polymorphism had a tendency of decreased risk to CRC risk (CG vs. CC: adjusted OR, 0.67, 95% CI = 0.43-1.04 for CG vs. CC, P = 0.073; GG vs. CC: adjusted OR, 0.68; 95% CI, 0.44 1.05; P = 0.078). The stratified analysis revealed PPARG rs1801282 C>G polymorphism also had a tendency of decreased risk to colon cancer (CG vs. CC: adjusted OR = 0.54, 95% CI = 0.27-1.08, P = 0.083). The results of subsequent meta-analysis suggested that PPARG rs1801282 C>G polymorphism might be a protective factor for CRC, especially in Asians, colon cancer and rectum cancer subgroups. In conclusion, our study indicates that PPARG rs1801282 C>G polymorphism might decrease the risk of overall CRC. Larger sample size and well designed case-control studies are needed to confirm the potential association. PMID- 29246002 TI - Smoking and risk of cholangiocarcinoma: a systematic review and meta-analysis. AB - Previous studies evaluating the association between smoking and risk of cholangiocarcinoma (CCA) have yielded controversial results. We conducted a meta analysis to evaluate the association based on available evidence. We searched the databases of Embase, PubMed and Cochrane Central Register of Controlled Trials from inception to April 11, 2017. Studies that investigated the association between smoking and risk of CCA were included. Pooled odds ratio (OR) estimates and 95% confidence intervals (CIs) were calculated using either a random-effects or a fixed-effects model. A total of 22 studies involving 324,333 participants were identified. The summary OR of CCA was 1.31 (95% CI, 1.15 to 1.51) for smokers versus nonsmokers. The increased risk was independent of diabetes mellitus, bilious tract stone disease, and liver cirrhosis. Smokers also had increased risk of intrahepatic CCA (12 studies; OR, 1.31; 95% CI, 1.06 to 1.63) and extrahepatic CCA (12 studies; OR, 1.32; 95% CI, 1.10 to 1.59) compared with nonsmokers. The results of our meta-analysis support the hypothesis that there is a moderate association between cigarette smoking and risk of CCA. PMID- 29246003 TI - Exogenous melatonin in the treatment of pain: a systematic review and meta analysis. AB - Melatonin is an important hormone for regulating mammalian circadian biology and cellular homeostasis. Recent evidence has shown that melatonin exerts anti nociception effects in both animals and humans. However, according to clinical trials, the anti-nociception effects of melatonin are still controversial. The aim of this meta-analysis was to investigate the anti-nociception effects of melatonin premedication. The primary outcome was the effects of melatonin on pain intensity. The secondary outcomes included the number of patients with analgesic requirements, total analgesic consumption, and brain-derived neurotrophic factor (BDNF) levels. In total, 19 studies were included in the current meta-analysis. The pooling data show that melatonin significantly decreased the pain intensity, as evidenced by the pain scores. Moreover, melatonin administration also reduced the proportion of patients with analgesic requirements and BDNF levels. However, the effects of melatonin on total analgesic consumption still require further confirmation. Collectively, the current meta-analysis supports the use of melatonin for anti-nociception. PMID- 29246004 TI - Comprehensive assessment of association between TLR4 gene polymorphisms and cancer risk: a systematic meta-analysis. AB - Previous studies have explored the association between toll-like receptor 4 (TLR4) polymorphisms and risk of various cancers, but the results remained controversial. To obtain an assessment of the effect of TLR4 polymorphisms (rs4986790, rs4986791 and rs11536889) on cancer risk, fifty-five articles (containing 20107 cases and 28244 controls) were recruited for meta-analysis. Our result indicated that two Single Nucleotide Polymorphisms (SNP) in TLR4 were associated with decreased cancer risk for rs4986791: OR = 0.764, 95% CI: 0.652 0.894, P = 0.001 in allele model; OR = 0.769, 95%CI: 0.650-0.909, P = 0.002 in recessive model; OR = 0.505, 95% CI: 0.352-0.726, P = 0.000 in dominant model; for 11536889: OR = 0.927, 95% CI: 0.872-0.984, P = 0.013 in allele model; OR = 0.926, 95% CI: 0.862-0.944,P = 0.034 in recessive model. In terms of subgroup analyses sorted by ethnicity, only polymorphism of rs4986791 had a significant influence on decrease of cancer risk among both Caucasian and Asian populations. The findings suggested that TLR4 polymorphisms may serve as a genetic risk factor for cancers. PMID- 29246005 TI - Potassium measurements and risk of type 2 diabetes: a dose-response meta-analysis of prospective cohort studies. AB - Objective: To clarify the relationship between serum, dietary, and urinary potassium and the risk of type 2 diabetes mellitus (T2DM). Materials and Methods: We searched PubMed and EMBASE through January 6, 2017 for studies reporting risk estimates on the association of potassium measurements and the risk of T2DM. The summary risk estimates were obtained through a random-effects model. Dose response analysis was conducted. Results: Eight studies involving 5,053 cases and 119,993 individuals were included. A trend toward significance was found in the highest versus lowest meta-analysis on serum potassium and T2DM risk (RR = 0.79; 95% CI 0.60-1.04); moreover, the RR per 1 mmol/L increase in serum potassium was 0.83 (95% CI 0.73-0.95). A non-significant association of dietary potassium and T2DM risk was detected (RR for the highest versus lowest category: 0.93; 95% CI 0.81-1.06; RR for every 1000mg increase per day: 1.00, 95% CI 0.96-1.05). A similar non-significant association was found for urinary potassium and T2DM risk (RR for the highest versus lowest category: 0.83; 95% CI 0.39-1.75; RR per 10 mmol increase: 1.00; 95% CI 0.95-1.05). Evidence of a linear association between serum, dietary, and urinary potassium and the risk of T2DM was found (all Pnon linearity > 0.05). Conclusions: Low serum potassium increases the risk of T2DM in a linear dose-response manner; nevertheless, neither dietary potassium nor urinary potassium shows any association with the risk of T2DM. However, these findings should be interpreted with caution due to limited studies. PMID- 29246007 TI - Diagnostic prediction of urinary [TIMP-2] x [IGFBP7] for acute kidney injury: A meta-analysis exploring detection time and cutoff levels. AB - Acute kidney injury (AKI) most commonly occurs in critically ill and postoperative patients. Tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are two newly-identified urinary biomarkers that can help to detect early AKI, yet their predictive accuracies range widely. Here, we conduct a systematic meta-analysis to evaluate the diagnostic values of [TIMP-2] x [IGFBP7] for AKI at different detection times and cutoff levels. Ten studies were meta-analyzed on 1606 patients. Overall, urinary [TIMP-2] x [IGFBP7] had a pooled sensitivity of 58% and specificity of 79%. Subgroup analysis showed that the sensitivity and specificity were 0.72 and 0.58 with a cutoff value of 0.3 (ng/mL)2/1000, and 0.38 and 0.94 with a cutoff value of 2.0 (ng/mL)2/1000, respectively. Moreover, when 0.3 was chosen as the cutoff value, restricting analysis to patients who were tested within 4 hours showed a sensitivity of 0.71 and specificity of 0.73, with the AUROC of 0.75. When 2.0 was chosen as the cutoff value, the sensitivity and specificity were 0.43 and 0.93, respectively in patients who were tested within 24 hours, with the AUROC of 0.70. In summary, urinary [TIMP-2] x [IGFBP7] can predict the occurrence of AKI with moderate diagnostic accuracy. In the earlier administrative periods (less than 4 hours), 0.3 (ng/mL)2/1000 is recommended to be used; whereas for patients who were administrated more than 24 hours, 2.0 (ng/mL)2/1000 is more appropriate. PMID- 29246006 TI - Significance of Ki-67 in non-muscle invasive bladder cancer patients: a systematic review and meta-analysis. AB - Purpose: This meta-analysis evaluated the prognostic significance of Ki-67 in non muscle invasive bladder cancer (NMIBC). Materials and Methods: We selected 39 articles including 5,229 patients from Embase, Scopus, and PubMed searches. The primary outcomes, recurrence-free survival (RFS), progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) were determined using time-to event hazard ratios (HRs) with 95% confidence intervals (CIs). Study heterogeneity was tested by chi-square and I2 statistics. Heterogeneity sources were identified by subgroup meta-regression analysis. Results: Two studies were prospective; 37 were retrospective. Immunohistochemistry was performed in tissue microarrays or serial sections. A wide range of antibody dilutions and Ki-67 positivity thresholds were used. Study heterogeneity was attributed to analysis results in studies of RFS (p < 0.0001). Meta-regression analysis revealed that region and analysis results accounted for heterogeneity in PFS studies (p = 0.00471, p < 0.0001). High Ki-67 expression was associated with poor RFS (pooled HR, 1.78; 95% CI, 1.48-2.15), poor PFS (pooled HR, 1.28; 95% CI, 1.13-2.15), poor DSS (pooled HR, 2.24; 95% CI, 1.47-2.15), and worse OS (pooled HR, 2.29; 95% CI, 1.24-4.22). Conclusions: The meta-analysis found that current evidence supports the prognostic value of Ki-67 in NMIBC patients. PMID- 29246008 TI - Effect of hyperthermic intrathoracic chemotherapy on the malignant pleural mesothelioma: a systematic review and meta-analysis. AB - Surgery-based multimodality therapies have been used to control the malignant effusion and its recurrence in malignant pleural mesothelioma (MPM). Hyperthermic intrathoracic chemotherapy (HITHOC) has been used in the treatment of malignant pleural mesothelioma, but the results were controversial. The aim of the current study was, therefore, to conduct a systematic review and meta-analysis on the effect of HITHOC on MPM therapy. After thorough searching of online databases, total 21 articles were included into qualitative systematic review and 5 of them were used to conduct qualitative meta-analysis. It was found that most of HITHOC was used in combination of surgical resection including extrapleural pneumonectomy or pleurectomy/decortication. Patients who received HITHOC had significantly longer median survival length compared to the patients without HITHOC (Hedges's g = 0.384 +/- 0.105, 95% CI: 0.178~0.591, P < 0.001). In addition, HITHOC as palliative therapy was favored (Hedges's g = 0.591 +/- 0.201, 95% CI: 0.196~0.967, P < 0.001) in terms of recurrence free interval. The findings of the current study suggested that HITHOC is one of the safe and effective therapies in prolonging patients' median survival time and extending recurrence free interval. PMID- 29246009 TI - Evaluation of the NMP22 BladderChek test for detecting bladder cancer: a systematic review and meta-analysis. AB - Background: We examined the usefulness of the nuclear matrix protein 22 (NMP22) BladderChek test for detecting bladder cancer. Materials and Methods: A literature search was performed using PubMed, Embase, the Cochrane Library, and Web of Science. The diagnostic accuracy of the NMP22 BladderChek test was evaluated via pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under curve (AUC). Inter-study heterogeneity was explored using meta-regression and subgroup analyses. Results: We included 23 studies in the systematic review and 19 in the quantitative meta-analysis. Overall sensitivity and specificity were 56% (52-59%) and 88% (87-89%), respectively; pooled PLR and NLR were 4.36 (3.02 6.29) and 0.51 (0.40-0.66), respectively; DOR was 9.29 (5.55-15.55) with an AUC of 0.8295. The mean sensitivity for Ta, T1, >= T2, Tis, G1, G2, and G3 disease was 13.68%, 29.49%, 74.03%, 34.62%, 44.16%, 56.25%, and 67.34%, respectively. Conclusions: The NMP22 BladderChek test shows good discrimination ability for detecting bladder cancer and a high-specificity algorithm that can be used for early detection to rule out patients with higher bladder cancer risk. It also has better potential for screening higher-grade and higher-stage tumors, and better diagnostic performance in Asians. PMID- 29246010 TI - The efficacy and safety of different pharmacological interventions for patients with advanced biliary tract cancer: A network meta-analysis. AB - Biliary tract cancer (BTC) is the second common cancer in liver cancer. Chemotherapy is the mainstay of treatments for patients with advanced or metastatic disease, while fluorouracil (FU)-based and gemcitabine (GEM)-based treatments are most widely applied. This NMA aimed to figure out whether the addition of platinum (PLA) and target agents (TAR) can influence the efficacy and safety of standard chemotherapy. Network meta-analysis (NMA) was conducted based on the records from PubMed, Embase and Cochrane. Eligible data was extracted from available qualified trials and outcomes. Software R 3.2.3 and STATA 13.0 were used to conduct the Bayesian NMA, calculating odds ratios (ORs) and hazard ratios (HRs) with 95% credible interval (CrI) to evaluate different treatments.Almost all treatments were superior to best supportive care (BSC) and FU in terms of 1 OS, 2-OS and 1-PFS. GEM+PLA and GEM+PLA+TAR exhibited better efficacy than most treatments in 1-OS, 2-OS and 1-PFS, and yielded better results than BSC and GEM+FU in terms of 2-PFS. Most drug-containing treatments reported higher overall response rate (ORR) than BSC. GEM and GEM+FU were associated with a higher risk of neutropenia and thrombocytopenia compared to FU, FU+PLA and GEM+PLA. No statistical difference was detected in terms of nausea and vomiting.GEM+PLA and GEM+PLA+TAR were both efficacious and were associated with fewer adverse events. In conclusion, the addition of PLA can significantly improve the efficacy of FU and GEM-based treatments, and the addition of TAR to GEM+PLA can contribute to further improvement, but with a mild increase of adverse events. PMID- 29246011 TI - Network meta-analysis of the efficacy of first-line chemotherapy regimens in patients with advanced colorectal cancer. AB - This network meta-analysis compared the short-term and long-term efficacies of first-line chemotherapy regimens in patients with advanced colorectal cancer (CRC). The 10 regimens included folinic acid + 5-fluorouracil + oxaliplatin (FOLFOX), folinic acid + 5-fluorouracil + irinotecan (FOLFIRI), folinic acid + 5 fluorouracil + gemcitabine (FFG), folinic acid + 5-fluorouracil + trimetrexate (FFT), folinic acid + 5-fluorouracil (FF), irinotecan + oxaliplatin (IROX), raltitrexed + oxaliplatin (TOMOX), folinic acid + tegafur-uracil (FTU), raltitrexed, and capecitabine. Electronic searches were performed in the Cochrane Library, PubMed and Embase databases from inception to June 2017. Network meta analysis combined direct and indirect evidence to obtain odds ratios (ORs) and surface under the cumulative ranking curves (SUCRA) of different chemotherapy regimens for advanced CRC. Fourteen randomized controlled trails (RCTs) covering 4,383 patients with advanced CRC were included. The results revealed that FOLFOX, FOLFIRI, IROX, and TOMOX all showed higher overall response rates (ORRs) than FF or raltitrexed. Compared with raltitrexed, the aforementioned four regimens also had higher 1-year progression-free survival (PFS) rates. In addition, FOLFOX and FOLFIRI exhibited higher disease control rates (DCRs) and 1-year PFS rates than FF or raltitrexed. Cluster analysis revealed that FOLFOX, FOLFIRI, and TOMOX had better short-term and long-term efficacies. These findings suggest FOLFOX, FOLFIRI, and TOMOX are superior to other regimens for advanced CRC. These three regimens are therefore recommended for clinical treatment of advanced CRC. PMID- 29246012 TI - Characterization of the urinary microbiota of elderly women and the effects of type 2 diabetes and urinary tract infections on the microbiota. AB - Evidence shows that urine has complex bacterial profiles with considerable variation between individuals. Aging and age-related conditions can lead to the changes to the composition of urine, which means that the available nutrition for bacteria in the bladder changes with age. We explored the characteristics of the urinary microbiota of elderly women and whether these are associated with age related conditions such as diabetes and urinary tract infections. An elderly and a non-elderly cohort of women were included. Magnetic beads were used to isolate bacterial genomic DNA, which was analyzed based on the V3-V4 hypervariable region of the 16S rRNA gene. There were significant differences between the elderly and non-elderly regarding thirteen genera of bacteria. For example, the relative abundance of Lactobacillus was dramatically reduced in the elderly compared with the non-elderly; it also decreased with age in the elderly cohort and it was not correlated with urine pH. The relative abundance of Peptococcus increased with age in the elderly while the abundance of Bifidobacteria decreased with age. The abundance of Escherichia coli was the same in the two cohorts, and it increased with water intake and was not associated with urinary tract infection events. Higher levels of Lactobacillus (including Lactobacillus iners) in the elderly were associated with diabetes, and lower levels of Peptoniphilus and Dialister were correlated with asymptomatic bacteriuria. The urinary microbiota of women is affected by ageing, type 2 diabetes mellitus and asymtomatic bacteriuria. PMID- 29246013 TI - The protective effect of PFTalpha on alcohol-induced osteonecrosis of the femoral head. AB - Epidemiologic studies have shown alcohol plays a pivotal role in the development of osteonecrosis of the femoral head (ONFH). The aim of this study was to explore the underlying mechanism of alcohol-induced ONFH and the protective effect of pifithrin-alpha (PFTalpha). In vitro, we found ethanol treatment significantly activated p53, suppressed Wnt/beta-catenin signaling and inhibited osteogenic related proteins. Furthermore, by separating the cytoplasmic and nuclear proteins, we found ethanol inhibited osteogenesis by impairing the accumulation of beta-catenin in both the cytoplasm and nucleus in human bone mesenchymal stem cells (hBMSCs), which resulted from activating glycogen synthase kinase-3beta (GSK-3beta). Therefore, PFTalpha, a p53 inhibitor, was introduced in this study to block the ethanol-triggered activation of p53 in hBMSCs and alcohol-induced ONFH in a rat model. In vivo, we established alcohol-induced ONFH in rats and investigated the protective effect of PFTalpha. Hematoxylin & eosin (H&E) staining combined with TdT-mediated dUTP nick end labeling (TUNEL), cleaved caspase-3 immunohistochemical staining, and micro-CT images revealed substantial ONFH in the alcohol-administered rats, whereas significantly less osteonecrosis developed in the rats injected with PFTalpha. Osteogenic-related proteins, including osteocalcin, osteopontin and collagen I, were significantly decreased in the alcohol-administered rats, whereas these results were reversed in the PFTalpha-injected rats. Fluorochrome labeling similarly showed that alcohol significantly reduced the osteogenic activity in the rat femoral head, which was blocked by the injection of PFTalpha. In conclusion, PFTalpha had an antagonistic effect against the effects of ethanol on hBMSCs and could be a clinical strategy to prevent the development of alcohol-induced ONFH. PMID- 29246014 TI - Outcome of oligoprogressing metastatic renal cell carcinoma patients treated with locoregional therapy: a multicenter retrospective analysis. AB - Locoregional treatment with radical intent should be considered during therapy with targeted agents in patients with metastatic renal cell carcinoma (mRCC) in order to achieve a complete response, especially in the setting of an oligo progression in one or more metastatic sites. We retrospectively enrolled 55 patients who experienced a disease oligo-progression after at least 6 months from the beginning of first-line therapy in one or more metastatic sites radically treated with locoregional treatments. Post-first-oligo-progression overall survival (PFOPOS) and post-first-oligo-progression free survival (PFOPFS) were evaluated. The global median PFOPOS and PFOPFS were 37 months and 14 months respectively. Patients who continued the same therapy after a locoregional treatment on a site of progression had a significantly longer mPFOPOS compared to patients who changed therapy (39 vs 11 months, p=0.014). An advantage in mPFOPOS was also observed in patients with a Memorial Sloan-Kettering Cancer Center (MSKCC) good risk score compared to patients of the intermediate risk group (39 vs 29 months, p=0.036); patients with bone metastases had a longer mPFOPOS compared to those with visceral metastases (not reached vs 31 months, p=0.045). The only independent predictor of poor prognosis, in terms of PFOPOS at multivariate analysis (p=0.007), proved out to be change of treatment after first progression. In this paper we aim to illustrate that continuing the same systemic therapy, after a radical locoregional treatment on a site of progression, seems to be associated with a prolongation of mPFOPOS. PMID- 29246016 TI - Optimal treatment strategies for clinically suspicious lateral pelvic lymph node metastasis in rectal cancer. AB - Background: Although lateral pelvic lymph node (LPN) metastasis is a major cause of local recurrence in patients with rectal cancer, controversy still remains on the treatment of suspected LPN metastasis, "suspicious LPN". We aimed to determine the optimal treatment strategies for suspicious LPN, in patients with locally advanced rectal cancer who underwent preoperative chemoradiotherapy (CRT). Materials and Methods: Of 377 patients who received preoperative CRT for rectal cancer between 2006 and 2013, 84 (22.3%) had suspicious LPNs on pretreatment MRI. Patients' characteristics, MRI findings, operative and pathologic findings, and oncologic outcomes were analyzed retrospectively. Results: Of 84 patients with suspicious LPNs, 61 showed good response to CRT on posttreatment MRI (short-axis LPN diameter < 5 mm). Among them, 31 patients underwent TME alone (group A), and 30 underwent TME plus LPND (group B). The remaining 23 patients had persistently suspicious LPNs on post-CRT MRI and underwent TME plus LPND (group C). Pathologic LPN metastasis was confirmed in five patients (16.7%) in group B and 15 (62.5%) in group C. Local recurrence developed in 7 (22.6%), 0 (0%), and 4 (17.4%) patients in groups A, B, and C, respectively. Five patients (16.1%) in group A developed in situ LPN recurrences. The 3-year disease-free survival rates were 53.7%, 74.2%, and 46.9% in groups A, B, and C, respectively. Conclusions: Study findings suggested that LPND cannot be omitted for patients with suspicious LPNs on pretreatment MRI even with good response to CRT. Findings from pretreatment MRI should be considered to determine whether LPND is indicated. PMID- 29246015 TI - Congenital heart defects of fetus after maternal exposure to organic and inorganic environmental factors: a cohort study. AB - Objective: Maternal exposure to various contaminants has been reported to be correlated with congetinal heart defects (CHDs). In this study, the effect of maternal exposure to organic and inorganic environmental factors upon the incidence of CHDs was investigated. We conducted a retrospective birth cohort study of infants born in the Maternal and Child Health Hospital of Panyu District in Guangzhou. Materials and Methods: A total of 5381 cases with complete medical records, including mothers, fathers, and infants, were enrolled. The relationship between maternal occupational exposure to hazardous substances and strong noise during pregnancy and CHDs was analyzed. Occupational exposure to hazardous substances increased the incidence of CHDs. Results: Forty-eight of 145 mothers (33.1%) in the CHDs group worked in hazardous and strong noise factories, while the corresponding percentage mothers in the control group was 22.8% (1193/5236). The percentage of mothers with a history of contact with organic solvents and exposure to strong noise in the CHDs group was significantly higher than the control group. There was no significant difference in the histories of contact with heavy metals, high temperatures, and other extreme environments between two groups. Conclusions: Hazardous substances in factories, especially organic solvents, were identified as potential risk factors for CHDs. Besides, exposure to high noise also increased the incidence of CHDs. PMID- 29246017 TI - Efficacy and safety of apatinib combined with transarterial chemoembolization for hepatocellular carcinoma with portal venous tumor thrombus: a retrospective study. AB - Objective: To investigate the efficacy and safety of combined therapy with apatinib and transarterial chemoembolization (TACE) for hepatocellular carcinoma with portal venous tumor thrombus (PVTT). Materials and Methods: We retrospectively analyzed 19 patients with hepatocellular carcinoma with PVTT who were treated with apatinib and TACE at a single center between January 2015 and January 2017. Clinical information on the patients was collected. Adverse events, overall survival, progression-free survival, objective response rate, and disease control rate based on mRECIST criteria (American Association for the Study of Liver Diseases, 2008) were reviewed and evaluated. Results: All patients had complete follow-up records and the median follow-up time was 13 months (1-24 months). Among the 19 patients, 63.16% achieved a partial response and 21.05% achieved stable disease. The objective response and disease-control rates for the tumor were 63.16% and 84.21%, respectively, and the objective response and disease-control rates for PVTT were 10.93% and 89.47%, respectively. The median overall survival was 11.9 months, and the 6-month and 1-year overall survival rates were 94.7% and 48.8%, respectively. The median progression-free survival rate was 8.1 months, and the 6-month and 1-year rates were 73.3% and 22.9%, respectively. The most common apatinib-related adverse events were hand-foot-skin reaction, fatigue, dyspepsia, diarrhea, and hypertension, and the most common TACE-related adverse event was fever. No procedure-related mortality or grade 4 adverse events were observed, but grade 3 adverse events were observed in two patients. Conclusions: This exploratory study suggested that apatinib combined with TACE treatment was safe and might improve overall and progression-free survival in patients with hepatocellular carcinoma with PVTT. Further randomized controlled trials are needed to clarify the potential role of apatinib in hepatocellular carcinoma with PVTT. PMID- 29246018 TI - Preoperative radiotherapy for patients with rectal cancer: a risk factor for non reversal of ileostomy caused by stenosis or stiffness proximal to colorectal anastomosis. AB - The influence of radiotherapy on permanent stoma and the bowel proximal to anastomosis was not well investigated. The current study aimed to analyze the effect of preoperative radiotherapy on colorectal anastomosis and incidence of non-reversal ileostomy. A total of 184 eligible patients with rectal cancer undergoing loop ileostomy were included. Patients were well selected by excluding some confounding factors and divided into two groups according to whether they received preoperative radiotherapy. Patients with preoperative radiotherapy had higher incidence of non-reversal stoma (12.8%, P = 0.004) and stenosis or stiffness around anastomosis (21.1%, P < 0.01) including 13 patients with stenosis or stiffness proximal to anastomosis. Stenosis proximal to anastomosis was different from anastomotic stricture caused by surgery and could be described by imaging findings. Preoperative radiotherapy prolonged the interval to closure (P = 0.008) and was defined as a significant risk factor for permanent stoma (HR, 0.627; 95% CI, 0.405-0.973; P = 0.04) by multivariate Cox regression analysis. In conclusion, Preoperative radiotherapy increased incidence of non-reversal ileostomy and stenosis or stiffness proximal to anastomosis in rectal cancer patients with radical resection and diverting ileostomy. PMID- 29246019 TI - Clinicopathological and genetic characteristics of pulmonary large cell carcinoma under 2015 WHO classification: a pilot study. AB - Pulmonary large cell carcinoma (LCC) was re-defined under the 2015 WHO classification criteria. However, the clinicopathological features and genetic mutation statuses of Chinese LCC patients based on the new classification have rarely been investigated. Twenty-four Chinese surgically resected LCC patients previously diagnosed under the 2004 WHO criteria were re-classified under the 2015 WHO criteria. Genetic analysis was performed using next-generation sequencing of 46 cancer-related genes. The correlation of clinicopathological and genetic data was further analyzed. Eight patients were re-defined as LCCs, and 16 patients were defined as non-LCCs under the refined criteria. All LCC patients were male, and 7 patients were smokers. No significant differences in age, gender, smoking status, primary site, TNM staging and overall survival were observed between the LCC and non-LCC patients under the refined criteria. Four of the 8 LCC patients presented TP53 mutations, and no somatic mutations were detected in the other 4 LCCs under the refined criteria. For the 16 non-LCCs, not only TP53 and KRAS but also EGFR, KIT, PIK3CA, PTEN, IDH1, APC, ATM and BRAF mutations were also observed. In addition, LCCs without TP53 mutations did not present any gene mutations under the 2004 or 2015 WHO criteria. Importantly, the patients with TP53 mutation exhibited a trend with a worse survival outcome at the time of follow-up. The new WHO diagnosis criteria have superior performance in precise molecular classification for LCC patients. PMID- 29246020 TI - Neoadjuvant chemotherapy with different dose regimens of docetaxel, cisplatin and fluorouracil (TPF) for locoregionally advanced nasopharyngeal carcinoma: a retrospective study. AB - Objective: Compare high- vs. low-dose TPF neoadjuvant chemotherapy with chemoradiotherapy in Chinese patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Materials and Methods: Retrospective analysis of 210 stage III/IV NPC patients treated between April 1, 2012 and April 1, 2014; 138 received three cycles of high-dose TPF (H-TPF) every 3 weeks at Zhejiang Cancer Hospital and 72, three cycles of low-dose TPF (L-TPF) every 3 weeks at Sun Yat-Sen University Cancer Center. H-TPF was docetaxel (75 mg/m2; 1 h infusion), cisplatin (75 mg/m2; 0.5-3 h), then 5-fluorouracil (600 mg/m2/day; 4 days). L-TPF was docetaxel (60 mg/m2), cisplatin (65 mg/m2), then 5-fluorouracil (550 mg/m2/day; 5 days). All patients received chemoradiotherapy. Results: During neoadjuvant chemotherapy, treatment delays were more frequent for H-TPF than L-TPF (33.3% vs. 19.4%; P = 0.034). During chemoradiotherapy, grade III-IV anemia, thrombocytopenia and neutropenia were more common for H-TPF than L-TPF (P < 0.001, P < 0.001, P = 0.048). Fewer patients in the H-TPF group finished two cycles of concurrent chemotherapy (81.2% vs. 100%, P < 0.001). Three-year PFS (84.5% vs. 80.6%, P = 0.484) and OS (91.1% vs. 93.5%, P = 0.542) were not significantly different between H-TPF and L-TPF. Conclusions: L-TPF neoadjuvant chemotherapy has substantially better tolerance and compliance rates and similar treatment efficacy to H-TPF neoadjuvant chemotherapy in locoregionally-advanced NPC. PMID- 29246021 TI - Ovarian stimulated cycle: not a better alternative for women without ovulation disorder in intrauterine insemination. AB - To explore the related factors on the clinical pregnancy outcome in intrauterine insemination, a retrospective study was conducted on the clinical data of 580 cycles for 301 infertile couples who were treated with intrauterine insemination. The female age, male age, duration of infertility, treatment protocols, endometrial thickness and sperm parameters were compared between pregnant group and non-pregnant group. The results showed that there were statistical differences in female age, duration of infertility and endometrial thickness between the two groups. The pregnancy rate was 19.34% in Group A (female age <= 30 y) compared with 10.91% in Group B (female age > 30 y). The pregnancy rate was 18.44% when the duration of infertility <= 2 years, which was higher than another group 10.73% when the duration of infertility > 2 years. Group analysis according to endometrial thickness (Group1: < 8 mm; Group 2: >= 8 mm and <= 12 mm; Group 3: > 12 mm) demonstrated significant differences in clinical pregnancy rate (7.41%, 18.00% and 11.48% respectively). For those infertile female without ovulation failure, the higher clinical pregnancy rates were observed in patients undergoing intrauterine insemination in natural cycle 16.12% when compared with the patients in ovarian stimulated cycles 10.48%. Thus, we demonstrate that the pregnancy rate is related with female age, duration of infertility and endometrial thickness. The ovarian stimulated cycle couldn't improve the pregnancy outcome for those women without ovulation disorder in intrauterine insemination. PMID- 29246022 TI - Tumor-derived exosomes in colorectal cancer progression and their clinical applications. AB - Colorectal cancer (CRC) ranks as the third leading cause of cancer mortality in both of men and women worldwide due to its metastatic properties and resistance to current treatment. Recent studies have shown that tumor-derived exosomes play emerging roles in the development of cancer. Exosomes are nano-sized extracellular vesicles (EVs) that contain lipids, proteins, DNAs, and RNA species (mRNA, miRNA, long non-coding RNA). These exosomal cargos can be transferred locally and systemically, after taken by recipient cells, so exosomes represent a new form of intercellular communication. There is increasing evidence demonstrating that exosomes control a wide range of pathways bolstering tumor development, metastasis and drug resistance. This review provides an in-depth and timely summary of the role of exosomes in CRC. We first describe the common features and biogenesis of exosomes. We then highlight important findings that support the emerging roles of exosomes in CRC cell growth, invasion and metastasis, as well as resistance to treatment. Finally, we discuss the clinical application of exosomes as diagnostic biomarkers, in vivo drug delivery system and the potential of novel exosome-based immunotherapy for CRC. PMID- 29246023 TI - Does primary tumor location impact the prognosis of colorectal liver metastases patients after microwave ablation? - Lessons from 10 years' experience. AB - Thermal ablation has been considered as an alternative for local curative intent in patients with unresectable colorectal liver metastases. The influence of primary tumor location on the prognosis of colorectal liver metastases patients who have undergone microwave ablation has yet to be determined. We reviewed 295 patients who underwent microwave ablation for colorectal liver metastases at our institution between March 2006 and March 2016. Univariate and multivariate analyses were performed to identify predictors of overall and progression-free survival. Technical success was achieved in 96.6% of patients (n = 289), with a post-procedural complication rate of 2.0% (n = 6). After a median follow-up of 24 (range, 2-86) months, comparable overall survival rates (p = 0.583) were observed in patients with different primary tumor locations. Patients with colorectal liver metastases originating from left-sided primary colon cancer exhibited a better progression-free survival than patients whose colorectal liver metastases had originated from right-sided primary colon cancer (hazard ratio: 0.67, 95.0% confidence interval: 0.48-0.94; p = 0.012), which was further confirmed in a multivariate analysis after adjustment for other potential prognostic factors. Stratification based on primary tumor location should be taken into consideration in the assessment of disease progression in patients who intend to undergo microwave ablation for colorectal liver metastases. PMID- 29246024 TI - Comparison of cross-platform technologies for EGFR T790M testing in patients with non-small cell lung cancer. AB - Somatic mutations in the gene encoding epidermal growth factor receptor (EGFR) play an important role in determining targeted treatment modalities in non-small cell lung cancer (NSCLC). The EGFR T790M mutation emerges in approximately 50% of cases who acquire resistance to tyrosine kinase inhibitors. Detecting EGFR T790M mutation in tumor tissue is challenging due to heterogeneity of the tumor, low abundance of the mutation and difficulty for re-biopsy in patients with advanced disease. Alternatively, circulating tumor DNA (ctDNA) has been proposed as a non invasive method for mutational analysis. The presence of EGFR mutations in ctDNA predicts response to the EGFR TKIs in the first-line setting. Molecular testing is now considered a standard care for NSCLC. The advent of standard commercially available kits and targeted mutational analysis has revolutionized the accuracy of mutation detection platforms for detection of EGFR mutations. Our review provides an overview of various commonly used platforms for detecting EGFR T790M mutation in tumor tissue and plasma. PMID- 29246025 TI - miRNA and lncRNA as biomarkers in cholangiocarcinoma(CCA). AB - The microRNAs are a group of 20 nucleotides-long non-coding RNAs. By binding to the 3'UTR region of target mRNA, microRNAs can perform extensive actions mediating gene expression at post-trancriptional stages. It makes microRNAs serve as very crucial regulators in various biological progress including carcinogenesis. Long non-coding RNAs, however, are a subgroup of RNA with the length of 200 nucleotides. Unlike microRNAs, long non-coding RNAs can form secondary of tertiary domain based on their length. With the ability of directly interacting with DNA, RNA, protein, long non-coding RNAs have promoting or inhibitive functions in gene expression regulation. Furthermore, the abnormal expression of certain long non-coding RNAs has roused people's interest in the role of long non-coding RNAs in tumorigenesis. Although the connection between microRNA/long non-coding RNA and CCA has been a hot field to researchers, the link between molecular mechanism and clinical outcome has been barely built. This review takes a retrospect at the latest researches on the link between microRNA/long non-coding RNA and cholangiocarcinoma and the potential of microRNA/long non-coding RNA serving as distinctive biomarkers for CCA in clinical practice. PMID- 29246027 TI - Recent advances on uric acid transporters. AB - Uric acid is the product of purine metabolism and its increased levels result in hyperuricemia. A number of epidemiological reports link hyperuricemia with multiple disorders, such as kidney diseases, cardiovascular diseases and diabetes. Recent studies also showed that expression and functional changes of urate transporters are associated with hyperuricemia. Uric acid transporters are divided into two categories: urate reabsorption transporters, including urate anion transporter 1 (URAT1), organic anion transporter 4 (OAT4) and glucose transporter 9 (GLUT9), and urate excretion transporetrs, including OAT1, OAT3, urate transporter (UAT), multidrug resistance protein 4 (MRP4/ABCC4), ABCG-2 and sodium-dependent phosphate transport protein. In the kidney, uric acid transporters decrease the reabsorption of urate and increase its secretion. These transporters' dysfunction would lead to hyperuricemia. As the function of urate transporters is important to control the level of serum uric acid, studies on the functional role of uric acid transporter may provide a new strategy to treat hyperuricemia associated diseases, such as gout, chronic kidney disease, hyperlipidemia, hypertension, coronary heart disease, diabetes and other disorders. This review article summarizes the physiology of urate reabsorption and excretion transporters and highlights the recent advances on their roles in hyperuricemia and various diseases. PMID- 29246026 TI - Circulating biomarkers in osteosarcoma: new translational tools for diagnosis and treatment. AB - Osteosarcoma (OS) is a rare primary malignant bone tumour arising from primitive bone-forming mesenchymal cells, with high incidence in children and young adults, accounting for approximately 60% of all malignant bone tumours. Currently, long term disease-free survival can be achieved by surgical treatment plus chemotherapy in approximately 60% of patients with localized extremity disease, and in 20-30% of patients with metastatic lung or bone disease. Diagnosis of primary lesions and recurrences is achieved by using radiological investigations and standard tissue biopsy, the latter being costly, painful and hardly repeatable for patients. Therefore, despite some recent advances, novel biomarkers for OS diagnosis, prediction of response to therapy, disease progression and chemoresistance, are urgently needed. Biological fluids such as blood represent a rich source of non-invasive cancer biomarkers, which allow to understand what is really happening inside the tumour, either at diagnosis or during disease progression. In this regard, liquid biopsy potentially represents an alternative and non-invasive method to detect tumour onset, progression and response to therapy. In this review, we will summarize the state of the art in this novel area, illustrating recent studies on OS. Although the data reported in literature seem preliminary, liquid biopsy represents a promising tool with the potential to be rapidly translated in the clinical practice. PMID- 29246029 TI - The role of microbiota in the pathogenesis of schizophrenia and major depressive disorder and the possibility of targeting microbiota as a treatment option. AB - The importance of interactions between the brain and the gastrointestinal tract has been increasingly recognized in recent years. It has been proposed that dysregulation and abnormalities in the brain-gut axis contribute to the etiology of a variety of central nervous system disorders. Particularly, dysbiosis, or impaired microbiota, has been implicated in multiple neurological and psychological disorders. The present paper reviews current evidence and theories concerning the possible mechanisms by which microbiota dysfunction contributes to the pathogenesis of schizophrenia and major depressive disorder. Clinical trials that investigated the possibility of treating both illnesses by correcting and rebalancing microbiota with probiotics are also reviewed. Overall, despite the accumulated knowledge in this field, more studies are warranted and required to further our understanding of the brain-gut axis and the possibility of targeting microbiota as a treatment option for schizophrenia and major depressive disorder. PMID- 29246028 TI - Challenges and future of biomarker tests in the era of precision oncology: Can we rely on immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to select the optimal patients for matched therapy? AB - Molecular techniques have improved our understanding of the pathogenesis of cancer development. These techniques have also fueled the rational development of targeted drugs for patient populations stratified by their genetic characteristics. These novel methods have changed the classic paradigm of diagnostic pathology; among them are IHC, FISH, polymerase chain reaction (PCR) and microarray technology. IHC and FISH detection methods for human epidermal growth factor receptor-2 (HER2), epidermal growth factor receptor (EGFR) and programmed death ligand-1 (PD-L1) were recently approved by the Food and Drug Administration (FDA) as routine clinical practice for cancer patients. Here, we discuss general challenges related to the predictive power of these molecular biomarkers for targeted therapy in cancer medicine. We will also discuss the prospects of utilizing new biomarkers for fibroblast growth factor receptor (FGFR) and hepatocyte growth factor receptor (cMET/MET) targeted therapies for developing new and robust predictive biomarkers in oncology. PMID- 29246033 TI - Quantifying Macroscopic Friction of Diamond-like Carbon Films by Microscopic Adsorption and Removal of Water Molecules. AB - The adsorption and desorption of water molecules, which affect the physical and chemical properties of the sliding interface, are critical for the friction behaviors of two solid contacts in atmosphere environment. The amount of water adsorbed on the open surface is a function of gas pressure according to an adsorption equation. However, for a confined sliding interface, the variation of surface fraction covered by gas molecules with water vapor pressure and its induced effects on friction have not been figured out. In this work, the macroscopic friction of diamond-like carbon (DLC) films in a water vapor atmosphere is quantified on the basis of microscopic adsorption and removal of water molecules. The studies correlate the fraction of water molecules adsorbed on the interface of self-mated DLC films with water vapor pressure to illustrate the direct relationship between friction coefficient and gas pressure by first principles calculations and model fitting. The calculated results revealed that chemisorption and physisorption of water molecules occur on the surfaces of hydrogen-free DLC films (ta-C) and hydrogenated DLC films (HCF). Then, the relation between friction and gas pressure was built by employing a fractional coverage model based on the linear adsorption equation and gas removal. The obtained model agrees well with the typical experimental results about the steady state friction coefficient of both highly hydrogenated DLC film (HCF) and tetrahedral amorphous carbon (ta-C) film during sliding at various water vapor pressures. In addition, it gave the curves of fractional surface coverage as a function of water vapor pressure. These results show that the frictional coefficient of DLC films could be predicted on the basis of fractional surface coverage as well as the intrinsic characters on surface chemistry. We suggest that the model may be thus extended to understand and predict the friction of DLC films under a specific gas pressure at a low load and speed. PMID- 29246032 TI - A rare case of esophageal metastasis from pancreatic ductal adenocarcinoma: a case report and literature review. AB - Purpose: We report a very unique case of an esophageal metastasis from a pancreatic ductal adenocarcinoma (PDAC) primary. Methods: After obtaining consent from the patient, all relevant records of the case were obtained and retrospectively reviewed. Results: At presentation, the patient was diagnosed with synchronous pancreatic and esophageal cancer. He received six months of neoadjuvant therapy including FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) and stereotactic body radiation therapy (SBRT) to the pancreatic tumor followed by a combined pancreaticoduodenectomy and Ivor Lewis esophagectomy. Review of the final esophageal specimen revealed normal overlying squamous mucosa with an underlying focus of metastatic PDAC. The patient remains alive with no evidence of disease 17 months from surgery and 25 months from diagnosis. Conclusions: Differentiating an esophageal metastasis from a PDAC primary versus a synchronous esophageal carcinoma is very difficult despite state of-the-art diagnostic techniques performed at a high-volume tertiary cancer center. Extensive evaluation and continued follow-up of PDAC patients presenting with a synchronous esophageal lesion in a multidisciplinary setting may help ensure efficient and accurate management. In our case, neoadjuvant FOLFIRINOX and SBRT to the primary PDAC tumor followed by surgery has been an effective approach for this patient. PMID- 29246034 TI - Editorial: In Focus Issue on Bacterial-Surface Interactions. PMID- 29246031 TI - A molecular view of the radioresistance of gliomas. AB - Gliomas originate from glial cells and are the most frequent primary brain tumors. High-grade gliomas occur ~4 times more frequently than low-grade gliomas, are highly malignant, and have extremely poor prognosis. Radiotherapy, sometimes combined with chemotherapy, is considered the treatment of choice for gliomas and is used after resective surgery. Despite great technological improvements, the radiotherapeutic effect is generally limited, due to the marked radioresistance exhibited by gliomas cells, especially glioma stem cells (GSCs). The mechanisms underlying this phenomenon are multiple and remain to be fully elucidated. This review attempts to summarize current knowledge on the molecular basis of glioma radioresistance by focusing on signaling pathways, microRNAs, hypoxia, the brain microenvironment, and GSCs. A thorough understanding of the complex interactions between molecular, cellular, and environmental factors should provide new insight into the intrinsic radioresistance of gliomas, potentially enabling improvement, through novel concurrent therapies, of the clinical efficacy of radiotherapy. PMID- 29246030 TI - Venom-based peptide therapy: insights into anti-cancer mechanism. AB - The 5-year relative survival rate of all types of cancer has increased significantly over the past three decades partly due to the targeted therapy. However, still there are many targeted therapy drugs could play a role only in a portion of cancer patients with specific molecular alternation. It is necessary to continue to develop new biological agents which could be used alone and/or in combination with current FDA approved drugs to treat complex cancer diseases. Venom-based drugs have been used for hundreds of years in human history. Nevertheless, the venom-origin of the anti-cancer drug do rarely appear in the pharmaceutical market; and this is due to the fact that the mechanism of action for a large number of the venom drug such as venom-based peptide is not clearly understood. In this review, we focus on discussing some identified venom-based peptides and their anti-cancer mechanisms including the blockade of cancer cell proliferation, invasion, angiogenesis, and metastasis (hallmarks of cancer) to fulfill the gap which is hindering their use in cancer therapy. Furthermore, it also highlights the importance of immunotherapy based on venom peptide. Overall, this review provides readers for further understanding the mechanism of venom peptide and elaborates on the need to explore peptide-based therapeutic strategies. PMID- 29246035 TI - Enhancing cell and gene therapy manufacture through the application of advanced fluorescent optical sensors (Review). AB - Cell and gene therapies (CGTs) are examples of future therapeutics that can be used to cure or alleviate the symptoms of disease, by repairing damaged tissue or reprogramming defective genetic information. However, despite the recent advancements in clinical trial outcomes, the path to wide-scale adoption of CGTs remains challenging, such that the emergence of a "blockbuster" therapy has so far proved elusive. Manufacturing solutions for these therapies require the application of scalable and replicable cell manufacturing techniques, which differ markedly from the existing pharmaceutical incumbent. Attempts to adopt this pharmaceutical model for CGT manufacture have largely proved unsuccessful. The most significant challenges facing CGT manufacturing are process analytical testing and quality control. These procedures would greatly benefit from improved sensory technologies that allow direct measurement of critical quality attributes, such as pH, oxygen, lactate and glucose. In turn, this would make manufacturing more robust, replicable and standardized. In this review, the present-day state and prospects of CGT manufacturing are discussed. In particular, the authors highlight the role of fluorescent optical sensors, focusing on their strengths and weaknesses, for CGT manufacture. The review concludes by discussing how the integration of CGT manufacture and fluorescent optical sensors could augment future bioprocessing approaches. PMID- 29246037 TI - Generalization of the swelling method to measure the intrinsic curvature of lipids. AB - Via computer simulation of a coarse-grained model of two-component lipid bilayers, we compare two methods of measuring the intrinsic curvatures of the constituting monolayers. The first one is a generalization of the swelling method that, in addition to the assumption that the spontaneous curvature linearly depends on the composition of the lipid mixture, incorporates contributions from its elastic energy. The second method measures the effective curvature composition coupling between the apposing leaflets of bilayer structures (planar bilayers or cylindrical tethers) to extract the spontaneous curvature. Our findings demonstrate that both methods yield consistent results. However, we highlight that the two-leaflet structure inherent to the latter method has the advantage of allowing measurements for mixed lipid systems up to their critical point of demixing as well as in the regime of high concentration (of either species). PMID- 29246036 TI - Cholesteric and screw-like nematic phases in systems of helical particles. AB - Recent numerical simulations of hard helical particle systems unveiled the existence of a novel chiral nematic phase, termed screw-like, characterised by the helical organization of the particle C2 symmetry axes round the nematic director with periodicity equal to the particle pitch. This phase forms at high density and can follow a less dense uniform nematic phase, with relative occurrence of the two phases depending on the helix morphology. Since these numerical simulations were conducted under three-dimensional periodic boundary conditions, two questions could remain open. First, the real nature of the lower density nematic phase, expected to be cholesteric. Second, the influence that the latter, once allowed to form, may have on the existence and stability of the screw-like nematic phase. To address these questions, we have performed Monte Carlo and molecular dynamics numerical simulations of helical particle systems confined between two parallel repulsive walls. We have found that the removal of the periodicity constraint along one direction allows a relatively-long-pitch cholesteric phase to form, in lieu of the uniform nematic phase, with helical axis perpendicular to the walls while the existence and stability of the screw like nematic phase are not appreciably affected by this change of boundary conditions. PMID- 29246038 TI - Molecular modeling of the microstructure evolution during carbon fiber processing. AB - The rational design of carbon fibers with desired properties requires quantitative relationships between the processing conditions, microstructure, and resulting properties. We developed a molecular model that combines kinetic Monte Carlo and molecular dynamics techniques to predict the microstructure evolution during the processes of carbonization and graphitization of polyacrylonitrile (PAN)-based carbon fibers. The model accurately predicts the cross-sectional microstructure of the fibers with the molecular structure of the stabilized PAN fibers and physics-based chemical reaction rates as the only inputs. The resulting structures exhibit key features observed in electron microcopy studies such as curved graphitic sheets and hairpin structures. In addition, computed X ray diffraction patterns are in good agreement with experiments. We predict the transverse moduli of the resulting fibers between 1 GPa and 5 GPa, in good agreement with experimental results for high modulus fibers and slightly lower than those of high-strength fibers. The transverse modulus is governed by sliding between graphitic sheets, and the relatively low value for the predicted microstructures can be attributed to their perfect longitudinal texture. Finally, the simulations provide insight into the relationships between chemical kinetics and the final microstructure; we observe that high reaction rates result in porous structures with lower moduli. PMID- 29246039 TI - Computation of forces arising from the polarizable continuum model within the domain-decomposition paradigm. AB - The domain-decomposition (dd) paradigm, originally introduced for the conductor like screening model, has been recently extended to the dielectric Polarizable Continuum Model (PCM), resulting in the ddPCM method. We present here a complete derivation of the analytical derivatives of the ddPCM energy with respect to the positions of the solute's atoms and discuss their efficient implementation. As it is the case for the energy, we observe a quadratic scaling, which is discussed and demonstrated with numerical tests. PMID- 29246040 TI - Low-temperature binding of NO adsorbed on MIL-100(Al)-A case study for the application of high resolution pulsed EPR methods and DFT calculations. AB - The low-temperature binding of nitric oxide (NO) in the metal-organic framework MIL-100(Al) has been investigated by pulsed electron nuclear double resonance and hyperfine sublevel correlation spectroscopy. Three NO adsorption species have been identified. Among them, one species has been verified experimentally to bind directly to an 27Al atom and all its relevant 14N and 27Al hyperfine interaction parameters have been determined spectroscopically. Those parameters fit well to the calculated ones of a theoretical cluster model, which was derived by density functional theory (DFT) in the present work and describes the low temperature binding of NO to the regular coordinatively unsaturated Al3+ site of the MIL 100(Al) structure. As a result, the Lewis acidity of that site has been characterized using the NO molecule as an electron paramagnetic resonance active probe. The DFT derived wave function analysis revealed a bent end-on coordination of the NO molecule adsorbed at that site which is almost purely ionic and has a weak binding energy. The calculated flat potential energy surface of this species indicates the ability of the NO molecule to freely rotate at intermediate temperatures while it is still binding to the Al3+ site. For the other two NO adsorption species, no structural models could be derived, but one of them is indicated to be adsorbed at the organic part of the metal-organic framework. Hyperfine interactions with protons, weakly coupled to the observed NO adsorption species, have also been measured by pulsed electron paramagnetic resonance and found to be consistent with their attribution to protons of the MIL-100(Al) benzenetricarboxylate ligand molecules. PMID- 29246041 TI - Testing the mutual information expansion of entropy with multivariate Gaussian distributions. AB - The mutual information expansion (MIE) represents an approximation of the configurational entropy in terms of low-dimensional integrals. It is frequently employed to compute entropies from simulation data of large systems, such as macromolecules, for which brute-force evaluation of the full configurational integral is intractable. Here, we test the validity of MIE for systems consisting of more than m = 100 degrees of freedom (dofs). The dofs are distributed according to multivariate Gaussian distributions which were generated from protein structures using a variant of the anisotropic network model. For the Gaussian distributions, we have semi-analytical access to the configurational entropy as well as to all contributions of MIE. This allows us to accurately assess the validity of MIE for different situations. We find that MIE diverges for systems containing long-range correlations which means that the error of consecutive MIE approximations grows with the truncation order n for all tractable n ? m. This fact implies severe limitations on the applicability of MIE, which are discussed in the article. For systems with correlations that decay exponentially with distance, MIE represents an asymptotic expansion of entropy, where the first successive MIE approximations approach the exact entropy, while MIE also diverges for larger orders. In this case, MIE serves as a useful entropy expansion when truncated up to a specific truncation order which depends on the correlation length of the system. PMID- 29246042 TI - Transport coefficients of helium-neon mixtures at low density computed from ab initio potentials. AB - The viscosity, thermal conductivity, diffusion coefficient, and thermal diffusion factor of helium-neon mixtures at low density are calculated for a wide range of temperature and for various molar fractions. The Chapman-Enskog method is employed considering the 10th order of the Sonine polynomial expansion. Ab initio potentials for intermolecular interactions are used to calculate the omega integrals. The relative numerical error of the present results obtained for the potentials used here is less than 7 * 10-5 for the thermal diffusion factor and 2 * 10-5 for all the other coefficients. Since each employed potential has a different accuracy, the uncertainty related to such accuracies was analyzed, considering the contribution of each potential uncertainty. It was found that the total uncertainty due to the potentials is larger than the numerical error and it varies depending on the temperature and molar fraction. A comparison of the calculated transport coefficients with those available in the open literature shows that the present calculations provide the most accurate values currently available for the transport coefficients of helium-neon binary mixtures at low density. PMID- 29246043 TI - Hierarchical bounding structures for efficient virial computations: Towards a realistic molecular description of cholesterics. AB - We detail the application of bounding volume hierarchies to accelerate second virial evaluations for arbitrary complex particles interacting through hard and soft finite-range potentials. This procedure, based on the construction of neighbour lists through the combined use of recursive atom-decomposition techniques and binary overlap search schemes, is shown to scale sub logarithmically with particle resolution in the case of molecular systems with high aspect ratios. Its implementation within an efficient numerical and theoretical framework based on classical density functional theory enables us to investigate the cholesteric self-assembly of a wide range of experimentally relevant particle models. We illustrate the method through the determination of the cholesteric behavior of hard, structurally resolved twisted cuboids, and report quantitative evidence of the long-predicted phase handedness inversion with increasing particle thread angles near the phenomenological threshold value of 45 degrees . Our results further highlight the complex relationship between microscopic structure and helical twisting power in such model systems, which may be attributed to subtle geometric variations of their chiral excluded-volume manifold. PMID- 29246044 TI - Quantum control of coherent pi-electron ring currents in polycyclic aromatic hydrocarbons. AB - We present results for quantum optimal control (QOC) of the coherent pi electron ring currents in polycyclic aromatic hydrocarbons (PAHs). Since PAHs consist of a number of condensed benzene rings, in principle, there exist various coherent ring patterns. These include the ring current localized to a designated benzene ring, the perimeter ring current that flows along the edge of the PAH, and the middle ring current of PAHs having an odd number of benzene rings such as anthracene. In the present QOC treatment, the best target wavefunction for generation of the ring current through a designated path is determined by a Lagrange multiplier method. The target function is integrated into the ordinary QOC theory. To demonstrate the applicability of the QOC procedure, we took naphthalene and anthracene as the simplest examples of linear PAHs. The mechanisms of ring current generation were clarified by analyzing the temporal evolutions of the electronic excited states after coherent excitation by UV pulses or (UV+IR) pulses as well as those of electric fields of the optimal laser pulses. Time-dependent simulations of the perimeter ring current and middle ring current of anthracene, which are induced by analytical electric fields of UV pulsed lasers, were performed to reproduce the QOC results. PMID- 29246045 TI - Quantum confinement effects on electronic photomobilities at nanostructured semiconductor surfaces: Si(111) without and with adsorbed Ag clusters. AB - The conductivity of holes and electrons photoexcited in Si slabs is affected by the slab thickness and by adsorbates. The mobilities of those charged carriers depend on how many layers compose the slab, and this has important scientific and technical consequences for the understanding of photovoltaic materials. A previously developed general computational procedure combining density matrix and electronic band structure treatments has been applied to extensive calculations of mobilities of photoexcited electrons and holes at Si(111) nanostructured surfaces with varying slab thickness and for varying photon energies, to investigate the expected change in mobility magnitudes as the slab thickness is increased. Results have been obtained with and without adsorbed silver clusters for comparison of their optical and photovoltaic properties. Band states were generated using a modified ab initio density functional treatment with the PBE exchange and correlation density functionals and with periodic boundary conditions for large atomic supercells. An energy gap correction was applied to the unoccupied orbital energies of each band structure by running more accurate HSE hybrid functional calculations for a Si(111) slab. Photoexcited state populations for slabs with 6, 8, 10, and 12 layers were generated using a steady state reduced density matrix including dissipative effects due to energy exchange with excitons and phonons in the medium. Mobilities have been calculated from the derivatives of voltage-driven electronic energies with respect to electronic momentum, for each energy band and for the average over bands. Results show two clear trends: (a) adding Ag increases the hole photomobilities and (b) decreasing the slab thickness increases hole photomobilities. The increased hole populations in 6- and 8-layer systems and the large increase in hole mobility for these thinner slabs can be interpreted as a quantum confinement effect of hole orbitals. As the slab thickness increases to ten and twelve layers, the effect of silver adsorbates decreases leading to smaller relative enhancements to the conduction electron and hole mobilities, but the addition of the silver nanoclusters still increases the absorbance of light and the mobility of holes compared to their mobilities in the pure Si slabs. PMID- 29246046 TI - Resonance Raman excitation profiles of CdS in pure CdS and CdSe/CdS core/shell quantum dots: CdS-localized excitons. AB - Resonance Raman excitation profiles have been measured for the longitudinal optical phonon in two sizes of CdS quantum dots and in CdSe/CdS core/shell quantum dots. In pure CdS, the resonance Raman cross section for the fundamental transition is sharply peaked around the lowest-energy excitonic transition and becomes weaker with higher-energy excitation even though the absorbance continues to increase to higher energies. This effect, also observed in earlier studies of CdSe quantum dots, is attributed largely to interferences among multiple excitonic transitions contributing to the resonance Raman polarizability. No variation in exciton-phonon coupling strength with exciton energy is required to explain the decrease in the ratio of the Raman cross section to absorption cross section at shorter wavelengths. In core/shell structures, the CdSe phonons are relatively strong when exciting on resonance with the lower excitonic transitions, in which the hole is largely localized to the CdSe core, but become nearly undetectable at excitation wavelengths >0.6 eV above the lowest exciton, where both electrons and holes are largely localized in the CdS shell. The CdS phonon Raman cross section exhibits a maximum 0.6-0.7 eV above the lowest exciton and then decreases at higher energies for the same reasons as in pure CdS. PMID- 29246047 TI - Synthesis of complex organic molecules in simulated methane rich astrophysical ices. AB - It has been proposed that organic molecules required for life on earth may be formed by the radiation processing of molecular ices in space environments, e.g., within our solar system. Such processes can be studied in the laboratory with surface science analytical techniques and by using low-energy electron (LEE) irradiation to simulate the effects of the secondary electrons that are generated in great abundance whenever ionizing radiation interacts with matter. Here we present new measurements of 70 eV LEE irradiation of multilayer films of CH4, 18O2, and CH4/18O2 mixtures (3:1 ratio) at 22 K. The electron stimulated desorption (ESD) yields of cations and anions have been recorded as a function of electron fluence. At low fluence, the prompt desorption of more massive multi carbon or C-O containing cationic fragments agrees with our earlier measurements. However, new anion ESD signals of C2-, C2H-, and C2H2- from CH4/18O2 mixtures increase with fluence, indicating the gradual synthesis (and subsequent electron induced fragmentation) of new, more complex species containing several C and possibly O atoms. Comparisons between the temperature programed desorption (TPD) mass spectra of irradiated and unirradiated films show the electron-induced formation of new chemical species, the identities of which are confirmed by reference to the NIST database of electron impact mass spectra and by TPD measurements of films composed of the proposed products. New species observed in the TPD of irradiated mixture films include C3H6, C2H5OH, and C2H6. Furthermore, X-ray photoelectron spectroscopy of irradiated films confirms the formation of C O, C=O, and O=C-O- bonds of newly formed molecules. Our experiments support the view that secondary LEEs produced by ionizing radiation drive the chemistry in irradiated ices in space, irrespective of the radiation type. PMID- 29246048 TI - Absolute cross section measurements for the scattering of low- and intermediate energy electrons from PF3. I. Elastic scattering. AB - We report absolute elastic differential cross sections (DCSs) for electron collisions with phosphorus trifluoride, PF3, molecules (e- + PF3) in the impact energy range of 2.0-200 eV and over a scattering angle range of 10 degrees -150 degrees . Measured angular distributions of scattered electron intensities were normalized by reference to the elastic DCSs of He. Corresponding integral and momentum-transfer cross sections were derived by extrapolating the angular range from 0 degrees to 180 degrees with the help of a modified phase-shift analysis. In addition, due to the large dipole moment of the considered molecule, the dipole-Born correction for the forward scattering angles has also been applied. As a part of this study, independent atom model calculations in combination with screening corrected additivity rule were also performed for elastic and inelastic (electronic excitation plus ionization) scattering using a complex optical potential method. Rotational excitation cross sections have been estimated with a dipole-Born approximation procedure. Vibrational excitations are not considered in this calculation. Theoretical data, at the differential and integral levels, were found to reasonably agree with the present experimental results. Furthermore, we explore the systematics of the elastic DCSs for the four-atomic trifluoride molecules of XF3 (X = B, N, and P) and central P-atom in PF3, showing that, owing to the comparatively small effect of the F-atoms, the present angular distributions of elastic DCSs are essentially dominated by the characteristic of the central P-atom at lower impact energies. Finally, these quantitative results for e- - PF3 collisions were compiled together with the previous data available in the literature in order to obtain a cross section dataset for modeling purposes. To comprehensively describe such a considerable amount of data, we proceed by first discussing, in this paper, the vibrationally elastic scattering processes whereas vibrational and electronic excitation shall be the subject of our following paper devoted to inelastic collisions. PMID- 29246049 TI - Beating maps of singlet fission: Simulation of coherent two-dimensional electronic spectroscopy by Davydov ansatz in organic molecules. AB - The coherent two-dimensional (2D) electronic spectra for both the intra- and inter-molecular singlet fission (SF) processes in organic molecules are simulated by the Davydov ansatz combined with the Frenkel-Dirac time-dependent variational algorithm. By virtue of the dynamical approach, we are able to identify the signals of triplet excitation in the excited-state absorption contribution of the 2D spectra. In order to discuss whether a mediative charge-transfer (CT) state is necessary to SF, we increase the CT-state energy and find, in a theoretical manner, that the beating signal related to the triplet is inhibited. The vibronic coherence is then studied in the beating maps for both the ground and excited states. Except for the normal beating modes adhering to the relevant electronic state, we observe signals that are explicitly related to the triplet excitations. The pathways of transition corresponding to these signals are clarified in the respective Feynman diagram, which can help the experimenters determine the physical origin of relevant measurements. PMID- 29246050 TI - Accelerated path-integral simulations using ring-polymer interpolation. AB - Imaginary-time path-integral (PI) molecular simulations can be used to calculate exact quantum statistical mechanical properties for complex systems containing many interacting atoms and molecules. The limiting computational factor in a PI simulation is typically the evaluation of the potential energy surface (PES) and forces at each ring-polymer "bead"; for an n-bead ring-polymer, a PI simulation is typically n times greater than the corresponding classical simulation. To address the increased computational effort of PI simulations, several approaches have been developed recently, most notably based on the idea of ring-polymer contraction which exploits either the separation of the PES into short-range and long-range contributions or the availability of a computationally inexpensive PES which can be incorporated to effectively smooth the ring-polymer PES; neither approach is satisfactory in applications to systems modeled by PESs given by on the-fly ab initio calculations. In this article, we describe a new method, ring polymer interpolation (RPI), which can be used to accelerate PI simulations without any prior assumptions about the PES. In simulations of liquid water modeled by an empirical PES (or force field) under ambient conditions, where quantum effects are known to play a subtle role in influencing experimental observables such as radial distribution functions, we find that RPI can accurately reproduce the results of fully-converged PI simulations, albeit with far fewer PES evaluations. This approach therefore opens the possibility of large scale PI simulations using ab initio PESs evaluated on-the-fly without the drawbacks of current methods. PMID- 29246052 TI - A combined electronic structure and molecular dynamics approach to computing the OH vibrational feature of strongly hydrogen-bonded carboxylic acids. AB - Medium and strong hydrogen bonds give rise to vibrational features that can span several hundreds of wavenumbers and have unusual line shapes. For example, dimers consisting of carboxylic acids hydrogen-bonded to nitrogen-containing aromatic bases exhibit a vibrational feature that spans over 900 cm-1 and contains two very broad peaks. In this report, we demonstrate how this feature can be reproduced using a combined molecular dynamics (MD) and electronic structure "spectral map" approach, which has been very successful in modeling the vibrational spectrum of water in different environments. In this approach, spectral maps are created, relating the transition frequencies and probabilities to the electric field along the OH bond, which are obtained from the density functional theory calculations of snapshots taken from a classical MD simulation. This map was used to compute the spectral properties of thousands of geometries of the pyridine-acetic acid dimer sampled by a MD simulation, which were used to compute the overall spectral feature. It was found that this approach reproduced the experimental spectrum better than the previous dimer stretch approaches (which were based on describing the dimer geometries harmonically) through a more accurate sampling of dimer geometries. The broadness of these vibrational features largely originates from the range of geometries present in the condensed phase, while the unusual line shape is caused by strong Fermi resonances. PMID- 29246051 TI - Connectedness percolation of hard deformed rods. AB - Nanofiller particles, such as carbon nanotubes or metal wires, are used in functional polymer composites to make them conduct electricity. They are often not perfectly straight cylinders but may be tortuous or exhibit kinks. Therefore we investigate the effect of shape deformations of the rod-like nanofillers on the geometric percolation threshold of the dispersion. We do this by using connectedness percolation theory within a Parsons-Lee type of approximation, in combination with Monte Carlo integration for the average overlap volume in the isotropic fluid phase. We find that a deviation from a perfect rod-like shape has very little effect on the percolation threshold, unless the particles are strongly deformed. This demonstrates that idealized rod models are useful even for nanofillers that superficially seem imperfect. In addition, we show that for small or moderate rod deformations, the universal scaling of the percolation threshold is only weakly affected by the precise particle shape. PMID- 29246053 TI - Mixed quantum/semiclassical wave-packet dynamical method for condensed-phase molecular spectroscopy signals. AB - We report the successful application of a recently developed mixed quantum/semiclassical wave-packet dynamical theory to the calculation of a spectroscopic signal, the linear absorption spectrum of a realistic small molecule chromophore in a cryogenic environment. This variational fixed vibrational basis/Gaussian bath (FVB/GB) theory avails itself of an assumed time scale separation between a few, mostly intramolecular, high-frequency nuclear motions and a larger number of slower degrees of freedom primarily associated with an extended host medium. The more rapid, large-amplitude system dynamics is treated with conventional basis-set methods, while the slower time-evolution of the weakly coupled bath is subject to a semiclassical, thawed Gaussian trial form that honors the overall vibrational ground state, and hence the initial state prepared by its Franck-Condon transfer to an excited electronic state. We test this general approach by applying it to a small, symmetric iodine-krypton cluster suggestive of molecular iodine embedded in a low-temperature matrix. Because of the relative simplicity of this model complex, we are able to compare the absorption spectrum calculated via FVB/GB dynamics using Heller's time-dependent formula with one obtained from rigorously calculated eigenenergies and Franck Condon factors. The FVB/GB treatment proves to be accurate at approximately 15-cm 1 resolution, despite the presence of several thousand spectral lines and a sequence of various-order system-bath resonances culminating at the highest absorption frequencies in an inversion of the relative system and bath time scales. PMID- 29246054 TI - Finite-size corrections in simulation of dipolar fluids. AB - Monte Carlo simulations of dipolar fluids are performed at different numbers of particles N = 100-4000. For each size of the cubic cell, the non-spherically symmetric pair distribution function g(r,Omega) is accumulated in terms of projections gmnl(r) onto rotational invariants. The observed N dependence is in very good agreement with the theoretical predictions for the finite-size corrections of different origins: the explicit corrections due to the absence of fluctuations in the number of particles within the canonical simulation and the implicit corrections due to the coupling between the environment around a given particle and that around its images in the neighboring cells. The latter dominates in fluids of strong dipolar coupling characterized by low compressibility and high dielectric constant. The ability to clean with great precision the simulation data from these corrections combined with the use of very powerful anisotropic integral equation techniques means that exact correlation functions both in real and Fourier spaces, Kirkwood-Buff integrals, and bridge functions can be derived from box sizes as small as N ~ 100, even with existing long-range tails. In the presence of dielectric discontinuity with the external medium surrounding the central box and its replica within the Ewald treatment of the Coulombic interactions, the 1/N dependence of the gmnl(r) is shown to disagree with the, yet well-accepted, prediction of the literature. PMID- 29246055 TI - Motion of a Janus particle very near a wall. AB - This article describes the simulated Brownian motion of a sphere comprising hemispheres of unequal zeta potential (i.e., "Janus" particle) very near a wall. The simulation tool was developed and used to assist in the methodology development for applying Total Internal Reflection Microscopy (TIRM) to anisotropic particles. Simulations of the trajectory of a Janus sphere with cap density matching that of the base particle very near a boundary were used to construct 3D potential energy landscapes that were subsequently used to infer particle and solution properties, as would be done in a TIRM measurement. Results showed that the potential energy landscape of a Janus sphere has a transition region at the location of the boundary between the two Janus halves, which depended on the relative zeta potential magnitude. The potential energy landscape was fit to accurately obtain the zeta potential of each hemisphere, particle size, minimum potential energy position and electrolyte concentration, or Debye length. We also determined the appropriate orientation bin size and regimes over which the potential energy landscape should be fit to obtain system properties. Our simulations showed that an experiment may require more than 106 observations to obtain a suitable potential energy landscape as a consequence of the multivariable nature of observations for an anisotropic particle. These results illustrate important considerations for conducting TIRM for anisotropic particles. PMID- 29246056 TI - Analysis of X-ray adsorption edges: L2,3 edge of FeCl4. AB - We describe a detailed analysis of the features of the X-ray adsorption spectra at the Fe L2,3 edge of FeCl4-. The objective of this analysis is to explain the origin of the complex features in relation to properties of the wavefunctions, especially for the excited states. These properties include spin-orbit and ligand field splittings where a novel aspect of the dipole selection rules is applied to understand the influence of these splittings on the spectra. We also explicitly take account of the intermediate coupling of the open core and valence shell electrons. Our analysis also includes comparison of theory and experiment for the Fe L2,3 edge and comparison of theoretical predictions for the Fe3+ cation and FeCl4-. The electronic structure is obtained from theoretical wavefunctions for the ground and excited states. PMID- 29246057 TI - Microstructures and dynamics of tetraalkylphosphonium chloride ionic liquids. AB - Atomistic simulations have been performed to investigate the effect of aliphatic chain length in tetraalkylphosphonium cations on liquid morphologies, microscopic ionic structures, and dynamical quantities of tetraalkylphosphonium chloride ionic liquids. The liquid morphologies are characterized by sponge-like interpenetrating polar and apolar networks in ionic liquids consisting of tetraalkylphosphonium cations with short aliphatic chains. The lengthening aliphatic chains in tetraalkylphosphonium cations lead to polar domains consisting of chloride anions and central polar groups in cations being partially or totally segregated in ionic liquid matrices due to a progressive expansion of apolar domains in between. Prominent polarity alternation peaks and adjacency correlation peaks are observed at low and high q range in total X-ray scattering structural functions, respectively, and their peak positions gradually shift to lower q values with lengthening aliphatic chains in tetraalkylphosphonium cations. The charge alternation peaks registered in the intermediate q range exhibit complicated tendencies due to a cancellation of peaks and anti-peaks in partial structural functions for ionic subcomponents. The particular microstructures and liquid morphologies in tetraalkylphosphonium chloride ionic liquids intrinsically contribute to distinct dynamics characterized by mean square displacements, van Hove correlation functions, and non-Gaussian parameters for ionic species in the heterogeneous ionic environment. Most tetraalkylphosphonium cations have higher translational mobilities than their partner anions due to strong coordination of chloride anions with central polar groups in tetraalkylphosphonium cations through strong Coulombic and hydrogen bonding interactions. The increase of aliphatic chain length in tetraalkylphosphonium cations leads to a concomitant shift of van Hove correlation functions and non-Gaussian parameters to larger radial distances and longer time scales, respectively, indicating the enhanced translational dynamical heterogeneities of tetraalkylphosphonium cations and the corresponding chloride anions. PMID- 29246058 TI - Photoelectron angular distributions from rotationally resolved autoionizing states of N2. AB - The single-photon, photoelectron-photoion coincidence spectrum of N2 has been recorded at high (~1.5 cm-1) resolution in the region between the N2+ X Sigmag2+, v+ = 0 and 1 ionization thresholds by using a double-imaging spectrometer and intense vacuum-ultraviolet light from the Synchrotron SOLEIL. This approach provides the relative photoionization cross section, the photoelectron energy distribution, and the photoelectron angular distribution as a function of photon energy. The region of interest contains autoionizing valence states, vibrationally autoionizing Rydberg states converging to vibrationally excited levels of the N2+ X Sigmag2+ ground state, and electronically autoionizing states converging to the N2+A2Pi and B 2Sigmau+ states. The wavelength resolution is sufficient to resolve rotational structure in the autoionizing states, but the electron energy resolution is insufficient to resolve rotational structure in the photoion spectrum. A simplified approach based on multichannel quantum defect theory is used to predict the photoelectron angular distribution parameters, beta, and the results are in reasonably good agreement with experiment. PMID- 29246059 TI - Vibrational relaxation at a metal surface: Electronic friction versus classical master equations. AB - Within a 2-D scattering model, we investigate the vibrational relaxation of an idealized molecule colliding with a metal surface. Two perturbative nonadiabatic dynamics schemes are compared: (i) electronic friction (EF) and (ii) classical master equations. In addition, we also study a third approach, (iii) a broadened classical master equation that interpolates between approaches (i) and (ii). Two conclusions emerge. First, even though we do not have exact data to compare against, we find there is strong evidence suggesting that EF results may be spurious for scattering problems. Second, we find that there is an optimal molecule-metal coupling that maximizes vibrational relaxation rates by inducing large nonadiabatic interactions. PMID- 29246060 TI - Overstretching of B-DNA with various pulling protocols: Appearance of structural polymorphism and S-DNA. AB - We report a structural polymorphism of the S-DNA when a canonical B-DNA is stretched under different pulling protocols and provide a fundamental molecular understanding of the DNA stretching mechanism. Extensive all atom molecular dynamics simulations reveal a clear formation of S-DNA when the B-DNA is stretched along the 3' directions of the opposite strands (OS3) and is characterized by the changes in the number of H-bonds, entropy, and free energy. Stretching along the 5' directions of the opposite strands (OS5) leads to force induced melting form of the DNA. Interestingly, stretching along the opposite ends of the same strand leads to a coexistence of both the S- and melted M-DNA structures. We also do the structural characterization of the S-DNA by calculating various helical parameters. We find that the S-DNA has a twist of ~10 degrees which corresponds to a helical repeat length of ~36 base pairs in close agreement with the previous experimental results. Moreover, we find that the free energy barrier between the canonical and overstretched states of DNA is higher for the same termini pulling protocol in comparison to all other protocols considered in this work. Overall, our observations not only reconcile with the available experimental results qualitatively but also enhance the understanding of different overstretched DNA structures. PMID- 29246061 TI - Dissociation of biomolecules in liquid environments during fast heavy-ion irradiation. AB - The effect of aqueous environment on fast heavy-ion radiation damage of biomolecules was studied by comparative experiments using liquid- and gas-phase amino acid targets. Three types of amino acids with different chemical structures were used: glycine, proline, and hydroxyproline. Ion-induced reaction products were analyzed by time-of-flight secondary-ion mass spectrometry. The results showed that fragments from the amino acids resulting from the C-Calpha bond cleavage were the major products for both types of targets. For liquid-phase targets, specific products originating from chemical reactions in solutions were observed. Interestingly, multiple dissociated atomic fragments were negligible for the liquid-phase targets. We found that the ratio of multifragment to total fragment ion yields was approximately half of that for gas-phase targets. This finding agreed with the results of other studies on biomolecular cluster targets. It is concluded that the suppression of molecular multifragmentation is caused by the energy dispersion to numerous water molecules surrounding the biomolecular solutes. PMID- 29246062 TI - Complex band structure and electronic transmission eigenchannels. AB - It is natural to characterize materials in transport junctions by their conductance length dependence, beta. Theoretical estimations of beta are made employing two primary theories: complex band structure and density functional theory (DFT) Landauer transport. It has previously been shown that the beta value derived from total Landauer transmission can be related to the beta value from the smallest |ki| complex band; however, it is an open question whether there is a deeper relationship between the two. Here we probe the details of the relationship between transmission and complex band structure, in this case individual eigenchannel transmissions and different complex bands. We present calculations of decay constants for the two most conductive states as determined by complex band structure and standard DFT Landauer transport calculations for one semi-conductor and two molecular junctions. The molecular junctions show that both the length dependence of the total transmission and the individual transmission eigenvalues can be, almost always, found through the complex band structure. The complex band structure of the semi-conducting material, however, does not predict the length dependence of the total transmission but only of the individual channels, at some k-points, due to multiple channels contributing to transmission. We also observe instances of vertical bands, some of which are the smallest |ki| complex bands, that do not contribute to transport. By understanding the deeper relationship between complex bands and individual transmission eigenchannels, we can make a general statement about when the previously accepted wisdom linking transmission and complex band structure will fail, namely, when multiple channels contribute significantly to the transmission. PMID- 29246063 TI - Adiabatic perturbation theory for atoms and molecules in the low-frequency regime. AB - There is an increasing interest in the photoinduced dynamics in the low frequency, omega, regime. The multiphoton absorptions by molecules in strong laser fields depend on the polarization of the laser and on the molecular structure. The unique properties of the interaction of atoms and molecules with lasers in the low-frequency regime imply new concepts and directions in strong field light-matter interactions. Here we represent a perturbational approach for the calculations of the quasi-energy spectrum in the low-frequency regime, which avoids the construction of the Floquet operator with extremely large number of Floquet channels. The zero-order Hamiltonian in our perturbational approach is the adiabatic Hamiltonian where the atoms/molecules are exposed to a dc electric field rather than to ac-field. This is in the spirit of the first step in the Corkum three-step model. The second-order perturbation correction terms are obtained when ihomega??tau serves as a perturbation and tau is a dimensionless variable. The second-order adiabatic perturbation scheme is found to be an excellent approach for calculating the ac-field Floquet solutions in our test case studies of a simple one-dimensional time-periodic model Hamiltonian. It is straightforward to implement the perturbation approach presented here for calculating atomic and molecular energy shifts (positions) due to the interaction with low-frequency ac-fields using high-level electronic structure methods. This is enabled since standard quantum chemistry packages allow the calculations of atomic and molecular energy shifts due to the interaction with dc-fields. In addition to the shift of the energy positions, the energy widths (inverse lifetimes) can be obtained at the same level of theory. These energy shifts are functions of the laser parameters (low frequency, intensity, and polarization). PMID- 29246064 TI - Spectroscopy of N,N-dimethylformamide in the VUV and IR regions: Experimental and computational studies. AB - The electronic absorption spectrum of N,N-dimethylformamide (DMF) is studied in the 45 000-80 000 cm-1 (5.6-9.9 eV) region using synchrotron radiation. The vacuum ultraviolet (VUV) spectrum comprises mostly of Rydberg series of ns, np, and nd types converging to the first two ionization potentials (IPs). Quantum defect values obtained are consistent with excitation of an electron from the highest occupied molecular orbitals localized on nitrogen (4a") and oxygen (16a'); in addition, the 3s Rydberg transition converging to the third IP (3a") is observed at 8.95 eV. A reinvestigation of the infrared spectrum of DMF in the 500-4000 cm-1 region with the help of density functional theory (DFT) calculations establishes the planarity of the ground state and leads to revision of several vibrational assignments. Vertical excited state energies and their valence/Rydberg character are predicted using time dependent DFT calculations; excellent correlation is achieved between theoretical results and experimentally observed spectral features. Potential energy curves of the first few excited states give additional insights into the nature of the excited states and their role in photodissociation dynamics. The absorption spectrum of DMF in the region >63 400 cm-1 (7.85 eV) as well as a complete set of spectral assignments in the VUV region (45 000-80 000 cm-1) is reported for the first time. This work represents a comprehensive study of the absorption spectra of DMF in the VUV and infrared regions. PMID- 29246065 TI - A new generation of effective core potentials for correlated calculations. AB - We outline ideas on desired properties for a new generation of effective core potentials (ECPs) that will allow valence-only calculations to reach the full potential offered by recent advances in many-body wave function methods. The key improvements include consistent use of correlated methods throughout ECP constructions and improved transferability as required for an accurate description of molecular systems over a range of geometries. The guiding principle is the isospectrality of all-electron and ECP Hamiltonians for a subset of valence states. We illustrate these concepts on a few first- and second-row atoms (B, C, N, O, S), and we obtain higher accuracy in transferability than previous constructions while using semi-local ECPs with a small number of parameters. In addition, the constructed ECPs enable many-body calculations of valence properties with higher (or same) accuracy than their all-electron counterparts with uncorrelated cores. This implies that the ECPs include also some of the impacts of core-core and core-valence correlations on valence properties. The results open further prospects for ECP improvements and refinements. PMID- 29246066 TI - Note: Ultraviolet photodissociation dynamics of o-bromofluorobenzene in 234-267 nm. AB - Photodissociation dynamics of o-bromofluorobenzene in the 234-267 nm range has been experimentally investigated using the DC-slice velocity map imaging technique. It is found that Br(2P3/2) atoms produced from repulsive singlet state surfaces via excitation of one or more 1pipi* excited states dominate the Br photofragments. The quantum yield of spin-orbit excited Br(2P1/2) atoms was found to be only ~0.02, indicating weak spin-orbit couplings in the low-lying electronic states of o-bromofluorobenzene. PMID- 29246067 TI - Characterizing the geometric and electronic structure of defects in the "29" copper surface oxide. AB - The geometric and electronic structural characterization of thin film metal oxides is of fundamental importance to many fields such as catalysis, photovoltaics, and electrochemistry. Surface defects are also well known to impact a material's performance in any such applications. Here, we focus on the "29" oxide Cu2O/Cu(111) surface and we observe two common structural defects which we characterize using scanning tunneling microscopy/spectroscopy and density functional theory. The defects are proposed to be O vacancies and Cu adatoms, which both show unique topographic and spectroscopic signatures. The spatially resolved electronic and charge state effects of the defects are investigated, and implications for their reactivity are given. PMID- 29246068 TI - General application of Tolman's concept of activation energy. AB - We present a generalization of Tolman's concept of activation energy applicable to thermal and non-thermal reactions in molecular dynamics simulations of reactions in bulk gases. To illustrate the applicability of the method, molecular dynamics calculations were carried out for the NVT ensemble to determine the activation energies of O2 + H2 -> H + HO2 and 2O2 + H2 -> 2HO2 from MD simulation results for [H2]/[O2] = 1 at 3000 K using the reactive force field, ReaxFF. Assuming local thermodynamic equilibrium, we define the reaction cluster local energy, the energy of the atoms participating in an individual reaction, which is conserved. The generalized Tolman activation energy (GTEa) approach is applicable to reactions of any molecularity. Although we have applied GTEa for thermal conditions, it is applicable to chemistry occurring under non-thermal conditions because it rests upon local rather than global equilibrium. We have defined the transition configurations, unique points that define a seam separating reactants and products at which the local energies of the reactants and products become equal. PMID- 29246069 TI - Geometric integrator for Langevin systems with quaternion-based rotational degrees of freedom and hydrodynamic interactions. AB - We introduce new Langevin-type equations describing the rotational and translational motion of rigid bodies interacting through conservative and non conservative forces and hydrodynamic coupling. In the absence of non-conservative forces, the Langevin-type equations sample from the canonical ensemble. The rotational degrees of freedom are described using quaternions, the lengths of which are exactly preserved by the stochastic dynamics. For the proposed Langevin type equations, we construct a weak 2nd order geometric integrator that preserves the main geometric features of the continuous dynamics. The integrator uses Verlet-type splitting for the deterministic part of Langevin equations appropriately combined with an exactly integrated Ornstein-Uhlenbeck process. Numerical experiments are presented to illustrate both the new Langevin model and the numerical method for it, as well as to demonstrate how inertia and the coupling of rotational and translational motion can introduce qualitatively distinct behaviours. PMID- 29246070 TI - Propensity of a single-walled carbon nanotube-peptide to mimic a KK10 peptide in an HLA-TCR complex. AB - The application of nanotechnology to improve disease diagnosis, treatment, monitoring, and prevention is the goal of nanomedicine. We report here a theoretical study of a functionalized single-walled carbon nanotube (CNT) mimic binding to a human leukocyte antigen-T cell receptor (HLA-TCR) immune complex as a first attempt of a potential nanomedicine for human immunodeficiency virus (HIV) vaccine development. The carbon nanotube was coated with three arginine residues to imitate the HIV type 1 immunodominant viral peptide KK10 (gag 263 272: KRWIILGLNK), named CNT-peptide hereafter. Through molecular dynamics simulations, we explore the CNT-peptide and KK10 binding to an important HLA-TCR complex. Our results suggest that the CNT-peptide and KK10 bind comparably to the HLA-TCR complex, but the CNT-peptide forms stronger interactions with the TCR. Desorption simulations highlight the innate flexibility of KK10 over the CNT peptide, resulting in a slightly higher desorption energy required for KK10 over the CNT-peptide. Our findings indicate that the designed CNT-peptide mimic has favorable propensity to activate TCR pathways and should be further explored to understand therapeutic potential. PMID- 29246071 TI - Communication: The failure of correlation to describe carbon=carbon bonding in out-of-plane bends. AB - Carbon-carbon multiply bonded systems are improperly described with standard, wave function-based correlation methods and Gaussian one-particle basis sets implying that thermochemical, spectroscopic, and potential energy surface computations are consistently erroneous. For computations of vibrational modes, the out-of-plane bends can be reported as imaginary at worst or simply too low at best. Utilizing the simplest of aromatic structures (cyclopropenylidene) and various levels of theory, this work diagnoses this known behavior as a combined one-particle and n-particle basis set effect for the first time. In essence, standard carbon basis sets do not describe equally well sp, sp2, and sp3 hybridized orbitals, and this effect is exacerbated post-Hartree-Fock by correlation methods. The latter allow for occupation of the pi and pi* orbitals in the expanded wave function that combine with the hydrogen s orbitals. As a result, the improperly described space is non-physically stabilized by post Hartree-Fock correlation. This represents a fundamental problem in wavefunction theory for describing carbon. PMID- 29246072 TI - Another resolution of the configurational entropy paradox as applied to hard spheres. AB - Ozawa and Berthier [J. Chem. Phys. 146, 014502 (2017)] recently studied the configurational and vibrational entropies Sconf and Svib from the relation Stot = Sconf + Svib for polydisperse mixtures of spheres. They noticed that because the total entropy per particle Stot/N shall contain the mixing entropy per particle kBsmix and Svib/N shall not, the configurational entropy per particle Sconf/N shall diverge in the thermodynamic limit for continuous polydispersity due to the diverging smix. They also provided a resolution for this paradox and related problems-it relies on a careful redefining of Sconf and Svib. Here, we note that the relation Stot = Sconf + Svib is essentially a geometric relation in the phase space and shall hold without redefining Sconf and Svib. We also note that Stot/N diverges with N -> infinity with continuous polydispersity as well. The usual way to avoid this and other difficulties with Stot/N is to work with the excess entropy DeltaStot (relative to the ideal gas of the same polydispersity). Speedy applied this approach to the relation above in his work [Mol. Phys. 95, 169 (1998)] and wrote this relation as DeltaStot = Sconf + DeltaSvib. This form has flaws as well because Svib/N does not contain the kBsmix term and the latter is introduced into DeltaSvib/N instead. Here, we suggest that this relation shall actually be written as DeltaStot = DeltacSconf + DeltavSvib, where Delta = Deltac + Deltav, while DeltacSconf = Sconf - kBNsmix and DeltavSvib=Svib kBN1+lnVLambdadN+UNkBT with N, V, T, U, d, and Lambda standing for the number of particles, volume, temperature, internal energy, dimensionality, and de Broglie wavelength, respectively. In this form, all the terms per particle are always finite for N -> infinity and continuous when introducing a small polydispersity to a monodisperse system. We also suggest that the Adam-Gibbs and related relations shall in fact contain DeltacSconf/N instead of Sconf/N. PMID- 29246073 TI - Nonlinear dielectric features of highly polar glass formers: Derivatives of propylene carbonate. AB - We have measured the nonlinear dielectric behavior of several highly polar propylene carbonate (PC) derivatives in the vicinity of their glass transition temperatures. Focus is on the effects of a large static electric field on the frequency dependent permittivity and on the cubic susceptibility measured using sinusoidal fields of high amplitude. The case of vinyl-PC shows dielectric saturation as well as an electro-rheological effect, i.e., a field induced increase of dielectric relaxation times, whose magnitude changes linearly with the apparent activation energy. The extent of this shift of the loss profile caused by the field correlates strongly with the peak magnitude of the cubic susceptibility, |chi3|, underlining the notion of a link between the |chi3| "hump" and this electro-rheological behavior. Further support for this picture emerges from the observation that the most polar of these liquids, (S)-(-) methoxy-PC with epsilons ~ 250, lacks both the electro-rheological effect in epsilon"(omega) and the "hump" typically observed in |chi3(omega)|. The absence of any sensitivity of the dynamics to an electric field is contrary to the expectation that the electro-rheological effect correlates with the field induced entropy change, which is extraordinarily high for this liquid. The results suggest that the dependence of the relaxation time on the electric field is not directly linked to the entropy change. PMID- 29246074 TI - Nonequilibrium Green's function theory for nonadiabatic effects in quantum electron transport. AB - We develop nonequilibrium Green's function-based transport theory, which includes effects of nonadiabatic nuclear motion in the calculation of the electric current in molecular junctions. Our approach is based on the separation of slow and fast time scales in the equations of motion for Green's functions by means of the Wigner representation. Time derivatives with respect to central time serve as a small parameter in the perturbative expansion enabling the computation of nonadiabatic corrections to molecular Green's functions. Consequently, we produce a series of analytic expressions for non-adiabatic electronic Green's functions (up to the second order in the central time derivatives), which depend not solely on the instantaneous molecular geometry but likewise on nuclear velocities and accelerations. An extended formula for electric current is derived which accounts for the non-adiabatic corrections. This theory is concisely illustrated by the calculations on a model molecular junction. PMID- 29246075 TI - Perspective: Aerosol microphysics: From molecules to the chemical physics of aerosols. AB - Aerosols are found in a wide diversity of contexts and applications, including the atmosphere, pharmaceutics, and industry. Aerosols are dispersions of particles in a gas, and the coupling of the two phases results in highly dynamic systems where chemical and physical properties like size, composition, phase, and refractive index change rapidly in response to environmental perturbations. Aerosol particles span a wide range of sizes from 1 nm to tens of micrometres or from small molecular clusters that may more closely resemble gas phase molecules to large particles that can have similar qualities to bulk materials. However, even large particles with finite volumes exhibit distinct properties from the bulk condensed phase, due in part to their higher surface-to-volume ratio and their ability to easily access supersaturated solute states inaccessible in the bulk. Aerosols represent a major challenge for study because of the facile coupling between the particle and gas, the small amounts of sample available for analysis, and the sheer breadth of operative processes. Time scales of aerosol processes can be as short as nanoseconds or as long as years. Despite their very different impacts and applications, fundamental chemical physics processes serve as a common theme that underpins our understanding of aerosols. This perspective article discusses challenges in the study of aerosols and highlights recent chemical physics advancements that have enabled improved understanding of these complex systems. PMID- 29246076 TI - Construction of diabatic energy surfaces for LiFH with artificial neural networks. AB - A new set of diabatic potential energy surfaces (PESs) for LiFH is constructed with artificial neural networks (NNs). The adiabatic PESs of the ground state and the first excited state are directly fitted with NNs. Meanwhile, the adiabatic-to diabatic transformation (ADT) angles (mixing angles) are obtained by simultaneously fitting energy difference and interstate coupling gradients. No prior assumptions of the functional form of ADT angles are used before fitting, and the ab initio data including energy difference and interstate coupling gradients are well reproduced. Converged dynamical results show remarkable differences between adiabatic and diabatic PESs, which suggests the significance of non-adiabatic processes. PMID- 29246078 TI - Ordering nanoparticles with polymer brushes. AB - Ordering nanoparticles into a desired super-structure is often crucial for their technological applications. We use molecular dynamics simulations to study the assembly of nanoparticles in a polymer brush randomly grafted to a planar surface as the solvent evaporates. Initially, the nanoparticles are dispersed in a solvent that wets the polymer brush. After the solvent evaporates, the nanoparticles are either inside the brush or adsorbed at the surface of the brush, depending on the strength of the nanoparticle-polymer interaction. For strong nanoparticle-polymer interactions, a 2-dimensional ordered array is only formed when the brush density is finely tuned to accommodate a single layer of nanoparticles. When the brush density is higher or lower than this optimal value, the distribution of nanoparticles shows large fluctuations in space and the packing order diminishes. For weak nanoparticle-polymer interactions, the nanoparticles order into a hexagonal array on top of the polymer brush as long as the grafting density is high enough to yield a dense brush. An interesting healing effect is observed for a low-grafting-density polymer brush that can become more uniform in the presence of weakly adsorbed nanoparticles. PMID- 29246077 TI - Aging near rough and smooth boundaries in colloidal glasses. AB - We use a confocal microscope to study the aging of a bidisperse colloidal glass near rough and smooth boundaries. Near smooth boundaries, the particles form layers, and particle motion is dramatically slower near the boundary as compared to the bulk. Near rough boundaries, the layers nearly vanish, and particle motion is nearly identical to that of the bulk. The gradient in dynamics near the boundaries is demonstrated to be a function of the gradient in structure for both types of boundaries. Our observations show that wall-induced layer structures strongly influence aging. PMID- 29246079 TI - Curcumin pyrazole blocks lipopolysaccharide-induced inflammation via suppression of JNK activation in RAW 264.7 macrophages. AB - BACKGROUND: Targeting inflammatory macrophages and their products is an effective method for controlling inflammation. The pyrazole analog of curcumin (curcumin pyrazole, PYR) has been reported to possess superior anti-inflammatory activity to curcumin (CUR). However, the role of PYR anti-inflammatory activity in macrophages has not yet been elucidated. OBJECTIVE: To examine the anti inflammatory effects of PYR and CUR in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages and determine the role of mitogen-activated protein kinases (MAPK) in their activity. METHODS: Nitrite level was investigated by the Griess assay. The expression of inducible nitric oxide (NO) synthase, cyclooxygenase-2 (COX-2), and MAPK proteins were analyzed by western blot analysis. The pro inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay. RESULTS: LPS-induced NO secretion in RAW 264.7 macrophages was potently inhibited by PYR (IC50 = 3.7 +/- 0.16 MUM), at a higher efficacy than CUR (IC50 = 11.0 +/- 0.59 MUM). Treatment with identical concentrations of PYR and CUR demonstrated that PYR drastically inhibited iNOS and COX-2 expression, whereas CUR only blocked COX-2. PYR reduced the LPS-induced secretion of TNF-alpha to a greater extent than CUR and both similarly reduced IL-1beta and IL-6 levels. Activation of c-Jun N-terminal kinase (JNK) MAPK was significantly decreased in LPS activated RAW 264.7 macrophages upon PYR but not CUR treatment. CONCLUSION: PYR exhibited a more potent anti-inflammatory activity than CUR. This activity is partly mediated by PYR-depended inhibition of the JNK signaling pathway and underscores the utility of PYR as an anti-inflammatory agent in macrophages. PMID- 29246080 TI - Marginalization and health service coverage among indigenous, rural, and urban populations: a public health problem in Mexico. AB - INTRODUCTION: Marginalization is a significant issue in Mexico, involving a lack of access to health services with differential impacts on Indigenous, rural and urban populations. The objective of this study was to understand Mexico’s public health problem across three population areas, Indigenous, rural and urban, in relation to degree of marginalization and health service coverage. METHODS: The sampling universe of the study consisted of 107 458 geographic locations in the country. The study was retrospective, comparative and confirmatory. The study applied analysis of variance, parametric and non parametric, correlation and correspondence analyses. RESULTS: Significant differences were identified between the Indigenous, rural and urban populations with respect to their level of marginalization and access to health services. The most affected area was Indigenous, followed by rural areas. The sector that was least affected was urban. CONCLUSIONS: Although health coverage is highly concentrated in urban areas in Mexico, shortages are mostly concentrated in rural areas where Indigenous groups represent the extreme end of marginalization and access to medical coverage. Inadequate access to health services in the Indigenous and rural populations throws the gravity of the public health problem into relief. PMID- 29246081 TI - Uncovered Chimney Stent Graft for Renal Arteries With the Nellix Endovascular Aneurysm Sealing Technique. AB - PURPOSE: To describe the application of uncovered chimney stent grafts with the Nellix endovascular aneurysm sealing technique (ChEVAS) for juxtarenal abdominal aortic aneurysms (JAAAs). CASE REPORT: Two patients with JAAA and multiple comorbidities were considered unfit for open surgery and were selected for an endovascular approach. Fenestrated and branched endografts were too expensive, and a chimney endovascular approach was considered inappropriate for the relatively high incidence of proximal type I endoleak and graft migration. ChEVAS was performed successfully with the novel addition of uncovered chimney stents to further reduce costs and possibly improve target vessel patency. JAAA exclusion and visceral vessel patency was confirmed at 18-month follow-up. CONCLUSION: ChEVAS with bare chimney stents is technically less complex, potentially reduces access complications and procedural costs, and may improve long-term patency compared to alternative techniques. Results at 18 months seem promising, but strict follow-up is necessary as the long-term durability is unknown. PMID- 29246082 TI - Educators' Experiences Identifying Pain Among Students in Special Education Settings. AB - If special educators cannot identify pain in students with intellectual disability (ID), students cannot be referred to the school nurse for assessment and management. The purpose of this study was to examine how special educators identify pain in the school setting. Twenty-four special educators participated in focus groups aiming to (1) identify educators' observations and perceptions of pain in students with ID and (2) determine the decision-making processes educators use to determine the need for student presentation or referral to the health office. Overall, special educators know students well enough to differentiate pain-related behaviors from normal well-child behaviors, prioritize student safety, and draw on personal experiences with pain when addressing pain in students with ID. Special educators welcome opportunities to learn more about pain in children with ID. Teachers, nurses, and other professionals should share knowledge about and experiences of working with students in pain to improve practices. PMID- 29246083 TI - Researchers' experiences and lessons learned from doing mixed-methods research with a population with intellectual disabilities: Insights from the SOPHIE study. AB - Researchers are challenged to provide opportunities for people with intellectual disabilities (IDs) and their families to become participants in research. This article explores the processes and procedures involved in conducting a mixed methods study. The preparation for the study is described and explained. Recruitment is examined by describing the process and analysing phone calls made to potential participants. Reflections of research team members help to develop the analysis and contribute to a discussion of the fieldwork. Lessons learned show that research projects involving people with IDs and their families need careful planning and have additional costs. The research team requires a mix of expertise. Traditional recruitment methods may not be suitable, and researchers need to build good relationships with gatekeepers so that participants can be contacted directly. Good quality research with people with IDs and their families is possible once suitable strategies are employed throughout the research process. PMID- 29246085 TI - Development of the Family Stigma Stress Scale (FSSS) for Detecting Stigma Stress in Caregivers of People With Mental Illness. AB - People with mental illness and their family caregivers often perceive public stigma, which may lead to stigma-related stress (or stigma stress). However, no instruments have been developed to measure this stress for family caregivers of people with mental illness. We modified an instrument that measures the stigma stress of people with mental illness (i.e., the cognitive appraisal of stigma as a stressor) and examined the psychometric properties of the scores of the newly developed instrument: the Family Stigma Stress Scale (FSSS). Primary family caregivers of people with mental illness in Southern Taiwan ( n = 300; mean age = 53.08 +/- 13.80; 136 males) completed the FSSS. An exploratory factor analysis showed that the FSSS score had two factors; both factor scores had excellent internal consistency (alpha = .913 and .814) and adequate test-retest reliability ( r = .627 and .533; n = 197). Significant correlations between FSSS factor scores and other instruments supported its concurrent validity and the ability of the FSSS to differentiate between clinical characteristics, for example, having been previously hospitalized or not. The FSSS is a brief and effective measure of the stigma stress of family caregivers of people with mental illness. PMID- 29246084 TI - Dolutegravir plus rilpivirine dual therapy in treating HIV-1 infection. AB - INTRODUCTION: The HIV-infected population is aging and comorbidities and polypharmacological regimens are increasing. To reduce toxicity and drug burden researchers are evaluating the efficacy, safety and durability of dual therapies as a switch option in subjects who have achieved stable virologic suppression. Initially effective dual combinations relied on protease inhibitors but when dolutegravir, the first integrase inhibitor to display a high genetic barrier, became commercially available, many physicians began to use it in a variety of dual regimens, generating several observational cohorts. Areas covered: This review covers the most recent data from observational cohorts and randomized clinical trials concerning the switch to the dual combination of dolutegravir plus rilpivirine and the reasons that lead to consider this option. Also, viral failures, due to poor adherence or to other factors, and drug resistance are investigated. Articles which are searchable on MEDLINE/PubMed and from the main national/international congresses in the field of HIV therapy are reviewed. Expert opinion: The observation period for this regimen is getting longer and data showing its efficacy in maintaining HIV-1 RNA < 50 copies/mL are now consolidated. Metabolic data suggest some benefit in the lipid profile, improvement in bone mineral density and reduced bone reabsorption. PMID- 29246086 TI - Positive and Negative Affect Schedule (PANAS): Psychometric Properties and Discriminative Capacity in Several Chilean Samples. AB - We evaluated the factor structure, reliability, and discriminative capacity of the Positive and Negative Affect Schedule (PANAS) questionnaire in four different samples: two general adult populations ( N = 1,548, N = 964), one adolescent population ( N = 1,044), and young people with depressive symptomatology ( N = 307). Exploratory factor analyses (EFAs) were performed with subsamples from Studies 1 ( n = 773) and 2 ( n = 527), finding that the two- and three-factor solutions had a good fit. In a confirmatory factor analysis, the two-factor solution resulted in an adequate fit in a second set of subsamples from both studies ( n = 775, n = 517). In Study 3, we found good convergent and divergent validity with adequate and significant correlations found for depression (Beck's Depression Inventory), anxiety (State-Trait Anxiety Inventory), and neuroticism and extroversion (Big Five Inventory). In Study 4, the results of an EFA performed in a subsample ( n = 154) found that the two- and three-factor solutions were appropriate with the former solution being confirmed in a second subsample ( n = 153). Reliability was alpha = .85 for positive affect and alpha = .87 for negative affect. The PANAS questionnaire showed adequate indicators of validity and reliability in adult and adolescent populations as well as in a sample with depressive symptoms. PMID- 29246087 TI - In-silico interaction studies suggest RND efflux pump mediates polymyxin resistance in Acinetobacter baumannii. AB - Bacterial efflux pumps have emerged as antibiotic resistance determinants and confers multi-drug resistance to a broad range of antimicrobials as well as non antibiotic substances. A study about translocation of antibiotic molecules through the efflux transporter, will contribute in determining substrate specificity. In the present study, we have explored RND family efflux pump extensively found in Acinetobacter baumannii i.e. AdeABC. Besides, another well studied RND efflux pump, AcrAB-TolC together with a non-RND efflux pump, NorM was investigated for comparative analysis. We employed a series of computational techniques ranging from molecular docking to binding free energy estimation and molecular dynamics simulations to determine the binding affinity for different classes of drugs, namely aminoglycosides, polymyxins, beta-lactams, tetracyclines, glycylcyclines, quinolones and metronidazole with AdeB, AcrB, and NorM efflux proteins. Our results revealed that class polymyxins has the highest binding affinity with the RND efflux pumps i.e. AcrAB-TolC and AdeABC as well as non-RND efflux pump, NorM. The experimental validation study demonstrated bigger zone of inhibition in presence of efflux pump inhibitor than polymyxin alone thus unveiling its specificity toward efflux pump. The reported experimental data comprising of minimum inhibitory concentration of antibiotics toward these efflux pumps also support our finding based on in silico approach. To recapitulate the outcome, polymyxins shows maximum specificity toward RND as well as non-RND efflux pump and may unlatch the way to rationally develop new potential antibacterial agents as well as efflux pump inhibitors in order to combat resistance. PMID- 29246088 TI - A spoonful of care ethics: The challenges of enriching medical education. AB - BACKGROUND: Nursing Ethics has featured several discussions on what good care comprises and how to achieve good care practices. We should "nurse" ethics by continuously reflecting on the way we "do" ethics, which is what care ethicists have been doing over the past few decades and continue to do so. Ethics is not limited to nursing but extends to all caring professions. In 2011, Elin Martinsen argued in this journal that care should be included as a core concept in medical ethical terminology because of "the harm to which patients may be exposed owing to a lack of care in the clinical encounter," specifically between doctors and patients. However, Martinsen leaves the didactical challenges arising from such a venture open for further enquiry. OBJECTIVES: In this article, we explore the challenges arising from implementing care-ethical insights into medical education. RESEARCH DESIGN: Medical education in the Netherlands is investigated through a "care-ethical lens". This means exploring the possibility of enriching medical education with care-ethical insights, while at the same time discovering possible challenges emerging from such an undertaking. Participants and research context: This paper has been written from the academic context of a master in care ethics and policy. Ethical considerations: We have tried to be fair and respectful to the authors discussed and take a neutral stance towards the findings portrayed. FINDINGS: Several challenges are identified, which we narrow down to two types: didactical and non-didactical. DISCUSSION AND CONCLUSION: In order to overcome these challenges, we must not underestimate the possible resistance to a paradigm shift. Our efforts should mainly target the learning that takes place in the clinical phases of medical training and should be accompanied by the creation of awareness in healthcare practice. PMID- 29246090 TI - Exploring the nature of the H-bonds between the human class II MHC protein, HLA DR1 (DRB*0101) and the influenza virus hemagglutinin peptide, HA306-318, using the quantum theory of atoms in molecules. AB - The nature of the H-bonds between the human protein HLA-DR1 (DRB*0101) and the hemagglutinin peptide HA306-318 has been studied using the Quantum Theory of Atoms in Molecules for the first time. We have found four H-bond groups: one conventional CO..HN bond group and three nonconventional CO..HC, pi..HC involving aromatic rings and HN..HCaliphatic groups. The calculated electron density at the determined H-bond critical points suggests the follow protein pocket binding trend: P1 (2,311) >> P9 (1.109) > P4 (0.950) > P6 (0.553) > P7 (0.213) which agrees and reveal the nature of experimental findings, showing that P1 produces by a long way the strongest binding of the HLA-DR1 human protein molecule with the peptide backbone as consequence of the vast number of H-bonds in the P1 area and at the same time the largest specific binding of the peptide Tyr308 residue with aromatic residues located at the binding groove floor. The present results suggest the topological analysis of the electronic density as a valuable tool that allows a non-arbitrary partition of the pockets binding energy via the calculated electron density at the determined critical points. PMID- 29246089 TI - Expression and Regulation of Retinoic Acid Receptor Responders in the Human Placenta. AB - INTRODUCTION: Retinoic acid (RA) signaling through its receptors (RARA, RARB, RARG, and the retinoic X receptor RXRA) is essential for healthy placental and fetal development. An important group of genes regulated by RA are the RA receptor responders (RARRES1, 2, and 3). We set out to analyze their expression and regulation in healthy and pathologically altered placentas of preeclampsia (PE) and intrauterine growth restriction (IUGR) as well as in trophoblast cell lines. METHODS: We performed immunohistochemical staining on placental sections and analyzed gene expression by real-time polymerase chain reaction. Additionally, we performed cell culture experiments and stimulated Swan71 and Jeg 3 cells with different RA derivates and 2'-deoxy-5-azacytidine (AZA) to induce DNA demethylation. RESULTS: RARRES1, 2, and 3 and RARA, RARB, RARG, and RXRA are expressed in the extravillous part of the placenta. RARRES1, RARA, RARG, and RXRA were additionally detected in villous cytotrophoblasts. RARRES gene expression was induced via activation of RARA, RARB, and RARG in trophoblast cells. RARRES1 was overexpressed in villous trophoblasts and the syncytiotrophoblast from PE placentas, but not in IUGR without PE. Promoter methylation was detectable for RARRES1 and RARB based on their sensitivity toward AZA treatment of trophoblast cell lines. DISCUSSION: RARRES1, 2 and 3 are expressed in the functional compartments of the human placenta and can be regulated by RA. We hypothesize that the epigenetic suppression of trophoblast RARRES1 and RARB expression and the upregulation of RARRES1 in PE trophoblast cells suggest an involvement of environmental factors (eg, maternal vitamin A intake) in the pathogenesis of this pregnancy complication. PMID- 29246092 TI - Improvement of Self-Injury With Dopamine and Serotonin Replacement Therapy in a Patient With a Hemizygous PAK3 Mutation: A New Therapeutic Strategy for Neuropsychiatric Features of an Intellectual Disability Syndrome. AB - PAK3-related intellectual disability is caused by mutations in the gene encoding the p21-activated kinase (PAK) protein. It is characterized by mild to moderate cognitive impairment, micro/normocephaly, and a neurobehavioral phenotype characterized by short attention span, anxiety, restlessness, aggression, and self-abusive behaviors. The authors report a patient with a novel PAK3 mutation, who presented with intellectual disability, severe automutilation, and epilepsy. His magnetic resonance imaging changes were most likely secondary to lacerations from parenchymal contusions. His behavior was difficult to manage with behavior interventions or multiple medications. After finding low levels of dopamine and borderline low serotonin metabolites in the spinal fluid, treatment with low dose L-dopa/carbidopa and 5-hydroxytryptophan significantly improved his self injurious behavior. This is the first case of PAK3-related intellectual disability presenting with severe self-injury with improvement following treatment. The patient's response to neurotransmitter replacement therapy raises the question if this treatment intervention might help other individuals suffering genetic syndromes and self-injurious behaviors. PMID- 29246093 TI - Targeting the Mammalian Target of Rapamycin for Epileptic Encephalopathies and Malformations of Cortical Development. AB - Malformations of cortical development represent a common cause of epileptic encephalopathies and drug-resistant epilepsy in children. As current treatments are often ineffective, new therapeutic targets are needed for epileptic encephalopathies associated with cortical malformations. The mechanistic/mammalian target of rapamycin (mTOR) pathway constitutes a signaling pathway that drives cellular and molecular mechanisms of epileptogenesis in a variety of focal cortical malformations. mTOR inhibitors prevent epilepsy and associated pathogenic mechanisms of epileptogenesis in mouse models of tuberous sclerosis complex and are currently in clinical trials for drug-resistant seizures in these patients. A recent explosion of genetic studies has linked mutations in various genes regulating the mTOR pathway to other cortical malformations, such as focal cortical dysplasia and hemimegalencephaly. Thus, mTOR inhibitors represent promising candidates as novel antiseizure and antiepileptogenic therapies for epilepsy associated with a spectrum of cortical malformations. PMID- 29246094 TI - Gait, Balance, and Coordination Impairments in Niemann Pick Disease, Type C1. AB - This is the first study to objectively measure gait, balance, and upper limb coordination in a group of patients with NPC1 and compare the results to age and gender matched controls. This is also the first study to report effect sizes in these measures. Spatiotemporal gait analysis, static and dynamic posturography, and upper limb reaching motion analysis were performed. The findings showed that the NPC1 subjects had statistically significant deficits on 12 out of the 16 parameters investigated compared to controls, and large effect sizes for all but 1 parameter. When ranking the variables in terms of the effect sizes, the top 5 included at least 1 parameter from each of the 3 motor domains investigated. These results can provide insight to clinical researchers on the selection of outcome measures for longitudinal and interventional studies. PMID- 29246095 TI - Role of Neuroinflammation in Evolution of Childhood Epilepsy. AB - Until a decade ago, epilepsy research had focused mainly on alterations of neuronal activities and excitability. Such neurocentric emphasis has neglected the role of glia and involvement of inflammation in the pathogenesis of epilepsy. It is becoming clear that immune and inflammatory reactions do occur in the brain despite the brain's lack of conventional lymphatic drainage and graft acceptance and the presence of vascular brain barrier that tightly regulates infiltration of blood monocytes and lymphocytes. The critical roles of brain-resident immune mediators and of brain-infiltrating peripheral leukocytes are increasingly recognized. Inflammatory processes, including activation of microglia and astrocytes and production of proinflammatory cytokines and related molecules, occur in human epilepsy as well as in experimental models of epilepsy. Immune mechanism that underlies evolution of drug-resistant epilepsy and epileptic encephalopathy represents a new target and will aid in development of novel immunotherapeutic drugs and therapies against the key constituents in immune pathways. PMID- 29246096 TI - Pediatric-Onset Multiple Sclerosis: A Single Center Study. AB - Pediatric-onset multiple sclerosis (POMS), once thought to be rare, is now being diagnosed in increasing numbers in children. Despite improvements to diagnostic criteria, the diagnosis and management of POMS remains challenging. The aim of this study is to retrospectively describe a growing POMS patient population seen at a single center over a 13 year period. Epidemiologic, clinical, neuroimaging, laboratory features and therapeutic management and outcome data were collected and analyzed. These data support associations between MS and environmental triggers such as obesity and vitamin D deficiency. Presenting symptoms, magnetic resonance imaging and laboratory findings were consistent with the existing literature; however, the prevalence of cortical lesions and abnormal saccadic pursuit is higher than other reports. Data also demonstrate a shift in practice from first- to second-line therapies over the observed period. PMID- 29246097 TI - Neurofibromatosis Clinical Trial Consortium. AB - Neurofibromatosis type 1 and type 2, affecting both children and adults, often results in devastating complications. The rapid unravelling of the genetic underpinnings of these unique disorders has led to the development of novel therapies, especially molecular-targeted therapies. To facilitate clinical trial development, the Neurofibromatosis Clinical Trial Consortium (NFCTC) was established in 2006 by the Department of Defense. Over the past decade, the Consortium has successfully completed studies for children and adults with neurofibromatosis type 1 and plexiform neurofibromas, neurocognitive challenges, low-grade gliomas, and malignant peripheral nerve sheath tumors. In addition, a study for children and adults with neurofibromatosis type 2 and acoustic schwannomas is near completion. The NFCTC has now been expanded to 19 sites in the United Stated and Australia. Mechanisms have been put in place to work closely with other consortia, foundations, and industry to expeditiously translate preclinical discoveries into clinical trials. PMID- 29246099 TI - Younger Age of Migraine Onset in Children Than Their Parents: A Retrospective Cohort Study. AB - Migraine is known to run in families and has long been considered a strongly heritable disorder. We sought to investigate the age of onset of migraine between successive generations. Our retrospective cohort included 102 children with migraine who were referred to a pediatric headache clinic and their affected parent(s). Age at migraine onset was significantly lower in the children with a history of maternal or paternal migraine than in their mothers or fathers ( P < .001). In conclusion, data on parental history of migraine showed that children with migraine were significantly younger at first appearance of the disease than their affected parents. PMID- 29246098 TI - Optic Pathway Gliomas in Neurofibromatosis Type 1. AB - Neurofibromatosis type 1 (NF1) is one of the most common brain tumor predisposition syndromes, in which affected children are prone to the development of low-grade gliomas. While NF1-associated gliomas can be found in several brain regions, the majority arise in the optic nerves, chiasm, tracts, and radiations (optic pathway gliomas; OPGs). Owing to their location, 35-50% of affected children present with reduced visual acuity. Unfortunately, despite tumor stabilization following chemotherapy, vision does not improve in most children. For this reasons, more effective therapies are being sought that reflect a deeper understanding of the NF1 gene and the use of authenticated Nf1 genetically engineered mouse strains. The implementation of these models for drug discovery and validation has galvanized molecularly-targeted clinical trials in children with NF1-OPG. Future research focused on defining the cellular and molecular factors that underlie optic glioma development and progression also has the potential to provide personalized risk assessment strategies for this pediatric population. PMID- 29246100 TI - Investigating population continuity with ancient DNA under a spatially explicit simulation framework. AB - BACKGROUND: Recent advances in sequencing technologies have allowed for the retrieval of ancient DNA data (aDNA) from skeletal remains, providing direct genetic snapshots from diverse periods of human prehistory. Comparing samples taken in the same region but at different times, hereafter called "serial samples", may indicate whether there is continuity in the peopling history of that area or whether an immigration of a genetically different population has occurred between the two sampling times. However, the exploration of genetic relationships between serial samples generally ignores their geographical locations and the spatiotemporal dynamics of populations. Here, we present a new coalescent-based, spatially explicit modelling approach to investigate population continuity using aDNA, which includes two fundamental elements neglected in previous methods: population structure and migration. The approach also considers the extensive temporal and geographical variance that is commonly found in aDNA population samples. RESULTS: We first showed that our spatially explicit approach is more conservative than the previous (panmictic) approach and should be preferred to test for population continuity, especially when small and isolated populations are considered. We then applied our method to two mitochondrial datasets from Germany and France, both including modern and ancient lineages dating from the early Neolithic. The results clearly reject population continuity for the maternal line over the last 7500 years for the German dataset but not for the French dataset, suggesting regional heterogeneity in post-Neolithic migratory processes. CONCLUSIONS: Here, we demonstrate the benefits of using a spatially explicit method when investigating population continuity with aDNA. It constitutes an improvement over panmictic methods by considering the spatiotemporal dynamics of genetic lineages and the precise location of ancient samples. The method can be used to investigate population continuity between any pair of serial samples (ancient-ancient or ancient-modern) and to investigate more complex evolutionary scenarios. Although we based our study on mitochondrial DNA sequences, diploid molecular markers of different types (DNA, SNP, STR) can also be simulated with our approach. It thus constitutes a promising tool for the analysis of the numerous aDNA datasets being produced, including genome wide data, in humans but also in many other species. PMID- 29246102 TI - An Eigenvalue test for spatial principal component analysis. AB - BACKGROUND: The spatial Principal Component Analysis (sPCA, Jombart (Heredity 101:92-103, 2008) is designed to investigate non-random spatial distributions of genetic variation. Unfortunately, the associated tests used for assessing the existence of spatial patterns (global and local test; (Heredity 101:92-103, 2008) lack statistical power and may fail to reveal existing spatial patterns. Here, we present a non-parametric test for the significance of specific patterns recovered by sPCA. RESULTS: We compared the performance of this new test to the original global and local tests using datasets simulated under classical population genetic models. Results show that our test outperforms the original global and local tests, exhibiting improved statistical power while retaining similar, and reliable type I errors. Moreover, by allowing to test various sets of axes, it can be used to guide the selection of retained sPCA components. CONCLUSIONS: As such, our test represents a valuable complement to the original analysis, and should prove useful for the investigation of spatial genetic patterns. PMID- 29246101 TI - Diversification of defensins and NLRs in Arabidopsis species by different evolutionary mechanisms. AB - BACKGROUND: Genes encoding proteins underlying host-pathogen co-evolution and which are selected for new resistance specificities frequently are under positive selection, a process that maintains diversity. Here, we tested the contribution of natural selection, recombination and transcriptional divergence to the evolutionary diversification of the plant defensins superfamily in three Arabidopsis species. The intracellular NOD-like receptor (NLR) family was used for comparison because positive selection has been well documented in its members. Similar to defensins, NLRs are encoded by a large and polymorphic gene family and many of their members are involved in the immune response. RESULTS: Gene trees of Arabidopsis defensins (DEFLs) show a high prevalence of clades containing orthologs. This indicates that their diversity dates back to a common ancestor and species-specific duplications did not significantly contribute to gene family expansion. DEFLs are characterized by a pervasive pattern of neutral evolution with infrequent positive and negative selection as well as recombination. In comparison, most NLR alignment groups are characterized by frequent occurrence of positive selection and recombination in their leucine-rich repeat (LRR) domain as well negative selection in their nucleotide-binding (NB ARC) domain. While major NLR subgroups are expressed in pistils and leaves both in presence or absence of pathogen infection, the members of DEFL alignment groups are predominantly transcribed in pistils. Furthermore, conserved groups of NLRs and DEFLs are differentially expressed in response to Fusarium graminearum regardless of whether these genes are under positive selection or not. CONCLUSIONS: The present analyses of NLRs expands previous studies in Arabidopsis thaliana and highlights contrasting patterns of purifying and diversifying selection affecting different gene regions. DEFL genes show a different evolutionary trend, with fewer recombination events and significantly fewer instances of natural selection. Their heterogeneous expression pattern suggests that transcriptional divergence probably made the major contribution to functional diversification. In comparison to smaller families encoding pathogenesis-related (PR) proteins under positive selection, DEFLs are involved in a wide variety of processes that altogether might pose structural and functional trade-offs to their family-wide pattern of evolution. PMID- 29246103 TI - Correction to: Mapping of leptin and its syntenic genes to chicken chromosome 1p. AB - CORRECTION: After the publication of this work [1] an error was noticed in one of the author surnames. The author name Leif Anderson should be spelt as Leif Andersson. PMID- 29246104 TI - Mechanically tuned 3 dimensional hydrogels support human mammary fibroblast growth and viability. AB - BACKGROUND: Carcinoma associated fibroblasts (CAFs or myofibroblasts) are activated fibroblasts which participate in breast tumor growth, angiogenesis, invasion, metastasis and therapy resistance. As such, recent efforts have been directed toward understanding the factors responsible for activation of the phenotype. In this study, we have investigated how changes in the mechanical stiffness of a 3D hydrogel alter the behavior and myofibroblast-like properties of human mammary fibroblasts (HMFs). RESULTS: Here, we utilized microbial transglutaminase (mTG) to mechanically tune the stiffness of gelatin hydrogels and used rheology to show that increasing concentrations mTG resulted in hydrogels with greater elastic moduli (G'). Upon encapsulation of HMFs in 200 (compliant), 300 (moderate) and 1100 Pa (stiff) mTG hydrogels, it was found that the HMFs remained viable and proliferated over the 7 day culture period. Specifically, rates of proliferation were greatest for HMFs in moderate hydrogels. Regarding morphology, HMFs in compliant and moderate hydrogels exhibited a spindle-like morphology while HMFs in stiff hydrogels exhibited a rounded morphology with several large cellular protrusions. Quantification of cell morphology revealed that HMFs cultured in all mTG hydrogels overall assumed a more elongated phenotype over time in culture; however, few significant differences in morphology were observed between HMFs in each of the hydrogel conditions. To determine whether matrix stiffness upregulated expression of ECM and myofibroblast markers, western blot was performed on HMFs in compliant, moderate and stiff hydrogels. It was found that ECM and myofibroblast proteins varied in expression during both the culture period and according to matrix stiffness with no clear correlation between matrix stiffness and a myofibroblast phenotype. Finally, TGF-beta levels were quantified in the conditioned media from HMFs in compliant, moderate and stiff hydrogels. TGF-beta was significantly greater for HMFs encapsulated in stiff hydrogels. CONCLUSIONS: Overall, these results show that while HMFs are viable and proliferate in mTG hydrogels, increasing matrix stiffness of mTG gelatin hydrogels doesn't support a robust myofibroblast phenotype from HMFs. These results have important implications for further understanding how modulating 3D matrix stiffness affects fibroblast morphology and activation into a myofibroblast phenotype. PMID- 29246105 TI - The function and evolutionary significance of a triplicated Na,K-ATPase gene in a toxin-specialized insect. AB - BACKGROUND: The Na,K-ATPase is a vital animal cell-membrane protein that maintains the cell's resting potential, among other functions. Cardenolides, a group of potent plant toxins, bind to and inhibit this pump. The gene encoding the alpha-subunit of the pump has undergone duplication events in some insect species known to feed on plants containing cardenolides. Here we test the function of these duplicated gene copies in the cardenolide-adapted milkweed bug, Oncopeltus fasciatus, which has three known copies of the gene: alpha1A, alpha1B and alpha1C. RESULTS: Using RT-qPCR analyses we demonstrate that the alpha1C is highly expressed in neural tissue, where the pump is generally thought to be most important for neuron excitability. With the use of in vivo RNAi in adult bugs we found that alpha1C knockdowns suffered high mortality, where as alpha1A and alpha1B did not, supporting that alpha1C is most important for effective ion pumping. Next we show a role for alpha1A and alpha1B in the handling of cardenolides: expression results find that both copies are primarily expressed in the Malpighian tubules, the primary insect organ responsible for excretion, and when we injected either alpha1A or alpha1B knockdowns with cardenolides this proved fatal (whereas not in controls). CONCLUSIONS: These results show that the Na,K-ATPalpha gene-copies have taken on diverse functions. Having multiple copies of this gene appears to have allowed the newly arisen duplicates to specialize on resistance to cardenolides, whereas the ancestral copy of the pump remains comparatively sensitive, but acts as a more efficient ion carrier. Interestingly both the alpha1A and alpha1B were required for cardenolide handling, suggesting that these two copies have separate and vital functions. Gene duplications of the Na,K-ATPase thus represent an excellent example of subfunctionalization in response to a new environmental challenge. PMID- 29246106 TI - Effects of methanol and formic acid on human platelet aggregation. AB - BACKGROUND: Although ethanol is known to inhibit platelet aggregation, the effects of another variant of alcohol, methanol, have not been reported. The purpose of this study was to determine whether methanol and its metabolite, formic acid, affect Ca2+ entry into and subsequent aggregation of platelets in vitro. METHODS: Ca2+ entry into and aggregation of human platelets were measured by spectrofluorometry using Fura-2/AM as an indicator and the light transmission method, respectively. RESULTS: Thrombin-induced platelet aggregation was significantly augmented by methanol at pharmacological concentrations (0.5-2%) in a concentration-dependent manner. Methanol at 2% significantly attenuated thapsigargin-induced platelet aggregation, which was not significantly affected by lower concentrations (0.5 and 1%) of methanol. Methanol (0.5-2%) did not significantly affect platelet aggregation induced by 1-oleoyl-2-acetyl-sn glycerol (OAG), or Ca2+ entry into platelets induced by thrombin, thapsigargin, or OAG. Platelet aggregation induced by thrombin, thapsigargin, or OAG was significantly inhibited by formic acid at toxic concentrations (0.01% or higher). Ca2+ entry into platelets induced by thrombin or thapsigargin was also significantly inhibited by formic acid at 0.01% or higher, while that induced by OAG was not affected by formic acid at 0.005 and 0.01% and augmented by that at 0.02%. CONCLUSIONS: Methanol at pharmacological doses has diverse effects on platelet aggregation, depending on the aggregation stimuli, without affecting Ca2+ entry into platelets. Formic acid at toxic concentrations has an inhibitory action on platelets aggregation, which was partly explained by the reduction of Ca2+ entry into platelets. PMID- 29246107 TI - Canary: an atomic pipeline for clinical amplicon assays. AB - BACKGROUND: High throughput sequencing requires bioinformatics pipelines to process large volumes of data into meaningful variants that can be translated into a clinical report. These pipelines often suffer from a number of shortcomings: they lack robustness and have many components written in multiple languages, each with a variety of resource requirements. Pipeline components must be linked together with a workflow system to achieve the processing of FASTQ files through to a VCF file of variants. Crafting these pipelines requires considerable bioinformatics and IT skills beyond the reach of many clinical laboratories. RESULTS: Here we present Canary, a single program that can be run on a laptop, which takes FASTQ files from amplicon assays through to an annotated VCF file ready for clinical analysis. Canary can be installed and run with a single command using Docker containerization or run as a single JAR file on a wide range of platforms. Although it is a single utility, Canary performs all the functions present in more complex and unwieldy pipelines. All variants identified by Canary are 3' shifted and represented in their most parsimonious form to provide a consistent nomenclature, irrespective of sequencing variation. Further, proximate in-phase variants are represented as a single HGVS 'delins' variant. This allows for correct nomenclature and consequences to be ascribed to complex multi-nucleotide polymorphisms (MNPs), which are otherwise difficult to represent and interpret. Variants can also be annotated with hundreds of attributes sourced from MyVariant.info to give up to date details on pathogenicity, population statistics and in-silico predictors. CONCLUSIONS: Canary has been used at the Peter MacCallum Cancer Centre in Melbourne for the last 2 years for the processing of clinical sequencing data. By encapsulating clinical features in a single, easily installed executable, Canary makes sequencing more accessible to all pathology laboratories. Canary is available for download as source or a Docker image at https://github.com/PapenfussLab/Canary under a GPL-3.0 License. PMID- 29246109 TI - MetaGenyo: a web tool for meta-analysis of genetic association studies. AB - BACKGROUND: Genetic association studies (GAS) aims to evaluate the association between genetic variants and phenotypes. In the last few years, the number of this type of study has increased exponentially, but the results are not always reproducible due to experimental designs, low sample sizes and other methodological errors. In this field, meta-analysis techniques are becoming very popular tools to combine results across studies to increase statistical power and to resolve discrepancies in genetic association studies. A meta-analysis summarizes research findings, increases statistical power and enables the identification of genuine associations between genotypes and phenotypes. Meta analysis techniques are increasingly used in GAS, but it is also increasing the amount of published meta-analysis containing different errors. Although there are several software packages that implement meta-analysis, none of them are specifically designed for genetic association studies and in most cases their use requires advanced programming or scripting expertise. RESULTS: We have developed MetaGenyo, a web tool for meta-analysis in GAS. MetaGenyo implements a complete and comprehensive workflow that can be executed in an easy-to-use environment without programming knowledge. MetaGenyo has been developed to guide users through the main steps of a GAS meta-analysis, covering Hardy-Weinberg test, statistical association for different genetic models, analysis of heterogeneity, testing for publication bias, subgroup analysis and robustness testing of the results. CONCLUSIONS: MetaGenyo is a useful tool to conduct comprehensive genetic association meta-analysis. The application is freely available at http://bioinfo.genyo.es/metagenyo/ . PMID- 29246108 TI - Origin and cross-century dynamics of an avian hybrid zone. AB - BACKGROUND: Characterizations of the dynamics of hybrid zones in space and time can give insights about traits and processes important in population divergence and speciation. We characterized a hybrid zone between tanagers in the genus Ramphocelus (Aves, Thraupidae) located in southwestern Colombia. We evaluated whether this hybrid zone originated as a result of secondary contact or of primary differentiation, and described its dynamics across time using spatial analyses of molecular, morphological, and coloration data in combination with paleodistribution modeling. RESULTS: Models of potential historical distributions based on climatic data and genetic signatures of demographic expansion suggested that the hybrid zone likely originated following secondary contact between populations that expanded their ranges out of isolated areas in the Quaternary. Concordant patterns of variation in phenotypic characters across the hybrid zone and its narrow extent are suggestive of a tension zone, maintained by a balance between dispersal and selection against hybrids. Estimates of phenotypic cline parameters obtained using specimens collected over nearly a century revealed that, in recent decades, the zone appears to have moved to the east and to higher elevations, and may have become narrower. Genetic variation was not clearly structured along the hybrid zone, but comparisons between historical and contemporary specimens suggested that temporal changes in its genetic makeup may also have occurred. CONCLUSIONS: Our data suggest that the hybrid zone likey resulted from secondary contact between populations. The observed changes in the hybrid zone may be a result of sexual selection, asymmetric gene flow, or environmental change. PMID- 29246110 TI - DNA and RNA-sequence based GWAS highlights membrane-transport genes as key modulators of milk lactose content. AB - BACKGROUND: Lactose provides an easily-digested energy source for neonates, and is the primary carbohydrate in milk in most species. Bovine lactose is also a key component of many human food products. However, compared to analyses of other milk components, the genetic control of lactose has been little studied. Here we present the first GWAS focussed on analysis of milk lactose traits. RESULTS: Using a discovery population of 12,000 taurine dairy cattle, we detail 27 QTL for lactose concentration and yield, and subsequently validate the effects of 26 of these loci in a distinct population of 18,000 cows. We next present data implicating causative genes and variants for these QTL. Fine mapping of these regions using imputed, whole genome sequence-resolution genotypes reveals protein coding candidate causative variants affecting the ABCG2, DGAT1, STAT5B, KCNH4, NPFFR2 and RNF214 genes. Eleven of the remaining QTL appear to be driven by regulatory effects, suggested by the presence of co-locating, co-segregating eQTL discovered using mammary RNA sequence data from a population of 357 lactating cows. Pathway analysis of genes representing all lactose-associated loci shows significant enrichment of genes located in the endoplasmic reticulum, with functions related to ion channel activity mediated through the LRRC8C, P2RX4, KCNJ2 and ANKH genes. A number of the validated QTL are also found to be associated with additional milk volume, fat and protein phenotypes. CONCLUSIONS: Overall, these findings highlight novel candidate genes and variants involved in milk lactose regulation, whose impacts on membrane transport mechanisms reinforce the key osmo-regulatory roles of lactose in milk. PMID- 29246111 TI - Helios + Regulatory T cell frequencies are correlated with control of viral replication and recovery of absolute CD4 T cells counts in early HIV-1 infection. AB - BACKGROUND: The acute phase of HIV infection is characterized by massive depletion of CD4 T cells, high viral plasma levels and pronounced systemic immune activation. Regulatory T cells (Tregs) have the potential to control systemic immune activation but also to suppress antigen specific T and B cell response. The co-expression of FoxP3 and Helios transcription factors, has been described for identification of highly suppressive Tregs. The aim of this study was to characterize the phenotype of classic Tregs during early HIV infection, and to assess the correlations between the frequencies and phenotype of Tregs with the plasma viral load, CD4 counts, immune activation and the frequency of antibodies reactive to HIV-1 proteins, measured by an immunochromatographic test. RESULTS: The relative frequency of classic Tregs cells in peripheral blood correlated positively with HIV viral load and immune activation of CD8 T cells, and inversely with absolute CD4 counts and development of anti-HIV antibodies in subjects with early HIV infection. However, the expression of Helios in classic Tregs was inversely correlated with viral replication and immune activation, and positively with recovery of CD4 T cell counts and appearance of antibodies reactive to HIV-1 proteins. CONCLUSION: These results raise the hypothesis that classic Tregs are inefficient at controlling systemic immune activation in subjects with early HIV infection and may be associated with delayed production of antibodies against HIV proteins, delaying the control of viral replication. Conversely, Helios expressing Tregs might contribute to control of viral replication by mechanisms involving the limitation of systemic immune activation. PMID- 29246113 TI - Comparison of weighting approaches for genetic risk scores in gene-environment interaction studies. AB - BACKGROUND: Weighted genetic risk scores (GRS), defined as weighted sums of risk alleles of single nucleotide polymorphisms (SNPs), are statistically powerful for detection gene-environment (GxE) interactions. To assign weights, the gold standard is to use external weights from an independent study. However, appropriate external weights are not always available. In such situations and in the presence of predominant marginal genetic effects, we have shown in a previous study that GRS with internal weights from marginal genetic effects ("GRS-marginal internal") are a powerful and reliable alternative to single SNP approaches or the use of unweighted GRS. However, this approach might not be appropriate for detecting predominant interactions, i.e. interactions showing an effect stronger than the marginal genetic effect. METHODS: In this paper, we present a weighting approach for such predominant interactions ("GRS-interaction-training") in which parts of the data are used to estimate the weights from the interaction terms and the remaining data are used to determine the GRS. We conducted a simulation study for the detection of GxE interactions in which we evaluated power, type I error and sign-misspecification. We compared this new weighting approach to the GRS marginal-internal approach and to GRS with external weights. RESULTS: Our simulation study showed that in the absence of external weights and with predominant interaction effects, the highest power was reached with the GRS interaction-training approach. If marginal genetic effects were predominant, the GRS-marginal-internal approach was more appropriate. Furthermore, the power to detect interactions reached by the GRS-interaction-training approach was only slightly lower than the power achieved by GRS with external weights. The power of the GRS-interaction-training approach was confirmed in a real data application to the Traffic, Asthma and Genetics (TAG) Study (N = 4465 observations). CONCLUSION: When appropriate external weights are unavailable, we recommend to use internal weights from the study population itself to construct weighted GRS for GxE interaction studies. If the SNPs were chosen because a strong marginal genetic effect was hypothesized, GRS-marginal-internal should be used. If the SNPs were chosen because of their collective impact on the biological mechanisms mediating the environmental effect (hypothesis of predominant interactions) GRS-interaction training should be applied. PMID- 29246112 TI - Isolation and characterization of HepP: a virulence-related Pseudomonas aeruginosa heparinase. AB - BACKGROUND: Pseudomonas aeruginosa is an opportunistic pathogen that causes serious infections in immunocompromised hosts including severely burned patients. In burn patients, P. aeruginosa infection often leads to septic shock and death. Despite numerous studies, the influence of severe thermal injuries on the pathogenesis of P. aeruginosa during systemic infection is not known. Through RNA seq analysis, we recently showed that the growth of P. aeruginosa strain UCBPP PA14 (PA14) in whole blood obtained from severely burned patients significantly altered the expression of the PA14 transcriptome when compared with its growth in blood from healthy volunteers. The expression of PA14_23430 and the adjacent gene, PA14_23420, was enhanced by seven- to eightfold under these conditions. RESULTS: Quantitative real-time PCR analysis confirmed the enhancement of expression of both PA14_23420 and PA14_23430 by growth of PA14 in blood from severely burned patients. Computer analysis revealed that PA14_23430 (hepP) encodes a potential heparinase while PA14_23420 (zbdP) codes for a putative zinc binding dehydrogenase. This analysis further suggested that the two genes form an operon with zbdP first. Presence of the operon was confirmed by RT-PCR experiments. We characterized hepP and its protein product HepP. hepP was cloned from PA14 by PCR and overexpressed in E. coli. The recombinant protein (rHepP) was purified using nickel column chromatography. Heparinase assays using commercially available heparinase as a positive control, revealed that rHepP exhibits heparinase activity. Mutation of hepP resulted in delay of pellicle formation at the air-liquid interface by PA14 under static growth conditions. Biofilm formation by PA14DeltahepP was also significantly reduced. In the Caenorhabditis elegans model of slow killing, mutation of hepP resulted in a significantly lower rate of killing than that of the parent strain PA14. CONCLUSIONS: Changes within the blood of severely burned patients significantly induced expression of hepP in PA14. The heparinase encoded by hepP is a potential virulence factor for PA14 as HepP influences pellicle formation as well as biofilm development by PA14 and the protein is required for full virulence in the C. elegans model of slow killing. PMID- 29246114 TI - The influence of HK2 blood group antigen on human B cell activation for ABOi-KT conditions. AB - BACKGROUND: It is well known that ABO blood group system incompatible kidney transplantation (ABOi-KT) is an effective strategy for end-stage renal disease. The main barrier for ABOi-KT is how to keep host B cell activation and blood group antibody titer in low levels. Moreover, the mechanism of B cell activation induced by blood group antigen was unclear in ABOi-KT. RESULTS: In this study, HK2 cells were identified to express blood group B antigen when cocultured with lymphocytes of blood group A. Optical microscope observation demonstrated that HK2 cells in coculture group gradually decreased. Furthermore, flow cytometer assay identified that T cell phenotypes (CD3+, CD3+CD4+ and CD3+CD8+) had no significant change and B cell phenotypes (CD19+ and CD138+) were all significantly enhanced (3.07 and 3.02 folds) at day 4. In addition, immunoturbidimetry analysis demonstrated that blood group B antibody was significantly increased to 2.35 fold at day 4, IgG was significantly increased to 3.60 and 2.81 folds at days 4 and 8 respectively, while IgM had no significant change at the measured time points. CONCLUSIONS: Taken together, B cells were activated and secreted blood group B antibody after treatment with HK2 expressing blood group B antigen. The results of this study maybe useful for further determination of the mechanism of B cell activation after ABO incompatible kidney endothelial cells stimulation. PMID- 29246115 TI - Training the salmon's genes: influence of aerobic exercise, swimming performance and selection on gene expression in Atlantic salmon. AB - BACKGROUND: Farmed and wild Atlantic salmon are exposed to many infectious and non-infectious challenges that can cause mortality when they enter the sea. Exercise before transfer promotes growth, health and survival in the sea. Swimming performance in juveniles at the freshwater parr stage is positively associated with resistance to some diseases. Genetic variation is likely to affect response to exercise. In this study we map genetic differences associated with aerobic exercise, swimming performance and genetic origin. Eggs from the selectively bred Bolaks salmon and wild Laerdal River salmon strains were reared until parr in a common environment. Swimming performance was assessed by subjecting the fish to either continuous hard exercise or control conditions for 18 days. Heart was sampled for examination of gene expression using RNA-seq (~60 fish/treatment). RESULTS: Lower expression of genes affecting immune function was found in domesticated than wild parr. Among wild parr under control exercise the expression of a large number of genes involved in general metabolism, stress and immune response was lower in superior swimmers suggesting that minimisation of energy expenditure during periods of low activity makes parr better able to sustain bursts of swimming for predator avoidance. A similar set of genes were down-regulated with training among wild parr with inferior swimming performance. These parr react to training in a way that their cardiac expression patterns become like the superior performing wild parr under control exercise conditions. Diversifying selection caused by breeding of domesticated stock, and adaptive pressures in wild stock, has affected the expression and frequency of single nucleotide polymorphisms (SNPs) for multiple functional groups of genes affecting diverse processes. SNPs associated with swimming performance in wild parr map to genes involved in energetic processes, coding for contractile filaments in the muscle and controlling cell proliferation. CONCLUSIONS: Domesticated parr have less phenotypic plasticity in response to training and lower expression of genes with functions affecting immune response. The genetic response to training is complex and depends on the background of parr and their swimming ability. Exercise should be tailored to the genetics and swimming performance of fish. PMID- 29246117 TI - Prognostic significance of RBP2-H1 variant of JARID1B in melanoma. AB - BACKGROUND: Histone demethylase JARID1B plays several context dependent roles in epigenetic regulation of cellular differentiation in normal development and is highly expressed in multiple human cancers. The protein is a strong transcriptional repressor capable of downregulating numerous genes. There are three splicing isoforms of JARID1B, however the links between the protein structure and function are not clear. The expression pattern of JARID1B in human melanoma seems to be different from observed in other cancers. Moreover, up to now no data on the impact of JARID1B expression in cutaneous melanoma on the patients' prognosis have been reported. METHODS: We investigated immunohistochemically the association of intratumoral expression of total JARID1B protein and its RBP2-H1 isoform in primary and metastatic melanomas with prognosis for the patients. RESULTS: Expression of both total JARID1B protein and its RBP2-H1 variant was found in all the melanomas investigated. Our results indicate, however, that only high (above 90% of the cells) intratumoral expression of RBP2-H1 can be considered prognostic factor associated with worse overall survival of the patients. CONCLUSIONS: Such results if considered together with data demonstrating a switch to enhanced expression of RBP2-H1 at early stages of malignant transformation of melanocytes are in agreement with hypothetical crucial role of JARID1B in the course of melanoma development and progression and suggest that altered splicing of JARID1B may be important factor increasing melanoma aggressiveness. PMID- 29246116 TI - Identification of Sertoli cell-specific transcripts in the mouse testis and the role of FSH and androgen in the control of Sertoli cell activity. AB - BACKGROUND: The Sertoli cells act to induce testis differentiation and subsequent development in fetal and post-natal life which makes them key to an understanding of testis biology. As a major step towards characterisation of factors involved in Sertoli cell function we have identified Sertoli cell-specific transcripts in the mouse testis and have used the data to identify Sertoli cell-specific transcripts altered in mice lacking follicle-stimulating hormone receptors (FSHRKO) and/or androgen receptors (AR) in the Sertoli cells (SCARKO). RESULTS: Adult iDTR mice were injected with busulfan to ablate the germ cells and 50 days later they were treated with diphtheria toxin (DTX) to ablate the Sertoli cells. RNAseq carried out on testes from control, busulfan-treated and busulfan + DTX treated mice identified 701 Sertoli-specific transcripts and 4302 germ cell specific transcripts. This data was mapped against results from microarrays using testicular mRNA from 20 day-old FSHRKO, SCARKO and FSHRKO.SCARKO mice. Results show that of the 534 Sertoli cell-specific transcripts present on the gene chips, 85% were altered in the FSHRKO mice and 94% in the SCARKO mice (mostly reduced in both cases). In the FSHRKO.SCARKO mice additive or synergistic effects were seen for most transcripts. Age-dependent studies on a selected number of Sertoli cell specific transcripts, showed that the marked effects in the FSHRKO at 20 days had largely disappeared by adulthood although synergistic effects of FSHR and AR knockout were seen. CONCLUSIONS: These studies have identified the Sertoli cell specific transcriptome in the mouse testis and have shown that most genes in the transcriptome are FSH- and androgen-dependent at puberty although the importance of FSH diminishes towards adulthood. PMID- 29246118 TI - Socioeconomic inequality in periconceptional folic acid supplementation in China: a census of 0.9 million women in their first trimester of pregnancy. AB - BACKGROUND: To assess socioeconomic inequality in periconceptional folic acid supplementation in China. METHODS: We used data of periconceptional folic acid (FA) supplementation of rural Chinese women from the National Free Preconception Health Examination Project from 2010 to 2012 and socioeconomic level data from the National Bureau of Statistics. We used logistic models to assess the associations between the prevalence of taking FA and the sociodemographic characteristics of the participants, the couples, and the socioeconomic levels of their region of residence. RESULTS: Of the 907,720 included women, 682,315 (75.62%) of the women reported taking FA. The prevalence of FA supplementation was significantly higher in participants aged 21-29 (75.87%) than in those women aged 40-49 (68.44%, p < 0.01). The prevalence of FA supplementation was significantly higher in the region with the highest Per Capita Gross Regional Product than in the regions with lower Per Capita Gross Regional Product (aOR = 12.20 [95% CI:9.54-15.61]). The higher the per capita net income of farmer households in the region, the higher the prevalence of FA supplementation (aOR = 1.95 [95% CI:1.74-2.18]). CONCLUSIONS: The rate of periconceptional FA supplementation among rural Chinese women has increased with the support of China's Health System Reform policy. However, socioeconomic disparities in periconceptional folic acid supplementation remain. PMID- 29246119 TI - Overexpression of p53R2 is associated with poor prognosis in lung sarcomatoid carcinoma. AB - BACKGROUND: This study aimmed to evaluate the expression of p53-inducible RR small subunit 2 homologue (p53R2) in Lung sarcomatoid carcinoma (LSC) and its association with clinicopathological parameters and prognosis. METHODS: In this study, clinicopathological factors and prognostic significance of the expression of p53R2 was investigated by immunohistochemistry (IHC) in 100 cases of LSC. RESULTS: The results showed that the expression of p53R2 was significantly correlated with clinical stage (P<0.05). But there was no statistically correlation with gender, age, smoking, tumor size, pT stage, pN stage, pM stage, therapy and relapse. Kaplan-Meier analysis revealed that the expression of p53R2, clinical stage, pT stage, pN stage, pM stage and tumor size were closely related to patients' survival, and the analysis also revealed that patients with low expression of p53R2 had a longer overall survival than that with high expression (Mean overall survival: 84.8 months vs. 34.7 months, P<0.05). Further multivariate analysis indicated that the expression of p53R2 was identified as an independent prognostic factor in the prediction of the overall survival for patients with LSC (HR = 3.217, P<0.05). CONCLUSIONS: The expression of p53R2 was inversely associated with the proliferation and progression of LSC, and the results indicated that the high expression of p53R2 was an independent factor for unfavorable prognosis of patients with LSC. PMID- 29246120 TI - Depressive symptoms and negative life events: What psycho-social factors protect or harm left-behind children in China? AB - BACKGROUND: In China, children under 18 years old who are left at rural residences for at least 6 months by either one or both of their parents migrating to work in cities are called "left-behind children (LBC)". Due to restricted family support, they are at a greater risk of developing depressive symptoms than non-left-behind children (NLBC). The objective of this study is to explore how depressive symptoms and stress induced by negative life events such as interpersonal conflicts, punishment and loss, as well as their relationships vary for LBC with different left-behind-related characteristics. METHODS: Using data from a large school-based survey conducted in Chongqing between December 2012 and June 2013, we first identified the differences in depressive symptoms and negative-event-induced stress between LBC and NLBC, and then analyzed the variances among LBC with different left-behind-related characteristics. The data was analyzed with Chi-square test, MANCOVA, ANCOVA, ANOVA, T-test and hierarchical multiple regression analyses. RESULTS: We found that LBC were more stressed when experiencing negative events and had more depressive symptoms than NLBC. Children left behind by both parents were most depressed. Negative-event induced stress and communication on life difficulties with migrant parents were risk factors for depressive symptoms, whereas adequate communication on academic performance or children's feelings was a protective factor against depressive symptoms. Communication duration and frequency, communication by visiting, communication on academic performance, life difficulties and children's feelings moderated the relationship between stress and depressive symptoms, respectively. Duration of separation, communication duration and frequency, communication on academic performance, learning difficulties and children's feelings moderated the relation between the type of parental migration and depressive symptoms, respectively. CONCLUSIONS: Our findings suggest that children left behind by both parents should be the focus of public attention for their higher susceptibility to stress-related depression. To help LBC stay mentally healthy, governments need to formulate regulations contributing to LBC's family reunion, communities need to involve more residents to attend LBC as "surrogate parents" and teach migrant parents to communicate with LBC properly, and schools need to teach LBC how to deal with stress and communicate with migrant parents. PMID- 29246121 TI - Metabolic dysregulation and cancer mortality in a national cohort of blacks and whites. AB - BACKGROUND: We examined the association between metabolic dysregulation and cancer mortality in a prospective cohort of Black and White adults. METHODS: A total of 25,038 Black and White adults were included in the analysis. Metabolic dysregulation was defined in two ways: 1) using the joint harmonized criteria for metabolic syndrome (MetS) and 2) based on factor analysis of 15 variables characterizing metabolic dysregulation. We estimated hazards ratios (HRs) and 95% confidence intervals (CIs) for the association of MetS and metabolic dysregulation with cancer mortality during follow-up using Cox proportional hazards models. RESULTS: About 46% of Black and 39% of White participants met the criteria for MetS. Overall, participants with MetS (HR: 1.22, 95% CI: 1.03-1.45) were at increased risk of cancer-related death. In race-stratified analysis, Black participants with MetS had significantly increased risk of cancer mortality compared with those without MetS (HR: 1.32, 95% CI: 1.01-1.72), increasing to more than a 2-fold risk of cancer mortality among those with five metabolic syndrome components (HR: 2.35, 95% CI: 1.01-5.51). CONCLUSIONS: There are marked racial differences in the prevalence of metabolic dysregulation defined as MetS based on the harmonized criteria. The strong positive associations between MetS and cancer mortality suggests that efforts to improve cancer outcomes in general, and racial disparities in cancer outcomes specifically, may benefit from prevention and management of MetS and its components. PMID- 29246122 TI - Structural changes of the macula and optic nerve head in the remaining eyes after enucleation for retinoblastoma: an optical coherence tomography study. AB - BACKGROUND: To describe objectively the possible structural changes of the macula and optic nerve head in the free eyes of unilateral cured retinoblastoma patients and, also after enucleation using spectral domain optical coherence tomography. METHODS: A cross sectional study involving 60 patients subdivided into three groups; 15 unilateral RB patients in whom enucleation was indicated as a sole treatment performed earlier in life [(study group (I)], 15 unilateral RB patients who had completely regressed disease with a preserved eye [(study group (II)] and 30 age and sex matched healthy controls. The remaining and free eyes in study groups and right eyes of control group had full ophthalmological examination, static automated perimetry and optical coherence tomography of the macula and optic nerve head. RESULTS: In study group (II); a significant thinning of total macula, central fovea, ganglion cell layer (GCL), ganglion cell complex (GCC), and some sectors of outer nuclear layer (P- values <=0.05) was found with no significant difference in peripapillary nerve fiber layer (pRNFL) thickness and optic nerve head parameters compared to the control group and the study group (I). A significantly thickened total macula, GCL, GCC, and pRNFL in study group (I) compared to study group (II). Thickened pRNFL was significantly correlated to standard automated perimetry pattern deviations. No significant difference was found between study group (I) and control group. CONCLUSION: Retinoblastoma eyes characterized by thinning of central fovea, GCL, GCC compared to the control group. After unilateral enucleation, increased GCC and pRNFL thicknesses were detected compared to retinoblastoma group. PMID- 29246123 TI - Contraceptive use among lactating women in Ganta-Afeshum District, Eastern Tigray, Northern Ethiopia, 2015: a cross sectional study. AB - BACKGROUND: Women who are not exclusively breastfeeding are at risk of pregnancy after four to six weeks of childbirth. Postpartum contraceptive use is crucial to prevent unintended pregnancy, and to have spaced births. The study was conducted to determine the magnitude of modern contraceptive utilization and factors associated with it among lactating women in Ganta-Afeshum district. METHODS: A community based cross sectional study was conducted among lactating women with children in the age group of six to twelve months. A total of 605 women were included in the study. The study participants were selected using cluster sampling method. Data were collected using structured interviewer administered Tigrigna version questionnaire. Data were analyzed using SPSS version 21. Multivariable logistic regression was used to control the effect of confounders. RESULTS: The magnitude of institutional delivery was 96.5%. The mode of delivery of the participants was spontaneous, instrumental and caesarean section, 95.5%, 2.0%, and 2.5%, respectively. The magnitude of modern contraceptive (MC) utilization was 68.1% (95% CI: 64.4-71.8). The contraceptive method mix was dominated by Depo-Provera (58.8%) followed by implants (31.8%). Almost all the study participants had at least one antenatal care (ANC) visit (99.7%) during the pregnancy of their index child. Participants who had radio and those who delivered their recent child by assisted delivery had higher odds of modern contraceptive use. CONCLUSIONS: The magnitude of contraceptive utilization among lactating mothers in the study area was higher than the national survey reports. However, significant numbers of women are not using contraceptives in their postpartum period, making them at risk of pregnancy. Mode of delivery of the women and having radio at home were significantly associated with the women's contraceptive utilization. Family planning information dissemination using radio in rural settings should be encouraged to increase the uptake of contraceptives in the lactating women. PMID- 29246125 TI - Low birth weight contributed to increased serum IL-6 levels in infantile respiratory syncytial virus infection. AB - BACKGROUND: To evaluate the role of serum cytokines in the pathogenesis of respiratory syncytial virus (RSV) infection in infants with low birth weight (LBW). METHODS: A prospective observational study was performed, and hospitalized children with lower respiratory tract infection (LRTI) were recruited. Three hundred fifty-eight patients < 1 year met the inclusion criteria: 116 patients had only RSV infection (RSV group); 242 patients had no RSV or other specific pathogen (non-RSV group). Serum interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) were detected through flow cytometry. RESULTS: No significant differences in serum IL-2, 4, 6, 10, and IFN-gamma levels were observed between the RSV and non-RSV groups. For RSV infected infants with or without wheezing, delivery mode had no obvious effect on the changes of serum cytokine levels. However, the level of IL-6 in the RSV-infected infants with LBW was significantly higher than that in infants with normal birth weight. CONCLUSIONS: Serum IL-6 level was significantly increased in RSV infected infants with LBW. It is likely that the specific serum cytokine pattern will contribute to our understanding of the pathogenesis of RSV infections, especially in RSV-infected infants with LBW. PMID- 29246124 TI - Transcriptome analysis of genes associated with breast cancer cell motility in response to Artemisinin treatment. AB - BACKGROUND: Well-known anti-malarial drug artemisinin exhibits potent anti cancerous activities. In-vivo and in-vitro studies showed its anti-tumor and immunomodulatory properties signifying it as a potent drug candidate for study. The studies of mechanisms of cell movement are relevant which can be understood by knowing the involvement of genes in an effect of a drug. Although cytotoxicity and anti-proliferative activity of artemisinin is evident, the genes participating in its anti-migratory and reduced invasive effect are not well studied. The present study reports the alteration in the expression of 84 genes involved in cell motility upon artemisinin treatment in MCF-7 breast cancer cells using pathway focused gene expression PCR array. In addition, the effect of artemisinin on epigenetic modifier HDACs is studied. METHODS: We checked the functional stimulus of artemisinin on cell viability, migration, invasion and apoptosis in breast cancerous cell lines. Using qRT-PCR and western blot, we validated the altered expression of relevant genes associated with proliferation, migration, invasion, apoptosis and mammary gland development. RESULTS: Artemisinin inhibited cell proliferation of estrogen receptor negative breast cancer cells with fewer efficacies in comparison to estrogen receptor positive ones. At the same time, cell viability and proliferation of normal breast epithelial MCF10A cells was un-affected. Artemisinin strongly inhibited cancer cell migration and invasion. Along with orphan nuclear receptors (ERRalpha, ERRbeta and ERRgamma), artemisinin altered the ERalpha/ERbeta/PR/Her expression status of MCF-7 cells. The expression of genes involved in the signaling pathways associated with proliferation, migration, invasion and apoptosis was significantly altered which cooperatively resulted into reduced growth promoting activities of breast cancer cells. Interestingly, artemisinin exhibited inhibitory effect on histone deacetylases (HDACs). CONCLUSIONS: Upregulated expression of tumor suppressor genes along with reduced expression of oncogenes significantly associated with growth stimulating signaling pathways in response to artemisinin treatment suggests its efficacy as an effective drug in breast cancer treatment. PMID- 29246126 TI - Perceptions of colorectal cancer screening and recommendation behaviors among physicians in Korea. AB - BACKGROUND: Physician recommendations for colorectal cancer (CRC) screening have consistently been shown to be a strong predictor of screening. The aim of this study was to investigate perceptions of CRC screening modalities and recommendation behaviors among physicians in Korea. METHODS: A cross-sectional, nationally representative survey conducted between November 2013 and February 2014. In total, 379 physicians (241 primary care physicians and 138 physicians affiliated with the Korean Association for the Study of Intestinal Diseases responded to this survey (overall response rate of 31.4%). RESULTS: About 29% of all respondents "always" recommended and about 67% "sometimes" recommended CRC screening. Colonoscopy was perceived as an effective primary screening tool for CRC, and 80% of the physicians recommended colonoscopy for CRC screening. Only 7% recommended FOBT. In multivariate analysis, recommending FOBT was associated with stronger belief in the screening efficacy of FOBT (aOR 3.70, 95% CI 2.09, 6.57), weaker belief in the screening efficacy of colonoscopy (aOR 0.29, 95% CI 0.12, 0.69), and negative decisional balance for colonoscopy screening (aOR 0.82, 95% CI 0.71, 0.95). CONCLUSIONS: Although FOBT is provided free-of-charge through a nationwide CRC screening program, colonoscopy was more commonly recommended and preferred by physicians. PMID- 29246129 TI - Women's motivations for choosing a high risk birth setting against medical advice in the Netherlands: a qualitative analysis. AB - BACKGROUND: Home births in high risk pregnancies and unassisted childbirth seem to be increasing in the Netherlands. Until now there were no qualitative data on women's motivations for these choices in the Dutch maternity care system where integrated midwifery care and home birth are regular options in low risk pregnancies. We aimed to examine women's motivations for birthing outside the system in order to provide medical professionals with insight and recommendations regarding their interactions with women who have birth wishes that go against medical advice. METHODS: An exploratory qualitative research design with a constructivist approach and a grounded theory method were used. In-depth interviews were performed with 28 women on their motivations for going against medical advice in choosing a high risk childbirth setting. Open, axial and selective coding of the interview data was done in order to generate themes. A focus group was held for a member check of the findings. RESULTS: Four main themes were found: 1) Discrepancy in the definition of superior knowledge, 2) Need for autonomy and trust in the birth process, 3) Conflict during negotiation of the birth plan, and 4) Search for different care. One overarching theme emerged that covered all other themes: Fear. This theme refers both to the participants' fear (of interventions and negative consequences of their choices) and to the providers' fear (of a bad outcome). Where for some women it was a positive choice, for the majority of women in this study the choice for a home birth in a high risk pregnancy or an unassisted childbirth was a negative one. Negative choices were due to previous or current negative experiences with maternity care and/or conflict surrounding the birth plan. CONCLUSIONS: The main goal of working with women whose birthing choices do not align with medical advice should not be to coerce them into the framework of protocols and guidelines but to prevent negative choices. Recommendations for maternity caregivers can be summarized as: 1) Rethink risk discourse, 2) Respect a woman's trust in the birth process and her autonomous choice, 3) Have a flexible approach to negotiating the birth plan using the model of shared decision making, 4) Be aware of alternative delivery care providers and other sources of information used by women, and 5) Provide maternity care without spreading or using fear. PMID- 29246127 TI - High mobility group box 1 promotes sorafenib resistance in HepG2 cells and in vivo. AB - BACKGROUND: Primary liver cancer is a lethal malignancy with a high mortality worldwide. Currently, sorafenib is the most effective molecular-targeted drug against hepatocellular carcinoma (HCC). However, the sorafenib resistance rate is high. The molecular mechanism of this resistance has not been fully elucidated. High mobility group box 1 (HMGB1) is a multifaceted protein that plays a key role in the proliferation, apoptosis, metastasis and angiogenesis of HCC cells. In addition, HMGB1 has been suggested to contribute to chemotherapy resistance in tumours, including lung cancer, osteosarcoma, neuroblastoma, leukaemia, and colorectal cancer. This study investigated the association between HMGB1 and sorafenib resistance in HCC. METHODS: HepG2 cells with HMGB1 knockdown or overexpression were generated. The efficacy of sorafenib in these cells was tested using flow cytometry and a cell counting assay. The subcellular localization of HMGB1 in HepG2 cells following sorafenib treatment was measured by western blotting and confocal microscopy. A murine subcutaneous HCC model was generated to examine the association between HMGB1 and the sensitivity of sorafenib treatment. RESULTS: The HMGB1 knockdown cells exhibited a significantly higher apoptotic level and lower cell viability than the normal HMGB1 expressing cells following the sorafenib treatment. In addition, the cell viability observed in the HMGB1 overexpressing cells was higher than that observed in the control cells following the sorafenib intervention. Sorafenib had a better tumour inhibition effect in the HMGB1 knockdown group in vivo. The amount of mitochondrial HMGB1 decreased, while the amount of cytosolic HMGB1 increased following the exposure to sorafenib. Altogether, HMGB1 translocated from the mitochondria to the cytoplasm outside the mitochondria following the exposure of HepG2 cells to sorafenib. CONCLUSIONS: A novel potential role of HMGB1 in the regulation of sorafenib therapy resistance in HCC was observed. The knockdown of HMGB1 restores sensitivity to sorafenib and enhances HepG2 cell death, while HMGB1 overexpression blunts these effects. The translocation of HMGB1 from the mitochondria to the cytosol following sorafenib treatment provides new insight into sorafenib resistance in HCC. PMID- 29246128 TI - Maternal vitamin D status, gestational diabetes and infant birth size. AB - BACKGROUND: Maternal vitamin D status has been associated with both gestational diabetes mellitus (GDM) and fetal growth restriction, however, the evidence is inconsistent. In Finland, maternal vitamin D status has improved considerably due to national health policies. Our objective was to compare maternal 25-hydroxy vitamin D concentrations [25(OH)D] between mothers with and without GDM, and to investigate if an association existed between maternal vitamin D concentration and infant birth size. METHODS: This cross-sectional study included 723 mother child pairs. Mothers were of Caucasian origin, and infants were born at term with normal birth weight. GDM diagnosis and birth size were obtained from medical records. Maternal 25(OH)D was determined on average at 11 weeks of gestation in pregnancy and in umbilical cord blood (UCB) at birth. RESULTS: GDM was observed in 81 of the 723 women (11%). Of the study population, 97% were vitamin D sufficient [25(OH)D >= 50 nmol/L]. There was no difference in pregnancy 25(OH)D concentration between GDM and non-GDM mothers (82 vs 82 nmol/L, P = 0.99). Regression analysis confirmed no association between oral glucose tolerance test results and maternal 25(OH)D (P > 0.53). Regarding the birth size, mothers with optimal pregnancy 25(OH)D (>= 80 nmol/L) had heavier newborns than those with suboptimal pregnancy 25(OH)D (P = 0.010). However, mothers with optimal UCB 25(OH)D had newborns with smaller head circumference than those with suboptimal 25(OH)D (P = 0.003), which was further confirmed as a linear association (P = 0.024). CONCLUSIONS: Maternal vitamin D concentration was similar in mothers with and without GDM in a mostly vitamin D sufficient population. Associations between maternal vitamin D status and birth size were inconsistent. A sufficient maternal vitamin D status, specified as 25(OH)D above 50 nmol/L, may be a threshold above which the physiological requirements of pregnancy are achieved. TRIAL REGISTRATION: The project protocol is registered in ClinicalTrials.gov in November 8, 2012 ( NCT01723852 ). PMID- 29246130 TI - Enteral vitamin A for reducing severity of bronchopulmonary dysplasia in extremely preterm infants: a randomised controlled trial. AB - BACKGROUND: Intramuscular vitamin A supplementation decreases the risk of bronchopulmonary dysplasia (BPD) in very-low-birth-weight preterm infants without significant adverse effects. However, intramuscular vitamin A supplementation is not widely accepted because of the discomfort and risk of trauma associated with repeated injections. Enteral vitamin A supplementation has not been studied adequately in the clinical trials. Enterally administered water-soluble vitamin A is absorbed better than the fat-soluble form. We hypothesised that enteral administration of a water-soluble vitamin A preparation will decrease severity of BPD compared with a control group receiving placebo. METHODS: We plan a double blind randomised placebo-controlled trial at a tertiary neonatal-perinatal intensive care unit. Eligibility criteria include infants born at less than 28 weeks' gestational age and less than 72 h of life. Infants with major congenital gastrointestinal or respiratory tract abnormalities will be excluded. After parental consent, infants will be randomized to receive either enteral water soluble vitamin A (5000 IU once a day) or placebo. The intervention will be started within 24 h of introduction of feeds and continued until 34 weeks' post menstrual age (PMA). The primary outcome is severity of BPD at 36 weeks' PMA. Severity of BPD will be assessed objectively from the right-shift of the peripheral oxyhaemoglobin saturation versus partial pressure of inspired oxygen (SpO2-PiO2) curve. We require 188 infants for 80% power and 5% significance level based on an expected 20% decrease in the right shift of the SpO2-PiO2 curve in the vitamin A group (primary outcome) compared with control group at 36 weeks' PMA, and a 20% attrition rate. Secondary outcomes will be plasma and salivary concentrations of vitamin A on day 28 of the trial (first 30 infants), lung and diaphragm function, clinical outcomes at 36 week' PMA or before discharge/death, and safety of vitamin A. DISCUSSION: BPD poses a significant economic burden on the health-care system. If our study shows that enteral supplementation of water soluble vitamin A is safe and effective for decreasing the severity of BPD, it will provide the opportunity to further evaluate a simple, globally acceptable preventive therapy for BPD. TRIAL REGISTRATION: ANZCTR; ACTRN12616000408482 (30th March 2016). PMID- 29246131 TI - Mammographic density and risk of breast cancer by tumor characteristics: a case control study. AB - BACKGROUND: In a previous paper, we had assumed that the risk of screen-detected breast cancer mostly reflects inherent risk, and the risk of whether a breast cancer is interval versus screen-detected mostly reflects risk of masking. We found that inherent risk was predicted by body mass index (BMI) and dense area (DA) or percent dense area (PDA), but not by non-dense area (NDA). Masking, however, was best predicted by PDA but not BMI. In this study, we aimed to investigate if these associations vary by tumor characteristics and mode of detection. METHODS: We conducted a case-control study nested within the Melbourne Collaborative Cohort Study of 244 screen-detected cases matched to 700 controls and 148 interval cases matched to 446 controls. DA, NDA and PDA were measured using the Cumulus software. Tumor characteristics included size, grade, lymph node involvement, and ER, PR, and HER2 status. Conditional and unconditional logistic regression were applied as appropriate to estimate the Odds per Adjusted Standard Deviation (OPERA) adjusted for age and BMI, allowing the association with BMI to be a function of age at diagnosis. RESULTS: For screen-detected cancer, both DA and PDA were associated to an increased risk of tumors of large size (OPERA ~ 1.6) and positive lymph node involvement (OPERA ~ 1.8); no association was observed for BMI and NDA. For risk of interval versus screen detected breast cancer, the association with risk for any of the three mammographic measures did not vary by tumor characteristics; an association was observed for BMI for positive lymph nodes (OPERA ~ 0.6). No associations were observed for tumor grade and ER, PR and HER2 status of tumor. CONCLUSIONS: Both DA and PDA were predictors of inherent risk of larger breast tumors and positive nodal status, whereas for each of the three mammographic density measures the association with risk of masking did not vary by tumor characteristics. This might raise the hypothesis that the risk of breast tumours with poorer prognosis, such as larger and node positive tumours, is intrinsically associated with increased mammographic density and not through delay of diagnosis due to masking. PMID- 29246132 TI - Neuroprotective effects of hyperbaric oxygen (HBO) therapy on neuronal death induced by sciatic nerve transection in rat. AB - BACKGROUND: Recent studies shows that hyperbaric oxygen (HBO) therapy exerts some protective effects against neural injuries. The purpose of this study was to determine the neuroprotective effects of HBO following sciatic nerve transection (SNT). METHODS: Rats were randomly divided into five groups (n = 14 per group): Sham-operated (SH) group, SH + HBO group, SNT group, and SNT + pre- and SNT + post-HBO groups (100% oxygen at 2.0 atm absolute, 60 min/day for five consecutive days beginning on 1 day before and immediately after nerve transaction, respectively). Spinal cord segments of the sciatic nerve and related dorsal root ganglions (DRGs) were removed 4 weeks after nerve transection for biochemical assessment of malodialdehyde (MDA) levels in spinal cord, biochemical assessment of superoxide dismutase (SOD) and catalse (CAT) activities in spinal cord, immunohistochemistry of caspase-3, cyclooxigenase-2 (COX-2), S100beta (S100beta), and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) in spinal cord and DRG. RESULTS: The results revealed that MDA levels were significantly decreased in the SNT + pre-HBO group, while SOD and CAT activities were significantly increased in SNT + pre- and SNT + post-HBO treated rats. Attenuated caspase-3 and COX-2 expression, and TUNEL reaction could be significantly detected in the HBO-treated rats after nerve transection. Also, HBO significantly increased S100beta expression. CONCLUSIONS: Based on these results, we can conclude that pre- and post-HBO therapy had neuroprotective effects against sciatic nerve transection-induced degeneration. PMID- 29246133 TI - Prediction of fracture load and stiffness of the proximal femur by CT-based specimen specific finite element analysis: cadaveric validation study. AB - BACKGROUND: Finite element analysis (FEA) of the proximal femur has been previously validated with large mesh size, but these were insufficient to simulate the model with small implants in recent studies. This study aimed to validate the proximal femoral computed tomography (CT)-based specimen-specific FEA model with smaller mesh size using fresh frozen cadavers. METHODS: Twenty proximal femora from 10 cadavers (mean age, 87.1 years) were examined. CT was performed on all specimens with a calibration phantom. Nonlinear FEA prediction with stance configuration was performed using Mechanical Finder (mesh,1.5 mm tetrahedral elements; shell thickness, 0.2 mm; Poisson's coefficient, 0.3), in comparison with mechanical testing. Force was applied at a fixed vertical displacement rate, and the magnitude of the applied load and displacement were continuously recorded. The fracture load and stiffness were calculated from force displacement curve, and the correlation between mechanical testing and FEA prediction was examined. RESULTS: A pilot study with one femur revealed that the equations proposed by Keller for vertebra were the most reproducible for calculating Young's modulus and the yield stress of elements of the proximal femur. There was a good linear correlation between fracture loads of mechanical testing and FEA prediction (R2 = 0.6187) and between the stiffness of mechanical testing and FEA prediction (R2 = 0.5499). There was a good linear correlation between fracture load and stiffness (R2 = 0.6345) in mechanical testing and an excellent correlation between these (R2 = 0.9240) in FEA prediction. CONCLUSIONS: CT-based specimen-specific FEA model of the proximal femur with small element size was validated using fresh frozen cadavers. The equations proposed by Keller for vertebra were found to be the most reproducible for the proximal femur in elderly people. PMID- 29246134 TI - Influence of the anterior notch in mobile-bearing UKA on patellofemoral radiotracer uptake and clinical outcome. AB - BACKGROUND: Previous studies reported that in partial knee arthroplasty smooth transitions to the remaining native parts of the knee are important. However, in mobile-bearing unicondylar knee arthroplasty (UKA) it is mandatory to create an anterior osteochondral notch adjacent to the femoral component to get clearance for the anterior lip of the bearing in full knee extension. This notch is, however, part of the femoral trochlea. It was the aim of the study to test for a potential association between a) an obligatory anterior notch in mobile-bearing UKA located at the margin of the medial aspect of the femoral trochlea and b) postoperative patellofemoral joint (PFJ) bone remodelling and discomfort. METHODS: In patients who underwent routine mobile-bearing UKA (11 male, 13 female; 64.5 years / IQR 14) the following parameters were prospectively determined i) size of the surgically created anterior notch, ii) knee score sensitive to PFJ disorders, iii) bone remodelling in the PFJ (radiotracer uptake in SPECT-CT). RESULTS: Notch size was not correlated with radiotracer uptake at the PFJ. Similarly, no significant correlations were observed between radiotracer uptake (patella or trochleocondylar junction) and knee scores (KOOS or Kujala Score). Significant positive correlations were found between notch size and knee scores. CONCLUSIONS: From the findings made in our study it is concluded that a larger size of the anterior notch in mobile-bearing medial Oxford UKA is not associated with increased osteochondral remodelling processes at the patella or the trochleocondylar junction. Neither is a larger sized notch associated with worse clinical PFJ outcome. Surprisingly, a larger notch was even associated with superior clinical outcome. The exact mechanism for this contraintuitive finding remains unclear but may be the basis for future research. TRIAL REGISTRATION: The study is registered in a public trials registry. Link: (9/12/2017) ClinicalTrials.gov. NCT01407042 ; Date of registration: July, 26, 2011. PMID- 29246136 TI - Exploring the rewards and challenges of paediatric palliative care work - a qualitative study of a multi-disciplinary children's hospice care team. AB - BACKGROUND: Children's hospices are a key provider of palliative care for children and young people with life-limiting and life-threatening conditions. However, despite recent policy attention to the provision of paediatric palliative care, little is known about the role of children's hospice staff and the factors that may impact on their wellbeing at work. This study explored the rewards and challenges of working in a children's hospice with an aim to identify staff support and development needs. METHODS: We conducted an exploratory, qualitative study involving thematic analysis of semi-structured interviews with 34 staff and three focus groups with 17 staff working in a multi-disciplinary care team in a UK children's hospice. RESULTS: Participants identified rewards and challenges related to the direct work of caring for children and their families; team dynamics and organisational structures; and individual resilience and job motivation. Participants described the work as emotionally intensive and multi-faceted; 'getting it right' for children was identified as a strong motivator and reward, but also a potential stressor as staff strived to maintain high standards of personalised and emotional care. Other factors were identified as both a reward and stressor, including team functioning, the allocation of work, meeting parent expectations, and the hospice environment. Many participants identified training needs for different aspects of the role to help them feel more confident and competent. Participants also expressed concerns about work related stress, both for themselves and for colleagues, but felt unable to discuss this at work. Informal support from colleagues and group clinical reflection were identified as primary resources to reflect on and learn from work and for emotional support. However, opportunities for this were limited. CONCLUSIONS: Providing regular, structured, and dedicated clinical reflection provides a mechanism through which children's hospice staff can come together for support and learning, and demonstrates an organisational commitment to staff wellbeing and development. Being aware of children's hospice specific rewards and challenges can help to ensure that staff feel supported and competent in their role. Breaking down barriers to discussing work-related stress and enhancing awareness about early signs of burnout is also important. PMID- 29246135 TI - MOK, a pharmacopuncture medicine, regulates thyroid dysfunction in L-thyroxin induced hyperthyroidism in rats through the regulation of oxidation and the TRPV1 ion channel. AB - BACKGROUND: In this study, we evaluated the therapeutic effect of MOK, a pharmacopuncture medicine, on thyroid dysfunction in L-thyroxin (LT4)-induced hyperthyroidism rats. METHODS: The experimental hyperthyroidism model was prepared by the intraperitoneal injection of LT4 (0.5 mg/kg) once daily for 2 weeks in SD rats. MOK extract was injected at doses of 0.3 or 3 mg/kg on acupuncture points in the thyroid glands of LT4-induced hypothyroidism rats once a day for 2 weeks. The body temperature, body weight, and food/water intake were measured once a week for 2 weeks. The levels of thyroid hormones, total cholesterol, LDL-cholesterol, GOT, and GPT were measured in the sera of rats using ELISA and an automatic blood analyzer. The histological changes of thyroid tissues were observed by H&E staining. The expression of thermo-regulating protein, TRPV1 was determined by western blot in dorsal root ganglion (DRG) and brain tissues. We also measured the contents of GSH in the liver and antioxidant enzymes, SOD, and catalase in the liver, heart, and brain tissues by enzyme-based assay and Western blot, respectively. RESULTS: The acupuncture of MOK extract on the thyroid gland of LT4-induced hyperthyroidism rats significantly decreased the body temperature, and did not change body weight and food and water intakes. MOK acupuncture significantly increased the level of TSH, and decreased the levels of T3 and T4 in hyperthyroidism rats. The expression of TRPV1 was inhibited in both DRG and brain tissues after MOK acupuncture, and the levels of GOT, GPT, total cholesterol, and LDL-cholesterol were also decreased. MOK acupuncture also inhibited the pathological feature with follicular lining epithelial thicknesses and increased follicular colloid depositions in the thyroid glands of hypothyroidism. MOK acupuncture significantly increased hepatic GSH levels and decreased the expression of SOD and catalase in the liver, heart, and brain tissues of hyperthyroidism rats. CONCLUSIONS: These results suggest that the pharmacopuncture with MOK extract in hyperthyroidism can improve the pathophysiological changes through regulating the body temperature, thyroid hormones imbalance, lipid accumulation, and oxidation. This anti-hyperthyroidism effect of MOK pharmacopuncture is thought to be related to the control of thermo regulating protein TRPV1 in DRG and brain. PMID- 29246137 TI - Skin marker placement by technologist prior to knee MRI helps identify clinically relevant pathologies. AB - BACKGROUND: Majority of musculoskeletal cross-sectional imaging requests have a non-revealing and non-specific clinical history of pain. However, the location of pain is very relevant towards arriving at a specific orthopedic diagnosis. The purpose of this research was to study the impact of skin marker placement and training of technologists prior to knee MRI in detection of clinically important findings. METHODS: Total 200 consecutive left knee MRIs were evaluated before and after technologist training with regards to marker placement at the site of clinical symptoms or palpable finding. Marker location in relation to the knee was recorded and important findings were classified as correlated important finding, non-correlated important finding, other compartment important finding in non-correlated cases, and diffuse abnormality, i.e. tri-compartmental cartilage defects in both correlated and non-correlated cases. Differences among scans before and after technologist training were analyzed. RESULTS: The marker placement was observed in higher proportion of patients in post-training scans (78% vs 60%, p = 0.00). The most common location of the marker was in anterior or anterolateral knee (32% and 34% cases, respectively). The marker-important finding correlation was also higher post training, but not statistically significant (53% versus 38%, p = 0.57). Important findings correlated with the marker in more than 50% of the scans in the post-training set. CONCLUSION: Marker placement can aid in detection of clinically important imaging finding and technologist training aids in increased rates of marker placement and improved correlation. PMID- 29246138 TI - The immunomodulatory activities of licorice polysaccharides (Glycyrrhiza uralensis Fisch.) in CT 26 tumor-bearing mice. AB - BACKGROUND: The increasing use of complementary and alternative medicine (CAM) has kindled the need for scientific evaluation of the mechanism of action of CAMs. Although, licorice, a common ingredient in many Traditional Chinese medicine (TCM) has attracted great attention for its antitumor and immunomodulatory activities, the mechanism of action of its polysaccharides is still unclear. Here we report the immunomodulatory activity of licorice polysaccharides in vivo. METHODS: The differential anticancer activities of licorice polysaccharides by tumorigenesis and immunomodulation was evaluated in vivo. Six weeks old, 120 CT-26 tumor bearing BALB/c mice, weighing 20 +/- 2 g were used. They were randomly divided into six groups, three groups receiving high molecular weight (fraction A), low molecular weight (fraction B) polysaccharides and crude extract (fraction C); positive, negative and normal groups receiving cytoxin, saline and normal diet respectively. Weight of mice and tumors was determined and tumorigenicity assay calculated to determine the anticancer effects. Immunomodulatory potential was determined by immune organ indices, immune cell population and serum cytokine levels using immune organ weight and index, flow cytometry and cytokine/chemokine bead panel kit respectively. RESULTS: Licorice polysaccharides exhibited immunomodulatory activities in CT 26 tumor bearing BALB/c mice. The polysaccharides significantly suppressed tumor growth and increased immune organ index. Furthermore, the immunomodulatory effect was evident with activation of CD4+ and CD8+ immune cells population. The polysaccharides also affected the production of various cytokines, by increasing IL 2, IL 6, IL 7 levels and a decreasing TNFalpha levels. CONCLUSION: In summary, licorice polysaccharide especially of low molecular weight exhibit anticancer and immunomodulatory activities by suppressing tumor growth and improving general health of mice. They also augment the thymus/spleen index and population of T lymphocytes. Furthermore, the polysaccharides enhance the levels of serum antitumor cytokines, IL 2, IL 6 and IL 7 while decreasing pro-tumor cytokine TNFalpha. PMID- 29246139 TI - Impact of a structured multicomponent educational intervention program on metabolic control of patients with type 2 diabetes. AB - BACKGROUND: Diabetes is one of the most common metabolic disorders, with a high prevalence of patients with poor metabolic control. Worldwide, evidence highlights the importance of developing and implementing educational interventions that can reduce this burden. The main objective of this study was to analyse the impact of a lifestyle centred intervention on glycaemic control of poorly controlled type 2 diabetic patients, followed in a Community Care Centre. METHODS: A type 2 experimental design was conducted over 6 months, including 122 adults with HbA1c >= 7.5%, randomly allocated into Experimental group (EG) or Control Group (CG). EG patients attended a specific Educational Program while CG patients frequented usual care. Personal and health characterization variables, clinical metrics and self-care activities were measured before and after the implementation of the intervention. Analysis was done by comparing gains between groups (CG vs EG) through differential calculations (post minus pre-test results) and Longitudinal analysis. RESULTS: Statistical differences were obtained between groups for HbA1c and BMI: EG had a decrease in 11% more (effect-size r2 = .11) than CG for HbA1c (p < .001) and 4% more (effect-size r2 = .04) in BMI (p < .05). When controlling for socioeconomic characteristics and comorbidities that showed to be associated to each parameter in pre-test, from pre to post-test only EG participants significantly decreased HbA1c [Wilks' y = .702; F(1,57) = 24.16; p < .001; etap2 = .298; observed power = .998]; BMI values [Wilks' y = .900; F(1,59) = 6.57; p = .013; etap2 = .100; observed power = .713]; systolic Blood pressure [Wilks' y = .735; F(1,61) = 21.94; p < .001; etap2 = .265; observed power = .996] and diastolic Blood pressure [Wilks' y = .795; F(1,59) = 15.20; p < .001; etap2 = .205; observed power = .970]. CONCLUSIONS: The impact of a structured multicomponent educational intervention program by itself, beyond standard educational approach alone, supported in a Longitudinal analysis that controlled variables statistically associated with clinical metrics in pre-test measures, has demonstrated its effectiveness in improving HbA1c, BMI and Blood pressure values. TRIAL REGISTRATION: RBR-8ns8pb . (Retrospectively registered: October 30,2017). PMID- 29246140 TI - An association of spleen volume and aortic diameter in patients and in mice with abdominal aortic aneurysm. AB - BACKGROUND: To investigate the potential mechanism of splenic enlargement in Ang II/APOE model and the associations between the spleen volume and the indices of abdominal aortic aneurysm (AAA) in human. METHODS: To investigate the changes of spleen volume on AAA formation, apolipoprotein E knockout (Apo E-/-) mice were treated with Ang II (1000 ng/kg/min) up to 28 days to generate AAA. We used Magnetic Resonance Imaging (MRI), liquid measurement, H&E and immunohistochemistry to analyze the morphological or pathological changes of spleen. To investigate the changes of spleen volume in human, a retrospective case-control study involving 30 male AAA patients and 25 male controls were performed. Spleen volume was measured on computed tomography images. Univariate analysis and multivariable sequential logistic regression analyses were used to analyze the association between spleen volume and maximal diameter (Dmax). RESULTS: In Ang II/APOE model, we found splenic enlargement in mice with AAA compared with the sham group. Histopathological investigations revealed hypertrophies of splenic follicles and increased populations of CD3+ T cells. In clinic cohort study, univariate analysis revealed higher values in large AAA (Dmax > 5.5 cm,n = 15) compared with the small (Dmax < 5.5 cm,n = 15) for spleen volume (230.6 +/- 64.5 cm3 vs. 170.0 +/- 32.8 cm3; P = 0.0030). Regression analysis revealed a statistically significant positive linear correlation of spleen volume and Dmax of AAA (r = 0.3611;P = 0.0423). CONCLUSIONS: Mimicking the splenic pathology observed in murine AAA model, there is a strong positive correlation between spleen volume and the Dmax in male AAA patients. As Dmax is a valuable predictor of AAA rupture, the spleen enlargement may be another indicator. PMID- 29246141 TI - Multisite peripheral joint pain: a cross-sectional study of prevalence and impact on general health, quality of life, pain intensity and consultation behaviour. AB - BACKGROUND: Research into musculoskeletal conditions often focusses on pain at single sites, such as the knee, yet several studies have previously reported the high prevalence of multiple sites of musculoskeletal pain. The most common form of musculoskeletal condition is arthritis, with osteoarthritis (OA) the most common cause of joint pain in adults 45 years and over. However, there is limited recognition of the prevalence of multisite peripheral joint pain in those either living with or at risk of OA, therefore this study set out to estimate the prevalence of multisite peripheral joint pain in adults 45 years and older, and its impact on several dimensions of health. METHODS: A cross-sectional population survey was mailed to adults (n = 28,443) aged 45 years and over from eight general practices in the North West Midlands, United Kingdom (UK). Prevalence rates were established for multisite peripheral joint pain (pain in two or more sites; hands, hips, knees, feet). Impact was measured for general health (SF-12 MCS & PCS), QoL (EQ-5D), pain intensity (0-10 numerical ratings scale) and the number of consultations with a range of health care professionals. RESULTS: Of 15,083 responders (53%), multisite peripheral joint pain was reported by 54%. Peripheral joint pain was present in n = 11,928, of which 68% reported pain in multiple sites. Multisite peripheral joint pain was shown to be significantly associated with reduced physical (Mean difference = -5.9 95% CI -6.3,-5.5) and mental (-2.8 95% CI -3.2,-2.4) components of the SF-12, reduced QoL (-0.14 95% CI -0.15, -0.13), increased pain (+0.70 95% CI 0.62, 0.79) and increased odds of consultations with GPs (OR 2.4 95% CI 2.2, 2.6) and practice nurses (OR 2.6 (95% CI 2.1, 3.2) when compared to single site pain. CONCLUSIONS: Multisite peripheral joint pain is prevalent in the population in adults 45 years and over and has a significant negative impact on several dimensions of health. Health care professionals should consider joint pain beyond the index site in order to address holistic management. PMID- 29246142 TI - Association between metabolic syndrome and knee osteoarthritis: a cross-sectional study. AB - BACKGROUND: Osteoarthritis (OA) is the most prevalent chronic joint disease in China. The aim of this study was to examine the association between metabolic syndrome (MetS) and knee OA in a population-based Chinese study. METHODS: Data included in this analysis is from a cross-sectional study, i.e., the Xiangya Hospital Health Management Center Study. MetS was diagnosed according to the criteria defined by the Chinese Diabetes Society. Radiographic knee OA was defined as changes equivalent to Kellgren-Lawrence (K-L) grade 2 or above at least one side. Associations between MetS and its components with OA were evaluated by conducting multivariable adjusted logistic regression. RESULTS: A total of 5764 participants were included in the present study. The unadjusted OR (1.27, 95%CI: 1.10-1.47, P = 0.001), age-sex adjusted OR (1.17, 95%CI: 1.01-1.36, P = 0.041) and multivariable adjusted OR (1.17, 95%CI: 1.01-1.36, P = 0.043) all suggested a positive association between MetS and knee OA. Besides, its components (e.g., overweight, hypertension and dyslipidemia) were also associated with the prevalence of radiographic knee OA respectively, after adjusting for some confounding factors. In addition, with the accumulation of MetS components, the prevalence of knee OA increased. Furthermore, MetS as a whole was associated with the prevalence of knee osteophyte (OSP) (OR = 1.72, 95%CI: 1.42-2.09, P < 0.001), but not joint space narrowing (JSN) (OR = 1.06, 95%CI: 0.91-1.23, P = 0.449). CONCLUSIONS: The findings of the present study indicated that there was a positive association between the prevalence of MetS and knee OA. However, MetS as a whole was associated with the higher prevalence of knee OSP, but not JSN, which should shed light on our understanding the association between MetS and OA. PMID- 29246144 TI - Living with ongoing whiplash associated disorders: a qualitative study of individual perceptions and experiences. AB - BACKGROUND: Whiplash associated disorders (WAD) are the most common non hospitalised injury resulting from a motor vehicle crash. Approximately 50% of individuals with WAD experience on-going pain and disability. Results from intervention trials for individuals with chronic WAD are equivocal and optimal treatment continues to be a challenge. It may be that traditional quantitative measures included in treatment trials have not captured the full benefits patients experience through participation in an intervention. The aim of the present study was to explore participant subjective experiences and perceptions of living with on-going WAD. METHODS: Twenty-seven individuals with chronic WAD participated in a one-on-one, semi-structured individual telephone interview. All interviews were audio-taped, transcribed verbatim and data were analysed using an inductive thematic analysis process. RESULTS: Two themes emerged that described the experience of living with chronic WAD. First, all participants described navigating the healthcare system after their whiplash injury to help understand their injury and interpret therapeutic recommendations. Participants highlighted the need to 'find the right healthcare practitioner (HCP)' to help with this process. Many participants also described additional complexities in navigating and understanding healthcare incurred by interactions with compensation and funding systems. Second, participants described a journey of realisation, and the trial and error used to establish self-management strategies to both prevent and relieve pain. Participants described trying to understand the impact of their initial injury in relation to the gradual realisation that there may be on-going residual deficit. Seeking information from multiple sources, including personal experience gained through trial and error, was important in the search for acceptable management strategies. CONCLUSION: Recovery from a whiplash injury is an adaptive process and more than elimination of pain or disability, therefore may be different from common clinical patient reported outcomes. Early identification of patient understandings of pain, expectations of recovery, symptoms and therapy may help merge patient and HCP understandings. Additionally, helping individuals to recognise symptom triggers and develop appropriate strategies to minimise triggers may actively engage patients in their recovery. Finally, acknowledgement and validation of the whiplash injury by HCPs is seen by many as a necessary step in the recovery process. PMID- 29246143 TI - Modulation of the regioselectivity of Thermomyces lanuginosus lipase via biocatalyst engineering for the Ethanolysis of oil in fully anhydrous medium. AB - BACKGROUND: Enzymatic ethanolysis of oils (for example, high oleic sunflower oil containing 90% of oleic acid) may yield two different reaction products depending on the regioselectivity of the immobilized lipase biocatalyst. Some lipase biocatalysts exhibit a 1,3-regioselectivity and they produced 2 mols of fatty acid ethyl ester plus 1 mol of sn2-monoacylglycerol (2-MAG) per mol of triglyceride without the release of glycerol. Other lipase biocatalysts are completely non-regioselective releasing 3 mols of fatty acid ethyl ester and 1 mol of glycerol per mol of triglyceride. Lipase from Thermomyces lanuginosus (TLL) adsorbed on hydrophobic supports is a very interesting biocatalyst for the ethanolysis of oil. Modulation of TLL regioselectivity in anhydrous medium was intended via two strategies of TLL immobilization: a. - interfacial adsorption on different hydrophobic supports and b.- interfacial adsorption on a given hydrophobic support under different experimental conditions. RESULTS: Immobilization of TLL on supports containing divinylbenezene moieties yielded excellent 1,3-regioselective biocatalysts but immobilization of TLL on supports containing octadecyl groups yielded non-regioselective biocatalysts. On the other hand, TLL immobilized on Purolite C18 at pH 8.5 and 30 degrees C in the presence of traces of CTAB yielded a biocatalyst with a perfect 1,3-regioselectivity and a very interesting activity: 2.5 MUmols of oil ethanolyzed per min per gram of immobilized derivative. This activity is 10-fold higher than the one of commercial Lipozyme TL IM. Immobilization of the same enzyme on the same support, but at pH 7.0 and 25 degrees C, led to a biocatalyst which can hydrolyze all ester bonds in TG backbone. CONCLUSIONS: Activity and regioselectivity of TLL in anhydrous media can be easily modulated via Biocatalysis Engineering producing very active immobilized derivatives able to catalyze the ethanolysis of triolein. When the biocatalyst was 1,3-regioselective a 33% of 2-monoolein was obtained and it may be a very interesting surfactant. When biocatalyst catalyzed the ethanolysis of the 3 positions during the reaction process, a 99% of ethyl oleate was obtained and it may be a very interesting drug-solvent and surfactant. The absence of acyl migrations under identical reaction conditions is clearly observed and hence the different activities and regioselectivities seem to be due to the different catalytic properties of different derivatives of TLL. PMID- 29246145 TI - Legionella pneumonia due to non-Legionella pneumophila serogroup 1: usefulness of the six-point scoring system. AB - BACKGROUND: Because of a limited number of reports, we aimed to investigate the clinical characteristics of patients with Legionella pneumonia due to non Legionella pneumophila serogroup 1 and the diagnostic usefulness of the six-point scoring system for such patients compared with patients with pneumonia caused by L. pneumophila serogroup 1. METHODS: We retrospectively analysed patients diagnosed with Legionella pneumonia due to non-L. pneumophila serogroup 1 between March 2001 and June 2016. We examined the clinical characteristics, including symptoms, laboratory findings, radiologic findings, pneumonia severity, initial treatment and prognosis. We also calculated scores using the six-point scoring system in these patients. Furthermore, we compared the clinical characteristics and six-point scores between non-L. pneumophila serogroup 1 patients and L. pneumophila serogroup 1 patients among hospitalized community-acquired pneumonia patients enrolled prospectively between October 2010 and July 2016. RESULTS: Eleven patients had pneumonia due to non-L. pneumophila serogroup 1; their median age was 66 years and 8 patients (72.7%) were male. The most common pathogen was L. pneumophila serogroup 3 (6/11), followed by L. pneumophila serogroup 9 (3/11), L. pneumophila serogroup 6 (1/11) and L. longbeachae (1/11). Non-specific symptoms, such as fever and cough, were common. Six patients (54.5%) had liver enzyme elevation, but no patient developed hyponatraemia at <130 mEq/L. Nine patients (81.8%) showed lobar pneumonia and 7 patients (63.6%) manifested with consolidation and ground-glass opacity. Patients with mild to moderate severity comprised 10 (90.9%) by CURB-65 and 5 (45.5%) by the Pneumonia Severity Index. Of all patients, 4 were admitted to the intensive care unit and 3 died despite appropriate empiric therapy. The clinical characteristics were not significantly different between non-L. pneumophila serogroup 1 patients and L. pneumophila serogroup 1 patients (n = 23). At a cut-off value of >= 2 points, the sensitivity of the six-point scoring system was 54.5% (6/11) for non-L. pneumophila serogroup 1 patients and 95.7% (22/23) for L. pneumophila serogroup 1 patients. CONCLUSIONS: Cases of non-L. pneumophila serogroup 1 pneumonia varied in severity from mild to severe and the clinical characteristics were often non-specific. The six-point scoring system was not useful in predicting such Legionella pneumonia cases. PMID- 29246146 TI - Combined bladder neck preservation and posterior musculofascial reconstruction during robotic assisted radical prostatectomy: effects on early and long term urinary continence recovery. AB - BACKGROUND: To evaluate the effects of combined bladder neck preservation and posterior reconstruction techniques on early and long term urinary continence in patients treated by robotic assisted radical prostatectomy (RARP). METHODS: Two hundred ninety-two patients who previously underwent radical prostatectomy were retrospectively selected for a case-control study, excluding those with anastomotic strictures and significant perioperative complications and re-called for a medical follow-up visit after their consent to participate the study. They were divided in 3 different groups according to the surgical technique previously received: radical retropubic prostatectomy (RRP) combined with bladder neck preservation (BNP), RARP with bladder neck resection, and RARP combined with BNP and posterior musculofascial reconstruction (PRec). Functional and oncologic outcomes evaluation were integrated by a questionnaire on urinary continence status, abdominal ultrasound scan, uroflowmetry and post-void urine volume measurement. Urinary continence definition included the terms "no pad" or "safety pad". RESULTS: Two hundred thirty-two patients responded to the phone call interview and were enrolled in the study. They presented comparable age, prostate volume and BMI. Differences in comorbidities, ASA score and medications, did not influence the postoperative functional results, focused on continence outcome. Early urinary continence was achieved in 49.38% and 24.73% of patients who previously underwent RARP + BNP + PRec and simple RARP respectively (p = 0.000)as well as late 12-months urinary continence was obtained in 92.59% and 79.56% of patients.(p = 0.01). Late urinary continence in the RRP + BNP group was comparable to the result obtained in the simple RARP group. The potential effects of nerve sparing technique on urinary continence have not been evaluated. CONCLUSIONS: The combined technique of RARP + BNP + PRec seems to be effective to determine early and long term significant effects on urinary continence of patients with comparable body mass index, age and prostate volume. No statistically significant differences were found between the simple RARP and the RRP + BNP groups. PMID- 29246147 TI - Health care professionals' attitudes towards population-based genetic testing and risk-stratification for ovarian cancer: a cross-sectional survey. AB - BACKGROUND: Ovarian cancer is usually diagnosed at a late stage when outcomes are poor. Personalised ovarian cancer risk prediction, based on genetic and epidemiological information and risk stratified management in adult women could improve outcomes. Examining health care professionals' (HCP) attitudes to ovarian cancer risk stratified management, willingness to support women, self-efficacy (belief in one's own ability to successfully complete a task), and knowledge about ovarian cancer will help identify training needs in anticipation of personalised ovarian cancer risk prediction being introduced. METHODS: An anonymous survey was distributed online to HCPs via relevant professional organisations in the UK. Kruskal-Wallis tests and pairwise comparisons were used to compare knowledge and self-efficacy scores between different types of HCPs, and attitudes toward population-based genetic testing and risk stratified management were described. Content analysis was undertaken of free text responses concerning HCPs willingness to discuss risk management options with women. RESULTS: One hundred forty-six eligible HCPs completed the survey: oncologists (31%); genetics clinicians (30%); general practitioners (22%); gynaecologists (10%); nurses (4%); and 'others'. Scores for knowledge of ovarian cancer and genetics, and self-efficacy in conducting a cancer risk consultation were generally high but significantly lower for general practitioners compared to genetics clinicians, oncologists, and gynaecologists. Support for population based genetic testing was not high (<50%). Attitudes towards ovarian cancer risk stratification were mixed, although the majority of participants indicated a willingness to discuss management options with patients. CONCLUSIONS: Larger samples are required to investigate attitudes to population-based genetic testing for ovarian cancer risk and to establish why some HCPs are hesitant to offer testing to all adult female patients. If ovarian cancer risk assessment using genetic testing and non-genetic information including epidemiological information is rolled out on a population basis, training will be needed for HCPs in primary care to enable them to provide appropriate support to women at each stage of the process. PMID- 29246148 TI - The concentration of D-dimers in portal blood positively correlates with overall survival in patients with non-resectable pancreatic cancer. AB - BACKGROUND: Several recent studies provide evidence that D-dimer (DD) concentration in peripheral blood correlates negatively with overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC). Contrarily, there are recent evidence indicating that preoperative plasma fibrinogen, but not D dimer might represent a prognostic factor in non-metastatic gastrointestinal cancers. METHODS: In a single-center prospective study, we enrolled 62 patients undergoing surgery for pathologically confirmed PDAC without detectable venous thrombosis. Intraoperatively, the sample of the blood from the portal vein was obtained. DD concentration in these samples was measured. Patients were followed postoperatively until time of death from any cause. RESULTS: We found that OS for patients with portal blood DD values above 2700 (ng/mL) (n = 22 from 62 patients) was higher by 158% than that for the patients (n = 42) with DD values <= 2700 (416 days versus 161 days, p = 0.05). On the contrary to the studies investigating DD concentration in peripheral blood, we have found that patients with higher DD level in the portal vein had longer mean OS than patients with lower ones. CONCLUSIONS: Further investigation is necessary both to confirm our results in a larger patient population and to elucidate the mechanism for the correlation between portal blood D-dimer concentrations and survival time. Along with other authors, we conclude that portal circulation is characterized by unique, biological environment that requires further evaluation. PMID- 29246149 TI - Human resource for health reform in peri-urban areas: a cross-sectional study of the impact of policy interventions on healthcare workers in Epworth, Zimbabwe. AB - BACKGROUND: The need to understand how healthcare worker reform policy interventions impact health personnel in peri-urban areas is important as it also contributes towards setting of priorities in pursuing the universal health coverage goal of health sector reform. This study explored the impact of post 2008 human resource for health reform policy interventions on healthcare workers in Epworth, a peri-urban community in Harare, Zimbabwe, and the implications towards health sector reform policy in peri-urban areas. METHODS: The study design was exploratory and cross-sectional and involved the use of qualitative and quantitative methods in data collection, presentation, and analysis. A qualitative study in which data were collected through a documentary search, five key informant interviews, seven in-depth interviews, and five focus group discussions was carried out first. This was followed by a quantitative study in which data were collected through a documentary search and 87 semi-structured sample interviews with healthcare workers. Qualitative data were analyzed thematically whilst descriptive statistics were used to examine quantitative data. All data were integrated during analysis to ensure comprehensive, reliable, and valid analysis of the dataset. RESULTS: Three main factors were identified to help interpret findings. The first main factor consisted policy result areas that impacted most successfully on healthcare workers. These included the deployment of community health workers with the highest correlation of 0.83. Policy result areas in the second main factor included financial incentives with a correlation of 0.79, training and development (0.77), deployment (0.77), and non-financial incentives (0.75). The third factor consisted policy result areas that had the lowest satisfaction amongst healthcare workers in Epworth. These included safety (0.72), equipment and tools of trade (0.72), health welfare (0.65), and salaries (0.55). CONCLUSIONS: The deployment of community health volunteers impacted healthcare workers most successfully. This was followed by salary top-up allowances, training, deployment, and non-financial incentives. However, health personnel were least satisfied with their salaries. This had negative implications towards health sector reform interventions in Epworth peri-urban community between 2009 and 2014. PMID- 29246150 TI - Low-dose lymphocyte immunotherapy rebalances the peripheral blood Th1/Th2/Treg paradigm in patients with unexplained recurrent miscarriage. AB - BACKGROUND: The published results regarding lymphocytes immunotherapy for unexplained recurrent miscarriage (uRM) patients are conflicting due to different screening criteria and therapeutic protocols. The objective of the present study is to evaluate the effectiveness of immunotherapy using low-dose lymphocytes in patients with uRM and Th1/Th2/Treg paradigm disorders. METHODS: Sixty-four uRM patients who received low-dose lymphocytes immunotherapy served as the immunotherapy group, while the other 35 women who did not receive the treatment served as the control group. The proportions of peripheral blood Th1 cells, Th2 cells and Treg cells; and the concentration of TGF-beta1 in serum were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively, before and after the immunotherapy. RESULTS: The proportion of Th1 cells was significantly decreased while the proportions of Th2 cells and Treg cells were significantly increased in immunotherapy group patients after treatment. In addition, the concentration of TGF-beta1 in serum was significantly higher after immunotherapy than before. Forty-three uRM patients achieved pregnancy after receiving immunotherapy and 5 patients underwent miscarriages in the immunotherapy group (11.6%, 5/43), while 8 of the 23 pregnant patients experienced a miscarriage in the control group (34.8%, 8/23; p < 0.05). CONCLUSIONS: Low-dose lymphocyte immunotherapy is beneficial for restoring balance in the Th1/Th2/Treg paradigm and improving pregnancy outcome in uRM patients. TRIAL REGISTRATION: NCT03081325 . ClinicalTrials.gov . Retrospectively registered July 2015. PMID- 29246151 TI - Suboptimal control of lipid levels: results from the non-interventional Centralized Pan-Russian Survey of the Undertreatment of Hypercholesterolemia II (CEPHEUS II). AB - BACKGROUND: Elevated levels of low-density lipoprotein cholesterol (LDL-C) and glycosylated hemoglobin (HbA1c) are risk factors for cardiovascular complications. This study evaluated LDL-C goal attainment in Russian clinical practice among patients with moderate to very high cardiovascular risk. The study also assessed LDL-C goal attainment in patients prescribed lipid-lowering therapy for primary compared with secondary cardiovascular disease (CVD) prevention, predictors of LDL-C goal attainment, and the proportion of individuals with diabetes mellitus who achieved HbA1c < 7%. METHODS: The Centralized Pan-Russian Survey on the Undertreatment of Hypercholesterolemia in Russia II (CEPHEUS II) was a multicenter, non-interventional, cross-sectional study conducted in the Russian Federation from September 2014 to November 2015. Participants were aged >= 18 years, were receiving a stable dose of lipid-lowering medication and had a moderate to very high cardiovascular risk. The primary variable was the proportion of patients reaching LDL-C goals established by the Fifth Joint European Task Force guidelines. Secondary analyses used McNemar and chi2 tests. RESULTS: Data from 2703 patients were analyzed; 91.2% had a very high cardiovascular risk and 24.0% had been diagnosed with diabetes mellitus. Overall, 17.4% of patients (95% confidence interval [CI] 15.9-18.8%) achieved LDL-C goals. Investigators estimated this proportion at 21.8% (95% CI 20.3-23.4%). LDL-C goals were achieved by more patients in the primary CVD prevention subgroup than in the secondary CVD prevention subgroup (19.7% vs 16.1%, p = 0.017). Patient-related factors associated with a decreased likelihood of achieving LDL-C goals included having ischemic heart disease or a family history of premature coronary heart disease, forgetting to take hypercholesterolemia treatment or considering it acceptable to miss prescribed doses more than once per week, and dissatisfaction with or concern about lipid-lowering therapy. Overall, 367/593 (61.9%) patients with diabetes mellitus and interpretable HbA1c results achieved HbA1c < 7%. CONCLUSIONS: Hypercholesterolemia management is suboptimal in patients with moderate to very high cardiovascular risk in Russian clinical practice. Substantial opportunity remains to improve treatment target attainment and reduce the risk of cardiovascular complications. Lipid-modifying strategies may need to be intensified to reduce CVD risk in this setting. Trial registration ClinicalTrials.gov: NCT02230241 (registered 26 August 2014). PMID- 29246152 TI - Linking physiologically-based pharmacokinetic and genome-scale metabolic networks to understand estradiol biology. AB - BACKGROUND: Estrogen is a vital hormone that regulates many biological functions within the body. These include roles in the development of the secondary sexual organs in both sexes, plus uterine angiogenesis and proliferation during the menstrual cycle and pregnancy in women. The varied biological roles of estrogens in human health also make them a therapeutic target for contraception, mitigation of the adverse effects of the menopause, and treatment of estrogen-responsive tumours. In addition, endogenous (e.g. genetic variation) and external (e.g. exposure to estrogen-like chemicals) factors are known to impact estrogen biology. To understand how these multiple factors interact to determine an individual's response to therapy is complex, and may be best approached through a systems approach. METHODS: We present a physiologically-based pharmacokinetic model (PBPK) of estradiol, and validate it against plasma kinetics in humans following intravenous and oral exposure. We extend this model by replacing the intrinsic clearance term with: a detailed kinetic model of estrogen metabolism in the liver; or, a genome-scale model of liver metabolism. Both models were validated by their ability to reproduce clinical data on estradiol exposure. We hypothesise that the enhanced mechanistic information contained within these models will lead to more robust predictions of the biological phenotype that emerges from the complex interactions between estrogens and the body. RESULTS: To demonstrate the utility of these models we examine the known drug-drug interactions between phenytoin and oral estradiol. We are able to reproduce the approximate 50% reduction in area under the concentration-time curve for estradiol associated with this interaction. Importantly, the inclusion of a genome-scale metabolic model allows the prediction of this interaction without directly specifying it within the model. In addition, we predict that PXR activation by drugs results in an enhanced ability of the liver to excrete glucose. This has important implications for the relationship between drug treatment and metabolic syndrome. CONCLUSIONS: We demonstrate how the novel coupling of PBPK models with genome-scale metabolic networks has the potential to aid prediction of drug action, including both drug-drug interactions and changes to the metabolic landscape that may predispose an individual to disease development. PMID- 29246153 TI - Referral patterns, delays, and equity in access to advanced paediatric emergency care in Vietnam. AB - BACKGROUND: Quality emergency care is a critical component of a well-functioning health system. However, severely ill children often face barriers to timely, appropriate care in less-developed health systems. Such barriers disproportionately affect poorer children, and may be particularly acute when children seek advanced emergency care. We examine predictors of increased acuity and patient outcomes at a tertiary paediatric emergency department to identify barriers to advanced emergency care among children. METHODS: We analysed a sample of 557 children admitted to a paediatric referral hospital in Hanoi, Vietnam. We examined associations between socio-demographic and facility characteristics, referrals and transfers, and patient outcomes. We used generalized ordered logistic regression to examine predictors of increased acuity on arrival. RESULTS: Most children accessing advanced emergency care were under two years of age (68.4%). Pneumonia was the most prevalent diagnosis (23.7%). Children referred from lower-level facilities experienced higher acuity on arrival (p = .000), were more likely to be admitted to an ICU (p = .000), and were more likely to die during hospitalization (p = .009). The poorest children [OR = 4.98, (1.82 13.61)], and children entering care at provincial hospitals [OR = 3.66, (2.39 5.63)] and other lower-level facilities [OR = 3.24, (1.78-5.88)] had significantly higher odds of increased acuity on arrival. CONCLUSIONS: The poorest children, who were more likely to enter care at lower-level facilities, were especially disadvantaged. While delays in entry to care were not predictive of acuity, children referred to tertiary care from lower-level facilities experienced worse outcomes. Improvements in triage, stabilization, and referral linkages at all levels should reduce within-system delays, increasing timely access to advanced emergency care for all children. PMID- 29246154 TI - Dexamethasone implants in paediatric patients with noninfectious intermediate or posterior uveitis: first prospective exploratory case series. AB - BACKGROUND: To evaluate the efficacy and safety of dexamethasone (DEX) implants in paediatric patients with noninfectious intermediate or posterior uveitis. METHODS: Prospective single center exploratory case series. Children and adolescents, 6 to 17 years old, with a vitreous haze score of >=1.5+ or cystoid macular edema (CME) of >300 MUm were enrolled. Vitreous haze score at month 2 was chosen as primary endpoint. Best corrected visual acuity (BCVA), central retinal thickness (CRT) and concomitant medication at month 6 were defined as secondary endpoints. Intraocular pressure (IOP) and cataract formation were determined as safety endpoints. RESULTS: Three out of 6 eligible patients participated in the case series. At month 2, vitreous haze was reduced from a score of 1.5+ to 0.5+ and 0 and BCVA improved by >=3 lines, >=4 lines and >=2 lines of Early Treatment of Diabetic Retinopathy (ETDRS)-letters, respectively. Visual acuity gain was accompanied by a CRT reduction of -186 MUm and -83 MUm in the first and third patient, in whom CME was the indication for DEX implantation. A reduction of concomitant medication was achieved in 1 patient. IOP increase was seen in all 3 patients, but could be treated sufficiently with primarily IOP lowering medications and without need for glaucoma surgery. Cataract progression did not occur. CONCLUSIONS: DEX implants led to an improvement in all endpoints, especially BCVA. This study confirms that IOP rises may also occur in the paediatric population and should be monitored and treated appropriately. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials (EudraCT)- nr: 2013-000541-39. PMID- 29246155 TI - ZnO nanoparticles modulate the ionic transport and voltage regulation of lysenin nanochannels. AB - BACKGROUND: The insufficient understanding of unintended biological impacts from nanomaterials (NMs) represents a serious impediment to their use for scientific, technological, and medical applications. While previous studies have focused on understanding nanotoxicity effects mostly resulting from cellular internalization, recent work indicates that NMs may interfere with transmembrane transport mechanisms, hence enabling contributions to nanotoxicity by affecting key biological activities dependent on transmembrane transport. In this line of inquiry, we investigated the effects of charged nanoparticles (NPs) on the transport properties of lysenin, a pore-forming toxin that shares fundamental features with ion channels such as regulation and high transport rate. RESULTS: The macroscopic conductance of lysenin channels greatly diminished in the presence of cationic ZnO NPs. The inhibitory effects were asymmetrical relative to the direction of the electric field and addition site, suggesting electrostatic interactions between ZnO NPs and a binding site. Similar changes in the macroscopic conductance were observed when lysenin channels were reconstituted in neutral lipid membranes, implicating protein-NP interactions as the major contributor to the reduced transport capabilities. In contrast, no inhibitory effects were observed in the presence of anionic SnO2 NPs. Additionally, we demonstrate that inhibition of ion transport is not due to the dissolution of ZnO NPs and subsequent interactions of zinc ions with lysenin channels. CONCLUSION: We conclude that electrostatic interactions between positively charged ZnO NPs and negative charges within the lysenin channels are responsible for the inhibitory effects on the transport of ions. These interactions point to a potential mechanism of cytotoxicity, which may not require NP internalization. PMID- 29246156 TI - The tunable pReX expression vector enables optimizing the T7-based production of membrane and secretory proteins in E. coli. AB - BACKGROUND: To optimize the production of membrane and secretory proteins in Escherichia coli, it is critical to harmonize the expression rates of the genes encoding these proteins with the capacity of their biogenesis machineries. Therefore, we engineered the Lemo21(DE3) strain, which is derived from the T7 RNA polymerase-based BL21(DE3) protein production strain. In Lemo21(DE3), the T7 RNA polymerase activity can be modulated by the controlled co-production of its natural inhibitor T7 lysozyme. This setup enables to precisely tune target gene expression rates in Lemo21(DE3). The t7lys gene is expressed from the pLemo plasmid using the titratable rhamnose promoter. A disadvantage of the Lemo21(DE3) setup is that the system is based on two plasmids, a T7 expression vector and pLemo. The aim of this study was to simplify the Lemo21(DE3) setup by incorporating the key elements of pLemo in a standard T7-based expression vector. RESULTS: By incorporating the gene encoding the T7 lysozyme under control of the rhamnose promoter in a standard T7-based expression vector, pReX was created (ReX stands for Regulated gene eXpression). For two model membrane proteins and a model secretory protein we show that the optimized production yields obtained with the pReX expression vector in BL21(DE3) are similar to the ones obtained with Lemo21(DE3) using a standard T7 expression vector. For another secretory protein, a c-type cytochrome, we show that pReX, in contrast to Lemo21(DE3), enables the use of a helper plasmid that is required for the maturation and hence the production of this heme c protein. CONCLUSIONS: Here, we created pReX, a T7 based expression vector that contains the gene encoding the T7 lysozyme under control of the rhamnose promoter. pReX enables regulated T7-based target gene expression using only one plasmid. We show that with pReX the production of membrane and secretory proteins can be readily optimized. Importantly, pReX facilitates the use of helper plasmids. Furthermore, the use of pReX is not restricted to BL21(DE3), but it can in principle be used in any T7 RNAP-based strain. Thus, pReX is a versatile alternative to Lemo21(DE3). PMID- 29246157 TI - Spatial smoothing in Bayesian models: a comparison of weights matrix specifications and their impact on inference. AB - BACKGROUND: When analysing spatial data, it is important to account for spatial autocorrelation. In Bayesian statistics, spatial autocorrelation is commonly modelled by the intrinsic conditional autoregressive prior distribution. At the heart of this model is a spatial weights matrix which controls the behaviour and degree of spatial smoothing. The purpose of this study is to review the main specifications of the spatial weights matrix found in the literature, and together with some new and less common specifications, compare the effect that they have on smoothing and model performance. METHODS: The popular BYM model is described, and a simple solution for addressing the identifiability issue among the spatial random effects is provided. Seventeen different definitions of the spatial weights matrix are defined, which are classified into four classes: adjacency-based weights, and weights based on geographic distance, distance between covariate values, and a hybrid of geographic and covariate distances. These last two definitions embody the main novelty of this research. Three synthetic data sets are generated, each representing a different underlying spatial structure. These data sets together with a real spatial data set from the literature are analysed using the models. The models are evaluated using the deviance information criterion and Moran's I statistic. RESULTS: The deviance information criterion indicated that the model which uses binary, first-order adjacency weights to perform spatial smoothing is generally an optimal choice for achieving a good model fit. Distance-based weights also generally perform quite well and offer similar parameter interpretations. The less commonly explored options for performing spatial smoothing generally provided a worse model fit than models with more traditional approaches to smoothing, but usually outperformed the benchmark model which did not conduct spatial smoothing. CONCLUSIONS: The specification of the spatial weights matrix can have a colossal impact on model fit and parameter estimation. The results provide some evidence that a smaller number of neighbours used in defining the spatial weights matrix yields a better model fit, and may provide a more accurate representation of the underlying spatial random field. The commonly used binary, first-order adjacency weights still appear to be a good choice for implementing spatial smoothing. PMID- 29246159 TI - Prognostic value of MIB-1 proliferation index in solitary fibrous tumors of the pleura implemented in a new score - a multicenter study. AB - BACKGROUND: Although the majority of solitary fibrous tumors of the pleura (SFTP) follow a benign course, 10-25% of patients suffer from recurrence or metastatic disease. Several scoring models have been proposed to predict the outcome. However, none of these included immunohistochemical (IHC) markers as possible prognosticators. METHODS: In this multicenter study, we collected clinical data and formalin-fixed and paraffin-embedded (FFPE) tissue blocks of patients with histologically proven SFTP which had been surgically resected between 2000 und 2015. After systematic and extensive IHC staining on tissue microarrays, the results were analyzed and compared to histomorphological and clinical data for their possible prognostic value. RESULTS: In total, 78 patients (mean age 61 +/- 11 years) were included. Of these, 9 patients (11%) had an adverse outcome including SFTP recurrence (n = 6) or SFTP-related death (n = 3). Mean overall survival was 172 +/- 13 months. 1 and 10-year event-free survival rates were 99% and 93%. In the multivariable analysis only MIB-1 proliferation index (Ki-67) >=10% (HR 12.3, CI 1.1-139.5, p = 0.043), >=4 mitoses per 10 high power fields (HR 36.5, CI 1.2-1103.7, p = 0.039) and tumor size larger than 10 cm (HR 81.8, CI 1.7-4016.8, p = 0.027) were independently associated with adverse outcome. CONCLUSION: A high proliferation rate by MIB-1 IHC was associated with impaired outcome. Upon this, we established a new score using mitosis, necrosis, size of the tumor and MIB-1, which performed better than the traditional scores in our data set. This prognostic score could help to better evaluate outcome of SFTP, but requires external validation. PMID- 29246158 TI - A deep sequencing approach to estimate Plasmodium falciparum complexity of infection (COI) and explore apical membrane antigen 1 diversity. AB - BACKGROUND: Humans living in regions with high falciparum malaria transmission intensity harbour multi-strain infections comprised of several genetically distinct malaria haplotypes. The number of distinct malaria parasite haplotypes identified from an infected human host at a given time is referred to as the complexity of infection (COI). In this study, an amplicon-based deep sequencing method targeting the Plasmodium falciparum apical membrane antigen 1 (pfama1) was utilized to (1) investigate the relationship between P. falciparum prevalence and COI, (2) to explore the population genetic structure of P. falciparum parasites from malaria asymptomatic individuals participating in the 2007 Demographic and Health Survey (DHS) in the Democratic Republic of Congo (DRC), and (3) to explore selection pressures on geospatially divergent parasite populations by comparing AMA1 amino acid frequencies in the DRC and Mali. RESULTS: A total of 900 P. falciparum infections across 11 DRC provinces were examined. Deep sequencing of both individuals, for COI analysis, and pools of individuals, to examine population structure, identified 77 unique pfama1 haplotypes. The majority of individual infections (64.5%) contained polyclonal (COI > 1) malaria infections based on the presence of genetically distinct pfama1 haplotypes. A minimal correlation between COI and malaria prevalence as determined by sensitive real time PCR was identified. Population genetic analyses revealed extensive haplotype diversity, the vast majority of which was shared across the sites. AMA1 amino acid frequencies were similar between parasite populations in the DRC and Mali. CONCLUSIONS: Amplicon-based deep sequencing is a useful tool for the detection of multi-strain infections that can aid in the understanding of antigen heterogeneity of potential malaria vaccine candidates, population genetics of malaria parasites, and factors that influence complex, polyclonal malaria infections. While AMA1 and other diverse markers under balancing selection may perform well for understanding COI, they may offer little geographic or temporal discrimination between parasite populations. PMID- 29246160 TI - Serum lipid profiles in patients with acute myocardial infarction in Hakka population in southern China. AB - BACKGROUND: Little is known about serum lipid levels comparison of patients with acute myocardial infarction (AMI) in Hakka patients in southern China. To estimate the prevalence lipid profiles in Hakka patients with AMI in southern China. METHOD: We analyzed 1382 patients with a first AMI in Hakka patients in southern China between Jan. 2015 and Dec. 2015. RESULTS: Our findings demonstrated that low-density lipoprotein cholesterol (LDL), total cholesterol (TC), and triglyceride (TG) were higher in nonelderly than in elderly for males. There were significant differences in TC, LDL, HDL, and TG among various age groups for both males and female patients (P < .05). TC, LDL, HDL, and TG were higher in females than males for the elderly, and the LDL levels of females were higher in 70-79,80-89 year age groups than males. The HDL level of female patients was higher than males in those 50-59, 60-69, and 70-79 year age groups. Compared with males, females had higher level of TG in the 60-69, 70-79, and 80 89 year age groups and had higher level of TC in the 50-59, 70-79, and 80-89 year age groups, respectively. Isolated high TG (normal LDL + normal HDL+ high TG) was most common type of combined dyslipidemia for female elderly (22.2%), female nonelderly (23.2%) and male elderly (24.1%) patients. CONCLUSION: Our results confirmed that serum lipid levels varied in age and gender in Hakka patients with acute myocardial infarction. Dyslipidemia is more prevalent in the non-elderly than in the elderly for males. Levels of TC, LDL, HDL, and TG were higher in females than males for the elderly Hakka population in southern China. PMID- 29246162 TI - Use of a baseline risk score to identify the risk of serious infectious events in patients with rheumatoid arthritis during certolizumab pegol treatment. AB - BACKGROUND: The risk of serious infectious events (SIEs) is increased in patients with rheumatoid arthritis (RA). The aim of this study was to develop an age adjusted comorbidity index (AACI) to predict, using baseline characteristics, the SIE risk in patients with RA treated with certolizumab pegol (CZP). METHODS: Data of CZP-treated patients with RA were pooled from the RAPID1/RAPID2 randomized controlled trials (RCT CZP) and their open-label extensions (All CZP). Predictors of the first SIE were examined using multivariate Cox models. The AACI was developed by assigning specific weights to patient age and comorbidities on the basis of relative SIE risk. SIE rates were predicted using AACI score and baseline glucocorticoid use, and they were compared with observed rates. The percentage of patients in each SIE risk group achieving low disease activity (LDA)/remission was examined at 1 year of treatment. RESULTS: Among 1224 RCT CZP patients, 40 reported >= 1 SIE (incidence rate [IR] 5.09/100 patient-years [PY]), and 201 of 1506 All CZP patients reported >= 1 SIE (IR 3.66/100 PY). Age >= 70 years, diabetes mellitus, and chronic obstructive pulmonary disease/asthma made the greatest contributions to AACI score. SIE rates predicted using AACI and glucocorticoid use at baseline showed good agreement with observed SIE rates across low-risk and high-risk groups. At 1 year, more high-risk All CZP patients than low-risk All CZP patients reported SIEs (IR 8.4/100 PY vs. IR 3.4/100 PY). Rates of LDA/remission were similar between groups. CONCLUSIONS: AACI and glucocorticoid use were strong baseline predictors of SIE risk in CZP-treated patients with RA. Predicted SIE risk was not associated with patients' likelihood of clinical response. This SIE risk score may provide a valuable tool for clinicians when considering the risk of infection in individual patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00152386 (registered 7 September 2005); NCT00160602 (registered 8 September 2005); NCT00175877 (registered 9 September 2005); and NCT00160641 (registered 8 September 2005). PMID- 29246163 TI - Identification of regulatory modules in genome scale transcription regulatory networks. AB - BACKGROUND: In gene regulatory networks, transcription factors often function as co-regulators to synergistically induce or inhibit expression of their target genes. However, most existing module-finding algorithms can only identify densely connected genes but not co-regulators in regulatory networks. METHODS: We have developed a new computational method, CoReg, to identify transcription co regulators in large-scale regulatory networks. CoReg calculates gene similarities based on number of common neighbors of any two genes. Using simulated and real networks, we compared the performance of different similarity indices and existing module-finding algorithms and we found CoReg outperforms other published methods in identifying co-regulatory genes. We applied CoReg to a large-scale network of Arabidopsis with more than 2.8 million edges and we analyzed more than 2,300 published gene expression profiles to charaterize co-expression patterns of gene moduled identified by CoReg. RESULTS: We identified three types of modules in the Arabidopsis network: regulator modules, target modules and intermediate modules. Regulator modules include genes with more than 90% edges as out-going edges; Target modules include genes with more than 90% edges as incoming edges. Other modules are classified as intermediate modules. We found that genes in target modules tend to be highly co-expressed under abiotic stress conditions, suggesting this network struture is robust against perturbation. CONCLUSIONS: Our analysis shows that the CoReg is an accurate method in identifying co-regulatory genes in large-scale networks. We provide CoReg as an R package, which can be applied in finding co-regulators in any organisms with genome-scale regulatory network data. PMID- 29246161 TI - Bioactive lipids are altered in the kidney of chronic undernourished rats: is there any correlation with the progression of prevalent nephropathies? AB - BACKGROUND: Undernutrition during childhood leads to chronic diseases in adult life including hypertension, diabetes and chronic kidney disease. Here we explore the hypothesis that physiological alterations in the bioactive lipids pattern within kidney tissue might be involved in the progression of chronic kidney disease. METHODS: Membrane fractions from kidney homogenates of undernourished rats (RBD) were submitted to lipid extraction and analysis by thin layer chromatography and cholesterol determination. RESULTS: Kidneys from RBD rats had 25% lower cholesterol content, which disturb membrane microdomains, affecting Ca2+ homeostasis and the enzymes responsible for important lipid mediators such as phosphatidylinositol-4 kinase, sphingosine kinase, diacylglicerol kinase and phospholipase A2. We observed a decrease in phosphatidylinositol(4)-phosphate (8.8 +/- 0.9 vs. 3.6 +/- 0.7 pmol.mg-1.mim-1), and an increase in phosphatidic acid (2.2 +/- 0.8 vs. 3.8 +/- 1.3 pmol.mg-1.mim-1), being these lipid mediators involved in the regulation of key renal functions. Ceramide levels are augmented in kidney tissue from RBD rats (18.7 +/- 1.4 vs. 21.7 +/- 1.5 fmol.mg-1.min-1) indicating an ongoing renal lesion. CONCLUSION: Results point to an imbalance in the bioactive lipid generation with further consequences to key events related to kidney function, thus contributing to the establishment of chronic kidney disease. PMID- 29246164 TI - Incidence of giant cell arteritis in Western Norway 1972-2012: a retrospective cohort study. AB - BACKGROUND: Giant cell arteritis (GCA) is the most common systemic vasculitis in persons older than 50 years. The highest incidence rates of the disease have been reported in Scandinavian countries. Our objective was to determine the epidemiology of GCA in an expected high-incidence region during a 41-year period. METHODS: This is a hospital-based, retrospective, cohort study. Patients diagnosed with GCA in Bergen health area during 1972-2012 were identified through computerized hospital records (n = 1341). Clinical information was extracted from patients' medical journals, which were reviewed by a standardized method. We excluded patients if data were unavailable (n = 253), if the reviewing rheumatologist found GCA to be an implausible diagnosis (n = 207) or if the American College of Rheumatology (ACR) 1990 classification criteria for GCA were not fulfilled (n = 89). Descriptive methods were used to characterize the sample. Incidence was analyzed by graphical methods and Poisson regression. RESULTS: A total of 792 patients were included. The average annual cumulative incidence of GCA was 16.7 (95% CI 15.5-18.0) per 100,000 of the population >= 50 years old. The corresponding incidence for biopsy-verified GCA was 11.2 (95% CI 10.2-12.3). The annual cumulative incidence increased with time in the period 1972-1992 (relative risk (RR) 1.1, p < 0.001) but not in 1993-2012 (RR 1.0, p = 0.543). The incidence was higher in women compared to men (average annual incidence 37.7 (95% CI 35.8-39.6) vs. 14.3 (95% CI 13.2-15.5), p < 0.001) with women having a twofold to threefold higher incidence rate throughout the study period. Average annual incidence increased with age until the 7th decade of life in both sexes throughout the study period (2.8 (95% CI 2.3-3.3) for age <60, 15.5 (95% CI 14.4 16.8) for age 60-69, 34.5 (95% CI 32.8-36.4) for age 70-79 and 26.8 (95% CI 25.3 28.4) for age >=80 years, p < 0.001 for all age adjustments). CONCLUSIONS: Our study confirms an incidence of GCA comparable to previous reports on Scandinavian populations. Our results show increasing incidence from 1972 through 1992, after which the incidence has levelled out. PMID- 29246166 TI - Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter. AB - BACKGROUND: Gliomas are the most common primary tumors in central nervous system. The prognosis of the patients with glioma is poor regardless of the development of therapeutic strategies. Its aggressive behavior mainly depends on the potent ability of proliferation. The transcription factor EGR1 (early growth response 1) is a member of a zinc finger transcription factor family which plays an essential role in cell growth and proliferation. METHODS: EGR1 expression levels in 39 glioma tissues and 10 normal brain tissues were tested by RT-qPCR and Western blotting. The effects of EGR1 on U251 cells, U251 stem-like cells (GSCs), and U87 cells proliferation were assessed using in vitro and in vivo cell proliferation assays. The specific binding between EGR1 and CCND1 promoter was confirmed by CHIP assay. EGF was used to improve EGR1 expression in this assay. RESULTS: EGR1 expression levels in human gliomas are decreased compared with normal brain tissues, however, the patients with low EGR1 expression level showed significantly enhanced patient survival in all glioma patients. EGR1 silencing inhibited proliferation and induced G1 phase arrest in glioma cells. EGR1 contributed to proliferation by directly raising CCND1. Meanwhile, EGR1 overexpression induced by EGF was able to promote the proliferation of glioma cells. CONCLUSIONS: Our results show that stable knockdown EGR1 would inhibit glioma proliferation. The results suggest EGR1 showing lower expression in cancer tissues compared with normal tissues maybe still play an important role in tumor proliferation. PMID- 29246165 TI - A veterinary perspective on One Health in the Arctic. AB - Exposure to long-range transported industrial chemicals, climate change and diseases is posing a risk to the overall health and populations of Arctic wildlife. Since local communities are relying on the same marine food web as marine mammals in the Arctic, it requires a One Health approach to understand the holistic ecosystem health including that of humans. Here we collect and identify gaps in the current knowledge of health in the Arctic and present the veterinary perspective of One Health and ecosystem dynamics. The review shows that exposure to persistent organic pollutants (POPs) is having multiple organ-system effects across taxa, including impacts on neuroendocrine disruption, immune suppression and decreased bone density among others. Furthermore, the warming Arctic climate is suspected to influence abiotic and biotic long-range transport and exposure pathways of contaminants to the Arctic resulting in increases in POP exposure of both wildlife and human populations. Exposure to vector-borne diseases and zoonoses may increase as well through range expansion and introduction of invasive species. It will be important in the future to investigate the effects of these multiple stressors on wildlife and local people to better predict the individual-level health risks. It is within this framework that One Health approaches offer promising opportunities to survey and pinpoint environmental changes that have effects on wildlife and human health. PMID- 29246167 TI - The Candida species that are important for the development of atrophic glossitis in xerostomia patients. AB - BACKGROUND: The purpose of this study was to clarify the species of Candida that are important for the development of atrophic glossitis in xerostomia patients. METHODS: A total of 231 patients with subjective dry mouth were enrolled in the present study. Logistic regression analysis was performed to clarify the contribution of each Candida species and other variables to the development of atrophic glossitis. The dependent variable was the absence/presence of atrophic glossitis. The Candida colony-forming units (CFU) of C. albicans, C. glabrata, C. tropicalis, and C. krusei, as well as age, gender, resting (RSFR) and stimulated (SSFR) whole salivary flow rate, and denture-wearing status, were treated as explanatory variables. RESULTS: Logistic regression analysis showed that two factors were closely associated with the presence of atrophic glossitis: an increase in C. albicans CFU and a decrease in the SSFR. CONCLUSIONS: C. albicans, but not non-albicans Candida, was associated with atrophic glossitis in xerostomia patients who had no systemic predisposing factors, indicating that C. albicans remains a treatment target for Candida-related atrophic glossitis. PMID- 29246168 TI - Trichinella spp. biomass has increased in raccoon dogs (Nyctereutes procyonoides) and red foxes (Vulpes vulpes) in Estonia. AB - BACKGROUND: Raccoon dogs and red foxes are well-adapted hosts for Trichinella spp. The aims of this study were to estimate Trichinella infection prevalence and biomass and to investigate which Trichinella species circulated in these indicator hosts in Estonia. METHODS: From material collected for evaluating the effectiveness of oral vaccination program for rabies eradication in wildlife, samples from 113 raccoon dogs and 87 red foxes were included in this study. From each animal, 20 g of masseter muscle tissue was tested for the presence of Trichinella larvae using an artificial digestion method. The Trichinella larvae were identified to species level by multiplex polymerase chain reaction method. RESULTS: The majority of tested animals were infected with Trichinella spp. The parasite species identified were T. nativa and T. britovi. The apparent infection prevalence was 57.5% in raccoon dogs and 69.0% in red foxes, which were higher than previous estimates. In addition, the larval burden had also increased in both hosts. We estimated that in 2011-2012, the Trichinella spp. biomass was more than 15 times higher in raccoon dogs and almost two times higher in red foxes than in 1992-2000 (based on mean larval burden), and almost 20 times higher in raccoon dogs and almost five times higher in red foxes than in 2000-2002 (based on median larval burden). CONCLUSIONS: Raccoon dogs and red foxes are relevant reservoirs for Trichinella spp. in Estonia. The biomass of Trichinella circulating in sylvatic cycles was substantial and had increased: there is substantial infection pressure in the sylvatic cycle. PMID- 29246171 TI - Correction to: Concomitant, sequential, and 7-day triple therapy in first-line treatment of Helicobacter pylori infection in Korea: study protocol for a randomized controlled trial. AB - CORRECTION: In the original publication [1] was an error in the grant number in the funding section. The correct version can be found in this Erratum. PMID- 29246170 TI - Functional treatment for fractures to the base of the 5th metatarsal - influence of fracture location and fracture characteristics. AB - BACKGROUND: Fractures to the base of the fifth metatarsal are common, but their treatment remains controversial. Especially for Lawrence and Botte (L&B) type II fractures, there is conflicting evidence and consequently no consensus. Further, many authors consider displacement, articular involvement, and number of fragments an indication for surgery, although evidence is missing. The aim of this study was to evaluate the outcome of functional treatment for all L&B type I and II fractures. Of special interest were the influence of (1) the fracture location (L&B type I vs. II) and (2) the fracture characteristics (displacement, intra-articular involvement, communition) on the subjective outcome. METHODS: Retrospective registry study with a prospective follow-up. Patients with an acute, isolated, epi-metaphyseal fracture to the fifth metatarsal bone (L&B type I and II) treated by full weightbearing with a minimum follow-up of 6 months were included. Fracture location (L&B type I and II) and characteristics (displacement <2 mm or >2 mm, intra-articular involvement, and number of fragments) were assessed. Outcome parameters were return to work, return to sports, VAS-FA, and SF-12. The influence of the fracture (1) location and (2) -characteristics on these parameters was tested. RESULTS: Thirty-nine patients (40 +/- 15 years, 56% female) were enrolled with a mean follow-up of 22 +/- 10 months. L&B type I fractures occurred in 59%, type II in 41%. Thirty-one percent of all fractures were dislocated, 74% intra-articular, and 41% multi-fragmentary. Patients returned to work after 17 +/- 12 days, to sports after 53 +/- 22 days. The VAS-FA score at the final follow-up was 96 +/- 4, SF-12 PCS score 57 +/- 5 and MCS score 51 +/- 8. No complications were reported, no patient required surgery. None of the assessed outcome parameters differed significantly between (1) the different fracture locations (L&B type I vs. II) or (2) the different fracture characteristics (displacement, intra-articular involvement, and number of fragments). CONCLUSIONS: (1) Both, L&B I and II fractures featured excellent results with immediate full weightbearing. Consequently, L&B type I and II fractures should be summarized as epi-metaphyseal fractures. (2) Fracture displacement, articular involvement, and number of fragments did not influence the outcome. Therefore, functional treatment should be recommended for all epi metaphyseal fractures. PMID- 29246169 TI - Ancylostoma ceylanicum infective third-stage larvae are activated by co-culture with HT-29-MTX intestinal epithelial cells. AB - BACKGROUND: Human hookworm larvae arrest development until they enter an appropriate host. This makes it difficult to access the larvae for studying larval development or host-parasite interactions. While there are in vivo and in vitro animal models of human hookworm infection, there is currently no human, in vitro model. While animal models have provided much insight into hookworm biology, there are limitations to how closely this can replicate human infection. Therefore, we have developed a human, in vitro model of the initial phase of hookworm infection using intestinal epithelial cell culture. RESULTS: Co-culture of the human hookworm Ancylostoma ceylanicum with the mucus-secreting, human intestinal epithelial cell line HT-29-MTX resulted in activation of infective third-stage larvae, as measured by resumption of feeding. Larvae were maximally activated by direct contact with fully differentiated HT-29-MTX intestinal epithelial cells. HT-29-MTX cells treated with A. ceylanicum larvae showed differential gene expression of several immunity-related genes. CONCLUSIONS: Co culture with HT-29-MTX can be used to activate A. ceylanicum larvae. This provides an opportunity to study the interaction of activated larvae with the human intestinal epithelium. PMID- 29246172 TI - Morphoproteomics and biomedical analytics coincide with clinical outcomes in supporting a constant but variable role for the mTOR pathway in the biology of congenital hyperinsulinism of infancy. AB - We first introduced the concept of the mTOR pathway's involvement in congenital hyperinsulinism of infancy (CHI), based largely on morphoproteomic observations and clinical outcomes using sirolimus (rapamycin) as a therapeutic agent in infants refractory to octreotide and diazoxide treatment. Subsequent publications have verified the efficacy of such treatment in some cases but limited and variable in others. We present further evidence of a constant but variable role for the mTOR pathway in the biology of CHI and provide a strategy that allows for the short-term testing of sirolimus in individual CHI patients. PMID- 29246173 TI - Correction to Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial. AB - CORRECTION: The title of the original publication [1] had an error; furthermore there were errors in Fig. 2. The corrected version of the title and of Fig. 2 can be found below in this Erratum. PMID- 29246174 TI - Changes of liver hemodynamic and elastography parameters in patients with colorectal liver metastases receiving preoperative chemotherapy: "a note of caution". AB - BACKGROUND: New systemic chemotherapy agents have improved prognosis in patients with colorectal liver metastases (CLM), but some of them damage the liver parenchyma and ultimately increase postoperative morbidity and mortality after liver resection. The aims of our study were to determine the degree of hemodynamic and pathological liver injury in CLM patients receiving preoperative chemotherapy and to identify an association between these injuries and postoperative complications after liver resection. METHODS: This is a prospective descriptive study of patients with CLM receiving preoperative chemotherapy before curative liver resection from November 2013 to June 2014. All patients had preoperative elastography and hepatic hemodynamic evaluation. We analyzed clinical preoperative data and postoperative outcomes after grouping the patients by chemotherapy type, development of sinusoidal obstructive syndrome (SOS), and development of major complications. RESULTS: Eleven from the 20 patients included in the study received preoperative oxaliplatin-based chemotherapy (OBC). Nine patients had SOS at pathological analysis and five patients developed major complications. Patients receiving preoperative OBC had higher values of hepatic venous pressure gradient (HVPG) and developed more SOS and major complications. Patients developing SOS had higher values of HVPG and developed more major complications. Patients with major complications had higher values of HVPG, and patients with a HVPG of 5 mmHg or greater had more major complications than those under 5 mmHg (20 vs 80%, p = 0.005). CONCLUSIONS: OBC and SOS impair liver hemodynamics in CLM patients. An increase in major complications after liver resection in these patients develops at subclinical HVPG levels. PMID- 29246175 TI - Psychosocial vulnerability underlying four common unhealthy behaviours in 15-16 year-old Swedish adolescents: a cross-sectional study. AB - BACKGROUND: Factors that influence unhealthy behaviours in adolescents may have different impacts in different sociocultural settings. There is lack of research on the association between psychosocial vulnerability and unhealthy behaviours in adolescents, particularly outside the United States. The aim was to investigate both direct and indirect relationships between psychosocial conditions (subjective well-being, social relationships and self-esteem) and four health related behaviours (smoking, alcohol consumption, meal frequency and physical activity) in Swedish adolescents aged 15-16 years. Socio-demographic variables (socio-economic status, gender and age) were also investigated. METHODS: To study these associations, a hypothesised model was tested using structural equation modelling. In the hypothesised model, interrelated psychosocial conditions (low well-being, poor social relationships and low self-esteem) and socio-demographic factors (low self-perceived socio-economic status, being female and higher age) together represented a vulnerability underlying smoking, alcohol consumption, irregular meal frequency and low level of physical activity. In this cross sectional study, self-report questionnaires were used to collect data from 492 adolescents. RESULTS: Hypothesised pathways between psychosocial conditions, socio-demographic factors and the four unhealthy behaviours were confirmed. Low well-being was strongly associated with unhealthy behaviours, and poor social relationships showed a strong indirect association with the unhealthy behaviours. Low self-esteem, low self-perceived socio-economic status and female gender were also vulnerability factors for the unhealthy behaviours. CONCLUSIONS: Vulnerability for four common unhealthy behaviours was found in Swedish adolescents. This study presents the interrelationships of psychosocial and socio demographic factors and how they were related with unhealthy behaviours. The results bring new insight into how psychosocial factors are related to unhealthy behaviours in adolescents living in northern Europe. PMID- 29246176 TI - Evaluation of three-dimensional SonoAVC ultrasound for antral follicle count in infertile women: its agreement with conventional two-dimensional ultrasound and serum levels of anti-Mullerian hormone. AB - BACKGROUND: Several studies have reported a correlation between antral follicle count by conventional 2D transvaginal sonography and serum anti-Mullerian hormone levels. However, few studies have investigated the effectiveness of 3D SonoAVC transvaginal ultrasound technology, particularly in infertile women. Therefore, this study aims to evaluate the usefulness of three-dimensional (3D) SonoAVC transvaginal ultrasound technology for antral follicle count and its correlation to conventional two-dimensional (2D) transvaginal ultrasound and serum levels of anti-Mullerian hormone in infertile women. METHODS: This cross-sectional study included 42 infertile women with age lower than 40 years that underwent treatment at a private fertility clinic between June and December 2015. Patient data included age, body mass index and cause of infertility. On cycle day 3 the following hormone levels were measured: serum levels of anti-Mullerian hormone, follicle-stimulating hormone, cancer antigen 125, prolactin, thyroid-stimulating hormone and oestradiol; the number of antral follicles was counted as well. The scanning were performed through 2D and 3D technology transvaginal ultrasound. RESULTS: Using a Bland-Altman test we demonstrated that both technologies are quite equivalent. However, antral follicle count is higher using 3D ultrasound technology compared to 2D technology (p < 0.001; Wilcoxon test), this finding is mainly remarkable in ovaries with more than 20 antral follicles. Moreover, the mean time required for manual 2D ultrasound and 3D SonoAVC measurements were 275 +/- 109 and 103 +/- 57 s, respectively (p < 0.001). Serum AMH concentration correlated to the total number of early antral follicles (correlation coefficients = 0.678 and 0.612; p < 0.001 by 2D ultrasound and 3D SonoAVC, respectively; Spearman's correlation test). CONCLUSIONS: Antral follicle count is better estimated using 3D ultrasound compared to 2D technology. A great advantage of 3D SonoAVC was less time required for an examination and the visual advantage when it need to count more than 20 follicles. TRIAL REGISTRATION: CAAE: 35141114.4.0000.5327 . Registered 10 June 2015. PMID- 29246177 TI - SCORE-IT (Selecting Core Outcomes for Randomised Effectiveness trials In Type 2 diabetes): a systematic review of registered trials. AB - BACKGROUND: Outcomes measured in clinical trials should be meaningful to patients, healthcare professionals and researchers, yet there is heterogeneity in the outcomes used across trials. This inconsistency impacts on the ability to compare findings and may mean that the results have little importance to healthcare professionals and the patients that they care for. The aim of the present study is to review the outcomes used in registered trials of therapies for type 2 diabetes mellitus as the first step in the development of a core outcome set for effectiveness trials in type 2 diabetes. METHODS: A systematic review of clinicaltrials.gov entries was completed for randomised, open (actively recruiting or in follow-up period), phase 3 and 4 trials of type 2 diabetes mellitus in adults. Trials of the treatment of diabetes complications, co morbidities, prevention and surgery were excluded. Each trial was screened for eligibility and outcomes extracted from the primary and secondary outcomes data fields and free text study information. The outcomes were recorded verbatim and classified into core outcome domains according to the COMET taxonomy. RESULTS: A total of 354 trial registrations were reviewed for eligibility and 138 trials included. In total, 1444 outcomes were extracted with a median of eight outcomes per trial (range = 1-60). Outcomes were categorised into 30 different outcome domains according to the COMET taxonomy, but no single domain or outcome was measured in 100% of trials. The majority of trials (88%) included outcomes in the 'metabolism and nutrition' domain, such as lipids and lipoproteins (21%), HbA1c (18%), hypoglycaemia (14%), fasting plasma/blood glucose (11%), glycaemic variability (8%), postprandial response (8%) and insulin sensitivity (5%). Only 10% of trials included one or more patient reported outcomes; of these, 29% included the Diabetes Treatment Satisfaction Questionnaire. CONCLUSIONS: There is marked heterogeneity in the outcomes measured in registered therapeutic intervention trials for type 2 diabetes. The use of an agreed set of core outcomes will improve the consistency of reporting in clinical trials for type 2 diabetes. TRIAL REGISTRATION: The core outcome set study, of which this is a part, is registered in the COMET database, http://www.comet initiative.org/studies/details/956 . Registered on 24 January 2017. PMID- 29246178 TI - Discovery of the fourth mobile sulfonamide resistance gene. AB - BACKGROUND: Over the past 75 years, human pathogens have acquired antibiotic resistance genes (ARGs), often from environmental bacteria. Integrons play a major role in the acquisition of antibiotic resistance genes. We therefore hypothesized that focused exploration of integron gene cassettes from microbial communities could be an efficient way to find novel mobile resistance genes. DNA from polluted Indian river sediments were amplified using three sets of primers targeting class 1 integrons and sequenced by long- and short-read technologies to maintain both accuracy and context. RESULTS: Up to 89% of identified open reading frames encode known resistance genes, or variations thereof (> 1000). We identified putative novel ARGs to aminoglycosides, beta-lactams, trimethoprim, rifampicin, and chloramphenicol, including several novel OXA variants, providing reduced susceptibility to carbapenems. One dihydropteroate synthase gene, with less than 34% amino acid identity to the three known mobile sulfonamide resistance genes (sul1-3), provided complete resistance when expressed in Escherichia coli. The mobilized gene, here named sul4, is the first mobile sulfonamide resistance gene discovered since 2003. Analyses of adjacent DNA suggest that sul4 has been decontextualized from a set of chromosomal genes involved in folate synthesis in its original host, likely within the phylum Chloroflexi. The presence of an insertion sequence common region element could provide mobility to the entire integron. Screening of 6489 metagenomic datasets revealed that sul4 is already widespread in seven countries across Asia and Europe. CONCLUSIONS: Our findings show that exploring integrons from environmental communities with a history of antibiotic exposure can provide an efficient way to find novel, mobile resistance genes. The mobilization of a fourth sulfonamide resistance gene is likely to provide expanded opportunities for sulfonamide resistance to spread, with potential impacts on both human and animal health. PMID- 29246179 TI - Smoldering mantle cell lymphoma. AB - BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive disease, with poor prognosis and a limited survival. However, some patients with indolent MCL can survive beyond 7~10 years. These patients remain largely asymptomatic and can be in observation for a long time without any treatment. The process of "wait and watch" leaves these patients with the potential risk of evolution to classic, aggressive MCL. On the other hand, early treatment for these patients may not impact overall survival but rather affects the quality of life. Therefore, it is essential to clearly identify this type of indolent MCL at the time of diagnosis. RESULTS: Reported findings of indolent presentation of MCL include: lack of B symptoms, normal serum lactic dehydrogenase (LDH) and beta2-microglobulin levels (beta2M), low MCL-International Prognostic Index (MIPI) score, maximum tumor diameter less than 3 cm, spleen size < 20 cm, positron emission tomography/computerized tomography with the Standard Uptake Value max <6, Ki-67 less than 30%, with some particular immunophenotype, such as CD5 and CD38 negative, markedly increased CD23 positive lymphocytes proportions, high expression of CD200, kappa light chain restriction, without C-myc, TP53 and NOTCH1/2 mutations, non-blastoid/pleomorphic histology, and no tumor growth on reevaluation every 2~3 months (followed for at least 6 months). Imaging evaluation may only be performed in the presence of disease-related symptoms or organ involvement. Meanwhile, if novel nodal or extranodal lesion is found, biopsy is mandatory to exclude lymphoma. Common clinopathological forms of indolent presentations include monoclonal B lymphocytosis with t (11; 14); "indolent leukemic" presentation of MCL with involvement of peripheral blood, bone marrow involvement, splenomegaly, and minimal lymphadenopathies and in situ lymphoma (often found in lymph nodes removed for other reasons, and in gastrointestinal biopsies). CONCLUSIONS: Considering these distinct indolent clinical presentations with particular features in cytology and gene mutational status, we propose to include these MCL clinical presentations under the umbrella of "Smoldering Mantle Cell Lymphoma". PMID- 29246180 TI - Lipophosphoglycan polymorphisms do not affect Leishmania amazonensis development in the permissive vectors Lutzomyia migonei and Lutzomyia longipalpis. AB - BACKGROUND: Lipophosphoglycan (LPG) is a dominant surface molecule of Leishmania promastigotes. Its species-specific polymorphisms are found mainly in the sugars that branch off the conserved Gal(beta1,4)Man(alpha1)-PO4 backbone of repeat units. Leishmania amazonensis is one of the most important species causing human cutaneous leishmaniasis in the New World. Here, we describe LPG intraspecific polymorphisms in two Le. amazonensis reference strains and their role during the development in three sand fly species. RESULTS: Strains isolated from Lutzomyia flaviscutellata (PH8) and from a human patient (Josefa) displayed structural polymorphism in the LPG repeat units, possessing side chains with 1 and 2 beta glucose or 1 to 3 beta-galactose, respectively. Both strains successfully infected permissive vectors Lutzomyia longipalpis and Lutzomyia migonei and could colonize their stomodeal valve and differentiate into metacyclic forms. Despite bearing terminal galactose residues on LPG, Josefa could not sustain infection in the restrictive vector Phlebotomus papatasi. CONCLUSIONS: LPG polymorphisms did not affect the ability of Le. amazonensis to develop late-stage infections in permissive vectors. However, the non-establishment of infection in Ph. papatasi by Josefa strain suggested other LPG-independent factors in this restrictive vector. PMID- 29246181 TI - Detection and identification of antimicrobial-resistant Salmonella in raw beef at Wolaita Sodo municipal abattoir, Southern Ethiopia. AB - BACKGROUND: The consumption of multidrug resistant Salmonella isolates along with a raw meat dish is directly relevant to the global public health crisis of antimicrobial resistance. All countries around the globe are suffering from food borne diseases. In developing countries, more than one billion individuals suffering from gastroenteritis and around five million infected individuals die annually. METHODS: A cross-sectional study was carried out from December 2015 to May 2016 to show the risk of Salmonella associated with consuming traditional raw meat dishes and to characterize the antimicrobial resistance profile at Wolaita Sodo municipal abattoir. Animals were being processed as part of the normal work of the abattoir, and 448 carcass samples were taken after getting a written consent from the municipality. Samples were transported to Wolaita Sodo University Microbiology Laboratory in an ice box within an hour of collection. Swab samples were pre-enriched in tetrathionate broth and Rappaport-Vassiliadis R10 broth. Broth culture was sub-cultured on xylose lysine deoxycholate and brilliant green agar and incubated at a temperature of 37 degrees C for overnight. Antimicrobial susceptibility test was done by disk diffusion method. Microbiological and observational data entry and analysis were done using Microsoft Excel 2007. RESULTS: From the total 448 sampled carcasses, Salmonella growth was observed in 56 (12.5%) samples. The isolates had various resistance profiles, with resistance to 1 to 12 antimicrobial drugs. Tetracycline- and nitrofurantion-resistant isolates were frequent, 83.93 and 73.21% respectively, and followed by streptomycin-resistant isolates (66%). Ciprofloxacin-resistant isolates were rare (7%). CONCLUSION: Salmonella species contamination frequency was high in raw beef, and most of the isolates exhibited resistance to commonly used antibiotics. People living in the town and consuming the raw meat are at risk for developing diseases, and attention should be given to select antimicrobials in treating Salmonella infections in both animals and human being based on antimicrobial susceptibility test. Moreover, intersectoral working and developing one health approach is essential. Health information should be given to individuals who have the habit of eating raw meat. Training on sanitary and hygiene practice should be given to the abattoir workers. PMID- 29246183 TI - The biological functions of DNA: from the sublime to the slime. PMID- 29246182 TI - Expression and clinical value of programmed cell death-ligand 1 (PD-L1) in diffuse large B cell lymphoma: a retrospective study. AB - BACKGROUND: The programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses. Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis. METHODS: We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical (IHC) assay. The expression of anaplastic lymphoma kinase (ALK), CD5, CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein-Barr virus (EBV)-encoded RNAs (EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis. RESULTS: Of the 204 patients, 100 (49.0%) were PD-L1 positive in tumor cells and 44 (21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like (GCB) subtype than in the GCB subtype (P = 0.02 and P = 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment (P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression (r = - 0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival (OS) rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells (P = 0.02). PD-L1 expression in tumor cells was an independent risk predictor for OS (P < 0.01). CONCLUSIONS: PD L1 expression is more common in the non-GCB subtype than in the GCB subtype. PD L1 expression in tumor microenvironment has a negative correlation with C-Myc. PD L1 positivity predicts short survival in DLBCL patients. For patients with PD-L1 expression, more strategy such as anti-PD-L1 antibody treatment should be recommended. PMID- 29246184 TI - Liraglutide modulates GABAergic signaling in rat hippocampal CA3 pyramidal neurons predominantly by presynaptic mechanism. AB - BACKGROUND: gamma-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain where it regulates activity of neuronal networks. The receptor for glucagon-like peptide-1 (GLP-1) is expressed in the hippocampus, which is the center for memory and learning. In this study we examined effects of liraglutide, a GLP-1 analog, on GABA signaling in CA3 hippocampal pyramidal neurons. METHODS: We used patch-clamp electrophysiology to record synaptic and tonic GABA-activated currents in CA3 pyramidal neurons in rat hippocampal brain slices. RESULTS: We examined the effects of liraglutide on the neurons at concentrations ranging from one nM to one MUM. Significant changes of the spontaneous inhibitory postsynaptic currents (sIPSCs) were only recorded with 100 nM liraglutide and then in just ~50% of the neurons tested at this concentration. In neurons affected by liraglutide both the sIPSC frequency and the most probable amplitudes increased. When the action potential firing was inhibited by tetrodotoxin (TTX) the frequency and amplitude of IPSCs in TTX and in TTX plus 100 nM liraglutide were similar. CONCLUSIONS: The results demonstrate that liraglutide regulation of GABA signaling of CA3 pyramidal neurons is predominantly presynaptic and more limited than has been observed for GLP-1 and exendin-4 in hippocampal neurons. PMID- 29246186 TI - "When a woman is pregnant, her grave is open": health beliefs concerning dietary practices among pregnant Kalenjin women in rural Uasin Gishu County, Kenya. AB - BACKGROUND: Reducing malnutrition remains a major global challenge especially in low- and middle-income countries. Lack of knowledge on the motive of nutritional behaviour could ultimately cripple nutrition intervention outcomes. The purpose of this study was to investigate how health beliefs influence nutritional behaviour intention of the pregnant Kalenjin women of rural Uasin Gishu County in Kenya. The study findings provide useful information for culturally congruent nutrition counselling and intervention. METHODS: In this qualitative study semi structured interviews were conducted with 42 pregnant and post-natal (with children less than one year) Kalenjin women in selected rural public health facilities of Uasin Gishu County Kenya. Furthermore, key informant interviews took place with 6 traditional birth attendants who were also pregnancy herbalists, two community health workers and one nursing officer in charge of Maternal and Child Health (MCH) for triangulation and provision of in-depth information. Content analysis of interview transcripts followed a grounded theory (Protection Motivation Theory) approach, using software MAXQDA version 12.1.3. RESULTS: Abstracted labour (big babies and lack of maternal strength), haemorrhage (low blood), or having other diseases and complications (evil or bad food) were the major perceived health threats that influence nutritional behaviour intention of the pregnant Kalenjin women in rural Uasin Gishu County in Kenya. CONCLUSION: The pregnancy nutritional behaviour and practices of the Kalenjin women in rural Uasin Gishu County act as an adaptive response to the perceived health threats, which seem to be within the agency of pregnant women. As a result, just giving antenatal nutritional counselling without addressing these key health assumptions that underlie a successful pregnancy outcome is unlikely to lead to changes in nutritional behaviour. PMID- 29246187 TI - Muscle co-contraction in elderly people change due to postural stability during single-leg standing. AB - BACKGROUND: Muscle co-contraction is the simultaneous contraction of agonist and antagonist muscles crossing a joint, and it increases with age. This study primarily aimed to clarify the difference in the effect of a light fingertip contact to stationary surface on postural sway and muscle co-contraction during single-leg standing (SLS) between young and elderly groups; the secondary aim was to reveal the quantitative difference in the muscle co-contraction of the ankle joint among the three different support structure conditions in the elderly group. METHODS: This study included eight young adults (age 23.4 +/- 2.6 years) and nine community dwelling older adults (age 74.7 +/- 3.4 years). The task was SLS under the following conditions: (1) no supporting structure, FR; (2) light index fingertip contact to a stationary supporting structure (to touch in force < 1 N), LT; and (3) dependence on a supporting structure for stabilization as desired, DO. Center of pressure (COP) variables [root-mean-square distance (RDIST), total excursion (TOTEX), mean velocity (MVELO), and standard deviation area (AREA-SD)] and the co-contraction index (CI) between the tibialis anterior and soleus were measured using surface electromyography. RESULTS: With regard to the effect of the light fingertip contact to stationary surface, in the young group, TOTEX, MVELO, AREA-SD, and CI during SLS were smaller under the LT condition than under the FR condition. However, in the elderly group, only AREA SD and CI were smaller under the LT condition than under the FR condition. No significant difference was observed in COP variables and CI under the DO condition between the young and elderly groups. CONCLUSION: Both young and elderly groups could decrease muscle co-contraction using the light fingertip contact. On the other hand, in the elderly group, COP variables showed a limited effect from the light fingertip contact; only the "sway" domain measure (AREA SD). Both young and elderly groups showed the smallest CI under the DO condition. Therefore, the elderly group could decrease muscle co-contraction of the ankle joint depending on postural stability. PMID- 29246185 TI - Early-life adversity and long-term neurobehavioral outcomes: epigenome as a bridge? AB - Accumulating evidence suggests that adversities at critical periods in early life, both pre- and postnatal, can lead to neuroendocrine perturbations, including hypothalamic-pituitary-adrenal axis dysregulation and inflammation persisting up to adulthood. This process, commonly referred to as biological embedding, may cause abnormal cognitive and behavioral functioning, including impaired learning, memory, and depressive- and anxiety-like behaviors, as well as neuropsychiatric outcomes in later life. Currently, the regulation of gene activity by epigenetic mechanisms is suggested to be a key player in mediating the link between adverse early-life events and adult neurobehavioral outcomes. Role of particular genes, including those encoding glucocorticoid receptor, brain derived neurotrophic factor, as well as arginine vasopressin and corticotropin releasing factor, has been demonstrated in triggering early adversity-associated pathological conditions. This review is focused on the results from human studies highlighting the causal role of epigenetic mechanisms in mediating the link between the adversity during early development, from prenatal stages through infancy, and adult neuropsychiatric outcomes. The modulation of epigenetic pathways involved in biological embedding may provide promising direction toward novel therapeutic strategies against neurological and cognitive dysfunctions in adult life. PMID- 29246189 TI - Colonoscopy overuse in colorectal cancer screening and associated factors in Argentina: a retrospective cohort study. AB - BACKGROUND: In recent years, there has been growing concern about the overuse of colonoscopy (CC). Our objective was to evaluate the incidence rate and cumulative probability of having a potentially inadequate CC (PI-CC, e.g. a CC that was performed earlier that recommended) and the association between the report of a hyperplastic polyp in the baseline CC report and the probability of having a PI CC. METHODS: A retrospective cohort of adults 50y/o or older with a complete baseline CC between January 1st and December 31st 2005, without reported lesions or with hyperplastic polyps, based on secondary data extracted from the electronic medical record of the Hospital Italiano of Buenos Aires. The outcome consisted of time until a PI-CC, defined as the time measured between basal colonoscopy and a colonoscopy performed earlier than the inter-screening interval recommended by the USPSTF and the USMSTF. RESULTS: 389 patients were included. The cumulative probability of receiving a PI-CC over 10 years was 0.29 (95% CI 0.241, 0.342). The incidence rate resulted in 30.91 PI-CC per 1000 person-years (95% CI 25.14, 38). The crude analysis of the association between the outcome and the presence of hyperplastic polyps in the baseline CC, showed a statistically significant difference between both groups (log rank, p 0.036). The multivariate analysis yielded a hazard ratio of 1.67 (95% CI 1.02-2.73). CONCLUSION: We observed that 3 in every 10 patients treated in our health system received a PI CC during the first ten consecutive years after a normal complete CC. Furthermore, this could be in part attributed to the presence of a hyperplastic polyp in the baseline CC. PMID- 29246188 TI - Antibiotic treatment In patients with chronic low back pain and Modic changes (the AIM study): study protocol for a randomised controlled trial. AB - BACKGROUND: A previous randomised controlled trial (RCT) of patients with chronic low back pain (LBP) and vertebral bone marrow (Modic) changes (MCs) on magnetic resonance imaging (MRI), reported that a 3-month, high-dose course of antibiotics had a better effect than placebo at 12 months' follow-up. The present study examines the effects of antibiotic treatment in chronic LBP patients with MCs at the level of a lumbar disc herniation, similar to the previous study. It also aims to assess the cost-effectiveness of the treatment, refine the MRI assessment of MCs, and further evaluate the impact of the treatment and the pathogenesis of MCs by studying genetic variability and the gene and protein expression of inflammatory biomarkers. METHODS/DESIGN: A double-blinded RCT is conducted at six hospitals in Norway, comparing orally administered amoxicillin 750 mg, or placebo three times a day, over a period of 100 days in patients with chronic LBP and type I or II MCs at the level of a MRI-confirmed lumbar disc herniation within the preceding 2 years. The inclusion will be stopped when at least 80 patients are included in each of the two MC type groups. In each MC type group, the study is designed to detect (beta = 0.1, alpha = 0.05) a mean difference of 4 (standard deviation 5) in the Roland Morris Disability Questionnaire score between the two treatment groups (amoxicillin or placebo) at 1-year follow-up. The study includes cost-effectiveness measures. Blood samples are assessed for security measures and for possible inflammatory mediators and biomarkers at different time points. MCs are evaluated on MRI at baseline and after 12 months. A blinded intention-to treat analysis of treatment effects will be performed in the total sample and in each MC type group. DISCUSSION: To ensure the appropriate use of antibiotic treatment, its effect in chronic LBP patients with MCs should be re-assessed. This study will investigate the effects and cost-effectiveness of amoxicillin in patients with chronic LBP and MCs at the level of a disc herniation. The study may also help to refine imaging and characterise the biomarkers of MCs. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02323412 . Registered on 21 November 2014. PMID- 29246190 TI - Comparative metabolite profiling of drought stress in roots and leaves of seven Triticeae species. AB - BACKGROUND: Drought is a lifestyle disease. Plant metabolomics has been exercised for understanding the fine-tuning of the potential pathways to surmount the adverse effects of drought stress. A broad spectrum of morphological and metabolic responses from seven Triticeae species including wild types with different drought tolerance/susceptibility level was investigated under control and water scarcity conditions. RESULTS: Significant morphological parameters measured were root length, surface area, average root diameter and overall root development. Principal Component Analysis, Partial Least-Squares-Discriminant Analysis and Hierarchical Cluster Analysis were applied to the metabolomic data obtained by Gas Chromatography-Mass Spectrometry technique in order to determine the important metabolites of the drought tolerance across seven different Triticeae species. The metabolites showing significant accumulation under the drought stress were considered as the key metabolites and correlated with potential biochemical pathways, enzymes or gene locations for a better understanding of the tolerance mechanisms. In all tested species, 45 significantly active metabolites with possible roles in drought stress were identified. Twenty-one metabolites out of forty-five including sugars, amino acids, organic acids and low molecular weight compounds increased in both leaf and root samples of TR39477, IG132864 and Bolal under the drought stress, contrasting to TTD-22, Tosunbey, Ligustica and Meyeri samples. Three metabolites including succinate, aspartate and trehalose were selected for further genome analysis due to their increased levels in TR39477, IG132864, and Bolal upon drought stress treatment as well as their significant role in energy producing biochemical pathways. CONCLUSION: These results demonstrated that the genotypes with high drought tolerance skills, especially wild emmer wheat, have a great potential to be a genetic model system for experiments aiming to validate metabolomics-genomics networks. PMID- 29246191 TI - Bioinformatically predicted deleterious mutations reveal complementation in the interior spruce hybrid complex. AB - BACKGROUND: Mutation load is expected to be reduced in hybrids via complementation of deleterious alleles. While local adaptation of hybrids confounds phenotypic tests for reduced mutation load, it may be possible to assess variation in load by analyzing the distribution of putatively deleterious alleles. Here, we use this approach in the interior spruce (Picea glauca x P. engelmannii) hybrid complex, a group likely to suffer from high mutation load and in which hybrids exhibit local adaptation to intermediate conditions. We used PROVEAN to bioinformatically predict whether non-synonymous alleles are deleterious, based on conservation of the position and abnormality of the amino acid change. RESULTS: As expected, we found that predicted deleterious alleles were at lower average allele frequencies than alleles not predicted to be deleterious. We were unable to detect a phenotypic effect on juvenile growth rate of the many rare alleles predicted to be deleterious. Both the proportion of alleles predicted to be deleterious and the proportion of loci homozygous for predicted deleterious alleles were higher in P. engelmannii (Engelmann spruce) than in P. glauca (white spruce), due to higher diversity and frequencies of rare alleles in Engelmann. Relative to parental species, the proportion of alleles predicted to be deleterious was intermediate in hybrids, and the proportion of loci homozygous for predicted deleterious alleles was lowest. CONCLUSION: Given that most deleterious alleles are recessive, this suggests that mutation load is reduced in hybrids due to complementation of deleterious alleles. This effect may enhance the fitness of hybrids. PMID- 29246192 TI - Accounting for parameter uncertainty in the definition of parametric distributions used to describe individual patient variation in health economic models. AB - BACKGROUND: Parametric distributions based on individual patient data can be used to represent both stochastic and parameter uncertainty. Although general guidance is available on how parameter uncertainty should be accounted for in probabilistic sensitivity analysis, there is no comprehensive guidance on reflecting parameter uncertainty in the (correlated) parameters of distributions used to represent stochastic uncertainty in patient-level models. This study aims to provide this guidance by proposing appropriate methods and illustrating the impact of this uncertainty on modeling outcomes. METHODS: Two approaches, 1) using non-parametric bootstrapping and 2) using multivariate Normal distributions, were applied in a simulation and case study. The approaches were compared based on point-estimates and distributions of time-to-event and health economic outcomes. To assess sample size impact on the uncertainty in these outcomes, sample size was varied in the simulation study and subgroup analyses were performed for the case-study. RESULTS: Accounting for parameter uncertainty in distributions that reflect stochastic uncertainty substantially increased the uncertainty surrounding health economic outcomes, illustrated by larger confidence ellipses surrounding the cost-effectiveness point-estimates and different cost-effectiveness acceptability curves. Although both approaches performed similar for larger sample sizes (i.e. n = 500), the second approach was more sensitive to extreme values for small sample sizes (i.e. n = 25), yielding infeasible modeling outcomes. CONCLUSIONS: Modelers should be aware that parameter uncertainty in distributions used to describe stochastic uncertainty needs to be reflected in probabilistic sensitivity analysis, as it could substantially impact the total amount of uncertainty surrounding health economic outcomes. If feasible, the bootstrap approach is recommended to account for this uncertainty. PMID- 29246193 TI - How to choose the most appropriate cognitive test to evaluate cognitive complaints in primary care. AB - BACKGROUND: Despite the wealth of research devoted to the performance of individual cognitive tests for diagnosing cognitive impairment (including mild cognitive impairment and dementia), it can be difficult for general practitioners to choose the most appropriate test for a patient with cognitive complaints in daily practice. In this paper we present a diagnostic algorithm for the evaluation of cognitive complaints in primary care. The rationale behind this algorithm is that the likelihood of cognitive impairment -which can be determined after history taking and an informant interview- should determine which cognitive test is most suitable. METHODS: We distinguished three likelihoods of cognitive impairment: not likely, possible or likely. We selected cognitive tests based on pre-defined required test features for each of these three situations and a review of the literature. We incorporated the cognitive tests in a practical diagnostic algorithm. RESULTS: Based on the available literature, in patients with complaints but where cognitive impairment is considered to be unlikely the clock-drawing test can be used to rule out cognitive impairment. When cognitive impairment is possible the Montreal cognitive assessment can be used to rule out cognitive impairment or to make cognitive impairment more likely. When cognitive impairment is likely the Mini-Mental State Examination can be used to confirm the presence of cognitive impairment. CONCLUSIONS: We propose a diagnostic algorithm to increase the efficiency of ruling out or diagnosing cognitive impairment in primary care. Further study is needed to validate and evaluate this stepwise diagnostic algorithm. PMID- 29246194 TI - Engaging men to promote and support exclusive breastfeeding: a descriptive review of 28 projects in 20 low- and middle-income countries from 2003 to 2013. AB - BACKGROUND: Lay support has been associated with improved breastfeeding practices, but studies of programs that engage men in breastfeeding support have shown mixed results and most are from high-income countries. The purpose of our research is to review strategies to engage men in exclusive breastfeeding (EBF) promotion or support in 28 project areas across 20 low- and middle-income countries. This information may be used to inform program implementers and policymakers seeking to increase EBF. METHODS: We tested the difference between baseline and final EBF proportions using Pearson's chi-square (a = 0.05) and identified project areas with a significant increase. We categorized male engagement strategies as low- and high-intensity, using information from project reports. We looked for patterns by intensity and geography and described strategies used to engage men in different places. RESULTS: Twenty-eight projects were reviewed; 21 (75%) were in areas where a statistically significant increase in EBF was observed between the beginning and end of the project. A variety of high- and low-intensity male engagement strategies was used in areas with an increase in EBF prevalence and in all geographic regions. High-intensity strategies engaged men directly during home or health visits by forming men's groups and by working with male community leaders or members to promote EBF. Low intensity strategies included large community meetings that included men, and radio messages, and other behavior change materials directed towards men. CONCLUSION: Male engagement strategies took many forms in these project areas. We did not find consistent associations between the intensities or types of male engagement strategies and increases in EBF proportions. There is a gap in understanding how gender norms might impact male involvement in women's health behaviors. This review does not support the broad application of male engagement to improve EBF practices, and we recommend considering local gender norms when designing programs to support women to EBF. PMID- 29246196 TI - A two-month follow-up evaluation testing interventions to limit the emergence and spread of antimicrobial resistant bacteria among Maasai of northern Tanzania. AB - BACKGROUND: In sub-Saharan Africa, efforts to control antimicrobial resistance (AMR) are aggravated by unregulated drug sales and use, and high connectivity between human, livestock, and wildlife populations. Our previous research indicates that Maasai agropastoralists-who have high exposure to livestock and livestock products and self-administer veterinary antibiotics-harbor antibiotic resistant Escherichia coli (E. coli). Here, we report the results of a public health intervention project among Maasai aimed at reducing selection and transmission of E. coli bacteria. METHODS: Research was conducted in two Maasai communities in Northern Tanzania. Participants were provided with health knowledge and technological innovations to facilitate: 1) the prudent use of veterinary antibiotics (tape measures and dosage charts to calculate livestock weight for more accurate dosage), and, 2) the pasteurization of milk (thermometers), the latter of which was motivated by findings of high levels of resistant E. coli in Maasai milk. To determine knowledge retention and intervention adoption, we conducted a two-month follow-up evaluation in the largest of the two communities. RESULTS: Retention of antimicrobial knowledge was positively associated with retention of bacterial knowledge and, among men, retention of bacterial knowledge was associated with greater wealth. Bacterial and AMR knowledge were not, however, associated with self-reported use of the innovations. Among women, self-reported use of the thermometers was associated with having more children and greater retention of knowledge about the health benefits of the innovations. Whereas 70% of women used their innovations correctly, men performed only 18% of the weight-estimation steps correctly. Men's correct use was associated with schooling, such that high illiteracy rates remain an important obstacle to the dissemination and diffusion of weight-estimation materials. CONCLUSION: Our results indicate that dietary preferences for unboiled milk, concerns over child health, and a desire to improve the health of livestock are important cultural values that need to be incorporated in future AMR prevention interventions that target Maasai populations. More generally, these findings inform future community-health interventions to limit AMR. PMID- 29246195 TI - Co-infection of sexually transmitted pathogens and Human Papillomavirus in cervical samples of women of Brazil. AB - BACKGROUND: Some sexually transmitted infectious agents, such as Chlamydia trachomatis and Herpes simplex, cause local inflammation, and could contribute to Human Papillomavirus (HPV) and cervical lesion progression. Thus, the aim of this study was to determine any association between the presence of microorganisms of gynecological importance, sexual behavior, clinical and demographical variables to the development and progress of cervical lesions. METHODS: One hundred and thirty-two women between 14 and 78 years and living at Vitoria da Conquista, Bahia, Brazil, were included (62 individuals with cervical lesions and 70 without lesions). They answered a questionnaire to provide data for a socioeconomic and sexual activity profile. Samples of cervical swabs were collected and analyzed by PCR to detect genital microorganisms and HPV. Quantitative PCR was used to detect and quantify Ureaplasma urealyticum and Ureaplasma parvum. Univariate and multiple logistic regression were performed to measure the association with the cervical lesions, and an odds ratio (OR) with 95% confidence intervals (95%CI) were calculated. The Mann-Whitney U test was also used to compare the microorganism load in the case and control groups. The significance level was 5% in all hypotheses tested. RESULTS: Cervical lesions were associated with: women in a stable sexual relationship (OR = 14.21, 95%CI = 3.67-55.018), positive PCR for HPV (OR = 16.81, 95%CI = 4.19-67.42), Trichomonas vaginalis (OR = 8.566, 95%CI = 2.04-35.94) and Gardnerella vaginalis (OR = 6.13, 95%CI = 1.53-24.61), adjusted by age and qPCR for U. parvum. U. parvum load showed a statistical difference between the case and control groups (p-value = 0.002). CONCLUSION: Variables such as stable relationship, HPV, T. vaginalis, G. vaginalis were associated with cervical lesions in epidemiological studies. U. parvum load was higher in woman with cervical lesions compared with women without lesions. Additional studies are needed to better understand the role of these factors in cervical lesion development. PMID- 29246197 TI - A higher CD4/CD8 ratio correlates with an ultralow cell-associated HIV-1 DNA level in chronically infected patients on antiretroviral therapy: a case control study. AB - BACKGROUND: The HIV-1 DNA reservoir is an important marker that reflects viro immunological status and can be affected by multiple viral or cellular factors. Determining the potential factors associated with the size of the HIV-1 DNA reservoir benefits the surveillance of disease progression and antiretroviral treatments. METHODS: We conducted a case control study to explore the factors that may affect the level of HIV-1 DNA. The level of HIV-1 total DNA in peripheral blood at 5 time points was quantified by quantitative PCR. Chronically HIV-1-infected patients whose cell-associated HIV-1 DNA levels were below the detection limit after receiving antiretroviral therapy (ART) for 96 weeks were identified (group 1), and patients who still had detectable levels of cell associated HIV-1 DNA after ATR treatment were used as the control (group 2). RESULTS: Twenty-one patients with ultralow levels of cell-associated HIV-1 DNA [<20 copies/106 peripheral blood mononuclear cells (PBMCs)] presented with a lower CD8+ T-cell count (average: 511 +/- 191 versus 715 +/- 256 cells/MUL, p = 0.013) and a higher CD4/CD8 ratio (average: 1.04 +/- 0.37 versus 0.72 +/- 0.32, respectively, p = 0.002) at week 96. In the multivariate analysis, patients with a higher CD4/CD8 ratio at week 96 were more likely to have levels of HIV-1 DNA below the detection limit (per 0.1 increase, OR = 1.29, 95% CI, 1.05-1.59, p = 0.017). CONCLUSION: After matching baseline HIV-1 DNA levels, a higher CD4/CD8 ratio at week 96 was the only factor associated with an ultralow level of HIV-1 DNA. The CD4/CD8 ratio can be used as an easy biomarker to help monitor patients on ART who will be selected to participate in eradication studies. PMID- 29246198 TI - Cortical vein thrombosis in adult patients of cerebral venous sinus thrombosis correlates with poor outcome and brain lesions: a retrospective study. AB - BACKGROUND: Cortical vein thrombosis (CVT) receives little attention in adult patients with cerebral venous sinus thrombosis (CVST). This study aimed to investigate the clinical and radiological features of adult CVST patients with concomitant CVT. METHODS: From May 2009 to May 2016, we recruited 44 adult CVST patients (diagnosed within 1 month of onset; 33.8 +/- 14.0 years of age, 28 males). CVT was primarily confirmed using computed tomography venography and magnetic resonance imaging sequence of contrast enhanced three dimensions magnetization prepared rapid acquisition with gradient echo. Patients with concomitant CVT were divided into the CVT group; otherwise, the patients were placed into the non-CVT group. The clinico-radiological characteristics were compared between the two groups. RESULTS: The CVT group included 27 patients (61.4%), and the non-CVT group included 17 patients (38.6%). Seizure (63.0% versus 11.8%), focal neurological deficits (44.4% versus 5.9%), and consciousness disorders (33.3% versus 0) occurred more frequently in the patients in the CVT group than in those of the non-CVT group (P < 0.05). The modified Rankin Scale (mRS) score at discharge was higher for the CVT group patients (median 2, range 1 4) than for the non-CVT group patients (median 0, range 0-4) (P < 0.001). Venous infarction (63.0% versus 11.8%), parenchymal hemorrhage (40.7% versus 5.9%), and subarachnoid hemorrhage (22.2% versus 0) were identified more frequently in the CVT group than in the non-CVT group (P < 0.05). CONCLUSIONS: This study demonstrates that concomitant CVT is a common finding in adult patients with CVST and is associated with severe clinical manifestations, poor short-term outcomes, and brain lesions. PMID- 29246199 TI - Possible interference between seasonal epidemics of influenza and other respiratory viruses in Hong Kong, 2014-2017. AB - BACKGROUND: Unlike influenza viruses, little is known about the prevalence and seasonality of other respiratory viruses because laboratory surveillance for non influenza respiratory viruses is not well developed or supported in China and other resource-limited countries. We studied the interference between seasonal epidemics of influenza viruses and five other common viruses that cause respiratory illnesses in Hong Kong from 2014 to 2017. METHODS: The weekly laboratory-confirmed positive rates of each virus were analyzed from 2014 to 2017 in Hong Kong to describe the epidemiological trends and interference between influenza viruses, respiratory syncytial virus (RSV), parainfluenza virus (PIV), adenovirus, enterovirus and rhinovirus. A sinusoidal model was established to estimate the peak timing of each virus by phase angle parameters. RESULTS: Seasonal features of the influenza viruses, PIV, enterovirus and adenovirus were obvious, whereas annual peaks of RSV and rhinovirus were not observed. The incidence of the influenza viruses usually peaked in February and July, and the summer peaks in July were generally caused by the H3 subtype of influenza A alone. When influenza viruses were active, other viruses tended to have a low level of activity. The peaks of the influenza viruses were not synchronized. An epidemic of rhinovirus tended to shift the subsequent epidemics of the other viruses. CONCLUSION: The evidence from recent surveillance data in Hong Kong suggests that viral interference during the epidemics of influenza viruses and other common respiratory viruses might affect the timing and duration of subsequent epidemics of a certain or several viruses. PMID- 29246200 TI - Delayed-onset of progressive pseudorheumatoid dysplasia in a Chinese adult with a novel compound WISP3 mutation: a case report. AB - BACKGROUND: Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive genetic disease that is characterized by pain, stiffness and enlargement of multiple joints with an age of onset between 3 and 8 years old. Mutations in the WISP3 (Wnt1-inducible signal pathway) gene are known to be the cause of PPD. CASE PRESENTATION: We present a case of delayed-onset PPD in a Chinese man. The 35-year-old proband presented with an almost 20-year history of pain and limitations in mobility in multiple joints. Based on the clinical manifestations, the patient was diagnosed with PPD; however, there was no specific evidence to confirm this diagnosis. Through mutational analyses, two WIPS3 mutations in exon 4, including a novel frameshift mutation (c.670dupA) in the paternal allele and an already described nonsense mutation (c.756C > A, p.Cys252*) in the maternal allele, were identified in the proband. Thus, the patient was diagnosed with PPD. Furthermore, we found that the proband's son only carried one of the mutations (c.670dupA) and therefore determined that he would not be affected by PPD in the future. CONCLUSIONS: In this case, we successfully diagnosed the disease that the proband was affected precisely after the reunion of clinical diagnosis and genetic analysis. These findings demonstrate the clinical utility of genetic analysis to diagnose skeletal dysplasia and guide genetic counseling. PMID- 29246201 TI - Multiparametric functional magnetic resonance imaging for evaluation of hepatic warm ischemia-reperfusion injury in a rabbit model. AB - BACKGROUND: To assess the feasibility of noninvasive and quantitative evaluation of hepatic pathophysiological changes in rabbit hepatic warm ischemia-reperfusion injury (WIRI) models by using intravoxel incoherent motion (IVIM), diffusion tensor imaging (DTI) and blood oxygen level dependent (BOLD) MRI. METHODS: Twenty rabbits were randomly divided into hepatic WIRI model group and sham-operation group (n = 10 for each group). Hepatic WIRI was induced in rabbit by occluding hepatic inflow for 30 min and reperfusion for 6 h. The control group only underwent laparotomy and liver ligament dissection. IVIM with 11 b values (0 to 800 s/mm2), DTI with 2 b values (0 and 500 s/mm2) on 12 diffusion directions, and BOLD MRI with 9 TE (2.57 to 24.25 ms) were performed at 3 T clinical MR scanner. Rabbits were sacrificed for biochemical and histopathological analysis after MR scanning. All of functional MR, biochemical and histopathological parameters were analyzed by independent sample t test, Mann-Whitney U test, Pearson and Spearman correlation methods. RESULTS: All of MR parameters showed moderate to excellent interobserver reproducibility. True diffusion (Dslow), pseudodiffusion (Dfast), perfusion fraction (PF), and mean diffusitivity (MD) were lower in WIRI models than in control rabbits (P < 0.01), R2* was higher in WIRI models than in control rabbits (P < 0.001), while fractional anisotropy (FA) showed no statistical difference. There were significant differences in I score and all of biochemical parameters between the two groups (P < 0.01). Functional MR parameters corresponded well with all of biochemical parameters and some of histopathological parameters (P < 0.05). Histopathological analysis showed the structure and morphology of hepatic lobule was normal and clear in control rabbits, while diffuse hepatocyte swelling, central vein and sinusoids congestion, and inflammatory cell infiltration in WIRI models. CONCLUSIONS: IVIM, DTI, and BOLD MRI are noninvasive and useful techniques for assessing the microenvironment changes of hepatic WIRI in rabbit models. PMID- 29246202 TI - Ability of ecological deprivation indices to measure social inequalities in a French cohort. AB - BACKGROUND: Despite the increasing interest in place effect to explain health inequalities, there is currently no consensus on which kind of area-based socioeconomic measures researchers should use to assess neighborhood socioeconomic position (SEP). The study aimed to evaluate the reliability of different area-based deprivation indices (DIs) in capturing socioeconomic residential conditions of French elderly women cohort. METHODS: We assessed area based SEP using 3 DIs: Townsend Index, French European Deprivation Index (FEDI) and French Deprivation index (FDep), among women from E3N (Etude epidemiologique aupres des femmes de la Mutuelle Generale de l'Education Nationale). DIs were derived from the 2009 French census at IRIS level (smallest geographical units in France). Educational level was used to evaluate individual-SEP. To evaluate external validity of the 3 DIs, associations between two well-established socially patterned outcomes among French elderly women (smoking and overweight) and SEP, were compared. Odd ratios were computed with generalized estimating equations to control for clustering effects from participants within the same IRIS. RESULTS: The analysis was performed among 63,888 women (aged 64, 47% ever smokers and 30% overweight). Substantial agreement was observed between the two French DIs (Kappa coefficient = 0.61) and between Townsend and FEDI (0.74) and fair agreement between Townsend and FDep (0.21). As expected among French elderly women, those with lower educational level were significantly less prone to be ever smoker (Low vs. High; OR [95% CI] = 0.43 [0.40-0.46]) and more prone to being overweight (1.89 [1.77-2.01]) than women higher educated. FDep showed expected associations at area-level for both smoking (most deprived vs. least deprived quintile; 0.77 [0.73-0.81]) and overweight (1.52 [1.44-1.62]). For FEDI opposite associations with smoking (1.13 [1.07-1.19]) and expected association with overweight (1.20 [1.13-1.28]) were observed. Townsend showed opposite associations to those expected for both smoking and overweight (1.51 [1.43-1.59]; 0.93 [0.88-0.99], respectively). CONCLUSION: FDep seemed reliable to capture socioeconomic residential conditions of the E3N women, more educated in average than general French population. Results varied strongly according to the DI with unexpected results for some of them, which suggested the importance to test external validity before studying social disparities in health in specific populations. PMID- 29246203 TI - Comprehensive analysis of differentially expressed genes associated with PLK1 in bladder cancer. AB - BACKGROUND: The significance of PLK1 (polo-like kinase 1) has become increasingly essential as both a biomarker and a target for cancer treatment. Here, we aimed to determine the downstream genes of PLK1 and their effects on the carcinogenesis and progression of bladder cancer. METHODS: Specific siRNA was utilized to silence the target gene expression. The cell proliferation, invasion and migration of bladder cancer cells by MTT assay, BrdU assay and transwell assay. The differential expression genes were identified using Affymetrix HTA2.0 Array. The KEGG, GO and STRING analysis were used to analyze the signaling pathway and protein-protein interaction. Spearman analysis was used to analyze the correlation between protein and protein, between protein and clincopathologic characteristics. RESULTS: PLK1 siRNA hindered the proliferation, invasion and migration of bladder cancer cells, as determined by the MTT, BrdU and transwell assays. A total of 561 differentially expressed genes were identified using an Affymetrix HTA2.0 Array in PLK1 knockdown T24 cells. According to KEGG, GO and STRING analysis, five key genes (BUB1B, CCNB1, CDC25A, FBXO5, NDC80) were determined to be involved in cell proliferation, invasion and migration. PLK1 knockdown decreased BUB1B, CCNB1, CDC25A and NDC80 expressions but increased FBXO5 expression. BUB1B, CCNB1, CDC25A and NDC80 were positively correlated with cell proliferation, invasion, migration and PLK1 expression in tissues, but FBXO5 was negatively correlated with each of those factors. The results showed that the five genes expressions were significantly correlation with the PLK1 expression in normal bladder tissues and bladder cancer tissues. Four of them (BUB1B, CCNB1, CDC25A, NDC80) were obviously positive correlations with pT stage and metastasis. But FBXO5 was negative correlated with pT stage and metastasis. Furthermore, significant correlations were found between CCNB1 or CDC25A or NDC80 and histological grade; between BUB1B or NDC80 and recurrence. CONCLUSION: Five downstream genes of PLK1 were associated with the regulation of cell proliferation, invasion and migration in bladder cancer. Furthermore, these genes may play important roles in bladder cancer and become important biomarkers and targets for cancer treatment. PMID- 29246204 TI - The application of wide-field laser ophthalmoscopy in fundus examination before myopic refractive surgery. AB - BACKGROUND: To evaluate wide-field laser ophthalmoscopy (Optomap 200Tx) for screening retinal lesions before myopic refractive surgery. METHODS: Seventy eight eyes of 78 consecutive refractive surgery candidates were included in this study. All subjects underwent Optomap 200Tx, mydriatic slit-lamp lens examination and the Goldmann three-mirror contact lens examination, which was considered as the reference method for determining retinal lesions. RESULTS: Forty of 78 eyes had retinal lesions (51.28%) and three eyes had retinal breaks (3.85%), which were diagnosed by the Goldmann three-mirror contact lens examination. Compared to the Goldmann three-mirror contact lens examination, the detection rate with the Optomap 200Tx was 91.73%% for retinal lesions, while the detection rate of mydriatic slit-lamp lens exams was 81.20%. There were no statistically significant differences among the three methods used for the diagnoses of myopic conus, tessellation and retinal breaks(all p > 0.05). For peripheral retinal lesions, the detection rate of the Optomap 200Tx examinations were similar to the Goldmann three-mirror contact lens exams (all p > 0.05), but were higher than the results of slit-lamp lens examinations (all p < 0.05). Regarding the vitreoretinal adhesions, the Goldmann three-mirror contact lens examinations had higher detection rates than did the Optomap 200Tx examinations (p = 0.031). CONCLUSIONS: The Optomap 200Tx examinations is a convenient and feasible method to determine fundus pathological changes in myopic patients, especially for patients who can not endure pupil dilation. In order to avoid misdiagnosis of peripheral retinal lesions, Goldmann three-mirror contact lens examination is needed. PMID- 29246205 TI - The Autism-Tics, ADHD and other Comorbidities inventory (A-TAC): previous and predictive validity. AB - BACKGROUND: Reliable and easy to administer screening instruments focusing on neurodevelopmental disorders and associated conditions are scarce. The Autism Tics, AD/HD and other Comorbidities inventory (A-TAC) has previously been validated and reporting good- excellent validity for several disorders. This article aims to expand these findings by including more conditions in a substantially larger sample augmented with the Swedish National Patient Register (NPR). METHODS: Since 2004 parents of all 9-year-old Swedish twins have been invited to participate in a telephone interview in the Child and Adolescent Twin Study in Sweden, CATSS. The CATSS is linked to the NPR which includes data from in- and outpatient care. Data on neurodevelopmental disorders (A-TAC) collected in CATSS were compared with diagnoses from the NPR. We investigated diagnoses that had been made both before (previous validity) and after (predictive validity) the interview. RESULTS: Sensitivity and specificity of A-TAC scores for predicting earlier or later clinical diagnoses were mostly good-excellent, with values of the area under the curve for a clinical diagnosis of autism spectrum disorder (ASD) of .98, attention deficit hyperactivity disorder (ADHD) .93, learning disorder (LD) .92, and oppositional defiant disorder (ODD) .99, with small differences in terms of previous and predictive analyses. A-TAC provided little validity for eating disorders. CONCLUSION: The result support previous claims: A-TAC is a broad screening instrument with a particular strength in assessing ASD, ADHD, LD, and ODD at ages 9 and 12, and also provides phenotypic information about other child psychiatric disorders. PMID- 29246207 TI - Plasma surfactant protein-D as a diagnostic biomarker for acute respiratory distress syndrome: validation in US and Korean cohorts. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is potentially underrecognized by clinicians. Early recognition and subsequent optimal treatment of patients with ARDS may be facilitated by usage of biomarkers. Surfactant protein D (SP-D), a marker of alveolar epithelial injury, has been proposed as a potentially useful biomarker for diagnosis of ARDS in a few studies. We tried to validate the performance of plasma SP-D levels for diagnosis of ARDS. METHODS: We conducted a retrospective analysis using data from three (two in USA and one in Korea) prospective biobank cohorts involving 407 critically ill patients admitted to medical intensive care unit (ICU). A propensity score matched analysis (patients with versus without ARDS, matched 1:1) was carried out using significant variables from multiple logistic regression. The diagnostic accuracy of plasma SP-D as a diagnostic marker of ARDS was assessed by receiver operating characteristic curve analysis. RESULTS: Out of the 407 subjects included in this study, 39 (10%) patients fulfilled ARDS criteria. Patients with ARDS had higher SP-D levels in plasma (p < 0.01) and higher hospital-mortality (p < 0.001) than those without ARDS. Thirty eight subjects with ARDS (cases) were successfully matched for propensity for ARDS with 38 subjects without ARDS (controls). Plasma levels of SP-D were higher in cases with ARDS compared to their matched controls without ARDS [median 20.8 ng/mL (interquartile range, 12.7-38.4) versus 7.9 (4.1 17.0); p = 0.001]. The area under the receiver operating characteristic curve for SP-D for the diagnosis of ARDS was 0.71 (95% confidence intervals, 0.60-0.83). A cut-off point of 12.7 ng/mL for SP-D yielded sensitivity of 74% and specificity of 63%. CONCLUSIONS: High levels of SP-D within 48 h after ICU admission might serve as a diagnostic marker for ARDS in patients hospitalized in medical ICU. Further prospective trials are required to validate the diagnostic role of SP-D in ARDS, and if its usefulness is greater in direct than in indirect ARDS, as well as across different strata of severity of ARDS. PMID- 29246206 TI - The association between HIV and atherosclerotic cardiovascular disease in sub Saharan Africa: a systematic review. AB - BACKGROUND: Sub-Saharan Africa (SSA) has confronted decades of the HIV epidemic with substantial improvements in access to life-saving antiretroviral therapy (ART). Now, with improved survival, people living with HIV (PLWH) are at increased risk for non-communicable diseases (NCDs), including atherosclerotic cardiovascular disease (CVD). We assessed the existing literature regarding the association of CVD outcomes and HIV in SSA. METHODS: We used the PRISMA guidelines to perform a systematic review of the published literature regarding the association of CVD and HIV in SSA with a focus on CVD surrogate and clinical outcomes in PLWH. RESULTS: From January 2000 until March 2017, 31 articles were published regarding CVD outcomes among PLWH in SSA. Data from surrogate CVD outcomes (n = 13) suggest an increased risk of CVD events among PLWH in SSA. Although acute coronary syndrome is reported infrequently in SSA among PLWH, limited data from five studies suggest extensive thrombus and hypercoagulability as contributing factors. Additional studies suggest an increased risk of stroke among PLWH (n = 13); however, most data are from immunosuppressed ART-naive PLWH and thus are potentially confounded by the possibility of central nervous system infections. CONCLUSIONS: Given ongoing gaps in our current understanding of CVD and other NCDs in PLWH in SSA, it is imperative to ascertain the burden of CVD outcomes, and to examine strategies for intervention and best practices to enhance the health of this vulnerable population. PMID- 29246209 TI - Airway administration of corticosteroids for prevention of bronchopulmonary dysplasia in premature infants: a meta-analysis with trial sequential analysis. AB - BACKGROUND: Uncertainly prevails with regard to the use of inhalation or instillation steroids to prevent bronchopulmonary dysplasia in preterm infants. The meta-analysis with sequential analysis was designed to evaluate the efficacy and safety of airway administration (inhalation or instillation) of corticosteroids for preventing bronchopulmonary dysplasia (BPD) in premature infants. METHODS: We searched MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL from their inceptions to February 2017. All published randomized controlled trials (RCTs) evaluating the effect of airway administration of corticosteroids (AACs) vs placebo or systemic corticosteroid in prematurity were included. All meta analyses were performed using Review Manager 5.3. RESULTS: Twenty five RCTs retrieved (n = 3249) were eligible for further analysis. Meta-analysis and trial sequential analysis corrected the 95% confidence intervals estimated a lower risk of the primary outcome of BPD (relative risk 0.71, adjusted 95% confidence interval 0.57-0.87) and death or BPD (relative risk 0.81, adjusted 95% confidence interval 0.71-0.97) in AACs group than placebo and it is equivalent for preventing BPD than systemic corticosteroids. Moreover, AACs fail to increasing risk of death compared with placebo (relative risk 0.90, adjusted 95% confidence interval 0.40-2.03) or systemic corticosteroids (relative risk 0.81, 95% confidence interval 0.62-1.06). CONCLUSIONS: Our findings suggests that AACs (especially instillation of budesonide using surfactant as a vehicle) are an effective and safe option for preventing BPD in preterm infants. Furthermore, the appropriate dose and duration, inhalation or instillation with surfactant as a vehicle and the long-term safety of airway administration of corticosteroids needs to be assessed in large trials. PMID- 29246210 TI - Rates and risk factors associated with hospitalization for pneumonia with ICU admission among adults. AB - BACKGROUND: Pneumonia poses a significant burden to the U.S. health-care system. However, there are few data focusing on severe pneumonia, particularly cases of pneumonia associated with specialized care in intensive care units (ICU). METHODS: We used administrative and electronic medical record data from six integrated health care systems to estimate rates of pneumonia hospitalizations with ICU admissions among adults during 2006 through 2010. Pneumonia hospitalization was defined as either a primary discharge diagnosis of pneumonia or a primary discharge diagnosis of sepsis or respiratory failure with a secondary diagnosis of pneumonia in administrative data. ICU admissions were collected from internal electronic medical records from each system. Comorbidities were identified by ICD-9-CM codes coded during the current pneumonia hospitalization, as well as during medical visits that occurred during the year prior to the date of admission. RESULTS: We identified 119,537 adult hospitalizations meeting our definition for pneumonia. Approximately 19% of adult pneumonia hospitalizations had an ICU admission. The rate of pneumonia hospitalizations requiring ICU admission during the study period was 76 per 100,000 population/year; rates increased for each age-group with the highest rates among adults aged >=85 years. Having a co-morbidity approximately doubled the risk of ICU admission in all age-groups. CONCLUSIONS: Our study indicates a significant burden of pneumonia hospitalizations with an ICU admission among adults in our cohort during 2006 through 2010, especially older age-groups and persons with underlying medical conditions. These findings reinforce current strategies aimed to prevent pneumonia among adults. PMID- 29246208 TI - When it just won't go away: oral artemisinin monotherapy in Nigeria, threatening lives, threatening progress. AB - BACKGROUND: Oral artemisinin monotherapy (AMT), an important contributor to multi drug resistant malaria, has been banned in Nigeria. While oral AMT has scarcely been found for several years now in other malaria-endemic countries, availability has persisted in Nigeria's private sector. In 2015, the ACTwatch project conducted a nationally representative outlet survey. Results from the outlet survey show the extent to which oral AMT prevails in Nigeria's anti-malarial market, and provide key product information to guide strategies for removal. RESULTS: Between August 10th and October 3rd, 2015 a total of 13,480 outlets were screened for availability of anti-malarials and/or malaria blood testing services. Among the 3624 anti-malarial outlets, 33,539 anti-malarial products were audited, of which 1740 were oral AMT products, primarily artesunate (n = 1731). Oral AMT was imported from three different countries (Vietnam, China and India), representing six different manufacturers and 11 different brands. Availability of oral AMT was highest among pharmacies (84.0%) and Patent Propriety Medicine Vendors (drug stores, PPMVs) (38.7%), and rarely found in the public sector (2.0%). Oral AMT consisted of 2.5% of the national anti-malarial market share. Of all oral AMT sold or distributed, 52.3% of the market share comprised of a Vietnamese product, Artesunat(r), manufactured by Mekophar Chemical Pharmaceutical Joint Stock Company. A further 35.1% of the market share were products from China, produced by three different manufacturers and 12.5% were from India by one manufacturer, Medrel Pharmaceuticals. Most of the oral AMT was distributed by PPMVs accounting for 82.2% of the oral AMT market share. The median price for a package of artesunate ($1.78) was slightly more expensive than the price of quality-assured (QA) artemether lumefantrine (AL) for an adult ($1.52). The median price for a package of artesunate suspension ($2.54) was three times more expensive than the price of a package of QA AL for a child ($0.76). CONCLUSION: Oral AMT is commonly available in Nigeria's private sector. Cessation of oral AMT registration and enforcement of the oral AMT ban for removal from the private sector are needed in Nigeria. Strategies to effectively halt production and export are needed in Vietnam, China and India. PMID- 29246211 TI - A cluster analysis of chronic obstructive pulmonary disease in dusty areas cohort identified three subgroups. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with variable clinical manifestations, structural changes, and treatment responses. In a cohort study, we performed a baseline cluster analysis to identify the subgroups of COPD and to assess the clinical outcomes of each subgroup during a 1-year follow-up. METHODS: We analyzed dusty areas cohort comprising 272 patients with COPD. The main factors with the highest loading in 15 variables were selected using principal component analysis (PCA) at baseline. The COPD patients were classified by hierarchical cluster analysis using clinical, physiological, and imaging data based on PCA-transformed data. The clinical parameters and outcomes during the 1-year follow-up were evaluated among the subgroups. RESULTS: PCA revealed that six independent components accounted for 77.3% of variance. Three distinct subgroups were identified through the cluster analysis. Subgroup 1 included younger subjects with fewer symptoms and mild airflow obstruction, and they had fewer exacerbations during the 1-year follow-up. Subgroup 2 comprised subjects with additional symptoms and moderate airflow obstruction, and they most frequently experienced exacerbations requiring hospitalization during the 1-year follow-up. Subgroup 3 included subjects with additional symptoms and mild airflow obstruction; this group had more female patients and a modest frequency of exacerbations requiring hospitalization. CONCLUSIONS: Cluster analysis using the baseline data of a COPD cohort identified three distinct subgroups with different clinical parameters and outcomes. These findings suggest that the identified subgroups represent clinically meaningful subtypes of COPD. PMID- 29246212 TI - Association between ATM gene polymorphisms, lung cancer susceptibility and radiation-induced pneumonitis: a meta-analysis. AB - BACKGROUND: Previous studies have suggested that DNA double-strand break (DSB) repair is an important protective pathway after damage. The ataxia telangiectasia mutated (ATM) gene plays an important role in the DNA DSB repair pathway. DNA damage is a major cytotoxic effect that can be caused by radiation, and the ability to repair DNA after damage varies among different tissues. Impaired DNA repair pathways are associated with high sensitivity to radiation exposure. Hence, ATM gene polymorphisms are thought to influence the risk of cancer and radiation-induced pneumonitis (RP) risk in cancer patients treated with radiotherapy. However, the results of previous studies are inconsistent. We therefore conducted this comprehensive meta-analysis. METHODS: A systematic literature search was performed in the PubMed, Embase, China National Knowledge Internet (CNKI) and Wanfang databases to identify studies that investigated the association between the ATM gene polymorphisms and both lung cancer and RP radiotherapy-treated lung cancer (the last search was conducted on Dec.10, 2015). The odds ratio (OR) and 95% confidence interval (CI) were used to investigate the strength of these relationships. Funnel plots and Begg's and Egger's tests were conducted to assess the publication bias. All analyses were performed in STATA 13.0 software. RESULTS: Ten eligible case-control studies (4731 cases and 5142 controls) on lung cancer susceptibility and four (192 cases and 772 controls) on RP risk were included. The results of the overall and subgroup analyses indicated that in the ATM gene, the rs189037 (-111G > A, -4519G > A), rs664677 (44831C > T, 49238C > T) and rs664143 (131,717 T > G) polymorphisms were significantly associated with lung cancer susceptibility (OR = 1.21, 95% CI = 1.04-1.39, P = 0.01; OR = 1.26, 95% CI = 1.06-1.49, P = 0.01; OR = 1.43, 95% CI = 1.15-1.78, P < 0.01). Additionally, the rs189037 variant was significantly associated with RP risk (OR = 1.74, 95% CI = 1.02-2.97, P = 0.04). No publication bias was found in the funnel plots, Begg's tests or Egger's tests. CONCLUSIONS: The results indicate that the ATM rs189037, rs664677 and rs664143 gene polymorphisms are risk factors for lung cancer, while the ATM rs189037 variant was significantly associated with RP risk. PMID- 29246214 TI - Learning effects of different training models for border molding from the perspective of dental students. AB - BACKGROUND: The aim of this study was to investigate the effects of different practical training models on the comprehension and evaluation of practical training among dental students. METHODS: The study subjects were all sixth-year dental students at our institute, and the study took place over three consecutive years (n = 58, 63, and 65, respectively). In practical training, all students learned border molding, and practical models were modified each year from plaster models to silicone models and then to silicone models mounted in mannequins. Immediately after completing clinical training, all students were asked to complete questionnaires consisting of 21 items regarding their overall practical training and their clinical comprehension of border molding. All items were rated on a five-point Likert scale, and in order to reduce the large number of interrelated questions, exploratory factor analysis was carried out using maximum likelihood estimation with promax rotation (kappa = 4) and Kaiser normalization. The number of factors was chosen using the Kaiser-Guttman rule, which states that the eigenvalue should be larger than 1, and the scree plot criteria. Items that scored less than 0.25 in communality and exhibited factor loading greater than 0.35 for more than one item were excluded. The defined factors were analyzed for the plaster models, the silicone models alone, and the silicone models with mannequins using the Kruskal-Wallis test and follow-up tests using Bonferroni corrected Mann-Whitney U tests. The significance level was set at p < 0.05. RESULTS: Exploratory factor analysis identified the following three factors: "knowledge of border molding"; "contents of practical training"; and "personal learning attitude". The students who used silicone models and mannequins gave significantly better evaluations on the "knowledge of border molding" (p < 0.001, both) and "contents of practical training" (p = 0.046, p < 0.001, respectively) subscales than those who used plaster models. No significant differences were observed between those who used silicone models and those who used mannequins. Moreover, no significant differences were found on the "personal learning attitude" subscale among students for any model. CONCLUSIONS: The change in practical training models from plaster to silicone improved student evaluations of border molding training. PMID- 29246213 TI - The role of emotion in clinical decision making: an integrative literature review. AB - BACKGROUND: Traditionally, clinical decision making has been perceived as a purely rational and cognitive process. Recently, a number of authors have linked emotional intelligence (EI) to clinical decision making (CDM) and calls have been made for an increased focus on EI skills for clinicians. The objective of this integrative literature review was to identify and synthesise the empirical evidence for a role of emotion in CDM. METHODS: A systematic search of the bibliographic databases PubMed, PsychINFO, and CINAHL (EBSCO) was conducted to identify empirical studies of clinician populations. Search terms were focused to identify studies reporting clinician emotion OR clinician emotional intelligence OR emotional competence AND clinical decision making OR clinical reasoning. RESULTS: Twenty three papers were retained for synthesis. These represented empirical work from qualitative, quantitative, and mixed-methods approaches and comprised work with a focus on experienced emotion and on skills associated with emotional intelligence. The studies examined nurses (10), physicians (7), occupational therapists (1), physiotherapists (1), mixed clinician samples (3), and unspecified infectious disease experts (1). We identified two main themes in the context of clinical decision making: the subjective experience of emotion; and, the application of emotion and cognition in CDM. Sub-themes under the subjective experience of emotion were: emotional response to contextual pressures; emotional responses to others; and, intentional exclusion of emotion from CDM. Under the application of emotion and cognition in CDM, sub-themes were: compassionate emotional labour - responsiveness to patient emotion within CDM; interdisciplinary tension regarding the significance and meaning of emotion in CDM; and, emotion and moral judgement. CONCLUSIONS: Clinicians' experienced emotions can and do affect clinical decision making, although acknowledgement of that is far from universal. Importantly, this occurs in the in the absence of a clear theoretical framework and educational preparation may not reflect the importance of emotional competence to effective CDM. PMID- 29246215 TI - Oral cancer screening practices of oral health professionals in Australia. AB - BACKGROUND: To evaluate oral cancer-related screening practices of Oral Health Professionals (OHPs - dentists, dental hygienists, dental therapists, and oral health therapists) practising in Victoria, Australia. METHODS: A 36-item survey was distributed to 3343 OHPs. Items included socio-demographic and work-related characteristics; self-assessed knowledge of oral cancer; perceived level of confidence in discussing oral health behaviors with patients; oral cancer screening practices; and self-evaluated need for additional training on screening procedures for oral cancer. RESULTS: A total of 380 OHPs responded this survey, achieving an overall response rate of 9.4%. Forty-five were excluded from further analysis. Of these 335 OHP, 72% were dentists; (n = 241); either GDP or Dental Specialists; 13.7% (n = 46) were dental hygienists; 12.2% (n = 41) were oral health therapists, and the remaining 2.1% (n = 7) were dental therapists. While the majority (95.2%) agreed that oral cancer screening should be routinely performed, in actual practice around half (51.4%) screened all their patients. Another 12.8% "Very rarely" conducted screening examinations. The probability of routinely conducting an oral cancer screening was explored utilising Logistic Regression Analysis. Four variables remained statistically significant (p < 0.0001). Results indicate that the likelihood of conducting an oral cancer screening rose with increasing levels of OHPs' confidence in oral cancer-related knowledge (OR = 1.35; 95% CI: 1.09-1.67) and with higher levels of confidence in discussing oral hygiene practices with patients (OR = 1.25; 95% CI: 1.03-1.52). Results also showed that dental specialists were less likely to perform oral cancer screening examinations compared with other OHPs (OR = 0.18; 95% CI: 0.07 0.52) and the likelihood of performing an oral cancer screening decreased when the "patient complained of a problem" (OR = 0.21; 95% CI: 0.10-0.44). CONCLUSION: Only half the study sample performed oral cancer screening examinations for all of their patients. This study provides evidence of the need for further oral cancer-related education and screening training for OHPs, which is vital to enhance oral cancer prevention and early detection. PMID- 29246216 TI - Association analysis of ILVBL gene polymorphisms with aspirin-exacerbated respiratory disease in asthma. AB - BACKGROUND: We previously reported that the ILVBL gene on chromosome 19p13.1 was associated with the risk for aspirin-exacerbated respiratory disease (AERD) and the percent decline of forced expired volume in one second (FEV1) after an oral aspirin challenge test. In this study, we confirmed the association between polymorphisms and haplotypes of the ILVBL gene and the risk for AERD and its phenotype. METHODS: We recruited 141 AERD and 995 aspirin-tolerant asthmatic (ATA) subjects. All study subjects underwent an oral aspirin challenge (OAC). Nine single nucleotide polymorphisms (SNPs) with minor allele frequencies above 0.05, which were present in the region from 2 kb upstream to 0.5 kb downstream of ILVBL in Asian populations, were selected and genotyped. RESULTS: In an allelic association analysis, seven of nine SNPs were significantly associated with the risk for AERD after correction for multiple comparisons. In a codominant model, the five SNPs making up block2 (rs2240299, rs7507755, rs1468198, rs2074261, and rs13301) showed significant associations with the risk for AERD (corrected P = 0.001-0.004, OR = 0.59-0.64). Rs1468198 was also significantly associated with the percent decline in FEV1 in OAC tests after correction for multiple comparisons in the codominant model (corrected P = 0.033), but the other four SNPs in hapblock2 were not. CONCLUSION: To the best of our knowledge, this is the first report of an association between SNPs on ILVBL and AERD. SNPs on ILVBL could be promising genetic markers of this condition. PMID- 29246217 TI - Spatial clustering of measles vaccination coverage among children in sub-Saharan Africa. AB - BACKGROUND: During the past two decades, vaccination programs have greatly reduced global morbidity and mortality due to measles, but recently this progress has stalled. Even in countries that report high vaccination coverage rates, transmission has continued, particularly in spatially clustered subpopulations with low vaccination coverage. METHODS: We examined the spatial heterogeneity of measles vaccination coverage among children aged 12-23 months in ten Sub-Saharan African countries. We used the Anselin Local Moran's I to estimate clustering of vaccination coverage based on data from Demographic and Health Surveys conducted between 2008 and 2013. We also examined the role of sociodemographic factors to explain clustering of low vaccination. RESULTS: We detected 477 spatial clusters with low vaccination coverage, many of which were located in countries with relatively high nationwide vaccination coverage rates such as Zambia and Malawi. We also found clusters in border areas with transient populations. Clustering of low vaccination coverage was related to low health education and limited access to healthcare. CONCLUSIONS: Systematically monitoring clustered populations with low vaccination coverage can inform supplemental immunization activities and strengthen elimination programs. Metrics of spatial heterogeneity should be used routinely to determine the success of immunization programs and the risk of disease persistence. PMID- 29246218 TI - The health-related social costs of alcohol in Belgium. AB - BACKGROUND: Alcohol is associated with adverse health effects causing a considerable economic impact to society. A reliable estimate of this economic impact for Belgium is lacking. This is the aim of the study. METHODS: A prevalence-based approach estimating the direct, indirect and intangible costs for the year 2012 was used. Attributional fractions for a series of health effects were derived from literature. The human capital approach was used to estimate indirect costs, while the concept of disability-adjusted life years was used to estimate intangible costs. Sensitivity and scenario analyses were conducted to assess the uncertainty around cost estimates and to evaluate the impact of alternative modelling assumptions. RESULTS: In 2012, total alcohol attributable direct costs were estimated at ?906.1 million, of which the majority were due to hospitalization (?743.7 million, 82%). The indirect costs amounted to ?642.6 million, of which 62% was caused by premature mortality. Alcohol was responsible for 157,500 disability-adjusted life years representing ?6.3 billion intangible costs. CONCLUSIONS: Despite a number of limitations intrinsic to this kind of research, the study can be considered as the most comprehensive analysis thus far of the health-related social costs of alcohol in Belgium. PMID- 29246220 TI - Inhibition of autophagy enhances synergistic effects of Salidroside and anti tumor agents against colorectal cancer. AB - BACKGROUND: Various plant extracts have been suggested to be used as auxiliary agents in chemotherapy considering their anti-proliferative effect on cancer cells. However, recent reports reveal that plant extracts may function as inducers of autophagy of cancer cells. In general, autophagy confers survival advantage for cells responding to stress conditions, thus representing an important mechanism for chemo-resistance. This study was aimed to investigate the effectiveness of combined use of Salidroside (Sal, a phenylpropanoid glycosides from Rhodiola rosea L) with anti-tumor agents against colorectal cancer (CRC) cells, and moreover to evaluate the potential role of autophagy in the combined therapy. METHODS: CRC cells, HCT-116, were incubated with Sal alone or in combination with conventional chemotherapy agents including oxaliplatin (OXA), 5 fluorouracil (5-FU) and Doxorubicin (ADM). Cell proliferative characteristics were evaluated by cell viability and apoptosis rate. The protein expression was assessed by Immunofluorescent and Western blot assays. RESULTS: Sal, alone or in combination with anti-tumor agents, increased expression of autophagic biomarkers, including LC3B and Becline-1, suggesting an autophagy induction. Except for the up-regulation of p-AMPK, p-mTOR, p-NF-kappaB (p65), TGF-beta, p JAK2 and p-STAT3 were down-regulated by Sal. Because autophagy is positively correlated with the activation of AMPK/mTOR, NF-kappaB, TGFbeta1 and JAK2/STAT3 cascades, the autophagy induced by Sal may associate with AMPK activation. Indeed, blockage of AMPK signaling via Compound C or AMPK knockdown inhibited the autophagy. The blockage of AMPK signaling or a direct inhibition of autophagy via 3-MA increased effectiveness of combined use of Sal with anti-tumor agents against CRC. CONCLUSIONS: Inhibition of autophagy enhances synergistic effects of Sal and anti-tumor agents against colorectal cancer. This study provides experimental evidence and theoretical reference for improvement of a novel chemotherapy treatment protocol. PMID- 29246219 TI - Cellular pharmacodynamic effects of Pycnogenol(r) in patients with severe osteoarthritis: a randomized controlled pilot study. AB - BACKGROUND: The standardized maritime pine bark extract (Pycnogenol(r)) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol(r) and its in vivo mechanism of action in OA patients. METHODS: Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol(r) twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients' chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples. RESULTS: The oral intake of Pycnogenol(r) downregulated the gene expression of various cartilage degradation markers in the patients' chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p <= 0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p <= 0.05) after three weeks intake of the pine bark extract. CONCLUSIONS: This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol(r) on symptom scores of patients suffering from OA. TRIAL REGISTRATION: ISRCTN10754119 . Retrospectively registered 08/10/2015. PMID- 29246221 TI - The determinants and consequences of adult nursing staff turnover: a systematic review of systematic reviews. AB - BACKGROUND: Nurses leaving their jobs and the profession are an issue of international concern, with supply-demand gaps for nurses reported to be widening. There is a large body of existing literature, much of which is already in review form. In order to advance the usefulness of the literature for nurse and human resource managers, we undertook an overview (review of systematic reviews). The aim of the overview was to identify high quality evidence of the determinants and consequences of turnover in adult nursing. METHODS: Reviews were identified which were published between 1990 and January 2015 in English using electronic databases (the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE, Applied Social Sciences Index and Abstracts, CINAHL plus and SCOPUS) and forward searching. All stages of the review were conducted in parallel by two reviewers. Reviews were quality appraised using the Assessment of Multiple Systematic Reviews and their findings narratively synthesised. RESULTS: Nine reviews were included. We found that the current evidence is incomplete and has a number of important limitations. However, a body of moderate quality review evidence does exist giving a picture of multiple determinants of turnover in adult nursing, with - at the individual level - nurse stress and dissatisfaction being important factors and -at the organisational level - managerial style and supervisory support factors holding most weight. The consequences of turnover are only described in economic terms, but are considered significant. CONCLUSIONS: In making a quality assessment of the review as well as considering the quality of the included primary studies and specificity in the outcomes they measure, the overview found that the evidence is not as definitive as previously presented from individual reviews. Further research is required, of rigorous research design, whether quantitative or qualitative, particularly against the outcome of actual turnover as opposed to intention to leave. TRIAL REGISTRATION: PROSPERO Registration 17 March 2015: CRD42015017613 . PMID- 29246222 TI - Like a hotel, but boring: users' experience with short-time community-based residential aftercare. AB - BACKGROUND: The discharge process from hospital to home for patients with severe mental illness (SMI) is often complex, and most are in need of tailored and coordinated community services at home. One solution is to discharge patients to inpatient short-stay community residential aftercare (CRA). The aim of this study was to explore how patients with SMI experience a stay in CRA established in a City in Central Norway. METHODS: A descriptive qualitative study with individual interviews and a group interview with 13 persons. The CRA aims to improve the discharge process from hospital to independent supported living by facilitating the establishment of health and social services and preparing the patients. The philosophy is to help patients use community resources by e.g. not offering any organized in-house activities. The main question in the interviews was "How have you experienced the stay at the CRA?" The interviews were analyzed with a thematic approach using systematic text condensation. RESULTS: The participants experienced the stay at the CRA "Like a hotel" but also boring, due to the lack of organized in-house activities. The patients generally said they were not informed about the philosophy of the CRA before the stay. The participants had to come up with activities outside the CRA and said they got active help from the staff to do so; some experienced this as positive, whereas others wanted more organized in-house activities like they were used to from mental health hospital stays. Participants described the staff in the CRA to be helpful and forthcoming, but they did not notice the staff being active in organizing the aftercare. CONCLUSIONS: The stay at the CRA was experienced as different from other services, with more freedom and focus on self-care, and lack of in-house activities. This led to increased self-activity among the patients, but some wanted more in-house activities. To prepare the patients better for the stay at the CRA, more information about the philosophy is needed in the pre-admission process. PMID- 29246223 TI - Construction of a simulation model and evaluation of the effect of potential interventions on the incidence of diabetes and initiation of dialysis due to diabetic nephropathy in Japan. AB - BACKGROUND: The prevalence of diabetes mellitus is a growing public health concern in Japan. We developed a simulation model to predict the number of people with diabetes and those on dialysis due to diabetic nephropathy. In addition, we used the model to simulate the impact of possible interventions on the number of people with diabetes and those on dialysis due to diabetic nephropathy in the near future. METHODS: A simulation model with aging chains for diabetes management was built using system dynamics. The model was calibrated to population data from 2000 to 2015 (sex- and age category-specific population, the prevalence of diabetes, and the number of patients on dialysis due to diabetic nephropathy). We extrapolated the model up to 2035 in order to predict future prevalence of diabetes and related dialysis (base run). We also ran the model, hypothesizing that incidence of diabetes and/or related dialysis would be reduced by half from 2015 to 2025 and that this rate would be maintained until 2035, in order to investigate the effects of hypothetical interventions on future prevalence. RESULTS: The developed model forecasted the population with diabetes to increase until 2028 (5.58 million males and 3.34 million females), and the population on dialysis due to diabetic nephropathy to increase until 2035 (113,000 males and 48,000 females). Simulation experiments suggested that diabetes prevention interventions would decrease the number of patients on dialysis in 2035 by 13.8% in males and 12.6% in females compared to the base run. In contrast, interventions aiming to avoid dialysis initiation for patients with diabetes would decrease the number of patients on dialysis by 37.8% in males and 38.1% in females. CONCLUSIONS: We successfully developed a simulation model to project the number of patients with diabetes and those on dialysis due to diabetic nephropathy. Simulation experiments using the model suggested that, as far as the perspective of the next 20 years, intervention to prevent dialysis is an important means of bending the increasing curve of dialysis in the population with diabetes. Simulation analysis may be useful when making and evaluating health policies related to diabetes and other chronic diseases. PMID- 29246225 TI - PCR-diagnosis of Anaplasma marginale in cattle populations of Ecuador and its molecular identification through sequencing of ribosomal 16S fragments. AB - BACKGROUND: Bovine anaplasmosis is an endemic disease in tropical and subtropical areas. It is caused by a bacterium named Anaplasma marginale, and represents an economic problem for cattle farmers due to the losses it generates, such as: mortalities, reduced production, quarantine measures, treatments and control of vectors. The method most often used to diagnose this haemotrophic bacterium is direct examination on blood smear, which sensitivity and specificity are limited compared to other methods such as PCR. The present study aimed at investigating the presence of A. marginale in dairy cattle of Luz de America commune, province of Santo Domingo de los Tsachilas. Two PCRs were used to amplify specific regions of the Rickettsia for its molecular identification. RESULTS: At first, 151 blood samples were tested: msp5 specific gene of A. marginale was identified in 130 samples, meaning 86.1% of them were infected by the rickettsia. Two positive samples were further randomly selected to confirm the presence of A. marginale through amplification, cloning and sequencing of the conserved region of gene 16S rRNA. The analysis of sequences obtained through cloning revealed a 100% identity between both samples and those registered in GenBank for A. marginale. CONCLUSION: This is the first report and molecular identification of A. marginale in the bovine population of Ecuador and its prevalence was high at the level of farms and animals. These results demonstrate the importance of proceeding to evaluate and characterize bovine Anaplasmosis in Ecuador in order to establish control measures and reduce their impact. PMID- 29246226 TI - Factors associated with health-related quality of life in Koreans aged over 50 Years: the fourth and fifth Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: To evaluate and analyse the factors associated with health-related quality of life (HR-QoL) in the Korean population aged 50 years and older. METHODS: We used data obtained from the fourth and fifth Korea National Health and Nutrition Examination Survey (KNHANES IV-V) 2007-2012, a national, cross sectional health examination and survey, for which representative data on the health, nutritional status, and physical activities of the Korean general population are collected by the Korea Centres for Disease Control and Prevention (KCDC). The sampling protocol for the KNHANES was designed to involve a complex, stratified, multistage probability cluster survey of a representative sample of the noninstitutionalized civilian population in South Korea using a cross sectional design. The association between HR-QoL and socio-economic factors and medical comorbidities in adults aged 50 years and older was investigated using data from the KNHANES IV-V from 2007 to 2012 (n = 17,937). The EuroQol 5 Dimension Questionnaire (EQ-5D) was used to evaluate HR-QoL, and the factors associated with HR-QoL were analysed after adjusting for socio-economic and demographic factors, anthropometric measurements and clinical comorbidities. RESULTS: Health status declined with ageing, and low socio-economic status had negative associations with health status. Gender had no association with health status. Among chronic medical conditions, arthritis and depression had significant associations with health status in older people when stratified by age and gender (P < 0.05). CONCLUSIONS: These findings suggest that older people may value the ability to perform daily activities, which may mean that it is necessary to pay more attention to the factors associated with musculoskeletal pain and emotional distress, as well as socio-economic status or chronic diseases. TRIAL REGISTRATION: The Korea National Health and Nutrition Examination Survey (KNHNES) is not a clinical trial registry, but the national health survey conducted by the Government of the Republic of Korea, to gather information on health and nutritional status of Korean population, to plan public health services and health education programs, and to do statistical studies of the efficiency of public health services required for setting up welfare and healthcare policies. PMID- 29246224 TI - Optimizing clinical and organizational practice in cancer survivor transitions between specialized oncology and primary care teams: a realist evaluation of multiple case studies. AB - BACKGROUND: Cancer is now viewed as a chronic disease, presenting challenges to follow-up and survivorship care. Models to shift from haphazard, suboptimal and fragmented episodes of care to an integrated cancer care continuum must be developed, tested and implemented. Numerous studies demonstrate improved care when follow-up is assured by both oncology and primary care providers rather than either group alone. However, there is little data on the roles assumed by specialized oncology teams and primary care providers and the extent to which they work together. This study aims to develop, pilot test and measure outcomes of an innovative risk-based coordinated cancer care model for patients transitioning from specialized oncology teams to primary care providers. METHODS/DESIGN: This multiple case study using a sequential mixed-methods design rests on a theory-driven realist evaluation approach to understand how transitions might be improved. The cases are two health regions in Quebec, Canada, defined by their geographic territory. Each case includes a Cancer Centre and three Family Medicine Groups selected based on differences in their determining characteristics. Qualitative data will be collected from document review (scientific journal, grey literature, local documentation), semi-directed interviews with key informants, and observation of care coordination practices. Qualitative data will be supplemented with a survey to measure the outcome of the coordinated model among providers (scope of practice, collaboration, relational coordination, leadership) and patients diagnosed with breast, colorectal or prostate cancer (access to care, patient-centredness, communication, self-care, survivorship profile, quality of life). Results from descriptive and regression analyses will be triangulated with thematic analysis of qualitative data. Qualitative, quantitative, and mixed methods data will be interpreted within and across cases in order to identify context-mechanism associations that explain outcomes. DISCUSSION: The study will provide empirical data on a risk-based coordinated model of cancer care to guide actions at different levels in the health system. This in-depth multiple case study using a realist approach considers both the need for context-specific intervention research and the imperative to address research gaps regarding coordinated models of cancer care. PMID- 29246227 TI - Statin consumption as a risk factor for developing colorectal cancer: a retrospective case study. AB - BACKGROUND: Statins are the backbone of lipid-lowering therapy and are among the most commonly prescribed drugs in the elderly population in Sweden today. Colorectal cancer is the second most common cancer in men and women, after prostate and breast cancer, respectively, with a median age of 72 years at diagnosis. Statins induce mitochondrial damage leading to accumulation of reactive oxygen species in the cell. Reactive oxygen species can cause mutations in mitochondrial as well as nuclear DNA leading to the development of cancer. Our hypothesis was that statins increase the risk for colorectal cancer. METHODS: A case study was performed on consecutive cases of colorectal cancer diagnosed at Norrlands University Hospital (NUS) in Umea between 2012 and 2015 (n = 325). Patients diagnosed with diabetes mellitus type II (DM II n = 65) were excluded in the primary endpoint analysis (occurrence of colorectal cancer). As control, three databases were used to create an age-matched population in order to calculate the proportion of inhabitants using statins in the county of Vasterbotten, Sweden. A secondary endpoint was cancer-specific survival among our study group of colorectal cancer patients, including those with DM II, investigating whether there was a difference if the patient was a 'recent' statin user or not at the time of diagnosis. RESULTS: Statin use at the time of colorectal cancer diagnosis in the study group was 23.8%. The corresponding figure in an age-matched population in Vasterbotten was 24.6%. Using a one proportional one-sided z test, there was no significant difference between these (23.8%, 95% CI 18.6-29.0%, p = 0.601). When comparing groups 20-64 years of age, the difference was greater with recent statin use in 17.8% in the study population and 11.9% in Vasterbotten (17.8%, 95% CI 9.0-26.6%, p = 0.059). When considering cancer-specific survival, no significant difference in survival was seen when comparing 'former/never' statin users as reference category with 'recent' users diagnosed with colorectal cancer (HR 1.39, 95% CI 0.89-2.16). CONCLUSIONS: No significant increase in risk for developing colorectal cancer among patients (type II diabetics excluded) medicated with statins was found. We found no correlation between 'recent' statin use at the time of diagnosis and cancer-specific survival. PMID- 29246229 TI - Medical student researchers in Colombia and associated factors with publication: a cross-sectional study. AB - BACKGROUND: Gaps between evidence-based research and clinical-public health practice have been evident for decades. One of the aims of medical student research is to close this gap. Accordingly, evaluating individual and environmental factors that influence participation of medical students in research are needed to understand and identify potential targets for action. This study aims to identify characteristics of medical student researchers in Colombia and the associated factors with scientific publications. METHODS: A cross sectional study of Colombian medical students involved in research using a validated, self-administered, online survey. The survey was distributed through the Colombian Association of Medical Students' Associations (ASCEMCOL). Data sets were analyzed using descriptive and summary statistics. Bivariate analysis and a multiple logistic regression model were conducted to identify predictors of scientific publications. RESULTS: A total of 133 responses were analyzed from students at 12 Colombian cities and 20 higher-education institutions. Although 94% of responders had at least one research proposal, only 57% had completed a project, and 17% had published their findings. Barriers for undertaking research included time restrictions and a lack of mentorship. Motivational factors included opportunity to publish findings and good mentorship. Students planning to do a specialization (OR = 3.25; 95% Confidence interval [CI] = 1.27-8.30), innovators (OR = 3.52; 95%CI = 1.30-9.52) and committed (OR = 3.39; 95%CI = 1.02 11.29), those who had previously published their findings (OR 9.13 IC95% 2.57 32.48), and were further in their medical education (OR 2.26 IC95% 1.01-5.07), were more likely to publish scientific papers. CONCLUSIONS: Our findings describe medical students understanding of the process of conducting research in Colombia. Although there appears to be motivation to participate in research, very few students achieve publication. Barriers such as time constraints and mentorship seem to play a critical role. This highlights opportunities where barriers to research can be overcome in medical school and other levels. PMID- 29246228 TI - Genetic diversity assessment of Tunisian Mycobacterium bovis population isolated from cattle. AB - BACKGROUND: The genetic diversity of M. bovis in Tunisia is still underestimated despite the implementation of an eradication program. The lack of data about spatial distribution of the M. bovis population hinders the control of bovine tuberculosis (bTB) progress. This study represents the largest molecular analysis of M. bovis isolates in Tunisia. It is aimed to upgrade the understanding of bTB epidemiology and the geographical distribution of the infection. Tuberculosis research was performed in cattle (n = 149) with TB-compatible lesions collected over 5 months from a slaughterhouse located in Sfax, Tunisia. RESULTS: Ninety four animals were found to be infected by M. bovis and two others by M. caprae. Spoligotyping revealed twenty-five patterns, SB0120, SB0134, and SB0121 being the most prevalent profiles (36.4%, 11.4%, and 7.2%, respectively). Three new spoligotypes were detected: SB2345, SB2344 and SB2343. MIRU-VNTR analysis classified the isolates in seventy-three profiles and showed a large genotypic variety observed within the main spoligotype which was split into several MIRU VNTR types: 29 in SB0120 (h = 0.983), 10 in SB0134 (h = 0.981) and 7 in SB0121 (h = 1). Genotyping revealed a common pattern in different geographic regions. It also showed that Sfax, located in southern-Tunisia, represents a high-risk area with an elevated genetic diversity. CONCLUSIONS: Spatial analysis may provide insights into disease transmission, which affects the effectiveness of eradication campaigns in cattle. PMID- 29246230 TI - Bifunctional enzyme ATIC promotes propagation of hepatocellular carcinoma by regulating AMPK-mTOR-S6 K1 signaling. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the cancer types with poor prognosis. To effectively treat HCC, new molecular targets and therapeutic approaches must be identified. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate (IMP) cyclohydrolase (ATIC), a bifunctional protein enzyme, catalyzes the last two steps of the de novo purine biosynthetic pathway. Whether ATIC contributes to cancer development remains unclear. METHODS: ATIC mRNA levels in different types of human HCC samples or normal tissues were determined from Gene Expression across Normal and Tumor tissue (GENT) database. The expression level of ATIC in human HCC samples or cell lines were examined by RT-PCR and western blot. Overall survival and disease-free survival of HCC patients in the ATIC low and ATIC high groups were determined by Kaplan-Meier analysis. Effects of ATIC knockdown by lentivirus infection were evaluated on cell-proliferation, cell-apoptosis, colony formation and migration. The mechanisms involved in HCC cells growth, apoptosis and migration were analyzed by western blot and Compound C (C-C) rescue assays. RESULTS: Here, we first demonstrated that expression of ATIC is aberrantly up-regulated in HCC tissues and high level of ATIC is correlated with poor survival in HCC patients. Knockdown of ATIC expression resulted in a dramatic decrease in proliferation, colony formation and migration of HCC cells. We also identified ATIC as a novel regulator of adenosine monophosphate-activated protein kinase (AMPK) and its downstream signaling mammalian target of rapamycin (mTOR). ATIC suppresses AMPK activation, thus activates mTOR-S6 K1-S6 signaling and supports growth and motility activity of HCC cells. CONCLUSION: Taken together, our results indicate that ATIC acts as an oncogenic gene that promotes survival, proliferation and migration by targeting AMPK-mTOR-S6 K1 signaling. PMID- 29246231 TI - Perceived Medical School stress of undergraduate medical students predicts academic performance: an observational study. AB - BACKGROUND: Medical students are exposed to high amounts of stress. Stress and poor academic performance can become part of a vicious circle. In order to counteract this circularity, it seems important to better understand the relationship between stress and performance during medical education. The most widespread stress questionnaire designed for use in Medical School is the "Perceived Medical School Stress Instrument" (PMSS). It addresses a wide range of stressors, including workload, competition, social isolation and financial worries. Our aim was to examine the relation between the perceived Medical School stress of undergraduate medical students and academic performance. METHODS: We measured Medical School stress using the PMSS at two different time points (at the end of freshman year and at the end of sophomore year) and matched stress scores together with age and gender to the first medical examination (M1) grade of the students (n = 456). RESULTS: PMSS scores from 2 and 14 months before M1 proved to be significant predictors for medical students' M1 grade. Age and gender also predict academic performance, making older female students with high stress scores a potential risk group for entering the vicious circle of stress and poor academic performance. CONCLUSIONS: PMSS sum scores 2 and 14 months before the M1 exam seem to have an independent predictive validity for medical students' M1 grade. More research is needed to identify potential confounders. PMID- 29246233 TI - Correction to: Medicinal plants used by women in Mecca: urban, Muslim and gendered knowledge. AB - In the original publication [1] were the Arabic letters in Table 2 incorrect. The corrected version of Table 2 can be found as Additional file 1 in this Erratum. PMID- 29246232 TI - Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia. AB - BACKGROUND: Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated. METHODS: We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-alpha, IL-6, IFN-gamma, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures. RESULTS: We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-alpha, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-gamma was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells. CONCLUSION: Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory pathways for its treatment. PMID- 29246234 TI - Methodological considerations for observational coding of eating and feeding behaviors in children and their families. AB - BACKGROUND: Behavioral coding of videotaped eating and feeding interactions can provide researchers with rich observational data and unique insights into eating behaviors, food intake, food selection as well as interpersonal and mealtime dynamics of children and their families. Unlike self-report measures of eating and feeding practices, the coding of videotaped eating and feeding behaviors can allow for the quantitative and qualitative examinations of behaviors and practices that participants may not self-report. While this methodology is increasingly more common, behavioral coding protocols and methodology are not widely shared in the literature. This has important implications for validity and reliability of coding schemes across settings. Additional guidance on how to design, implement, code and analyze videotaped eating and feeding behaviors could contribute to advancing the science of behavioral nutrition. The objectives of this narrative review are to review methodology for the design, operationalization, and coding of videotaped behavioral eating and feeding data in children and their families, and to highlight best practices. METHODS: When capturing eating and feeding behaviors through analysis of videotapes, it is important for the study and coding to be hypothesis driven. Study design considerations include how to best capture the target behaviors through selection of a controlled experimental laboratory environment versus home mealtime, duration of video recording, number of observations to achieve reliability across eating episodes, as well as technical issues in video recording and sound quality. Study design must also take into account plans for coding the target behaviors, which may include behavior frequency, duration, categorization or qualitative descriptors. Coding scheme creation and refinement occur through an iterative process. Reliability between coders can be challenging to achieve but is paramount to the scientific rigor of the methodology. Analysis approach is dependent on the how data were coded and collapsed. CONCLUSIONS: Behavioral coding of videotaped eating and feeding behaviors can capture rich data "in-vivo" that is otherwise unobtainable from self-report measures. While data collection and coding are time-intensive the data yielded can be extremely valuable. Additional sharing of methodology and coding schemes around eating and feeding behaviors could advance the science and field. PMID- 29246235 TI - Comparative satisfaction of receiving medical abortion service from nurses and auxiliary nurse-midwives or doctors in Nepal: results of a randomized trial. AB - BACKGROUND: Early first-trimester medical abortion (MA) service (<= 63 days) has been provided by doctors and nurses under doctors' supervision since 2009 in Nepal. This paper assesses whether MA services provided by specifically trained and certified nurses and auxiliary nurse-midwives independently from doctors' supervision, is considered as satisfactory by women as those provided by doctors. METHODS: The data come from a multi-center, randomized, controlled equivalence trial conducted between April 2009 and March 2010 in five district hospitals in Nepal. Women seeking MA were randomly assigned to doctors or nurses and auxiliary nurse-midwives(ANMs).Eligible women were administered 200 mg mifepristone orally followed by 800 MUg misoprostol vaginally two days later by their assigned providers and followed up 10-14 days later. At the follow-up visit women's reported satisfaction with MA service they received was measured. RESULTS: Of 1295 women screened for eligibility, 535 were randomly assigned to a doctor and 542 to a nurse or ANM. Nineteen women were lost-to-follow up in the former group and 27 were lost-to-follow up or did not complete the acceptability interview in the latter group. This study is, therefore, based on516womenin the doctor's group and 515 women in the nurse or ANM group. All women in the nurse or ANM group reported being satisfied or highly satisfied by MA compared to 99% in the doctor's group. Satisfaction was similar regardless of the type of provider; 38% among nurse or ANM and 35% among the doctor group were "highly satisfied", and 62% and 64%, respectively, were "satisfied". Women's experiences such as 'less than expected amount or duration of bleeding following MA', 'shorter than expected duration of the abortion process', and 'able to manage symptoms', were found to be associated with women's higher satisfaction with MA. Counseling and information on the method, potential complications of MA and post-abortion contraception was nearly universal. No statistically significant differences were found in the level of satisfaction by age, parity, marital status, education or occupation of women. CONCLUSIONS: Women's satisfaction with MA service provided by trained nurses or auxiliary nurse-midwives was similar to that provided by doctors. The findings, therefore, provide support for extending safe and accessible medical abortion services by government-trained nurses and auxiliary nurse midwives to women seeking early first trimester pregnancy termination. TRIAL REGISTRATION: The trial was retrospectively registered with ClinicalTrials.gov (identifier: NCT01186302 ). Registered August 20, 2010. PMID- 29246237 TI - Zika virus can be venereally transmitted between Aedes aegypti mosquitoes. AB - BACKGROUND: Alternative transmission routes have been described for Zika virus (ZIKV). Here, we assessed for the first time the venereal transmission of ZIKV between Aedes aegypti under laboratory conditions. RESULTS: Orally-infected mosquito females were able to transmit the virus to males venereally, and males inoculated intrathoracically were capable of infecting females during mating. The genome of venereally-transmitted virus recovered from males was identical to that of ZIKV ingested by mated females. CONCLUSION: We conclude that venereal transmission between Aedes mosquitoes might contribute to Zika virus maintenance in nature. PMID- 29246236 TI - Feasibility and acceptability of two incentive-based implementation strategies for mental health therapists implementing cognitive-behavioral therapy: a pilot study to inform a randomized controlled trial. AB - BACKGROUND: Informed by our prior work indicating that therapists do not feel recognized or rewarded for implementation of evidence-based practices, we tested the feasibility and acceptability of two incentive-based implementation strategies that seek to improve therapist adherence to cognitive-behavioral therapy for youth, an evidence-based practice. METHODS: This study was conducted over 6 weeks in two community mental health agencies with therapists (n = 11) and leaders (n = 4). Therapists were randomized to receive either a financial or social incentive if they achieved a predetermined criterion on adherence to cognitive-behavioral therapy. In the first intervention period (block 1; 2 weeks), therapists received the reward they were initially randomized to if they achieved criterion. In the second intervention period (block 2; 2 weeks), therapists received both rewards if they achieved criterion. Therapists recorded 41 sessions across 15 unique clients over the project period. Primary outcomes included feasibility and acceptability. Feasibility was assessed quantitatively. Fifteen semi-structured interviews were conducted with therapists and leaders to assess acceptability. Difference in therapist adherence by condition was examined as an exploratory outcome. Adherence ratings were ascertained using an established and validated observational coding system of cognitive-behavioral therapy. RESULTS: Both implementation strategies were feasible and acceptable however, modifications to study design for the larger trial will be necessary based on participant feedback. With respect to our exploratory analysis, we found a trend suggesting the financial reward may have had a more robust effect on therapist adherence than the social reward. CONCLUSIONS: Incentive-based implementation strategies can be feasibly administered in community mental health agencies with good acceptability, although iterative pilot work is essential. Larger, fully powered trials are needed to compare the effectiveness of implementation strategies to incentivize and enhance therapists' adherence to evidence-based practices such as cognitive-behavioral therapy. PMID- 29246238 TI - Absence of MGMT promoter methylation in diffuse midline glioma, H3 K27M-mutant. PMID- 29246239 TI - Individualized coracoid osteotomy and 3D congruent arc reconstruction of glenoid for the treatment of recurrent anterior shoulder dislocation. AB - BACKGROUND: The present study investigated individualized coracoid osteotomy for 3D congruent arc glenoid reconstruction and evaluated the clinical outcomes in recurrent anterior shoulder dislocation. METHODS: From January 2005 to July 2015, 78 patients with glenoid defect underwent coracoid and conjoint tendon transposition. The patients were divided into the individualized group (n = 34) and the non-individualized group (n = 44). All patients had CT data to reconstruct the shoulder model using Mimics software. In the individualized group, the individual coracoid osteotomy and bone fixation position parameters were measured from preoperative planification through simulating a 3D congruent arc glenoid reconstruction model. The non-individualized group underwent classic Bristow-Latarjet (B-L) procedure. The postoperative evaluation parameters included 3D congruent arc index, coracoid bone position, shoulder osteoarthritis index (Samilson-Prieto) and shoulder function score (Rowe, Constant-Murley score). RESULTS: The mean follow-up time was 51.0 months (ranging from 24 to 146). The individualized group got 3D congruent arc reconstruction of the glenoid by postoperative CT scanning. Bone position was more precise in the individual group than that in the B-L group. There was a lower incidence of shoulder osteoarthritis (Samilson-Prieto) in the individual group compared with that in the B-L group: 0 vs 13.6% (mild 6/44, P = 0.027), respectively. No significant difference was observed between the individual and B-L groups in rate of re dislocation: 0 vs 4.5% (2/44, P = 0.315), respectively. The postoperative Rowe and Constant score was significantly improved but was not significantly different between the two groups. CONCLUSION: The individual procedure achieved 3D congruent arc glenoid reconstruction. The clinical effects in patients with medium glenoid defect were good, especially the low incidence of shoulder osteoarthritis in middle-term follow-up. PMID- 29246240 TI - Myocardial inflammation, injury and infarction during on-pump coronary artery bypass graft surgery. AB - BACKGROUND: Myocardial inflammation and injury occur during coronary artery bypass graft (CABG) surgery. We aimed to characterise these processes during routine CABG surgery to inform the diagnosis of type 5 myocardial infarction. METHODS: We assessed 87 patients with stable coronary artery disease who underwent elective CABG surgery. Myocardial inflammation, injury and infarction were assessed using plasma inflammatory biomarkers, high-sensitivity cardiac troponin I (hs-cTnI) and cardiac magnetic resonance imaging (CMR) using both late gadolinium enhancement (LGE) and ultrasmall superparamagnetic particles of iron oxide (USPIO). RESULTS: Systemic humoral inflammatory biomarkers (myeloperoxidase, interleukin-6, interleukin-8 and c-reactive protein) increased in the post-operative period with C-reactive protein concentrations plateauing by 48 h (median area under the curve (AUC) 7530 [interquartile range (IQR) 6088 to 9027] mg/L/48 h). USPIO-defined cellular myocardial inflammation ranged from normal to those associated with type 1 myocardial infarction (median 80.2 [IQR 67.4 to 104.8] /s). Plasma hs-cTnI concentrations rose by >=50-fold from baseline and exceeded 10-fold the upper limit of normal in all patients. Two distinct patterns of peak cTnI release were observed at 6 and 24 h. After CABG surgery, new LGE was seen in 20% (n = 18) of patients although clinical peri-operative type 5 myocardial infarction was diagnosed in only 9% (n = 8). LGE was associated with the delayed 24-h peak in hs-cTnI and its magnitude correlated with AUC plasma hs-cTnI concentrations (r = 0.33, p < 0.01) but not systemic inflammation, myocardial inflammation or bypass time. CONCLUSION: Patients undergoing CABG surgery invariably have plasma hs-cTnI concentrations >10-fold the 99th centile upper limit of normal that is not attributable to inflammatory or ischemic injury alone. Peri-operative type 5 myocardial infarction is often unrecognised and is associated with a delayed 24-h peak in plasma hs-cTnI concentrations. PMID- 29246241 TI - A cross-sectional study on the use and misuse of trypanocides in selected pastoral and agropastoral areas of eastern and northeastern Tanzania. AB - BACKGROUND: Tsetse-borne African animal trypanosomosis (AAT) greatly influences livestock distribution and significantly slows livestock productivity in sub Saharan Africa. While a number of control methods targeting the vector tsetse are in field application, treatment with the few available trypanocides continues to be the most widely applied control method. Unfortunately, improper and frequent use of these few available drugs, accelerated by poor veterinary service delivery, promotes trypanosome drug resistance, the magnitude of which has not been delineated. In the present study, current practices on trypanocide application for the control of bovine trypanosomosis in the field in Tanzania were studied with a view to providing policy advice on the safe and sustainable use of trypanocides. METHODS: A cross-sectional study was conducted using a semi structured questionnaire administered to a total of 200 randomly selected livestock keepers in selected pastoral and agropastoral areas within three districts in eastern and north eastern Tanzania. RESULTS: In total, 50% of respondents in all three study districts had primary level education; over 40% had informal education and only 5% with university education (all from one district, Pangani). Age-wise, most respondents were aged 30-59 years with exception of Korogwe where 35% were aged 20-29 years. Over 95% of respondents had knowledge on tsetse as a vector of trypanosomosis and correctly identified tsetse in provided pictures. Furthermore, 98.7% of the respondents applied pyrethroids for vector control. Regarding parasite control practices, this study revealed a high degree of variation in trypanocides usage and the intervals of their application. Whereas only 20% of respondents use chemoprophylaxis for trypanosomosis control, the majority (69-95%) wrongly use diminazene aceturate thinking it is prophylactic, while only 5-30% used the prophylactic drug isometamidium chloride. Most of the respondents (95% in Korogwe, 60% in Pangani and 93.1% in Mvomero) administered the drugs on their own. Improper trypanocides administration was high as respondents in Korogwe (75%) and Mvomero (72%) administered the drugs intravenously with a view to achieving faster drug effect contrary to manufacturers' recommendations, while 40% of respondents from Pangani used both intravenous and intramuscular routes. Additionally, respondents did not observe the recommended withdrawal periods for the drugs. CONCLUSIONS: This study revealed a high level of trypanocides misuse which poses a high risk of trypanosome drug resistance development as well as risks to human health from drug residues in consumed animal products. This calls for improvements in veterinary service delivery in pastoral and agropastoral areas of Tanzania to counteract the misuse of chemotherapeutics. PMID- 29246242 TI - The use of the tyrosine kinase inhibitor Nilotinib in Spondyloarthritis: does targeting inflammatory pathways with a treatment lead to vascular toxicity? AB - Spondylarthritis (SpA) is an inflammatory rheumatic disease associated with increased incidence of major adverse cardiovascular events (MACEs). Recently, Paramarta et al. proposed the use of the tyrosine kinase inhibitor Nilotinib in Spondyloarthritis to target certain inflammatory pathways. However, Nilotinib, which is highly effective for the treatment of patients with chronic myeloid leukaemia (CML), is also associated with an increased risk of MACEs. The authors suggest that Nilotinib may be effective in peripheral SpA by modulating inflammation, but not in axial SpA. Considering the vascular toxicity of Nilotinib and the acceleration of atherosclerosis in SpA patients, we suggest taking MACEs as an end-point in future trials. PMID- 29246243 TI - The risk of malignancy and its incidence in early rheumatoid arthritis patients treated with biologic DMARDs. AB - BACKGROUND: Treatment with disease-modifying anti-rheumatic drugs (DMARDs) has raised concerns about the risk of malignancies in rheumatoid arthritis (RA) patients. However, the association between biologic DMARDs (bDMARDs) and malignancy in previous reports remains controversial. Therefore we aimed to estimate the incidence of malignancy in early RA patients and to evaluate the relative risk of malignancy with use of bDMARDs. METHODS: A retrospective cohort of incident RA patients was established using the Korean National Claims Database. Among a total of 14,081 RA patients identified, 1684 patients with a history of malignancy were excluded. We calculated the incidence rate of overall and individual malignancies. The standardized incidence ratio (SIR) of malignancies in bDMARD users was compared to that in nonusers. Multivariable logistic regression analysis was used to evaluate the impact of bDMARDs on the development of malignancies in early RA patients. RESULTS: A total of 12,397 early RA patients without a history of malignancy were enrolled. During 41,599 person-years (PY) of follow-up, 725 malignancies developed in 561 patients (174.3/10,000 PY) and 21 hematologic malignancies developed (5.0/10,000 PY). Patients treated with bDMARDs had a significantly lower incidence of overall malignancy compared to those not treated with bDMARDs (SIR 0.45 (95% CI 0.28 0.70)). However, this relationship was not significant with regard to hematologic malignancies (SIR 2.65 (95% CI 0.55-7.76)). On multivariable analysis, bDMARD use was a protective factor against the development of overall malignancy (odds ratio 0.42 (95% CI 0.25-0.73)). However, bDMARD use had no significant protective effect against the development of hematologic malignancies (odds ratio 1.69 (95% CI 0.38-7.59)). CONCLUSIONS: In early RA patients, bDMARD use decreases the overall risk of developing malignancies; however, it does not affect the risk of developing hematologic malignancies. PMID- 29246244 TI - Infiltration and persistence of lymphocytes during late-stage cerebral ischemia in middle cerebral artery occlusion and photothrombotic stroke models. AB - BACKGROUND: Evidence suggests that brain infiltration of lymphocytes contributes to acute neural injury after cerebral ischemia. However, the spatio-temporal dynamics of brain-infiltrating lymphocytes during the late stage after cerebral ischemia remains unclear. METHODS: C57BL/6 (B6) mice were subjected to sham, photothrombosis, or 60-min transient middle cerebral artery occlusion (MCAO) procedures. Infarct volume, neurodeficits, production of reactive oxygen species (ROS) and inflammatory factors, brain-infiltrating lymphocytes, and their activation as well as pro-inflammatory cytokine IFN-gamma production were assessed. Brain-infiltrating lymphocytes were also measured in tissue sections from post-mortem patients after ischemic stroke by immunostaining. RESULTS: In mice subjected to transient MCAO or photothrombotic stroke, we found that lymphocyte infiltration persists in the ischemic brain until at least day 14 after surgery, during which brain infarct volume significantly diminished. These brain-infiltrating lymphocytes express activation marker CD69 and produce proinflammatory cytokines such as IFN-gamma, accompanied with a sustained increase of reactive oxygen species (ROS) and inflammatory cytokines release in the brain. In addition, brain-infiltrating lymphocytes were observed in post mortem brain sections from patients during the late stage of ischemic stroke. CONCLUSION: Our results demonstrate that brain-infiltration of lymphocytes persists after the acute stage of cerebral ischemia, facilitating future advanced studies to reveal the precise role of lymphocytes during late stage of stroke. PMID- 29246245 TI - ABO and Rhesus blood group distribution and frequency among blood donors at Kilimanjaro Christian Medical Center, Moshi, Tanzania. AB - OBJECTIVE: This study aims to determine the distribution of blood groups and the demographic background of blood donors in a referral hospital in Northern Tanzania. RESULTS: The most common blood group was O (52.3%) and the least common was AB (3.18%). 97.7% of the blood donors were Rh positive and the rest were Rh negative. Most donors were young adults, representing the age group of 19-29. The majority of donors were male (88.1%) and the majority (90.8%) were replacement while the remainder was voluntary donors. PMID- 29246246 TI - Rho GTPases as therapeutic targets in Alzheimer's disease. AB - The progress we have made in understanding Alzheimer's disease (AD) pathogenesis has led to the identification of several novel pathways and potential therapeutic targets. Rho GTPases have been implicated as critical components in AD pathogenesis, but their various functions and interactions make understanding their complex signaling challenging to study. Recent advancements in both the field of AD and Rho GTPase drug development provide novel tools for the elucidation of Rho GTPases as a viable target for AD. Herein, we summarize the fluctuating activity of Rho GTPases in various stages of AD pathogenesis and in several in vitro and in vivo AD models. We also review the current pharmacological tools such as NSAIDs, RhoA/ROCK, Rac1, and Cdc42 inhibitors used to target Rho GTPases and their use in AD-related studies. Finally, we summarize the behavioral modifications following Rho GTPase modulation in several AD mouse models. As key regulators of several AD-related signals, Rho GTPases have been studied as targets in AD. However, a consensus has yet to be reached regarding the stage at which targeting Rho GTPases would be the most beneficial. The studies discussed herein emphasize the critical role of Rho GTPases and the benefits of their modulation in AD. PMID- 29246247 TI - Intervention to improve the appropriate use of polypharmacy for older patients with hip fractures: an observational study. AB - BACKGROUND: Polypharmacy is frequently observed in hip fracture patients. Although it is associated with an increased risk of hip fracture, polypharmacy often continues after hip fracture recovery. This study aimed to evaluate the effectiveness of an intervention to improve appropriate polypharmacy for elderly patients admitted to the hospital for hip fractures. METHODS: We conducted a retrospective observational study to compare the outcomes of patients receiving the intervention (n = 32) with those of patients who received usual care (n = 132). All hip fracture patients aged 65 years or older and prescribed 5 or more medications at admission from January 2015 to December 2016 were included in the study. The intervention consisted of an assessment by internal medicine physicians of the appropriateness of polypharmacy and the de-prescription of any unnecessary medications during the patients' hospital stay. The primary composite outcome was death or the first occurrence of any new fracture. Comparisons between the intervention and usual care groups were analyzed using binary logistic regression. RESULTS: A total of 164 patients were included in the study. The mean patient age was 84.8 years, and the mean numbers of prescribed medications and potentially inappropriate medications at admission were 8.0 and 1.3, respectively. The mean follow-up period was 8.0 months. The primary composite outcome occurred in 35 (21.3%) patients. The total number of potentially inappropriate medications at discharge was significantly lower in the intervention group than in the usual care group (0.8 +/- 0.8 for the intervention group vs 1.1 +/- 1.0 for the usual care group; p = 0.03). However, no significant differences in the primary composite outcome were found between the intervention and usual care groups (7 in the intervention group and 28 in the usual care group, odds ratio 1.04, 95% CI 0.41-2.65; p = 1.00). CONCLUSIONS: The intervention to improve appropriate polypharmacy was associated with a reduction in potentially inappropriate medications but not an improvement in clinical outcomes. This intervention, which focused only on polypharmacy, may not effectively improve outcomes for elderly patients with hip fractures. TRIAL REGISTRATION: UMIN-CTR UMIN000025495 . Retrospectively registered 2 January 2017. PMID- 29246248 TI - Factors associated with the 6-minute walk distance in patients with systemic sclerosis. AB - BACKGROUND: There is an ongoing debate regarding the relevance of the 6-minute walking distance (6MWD) in systemic sclerosis (SSc) assessment, widely used as a usual test in these patients as well as an outcome measure in clinical trials. In this work, we aimed to assess the associations between the 6MWD and various disease parameters in patients with SSc. METHODS: Consecutive patients followed in our SSc National Reference Centre were included in this cross-sectional study if they fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism criteria for SSc. Data were systematically collected during a comprehensive standardized evaluation that included a 6-minute walk test, clinical assessment, biological results, pulmonary function tests, transthoracic echocardiography, composite scores (European Scleroderma Study Group Activity Index, Medsger severity score, Health Assessment Questionnaire-Disability Index (HAQ-DI)) and treatments. Associations of the 6MWD with various disease parameters were assessed by linear regression in univariate and multivariate analyses. RESULTS: The study population comprised 298 patients (females 81%; mean age 58.2 +/- 13.3 years; limited cutaneous SSc 82%; interstitial lung disease (ILD) 42%; pulmonary arterial hypertension (PAH) 6%). The 6MWD was significantly and independently associated with gender, age, body mass index, baseline heart rate (HR), HR variation during the test, PAH, history of arterial thrombosis and C-reactive protein levels, as well as with the HAQ-DI score in a sensitivity analysis. Muscle involvement, joint involvement and ILD were not independently associated with the 6MWD. CONCLUSIONS: During SSc, the 6MWD is independently associated with initial HR and HR variation; with PAH but not ILD, suggesting that pulmonary vasculopathy may have a greater impact than parenchymal involvement on functional limitation; and with global markers of disease activity and patient disability. These results give clinicians further insight into how to interpret the 6MWD in the context of SSc. PMID- 29246249 TI - Oligomeric forms of amyloid-beta protein in plasma as a potential blood-based biomarker for Alzheimer's disease. AB - BACKGROUND: Soluble amyloid-beta (Abeta) oligomers are the major toxic substances associated with the pathology of Alzheimer's disease (AD). The ability to measure Abeta oligomer levels in the blood would provide simple and minimally invasive tools for AD diagnostics. In the present study, the recently developed Multimer Detection System (MDS) for AD, a new enzyme-linked immunosorbent assay for measuring Abeta oligomers selectively, was used to detect Abeta oligomers in the plasma of patients with AD and healthy control individuals. METHODS: Twenty-four patients with AD and 37 cognitively normal control individuals underwent extensive clinical evaluations as follows: blood sampling; detailed neuropsychological tests; brain magnetic resonance imaging; cerebrospinal fluid (CSF) measurement of Abeta42, phosphorylated tau protein (pTau), and total tau protein (tTau); and 11C-Pittsburgh compound B (PIB) positron emission tomography. Pearson's correlation analyses between the estimations of Abeta oligomer levels by MDS and other conventional AD biomarkers (CSF Abeta42, pTau, and tTau, as well as PIB standardized uptake value ratio [PIB SUVR]) were conducted. ROC analyses were used to compare the diagnostic performance of each biomarker. RESULTS: The plasma levels of Abeta oligomers by MDS were higher in patients with AD than in normal control individuals, and they correlated well with conventional AD biomarkers (levels of Abeta oligomers by MDS vs. CSF Abeta42, r = -0.443; PIB SUVR, r = 0.430; CSF pTau, r = 0.530; CSF tTau, r = 0.604). The sensitivity and specificity of detecting plasma Abeta oligomers by MDS for differentiating AD from the normal controls were 78.3% and 86.5%, respectively. The AUC for plasma Abeta oligomers by MDS was 0.844, which was not significantly different from the AUC of other biomarkers (p = 0.250). CONCLUSIONS: Plasma levels of Abeta oligomers could be assessed using MDS, which might be a simple, noninvasive, and accessible assay for evaluating brain amyloid deposition related to AD pathology. PMID- 29246251 TI - Association between social capital and health-related quality of life among left behind and not left behind older people in rural China. AB - BACKGROUND: The association between social capital and health-related quality of life (HRQoL) has not been thoroughly studied among older persons in rural China, especially among those who were left behind or not. This study investigates the association between social capital and HRQoL and examines possible differences of this association between being left behind or not in rural China. METHODS: A cross-sectional survey of 825 people aged 60 years and older, residing in three rural counties in Jiangsu Province in China, was conducted in 2013. Factor analysis was performed to measure social capital. EQ-5D was used to measure HRQoL. Tobit regression analysis with upper censoring was conducted to explore the association between social capital and EQ-5D index. RESULTS: After controlling for individual characteristics, low social capital and being left behind were significantly associated with low HRQoL. Old people with low social capital had 0.055 lower EQ-5D index compared to those with high social capital. Old people being left behind had 0.040 lower EQ-5D index compared to those who were not left behind. For different dimensions of social capital, the main effects came from the domain of trust and reciprocity. There was a significant interaction between low social capital and being left behind on HRQoL, suggesting that low social capital was associated with low HRQoL among persons left behind. CONCLUSIONS: Our findings indicate that the left behind old people with low social capital were a potentially vulnerable group in rural China. Formulating and implementing initiatives and strategies which increase social capital may foster better HRQoL, especially for old people who were left behind. PMID- 29246250 TI - Posterior atrophy predicts time to dementia in patients with amyloid-positive mild cognitive impairment. AB - BACKGROUND: In patients with amyloid-positive mild cognitive impairment (MCI), neurodegenerative biomarkers such as medial temporal lobe atrophy (MTA) are useful to predict disease progression to dementia. Although posterior atrophy (PA) is a well-known neurodegenerative biomarker of Alzheimer's disease, little is known about PA as a predictor in patients with amyloid-positive MCI. METHODS: We included 258 patients with amyloid-positive MCI with at least one follow-up visit, and who had low cerebrospinal fluid (CSF) beta-amyloid1-42 concentration. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative study. We assessed PA and MTA on magnetic resonance imaging (MRI) using visual rating scales and retrospectively determined progression to dementia during the follow up period of up to 3 years (median 24 months). The Cox proportional hazards model was used to analyze hazard ratios (HRs) of PA and MTA for disease progression. Additionally, subjects were divided into four groups according to brain atrophy pattern (no atrophy, MTA only, PA only, both MTA and PA), and HRs for disease progression were compared with the no atrophy reference group. Analyses were conducted with and without adjustment for CSF phosphorylated tau181p (p-tau) and baseline demographics. RESULTS: A total of 123 patients (47.7%) showed MTA and 174 patients (67.4%) showed PA. Of the total cohort, 139 cases (53.9%) progressed to dementia. PA and MTA were associated with an increased risk for progression to dementia (HR 2.244, 95% confidence interval (CI) 1.497-3.364, and HR 1.682, 95% CI 1.203-2.352, respectively). In the analysis according to atrophy pattern, HR (95% CI) for progression was 2.998 (1.443-6.227) in the MTA only group, 3.126 (1.666-5.864) in the PA only group, and 3.814 (2.045-7.110) in both MTA and PA group. These results remained significant after adjustment. CONCLUSIONS: In patients with amyloid-positive MCI, PA could predict progression to dementia independently of MTA. PMID- 29246252 TI - Fever with lymphadenopathy - Kikuchi Fujimoto disease, a great masquerader: a case report. AB - BACKGROUND: Kikuchi Fujimoto disease is an uncommon benign condition of necrotizing histiocytic lymphadenitis commonly seen in East Asian and Japanese populations. It commonly presents with fever, cervical lymphadenopathy, and elevated inflammatory markers. Diagnosis of Kikuchi Fujimoto disease is based on histopathological studies of the involved lymph nodes. The presentation of Kikuchi Fujimoto disease can mimic many sinister conditions including lymphoma. Treatment is mainly supportive provided that accurate diagnosis is made and sinister conditions like lymphoma ruled out. CASE PRESENTATION: We report the case of an 18-year-old Sri Lankan Moor woman who presented with fever and cervical lymphadenopathy for 1 month. She had elevated inflammatory markers with high lactate dehydrogenase and ferritin levels. She had an extensive work-up including an excision biopsy of an involved lymph node and bone marrow biopsy. Finally, a diagnosis of Kikuchi Fujimoto disease was based on histopathology of the lymph node and negative bone marrow biopsy. CONCLUSIONS: Although Kikuchi Fujimoto disease is a self-limiting condition, it is a great masquerader which mimics the clinical features of many sinister conditions including tuberculosis, lymphoma, and adult-onset Still's disease. Early recognition of the disease is of crucial importance in minimizing potentially harmful and unnecessary evaluations and treatments. PMID- 29246253 TI - Prevalence and pattern of co-occurring musculoskeletal pain and its association with back-related disability among people with persistent low back pain: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Individuals with persistent low back pain commonly have a broad range of other health concerns including co-occurring musculoskeletal pain, which significantly affect their quality of life, symptom severity, and treatment outcomes. The purpose of this review is to get a better understanding of prevalence and patterns of co-occurring musculoskeletal pain complaints in those with persistent low back pain and its potential association with age, sex, and back-related disability as it might affect prognosis and management. METHODS: This systematic review protocol has been designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. We will perform a comprehensive search, with no date limit, in the following bibliographic databases: MEDLINE and Embase (via Ovid), CINAHL, and Scopus for citation tracking, based on the following domains: back pain, co-occurring musculoskeletal pain, combined with a focus group that emphasizes study design. Appropriate papers will be screened against the eligibility criteria by three reviewers independently, data extracted by two independent author pairs and disagreement resolved by consensus meetings or other reviewers if required. Assessment of methodological quality and risk of bias will be conducted using a modified version of the Risk of Bias Tool for Prevalence Studies developed by Hoy and colleagues. The overall risk of bias will be determined for each included study based on the raters' consensus of the responses to the items in this tool. In case of sufficiently homogenous studies, meta-analysis will be performed. DISCUSSION: Given the lack of standard terms used to define co-occurring musculoskeletal pain, the search strategy will include the broader term "back pain," different terms for the "other co-occurring pain," and specific study designs combined with several exclusion terms. The results of this proposed review will identify the prevalence and patterns of co-occurring musculoskeletal pain among those with persistent low back pain, which is likely to inform clinical management, research, and policy in management of musculoskeletal disorders. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017068807. PMID- 29246254 TI - Disclosure of domestic violence and sexual assault within the context of abortion: meta-ethnographic synthesis of qualitative studies protocol. AB - BACKGROUND: One third of women will have an abortion in their lifetime (Kerr, QUT Law Rev 14:15, 2014; Aston and Bewley, Obstetrician & Gynaecologist 11:163-8, 2009). These women are more likely to have experienced domestic violence or sexual assault than women who continue with their pregnancies. Frontline health personnel involved in the care of women seeking abortions are uniquely positioned to support patients who choose to disclose their violence. Yet, the disclosure of domestic violence or sexual assault within the context of abortion is not well understood. To enhance service provision, it is important to understand the disclosure experience, that is, how frontline health personnel manage such disclosures and how victims/survivors perceive this experience. This review aims to provide a systematic synthesis of qualitative literature to increase understanding of the phenomena and identify research gaps. METHODS: A meta ethnography of qualitative evidence following PRISMA-P recommendations for reporting systematic reviews will be performed to better understand the experiences of domestic violence and sexual assault disclosure from the perspective of frontline health personnel providing support and women seeking an abortion. A three-stage search strategy including database searching, citation searching and Traditional Pearl Growing will be applied starting with the terms "domestic violence", "sexual assault", "disclosure" and "abortion", their common synonyms and MeSH terms. The database search will include CINAHL, MEDLINE, Embase and PsycINFO. Published studies from 1970, written in English and from all countries will be included. Two reviewers will screen titles and abstracts and if suitable will then perform a full-text review. To attribute weight to each study, two reviewers will perform the critical appraisal using a modified version of the "Guidelines for Extracting Data and Quality Assessing Primary Studies in Educational Research". Data extraction and coding will occur using EPPI-Reviewer 4 and will be carried out by two reviewers. DISCUSSION: The reviewers will illuminate what transpires at the interface when women seeking an abortion in the context of domestic violence and sexual assault meet frontline health personnel. Increased knowledge in this area will improve the frontline health personnel's practices and responsiveness to women who seek out healthcare in the context of violence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016051136. PMID- 29246255 TI - Troubling disease syndrome in endangered live Patagonian huemul deer (Hippocamelus bisulcus) from the Protected Park Shoonem: unusually high prevalence of osteopathology. AB - OBJECTIVE: The last 1500 endangered Patagonian huemul deer (Hippocamelus bisulcus) exist in > 100 groups which are not recovering. Prevalence of osteopathology in dead huemul was 57+% (Argentina), whereas similar cases in Chile were accompanied by selenium deficiency. The first clinical cases from live wild huemul confirm widespread osteopathology which explains short life spans, low recruitment, and thus absence of population recovery. RESULTS: The first-ever radio-collaring of 3 male huemul in Argentina and 3 females, plus a fresh female carcass allowed examination of 7 huemul. Of these, 86% were diseased and clinical pathophysiognomy included lameness, affected hoof, exfoliation of 2-7 incisors, other cranial osteopathologies, and muscle atrophy. The parsimonious explanation for absent population recovery is high prevalence of osteopathology as evidenced earlier in carcasses, and now by these clinical cases. Areas currently used by huemul have reduced selenium bioavailability, very deficient soil levels, and overt selenium deficiency in local livestock and plants. These areas are known to result in primary iodine deficiency which is aggravated by selenium deficiency. The nexus to nutritional ecology of huemul likely is inaccessibility to most fertile lowlands and traditional winter ranges, elimination of migratory traditions, and concomitant elimination of source populations. PMID- 29246256 TI - Effect of oral glycine on the clinical, spirometric and inflammatory status in subjects with cystic fibrosis: a pilot randomized trial. AB - BACKGROUND: Patients with cystic fibrosis (CF) have airway inflammation that contributes to symptoms and to pulmonary function derangement. Current drugs used to diminish airway inflammation improve the clinical and spirometric status of patients with CF, but their use is limited due to their undesired side effects, for example, glucose intolerance, growth retardation, and cataracts with corticosteroids, gastrointestinal toxicity with ibuprofen, and macrolide resistance with azythromycin. Glycine is known to decrease activation of inflammatory cells, including alveolar macrophages and neutrophils, and is relatively inexpensive, palatable, and virtually devoid of untoward effects. These features make glycine a good candidate for antiinflammatory treatment of CF. Thus, we aimed to explore whether glycine can exert a beneficial effect in a population of patients with CF. METHODS: This was a randomized, double blinded, cross-over pilot clinical trial. Subjects with CF received, in random order, oral glycine (0.5 g/kg/day, dissolved in any liquid) and placebo (glass sugar), each during 8 weeks with an intermediate 2-week wash-out period. RESULTS: Thirteen subjects aged 6-23 years, 8 females, completed the two arms of the study. As compared with placebo, after glycine intake patients had better symptom questionnaire scores (p = 0.02), mainly regarding sputum features and dyspnea. While spirometric variables tended to decline during placebo intake, they remained stable or even increased during glycine treatment (p = 0.04 to p = 0.003). In this context, FEV1 declined 8.6% after placebo and increased 9.7% at the end of the glycine period. Pulse oximetry improved after glycine intake (p = 0.04 vs. placebo). TNF-alpha in serum and IL-6 and G-CSF in sputum tended to decline at the end of the glycine period (p = 0.061, p = 0.068 and p = 0.04, respectively, vs placebo). Glycine was remarkably well tolerated. CONCLUSIONS: The clinical, spirometric and inflammatory status of subjects with CF improved after just 8 weeks of glycine intake, suggesting that this amino acid might constitute a novel therapeutic tool for these patients. Thus, further studies are warranted. TRIAL REGISTRATION: www.clinicaltrials.gov , registration number: NCT01417481 , date of registration: March 12, 2012. PMID- 29246257 TI - Comparing multidisciplinary and brief intervention in employees with different job relations on sick leave due to low back pain: protocol of a randomised controlled trial. AB - BACKGROUND: Low back pain (LBP) is a common problem that affects the lives of many individuals and is a frequent cause of sickness absence. To help this group of individuals resume work, several interventions have been studied. However, not all individuals may profit from the same intervention and the effect of a given intervention on return to work (RTW) may depend on their work situation. The aim of this study is to evaluate whether employees on sick leave due to LBP and with poor job relations will benefit more from a multidisciplinary intervention, while patients with strong job relations will benefit more from a brief intervention. METHODS: The study is designed as a randomised controlled trial with up to five years of follow-up comparing brief intervention with brief intervention plus multidisciplinary intervention. Employees, aged 18-60 years, are included in the study from March 2011 to August 2016 if they have been on sick leave for 4-12 weeks due to LBP with or without radiculopathy. They are divided into two groups, a group with poor job relations and a group with strong job relations based on their answers in the baseline questionnaire. Each group is randomised 1:1 to receive the brief intervention or brief intervention plus multidisciplinary intervention. The brief intervention comprises a clinical examination and advice offered by a rheumatologist and a physiotherapist, whereas the supplementary multidisciplinary intervention comprises the assignment of a case manager who draws up a rehabilitation plan in collaboration with the participant and the multidisciplinary team. The primary outcome is duration of sickness absence measured by register data. Secondary outcomes include sustainable RTW and questionnaire-based measures of functional capacity. Outcomes will be assessed at one, two and five years of follow-up. DISCUSSION: This trial will evaluate the effect of brief and multidisciplinary intervention on RTW and functional capacity among employees on sick leave due to LBP with poor or strong job relations. This will indicate whether work-related characteristics should be considered when providing treatment of LBP patients in the health care sector. TRIAL REGISTRATION: Current Controlled Trials ISRCTN14136384 . Registered 4 August 2015. PMID- 29246258 TI - Palliative care and the arts: vehicles to introduce medical students to patient centred decision-making and the art of caring. AB - BACKGROUND: Medical Schools are challenged to improve palliative care education and to find ways to introduce and nurture attitudes and behaviours such as empathy, patient-centred care and wholistic care. This paper describes the curriculum and evaluation results of a unique course centred on palliative care decision-making but aimed at introducing these other important competencies as well. METHODS: The 20 h-long optional course, presented in an art museum, combined different learning methods, including reflections on art, case studies, didactic sessions, personal experiences of faculty, reflective trigger videos and group discussions. A mixed methods approach was used to evaluate the course, including a) a post-course reflective exercise; b) a standardized evaluation form used by the University for all courses; and c) a focus group. RESULTS: Twenty students (2nd to 6th years) participated. The course was rated highly by the students. Their understanding of palliative care changed and misconceptions were dispelled. They came to appreciate the multifaceted nature of decision-making in the palliative care setting and the need to individualize care plans. Moreover, the course resulted in a re-conceptualization of relationships with patients and families, as well as their role as future physicians. CONCLUSIONS: Palliative care decision-making therefore, augmented by the visual arts, can serve as a vehicle to address several competencies, including the introduction of competencies related to being patient-centred and empathic. PMID- 29246260 TI - Microsatellite marker development from next-generation sequencing in the New England cottontail (Sylvilagus transitionalis) and cross-amplification in the eastern cottontail (S. floridanus). AB - OBJECTIVE: The New England cottontail (Sylvilagus transitionalis) is a species of high conservation priority in the Northeastern United States, and was a candidate for federal listing under the Endangered Species Act until a recent decision determined that conservation actions were sufficient to preclude listing. The aim of this study was to develop a suite of microsatellite loci to guide future research efforts such as the analysis of population genetic structure, genetic variation, dispersal, and genetic mark-recapture population estimation. RESULTS: Thirty-five microsatellite markers containing tri- and tetranucleotide sequences were developed from shotgun genomic sequencing of tissue from S. transitionalis, S. obscurus, and S. floridanus. These loci were screened in n = 33 wild S. transitionalis sampled from a population in eastern Massachusetts, USA. Thirty two of the 35 loci were polymorphic with 2-6 alleles, and observed heterozygosities of 0.06-0.82. All loci conformed to Hardy-Weinberg Equilibrium proportions and there was no evidence of linkage disequilibrium or null alleles. Primers for 33 of the 35 loci amplified DNA extracted from n = 6 eastern cottontail (S. floridanus) samples, of which nine revealed putative species diagnostic alleles. These loci will provide a useful tool for conservation genetics investigations of S. transitionalis and a potential diagnostic species assay for differentiating sympatric eastern and New England cottontails. PMID- 29246259 TI - Macrophages in trigeminal ganglion contribute to ectopic mechanical hypersensitivity following inferior alveolar nerve injury in rats. AB - BACKGROUND: Accidental mandibular nerve injury may occur during tooth extraction or implant procedures, causing ectopic orofacial pain. The exact mechanisms underlying ectopic orofacial pain following mandibular nerve injury is still unknown. Here, we investigated the role of macrophages and tumor necrosis factor alpha (TNFalpha) in the trigeminal ganglion (TG) in ectopic orofacial pain following inferior alveolar nerve transection (IANX). METHODS: IANX was performed and the mechanical head-withdrawal threshold (MHWT) in the whisker pad skin ipsilateral to IANX was measured for 15 days. Expression of Iba1 in the TG was examined on day 3 after IANX, and the MHWT in the whisker pad skin ipsilateral to IANX was measured following successive intra-ganglion administration of the macrophage depletion agent liposomal clodronate Clophosome-A (LCCA). TNFalpha expression in the TG and the MHWT in the whisker pad skin ipsilateral to IANX following successive intra-ganglion administration of the TNFalpha blocker etanercept were measured on day 3 after IANX, and tumor necrosis factor receptor 1 (TNFR1) immunoreactive (IR) cells in the TG were analyzed immunohistochemically on day 3. RESULTS: The MHWT in the whisker pad skin was significantly decreased for 15 days, and the number of Iba1-IR cells was significantly increased in the TG on day 3 after IANX. Successive intra-ganglion administration of the macrophage depletion agent LCCA significantly reduced the increased number of Iba1-IR cells in the TG and reversed the IANX-induced decrease in MHWT in the whisker pad skin. TNFalpha expression was increased in the TG on day 3 after IANX and was reduced following successive intra-ganglion administration of the TNFalpha inhibitor etanercept. The decreased MHWT was also recovered by etanercept administration, and TNFR1-IR cells in the TG were increased on day 3 following IANX. CONCLUSIONS: These findings suggest that signaling cascades resulting from the production of TNFalpha by infiltrated macrophages in the TG contributes to the development of ectopic mechanical allodynia in whisker pad skin following IANX. PMID- 29246261 TI - Content validation of an interprofessional learning video peer assessment tool. AB - BACKGROUND: Large scale models of interprofessional learning (IPL) where outcomes are assessed are rare within health professional curricula. To date, there is sparse research describing robust assessment strategies to support such activities. We describe the development of an IPL assessment task based on peer rating of a student generated video evidencing collaborative interprofessional practice. We provide content validation evidence of an assessment rubric in the context of large scale IPL. METHODS: Two established approaches to scale development in an educational setting were combined. A literature review was undertaken to develop a conceptual model of the relevant domains and issues pertaining to assessment of student generated videos within IPL. Starting with a prototype rubric developed from the literature, a series of staff and student workshops were undertaken to integrate expert opinion and user perspectives. Participants assessed five-minute videos produced in a prior pilot IPL activity. Outcomes from each workshop informed the next version of the rubric until agreement was reached on anchoring statements and criteria. At this point the rubric was declared fit to be used in the upcoming mandatory large scale IPL activity. RESULTS: The assessment rubric consisted of four domains: patient issues, interprofessional negotiation; interprofessional management plan in action; and effective use of video medium to engage audience. The first three domains reflected topic content relevant to the underlying construct of interprofessional collaborative practice. The fourth domain was consistent with the broader video assessment literature calling for greater emphasis on creativity in education. CONCLUSIONS: We have provided evidence for the content validity of a video-based peer assessment task portraying interprofessional collaborative practice in the context of large-scale IPL activities for healthcare professional students. Further research is needed to establish the reliability of such a scale. PMID- 29246263 TI - The complete chloroplast genome sequence of Asian Palmyra palm (Borassus flabellifer). AB - OBJECTIVE: Borassus flabellifer or Asian Palmyra palm is widely distributed in South and Southeast Asia and is horticultural and economic importance for its fruit and palm sugar production. However, its population is in rapid decline, and only a few genetic data are available. We sequenced the complete chloroplast (cp) genome of B. flabellifer to provide its genetic data for further utilization. RESULTS: The cp genome was obtained by Illumina sequencing and manual gap fillings providing 160,021 bp in length containing a pair of inverted repeats (IRs) with 27,256 bp. These IRs divide the genome into a large single copy region 87,444 bp and a small single copy region 18,065 bp. In total, 113 unique genes, 134 SSRs and 47 large repeats were identified. This is the first complete cp genome reported in the genus Borassus. A comparative analysis among members of the Borasseae tribe revealed that the B. flabellifer cp genome is, so far, the largest and the cp genomes of this tribe have a similar structure, gene number and gene arrangement. A phylogenetic tree reconstructed based on 74 protein coding genes from 70 monocots demonstrates short branch lengths indicating slow evolutionary rates of cp genomes in family Arecaceae. PMID- 29246262 TI - EBI2 receptor regulates myelin development and inhibits LPC-induced demyelination. AB - BACKGROUND: The G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2) is activated by 7alpha, 25-dihydroxycholesterol (7alpha25HC) and plays a role in T cell-dependant antibody response and B cell migration. Abnormal EBI2 signaling is implicated in a range of autoimmune disorders; however, its role in the CNS remains poorly understood. METHODS: Here we characterize the role of EBI2 in myelination under normal and pathophysiological conditions using organotypic cerebellar slice cultures and EBI2 knock-out (KO) animals. RESULTS: We find that MBP expression in brains taken from EBI2 KO mice is delayed compared to those taken from wild type (WT) mice. In agreement with these in vivo findings, we show that antagonism of EBI2 reduces MBP expression in vitro. Importantly, we demonstrate that EBI2 activation attenuates lysolecithin (LPC)-induced demyelination in mouse organotypic slice cultures. Moreover, EBI2 activation also inhibits LPC-mediated release of pro-inflammatory cytokines such as IL6 and IL1beta in cerebellar slices. CONCLUSIONS: These results, for the first time, display a role for EBI2 in myelin development and protection from demyelination under pathophysiological conditions and suggest that modulation of this receptor may be beneficial in neuroinflammatory and demyelinating disorders such as multiple sclerosis. PMID- 29246264 TI - Clinical Trial Enrollment Enrichment in Resource-Constrained Research Environments: Multivariable Apnea Prediction (MAP) Index in SCIP-PA Trial. AB - STUDY OBJECTIVES: Determine the Multivariable Apnea Prediction (MAP) index predictive utility for enrollment enrichment in a clinical trial wherein enrollment was prior to obstructive sleep apnea diagnosis. METHODS: Secondary analysis of screening data (n = 264) from randomized, double-blind, pilot trial. Clinical sleep center patients with complete screening and polysomnography data were included. To determine diagnostic test accuracy of the MAP index using apnea hypopnea index criterion >= 10 events/h (primary) and >= 5, >= 15, and >= 30 events/h (secondary), sensitivity, specificity, negative and positive predictive values, likelihood positive and negative ratios, and receiver operating characteristic curves were calculated. Predictive utility was examined by characteristic variables. RESULTS: Middle-aged, overweight or obese, men and women were included. Employing a MAP index threshold >= 0.5, sensitivity for obstructive sleep apnea (apnea-hypopnea index >= 10 events/h) was 83.6%; specificity was 46.4%; area under the curve = 0.74. Sensitivity was higher in males than females (95.3%, 68.7%, respectively); specificity was lower in males than females (30.4%, 57.6%, respectively) with similar area under the curve (0.74 versus 0.72, respectively). MAP accuracy was higher in younger versus older adults (younger than 50 years, or 50 years or older; area under the curve 0.82 versus 0.63, respectively). Varied apnea-hypopnea index criteria produced stable accuracy estimates. CONCLUSIONS: Recruitment/enrollment is a high-cost endeavor. Screening procedures may confer resource savings but careful evaluation prior to study implementation assures effectiveness and efficiency. CLINICAL TRIAL REGISTRATION: The secondary analysis reports data from the SCIP-PA Trial (NCT 01454830); study information available at: https://clinicaltrials.gov. PMID- 29246265 TI - Improvement of Neuropathy Symptoms With Treatment of Obstructive Sleep Apnea in a Patient With Charcot-Marie-Tooth Disease. AB - ABSTRACT: This is a case report describing a 53-year-old woman with Charcot-Marie Tooth disease, obstructive sleep apnea, and a 6-year history of numbness in bilateral upper extremities, feet, and in the trunk that resolved with initiation of continuous positive airway pressure for her obstructive sleep apnea. PMID- 29246266 TI - Dream Content in Patients With Sleep Apnea: A Prospective Sleep Laboratory Study. AB - STUDY OBJECTIVES: Few studies have addressed dreaming in patients with sleep apnea. We hypothesized that respiratory events and subsequent oxygen desaturation act as an important physiological trigger and may thus influence dream content in patients with a sleep-related breathing disorder. METHODS: Seventy-six patients (28 women, mean age 54 years, range 20-82) who underwent polysomnography because of suspected sleep apnea participated in this study. Dream reports and dream questionnaires were collected immediately after first morning awakening, at 5:30 AM, at the sleep laboratory. Dream content analysis with respect to possible respiratory-related content was performed. Patients were stratified into primary snoring, mild, moderate, and severe sleep apnea groups. RESULTS: In 63 patients sleep apnea was diagnosed (mild n = 31, 49.2%, moderate n = 13, 20.6%, severe n = 19, 30.2%), and 13 subjects in whom a sleep-related breathing disorder was not confirmed were included as a control group with primary snoring. There was no significant difference in respiratory-related dream topics between patients and controls. Also, no influence of respiratory parameters measured during polysomnography on dream content was detectable. CONCLUSIONS: We failed to detect a difference in dream content between patients with sleep apnea and controls. Further studies are required to determine whether these results indicate that the incorporation of respiratory events into dreams is absent in patients with sleep apnea or represents a bias due to the collection of dream content in the early morning hours. PMID- 29246267 TI - Autonomic Nervous System Functioning Related to Nocturnal Sleep in Patients With Chronic Fatigue Syndrome Compared to Tired Controls. AB - STUDY OBJECTIVES: Autonomic nervous system (ANS) dysfunction is common in chronic fatigue syndrome (CFS). One of the main complaints in CFS is unrefreshing sleep. We aimed to study the nocturnal cardiac ANS in different sleep stages in patients filling the 2015 Institute of Medicine CFS diagnostic criteria. METHODS: In this case series study, the nocturnal heart rate variability and blood pressure (BP) variables in polysomnography were studied in groups of patients with CFS (n = 8) and tired controls (n = 8) aged 16-49 years. Five of the patients with CFS and controls were female. The heart rate variability and BP parameters and heart rate were studied in all sleep stages and wake. RESULTS: The amount of low-frequency oscillations of the electrocardiography R-R-intervals spectra (LF; predominantly reflects sympathetic activity) was higher for patients with CFS in all sleep stages compared to controls (P < .001). During wake, the amount of LF was lower for the patients with CFS (P < .05). The amount of high-frequency oscillations (HF; reflects parasympathetic activity) was lower in stage N3 sleep in the patients with CFS than for the controls (P < .0001), but, in total, HF was higher in patients with CFS (P < .001). Patients with CFS had higher overall nocturnal systolic and mean BP (P < .0001) and lower heart rate (P < .0001) than controls. No significant differences were found in sleep stage distributions. CONCLUSIONS: The results suggest a nocturnal dysfunction of the cardiac ANS in CFS, presenting as lower parasympathetic tone in deep sleep and higher sympathetic tone asleep. PMID- 29246268 TI - Sleep-Related Orgasms in a 57-Year-Old Woman: A Case Report. AB - ABSTRACT: We report a case of problematic spontaneous orgasms during sleep in a 57-year-old woman who also complained of hypnic jerks and symptoms of exploding head syndrome. To our knowledge, this is the first case report in the English language literature of problematic spontaneous orgasms during sleep. She had a complex medical and psychiatric history, and was taking oxycontin, venlafaxine, amitriptyline, and lurasidone. Prolonged video electroencephalogram monitoring did not record any ictal or interictal electroencephalogram discharges, and nocturnal video polysomnography monitoring did not record any behavioral or orgasmic event. Periodic limb movement index was zero events/h. Severe central sleep apnea was detected with apnea-hypopnea index = 130 events/h, but she could not tolerate positive airway pressure titration. Sleep architecture was disturbed, with 96.4% of sleep spent in stage N2 sleep. Bedtime clonazepam therapy (1.5 mg) was effective in suppressing the sleep-related orgasms and hypnic jerks. PMID- 29246269 TI - Adult-Onset Sleepwalking Secondary to Hyperthyroidism: Polygraphic Evidence. AB - ABSTRACT: Sleepwalking is a disorder characterized by complex motor behaviors arising from slow wave sleep usually occurring in children. The adult onset of sleepwalking suggests the presence of an external precipitating factor leading to the occurrence of the disorder. Hyperthyroidism has been reported to be the possible cause of sleepwalking in a few cases. We present the case of a 36-year old man who reported a sudden appearance of nocturnal episodes of sleepwalking. He underwent a complete video polysomnography (VPSG), which showed a polygraphic pattern arising from stage N3 sleep related to the presence of simple motor behaviors. Routine blood tests showed a mild hyperthyroidism. After 4 months of thyrostatic treatment, the patient reported no more sleepwalking events. A VPSG performed at the last follow-up showed the absence of pathological electroclinical events arising from stage N3 sleep. Therefore, we hypothesize that there is a link between sleepwalking and thyroid dysfunction in our patient. PMID- 29246271 TI - A New Stage for the Journal of Clinical Sleep Medicine: REM. PMID- 29246272 TI - More Than the Trajectory of the Teeth, We Need to Know About the Treatment Trajectory of Patients. PMID- 29246273 TI - Crowdsourcing, a novel platform to generate scientific manuscripts, now in cardiology. PMID- 29246274 TI - Warfarin Prophylaxis for Anterior Infarction: Another Black Mark for Triple Therapy. PMID- 29246275 TI - Reducible complexity: NASS 2017 presidential address. PMID- 29246276 TI - Nutrition management for head and neck cancer patients improves clinical outcome and survival. AB - Up to 80% of patients with head and neck cancers are malnourished because of their lifestyle and the risk factors associated with this disease. Unfortunately, nutrition management systems are not implemented in most head and neck cancer clinics. Even worse, many head and neck surgeons as well as hospital management authorities disregard the importance of nutrition management in head and neck cancer patients. In addition, the often extensive resection and reconstruction required for tumors in the upper aerodigestive tract pose special challenges for swallowing and sufficient food intake, placing special demands on nutrition management. This article presents the basics of perioperative metabolism and nutrition management of head and neck cancer patients and makes recommendations for clinical practice. Implementing a nutrition management system in head and neck cancer clinics will improve the clinical outcome and the survival of the patients. PMID- 29246277 TI - beta-Alanine supplementation elevates intramuscular carnosine content and attenuates fatigue in men and women similarly but does not change muscle l histidine content. AB - beta-Alanine (BA) supplementation results in elevated intramuscular carnosine content, enhancing buffering capacity during intense exercise. Although men have greater muscle carnosine content than women, elevations still appear to occur despite high baseline levels. Recent research has suggested that BA supplementation may also reduce muscle l-histidine. Thus, the purpose of this investigation was to compare 28 days of BA (6 g.d-1) supplementation in men and women on performance and muscle carnosine, l-histidine, and BA. We hypothesized that supplementation would result in similar elevations in carnosine and performance between sexes and decrease l-histidine. Twenty-six men and women were assigned either BA or placebo (PLA). At baseline, a trend toward greater carnosine (P = .069) was observed in men, and intramuscular BA content was significantly (P <= .05) greater in men. Statistical analysis was performed using magnitude-based inferences. Changes in muscle carnosine were likely and very likely greater after BA supplementation compared with PLA in men and women, respectively, but changes were unclear between sexes (mean sex difference: 2.50 +/- 4.30 mmol.kg-1 ww). The attenuation of exercise fatigue was likely greater in BA compared with PLA, but the change was unclear between sexes (mean sex difference: 14.0 +/- 39.0 Nm). Changes in muscle BA following supplementation was unclear in men, likely elevated in women, but unclear between sexes (mean sex difference: 0.03 +/- 0.42 mmol.kg-1 ww). Changes in muscle l-histidine were unclear in men and women, and unclear between sexes (mean sex difference: 0.09 +/ 0.13 mmol.kg-1 ww). In conclusion, BA supplementation increased muscle carnosine and attenuated fatigue in men and women similarly but did not reduce muscle l histidine. PMID- 29246278 TI - Maillard reaction products from highly heated food prevent mast cell number increase and inflammation in a mouse model of colitis. AB - Links between food and inflammatory bowel diseases (IBDs) are often suggested, but the role of food processing has not been extensively studied. Heat treatment is known to cause the loss of nutrients and the appearance of neoformed compounds such as Maillard reaction products. Their involvement in gut inflammation is equivocal, as some may have proinflammatory effects, whereas other seem to be protective. As IBDs are associated with the recruitment of immune cells, including mast cells, we raised the hypothesis that dietary Maillard reaction products generated through heat treatment of food may limit the colitic response and its associated recruitment of mast cells. An experimental model of colitis was used in mice submitted to mildly and highly heated rodent food. Adult male mice were divided in 3 groups and received nonheated, mildly heated, or highly heated chow during 21 days. In the last week of the study, each group was split into 2 subgroups, submitted or not (controls) to dextran sulfate sodium (DSS) colitis. Weight variations, macroscopic lesions, colonic myeloperoxidase activity, and mucosal mast cell number were evaluated at the end of the experiment. Only highly heated chow significantly prevented DSS-induced weight loss, myeloperoxidase activity, and mast cell number increase in the colonic mucosa of DSS-colitic mice. We suggest that Maillard reaction products from highly heated food may limit the occurrence of inflammatory phases in IBD patients. PMID- 29246279 TI - Indirect calorimetry using a ventilated hood may be easier than using a facemask to achieve steady state when measuring resting energy expenditure. AB - Previous studies have demonstrated differences in subjective comfort between different gas collecting methods during resting energy expenditure (REE) measurement. We hypothesized that gas collecting methods may have an influence on the time to achieve steady state and the optimum abbreviated period to estimate REE. Gas exchange variables were obtained using IIM-IC-100 (ventilated hood) and VO2000 (facemask) alternately among 32 healthy adults. A 10-minute test period was divided into 5-minute sliding time windows to obtain a subtle profile process of the coefficient of variation (CV) and REE. Friedman's test was used to compare the CVs during the test process. To compare the REE between abbreviated measurements and the reference, paired t test, linear regression, and Bland Altman test were used. There were no significant differences between the CVs in each adjacent group of 5-minute intervals for IIM-IC-100 (P = .896). CV1 and CV2 were significantly higher than CV3-CV6 for VO2000 (P = .001). The proportion of subjects achieving steady state was lower with VO2000 (59.4-81.3%) than with IIM IC-100 (84.4-91.8%). REE of the 2nd and 3rd 5-minute intervals did not differ from the reference, and they explained 94.7% (P < .001) and 94.9% (P < .001) of the last 5-minute REE variance, with the 95% limits of agreement ranging from 100.0 to 139.2 kcal/d and -139.5 to 182.5 kcal/d for IIM-IC-100 and VO2000, respectively. In conclusion, using a ventilated hood may be easier than using a facemask to achieve steady state and reduce the time required to estimate REE. PMID- 29246280 TI - Continuous astaxanthin intake reduces oxidative stress and reverses age-related morphological changes of residual skin surface components in middle-aged volunteers. AB - Oxidative stress accelerates skin aging, and dietary supplementation with antioxidants may alleviate it. Morphological analysis of the residual skin surface components (RSSCs) allows detecting age-related changes in corneocyte desquamation, microbial presence, and lipid droplet size. We hypothesized that continuous ingestion of carotenoid antioxidant astaxanthin (4 mg/d) for 4 weeks could influence RSCC morphology and evaluated RSSC samples taken from middle-aged subjects before and after this dietary intervention. The study included 31 volunteers (17 men and 14 women) over the age of 40. RSSC samples were collected from the surface of the facial skin at the beginning (day 0) and end (day 29) of the study. In addition, blood samples were taken on days 0, 15, and 29 for measuring plasma levels of malondialdehyde that allowed assessing systemic oxidative stress. The results demonstrated that plasma malondialdehyde consistently decreased during astaxanthin consumption (by 11.2% on day 15 and by 21.7% on day 29). The analysis of RSSC samples has revealed significantly decreased levels of corneocyte desquamation (P=.0075) and microbial presence (P=.0367) at the end of the study. These phenomena as well as a significant (P=.0214) increase in lipid droplet size were more strongly manifested among obese (body mass index >30 kg/m2) subjects. All described RSSC changes correspond to a shift toward characteristics of skin associated with a younger age. The results confirm our hypothesis by demonstrating that continuous astaxanthin consumption produces a strong antioxidant effect resulting in facial skin rejuvenation which is especially pronounced in obese subjects. PMID- 29246281 TI - alpha-Lipoic acid ameliorated oxidative stress induced by perilla oil, but the combination of these dietary factors was ineffective to cause marked deceases in serum lipid levels in rats. AB - Dietary perilla oil rich in alpha-linolenic acid and alpha-lipoic acid lowers the serum lipid level through changes in hepatic fatty acid metabolism. We therefore hypothesized that the combination of these dietary factors may ameliorate lipid metabolism more than the factors individually. Moreover, alpha-lipoic acid exerts strong anti-oxidative activity. Hence, we also hypothesized that alpha-lipoic acid may attenuate perilla oil-mediated oxidative stress. We therefore studied the combined effects of perilla oil and alpha-lipoic acid on lipid metabolism and parameters of oxidative stress. Male rats were fed diets supplemented with 0 or 2.0 g/kg R-alpha-lipoic acid and containing 120 g/kg of palm (saturated fat), corn (linoleic acid), or perilla oil (alpha-linolenic acid) for 23 days. Perilla oil compared with other fats decreased serum lipid concentrations in rats fed alpha-lipoic acid-free diets; however, the combination of perilla oil with alpha lipoic acid was ineffective for observing more marked decreases in serum lipid levels. Alterations in hepatic fatty acid synthesis and oxidation may account for the observed changes. Perilla oil, compared with palm and corn oils, strongly increased the malondialdehyde level in the serum and liver. alpha-Lipoic acid counteracted the increases in these parameters even though the effects were attenuated in the liver. alpha-Lipoic acid increased the parameters of the anti oxidant system. The results suggested that alpha-lipoic acid can ameliorate oxidative stress induced by perilla oil, but the combination of these dietary factors was ineffective for additionally reducing serum lipid levels. PMID- 29246282 TI - Impulsiveness, postprandial blood glucose, and glucoregulation affect measures of behavioral flexibility. AB - Behavioral flexibility (BF) performance is influenced by both psychological and physiological factors. Recent evidence suggests that impulsivity and blood glucose can affect executive function, of which BF is a subdomain. Here, we hypothesized that impulsivity, fasting blood glucose (FBG), glucose changes (ie, glucoregulation) from postprandial blood glucose (PBG) following the intake of a 15-g glucose beverage could account for variability in BF performance. The Stroop Color-Word Test and the Wisconsin Card Sorting Test (WCST) were used as measures of BF, and the Barratt Impulsiveness Scale (BIS-11) to quantify participants' impulsivity. In Study 1, neither impulsivity nor FBG could predict performance on the Stroop or the WCST. In Study 2, we tested whether blood glucose levels following the intake of a sugary drink, and absolute changes in glucose levels following the intake of the glucose beverage could better predict BF. Results showed that impulsivity and the difference in blood glucose between time 1 (postprandial) and time 2, but not blood glucose levels at time 2 per se could account for variation in performance on the WCST but not on the Stroop task. More specifically, lower impulsivity scores on the BIS-11, and smaller differences in blood glucose levels from time 1 to time 2 predicted a decrease in the number of total and perseverative errors on the WCST. Our results show that measures of impulsivity and glucoregulation can be used to predict BF. Importantly our data extend the work on glucose and cognition to a clinically relevant domain of cognition. PMID- 29246283 TI - Greater adherence to a Mediterranean diet is associated with lower prevalence of colorectal adenomas in men of all races. AB - To examine potential racial differences in Mediterranean diet scores and whether these differences are associated with the prevalence of colorectal adenoma (CRA), a cross-sectional analysis of data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was performed. The authors hypothesize that people consuming a more Mediterranean-like diet have lower odds of CRA. Flexible sigmoidoscopy was used to determine the presence of colorectal adenoma. Mediterranean diet scores were calculated from food frequency questionnaire responses. Logistic regression was used to determine the association between Mediterranean diet scores and the odds of prevalent CRA, as well as the joint effects of race and diet. Asians, followed by blacks, had higher Mediterranean diet scores than whites. Generally, men with better Mediterranean diet scores (altMED) had lower odds of CRA, but black and Asian men had even lower odds of prevalent CRA with better altMED diet scores than did white men with higher altMED diet scores. In this study population, all men had lower odds of prevalent CRA, but black and Asian men, who had higher (more favorable) altMED diet scores than whites, had even lower odds of prevalent CRA compared with white men. An altMED diet prescription may be especially beneficial for certain subpopulations who may be at higher risk of CRA. PMID- 29246284 TI - Consumption of alpha-linolenic acid-enriched diacylglycerol induces increase in dietary fat oxidation compared with alpha-linolenic acid-enriched triacylglycerol: A randomized, double-blind trial. AB - Fat metabolism is an important consideration in obesity. Alpha-linolenic acid enriched diacylglycerol (ALA-DAG), which mainly occurs as ALA esterifies to 1,3 diacyl-sn-glycerol (1,3-DAG), has beneficial effects on fat metabolism and body weight compared with triacylglycerol (TAG). Moreover, compared with ALA-TAG, ALA DAG enhances beta-oxidation activity in the small intestine and liver in rodents. We hypothesized that ALA-DAG consumption may increase dietary fat oxidation compared with ALA-TAG in humans. To examine this hypothesis, we conducted a randomized double-blind cross-over trial in 17 normal and moderately obese men and women (BMI: 25.7+/-2.0 kg/m2, mean+/-SD). Each participant was assigned to a 4-week intervention period with 2.5 g/day of ALA-DAG or ALA-TAG consumption, followed by a 4-week washout period between consumption of each diet. Dietary fat oxidation, assessed based on the 13CO2 recovery rate in the breath, was significantly increased by ALA-DAG consumption compared with ALA-TAG consumption (17.0+/-4.5% and 14.1+/-5.9%, respectively, P<.05). In addition, ALA-DAG consumption significantly decreased the visceral fat area compared with ALA-TAG (102.9+/-51.9 cm2 and 110.9+/-51.7 cm2, respectively; P<.05). These results indicate that ALA-DAG consumption may be useful for preventing obesity. PMID- 29246286 TI - Sixty-six years of Metabolism, Clinical and Experimental: The journey of a journal and opportunities and challenges looking ahead. PMID- 29246285 TI - Total homocysteine is positively correlated with body mass index, waist-to-hip ratio, and fat mass among overweight reproductive women: A cross-sectional study. AB - Conflicting associations between total homocysteine (tHcy), body mass index (BMI) lean body mass, and fat mass in the general population have been reported. We investigated the hypothesis that elevated tHcy levels are associated with increased BMI, waist-to-hip ratio (WHR), and body fat mass percent. In Jordan, obesity and overweight are prevalent among reproductive women and hyperhomocysteinemia, along with obesity and overweight, are independent risk factors for cardiovascular diseases. The participants used in this cross sectional study were 325 overweight Jordanian women aged between 18 and 49 years old. The main outcome measures were tHcy, BMI, WHR, fat mass, fat-free mass, and total body water. Serum tHcy was analyzed using a liquid chromatography tandem mass spectrophotometry (LC-MS/MS) complete kit. The body compositions were measured using a bioelectrical impedance analyzer. Study participants were stratified according to their tHcy level into two groups, <=10 MUmol/L and >10 MUmol/L, and the difference between mean values of body compositions was evaluated. The tHcy was significantly and negatively correlated with age, fat free mass, and total body water, and significantly and positively correlated with BMI, hip circumference, WHR, fat mass, and dry lean weight. The chi-square and the independent sample t-tests showed statistically significant (P <= .05) differences between tHcy and BMI, WHR, fat and fat-free mass, and total body water percentages. In conclusion, BMI, WHR and body fat mass were found to be associated with elevated tHcy levels among overweight reproductive women, and they might be used as independent predictors of the tHcy level. PMID- 29246287 TI - Long-Term PEDF Release in Rat Iris and Retinal Epithelial Cells after Sleeping Beauty Transposon-Mediated Gene Delivery. AB - Pigment epithelium derived factor (PEDF) is a potent antiangiogenic, neurotrophic, and neuroprotective molecule that is the endogenous inhibitor of vascular endothelial growth factor (VEGF) in the retina. An ex vivo gene therapy approach based on transgenic overexpression of PEDF in the eye is assumed to rebalance the angiogenic-antiangiogenic milieu of the retina, resulting in growth regression of choroidal blood vessels, the hallmark of neovascular age-related macular degeneration. Here, we show that rat pigment epithelial cells can be efficiently transfected with the PEDF-expressing non-viral hyperactive Sleeping Beauty transposon system delivered in a form free of antibiotic resistance marker miniplasmids. The engineered retinal and iris pigment epithelium cells secrete high (141 +/- 13 and 222 +/- 14 ng) PEDF levels in 72 hr in vitro. In vivo studies showed cell survival and insert expression during at least 4 months. Transplantation of the engineered cells to the subretinal space of a rat model of choroidal neovascularization reduces almost 50% of the development of new vessels. PMID- 29246288 TI - The lncRNA PDIA3P Interacts with miR-185-5p to Modulate Oral Squamous Cell Carcinoma Progression by Targeting Cyclin D2. AB - Long noncoding RNAs (lncRNAs) are emerging as important regulators during tumorigenesis by serving as competing endogenous RNAs (ceRNAs). In this study, the qRT-PCR results indicated that the lncRNA protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P) was overexpressed in oral squamous cell carcinoma (OSCC) and decreased the survival rate of OSCC patients. CCK-8 and clonal colony formation assays were used to detect the effects of PDIA3P on proliferation. Results revealed that silencing PDIA3P by small interfering RNA (siRNA) inhibited OSCC cell proliferation and repressed tumor growth and reduced the expression of proliferation antigen Ki-67 in vivo. Furthermore, the interaction between PDIA3P and miRNAs was then analyzed by qRT-PCR and luciferase reporter gene assay. We found that PDIA3P negatively regulated miR-185-5p in OSCC cells. Simultaneously, we found that silencing PDIA3P by siRNA suppressed proliferation via miR-185-5p in OSCC cells. Moreover, silencing PDIA3P by siRNA inhibited CCND2 protein (no influence on mRNA levels) expression via miR-185-5p in OSCC cells, and CCND2 facilitated cell proliferation of SCC4 and SCC15 cells induced by sh-PDIA3P#1. Therefore, our study demonstrated that PDIA3P may be a therapeutic target for the treatment of OSCC. PMID- 29246289 TI - Anti-tumor Activity of miniPEG-gamma-Modified PNAs to Inhibit MicroRNA-210 for Cancer Therapy. AB - MicroRNAs (miRs) are frequently overexpressed in human cancers. In particular, miR-210 is induced in hypoxic cells and acts to orchestrate the adaptation of tumor cells to hypoxia. Silencing oncogenic miRs such as miR-210 may therefore offer a promising approach to anticancer therapy. We have developed a miR-210 inhibition strategy based on a new class of conformationally preorganized antisense gamma peptide nucleic acids (gammaPNAs) that possess vastly superior RNA-binding affinity, improved solubility, and favorable biocompatibility. For cellular delivery, we encapsulated the gammaPNAs in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). Our results show that gammaPNAs targeting miR-210 cause significant delay in growth of a human tumor xenograft in mice compared to conventional PNAs. Further, histopathological analyses show considerable necrosis, fibrosis, and reduced cell proliferation in gammaPNA-treated tumors compared to controls. Overall, our work provides a chemical framework for a novel anti-miR therapeutic approach using gammaPNAs that should facilitate rational design of agents to potently inhibit oncogenic microRNAs. PMID- 29246290 TI - Aptamer-Targeted Plasmonic Photothermal Therapy of Cancer. AB - Novel nanoscale bioconjugates combining unique plasmonic photothermal properties of gold nanoparticles (AuNPs) with targeted delivery using cell-specific DNA aptamers have a tremendous potential for medical diagnostics and therapy of many cell-based diseases. In this study, we demonstrate the high anti-cancer activity of aptamer-conjugated, 37-nm spherical gold nanoparticles toward Ehrlich carcinoma in tumor-bearing mice after photothermal treatment. The synthetic anti tumor aptamers bring the nanoparticles precisely to the desired cells and selectively eliminate cancer cells after the subsequent laser treatment. To prove tumor eradication, we used positron emission tomography (PET) utilizing radioactive glucose and computer tomography, followed by histological analysis of cancer tissue. Three injections of aptamer-conjugated AuNPs and 5 min of laser irradiations are enough to make the tumor undetectable by PET. Histological analysis proves PET results and shows lower damage of healthy tissue in addition to a higher treatment efficiency and selectivity of the gold nanoparticles functionalized with aptamers in comparison to control experiments using free unconjugated nanoparticles. PMID- 29246291 TI - Tween 85-Modified Low Molecular Weight PEI Enhances Exon-Skipping of Antisense Morpholino Oligomer In Vitro and in mdx Mice. AB - We investigated a series of Tween 85 modified low molecular weight polyethylenimine (LPEI, 0.8k/1.2k/2.0k)-copolymers (Zs) through simple formulation and covalent conjugation with phosphorodiamidate morpholino oligomer (PMO) for their potential to enhance delivery in vitro and in dystrophic mdx mice. Z polymers significantly enhanced PMO-induced exon-skipping in a GFP reporter-based cell culture system. Application of optimized formulations of Zs with PMO targeted to dystrophin exon 23 demonstrated a significant increase in exon-skipping efficiency in mdx mice. Consistent with our observations in vitro, optimization of molecular size and hydropholic-lipopholic balance (HLB) of polymers are important factors to achieve enhanced PMO delivery in vivo. The best formulation of Zs enhanced PMO delivery with 20- and 6-fold over PMO alone in vitro and in vivo, respectively. Further, chemical conjugation of the polymer and PMO exhibits greater benefit than polymer/PMO simple formulation in PMO delivery efficiency. Observed cytotoxicity of the Zs was lower than Endo-porter and PEI 25k in vitro, and no tissue toxicity was clearly detected with the Zs at the dosage tested. These results indicate the potential of the Zs as effective and safe PMO delivery carriers for treating diseases such as muscular dystrophy. PMID- 29246293 TI - miR-124 Inhibits Lung Tumorigenesis Induced by K-ras Mutation and NNK. AB - Dysregulated miRNAs play important role in K-ras mutation or smoking caused lung tumorigenesis. Here, we investigate the role and mechanism of miR-124 in K-ras mutation or smoking-caused lung tumorigenesis and evaluate the therapeutic potential of miR-124 agomiR in K-ras mutation or smoking-caused lung cancer treatment. Our data show that smoking suppresses miR-124 expression, and decreased miR-124 expression is inversely correlated with the p-Akt level and predicts poor overall survival in non-small-cell lung cancer (NSCLC) patients. The overexpression of miR-124 suppressed NSCLC growth by inhibiting the Akt pathway by targeting Akt1 and Akt2. In addition, the systemic delivery of miR-124 agomiR dramatically suppressed tumorigenesis in both NNK-induced lung cancer model and K-rasLA1 transgenic mice by increasing apoptosis and inhibiting cell proliferation. Our findings suggest that smoking inhibits the expression of miR 124, and decreased miR-124 contributes to Akt activation, thereby promoting NSCLC progression. Our findings also represent a novel potential therapeutic strategy for lung cancer. PMID- 29246292 TI - Control of HIV Infection In Vivo Using Gene Therapy with a Secreted Entry Inhibitor. AB - HIV entry inhibitors are highly effective in controlling virus replication. We have developed a lentiviral vector that expresses a secreted entry inhibitor, soluble CD4 (sCD4), which binds to the HIV envelope glycoproteins and inactivates the virus. We have shown that sCD4 was secreted from gene-modified CD4+ T cells, as well as from human umbilical cord blood-derived CD34+ hematopoietic stem/progenitor cells (HSPCs), and protected unmodified HIV target cells from infection in vitro. To investigate the in vivo application of our approach, we injected gene-modified HSPCs into NOD/SCID/gammacnull (NSG) mice. NSG hosts supported multi-lineage differentiation of human gene-modified HSPCs. Upon challenge with HIV, humanized mice capable of secreting sCD4 demonstrated a reduction of viral load over time compared to control humanized mice. In contrast to gene therapy approaches that render only gene-modified HIV target cells resistant to infection, our approach also showed protection of unmodified CD4+ T cells in the peripheral blood and tissues. Our findings provide support for the continuous delivery of secreted entry inhibitors via gene therapy as an alternative to oral administration of antiretroviral drugs or injection of antiretroviral proteins, including antibodies. PMID- 29246294 TI - Rational Design of Short Locked Nucleic Acid-Modified 2'-O-Methyl Antisense Oligonucleotides for Efficient Exon-Skipping In Vitro. AB - Locked nucleic acid is a prominent nucleic acid analog with unprecedented target binding affinity to cDNA and RNA oligonucleotides and shows remarkable stability against nuclease degradation. Incorporation of locked nucleic acid nucleotides into an antisense oligonucleotide (AO) sequence can reduce the length required without compromising the efficacy. In this study, we synthesized a series of systematically truncated locked nucleic acid-modified 2'-O-methyl AOs on a phosphorothioate (PS) backbone that were designed to induce skipping exon 23 from the dystrophin transcript in H-2Kb-tsA58 mdx mouse myotubes in vitro. The results clearly demonstrated that shorter AOs (16- to 14-mer) containing locked nucleic acid nucleotides efficiently induced dystrophin exon 23 skipping compared with the corresponding 2'-O-methyl AOs. Our remarkable findings contribute significantly to the existing knowledge about the designing of short LNA-modified oligonucleotides for exon-skipping applications, which will help reduce the cost of exon-skipping AOs and potential toxicities, particularly the 2'-OMe-based oligos, by further reducing the length of AOs. PMID- 29246295 TI - Role of Cell-Penetrating Peptides in Intracellular Delivery of Peptide Nucleic Acids Targeting Hepadnaviral Replication. AB - Peptide nucleic acids (PNAs) are potentially attractive antisense agents against hepatitis B virus (HBV), although poor cellular uptake limits their therapeutic application. In the duck HBV (DHBV) model, we evaluated different cell penetrating peptides (CPPs) for delivery to hepatocytes of a PNA-targeting hepadnaviral encapsidation signal (epsilon). This anti-epsilon PNA exhibited sequence-specific inhibition of DHBV RT in a cell-free system. Investigation of the best in vivo route of delivery of PNA conjugated to (D-Arg)8 (P1) showed that intraperitoneal injection to ducklings was ineffective, whereas intravenously (i.v.) injected fluorescein-P1-PNA reached the hepatocytes. Treatment of virus carriers with i.v.-administered P1-PNA resulted in a decrease in viral DNA compared to untreated controls. Surprisingly, a similar inhibition of viral replication was observed in vivo as well as in vitro in primary hepatocyte cultures for a control 2 nt mismatched PNA conjugated to P1. By contrast, the same PNA coupled to (D-Lys)4 (P2) inhibited DHBV replication in a sequence specific manner. Interestingly, only P1, but not P2, displayed anti-DHBV activity in the absence of PNA cargo. Hence, we provide new evidence that CPP-PNA conjugates inhibit DHBV replication following low-dose administration. Importantly, our results demonstrate the key role of CPPs used as vehicles in antiviral specificity of CPP-PNA conjugates. PMID- 29246296 TI - Antisense Oligonucleotides Targeting Y-Box Binding Protein-1 Inhibit Tumor Angiogenesis by Downregulating Bcl-xL-VEGFR2/-Tie Axes. AB - Y-box binding protein-1 (YB-1), involved in cancer progression and chemoradiation resistance, is overexpressed in not only cancer cells but also tumor blood vessels. In this study, we investigated the potential value of amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting YB-1 (YB 1 ASOA) as an antiangiogenic cancer therapy. YB-1 ASOA was superior to natural DNA-based ASO or locked nucleic acid (LNA)-modified YB-1 ASO in both knockdown efficiency and safety, the latter assessed by liver function. YB-1 ASOA administered i.v. significantly inhibited YB-1 expression in CD31-positive angiogenic endothelial cells, but not in cancer cells, in the tumors. With regard to the mechanism of its antiangiogenic effects, YB-1 ASOA downregulated both Bcl xL/VEGFR2 and Bcl-xL/Tie signal axes, which are key regulators of angiogenesis, and induced apoptosis in vascular endothelial cells. In the xenograft tumor model that had low sensitivity to anti-VEGF antibody, YB-1 ASOA significantly suppressed tumor growth; not only VEGFR2 but also Tie2 expression was decreased in tumor vessels. In conclusion, YB-1/Bcl-xL/VEGFR2 and YB-1/Bcl-xL/Tie signal axes play pivotal roles in tumor angiogenesis, and YB-1 ASOA may be feasible as an antiangiogenic therapy for solid tumors. PMID- 29246297 TI - Distinct Expression Profiles and Novel Targets of MicroRNAs in Human Spermatogonia, Pachytene Spermatocytes, and Round Spermatids between OA Patients and NOA Patients. AB - Human spermatogenesis includes three main stages, namely, the mitosis of spermatogonia, meiosis of spermatocytes, and spermiogenesis of spermatids, which are precisely regulated by epigenetic and genetic factors. Abnormality of epigenetic and genetic factors can result in aberrant spermatogenesis and eventual male infertility. However, epigenetic regulators in controlling each stage of normal and abnormal human spermatogenesis remain unknown. Here, we have revealed for the first time the distinct microRNA profiles in human spermatogonia, pachytene spermatocytes, and round spermatids between obstructive azoospermia (OA) patients and non-obstructive azoospermia (NOA) patients. Human spermatogonia, pachytene spermatocytes, and round spermatids from OA patients and NOA patients were isolated using STA-PUT velocity sedimentation and identified by numerous hallmarks for these cells. RNA deep sequencing showed that 396 microRNAs were differentially expressed in human spermatogonia between OA patients and NOA patients and 395 differentially expressed microRNAs were found in human pachytene spermatocytes between OA patients and NOA patients. Moreover, 378 microRNAs were differentially expressed in human round spermatids between OA patients and NOA patients. The differential expression of numerous microRNAs identified by RNA deep sequencing was verified by real-time PCR. Moreover, a number of novel targeting genes for microRNAs were predicted using various kinds of software and further verified by real-time PCR. This study thus sheds novel insights into epigenetic regulation of human normal spermatogenesis and the etiology of azoospermia, and it could offer new targets for molecular therapy to treat male infertility. PMID- 29246299 TI - A New Long Noncoding RNA ALB Regulates Autophagy by Enhancing the Transformation of LC3BI to LC3BII during Human Lens Development. AB - Autophagy is essential in lens organelle degradation. This study aimed to seek potential autophagy-associated long noncoding RNAs (lncRNAs) and their relative mechanisms in human lens development using the "fried egg" lentoid body (LB) generation system. The expression pattern of LC3B in differentiating LBs was similar to that in developing a mouse lens in vivo. Among the massive lncRNAs expressed with a significant difference between induced pluripotent stem cells (iPSCs) and LBs, lncRNA affecting LC3B (ALB), which was predicted to have a co relationship with the autophagy marker LC3B, was highly expressed in differentiating lens fibers in LBs. This result was consistent with its high expression in human embryonic lenses compared to those in embryonic stem cells (ESCs). Furthermore, lncRNA ALB knockdown resulted in the downregulation of LC3BII at the protein level, therefore inhibiting the autophagy process in human lens epithelial cells (HLECs). Our results identify lncRNA ALB, a potential autophagy regulator in organelle degradation during human lens development, highlighting the importance of lncRNAs in lens development. PMID- 29246298 TI - Alleviation of Toxicity Caused by Overactivation of Pparalpha through Pparalpha Inducible miR-181a2. AB - Widely varied compounds, including certain plasticizers, hypolipidemic drugs (e.g., ciprofibrate, fenofibrate, WY-14643, and clofibrate), agrochemicals, and environmental pollutants, are peroxisome proliferators (PPs). Appropriate dose of PPs causes a moderate increase in the number and size of peroxisomes and the expression of genes encoding peroxisomal lipid-metabolizing enzymes. However, high-dose PPs cause varied harmful effects. Chronic administration of PPs to mice and rats results in hepatomegaly and ultimately carcinogenesis. Nuclear receptor protein peroxisome proliferator-activated receptor-alpha (Pparalpha) was shown to be required for this process. However, biological adaptations to minimize this risk are poorly understood. In this study, we found that miR-181a2 expression was induced by the Pparalpha agonist WY-14643. Moreover, exogenous expression of miR 181a-5p dramatically alleviated the cell toxicity caused by overactivation of Pparalpha. Further studies showed that miR-181a-5p directly targeted the Pparalpha 3' untranslated region and depressed the Pparalpha protein level. This study identified a feedback loop between miR-181a-5p and Pparalpha, which allows biological systems to approach a balance when Pparalpha is overactivated. PMID- 29246300 TI - The Bioactivity of D-/L-Isonucleoside- and 2'-Deoxyinosine-Incorporated Aptamer AS1411s Including DNA Replication/MicroRNA Expression. AB - In this study, chemical modification of 2'-deoxyinosine (2'-dI) and D-/L isothymidine (D-/L-isoT) was performed on AS1411. They could promote the nucleotide-protein interaction by changing the local conformation. Twenty modified sequences were obtained, FCL-I and FCL-II showed the most noticeable activity improvement. They stabilized the G-quadruplex, remained highly resistant to serum degradation and specificity for nucleolin, further inhibited tumor cell growth, exhibited a stronger ability to influence the different phases of the tumor cell cycle, induced S-phase arrest, promoted the inhibition of DNA replication, and suppressed the unwound function of a large T antigen as powerful as AS1411. The microarray analysis and TaqMan PCR results showed that FCL-II can upregulate the expression of four breast-cancer-related, lowly expressed miRNAs and downregulate the expression of three breast-cancer-related, highly expressed miRNAs (>2.5-fold). FCL-II resulted in enhanced treatment effects greater than AS1411 in animal experiments (p < 0.01). The computational results further proved that FCL-II exhibits more structural advantages than AS1411 for binding to the target protein nucleolin, indicating its great potential in antitumor therapy. PMID- 29246301 TI - Profiling the Mismatch Tolerance of Argonaute 2 through Deep Sequencing of Sliced Polymorphic Viral RNAs. AB - Low allelic and clonal variability among endogenous RNAi targets has focused mismatch tolerance studies to RNAi-active guide strands. However, the inherent genomic instability of RNA viruses such as hepatitis C virus (HCV) gives rise to quasi-species mutants within discrete clones: this facilitates mismatch tolerance studies from a target perspective. We recently quantified the slicing imprecision of Argonaute 2 using small interfering RNA (siRNA) analogs of the DNA-directed RNAi drug TT-034 and next-generation sequencing of 5' RNA ligase-mediated rapid amplification of cDNA ends (RACE-SEQ). Here, we present an open-source, customizable, and computationally light RACE-SEQ bioinformatic pipeline, describing adaptations that semiquantitatively report the impact of RNAi hybridization site mismatches from the target perspective. The analysis shows that Argonaute 2 has a substitution-specific, 3- to 5-log activity window between fully complementary targets and targets with mismatches across positions 10-11. It further focuses the endonucleotic Slicer imprecision around positions 13-17, demonstrating its dependence on guide strand central region complementarity, and potentiation by even a single mismatch. We further propose pharmacogenomics value in testing endogenous targets using recombinant replicon systems and RACE-SEQ to report the pharmacodynamics of sequence-specific oligonucleotide therapeutics against all possible polymorphisms in a population, in a minimally biased, patient-free manner. PMID- 29246303 TI - Site-Specific Modification Using the 2'-Methoxyethyl Group Improves the Specificity and Activity of siRNAs. AB - Rapid progress has been made toward small interfering RNA (siRNA)-based therapy for human disorders, but rationally optimizing siRNAs for high specificity and potent silencing remains a challenge. In this study, we explored the effect of chemical modification at the cleavage site of siRNAs. We found that modifications at positions 9 and 10 markedly reduced the silencing potency of the unmodified strand of siRNAs but were well tolerated by the modified strand. Intriguingly, addition of the 2'-methoxyethyl (MOE) group at the cleavage site improved both the specificity and silencing activity of siRNAs by facilitating the oriented RNA induced silencing complex (RISC) loading of the modified strand. Furthermore, we combined MOE modifications at positions 9 and 10 of one strand together with 2'-O methylation (OMe) at position 14 of the other strand and found a synergistic effect that improved the specificity of siRNAs. The surprisingly beneficial effect of the combined modification was validated using siRNA-targeting endogenous gene intercellular adhesion molecule 1 (ICAM1). We found that the combined modifications eliminated its off-target effects. In conclusion, we established effective strategies to optimize siRNAs using site-specific MOE modifications. The findings may allow the creation of superior siRNAs for therapy in terms of activity and specificity. PMID- 29246304 TI - Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models. AB - Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK) has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER), and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.]) administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer. PMID- 29246305 TI - Induced-Decay of Glycine Decarboxylase Transcripts as an Anticancer Therapeutic Strategy for Non-Small-Cell Lung Carcinoma. AB - Self-renewing tumor-initiating cells (TICs) are thought to be responsible for tumor recurrence and chemo-resistance. Glycine decarboxylase, encoded by the GLDC gene, is reported to be overexpressed in TIC-enriched primary non-small-cell lung carcinoma (NSCLC). GLDC is a component of the mitochondrial glycine cleavage system, and its high expression is required for growth and tumorigenic capacity. Currently, there are no therapeutic agents against GLDC. As a therapeutic strategy, we have designed and tested splicing-modulating steric hindrance antisense oligonucleotides (shAONs) that efficiently induce exon skipping (half maximal inhibitory concentration [IC50] at 3.5-7 nM), disrupt the open reading frame (ORF) of GLDC transcript (predisposing it for nonsense-mediated decay), halt cell proliferation, and prevent colony formation in both A549 cells and TIC enriched NSCLC tumor sphere cells (TS32). One candidate shAON causes 60% inhibition of tumor growth in mice transplanted with TS32. Thus, our shAONs candidates can effectively inhibit the expression of NSCLC-associated metabolic enzyme GLDC and may have promising therapeutic implications. PMID- 29246302 TI - CRISPR/Cas9 Genome-Editing System in Human Stem Cells: Current Status and Future Prospects. AB - Genome-editing involves the insertion, deletion, or replacement of DNA in the genome of a living organism using "molecular scissors." Traditional genome editing with engineered nucleases for human stem cells is limited by its low efficiency, high cost, and poor specificity. The CRISPR system has recently emerged as a powerful gene manipulation technique with advantages of high editing efficiency and low cost. Although this technique offers huge potential for gene manipulation in various organisms ranging from prokaryotes to higher mammals, there remain many challenges in human stem cell research. In this review, we highlight the basic biology and application of the CRISPR/Cas9 system in current human stem cell research, discuss its advantages and challenges, and debate the future prospects for human stem cells in regenerative medicine. PMID- 29246306 TI - Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common and aggressive malignancies worldwide. Treatment outcomes remain poor mainly due to lack of good diagnostic/prognostic markers and limited therapeutic strategies. We previously characterized aberrant activation of the TF/FVII/PAR2 pathway, which subsequently results in decreased autophagy, as a crucial event in malignant progression of HCC. Here, we identified miR-135a as a highly upregulated miRNA in HCC in response to TF/FVII/PAR2 activation. Analyzing 103 HCC patient specimens, we confirmed that miR-135a was frequently elevated in HCC tissues with higher FVII expression compared to adjacent non-cancerous counterparts. Increased miR-135a levels in HCC were also associated with tumor staging, recurrence, microvascular invasion, and decreased disease-free survival. We subsequently identified Atg14, a key component that regulates the formation of autophagosome as a direct target of miR-135a. Ectopic expression of miR-135a suppressed Atg14 levels and inhibited the autophagic processes. Our results indicate strong positive correlations between miR-135a levels and malignant behaviors in HCC patients and also suggest novel functions of miR-135a in regulation of autophagy, which could be useful as a potential target for prognostic and therapeutic uses. PMID- 29246307 TI - An Albumin-Oligonucleotide Assembly for Potential Combinatorial Drug Delivery and Half-Life Extension Applications. AB - The long blood circulatory property of human serum albumin, due to engagement with the cellular recycling neonatal Fc receptor (FcRn), is an attractive drug half-life extension enabling technology. This work describes a novel site specific albumin double-stranded (ds) DNA assembly approach, in which the 3' or 5' end maleimide-derivatized oligodeoxynucleotides are conjugated to albumin cysteine at position 34 (cys34) and annealed with complementary strands to allow single site-specific protein modification with functionalized ds oligodeoxynucleotides. Electrophoretic gel shift assays demonstrated successful annealing of complementary strands bearing Atto488, 6-carboxyfluorescein (6-FAM), or a factor IXa aptamer to the albumin-oligodeoxynucleotide conjugate. A fluorometric factor IXa activity assay showed retained aptamer inhibitory activity upon assembly with the albumin and completely blocked factor IXa at a concentration of 100 nM for 2 hr. The assembled construct exhibited stability in serum-containing buffer and FcRn engagement that could be increased using an albumin variant engineered for higher FcRn affinity. This work presents a novel albumin-oligodeoxynucleotide assembly technology platform that offers potential combinatorial drug delivery and half-life extension applications. PMID- 29246308 TI - miR-3174 Contributes to Apoptosis and Autophagic Cell Death Defects in Gastric Cancer Cells by Targeting ARHGAP10. AB - Gastric cancer (GC) is a major health problem worldwide because of its high morbidity and mortality. Considering the well-established roles of miRNA in the regulation of GC carcinogenesis and progression, we screened differentially expressed microRNAs (miRNAs) by using The Cancer Genome Atlas (TCGA) and the GEO databases. We found that miR-3174 was the most significantly differentially expressed miRNA in GC. Ectopic miR-3174 expression was also detected in clinical GC patient samples and cell lines and associated with poor patient prognosis. Apoptosis and autophagic cell death are two types of programmed cell death, whereas both are deficient in gastric cancer. Our functional analyses demonstrated that miR-3174 inhibited mitochondria-dependent apoptosis and autophagic cell death in GC. Moreover, high expression of miR-3174 also resulted in Cisplatin resistance in GC cells. Using bioinformatics analyses combined with in vitro and in vivo experiments, we determined that miR-3174 directly targets ARHGAP10. Notably, ARHGAP10 promoted mitochondria-dependent apoptosis by enhancing p53 expression, which was followed by Bax trans-activation and caspase cleavage. ARHGAP10 also facilitated autophagic cell death by suppressing mammalian target of rapamycin complex 1 (mTOC1) activity. Our results reveal a potential miRNA-based clinical therapeutic target that may also serve as a predictive marker for GC. PMID- 29246309 TI - Fine and Predictable Tuning of TALEN Gene Editing Targeting for Improved T Cell Adoptive Immunotherapy. AB - Using a TALEN-mediated gene-editing approach, we have previously described a process for the large-scale manufacturing of "off-the-shelf" CAR T cells from third-party donor T cells by disrupting the gene encoding TCRalpha constant chain (TRAC). Taking advantage of a previously described strategy to control TALEN targeting based on the exclusion capacities of non-conventional RVDs, we have developed highly efficient and specific nucleases targeting a key T cell immune checkpoint, PD-1, to improve engineered CAR T cells' functionalities. Here, we demonstrate that this approach allows combined TRAC and PDCD1 TALEN processing at the desired locus while eliminating low-frequency off-site processing. Thus, by replacing few RVDs, we provide here an easy and rapid redesign of optimal TALEN combinations. We anticipate that this method can greatly benefit multiplex editing, which is of key importance especially for therapeutic applications where high editing efficiencies need to be associated with maximal specificity and safety. PMID- 29246311 TI - CRISPR/Cas9: A Potential Life-Saving Tool. What's next? PMID- 29246310 TI - Inhibition of Murine Cytomegalovirus Infection in Animals by RNase P-Associated External Guide Sequences. AB - External guide sequence (EGS) RNAs are associated with ribonuclease P (RNase P), a tRNA processing enzyme, and represent promising agents for gene-targeting applications as they can direct RNase-P-mediated cleavage of a target mRNA. Using murine cytomegalovirus (MCMV) as a model system, we examined the antiviral effects of an EGS variant, which was engineered using in vitro selection procedures. EGSs were used to target the shared mRNA region of MCMV capsid scaffolding protein (mCSP) and assemblin. In vitro, the EGS variant was 60 times more active in directing RNase P cleavage of the target mRNA than the EGS originating from a natural tRNA. In MCMV-infected cells, the variant reduced mCSP expression by 92% and inhibited viral growth by 8,000-fold. In MCMV-infected mice hydrodynamically transfected with EGS-expressing constructs, the EGS variant was more effective in reducing mCSP expression, decreasing viral production, and enhancing animal survival than the EGS originating from a natural tRNA. These results provide direct evidence that engineered EGS variants with higher targeting activity in vitro are also more effective in reducing gene expression in animals. Furthermore, our findings imply the possibility of engineering potent EGS variants for therapy of viral infections. PMID- 29246312 TI - CRISPR/Cas9-Mediated Deletion of CTG Expansions Recovers Normal Phenotype in Myogenic Cells Derived from Myotonic Dystrophy 1 Patients. AB - Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy, characterized by progressive myopathy, myotonia, and multi-organ involvement. This dystrophy is an inherited autosomal dominant disease caused by a (CTG)n expansion within the 3' untranslated region of the DMPK gene. Expression of the mutated gene results in production of toxic transcripts that aggregate as nuclear foci and sequester RNA-binding proteins, resulting in mis-splicing of several transcripts, defective translation, and microRNA dysregulation. No effective therapy is yet available for treatment of the disease. In this study, myogenic cell models were generated from myotonic dystrophy patient-derived fibroblasts. These cells exhibit typical disease-associated ribonuclear aggregates, containing CUG repeats and muscleblind-like 1 protein, and alternative splicing alterations. We exploited these cell models to develop new gene therapy strategies aimed at eliminating the toxic mutant repeats. Using the CRISPR/Cas9 gene-editing system, the repeat expansions were removed, therefore preventing nuclear foci formation and splicing alterations. Compared with the previously reported strategies of inhibition/degradation of CUG expanded transcripts by various techniques, the advantage of this approach is that affected cells can be permanently reverted to a normal phenotype. PMID- 29246313 TI - Assessment of the Drug Interaction Potential of Unconjugated and GalNAc3 Conjugated 2'-MOE-ASOs. AB - Antisense oligonucleotides are metabolized by nucleases and drug interactions with small drug molecules at either the cytochrome P450 (CYP) enzyme or transporter levels have not been observed to date. Herein, a comprehensive in vitro assessment of the drug-drug interaction (DDI) potential was carried out with four 2'-O-(2-methoxyethyl)-modified antisense oligonucleotides (2'-MOE ASOs), including a single triantennary N-acetyl galactosamine (GalNAc3) conjugated ASO. Several investigations to describe the DDI potential of a 2'-MOE ASO conjugated to a high-affinity ligand for hepatocyte-specific asialoglycoprotein receptors are explored. The inhibition on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 and induction on CYP1A2, CYP2B6, and CYP3A4 were investigated in cryopreserved hepatocytes using up to 100 MUM of each ASO. No significant inhibition (half maximal inhibitory concentration [IC50] > 100 MUM) or induction was observed based on either enzymatic phenotype or mRNA levels. In addition, transporter interaction studies were conducted with nine major transporters per recommendations from regulatory guidances and included three hepatic uptake transporters, organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B1 (OATP1B1), and OATP1B3; three renal uptake transporters, organic anion transporter 1 (OAT1), OAT3, and OCT2; and three efflux transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump (BSEP). None of the four ASOs (10 MUM) were substrates of any of the nine transporters, with uptake <2-fold compared to controls, and efflux ratios were below 2.0 for BCRP and P-gp. Additionally, neither of the four ASOs showed meaningful inhibition on any of the nine transporters tested, with the mean percent inhibition ranging from -38.3% to 24.2% with 100 MUM ASO. Based on these findings, the unconjugated and GalNAc3 conjugated 2'-MOE-ASOs would have no or minimal DDI with small drug molecules via any major CYP enzyme or drug transporters at clinically relevant exposures. PMID- 29246315 TI - Targeting Herpes Simplex Virus-1 gD by a DNA Aptamer Can Be an Effective New Strategy to Curb Viral Infection. AB - Herpes simplex virus type 1 (HSV-1) is an important factor for vision loss in developed countries. A challenging aspect of the ocular infection by HSV-1 is that common treatments, such as acyclovir, fail to provide effective topical remedies. Furthermore, it is not very clear whether the viral glycoproteins, required for HSV-1 entry into the host, can be targeted for an effective therapy against ocular herpes in vivo. Here, we demonstrate that HSV-1 envelope glycoprotein gD, which is essential for viral entry and spread, can be specifically targeted by topical applications of a small DNA aptamer to effectively control ocular infection by the virus. Our 45-nt-long DNA aptamer showed high affinity for HSV-1 gD (binding affinity constant [Kd] = 50 nM), which is strong enough to disrupt the binding of gD to its cognate host receptors. Our studies showed significant restriction of viral entry and replication in both in vitro and ex vivo studies. In vivo experiments in mice also resulted in loss of ocular infection under prophylactic treatment and statistically significant lower infection under therapeutic modality compared to random DNA controls. Thus, our studies validate the possibility that targeting HSV-1 entry glycoproteins, such as gD, can locally reduce the spread of infection and define a novel DNA aptamer based approach to control HSV-1 infection of the eye. PMID- 29246314 TI - Characterization and Molecular Mechanism of Peptide-Conjugated Gold Nanoparticle Inhibiting p53-HDM2 Interaction in Retinoblastoma. AB - Inhibition of the interaction between p53 and HDM2 is an effective therapeutic strategy in cancers that harbor a wild-type p53 protein such as retinoblastoma (RB). Nanoparticle-based delivery of therapeutic molecules has been shown to be advantageous in localized delivery, including to the eye, by overcoming ocular barriers. In this study, we utilized biocompatible gold nanoparticles (GNPs) to deliver anti-HDM2 peptide to RB cells. Characterization studies suggested that GNP-HDM2 was stable in biologically relevant solvents and had optimal cellular internalization capability, the primary requirement of any therapeutic molecule. GNP-HDM2 treatment in RB cells in vitro suggested that they function by arresting RB cells at the G2M phase of the cell cycle and initiating apoptosis. Analysis of molecular changes in GNP-HDM2-treated cells by qRT-PCR and western blotting revealed that the p53 protein was upregulated; however, transactivation of its downstream targets was minimal, except for the PUMA-BCl2 and Bax axis. Global gene expression and in silico bioinformatic analysis of GNP-HDM2-treated cells suggested that upregulation of p53 might presumptively mediate apoptosis through the induction of p53-inducible miRNAs. PMID- 29246316 TI - As Technologies for Nucleotide Therapeutics Mature, Products Emerge. AB - The long path from initial research on oligonucleotide therapies to approval of antisense products is not unfamiliar. This lag resembles those encountered with monoclonal antibodies, gene therapies, and many biological targets and is consistent with studies of innovation showing that technology maturation is a critical determinant of product success. We previously described an analytical model for the maturation of biomedical research, demonstrating that the efficiency of targeted and biological development is connected to metrics of technology growth. The present work applies this model to characterize the advance of oligonucleotide therapeutics. We show that recent oligonucleotide product approvals incorporate technologies and targets that are past the established point of technology growth, as do most of the oligonucleotide products currently in phase 3. Less mature oligonucleotide technologies, such as miRNAs and some novel gene targets, have not passed the established point and have not yielded products. This analysis shows that oligonucleotide product development has followed largely predictable patterns of innovation. While technology maturation alone does not ensure success, these data show that many oligonucleotide technologies are sufficiently mature to be considered part of the arsenal for therapeutic development. These results demonstrate the importance of technology assessment in strategic management of biomedical technologies. PMID- 29246317 TI - Shrimp miR-34 from Shrimp Stress Response to Virus Infection Suppresses Tumorigenesis of Breast Cancer. AB - During host stress response against virus infection, some animal microRNAs (miRNAs) can be upregulated to restore the virus-caused metabolic disorder of host cells via suppressing the expressions of miRNAs' target genes. These antiviral miRNAs may have antitumor capacity, because tumorigenesis results from metabolic disorder of cells. However, this subject has not been explored. In this study, the results showed that shrimp miR-34, which was upregulated during white spot syndrome virus (WSSV) infection, had antiviral activity in shrimp. The expression of shrimp miR-34 in breast cancer cells and in mice suppressed the growth and metastasis of breast cancer by targeting human CCND1, CDK6, CCNE2, E2F3, FOSL1, and MET genes in a cross-phylum manner. The results of this study indicated that miRNAs with antiviral activities can be promising sources for antitumor drug discovery. PMID- 29246319 TI - Link between MHC Fiber Type and Restoration of Dystrophin Expression and Key Components of the DAPC by Tricyclo-DNA-Mediated Exon Skipping. AB - Exon skipping mediated by tricyclo-DNA (tc-DNA) antisense oligonucleotides has been shown to induce significant levels of dystrophin restoration in mdx, a mouse model of Duchenne muscular dystrophy. This translates into significant improvement in key disease indicators in muscle, cardio-respiratory function, heart, and the CNS. Here we examine the relationship between muscle fiber type, based on myosin heavy chain (MHC) profile, and the ability of tc-DNA to restore not only dystrophin but also other members of the dystrophin-associated glycoprotein complex (DAPC). We first profiled this relationship in untreated mdx muscle, and we found that all fiber types support reversion events to a dystrophin-positive state, in an unbiased manner. Importantly, we show that only a small fraction of revertant fibers expressed other members of the DAPC. Immunoblot analysis of protein levels, however, revealed robust expression of these components, which failed to correctly localize to the sarcolemma. We then show that tc-DNA treatment leads to nearly all fibers expressing not only dystrophin but also other key components of the DAPC. Of significance, our work shows that MHC fiber type does not bias the expression of any of these important proteins. This work also highlights that the improved muscle physiology following tc-DNA treatment reported previously results from the complete restoration of the dystrophin complex in all MHCII fibers with equal efficiencies. PMID- 29246318 TI - Size, Shape, and Sequence-Dependent Immunogenicity of RNA Nanoparticles. AB - RNA molecules have emerged as promising therapeutics. Like all other drugs, the safety profile and immune response are important criteria for drug evaluation. However, the literature on RNA immunogenicity has been controversial. Here, we used the approach of RNA nanotechnology to demonstrate that the immune response of RNA nanoparticles is size, shape, and sequence dependent. RNA triangle, square, pentagon, and tetrahedron with same shape but different sizes, or same size but different shapes were used as models to investigate the immune response. The levels of pro-inflammatory cytokines induced by these RNA nanoarchitectures were assessed in macrophage-like cells and animals. It was found that RNA polygons without extension at the vertexes were immune inert. However, when single-stranded RNA with a specific sequence was extended from the vertexes of RNA polygons, strong immune responses were detected. These immunostimulations are sequence specific, because some other extended sequences induced little or no immune response. Additionally, larger-size RNA square induced stronger cytokine secretion. 3D RNA tetrahedron showed stronger immunostimulation than planar RNA triangle. These results suggest that the immunogenicity of RNA nanoparticles is tunable to produce either a minimal immune response that can serve as safe therapeutic vectors, or a strong immune response for cancer immunotherapy or vaccine adjuvants. PMID- 29246320 TI - Skin Delivery of Clec4a Small Hairpin RNA Elicited an Effective Antitumor Response by Enhancing CD8+ Immunity In Vivo. AB - Clec4a has been reported to be an immune suppressor of dendritic cells (DCs), but its potential role in cancer therapy remains to be elucidated. The present study investigated whether downregulating the expression of Clec4a via skin delivery of small hairpin RNA (shRNA) using a gene gun produced stronger host immunity and inhibited tumor progression in animal models. Administration of Clec4a2 shRNA delayed tumor growth in both mouse bladder and lung tumor-bearing mouse models. The result was further confirmed with a compensation experiment showing that the antitumor effects induced by Clec4a2 shRNA were restored by co-injection of a plasmid expressing exogenous Clec4a2. Increased numbers of infiltrating CD4+ and CD8+ T cells at tumor sites were observed in mice treated with Clec4a2 shRNA. Splenocytes from mice with Clec4a2 shRNA administration exhibited stronger cytotoxic activity compared with splenocytes from control mice. CD8-deletion in vivo abrogated the antitumor effects elicited by Clec4a2 shRNA. Additionally, shClec4a enhanced the antitumor effects of the Neu DNA vaccine in the MBT-2 tumor model. In summary, the findings provide evidence that silencing of Clec4a2 expression via skin delivery of shRNA produces an effective antitumor response and that Clec4a2 shRNA may have therapeutic potential as an adjuvant for cancer immunotherapy. PMID- 29246321 TI - Blockade of Inflammation and Apoptosis Pathways by siRNA Prolongs Cold Preservation Time and Protects Donor Hearts in a Porcine Model. AB - In donor hearts from mini pigs, overtime cold preservation and ischemia reperfusion injury cause poor graft quality and impaired heart function. Blockage of complement, apoptosis, and inflammation is considered a strategy for attenuating ischemia-reperfusion injury and protecting cardiac function. Minipig donor hearts were perfused and preserved in Celsior solution or transfection reagent containing Celsior solution with scramble siRNA or siRNAs targeting complement 3, caspase-8, caspase-3, and nuclear factor kappaB-p65 genes at 4 degrees C and subsequently hemo-reperfused ex vivo (38 degrees C) or transplanted into recipients. The protective effect of the siRNA solution was evaluated by measuring cell apoptosis, structural alteration, protein markers for tissue damage and oxidative stress, and cardiac function. We found a reduction in cell apoptosis, myocardial damage, and tissue inflammation by reduced biochemistry and markers and protein expression of proinflammatory cytokines and improvement in cardiac function, as shown by the improved hemodynamic indices in 12-hr-preserved siRNA-treated hearts of both ex vivo and orthotopic transplantation models. These findings demonstrate that blockade of inflammation and apoptosis pathways using siRNA can prolong cold preservation time and better protect donor heart function in cardiac transplantation of large animals, which may be beneficial for human heart preservation. PMID- 29246322 TI - Long Noncoding RNA HCAL Facilitates the Growth and Metastasis of Hepatocellular Carcinoma by Acting as a ceRNA of LAPTM4B. AB - Long noncoding RNAs (lncRNAs) are a new class of regulatory noncoding RNAs. Emerging evidences indicate that lncRNAs play a critical role in the development of hepatocellular carcinoma (HCC). Although several lncRNAs have been annotated, the association of most lncRNAs with HCC is unknown. In this study, we investigated lncRNA alterations in HCC by performing lncRNA microarray analysis. We identified a novel lncRNA called HCC-associated lncRNA (HCAL) that was highly expressed in HCC tissues. HCAL upregulation was clinically associated with poor differentiation, intravascular cancer embolus, and decreased survival of patients with HCC. HCAL silencing significantly inhibited the growth and metastasis of HCC cells both in vitro and in vivo. Interestingly, transcriptome-sequencing analysis of HCAL-knockdown cells showed alterations in some cancer-related pathways. Mechanistically, HCAL directly interacted with and functioned as a sponge for microRNAs such as miR-15a, miR-196a, and miR-196b to modulate LAPTM4B expression. Taken together, our findings suggest the presence of a novel lncRNA-miRNA-mRNA regulatory network, i.e., the HCAL-miR-15a/miR-196a/miR-196b-LAPTM4B network, in HCC and indicate that HCAL may be a potential target for treating HCC. PMID- 29246324 TI - Polyethylenimine Nanoparticle-Mediated siRNA Delivery to Reduce alpha-Synuclein Expression in a Model of Parkinson's Disease. AB - RNA interference (RNAi)-based strategies that mediate the specific knockdown of target genes by administration of small interfering RNAs (siRNAs) could be applied for treatment of presently incurable neurodegenerative diseases such as Parkinson's disease. However, inefficient delivery of siRNA into neurons hampers in vivo application of RNAi. We have previously established the 4-12 kDa branched polyethylenimine (PEI) F25-LMW with superior transfection efficacy for delivery of siRNA in vivo. Here, we present that siRNA complexed with this PEI extensively distributes across the CNS down to the lumbar spinal cord after a single intracerebroventricular infusion. siRNA against alpha-synuclein (SNCA), a pre synaptic protein that aggregates in Parkinson's disease, was complexed with PEI F25-LMW and injected into the lateral ventricle of mice overexpressing human wild type SNCA (Thy1-aSyn mice). Five days after the single injection of 0.75 MUg PEI/siRNA, SNCA mRNA expression in the striatum was reduced by 65%, accompanied by reduction of SNCA protein by ~50%. Mice did not show signs of toxicity or adverse effects. Moreover, ependymocytes and brain parenchyma were completely preserved and free of immune cell invasion, astrogliosis, or microglial activation. Our results support the efficacy and safety of PEI nanoparticle mediated delivery of siRNA to the brain for therapeutic intervention. PMID- 29246323 TI - Triptolide Restores Autophagy to Alleviate Diabetic Renal Fibrosis through the miR-141-3p/PTEN/Akt/mTOR Pathway. AB - Fibrosis is the major pathological feature of diabetic kidney disease (DKD). Autophagy, a process to maintain metabolic homeostasis, is obviously inhibited in DKD. Triptolide (TP) is a traditional Chinese medicine extract known for immune suppression and anti-inflammatory and anti-cancer activities. In this study, we investigated the effects of TP on autophagy and fibrosis in DKD. TP restored autophagy and alleviated fibrosis in DKD rats and high-glucose-incubated human mesangial cells. After we applied 3-methyladenine (an autophagy inhibitor) and autophagy-related gene 5-small interfering RNA (siRNA), we found that the improvement of fibrosis on TP was related to the restoration of autophagy. In addition, miR-141-3p levels were increased under high glucose but reduced after TP treatment. miR-141-3p overexpression aggravated the fibrosis and restrained the autophagy further, while miR-141-3p inhibition imitated the effects of TP. As an action target, phosphatase and tensin homolog (PTEN) showed corresponding opposite changes. After PTEN-siRNA transfection, the effects of TP on autophagy and fibrosis were inhibited. PTEN levels were downregulated, with downstream phosphorylated protein kinase B (Akt) and the mammalian target of rapamycin (mTOR) upregulated in high glucose, which were reversed by TP treatment. These findings indicate that TP alleviates fibrosis by restoring autophagy through the miR-141-3p/PTEN/Akt/mTOR pathway and is a novel therapeutic option for DKD. PMID- 29246325 TI - AP-1 Oligodeoxynucleotides Reduce Aortic Elastolysis in a Murine Model of Marfan Syndrome. AB - Marfan syndrome is characterized by high expression of matrix metalloproteinases (MMPs) in aortic smooth muscle cells (AoSMCs) associated with medial elastolysis and aortic root aneurysm. We aimed to reduce aortic elastolysis through decrease of MMP expression with decoy oligodeoxynucleotides (dODNs) neutralizing the transcription factor activating factor-1 (AP-1). AP-1 abundance in nuclear extracts as well as MMP-2 and MMP-9 expression were significantly increased in isolated mAoSMC of mgR/mgR Marfan mice compared to wild-type cells. Exposure to AP-1 neutralizing dODNs resulted in a significant reduction of basal and interleukin-1beta-stimulated MMP expression and activity in mAoSMCs. Moreover, increased migration and formation of superoxide radical anions was substantially decreased in mAoSMCs by AP-1 dODN treatment. Aortic grafts from donor Marfan mice were treated with AP-1- dODN ex vivo and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Pretreatment of aortic grafts with AP-1 dODN led to reduced elastolysis, macrophage infiltration, and MMP activity. Permeability of the endothelial monolayer was increased for dODN in mgR/mgR aortae with observed loss of tight junction proteins ZO-1 and occludin, enabling dODN to reach the tunica media. Targeting AP-1 activity offers a new potential strategy to treat the vascular phenotype associated with Marfan syndrome. PMID- 29246327 TI - In Vivo Knockout of the Vegfa Gene by Lentiviral Delivery of CRISPR/Cas9 in Mouse Retinal Pigment Epithelium Cells. AB - Virus-based gene therapy by CRISPR/Cas9-mediated genome editing and knockout may provide a new option for treatment of inherited and acquired ocular diseases of the retina. In support of this notion, we show that Streptococcus pyogenes (Sp) Cas9, delivered by lentiviral vectors (LVs), can be used in vivo to selectively ablate the vascular endothelial growth factor A (Vegfa) gene in mice. By generating LVs encoding SpCas9 targeted to Vegfa, and in parallel the fluorescent eGFP marker protein, we demonstrate robust knockout of Vegfa that leads to a significant reduction of VEGFA protein in transduced cells. Three of the designed single-guide RNAs (sgRNAs) induce in vitro indel formation at high frequencies (44%-93%). A single unilateral subretinal injection facilitates RPE-specific localization of the vector and disruption of Vegfa in isolated eGFP+ RPE cells obtained from mice five weeks after LV administration. Notably, sgRNA delivery results in the disruption of Vegfa with an in vivo indel formation efficacy of up to 84%. Sequencing of Vegfa-specific amplicons reveals formation of indels, including 4-bp deletions and 2-bp insertions. Taken together, our data demonstrate the capacity of lentivirus-delivered SpCas9 and sgRNAs as a developing therapeutic path in the treatment of ocular diseases, including age related macular degeneration. PMID- 29246326 TI - Efficacy and Safety of Pancreas-Targeted Hydrodynamic Gene Delivery in Rats. AB - Development of an effective, safe, and convenient method for gene delivery to the pancreas is a critical step toward gene therapy for pancreatic diseases. Therefore, we tested the possibility of applying the principle of hydrodynamic gene delivery for successful gene transfer to pancreas using rats as a model. The established procedure involves the insertion of a catheter into the superior mesenteric vein with temporary blood flow occlusion at the portal vein and hydrodynamic injection of DNA solution. We demonstrated that our procedure achieved efficient pancreas-specific gene expression that was 2,000-fold higher than that seen in the pancreas after the systemic hydrodynamic gene delivery. In addition, the level of gene expression achieved in the pancreas by the pancreas specific gene delivery was comparable to the level in the liver achieved by a liver-specific hydrodynamic gene delivery. The optimal level of reporter gene expression in the pancreas requires an injection volume equivalent to 2.0% body weight with flow rate of 1 mL/s and plasmid DNA concentration at 5 MUg/mL. With the exception of transient expansion of intercellular spaces and elevation of serum amylase levels, which recovered within 3 days, no permanent tissue damage was observed. These results suggest that pancreas-targeted hydrodynamic gene delivery is an effective and safe method for gene delivery to the pancreas and clinically applicable. PMID- 29246328 TI - Newborn screening in the United States may miss mild persistent hypothyroidism. PMID- 29246329 TI - The uncomfortable problem of unbound bilirubin in extremely preterm infants. PMID- 29246330 TI - 50 Years Ago in The Journal of Pediatrics: Comment on IgA Deficiency and Susceptibility to Infection. PMID- 29246331 TI - Impact of Severe Obesity on Cardiovascular Risk Factors in Youth. AB - OBJECTIVE: To compare cardiovascular risk factor clustering (CVRFC) in severely obese youth with those with lower degrees of obesity. STUDY DESIGN: We divided a childhood obesity clinic derived cohort into the degrees of obesity (class I, II, and III) and added a "class IV" category corresponding to >160% of the 95th centile of body mass index (BMI) for age and sex. In a cross-sectional analysis, we investigated the presence of CVRFC in 2244 participants; in 621 who were followed longitudinally, we investigated the determinants of endpoint CVRFC. RESULTS: Class IV obesity was associated with increased risk for CVRFC compared with overweight (OR = 17.26, P < .001) at a similar magnitude to class III obesity (OR = 17.26, P < .001). Male children were at greater risk for presence of CVRFC (OR = 1.57, P = .03) compared with female children. Adiponectin (OR = 0.90, P < .001) and leptin levels (OR = 0.98, P = .008) were protective, independent of degree of obesity. Baseline class IV obesity was associated with increased risk compared with overweight of having CVRFC at follow-up (OR = 5.76, P = .001), to a similar extent as class III obesity (OR = 5.36, P = .001). Changes in the degree of obesity were significant predictors of CVRFC on follow up (OR = 1.04, P < .01 per percent BMI change). CONCLUSIONS: The metabolic risk associated with obesity in childhood is conferred prior to reaching class IV obesity. An individualized risk stratification approach in children with severe obesity should be based on presence of complications rather than simple BMI cutoffs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01967849. PMID- 29246332 TI - Parent Recommendations to Enhance Enrollment in Multidisciplinary Clinical Care for Pediatric Weight Management. AB - OBJECTIVE: To explore parents' recommendations to enhance enrollment in multidisciplinary clinical care for managing pediatric obesity. STUDY DESIGN: Data for this interpretative description study were collected through individual, semistructured interviews that were audiorecorded, transcribed verbatim, and analyzed thematically. Parents (n = 79) were recruited from 4 multidisciplinary weight management clinics in Canada located in Edmonton, Hamilton, Montreal, and Vancouver. RESULTS: Most interviewed parents had children with obesity (body mass index >=95th percentile; 84.2%), were female (87.3%), had postsecondary education (69.6%), and were white (75.9%). Parents' recommendations referred to enrollment opportunities, information about obesity services, motivation for treatment, and accessibility to obesity services. Specifically, parents recommended to increase referral options and follow-up contacts with families during the enrollment process, inform referring physicians and families about the availability and characteristics of obesity services, enhance families' motivation for treatment, prevent families from getting discouraged, make services more appealing to families, and address accessibility issues (eg, offering multiple options for appointment times, providing support for transportation). CONCLUSIONS: Parents' recommendations support the need for family-centered approaches to enhance enrollment; however, their feasibility, acceptability, and effectiveness remain to be tested empirically. PMID- 29246333 TI - 50 Years Ago in The Journal of Pediatrics: A Familial Syndrome of Renal, Genital, and Middle Ear Anomalies. PMID- 29246334 TI - Cardiorespiratory Fitness and Blood Pressure: A Longitudinal Analysis. AB - OBJECTIVES: To examine the association between cardiorespiratory fitness and cardiovascular indices 2 years later, and to determine whether changes in cardiorespiratory fitness are associated with cardiovascular indices at a 2-year follow-up in adolescents. STUDY DESIGN: The sample comprised 734 adolescents (349 girls) aged 12-18 years followed for 3 years from the LabMed Physical Activity Study. Cardiorespiratory fitness was assessed by the 20-meter shuttle run test. Height, weight, waist circumference, and resting blood pressure (BP) were measured according to standard procedures. RESULTS: Regression analyses showed a significant inverse association between cardiorespiratory fitness at baseline and systolic BP (B = -0.126; P = .047) and rate pressure product (B = -29.94; P = .016), at follow-up after adjustments for age, sex, height, pubertal stage, socioeconomic status, and waist circumference. Significant differences were found between cardiorespiratory fitness groups (fit vs unfit) at baseline and systolic BP and rate pressure product at follow-up (P < .05 for all). Analysis of covariance showed a significant association between cardiorespiratory fitness changes and systolic BP (P = .024) and rate pressure product (P = .014), after adjustment for age, sex, height, pubertal status, socioeconomic status, and waist circumference. CONCLUSIONS: Changes in cardiorespiratory fitness during adolescence were associated with cardiovascular indices over a 2-year period. Adolescents with persistently low levels of cardiorespiratory fitness exhibited the highest levels of systolic BP and rate pressure product. PMID- 29246336 TI - Hearing Loss after Cardiac Surgery in Infancy: An Unintended Consequence of Life Saving Care. AB - OBJECTIVES: To investigate the prevalence of hearing loss after cardiac surgery in infancy, patient and operative factors associated with hearing loss, and the relationship of hearing loss to neurodevelopmental outcomes. STUDY DESIGN: Audiologic and neurodevelopmental evaluations were conducted on 348 children who underwent repair of congenital heart disease at the Children's Hospital of Philadelphia as part of a prospective study evaluating neurodevelopmental outcomes at 4 years of age. A prevalence estimate was calculated based on presence and type of hearing loss. Potential risk factors and the impact of hearing loss on neurodevelopmental outcomes were evaluated. RESULTS: The prevalence of hearing loss was 21.6% (95% CI, 17.2-25.9). The prevalence of conductive hearing loss, sensorineural hearing loss, and indeterminate hearing loss were 12.4% (95% CI, 8.8-16.0), 6.9% (95% CI, 4.1-9.7), and 2.3% (95% CI, 0.6 4.0), respectively. Only 18 of 348 subjects (5.2%) had screened positive for hearing loss before this study and 10 used a hearing aid. After adjusting for patient and operative covariates, younger gestational age, longer postoperative duration of stay, and a confirmed genetic anomaly were associated with hearing loss (all P < .01). The presence of hearing loss was associated with worse language, cognition and attention (P <.01). CONCLUSIONS: These findings suggest that the prevalence of hearing loss in preschool children after heart surgery in infancy may be 20-fold higher than in the 1% prevalence seen in the general population. Younger gestational age, presence of a genetic anomaly, and longer postoperative duration of stay were associated with hearing loss. Hearing loss was associated with worse neurodevelopmental outcomes. PMID- 29246337 TI - 50 Years Ago in The Journal of Pediatrics: Epidemiology and Etiology of Severe Infantile Diarrhea. PMID- 29246338 TI - Cardiorespiratory Capacity and Strength Remain Attenuated in Children with Severe Burn Injuries at Over 3 Years Postburn. AB - OBJECTIVES: To compare physical capacity and body composition between children with burn injuries at approximately 4 years postburn and healthy, fit children. STUDY DESIGN: In this retrospective, case-control study, we analyzed the strength, aerobic capacity, and body composition of children with severe burn injuries (n = 40) at discharge, after completion of a 6- to 12-week rehabilitative exercise training program, and at 3-4 years postburn. Values were expressed as a relative percentage of those in age- and sex-matched children for comparison (n = 40 for discharge and postexercise; n = 40 for 3.5 years postburn). RESULTS: At discharge, lean body mass was 89% of that in children without burn injuries, and exercise rehabilitation restored this to 94% (P < .01). At 3.5 years postburn, lean body mass (94%), bone mineral content (89%), and bone mineral density (93%; each P <= .02) remained reduced, whereas total body fat was increased (148%, P = .01). Cardiorespiratory fitness remained lower in children with burn injuries both after exercise training (75%; P < .0001) and 3.5 years later (87%; P < .001). Peak torque (60%; P < .0001) and average power output (58%; P < .0001) were lower after discharge. Although exercise training improved these, they failed to reach levels achieved in healthy children without burns (83-84%; P < .0001) but were maintained at 85% and 82%, respectively, 3.5 years later (P < .0001). CONCLUSIONS: Although the benefits of rehabilitative exercise training on strength and cardiorespiratory capacity are maintained at almost 4 years postburn, they are not restored fully to the levels of healthy children. Although the underlying mechanism of this phenomenon remains elusive, these findings suggest that future development of continuous exercise rehabilitation interventions after discharge may further narrow the gap in relation to healthy adolescents. PMID- 29246339 TI - Straight to the Operating Room: An Emergent Surgery Track for Acute Testicular Torsion Transfers. AB - OBJECTIVE: To assess the effect of implementing an emergency surgery track for testicular torsion transfers. We hypothesized that transferring children from other facilities diagnosed with torsion straight to the operating room (STOR) would decrease ischemia time, lower costs, and reduce testicular loss. STUDY DESIGN: Demographics, arrival to incision time, hospital cost in dollars, and testicular outcome (determined by testicular ultrasound) at follow-up were retrospectively compared in all patients transferred to our tertiary care children's hospital with a diagnosis of testicular torsion from 2012 to 2016. Clinical data for STOR and non-STOR patients were compared by Wilcoxon rank-sum, 2-tailed t test, or Fisher exact test as appropriate. RESULTS: Sixty-eight patients met inclusion criteria: 35 STOR and 33 non-STOR. Children taken STOR had a shorter median arrival to incision time (STOR: 54 minutes vs non-STOR: 94 minutes, P < .0001) and lower median total hospital costs (STOR: $3882 vs non STOR: $4419, P < .0001). However, only 46.8% of STOR patients and 48.4% of non STOR patients achieved surgery within 6 hours of symptom onset. Testicular salvage rates in STOR and non-STOR patients were not significantly different (STOR: 68.4% vs non-STOR: 36.8%, P = .1), but follow-up was poor. CONCLUSIONS: STOR decreased arrival to incision time and hospital cost but did not affect testicular loss. The bulk of ischemia time in torsion transfers occurred before arrival at our tertiary care center. Further interventions addressing delays in diagnosis and transfer are needed to truly improve testicular salvage rates in these patients. PMID- 29246340 TI - Predicting Pressure Injury Risk in Pediatric Patients: The Braden QD Scale. AB - OBJECTIVE: To describe the development and initial testing of the Braden QD Scale to predict both immobility-related and medical device-related pressure injury risk in pediatric patients. STUDY DESIGN: This was a multicenter, prospective cohort study enrolling hospitalized patients, preterm to 21 years of age, on bedrest for at least 24 hours with a medical device in place. Receiver operating characteristic curves using scores from the first observation day were used to characterize Braden QD Scale performance, including areas under the curve (AUC) with 95% CIs. RESULTS: Eight centers enrolled 625 patients. A total of 86 hospital-acquired pressure injures were observed in 49 (8%) patients: 22 immobility-related pressure injuries in 14 (2%) patients and 64 medical device related pressure injuries in 42 (7%) patients. The Braden QD Scale performed well in predicting immobility-related and medical device-related pressure injuries in the overall sample, with an AUC of 0.78 (95% CI 0.73-0.84). At a cutoff score of 13, the AUC was 0.72 (95% CI 0.67-0.78), providing a sensitivity of 0.86 (95% CI 0.76-0.92), specificity of 0.59 (95% CI 0.55-0.63), positive predictive value of 0.15 (95% CI 0.11-0.19), negative predictive value of 0.98 (95% CI 0.97-0.99), and a positive likelihood ratio of 2.09 (95% CI 0.95-4.58). CONCLUSIONS: The Braden QD Scale reliably predicts both immobility-related and device-related pressure injuries in the pediatric acute care environment and will be helpful in monitoring care and in guiding resource use in the prevention of hospital acquired pressure injuries. PMID- 29246342 TI - Is it the baby or the beds? PMID- 29246343 TI - The need to prevent cardiovascular disease in youth onset type 2 diabetes. PMID- 29246341 TI - Comorbidity of Type 1 Diabetes Mellitus in Patients with Juvenile Idiopathic Arthritis. AB - OBJECTIVES: To determine the prevalence of type 1 diabetes mellitus (T1D) in patients with juvenile idiopathic arthritis (JIA) and to characterize patients having both. STUDY DESIGN: Diabetes comorbidity was recorded in the National Pediatric Rheumatologic Database since 2012. Data from the North Rhine Westphalian diabetes registry served as the reference population for the prevalence of diabetes in the general population. The National Pediatric Rheumatologic Database data were indirectly standardized for age and sex for comparison with the general population. The diabetes prevalence ratio was calculated using the Poisson regression model. RESULTS: The analysis included 12 269 patients with JIA. A total of 58 patients had comorbid T1D, and the diabetes prevalence was 0.5%. The mean age was 11.6 years at the time of documentation, and the mean disease duration was 4.2 years. Compared with the general population, the prevalence of diabetes in patients with JIA was significantly increased (prevalence ratio 1.76 [95% CI 1.34; 2.28], P < .001). The onset of diabetes in patients with JIA was earlier than that reported in the reference data. Sixty-three percent of patients developed T1D before JIA. On average, diabetes onset was 56 months before the onset of JIA. Patients who first developed JIA developed T1D on average 40 months later. The majority of patients had not received disease-modifying antirheumatic drugs before diabetes onset. CONCLUSIONS: T1D occurs more frequently in patients with JIA than in the general population. The likelihood of T1D occurrence appears to be slightly higher before JIA manifestation and without disease-modifying antirheumatic drug therapy after JIA onset. PMID- 29246335 TI - Somatic Development in Children with Congenital Heart Defects. AB - OBJECTIVES: Somatic development is impaired in children with congenital heart defects (CHDs), and head circumference seems to be a strong predictor of neurodevelopmental prognosis. The aim of this study was to generate up-to-date reference values for the somatic development (head circumference, body weight, and length/height) of children with CHDs. STUDY DESIGN: Our study population consisted of all patients included in the PAN study (Pravalenz angeborener Herzfehler bei Neugeborenen in Deutschland), which was conducted prospectively over a 3-year study period by the Competence Network for Congenital Heart Defects. All children with mild, moderate, and severe CHDs born in 2006-2009 in Germany were enrolled. For computing of z-scores, only children with the following characteristics were included: appropriate for gestational age, nonsyndromic disease, term or post-term delivery, and no cardiac surgery. RESULTS: There were 2818 patients included. New z-scores for the described somatic measures of children with mild, moderate, and severe CHDs were computed. Comparisons with the KiGGS study (Gesundheit von Kindern und Jugendlichen in Deutschland) and the Berlin Longitudinal Study revealed significantly lower measurements for all measures-most notably in children with severe CHDs and/or cardiac surgery. In our cohort, no catch-up growth was seen after cardiac surgery. CONCLUSION: Children with severe CHDs demonstrated the most abnormal pattern in growth, including head circumference before and after cardiac surgery, which is indicative of accompanying brain pathology unrelated to operative injury. PMID- 29246345 TI - Prevalence of Adverse Childhood Experiences in Low-Income Latino Immigrant and Nonimmigrant Children. AB - OBJECTIVE: To estimate the prevalence of adverse childhood experiences in low income Latino children and examine differences in the prevalence of adverse childhood experiences by immigrant generational status. STUDY DESIGN: This is a secondary data analysis of the 2011-2012 National Survey of Children's Health, a telephone survey of parents/caregivers of a nationally representative sample of US children. The study sample was limited to Latino children in households with an annual income <=200% of the federal poverty level (FPL) whose parents responded to a 9-item inventory of adverse childhood experiences. Descriptive statistics estimated the prevalence of adverse childhood experiences and examined differences in prevalence by immigrant generational status. RESULTS: Of 22 297 children, 29% (n = 6483) were Latino (9% first generation, 57% second generation, 30% third or higher generation); 25% (n = 1692) of all Latino children were exposed to 2 or more adverse childhood experiences. Latino immigrant children had a lower prevalence (13%; n = 801) compared with nonimmigrant Latino children (40%; n = 772). The most common adverse childhood experiences were financial hardship and parent divorce/separation. The total number and mean number of adverse childhood experiences differed by child generational status, and the differences persisted after stratification by age and FPL. The prevalence of exposure to adverse childhood experiences was highest among third- or higher generation nonimmigrant children and lowest among second-generation immigrant children. CONCLUSIONS: The prevalence of adverse childhood experiences in low income Latino children is similar to the prevalence for all US children; however, the prevalence is significantly higher in nonimmigrant children. Targeted screening to address adverse childhood experiences, policy changes, and guidance regarding care practices to address adverse childhood experiences in Latino children are needed. PMID- 29246346 TI - Peanut Allergy: An Epidemiologic Analysis of a Large Database. AB - OBJECTIVE: To confirm new observations on peanut allergy and answer current concerns that families and healthcare providers have about peanut allergy. STUDY DESIGN: Children who presented with a story of peanut allergy or peanut sensitization were asked to participate in a registry, which allowed an analysis focused on questions that a food allergy support group had about children with peanut allergy or sensitization. RESULTS: A total of 1070 children were entered into the registry over 5 years. Two-thirds had a reaction to peanut. Children with peanut allergy were predominantly male (63%), white (78%), and with private health insurance (80%). Most reactions involved the skin (55%) and anaphylaxis occurred in 35%. The median age of a reaction was 1 year old. Atopic dermatitis was noted in 60% and asthma in 41%. Additional food allergy was noted in 58%. When second exposures occurred 28% had a more severe reaction. Skin test size did not differentiate the type of a reaction and children with anaphylaxis had slightly higher specific IgE levels. Severe reactions with inadvertent exposure in children who were peanut sensitized was rare (<1%). CONCLUSIONS: The strategies for peanut allergy prevention and treatment have evolved. The data obtained in this large registry can answer many questions that families and healthcare providers have during this transition. PMID- 29246344 TI - Newborn Screening in the US May Miss Mild Persistent Hypothyroidism. AB - OBJECTIVE: To determine if newborn screening (NBS) programs for congenital hypothyroidism in the US use thyroid-stimulating hormone (TSH) cutoffs that are age adjusted to account for the physiologic 4-fold reduction in TSH concentrations over the first few days of life. STUDY DESIGN: All NBS programs in the US were contacted and asked to provide information on their NBS protocols, TSH cutoffs, and whether these cutoffs were age adjusted. RESULTS: Of 51 NBS programs, 28 request a repeat specimen if the initial eluted serum TSH concentration is mildly increased (between the cutoff and a median upper limit of 50 mU/L), whereas 14 programs perform a routine second screen in all infants. Although these specimens are typically collected between 1 week and 1 month of life, 16 of the 28 programs with a discretionary second test and 8 of 14 programs with a routine second test do not have age-adjusted TSH cutoffs after the first 48 hours of life. CONCLUSIONS: There is variation in NBS practices for screening for congenital hypothyroidism across the US, and many programs do not adjust the TSH cutoff beyond the first 2 days of life. Samples are processed when received from older infants, often to retest borderline initial results. This approach will miss congenital hypothyroidism in infants with persistent mild TSH elevations. We recommend that all NBS programs provide age-adjusted TSH cutoffs, and suggest developing a standard approach to screening for congenital hypothyroidism in the US. PMID- 29246347 TI - Temporal Association Between Rhinovirus Activity and Kingella kingae Osteoarticular Infections. AB - OBJECTIVE: To determine whether the seasonal distribution of Kingella kingae osteoarticular infections is similar to that of common respiratory viruses. STUDY DESIGN: Between October 2009 and September 2016, we extracted the results of K kingae-specific real-time polymerase chain reaction analyses performed for bone or joint specimens in patients from 2 pediatric tertiary care centers in Paris. We used data of respiratory virus detection from the Reseau National des Laboratoires network with coordination with the National Influenza Center of France. The Spearman rank correlation was used to assess a correlation between weekly distributions, with P < .05 denoting a significant correlation. RESULTS: During the 7-year study period, 322 children were diagnosed with K kingae osteoarticular infection, and 317 testing episodes were K kingae-negative. We observed high activity for both K kingae osteoarticular infection and human rhinovirus (HRV) during the fall (98 [30.4%] and 2401 [39.1%] cases, respectively) and low activity during summer (59 [18.3%] and 681 [11.1%] cases, respectively). Weekly distributions of K kingae osteoarticular infection and rhinovirus activity were significantly correlated (r = 0.30; P = .03). In contrast, no significant correlation was found between the weekly distribution of K kingae osteoarticular infection and other respiratory viruses (r = -0.17, P = .34 compared with respiratory syncytial virus; r = -0.13, P = .34 compared with influenza virus; and r = -0.22, P = .11 compared with metapneumovirus). CONCLUSION: A significant temporal association was observed between HRV circulation and K kingae osteoarticular infection, strengthening the hypothesis of a role of viral infections in the pathophysiology of K kingae invasive infection. PMID- 29246349 TI - Stippled Chondral Calcifications of the Patella in Zellweger Syndrome. PMID- 29246348 TI - Effectiveness of a Pediatric Primary Care Intervention to Increase Maternal Folate Use: Results from a Cluster Randomized Controlled Trial. AB - OBJECTIVE: To assess the impact of provision of folate vitamins and a preconception health intervention on folate use among mothers bringing infants to pediatric primary care. STUDY DESIGN: We conducted a cluster randomized trial in mothers presenting with their infants (<12 months) at 4 urban pediatric practices in the Baltimore, Maryland, metropolitan area. There were 45 clinicians randomized into an intervention group (15-item preconception health screening and counseling and 90-day multivitamin supply) and control group (preconception health and community resource handouts and 90-day multivitamin supply). Participating mothers were enrolled in the study group assigned to their child's clinician. Baseline and 6-month follow-up interviews were performed. The outcome was daily use of folate, multivitamin, and a prenatal vitamin containing folate. Primary independent variables were time of assessment and mother's study group (intervention or control groups). Covariates investigated were mother's and child's age, race/ethnicity, education, marital status, income, insurance status, previous live births, and intention to have a pregnancy in the next 6 months. RESULTS: We enrolled 415 mothers at baseline who were majority African American and low income. Of the 415 enrolled participants, 352 (85%) completed follow-up interviews. Among all participants, daily vitamin intake increased from baseline to 6-month follow-up (33.8% vs 42.6%; P = .016). After adjustment for covariates and clustered design, there was an augmented effect in the intervention vs control group (aOR, 2.04; 95% CI, 1.04-3.98). CONCLUSIONS: Offering vitamins and recommending folate intake to mothers within pediatric practice can increase use. Pediatric practice is an important contact point and context for improving maternal folate use. TRIAL REGISTRATION: ClinicalTrials.govNCT02049554. PMID- 29246350 TI - Mite-impermeable bedding casings and severe asthma exacerbations. PMID- 29246351 TI - Early-onset sepsis risk calculator reduces empiric antibiotic use. PMID- 29246352 TI - Clinical examination not strongly associated with pneumonia diagnosis. PMID- 29246353 TI - Early childhood sedentary behavior associated with worse working memory. PMID- 29246354 TI - Live, attenuated influenza vaccine demonstrated ineffective. PMID- 29246357 TI - 50 Years Ago in The Journal of Pediatrics: Isoniazid Prophylaxis in Tuberculin Reactors. PMID- 29246356 TI - A Novel Magnetic Resonance Imaging Score Predicts Neurodevelopmental Outcome After Perinatal Asphyxia and Therapeutic Hypothermia. AB - OBJECTIVE: To assess the predictive value of a novel magnetic resonance imaging (MRI) score, which includes diffusion-weighted imaging as well as assessment of the deep grey matter, white matter, and cerebellum, for neurodevelopmental outcome at 2 years and school age among term infants with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia. STUDY DESIGN: This retrospective cohort study (cohort 1, The Netherlands 2008-2014; cohort 2, Sweden 2007-2012) including infants born at >36 weeks of gestational age treated with therapeutic hypothermia who had an MRI in the first weeks of life. The MRI score consisted of 3 subscores: deep grey matter, white matter/cortex, and cerebellum. Primary adverse outcome was defined as death, cerebral palsy, Bayley Scales of Infant and Toddler Development, third edition, motor or cognitive composite scores at 2 years of <85, or IQ at school age of <85. RESULTS: In cohort 1 (n = 97) and cohort 2 (n = 76) the grey matter subscore was an independent predictor of adverse outcome at 2 years (cohort 1, OR, 1.6; 95% CI, 1.3-1.9; cohort 2, OR, 1.4; 95% CI, 1.2-1.6), and school age (cohort 1, OR, 1.3; 95% CI, 1.2-1.5; cohort 2, OR, 1.3; 95% CI, 1.1-1.6). The white matter and cerebellum subscore did not add to the predictive value. The positive predictive value, negative predictive value, and area under the curve for the grey matter subscore were all >0.83 in both cohorts, whereas the specificity was >0.91 with variable sensitivity. CONCLUSION: A novel MRI score, which includes diffusion-weighted imaging and assesses all brain areas of importance in infants with therapeutic hypothermia after perinatal asphyxia, has predictive value for outcome at 2 years of age and at school age, for which the grey matter subscore can be used independently. PMID- 29246359 TI - 50 Years Ago in The Journal of Pediatrics: Editorial Comment: Therapeutic Orphans. PMID- 29246360 TI - Revisiting Type 1 Diabetes as a Comorbidity in Patients with Juvenile Idiopathic Arthritis. PMID- 29246361 TI - Neonatal and Infant Mortality Risk Associated with Preterm and Small for Gestational Age Births in Tanzania: Individual Level Pooled Analysis Using the Intergrowth Standard. AB - OBJECTIVES: To evaluate the risk of newborn and infant mortality associated with preterm, small for gestational age (SGA), and low birth weight (LBW) stratified by maternal HIV status and the location of birth. STUDY DESIGN: We created a prospective cohort by pooling 5 individually randomized trials. We used Cox proportional hazard models to estimate the risk of mortality for SGA defined using the recently published Intergrowth standard, preterm, LBW, and gestational age and size for gestational age categories (preterm- appropriate for gestational age [AGA], term-SGA, and preterm-SGA). Effect modification by maternal HIV status and place of residence was assessed using the likelihood ratio test. RESULTS: Of the 31 988 infants, 15.3% were preterm, 16.6% were SGA, and 7.3% were LBW. The proportion of preterm and SGA births was higher among the HIV-infected cohort than in the uninfected cohort. Compared with term-AGA groups, infants born both preterm and SGA had a greater risk of neonatal mortality (hazard ratio [HR] 5.43, 95% CI 2.01-14.63) than preterm-AGA infants (HR 2.40, 95% CI 1.89-3.05) and term SGA infants (HR 2.56, 95% CI 1.96-3.34). Maternal HIV infection modified the risk of infant mortality associated with being born preterm or LBW, with a higher relative risk among those born to HIV-uninfected women. Rural residence significantly modified the risk of neonatal mortality associated with being LBW (P for interaction = .005). CONCLUSIONS: Preterm and SGA newborns had an increased risk of mortality during the first year of life. Interventions targeting these conditions, especially in HIV-exposed and rural populations, should be integrated into existing maternal and child health programs. PMID- 29246355 TI - Creating the Subspecialty Pediatrics Investigator Network. PMID- 29246358 TI - Admission Temperature and Associated Mortality and Morbidity among Moderately and Extremely Preterm Infants. AB - OBJECTIVE: To evaluate the temperature distribution among moderately preterm (MPT, 29-33 weeks) and extremely preterm (EPT, <29 weeks) infants upon neonatal intensive care unit (NICU) admission in 2012-2013, the change in admission temperature distribution for EPT infants between 2002-2003 and 2012-2013, and associations between admission temperature and mortality and morbidity for both MPT and EPT infants. STUDY DESIGN: Prospectively collected data from 18 centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were used to examine NICU admission temperature of inborn MPT and EPT infants. Associations between admission temperature and mortality and morbidity were determined by multivariable logistic regression. EPT infants from 2002-2003 and 2012-2013 were compared. RESULTS: MPT and EPT cohorts consisted of 5818 and 3213 infants, respectively. The distribution of admission temperatures differed between the MPT vs EPT (P < .01), including the percentage <36.5 degrees C (38.6% vs 40.9%), 36.5 degrees C-37.5 degrees C (57.3% vs 52.9%), and >37.5 degrees C (4.2% vs 6.2%). For EPT infants in 2012-2013 compared with 2002-2003, the percentage of temperatures between 36.5 degrees C and 37.5 degrees C more than doubled and the percentage of temperatures >37.5 degrees C more than tripled. Admission temperature was inversely associated with in-hospital mortality. CONCLUSIONS: Low and high admission temperatures are more frequent among EPT than MPT infants. Compared with a decade earlier, fewer EPT infants experience low admission temperatures but more have elevated temperatures. In spite of a change in distribution of NICU admission temperature, an inverse association between temperature and mortality risk persists. PMID- 29246365 TI - 50 Years Ago in The Journal of Pediatrics: Familial Holoprosencephaly with Endocrine Dysgenesis. PMID- 29246364 TI - Assessment of Carina Position Antenatally and Postnatally in Infants with Congenital Diaphragmatic Hernia. AB - OBJECTIVE: To determine whether endotracheal tube (ETT) insertion depth should be modified in infants with congenital diaphragmatic hernia (CDH) to reduce the risk of main-stem intubation. STUDY DESIGN: The distance from the thoracic inlet to the carina was measured antenatally by fetal magnetic resonance imaging (MRI) between 20-28 weeks' (early) and 30-34 weeks' (late) gestation in 30 infants with CDH and compared with 12 early and 36 late MRIs in control infants without CDH. Postnatal tube position was assessed by chest radiograph in the same 30 infants with CDH and compared with 20 control infants with postnatal birth depression. RESULTS: The carina position was displaced upward in fetuses and newborns with CDH. Distance from the thoracic inlet to the carina compared with controls was 1.04 +/- 0.1 cm vs 1.42 +/- 0.07 cm on early MRI (P < .05), 1.43 +/- 0.14 cm vs 1.9 +/- 0.04 cm on late MRI (P < .01), and 2.36 +/- 0.07 cm vs 3.28 +/- 0.05 cm on postnatal radiographs (P < .01). Adjusting the ETT depth by 1 cm resulted in a median distance of 1.27 cm from the tip of the ETT to the carina. CONCLUSION: Cephalad displacement of the carina in infants with CDH may predispose them to right main-stem intubation and subsequent development of pneumothorax. We speculate that modifying the ETT insertion depth to 5.5 cm + weight in newborns born at term may prevent pneumothoraces and improve outcomes for infants with CDH. PMID- 29246366 TI - Quality of Operative Performance Feedback Given to Thoracic Surgery Residents Using an App-Based System. AB - OBJECTIVE: Residents frequently report inadequate feedback both in quantity and quality. The study evaluates the quality of faculty feedback about operative performance given using an app-based system. DESIGN: Residents requested operative performance evaluation from faculty on a real-time basis using the "Zwisch Me!!" mobile application which allows faculty to provide brief written feedback. Qualitative analysis of feedback was performed using grounded theory. SETTING: The 7 academic medical centers with thoracic surgery training programs. PARTICIPANTS: Volunteer thoracic surgery residents in both integrated and traditional training pathways and their affiliated cardiothoracic faculty. RESULTS: Residents (n = 33) at 7 institutions submitted a total of 596 evaluations to faculty (n = 48). Faculty acknowledged the evaluation request in 476 cases (80%) and in 350 cases (74%) provided written feedback. Initial open coding generated 12 categories of feedback type. We identified 3 overarching themes. The first theme was the tone of the feedback. Encouraging elements were identified in 162 comments (46%) and corrective elements in 230 (65%). The second theme was the topic of the feedback. Surgical technique was the most common category at 148 comments (42.2%) followed by preparation for case (n = 69, 19.7%). The final theme was the specificity of the feedback. Just over half of comments (n = 190, 54.3%) contained specific feedback, which could be applied to future cases. However, 51 comments (14.6%) contained no useful information for the learners. CONCLUSIONS: An app-based system resulted in thoracic surgery residents receiving identifiable feedback in a high proportion of cases. In over half of comments the feedback was specific enough to allow improvement. Feedback was better quality when addressing error prevention and surgical technique but was less useful when addressing communication, flow of the case, and assisting. Faculty development around feedback should focus on making feedback specific and actionable, avoiding case descriptions, or simple platitudes. PMID- 29246367 TI - A 12-Day Course of Imiquimod 5% for the Treatment of Actinic Keratosis: Effectiveness and Local Reactions. AB - INTRODUCTION AND OBJECTIVES: Imiquimod is an excellent option for patients with actinic keratosis, although its use may be limited by the long course of treatment required (4 weeks) and the likelihood of local skin reactions. The objectives of the present study were to demonstrate the effectiveness of a 12-day course of imiquimod 5% for the treatment of actinic keratosis and to examine the association between treatment effectiveness and severity of local reactions. PATIENTS AND METHODS: We included patients with at least 8 actinic keratoses treated with imiquimod 5% cream for 12 consecutive days. Local reactions were classified as mild, moderate, or severe. The statistical analysis of the association between local reactions and clinical response was based on the Pearson chi2 test and the Spearman rank correlation test. RESULTS: Sixty-five patients completed the study. Complete response was recorded in 52.3% and partial response in 75.4%. We found a statistically significant association between severity of the local reaction and response to treatment in both the Pearson chi2 test and the Spearman rank correlation test. CONCLUSIONS: A 12-day course of imiquimod 5% proved effective for the treatment of actinic keratosis. Severity of local reactions during treatment was correlated with clinical response. PMID- 29246369 TI - Editorial overview: Glial biology. PMID- 29246368 TI - Editorial: Non-coding RNA in aging and age-associated diseases - from intracellular regulators to hormone like actions. PMID- 29246362 TI - The Association of Breastfeeding Duration and Early Childhood Cardiometabolic Risk. AB - OBJECTIVE: To evaluate the association between breastfeeding duration and early childhood cardiometabolic risk. STUDY DESIGN: A cross-sectional study of 1539 healthy children, 3-6 years of age, recruited through The Applied Research Group for Kids! practice-based research network between October 2009 and August 2015. Adjusted multivariable linear regression was used to examine the association between breastfeeding duration and cardiometabolic risk z score and individual cardiometabolic risk factors of waist circumference, systolic blood pressure, glucose, high-density lipoprotein cholesterol, and triglycerides. RESULTS: The mean breastfeeding duration was 12.5 months (SD = 8.4). Breastfeeding duration was associated with lower cardiometabolic risk z score (beta = -0.03; 95% CI 0.05, -0.01). In analysis of cardiometabolic risk factors, each additional 3 months of breastfeeding was associated with a 0.13 cm (95% CI -0.20, -0.05) lower waist circumference and 0.16 mm Hg (95% CI -0.30, -0.02) lower systolic blood pressure. Compared with children who breastfed for 6-12 months, those who breastfed for 12-24 months had a lower systolic blood pressure of 1.07 mm Hg (95% CI -2.04, -0.10). There was no association between breastfeeding duration and cardiometabolic risk for those who breastfed beyond 24 months. CONCLUSIONS: Breastfeeding duration is associated with lower cardiometabolic risk, although the magnitude of association is small. Causation cannot be inferred. Breastfeeding beyond 24 months may not have an added benefit for cardiometabolic health. PMID- 29246370 TI - Editorial overview: New technologies: drug delivery and medical devices combinations, more than the sum of the parts. PMID- 29246372 TI - John I. Ingle, DDS, MSD, 1919-2017: The Legacy of an Extraordinary Leader. PMID- 29246371 TI - Editorial overview: Use of PK-PD for antibacterial drug development: decreasing risk and paths forward for resistant pathogens. PMID- 29246373 TI - Periodontal Blood Flow Protects the Alveolar Bone from Thermal Injury during Thermoplasticized Obturation: A Finite Element Analysis Study. AB - INTRODUCTION: The purpose of this study was to investigate the heat transfer during thermoplastic obturation and the cooling capacity of blood flow in the periodontal ligament (PDL) using finite element analysis (FEA). METHODS: A 3 dimensional digital tooth model was constructed based on micro-computed tomographic scanning of a mandibular first molar after chemomechanical preparation in vitro. A layer of PDL with or without simulated blood flow was built on the root portion of the tooth in software. Two heat-assisted obturation techniques (ie, the single-wave condensation technique and the warm vertical compaction technique followed by backfilling with injectable gutta-percha) were examined using an FEA package. RESULTS: In the model without blood flow, the highest temperature at the alveolar bony aspect of the PDL was 50.0 degrees C along the distal canal and 52.5 degrees C for the mesiolingual canal when the single-wave technique was used. With the warm vertical compaction technique, the highest temperature was 47.3 degrees C for the distal canal and 47.8 degrees C for the mesiolingual canal. In the model with simulated periodontal blood flow, a notable drop in the peak temperatures at the root surface and at the adjoining alveolar bone was observed for both the distal and mesiolingual canals; all peak temperatures at the PDL fell below 47 degrees C regardless of the obturation techniques used. The greatest rise in temperature was situated at the furcation aspect of the middle third of both roots. CONCLUSIONS: The cooling capacity of blood flow in the PDL is a factor that must be considered in the investigation of heat transfer during thermoplastic obturation. PMID- 29246375 TI - Corrigendum. PMID- 29246374 TI - Effects of Photodynamic Therapy on the Adhesive Interface of Fiber Posts Cementation Protocols. AB - INTRODUCTION: The aim of this study was to evaluate the effects of photodynamic therapy (PDT) on the bond strength and dentinal penetrability of cementation protocols using conventional resin cement (Relyx ARC; 3M ESPE, St Paul, MN) or self-adhesive (Relyx U200, 3M ESPE) after the glass fiber post cementation. METHODS: Forty human canine roots were endodontically treated and prepared for a fiber post. The roots were divided into 4 groups according to the cementation protocol and PDT use: conventional cement (CC), Relyx ARC; self-adhesive cement (SAC), Relyx U200 cement; PDT/CC, PDT + Relyx ARC; and PDT/SAC, PDT + Relyx U200. After cementation of the fiber posts, the roots were cross sectioned, and then specimens from the cervical, middle, and apical thirds of the prosthetic space were obtained. The specimens were submitted to the pushout test and dentinal penetration evaluation of the cementation protocol using laser confocal microscopy. RESULTS: PDT/CC presented the lowest bond strength to root dentin in the cervical third (P < .05). In the middle and apical thirds, all groups presented a similar bond strength (P > .05). PDT/CC presented the lowest dentinal penetration of the adhesive system in the cervical and apical thirds (P < .05). CONCLUSIONS: PDT presented negative effects on the bond strength to dentin in the cervical third after cementation using Relyx ARC and on the dentinal penetrability of the etch-and-rinse adhesive system in the cervical and apical thirds of the prosthetic space. PMID- 29246376 TI - Evaluation of Related Factors in the Failure of Endodontically Treated Teeth: A Cross-sectional Study. AB - INTRODUCTION: The aim of this study was to review the factors related to the failure and extraction of unsuccessful endodontically treated teeth. METHODS: A total of 1000 teeth treated with nonsurgical root canal therapy were analyzed, and the following information was recorded for each patient: reasons for failure and extraction, type of tooth, presence and type of coronal restoration, smoking status, age, gender, and level of education. One main reason was recorded for each failed tooth. The associations between reasons for failure, patient, and tooth were tested by using chi2 analysis. RESULTS: Of the 1000 endodontically failed teeth analyzed in this study, 28.1% (n = 281) were extracted, 66% (n = 660) were re-treated, and 5.9% (n = 59) were treated with apical surgery. Among the reasons for failure, restorative and endodontic reasons were seen most frequently (43.9%, n = 439), whereas orthodontic reasons were seldom seen (0.1%, n = 1). The most common reason for extraction was for prosthetic reasons (40.8%), and perforation/stripping was the least common (2.9%). The mandibular first molars were the most frequently extracted teeth (27.4%, n = 77). CONCLUSIONS: The most common reason for the extraction of endodontically treated teeth was for prosthetic reasons. Among the reasons for failure, restorative and endodontic reasons were the most frequently seen, and orthodontic reasons were the most seldom. The teeth that failed most frequently were mandibular first molars, and the teeth that failed least frequently were maxillary third molars. The most common reason for the extraction of failed endodontically treated teeth was for prosthetic reasons. PMID- 29246363 TI - Cardiac Biomarkers in Youth with Type 2 Diabetes Mellitus: Results from the TODAY Study. AB - OBJECTIVES: To examine cardiac biomarkers over time in youth-onset type 2 diabetes, and relate serum concentrations to cardiovascular disease risk factors, and left ventricular structure and function. STUDY DESIGN: TODAY (Treatment Options for type 2 Diabetes in Adolescents and Youth) was a multicenter randomized trial of 3 treatments including 521 participants with type 2 diabetes, aged 10-17 years, and with 2-6 years of follow-up. Participants were 36% male, obese, and ethnically diverse. Annual serum concentrations of brain natriuretic peptide, troponin, tumor necrosis factor (TNF)-alpha, receptors 1 and 2 were related to blood pressure, body mass index, hemoglobin A1c, and left ventricular ejection fraction, diastolic function, relative wall thickness, and mass. RESULTS: Elevated concentrations of brain natriuretic peptide (>=100 pg/mL), TNF alpha (>=5.6 pg/mL) and troponin (>=0.01 ng/mL), were present in 17.8%, 18.3%, and 34.2% of the cohort, respectively, at baseline, and in 15.4%, 17.1%, and 31.1% at the end of the study, with wide variability over time, without persistence in individuals or clear relationship to glycemia or cardiovascular structure/function. TNF receptors concentrations were increased at baseline and not significantly different from end-of-study concentrations. Adverse echocardiographic measures were more likely in the highest TNF receptor tertile (all P < .05): higher left ventricular mass (39.3 +/- 9.0 g/m2.7), left atrial internal dimension (3.7 +/- 0.4 cm) and E/Em ratio, a measure of diastolic dysfunction (6.2 +/- 1.9). After adjustment for body mass index, these relationships were no longer significant. CONCLUSIONS: Elevated serum concentrations of cardiac biomarkers were common in youth with type 2 diabetes, but their clinical significance is unclear and will require further long-term study. TRIAL REGISTRATION: ClinicalTrials.govNCT00081328. PMID- 29246379 TI - From the Editor. PMID- 29246377 TI - Dimethyloxalylglycine-embedded Poly(epsilon-caprolactone) Fiber Meshes Promote Odontoblastic Differentiation of Human Dental Pulp-derived Cells. AB - INTRODUCTION: The in vivo effect of prolyl hydroxylase inhibitors on the regeneration of the pulp-dentin complex is unclear. The purpose of this study was to investigate the effect of dimethyloxalylglycine (DMOG)-embedded poly(epsilon caprolactone) fiber (PCLF/DMOG) on odontoblastic differentiation of human dental pulp-derived cells (hDPCs) by transplantation of the dentin slice model. METHODS: The hDPCs were seeded onto electrospun PCLF and PCLF/DMOG in dentin slices and then transplanted into nude mice. The surface topography was evaluated for both PCLFs, and DMOG release from the PCLF/DMOG was examined. The effects of the PCLF/DMOG were assessed by histology and quantitative reverse transcription polymerase chain reaction. RESULTS: The PCLF/DMOG-treated dentin slices showed higher cellularity with a palisading arrangement of hDPCs and organized collagen fibers. We found that the PCLF/DMOG significantly stimulated the expression of vascular endothelial growth factor, dentin sialoprotein, and bone sialoprotein in the hDPCs (P < .05) and mouse vascular endothelial growth factor A, mouse platelet endothelial cell adhesion molecule 1, and mouse neurofilament light polypeptide in the surrounding host cells (P < .05). CONCLUSIONS: These results show that PCLF/DMOG has potential in pulp-dentin complex regeneration by promoting odontoblastic differentiation of hDPCs and by enhancing host cell recruitment, angiogenesis, and neurogenesis through the released DMOG-mediated cell responses. PMID- 29246380 TI - Foreword: The Nuts and Bolts of Breastfeeding and Having Success Supporting Breastfeeding Mothers in the Outpatient Setting. PMID- 29246378 TI - [Agomelatine in real-life condition: A safe context of prescription? Results of a one-year single-center evaluation]. PMID- 29246381 TI - The Nuts and Bolts of Breastfeeding: Anatomy and Physiology of Lactation. AB - Breastmilk is the physiologic norm for infant nutrition. Despite recommendations from major health organizations, many women in the U.S. are not achieving this metric. Understanding breast anatomy and lactation physiology will allow physicians to gain knowledge of the processes, which control lactation enabling physicians to appropriately manage the breastfeeding dyad. The interplay of hormones involved in lactation and milk management affect milk initiation, as well as ongoing milk production (galactopoesis). The unique components of breastmilk that provide protection against infection and chronic diseases also change between and during feeds. Colostrum and the importance of early skin-to skin after delivery will also be discussed. PMID- 29246382 TI - Promote Breastfeeding in the Outpatient Setting: It's Easy! AB - The numerous benefits for both mother and baby of breastfeeding are evidence based and well-defined. Breastmilk is the physiologic norm for infant nutrition, offering multiple health benefits and protections for mothers and babies. Although major medical and health organizations, which represent the health of women and children, such as the American Academy of Pediatrics (AAP), American College of Obstetrics and Gynecology (ACOG), American Academy of Family Practice (AAFP), Centers for Disease Control (CDC), UNICEF, the World Health Organization (WHO) and the National Public Health Service (NPHS), all recommend exclusive breastfeeding, few women meet the recommended goals for duration and exclusivity, despite high initiation rates. This article will discuss the barriers women face when breastfeeding. Strategies will be discussed on how physicians and health care providers can assist and advocate for their mothers while helping to improve the health of women and children. Physicians/pediatricians can support women and design interventions that can help patients' mothers overcome these challenges. PMID- 29246384 TI - Corrigendum to "New Treatment Option for COPD: Two Long-Acting Bronchodilators in a Single Metered Dose Inhaler" The American Journal of Medicine, 2017: 130(11): 1251-1254. PMID- 29246383 TI - Study of the metabolomics characteristics of patients with metabolic syndrome based on liquid chromatography quadrupole time-of-flight mass spectrometry. AB - BACKGROUND: Metabolic syndrome (MS) is a disease with complex pathophysiology and pathogenesis involving multiple systems of the human body. This study aimed to identify serum metabolites that are relevant to MS. MATERIAL AND METHODS: This study involved 40 patients with MS and 28 healthy adults, and the following data were statistically analyzed: basic clinical data, blood lipids, fasting blood glucose, blood pressure, waist circumference, and visceral fat coefficient. Serum samples from both groups were collected and analyzed by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF/MS); multivariate and univariate statistical methods were used to identify potential MS biomarkers and MS-related metabolic pathways. In addition, leucine and valine levels in serum from MS patients and normal subjects were measured using enzyme-linked immunosorbent assays (ELISAs). RESULTS: In this study, 23 potential biomarkers were identified in the plasma of MS patients. These biomarkers were mainly related to metabolism; the tricarboxylic acid cycle; galactose metabolism; arachidonic acid metabolism; valine, leucine, and isoleucine degradation; and valine, leucine, and isoleucine biosynthesis. ELISAs were utilized to verify serum leucine and valine levels, and the results supported the experimental metabolomics results. CONCLUSIONS: In total, 23 MS-related metabolites were identified in the serum; these differential metabolites were mainly associated with lipid metabolism, amino acid metabolism, glucose metabolism, purine metabolism, and other related metabolic pathways. This study shows that LC/MS based metabolomics methods can be used to investigate the pathological changes in MS patients and identify biomarkers for the early diagnosis of MS. PMID- 29246385 TI - Sclerotic scatter. AB - Sclerotic scatter involves the scattering of incident light by the limbal sclera followed by entry of part of the scattered light into the cornea, where some of the light travels through total internal reflection to the other side, where it scatters a second time in the limbal sclera. It is then visible in the form of a limbal scleral arc of light. Sclerotic scatter has been used for decades to spot and delineate corneal opacities, which disrupt and scatter the light travelling through total internal reflection. To implement the technique, the slit beam and the binoculars of the slit lamp should be dissociated so that the limbal sclera is illuminated, while the binoculars are centered on the cornea. The technique does not provide any information as to the depth of corneal opacities and therefore needs to be complemented by direct illumination. The second sclerotic scatter may also be used clinically, for instance for diode cycloablation, the posterior part of the arc of light projecting 0.5mm behind the scleral spur. This article aims to describe the phenomenon of sclerotic scatter, explaining how the slit-lamp should be set to use this technique, describing its clinical applications (in the opacified cornea and in the normal sclera), showing that the limbal scleral arc of light of sclerotic scatter may be seen under certain circumstances in daily life with the naked eye and, finally, explaining how the arc of light differs from peripheral light focusing ("Coroneo effect"). PMID- 29246386 TI - Role of synchronized physiological and interpersonal rhythms in typical and atypical development. PMID- 29246387 TI - Confirmation of the immunoreactivity of monoclonal anti-human C-terminal EGFR antibodies in bronze Corydoras Corydoras aeneus (Callichthyidae Teleostei) by Western Blot method. AB - Bronze corydoras (Corydoras aeneus) uses the distal part of the intestine as accessory respiratory organ. Our previous study showed the presence of epidermal growth factor receptor (EGFR) cytoplasmic domain in the digestive tract of the bronze corydoras. In this study, using Western Blot method, we validated the results presented in the previous research. In detail, results of Western Blot analysis on digestive and respiratory part of bronze corydoras intestine homogenates confirmed the immunoreactivity of anti-cytoplasmic domain (C terminal) human EGFR antibodies with protein band of approximately 180kDa (EGFR molecular weight). This indicates a high homology of EGFR domain between these species and the possibility of such antibody use in bronze corydoras. Statistically significantly higher EGFR expression was observed in the respiratory part of intestine when compared to the digestive part. This implies higher proliferation activity and angiogenesis of epithelium in this part of intestine, creating conditions for air respiration. Therefore, Corydoras aeneus may be considered as a model organism for the molecular studies of the mechanisms of epithelial proliferation initiation and inhibition depending on hypoxia and normoxia. PMID- 29246388 TI - Guillain-Barre Syndrome secondary to tacrolimus in a patient with corticoresistant nephrotic syndrome caused by focal and segmental glomerulonephritis and IgA nephropathy. PMID- 29246389 TI - Mitigating passive fatigue during monotonous drives with thermal stimuli: Insights into the effect of different stimulation durations. AB - Driving on monotonous roads has been shown to cause passive fatigue as even non sleep-deprived drivers suffer from the lack of stimuli. Consequently, alertness is reduced and the risk of accidents increases. To counteract this risk, measures need to be taken to mitigate driver fatigue. While in the past, some studies have been focused on the potential of thermal stimuli to reduce fatigue, their results seem inconclusive. Examining the study conditions in which the thermal stimuli were studied, it becomes obvious that the duration of the thermal stimulus strongly affects perceived fatigue. To better understand this relation, a driving simulator study (n=33) was conducted investigating both a 2min and a 4min thermal stimulus (15oC), where air was circulated on non-sleep-deprived drivers. For the 4min stimulus, patterns of increased sympathetic activity (i.e. significant pupil dilatation and bradycardia) were recorded. Furthermore, participants subjectively rated fatigue significantly lower when the stimuli were applied, and preferred driving with the stimulus. The superior performance of the 4min stimulus can be derived from a longer effect on the physiological data as well as even lower subjective fatigue ratings. Results also point to the limits of thermal stimulation: 6min after the stimuli, the participants no longer feel an effect (based on subjective ratings). Future research on passive fatigue countermeasures should hence build on the identified effect of a 4min cooling stimulus to increase physiological arousal and focus on the opportunities to increase effect duration. PMID- 29246390 TI - The extent of surgery for benign parotid pathology and its influence on complications: A prospective cohort analysis. AB - BACKGROUND: The surgical management of benign parotid tumors is aimed at complete extirpation of the mass with preservation of facial nerve function. There is a relative paucity of literature pertaining to complications after benign parotid surgery and related risk factors. We aim to critically review the outcomes following treatment of benign parotid pathology when surgery entailed either complete superficial parotidectomy (CSP), partial superficial parotidectomy (PSP) or extracapsular dissection (ECD). MATERIAL AND METHODS: This is a review of prospectively collected data of all parotidectomies performed between June 2006 to June 2016 for histologically-proven benign pathology of the parotid. Median follow-up time was 31.6weeks. RESULTS: A total of 101 parotidectomies were carried out on 97 patients (40 CSP, 56 PSP and 5 ECD). Pleomorphic adenoma (48.4%) and Warthin's tumors (32.7%) were the most common pathologies. Temporary facial weakness occurred after 7 operations (6.9%). Facial weakness was permanent in 4 cases (3.9%). The rates of sialocele and salivary fistula were 4.9% and 0.9%, respectively. Only one patient (0.9%) developed Frey Syndrome postoperatively. No significant associations between extent of parotid surgery and postoperative facial nerve dysfunction (p=0.674) or wound complications (p=0.433) were observed. Univariate analyses for potential contributing factors such as advanced age, smoking status, tumor location or histology did not demonstrate any increased risk with developing postoperative complications. CONCLUSION: Partial superficial parotidectomy was associated with low rates of morbidity to the facial nerve and surgical wound. The results were comparable to complete superficial parotidectomy. We recommend offering patient partial superficial parotidectomy where appropriate and this is in line with the current trend of minimising surgical dissection, thereby potentially decreasing the risk of short-term and long-term complications. PMID- 29246391 TI - Is an endoscopic or a microscopic approach optimal for management of attic cholesteatoma? PMID- 29246392 TI - Image analysis of interarytenoid area to detect cases of Laryngopharyngeal Reflux: An objective method. AB - PURPOSE: To diagnose Laryngopharyngeal Reflux by observing colour (Red, Green, Blue) at the interarytenoid area during 70 degrees laryngeal endoscopy. MATERIALS AND METHODS: Endoscopic images from 50 normal controls and 50 patients of LPR were obtained in this observational study. LPR patients were selected on the basis of RSI and RFS. Images were analysed using ImageJ, a free image analysis software, developed by the National Institute of Health (NIH). Colour changes in the form of RGB (red, green, blue) values were calculated and analysed at the interarytenoid area. The values in the normal and patient group were compared and correlated with RSI and RFS. RESULTS: RGB values of the LPR group and the normal group were statistically different (P value<0.01). Strong correlation was also found between R and G values and both RFS and RSI. However, no correlation was seen with B values. CONCLUSION: Image analysis is an easy, economical and objective method to diagnose LPR. PMID- 29246393 TI - Effect of repeat prostate biopsies on functional outcomes after radical prostatectomy. AB - PURPOSE: Growing acceptance of active surveillance (AS) results in a relevant number of patients who will undergo radical prostatectomy (RP) after multiple biopsy sessions (Bx) due to cancer progression. The effect of repeat Bx on functional outcomes after RP remains controversial. METHODS: Overall, 11,140 patients who underwent RP from 2007 to 2015 were analyzed. Number of Bx sessions (1 vs. 2 vs. >=3) before RP was examined. Association between number of Bx sessions and erectile dysfunction (ED) and urinary incontinence (UI) was assessed by univariable and multivariable logistic regressions. RESULTS: A total of 9,797 (87.9%) had 1 Bx, 937 (8.4%) had 2 Bx, and 406 (3.6%) had 3 or more Bx. Median age was 65 years (IQR: 59-69). Increasing Bx sessions were associated with advanced age at surgery (1, 2, and >=3 Bx: 65, 65, and 67 years, P<0.001); 982 (45.9%), 906 (57.9%), and 597 (60.9%) patients achieved potency at 1, 2, and 3 years after RP, respectively. On adjusted analysis repeat Bx compared to initial Bx had no influence on ED at 1, 2, and 3 years. At 1, 2, and 3 years after RP, 6,107 (87.9%), 4,825 (90.9%), and 3,696 (91.6%) patients achieved continence. Number of Bx session had no influence on UI at follow up. CONCLUSION: Our findings demonstrate that ED and UI rates are comparable among patients undergoing RP after initial and repeat Bx sessions. This is of importance when counseling AS patients. No adverse functional outcomes are expected if AS has to be discontinued and RP as curative option is contemplated. PMID- 29246394 TI - Progression of pulmonary artery dilatation in patients with pulmonary hypertension coexisting with a pulmonary artery aneurysm. AB - BACKGROUND: Pulmonary artery (PA) dilatation is usually observed in patients with pulmonary hypertension (PH), but a PA aneurysm (PA diameter > 40mm) is rare. The difference between characteristics of patients with and those without progression of PA diameter remains poorly understood. We assessed the changes in PA diameter in patients with PH coexisting with and without a PA aneurysm. METHODS: We investigated the changes in PA diameter by multi-detector computed tomography performed twice with an interval of more than one year in 44 patients with PH. Seventeen patients had a PA aneurysm and 27 patients did not have a PA aneurysm at baseline. RESULTS: The median follow-up period was 3.6 years. All patients received medical or invasive treatment for PH. At baseline, main PA diameters were 52+/-15mm in patients with a PA aneurysm and 33+/-3mm in patients without a PA aneurysm. Mean PA pressure was higher in patients with a PA aneurysm than in those without a PA aneurysm (61+/-15mmHg vs. 51+/-16mmHg, p=0.04). At follow-up, mean PA pressure significantly decreased in both patients with a PA aneurysm (44+/-11mmHg) and patients without a PA aneurysm (41+/-18mmHg). Main PA diameter significantly increased in patients with a PA aneurysm (65+/-28mm, change ratio: 23.3%), while it did not increase in patients without a PA aneurysm (32+/-3mm, change ratio: -3.1%). CONCLUSIONS: PA dilatation progressed in patients with a PA aneurysm despite treatment of PH. The progression of PA dilatation is independent of reduction of PA pressure by PH treatment. PMID- 29246395 TI - Cardiac arrest related to anaesthesia in Williams-Beuren syndrome. AB - Williams-Beuren syndrome is the clinical manifestation of a congenital genetic disorder in the elastin gene, among others. There is a history of cardiac arrest refractory to resuscitation manoeuvres in anaesthesia. The incidence of myocardial ischaemia is high during anaesthetic induction, but there are patients who do not have this condition yet also have had very serious cardiac events, and issues that are still to be resolved. Case descriptions will enable the common pathophysiological factors to be defined, and decrease morbidity and mortality. We report the case of a 3-year-old boy with cardiac arrest at induction, rescued with circulatory assistance with extracorporeal membrane oxygenation and hypothermia induced for cerebral protection. PMID- 29246396 TI - Non-invasive multi-parametric cardiorespiratory assessment of the hemodynamically unstable patient. PMID- 29246397 TI - Reliability of High-speed Videoendoscopic Ratings of Essential Voice Tremor and Adductor Spasmodic Dysphonia. AB - OBJECTIVES: The main objectives of this study were to (1) examine intrarater and inter-rater reliabilities in perceptual ratings of vocal fold vibratory patterns and supraglottic characteristics for essential vocal tremor and adductor spasmodic dysphonia (AdSD) using high-speed videoendoscopy (HSV), and (2) to investigate the specificity of the parameters in differentiating these two voice disorders. METHODS: HSV recordings of 34 cases diagnosed with essential vocal tremor, AdSD, or AdSD with vocal tremor were evaluated blindly by two voice speech pathologists. The two raters examined all HSV video segments twice across nine supraglottic and vocal fold vibratory characteristics for inter-rater and intrarater reliabilities. A separate consensus rating was then developed, with the results analyzed to explore differentiation. RESULTS: Raters demonstrated moderate intrarater reliability with mean Spearman's rho correlation coefficients of 0.68 (rater 1) and 0.73 (rater 2). Moderate inter-rater reliability for the two raters was seen across all parameters with a mean Cohen's kappa coefficient of 0.51. Raters showed higher intrarater and inter-rater reliabilities for supraglottic parameters. Only the presence of tremor differentiated between the two voice disorders in cases with a consistent diagnosis. CONCLUSIONS: The high level of concomitance between vocal tremor and AdSD may affect subjective perceptual analysis of supraglottic and vocal fold vibratory patterns. Results indicate similar global involvement of supraglottic laryngeal structures for both vocal tremor and AdSD. PMID- 29246398 TI - DOCA/salt hypertension alters Period1 and orexin-related gene expression in the medulla and hypothalamus of male rats: Diurnal influences. AB - In peripheral tissues, aldosterone alters expression of multiple genes, including the clock gene Period 1 (Per1), 11 beta-hydroxysteroid dehydrogenase-2 (11-HSD2), and alpha-ENAC, the epithelial sodium channel subunit. We evaluated the impact of chronic aldosterone exposure (DOCA) and salt intake on nocturnal changes in gene expression in the male Sprague Dawley rat brain. Additionally, genes associated with the orexin (ORX) system were also evaluated based on the role of this neuropeptide in arousal, feeding and hypertension and an interconnection with Per1 expression. DOCA/salt treatment increased saline intake primarily at night, elevated arterial pressure and lowered heart rate. In the medulla oblongata, DOCA/salt upregulated Per1, 11-HSD2, and alpha-ENAC expression independent of time of day, but did not change ORX receptor type 1 (ORX-R1) or type 2 (ORX-R2) expression. ORX-R1, and ORX-R2 expression in the medulla did however correlate with Per1 expression following DOCA/salt treatment but not in controls. In the hypothalamus, DOCA/salt treatment upregulated Per1, ORX-A, and ORX-R2 expression, in general, and Per1 and ORX-A expression at night. ORX-A, ORX-R1 and ORX-R2 expression in the hypothalamus correlated with Per1 expression following DOCA/salt but not in controls. These findings demonstrate for the first time that DOCA/salt hypertension modulates ORX gene expression in the brain and suggest that changes in expression in the ORX system may occur directly or indirectly via aldosterone-induced changes in Per1 expression. Our findings also build on emerging evidence that monitoring gene expression during both the day and night is critical to understanding the role of specific genes in hypertension. PMID- 29246399 TI - Differentiating abdominal procedures in pediatric surgery: The inadequacy of current procedural terminology codes. AB - INTRODUCTION: The ability to use detailed, accurate current procedural terminology (CPT) codes is a key component of effective research. We examined the effectiveness of CPT codes to accurately reflect care in patients undergoing surgery for necrotizing enterocolitis (NEC). METHODS: A multicenter retrospective analysis of operations on patients with NEC was conducted across 4 institutions between 2011 and 2016. Correlation between operative dictation and CPT coding was analyzed. RESULTS: A total of 124 patients with NEC diagnosis undergoing exploratory abdominal operations were identified. NEC was improperly diagnosed in 25 patients, who were excluded from further analysis. Of the 99 patients reviewed, the initial exploratory abdominal operation was coded inaccurately in 58 cases (59%). Within these, 15 (26%) had multiple coding errors such that the nature of the original operation was not discernable from the applied codes. Inaccurate codes often did not describe the presence of a mucous fistula (n=27, 44%), ostomy (n=24, 39%), or extra segments of bowel resected (n=9, 16%). The length of bowel resected is not currently described by any CPT codes. CONCLUSION: CPT coding for abdominal operations does not sufficiently reflect complexity of pediatric surgeries. This study highlights the significance of this inadequacy and its implications in future database studies in the era of electronic medical records. LEVEL OF EVIDENCE: Level IV. TYPE OF STUDY: Clinical research study. PMID- 29246400 TI - Immunomodulatory effects of myeloid-derived suppressor cells in diseases: Role in cancer and infections. AB - Myeloid-derived suppressor cells (MDSCs) are heterogeneous cells capable of abrogating T and B cells responses and have been identified in numerous cancers. As with other regulatory cell populations, they aim to maintain balance between host-defence-associated inflammation and ensuing tissue pathology. MDSC accumulation and/or activation involve several growth factors and cytokines including Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Interleukin (IL)-6 and suppression has been linked to receptors such as IL 4Ralpha. Other immune pathways, such as Toll-like receptors (TLRs) have also been shown to interfere in MDSC activity adding to the complexity in clarifying their pathways. Monocytic- (Mo-MDSCs) and polymorphonuclear- (PMN-MDSCs) cells are two subsets of MDSCs that have been well characterized and have been shown to function through different mechanisms although both appear to require nitric oxide. In human and murine model settings, MDSCs have been shown to have inhibitory effects on T cell responses during bacterial, parasitic and viral pathologies and an increase of MDSC numbers has been associated with pathological conditions. Interestingly, the environment impacts on MDSC activity and regulatory T cells (Tregs), mast cells and a few cells that may help MDSC in order to regulate immune responses. Since the majority of pioneering data on MDSCs has stemmed from research on malignancies, this review will summarize MDSC biology and function in cancer and highlight current knowledge about these cells during infectious pathologies as well. PMID- 29246403 TI - Considerations for sentinel lymph node biopsy in breast cancer patients with biopsy proven axillary disease prior to neoadjuvant treatment. AB - BACKGROUND: Axillary disease can be downstaged with neoadjuvant treatment for breast cancer. We attempted to identify factors to consider in determining whether to perform a sentinel lymph node biopsy in patients with biopsy proven axillary metastases (cN+) prior to neoadjuvant treatment. METHODS: A retrospective chart review was conducted on patients at a single tertiary care center who underwent neoadjuvant treatment followed by surgery between 9/2013 and 2/2017. RESULTS: 47% of patients with node positive disease prior to neoadjuvant treatment were downstaged to node negative (ypN0) disease. These patients were more likely to have triple negative or Her2 positive disease than those patients who remained node positive (ypN+) as these were more likely to have hormone receptor positive disease. These patients were also more likely to demonstrate complete clinical imaging response of the primary tumor and axilla on preoperative breast MRI. CONCLUSIONS: Tumor biology and clinical response noted on breast MRI can help guide the decision to perform sentinel lymph node biopsy in patients with axillary node positive disease prior to neoadjuvant treatment. PMID- 29246404 TI - Ethnic specific differences in endocrine neoplasms: The role of susceptibility genes. AB - Ethnic disparity in disease incidence, prevalence, and outcome has been documented for a variety of diseases and cancers. Dr. LaSalle D. Leffall was one of the first to note that genetic susceptibility is one important aspect that needed to be studied to better understand cancer disparity. In this article, we cover disparity in endocrine neoplasm presentation and new, emerging genetic data that may explain this disparity. PMID- 29246402 TI - Selective sentinel lymph node biopsy in male breast cancer. AB - OBJECTIVE: To evaluate the reproducibility of the sentinel lymph node (SLN) technique in male breast cancer. MATERIAL AND METHODS: We retrospectively analysed 21 male patients diagnosed with breast cancer in our hospital from 2008 to 2016 with, at least, 18 months follow-up. Fifteen patients underwent selective sentinel lymph node biopsy (SLNB) following the usual protocols with peritumoral injection of 18.5-111MBq of 99mTc-nanocoloides and acquisition of planar images 2hours after the injection. In 2 cases it was necessary to perform a SPECT/CT to locate the SLN. Immunohistochemistry and molecular techniques (OSNA) were used for their analysis. Six patients did not undergo SLNB because they had pathological nodes or distant disease at the time of diagnosis. RESULTS: SLNB was performed in 15 patients. The SLN was negative in 6 patients and positive in the remaining 9. Three patients with positive SLNB did not need axillary lymphadenectomy because of the low number of copies by molecular analysis OSNA. Axillary lymphadenectomy was performed in the remaining 6 patients with the result of 4 positive axillary lymphadenectomies and 2 that did not show further extension of the disease. CONCLUSIONS: According to our experience, SLNB in males is a reproducible, useful, safe and reliable technique which avoids unnecessary axillary lymphadenectomy and prevents the appearance of undesirable effects. PMID- 29246405 TI - Tropism of liver epithelial cells toward hepatocellular carcinoma in vitro and in vivo with altering gene expression of cancer stem cells. AB - BACKGROUND: Rat liver epithelial (RLE) cells could inhibit the proliferation and invasiveness of hepatoma cells in vitro. This study is to understand the tropism and the effect of RLE cells on mouse hepatoma cells both in vitro and in vivo. METHODS: RLE cells were isolated from new-born rats and characterized their stem cell markers. Co-culture and HCC mouse model was established to detect therapeutic effect of RLE cells. RESULTS: RLE cells (including Thy-1+ RLE cells, Thy-1- RLE cells, RLE cells) displayed a selective tropism toward ML-1 hepatoma cells both in vitro and in vivo. They altered the gene expression of some cancer stem cell markers in the liver tumor. CONCLUSION: Liver epithelial cells have a selective tropism toward HCC in vitro and in vivo. They could alter the gene expression of cancer stem cells. PMID- 29246406 TI - General surgery education across three continents. AB - Surgical education has seen tremendous changes in the US over the past decade. The Halstedian training model of see one, do one, teach one that governed surgical training for almost 100 years has been replaced by the achievement of the ACGME competencies, milestones, entrustable professional activities (EPAs), and acquisition of surgical skill outside the operating room on simulators. Several of these changes in American medical education have been influenced by educators and training paradigms abroad. In this paper, we review the training paradigms for surgeons in the UK, Japan, and Mexico to allow comparisons with the US training paradigm and promote the exchange of ideas. PMID- 29246401 TI - Applications of chemokines as adjuvants for vaccine immunotherapy. AB - Vaccinations are expected to aid in building immunity against pathogens. This objective often requires the addition of an adjuvant with certain vaccine formulations containing weakly immunogenic antigens. Adjuvants can improve antigen processing, presentation, and recognition, thereby improving the immunogenicity of a vaccine by simulating and eliciting an immune response. Chemokines are a group of small chemoattractant proteins that are essential regulators of the immune system. They are involved in almost every aspect of tumorigenesis, antitumor immunity, and antimicrobial activity and also play a critical role in regulating innate and adaptive immune responses. More recently, chemokines have been used as vaccine adjuvants due to their ability to modulate lymphocyte development, priming and effector functions, and enhance protective immunity. Chemokines that are produced naturally by the body's own immune system could serve as potentially safer and more reliable adjuvant options versus synthetic adjuvants. This review will primarily focus on chemokines and their immunomodulatory activities against various infectious diseases and cancers. PMID- 29246407 TI - Can CT imaging of the chest, abdomen, and pelvis identify all vertebral injuries of the thoracolumbar spine without dedicated reformatting? AB - BACKGROUND: The main objective of this study was to compare detection rates of clinically significant thoracolumbar spine (TLS) fracture between computed tomography (CT) imaging of the chest, abdomen, and spine (CT CAP) and CT for the thoracolumbar spine (CT TL). METHODS: We retrospectively identified patients at our institution with a TLS fracture over a two-year period that had both CT CAP and reformatted CT TL imaging. The sensitivity of CT CAP to identify fracture was calculated for each fracture type. RESULTS: A total of 516 TLS fractures were identified in 125 patients using reformatted CT TL spine imaging. Overall, 69 of 512 fractures (13%) were missed on CT CAP that were identified on CT TL. Of those, there were no clinically significant missed fractures. CONCLUSIONS: CT CAP could potentially be used as a screening tool for clinically significant TLS injuries. PMID- 29246408 TI - Cystic echinococcosis in Jordan: A review of causative species, previous studies, serological and radiological diagnosis. AB - Cystic echinococcosis (CE)/hydatidosis is a zoonotic disease which occur in human and herbivore animals as a result of infection with the larval stage of the taeniid cestode Echinococcus granulosus sensu lato (s. l.). In human, CE is a serious public health concern in many parts of the world including Jordan. The present review will cover CE causative agent: E. granulosus species/genotypes; life cycle of E. granulosus parasite, all published previous studies on CE in Jordan (humans, intermediate hosts, definitive host) as well as its diagnostic methods in human. PMID- 29246409 TI - The behavioural and physiological stress responses are linked to plumage coloration in the rock pigeon (Columbia livia). AB - In wild vertebrates, conspicuousness often signals a high phenotypic quality and is therefore associated with fitness benefits ("the handicap principle hypothesis"). However, conspicuous individuals usually face a higher risk of predation because they are easier to detect. Therefore, conspicuous individuals are expected to modify their behavioural and their physiological stress responses to limit the negative effect of their conspicuousness on survival. We examined the link between plumage coloration and the stress response in a bird species (the rock pigeon, Columbia livia) by comparing two groups of pigeons with different plumage characteristics: 'blue-bar' birds (lighter birds) and 'checker' birds (darker birds). Specifically, we measured several behavioural and physiological components of the stress response (breath rate, corticosterone, and tonic immobility). Although breath rate did not differ between 'checker' and 'blue bar' birds, the corticosterone stress response of 'blue-bar' birds was greater relative to that of 'checker' birds. Moreover, 'checker' birds were more likely to initiate tonic immobility relative to 'blue bar' birds. Therefore, this study suggests that the behavioural and physiological stress responses of wild birds may differ according to their plumage coloration. To conclude, our results suggest that plumage colorations may be functionally linked to specific behavioural and physiological sensitivities to stressors. PMID- 29246410 TI - Guided bone regeneration with nonresorbable and resorbable membranes may not result in different rates of complications or achieve different vertical bone growth. PMID- 29246411 TI - No apparent differences in postoperative pain and treatment success between mature permanent teeth with carious pulp exposure treated with pulpotomy or root canal treatment after 1 and one-half years. PMID- 29246412 TI - Cold irrigation results in less severe pain after root canal treatment than conventional irrigation in teeth with symptomatic apical periodontitis, but the difference may be negligible after the first day. PMID- 29246413 TI - Low-certainty evidence suggests high 5-year survival rate of all-ceramic resin bonded fixed dental prostheses, and framework design and ceramic material may be associated with survival and complication rates. PMID- 29246414 TI - HPV vaccination. PMID- 29246415 TI - Beneficial association between active travel and metabolic syndrome in Latin America: A cross-sectional analysis from the Chilean National Health Survey 2009 2010. AB - BACKGROUND: There is limited evidence on potential health benefits of active travel, independently of leisure-time physical activity (PA), with metabolic syndrome (MetS) in Latin-America. OBJECTIVE: To investigate the relationship between active travel and metabolic syndrome (MetS) and its components in a national representative sample of Chilean adults. METHODS: Cross-sectional study of 2864 randomly selected adults' participants enrolled in the 2009-2010 Chilean National Health Survey (CNHS). Self-reported PA was obtained with the validated Global PA Questionnaire and classifying participants into insufficiently active (<150min/week) or active (>=150min/week). MetS was diagnosed from the modified Adult Treatment Panel (ATP) III criteria with national-specific abdominal obesity cut points. Multilevel logistic regression analysis was applied to estimate associations of travel PA with MetS and its components at a regional level, adjusted for socio-demographic characteristics and other types of PA. RESULTS: 46.2% of the sample engaged in 150min/week of active travel and the prevalence of MetS was 33.7%. Mets was significantly lower among active travel participants. Active travel was associated with lower odds of MetS (OR 0.72; 95%CI 0.61-0.86), triglycerides (OR 0.77; 95%CI 0.64-0.92) and abdominal obesity (OR 0.82; 95%CI 0.69-0.97) after controlling for socio-demographics and other types of PA. CONCLUSION: Active travel was negatively associated with MetS, triglycerides and abdominal obesity. Efforts to increase regional active travel should be addressed as a measure to prevent and reduce the prevalence of MetS and disease burden in middle income countries. PMID- 29246416 TI - Hepatobiliary involvement in systemic sclerosis and the cutaneous subsets: Characteristics and survival of patients from the Spanish RESCLE Registry. AB - OBJECTIVE: To assess the prevalence and causes of hepatobiliary involvement (HBI) in systemic sclerosis (SSc), to investigate the clinical characteristics and prognosis of SSc patients with HBI (SSc-HBI) and without HBI (SSc-non-HBI), and to compare both groups according to the cutaneous SSc subsets. METHODS: In all, 1572 SSc patients were collected in the RESCLE registry up to January 2015, and all hepatobiliary disturbances were recorded. We investigated the HBI-related characteristics and survival from the entire SSc cohort and according to the following cutaneous subsets: diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and SSc sine scleroderma (ssSSc). RESULTS: Out of 1572, 118 (7.5%) patients had HBI. Primary biliary cholangitis (PBC) was largely the main cause (n = 67, 4.3%), followed by autoimmune hepatitis (n = 19, 1.2%), and anti mitochondrial negative PBC (n = 6, 0.4%). Other causes of HBI were as follows: secondary liver diseases (n = 11, 0.7%), SSc-related HBI (n = 7, 0.4%), nodular regenerative hyperplasia (n = 3, 0.2%), liver cirrhosis (n = 3, 0.2%), and HBI of unknown origin (n = 2, 0.1%). In multivariate analysis, HBI was independently associated to lesser risk of dcSSc (5.1% vs. 24.4%), and higher frequency of calcinosis (26% vs. 18%), left ventricular diastolic dysfunction (46% vs. 27%), sicca syndrome (51% vs. 29%), and anti-centromere antibodies (ACA, 73% vs. 44%). According to the cutaneous subsets, HBI was associated (1) in lcSSc, to longer time from SSc onset to diagnosis (10.8 +/- 12.5 vs. 7.2 +/- 9.3 years), sicca syndrome (54% vs. 33%), and ACA (80% vs. 56%); (2) in ssSSc, to sicca syndrome (44% vs. 19%), and (3) in dcSSc, no associations were found. HBI was the cause of death in 2.3% patients but the cumulative survival according to the presence or absence of HBI showed no differences. CONCLUSIONS: HBI prevalence in SSc is 7.5% and dcSSc is the least involved subset. PBC is the main cause of HBI. Patients with SSc-HBI exhibited specific clinical and immunologic profile. Survival is similar for SSc patients with HBI. PMID- 29246419 TI - HLA Epitope Matching in Kidney Transplantation: An Overview for the General Nephrologist. AB - Rapid changes in tissue-typing technology, including the widespread availability of highly specific molecular typing methods and solid-phase assays for the detection of allele-specific anti-HLA antibodies, make it increasingly challenging to remain up to date with developments in organ matching. Terms such as epitopes and eplets abound in the transplantation literature, but often it can be difficult to see what they might mean for the patient awaiting transplantation. In this review, we provide the historical context for current practice in tissue typing and explore the potential role of HLA epitopes in kidney transplantation. Despite impressive gains in preventing and managing T cell-mediated rejection and the associated improvements in graft survival, the challenge of the humoral alloresponse remains largely unmet and is the major cause of late graft loss. Describing HLA antigens as a series of antibody targets, or epitopes, rather than based on broad seroreactivity patterns or precise amino acid sequences may provide a more practical and clinically relevant system to help avoid antibody-mediated rejection, reduce sensitization, and select the most appropriate organs in the setting of pre-existing alloantibodies. We explain the systems proposed to define HLA epitopes, summarize the evidence to date for their role in transplantation, and explore the potential benefits of incorporating HLA epitopes into clinical practice as this field continues to evolve toward everyday practice. PMID- 29246417 TI - What Is the Outcome of an Incision and Drainage Procedure in Endodontic Patients? A Prospective, Randomized, Single-blind Study. AB - INTRODUCTION: There are no prospective endodontic studies to determine the outcome of an incision and drainage (I&D) procedure for swelling in healthy, endodontic patients. The purpose of this prospective, randomized, single-blind study was to compare the postoperative course of I&D with drain placement versus a mock I&D procedure with mock drain placement after endodontic debridement in swollen emergency patients with symptomatic teeth and a pulpal diagnosis of necrosis. METHODS: Eighty-one adult emergency patients presenting with clinical swelling received either penicillin or, if allergic, clindamycin and complete endodontic debridement, and then were randomly divided into 2 treatment groups: I&D with drain placement or a mock I&D procedure with mock drain placement. At the end of the appointment, all patients received a combination of ibuprofen/acetaminophen and, if needed, an opioid-containing escape medication. Patients recorded their pain and medication use for 4 days postoperatively. Success was defined as no or mild postoperative pain and no use of an opioid containing escape medication. Success was evaluated using repeated measure mixed model logistic regression. RESULTS: Both groups had a decrease in postoperative pain and medication use over the 4 days. The mock I&D group had significantly higher success than the I&D group (odds ratio = 2.00; 95% confidence interval, 1.16-3.41). The success rate was 45% with the mock I&D and 33% with the I&D. CONCLUSIONS: After endodontic debridement, patients who received a mock I&D procedure with mock drain placement had more success than patients who received I&D with drain placement. Both groups clinically improved over 4 days. PMID- 29246418 TI - Assessment of adrenomedullin and proadrenomedullin as predictors of mortality in septic patients: A systematic review and meta-analysis. AB - OBJECTIVE: To ascertain the ability of adrenomedullin (ADM) and proadrenomedullin (proADM) to predict mortality in sepsis patients. DESIGN: A systematic literature search was made of the PubMed, EMBASE, Cochrane and China National Knowledge Infrastructure (CNKI) databases before May 2017, supplemented by manual searches of references. A meta-analysis of high-quality clinical studies was subsequently performed to assess the association between ADM/proADM and mortality risk among patients with sepsis. PATIENTS: Thirteen studies involving 2556 patients were included in the study. INTERVENTIONS: Two reviewers independently identified articles, extracted data, assessed quality and cross-checked the results. The predictive values of ADM and proADM referred to mortality were assessed by relative risk (RR). The overall diagnostic accuracy of ADM and proADM in application to sepsis was pooled according to a bivariate model. Publication bias was assessed using Deek's funnel plot asymmetry test. RESULTS: Elevated ADM or proADM levels were associated with increased mortality (pooled RR=3.31; 95%CI 2.31-4.75). Subgroup analyses indicated the pooled RRs were 3.12 (95%CI 1.75 5.56) and 3.43 (95%CI 2.21-5.31) for ADM and proADM, respectively. The pooled sensitivity and specificity were 0.72 (95%CI 0.64-0.78) and 0.77 (95%CI 0.69 0.83), respectively. The overall area under the summary receiver operating characteristic (SROC) curve was 0.80 (95%CI 0.77-0.84). Publication bias was not statistically significant. CONCLUSIONS: Both ADM and proADM might serve as useful markers for predicting the prognosis of sepsis. PMID- 29246420 TI - LMX1B-Associated Nephropathy With Type III Collagen Deposition in the Glomerular and Tubular Basement Membranes. AB - Variants in the LMX1B gene cause nail-patella syndrome, a rare autosomal dominant disorder characterized by dysplasia of nails, patella and elbow abnormalities, iliac "horns," and glaucoma. We describe an adult man with nephrotic syndrome and no systemic manifestations of nail-patella syndrome at the time of his initial kidney biopsy. His kidney biopsy was initially interpreted as a form of segmental sclerosis with unusual fibrillar deposits. At the time of consideration for kidney transplantation, a family history was notable for end-stage renal disease in 3 generations. Subsequent reanalysis of the initial biopsy showed infiltration of the lamina densa by type III collagen fibrils, and molecular studies identified a pathogenic variant in one allele of LMX1B (a guanine to adenine substitution at nucleoide 737 of the coding sequence [c.737G>A], predicted to result in an arginine to glutamine substitution at amino acid 246 [p.Arg246Gln]). This variant has been described previously in multiple unrelated families who presented with autosomal dominant nephropathy without nail and patellar abnormalities. PMID- 29246422 TI - Performance comparison of chiral separation materials derived from N cyclohexylcarbonyl and N-hexanoyl chitosans. AB - Chitosan bis(phenylcarbamate)-(N-cyclohexylformamide)s and chitosan bis(phenylcarbamate)-(N-hexanamide)s were synthesized as chiral selectors for enantiomeric separation. Since two types of substituents with different structures were, respectively, introduced onto the 2-position and the 3-/6 positions of the glucose skeleton in the chitosans through a "heterogeneous" modification pathway, the enantioseparation performances of the chiral selectors could be improved. Influence of the type and position of the substituents on chiral recognition and enantioseparation abilities was studied in detail, and the structural dependence on enantioseparation performance was particularly demonstrated. It was found that methyl- and chloro-substituted chitosan bis(phenylcarbamate)-(N-hexanamide)s possessed comparable enantioseparation performances, whereas chloro-substituted chitosan bis(phenylcarbamate)-(N cyclohexylformamide)s exhibited much more powerful chiral recognition and enantioseparation abilities than the methyl-substituted ones. Among all the prepared chiral selectors, those with the combination of the cyclohexyl group at the 2-position of the glucose skeleton in the chitosan derivatives and the chlorophenyl group at the 3-/6-positions seemed to be more preferable for enantiomeric separation. As a result, the chitosan bis(3,4 dichlorophenylcarbamate)-(N-cyclohexylformamide) possessed the best enantioseparation performance. The solvent tolerability of the prepared chiral selectors was also investigated in the present study. Compared with the classical coated-type chiral separation materials derived from cellulose/amylose derivatives, the N-cyclohexylcarbonyl and N-hexanoyl chitosans based chiral stationary phases were observed to possess more favorable solvent tolerability, thus possibly widening their applications for various practical enantioseparations. PMID- 29246421 TI - Evaluation of mutual interference between bovine alpha-lactalbumin peptide and its isotope-labeled peptide in whey protein analysis using liquid chromatography tandem mass spectrometry. AB - Internal standard (IS) method is commonly used to correct the matrix effect of samples in the liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis of whey proteins. However, the presence of mutual interference between some peptides and their isotope-labeled peptides distorts the MS signals, requiring a fundamental evaluation to understand the phenomenon of signal variations. In this study, a simple strategy is proposed to evaluate the effects of sample pretreatment, materials and dilution of solutions on the MS signals of alpha-lactalbumin (VGINYWLAHK) and beta-lactoglobulin peptides using two typical LC-MS/MS systems, Q-Trap and Q-Orbitrap. The strategy adapts the experimental MS data to optimize methods, thus providing meaningful solutions to suppress the mutual interference presented in the analysis of peptides. As a result, the strategy through the combination of 100-fold dilution and plastic injection vial improves the quantitation results of alpha-lactalbumin peptide significantly. While the beta-lactoglobulin peptide presents different phenomenon of signal variations when compared with that of alpha-lactalbumin peptide, revealing that each peptide needs to be optimized individually. The calibration effect of different IS was also studied in fifteen infant milk powders to confirm the mutual interference impact to quantification result. These results indicated that a simple strategy through the combination of sample dilution and plastic injection vial could be well extended to quantitative analysis of any other peptide in the complex systems. PMID- 29246423 TI - Sequencing of bimaxillary surgery in the correction of vertical maxillary excess: retrospective study. AB - The aim of this study was to evaluate the precision of bimaxillary surgery performed to correct vertical maxillary excess, when the procedure is sequenced with mandibular surgery first or maxillary surgery first. Thirty-two patients, divided into two groups, were included in this retrospective study. Group 1 comprised patients who received bimaxillary surgery following the classical sequence with repositioning of the maxilla first. Patients in group 2 received bimaxillary surgery, but the mandible was operated on first. The precision of the maxillomandibular repositioning was determined by comparison of the digital prediction and postoperative tracings superimposed on the cranial base. The data were tabulated and analyzed statistically. In this sample, both surgical sequences provided adequate clinical accuracy. The classical sequence, repositioning the maxilla first, resulted in greater accuracy for A-point and the upper incisor edge vertical position. Repositioning the mandible first allowed greater precision in the vertical position of pogonion. In conclusion, although both surgical sequences may be used, repositioning the mandible first will result in greater imprecision in relation to the predictive tracing than repositioning the maxilla first. The classical sequence resulted in greater accuracy in the vertical position of the maxilla, which is key for aesthetics. PMID- 29246424 TI - Comparative study of volumetric changes and trabecular microarchitecture in human maxillary sinus bone augmentation with bioactive glass and autogenous bone graft: a prospective and randomized assessment. AB - The aim of this study was to compare the volumetric changes and the new bone microarchitecture in human maxillary sinuses augmented with bioactive glass (Biogran) alone, bioactive glass combined with autogenous bone graft (1:1), or autogenous bone graft alone. Twelve maxillary sinuses were grafted with bioactive glass (group 1), nine with bioactive glass mixed with autogenous bone graft 1:1 (group 2), and 12 with autogenous bone graft (group 3). Patients underwent cone beam computed tomography 15days after the procedure to determine the initial volume of the graft (T1) and again 6 months later (T2). Biopsies were obtained at the time of dental implant placement and were subjected to micro-computed tomography. The volumetric change was 44.2% in group 1, 37.9% in group 2, and 45.7% in group 3 (P>0.05). The trabecular microarchitecture results showed that the materials used in groups 1 and 2 were good bone substitutes. However, the addition of 50% bioactive glass to autogenous bone graft improved the microarchitecture of the graft. Furthermore, the results for volumetric changes indicated that bioactive glass, its association with autogenous bone graft in a 1:1 ratio, and autogenous bone graft alone have similar resorption. PMID- 29246425 TI - Fatal attraction - A brief pathophysiology of the interaction between atrial fibrillation and myocardial ischemia. AB - Atrial fibrillation and coronary artery disease are highly prevalent diseases in an aging population. They share risk factors and are frequently associated. Beyond their mere association, they impact on each other. The positive feed-back between atrial fibrillation and acute myocardial ischemia involves sympathetic activation and may result in sudden death. PMID- 29246426 TI - Adverse outcome has a U-shaped relation with acute phase change in insulin sensitivity after ST-Elevation Myocardial Infarction. AB - BACKGROUND: Although stress hyperglycemia after myocardial infarction (MI) is consistently associated with increased mortality, recent studies suggest that the addition of upstream markers of glucose metabolism may improve risk identification. Hence, our aim was to evaluate the association between insulin sensitivity changes during MI hospitalization and outcomes. METHODS: A prospective cohort of 331 consecutive ST-Elevation MI (STEMI) patients without insulin provision therapy was used for the analyses. Blood samples were collected upon admission (D1) and after 5days (D5) of the inciting event. We measured blood glucose and insulin to estimate insulin sensitivity using the updated Homeostasis Model Assessment (HOMA2S). Patients were assessed for intra-hospital death and major adverse cardiac events (MACE) during follow-up. RESULTS: HOMA2S was 62%+/ 52% on D1 and 86%+/-57% on D5 (p<0.001). Total follow-up was a median of 2 (0.9 2.8) years and found a U-shaped relation between the change in HOMA2S from D1 to D5 (DeltaHOMA2S) and major adverse cardiac events (MACE) (p=0.017). Fully adjusted cox-regression models showed that patients from T1 and T3 were about 2.5 times more prone to suffer from MACE than those in T2. Net Reclassification Index adding DeltaHOMA2S as a categorical variable dichotomized as T2 and T1 or T3 to a model of GRACE risk score with glucose D1 yielded a better predictive model (0.184 [95% CI 0.124-0.264]; p=0.032). CONCLUSION: A U-shaped curve describes the relation between insulin sensitivity change and MACE during acute phase STEMI and, thus indicating that acute dysglycemia must be appreciated in light of a time spectrum and insulin levels. PMID- 29246427 TI - Diverging patterns of cardiovascular diseases across immigrant groups in Northern Italy. AB - BACKGROUND: Only fragmentary data are available on the burden of non-communicable diseases among immigrants in Europe, mostly limited to mortality by cause. Aim of the study is to investigate the prevalence of cardiovascular diseases across different immigrant groups in the Veneto Region (North-Eastern Italy). METHODS: The resident population aged 20-59 was classified according to country of citizenship. The Adjusted Clinical Groups System was adopted to identify selected cardiovascular conditions by linkage of Hospital Discharge Records, Emergency Room visits, Chronic disease registry for copayment exemptions, the Home care database, and drugs reimbursed by the Regional Health Service. Age standardized prevalence rates were compared across population groups, and rate ratios (RR) with 95% confidence intervals (CI) were computed taking the Italian population as reference. RESULTS: The prevalence of diabetes was higher across all immigrant groups compared to Italians. Specific risk patterns could be identified associated to different ethnicities: South Asian immigrants were at very high risk of diabetes, dyslipidemia, and ischemic heart disease (males RR 2.3, CI 1.9 2.8; females RR 2.0, CI 1.2-3.5). Immigrants from Africa were affected by high rates of hypertension, cerebrovascular diseases, and heart failure, with a more pronounced unfavorable profile among females (hypertension RR 3.0, CI 2.6-3.3; cerebrovascular diseases RR 1.7, CI 1.1-2.7). CONCLUSIONS: Wide differences in the prevalence of cardiovascular diseases could be detected across immigrant groups. These findings represent a first step towards systematic chronic disease surveillance by ethnicity, a fundamental tool for shaping culturally-tailored prevention strategies. PMID- 29246428 TI - Comparison of procedural, clinical and valve performance results of transcatheter aortic valve replacement in patients with bicuspid versus tricuspid aortic stenosis. AB - BACKGROUND: Limited date describing the procedural, clinical and valve performance results of transcatheter aortic valve replacement (TAVR) in patients with bicuspid versus tricuspid aortic stenosis (TAV). METHODS: Procedural and clinical results were defined and reported according to VARC-2 criteria. RESULTS: Consecutive 87 patients with BAV and 70 patients with TAV were included. Compared to patients with TAV, patients with BAV had similar incidence of second valve implantation (14.9% vs 12.9%, p=0.708), more than mild paravalvular leakage (PVL, 40.2% vs 31.9%, p=0.288), permanent pacemaker implantation (PPM, 24.1% vs 28.6%, p=0.53). Furthermore, the procedural and clinical results of TAVR also did not differ between patients with type 0 and type 1 (second valve implantation: 18.4% vs 11.8%, p=0.71, PVL: 38.8% vs 41.2%, p=0.83, PPM: 18.4% vs 31.6%, p=0.16). The hemodynamic outcomes were similar in patients with BAV and TAV at 1-year (maximum velocity, 2.3 vs 2.2m/s, p=0.307) and 2-year (2.3 vs 2.1m/s, p=0.184) follow-up respectively. Adjusted binary logistic regression analysis found oversizing ratio at 14.45-20.57% is at lower risk for more than mild PVL (OR, 0.069, 95% CI, 0.011 0.428, p=0.004). Moreover, the Kaplan-Meier survival analysis revealed that TAVR in type 0 BAV, type 1 BAV and TAV have comparable risk for midterm mortality (Log rank, p=0.772). CONCLUSION: TAVR in whatever type of BAV appeared to be safe and efficacy, and TAVR in BAV was associated with comparable bioprosthetic function during follow up compared to patients with TAV. PMID- 29246429 TI - Statistical models to predict adverse perioperative outcomes: A case for longer follow up time frames. PMID- 29246430 TI - Impacts of Implantable Collamer Lens V4c Placement on Angle Measurements Made by Optical Coherence Tomography: Two-Year Follow-up. PMID- 29246431 TI - Bypassing human CoQ10 deficiency. AB - Primary disorders of the human coenzyme Q10 (CoQ10) biosynthesis pathway are a known cause of severe pediatric diseases. So far, oral administration of CoQ10 is the only treatment strategy for affected individuals. However, the real benefit of CoQ10 supplementation remains questionable and clinical studies regarding efficiency are lacking. Here we provide an outlook on novel treatment approaches using CoQ precursor compounds. These metabolic bypass strategies might be a promising alternative for oral CoQ10 supplementation regimens. PMID- 29246433 TI - Clinical Utility of Noninvasive Method to Measure Specific Gravity in the Pediatric Population. AB - BACKGROUND: Clinicians rely on any combination of signs and symptoms, clinical scores, or invasive procedures to assess the hydration status in children. Noninvasive tests to evaluate for dehydration in the pediatric population are appealing. OBJECTIVE: The objective of our study is to assess the utility of measuring specific gravity of tears compared to specific gravity of urine and the clinical assessment of dehydration. METHODS: We conducted a prospective cohort convenience sample study, in a pediatric emergency department at a tertiary care children's hospital. We approached parents/guardians of children aged 6 months to 4 years undergoing transurethral catheterization for evaluation of urinary tract infection for enrollment. We collected tears and urine for measurement of tear specific gravity (TSG) and urine specific gravity (USG), respectively. Treating physicians completed dehydration assessment forms to assess for hydration status. RESULTS: Among the 60 participants included, the mean TSG was 1.0183 (SD = 0.007); the mean USG was 1.0186 (SD = 0.0083). TSG and USG were positively correlated with each other (Pearson Correlation = 0.423, p = 0.001). Clinical dehydration scores ranged from 0 to 3, with 87% assigned a score of 0, by physician assessment. Mean number of episodes of vomiting and diarrhea in a 24 hour period were 2.2 (SD = 3.9) and 1.5 (SD = 3.2), respectively. Sixty-two percent of parents reported decreased oral intake. CONCLUSION: TSG measurements yielded similar results compared with USG. Further studies are needed to determine if TSG can be used as a noninvasive method of dehydration assessment in children. PMID- 29246432 TI - Adolescents exposed to the World Trade Center collapse have elevated serum dioxin and furan concentrations more than 12years later. AB - BACKGROUND: The collapse of the World Trade Center (WTC) on September 11, 2001 released a dust cloud containing numerous environmental contaminants, including polychlorinated dibenzo-para-dioxins and polychlorinated dibenzofurans (PCDD/Fs). PCDD/Fs are toxic and are associated with numerous adverse health outcomes including cancer, diabetes, and impaired reproductive and immunologic function. Prior studies have found adults exposed to the WTC disaster to have elevated levels of PCDD/Fs. This is the first study to assess PCDD/F levels in WTC-exposed children. METHODS: This analysis includes 110 participants, a subset of the 2014 2016 WTC Adolescent Health Study, a group of both exposed youths who lived, attended school, or were present in lower Manhattan on 9/11 recruited from the WTC Health Registry (WTCHR) and unexposed youths frequency matched on age, sex, race, ethnicity, and income. Our sample was selected to maximize the contrast in their exposure to dust from the WTC collapse. Questionnaire data, including items about chronic home dust and acute dust cloud exposure, anthropometric measures, and biologic specimens were collected during a clinic visit. Serum PCDD/F concentrations were measured according to a standardized procedure at the New York State Department of Health Organic Analytical Laboratory. We used multivariable linear regression to assess differences in PCCD/Fs between WTCHR and non-WTCHR participants. We also compared mean and median PCDD/F and toxic equivalency (TEQ) concentrations in our cohort to 2003-4 National Health and Nutrition Examination Survey (NHANES) levels for youths age 12-19. RESULTS: Median PCDD/F levels were statistically significantly higher among WTCHR participants compared to non-WTCHR participants for 16 out of 17 congeners. Mean and median TEQ concentrations in WTCHR participants were >7 times those in non WTCHR participants (72.5 vs. 10.1 and 25. 3 vs. 3.39pg/g lipid, respectively). Among WTCHR participants, median concentrations of several PCDD/Fs were higher than the NHANES 95th percentiles. After controlling for dust cloud exposure, home dust exposure was significantly associated with higher PCDD/F level. CONCLUSIONS: Adolescents in lower Manhattan on the day of the WTC attack and exposed to particulate contamination from the WTC collapse had significantly elevated PCDD/F levels >12years later compared to a matched comparison group, driven by chronic home dust exposure rather than acute dust cloud exposure. PCDD/F and TEQ levels substantially exceeded those in similar-aged NHANES participants. Future studies are warranted to explore associations of PCDD/Fs with health and developmental outcomes among individuals exposed to the WTC disaster as children. PMID- 29246434 TI - Endovascular Repair of Acute Thoraco-abdominal Aortic Aneurysms. AB - OBJECTIVES: The outcome of endovascular repair (EVAR) for acute thoraco-abdominal aortic aneurysm (TAAA) is reported and the applicability of the t-Branch off the shelf (OTS) device is determined. METHODS: Interrogation of a prospectively maintained database identified all patients who underwent EVAR for acute TAAA between September 2012 (when the first non-elective t-Branch case was performed) and November 2015. Early and medium-term outcomes were analysed. Survival and re intervention-free survival were calculated by Kaplan-Meier analysis. RESULTS: A total of 39 patients (27 men; mean +/- SD age, 72 +/- 8 years) were treated for acute symptomatic (n = 29) or ruptured (n = 10) TAAA (20 anatomical extent I-III, 19 extent IV). Fourteen patients had mycotic aneurysms. The mean aneurysm diameter was 80 +/- 20 mm. The mean +/- SD follow-up was 21.4 +/- 15.4 months. Surgeon modified fenestrated EVAR was used in 24 patients, chimney/periscope EVAR in two, and t-Branch in 13 (33%) patients. Aortic coverage was greater than 40 mm above the coeliac axis in all patients. A total of 127 target vessels (TVs) were preserved (mean 3.3 per patient) and two occluded within 30 days. The 30 day mortality was 26%. Four (10%) patients developed spinal cord ischaemia (SCI): two with paraplegia died within 30 days, and two with paraparesis recovered completely with blood pressure manipulation and cerebrospinal fluid drainage. Estimated overall survival (+/-SD) at 12 and 24 months was 71.8 +/- 7.2% and 63.2 +/- 7.9%, respectively. Estimated freedom from re-intervention at 12 and 24 months was 93 +/- 4.8% and 85.3 +/- 6.8%, respectively. CONCLUSIONS: EVAR for acute TAAA is associated with acceptable early and mid-term results in patients who have no other treatment options. Only one third of these patients were suitable for the t-Branch device, indicating that further advances in device design are required to treat the majority of acute TAAA patients with commercially available OTS technology. PMID- 29246435 TI - Re: "Catheter Foam Sclerotherapy of the Great Saphenous Vein, with Peri-saphenous Tumescence Infiltration and Saphenous Irrigation"-Is Modified Catheter Foam Sclerotherapy a Step Back in the Evolution of Endovenous Ablation for Varicose Veins? PMID- 29246437 TI - (-)-P7C3-S243 Protects a Rat Model of Alzheimer's Disease From Neuropsychiatric Deficits and Neurodegeneration Without Altering Amyloid Deposition or Reactive Glia. AB - BACKGROUND: In addition to cognitive deficits, Alzheimer's disease (AD) is associated with other neuropsychiatric symptoms, including severe depression. Indeed, depression often precedes cognitive deficits in patients with AD. Unfortunately, the field has seen only minimal therapeutic advances, underscoring the critical need for new treatments. P7C3 aminopropyl carbazoles promote neuronal survival by enhancing nicotinamide adenine dinucleotide flux in injured neurons. Neuroprotection with P7C3 compounds has been demonstrated in preclinical models of neurodegeneration by virtue of promoting neuronal survival independently of early disease-specific pathology, resulting in protection from cognitive deficits and depressive-like behavior. We hypothesize that P7C3 compounds might be uniquely applicable to patients with AD, given the comorbid presentation of depression and cognitive deficits. METHODS: Aging male and female wild-type and TgF344-AD rats, a well-characterized preclinical AD model, were administered (-)-P7C3-S243 daily for 9 and 18 months, beginning at 6 months of age. Behavioral phenotypes related to cognition and depression were assessed at 15 and 24 months, and brain pathology and biochemistry were assessed at 24 months. RESULTS: (-)-P7C3-S243 safely protected aging male and female wild-type and TgF344-AD rats from cognitive deficits and depressive-like behavior. Depressive-like behavior occurred earlier than cognitive deficits in TgF344-AD rats, consistent with AD in many patients. Treatment with (-)-P7C3-S243 blocked neurodegeneration in TgF344-AD rats, without altering amyloid deposition or indicators of neuroinflammation. CONCLUSIONS: Neuronal cell death-specific treatment approaches, such as P7C3 compounds, may represent a new treatment approach for patients experiencing the combination of cognitive deficits and depression associated with AD. PMID- 29246436 TI - Prefrontal Cortex Stimulation Enhances Fear Extinction Memory in Humans. AB - BACKGROUND: Animal fear conditioning studies have illuminated neuronal mechanisms of learned associations between sensory stimuli and fear responses. In rats, brief electrical stimulation of the infralimbic cortex has been shown to reduce conditioned freezing during recall of extinction memory. Here, we translated this finding to humans with magnetic resonance imaging-navigated transcranial magnetic stimulation (TMS). METHODS: Subjects (N = 28) were aversively conditioned to two different cues (day 1). During extinction learning (day 2), TMS was paired with one of the conditioned cues but not the other. TMS parameters were similar to those used in rat infralimbic cortex: brief pulse trains (300 ms at 20 Hz) starting 100 ms after cue onset, total of four trains (28 TMS pulses). TMS was applied to one of two targets in the left frontal cortex, one functionally connected (target 1) and the other unconnected (target 2, control) with a human homologue of infralimbic cortex in the ventromedial prefrontal cortex. Skin conductance responses were used as an index of conditioned fear. RESULTS: During extinction recall (day 3), the cue paired with TMS to target 1 showed significantly reduced skin conductance responses, whereas TMS to target 2 had no effect. Further, we built group-level maps that weighted TMS-induced electric fields and diffusion magnetic resonance imaging connectivity estimates with fear level. These maps revealed distinct cortical regions and large-scale networks associated with reduced versus increased fear. CONCLUSIONS: The results showed that spatiotemporally focused TMS may enhance extinction learning and/or consolidation of extinction memory and suggested novel cortical areas and large scale networks for targeting in future studies. PMID- 29246438 TI - Nano-scale and molecular-level understanding of wet-milled indomethacin/poloxamer 407 nanosuspension with TEM, suspended-state NMR, and Raman measurements. AB - We investigated the formation and stabilization mechanisms of indomethacin (IMC)/poloxamer 407 nanosuspensions. Stable nanosuspensions were prepared via 24 h wet-milling of three IMC forms (gamma form, alpha form, and amorphous) with poloxamer 407. Cryogenic-transmission electron microscopy images of nanoparticles obtained using gamma-form IMC indicated a rhombic-plate shape. In contrast, needle-like nanoparticles were observed in the nanosuspensions of alpha-form and amorphous IMC. Suspended-state cross polarization 13C NMR and Raman measurements directly detected the molecular states of IMC in nanosuspensions. IMC existed in its initial crystal form when gamma-form and alpha-form IMC were used; amorphous IMC transformed into crystalline alpha-form IMC. Suspended-state 13C pulse saturation transfer NMR measurements revealed the molecular state of poloxamer 407 on the surface of IMC crystals. The polypropylene oxide group adsorbed to the IMC crystal surface via hydrophobic interactions, while the polyethylene oxide group on the surface was as flexible as that in polymeric micelles. The equilibrium of poloxamer 407 between micelle and nanocrystal surfaces was slower than the NMR time scale, which could stabilize the dispersion of the nanoparticles in water. The time interval evaluation during the wet-milling process revealed that alpha-form IMC nanocrystals could be efficiently prepared via wet-milling using amorphous IMC as the starting material. PMID- 29246439 TI - Development of solidified self-microemulsifying drug delivery systems containing l-tetrahydropalmatine: Design of experiment approach and bioavailability comparison. AB - The study first aimed to apply a design of experiment (DoE) approach to investigate the influences of excipients on the properties of liquid self microemulsifying drug delivery system (SMEDDS) and SMEDDS loaded in the pellet (pellet-SMEDDS) containing l-tetrahydropalmatine (l-THP). Another aim of the study was to compare the bioavailability of l-THP suspension, liquid SMEDDS and pellet-SMEDDS in the rabbit model. By using Central Composite Face design (CCF), the optimum ratio of Capryol 90, and Smix '(Cremophor RH 40: Transcutol HP) in the formulation of SMEDDS was determined. This optimum SMEDDS was absorbed on the solid carrier (Avicel or Aerosil) for the preparation of pellet-SMEDDS by extrusion and spheronization method. The ANOVA table indicated that Avicel was more effective than Aerosil, the traditional solid carrier, in both terms of preservation of dissolution rate of l-THP from the original SMEDDS and pelletization yield. Results obtained from scanning electron microscopy (SEM) indicated that the existence of liquid SMEDDS droplets on the surface of pellet SMEDDS was due to the absorption on Avicel. The powder X-ray diffractometry proved the amorphous state of l-THP in pellet-SMEDDS. Pharmacokinetic study in the rabbit model using liquid chromatography tandem mass spectrometry showed that the SMEDDS improved the oral bioavailability of l-THP by 198.63% compared to l THP suspension. Besides, pharmacokinetics study also proved that the mean relative bioavailability (AUC) and mean maximum concentration (Cmax) of pellet SMEDDS were not significantly different from the original liquid SMEDDS (p > 0.05). PMID- 29246440 TI - Design and characterization of a perivascular PLGA coated PET mesh sustaining the release of atorvastatin for the prevention of intimal hyperplasia. AB - Following vascular bypass interventions, autologous saphenous vein grafts are prone to fail due to intimal hyperplasia development. An atorvastatin (ATV) eluting tubular mesh coated with poly(d,l-lactide-co-glycolisde) acid (PLGA) was designed for perivascular application, in order to prevent the development of this pathology. Formulation parameters such as PLGA molecular weight, concentration of ATV and PLGA in the coating solution and number of coatings were investigated to optimise the mesh in terms of drug loading efficacy, drug release kinetics and mechanical properties. Using the dip-coating technique, 1.6 mg of ATV was loaded on a tubular 5 cm long mesh. The most important parameter influencing ATV loading was the concentration of the drug in the coating solution. In vitro an ATV release profile combining an initial fast release over 3 days and a sustained release over 40 days was obtained; consistent with the timeframe of hyperplasia development. The amount of PLGA polymer coating as well as the molecular weight of the polymer were optimized to achieve these kinetics. A poly(d,l-lactide-co-caprolactone) (PLCL) layer was sprayed on the external side of the PLGA coated tubular mesh to restrict the ATV release to the vascular tissue. Scanning electron microscopy observation showed that the macroporosity of the mesh was preserved after coating, while texture analysis demonstrated that its elasticity decreased slightly. PMID- 29246441 TI - Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells. AB - Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17~92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells. PMID- 29246443 TI - Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection. AB - During chronic stimulation, CD8+ T cells acquire an exhausted phenotype characterized by expression of inhibitory receptors, down-modulation of effector function, and metabolic impairments. T cell exhaustion protects from excessive immunopathology but limits clearance of virus-infected or tumor cells. We transcriptionally profiled antigen-specific T cells from mice infected with lymphocytic choriomeningitis virus strains that cause acute or chronic disease. T cell exhaustion during chronic infection was driven by high amounts of T cell receptor (TCR)-induced transcription factors IRF4, BATF, and NFATc1. These regulators promoted expression of inhibitory receptors, including PD-1, and mediated impaired cellular metabolism. Furthermore, they repressed the expression of TCF1, a transcription factor required for memory T cell differentiation. Reducing IRF4 expression restored the functional and metabolic properties of antigen-specific T cells and promoted memory-like T cell development. These findings indicate that IRF4 functions as a central node in a TCR-responsive transcriptional circuit that establishes and sustains T cell exhaustion during chronic infection. PMID- 29246442 TI - Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA. AB - The immunosuppressive protein PD-L1 is upregulated in many cancers and contributes to evasion of the host immune system. The relative importance of the tumor microenvironment and cancer cell-intrinsic signaling in the regulation of PD-L1 expression remains unclear. We report that oncogenic RAS signaling can upregulate tumor cell PD-L1 expression through a mechanism involving increases in PD-L1 mRNA stability via modulation of the AU-rich element-binding protein tristetraprolin (TTP). TTP negatively regulates PD-L1 expression through AU-rich elements in the 3' UTR of PD-L1 mRNA. MEK signaling downstream of RAS leads to phosphorylation and inhibition of TTP by the kinase MK2. In human lung and colorectal tumors, RAS pathway activation is associated with elevated PD-L1 expression. In vivo, restoration of TTP expression enhances anti-tumor immunity dependent on degradation of PD-L1 mRNA. We demonstrate that RAS can drive cell intrinsic PD-L1 expression, thus presenting therapeutic opportunities to reverse the innately immunoresistant phenotype of RAS mutant cancers. PMID- 29246446 TI - Febrile temperature reprograms by redox-mediated signaling the mitochondrial metabolic phenotype in monocyte-derived dendritic cells. AB - Fever-like hyperthermia is known to stimulate innate and adaptive immune responses. Hyperthermia-induced immune stimulation is also accompanied with, and likely conditioned by, changes in the cell metabolism and, in particular, mitochondrial metabolism is now recognized to play a pivotal role in this context, both as energy supplier and as signaling platform. In this study we asked if challenging human monocyte-derived dendritic cells with a relatively short-time thermal shock in the fever-range, typically observed in humans, caused alterations in the mitochondrial oxidative metabolism. We found that following hyperthermic stress (3h exposure at 39 degrees C) TNF-alpha-releasing dendritic cells undergo rewiring of the oxidative metabolism hallmarked by decrease of the mitochondrial respiratory activity and of the oxidative phosphorylation and increase of lactate production. Moreover, enhanced production of reactive oxygen and nitrogen species and accumulation of mitochondrial Ca2+ was consistently observed in hyperthermia-conditioned dendritic cells and exhibited a reciprocal interplay. The hyperthermia-induced impairment of the mitochondrial respiratory activity was (i) irreversible following re-conditioning of cells to normothermia, (ii) mimicked by exposing normothermic cells to the conditioned medium of the hyperthermia-challenged cells, (iii) largely prevented by antioxidant and inhibitors of the nitric oxide synthase and of the mitochondrial calcium porter, which also inhibited release of TNF-alpha. These observations combined with gene expression analysis support a model based on a thermally induced autocrine signaling, which rewires and sets a metabolism checkpoint linked to immune activation of dendritic cells. PMID- 29246444 TI - Cystic Fibrosis Transmembrane Conductance Regulator Attaches Tumor Suppressor PTEN to the Membrane and Promotes Anti Pseudomonas aeruginosa Immunity. AB - The tumor suppressor PTEN controls cell proliferation by regulating phosphatidylinositol-3-kinase (PI3K) activity, but the participation of PTEN in host defense against bacterial infection is less well understood. Anti inflammatory PI3K-Akt signaling is suppressed in patients with cystic fibrosis (CF), a disease characterized by hyper-inflammatory responses to airway infection. We found that Ptenl-/- mice, which lack the NH2-amino terminal splice variant of PTEN, were unable to eradicate Pseudomonas aeruginosa from the airways and could not generate sufficient anti-inflammatory PI3K activity, similar to what is observed in CF. PTEN and the CF transmembrane conductance regulator (CFTR) interacted directly and this interaction was necessary to position PTEN at the membrane. CF patients under corrector-potentiator therapy, which enhances CFTR transport to the membrane, have increased PTEN amounts. These findings suggest that improved CFTR trafficking could enhance P. aeruginosa clearance from the CF airway by activating PTEN-mediated anti-bacterial responses and might represent a therapeutic strategy. PMID- 29246447 TI - Factor VII deficiency: Unveiling the cellular and molecular mechanisms underlying three model alterations of the enzyme catalytic domain. AB - Activated factor (F) VII is a vitamin K-dependent glycoprotein that initiates blood coagulation upon interaction with tissue factor. FVII deficiency is the most common of the rare congenital bleeding disorders. While the mutational pattern has been extensively characterized, the pathogenic molecular mechanisms of mutations, particularly at the intracellular level, have been poorly defined. Here, we aimed at elucidating the mechanisms underlying altered FVII biosynthesis in the presence of three mutation types in the catalytic domain: a missense change, a microdeletion and a frameshift/elongation, associated with severe or moderate to severe phenotypes. Using CHO-K1 cells transiently transfected with expression vectors containing the wild-type FVII cDNA (FVIIwt) or harboring the p.I289del, p.G420V or p.A354V-p.P464Hfs mutations, we found that the secretion of the FVII mutants was severely decreased compared to FVIIwt. The synthesis rate of the mutants was slower than the FVIIwt and delayed, and no degradation of the FVII mutants by proteasomes, lysosomes or cysteine proteases was observed. Confocal immunofluorescence microscopy studies showed that FVII variants were localized into the endoplasmic reticulum (ER) but were not detectable within the Golgi apparatus. These findings suggested that a common pathogenic mechanism, possibly a defective folding of the mutant proteins, was triggered by the FVII mutations. The misfolded state led to impaired trafficking of these proteins causing ER retention, which would explain the low to very low FVII plasma levels observed in patients carrying these mutations. PMID- 29246448 TI - Common variants of ROCKs and the risk of hypertension, and stroke: Two case control studies and a follow-up study in Chinese Han population. AB - The Rho kinases (ROCKs) are recognized as a critical regulator of vascular functions in cardiovascular disorders. It is crucial to illustrate the association of ROCKs genetic variation and hypertension and/or stroke events. Herein we aimed at investigating the association of ROCK1 and ROCK2 with hypertension and stroke in Chinese Han population. Seven tagSNPs at ROCK1 and ROCK2 were genotyped in a community-based case-control study consisting of 2012 hypertension cases and 2210 normotensive controls and 4128 subjects were further followed up. In stroke case-control study, 1471 ischemic stroke (IS) inpatients and 607 hemorrhagic stroke (HS) inpatients were collected, and 2443 age-matched controls were selected from the follow-up population. Risks were estimated as odds ratio (OR) and hazard ratio (HR) by logistic and Cox regression. The community-based case-control study didn't identify any significant tagSNPs associated with hypertension even after adjustment for covariates. The follow-up analysis showed that rs1481280 of ROCK1 significantly associated with incident hypertension (HR=1.130, P=0.048) after adjusting for covariates. rs7589629 and rs978906 of ROCK2 were significantly associated with incident IS (HR=1.373, P=0.004; HR=1.284, P=0.026) respectively. In stroke case-control study, rs288980, rs1481280 and rs7237677 were significantly associated with IS and the adjusted ORs (P values) of additive model were 0.879 (0.010), 0.895 (0.036) and 0.857 (0.002) respectively. Furthermore, rs288980, rs7237677 and rs978906 were significantly associated with HS and the adjusted ORs (P values) of additive model were 0.857 (0.025), 0.848 (0.018) and 0.856 (0.027) respectively. Our findings suggest that ROCK1 and ROCK2 contribute to the genetic susceptibility of hypertension and stroke. PMID- 29246445 TI - Protective effect of genetic deletion of pannexin1 in experimental mouse models of acute and chronic liver disease. AB - Pannexins are transmembrane proteins that form communication channels connecting the cytosol of an individual cell with its extracellular environment. A number of studies have documented the presence of pannexin1 in liver as well as its involvement in inflammatory responses. In this study, it was investigated whether pannexin1 plays a role in acute liver failure and non-alcoholic steatohepatitis, being prototypical acute and chronic liver pathologies, respectively, both featured by liver damage, oxidative stress and inflammation. To this end, wild type and pannexin1-/- mice were overdosed with acetaminophen for 1, 6, 24 or 48h or were fed a choline-deficient high-fat diet for 8weeks. Evaluation of the effects of genetic pannexin1 deletion was based on a number of clinically relevant read-outs, including markers of liver damage, histopathological analysis, lipid accumulation, protein adduct formation, oxidative stress and inflammation. In parallel, in order to elucidate molecular pathways affected by pannexin1 deletion as well as to mechanistically anchor the clinical observations, whole transcriptome analysis of liver tissue was performed. The results of this study show that pannexin1-/- diseased mice present less liver damage and oxidative stress, while inflammation was only decreased in pannexin1-/ mice in which non-alcoholic steatohepatitis was induced. A multitude of genes related to inflammation, oxidative stress and xenobiotic metabolism were differentially modulated in both liver disease models in wild-type and in pannexin1-/- mice. Overall, the results of this study suggest that pannexin1 may play a role in the pathogenesis of liver disease. PMID- 29246450 TI - A new principle of figure-ground segregation: The accentuation. AB - The problem of perceptual organization was studied by Gestalt psychologists in terms of figure-ground segregation. In this paper we explore a new principle of figure-ground segregation: accentuation. We demonstrate the effectiveness of accentuation relative to other Gestalt principles, and also consider it autonomous as it can agree with or oppose them. We consider three dynamic aspects of the principle, namely: attraction, accentuation and assignment. Each creature needs to attract, fascinate, seduce, draw attention (e.g., a mate or a prey animal) or distract, refuse, dissuade, discourage, repulse (e.g., a predator). Similarly, each organism needs to accentuate, highlight, stress, underline, emphasize or distract from another. Thus, accentuation assigns meaning to a visual pattern such as a coat, a plumage or a flower. False eyes (ocelli) and dots (diematic patterns) demonstrate "deceiving camouflage by accentuation" that confuses predators/preys and hides or highlights vital body parts (butterflies/flowers). They also display the deceiving appearance and exhibition of biological fitness. The same accents may serve different or even opposite goals. We conclude that accentuation improves the adaptive fitness of organisms in multifarious ways. PMID- 29246449 TI - Contribution of relative leptin and adiponectin deficiencies in premature infants to chronic intermittent hypoxia: Exploring a new hypothesis. AB - Chronic intermittent hypoxia (CIH) occurs frequently in premature infants who have apnea of prematurity. Immaturity of the respiratory network from low central respiratory drive and the greater contribution of the carotid body on baseline breathing leads to respiratory instability in premature infants presenting as apnea and periodic breathing. During the 2nd week after birth, the smallest and the youngest premature infants have increased frequency of apnea and periodic breathing and associated oxygen desaturations that can persist for weeks after birth. CIH increases the production of reactive oxygen species that causes tissue damage. Premature infants have decreased capacity to scavenge reactive oxygen species. Oxidative injury is the cause of many of the co-morbidities that are seen in premature infants. In this review we discuss who low fat mass and the resulting relative deficiencies in leptin and adiponectin could contribute to the increase frequency of oxygen desaturations that occurs days after birth in the smallest and youngest premature infants. Leptin is a central respiratory stimulant and adiponectin protects the lung from vascular leak, oxidative injury and vascular remodeling. PMID- 29246452 TI - The iceberg model of self-harm: new evidence and insights. PMID- 29246451 TI - Molecular insights into the classification of high-grade endometrial carcinoma. AB - Endometrial carcinoma, which is associated with a mortality rate of approximately 20%, is the most common gynecological malignancy in the Western world. It is a heterogeneous disease, with multiple histotypes, each constituting a different disease entity. However, interobserver diagnostic agreement is suboptimal, particularly among the most lethal histotypes. Most recent data also indicate that histotype assignment is not independently associated with survival, while in contrast, clinicopathological risk stratification and genomic classification are significantly prognostic. Recent work has shown that there are four molecular subgroups of endometrioid carcinomas instead of the two types proposed by Bokhman in the 1970s. Carcinomas with polymerase E (POLE) exonuclease domain hotspot mutations are highly prognostically favourable; those with copy-number alterations and TP53 mutations are highly aggressive; and microsatellite unstable and 'copy-number low' endometrioid carcinomas are associated with intermediate prognoses. This review summarises the genetic foundations of the various histotypes of endometrial carcinoma and synthesises this information in the form of algorithms, or classifiers, that recapitulate genomic classification that is not only prognostic, but also potentially diagnostic and therapeutically predictive. A review of Lynch syndrome and Lynch-like syndrome is also provided. PMID- 29246453 TI - Incidence of suicide, hospital-presenting non-fatal self-harm, and community occurring non-fatal self-harm in adolescents in England (the iceberg model of self-harm): a retrospective study. AB - BACKGROUND: Little is known about the relative incidence of fatal and non-fatal self-harm in young people. We estimated the incidence of suicide, hospital presenting non-fatal self-harm, and community-occurring non-fatal self-harm in adolescents in England. METHODS: We used national mortality statistics (Jan 1, 2011, to Dec 31, 2013), hospital monitoring data for five hospitals derived from the Multicentre Study of Self-Harm in England (Jan 1, 2011, to Dec 31, 2013), and data from a schools survey (2015) to estimate the incidence of fatal and non fatal self-harm per 100 000 person-years in adolescents aged 12-17 years in England. We described these incidences in terms of an iceberg model of self-harm. FINDINGS: During 2011-13, 171 adolescents aged 12-17 years died by suicide in England (119 [70%] male and 133 [78%] aged 15-17 years) and 1320 adolescents presented to the study hospitals following non-fatal self-harm (1028 [78%] female and 977 [74%] aged 15-17 years). In 2015, 322 (6%) of 5506 adolescents surveyed reported self-harm in the past year in the community (250 [78%] female and 164 [51%] aged 15-17 years). In 12-14 year olds, for every boy who died by suicide, 109 attended hospital following self-harm and 3067 reported self-harm in the community, whereas for every girl who died by suicide, 1255 attended hospital for self-harm and 21 995 reported self-harm in the community. In 15-17 year olds, for every male suicide, 120 males presented to hospital with self-harm and 838 self harmed in the community; whereas for every female suicide, 919 females presented to hospital for self-harm and 6406 self-harmed in the community. Hanging or asphyxiation was the most common method of suicide (125 [73%] of 171), self poisoning was the main reason for presenting to hospital after self-harm (849 [71%] of 1195), and self-cutting was the main method of self-harm used in the community (286 [89%] of 322). INTERPRETATION: Ratios of fatal to non-fatal rates of self-harm differed between males and females and between adolescents aged 12 14 years and 15-17 years, with a particularly large number of females reporting self-harm in the community. Our findings emphasise the need for well resourced community and hospital-based mental health services for adolescents, with greater investment in school-based prevention. FUNDING: UK Department of Health. PMID- 29246454 TI - Reliability, Construct Validity and Interpretability of the Brazilian version of the Rapid Upper Limb Assessment (RULA) and Strain Index (SI). AB - BACKGROUND: There are very few observational methods for analysis of biomechanical exposure available in Brazilian-Portuguese. OBJECTIVE: This study aimed to cross-culturally adapt and test the measurement properties of the Rapid Upper Limb Assessment (RULA) and Strain Index (SI). METHODS: The cross-cultural adaptation and measurement properties test were established according to Beaton et al. and COSMIN guidelines, respectively. Several tasks that required static posture and/or repetitive motion of upper limbs were evaluated (n>100). RESULTS: The intra-raters' reliability for the RULA ranged from poor to almost perfect (k: 0.00-0.93), and SI from poor to excellent (ICC2.1: 0.05-0.99). The inter-raters' reliability was very poor for RULA (k: -0.12 to 0.13) and ranged from very poor to moderate for SI (ICC2.1: 0.00-0.53). The agreement was good for RULA (75-100% intra-raters, and 42.24-100% inter-raters) and to SI (EPM: -1.03% to 1.97%; intra raters, and -0.17% to 1.51% inter-raters). The internal consistency was appropriate for RULA (alpha=0.88), and low for SI (alpha=0.65). Moderate construct validity were observed between RULA and SI, in wrist/hand-wrist posture (rho: 0.61) and strength/intensity of exertion (rho: 0.39). CONCLUSION: The adapted versions of the RULA and SI presented semantic and cultural equivalence for the Brazilian Portuguese. The RULA and SI had reliability estimates ranged from very poor to almost perfect. The internal consistency for RULA was better than the SI. The correlation between methods was moderate only of muscle request/movement repetition. Previous training is mandatory to use of observations methods for biomechanical exposure assessment, although it does not guarantee good reproducibility of these measures. PMID- 29246456 TI - Scavenger Receptor-A deficiency impairs immune response of microglia and astrocytes potentiating Alzheimer's disease pathophysiology. AB - Late onset Alzheimer disease's (LOAD) main risk factor is aging. Although it is not well known which age-related factors are involved in its development, evidence points out to the involvement of an impaired amyloid-beta (Abeta) clearance in the aged brain among possible causes. Glial cells are the main scavengers of the brain, where Scavenger Receptor class A (SR-A) emerges as a relevant player in AD because of its participation in Abeta uptake and in the modulation of glial cell inflammatory response. Here, we show that SR-A expression is reduced in the hippocampus of aged animals and APP/PS1 mice. Given that Abeta deposition increases in the aging brain, we generated a triple transgenic mouse, which accumulates Abeta and is knockout for SR-A (APP/PS1/SR-A /-) to evaluate Abeta accumulation and the inflammatory outcome of SR-A depletion in the aged brain. The lifespan of APP/PS1/SR-A-/- mice was greatly reduced, accompanied by a 3-fold increase in plasmatic pro-inflammatory cytokines, and reduced performance in a working memory behavioral assessment. Microglia and astrocytes lacking SR-A displayed impaired oxidative response and nitric oxide production, produced up to 7-fold more pro-inflammatory cytokines and showed a 12 fold reduction in anti-inflammatory cytokines release, with conspicuous changes in lipopolysaccharide-induced glial activation. Isolated microglia from young and adult mice lacking SR-A showed a 50% reduction in phagocytic activity. Our results indicate that reduced expression of SR-A can deregulate glial inflammatory response and potentiate Abeta accumulation, two mechanisms that could contribute to AD progression. PMID- 29246455 TI - Effect of the provision of a cane on walking and social participation in individuals with stroke: protocol for a randomized trial. AB - BACKGROUND: Canes are usually prescribed for individuals with stroke with the purpose of improving walking and increasing safety. However, there is no consensus regarding the clinical effects of these aids on walking and participation. OBJECTIVE: This study will examine the efficacy of the provision of a cane to improve walking and increase participation after stroke. METHODS: This is a two-arm, prospectively registered, randomized trial with concealed allocation, blinded measurers, and intention-to-treat analysis. Fifty individuals with chronic stroke, categorized as slow or intermediate walkers (walking speeds <=0.8m/s), will participate. The experimental group will receive a single-point cane and instructions to use the cane anytime they need to walk. The control group will receive a placebo intervention, consisting of self-stretching exercises of the lower limb muscles and instructions to not use assistive devices. The primary outcome will be comfortable walking speed. Secondary outcomes will include walking step length, walking cadence, walking capacity, walking confidence, and participation. Outcomes will be collected by a researcher blinded to group allocation at baseline (Week 0), after intervention (Week 4), and one month beyond intervention (Week 8). CONCLUSION: The provision of a single point cane may help improving walking of slow and intermediate walkers after stroke. If walking is enhanced, the benefits may be carried over to participation, and individuals may experience greater free-living physical activity at home and in the community. PMID- 29246457 TI - The effectiveness and safety of laparoscopic sleeve gastrectomy with different sizes of bougie calibration: A systematic review and meta-analysis. AB - OBJECTIVES: This systematic review and meta-analysis was performed to compare the influence of different calibrating bougie sizes on clinical outcomes in laparoscopic sleeve gastrectomy (LSG) for patients with obesity. MATERIALS AND METHODS: A systematic review of the literature was performed using the key words: "laparoscopic sleeve gastrectomy", "bougie size", "calibration", "obesity", and "obese" for searches of electronic databases up to October 2017. Clinical characteristics such as, the percentage of excess weight loss (%EWL), overall complications, gastrointestinal leaks, gastroesophageal reflux disease (GERD) were pooled by meta-analysis. Stata 12.0 (Stata Corp, College Station, TX, USA) was used to perform the meta-analysis. RESULTS: Data were extracted from 11 original studies matching our inclusion criteria. In our review, the group of patients who had operations with thinner bougies had a greater %EWL (SMD 0.23, 95% CI 0.14-0.33, P < .001) than the group where larger diameters were used. Furthermore, no significant differences were found in the incidence of overall complications (OR 1.00, 95% CI 0.73-1.37, P = .978), postoperative gastrointestinal leaks (OR 0.91, 95% CI 0.67-1.24, P = .554), and GERD (OR 0.77, 95% CI 0.37-1.59, P = .476) between the two groups. A robust result could not be made about remission of comorbidities using differing diameter bougies due to insufficient data. CONCLUSIONS: Use of thinner diameter bougies in LSG was more effective in enabling weight loss and did not increase the risk of overall complications, gastrointestinal leaks or GERD compared with larger diameter bougies. PMID- 29246458 TI - Next generation microbiological risk assessment: opportunities of whole genome sequencing (WGS) for foodborne pathogen surveillance, source tracking and risk assessment. AB - Whole genome sequencing (WGS) of important foodborne pathogens is a technology under development, but is already employed in routine surveillance by public health agencies and is being increasingly exploited in tracing transmission routes and identifying contamination events (source tracking) that take place in the farm-to-fork continuum. Furthermore, data generated from WGS, complemented by other -omics data, have the potential to be integrated into and strengthen microbiological risk assessment. In this paper, we discuss the contribution of WGS in diverse areas important to food safety and public health. Additionally, an outlook of future WGS applications, which should contribute to our understanding of the ecology and physiology of foodborne microorganisms, is presented. PMID- 29246459 TI - Rapid adaptation in large populations with very rare sex: Scalings and spontaneous oscillations. AB - Genetic exchange in microbes and other facultative sexuals can be rare enough that evolution is almost entirely asexual and populations almost clonal. But the benefits of genetic exchange depend crucially on the diversity of genotypes in a population. How very rare recombination together with the accumulation of new mutations shapes the diversity of large populations and gives rise to faster adaptation is still poorly understood. This paper analyzes a particularly simple model: organisms with two asexual chromosomes that can reassort during rare matings that occur at a rate r. The speed of adaptation for large population sizes, N, is found to depend on the ratio ~log(Nr)/log(N). For larger populations, the r needed to yield the same speed decreases as a power of N. Remarkably, the population undergoes spontaneous oscillations alternating between phases when the fittest individuals are created by mutation and when they are created by reassortment, which - in contrast to conventional regimes - decreases the diversity. Between the two phases, the mean fitness jumps rapidly. The oscillatory dynamics and the strong fluctuations this induces have implications for the diversity and coalescent statistics. The results are potentially applicable to large microbial populations, especially viruses that have a small number of chromosomes. Some of the key features may be more broadly applicable for large populations with other types of rare genetic exchange. PMID- 29246460 TI - Establishment in a new habitat by polygenic adaptation. AB - Maladapted individuals can only colonise a new habitat if they can evolve a positive growth rate fast enough to avoid extinction, a process known as evolutionary rescue. We treat log fitness at low density in the new habitat as a single polygenic trait and use the infinitesimal model to follow the evolution of the growth rate; this assumes that the trait values of offspring of a sexual union are normally distributed around the mean of the parents' trait values, with variance that depends only on the parents' relatedness. The probability that a single migrant can establish depends on just two parameters: the mean and genetic variance of the trait in the source population. The chance of success becomes small if migrants come from a population with mean growth rate in the new habitat more than a few standard deviations below zero; this chance depends roughly equally on the probability that the initial founder is unusually fit, and on the subsequent increase in growth rate of its offspring as a result of selection. The loss of genetic variation during the founding event is substantial, but highly variable. With continued migration at rate M, establishment is inevitable; when migration is rare, the expected time to establishment decreases inversely with M. However, above a threshold migration rate, the population may be trapped in a 'sink' state, in which adaptation is held back by gene flow; above this threshold, the expected time to establishment increases exponentially with M. This threshold behaviour is captured by a deterministic approximation, which assumes a Gaussian distribution of the trait in the founder population with mean and variance evolving deterministically. By assuming a constant genetic variance, we also develop a diffusion approximation for the joint distribution of population size and trait mean, which extends to include stabilising selection and density regulation. Divergence of the population from its ancestors causes partial reproductive isolation, which we measure through the reproductive value of migrants into the newly established population. PMID- 29246461 TI - Measures of frequency used in cohorts studies to evaluate the suicidal behaviour in young people (12-26 years): A systematic review. AB - INTRODUCTION: A priority for the WHO by 2020 is to have reduced the rates of suicide; they indicate difficulties in giving precise estimations due to a wide variety of factors, which include aspects related to the statistical measurements themselves of suicidal behaviour. The proportion of deaths from suicide is 8.5% among young people between 15-29 years of age. OBJECTIVE: To review the methodology used to express the frequency of suicidal behaviour in young people and to describe the methodological characteristics of the studies reviewed. METHOD: A systematic review of longitudinal studies registered on PROSPERO. The extracted information included the following: year of publication, journal, population size, sample, country, design, age, percentage of men, follow-up time and losses, suicidal behaviour, risk factors, ethical aspects, fundamentally, evaluating the measures of frequency used. RESULTS: Eighty-two articles were selected from 37,793 documents. None of the studies define the measure of frequency used for suicidal behaviour, there are currently up to 9 different ways of measuring it. The populations are students or the general population (66%), birth cohorts (16%) and specific groups. Follow-up was from 24 weeks to 30 years. Only 24.1% of the studies took ethical aspects into consideration. CONCLUSIONS: Researchers must make an effort to reach an agreement on the measures of frequency used in suicidal behaviour studies, as the methodological and terminological variability currently used impedes making any comparisons between different studies or understanding the real dimension of the problem. PMID- 29246462 TI - OPPE, FPPE, QPS, and why the alphabet soup of physician assessment is essential for safer patient care. AB - Creating a successful quality and patient safety program requires a multifaceted approach that systematically reviews overall systems and processes, but also creates a standardized framework for evaluating individual practitioner performance on a routine basis. There are two required elements of competency assessment that are typically tied to the hospital credentialing process: ongoing professional practice evaluation (OPPE) and focused professional practice evaluation (FPPE). Each of these processes are mandated by the Joint Commission, and form an important cornerstone for ensuring adequate physician performance and knowledge base. PMID- 29246464 TI - An Attempt to Standardize the Calculation of Growth Velocity of Preterm Infants Evaluation of Practical Bedside Methods. AB - OBJECTIVE: To examine how well growth velocity recommendations for preterm infants fit with current growth references: Fenton 2013, Olsen 2010, INTERGROWTH 2015, and the World Health Organization Growth Standard 2006. STUDY DESIGN: The Average (2-point), Exponential (2-point), Early (1-point) method weight-gains were calculated for 1,4,8,12, and 16-week time-periods. Growth references' weekly velocities (g/kg/d, gram/day and cm/week) were illustrated graphically with frequently-quoted 15 g/kg/d, 10-30 grams/day and 1 cm/week rates superimposed. The 15 g/kg/d and 1 cm/week growth velocity rates were calculated from 24-50 weeks, superimposed on the Fenton and Olsen preterm growth charts. RESULTS: The Average and Exponential g/kg/d estimates showed close agreement for all ages (range 5.0-18.9 g/kg/d), while the Early method yielded values as high as 41 g/kg/d. All 3 preterm growth references were similar to 15 g/kg/d rate at 34 weeks, but rates were higher prior and lower at older ages. For gram/day, the growth references changed from 10 to 30 grams/day for 24-33 weeks. Head growth rates generally fit the 1 cm/week velocity for 23-30 weeks, and length growth rates fit for 37-40 weeks. The calculated g/kg/d curves deviated from the growth charts, first downward, then steeply crossed the median curves near term. CONCLUSIONS: Human growth is not constant through gestation and early infancy. The frequently-quoted 15 g/kg/d, 10-30 gram/day and 1 cm/week only fit current growth references for limited time periods. Rates of 15-20 g/kg/d (calculated using average or exponential methods) are a reasonable goal for infants 23-36 weeks, but not beyond. PMID- 29246463 TI - [Multidrug-resistant tuberculosis (MDR-TB) in a black African carceral area: Experience of Mali]. AB - INTRODUCTION: Prison constitutes a risk factor for the emergence of multi-drug resistance of tuberculosis (MDR-TB). The aim of this work was to study MDR-TB in a black African carceral center. MATERIAL AND METHODS: Prospective study from January to December 2016 at the central house of arrest for men, Bamako. The study population was composed of tuberculous detainee. The suspicion of MDR-TB was done in any tuberculosis case remained positive in the second month of first line treatment or in contact with an MDR-TB case. RESULT: Among 1622 detainee, 21 cases of pulmonary tuberculosis were notified (1.29%), with an annual incidence of 13 cases/1000 detainee, they were 16 cases of SP-PTB (microscopy smear positive tuberculosis) and five cases of microscopy smear negative tuberculosis. The mean age was 28+/-7 years, extremes of 18 and 46 years. A negative association was found between the notion of smoking and occupation in the occurrence of tuberculosis (OR=0.036, [95% CI: 0.03-0.04], P=0.03. Among the 21 tuberculosis cases notified, one confirmed case of MDR-TB was detected (4.7%). In the first semester of 2016 cohort, we notified a cure rate of 87.5% (7/8 SP-PTB cases), and the confirmed MDR-TB case on treatment (21-month regimen), evolution enameled of pulmonary and hearing sequelae at seven months treatment. CONCLUSION: It was the first case of MDR-TB detected in a prison in Mali. Late diagnosis, evolution is enameled of sequelae and side effects. PMID- 29246465 TI - Resource Use and Morbidities in Pediatric Cardiac Surgery Patients with Genetic Conditions. AB - OBJECTIVE: To evaluate and describe resource use and perioperative morbidities among those patients with genetic conditions undergoing cardiac surgery. STUDY DESIGN: Using the Pediatric Health Information System database, we identified patients <=18 years old with cardiac surgery classified by Risk Adjustment for Congenital Heart Surgery (RACHS) during 2003-2014. A total of 95 253 patients met study criteria and included no genetic conditions (84.6%), trisomy 21 (9.9%), trisomy 13 or 18 (0.2%), 22q11 deletion (0.8%), Turner syndrome (0.4%), and "other" genetic conditions (4.2%). We compared perioperative complications and procedures in each genetic condition with patients without genetic conditions using regression analysis. RESULTS: All groups with genetic conditions, excluding trisomy 21 RACHS 3-5, experienced increased length of stay and cost among survivors. Complications varied by genetic condition, with patients with trisomy 21 having increased odds of pulmonary hypertension and nosocomial infections. Patients with 22q11 only had increased odds of infection. Patients with Turner syndrome had increased odds of acute renal failure (OR 2.35). Patients with trisomy 13 or 18 had increased odds of pulmonary hypertension (OR 3.13), acute renal failure (OR 2.93), cardiac arrest (OR 2.84), and nosocomial infections (OR 3.53), and those with "other" genetic conditions had increased odds of all complications. CONCLUSIONS: Children with congenital heart disease and genetic conditions, except trisomy 21 RACHS 3-5, had increased costs and length of stay. Perioperative morbidities were more common and differed across genetic condition subgroups. Patient-specific risk factors are important for risk stratification, benchmarking, and counseling with families. PMID- 29246466 TI - The First International Conference on Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis Syndrome. PMID- 29246467 TI - A Randomized Clinical Trial of Umbilical Cord Milking vs Delayed Cord Clamping in Preterm Infants: Neurodevelopmental Outcomes at 22-26 Months of Corrected Age. AB - OBJECTIVE: To compare the effect of umbilical cord milking vs delayed cord clamping (DCC) on neurodevelopmental and health outcomes in very preterm infants at 22-26 months of corrected age. STUDY DESIGN: Neurodevelopmental outcomes at 2 years of age were assessed using the Bayley Scales of Infant Development, third edition, and a standardized neurologic examination. Data regarding pulmonary morbidities, neurosensory impairments, and hospitalizations were obtained by parental interview. Intention-to-treat was used for primary analyses. RESULTS: Of the 197 infants enrolled in the original study there were 15 deaths, 5 in the umbilical cord milking group and 10 in DCC group. Of the remaining infants, 135 (74%) were assessed at 22-26 months of corrected age. Demographics in umbilical cord milking (n = 70) and DCC (n = 65) groups were similar. Infants randomized to umbilical cord milking at birth had significantly higher cognitive and language composite scores, and were less likely to have a cognitive composite score of <85 (4% vs 15%; P = .04). Motor function was similar in both groups. There were no differences in the incidences of mild or moderate to severe neurodevelopmental impairment, hearing or visual impairments, pulmonary morbidities, or rehospitalizations between the 2 groups. CONCLUSIONS: Infants randomized to umbilical cord milking had higher language and cognitive scores compared with those randomized to DCC. There was no difference in rates of mild or moderate to severe neurodevelopmental impairment. TRIAL REGISTRATION: clinicaltrials.gov: NCT01434732. PMID- 29246468 TI - Enuresis Management in Children: Retrospective Clinical Audit of 2861 Cases Treated with Practitioner-Assisted Bell-and-Pad Alarm. AB - OBJECTIVE: To establish the treatment efficacy of practitioner-assisted bell-and pad alarm therapy in children with enuresis between the ages of 5 and 16 years by retrospective medical chart review of 2861 children in multiple clinical settings. STUDY DESIGN: This review was conducted across 7 Australian clinical practices. The primary outcome measure was the time taken for children with either primary, secondary, monosymptomatic, or nonmonosymptomatic enuresis to be dry for 14 consecutive nights. The secondary outcome measure was to determine relapse rates, defined as 1 symptom recurrence per month post interruption of treatment. Data were analyzed by correlation and chi2 test via IBM SPSS Statistics (version 22). RESULTS: The overall success rate of the bell and pad treatment was 76%, irrespective of age. The mean treatment time to achieve dryness was 62.1 +/- 30.8 days, and the relapse rate was 23%. Concurrent bowel dysfunction was associated with a slightly lower success rate (74%). Concurrent lower urinary tract symptoms were associated with a lower success rate (73%) and greater relapse (1.75 times more likely to relapse). Children with secondary enuresis had significantly greater success than those with primary enuresis (82% vs 74%). CONCLUSION: The type of alarm therapy reported in this study is highly effective. This study will provide the basis for clinical guidelines and practice tools for clinicians, which will help to reduce variation in care pathways for alarm treatment for enuresis. PMID- 29246469 TI - Parkinson's disease physiotherapy: specialisation adds value. PMID- 29246470 TI - Effectiveness and costs of specialised physiotherapy given via ParkinsonNet: a retrospective analysis of medical claims data. AB - BACKGROUND: Parkinson's disease is a complex condition that is best managed by specialised professionals. Trials show that specialised allied health interventions are cost-effective, as compared with usual care. We aimed to study the long-term benefits of specialised physiotherapy using the ParkinsonNet approach in real-world practice. METHODS: We did an observational study, retrospectively analysing a database of health insurance claims that included a representative population of Dutch patients with Parkinson's disease, who were followed for up to 3 years (Jan 1, 2013, to Dec 31, 2015). Eligibility criteria included having both a diagnosis of Parkinson's disease and having received physiotherapy for the disease. Allocation to specialised or usual care physiotherapy was based on the choices of patients and referring physicians. We used a mixed-effects model to compare health-care use and outcomes between patients treated by specialised or usual care physiotherapists. The primary outcome was the percentage of patients with a Parkinson's disease-related complication (ie, visit or admission to hospital because of fracture, other orthopaedic injuries, or pneumonia) adjusted for baseline variables. We compared physiotherapist caseload, the number of physiotherapy sessions, physiotherapy costs, and total health-care costs (including hospital care, but excluding community care, long-term care, and informal care) between the groups, and used a Cox's proportional hazard model for survival time to establish whether mortality was influenced by treatment by a specialised physiotherapist. FINDINGS: We analysed 2129 patients (4649 observations) receiving specialised physiotherapy and 2252 patients (5353 observations) receiving usual care physiotherapy. Significantly fewer patients treated by a specialised physiotherapist had a Parkinson's disease-related complication (n=368 [17%]) than patients treated by a usual care physiotherapist (n=480 [21%]; odds ratio 0.67, 95% CI 0.56-0.81, p<0.0001). The annual caseload of patients per therapist was significantly higher for specialised physiotherapists (mean 3.89 patients per therapist [SD 3.91]) than usual care physiotherapists (1.48 [1.24]). Patients who saw specialised physiotherapists received fewer treatment sessions (mean 33.72 [SD 26.70]) than usual care physiotherapists (47.97 [32.11]). Consequently, expenditure was lower for specialised than usual care physiotherapists, both for direct costs (mean ?933 [SD 843] vs ?1329 [1021]; annual difference ?395, 95% CI 358-432, p<0.0001) and total health-care expenditure (?2056 [3272] vs ?2586 [3756]; ?530, 391-669, p<0.0001). Mortality risk was lower for patients receiving specialised physiotherapy (134 [6%]) compared with patients receiving usual care physiotherapy (205 [9%], p=0.001) before correction for baseline variables, although Cox's survival model showed no significant difference between the two (hazard ratio 0.86, 95% CI 0.69-1.07, p=0.195). INTERPRETATION: These results confirm the findings from controlled trials, and offer evidence that specialised physiotherapy as delivered through ParkinsonNet is associated with fewer Parkinson's disease-related complications and lower costs in real-world practice. Neurologists can facilitate specialised physiotherapy by specific referral to such experts. FUNDING: None. PMID- 29246472 TI - Muscle tension increases impact force but decreases energy absorption and pain during visco-elastic impacts to human thighs. AB - Despite uncertainty of its exact role, muscle tension has shown an ability to alter human biomechanical response and may have the ability to reduce impact injury severity. The aim of this study was to examine the effects of muscle tension on human impact response in terms of force and energy absorbed and the subjects' perceptions of pain. Seven male martial artists had a 3.9 kg medicine ball dropped vertically from seven different heights, 1.0-1.6 m in equal increments, onto their right thigh. Subjects were instructed to either relax or tense the quadriceps via knee extension (>=60% MVC) prior to each impact. F-scan pressure insoles sampling at 500 Hz recorded impact force and video was recorded at 1000 Hz to determine energy loss from the medicine ball during impact. Across all impacts force was 11% higher, energy absorption was 15% lower and time to peak force was 11% lower whilst perceived impact intensity was significantly lower when tensed. Whether muscle is tensed or not had a significant and meaningful effect on perceived discomfort. However, it did not relate to impact force between conditions and so tensing may alter localised injury risk during human on human type impacts. PMID- 29246471 TI - Assessment of anticoagulation treatments in non-valvular atrial fibrillation patients diagnosed in a basic health area. AB - INTRODUCTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia. To assess the need for anticoagulation is essential for its management. Our objective was to investigate whether the indication of anticoagulation was adequate in patients diagnosed with non-valvular AF, given the CHA2-DS2-VASc scale, measuring the International Normalizad Ratio range (INR) in patients treated with anti-vitamin K drugs. METHODS: This is an observational and cross sectional study. 232 patients with atrial fibrillation were included. We analyzed demographic, the CHA2-DS2-VASc and HAS-BLED variables, the treatment and INR values for 6 consequentive months. The confrontation of variables was performed using chi-square and Mantel-Haenzel test. RESULTS: The prevalence of AF was 1.05%. The 88.4% had CHA2-DS2-VASc >= 2. The 71.1% were taking anticoagulants, of which 58.2% were under antivitamin k. The 46.7% of patients taking antivitamin K, presented inadequate range of INR. There was a greater prescription of antivitamin k in patients with persistent or permanent AF compared to the paroxysmal form (62.8 vs. 37.2% p<.001). The use of drugs that increase bleeding was associated with a worse control of INR after adjustment for the main variables of clinical relevance (odds ratio 2.17 [1.02-4.59], p=.043). CONCLUSIONS: The level of anticoagulation with antivitamin K was inadequate in our sample, despite a proper follow up and adherence to treatment. Patients with paroxysmal AF received less antivitamin K than those with persistent/permanent AF. PMID- 29246473 TI - Coupled motions in human and porcine thoracic and lumbar spines. AB - Coupled motions, i.e., motions along axes other than the loaded axis, have been reported to occur in the human spine, and are likely to be influenced by inclined local axes due to the sagittal plane spine curvature. Furthermore, the role of facet joints in such motions is as yet unclear. Therefore, this study aimed at assessing coupled motions in multiple spine sections in vitro, before and after removal of posterior elements. Six elderly human and 6 young porcine spines were sectioned in four segments (high thoracic, mid thoracic, low thoracic and lumbar), each consisting of four vertebrae and three intervertebral discs. Segments were loaded along each of the three axes, and three-dimensional rotations of the middle segment were quantified. Subsequently, posterior elements were removed and the protocol was repeated. To avoid mixed loading between Axial Rotation (AR) and Lateral Bending (LB), in contrast to other studies, local axes at the vertebrae were defined as aligned with the loading device prior to each load application. Expressed as a percentage of motion in the loaded direction, coupled motions were on average larger in human (22.7%, SD = 2.2%) than in porcine (11.9%, SD = 1.2%) spines (p < .001). Largest coupled motions were obtained in AR loading of the lumbar spine segments, with mean magnitudes averaged over coupling axes for human L2-L3 joints of 48.9% (SD = 13.2%), including somewhat more LB (56.4%, SD = 18.6) than FE (41.4%, SD = 14.1%) coupling. For porcine L3-L4 joints average coupling in AR loading was 29.3% (SD = 8.2%). In human segments removal of posterior elements only had substantial effects in the lumbar spine segments, where posterior element removal decreased coupled motion during AR loading, averaged over LB and FE coupling, from 48.9% (SD = 13.2%) to 27.7% (SD = 6.1%), mainly through increased motion in the loaded direction. The present results indicate that coupled motions were largest in the lumbar spine. In human spines, posterior elements only contributed to coupled motions in lumbar axial rotation loading. PMID- 29246474 TI - Functionality and avidity of norovirus-specific antibodies and T cells induced by GII.4 virus-like particles alone or co-administered with different genotypes. AB - Norovirus (NoV) is the main cause of acute gastroenteritis worldwide across all age groups. Current NoV vaccine candidates are based on non-infectious highly immunogenic virus-like particles (VLPs) produced in cell cultures in vitro. As NoVs infecting human population are highly divergent, it is proposed that the vaccine should contain at least two different NoV genotypes, potentially affecting the immunogenicity of each other. We investigated the immunogenicity of NoV GII.4 VLPs administered by intramuscular (IM) or intradermal (ID) injections to BALB/c mice either alone or co-delivered with genogroup I (GI) and other genogroup GII VLPs. Serum NoV-specific IgG binding antibody titers and antibody functionality in terms of avidity and blocking potential were assessed. Furthermore, the specificity and functional avidity of CD4+ and CD8+ T cell responses were analyzed using synthetic peptides previously identified to contain NoV VP1 P2 domain-specific H-2d epitopes. The results showed that IM and ID immunization induced comparable GII.4-specific antibodies and T cell responses. Similar magnitude and functionality of antibodies and interferon-gamma producing T cells were developed using monovalent GII.4 VLPs or different genotype combinations. For the first time, degranulation assay using multicolor flow cytometry showed that NoV GII.4-specific CD8+ T cells had cytotoxic T lymphocyte phenotype. To conclude, our results demonstrate that there is no immunological interference even if up to five different NoV VLP genotypes were co-administered at the same time. Furthermore, no inhibition of NoV-specific antibody functionality or the magnitude, specificity and affinity of T cell responses was observed in any of the immunized animals, observations relevant for the development of a multivalent NoV VLP vaccine. PMID- 29246475 TI - Estimating primary care attendance rates for fever in infants after meningococcal B vaccination in England using national syndromic surveillance data. AB - BACKGROUND: In September 2015, the United Kingdom became the first country to introduce the multicomponent group B meningococcal vaccine (4CMenB) into a national infant immunisation programme. In early clinical trials 51-61% of infants developed a fever when 4CMenB was administered with other routine vaccines. Whilst administration of prophylactic paracetamol is advised, up to 3% of parents may seek medical advice for fever following vaccination. We used research-level general practitioner consultations to identify any increase in attendances for all-cause fever in vaccine-eligible infants following 4CMenB introduction in England. METHODS: Consultations for infant all-cause fever in the year following the vaccine introduction were identified from The Phoenix Partnership (TPP) ResearchOne general practice database using Read (CTV3) codes. Average daily consultation rates and incidence rate ratios (IRRs) were calculated for vaccine-eligible age groups and compared to the two years preceding vaccine introduction. The difference between pre- and post-vaccine all-cause fever consultations was estimated. RESULTS: All-cause fever consultations in vaccine eligible 7-10 week olds were 1.6-fold higher (IRR, 1.58; 95% CI, 1.22-2.05) compared to the two previous years and 1.5-fold higher (IRR 1.47; 95% CI, 1.17 1.86) in 15-18 week-olds. There were no significant differences in 0-6 or 11-14 week-olds. Applying the difference between pre- and post-vaccine consultation rates to the 4CMenB vaccine-eligible age groups across England estimated 1825 additional fever consultations in the year following 4CMenB introduction. CONCLUSIONS: We found a small but significant difference in all-cause fever consultation rates in vaccine-eligible infants who would have received 4CMenB with other vaccines. PMID- 29246476 TI - Willingness to accept a future influenza A(H7N9) vaccine in Beijing, China. AB - BACKGROUND: The present study aimed to estimate residents' willingness to accept a future H7N9 vaccine and its determinants in the general adult population in Beijing, China. METHODS: We conducted a multi-stage sampling, cross-sectional survey using self-administered anonymous questionnaires from May to June, in 2014. The main outcome variable was residents' willingness to accept a future H7N9 vaccine. Logistic regression was used to identify the predictors of vaccination willingness. RESULTS: Of the 7264 eligible participants, 14.5% of Beijing residents reported that they had not heard of H7N9. Among those who had heard of H7N9, 59.5% of the general adult population would be willing to accept a future H7N9 vaccine, and approximately half of them reported 'I am afraid of being infected by H7N9' and 'H7N9 vaccine can prevent infections', and 28.1% reported 'my daily life is affected by H7N9'. The variables that were significantly associated with a higher likelihood of reporting willingness were being younger adults (aged 18-29 years: OR = 1.52, 95% CI: 1.17-1.97; aged 30-39 years: OR = 1.39, 95% CI: 1.08-1.78), being farmers (OR = 1.61; 95% CI: 1.32 1.96), being unemployed people (OR = 1.36; 95% CI: 1.04-1.78), living in suburban areas (OR = 2.18; 95% CI: 1.89-2.51), having >=2 children in the family (OR = 1.41; 95% CI: 1.03-1.92), perceived risk in China (OR = 1.30; 95% CI: 1.15-1.48), perceived susceptibility to disease (OR = 3.13; 95% CI: 2.73-3.58), perceived negative effect on daily life (OR = 1.32; 95% CI: 1.13-1.55), perceived effectiveness of vaccination (OR = 2.34; 95% CI: 2.07-2.64), and recent uptake of influenza vaccine (OR = 2.26; 95% CI: 1.92-2.66). CONCLUSIONS: A great number of Beijing residents had doubts about the vaccine's effectiveness and were not concerned about disease risk, which were the factors affecting willingness to be vaccinated. Targeted education programs on disease risk as well as vaccine's effectiveness are needed to improve the willingness of vaccination for potential H7N9 pandemic preparedness. PMID- 29246477 TI - Protein-Based Therapeutic Killing for Cancer Therapies. AB - The treatment of some high-incidence human diseases is based on therapeutic cell killing. In cancer this is mainly achieved by chemical drugs that are systemically administered to reach effective toxic doses. As an innovative alternative, cytotoxic proteins identified in nature can be adapted as precise therapeutic agents. For example, individual toxins and venom components, proapoptotic factors, and antimicrobial peptides from bacteria, animals, plants, and humans have been engineered as highly potent drugs. In addition to the intrinsic cytotoxic activities of these constructs, their biological fabrication by DNA recombination allows the recruitment, in single pharmacological entities, of diverse functions of clinical interest such as specific cell-surface receptor binding, self-activation, and self-assembling as nanoparticulate materials, with wide applicability in cell-targeted oncotherapy and theragnosis. PMID- 29246478 TI - A Phase III Diagnostic Accuracy Study of a Rapid Diagnostic Test for Diagnosis of Second-Stage Human African Trypanosomiasis in the Democratic Republic of the Congo. AB - OBJECTIVES: To estimate the diagnostic accuracy of HAT Sero K-SeT for the field diagnosis of second-stage human African trypanosomiasis (HAT). DESIGN: A phase III diagnostic accuracy design. Consecutive patients with symptoms clinically suggestive of HAT were prospectively enrolled. We compared results of the index test HAT Sero K-SeT with those of a composite reference standard: demonstration of trypanosomes in cerebrospinal fluid (CSF), or trypanosomes detected in any other body fluid AND white blood cell count in CSF >5/MUl. SETTING: Rural hospital in the Democratic Republic of the Congo. PARTICIPANTS: All patients above five years old presenting at Mosango hospital with a neurological problem of recent onset at the exclusion of trauma. INTERVENTIONS: n.a. MAIN OUTCOME MEASURES: Sensitivity and specificity of HAT Sero K-SeT test. RESULTS: The sensitivity of the HAT Sero K-SeT was 8/8 or 100.0% (95% confidence interval: 67.6 to 100.0%) and the specificity was 258/266 or 97.0% (94.2% to 98.5%). CONCLUSION: The high sensitivity of the HAT Sero K-SeT is in line with previously published estimates, though the sample of HAT cases in this study was small. The specificity estimate was very high and precise. This test, when negative, allows the clinician to rule out HAT in a clinical suspect in a hospital setting in this endemic region. PMID- 29246480 TI - Treatment of infected non-unions of the femur and tibia in a French referral center for complex bone and joint infections: Outcomes of 55 patients after 2 to 11 years. AB - INTRODUCTION: An infected non-union is a major complication following bone fracture. While bone union can be obtained in 70% to 100% of cases, treatment of osteomyelitis is less predictable, with reported healing rates ranging from 40% to 100%. The primary aim of this study was to assess the success rate of treating infected non-unions of the tibia and femur by a team specializing in complex bone and joint infections. MATERIAL AND METHODS: This single-center retrospective study included all patients operated between 2002 and 2012 due to an infected non union of the femur or tibia using standardized surgical methods. The procedure was typically done in two phases: excision of the infected site and stabilization, followed by bone reconstruction after a waiting period. Additional procedures (lavage and/or bone grafting) were performed in some cases. A minimum 6-week course of antibiotic therapy was given. The primary endpoint was successful medical and surgical treatment after a minimum 2 years' follow-up defined as healing of the infection (no local clinical signs of infection, ESR<=20mm and CRP<=10mg/L, no mortality attributed to the infection) and radiological and clinical bone union, with the lower limb spared. RESULTS: Fifty five patients (39 men, 16 women) were included with an average age of 37+/-11 years. There were 40 tibial fractures and 15 femur fractures. A polymicrobial infection was present in 47% of cases. Repeat surgery was required in 56.4% of patients. At an average of 4+/-2 years from the first surgical procedure, the treatment was successful in 49 patients (89%): 36 tibia (90%) and 13 femur (87%). The mean time to union was 9+/-4 months. There were six failures: 3 amputations at 5, 6 and 16 months; 1 mechanical and infection-related failure; 2 failed union. CONCLUSION: This study found that 89% of patients with an infected tibial or femoral non-union treated by a team specialized in complex bone and joint infections using a standardized surgical protocol had bone union and healing of the infection in an average of 9 months. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 29246479 TI - Elevated Plasma Levels of 3-Hydroxyisobutyric Acid Are Associated With Incident Type 2 Diabetes. AB - Branched-chain amino acids (BCAAs) metabolite, 3-Hydroxyisobutyric acid (3-HIB) has been identified as a secreted mediator of endothelial cell fatty acid transport and insulin resistance (IR) using animal models. To identify if 3-HIB is a marker of human IR and future risk of developing Type 2 diabetes (T2D), we measured plasma levels of 3-HIB and associated metabolites in around 10,000 extensively phenotyped individuals. The levels of 3-HIB were increased in obesity but not robustly associated with degree of IR after adjusting for BMI. Nevertheless, also after adjusting for obesity and plasma BCAA, 3-HIB levels were associated with future risk of incident T2D. We also examined the effect of 3-HIB on fatty acid uptake in human cells and found that both HUVEC and human cardiac endothelial cells respond to 3-HIB whereas human adipose tissue-derived endothelial cells do not respond to 3-HIB. In conclusion, we found that increased plasma level of 3-HIB is a marker of future risk of T2D and 3-HIB may be important for the regulation of metabolic flexibility in heart and muscles. PMID- 29246481 TI - Shoulder patient-specific guide: First experience in 10 patients indicates room for improvement. AB - BACKGROUND: Implantation of the glenoid component of a total shoulder prosthesis can be facilitated by using a patient-specific guide (PSG) designed to ensure replication of the preoperatively planned position. The objective of this study was to assess the reliability and accuracy of a PSG in replicating the planned glenoid component position during total shoulder arthroplasty (TSA). HYPOTHESIS: Additional criteria should be used for 3D preoperative planning and PSG design to further improve the accuracy of glenoid component positioning. MATERIAL AND METHODS: We studied 10 patients who underwent TSA with use of a PSG to position the glenoid component after preoperative 3D planning. Postoperative glenoid version and tilt were measured and compared to the planned values. We also used new criteria to assess implant rotation and global 3D position, as well as accuracy of the 3D pilot hole for the glenoid guide-pin. RESULTS: Mean errors in glenoid position were -1.7 degrees +/-4.4 degrees for version, -0.4 degrees +/ 4.9 degrees for tilt, and 6.0 degrees +/-13.5 degrees for rotation. Mean difference in global orientation of the glenoid implant versus the planned value was 4.9 degrees +/-2.5 degrees . Mean 3D discrepancy in glenoid pilot hole position was 2.9+/-0.5mm; the discrepancy was greater in the mediolateral direction (1.9+/-0.9mm) than in the supero-inferior (1.1+/-1.2mm) and antero posterior (0.8+/-1.2mm) directions. DISCUSSION: The poor performance of the PSG in controlling rotation and reaming may explain the difference in global glenoid position compared to the planned value. Improvements in PSG design to incorporate these two parameters deserve consideration. LEVEL OF EVIDENCE: II, prospective cohort study. PMID- 29246482 TI - Percutaneous fixation of valgus displaced fracture of the proximal humerus using a single screw. AB - Valgus-impacted proximal humerus fracture is a classic but rare entity in shoulder traumatology. Surgical treatment is controversial, with increasing use of minimally invasive techniques. Our technique uses a minimally invasive approach under fluoroscopic control. Raising the humeral head to reduce the valgus enables spontaneous and well-positioned reduction of the tuberosities and screw fixation between the greater tuberosity and the humeral shaft. Indications comprise valgus-impacted fracture without comminution of the medial epiphyseal metaphyseal hinge or greater tuberosity; the rotator cuff contributes to reduction and must be intact. This type of fixation restores proximal humerus anatomy and achieves consolidation with low risk of secondary necrosis. Minimally invasive single-screw fixation is an alternative of choice for surgical treatment of valgus-impacted proximal humerus fracture. PMID- 29246483 TI - Management of the floating shoulder: Does the glenopolar angle influence outcomes? A systematic review. AB - INTRODUCTION: Currently there is no consensus on the optimal treatment of the "floating shoulder". We aim to perform a systematic review to determine outcomes in the management of this condition. MATERIALS AND METHODS: Studies related to the management of the "floating shoulder" were identified by a review of medline using platform Pubmed/Ovid, Scopus and Cochrane library data bases. Studies were included if they: (1) are published in the English language and (2) reported outcomes of at least 2 or more cases of floating shoulder injuries using at least one objective shoulder scoring system. Exclusion criteria were (1) non-human and biomechanical studies and (2) studies with a clear selection bias. Three treatment groups were identified. Group 1-non-operative, Group 2-fixation of clavicle only, and Group 3-fixation of clavicle and scapula neck. RESULTS: Thirteen studies gave a population of 244 subjects of which 104 had non-operative treatment, 98 had internal fixation of the clavicle only and 42 had fixation of both the clavicle and the scapula. There were no differences in the outcome scores among the 3 treatment arms as the patients with undisplaced or minimally displaced fractures had conservative treatment and those with displaced fractures were surgically stabilised. There was a positive correlation between the final glenopolar angle and the Constant score. CONCLUSIONS: The review was unable to show a difference in outcomes among the 3 treatment groups. Any treatment modality that restores the glenopolar angle is likely to result in a good outcome. LEVEL OF EVIDENCE: Therapeutic level IV. PMID- 29246484 TI - Testing native language neural commitment at the brainstem level: A cross linguistic investigation of the association between frequency-following response and speech perception. AB - A current topic in auditory neurophysiology is how brainstem sensory coding contributes to higher-level perceptual, linguistic and cognitive skills. This cross-language study was designed to compare frequency following responses (FFRs) for lexical tones in tonal (Mandarin Chinese) and non-tonal (English) language users and test the correlational strength between FFRs and behavior as a function of language experience. The behavioral measures were obtained in the Garner paradigm to assess how lexical tones might interfere with vowel category and duration judgement. The FFR results replicated previous findings about between group differences, showing enhanced pitch tracking responses in the Chinese subjects. The behavioral data from the two subject groups showed that lexical tone variation in the vowel stimuli significantly interfered with vowel identification with a greater effect in the Chinese group. Moreover, the FFRs for lexical tone contours were significantly correlated with the behavioral interference only in the Chinese group. This pattern of language-specific association between speech perception and brainstem-level neural phase-locking of linguistic pitch information provides evidence for a possible native language neural commitment at the subcortical level, highlighting the role of experience dependent brainstem tuning in influencing subsequent linguistic processing in the adult brain. PMID- 29246485 TI - Autobiographical memory: From experiences to brain representations. PMID- 29246486 TI - Effects of global and local contexts on chord processing: An ERP study. AB - In real life, the processing of an incoming event is continuously influenced by prior information at multiple timescales. The present study investigated how harmonic contexts at both local and global levels influence the processing of an incoming chord in an event-related potentials experiment. Chord sequences containing two phrases were presented to musically trained listeners, with the last critical chord either harmonically related or less related to its preceding context at local and/or global levels. ERPs data showed an ERAN-like effect for local context in early time window and a N5-like component for later interaction between the local context and global context. These results suggest that both the local and global contexts influence the processing of an incoming music event, and the local effect happens earlier than the global. Moreover, the interaction between the local context and global context in N5 may suggest that music syntactic integration at local level takes place prior to the integration at global level. PMID- 29246487 TI - Practice effects in healthy older adults: Implications for treatment-induced neuroplasticity in Aphasia. AB - In treating aphasic individuals with anomia, practice naming pictures leads to better performance as measured by accuracy and reaction time. The neurocognitive mechanisms supporting such improvements remain elusive, in part due to gaps in understanding the influence of practice on neurotypical older adults. The current study investigated the influence of practice naming one set of low frequency pictures of actions and objects in 18 healthy older adults, ten of whom were tested twice approximately one month apart. Both item and task practice effects were observed in improved accuracy and response latencies naming pictures in the scanner. This same facilitation effect was observed in neuroimaging results. For example, a significant main effect of practice was observed in bilateral precuneus and left inferior parietal lobule, characterized by greater activity for naming practiced vs. unpracticed pictures. This difference was significantly diminished in subsequent runs after exposure to unpracticed pictures. Whole brain analyses across two sessions showed that practice effects were specific to practice, i.e., there were not similar observable changes in contrasts examining actions vs. objects over time. These findings have important implications for understanding treatment-induced neuroplasticity in anomia treatment. PMID- 29246488 TI - Item and source memory for emotional associates is mediated by different retrieval processes. AB - Recent event-related potential (ERP) data showed that neutral objects encoded in emotional background pictures were better remembered than objects encoded in neutral contexts, when recognition memory was tested one week later. In the present study, we investigated whether this long-term memory advantage for items is also associated with correct memory for contextual source details. Furthermore, we were interested in the possibly dissociable contribution of familiarity and recollection processes (using a Remember/Know procedure). The results revealed that item memory performance was mainly driven by the subjective experience of familiarity, irrespective of whether the objects were previously encoded in emotional or neutral contexts. Correct source memory for the associated background picture, however, was driven by recollection and enhanced when the content was emotional. In ERPs, correctly recognized old objects evoked frontal ERP Old/New effects (300-500ms), irrespective of context category. As in our previous study (Ventura-Bort et al., 2016b), retrieval for objects from emotional contexts was associated with larger parietal Old/New differences (600 800ms), indicating stronger involvement of recollection. Thus, the results suggest a stronger contribution of recollection-based retrieval to item and contextual background source memory for neutral information associated with an emotional event. PMID- 29246490 TI - Accuracy and precision of 3 intraoral scanners and accuracy of conventional impressions: A novel in vivo analysis method. AB - OBJECTIVE: To evaluate a novel methodology using industrial scanners as a reference, and assess in vivo accuracy of 3 intraoral scanners (IOS) and conventional impressions. Further, to evaluate IOS precision in vivo. METHODS: Four reference-bodies were bonded to the buccal surfaces of upper premolars and incisors in five subjects. After three reference-scans, ATOS Core 80 (ATOS), subjects were scanned three times with three IOS systems: 3M True Definition (3M), CEREC Omnicam (OMNI) and Trios 3 (TRIOS). One conventional impression (IMPR) was taken, 3M Impregum Penta Soft, and poured models were digitized with laboratory scanner 3shape D1000 (D1000). Best-fit alignment of reference-bodies and 3D Compare Analysis was performed. Precision of ATOS and D1000 was assessed for quantitative evaluation and comparison. Accuracy of IOS and IMPR were analyzed using ATOS as reference. Precision of IOS was evaluated through intra system comparison. RESULTS: Precision of ATOS reference scanner (mean 0.6 MUm) and D1000 (mean 0.5 MUm) was high. Pairwise multiple comparisons of reference bodies located in different tooth positions displayed a statistically significant difference of accuracy between two scanner-groups: 3M and TRIOS, over OMNI (p value range 0.0001 to 0.0006). IMPR did not show any statistically significant difference to IOS. However, deviations of IOS and IMPR were within a similar magnitude. No statistical difference was found for IOS precision. CONCLUSION: The methodology can be used for assessing accuracy of IOS and IMPR in vivo in up to five units bilaterally from midline. 3M and TRIOS had a higher accuracy than OMNI. IMPR overlapped both groups. CLINICAL SIGNIFICANCE: Intraoral scanners can be used as a replacement for conventional impressions when restoring up to ten units without extended edentulous spans. PMID- 29246489 TI - Post-secondary maternal education buffers against neural risk for psychological vulnerability to future life stress. AB - We have previously reported that threat-related amygdala activity measured during a baseline fMRI scan predicts the experience of depression and anxiety associated with stressful life events years later. Here, we examine whether two broad measures of childhood environmental enrichment, namely parental educational achievement and subjective parental socioeconomic status, buffer against the effects of amygdala activity on future vulnerability to stress. Analyses of data available from 579 young adults revealed that maternal, but not paternal, educational achievement moderates the association between amygdala activity, recent life stress, and changes in mood and anxiety symptoms, even when controlling for participants' current subjective socioeconomic status. Specifically, only participants reporting lower maternal educational achievement exhibited our previously observed interaction between amygdala activity and future life stress predicting increases in depression and anxiety. These results suggest that higher maternal educational achievement may help buffer stress sensitivity associated with heightened threat-related amygdala activity. PMID- 29246492 TI - Three steroid-binding globulins, their localization in the brain and nose, and what they might be doing there. AB - Steroid-binding globulins (SBGs) such as sex hormone binding globulin, corticosteroid binding globulin, and vitamin-D binding protein are receiving increasing notice as being actively involved in steroid actions. This paper reviews data of all three of these SBGs, focusing on their presence and possible activity in the brain and nose. We have found all three proteins in the brain in limbic areas such as the paraventricular (PVN) and supraoptic nuclei (SON) as well as other areas of the hypothalamus, hippocampus, and medial preoptic area. There is also evidence that all three are made in the PVN and SON, in conjunction with the neuropeptides oxytocin and vasopressin. The localization of these three SBGs is more variable within areas of the main olfactory area and the vomeronasal organ. However, all three are found in the mucus of these areas, suggesting that one of their functions is to sequester aerosol steroids, such as pheromones, and deliver them to sensory cells and then to deeper sensory areas. In this manuscript, we present multiple models of SBG action including: A) SBG binding to a membrane receptor, B) this SBG receptor being associated with a larger protein complex including cytoplasmic steroid receptors, C) when the SBGs binds to their SBG receptors, second messengers within the cells respond, D) after SBG binding to its receptor, it releases its associated steroid into the membrane's lipid bilayer, from which it gains access into the cell only when bound by an internal protein, E) the SBG, possibly with its bound SBG receptor, is internalized into the cell from which it can gain access to numerous organelles and possibly the cell's nucleus or F) associate with intracellular steroid receptors, G) SBGs produced in target cells are released from those cells upon specific stimulation, and H) according to the Free Steroid Hypothesis steroids released from the extracellular SBG passively diffuse across the plasma membrane of the cell. These models move the area of steroid endocrinology forward by providing important paths of steroid activity within many steroid target cells. PMID- 29246491 TI - Impact of loss of SOAT2 function on disease progression in the lysosomal acid lipase-deficient mouse. AB - Although only a small proportion of cholesterol in the body is esterified, in several diseases marked expansion of the esterified cholesterol (EC) pool occurs. These include Wolman disease (WD) and Cholesteryl Ester Storage Disease (CESD) which both result from mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). The respective contributions that our three cholesterol esterifying enzymes make to EC production, especially in disorders like CESD, are not well defined. The current studies represent a detailed exploration of our earlier findings in young male LAL-deficient mice also missing sterol O-acyltransferase 2 (SOAT2, also called ACAT2). Here we show that, even as they aged, male and female Lal-/-: Soat2- /- mice, compared to Lal-/-: Soat2+/+ littermates, had appreciably less hepatomegaly as well as a marked reduction in the level of sequestration of EC, in liver transaminase activities, and in hepatic mRNA expression levels for markers of inflammation. Loss of SOAT2 function also dramatically curtailed EC entrapment in the small intestine of the LAL-deficient mice. Together, these data imply that SOAT2 inhibition, if applied concurrently with enzyme replacement therapy for LAL deficiency, may blunt the re-esterification of newly released unesterified cholesterol thereby improving clinical outcomes. PMID- 29246493 TI - What are the contents of patient engagement interventions for older adults? A systematic review of randomized controlled trials. AB - OBJECTIVE: To describe the contents of interventions reported in RCTs focusing on patient engagement of older adults. METHODS: A systematic literature review based on a search for "patient engagement/activation/empowerment/involvement/participation". Interventions were classified according to: (i) specific components (micro level), (ii) single/multiple dimensions (educational, behavioral, affective) (meso level), and (iii) the studies' main educational, behavioral or affective dimension (macro level). RESULTS: After screening 2749 articles, 35 were included. 20 unique components were identified, mostly behavioral or educational (45.5% each) (e.g., goal setting or written informational materials). Most interventions with a single-focus were classified as educational (31%), one was solely affective (3%). Half of the interventions covered more than one dimension, with four (11%) combining all three dimensions. Studies mainly focusing on the affective dimension included older participants (72 vs. 67 years), had a higher proportion of females (71% vs. 44%), and included other dimensions more frequently (67% vs. 31%) than did studies with a main focus on the educational dimension. CONCLUSION: The contents of the interventions that focused on patient engagement of older adults tend to focus more on behavioral and educational dimensions than the affective dimension. PRACTICE IMPLICATIONS: The possibility of adding the affective dimension into behavioral and/or educational interventions should be explored. PMID- 29246494 TI - This Month in AJP. AB - The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID- 29246495 TI - Elevated Peripheral Myelin Protein 22, Reduced Mitotic Potential, and Proteasome Impairment in Dermal Fibroblasts from Charcot-Marie-Tooth Disease Type 1A Patients. AB - A common form of hereditary autosomal dominant demyelinating neuropathy known as Charcot-Marie-Tooth disease type 1A (CMT1A) is linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Although studies from animal models have led to better understanding of the pathobiology of these neuropathies, there continues to be a gap in the translation of findings from rodents to humans. Because PMP22 was originally identified in fibroblasts as growth arrest specific gene 3 (gas3) and is expressed broadly in the body, it was tested whether skin cells from neuropathic patients would display the cellular pathology observed in Schwann cells from rodent models. Dermal fibroblasts from two CMT1A pedigrees with confirmed PMP22 gene duplication were studied. Samples from age-matched non neuropathic individuals were used as controls. CMT1A patient-derived cultures contain approximately 1.5-fold elevated levels of PMP22 mRNA, exhibit reduced mitotic potential, and display intracellular protein aggregates as compared to cells from unaffected individuals. The presence of cytosolic PMP22 coincides with a decrease in proteasome activity and an increase in autophagy-lysosomal proteins, including LC3-II and LAMP1. These results indicate that the abnormalities in the subcellular processing of excess PMP22 elicit a detectable response in human CMT1A fibroblasts, a phenotype that resembles Schwann cells from neuropathic mice. These findings support the use of human CMT1A fibroblasts as a platform for therapy testing. PMID- 29246497 TI - Improved in vitro corneal delivery of a thrombospondin-1-derived peptide using a liposomal formulation. AB - Peptide delivery to and through ocular sites is a growing field of research interest. However, several barriers restrict the permeation and bioavailability of these molecules to target tissues. The main pharmacological barriers of topical administration are the tear film, rapid drainage of the tear film, and poor corneal permeation. If the administered molecule is a peptide, instability and enzymatic degradation can be significant. Novel approaches such as the design and development of nanocarriers to overcome these drawbacks have been investigated with promising results. Therefore, in continuation of our previous study using a liposome-based (LP) formulation as topical drug delivery system, the aim of this work was to efficiently encapsulate a thrombospondin-1-derived peptide, KRFK, in this formulation and to assess peptide permeability through different ocular surface epithelia. LPs were prepared by the solvent evaporation technique and the labeled peptide FITC-KRFK was incorporated in the aqueous core. Different sonication times were used to optimize encapsulation efficiency. The selected formulation was further analyzed in terms of size, pH, osmolarity, and corneal epithelial cytotoxicity. The permeabilities of the LP-encapsulated and free labeled KRFK peptides were assessed with in vitro models of conjunctival and corneal epithelia. Our results provide a proof of concept that the LP formulation efficiently encapsulates the KRFK peptide and improves corneal permeation. Data reported in this study strongly support that this formulation could be a more effective therapeutic approach than free peptide instillation and warrant further analysis using experimental in vivo models. PMID- 29246496 TI - miRNAs as Biomarkers for Predicting the Progression of Ductal Carcinoma in Situ. AB - Ductal carcinoma in situ (DCIS) is defined as a proliferation of neoplastic cells within the duct of the mammary gland that have not invaded into the surrounding stroma. DCIS is considered a precursor to invasive ductal carcinoma (IDC); however, approximately half of DCIS may progress to IDC, if left untreated. Current research has shown that the genomic and transcriptomic changes are present in DCIS before the emergence of invasive disease, indicating that the malignant nature of the DCIS is defined before invasion. However, important questions remain surrounding the specific changes and processes required for malignant progression and identification of prognostic indicators of aggressiveness. miRNAs are small regulatory RNAs that can modulate gene expression by complementary binding to target mRNAs and inducing translational repression and/or mRNA degradation. In the past decade, research has shown that miRNA expression is dysregulated in IDC and that these changes are already present at the DCIS stage. Therefore, changes in miRNA expression may provide the necessary information to identify a clinical indicator of the aggressiveness of DCIS. Herein, we review the miRNA signatures identified in DCIS, describe how these signatures may be used to predict the aggressiveness of DCIS, and discuss future perspectives for DCIS biomarker discovery. PMID- 29246498 TI - Epithelium-derived miR-204 inhibits corneal neovascularization. AB - MicroRNA-204 (miR-204) is highly expressed in cornea, here we explored the role and mechanism of miR-204 in corneal neovascularization (CNV). Mouse CNV was induced by intrastromal placement of suture in BALB/c mice with the subconjunctival injection of miR-204 agomir or negative control. Human primary limbal epithelial cells (LECs) and immortalized microvascular endothelial cells (HMECs) were used to evaluate the expression changes and anti-angiogenic effects of miR-204 under biomechanical stress (BS). The expression and localization of miR-204, vascular endothelial growth factor (VEGF) and their receptors were detected by quantitative real-time PCR, in situ hybridization, immunohistochemistry and Western blot. The results showed that miR-204 expression was mainly localized in epithelium and down-expressed in vascularized cornea. Subconjunctival injection of miR-204 agomir inhibited CNV and reduced the expression of VEGF and VEGF receptor 2. Similarly, miR-204 overexpression attenuated the increased expression of VEGF by biomechanical stress in LECs, and suppressed the proliferation, migration, and tube formation of HMECs. These novel findings indicate that epithelium-derived miR-204 inhibits suture-induced CNV through regulating VEGF and VEGF receptor 2. PMID- 29246499 TI - [Future status of ischaemic heart disease in the state of San Luis Potosi: A predictive dynamic model]. AB - OBJECTIVE: To develop a predictive dynamic model to generate and analyse the future status of the incidence rate of ischaemic heart disease in a population of 25 years and over in Mexico, according to the variation in time of some risk factors. METHOD: Retrospective ecological study performed during the period 2013 2015, in San Luis Potosi City, Mexico. Secondary databases that corresponded to the years 2000, 2005, and 2010, were used along with official indicators of the 58 municipalities of the state of San Luis Potosi. Eight indicators were analysed at municipality level, using principal components analysis, structural equation modelling, dynamic modelling, and simulation software methods. RESULTS: Three components were extracted, which together explained 80.43% of the total variance of the official indicators used. The second component had a weight of 16.36 units that favoured an increase of the disease analysed. This component was integrated only by the indicator AGE 60-64 and the expected stage of it increasing. The structural model confirmed that the indicators explain 42% of the variation of this disease. The possible stages for the years 2015, 2020, and 2025 are 195.7, 240.7, and 298.0, respectively for every 100,000 inhabitants aged 25 and over. CONCLUSIONS: An exponential increase in the incidence rate of ischaemic heart disease is expected, with the age of 60-64 years being identified as the highest risk factor. PMID- 29246500 TI - Fever in pregnancy and offspring head circumference. AB - PURPOSE: To examine whether maternal fever during pregnancy is associated with reduced head circumference and risk of microcephaly at birth. METHODS: A prospective study of 86,980 live-born singletons within the Danish National Birth Cohort was carried out. Self-reported maternal fever exposure was ascertained in two interviews during pregnancy and information on head circumference at birth was extracted from the Danish Medical Birth Registry. RESULTS: Fever in pregnancy was reported by 27% of the mothers, and we identified 3370 cases of microcephaly (head circumference less than or equal to third percentile for sex and gestational age) and 1140 cases of severe microcephaly (head circumference less than or equal to first percentile for sex and gestational age). In this study, maternal fever exposure was not associated with reduced head circumference (adjusted beta = 0.03, 95% confidence intervals [CI]: 0.01-0.05), increased risk of microcephaly (odds ratio: 0.95, 95% CI: 0.88-1.03) nor severe microcephaly (odds ratio: 1.01, 95% CI: 0.88-1.15) in the offspring. These findings were consistent for increasing numbers of fever episodes, for increasing fever severity, and for exposure in both early pregnancy and midpregnancy. CONCLUSIONS: In this most comprehensive study to date, we found no indication that maternal fever in pregnancy is associated with small head size in the offspring. PMID- 29246501 TI - MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease: cohort recruitment and baseline characteristics. AB - PURPOSE: MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease (MINERVA) was designed to answer the question of whether a novel continuous breast arterial calcification (BAC) mass score improves cardiovascular risk stratification among asymptomatic postmenopausal women. This article describes recruitment and baseline characteristics. METHODS: MINERVA is a multiethnic longitudinal cohort study. The phenotype data include BAC mass by densitometry applied to digital mammograms, sociodemographic factors, self reported medical history, medications, parental history, reproductive history, smoking, alcohol consumption, physical activity, anthropometry, ankle-brachial index, blood pressure, laboratory panel, breast volumes, cognitive function, bioelectrical impedance, habitual diet, dietary supplements, sleep, psychosocial factors, and sun exposure. RESULTS: A total of 5145 women aged 60 to 79 years with available digital, uncompressed mammograms were recruited from the membership of Kaiser Permanente of Northern California between October 24, 2012 and February 13, 2015 and completed a baseline clinic visit or an abbreviated phone questionnaire. Of those, 4153 underwent phlebotomy and have blood biomarkers. Overall prevalence of BAC was 26%, and it varied by age and race. The mean (SD) BAC mass was 12 (23) mg and the range 0-342 mg. CONCLUSIONS: MINERVA is the first cohort with a continuous measure of BAC. The cohort is large, ethnically diverse, and deeply phenotyped in terms of socioeconomic, behavioral, and clinical factors, and blood biomarkers. PMID- 29246503 TI - Promoting Excellence in Pediatric Nursing Practice and Science. PMID- 29246502 TI - The genus Polygonatum: A review of ethnopharmacology, phytochemistry and pharmacology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The genus Polygonatum (Asparagaceae) comprises 71 species distributed throughout the temperate Northern Hemisphere. The medicinal plants of Polygonatum have been traditionally used as tonics in China, India, Pakistan, Iran and Japan, and have been demonstrated to be highly effective in clinical practice for treating age-related diseases, diabetes, lung diseases, fatigue, feebleness and indigestion. AIM OF THE REVIEW: This paper aims to provide the links among traditional uses, chemical constituents, pharmacological effects and toxicity to support their therapeutic potential and uncover opportunities for future research. MATERIALS AND METHODS: The relevant information on the genus Polygonatum was gathered from scientific databases (Google Scholar, Web of Science, SciFinder, ScienceDirect, ACS Publications, PubMed, Wiley Online Library, CNKI). Information was also obtained from online databases, books, Ph.D. dissertations and M.Sc. theses. The literature cited in this review dates from 1917 to June 2017. RESULTS: At least 37 species and 1 variety of Polygonatum plants have been used as traditional medicine and functional food. The major chemical constituents of Polygonatum plants are steroidal saponins, triterpenoid saponins, homoisoflavanones, polysaccharides and lectins. A putative biosynthetic pathway of steroidal saponins and triterpenoid saponins has been established based on the compounds isolated from Polygonatum plants. The crude extracts and certain pure compounds from Polygonatum plants have shown a wide range of pharmacological effects such as anti-aging, anti diabetic, anti-fatigue, and anticancer effects. The rhizomes of Polygonatum plants have a low degree of toxicity after processing. CONCLUSIONS: Based on this review, some traditional uses of Polygonatum species have been confirmed by pharmacological studies, such as its anti-osteoporosis, neuroprotective, immunomodulatory, anti-diabetic and anti-fatigue effects. Most of the pharmacological effects of this genus can be attributed to its polysaccharides, saponins and lectins. However, to clarify the chemical differences that lead to the different traditional uses between "Huangjing" (derived from P. sibiricum, P. kingianum, P. cyrtonema) and "Yuzhu" (derived from P. odoratum), a systematic comparison of the small molecule compositions and polysaccharides of these four species is needed. In addition to these four species, other locally used medicinal Polygonatum species should be the subject of research, and the chemical and pharmacological relationships of these species should be investigated to expand the medicinal resources and standardize the use of Polygonatum species. PMID- 29246504 TI - A recombinant VSV-vectored MERS-CoV vaccine induces neutralizing antibody and T cell responses in rhesus monkeys after single dose immunization. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) has been a highly threatening zoonotic pathogen since its outbreak in 2012. Similar to SARS-CoV, MERS-CoV belongs to the coronavirus family and can induce severe respiratory symptoms in humans, with an average case fatality rate of 35% according to the World Health Organization. Spike (S) protein of MERS-CoV is immunogenic and can induce neutralizing antibodies, thus is a potential major target for vaccine development. Here we constructed a chimeric virus based on the vesicular stomatitis virus (VSV) in which the G gene was replaced by MERS-CoV S gene (VSVDeltaG-MERS). The S protein efficiently incorporated into the viral envelope and mediated cell entry through binding its receptor, human DPP4. Knockdown of clathrin expression by siRNA drastically abrogated the infection of VSVDeltaG MERS in Vero cells. Furthermore, in animal studies, the recombinant virus induced neutralizing antibodies and T cell responses in rhesus monkeys after a single intramuscular or intranasal immunization dose. Our findings indicate the potential of the chimeric VSVDeltaG-MERS as a rapid response vaccine candidate against emerging MERS-CoV disease. PMID- 29246506 TI - Age-related changes of skeletal muscle mass and strength among Italian and Taiwanese older people: Results from the Milan EXPO 2015 survey and the I-Lan Longitudinal Aging Study. AB - BACKGROUND: Muscle mass and strength ineluctably decline with advancing age. Yet, the impact of ethnicity on the pattern of changes and their magnitude is unclear. The aims of the present study were to analyze age- and gender-specific changes in measures of muscle mass and strength among community-living persons and to identify differences between Caucasian and Asian participants. METHODS: The Italian survey ("Longevity Check-up"), conducted during Milan EXPO 2015, consisted of a population assessment aimed at evaluating the prevalence of specific health metrics in persons outside of a conventional research setting (n=1924), with a special focus on muscle mass and strength. The Taiwanese survey used the first-wave sampling from the I-Lan Longitudinal Aging Study (ILAS) collected from August 2011 to August 2013 (n=1839). ILAS was designed to explore the interrelationship between sarcopenia and frailty in community-dwelling older people in Taiwan. In both studies, muscle mass was estimated by measuring the calf circumference (CC), whereas muscle strength was assessed by handgrip strength testing. RESULTS: The mean age of the 1924 Italian participants was 62.5years (standard deviation 8.3, range from 50 to 98years), of whom 1031 (53.6%) were women. Similarly, the mean age of the Taiwanese sample was 63.9years (standard deviation 9.3, range from 50 to 92years), with 966 (52.5%) women. CC declined with age in both genders and was significantly greater among Italian participants compared with Taiwanese people in all age groups. A similar effect of age was observed for muscle strength. As for CC, muscle strength was significantly greater among Italian persons relative to Taiwanese participants. CONCLUSION: Muscle mass and strength declined with age in both ethnic groups. Caucasians showed greater muscle mass and performed better than their Asian counterparts. However, the age at which declines began to appear and the rate of decline during aging were comparable between the two populations. PMID- 29246505 TI - RIFM fragrance ingredient safety assessment 2,4-dimethylbenzyl acetate, CAS Registry Number 62346-96-7. PMID- 29246507 TI - A tritherapy combination of inactivated allogeneic leukocytes infusion and cell vaccine with cyclophosphamide in a sequential regimen enhances antitumor immunity. AB - BACKGROUND: Tumor-induced immunosuppression can impede tumor-specific immune responses and limit the effects of cancer immunotherapy. The aim of this study was to investigate the possible effects of sequential chemoimmunotherapeutic strategies to enhance antitumor immune responses. METHODS: Using the E7 expressing tumor TC-1 as the tumor model, the treatment groups were divided into the following groups: (1) inactivated allogeneic leukocyte infusion (ALI), (2) ALI + MMC-inactivated TC-1 cell vaccine, and (3) ALI + MMC-inactivated TC-1 cell vaccine + cyclophosphamide (CTX). RESULTS: In our study, we demonstrated that treatment with immune-modulating doses of CTX results in a beneficial tumor microenvironment with the suppression of Tregs. ALI has a limited therapeutic effect, as does the MMC-inactivated TC-1 cell vaccine. Our results showed that CTX preconditioning and persistent ALI treatment along with the MMC-inactivated TC-1 cell vaccine resulted in significant inhibition of tumor growth and extended survival. CONCLUSION: Our study illustrated the effects of immune-modulating doses of a sequential chemoimmunotherapeutic strategy targeting the tumor and its microenvironment. The results suggest potential clinical effects for the immunotherapy of HPV-associated malignancies. PMID- 29246508 TI - Structural and thermodynamic characterization of endo-1,3-beta-glucanase: Insights into the substrate recognition mechanism. AB - Endo-1,3-beta-glucanase from Cellulosimicrobium cellulans is composed of a catalytic domain and a carbohydrate-binding module. We have determined the X-ray crystal structure of the catalytic domain at a high resolution of 1.66A. The overall fold is a sandwich-like beta-jelly roll architecture like the enzymes in the glycoside hydrolase family 16. The substrate-binding cleft has a length and a width of ~28 and ~15A, respectively, which is thought to be capable of accommodating at least six glucopyranose units. Laminarihexaose was placed into the substrate-binding cleft, namely at the subsites +2 to -4 from the reducing end, and the complex structure was analyzed using molecular dynamics simulations (MD) and using a rotamer search of the pocket. During the MD simulations, the substrate fluctuated more than the enzyme, where the residues at the subsites toward the non-reducing end fluctuated more than those toward the reducing end. Little conformational change of the protein was observed for the subsites +1 and +2, indicating that the glucose's position could be tightly restricted inside the pocket. Substrate binding experiments using isothermal titration calorimetry showed that the binding affinity of laminaritriose was higher than that of laminaribiose and similar to those of other longer laminarioligosaccharides. Taken together, the substrates mainly bind to the subsites -1 to -3 with the highest affinity, while the part bound to the reducing end would be hydrolyzed. PMID- 29246509 TI - Diagnostic Concordance and Clinical Outcomes in Patients Undergoing Fractional Flow Reserve and Stress Echocardiography for the Assessment of Coronary Stenosis of Intermediate Severity. AB - BACKGROUND: The ischemic consequences of coronary artery stenosis can be assessed by invasive fractional flow reserve (FFR) or by noninvasive imaging. We sought to determine (1) the concordance between wall thickening assessment during clinically indicated stress echocardiography (SE) and FFR measurements and (2) the factors associated with hard events in these patients. METHODS: Two hundred twenty-three consecutive patients who underwent SE and invasive FFR measurements in close succession were analyzed retrospectively for diagnostic concordance and clinical outcomes. RESULTS: At the vessel level, the sensitivity, specificity, positive predictive value, and negative predictive value of SE for identifying significant disease as assessed by FFR was 68%, 75%, 43%, and 89%, respectively. The greatest discordance was seen in patients with wall thickening abnormalities (WTAs) and negative FFR. During a follow-up of 3.6 +/- 2.2 years, there were 23 cardiovascular (CV) events (death and nonfatal myocardial infarction). The number of wall segments with inducible WTAs emerged as the strongest factor associated with CV events (hazard ratio, 1.18 [1.05-1.34]; P = .008). FFR was not associated with outcome. There was a significant increase in event rate in patients with WTA/negative FFR versus no WTA/negative FFR (P = .01), but no significant difference versus WTA/positive FFR (P = .85). CONCLUSIONS: In a patient population with significant CV risk factors, a normal SE had a high negative predictive value for excluding abnormal FFR. WTAs were associated with outcomes regardless of FFR value, suggesting that this is a superior marker of ischemia to FFR. PMID- 29246510 TI - Echocardiographic Detection of Increased Ventricular Diastolic Stiffness in Pediatric Heart Transplant Recipients: A Pilot Study. AB - BACKGROUND: Pediatric heart transplant recipients are at risk for increased left ventricular (LV) diastolic stiffness. However, the noninvasive evaluation of LV stiffness has remained elusive in this population. The objective of this study was to compare novel echocardiographic measures of LV diastolic stiffness versus gold-standard measures derived from pressure-volume loop (PVL) analysis in pediatric heart transplant recipients. METHODS: Patients undergoing left heart catheterization were prospectively enrolled. PVLs were obtained via conductance. The end-diastolic pressure-volume relationship was obtained via balloon occlusion. The stiffness constant, beta, was calculated. Echocardiographic measures of diastolic function were derived from spectral and tissue Doppler and two-dimensional speckle-tracking. Ventricular volumes were measured using three dimensional echocardiography. The novel echocardiographic estimates of ventricular stiffness included E:e'/end-diastolic volume (EDV) and E:early diastolic strain rate/EDV. RESULTS: Of 24 children, 18 were heart transplant recipients. Six control patients had hemodynamically insignificant patent ductus arteriosus or coronary fistula. The mean age was 9.1 +/- 5.6 years. Median end diastolic pressure was 9 mm Hg (interquartile range, 8-13 mm Hg). Lateral E:e'/EDV (r = 0.59, P < .01), septal E:e'/EDV (r = 0.57, P < .01), and (E:circumferential early diastolic strain rate)/EDV (r = 0.54, P < .01) correlated with beta. Lateral E:e'/EDV displayed a C statistic of 0.93 in detecting patients with abnormal LV stiffness (beta > 0.015 mL-1). A lateral E:e'/EDV of >0.15 mL-1 had 89% sensitivity and 93% specificity in detecting an abnormal beta. CONCLUSIONS: Echocardiographic estimates of ventricular stiffness may be accurate compared with the gold standard in pediatric heart transplant recipients. The clinical usefulness of these noninvasive measures in assessing LV stiffness merits further study in children. PMID- 29246511 TI - Fetal Cardiac Function in Maternal Diabetes: A Conventional and Speckle-Tracking Echocardiographic Study. AB - BACKGROUND: Intrauterine exposure to a diabetic environment is associated with adverse fetal myocardial remodeling. The aim of this study was to assess the biventricular systolic and diastolic function of fetuses exposed to maternal diabetes (MD) compared with control subjects, using a comprehensive cardiac functional assessment and exploring the role of speckle-tracking to assess myocardial deformation. The authors hypothesized that fetuses exposed to MD present signs of biventricular dysfunction, which can be detected by deformation analysis. METHODS: A cross-sectional study was conducted in 129 fetuses with structurally normal hearts, including 76 fetuses of mothers with diabetes and 53 of mothers without diabetes. Maternal baseline characteristics, standard fetoplacental Doppler indices, and conventional echocardiographic and myocardial deformation parameters were prospectively collected at 30 to 33 weeks of gestation. RESULTS: Fetuses of mothers with diabetes had a significantly thicker interventricular septum compared with control subjects (median, 4.25 mm [interquartile range (IQR), 3.87-4.50 mm] vs 3.67 mm [IQR, 3.40-3.93 mm), P < .001), but no effect modification was demonstrated on myocardial deformation analysis. No significant differences were found in conventional systolic and diastolic functional parameters for the left ventricle and right ventricle, except for lower left ventricular cardiac output in the MD group (median, 320 mL/min [IQR, 269-377 mL/min] vs 365 mL/min [IQR, 311-422 mL/min], P < .05]. Deformation analysis demonstrated a significantly lower early diastolic strain rate (SRe) and late diastolic strain rate (SRa) for both ventricles in the MD group (left ventricle: SRe 1.85 +/- 0.72 vs 2.26 +/- 0.68 sec-1, SRa 1.50 +/- 0.52 vs 1.78 +/- 0.57 sec-1; right ventricle: SRe 1.57 +/- 0.73 vs 1.97 +/- 0.73 sec-1, SRa 2 +/- 0.77 vs 1.68 +/- 0.79 sec-1; P < .05), suggesting biventricular diastolic impairment. Additionally, the right ventricle presented a lower global longitudinal strain in the study group (-13.67 +/- 4.18% vs -15.52 +/- 3.86%, P < .05). Multivariate analysis revealed that maternal age is an independent predictor of left and right ventricular global longitudinal strain (P < .05), with a significant effect only in MD after group stratification. CONCLUSIONS: Fetuses of mothers with diabetes present signs of biventricular diastolic dysfunction and right ventricular systolic dysfunction by deformation analysis in the third trimester of pregnancy. They may represent a special indication group for functional cardiac assessment, independently of septal hypertrophy. Two dimensional speckle-tracking could offer an additional benefit over conventional echocardiography to detect subclinical unfavorable changes in myocardial function in this population. PMID- 29246512 TI - Comparison of Feasibility, Accuracy, and Reproducibility of Layer-Specific Global Longitudinal Strain Measurements Among Five Different Vendors: A Report from the EACVI-ASE Strain Standardization Task Force. AB - BACKGROUND: Despite standardization efforts, vendors still use information from different myocardial layers to calculate global longitudinal strain (GLS). Little is known about potential advantages or disadvantages of using these different layers in clinical practice. The authors therefore investigated the reproducibility and accuracy of GLS measurements from different myocardial layers. METHODS: Sixty-three subjects were prospectively enrolled, in whom the intervendor bias and test-retest variability of endocardial GLS (E-GLS) and midwall GLS (M-GLS) were calculated, using software packages from five vendors that allow layer-specific GLS calculation (GE, Hitachi, Siemens, Toshiba, and TomTec). The impact of tracking quality and the interdependence of strain values from different layers were assessed by comparing test-retest errors between layers. RESULTS: For both E-GLS and M-GLS, significant bias was found among vendors. Relative test-retest variability of E-GLS values differed significantly among vendors, whereas M-GLS showed no significant difference (range, 5.4%-9.5% [P = .032] and 7.0%-11.2% [P = .200], respectively). Within-vendor test-retest variability was similar between E-GLS and M-GLS for all but one vendor. Absolute test-retest errors were highly correlated between E-GLS and M-GLS for all vendors. CONCLUSIONS: E-GLS and M-GLS measurements showed no relevant differences in robustness among vendors, although intervendor bias was higher for M-GLS compared with E-GLS. These data provide no technical argument in favor of a certain myocardial layer for global left ventricular functional assessment. Currently, the choice of which layer to use should therefore be based on the available clinical evidence in the literature. PMID- 29246513 TI - Value of Myocardial Work Estimation in the Prediction of Response to Cardiac Resynchronization Therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) in heart failure is plagued by too many nonresponders. The aim of the present study is to evaluate whether the estimation of myocardial performance by pressure-strain loops (PSLs) is useful for the selection of CRT candidates. METHODS: Ninety-seven patients undergoing CRT were included in the study. Bidimensional and speckle-tracking echocardiography were performed before CRT and at the 6-month follow-up (FU). Conventional dyssynchrony parameters were evaluated. Left ventricular (LV) constructive work (CW) and wasted work (WW) were estimated by PSLs. Positive response to CRT (CRT+) was defined as >=15% reduction in LV end-systolic volume at FU and was observed in 63 (65%) patients. RESULTS: The addition of CW > 1,057 mm Hg% (area under the curve, 0.72, P < .0001) and WW > 384 mm Hg% (area under the curve, 0.67, P = .005) to a baseline model including clinical, echocardiographic, and conventional dyssynchrony parameters significantly increased the model power (chi2, 25.11 vs 47.5, P < .0001). In this model, septal flash (odds ratio [OR] = 2.78; P = .001), CW > 1,057 mm Hg% (OR = 9.49; P = .002), and WW > 384 mm Hg% (OR = 16.24, P < .006) remained the only parameters associated with CRT+. The combination of CW > 1,057 mm Hg% and WW > 384 mm Hg% showed a good specificity (100%) and positive predictive value (100%) but a low sensitivity (22%), negative predictive value (41%), and accuracy (49%) for the identification of CRT+. CONCLUSIONS: The estimation of CW and WW by PSLs is a novel tool for the assessment of CRT patients. Although these parameters cannot be used by their own to select CRT candidates, they can provide further insights into the comprehension of dyssynchrony mechanisms and contribute to improving the identification of CRT responders. PMID- 29246514 TI - Atrial Enlargement in the Athlete's Heart: Assessment of Atrial Function May Help Distinguish Adaptive from Pathologic Remodeling. AB - Intensive training is associated with hemodynamic changes that typically induce an enlargement of cardiac chambers, involving not only the ventricles but also the atria. The hearts of competitive athletes are characterized by increases in left and right atrial dimensions that have been interpreted as a physiologic adaptation to training. Conversely, some authors have hypothesized maladaptive remodeling; furthermore, the extent of left atrial dimensional remodeling may overlap atrial dilation observed in patients with cardiac disease, representing a challenge for clinicians. However, studies investigating left and right atrial function in athletes have demonstrated that atrial size is insufficient to provide mechanistic information about the atrium itself, and an increase in atrial size is not intrinsically an expression of atrial dysfunction. The authors critically analyze training-induced atrial remodeling, taking into account not only the assessment of atrial size but also the evaluation of atrial function, suggesting that the characterization of atrial function plays a fundamental role in the evaluation of athlete's heart, being useful to differentiate physiologic remodeling induced by exercise from pathologic changes occurring in cardiac disorders. PMID- 29246515 TI - Complex Association of Sex Hormones on Left Ventricular Systolic Function: Insight into Sexual Dimorphism. AB - BACKGROUND: Normal values of left ventricular ejection fraction (LVEF) and absolute values of global longitudinal strain (GLS) are lower in men than in women. Data concerning the association of sex hormone levels on these left ventricular systolic function surrogates are scarce. The aim of this study was to determine the association of sex hormones with systolic left ventricular function in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of testosterone dysregulation. METHODS: Eighty-four adult patients with CAH (58 women; median age, 27 years; interquartile range, 23-36 years) and 84 healthy subjects matched for sex and age were prospectively included. Circulating concentrations of sex hormones were measured within 48 hours of echocardiography with assessment of LVEF and left ventricular longitudinal, radial, and circumferential strain. RESULTS: LVEF and GLS were higher in healthy women than in healthy men (63.9 +/- 4.2% vs 60.9 +/- 5.1% [P < .05] and 20.0 +/- 1.9% vs 17.9 +/- 2.4% [P < .001], respectively), while there was no difference in LVEF or GLS between women and men with CAH (63.9 +/- 4.5% vs 63.0 +/- 4.6% [P = NS] and 19.4 +/- 2.2% vs 18.3 +/- 1.8% [P = NS], respectively). Bioavailable testosterone levels were higher in women with CAH than in female control subjects (0.08 ng/mL [interquartile range, 0.04-0.14 ng/mL] vs 0.16 ng/mL [interquartile range, 0.04 0.3 ng/mL], P < .001) and lower in men with CAH than in male control subjects (2.3 ng/mL [interquartile range, 1.3-3 ng/mL] vs 2.9 ng/mL [interquartile range, 2.5-3.4 ng/mL], P < .05). In men, LVEF and GLS were negatively correlated with bioavailable testosterone levels (r = -0.3, P <= .05, and r = -0.45, P < .01, respectively), while midventricular radial strain was positively correlated with bioavailable testosterone level (r = 0.38, P < .05). The absolute value of circumferential strain was positively correlated with follicle-stimulating hormone (r = 0.65, P < .0001). CONCLUSIONS: These data support that the existence of sex dimorphism concerning left ventricular systolic cardiac function is significantly associated with testosterone levels. PMID- 29246516 TI - Isolation of recombinant Hepatitis B surface antigen with antibody-conjugated superparamagnetic Fe3O4/SiO2 core-shell nanoparticles. AB - In the production process of recombinant Hepatitis B surface antigen (rHBsAg) various separation techniques are used to purify this virus-like particle (VLP). In this study, we developed antibody-conjugated super-paramagnetic Fe3O4/SiO2 core-shell nanoparticles as a highly selective method for isolation of expressed rHBsAg in yeast Pichia pastoris. For this purpose, first, iron oxide magnetic nanoparticles (MNPs) were prepared by co-precipitation method in alkali media and coated with silica. Then the surface was activated by amine groups and conjugated with oxidized antibodies. X-ray diffraction (XRD), transmission electron microscopy (TEM), and vibrating sample magnetometer (VSM) were used to study the physical properties of MNPs. To evaluate the efficacy of these MNPs as a purification technique successfully synthesized MNPs were added to the rHBsAg sample to couple with the antigen and then be isolated based on their magnetic property. In the present research, in the optimum condition, we could isolate 65% of total rHBsAg from the final vaccine sample with purity above 95%. In this procedure, the maximum obtained specific yield (mg HBsAg/mg MNPs) was equal to 37.6. These results underline the potential application of the immune-magnetic separation (IMS) in the future bioseparation systems. PMID- 29246517 TI - Enabling the valorization of guaiacol-based lignin: Integrated chemical and biochemical production of cis,cis-muconic acid using metabolically engineered Amycolatopsis sp ATCC 39116. AB - Lignin is nature's second most abundant polymer and displays a largely unexploited renewable resource for value-added bio-production. None of the lignin based fermentation processes so far managed to use guaiacol (2-methoxy phenol), the predominant aromatic monomer in depolymerized lignin. In this work, we describe metabolic engineering of Amycolatopsis sp. ATCC 39116 to produce cis,cis muconic acid (MA), a precursor of recognized industrial value for commercial plastics, from guaiacol. The microbe utilized a very broad spectrum of lignin based aromatics, such as catechol, guaiacol, phenol, toluene, p-coumarate, and benzoate, tolerated them in elevated amounts and even preferred them over sugars. As a next step, we developed a novel approach for genomic engineering of this challenging, GC-rich actinomycete. The successful introduction of conjugation and blue-white screening, using beta-glucuronidase, enabled tailored genomic modifications within ten days. Successive deletion of two putative muconate cycloisomerases from the genome provided the mutant Amycolatopsis sp. ATCC 39116 MA-2, which accumulated 3.1gL-1 MA from guaiacol within 24h, achieving a yield of 96%. The mutant was found also capable to produce MA from a guaiacol-rich true lignin hydrolysate, obtained from pine through hydrothermal conversion. This provides an important proof-of-concept to successfully coupling chemical and biochemical process steps into a value chain from the lignin polymer to an industrial chemical. In addition, Amycolatopsis sp. ATCC 39116 MA-2 was able to produce 2-methyl MA from o-cresol (2-methyl phenol), which opens possibilities towards polymers with novel architecture and properties. PMID- 29246519 TI - Hybrid Method Based on Information Gain and Support Vector Machine for Gene Selection in Cancer Classification. AB - It remains a great challenge to achieve sufficient cancer classification accuracy with the entire set of genes, due to the high dimensions, small sample size, and big noise of gene expression data. We thus proposed a hybrid gene selection method, Information Gain-Support Vector Machine (IG-SVM) in this study. IG was initially employed to filter irrelevant and redundant genes. Then, further removal of redundant genes was performed using SVM to eliminate the noise in the datasets more effectively. Finally, the informative genes selected by IG-SVM served as the input for the LIBSVM classifier. Compared to other related algorithms, IG-SVM showed the highest classification accuracy and superior performance as evaluated using five cancer gene expression datasets based on a few selected genes. As an example, IG-SVM achieved a classification accuracy of 90.32% for colon cancer, which is difficult to be accurately classified, only based on three genes including CSRP1, MYL9, and GUCA2B. PMID- 29246518 TI - Interactome Analysis of Microtubule-targeting Agents Reveals Cytotoxicity Bases in Normal Cells. AB - Cancer causes millions of deaths annually and microtubule-targeting agents (MTAs) are the most commonly-used anti-cancer drugs. However, the high toxicity of MTAs on normal cells raises great concern. Due to the non-selectivity of MTA targets, we analyzed the interaction network in a non-cancerous human cell. Subnetworks of fourteen MTAs were reconstructed and the merged network was compared against a randomized network to evaluate the functional richness. We found that 71.4% of the MTA interactome nodes are shared, which affects cellular processes such as apoptosis, cell differentiation, cell cycle control, stress response, and regulation of energy metabolism. Additionally, possible secondary targets were identified as client proteins of interphase microtubules. MTAs affect apoptosis signaling pathways by interacting with client proteins of interphase microtubules, suggesting that their primary targets are non-tumor cells. The paclitaxel and doxorubicin networks share essential topological axes, suggesting synergistic effects. This may explain the exacerbated toxicity observed when paclitaxel and doxorubicin are used in combination for cancer treatment. PMID- 29246521 TI - Fertility-preserving surgery for post-Caesarean uterine scar dehiscence in a pregnant patient. PMID- 29246520 TI - A Stack-based Ensemble Framework for Detecting Cancer MicroRNA Biomarkers. AB - MicroRNA (miRNA) plays vital roles in biological processes like RNA splicing and regulation of gene expression. Studies have revealed that there might be possible links between oncogenesis and expression profiles of some miRNAs, due to their differential expression between normal and tumor tissues. However, the automatic classification of miRNAs into different categories by considering the similarity of their expression values has rarely been addressed. This article proposes a solution framework for solving some real-life classification problems related to cancer, miRNA, and mRNA expression datasets. In the first stage, a multiobjective optimization based framework, non-dominated sorting genetic algorithm II, is proposed to automatically determine the appropriate classifier type, along with its suitable parameter and feature combinations, pertinent for classifying a given dataset. In the second page, a stack-based ensemble technique is employed to get a single combinatorial solution from the set of solutions obtained in the first stage. The performance of the proposed two-stage approach is evaluated on several cancer and RNA expression profile datasets. Compared to several state-of the-art approaches for classifying different datasets, our method shows supremacy in the accuracy of classification. PMID- 29246523 TI - [Child protection: Pediatricians' knowledge and practices in Brittany]. AB - BACKGROUND AND AIMS: On 5 March 2007, the law concerning the child protection system was reformed. Since then, child protection services have been responsible for the management of child abuse and neglect. Reporting and asking for child protection is now easier for every physician by submitting a "preoccupying information" form. A study conducted in 2014 in the general practitioners (GP) in the Ille-et-Vilaine department showed that they were quite unfamiliar with the child protection updates and that they needed special training. We wished to study the knowledge and practices of the pediatricians in Brittany and compare these results to the previous study. METHODS: An anonymous postal investigation was conducted between May and July 2014. The questionnaire was referred to the previous study so the results would be comparable. RESULTS: A total of 134 pediatricians (including 99 women) of the 316 pediatricians of Brittany answered our questionnaire regarding their activity and their knowledge about child abuse and neglect. These results were analyzed and compared to the data of GPs in Ille et-Vilaine. Only 4.4 % of the pediatricians obtained more than 80 % correct answers and 12 % of the pediatricians obtained fewer than 50 % correct answers. Among the pediatricians, 41 % of them had not reported a single time since 2007. The pediatricians who obtained better results (P<0.001) had more training and were more often in contact with child abuse and neglect than the GPs. The most common reasons that clinicians gave for not reporting were lack of a return from social services after a report, lack of training and the fear of making a misdiagnosis. Indeed only 9 % had received feedback from social services. To make reporting easier, 92 % of the pediatricians would like training and 97 % found a simple practice guide on child abuse useful. CONCLUSION: Child protection is a neglected subject, including by pediatricians. To fight against professional denial and isolation, a substantial effort is still needed concerning caregivers' training as well as pediatric care organization. PMID- 29246524 TI - Clinical manifestations of the Mmalton alpha-1 antitrypsin deficiency variant. PMID- 29246522 TI - Children and screens: A survey by French pediatricians. AB - INTRODUCTION: Screens are increasingly prevalent within families. The excessive use of screens by children has negative consequences. To measure the use of screens, we undertook an investigation among children being followed by pediatricians. METHODS: An invitation to participate was sent electronically to 1460 private practice pediatricians. They were asked to complete the questionnaire on screen use by children under 12 years of age during a consultation, according to statements made by parents. RESULTS: One hundred and forty-four pediatricians submitted completed questionnaires involving 428 children. Among the 197 children under 3 years of age, 92 had played with an interactive screen for a median duration of 30min during the preceding week; 29% of the children were alone at the time. One hundred and thirty-nine children had watched television for a median weekly duration of 75min. Of the 231 children 3 11 years of age, 108 had played with an interactive screen for a median time of 30min the day before the consultation, and 50% of them were alone at the time. One hundred and seventy-two children watched television for a median daily duration of 45min. There was a correlation between these children's screen time and their mother's (r=0.36). The television was on during meals and continuously in 35% and 21% of the families, respectively. CONCLUSIONS: Children start looking at screens early, too often watching unsuitable programs, and too often without a parent's present. Regardless of the child's age, pediatricians must ask parents how much time their children are viewing screens, advise them accordingly, and warn them of the consequences of excessive use. PMID- 29246525 TI - Comparative Trends in Utilization of MRI and Ultrasound to Evaluate Nonspine Joint Disease 2003 to 2015. AB - PURPOSE: MRI and ultrasound (US) are effective diagnostic tools to evaluate extremities. In this study, we analyze utilization trends in musculoskeletal (MSK) US and MRI from 2003 to 2015 within the Medicare population. METHODS: Our data sources were the Medicare Part B Physician/Supplier Procedure Summary Master Files for 2003 to 2015. They cover all Medicare fee-for-service enrollees (37.5 million in 2015). Current Procedural Terminology codes for nonvascular, nonspine joint MRI and extremity US were selected and volumes within these codes were determined. Medicare's physician specialty codes were used to identify provider specialty. We accounted for the 2011 code change that created both complete and limited US examinations. RESULTS: Total Medicare joint MRI volume increased from 738,509 in 2003 to 1,131,503 in 2015 (+53%), although there was little change after 2007. Radiologist MRI share in 2015 was 93%, followed by orthopedic surgeons at 5%. Total MSK US volume grew from 96,235 in 2003 to 429,695 in 2015 (+347%). Radiologists' market share of US decreased from 65% in 2003 to 37% in 2015, with nonradiologists now representing a majority of ultrasound examinations. Multiple nonradiology subspecialties also exceed radiology in volume of complete ultrasounds. CONCLUSION: The potential negative impact of MSK US on MSK MRI volume is likely overestimated because MRI volume has remained stable. MSK ultrasound is increasingly utilized outside radiology. If radiologists want to maintain their market share as MSK imaging leaders, more emphasis should be placed on increasing their involvement and expertise in MSK US. PMID- 29246527 TI - The impact of smoking on rheumatoid arthritis outcomes. PMID- 29246526 TI - Trends and predictions to 2020 in breast cancer mortality: Americas and Australasia. AB - OBJECTIVES: We considered trends in breast cancer mortality for 12 American and 8 Australasian countries during 1970-2014, and predicted rates for 2020. MATERIALS AND METHODS: We obtained official death certification data for breast cancer and population figures from the World Health Organization, Pan American Health Organization and United Nations databases. We derived age-standardized rates (world standard population), and predictions for 2020 using joinpoint regression. RESULTS: Breast cancer mortality trends were favourable in North America and Oceania, and a further 10% reduction in their overall rates is predicted for 2020, to reach values of 11-12/100,000 women, i.e. about 50% lower than their top rates in the later 1980's. Hong Kong, Japan and Korea did not show appreciable trends, but their rates remained below 10/100,000. Mexico, Chile, Colombia, Brazil also had stable rates, below or around 10/100,000. Breast cancer mortality was higher in Argentina, Cuba and Venezuela, and only Argentina showed some favourable trends over recent years, and predictions to 2020 around 16/100,000. Trends and predictions were less favourable in Israel, New Zealand, and the Philippines than in most other countries with predicted rates in 2020 between 13 and 16/100,000. CONCLUSION: In several high-income countries, the fall in breast cancer mortality, due to improved treatment and diagnosis, has been the major success in the management of any common cancer over the last three decades. There are, however, persistent disparities in the global decline in breast cancer, which call for urgent management improvements in several areas of the world, particularly in middle-income countries. PMID- 29246528 TI - Epigenetics of bone diseases. AB - Histone deacetylation, DNA methylation, and micro-RNAs (miRNAs) are the three main epigenetic mechanisms that regulate gene expression. All the physiological processes involved in bone remodeling are tightly regulated by epigenetic factors. This review discusses the main epigenetic modifications seen in tumoral and non-tumoral bone diseases, with emphasis on miRNAs. The role for epigenetic modifications of gene expression in the most common bone diseases is illustrated by drawing on the latest publications in the field. In multifactorial bone diseases such as osteoporosis, many epigenetic biomarkers, either alone or in combination, have been associated with bone mineral density or suggested to predict osteoporotic fractures. In addition, treatments designed to modulate bone remodeling by selectively targeting the function of specific miRNAs are being evaluated. Advances in the understanding of epigenetic regulation shed new light on the pathophysiology of other non-tumoral bone diseases, including genetic conditions inherited on a Mendelian basis. Finally, in the area of primary and metastatic bone tumors, the last few years have witnessed considerable progress in elucidating the epigenetic regulation of oncogenesis and its local interactions with bone tissue. These new data may allow the development of epigenetic outcome predictors, which are in very high demand, and of innovative therapeutic agents acting via miRNA modulation. PMID- 29246529 TI - Teriparatide treatment in an adult patient with hypophosphatasia exposed to bisphosphonate and revealed by bilateral atypical fractures. AB - Atypical femoral fractures are defined as atraumatic fractures located in the subtrochanteric region or femoral shaft. They have been mainly reported in patients taking bisphosphonates. We report the case of a 67-year-old female with osteoporosis treated by alendronate during ten years. Radiographies showed atypical femoral fractures. Serum levels of total and bone-specific alkaline phosphatase were low. In order to accelerate bone healing, teriparatide was introduced. After one year of teriparatide treatment, pain and functional difficulty have decreased, and alkaline phosphatase levels were normalized. In view of this history of recurrent fractures, of atypical femoral fractures, of early spontaneous loss of teeth, and of low serum total and bone-specific alkaline phosphatase levels, the diagnosis of hypophosphatasia has been considered and confirmed by genetic research. Other conditions than exposure to anti-resorptive therapies may promote atypical femoral fractures, such as in conditions associated with abnormal bone structures, as hypophosphatasia, a rare inherited bone metabolism disorder. A few case reports have reported adult hypophosphatasia treated by teriparatide with a good efficacy on bone pain and consolidation but with mixed results on biological markers. Teriparatide may be therefore a treatment option in adult hypophosphatasia. ALP levels should be carefully checked among osteoporotic patients and specially before introducing a bone resorption inhibitor. Low alkaline phosphatase levels have to be taken into account and an evocative history of hypophosphatasia has to be sought because this condition may expose patients to develop atypical femoral fractures during bisphosphonate treatment. PMID- 29246530 TI - Controversies in rheumatoid arthritis glucocorticoid therapy. AB - Despite therapeutic innovations in the past 20 years, glucocorticoids (GC) are still widely used for the symptomatic treatment of rheumatoid arthritis (RA). Studies have demonstrated the clinical and structural efficacy of moderate doses (i.e. 30-60 mg/d) GC in addition to disease modifying anti-rheumatic drug (DMARD) initiation in early RA. A combination of a low dose of GC (i.e. 7.5-10 mg/d) and DMARDs increases remission rates and decreases the risk of medium-term structural progression in early RA. Intravenous and intramuscular administration of GC associated with DMARD initiation or intra-articular GC injections in symptomatic joints in tight control strategies increase remission rates in early RA. However, due to the risk of adverse events such as infections, cardiovascular events, or increased mortality induced by long-term use of GC, even at low-doses (e.g. 5 mg/d), GC should be prescribed at a minimal dose, for the shortest possible duration, and in association with DMARD initiation in early RA or DMARD change in active established RA. PMID- 29246531 TI - e-Health, social media, and rheumatology: Can they get along? PMID- 29246533 TI - Lessons learned from rheumatoid arthritis registries. PMID- 29246532 TI - An e-health interactive self-assessment website (Sanoia(r)) in rheumatoid arthritis. A 12-month randomized controlled trial in 320 patients. AB - INTRODUCTION: Sanoia is an online interactive electronic e-health platform developed to allow patient self-assessment and self-monitoring. The objective was to assess in rheumatoid arthritis (RA) patients, the efficacy on patient physician interactions, of giving access to Sanoia. METHODS: In this French, multi-center, 12-months randomized controlled trial (CarNET: NCT02200068), patients with RA and internet access were randomized to: access without incentives to the Sanoia platform after minimal training, or usual care. The primary outcome was the change from baseline in patient-physician interactions, by the patient-reported Perceived Efficacy in Patient-Physician Interactions (PEPPI-5) questionnaire. The number of accesses to Sanoia was recorded and satisfaction with the platform was assessed through a 0-10 numeric rating scale. Analyses were in intention to treat (ITT), on SAS. RESULTS: Of 320 RA patients (159 Sanoia versus 161 usual care), mean (standard deviation) age was 57.0 (12.7) years, mean (SD) disease duration was 14.6 (11.1) years, 216 (67.5%) were taking a biologic and 253 (79.1%) were female. Mean (SD) PEPPI scores at baseline and 12 months were 38.6 (8.2) and 39.2 (8.0) (delta=+0.60 [5.52]) versus 39.7 (7.3) and 38.8 (8.0) (delta=-0.91 [6.08]) in the Sanoia and control group, respectively (P=0.01). Although mean satisfaction with the platform was very high (1.46 [1.52]), 41 patients (25.7%) never accessed Sanoia. CONCLUSION: Giving RA patients access to the interactive Sanoia e-health platform led to a small improvement in patient-perceived patient-physician interactions. A disjunction between patient satisfaction and access to the platform was noted. E-Health platforms are promising in RA. PMID- 29246534 TI - Next Generation Sequencing approach to molecular diagnosis of Duchenne muscular dystrophy; identification of a novel mutation. AB - Duchenne Muscular Dystrophy (DMD; MIM 310200) is one of the most common and severe type of hereditary muscular dystrophies. The disease is caused by mutations in the dystrophin gene. The dystrophin gene is associated with X-linked recessive Duchenne and Becker muscular dystrophy. This disease occurs almost exclusively in males. The clinical symptoms of muscle weakness usually begin at childhood. The main symptoms of this disorder are gradually muscular weakness. The affected patients have inability to standing up and walking. Death is usually due to respiratory infection or cardiomyopathy. In this article, we have reported the discovery of a new nonsense mutation that creates abnormal stop codon in the dystrophin gene. This mutation was detected using Next Generation Sequencing (NGS) technique. The subject was a 17-year-old male with muscular dystrophy that who was suspected of having DMD. He was referred to Hakim medical genetics center of Neyshabur, IRAN. PMID- 29246535 TI - Cytogenomic analysis of several repetitive DNA elements in turbot (Scophthalmus maximus). AB - Repetitive DNA plays a fundamental role in the organization, size and evolution of eukaryotic genomes. The sequencing of the turbot revealed a small and compact genome, as in all flatfish studied to date. The assembly of repetitive regions is still incomplete because it is difficult to correctly identify their position, number and array. The combination of classical cytogenetic techniques along with high quality sequencing is essential to increase the knowledge of the structure and composition of these sequences and, thus, of the structure and function of the whole genome. In this work, the in silico analysis of H1 histone, 5S rDNA, telomeric and Rex repetitive sequences, was compared to their chromosomal mapping by fluorescent in situ hybridization (FISH), providing a more comprehensive picture of these elements in the turbot genome. FISH assays confirmed the location of H1 in LG8; 5S rDNA in LG4 and LG6; telomeric sequences at the end of all chromosomes whereas Rex elements were dispersed along most chromosomes. The discrepancies found between both approaches could be related to the sequencing methodology applied in this species and also to the resolution limitations of the FISH technique. Turbot cytogenomic analyses have proven to add new chromosomal landmarks in the karyotype of this species, representing a powerful tool to investigate targeted genomic sequences or regions in the genetic and physical maps of this species. PMID- 29246536 TI - Overexpressed long noncoding RNA Sox2ot predicts poor prognosis for cholangiocarcinoma and promotes cell proliferation and invasion. AB - SOX2 overlapping transcript (Sox2ot), a long noncoding RNA (lncRNA), was initially found a close concomitant expression pattern of SOX2 gene. Multiple studies have demonstrated that the relatively upregulated Sox2ot could be observed in different types of cancer tissues and effectively promotes cell proliferation, invasion, and tumorigenesis in vitro. In the present study, we aimed to detect the crucial prognostic role of Sox2ot in cholangiocarcinoma (CCA) patients' clinicopathologic features and evaluated the correlation between Sox2ot expression and CCA patients overall survival. 58 CCA patients who underwent surgical treatment were recruited for the investigation. Sox2ot expression levels estimated by the quantitative real-time PCR (qRT-PCR) showed that both clinical tissues and cell lines possessed the overexpressed states and the upregulation of Sox2ot significantly associated with lymph node invasion (p=0.0308), TNM stage (p=0.0072) and postoperative recurrence (p=0.0019). The Kaplan-Meier curve showed a strong association between Sox2ot and overall survival (OS) and multivariate analysis confirmed this finding. Furthermore, the proliferation, migration and invasion assays were carried out with RBE and QBC939 cell lines and the knockdown of Sox2ot in all experiments could remarkably decrease malignant biological behaviors. Taken together, lncRNA Sox2ot indicates an unfavorable prognostic biomarker and potential therapeutics target for CCA patients. PMID- 29246537 TI - Heat shock stress: Profile of differential expression in Corynebacterium pseudotuberculosis biovar Equi. AB - Transcriptome studies on Corynebacterium pseudotuberculosis have recently contributed to the understanding about this microorganism's survival mechanisms in various hostile conditions. The gene expression profile of the C. pseudotuberculosis strain 1002 (Ovis biovar), has revealed genes that are possible candidates responsible for its maintenance in adverse environments, such as those found in the host. In another strain of this bacterium, 258 (Equi biovar), a high temperature condition was simulated, in order to verify which genes are responsible for promoting the persistence of the bacterium in these conditions, since it tolerates temperatures higher than 40 degrees C, despite being a mesophilic bacterium. It was possible to generate a list of genes using RNAseq technology that possibly contribute to the survival of the bacteria in this hostile environment. A total of 562 genes were considered as differentially expressed, then, after the fold-change cutoff, 113 were considered induced and 114 repressed, resulting in a total of 227 genes. Therefore, hypothetical proteins presented a fold change above 6, and genes characteristically in control for this type of stress, such as hspR, grpE, and dnaK, presented a fold change above 3. The clpB gene, a chaperone, drew attention due to presenting a fold change above 3 and located in a pathogenicity island. These genes may contribute towards efficient solutions to the effects caused by ulcerative lymphangitis in equines, thus attenuating the damage it causes to agribusiness. PMID- 29246538 TI - Sumoylation and ubiquitylation crosstalk in the control of DeltaNp63alpha protein stability. AB - DeltaNp63alpha is finely and strictly regulated during embryogenesis and differentiation. DeltaNp63alpha is the only p63 isoform degraded by the proteasome after Ubiquitin and SUMO (Small Ubiquitin-like MOdifier) conjugation. Here, we show that p63 ubiquitylation per se is not the signal triggering p63 proteasomal degradation. Taking advantage of natural DeltaNp63alpha mutants isolated by patients with Split Hand and Foot Malformation IV syndrome, we found that SUMO and Ub modifications are not redundant and both are required to guarantee efficient DeltaNp63alpha degradation. Here, we present evidence that sumoylation and ubiquitylation of DeltaNp63alpha are strongly intertwined, and none of the two can efficiently occur if the other is impaired. PMID- 29246539 TI - Using Lean methodologies to streamline processing of requests for durable medical equipment and supplies for children with complex conditions. AB - BACKGROUND: An improvement team from the Complex Care Center at our large pediatric medical center participated in a 60-day initiative to use Lean methodologies to standardize their processes, eliminate waste and improve the timely and reliable provision of durable medical equipment and supplies. METHODS: The team used value stream mapping to identify processes needing improvement. Improvement activities addressed the initial processing of a request, provider signature on the form, returning the form to the sender, and uploading the completed documents to the electronic medical record. Data on lead time (time between receiving a request and sending the completed request to the Health Information Management department) and process time (amount of time the staff worked on the request) were collected via manual pre- and post-time studies. RESULTS: Following implementation of interventions, the median lead time for processing durable medical equipment and supply requests decreased from 50 days to 3 days (p < 0.0001). Median processing time decreased from 14min to 9min (p < 0.0001). The decrease in processing time realized annual cost savings of approximately $11,000. CONCLUSIONS: Collaborative leadership and multidisciplinary training in Lean methods allowed the CCC staff to incorporate common sense, standardize practices, and adapt their work environment to improve the timely and reliable provision of equipment and supplies that are essential for their patients. IMPLICATIONS: The application of Lean methodologies to processing requests for DME and supplies could also result in a natural spread to other paperwork and requests, thus avoiding delays and potential risk for clinical instability or deterioration. PMID- 29246540 TI - Exploration of bimodal kinetics in marker digesta outflows using compartmental models. AB - A deterministic compartmental model is developed for examining the dynamics of digesta marker outflows in animals, focussing on models which will simulate bimodal kinetics with two peaks in the time course of marker outflow. First, to establish the background to the subsequent modelling of bimodal flow, we examine the compartmental scheme which gives rise mechanistically to the gamma function, and derive or describe various useful properties. This is illustrated by varying two key parameters of the gamma function, n (the number of compartments), and k (the rate constant for compartment emptying). Next, a more articulated compartmental scheme is constructed, and by progressive parameter changes, it is shown how bimodal faecal marker outflow can be achieved. Last, progressive simplification is applied to this scheme to arrive at what is (hopefully) the simplest compartmental scheme which can be used to simulate bimodal kinetics. This may be used mechanistically to describe the role of digesta flow in animals which exhibit such characteristics. PMID- 29246541 TI - Autobiographical memory, the ageing brain and mechanisms of psychological interventions. AB - Elucidating the impact of healthy cognitive ageing and dementia on autobiographical memory (AM) may help deepen our theoretical understanding of memory and underlying neural changes. The distinction between episodic and semantic autobiographical memory is particularly informative in this regard. Psychological interventions, particularly those involving reminiscence or music, have led to differential effects on episodic and semantic autobiographical memory. We propose that executive function is a key mediator of psychological therapies on autobiographical memory. We also highlight that interventions that alleviate stress and improve mood, including in major depression, can enhance autobiographical memory. Future research employing more longitudinal approaches and examining moderating factors such as gender and education level will deepen our understanding of changes in AM in later life, enhance our theoretical understanding of the neuroscience of AM and ageing, and help to develop better targeted interventions for preserving AM in older adults. PMID- 29246542 TI - [2016: Inflammatory bowel disease epidemic in Asturias]. PMID- 29246543 TI - Oncostatin M upregulates HIF-1alpha in breast tumor associated macrophages independent of intracellular oxygen concentration. AB - AIMS: HIF is an important transcription-regulator for adaptation to cellular stress in cells of myeloid origin. Classically, expression and activity of HIF1 alpha is regulated by oxygen-concentration within cell. However, there exists an alternative regulatory mechanism affecting HIF1-alpha levels independent of oxygen concentration particularly in inflammatory cells like macrophages. Here we report the mechanism of HIF1-alpha upregulation in TAMs by Oncostatin-M (OSM) independent of cellular oxygen concentration. MAIN METHODS: THP-1 derived macrophages were treated with OSM. HIF1-alpha levels and interaction with pVHL were evaluated via immunoblot-analysis and Co-immunoprecipitation. Translocation of HIF1-alpha to nucleus was visualized using confocal-microscopy. Fold change in mRNA levels of ARG-1 and COX-2 was analyzed using RT-PCR. KEY FINDINGS: Current study demonstrates that OSM treatment to TAMs led to an increased expression of HIF1-alpha under normoxic conditions via activation of mTORC2. This HIF1-alpha upregulation was dependent on both de novo synthesis of HIF1-alpha and its enhanced stability due to disruption of its binding to pVHL. Furthermore, we evaluated that OSM not only enhances the expression of HIF1-alpha but also increases its localization to nucleus where it acts as a transcription factor regulating expression of genes like ARG-1 and COX-2. SIGNIFICANCE: Inflammation is a critical hallmark of cancer as tumor microenvironment is largely infiltrated with macrophages. These tumor associated macrophages (TAMs) display a M2 skewed phenotype. Many target genes of TAMs are HIF1-alpha responsive. These TAMs are involved in tumor progression, metastasis and angiogenesis. Targeting of HIF1 alpha/OSM can lead to devising of better therapeutic strategy against cancer. PMID- 29246546 TI - Surgical unroofing of intramural anomalous aortic origin of a coronary artery in pediatric patients: Single-center perspective. AB - BACKGROUND: Intramural anomalous aortic origin of a coronary artery (AAOCA) is associated with an increased risk of sudden cardiac death. This is amenable to surgical coronary unroofing, but outcomes studies are lacking. OBJECTIVE: To perform a comprehensive review of our institutional experience with pediatric patients with AAOCA who underwent surgical repair with unroofing of the intramural segment, focusing on preoperative and postoperative course and testing as well as intraoperative findings. METHODS: A retrospective cohort study was conducted to evaluate patients with AAOCA status post-coronary unroofing at Children's Hospital of Wisconsin. Data extraction included symptoms, preoperative and postoperative imaging and testing, surgical findings, and postoperative clinical course. RESULTS: From January 1999 to December 12, 2015, 63 patients underwent unroofing at a median age of 13 years (0.5-18 years). The majority underwent unroofing of an intramural right coronary (79%); 21% had an intramural left AAOCA. Symptoms suggestive of possible ischemia were present in about 50%. Additional structural cardiac anomalies were present in 33%. Transthoracic echocardiography was diagnostic in 60 of 63 (95%) and correlated with surgical findings in all cases. There was no surgical mortality associated with the unroofing, and no additional coronary reinterventions were performed. The median duration of postoperative follow-up was 3.1 years (7 days to 13.6 years). Symptoms either persisted or developed in 46% postoperatively. Postoperative exercise stress testing, stress echocardiography, and cardiac magnetic resonance imaging were performed in 76%, 8%, and 20%, respectively, of the cohort. None identified findings consistent with reversible coronary ischemia. Three patients had sudden cardiac arrest (1 death) after surgery without an identified residual coronary abnormality. CONCLUSIONS: Transthoracic echocardiography, with carefully designed coronary imaging protocols, can be diagnostic in accurately identifying intramural AAOCA in pediatric patients. Unroofing can be performed safely with no early morbidity, but symptoms can persist (including rare life-threatening events) without evidence of ischemia by postoperative provocative testing. PMID- 29246545 TI - Severity of tricuspid regurgitation is associated with long-term mortality. AB - OBJECTIVES: To determine the association between intraoperative/presurgical grade of tricuspid regurgitation (TR) and mortality, and to determine whether surgical correction of TR correlated with an increased chance of survival compared with patients with uncorrected TR. METHODS: The grade of TR assessed by intraoperative transesophageal echocardiography (TEE) before surgical intervention was reviewed for 23,685 cardiac surgery patients between 1990 and 2014. Cox proportional hazard regression models were used to determine association between grade of TR and the primary endpoint of all-cause mortality. Association between tricuspid valve (TV) surgery and survival was determined with Cox proportional hazard regression models after matching for grade of TR. RESULTS: Kaplan-Meier survival curves demonstrated a relationship between all grades of TR. Multivariable analysis of the entire cohort demonstrated significantly increased mortality for moderate (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.1-1.4; P < .0001) and severe TR (HR, 2.02; 95% CI, 1.57-2.6; P < .0001). Mild TR displayed a trend for mortality (HR, 1.07; 95% CI, 0.99-1.16; P = .075). After matching for grade of TR and additional confounders, patients who underwent TV surgery had a statistically significant increased likelihood of survival (HR, 0.74; 95% CI, 0.61-0.91; P = .004). CONCLUSIONS: Our study of more than 20,000 patients demonstrates that grade of TR is associated with increased risk of mortality after cardiac surgery. In addition, all patients who underwent TV surgery had a statistically significantly increased likelihood of survival compared with those with the same degree of TR who did not undergo TV surgery. PMID- 29246544 TI - Long-term outcome following concomitant mitral valve surgery and Cox maze procedure for atrial fibrillation. AB - OBJECTIVE: Atrial fibrillation (AF) is associated with increased early and long term morbidity/mortality following valve surgery. This study examined long-term influence of concomitant full Cox maze (CM) and mitral valve procedures on freedom from atrial arrhythmia and stroke. METHODS: This sample comprised patients who underwent CM with a mitral valve procedure (N = 473). Data on rhythm, medication status, and clinical events captured according to Heart Rhythm Society guidelines at 6, 9, 12, 18, and 24 months and yearly thereafter up to 7 years. RESULTS: Mean age was 65 years, mean left atrium size was 5.3 cm, and 15% had paroxysmal AF. Perioperative stroke occurred in 2 patients (0.4%) and operative mortality was 2.7% (n = 13). Return to sinus rhythm regardless of antiarrhythmic drugs at 1, 5, and 7 years was 90%, 80%, and 66%. Sinus rhythm off antiarrhythmic drugs at 1, 5, and 7 years was 83%, 69%, and 55%. Freedom from embolic stroke at 7 years was 96.6% (0.4 strokes per 100 patient-years) with a majority of patients off anticoagulation medication. Greater odds of atrial arrhythmia recurrence during 7 years was associated with longer AF duration (odds ratio [OR], 1.07; P = .001), whereas lower odds were associated with cryothermal energy only (OR, 0.64; P = .045) and greater surgeon experience (OR, 0.98; P = .025). CONCLUSIONS: This study suggests that the addition of CM to mitral valve procedures, even with a high degree of complexity, did not increase operative risk. In long-term follow-up, the CM procedure demonstrated acceptable rhythm success, reduced AF burden, and remarkably low stroke rate. Individual surgeon experience and training may notably influence long-term surgical ablation for AF success. PMID- 29246548 TI - Discussion. PMID- 29246547 TI - Retrieval of severe acute respiratory failure patients on extracorporeal membrane oxygenation: Any impact on their outcomes? AB - OBJECTIVE: Mobile extracorporeal membrane oxygenation (ECMO) retrieval teams (MERTs) assure ECMO implantation and under-ECMO retrieval of patients with most severe acute respiratory failure (ARF) to experienced ECMO centers. Although described as feasible, mobile ECMO has only been poorly evaluated in comparison with on-site implantation. This study was undertaken to compare the indications, characteristics, and outcomes of MERT-implanted patients with venovenous (VV) ECMO versus those implanted on site in our intensive care unit (ICU). METHODS: Retrospective, single-center study. RESULTS: Among 157 VV-ECMO implantations from 2008 to 2012, the MERT hooked up 118 (75%) patients with refractory ARF, as reflected by their median partial pressure of O2 in arterial blood/fraction of inspired oxygen of 58 (interquartile range, 50-73). ARF was accompanied by severe multiorgan failure, with a median Simplified Acute Physiology Score-II of 71 (61 81), median Sequential Organ Failure Assessment score of 14 (10-16), and with 82% of the patients receiving inotropes. All patients were transported by ground ambulance: median distance was 15 (6-25) km, and median transport time was 35 (25 35) minutes, during which no major ECMO system-related event occurred. For the MERT- and on-site-implanted groups, ICU mortality was comparable (46.6% vs 53.8%, respectively, P = .5), as were ECMO-related complication rates (53.4% of MERT vs 53.8% of on-site-implanted groups, P = 1.0). According to multivariable analysis, MERT ECMO implantation was not associated with ICU mortality (odds ratio, 1.1; 95% confidence interval, 0.4-2.7; P = .85). CONCLUSIONS: ICU mortality and ECMO related complications of patients with MERT-implanted VV-ECMO who were transferred to our ECMO referral center were comparable with those implanted on site by the same team, thereby supporting this strategy to manage patients with severe ARF. PMID- 29246550 TI - Discussion. PMID- 29246549 TI - Factors associated with distant recurrence following R0 lobectomy for pN0 lung adenocarcinoma. AB - OBJECTIVE: We investigated factors associated with distant recurrence, disease free survival (DFS), and overall survival (OS) following R0 lobectomy for pathologic node-negative (pN0) lung adenocarcinoma. METHODS: We performed a retrospective analysis of a prospectively maintained database of patients with pT1-3N0M0 non-small cell lung cancer. Exclusion criteria included metachronous lung cancer, sublobar/incomplete resection, nonadenocarcinoma histology, and induction/adjuvant therapy. The primary outcome was distant recurrence; secondary outcomes were DFS and OS. Associations between variables and outcomes were assessed by Fine-Gray competing-risk regression for distant recurrence and Cox proportional hazard models for DFS and OS. RESULTS: Of 2392 patients identified with pT1-3N0M0 lung adenocarcinoma, 893 met the inclusion criteria. Median follow up was 35.0 months (range, 0.1-202 months). Thirteen percent of patients developed recurrence (n = 115), of which 86% (n = 99) were distant. The 5-year cumulative incidence of distant recurrence was 14% (95% confidence interval [CI], 11%-17%). On multivariable analysis, pT2a (hazard ratio [HR], 2.84; 95% CI, 1.56 5.16; P = .001) and pT2b/3 (HR, 6.53; 95% CI, 3.17-13.5; P < .001) tumors were associated with distant recurrence. Recent surgery was associated with decreased distant recurrence (HR, 0.43; 95% CI, 0.20-0.91; P = .028), and lymphovascular invasion was strongly associated with distant recurrence (HR, 1.62; 95% CI, 1.00 2.63; P = .05). DFS was independently associated with pT stage (P < .001) and lymphovascular invasion (P = .004). CONCLUSIONS: In patients undergoing R0 lobectomy with pN0 lung adenocarcinoma, pT stage and lymphovascular invasion were associated with distant recurrence and decreased DFS. These observations support the inclusion of these patients in future clinical trials investigating adjuvant targeted and immunotherapies. PMID- 29246551 TI - Comparative effectiveness of coronary screening in heart valve surgery: Computed tomography versus conventional coronary angiography. AB - BACKGROUND: Although conventional coronary angiography (CAG) is considered the gold standard for coronary artery disease (CAD) screening in the setting of heart valve surgery, coronary artery computed tomography angiography (CCTA) has emerged as an alternative modality. This study was conducted to evaluate the clinical outcomes of CCTA compared with conventional CAG for CAD screening in patients undergoing heart valve surgery. METHODS: A total of 3150 consecutive patients aged >40 years or with coronary risk factors undergoing elective valve operations between 2001 and 2015 were evaluated. Of these, 1402 patients underwent CCTA (CT group) and 1748 patients underwent conventional CAG (CAG group) for CAD screening. RESULTS: The 30-day mortality rates were similar in the 2 groups (2.1% in the CT group vs 1.7% in the CAG group; P = .463); however, the incidence of low cardiac output syndrome was higher in the CT group (2.3% vs 1.0%; P = .008). The final rate of detection of significant CAD (>=50% stenosis) (4.9% vs 9.7%; P < .001) and proportion of receiving coronary bypass grafting (CABG) (2.9% vs 4.3%; P = .041) were lower in the CT group. After adjustment by propensity score matching (563 pairs), the main findings of our crude analyses did not change, with lower rates of CAD detection (odds ratio [OR], 0.56; 95% confidence interval [CI], 0.36-0.85) and CABG (OR, 0.47; 95% CI, 0.26-0.81), a similar risk of early mortality (OR, 1.51; 95% CI, 0.54-4.52), but a higher risk of low cardiac output syndrome (OR, 3.30; 95% CI, 1.16-11.78) in the CT group compared with the CAG group. CONCLUSIONS: The detection of significant CAD and identification of candidates for CABG were inferior with CCTA compared with conventional CAG in patients scheduled for elective heart valve operations. PMID- 29246552 TI - The use of del Nido cardioplegia in adult cardiac surgery: A prospective randomized trial. AB - OBJECTIVES: The del Nido cardioplegia solution has been used extensively in congenital heart surgery for more than 20 years and more recently for adults. This randomized controlled trial examined whether expanding this technique to adult cardiac surgery confers benefits in surgical workflow and clinical outcome compared with blood-based cardioplegia. METHODS: Adult first-time coronary artery bypass grafting (CABG), valve, or CABG/valve surgery patients requiring cardiopulmonary bypass (CPB) were randomized to del Nido cardioplegia (n = 48) or whole blood cardioplegia (n = 41). Primary outcomes assessed myocardial preservation. Troponin I was measured at baseline, 2 hours after CPB termination, 12 and 24 hours after cardiovascular intensive care unit admission. Alpha was set at P < .001. RESULTS: Preoperative characteristics were similar between groups, including age, Society of Thoracic Surgeons risk score, CABG, and valve procedures. There was no significant difference on CPB time (97 vs 103 minutes; P = .288) or crossclamp time (70 vs 83 minutes; P = .018). The del Nido group showed higher return to spontaneous rhythm (97.7% vs 81.6%; P = .023) and fewer patients required inotropic support (65.1% vs 84.2%; P = .050), but did not reach statistical significance. Incidence of Society of Thoracic Surgeons-defined morbidity was low, with no strokes, myocardial infarctions, renal failure, or operative deaths. For del Nido group patients, troponin levels did not increase as much as for control patients (P = .040), but statistical significance was not reached. CONCLUSIONS: Evidence from this study suggests del Nido cardioplegia use in routine adult cases may be safe, result in comparable clinical outcomes, and streamline surgical workflow. The trend for troponin should be investigated further because it may suggest superior myocardial protection with the del Nido solution. PMID- 29246553 TI - Intraoperative cardiac arrest caused by air embolism during video-assisted thoracoscopic segmentectomy. PMID- 29246555 TI - Detection of the smaller window of maximal receptivity: timing isn't everything. PMID- 29246556 TI - Uterus transplantation:robotic surgeon perspective. AB - OBJECTIVE: To study the safety and feasibility of robotic dissection of deep pelvic vessels as applied to the robotic harvesting of a uterus from live transplant donor. DESIGN: Surgical video. SETTING: Gynecologic oncology practice of a tertiary community cancer center. PATIENT(S): Two patients undergoing robotic nerve-sparing radical hysterectomy for International Federation of Gynecology and Obstetrics (FIGO) stage Ib1 cervical cancer. INTERVENTION(S): Application of robotic platform to precise dissection of internal iliac artery and vein, their branches, including the superficial and deep uterine artery and vein. The robotic technique for deep pelvic dissection in gynecologic oncology demonstrated here provides superior outcomes compared with the open technique. In our settings, a typical robotic nerve-sparing radical hysterectomy takes 3 hours from completion of the pelvic lymphadenectomy to the moment when the patient leaves the operating room. MAIN OUTCOME MEASURE(S): Safety and adequacy of robotic dissection of deep pelvic vessels. The procedure's modification to the current technique demonstrated improved transplant blood supply and outflow. Demonstration of modification to current technique, that has potential to improve transplant blood supply and outflow. RESULT(S): Using the robotic technique for nerve-sparing radical hysterectomy, the pelvic vessels can be dissected with superior precision, hemostasis, efficiency, and clinical outcomes. Due to its difficulty, nerve-sparing radical hysterectomy is not even performed via a laparotomy approach in the United States. Robotic dissection allows for better exposure of the pelvic vessels, which may allow for harvesting intact uterine vessels with internal iliac artery and vein patches, thus facilitating wider vascular anastomosis and superior blood supply and outflow of the transplant. CONCLUSION(S): Uterine harvesting from a live donor is currently being performed via a laparotomy technique, resulting in long procedures associated with significant morbidity. Based on our gynecologic oncology experience, a robotic approach to deep pelvic dissection is superior to laparotomy. Robotic nerve sparing radical hysterectomy is a difficult procedure that requires knowledge of deep pelvic vessels' anatomy, precise dissection techniques, and repetition. Robotic harvesting of the uterus for transplantation from a live donor may provide better results in terms of transplant survival and donor outcomes. This type of procedure should be attempted by a robotic team that has experience in working with deep and large pelvic vessels. PMID- 29246557 TI - Erratum. PMID- 29246559 TI - Erratum. PMID- 29246560 TI - Transvaginal natural orifice transluminal endoscopic surgery: a new approach to ovarian cystectomy. AB - OBJECTIVE: To demonstrate a new approach for performing an ovarian cystectomy via transvaginal natural orifice transluminal endoscopic surgery (vNOTES) as an alternative for a laparoscopic ovarian cystectomy. DESIGN: Stepwise explanation of the technique using original video footage. SETTING: Hospital. PATIENT(S): Fourteen patients who provided informed consent and were treated transvaginally to remove a benign ovarian cyst. INTERVENTION(S): The patient was placed in the lithotomy position under general anaesthesia. A 2.5-cm posterior colpotomy was made. The pouch of Douglas was opened and a transvaginal natural orifice transluminal endoscopic surgery (vNOTES) port was inserted transvaginally. A pneumoperitoneum was created, and the ovarian cyst was identified. Conventional endoscopic instruments and a standard endoscope were inserted transvaginally through the vNOTES port. The ovarian cortex was incised over the cyst using cold scissors. The cyst was dissected from the ovarian cortex by a combination of blunt and sharp dissection. Ovarian hemostasis was achieved using bipolar forceps. The ovarian cyst was removed through the colpotomy in an endobag. The vNOTES port was removed, and the colpotomy was sutured using a resorbable suture. The following data were collected: age, body mass index, parity, number of previous abdominal procedures, ovarian cyst diameter, operating time, length of hospital stay, and visual analog scale score. MAIN OUTCOME MEASURE(S): Successful minimally invasive ovarian cystectomy via vNOTES without abdominal scars. RESULT(S): An ovarian cystectomy was successfully completed in all patients without conversions to standard laparoscopy, and no complications occurred. A fertility sparing cystectomy was performed via vNOTES in all patients; no ovariectomies were performed. All patients were discharged within 30 hours, and nine patients were discharged within 12 hours. Benign ovarian cysts can be treated by vNOTES through a posterior colpotomy via the pouch of Douglas. In a low-resource setting, a self-constructed gloveport and standard reusable endoscopic instruments can be used. In a first-world setting the surgical time can be reduced using a commercially available vNOTES port. CONCLUSION(S): Transvaginal natural orifice transluminal endoscopic surgery provides a new, less invasive approach for performing an ovarian cystectomy. This first IDEAL (idea, development, exploration, assessment, long-term study) stage 1 study confirms the feasibility of vNOTES ovarian cystectomy although it remains a novel approach that requires further investigation. It can provide improved patient comfort and better cosmetic results. PMID- 29246558 TI - Public support for intergenerational oocyte donation in the United States. AB - OBJECTIVE: To determine whether the general public supports intergenerational oocyte donation. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A nationally representative sample based on age distribution of United States residents. INTERVENTIONS(S): Not applicable. MAIN OUTCOME MEASURE(S): Characteristics of respondents who supported (strongly agree and agree) various oocyte donation practices were compared with participants who did not support them (disagree and strongly disagree) using log binomial regression to calculate risk ratios (RRs) and 95% confidence intervals of support (95% CIs). Models were adjusted for age, gender, and religion to yield adjusted risk ratios (aRR). RESULT(S): A total of 1,915 people responded to the Web-based survey; 53% were female, and 24% were racial/ethnic minorities. Eighty-five percent had prior knowledge of oocyte donation, and 74% felt that a woman should be able to donate oocytes to a family member. The desire to help a family member was the most commonly perceived motivation for donors (79%). Christian-Catholics compared with Christian-non-Catholics (aRR 0.91, 95% CI 0.86-0.98), African Americans compared with non-Hispanic Caucasians (aRR 0.86, 95% CI 0.76-0.97), and Republicans compared with Democrats (RR 0.93, 95% CI 0.88-0.98) were less likely to support intergenerational oocyte donation. Respondents with three or more biological children (RR 1.06, 95% CI 1.00-1.11) compared with those with no children were less likely to support this practice. Eight percent of participants disapproved of donation to any family member. The most common reason for disapproval was the potential negative impact on the child (53%). CONCLUSION(S): A majority of Americans support the practice of intergenerational oocyte donation; however, support varies according to demographic characteristics. PMID- 29246561 TI - Successful quintuplet pregnancy of monochorionic male quadruplets and single female after double embryo transfer: case report and review of the literature. AB - OBJECTIVE: To report a rare case of quintuplets with monochorionic male quadruplets and a single female after two-blastocyst transfer. DESIGN: Case report. SETTING: University teaching hospital. PATIENT(S): A 37-year-old gravida 1, para 1, presenting after two-embryo IVF with monochorionic male quadruplets and a single female. INTERVENTION(S): Ultrasound examinations and cesarean delivery. MAIN OUTCOME MEASURE(S): Successful delivery of five live-born infants at 28 weeks and 6 days of gestation for preterm labor. RESULT(S): The patient was diagnosed with quintuplets consisting of monochorionic male quadruplets and a single female after the placement of two embryos in blastocyst stage. She was followed closely with ultrasound examinations and hospitalized at 23 weeks' gestation. Cesarean delivery was performed at 28 weeks and 6 days of gestation, with eventual discharge of all infants in healthy condition. CONCLUSION(S): This case represents successful assisted reproductive technology quintuplets with monochorionic quadruplets and a co-sibling. Higher-order monozygotic pregnancies with monochorionic quadruplets are exceedingly rare and a potential complication of IVF. PMID- 29246563 TI - Post-traumatic haemato-pneumatocele. PMID- 29246562 TI - Crohn's disease. AB - Crohn's disease is a chronic inflammatory bowel disease of unknown etiology associated with an impaired immune response, with periods of activity and remission. It is characterised by patchy and transmural lesions which can affect the entire gastrointestinal tract, from the mouth to the anus. The most frequent symptoms are abdominal pain and diarrhoea, which can seriously affect patients' quality of life. The increasing incidence and prevalence of the disease in our area has had a large impact on clinical practice, with the rapid development of diagnostic and therapeutic techniques. To reduce the risk of complications, primary care physicians and gastroenterologists should be familiar with the management of the disease. PMID- 29246564 TI - Clinical and psychological outcome after surgery for lumbar spinal stenosis: A prospective observational study with analysis of prognostic factors. AB - BACKGROUND: The identification of psychological risk factors is important for the selection of patients before spinal surgery. Moreover, the effect of surgical decompression in lumbar spinal stenosis (LSS) on psychological outcome is not previously well analyzed. AIM OF PAPER: to investigate clinical and psychological outcome after surgery for LSS and the effect of depressive symptoms and anxiety on the clinical outcome. MATERIALS AND METHODS: A total of 25 patients with symptomatic LSS underwent decompressive surgery with or without spinal stabilization were prospectively enrolled in this observational surgery. The Symptom Checklist-90-Revised (SCL-90-R) was used to assess global psychological distress with a summary score termed Global Severity Index (GSI) and single psychological disorders including depression (DEP) and anxiety (ANX). The clinical outcome of surgery was evaluated with the Oswestry Disability Index (ODI) and visual analogue scale (VAS) pain assessment. RESULTS: Compared with baseline, there was a statistically significant improvement in VAS, ODI and GSI after surgery (p<0.05) in all patients. Univariate analysis revealed that patients with high GSI and anxiety and depression scores had significantly higher ODI and VAS scores in the follow-up with a bad outcome. CONCLUSIONS: Surgery for spinal stenosis was effective to treat pain and disability. In this prospective study baseline global psychological distress, depression and anxiety were associated with poorer clinical outcome. PMID- 29246565 TI - In vitro simulation of intraoperative vertebroplasty applied for pedicle screw augmentation. A biomechanical evaluation. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the effect of an in vitro simulation of intraoperative vertebroplasty on embedded pedicle screws resistance to pullout. This method involved an application of acrylic cement into the vertebral bodies only after pedicle screws implementation. MATERIALS AND METHODS: For the purpose of conducting this research, the authors used the spines of fully-grown pigs. The procedure was as follows: firstly, the pedicle screws were bilaterally implemented in 10 vertebrae; secondly, cancellous bone was removed from vertebral bodies selected for screws augmentation and lastly it was replaced by polymethylmethacrylate (PMMA). Six vertebrae with implemented pedicle screws served as a control group. The pullout strength of thirty-two screws (20 augmented and 12 control) was tested. All screws were pulled out at a crosshead speed of 5mm/min. RESULTS: The PMMA-augmented screws showed a 1.3 times higher average pullout force than the control group: respectively 1539.68N and 1156.59N. In essence, no significant discrepancy was determined between average pullout forces of screws which were pulled as first when compared with consecutive contralateral ones. CONCLUSIONS: An in vitro simulation of intraoperative injection of PMMA in the vertebral body instrumented with screws (intraoperative vertebroplasty) resulted in enhancing its pullout strength by 33%. Pulling of one of the pedicular screws from the augmented vertebral body did not affect the pullout resistance of the contralateral one. PMID- 29246566 TI - Food Behaviors and Dietary Acculturation of Asian Indians in the US. AB - OBJECTIVE: To examine food behaviors and dietary acculturation of Asian Indians in the US. DESIGN: Qualitative focus group discussions. SETTING: Public library and university. PARTICIPANTS: Thirty Asian Indian adults in a US Midwestern state. MAIN OUTCOME MEASURES: Participant perceptions of food behaviors and 24 hour modified weekday and weekend dietary recalls. ANALYSIS: Eight focus group transcripts and participant dietary recalls were independently analyzed by 2 Asian Indian moderators using the constant comparison method. RESULTS: The sample (n = 16 males and 14 females) consisted of a variable group of Asian Indians from different generations, religions, and places of origin in India. Key themes associated with modification of traditional behaviors were social independence, social network influences, increased health awareness, cost and quality of Asian Indian foods, and time constraints and convenience. CONCLUSIONS AND IMPLICATIONS: This study elucidated dietary behaviors and factors that contribute to dietary acculturation of Asian Indians, which are important considerations for health professionals. These findings inform researchers regarding the development of culturally appropriate dietary assessment measures targeted at Asian Indian individuals. PMID- 29246568 TI - Validation of a Collaboration Readiness Assessment Tool for Use by Supplemental Nutrition Assistance Program-Education (SNAP-Ed) Agencies and Partners. AB - OBJECTIVE: To evaluate content and face validity of a collaboration readiness assessment tool developed to facilitate collaborative efforts to implement policy, systems, and environment changes in Supplemental Nutrition Assistance Program-Education (SNAP-Ed). METHODS: Evaluation of the validity of the tool involved 2 steps. Step 1 was conducted with 4 subject matter experts to evaluate content validity. Step 2 used an iterative cognitive testing process with 4 rounds and 16 SNAP-Ed staff and community partners to evaluate face validity. RESULTS: Subject matter experts found that survey items appropriately matched the content area indicated and adequately covered collective efficacy, change efficacy, and readiness. Cognitive testing with SNAP-Ed staff and partners informed modifications and resulted in adequate face validity. CONCLUSIONS AND IMPLICATIONS: The ability to measure collaboration readiness will allow agencies and community partners that implement SNAP-Ed to target areas that facilitate collaboration efforts needed for policy, systems, and environment change and collective efficacy. Further cognitive testing of the tool with other populations is needed to ensure its applicability and usefulness. Evaluation of the reliability of the tool with a broad range of SNAP-Ed programs and community agencies is also recommended. PMID- 29246567 TI - The Nutrition Literacy Assessment Instrument is a Valid and Reliable Measure of Nutrition Literacy in Adults with Chronic Disease. AB - OBJECTIVE: To test the reliability and validity of the Nutrition Literacy Assessment Instrument (NLit) in adult primary care and identify the relationship between nutrition literacy and diet quality. DESIGN: This instrument validation study included a cross-sectional sample participating in up to 2 visits 1 month apart. SETTING/PARTICIPANTS: A total of 429 adults with nutrition-related chronic disease were recruited from clinics and a patient registry affiliated with a Midwestern university medical center. MAIN OUTCOME MEASURES: Nutrition literacy was measured by the NLit, which was composed of 6 subscales: nutrition and health, energy sources in food, food label and numeracy, household food measurement, food groups, and consumer skills. Diet quality was measured by Healthy Eating Index-2010 with nutrient data from Diet History Questionnaire II surveys. ANALYSIS: The researchers measured factor validity and reliability by using binary confirmatory factor analysis; test-retest reliability was measured by Pearson r and the intraclass correlation coefficient, and relationships between nutrition literacy and diet quality were analyzed by linear regression. RESULTS: The NLit demonstrated substantial factor validity and reliability (0.97; confidence interval, 0.96-0.98) and test-retest reliability (0.88; confidence interval, 0.85-0.90). Nutrition literacy was the most significant predictor of diet quality (beta = .17; multivariate coefficient = 0.10; P < .001). CONCLUSIONS: The NLit is a valid and reliable tool for measuring nutrition literacy in adult primary care patients. PMID- 29246569 TI - Nutrition Knowledge, Attitudes, and Fruit and Vegetable Intake as Predictors of Head Start Teachers' Classroom Mealtime Behaviors. AB - OBJECTIVE: To examine the association between nutrition knowledge, attitudes, and fruit/vegetable intake among Head Start teachers and their classroom mealtime behaviors (self-reported and observed). DESIGN: Cross-sectional design using observation and survey. SETTING: Sixteen Head Start centers across Rhode Island between September, 2014 and May, 2015. PARTICIPANTS: Teachers were e-mailed about the study by directors and were recruited during on-site visits. A total of 85 participants enrolled through phone/e-mail (19%) or in person (81%). MAIN OUTCOME MEASURES: Independent variables were nutrition knowledge, attitudes, and fruit/vegetable intake. The dependent variable was classroom mealtime behaviors (self-reported and observed). ANALYSIS: Regression analyses conducted on teacher mealtime behavior were examined separately for observation and self-report, with knowledge, attitudes, and fruit and vegetable intake as independent variables entered into the models, controlling for covariates. RESULTS: Nutrition attitudes were positively associated with teacher self-reported classroom mealtime behavior total score. Neither teacher nutrition knowledge nor fruit/vegetable intake was associated with observed or self-reported classroom mealtime behavior total scores. CONCLUSION AND IMPLICATIONS: There was limited support for associations among teacher knowledge, attitudes, and fruit/vegetable intake, and teacher classroom mealtime behavior. Findings showed that teacher mealtime behavior was significantly associated with teacher experience. PMID- 29246570 TI - Integration-free induced pluripotent stem cells derived from a patient with autosomal recessive Alport syndrome (ARAS). AB - A skin biopsy was obtained from a 25-year-old female patient with autosomal recessive Alport syndrome (ARAS) with the homozygous COL4A3 mutation c.345delG, p.(P166Lfs*37). Dermal fibroblasts were derived and reprogrammed by nucleofection with episomal plasmids carrying OCT3/4, SOX2, KLF4 LIN28, L-MYC and p53shRNA. The generated induced Pluripotent Stem Cell (iPSC) clone AS FiPS1 Ep6F-2 was free of genomically integrated reprogramming genes, had the specific homozygous mutation, a stable karyotype, expressed pluripotency markers and generated embryoid bodies which were differentiated towards the three germ layers in vitro. This iPSC line offers a useful resource to study Alport syndrome pathomechanisms and drug testing. PMID- 29246571 TI - Generation and characterization of human induced pluripotent stem cell (hiPSC) lines from an Alzheimer's disease (ASUi003-A) and non-demented control (ASUi004 A) patient homozygous for the Apolipoprotein e4 (APOE4) risk variant. AB - Although the majority of late-onset Alzheimer's disease (AD) patients are labeled sporadic, multiple genetic risk variants have been identified, the most powerful and prevalent of which is the e4 variant of the Apolipoprotein E (APOE) gene. Here, we generated human induced pluripotent stem cell (hiPSC) lines from the peripheral blood mononuclear cells (PBMCs) of a clinically diagnosed AD patient [ASUi003-A] and a non-demented control (NDC) patient [ASUi004-A] homozygous for the APOE4 risk allele. These hiPSCs maintained their original genotype, expressed pluripotency markers, exhibited a normal karyotype, and retained the ability to differentiate into cells representative of the three germ layers. PMID- 29246572 TI - Generation of two H1 hESC sublines carrying a heterozygous and homozygous knock out of RB1. AB - Retinoblastoma is a childhood cancer of the retina caused by biallelic inactivation of the tumor suppressor gene RB1. In heritable retinoblastoma, one allele is inherited in mutant form via one of the parental germ cells. To study molecular mechanisms in retinoblastoma, two sublines of H1 hESCs were generated, carrying a knock-out allele of RB1 in the heterozygous or homozygous state. Exon 3 of RB1 was targeted and modified by nucleotide deletions using the CRISPR/Cas9 nuclease system. Based on a nearby single nucleotide polymorphism, the modification could be assigned to one allele. PMID- 29246573 TI - Establishment of 2 control and 2 hPSC cell lines constitutively expressing the Notch ligand DLL4. AB - The Notch ligand DLL4 has key roles during embryonic development of different tissues, but most of the data comes from animal models. Here we describe the generation and characterization of 2 human Pluripotent Stem Cell (hPSC) lines that overexpress DLL4, as well as the two corresponding control hPSC lines. DLL4 expression can be detected at the mRNA and protein level, and does not affect the pluripotency of the cells. These hPSC lines can be used to study the role of DLL4 during human embryonic development. PMID- 29246574 TI - Murine transgenic embryonic stem cell lines for the investigation of sinoatrial node-related molecular pathways. AB - The elucidation of molecular mechanisms that restrict the potential of pluripotent stem cells and promote cardiac lineage differentiation is of crucial relevance, since embryonic stem cells (ESCs) hold great potential for cell based heart therapies. The homeodomain transcription factor Shox2 is essential for the development and proper function of the native cardiac pacemaker, the sinoatrial node. This prompted us to develop a cardiac differentiation model using ESC lines isolated from blastocysts of Shox2-deficient mice. The established cell model provides a fundamental basis for the investigation of molecular pathways under physiological and pathophysiological conditions for evaluating novel therapeutic approaches. PMID- 29246575 TI - Development of one control and one tumor-specific induced pluripotent stem cell line from laryngeal carcinoma patient. AB - Skin fibroblasts and tumor fibroblasts were extracted from a 64-year old male patient clinically diagnosed with laryngeal carcinoma. Control and tumor specific induced pluripotent stem cells were reprogrammed with 5 reprogramming factors, Klf-4, c-Myc, Oct-4, Sox-2, and Lin-28, using the messenger RNA reprogramming system. The transgene-free iPSC lines showed pluripotency, confirmed by immunofluorescence staining. The iPSC lines also showed normal karyotype, and could form embryoid bodies in vitro and differentiate into the 3 germ layers in vivo. This in vitro cellular model can be used to study the oncogenesis and pathogenesis of laryngeal carcinoma. PMID- 29246576 TI - Hoxa9 and EGFP reporter expression in human Embryonic Stem Cells (hESC) as useful tools for studying human development. AB - HoxA9 is an evolutionarily conserved homeobox gene implicated in embryo development. To study the roles of Hoxa9 during human development we generated a transgenic H9 (hESC) line that overexpresses HoxA9 and the Enhanced Green Fluorescent Protein (EGFP), and a control H9 with a stable expression of the EGFP. The resulting H9-HoxA9-EGFP and H9-EGFP cell lines allow an efficient visualization of hESCs by fluorescent microscopy, quantification by flow cytometry and cell differentiation tracking. Both transgenic cell lines maintained the pluripotent phenotype, the ability to differentiate into all three germ layers and a normal karyotype. PMID- 29246577 TI - The Management of Myelomeningocele Study: full cohort 30-month pediatric outcomes. AB - BACKGROUND: Previous reports from the Management of Myelomeningocele Study demonstrated that prenatal repair of myelomeningocele reduces hindbrain herniation and the need for cerebrospinal fluid shunting, and improves motor function in children with myelomeningocele. The trial was stopped for efficacy after 183 patients were randomized, but 30-month outcomes were only available at the time of initial publication in 134 mother-child dyads. Data from the complete cohort for the 30-month outcomes are presented here. Maternal and 12-month neurodevelopmental outcomes for the full cohort were reported previously. OBJECTIVE: The purpose of this study is to report the 30-month outcomes for the full cohort of patients randomized to either prenatal or postnatal repair of myelomeningocele in the original Management of Myelomeningocele Study. STUDY DESIGN: Eligible women were randomly assigned to undergo standard postnatal repair or prenatal repair <26 weeks gestation. We evaluated a composite of mental development and motor function outcome at 30 months for all enrolled patients as well as independent ambulation and the Bayley Scales of Infant Development, Second Edition. We assessed whether there was a differential effect of prenatal surgery in subgroups defined by: fetal leg movements, ventricle size, presence of hindbrain herniation, gender, and location of the myelomeningocele lesion. Within the prenatal surgery group only, we evaluated these and other baseline parameters as predictors of 30-month motor and cognitive outcomes. We evaluated whether presence or absence of a shunt at 1 year was associated with 30-month motor outcomes. RESULTS: The data for the full cohort of 183 patients corroborate the original findings of Management of Myelomeningocele Study, confirming that prenatal repair improves the primary outcome composite score of mental development and motor function (199.4 +/- 80.5 vs 166.7 +/- 76.7, P = .004). Prenatal surgery also resulted in improvement in the secondary outcomes of independent ambulation (44.8% vs 23.9%, P = .004), WeeFIM self-care score (20.8 vs 19.0, P = .006), functional level at least 2 better than anatomic level (26.4% vs 11.4%, P = .02), and mean Bayley Scales of Infant Development, Second Edition, psychomotor development index (17.3% vs 15.1%, P = .03), but does not affect cognitive development at 30 months. On subgroup analysis, there was a nominally significant interaction between gender and surgery, with boys demonstrating better improvement in functional level and psychomotor development index. For patients receiving prenatal surgery, the presence of in utero ankle, knee, and hip movement, absence of a sac over the lesion and a myelomeningocele lesion of <=L3 were significantly associated with independent ambulation. Postnatal motor function showed no correlation with either prenatal ventricular size or postnatal shunt placement. CONCLUSION: The full cohort data of 30-month cognitive development and motor function outcomes validate in utero surgical repair as an effective treatment for fetuses with myelomeningocele. Current data suggest that outcomes related to the need for shunting should be counseled separately from the outcomes related to distal neurologic functioning. PMID- 29246579 TI - Reading Speed and Reading Comprehension in Age-related Macular Degeneration. AB - PURPOSE: To evaluate the impact of age-related macular degeneration (AMD) on short out-loud and sustained silent reading speeds, and reading comprehension. DESIGN: Prospective, cross-sectional. METHODS: Setting: Wilmer Eye Institute. POPULATION: Literate, native-English speakers with and without AMD. AMD participants had better-eye visual acuity (VA) <20/32 and >20/100, while controls had binocular VA >20/32. PROCEDURES: MNRead was used to assess short-duration out loud reading speed. Sustained silent reading test was used to evaluate sustained silent reading speeds, while reading comprehension was assessed based on silent reading test text. OUTCOME MEASURES: MNRead maximum reading speed, sustained silent reading speed, and comprehension score. RESULTS: Analyses included 24 AMD patients and 22 controls. In age-adjusted regressions, AMD participants, compared to controls, read 46 words per minute (wpm) slower on MNRead (95% confidence interval [CI]: -66, -26, P < .001), but there was no difference in sustained reading speeds between groups (beta = 0.99, 95% CI: -41.8, 43.8, P = .96). In other models, there was a decrement of 12.6 wpm on MNRead per 0.1 worsening logMAR (95% CI: -18.7, -6.6, P < .001), but VA was not associated with a decrement in sustained reading speed (beta = -10.1, 95% CI: -22.4, 2.1, P = .10). However, AMD participants had substantially lower comprehension scores than controls (53% vs 85% correct, P < .001), and each 1-line VA decrement was associated with 5.9% lower comprehension score (95% CI: -9.1, -2.7, P = .001). CONCLUSIONS: AMD patients read slower than controls when forced to read out loud. When asked to read silently over a longer duration, both groups read at similar speeds, though AMD patients demonstrated substantially lower comprehension scores, suggesting that they chose to sacrifice comprehension for speed. PMID- 29246580 TI - Measurement and Associations of the Optic Nerve Subarachnoid Space in Normal Tension and Primary Open-Angle Glaucoma. AB - PURPOSE: To measure the area of the optic nerve subarachnoid space (ONSASA) in patients with normal tension glaucoma (NTG), primary open-angle glaucoma (POAG), and controls and examine its association with relevant ocular and systemic parameters. DESIGN: Cross-sectional study. METHODS: The study included 40 patients with NTG, 42 with POAG, and 45 healthy controls. B-scan ultrasound was performed binocularly, using a 12.5-MHz linear array probe. The measurement of the optic nerve subarachnoid space (ONSAS) and calculation of the ONSASA using ImageJ 1.51e analysis software was done by 2 experienced observers in a masked manner. RESULTS: The ONSASA between 3 and 7 mm behind the globe in NTG (5.15 +/- 0.81 mm2) was significantly smaller than that in the POAG (6.24 +/- 1.62 mm2, P = .0008) or control (6.40 +/- 2.20 mm2; P = .0007) groups. ONSASA in the POAG and control groups were not significantly different (P = .13). ONSASA was significantly associated with mean IOP (P = .0004) and highest IOP (P = .0007). The optic nerve sheath diameter in NTG compared to POAG was significantly different at 3 mm (4.46 +/- 0.43 mm vs 4.79 +/- 0.40 mm, P = .0007), 5 mm (4.40 +/- 0.39 mm vs 4.65 +/- 0.47 mm, P = .003), and 7 mm (4.36 +/- 0.35 mm vs 4.61 +/ 0.30 mm, P = .004) behind the globe. CONCLUSIONS: The ONSASA is smaller in NTG as compared to normal control. This is compatible with a lower cerebrospinal fluid pressure in the optic nerve in NTG, implying that trans-lamina cribrosa pressure difference might be abnormally higher in the NTG group than in normal controls. PMID- 29246578 TI - Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target. AB - PURPOSE: To profile vitreous cytokine expression of proliferative vitreoretinopathy (PVR) patients. DESIGN: Case-control study. METHODS: Liquid biopsies were collected from 2 groups: control subjects (n = 3) undergoing pars plana vitrectomy to remove an epiretinal membrane (ERM), and test subjects (n = 7) with varying degrees of PVR. A high-throughput cytokine screen measured expression of 200 cytokines. Cytokine expression patterns were prospectively validated in separate cohorts of control patients and those with PVR-A, PVR-B, and PVR-C (n = 10 for each group). Expression changes were evaluated by analysis of variance (significant P value < .05), hierarchical cluster algorithm, and pathway analysis, to identify candidate pathways for prospective studies. RESULTS: In PVR vitreous, 29 cytokines were upregulated compared to controls. Early PVR vitreous showed upregulation of T-cell markers, profibrotic cytokines, and cytokines downstream of mTOR activation (IL-2, IL-6, and IL-13), whereas in late PVR vitreous, cytokines driving monocyte responses and stem-cell recruitment (SDF-1) prevailed. Prospective validation confirmed the differential expression of specific cytokines from PVR-A to C. CONCLUSIONS: Early PVR is characterized by activation of T cells and mTOR signaling, whereas advanced PVR is characterized by a chronic monocyte response. PVR might be treated by rational repositioning of existing drugs that target mTOR and IL-6. Our analysis demonstrates that successful therapeutic intervention will be highly dependent on the specific therapeutic target and the stage of PVR. This study provides insights into cytokines that will serve as biomarkers and therapeutic targets. These biomarkers will help design clinical trials that intervene at appropriate times. PMID- 29246581 TI - Combined therapy with gas gangrene antitoxin and recombinant human soluble thrombomodulin for Clostridium perfringens sepsis in a rat model. AB - Cases of Clostridium perfringens septicemia, such as liver abscess, often develop a rapidly progressive intravascular hemolysis and coagulation; the mortality rate with current standard care including antibiotics and surgery is high. Herein, we firstly investigated the effects of gas gangrene antitoxin (GGA) (antitoxin against C. perfringens) and recombinant human soluble thrombomodulin (rTM) on the hemolysis, coagulation status, inflammatory process, and mortality in alpha-toxin treated rats. Male 11-week-old Sprague Dawley rats were randomly divided into five groups: control group, alpha-toxin group, GGA group, rTM group, and combined GGA and rTM (combination group). After alpha-toxin injection, mortality and platelet counts, and hemolysis were observed for 6 h. The fibrin/fibrinogen degradation products (FDP), and plasma high-mobility group box 1 (HMGB1) were also measured at 6 h. The combination group demonstrated 100% survival compared with 50% survival in the alpha-toxin group and demonstrated significantly improved hemolysis, platelet counts, and lactate levels compared with those in the alpha-toxin group (p < .01). The FDP and HMGB1 levels in the combination therapy group were significantly lower than those in the alpha-toxin group (p < .05). Combination therapy with GGA and rTM administration is applicable as adjunct therapy for fatal C. perfringens sepsis. PMID- 29246582 TI - Could some procedures commonly used in bioassays with the copepod Acartia tonsa Dana 1849 distort results? AB - Many organizations have suggested the use of the Calanoid copepod Acartia tonsa in protocols for acute toxicity tests. Nevertheless, these protocols present some problems, such as using 60-180um meshes to separate specific stages of A. tonsa or carrying out the tests using small volumes that reflect high densities of A. tonsa that do not occur in nature, which could lead to distorted results. In addition, ecotoxicological studies may use statistical approaches that are inadequate for the type of data being analysed. For these reasons, some methodological approaches for bioassays using A. tonsa need to be clarified and revised. In this study, we present information about (i) the retention of copepodite stages of A. tonsa on 180, 330 and 500um net meshes; (ii) tested storage volumes of 1 organism per 5, 10 or 20mL in each test container (TC); and (iii) considerations about the statistics employed. The results demonstrated that a net mesh of 180um is capable of retaining all copepodite stages (CI to CVI), contrasting with the recommendation of using a 180um mesh to separate out adults only. Coarser meshes (330 and 500um) can also retain different proportions of all copepodite stages, but cannot separate out one developmental stage only. Twenty five millilitres of medium in an open TC, commonly employed in bioassays simulating densities of 1 organism 5mL-1, completely evaporated, and the results showed that the TCs need to be covered (e.g., PVC film) and filled with a minimum of 100mL of culture medium (simulating densities of 1 organism 20mL-1) to avoid evaporation and increases in salinity. The current use of ANOVA in ecotoxicological studies with proportions of surviving organisms should also be reconsidered since the data are discrete and have a binomial distribution; general linear models (GLMs) are considered more adequate. The information presented here suggests some adjustments that hopefully will enable the improvement of the procedures and methods employed in studies of acute toxicity using the copepod A. tonsa. PMID- 29246583 TI - DNA structural basis for fragility at peak III of BCL2 major breakpoint region associated with t(14;18) translocation. AB - Maintaining genome integrity is crucial for normal cellular functions. DNA double strand breaks (DSBs), when unrepaired, can potentiate chromosomal translocations. t(14;18) translocation involving BCL2 gene on chromosome 18 and IgH loci at chromosome 14, could lead to follicular lymphoma. Molecular basis for fragility of translocation breakpoint regions is an active area of investigation. Previously, formation of non-B DNA structures like G-quadruplex, triplex, B/A transition were investigated at peak I of BCL2 major breakpoint region (MBR); however, it is less understood at peak III. In vitro gel shift assays show faster mobility for MBR peak III sequences, unlike controls. CD studies of peak III sequences reveal a spectral pattern different from B-DNA. Although complementary C-rich stretches exhibit single-strandedness, corresponding guanine-rich sequences do not show DMS protection, ruling out G-quadruplex and triplex DNA. Extrachromosomal assay indicates that peak III halts transcription, unlike its mutated version. Taken together, multiple lines of evidence suggest formation of potential cruciform DNA structure at MBR peak III, which was also supported by in silico studies. Thus, our study reveals formation of non-B DNA structure which could be a basis for fragility at BCL2 breakpoint regions, eventually leading to chromosomal translocations. PMID- 29246584 TI - Serial 4DCT/4DPET imaging to predict and monitor response for locally-advanced non-small cell lung cancer chemo-radiotherapy. AB - BACKGROUND AND PURPOSE: A FDG-PET/CT image feature with optimal prognostic potential for locally-advanced non-small cell lung cancer (LA-NSCLC) patients has yet to be identified, and neither has the optimal time for FDG-PET/CT response assessment; furthermore, nodal features have been largely ignored in the literature. We propose to identify image features or imaging time point with maximal prognostic power. MATERIALS AND METHODS: Consecutive consenting patients with LA-NSCLC receiving curative intent CRT were enrolled. 4DPET/4DCT scans were acquired 0, 2, 4, and 7 weeks during IMRT treatment. Eleven image features and their rates of change were recorded for each time point and tested for each of the possible outcome 2 years post CRT using the Kaplan-Meier method. RESULTS: 32 consecutive patients were recruited, 27 completing all scans. Restricting analysis to 4DPET/4DCT features and rates of change with p < 0.005, several volume-based features and their rates of change reached significance. Image features involving nodal disease were the only ones associated with overall survival. CONCLUSIONS: Several 4DPET/CT features and rates of change can reach significant association (p < 0.005) with outcomes, including overall survival, at many time points. The optimal time for adaptive CRT is therefore not constrained uniquely on imaging. PMID- 29246585 TI - Exposure of the lungs in breast cancer radiotherapy: A systematic review of lung doses published 2010-2015. AB - BACKGROUND AND PURPOSE: We report a systematic review of lung radiation doses from breast cancer radiotherapy. METHODS AND MATERIALS: Studies describing breast cancer radiotherapy regimens published during 2010-2015 and reporting lung dose were included. Doses were compared between different countries, anatomical regions irradiated, techniques and use of breathing adaptation. RESULTS: 471 regimens from 32 countries were identified. The average mean ipsilateral lung dose (MLDipsi) was 9.0 Gy. MLDipsi for supine radiotherapy with no breathing adaption was 8.4 Gy for whole breast/chest wall (WB/CW) radiotherapy, 11.2 Gy when the axilla/supraclavicular fossa was irradiated, and 14.0 Gy with the addition of internal mammary chain irradiation; breathing adaptation reduced MLDipsi by 1 Gy, 2 Gy and 3 Gy respectively (p < 0.005). For WB/CW radiotherapy, MLDipsi was lowest for tangents in prone (1.2 Gy) or lateral decubitus (0.8 Gy) positions. The highest MLDipsi was for IMRT in supine position (9.4 Gy). The average mean contralateral lung dose (MLDcont) for WB/CW radiotherapy was higher for IMRT (3.0 Gy) than for tangents (0.8 Gy). CONCLUSIONS: Lung doses from breast cancer radiotherapy varied substantially worldwide, even between studies describing similar regimens. Lymph node inclusion and IMRT use increased exposure, while breathing adaptation and prone/lateral decubitus positioning reduced it. PMID- 29246586 TI - Diagnostic per-lesion performance of a simulated gadoxetate disodium-enhanced abbreviated MRI protocol for hepatocellular carcinoma screening. AB - AIM: To evaluate the diagnostic per-lesion performance of a simulated gadoxetate disodium-enhanced abbreviated MRI (AMRI) in cirrhotic and chronic hepatitis B (CHB) patients for hepatocellular carcinoma (HCC) screening. MATERIALS AND METHODS: Seventy-nine consecutive patients at risk for HCC due to cirrhosis and/or CHB were included in this retrospective study. For each patient, the first gadoxetate disodium-enhanced MRI between 2008 through 2014 was analysed. Two independent readers read an anonymised abbreviated image set comprising axial T1 weighted (W) images with fat saturation in the hepatobiliary phase, 20 minutes or more after gadoxetate injection, and axial T2W single-shot fast spin echo images. Each observation >10 mm was scored as negative or suspicious for HCC. Inter reader agreement was assessed. A composite reference standard was used to determine the per-lesion diagnostic performance for each reader. RESULTS: Inter reader agreement was substantial (kappa = 0.75). The final reference standard showed 27 HCCs in 13 patients (median 21 mm, range 11-100 mm). The two readers each correctly scored 23 as suspicious for HCC (sensitivity = 85.2%), scored a total of 27 and 32 observations as suspicious for HCC (positive predictive value [PPV] = 85.2% and 71.9%), and scored 83 and 78 observations or complete examinations as negative for HCC (negative predictive value [NPV] = 95.2% and 94.9%). CONCLUSIONS: The AMRI protocol provides higher per-lesion sensitivity and NPV than reported values for ultrasound, the current recommended technique for screening, and similar per-lesion sensitivity and PPV to reported values for complete dynamic contrast-enhanced MRI. PMID- 29246587 TI - Endometrial carcinoma: diffusion-weighted imaging diagnostic accuracy and correlation with Ki-67 expression. AB - AIM: To evaluate the role of diffusion-weighted imaging (DWI) in the detection of endometrial carcinoma and to correlate the apparent diffusion coefficient (ADC) value with Ki-67 expression. MATERIALS AND METHODS: Fifty-two patients with invasive cancer who underwent pelvic MRI were prospectively evaluated using DWI with b-values of 0 and 1000 s/mm2.The ADC values from standard DWI were measured. The expression of Ki-67 in histological specimens was analysed using immunohistochemistry. The ADC values of endometrial carcinoma and normal endometrial parenchyma were compared. Relationships between ADC values and Ki-67 expression were determined using Wilcoxon's signed rank test and the Kruskal Wallis test. RESULTS: Endometrial carcinoma was detected at DWI as a hyperintense area in 92.3% (48/52) of patients. There was a significant difference in the mean ADC values between endometrial carcinoma and normal endometrial parenchyma (1.39+/-0.27*10-3 versus 0.93+/-0.21*10-3 mm2/s, p<0.001). The mean ADC values of grade 1 patients were significantly higher than those of grade 3 patients (1.01+/ 0.16*10-3 versus 0.83+/-0.21*10-3 mm2/s, p<0.05). The mean ADC values of stage IB patients were significantly lower than those of stage IA patients (0.86+/-0.16*10 3 versus 1.04+/-0.21*10-3 mm2/s, p<0.01). The mean ADC values of high Ki-67 expression patients were significantly lower than those of low Ki-67 expression patients (0.82+/-0.12*10-3 versus 1.16+/-0.12*10-3 mm2/s, p<0.001). There was a significant negative correlation between the mean ADC value and Ki-67 expression (r=-0.82, p<0.001). CONCLUSION: The ADC value was a helpful parameter for detecting the tumour grade, stage, and proliferation of endometrial carcinoma, and may further improve patient prognosis and contribute to the development of more effective treatment programmes. PMID- 29246588 TI - Immediate reporting of chest X-rays referred from general practice by reporting radiographers: a single centre feasibility study. AB - AIM: To investigate the feasibility of radiographer-led immediate reporting of chest radiographs (CXRs) referred from general practice. MATERIALS AND METHODS: This 4-month feasibility study (November 2016 to March 2017) was carried out in a single radiology department at an acute general hospital. Comparison was made between CXRs that received an immediate and routine report to determine the number of lung cancers diagnosed, time to diagnosis of lung cancer, time to computed tomography (CT), and number of urgent referrals to respiratory medicine. RESULTS: Forty of 186 sessions (22%) were covered by radiographer immediate reporting. Of the 1,687 CXRs referred from general practice, 558 (33.1%) received an immediate report (radiographer or radiologist). Twenty-two (of 36) CT examinations performed were following an abnormal CXR with an immediate report (mean 0.8 scans/week). Time from CXR to CT was shorter in the immediate report group (n=22 mean 0.9 days SD=2.3) compared to routine reporting (n=14; mean 6.5 SD=3.2; F=27.883, p<0.0001). Time to multidisciplinary team (MDT) discussion was shorter in the immediate reporting group (mean 4.1 SD=2.9) compared to routine reporting (mean 10.6; SD=4.5; F=11.59, p<0.0001). No apparent difference was found for time to discussion at treatment MDT. CONCLUSION: It is feasible to introduce a radiographer-led immediate CXR reporting service. Patients can be taken off the lung cancer pathway sooner with the introduction of radiographer immediate reporting of CXRs and this may improve outcomes for patients. A definitive study assessing outcomes is required to determine whether this will have an impact mortality and morbidity for patients. PMID- 29246590 TI - Developing a National, Simulation-Based, Surgical Skills Bootcamp in General Thoracic Surgery. AB - BACKGROUND: The use surgical simulation across all subspecialties has gained widespread adoption in the last decade. A number of factors, including the small number of trainees, identified gaps in surgical skill training from cross sectional surveys, increased national collaboration, and support from the national specialty committee identified a need to construct a surgical skills "bootcamp" in thoracic surgery in Canada. OBJECTIVE: The goals of the surgical skills bootcamp, as identified by the residency training program directors and the national specialty committee were to create a national, centralized, simulation-based skills workshop that focused on key foundational procedures within thoracic surgery, particularly those identified as areas of weakness by former residents; to smooth the transition to intraoperative teaching; to provide exposure to important but not necessarily universally available procedures such as advanced endoscopy; to teach non-medical expert competencies, and lastly to provide a venue for networking for residents across the country. DESIGN: The curriculum committee has constructed a 3.5 day curriculum, with a focus on hands on skills simulation, as well as lectures, on a breadth of topics including benign esophageal disorders, lung cancer staging, minimally invasive lung surgery, crisis management and advanced bronchoscopy and endoscopy. All residents across the country attend as well as faculty from a variety of institutions. SETTING: The course is hosted centrally at the University of Toronto, Ontario over 3.5 days. A combination of auditorium and both animal and human operating room facilities are utilized. METHODS: A needs-assessment based on a formal meeting of the program directors, as well feedback from surveys identified the target areas for curriculum development. A committee of interested faculty developed the content as well as the local construct and logistics required. Iterative feedback has evolved the duration and content over the initial 3 years. RESULTS: Through formal resident feedback, national subspecialty committee review, and program director meetings the support for the bootcamp has been overwhelmingly positive. Specific resident feedback for structure, content and specific simulations has been favorable, but has also been used to modify the program. CONCLUSION: In response to identified weaknesses in training, with the support of the national specialty committee, the residency program directors, and the faculty at the University of Toronto, an intensive simulation based thoracic surgery bootcamp has successfully been created for Canadian thoracic surgery residents. PMID- 29246589 TI - Results of the national survey on the treatment of chronic anal fissure in Spanish hospitals. AB - INTRODUCTION: The treatment of chronic anal fissure (FAC) differs depending on the professional. To come to a consensus, the current situation in Spain should be studied. The aim of this study is to evaluate the current situation of the management of FAC in Spanish hospitals. METHODS: Descriptive study, with data from a survey of surgeons of the Spanish Association of Coloproctology. Data was collected according to the doctor's autonomous community, type of hospital and professional category; FAC management data and 3 clinical cases. RESULTS: Response was obtained from 152 surgeons. Pharmacological measures stand out as the first therapeutic step (93.38%). In patients with hypertonia and with no risk factors for fecal incontinence (FI), 55.9% use hygienic-dietary measures associated with nitroglycerin ointment (MHG+NTG). The second step is internal lateral sphincterotomy (ELI) (43.4%). MHG+NTG (75.7%) is used in patients with FI risk factors and in case of failure, ELI is used with a prior ultrasound and/or manometry. In young patients with unexplained hypertonia and incapacitating proctalgia with no risk factors for FI, MHG+NTG (55.9%) is used and, if it is not successful, they are treated with ELI (46.1%). CONCLUSIONS: The management of FAC in Spain shows similarities with the international guideline suggestions. Nevertheless, some differences can be seen from the first stages of treatment. PMID- 29246591 TI - The effect of metabolic syndrome and obesity on outcomes of acute ischemic stroke patients treated with systemic thrombolysis. AB - Metabolic syndrome (MetS) is associated with increased risk of ischemic stroke; while central obesity has controversial effects on ischemic stroke. We investigated effects of MetS and obesity on clinical courses and outcomes of patients treated with intravenous recombinant tissue-type plasminogen activator (iv rt-PA). 319 patients treated with intravenous thrombolysis were included to our study. Metabolic syndrome was determined if >=3 of following criteria are present: elevated waist circumference; elevated triglycerides; reduced high density-lipoprotein cholesterol (HDL-C); elevated blood pressure; elevated fasting glucose. Obesity was defined as BMI>=30. Clinical features at baseline, 24th hour and 3rd month were examined. Computed tomography (CT) findings for ASPECT scores and hemorrhagic transformation were analyzed. 182 patients were MetS+; they were older (p=0.035), had similar ASPECT scores (p=0.477) and NIHSS scores (p=0.167) at admission; had significantly higher NIHSS scores at 24th hour (p<0.001) and worse outcome at 3rd month (p<0.001). Logistic regression analysis showed that either MetS, obesity or age were not independent predictors of poor outcome. Obese patients (n:72) had slight but significantly lower NIHSS scores at admission (p=0.049) compared to non-obese patients; meanwhile there was no significant difference between NIHSS scores at 24th hour (p=0.736) and 3rd month mRS scores (p=0.145). Hemorrhagic transformation and mortality rates were not affected with MetS or obesity. MetS is not an independent factor on clinical outcome but its presence may have a relationship with poor outcome; but obesity was not found to have any significant role on clinical course and outcome of patients treated with iv rt-PA. PMID- 29246592 TI - Risk factors associated with baseline King-Devick performance. AB - OBJECTIVE: This study examined the effect of baseline risk factors on the King Devick (K-D) test in youth athletes, including of age, sex, and history of concussion. METHODS: A total of 422 youth football and soccer athletes between the ages of 8 and 14 completed a baseline K-D test prior to the start of their respective seasons. Participant age, sex, and history of concussion were analyzed for K-D performance (i.e., errors and baseline time). A series of Mann-Whitney U tests were conducted to determine the effects of risk factors on performance. Correlations and regression analyses were conducted to assess the relationship between risk factors and K-D time and errors. RESULTS: Differences in age (p<0.001) and sex (p<0.001) were reported on K-D time and errors. A history of concussion did not have an effect on K-D time (p=0.15) or errors (p range=0.15 0.17). Overall, weak to moderate correlations were observed between risk factors and K-D performance (r range=-0.43-0.23). Baseline K-D time and total errors improved with increasing participant age (p<0.001). Sex was also able to predict K-D time and errors (p<0.001). History of concussion was not able to predict K-D time (p=0.18) or errors (p>0.05). CONCLUSIONS: This study demonstrates the influence of risk factors such as sex and age on baseline K-D assessment. Associated risk factors at baseline further emphasize the need for individualized, multifaceted assessment for sport-related concussion diagnosis and management. PMID- 29246593 TI - Gait stability in patients treated by fingolimod: A longitudinal pilot study on 9 patients with multiple sclerosis. PMID- 29246594 TI - Evaluation of the retinal nerve fiber layer in neuromyelitis optica spectrum disorders: A systematic review and meta-analysis. AB - BACKGROUND: An increasing number of studies have investigated the value of optical coherence tomography in patients with neuromyelitis optica (NMO) spectrum disorders; however, no systematic review has been performed to date. We aimed to systematically review and investigate the possibility of differentiating NMO and multiple sclerosis (MS) via an optical coherence tomography measurement. METHODS: Electronic databases, including MEDLINE, EMBASE and Web of Science, were systematically searched up to June 2017. A meta-analysis was performed to compare the retinal nerve fiber layer (RNFL) thickness between patients with NMO and MS (or healthy controls). RESULTS: Twenty-four studies were identified. The meta analysis demonstrated that the RNFL loss was substantially more severe in NMO than in MS; however, subclinical axon damage was also found in eyes without optic neuritis in NMO. The intereye RNFL difference between eyes with or without optic neuritis was more prominent in NMO (-30.98MUm) than in MS (-9.87MUm). CONCLUSION: The RNFL loss was more severe in NMO than in MS, and the intereye RNFL difference between eyes with or without optic neuritis may be useful in differentiating NMO from MS. PMID- 29246596 TI - A MDS-UPDRS Part II (motor experiences of daily living) score to predict recurrent falls in people with Parkinson's disease. PMID- 29246595 TI - Identification of post-translational modifications of Abeta peptide in platelet membranes from patients with cerebral amyloid angiopathy. AB - Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid deposition. It contributes to the rate of cognitive decline in older individuals and is present in >90% of patients with Alzheimer's disease (AD), with no cure so far. Molecular modifications during CAA should be elucidated to improve its diagnosis and treatment. In this study, amyloid-beta (Abeta) aggregates in platelet membranes from 65 patients with CAA and 66 healthy volunteers (controls) were confirmed through thioflavin T (ThT) assay and Western blot analysis. Further, post-translational modifications (PTMs) of Abeta in platelet membranes were analyzed using ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC/ESI-Q-TOF/MS). ThT assay results indicated that there were amyloid components in platelets from both patients with CAA and controls. Western blot analysis showed that different molecular weight (MW) Abeta aggregates were found in platelet membranes. LC-MS analysis showed that PTMs including methylation, phosphopantetheine, phosphorylation, deamidation, and acetylation, occurred in Abeta peptide in platelet membranes from both patients with CAA and controls, while Met35 oxidation (MetOX) and Gln15 deamidation were identified only from patients with CAA. Thus, this study identified potential biomarkers of CAA and characterized the mechanism underlying amyloidogenesis in CAA. PMID- 29246597 TI - Passively acquired thyroid autoantibodies from intravenous immunoglobulin in autoimmune encephalitis: Two case reports. PMID- 29246599 TI - Manifestations of neurological symptoms and thromboembolism in adults with MTHFR deficiency. AB - BACKGROUND: Methylenetetrahydrofolate-reductase (MTHFR) deficiency is a rare autosomal recessive disorder affecting intracellular folate metabolism with affection of different organ systems and clinical manifestation usually in childhood. OBJECTIVE: We report on four adult members of a family with MTHFR deficiency presenting with neurological and thromboembolic complications in adulthood. METHODS: Extensive diagnostic work-up including genetic testing was performed in four adult members. RESULTS: The male siblings aged 42 and 32years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135MUmol/L and 231MUmol/L. and compound heterozygosity for two novel MTHFR gene mutations in exon 2 (c.202C>G, p.Arg68Gly) and intron 10 (c.1632+2T>G), and the known polymorphic variant MTHFR c.665C>T (p.Ala222Val, MTHFR 677C>T). Their mother was heterozygous for MTHFR c.1632+2T>G and c.665C>T, and a paternal relative was heterozygous for MTHFR c.202.C>G and MTHFR c.665C>T mutation. Both brothers showed partial response to therapy with betaine and multivitamins with clinical improvement. MTHFR activity was determined in fibroblast extracts and was around 4% of the mean control. Cell culture analysis indicated a re-methylation defect due to MTHFR deficiency. CONCLUSION: Severe hyperhomocysteinemia due to two mutations of the MTHFR gene resulted in severe neurological symptoms in adulthood. Vitamin and methionine supplementation stabilize tHcy plasma levels. Severity of clinical manifestation varied greatly between the siblings. Damages to the nervous system may be present for years before becoming clinically manifest. PMID- 29246598 TI - Intravenous immunoglobulin as monotherapy for myasthenia gravis during pregnancy. AB - INTRODUCTION: Pregnant women with myasthenia gravis (MG) are at increased risk of complications and adverse outcomes, including the teratogenic effects of many drugs used to treat MG women of childbearing age. The effectiveness of intravenous immunoglobulins (IVIg) on other autoimmune mediated diseases has been extensively reported in recent years, although little is known about the role of IVIg in the treatment of MG during pregnancy. We designed this study to determine the effectiveness of IVIg as monotherapy during pregnancy for women with MG. MATERIAL AND METHODS: Five pregnant MG patients (mean age at delivery 36.4years, SD 5.8, range 29.4-45.2) were studied in 2013-14. Their treatment was switched to monthly IVIg cycles 2months before the pregnancy. Follow-up included monthly neurological QMG throughout the pregnancy and postpartum, obstetrical monitoring during monthly visits in the first two trimesters of the pregnancy, fortnightly visits between week 32 and week 36, and weekly visits after 36weeks, and neonatal follow-up after delivery. RESULTS: We observed no exacerbations during pregnancy, delivery or post-partum. The mean QMG score at baseline (before pregnancy) was 7.4 points in five women with generalized forms of MG. The maximum mean value reached during pregnancy was 8.6 points. The mean pregnancy duration was 38 w+5 d. No infant with transient neonatal myasthenia gravis. CONCLUSIONS: These results suggest that monotherapy with IVIg during pregnancy in MG patients could be promising, although confirmation is required in studies with larger populations. PMID- 29246600 TI - Prediction of conscious awareness recovery after severe acute ischemic stroke. AB - BACKGROUND: Ischemic stroke that is sufficiently severe to cause loss of consciousness has a high rate of morbidity and mortality. Many individuals who suffer from these disorders never recover conscious awareness. In this study, we aimed to identify an accurate and simple bedside method to predict awareness recovery after severe acute ischemic stroke. METHODS: Between 2013 and 2017, all consecutive patients with consciousness disorders after acute ischemic stroke were recruited to the study. The demographic data, Full Outline of UnResponsiveness (FOUR) score, Glasgow Coma Scale (GCS) and Bispectral Index (BIS) were recorded at study entry and each day of Days 3-8 during the stroke period. We followed patients for 90days to assess whether the subjects recovered conscious awareness. Logistic regression and receiver operating characteristic (ROC) curve analyses were used to evaluate the predictors' abilities for outcome prognosis. RESULTS: We assessed a total of 102 patients. 23 (23%) patients died without awareness recovery, whereas 61 (60%) patients regained conscious awareness. The earliest time with the greatest ability to predict conscious awareness recovery occurred at Day 3 after stroke, and the area under the ROC curve (AUC) of the multivariate model was 0.948 (95% confidence interval (CI) 0.885 to 0.982). Age, BIS, motor response and brainstem responses were independent predictors for conscious awareness recovery. We subsequently created a 20-point score termed "ABMB" based on their coefficients in the Day 3 model. The AUC of ABMB at Day 3 was 0.931 (95% CI 0.882 to 0.980). The ABMB also showed good predictive ability at Days 4 and 5. CONCLUSIONS: The ABMB score accurately identified patients who will recover conscious awareness within 90days after acute severe ischemic stroke and thus provides a useful outcome message for clinicians and relatives. PMID- 29246601 TI - Infection related to deep brain stimulation in patients with Parkinson disease: Clinical characteristics and risk factors. AB - OBJECTIVE: Risk factors of infection after deep brain stimulation (DBS) surgery in patients with Parkinson disease (PD) have been controversial. We aimed to investigate the clinical characteristics and risk factors of infection after DBS surgery in PD patients. METHODS: We retrospectively investigated 246 consecutive DBS surgeries in 169 advanced PD patients. Clinical data were collected and analyzed to clarify the clinical characteristics associated with infection after DBS surgery. Multivariate logistic regression analysis was used to assess risk factors for infection after DBS surgery. RESULTS: Infection occurred in 5% of all DBS surgeries and in 7% of all PD patients who received DBS surgery. Most infections (75%) occurred within 3months after DBS surgery but it also occurred 21months after DBS surgery. Gram-positive bacteria were the most common pathogens (75%). Infection after DBS surgery was associated with short period of prophylactic antibiotic therapy (OR=0.62, 95% CI=0.45-0.85, P=0.002) and intensive care unit (ICU) management immediate after DBS surgery (OR=5.43, 95% CI=1.12-26.45, P=0.036). CONCLUSION: Our study suggests that short period of prophylactic antibiotic therapy and ICU management after surgery may increase the risk of infection in PD patients who received DBS surgery. PMID- 29246602 TI - Variable tau accumulation in murine models with abnormal prion protein deposits. AB - The conversion of cellular prion protein (PrP) into a misfolded isoform is central to the development of prion diseases. However, the heterogeneous phenotypes observed in prion disease may be linked with the presence of other misfolded proteins in the brain. While hyperphosphorylated tau (p.tau) is characteristic of Alzheimer's disease (AD), p.tau is also observed in human prion diseases. To explore this association in the absence of potential effects due to aging, drug treatment, agonal stage and postmortem delay we analyzed p.tau and PrP immunopositivity in mouse models. Analyses were performed on mice inoculated with prion agents, and mice with PrP amyloid in the absence of prion disease. We observed that p.tau was consistently present in animals with prion infectivity (models that transmit disease upon serial passage). In contrast, p.tau was very rarely observed or absent in mice with PrP amyloid plaques in the absence of prion replication. These data indicate that the formation of p.tau is not linked to deposition of misfolded PrP, but suggest that the interaction between replication of infectivity and host factors regulate the formation of p.tau and may contribute to the heterogeneous phenotype of prion diseases. PMID- 29246603 TI - A stress-system model for functional neurological symptoms. PMID- 29246604 TI - Long-term clinical outcome of bilateral pallidal stimulation for intractable craniocervical dystonia (Meige syndrome). Report of 6 patients. AB - BACKGROUND: The aim of the present study was to report the short-term as well long-term results of bilateral pallidal stimulation in 6 consecutive patients for severe debilitating craniocervical dystonia (Meige syndrome) using Burke-Fahn Marsden Dystonia Rating Scale (BFMDRS). METHODS: We evaluated 6 consecutive patients with the diagnosis of intractable long-standing craniocervical dystonia. The formal objective assessment included the motor and disability BFMDRS scores. The BFMDRS assessment was performed before and after it roughly annually up to 60months when bilateral pallidal stimulation was switched on and compared to baseline BFMDRS scores. We present short-term (3months postoperatively) follow-up as well long-term (from 6 to 60months) results. Baseline BFMDRS scores and subsequent follow-up BFMDRS scores were compared with the use of a Wilcoxon signed-rank test for matched pairs. A two-tailed probability level of 5% (p<0.05) was considered significant. RESULTS: Bilateral GPi DBS improved the BFMDRS total movement score by 65% at short-term follow-up and by 53% at long-term follow-up when compared to baseline scores. Subscores for eyes at short-term follow-up were reduced by 78%, for mouth by 58%, and for speech/swallowing by 49%. This improvements for individual subscores were maintained at long-term follow-up and were as follows for eyes by 67%, mouth by 50% and speech/swallowing by 39%. The BFMDRS disability score was reduced by 48% at short-term follow-up and by 55% at long-term follow-up when compared to baseline scores. CONCLUSION: Our results showed that bilateral GPi DBS in craniocervical dystonia is effective and safe. Phasic dystonic movements like blepharospasm or oromandibular dystonia responded very fast and favorable to pallidal stimulation reducing disabilities. PMID- 29246605 TI - The role of the cerebellum in rock climbing. PMID- 29246606 TI - Sensory training with vibration-induced kinesthetic illusions improves proprioceptive integration in patients with Parkinson's disease. AB - The present study investigates whether proprioceptive training, based on kinesthetic illusions, can help in re-educating the processing of muscle proprioceptive input, which is impaired in patients with Parkinson's disease (PD). The processing of proprioceptive input before and after training was evaluated by determining the error in the amplitude of voluntary dorsiflexion ankle movement (20 degrees ), induced by applying a vibration on the tendon of the gastrocnemius-soleus muscle (a vibration-induced movement error). The training consisted of the subjects focusing their attention upon a series of illusory movements of the ankle. Eleven PD patients and eleven age-matched control subjects were tested. Before training, vibration reduced dorsiflexion amplitude in controls by 4.3 degrees (P<0.001); conversely, vibration was inefficient in PD's movement amplitude (reduction of 2.1 degrees , P=0.20). After training, vibration significantly reduced the estimated movement amplitude in PD patients by 5.3 degrees (P=0.01). This re-emergence of a vibration-induced error leads us to conclude that proprioceptive training, based on kinesthetic illusions, is a simple means for re-educating the processing of muscle proprioceptive input in PD patients. Such complementary training should be included in rehabilitation programs that presently focus on improving balance and motor performance. PMID- 29246607 TI - Smart watch, smarter EDSS: Improving disability assessment in multiple sclerosis clinical practice. AB - BACKGROUND: Patients' walking ability is critical for assessing the EDSS, the disability scale commonly used in MS clinical practice. Such assessment is usually based on patients' estimates or on the measures the neurologists observe during periodic visits. OBJECTIVES AND METHODS: We evaluated the agreement between patients' and neurologists' estimates of maximum walking ability and patients' mean maximum walking ability measured in their daily life through a GPS smartwatch, and assessed limitations of the current methods. RESULTS: Seventy three patients with a median walking ability of 500m (IQR 400-800) were enrolled in the study. The agreement between patients' estimates and GPS measurements was modest (ICC 0.29, 95% CIs 0.06-0.49) and was influenced by course of the disease, patients' mood and inaccuracy at estimating long distances. A better reliability was found between neurologists' and GPS measures (ICC 0.68, 95% CIs 0.53-0.78), but the variability increased for longer distances and was influenced by patients' depressive symptoms, fatigue and course of the disease. CONCLUSIONS: This study showed a poor agreement between patients' and neurologists' estimates of maximum walking ability and patients' mean maximum walking ability measured in their daily life through a GPS smartwatch, with many factors affecting patient's and neurologists' estimates of the EDSS. The use of remote measurement technologies may provide a better understanding of the impact of MS in a patient's life. PMID- 29246608 TI - Patterns and modulations of Pendular nystagmus in a family with hereditary spastic paraplegia. AB - Hereditary spastic paraplegia (HSP) is characterized by progressive spasticity and weakness of the lower extremities. Additional findings include ataxia, extrapyramidal signs, and dementia. Pendular nystagmus (PN) has been reported in some subtypes of HSP caused by PLP1 (SPG2) or paraplegin (SPG7) mutation. To describe the patterns and modulation of PN in HSP, we performed eye movement recording using video-oculography in a Korean family with HSP and PN. The PN was convergent-divergent in the oblique plane with a frequency of 6 to 7Hz and maximum amplitude at about 1.5 degrees . The nystagmus diminished briefly after blinks and horizontal saccades, and decreased during eccentric gaze and convergence. Horizontal saccades shifted the phase of the oscillations. During lateral gazes, the PN increased in the abducting eye, but decreased in the adducting eye. Vibratory stimuli decreased the nystagmus mostly in the left but not in the right eye. No pathogenic mutation was found in the genetic loci known for causing spastic paraplegia by whole-exome sequencing. The unusual features and modulation of PN in our patients with HSP emphasize the role of disconjugate and disjunctive capabilities of the brain in ocular motor control, and exemplify what can go wrong. PMID- 29246609 TI - Safety and preliminary efficacy of intravenous tirofiban in acute ischemic stroke patient without arterial occlusion on neurovascular imaging studies. AB - BACKGROUND: There has been no effective treatment for acute ischemic stroke (AIS) patients who presented to the Emergency Department >4.5h without a visible arterial occlusion on the neurovascular imaging studies. In this study, we aimed to investigate whether intravenous antiplatelet agent tirofiban was safe and potentially effective in AIS patients who had no visible arterial occlusion and was outside of treatment window for Alteplase. The goal of this study was to collect preliminary data to plan a future phase II study. METHOD: Twenty-five patients received intravenous tirofiban therapy. The safety outcomes were assessed by the incidence of symptomatic intracerebral hemorrhage (sICH), systematic bleeding and mortality. Efficacy outcomes were evaluated with National Institutes of Health Stroke Scale (NIHSS) score at day 7 (or discharge) and modified Rankin Scale (mRS) at 90days. Outcomes for these patients were compared with a historical age-gender-admission-NIHSS matched cohort treated with aspirin and/or clopidogrel. RESULTS: The rate of intracerebral hemorrhage, systematic bleedings, and death were not found in both groups. At day 7 or discharge, the neurological function improved significantly in both treatment groups. However, the NIHSS score was lower in tirofiban group compared with the control group (2 vs.3, p=0.045). At 3months, more patients in tirofiban group had favorable outcomes (mRS 0-1) compared with control group (84% vs. 52%; adjusted odds ratio: 10.57; 95% CI: 1.54-72.33; p=0.016). CONCLUSIONS: Intravenous tirofiban appears to be safe and potentially effective for the ischemic stroke patients with no artery occlusion on neurovascular imaging studies and being out of the window for thrombolytic therapy. A next logic step is to plan for a phase II study. PMID- 29246610 TI - Clinical and molecular characterization of hereditary spastic paraplegias: A next generation sequencing panel approach. AB - BACKGROUND: Molecular diagnosis of hereditary spastic paraplegias (HSP) is a difficult task due to great clinical and genetic heterogeneity. We aimed to characterize clinical and molecular findings of HSP families from Rio Grande do Sul, Brazil; and to evaluate the diagnostic yield of a next-generation sequencing (NGS) panel with twelve HSP-related genes. METHODS: A consecutive series of HSP index cases with familial recurrence of spasticity, consanguinity or thin corpus callosum (TCC) were included in this cross-sectional study. RESULTS: Among the 29 index cases, 51.7% (15/29) received at least a likely molecular diagnosis, and 48.3% (14/29) a defined diagnosis. NGS panel diagnostic yield was 60% for autosomal dominant HSP (6/10, all SPG4), 47.4% for autosomal recessive HSP (9/19: 5 SPG11, 2 SPG7, 1 SPG5 and 1 cerebrotendinous xanthomatosis), and 50% for patients with TCC (3/6, all SPG11). Remarkably, 2/6 SPG11 patients presented keratoconus, and tendon xanthomas were absent in the patient with cerebrotendinous xanthomatosis. CONCLUSION: A likely molecular diagnosis was obtained for more than half of families with the NGS panel, indicating that this approach could be employed as a first-line investigation for HSP. SPG4 is the most frequent form of autosomal dominant and SPG11 of autosomal recessive HSP in Southern Brazil. PMID- 29246611 TI - Effect of Lee Silverman Voice Treatment (LSVT LOUD(r)) on swallowing and cough in Parkinson's disease: A pilot study. AB - PURPOSE: Lee Silverman Voice Treatment (LSVT LOUD(r)) is an effective therapy for phonation in Parkinson's Disease (PD) but little is known about any additional spread of effects to swallowing and cough function. This pilot study examined the effect of LSVT LOUD on pharyngeal swallowing parameters and reflexive cough strength. METHODS: Twenty participants (14 men, 6 women; mean 68years, SD3.5) with PD referred for LSVT LOUD with complaints of voice deterioration were recruited. Mean duration of PD was 6yrs., SD 3. Self-reported Eating Assessment Tool-10 scores ranging from 0 to 25 (normal<3). Prior to LSVT LOUD, 1-week post- and 6-months post-treatment, participants undertook a videofluoroscopic study of swallowing and aerodynamic measures of involuntary cough. RESULTS: All participants completed the LSVT LOUD programme; 3 participants were lost to follow-up at 6-months. All participants made significant gains in average sound pressure level (dB SPL). Aspiration was not observed. Pharyngeal residue (p<0.05) and pharyngeal area at rest reduced (p<0.01) while maximal opening of pharyngoesophageal segment (PES) (p<0.05) and PES opening duration (p<0.05) significantly increased. There was a significant improvement in involuntary cough peak expiratory flow rate and peak expiratory flow rise time. All changes were maintained at 6-months. CONCLUSION: LSVT LOUD demonstrates additional spread effects on pharyngoesophageal deglutitive function and involuntary cough effectiveness in people with mild PD referred with voice complaints. Consequently, LSVT LOUD has potential to provide additional benefits for swallowing safety and efficiency in this patient group. PMID- 29246613 TI - Clinical management of tardive dyskinesia: Five steps to success. AB - Tardive dyskinesia (TD) has long been thought to be a generally irreversible consequence of the use of dopamine receptor blocking agents. There is now an opportunity to successfully manage this condition with agents approved by the US Food and Drug Administration. This is important because TD has not been eliminated with the use of second-generation antipsychotics, and the expansion of antipsychotics to treat conditions other than schizophrenia has resulted in millions of additional individuals at risk for developing TD. Recognition of TD requires careful observation; a structured approach using the Abnormal Involuntary Movement Scale is encouraged. Harm reduction can be achieved by using antipsychotics judiciously when possible and by paying attention to other modifiable risk factors such as drug-induced parkinsonian symptoms and the use of anticholinergic medication. Once TD has emerged and is associated with dysfunction or distress, treatment with a VMAT2 inhibitor such as deutetrabenazine or valbenazine is well supported by several controlled clinical trials. PMID- 29246612 TI - Extracellular miR-145, miR-223 and miR-326 expression signature allow for differential diagnosis of immune-mediated neuroinflammatory diseases. AB - BACKGROUND: Although misdiagnosis of neuromyelitis optica spectrum disorder (NMOSD) with neuropsychiatric systemic lupus erythematosus (NPSLE) or multiple sclerosis (MS) is not infrequent, reliable biomarkers remains an unmet need. Extracellular microRNAs (miRNAs) represent a worthy avenue to identify biomarkers for differential diagnosis. We aimed to explore the potential role of some selected circulating miRNAs as biomarkers for the differential diagnosis in immune-mediated neuroinflammatory diseases. METHODS: A total of 80 subjects were enrolled in the present study, including 37 patients with MS (relapsing-remitting MS [RRMS; n=18] and secondary progressive MS [SPMS; n=19]), 10 patients with NMOSD and 10 patients with NPSLE as well as 23 healthy subjects. Serum expression levels of three selected miRNAs (miR-145, miR-223 and miR-326) were measured using quantitative real-time polymerase chain reaction (qRT-PCR). Whole blood expression levels of cellular immune response-relevant target genes, including signaling mother against decapentaplegic peptide 3 (SMAD3) and specificity protein 1 (SP1), were also measured using qRT-PCR. RESULTS: In comparison to healthy subjects, only miR-145 and miR-223 were significantly up-regulated in MS patients, whereas, all the analyzed miRNAs revealed insignificant upregulation in NMOSD patients. All the examined miRNAs were significantly down-regulated in NPSLE patients compared to healthy subjects. miR-145, miR-223 and miR-326 expression profile is a promising diagnostic biomarker for MS and NPSLE, but not for NMOSD. This expression profile is capable of differentiating not only among MS, NMOSD and NPSLE, but also between RRMS and SPMS. CONCLUSION: Specific circulating miRNAs expression signature may have the potential to differentially diagnose immune-mediated neuroinflammatory diseases. PMID- 29246614 TI - Perceived embarrassment and caregiver burden in essential tremor caregivers. AB - Essential tremor (ET) is a progressive neurological disease associated with functional disability, diminished quality of life and, in some individuals, poorer balance, cognitive impairment, depression and sleep dysregulation. Individuals with ET may rely on family members and friends to act as informal caregivers to assist with daily activities and provide emotional support. There is a high prevalence of embarrassment among individuals with ET, which may be a result of the outwardly visible nature of tremor. Studies in populations with outwardly visible disability have shown that perception by caregivers of a care recipient's social distress can contribute to caregiver burden. We hypothesize that in ET, perception by caregivers of ET participant embarrassment is a predictor for caregiver burden. Data were collected from 57 ET participants and their caregivers. We measured ET participant embarrassment using the Essential Tremor Embarrassment Assessment (ETEA), and measured perception by caregivers of ET participant embarrassment using a modified version of the ETEA. The Zarit Burden Interview was used to measure caregiver burden. Perceived embarrassment was associated with ET participant embarrassment. In linear regression models, perceived embarrassment was a stronger predictor for caregiver burden than measures of ET participant cognitive and physical impairment. The results indicate that perception of ET participant embarrassment can be burdensome for caregivers. Clinicians may wish to address patient embarrassment and perceived embarrassment to better support caregivers and ET patients. PMID- 29246615 TI - Impact of anaemia on acute stroke outcomes depends on the type of anaemia: Evidence from a UK stroke register. AB - BACKGROUND: Previous research has demonstrated an association between anaemia and poor outcomes in acute stroke. This study aimed to assess the impact of anaemia on stroke by anaemia subtype. METHODS: Data from a prospective UK Regional Stroke Register were used to assess the association between hypochromic microcytic and normochromic normocytic anaemia on inpatient-mortality, length of stay (LOS) and discharge modified Rankin scale (mRS). Analysis was stratified by stroke subtypes and multivariable logistic regression, adjusting for potential confounders, was used to quantify this association. Patients who were not anaemic were the reference category. RESULTS: A total of 8167 stroke patients (admitted between 2003 and 2015) were included, mean age (SD) 77.39+/-11.90years. Of these, 3.4% (n=281) had hypochromic microcytic anaemia and 15.5% (n=1262) had normochromic normocytic anaemia on admission. Normochromic normocytic anaemia was associated with increased odds of in-patient mortality OR 1.48 (1.24-1.77), 90-day mortality OR 1.63 (1.38-1.92), longer LOS OR 1.21 (1.06-1.40), defined as >7days, and severe disability defined as discharge mRS>=3 OR 1.31 (1.06-1.63), in patients with ischaemic stroke. Hypochromic microcytic anaemia was associated with 90-day mortality OR 1.90 (1.40-2.58) and a longer LOS OR 1.57 (1.20-2.05) in patients with ischaemic stroke. CONCLUSIONS: Hypochromic microcytic and normochromic normocytic anaemia are associated with differing outcomes in terms of inpatient mortality and post stroke disability. While it is unclear if anaemia per se or another underlying cause is responsible for adverse outcomes, subtype of anaemia appears to be relevant in stroke prognosis. PMID- 29246616 TI - NEDA treatment target? No evident disease activity as an actionable outcome in practice. AB - "No evident disease activity" (NEDA) is a proposed measure of disease activity free status in multiple sclerosis (MS) that is typically defined as absence of relapses, disability progression, and MRI activity over a defined time period. NEDA is increasingly reported in randomized controlled trials of MS disease modifying therapies where it has some perceived advantages over outcomes such as annualized relapse rate. NEDA has also been proposed as a treatment goal in clinical care. At this point, the long-term implications of early NEDA remain largely unknown. We review current NEDA definitions, use in clinical trials, and its prospects for routine use as an actionable treatment target in clinical practice. PMID- 29246617 TI - Multiple simultaneous intracerebral hemorrhages: Clinical presentations and risk factors. AB - OBJECTIVE: Multiple simultaneous intracerebral hemorrhages (MSICH) are a rare clinical entity. The mechanism and risk factors have yet to be elucidated. The purpose of this study was to clarify clinical presentations and risk factors of MSICH compared with solitary intracerebral hemorrhages (ICH). PATIENTS AND METHODS: Medical records of 313 consecutive patients with ICH admitted to our institution between April 2011 and September 2014 were retrospectively reviewed. Seventeen cases of MSICH were identified, and 10 clinical and neuroimaging variables were compared between MSICH cases and solitary ICH cases using the unpaired t-test, chi-square test, and multiple logistic regression analysis. RESULTS: There were significant differences in size between larger hematomas (mean 59.2+/-69.1mL) and smaller hematomas (mean 1.7+/-2.1mL) in patients with MSICH (p=0.001). Larger hematoma volume was the only independent risk factor for MSICH in multiple logistic regression analysis (OR=1.012, 95%CI 1.004-1.021, p=0.004). CONCLUSIONS: Patients with MSICH have clinical characteristics and outcomes similar to patients with solitary ICH. They present with two significantly different hematoma sizes, both of which are significantly larger than patients with solitary ICH, suggesting that a larger hematoma can trigger smaller hematomas. A future prospective study with a larger number of patients will explore the precise mechanism of this rare entity. PMID- 29246618 TI - SPG5 siblings with different phenotypes showing reduction of 27 hydroxycholesterol after simvastatin-ezetimibe treatment. PMID- 29246619 TI - Symptomatic, non-infectious, non-hemorrhagic edema after subthalamic nucleus deep brain stimulation surgery for Parkinson's disease. AB - OBJECT: We review our experience with Parkinson's disease (PD) patients who underwent subthalamic nucleus (STN) deep brain stimulation (DBS) and then developed noninfectious, non-hemorrhagic, delayed, symptomatic brain edema associated with a DBS lead. METHODS: All PD patients who underwent STN DBS lead implantation from 2007 to 2015 were included. The same neurosurgeon performed all surgeries, typically in staged fashion, utilizing single pass microelectrode recordings (MER) within a stereotactic frame. A brain CT was obtained in recovery and subsequently if indicated. RESULTS: There were 189 patients who underwent 363 STN lead implantations among which 35 (9.6%) represent re-implantations of removed leads in 28 (14.8%) patients. Among the 363 STN leads implanted, there were 12 (3.3%) cases of delayed symptomatic edema associated with a DBS lead involving 10 (5.3%) of the patients studied. Of the 328 leads representing first time operations, there were 9 (2.1%) cases of delayed symptomatic edema in 7 (3.7%) patients, one of whom (14.3%) presented with seizures. For lead re implantations, there were 3 (8.6%) cases of the brain edema in 3 (10.7%) patients; all presenting with seizures. For the 35 re-implantations, the trajectory to target was the same or very similar via the same burr hole as prior surgery in 17 (48.6%); 3 (17.6%) of whom developed edema. There was no case of brain edema in the 18 re-operated cases using a different burr opening. Edema patients were treated with a course of anticonvulsant medication and dexamethasone. Lead-associated edema resolved over generally a 4 to 6-week course. CONCLUSIONS: Noninfectious, non-hemorrhagic, delayed, symptomatic brain edema occurs in approximately 3% of implanted leads and is more common in re implantations (9%) compared to new implantations (2%). In re-implantations, the edema is more common when the same trajectory is used (18%) compared to a new trajectory (0%). The edema generally occurs 3 to 8 days after implantation, although immediate post-op CT is normal and seizures are a common presenting feature. PMID- 29246620 TI - Discrepant relationships between admission blood pressure and mortality in different stroke subtypes. AB - The relationship between blood pressure(BP) and clinical outcome in patients with acute stroke is still controversial. The present study aimed to elucidate the impact of admission blood pressure on mortality in patients with acute stroke of different subtypes. Data were from ChinaQUEST (QUality Evaluation of Stroke Care and Treatment), a multicenter, prospective hospital registry study in 37 cities across China. A total of 6427 patients were admitted within 24h of onset and after following up for 12months, 5501 were included in the final analysis. Multivariate Cox regression model were used in data analysis. A "U-curve shaped" relationship was observed between admission systolic or diastolic BP and mortality at 12months in the overall study population. Compared to first quartile, the Hazard ratio (HR) for the systolic BP of top quartile was 1.444 (95%CI 1.854-1.636), while the HR was 0.692 (95%CI 0.802-0.930) for the second quartile. Similar associations were observed when we applied admission diastolic BP. In subgroup analysis, the U-shaped effect was remained only in patients with intracranial hemorrhage (ICH). The HR for the systolic BP of top quartile was 2.274 (95%CI 1.878-2.755), while the HR was 0.751 (95%CI 0.571-0.986) for the second quartile. Moreover, admission diastolic BP of top quartile was significantly associated with elevated risk of death for patients with ischemic stroke caused by small vessel diseases (LACI)(HR 1.470; CI 1.040-2.078). In addition, we found a heterogeneity of the admission BP distribution among different subtypes, which may explain the "U-curve" effect. PMID- 29246622 TI - Editor's update and selected articles from the Journal of the Neurological Sciences. PMID- 29246621 TI - Association between increased N-terminal pro-brain natriuretic peptide level and poor clinical outcomes after acute ischemic stroke. AB - BACKGROUND AND PURPOSE: N-terminal pro-brain natriuretic peptide (NT-proBNP) has been shown to be associated with the prognosis of cardiovascular diseases and NT proBNP level is elevated in patients with acute ischemic stroke. However, the association between NT-proBNP and poor prognosis after ischemic stroke is still uncertain. The aim of this study was to examine whether serum NT-proBNP is associated with global clinical outcomes in a large cohort of patients with acute ischemic stroke. METHODS: Baseline serum NT-proBNP level was measured in a subset of 3126 patients with acute ischemic stroke, and the patients were followed up to assess their clinical outcomes within 1year after the stroke. Cox proportional hazard models and logistic regression models were used to assess the effects of NT-proBNP on the primary outcome (composite outcome of death and vascular events) and poor functional outcomes. RESULTS: During 1year of follow-up, 278 (9.0%) patients with a primary outcome and 685 (22.1%) patients with a poor functional outcome were identified. The cumulative incidence of primary outcomes increased across serum NT-proBNP quartiles (log-rank P<0.001). Hazard ratios (95% confidence interval) of the highest quartile compared with the lowest quartile were 1.47 (1.01-2.13) for the primary outcome, 1.79 (1.07-2.98) for death after multivariable adjustment. In addition, serum NT-proBNP was also associated with poor functional outcomes (odds ratio, 1.47; 95% confidence interval, 1.11-1.94; Ptrend=0.008). CONCLUSIONS: This study showed that high NT-proBNP levels increased the risk of a composite outcome of death and vascular events and poor functional outcomes at 1year after stroke onset among ischemic stroke patients with elevated blood pressure, suggesting that NT-proBNP might be a potential prognostic factor for ischemic stroke. PMID- 29246623 TI - Immune-mediated rippling muscle disease in a patient with treated hypothyroidism. PMID- 29246624 TI - LRIG proteins in glioma: Functional roles, molecular mechanisms, and potential clinical implications. AB - Gliomas are the most common intracranial tumors of the nervous system. These tumors are characterized by unlimited cell proliferation and excessive invasiveness. Despite the advances in diagnostic imaging, microneurosurgical techniques, radiation therapy, and chemotherapy, significant increases in the progression free survival of glioma patients have not been achieved. Improvements in our understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways may impact both the diagnosis and the treatment strategies for patients with gliomas. Growth factors and their corresponding receptor tyrosine kinases are associated with oncogenesis and development of tumors in numerous human cancer types, including glioma. Leucine rich repeats and immunoglobulin-like domains (LRIG) are integral membrane proteins which contain three vertebrate members including LRIG1, LRIG2 and LRIG3. They mainly function as regulators of growth factor signaling. Specifically, LRIG1 has been identified as a tumor suppressor in human cancers. In contrast, LRIG2 appears to function as a tumor promoter, while LRIG3 appears to have a function similar to that of LRIG1. In the present review, we summarize the functional roles, molecular mechanisms, and clinical perspectives of LRIG proteins in gliomas and propose that these proteins may be useful in the future as targets for treatment and prognostication in glioma patients. PMID- 29246625 TI - Clinical and genetic diversity of nemaline myopathy from a single neuromuscular center in Korea. AB - Nemaline myopathy (NM), the most common of the congenital myopathies, is caused by various genetic mutations. In this study, we attempted to identify the causative mutations of NM and to reveal any specific genotype-phenotype relationship in Korean patients with this disease. We investigated the clinical features and genotypes in 15 pathologically diagnosed NM patients, using whole exome sequencing (WES) combined with targeted sequencing and array-based comparative genomic hybridization. This strategy revealed pathogenic causative mutations in seven patients (46.7%), among whom mutations in the nebulin gene (NEB) were the most frequent (5 patients, 33.3%). Copy number variation (CNV) abnormality in NEB was not observed in any of our patients. In those with NEB associated NM, the clinical spectrum was highly variable regardless of the mutation type. However, the majority of patients showing anterior lower leg weakness were associated with mutations located between NEB exons 166 and 177. We concluded that the combination of WES and targeted Sanger sequencing is an effective strategy for analyzing genotypes in patients with NM, and that CNV in NEB may not be a frequent cause of this disease among Koreans. PMID- 29246626 TI - Re: Apraclonidine in the treatment of ptosis. PMID- 29246627 TI - Common and specific risk factors for ischemic stroke in elderly: Differences based on type of ischemic stroke and aging; methodological issues. PMID- 29246629 TI - One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan. AB - BACKGROUND: Epidemiological studies have repeatedly reported that increased serum urate level is associated with a slower progress of Parkinson's disease (PD). The urate precursor, inosine, raises the serum urate level and is therefore a candidate for a disease modifying treatment. However, an elevated serum urate level is a risk factor for gout, urolithiasis, and cardiovascular diseases. Although there have been previous clinical studies, the use of inosine in a clinical setting is still limited, and its safety is unclear, especially in an Asian population. METHODS: We conducted a single-arm, single-center clinical trial to assess the safety of inosine for PD patients with relatively low urate levels. After informed consent, 10 subjects were orally administered inosine to maintain a target urate level between 6.0mg/dl and 8.0mg/dl for one year. All adverse effects were recorded and categorized by severity. Also, the efficacy of using inosine to raise the serum urate level was reported. RESULTS: We did not observe any adverse events requiring termination or reduction of the study drug, although uric acid crystalluria was transiently observed in a single subject. An inosine dosage of 1070 (SD=501) mg/day significantly raises the urate level from 3.5 (0.84)mg/dl at baseline to 6.68 (1.11)mg/dl at the 52nd week. CONCLUSIONS: Inosine was safely used for one year and effectively raised urate levels in a small group of subjects. Our study is the first report to use inosine for patients with PD in an Asian population. PMID- 29246628 TI - Anti-NMDA receptor encephalitis due to large-cell neuroendocrine carcinoma of the uterus. AB - A 44-year-old woman presented with a large-cell neuroendocrine carcinoma and uterine endometrioid carcinoma with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. Following the diagnosis of uterine cancer, the patient suddenly developed psychosis with abnormal behaviors, delusions, irritability, and forgetfulness. The cerebrospinal fluid tested positive for anti-NMDAR antibodies (encoding the NR1 subunit). The patient was diagnosed with paraneoplastic limbic encephalitis due to uterine cancer. Histology of multiple abdominal metastatic samples revealed a neuroendocrine tumor. Her consciousness improved temporarily after tumor resection and comprehensive immunomodulatory therapy. On day 104 after admission, the patient died of multiple organ failure. The autopsy revealed a perivascular infiltration of inflammatory cells in the amygdala and NMDAR positive cells in the primary uterine cancer. Our findings demonstrated that neuroendocrine tumors can induce anti-NMDAR encephalitis, which is consistent with three previous reports. A comprehensive treatment with resection of the carcinoma, immunoglobulins, and plasma exchange can induce a partial improvement of the symptoms. PMID- 29246630 TI - Expression of RGMb in brain tissue of MCAO rats and its relationship with axonal regeneration. AB - OBJECTIVE: To investigate the changes in the expression of repulsive guidance molecule b (RGMb) in brain tissue of rats with ischemic cerebral infarction and determine its relationship with axonal regeneration, synapse remodeling and magnetic resonance imaging (MRI) parameters with magnetic resonance diffusion tensor imaging as the dynamic continuous monitoring method in vivo, so as to explore the pathophysiological mechanism of the occurrence, development and prognosis of cerebral infarction. METHODS: Ninety Sprague-Dawley (SD) rats were randomly divided into six groups, namely control group, middle cerebral artery occlusion (MCAO) 12-h group, MCAO 24-h group, MCAO 48-h group, MCAO 7-day group and MCAO 10-day group, each of 15 animals. Rats were examined by head MRI at corresponding time points, followed by measurement of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values. Subsequently, brain tissues were taken to detect the expression of RGMb, axonal regeneration and synapse remodeling. RESULTS: After infarction, ADC and FA values of the infarcted core area were lower in rats of each group compared to those in rats of normal group (P<0.05), which was lowest at 12h. The positive expressions of RGMb and synaptophysin were continuously increased from the 12th hour after operation, which reached a peak at 48h; while axonas was gradually reduced after operation in each group, which revealed the most obvious damage in the MCAO 24-h group. The protein expression of RGMb was negatively correlated with MRI parameters and axon growth. CONCLUSION: After supratentorial cerebral infarction, the expressions of RGMb and synaptophysin were up-regulated in rats, neurofilament protein (NF-200) expression was decreased, and MRI parameters (ADC and FA values) were reduced, indicating that RGMb protein may be involved in the regeneration and remodeling of axons and synapses, and exert an important role in pathophysiological processes such as nerve regeneration disturbance and neuron apoptosis after cerebral ischemia injury. In vivo MRI can be a noninvasive technique to monitor the areas of cerebral infarction and the recovery of neurological function. PMID- 29246631 TI - Assessment of Percheron infarction in images and clinical findings. AB - OBJECTIVE: To assess the imaging and clinical features of patients with an artery of Percheron infarction comprehensively. METHODS: Of 6539 patients with a first ever stroke, 18 patients with a Percheron infarction were enrolled, and their images and clinical data were retrospectively investigated. RESULTS: All patients underwent neurological intensive care unit (NICU) management. The initial symptom of a Percheron infarction included dizziness, transient blurred vision, double vision, barylalia, cerebellar ataxia, drowsiness, and a coma. Subsequent symptoms differed for the three subtypes of Percheron infarction, and the three subtypes are bilateral paramedian thalamic infarction with midbrain involvement, bilateral paramedian thalamic infarction without midbrain involvement, and bilateral paramedian and anterior thalamic infarction without midbrain involvement. Between favorable and unfavorable outcomes, there was no significant difference in the following patient characteristics including current smoking, hypertension, diabetes, hyperlipidemia, hyperhomocysteinemia, heart disease, time from stroke onset to medical care, and Glasgow Coma Scale score at admission (P>0.05), but there were significant differences in both the National Institute of Health stroke scale (NIHSS) and Acute Physiology and Chronic Health Evaluation II (APACHE II) score at admission (P<0.05). If the midbrain or larger infarct volume was involved or hemorrhagic transformation occurred, outcomes of a Percheron infarction were frequently unfavorable. CONCLUSION: The clinical presentation of patients with a Percheron infarction is variable; early recognition, image performance, NICU management, NIHSS, and APACHE II score would help in diagnosis, evaluation, and treatment. PMID- 29246632 TI - Different neurologic outcomes of myasthenia gravis with thymic hyperplasia and thymoma after extended thymectomy: A single center experience. AB - This study aimed to reveal the clinical course and outcomes of myasthenia gravis (MG) in patients with thymic lymphoid hyperplasia and thymoma undergoing extended thymectomy and to identify the clinical prognostic factors of remission for MG. In total, 73 patients undergoing extended thymectomy were divided into two groups: group A with lymphoid hyperplasia (n=39) and group B with thymoma (n=34). According to the MG Foundation of America (MGFA) post-intervention status, the primary endpoint was a composite measure defined as achievement of complete stable remission (CSR), pharmacologic remission (PR), minimal manifestations (MM) or improvement (IM). The secondary endpoint was CSR. The cumulative probabilities of reaching the primary endpoint were 71.8% in group A and 85.3% in group B (p=0.164), respectively. Using Kaplan-Meier survival analysis, the probability of reaching the primary endpoint in group B was remarkably greater than group A (p=0.036). Cox multivariate analysis indicated that pre-operative MGFA class I (HR: 3.019, 95% CI: 1.084-8.410) and MGFA II (2.665, 95% CI: 1.033-6.873) compared to MGFA III and presence of thymoma (HR: 2.229, 95% CI: 1.079-4.606), showed the most consistent association with remission of MG after thymectomy. Finally, thymic lymphoid hyperplasia and severe symptoms may negatively affect prognosis of MG following thymectomy. PMID- 29246633 TI - Pseudotumor cerebri syndrome without cerebral venous sinus thrombosis in Behcet's disease. PMID- 29246634 TI - Genetics of bi-component leukocidin and drug resistance in nasal and clinical Staphylococcus aureus in Lagos, Nigeria. AB - BACKGROUND: Resistant and virulent Staphylococcus aureus is a global public health challenge. Staphylococcal Bi-component leukotoxins are cytolytic to immune cells and evolve to disarm the innate immunity during infections, hence the severity of the disease. OBJECTIVE: We studied drug resistance profile and the occurrence of bi-component leukocidin in clinical and nasal S. aureus in Lagos, Nigeria. METHOD: Ninety-two S. aureus (70 clinical and 22 nasal) strains were characterized by conventional and molecular methods. RESULT: Of the resistance profiles generated, no isolate was resistant to fosfomycin, fusidic acid, teicoplanin, vancomycin, linezolid, mupirocin, nitrofurantoin and tigecycline. Twelve MRSA carrying staphylococcal cassette chromosome mecA gene types I, III, and IV elements were identified only in the clinical samples and type I dominated. High rates of lukE/D (100% among MRSA) and lukPV (dominated MSSA) were recorded among the nasal and clinical isolates. Staphylococcus aureus harboring only lukE/D (from clinical & colonizing MSSA) and combined lukE/D and lukPV (mostly from clinical MSSA, colonizing MSSA and clinical MRSA) toxins were found. CONCLUSION: Although, mecA resistant genes were found only among clinical MRSA, the occurrence of other bi-component leukocidin genes in a large proportion among the isolates from both community and clinical settings is a major concern. The need for effective resistance and virulence factor surveillance, re-enforcement of antibiotic stewardship and good infection control policy, to prevent dissemination of epidemic strains is highlighted. PMID- 29246635 TI - The evaluation of immunogenic impact of selected bacterial, recombinant Hsp60 antigens in DBA/2J mice. AB - Heat Shock Proteins (HSP) are highly conserved proteins that are widely spread throughout all organisms. They function in the cytoplasm as chaperones; however, they could be expressed on the cell surface. It has been shown that Hsp60 obtained from gram-negative bacteria are able to stimulate cells of the acquired and innate immune system. The aim of this study was the evaluation of the immunogenic properties of recombinant Hsp60 proteins derived from four common pathogenic bacteria: Escherichia coli, Histophilus somni, Pasteurella multocida and Salmonella Enteritidis. The analysis of the humoral immune response in DBA/2J mice hyperimmunized with selected rHsp60 revealed high levels of IgG rHsp60 antibody with the predominance of the IgG1 subclass, in the reaction with both homologous and heterologous antigens. The presence of IgG2a and IgG2b was also observed; however, no antibodies of subclass IgG3 were detected. The comparison of plasma IgG antibody reactivity of mice immunized with two different doses of rHsp60 (10/20 MUg) showed that the lower dose was sufficient to induce a strong humoral response. The reactivity of the IgG rHsp60-antibody with whole bacterial cells showed a significantly higher reaction with H. somni compared with other pathogens. It was demonstrated that the addition of all rHsp60 with polymyxin B to the culture medium stimulated splenocytes isolated from hyperimmunized mice to release IL-1beta and IL-6. As a strong stimulator of the immune system, bacterial origin Hsp60 seems to be an interesting potential component of subunit vaccines aimed at the development of protection for animals during infections caused by gram-negative bacteria. PMID- 29246636 TI - Total Laparoscopic Hysterectomy with Pelvic/Aortic Lymph Node Dissection for Endometrial Cancer Using Passive Instrument Positioners: A Retrospective Case Control Series. AB - STUDY OBJECTIVE: To investigate the influence of the use of passive instrument positioners (PIPs) on laparoscopic operative outcomes for endometrial cancer relative to other independent variables. DESIGN: Retrospective case-controlled study (Canadian Task Force classification II-2). SETTING: Laparoscopies performed by the author in multiple community hospitals. PATIENTS: A total of 297 consecutive patients between December 2009 and October 2016 with clinically isolated endometrial cancer or retroperitoneal lymphadenopathy on imaging studies. INTERVENTIONS: Total laparoscopic hysterectomy with bilateral salpingo oophorectomy and pelvic/aortic lymph node dissection using passive instrument positioners to secure the laparoscope (PIP group) and using instruments providing exposure and historical control by hand control of all instruments (HC group). MEASUREMENTS AND MAIN RESULTS: The overall group mean age was 63.2 years (range, 32.4-90.9 years), and patient characteristics were equivalent in the 2 groups. In the PIP group, 1 procedure was converted to a laparotomy (0.5%), and in the HC group, 6 procedures were converted (5.4%; p = .008). The mean operative time was 140.1 minutes for the PIP group and 153.8 minutes for the HC group (p < .001). The mean length of hospital stay was 44.8 hours for the PIP group and 58.6 hours for the HC group (p < .001). Multivariate analysis confirmed that study group (PIP vs HC; p = .014) and the presence vs absence of metastatic disease (p = .001) influenced conversion; study group (PIP vs HC; p < .001), body mass index (p < .001), past surgical history (p = .010), and assistant training (p = .011) influenced operative time; and study group (PIP vs HC; p < .001), Eastern Cooperative Oncology Group performance status (p < .001), and operative time (p = .051) influenced hospital stay. CONCLUSION: For clinically localized endometrial cancer managed laparoscopically, the use of PIPs reduces conversions, operative time, and hospital stay. PMID- 29246637 TI - Usefulness of midregional pro-adrenomedullin as a marker of organ damage and predictor of mortality in patients with sepsis. AB - BACKGROUND: Midregional proadrenomedullin (MR-proADM) is a prognostic biomarker in patients with community-acquired pneumonia (CAP) and sepsis. In this paper, we examined the ability of MR-proADM to predict organ damage and long-term mortality in sepsis patients, compared to that of procalcitonin, C-reactive protein and lactate. METHODS: This was a prospective observational cohort, enrolling severe sepsis or septic shock patients admitted to internal service department. The association between biomarkers and 90-day mortality was assessed by Cox regression analysis and Kaplan-Meier curves. The accuracy of biomarkers for mortality was determined by area under the receiver operating characteristic curve (AUROC) analysis. RESULTS: A total of 148 patients with severe sepsis, according to the criteria of the campaign to survive sepsis, were enrolled. Eighty-five (57.4%) had sepsis according to the new criteria of Sepsis-3. MR proADM showed the best AUROC to predict sepsis as defined by the Sepsis-3 criteria (AUROC of 0.771, 95% CI 0.692-0.850, p <0.001) and was the only marker independently associated with Sepsis-3 criteria (OR = 4.78, 95% CI 2.25-10.14; p < 0.001) in multivariate analysis. MR-proADM was the biomarker with the best AUROC to predict mortality in 90 days (AUROC of 0.731, CI 95% 0.612-0.850, p <0.001) and was the only marker that kept its independence [hazard ratio (HR) of 1.4, 95% CI 1.2-1.64, p <0.001] in multivariate analysis. The cut-off point of MR proADM of 1.8 nmol/L (HR of 4.65, 95% CI 6.79-10.1, p < 0.001) was the one that had greater discriminative capacity to predict 90 days mortality. All patients with MR-proADM concentrations <=0.60 nmol/L survived up to 90 days. In patients with SOFA <= 6, the addition of MR-proADM to SOFA score increased the ability of SOFA to identify non-survivors, AUROC of 0.65 (CI 95% 0.537-0.764) and AUROC of 0.700 (CI 95% 0.594-0.800), respectively (p < 0.05 for both). CONCLUSIONS: MR proADM is a good biomarker in the early identification of high risk septic patients and may contribute to improve the predictive capacity of SOFA scale, especially when scores are low. PMID- 29246638 TI - Genetic diversity and dissemination pathways of highly pathogenic H5N6 avian influenza viruses from birds in Southwestern China along the East Asian Australian migration flyway. PMID- 29246639 TI - Prevalence and Risk Factors of Type 2 Diabetes in Major Depression: A Study on 703 Individuals Referred for Sleep Examinations. AB - BACKGROUND: Several studies have investigated the prevalence and risk factors of depression in individuals with type 2 diabetes. However, few studies have investigated the prevalence and risk factors for type 2 diabetes in major depression. OBJECTIVE: The aim of this study was to examine the prevalence and risk factors of type 2 diabetes in a large sample of individuals with major depression. METHODS: Data from 703 individuals with major depression recruited from the research database of the sleep laboratory of the Erasme Hospital were analysed. Only individuals with a diagnosis of type 2 diabetes according to the diagnostic criteria of the American Diabetes Association were included in the diabetes group. Logistic regression analyses were conducted to examine clinical and demographic risk factors of type 2 diabetes in major depression. RESULTS: The prevalence of type 2 diabetes in major depression is 21.2%. Multivariate logistic regression analysis revealed that male sex, high blood pressure, hypertriglyceridemia, BMI >=30kg/m2, age >=50 years, sleep duration <6.5 hours, C reactive protein >=4.5mg/L, Beck Depression Inventory >12, and apnea-hypopnea index >=5/h were significant risk factors of type 2 diabetes in major depression. CONCLUSION: Type 2 diabetes is a common condition in major depression. In this subpopulation, most of the risk factors for type 2 diabetes are reversible, which justifies better prevention and management of this disorder to avoid its negative consequences. PMID- 29246640 TI - Computational fluid dynamic comparison between patch-based and primary closure techniques after carotid endarterectomy. AB - OBJECTIVE: The aim of the study was to provide, by means of computational fluid dynamics, a comparative analysis after carotid endarterectomy (CEA) between patch graft (PG) and primary closure (PC) techniques performed in real carotid geometries to identify disturbed flow conditions potentially involved in the development of restenosis. METHODS: Eight carotid geometries in seven asymptomatic patients who underwent CEA were analyzed. In six cases (A-F), CEA was performed using PG closure; in two cases (G and H), PC was performed. Three dimensional carotid geometries, derived from postoperative magnetic resonance angiography, were reconstructed, and a computational fluid dynamics analysis was performed. A virtual scenario with PC closure was designed in patients in whom PG was originally inserted and vice versa. This allowed us to compare for each patient hemodynamic effects in the PG and PC scenarios in terms of oscillatory shear index (OSI) and relative residence time (RRT), considered indicators of disturbed flow. RESULTS: For the six original PG cases, the mean averaged-in space OSI was 0.07 +/- 0.01 for PG and 0.03 +/- 0.02 for virtual-PC (difference, 0.04 +/- 0.01; P = .0016). The mean of the percentage of area (%A) with OSI >0.2 resulted in 10.08% +/- 3.38% for PG and 3.80% +/- 3.22% for virtual-PC (difference, 6.28 +/- 1.91; P = .008). For the same cases, the mean of the averaged-in-space RRT resulted in 5.48 +/- 3.40 1/Pa for PG and 2.62 +/- 1.12 1/Pa for virtual-PC (difference, 2.87 +/- 1.46; P = .097). The mean of %A RRT >4.0 1/Pa resulted in 26.53% +/- 12.98% for PG and 9.95% +/- 6.53% for virtual-PC (difference, 16.58 +/- 5.93; P = .025). For the two original PC cases, the averaged-in-space OSIs were 0.02 and 0.04 for PC and 0.03 and 0.02 for virtual PG; the %A OSIs >0.2 were 0.9% and 7.6% for PC and 3.0% and 2.2% for virtual-PG; the averaged-in-space RRTs were 1.8 and 2.0 1/Pa for PC and 2.9 and 1.9 1/Pa for virtual-PG; the %A RRTs >4.0 1/Pa were 6.8% and 9.8% for PC and 9.4% and 6.2% for virtual-PG. These results revealed generally higher disturbed flows in the PG configurations with respect to the PC ones. CONCLUSIONS: OSI and RRT values were generally higher in PG cases with respect to PC, especially for high carotids or when the arteriotomy is mainly at the bulb region. Thus, an elective use of patch should be considered to prevent disturbed flows. PMID- 29246641 TI - Comments on "Solid pseudopapillary neoplasm of the pancreas: Management and long term outcome". PMID- 29246642 TI - Reply to Georgios Papadopoulos, Charalampos Fragkoulis, and Konstantinos Ntoumas' Letter to the Editor re: Bimal Bhindi, Igor Frank, Ross J. Mason, et al. Oncologic Outcomes for Patients with Residual Cancer at Cystectomy Following Neoadjuvant Chemotherapy: A Pathologic Stage-matched Analysis. Eur Urol 2017;72:660-4. PMID- 29246643 TI - Tony Capon: the world's first professor of planetary health. PMID- 29246644 TI - Docetaxel-mediated autophagy promotes chemoresistance in castration-resistant prostate cancer cells by inhibiting STAT3. AB - Signal transducer and activator of transcription (STAT)3 expression is correlated with neoplasm growth, metastasis, and prognosis; it has also been implicated in the regulation of autophagy, which may in turn contribute to tumor chemoresistance. However, it is unknown whether STAT3 is involved in cancer cell survival in response to chemotherapy. In this study, we show that autophagy is triggered during chemotherapy and that inhibiting autophagy increased chemosensitivity of castration-resistant prostate cancer (CRPC) cells. Meanwhile, docetaxel induced autophagy was inhibited by STAT3 activation, which increased mitochondrial damage and decreased CRPC cell viability. These results suggest that STAT3 contributes to CRPC cell survival and chemoresistance by modulating autophagy. PMID- 29246645 TI - Therapeutic potential of gambogic acid, a caged xanthone, to target cancer. AB - Natural compounds have enormous biological and clinical activity against dreadful diseases such as cancer, as well as cardiovascular and neurodegenerative disorders. In spite of the widespread research carried out in the field of cancer therapeutics, cancer is one of the most prevalent diseases with no perfect treatment till date. Adverse side effects and the development of chemoresistance are the imperative limiting factors associated with conventional chemotherapeutics. For this reason, there is an urgent need to find compounds that are highly safe and efficacious for the prevention and treatment of cancer. Gambogic acid (GA) is a xanthone structure extracted from the dry, brownish gamboge resin secreted from the Garcinia hanburyi tree in Southeast Asia and has inherent anti-cancer properties. In this review, the molecular mechanisms underlying the targets of GA that are liable for its effective anti-cancer activity are discussed that reveal the potential of GA as a pertinent candidate that can be appropriately developed and designed into a capable anti-cancer drug. PMID- 29246646 TI - The dialkyl resorcinol stemphol disrupts calcium homeostasis to trigger programmed immunogenic necrosis in cancer. AB - Stemphol (STP) is a novel druggable phytotoxin triggering mixed apoptotic and non apoptotic necrotic-like cell death in human acute myeloid leukemia (AML). Use of several chemical inhibitors highlighted that STP-induced non-canonical programmed cell death was Ca2+-dependent but independent of caspases, poly (ADP-ribose) polymerase-1, cathepsin, or calpains. Similar to thapsigargin, STP led to increased cytosolic Ca2+ levels and computational docking confirmed binding of STP within the thapsigargin binding pocket of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA). Moreover, the inositol 1,4,5-trisphosphate receptor is implicated in STP-modulated cytosolic Ca2+ accumulation leading to ER stress and mitochondrial swelling associated with collapsed cristae as observed by electron microscopy. Confocal fluorescent microscopy allowed identifying mitochondrial Ca2+ overload as initiator of STP-induced cell death insensitive to necrostatin-1 or cycloheximide. Finally, we observed that STP-induced necrosis is dependent of mitochondrial permeability transition pore (mPTP) opening. Importantly, the translational immunogenic potential of STP was validated by HMGB1 release of STP treated AML patient cells. STP reduced colony and in vivo tumor forming potential and impaired the development of AML patient-derived xenografts in zebrafish. PMID- 29246647 TI - Anticancer activity of osmium(VI) nitrido complexes in patient-derived glioblastoma initiating cells and in vivo mouse models. AB - Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor with a median patient survival of less than two years, even with the optimal standard of care, namely, surgical resection followed by radiotherapy with adjuvant temozolomide chemotherapy. Long-term survival is extremely rare and there is a tremendous need for novel GBM therapies. Following our prior reports on the anticancer activity of osmium(VI) nitrido compounds and their effectiveness against cancer initiating cells, we investigated the efficacy of Os(VI) on GBM initiating cells in vitro and in vivo. Conventional MTT and 3D cytotoxicity assays revealed that patient-derived GBM models were sensitive to cisplatin, TMZ, and two Os(IV) derivatives. Rapid cell death occurred at low micromolar concentrations of the Os(IV) compounds. Cell cycle analysis, Os uptake studies, and cellular distribution experiments provided further insight into the anticancer properties of these compounds, indicating differential uptake for both compounds and a modest G2/M arrest after treatment. Moreover, in vivo experiments showed a significant increase in survival after a single intracranial chemotherapeutic injection, results that warrant further studies using this approach. PMID- 29246649 TI - Utility of routine evaluation of sterility of cellular therapy products with or without extensive manipulation: Best practices and clinical significance. AB - BACKGROUND: We analyzed the results of routine sterility testing performed in our center over the last 10 years, in the context both hematopoietic stem cell transplantation (HSCT) and Advanced Therapeutic Medicinal Products (ATMPs). METHODS: For sterility tests 14-day cultures were performed in culture media detecting aerobic and anaerobic microorganisms. RESULTS: In this study, 22/1643 (1.3%) of apheretic products for autologous or allogeneic HSCT were contaminated, whereas 14/73 bone marrow (BM) harvests (17.8%) were positive. In 22 cases, the contaminated HSCs were infused to patients, but there was no evidence of any adverse impact of contamination on the hematologic engraftment or on infections. Indeed none of the five positive hemocultures detected in patients following infusion could be linked to the contaminated stem cell product. Our Cell Factory also generated 286 ATMPs in good manufacturing practice (GMP) conditions since 2007 and all final products were sterile. In three cases of mesenchymal stromal cell expansions, the starting BM harvests were contaminated, but the cell products at the end of expansion were sterile, presumably thanks to the presence of an antibiotic in the culture medium. DISCUSSION: The decreased rate of contamination of cell harvests observed with time suggests that routine sterility testing and communication of the results to the collecting centers may improve clinical practices. Furthermore, we recommend the use of antibiotics in the medium for ATMP expansion, to decrease the likelihood of expanding microorganisms within clean rooms. Finally we discuss the costs of sterility testing of ATMPs by GMP-approved external laboratories. PMID- 29246648 TI - Human mesenchymal stromal cell therapy for damaged cochlea repair in nod-scid mice deafened with kanamycin. AB - BACKGROUND: Kanamycin, mainly used in the treatment of drug-resistant tuberculosis, is known to cause irreversible hearing loss. Using the xeno transplant model, we compared both in vitro and in vivo characteristics of human mesenchymal stromal cells (MSCs) derived from adult tissues, bone marrow (BM MSCs) and adipose tissue (ADSCs). These tissues were selected for their availability, in vitro multipotency and regenerative potential in vivo in kanamycin-deafened nod-scid mice. METHODS: MSCs were isolated from informed donors and expanded ex vivo. We evaluated their proliferation capacity in vitro using the hexosaminidase assay, the phenotypic profile using flow-cytometry of a panel of surface antigens, the osteogenic potential using alkaline phosphatase activity and the adipogenic potential using oil-red-O staining. MSCs were intravenously injected in deafened mice and cochleae, liver, spleen and kidney were sampled 7 and 30 days after transplantation. The dissected organs were analyzed using lectin histochemistry, immunohistochemistry, polymerase chain reaction (PCR) and dual color fluorescence in situ hybridization (DC-FISH). RESULTS: MSCs showed similar in vitro characteristics, but ADSCs appeared to be more efficient after prolonged expansion. Both cell types engrafted in the cochlea of damaged mice, inducing regeneration of the damaged sensory structures. Several hybrid cells were detected in engrafted tissues. DISCUSSION: BM-MSCs and ADSCs showed in vitro characteristics suitable for tissue regeneration and fused with resident cells in engrafted tissues. The data suggest that paracrine effect is the prevalent mechanism inducing tissue recovery. Overall, BM-MSCs and ADSCs appear to be valuable tools in regenerative medicine for hearing loss recovery. PMID- 29246651 TI - Clinically advancing and promising polymer-based therapeutics. AB - In this review article, we will examine the history of polymers and their evolution from provisional World War II materials to medical therapeutics. To provide a comprehensive look at the current state of polymer-based therapeutics, we will classify technologies according to targeted areas of interest, including central nervous system-based and intraocular-, gastrointestinal-, cardiovascular , dermal-, reproductive-, skeletal-, and neoplastic-based systems. Within each of these areas, we will consider several examples of novel, clinically available polymer-based therapeutics; in addition, this review will also include a discussion of developing therapies, ranging from the in vivo to clinical trial stage, for each targeted area of treatment. Finally, we will emphasize areas of patient care in need of more effective, accessible, and targeted treatment approaches where polymer-based therapeutics may offer potential solutions. PMID- 29246650 TI - PEG hydrogel containing calcium-releasing particles and mesenchymal stromal cells promote vessel maturation. AB - : The use of human mesenchymal stromal cells (hMSC) for treating diseased tissues with poor vascularization has received significant attention, but low cell survival has hampered its translation to the clinic. Bioglasses and glass ceramics have also been suggested as therapeutic agents for stimulating angiogenesis in soft tissues, but these effects need further evaluation in vivo. In this study, calcium-releasing particles and hMSC were combined within a hydrogel to examine their vasculogenic potential in vitro and in vivo. The particles provided sustained calcium release and showed proangiogenic stimulation in a chorioallantoic membrane (CAM) assay. The number of hMSC encapsulated in a degradable RGD-functionalized PEG hydrogel containing particles remained constant over time and IGF-1 release was increased. When implanted in the epidydimal fat pad of immunocompromised mice, this composite material improved cell survival and stimulated vessel formation and maturation. Thus, the combination of hMSC and calcium-releasing glass-ceramics represents a new strategy to achieve vessel stabilization, a key factor in the revascularization of ischemic tissues. STATEMENT OF SIGNIFICANCE: Increasing blood vessel formation in diseased tissues with poor vascularization is a current clinical challenge. Cell therapy using human mesenchymal stem cells has received considerable interest, but low cell survival has hampered its translation to the clinic. Bioglasses and glass ceramics have been explored as therapeutic agents for stimulating angiogenesis in soft tissues, but these effects need further evaluation in vivo. By incorporating both human mesenchymal stem cells and glass-ceramic particles in an implantable hydrogel, this study provides insights into the vasculogenic potential in soft tissues of the combined strategies. Enhancement of vessel formation and maturation supports further investigation of this strategy. PMID- 29246652 TI - The effect of minocycline on indolamine 2, 3 dioxygenase expression and the levels of kynurenic acid and quinolinic acid in LPS-activated primary rat microglia. AB - Microglia are one of the most important neural cells in the central nervous system (CNS) which account for 10-15% of all cells found in the brain. A vast majority of studies indicate that microglia play a pivotal role in protection and damage of the CNS. It has been shown that microglia are mainly scavenger cells but also produce a barrage of factors that are involved in tissue repair and neural regeneration. Several lines of evidence indicate that unregulated activation of microglia in response to either endogenous or exogenous insults results in the production of toxic factors that propagate neuronal injury. Studies demonstrated that the activated microglia secret the excessive amounts of quinolinic acid (QA) and kynurenic acid (KYNA) which are highly toxic for the neuronal cells. In line with this, indolamine 2, 3 dioxygenase (IDO), an enzyme producing KYNA and QA has been shown to be elevated during the inflammation in microglia. In this study, we established primary microglial cell cultures obtained from cerebral cortices of 1-day neonatal Wistar rats. Minocycline (20-60 uM) or its vehicle was added to the culture media 60 min prior to 48 h incubation with lipopolysaccharide (LPS; 10 ng/mL). Using a specific process of adhesion and shaking of the cultured glial cells, a purified culture of approximately 94% enriched microglia was obtained and then, corroborated by immunocytochemistry (ICC). The cell viability after minocycline treatments was assessed using the MTT colorimetric assay. The expression of IDO was evaluated using qPCR. The levels of KYNA and QA were determined using enzyme-linked immunosorbent assay (ELISA). The results showed that minocycline significantly decreased the levels of both KYNA and QA in glia cells exposed to LPS. Moreover, minocycline decreased the expression of IDO in treated LPS-induced microglia. It seems that minocycline has a potent ability to oppress the inflammatory process via the decrease in production of IDO expression and the concentrations of KYNA and QA. PMID- 29246653 TI - Myostatin and adipokines: The role of the metabolically unhealthy obese phenotype in muscle function and aerobic capacity in young adults. AB - Obesity is often associated with metabolic disorders. However, some obese people can present a metabolically healthy phenotype, despite having excessive body fat. Obesity-related cytokines, such as myostatin (MSTN), leptin (LP) and adiponectin (ADP) appear to be key factors for the regulation of muscle and energy metabolism. Our aim was to compare lipid, glucose-insulin and inflammatory (tumor necrosis factor alpha; TNF-alpha) profiles, muscle function, energy expenditure and aerobic capacity between healthy normal-weight (NW) adults, metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) adults; to study the associations between these outcomes and the cytokines MSTN, ADP, LP; and to establish cutoffs for MSTN and LP/ADP to identify the MUHO phenotype. Sixty-one young adults (NW, n = 24; MHO, n = 16; MUHO, n = 21) underwent body composition (body fat -BF and muscle mass - MM), energy expenditure at rest (RER) and aerobic capacity (VO2peak) evaluation, muscle strength and endurance tests and blood profile characterization (glucose-insulin homeostasis and serum MSTN, ADP, LP and TNF-alpha). MHO and MUHO had a BMI >= 30 kg m-2. MUHO was defined as presenting >=3 criteria for metabolic syndrome (NCEP/ATPIII) in association with insulin resistance (HOMA-IR >=3.46). MSTN and LP/ADP were associated with MM, MetS and glucose-insulin profile; MSTN was associated with TNF-alpha and only LP/ADP was associated with parameters of obesity and VO2peak. Neither MSTN nor LP/ADP was associated with muscle functions (p < .05 for adjusted correlations). Both of them were able to discriminate the MUHO phenotype: MSTN [AUC(95%CI) = 0.71(0.55 0.86), MSTN > 517.3 pg/mL] and LP/ADP [AUC(95%CI) = 0.89(0.81-0.97), LP/ADP > 2.14 pg/ng]. In conclusion, high MSTN and LP/ADP are associated with MetS, glucose-insulin homeostasis impairment and low muscle mass. Myostatin is associated with TNF-alpha and leptin-to-adiponectin ratio is associated with body fatness and aerobic capacity. Neither MSTN nor LP/ADP is associated with energy expenditure, muscle strength and endurance. Myostatin and adipokines cutoffs can identify the metabolically unhealthy obese phenotype in young adults with acceptable accuracy. PMID- 29246654 TI - Proinflammatory cytokines in early childhood caries: Salivary analysis in the mother/children pair. AB - HYPOTHESIS: Proinflammatory cytokines are increased in saliva of mother/children pairs with caries. DESIGN: Case-control study involving caries-free children (n = 20) and children with early childhood caries (ECC) (n = 20), and their mothers (n = 40). The maternal variables analyzed were waist circumference (WC), decayed, missing and filled teeth (DMFT) and sugar intake; and in the children were body mass index (BMI), def-t and sugar intake. Salivary levels of VEGF, IL-6 and TNF alpha were analyzed of mother/children pairs. RESULTS: In the mothers, salivary VEGF levels were correlated with DMFT (r = 0.35; p = .03), WC (r = 0.35; p = .02), and sugar intake (r = 0.32; p = .04). Higher salivary IL-6 levels were also correlated with maternal DMFT (r = 0.45; p = .004) and WC (r = 0.32; p = .04). In the children, higher salivary VEGF levels were correlated with higher def-t scores (r = 0.42; p = .008). Children with caries had a 63% higher median salivary VEGF and twofold higher mean IL-6 levels compared to caries-free children. Mothers of children with ECC showed higher mean of salivary IL-6 levels compared to those of children without ECC (p = .03). CONCLUSION: Salivary proinflammatory cytokines are correlated with the severity of caries in the mother-children pair. Obesity and excessive sugar consumption seem to underlie the associations between proinflammatory cytokines and caries in the family environment. PMID- 29246655 TI - The c.305del3 in IL-2 gene in Homonoidea theoretically affects IL-2/IL-2Ralpha interaction as well as lymphocyte homeostasis. AB - Interleukin-2 (IL-2) is a well-known monomeric T-cell growth factor that is produced primarily by activated CD4+ T cells following exposure to antigen. IL-2 structural analysis among primates showed a few polymorphisms as well as a 3 nucleotide deletion (c.305del3) in Hominoidea superfamily including Homo sapiens. On the other hand, the interaction of IL-2 with its alpha subunit of the receptor (IL-2Ralpha) is the first step for assembly of the whole IL-2R and considered as a species-specific phase. Four models of human IL-2, IL-2Ralpha, and their ancestral forms were made and were used for molecular dynamics (MD) simulation. Subsequently, the final structures were docked to each other and finally, the complexes were used for MD simulation. Our results showed that the above mentioned deletion led to weaker interaction of human IL-2 to its receptor relative toancestral IL-2. Association study of lymphocyte counts, as an indicator of IL-2 function, in 78 primate species with or without this deletion showed significant association of this deletion with their overall lymphocyte counts (P < .01). Therefore, it can be suggested that p.81delThr in IL-2 in Hominides superfamily interfered with interaction of IL-2 and IL-2Ralpha and led to overall decrease in lymphocyte counts in this superfamily of primates in comparison with other primates. PMID- 29246656 TI - Trauma care system in China. AB - With the development of modern society, high-energy trauma has become an increasing tendency, which brings a great challenge for trauma care. A well running trauma care system that is composed by pre-hospital and in-hospital care has been proved to decrease the death and disability rate of trauma patients. However, establishment of trauma care system in China is still at the initial stage. Trauma care systems in China and developed countries represented by the United States and Germany are introduced respectively in this article. Construction of regional and hierarchical trauma center, training of specific trauma care team and performance of integrative trauma rescue model are recommended in China. PMID- 29246657 TI - Consequences of restricted STI testing for young heterosexuals in the Netherlands on test costs and QALY losses. AB - BACKGROUND: Due to rising costs caused by increasing demand for sexually transmitted infection (STI) care, the Dutch government changed the funding of STI clinics. In 2015, a more restrictive testing policy was introduced with syphilis and HIV tests only on indication for younger, heterosexual clients. We evaluated intended savings and missed syphilis and/or HIV infections and explored efficiency of possible test policies. METHODS: Using surveillance data from 2011 to 2013 with extensive testing for all, we estimated effects of restrictive testing on test costs, number of infections missed, costs per Quality Adjusted Life Year (QALY) lost, and calculated the net monetary benefit from a government perspective. RESULTS: The 2015 policy led to estimated savings of ?1.1 million, while missing approximately three HIV infections and seven syphilis infections annually. Savings were ?435,000/QALY lost. If testing second-generation immigrants for syphilis and HIV, savings rose to ?525,000/QALY lost. Offering an HIV test when diagnosed with chlamydia or gonorrhoea savings were ?568,000/QALY lost. In a sensitivity analysis, the willingness-to-pay threshold had the highest impact on results. CONCLUSIONS: The 2015 testing policy resulted in a modest decline of detected HIV and syphilis infections, generating substantial savings. Syphilis and HIV tests for both first- and second-generation immigrants and an HIV test in case of positive chlamydia or gonorrhoea diagnosis could reduce missed infections in a cost-effective way. PMID- 29246658 TI - Aberrant subcellular localization of SQSTM1/p62 contributes to increased vulnerability to proteotoxic stress recovery in Huntington's disease. AB - Proteotoxic stress plays an important role in the pathogenesis of Huntington's disease (HD). Autophagy is proposed as a compensatory mechanism to remove protein aggregates under proteotoxic stress by up-regulating p62 expression. In the present study, we investigated the molecular action of p62 to proteotoxic stress in HD cells. Using two different HD cellular models, STHdhQ7 and STHdhQ111 cells derived from wild type and HD knock-in mice and human fibroblasts from healthy and HD patients, we found that HD cells are more vulnerable to cell death under proteotoxic stress and during stress recovery. We further showed that P62 was up regulated in both STHdhQ7 and STHdhQ111 cells in response to the stress with distinct subcellular localization patterns. While dispersed p62 puncti were found in STHdhQ7 cells, p62 bodies were initially present in the lysosomes and accumulated to the juxtanuclear regions of STHdhQ111 cells as MG132 incubation continued. Unlike in STHdhQ7 cells, p62 puncti were not associated with K48 linked polyubiquitinated protein aggregates or proteasomal components in STHdhQ111. Interestingly, addition of cysteine during MG132 incubation rescued cell death in STHdhQ111 cells caused by stress recovery and altered the subcellular distribution of p62. Our data suggest that aberrant positioning of p62 affects the proteasomal clearance of protein aggregates and may contribute to the increased vulnerability to proteotoxic stress-induced cell death in HD cells. PMID- 29246659 TI - Bayesian informed evidence against modulation of androstadienone-effects by genotypic receptor variants and participant sex: A study assessing Stroop interference control, mood and olfaction. AB - The androgen derivative androstadienone (AND) is present in human sweat and may act as human chemosignal. Though effects of AND have been reported with respect to emotional and cognitive processes, results have been highly inconsistent. For this reason, it is likely that AND-action is dependent on modulatory factors. Here we wanted to specifically investigate the impact of genotypic variations of the AND-receptor OR7D4, as well as the influence of participant sex and concomitant hormonal fluctuations on AND-action during emotional interference processing, olfactory performance and mood assessments. To this end 80 healthy individuals (women taking oral contraceptives; naturally cycling women measured during the luteal phase and men) were tested twice on two consecutive days (AND vs. placebo exposure) with an emotional Stroop task. Also, olfactory performance and mood was assessed. Participants provided saliva samples to measure testosterone, progesterone and estradiol and a blood sample to assess genotypic variations of the AND-receptor OR7D4. We found a small task-dependent reduction of overall error rates under AND but no modulation of effects by genetic variation or group (female OC, female NC, male) with respect to olfactory performance and mood. Additional analyses with help of Bayesian statistics gave strong evidence in favor of specific null hypotheses suggesting that the action of AND was not modulated by either genotypic variations or sex of participants with respect to interference control (bias indices), olfactory self-reports and mood parameters. Additional effects of AND in connection with hormonal fluctuations are reported. PMID- 29246660 TI - [Contribution of computer-aided design for the conception of custom-made implants in Pectus Excavatum surgical treatment. Experience of the Nantes plastic surgery unit]. AB - INTRODUCTION: Pectus excavatum is the most common congenital chest malformation and is a common reason for consultation in plastic surgery. Our attitude is most often a filling of the depression with a custom-made silicone prosthesis. The objective of this work was to evaluate the interest of computer-aided design (CAD) of implants compared to the conventional plaster molds method. PATIENTS AND METHODS: We have collected all the cases of custom-made silicone implants to treat funnel chests in our plastic surgery department. The quality of the results was evaluated by the patient, and in a blind manner by the surgical team using photographs and standardized surveys. The pre-operative delays, the operating time and length of hospital stays, the number of surgical recoveries, and the post-operative surgical outcomes were recorded. RESULTS: Between 1990 and 2016, we designed 29 silicone thoracic implants in our department. Before 2012, implants were made from plaster chest molds (n=13). After this date, implants were designed by CAD (n=16). Patients rated their results as "good" or "excellent" in 77% and 86% of cases respectively in the plaster and CAD groups. The surgical team's ratings for CAD implant reconstructions were better than in the plaster group: 8.17 versus 6.96 (P=0.001). CAD implants were significantly less detectable than the plaster group implants. The operating time was reduced in the CAO group: 60.2 compared to 74.7minutes in the plaster group (P=0.04), as was the length of hospitalization: 3.5 versus 5.3 days (P=0.01). There were no significant differences between the two groups in terms of post-operative complications. CONCLUSION: The management of pectus excavatum by a custom-made silicone implant is a minimally invasive method that provides good cosmetic results. The design of these implants is facilitated and qualitatively improved by CAD. PMID- 29246662 TI - Corrigendum to "A homozygous DPM3 mutation in a patient with alpha-dystroglycan related limb girdle muscular dystrophy" [Neuromuscular disorders 27/11 (2017) 1043-1046]. PMID- 29246661 TI - A quantitative approach to neuropsychiatry: The why and the how. AB - The current nosology of neuropsychiatric disorders allows for a pragmatic approach to treatment choice, regulation and clinical research. However, without a biological rationale for these disorders, drug development has stagnated. The recently EU-funded PRISM project aims to develop a quantitative biological approach to the understanding and classification of neuropsychiatric diseases to accelerate the discovery and development of better treatments. By combining clinical data sets from major worldwide disease cohorts and by applying innovative technologies to deeply phenotype stratified patient groups, we will define a set of quantifiable biological parameters for social withdrawal and cognitive deficits common to Schizophrenia (SZ), Major Depression (MD), and Alzheimer's Disease (AD). These studies aim to provide new classification and assessment tools for social and cognitive performance across neuropsychiatric disorders, clinically relevant substrates for treatment development, and predictive, preclinical animal systems. With patients and regulatory agencies, we seek to provide clear routes for the future translation and regulatory approval for new treatments and provide solutions to the growing public health challenges of psychiatry and neurology. PMID- 29246663 TI - Secretory lipase from the human pathogen Leishmania major: Heterologous expression in the yeast Pichia pastoris and biochemical characterization. AB - Leishmaniasis is a parasitic reticuloendotheliosis whose pathogen is a zooflagellate belonging to the genus Leishmania transmitted by the bite of an infected phlebotome. Recently, a unique secretory lipase from the human pathogen Leishmania donovani Ldlip3 has been identified and characterized. This lipase has a high identity with a putative triacylglycerol lipase of Leishmania major (Lmlip2). In the present study, Lmlip2 was expressed in the eukaryotic heterologous expression system Pichia pastoris as tagged enzyme of 308 amino acids. Maximal protein production was reached after 2 days of fermentation. Optimal Lmlip2 lipase activity was measured using the pH stat technique at pH 8 at 26 degrees C using vinyl esters and triacylglycerols (true lipids) as substrates. Moreover, biochemical characterization of Lmlip2 contained in culture supernatant, illustrates that L. major secreted lipase is active and stable at low temperatures especially 26 degrees and prefer neutral pH; concerning substrate specificityLmlip2 presents a preference for short chains lipid substrates vinyl esters such as VC2, VC3 and VC4 likewise, it is capable to hydrolyze long chain triacylglycerols like olive oil. Metal ions and surfactants tested in this study decrease Lmlip2 activity. Further studies are needed to clarify the relation between the lipase activity and the virulence. Thus, it could lead to the identification of novel targets to block cutaneous Leishmaniasis in human hosts. PMID- 29246664 TI - Phenolic content and antibacterial activity of extracts of Hamelia patens obtained by different extraction methods. AB - Hamelia patens, is a plant traditionally used to treat a variety of conditions among the Huastec people of Mexico. The objective of this study is to characterize the phenolic content and critically examine the antimicrobial activity of leaf extracts H. patens, obtained by maceration, Soxhlet and percolation, using ethanol as 70% solvent. Phenolic compounds are characterized by liquid chromatography, coupled to a High Resolution Mass Spectrometry, and the antimicrobial activity was studied from the inhibitory effect of each extract for Escherichia coli, Staphylococcus aureus, Salmonella typhi and S. paratyphi, and by the Minimum Bactericidal Concentration, the percentage of activity and the Index of Bacterial Susceptibility of each extract. The phenolic compound identified in different concentrations in the three extracts was epicatechin. The extracts obtained by the three methods had antimicrobial activity, however, there was no significant difference (p<0.05) between the Minimum Bactericidal Concentration of the extracts obtained by maceration, percolation and Soxhlet. The results of this study contribute to the body of knowledge on the use of extracts in controlling microorganisms with natural antimicrobials. PMID- 29246665 TI - Long-term leaching of nutrients and contaminants from wood combustion ashes. AB - With increasing amounts of woody biomass being combusted for energy purposes worldwide, more wood ash is being generated and needs management. As an alternative to landfilling, residues may be utilised for liming and fertilising purposes on forest soils. Comprehensive evaluations of long-term leaching from these residues are needed in order to assess potential environmental impacts associated with their utilisation. Two Danish wood ash samples, one fly ash and one mixed ash (a combination of fly ash and bottom ash), were evaluated in long term percolation column tests (up to L/S ~2000 L/kg), in order to quantify the release of major, minor and trace metal(loid)s. While columns of three different lengths were used, the leaching of individual elements could be described as a function of the L/S ratio - irrespective of the column length. At L/S 1000 L/kg, the cumulative releases of K, S, Na, Ca and Rb were at 40-100% of their respective solid contents, followed by Ba, Cr, Sb, Sr and V at 15-40% and Al, Mg, Zn, Cd, Co, Fe, Pb, Tl, Mn and P at < 5%. Speciation calculations indicated that (i) the observed concentrations of Ca, Mg, Al, Ba, Si and sulphate from both ash types could be described through the dissolution/precipitation of a limited set of minerals and that (ii) leaching of silicates should be included in long-term assessment of alkalinity release from wood ashes. Non-equilibrium conditions were indicated by flow interruptions. However, the presence of non-equilibrium did not have significant effect on the calculated cumulative releases at high L/S ratios. Based on the assessment of cumulative releases at L/S 10 L/kg and L/S 1000 L/kg it is concluded that low L/S-based data may not provide sufficient background for prediction of long-term release from wood ash, in particular for Ba, Cr, Sb and V, and less critically also for As, Cd, Cu, Mo and Ni. PMID- 29246666 TI - Quantification of CSF cystatin C using liquid chromatography tandem mass spectrometry. AB - BACKGROUND: Cystatin C (CST3), a ubiquitously expressed cysteine protease inhibitor, is implicated in several neurological diseases. Here, we have developed an accurate CST3 measurement system based on liquid chromatography tandem mass spectrometry (LC-MS/MS). METHODS: LC-MS/MS based measurement for CSF CST3 was validated by determination of assay precision, accuracy and recovery. The values were compared with those measured by immunoassay. Glycosylation of CST3 in CSF was analyzed by Western blotting and lectin blotting. RESULTS: Measuring standard CST3 by LC-MS/MS produced a linear standard curve that correlated with assigned values (r2=0.99). Both intra- and inter-assay variation was <10%. Although showed a correlation, the average CST3 concentration measured by LC-MS/MS was significantly higher than that of immunoassay. Western blotting showed the presence of a 25KDa species along with CST3 monomer (14KDa) in CSF. The volume of 25KDa species was decreased by deglycosylation. Lectin blotting revealed a 25KDa glycosylated protein in sialidase-treated CSF, which was decreased by deglycosylation. However, deglycosylation did not alter CST3 concentration measured by immunoassay. CONCLUSIONS: Our results suggest that LC MS/MS-based CST3 measurement is a robust method with higher detection ability. Such method could be useful for the diagnosis and monitoring of neurological diseases. PMID- 29246668 TI - Editorial: Applying 'omics technologies in chemicals risk assessment. PMID- 29246667 TI - Serum 25-hydroxyvitamin D, bone turnover markers and bone mineral density in postmenopausal women with hip fractures. AB - BACKGROUND: Vitamin D and bone turnover markers (BTMs) might have an effect on the occurrence of acute hip fracture, while the current results are conflicting. The purpose of this study is to explore the relationship between serum 25(OH)D, bone turnover markers and bone mineral density in Chinese postmenopausal women with hip fracture. METHODS: A total of 277 patients with hip fractures and 272 patients without fractures were included in this study. The serum 25(OH)D, bone formation markers, including N-terminal extension propeptide of type-I collagen (P1NP), alkaline phosphatase (ALP) and osteocalcin(OC), bone resorption markers, including C-terminal telopeptide of type-I collagen (CTX-1), and bone mineral density were collected and analyzed. RESULTS: Women with hip fractures had significantly lower concentrations of serum 25(OH)D, higher concentrations of serum CTX-1, P1NP and OC, lower concentrations of femoral neck and total hip bone mineral density (P<0.05). After adjustment for age and other confounding factors, multiple logistic regression analysis showed that serum 25(OH)D (OR=0.878, 95%CI=0.855-0.902, P<0.001), CTX-1 (OR=4.884, 95%CI=2.419-9.861, P<0.001)and total hip BMD (OR=0.141, 95%CI=0.034-0.577, P=0.006) were independent risk factors for hip fractures in postmenopausal women. The receiver operating characteristics curves showed that serum 25(OH)D had a good AUC value (0.830). CONCLUSIONS: In this study, lower concentrations of serum 25(OH)D and total hip bone mineral density were widely existed in Chinese postmenopausal women with hip fractures. Furthermore, bone resorption was more active than bone formation in senile postmenopausal women. Therefore, monitoring the alteration of serum CTX-1 in clinically might be useful for fracture prevention. PMID- 29246669 TI - [Home care ventilator's settings]. PMID- 29246670 TI - Dural Sinus Malformation Imaging in the Fetus: Based on 4 Cases and Literature Review. AB - BACKGROUND: This study aims to describe the imaging characteristic of dural sinus malformation in 4 fetuses with different locations. MATERIALS AND METHODS: We report a series of 4 fetuses with dural sinus malformation in Hubei Maternal and Children's Hospital from July 2013 to February 2016. All the mothers undertook the prenatal magnetic resonance (MRI) imaging because of the intracranial space occupying lesions discovered by prenatal ultrasound. RESULTS: Two of the 4 cases demonstrated typical MRI of dural sinus malformation with thrombosis in the vicinity of torcular herophili (also known as sinus confluence), whereas the other 2 cases showed lesions in the superior sagittal sinus and transverse sinus separately. Three pregnancies were terminated, whereas the other one was delivered in the local hospital. CONCLUSIONS: Sonographer should realize the sign of dural sinus malformation. Atypical location of the dural sinus malformation, such as superior sagittal sinus and transverse sinus, should be paid special attention to. Further, prenatal MRI is necessary to identify the lesion. PMID- 29246671 TI - Histology of Thrombectomy Specimen Reveals Cardiac Tumor Embolus in Cryptogenic Young Stroke. AB - A 25-year-old woman presented with acute onset of right hemiplegia and global aphasia with National Institutes of Health Stroke Scale score of 19. Computed tomography angiography demonstrated occlusion of the left proximal middle cerebral artery. She was thrombolysed with intravenous recombinant tissue plasminogen activator (0.6 mg/kg) within 3 hours of onset of symptoms and was taken up for mechanical thrombectomy. The retrieved specimen appeared pale white and soft; histopathologic examination revealed a papillary neoplasm composed of papillae with hyalinized cores lined by endothelium, consistent with papillary fibroelastoma of cardiac origin. Transesophageal echocardiography showed no abnormalities, which can be explained by complete embolization of the mass into the cerebral circulation. On follow-up after 5 months, the patient recovered with only minimal aphasia and no cardiac symptoms. Our experience with this case highlights the importance of histopathologic examination of the mechanical thrombectomy specimen, as it provided the only clue to the etiology of stroke. PMID- 29246672 TI - Recurrent Stroke and Bleeding Events after Acute Cardioembolic Stroke-Analysis Using Japanese Healthcare Database from Acute-Care Institutions. AB - BACKGROUND: To understand the reality of patients who experienced a cardioembolic stroke (CES) is important because of the high incidence of recurrent stroke and the need to account for bleeding risk in relation to the need for anticoagulation treatment. We elucidated the current real-world medical care in patients who had a CES and identified the risk factors for recurrent stroke. METHODS AND RESULTS: The study comprised 9804 patients who were diagnosed with CES between April 2008 and September 2013 as identified in a healthcare database used by acute-care institutions in Japan. We analyzed the incidence and risk factors of stroke and bleeding events in CES patients. The incidence of stroke was 10.3% during the median observation period of 68 days, mainly consisting of recurrent CES (8.5%). The incidence of bleeding events and intracranial bleeding was 10.3% and 7.0%, respectively. The recurrence of ischemic stroke was significantly lower, and brain hemorrhage was significantly higher in the anticoagulation treatment group. The factors related to an increased risk of stroke were a history of cerebral infarction or transient ischemic attack, diabetes, and increase of CHA2DS2-VASc and CHADS2 scores. The risk factors for bleeding events were hypertension, renal dysfunction, and use of proton pump inhibitors (PPIs). CONCLUSIONS: The patients who experienced CES had a high rate of recurrent stroke or CES, mainly consisting of recurrent CES. Although anticoagulation may be beneficial for reducing recurrence of ischemic stroke, careful management is required given consideration of increased risk of brain hemorrhage during anticoagulation treatment, especially for patients with hypertension, renal dysfunction, and use of PPIs. PMID- 29246673 TI - Environmental Supports for Physical Activity, National Health Interview Survey 2015. AB - INTRODUCTION: The Guide to Community Preventive Services recommends combined built environment approaches to increase physical activity, including new or enhanced transportation infrastructure (e.g., sidewalks) and land use and environmental design interventions (e.g., close proximity of local destinations). The aim of this brief report is to provide nationally representative estimates of two types of built environment supports for physical activity: near-home walkable infrastructure and destinations, from the 2015 National Health Interview Survey. METHODS: Adults (n=30,453) reported the near-home presence of walkable transportation infrastructure (roads, sidewalks, paths, or trails where you can walk; and whether most streets have sidewalks) and four walkable destination types (shops, stores, or markets; bus or transit stops; movies, libraries, or churches; and places that help you relax, clear your mind, and reduce stress). The prevalence of each, and the count of destination types, was calculated (in 2017) and stratified by demographic characteristics. RESULTS: Overall, 85.1% reported roads, sidewalks, paths, or trails on which to walk, and 62.6% reported sidewalks on most streets. Among destinations, 71.8% reported walkable places to relax; followed by shops (58.0%); transit stops (53.2%); and movies, libraries, or churches (47.5%). For most design elements, prevalence was similar among adults aged 18-24 and 25-34 years, but decreased with age >35 years. Adults in the South reported a lower prevalence of all elements compared with those in other Census regions. CONCLUSIONS: Many U.S. adults report walkable built environment elements near their home; future efforts might target areas with many older adult residents or those living in the South. PMID- 29246674 TI - Immunization Practices of U.S. Obstetrician/Gynecologists for Pregnant Patients. AB - INTRODUCTION: U.S. obstetrician/gynecologists play a critical role as vaccinators of pregnant women. However, little is known about their current immunization practices. Thus, study objectives were to determine (1) practices related to assessment of vaccination status and vaccine delivery for pregnant patients; (2) barriers to stocking and administering vaccines; and (3) factors associated with administering both influenza and tetanus, diphtheria, and acellular pertussis (Tdap) vaccines. METHODS: An e-mail and mail survey among a national sample of obstetrician/gynecologists conducted July-October 2015 (analysis August 2016 August 2017). RESULTS: The response rate was 73.2% (353/482). Among obstetrician/gynecologists caring for pregnant women (n=324), vaccination status was most commonly assessed for influenza (97%), Tdap (92%), and measles, mumps, and rubella vaccines (88%). Vaccines most commonly administered included influenza (85%) and Tdap (76%). Few respondents reported administering other vaccines to pregnant patients. More physicians reported using standing orders for influenza (66%) than Tdap (39%). Other evidence-based strategies for increasing vaccine uptake were less frequently used (electronic decision support, 42%; immunization information system to record [13%] or assess vaccination status [11%]; reminder/recall, 7%). Barriers most commonly reported were provider financial barriers, yet provider attitudinal barriers were rare. Providers who administered both influenza and Tdap vaccines were more likely to be female, perceive fewer financial and practice barriers, less likely to be in private practice, and perceive more patient barriers. CONCLUSIONS: Although most obstetrician/gynecologists administer some vaccines to pregnant women, the focus remains on influenza and Tdap. Financial barriers and infrequent use of evidence based strategies for increasing vaccination uptake may be hindering delivery of a broader complement of adult vaccines in obstetrician/gynecologist offices. PMID- 29246675 TI - "Doubling Up" on Produce at Detroit Farmers Markets: Patterns and Correlates of Use of a Healthy Food Incentive. AB - INTRODUCTION: Federal food assistance programs such as the Supplemental Nutrition Assistance Program (SNAP) help address food insecurity, yet many participants still struggle to afford nutritionally adequate foods. The U.S. Department of Agriculture has committed $100 million to the expansion and evaluation of SNAP healthy food incentives, which match SNAP funds spent on produce. However, little is known about who uses SNAP incentives or how often they are used. This study examines patterns and correlates of use of the SNAP incentive Double Up Food Bucks at all eight participating Detroit farmers markets during 2012-2013. METHODS: SNAP/Double Up Food Bucks transactions from handwritten farmers market logs (n=21,541) were linked with state administrative SNAP enrollment data. Frequency of incentive use and characteristics of Double Up Food Bucks users relative to the overall Detroit SNAP-enrolled population were examined, as were market-level characteristics associated with program use. Negative binomial regression was used to estimate predictors of repeat transactions (analyses conducted 2015-2017). RESULTS: Although demographic characteristics of Double Up Food Bucks users reflected those of the overall Detroit SNAP-enrolled population, Double Up Food Bucks users were poorer and disproportionately female. One third of Double Up Food Bucks users had more than one transaction during the 2-year period. Repeat transactions were directly correlated with identifying as white (incidence rate ratio=2.34, 95% CI=2.11, 2.59, p<0.001), and inversely correlated with driving distance from market of first transaction (incidence rate ratio=0.98 per mile, 95% CI=0.98, 0.99, p<0.001). Rates of repeat transactions also varied significantly by market. CONCLUSIONS: Addressing barriers to initial use and return visits can help maximize the impact and reach of SNAP incentives among Americans at highest risk of diet-related disease. PMID- 29246676 TI - Time to Track Health Outcomes of Smoke-Free Multiunit Housing. PMID- 29246677 TI - Secular Trends in Dementia and Cognitive Impairment of U.S. Rural and Urban Older Adults. AB - INTRODUCTION: This is a nationally representative study of rural-urban disparities in the prevalence of probable dementia and cognitive impairment without dementia (CIND). METHODS: Data on non-institutionalized U.S. adults from the 2000 (n=16,386) and 2010 (n=16,311) cross-sections of the Health and Retirement Study were linked to respective Census assessments of the urban composition of residential census tracts. Relative risk ratios (RRR) for rural urban differentials in dementia and CIND respective to normal cognitive status were assessed using multinomial logistic regression. Analyses were conducted in 2016. RESULTS: Unadjusted prevalence of dementia and CIND in rural and urban tracts converged so that rural disadvantages in the relative risk of dementia (RRR=1.42, 95% CI=1.10, 1.83) and CIND (RRR=1.35, 95% CI=1.13, 1.61) in 2000 no longer reached statistical significance in 2010. Adjustment for the strong protective role of educational attainment reduced rural disadvantages in 2000 to statistical nonsignificance, whereas adjustment for race/ethnicity resulted in a statistically significant increase in RRRs in 2010. Full adjustment for sociodemographic and health factors revealed persisting rural disadvantages for dementia and CIND in both periods with RRR in 2010 for dementia of 1.79 (95% CI=1.31, 2.43) and for CIND of 1.38 (95% CI=1.14, 1.68). CONCLUSIONS: Larger gains in rural adults' cognitive functioning between 2000 and 2010 that are linked with increased educational attainment demonstrate long-term public health benefits of investment in secondary education. Persistent disadvantages in cognitive functioning among rural adults compared with sociodemographically similar urban peers highlight the importance of public health planning for more rapidly aging rural communities. PMID- 29246678 TI - Individualized Fracture Risk Feedback and Long-term Benefits After 10 Years. AB - INTRODUCTION: This study aimed to determine if beneficial effects of individualized feedback of fracture risk on osteoporosis preventive behaviors and bone mineral density observed in a 2-year trial were sustained long-term. METHODS: This was a 10-year follow-up of a 2-year RCT in 470 premenopausal women aged 25-44 years, who were randomized to one of two educational interventions (the Osteoporosis Prevention and Self-Management Course [OPSMC] or an osteoporosis information leaflet) and received tailored feedback of their relative risk of fracture in later life (high versus normal risk groups). Bone mineral density of lumbar spine and femoral neck were measured by dual-energy X ray absorptiometry. Physical activity, dietary calcium intake, calcium and vitamin D supplements, and smoking status were measured by questionnaires. RESULTS: From 2 to 12 years, the high-risk group had a smaller decrease in femoral neck bone mineral density (beta=0.023, 95% CI=0.005, 0.041 g/cm2) but similar lumbar spine bone mineral density change as the normal-risk group. They were more likely to use calcium (relative risk=1.66, 95% CI=1.22, 2.24) and vitamin D supplements (1.99, 95% CI=1.27, 3.11). The OPSMC had no effects on bone mineral density change. Both high-risk (versus normal-risk) and the OPSMC groups (versus leaflet) had a more favorable pattern of smoking behavior change (relative risk=1.85, 95% CI=0.70, 4.89 and relative risk=2.27, 95% CI=0.86, 6.01 for smoking cessation; relative risk=0.33, 95% CI=0.13, 0.80 and relative risk=0.28, 95% CI=0.10, 0.79 for commenced or persistent smoking). CONCLUSIONS: Feedback of high fracture risk to younger women was associated with long-term improvements in osteoporosis preventive behaviors and attenuated femoral neck bone mineral density loss. Therefore, this could be considered as a strategy to prevent osteoporosis. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) NCT00273260. PMID- 29246680 TI - Early Outcomes After Mitral Valve Repair vs. Replacement in the Elderly: A Propensity Matched Analysis. AB - BACKGROUND: To compare early outcomes of mitral valve repair versus replacement in elderly patients with degenerative mitral valve disease. METHODS: A retrospective review of prospectively collected clinical data of patients over 75 years of age, who underwent mitral valve surgery for degenerative disease, between 2010 and 2013, was carried out. Those undergoing mitral valve repair and replacement were propensity matched to adjust for baseline clinical differences. RESULTS: A total 260 patients were identified: mitral valve repair was undertaken in 145 and replacement in 115 patients. After propensity matching, 78 patients were included in each group. In the entire, unmatched population, in-hospital mortality was significantly higher in those undergoing replacement compared with those undergoing repair (9.6% vs 1.4%, p=0.003). In-hospital death occurred in six (7.7%) of the propensity matched replacement group and none in the repair group (p=0.012). Amongst the propensity matched groups, probability of survival at 1, 2 and 3 years were 0.94, 0.90 and 0.86 respectively for the repair group and 0.85, 0.77 and 0.69 for the replacement group: the HR for death between replacement and repair is 2.5 (1.2-5.4), p=0.012. CONCLUSIONS: Within the limitations imposed by retrospective analyses, our study demonstrates that, in elderly patients with degenerative disease of the mitral valve, repair is associated with improved short-term and mid-term outcomes compared with mitral valve replacement. PMID- 29246679 TI - Radiographic comparison of finned, cementless central pegged glenoid component and conventional cemented pegged glenoid component in total shoulder arthroplasty: a prospective randomized study. AB - BACKGROUND: Radiographic lucency of the glenoid component remains a problem after cement fixation in primary total shoulder arthroplasty. Glenoid component design likely contributes to rates of glenoid lucency. The purpose of this study was to prospectively compare radiographic lucency between a finned, cementless central pegged glenoid component (CL component) and a conventional cemented pegged glenoid component (P component) on immediate postoperative and minimum 2-year follow-up radiographs. METHODS: Fifty-four patients undergoing total shoulder arthroplasty were prospectively randomized to receive an all-polyethylene CL component or a conventional all-polyethylene P component. Three raters graded glenoid lucency and bone interdigitation on immediate postoperative and latest follow-up radiographs. Patients who had undergone revision surgery or had died before evaluation were excluded. Minimum 2-year follow-up was required for inclusion of radiographic evaluation. RESULTS: Fifty patients met inclusion criteria; 42 patients (84%; 20 CL and 22 P) were available for follow-up with the original glenoid implant in place. The mean follow-up duration was 35 months (24 64 months). There were no significant differences in glenoid radiolucency between CL (1/20 [5%]) and P (2/22 [9%]) components at last follow-up (P = .999). Five patients (25%) in the CL group had bone interdigitation. No instances of aseptic glenoid loosening occurred. CONCLUSION: There were no significant differences in the rate of glenoid lucency between the 2 groups at immediate or an average 35 month follow-up. Both techniques appear to be viable options for initial glenoid component fixation, with CL components allowing possible osseointegration, imparting potential long-term stability. PMID- 29246681 TI - A Flowmeter Technique to Exclude Internal Mammary Artery Anastomosis Error in an Arrested Heart. AB - The revision of an internal mammary artery graft anastomosis because of a technical error can be time-consuming and complicated and may lead to complications. Here, we describe the technical details and our early experience of using a standard transit-time flowmeter to exclude technical errors and facilitate rapid decision making for anastomosis revision in an arrested heart during aortic cross-clamping in the absence of ultrasound guidance. PMID- 29246682 TI - Non-Infectious, Non-Inflammatory Late Dehiscence of Prosthetic Aortic Valve: A "Rocking" Catastrophe. PMID- 29246683 TI - Optogenetic activation of granule cells in the dorsal dentate gyrus enhances dopaminergic neurotransmission in the Nucleus Accumbens. AB - The dentate gyrus (DG) has distinct roles along its dorso-ventral axis. In the mouse, we recently demonstrated that dorsal DG (dDG) stimulation enhances exploratory behavior (Kheirbek et al., 2013). Dopamine (DA) release in the Nucleus Accumbens (NAcc), which belongs to the reward system, could be a key target of dDG mediating this motivation-related behavior. Here, an optogenetic stimulation of either ventral (vDG) or dDG granule cells was coupled with NAcc DA release monitoring using in vivo microdialysis. Only dDG stimulation enhanced NAcc DA release, indicating differential interconnections between dDG and vDG to the reward system. PMID- 29246684 TI - Control the intracellular NF-kappaB activity by a sensor consisting of miRNA and decoy. AB - Many diseases are associated with the abnormal activation of NF-kappaB and its signaling pathway. NF-kappaB has become an important target for disease treatment and development of new drugs. Many various NF-kappaB inhibitors were therefore developed; however, they have difficulties to become clinical drugs due to their adverse side effects resulted from the affected normal physiological functions of this transcription factor. To overcome this limitation, this study construct a transgenic vector that can express an artificial miRNA targeting NF-kappaB RelA under the control of a NF-kappaB-specific promoter. The promoter consists of a NF kappaB decoy and a minimal promoter. The vector was named as decoy minimal promoter-artificial microRNA (DMP-amiRNA). This study verified that this vector can sense and control the intracellular NF-kappaB activity upon transfection. Working of the vector forms a perfect feedback loop that realizes the NF-kappaB self-control. With the vector in cells, the higher NF-kappaB activity, the higher DMP transcriptional activity, and the more amiR533 expression. DMP-amiRNA can moderately inhibit the intracellular NF-kappaB activity but exert no significant effect on cell viability. This study therefore develops a new strategy for inhibiting over activity of NF-kappaB, which should has great potential in clinical application. PMID- 29246686 TI - Relation of urinary endothelin-1 to stress-induced pressure natriuresis in healthy adolescents. AB - We hypothesize that delayed natriuresis during mental stress increases the risk of hypertension and other diseases. Our preclinical studies demonstrate an important role for renal endothelin-1 (ET-1) in regulating sodium excretion. Thus, we predict ET-1 may be linked to the delayed stress response in at-risk individuals. We hypothesize that reduced renal ET-1 accounts for derangements in sodium handling under stress, a link never explored in a large human cohort. We determined urinary ET-1 excretion in three observational studies of changes in sodium excretion during mental stress, in which 776 healthy youth (15-19 years) enrolled in a 5-hour protocol (2 hours of rest before and after 1 hour of mental stress). In all studies, 60-minute urine samples were obtained throughout the protocol. Subjects were grouped as retainers (reduced sodium excretion during stress relative to baseline) or excreters (increased sodium excretion during stress relative to baseline). In excreters, ET-1 excretion was significantly increased from baseline to stress (+0.02 pg/min; P < .001). In contrast, ET-1 excretion was significantly higher (P = .028) in retainers than excreters at baseline but significantly reduced in retainers under stress (-0.02 pg/min; P < .001). ET-1 excretion declined further in retainers during recovery but returned to prestress levels in excreters. Albumin excretion and albumin-to-creatinine ratio were significantly higher in retainers (P = .022, P < .001, respectively). Thus, loss of ET-1-dependent natriuresis may account for sodium retention during stress and may predispose retainers to renal diseases such as hypertension and kidney disease. PMID- 29246685 TI - Silica nanoparticle releases SIRT6-induced epigenetic silencing of follistatin. AB - Follistatin (FST) plays a protective role during silica nanoparticle (SiO2 NP) exposure. SiO2 NP treatment induces FST transcription with an unknown mechanism. We herein reported that SIRT6, one of the sirtuin family members, induced epigenetic silencing of FST. The expression of FST was elevated after SIRT6 knockdown while reduced after SIRT6 overexpression. Chromatin immunoprecipitation revealed a direct interaction between SIRT6 with FST promoter. Knockdown of SIRT6 increased both Ac-H3K9 level and Ac-H3K56 level at FST promoter region. SiO2 NP treatment de-stabilized SIRT6 mRNA and reduced SIRT6 expression, leading to the activation of FST transcription. Finally, over-expression of SIRT6 increased SiO2 NP-induced apoptosis. Collectively, this study provided evidence that SIRT6 is a negative regulator of FST transcription and participates in the regulation of cell survival during silica nanoparticle exposure. PMID- 29246687 TI - WITHDRAWN: Optimal Integrated Scheduling of Distributed Energy Resources in Power Systems by Virtual Power Plant. AB - This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. PMID- 29246688 TI - Stochastic multi-objective model for optimal energy exchange optimization of networked microgrids with presence of renewable generation under risk-based strategies. AB - The inherent volatility and unpredictable nature of renewable generations and load demand pose considerable challenges for energy exchange optimization of microgrids (MG). To address these challenges, this paper proposes a new risk based multi-objective energy exchange optimization for networked MGs from economic and reliability standpoints under load consumption and renewable power generation uncertainties. In so doing, three various risk-based strategies are distinguished by using conditional value at risk (CVaR) approach. The proposed model is specified as a two-distinct objective function. The first function minimizes the operation and maintenance costs, cost of power transaction between upstream network and MGs as well as power loss cost, whereas the second function minimizes the energy not supplied (ENS) value. Furthermore, the stochastic scenario-based approach is incorporated into the approach in order to handle the uncertainty. Also, Kantorovich distance scenario reduction method has been implemented to reduce the computational burden. Finally, non-dominated sorting genetic algorithm (NSGAII) is applied to minimize the objective functions simultaneously and the best solution is extracted by fuzzy satisfying method with respect to risk-based strategies. To indicate the performance of the proposed model, it is performed on the modified IEEE 33-bus distribution system and the obtained results show that the presented approach can be considered as an efficient tool for optimal energy exchange optimization of MGs. PMID- 29246689 TI - Diagnostic value of magnetic resonance cholangiopancreatography to detect bile duct stones in acute biliary pancreatitis. AB - OBJECTIVES: This study aims to evaluate the diagnostic value of magnetic resonance cholangiopancreatography (MRCP) in detecting common bile duct (CBD) stones in acute biliary pancreatitis (ABP). METHODS: The medical records of patients presenting with ABP from January 2008 to July 2013 were reviewed to assess the value of MRCP in detecting CBD stones in ABP. Endoscopic retrograde cholangiopancreatography (ERCP) was used as the reference standard to assess the diagnostic yield of MRCP in detecting choledocholithiasis. When ERCP was unavailable, intraoperative cholangiography or clinical follow-up was used as the reference standard. RESULTS: Seventy-eight patients who underwent MRCP were diagnosed with ABP, and thirty of the 78 patients (38%) were confirmed to have CBD stones per the study protocol. The sensitivity of MRCP in detecting CBD stones in ABP was 93.3% compared to 66.7% for abdominal CT (P < 0.008). The overall accuracy of MRCP in detecting choledocholithiasis was 85.9% compared to 74.0% for abdominal CT (P < 0.041). The area under the receiver operating characteristic curve (AUC) of MRCP in detecting CBD stones was 0.882, which was more accurate than the AUC of 0.727 for abdominal CT (P = 0.039). In 38 patients who underwent ERCP, the sensitivity and negative predictive value of MRCP in detecting CBD stones were both 100% regardless of the dilatation of the bile duct (>=7 mm versus < 7 mm). CONCLUSION: MRCP is an effective, noninvasive modality to detect CBD stones in ABP and can help identify patients who require ERCP. PMID- 29246690 TI - Trophic links and nutritional condition of fish early life stages in a temperate estuary. AB - The physiological and nutritional condition of fish larvae affect their survival and thus, the success of estuaries as nursery areas. Fatty acid composition has been useful to determine fish nutritional condition, as well as trophic relationships in marine organisms. The present study analyses the fatty acid (FA) composition of fish larvae during spring and summer in the Mondego estuary, Portugal. FA composition, trophic markers (FATM) and fish nutritional condition was analysed for Gobiidae and Sardina pilchardus larvae and the relationships with the local environment evaluated. Results showed that both taxa differed mainly in the stearic acid (C18:0) and eicosapentaenoic acid (EPA) content, with important amounts in Gobiidae and S. pilchardus, respectively. Gobiidae larvae presenting high nutritional condition and omnivore FATM. Fatty acid composition seems to be related with their natural habitat selection and food availability, while fish larvae nutritional condition also showed a strong link with the water temperature and presence of potential predators. This study suggests that FA composition can be a useful tool in assessing planktonic trophic relationships and in identifying species natural habitat. PMID- 29246691 TI - Intravenous Iron Therapy in Patients Undergoing Cardiovascular Surgery: A Narrative Review. PMID- 29246692 TI - Dilemmas for the Cardiac Anesthesiologist: Managing Conflicting Fluid Management Strategies During Combined Heart-Kidney Transplantation. PMID- 29246693 TI - Advancing learning to advance pharmacy practice. AB - OBJECTIVES: The objectives of this commentary are to: 1) describe advancements in the continuing professional development (CPD) model over the past decade; 2) detail an updated CPD cycle; and 3) describe how practitioners' adoption of the CPD approach may facilitate the advancement of pharmacy practice. SUMMARY: CPD is a self-directed, ongoing, systematic, and outcomes-focused approach to an individual's lifelong learning that is applied into practice. The 6 components of reflect, plan, learn, evaluate, apply, and record + review, described in a revised depiction of the CPD cycle, have evolved over the past 10 years alongside the evolution of the profession of pharmacy. The thinking around the value of building CPD habits has also advanced. New emphasis is being placed on mechanisms for applying and sharing CPD-related work, as well as the importance of employer support of CPD. CONCLUSION: As practice change has progressed, the individual's need to learn has also changed. To succeed in the evolving health care system, regular, robust, and intentional CPD is needed. Moreover, for learning to have maximum impact, it must facilitate, motivate and result in changes in learner behavior. Employers, educators, and pharmacy organizations should facilitate lifelong learning by creating CPD supportive environments that foster learner success and community. The adoption of a CPD approach by pharmacy practitioners may facilitate the advancement of pharmacy practice. PMID- 29246695 TI - Cost-effectiveness and Decision Analysis in Clinical Gastroenterology and Hepatology: From Evidence to Informed Decision Making. PMID- 29246694 TI - Effects of Diabetes and Glycemic Control on Risk of Hepatocellular Carcinoma After Seroclearance of Hepatitis B Surface Antigen. AB - BACKGROUND & AIMS: Diabetes is associated with a 2-fold increase in risk of hepatocellular carcinoma (HCC) among patients with chronic hepatitis B virus (HBV) infection. However, we know little about the effect of diabetes on HCC risk after seroclearance of hepatitis B surface antigen (HBsAg). We evaluated the effect of diabetes and glycemic control on HCC development after HBsAg seroclearance in a population-wide study in Hong Kong. METHODS: We performed a retrospective study of 4568 patients with chronic HBV infection who cleared HBsAg from January 2000 through August 2016, using the Clinical Data Analysis and Reporting System of the Hospital Authority, Hong Kong. We collected and analyzed data on patient demographics, comorbidities, medications, laboratory test results, and subsequent development of HCC. The presence of diabetes was defined by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code, with level of hemoglobin A1c (HbA1c) above 6.5%, fasting glucose level of 7 mmol/L or more, or treatment with any antidiabetic agent. RESULTS: We identified 1560 patients with diabetes; 29 patients (1.9%) developed HCC after a median follow-up time of 3.4 years (interquartile range, 1.5-5.0 years). Diabetes was associated with increased risk of HCC after adjustment of age, sex, presence of cirrhosis, and the use of medications (adjusted hazard ratio, 1.85; 95% CI, 1.04-3.28; P = .036). Among patients with diabetes, time-weighted average level of HbA1c was an independent risk factor for HCC, after adjustment for age at clearance, use of statins, and other important covariates (adjusted hazard ratio: 1.51; 95% CI, 1.20-1.91; P < .001). A time weighted average level of HbA1c of 7% or more was associated with a higher 5-year cumulative incidence of HCC (4.0%) than a time-weighted average HbA1c level below 7% (1.8%; log-rank test P = .035). CONCLUSIONS: In a population-based analysis of patients with chronic HBV infection in Hong Kong, we found diabetes to be an independent risk factor for HCC after HBsAg seroclearance. However, glycemia control appears to reduce the risk of HCC. PMID- 29246696 TI - Primary Adenocarcinoma Arising at a Colostomy Site. PMID- 29246697 TI - Double Pylorus: A Rare Complication of Peptic Ulcer Disease. PMID- 29246698 TI - Acute-on-Chronic Liver Failure, Human Serum Albumin, and Immune Modulation: The Beginning of an Exciting Adventure. PMID- 29246699 TI - Is the Over-the-Scope Clip Device a First-Line or Rescue Therapy for Patients at High Risk for Gastrointestinal Bleeding? PMID- 29246700 TI - A Rare Cause of Progressive Constipation, Abdominal Distension, and Weight Loss. PMID- 29246701 TI - Stool Donor Body Mass Index Does Not Affect Recipient Weight After a Single Fecal Microbiota Transplantation for Clostridium difficile Infection. PMID- 29246702 TI - Nomogram to Predict Survival of Patients With Recurrence of Hepatocellular Carcinoma After Surgery. AB - BACKGROUND & AIMS: We aimed to establish and validate a nomogram to predict survival at 2 and 5 years after recurrence of hepatocellular carcinoma (HCC) in patients who have undergone curative resection. METHODS: We developed a nomogram using data from a training cohort of 638 patients (most with hepatitis B virus infection) with recurrence of HCC after curative resection at Sun Yat-sen University Cancer Center, in Guangzhou, China from 2007 through 2013. The median follow-up time was 39.7 months. Patients were evaluated every 3-4 months for the first 2 years after resection and every 3-6 months thereafter. The nomogram was based on variables independently associated with survival after HCC recurrence, including antiviral treatment; albumin-bilirubin grade and alpha-fetoprotein level at recurrence; time from primary resection to recurrence; size, site, number of recurrences; and treatment for recurrence. We validated the nomogram using data from an independent internal cohort of 213 patients treated at the same institution and an external cohort of 127 patients treated at 2 other centers in China, from 2002 through 2009. The predictive accuracy of the nomogram was measured using Harrell's concordance index (C index) and compared with the Barcelona Clinic Liver Cancer staging system of recurrence. RESULTS: Our nomogram predicted survival of patients in the training cohort with a C-index of 0.797 (95% CI, 0.765-0.830)-greater than that of the Barcelona Clinic Liver Cancer staging system for recurrence (C-index score, 0.713; 95% CI, 0.680-0.745) (P < .001). This nomogram accurately stratified patients into subgroups with predicted long, medium, and short survival times: the proportions of patients in each group who survived 2 years after HCC recurrence were 91.2%, 67.6%, and 23.8%; the proportions of patients in each group who survived 5 years after HCC recurrence were 74.9%, 53.3%, and 9.1%. Our nomogram predicted patient survival times with C index scores of 0.756 (95% CI, 0.703-0.808) in the internal validation cohort and 0.747 (95% CI, 0.701-0.794) in the external validation cohorts. CONCLUSIONS: We developed a nomogram to determine the probability of survival, at different time points, of patients with recurrence of HCC (most with hepatitis B virus infection), after curative resection and validated it internally and externally. PMID- 29246703 TI - Evaluation of Discordance in Primary Tumor and Lymph Node Response After Neoadjuvant Therapy in Breast Cancer. AB - BACKGROUND: Neoadjuvant therapy (NAT) offers a unique opportunity to assess tumor response to systemic agents. However, a discrepancy may exist between the response of the primary tumor and involved nodes. We report on the frequency of response discordance after NAT in breast cancer. PATIENTS AND METHODS: All consecutive node-positive patients receiving NAT in our department from 2009 to 2014 were identified. Patient demographics, and radiologic and pathologic features were tabulated. Tumor response was estimated by magnetic resonance imaging of the breast. Lymph node (LN) response was estimated from pathologic treatment response measurements. Statistical analysis was performed. RESULTS: A total of 108 node-positive patients treated with NAT were eligible for inclusion. Median age was 51.73 years (range, 20-87 years). All patients underwent axillary clearance, and 62% underwent mastectomy. A 40% mean reduction in tumor size was observed. Statistically, a positive correlation between tumor and LN response after NAT was observed (Spearman correlation coefficient, r = 0.46, P < .001). Complete pathologic response was observed in 17 patients (15.7%). However, 21 patients experienced complete LN response, with only 81% of these patients (n = 17) experiencing a complete response in tumor also. A complete response was observed in tumor in 20 patients, and this predicted complete nodal response in 85% of cases (n = 17). Fifteen percent of primary tumors with complete pathologic response had persistently positive LNs. CONCLUSION: A significant discordance exists between the primary tumor and LN response, representing a concern for the lack of response of occult regional or systemic metastases due to potential biologic heterogeneity. PMID- 29246704 TI - The effect of within-instar development on tracheal diameter and hypoxia inducible factors alpha and beta in the tobacco hornworm, Manduca sexta. AB - : As insects grow within an instar, body mass increases, often more than doubling. The increase in mass causes an increase in metabolic rate and hence oxygen demand. However, the insect tracheal system is hypothesized to increase only after molting and may be compressed as tissues grow within an instar. The increase in oxygen demand in the face of a potentially fixed or decreasing supply could result in hypoxia as insects near the end of an instar. To test these hypotheses, we first used synchrotron X-ray imaging to determine how diameters of large tracheae change within an instar and after molting to the next instar in the tobacco hornworm, Manduca sexta. Large tracheae did not increase in diameter within the first, second, third, and fourth instars, but increased upon molting. To determine if insects are hypoxic at the end of instars, we used the presence of hypoxia-inducible factors (HIFs) as an index. HIF-alpha and HIF-beta dimerize in hypoxia and act as a transcription factor that turns on genes that will increase oxygen delivery. We sequenced both of these genes and measured their mRNA levels at the beginning and end of each larval instar. Finally, we obtained an antibody to HIF-alpha and measured protein expression during the same time. Both mRNA and protein levels of HIFs were increased at the end of most instars. These data support the hypothesis that some insects may experience hypoxia at the end of an instar, which could be a signal for molting. SUMMARY STATEMENT: As caterpillars grow within an instar, major tracheae do not increase in size, while metabolic demand increases. At the same life stages, caterpillars increased expression of hypoxia inducible factors, suggesting that they become hypoxic near the end of an instar. PMID- 29246705 TI - A Randomized Controlled Trial Evaluating the Impact of Web-Based Information on Breast Cancer Patients' Knowledge of Surgical Treatment Options. AB - BACKGROUND: Previous research suggests that providing information to women newly diagnosed with breast cancer, during the gap between cancer diagnosis and their first surgeon consultation, may support decision making. Our objective was to compare patients' knowledge after the pre-consultation delivery of standard websites vs a web-based decision aid (DA). STUDY DESIGN: We randomized women with stage 0 to III breast cancer, within an academic and community breast clinic, to be emailed a link to selected standard websites (National Cancer Institute, American Cancer Society, Breastcancer.org,) vs the Health Dialog DA (Clinicaltrials.govNCT03116035). Patients seeking second opinions, diagnosed by excisional biopsy, or without an email address, were ineligible. Pre-consultation knowledge was assessed using the Breast Cancer Surgery Decision Quality Instrument. We compared differences in knowledge using t-test. RESULTS: Median patient age was 59 years, 99% were white, and 65% had a college degree or higher, with no differences in demographics between study arms. Knowledge was higher in patients who received the DA (median 80% vs 66% correct, p = 0.01). Decision-aid patients were more likely to know that waiting a few weeks to make a treatment decision would not affect survival (72% vs 54%, p < 0.01). Patients in both arms found the information helpful (median score 8 of 10). CONCLUSIONS: Although patients found receipt of any pre-consultation information helpful, the DA resulted in improved knowledge over standard websites and effectively conveyed that there is time to make a breast cancer surgery decision. Decreasing the urgency patients feel may improve the quality of patient-surgeon interactions and lead to more informed decision-making. PMID- 29246706 TI - How Well Informed Do Patients Feel about Their Breast Cancer Surgery Options? Findings from a Nationwide Survey of Women after Lumpectomy and/or Mastectomy. AB - BACKGROUND: Women diagnosed with breast cancer often describe the process of treatment decision making as bewildering and worrisome. Patients who do not feel completely informed about their surgical options might make choices that are suboptimal or regretted later. The Institute of Medicine has called for more research on why breast cancer patients are inadequately informed about treatment options. The aims of the study were to explore how women become informed about their breast cancer surgery treatment options and to identify improvement opportunities. STUDY DESIGN: A nationwide internet survey was conducted among women who reported being surgically treated by lumpectomy only (n = 215), mastectomy only (n = 140), or by both procedures (n = 132) for breast cancer. To improve generalizability, Census-based enrollment quotas were applied for geographic region, health insurance, and income. RESULTS: Only 47% (95% CI 41% to 54%) of lumpectomy-only patients, 67% (95% CI 59% to 75%) of mastectomy-only patients, and 28% (95% CI 21% to 35%) of patients having both procedures said they felt "completely informed" about treatment options before their operations. "Making a quick decision" was more important than "thoroughly researching all options" for 35% of lumpectomy-only patients, 31% of mastectomy-only patients, and 22% of patients having both procedures. Nearly all women used some other source of information to research treatment options. Lumpectomy-only and mastectomy-only patients who relied on their surgeon's recommendation without additional research were significantly less likely to report feeling "completely informed" (odds ratio 0.6; 95% CI 0.4 to 0.9; p < 0.02). CONCLUSIONS: Many women who had surgery for breast cancer did not feel completely informed about their surgical options. This appears to be due, in part, to a false sense of urgency and perhaps insufficient or misdirected information gathering by patients. The responsibility for fully informing patients about their treatment options must be better fulfilled by surgeons. PMID- 29246707 TI - Reprint of: Efficacy and safety of different doses of dezocine for preemptive analgesia in gynecological laparoscopic surgeries: A prospective, double blind and randomized controlled clinical trial. AB - BACKGROUND: The incidence of reproductive system tumors in Chinese females is increasing year by year, with the trend of younger onset ages. Laparoscopic surgery has been recognized by the majority of medical staff and patients, but the postoperative pain still exists. Therefore, it has become the focus of attention of medical workers to take effective analgesia measures to alleviate postoperative pain as well as to improve the degree of comfort and satisfaction for the patients. OBJECTIVES: The research objective was to study the effect of different doses of dezocine preemptive analgesia on the safety and the pain post laparoscopic surgeries, in order to explore the best dose of dezocine for postoperative analgesia in gynecological laparoscopic surgeries. METHODS: Gynecological laparoscopic surgery patients conformed to the criteria (n = 390) were randomly divided into three groups (group A, B and C) by the methods of randomized, double-blind studies. 0.1 mg/kg, 0.15 mg/kg or 0.2 mg/kg dezocine was intravenously injected 15 min before surgeries for preemptive analgesia. VAS score, Ramsay score and MMSE score were used to evaluate the efficacy and safety of dezocine in preemptive analgesia and sedation, and the use of adjuvant analgesic drugs and the incidence of adverse reactions were also observed. RESULTS: The VAS scores of the 0.15 mg/kg and 0.2 mg/kg dezocine groups were significantly lower than that of the 0.1 mg/kg group at 2h, 4h, 6h, 8h, 12h and 24h post-surgery, and the difference was statistically significant (p < 0.05). There was no statistically significant difference between the 0.15 mg/kg and 0.2 mg/kg groups (p > 0.05) except for the 12h time point. The MMSE scores 12h post surgery of the three groups were compared with those 12h prior-to-surgery, and the differences were not statistically significant (p > 0.05) and no increase in the incidence of cognitive impairment was observed. The use rate of analgesic drugs in the 0.1 mg/kg group was significantly higher than those in the 0.15 mg/kg and 0.2 mg/kg groups, and the difference was statistically significant (p < 0.05). There were no significant differences in the incidence of adverse events between the three groups (P > 0.05). CONCLUSIONS: The analgesia and sedation effects of dezocine were enhanced with the increase of usage dose, which suggested that the effects of dezocine were dose-dependent. Intravenous injection of 0.15 mg/kg dezocine 15 min before gynecological laparoscopic surgery showed better analgesic and sedative effects as well as less adverse reactions, and should be the appropriate dose to be used in the preemptive analgesia in gynecological laparoscopic surgeries. PMID- 29246709 TI - Discussion on reply to Foley et al., 'Acute myeloid leukemia with t(14;21) involving RUNX1 and SYNE2: A novel favorable-risk translocation?' PMID- 29246708 TI - Prescription of DPP-4 Inhibitors to Type 2 Diabetes Mellitus Patients With Renal Impairment: A UK Primary Care Experience. AB - Members of the dipeptidyl peptidase-4 inhibitor drug class are indicated for glycemic control in patients with type 2 diabetes mellitus and all, except linagliptin, require dose adjustment in renal impairment. A cross-sectional analysis of a cohort of type 2 diabetes mellitus patients treated with dipeptidyl peptidase-4 inhibitors identified in the Clinical Practice Research Datalink was conducted to explore compliance with the renal adjustment requirements of the Summaries of Product Characteristics. Approximately one third of type 2 diabetes mellitus patients with creatinine clearance <50 mL/min who were at risk of inappropriate prescribing, were initiated on a DPP-4 inhibitor at a higher dose than the specified in their respective Summary of Product Characteristics. PMID- 29246710 TI - Hybrid Procedures for Pulmonary Nodule Resection: The Beginning of a New Era. PMID- 29246711 TI - Validity and reliability of Doppler ultrasonography and direct arterial blood pressure measurements in anaesthetized dogs weighing less than 5 kg. AB - OBJECTIVE: To assess the validity and reliability of Doppler ultrasonography (DOP) as compared with invasive arterial blood pressure measurements in anaesthetized dogs weighing less than 5 kg. STUDY DESIGN: Controlled, prospective, clinical study. ANIMALS: A total of 41 privately owned dogs weighing less than 5 kg. METHODS: The dogs were anaesthetized, and an intra-arterial catheter was placed aseptically in the dorsal pedal artery of the pelvic limb to perform invasive blood pressure (IBP) measurement. The contralateral metatarsal surface of the foot was clipped in order to perform DOP. Both techniques were used to record blood pressure measurements every 5 minutes during surgical procedures. The blood pressure measurements were categorized into two groups: hypotensive [mean arterial pressure (MAP) < 60 mmHg] and normotensive (MAP between 60 and 120 mmHg). A linear mixed model was used to compare the DOP and IBP values. The results were evaluated according to the requirements of the American College of Veterinary Internal Medicine (ACVIM) guidelines for the validation of devices. RESULTS: DOP provided higher values compared to the systolic arterial blood pressure (SAP) and MAP of IBP measurements. The closest agreement between the two techniques was found for SAP; the bias was 8.8, and limits of agreement (LOA) were -32.9 and 50.4. Similar results were observed when the IBP technique was categorized. The closest agreement was for SAP in animals categorized as normotensive; the bias was 8.2, and LOAs were -32.8 and 49.2. The level of agreement between DOP and IBP did not meet the ACVIM recommendations. CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest there is poor agreement between DOP and IBP measurements in anaesthetized dogs weighing less than 5 kg. Hence, the use of DOP in these animals could be misleading. PMID- 29246712 TI - Selection of appropriate endotracheal tube size using thoracic radiography in Beagle dogs. AB - OBJECTIVE: To determine the optimal endotracheal tube size in Beagle dogs using thoracic radiography. STUDY DESIGN: Prospective, randomized, crossover experimental study. ANIMALS: A total of eight healthy adult Beagle dogs. METHODS: Lateral thoracic radiographs were used to measure the internal tracheal diameter at the thoracic inlet. This measurement was multiplied by 60, 70 and 80% to determine the outer diameter of the endotracheal tube for each dog. In each treatment, medetomidine (5 MUg kg-1) was administered intravenously (IV) for premedication. Anesthesia was induced with alfaxalone (2 mg kg-1) IV and maintained with isoflurane. After induction of anesthesia, the resistance to passage of the endotracheal tube through the trachea was scored by a single anesthesiologist. Air leak pressures (Pleak) were measured at intracuff pressures (Pcuff) of 20 and 25 mmHg (27 and 34 cmH2O). The results were analyzed using Friedman tests and repeated measures anova. RESULTS: There were statistically significant increases in resistance as the endotracheal tube size increased (p = 0.003). When Pcuff was 20 mmHg, mean Pleak for the 60, 70 and 80% treatments were 9.7 +/- 6.7, 16.2 +/- 4.2 and 17.4 +/- 3.9 cmH2O, respectively, but no significant differences were found. When Pcuff was 25 mmHg, mean Pleak for the 60, 70 and 80% treatments were 10.6 +/- 8.5, 19.7 +/- 4.9 and 20.8 +/- 3.6 cmH2O, respectively, and statistically significant increases were found between treatments 60 and 70% (p = 0.011) and between treatments 60 and 80% (p = 0.020). Three dogs in the 80% treatment had bloody mucus on the endotracheal tube cuff after extubation. CONCLUSIONS AND CLINICAL RELEVANCE: Results based on resistance to insertion of the endotracheal tube and the ability to achieve an air-tight seal suggest that an appropriately sized endotracheal tube for Beagle dogs is 70% of the internal tracheal diameter measured on thoracic radiography. PMID- 29246714 TI - Public Perceptions About Nerve Injury From Hip Replacement Surgery. AB - BACKGROUND: Nerve injury is a distressing complication for patients and surgeons that is difficult and frustrating to understand and treat. Whether the standard of care has been met when this complication occurs is a common question for both patients and surgeons but there is no information about how the public feels about nerve injury. METHODS: The author surveyed 1409 individuals insured in a senior products health program using a 22-item questionnaire about nerve injury during hip replacement. Participants were given written descriptions of total hip arthroplasty, nerve injury, and the standard of care. RESULTS: Seventeen percent of participants indicated that a direct nerve laceration is a standard of care violation. Respectively, 98%, 100%, 94%, and 97% of participants responded that the standard of care requires the surgeon to promptly identify the nerve injury, completely inform the patient about the nature and prognosis of the injury, and present options for treating the nerve injury. Eleven percent indicated that they lack trust in health care. Participants with distrust were more likely to find a standard of care violation than other participants. Women and non-white participants responded more commonly that a standard of care violation occurred with the nerve injury. Income level, age, prior surgery, and educational background were not differentiating factors as to whether participants found that a violation of the standard of care had occurred. CONCLUSION: Most participants would accept the possibility of nerve injury during hip replacement but they would expect to be informed in advance that this complication is possible. PMID- 29246713 TI - Determination of physiological dead space in anaesthetized horses: a method comparison study. AB - OBJECTIVE: To compare two methods of Bohr-Enghoff physiological dead space to tidal volume ratio (Vd/VtBohr-Enghoff) determination using a mixing chamber and an E-CAiOVX metabolic monitor. STUDY DESIGN: Prospective, clinical, method comparison study. ANIMALS: Twenty horses anaesthetized for elective orthopaedic procedures. METHODS: Horses were anaesthetized with isoflurane in oxygen and the lungs were mechanically ventilated (Vt 15+/-2 mL kg-1). Arterial blood was sampled to provide arterial partial pressure of carbon dioxide (PaCO2) for dead space calculation using a metabolic monitor. Mixed expired partial pressure of carbon dioxide (PeCO2) obtained from the custom-made mixing chamber was recorded at the time of arterial blood sampling. Dead space fraction was calculated using the Enghoff modification of the Bohr equation. Agreement between the methods was assessed by Bland-Altman test. A clinically acceptable error was defined to be <= 10%. RESULTS: Forty-nine simultaneous Vd/VtBohr-Enghoff results were obtained. There was no clinically significant bias between the mixing chamber and E-CAiOVX. The limits of agreement were within a priori defined error (bias+/-95% limits of agreement: -0.022+/-0.078). CONCLUSIONS AND CLINICAL RELEVANCE: Acceptable agreement was found between the two methods. The E-CAiOVX metabolic monitor might be a suitable device for measuring Vd/VtBohr-Enghoff in anaesthetized horses. PMID- 29246715 TI - Comparable Cumulative Incidence of Late Periprosthetic Femoral Fracture and Aseptic Stem Loosening in Uncemented Total Hip Arthroplasty-A Concise Follow-Up Report at a Minimum of 20 Years. AB - BACKGROUND: There is a lack of long-term studies into the third decade reporting on the incidence of periprosthetic femoral fracture (PPFF) and aseptic stem loosening (ASL) after cementless total hip arthroplasty (THA). The aim of the present retrospective, longitudinal cohort study was to compare the cumulative incidence of PPFF and ASL in a consecutive cohort of 326 patients with 354 primary uncemented THAs after 20-25 years and to identify risk factors being associated with PPFFs. METHODS: Postoperative femoral fractures were investigated for timing, mechanism of injury, Vancouver classification, and subsequent treatment. The cumulative incidence of PPFF and ASL was estimated using Kaplan Meier survival analysis. Risk factors for PPFFs were analyzed using a Cox proportional hazards regression model. RESULTS: One hundred sixty-three patients (180 hips) were available for follow-up at a mean of 22 years. Twenty-one fractures occurred during the follow-up period. The cumulative incidence of PPFF was 1.6% at 10 years, 4.5% at 17 years, and 9.4% at 22 years after surgery. The cumulative incidence of PPFF and ASL after 22 years was comparable (9.4% [95% confidence interval, 5.9%-14.7%] and 6.9% [95% confidence interval, 4.5%-10.5%]). Gender, age at surgery, diagnosis, cup revision, and canal fill index of the stem in the proximal femur were no risk factors for the occurrence of a PPFF. CONCLUSION: The cumulative incidence of PPFF after primary uncemented THA further increased in the second decade and reached the incidence of ASL in the third decade, while no risk factors for the occurrence of a PPFF could be identified. PMID- 29246716 TI - Clinical Performance, Patient Reported Outcome, and Radiological Results of a Short, Tapered, Porous, Proximally Coated Cementless Femoral Stem: Results up to Seven Years of Follow-Up. AB - BACKGROUND: The primary aim of our study was to assess clinical performance, patient reported outcome and radiological results of cementless primary total hip arthroplasty using Tri-Lock Bone Preservation Stem. METHODS: Between March 2010 and June 2012, 163 consecutive patients, were enrolled in the study. Patients were assessed clinically and radiographically prior to surgery as well as at 6, 12, 24 months and then at 5, 6, and 7 years postoperatively. RESULTS: Using the Dorr classification, 39 patients (23.9%) were classified as Dorr A, 116 patients (71.2%) as Dorr B, and 8 patients (4.9%) as Dorr C. A total of 139 patients (85.3%) received a high offset, whereas 24 patients (14.7%) received a standard offset stem. Total Harris Hip Score of the patients increased from a mean of 27.29 (+/-4.6) preoperatively, upto 97.28 (+/-9.0) after 5 years. Mean preoperative Short Form-12 (SF-12) Physical Health Composite Scale score was 27.31 (+/-3.8). After 5 year was 55.3 (34-57). The mean preoperative SF-12 Mental Health Composite Scale score was 57.02 (+/-5.9). After 5 year was 59.3 (28.7 60.8). Only one patient underwent revision surgery for dislocation and revision of the head. CONCLUSION: Tri-lock Bone Preservation Stem DePuy proved to be an easy-to-use device. Results obtained up to 7 years of FU show excellent clinical performance, as well as radiographic osseointegration, with no cases of aseptic loosening and no images of progressive radiolucent lines or periprosthetic osteolysis. PMID- 29246717 TI - Comparative Analysis of the Reconstruction of Individual Hip Anatomy Using 3 Different Cementless Stem Designs in Patients With Primary Hip Osteoarthritis. AB - BACKGROUND: We questioned whether there was a radiographic difference in hip geometry reconstruction and implant fixation between 3 different cementless stem design concepts in patients with primary end-stage hip osteoarthritis. METHODS: We retrospectively evaluated the preoperative and postoperative radiographs by 2 independent and blinded reviewers in a series of 264 consecutive patients who had received either a straight double-tapered stem with 3 offset options (group A), a straight double-tapered stem with 2 shape options and modular necks (group B), and a bone-preserving curved tapered stem with 4 offset options (group C). The following parameters were assessed: acetabular, femoral and hip offset (HO), center of rotation height, leg length difference (LLD), and the endosteal fit of stem in the proximal femur (canal fill index). Group comparisons were performed using a one-way analysis of variance and subsequent pairwise comparisons (t test). RESULTS: Postoperatively, HO could be equally restored with all 3 stem designs (P = .079). The postoperative LLD was smaller in group C compared to group A (0.8 mm [standard deviation, 3.2] vs 2.6 mm [standard deviation, 4.5], P = .002). Best combined reconstruction of HO and LLD could be achieved with the short curved stem by junior and senior surgeons (HO: -2.0 and -2.1 mm; LLD: 1.9 and 0.7 mm, respectively). The proximal and mid-height canal fill indexes were higher in groups B and C compared to group A, indicating a better metaphyseal and diaphyseal fit in the proximal femur (both P < .001). CONCLUSION: All 3 cementless stem designs allowed for good hip geometry reconstruction. Multiple shape and offset options allowed for a better metaphyseal stem fit and offered minor clinical advantages for leg length reconstruction. Modular necks did not provide reconstructive advantages in patients with primary hip osteoarthritis. PMID- 29246718 TI - Lower Extremity Arterial Calcification on Preoperative Knee Radiographs as a Predictor of Postoperative Cardiovascular Events After Primary Total Knee Arthroplasty. AB - BACKGROUND: A cross-sectional study of total knee arthroplasty (TKA) patients was conducted to determine the association of lower-extremity arterial calcification (LEAC) with acute perioperative cardiovascular events (CVEs). METHODS: Regression modeling was used to examine the association of radiographic presence of LEAC and acute myocardial infarction (MI), perioperative CVE, 30-day CVE readmit, and 30 day and 1-year mortality. RESULTS: Of 900 TKA patients, LEAC was identified in 21.1%. Of LEAC cases, 1.6% had an acute MI vs 0.1% of non-LEAC cases (P = .031). Perioperative CVE rate was 5.8% for LEAC vs 1.5% for non-LEAC (P = .002). Having LEAC was identified as a significant risk factor for a perioperative CVE (odds ratio [OR] 2.83; 95% confidence interval [CI] 1.09-7.35). Because of limited number of acute MI events, absence of 30-day CVE readmit, 30-day mortality, and few 1-year mortality events, computing OR for these was not possible. Likewise, because of small number of events (n = 3), estimates for the odds of LEAC cases having an acute MI are less reliable, yielding extremely large random errors (OR 11.37; 95% CI 0.09-597.93) and must be interpreted with caution. The OR for 1 year mortality was 1.88 (95% CI 0.17-13.20), but again with large random errors. CONCLUSION: Our study shows that LEAC around the knee is associated with an increased risk of having a perioperative CVE. Crude radiographic detection of LEAC around the knee has the potential to improve risk stratification for TKA patients by informing the surgeon of the need for further preoperative cardiac workup. PMID- 29246719 TI - Increase in Benign Squeaking Rate at Five-Year Follow-Up: Results of a Large Diameter Ceramic-on-Ceramic Bearing in Total Hip Arthroplasty. AB - BACKGROUND: Squeaking is an on-going complication with a variable incidence of 0.5%-20.7%. The mechanism of squeaking has not been understood completely and is most likely multifactorial in nature. Previously, we have reported on a squeaking rate of 7.3% at 2 years. Our current results show a substantial increase in the squeaking incidence from 7.3% to 17.4% with the DeltaMotion articulation at the 5 year follow-up. METHODS: Two hundred six total hip arthroplasties with a large ceramic-on-ceramic bearing were performed on 195 patients by 2 senior authors. The minimum duration of follow-up was 5 years (range 5-6.2). RESULTS: The mean Harris Hip Score remained stable at 91.7 at 5 years compared to 92 after 2 years. However, we observed an increase in the squeaking rate from 7.3% after 2 years to 17.4% after 5 years. As in previous studies, we did not find significant differences between the silent and squeaking group in relation to age, height, weight, and femoral head diameter. In contrast, others reported no significant differences regarding range of motion and gender between the silent and the squeaking hip group at 2 years of follow-up, whereas at 5 years, the squeaking group showed a significantly higher combined range of motion and a higher relative risk of squeaking in women compared to the silent group. CONCLUSION: While large diameter ceramic bearings may produce squeaking, especially in female patients, our mid-term clinical results of a large ceramic-on-ceramic bearing in total hip arthroplasty are encouraging. Nevertheless, long-term follow-up is recommended. PMID- 29246720 TI - A techno-economic evaluation of anaerobic biogas producing systems in developing countries. AB - Biogas production has been the focus of many individuals in the developing world; there have been several investigations that focus on improving the production process and product quality. In the developing world the lack of advanced technology and capital has hindered the development of energy production. Renewable energy has the potential to improve the standard of living for most of the 196 countries which are classified as developing economies. One of the easiest renewable energy compounds that can be produced is biogas (bio-methane). Biogas can be produced from almost any source of biomass through the anaerobic respiration of micro-organisms. Low budget energy systems are reviewed in this article along with various feedstock sources. Adapted gas purification and storage systems are also reviewed, along with the possible economic, social, health and environmental benefits of its implementation. PMID- 29246721 TI - Functional Outcomes After De-escalated Chemoradiation Therapy for Human Papillomavirus-Positive Oropharyngeal Cancer: Secondary Analysis of a Phase 2 Trial. AB - PURPOSE: To analyze functional outcomes for patients treated on a phase 2 trial of de-escalated chemoradiation therapy for human papillomavirus-positive oropharyngeal cancer. METHODS AND MATERIALS: Patient eligibility included p16 positive, stage III or IV oropharyngeal squamous cell carcinoma and a Zubrod performance status of 0 to 1. Treatment was induction chemotherapy with paclitaxel, 175 mg/m2, and carboplatin, area under the curve (AUC) of 6 mg/ml/min, for 2 cycles every 21 days, followed by concurrent paclitaxel, 30 mg/m2, every 7 days with dose-reduced radiation therapy of 54 or 60 Gy. Trends in body weight and body mass index (BMI) were analyzed with gastrostomy tube and narcotic use rates. Functional outcomes were assessed using the University of Washington Quality of Life Scale and the Functional Assessment of Cancer Therapy Head and Neck Scale. RESULTS: Forty-five patients were registered, of whom 40 were evaluable. Only 1 patient had a BMI deemed unhealthy at the completion of treatment. For the 15 patients (38%) with a normal BMI (18-25 kg/m2) before treatment, recovery back to baseline occurred at approximately 18 months (average BMI, 23.2 kg/m2 vs 22.3 kg/m2; P=.09). In 2 patients (5%), gastrostomy tubes were placed during treatment. No patient was enteral feeding tube-dependent at 6 months after treatment. Ninety-five percent of patients tolerated a normal regular diet at last follow-up. CONCLUSIONS: De-escalated chemoradiation therapy may improve functional outcomes as indicated by the relatively low incidence of gastrostomy tube placement and long-term dysphagia. In patients with a normal BMI prior to chemoradiation therapy, BMI recovered to baseline levels. PMID- 29246722 TI - Development and Validation of a Predictive Radiomics Model for Clinical Outcomes in Stage I Non-small Cell Lung Cancer. AB - PURPOSE: To develop and validate a radiomics signature that can predict the clinical outcomes for patients with stage I non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: We retrospectively analyzed contrast-enhanced computed tomography images of patients from a training cohort (n = 147) treated with surgery and an independent validation cohort (n = 295) treated with stereotactic ablative radiation therapy. Twelve radiomics features with established strategies for filtering and preprocessing were extracted. The random survival forests (RSF) method was used to build models from subsets of the 12 candidate features based on their survival relevance and generate a mortality risk index for each observation in the training set. An optimal model was selected, and its ability to predict clinical outcomes was evaluated in the validation set using predicted mortality risk indexes. RESULTS: The optimal RSF model, consisting of 2 predictive features, kurtosis and the gray level co-occurrence matrix feature homogeneity2, allowed for significant risk stratification (log-rank P < .0001) and remained an independent predictor of overall survival after adjusting for age, tumor volume and histologic type, and Karnofsky performance status (hazard ratio [HR] 1.27; P < 2e-16) in the training set. The resultant mortality risk indexes were significantly associated with overall survival in the validation set (log-rank P = .0173; HR 1.02, P = .0438). They were also significant for distant metastasis (log-rank P < .05; HR 1.04, P = .0407) and were borderline significant for regional recurrence on univariate analysis (log-rank P < .05; HR 1.04, P = .0617). CONCLUSIONS: Our radiomics model accurately predicted several clinical outcomes and allowed pretreatment risk stratification in stage I NSCLC, allowing the choice of treatment to be tailored to each patient's individual risk profile. PMID- 29246724 TI - Toxic properties of microsome-associated alpha-synuclein species in mouse primary neurons. AB - alpha-synuclein (alphaS) is a small protein that self-aggregates into alpha helical oligomer species and subsequently into larger insoluble amyloid fibrils that accumulate in intraneuronal inclusions during the development of Parkinson's disease. Toxicity of alphaS oligomers and fibrils has been long debated and more recent data are suggesting that both species can induce neurodegeneration. However while most of these data are based on differences in structure between oligomer and aggregates, often preassembled in vitro, the in vivo situation might be more complex and subcellular locations where alphaS species accumulate, rather than their conformation, might contribute to enhanced toxicity. In line with this observation, we have shown that alphaS oligomers and aggregates are associated with the endoplasmic reticulum/microsomes (ER/M) membrane in vivo and how accumulation of soluble alphaS oligomers at the ER/M level precedes neuronal degeneration in a mouse model of alpha-synucleinopathies. In this paper we took a further step, investigating the biochemical and functional features of alphaS species associated with the ER/M membrane. We found that by comparison with non microsomal associated alphaS (P10), the ER/M-associated alphaS pool is a unique population of oligomers and aggregates with specific biochemical traits such as increased aggregation, N- and C-terminal truncations and phosphorylation at serine 129. Moreover, when administered to murine primary neurons, ER/M associated alphaS species isolated from diseased A53T human alphaS transgenic mice induced neuronal changes in a time- and dose-dependent manner. In fact the addition of small amounts of ER/M-associated alphaS species from diseased mice to primary cultures induced the formation of beads-like structures or strings of fibrous alphaS aggregates along the neurites, occasionally covering the entire process or localizing at the soma level. By comparison treatment with P10 fractions from the same diseased mice resulted in the formation of scarce and small puncta only when administered at high amount. Moreover, increasing the amount of P100/M fractions obtained from diseased and, more surprisingly, from presymptomatic mice induced a significant level of neuronal death that was prevented when neurons were treated with ER/M fractions immunodepleted of alphaS high molecular weight (HMW) species. These data provide the first evidence of the existence of two different populations of alphaS HMW species in vivo, putting the spotlight on the association to ER/M membrane as a necessary step for the acquisition of alphaS toxic features. PMID- 29246723 TI - Familial knockin mutation of LRRK2 causes lysosomal dysfunction and accumulation of endogenous insoluble alpha-synuclein in neurons. AB - Missense mutations in the multi-domain kinase LRRK2 cause late onset familial Parkinson's disease. They most commonly with classic proteinopathy in the form of Lewy bodies and Lewy neurites comprised of insoluble alpha-synuclein, but in rare cases can also manifest tauopathy. The normal function of LRRK2 has remained elusive, as have the cellular consequences of its mutation. Data from LRRK2 null model organisms and LRRK2-inhibitor treated animals support a physiological role for LRRK2 in regulating lysosome function. Since idiopathic and LRRK2-linked PD are associated with the intraneuronal accumulation of protein aggregates, a series of critical questions emerge. First, how do pathogenic mutations that increase LRRK2 kinase activity affect lysosome biology in neurons? Second, are mutation-induced changes in lysosome function sufficient to alter the metabolism of alpha-synuclein? Lastly, are changes caused by pathogenic mutation sensitive to reversal with LRRK2 kinase inhibitors? Here, we report that mutation of LRRK2 induces modest but significant changes in lysosomal morphology and acidification, and decreased basal autophagic flux when compared to WT neurons. These changes were associated with an accumulation of detergent-insoluble alpha-synuclein and increased neuronal release of alpha-synuclein and were reversed by pharmacologic inhibition of LRRK2 kinase activity. These data demonstrate a critical and disease-relevant influence of native neuronal LRRK2 kinase activity on lysosome function and alpha-synuclein homeostasis. Furthermore, they also suggest that lysosome dysfunction, altered neuronal alpha-synuclein metabolism, and the insidious accumulation of aggregated protein over decades may contribute to pathogenesis in this late-onset form of familial PD. PMID- 29246725 TI - Memory and Brain Amyloid and Tau Effects of a Bioavailable Form of Curcumin in Non-Demented Adults: A Double-Blind, Placebo-Controlled 18-Month Trial. AB - OBJECTIVE: Because curcumin's anti-inflammatory properties may protect the brain from neurodegeneration, we studied its effect on memory in non-demented adults and explored its impact on brain amyloid and tau accumulation using 2-(1-{6-[(2 [F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile positron emission tomography (FDDNP-PET). METHODS: Forty subjects (age 51-84 years) were randomized to a bioavailable form of curcumin (Theracurmin(r) containing 90 mg of curcumin twice daily [N = 21]) or placebo (N = 19) for 18 months. Primary outcomes were verbal (Buschke Selective Reminding Test [SRT]) and visual (Brief Visual Memory Test-Revised [BVMT-R]) memory, and attention (Trail Making A) was a secondary outcome. FDDNP-PET signals (15 curcumin, 15 placebo) were determined in amygdala, hypothalamus, medial and lateral temporal, posterior cingulate, parietal, frontal, and motor (reference) regions. Mixed effects general linear models controlling for age and education, and effect sizes (ES; Cohen's d) were estimated. RESULTS: SRT Consistent Long-Term Retrieval improved with curcumin (ES = 0.63, p = 0.002) but not with placebo (ES = 0.06, p = 0.8; between-group: ES = 0.68, p = 0.05). Curcumin also improved SRT Total (ES = 0.53, p = 0.002), visual memory (BVMT-R Recall: ES = 0.50, p = 0.01; BVMT-R Delay: ES = 0.51, p = 0.006), and attention (ES = 0.96, p < 0.0001) compared with placebo (ES = 0.28, p = 0.1; between-group: ES = 0.67, p = 0.04). FDDNP binding decreased significantly in the amygdala with curcumin (ES = -0.41, p = 0.04) compared with placebo (ES = 0.08, p = 0.6; between-group: ES = 0.48, p = 0.07). In the hypothalamus, FDDNP binding did not change with curcumin (ES = -0.30, p = 0.2), but increased with placebo (ES = 0.26, p = 0.05; between-group: ES = 0.55, p = 0.02). CONCLUSIONS: Daily oral Theracurmin may lead to improved memory and attention in non-demented adults. The FDDNP-PET findings suggest that symptom benefits are associated with decreases in amyloid and tau accumulation in brain regions modulating mood and memory. PMID- 29246726 TI - K-ras mutation promotes ionizing radiation-induced invasion and migration of lung cancer in part via the Cathepsin L/CUX1 pathway. AB - K-ras mutation is involved in cancer progression including invasion and migration, but the underlying mechanism is not yet clear. Cathepsin L is a lysosomal cysteine protease and has recently been associated with invasion and migration in human cancers when it is overexpressed. Our recent studies have shown that ionizing radiation (IR) enhanced expression of cathepsin L and increased invasion and migration of tumor cells, but the molecular mechanism is still unclear. In the present study, the effects of K-ras mutation and IR induced invasion and migration of lung cancer as well as the underlying mechanisms were investigated both in vitro and in vivo. Firstly, the levels of cathepsin L and epithelial mesenchymal transition (EMT) marker proteins remarkably changed in A549 (K-ras mutant) after irradiation compared with H1299 (K-ras wild), thereby promoting invasion and migration. Additionally, cathepsin L and its downstream transcription factor CUX1/p110 were increased after irradiation in A549 transfected with CUX1/p200, and the proteolytic processing of CUX1 by cathepsin L was remarkably increased after co-transfection of CUX1/p200 and cathepsin L lentivirus in H1299. In addition, delivery of a mutant K-ras (V12) into HEK 293 cells stimulated EMT after irradiation due to the accumulation of cathepsin L. Moreover, mutated K-ras was associated with IR-induced cathepsin L and EMT in BALB/c nude mice. Finally, the level of cathepsin L expression was higher in samples carrying a K-ras mutation than in wild-type K-ras samples and the mesenchymal markers were upregulated in the samples of mutant K-ras, whereas the epithelial marker E-cadherin was downregulated in non-small cell lung cancers tissues. In conclusion, the findings demonstrated that mutated K-ras promotes cathepsin L expression and plays a pivotal role in EMT of human lung cancer. The regulatory effect of IR-induced cathepsin L on lung cancer invasion and migration was partially attributed to the Cathepsin L /CUX1-mediated EMT signaling pathway. This study will provide cathepsin L as a potential target for tumor therapy. PMID- 29246727 TI - Examination of environmentally friendly "green" logistics behavior of managers in the pharmaceutical sector using the Theory of Planned Behavior. AB - BACKGROUND: Logistics activities play a prominent role in enabling manufacturers, distribution channels, and pharmacies to work in harmony. Nowadays these activities have become increasingly striking in the pharmaceutical industry and seen as a development area for this sector. Additionally, green practices are beginning to be more attracting particularly in decreasing costs and increasing image of pharmaceutical companies. OBJECTIVE: The main objective of this study was modeling green logistics (GL) behavior of the managers in the pharmaceutical sector in the theory of planned behavior (TPB) frame via structural equation modeling (SEM). METHODS: A measurement tool was developed according to TPB. Exploratory factor analysis was conducted to determine subfactors of GL behavior. In the second step, confirmatory factor analysis (CFA) was conducted for confirming whether there is a relationship between the observed variables and their underlying latent constructs. Finally, structural equation model was conducted to specify the relationships between latent variables. RESULTS: In the proposed green logistics behavior (GLB) model, the positive effect of environmental attitude towards GL, perceived behavioral control related GL, and subjective norm about GL on intention towards GL were found statistically significant. Nevertheless, the effect of attitude towards costs of GL on intention towards GL was not found statistically significant. Intention towards GL has been found to have a positive statistically significant effect on the GL behavior. CONCLUSIONS: Based on the results of this study, it is possible to say that TPB is an appropriate theory for modeling green logistics behavior of managers. This model can be seen as a guide to the companies in the pharmaceutical sector to participate in green logistics. PMID- 29246728 TI - An enzyme-linked immunosorbent assay for measuring GPIHBP1 levels in human plasma or serum. AB - BACKGROUND: Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), a glycosylphosphatidylinositol (GPI)-anchored protein of capillary endothelial cells, transports lipoprotein lipase to the capillary lumen and is essential for the lipolytic processing of triglyceride rich lipoproteins. OBJECTIVE: Because some GPI-anchored proteins have been detected in plasma, we tested whether GPIHBP1 is present in human blood and whether GPIHBP1 deficiency or a history of cardiovascular disease affected GPIHBP1 circulating levels. METHODS: We developed 2 monoclonal antibodies against GPIHBP1 and used the antibodies to establish a sandwich enzyme-linked immunosorbent assay (ELISA) to measure GPIHBP1 levels in human blood. RESULTS: The GPIHBP1 ELISA was linear in the 8 to 500 pg/mL range and allowed the quantification of GPIHBP1 in serum and in pre- and post-heparin plasma (including lipemic samples). GPIHBP1 was undetectable in the plasma of subjects with null mutations in GPIHBP1. Serum GPIHBP1 median levels were 849 pg/mL (range: 740 1014) in healthy volunteers (n = 28) and 1087 pg/mL (range: 877-1371) in patients with a history of cardiovascular or metabolic disease (n = 415). There was an extremely small inverse correlation between GPIHBP1 and triglyceride levels (r = 0.109; P < .0275). GPIHBP1 levels tended to be slightly higher in patients who had a major cardiovascular event after revascularization. CONCLUSION: We developed an ELISA for quantifying GPIHBP1 in human blood. This assay will be useful to identify patients with GPIHBP1 deficiency and patients with GPIHBP1 autoantibodies. The potential of plasma GPIHBP1 as a biomarker for metabolic or cardiovascular disease is yet questionable but needs additional testing. PMID- 29246729 TI - A comparison of the effects of low- and high-dose atorvastatin on lipoprotein metabolism and inflammatory cytokines in type 2 diabetes: Results from the Protection Against Nephropathy in Diabetes with Atorvastatin (PANDA) randomized trial. AB - BACKGROUND: Statin therapy is recommended in type 2 diabetes (T2DM) although views on treatment intensity and therapeutic targets remain divided. OBJECTIVES: Our objectives were to compare the effects of high-intensity and moderate intensity atorvastatin treatment on lipoprotein metabolism and inflammatory markers and how frequently treatment goals are met in high-risk T2DM patients. METHODS: Patients with T2DM and albuminuria (urinary albumin:creatinine ratio >5 mg/mmol, total cholesterol <7 mmol/L, proteinuria <2 g/d, creatinine <200 MUmol/L) were randomized to receive atorvastatin 10 mg (n = 59) or 80 mg (n = 60) daily. Baseline and 1-year follow-up data are reported. RESULTS: Patients were at high cardiovascular disease risk (observed combined mortality and nonfatal cardiovascular disease annual event rate 4.8%). The non-high-density lipoprotein cholesterol (HDL-C) goal of <2.6 mmol/L was achieved in 72% of participants receiving high-dose atorvastatin, but only in 40% on low-dose atorvastatin (P < .005). The proportion achieving apolipoprotein B (apoB) <0.8 g/L on high-dose and low-dose atorvastatin was 82% and 70%, respectively (NS). Total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, non-HDL-C, oxidized LDL, apoB, glyc-apoB, apolipoprotein E, and lipoprotein-associated phospholipase A2 decreased significantly, more so in participants on high-dose atorvastatin. Adiponectin increased and serum amyloid A decreased without dose dependency. Neither dose produced significant changes in HDL-C, cholesterol efflux, high sensitivity C-reactive protein, glycated hemoglobin, serum paraoxonase-1, lecithin:cholesterol acyltransferase, or cholesteryl ester transfer protein. CONCLUSIONS: High-dose atorvastatin is more effective in achieving non-HDL-C therapeutic goals and in modifying LDL-related parameters. Recommended apoB treatment targets may require revision. Despite the increase in adiponectin and the decrease in serum amyloid A, HDL showed no change in functionality. PMID- 29246730 TI - A case of sitosterolemia misdiagnosed as familial hypercholesterolemia: A 4-year follow-up. AB - Familial hypercholesterolemia (FH) is a common inherited disease that exhibits significantly increased levels of low-density lipoprotein cholesterol (LDL-C), skin or tendon xanthomas, corneal arcus and premature coronary heart disease (CHD). The prevalence of heterozygous FH is nearly 1/300 worldwide, and the prevalence of homozygous FH (HoFH) is 1/160,000 - 1/300,000. The Dutch Lipid Clinic Network diagnostic (DLCN) criteria is the most commonly recommended criteria for diagnosing FH patients. However, another disease with a similar clinical phenotype to FH must be differentiated from FH. This disease is a rare autosomal recessive disorder, sitosterolemia, and its incidence rate is approximately 1/5 million. We report a 16-month-old child with suspected HoFH and LDL-C levels that were reduced from 14.69 mmol/L to 3.24 mmol/L after dietary control without statin therapy. Gas chromatography detection of plant sterol levels and targeted exon sequencing chips for genetic testing were used to reach confirmed the diagnosis of sitosterolemia. PMID- 29246731 TI - A common variant in ARHGEF10 alters delta-6 desaturase activity and influence susceptibility to hypertriglyceridemia. AB - BACKGROUND: Numbers of single nucleotide polymorphisms (SNPs) associated with fatty acid desaturase activities have been previously identified within the FADS1 FADS2 gene cluster, which encodes delta-5 (D5D) and delta-6 (D6D) desaturases, respectively. OBJECTIVE: We aimed at further characterizing the genetic variability associated with D5D and D6D activities on a genome-wide scale. METHODS: We conducted a genome-wide association study of D5D and D6D activities in a cohort of 141 individuals from the greater Quebec City metropolitan area using the Illumina HumanOmni5-Quad BeadChip. Estimates of D5D and D6D activities were computed using product-to-precursor fatty acid ratios, arachidonic acid (AA)/dihomo-gamma-linolenic acid (DGLA) for D5D, and DGLA/linoleic acid (LA) for D6D. Levels of fatty acids were measured by gas chromatography in plasma phospholipids. RESULTS: We identified 24 previously reported SNPs associated with fatty acid levels and desaturase activities as significantly associated with D5D activity within the FADS1-FADS2 gene cluster (lead SNP rs174566/A>G). Furthermore, we identified 5 novel loci potentially associated with D5D activity at chromosomes 1, 6, 4, 8 and 19. A novel SNP associated with D6D activity and mapped to the ARHGEF10 locus (rs2280885/A>G) was identified, with carriers of the rare allele showing a significant increase in D6D activity and plasma triglyceride levels. After multiple testing correction by permutation, only rs174566 and rs2280885 remained significantly associated to D5D and D6D activity estimates, respectively. CONCLUSIONS: These results confirm previous genetic associations within the FADS1-FADS2 gene cluster with D5D activity. A novel genetic variation associated with higher D6D activity within the ARHGEF10 gene is potentially altering plasma triglyceride levels. PMID- 29246732 TI - Inflammation on Prostate Needle Biopsy is Associated with Lower Prostate Cancer Risk: A Meta-Analysis. AB - PURPOSE: We performed a comprehensive literature review and meta-analysis to evaluate the association of inflammation on prostate needle biopsies and prostate cancer risk. MATERIALS AND METHODS: We searched Embase(r), PubMed(r) and Web of ScienceTM from January 1, 1990 to October 1, 2016 for abstracts containing the key words prostate cancer, inflammation and biopsy. Study inclusion criteria were original research, adult human subjects, cohort or case-control study design, histological inflammation on prostate needle biopsy and prostate cancer on histology. Two independent teams reviewed abstracts and extracted data from the selected manuscripts. Combined ORs and 95% CIs of any, acute and chronic inflammation were calculated using the random effects method. RESULTS: Of the 1,030 retrieved abstracts 46 underwent full text review and 25 were included in the final analysis, comprising a total of 20,585 subjects and 6,641 patients with prostate cancer. There was significant heterogeneity among studies (I2 = 84.4%, p <0.001). The presence of any inflammation was significantly associated with a lower prostate cancer risk in 25 studies (OR 0.455, 95% CI 0.337-0.573). There was no evidence of publication bias (p >0.05). When subanalyzed by inflammation type, acute inflammation in 4 studies and chronic inflammation in 15 were each associated with a lower prostate cancer risk (OR 0.681, 95% CI 0.450-0.913 and OR 0.499, 95% CI 0.334-0.665, respectively). CONCLUSIONS: In a meta-analysis of 25 studies inflammation on prostate needle biopsy was associated with a lower prostate cancer risk. Clinically the presence of inflammation on prostate needle biopsy may lower the risk of a subsequent prostate cancer diagnosis. PMID- 29246733 TI - Individualizing Urinary Incontinence Treatment: Research Needs Identified at NIDDK Workshop. PMID- 29246734 TI - Assessment of Serum microRNA Biomarkers to Predict Reclassification of Prostate Cancer in Patients on Active Surveillance. AB - PURPOSE: Conventional clinical variables cannot accurately differentiate indolent from aggressive prostate cancer in patients on active surveillance. We investigated promising circulating miRNA biomarkers to predict the reclassification of active surveillance cases. MATERIALS AND METHODS: We collected serum samples from 2 independent active surveillance cohorts of 196 and 133 patients for the training and validation, respectively, of candidate miRNAs. All patients were treatment naive and diagnosed with Gleason score 6 prostate cancer. Samples were collected prior to potential reclassification. We analyzed 9 circulating miRNAs previously shown to be associated with prostate cancer progression. Logistic regression and ROC analyses were performed to assess the predictive ability of miRNAs and clinical variables. RESULTS: A 3-miR (miRNA-223, miRNA-24 and miRNA-375) score was significant to predict patient reclassification (training OR 2.72, 95% CI 1.50-4.94 and validation OR 3.70, 95% CI 1.29-10.6). It was independent of clinical characteristics in multivariable models. The ROC AUC was maximized when combining the 3-miR score and prostate specific antigen, indicating additive predictive value. The 3-miR score plus the prostate specific antigen panel cutoff achieved 89% to 90% negative predictive value and 66% to 81% specificity. CONCLUSIONS: The 3-miR score combined with prostate specific antigen represents a noninvasive biomarker panel with high negative predictive value. It may be used to identify patients on active surveillance who have truly indolent prostate cancer. PMID- 29246735 TI - Cardiac arrest in pregnancy. AB - Cardiac arrest in pregnancy is a rare and frightening event. Although not every obstetrician will encounter cardiac arrest in pregnancy during their career, it is imperative to be prepared to manage this acute emergency. The management is particularly complex due to maternal physiologic changes from pregnancy and the simultaneous management of two patients, the mother and fetus. In 2010, the American Heart Association released their first scientific statement on guidelines for management of cardiac arrest in pregnancy that has since been updated in 2015. All providers who care for pregnant patients should be aware of these guidelines and ready to manage cardiac arrest in pregnancy because correct and timely interventions can affect real world outcomes. PMID- 29246736 TI - Analysis of the correlation between deformational plagiocephaly and neurodevelopment delay: Methodological issues. PMID- 29246737 TI - Immediate nipple reconstruction during skin-sparing mastectomy utilising the nipple sharing technique and harvesting the nipple graft from the mastectomy specimen. PMID- 29246738 TI - Liposuction as an effective treatment for lower extremity lymphoedema: A single surgeon's experience over nine years. AB - BACKGROUND: Lymphoedema is a chronic, debilitating condition caused by a compromised lymphatic system. In recent years, the success of treating upper extremity lymphoedema with liposuction has been translated to patients with lower extremity lymphoedema (LEL), yet there remains a paucity of clinical evidence firmly supporting its use within this patient group. METHODS: 69 patients with LEL (72 legs) were consecutively treated with liposuction by a single surgeon. Compression garments were applied in theatre and continued postoperatively. RESULTS: Mean preoperative volume of oedema was 4372 mL (range 229-15,166 mL), and mean volume of aspirate was 4550 mL (range 575-12,150 mL). There were no major surgical complications. An average reduction in volume of leg oedema of 85% was found at 3 months (n = 72), 88% at 1 year (n = 60), 94% at 2 years (n = 41) and 90% at 5 years (n = 15). CONCLUSIONS: We have demonstrated that liposuction combined with continuous compression therapy (CCT) is a safe and effective technique for treatment of primary and secondary LEL, with a significant reduction of the original excess limb volume. Male patients with primary lymphoedema have the poorest outcomes. Limbs with secondary lymphoedema respond best to this treatment. PMID- 29246739 TI - Surgical-site infection following lymph node excision indicates susceptibility for lymphedema: A retrospective cohort study of malignant melanoma patients. AB - BACKGROUND AND OBJECTIVES: Cancer-related lymphedema is a common complication following lymph node excision. Prevention of lymphedema is essential, as treatment options are limited. Known risk factors are firmly anchored to the cancer treatment itself; however potentially preventable factors such as seroma and surgical-site infection (SSI) have yet to be asserted. METHODS: All malignant melanoma patients treated with sentinel lymph node biopsy (SNB) and/or complete lymph node dissection (CLND) in the axilla or groin between January 2008 and December 2014 were retrospectively identified. Identified patients were followed until March 2017 for the incidence of lymphedema. RESULTS: We identified 70 cases of extremity lymphedema following 640 SNB/CLND. SSI was an independent risk factor for developing lymphedema (HR 8.46, 95%CI 4.37-16.36, p < 0.001), whilst seroma was an independent risk factor for developing SSI (OR 6.92, 95%CI 4.11 12.54, p < 0.001). In addition, the risk of lymphedema was significantly larger following inguinal incisions compared to axillary incisions (HR 2.49, 95%CI 1.36 4.55, p < 0.05). CONCLUSION: SSI was the greatest independent risk factor for developing lymphedema. Additionally, patients' that developed postoperative seroma were at an increased risk of also developing SSI. Future studies should examine if lymphedema can be prevented, by reducing seroma and SSI. PMID- 29246740 TI - Skin tattooing following correction of prominent ears. PMID- 29246741 TI - Influence of chest compression artefact on capnogram-based ventilation detection during out-of-hospital cardiopulmonary resuscitation. AB - BACKGROUND: Capnography has been proposed as a method for monitoring the ventilation rate during cardiopulmonary resuscitation (CPR). A high incidence (above 70%) of capnograms distorted by chest compression induced oscillations has been previously reported in out-of-hospital (OOH) CPR. The aim of the study was to better characterize the chest compression artefact and to evaluate its influence on the performance of a capnogram-based ventilation detector during OOH CPR. METHODS: Data from the MRx monitor-defibrillator were extracted from OOH cardiac arrest episodes. For each episode, presence of chest compression artefact was annotated in the capnogram. Concurrent compression depth and transthoracic impedance signals were used to identify chest compressions and to annotate ventilations, respectively. We designed a capnogram-based ventilation detection algorithm and tested its performance with clean and distorted episodes. RESULTS: Data were collected from 232 episodes comprising 52 654 ventilations, with a mean (+/-SD) of 227 (+/-118) per episode. Overall, 42% of the capnograms were distorted. Presence of chest compression artefact degraded algorithm performance in terms of ventilation detection, estimation of ventilation rate, and the ability to detect hyperventilation. CONCLUSION: Capnogram-based ventilation detection during CPR using our algorithm was compromised by the presence of chest compression artefact. In particular, artefact spanning from the plateau to the baseline strongly degraded ventilation detection, and caused a high number of false hyperventilation alarms. Further research is needed to reduce the impact of chest compression artefact on capnographic ventilation monitoring. PMID- 29246742 TI - Timing of focused cardiac ultrasound during advanced life support - A prospective clinical study. AB - INTRODUCTION: Focused cardiac ultrasound can potentially identify reversible causes of cardiac arrest during advanced life support (ALS), but data on the timing of image acquisition are lacking. This study aimed to compare the quality of images obtained during rhythm analysis, bag-mask ventilations, and chest compressions. METHODS: Adult patients in cardiac arrest were prospectively included during 23 months at a Danish community hospital. Physicians who had completed basic ultrasound training performed subcostal focused cardiac ultrasound during rhythm analysis, bag-mask ventilations, and chest compressions. Image quality was categorised as either useful for interpretation or not. Two echocardiography experts rated images useful for interpretation if all the following characteristics could be determined: 1) right ventricle larger than left ventricle, 2) pericardial fluid, and 3) collapsing ventricles. RESULTS: Images were obtained from 60 of 114 patients undergoing ALS. A higher proportion of the images obtained during rhythm analysis and bag-mask ventilations were useful for interpretation when compared with chest compressions (rhythm analysis vs chest compressions: OR 2.2 (95%CI 1.3-3.8), P = 0.005; bag mask ventilations vs chest compressions: OR 2.0 (95%CI 1.1-3.7), P = 0.03). There was no difference between images obtained during rhythm analysis and bag-mask ventilations (OR 1.1 (95%CI 0.6-2.0), P = 0.74). CONCLUSION: The quality of focused cardiac ultrasound images obtained during rhythm analysis and bag-mask ventilations was superior to that of images obtained during chest compressions. There was no difference in the quality of images obtained during rhythm analysis and bag-mask ventilations. Bag mask ventilations may constitute an overlooked opportunity for image acquisition during ALS. PMID- 29246743 TI - Seize the day and seize seizures after cardiac arrest. PMID- 29246745 TI - Effectiveness of topical gel of medical leech (Hirudo medicinalis) saliva extract on patients with knee osteoarthritis: A randomized clinical trial. AB - Leech saliva extract (LSE) in the liposome-based gel was used as a supplementary treatment to relief the signs and symptoms of osteoarthritis (OA). The saliva of medical leech was extracted and nano liposomes were used to formulate the supplement to enhance skin absorption. A clinical trial was designed to evaluate the therapeutic effects of LSE liposomal gel. Lenquesne and VAS questionnaires were used as indexes of this supplement therapy efficacy for 30 days. Questionnaires analysis showed that after one-month administration of LSE liposomal gel, patients' pain was relieved approximately up to 50%; also, due to reduction in joint inflammation and stiffness, the range of motion was increased and the patients' quality of life was enhanced (p < 0.001). LSE nano scaled liposomal gel as an innovative supplement therapy in OA patients, makes desirable therapeutic approach, which seems to make a significant impact on patient's quality of life and self-care capability. PMID- 29246744 TI - Determinants of occurrence and survival after sudden cardiac arrest-A European perspective: The ESCAPE-NET project. AB - AIMS: The ESCAPE-NET project ("European Sudden Cardiac Arrest network- towards Prevention, Education and New Effective Treatments") aims to study: (1) risk factors and mechanisms for the occurrence of sudden cardiac arrest (SCA) in the population, and (2) risk factors and treatment strategies for survival after SCA on a European scale. METHODS: This is an Horizon2020 funded program of the European Union, performed by a European public-private consortium of 16 partners across 10 EU countries. There are 11 deep-phenotyped SCA cohorts for the study of risk factors and treatment strategies for survival after SCA, and 5 deep phenotyped observational prospective population cohorts for the study of risk factors for occurrence of SCA. Personalized risk scores for predicting SCA onset and for predicting survival after SCA will be derived and validated. RESULTS: The 11 clinical studies with SCA cases comprise 85,790 SCA cases; the 5 observational prospective population cohorts include 53,060 subjects. A total of 15,000 SCA samples will be genotyped for common and rare variants at the Helmholtz Zentrum Munchen (Germany) using the Illumina Global Screening Array which contains > 770,000 SNPs, and after imputation, a database of an estimated > 9 million variants will be available for genome wide association studies. Standardization of risk factors definition and outcomes is ongoing. An Executive Committee has been created along with a Collaboration Policy document. CONCLUSION: ESCAPE-NET will complement ongoing efforts on SCA outside Europe and within Europe including the EuReCa project. PMID- 29246747 TI - TMS over posterior parietal cortex disrupts trans-saccadic visual stability. AB - BACKGROUND: Saccadic eye movements change the retinal location of visual objects, but we do not experience the visual world as constantly moving, we perceive it as seamless and stable. This visual stability may be achieved by an internal or efference copy of each saccade that, combined with the retinal information, allows the visual system to cancel out or ignore the self-caused retinal motion. OBJECTIVE: The current study investigated the underlying brain mechanisms responsible for visual stability in humans with online transcranial magnetic stimulation (TMS). METHODS: We used two classic tasks that measure efference copy: the double-step task and the in-flight displacement task. The double-step task requires subjects to make two memory-guided saccades, the second of which depends on an accurate internal copy of the first. The in-flight displacement task requires subjects to report the relative location of a (possibly displaced) target across a saccade. In separate experimental sessions, subjects participated in each task while we delivered online 3-pulse TMS over frontal eye fields (FEF), posterior parietal cortex, or vertex. TMS was contingent on saccade execution. RESULTS: Second saccades were not disrupted in the double-step task, but surprisingly, TMS over FEF modified the metrics of the ongoing saccade. Spatiotopic performance in the in-flight displacement task was altered following TMS over parietal cortex, but not FEF or vertex. CONCLUSION: These results suggest that TMS disrupted eye-centered position coding in the parietal cortex. Trans-saccadic correspondence, and visual stability, may therefore causally depend on parietal maps. PMID- 29246746 TI - Chronic deep brain stimulation in an Alzheimer's disease mouse model enhances memory and reduces pathological hallmarks. AB - BACKGROUND: Alzheimer's disease (AD) is a progressive degenerative disorder that currently remains extremely disabling. Recent work has shown that deep brain stimulation (DBS) has promising effects in AD patients. In parallel to the clinical trials, we investigated the impact of chronic DBS in 3xTg mice, a well established animal model of AD. METHODS: AD mice were assigned to control (Cont), non-stimulation (NS) and stimulation (DBS) groups, along with age matched wild type controls (WT-Cont). Bilateral electrodes were implanted in the entorhinal cortex to deliver chronic high frequency stimulation for 25 days. Animals were tested in memory behavioral tasks, with post-mortem measurements of pathological markers. RESULTS: We found that chronic DBS in AD mice normalized their impaired performance in the Morris water maze task to that of the WT group in the probe test. In the novel object and novel place preference tasks, AD-DBS mice spent more time at the novel object and novice location compared to AD-NS mice. These cognitive improvements in AD-DBS mice were associated with DBS induced increased neurogenesis in the dentate gyrus, a significant reduction in beta-amyloid plaques, a reduction in CA-1 cellular beta-amyloid-42 levels, decreased cortical total-tau and phosphorylated-tau, along with decreased hippocampal total-tau. CONCLUSION: Overall, we show that chronic DBS of the entorhinal cortex in AD mice improves both memory and AD specific pathological markers. These results support further testing of DBS as a potential treatment in AD patients. PMID- 29246748 TI - Impact of brain shift on subcallosal cingulate deep brain stimulation. AB - BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) is an emerging experimental therapy for treatment-resistant depression. New developments in SCC DBS surgical targeting are focused on identifying specific axonal pathways for stimulation that are estimated from preoperatively collected diffusion-weighted imaging (DWI) data. However, brain shift induced by opening burr holes in the skull may alter the position of the target pathways. OBJECTIVES: Quantify the effect of electrode location deviations on tractographic representations for stimulating the target pathways using longitudinal clinical imaging datasets. METHODS: Preoperative MRI and DWI data (planned) were coregistered with postoperative MRI (1 day, near-term) and CT (3 weeks, long term) data. Brain shift was measured with anatomical control points. Electrode models corresponding to the planned, near-term, and long-term locations were defined in each hemisphere of 15 patients. Tractography analyses were performed using estimated stimulation volumes as seeds centered on the different electrode positions. RESULTS: Mean brain shift of 2.2 mm was observed in the near-term for the frontal pole, which resolved in the long-term. However, electrode displacements from the planned stereotactic target location were observed in the anterior-superior direction in both the near-term (mean left electrode shift: 0.43 mm, mean right electrode shift: 0.99 mm) and long-term (mean left electrode shift: 1.02 mm, mean right electrode shift: 1.47 mm). DBS electrodes implanted in the right hemisphere (second-side operated) were more displaced from the plan than those in the left hemisphere. These displacements resulted in 3.6% decrease in pathway activation between the electrode and the ventral striatum, but 2.7% increase in the frontal pole connection, compared to the plan. Remitters from six month chronic stimulation had less variance in pathway activation patterns than the non-remitters. CONCLUSIONS: Brain shift is an important concern for SCC DBS surgical targeting and can impact connectomic analyses. PMID- 29246749 TI - Real-time RPA assay for rapid detection and differentiation of wild-type pseudorabies and gE-deleted vaccine viruses. AB - The objective of this study was to develop a dual real-time recombinase polymerase amplification (RPA) assay using exo probes for the detection and differentiation of pseudorabies virus (PRV). Specific RPA primers and probes were designed for gB and gE genes of PRV within the conserved region of viral genome. The reaction process can be completed in 20 min at 39 degrees C. The dual real time RPA assay performed in the single tube was capable of specific detecting and differentiating of the wild-type PRV and gE-deleted vaccine strains, without cross-reactions with other non-targeted pig viruses. The analytical sensitivity of the assay was 102 copies for gB and gE genes. The dual real-time RPA demonstrated a 100% diagnostic agreement with the real-time PCR on 4 PRV strains and 37 clinical samples. Through the linear regression analysis, the R2 value of the real-time RPA and the real-time PCR for gB and gE was 0.983 and 0.992, respectively. The dual real-time RPA assay provides an alternative useful tool for rapid, simple, and reliable detection and differentiation of PRV, especially in remote and rural areas. PMID- 29246750 TI - False positives in using the zymogram assay for identification of peptidoglycan hydrolases. AB - Zymogram assays have been used extensively to identify novel peptidoglycan hydrolases. In this study it is reported that the zymogram is susceptible to false positive results when highly positively charged proteins are assayed. As an example, we report on the case of the ChiZ membrane protein from the Mycobacterium tuberculosis divisome, which previously was described as a peptidoglycan hydrolase. Even though the full length ChiZ protein was able to produce positive assay results, other direct methods for measuring peptidoglycan hydrolysis do not provide convincing evidence that ChiZ has peptidoglycan hydrolysis activity. We show that the false positive result is produced by the highly positively charged N-terminal region of ChiZ. Thus, we developed a zymogram control that can be used to identify false positives results. This control assay lacks the refolding step in the normal zymogram assay. For lysozyme the control assay shows no activity, while the N-terminal region of ChiZ shows a false positive result. Given the limitations of the zymogram assay to reliably identify peptidoglycan hydrolases, we recommend using the zymogram control assay together with other methods to evaluate possible peptidoglycan hydrolysis activity. PMID- 29246751 TI - Generation and characterization of an anti-delta like ligand-4 Nanobody to induce non-productive angiogenesis. AB - Antibody-based targeting of angiogenesis is a key approach for cancer treatment. Delta-like ligand 4 (DLL4) plays a pivotal role in tumor neovascular development and angiogenesis during tumor progression. It forecasts the prognosis of human malignancies and blocking its signaling can help to inhibit neovascularization and tumor metastasis. Nanobodies are the smallest antigen-binding domains of heavy chain antibodies in camelidae. The aim of this study was to develop a Nanobody against DLL4 and apply binding and functional approaches to target it. In this work, a Nanobody library against human recombinant DLL4 was developed. After panning, the periplasmic-extract (PE) of individual colonies were screened through ELISA. The interactions between Nanobody and DLL4 were assessed using immunohistochemistry and FACS. The functional assessment was carried out via tube formation assay. We selected a Nanobody (3Nb3) with a high binding signal to DLL4, associated with a binding affinity of 3.6 nM. It was demonstrated that 3Nb3 binds to native DLL4 on the surface of MKN cells and gastric carcinoma tissue, and also inhibits the maturation of capillary-like structures in HUVECs. The results were indicative of the potential of Nanobody for DLL4 identification and can broaden the scope for development of cancer diagnosis and treatment techniques. PMID- 29246752 TI - Autoimmune thyroid disease during pregnancy. AB - Understanding of changes in thyroid function and the consequences of thyroid disease during pregnancy has rapidly grown in the past two decades, and revised American Thyroid Association guidelines on this topic were published in 2017. This Review explores the association between thyroid autoimmunity and complications during and after pregnancy. Thyroid autoimmunity refers to the presence of antibodies to thyroperoxidase or thyroglobulin, or thyroid stimulating hormone receptor antibodies (TRAbs), or a combination of these, and is present in up to 18% of pregnant women. Thyroid antibodies in pregnant women with normal functioning thyroids (ie, euthyroid) have been associated with several complications, including miscarriage and premature delivery. Treatments to improve pregnancy outcomes are being studied. Whether thyroid antibodies are associated with infertility and assisted reproductive technology outcomes is unclear; although, treatment with low doses of levothyroxine, which is usually used to treat hypothyroidism, can be considered in such situations. Additionally, thyroid antibodies have been associated with other neonatal and maternal complications. All these associations require confirmation in larger prospective studies, and their pathogenic mechanisms need to be better understood. Post partum thyroiditis is substantially more frequent in women who have thyroid antibodies during pregnancy than in those who do not have thyroid antibodies; however, whether treatment can prevent post-partum thyroiditis in women who are or have been antibody positive is unknown. Finally, TRAbs cross the placenta from the mother to the fetus and can cause fetal or neonatal hyperthyroidism. Therefore, women who are positive for TRAbs during pregnancy should be monitored. PMID- 29246753 TI - Laugier-Hunziker syndrome: A case report. AB - Laugier-Hunziker syndrome (LHS) is a rare, benign, acquired pigmentary condition mainly affecting lips, oral mucosa and acral area, frequently associated with longitudinal melanonychia. Herein, we reported a 45-year-old female case with LHS. The clinical, dermoscopic, histopathologic features of LHS were reviewed and the important differential diagnosis was discussed. PMID- 29246754 TI - Thioctic acid in oral submucous fibrosis (India's disease) - A better tomorrow. AB - Oral submucous fibrosis (OSMF), because of its common occurrence in Indian population is known as India's disease. Regardless of diagnostic and therapeutic developments, oral potentially malignant disorders (PMD) and cancers are disseminating at a distressing rate. There is this prerequisite for unrelenting determination to find out apt treatment options so that malignant transformation may be prevented and more so the prevailing morbidity and mortality. Considering the frequency with which oral submucous fibrosis undergoes malignant transformation with free radicals playing a major part, the role of antioxidants in general and thioctic acid also known as alpha lipoic acid (ALA) in particular need to be studied in these individuals. Previous few studies indicated the use of alpha lipoic acid in oral submucous fibrosis patients leading to improvement in signs and symptoms. So, it led us to set forth and propose probable role of thioctic acid in improving symptoms in these patients. As oral submucous fibrosis poses as a threat with its various signs and symptoms and as a potentially malignant disorder as well as considering the role of free radicals in malignant transformation, we proposed the possible mechanisms behind the commonest signs and symptoms in oral submucous fibrosis and role of alpha lipoic acid in managing these signs and symptoms. PMID- 29246755 TI - The significance of age group, gender and skin complexion in relation to the clinical distribution of developmental oral mucosal alterations in 5-13 year-old children. AB - INTRODUCTION: To describe the relationship and impact of age group, gender and skin complexion on the prevalence and clinical distribution of oral mucosal alterations of developmental origin (OMA-DO) among school children aged 5-13 years. METHODS: A randomized representative national survey of Jordanian school children including all Country geographic areas was performed. Cut-off age that significantly correlated with presence and distribution of OMA-DO was identified (ROC curve). Skin complexion was classified into light/fair, intermediate/tan, dark/brown based on skin complexion index. Chi square test with P value<=0.05 was used for significance of correlations. RESULTS: Two thousand two hundred and fifty one children were clinically examined. The average age that significantly correlated with prevalence and distribution of OMA-DO was 9.9 years. Female gender was significantly correlated with four OMA-DO: leukoedema (L), linea Alba (LA), Fordyce's granules (FG), commissural lip pits (CLP) and wider distribution of racial pigmentations (RP) (P<0.05, chi2 test). Older age group (9.9-13 years) was significantly correlated with 7 OMA-DO: L, LA, FG, frenal tag, CLP, mandibular and maxillary tori (MT) as well as wider clinical distribution of RP, FG, L (P<0.05 chi2 test). Dark skin complexion significantly correlated with 5 OMA-DO: L, LA, FG, RP, MT and wider clinical distribution of RP (P<0.02, chi2 test). CONCLUSIONS: Increased prevalence and wider clinical distribution of OMA DO are significantly associated with older age group of 9.9-13 years, female gender, and dark skin complexion. Oral health care provides are encouraged to be familiar with these correlations. This knowledge is expected to improve OMA-DO diagnosis and clinical management. Continuous education programs in this field are recommended. PMID- 29246756 TI - Tessier number 4 bilateral craniofacial cleft associated with amniotic band syndrome: 22 years of follow-up. AB - Tessier clefts are a very rare entity. Number 4 Tessier cleft is describe like an orbito-facial cleft with trajectory between the lower eyelid and the lip. We report management of a bilateral number 4 Tessier cleft with amniotic band syndrome with 22 years of follow-up. After reviewing literature, we talk about difficulty to manage these kinds of rare Tessier clefts. PMID- 29246757 TI - Closed technique for naso-orbito-ethmoid fracture management: Technical note. AB - Trauma to the naso-orbito-ethmoid region invariably results in detachment of medial canthal tendon. The shape of medial canthus is of important esthetic and functional concern. Accurate reposition of the medial canthus is important to achieve normal form and function. The various available techniques advocate open approach leaving an obvious scar in the esthetically prominent region. This technique intends to address these fractures through a closed approach with the possibility to make finer adjustments as and when required. We report the experience of treating 4 naso-orbito-ethmoid fractures with a new innovative technique with predictable results. PMID- 29246758 TI - Is It Our Duty To Hunt for Pathogenic Mutations? AB - Should professionals systematically screen whole-genome sequencing (WGS) data to check for life-threatening mutations? Alternatively, should genome analysis focus on the primary reason for testing - that is, aiming to achieve precision medicine? We present an ethical review of the arguments and compare the act of searching for mutations with disclosing mutations that are discovered incidentally. PMID- 29246760 TI - Noncoding RNAs: Master Regulators of Inflammatory Signaling. AB - Inflammatory signaling underlies many diseases, from arthritis to cancer. Our understanding of inflammation has thus far been limited to the world of proteins, because we are only just beginning to understand the role that noncoding RNAs (ncRNA) might play. It is now clear that ncRNA do not constitute transcriptional 'noise' but instead harbor physiological functions in controlling signaling pathways. In this review, we cover the newly discovered mechanisms and functions of ncRNAs in the regulation of inflammatory signaling. We also describe advances in experimental techniques allowing this field of research to take root. These findings have opened new avenues for putative therapeutic intervention in inflammatory diseases, which may be seen translated into clinical outcomes in the future. PMID- 29246759 TI - Metabolic Control of CD8+ T Cell Fate Decisions and Antitumor Immunity. AB - CD8+ T cells are central players in controlling infections and cancer. Longevity, functionality, and metabolic fitness are critical determinants of T cell efficacy in cancer immunotherapy. Tumor-infiltrating CD8+ T cells undergo metabolic 'exhaustion' in the nutrient- and oxygen-deprived tumor microenvironment (TME). Thus, reprograming CD8+ T cell metabolism may provide important therapeutic strategies for cancer treatment. Indeed, the adoptive transfer of memory CD8+ T cells with sustained metabolic fitness may yield better antitumor protection in both mouse models and the clinic. Here, we discuss recent progress on how cellular metabolism is linked to CD8+ T cell fate decisions and on how metabolic intermediates can impact gene expression via modulation of the epigenome. We examine the feasibility of developing potential strategies to improve antitumor immunity through the modulation of T cell metabolic activity. PMID- 29246761 TI - A potential impact of Helicobacter pylori-related galectin-3 in neurodegeneration. AB - Neurodegeneration represents a component of the central nervous system (CNS) diseases pathogenesis, either as a disability primary source in the frame of prototype neurodegenerative disorders, or as a secondary effect, following inflammation, hypoxia or neurotoxicity. Galectins are members of the lectin superfamily, a group of endogenous glycan-binding proteins, able to interact with glycosylated receptors expressed by several immune cell types. Glycan-lectin interactions play critical roles in the living systems by involving and mediating a variety of biologically important normal and pathological processes, including cell-cell signaling shaping cell communication, proliferation and migration, immune responses and fertilization, host-pathogen interactions and diseases such as neurodegenerative disorders and tumors. This review focuses in the role of Galectin-3 in shaping responses of the immune system against microbial agents, and concretely, Helicobacter pylori (Hp), thereby potentiating effect of the microbe in areas distant from the ordinary site of colonization, like the CNS. We hereby postulate that gastrointestinal Hp alterations in terms of immune cell functional phenotype, cytokine and chemokine secretion, may trigger systemic responses, thereby conferring implications for remote processes susceptible in immunity disequilibrium, namely, the CNS inflammation and/or neurodegeneration. PMID- 29246762 TI - Hemoglobin crystals immersed in liquid oxygen reveal diffusion channels. AB - Human hemoglobin (HbA) transports molecular oxygen (O2) from the lung to tissues where the partial pressure of O2 is lower. O2 binds to HbA at the heme cofactor and is stabilized by a distal histidine (HisE7). HisE7 has been observed to occupy opened and closed conformations, and is postulated to act as a gate controlling the binding/release of O2. However, it has been suggested that HbA also contains intraprotein oxygen channels for entrances/exits far from the heme. In this study, we developed a novel method of crystal immersion in liquid oxygen prior to X-ray data collection. In the crystals immersed in liquid oxygen, the heme center was oxidized to generate aquomethemoglobin. Increases of structural flexibility were also observed in regions that are synonymous with previously postulated oxygen channels. These regions also correspond to medically relevant mutations which affect O2 affinity. The way HbA utilizes these O2 channels could have a profound impact on understanding the relationship of HbA O2 transport within these disease conditions. Finally, the liquid oxygen immersion technique can be utilized as a new tool to crystallographically examine proteins and protein complexes which utilize O2 for enzyme catalysis or transport. PMID- 29246763 TI - Wnt/beta-catenin pathway promotes acute lung injury induced by LPS through driving the Th17 response in mice. AB - T helper cell 17 (Th17), one type of CD4+ T cell, plays an important role in regulating the acute lung injury (ALI) inflammatory response. Recent studies showed that Wnt/beta-catenin pathway could modulate the differentiation and the function of CD4+ T cell. However, whether Wnt/beta-catenin could regulate the differentiation and function of Th17 in the development and progress of ALI induced by lipopolysaccharide (LPS) is still unknown. To test this, we used dickkopf1 (Dkk-1) to block the Wnt/beta-catenin pathway and LiCl to activate the Wnt/beta-catenin pathway by instillation to the murine model of ALI. Our results revealed that activation of Wnt/beta-catenin pathway significantly aggravated the LPS-induced lung inflammation. Meanwhile, we observed that activation of Wnt/beta catenin pathway promoted Th17 response by analyzing CD4+ T cells and the related cytokines secretions. Enhanced Th17 response was responsible for the further neutrophils infiltration and pro-inflammatory cytokines production. In addition, activation of Wnt/beta-catenin pathway resulted in induced expression of retinoic acid related orphan receptor-gammat (RORgammat) via histone acetyltransferase p300. These data suggested that Wnt/beta-catenin pathway might be a potential target to treat the LPS-induced inflammation in ALI. PMID- 29246764 TI - Age-dependent changes in brain hydration and synaptic plasticity. AB - Aging in humans and animals is associated with gradual and variable changes in some cognitive functions, but what causes them and explains individual variations remains unclear. Hydration decreases with aging but whether dehydration contributes to cognitive dysfunction is not known. The brain hydration of aging mice was determined by colloidosmotic-pressure titration. Dehydration increased with age from ~76 mmHg at 6 weeks to ~105 mmHg at 40 weeks, or a progressive ~10 percent loss of brain water but seemed to level off afterward. When we adjusted dehydration in hippocampal slices of <8-week-old mice to the levels seen in mice 40 weeks and older, their basal synaptic responses were amplified at all stimulus voltages tested, but induction of late-phase long-term potentiation was impaired. Our results document progressive brain dehydration with age in inbred mice to levels at which in vitro synaptic plasticity appears dysregulated. They also suggest that dehydration contributes to some of the changes in synaptic plasticity observed with aging, possibly due to adjustments in neuronal excitation mechanisms. PMID- 29246765 TI - FKBP12-immunopositive inclusions in patients with alpha-synucleinopathies. AB - alpha-Synuclein (alpha-SYN), a presynaptic protein with the tendency to aggregate, is linked to alpha-synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). alpha-SYN is the main component of round intracytoplasmic inclusions called Lewy bodies (LBs), which are the hallmark of PD and DLB. In addition, accumulation of amyloid-beta and neurofibrillary tangles as in the pathology of Alzheimer's disease has been found in the DLB brain. Glial cytoplasmic inclusions are an MSA-specific type of inclusion found in oligodendrocytes and mainly comprise alpha-SYN. FK506-binding protein (FKBP) 12 is a member of the immunophilin family with peptidyl-prolyl isomerase activity that promotes protein folding and is believed to act as a chaperone protein. Previous in vitro work indicated that FKBP12 accelerated alpha SYN aggregation more than other peptidyl-prolyl isomerases. The enzymatic activity of FKBP12 increases the formation of alpha-SYN fibrils at subnanomolar concentrations. In this study, we found that FKBP12 colocalized with alpha-SYN in LBs and neurites in PD and DLB brains. Furthermore, FKBP12-immunopositive neurofibrillary tangles colocalized with phosphorylated tau in DLB and FKBP12 immunopositive glial cytoplasmic inclusions colocalized with alpha-SYN in MSA. These findings suggest that FKBP12 is linked to the accumulation of alpha-SYN and phosphorylated tau protein in alpha-synucleinopathies. FKBP12 may play important roles in the pathogenesis of alpha-synucleinopathies through its strong aggregation function. Thus, FKBP12 could be an important drug target for alpha synucleinopathies. PMID- 29246766 TI - SRP, FtsY, DnaK and YidC Are Required for the Biogenesis of the E. coli Tail Anchored Membrane Proteins DjlC and Flk. AB - Tail-anchored membrane proteins (TAMPs) are relatively simple membrane proteins characterized by a single transmembrane domain (TMD) at their C-terminus. Consequently, the hydrophobic TMD, which acts as a subcellular targeting signal, emerges from the ribosome only after termination of translation precluding canonical co-translational targeting and membrane insertion. In contrast to the well-studied eukaryotic TAMPs, surprisingly little is known about the cellular components that facilitate the biogenesis of bacterial TAMPs. In this study, we identify DjlC and Flk as bona fide Escherichia coli TAMPs and show that their TMDs are necessary and sufficient for authentic membrane targeting of the fluorescent reporter mNeonGreen. Using strains conditional for the expression of known E. coli membrane targeting and insertion factors, we demonstrate that the signal recognition particle (SRP), its receptor FtsY, the chaperone DnaK and insertase YidC are each required for efficient membrane localization of both TAMPs. A close association between the TMD of DjlC and Flk with both the Ffh subunit of SRP and YidC was confirmed by site-directed in vivo photo crosslinking. In addition, our data suggest that the hydrophobicity of the TMD correlates with the dependency on SRP for efficient targeting. PMID- 29246767 TI - Detection of Changes in Cervical Softness Using Shear Wave Speed in Early versus Late Pregnancy: An in Vivo Cross-Sectional Study. AB - The aim of this study was to assess the ability of shear wave elasticity imaging (SWEI) to detect changes in cervical softness between early and late pregnancy. Using a cross-sectional study design, shear wave speed (SWS) measurements were obtained from women in the first trimester (5-14 wk of gestation) and compared with estimates from a previous study of women at term (37-41 wk). Two sets of five SWS measurements were made using commercial SWEI applications on an ultrasound system equipped with a prototype catheter transducer (128 elements, 3 mm diameter, 14-mm aperture). Average SWS estimates were 4.42 +/- 0.32 m/s (n = 12) for the first trimester and 2.13 +/- 0.66 m/s (n = 18) for the third trimester (p <0.0001). The area under the curve was 0.95 (95% confidence interval: 0.82-0.99) with a sensitivity and specificity of 83%. SWS estimates indicated that the third-trimester cervix is significantly softer than the first trimester cervix. SWEI methods may be promising for assessing changes in cervical softness. PMID- 29246768 TI - PIP2 epigenetically represses rRNA genes transcription interacting with PHF8. AB - Phosphoinositides are present in the plasma membrane, cytoplasm and inside the cell nucleus. Here we identify phosphatidylinositol-4,5-bisphosphate (PIP2) as a regulator of rRNA genes transcription at the epigenetic level. We show that PIP2 directly interacts with histone lysine demethylase PHF8 (PHD finger protein 8) and represses demethylation of H3K9me2 through this interaction. We identify the C-terminal K/R-rich motif as PIP2-binding site within PHF8, and address the function of this PIP2-PHF8 complex. PIP2-binding mutant of PHF8 has increased the activity of rDNA promoter (20%) and expression of pre-rRNA genes (47S-100%; 45S 66%). Furthermore, trypsin digestion reveals a potential conformational change of PHF8 upon PIP2 binding. These observations identify the function of nuclear PIP2, and suggest that PIP2 contributes to the fine-tuning of rDNA transcription. PMID- 29246769 TI - Impact of a Non-small Cell Lung Cancer Educational Program for Interdisciplinary Teams. AB - BACKGROUND: Successful implementation of non-small cell lung cancer (NSCLC) evidence-based guideline recommendations requires effective educational programs that target all clinicians from interdisciplinary teams. This study describes and evaluates the Engaging an Interdisciplinary Team for NSCLC (GAIN 3.0) experiential learning-based educational curriculum. METHODS: GAIN 3.0 was designed to enhance interdisciplinary collaboration for effective NSCLC diagnosis, assessment, and treatment. The program used a flipped classroom model that included an e-learning component prior to a live 6-hour interactive program. The interactive program included hands-on simulations, small group workshops, gamification, and case discussions. Participants included academic and community members of multidisciplinary lung cancer teams. Assessments included an online baseline survey, a pretest and posttest, a program evaluation, a long-term survey (LTS), and on-site faculty evaluation of participants. RESULTS: Of 416 attendees to 13 live GAIN 3.0 programs (nine in the United States and four in Europe), 304 (73%) completed the pretest and 187 (45%) completed the posttest. Out of a perfect score of 12 points, program participants had a mean test score of 6.3 +/- 2.1 on the pretest (52%) and 7.8 +/- 2.1 on the posttest (65%) (P = .03). There was an overall knowledge increase of 13% from pretest to posttest. Most LTS respondents (65%) rated the GAIN 3.0 live programs as "high impact." On the LTS, the areas with the greatest gains in participants who had very high confidence were communication across disciplines, use of a team-based approach, and personalized treatment. CONCLUSIONS: GAIN 3.0 was a highly successful interdisciplinary activity that improved participants' knowledge, competence, and likely the clinical care provided to patients with NSCLC. PMID- 29246771 TI - Antagonism of the D1- and D2-like dopamine receptors in the nucleus accumbens attenuates forced swim stress- and morphine priming-induced reinstatement of extinguished rats. AB - Dopaminergic pathways from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) play a critical role in reward-related phenomena as well as in the reinstatement of drug-seeking behavior. Stress is a major trigger for inducing reinstatement, however, the interaction between stress and the dopaminergic system is not well known. The present study was undertaken to investigate the effect of D1- and D2-like dopamine receptors within the NAc in forced swim stress (FSS)- and priming-induced reinstatement of morphine-seeking behaviors. The conditioned place preference (CPP) was induced by injecting morphine (5 mg/kg, SC for 3 days) and lasted for eight days after cessation of the morphine treatment. The FSS (6 min) and effective priming dose of morphine (1 mg/kg, sc) reinstated the extinguished morphine-induced CPP. In order to investigate the effect of intra-accumbal injection of SCH23390 as a D1-like receptor antagonist, or Sulpiride as a D2-like receptor antagonist on the FSS induced reinstatement of morphine extinguished rats, animals received bilaterally intra-NAc injection of SCH23390 or Sulpiride (0.25, 1 and 4 MUg/side) before application of FSS, and then, they were tested in the reinstatement day. Our results showed that the intra-accumbal administration of D1- and D2-like receptors antagonists dose-dependently blocked the effect of FSS on the reinstatement and significantly modulated morphine priming-induced reinstatement as well. These findings suggested that the D1- and D2-like dopamine receptors in the NAc involve in morphine-seeking behaviors and antagonism of these receptors can reduce the effect of stress on rewarding properties of morphine. PMID- 29246770 TI - A Longitudinal Cohort Study of Aspirin Use and Progression of Emphysema-like Lung Characteristics on CT Imaging: The MESA Lung Study. AB - BACKGROUND: Platelet activation reduces pulmonary microvascular blood flow and contributes to inflammation; these factors have been implicated in the pathogenesis of COPD and emphysema. We hypothesized that regular use of aspirin, a platelet inhibitor, would be associated with a slower progression of emphysema like lung characteristics on CT imaging and a slower decline in lung function. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants 45 to 84 years of age without clinical cardiovascular disease from 2000 to 2002. The MESA Lung Study assessed the percentage of emphysema-like lung below -950 Hounsfield units ("percent emphysema") on cardiac (2000-2007) and full-lung CT scans (2010-2012). Regular aspirin use was defined as 3 or more days per week. Mixed-effect models adjusted for demographics, anthropometric features, smoking, hypertension, angiotensin-converting enzyme inhibitor or angiotensin II-receptor blocker use, C-reactive protein levels, sphingomyelin levels, and scanner factors. RESULTS: At baseline, the 4,257 participants' mean (+/- SD) age was 61 +/- 10 years, 54% were ever smokers, and 22% used aspirin regularly. On average, percent emphysema increased 0.60 percentage points over 10 years (95% CI, 0.35 0.94). Progression of percent emphysema was slower among regular aspirin users compared with patients who did not use aspirin (fully adjusted model: -0.34% /10 years, 95% CI, -0.60 to -0.08; P = .01). Results were similar in ever smokers and with doses of 81 and 300 to 325 mg and were of greater magnitude among those with airflow limitation. No association was found between aspirin use and change in lung function. CONCLUSIONS: Regular aspirin use was associated with a more than 50% reduction in the rate of emphysema progression over 10 years. Further study of aspirin and platelets in emphysema may be warranted. PMID- 29246772 TI - Extracellular regulated protein kinaseis critical for the role of 5-HT1a receptor in modulating nNOS expression and anxiety-related behaviors. AB - Our previous study found that serotonin 1A receptor (5-HT1aR) is an endogenous suppressor of nNOS expression in the hippocampus, which accounts for anxiolytic effect of fluoxetine. However, the precise molecular mechanism remains unknown. By using 8-OH-DPAT, a selective 5-HT1aR agonist, NAN-190, a selective 5-HT1aR antagonist, and U0126, an Extracellular Regulated Protein Kinases (ERK) phosphorylation inhibitor, we investigated the role of ERK in 5-HT1aR-nNOS pathway. Western blots analysis demonstrated that 5-HT1aR activation up-regulated the level of phosphorylated ERK (P-ERK) beginning at 5 min and down-regulated the expression of nNOS beginning at 20 min. Meanwhile, blockage of 5-HT1aR resulted in a decrease in P-ERK beginning at 20 min and caused an increase in nNOS expression beginning at 6 h. Although U0126 itself did not alter nNOS expression and activity, NO level, and anxiety-related behaviors, the treatment totally reversed 8-OH-DPAT-induced reduction in nNOS expression and function, and anxiolytic effect. Besides, our data showed that ERK phosphorylation was essential for 5-HT1aR activation-induced cAMP responsive element binding protein (CREB) phosphorylation, hippocampal neurogenesis and synaptogenesis of newborn neuron. Our study suggests a crucial role of ERK phosphorylation in the regulation of nNOS expression by 5-HT1aR, which is helpful for understanding the mechanism of 5-HT1aR-based anxiolytic treatment. PMID- 29246773 TI - Mathematical modelling and numerical simulations of the influence of hygiene and seasons on the spread of cholera. AB - Cholera is a bacterial disease, its spread is strongly influenced by environmental factors and some socio-economic factors such as hygiene standards and nutrition of the population. This paper is devoted to the modelling of the impact of climatic factors and human behaviour on the spread of cholera. The mathematical modelling incorporates the direct transmission and the indirect transmission due to environmental knowledge. Taking into account the effect of the intra-annual variation of climatic factors on the transmission of cholera, a non-autonomous ordinary differential equations is proposed to describe the dynamics of the transmission of cholera. When the intra-annual variation of climate is not incorporated into the model, the latter becomes autonomous. The basic reproductive number is calculated and the stabilities of equilibria are investigated. In the non-autonomous case, the disease extinction and uniform persistence of disease are investigated. The results suggest that the transmission and spread of cholera can be affected by climatic factors, the proportion of the undernourished individuals and the proportion of people who respect the hygiene standards. Finally, some numerical simulations are proposed using the parameters values of climatic factors and socio-economic factors of some localities situated in Lake Chad border between Chad, Cameroon and Nigeria. PMID- 29246774 TI - When is it safe to exercise mechanically ventilated patients in the intensive care unit? An evaluation of consensus recommendations in a cardiothoracic setting. AB - RATIONALE: Consensus recommendations have been developed to guide exercise rehabilitation of mechanically ventilated patients in the intensive care unit. OBJECTIVE: This study aimed to investigate the safety of exercise rehabilitation of mechanically ventilated patients and evaluate the consensus recommendations. METHODS: This was a prospective, single-centre, cohort study conducted in a specialist cardiothoracic intensive care unit of a tertiary, university affiliated hospital in Australia. RESULTS: 91 mechanically ventilated participants; 54 (59.3%) male; mean age of 56.52 (16.3) years; were studied with 809 occasions of service recorded. Ten (0.0182%) minor adverse events were recorded, with only one adverse event occurring when a patient was receiving moderate level of vasoactive support. CONCLUSIONS: The consensus recommendations are a useful tool in guiding safe exercise rehabilitation of mechanically ventilated patients. Our findings suggest that there is further scope to safely commence exercise rehabilitation in patients receiving vasoactive support. PMID- 29246775 TI - Coronary ectasia in amyloid cardiomyopathy and neuropathy due to the transthyretin mutation c.323A>G. AB - BACKGROUND: atrial fibrillation(AF) is a frequent manifestation of cardiac involvement in genetic and wild-type transthyretin-related familial amyloidosis(TTR-FA). However, ectasia of coronary arteries and ablation for AF have not been reported in TTR-FA. METHODS AND RESULTS: A 65yo male developed progressive sensori-motor polyneuropathy since age 59y. At age 60y bifascicular block and myocardial thickening were recognised. At age 62y heart failure developed and work-up with cardiac MRI suggested amyloidosis but biopsy was non informative. Coronary angiography revealed ectasias of the coronary arteries. At age 65y AF developed, neither responding to electrical cardioversion nor ablation. Work-up for polyneuropathy revealed the point mutation c.323A>G (p.His108Arg) in the TTR-gene. Tafamidis was started but did not exhibit a beneficial effect after 7 months. CONCLUSIONS: TTR-FA may manifest in the coronary arteries with ectasia. Ablation for AF in TTR-FA may be unsuccessful. Tafamidis has been unsuccessful for cardiac or nerve involvement after the first seven months. PMID- 29246776 TI - Evaluation of LoopampTMMTBC detection kit for diagnosis of pulmonary tuberculosis at a peripheral laboratory in a high burden setting. AB - The LoopampTMMTBC detection kit (TB-LAMP) was designed to replace the sputum smear microscopy for the diagnosis of pulmonary tuberculosis. We evaluated its performance at a peripheral laboratory in Vietnam. The sensitivity of TB-LAMP was 45.5% (28.1%-63.6%), which was equal to 3-sputum smear microscopy but lower than that of Xpert MTB/RIF (87.8% [71.8%-96.6%]). In patients with culture-confirmed TB, sensitivity was 80% (51.9%-95.7%) in smear-positive and 16.7% (3.5%-41.4%) in smear-negative cases. The specificity of TB-LAMP was 95.1% (92.7%-96.9%), which was lower than that of smear microscopy (98.9% [97.5%-99.7%]) and Xpert MTB/RIF (99.3% [98.1%-99.9%]) (P<0.05). The probability of TB detection by TB-LAMP was more influenced by sample quality and viscosity than were smear microscopy, Xpert MTB/RIF, and culture. The present data do not support the use of TB-LAMP as a replacement test for smear microscopy in peripheral laboratories. PMID- 29246778 TI - Computed tomography whirl sign: An image-based indication for surgery. AB - Adhesive closed-loop small bowel obstruction can lead to volvulus and ischemia with risk of necrosis. The vital prognosis and bowel viability are highly dependent on rapid management. The physical examination is often insufficient to establish the diagnosis and computed tomography is ordered. The whirl sign provides the best imaging evidence of volvulus and can be sufficient to establish the indication for surgery. PMID- 29246777 TI - Teicoplanin resistance in Staphylococcus haemolyticus is associated with mutations in histidine kinases VraS and WalK. AB - We investigated the genetic basis of glycopeptide resistance in laboratory derived strains of S. haemolyticus with emphasis on differences between vancomycin and teicoplanin. The genomes of two stable teicoplanin-resistant laboratory mutants selected on vancomycin or teicoplanin were sequenced and compared to parental S. haemolyticus strain W2/124. Only the two non-synonymous mutations, VraS Q289K and WalK V550L were identified. No other mutations or genome rearrangements were detected. Increased cell wall thickness, resistance to lysostaphin-induced lysis and adaptation of cell growth rates specifically to teicoplanin were phenotypes observed in a sequenced strain with the VraS Q289K mutation. Neither of the VraS Q289K and WalK V550L mutations was present in the genomes of 121S. haemolyticus clinical isolates. However, all but two of the teicoplanin resistant strains carried non-synonymous SNPs in vraSRTU and walKR YycHIJ operons pointing to their importance for the glycopeptide resistance. PMID- 29246779 TI - Towards enhanced automated elution systems for waterborne protozoa using megasonic energy. AB - Continuous and reliable monitoring of water sources for human consumption is imperative for public health. For protozoa, which cannot be multiplied efficiently in laboratory settings, concentration and recovery steps are key to a successful detection procedure. Recently, the use of megasonic energy was demonstrated to recover Cryptosporidium from commonly used water industry filtration procedures, forming thereby a basis for a simplified and cost effective method of elution of pathogens. In this article, we report the benefits of incorporating megasonic sonication into the current methodologies of Giardia duodenalis elution from an internationally approved filtration and elution system used within the water industry, the Filta-Max(r). Megasonic energy assisted elution has many benefits over current methods since a smaller final volume of eluent allows removal of time-consuming centrifugation steps and reduces manual involvement resulting in a potentially more consistent and more cost-effective method. We also show that megasonic sonication of G. duodenalis cysts provides the option of a less damaging elution method compared to the standard Filta Max(r) operation, although the elution from filter matrices is not currently fully optimised. A notable decrease in recovery of damaged cysts was observed in megasonic processed samples, potentially increasing the abilities of further genetic identification options upon isolation of the parasite from a filter sample. This work paves the way for the development of a fully automated and more cost-effective elution method of Giardia from water samples. PMID- 29246780 TI - Comparison of two indirect ELISA coating antigens for the detection of dairy cow antibodies against Pasteurella multocida. AB - The ELISA is recognized as an efficient diagnostic tool for antibody detection, but there is no standard ELISA assay for detection of antibodies against hemorrhagic septicemia (HS) in cattle. The present study reports on an indirect ELISA assay for antibody detection of HS in dairy cows, and evaluates the sensitivity (Se) and specificity (Sp) of the method using a Bayesian approach. An indirect ELISA was developed with two types of heat extract antigens, Pasteurella multocida strains P-1256 and M-1404, as coating antigens. A checkerboard titration was employed using dairy cow sera immunized with P. multocida bacterin and colostrum-deprived calf sera. The concentrations of heat extract antigen (160MUg/mL), sample serum (1:100) and goat anti-bovine immunoglobulin G labeled with horseradish peroxidase (1:2000) were optimal for the assay. The cut-off values were 0.147 and 0.128 for P-1256 and M-1404 coating antigens, and there were no differences in the results of tests with positive and negative sera (p<0.05). The characteristics of three diagnostic tests were evaluated using a one-population Bayesian model, assuming conditional dependence between two types of coating antigen-based ELISAs and indirect hemagglutination assay (IHA). A total of 415 sera samples from dairy cows without HS vaccination and no history of disease were tested. The Se and Sp of the P-1256 and M-1404 ELISAs were higher than those of the IHA. The Se and Sp of the P-1256 ELISA were 90.3% and 90.1%, while the Se and Sp of the M-1404 ELISA were 92.1% and 71.9%. The median values of Se and Sp from the IHA were 36.0% and 58.2%. PMID- 29246781 TI - Modular assembling process of an in-silico protocell. AB - The bottom-up approach of synthetic biology is driven by the need for a deepened understanding of the interaction of functional modules in living or artificial systems. The hope is that the gained knowledge will help to optimize existing systems, or, as one long-term goal of synthetic biology, to build up artificial cell-like entities from single building blocks. This article focuses on a system theoretic approach to synthetic biology, and in particular on the construction of a protocell model by the modular assembling process. Different models for an in silico protocell are described that combines experimentally validated biological subsystems with theoretical assumptions. The in-silico protocell that is characterized consists of three different functional modules: the membrane proliferating module, the membrane contraction module, and a positioning module. Additional theoretical hypotheses are tested in order to merge the module models to one protocell model with synchronously working parts. The different approaches used here for developing a protocell model could be helpful for assembling the different modules to one system in reality. Depending on the objective one wants to achieve a more or less detailed modeling approach is appropriate. PMID- 29246782 TI - Biophysical and biological evaluation of optimized stapled peptide inhibitors of the linear ubiquitin chain assembly complex (LUBAC). AB - Linear ubiquitylation, in which ubiquitin units are covalently linked through N- and C-terminal amino acids, is a unique cellular signaling mechanism. This process is controlled by a single E3 ubiquitin ligase, the linear ubiquitin chain assembly complex (LUBAC), which is composed of three proteins - HOIL-1L, HOIP and SHARPIN. LUBAC is involved in the activation of the canonical NF-kappaB pathway and has been linked to NF-kappaB dependent malignancies. In this work, we present HOIP-based stapled alpha-helical peptides designed to inhibit LUBAC through the disruption of the HOIL-1L-HOIP interaction and loss of the functional complex. We find our HOIP peptides to be active LUBAC ubiquitylation inhibitors in vitro, though through interaction with HOIP rather than HOIL. Active peptides were shown to have inhibitory effects on cell viability, reduced NF-kappaB activity and decreased production of NF-kappaB related gene products. This work further demonstrates the potential of LUBAC as a therapeutic target and of the use of stapled peptides as inhibitors of protein-protein interactions. PMID- 29246783 TI - The response of glutathione peroxidase 1 and glutathione peroxidase 7 under different oxidative stresses in black tiger shrimp, Penaeus monodon. AB - Glutathione peroxidase (GPx) is part of the enzymatic antioxidant system that can eliminate the peroxides produced as effect of reactions of molecules with reactive oxygen species (ROS). We cloned two different GPx genes from Penaeus monodon (black tiger shrimp). Bioinformatics sequence analysis showed that PmGPx1 and PmGPx7 encoded polypeptides of 207 and 208 amino acids, respectively. PmGPx1 has a selenocysteine residue that is encoded by an opal codon 187TGA189. The PmGPx1 and PmGPx7 expression profiles were detected in the gills and hepatopancreas of the shrimps under osmotic stress, heavy metal exposure and bacterial infection, and the results suggested that PmGPx1 and PmGPx7 are involved in the responses to these stimuli. The recombinant PmGPx1 and PmGPx7 protein was expressed and purified through affinity chromatography and was refolded successfully using ion-exchange chromatography, which were used to measure antioxidant activity, and the results revealed that the rPmGPx1 and rPmGPx7 protein could catalyze the redox reaction between GSH and H2O2. This study provides useful information to help further understand the functional mechanism of the GPx family in the immunity of P. monodon. PMID- 29246784 TI - Micro-coil-induced Inhomogeneous Electric Field Produces sound-driven-like Neural Responses in Microcircuits of the Mouse Auditory Cortex In Vivo. AB - Magnetic stimulation is widely used in neuroscience research and clinical treatment. Despite recent progress in understanding the neural modulation mechanism of conventional magnetic stimulation methods, the physiological mechanism at the cortical microcircuit level is not well understood due to the poor stimulation focality and large electric artifact in the recording. To overcome these issues, we used a sub-millimeter-sized coil (micro-coil) to stimulate the mouse auditory cortex in vivo. To determine the mechanism, we conducted the first direct electrophysiological recording of micro-coil-driven neural responses at multiple sites on the horizontal surface and laminar areas of the auditory cortex. The laminar responses of local field potentials (LFPs) to the magnetic stimulation reached layer 6, and the spatiotemporal profiles were very similar to those of the acoustic stimulation, suggesting the activation of the same cortical microcircuit. The horizontal LFP responses to the magnetic stimulation were evoked within a millimeter-wide area around the stimulation coil. The activated cortical area was dependent on the coil orientation, providing useful information on the effective position of the coil relative to the brain surface for modulating cortical circuitry activity. In addition, numerical calculation of the induced electric field in the brain revealed that the inhomogeneity of the horizontal electric field to the surface is critical for micro-coil-induced cortical activation. The results suggest that our micro-coil technique has the potential to be used as a chronic, less-invasive and highly focal neuro-stimulator, and is useful for investigating microcircuit responses to magnetic stimulation for clinical treatment. PMID- 29246785 TI - Alternating Dynamics of Segregation and Integration in Human EEG Functional Networks During Working-memory Task. AB - Brain functional networks show high variability in short time windows but mechanisms governing these transient dynamics remain unknown. In this work, we studied the temporal evolution of functional brain networks involved in a working memory (WM) task while recording high-density electroencephalography (EEG) in human normal subjects. We found that functional brain networks showed an initial phase characterized by an increase of the functional segregation index followed by a second phase where the functional segregation faded after the prevailing the functional integration. Notably, wrong trials were associated with different or disrupted sequences of the segregation-integration profiles and measures of network centrality and modularity were able to identify crucial aspects of the oscillatory network dynamics. Additionally, computational investigations further supported the experimental results. The brain functional organization may respond to the information processing demand of a WM task following a 2-step atomic scheme wherein segregation and integration alternately dominate the functional configurations. PMID- 29246786 TI - Linkers: The key elements for the creation of efficient nanotherapeutics. AB - The limited efficiency of the conventional treatment options against a variety of disorders have created demands towards the development of more efficient theranostic strategies. Advances in nanomedicine have provided promising perspectives for the treatment of hard-to-treat diseases. Application of the high resolution imaging, multifunctional nanoparticles, and a wide variety of nanodevices for early diagnosis of disease, promoting tissue regeneration, and targeted delivery of therapeutic agents, may result in minimal side effects and improved treatment outcome. Meanwhile, a number of nanotherapeutics have shown poor efficiency that might be due to a variety of factors including the inappropriate design protocols or nonspecific drug release. Selective cell targeting and controlled drug release are the key elements which should be considered in designing the nanocarriers for targeted delivery of therapeutic agents. Linkers, the essential components incorporated in the building blocks of drug delivery systems, provide the stability, high payloads, targeted drug delivery, and controlled release, hence, they might be critically involved in the nanotherapeutic activity. In the present review, the significance of linkers in the development of effective drug delivery systems has been highlighted. PMID- 29246787 TI - An ELISA for quantification of recombinant human EGF in production process samples, serum and urine. AB - A sandwich enzyme-linked immunosorbent assay for quantifying a recombinant human Epidermal Growth Factor (rhEGF) protein used in a vacunal preparation is described. The protein was detected with high specificity in a short incubation time at elevated temperature, the assay showing a linear range between 0.0625 and 1 ng/mL. According to the regression analysis for the dilutional linearity data, r2 = 0.9998, slope = 1.07 and intercept = 0.05 were obtained. The intra- and inter-assay coefficient of variation, ranged from 0.79 to 2.87% and 4.87-9.69% respectively demonstrating high reproducibility and precision. The ANOVA test used in the specificity/interference study revealed parallelism among curves (p > 0.1), which indicated lack of interference in the working range. Recovery obtained in accuracy test for three concentration levels varied between 89 and 111%; evidencing a reliable analytical assay to characterize the quality of the recombinant protein in the manufacturing process at large scale, and other biological matrixes as: urine and serum. PMID- 29246788 TI - Alteration of Connexin43 expression in a rat model of obesity-related glomerulopathy. AB - It is accepted that alteration of connexin43 (Cx43) expression in glomeruli is a common pathological response in several forms of kidney diseases. To date, however the change of the Cx43 expression in obesity-related glomerulopathy (ORG) has not been reported. In this study, the alteration of Cx43 expression in the glomeruli of rat with ORG was defined. Five-week-old rats were fed with high-fat diet for 18weeks to establish the ORG model, then the histological change of glomeruli, the foot process effacement of podocyte, the markers for podocyte injury (nephrin,podocin and WT1) and Cx43 expression in glomeruli were examined respectively. The results demonstrated metabolic disorder, hyperinsulinemia, systemic inflammation and microalbuminuria in ORG rats. There was significant hypertrophy, glomerular expansion and inflammatory cell infiltration in the kidney of ORG rats compared to the control group. Significant foot process effacement of the podocyte in the glomeruli, nephrin loss and density reduction were shown in the ORG rats, and Cx43 expression was significant upregulated in glomeruli of ORG rats compared to the control group. The results indicate the correlation of overexpressed Cx43 with the obesity related renal inflammation and suggest that Cx43 might be a potential target in the development of obesity related glomerulopathy. PMID- 29246789 TI - LncRNA, CRNDE promotes osteosarcoma cell proliferation, invasion and migration by regulating Notch1 signaling and epithelial-mesenchymal transition. AB - Osteosarcoma is the most common bone malignancy in adolescence. Recently, the long non-coding RNAs (lncRNAs) were reported to play important roles in osteosarcoma progression. The present study examined the potential role of the lncRNA, Colorectal Neoplasia Differentially Expressed (CRNDE) and molecular mechanisms underlying osteosarcoma progression. In the present study, we identified that CRNDE was up-regulated in osteosarcoma tissues and cell lines, and CRNDE expression level was significantly higher in osteosarcoma tissues from patients with advanced stage and metastasis. Overexpression of CRNDE promoted cell growth, cell proliferation, cell invasion and migration, and increased cell population at S phase with a decreased cell population at G0/G1 phase in MG-63 cells. Knock-down of CRNDE suppressed cell growth, cell proliferation, cell invasion and migration, and decreased cell population at S phase with an increased cell population at G0/G1 phase in U2OS cells. Overexpression of CRNDE was found to enhance the activity of Notch1 signaling and promote epithelial mesenchymal transition (EMT) in MG-63 cells, while knock-down of CRNDE exerted the opposite effects in U2OS cells. The in vivo results showed that knock-down of CRNDE suppressed the tumor growth in the nude mice inoculated with osteosarcoma cells, and knock-down of CRNDE also suppressed the mRNA expression of Notch1, JAG1, N-cadherin, vimentin, and increased the mRNA expression of E-cadherin in the tumor tissues. Collectively, our results indicated that CRNDE functioned as an oncogene in osteosarcoma cell lines, and CRNDE may exert its oncogenic role via regulating Notch1 signaling and EMT in osteosarcoma. PMID- 29246790 TI - Clinical decision support models and frameworks: Seeking to address research issues underlying implementation successes and failures. AB - Computer-based clinical decision support (CDS) has been pursued for more than five decades. Despite notable accomplishments and successes, wide adoption and broad use of CDS in clinical practice has not been achieved. Many issues have been identified as being partially responsible for the relatively slow adoption and lack of impact, including deficiencies in leadership, recognition of purpose, understanding of human interaction and workflow implications of CDS, cognitive models of the role of CDS, and proprietary implementations with limited interoperability and sharing. To address limitations, many approaches have been proposed and evaluated, drawing on theoretical frameworks, as well as management, technical and other disciplines and experiences. It seems clear, because of the multiple perspectives involved, that no single model or framework is adequate to encompass these challenges. This Viewpoint paper seeks to review the various foci of CDS and to identify aspects in which theoretical models and frameworks for CDS have been explored or could be explored and where they might be expected to be most useful. PMID- 29246791 TI - A potential role for neuronal connexin 36 in the pathogenesis of amyotrophic lateral sclerosis. AB - Neuronal gap junctional protein connexin 36 (Cx36) contributes to neuronal death following a range of acute brain insults such as ischemia, traumatic brain injury and epilepsy. Whether Cx36 contributes to neuronal death and pathological outcomes in chronic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), is not known. We show here that the expression of Cx36 is significantly decreased in lumbar segments of the spinal cord of both human ALS subjects and SOD1G93A mice as compared to healthy human and wild-type mouse controls, respectively. In purified neuronal cultures prepared from the spinal cord of wild-type mice, knockdown of Cx36 reduces neuronal death caused by overexpression of the mutant human SOD1-G93A protein. Taken together, these data suggest a possible contribution of Cx36 to ALS pathogenesis. A perspective for the use of blockers of Cx36 gap junction channels for ALS therapy is discussed. PMID- 29246792 TI - Association of GPX1 and GPX4 polymorphisms with episodic memory and Alzheimer's disease. AB - It is well established that healthy aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD) are associated with substantial declines in episodic memory. However, there is still debate about the roles of GPX1 and GPX4 polymorphisms. The aim of this study was to investigate the association of rs1050450 and rs713041 polymorphisms with memory. This research was composed of a cross-sectional study (334 subjects) and a case-control study (108 healthy controls and 103 with AD-NINCDS/ARDA, DSM-IV-TR criteria). For the association of the genetic polymorphisms with memory or cognitive loss, the phenotypes were analyzed as follows: 1) each memory as a quantitative trait; 2) presence of deficit on a specific memory; 3) presence of MCI; 4) presence of AD. To assess verbal learning and the ability to store new information, we used the Rey Verbal Learning Test. Scores were recorded as a function of age as in the WMS-R testing battery. DNA was obtained from whole blood, and genotypes for GPX1 (rs1050450) and GPX4 (rs713041) were detected by allelic discrimination assay using TaqMan(r) MGB probes on a real-time PCR system. GPX1 TT homozygotes had lower long-term visual memory scores than CC/CT group (-0.28 +/- 1.03 vs. 0.13 +/- 1.03, respectively, p = 0.017). For the GPX4 rs713041, the frequency of the TT genotype was higher in the group with normal scores than in the group with long-term visual memory deficits (p = 0.025). In a multivariate logistic regression, GPX1 CC homozygotes had a 2.85 higher chance of developing AD (OR = 2.85, CI95% = 1.04 7.78, p = 0.041) in comparison to the reference genotype. No significant differences were observed regarding the MCI group between genetic variants. This study is one of the first to show that polymorphisms in GPX1 and GPX4 are significantly associated with episodic memory and AD in a South Brazilian population. PMID- 29246793 TI - Long-term treadmill exercise attenuates Abeta burdens and astrocyte activation in APP/PS1 mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a devastating disease characterized with progressive neurodegenerative disorders in the elderly. Epidemiological and clinical studies reported that lifestyle factors could halt the progression of AD, especially physical exercise. In the present work, we investigated the effects of long-term treadmill exercise on the pathological cascades of AD in APP/PS1 mice. After exercise for 5 months, Abeta deposition was significantly ameliorated in terms of Abeta area fraction, plaque number and size. We also found that long-term treadmill exercise increased neuronal density and attenuated activation of astrocytes. However, the activation of microglia was not affected in APP/PS1 mice treated with exercise intervention. In addition, the amyloidogenic pathway of amyloid precursor protein (APP) metabolism was inhibited, with the decrease of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and presenilin 1 (PS1). Nevertheless, the nonamyloidogenic pathway of APP metabolism was increased after exercise intervention. The expression levels of insulin-degrading enzyme (IDE) and receptor for advanced glycation end products (RAGE) also declined significantly. In conclusion, long-term treadmill exercise is neuroprotective against Abeta burdens and astrocyte activation, which contributes to the therapy for AD. PMID- 29246794 TI - Is core stability a risk factor for lower extremity injuries in an athletic population? A systematic review. AB - OBJECTIVES: To research and summarize the literature regarding the role of core stability as a risk factor in the development of lower extremity injuries in an athletic population. METHODS: Pubmed, Web of Science and Embase were searched in August 2016 to systematically review studies, which related core muscle functioning and core stability to lower extremity injuries. RESULTS: Nine articles were included in the systematic review. Various components of core stability were found to be related to lower extremity musculoskeletal injuries in healthy athletic populations. Core strength, core proprioception and neuromuscular control of the core were found to be a risk factor in the development of lower extremity injuries. However, conflicting evidence was found for core endurance as a risk factor for lower extremity injuries. CONCLUSION: This systematic review provides preliminary evidence for the association between impaired core stability and the development of lower extremity injuries in healthy athletes. Deficits in various aspects of core stability were identified as potential risk factors for lower extremity injuries. As such, core stability needs to be considered when screening athletes. PMID- 29246795 TI - ACCCN Workforce Standards for Intensive Care Nursing: Systematic and evidence review, development, and appraisal. AB - BACKGROUND: The intensive care nursing workforce plays an essential role in the achievement of positive healthcare outcomes. A growing body of evidence indicates that inadequate nurse staffing and poor skill mix are associated with negative outcomes for patients, and potentially compromises nurses' ability to maintain the safety of those in their care. In Australia, the Australian College of Critical Care Nurses (ACCCN) has previously published a position statement on intensive care staffing. There was a need for a stronger more evidence based document to support the intensive nursing workforce. OBJECTIVES: To undertake a systematic and evidence review of the evidence related to intensive care nurse staffing and quality of care, and determine evidence-based professional standards for the intensive care nursing workforce in Australia. METHODS: The National Health and Medical Research Council standard for clinical practice guidelines methodology was employed. The English language literature, for the years 2000 2015 was searched. Draft standards were developed and then peer- and consumer reviewed. RESULTS: A total of 553 articles was retrieved from the initial searches. Following evaluation, 231 articles met the inclusion criteria and were assessed for quality using established criteria. This evidence was used as the basis for the development of ten workforce standards, and to establish the overall level of evidence in support of each standard. All draft standards and their subsections were supported multi-professionally (median score >6) and by consumers (85-100% agreement). Following minor revisions, independent appraisal using the AGREE II tool indicated that the standards were developed with a high degree of rigour. CONCLUSION: The ACCCN intensive care nursing nurse workforce standards are the first to be developed using a robust, evidence-based process. The standards represent the optimal nurse workforce to achieve the best patient outcomes and to maintain a sustainable intensive care nursing workforce for Australia. PMID- 29246796 TI - Current state of renal tumor surgery among pediatric surgeons and pediatric urologists: A survey of American Pediatric Surgical Association (APSA) and Society for Pediatric Urology (SPU) members. AB - INTRODUCTION: Anecdotally, renal tumor (RT) surgery makes up a limited portion of the practice for most pediatric urologists and pediatric surgeons. Data are lacking on the current perceptions of RT surgery, both volume of surgery and issues related to surgical practice, among pediatric surgeons (PS) and pediatric urologists (PU). OBJECTIVES: To describe practice patterns of pediatric renal tumor (RT) surgery and identify factors related to higher reported volumes of RT surgery. STUDY DESIGN: The survey was developed and pilot-tested by the Children's Oncology Group (COG) RT surgery committee. The survey was distributed to APSA and SPU members. Logistic regression was performed to correlate surgeon reported factors with higher reported volumes of RT surgery. RESULTS: The survey was sent to 1,282 APSA and 426 SPU members, 367 (21.5%) surveys were completed from eligible responders, 244 (65.2%) and 123 (32.9%) from APSA and SPU invitations, respectively. Overall, 33.9% reported being part of a practice group in which RT surgical care is sub-specialized. A majority (50.7%) of respondents reported personally performing one to two RT surgeries annually, and 16.7% reported performing none. Multivariate logistic regression identified the following significant factors associated with increased individual RT surgical volume: group sub-specialization, COG/SIOP membership, regular tumor board attendance, and annual institutional volume >10 RT surgeries (Table). Accurate responses on the need for lymph node (LN) sampling in RT surgery were reported by 89.9%. Overall, 15.8% and 24.5% of respondents failed to correctly correlate local stage III disease in Wilms tumor (WT) with open or percutaneous biopsy, respectively (p < 0.001). DISCUSSION: While we found that reported RT surgery volume is low among both pediatric urologists and surgeons, we did identify surgeon-specific factors which correlated with higher RT surgical volume. Interested pediatric urologists and surgeons may use these data to tailor their practice if their goal is to increase RT surgery volume. Additionally, based on less than ideal rates of correct responses to nuance in the staging and treatment of WT, there are clear opportunities to increase education in this content area. However, the study is limited by use of a non-validated survey instrument and the relatively low response rates. CONCLUSION: Reported individual RT surgery volume is low. Factors associated with increased volume include sub-specialty practice, tumor board involvement, and higher institutional volume. Responses on LN sampling and biopsy in WT demonstrate opportunities for educational initiatives. PMID- 29246799 TI - Skin Commensal Malassezia globosa Secreted Protease Attenuates Staphylococcus aureus Biofilm Formation. AB - Skin provides the first defense against pathogenic micro-organisms and is also colonized by a diverse microbiota. Phylogenetic analysis of whole skin microbiome at different skin sites in health and disease has generated important insights on possible microbial involvement in modulating skin health. However, functional roles of the skin microbial community remain unclear. The most common sebaceous skin commensal yeasts are the basidiomycetes, Malassezia. Here, we characterized the dominant secreted Malassezia globosa protease in culture and subsequently named it Malassezia globosa Secreted Aspartyl Protease 1 (MgSAP1). We defined recombinant MgSAP1's substrate cleavage profile using an unbiased, mass spectrometry-based technique. We show that this enzyme is physiologically relevant as mgsap1 expression was detected on at least one facial skin site of 17 healthy human volunteers. In addition, we demonstrated that this protease rapidly hydrolyzes Staphylococcus aureus protein A, an important S. aureus virulence factor involved in immune evasion and biofilm formation. We further observed that MgSAP1 has anti-biofilm properties against S. aureus. Taken together, our study defines a role for the skin fungus Malassezia in inter-kingdom interactions and suggests that this fungus and the enzymes it produces may be beneficial for skin health. PMID- 29246797 TI - IL-1beta Production by Intermediate Monocytes Is Associated with Immunopathology in Cutaneous Leishmaniasis. AB - Cutaneous leishmaniasis due to Leishmania braziliensis infection is an inflammatory disease in which skin ulcer development is associated with mononuclear cell infiltrate and high levels of inflammatory cytokine production. Recently, NLRP3 inflammasome activation and IL-1beta production have been associated with increased pathology in murine cutaneous leishmaniasis. We hypothesized that cutaneous leishmaniasis patients have increased expression of NLRP3, leading to high levels of IL-1beta production. In this article we show high production of IL-1beta in biopsy samples and Leishmania antigen-stimulated peripheral blood mononuclear cells from patients infected with L. braziliensis and reduced IL-1beta levels after cure. IL-1beta production positively correlated with the area of necrosis in lesions and duration of the lesions. The main source of IL-1beta was intermediate monocytes (CD14++CD16+). Furthermore, our murine experiments show that IL-1beta production in response to L. braziliensis was dependent on NLRP3, caspase-1, and caspase-recruiting domain (ASC). Additionally, we observed an increased expression of the NLRP3 gene in macrophages and the NLRP3 protein in intermediate monocytes from cutaneous leishmaniasis patients. These results identify an important role for human intermediate monocytes in the production of IL-1beta, which contributes to the immunopathology observed in cutaneous leishmaniasis patients. PMID- 29246800 TI - Eosinophils Mediate Tissue Injury in the Autoimmune Skin Disease Bullous Pemphigoid. AB - Eosinophils are typically associated with unique inflammatory settings, including allergic inflammation and helminth infections. However, new information suggests that eosinophils contribute more broadly to inflammatory responses and participate in local immune regulation and the tissue remodeling/repair events linked with a variety of diseases. Eosinophilic infiltration has long been a histologic hallmark of bullous pemphigoid (BP), a subepidermal autoimmune blistering disease characterized by autoantibodies directed against basement membrane protein BP180. However, the exact role of eosinophils in disease pathogenesis remains largely unknown. We show here that eosinophils are necessary for IgE autoantibody-mediated BP blister formation in a humanized IgE receptor mouse model of BP. Disease severity is IgE dose dependent and correlates with the degree of eosinophil infiltration in the skin. Furthermore, IgE autoantibodies fail to induce BP in eosinophil-deficient mice, confirming that eosinophils are required for IgE-mediated tissue injury. Thus, eosinophils provide the cellular link between IgE autoantibodies and skin blistering in this murine model of BP. These findings suggest a role for eosinophils in autoimmune disease and have important implications for the treatment of BP and other antibody-mediated inflammatory and autoimmune diseases. PMID- 29246798 TI - DLX3-Dependent STAT3 Signaling in Keratinocytes Regulates Skin Immune Homeostasis. AB - Epidermal-specific deletion of the homeobox transcription regulator DLX3 disrupts keratinocyte differentiation and results in an IL-17-linked psoriasis-like skin inflammation. To identify the epidermal initiating signals produced by DLX3-null keratinocytes, we performed acute deletion of DLX3 in adult epidermis using a tamoxifen-inducible Krt14-cre/ERT system. K14CreERT;DLX3fl/fl skin exhibited dysregulated expression of differentiation-associated genes, upregulation of proinflammatory cytokines, and accumulation of Langerhans cells and macrophages within 3 days of tamoxifen-induced DLX3 ablation. We also observed increased accumulation of IL-17A-secreting Vgamma4 gammadelta T cells and heightened levels of IL-17 and IL-36 family of cytokines starting 1 week after DLX3 deletion. Interestingly, transcriptome profiling of K14CreERT;DLX3fl/fl epidermis at 3 days identified activated STAT3 as a transcriptional regulator and revealed differential expression of STAT3 signaling-related genes. Furthermore, activation of STAT3 was strongly increased in K14CreERT;DLX3fl/fl skin, and topical treatment with an inhibitor of STAT3 activation attenuated the immune phenotype. RNA-seq analysis of vehicle and STAT3 inhibitor treated K14CreERT;DLX3fl/fl skin identified differentially expressed genes associated with inhibition of leukocyte infiltration. Collectively, our results show that DLX3 is a critical regulator of STAT3 signaling network that maintains skin homeostasis. PMID- 29246801 TI - Regarding "Transcriptional and Cytokine Profiles Identify CXCL9 as a Biomarker of Disease Activity in Morphea". PMID- 29246802 TI - Population genetic data of 22 autosomal STRs in Guizhou Bouyei population, Southwestern China. PMID- 29246804 TI - Venetoclax: a chance for patients with chronic lymphocytic leukaemia previously treated with ibrutinib. PMID- 29246805 TI - Substrate specificity profiling of M32 metallocarboxypeptidases from Trypanosoma cruzi and Trypanosoma brucei. AB - Metallocarboxypeptidases (MCPs) of the M32 family, while broadly distributed among prokaryotic organisms, have so far been only found in a few eukaryotes including trypanosomatids. Among these organisms are human and animal pathogens of medical relevance such as Trypanosoma brucei and Trypanosoma cruzi, the respective causative agents of sleeping sickness and Chagas disease. The M32 MCP orthologues found in these parasites share 72% protein sequence identity. They also present a cytosolic localization, a similar pattern of expression and a marked preference for Arg/Lys residues at P1'. To further explore MCPs substrate specificity beyond the S1' subsite, we employed four positional scanning synthetic combinatorial libraries (PS-SC) of fluorescence resonance energy transfer (FRET) peptides. Our results indicated that the T. brucei enzyme has a restricted selectivity for Phe in P1 position compared to T. cruzi MCP-1, which presented a wider range of substrate acceptance. The S2, S3 and S4 subsites, on the other hand, could accommodate a broad range of residues. On the basis of these results, we synthesized for each enzyme a series of FRET substrates which contained the most favourable residues in every position. In particular, for both MCPs acting on FRET pentapeptide substrates, catalytic efficiencies were ~100 times higher compared with previously described chromogenic substrates. In fact, the fluorogenic peptide Abz-LLKFK(Dnp)-OH (Abz = ortho-aminobenzoic acid; Dnp = 2, 4-dinitrophenyl) described here can be used to monitor accurately TbMCP-1 activity in parasite cell-free extracts. These results provide valuable insights to develop selective substrates and inhibitors, to further understand the mechanisms and functions of M32 MCPs. PMID- 29246803 TI - Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. AB - BACKGROUND: Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy. METHODS: In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282. FINDINGS: Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8-18) for all 91 patients, 19 months (9-27) for the main cohort, and 12 months (8-15) for the expansion cohort. 59 (65%, 95% CI 53-74) of 91 patients had an overall response, including 30 (70%, 54-83) of 43 patients in the main cohort and 29 (60%, 43-72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred. INTERPRETATION: The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019. FUNDING: AbbVie, Genentech. PMID- 29246806 TI - Characterization of three salmon louse (Lepeophtheirus salmonis) genes with fibronectin II domains expressed by tegumental type 1 glands. AB - The salmon louse, Lepeophtheirus salmonis (Copepoda: Caligidae), is currently the most significant pathogen affecting the salmon farming industry in the Northern Hemisphere. Exocrine glands of blood-feeding parasites are believed to be important for the host-parasite interaction, but also in the production of substances for integument lubrication and antifouling. In L. salmonis; however, we have limited knowledge about the exocrine glands. The aim of this study was therefore to examine three genes containing fibronectin type II (FNII) domains expressed in L. salmonis tegumental type 1 (teg 1) glands, namely LsFNII1, 2 and 3. LsFNII1, 2 and 3 contains four, three, and two FNII domains respectively. Sequence alignment of LsFNII domains showed conservation of amino acids that may indicate a possible involvement of LsFNII domains in collagen binding. Ontogenetic analysis of LsFNII1, 2 and 3 revealed highest expression in pre-adult and adult lice. Localization of LsFNII1, 2 and 3 transcripts showed expression in teg 1 glands only, which are the most abundant exocrine gland type in L. salmonis. LsFNII1, 2 and 3 were successfully knocked-down by RNAi, however, alteration in gland morphology was not detected between the knock-down and control groups. Overall, this study gives first insight into FNII domain containing proteins in L. salmonis. PMID- 29246807 TI - Inappropriate Shock Due to Air Entrapment in the Pocket of a Subcutaneous Implantable Cardioverter-defibrillator. PMID- 29246808 TI - Effects of glutathione on the survival, growth performance and non-specific immunity of white shrimps (Litopenaeus vannamei). AB - Reduced glutathione (GSH) is the most abundant non-enzymatic antioxidant present in mammalian cells and the main intracellular defence mechanism against oxidative stress. This study investigated the effects of GSH on survival rate, mean body gain weight, feed efficiency (FE), phenoloxidase (PO) activity, superoxide dismutase (SOD) activity, acid phosphatase (ACP), alkaline phosphatase (AKP) activity, GSH peroxidase (GPx) and susceptibility to Vibrio alginolyticus when Pacific white shrimps (Litopenaeus vannamei) were fed with GSH-containing diets. GSH was added to diets at 0.10, 0.20 and 0.30 g/kg during the eight-week breeding experiment. Oral administration of GSH had significantly increased mean body weight gain, FE, PO activity, SOD activity, ACP activity, AKP activity, GPx activity and susceptibility to V. alginolyticus compared with those of the control group (p < .05). Results indicate that GSH exerts both growth-promoting and immunostimulatory effects on Pacific white shrimps (L. vannamei). PMID- 29246809 TI - Adaptive evolution of interferon regulatory factors is not correlated with body scale reduction or loss in schizothoracine fish. AB - Body scales in teleost fish are the first line of defense in protecting the fish from invading pathogens. However, the relationship between the adaptive evolution of immune-related genes and changes in the body scale-covering of fish has not been previously studied. Schizothoracine fish, characterized by progressive reduction of body scales from the primitive to the highly specialized species, are a good group to investigate this relationship. We obtained 11 IRF genes (IRF1 11) from 14 of schizothoracine fish representing primitive, specialized, and highly specialized species, of which seven IRF genes (IRF2, IRF3, IRF5, IRF6, IRF7, IRF8 and IRF9) contained the complete CDS. Sequence analysis demonstrated the deletion or insertion of 4-7 amino acids in IRF2, IRF3, IRF6 and IRF9, which seems to be a common phenomenon in the schizothoracine fish. Selection pressure analysis supported the hypothesis that positive selection has been driving the rapid evolution of IRFs in specific lineages of the schizothoracine fish. This, however, is not correlated with body scale reduction or loss in the evolution of these IRFs. Remarkably, the deletion or insertion found in IRF protein sequences presented a regular pattern corresponding to the scale-covering changes in schizothoracine fish. Our study provides evidence for positive selection in the IRF family, contributing to a better understanding of the adaptive evolution of immune-related genes in schizothoracine fish in response to environmental changes of the Qinghai-Tibetan Plateau. PMID- 29246810 TI - A new L-type lectin (LvLTLC1) from the shrimp Litopenaeus vannamei facilitates the clearance of Vibrio harveyi. AB - According to structures and functions of lectins found in shrimp, they are classified into seven types, namely, L-type, C-type, P-type, M-type, galectins, fibrinogen-like domain lectins, and calnexin/calreticulin. Until now, the researches of shrimp lectins are mainly focused on C-type lectins. In this study, we identified a new L-type lectin, designated as LvLTLC1, from the shrimp Litopenaeus vannamei. The cDNA of LvLTLC1 is 1184 bp with an open reading frame of 990 bp encoding a protein of 329 amino acids. The LvLTLC1 protein contained a putative signal peptide, an L-type lectin-like domain, and a transmembrane helix region. Phylogenetic analysis showed that LvLTLC1 belonged to VIP36-like family. LvLTLC1 was expressed in all examined tissues but had higher expression level in gills and hepatopancreas than other tissues. LvLTLC1 expression was up-regulated after immune challenge by Vibrio harveyi and lipopolysaccharide. The recombinant LvLTLC1 agglutinated Gram-positive (Staphylococcus aureus) and Gram-negative bacteria (V. harveyi, V. parahaemolyticus, V. alginolyticus, V. cholerae, V. vulnificus, Pseudomonas aeruginosa, P. fluorescens) in a calcium-independent manner. Recombinant LvLTLC1 exerted the ability of enhancing the clearance of V. harveyi injected in shrimp. Our results indicated that LvLTLC1 functions in anti pathogen innate immunity of shrimp. PMID- 29246812 TI - Sleep restriction undermines cardiovascular adaptation during stress, contingent on emotional stability. AB - Sleep loss is associated with increased cardiovascular disease, but physiological mechanisms accounting for this relationship are largely unknown. One possible mechanism is that sleep restriction exerts effects on cardiovascular stress responses, and that these effects vary between individuals. Emotional stability (ES) is a personality trait pertinent to sleep restriction and stress responding. However, no study to date has explored how ES and sleep-restriction interactively affect cardiovascular stress responses or processes of adaptation during stress. The present study sought to investigate the association between ES and impact of sleep restriction on cardiovascular function during stress, with particular regard to the trajectory of cardiovascular function change across time. Ninety female university students completed a laboratory vigilance stress task while undergoing continuous cardiovascular (SBP, DBP, HR, SV, CO, TPR) monitoring, after either a night of partial sleep restriction (40% of habitual sleep duration) or a full night's rest. Individuals high in ES showed stable and adaptive cardiovascular (SBP, SV, CO) responses throughout stress exposure, regardless of sleep. In contrast, individuals low in ES exhibited cardiovascular adaptation during stress exposure while rested, but disrupted adaption while sleep-restricted. These findings suggest that sleep-restriction undermines healthful cardiovascular adaptation to stress for individuals low in ES. PMID- 29246811 TI - Chemotactic effect of beta-defensin 1 on macrophages in Megalobrama amblycephala. AB - Besides their function as a physical barrier against pathogens, beta-defensins possess the ability to induce direct or indirect chemotaxis in leukocytes of mammals. However little is known about the ability of defensins to guide the migration of macrophages in fish. The objective of our study was to investigate whether beta-defensin 1 (maBD1) can recruit leukocytes (specifically macrophages) in vivo and in vitro in a farmed cyprinid fish Megalobrama amblycephala. The M. amblycephala beta-defensin 1 (maBD1) gene was amplified from the head-kidney transcriptome. Synthetic maBD1 polypeptide (as well as its N-terminus half, but not the C-terminus half) was capable of inducing the migration of leukocytes (specifically macrophages) at concentrations from 26.0 MUg/mL to 52.0 MUg/mL in head kidney tissue in vitro. When injected intraperitoneally in vivo, the number of leukocytes in the peritoneal cavity was in positive correlation with the maBD1 concentration. maBD1 also induced the expression of two proinflammatory cytokines (IL-1beta and TNF-alpha) in spleen, head and body kidney, and hepatopancreas. These results strongly indicate that BD1 has a chemoattractant capacity for macrophages, as well as the ability to modulate the expression of proinflammatory cytokines in fish. PMID- 29246814 TI - Neuroborreliosis and acute encephalopathy: The use of CXCL13 as a biomarker in CNS manifestations of Lyme borreliosis. AB - We report the case of an 80-year-old patient with acute onset confusion initially suspected to reflect delirium in incipient Alzheimer's disease. Cerebrospinal fluid tests revealed an unusually severe form of neuroborreliosis, which resolved following antibiotic treatment. This was mirrored in the measurement of CXCL13, which is suggested as a complementary biomarker. Clinical implications for screening, differential diagnosis and treatment are discussed. PMID- 29246815 TI - Neolyngbya gen. nov. (Cyanobacteria, Oscillatoriaceae): A new filamentous benthic marine taxon widely distributed along the Brazilian coast. AB - Brazil has an extensive and environmentally diverse coastline, which favors the occurrence of numerous cyanobacterial morpho- and ecotypes. Nevertheless, this coastline is still poorly studied and its diversity is underestimated. Considering the family Oscillatoriaceae, Lyngbya deserves special attention. It includes many clades which are phylogenetically non-related but morphologically similar. Such clades occur in marine and freshwater environments and are traditionally treated as a single genus. In the current study, we sampled both mediolittoral and estuarine zones along the Brazilian coast. Based on a polyphasic characterization, we described a new genus of marine filamentous cyanobacteria: Neolyngbya. It includes six new species sampled in Brazil, which are described in this study (N. maris-brasilis, N. granulosa, N. irregularis, N. nodulosa, N. arenicola and N. tenuis). Additionally, the characterization included a Neolyngbya sp. from Japan in the clade, but only based on molecular data. All species presented irregular arrangement of thylakoids as described for Oscillatoriaceae. The new genus shares morphological characteristics with species in different clades of the Lyngbya complex. The ultrastructural analyses of Neolyngbya, however, showed numerous gas vesicles, especially in the interthylakoid space; such feature is not observed in benthic Lyngbya species. Neolyngbya formed a well-supported clade (16S rRNA phylogeny), however distantly related to L. aestuarii and L. confervoides, both marine species clusters. The Limnoraphis clade is in a sister relationship to the Neolyngbya clade, however the former occurs in freshwater plankton. Secondary structures of 16S-23S rRNA ITS sequences were congruent with the phylogeny. The polyphasic characterization was helpful to clarify the diversity and ecological aspects of benthic filamentous cyanobacteria and the evolutionary history of the group. This favors a better understanding of inter and infrageneric taxa. The number of novel taxa described in this study emphasizes the importance of conducting additional floristic surveys, mainly in underexplored marine environments, to reveal the real cyanobacterial biodiversity in these areas. PMID- 29246813 TI - Simultaneous EEG-fMRI reveals attention-dependent coupling of early face processing with a distributed cortical network. AB - The speed of visual processing is central to our understanding of face perception. Yet the extent to which early visual processing influences later processing in distributed face processing networks, and the top-down modulation of such bottom-up effects, remains unclear. We used simultaneous EEG-fMRI to investigate cortical activity that showed unique covariation with ERP components of face processing (C1, P1, N170, P3), while manipulating sustained attention and transient cognitive conflict employing an emotional face-word Stroop task. ERP markers of visual processing within 100 ms after stimulus onset showed covariation with brain activation in precuneous, posterior cingulate gyrus, left middle temporal gyrus, left inferior frontal gyrus and frontal operculum, and a left lateral parietal-occipital cluster, illustrating the impact of early stage processing on higher-order mechanisms. Crucially, this covariation depended on sustained attentional focus and was absent for incongruent trials, suggesting flexible top-down gating of bottom-up processing. PMID- 29246816 TI - Discordance between genomic divergence and phenotypic variation in a rapidly evolving avian genus (Motacilla). AB - Generally, genotypes and phenotypes are expected to be spatially congruent; however, in widespread species complexes with few barriers to dispersal, multiple contact zones, and limited reproductive isolation, discordance between phenotypes and phylogeographic groups is more probable. Wagtails (Motacilla) are a genus of birds with striking plumage pattern variation across the Old World. Up to 13 subspecies are recognized within a single species, yet previous studies using mitochondrial DNA have supported polyphyletic phylogeographic groups that are inconsistent with subspecies plumage characteristics. In this study, we investigate the link between phenotypes and genotype by taking a phylogenetic approach. We use genome-wide SNPs, nuclear introns, and mitochondrial DNA to estimate population structure, isolation by distance, and species relationships. Together, our genetic sampling includes complete species-level sampling and comprehensive coverage of the three most phenotypically diverse Palearctic species. Our study provides strong evidence for species-level patterns of differentiation, however population-level differentiation is less pronounced. SNPs provide a robust estimate of species-level relationships, which are mostly corroborated by a combined analysis of mtDNA and nuclear introns (the first time calibrated species tree for the genus). However, the mtDNA tree is strongly incongruent and is considered to misrepresent the species phylogeny. The extant wagtail lineages originated during the Pliocene and the Eurasian lineage underwent rapid diversification during the Pleistocene. Three of four widespread Eurasian species exhibit an east-west divide that contradicts both subspecies taxonomy and phenotypic variation. Indeed, SNPs fail to distinguish between phenotypically distinct subspecies within the M. alba and M. flava complexes, and instead support geographical regions, each of which is home to two or more different looking subspecies. This is a major step towards our understanding of wagtail phylogeny compared to previous analyses of fewer species and considerably less sequence data. PMID- 29246818 TI - Increased 1-year continuation of DMPA among women randomized to self administration: results from a randomized controlled trial at Planned Parenthood. AB - OBJECTIVES: Self-administration of subcutaneous depot medroxyprogesterone acetate (DMPA-sc) is feasible, acceptable, and effective. Our objective was to compare one-year continuation of DMPA-sc between women randomized to self-administration versus clinic administration. STUDY DESIGN: We randomized 401 females ages 15-44 requesting DMPA at clinics in Texas and New Jersey to self-administration or clinic administration in a 1:1 allocation. Clinic staff taught participants randomized to self-administration to self-inject and observed the first injection; participants received instructions, a sharps container, and three doses for home use. Participants randomized to clinic administration received usual care. All participants received DMPA-sc at no cost and injection reminders via text message or email. We conducted follow-up surveys at six and 12 months. RESULTS: Three hundred thirty-six participants (84%) completed the 12-month survey; 316 completed both follow-up surveys (an 80% response rate excluding eight withdrawals). Participants ranged in age from 16-44. One-year DMPA continuous use was 69% in the self-administration group and 54% in the clinic group (p=.005). There were three self-reported pregnancies during the study period, all occurred in the clinic group; all three women had discontinued DMPA and one reported her pregnancy as intended. Among the self-administration group, 97% reported that self-administration was very or somewhat easy; 87% would recommend self-administration of DMPA-sc to a friend. Among the clinic group, 52% reported interest in self-administration in the future. Satisfaction was similar between groups. No serious adverse events were reported. CONCLUSIONS: DMPA self administration improves contraceptive continuation and is a feasible and acceptable option for women and adolescents. IMPLICATIONS: Self-administration of subcutaneous DMPA can improve contraceptive access, autonomy, and continuation, and is a feasible and acceptable option for women and adolescents. It should be made widely available as an option for women and adolescents. PMID- 29246817 TI - Diversity and biogeography of frogs in the genus Amnirana (Anura: Ranidae) across sub-Saharan Africa. AB - Frogs in the genus Amnirana (family Ranidae) are widely distributed across sub Saharan Africa and present a model system for exploring the relationship between diversification and geography across the continent. Using multiple loci from the mitochondrial (16S) and nuclear genomes (DISP2, FICD, KIAA2013, REV3L), we generated a strongly supported species-level phylogeny that provides insights into the continental biogeography of African species of Amnirana, which form a monophyletic group within the genus. Species delimitation analyses suggest that there may be as many as seven additional species of Amnirana in Africa. The biogeographic history of Amnirana is marked by several dispersal and vicariance events, including dispersal from the Lower Guinean Forest into the Congo Basin. In addition, phylogeographic patterns within two widespread species, A. albolabris and A. galamensis, reveal undescribed cryptic diversity. Populations assigned to A. albolabris in western Africa are more closely related to A. fonensis and require recognition as a distinct species. Our analyses reveal that the Lower and Upper Guinean Forest regions served as important centers of interspecific and intraspecific diversifications for Amnirana. PMID- 29246819 TI - Discordance between self-reported contraceptive use and detection of exogenous hormones among Malawian women enrolling in a randomized clinical trial. AB - OBJECTIVE: The objective was to assess the extent of concordance between self reported contraceptive use and the presence of contraceptive progestins in serum. STUDY DESIGN: We evaluated self-reported contraceptive use by using radioimmunoassay to examine baseline serum levels of medroxyprogesterone acetate (MPA) and levonorgestrel (LNG) among 97 Malawian women enrolling in a contraceptive trial. RESULTS: Twelve percent (12/97) of study participants who reported no hormonal contraceptive use in the previous 6months had either MPA or LNG detected in their serum. CONCLUSIONS: The observed discordance between self report and detection of exogenous hormones in serum indicates that caution is warranted when drawing conclusions based on self-reported contraceptive use. PMID- 29246820 TI - Mobilization of Hematopoietic Progenitor Cells with Standard- or Reduced-Dose Filgrastim after Vinorelbine in Multiple Myeloma Patients: A Randomized Prospective Single-Center Phase II Study. AB - Vinorelbine combined with filgrastim at a dose of 10 ug/kg of body weight (BW) per day is a reliable and well-tolerated regimen for mobilization of hematopoietic progenitor cells (HPCs) in patients with multiple myeloma. This prospective, randomized, phase II study was initiated to assess the feasibility of a reduced filgrastim dosage. Vinorelbine was combined with either standard dose filgrastim (10 ug/kg BW per day) or reduced-dose filgrastim (5 ug/kg BW per day). Leukapheresis sessions were planned to start at day 8 and were continued until the predefined target amount of 4 * 106 HPCs/kg BW was collected. The study demonstrated the feasibility of vinorelbine combined with reduced daily filgrastim with a mean of 1.29 leukapheresis sessions necessary per patient (95% confidence interval, .95 to 1.7). All patients could start leukapheresis as planned at day 8, and the collection success rate was 100% for the whole patient collective after a maximum of 2 leukapheresis sessions. No statistically significant differences with regard to the amount of HPCs collected between the 2 groups were observed (P = .99). Accordingly, no differences were seen with regard to length of hospitalization for autotransplant (P = .34) and duration of neutrophil (P = .93) and platelet engraftment (P = .42). Patients receiving reduced-dose filgrastim reported significantly lower peak pain values in a numeric analogue scale (P = .01), and the costs were significantly lower than in patients undergoing standard-dose chemomobilization (P = .001). Vinorelbine 35 mg/m2 plus filgrastim 5 ug/kg BW once per day until completion of HPC collection is feasible and appears to be advantageous with respect to the severity of pain intensity and treatment costs. PMID- 29246821 TI - Late Gastrointestinal Complications of Allogeneic Hematopoietic Stem Cell Transplantation in Adults. AB - Gastrointestinal (GI) complications including graft-versus-host disease (GVHD) are a major cause of morbidity and mortality in allogenic stem transplant recipients. Although several studies have previously looked into the acute GI complications, fewer smaller studies have reported late complications. In this large study we focus on the late (100 days post-transplant) GI complications in allogenic stem transplant recipients. In this single-center, retrospective study of all adult allogenic stem cell transplant recipients who had their transplant at Duke University over a 6-year period, 479 patients underwent allogenic stem cell transplant, of whom 392 recipients survived for at least 100 days post transplant. Late GI symptoms were noted in 71 patients, prompting endoscopic evaluation. The primary endpoint of our study was the diagnosis of GI-GVHD based on endoscopic findings, whereas overall survival and nonrelapse mortality were the secondary endpoints. Of the 71 patients who underwent endoscopy, 45 (63%) had GI-GVHD. Of these 45 patients, 39 (87%) had late acute GVHD, 1 (2%) had chronic GVHD, and 5 patients (11%) had overlap disease. Of the patients who did not have GVHD, the symptoms were mostly related to infectious and inflammatory causes. Less common causes included drug toxicity, food intolerance, disease relapse, and motility issues. In a multivariate analysis the factors most indicative of GI GVHD were histologic findings of apoptosis on the tissue specimen (odds ratio, 2.35; 95% confidence interval, 1.18 to 4.70; P = .015) and clinical findings of diarrhea (odds ratio, 5.43; 95% confidence interval, 1.25 to 23.54; P = .024). The median survival time from the first endoscopy was 8.5 months. The incidence of nonrelapse mortality at 6 months was 31% in patients with GI-GVHD and 19% in patients without GI-GVHD (P = .42). All patients with GI-GVHD were on steroid therapy, and 31% of them received total parenteral nutrition. In our population close to one-fifth of allogenic transplant recipients experienced late GI complications, warranting endoscopic evaluation. Most of these patients were found to have GI-GVHD that had a high incidence of nonrelapse mortality at 6 months and close to one-third of these patients needed total parenteral nutrition. PMID- 29246822 TI - Reply to: Comment on "Association of bullous pemphigoid with malignancy: A systematic review and meta-analysis". PMID- 29246823 TI - Classification of cutaneous manifestations in patients with non-celiac gluten sensitivity (NCGS) and wheat allergy (WA). PMID- 29246825 TI - Mohs micrographic surgery and dermatopathology concordance; An analysis of 1421 Mohs cases over 17 years. AB - BACKGROUND: The success of Mohs micrographic surgery depends on the surgeon's ability to correctly interpret intraoperative frozen sections. OBJECTIVE: This retrospective study analyzed the rate of concordance between Mohs surgeons and dermatopathologists in reading slides from Mohs surgery cases. METHODS: A dermatopathologist reviewed all the frozen sections and the corresponding Mohs map for every 30th Mohs case at a practice employing 6 different Mohs surgeons from 2001-2017. Cases in which the dermatopathologist and the Mohs surgeon disagreed on the interpretation were noted. RESULTS: The concordance rate between Mohs surgeons and dermatopathologists was 99.79%. The three discordant cases included one case each of squamous cell carcinoma, superficial basal cell carcinoma, and hypertrophic squamous cell carcinoma in situ. LIMITATIONS: This analysis is limited to fellowship-trained Mohs surgeons and therefore may not be applicable to all physicians who perform Mohs. CONCLUSIONS: Fellowship-trained Mohs surgeons show very high concordance with board-certified dermatopathologists in the accurate and precise interpretation of histology slides in the setting of Mohs micrographic surgery. PMID- 29246824 TI - Association of very preterm birth with decreased risk of eczema: A systematic review and meta-analysis. AB - BACKGROUND: Accumulating studies suggest that an association exists between preterm birth and eczema. OBJECTIVE: We performed a meta-analysis of the available evidence to determine whether the risk of developing eczema is affected by preterm birth. METHODS: We searched for observational studies using PubMed, Cochrane Library, Web of Science, and EMBASE databases from inception to February 1, 2017. Studies that met the inclusion criteria were evaluated. Unadjusted and adjusted effect estimates were pooled using a random-effects model. Subgroup analysis and sensitivity analysis were performed to assess the robustness of associations. RESULTS: Eighteen studies were included in this study. Compared with full-term birth, very preterm birth had a lower risk of eczema in unadjusted (relative risk [RR] 0.78, 95% confidence interval [CI] 0.72-0.85) and adjusted (RR 0.76, 95% CI 0.68-0.86) analyses. The risk became insignificant among children born moderate preterm (unadjusted RR 0.88, 95% CI 0.77-1.00; adjusted RR 0.86, 95% CI 0.73-1.01). LIMITATIONS: The included studies used different assessments of eczema, and gestational age varied among studies. CONCLUSION: The available evidence suggests an association between very preterm birth and a decreased risk of eczema. PMID- 29246826 TI - Metformin is associated with decreased skin cancer risk in Taiwanese patients with type 2 diabetes. AB - BACKGROUND: Metformin, an antidiabetic drug, is associated with decreased cancer risk, but its effect on skin cancer is unknown. OBJECTIVE: To evaluate skin cancer risk associated with metformin use. METHODS: In total, 16,237 matched pairs of ever and never metformin users with new-onset type 2 diabetes diagnosed during 1999-2005 were retrospectively enrolled and followed until December 31, 2011, using Taiwan's National Health Insurance database. Hazard ratios (HRs) were estimated using Cox regression weighted for propensity scores. RESULTS: Skin cancer incidence was 45.59 and 83.90 per 100,000 person-years among ever and never users, respectively (HR 0.540, 95% confidence interval [CI] 0.357-0.819). Among ever users, the HRs (95% CIs) for the first (<21.00 months), second (21.00 45.83 months), and third (>45.83 months) cumulative duration tertiles were 0.817 (0.448-1.489), 0.844 (0.504-1.412), and 0.114 (0.036-0.364), respectively, and the HRs (95% CIs) for the first, second, and third cumulative dose tertiles were 1.006 (0.579-1.748), 0.578 (0.317-1.051), and 0.229 (0.099-0.530), respectively. HRs (95% CIs) were 0.523 (0.175-1.562) for melanoma and 0.496 (0.319-0.772) for nonmelanoma skin cancer. LIMITATIONS: Few patients had skin cancer and information on ultraviolet light exposure and tumor histopathology was lacking. CONCLUSION: Metformin use is associated with a decreased skin cancer risk. PMID- 29246827 TI - Safety and efficacy of atrial antitachycardia pacing in congenital heart disease. AB - BACKGROUND: Intra-atrial reentrant tachycardia (IART) is a common sequela in the congenital heart disease (CHD) population, and it significantly increases morbidity and mortality. Atrial antitachycardia devices (ATDs) capable of atrial antitachycardia pacing (ATP) therapy have been used to manage IART in the CHD population, but there are limited data on their safety and efficacy. OBJECTIVES: To determine whether ATD implantation was associated with reduced direct current (DC) cardioversions and to compare ATP success between different CHD diagnoses and ATP programs. METHODS: A single-center retrospective chart review was performed on CHD patients with ATDs. Demographic data were collected in addition to the number of DC cardioversions required before and after ATD implantation; data on ATP efficacy and the specific ATP program utilized; and adverse events related to ATD implantation or subsequent ATP treatments. RESULTS: ATD implantation in 91 CHD patients was associated with a significant reduction in DC cardioversions (P < .01). Overall, 72% of IART episodes were successfully terminated by ATP. Patients with levo-transposition of the great arteries experienced lower rates of ATP success than the remainder of the cohort (P < .01). There was no evidence of degeneration to ventricular arrhythmia or death directly attributed to ATP. CONCLUSION: ATD implantation was associated with reduced DC cardioversion burden. Patients with levo-transposition of the great arteries may experience lower ATP efficacy than patients with other CHDs; however, a larger patient population is required to better determine subgroup efficacy. These results support the safety and efficacy of ATP in the CHD population. PMID- 29246828 TI - The pathophysiology of the vasovagal response. AB - In part I of this study, we found that the classical studies on vasovagal syncope, conducted in fit young subjects, overstated vasodilatation as the dominant hypotensive mechanism. Since 1980, blood pressure and cardiac output have been measured continuously using noninvasive methods during tilt, mainly in patients with recurrent syncope, including women and the elderly. This has allowed us to analyze in more detail the complex sequence of hemodynamic changes leading up to syncope in the laboratory. All tilt-sensitive patients appear to progress through 4 phases: (1) early stabilization, (2) circulatory instability, (3) terminal hypotension, and (4) recovery. The physiology responsible for each phase is discussed. Although the order of phases is consistent, the time spent in each phase may vary. In teenagers and young adults, progressive hypotension during phases 2 and 3 can be driven by vasodilatation or falling cardiac output. The fall in cardiac output is secondary to a progressive decrease in stroke volume because blood is pooled in the splanchnic veins. In adults a fall in cardiac output is the dominant hypotensive mechanism because systemic vascular resistance always remains above baseline levels. PMID- 29246830 TI - Relative timing of near-field and far-field electrograms can determine the tachyarrhythmia site of origin. AB - BACKGROUND: Despite improving algorithms, inappropriate shocks for supraventricular tachycardia (SVT) still occur in a significant number of patients with implantable cardioverter-defibrillators (ICDs). This makes the discovery of novel discriminators that use existing ICD hardware an attractive proposition. OBJECTIVE: We hypothesized that the delay of activation onset from the device-detected, far-field electrogram (EGM) to the near-field, bipole EGM would allow the differentiation of ventricular tachycardias (VTs) from SVTs. METHODS: Proof of principle was demonstrated by rapid pacing in the right atrium, right ventricle, and left ventricle in healthy patients undergoing atrial fibrillation ablation procedures (n = 17). Using real-life ICD recordings, the equivalent measurements were made in a derivation cohort (n = 26) and cutoff predictive values obtained. Finally, the selected values were validated in a separate group of recordings (n = 82). RESULTS: In healthy patients, significant differences in the far-field to near-field EGM activation onsets were observed between right atrial (14.7 +/- 2.7 ms), right ventricular (36.3 +/- 8 ms), and left ventricular (57.8 +/- 10.3 ms; P < .001) pacing. In the derivation ICD cohort, the median far-field to near-field onset delay was significantly shorter in SVT (24.5 ms; interquartile range, 15.3-47.5 ms) than in VT (118.5 ms; interquartile range, 102.5-131.5 ms) (P < .001). Using a cutoff of 100 ms in the validation cohort, SVT was successfully discriminated from VT with a sensitivity and specificity of 88% and a negative predictive value of 94.2%. CONCLUSION: The delay between far-field and near-field EGMs offers a potential new discrimination tool to reduce inappropriate ICD therapies and aid interpretation of single-lead device tracings. PMID- 29246829 TI - Hyperspectral imaging for label-free in vivo identification of myocardial scars and sites of radiofrequency ablation lesions. AB - BACKGROUND: Treatment of cardiac arrhythmias often involves ablating viable muscle tissue within or near islands of scarred myocardium. Yet, today there are limited means by which the boundaries of such scars can be visualized during surgery and distinguished from the sites of acute injury caused by radiofrequency (RF) ablation. OBJECTIVE: We sought to explore a hyperspectral imaging (HSI) methodology to delineate and distinguish scar tissue from tissue injury caused by RF ablation. METHODS: RF ablation of the ventricular surface of live rats that underwent thoracotomy was followed by a 2-month animal recovery period. During a second surgery, new RF lesions were placed next to the scarred tissue from the previous ablation procedure. The myocardial infarction model was used as an alternative way to create scar tissue. RESULTS: Excitation-emission matrices acquired from the sites of RF lesions, scar region, and the surrounding unablated tissue revealed multiple spectral changes. These findings justified HSI of the heart surface using illumination with 365 nm UV light while acquiring spectral images within the visible range. Autofluorescence-based HSI enabled to distinguish sites of RF lesions from scar or unablated myocardium in open-chest rats. A pilot version of a percutaneous HSI catheter was used to demonstrate the feasibility of RF lesion visualization in atrial tissue of live pigs. CONCLUSION: HSI based on changes in tissue autofluorescence is a highly effective tool for revealing-in vivo and with high spatial resolution-surface boundaries of myocardial scar and discriminating it from areas of acute necrosis caused by RF ablation. PMID- 29246831 TI - The effect of normal human serum on the mouse trypanosome Trypanosoma musculi in vitro and in vivo. AB - Trypanosoma musculi, a common blood flagellate found in mice, is similar in morphology and life cycle to the rat trypanosome T. lewisi. Both species belong to the subgenus Herpetosoma, and as T. lewisi has recently been shown to be a zoonotic pathogen, there is concern that T. musculi could also be potentially infective to humans. To test this hypothesis, a well-established method, the normal human serum (NHS) incubation test, was carried out which distinguishes human and non-human infective trypanosomes. We found that T. musculi could grow in 0.31% NHS in vitro, and even kept their infectivity to mice after incubation with 10% NHS for 24 h. In in vivo experiments, T. musculi were only slightly affected by NHS injection, confirming that it was less sensitive to the NHS than T. b. brucei, but more sensitive than T. lewisi. This resistance probably does not rely on a restricted uptake of ApoL-1. Due to this partial resistance, we cannot definitively confirm that T. musculi has the potential for infection to humans. As resistance is less than that of T. lewisi, our data suggest that it is unlikely to be a zoonotic pathogen although we would advise caution in the case of immunocompromised people such as AIDS and cancer patients. PMID- 29246833 TI - Influence of Ground Glass Opacity and the Corresponding Pathological Findings on Survival in Patients with Clinical Stage I Non-Small Cell Lung Cancer. AB - INTRODUCTION: The aim was to clarify the influence on patient prognosis of ground glass opacity (GGO) component in each new TNM stage and propose grouping reflecting the prognosis more accurately. METHODS: We examined the data on 1290 patients who underwent lung cancer resection from 2003 to 2011. The demographics and overall survival of patients with adenocarcinoma with and without GGO, squamous cell carcinoma, and the others were compared according to clinical stage from 0 to IB. In adenocarcinoma, we examined the distribution of histological subtypes of adenocarcinoma with and without GGO in each clinical stage. RESULTS: Each clinical stage differentiated overall survival well. However, the prognosis of the patients with adenocarcinoma with GGO was considerably more favorable than that of the others in clinical stage IA2 and IA3 but not of those in clinical stage IB. In clinical stage 0 to IA3, patients showing adenocarcinoma in situ, minimally invasive adenocarcinoma, and invasive lepidic predominant adenocarcinoma accounted for about 50% of the total number of patients with adenocarcinoma with GGO (stage 0, 16 of 21; stage IA1, 113 of 143; stage IA2, 80 of 157; and stage IA3, 45 of 94). In clinical stage IB, 20% of adenocarcinomas with GGO showed invasive solid predominant adenocarcinoma (IB, seven of 38). Most of the adenocarcinomas without GGO were in clinical stage IA2 to IB, and the distribution of histological subtypes was similar at each clinical stage. Invasive acinar and solid predominant adenocarcinomas were more common in adenocarcinoma without GGO. CONCLUSIONS: Clinical T classification considering GGO component may offer more accurate prognosis for patients with lung cancer less than 3 cm in invasive diameter. PMID- 29246832 TI - Use of Tc-rCRP as a target for lytic antibody titration after experimental Trypanosoma cruzi infection. AB - Experimental Chagas disease has been used as a model to identify several host/parasite interaction factors involved in immune responses to Trypanosoma cruzi infection. One of the factors inherent to this parasite is the complement regulatory protein (Tc-CRP), a major epitope that induces production of lytic antibodies during T. cruzi infections. Previous studies have evaluated the function of Tc-CRP as an antigenic marker via ELISAs, which demonstrated high sensitivity and specificity when compared to other methods. Therefore, this study aimed to assess and compare the levels of lytic antibodies induced by this protein following experimental infection using different T. cruzi strains. Our results demonstrated that infections induced by strains isolated from vectors resulted in subpatent parasitaemia and low reactivity, as assessed by Tc-rCRP ELISAs. On the other hand, mice inoculated with T. cruzi strains isolated from patients developed patent parasitaemia, and presented elevated lytic antibodies titres, as measured by Tc-rCRP ELISA. In addition, comparison between different mouse lineages demonstrated that Balb/c mice were more reactive than C57BL/6 mice in almost all types of infections, except those infected by the AQ-4 strain. Parasites from the Hel strain generated the greatest lytic antibody response in all evaluated models. Therefore, application of sensitive techniques for monitoring immune responses would enable us to establish growth curves for lytic antibodies during the course of the infection, and allow us to discriminate between T. cruzi strains that originate from different hosts. PMID- 29246834 TI - Geographic Variation in EGFR Mutation Frequency in Lung Adenocarcinoma May Be Explained by Interethnic Genetic Variation. AB - Our understanding of the etiology of EGFR-mutant lung cancer remains incomplete. One persistent finding in the literature is the geographic variation in the frequency of EGFR mutations in lung adenocarcinoma. We investigated the association between two biomarkers of East Asian ancestry, the genetic polymorphisms ectodysplasin A receptor gene (EDAR) V370A and ATP binding cassette subfamily C member 11 gene (ABCC11) G180A, and the frequency of EGFR mutations in patients with lung adenocarcinoma in a range of countries. The Pearson's linear correlation between the frequency of EGFR mutations and the EDAR polymorphism was 0.92 (p <2.2 * 10-10), and for the ABCC11 polymorphism it was 0.72 (p <1.6 * 10 4). These results suggest that the variation in the measured frequency of EGFR mutations in lung adenocarcinoma can be explained, at least in part, by interethnic genetic variation. To improve our understanding of this disease, studies exploring the genetic polymorphism(s) that cause these interethnic differences, as well as the mechanisms of actions through which they work, are warranted. PMID- 29246835 TI - PD-L1 Expression of Tumor Cells, Macrophages, and Immune Cells in Non-Small Cell Lung Cancer Patients with Malignant Pleural Effusion. AB - INTRODUCTION: Whether immunohistochemical staining of programmed death ligand 1 (PD-L1) on cells of pleural effusion could be used to predict response to immunotherapy treatment has not been reported. METHODS: We retrospectively enrolled patients who had undergone malignant pleural effusion drainage and had effusion cell block specimens from 2014 to 2016. Immunohistochemical staining for PD-L1 was performed with tumor cells, immune cells, and macrophages of all cell block specimens. Immunoactivity was scored as 0 for absence of staining and 1+ for faint, 2+ for moderate, and 3+ for intense membranous staining. Patients' clinicopathological characteristics were also collected. RESULTS: PD-L1 expression of pleural effusion tumor cells was associated with the PD-L1 expression of macrophages (p = 0.003) and immune cells (p < 0.001). However, the PD-L1 expression of immune cells was not associated with that of macrophages. The PD-L1 expression of tumor cells was correlated with sex (p = 0.012), smoking status (p = 0.032), and Eastern Cooperative Oncology Group performance status (p = 0.017). The PD-L1 expression of immune cells was associated with the overall survival of patients (p = 0.004). CONCLUSIONS: These results suggest that there might be an immune interaction between pleural effusion tumor cells and macrophages. The low intensity of PD-L1 expression in immune cells is associated with the poor survival of patients with lung cancer with malignant pleural effusion. PMID- 29246836 TI - Incidence of Guillain-Barre syndrome during Zika virus outbreak. PMID- 29246837 TI - Correction to Lancet Glob Health 2018; 6: e111-20. PMID- 29246838 TI - Imidacloprid, a neonicotinoid insecticide, facilitates tyrosine hydroxylase transcription and phenylethanolamine N-methyltransferase mRNA expression to enhance catecholamine synthesis and its nicotine-evoked elevation in PC12D cells. AB - Imidacloprid is a neonicotinoid insecticide acting as an agonist of nicotinic acetylcholine receptors (nAChRs) in the target insects. However, questions about the safety to mammals, including human have emerged. Overactivation of mammalian peripheral catecholaminergic systems leads to onset of tachycardia, hypertension, vomiting, etc., which have been observed in acutely imidacloprid-poisoned patients as well. Physiological activation of the nAChRs is known to drive catecholamine biosynthesis and secretion in mammalian adrenal chromaffin cells. Yet, the impacts of imidacloprid on the catecholaminergic function of the chromaffin cells remain to be evaluated. In this study using PC12D cells, a catecholaminergic cell line derived from the medulla chromaffin-cell tumors of rat adrenal gland, we examined whether imidacloprid itself could impact the catecholamine-synthesizing ability. Imidacloprid alone did facilitate tyrosine hydroxylase (TH) transcription via activation of alpha3beta4 nAChR and the alpha7 subunit-comprising receptor. The insecticide showed the TH transcription facilitating ability at the concentrations of 3 and 30 MUM, at which acetylcholine is known to produce physiological responses, including catecholamine secretion through the nAChRs in adrenal chromaffin cells. The insecticide-facilitated TH transcription was also dependent on PKA- and RhoA mediated signaling pathways. The insecticide coincidentally raised levels of TH and phenylethanolamine N-methyltransferase (PNMT) mRNA, and as a consequence, increased catecholamine production, although the efficacy of the neonicotinoid was lesser than that of nicotine, indicating its partial agonist-like action. Intriguingly, in cultured rat adrenal chromaffin cells, imidacloprid did increase levels of TH and PNMT protein. When the chromaffin cells were treated with nicotine in the presence of the insecticide, nicotine-elevated adrenaline production was enhanced due to facilitation of nicotine-increased TH and PNMT protein expression, and simultaneous enhancement of nicotine-elevated adrenaline secretion also took place. These findings thus suggest that imidacloprid may facilitate the physiological functions of adrenal glands in mammals. PMID- 29246839 TI - Fructooligosaccharides production by Schedonorus arundinaceus sucrose:sucrose 1 fructosyltransferase constitutively expressed to high levels in Pichia pastoris. AB - The non-saccharolytic yeast Pichia pastoris was engineered to express constitutively the mature region of sucrose:sucrose 1-fructosyltransferase (1 SST, EC 2.4.1.99) from Tall fescue (Schedonorus arundinaceus). The increase of the transgene dosage from one to nine copies enhanced 7.9-fold the recombinant enzyme (Sa1-SSTrec) yield without causing cell toxicity. Secretion driven by the Saccharomyces cerevisiae alpha-factor signal peptide resulted in periplasmic retention (38%) and extracellular release (62%) of Sa1-SSTrec to an overall activity of 102.1 U/ml when biomass reached (106 g/l, dry weight) in fed-batch fermentation using cane sugar for cell growth. The volumetric productivity of the nine-copy clone PGFT6x-308 at the end of fermentation (72 h) was 1422.2 U/l/h. Sa1-SSTrec purified from the culture supernatant was a monomeric glycoprotein optimally active at pH 5.0-6.0 and 45-50 degrees C. The removal of N-linked oligosaccharides by Endo Hf treatment decreased the enzyme stability but had no effect on the substrate and product specificities. Sa1-SSTrec converted sucrose (600 g/l) into 1-kestose (GF2) and nystose (GF3) in a ratio 9:1 with their sum representing 55-60% (w/w) of the total carbohydrates in the reaction mixture. Variations in the sucrose (100-800 g/l) or enzyme (1.5-15 units per gram of substrate) concentrations kept unaltered the product profile. Sa1-SSTrec is an attractive candidate enzyme for the industrial production of short-chain fructooligosaccharides, most particularly 1-kestose. PMID- 29246840 TI - Hypoxic challenge of hyperoxic pulmonary artery myocytes increases oxidative stress due to impaired mitochondrial superoxide dismutase activity. AB - Infants with lung disease may be exposed to high O2 concentrations, and may have transient hypoxic episodes due to worsening lung pathophysiology, aggravating pulmonary arterial (PA) oxidative stress. NADPH oxidase (NOX) converts O2 to superoxide. Mitochondrial antioxidants such as superoxide dismutase (SOD) are sensitive to O2 tension. We previously reported decreased SOD2 activity in hypoxic PA myocytes due to nitration. In this study, we examined whether a transient hypoxic episode exposes antioxidant defense defects in hyperoxic PA myocytes. PA myocytes of term newborn piglets were cultured in hyperoxia (60% O2) or normoxia (21% O2) for 72 h; cells from both groups were challenged with transient hypoxia (10% O2) for 2 h. We measured NOX activity, SOD activities (fractionated by centrifugation and concavalin A- Sepharose chromatography), total ROS and superoxide generation, 8-isoprostane, and calcium responses to thromboxane mimetic. NOX activity increased in hyperoxic myocytes. Hyperoxia increased SOD1 activity but decreased SOD2 activity. Total ROS were reduced in hyperoxia, and hyperoxia + hypoxia groups. While hyperoxia alone did not alter superoxide content, superoxide increased after a hypoxic challenge of both normoxic and hyperoxic myocytes. Increased 8-isoprostane was seen only in hyperoxic myocytes challenged by transient hypoxia. We conclude that hyperoxic PA myocytes can limit total ROS despite increased NOX activity, but with inhibited SOD2 activity. Transient hypoxia increases superoxide formation; in the face of impaired SOD2, despite induction of SOD1, this oxidative stress causes increased 8-isoprostane generation. This may contribute to the mechanism of pulmonary arterial reactivity in infants with severe lung disease. PMID- 29246841 TI - Immunization with a nontoxic naturally occurring Clostridium perfringens alpha toxin induces neutralizing antibodies in rabbits. AB - Clostridium perfringens alpha toxin, encoded by plc gene, has been implicated in gas gangrene, a life threatening infection. Vaccination is considered one of the best solutions against Clostridium infections. Although studies have identified many low quality clostridial vaccines, the use of recombinant proteins has been considered a promising alternative. Previously, a naturally occurring alpha toxin isoform (alphaAV1b) was identified with a mutation at residue 11 (His/Tyr), which can affect its enzymatic activity. The aim of the present study was to evaluate whether the mutation in the alphaAV1b isoform could result in an inactive toxin and was able to induce protection against the native alpha toxin. We used recombinant protein techniques to determine whether this mutation in alphaAV1b could result in an inactive toxin compared to the active isoform, alphaZ23. Rabbits were immunized with the recombinant toxins (alphaAV1b and alphaZ23) and with native alpha toxin. alphaAV1b showed no enzymatic and hemolytic activities. ELISA titration assays showed a high titer of both anti-recombinant toxin (anti rec-alphaAV1b and anti-rec-alphaZ23) antibodies against the native alpha toxin. The alpha antitoxin titer detected in the rabbits' serum pool was 24.0 IU/mL for both recombinant toxins. These results demonstrate that the inactive naturally mutated alphaAV1b is able to induce an immune response, and suggest it can be considered as a target for the development of a commercial vaccine against C. perfringens alpha toxin. PMID- 29246842 TI - A helicase-containing module defines a family of pCD630-like plasmids in Clostridium difficile. AB - Clostridium difficile is a Gram-positive and sporulating enteropathogen that is a major cause of healthcare-associated infections. Even though a large number of genomes of this species have been sequenced, only a few plasmids have been described in the literature. Here, we use a combination of in silico analyses and laboratory experiments to show that plasmids are common in C. difficile. We focus on a group of plasmids that share similarity with the plasmid pCD630, from the reference strain 630. The family of pCD630-like plasmids is defined by the presence of a conserved putative helicase that is likely part of the plasmid replicon. This replicon is compatible with at least some other C. difficile replicons, as strains can carry pCD630-like plasmids in addition to other plasmids. We find two distinct sub-groups of pCD630-like plasmids that differ in size and accessory modules. This study is the first to describe a family of plasmids in C. difficile. PMID- 29246843 TI - Tonsillectomy for persistent MRSA carriage in the throat-Description of three cases. AB - In several countries, including the Netherlands, a search and destroy policy is part of the standard of care. Due to this policy and the restrictive use of antibiotics, the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the Netherlands - carrier state and infections - is among the lowest in the world. In the Netherlands, healthcare workers who are MRSA carriers are not allowed to perform work involving direct patient care. This means that treatment failure can have major implications for their working career. Despite repeated treatments according to guidelines, the eradication of MRSA fails in a minority of cases. It appears that performing a tonsillectomy can be part of the solution to this problem. As yet, tonsillectomy is not recommended as supplementary treatment for persistent MRSA carriage in the throat. There are a few expert opinions suggesting that tonsillectomy could possibly be helpful in decolonization. This article reports three recent cases in which MRSA eradication was successful only after tonsillectomy. It is believed that if eradication is necessary, tonsillectomy, if applicable, should be considered. PMID- 29246844 TI - SPG7 with parkinsonism responsive to levodopa and dopaminergic deficit. AB - We report a 55-year-old woman with a long history of a gait disturbance that was followed by dysarthria and urinary incontinence. She underwent brain MRI, SPECT with TRODAT imaging and whole-exome sequencing, revealing the diagnosis of SPG7. She developed parkinsonism responsive to levodopa, expanding the phenotype of complex SPG7. PMID- 29246845 TI - The role of the cerebellum in explicit and incidental processing of facial emotional expressions: A study with transcranial magnetic stimulation. AB - Growing evidence suggests that the cerebellum plays a critical role in non-motor functions, contributing to cognitive and affective processing. In particular, the cerebellum might represent an important node of the "limbic" network, underlying not only emotion regulation but also emotion perception and recognition. Here, we used transcranial magnetic stimulation (TMS) to shed further light on the role of the cerebellum in emotional perception by specifically testing cerebellar contribution to explicit and incidental emotional processing. In particular, in three different experiments, we found that TMS over the (left) cerebellum impaired participants' ability to categorize facial emotional expressions (explicit task) and to classify the gender of emotional faces (incidental emotional processing task), but not the gender of neutral faces. Overall, our results indicate that the cerebellum is involved in perceiving the emotional content of facial stimuli, even when this is task irrelevant. PMID- 29246846 TI - LEICA: Laplacian eigenmaps for group ICA decomposition of fMRI data. AB - Independent component analysis (ICA) is a data-driven method that has been increasingly used for analyzing functional Magnetic Resonance Imaging (fMRI) data. However, generalizing ICA to multi-subject studies is non-trivial due to the high-dimensionality of the data, the complexity of the underlying neuronal processes, the presence of various noise sources, and inter-subject variability. Current group ICA based approaches typically use several forms of the Principal Component Analysis (PCA) method to extend ICA for generating group inferences. However, linear dimensionality reduction techniques have serious limitations including the fact that the underlying BOLD signal is a complex function of several nonlinear processes. In this paper, we propose an effective non-linear ICA-based model for extracting group-level spatial maps from multi-subject fMRI datasets. We use a non-linear dimensionality reduction algorithm based on Laplacian eigenmaps to identify a manifold subspace common to the group, such that this mapping preserves the correlation among voxels' time series as much as possible. These eigenmaps are modeled as linear mixtures of a set of group-level spatial features, which are then extracted using ICA. The resulting algorithm is called LEICA (Laplacian Eigenmaps for group ICA decomposition). We introduce a number of methods to evaluate LEICA using 100-subject resting state and 100 subject working memory task fMRI datasets from the Human Connectome Project (HCP). The test results show that the extracted spatial maps from LEICA are meaningful functional networks similar to those produced by some of the best known methods. Importantly, relative to state-of-the-art methods, our algorithm compares favorably in terms of the functional cohesiveness of the spatial maps generated, as well as in terms of the reproducibility of the results. PMID- 29246847 TI - Individuals with lumbar spinal stenosis seek education and care focused on self management-results of focus groups among participants enrolled in a randomized controlled trial. AB - BACKGROUND CONTEXT: The effectiveness of treatments for chronic, degenerative conditions of the lumbar spine can be influenced by patient perceptions and expectations regarding treatment. PURPOSE: The primary purpose of this study was to understand the factors that are important to individuals with lumbar spinal stenosis (LSS) regarding different nonsurgical treatments. These factors were considered within the context of each treatment received as a part of the parent randomized controlled trial (RCT). STUDY DESIGN: Focus group study of RCT participants. PATIENT SAMPLE: Convenience sample of 50 individuals with LSS (28 female, average age 73+/-7.7 years) from an RCT participated in one of six focus groups. Focus groups consisted of patients previously randomized to one of three nonsurgical treatments: (1) medical care; (2) community-based group exercise; and (3) clinic-based manual therapy and individualized exercise. OUTCOME MEASURES: Experiences, opinions, and preferences of individuals with LSS who participated in an RCT. Inter-coder agreement for qualitative analysis was conducted with kappa statistics. METHODS: Participants discussed their experiences and perceptions regarding study treatment and their general experience with LSS using open-ended questions provided by a facilitator. Transcripts were coded according to modified grounded theory in an open approach, using codes that addressed the primary focus group discussion topics (primary coding) and codes for emerging topics (secondary coding). Secondary coding sought to identify themes concerning living with LSS and seeking treatment that were emergent from the focus groups. This study was funded by the Patient-Centered Research Outcomes Institute. The authors report no conflicts of interest. RESULTS: Three themes related to medical treatment and symptom management arose from analyses: (1) an emotional response to LSS; (2) a desire for education about LSS and motivation to pursue education from any available source; and (3) a desire for individualized care based on self management techniques and lifestyle changes. Emotional responses were more evident in individuals receiving medical care, whereas the other two themes were consistent across all three treatment groups. CONCLUSIONS: The chronic pain associated with LSS may result in negative emotional responses. Individuals with LSS may believe misinformation and information from nonmedical sources, especially when medical providers do not spend sufficient time explaining the disease process and the reasoning behind treatment strategies. Receiving individualized care focused on self-management led to fewer negative emotions toward care and the disease process. Clinicians should be prepared to address all three of these aspects when providing care to individuals with LSS. PMID- 29246848 TI - Does reduction in sciatica symptoms precede improvement in disability and physical health among those treated surgically for intervertebral disc herniation? Analysis of temporal patterns in data from the Spine Patient Outcomes Research Trial. AB - BACKGROUND CONTEXT: Pain, pain-related disability, and functional limitations are common consequences of intervertebral disc herniation (IDH). We hypothesized that surgical treatment reduces pain, leading to improvement in pain-related disability and, ultimately, better physical health. PURPOSE: The present study aims to evaluate pathways for improvements in quality of life during the first year after surgery for IDH by studying temporal relationships between sciatica symptoms, pain-related disability, and physical health. DESIGN: This is a secondary analysis of a randomized controlled trial using an "as treated" dataset. PATIENT SAMPLE: The sample comprised 803 patients in the Spine Patient Outcomes Research Trial. OUTCOME MEASURES: We used the Sciatica Bothersome Index, Oswestry Disability Index, and the Medical Outcomes Study Short Form 36 physical component score. METHODS: We included 803 patients in the Spine Patient Outcomes Research Trial who underwent elective decompressive surgery for IDH between 2000 and 2004. Sciatica, pain-related disability, and physical health were assessed preoperatively and at 3 and 12 months postoperatively using the Sciatica Bothersome Index, Oswestry Disability Index, and Medical Outcomes Study Short Form 36 physical component score, respectively. Temporal associations of improvement in sciatica with pain-related disability and physical health were assessed using cross-lagged path analysis. p<.05 was considered significant. No funding was received in support of the present study. The authors declare no conflicts of interest. RESULTS: Preoperatively, mean scores were 16.2+/-5.2 for sciatica, 54.2+/-20.7 for pain-related disability, and 29.8+/-8.4 for physical health. After adjustment for patient age and symptom duration, cross-lagged path analysis showed that sciatica reduction at 3 months was correlated with pain related disability reduction at 3 months (rho=.76, p<.001), and pain-related disability at 3 months was predictive of physical health at 12 months (beta=-.33, p<.001) and sciatica at 12 months (beta=.22, p<.001). CONCLUSION: Three months after surgery, patients reported reduced sciatica and pain-related disability. Improvements in pain and pain-related disability occurred within 3 months. Early reduction in pain-related disability is important because path analysis indicated that disability at 3 months was predictive of sciatica and physical health at 1 year. PMID- 29246849 TI - Can tranexamic acid conserve blood and save operative time in spinal surgeries? A meta-analysis. AB - BACKGROUND CONTEXT: It is widely accepted that tranexamic acid (TXA) effectively reduces blood losses and transfusions in major surgeries. However, limited studies investigated the role of TXA in conserving blood and saving operative time in spine surgeries. PURPOSE: This meta-analysis was conducted to gather scientific evidence for TXA efficacy on conserving blood and saving operative time in spine surgeries. STUDY DESIGN: A meta-analysis was performed. PATIENT SAMPLE: Eighteen RCTs and 18 non-RCT studies involving 2,572 patients were included in the final analyses, comparing the effectiveness of intravenous TXA with a placebo/no treatment group. OUTCOME MEASURES: Outcomes of interest included intraoperative, postoperative, and perioperative blood losses, allogeneic blood transfusion rates, cell salvage transfusion amounts, operative time, and the number of postoperative thrombosis events. METHODS: An exhaustive literature search was conducted in the MEDLINE and EMBASE databases from January 2000 through March 2017. Meta-analysis was performed using Review Manager (RevMan) version 5.0. For continuous outcomes, the means and standard deviations were pooled to a mean difference and 95% confidence interval (CI). Odds ratios (OR) and 95% CI were calculated for dichotomous outcomes. The quantity of heterogeneity was assessed using I2 statistics. When there was no statistical evidence of substantial heterogeneity (I2<=50%), a fixed-effect model was adopted; otherwise, a random-effect model was chosen. Subgroup analysis was performed when more than three studies were included on one issue, based on low or high the dose of TXA. Beijing Talent Fund (2016) was received to support this work. RESULTS: Significantly reduced intraoperative (weighted mean difference [WMD]=-280.09.00, p<.00001), postoperative (WMD=-120.15, p<.00001), perioperative (WMD=-310.86, p<.00001) blood losses, cell salvage transfusion amount (WMD= 471.79, p=.01), perioperative transfusion rate (odds ratio [OR], 0.33 [0.17, 0.65], p=.001), and operative time (WMD=-4.69, p=.003) were observed in TXA group. Furthermore, subgroup analysis revealed that high-dose TXA could reduce both intraoperative-perioperative allogeneic transfusion rates and operative time, whereas low dose of the drug does not convey such effects. CONCLUSIONS: With the most comprehensive literature inclusion up to the present, this meta analysis suggests that intravenous TXA use constitutes an important measure for conserving blood and saving operative time in spinal surgeries. High-dose TXA significantly reduces intraoperative-perioperative allogeneic transfusion rates and operative time, whereas low-dose TXA does not convey such efficacies. Larger prospective trials are still required to define the optimal regimen and to confirm the safety of TXA use in such surgeries. PMID- 29246850 TI - The association between tobacco smoking and surgical intervention for lumbar spinal stenosis: cohort study of 331,941 workers. AB - BACKGROUND CONTEXT: Tobacco smoking is an injurious habit associated with a number of chronic disorders. Its influence on disc metabolism and degeneration including lumbar spinal stenosis (LSS) has been investigated in the literature. PURPOSE: We aimed to investigate whether tobacco smoking is an independent risk factor for undergoing surgical intervention for LSS. STUDY DESIGN/SETTING: This is a prospective cohort study. PATIENT SAMPLE: The patient sample of 331,941 workers was derived from a Swedish nationwide occupational surveillance program for construction workers. OUTCOME MEASURE: The outcome measure included the incidence of undergoing surgical intervention for LSS in tobacco smokers versus no smokers. MATERIALS AND METHODS: At inclusion, age, sex, body mass index (BMI), workers' job title, and self-reported smoking habits were registered. The workers were divided into four categories: never smoked, former smoker, moderate current (1-14 cigarettes/day), and heavy current (>=15 cigarettes/day). Patients who underwent a surgically treated LSS were defined using the relevant International Classification of Diseases (ICD) disease code derived from the Swedish National Patient Register. RESULTS: A total of 331,941 participants were included in the analysis. Forty-four percent of the participants were non-smokers, 16% were former smokers, 26% were moderate smokers, and 14% were heavy smokers. The vast majority of construction workers were males (95%). During the average follow-up of 30.7 years, 1,623 participants were surgically treated for LSS. The incidence rate ratio (IRRs) of LSS varied across smoking categories, with the highest values found in heavy smokers. Compared with non-smokers, all smoking categories show an increased incidence of surgically treated LSS. The findings were consistent even when the comparison was performed for participants with BMIs between 18.5 and 25 and for participants aged between 40 and 74 years. CONCLUSIONS: Tobacco smoking is associated with an increased incidence of surgically treated LSS. The effect seems to be dose related, whereby heavy smokers have a higher risk than moderate or former smokers. PMID- 29246851 TI - Inhibition of dengue viral infection by diasarone-I is associated with 2'O methyltransferase of NS5. AB - Dengue virus (DENV) is the most prevalent mosquito borne viral pathogen worldwide. However, antiviral drugs against this infection are not available. To identify novel anti-DENV compound from traditional Chinese medicine, we discovered the ethanol extract of Acorus tatarinowii Schott containing potent anti-DENV activity and diasarone-I was isolated from this extract. Diasarone-I has antiviral effect with half maximal effective concentration (EC50) of 4.5MUM and half maximal cytotoxicity concentration (CC50) of >80MUM. Time of drug addition assay suggested that this compound inhibited at RNA replication step in the DENV life cycle. Further, in silico analysis indicated that diasarone-I might act as an inhibitor of 2'O Methyltransferase of NS5. Diasarone-I has also decreased the DENV2-induced STAT1 phosphorylation and ISGs. In summary, we suggest that diasarone-I may be a 2'O Methyltransferase inhibitor and might serve as a potential candidate for the treatment of DENV2 infections. PMID- 29246852 TI - Lin28b and Sox2 regulate anesthesia-induced neural degeneration in neural stem cell derived neurons. AB - Ketamine, a commonly used anesthetic compound, may cause neurotoxicity in immature or developing brains. In this study, we indented to understand the molecular expression and functional role of Lin-28 Homolog B (lin28b) in regulating ketamine-induced neurotoxicity in neural stem cells (NSCs) differentiated neurons. NSCs from embryonic rat brains were cultured in vitro, and induced toward neuronal differentiation. NSCs-differentiated neurons were treated with various concentrations of ketamine for 24h to evaluate the concentration-dependent effect of ketamine on endogenous lin28b mRNA level. QRT PCR showed that lin28b was downregulated by ketamine in NSCs-differentiated neurons, in concentration-dependent manner. Neurons were then transfected with adenovirus to ectopically upregulate lin28b. We found that ketamine-induced apoptosis and neurite retraction in NSCs-differentiated neurons were significantly reduced by adenovirus-mediated lin28b upregulation. Expression of sex determining region Y box 2 (Sox2) mRNA was examined in ketamine-injured and lin28b-upregulated NSCs-differentiated neurons. It was found Sox2 was downregulated by ketamine, and overexpressed by lin28b upregulation. Finally, Sox2 was downregulated by siRNA in NSCs-differentiated neurons. And we discovered that Lin28b-upregulation-associated neural protection was severely hampered by Sox2 downregulation in ketamine-injured neurons. Thus, Lin28b and Sox2 are important molecular components in ketamine-induced neurotoxicity. PMID- 29246853 TI - Cafestol, a coffee diterpene, inhibits urotensin II-induced interleukin-8 expression in human umbilical vein endothelial cells. AB - Cafestol, a diterpene molecule found in the berries of Coffea arabica L. (Rubiaceae), has been shown to exercise anti-angiogenic and anti-tumorigenic effects. However, cafestol's cellular mechanism has yet to be fully investigated. We previously demonstrated that urotensin II enhanced interleukin-8 secretion by endothelial cells, thereby increasing endothelial cell proliferation. Urotensin II may also participate in angiogenesis and tumor infiltration by macrophages. However, the effects of cafestol on urotensin II-induced interleukin-8 expression and cellular proliferation have not been determined. Here, we showed that pretreatment with cafestol inhibited urotensin II-stimulated endothelial cell proliferation. Further experiments demonstrated that cafestol increased translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and expression of enhanced heme oxygenase-1. Moreover, cafestol inhibited expression of urotensin II-induced interleukin-8. Cafestol's inhibitory effects on interleukin-8 expression and cellular proliferation induced by urotensin II were significantly abrogated by heme oxygenase-1 silencing, suggesting it may be involved in mediating the effects of cafestol. This study reports that cafestol inhibits urotensin II-induced interleukin-8 expression and cell proliferation via Nrf2/heme oxygenase-1-dependent mechanism in endothelial cells. These findings provide novel insight into the signaling pathways that may be important in mediating the effects of cafestol. PMID- 29246854 TI - Deoxynucleosides with benzimidazoles as aglycone moiety are potent anticancer agents. AB - Abnormally high levels of CK2 and PIM-1 serine/threonine kinases have been documented in many cases of cancer. The elevation of CK2 and PIM-1 in cells entails suppression of apoptosis and implies a protective role for the kinases against cell death. Downregulation of these enzymes by chemical methods promotes apoptosis in cells. The aim of the present study was to explore the anticancer activity of inhibitors of protein kinases CK2 and PIM-1 on neoplastic cell lines in vitro. We studied a series of deoxynucleosides with various tetrahalobenzimidazoles as aglycone moiety. Cytotoxicity, induction of apoptosis by the tested inhibitors, mitochondrial membrane potential, activity of caspases, changes in cell cycle progression, as well as a mechanism of action were determined by flow cytometry and other methods. The results indicate that the studied compounds, e.g., 1-(beta-D-2'-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H benzimidazole called K164 (also termed TDB), showed diverse cytotoxicity and proapoptotic efficacy in cell lines. Our results showed that the tested compounds are potential anticancer agents for targeted therapy, particularly in the treatment of myeloid leukaemia and androgen-responsive prostate cancer. PMID- 29246855 TI - Technological strategies to estimate and control diffusive passage times through the mucus barrier in mucosal drug delivery. AB - In mucosal drug delivery, two design goals are desirable: 1) insure drug passage through the mucosal barrier to the epithelium prior to drug removal from the respective organ via mucus clearance; and 2) design carrier particles to achieve a prescribed arrival time and drug uptake schedule at the epithelium. Both goals are achievable if one can control "one-sided" diffusive passage times of drug carrier particles: from deposition at the mucus interface, through the mucosal barrier, to the epithelium. The passage time distribution must be, with high confidence, shorter than the timescales of mucus clearance to maximize drug uptake. For 100nm and smaller drug-loaded nanoparticulates, as well as pure drug powders or drug solutions, diffusion is normal (i.e., Brownian) and rapid, easily passing through the mucosal barrier prior to clearance. Major challenges in quantitative control over mucosal drug delivery lie with larger drug-loaded nanoparticulates that are comparable to or larger than the pores within the mucus gel network, for which diffusion is not simple Brownian motion and typically much less rapid; in these scenarios, a timescale competition ensues between particle passage through the mucus barrier and mucus clearance from the organ. In the lung, as a primary example, coordinated cilia and air drag continuously transport mucus toward the trachea, where mucus and trapped cargo are swallowed into the digestive tract. Mucus clearance times in lung airways range from minutes to hours or significantly longer depending on deposition in the upper, middle, lower airways and on lung health, giving a wide time window for drug-loaded particle design to achieve controlled delivery to the epithelium. We review the physical and chemical factors (of both particles and mucus) that dictate particle diffusion in mucus, and the technological strategies (theoretical and experimental) required to achieve the design goals. First we describe an idealized scenario - a homogeneous viscous fluid of uniform depth with a particle undergoing passive normal diffusion - where the theory of Brownian motion affords the ability to rigorously specify particle size distributions to meet a prescribed, one-sided, diffusive passage time distribution. Furthermore, we describe how the theory of Brownian motion provides the scaling of one-sided diffusive passage times with respect to mucus viscosity and layer depth, and under reasonable caveats, one can also prescribe passage time scaling due to heterogeneity in viscosity and layer depth. Small-molecule drugs and muco-inert, drug-loaded carrier particles 100nm and smaller fall into this class of rigorously controllable passage times for drug delivery. Second we describe the prevalent scenarios in which drug-loaded carrier particles in mucus violate simple Brownian motion, instead exhibiting anomalous sub-diffusion, for which all theoretical control over diffusive passage times is lost, and experiments are prohibitive if not impossible to measure one-sided passage times. We then discuss strategies to overcome these roadblocks, requiring new particle-tracking experiments and emerging advances in theory and computation of anomalous, sub diffusive processes that are necessary to predict and control one-sided particle passage times from deposition at the mucosal interface to epithelial uptake. We highlight progress to date, remaining hurdles, and prospects for achieving the two design goals for 200nm and larger, drug-loaded, non-dissolving, nanoparticulates. PMID- 29246856 TI - The behavioral pharmacology and therapeutic potential of lorcaserin for substance use disorders. AB - Substance abuse is serious public health problem for which there are few effective pharmacotherapies. Traditional strategies for drug development have focused on antagonists to block the abuse-related effects of a drug at its site of action, and agonists to replace/mimic the effects of the abused substance. However, recent efforts have targeted receptors, such as serotonin (5-HT)2 receptors, that can indirectly modulate dopamine neurotransmission with the goal of developing a pharmacotherapy that might be effective at reducing the abuse related effects of drugs more generally. Lorcaserin is a 5-HT2C receptor preferring agonist that is approved by the US Food and Drug Administration for the treatment of obesity. Mounting evidence from preclinical and clinical studies suggests that lorcaserin might also be effective at reducing the abuse-related effects of drugs with different pharmacological mechanisms (e.g., cocaine, heroin, ethanol, and nicotine). Lorcaserin represents a promising and important first step towards the development a new class of pharmacotherapies that have the potential to dramatically improve the treatment of substance abuse. This article will review the behavioral pharmacology of 5-HT2C receptor-preferring agonists, with a focus on lorcaserin, and evaluate the preclinical evidence supporting the development of lorcaserin for treating substance abuse. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'. PMID- 29246858 TI - Significance and regulation of lipid metabolism. PMID- 29246859 TI - Dendritic cell subsets. AB - Dendritic cells (DC) are professional antigen presenting cells comprising a variety of subsets, as either resident or migrating cells, in lymphoid and non lymphoid organs. In the steady state DC continually process and present antigens on MHCI and MHCII, processes that are highly upregulated upon activation. By expressing differential sets of pattern recognition receptors different DC subsets are able to respond to a range of pathogenic and danger stimuli, enabling functional specialisation of the DC. The knowledge of functional specialisation of DC subsets is key to efficient priming of T cells, to the design of effective vaccine adjuvants and to understanding the role of different DC in health and disease. This review outlines mouse and human steady state DC subsets and key attributes that define their distinct functions. PMID- 29246860 TI - Dynamic patterns of gene expression during leaf initiation. PMID- 29246861 TI - Ribosome biogenesis protein Urb1 acts downstream of mTOR complex 1 to modulate digestive organ development in zebrafish. AB - Ribosome biogenesis is essential for the cell growth and division. Disruptions in ribosome biogenesis result in developmental defects and a group of diseases, known as ribosomopathies. Here, we report a mutation in zebrafish urb1, which encodes an essential ribosome biogenesis protein. The urb1cq31 mutant exhibits hypoplastic digestive organs, which is caused by impaired cell proliferation with the differentiation of digestive organ progenitors unaffected. Knockdown of mtor or raptor leads to similar hypoplastic phenotypes and reduced expression of urb1 in the digestive organs. Overexpression of Urb1 results in overgrowth of digestive organs, and can efficiently rescue the hypoplastic liver and pancreas in the mtor and raptor morphants. Reduced syntheses of free ribosomal subunits and impaired assembly of polysomes are observed in the urb1 mutant as well as in the mtor and raptor morphants, which can be rescued by the Urb1 overexpression. These data demonstrate that Urb1 plays an important role in governing ribosome biogenesis and protein synthesis downstream of mammalian/mechanistic target of rapamycin complex 1 (mTORC1), thus regulating the development of digestive organs. Our study indicates the requirement of hyperactive protein synthesis for the digestive organ development. PMID- 29246857 TI - New Cav2 calcium channel gating modifiers with agonist activity and therapeutic potential to treat neuromuscular disease. AB - Voltage-gated calcium channels (VGCCs) are critical regulators of many cellular functions, including the activity-dependent release of chemical neurotransmitter from nerve terminals. At nerve terminals, the Cav2 family of VGCCs are closely positioned with neurotransmitter-containing synaptic vesicles. The relationship between calcium ions and transmitter release is such that even subtle changes in calcium flux through VGCCs have a strong influence on the magnitude of transmitter released. Therefore, modulators of the calcium influx at nerve terminals have the potential to strongly affect transmitter release at synapses. We have previously developed novel Cav2-selective VGCC gating modifiers (notably GV-58) that slow the deactivation of VGCC current, increasing total calcium ion flux. Here, we describe ten new gating modifiers based on the GV-58 structure that extend our understanding of the structure-activity relationship for this class of molecules and extend the range of modulation of channel activities. In particular, we show that one of these new compounds (MF-06) was more efficacious than GV-58, another (KK-75) acts more quickly on VGCCs than GV-58, and a third (KK-20) has a mix of increased speed and efficacy. A subset of these new VGCC agonist gating modifiers can increase transmitter release during action potentials at neuromuscular synapses, and as such, show potential as therapeutics for diseases with a presynaptic deficit that results in neuromuscular weakness. Further, several of these new compounds can be useful tool compounds for the study of VGCC gating and function. PMID- 29246862 TI - The role of cystatin A in breast cancer and its functional link with ERalpha. PMID- 29246863 TI - Essential roles of stat5.1/stat5b in controlling fish somatic growth. AB - Signal transducer and activator of transcription 5b (STAT5b) has been identified as a key downstream mediator of growth hormone (GH) signaling in somatic growth of mammalian. However, the corresponding homologue gene of Stat5b is unknown in fish species. In this study, we generated loss-of-function mutants in stat5.1 and stat5.2, two stat5 homologues existing in zebrafish. In stat5.1-deficient zebrafish, a significant reduction of body length and body weight was detected in the embryos/larvae and adults compared with the wild-type control fish, and sexual size dimorphism in adult zebrafish was also eliminated. However, the stat5.2-deficient zebrafish displayed a normal developmental phenotype during all lifespan. Chromatin immunoprecipitation combined with deep sequencing (ChIP-seq) method was adopted to further investigate the potential transcriptional targets of Stat5 protein and cast much light upon the biological function of Stat5. We identified more than 800 genes as transcriptional targets of Stat5 during zebrafish embryogenesis. KEGG analysis indicated that the Stat5 target gene network is predominantly linked to the metabolic pathways, neuroactive ligand receptor interaction and JAK-STAT signaling pathways. Further validation studies suggested that Stat5.1 protein could directly regulate the expression of gh1, and stat5.1-mutated zebrafish showed a reduction of gh1 mRNA level. In the present study, stat5.1 was revealed as the corresponding homologue gene of Stat5b in fish species. Additionally, we found a novel molecular interaction between Stat5.1/Stat5b and GH, and unraveled a positive feedback loop Stat5.1-GH-Stat5.1 which is necessary for somatic growth and body development in zebrafish. PMID- 29246864 TI - Mediator complex components are frequent targets for genetic alterations in various types of human cancer. PMID- 29246865 TI - Chronic adolescent morphine exposure alters the responses of lateral paragigantocellular neurons to acute morphine administration in adulthood. AB - Accumulating evidence support the growing non-medical use of morphine during adolescence. Despite this concern which has recently been addressed in some studies, cellular mechanisms underlying the long-term neurobiological and behavioral effects of opiate exposure during this critical period have still remained largely unexplored. Several reports have proposed that subtle long lasting neurobiological alterations might be triggered by exposure to opiate derivatives or drugs of abuse particularly when this occurs during a critical phase of brain maturation such as adolescence. The present study was designed to investigate how chronic adolescent morphine exposure could affect the responsiveness of lateral paragigantocellular (LPGi) neurons to acute morphine administration in adult rats. Male Wistar rats received chronic escalating morphine or saline during adolescence (30-39d) for 10 days. During adulthood (65d), the extracellular unit activities of LPGi neurons were recorded in urethane-anesthetized animals. Results indicated that adolescent morphine treatment enhances the baseline activity of LPGi neurons. In addition, morphine induced inhibition of spontaneous discharge rate was potentiated in adult rats received morphine during adolescence. However, this pretreatment did not affect the extent of morphine excitatory effect, onset or peak of cellular response and regularity of unit discharge in LPGi neurons. Our study supports the hypothesis that adolescent morphine exposure induces long-lasting neurophysiological alterations in brain regions known to play a role in mediating opiate effects. This finding sheds light on the possible effect of opiate pre-exposure on addiction susceptibility in future. PMID- 29246866 TI - Similar effect of CRF1 and CRF2 receptor in the basolateral or central nuclei of the amygdala on tonic immobility behavior. AB - Studies have used paradigms based on animal models to understand human emotional behavior because they appear to be correlated with fear- and anxiety-related defensive patterns in non-human mammals. In this context, tonic immobility (TI) behavior is an innate response associated with extreme threat situations, such as predator attack. Some reports have demonstrated the involvement of corticotropin releasing factor (CRF) in regulation of the endocrine system, defensive behaviors and behavioral responses to stress. Particularly, a previous study showed that the activation of CRF receptors in the basolateral (BLA) or central (CeA) nuclei of the amygdala increased TI responses, whereas treatment with a non-selective CRF antagonist, alpha-helical-CRF9-41, decreased this innate fear response. However, while CRF1 receptors have pronounced effects in stress-induced anxiety, CRF2 receptors appear be involved in the expression of both stress-induced anxiety and spontaneous anxiety behavior. In this study, we investigated the effects of specific CRF receptors, CRF1 and CRF2, in the BLA and CeA on the duration of TI in guinea pigs. The results show that blockade of CRF1 and CRF2 receptors in the BLA and CeA produces a decrease in fear and/or anxiety, as suggested by a decrease in TI duration in the guinea pigs. Additionally, the specific antagonists for CRF1 and CRF2 receptors were able to prevent the increase in TI duration induced by CRF administration at the same sites. These results suggest that the modulation of fear and anxiety by the CRF system in the BLA and CeA occurs through concomitant effects on CRF1 and CRF2 receptors. PMID- 29246867 TI - A Roadmap for Research on Resident Well-Being. PMID- 29246868 TI - Clinical and demographic features of chronic progressive external ophthalmoplegia in a large adult-onset cohort. AB - Chronic progressive external ophthalmoplegia (CPEO) is a common mitochondrial disease. We evaluated the impact of sex and smoking status upon knee extension strength and the phenotypic spectrum of disease in a large cohort of adult-onset CPEO patients (N=116) using retrospective chart analysis. The CPEO patients showed significantly lower knee extension strength as compared to the age- and sex-matched control population (-37%, P<0.05). Smoking also negatively impacted knee extension strength only in women with CPEO (-26%, P<0.05). We conclude that smoking and female sex interact negatively in CPEO patients. PMID- 29246870 TI - Metabolic defects in multiple sclerosis. AB - Brain injuries in multiple sclerosis (MS) involve immunopathological, structural and metabolic defects on myelin sheath, oligodendrocytes (OLs), axons and neurons suggesting that different cellular mechanisms ultimately result in the formation of MS plaques, demyelination, inflammation and brain damage. Bioenergetics, oxygen and ion metabolism dominate the metabolic and biochemical pathways that maintain neuronal viability and impulse transmission which directly or indirectly point to mitochondrial integrity and adenosine triphosphate (ATP) availability indicating the involvement of mitochondria in the pathogenesis of MS. Loss of myelin proteins including myelin basic protein (MBP), proteolipid protein (PLP), myelin associated glycoprotein (MAG), myelin oligodendrocyte glycoproetin (MOG), 2, 3,-cyclic nucleotide phosphodiestarase (CNPase); microglia and microphage activation, oligodendrocyte apoptosis as well as expression of inducible nitric oxide synthase (i-NOS) and myeloperoxidase activities have been implicated in a subset of Balo's type and relapsing remitting MS (RRMS) lesions indicating the involvement of metabolic defects and oxidative stress in MS. Here, we provide an insighting review of defects in cellular metabolism including energy, oxygen and metal metabolism in MS as well as the relevance of animal models of MS in understanding the molecular, biochemical and cellular mechanisms of MS pathogenesis. Additionally, we also discussed the potential for mitochondrial targets and antioxidant protection for therapeutic benefits in MS. PMID- 29246869 TI - The essential role of mitochondrial dynamics in antiviral immunity. AB - Viruses alter cellular physiology and function to establish cellular environment conducive for viral proliferation. Viral immune evasion is an essential aspect of viral persistence and proliferation. The multifaceted mitochondria play a central role in many cellular events such as metabolism, bioenergetics, cell death, and innate immune signaling. Recent findings accentuate that viruses regulate mitochondrial function and dynamics to facilitate viral proliferation. In this review, we will discuss how viruses exploit mitochondrial dynamics to modulate mitochondria-mediated antiviral innate immune response during infection. This review will provide new insight to understanding the virus-mediated alteration of mitochondrial dynamics and functions to perturb host antiviral immune signaling. PMID- 29246871 TI - Injectable methylcellulose hydrogel containing calcium phosphate nanoparticles for bone regeneration. AB - A novel injectable methylcellulose (MC) hydrogel containing calcium phosphate nanoparticles (CaP NPs) was prepared by an in situ formation process, in which the precursor salts induced a salt-out effect in the MC solution. The thermo sensitive properties of MC-CaP NPs composite hydrogels with different crystalline phases were characterized by rheometry, infrared spectroscopy and injectability test. The as-prepared MC hydrogels with bioactive CaP NPs had a suitable injectability at the body temperature, irrespective of the crystalline phases of CaP NPs. At the physiological pH condition, the structure of the MC hydrogel containing CaP NPs was analyzed by scanning electron microscopy, X-ray diffraction (XRD). The XRD results indicate that the in situ synthesized CaP NPs had a crystalline phase of hydroxyapatite (HAP). The in vitro study using mesenchymal stem cells showed that MC-HAP NPs composite hydrogel was biocompatible. The in vivo study indicated that the regeneration rate of new mature bone was also higher in the MC-HAP NPs composite hydrogel than in the pure MC hydrogel. The results of this study indicate that injectable MC-HAP NPs composite hydrogel has a great potential for bone tissue regeneration. PMID- 29246872 TI - Immobilization of lipases in hydrophobic chitosan for selective hydrolysis of fish oil: The impact of support functionalization on lipase activity, selectivity and stability. AB - The objective of this paper was to carry out an integral study of the use of hydrophobic chitosan as a low-cost support for immobilizing lipases and their further application in the selective hydrolysis of fish oil. Chitosan functionalized with different alkyl chains (C4, C8, C12) were characterized by FTIR, TGA, SEM, and Rose Bengal adsorption. Lipase B from Candida antarctica (CalB) and lipase from Rhizomucor miehei (RML) were immobilized obtaining a higher expressed activity at a longer alkyl chain length of support. Biocatalyst thermal stability showed that the impact of the alkyl chain length on enzyme stabilization varied according to the lipase source. The biocatalysts were applied in menhaden oil hydrolysis. Total polyunsaturated fatty acids released after 30 h of reaction with lipases immobilized in butyl, octyl and dodecyl chitosan was 60, 107, and 90 mM for CalB biocatalysts, and 560, 392, and 50 mM for RML biocatalysts, respectively. Selectivity of CalB was not affected by the alkyl chain, while in the case of RML, a higher selectivity to cis 4,7,10,13,16,19-docohexaenoic acid release was obtained with dodecyl-chitosan. In conclusion, the adequate functionalization of chitosan varied according to lipase source, affecting their activity, stability and performance in the hydrolysis of fish oil. PMID- 29246873 TI - Unmethylated promoter DNA correlates with p53 expression and apoptotic levels only in Vitamin B9 and B12 deficient megaloblastic anemia but not in non megaloblastic anemia controls. AB - Cyanocobalamin (Vitamin B12, VB12) and Folic acid (Vitamin B9, VB9) deficiency leads to anemia in women. We have recently shown low VB12 and VB9 levels in the serum of megaloblastic anemia (MBA) patients. Further, our study demonstrated elevated homocysteine and p53, respectively, in the serum and bone marrow aspirates of MBA patients but not in non-MBA subjects. However, it is unknown whether any gender specific variation in VB12 and VB9 level exists in MBA and non MBA patients? In addition, it is unclear whether low VB12 and VB9 has a role in the regulation of p53 expression in MBA patients? And whether elevated p53 is functionally active? If so, does bone marrow aspirates of MBA patients show elevated apoptosis. Hence, we have analyzed VB12 and VB9 levels in MBA patients and compared with non-MBA subjects. Next, methylation status of p53 promoter was determined and correlated with p53 expression. Furthermore, the level of apoptosis in bone marrow aspirate paraffin blocks was estimated using TUNEL staining. In conclusion, low VB12 and VB9 in male and female patients directly correlate with p53 promoter unmethylation status, but, inversely correlate with p53 protein expression and its activity, only in MBA cases but not in non-MBA controls. PMID- 29246874 TI - Exploration of surface plasmon resonance for yam tyrosinase characterization. AB - Tyrosinase is a ubiquitous enzyme in nature. It catalyzes the reaction in melanin formation. In this investigation, tyrosinase from a Yam tuber (Amorphophallus paeoniifolius) was extracted and purified by ultra-centrifugal filtration followed by ion exchange chromatography. The purified enzyme was obtained with purification fold of 12.65 and specific activity of 60.25 U/mg. The molecular weight of purified enzyme was confirmed to be 45 kDa by SDS-PAGE. The enzyme activity was optimal at pH 6 and 30 degrees C with Km 10 mM. Further the kinetic study of purified yam tyrosinase was carried out using Surface Plasmon Resonance method. In brief, enzyme was immobilized on chip surface by amine coupling method and different small molecules were analyzed for their binding affinities at different concentrations (mM). The affinity of each compound for yam tyrosinase was different with KD values as tannic acid (5.13 * 10-5), gallic acid (2.05 * 10 8), ascorbic acid (0.004544), caffeic acid (3.09 * 10-9), pyrogallol (2.13 * 10 4) and catechol (1.09 * 10-4). The kinetics data results were confirmed by inhibition assays and IC50 values were calculated. This data will help to study the role of tyrosinase in hyperpigmentation which will create an avenue for tyrosinase inhibitors. Tyrosinase inhibitors have wide range of applications in cosmetics, medical and food industries. PMID- 29246875 TI - Proteomics analysis reveals differential pattern of widespread protein expression and novel role of histidine-rich glycoprotein and lipopolysaccharide-binding protein in rheumatoid arthritis. AB - Rheumatoid factor (RF) is an auto-antibody against antigen-antibody immune complexes. RF is valuable as a biomarker for the screening of autoimmune and infectious diseases. However, it is suggested that RF would be a more powerful biomarker when used complementarily with RF-correlated proteins. In this study, we utilized a proteomic approach to analyze global protein expression in RF-low and RF-high subjects using high-performance liquid chromatography tandem mass spectrometry. Histidine-rich glycoprotein (HRG) and lipopolysaccharide-binding protein (LBP) were found to be differentially expressed between RF-low and RF high subjects (cut-off > 2-fold, p < 0.05), which was validated by enzyme-linked immunosorbent assay. To evaluate whether both proteins allow discriminating rheumatoid arthritis patients from healthy controls, receiver-operating characteristic (ROC) curves were analyzed. Areas under the ROC curves of HRG and LBP were 0.861 and 0.888, respectively. The correlation between RF and HRG was statistically significant (p = 0.003), and LBP was also correlated with RF (p = 0.044), as indicated by correlation analysis. HRG and LBP are reportedly involved in RF-producing and RF-correlated diseases. Thus, we propose that HRG and LBP could be useful screening markers for RF-correlated diseases. PMID- 29246876 TI - Characterization of the bacteriophages binding to human matrix molecules. AB - Recent literature has suggested a novel symbiotic relationship between bacteriophage and metazoan host that provides antimicrobial defense protecting mucosal surface by binding to host matrix mucin glycoproteins. Here, we isolated and studied different bacteriophages that specifically interact with human extracellular matrix molecules such as fibronectin, gelatin, heparin and demonstrated their potency for protection to host against microbial infections. We showed that subpopulations of bacteriophages that work against clinical isolates of Escherichia coli can bind to pure gelatin, fibronectin and heparin and reduced bacterial load in human colon cell line HT29. The bacteriophages were characterized with respect to their genome sizes, melting curve patterns and host tropism (cross-reactivity with different hosts). Since, the bacteriophages are non-toxic to the host and can effectively reduce bacterial load in HT29 cell line their therapeutic potency against bacterial infection could be explored. PMID- 29246877 TI - A process for complete biodegradation of shrimp waste by a novel marine isolate Paenibacillus sp. AD with simultaneous production of chitinase and chitin oligosaccharides. AB - Disposal of chitinaceous waste is a major problem of seafood industry. Most of the known chitinolytic organisms have been studied with respect to pure chitin as substrate. Use of these organisms for degradation of seafood waste has not been explored much. In present study a marine bacterium capable of proficiently degrading shrimp waste with co-production of value added products like chitinase and chitin oligosaccharides was isolated from seafood waste dumping sites. On 16s rRNA and biochemical analysis bacterium was found to be a novel species of genus Paenibacillus.Under optimized condition complete shrimp waste degradation (99%) was achieved along with chitinase yield of 20.01 IUml-1. SEM and FTIR showed the structural changes and breakage of bonds typical to that of chitin, which indicated that this process can be used for the degradation of other chitinaceous material also. Thin layer chromatography revealed the presence of chitin oligosaccharides of various degree of polymerization in the hydrolysate. Complete degradation of shrimp waste by Paenibacillus sp. AD makes it a potential candidate for the bioremediation of seafood waste at large scale. Concomitant production of chitinase and chitin oligosaccharides further makes the process economical and commercially viable. PMID- 29246878 TI - De novo recipient-specific Glutathione S-transferase T1 antibody development after HLA-identical hematopoietic cell transplantation. AB - Donor-specific antibodies against Glutathione S-transferase T1 (GSTT1) have been associated with de novo immune hepatitis after liver transplantation. These antibodies have also been found very early in allo-HCT associated with acute hepatic GvHD but in all the cases the donor cells had experienced previous priming through pregnancies. It remained to be explored whether or not primary recognition of the antigen occurs after HCT and what could be the consequences in the long term outcome. We genotyped a cohort of 68 HCT patients and found 11 with the GSTT1 null donor/positive recipient mismatch. After testing 114 serum samples, we found a unique case of a 33-year-old patient transplanted from his HLA-identical sibling donor in which IgG GSTT1 antibodies were detected for the first time on day +178. After stimulation of peripheral blood mononuclear cells with GSTT1 peptides we could demonstrate that this patient also had GSTT1 specific T lymphocytes that became activated upon exposure to the GSTT1 antigen. In this report, we describe the first case in which simultaneous T and B cell response against GSTT1 is developed in HCT although the clinical consequences in GvHD are still unclear. PMID- 29246879 TI - Preoperative Embolization of Meningiomas: Differences in Surgical Operability and Histopathologic Changes Between Embosphere and N-butyl 2-cyanoacrylate. AB - OBJECTIVE: This study aimed to examine whether there is a difference in the difficulty of extirpation after use of Embosphere versus n-butyl 2-cyanoacrylate (NBCA) for the embolization of meningiomas. METHODS: Study subjects were 20 patients with meningioma who underwent embolization using either NBCA or Embosphere from April 2012 to December 2016. The difficulty of extirpation was compared and assessed in terms of objective indices, such as operative duration, perioperative bleeding, and Simpson grade, and in terms of subjective indices such as "impression on operative field" and "hardness of tumors" that the surgeon assessed using 3-point scales (dry, moderate, bloody, and soft, moderate, hard, respectively). Pathologic findings, including ischemia, necrosis, and inflammatory changes, were assessed. RESULTS: No significant differences were found between the 2 groups regarding the mean values of operative duration (P = 0.27), perioperative bleeding (P = 0.23), and Simpson grade (P = 0.39). On the other hand, there was a significant difference with respect to the "impression on operative field" and "hardness of tumors," with reports of dry (54%; P = 0.034) and soft (81%; P = 0.0001), respectively, in the Embosphere group exceeding those of the NBCA group. The pathologic findings showed that although ischemic change (P = 0.43) and necrosis (P = 0.79) were observed in both groups, perivascular inflammation was observed only in the NBCA group (P = 0.006). CONCLUSIONS: No relative merits were found regarding objective indices, whereas the Embosphere group had superior "ease of extirpation" as reported by the surgeon. PMID- 29246880 TI - The QardioArm App in the Assessment of Blood Pressure and Heart Rate: Reliability and Validity Study. AB - BACKGROUND: Self-measurement of blood pressure is a priority strategy for managing blood pressure. OBJECTIVE: The aim of this study was to evaluate the reliability and validity of blood pressure and heart rate following the European Society of Hypertension's international validation protocol, as measured with the QardioArm, a fully automatic, noninvasive wireless blood pressure monitor and mobile app. METHODS: A total of 100 healthy volunteers older than 25 years from the general population of Ciudad Real, Spain, participated in a test-retest validation study with two measurement sessions separated by 5 to 7 days. In each measurement session, seven systolic blood pressure, diastolic blood pressure, and heart rate assessments were taken, alternating between the two devices. The test device was the QardioArm and the previously validated criterion device was the Omron M3. Sessions took place at a single study site with an evaluation room that was maintained at an appropriate temperature and kept free from noises and distractions. RESULTS: The QardioArm displayed very consistent readings both within and across sessions (intraclass correlation coefficients=0.80-0.95, standard errors of measurement=2.5-5.4). The QardioArm measurements corresponded closely to those from the criterion device (r>.96) and mean values for the two devices were nearly identical. The QardioArm easily passed all validation standards set by the European Society of Hypertension International Protocol. CONCLUSIONS: The QardioArm mobile app has validity and it can be used free of major measurement error. PMID- 29246881 TI - Telemedicine in Primary Care for Patients With Chronic Conditions: The ValCronic Quasi-Experimental Study. AB - BACKGROUND: The increase of chronic diseases prevalence has created the need to adapt care models and to provide greater home supervision. OBJECTIVE: The objective of our study was to evaluate the impact of telemonitoring on patients with long-term conditions at high risk for rehospitalization or an emergency department visit, in terms of target disease control (diabetes, hypertension, heart failure, and chronic obstructive pulmonary disease). METHODS: We conducted a quasi-experimental study with a before-and-after analysis to assess the effectiveness of the ValCronic program after 1 year of primary care monitoring. The study included high-risk patients with 1 or more of the following conditions: diabetes, high blood pressure, heart failure, and chronic obstructive pulmonary disease. We assessed risk according to the Community Assessment Risk Screen. Participants used an electronic device (tablet) to self-report relevant health information, which was then automatically entered into their eHealth record for consultation. RESULTS: The total sample size was 521 patients. Compared with the preintervention year, there were significant reductions in weight (82.3 kg before vs 80.1 kg after; P=.001) and in the proportion of people with high systolic (>=140 mmHg; 190, 36.5% vs 170, 32.6%; P=.001) and diastolic (>=90 mmHg; 72, 13.8% vs 40, 7.7%; P=.01) blood pressures, and hemoglobin A1c >=8% (186, 35.7% vs 104, 20.0%; P=.001). There was also a decrease in the proportion of participants who used emergency services in primary care (68, 13.1% vs 33, 6.3%; P<.001) and in hospital (98, 18.8% vs 67, 12.8%; P<.001). Likewise, fewer participants required hospital admission due to an emergency (105, 20.2% vs 71, 13.6%; P<.001) or disease exacerbation (55, 10.5% vs 42, 8.1%; P<.001). CONCLUSIONS: The ValCronic telemonitoring program in patients at high risk for rehospitalization or an emergency department visit appears to be useful to improve target disease control and to reduce the use of resources. PMID- 29246882 TI - Viral Hepatitis Strategic Information to Achieve Elimination by 2030: Key Elements for HIV Program Managers. AB - Evidence documenting the global burden of disease from viral hepatitis was essential for the World Health Assembly to endorse the first Global Health Sector Strategy (GHSS) on viral hepatitis in May 2016. The GHSS on viral hepatitis proposes to eliminate viral hepatitis as a public health threat by 2030. The GHSS on viral hepatitis is in line with targets for HIV infection and tuberculosis as part of the Sustainable Development Goals. As coordination between hepatitis and HIV programs aims to optimize the use of resources, guidance is also needed to align the strategic information components of the 2 programs. The World Health Organization monitoring and evaluation framework for viral hepatitis B and C follows an approach similar to the one of HIV, including components on the following: (1) context (prevalence of infection), (2) input, (3) output and outcome, including the cascade of prevention and treatment, and (4) impact (incidence and mortality). Data systems that are needed to inform this framework include (1) surveillance for acute hepatitis, chronic infections, and sequelae and (2) program data documenting prevention and treatment, which for the latter includes a database of patients. Overall, the commonalities between HIV and hepatitis at the strategic, policy, technical, and implementation levels justify coordination, strategic linkage, or integration, depending on the type of HIV and viral hepatitis epidemics. Strategic information is a critical area of this alignment under the principle of what gets measured gets done. It is facilitated because the monitoring and evaluation frameworks for HIV and viral hepatitis were constructed using a similar approach. However, for areas where elimination of viral hepatitis requires data that cannot be collected through the HIV program, collaborations are needed with immunization, communicable disease control, tuberculosis, and hepatology centers to ensure collection of information for the remaining indicators. PMID- 29246885 TI - Bridging the Sex Gap in Early Myocardial Infarction Mortality: Why It Matters. PMID- 29246883 TI - Causes and Consequences of Missing Health-Related Quality of Life Assessments in Patients Who Undergo Mechanical Circulatory Support Implantation: Insights From INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). AB - BACKGROUND: Missing health-related quality of life (HRQOL) data in longitudinal studies can reduce precision and power and bias results. Using INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support), we sought to identify factors associated with missing HRQOL data, examine the impact of these factors on estimated HRQOL assuming missing at random missingness, and perform sensitivity analyses to examine missing not at random (MNAR) missingness because of illness severity. METHODS AND RESULTS: INTERMACS patients (n=3248) with a preimplantation profile of 1 (critical cardiogenic shock) or 2 (progressive decline) were assessed with the EQ-5D-3L visual analog scale and Kansas City Cardiomyopathy Questionnaire-12 summary scores pre-implantation and 3 months postoperatively. Mean and median observed and missing at random-imputed HRQOL scores were calculated, followed by sensitivity analyses. Independent factors associated with HRQOL scores and missing HRQOL assessments were determined using multivariable regression. Independent factors associated with preimplantation and 3-month HRQOL scores, and with the likelihood of missing HRQOL assessments, revealed few correlates of HRQOL and missing assessments (R2 range, 4.7%-11.9%). For patients with INTERMACS profiles 1 and 2 and INTERMACS profile 1 alone, missing at random-imputed mean and median HRQOL scores were similar to observed scores, before and 3 months after implantation, whereas MNAR imputed mean scores were lower (>=5 points) at baseline but not at 3 months. CONCLUSIONS: We recommend use of sensitivity analyses using an MNAR imputation strategy for longitudinal studies when missingness is attributable to illness severity. Conduct of MNAR sensitivity analyses may be less critical after mechanical circulatory support implant, when there are likely fewer MNAR data. PMID- 29246884 TI - Mortality of Myocardial Infarction by Sex, Age, and Obstructive Coronary Artery Disease Status in the ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines). AB - BACKGROUND: Sex differences in early mortality after myocardial infarction (MI) vary by age. MI with nonobstructive coronary arteries (MINOCA [<50% stenosis]) is more common among younger patients and women, and MINOCA has a better prognosis than MI with obstructive coronary artery disease (MI-CAD). The relationship between age, sex, and obstructive CAD status and outcomes post-MI has not been established. METHODS AND RESULTS: Adults who underwent coronary angiography for acute ST-segment-elevation and non-ST-segment-elevation MI in the National Cardiovascular Data Registry ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines) from 2007 to 2014 were identified. Patients with cardiac arrest, thrombolytic therapy, prior revascularization, or missing demographic or angiographic data were excluded. The primary outcome was all-cause, in-hospital mortality. Secondary outcomes included major adverse cardiovascular events. Demographics, clinical history, presentation, and in-hospital treatments were compared by sex and CAD status (MI CAD or MINOCA). Mortality and major adverse cardiovascular outcomes were analyzed by age, sex, and CAD status. Among 322 523 patients with MI, MINOCA occurred in 18 918 (5.9%). MINOCA was more common in women than men (10.5% versus 3.4%; P<0.0001), and women had higher mortality than men overall (3.6% versus 2.4%; P<0.0001). In-hospital mortality was lower after MINOCA than MI-CAD (1.1% versus 2.9%; P<0.0001). Among patients with MI-CAD, women had higher mortality than men (3.9% versus 2.4%; P<0.0001) while no sex difference in mortality was observed with MINOCA (1.1% versus 1.0%; P=0.84). The higher risk of post-MI death among women with MI-CAD was most pronounced at younger ages. CONCLUSIONS: MINOCA was associated with lower mortality than MI-CAD. Higher risk of post-MI death among women in comparison to men was restricted to patients with MI-CAD. PMID- 29246886 TI - Rates of colonization with extended-spectrum beta-lactamase-producing Escherichia coli in Canadian travellers returning from South Asia: a cross-sectional assessment. AB - BACKGROUND: A previous study in Calgary showed that travel to India was associated with high risk of community-onset infections with extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. We performed a follow-up study to determine the rate of rectal acquisition of ESBL-producing E. coli among travellers to South Asia and to identify the behaviours putting such travellers at high risk for acquiring ESBL-producing E. coli. METHODS: The study was performed at a travel clinic in Calgary. Travellers 18 years or older who were planning to visit South Asia for a period of at least 5 days were included. Three rectal swabs were obtained, and 2 questionaires were administered (before and after travel). RESULTS: A total of 149 travellers participated between January 2012 and July 2014; of these, 116 (78%) provided rectal swabs upon return to Calgary and completed both pre- and post-travel questionaires. Of the 109 travellers without colonization with ESBL-producing E. coli upon enrollment, 70 (64%) acquired ESBL-producing E. coli during travel. Of the 90 participants who visited India, 66 (73%) were positive for ESBL-producing E. coli upon their return to Calgary. Most ESBL-producing E. coli specimens were identified as producing the enzyme CTX-M-15. Behaviours associated with a statistically significant risk of acquiring ESBL-producing E. coli included visiting India (odds ratio [OR] 19.9, 95% confidence interval [CI] 4.5-88.8), consuming meals with the local population (OR 6.9, 95% CI 1.2-39.6), taking any type of antibiotic during travel (OR 4.3, 95% CI 1.3-14.3) and travelling for any purpose other than business (OR 12.4, 95% CI 2.8-55.2). INTERPRETATION: In this study, travel to India was associated with the highest risk of acquiring ESBL-producing E. coli relative to travel to other countries in South Asia. Nonbusiness travel, consuming foods with the local population and the use of antibiotics while travelling were associated with an increased risk of acquiring these antibiotic resistant organisms while in India. Trial registration: ClinicalTrials.gov, no. NCT01296165. PMID- 29246888 TI - Impact of Breast Cancer Resistance Protein Expression on the In Vitro Efficacy of Anticancer Drugs in Pancreatic Cancer Cell Lines. AB - Breast cancer resistance protein (BCRP) overexpression confers multidrug resistance to cancer cells, and the efficacy of anticancer drugs has been reported to be significantly affected by BCRP in cell lines transfected with BCRP or selected with drugs. It is unclear whether the in vitro efficacy of anticancer drugs is affected by endogenous BCRP, although cancer cell line panels consisting of defined tumor cell lines with endogenous BCRP have been used to screen for anticancer drugs in the pharmaceutical industry. We assessed the impact of BCRP expression on efficacy of anticancer drugs using pancreatic cancer cell lines expressing varying levels of endogenous BCRP. Pancreatic cancer cell lines were selected from the Cancer Cell Line Encyclopedia (CCLE). The EC50 of 7-ethyl-10 hydroxycamptothecin (SN-38), topotecan, and mitoxantrone decreased in the presence of a BCRP inhibitor in PANC-1 and AsPC-1 cells, which exhibit high BCRP expression. However, no significant alterations in EC50 were observed in HPAF-II, SW 1990, and MIA PaCa-2, which show moderate or low BCRP expression. The shift of EC50 of anticancer drugs with and without a BCRP inhibitor increased with an increase of BCRP mRNA expression levels; however, the shift was obvious only in cells highly expressing BCRP. Thus, the in vitro efficacy of anticancer drugs on cell proliferation may be minimally affected by BCRP in most pancreatic cancer cell lines, considering that 72% of pancreatic cancer cell lines in CCLE show moderate or low BCRP expression. The effect of BCRP should be carefully evaluated in pancreatic cell lines that highly express BCRP. PMID- 29246889 TI - Nerve terminals at the human corneoscleral limbus. AB - AIMS: To demonstrate and characterise distinct subepithelial compact nerve endings (CNE) at the human corneoscleral limbus. METHODS: Ten fresh human donor corneoscleral discs (mean age, 67 years) and 26 organ-cultured corneoscleral rims (mean age, 59 years) were studied. All samples were subjected to enzyme histochemical staining related to endogenous acetylcholinesterase present in nerve tissue and H&E staining. Whole-mount en face imaging with NanoZoomer digital pathology microscope and serial cross-section imaging with light microscope were undertaken. RESULTS: Nerves entering the corneoscleral limbus and peripheral cornea terminate under the epithelium as enlarged multiloculated and multinucleated ovoid structures within a 2 mm zone. They are closely associated with the rete pegs of the limbal palisades and the limbal epithelial crypts, often located within characteristic stromal invaginations of these structures. Their numbers ranged from 70 to 300 per corneoscleral rim. The size ranged from 20 to 100 um. They had one or more nerve connections and were interconnected to other similar endings and to the limbal nerve plexus. CONCLUSION: Human corneoscleral limbus demonstrates a population of nerve terminals resembling CNE with distinct morphological features. They are closely associated with the limbal stem cell niches, suggesting a potential contribution to the niche environment. PMID- 29246887 TI - Anticancer Activity of Natural and Synthetic Capsaicin Analogs. AB - The nutritional compound capsaicin is the major spicy ingredient of chili peppers. Although traditionally associated with analgesic activity, recent studies have shown that capsaicin has profound antineoplastic effects in several types of human cancers. However, the applications of capsaicin as a clinically viable drug are limited by its unpleasant side effects, such as gastric irritation, stomach cramps, and burning sensation. This has led to extensive research focused on the identification and rational design of second-generation capsaicin analogs, which possess greater bioactivity than capsaicin. A majority of these natural capsaicinoids and synthetic capsaicin analogs have been studied for their pain-relieving activity. Only a few of these capsaicin analogs have been investigated for their anticancer activity in cell culture and animal models. The present review summarizes the current knowledge of the growth inhibitory activity of natural capsaicinoids and synthetic capsaicin analogs. Future studies that examine the anticancer activity of a greater number of capsaicin analogs represent novel strategies in the treatment of human cancers. PMID- 29246891 TI - Corneal perforation from peripheral ulcerative keratopathy in patients with rheumatoid arthritis: epidemiological findings of the British Ophthalmological Surveillance Unit. AB - BACKGROUND/AIMS: This study quantifies the threat to vision and the survival in patients presenting with peripheral ulcerative keratopathy (PUK) corneal perforation associated with rheumatoid arthritis (RA) in the UK. METHODS: New cases of corneal perforation from PUK in patients with RA were prospectively collected from the UK via the British Ophthalmological Surveillance Unit from July 2012 to June 2014. An initial questionnaire collected data on presentation and the first 2 weeks' management, and a follow-up questionnaire collected 1-year data on ocular morbidity and mortality. RESULTS: 30 eyes of 28 patients were identified over 2 years, estimating a UK incidence of 0.234/million/year. 20/27 (74%) were female, with a median age of 68 years (range 41-84). The most common initial management was cyanoacrylate glue with a bandage contact lens, oral steroids, topical and oral antibiotics, and lubricants. Long-term management included corneal grafting in 12/20 (60%) eyes of patients living at 1 year. The 1 year all-cause mortality was 6/25 (24%), which increased to 1/2 (50%) if both eyes had perforated. In the remaining patients alive at 1-year follow-up, there was a 13/20 (65%) poor visual outcome of less than or equal to counting fingers. 8/25 (40%) patients had bilateral PUK, with 2/25 (8%) having bilateral perforation. 5/19 (26%) patients alive at 1-year follow-up were eligible for sight impairment registration. CONCLUSION: This study highlights the serious ocular morbidity and high mortality associated with corneal perforation from PUK in patients with RA despite treatment. The mortality doubled if both eyes perforated, which should serve as a harbinger of impending serious medical problems. PMID- 29246890 TI - Antivascular endothelial growth factor agents pretreatment before vitrectomy for complicated proliferative diabetic retinopathy: a meta-analysis of randomised controlled trials. AB - BACKGROUND/AIMS: To evaluate the efficacy of antivascular endothelial growth factor (anti-VEGF) agents pretreatment before vitrectomy for patients with complicated proliferative diabetic retinopathy (PDR). METHODS: The PubMed, Embase and the Cochrane Central Register of Controlled Trials were searched up to June 2017 to identify related studies. The Peferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed. The StataSE V.12.0 software was used to analyse the relevant data. The weighted mean difference, relative risk and their 95% CIs were used to assess the strength of the association. RESULTS: 14 randomised controlled trials involving 613 patients were assessed, the anti-VEGF pretreatment group included 289 patients and the control group included 324 patients. Our analysis indicated that anti-VEGF pretreatment before vitrectomy for complicated PDR could facilitate much easier surgery regarding less intraoperative bleeding, less endodiathermy, shorter duration of surgery, less iatrogenic retinal breaks, less frequency of using silicone oil and relaxing retinotomy (P<0.05). Additionally, anti-VEGF pretreatment could also achieve better postoperative best-corrected visual acuity, less early recurrent vitreous haemorrhage (VH) and quicker absorption of recurrent VH (P<0.05). However, the incidence of late recurrent VH, recurrent retinal detachment or related secondary surgery could not be reduced (P>0.05). CONCLUSION: The pretreatment of anti-VEGF agents before vitrectomy for patients with complicated PDR might facilitate much easier surgery and better visual rehabilitation, reduce the rate of early recurrent VH and accelerate its absorption. Moreover, future better-designed studies with larger sample sizes are required to further evaluate the efficacy of different anti-VEGF agents and reach a firmer conclusion. PMID- 29246892 TI - Baerveldt shunt surgery versus combined Baerveldt shunt and phacoemulsification: a prospective comparative study. AB - AIM: To examine the efficacy and safety of Baerveldt tube (BT) implantation compared with combined phacoemulsification and Baerveldt tube (PBT) implantation in patients with refractory glaucoma. METHODS: Seventy-six eyes of 76 patients were enrolled, 38 pseudophakic eyes underwent BT implantation alone and 38 phakic eyes underwent the BT implantation combined with phacoemulsification. Groups were matched for preoperative intraocular pressure (IOP) and number of glaucoma medications. Preoperative and postoperative measures recorded included patient demographics, visual acuity (VA), IOP, number of antiglaucoma medications and all complications. Patients were followed up for a minimum of 36 months. Failure was defined as: inadequate IOP control (IOP<=5 mm Hg/>21 mm Hg/<20% reduction from baseline, reoperation for glaucoma, loss of light perception vision, or removal of the implant). RESULTS: There was a significant difference in failure rates between groups at 36 months (PBT 37% vs BT 15%, P=0.02). There was no significant difference for PBT versus BT in preoperative baseline ocular characteristics. At 36 months: median IOP=14 mm Hg vs 12 mm Hg, P=0.04; mean number of antiglaucomatous medications=1.7 vs 1.3, P=0.61; median VA=0.8 vs 0.7, P=0.44. Postoperative complication rates were similar in both groups (n=5 vs 5; 13% vs 13%). CONCLUSIONS: Failure rates were significantly greater in the PBT group at 3 years. Median IOP was also significantly higher in the PBT group. These results suggest that combining phacoemulsification with aqueous shunt surgery may have a negative effect on long-term shunt bleb survival. PMID- 29246893 TI - Lid splinting eyelid retraction technique: a minimised sterile approach for intravitreal injections. AB - BACKGROUND/AIMS: To describe an alternative technique for avoiding contact with the lids and lashes, without the use of a lid speculum, during intravitreal anti vascular endothelial growth factor injections. METHODS: Retrospective case series of all patients undergoing intravitreal injections of bevacizumab and ranibizumab, with the lid splinting retraction technique from January 2010 to December 2015. Injections performed by six vitreoretinal specialists were included. The key preinjection ocular surface preparation includes topical anaesthetic, 5% povidone-iodine and a subconjunctival injection of 2% lidocaine with epinephrine. A second instillation of 5% povidone-iodine is given and the intravitreal injection is then performed. No lid speculum is used. A search of the electronic medical records identified patients diagnosed with postinjection endophthalmitis and charts were reviewed to ensure inclusion criteria were met. The main outcome measure was incidence of postinjection endophthalmitis. RESULTS: A total of 78 009 consecutive intravitreal injections were performed, of which 22 207 were bevacizumab and 55 802 were ranibizumab. In this cohort of patients (n=6320), 12 cases of endophthalmitis developed, corresponding to a rate of 0.015%. CONCLUSIONS: The technique of eyelid retraction for intravitreal injection has a low rate of endophthalmitis, similar to the reported rates using a metal lid speculum. This is beneficial for both the physician and the patient as it minimises patient discomfort as well as the duration of the procedure. To our knowledge, this is one of the largest studies performed to date evaluating intravitreal injection-related endophthalmitis. PMID- 29246894 TI - Global Pulmonary Vascular Remodeling in Pulmonary Hypertension Associated With Heart Failure and Preserved or Reduced Ejection Fraction. AB - BACKGROUND: We hypothesized that pulmonary venous hypertension in heart failure (HF) leads to predominate remodeling of pulmonary veins and that the severity of venous remodeling is associated with the severity of pulmonary hypertension (PH) in HF. METHODS: Patients with HF (n=108; 53 preserved and 55 reduced ejection fraction) with PH (HF-PH; pulmonary artery systolic pressure [PASP] >=40 mm Hg) were compared to normal controls (n=12) and patients with primary pulmonary veno occlusive disease (PVOD; n=17). In lung specimens from autopsy (control, HF-PH, and 7 PVOD) or surgery (10 PVOD), quantitative histomorphometry was performed in all analyzable arteries (n=4949), veins (n=7630), and small indeterminate vessels (IV; n=2168) to define percent medial thickness (arteries) and percent intimal thickness (%IT) (arteries, veins, and IV) relative to external diameter. RESULTS: The average arterial percent medial thickness (control, 6.9; HF-PH, 11.0; PVOD, 15.0), arterial %IT (control, 4.9; HF-PH, 14.9; PVOD, 31.1), venous %IT (control, 14.0; HF-PH, 24.9; PVOD, 43.9), and IV %IT (control, 10.6; HF-PH, 25.8; PVOD, 50.0) in HF-PH were higher than controls (P<0.0001 for all) but lower than PVOD (P<=0.005 for all). PASP (mm Hg) was lower in HF-PH (median, 59 [interquartile range, 50-70]) than in PVOD (median, 91 [interquartile range, 82-103]). PASP correlated with arterial percent medial thickness (r=0.41) and arterial %IT (r=0.35) but more strongly with venous %IT (r=0.49) and IV %IT (r=0.55) (P<0.0001 for all). Associations between PASP and venous or IV %IT remained significant after adjusting for arterial percent medial thickness and %IT and did not vary by HF type. In patients with right heart catheterization (30 HF-PH, 14 PVOD), similar associations between the transpulmonary gradient and pulmonary vascular remodeling existed, with numerically stronger associations for venous and IV %IT. Although the PASP was slightly higher in patients with HF-PH with right ventricular dysfunction, pulmonary vascular remodeling was not more severe. Pulmonary vascular remodeling severity was associated with reductions in the diffusing capacity of the lungs. CONCLUSIONS: In HF, PH is associated with global pulmonary vascular remodeling, but the severity of PH correlates most strongly with venous and small IV intimal thickening, similar to the pattern observed in PVOD. These findings expand our understanding of the pathobiology of PH in HF. PMID- 29246895 TI - miR-22 Is a Novel Mediator of Vascular Smooth Muscle Cell Phenotypic Modulation and Neointima Formation. AB - BACKGROUND: MicroRNA-22 (miR-22) has recently been reported to play a regulatory role during vascular smooth muscle cell (VSMC) differentiation from stem cells, but little is known about its target genes and related pathways in mature VSMC phenotypic modulation or its clinical implication in neointima formation following vascular injury. METHODS: We applied a wire-injury mouse model, and local delivery of AgomiR-22 or miR-22 inhibitor, as well, to explore the therapeutic potential of miR-22 in vascular diseases. Furthermore, normal and diseased human femoral arteries were harvested, and various in vivo, ex vivo, and in vitro models of VSMC phenotype switching were conducted to examine miR-22 expression during VSMC phenotype switching. RESULTS: Expression of miR-22 was closely regulated during VSMC phenotypic modulation. miR-22 overexpression significantly increased expression of VSMC marker genes and inhibited VSMC proliferation and migration, whereas the opposite effect was observed when endogenous miR-22 was knocked down. As expected, 2 previously reported miR-22 target genes, MECP2 (methyl-CpG binding protein 2) and histone deacetylase 4, exhibited a regulatory role in VSMC phenotypic modulation. A transcriptional regulator and oncoprotein, EVI1 (ecotropic virus integration site 1 protein homolog), has been identified as a novel miR-22 target gene in VSMC phenotypic modulation. It is noteworthy that overexpression of miR-22 in the injured vessels significantly reduced the expression of its target genes, decreased VSMC proliferation, and inhibited neointima formation in wire-injured femoral arteries, whereas the opposite effect was observed with local application of a miR-22 inhibitor to injured arteries. We next examined the clinical relevance of miR-22 expression and its target genes in human femoral arteries. We found that miR-22 expression was significantly reduced, whereas MECP2 and EVI1 expression levels were dramatically increased, in diseased in comparison with healthy femoral human arteries. This inverse relationship between miR-22 and MECP2 and EVI1 was evident in both healthy and diseased human femoral arteries. CONCLUSIONS: Our data demonstrate that miR-22 and EVI1 are novel regulators of VSMC function, specifically during neointima hyperplasia, offering a novel therapeutic opportunity for treating vascular diseases. PMID- 29246896 TI - Trends in the Use of Inotropes to List Adult Heart Transplant Candidates at Status 1A. AB - BACKGROUND: The number of adult heart transplant candidates waiting at the most urgent status 1A has increased over time despite the expansion of geographic sharing of hearts in 2006. We aimed to determine whether candidates listed with inotropes contribute to the excess status 1A candidates. METHODS AND RESULTS: The initial registrations of all adult heart-only candidates listed from 2000 to 2015 were analyzed using the Scientific Registry of Transplant Recipients data set. Trends in listing status, justifications, and candidate factors were measured. Adjusted trends in listing status pre- and post-geographic sharing were estimated using multilevel logistic regression. Competing risks models provided trends in transplant-free waitlist survival. There were 46 853 adult heart-alone listings during 2000 to 2015. Pre-sharing, status 1A listing was unchanged over time (adjusted odds ratio, 0.98; 95% confidence interval, 0.78-1.23). Post-sharing, the adjusted odds of status 1A listing increased 117% over 9 years (adjusted odds ratio 2.17, 95% confidence interval, 1.82-2.58). The number of candidates listed as status 1A with inotropes increased by 193 a year, whereas the dobutamine, dopamine, and milrinone doses used decreased 49%, 55%, and 29% (P<0.001). The risk of waitlist death or deterioration of status 1A inotrope candidates relative to status 2 candidates decreased 62% for 2006 to 2010 and 70% for 2011 to 2015 compared with that for 2003 to 2006. CONCLUSIONS: After the wider geographic sharing of hearts in 2006, transplant programs used multiple inotropes to list candidates at status 1A more frequently with progressively lower doses. Concurrently, the status 1A inotrope candidate waitlist outcomes improved substantially. These trends suggest that overtreatment with multiple inotropes contributes to the current critical excess of status 1A candidates. PMID- 29246898 TI - The Heart Transplant Waiting List and the Interplay of Policy and Practice: In Search of Fairness. PMID- 29246897 TI - Hemodynamics of Fontan Failure: The Role of Pulmonary Vascular Disease. AB - BACKGROUND: Nonpulsatile pulmonary blood flow in Fontan circulation results in pulmonary vascular disease, but the potential relationships between pulmonary vascular resistance index (PVRI) and Fontan failure have not been studied. The objective was to determine whether the absence of subpulmonary ventricle in the Fontan circulation would make patients more vulnerable to even low-level elevations in PVRI, and when coupled with low cardiac index, this would identify patients at increased risk of Fontan failure. METHODS AND RESULTS: Two hundred sixty-one adult Fontan patients underwent cardiac catheterization; age 26+/-3 years, men 146 (56%), atriopulmonary Fontan 144 (55%). Patients were divided into 2 groups: those with high PVRI (>2 WU.m2) and low cardiac index <2.5 L min-1 m-2 (group 1, n=70, 30%), and those with normal PVRI and normal cardiac index (group 2, n=182, 70%). Fontan failure was defined by the composite of all-cause mortality, listing for heart transplantation, or initiation of palliative care. There were 68 (26%) cases of Fontan failure during a mean follow-up of 8.6+/-2.4 years. When compared with group 2, freedom from Fontan failure was significantly lower in group 1: 66% versus 89% at 5 years. The combination of high PVRI and low cardiac index was an independent risk factor for Fontan failure (hazard ratio, 1.84; 95% confidence interval, 1.09-2.85). CONCLUSIONS: When coupled with low cardiac index, even mild elevations in PVRI identify patients at high risk of Fontan failure. This suggests that pulmonary vascular disease is a key mechanism underlying Fontan failure and supports further studies to understand the pathophysiology and target treatments to pulmonary vascular tone in this population. PMID- 29246899 TI - Genetic Identification of Separase Regulators in Caenorhabditis elegans. AB - Separase is a highly conserved protease required for chromosome segregation. Although observations that separase also regulates membrane trafficking events have been made, it is still not clear how separase achieves this function. Here, we present an extensive ENU mutagenesis suppressor screen aimed at identifying suppressors of sep-1(e2406), a temperature-sensitive maternal effect embryonic lethal separase mutant that primarily attenuates membrane trafficking rather than chromosome segregation. We screened nearly a million haploid genomes and isolated 68 suppressed lines. We identified 14 independent intragenic sep-1(e2406) suppressed lines. These intragenic alleles map to seven SEP-1 residues within the N-terminus, compensating for the original mutation within the poorly conserved N terminal domain. Interestingly, 47 of the suppressed lines have novel mutations throughout the entire coding region of the pph-5 phosphatase, indicating that this is an important regulator of separase. We also found that a mutation near the MEEVD motif of HSP-90, which binds and activates PPH-5, also rescues sep 1(e2406) mutants. Finally, we identified six potentially novel suppressor lines that fall into five complementation groups. These new alleles provide the opportunity to more exhaustively investigate the regulation and function of separase. PMID- 29246900 TI - Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. AB - Gene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX <=2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay, and all 10 were enrolled. A single dose of 5 * 1012 or 2 * 1013 genome copies of AMT-060/kilogram was administered to 5 participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8% to 4.6% (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts, and 8 of 9 participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n = 1) and higher-dose (n = 2) cohorts were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT 060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids. This trial was registered at www.clinicaltrials.gov as #NCT02396342; EudraCT #2013-005579-42. PMID- 29246901 TI - Evolutionary basis of HLA-DPB1 alleles affects acute GVHD in unrelated donor stem cell transplantation. AB - HLA-DPB1 T-cell epitope (TCE) mismatching algorithm and rs9277534 SNP at the 3' untranslated region (3'UTR) in the HLA-DPB1 gene are key factors for transplant related events in unrelated hematopoietic cell transplantation (UR-HCT). However, the association of these 2 mechanisms has not been elucidated. We analyzed 19 frequent HLA-DPB1 alleles derived from Japanese healthy subjects by next generation sequencing of the entire HLA-DPB1 gene region and multi-SNP data of the HLA region in 1589 UR-HCT pairs. The risk of acute graft-versus-host disease (aGVHD) was analyzed in 1286 patients with single HLA-DPB1 mismatch UR-HCT. The phylogenetic tree constructed using the entire gene region demonstrated that HLA DPB1 alleles were divided into 2 groups, HLA-DP2 and HLA-DP5. Although a phylogenetic relationship in the genomic region from exon 3 to 3'UTR (Ex3-3'UTR) obviously supported the division of HLA-DP2 and HLA-DP5 groups, which in exon 2 showed intermingling of HLA-DPB1 alleles in a non-HLA-DP2 and non-HLA-DP5-group manner. Multi-SNP data also showed 2 discriminative HLA-DPB1 groups according to Ex3-3'UTR. Risk of grade 2-4 aGVHD was significantly higher in patient HLA-DP5 group mismatch than patient HLA-DP2 group mismatch (hazard ratio, 1.28; P = .005), regardless of donor mismatch HLA-DP group. Regarding TCE mismatch, increasing risk of aGVHD in patient HLA-DP5 group mismatch and TCE-nonpermissive mismatch were observed only in patients with TCE-permissive mismatch and patient HLA-DP2 group mismatch, respectively. Evolutionary analysis revealed that rs9277534 represented a highly conserved HLA-DPB1 Ex3-3'UTR region and may provoke aGVHD differently to TCE mismatching algorithm, reflecting exon 2 polymorphisms. These findings enrich our understanding of the mechanism of aGVHD in HLA-DPB1 mismatch UR-HCT. PMID- 29246902 TI - Identification of the integrin-binding site on coagulation factor VIIa required for proangiogenic PAR2 signaling. AB - The tissue factor (TF) pathway serves both hemostasis and cell signaling, but how cells control these divergent functions of TF remains incompletely understood. TF is the receptor and scaffold of coagulation proteases cleaving protease-activated receptor 2 (PAR2) that plays pivotal roles in angiogenesis and tumor development. Here we demonstrate that coagulation factor VIIa (FVIIa) elicits TF cytoplasmic domain-dependent proangiogenic cell signaling independent of the alternative PAR2 activator matriptase. We identify a Lys-Gly-Glu (KGE) integrin-binding motif in the FVIIa protease domain that is required for association of the TF-FVIIa complex with the active conformer of integrin beta1. A point mutation in this motif markedly reduces TF-FVIIa association with integrins, attenuates integrin translocation into early endosomes, and reduces delayed mitogen-activated protein kinase phosphorylation required for the induction of proangiogenic cytokines. Pharmacologic or genetic blockade of the small GTPase ADP-ribosylation factor 6 (arf6) that regulates integrin trafficking increases availability of TF-FVIIa with procoagulant activity on the cell surface, while inhibiting TF-FVIIa signaling that leads to proangiogenic cytokine expression and tumor cell migration. These experiments delineate the structural basis for the crosstalk of the TF-FVIIa complex with integrin trafficking and suggest a crucial role for endosomal PAR2 signaling in pathways of tissue repair and tumor biology. PMID- 29246905 TI - Torcular dural sinus malformation. PMID- 29246904 TI - Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer. AB - Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response.Experimental Design: In this observational study, we sequenced tumor whole genomes (100* depth) and matched normals (60*) of 93 advanced-stage breast cancers (33 platinum treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI).Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3 month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04).Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials. Clin Cancer Res; 23(24); 7521-30. (c)2017 AACR. PMID- 29246906 TI - Comparison of the efficacy and safety of thrombectomy devices in acute stroke : a network meta-analysis of randomized trials. AB - INTRODUCTION: Mechanical thrombectomy (MT) is increasingly used for large-vessel occlusions (LVO), but randomized clinical trial (RCT) level data with regard to differences in clinical outcomes of MT devices are limited. We conducted a network meta-analysis (NMA) that enables comparison of modern MT devices (Trevo, Solitaire, Aspiration) and strategies (stent retriever vs aspiration) across trials. METHODS: Relevant RCTs were identified by a systematic review. The efficacy outcome was 90-day functional independence (modified Rankin Scale (mRS) score 0-2). Safety outcomes were 90-day catastrophic outcome (mRS 5-6) and symptomatic intracranial hemorrhage (sICH). Fixed-effect Bayesian NMA was performed to calculate risk estimates and the rank probabilities. RESULTS: In a NMA of six relevant RCTs (SWIFT, TREVO2, EXTEND-IA, SWIFT-PRIME, REVASCAT, THERAPY; total of 871 patients, 472 Solitaire vs medical-only, 108 Aspiration vs medical-only, 178 Trevo vs Merci, and 113 Solitaire vs Merci) with medical-only arm as the reference, Trevo had the greatest functional independence (OR 4.14, 95% credible interval (CrI) 1.41-11.80; top rank probability 92%) followed by Solitaire (OR 2.55, 95% CrI 1.75-3.74; top rank probability 72%). Solitaire and Aspiration devices had the greatest top rank probability with respect to low sICH and catastrophic outcomes (76% and 91%, respectively), but without significant differences between each other. In a separate network of seven RCTs (MR-CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, REVASCAT, THERAPY, ASTER; 1737 patients), first line stent retriever was associated with a higher top rank probability of functional independence than aspiration (95% vs 54%), with comparable safety outcomes. CONCLUSIONS: These findings suggest that Trevo and Solitaire devices are associated with a greater likelihood of functional independence whereas Solitaire and Aspiration devices appear to be safer. PMID- 29246907 TI - A new combined parameter predicts re-treatment for coil-embolized aneurysms: a computational fluid dynamics multivariable analysis study. AB - PURPOSE: Coil embolization is a minimally invasive method used to treat cerebral aneurysms. Although this endovascular treatment has a high success rate, aneurysmal re-treatment due to recanalization remains a major problem of this method. The purpose of this study was to determine a combined parameter that can be useful for predicting aneurysmal re-treatment due to recanalization. METHODS: Patient-specific geometries were used to retrospectively analyze the blood flow for 26 re-treated and 74 non-retreated aneurysms. Post-operatively aneurysms were evaluated at 12-month follow-up. The hemodynamic differences between the re treatment and non-retreatment aneurysms were analyzed before and after coil embolization using computation fluid dynamics. Basic fluid characteristics, rates of change, morphological factors of aneurysms and patient-specific clinical information were examined. Multivariable analysis and logistic regression analysis were performed to determine a combined parameter-re-treatment predictor (RP). RESULTS: Among examined hemodynamic, morphological, and clinical parameters, slight reduction of blood flow velocity rate in the aneurysm, slight increase of pressure rate at the aneurysmal neck and neck area, and hypertension were the main factors contributing to re-treatment. Notably, hemodynamic parameters between re-treatment and non-retreatment groups before embolization were similar: however, we observed significant differences between the groups in the post-embolization average velocity and the rate of reduction in this velocity in the aneurysmal dome. CONCLUSIONS: The combined parameter, RP, which takes into consideration hemodynamic, morphological, and clinical parameters, accurately predicts aneurysm re-treatment. Calculation of RP before embolization may be able to predict the aneurysms that will require re-treatment. PMID- 29246908 TI - Long-term follow-up of aneurysms treated electively with woven stent-assisted coiling. AB - BACKGROUND: Preliminary short-term results for stent-assisted coil embolization (SACE) using woven/braided stents have been promising. However, evidence supporting mid- to long-term efficacy and durability is lacking. OBJECTIVE: To report the long-term results for the durability of elective intracranial aneurysms treated with woven stents. MATERIALS AND METHODS: Between May 2012 and May 2015, 98 consecutive patients with 103 aneurysms underwent elective woven SACE across three Australian neurovascular centres. All patients had immediate, 6 and 18-month clinical and radiological follow-up. Radiological assessment was performed with modified Raymond-Roy occlusion scores based on angiography results, while clinical assessment was based on the modified Rankin Scale. RESULTS: Six-month follow-up was available in 100 aneurysms, and an 18-month follow-up in 97 aneurysms. Total occlusion rates of 82% were achieved at inception, 82% at 6 months, and 90% at 18 months. Satisfactory occlusion with small neck remnants was present in 17% at inception, 16% at 6 months, and 9% at 18 months. Good neurological outcomes were achieved in 95% at 18 months. Intraprocedural thromboembolic events were recorded in 3% and delayed events in 1% (all in patients taking clopidogrel). Aneurysm recurrence occurred in one patient (1%). Technical complications occurred in 5%. The total complication rate was 10%. CONCLUSIONS: Woven SACE is safe, efficacious, and durable at long-term 18-month follow-up, with very low recurrence and re-treatment rates. Preliminary results appear better than those for traditional laser-cut stents. PMID- 29246909 TI - Serial Assessment of Strut Coverage of Biodegradable Polymer Drug-Eluting Stent at 1, 2, and 3 Months After Stent Implantation by Optical Frequency Domain Imaging: The DISCOVERY 1TO3 Study (Evaluation With OFDI of Strut Coverage of Terumo New Drug Eluting Stent With Biodegradable Polymer at 1, 2, and 3 Months). AB - BACKGROUND: To assess the vessel-healing pattern of Ultimaster drug-eluting stent using optical frequency domain imaging. Our hypothesis is that biodegradable polymer-based drug-eluting technology allows complete very early strut coverage. METHODS AND RESULTS: The DISCOVERY 1TO3 study (Evaluation With OFDI of Strut Coverage of Terumo New Drug Eluting Stent With Biodegradable Polymer at 1, 2, and 3 Months) is a prospective, single-arm, multicenter study. A total of 60 patients with multivessel disease requiring staged procedure at 1 month were treated with Ultimaster. Optical frequency domain imaging was acquired at baseline, 1, 2, and 3 months. The primary end point is optical frequency domain imaging-assessed strut coverage at 3 months. Mean age of patients was 67.2+/-9.9 years, and 73.3% were male, and 36.7% presented with acute coronary syndrome. A total of 132 lesions were treated, with average 1.4 lesions per patient treated at baseline and 1.1 lesions treated at 1 month. Strut coverage at 3 months of single implanted stents (n=71, primary end point) was 95.2+/-5.2% and of combined single and overlapped stents was 95.4+/-4.9%. Strut coverage of combined single and overlapped stents at 1 (n=49) and 2 months (n=38) was 85.1+/-12.7% and 87.9+/ 10.8%, respectively. The median neointimal hyperplasia thickness was 0.04, 0.05, and 0.06 mm, whereas mean neointimal hyperplasia obstruction was 4.5+/-2.4%, 5.2+/-3.4%, and 6.6+/-3.3% at 1, 2, and 3 months, respectively. CONCLUSIONS: Nearly complete strut coverage was observed in this complex population very early after implantation of Ultimaster drug-eluting stent. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01844843. PMID- 29246910 TI - Radial Versus Femoral Access for Rotational Atherectomy: A UK Observational Study of 8622 Patients. AB - BACKGROUND: Rotational atherectomy (RA) is an important interventional tool for heavily calcified coronary lesions. We compared the early clinical outcomes in patients undergoing RA using radial or femoral access. METHODS AND RESULTS: We identified all patients in England and Wales who underwent RA between January 1, 2005, and March 31, 2014. Eight thousand six hundred twenty-two RA cases (3069 radial and 5553 femoral) were included in the analysis. The study primary outcome was 30-day mortality. Propensity scores were calculated to determine the factors associated with treatment assignment to radial or femoral access. Multivariable logistic regression analysis, using the calculated propensity scores, was performed. Thirty-day mortality was 2.2% in the radial and 2.3% in the femoral group (P=0.76). Radial access was associated with equivalent 30-day mortality (adjusted odds ratio [OR], 1.06; 95% confidence interval [CI], 0.77-1.46; P=0.71), procedural success (OR, 1.04; 95% CI, 0.84-1.29; P=0.73), major adverse cardiac and cerebrovascular events (OR, 1.05; 95% CI, 0.80-1.38; P=0.72), and net adverse clinical events (OR, 0.90; 95% CI, 0.71-1.15; P=0.41), but lower rates of in-hospital major bleeding (OR, 0.62; 95% CI, 0.40-0.98; P=0.04) and major access site complications (OR, 0.05; 95% CI, 0.01-0.38; P=0.004), compared with femoral access. CONCLUSIONS: In this large real-world study of patients undergoing RA, radial access was associated with equivalent 30-day mortality and procedural success, but reduced major bleeding and access site complications, compared with femoral access. PMID- 29246911 TI - Three-Year Outcomes of Surgical Versus Endovascular Revascularization for Critical Limb Ischemia: The SPINACH Study (Surgical Reconstruction Versus Peripheral Intervention in Patients With Critical Limb Ischemia). AB - BACKGROUND: The aim of this study was to compare clinical outcomes between surgical reconstruction and endovascular therapy (EVT) for critical limb ischemia (CLI) in today's real-world settings. METHODS AND RESULTS: This multicenter, prospective, observational study registered and followed 548 Japanese CLI patients. The registration was in advance of revascularization; 197 patients were scheduled to receive surgical reconstruction, and the remaining 351 were scheduled to receive EVT. The primary end point was 3-year amputation-free survival, compared between the 2 treatments in an intention-to-treat manner, using propensity score matching. Interaction analysis was additionally performed to explore which subgroups had better outcomes with surgical reconstruction or EVT. After propensity score matching, the 3-year amputation-free survival was not significantly different between the 2 groups (52% [95% confidence interval, 43% 60%] and 52% [95% confidence interval, 44-60%]; P=0.26). Subsequent interaction analysis identified (1) Wound, Ischemia, and foot Infection (WIfI) classification W-3, (2) fI-2/3, (3) history of ipsilateral minor amputation, (4) history of revascularization after CLI onset, and (5) bilateral CLI as the factors more favorable for surgical reconstruction, whereas (1) diabetes mellitus, (2) renal failure, (3) anemia, (4) history of nonadherence to cardiovascular risk management, and (5) contralateral major amputation were as those less favorable for surgical reconstruction. CONCLUSIONS: The 3-year amputation-free survival was not different between surgical reconstruction and EVT in the overall CLI population. The subsequent interaction analysis suggested that there would be a subgroup more suited for surgical reconstruction and another benefiting more from EVT. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN000007050. PMID- 29246912 TI - Outcomes of Saphenous Vein Graft Intervention With and Without Embolic Protection Device: A Comprehensive Review and Meta-Analysis. AB - BACKGROUND: Current guidelines give a class I recommendation to use of embolic protection devices (EPD) for saphenous vein graft (SVG) intervention; however, studies have shown conflicting results. The objective of this meta-analysis is to compare all-cause mortality, major adverse cardiovascular events, myocardial infarction (MI), or target vessel revascularization in SVG intervention with and without EPD. METHODS AND RESULTS: Literature was searched through October 2016. Eight studies (n=52 893) comparing SVG intervention performed with EPD (n=11 506) and without EPD (n=41 387) were included. There was no significant difference in all-cause mortality (odds ratio [OR], 0.79; confidence interval [CI], 0.55-1.12; P=0.19), major adverse cardiovascular events (OR, 0.73, CI, 0.51-1.05; P=0.09), target vessel revascularization (OR, 1.0; CI, 0.95-1.05; P=0.94), periprocedural MI (OR, 1.12; CI, 0.65-1.90, P=0.69), and late MI (OR, 0.80; CI, 0.52-1.23; P=0.30) between the 2 groups. Sensitivity analysis excluding CathPCI Registry study showed no difference in periprocedural MI, late MI, and target vessel revascularization; however, it favored EPD use in all-cause mortality and major adverse cardiovascular events. Further sensitivity analysis including only observational studies revealed no difference in all-cause mortality, major adverse cardiovascular events, target vessel revascularization, and late MI. Additional analysis after excluding CathPCI Registry study revealed no difference in outcomes. CONCLUSIONS: This study including 52 893 patients suggests no apparent benefit in routine use of EPD during SVG intervention in the contemporary real-world practice. Further randomized clinical trials are needed in current era to evaluate long-term outcomes in routine use of EPD, and meanwhile, current guideline recommendations on EPD use should be revisited. PMID- 29246913 TI - Postocclusional Hyperemia for Fractional Flow Reserve After Percutaneous Coronary Intervention. AB - BACKGROUND: Postocclusional hyperemia caused by balloon occlusion is a potential alternative method of inducing hyperemia for measuring post-percutaneous coronary intervention fractional flow reserve (FFR). The aim of this study was to investigate postocclusional hyperemia as a method of inducing hyperemia. METHODS AND RESULTS: FFR measured by postocclusional hyperemia (FFRoccl) caused by balloon occlusion after percutaneous coronary intervention was compared with FFR measured by drug-induced hyperemia (FFR measured by intravenous ATP; and FFR measured by intracoronary papaverine injection [FFRpap]) in 98 lesions from 98 patients. The hyperemia duration was also measured for FFRoccl and FFRpap. The correlation coefficient between FFRoccl, FFR measured by intravenous ATP (r=0.973; P<0.01), and FFRpap (r=0.975; P<0.01) showed almost identical values to those obtained for the correlation coefficient between FFR measured by intravenous ATP and FFRpap (r=0.967; P<0.01). No clear difference was observed on Bland-Altman analysis. Hyperemia duration was significantly longer with FFRoccl than with FFRpap (70+/-22 versus 51+/-25 s; P<0.01). CONCLUSIONS: Strong correlations were found between FFRoccl and FFR measured by intravenous ATP and FFRoccl and FFRpap. Hyperemia caused by FFRoccl was significantly longer than that caused by FFRpap. PMID- 29246914 TI - Successful Percutaneous Mitral Paravalvular Leak Closure Is Associated With Improved Midterm Survival. AB - BACKGROUND: Percutaneous closure of prosthetic mitral valve paravalvular leak (PVL) has emerged as an alternative to surgical treatment in high-risk patients. Limited data exist on the impact of successful percutaneous PVL closure on midterm outcomes. METHODS AND RESULTS: We examined consecutive patients who underwent percutaneous mitral PVL closure at Mayo Clinic, Rochester, MN, between January 2006 and January 2017. Procedural success, in-hospital outcomes, and midterm mortality were assessed. A total of 231 patients underwent percutaneous mitral PVL repair at a mean age of 67+/-12 years. Mean time from mitral valve replacement to percutaneous PVL repair was 1.25 (0.31-7.25) years. One hundred sixty-two patients (70%) had <=mild PVL after the procedure. Compared with those who had >mild residual PVL, patients with <=mild residual PVL had lower rates of repeat surgical interventions (6% versus 17%; P=0.004) and lower all-cause mortality at 30 days (1% versus 14%; P<0.001) and 1 year (15% versus 39%; P<0.001). Survival at 3 years was 61% in patients who had <=mild residual leak and 47% in patients with higher grade of residual PVL (P=0.002). CONCLUSIONS: In a large consecutive cohort of patients undergoing percutaneous mitral PVL closure, successful percutaneous reduction of the PVL to mild or less was associated with significant midterm survival benefit. PMID- 29246915 TI - First-in-Human Implantations of the NaviGate Bioprosthesis in a Severely Dilated Tricuspid Annulus and in a Failed Tricuspid Annuloplasty Ring. PMID- 29246916 TI - EROSION Study (Effective Anti-Thrombotic Therapy Without Stenting: Intravascular Optical Coherence Tomography-Based Management in Plaque Erosion): A 1-Year Follow Up Report. AB - BACKGROUND: The initial EROSION study (Effective Anti-Thrombotic Therapy Without Stenting: Intravascular Optical Coherence Tomography-Based Management in Plaque Erosion) demonstrated that patients with acute coronary syndrome caused by plaque erosion might be stabilized with aspirin and ticagrelor without stenting for <=1 month. However, a long-term evaluation of outcomes is lacking. The aim of this study was to assess whether the initial benefit of noninterventional therapy for patients with acute coronary syndrome caused by plaque erosion is maintained for <=1 year. METHODS AND RESULTS: Among 53 patients who completed clinical follow up, 49 underwent repeat optical coherence tomography imaging at 1 year. Median residual thrombus volume decreased significantly from 1 month to 1 year (0.3 mm3 (0.0-2.0 mm3] versus 0.1 mm3 [0.0-2.0 mm3]; P=0.001). Almost half of the patients (46.9%) had no residual thrombus at 1 year. Minimal effective flow area remained unchanged (2.1 mm2 [1.5-3.8 mm2] versus 2.1 mm2 [1.6-4.0 mm2]; P=0.152). Among 53 patients, 49 (92.5%) remained free from major adverse cardiovascular event for <=1 year: 3 (5.7%) patients required revascularization because of exertional angina and 1 (1.9%) patient had gastrointestinal bleeding. CONCLUSIONS: One-year follow-up optical coherence tomography demonstrated a further decrease in thrombus volume between 1-month and 1-year follow-up. A majority (92.5%) of patients with acute coronary syndrome caused by plaque erosion managed with aspirin and ticagrelor without stenting remained free of major adverse cardiovascular event for <=1 year. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02041650. PMID- 29246917 TI - ACIST-FFR Study (Assessment of Catheter-Based Interrogation and Standard Techniques for Fractional Flow Reserve Measurement). AB - BACKGROUND: Measurement of fractional flow reserve (FFR) to guide coronary revascularization lags despite robust supportive data, partly because of the handling characteristics of traditional coronary pressure wires. An optical pressure-monitoring microcatheter, which can be advanced over a traditional coronary guidewire, facilitates FFR assessment but may underestimate pressure wire-derived FFR. METHODS AND RESULTS: In this prospective, multicenter trial, 169 patients underwent FFR assessment with a pressure wire alone and with a pressure microcatheter over the pressure wire. An independent core laboratory performed quantitative coronary angiography and evaluated all pressure tracings. The primary end point was the bias or difference between the microcatheter FFR and the pressure wire FFR, as assessed by Bland-Altman analysis. The mean difference between the microcatheter and the pressure wire-derived FFR values was -0.022 (95% confidence interval, -0.029 to -0.015). On multivariable analysis, reference vessel diameter (P=0.027) and lesion length (P=0.044) were independent predictors of bias between the 2 FFR measurements. When the microcatheter FFR was added to this model, it was the only independent predictor of bias (P<0.001). The mean FFR value from the microcatheter was significantly lower than from the pressure wire (0.81 versus 0.83; P<0.001). In 3% of cases (95% confidence interval, 1.3%-6.7%), there was clinically meaningful diagnostic discordance, with the FFR from the pressure wire >0.80 and that from the microcatheter <0.75. These findings were similar when including all 210 patients with site-reported paired FFR data. CONCLUSIONS: An optical, pressure-monitoring microcatheter measures lower FFR compared with a pressure wire, but the diagnostic impact appears to be minimal in most cases. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02577484. PMID- 29246919 TI - Should We Care About Short-Term Readmissions After Percutaneous Coronary Intervention? PMID- 29246920 TI - Embolic Protection Devices in Saphenous Vein Graft Intervention: A Stitch in Time Saves Nine. PMID- 29246918 TI - Thirty-Day Readmission Rate and Costs After Percutaneous Coronary Intervention in the United States: A National Readmission Database Analysis. AB - BACKGROUND: The association of short-term readmissions after percutaneous coronary intervention (PCI) on healthcare costs has not been well studied. METHODS AND RESULTS: The Healthcare Cost and Utilization Project National Readmission Database encompassing 722 US hospitals was used to identify index PCI cases in patients >=18 years old. Hierarchical regression analyses were used to examine the factors associated with risk of 30-day readmission and higher cumulative costs. We evaluated 206 869 hospitalized patients who survived to discharge after PCI from January through November 2013 and analyzed readmissions over 30 days after discharge. A total of 24 889 patients (12%) were readmitted within 30 days, with rates ranging from 6% to 17% across hospitals. Among the readmitted patients, 13% had PCI, 2% had coronary artery bypass surgery, and 3% died during the readmission. The most common reasons for readmission included nonspecific chest pain/angina (24%) and heart failure (11%). Mean cumulative costs were higher for those with readmissions ($39 634 versus $22 058; P<0.001). The multivariable analyses showed that readmission increased the log10 cumulative costs by 45% (beta: 0.445; P<0.001). There was no significant difference in cumulative costs by the type of insurance. CONCLUSIONS: In a national sample of inpatient PCI cases, 30-day readmissions were associated with a significant increase in cumulative costs. The majority of readmissions were because of low risk chest pain that did not require any intervention. Ongoing effort is warranted to recognize and mitigate potentially preventable post-PCI readmissions. PMID- 29246922 TI - Challenges for Expanded Use of Transcatheter Aortic Valve Replacement. PMID- 29246921 TI - Antithrombotic Therapy Alone for Plaque Erosion: Ready for a Paradigm Shift in Acute Coronary Syndromes? PMID- 29246923 TI - Non-adherence to treatment with cytoreductive and/or antithrombotic drugs is frequent and associated with an increased risk of complications in patients with polycythemia vera or essential thrombocythemia (OUEST study). AB - The purpose of this study was to identify the incidence, causes and impact of non adherence to oral and subcutaneous chronic treatments for patients with polycythemia vera or essential thrombocythemia. Patients receiving cytoreductive drugs for polycythemia vera or essential thrombocythemia were recruited at our institution (Observatoire Brestois des Neoplasies Myeloproliferatives registry). They completed a one-shot questionnaire designed by investigators (Etude de l'Observance Therapeutique et des Effets Secondaires des Traitements study). Data about complications (thrombosis, transformation and death) at any time in the patient's life (before diagnosis, up until consultation and after the completion of the questionnaire) were collected. Sixty-five (22.7%) of 286 patients reported poor adherence (<90%) to their treatment with cytoreductive drugs and 46/255/18%) also declared non-adherence to antithrombotic drugs. In total, 85/286 patients (29.7%) declared they did not adhere to their treatment. Missing an intake was rare and was mostly due to forgetfulness especially during occupational travel and holidays. Patients who did not adhere to their treatment were characterized by younger age, living alone, having few medications but a high numbers of pills and determining their own schedule of drug intake. Having experienced thrombosis or hematologic evolution did not influence the adherence rate. Non-adherence to oral therapy was associated with a higher risk of phenotypic evolution (7.3 versus 1.8%, P=0.05). For patients treated for polycythemia vera or essential thrombocythemia, non-adherence to cytoreductive and/or antithrombotic therapies is frequent and is influenced by age, habitus and concomitant treatments, but not by disease history or treatment side effects. Phenotypic evolution seems to be more frequent in the non-adherent group. PMID- 29246924 TI - The prothrombotic state in paroxysmal nocturnal hemoglobinuria: a multifaceted source. AB - Paroxysmal nocturnal hemoglobinuria is a rare acquired hematologic disorder, the most serious complication of which is thrombosis. The increased incidence of thrombosis in paroxysmal nocturnal hemoglobinuria is still poorly understood, but unlike many other thrombotic disorders, predominantly involves complement mediated mechanisms. This review article discusses the different factors that contribute to the increased risk of thrombosis in paroxysmal nocturnal hemoglobinuria. Paroxysmal nocturnal hemoglobinuria leads to a complex and multifaceted prothrombotic state due to the pathological effects of platelet activation, intravascular hemolysis and neutrophil/monocyte activation. Platelet and endothelial microparticles as well as oxidative stress may play a role. Impaired fibrinolysis has also been observed and may be caused by several mechanisms involving interactions between complement activation, coagulation and fibrinolysis. While many factors may affect thrombosis in paroxysmal nocturnal hemoglobinuria, the relative contribution of each mechanism that has been implicated is difficult to quantify. Further studies, including novel in vivo and in vitro thrombosis models, are required in order to define the role of the individual mechanisms contributing to thrombosis, impaired fibrinolysis and clarify other complement-driven prothrombotic mechanisms in paroxysmal nocturnal hemoglobinuria. PMID- 29246925 TI - Abeta mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer's disease. AB - Dendritic spine loss is recognized as an early feature of Alzheimer's disease (AD), but the underlying mechanisms are poorly understood. Dendritic spine structure is defined by filamentous actin (F-actin) and we observed depolymerization of synaptosomal F-actin accompanied by increased globular-actin (G-actin) at as early as 1 month of age in a mouse model of AD (APPswe/PS1DeltaE9, male mice). This led to recall deficit after contextual fear conditioning (cFC) at 2 months of age in APPswe/PS1DeltaE9 male mice, which could be reversed by the actin-polymerizing agent jasplakinolide. Further, the F-actin depolymerizing agent latrunculin induced recall deficit after cFC in WT mice, indicating the importance of maintaining F-/G-actin equilibrium for optimal behavioral response. Using direct stochastic optical reconstruction microscopy (dSTORM), we show that F-actin depolymerization in spines leads to a breakdown of the nano-organization of outwardly radiating F-actin rods in cortical neurons from APPswe/PS1DeltaE9 mice. Our results demonstrate that synaptic dysfunction seen as F-actin disassembly occurs very early, before onset of pathological hallmarks in AD mice, and contributes to behavioral dysfunction, indicating that depolymerization of F-actin is causal and not consequent to decreased spine density. Further, we observed decreased synaptosomal F-actin levels in postmortem brain from mild cognitive impairment and AD patients compared with subjects with normal cognition. F-actin decrease correlated inversely with increasing AD pathology (Braak score, Abeta load, and tangle density) and directly with performance in episodic and working memory tasks, suggesting its role in human disease pathogenesis and progression.SIGNIFICANCE STATEMENT Synaptic dysfunction underlies cognitive deficits in Alzheimer's disease (AD). The cytoskeletal protein actin plays a critical role in maintaining structure and function of synapses. Using cultured neurons and an AD mouse model, we show for the first time that filamentous actin (F-actin) is lost selectively from synapses early in the disease process, long before the onset of classical AD pathology. We also demonstrate that loss of synaptic F-actin contributes directly to memory deficits. Loss of synaptosomal F-actin in human postmortem tissue correlates directly with decreased performance in memory test and inversely with AD pathology. Our data highlight that synaptic cytoarchitectural changes occur early in AD and they may be targeted for the development of therapeutics. PMID- 29246927 TI - Disruption of Interneuron Neurogenesis in Premature Newborns and Reversal with Estrogen Treatment. AB - Many Preterm-born children suffer from neurobehavioral disorders. Premature birth terminates the hypoxic in utero environment and supply of maternal hormones. As the production of interneurons continues until the end of pregnancy, we hypothesized that premature birth would disrupt interneuron production and that restoration of the hypoxic milieu or estrogen treatment might reverse interneuron generation. To test these hypotheses, we compared interneuronal progenitors in the medial ganglionic eminences (MGEs), lateral ganglionic eminences (LGEs), and caudal ganglionic eminences (CGEs) between preterm-born [born on embryonic day (E) 29; examined on postnatal day (D) 3 and D7] and term-born (born on E32; examined on D0 and D4) rabbits at equivalent postconceptional ages. We found that both total and cycling Nkx2.1+, Dlx2+, and Sox2+ cells were more abundant in the MGEs of preterm rabbits at D3 compared with term rabbits at D0, but not in D7 preterm relative to D4 term pups. Total Nkx2.1+ progenitors were also more numerous in the LGEs of preterm pups at D3 compared with term rabbits at D0. Dlx2+ cells in CGEs were comparable between preterm and term pups. Simulation of hypoxia by dimethyloxalylglycine treatment did not affect the number of interneuronal progenitors. However, estrogen treatment reduced the density of total and proliferating Nkx2.1+ and Dlx2+ cells in the MGEs and enhanced Ascl1 transcription factor. Estrogen treatment also reduced Ki67, c-Myc, and phosphorylation of retinoblastoma protein, suggesting inhibition of the G1-to-S phase transition. Hence, preterm birth disrupts interneuron neurogenesis in the MGE and estrogen treatment reverses interneuron neurogenesis in preterm newborns by cell-cycle inhibition and elevation of Ascl1. We speculate that estrogen replacement might partially restore neurogenesis in human premature infants.SIGNIFICANCE STATEMENT Prematurity results in developmental delays and neurobehavioral disorders, which might be ascribed to disturbances in the development of cortical interneurons. Here, we show that preterm birth disrupts interneuron neurogenesis in the medial ganglionic eminence (MGE) and, more importantly, that estrogen treatment reverses this perturbation in the population of interneuron progenitors in the MGE. The estrogen seems to restore neurogenesis by inhibiting the cell cycle and elevating Ascl1 expression. As preterm birth causes plasma estrogen level to drop 100-fold, the estrogen replacement in preterm infants is physiological. We speculate that estrogen replacement might ameliorate disruption in production of interneurons in human premature infants. PMID- 29246926 TI - Combined Active Humoral and Cellular Immunization Approaches for the Treatment of Synucleinopathies. AB - Dementia with Lewy bodies, Parkinson's disease, and Multiple System Atrophy are age-related neurodegenerative disorders characterized by progressive accumulation of alpha-synuclein (alpha-syn) and jointly termed synucleinopathies. Currently, no disease-modifying treatments are available for these disorders. Previous preclinical studies demonstrate that active and passive immunizations targeting alpha-syn partially ameliorate behavioral deficits and alpha-syn accumulation; however, it is unknown whether combining humoral and cellular immunization might act synergistically to reduce inflammation and improve microglial-mediated alpha syn clearance. Since combined delivery of antigen plus rapamycin (RAP) in nanoparticles is known to induce antigen-specific regulatory T cells (Tregs), we adapted this approach to alpha-syn using the antigen-presenting cell-targeting glucan microparticle (GP) vaccine delivery system. PDGF-alpha-syn transgenic (tg) male and female mice were immunized with GP-alone, GP-alpha-syn (active humoral immunization), GP+RAP, or GP+RAP/alpha-syn (combined active humoral and Treg) and analyzed using neuropathological and biochemical markers. Active immunization resulted in higher serological total IgG, IgG1, and IgG2a anti-alpha-syn levels. Compared with mice immunized with GP-alone or GP-alpha-syn, mice vaccinated with GP+RAP or GP+RAP/alpha-syn displayed increased numbers of CD25-, FoxP3-, and CD4 positive cells in the CNS. GP-alpha-syn or GP+RAP/alpha-syn immunizations resulted in a 30-45% reduction in alpha-syn accumulation, neuroinflammation, and neurodegeneration. Mice immunized with GP+RAP/alpha-syn further rescued neurons and reduced neuroinflammation. Levels of TGF-beta1 were increased with GP+RAP/alpha-syn immunization, while levels of TNF-alpha and IL-6 were reduced. We conclude that the observed effects of GP+RAP/alpha-syn immunization support the hypothesis that cellular immunization may enhance the effects of active immunotherapy for the treatment of synucleinopathies.SIGNIFICANCE STATEMENT We show that a novel vaccination modality combining an antigen-presenting cell targeting glucan particle (GP) vaccine delivery system with encapsulated antigen (alpha-synuclein) + rapamycin (RAP) induced both strong anti-alpha-synuclein antibody titers and regulatory T cells (Tregs). This vaccine, collectively termed GP+RAP/alpha-syn, is capable of triggering neuroprotective Treg responses in synucleinopathy models, and the combined vaccine is more effective than the humoral or cellular immunization alone. Together, these results support the further development of this multifunctional vaccine approach for the treatment of synucleinopathies, such as Parkinson's disease, dementia with Lewy bodies, and multiple systems atrophy. PMID- 29246928 TI - Identification of miR-29b targets using 3-cyanovinylcarbazole containing mimics. AB - MicroRNAs (miRNAs) are highly conserved ~22 nt small noncoding RNAs that bind partially complementary sequences in target transcripts. MicroRNAs regulate both translation and transcript stability, and play important roles in development, cellular homeostasis, and disease. There are limited approaches available to agnostically identify microRNA targets transcriptome-wide, and methods using miRNA mimics, which in principle identify direct miRNA:transcript pairs, have low sensitivity and specificity. Here, we describe a novel method to identify microRNA targets using miR-29b mimics containing 3-cyanovinylcarbazole (CNVK), a photolabile nucleoside analog. We demonstrate that biotin-tagged, CNVK-containing miR-29b (CNVK-miR-29b) mimics are nontoxic in cell culture, associate with endogenous mammalian Argonaute2, are sensitive for known targets and recapitulate endogenous transcript destabilization. Partnering CNVK-miR-29b with ultra-low input RNA sequencing, we recover ~40% of known miR-29b targets and find conservation of the focal adhesion and apoptotic target pathways in mouse and human. We also identify hundreds of novel targets, including NRAS, HOXA10, and KLF11, with a validation rate of 71% for a subset of 73 novel target transcripts interrogated using a high-throughput luciferase assay. Consistent with previous reports, we show that both endogenous miR-29b and CNVK-miR-29b are trafficked to the nucleus, but find no evidence of nuclear-specific miR-29b transcript binding. This may indicate that miR-29b nuclear sequestration is a regulatory mechanism in itself. We suggest that CNVK-containing small RNA mimics may find applicability in other experimental models. PMID- 29246929 TI - Sarcoidosis-lymphoma syndrome: a diagnostic dilemma. AB - Sarcoidosis and lymphoma are generally thought of as being two mutually exclusive diseases that need to be considered in the differential diagnosis of patients with hilar/mediastianal lymphadenopathy. However, there are rare patients in whom both of these diseases coexist. These patients constitute a diagnostic challenge because their presentation (ie, clinical symptoms, imaging abnormalities and even pathology) may all be atypical when each individual disease is considered separately. In this report, we describe a patient who presented with such atypical features and was eventually diagnosed as having both sarcoidosis and a B cell lymphoma with features of splenic marginal zone lymphoma (SMZL) simultaneously. To our knowledge, this is only the second reported case of SMZL and sarcoidosis in the same patient. PMID- 29246930 TI - Congenital scoliosis: an anomalous association with endosulfan. AB - Endosulfan is an organochlorine pesticide that is used extensively across the world to kill insects. Incidence of acute and chronic toxicity with endosulfan poisoning has been reported, and nearly 80 countries have banned its use. However, it is still being used in many low-income/middle-income countries. One of the most severe tragedies because of endosulfan poisoning has taken place in the Indian state of Kerala due to persistent aerial spraying of endosulfan. Even though there are reports of skeletal and other congenital abnormalities in humans and experimental animals following exposure to endosulfan, very few have been documented. We report two cases of congenital scoliosis in siblings living in a community affected by high levels of endosulfan in the environment. High index of suspicion is essential during the screening of school children exposed to endosulfan. Congenital scoliosis is a progressive deformity that leads to severe disability, unless detected and corrected at an early stage. PMID- 29246931 TI - Periosteal desmoid tumour: a rare finding in the oral cavity. AB - A 55-year-old female patient reported with an intraoral well-localised asymptomatic swelling on the right side of the mandible in relation to the right mandibular first molar along with a history of trauma 6 months back. Panoramic radiograph revealed normal trabecular bone pattern in relation to the lesion. The lesion was excised along with the associated buccal cortical plate and tooth. The microscopic examination revealed a well-circumscribed lesion consisting of spindle cells arranged in storiform pattern associated with the buccal cortical plate. The key feature to note was presence of reactive periosteum, which was in continuum with the lesion. Immunohistochemistry (IHC) revealed faint nuclear positivity for beta-catenin. The above findings led to our diagnosis of periosteal desmoid, which is rarely reported in the head-and-neck region. The major challenge in the diagnosis of such lesions is good clinicopathological correlation as the differential diagnosis of spindle-cell lesions is vast and needs IHC confirmation. PMID- 29246932 TI - Stent extrusion on the external surface of the transplanted kidney: unusual occurrence. AB - Here we present the case of a 40-year-old man, who underwent deceased donor renal transplantation. Towards the end of this operation, open-ended double J stent was inserted in the transplanted kidney. Modified Lich-Gregoir ureterovesical anastomosis was performed. Prior to the abdominal closure, it was discovered that proximal end of the stent had pierced the renal parenchyma and extruded on the external surface of the transplanted kidney. We contemplated removing the stent and reinserting it but decided against that due to various reasons. The stent was left as such. The patient was managed conservatively with satisfactory outcome in the postoperative period. To the best of our knowledge, this is first such report of conservative management of stent extrusion in transplanted kidney in the literature. PMID- 29246933 TI - Iatrogenic propagation of coronary dissection during diagnostic coronary angiography: an uncommon but important procedural consideration. AB - Spontaneous coronary artery dissection is an uncommon cause of acute myocardial infarction in the general population but is relatively more common in the peripartum period. Regardless of clinical setting, the management strategy is individualised, ranging from conservative to invasive. We report a case of peripartum myocardial infarction due to spontaneous coronary dissection that propagated during diagnostic angiography and ultimately required emergent bypass surgery. PMID- 29246934 TI - Left ventricular pseudoaneurysm formation in a patient presenting with a subacute myocardial infarction. AB - Left ventricular pseudoaneurysm is a rare mechanical complication of acute myocardial infarction. In the present case, an 80-year-old man presenting with a subacute non-ST segment elevation myocardial infarction was found to have an occluded second obtuse marginal branch of the left circumflex coronary artery. Following the implantation of two drug-eluting stents, the patient developed no reflow phenomenon. Coronary angiography 6 weeks later revealed persistence of the no-reflow phenomenon. During the left ventriculogram, a massive pseudoaneurysm was diagnosed and the patient successfully underwent emergency surgery. The persistence of no-reflow was likely due to the fact that the myocardial territory supplied by the infarct-related artery was completely necrosed resulting in persistent flow impairment through the vessel. PMID- 29246935 TI - Cocaine-induced pseudo-Wellens' syndrome: a Wellens' phenocopy. AB - Wellens' syndrome represents critical occlusion of the proximal left anterior descending coronary artery. Electrocardiographic changes similar to Wellens' wave are not exceptional to acute coronary occlusion and can also be seen in cardiac and non-cardiac conditions, such as left ventricular hypertrophy, persistent juvenile T wave, bundle branch blocks, cerebral haemorrhage, pulmonary oedema, pulmonary embolism, pheochromocytoma, Takotsubo syndrome, digitalis and cocaine induced coronary vasospasm. Cocaine-induced pseudo-Wellens' syndrome should be considered as one of the differentials, since cocaine is used frequently by young adults and can cause left anterior descending coronary vasospasm mimicking Wellens' syndrome. Initiation of the beta-blocking agent in pseudo-Wellens' syndrome as a part of acute coronary syndrome management can be disastrous. We illustrated a case of cocaine-induced pseudo-Wellens' syndrome presented with typical chest pain associated with Wellenoid ECG. PMID- 29246936 TI - Pneumatosis intestinalis with extensive intrahepatic portal venous gas secondary to intra-abdominal sepsis: a rare occurrence. PMID- 29246937 TI - Genome-Wide Association Study Identifies a New Locus at 7q21.13 Associated with Hepatitis B Virus-Related Hepatocellular Carcinoma. AB - Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In this study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC.Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls.Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, OR = 1.28, P = 9.46 * 10-10). Furthermore, we observed that the at risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10272859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients.Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus. Clin Cancer Res; 24(4); 906-15. (c)2017 AACR. PMID- 29246938 TI - Ipilimumab plus Lenalidomide after Allogeneic and Autologous Stem Cell Transplantation for Patients with Lymphoid Malignancies. AB - Purpose: Prevention or treatment of relapsed lymphoid malignancies after hematopoietic stem cell transplantation (HSCT) requires novel strategies. We hypothesized that antitumor-cell responses could be enhanced by the addition of lenalidomide to the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab.Experimental Design: We conducted a phase II investigator-initiated trial to assess the safety and activity of ipilimumab and lenalidomide in patients with lymphoid malignancies that relapsed after allogeneic HSCT and in high-risk patients after autologous HSCT. Patients received 10 mg of oral lenalidomide daily for 21 days followed by intravenous ipilimumab at 3 mg/kg bodyweight. The regimen was repeated 4 weeks later for a total of four treatments.Results: We enrolled 17 patients (10 allogeneic and seven autologous transplant recipients). Immune-mediated toxicity was limited to one patient with asymptomatic hypothyroidism and one with dermatitis in the allogeneic and autologous groups, respectively. One allogeneic transplant recipient had a flare of prior GVHD while taking lenalidomide that precluded further treatment. All others finished treatment without GVHD. Four of 10 patients in the allogeneic group had complete responses (three of which were durable at 19+, 21+, and 32+ months), and three had partial responses. The disease in six of seven patients in the autologous group remains in remission. The groups had similar immune responses, including a two- to threefold increase in inducible ICOS+CD4+FoxP3- T cell number.Conclusions: Our early-phase data suggested that ipilimumab plus lenalidomide is well tolerated after HSCT. Adverse events did not differ significantly between the allogeneic and autologous groups. Clin Cancer Res; 24(5); 1011-8. (c)2017 AACR. PMID- 29246939 TI - Merkel Cell Carcinoma Patients Presenting Without a Primary Lesion Have Elevated Markers of Immunity, Higher Tumor Mutation Burden, and Improved Survival. AB - Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared with similarly staged patients with known primary lesions (MCC KP). The basis of this previously reported finding is unclear.Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole-exome sequence data were analyzed from 16 tumors.Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared with MCC-KP patients (HR, 0.297; P < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR, 0.296; P = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (P < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; P < 0.001). In addition, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, P = 0.016).Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. In addition, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival. Clin Cancer Res; 24(4); 963-71. (c)2017 AACR. PMID- 29246940 TI - HSP27-Mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemoresistance in Squamous Cell Carcinoma of Tongue. AB - Purpose: Squamous cell carcinoma of tongue (SCCT) is the most common type of oral cavity carcinoma. Chemoresistance in SCCT is common, and the underlying mechanism remains largely unknown. We aimed to identify key molecules and signaling pathways mediating chemoresistance in SCCT.Experimental Design: Using a proteomic approach, we found that the HSP27 was a potential mediator for chemoresistance in SCCT cells. To further validate this role of HSP27, we performed various mechanistic studies using in vitro and in vivo models as well as serum and tissue samples from SCCT patients.Results: The HSP27 protein level was significantly increased in the multidrug-resistant SCCT cells and cell culture medium. Both HSP27 knockdown and anti-HSP27 antibody treatment reversed chemoresistance. Inversely, both HSP27 overexpression and recombinant human HSP27 protein treatment enhanced chemoresistance. Moreover, chemotherapy significantly induced HSP27 protein expression in both SCCT cells and their culture medium, as well as in tumor tissues and serum of SCCT patients. HSP27 overexpression predicts a poor outcome for SCCT patients receiving chemotherapy. Mechanically, extracellular HSP27 binds to TLR5 and then activates NF-kappaB signaling to maintain SCCT cell survival. TLR5 knockdown or restored IkappaBalpha protein level disrupts extracellular HSP27-induced NF-kappaB transactivation and chemoresistance. Moreover, intracellular HSP27 binds to BAX and BIM to repress their translocation to mitochondrion and subsequent cytochrome C release upon chemotherapy, resulting in inhibition of the mitochondrial apoptotic pathway.Conclusions: HSP27 plays a pivotal role in chemoresistance of SCCT cells via a synergistic extracellular and intracellular signaling. HSP27 may represent a potential biomarker and therapeutic target for precision SCCT treatment. Clin Cancer Res; 24(5); 1163-75. (c)2017 AACR. PMID- 29246941 TI - Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor. AB - Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) 18F FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib treated GIST is largely unknown.Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed.Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In KitV558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib.Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST, and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST. Clin Cancer Res; 24(4); 972-84. (c)2017 AACR. PMID- 29246943 TI - Tight junctions negatively regulate mechanical forces applied to adherens junctions in vertebrate epithelial tissue. AB - Epithelia are layers of polarised cells tightly bound to each other by adhesive contacts. Epithelia act as barriers between an organism and its external environment. Understanding how epithelia maintain their essential integrity while remaining sufficiently plastic to allow events such as cytokinesis to take place is a key biological problem. In vertebrates, the remodelling and reinforcement of adherens junctions maintains epithelial integrity during cytokinesis. The involvement of tight junctions in cell division, however, has remained unexplored. Here, we examine the role of tight junctions during cytokinesis in the epithelium of the Xenopus laevis embryo. Depletion of the tight junction associated proteins ZO-1 and GEF-H1 leads to altered cytokinesis duration and contractile ring geometry. Using a tension biosensor, we show that cytokinesis defects originate from misregulation of tensile forces applied to adherens junctions. Our results reveal that tight junctions regulate mechanical tension applied to adherens junctions, which in turn impacts cytokinesis.This article has an associated First Person interview with the first author of the paper. PMID- 29246944 TI - EFA6 proteins regulate lumen formation through alpha-actinin 1. AB - A key step of epithelial morphogenesis is the creation of the lumen. Luminogenesis by hollowing proceeds through the fusion of apical vesicles at cell cell contacts. The small nascent lumens grow through extension, coalescence and enlargement, coordinated with cell division, to give rise to a single central lumen. Here, by using MDCK cells grown in 3D-culture, we show that EFA6A (also known as PSD) participates in luminogenesis. EFA6A recruits alpha-actinin 1 (ACTN1) through direct binding. In polarized cells, ACTN1 was found to be enriched at the tight junction where it acts as a primary effector of EFA6A for normal luminogenesis. Both proteins are essential for the lumen extension and enlargement, where they mediate their effect by regulating the cortical acto myosin contractility. Finally, ACTN1 was also found to act as an effector for the isoform EFA6B (also known as PSD4) in the human mammary tumoral MCF7 cell line. EFA6B restored the glandular morphology of this tumoral cell line in an ACTN1 dependent manner. Thus, we identified new regulators of cyst luminogenesis essential for the proper maturation of a newly-formed lumen into a single central lumen. PMID- 29246942 TI - Synergistic Targeting of the Regulatory and Catalytic Subunits of PI3Kdelta in Mature B-cell Malignancies. AB - Purpose: Aberrant activation of the B-cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kdelta. These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here, we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, toward identifying a novel mechanism-based combinatorial strategy to attack BCR dependency in mature B-cell malignancies.Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to preclinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were used to map multiple signaling intermediaries downstream of the BCR.Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK.Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR dependent malignancies is warranted. Clin Cancer Res; 24(5); 1103-13. (c)2017 AACR. PMID- 29246945 TI - Psychiatrist who saw patients after being told to stop practising is struck off. PMID- 29246947 TI - GAPs in early life facilitate immune tolerance. AB - Goblet cells deliver microbial antigens to generate regulatory T cells before and during weaning to induce long-term tolerance to symbionts. PMID- 29246948 TI - Correction: FOXP1-related intellectual disability syndrome: a recognisable entity. PMID- 29246946 TI - Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria. AB - We have a mutually beneficial relationship with the trillions of microorganisms inhabiting our gastrointestinal tract. However, maintaining this relationship requires recognizing these organisms as affable and restraining inflammatory responses to these organisms when encountered in hostile settings. How and when the immune system develops tolerance to our gut microbial members is not well understood. We identify a specific preweaning interval in which gut microbial antigens are encountered by the immune system to induce antigen-specific tolerance to gut bacteria. For some bacterial taxa, physiologic encounters with the immune system are restricted to this interval, despite abundance of these taxa in the gut lumen at later times outside this interval. Antigen-specific tolerance to gut bacteria induced during this preweaning interval is stable and maintained even if these taxa are encountered later in life in an inflammatory setting. However, inhibiting microbial antigen encounter during this interval or extending these encounters beyond the normal interval results in a failure to induce tolerance and robust antigen-specific effector responses to gut bacteria upon reencounter in an inflammatory setting. Thus, we have identified a defined preweaning interval critical for developing tolerance to gut bacteria and maintaining the mutually beneficial relationship with our gut microbiota. PMID- 29246949 TI - Five-Year Cost-effectiveness of the Multidisciplinary Risk Assessment and Management Programme-Diabetes Mellitus (RAMP-DM). AB - OBJECTIVE: To estimate the cost-effectiveness of the multidisciplinary Risk Assessment and Management Programme-Diabetes Mellitus (RAMP-DM) in primary care patients with type 2 diabetes in comparison with usual primary care in a cohort with 5 years' follow-up. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study among 17,140 propensity score-matched participants in RAMP-DM and those under usual primary care. The effectiveness measures were cumulative incidences of complications and all-cause mortality over 5 years. In a bottom-up approach, we estimated the program costs of RAMP-DM and health service utilization from the public health service provider's perspective. The RAMP-DM program costs included the setup costs, ongoing intervention costs, and central administrative costs. We calculated the incremental cost-effectiveness ratio by dividing the incremental costs by the incremental effectiveness of the RAMP-DM group compared with those of the usual-care group. RESULTS: There were significantly lower cumulative incidences of individual on any complications (15.34% vs. 28.65%, P < 0.001) and all-cause mortality (7.96% vs. 21.35%, P < 0.001) in the RAMP-DM group compared with the usual-care group. The mean program cost of RAMP-DM was 157 U.S. dollars (range 66-209) per participant over 5 years. The costs of health service utilization among participants in RAMP-DM group was 7,451 USD less than that of the usual-care group, resulting in a net savings of 7,294 USD per individual. CONCLUSIONS: RAMP-DM added to usual primary care was a cost-saving intervention in managing diabetes in patients over 5 years. These findings support the integration of RAMP-DM as part of routine primary care for all patients with diabetes. PMID- 29246950 TI - Efficacy and Safety of Once-Weekly Semaglutide Versus Exenatide ER in Subjects With Type 2 Diabetes (SUSTAIN 3): A 56-Week, Open-Label, Randomized Clinical Trial. AB - OBJECTIVE: To compare the efficacy and safety of once-weekly semaglutide 1.0 mg s.c. with exenatide extended release (ER) 2.0 mg s.c. in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this phase 3a, open-label, parallel group, randomized controlled trial, 813 subjects with type 2 diabetes taking oral antidiabetic drugs were randomized (1:1) to semaglutide 1.0 mg or exenatide ER 2.0 mg for 56 weeks. The primary end point was change from baseline in HbA1c at week 56. RESULTS: Mean HbA1c (8.3% [67.7 mmol/mol] at baseline) was reduced by 1.5% (16.8 mmol/mol) with semaglutide and 0.9% (10.0 mmol/mol) with exenatide ER (estimated treatment difference vs. exenatide ER [ETD] -0.62% [95% CI -0.80, 0.44] [-6.78 mmol/mol (95% CI -8.70, -4.86)]; P < 0.0001 for noninferiority and superiority). Mean body weight (95.8 kg at baseline) was reduced by 5.6 kg with semaglutide and 1.9 kg with exenatide ER (ETD -3.78 kg [95% CI -4.58, -2.98]; P < 0.0001). Significantly more subjects treated with semaglutide (67%) achieved HbA1c <7.0% (<53 mmol/mol) versus those taking exenatide ER (40%). Both treatments had similar safety profiles, but gastrointestinal adverse events were more common in semaglutide-treated subjects (41.8%) than in exenatide ER-treated subjects (33.3%); injection-site reactions were more frequent with exenatide ER (22.0%) than with semaglutide (1.2%). CONCLUSIONS: Semaglutide 1.0 mg was superior to exenatide ER 2.0 mg in improving glycemic control and reducing body weight after 56 weeks of treatment; the drugs had comparable safety profiles. These results indicate that semaglutide treatment is highly effective for subjects with type 2 diabetes who are inadequately controlled on oral antidiabetic drugs. PMID- 29246951 TI - Metformin Mediates Protection against Legionella Pneumonia through Activation of AMPK and Mitochondrial Reactive Oxygen Species. AB - In Legionella pneumophila infection, macrophages play a critical role in the host defense response. Metformin, an oral drug for type 2 diabetes, is attracting attention as a new supportive therapy against a variety of diseases, such as cancer and infectious diseases. The novel mechanisms for metformin actions include modulation of the effector functions of macrophages and other host immune cells. In this study, we have examined the effects of metformin on L. pneumophila infection in vitro and in vivo. Metformin treatment suppressed growth of L. pneumophila in a time- and concentration-dependent fashion in bone marrow-derived macrophages, RAW cells (mouse), and U937 cells (human). Metformin induced phosphorylation of AMP-activated protein kinase (AMPK) in L. pneumophila-infected bone marrow-derived macrophages, and the AMPK inhibitor Compound C negated metformin-mediated growth suppression. Also, metformin induced mitochondrial reactive oxygen species but not phagosomal NADPH oxidase-derived reactive oxygen species. Metformin-mediated growth suppression was mitigated in the presence of the reactive oxygen species scavenger glutathione. In a murine L. pneumophila pneumonia model, metformin treatment improved survival of mice, which was associated with a significant reduction in bacterial number in the lung. Similar to in vitro observations, induction of AMPK phosphorylation and mitochondrial ROS was demonstrated in the infected lungs of mice treated with metformin. Finally, glutathione treatment abolished metformin effects on lung bacterial clearance. Collectively, these data suggest that metformin promotes mitochondrial ROS production and AMPK signaling and enhances the bactericidal activity of macrophages, which may contribute to improved survival in L. pneumophila pneumonia. PMID- 29246952 TI - Cutting Edge: CCR2 Is Not Required for Ly6Chi Monocyte Egress from the Bone Marrow but Is Necessary for Migration within the Brain in La Crosse Virus Encephalitis. AB - Inflammatory monocyte (iMO) recruitment to the brain is a hallmark of many neurologic diseases. Prior to entering the brain, iMOs must egress into the blood from the bone marrow through a mechanism, which for known encephalitic viruses, is CCR2 dependent. In this article, we show that during La Crosse Virus-induced encephalitis, egress of iMOs was surprisingly independent of CCR2, with similar percentages of iMOs in the blood and brain of heterozygous and CCR2-/- mice following infection. Interestingly, CCR2 was required for iMO trafficking from perivascular areas to sites of virus infection within the brain. Thus, CCR2 was not essential for iMO trafficking to the blood or the brain but was essential for trafficking within the brain parenchyma. Analysis of other orthobunyaviruses showed that Jamestown Canyon virus also induced CCR2-independent iMO egress to the blood. These studies demonstrate that the CCR2 requirement for iMO egress to the blood is not universal for all viruses. PMID- 29246953 TI - Ca2+-Dependent Regulation of NFATc1 via KCa3.1 in Inflammatory Osteoclastogenesis. AB - In inflammatory arthritis, the dysregulation of osteoclast activity by proinflammatory cytokines, including TNF, interferes with bone remodeling during inflammation through Ca2+-dependent mechanisms causing pathological bone loss. Ca2+-dependent CREB/c-fos activation via Ca2+-calmodulin kinase IV (CaMKIV) induces transcriptional regulation of osteoclast-specific genes via NFATc1, which facilitate bone resorption. In leukocytes, Ca2+ regulation of NFAT-dependent gene expression oftentimes involves the activity of the Ca2+-activated K+ channel KCa3.1. In this study, we evaluate KCa3.1 as a modulator of Ca2+-induced NFAT dependent osteoclast differentiation in inflammatory bone loss. Microarray analysis of receptor activator of NF-kappaB ligand (RANKL)-activated murine bone marrow macrophage (BMM) cultures revealed unique upregulation of KCa3.1 during osteoclastogenesis. The expression of KCa3.1 in vivo was confirmed by immunofluorescence staining on multinucleated cells at the bone surface of inflamed mouse joints. Experiments on in vitro BMM cultures revealed that KCa3.1 /- and TRAM-34 treatment significantly reduced the expression of osteoclast specific genes (p < 0.05) alongside decreased osteoclast formation (p < 0.0001) in inflammatory (RANKL+TNF) and noninflammatory (RANKL) conditions. In particular, live cell Ca2+ imaging and Western blot analysis showed that TRAM-34 pretreatment decreased transient RANKL-induced Ca2+ amplitudes in BMMs by ~50% (p < 0.0001) and prevented phosphorylation of CaMKIV. KCa3.1-/- reduced RANKL+/-TNF stimulated phosphorylation of CREB and expression of c-fos in BMMs (p < 0.01), culminating in decreased NFATc1 protein expression and transcriptional activity (p < 0.01). These data indicate that KCa3.1 regulates Ca2+-dependent NFATc1 expression via CaMKIV/CREB during inflammatory osteoclastogenesis in the presence of TNF, corroborating its role as a target candidate for the treatment of bone erosion in inflammatory arthritis. PMID- 29246954 TI - Immunoregulatory Activity of the Natural Product Laminarin Varies Widely as a Result of Its Physical Properties. AB - Ligation of Dectin-1 by fungal glucans elicits a Th17 response that is necessary for clearing many fungal pathogens. Laminarin is a (1->3, 1->6)-beta-glucan that is widely reported to be a Dectin-1 antagonist, however, there are reports that laminarin is also a Dectin-1 agonist. To address this controversy, we assessed the physical properties, structure, purity, Dectin-1 binding, and biological activity of five different laminarin preparations from three different commercial sources. The proton nuclear magnetic resonance analysis indicated that all of the preparations contained laminarin although their molecular mass varied considerably (4400-34,400 Da). Two of the laminarins contained substantial quantities of very low m.w. compounds, some of which were not laminarin. These low m.w. moieties could be significantly reduced by extensive dialysis. All of the laminarin preparations were bound by recombinant human Dectin-1 and mouse Dectin-1, but the affinity varied considerably, and binding affinity did not correlate with Dectin-1 agonism, antagonism, or potency. In both human and mouse cells, two laminarins were Dectin-1 antagonists and two were Dectin-1 agonists. The remaining laminarin was a Dectin-1 antagonist, but when the low m.w. moieties were removed, it became an agonist. We were able to identify a laminarin that is a Dectin-1 agonist and a laminarin that is Dectin-1 antagonist, both of which are relatively pure preparations. These laminarins may be useful in elucidating the structure and activity relationships of glucan/Dectin-1 interactions. Our data demonstrate that laminarin can be either a Dectin-1 antagonist or agonist, depending on the physicochemical properties, purity, and structure of the laminarin preparation employed. PMID- 29246955 TI - A BET Bromodomain Inhibitor Suppresses Adiposity-Associated Malignant Transformation. AB - Almost half a million of all new cancers have been attributed to obesity and epidemiologic evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed an HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes, including c-Myc; however, their chemopreventive activity is unknown. We show herein that mice with visceral adiposity have elevated nuclear c-Myc expression in their epidermis. We hypothesized that the bromodomain inhibitor I BET-762 (I-BET) would have efficacy in the prevention of malignant transformation by VAT and FGF2. We tested this hypothesis using our novel models of VAT stimulated transformation in vitro and FGF2- stimulated tumor formation in vivo We found that I-BET significantly attenuates VAT and FGF2-stimulated transformation and inhibits VAT-induced c-Myc protein expression in several skin and breast epithelial cell lines. Moreover, I-BET attenuated tumor growth significantly in FGF2-treated nude mice. Work is ongoing to determine the role of visceral adiposity in c-Myc activity in several tissues and determine the inhibitory effect of I-BET on VAT-promoted tumors in vivoCancer Prev Res; 11(3); 129-42. (c)2017 AACRSee related editorial by Berger and Scacheri, p. 125. PMID- 29246956 TI - Marshaling the Translational Potential of MC1R for Precision Risk Assessment of Melanoma. AB - Melanoma rates have been increasing in the United States, and neither primary (sun protection and avoidance) nor secondary (skin examination) prevention is practiced consistently, even by those with melanoma risk factors. Inherited variation at MC1R is a robust marker for increased risk of melanoma, even among individuals with "sun-resistant" phenotypes. Although MC1R conveys important information about inherited melanoma risk for a broad spectrum of individuals, concerns that MC1R feedback could have negative consequences, including increased distress about melanoma, inappropriate use of health services, and development of a false sense of security, are valid and require empirical examination. The time is right for high-quality research focusing on the translation of MC1R genotype into clinical and public health practice. If studies show MC1R genetic risk screening is effective at motivating behavior change, more melanomas may be detected at earliest stages for which surgical excision is highly curative or a large number of melanomas may be prevented altogether. While other genetic markers for melanoma susceptibility may emerge in the coming years, the burgeoning research agenda on the public health translational potential of MC1R genetic risk screening will inform and usefully advance current and future precision risk assessment of melanoma. Cancer Prev Res; 11(3); 121-4. (c)2017 AACR. PMID- 29246957 TI - Chemoprevention of Preclinical Breast and Lung Cancer with the Bromodomain Inhibitor I-BET 762. AB - Breast cancer and lung cancer remain the top two leading causes of cancer-related deaths in women. Because of limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extraterminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3, and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment. Cancer Prev Res; 11(3); 143-56. (c)2017 AACR. PMID- 29246958 TI - Antibody Profiling of Kawasaki Disease Using Escherichia coli Proteome Microarrays. AB - Kawasaki disease (KD) is a form of systemic vasculitis that generally occurs in children under 5 years old. Currently, KD is still diagnosed according to its clinical symptoms, including prolonged fever, skin rash, conjunctivitis, neck lymphadenopathy, palm erythema, and oral mucosa changes. Because KD is a type of inflammation without specific marker for diagnosis, we plan to profile the plasma antibodies by using E. coli proteome microarray and analyze the differences between KD and healthy subjects. Plasmas were collected from KD patient before intravenous immunoglobulin treatment (KD1), at least 3 weeks after treatment (KD3), nonfever control (NC), and fever control (FC) children. The initial screening, which consisted of 20 KD1, 20 KD3, 20 NC, and 20 FC, were explored using E. coli proteome microarrays (~4200 unique proteins). About ~70 proteins were shown to have high accuracy, e.g. 0.78~0.92, with regard to separating KD1, KD3, NC, and FC. Those proteins were then purified to fabricate KD focus arrays for training (n = 20 each) and blind-testing (n = 20 each). It only took 125 pl of plasma, less than a drop of blood, in the focus array assays. The AUC scores for blind tests of KD1 versus NC (17 protein markers), KD1 versus FC (20 protein markers), KD3 versus NC (9 protein markers), and KD1 versus KD3 (6 protein markers) were 0.84, 0.75, 0.99 and 0.98, respectively. This study is the first to profile plasma antibodies in KD and demonstrate that an E. coli proteome microarray can screen differences among patients with KD, nonfever controls, and fever controls. PMID- 29246959 TI - Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease. AB - BACKGROUND: Aortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS. METHODS AND RESULTS: We identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni- and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07-1.55]), but not in 132 patients without CAD (1.04 [0.83 1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16-1.76]) but not in those without CAD (0.87 [0.69-1.10]). CONCLUSIONS: High levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population. PMID- 29246961 TI - First-Line Antiarrhythmic Transplacental Treatment for Fetal Tachyarrhythmia: A Systematic Review and Meta-Analysis. AB - BACKGROUND: There is no consensus on the most effective and best tolerated first line antiarrhythmic treatment for fetal tachyarrhythmia. The purpose of this systematic review and meta-analysis was to compare the efficacy, safety, and fetal-maternal tolerance of first-line monotherapies for fetal supraventricular tachycardia and atrial flutter. METHODS AND RESULTS: A comprehensive search of several databases was conducted through January 2017. Only studies that made a direct comparison between first-line treatments of fetal tachyarrhythmia were included. Outcomes of interest were termination of fetal tachyarrhythmia, fetal demise, and maternal complications. Ten studies met inclusion criteria, with 537 patients. Overall, 291 patients were treated with digoxin, 137 with flecainide, 102 with sotalol, and 7 with amiodarone. Digoxin achieved a lower rate of supraventricular tachycardia termination compared with flecainide (odds ratio [OR]: 0.773; 95% confidence interval [CI], 0.605-0.987; I2=34%). In fetuses with hydrops fetalis, digoxin had lower rates of tachycardia termination compared with flecainide (OR: 0.412; 95% CI, 0.268-0.632; I2=0%). There was no significant difference in the incidence of maternal side effects between digoxin and flecainide groups (OR: 1.134; 95% CI, 0.129-9.935; I2=80.79%). The incidence of maternal side effects was higher in patients treated with digoxin compared with sotalol (OR: 3.148; 95% CI, 1.468-6.751; I2=0%). There was no difference in fetal demise between flecainide and digoxin (OR: 0.767; 95% CI, 0.140-4.197; I2=44%). CONCLUSIONS: Flecainide may be more effective treatment than digoxin as a first line treatment for fetal supraventricular tachycardia. PMID- 29246960 TI - Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial. AB - BACKGROUND: Although statins reduce cardiovascular events, residual risk remains. Therefore, additional modalities are needed to reduce risk. We evaluated the effect of eicosapentaenoic acid and docosahexaenoic acid in pharmacologic doses added to statin treatment on coronary artery plaque volume. METHODS AND RESULTS: A total of 285 subjects with stable coronary artery disease on statins were randomized to omega-3 ethyl-ester (1.86 g of eicosapentaenoic acid and 1.5 g of docosahexaenoic acid daily) or no omega-3 (control) for 30 months. Coronary plaque volume was assessed by coronary computed tomographic angiography. Mean (SD) age was 63.0 (7.7) years; mean low-density lipoprotein cholesterol <=80 mg/dL. In the intention-to-treat analysis, our primary endpoint, noncalcified plaque volume, was not different between groups (P=0.14) but approached significance in the per protocol analysis (P=0.07). When stratified by age in the intention-to-treat analysis, younger omega-3 subjects had significantly less progression of the primary endpoint, noncalcified plaque (P=0.013), and fibrous, calcified and total plaque. In plaque subtype analysis, controls had significant progression of fibrous plaque compared to no change in the omega-3 ethyl-ester group (median % change [interquartile range], 5.0% [-5.7, 20.0] versus -0.1% [ 12.3, 14.5], respectively; P=0.018). Among those on low-intensity statins, omega 3 ethyl-ester subjects had attenuation of fibrous plaque progression compared to controls (median % change [interquartile range], 0.3% [-12.8, 9.0] versus 4.8% [ 5.1, 19.0], respectively; P=0.032). In contrast, those on high-intensity statins had no difference in plaque change in either treatment arm. CONCLUSIONS: High dose eicosapentaenoic acid and docosahexaenoic acid provided additional benefit to statins in preventing progression of fibrous coronary plaque in subjects adherent to therapy with well-controlled low-density lipoprotein cholesterol levels. The benefit on low-intensity statin, but not high-intensity statin, suggests that statin intensity affects plaque volume. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01624727. PMID- 29246967 TI - Targeting and translocation of proteins to the endoplasmic reticulum at a glance. AB - The evolutionary emergence of organelles was a defining process in diversifying biochemical reactions within the cell and enabling multicellularity. However, compartmentalization also imposed a great challenge-the need to import proteins synthesized in the cytosol into their respective sites of function. For example, one-third of all genes encode for proteins that must be targeted and translocated into the endoplasmic reticulum (ER), which serves as the entry site to the majority of endomembrane compartments. Decades of research have set down the fundamental principles of how proteins get from the cytosol into the ER, and recent studies have brought forward new pathways and additional regulators enabling better definition of the rules governing substrate recognition. In this Cell Science at a Glance article and the accompanying poster, we give an overview of our current understanding of the multifaceted and regulated processes of protein targeting and translocation to the ER. PMID- 29246962 TI - Subclinical Cardiac Dysfunction and Brain Health in Midlife: CARDIA (Coronary Artery Risk Development in Young Adults) Brain Magnetic Resonance Imaging Substudy. AB - BACKGROUND: We investigated whether cardiac parameters in young adulthood are associated with indicators of brain health in midlife. METHODS AND RESULTS: This study includes 648 participants from the CARDIA (Coronary Artery Risk Development in Young Adults) study (52% women, 38% black). We studied associations of cardiac parameters assessed by echocardiography (left ventricular ejection fraction, left atrial volume, and left ventricular mass) in young adulthood (mean age: 30 years) with brain measures obtained by magnetic resonance imaging (total brain, gray and white matter volume, white matter integrity, abnormal white matter) in midlife (mean age: 50 years). In 406 individuals with complete measurements, higher left atrial volume was associated with lower white matter fractional anisotropy, independent of traditional cardiovascular risk factors (beta=-0.002; P <0.02). The association was strongest in black participants and in men. CONCLUSIONS: Higher left atrial volume in early adulthood is associated with impairment of white matter integrity in midlife. Interventions to improve cardiac function in young adults may benefit brain health and should be targeted in particular at black men. PMID- 29246963 TI - Associations of Lipoprotein(a) Levels With Incident Atrial Fibrillation and Ischemic Stroke: The ARIC (Atherosclerosis Risk in Communities) Study. AB - BACKGROUND: Lipoprotein(a) (Lp[a]) is proatherosclerotic and prothrombotic, causally related to coronary disease, and associated with other cardiovascular diseases. The association of Lp(a) with incident atrial fibrillation (AF) and with ischemic stroke among individuals with AF remains to be elucidated. METHODS AND RESULTS: In the community-based ARIC (Atherosclerosis Risk in Communities) study cohort, Lp(a) levels were measured by a Denka Seiken assay at visit 4 (1996 1998). We used multivariable-adjusted Cox models to compare AF and ischemic stroke risk across Lp(a) levels. First, we evaluated incident AF in 9908 participants free of AF at baseline. AF was ascertained by electrocardiography at study visits, hospital International Statistical Classification of Diseases, 9th Revision (ICD-9) codes, and death certificates. We then evaluated incident ischemic stroke in 10 127 participants free of stroke at baseline. Stroke was identified by annual phone calls, hospital ICD-9 Revision codes, and death certificates. The baseline age was 62.7+/-5.6 years. Median Lp(a) levels were 13.3 mg/dL (interquartile range, 5.2-39.7 mg/dL). Median follow-up was 13.9 and 15.8 years for AF and stroke, respectively. Lp(a) was not associated with incident AF (hazard ratio, 0.98; 95% confidence interval, 0.82-1.17), comparing those with Lp(a) >=50 with those with Lp(a) <10 mg/dL. High Lp(a) was associated with a 42% relative increase in stroke risk among participants without AF (hazard ratio, 1.42; 95% confidence interval, 1.07-1.90) but not in those with AF (hazard ratio, 1.06; 95% confidence interval, 0.70-1.61 [P interaction for AF=0.25]). There were no interactions by race or sex. No association was found for cardioembolic stroke subtype. CONCLUSIONS: High Lp(a) levels were not associated with incident AF. Lp(a) levels were associated with increased ischemic stroke risk, primarily among individuals without AF but not in those with AF. PMID- 29246968 TI - Correction: The Drosophila centriole - conversion of doublets into triplets within the stem cell niche (doi: 10.1242/jcs.172627). PMID- 29246969 TI - Allele-specific silencing therapy for Dynamin 2-related dominant centronuclear myopathy. AB - Rapid advances in allele-specific silencing by RNA interference established a strategy of choice to cure dominant inherited diseases by targeting mutant alleles. We used this strategy for autosomal-dominant centronuclear myopathy (CNM), a rare neuromuscular disorder without available treatment due to heterozygous mutations in the DNM2 gene encoding Dynamin 2. Allele-specific siRNA sequences were developed in order to specifically knock down the human and murine DNM2-mRNA harbouring the p.R465W mutation without affecting the wild-type allele. Functional restoration was achieved in muscle from a knock-in mouse model and in patient-derived fibroblasts, both expressing the most frequently encountered mutation in patients. Restoring either muscle force in a CNM mouse model or DNM2 function in patient-derived cells is an essential breakthrough towards future gene-based therapy for dominant centronuclear myopathy. PMID- 29246970 TI - Compounds producing an effective combinatorial regimen for disruption of HIV-1 latency. AB - Highly active antiretroviral therapy (HAART) has improved the outlook for the HIV epidemic, but does not provide a cure. The proposed "shock-and-kill" strategy is directed at inducing latent HIV reservoirs, which may then be purged via boosted immune response or targeting infected cells. We describe five novel compounds that are capable of reversing HIV latency without affecting the general T-cell activation state. The new compounds exhibit synergy for reactivation of latent provirus with other latency-reversing agents (LRAs), in particular ingenol-3 angelate/PEP005. One compound, designated PH02, was efficient at reactivating viral transcription in several cell lines bearing reporter HIV-1 at different integration sites. Furthermore, it was capable of reversing latency in resting CD4+ T lymphocytes from latently infected aviremic patient cells on HAART, while producing minimal cellular toxicity. The combination of PH02 and PEP005 produces a strong synergistic effect for reactivation, as demonstrated through a quantitative viral outgrowth assay (qVOA), on CD4+ T lymphocytes from HIV-1 infected individuals. We propose that the PH02/PEP005 combination may represent an effective novel treatment for abrogating persistent HIV-1 infection. PMID- 29246971 TI - In vivo quantification of mechanical properties of caudal fins in adult zebrafish. AB - The caudal fins of adult zebrafish are supported by multiple bony rays that are laterally interconnected by soft interray tissue. Little is known about the fin's mechanical properties that influence bending in response to hydrodynamic forces during swimming. Here, we developed an experimental setup to measure the elastic properties of caudal fins in vivo by applying micro-Newton forces to obtain bending stiffness and a tensional modulus. We detected overall bending moments of 1.5*10-9-4*10-9 N m2 along the proximal-distal axis of the appendage showing a non-monotonous pattern that was not due to the geometry of the fin itself. Surgical disruption of the interray tissues along the proximal-distal axis revealed no significant changes to the overall bending stiffness, which we confirmed by determining a tensional modulus of the interray tissue. Thus, the biophysical values suggest that the flexibility of the fin during its hydrodynamic performance predominantly relies on the mechanical properties of the rays. PMID- 29246972 TI - Increased capillary tortuosity and pericapillary basement membrane thinning in skeletal muscle of mice undergoing running wheel training. AB - To work out which microvascular remodeling processes occur in murine skeletal muscle during endurance exercise, we subjected C57BL/6 mice to voluntary running wheel training for 1 week (1 wk-t) or 6 weeks (6 wks-t). By means of morphometry, the capillarity as well as the compartmental and sub-compartmental structure of the capillaries were quantitatively described at the light microscopy level and at the electron microscopy level, respectively, in the plantaris (PLNT) muscle of the exercising mice in comparison to untrained littermates. In the early phase of the training (1 wk-t), angiogenesis [32% higher capillary/fiber (C/F) ratio; P<0.05] in PLNT muscle was accompanied by a tendency for capillary lumen enlargement (30%; P=0.06) and a reduction of the pericapillary basement membrane thickness [(CBMT) 12.7%; P=0.09] as well as a 21% shortening of intraluminal protrusion length (P<0.05), all compared with controls. After long-term training (6 wks-t), when the mice reached a steady state in running activity, additional angiogenesis (C/F ratio: 76%; P<0.05) and a 16.3% increase in capillary tortuosity (P<0.05) were established, accompanied by reversal of the lumen expansion (23%; P>0.05), further reduction of the CBMT (16.5%; P<0.05) and additional shortening of the intraluminal protrusion length (23%; P<0.05), all compared with controls. Other structural indicators, such as capillary profile sizes, profile area densities, perimeters of the capillary compartments and concentrations of endothelium-pericyte peg-socket junctions, were not significantly different between the mouse groups. Besides angiogenesis, increase of capillary tortuosity and reduction of CBMT represent the most striking microvascular remodeling processes in skeletal muscle of mice that undergo running wheel training. PMID- 29246975 TI - Exams are eroding anaesthetic trainees' work-life balance, college warns. PMID- 29246973 TI - SRp55 Regulates a Splicing Network That Controls Human Pancreatic beta-Cell Function and Survival. AB - Progressive failure of insulin-producing beta-cells is the central event leading to diabetes, but the signaling networks controlling beta-cell fate remain poorly understood. Here we show that SRp55, a splicing factor regulated by the diabetes susceptibility gene GLIS3, has a major role in maintaining the function and survival of human beta-cells. RNA sequencing analysis revealed that SRp55 regulates the splicing of genes involved in cell survival and death, insulin secretion, and c-Jun N-terminal kinase (JNK) signaling. In particular, SRp55 mediated splicing changes modulate the function of the proapoptotic proteins BIM and BAX, JNK signaling, and endoplasmic reticulum stress, explaining why SRp55 depletion triggers beta-cell apoptosis. Furthermore, SRp55 depletion inhibits beta-cell mitochondrial function, explaining the observed decrease in insulin release. These data unveil a novel layer of regulation of human beta-cell function and survival, namely alternative splicing modulated by key splicing regulators such as SRp55, that may cross talk with candidate genes for diabetes. PMID- 29246974 TI - Pancreatic Pericytes Support beta-Cell Function in a Tcf7l2-Dependent Manner. AB - Polymorphism in TCF7L2, a component of the canonical Wnt signaling pathway, has a strong association with beta-cell dysfunction and type 2 diabetes through a mechanism that has yet to be defined. beta-Cells rely on cells in their microenvironment, including pericytes, for their proper function. Here, we show that Tcf7l2 activity in pancreatic pericytes is required for beta-cell function. Transgenic mice in which Tcf7l2 was selectively inactivated in their pancreatic pericytes exhibited impaired glucose tolerance due to compromised beta-cell function and glucose-stimulated insulin secretion. Inactivation of pericytic Tcf7l2 was associated with impaired expression of genes required for beta-cell function and maturity in isolated islets. In addition, we identified Tcf7l2 dependent pericytic expression of secreted factors shown to promote beta-cell function, including bone morphogenetic protein 4 (BMP4). Finally, we show that exogenous BMP4 is sufficient to rescue the impaired glucose-stimulated insulin secretion of transgenic mice, pointing to a potential mechanism through which pericytic Tcf7l2 activity affects beta-cells. To conclude, we suggest that pancreatic pericytes produce secreted factors, including BMP4, in a Tcf7l2 dependent manner to support beta-cell function. Our findings thus propose a potential cellular mechanism through which abnormal TCF7L2 activity predisposes individuals to diabetes and implicates abnormalities in the islet microenvironment in this disease. PMID- 29246976 TI - Glutamate receptor GluA1 subunit is implicated in capsaicin induced modulation of amygdala LTP but not LTD. AB - Capsaicin has been shown to modulate synaptic plasticity in various brain regions including the amygdala. Whereas in the lateral amygdala the modulatory effect of capsaicin on long-term potentiation (LA-LTP) is mediated by TRPV1 channels, we have recently shown that capsaicin-induced enhancement of long term depression (LA-LTD) is mediated by TRPM1 receptors. However, the underlying mechanism by which capsaicin modulates synaptic plasticity is poorly understood. In the present study, we investigate the modulatory effect of capsaicin on synaptic plasticity in mice lacking the AMPAR subunit GluA1. Capsaicin reduced the magnitude of LA-LTP in slices derived from wild-type mice as previously described, whereas this capsaicin-induced suppression was absent in GluA1 deficient mice. In contrast, neither LA-LTD nor the capsaicin-mediated enhancement of LA-LTD was changed in GluA1 knockout mice. Our data indicate that capsaicin-induced modulation of LA-LTP via TRPV1 involves GluA1-containing AMPARs whereas capsaicin-induced modulation of LA-LTD via TRPM1 is independent of the expression of the AMPAR GluA1 subunit. PMID- 29246977 TI - Temporal specificity in Pavlovian-to-instrumental transfer. AB - Presentation of a previously trained Pavlovian conditioned stimulus while an organism is engaged in operant responding can moderate the rate of responding, a phenomenon known as Pavlovian-to-instrumental transfer. Although it is well known that Pavlovian contingencies will generate conditioned behavior that is temporally organized with respect to the arrival of the predicted outcome, little work has examined the temporal dynamics of responding during Pavlovian instrumental transfer. We trained rats using a fixed time 60-sec, fixed time 120 sec, or random time 60-sec schedule in an appetitive Pavlovian task, and found that presentation of the conditioned stimulus potentiated operant responding in a manner that reflected these previously established temporal expectancies. Further, this temporal specificity conformed to the scalar property as seen with other forms of interval timing behavior. Surprisingly, this effect was only seen when the conditioned stimulus was a visual cue, but not when it was an auditory cue. These data suggest that the motivational processes triggered by Pavlovian cues are not static, but fluctuate in strength as a function of temporally specific expectations of reward. PMID- 29246978 TI - Stress leads to aberrant hippocampal involvement when processing schema-related information. AB - Prior knowledge, represented as a mental schema, has critical impact on how we organize, interpret, and process incoming information. Recent findings indicate that the use of an existing schema is coordinated by the medial prefrontal cortex (mPFC), communicating with parietal areas. The hippocampus, however, is crucial for encoding schema-unrelated information but not for schema-related information. A recent study indicated that stress mediators may affect schema-related memory, but the underlying neural mechanisms are currently unknown. Here, we thus tested the impact of acute stress on neural processing of schema-related information. We exposed healthy participants to a stress or control manipulation before they processed, in the MRI scanner, words related or unrelated to a preexisting schema activated by a specific cue. Participants' memory for the presented material was tested 3-5 d after encoding. Overall, the processing of schema-related information activated the mPFC, the precuneus, and the angular gyrus. Stress resulted in aberrant hippocampal activity and connectivity while participants processed schema-related information. This aberrant engagement of the hippocampus was linked to altered subsequent memory. These findings suggest that stress may interfere with the efficient use of prior knowledge during encoding and may have important practical implications, in particular for educational settings. PMID- 29246980 TI - Savings memory is accompanied by transcriptional changes that persist beyond the decay of recall. AB - Most long-term memories are forgotten. What happens, then, to the changes in neuronal gene expression that were initially required to encode and maintain the memory? Here we show that the decay of recall for long-term sensitization memory in Aplysia is accompanied both by a form of savings memory (easier relearning) and by persistent transcriptional regulation. A behavioral experiment (N = 14) shows that sensitization training produces a robust long-term sensitization memory, but that recall fades completely within 1 wk. This apparent forgetting, though, is belied by persistent savings memory, as we found that a weak reminder protocol reinstates a long-term sensitization memory only on the previously trained side of the body. Using microarray (N = 8 biological replicates), we found that transcriptional regulation largely decays along with recall. Of the transcripts known to be regulated 1 d after training, 98% (1172/1198) are no longer significantly regulated 7 d after training. Still, there is a small set of transcripts which remain strongly regulated even when recall is absent. Using qPCR (N = 11 additional biological replicates) we confirmed that these include the peptide transmitter FMRFamide, a transcript encoding a putative homolog of spectrin beta chain (Genbank: EB255259) , a transcript encoding a protein with a predicted EF-hand calcium-binding domain (Genbank: EB257711), and eight uncharacterized transcripts. To our knowledge, this is the first work to show that transcriptional changes evoked by learning can outlast recall. The small set of transcriptional changes that persist could mediate the rapid relearning of the memory (savings), or the decay of recall, or both, or neither. PMID- 29246982 TI - At last! Action to stop brachy dogs ads. PMID- 29246981 TI - Sex differences in fear discrimination do not manifest as differences in conditioned inhibition. AB - Distinguishing safety from danger is necessary for survival, but is aberrant in individuals with post-traumatic stress disorder (PTSD). While PTSD is more prevalent in women than men, research on sex differences in safety learning is limited. Here, female rats demonstrated greater fear discrimination than males in a CS+/CS- paradigm. To determine if this sex difference transferred to fear inhibition, rats were tested for conditioned inhibition in a summation test with the CS+ and CS- presented in compound; no sex difference emerged. The results suggest sex differences in the neural mechanisms of discrimination learning but not recall of a fear inhibitor. PMID- 29246983 TI - Enough is enough with brachy advertising. PMID- 29246984 TI - 'Bold and welcome' move as government recognises sentience and increases maximum sentences for cruelty. PMID- 29246979 TI - Dissociable contributions of thalamic nuclei to recognition memory: novel evidence from a case of medial dorsal thalamic damage. AB - The thalamic nuclei are thought to play a critical role in recognition memory. Specifically, the anterior thalamic nuclei and medial dorsal nuclei may serve as critical output structures in distinct hippocampal and perirhinal cortex systems, respectively. Existing evidence indicates that damage to the anterior thalamic nuclei leads to impairments in hippocampal-dependent tasks. However, evidence for the opposite pattern following medial dorsal nuclei damage has not yet been identified. In the present study, we investigated recognition memory in NC, a patient with relatively selective medial dorsal nuclei damage, using two object recognition tests with similar foils: a yes/no (YN) test that requires the hippocampus, and a forced choice corresponding test (FCC) that is supported by perirhinal cortex. NC performed normally in the YN test, but was impaired in the FCC test. Critically, FCC performance was impaired only when the study-test delay period was filled with interference. We interpret these results in the context of the representational-hierarchical model, which predicts that memory deficits following damage to the perirhinal system arise due to increased vulnerability to interference. These data provide the first evidence for selective deficits in a task that relies on perirhinal output following damage to the medial dorsal nuclei, providing critical evidence for dissociable thalamic contributions to recognition memory. PMID- 29246985 TI - Cage fighting: vets divided over poultry management. PMID- 29246986 TI - African swine fever and the risks of feeding food waste to pigs. PMID- 29246987 TI - Environment's role in global antibiotic resistance 'overlooked' until now. PMID- 29246990 TI - Mortality due to pulpy kidney in beef calves and goats. PMID- 29246991 TI - Clostridium perfringens type D enterotoxaemia in cattle, goats and sheep. PMID- 29246992 TI - Diagnostic imaging of tendinopathies of the superficial flexor tendon in horses. PMID- 29246994 TI - Animal sentience. PMID- 29246995 TI - John Fishwick, BVA President, responds. PMID- 29246996 TI - Porcine circovirus type 3: a threat to the pig industry? PMID- 29246997 TI - Changes to ionising radiation regulations. PMID- 29246998 TI - Changes to APHA laboratory testing locations. PMID- 29246999 TI - Diagnosis of colic. PMID- 29247000 TI - Who owns the countryside? PMID- 29247001 TI - Hospice and Palliative Care for Companion Animals: Principles and Practice. PMID- 29247005 TI - Distinct pH dependencies of Na+/K+ selectivity at the two faces of Na,K-ATPase. AB - The sodium pump (Na,K-ATPase) in animal cells is vital for actively maintaining ATP hydrolysis-powered Na+ and K+ electrochemical gradients across the cell membrane. These ion gradients drive co- and countertransport and are critical for establishing the membrane potential. It has been an enigma how Na,K-ATPase discriminates between Na+ and K+, despite the pumped ion on each side being at a lower concentration than the other ion. Recent crystal structures of analogs of the intermediate conformations E2.Pi.2K+ and Na+-bound E1~P.ADP suggest that the dimensions of the respective binding sites in Na,K-ATPase are crucial in determining its selectivity. Here, we found that the selectivity at each membrane face is pH-dependent and that this dependence is unique for each face. Most notable was a strong increase in the specific affinity for K+ at the extracellular face (i.e. E2 conformation) as the pH is lowered from 7.5 to 5. We also observed a smaller increase in affinity for K+ on the cytoplasmic side (E1 conformation), which reduced the selectivity for Na+ Theoretical analysis of the pKa values of ion-coordinating acidic amino acid residues suggested that the face specific pH dependences and Na+/K+ selectivities may arise from the protonation or ionization of key residues. The increase in K+ selectivity at low pH on the cytoplasmic face, for instance, appeared to be associated with Asp808 protonation. We conclude that changes in the ionization state of coordinating residues in Na,K-ATPase could contribute to altering face-specific ion selectivity. PMID- 29247004 TI - Caveolin-1 promotes the tumor suppressor properties of oncogene-induced cellular senescence. AB - Oncogene-induced senescence (OIS) is considered a powerful tumor suppressor mechanism. Caveolin-1 acts as a scaffolding protein to functionally regulate signaling molecules. We demonstrate that a lack of caveolin-1 expression inhibits oncogenic K-Ras (K-RasG12V)-induced premature senescence in mouse embryonic fibroblasts and normal human bronchial epithelial cells. Oncogenic K-Ras induces senescence by limiting the detoxification function of MTH1. We found that K RasG12V promotes the interaction of caveolin-1 with MTH1, which results in inhibition of MTH1 activity. Lung cancer cells expressing oncogenic K-Ras have bypassed the senescence barrier. Interestingly, overexpression of caveolin-1 restores cellular senescence in both A549 and H460 lung cancer cells and inhibits their transformed phenotype. In support of these findings, our in vivo data demonstrate that overexpression of oncogenic K-Ras (K-RasG12D) induces cellular senescence in the lung of wildtype but not caveolin-1-null mice. A lack of K RasG12D-induced premature senescence in caveolin-1-null mice results in the formation of more abundant lung tumors. Consistent with these data, caveolin-1 null mice overexpressing K-RasG12D display accelerated mortality. Finally, our animal data were supported by human sample analysis in which we show that caveolin-1 expression is dramatically down-regulated in lung adenocarcinomas from lung cancer patients, both at the mRNA and protein levels, and that low caveolin 1 expression is associated with poor survival. Together, our data suggest that lung cancer cells escape oncogene-induced premature senescence through down regulation of caveolin-1 expression to progress from premalignant lesions to cancer. PMID- 29247006 TI - A novel fluorescence assay for measuring phosphatidylserine decarboxylase catalysis. AB - Phosphatidylserine decarboxylases (PSDs) are central enzymes in phospholipid metabolism that produce phosphatidylethanolamine (PE) in bacteria, protists, plants, and animals. We developed a fluorescence-based assay for selectively monitoring production of PE in reactions using a maltose-binding protein fusion with Plasmodium knowlesi PSD (MBP-His6-Delta34PkPSD) as the enzyme. The PE detection by fluorescence (lambdaex = 403 nm, lambdaem = 508 nm) occurred after the lipid reacted with a water-soluble distyrylbenzene-bis-aldehyde (DSB-3), and provided strong discrimination against the phosphatidylserine substrate. The reaction conditions were optimized for enzyme, substrate, product, and DSB-3 concentrations with the purified enzyme and also tested with crude extracts and membrane fractions from bacteria and yeast. The assay is readily amenable to application in 96- and 384-well microtiter plates and should prove useful for high-throughput screening for inhibitors of PSD enzymes across diverse phyla. PMID- 29247007 TI - Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. AB - A variety of mechanisms deliver cytosolic materials to the lysosomal compartment for degradation through autophagy. Here, we focus on two autophagic pathways, the chaperone-mediated autophagy and the endosomal microautophagy that rely on the cytosolic chaperone hsc70 for substrate targeting. Although hsc70 participates in the triage of proteins for degradation by different proteolytic systems, the common characteristic shared by these two forms of autophagy is that hsc70 binds directly to a specific five-amino acid motif in the cargo protein for its autophagic targeting. We summarize the current understanding of the molecular machineries behind each of these types of autophagy. PMID- 29247008 TI - Structural basis for lipid binding and mechanism of the Mycobacterium tuberculosis Rv3802 phospholipase. AB - The Mycobacterium tuberculosis rv3802c gene encodes an essential enzyme with thioesterase and phospholipase A activity. Overexpression of Rv3802 orthologs in Mycobacterium smegmatis and Corynebacterium glutamicum increases mycolate content and decreases glycerophospholipids. Although a role in modulating the lipid composition of the unique mycomembrane has been proposed, the true biological function of Rv3802 remains uncertain. In this study, we present the first M. tuberculosis Rv3802 X-ray crystal structure, solved to 1.7 A resolution. On the basis of the binding of PEG molecules to Rv3802, we identified its lipid-binding site and the structural basis for phosphatidyl-based substrate binding and phospholipase A activity. We found that movement of the alpha8-helix affords lipid binding and is required for catalytic turnover through covalent tethering. We gained insights into the mechanism of acyl hydrolysis by observing differing arrangements of PEG and water molecules within the active site. This study provides structural insights into biological function and facilitates future structure-based drug design toward Rv3802. PMID- 29247009 TI - Nonhomologous DNA end-joining for repair of DNA double-strand breaks. AB - Nonhomologous DNA end-joining (NHEJ) is the predominant double-strand break (DSB) repair pathway throughout the cell cycle and accounts for nearly all DSB repair outside of the S and G2 phases. NHEJ relies on Ku to thread onto DNA termini and thereby improve the affinity of the NHEJ enzymatic components consisting of polymerases (Pol MU and Pol lambda), a nuclease (the Artemis.DNA-PKcs complex), and a ligase (XLF.XRCC4.Lig4 complex). Each of the enzymatic components is distinctive for its versatility in acting on diverse incompatible DNA end configurations coupled with a flexibility in loading order, resulting in many possible junctional outcomes from one DSB. DNA ends can either be directly ligated or, if the ends are incompatible, processed until a ligatable configuration is achieved that is often stabilized by up to 4 bp of terminal microhomology. Processing of DNA ends results in nucleotide loss or addition, explaining why DSBs repaired by NHEJ are rarely restored to their original DNA sequence. Thus, NHEJ is a single pathway with multiple enzymes at its disposal to repair DSBs, resulting in a diversity of repair outcomes. PMID- 29247010 TI - Cell-penetrating peptides derived from Clostridium difficile TcdB2 and a related large clostridial toxin. AB - Clostridium difficile TcdB (2366 amino acid residues) is an intracellular bacterial toxin that binds to cells and enters the cytosol where it glucosylates small GTPases. In the current study, we examined a putative cell entry region of TcdB (amino acid residues 1753-1851) for short sequences that function as cell penetrating peptides (CPPs). To screen for TcdB-derived CPPs, a panel of synthetic peptides was tested for the ability to enhance transferrin (Tf) association with cells. Four candidate CPPs were discovered, and further study on one peptide (PepB2) pinpointed an asparagine residue necessary for CPP activity. PepB2 mediated the cell entry of a wide variety of molecules including dextran, streptavidin, microspheres, and lentivirus particles. Of note, this uptake was dramatically reduced in the presence of the Na+/H+ exchange blocker and micropinocytosis inhibitor amiloride, suggesting that PepB2 invokes macropinocytosis. Moreover, we found that PepB2 had more efficient cell penetrating activity than several other well-known CPPs (TAT, penetratin, Pep-1, and TP10). Finally, Tf assay-based screening of peptides derived from two other large clostridial toxins, TcdA and TcsL, uncovered two new TcdA-derived CPPs. In conclusion, we have identified six CPPs from large clostridial toxins and have demonstrated the ability of PepB2 to promote cell association and entry of several molecules through a putative fluid-phase macropinocytotic mechanism. PMID- 29247011 TI - Histone Demethylase Activity of Utx Is Essential for Viability and Regulation of HOX Gene Expression in Drosophila. AB - The trimethylation of histone H3 at lysine 27 (H3K27me3) by Polycomb Repressive Complex 2 (PRC2) is essential for the repression of Polycomb target genes. However, the role of enzymatic demethylation of H3K27me3 by the KDM6-family demethylases Utx, Uty, and JmjD3 is less clear. Studies in both mice and worms led to the proposal that KDM6 proteins, but not their H3K27me3 demethylase activity, is critical for normal development. Here, we investigated the requirement of the demethylase activity of the single KDM6 family member Utx in Drosophila We generated Drosophila expressing a full-length but catalytically inactive Utx protein and found that these mutants show the same phenotypes as animals lacking the Utx protein. Specifically, animals lacking maternally deposited active Utx demethylase in the early embryo show stochastic loss of HOX gene expression that appears to be propagated in a clonal fashion. This suggests that Utx demethylase activity is critical for the removal of ectopic H3K27 trimethylation from active HOX genes during the onset of zygotic gene transcription, and thereby prevents the inappropriate installment of long-term repression by Polycomb. Conversely, maternally deposited catalytically active Utx protein suffices to permit animals that lack zygotic expression of enzymatically active Utx to develop into morphologically normal adults, which eclose from the pupal case but die shortly thereafter. Utx demethylase activity is therefore also essential to sustain viability in adult flies. Together, these analyses identify the earliest embryonic stages and the adult stage as two phases during the Drosophila life cycle that critically require H3K27me3 demethylase activity. PMID- 29247014 TI - Response to Immune Checkpoint Blockade is Influenced by HLA-I Genotype. AB - Maximal HLA-I loci heterozygosity is linked to improved survival after immune checkpoint blockade. PMID- 29247012 TI - Loss of Drosophila Mei-41/ATR Alters Meiotic Crossover Patterning. AB - Meiotic crossovers must be properly patterned to ensure accurate disjunction of homologous chromosomes during meiosis I. Disruption of the spatial distribution of crossovers can lead to nondisjunction, aneuploidy, gamete dysfunction, miscarriage, or birth defects. One of the earliest identified genes involved in proper crossover patterning is Drosophila mei-41, which encodes the ortholog of the checkpoint kinase ATR. Analysis of hypomorphic mutants suggested the existence of crossover patterning defects, but it was not possible to assess this in null mutants because of maternal-effect embryonic lethality. To overcome this lethality, we constructed mei-41 null mutants in which we expressed wild-type Mei 41 in the germline after completion of meiotic recombination, allowing progeny to survive. We find that crossovers are decreased to about one-third of wild-type levels, but the reduction is not uniform, being less severe in the proximal regions of chromosome 2L than in medial or distal 2L or on the X chromosome. None of the crossovers formed in the absence of Mei-41 require Mei-9, the presumptive meiotic resolvase, suggesting that Mei-41 functions everywhere, despite the differential effects on crossover frequency. Interference appears to be significantly reduced or absent in mei-41 mutants, but the reduction in crossover density in centromere-proximal regions is largely intact. We propose that crossover patterning is achieved in a stepwise manner, with the crossover suppression related to proximity to the centromere occurring prior to and independently of crossover designation and enforcement of interference. In this model, Mei-41 has an essential function in meiotic recombination after the centromere effect is established but before crossover designation and interference occur. PMID- 29247015 TI - CAR T-cell Therapy Impresses in Multiple Myeloma. AB - CAR T cells that target the B-cell maturation antigen produce remissions in patients with relapsed or refractory multiple myeloma. Updated results from a phase I study suggest that 94% of patients treated with the highest doses showed complete or partial remissions and high rates of progression-free survival. PMID- 29247013 TI - Whole-genome sequencing reveals transmission of gonococcal antibiotic resistance among men who have sex with men: an observational study. AB - OBJECTIVES: Drug-resistant Neisseria gonorrhoeae are now a global public health threat. Direct transmission of antibiotic-resistant gonococci between individuals has been proposed as a driver for the increased transmission of resistance, but direct evidence of such transmission is limited. Whole-genome sequencing (WGS) has superior resolution to investigate outbreaks and disease transmission compared with traditional molecular typing methods such as multilocus sequence typing (MLST) and N. gonorrhoeae multiantigen sequence (NG-MAST). We therefore aimed to systematically investigate the transmission of N. gonorrhoeae between men in sexual partnerships using WGS to compare isolates and their resistance to antibiotics at a genome level. METHODS: 458 couples from a large prospective cohort of men who have sex with men (MSM) tested for gonorrhoea together between 2005 and 2014 were included, and WGS was conducted on all isolates from couples where both men were culture-positive for N. gonorrhoeae. Resistance-determining sequences were identified from genome assemblies, and comparison of isolates between and within individuals was performed by pairwise single nucleotide polymorphism and pangenome comparisons, and in silico predictions of NG-MAST and MLST. RESULTS: For 33 of 34 (97%; 95% CI 85% to 100%) couples where both partners were positive for gonorrhoea, the resistance-determining genes and mutations were identical in isolates from each partner (94 isolates in total). Resistance determinants in isolates from 23 of 23 (100%; 95% CI 86% to 100%) men with multisite infections were also identical within an individual. These partner and within-host isolates were indistinguishable by NG-MAST, MLST and whole genomic comparisons. CONCLUSIONS: These data support the transmission of antibiotic resistant strains between sexual partners as a key driver of resistance rates in gonorrhoea among MSM. This improved understanding of the transmission dynamics of N. gonorrhoeae between sexual partners will inform treatment and prevention guidelines. PMID- 29247017 TI - The Alcohol-Abuse Drug Disulfiram Targets NPL4 to Exert Antitumor Effects. AB - Disulfiram reduced cancer mortality in patients who continued disulfiram for alcohol dependency. PMID- 29247018 TI - Value in Using CAR T Cells for DLBCL. AB - The phase II JULIET trial suggests that the CD19-targeting CAR T-cell therapy tisagenlecleucel produces durable responses in patients with relapsed and refractory diffuse large B-cell lymphoma. Three months after the therapy, 32% of the patients showed complete responses and 6% showed partial responses. After 6 months, those rates were 30% and 7%. PMID- 29247019 TI - KAT2A Is a alpha-KGDH-Dependent Histone Succinyltransferase. AB - Succinylation of histone H3K79 induces changes in gene expression that promote glioblastoma growth. PMID- 29247016 TI - Accelerating Discovery of Functional Mutant Alleles in Cancer. AB - Most mutations in cancer are rare, which complicates the identification of therapeutically significant mutations and thus limits the clinical impact of genomic profiling in patients with cancer. Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced patients with advanced disease to identify mutant residues arising more frequently than expected in the absence of selection. We identified 1,165 statistically significant hotspot mutations of which 80% arose in 1 in 1,000 or fewer patients. Of 55 recurrent in-frame indels, we validated that novel AKT1 duplications induced pathway hyperactivation and conferred AKT inhibitor sensitivity. Cancer genes exhibit different rates of hotspot discovery with increasing sample size, with few approaching saturation. Consequently, 26% of all hotspots in therapeutically actionable oncogenes were novel. Upon matching a subset of affected patients directly to molecularly targeted therapy, we observed radiographic and clinical responses. Population scale mutant allele discovery illustrates how the identification of driver mutations in cancer is far from complete.Significance: Our systematic computational, experimental, and clinical analysis of hotspot mutations in approximately 25,000 human cancers demonstrates that the long right tail of biologically and therapeutically significant mutant alleles is still incompletely characterized. Sharing prospective genomic data will accelerate hotspot identification, thereby expanding the reach of precision oncology in patients with cancer. Cancer Discov; 8(2); 174-83. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 127. PMID- 29247020 TI - YY1 Facilitates Enhancer-Promoter Contacts to Promote Gene Expression. AB - YY1 preferentially occupies active enhancers and promoters and forms dimers to promote DNA looping. PMID- 29247022 TI - Preventing fractures in the masters athlete: we can do better. PMID- 29247023 TI - Injury in teenage Gaelic games. PMID- 29247021 TI - First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. AB - Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600-, and non-V600 BRAF-mutant solid tumors.Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non V600-mutant solid-tumor malignancies. Cancer Discov; 8(2); 184-95. (c)2017 AACR.See related commentary by Smalley and Smalley, p. 140This article is highlighted in the In This Issue feature, p. 127. PMID- 29247024 TI - Is live high-train low altitude training relevant for elite athletes? Flawed analysis from inaccurate data. PMID- 29247025 TI - Evolution of the process underlying floral zygomorphy development in pentapetalous angiosperms. AB - PREMISE OF THE STUDY: Observations of floral ontogeny indicated that floral organ initiation in pentapetalous flowers most commonly results in a median-abaxial (MAB) petal during early development, a median-adaxial (MAD) petal being less common. Such different patterns of floral organ initiation might be linked with different morphologies of floral zygomorphy that have evolved in Asteridae. Here, we provide the first study of zygomorphy in pentapetalous angiosperms placed in a phylogenetic framework, the goal being to find if the different patterns of floral organ initiation are connected with particular patterns of zygomorphy. METHODS: We analyzed patterns of floral organ initiation and displays of zygomorphy, extracted from floral diagrams representing 405 taxa in 330 genera, covering 83% of orders (30 out of 36) and 37% of families (116 out of 313) in core eudicots in the context of a phylogeny using ancestral state reconstructions. KEY RESULTS: The MAB petal initiation is the ancestral state of the pattern of floral organ initiation in pentapetalous angiosperms. Taxa with MAD petal initiation represent ~30 independent origins from the ancestral MAB initiation. There are distinct developmental processes that give rise to zygomorphy in different lineages of pentapetalous angiosperms, closely related lineages being likely to share similar developmental processes. CONCLUSIONS: We have demonstrated that development indeed constrains the processes that give rise to floral zygomorphy, while phylogenetic distance allows relaxation of these constraints, which provides novel insights on the role that development plays in the evolution of floral zygomorphy. PMID- 29247027 TI - Sexual expression and reproductive output in the ephemeral Geranium transversale are correlated with environmental conditions. AB - PREMISE OF THE STUDY: Abiotic environmental factors are often considered to be important in the distribution and maintenance of variation in sexual systems in flowering plants. Associations between sexes and abiotic factors are well documented in dioecious systems, but much less is known about this relationship in other sexually polymorphic systems. Species that are highly variable in sexual expression and habitat distribution can provide insights into the role of abiotic factors in maintaining variation in sexual expression. METHODS: Focusing on a sexually polymorphic species, Geranium transversale, we measured sexual expression at both the flower and the plant level and examined vegetative and floral traits, pollen deposition, and reproductive success. We also tested for correlations between sexual expression and other traits and examined whether and how these traits covaried with abiotic environmental conditions. KEY RESULTS: We identified unique variation of sexual expression in G. transversale. There are four sexual morphs that display different combinations of the three flower types (pistillate, staminate, and perfect). Sexual morphs that are phenotypically more female (i.e., female and gynomonoecious morphs) are found in wetter and milder environments, and flower earlier than morphs that are more male (i.e., hermaphroditic and andromonoecious morphs). Additionally, floral organ size and reproductive success are influenced not only by the flower type but also by the sexual morph of the plant. CONCLUSIONS: Environmental conditions are likely to cause some of the variation in sexual expression found in G. transversale. Both genetic and ecological factors likely contribute to the maintenance of sexual variation in this species. PMID- 29247028 TI - Genetic, morphological, and spectral characterization of relictual Niobrara River hybrid aspens (Populus * smithii). AB - PREMISE OF THE STUDY: Aspen groves along the Niobrara River in Nebraska have long been a biogeographic curiosity due to morphological differences from nearby remnant Populus tremuloides populations. Pleistocene hybridization between P. tremuloides and P. grandidentata has been proposed, but the nearest P. grandidentata populations are currently several hundred kilometers east. We tested the hybrid-origin hypothesis using genetic data and characterized putative hybrids phenotypically. METHODS: We compared nuclear microsatellite loci and chloroplast sequences of Niobrara River aspens to their putative parental species. Parental species and putative hybrids were also grown in a common garden for phenotypic comparison. On the common garden plants, we measured leaf morphological traits and leaf-level spectral reflectance profiles, from which chemical traits were derived. KEY RESULTS: The genetic composition of the three unique Niobrara aspen genotypes is consistent with the hybridization hypothesis and with maternal chloroplast inheritance from P. grandidentata. Leaf margin dentition and abaxial pubescence differentiated taxa, with the hybrids showing intermediate values. Spectral profiles allowed statistical separation of taxa in short-wave infrared wavelengths, with hybrids showing intermediate values, indicating that traits associated with internal structure of leaves and water absorption may vary among taxa. However, reflectance values in the visible region did not differentiate taxa, indicating that traits related to pigments are not differentiated. CONCLUSIONS: Both genetic and phenotypic results support the hypothesis of a hybrid origin for these genetically unique aspens. However, low genetic diversity and ongoing ecological and climatic threats to the hybrid taxon present a challenge for conservation of these relictual boreal communities. PMID- 29247029 TI - Time-to-Effect-Based Dosing Strategy for Cryoballoon Ablation in Patients With Paroxysmal Atrial Fibrillation: Results of the plusONE Multicenter Randomized Controlled Noninferiority Trial. AB - BACKGROUND: The optimal dosage of cryotherapy during cryoballoon ablation of pulmonary veins is still unclear. This trial tested the noninferiority of a novel, individualized, cryotherapy-dosing strategy for each vein. METHODS AND RESULTS: This prospective, randomized, multicenter, noninferiority study included 140 patients with paroxysmal atrial fibrillation, which was refractory to antiarrhythmic drugs. Patients were randomly assigned to a conventional strategy of 180-second cryoballoon applications per vein with a bonus freeze (control group, n=70) or to a shorter-time application protocol, with 1 application that lasted the time required for electric block time to effect plus 60- and a 120 second freeze bonus (study group, n=70). Patients were followed with a long-term monitoring system of 30 days. At 1-year follow-up, no difference was observed in terms of free atrial fibrillation-recurrence rates: 79.4% in control versus 78.3% in study group (Delta=1.15%; 90% confidence interval, -10.33% to 12.63%; P=0.869). Time to effect was detected in 72.1% of veins. The control and study groups had similar mean number of applications per patient (9.6+/-2 versus 9.9+/ 2.4; P=0.76). Compared with controls, the study group had a significantly shorter cryotherapy time (28.3+/-7 versus 19.4+/-4.3 minutes; P<0.001), left atrium time (104+/-25 versus 92+/-23 minutes; P<0.01), and total procedure time (135+/-35 versus 119+/-31 minutes; P<0.01). No differences were observed in complications or acute reconnections. CONCLUSIONS: The new time-to-effect-based cryotherapy dosage protocol led to shorter cryotherapy and procedure times, with equal safety, and similar acute and 1-year follow-up results, compared with the conventional approach. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02789358. PMID- 29247030 TI - Radiofrequency Catheter Ablation of Atrial Tachycardias in Congenital Heart Disease: Results With Special Reference to Complexity of Underlying Anatomy. AB - BACKGROUND: Radiofrequency catheter ablation has become the treatment strategy of choice for atrial tachyarrhythmias in patients with congenital heart disease (CHD). We analyzed results of radiofrequency catheter ablation in a large cohort of patients with CHD with special reference to complexity of underlying anatomy. METHODS AND RESULTS: One hundred and forty-four patients with CHD and atrial tachyarrhythmias undergoing radiofrequency catheter ablation were classified according to complexity of underlying CHD: simple CHD, n=18 (12%); moderate CHD, n=53 (37%); and complex CHD, n=73 (51%). Overall acute success was achieved in 81% of the patients. Acute success was lower for tachycardias involving the left atrium compared with right atrial tachycardias. Complexity of CHD was associated with longer procedure duration. Tachycardia recurrence was observed in 54% of the patients after a total follow-up of 7.4 years. 75% of all recurrences occurred within the first year. Recurrence of tachycardia was more likely in patients with complex surgical atrial anatomy (ie, Fontan palliation or atrial switch procedure). Major complications occurred in 4 patients and were related to vascular access. CONCLUSIONS: Acute procedural success of atrial tachycardia ablation in congenital heart patients was not influenced by complexity of CHD. Long-term outcome with regard to tachycardia recurrence was worse in patients with complex surgical atrial anatomy. PMID- 29247031 TI - Endocardial Activation Drives Activation Patterns During Long-Duration Ventricular Fibrillation and Defibrillation. AB - BACKGROUND: Understanding the mechanisms that drive ventricular fibrillation is essential for developing improved defibrillation techniques to terminate ventricular fibrillation (VF). Distinct organization patterns of chaotic, regular, and synchronized activity were previously demonstrated in VF that persisted over 1 to 2 minutes (long-duration VF [LDVF]). We hypothesized that activity on the endocardium may be driving these activation patterns in LDVF and that unsuccessful defibrillation shocks may alter activation patterns. METHODS AND RESULTS: The study was performed using a 64-electrode basket catheter on the left ventricle endocardium and 54 6-electrode plunge needles inserted into the left ventricles of 6 dogs. VF was induced electrically, and after short-duration VF (10 seconds) and LDVF (7 minutes), shocks of increasing strengths were delivered every 10 seconds until VF was terminated. Endocardial activation patterns were classified as chaotic (varying cycle lengths and nonsynchronous activations), regular (highly repeatable cycle lengths), and synchronized (activation that spreads rapidly over the endocardium with diastolic periods between activations). CONCLUSIONS: The results showed that the chaotic pattern was predominant in early VF, but the regular pattern emerges as VF progressed. The synchronized pattern only emerged occasionally during late VF. Failed defibrillation shocks changed chaotic and regular activation patterns to synchronized patterns in LDVF but not in short-duration VF. The regular and synchronized patterns of activation were driven by rapid activations on the endocardial surface that blocked and broke up transmurally, leading to an endocardial to epicardial activation rate gradient as LDVF progressed. PMID- 29247033 TI - More Bubble, More Trouble? Insights into Microembolic Events During Left Atrial Ablation. PMID- 29247032 TI - Thromboembolic Risks of the Procedural Process in Second-Generation Cryoballoon Ablation Procedures: Analysis From Real-Time Transcranial Doppler Monitoring. AB - BACKGROUND: Atrial fibrillation ablation is associated with substantial risks of silent cerebral events (SCEs) or silent cerebral lesions. We investigated which procedural processes during cryoballoon procedures carried a risk. METHODS AND RESULTS: Forty paroxysmal atrial fibrillation patients underwent pulmonary vein isolation using second-generation cryoballoons with single 28-mm balloon 3-minute freeze techniques. Microembolic signals (MESs) were monitored by transcranial Doppler throughout all procedures. Brain magnetic resonance imaging was obtained pre- and post-procedure in 34 patients (85.0%). Of 158 pulmonary veins, 152 (96.2%) were isolated using cryoablation, and 6 required touch-up radiofrequency ablation. A mean of 5.0+/-1.2 cryoballoon applications was applied, and the left atrial dwell time was 76.7+/-22.4 minutes. The total MES counts/procedures were 522 (426-626). Left atrial access and Flexcath sheath insertion generated 25 (11 44) and 34 (24-53) MESs. Using radiofrequency ablation for transseptal access increased the MES count during transseptal punctures. During cryoapplications, MES counts were greatest during first applications (117 [81-157]), especially after balloon stretch/deflations (43 [21-81]). Pre- and post-pulmonary vein potential mapping with Lasso catheters generated 57 (21-88) and 61 (36-88) MESs. Reinsertion of once withdrawn cryoballoons and subsequent applications produced 205 (156-310) MESs. Touch-up ablation generated 32 (19-62) MESs, whereas electric cardioversion generated no MESs. SCEs and silent cerebral lesions were detected in 11 (32.3%) and 4 (11.7%) patients, respectively. The patients with SCEs were older than those without; however, there were no significant factors associated with SCEs. CONCLUSIONS: A significant number of MESs and SCE/silent cerebral lesion occurrences were observed during second-generation cryoballoon ablation procedures. MESs were recorded during a variety of steps throughout the procedure; however, the majority occurred during phases with a high probability of gaseous emboli. PMID- 29247034 TI - Ventricular Fibrillation: Rotors or Foci? Both! PMID- 29247035 TI - Ablation of Atrial Arrhythmias in Postoperative Congenital Heart Disease Patients: Have We Reached the Upper Limit of Success or Is It Time for a Paradigm Shift in Strategy? PMID- 29247036 TI - Erratum for Ito et al., "Identification of the hcb Gene Operon Involved in Catalyzing Aerobic Hexachlorobenzene Dechlorination in Nocardioides sp. Strain PD653". PMID- 29247040 TI - Correction: JARID1B Enables Transit between Distinct States of the Stem-like Cell Population in Oral Cancers. PMID- 29247039 TI - H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma. AB - Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B 6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. Cancer Res; 77(24); 6999-7013. (c)2017 AACR. PMID- 29247042 TI - Intravenous versus oral paracetamol for acute pain in adults in the emergency department setting: a prospective, double-blind, double-dummy, randomised controlled trial. AB - OBJECTIVE: To determine if intravenous paracetamol was superior to oral paracetamol as an adjunct to opioids in the management of moderate to severe pain in the ED setting. METHODS: A prospective, randomised, double-blind, double dummy, controlled trial was conducted at a single academic tertiary care ED. Adult patients with moderate to severe pain were randomly assigned to receive either the intravenous paracetamol or oral paracetamol. The primary outcome was Visual Analogue Scale (VAS) pain reduction at 30 min. A clinically significant change in pain was defined as 13 mm. RESULTS: 87 participants were included in the final analysis, with a median age of 43.5 years and 59.8% were female. Overall mean baseline VAS pain score was 67.9 mm (+/-16.0). Both formulations achieved a clinically significant mean pain score reduction at 30 min, with no significant difference between the groups with 16.0 mm (SD 19.1 mm) in the intravenous group and 14.6 mm (SD 26.4) in the oral group; difference -1.4 mm (95% CI -11.6 to 8.8, P=0.79). Secondary outcomes, including postintervention intravenous opioid administration, patient satisfaction, side effects and length of stay, did not differ between groups. CONCLUSIONS: Overall, there was a small but clinically significant decrease in pain in each group. No superiority was demonstrated in this trial with intravenous paracetamol compared with oral paracetamol in terms of efficacy of analgesia and no difference in length of stay, patient satisfaction, need for rescue analgesia or side effects. PMID- 29247038 TI - Discovery of IDO1 Inhibitors: From Bench to Bedside. AB - Small-molecule inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1) are emerging at the vanguard of experimental agents in oncology. Here, pioneers of this new drug class provide a bench-to-bedside review on preclinical validation of IDO1 as a cancer therapeutic target and on the discovery and development of a set of mechanistically distinct compounds, indoximod, epacadostat, and navoximod, that were first to be evaluated as IDO inhibitors in clinical trials. As immunometabolic adjuvants to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also chemotherapy and radiotherapy as standards of care in the oncology clinic. Cancer Res; 77(24); 6795-811. (c)2017 AACR. PMID- 29247043 TI - Serum amyloid A3 is a high density lipoprotein-associated acute-phase protein. AB - Serum amyloid A (SAA) is a family of acute-phase reactants. Plasma levels of human SAA1/SAA2 (mouse SAA1.1/2.1) can increase >=1,000-fold during an acute phase response. Mice, but not humans, express a third relatively understudied SAA isoform, SAA3. We investigated whether mouse SAA3 is an HDL-associated acute phase SAA. Quantitative RT-PCR with isoform-specific primers indicated that SAA3 and SAA1.1/2.1 are induced similarly in livers (~2,500-fold vs. ~6,000-fold, respectively) and fat (~400-fold vs. ~100-fold, respectively) of lipopolysaccharide (LPS)-injected mice. In situ hybridization demonstrated that all three SAAs are produced by hepatocytes. All three SAA isoforms were detected in plasma of LPS-injected mice, although SAA3 levels were ~20% of SAA1.1/2.1 levels. Fast protein LC analyses indicated that virtually all of SAA1.1/2.1 eluted with HDL, whereas ~15% of SAA3 was lipid poor/free. After density gradient ultracentrifugation, isoelectric focusing demonstrated that ~100% of plasma SAA1.1 was recovered in HDL compared with only ~50% of SAA2.1 and ~10% of SAA3. Thus, SAA3 appears to be more loosely associated with HDL, resulting in lipid poor/free SAA3. We conclude that SAA3 is a major hepatic acute-phase SAA in mice that may produce systemic effects during inflammation. PMID- 29247044 TI - Stochasticity enables BCR-independent germinal center initiation and antibody affinity maturation. AB - Two immunoglobulin (Ig) diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo somatic hypermutation (SHM) and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i.e., cognate Igs) because of chance generation during preimmune Ig diversification. However, whether stochastic activation of noncognate B cells can generate new affinity to antigen in GCs is unclear. Using a mouse model whose knock-in BCR does not functionally engage with immunizing antigen, we found that chronic immunization induced antigen-specific serological responses with diverse SHM-mediated antibody affinity maturation pathways and divergent epitope targeting. Thus, intrinsic GC B cell flexibility allows for somatic, noncognate B cell evolution, permitting de novo antigen recognition and subsequent antibody affinity maturation without initial preimmune BCR engagement. PMID- 29247045 TI - The immunology of hypertension. AB - Although systemic hypertension affects a large proportion of the population, its etiology remains poorly defined. Emerging evidence supports the concept that immune cells become activated and enter target organs, including the vasculature and the kidney, in this disease. Mediators released by these cells, including reactive oxygen species, metalloproteinases, cytokines, and antibodies promote dysfunction of the target organs and cause damage. In vessels, these factors enhance constriction, remodeling, and rarefaction. In the kidney, these mediators increase expression and activation of sodium transporters, and cause interstitial fibrosis and glomerular injury. Factors common to hypertension, including oxidative stress, increased interstitial sodium, cytokine production, and inflammasome activation promote immune activation in hypertension. Recent data suggest that isolevuglandin-modified self-proteins in antigen-presenting cells are immunogenic, promoting cytokine production by the cells in which they are formed and T cell activation. Efforts to prevent and reverse immune activation may prove beneficial in preventing the long-term sequelae of hypertension and its related cardiovascular diseases. PMID- 29247047 TI - Correction: Role of conformational change and K-path ligands in controlling cytochrome c oxidase activity. PMID- 29247046 TI - Mannose receptor high, M2 dermal macrophages mediate nonhealing Leishmania major infection in a Th1 immune environment. AB - The origin and functional specialization of dermal macrophages in cutaneous infections have been little studied. In this paper, we show that a strain of Leishmania major (L. major Seidman [LmSd]) that produces nonhealing cutaneous lesions in conventionally resistant C57BL/6 mice was more efficiently taken up by M2-polarized bone marrow (BM)-derived macrophages (BMDMs) in vitro and by mannose receptor (MR)hi dermal macrophages in vivo compared with a healing strain (L. major Friedlin V1). Both in steady and in T helper type 1 (Th1) cell-driven inflammatory states, the MRhi dermal macrophages showed M2 characteristics. The dermal macrophages were radio resistant and not replaced by monocytes or adult BM derived cells during infection, but were locally maintained by IL-4 and IL-10. Notably, the favored infection of M2 BMDMs by LmSd in vitro was MR dependent, and genetic deletion of MR or selective depletion of MRhi dermal macrophages by anti CSF-1 receptor antibody reversed the nonhealing phenotype. We conclude that embryonic-derived, MRhi dermal macrophages are permissive for parasite growth even in a strong Th1-immune environment, and the preferential infection of these cells plays a crucial role in the severity of cutaneous disease. PMID- 29247049 TI - Directional vibration sensing in the leafcutter ant Atta sexdens. AB - Leafcutter ants communicate with the substrate-borne component of the vibratory emission produced by stridulation. Stridulatory signals in the genus Atta have been described in different behavioural contexts, such as foraging, alarm signalling and collective nest building. Stridulatory vibrations are employed to recruit nestmates, which can localize the source of vibration, but there is little information about the underlying mechanisms. Our experiments reveal that time-of-arrival delays of the vibrational signals are used for tropotactic orientation in Atta sexdens The detected time delays are in the same range as the time delays detected by termites. Chemical communication is also of great importance in foraging organization, and signals of different modalities may be combined in promoting the organization of collective foraging. Here we show that the tropotactic orientation to vibrational signals interacts with chemical communication signals. PMID- 29247048 TI - Testing a key assumption in animal communication: between-individual variation in female visual systems alters perception of male signals. AB - Variation in male signal production has been extensively studied because of its relevance to animal communication and sexual selection. Although we now know much about the mechanisms that can lead to variation between males in the properties of their signals, there is still a general assumption that there is little variation in terms of how females process these male signals. Variation between females in signal processing may lead to variation between females in how they rank individual males, meaning that one single signal may not be universally attractive to all females. We tested this assumption in a group of female wild caught brown-headed cowbirds (Molothrus ater), a species that uses a male visual signal (e.g. a wingspread display) to make its mate-choice decisions. We found that females varied in two key parameters of their visual sensory systems related to chromatic and achromatic vision: cone densities (both total and proportions) and cone oil droplet absorbance. Using visual chromatic and achromatic contrast modeling, we then found that this between-individual variation in visual physiology leads to significant between-individual differences in how females perceive chromatic and achromatic male signals. These differences may lead to variation in female preferences for male visual signals, which would provide a potential mechanism for explaining individual differences in mate-choice behavior. PMID- 29247052 TI - Structural predictor for nonlinear sheared dynamics in simple glass-forming liquids. AB - Glass-forming liquids subjected to sufficiently strong shear universally exhibit striking nonlinear behavior; for example, a power-law decrease of the viscosity with increasing shear rate. This phenomenon has attracted considerable attention over the years from both fundamental and applicational viewpoints. However, the out-of-equilibrium and nonlinear nature of sheared fluids have made theoretical understanding of this phenomenon very challenging and thus slower to progress. We find here that the structural relaxation time as a function of the two-body excess entropy, calculated for the extensional axis of the shear flow, collapses onto the corresponding equilibrium curve for a wide range of pair potentials ranging from harsh repulsive to soft and finite. This two-body excess entropy collapse provides a powerful approach to predicting the dynamics of nonequilibrium liquids from their equilibrium counterparts. Furthermore, the two body excess entropy scaling suggests that sheared dynamics is controlled purely by the liquid structure captured in the form of the two-body excess entropy along the extensional direction, shedding light on the perplexing mechanism behind shear thinning. PMID- 29247051 TI - Viruses causing lower respiratory symptoms in young children: findings from the ORChID birth cohort. AB - INTRODUCTION: Viral acute respiratory infections (ARIs) cause substantial child morbidity. Sensitive molecular-based assays aid virus detection, but the clinical significance of positive tests remains uncertain as some viruses may be found in both acutely ill and healthy children. We describe disease-pathogen associations of respiratory viruses and quantify virus-specific attributable risk of ARIs in healthy children during the first 2 years of life. METHODS: One hundred fifty eight term newborn babies in Brisbane, Australia, were recruited progressively into a longitudinal, community-based, birth cohort study conducted between September 2010 and October 2014. A daily tick-box diary captured predefined respiratory symptoms from birth until their second birthday. Weekly parent collected nasal swabs were batch-tested for 17 respiratory viruses by PCR assays, allowing calculation of virus-specific attributable fractions in the exposed (AFE) to determine the proportion of virus-positive children whose ARI symptoms could be attributed to that particular virus. RESULTS: Of 8100 nasal swabs analysed, 2646 (32.7%) were virus-positive (275 virus codetections, 3.4%), with human rhinoviruses accounting for 2058/2646 (77.8%) positive swabs. Viruses were detected in 1154/1530 (75.4%) ARI episodes and in 984/4308 (22.8%) swabs from asymptomatic periods. Respiratory syncytial virus (AFE: 68% (95% CI 45% to 82%)) and human metapneumovirus (AFE: 69% (95% CI 43% to 83%)) were strongly associated with higher risk of lower respiratory symptoms. DISCUSSION: The strong association of respiratory syncytial virus and human metapneumovirus with ARIs and lower respiratory symptoms in young children managed within the community indicates successful development of vaccines against these two viruses should provide substantial health benefits. PMID- 29247050 TI - Voltage modulates halothane-triggered Ca2+ release in malignant hyperthermia susceptible muscle. AB - Malignant hyperthermia (MH) is a fatal hypermetabolic state that may occur during general anesthesia in susceptible individuals. It is often caused by mutations in the ryanodine receptor RyR1 that favor drug-induced release of Ca2+ from the sarcoplasmic reticulum. Here, knowing that membrane depolarization triggers Ca2+ release in normal muscle function, we study the cross-influence of membrane potential and anesthetic drugs on Ca2+ release. We used short single muscle fibers of knock-in mice heterozygous for the RyR1 mutation Y524S combined with microfluorimetry to measure intracellular Ca2+ signals. Halothane, a volatile anesthetic used in contracture testing for MH susceptibility, was equilibrated with the solution superfusing the cells by means of a vaporizer system. In the range 0.2 to 3%, the drug causes significantly larger elevations of free myoplasmic [Ca2+] in mutant (YS) compared with wild-type (WT) fibers. Action potential-induced Ca2+ signals exhibit a slowing of their time course of relaxation that can be attributed to a component of delayed Ca2+ release turnoff. In further experiments, we applied halothane to single fibers that were voltage clamped using two intracellular microelectrodes and studied the effect of small (10-mV) deviations from the holding potential (-80 mV). Untreated WT fibers show essentially no changes in [Ca2+], whereas the Ca2+ level of YS fibers increases and decreases on depolarization and hyperpolarization, respectively. The drug causes a significant enhancement of this response. Depolarizing pulses reveal a substantial negative shift in the voltage dependence of activation of Ca2+ release. This behavior likely results from the allosteric coupling between RyR1 and its transverse tubular voltage sensor. We conclude that the binding of halothane to RyR1 alters the voltage dependence of Ca2+ release in MH-susceptible muscle fibers such that the resting membrane potential becomes a decisive factor for the efficiency of the drug to trigger Ca2+ release. PMID- 29247054 TI - Condensed tannins affect bacterial and fungal microbiomes and mycotoxin production during ensiling and upon aerobic exposure. AB - Purple prairie clover (PPC; Dalea purpurea Vent.) containing 84.5 g/kg DM of condensed tannin (CT) was ensiled without (Control) or with polyethylene glycol (PEG) for 76 days, followed by 14 days of aerobic exposure. Changes in fermentation characteristics were determined and bacterial and fungal communities were assessed using metagenomic sequencing. Addition of PEG that deactivated CT at ensiling increased (P < 0.05~0.001) soluble N, non-protein N, lactic acid, total volatile fatty acids, ammonia N, deoxynivalenol (DON) and ochratoxin A (OTA), but decreased (P < 0.001) pH and water soluble carbohydrates. Concentration of DON and OTA increased (P < 0.001) for both silages with the extent of increase being greater for Control than for PEG treated silage during aerobic exposure. The PEG treated silage exhibited higher (P < 0.01~0.001) copy numbers of total bacteria, Lactobacillus, yeasts and fungi than Control. Addition of PEG decreased (P < 0.01) bacterial diversity during both ensiling and aerobic exposure, whereas it increased (P < 0.05) fungal diversity during aerobic exposure. Addition of PEG at ensiling increased (P < 0.05) abundances of Lactobacillus and Pediococcus, but decreased (P < 0.01) abundances of Lactococcus and Leuconostoc Filamentous fungi were found in the microbiome at ensiling and after aerobic exposure, whereas the Bacillus were the dominate bacteria after aerobic exposure. In conclusion, CT decreased protein degradation and improved aerobic stability of silage. These desirable outcomes likely reflect the ability of PPC CT to inhibit those microorganisms involved in lowering silage quality and in the production of mycotoxins.IMPORTANCE The present study reports the effects of condensed tannins on the complex microbial communities involved in ensiling and aerobic exposure of purple prairie clover. This study documents the ability of condensed tannins to lower mycotoxin production and associated microbiome. Taxonomic bacterial community profiles were dominated by the Lactobacillales after fermentation, with a notable increase in Bacillus as a result of aerobic exposure. It is interesting to observe that condensed tannins decreased bacterial diversity during both ensiling and aerobic exposure but increased fungal diversity during aerobic exposure only. The present study indicates that the effects of condensed tannins on microbial communities lead to a reduced lactic acid and total volatile fatty acids production, proteolysis and mycotoxin concentration in the terminal silage and an improved aerobic stability. Condensed tannins could be used as additive to control unfavorable microbial development and maybe enhanced feed safety. PMID- 29247053 TI - Affimer proteins inhibit immune complex binding to FcgammaRIIIa with high specificity through competitive and allosteric modes of action. AB - Protein-protein interactions are essential for the control of cellular functions and are critical for regulation of the immune system. One example is the binding of Fc regions of IgG to the Fc gamma receptors (FcgammaRs). High sequence identity (98%) between the genes encoding FcgammaRIIIa (expressed on macrophages and natural killer cells) and FcgammaRIIIb (expressed on neutrophils) has prevented the development of monospecific agents against these therapeutic targets. We now report the identification of FcgammaRIIIa-specific artificial binding proteins called "Affimer" that block IgG binding and abrogate FcgammaRIIIa-mediated downstream effector functions in macrophages, namely TNF release and phagocytosis. Cocrystal structures and molecular dynamics simulations have revealed the structural basis of this specificity for two Affimer proteins: One binds directly to the Fc binding site, whereas the other acts allosterically. PMID- 29247055 TI - The 14-3-3 Protein Homolog ArtA Regulates Development and Secondary Metabolism in the Opportunistic Plant Pathogen Aspergillus flavus. AB - The opportunistic plant-pathogenic fungus Aspergillus flavus produces carcinogenic mycotoxins termed aflatoxins (AF). Aflatoxin contamination of agriculturally important crops, such as maize, peanut, sorghum, and tree nuts, is responsible for serious adverse health and economic impacts worldwide. In order to identify possible genetic targets to reduce AF contamination, we have characterized the artA gene, encoding a putative 14-3-3 homolog in A. flavus The artA deletion mutant presents a slight decrease in vegetative growth and alterations in morphological development and secondary metabolism. Specifically, artA affects conidiation, and this effect is influenced by the type of substrate and culture condition. In addition, normal levels of artA are required for sclerotial development. Importantly, artA negatively regulates AF production as well as the concomitant expression of genes in the AF gene cluster. An increase in AF is also observed in seeds infected with the A. flavus strain lacking artA Furthermore, the expression of other secondary metabolite genes is also artA dependent, including genes in the cyclopiazonic acid (CPA) and ustiloxin gene clusters, in this agriculturally important fungus.IMPORTANCE In the current study, artA, which encodes a 14-3-3 homolog, was characterized in the agriculturally and medically important fungus Aspergillus flavus, specifically, its possible role governing sporulation, formation of resistant structures, and secondary metabolism. The highly conserved artA is necessary for normal fungal morphogenesis in an environment-dependent manner, affecting the balance between production of conidiophores and the formation of resistant structures that are necessary for the dissemination and survival of this opportunistic pathogen. This study reports a 14-3-3 protein affecting secondary metabolism in filamentous fungi. Importantly, artA regulates the biosynthesis of the potent carcinogenic compound aflatoxin B1 (AFB1) as well as the production of other secondary metabolites. PMID- 29247056 TI - Genome Sequencing Links Persistent Outbreak of Legionellosis in Sydney (New South Wales, Australia) to an Emerging Clone of Legionella pneumophila Sequence Type 211. AB - The city of Sydney, Australia, experienced a persistent outbreak of Legionella pneumophila serogroup 1 (Lp1) pneumonia in 2016. To elucidate the source and guide public health actions, the genomes of clinical and environmental Lp1 isolates recovered over 7 weeks were examined. A total of 48 isolates from human cases and cooling towers were sequenced and compared using single-nucleotide polymorphism (SNP)-based core-genome multilocus sequencing typing (MLST) and pangenome approaches. All three methods confirmed phylogenetic relatedness between isolates associated with outbreaks in the Central Business District (CBD) in March and May and those in suburb 1. These isolates were designated the "main cluster" and consisted of isolates from two patients from the CBD March outbreak, one patient and one tower isolate from suburb 1, and isolates from two cooling towers and three patients from the CBD May outbreak. All main cluster isolates were sequence type 211 (ST211), which previously has only been reported in Canada. Significantly, pangenome analysis identified mobile genetic elements containing a unique type IV A F-type secretion system (T4ASS), which was specific to the main cluster, and cocirculating clinical strains, suggesting a potential mechanism for increased fitness and persistence of the outbreak clone. Genome sequencing enabled linking of the geographically dispersed environmental sources of infection among the spatially and temporally coinciding cases of legionellosis in a highly populated urban setting. The discovery of a unique T4ASS emphasizes the role of genome recombination in the emergence of successful Lp1 clones.IMPORTANCE A new emerging clone has been responsible for a prolonged legionellosis outbreak in Sydney, Australia. The use of whole-genome sequencing linked two outbreaks thought to be unrelated and confirmed the outliers. These findings led to the resampling and subsequent identification of the source, guiding public health actions and bringing the outbreak to a close. Significantly, the outbreak clone was identified as sequence type 211 (ST211). Our study reports this ST in the Southern Hemisphere and presents a description of ST211 genomes from both clinical and environmental isolates. A unique mobile genetic element containing a type IV secretion system was identified in Lp1 ST211 isolates linked to the main cluster and Lp1 ST42 isolates that were cocirculating at the time of the outbreak. PMID- 29247057 TI - Differential Engagement of Fermentative Taxa in Gut Contents of the Earthworm Lumbricus terrestris. AB - The earthworm gut is an anoxic, saccharide-rich microzone in aerated soils. The apparent degradation of diverse saccharides in the alimentary canal of the model earthworm Lumbricusterrestris is concomitant with the production of diverse organic acids, indicating that fermentation is an ongoing process in the earthworm gut. However, little is known about how different gut-associated saccharides are fermented. The hypothesis of this investigation was that different gut-associated saccharides differentially stimulate fermentative microorganisms in gut contents of L. terrestris This hypothesis was addressed by (i) assessing the fermentation profiles of anoxic gut content microcosms that were supplemented with gut-associated saccharides and (ii) the concomitant phylogenic analysis of 16S rRNA sequences. Galactose, glucose, maltose, mannose, arabinose, fucose, rhamnose, and xylose stimulated the production of fermentation products, including H2, CO2, acetate, lactate, propionate, formate, succinate, and ethanol. Fermentation profiles were dependent on the supplemental saccharide (e.g., glucose yielded large amounts of H2 and ethanol, whereas fucose did not, and maltose yielded large amounts of lactate, whereas mannose did not). Approximately 1,750,000 16S rRNA sequences were affiliated with 37 families, and phylogenic analyses indicated that a respective saccharide stimulated a subset of the diverse phylotypes. An Aeromonas-related phylotype displayed a high relative abundance in all treatments, whereas key Enterobacteriaceae-affiliated phylotypes were stimulated by some but not all saccharides. Collectively, these results reinforce the likelihood that (i) different saccharides stimulate different fermentations in gut contents of the earthworm and (ii) facultative aerobes related to Aeromonadaceae and Enterobacteriaceae can be important drivers of these fermentations.IMPORTANCE The feeding habits of earthworms influence the turnover of elements in the terrestrial biosphere. The alimentary tract of the earthworm constitutes an anoxic saccharide-rich microzone in aerated soils that offers ingested microbes a unique opportunity for anaerobic growth. The fermentative activity of microbes in the alimentary tract are responsible for the in situ production of (i) organic compounds that can be assimilated by the earthworm and (ii) H2 that is subject to in vivo emission by the earthworm and can be trophically linked to secondary microbial events in soils. To gain insight on how fermentative members of the gut microbiome might respond to the saccharide rich alimentary canal, this study examines the impact of diverse gut-associated saccharides on the differential activation of fermentative microbes in gut contents of the model earthworm L. terrestris. PMID- 29247058 TI - Frankia Diversity in Host Plant Root Nodules Is Independent of Abundance or Relative Diversity of Frankia Populations in Corresponding Rhizosphere Soils. AB - Actinorhizal plants form nitrogen-fixing root nodules in symbiosis with soil dwelling actinobacteria within the genus Frankia, and specific Frankia taxonomic clusters nodulate plants in corresponding host infection groups. In same-soil microcosms, we observed that some host species were nodulated (Alnus glutinosa, Alnus cordata, Shepherdia argentea, Casuarina equisetifolia) while others were not (Alnus viridis, Hippophae rhamnoides). Nodule populations were represented by eight different sequences of nifH gene fragments. Two of these sequences characterized frankiae in S. argentea nodules, and three others characterized frankiae in A. glutinosa nodules. Frankiae in A. cordata nodules were represented by five sequences, one of which was also found in nodules from A. glutinosa and C. equisetifolia, while another was detected in nodules from A. glutinosa Quantitative PCR assays showed that vegetation generally increased the abundance of frankiae in soil, independently of the target gene (i.e., nifH or the 23S rRNA gene). Targeted Illumina sequencing of Frankia-specific nifH gene fragments detected 24 unique sequences from rhizosphere soils, 4 of which were also found in nodules, while the remaining 4 sequences in nodules were not found in soils. Seven of the 24 sequences from soils represented >90% of the reads obtained in most samples; the 2 most abundant sequences from soils were not found in root nodules, and only 2 of the sequences from soils were detected in nodules. These results demonstrate large differences between detectable Frankia populations in soil and those in root nodules, suggesting that root nodule formation is not a function of the abundance or relative diversity of specific Frankia populations in soils.IMPORTANCE The nitrogen-fixing actinobacterium Frankia forms root nodules on actinorhizal plants, with members of specific Frankia taxonomic clusters nodulating plants in corresponding host infection groups. We assessed Frankia diversity in root nodules of different host plant species, and we related specific populations to the abundance and relative distribution of indigenous frankiae in rhizosphere soils. Large differences were observed between detectable Frankia populations in soil and those in root nodules, suggesting that root nodule formation is not a function of the abundance or relative diversity of specific Frankia populations in soils but rather results from plants potentially selecting frankiae from the soil for root nodule formation. These data also highlight the necessity of using a combination of different assessment tools so as to adequately address methodological constraints that could produce contradictory data sets. PMID- 29247059 TI - Rice Paddy Nitrospirae Carry and Express Genes Related to Sulfate Respiration: Proposal of the New Genus "Candidatus Sulfobium". AB - Nitrospirae spp. distantly related to thermophilic, sulfate-reducing Thermodesulfovibrio species are regularly observed in environmental surveys of anoxic marine and freshwater habitats. Here we present a metaproteogenomic analysis of Nitrospirae bacterium Nbg-4 as a representative of this clade. Its genome was assembled from replicated metagenomes of rice paddy soil that was used to grow rice in the presence and absence of gypsum (CaSO4.2H2O). Nbg-4 encoded the full pathway of dissimilatory sulfate reduction and showed expression of this pathway in gypsum-amended anoxic bulk soil as revealed by parallel metaproteomics. In addition, Nbg-4 encoded the full pathway of dissimilatory nitrate reduction to ammonia (DNRA), with expression of its first step being detected in bulk soil without gypsum amendment. The relative abundances of Nbg-4 were similar under both treatments, indicating that Nbg-4 maintained stable populations while shifting its energy metabolism. Whether Nbg-4 is a strict sulfate reducer or can couple sulfur oxidation to DNRA by operating the pathway of dissimilatory sulfate reduction in reverse could not be resolved. Further genome reconstruction revealed the potential to utilize butyrate, formate, H2, or acetate as an electron donor; the Wood-Ljungdahl pathway was expressed under both treatments. Comparison to publicly available Nitrospirae genome bins revealed the pathway for dissimilatory sulfate reduction also in related Nitrospirae recovered from groundwater. Subsequent phylogenomics showed that such microorganisms form a novel genus within the Nitrospirae, with Nbg-4 as a representative species. Based on the widespread occurrence of this novel genus, we propose for Nbg-4 the name "Candidatus Sulfobium mesophilum," gen. nov., sp. nov.IMPORTANCE Rice paddies are indispensable for the food supply but are a major source of the greenhouse gas methane. If it were not counterbalanced by cryptic sulfur cycling, methane emission from rice paddy fields would be even higher. However, the microorganisms involved in this sulfur cycling are little understood. By using an environmental systems biology approach with Italian rice paddy soil, we could retrieve the population genome of a novel member of the phylum Nitrospirae This microorganism encoded the full pathway of dissimilatory sulfate reduction and expressed it in anoxic paddy soil under sulfate-enriched conditions. Phylogenomics and comparison to the results of environmental surveys showed that such microorganisms are actually widespread in freshwater and marine environments. At the same time, they represent an undiscovered genus within the little-explored phylum Nitrospirae Our results will be important for the design of enrichment strategies and postgenomic studies to further understanding of the contribution of these novel Nitrospirae spp. to the global sulfur cycle. PMID- 29247060 TI - Interactions of Salmonella enterica Serovar Typhimurium and Pectobacterium carotovorum within a Tomato Soft Rot. AB - Salmonella spp. are remarkably adaptable pathogens, and this adaptability allows these bacteria to thrive in a variety of environments and hosts. The mechanisms with which these pathogens establish within a niche amid the native microbiota remain poorly understood. Here, we aimed to uncover the mechanisms that enable Salmonella enterica serovar Typhimurium strain ATCC 14028 to benefit from the degradation of plant tissue by a soft rot plant pathogen, Pectobacterium carotovorum The hypothesis that in the soft rot, the liberation of starch (not utilized by P. carotovorum) makes this polymer available to Salmonella spp., thus allowing it to colonize soft rots, was tested first and proven null. To identify the functions involved in Salmonella soft rot colonization, we carried out transposon insertion sequencing coupled with the phenotypic characterization of the mutants. The data indicate that Salmonella spp. experience a metabolic shift in response to the changes in the environment brought on by Pectobacterium spp. and likely coordinated by the csrBC small regulatory RNA. While csrBC and flhD appear to be of importance in the soft rot, the global two-component system encoded by barA sirA (which controls csrBC and flhDC under laboratory conditions) does not appear to be necessary for the observed phenotype. Motility and the synthesis of nucleotides and amino acids play critical roles in the growth of Salmonella spp. in the soft rot.IMPORTANCE Outbreaks of produce-associated illness continue to be a food safety concern. Earlier studies demonstrated that the presence of phytopathogens on produce was a significant risk factor associated with increased Salmonella carriage on fruits and vegetables. Here, we genetically characterize some of the requirements for interactions between Salmonella and phytobacteria that allow Salmonella spp. to establish a niche within an alternate host (tomato). Pathways necessary for nucleotide synthesis, amino acid synthesis, and motility are identified as contributors to the persistence of Salmonella spp. in soft rots. PMID- 29247061 TI - Impact of Cell Surface Molecules on Conjugative Transfer of the Integrative and Conjugative Element ICESt3 of Streptococcus thermophilus. AB - Integrative conjugative elements (ICEs) are chromosomal elements that are widely distributed in bacterial genomes, hence contributing to genome plasticity, adaptation, and evolution of bacteria. Conjugation requires a contact between both the donor and the recipient cells and thus likely depends on the composition of the cell surface envelope. In this work, we investigated the impact of different cell surface molecules, including cell surface proteins, wall teichoic acids, lipoteichoic acids, and exopolysaccharides, on the transfer and acquisition of ICESt3 from Streptococcus thermophilus The transfer of ICESt3 from wild-type (WT) donor cells to mutated recipient cells increased 5- to 400-fold when recipient cells were affected in lipoproteins, teichoic acids, or exopolysaccharides compared to when the recipient cells were WT. These mutants displayed an increased biofilm-forming ability compared to the WT, suggesting better cell interactions that could contribute to the increase of ICESt3 acquisition. Microscopic observations of S. thermophilus cell surface mutants showed different phenotypes (aggregation in particular) that can also have an impact on conjugation. In contrast, the same mutations did not have the same impact when the donor cells, instead of recipient cells, were mutated. In that case, the transfer frequency of ICESt3 decreased compared to that with the WT. The same observation was made when both donor and recipient cells were mutated. The dominant effect of mutations in donor cells suggests that modifications of the cell envelope could impair the establishment or activity of the conjugation machinery required for DNA transport.IMPORTANCE ICEs contribute to horizontal gene transfer of adaptive traits (for example, virulence, antibiotic resistance, or biofilm formation) and play a considerable role in bacterial genome evolution, thus underlining the need of a better understanding of their conjugative mechanism of transfer. While most studies focus on the different functions encoded by ICEs, little is known about the effect of host factors on their conjugative transfer. Using ICESt3 of S. thermophilus as a model, we demonstrated the impact of lipoproteins, teichoic acids, and exopolysaccharides on ICE transfer and acquisition. This opens up new avenues to control gene transfer mediated by ICEs. PMID- 29247062 TI - CerR, a Single-Domain Regulatory Protein of the LuxR Family, Promotes Cerecidin Production and Immunity in Bacillus cereus. AB - Cerecidins are small lantibiotics from Bacillus cereus that were obtained using a semi-in vitro biosynthesis strategy and showed prominent antimicrobial activities against certain Gram-positive bacteria. However, the parental strain B. cereus As 1.1846 is incapable of producing cerecidins, most probably due to the transcriptional repression of the cerecidin gene cluster. Located in the cerecidin gene cluster, cerR encodes a putative response regulator protein that belongs to the LuxR family transcriptional regulators. CerR (84 amino acids) contains only a conserved DNA binding domain and lacks a conventional phosphorylation domain, which is rarely found in lantibiotic gene clusters. To investigate its function in cerecidin biosynthesis, cerR was constitutively expressed in B. cereus As 1.1846. Surprisingly, Constitutive expression of cerR enabled the production of cerecidins and enhanced self-immunity of B. cereus toward cerecidins. Reverse transcription-PCR analysis and electrophoresis mobility shift assays indicated, respectively, that the cer cluster was transcribed in two transcripts (cerAM and cerRTPFE) and that CerR regulated the cerecidin gene cluster directly by binding to the two predicted promoter regions of cerA and cerR DNase I footprinting experiments further confirmed that CerR specifically bound to the two promoter regions at a conserved inverted repeat sequence that was designated a CerR binding motif (cerR box). The present study demonstrated that CerR, as the first single-domain LuxR family transcriptional regulator, serves as a transcriptional activator in cerecidin biosynthesis and activates the cerecidin gene cluster, which was otherwise cryptic in B. cereusIMPORTANCE Lantibiotics with intriguing and prominent bioactivities are potential peptide antibiotics that could be applied in many areas, including food and pharmaceutical industries. The biosynthesis of lantibiotics is generally controlled by two-component regulatory systems consisting of histidine kinases and response regulators, while some unique and interesting regulatory systems are also revealed with the ever-increasing discovery of lantibiotic gene clusters among diverse microorganisms. Dissection of diverse lantibiotic regulation machineries would permit deep understanding of the biological functions of lantibiotics in different niches and even enable genetic activation of lantibiotic gene clusters that are otherwise cryptic. The significance of our study is to illuminate the regulatory mechanism of a special single-domain protein, CerR, in regulating cerecidin biosynthesis in Bacillus cereus, providing a possible novel approach to activate cryptic lantibiotic clusters. PMID- 29247063 TI - Near-infrared fluorescence molecular endoscopy detects dysplastic oesophageal lesions using topical and systemic tracer of vascular endothelial growth factor A. PMID- 29247064 TI - Exosomal adrenomedullin derived from cancer-associated fibroblasts promotes lipolysis in adipose tissue. PMID- 29247065 TI - Sebaceous tumours: more than skin deep. AB - : CLINICAL PRESENTATION: A 77-year-old man presented to our skin cancer centre with various cutaneous tumours occurring in 2006-2017. Histopathology showed a 'hidradenocarcinoma' on the left upper back (2006) and a sebaceous adenoma (figure 1) on the left shoulder (2011). In 2017, he developed a sebaceous carcinoma on the middle upper back, which manifested as a slowly enlarging, asymptomatic nodule. Medical history was significant for curative resection of colorectal cancer in 1988.gutjnl;67/11/1957/F1F1F1Figure 1Clinical appearance of the sebaceous adenoma on the patient's left shoulder in 2011.The most recent lesion was subjected to extensive immunohistochemical assessment. The neoplastic cells were positive for cytokeratin 5/6, cytokeratin 7, cluster of differentiation antigen 10, adipophilin, androgen receptor, epithelial membrane antigen, KI67 antigen, MLH1 and PMS2, but stained negative for gross cystic disease fluid protein 15, prostate-specific antigen, carbohydrate antigen 19/9, CDX2 protein, hepatocyte-specific antigen, carcinoembryonic antigen, cluster of differentiation antigen 117 and cytokeratin 19. Given the variety of histological manifestations of the patient's skin neoplasms, further studies were performed. They revealed positive nuclear expression signals for MLH1, MSH6 and PMS2, whereas MSH2 expression was absent in almost all tumour cells (figure 2). Positron emission tomography (PET)/CT and colonoscopy did not detect any pathological findings. However, molecular genetic analysis of peripheral blood showed a heterozygous deletion of exon 7 of the MSH2 gene. Subsequently, several family members tested positive for MSH2 mutations and underwent genetic counselling.gutjnl;67/11/1957/F2F2F2Figure 2(A-D) Histopathological images of the patient's most recent lesion (diaminobenzidine, original magnification, *100). The tumour cells demonstrated strong nuclear positivity for MLH1 (A) and PMS2 (B), but were essentially negative for MSH6 (C) and MSH2 (D). QUESTION: What is your diagnosis? DIAGNOSIS: Muir-Torre syndrome (MTS). PMID- 29247066 TI - Helicobacter pylori eradication failure may have confounded the recent large scale health database study that showed proton pump inhibitors increase gastric cancer risk. PMID- 29247067 TI - Chronic cough in Swiss bagpipe player. PMID- 29247068 TI - Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II). AB - OBJECTIVE: Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn's disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported. DESIGN: Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28 week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up. RESULTS: 247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn's Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis. CONCLUSIONS: PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development. TRIAL REGISTRATION NUMBER: NCT01287897 and NCT01345318. PMID- 29247069 TI - Prospective study of restless legs syndrome and total and cardiovascular mortality among women. AB - OBJECTIVE: We prospectively examined whether women with physician-diagnosed restless legs syndrome (RLS) had a higher risk of total and cardiovascular disease (CVD) mortality relative to those without RLS. METHODS: The current study included 57,417 women (mean age 67 years) from the Nurses' Health Study without cancer, renal failure, and CVD at baseline (2002). Main outcomes were total and CVD mortality. We used the Cox proportional hazards model to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CVD-specific mortality based on RLS status, adjusting for age, presence of major chronic diseases, and other potential confounders. RESULTS: We documented 6,448 deaths during 10 years of follow-up. We did not observe a significant association between presence of physician-diagnosed RLS and high risk of total mortality (adjusted HR 1.15, 95% CI 0.98-1.34). When cause-specific mortality was studied, participants with RLS had a significantly higher risk of CVD mortality (adjusted HR 1.43, 95% CI 1.02-2.00) relative to those without RLS after adjustment for potential confounders. Longer duration of RLS diagnosis was significantly associated with a higher risk of CVD mortality (p for trend = 0.04). Excluding participants with common RLS comorbidities strengthened the association between RLS and total (adjusted HR 1.43, 95% CI 1.03-1.97) and CVD mortality (adjusted HR 2.27, 95% CI 1.21-4.28). However, we did not find a significant association between RLS and mortality due to cancer and other causes. CONCLUSIONS: Women with RLS had a higher CVD mortality rate, which may not be fully explained by common co-occurring disorders of RLS. PMID- 29247071 TI - Evaluation of idiopathic transverse myelitis revealing specific myelopathy diagnoses. AB - OBJECTIVE: To evaluate specific myelopathy diagnoses made in patients with suspected idiopathic transverse myelitis (ITM). METHODS: A total of 226 patients 18 years and older were referred to Mayo Clinic Neurology for suspected ITM from December 1, 2010, to December 31, 2015. Electronic medical records were reviewed for detailed clinical presentation and course, laboratory and electrophysiologic investigations, and neuroimaging to determine the etiology. Current diagnostic criteria for ITM and alternative myelopathy diagnoses were applied. All cases where any discrepancy was suspected from the final reported clinical diagnosis were reviewed by each author and a consensus final diagnosis was made. RESULTS: The diagnostic criteria for ITM were met in 41 of 226 patients (18.1%). In 158 patients (69.9%), an alternative specific myelopathy diagnosis was made: multiple sclerosis or clinically isolated syndrome, 75; vascular myelopathy, 41; neurosarcoidosis, 12; neuromyelitis optica spectrum disorder, 12; myelin oligodendrocyte glycoprotein myelopathy, 5; neoplastic, 4; compressive, 3; nutritional, 3; infectious, 2; and other, 2. A myelopathy was not confirmed in 27 patients. Time from symptom onset to final clinical diagnosis in patients without ITM was a median of 9 months (range 0-288). Fifty-five patients (24%) required treatment changes according to their final clinical diagnosis. CONCLUSIONS: The majority of patients with suspected ITM have an alternative specific myelopathy diagnosis. A presumptive diagnosis of ITM can lead to premature diagnostic conclusions affecting patient treatment. PMID- 29247070 TI - Mixed-location cerebral hemorrhage/microbleeds: Underlying microangiopathy and recurrence risk. AB - OBJECTIVE: To assess the predominant type of cerebral small vessel disease (SVD) and recurrence risk in patients who present with a combination of lobar and deep intracerebral hemorrhage (ICH)/microbleed locations (mixed ICH). METHODS: Of 391 consecutive patients with primary ICH enrolled in a prospective registry, 75 (19%) had mixed ICH. Their demographics, clinical/laboratory features, and SVD neuroimaging markers were compared to those of 191 patients with probable cerebral amyloid angiopathy (CAA-ICH) and 125 with hypertensive strictly deep microbleeds and ICH (HTN-ICH). ICH recurrence and case fatality were also analyzed. RESULTS: Patients with mixed ICH showed a higher burden of vascular risk factors reflected by a higher rate of left ventricular hypertrophy, higher creatinine values, and more lacunes and severe basal ganglia (BG) enlarged perivascular spaces (EPVS) than patients with CAA-ICH (all p < 0.05). In multivariable models mixed ICH diagnosis was associated with higher creatinine levels (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.2-5.0, p = 0.010), more lacunes (OR 3.4, 95% CI 1.7-6.8), and more severe BG EPVS (OR 5.8, 95% CI 1.7-19.7) than patients with CAA-ICH. Conversely, when patients with mixed ICH were compared to patients with HTN-ICH, they were independently associated with older age (OR 1.03, 95% CI 1.02-1.1), more lacunes (OR 2.4, 95% CI 1.1-5.3), and higher microbleed count (OR 1.6, 95% CI 1.3-2.0). Among 90-day survivors, adjusted case fatality rates were similar for all 3 categories. Annual risk of ICH recurrence was 5.1% for mixed ICH, higher than for HTN-ICH but lower than for CAA-ICH (1.6% and 10.4%, respectively). CONCLUSIONS: Mixed ICH, commonly seen on MRI obtained during etiologic workup, appears to be driven mostly by vascular risk factors similar to HTN-ICH but demonstrates more severe parenchymal damage and higher ICH recurrence risk. PMID- 29247072 TI - Vascular and dopaminergic contributors to mild parkinsonian signs in older adults. AB - OBJECTIVE: Mild parkinsonian signs (MPS) are an underappreciated neurologic condition in older adults; we assessed associations of MPS with measures of dopaminergic (catechol-O-methyltransferase [COMT] genotype, an indicator of synaptic dopamine levels) and vascular (white matter hyperintensities [WMH], an indicator of cerebral small vessel disease) factors. METHODS: In a cohort of older adults (mean age 82.6 years [SD 2.6]; 58.0% female; 38.8% black), we assessed cross-sectional associations of WMH volume and COMT Val158Met (rs4680) genotype (n = 35 Met/Met, n = 180 Val carriers) with MPS by regression models adjusted for demographic and health characteristics. Interactions between WMH and COMT were assessed and analyses were repeated stratified by COMT genotype (Met/Met related to higher synaptic dopamine vs Val carriers related to lower synaptic dopamine). RESULTS: MPS was present in 42.3% of our sample. WMH (odds ratio [OR] 1.16, confidence interval [CI] 1.05-1.27) but not COMT (Met/Met compared to Val carrier: OR 0.62, CI 0.27-1.42) was related to MPS. There was a significant interaction between WMH and COMT (p = 0.03). Stratified analyses reveled a strong association between WMH and MPS among COMT Val carriers (OR 1.23, CI 1.09-1.38), but not for Met/Met (OR 0.68, CI 0.45-1.02), independent of covariates. CONCLUSIONS: WMH had a direct relation with MPS. In contrast, COMT was not associated with MPS, but it did modify the effect of WMH on MPS. The dopaminergic system may provide compensation for the effects of WMH on MPS. These findings suggest that MPS has a vascular rather than dopaminergic origin in older adults, but both factors are important in MPS manifestation. PMID- 29247073 TI - Comparative effect of statins on the risk of incident Alzheimer disease. AB - OBJECTIVE: To investigate whether fungus-derived statins are associated with a lower risk of incident Alzheimer disease (AD) compared with synthetic statins using real-world clinical practice data. METHODS: We identified a population based retrospective cohort of patients aged >=60 years newly prescribed a statin between January 1, 1994, and December 31, 2012, and followed until March 31, 2015, using the UK Clinical Practice Research Datalink. Statins were consecutively classified according to their type, lipophilicity, and potency. For each group, we calculated the crude AD incidence rates per 1,000 person-years. Time-dependent Cox proportional hazards models adjusted for propensity score deciles were used to estimate hazard ratios (HRs) with 95% confidence interval (CIs) of incident AD associated with different statin categories. RESULTS: Over the 18-year study period, we identified 465,085 statin users, including 7,669 patients who developed AD during 2,891,268 person-years of follow-up (incidence rate 2.65 [95% CI 2.59-2.71] per 1,000 person-years). Compared to synthetic, fungus-derived statins were associated with an increased risk of AD (HR 1.09, 95% CI 1.03-1.15). Lipophilic statins also were associated with higher AD risk (HR 1.18, 95% CI 1.09-1.27) compared to hydrophilic statins, while statin potency did not modify the risk of AD (adjusted HR 1.03, 95% CI 0.98-1.08). The risk was further reduced in sensitivity analyses. CONCLUSION: Fungus-derived and lipophilic statins were not associated with decreased incidence of AD compared to synthetic and hydrophilic statins. The modest variations in the risk of incident AD observed between statin characteristics needs to be evaluated in future studies on their possible heterogeneous neuroprotective effect. PMID- 29247074 TI - Statin use and risk of Alzheimer disease: A new view on an old relationship. PMID- 29247075 TI - Specific myelopathy diagnoses using advancing diagnostics: Idiopathic no more. PMID- 29247076 TI - Quality improvement in neurology: Child neurology quality measure set: Executive summary. PMID- 29247077 TI - Mixed emotions: What to do with patients who have lobar and deep hemorrhages on MRI? PMID- 29247079 TI - Public engagement and communication: who is in charge? PMID- 29247078 TI - High capacity of the endoplasmic reticulum to prevent secretion and aggregation of amyloidogenic proteins. AB - Protein aggregation is associated with neurodegeneration and various other pathologies. How specific cellular environments modulate the aggregation of disease proteins is not well understood. Here, we investigated how the endoplasmic reticulum (ER) quality control system handles beta-sheet proteins that were designed de novo to form amyloid-like fibrils. While these proteins undergo toxic aggregation in the cytosol, we find that targeting them to the ER (ER-beta) strongly reduces their toxicity. ER-beta is retained within the ER in a soluble, polymeric state, despite reaching very high concentrations exceeding those of ER-resident molecular chaperones. ER-beta is not removed by ER associated degradation (ERAD) but interferes with ERAD of other proteins. These findings demonstrate a remarkable capacity of the ER to prevent the formation of insoluble beta-aggregates and the secretion of potentially toxic protein species. Our results also suggest a generic mechanism by which proteins with exposed beta sheet structure in the ER interfere with proteostasis. PMID- 29247080 TI - Celebrating the 25th birthday of intracytoplasmic sperm injection. PMID- 29247081 TI - Risk factors for feelings of sadness and suicide attempts among cancer survivors in South Korea: findings from nationwide cross-sectional study (KNHANES IV-VI). AB - INTRODUCTION: As the number of cancer survivors is rapidly increasing with the increased incidence of the disease and improved survival of patients, the prevalence of, and risk factors for, mental health problems and suicidality among cancer survivors should be examined. METHODS AND ANALYSIS: Using data obtained from the Korean National Health and Nutrition Examination Survey (2007-2013), we examined 1285 and 33 772 participants who had been and never been diagnosed with cancer, respectively. We investigated the risks of feelings of sadness and suicide attempts among cancer survivors and general population and examined differences in the risks of cancer survivors among subgroups according to cancer related characteristics. RESULTS: The median age of survivors at the time of the survey and at diagnosis was 63 and 54 years, respectively. After adjusting for sex, level of education, household income, occupation, marital status, cancer type, current status of treatment, age at diagnosis and years since diagnosis, the risk of suicide attempts was significantly higher in participants diagnosed with cancer before 45 years of age compared with those diagnosed at 45-64 years (adjusted OR=3.81, 95% CI 1.07 to 13.60, P=0.039), and the higher risk of suicide attempts with borderline significance was found in those for whom more than 10 years had passed since diagnosis compared with those for whom the diagnosis was made only 2-10 years ago (adjusted OR=3.38, 95% CI 0.98 to 11.70, P=0.055). However, feelings of sadness were not significantly associated with any cancer related characteristic. CONCLUSION: Our results reveal an increased risk of suicide attempts among cancer survivors diagnosed early in life and in those for whom more than 10 years has passed since the diagnosis, suggesting the need for intensive monitoring and support for mental health problems and suicidal risks in this population. PMID- 29247082 TI - Healthcare resource availability and cardiovascular health in the USA. AB - OBJECTIVES: Cardiovascular disease (CVD) remains the leading cause of death in the USA. Reducing the population-level burden of CVD disease will require a better understanding and support of cardiovascular health (CVH) in individuals and entire communities. The objectives for this study were to examine associations between community-level healthcare resources (HCrRes) and CVH in individuals and entire communities. SETTING: This study consisted of a retrospective, cross-sectional study design, using multivariable epidemiological analyses. PARTICIPANTS: All participants in the 2011 Behavioral Risk Factor Surveillance System (BRFSS) survey were examined for eligibility. CVH, defined using the American Heart Association CVH Index (CVHI), was determined using self reported responses to 2011 BRFSS questions. Data for determining HCrRes were obtained from the Area Health Resource File. Regression analysis was performed to examine associations between healthcare resources and CVHI in communities (linear regression) and individuals (Poisson regression). RESULTS: Mean CVHI was 3.3+/ 0.005 and was poorer in the Southeast and Appalachian regions of the USA. Supply of primary care physicians and physician assistants were positively associated with individual and community-level CVHI, while CVD specialist supply was negatively associated with CVHI. Individuals benefiting most from increased supply of primary care providers were: middle aged; female; had non-Hispanic other race/ethnicity; those with household income <$25 000/year; and those in non urban communities with insurance coverage. CONCLUSIONS: Our results support the importance of primary care provider supply for both individual and community CVHI, though not all sociodemographic groups benefited equally from additional primary care providers. Further research should investigate policies and factors that can effectively increase primary care provider supply and influence where they practice. PMID- 29247083 TI - Study protocol for a randomised controlled trial of Allen Carr's Easyway programme versus Lambeth and Southwark NHS for smoking cessation. AB - INTRODUCTION: Smoking is a major cause of ill health and is associated with several diseases including cancer, coronary heart disease and stroke. Many psychological and pharmacological smoking cessation treatments are available and although they are undoubtedly the most cost-effective health interventions available, many people still fail to maintain cessation in the longer term. Recently, National Institute for Health and Care Excellence called for comparative studies to determine the short-term and long-term effectiveness of Allen Carr's Easyway (ACE) method of stopping smoking. This study will compare the efficacy of the ACE programme and a 1-1 counselling service available via the National Health Service. METHODS AND ANALYSIS: A two-arm, parallel-group, blinded, randomised controlled trial will be conducted with people who smoke tobacco cigarettes, are aged >=18 years and are motivated to quit. Exclusion criteria comprise self-reported mental health condition, pregnancy or respiratory disease such as chronic obstructive pulmonary disease or emphysema. The primary treatment outcome is smoking cessation 26 weeks after treatment. Participants will be analysed on an intention to treat basis at the point of randomisation. Before being randomised, the research team will not inform participants which two treatments are being compared. Once randomised researchers will be blinded to participant condition, and participants will be blinded to the condition they are not assigned to. Logistic regression will be used to estimate the effectiveness of the treatment condition on smoking cessation at 26 weeks. The following covariates will be included: baseline quit efficacy (at inclusion), age (at inclusion), gender and baseline nicotine dependency. ETHICS AND DISSEMINATION: Approval was granted by London-Fulham Research Ethics Committee (ref: 16/LO/1657). The study's findings will be published in peer-reviewed journals and disseminated at national and international conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier number: NCT02855255. ISRCTN registration number: ISRCTN23584477; Pre-results. PMID- 29247084 TI - Protocol of a single group prospective observational study on the diagnostic value of 3T susceptibility weighted MRI of nigrosome-1 in patients with parkinsonian symptoms: the N3iPD study (nigrosomal iron imaging in Parkinson's disease). AB - INTRODUCTION: Parkinson's disease (PD) is the most common movement disorder in the elderly and is characterised clinically by bradykinesia, tremor and rigidity. Diagnosing Parkinson's can be difficult especially in the early stages. High resolution nigrosome MRI offers promising diagnostic accuracy of patients with established clinical symptoms; however, it is unclear whether this may help to establish the diagnosis in the early stages of PD, when there is diagnostic uncertainty. In this scenario, a single photon emission CT scan using a radioactive dopamine transporter ligand can help to establish the diagnosis, or clinical follow-up may eventually clarify the diagnosis. A non-invasive, cost effective diagnostic test that could replace this would be desirable. We therefore aim to prospectively test whether nigrosome MRI is as useful as DaTSCAN to establish the correct diagnosis in people with minor or unclear symptoms suspicious for PD. METHODS AND ANALYSIS: In a prospective study we will recruit 145 patients with unclear symptoms possibly caused by Parkinson's from three movement disorder centres in the UK to take part in the study. We will record the Movement Disorder Society - Unified Parkinson's Disease Rating Scale, and participants will undergo DaTSCAN and high-resolution susceptibility weighted MRI at a field strength of 3T. DaTSCANs will be assessed visually and semiquantitatively; MRI scans will be visually assessed for signal loss in nigrosome-1 by blinded investigators. We will compare how the diagnosis suggested by MRI compares with the diagnosis based on DaTSCAN and will also validate the diagnosis based on the two tests with a clinical examination performed at least 1 year after the initial presentation as a surrogate gold standard diagnostic test. ETHICS AND DISSEMINATION: The local ethics commission (Health Research Authority East Midlands - Derby Research Ethics Committee) has approved this study (REC ref.: 16/EM/0229). The study is being carried out under the principles of the Declaration of Helsinki (64th, 2013) and Good Clinical Practice standards. We have included a number of 15 research-funded DaTSCAN in the research protocol. This is to compensate for study site-specific National Health Service funding for this investigation in affected patients. We therefore have also obtained approval from the Administration of Radioactive Substances Administration Committee (ARSAC Ref 253/3629/35864). All findings will be presented at relevant scientific meetings and published in peer-reviewed journals, on the study website, and disseminated in lay and social media where appropriate. TRIAL REGISTRATION NUMBER: NCT03022357; Pre-results. PMID- 29247085 TI - Temporal trend in socioeconomic inequalities in the uptake of cancer screening programmes in France between 2005 and 2010: results from the Cancer Barometer surveys. AB - OBJECTIVES: Cancer screening is a form of secondary prevention for a disease which is now the leading cause of death in France. Various socioeconomic indicators have been identified as potential factors for disparities in breast, cervical and colorectal cancer screening uptake. We aimed to identify the socioeconomic inequalities, which persisted in screening uptake for these cancers, and to quantify these disparities over a 5-year period. SETTING: The Cancer Barometer was a population-based-survey carried out in 2005 and 2010 in France. PARTICIPANTS: A randomly selected sample of participants aged 15-85 years (n=3820 in 2005 and n=3727 in 2010) were interviewed on their participation in breast, cervical and colorectal cancer screening-programmes and their socioeconomic profile. PRIMARY AND SECONDARY OUTCOME MEASURES: For each type of screening programme, we calculated participation rates, OR and relative inequality indices (RII) for participation, derived from logistic regression of the following socioeconomic variables: income, education, occupation, employment and health insurance. Changes in participation between 2005 and 2010 were then analysed. RESULTS: Participation rates for breast and colorectal screening increased significantly among the majority of socioeconomic categories, whereas for cervical cancer screening there were no significant changes between 2005 and 2010. RIIs for income remained significant for cervical smear in 2005 (RII=0.25, 95% CI 0.13 to 0.48) and in 2010 (RII=0.31, 95% CI 0.15 to 0.64). RIIs for education in mammography (RII=0.43, 95% CI 0.19 to 0.98) and cervical smear (RII=0.36, 95% CI 0.21 to 0.64) were significant in 2005 and remained significant for cervical smear (RII=0.40, 95% CI 0.22 to 0.74) in 2010. CONCLUSIONS: There was a persistence of socioeconomic inequalities in the uptake of opportunistic cervical cancer screening. Conversely, organised screening programmes for breast and colorectal cancer saw a reduction in relative socioeconomic inequalities, even though the results were not statistically significant. The findings suggest that organised cancer screening programmes may have the potential to reduce socioeconomic disparities in participation. PMID- 29247086 TI - Risk of high-grade lesions after atypical glandular cells in cervical screening: a population-based cohort study. AB - OBJECTIVES: To determine how human papillomavirus (HPV) positivity of atypical glandular cells (AGCs) affects the predictive values for the presence of high grade cervical lesions. DESIGN: Population-based cohort study. SETTING: Stockholm Gotland region, Sweden. PARTICIPANTS: Between 17 February 2014 and 30 June 2016, there were 562 women with AGC detected in a cervical sample. Registry linkages up to 30 June 2016 identified 392 women with an associated HPV test and a histopathological follow-up. MAIN OUTCOME MEASURE: Presence of a high-grade cervical lesion in the cervical biopsy taken after the AGC smear, in relation to the HPV status of the AGC-containing index smear. RESULTS: The proportion of HPV positive AGC was 56% (n=222). In this group, there were six cases of invasive cervical adenocarcinoma, 33 cases of cervical adenocarcinoma in situ and 93 cases of high-grade squamous intraepithelial lesion (HSIL), giving a positive predictive value (PPV) for a cervical high-grade lesion of 60% (132/222). Among the 170 women with HPV-negative AGC, there was one invasive cervical squamous cell cancer and four HSIL, giving an PPV for a cervical high-grade lesion of 2.9% (5/170). This group also contained five endometrial cancers and one breast cancer. CONCLUSIONS: HPV triaging of AGC will greatly increase the predictive ability for identifying cervical high-grade lesions (OR: 48.4 (95% CI 19.1 to122.6)) and the high sensitivity (96%; 132/137 women) implies safety of primary HPV screening strategies, with regard to this subset of patients. The measurable risk for endometrial cancer among women with HPV-negative AGC (2.9%) suggests that research on screening for endometrial cancer is needed. PMID- 29247088 TI - Sex differences in non-communicable disease prevalence in China: a cross sectional analysis of the China Health and Retirement Longitudinal Study in 2011. AB - OBJECTIVES: To describe the sex differences in the prevalence of non-communicable diseases (NCDs) in adults aged 45 years or older in China. DESIGN: Cross sectional study. SETTING: Nationally representative sample of the Chinese population 2011. PARTICIPANTS: 8401 men and 8928 women over 45 years of age who participated in the first wave of the China Health and Retirement Longitudinal Study (CHARLS). OUTCOME MEASURES: Self-reported data on overall health and diagnosis of hypertension, dyslipidaemia, diabetes, heart disease, stroke, chronic lung disease, cancer or arthritis. Sex differences in NCDs were described using logistic regression to generate odds ratios (OR) with adjustment for sociodemographic factors and health-related behaviours. All analyses were stratified by age group for 45-64-year-old and >=65-year-old participants. RESULTS: In both age groups, men reported better overall health than women. The crude prevalence of heart disease, cancer and arthritis was higher while that of stroke and chronic lung disease was lower in women than in men. After adjustment, ORs (95% CI) for the 45-64 and >=65 year age groups were 0.70 (0.58 to 0.84) and 0.66 (0.54 to 0.80), respectively, for arthritis for men compared with women. In contrast, ORs were 1.66 (1.09 to 2.52) and 2.12 (1.36 to 3.30) for stroke and 1.51 (1.21 to 1.89) and 1.43 (1.09 to 1.88) for chronic lung disease for men compared with women. ORs for heart disease (0.65 (0.52 to 0.80)) were lower in men than in women only in the 45-64 year age group. CONCLUSIONS: Odds of arthritis were lower while those of stroke and chronic lung disease were higher in men than in women in both age groups. However, odds of heart disease were lower in men than in women, but only in the group of individuals aged 45-64 years. PMID- 29247087 TI - Accuracy of recall of musculoskeletal injuries in elite military personnel: a cross-sectional study. AB - BACKGROUND: Self-reported data are often used in research studies among military populations. OBJECTIVE: The accuracy of self-reported musculoskeletal injury data among elite military personnel was assessed for issues with recall. DESIGN: Cross sectional study. SETTING: Applied research laboratory at a military installation. PARTICIPANTS: A total of 101 subjects participated (age 28.5+/-5.6 years). Study participants were active duty military personnel, with no conditions that precluded them from full duty. PRIMARY AND SECONDARY OUTCOME MEASURES: Self reported and medical record reviewed injuries that occurred during a 1-year period were matched by anatomic location, injury side (for extremity injuries), and injury year and type. The accuracy of recall was estimated as the per cent of medical record reviewed injuries correctly recalled in the self-report. The effect of injury anatomic location, injury type and severity and time since injury, on recall, was also assessed. Injuries were classified as recent (<=4 years since injury) or old injuries (>4 years since injury). Recall proportions were compared using Fisher's exact tests. RESULTS: A total of 374 injuries were extracted from the subjects' medical records. Recall was generally low (12.0%) and was not different between recent and old injuries (P=0.206). Injury location did not affect recall (P=0.418). Recall was higher for traumatic fractures as compared with less severe non-fracture injuries (P values 0.001 to <0.001). Recall for non-fracture injuries was higher for recent as compared with old injuries (P=0.033). This effect of time since injury on recall was not observed for fractures (P=0.522). CONCLUSIONS: The results of this study highlight the importance of weighing the advantages and disadvantages of self-reported injury data before their use in research studies in military populations and the need for future research to identify modifiable factors that influence recall. PMID- 29247089 TI - Study protocol for Smartphone Monitoring for Atrial fibrillation in Real-Time in India (SMART-India): a community-based screening and referral programme. AB - INTRODUCTION: Atrial fibrillation (AF), the world's most common arrhythmia, often goes undetected and untreated in low-resource communities, including India, where AF epidemiology is undefined. AF is an important risk factor for stroke, which plagues an estimated 1.6 million Indians annually. As such, early detection of AF and management of high-risk patients is critically important to decrease stroke burden in individuals with AF. This study aims to describe the epidemiology of AF in Anand District, Gujarat, India, characterise the clinical profile of individuals who are diagnosed with AF and determine the performance of two mobile technologies for community-based AF screening. METHODS: This observational study builds on findings from a previous feasibility study and leverages two novel technologies as well as an existing community health programme to perform door-to door AF screening for 2000 people from 60 villages of Anand District, Gujarat, India using local health workers. A single-lead ECG and a pulse-based application is used to screen each individual for AF three times over a period of 5 days. Participants with suspected arrhythmias are followed up by study cardiologist who makes final diagnoses. Participants diagnosed with AF are initiated on treatment based on current anticoagulation guidelines and clinical reasoning. ANALYTICAL PLAN: Age-stratified and sex-stratified prevalence of AF in the Anand District will be calculated for sample and estimated for Anand distribution using survey design weights. Sociodemographic and clinical factors associated with AF will be evaluated using multivariable regression methods. Performance of each mobile technology in detecting AF will be evaluated using a 12-lead ECG interpretation as the gold standard. ETHICS AND DISSEMINATION: This protocol was approved separately by the Institutional Review Board of University of Massachusetts Medical School and the Human Research Ethics Committee at Charutar Arogya Mandal. The findings of this study will be disseminated through peer-reviewed journals and scientific conferences. PMID- 29247090 TI - Health inequity on access to services in the ethnic minority regions of Northeastern Myanmar: a cross-sectional study. AB - OBJECTIVES: To evaluate health inequity on access to services in the ethnic regions of Northeastern Myanmar from three points of analysis: geographic barrier, gender-based disparity and financial burden of health services. SETTING: A multistage-stratified random cluster survey was conducted in Shan State Special Region 2 and Eastern Shan State Special Region 4 of Northeastern Myanmar in 2016, including a total number of 774 households. PARTICIPANTS: A total number of 4235 participants were recruited during the survey. PRIMARY AND SECONDARY OUTCOME MEASURES: Geographic distance, gender, household income and inpatient/outpatient service utilisation. RESULTS: The study results showed that residents living within 5 km of any form of healthcare facilities paid more outpatient visits (90.06 visits per thousand population) in the past 2 weeks, compared with those living 5-20 km and over 20 km (54.84 and 54.02 per thousand population, respectively) from healthcare facilities. A similar trend with little significant differences was found for inpatient service use. Regarding household income, adults with an annual household income of above US$720 were more likely to seek outpatient service (OR=1.43, 95% CI 0.98 to 2.10) compared with those with an annual income of =18 years from 10 Brazilian cities. Sociodemographic, behavioural and clinical data were obtained through interviews. MAIN OUTCOME MEASURES: HbA1c level was measured by liquid chromatography. Hierarchical multiple variable linear regression models were used to identify factors correlated with high levels of HbA1c. RESULTS: Of 979 patients with DM1, 63.8% were women, and the mean age was 40 (SD 14.6) years. The mean HbA1c level was 9.4% (SD 2.2%), and 89.6% of the patients had HbA1c >=7.0%. Factors independently correlated with increased HbA1c levels included: lower education, non-participation in diabetes classes/lecture during the year before, having a self-perception of poor adherence to diet and insulin, not having private medical care and not measuring the HbA1c levels in the prior year. Of note, poor adherence to diet and insulin were the independent factors most strongly associated with high levels of HbA1c (mean increment in HbA1c levels of 0.88% and 1.25%, respectively). CONCLUSION: Poor glycaemic control, which is common among Brazilian patients with DM1, is associated with lower education, self-perception of insufficient adherence to diet and insulin and inadequate monitoring of HbA1c levels. Specific actions, particularly those targeting improving adherence to diet and insulin, may contribute to successful management of patients with DM1. PMID- 29247093 TI - Feasibility of a hyper-acute stroke unit model of care across England: a modelling analysis. AB - OBJECTIVES: The policy of centralising hyperacute stroke units (HASUs) in England aims to provide stroke care in units that are both large enough to sustain expertise (>600 admissions/year) and dispersed enough to rapidly deliver time critical treatments (<30 min maximum travel time). Currently, just over half (56%) of patients with stroke access care in such a unit. We sought to model national configurations of HASUs that would optimise both institutional size and geographical access to stroke care, to maximise the population benefit from the centralisation of stroke care. DESIGN: Modelling of the effect of the national reconfiguration of stroke services. Optimal solutions were identified using a heuristic genetic algorithm. SETTING: 127 acute stroke services in England, serving a population of 54 million people. PARTICIPANTS: 238 887 emergency admissions with acute stroke over a 3-year period (2013-2015). INTERVENTION: Modelled reconfigurations of HASUs optimised for institutional size and geographical access. MAIN OUTCOME MEASURE: Travel distances and times to HASUs, proportion of patients attending a HASU with at least 600 admissions per year, and minimum and maximum HASU admissions. RESULTS: Solutions were identified with 75-85 HASUs with annual stroke admissions in the range of 600-2000, which achieve up to 82% of patients attending a stroke unit within 30 min estimated travel time (with at least 95% and 98% of the patients being within 45 and 60 min travel time, respectively). CONCLUSIONS: The reconfiguration of hyperacute stroke services in England could lead to all patients being treated in a HASU with between 600 and 2000 admissions per year. However, the proportion of patients within 30 min of a HASU would fall from over 90% to 80%-82%. PMID- 29247094 TI - Oral medicine modification for older adults: a qualitative study of nurses. AB - OBJECTIVE: Oral medicines are frequently modified (eg, tablets crushed) for older adults. However, these modifications can have clinical, legal and/or ethical implications. Nurses bear responsibility for medicine administration and hence, perform these modifications. The aim of this study was to investigate the knowledge, attitudes and beliefs of nurses about oral medicine modification for older adults. DESIGN: A qualitative study was conducted using semi-structured, face-to-face interviews with nurses providing care to older adults in acute and long-term care settings. Interviews were audio-recorded, transcribed verbatim and analysed thematically. SETTINGS: Sixteen purposively selected care settings; 4 acute-care and 12 long-term care settings were included. Nurses were recruited by convenience sampling at these sites. PARTICIPANTS: Eighteen nurses participated (83% female, 67% long-term care, 33% acute-care, median age (IQR) 38 years (32.5 52.0)). RESULTS: Three major themes: modifying-a necessary evil, nurses' role as patient advocate and modifying-we are working very much as a team and two minor themes: fractional dosing, and covert administration emerged from the data. Nurses viewed oral medicine modifications as being a routine and necessary occurrence in geriatric patient care due to limitations of available formulations and the presence of age-related challenges in drug administration. Nurses' knowledge of residents' requirements ensured that they advocate for those with individualised formulation needs, however, nurses rely on pharmacists for information about modifications. Nurses expressed a desire for supports including increased education and ward-specific, pharmacist-developed recommendations on common modifications. CONCLUSIONS: This study has provided useful insights into the views of nurses regarding oral medicine modification for older adults. The unique and varied formulation requirements of older adults must be acknowledged. Increased engagement by healthcare professionals, the pharmaceutical industry, regulatory agencies and policy-makers is required to facilitate the development of age-appropriate formulations. In the interim, practical interventions, informed by the findings of this study, are required. PMID- 29247095 TI - Effectiveness and cost-effectiveness of implementing HIV testing in primary care in East London: protocol for an interrupted time series analysis. AB - INTRODUCTION: HIV remains underdiagnosed. Guidelines recommend routine HIV testing in primary care, but evidence on implementing testing is lacking. In a previous study, the Rapid HIV Assessment 2 (RHIVA2) cluster randomised controlled trial, we showed that providing training and rapid point-of-care HIV testing at general practice registration (RHIVA2 intervention) in Hackney led to cost effective, increased and earlier diagnosis of HIV. However, interventions effective in a trial context may be less so when implemented in routine practice. We describe the protocol for an MRC phase IV implementation programme, evaluating the impact of rolling out the RHIVA2 intervention in a post-trial setting. We will use a longitudinal study to examine if the post-trial implementation in Hackney practices is effective and cost-effective, and a cross-sectional study to compare Hackney with two adjacent boroughs providing usual primary care (Newham) and an enhanced service promoting HIV testing in primary care (Tower Hamlets). METHODS AND ANALYSIS: Service evaluation using interrupted time series and cost effectiveness analyses. We will include all general practices in three contiguous high HIV prevalence East London boroughs. All adults aged 16 and above registered with the practices will be included. The interventions to be examined are: a post trial RHIVA2 implementation programme (including practice-based education and training, external quality assurance, incentive payments for rapid HIV testing and incorporation of rapid HIV testing in the sexual health Local Enhanced Service) in Hackney; the general practice sexual health Network Improved Service in Tower Hamlets and usual care in Newham. Coprimary outcomes are rates of HIV testing and new HIV diagnoses. ETHICS AND DISSEMINATION: The chair of the Camden and Islington NHS Research Ethics Committee, London, has endorsed this programme as an evaluation of routine care. Study results will be published in peer reviewed journals and reported to commissioners. PMID- 29247096 TI - What are the experiences of seeking, receiving and providing FGM-related healthcare? Perspectives of health professionals and women/girls who have undergone FGM: protocol for a systematic review of qualitative evidence. AB - INTRODUCTION: Female genital mutilation (FGM) is an issue of global concern. High levels of migration mean that healthcare systems in higher-income western countries are increasingly being challenged to respond to the care needs of affected communities. Research has identified significant challenges in the provision of, and access to, FGM-related healthcare. There is a lack of confidence and competence among health professionals in providing appropriate care, suggesting an urgent need for evidence-based service development in this area. This study will involve two systematic reviews of qualitative evidence to explore the experiences, needs, barriers and facilitators to seeking and providing FGM-related healthcare in high-income (Organisation for Economic Cooperation and Development) countries, from the perspectives of: (1) women and girls who have undergone FGM and (2) health professionals. REVIEW METHODS: Twelve databases including MEDLINE, EMBASE, PsycINFO, ASSIA, Web of Science, ERIC, CINAHL, and POPLINE will be searched with no limits on publication year. Relevant grey literature will be identified from digital sources and professional networks.Two reviewers will independently screen, select and critically appraise the studies. Study quality will be assessed using the Joanna Briggs Institute Qualitative Assessment and Review Instrument appraisal tool. Findings will be extracted into NVivo software. Synthesis will involve inductive thematic analysis, including in-depth reading, line by line coding of the findings, development of descriptive themes and re-coding to higher level analytical themes. Confidence in the review findings will be assessed using the CERQual approach. Findings will be integrated into a comprehensive set of recommendations for research, policy and practice. DISSEMINATION: The syntheses will be reported as per the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) statement. Two reviews will be published in peer-reviewed journals and an integrated report disseminated at stakeholder engagement events. PROSPEROREGISTRATION NUMBER: CRD42015030001: 2015 and CRD42015030004: 2015. PMID- 29247097 TI - Which outcomes are important to patients and families who have experienced paediatric acute respiratory illness? Findings from a mixed methods sequential exploratory study. AB - OBJECTIVES: To identify the outcome priorities of parents of children who had experienced an acute respiratory infection (ARI). DESIGN: This was a two-phase, mixed methods study with a sequential exploratory design. We used a cross sectional quantitative web-based survey to elicit parents' priorities for paediatric ARI. We then used a discussion moderated via Facebook to elucidate richer descriptions of parents' priorities. SETTING: Survey and discussion data were collected via the internet. PARTICIPANTS: 110 parents (90% women, median age 35 years, 92.7% urban dwelling, 94.5% with a postsecondary education) with a child who had experienced an ARI responded to the survey. Four parents participated in the Facebook discussion. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was parents' rankings of outcomes related to paediatric ARI. The secondary outcomes were the alignment of parent-reported important outcomes with those commonly reported in Cochrane systematic reviews (SRs). RESULTS: Commonly reported ARIs included croup (44.5%), wheezing (43.6%) and influenza (38.2%). Parents ranked major complications, illness symptoms and length of stay as the most important outcome categories. With respect to specific outcomes, severe complications, major side effects, doctor's assessment, relapse, oxygen supplementation and results from laboratory measures were reported as most important (75th-99th percentile). Taking time off work, mild complications, interference with daily activities, treatment costs, absenteeism, follow-up visits and other costs were deemed minimally important (<25th percentile). In 35 Cochrane SRs, 29 unique outcomes were reported. Although participants' priorities sometimes aligned with outcomes frequently reported in the literature, this was not always true. Additional priorities from the survey (n=50) and Facebook discussions (n=4) included healthcare access, interacting with healthcare providers, education, impact on daily activities and child well-being. CONCLUSIONS: In the context of paediatric ARI, parents' priorities did not always align with commonly researched outcomes. Appealing and efficient strategies to engage patients and parents in research should be developed. PMID- 29247098 TI - Dialogues between nurses, patients with heart failure and their partners during a dyadic psychoeducational intervention: a qualitative study. AB - OBJECTIVES: To describe nurses' documentation of the content in a psychoeducational intervention inspired by Stuifbergen's model addressing cognitive, supportive and behavioural needs of patient-partner dyads affected by heart failure. DESIGN: A descriptive qualitative design was used analysing nurses' documentation in a dialogue guide based on a health promotion model. SETTINGS: The dialogue guide was used during three nurse-led sessions at two heart failure clinics in Sweden with patients affected with heart failure and their partners during the years 2005-2008. PARTICIPANTS: The dialogue guides from 71 patient-partner dyads were analysed using direct deductive content analyses. Patients' mean age was 69 years and 31% were female, partners' mean age was 67 years and 69% were female. RESULTS: The findings supported the conceptual health promotion model and identified barriers, recourses and self-efficacy described by the dyads within each category. CONCLUSION: The dyads described that during the sessions, they had gained enhanced knowledge and greater confidence to handle their life situation and expressed that they needed psychoeducational support during the whole illness trajectory. The results may guide and help to improve content and quality when caring for patients affected with heart failure and their partners and also when designing new interventions. TRIAL REGISTRATION NUMBER: NCT02398799; Post-results. PMID- 29247099 TI - Evidence assessing the diagnostic performance of medical smartphone apps: a systematic review and exploratory meta-analysis. AB - OBJECTIVE: The number of mobile applications addressing health topics is increasing. Whether these apps underwent scientific evaluation is unclear. We comprehensively assessed papers investigating the diagnostic value of available diagnostic health applications using inbuilt smartphone sensors. METHODS: Systematic Review-MEDLINE, Scopus, Web of Science inclusive Medical Informatics and Business Source Premier (by citation of reference) were searched from inception until 15 December 2016. Checking of reference lists of review articles and of included articles complemented electronic searches. We included all studies investigating a health application that used inbuilt sensors of a smartphone for diagnosis of disease. The methodological quality of 11 studies used in an exploratory meta-analysis was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 tool and the reporting quality with the 'STAndards for the Reporting of Diagnostic accuracy studies' (STARD) statement. Sensitivity and specificity of studies reporting two-by-two tables were calculated and summarised. RESULTS: We screened 3296 references for eligibility. Eleven studies, most of them assessing melanoma screening apps, reported 17 two-by-two tables. Quality assessment revealed high risk of bias in all studies. Included papers studied 1048 subjects (758 with the target conditions and 290 healthy volunteers). Overall, the summary estimate for sensitivity was 0.82 (95 % CI 0.56 to 0.94) and 0.89 (95 %CI 0.70 to 0.97) for specificity. CONCLUSIONS: The diagnostic evidence of available health apps on Apple's and Google's app stores is scarce. Consumers and healthcare professionals should be aware of this when using or recommending them. PROSPERO REGISTRATION NUMBER: 42016033049. PMID- 29247100 TI - Mapping Evidence of Patients' Experiences in Integrated Care Settings: A Protocol for a Scoping Review. AB - INTRODUCTION: Integrated care (IC) models have emerged to address gaps in care for individuals with complex healthcare needs. Although the clinical and cost effectiveness of IC models are well-established, our understanding of whether IC models facilitate a patient-centred care experience from the patients' perspective is not well understood. This scoping review aims to comprehensively map the literature to provide a broad overview of patients' experiences in IC settings with a focus on the experiences of complex patients with comorbid mental and physical illnesses. It also aims to describe current gaps identified in the literature in our understanding of aspects of care that are often unrecognised. METHODS AND ANALYSIS: Using established scoping review frameworks and guidelines, we will perform a comprehensive search in the following databases: MEDLINE, EMBASE, PsycINFO, CINAHL, AMED and the Cochrane Library to identify relevant studies on patients' experiences in IC models. Grey literature sources and studies bibliographies will also be searched to identify relevant studies and documents. Data will be extracted and summarised using descriptive statistical and qualitative analyses. We will also consult with stakeholders from various backgrounds to enhance the comprehensiveness of this review. ETHICS AND DISSEMINATION: This review requires no ethical approval. Findings from this study will be disseminated through publication in a peer-reviewed journal, clinical conferences and in knowledge translation settings, aiming to improve clinical practice and care delivery. PMID- 29247101 TI - Therapist-guided internet-delivered cognitive-behavioural therapy supplemented with group exposure sessions for adolescents with social anxiety disorder: a feasibility trial. AB - OBJECTIVES: Social anxiety disorder (SAD) is one of the most common psychiatric disorders in youth, with a prevalence of about 3%-4% and increased risk of adverse long-term outcomes, such as depression. Cognitive-behavioural therapy (CBT) is considered the first-line treatment for youth with SAD, but many adolescents remain untreated due to limited accessibility to CBT. The aim of this study was to develop and evaluate the feasibility and preliminary efficacy of a therapist-guided internet-delivered CBT treatment, supplemented with clinic-based group exposure sessions (BIP SOFT). DESIGN: A proof-of-concept, open clinical trial with 6-month follow-up. PARTICIPANTS: The trial was conducted at a child and adolescent psychiatric research clinic, and participants (n=30) were 13-17 years old (83% girls) with a principal diagnosis of SAD. INTERVENTION: 12 weeks of intervention, consisting of nine remote therapist-guided internet-delivered CBT sessions and three group exposure sessions at the clinic for the adolescents and five internet-delivered sessions for the parents. RESULTS: Adolescents were generally satisfied with the treatment, and the completion rate of internet modules, as well as attendance at group sessions, was high. Post-treatment assessment showed a significant decrease in clinician-rated, adolescent-rated and parent-rated social anxiety (d=1.17, 0.85 and 0.79, respectively), as well as in general self-rated and parent-rated anxiety and depression (d=0.76 and 0.51), compared with pretreatment levels. Furthermore, 47% of participants no longer met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for SAD at post-treatment. At a 6-month follow-up, symptom reductions were maintained, or further improved, and 57% of participants no longer met criteria for SAD. CONCLUSION: Therapist-guided and parent-guided internet delivered CBT, supplemented with a limited number of group exposure sessions, is a feasible and promising intervention for adolescents with SAD. TRIAL REGISTRATION NUMBER: NCT02576171; Results. PMID- 29247102 TI - Influence of overstated abstract conclusions on clinicians: a web-based randomised controlled trial. AB - OBJECTIVES: To investigate whether overstatements in abstract conclusions influence primary care physicians' evaluations when they read reports of randomised controlled trials (RCTs) DESIGN: RCT setting: This study was a parallel-group randomised controlled survey, conducted online while masking the study hypothesis. PARTICIPANTS: Volunteers were recruited from members of the Japan Primary Care Association in January 2017. We sent email invitations to 7040 primary care physicians. Among the 787 individuals who accessed the website, 622 were eligible and automatically randomised into 'without overstatement' (n=307) and 'with overstatement' (n=315) groups. INTERVENTIONS: We selected five abstracts from published RCTs with at least one non-significant primary outcome and overstatement in the abstract conclusion. To construct a version without overstatement, we rewrote the conclusion sections. The methods and results sections were standardised to provide the necessary information of primary outcome information when it was missing in the original abstract. Participants were randomly assigned to read an abstract either with or without overstatements and asked to evaluate the benefit of the intervention. OUTCOME MEASURES: The primary outcome was the participants' evaluation of the benefit of the intervention discussed in the abstract, on a scale from 0 to 10. A secondary outcome was the validity of the conclusion. RESULTS: There was no significant difference between the groups with respect to their evaluation of the benefit of the intervention (mean difference: 0.07, 95% CI -0.28 to 0.42, p=0.69). Participants in the 'without' group considered the study conclusion to be more valid than those in the 'with' group (mean difference: 0.97, 95% CI 0.59 to 1.36, P<0.001). CONCLUSION: The overstatements in abstract conclusions did not significantly influence the primary care physicians' evaluations of the intervention effect when necessary information about the primary outcomes was distinctly reported. TRIAL REGISTRATION NUMBER: UMIN000025317; Pre-results. PMID- 29247103 TI - Effects of perioperative briefing and debriefing on patient safety: a prospective intervention study. AB - OBJECTIVES: This study was carried out to improve patient safety in the operating theatre by the introduction of perioperative briefing and debriefing, which focused on an optimal collaboration between surgical team members. DESIGN: A prospective intervention study with one pretest and two post-test measurements: 1 month before and 4 months and 2.5 years after the implementation of perioperative briefing and debriefing, respectively. SETTING: Operating theatres of a tertiary care hospital with 875 beds in the Netherlands. PARTICIPANTS: All members of five surgical teams participated in the perioperative briefing and debriefing. INTERVENTION: The implementation of perioperative briefing and debriefing from July 2012 to January 2014. PRIMARY AND SECONDARY OUTCOMES: The primary outcome was changes in the team climate, measured by the Team Climate Inventory. Secondary outcomes were the experiences of surgical teams with perioperative briefing and debriefing, measured with a structured questionnaire, and the duration of the briefings, measured by an independent observer. RESULTS: Two and a half years after the introduction of perioperative briefing and debriefing, the team climate increased statistically significant (p<=0.05). Members of the five surgical teams strongly agreed with the positive influence of perioperative briefing and debriefing on clear agreements and reminding one another of the agreements of the day. They perceived a higher efficiency of the surgical programme with more operations starting on time and less unexpectedly long operation time. The perioperative briefing took less than 4 min to conduct. CONCLUSIONS: Perioperative briefing and debriefing improved the team climate of surgical teams and the efficiency of their work within the operating theatre with acceptable duration per briefing. Surgical teams with alternating team compositions have the most benefit of briefing and debriefing. PMID- 29247104 TI - Comparing four service delivery models for adolescent girls and young women through the 'Girl Power' study: protocol for a multisite quasi-experimental cohort study. AB - INTRODUCTION: In sub-Saharan Africa, adolescent girls and young women (AGYW) face a range of sexual and reproductive health (SRH) challenges. Clinical, behavioural and structural interventions have each reduced these risks and improved health outcomes. However, combinations of these interventions have not been compared with each other or with no intervention at all. The 'Girl Power' study is designed to systematically make these comparisons. METHODS AND ANALYSIS: Four comparable health facilities in Malawi and South Africa (n=8) were selected and assigned to one of the following models of care: (1) Standard of care: AGYW can receive family planning, HIV testing and counselling (HTC), and sexually transmitted infection (STI) syndromic management in three separate locations with three separate queues with the general population. No youth-friendly spaces, clinical modifications or trainings are offered, (2) Youth-Friendly Health Services (YFHS): AGYW are meant to receive integrated family planning, HTC and STI services in dedicated youth spaces with youth-friendly modifications and providers trained in YFHS, (3) YFHS+behavioural intervention (BI): In addition to YFHS, AGYW can attend 12 monthly theory-driven, facilitator-led, interactive sessions on health, finance and relationships, (4) YFHS+BI+conditional cash transfer (CCT): in addition to YFHS and BI, AGYW receive up to 12 CCTs conditional on monthly BI session attendance.At each clinic, 250 AGYW 15-24 years old (n=2000 total) will be consented, enrolled and followed for 1 year. Each participant will complete a behavioural survey at enrolment, 6 months and 12 months . All clinical, behavioural and CCT services will be captured. Outcomes of interest include uptake of each package element and reduction in HIV risk behaviours. A qualitative substudy will be conducted. ETHICS/DISSEMINATION: This study has received ethical approval from the University of North Carolina Institutional Review Board, the University of Cape Town Human Research Ethics Committee and Malawi's National Health Sciences Research Committee. Study plans, processes and findings will be disseminated to stakeholders, in peer-reviewed journals and at conferences. PMID- 29247105 TI - Association of sleep duration and quality with blood lipids: a systematic review and meta-analysis of prospective studies. AB - OBJECTIVES: To assess the longitudinal evidence of the relationships between sleep disturbances (of quantity and quality) and dyslipidaemia in the general population and to quantify such relationships. SETTING: Systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. METHODS: We performed a systematic search of PubMed and Embase (up to 9 September 2017), complemented with manual searches, of prospective population studies describing the association between sleep duration and quality and the incidence of dyslipidaemias. Relative risks (95% CIs) were extracted and pooled using a random effects model. Subgroup analyses by lipid type were performed. Heterogeneity and publication bias were also assessed. Quality was assessed with Downs and Black score. PARTICIPANTS: Studies were included if they were prospective, had measured sleep quantity and/or quality at baseline and either incident cases of dyslipidaemia or changes in blood lipid fractions assessed prospectively. PRIMARY OUTCOME MEASURES: Incidence of dyslipidaemia and changes in lipid fractions. Dyslipidaemia was defined as a high total cholesterol, triglycerides, low-density lipoprotein cholesterol or low high density lipoprotein cholesterol compared with the reference group. RESULTS: Thirteen studies were identified (eight using sleep duration, four sleep quality and one both). There was heterogeneity in the sleep quality aspects and types of lipids assessed. Classification of sleep duration (per hour/groups) also varied widely. In the pooled analysis of sleep duration (6 studies, 16 cohort samples; 30 033 participants; follow-up 2.6-10 years), short sleep was associated with a risk of 1.01 (95% CI 0.93 to 1.10) of developing dyslipidaemia, with moderate heterogeneity (I2=56%, P=0.003) and publication bias (P=0.035). Long sleep was associated with a risk of 0.98 (95% CI 0.87 to 1.10) for dyslipidaemia, with heterogeneity (I2=63%, P<0.001) and no significant publication bias (P=0.248). CONCLUSION: The present analysis was unable to find supportive evidence of a significant relationship between sleep duration and the development of dyslipidaemia. However, heterogeneity and small number of studies limit the interpretation. PROSPERO REGISTRATION NUMBER: CRD42016045242. PMID- 29247106 TI - Sharing and reuse of individual participant data from clinical trials: principles and recommendations. AB - OBJECTIVES: We examined major issues associated with sharing of individual clinical trial data and developed a consensus document on providing access to individual participant data from clinical trials, using a broad interdisciplinary approach. DESIGN AND METHODS: This was a consensus-building process among the members of a multistakeholder task force, involving a wide range of experts (researchers, patient representatives, methodologists, information technology experts, and representatives from funders, infrastructures and standards development organisations). An independent facilitator supported the process using the nominal group technique. The consensus was reached in a series of three workshops held over 1 year, supported by exchange of documents and teleconferences within focused subgroups when needed. This work was set within the Horizon 2020-funded project CORBEL (Coordinated Research Infrastructures Building Enduring Life-science Services) and coordinated by the European Clinical Research Infrastructure Network. Thus, the focus was on non-commercial trials and the perspective mainly European. OUTCOME: We developed principles and practical recommendations on how to share data from clinical trials. RESULTS: The task force reached consensus on 10 principles and 50 recommendations, representing the fundamental requirements of any framework used for the sharing of clinical trials data. The document covers the following main areas: making data sharing a reality (eg, cultural change, academic incentives, funding), consent for data sharing, protection of trial participants (eg, de-identification), data standards, rights, types and management of access (eg, data request and access models), data management and repositories, discoverability, and metadata. CONCLUSIONS: The adoption of the recommendations in this document would help to promote and support data sharing and reuse among researchers, adequately inform trial participants and protect their rights, and provide effective and efficient systems for preparing, storing and accessing data. The recommendations now need to be implemented and tested in practice. Further work needs to be done to integrate these proposals with those from other geographical areas and other academic domains. PMID- 29247108 TI - Informatics competencies for nurse leaders: protocol for a scoping review. AB - INTRODUCTION: Globally, health information technologies are now being used by nurses in a variety of settings. However, nurse leaders often do not have the necessary strategic and tactical informatics competencies to adequately ensure their effective adoption and use. Although informatics competencies and competency frameworks have been identified and developed, to date there has not been review or consolidation of the work completed in this area. In order to address this gap, a scoping review is being conducted. The objectives of this scoping review are to: (1) identify informatics competencies of relevance to nurse leaders, (2) identify frameworks or theories that have been used to develop informatics competencies for nurse leaders, (3) identify instruments used to assess the informatics competencies of nurse leaders and (4) examine the psychometric properties of identified instruments. METHODS: Using the Arksey and O'Malley five-step framework, a literature review will be conducted using a scoping review methodology. The search will encompass academic and grey literature and include two primary databases and five secondary databases. Identified studies and documents will be independently screened for eligibility by two reviewers. Data from the studies and documents will be extracted and compiled into a chart. Qualitative data will be subject to a thematic analysis and descriptive statistics applied to the quantitative data. ETHICS AND DISSEMINATION: Ethical approval was not required for this study. Results will be used to inform a future study designed to validate an instrument used to evaluate informatics competencies for nurse leaders within a Canadian context. PMID- 29247109 TI - Evaluation of anticoagulation status for atrial fibrillation on early ischaemic stroke outcomes: a registry-based, prospective cohort study of acute stroke care in Surrey, UK. AB - OBJECTIVE: The relationship of anticoagulation therapies with stroke severity and outcomes have been well documented in the literature. However, none of the previous research has reported the relationship of atrial fibrillation (AF)/anticoagulation therapies with urinary tract infection (UTI), pneumonia and length of stay in hyperacute stroke units (HASUs). The present study aimed to evaluate AF and anticoagulation status in relation to early outcomes in 1387 men (median age=75 years, IQR=65-83) and 1371 women (median age=83 years, IQR=74-89) admitted with acute ischaemic stroke to HASUs in Surrey between 2014 and 2016. METHODS: We conducted this registry-based, prospective cohort study using data from the Sentinel Stroke National Audit Programme. Association between AF anticoagulation status with severe stroke on arrival (National Institutes of Health Stroke Scale score >=16), prolonged HASU stay (>3 weeks), UTI and pneumonia within 7 days of admission, severe disability on discharge (modified Rankin Scale score=4 and 5) and inpatient mortality was assessed by logistic regression, adjusted for age, sex, hypertension, congestive heart failure, diabetes and previous stroke. RESULTS: Compared with patients with stroke who are free from AF, those with AF without anticoagulation had an increased adjusted risk of having more severe stroke: 5.8% versus 14.0%, OR=2.4 (95% CI 1.6 to 3.6, P<0.001), prolonged HASU stay: 21.5% versus 32.0%, OR=1.4 (1.0-2.0, P=0.027), pneumonia: 8.2% versus 19.1%, OR=2.1 (1.4-2.9, P<0.001), more severe disability: 24.2% versus 40.4%, OR=1.6 (1.2-2.1, P=0.004) and mortality: 9.3% versus 21.7%, OR=1.9 (1.4-2.8, P<0.001), and AF patients with anticoagulation also had greater risk for having UTI: 8.6% versus 12.3%, OR=1.9 (1.2-3.0, P=0.004), pneumonia: 8.2% versus 11.5%, OR=1.6 (1.1-2.4, P=0.025) and mortality: 9.7% versus 21.7%, OR=1.9 (1.4-2.8, P<0.001). The median HASU stay for stroke patients with AF without anticoagulation was 10.6 days (IQR=2.8-26.4) compared with 5.8 days (IQR=2.3-17.5) for those free from AF (P<0.001). CONCLUSIONS: Patients with AF, particularly those without anticoagulation, are at increased risk of severe stroke, associated with prolonged HASU stay and increased risk of early infection, disability and mortality. PMID- 29247110 TI - Prospective economic evaluation of an electronic discharge communication tool: analysis of a randomised controlled trial. AB - OBJECTIVE: To complete an economic evaluation within a randomised controlled trial (RCT) comparing the use of an electronic discharge communication tool (eDCT) compared with usual care. SETTING: Patients being discharged from a single tertiary care centre's internal medicine Medical Teaching Units. PARTICIPANTS: Between January 2012 and December 2013, 1399 patients were randomised to a discharge mechanism. Forty-five patients were excluded from the economic evaluation as they did not have data for the index hospitalisation cost; 1354 patients contributed to the economic evaluation. INTERVENTION: eDCT generated at discharge containing structured content on reason for admission, details of the hospital stay, treatments received and follow-up care required. The control group was discharged via traditional dictation methods. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary economic outcome was the cost per quality-adjusted life year (QALY) gained. Secondary outcomes included the cost per death avoided and the cost per readmission avoided. RESULTS: The average transcription cost was $C22.28 per patient, whereas the estimated cost of the eDCT was $C13.33 per patient. The cost per QALY gained was $C239 933 in the eDCT arm compared with usual care due to the very small gains in effectiveness and approximately $C800difference in resource utilisation costs. The bootstrap analyses resulted in eDCT being more effective and more costly in 29.2% of samples, less costly and more effective in 29.2% of samples, less effective and more costly in 23.9% of samples and finally, less costly and less effective in 17.7% of samples. CONCLUSIONS: The eDCT reduced per patient costs of the generation of discharge summaries. The bootstrap estimates demonstrate considerable uncertainty supporting the finding of neutrality reported in the clinical component of the RCT. The immediate transcription cost savings and previously documented provider and patient satisfaction may increase the impetus for organisations to invest in such systems, provided they have a foundation of eHealth infrastructure and readiness. TRIAL REGISTRATION NUMBER: NCT01402609. PMID- 29247107 TI - Low-dose glucocorticoids plus rituximab versus high-dose glucocorticoids plus rituximab for remission induction in ANCA-associated vasculitis (LoVAS): protocol for a multicentre, open-label, randomised controlled trial. AB - INTRODUCTION: Antineutrophil cytoplasm antibody-associated vasculitis (AAV) is a form of systemic vasculitis. The current standard induction therapy with the combination of high-dose glucocorticoids and cyclophosphamide or rituximab has high remission rates of 80%-90%. However, it is also associated with various side effects, including death due to infection or cardiovascular disease. There is an unmet medical need of a new therapy to reduce side effects. METHODS AND ANALYSIS: This is a phase IV multicentre, open-label, randomised controlled trial that aims to evaluate the efficacy and safety of a new remission induction regimen with the combination of low-dose glucocorticoids and rituximab. Newly diagnosed patients with AAV will be assessed for eligibility at 34 tertiary rheumatology/nephrology centres in Japan. One hundred and forty patients will be randomised (1:1) to receive low-dose prednisolone (0.5 mg/kg daily) plus rituximab (375 mg/m2 weekly) or high-dose prednisolone (1 mg/kg daily) plus rituximab. The trial consists of remission induction and maintenance phases. The primary endpoint of the study is the remission rate at 6 months (induction phase). Relapse and long-term safety profile will also be assessed until 24 months (maintenance phase). ETHICS AND DISSEMINATION: The protocol was first approved by the Institutional Review Board of Chiba University Hospital (reference number: G25051), and then approved by each participating site. The trial was registered at the University hospital Medical Information Network (UMIN) clinical registry (UMIN000014222) and ClinicalTrials.gov registry (NCT02198248). The Low-dose Glucocorticoid Vasculitis Induction Study (LoVAS) trial is currently ongoing and is due to finish in September 2019. The findings of this trial will be disseminated to participants through peer-reviewed publications and presented at national and international conferences in accordance with the Consolidated Standards of Reporting Trials (CONSORT) Statement. TRIAL REGISTRATION NUMBER: UMIN000014222; NCT02198248. PMID- 29247111 TI - What interventions are used to improve exercise adherence in older people and what behavioural techniques are they based on? A systematic review. AB - OBJECTIVES: To conduct a systematic review of interventions used to improve exercise adherence in older people, to assess the effectiveness of these interventions and to evaluate the behavioural change techniques underpinning them using the Behaviour Change Technique Taxonomy (BCTT). DESIGN: Systematic review. METHODS: A search was conducted on AMED, BNI, CINAHL, EMBASE, MEDLINE and PsychINFO databases. Randomised controlled trials that used an intervention to aid exercise adherence and an exercise adherence outcome for older people were included. Data were extracted with the use of a preprepared standardised form. Risk of bias was assessed with the Cochrane Collaboration's tool for assessing risk of bias. Interventions were classified according to the BCTT. RESULTS: Eleven studies were included in the review. Risk of bias was moderate to high. Interventions were classified into the following categories: comparison of behaviour, feedback and monitoring, social support, natural consequences, identity and goals and planning. Four studies reported a positive adherence outcome following their intervention. Three of these interventions were categorised in the feedback and monitoring category. Four studies used behavioural approaches within their study. These were social learning theory, socioemotional selectivity theory, cognitive behavioural therapy and self efficacy. Seven studies did not report a behavioural approach. CONCLUSIONS: Interventions in the feedback and monitoring category showed positive outcomes, although there is insufficient evidence to recommend their use currently. There is need for better reporting, use and the development of theoretically derived interventions in the field of exercise adherence for older people. Robust measures of adherence, in order to adequately test these interventions would also be of use. PROSPERO REGISTRATION NUMBER: CRD42015020884. PMID- 29247112 TI - Protocol for a randomised pilot multiple centre trial of conservative versus liberal oxygenation targets in critically ill children (Oxy-PICU). AB - INTRODUCTION: Optimal targets for systemic oxygenation in paediatric critical illness are unknown. Observational data indicate that high levels of arterial oxygenation are associated with poor outcomes in resuscitation of the newborn and in adult critical illness. Within paediatric intensive care units (PICUs), staff prevent severe hypoxia wherever possible, but beyond this there is no consensus. Practice varies widely with age, diagnosis, treating doctor and local or national guidelines followed, though peripheral blood oxygen saturations (SpO2) of >95% are often targeted. The overall aim of this pilot study is to determine the feasibility of performing a randomised trial in critically ill children comparing current practice of liberal SpO2 targets with a more conservative target. METHODS AND ANALYSIS: Oxy-PICU is a pragmatic, open, pilot randomised controlled trial in infants and children requiring mechanical ventilation and receiving supplemental oxygen for abnormal gas exchange accepted for emergency admission to one of three participating UK PICUs. The study groups will be either a conservative SpO2 target of 88%-92% (inclusive) or a liberal SpO2 target of >94%. Infants and children who fulfil all inclusion criteria and none of the exclusion criteria will be randomised 1:1 by a secure web-based system to one of the two groups. Baseline demographics and clinical status will be recorded as well as daily measures of oxygenation and organ support. Discharge outcomes will also be recorded. In addition to observational data, blood and urine samples will be taken to identify biochemical markers of oxidative stress. Outcomes are targeted at assessing study feasibility with a primary outcome of adequate study recruitment (target: 120 participants). ETHICS AND DISSEMINATION: The trial received Health Research Authority approval on 1 June 2017 (16/SC/0617). Study findings will be disseminated in national and international conferences and peer reviewed journals. TRIAL REGISTRATION NUMBER: NCT03040570. PMID- 29247113 TI - Outcomes of specialist discharge coordination and intermediate care schemes for patients who are homeless: analysis protocol for a population-based historical cohort. AB - INTRODUCTION: People who are homeless often experience poor hospital discharge arrangements, reflecting ongoing care and housing needs. Specialist integrated homeless health and care provision (SIHHC) schemes have been developed and implemented to facilitate the safe and timely discharge of homeless patients from hospital. Our study aims to investigate the health outcomes of patients who were homeless and seen by a selection of SIHHC services. METHODS AND ANALYSIS: Our study will employ a historical population-based cohort in England. We will examine health outcomes among three groups of adults: (1) homeless patients seen by specialist discharge schemes during their hospital admission; (2) homeless patients not seen by a specialist scheme and (3) admitted patients who live in deprived neighbourhoods and were not recorded as being homeless. Primary outcomes will be: time from discharge to next hospital inpatient admission; time from discharge to next accident and emergency attendance and 28-day emergency readmission. Outcome data will be generated through linkage to hospital admissions data (Hospital Episode Statistics) and mortality data for November 2013 to November 2016. Multivariable regression will be used to model the relationship between the study comparison groups and each of the outcomes. ETHICS AND DISSEMINATION: Approval has been obtained from the National Health Service (NHS) Confidentiality Advisory Group (reference 16/CAG/0021) to undertake this work using unconsented identifiable data. Health Research Authority Research Ethics approval (REC 16/EE/0018) has been obtained in addition to local research and development approvals for data collection at NHS sites. We will feedback the results of our study to our advisory group of people who have lived experience of homelessness and seek their suggestions on ways to improve or take this work further for their benefit. We will disseminate our findings to SIHHC schemes through a series of regional workshops. PMID- 29247114 TI - Protocol for the ROBUST (Registry Of type B aortic dissection with the Utility of STent graft) study: an ambispective, multicentre, open cohort study. AB - INTRODUCTION: Thoracic endovascular aortic repair (TEVAR) is widely used for type B aortic dissection, although with satisfactory outcome in a limited proportion of patients. To better inform patient prognostication, the Registry Of type B aortic dissection with the Utility of STent graft (ROBUST) study aims to identify imaging-based predictors of post-TEVAR adverse outcomes up to 10-year follow-up. METHODS AND ANALYSIS: ROBUST is designed as an ambispective, multicentre, open cohort study. All patients undergoing TEVAR from 1 January 2008 to 1 July 2027 at participating centres will be invited to join the study. It is conservatively estimated that over 2000 patients will join the study. Data on demographics, disease history, procedural details, imaging features and follow-up will be collected after discharge. Cox proportional-hazards analysis will be used to identify independent predictors of primary outcomes. Stratification analysis will be performed to identify which subgroup of patients would benefit the most from TEVAR. ETHICS AND DISSEMINATION: The protocol has been approved by the ethics committee of the coordinating centre. Findings will be disseminated in professional peer-reviewed journals to promote understanding of the rehabilitation process. TRIAL REGISTRATION NUMBER: ChiCTR-POC-17011726; Pre results. PMID- 29247115 TI - Mystery shopping and coaching as a form of audit and feedback to improve community pharmacy management of non-prescription medicine requests: an intervention study. AB - OBJECTIVES: To determine whether repeated mystery shopping visits with feedback improve pharmacy performance over nine visits and to determine what factors predict an appropriate outcome. DESIGN: Prospective, parallel, repeated intervention, repeated measures mystery shopping (pseudopatient) design. SETTING: Thirty-six community pharmacies in metropolitan Sydney, Australia in March October 2015. PARTICIPANTS: Sixty-one University of Sydney pharmacy undergraduates acted as mystery shoppers. Students enrolled in their third year of Bachelor of Pharmacy in 2015 were eligible to participate. Any community pharmacy in the Sydney metropolitan region was eligible to take part and was selected through convenience sampling. INTERVENTION: Repeated mystery shopping with immediate feedback and coaching. OUTCOME MEASURES: Outcome for each given scenario (appropriate or not) and questioning scores for each interaction. RESULTS: Five hundred and twenty-one visits were analysed, of which 54% resulted in an appropriate outcome. Questioning scores and the proportion of interactions resulting in an appropriate outcome significantly improved over time (P<0.001). Involvement of pharmacists, visit number, increased questioning score and the prescribed scenario were predictors of an appropriate outcome (P=0.008, P=0.022, P<0.001 and P<0.001, respectively). Interactions involving a pharmacist had greater scores than those without (P<0.001). CONCLUSIONS: Repeated mystery shopping visits with feedback were associated with improved pharmacy performance over time. Future work should focus on the role of non-pharmacist staff and design interventions accordingly. PMID- 29247117 TI - Preterm Birth and Future Childbearing: More Questions Than Answers. PMID- 29247116 TI - Temporal changes in the documentation of neurological findings among patients with acute ischaemic stroke in a single centre in Japan: a retrospective cross sectional study. AB - OBJECTIVE: To evaluate temporal differences in the documentation of neurological findings by the same physicians in patients with ischaemic stroke while in hospital. We also investigated differences in the rate of documentation of neurological findings in patients with stroke between internists and neurosurgeons. DESIGN: A retrospective medical chart review. PARTICIPANTS: Hospitalised adult patients with acute ischaemic stroke who stayed 7 or more days in our hospital. Neurosurgeons (n=8) and internists (n=19) caring for these patients (including up to 10 patients per physician). MAIN OUTCOME MEASURES: The documentation rate of any neurological finding in the patients on each day (from day 1 to 7 and on discharge). The documentation rates of eight neurological finding components (consciousness, mental status, cranial nerves, motor function, sensory function, coordination, reflexes and gait). We included only documentation by the same physician. Fisher's exact test was used to evaluate differences in outcomes between neurosurgeons and internists. RESULTS: During the study period, we identified 172 patients with stroke who were cared for by 27 physicians. The documentation rates of any neurological findings were 94% (day 1), 58% (day 2), 35% (day 3), 40% (day 4), 32% (day 5), 30% (day 6) and 23% (day 7). On discharge, all eight neurological finding components were documented in less than 10% of all cases. The documentation rate was significantly higher by internists than that by neurosurgeons on each day but not on discharge. CONCLUSIONS: The documentation rate of neurological findings by physicians during usual stroke care decreased to less than 50% after the third hospital day. Given the importance of temporal changes in the neurological symptoms of patients with stroke, further study is needed to determine whether this low documentation rate after the third hospital day was due to a lack of physician interest in neurological findings or other factors. PMID- 29247118 TI - The Missing Siblings of Infants Born Preterm. AB - BACKGROUND: Parents of very or extremely low birth weight infants have fewer subsequent children after preterm birth. Whether this applies to parents of less preterm infants is unknown. METHODS: In this nationwide cohort study, we identified all 230 308 traceable (>99%) singletons (9983 preterm, 4.3%) live born in Finland between January 1, 1987, and September 30, 1990, and their parents. Quantitative contribution of gestational age of child to the birth of parental subsequent children was assessed by multivariate Cox regression models, stratifying by the number of previous children. The impact of gestational age on sibling count was estimated at individual and population level. RESULTS: Mothers of extremely preterm (23-27 completed weeks) infants were, compared with mothers of term infants (39-41 weeks), less likely to have a subsequent live-born child (adjusted hazard ratio [HR]: 0.74; 95% confidence interval: 0.63-0.86). Corresponding HRs and confidence intervals were as follows: 28 to 31 weeks: 0.72 (0.65-0.80), 32 to 33 weeks: 0.82 (0.74-0.90), and 34 to 36 weeks: 0.90 (0.87 0.93). These HRs were consistent with those of fathers and couples. The cohort included 8002 firstborn preterm children, of whom 356 (4.4%) died in infancy. The 8002 children had a total of 13 826 subsequent siblings (1138 less than expected); per 1000 preterm births, this translates to the death of 44 preterm infants and 142 missing subsequent siblings. CONCLUSIONS: Families with a preterm singleton child have fewer subsequent children. In a high-income country, the main population effect of preterm birth is caused by these "missing siblings," whose number exceeds the number of those preterm infants who die. PMID- 29247120 TI - Surviving Sudden Death: Where Does Next-Generation Sequencing Fit in the Assessment of Sudden Death Victims and Their Families. PMID- 29247119 TI - Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. AB - BACKGROUND: Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office. METHODS AND RESULTS: The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years). Eighty-nine cardiac disease genes were evaluated. Using a high-resolution variant interpretation workflow, we classified 17 variants as pathogenic or likely pathogenic (2 of which were incidental findings and excluded in testing yield analysis), 46 novel variants of uncertain significance, and 130 variants of uncertain significance. Nine pathogenic or likely pathogenic variants in ClinVar were reclassified to likely benign and excluded in testing yield analysis. The yields of positive cases by ethnicity and age were 21.4% in mixed ethnicities, 10.2% Whites, 4.5% Asians, 3.1% Hispanics, and 2% Blacks; 7.7% children, 7.3% in adults, 5.4% young adults, and 2.8% infants. The percentages of uncertain cases with variants of uncertain significance by ethnicity were 45.5% in Asians, 45.3% Hispanics, 44.20% Blacks, 36.7% Whites, and 14.3% in mixed ethnicities. CONCLUSIONS: High resolution variant interpretation provides diagnostic accuracy and healthcare efficiency. Under-represented populations warrant greater inclusion in future studies. PMID- 29247122 TI - Prostaglandin I2 suppresses the development of diet-induced nonalcoholic steatohepatitis in mice. AB - Nonalcoholic steatohepatitis (NASH) is a hepatic manifestation of metabolic syndrome. Although the prostaglandin (PG)I2 receptor IP is expressed broadly in the liver, the role of PGI2-IP signaling in the development of NASH remains to be determined. Here, we investigated the role of the PGI2-IP system in the development of steatohepatitis using mice lacking the PGI2 receptor IP [IP knockout (IP-KO) mice] and beraprost (BPS), a specific IP agonist. IP-KO and wild type (WT) mice were fed a methionine- and choline-deficient diet (MCDD) for 2, 5, or 10 wk. BPS was administered orally to mice every day during the experimental periods. The effect of BPS on the expression of chemokine and inflammatory cytokines was examined also in cultured Kupffer cells. WT mice fed MCDD developed steatohepatitis at 10 wk. IP-KO mice developed steatohepatitis at 5 wk with augmented histologic derangements accompanied by increased hepatic monocyte chemoattractant protein-1 (MCP-1) and TNF-alpha concentrations. After 10 wk of MCDD, IP-KO mice had greater hepatic iron deposition with prominent oxidative stress, resulting in hepatocyte damage. In WT mice, BPS improved histologic and biochemical parameters of steatohepatitis, accompanied by reduced hepatic concentration of MCP-1 and TNF-alpha. Accordingly, BPS suppressed the LPS stimulated Mcp-1 and Tnf-alpha mRNA expression in cultured Kupffer cells prepared from WT mice. PGI2-IP signaling plays a crucial role in the development and progression of steatohepatitis by modulating the inflammatory response, leading to augmented oxidative stress. We suggest that the PGI2-IP system is an attractive therapeutic target for treating patients with NASH.-Kumei, S., Yuhki, K.-I., Kojima, F., Kashiwagi, H., Imamichi, Y., Okumura, T., Narumiya, S., Ushikubi, F. Prostaglandin I2 suppresses the development of diet-induced nonalcoholic steatohepatitis in mice. PMID- 29247121 TI - LRX Proteins Play a Crucial Role in Pollen Grain and Pollen Tube Cell Wall Development. AB - Leu-rich repeat extensins (LRXs) are chimeric proteins containing an N-terminal Leu-rich repeat (LRR) and a C-terminal extensin domain. LRXs are involved in cell wall formation in vegetative tissues and required for plant growth. However, the nature of their role in these cellular processes remains to be elucidated. Here, we used a combination of molecular techniques, light microscopy, and transmission electron microscopy to characterize mutants of pollen-expressed LRXs in Arabidopsis (Arabidopsisthaliana). Mutations in multiple pollen-expressed lrx genes cause severe defects in pollen germination and pollen tube growth, resulting in a reduced seed set. Physiological experiments demonstrate that manipulating Ca2+ availability partially suppresses the pollen tube growth defects, suggesting that LRX proteins influence Ca2+-related processes. Furthermore, we show that LRX protein localizes to the cell wall, and its LRR domain (which likely mediates protein-protein interactions) is associated with the plasma membrane. Mechanical analyses by cellular force microscopy and finite element method-based modeling revealed significant changes in the material properties of the cell wall and the fine-tuning of cellular biophysical parameters in the mutants compared to the wild type. The results indicate that LRX proteins might play a role in cell wall-plasma membrane communication, influencing cell wall formation and cellular mechanics. PMID- 29247123 TI - Taurine chloramine potentiates phagocytic activity of peritoneal macrophages through up-regulation of dectin-1 mediated by heme oxygenase-1-derived carbon monoxide. AB - Resolution of inflammation that occurs after microbial infection or tissue damage is an important physiologic process in maintaining or restoring host homeostasis. Taurine chloramine (TauCl) is formed by a reaction between taurine and hypochlorite in leukocytes, and it is especially abundant in activated neutrophils that encounter an oxidative burst. As neutrophils undergo apoptosis, TauCl is released to the extracellular matrix at the inflamed sites, thereby affecting coexisting macrophages in the inflammatory microenvironment. In this study, we investigated the role of TauCl in phagocytosis by macrophages during resolution of fungal infection-induced inflammation. We found that exogenous TauCl substantially increased the phagocytic efficiency of macrophages through up regulation of dectin-1, a receptor for fungal beta-1,3-glucans, which is present on the membrane of macrophages. Our previous studies demonstrated the induction of heme oxygenase-1 (HO-1) expression in murine peritoneal macrophages treated with TauCl. In the present study, knocking out HO-1 or pharmacologic inhibition of HO-1 with zinc protoporphyrin IX attenuated the TauCl-induced expression of dectin-1 and subsequent phagocytosis. Furthermore, carbon monoxide (CO), a by product of the HO-1-catalyzed reaction, induced expression of dectin-1 and potentiated phagocytic capability of the macrophages, which appeared to be mediated through up-regulation of peroxisome proliferator-activated receptor gamma. Taken together, induction of HO-1 expression and subsequent CO production by TauCl are essential for phagocytosis of fungi by macrophages. Our results suggest that TauCl has important roles in host defense against fungal infection and has therapeutic potential in the management of inflammatory diseases.-Kim, S. H., Zhong, X., Kim, W., Kim, K., Suh, Y.-G., Kim, C., Joe, Y., Chung, H. T., Cha, Y.-N., Surh, Y.-J. Taurine chloramine potentiates phagocytic activity of peritoneal macrophages through up-regulation of dectin-1 mediated by heme oxygenase-1-derived carbon monoxide. PMID- 29247124 TI - Response to: '2017 EULAR/ACR classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: little emphasis on autoantibodies, why?' by Malaviya. PMID- 29247125 TI - Incidence of hip and knee replacement in patients with rheumatoid arthritis following the introduction of biological DMARDs: an interrupted time-series analysis using nationwide Danish healthcare registers. AB - OBJECTIVES: To study the impact of the introduction of biological disease modifying anti-rheumatic drugs (bDMARDs) and associated rheumatoid arthritis (RA) management guidelines on the incidence of total hip (THR) and knee replacements (TKR) in Denmark. METHODS: Nationwide register-based cohort and interrupted time series analysis. Patients with incident RA between 1996 and 2011 were identified in the Danish National Patient Register. Patients with RA were matched on age, sex and municipality with up to 10 general population comparators (GPCs). Standardised 5-year incidence rates of THR and TKR per 1000 person-years were calculated for patients with RA and GPCs in 6-month periods. Levels and trends in the pre-bDMARD (1996-2001) were compared with the bDMARD era (2003-2016) using segmented linear regression interrupted by a 1-year lag period (2002). RESULTS: We identified 30 404 patients with incident RA and 297 916 GPCs. In 1996, the incidence rate of THR and TKR was 8.72 and 5.87, respectively, among patients with RA, and 2.89 and 0.42 in GPCs. From 1996 to 2016, the incidence rate of THR decreased among patients with RA, but increased among GPCs. Among patients with RA, the incidence rate of TKR increased from 1996 to 2001, but started to decrease from 2003 and throughout the bDMARD era. The incidence of TKR increased among GPCs from 1996 to 2016. CONCLUSION: We report that the incidence rate of THR and TKR was 3-fold and 14-fold higher, respectively among patients with RA compared with GPCs in 1996. In patients with RA, introduction of bDMARDs was associated with a decreasing incidence rate of TKR, whereas the incidence of THR had started to decrease before bDMARD introduction. PMID- 29247126 TI - Preference phenotypes to facilitate shared decision-making in rheumatoid arthritis. AB - OBJECTIVE: Implementing treat-to-target (TTT) strategies requires that patients with rheumatoid arthritis (RA) and their rheumatologists decide on how best to escalate care when indicated. The objective of this study was to develop preference phenotypes to facilitate shared decision-making at the point of care for patients failing methotrexate monotherapy. METHODS: We developed a conjoint analysis survey to measure the preferences of patient with RA for triple therapy, biologics and Janus kinase (JAK) inhibitors. The survey included seven attributes: administration, onset, bothersome side effects, serious infection, very rare side effects, amount of information and cost. Each choice set (n=12) included three hypothetical profiles. Preference phenotypes were identified by applying latent class analysis to the conjoint data. RESULTS: 1273 participants completed the survey. A five-group solution was chosen based on progressively lower values of the Akaike and Bayesian information criteria. Members of the largest group (group 3: 38.4%) were most strongly impacted by the cost of the medication. The next largest group (group 1: 25.8%) was most strongly influenced by the risk of bothersome side effects. Members of group 2 (11.2%) were also risk averse, but were most concerned with the risk of very rare side effects. Group 4 (6.6%) strongly preferred oral over parenteral medications. Members of group 5 (18.0%) were most strongly and equally influenced by onset of action and the risk of serious infections. CONCLUSIONS: Treatment preferences of patients with RA can be measured and represented by distinct phenotypes. Our results underscore the variability in patients' values and the importance of using a shared decision making approach to implement TTT. PMID- 29247127 TI - Disease activity in ankylosing spondylitis: the global therapeutic target. PMID- 29247128 TI - Mitochondrial genetic variation and gout in Maori and Pacific people living in Aotearoa New Zealand. AB - OBJECTIVE: Mitochondria have an important role in the induction of the NLRP3 inflammasome response central in gout. The objective was to test whether mitochondrial genetic variation and copy number in New Zealand Maori and Pacific (Polynesian) people in Aotearoa New Zealand associate with susceptibility to gout. METHODS: 437 whole mitochondrial genomes from Maori and Pacific people (predominantly men) from Aotearoa New Zealand (327 people with gout, 110 without gout) were sequenced. Mitochondrial DNA copy number variation was determined by assessing relative read depth using data produced from whole genome sequencing (32 cases, 43 controls) and targeted resequencing of urate loci (151 cases, 222 controls). Quantitative PCR was undertaken for replication of copy number findings in an extended sample set of 1159 Maori and Pacific men and women (612 cases, 547 controls). RESULTS: There was relatively little mitochondrial genetic diversity, with around 96% of those sequenced in this study belonging to the B4a1a and derived sublineages. A B haplogroup heteroplasmy in hypervariable region I was found to associate with a higher risk of gout among the mitochondrial sequenced sample set (position 16181: OR=1.57, P=0.001). Increased copies of mitochondrial DNA were found to protect against gout risk with the effect being consistent when using hyperuricaemic controls across each of the three independent sample sets (OR=0.89, P=0.007; OR=0.90, P=0.002; OR=0.76, P=0.03). Paradoxically, an increase of mitochondrial DNA also associated with an increase in gout flare frequency in people with gout in the two larger sample sets used for the copy number analysis (beta=0.003, P=7.1*10-7; beta=0.08, P=1.2*10-4). CONCLUSION: Association of reduced copy number with gout in hyperuricaemia was replicated over three Polynesian sample sets. Our data are consistent with emerging research showing that mitochondria are important for the colocalisation of the NLRP3 and ASC inflammasome subunits, a process essential for the generation of interleukin-1beta in gout. PMID- 29247130 TI - A centrosomal scaffold shows some self-control. AB - The scaffolding protein AKAP350A is known to localize to the centrosome and the Golgi, but the molecular details of its function at the centrosome remain elusive. Using structure-function analyses, protein interaction assays, and super resolution microscopy, Kolobova et al. now identify AKAP350A's specific location and protein partners at the centrosome. The authors further define an autoregulatory mechanism that likely controls AKAP350A's ability to nucleate microtubule growth. PMID- 29247131 TI - N-terminal prion protein peptides (PrP(120-144)) form parallel in-register beta sheets via multiple nucleation-dependent pathways. PMID- 29247132 TI - The heme synthesis defect of mutants impaired in mitochondrial iron-sulfur protein biogenesis is caused by reversible inhibition of ferrochelatase. PMID- 29247135 TI - Don't neglect the clock drawing test. AB - INTRODUCTION: A 63-year-old, right-handed woman with a history of hypertension presented to the ED with left arm paresis of 2 days duration. Three weeks before admission, she had flu-like symptoms with intermittent left arm weakness that had recovered briefly but recurred 2 days prior to her presentation. On neurological examination, GCS was 15 and cranial nerves' function was normal. Left upper limb strength was 4/5. There was left arm drift and pronation but the patient denied noticing any difference between the positions of her arms. Hyper-reflexion was presented in the left arm. The rest of her motor, cerebellar, sensation and gait functions were normal. She was asked to draw a clock and set it to 15:30 (figure 1).emermed;35/1/38/F1F1F1Figure 1Clock drawing test results. QUESTION: What is the most probable aetiology?Right cerebral bleeding involving the occipital lobeRight middle cerebral artery occlusionRight parietal lesion, likely neoplasmLeft cortical stroke. PMID- 29247133 TI - Dihydrotestosterone induces pro-angiogenic factors and assists homing of MSC into the cardiac tissue. AB - The use of mesenchymal stem cells (MSC) as a therapeutic tool in cardiovascular diseases is promising. Since androgens exert some beneficial actions on the cardiovascular system, we tested our hypothesis that this hormone could promote MSC-mediated repair processes, also. Cultured MSCs isolated from Wharton's jelly were exposed to 30 nM dihydrotestosterone (DHT) for 1 or 4 days and the effects of the hormone on their growth/migration/adhesion and the underlying mechanisms were assessed. Results were obtained by real-time cell impedance measurements, and DNA quantification showed that DHT increased MSC proliferation by ~30%. As determined by xCELLigence system, DHT augmented (~2 folds) the migration of MSC toward cardiac tissue slices (at 12 h), and this effect was blocked by flutamide, an androgen receptor (AR) antagonist. Exposure of cells to DHT, upregulated the gene and protein expression of AR, EMMPRIN and MMP-9 and downregulated the expression of MMP-2 DHT significantly induced the release of nitric oxide by MSC (>=2-fold) and flutamide blocked this effect. When MSCs were co-cultured with cardiac slices, immunohistochemical analysis and qRT-PCR showed that the integration of DHT-stimulated MSC was significantly higher than that of in controls. In conclusion, our findings provide the first evidence that DHT promotes MSC growth, migration and integration into the cardiac slices. The modulating effects of DHT were associated with upregulation of ARs and of key molecules known to promote tissue remodeling and angiogenesis. Our findings suggest that priming of MSC with DHT may potentially increase their capability to regenerate cardiac tissue; in vivo studies are needed to confirm our in vitro findings. PMID- 29247136 TI - BET 1: Continuous flow insufflation of oxygen in out-of-hospital cardiac arrest. AB - A short cut review was carried out to establish whether continuous flow insufflation of oxygen (CFIO) is better than standard ventilation strategies at improving outcome in adults who have suffered an out-of-hospital cardiac arrest (OHCA). Papers were found in Medline and Embase using the reported searches of which four presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that CFIO does not improve survival or return of spontaneous circulation compared with standard ventilation strategies in OHCA. PMID- 29247139 TI - Correction: Testing of the 'always events' approach to improve the patient experience in the emergency department. PMID- 29247138 TI - BET 2: NSAIs and chickenpox. AB - A shortcut review was carried out to establish whether non-steroidal anti inflammatory drugs (NSAIDs) is safe to prescribe in patients with chicken pox. 66 unique papers were found in CINAHL, Medline, Embase and Cochrane using the reported searches of which 6 presented the best evidence to answer the clinical question. The author, date and country of publication; patient group studied; study type; relevant outcomes; results and study weaknesses of these best papers are tabulated. It is concluded that, pending further research, it is advisable to avoid NSAID use in cases of primary varicella due to the potential increased risk of severe bacterial skin infections. Paracetamol should be given instead. PMID- 29247140 TI - Genetic dissection of cyclic pyranopterin monophosphate biosynthesis in plant mitochondria. AB - Mitochondria play a key role in the biosynthesis of two metal cofactors, iron sulfur (FeS) clusters and molybdenum cofactor (Moco). The two pathways intersect at several points, but a scarcity of mutants has hindered studies to better understand these links. We screened a collection of sirtinol-resistant Arabidopsis thaliana mutants for lines with decreased activities of cytosolic FeS enzymes and Moco enzymes. We identified a new mutant allele of ATM3 (ABC transporter of the mitochondria 3), encoding the ATP-binding cassette transporter of the mitochondria 3 (systematic name ABCB25), confirming the previously reported role of ATM3 in both FeS cluster and Moco biosynthesis. We also identified a mutant allele in CNX2, cofactor of nitrate reductase and xanthine dehydrogenase 2, encoding GTP 3',8-cyclase, the first step in Moco biosynthesis which is localized in the mitochondria. A single-nucleotide polymorphism in cnx2 2 leads to substitution of Arg88 with Gln in the N-terminal FeS cluster-binding motif. cnx2-2 plants are small and chlorotic, with severely decreased Moco enzyme activities, but they performed better than a cnx2-1 knockout mutant, which could only survive with ammonia as a nitrogen source. Measurement of cyclic pyranopterin monophosphate (cPMP) levels by LC-MS/MS showed that this Moco intermediate was below the limit of detection in both cnx2-1 and cnx2-2, and accumulated more than 10-fold in seedlings mutated in the downstream gene CNX5 Interestingly, atm3-1 mutants had less cPMP than wild type, correlating with previous reports of a similar decrease in nitrate reductase activity. Taken together, our data functionally characterize CNX2 and suggest that ATM3 is indirectly required for cPMP synthesis. PMID- 29247141 TI - Sodium Valproate, a Histone Deacetylase Inhibitor, Is Associated With Reduced Stroke Risk After Previous Ischemic Stroke or Transient Ischemic Attack. AB - BACKGROUND AND PURPOSE: A variant in the histone deacetylase 9 (HDAC9) gene is associated with large artery stroke. Therefore, inhibiting HDAC9 might offer a novel secondary preventative treatment for ischemic stroke. The antiepileptic drug sodium valproate (SVA) is a nonspecific inhibitor of HDAC9. We tested whether SVA therapy given after ischemic stroke was associated with reduced recurrent stroke rate. METHODS: Data were pooled from 3 prospective studies recruiting patients with previous stroke or transient ischemic attack and long term follow-up: the South London Stroke Register, The Vitamins to Prevent Stroke Study, and the Oxford Vascular Study. Patients receiving SVA were compared with patients who received antiepileptic drugs other than SVA using survival analysis and Cox Regression. RESULTS: A total of 11 949 patients with confirmed ischemic event were included. Recurrent stroke rate was lower in patient taking SVA (17 of 168) than other antiepileptic drugs (105 of 530; log-rank survival analysis P=0.002). On Cox regression, controlling for potential cofounders, SVA remained associated with reduced stroke (hazard ratio=0.44; 95% confidence interval: 0.3 0.7; P=0.002). A similar result was obtained when patients taking SVA were compared with all cases not taking SVA (Cox regression, hazard ratio=0.47; 95% confidence interval: 0.29-0.77; P=0.003). CONCLUSIONS: These results suggest that exposure to SVA, an inhibitor of HDAC, may be associated with a lower recurrent stroke risk although we cannot exclude residual confounding in this study design. This supports the hypothesis that HDAC9 is important in the ischemic stroke pathogenesis and that its inhibition, by SVA or a more specific HDAC9 inhibitor, is worthy of evaluation as a treatment to prevent recurrent ischemic stroke. PMID- 29247142 TI - Novel Telestroke Program Improves Thrombolysis for Acute Stroke Across 21 Hospitals of an Integrated Healthcare System. AB - BACKGROUND AND PURPOSE: Faster treatment with intravenous alteplase in acute ischemic stroke is associated with better outcomes. Starting in 2015, Kaiser Permanente Northern California redesigned its acute stroke workflow across all 21 Kaiser Permanente Northern California stroke centers to (1) follow a single standardized version of a modified Helsinki model and (2) have all emergency stroke cases managed by a dedicated telestroke neurologist. We examined the effect of Kaiser Permanente Northern California's Stroke EXpediting the PRrocess of Evaluating and Stopping Stroke program on door-to-needle (DTN) time, alteplase use, and symptomatic intracranial hemorrhage rates. METHODS: The program was introduced in a staggered fashion from September 2015 to January 2016. We compared DTN times for a seasonally adjusted 9-month period at each center before implementation to the corresponding 9-month calendar period from the start of implementation. The primary outcome was the DTN time for alteplase administration. Secondary outcomes included rate of alteplase administrations per month, symptomatic intracranial hemorrhage, and disposition at time of discharge. RESULTS: This study included 310 patients treated with alteplase in the pre EXpediting the PRrocess of Evaluating and Stopping Stroke period and 557 patients treated with alteplase in the EXpediting the PRrocess of Evaluating and Stopping Stroke period. After implementation, alteplase administrations increased to 62/mo from 34/mo at baseline (P<0.001). Median DTN time decreased to 34 minutes after implementation from 53.5 minutes prior (P<0.001), and DTN time of <60 minutes was achieved in 87.1% versus 61.0% (P<0.001) of patients. DTN times <30 minutes were much more common in the Stroke EXpediting the PRrocess of Evaluating and Stopping Stroke period (40.8% versus 4.2% before implementation). There was no significant difference in symptomatic intracranial hemorrhage rates in the 2 periods (3.8% versus 2.2% before implementation; P=0.29). CONCLUSIONS: Introduction of a standardized modified Helsinki protocol across 21 hospitals using telestroke management was associated with increased alteplase administrations, significantly shorter DTN times, and no increase in adverse outcomes. PMID- 29247143 TI - Cognitive Impairment Before Intracerebral Hemorrhage Is Associated With Cerebral Amyloid Angiopathy. AB - BACKGROUND AND PURPOSE: Although the association between cerebral amyloid angiopathy (CAA) and cognitive impairment is increasingly recognized, it is not clear whether this is because of the impact of recurrent intracerebral hemorrhage (ICH) events, disruptions caused by cerebral small vessel damage, or both. We investigated this by considering whether cognitive impairment before ICH was associated with neuroimaging features of CAA on magnetic resonance imaging. METHODS: We studied 166 patients with neuroimaging-confirmed ICH recruited to a prospective multicentre observational study. Preexisting cognitive impairment was determined using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Magnetic resonance imaging markers of cerebral small vessel disease, including CAA, were rated by trained observers according to consensus guidelines. RESULTS: The prevalence of cognitive impairment before ICH was 24.7% (n=41) and, in adjusted analyses, was associated with fulfilling the modified Boston criteria for probable CAA at presentation (odds ratio, 4.01; 95% confidence interval, 1.53 10.51; P=0.005) and a higher composite CAA score (for each point increase, odds ratio, 1.42; 95% confidence interval, 1.03-1.97; P=0.033). We also found independent associations between pre-ICH cognitive decline and the presence of cortical superficial siderosis, strictly lobar microbleeds, and lobar ICH location, but not with other neuroimaging markers, or a composite small vessel disease score. CONCLUSIONS: CAA (defined using magnetic resonance imaging markers) is associated with cognitive decline before symptomatic ICH. This provides evidence that small vessel disruption in CAA makes an independent contribution to cognitive impairment, in addition to effects due to brain injury caused directly by ICH. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02513316. PMID- 29247144 TI - NFIA and GATA3 are crucial regulators of embryonic articular cartilage differentiation. AB - During appendicular skeletal development, the bi-potential cartilage anlagen gives rise to transient cartilage, which is eventually replaced by bone, and to articular cartilage that caps the ends of individual skeletal elements. While the molecular mechanism that regulates transient cartilage differentiation is relatively well understood, the mechanism of articular cartilage differentiation has only begun to be unraveled. Furthermore, the molecules that coordinate the articular and transient cartilage differentiation processes are poorly understood. Here, we have characterized in chick the regulatory roles of two transcription factors, NFIA and GATA3, in articular cartilage differentiation, maintenance and the coordinated differentiation of articular and transient cartilage. Both NFIA and GATA3 block hypertrophic differentiation. Our results suggest that NFIA is not sufficient but necessary for articular cartilage differentiation. Ectopic activation of GATA3 promotes articular cartilage differentiation, whereas inhibition of GATA3 activity promotes transient cartilage differentiation at the expense of articular cartilage. We propose a novel transcriptional circuitry involved in embryonic articular cartilage differentiation, maintenance and its crosstalk with the transient cartilage differentiation program. PMID- 29247146 TI - Synoviocytes-derived Interleukin 35 Potentiates B Cell Response in Patients with Osteoarthritis and Rheumatoid Arthritis. AB - OBJECTIVE: Elevated expression of interleukin 35 (IL-35) is associated with autoimmune disease, including rheumatoid arthritis (RA). The present study was undertaken to determine the functional interaction among IL-35, B cells, and stromal cells residing in the synovium of patients with RA and osteoarthritis (OA). METHODS: IL-35 (EBI-3/p35) expression was investigated in RA and OA synovium using quantitative real-time PCR (qRT-PCR) and immunohistochemistry. IL 35 receptor (IL-35R) expression on B cells dissociated from synovium and periphery of patients with RA, OA, and healthy donor controls (HC) was determined by flow cytometry. The degree of B cells activation after IL-4 and/or IL-35 stimulation was measured by flow cytometry and qRT-PCR. Synovial fibroblasts (SF) purified from RA and OA synovium were cocultured with peripheral HC B cells in the presence/absence of tumor necrosis factor-alpha (TNF-alpha) and with/without anti-IL-35-blocking antibodies. RESULTS: EBI-3/p35 transcripts were expressed in close proximity to B cells residing in RA and OA synovium. IL-35R subunits, gp130 and IL-27Ralpha, but not IL-12Rbeta2, were expressed in B cells extracted from the synovium and periphery of patients with RA/OA. Notably, RA synovium expressed the highest level of IL-27Ralpha on their cell surface. IL-35 induced proliferation and IgG production in HC B cells. Cocultures of HC B cells with RASF, but not OASF, exhibited significantly elevated B cells activation. TNF alpha-induced, RASF-dependent secretion of IgG in B cells is partly IL-35 dependent. CONCLUSION: To our knowledge, for the first time we demonstrated that synovial/peripheral B cells expressed IL-35R and were responsive to IL-35 stimulation. SF residing in RA synovium can be linked to B cell activation and maintenance in RA synovium through IL-35. PMID- 29247145 TI - Distinct subsets of Eve-positive pericardial cells stabilise cardiac outflow and contribute to Hox gene-triggered heart morphogenesis in Drosophila. AB - The Drosophila heart, composed of discrete subsets of cardioblasts and pericardial cells, undergoes Hox-triggered anterior-posterior morphogenesis, leading to a functional subdivision into heart proper and aorta, with its most anterior part forming a funnel-shaped cardiac outflow. Cardioblasts differentiate into Tin-positive 'working myocytes' and Svp-expressing ostial cells. However, developmental fates and functions of heart-associated pericardial cells remain elusive. Here, we show that the pericardial cells that express the transcription factor Even Skipped adopt distinct fates along the anterior-posterior axis. Among them, the most anterior Antp-Ubx-AbdA-negative cells form a novel cardiac outflow component we call the outflow hanging structure, whereas the Antp-expressing cells differentiate into wing heart precursors. Interestingly, Hox gene expression in the Even Skipped-positive cells not only underlies their antero posterior diversification, but also influences heart morphogenesis in a non-cell autonomous way. In brief, we identify a new cardiac outflow component derived from a subset of Even Skipped-expressing cells that stabilises the anterior heart tip, and demonstrate non-cell-autonomous effects of Hox gene expression in the Even Skipped-positive cells on heart morphogenesis. PMID- 29247129 TI - WNT Signaling in Cardiac and Vascular Disease. AB - WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signaling molecules. WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies of heart and blood vessels. The high prevalence of these pathologies and their significant contribution to human disease burden has raised interest in WNT signaling as a potential target for therapeutic intervention. In this review, we first will focus on the constituents of the pathway and their regulation and the different signaling routes. Subsequently, the role of WNT signaling in cardiovascular development is addressed, followed by a detailed discussion of its involvement in vascular and cardiac disease. After highlighting the crosstalk between WNT, transforming growth factor-beta and angiotensin II signaling, and the emerging role of WNT signaling in the regulation of stem cells, we provide an overview of drugs targeting the pathway at different levels. From the combined studies we conclude that, despite the sometimes conflicting experimental data, a general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology. The rapidly increasing collection of drugs interfering at different levels of WNT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future, translating the outcomes of the many preclinical studies into a clinically relevant context. PMID- 29247147 TI - Variability in the Reporting of Serum Urate and Flares in Gout Clinical Trials: Need for Minimum Reporting Requirements. AB - OBJECTIVE: To describe the ways in which serum urate (SU) and gout flares are reported in clinical trials, and to propose minimum reporting requirements. METHODS: This analysis was done as part of a systematic review aiming to validate SU as a biomarker for gout. The ways in which SU and flares were reported were extracted from each study by 2 reviewers. RESULTS: A total of 22 studies (10 randomized controlled trials, 3 open-label extension studies, and 9 observational studies) were identified. There were 3 broad categories of SU reporting: percentage at target SU, mean SU, and change in SU. A median of 2 (range 1-3) categories were reported across all studies. The most common method of reporting SU was percentage at target in 17/22 (77.3%) studies, with all studies reporting a target of SU < 6 mg/dl. There were 12/22 (54.5%) studies reporting mean SU at some time after study entry, with 7 (58.3%) of these reporting at more than just the final study visit. Two ways of reporting gout flares were identified: mean flare rate and percentage of participants with flares. There was variability in time periods over which flares rates were reported. CONCLUSION: There is inconsistent reporting of SU and flares in gout studies. Reporting the percentage of participants who achieve a target SU reflects international treatment guidelines. SU should also be reported as a continuous variable with a relevant central and dispersion estimate. Gout flares should be reported as both percentage of participants and mean flare rates at each timepoint. PMID- 29247149 TI - Two-year Efficacy and Safety of Subcutaneous Tocilizumab in Combination with Disease-modifying Antirheumatic Drugs Including Escalation to Weekly Dosing in Rheumatoid Arthritis. AB - OBJECTIVE: To evaluate the longterm efficacy and safety of subcutaneous tocilizumab (TCZ-SC) every 2 weeks (q2w) over 2 years in patients with rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARD). METHODS: Patients (n = 656) were randomized 2:1 to TCZ-SC 162 mg q2w or placebo-SC q2w plus DMARD. After a 24-week double-blind period, patients (n = 457) were rerandomized to open-label TCZ-SC q2w by means of prefilled syringe or autoinjector. Escape therapy with weekly TCZ-SC was available for patients with inadequate efficacy from Week 12. Maintenance of response and safety to 2 years was assessed. Analyses used nonresponder imputation. RESULTS: The American College of Rheumatology (ACR) 20 response after TCZ-SC was maintained beyond Week 24 and was > 70% at each timepoint. ACR50/70, 28-joint Disease Activity Score remission, and >= 0.30 decrease from baseline in the Health Assessment Questionnaire-Disability Index response rates were also maintained after Week 24 in the TCZ-SC arm (>= 50%, > 25%,> 32% and > 56%, respectively). Following escape for inadequate efficacy, many patients achieved ACR20 at the end of the study, 35% after escape from TCZ-SC, and 63% from placebo. The rates of serious adverse events [(11.20/100 patient-years (PY)] including serious infections (3.25/100 PY) were stable through Week 96. No association between anti-TCZ antibody development and loss of efficacy or adverse events was observed. CONCLUSION: Efficacy and safety of TCZ-SC q2w was maintained up to 2 years and remained comparable with previously published data for intravenous TCZ. Dose escalation to weekly TCZ-SC was associated with ACR responses in prior nonresponders and was well tolerated. PMID- 29247148 TI - Efficacy and Safety of Ixekizumab in Patients with Active Psoriatic Arthritis: 52 week Results from a Phase III Study (SPIRIT-P1). AB - OBJECTIVE: To evaluate the efficacy and safety of ixekizumab (IXE), an interleukin 17A antagonist, in patients with psoriatic arthritis (PsA) after 52 weeks in a phase III study. METHODS: Patients were initially randomly assigned to IXE 80 mg every 2 weeks (IXEQ2W) or every 4 weeks (IXEQ4W) after a 160-mg starting dose, placebo (PBO), or adalimumab (ADA) 40 mg Q2W. At Week 24 (Week 16 for inadequate responders), ADA (8-week washout before starting IXE) and PBO patients were rerandomized to IXEQ2W or IXEQ4W. Six treatment groups were evaluated in the extension period (weeks 24-52): IXEQ2W/IXEQ2W, IXEQ4W/IXEQ4W, ADA/IXEQ2W, ADA/IXEQ4W, PBO/IXEQ2W, and PBO/IXEQ4W. The extension period population (EPP) included patients who received >= 1 dose of study medication during the extension period. RESULTS: There were 381/417 (91.4%) patients who entered the extension period. In the IXEQ4W/IXEQ4W and IXEQ2W/IXEQ2W groups (EPP), respectively, American College of Rheumatology (ACR)20 (69.1% and 68.8%), ACR50 (54.6% and 53.1%), and ACR70 (39.2% and 39.6%) response rates were sustained at Week 52. Patients rerandomized to IXE also demonstrated efficacy measured by ACR response rates at Week 52. A similar pattern was observed for Psoriasis Area and Severity Index outcomes. Radiographic progression in all 6 groups was minimal. The most frequently reported treatment-emergent adverse events (>= 4%) were nasopharyngitis, injection site reaction, injection site erythema, upper respiratory tract infection, and back pain. No deaths were reported, and serious adverse event frequency was 0-4% with IXE. CONCLUSION: During the extension period, IXEQ4W or IXEQ2W treatment demonstrated sustained efficacy in key PsA domains with a safety profile consistent with other studies investigating IXE. Clinical trial number: NCT01695239; EudraCT 2011-002326-49. PMID- 29247150 TI - Adiposity in Juvenile Psoriatic Arthritis. AB - OBJECTIVE: Adult patients with psoriatic arthritis are at increased risk for obesity and metabolic syndrome, but data regarding adiposity in children with juvenile psoriatic arthritis (JPsA) are limited. Our study assessed adiposity in children with JPsA in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. METHODS: Patients with JPsA in the CARRA registry were divided into nonoverweight and overweight groups using recommendations from the US Centers for Disease Control, and differences in demographic and clinical characteristics between groups at baseline and after 1-year followup were assessed using chi-square test, Fisher's exact test, T test, or Mann-Whitney U test, as appropriate. The prevalence of overweight status in the JPsA registry patients was compared to rheumatoid factor-positive and -negative polyarticular juvenile idiopathic arthritis (RF+polyJIA; RF-polyJIA) registry cohorts and the US pediatric population, using a chi-square goodness-of-fit test. RESULTS: Overweight children represented 36.3% of this JPsA cohort (n = 320). Compared to nonoverweight children, they were significantly older at symptom onset and rheumatologist's first assessment, and scored significantly worse on patient/physician outcome measures. At 1-year followup, changes in body mass index were not associated with changes in clinical features or outcome measures. The prevalence of overweight and obesity in patients with JPsA was significantly higher than in RF+polyJIA patients, RF-polyJIA patients, and the US pediatric population. CONCLUSION: In this registry, almost 1 in 5 patients with JPsA were obese and more than one-third were overweight. This is significantly more than expected compared to the US pediatric population, and appropriate longterm followup of this JPsA subgroup is warranted. PMID- 29247151 TI - The Rising Incidence of Gout and the Increasing Burden of Comorbidities: A Population-based Study over 20 Years. AB - OBJECTIVE: To examine the incidence of gout over the last 20 years and to evaluate possible changes in associated comorbid conditions. METHODS: The medical records were reviewed of all adults with a diagnosis of incident gout in Olmsted County, Minnesota, USA, during 2 time periods (January 1, 1989-December 31, 1992, and January 1, 2009-December 31, 2010). Incident cases had to fulfill at least 1 of 3 criteria: the American Rheumatism Association 1977 preliminary criteria for gout, the Rome criteria, or the New York criteria. RESULTS: A total of 158 patients with new-onset gout were identified during 1989-1992 and 271 patients during 2009-2010, yielding age- and sex-adjusted incidence rates of 66.6/100,000 (95% CI 55.9-77.4) in 1989-1992 and 136.7/100,000 (95% CI 120.4-153.1) in 2009 2010. The incidence rate ratio was 2.62 (95% CI 1.80-3.83). At the time of their first gout flare, patients diagnosed with gout in 2009-2010 had higher prevalence of comorbid conditions compared with 1989-1992, including hypertension (69% vs 54%), diabetes mellitus (25% vs 6%), renal disease (28% vs 11%), hyperlipidemia (61% vs 21%), and morbid obesity (body mass index >= 35 kg/m2; 29% vs 10%). CONCLUSION: The incidence of gout has more than doubled over the recent 20 years. This increase together with the more frequent occurrence of comorbid conditions and cardiovascular risk factors represents a significant public health challenge. PMID- 29247152 TI - Prevalence of Comorbidities and Risk Factors for Comorbidities in Patients with Spondyloarthritis in Latin America: A Comparative Study with the General Population and Data from the ASAS-COMOSPA Study. AB - OBJECTIVE: Increased risk of comorbidities has been reported in spondyloarthritis (SpA). The objective of this study was to determine the prevalence and risk of developing comorbidities in patients with SpA in 3 Latin American (LA) countries, and to compare that prevalence with the general population. METHODS: Data were analyzed from 390 patients with SpA enrolled in the Assessment of SpondyloArthritis international Society of Comorbidities in SpA study from Argentina, Colombia, and Mexico. Age- and sex-standardized prevalence (95% CI) was estimated for arterial hypertension (AHT), tuberculosis (TB), and malignancies. Age- and sex-specific data from the general population were obtained from the Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study for AHT, the Global TB report, and the GLOBOCAN project for malignancies. Data analyzed for AHT were confined to Colombia and Mexico. The prevalence in patients with SpA was compared with the prevalence in the general population per age- and sex-specific stratum, resulting in standardized risk ratios (SRR). RESULTS: In total, 64% of the patients with SpA were male, with a mean age of 45 years (SD 14.7). The most common comorbidities in the 3 LA countries were AHT (25.3%, 95% CI 21.2-30.0), hypercholesterolemia (21.5%, 95% CI 17.6-26.0), and osteoporosis (9.4%, 95% CI 6.8-12.9). AHT prevalence in Colombia and Mexico was 21.4% (95% CI 15.4-28.9) and was higher than the general population (12.5%, 95% CI 11.4-13.7), resulting in an SRR of 1.5. TB prevalence in the 3 LA countries was 3.3% (95% CI 1.8-5.7), which was significantly higher than in the general population (0.32%), leading to an SRR of 10.3. The prevalence of malignancies was not increased. CONCLUSION: Patients with SpA in LA are at increased risk of AHT and TB in comparison to the general population. While this sample of patients may not be entirely representative of the patient population in each country, a systematic evaluation of these comorbidities in all patients with SpA still may help to monitor these conditions better. PMID- 29247154 TI - Safety and Efficacy of Golimumab Administered Intravenously in Adults with Ankylosing Spondylitis: Results through Week 28 of the GO-ALIVE Study. AB - OBJECTIVE: To evaluate the safety and efficacy of intravenous golimumab (GOL) in patients with active ankylosing spondylitis (AS). METHODS: In a phase III, randomized, double-blind, placebo (PBO)-controlled trial, 208 patients were randomized (1:1) to intravenous (IV) infusions of GOL 2 mg/kg (n = 105) at weeks 0, 4, 12, and every 8 weeks, or PBO (n = 103) at weeks 0, 4, and 12, with crossover to GOL at Week 16. The primary endpoint was >= 20% improvement from baseline in the Assessment of Spondyloarthritis International Society Criteria (ASAS20) at Week 16. Secondary endpoints included ASAS40, >= 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50), and change in the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 16. Safety was monitored through Week 28. RESULTS: Significantly greater proportions of GOL treated patients had ASAS20 response at Week 2 (37.1% vs 19.4%; p = 0.005) and at Week 16 (73.3% vs 26.2%; p < 0.001). At Week 16, 41.0% of those receiving GOL achieved BASDAI50 compared with 14.6% of those taking PBO (p < 0.001), and the GOL group had greater mean improvement in BASFI (-2.4 vs -0.5; p < 0.001). Through Week 16, 23.3% of patients in the PBO group and 32.4% of patients in the GOL group had >= 1 adverse event (AE); infections being the commonest type of AE. Through Week 28, two GOL-treated patients had a serious AE. CONCLUSION: GOL 2 mg/kg administered IV at weeks 0, 4, and every 8 weeks significantly reduced the signs and symptoms of AS in adults. AE were consistent with other antitumor necrosis factor therapies, with no new safety signals (Clinicaltrials.gov: NCT02186873). PMID- 29247153 TI - The Use of the OMERACT Ultrasound Tenosynovitis Scoring System in Multicenter Clinical Trials. AB - OBJECTIVE: To test the sensitivity to change of the Outcome Measures in Rheumatology Clinical Trials (OMERACT) ultrasound (US) scoring system for tenosynovitis when applied in a multicenter design. METHODS: RA patients with US verified tenosynovitis were recruited when scheduled for treatment intensification. Tenosynovitis was assessed at baseline, and 3 and 6 months followup, using the semiquantitative OMERACT scoring system. RESULTS: Expressed in median (25th; 75th percentiles), the overall greyscale and Doppler score decreased significantly from baseline at 4 (2; 7) and 3 (2; 6), to 6 months at 2 (0; 3) and 0 (0; 1, p < 0.01), respectively, and showed high responsiveness (standardized response mean >= 0.8). CONCLUSION: The OMERACT US scoring system for tenosynovitis showed high responsiveness, supporting its use for diagnosing and monitoring tenosynovitis in multicenter trials. PMID- 29247155 TI - CXCL10 and TRAIL Are Upregulated by TXNDC5 in Rheumatoid Arthritis Fibroblast like Synoviocytes. AB - OBJECTIVE: Thioredoxin domain containing 5 (TXNDC5) is highly expressed in synovial membranes of rheumatoid arthritis (RA). Our study aimed to investigate the pathogenic role of TXNDC5 in RA. METHODS: PCR arrays, CCK-8 assays, flow cytometry, and transwell migration assays were used to analyze cultured rheumatoid arthritis synovial fibroblasts (RASF). RESULTS: Increased CXCL10 and tumor necrosis factor-related apoptosis-inducing ligand levels were detected in RASF transfected with anti-TXNDC5 small interfering RNA (siRNA), and decreased expression was detected in RASF transfected with TXNDC5-expressing plasmids. Significantly attenuated RASF proliferation and migration, and increased RASF apoptosis, were observed in the siRNA-transfected RASF. CONCLUSION: Downregulation of TXNDC5 could contribute to RASF antiangiogenic and proapoptotic features through the suppression of CXCL10 and TRAIL (tumor necrosis factor related apoptosis-inducing ligand). PMID- 29247156 TI - Melatonin Promotes Brain-Derived Neurotrophic Factor (BDNF) Expression and Anti Apoptotic Effects in Neonatal Hemolytic Hyperbilirubinemia via a Phospholipase (PLC)-Mediated Mechanism. AB - BACKGROUND Melatonin therapy shows positive effects on neuroprotective factor brain-derived neurotrophic factor (BDNF) expression and neuronal apoptosis in neonatal hemolytic hyperbilirubinemia. We hypothesized that melatonin promotes BDNF expression and anti-apoptotic effects in neonatal hemolytic hyperbilirubinemia through a phospholipase (PLC)-mediated mechanism. MATERIAL AND METHODS A phenylhydrazine hydrochloride (PHZ)-induced neonatal hemolytic hyperbilirubinemia model was constructed in neonatal rats. Four experimental groups - a control group (n=30), a PHZ group (n=30), a PHZ + melatonin group (n=30), and a PHZ + melatonin+U73122 (a PLC inhibitor) group (n=30) - were constructed. Trunk blood was assayed for serum hemoglobin, hematocrit, total and direct bilirubin, BDNF, S100B, and tau protein levels. Brain tissue levels of neuronal apoptosis, BDNF expression, PLC activity, IP3 content, phospho- and total Ca2+/calmodulin-dependent protein kinase type IV (CaMKIV) expression, and phospho- and total cAMP response element binding protein (CREB) expression were also assayed. RESULTS PHZ-induced hemolytic hyperbilirubinemia was validated by significantly decreased serum hemoglobin and hematocrit as well as significantly increased total and direct serum bilirubin (p<0.05). Neonatal bilirubin-induced neurotoxicity was validated by significantly decreased serum BDNF, brain BDNF, and serum S100B, along with significantly increased serum tau protein (p<0.05). PHZ-induced hemolytic hyperbilirubinemia significantly decreased serum BDNF, brain BDNF, and PLC/IP3/Ca2+ pathway activation while increasing neuronal apoptosis levels (p<0.05), all of which were partially rescued by melatonin therapy (p<0.05). Pre-treatment with the PLC inhibitor U73122 largely abolished the positive effects of melatonin on PLC/IP3/Ca2+ pathway activation, downstream BDNF levels, and neuronal apoptosis (p<0.05). CONCLUSIONS Promotion of BDNF expression and anti-apoptotic effects in neonatal hemolytic hyperbilirubinemia by melatonin largely operates via a PLC-mediated mechanism. PMID- 29247157 TI - A Case of Subacute Bioresorbable Vascular Scaffold Thrombosis, What was Wrong? AB - BACKGROUND The introduction of bioresorbable vascular scaffolds (BVS) into the field of percutaneous coronary intervention (PCI) was thought to be a promising step in solving the issues raised with the use of early bare metal stents (BMS) and drug eluting stents (DES); however, studies have raised concerns regarding thrombosis risk associated with the use of these stents. CASE REPORT A 42-year old male presented with acute coronary syndrome (ACS), on diagnostic coronary angiography he had 75% and 70% stenosis in mid and distal left anterior descending artery (LAD) respectively, PCI with BVS implantation was done. A week later, he came with non-ST segment elevation myocardial infarction due to an in stent thrombosis. Procedures to open the LAD were done with multiple balloon angioplasties and aspiration thrombectomy, following aggressive dilatation there was a class-III perforation which was sealed by covered stent. A second look angiography was done which showed patent LAD and well expanded stents. CONCLUSIONS Since several factors play a role in decision-making regarding the selection of patient in whom BVS usage can be beneficial, larger studies are needed. Moreover, the safety profile of BVS should be investigated thoroughly. PMID- 29247158 TI - Hydrologically-driven crustal stresses and seismicity in the New Madrid Seismic Zone. AB - The degree to which short-term non-tectonic processes, either natural and anthropogenic, influence the occurrence of earthquakes in active tectonic settings or 'stable' plate interiors, remains a subject of debate. Recent work in plate-boundary regions demonstrates the capacity for long-wavelength changes in continental water storage to produce observable surface deformation, induce crustal stresses and modulate seismicity rates. Here we show that a significant variation in the rate of microearthquakes in the intraplate New Madrid Seismic Zone at annual and multi-annual timescales coincides with hydrological loading in the upper Mississippi embayment. We demonstrate that this loading, which results in geodetically observed surface deformation, induces stresses within the lithosphere that, although of small amplitude, modulate the ongoing seismicity of the New Madrid region. Correspondence between surface deformation, hydrological loading and seismicity rates at both annual and multi-annual timescales indicates that seismicity variations are the direct result of elastic stresses induced by the water load. PMID- 29247159 TI - Neurons along the auditory pathway exhibit a hierarchical organization of prediction error. AB - Perception is characterized by a reciprocal exchange of predictions and prediction error signals between neural regions. However, the relationship between such sensory mismatch responses and hierarchical predictive processing has not yet been demonstrated at the neuronal level in the auditory pathway. We recorded single-neuron activity from different auditory centers in anaesthetized rats and awake mice while animals were played a sequence of sounds, designed to separate the responses due to prediction error from those due to adaptation effects. Here we report that prediction error is organized hierarchically along the central auditory pathway. These prediction error signals are detectable in subcortical regions and increase as the signals move towards auditory cortex, which in turn demonstrates a large-scale mismatch potential. Finally, the predictive activity of single auditory neurons underlies automatic deviance detection at subcortical levels of processing. These results demonstrate that prediction error is a fundamental component of singly auditory neuron responses. PMID- 29247160 TI - The proper use of coronary calcium score and coronary computed tomography angiography for screening asymptomatic patients with cardiovascular risk factors. AB - Early detection and treatment of coronary artery disease (CAD) can reduce incidences of acute myocardial infarction. In this study, we determined the proper use of contributing risk factors and coronary artery calcium score (CACS) when screening asymptomatic patients with coronary arterial stenoses using coronary computed tomography angiography (CCTA). We reviewed 934 consecutive patients who received CACS and CCTA between December 2013 and November 2016. At least one cardiovascular disease risk factor was present in each of the 509 asymptomatic participants. Patients were grouped based on CACS into "zero," "minimal" (0 < CACS <= 10), "mild" (10 < CACS <= 100), "moderate" (100 < CACS <= 400), and "excessive" (CACS > 400). Males over 45 years old with diabetes mellitus and hypertension had a higher risk of significant coronary stenosis. In multivariate analysis, age, sex, hypertension, and diabetes mellitus remained significant predictors of stenosis. A CACS of zero occurred in 227 patients (44.6%). There were no significant differences between the "zero" and "minimal" groups (p = 0.421), but the "mild," "moderate," and "excessive" groups showed correlations with significant coronary stenosis. Age, sex, diabetes mellitus, and hypertension were associated with higher risk of significant coronary stenosis. Asymptomatic patients with CACSs of zero do not require CCTA, and thereby avoid unnecessary radiation exposure. PMID- 29247161 TI - Association between Neuroticism and Emotional Face Processing. AB - Neuroticism is one of the "Big Five" personality factors and is characterized by a tendency to experience negative affect. We aimed to investigate how neuroticism influences the neural correlates for processing of emotional facial expressions. 68 healthy participants were presented with emotional dynamic facial stimuli, i.e. happy, neutral or angry, during functional MRI. Brain activations for the contrasts emotional vs. neutral, happy vs. neutral and angry vs. neutral were correlated with individuals' neuroticism scores as obtained by the NEO Five Factor Inventory questionnaire and additionally investigated for gender differences. The bilateral medial temporal gyrus (MTG) was identified as key region in the processing of emotional faces and activations within this region correlated with individual neuroticism scores. Although female participants showed significantly stronger activation differences between emotional and neutral facial expressions in the left MTG, the correlation between activation and neuroticism scores did not show any significant gender differences. Our results offer for the first time a biological correlate within the face processing network for enhanced reactivity of neurotic individuals to emotional facial expressions which occurs similarly for both male and female participants. PMID- 29247162 TI - Peripersonal space representation develops independently from visual experience. AB - Our daily-life actions are typically driven by vision. When acting upon an object, we need to represent its visual features (e.g. shape, orientation, etc.) and to map them into our own peripersonal space. But what happens with people who have never had any visual experience? How can they map object features into their own peripersonal space? Do they do it differently from sighted agents? To tackle these questions, we carried out a series of behavioral experiments in sighted and congenitally blind subjects. We took advantage of a spatial alignment effect paradigm, which typically refers to a decrease of reaction times when subjects perform an action (e.g., a reach-to-grasp pantomime) congruent with that afforded by a presented object. To systematically examine peripersonal space mapping, we presented visual or auditory affording objects both within and outside subjects' reach. The results showed that sighted and congenitally blind subjects did not differ in mapping objects into their own peripersonal space. Strikingly, this mapping occurred also when objects were presented outside subjects' reach, but within the peripersonal space of another agent. This suggests that (the lack of) visual experience does not significantly affect the development of both one's own and others' peripersonal space representation. PMID- 29247163 TI - Conserved molecular structure of the centromeric histone CENH3 in Secale and its phylogenetic relationships. AB - It has been repeatedly demonstrated that the centromere-specific histone H3 (CENH3), a key component of the centromere, shows considerable variability between species within taxa. We determined the molecular structure and phylogenetic relationships of CENH3 in 11 Secale species and subspecies that possess distinct pollination systems and are adapted to a wide range of abiotic and biotic stresses. The rye (Secale cereale) genome encodes two paralogous CENH3 genes, which differ in intron-exon structure and are transcribed into two main forms of the protein, alphaCENH3 and betaCENH3. These two forms differ in size and amino acid substitutions. In contrast to the reported differences in CENH3 structure between species within other taxa, the main forms of this protein in Secale species and subspecies have a nearly identical structure except some nonsynonymous substitutions. The CENH3 proteins are strictly controlled by genetic factors responsible for purifying selection. A comparison between Hordeum, Secale and Triticum species demonstrates that the structure of CENH3 in the subtribes Hordeinae and Triticinae evolved at different rates. The assumption that reticulate evolution served as a factor stabilizing the structure and evolutionary rate of CENH3 and that this factor was more powerful within Secale and Triticum than in Hordeum, is discussed. PMID- 29247164 TI - Heatwaves diminish the survival of a subtidal gastropod through reduction in energy budget and depletion of energy reserves. AB - Extreme climatic events, such as heatwaves, are predicted to be more prevalent in future due to global climate change. The devastating impacts of heatwaves on the survival of marine organisms may be further intensified by ocean acidification. Here, we tested the hypothesis that prolonged exposure to heatwave temperatures (24 degrees C, +3 degrees C summer seawater temperature) would diminish energy budget, body condition and ultimately survival of a subtidal gastropod (Thalotia conica) by pushing close to its critical thermal maximum (CTmax). We also tested whether ocean acidification (pCO2: 1000 ppm) affects energy budget, CTmax and hence survival of this gastropod. Following the 8-week experimental period, mortality was markedly higher at 24 degrees C irrespective of pCO2 level, probably attributed to energy deficit (negative scope for growth) and concomitant depletion of energy reserves (reduced organ weight to flesh weight ratio). CTmax of T. conica appeared at 27 degrees C and was unaffected by ocean acidification. Our findings imply that prolonged exposure to heatwaves can compromise the survival of marine organisms below CTmax via disruption in energy homeostasis, which possibly explains their mass mortality in the past heatwave events. Therefore, heatwaves would have more profound effects than ocean acidification on future marine ecosystems. PMID- 29247165 TI - Spin-momentum locked interaction between guided photons and surface electrons in topological insulators. AB - The propagation of electrons and photons can respectively have the spin-momentum locking effect which correlates spin with linear momentum. For surface electrons in three-dimensional topological insulators (TIs), their spin is locked to the transport direction. Analogously, photons in optical waveguides carry transverse spin angular momentum which is also locked to the propagation direction. A direct connection between electron and photon spins occurs in TIs due to spin-dependent selection rules of optical transitions. Here we demonstrate an optoelectronic device that integrates a TI with a photonic waveguide. Interaction between photons in the waveguide and surface electrons in a Bi2Se3 layer generates a directional, spin-polarized photocurrent. Because of spin-momentum locking, changing light propagation direction reverses photon spin and thus the direction of the photocurrent. Our device represents a way of implementing coupled spin orbit interaction between electrons and photons and may lead to applications in opto-spintronics and quantum information processing. PMID- 29247166 TI - Increasing the permeability of Escherichia coli using MAC13243. AB - The outer membrane of gram-negative bacteria is a permeability barrier that prevents the efficient uptake of molecules with large scaffolds. As a consequence, a number of antibiotic classes are ineffective against gram-negative strains. Herein we carried out a high throughput screen for small molecules that make the outer membrane of Escherichia coli more permeable. We identified MAC13243, an inhibitor of the periplasmic chaperone LolA that traffics lipoproteins from the inner to the outer membrane. We observed that cells were (1) more permeable to the fluorescent probe 1-N-phenylnapthylamine, and (2) more susceptible to large-scaffold antibiotics when sub-inhibitory concentrations of MAC13243 were used. To exclude the possibility that the permeability was caused by an off-target effect, we genetically reconstructed the MAC13243-phenotype by depleting LolA levels using the CRISPRi system. PMID- 29247168 TI - Attribution of recent temperature behaviour reassessed by a neural-network method. AB - Attribution studies on recent global warming by Global Climate Model (GCM) ensembles converge in showing the fundamental role of anthropogenic forcings as primary drivers of temperature in the last half century. However, despite their differences, all these models pertain to the same dynamical approach and come from a common ancestor, so that their very similar results in attribution studies are not surprising and cannot be considered as a clear proof of robustness of the results themselves. Thus, here we adopt a completely different, non-dynamical, data-driven and fully nonlinear approach to the attribution problem. By means of neural network (NN) modelling, and analysing the last 160 years, we perform attribution experiments and find that the strong increase in global temperature of the last half century may be attributed basically to anthropogenic forcings (with details on their specific contributions), while the Sun considerably influences the period 1910-1975. Furthermore, the role of sulphate aerosols and Atlantic Multidecadal Oscillation for better catching interannual to decadal temperature variability is clarified. Sensitivity analyses to forcing changes are also performed. The NN outcomes both corroborate our previous knowledge from GCMs and give new insight into the relative contributions of external forcings and internal variability to climate. PMID- 29247169 TI - Cardiometabolic Risk Factors in Childhood, Adolescent and Young Adult Survivors of Acute Lymphoblastic Leukemia - A Petale Cohort. AB - Our objectives were to assess the prevalence of cardiometabolic complications in children, adolescents, and young adult survivors of childhood acute lymphoblastic leukemia (cALL), to identify their predictors and the risk compared to the Canadian population. We performed a cardiometabolic assessment of cALL survivors from the PETALE cohort (n = 247, median age at visit of 21.7 years). In our group, overweight and obesity affected over 70% of women. Pre-hypertension and hypertension were mostly common in men, both adults (20%) and children (19%). Prediabetes was mainly present in women (6.1% of female adult survivors) and 41.3% had dyslipidemia. Cranial radiation therapy was a predictor of dyslipidemia (RR: 1.60, 95% CI: 1.07-2.41) and high LDL-cholesterol (RR: 4.78, 95% CI: 1.72 13.28). Male gender was a predictor for pre-hypertension and hypertension (RR: 5.12, 95% CI: 1.81-14.46). Obesity at the end of treatment was a predictor of obesity at interview (RR: 2.07, 95% CI: 1.37-3.14) and of metabolic syndrome (RR: 3.04, 95% CI: 1.14-8.09). Compared to the general population, cALL survivors were at higher risk of having the metabolic syndrome, dyslipidemia, pre hypertension/hypertension and high LDL-cholesterol, while the risk for obesity was not different. Our results support the need for early screening and lifestyle intervention in this population. PMID- 29247170 TI - Harnessing the microbiomes of Brassica vegetables for health issues. AB - Plant health is strongly connected with plants' microbiome. In case of raw-eaten plants, the microbiome can also affect human health. To study potential impacts on health issues of both hosts, the microbiome composition of seven different Brassica vegetables, originating from different food processing pathways, was analyzed by a combined approach of amplicon sequencing, metagenomic mining and cultivation. All Brassica vegetables harbored a highly diverse microbiota as identified by 16S rRNA gene amplicon sequencing. The composition of the microbiota was found to be rather driven by the plant genotype than by the processing pathway. We characterized isolates with potential cancer-preventing properties by tracing myrosinase activity as well as isolates with biological control activity towards plant pathogens. We identified a novel strain with myrosinase activity and we found bacterial myrosinase genes to be enriched in rhizosphere and phyllosphere metagenomes of Brassica napus and Eruca sativa in comparison to the surrounding soil. Strains which were able to suppress plant pathogens were isolated from naturally processed vegetables and represent a substantial part (4.1%) of all vegetable microbiomes. Our results shed first light on the microbiome of edible plants and open the door to harnessing the Brassica microbiome for plant disease resistance and human health. PMID- 29247167 TI - Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. AB - Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering. PMID- 29247171 TI - Computer-Aided Nodule Assessment and Risk Yield (CANARY) may facilitate non invasive prediction of EGFR mutation status in lung adenocarcinomas. AB - Computer-Aided Nodule Assessment and Risk Yield (CANARY) is quantitative imaging analysis software that predicts the histopathological classification and post treatment disease-free survival of patients with adenocarcinoma of the lung. CANARY characterizes nodules by the distribution of nine color-coded texture based exemplars. We hypothesize that quantitative computed tomography (CT) analysis of the tumor and tumor-free surrounding lung facilitates non-invasive identification of clinically-relevant mutations in lung adenocarcinoma. Comprehensive analysis of targetable mutations (50-gene-panel) and CANARY analysis of the preoperative (<=3 months) high resolution CT (HRCT) was performed for 118 pulmonary nodules of the adenocarcinoma spectrum surgically resected between 2006-2010. Logistic regression with stepwise variable selection was used to determine predictors of mutations. We identified 140 mutations in 106 of 118 nodules. TP53 (n = 48), KRAS (n = 47) and EGFR (n = 15) were the most prevalent. The combination of Y (Yellow) and G (Green) exemplars, fibrosis within the surrounding lung and smoking status were the best discriminators for an EGFR mutation (AUC 0.77 and 0.87, respectively). None of the EGFR mutants expressing TP53 (n = 5) had a good prognosis based on CANARY features. No quantitative features were significantly associated with KRAS mutations. Our exploratory analysis indicates that quantitative CT analysis of a nodule and surrounding lung may noninvasively predict the presence of EGFR mutations in pulmonary nodules of the adenocarcinoma spectrum. PMID- 29247172 TI - Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy. AB - Anaemia and malaria are both common in pregnant women in Sub-Saharan Africa. Previous evidence has shown that iron supplementation may increase malaria risk. In this observational cohort study, we evaluated P. falciparum pathogenesis in vitro in RBCs from pregnant women during their 2nd and 3rd trimesters. RBCs were collected and assayed before (n = 327), 14 days (n = 82), 49 days (n = 112) and 84 days (n = 115) after iron supplementation (60 mg iron as ferrous fumarate daily). P. falciparum erythrocytic stage growth in vitro is reduced in anaemic pregnant women at baseline, but increased during supplementation. The elevated growth rates parallel increases in circulating CD71-positive reticulocytes and other markers of young RBCs. We conclude that Plasmodium growth in vitro is associated with elevated erythropoiesis, an obligate step towards erythroid recovery in response to supplementation. Our findings support current World Health Organization recommendations that iron supplementation be given in combination with malaria prevention and treatment services in malaria endemic areas. PMID- 29247174 TI - Genomic footprints of dryland stress adaptation in Egyptian fat-tail sheep and their divergence from East African and western Asia cohorts. AB - African indigenous sheep are classified as fat-tail, thin-tail and fat-rump hair sheep. The fat-tail are well adapted to dryland environments, but little is known on their genome profiles. We analyzed patterns of genomic variation by genotyping, with the Ovine SNP50K microarray, 394 individuals from five populations of fat-tail sheep from a desert environment in Egypt. Comparative inferences with other East African and western Asia fat-tail and European sheep, reveal at least two phylogeographically distinct genepools of fat-tail sheep in Africa that differ from the European genepool, suggesting separate evolutionary and breeding history. We identified 24 candidate selection sweep regions, spanning 172 potentially novel and known genes, which are enriched with genes underpinning dryland adaptation physiology. In particular, we found selection sweeps spanning genes and/or pathways associated with metabolism; response to stress, ultraviolet radiation, oxidative stress and DNA damage repair; activation of immune response; regulation of reproduction, organ function and development, body size and morphology, skin and hair pigmentation, and keratinization. Our findings provide insights on the complexity of genome architecture regarding dryland stress adaptation in the fat-tail sheep and showcase the indigenous stocks as appropriate genotypes for adaptation planning to sustain livestock production and human livelihoods, under future climates. PMID- 29247173 TI - Estrogen-related receptor gamma causes osteoarthritis by upregulating extracellular matrix-degrading enzymes. AB - The estrogen-related receptor (ERR) family of orphan nuclear receptor is composed of ERRalpha, ERRbeta, and ERRgamma, which are known to regulate various isoform specific functions under normal and pathophysiological conditions. Here, we investigate the involvement of ERRs in the pathogenesis of osteoarthritis (OA) in mice. Among ERR family members, ERRgamma is markedly upregulated in cartilage from human OA patients and various mouse models of OA. Adenovirus-mediated overexpression of ERRgamma in mouse knee joint or transgenic expression of ERRgamma in cartilage leads to OA. ERRgamma overexpression in chondrocytes directly upregulates matrix metalloproteinase (MMP)-3 and MMP13, which are known to play crucial roles in cartilage destruction in OA. In contrast, genetic ablation of Esrrg or shRNA-mediated downregulation of Esrrg in joint tissues abrogates experimental OA in mice. Our results collectively indicate that ERRgamma is a novel catabolic regulator of OA pathogenesis. PMID- 29247177 TI - Frequency-specific genetic influence on inferior parietal lobule activation commonly observed during action observation and execution. AB - Brain activity relating to recognition of action varies among subjects. These differences have been hypothesised to originate from genetic and environmental factors although the extent of their effect remains unclear. Effects of these factors on brain activity during action recognition were evaluated by comparing magnetoencephalography (MEG) signals in twins. MEG signals of 20 pairs of elderly monozygotic twins and 11 pairs of elderly dizygotic twins were recorded while they observed finger movements and copied them. Beamformer and group statistical analyses were performed to evaluate spatiotemporal differences in cortical activities. Significant event-related desynchronisation (ERD) of the beta band (13-25 Hz) at the left inferior parietal lobule (IPL) was observed for both action observation and execution. Moreover, beta-band ERD at the left IPL during action observation was significantly better correlated among monozygotic twins compared to unrelated pairs (Z-test, p = 0.027). beta-band ERD heritability at the left IPL was 67% in an ACE model. These results demonstrate that beta-band ERD at the IPL, which is commonly observed during action recognition and execution, is affected by genetic rather than environmental factors. The effect of genetic factors on the cortical activity of action recognition may depend on anatomical location and frequency characteristics. PMID- 29247175 TI - An Implantable Micro-Caged Device for Direct Local Delivery of Agents. AB - Local and controlled delivery of therapeutic agents directly into focally afflicted tissues is the ideal for the treatment of diseases that require direct interventions. However, current options are obtrusive, difficult to implement, and limited in their scope of utilization; the optimal solution requires a method that may be optimized for available therapies and is designed for exact delivery. To address these needs, we propose the Biocage, a customizable implantable local drug delivery platform. The device is a needle-sized porous container capable of encasing therapeutic molecules and matrices of interest to be eluted into the region of interest over time. The Biocage was fabricated using the Nanoscribe Photonic Professional GT 3D laser lithography system, a two-photon polymerization (2PP) 3D printer capable of micron-level precision on a millimeter scale. We demonstrate the build consistency and features of the fabricated device; its ability to release molecules; and a method for its accurate, stable delivery in mouse brain tissue. The Biocage provides a powerful tool for customizable and precise delivery of therapeutic agents into target tissues. PMID- 29247178 TI - Changes in hyaluronan deposition in the rat myenteric plexus after experimentally induced colitis. AB - Myenteric plexus alterations hamper gastrointestinal motor function during intestinal inflammation. Hyaluronan (HA), an extracellular matrix glycosaminoglycan involved in inflammatory responses, may play a role in this process. In the colon of control rats, HA-binding protein (HABP), was detected in myenteric neuron soma, perineuronal space and ganglia surfaces. Prominent hyaluronan synthase 2 (HAS2) staining was found in myenteric neuron cytoplasm, suggesting that myenteric neurons produce HA. In the myenteric plexus of rats with 2, 4-dinitrobenzene sulfonic (DNBS)-induced colitis HABP staining was altered in the perineuronal space, while both HABP staining and HA levels increased in the muscularis propria. HAS2 immunopositive myenteric neurons and HAS2 mRNA and protein levels also increased. Overall, these observations suggest that inflammation alters HA distribution and levels in the gut neuromuscular compartment. Such changes may contribute to alterations in the myenteric plexus. PMID- 29247176 TI - She1 affects dynein through direct interactions with the microtubule and the dynein microtubule-binding domain. AB - Cytoplasmic dynein is an enormous minus end-directed microtubule motor. Rather than existing as bare tracks, microtubules are bound by numerous microtubule associated proteins (MAPs) that have the capacity to affect various cellular functions, including motor-mediated transport. One such MAP is She1, a dynein effector that polarizes dynein-mediated spindle movements in budding yeast. Here, we characterize the molecular basis by which She1 affects dynein, providing the first such insight into which a MAP can modulate motor motility. We find that She1 affects the ATPase rate, microtubule-binding affinity, and stepping behavior of dynein, and that microtubule binding by She1 is required for its effects on dynein motility. Moreover, we find that She1 directly contacts the microtubule binding domain of dynein, and that their interaction is sensitive to the nucleotide-bound state of the motor. Our data support a model in which simultaneous interactions between the microtubule and dynein enables She1 to directly affect dynein motility. PMID- 29247180 TI - Generation of bioinspired structural colors via two-photon polymerization. AB - Colors of crystals, pigments, metals, salt solutions and bioluminescence occur in nature due to the optical properties of electrons in atoms and molecules. However, colors can also result from interference effects on nanostructures. In contrast to artificial coloration, which are caused by well-defined regular structures, the structural colors of living organisms are often more intense and almost angle-independent. In this paper, we report the successful manufacturing of a lamellar nanostructure that mimics the ridge shape of the Morpho butterfly using a 3d-direct laser writing technique. The viewing angle dependency of the color was analyzed via a spectrometer and the structure was visualized using a scanning electron microscope. The generated nano- and micro-structures and their optical properties were comparable to those observed in the Morpho butterfly. PMID- 29247179 TI - Iron-based nanocatalyst for the acceptorless dehydrogenation reactions. AB - Development of sustainable catalytic systems for fundamentally important synthetic transformations and energy storage applications is an intellectually stimulating challenge. Catalytic dehydrogenation of feedstock chemicals, such as alcohols and amines to value-added products with the concomitant generation of dihydrogen is of much interest in the context of hydrogen economy and is an effective alternative to the classical oxidation reactions. Despite a number of homogeneous catalysts being identified for the acceptorless dehydrogenation, the use of high price and limited availability of precious metals and poor recovery of the catalyst have spurred interest in catalysis with more earth-abundant alternatives, especially iron. However, no report has described a reusable iron based heterogeneous catalyst for oxidant-free and acceptorless dehydrogenation reactions. Here we replace expensive noble metal catalysts with an inexpensive, benign, and sustainable nanoscale iron catalyst for the efficient acceptorless dehydrogenation of N-heterocycles and alcohols with liberation of hydrogen gas. PMID- 29247181 TI - Culture and Next-generation sequencing-based drug susceptibility testing unveil high levels of drug-resistant-TB in Djibouti: results from the first national survey. AB - Djibouti is a small country in the Horn of Africa with a high TB incidence (378/100,000 in 2015). Multidrug-resistant TB (MDR-TB) and resistance to second line agents have been previously identified in the country but the extent of the problem has yet to be quantified. A national survey was conducted to estimate the proportion of MDR-TB among a representative sample of TB patients. Sputum was tested using XpertMTB/RIF and samples positive for MTB and resistant to rifampicin underwent first line phenotypic susceptibility testing. The TB supranational reference laboratory in Milan, Italy, undertook external quality assurance, genotypic testing based on whole genome and targeted-deep sequencing and phylogenetic studies. 301 new and 66 previously treated TB cases were enrolled. MDR-TB was detected in 34 patients: 4.7% of new and 31% of previously treated cases. Resistance to pyrazinamide, aminoglycosides and capreomycin was detected in 68%, 18% and 29% of MDR-TB strains respectively, while resistance to fluoroquinolones was not detected. Cluster analysis identified transmission of MDR-TB as a critical factor fostering drug resistance in the country. Levels of MDR-TB in Djibouti are among the highest on the African continent. High prevalence of resistance to pyrazinamide and second-line injectable agents have important implications for treatment regimens. PMID- 29247182 TI - Ag-doping regulates the cytotoxicity of TiO2 nanoparticles via oxidative stress in human cancer cells. AB - We investigated the anticancer potential of Ag-doped (0.5-5%) anatase TiO2 NPs. Characterization study showed that dopant Ag was well-distributed on the surface of host TiO2 NPs. Size (15 nm to 9 nm) and band gap energy (3.32 eV to 3.15 eV) of TiO2 NPs were decreases with increasing the concentration of Ag dopant. Biological studies demonstrated that Ag-doped TiO2 NP-induced cytotoxicity and apoptosis in human liver cancer (HepG2) cells. The toxic intensity of TiO2 NPs was increases with increasing the amount of Ag-doping. The Ag-doped TiO2 NPs further found to provoke reactive oxygen species (ROS) generation and antioxidants depletion. Toxicity induced by Ag-doped TiO2 NPs in HepG2 cells was efficiently abrogated by antioxidant N-acetyl-cysteine (ROS scavenger). We also found that Ag-doped TiO2 NPs induced cytotoxicity and oxidative stress in human lung (A549) and breast (MCF-7) cancer cells. Interestingly, Ag-doped TiO2 NPs did not cause much toxicity to normal cells such as primary rat hepatocytes and human lung fibroblasts. Overall, we found that Ag-doped TiO2 NPs have potential to selectively kill cancer cells while sparing normal cells. This study warranted further research on anticancer potential of Ag-doped TiO2 NPs in various types of cancer cells and in vivo models. PMID- 29247183 TI - Rab-GTPase binding effector protein 2 (RABEP2) is a primed substrate for Glycogen Synthase kinase-3 (GSK3). AB - Glycogen synthase kinase-3 (GSK3) regulates many physiological processes through phosphorylation of a diverse array of substrates. Inhibitors of GSK3 have been generated as potential therapies in several diseases, however the vital role GSK3 plays in cell biology makes the clinical use of GSK3 inhibitors potentially problematic. A clearer understanding of true physiological and pathophysiological substrates of GSK3 should provide opportunities for more selective, disease specific, manipulation of GSK3. To identify kinetically favourable substrates we performed a GSK3 substrate screen in heart tissue. Rab-GTPase binding effector protein 2 (RABEP2) was identified as a novel GSK3 substrate and GSK3 phosphorylation of RABEP2 at Ser200 was enhanced by prior phosphorylation at Ser204, fitting the known consensus sequence for GSK3 substrates. Both residues are phosphorylated in cells while only Ser200 phosphorylation is reduced following inhibition of GSK3. RABEP2 function was originally identified as a Rab5 binding protein. We did not observe co-localisation of RABEP2 and Rab5 in cells, while ectopic expression of RABEP2 had no effect on endosomal recycling. The work presented identifies RABEP2 as a novel primed substrate of GSK3, and thus a potential biomarker for GSK3 activity, but understanding how phosphorylation regulates RABEP2 function requires more information on physiological roles of RABEP2. PMID- 29247184 TI - Testosterone-like immunoreactivity in hair measured in minute sample amounts - a competitive radioimmunoassay with an adequate limit of detection. AB - The concentrations of testosterone deposited in hair during hair growth may provide a retrospective reflection of the concentrations of bioactive testosterone in plasma. The objective of this study was to develop a radioimmunoassay with a sufficiently low limit of detection to measure the testosterone-like immunoreactivity in smaller hair samples (5 mg) than used in earlier studies, and to compare three different extraction procedures. The competitive radioimmunoassay consisted of a polyclonal antiserum (immunogen testosterone-7alpha-BSA) and a radioligand synthesised from testosterone-3-CMO histamine. The within-assay and total coefficients of variation in the working range was 3% and 4.5%, respectively. The limit of detection was 0.87 pg/mL, which is equivalent to 0.12 pg/mg testosterone in 5 mg of hair. The concentration of testosterone-like immunoreactivity in hair samples was 1.23 (SD 0.47) pg/mg in women and 2.67 (SD 0.58) pg/mg in men (pulverised hair). Significantly improved precision was found when pulverised hair was used compared to non-pulverised hair. Our data indicate that pulverisation of the hair prior to hormone extraction is crucial. Detection limits fit for the intended purpose are achievable with 5 mg samples of hair. PMID- 29247185 TI - Increasing gap in human height between rich and poor countries associated to their different intakes of N and P. AB - We analyzed mean height of men born in the 1960s, 1970s and 1980s in 80 countries. Both height and the change in height during the last decades were correlated with N and P intake, as well as the N:P intake ratio. Rich countries had higher per capita N and P intake than poor countries (on average 19.5 +/- 0.3 versus 9.66 +/- 0.18 kg N y-1 and 2.17 +/- 0.04 versus 1.35 +/- 0.02 kg P y-1), and also larger increases in per capita N intake (12.1 +/- 2.0% vs. 7.0 +/- 2.1%) and P intake (7.6 +/- 1.0% vs 6.01 +/- 0.7%), during the period 1961-2009. The increasing gap in height trends between rich and poor countries is associated with an increasing gap in nutrition, so a more varied diet with higher N, P, and N:P intake is a key factor to improve food intake quality in poor countries and thus shorten the gap with rich countries. More N and P are needed with the consequent requirements for a better management of the socioeconomic and environmental associated problems. PMID- 29247186 TI - Evidence for topological type-II Weyl semimetal WTe2. AB - Recently, a type-II Weyl fermion was theoretically predicted to appear at the contact of electron and hole Fermi surface pockets. A distinguishing feature of the surfaces of type-II Weyl semimetals is the existence of topological surface states, so-called Fermi arcs. Although WTe2 was the first material suggested as a type-II Weyl semimetal, the direct observation of its tilting Weyl cone and Fermi arc has not yet been successful. Here, we show strong evidence that WTe2 is a type-II Weyl semimetal by observing two unique transport properties simultaneously in one WTe2 nanoribbon. The negative magnetoresistance induced by a chiral anomaly is quite anisotropic in WTe2 nanoribbons, which is present in b axis ribbon, but is absent in a-axis ribbon. An extra-quantum oscillation, arising from a Weyl orbit formed by the Fermi arc and bulk Landau levels, displays a two dimensional feature and decays as the thickness increases in WTe2 nanoribbon. PMID- 29247187 TI - Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer. AB - Oral squamous cell carcinomas are a major cause of morbidity and mortality, and tobacco usage, alcohol consumption, and poor oral hygiene are established risk factors. To date, no large-scale case-control studies have considered the effects of these risk factors on the composition of the oral microbiome, nor microbial community associations with oral cancer. We compared the composition, diversity, and function of the oral microbiomes of 121 oral cancer patients to 242 age- and gender-matched controls using a metagenomic multivariate analysis pipeline. Significant shifts in composition and function of the oral microbiome were observed with poor oral hygiene, tobacco smoking, and oral cancer. Specifically, we observed dramatically altered community composition and function after tooth loss, with smaller alterations in current tobacco smokers, increased production of antioxidants in individuals with periodontitis, and significantly decreased glutamate metabolism metal transport in oral cancer patients. Although the alterations in the oral microbiome of oral cancer patients were significant, they were of substantially lower effect size relative to microbiome shifts after tooth loss. Alterations following tooth loss, itself a major risk factor for oral cancer, are likely a result of severe ecological disruption due to habitat loss but may also contribute to the development of the disease. PMID- 29247189 TI - What is the temperature of a moving body? AB - The construction of a relativistic thermodynamics theory is still controversial after more than 110 years. To the date there is no agreement on which set of relativistic transformations of thermodynamic quantities is the correct one, or if the problem even has a solution. Starting from Planck and Einstein, several authors have proposed their own reasoning, concluding that a moving body could appear cooler, hotter or at the same temperature as measured by a local observer. In this article we present a review of the main theories of relativistic thermodynamics, with an special emphasis on the physical assumptions adopted by each one. We also present a set of relativistic transformations that we have derived by assuming the laws of Thermodynamics to be covariant. We found that under such assumptions a moving body appears to be hotter. Since relativistic thermodynamics is a topic that can be treated as part of an undergraduate course of classical thermodynamics or modern physics, the review and our own derivations presented here aim to encourage undergraduate physics students to open a discussion on the fundamental assumptions in thermodynamics and to engage in research activities early in their scientific career. PMID- 29247188 TI - Hepatocytic expression of human sodium-taurocholate cotransporting polypeptide enables hepatitis B virus infection of macaques. AB - Hepatitis B virus (HBV) is a major global health concern, and the development of curative therapeutics is urgently needed. Such efforts are impeded by the lack of a physiologically relevant, pre-clinical animal model of HBV infection. Here, we report that expression of the HBV entry receptor, human sodium-taurocholate cotransporting polypeptide (hNTCP), on macaque primary hepatocytes facilitates HBV infection in vitro, where all replicative intermediates including covalently closed circular DNA (cccDNA) are present. Furthermore, viral vector-mediated expression of hNTCP on hepatocytes in vivo renders rhesus macaques permissive to HBV infection. These in vivo macaque HBV infections are characterized by longitudinal HBV DNA in serum, and detection of HBV DNA, RNA, and HBV core antigen (HBcAg) in hepatocytes. Together, these results show that expressing hNTCP on macaque hepatocytes renders them susceptible to HBV infection, thereby establishing a physiologically relevant model of HBV infection to study immune clearance and test therapeutic and curative approaches. PMID- 29247190 TI - Extracellular Cyclic GMP Modulates Membrane Expression of The GluA1 and GluA2 Subunits of AMPA Receptor in Cerebellum: Molecular Mechanisms Involved. AB - There is increasing evidence that extracellular cGMP modulates glutamatergic neurotransmission and some forms of learning. However, the underlying mechanisms remain unknown. We proposed the hypotheses that extracellular cGMP may regulate membrane expression of AMPA receptors. To do this extracellular cGMP should act on a membrane protein and activate signal transduction pathways modulating phosphorylation of the GluA1 and/or GluA2 subunits. It has been shown that extracellular cGMP modulates glycine receptors. The aims of this work were to assess: 1) whether extracellular cGMP modulates membrane expression of GluA1 and GluA2 subunits of AMPA receptors in cerebellum in vivo; 2) whether this is mediated by glycine receptors; 3) the role of GluA1 and GluA2 phosphorylation and 4) identify steps of the intracellular pathways involved. We show that extracellular cGMP modulates membrane expression of GluA1 and GluA2 in cerebellum in vivo and unveil the mechanisms involved. Extracellular cGMP reduced glycine receptor activation, modulating cAMP, protein kinases and phosphatases, and GluA1 and GluA2 phosphorylation, resulting in increased GluA1 and reduced GluA2 membrane expression. Extracellular cGMP therefore modulates membrane expression of AMPA receptors and glutamatergic neurotransmission. The steps identified may be therapeutic targets to improve neurotransmission and neurological function in pathological situations with abnormal glutamatergic neurotransmission. PMID- 29247191 TI - Cellulose long fibers fabricated from cellulose nanofibers and its strong and tough characteristics. AB - Cellulose nanofiber (CNF) with high crystallinity has great mechanical stiffness and strength. However, its length is too short to be used for fibers of environmentally friendly structural composites. This paper presents a fabrication process of cellulose long fiber from CNF suspension by spinning, stretching and drying. Isolation of CNF from the hardwood pulp is done by using (2, 2, 6, 6 tetramethylpiperidine-1-yl) oxidanyl (TEMPO) oxidation. The effect of spinning speed and stretching ratio on mechanical properties of the fabricated fibers are investigated. The modulus of the fabricated fibers increases with the spinning speed as well as the stretching ratio because of the orientation of CNFs. The fabricated long fiber exhibits the maximum tensile modulus of 23.9 GPa with the maximum tensile strength of 383.3 MPa. Moreover, the fabricated long fiber exhibits high strain at break, which indicates high toughness. The results indicate that strong and tough cellulose long fiber can be produced by using ionic crosslinking, controlling spinning speed, stretching and drying. PMID- 29247192 TI - Exploring Feature Dimensions to Learn a New Policy in an Uninformed Reinforcement Learning Task. AB - When making a choice with limited information, we explore new features through trial-and-error to learn how they are related. However, few studies have investigated exploratory behaviour when information is limited. In this study, we address, at both the behavioural and neural level, how, when, and why humans explore new feature dimensions to learn a new policy for choosing a state-space. We designed a novel multi-dimensional reinforcement learning task to encourage participants to explore and learn new features, then used a reinforcement learning algorithm to model policy exploration and learning behaviour. Our results provide the first evidence that, when humans explore new feature dimensions, their values are transferred from the previous policy to the new online (active) policy, as opposed to being learned from scratch. We further demonstrated that exploration may be regulated by the level of cognitive ambiguity, and that this process might be controlled by the frontopolar cortex. This opens up new possibilities of further understanding how humans explore new features in an open-space with limited information. PMID- 29247193 TI - Comparing two remote video survey methods for spatial predictions of the distribution and environmental niche suitability of demersal fishes. AB - Information on habitat associations from survey data, combined with spatial modelling, allow the development of more refined species distribution modelling which may identify areas of high conservation/fisheries value and consequentially improve conservation efforts. Generalised additive models were used to model the probability of occurrence of six focal species after surveys that utilised two remote underwater video sampling methods (i.e. baited and towed video). Models developed for the towed video method had consistently better predictive performance for all but one study species although only three models had a good to fair fit, and the rest were poor fits, highlighting the challenges associated with modelling habitat associations of marine species in highly homogenous, low relief environments. Models based on baited video dataset regularly included large-scale measures of structural complexity, suggesting fish attraction to a single focus point by bait. Conversely, models based on the towed video data often incorporated small-scale measures of habitat complexity and were more likely to reflect true species-habitat relationships. The cost associated with use of the towed video systems for surveying low-relief seascapes was also relatively low providing additional support for considering this method for marine spatial ecological modelling. PMID- 29247194 TI - Elucidating the 16S rRNA 3' boundaries and defining optimal SD/aSD pairing in Escherichia coli and Bacillus subtilis using RNA-Seq data. AB - Bacterial translation initiation is influenced by base pairing between the Shine Dalgarno (SD) sequence in the 5' UTR of mRNA and the anti-SD (aSD) sequence at the free 3' end of the 16S rRNA (3' TAIL) due to: 1) the SD/aSD sequence binding location and 2) SD/aSD binding affinity. In order to understand what makes an SD/aSD interaction optimal, we must define: 1) terminus of the 3' TAIL and 2) extent of the core aSD sequence within the 3' TAIL. Our approach to characterize these components in Escherichia coli and Bacillus subtilis involves 1) mapping the 3' boundary of the mature 16S rRNA using high-throughput RNA sequencing (RNA Seq), and 2) identifying the segment within the 3' TAIL that is strongly preferred in SD/aSD pairing. Using RNA-Seq data, we resolve previous discrepancies in the reported 3' TAIL in B. subtilis and recovered the established 3' TAIL in E. coli. Furthermore, we extend previous studies to suggest that both highly and lowly expressed genes favor SD sequences with intermediate binding affinity, but this trend is exclusive to SD sequences that complement the core aSD sequences defined herein. PMID- 29247195 TI - Prevalence of Metabolic Syndrome and its Associated Factors among Multi-ethnic Adults in Rural Areas in Xinjiang, China. AB - Metabolic syndrome (MetS) has become a global public health problem affecting all nations and races. Few studies on the epidemic of metabolic syndrome (MetS) examined multi-ethnic adults in rural areas in Xinjiang, China. We thus investigated the prevalence and risk factors of MetS there. A cross-sectional study was performed in a representative sample of 15020 rural multi-ethnic adults from 2009 to 2010. Four widely used criteria (ATPIII?IDF?JIS?CDS) were used to measure the prevalence of MetS. Multiple logistic regression analysis was used to explore the risk factors of MetS. The age-adjusted prevalence of MetS was 14.43%, 21.33%, 26.50%, and 19.89% based on the ATP III, IDF, JIS and CDS criterion, respectively. The prevalence of MetS was higher in women and increased with age. According to JIS criterion, the prevalence of components in MetS was 57.75% for abdominal obesity, 44.05% for elevated blood pressure, 40.98% for reduced HDL cholesterol, 23.33% for elevated triglycerides, 18.95% for raised fasting plasma glucose. Lower consumption of vegetables, milk, and higher consumption of red meat were associated with higher likelihood of having MetS. The prevalence of MetS in Xinjiang rural multi-ethnic adults was high. Diet factors were associated with the prevalence of MetS. PMID- 29247196 TI - AICAR suppresses TNF-alpha-induced complement factor B in RPE cells. AB - Age related macular degeneration is the leading cause of blindness in the developed world. Although its precise cause remains elusive, dysfunction of the retinal pigment epithelium (RPE) and dysregulation of complement have been implicated in its pathogenesis. The goal of this study was to evaluate the role of an AMP-dependent kinase (AMPK) activator, 5-aminoimidazole-4-carboxamide riboside (AICAR), on tumor necrosis factor alpha (TNF-alpha) induction of complement factor B (CFB) in RPE cells. We found that AICAR inhibited TNF-alpha induced CFB expression in ARPE-19 and human primary RPE cells in a dose-dependent fashion. Treatment of cells with dipyridamole, which blocks AICAR cellular uptake abolished these effects. In contrast, the adenosine kinase inhibitor, 5 iodotubericidin, which inhibits the conversion of AICAR to the direct activator of AMPK, ZMP, did not reverse the effects on TNF-alpha-induced CFB expression, suggesting AMPK-independent effects. Indeed, knockout of AMPK in RPE cells using Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 did not abolish the inhibitory effects of AICAR on RPE CFB expression. Collectively, our results suggest that AICAR can suppress TNF-alpha-induced CFB expression in RPE cells in an AMPK-independent mechanism, and could be used as a therapeutic target in certain complement over-activation scenarios. PMID- 29247197 TI - PD-1/PD-L1 binding studies using microscale thermophoresis. AB - The characterization of protein interactions has become essential in many fields of life science, especially drug discovery. Microscale thermophoresis (MST) is a powerful new method for the quantitative analysis of protein-protein interactions (PPIs) with low sample consumption. In addition, one of the major advantages of this technique is that no tedious purification step is necessary to access the protein of interest. Here, we describe a protocol using MST to determine the binding affinity of the PD-1/PD-L1 couple, which is involved in tumour escape processes, without purification of the target protein from cell lysates. The method requires the overexpression of fluorescent proteins in CHO-K1 cells and describes the optimal conditions for determining the dissociation constant. The protocol has a variety of potential applications in studying the interactions of these proteins with small molecules and demonstrates that MST is a valuable method for studying the PD-1/PD-L1 pathway. PMID- 29247198 TI - Cell shape information is transduced through tension-independent mechanisms. AB - The shape of a cell within tissues can represent the history of chemical and physical signals that it encounters, but can information from cell shape regulate cellular phenotype independently? Using optimal control theory to constrain reaction-diffusion schemes that are dependent on different surface-to-volume relationships, we find that information from cell shape can be resolved from mechanical signals. We used microfabricated 3-D biomimetic chips to validate predictions that shape-sensing occurs in a tension-independent manner through integrin beta3 signaling pathway in human kidney podocytes and smooth muscle cells. Differential proteomics and functional ablation assays indicate that integrin beta3 is critical in transduction of shape signals through ezrin-radixin moesin (ERM) family. We used experimentally determined diffusion coefficients and experimentally validated simulations to show that shape sensing is an emergent cellular property enabled by multiple molecular characteristics of integrin beta3. We conclude that 3-D cell shape information, transduced through tension independent mechanisms, can regulate phenotype. PMID- 29247199 TI - Lipidomics Reveals Cerebrospinal-Fluid Signatures of ALS. AB - Amyotrophic lateral sclerosis (ALS), the commonest adult-onset motor neuron disorder, is characterized by a survival span of only 2-5 years after onset. Relevant biomarkers or specific metabolic signatures would provide powerful tools for the management of ALS. The main objective of this study was to investigate the cerebrospinal fluid (CSF) lipidomic signature of ALS patients by mass spectrometry to evaluate the diagnostic and predictive values of the profile. We showed that ALS patients (n = 40) displayed a highly significant specific CSF lipidomic signature compared to controls (n = 45). Phosphatidylcholine PC(36:4), higher in ALS patients (p = 0.0003) was the most discriminant molecule, and ceramides and glucosylceramides were also highly relevant. Analysis of targeted lipids in the brain cortex of ALS model mice confirmed the role of some discriminant lipids such as PC. We also obtained good models for predicting the variation of the ALSFRS-r score from the lipidome baseline, with an accuracy of 71% in an independent set of patients. Significant predictions of clinical evolution were found to be correlated to sphingomyelins and triglycerides with long-chain fatty acids. Our study, which shows extensive lipid remodelling in the CSF of ALS patients, provides a new metabolic signature of the disease and its evolution with good predictive performance. PMID- 29247200 TI - Association of plasma free amino acids with hyperuricemia in relation to diabetes mellitus, dyslipidemia, hypertension and metabolic syndrome. AB - Previous studies demonstrated independent contributions of plasma free amino acids (PFAAs) and high uric acid (UA) concentrations to increased risks of lifestyle-related diseases (LSRDs), but the important associations between these factors and LSRDs remain unknown. We quantified PFAAs and UA amongst Japanese subjects without LSRDs (no-LSRD, n = 2805), and with diabetes mellitus (DM, n = 415), dyslipidemia (n = 3207), hypertension (n = 2736) and metabolic syndrome (MetS, n = 717). The concentrations of most amino acids differed significantly between the subjects with and without hyperuricemia (HU) and also between the no LSRD and LSRD groups (p < 0.05 to 0.001). After adjustment, the logistic regression analyses revealed that lysine in DM, alanine, proline and tyrosine in dyslipidemia, histidine, lysine and ornithine in hypertension, and lysine and tyrosine in MetS demonstrated significant positive associations with HU among the patients with LSRDs only (p < 0.05 to 0.005). By contrast, arginine, asparagine and threonine showed significant inverse associations with HU in the no-LSRD group only (p < 0.05 to 0.01). For the first time, we provide evidence for distinct patterns of association between PFAAs and HU in LSRDs, and postulate the possibility of interplay between PFAAs and UA in their pathophysiology. PMID- 29247201 TI - SOX30 is required for male fertility in mice. AB - Male infertility is a major and growing problem and, in most cases, the specific root cause is unknown. Here we show that the transcription factor SOX30 plays a critical role in mouse spermatogenesis. Sox30-null mice are healthy and females are fertile, but males are sterile. In the absence of Sox30 meiosis initiates normally in both sexes but, in males, germ cell development arrests during the post-meiotic round spermatid period. In the mutant testis, acrosome and axoneme development are aberrant, multinucleated germ cells (symplasts) form and round spermatids unable to process beyond step 3 of spermiogenesis. No elongated spermatids nor spermatozoa are produced. Thus, Sox30 represents a rare example of a gene for which loss of function results in a complete arrest of spermatogenesis at the onset of spermiogenesis. Our results suggest that SOX30 mutations may underlie some instances of unexplained non-obstructive azoospermia in humans. PMID- 29247202 TI - Author Correction: Mild hypothermia provides Treg stability. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29247203 TI - Host species adaptation of TLR5 signalling and flagellin recognition. AB - Toll-like receptor 5 (TLR5) recognition of flagellin instigates inflammatory signalling. Significant sequence variation in TLR5 exists between animal species but its impact on activity is less well understood. Building on our previous research that bovine TLR5 (bTLR5) is functional, we compared human and bovine TLR5 activity and signalling in cognate cell lines. bTLR5 induced higher levels of CXCL8 when expressed in bovine cells and reciprocal results were found for human TLR5 (hTLR5) in human cells, indicative of host cell specificity in this response. Analysis of Toll/interleukin-1 receptor (TIR) sequences indicated that these differential responses involve cognate MyD88 recognition. siRNA knockdowns and inhibitor experiments demonstrated that there are some host differences in signalling. Although, PI3K activation is required for bTLR5 signalling, mutating bTLR5 F798 to hTLR5 Y798 within a putative PI3K motif resulted in a significantly reduced response. All ruminants have F798 in contrast to most other species, suggesting that TLR5 signalling has evolved differently in ruminants. Evolutionary divergence between bovine and human TLR5 was also apparent in relation to responses measured to diverse bacterial flagellins. Our results underscore the importance of species specific studies and how differences may alter efficacy of TLR-based vaccine adjuvants. PMID- 29247204 TI - Antibacterial activity of ceramide and ceramide analogs against pathogenic Neisseria. AB - Certain fatty acids and sphingoid bases found at mucosal surfaces are known to have antibacterial activity and are thought to play a more direct role in innate immunity against bacterial infections. Herein, we analysed the antibacterial activity of sphingolipids, including the sphingoid base sphingosine as well as short-chain C6 and long-chain C16-ceramides and azido-functionalized ceramide analogs against pathogenic Neisseriae. Determination of the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) demonstrated that short-chain ceramides and a omega-azido-functionalized C6-ceramide were active against Neisseria meningitidis and N. gonorrhoeae, whereas they were inactive against Escherichia coli and Staphylococcus aureus. Kinetic assays showed that killing of N. meningitidis occurred within 2 h with omega-azido-C6 ceramide at 1 X the MIC. Of note, at a bactericidal concentration, omega-azido-C6 ceramide had no significant toxic effect on host cells. Moreover, lipid uptake and localization was studied by flow cytometry and confocal laser scanning microscopy (CLSM) and revealed a rapid uptake by bacteria within 5 min. CLSM and super-resolution fluorescence imaging by direct stochastic optical reconstruction microscopy demonstrated homogeneous distribution of ceramide analogs in the bacterial membrane. Taken together, these data demonstrate the potent bactericidal activity of sphingosine and synthetic short-chain ceramide analogs against pathogenic Neisseriae. PMID- 29247205 TI - Prostaglandin D2 metabolite in urine is an index of food allergy. AB - Food allergy is immediate hypersensitive reactions to ingested foods. Since early diagnosis is effective for disease control, development of an objective diagnostic index is required. Using mediator-lipidomics, we found that levels of the urinary prostaglandin D2 (PGD2) metabolite, tetranor-PGDM, reflected the severity of the allergic symptoms and intestinal mast cell hyperplasia in mice. Repeated oral challenges with ovalbumin promoted allergic symptoms in sensitized mice. Particularly, the allergic mice presented with increased numbers of intestinal mast cells, which strongly expressed hematopoietic PGD synthase (H PGDS). The levels of urinary tetranor-PGDM increased as the disease progressed. Treatment with a mast cell inactivator or an anti-inflammatory steroid attenuated these symptoms and decreased the tetranor-PGDM urinary levels. The levels of urinary tetranor-PGDM did not correlate with the disease severity in murine models of colitis, asthma, or allergic dermatitis. Furthermore, we have shown that urinary levels of tetranor-PGDM were significantly higher in patients with food allergy than those in healthy volunteers and patients with other types of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. These findings suggest that urinary tetranor-PGDM is a useful diagnostic index of food allergy in both mice and humans. PMID- 29247206 TI - A next-generation newborn screening pilot study: NGS on dried blood spots detects causal mutations in patients with inherited metabolic diseases. AB - The range of applications performed on dried blood spots (DBS) widely broadened during the past decades to now include next-generation sequencing (NGS). Previous publications provided a general overview of NGS capacities on DBS-extracted DNA but did not focus on the identification of specific disorders. We thus aimed to demonstrate that NGS was reliable for detecting pathogenic mutations on genomic material extracted from DBS. Assuming the future implementation of NGS technologies into newborn screening (NBS), we conducted a pilot study on fifteen patients with inherited metabolic disorders. Blood was collected from DBS. Whole exome sequencing was performed, and sequences were analyzed with a specific focus on genes related to NBS. Results were compared to the known pathogenic mutations previously identified by Sanger sequencing. Causal mutations were readily characterized, and multiple polymorphisms have been identified. According to variant database prediction, an unexplained homozygote pathogenic mutation, unrelated to patient's disorder, was also found in one sample. While amount and quality of DBS-extracted DNA are adequate to identify causal mutations by NGS, bioinformatics analysis revealed critical drawbacks: coverage fluctuations between regions, difficulties in identifying insertions/deletions, and inconsistent reliability of database-referenced variants. Nevertheless, results of this study lead us to consider future perspectives regarding "next-generation" NBS. PMID- 29247207 TI - A rapid review examining purchasing changes resulting from fiscal measures targeted at high sugar foods and sugar-sweetened drinks. AB - To aim of the review was to examine the most recent (2010 onwards) research evidence on the health and behavioural impacts, in adults and children, of fiscal strategies that target high sugar foods and sugar-sweetened drinks (SSDs). A pragmatic rapid review was undertaken using a systematic search strategy. The review was part of a programme of work to support policy development in relation to high sugar food and SSDs. A total of 11 primary research publications were included, describing evidence from France (n = 1), the Netherlands (n = 3), and the United States of America (n = 7), assessed through a variety of study designs, with the majority in adult populations (n = 10). The evidence reviewed focused on consumer behaviour outcomes and suggested that fiscal strategies can influence purchases of high sugar products. Although the majority of studies (n = 10), including three field studies, demonstrated that an increase in the price of high sugar foods and SSDs resulted in a decrease in purchases, eight studies were conducted in a laboratory or virtual setting which may not reflect real-life situations.Findings from this review support evidence from the broader literature that suggests that fiscal measures can be effective in influencing the purchasing of high sugar foods and SSDs. PMID- 29247208 TI - Molecular Characterization and Co-expression Analysis of the SnRK2 Gene Family in Sugarcane (Saccharum officinarum L.). AB - In plants, both abscisic acid (ABA) dependent and independent pathways form the basis for the response to environmental stresses. Sucrose non-fermenting 1 related protein kinase 2 (SnRK2) plays a central role in plant stress signal transduction. However, complete annotation and specific expression patterns of SnRK2s in sugarcane remain unclear. For the present study, we performed a full length cDNA library survey of sugarcane, thus identifying ten SoSnRK2 genes via phylogenetic, local BLAST methods, and various bioinformatics analyses. Phylogenetic analysis indicated division of SoSnRK2 genes into three subgroups, similar to other plant species. Gene structure comparison with Arabidopsis suggested a unique evolutionary imprint of the SnRK2 gene family in sugarcane. Both sequence alignment and structural annotation provided an overview of the conserved N-terminal and variations of the C-terminal, suggesting functional divergence. Transcript and transient expression assays revealed SoSnRK2s to be involved in the responses to diverse stress signals, and strong ABA induction of SoSnRK2s in subgroup III. Co-expression network analyses indicated the existence of both conserved and variable biological functions among different SoSnRK2s members. In summary, this comprehensive analysis will facilitate further studies of the SoSnRK2 family and provide useful information for the functional validation of SoSnRK2s. PMID- 29247209 TI - Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD. AB - Recent studies have started to elucidate the effects of lysergic acid diethylamide (LSD) on the human brain but the underlying dynamics are not yet fully understood. Here we used 'connectome-harmonic decomposition', a novel method to investigate the dynamical changes in brain states. We found that LSD alters the energy and the power of individual harmonic brain states in a frequency-selective manner. Remarkably, this leads to an expansion of the repertoire of active brain states, suggestive of a general re-organization of brain dynamics given the non-random increase in co-activation across frequencies. Interestingly, the frequency distribution of the active repertoire of brain states under LSD closely follows power-laws indicating a re-organization of the dynamics at the edge of criticality. Beyond the present findings, these methods open up for a better understanding of the complex brain dynamics in health and disease. PMID- 29247210 TI - Estimating and mitigating amplification bias in qualitative and quantitative arthropod metabarcoding. AB - Amplicon based metabarcoding promises rapid and cost-efficient analyses of species composition. However, it is disputed whether abundance estimates can be derived from metabarcoding due to taxon specific PCR amplification biases. PCR free approaches have been suggested to mitigate this problem, but come with considerable increases in workload and cost. Here, we analyze multilocus datasets of diverse arthropod communities, to evaluate whether amplification bias can be countered by (1) targeting loci with highly degenerate primers or conserved priming sites, (2) increasing PCR template concentration, (3) reducing PCR cycle number or (4) avoiding locus specific amplification by directly sequencing genomic DNA. Amplification bias is reduced considerably by degenerate primers or targeting amplicons with conserved priming sites. Surprisingly, a reduction of PCR cycles did not have a strong effect on amplification bias. The association of taxon abundance and read count was actually less predictable with fewer cycles. Even a complete exclusion of locus specific amplification did not exclude bias. Copy number variation of the target loci may be another explanation for read abundance differences between taxa, which would affect amplicon based and PCR free methods alike. As read abundance biases are taxon specific and predictable, the application of correction factors allows abundance estimates. PMID- 29247211 TI - Stim2-Eb3 Association and Morphology of Dendritic Spines in Hippocampal Neurons. AB - Mushroom spines form strong synaptic contacts and are essential for memory storage. We have previously demonstrated that neuronal store-operated calcium entry (nSOC) in hippocampal neurons is regulated by STIM2 protein. This pathway plays a key role in stability of mushroom spines and is compromised in different mice models of Alzheimer's disease (AD). Actin was thought to be the sole cytoskeleton compartment presented in dendritic spines, however, recent studies demonstrated that dynamic microtubules with EB3 capped plus-ends transiently enter spines. We showed that STIM2 forms an endoplasmic reticulum (ER) Ca2+ dependent complex with EB3 via Ser-x-Ile-Pro aminoacid motif and that disruption of STIM2-EB3 interaction resulted in loss of mushroom spines in hippocampal neurons. Overexpression of EB3 causes increase of mushroom spines fraction and is able to restore their deficiency in hippocampal neurons obtained from PS1-M146V KI AD mouse model. STIM2 overexpression failed to restore mushroom dendritic spines after EB3 knockdown, while in contrast EB3 overexpression rescued loss of mushroom spines resulting from STIM2 depletion. We propose that EB3 is involved in regulation of dendritic spines morphology, in part due to its association with STIM2, and that modulation of EB3 expression is a potential way to overcome synaptic loss during AD. PMID- 29247213 TI - Non-Newtonian Flow to the Theoretical Strength of Glasses via Impact Nanoindentation at Room Temperature. AB - In many daily applications glasses are indispensable and novel applications demanding improved strength and crack resistance are appearing continuously. Up to now, the fundamental mechanical processes in glasses subjected to high strain rates at room temperature are largely unknown and thus guidelines for one of the major failure conditions of glass components are non-existent. Here, we elucidate this important regime for the first time using glasses ranging from a dense metallic glass to open fused silica by impact as well as quasi-static nanoindentation. We show that towards high strain rates, shear deformation becomes the dominant mechanism in all glasses accompanied by Non-Newtonian behaviour evident in a drop of viscosity with increasing rate covering eight orders of magnitude. All glasses converge to the same limit stress determined by the theoretical hardness, thus giving the first experimental and quantitative evidence that Non-Newtonian shear flow occurs at the theoretical strength at room temperature. PMID- 29247212 TI - Anti-Mullerian Hormone-to-Testosterone Ratio is Predictive of Positive Sperm Retrieval in Men with Idiopathic Non-Obstructive Azoospermia. AB - The lack of clinically-reliable biomarkers makes impossible to predict sperm retrieval outcomes at testicular sperm extraction (TESE) in men with non obstructive azoospermia (NOA), resulting in up to 50% of unnecessary surgical interventions. Clinical data, hormonal profile and histological classification of testis parenchyma from 47 white-Caucasian idiopathic NOA (iNOA) men submitted to microdissection TESE (microTESE) were analyzed. Logistic regression analyses tested potential clinical predictors of positive sperm retrieval. The predictive accuracy of all variables was evaluated using the receiver operating characteristic-derived area under the curve, and the clinical net benefit estimated by a decision-curve analysis (DCA). Overall, 23 (49%) and 24 (51%) patients were classified as positive and negative sperm retrievals at microTESE. While circulating hormones associated to a condition of primary hypogonadism did not predict sperm retrieval, levels of anti-Mullerian hormone (AMH) and the ratio AMH-to-total Testosterone (AMH/tT) achieved independent predictor status for sperm retrieval at microTESE, with a predictive accuracy of 93% and 95%. Using cutoff values of <4.62 ng/ml for AMH and <1.02 for AMH/tT, positive sperm retrieval was predicted in all individuals, with 19 men out of 47 potentially spared from surgery. DCA findings demonstrated clinical net benefit using AMH and AMH/tT for patient selection at microTESE. PMID- 29247214 TI - Dysregulation of Iron Metabolism in Cholangiocarcinoma Stem-like Cells. AB - Cholangiocarcinoma (CCA) is a devastating liver tumour arising from malignant transformation of bile duct epithelial cells. Cancer stem cells (CSC) are a subset of tumour cells endowed with stem-like properties, which play a role in tumour initiation, recurrence and metastasis. In appropriate conditions, CSC form 3D spheres (SPH), which retain stem-like tumour-initiating features. Here, we found different expression of iron proteins indicating increased iron content, oxidative stress and higher expression of CSC markers in CCA-SPH compared to tumour cells growing as monolayers. Exposure to the iron chelator desferrioxamine decreased SPH forming efficiency and the expression of CSC markers and stem-like genes, whereas iron had an opposite effect. Microarray profiles in CCA samples (n = 104) showed decreased H ferritin, hepcidin and ferroportin expression in tumours respect to surrounding liver, whereas transferrin receptor was up regulated. Moreover, we found a trend toward poorer outcome in CCA patients with elevated expression of ferritin and hepcidin, two major proteins of iron metabolism. These findings, which represent the first evidence of a role for iron in the stem cell compartment as a novel metabolic factor involved in CCA growth, may have implications for a better therapeutic approach. PMID- 29247215 TI - The transcriptome of Mycobacterium tuberculosis in a lipid-rich dormancy model through RNAseq analysis. AB - Tuberculosis (TB) is currently the number one killer among infectious diseases worldwide. Lipids are abundant molecules during the infectious cycle of Mycobacterium tuberculosis (Mtb) and studies better mimicking its actual metabolic state during pathogenesis are needed. Though most studies have focused on the mycobacterial lipid metabolism under standard culture conditions, little is known about the transcriptome of Mtb in a lipid environment. Here we determined the transcriptome of Mtb H37Rv in a lipid-rich environment (cholesterol and fatty acid) under aerobic and hypoxic conditions, using RNAseq. Lipids significantly induced the expression of 368 genes. A main core lipid response was observed involving efflux systems, iron caption and sulfur reduction. In co-expression with ncRNAs and other genes discussed below, may act coordinately to prepare the machinery conferring drug tolerance and increasing a persistent population. Our findings could be useful to tag relevant pathways for the development of new drugs, vaccines and new strategies to control TB. PMID- 29247216 TI - Vitamin K epoxide reductase and its paralogous enzyme have different structures and functions. AB - Vitamin K epoxide reductase (VKOR) is an essential enzyme for vitamin K-dependent carboxylation, while the physiological function of its paralogous enzyme VKOR like (VKORL) is yet unknown. Although these two enzymes share approximately 50% protein sequence homology, the membrane topology of VKOR is still in debate. Here, we explored the differences in the membrane topology and disulfide-linked oligomerization of these two enzymes. Results from mutating the critical amino acid residues in the disputed transmembrane (TM) regions revealed that the second TM domain in the proposed 4-TM model of VKOR does not function as an authentic TM helix; supporting VKOR is a 3-TM protein, which is different from VKORL. Additionally, altering the loop sequence between the two conserved cysteine residues of VKORL affects its activity, supporting the notion that the conserved loop cysteines of VKORL are involved in its active site regeneration. However, a similar mutation in VKOR does not affect its enzymatic activity. Finally, our results show that although both VKOR and VKORL form disulfide-linked oligomers, the cysteine residues involved in the oligomerization appear to be different. Overall, the structural and functional differences between VKOR and VKORL shown here indicate that VKORL might have a different physiological function other than recycling vitamin K. PMID- 29247217 TI - Automated computer-based detection of encounter behaviours in groups of honeybees. AB - Honeybees form societies in which thousands of members integrate their behaviours to act as a single functional unit. We have little knowledge on how the collaborative features are regulated by workers' activities because we lack methods that enable collection of simultaneous and continuous behavioural information for each worker bee. In this study, we introduce the Bee Behavioral Annotation System (BBAS), which enables the automated detection of bees' behaviours in small observation hives. Continuous information on position and orientation were obtained by marking worker bees with 2D barcodes in a small observation hive. We computed behavioural and social features from the tracking information to train a behaviour classifier for encounter behaviours (interaction of workers via antennation) using a machine learning-based system. The classifier correctly detected 93% of the encounter behaviours in a group of bees, whereas 13% of the falsely classified behaviours were unrelated to encounter behaviours. The possibility of building accurate classifiers for automatically annotating behaviours may allow for the examination of individual behaviours of worker bees in the social environments of small observation hives. We envisage that BBAS will be a powerful tool for detecting the effects of experimental manipulation of social attributes and sub-lethal effects of pesticides on behaviour. PMID- 29247219 TI - Therapeutic efficacy of azathioprine in addition to prednisone-based regimens as first-line chronic graft-versus-host disease treatment. PMID- 29247218 TI - Wavevector multiplexed atomic quantum memory via spatially-resolved single-photon detection. AB - Parallelized quantum information processing requires tailored quantum memories to simultaneously handle multiple photons. The spatial degree of freedom is a promising candidate to facilitate such photonic multiplexing. Using a single photon resolving camera, we demonstrate a wavevector multiplexed quantum memory based on a cold atomic ensemble. Observation of nonclassical correlations between Raman scattered photons is confirmed by an average value of the second-order correlation function [Formula: see text] in 665 separated modes simultaneously. The proposed protocol utilizing the multimode memory along with the camera will facilitate generation of multi-photon states, which are a necessity in quantum enhanced sensing technologies and as an input to photonic quantum circuits. PMID- 29247220 TI - Health-care professionals' perspective on discussing sexual issues in adult patients after haematopoietic cell transplantation. AB - The majority of adult patients have sexual concerns after post-haematopoietic cell transplantation. Even so, health-care professionals (HCP) do not routinely discuss these problems. We, therefore, surveyed all the members of the European Society for Blood and Marrow Transplantation to evaluate the barriers and facilitators to discussing sexual issues. The 73-item web-survey was completed by 166 registered nurses (RNs) and 126 medical doctors (MDs). Sixty-eight percent reported that they seldom discussed sexual issues. Younger MDs (p < 0.001) and those who work in non-western European countries (p = 0.003), RNs with probably less sexual education themselves (p = 0.002), MDs and RNs who have limited knowledge about sexual complications (p < 0.001) and MDs and RNs who feel uncomfortable discussing sexual issues (p < 0.001) are all less likely to discuss these matters. The major perceived barriers were that patients might be embarrassed if sexual issues were discussed in the presence of a relative (60% RNs, 67% MDs) and that professionals prefer patients to raise sexual issues themselves (54% RNs, 44% MDs). The most important perceived facilitator was for the patient to initiate discussion (>= 90% for RNs and MDs). Overall, haematopoietic cell transplantation survivors may not be receiving the support on sexual issues they probably need. PMID- 29247221 TI - Fibronectin is a stress responsive gene regulated by HSF1 in response to geldanamycin. AB - Fibronectin is an extracellular matrix glycoprotein with key roles in cell adhesion and migration. Hsp90 binds directly to fibronectin and Hsp90 depletion regulates fibronectin matrix stability. Where inhibition of Hsp90 with a C terminal inhibitor, novobiocin, reduced the fibronectin matrix, treatment with an N-terminal inhibitor, geldanamycin, increased fibronectin levels. Geldanamycin treatment induced a stress response and a strong dose and time dependent increase in fibronectin mRNA via activation of the fibronectin promoter. Three putative heat shock elements (HSEs) were identified in the fibronectin promoter. Loss of two of these HSEs reduced both basal and geldanamycin-induced promoter activity, as did inhibition of the stress-responsive transcription factor HSF1. Binding of HSF1 to one of the putative HSE was confirmed by ChIP under basal conditions, and occupancy shown to increase with geldanamycin treatment. These data support the hypothesis that fibronectin is stress-responsive and a functional HSF1 target gene. COLA42 and LAMB3 mRNA levels were also increased with geldanamycin indicating that regulation of extracellular matrix (ECM) genes by HSF1 may be a wider phenomenon. Taken together, these data have implications for our understanding of ECM dynamics in stress-related diseases in which HSF1 is activated, and where the clinical application of N-terminal Hsp90 inhibitors is intended. PMID- 29247222 TI - Modelling mosquito infection at natural parasite densities identifies drugs targeting EF2, PI4K or ATP4 as key candidates for interrupting malaria transmission. AB - Eradication of malaria requires a novel type of drug that blocks transmission from the human to the mosquito host, but selection of such a drug is hampered by a lack of translational models. Experimental mosquito infections yield infection intensities that are substantially higher than observed in natural infections and, as a consequence, underestimate the drug effect on the proportion of mosquitoes that become infected. Here we introduce a novel experimental and computational method to adequately describe drug efficacy at natural parasite densities. Parameters of a beta-binomial infection model were established and validated using a large number of experimental mosquito infections at different parasite densities. Analyses of 15 experimental and marketed drugs revealed a class-specific ability to block parasite transmission. Our results highlight the parasite's elongation factor EF2, PI4 kinase and the ATP4 sodium channel as key targets for interruption of transmission, and compounds DDD107498 and KAE609 as most advanced drug candidates. PMID- 29247223 TI - Highly efficient upconversion of Er3+ in Yb3+ codoped non-cytotoxic strontium lanthanum aluminate phosphor for low temperature sensors. AB - Er3+ and Er3+/Yb3+ melilite-based SrLaAl3O7 (SLA) phosphors were synthesized by a facile Pechine method. The differences in emission intensities of 4I13/2 -> 4I15/2 transition in NIR region when excited with Ar+ and 980 nm lasers were explained in terms of energy transfer mechanisms. Temperature and power dependence of upconversion bands in the visible region centered at 528, 548 and 660 nm pertaining to 2H11/2, 4S3/2 and 4F9/2 -> 4I15/2 transitions were investigated. Fluorescence intensity ratio (FIR) technique was used to explore temperature sensing behaviour of the thermally coupled levels 2H11/2/4S3/2 of Er3+ ions in the phosphors within the temperature range 14-300 K and the results were extrapolated up to 600 K. Anomalous intensity trend observed in Er3+ doped SLA phosphor was discussed using energy level structure. Cytotoxicity of phosphors has been evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay in Bluegill sunfish cells (BF-2). The non cytotoxic nature and high sensitivity of the present phosphors pay a way for their use in vitro studies and provide potential interest as a thermo graphic phosphor at the contact of biological products. PMID- 29247224 TI - New twinning route in face-centered cubic nanocrystalline metals. AB - Twin nucleation in a face-centered cubic crystal is believed to be accomplished through the formation of twinning partial dislocations on consecutive atomic planes. Twinning should thus be highly unfavorable in face-centered cubic metals with high twin-fault energy barriers, such as Al, Ni, and Pt, but instead is often observed. Here, we report an in situ atomic-scale observation of twin nucleation in nanocrystalline Pt. Unlike the classical twinning route, deformation twinning initiated through the formation of two stacking faults separated by a single atomic layer, and proceeded with the emission of a partial dislocation in between these two stacking faults. Through this route, a three layer twin was nucleated without a mandatory layer-by-layer twinning process. This route is facilitated by grain boundaries, abundant in nanocrystalline metals, that promote the nucleation of separated but closely spaced partial dislocations, thus enabling an effective bypassing of the high twin-fault energy barrier. PMID- 29247225 TI - Ginsenoside Rg3 Decreases Fibrotic and Invasive Nature of Endometriosis by Modulating miRNA-27b: In Vitro and In Vivo Studies. AB - This research aimed to evaluate the potential therapeutic effects of Rg3 on endometriosis and identify target miRNAs. We designed an in vitro study using human endometrial stromal cells (HESCs) obtained from patients with endometriosis and an in vivo study using mouse models. HESCs were treated with Rg3-enhanced red ginseng extract (Rg3E); real-time PCR and microarray profiling, transfection, and western blot were performed. Mouse endometriosis models were developed and supplemented with Rg3E for 8 weeks. Gross lesion size and fibrotic character were analyzed in the mouse models. RNA levels of Ki-67, col-1, CTGF, fibronectin, TGF beta1, MMP2 and MMP9 significantly decreased in HESCs after Rg3E treatment. Microarray analysis revealed downregulation of miR-27b-3p, which is related to fibrosis modulation. Expression of miR-27b-3p was significantly higher in HESCs from patients with endometriosis than that of controls, and Rg3E treatment significantly decreased its expression; the contraction and migration assay revealed significant reductions in both fibrosis and migration potential in Rg3E treated HESCs from endometriosis patients. A decrease in size and fibrotic character of endometrial lesions from the Rg3E groups was observed in vivo. In conclusion, Rg3 effectively altered fibrotic properties of HESCs from patients with endometriosis, which is likely associated with miR-27b-3p modulation. PMID- 29247226 TI - Eco-evolutionary Red Queen dynamics regulate biodiversity in a metabolite-driven microbial system. AB - The Red Queen Hypothesis proposes that perpetual co-evolution among organisms can result from purely biotic drivers. After more than four decades, there is no satisfactory understanding as to which mechanisms trigger Red Queen dynamics or their implications for ecosystem features such as biodiversity. One reason for such a knowledge gap is that typical models are complicated theories where limit cycles represent an idealized Red Queen, and therefore cannot be used to devise experimental setups. Here, we bridge this gap by introducing a simple model for microbial systems able to show Red Queen dynamics. We explore diverse biotic sources that can drive the emergence of the Red Queen and that have the potential to be found in nature or to be replicated in the laboratory. Our model enables an analytical understanding of how Red Queen dynamics emerge in our setup, and the translation of model terms and phenomenology into general underlying mechanisms. We observe, for example, that in our system the Red Queen offers opportunities for the increase of biodiversity by facilitating challenging conditions for intraspecific dominance, whereas stasis tends to homogenize the system. Our results can be used to design and engineer experimental microbial systems showing Red Queen dynamics. PMID- 29247227 TI - Superoxide stability for reversible Na-O2 electrochemistry. AB - Stabilizing superoxide (O2-) is one of the key issues of sodium-air batteries because the superoxide-based discharge product (NaO2) is more reversibly oxidized to oxygen when compared with peroxide (O22-) and oxide (O2-). Reversibly outstanding performances of sodium-oxygen batteries have been realized with the superoxide discharge product (NaO2) even if sodium peroxide (Na2O2) have been also known as the discharge products. Here we report that the Lewis basicity of anions of sodium salts as well as solvent molecules, both quantitatively represented by donor numbers (DNs), determines the superoxide stability and resultantly the reversibility of sodium-oxygen batteries. A DN map of superoxide stability was presented as a selection guide of salt/solvent pair. Based on sodium triflate (CF3SO3-)/dimethyl sulfoxide (DMSO) as a high-DN-pair electrolyte system, sodium ion oxygen batteries were constructed. Pre-sodiated antimony (Sb) was used as an anode during discharge instead of sodium metal because DMSO is reacted with the metal. The superoxide stability supported by the high DN anion/solvent pair ([Formula: see text] -/DMSO) allowed more reversible operation of the sodium ion oxygen batteries. PMID- 29247228 TI - Nanoimprinted High-Refractive Index Active Photonic Nanostructures Based on Quantum Dots for Visible Light. AB - A novel method to realizing printed active photonic devices was developed using nanoimprint lithography (NIL), combining a printable high-refractive index material and colloidal CdSe/CdS quantum dots (QDs) for applications in the visible region. Active media QDs were applied in two different ways: embedded inside a printable high-refractive index matrix to form an active printable hybrid nanocomposite, and used as a uniform coating on top of printed photonic devices. As a proof-of-demonstration for printed active photonic devices, two dimensional (2-D) photonic crystals as well as 1D and 2D photonic nanocavities were successfully fabricated following a simple reverse-nanoimprint process. We observed enhanced photoluminescence from the 2D photonic crystal and the 1D nanocavities. Outstandingly, the process presented in this study is fully compatible with large-scale manufacturing where the patterning areas are only limited by the size of the corresponding mold. This work shows that the integration of active media and functional materials is a promising approach to the realization of integrated photonics for visible light using high throughput technologies. We believe that this work represents a powerful and cost-effective route for the development of numerous nanophotonic structures and devices that will lead to the emergence of new applications. PMID- 29247229 TI - Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD): follow-up interviews on patient-centred outcomes. AB - This study investigated patient perceptions, experiences and management of COPD throughout the SLS COPD study. Follow-up interviews were conducted with 400 patients who completed SLS COPD; a mixed-methods approach was used to collect quantitative and qualitative information. Structured interviews using closed ended questions were conducted with 360 patients, detailing aspects of background/lifestyle information and COPD. Extended interviews containing open ended questions on perceptions of COPD and quality of life (QoL) in addition to the closed-ended questions were completed by 40 further patients. Participants also completed the Adherence Starts with Knowledge-12 (ASK-12) and the COPD and Asthma Sleep Impact Scale (CASIS) questionnaire. Quantitative data were analysed descriptively; qualitative data were analysed using qualitative description. The participants (n = 400) were reasonably representative of the SLS COPD population; mean age was 66.2 years. Breathlessness was the most commonly recalled symptom of/associated with COPD (88.5% of patients) and was the symptom that changed the most (improved, 26.8%/worsened, 20.9%) throughout the study. Participants' daily functioning and activities were most affected by symptoms of/associated with COPD, followed by relationships and psychological issues. 66.5% of participants experienced exacerbations, 60.5% of whom reported self-management as their first treatment strategy (taking antibiotics, resting and/or corticosteroids). Qualitative analysis revealed COPD symptoms, breathlessness in particular, to have a significant impact on mobility and in turn QoL. In conclusion, breathlessness was cited in these interviews as the COPD symptom with the greatest impact on participants' daily functioning, activities and self-care. The findings provided significant additional knowledge to the SLS COPD study findings. PMID- 29247230 TI - Gene-activated matrix/bone marrow-derived mesenchymal stem cells constructs regenerate sweat glands-like structure in vivo. AB - It is a significant challenge to regenerate full-thickness skin defects with sweat glands. Various skin substitutes have been developed to resolve this issue with minimal success. In this study, to yield a novel construct for in situ regeneration of sweat glands, the collagen-chitosan porous scaffold was combined with Lipofectamine 2000/pDNA-EGF complexes to obtain the gene-activated scaffold (GAS), which was then seeded with bone marrow-derived mesenchymal stem cells (BM MSCs). The porous scaffold functionalized as a reservoir for the incorporated gene complexes which were released in a sustained manner. The seeded BM-MSCs were transfected in situ by the released complexes and specially differentiated into sweat gland cells in vitro under the induction of the expressed epidermal growth factor (EGF). Application in vivo of the GAS/BM-MSCs constructs on the full thickness skin defects of SD rats confirmed that GAS/BM-MSCs could accelerate the wound healing process and induce the in situ regeneration of the full-thickness skin with sweat gland-like structures. Analyzed by immunohistochemical staining, RT-qPCR and Western-blotting, the levels of the major sweat gland markers such as carcino-embryonic antigen (CEA), cytokeratin 8 (CK8) and cytokeratin 14 (CK14) were all up-regulated, indicating that GAS/BM-MSCs can facilitate the regeneration of sweat glands-like structure in vivo. PMID- 29247231 TI - Prediction of Mechanical Twinning in Magnesium Silicate Post-Perovskite. AB - The plastic properties of MgSiO3 post-perovskite are considered to be one of the key issues necessary for understanding the seismic anisotropy at the bottom of the mantle in the so-called D" layer. Although plastic slip in MgSiO3 post perovskite has attracted considerable attention, the twinning mechanism has not been addressed, despite some experimental evidence from low-pressure analogues. On the basis of a numerical mechanical model, we present a twin nucleation model for post-perovskite involving the emission of 1/6 <110> partial dislocations. Relying on first-principles calculations with no adjustable parameters, we show that {110} twin wall formation resulting from the interaction of multiple twin dislocations occurs at a twinning stress comparable in magnitude to the most readily occurring slip system in post-perovskite. Because dislocation activities and twinning are competitive strain-producing mechanisms, twinning should be considered in future models of crystallographic preferred orientations in post perovskite to better interpret seismic anisotropy in the lowermost lower mantle. PMID- 29247232 TI - Tunable two-phonon higher-order sideband amplification in a quadratically coupled optomechanical system. AB - We propose an efficient scheme for the controllable amplification of two-phonon higher-order sidebands in a quadratically coupled optomechanical system. In this scheme, a strong control field and a weak probe pulse are injected into the cavity, and the membrane located at the middle position of the cavity is driven resonantly by a weak coherent mechanical pump. Beyond the conventional linearized approximation, we derive analytical expressions for the output transmission of probe pulse and the amplitude of second-order sideband by adding the nonlinear coefficients into the Heisenberg-Langevin formalism. Using experimentally achievable parameters, we identify the conditions under which the mechanical pump and the frequency detuning of control field allow us to modify the transmission of probe pulse and improve the amplitude of two-phonon higher-order sideband generation beyond what is achievable in absence of the mechanical pump. Furthermore, we also find that the higher-order sideband generation depends sensitively on the phase of mechanical pump when the control field becomes strong. The present proposal offers a practical opportunity to design chip-scale optical communications and optical frequency combs. PMID- 29247233 TI - Effect of S267F variant of NTCP on the patients with chronic hepatitis B. AB - Sodium taurocholate cotransporting polypeptide (NTCP) was identified as an entry receptor for hepatitis B virus (HBV) infection. The substitution of serine at position 267 of NTCP with phenylalanine (S267F) is an Asian-specific variation that hampers HBV entry in vitro. In this study, we aimed to evaluate the prevalence of S267F polymorphism in Korean patients with chronic hepatitis B (CHB) and its association with disease progression and potential viral evolution in the preS1 domain of HBV. We found that the frequency of the S267F variant of NTCP in CHB patients and controls was 2.7% and 5.7% (P = 0.031), respectively, and that those who had S267F variant were less susceptible to chronic HBV infection. The frequency of the S267F variant in CHB, cirrhosis and hepatocellular carcinoma (HCC) patients was 3.3%, 0.9%, and 3.5%, respectively. Thus, the S267F variant correlated significantly with a lower risk for cirrhosis (P = 0.036). Sequencing preS1 domain of HBV from the patients who had S267F variant revealed no significant sequence change compared to the wild type. In conclusion, the S267F variant of NTCP is clinically associated with a lower risk of chronic HBV infection and cirrhosis development, which implicates suppressing HBV entry could reduce the disease burden. PMID- 29247235 TI - Effects of snow properties on humans breathing into an artificial air pocket - an experimental field study. AB - Breathing under snow, e.g. while buried by a snow avalanche, is possible in the presence of an air pocket, but limited in time as hypoxia and hypercapnia rapidly develop. Snow properties influence levels of hypoxia and hypercapnia, but their effects on ventilation and oxygenation in humans are not fully elucidated yet. We report that in healthy subjects breathing into snow with an artificial air pocket, snow density had a direct influence on ventilation, oxygenation and exhaled CO2. We found that a rapid decline in O2 and increase in CO2 were mainly associated with higher snow densities and led to premature interruption due to critical hypoxia (SpO2 <= 75%). However, subjects in the low snow density group demonstrated a higher frequency of test interruptions than expected, due to clinical symptoms related to a rapid CO2 accumulation in the air pocket. Snow properties determine the oxygen support by diffusion from the surrounding snow and the clearance of CO2 by diffusion and absorption. Thus, snow properties are co-responsible for survival during avalanche burial. PMID- 29247234 TI - Phospholipid flipping involves a central cavity in P4 ATPases. AB - P4 ATPase flippases translocate phospholipids across biomembranes, thus contributing to the establishment of transmembrane lipid asymmetry, a feature important for multiple cellular processes. The mechanism by which such phospholipid flipping occurs remains elusive as P4 ATPases transport a giant substrate very different from that of other P-type ATPases such as Na+/K+- and Ca2+-ATPases. Based on available crystal structures of cation-transporting P-type ATPases, we generated a structural model of the broad-specificity flippase ALA10. In this model, a cavity delimited by transmembrane segments TM3, TM4, and TM5 is present in the transmembrane domain at a similar position as the cation-binding region in related P-type ATPases. Docking of a phosphatidylcholine headgroup in silico showed that the cavity can accommodate a phospholipid headgroup, likely leaving the fatty acid tails in contact with the hydrophobic portion of the lipid bilayer. Mutagenesis data support this interpretation and suggests that two residues in TM4 (Y374 and F375) are important for coordination of the phospholipid headgroup. Our results point to a general mechanism of lipid translocation by P4 ATPases, which closely resembles that of cation-transporting pumps, through coordination of the hydrophilic portion of the substrate in a central membrane cavity. PMID- 29247236 TI - Giant coercivity and high magnetic blocking temperatures for N23- radical-bridged dilanthanide complexes upon ligand dissociation. AB - Increasing the operating temperatures of single-molecule magnets-molecules that can retain magnetic polarization in the absence of an applied field-has potential implications toward information storage and computing, and may also inform the development of new bulk magnets. Progress toward these goals relies upon the development of synthetic chemistry enabling enhancement of the thermal barrier to reversal of the magnetic moment, while suppressing alternative relaxation processes. Herein, we show that pairing the axial magnetic anisotropy enforced by tetramethylcyclopentadienyl (CpMe4H) capping ligands with strong magnetic exchange coupling provided by an N23- radical bridging ligand results in a series of dilanthanide complexes exhibiting exceptionally large magnetic hysteresis loops that persist to high temperatures. Significantly, reducing the coordination number of the metal centers appears to increase axial magnetic anisotropy, giving rise to larger magnetic relaxation barriers and 100-s magnetic blocking temperatures of up to 20 K, as observed for the complex [K(crypt 222)][(CpMe4H2Tb)2(MU-[Formula: see text])]. PMID- 29247237 TI - Transcription of a B chromosome CAP-G pseudogene does not influence normal Condensin Complex genes in a grasshopper. AB - Parasitic B chromosomes invade and persist in natural populations through several mechanisms for transmission advantage (drive). They may contain gene-derived sequences which, in some cases, are actively transcribed. A further interesting question is whether B-derived transcripts become functional products. In the grasshopper Eyprepocnemis plorans, one of the gene-derived sequences located on the B chromosome shows homology with the gene coding for the CAP-G subunit of condensin I. We show here, by means of fluorescent in situ hybridization coupled with tyramide signal amplification (FISH-TSA), that this gene is located in the distal region of the B24 chromosome variant. The DNA sequence located in the B chromosome is a pseudogenic version of the CAP-G gene (B-CAP-G). In two Spanish populations, we found active transcription of B-CAP-G, but it did not influence the expression of CAP-D2 and CAP-D3 genes coding for corresponding condensin I and II subunits, respectively. Our results indicate that the transcriptional regulation of the B-CAP-G pseudogene is uncoupled from the standard regulation of the genes that constitute the condensin complex, and suggest that some of the B chromosome known effects may be related with its gene content and transcriptional activity, thus opening new exciting avenues for research. PMID- 29247238 TI - TRPV1-mediated Pharmacological Hypothermia Promotes Improved Functional Recovery Following Ischemic Stroke. AB - Hypothermia shows promise for stroke neuroprotection, but current cooling strategies cause undesirable side effects that limit their clinical applications. Increasing efforts have focused on pharmacological hypothermia as a treatment option for stroke. Previously, we showed that activation of a thermoregulatory ion channel, transient receptor potential vanilloid 1 (TRPV1), by dihydrocapsaicin (DHC) produces reliable hypothermia. In this study, we investigate the effects of TRPV1-mediated hypothermia by DHC on long-term ischemic stroke injury and functional outcome. Hypothermia initiated at 3.5 hours after stroke significantly reduced primary cortical injury. Interestingly, hypothermia by DHC also significantly reduced secondary thalamic injury, as DHC treated stroke mice exhibited 53% smaller thalamic lesion size. DHC-treated stroke mice further demonstrated decreased neuronal loss and astrogliosis in the thalamus and less thalamic fiber loss by diffusion tensor imaging (DTI). Importantly, a single 8 hour treatment of hypothermia by DHC after stroke provided long-term improvement in functional outcome, as DHC-treated mice exhibited improved behavioral recovery at one month post-stroke. These findings indicate that TRPV1-mediated hypothermia is effective in reducing both primary cortical injury and remote secondary thalamic injury, and a single treatment can produce persistent effects on functional recovery. These data highlight the therapeutic potential for TRPV1 agonism for stroke treatment. PMID- 29247239 TI - Biogas production from food waste via co-digestion and digestion- effects on performance and microbial ecology. AB - In this work, performance and microbial structure of a digestion (food waste only) and a co-digestion process (mixture of cow manure and food waste) were studied at mesophilic (37 degrees C) and thermophilic (55 degrees C) temperatures. The highest methane yield (480 mL/g VS) was observed in the mesophilic digester (MDi) fed with food waste alone. The mesophilic co-digestion of food waste and manure (McoDi) yielded 26% more methane than the sum of individual digestions of manure and food waste. The main volatile fatty acid (VFA) in the mesophilic systems was acetate, averaging 93 and 172 mg/L for McoDi and MDi, respectively. Acetate (2150 mg/L) and propionate (833 mg/L) were the main VFAs in the thermophilic digester (TDi), while propionate (163 mg/L) was the major VFA in the thermophilic co-digester (TcoDi). The dominant bacteria in MDi was Chloroflexi (54%), while Firmicutes was dominant in McoDi (60%). For the mesophilic reactors, the dominant archaea was Methanosaeta in MDi, while Methanobacterium and Methanosaeta had similar abundance in McoDi. In the thermophilic systems, the dominant bacteria were Thermotogae, Firmicutes and Synergistetes in both digesters, however, the relative abundance of these phyla were different. For archaea, the genus Methanothermobacter were entirely dominant in both TDi and TcoDi. PMID- 29247240 TI - Genetic and Neurobiological Analyses of the Noradrenergic-like System in Vulnerability to Sugar Overconsumption Using a Drosophila Model. AB - Regular overconsumption of sugar is associated with obesity and type-2 diabetes, but how genetic factors contribute to variable sugar preferences and intake levels remains mostly unclear. Here we provide evidence for the usefulness of a Drosophila larva model to investigate genetic influence on vulnerability to sugar overconsumption. Using genetic and RNA interference approaches, we show that the activity of the Oamb gene, which encodes a receptor for octopamine (OA, the invertebrate homologue of norepinephrine), plays a major role in controlled sugar consumption. Furthermore, Oamb appears to suppress sugar food intake in fed larvae in an acute manner, and neurons expressing this Oamb receptor do not overlap with neurons expressing Octbeta3R, another OA receptor previously implicated in hunger-driven exuberant sugar intake. Together, these results suggest that two separate sub-circuits, defined by Oamb and Octbeta3R respectively, co-regulate sugar consumption according to changes in energy needs. We propose that the noradrenergic-like system defines an ancient regulatory mechanism for prevention of sugar overload. PMID- 29247241 TI - Beneficial effects of melittin on ovalbumin-induced atopic dermatitis in mouse. AB - Atopic dermatitis (AD) is an inflammatory skin disease characterized by intense pruritus and relapsable eczematous lesions. The hallmarks of AD are defects in the epidermal barrier and immunoglobulin E (IgE)-mediated sensitization to several environmental allergens, as well as an immune disorder mediated by an imbalance toward T-helper-2 response. Melittin, a major component of bee venom, has been studied in various inflammatory diseases. However, the beneficial effects of melittin on mouse with AD-like symptoms have not been explored. Therefore, we investigated the anti-allergic effects of melittin. AD was induced by ovalbumin (OVA) patch. After agent treatment, skin tissues and sera were extracted from the sacrificed mice were used to demonstrate the effects of melittin through various molecular biological methods. The results showed that OVA-induced skin thickening and inflammatory infiltration were decreased in the melittin-treated group. Melittin prevented OVA-induced filaggrin deficiency and imbalanced inflammatory mediators. Furthermore, melittin inhibited IL-4/IL-13 induced filaggrin downregulation through the blockade of STAT3 activation in human keratinocytes. In summary, this study has shown that melittin ameliorated OVA-induced AD-like symptoms from various perspectives. The findings of this study may be the first evidence of the anti-inflammatory effects of melittin on OVA-induced AD. PMID- 29247242 TI - Myeloid differentiation primary response gene (MyD) 88 signalling is not essential for intestinal fibrosis development. AB - Dysregulation of the immune response to microbiota is associated with inflammatory bowel disease (IBD), which can trigger intestinal fibrosis. MyD88 is a key component of microbiota signalling but its influence on intestinal fibrosis has not been clarified. Small bowel resections from donor-mice were transplanted subcutaneously into the neck of recipients C57BL/6 B6-MyD88tm1 Aki (MyD88-/-) and C57BL/6-Tg(UBC-green fluorescence protein (GFP))30Scha/J (GFP-Tg). Grafts were explanted up to 21 days after transplantation. Collagen layer thickness was determined using Sirius Red stained slides. In the mouse model of fibrosis collagen deposition and transforming growth factor-beta 1 (TGF-beta1) expression was equal in MyD88+/+ and MyD88-/-, indicating that MyD88 was not essential for fibrogenesis. Matrix metalloproteinase (Mmp)9 expression was significantly decreased in grafts transplanted into MyD88-/- recipients compared to MyD88+/+ recipients (0.2 +/- 0.1 vs. 153.0 +/- 23.1, respectively, p < 0.05), similarly recruitment of neutrophils was significantly reduced (16.3 +/- 4.5 vs. 25.4 +/- 3.1, respectively, p < 0.05). Development of intestinal fibrosis appears to be independent of MyD88 signalling indicating a minor role of bacterial wall compounds in the process which is in contrast to published concepts and theories. Development of fibrosis appears to be uncoupled from acute inflammation. PMID- 29247243 TI - Leukotriene B4 is essential for lung host defence and alpha-defensin-1 production during Achromobacter xylosoxidans infection. AB - Leukotriene B4 (LTB4) is essential for host immune defence. It increases neutrophil recruitment, phagocytosis and pathogen clearance, and decreases oedema and inflammasome activation. The host response and the role of LTB4 during Achromobacter xylosoxidans infection remain unexplored. Wild-type (129sv) and LTB4 deficient (Alox5 -/-) mice were intratracheally infected with A. xylosoxidans. Wild-type 129sv infected mice survived beyond the 8th day post infection, exhibited increased levels of LTB4 in the lung on the 1st day, while levels of PGE2 increased on the 7th day post-infection. Infected Alox5 -/- mice showed impaired bacterial clearance, increased lung inflammation, and succumbed to the infection by the 7th day. We found that exogenous LTB4 does not affect the phagocytosis of A. xylosoxidans by alveolar macrophages in vitro. However, treatment of infected animals with LTB4 protected from mortality, by reducing the bacterial load and inflammation via BLT1 signalling, the high affinity receptor for LTB4. Of importance, we uncovered that LTB4 induces gene and protein expression of alpha-defensin-1 during the infection. This molecule is essential for bacterial clearance and exhibits potent antimicrobial activity by disrupting A. xylosoxidans cell wall. Taken together, our data demonstrate a major role for LTB4 on the control of A. xylosoxidans infection. PMID- 29247245 TI - Author Correction: Anomalous in-plane anisotropic Raman response of monoclinic semimetal 1 T'-MoTe2. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29247244 TI - Proteasome stress sensitizes malignant pleural mesothelioma cells to bortezomib induced apoptosis. AB - Based on promising results in preclinical models, clinical trials have been performed to evaluate the efficacy of the first-in-class proteasome inhibitor bortezomib towards malignant pleural mesothelioma (MPM), an aggressive cancer arising from the mesothelium of the serous cavities following exposure to asbestos. Unexpectedly, only minimal therapeutic benefits were observed, thus implicating that MPM harbors inherent resistance mechanisms. Identifying the molecular bases of this primary resistance is crucial to develop novel pharmacologic strategies aimed at increasing the vulnerability of MPM to bortezomib. Therefore, we assessed a panel of four human MPM lines with different sensitivity to bortezomib, for functional proteasome activity and levels of free and polymerized ubiquitin. We found that highly sensitive MPM lines display lower proteasome activity than more bortezomib-resistant clones, suggesting that reduced proteasomal capacity might contribute to the intrinsic susceptibility of mesothelioma cells to proteasome inhibitors-induced apoptosis. Moreover, MPM equipped with fewer active proteasomes accumulated polyubiquitinated proteins, at the expense of free ubiquitin, a condition known as proteasome stress, which lowers the cellular apoptotic threshold and sensitizes mesothelioma cells to bortezomib-induced toxicity as shown herein. Taken together, our data suggest that an unfavorable load-versus-capacity balance represents a critical determinant of primary apoptotic sensitivity to bortezomib in MPM. PMID- 29247246 TI - New microsatellite markers for population studies of Phytophthora cinnamomi, an important global pathogen. AB - Phytophthora cinnamomi is the causal agent of root rot, canker and dieback of thousands of plant species around the globe. This oomycete not only causes severe economic losses but also threatens natural ecosystems. In South Africa, P. cinnamomi affects eucalyptus, avocado, macadamia and indigenous fynbos. Despite being one of the most important plant pathogens with a global distribution, little information is available regarding origin, invasion history and population biology. This is partly due to the limited number of molecular markers available for studying P. cinnamomi. Using available genome sequences for three isolates of P. cinnamomi, sixteen polymorphic microsatellite markers were developed as a set of multiplexable markers for both PCR and Gene Scan assays. The application of these markers on P. cinnamomi populations from avocado production areas in South Africa revealed that they were all polymorphic in these populations. The markers developed in this study represent a valuable resource for studying the population biology and movement of P. cinnamomi and will aid in the understanding of the origin and invasion history of this important species. PMID- 29247247 TI - Aedes aegypti microRNA miR-2b regulates ubiquitin-related modifier to control chikungunya virus replication. AB - Arboviruses that replicate in mosquitoes activate innate immune response within mosquitoes. Regulatory non-coding microRNAs (miRNA) are known to be modulated in mosquitoes during chikungunya infection. However, information about targets of these miRNAs is scant. The present study was aimed to identify and analyze targets of miRNAs that are regulated during chikungunya virus (CHIKV) replication in Aedes aegypti cells and in the mosquito. Employing next-generation sequencing technologies, we identified a total of 126 miRNAs from the Ae. aegypti cell line Aag2. Of these, 13 miRNAs were found to be regulated during CHIKV infection. Putative targets of three of the most significantly regulated miRNAs- miR-100, miR-2b and miR-989 were also analyzed using quantitative PCRs, in cell lines and in mosquitoes, to validate whether they were the targets of the miRNAs. Our study expanded the list of miRNAs known in Ae. aegypti and predicted targets for the significantly regulated miRNAs. Further analysis of some of these targets revealed that ubiquitin-related modifier is a target of miRNA miR-2b and plays a significant role in chikungunya replication. PMID- 29247248 TI - Electrical semiconduction modulated by light in a cobalt and naphthalene diimide metal-organic framework. AB - Metal-organic frameworks (MOFs) have emerged as an exciting class of porous materials that can be structurally designed by choosing particular components according to desired applications. Despite the wide interest in and many potential applications of MOFs, such as in gas storage, catalysis, sensing and drug delivery, electrical semiconductivity and its control is still rare. The use and fabrication of electronic devices with MOF-based components has not been widely explored, despite significant progress of these components made in recent years. Here we report the synthesis and properties of a new highly crystalline, electrochemically active, cobalt and naphthalene diimide-based MOF that is an efficient electrical semiconductor and has a broad absorption spectrum, from 300 to 2500 nm. Its semiconductivity was determined by direct voltage bias using a four-point device, and it features a wavelength dependant photoconductive photoresistive dual behaviour, with a very high responsivity of 2.5 * 105 A W-1. PMID- 29247250 TI - Generation of steady entanglement via unilateral qubit driving in bad cavities. AB - We propose a scheme for generating an entangled state for two atoms trapped in two separate cavities coupled to each other. The scheme is based on the competition between the unitary dynamics induced by the classical fields and the collective decays induced by the dissipation of two non-local bosonic modes. In this scheme, only one qubit is driven by external classical fields, whereas the other need not be manipulated via classical driving. This is meaningful for experimental implementation between separate nodes of a quantum network. The steady entanglement can be obtained regardless of the initial state, and the robustness of the scheme against parameter fluctuations is numerically demonstrated. We also give an analytical derivation of the stationary fidelity to enable a discussion of the validity of this regime. Furthermore, based on the dissipative entanglement preparation scheme, we construct a quantum state transfer setup with multiple nodes as a practical application. PMID- 29247249 TI - Baculovirus-assisted Reovirus Infection in Monolayer and Spheroid Cultures of Glioma cells. AB - The mammalian orthoreovirus Type 3 Dearing has great potential as oncolytic agent in cancer therapy. One of the bottlenecks that hampers its antitumour efficacy in vivo is the limited tumour-cell infection and intratumoural distribution. This necessitates strategies to improve tumour penetration. In this study we employ the baculovirus Autographa californica multiple nucleopolyhedrovirus as a tool to expand the reovirus' tropism and to improve its spread in three-dimensional tumour-cell spheroids. We generated a recombinant baculovirus expressing the cellular receptor for reovirus, the Junction Adhesion Molecule-A, on its envelope. Combining these Junction Adhesion Molecule-A-expressing baculoviruses with reovirus particles leads to the formation of biviral complexes. Exposure of the reovirus-resistant glioblastoma cell line U-118 MG to the baculovirus reovirus complexes results in efficient reovirus infection, high reovirus yields, and significant reovirus-induced cytopathic effects. As compared to the reovirus only incubations, the biviral complexes demonstrated improved penetration and increased cell killing of three-dimensional U-118 MG tumour spheroids. Our data demonstrate that reovirus can be delivered with increased efficiency into two- and three-dimensional tumour-cell cultures via coupling the reovirus particles to baculovirus. The identification of baculovirus' capacity to penetrate into tumour tissue opens novel opportunities to improve cancer therapy by improved delivery of oncolytic viruses into tumours. PMID- 29247252 TI - Lessons Learned From Kinematics Research Applied to Medical Device Design. PMID- 29247251 TI - A Novel Small-Specimen Planar Biaxial Testing System With Full In-Plane Deformation Control. AB - Simulations of soft tissues require accurate and robust constitutive models, whose form is derived from carefully designed experimental studies. For such investigations of membranes or thin specimens, planar biaxial systems have been used extensively. Yet, all such systems remain limited in their ability to: (1) fully prescribe in-plane deformation gradient tensor F2D, (2) ensure homogeneity of the applied deformation, and (3) be able to accommodate sufficiently small specimens to ensure a reasonable degree of material homogeneity. To address these issues, we have developed a novel planar biaxial testing device that overcomes these difficulties and is capable of full control of the in-plane deformation gradient tensor F2D and of testing specimens as small as ~4 mm * ~4 mm. Individual actuation of the specimen attachment points, combined with a robust real-time feedback control, enabled the device to enforce any arbitrary F2D with a high degree of accuracy and homogeneity. Results from extensive device validation trials and example tissues illustrated the ability of the device to perform as designed and gather data needed for developing and validating constitutive models. Examples included the murine aortic tissues, allowing for investigators to take advantage of the genetic manipulation of murine disease models. These capabilities highlight the potential of the device to serve as a platform for informing and verifying the results of inverse models and for conducting robust, controlled investigation into the biomechanics of very local behaviors of soft tissues and membrane biomaterials. PMID- 29247254 TI - Dynamic Hydrostatic Pressure Regulates Nucleus Pulposus Phenotypic Expression and Metabolism in a Cell Density-Dependent Manner. AB - Dynamic hydrostatic pressure (HP) loading can modulate nucleus pulposus (NP) cell metabolism, extracellular matrix (ECM) composition, and induce transformation of notochordal NP cells into mature phenotype. However, the effects of varying cell density and dynamic HP magnitude on NP phenotype and metabolism are unknown. This study examined the effects of physiological magnitudes of HP loading applied to bovine NP cells encapsulated within three-dimensional (3D) alginate beads. Study 1: seeding density (1 M/mL versus 4 M/mL) was evaluated in unloaded and loaded (0.1 MPa, 0.1 Hz) conditions. Study 2: loading magnitude (0, 0.1, and 0.6 MPa) applied at 0.1 Hz to 1 M/mL for 7 days was evaluated. Study 1: 4 M/mL cell density had significantly lower adenosine triphosphate (ATP), glycosaminoglycan (GAG) and collagen content, and increased lactate dehydrogenase (LDH). HP loading significantly increased ATP levels, and expression of aggrecan, collagen I, keratin-19, and N-cadherin in HP loaded versus unloaded groups. Study 2: aggrecan expression increased in a dose dependent manner with HP magnitude, whereas N cadherin and keratin-19 expression were greatest in low HP loading compared to unloaded. Overall, the findings of the current study indicate that cell seeding density within a 3D construct is a critical variable influencing the mechanobiological response of NP cells to HP loading. NP mechanobiology and phenotypic expression was also found to be dependent on the magnitude of HP loading. These findings suggest that HP loading and culture conditions of NP cells may require complex optimization for engineering an NP replacement tissue. PMID- 29247253 TI - Perspectives on Sharing Models and Related Resources in Computational Biomechanics Research. AB - The role of computational modeling for biomechanics research and related clinical care will be increasingly prominent. The biomechanics community has been developing computational models routinely for exploration of the mechanics and mechanobiology of diverse biological structures. As a result, a large array of models, data, and discipline-specific simulation software has emerged to support endeavors in computational biomechanics. Sharing computational models and related data and simulation software has first become a utilitarian interest, and now, it is a necessity. Exchange of models, in support of knowledge exchange provided by scholarly publishing, has important implications. Specifically, model sharing can facilitate assessment of reproducibility in computational biomechanics and can provide an opportunity for repurposing and reuse, and a venue for medical training. The community's desire to investigate biological and biomechanical phenomena crossing multiple systems, scales, and physical domains, also motivates sharing of modeling resources as blending of models developed by domain experts will be a required step for comprehensive simulation studies as well as the enhancement of their rigor and reproducibility. The goal of this paper is to understand current perspectives in the biomechanics community for the sharing of computational models and related resources. Opinions on opportunities, challenges, and pathways to model sharing, particularly as part of the scholarly publishing workflow, were sought. A group of journal editors and a handful of investigators active in computational biomechanics were approached to collect short opinion pieces as a part of a larger effort of the IEEE EMBS Computational Biology and the Physiome Technical Committee to address model reproducibility through publications. A synthesis of these opinion pieces indicates that the community recognizes the necessity and usefulness of model sharing. There is a strong will to facilitate model sharing, and there are corresponding initiatives by the scientific journals. Outside the publishing enterprise, infrastructure to facilitate model sharing in biomechanics exists, and simulation software developers are interested in accommodating the community's needs for sharing of modeling resources. Encouragement for the use of standardized markups, concerns related to quality assurance, acknowledgement of increased burden, and importance of stewardship of resources are noted. In the short-term, it is advisable that the community builds upon recent strategies and experiments with new pathways for continued demonstration of model sharing, its promotion, and its utility. Nonetheless, the need for a long-term strategy to unify approaches in sharing computational models and related resources is acknowledged. Development of a sustainable platform supported by a culture of open model sharing will likely evolve through continued and inclusive discussions bringing all stakeholders at the table, e.g., by possibly establishing a consortium. PMID- 29247255 TI - [Adequate prescription and application of topicals : How to calculate the right volume for the prescription of ointment needed?] AB - BACKGROUND: Uncertainty regarding the suitable amount of prescribed ointment and its application by patients may cause insufficient or uneconomic health care provision. To address this issue, standardized methods and experts' knowledge on the suitable amount and coherent patient's elucidation for application of topicals are needed. OBJECTIVES: Presented are current data in routine care and scientific evidence on the prescribed amount of topical agents as well as its application by patients in dermatological care. MATERIALS AND METHODS: A literature review was conducted via PubMed using the keywords as individual and pooled search terms: "local therapy", "topical treatment", "prescription", "amount of ointment needed", "involved area", "BSA", "finger-tip-unit", "Rule of Hand", "calculated dosage" and "rule of nines". We included original studies by manually screening title and abstract according to the relevance of the topic. RESULTS: The search strategy identified 19 clinical trials. The fingertip unit (FTU) is the most frequently used measurement for accurate application of external agents. Appropriate prescribed amount is calculated by required topical agent per involved surface area. CONCLUSIONS: There is still a need for clarification to which extent the optimized amount of ointment is prescribed and advice for its application in routine care is given. The FTU combined with the "Rule of Hand" is an adequate measurement for patient's guidance on self application. PMID- 29247256 TI - miR-498 promotes cell proliferation and inhibits cell apoptosis in retinoblastoma by directly targeting CCPG1. AB - PURPOSE: Retinoblastoma (Rb) is the most common intraocular tumor in children. MicroRNAs (miRNAs) play a crucial role in gene regulation and cell growth/apoptosis/differentiation. The current study aimed to investigate the role of miR-498 in Rb. METHODS: Quantitative real-time polymerase chain reaction (QRT PCR) was used to test mRNA level of miR-498. http://www.targetscan.org and http://www.microrna.org were applied to predict target of miR-498. Dual luciferase reporter assay was applied to investigate if miR-498 targeted cell cycle progression 1 (CCPG1). Western blot (WB) was carried out to assess CCPG1 protein levels. 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to evaluate cell proliferation. Annexin-V Fluorescein (FITC) was adopted to explore cell apoptosis. RESULTS: In Y79 cells, miR-498 was higher than in normal ARPE-19 cells. MiR-498 could recognize CCPG1-3' untranslated region (UTR). CCPG1 protein level was remarkably decreased when overexpressed miR-498, nevertheless, significantly increased when inhibiting miR 498. Y79 cells that were transfected with miR-498 mimics manifested notable cell apoptosis down-regulation and cell proliferation promotion; whereas, those transfected with miR-498 inhibitor displayed significant cell apoptosis up regulation and cell proliferation inhibition compared with control group. CONCLUSION: Taken together, miR-498 promotes cell proliferation and inhibits cell apoptosis in Rb by directly targeting CCPG1. PMID- 29247257 TI - Application of a partitioning procedure based on Rao quadratic entropy index to characterize the temporal evolution of in situ varietal and genetic diversity of bread wheat in France over the period 1981-2006. AB - KEY MESSAGE: We present and highlight a partitioning procedure based on the Rao quadratic entropy index to assess temporal in situ inter-annual varietal and genetic changes of crop diversity. For decades, Western-European agroecosystems have undergone profound changes, among which a reduction of crop genetic diversity. These changes have been highlighted in numerous studies, but no unified partitioning procedure has been proposed to compute the inter-annual variability in both varietal and genetic diversity. To fill this gap, we tested, adjusted and applied a partitioning procedure based on the Rao quadratic entropy index that made possible to describe the different components of crop diversity as well as to account for the relative acreages of varieties. To emphasize the relevance of this procedure, we relied on a case study focusing on the temporal evolution of bread wheat diversity in France over the period 1981-2006 at both national and district scales. At the national scale, we highlighted a decrease of the weighted genetic replacement indicating that varieties sown in the most recent years were more genetically similar than older ones. At the district scale, we highlighted sudden changes in weighted genetic replacement in some agricultural regions that could be due to fast shifts of successive leading varieties over time. Other regions presented a relatively continuous increase of genetic similarity over time, potentially due to the coexistence of a larger number of co-leading varieties that got closer genetically. Based on the partitioning procedure, we argue that a tendency of in situ genetic homogenization could be compared to some of its potential causes, such as a decrease in the speed of replacement or an increase in between-variety genetic similarity over time. PMID- 29247258 TI - Fine mapping a self-fertility locus in perennial ryegrass. AB - KEY MESSAGE: A self-fertility locus was fine mapped to a 1.6 cM region on linkage group 5 in a perennial ryegrass population. This locus was the main determinant of pollen self-compatibility. In grasses, self-incompatibility (SI) is characterized by a two-loci gametophytic (S and Z) mechanism acting together in the recognition and inhibition of self-pollen. Mutations affecting the expression of SI have been reported in a few grass species. In perennial ryegrass (Lolium perenne L.), a mutation independent from S and Z, and mapping on linkage group 5 (LG 5), was previously reported to produce self-fertile plants. Here, we describe fine mapping of the self-fertility (SF) gene in a perennial ryegrass population and determine whether there is any effect of other genomic regions on the pollen compatibility. The phenotypic segregation of SF showed a bimodal distribution with one mean at 49% pollen compatibility and the other at 91%. Marker-trait association analysis showed that only markers on LG 5 were significantly associated with the trait. A single gene model explained 82% of the observed variability and no effects of the other regions were detected. Using segregation and linkage analysis, the SF locus was located to a 1.6 cM region on LG 5. The flanking marker sequences were aligned to rice and Brachypodium distachyon reference genomes to estimate the physical distance. We provide markers tightly linked to SF that can be used for introgression of this trait into advanced breeding germplasm. Moreover, our results represent a further step towards the identification of the SF gene in LG 5. PMID- 29247259 TI - Effect of sarcopenia on clinical and surgical outcome in elderly patients with proximal femur fractures. AB - PURPOSE: To investigate the relationship between sarcopenia with short-term surgical outcome in elderly patients with proximal femur fractures. METHODS AND MATERIALS: Following Institutional Review Board approval, a database of patients receiving a pelvis CT scan for acute trauma between January 2000-August 2016 was screened for an isolated proximal femur fracture. Patients were excluded if they were: < 50 years old, had conditions predisposing to sarcopenia (renal failure, congestive heart failure, muscular dystrophies), had undergone no surgical treatment, had other major traumatic injuries, or had a pathologic femur fracture. The paraspinal muscle density (PSD) at the L4 level was measured in Hounsfield units. The skeletal muscle index (SMI) was measured as the total skeletal muscle area at L4 divided by patient height.2 PSD and SMI were tested for association with surgical outcome measures: length of hospital stay, perioperative mortality, medical complications, in-hospital blood transfusion volume, and 90-day readmission rate, using multiple variable regression analysis. Pearson correlation of PSD and SMI was performed. RESULTS: Controlling for age, gender, body mass index (BMI), and fracture type, low PSD and SMI were both independently associated with longer length of hospitalization (p = 0.008 and p = 0.032, respectively). Low PSD was associated with a higher amount of blood transfusion volume during the perioperative period (p = 0.004). Pearson correlation revealed moderate positive correlation between the SMI and PSD (r = 0.579, p < 0.001). CONCLUSION: In proximal femur fractures, elderly patients with sarcopenia are more likely to have prolonged hospitalization following surgery and require more blood transfusion volume during the perioperative period. PMID- 29247260 TI - Adolescent cocaine exposure induces prolonged synaptic modifications in medial prefrontal cortex of adult rats. AB - Substance used during adolescent period increases the risk of psychiatric disorders in later life, but the underlying neural mechanisms remain unclear. We hypothesize that synaptic remodeling and changes of homeostasis in the medial prefrontal cortex (mPFC) following adolescent cocaine exposure may last for a long time, and these modifications may contribute to behavioral deficiencies in adulthood. To address this hypothesis, rats were exposed to cocaine hydrochloride from postnatal day 28 (P28) to P42. When reared to adulthood, rats were subjected to behavioral tests. On P75 and P76, cocaine-experienced rats exhibited increased locomotive and anxiety-like behaviors, as well as impaired non-selective attention. In the cocaine-experienced rats, both levels of synapse-related proteins (synapsin I and PSD-95) and density of synapse and dendrite spine in mPFC were significantly decreased when compared to controls. Unexpected, the expression of molecules related to oxidative stress, inflammation and apoptosis showed no significant changes in mPFC following adolescent cocaine exposure. These findings suggested that adolescent exposure to cocaine induce long-term modification on synapses in mPFC, which might contribute to long-term behavioral outcomes in adulthood. PMID- 29247261 TI - Embedded Si/Graphene Composite Fabricated by Magnesium-Thermal Reduction as Anode Material for Lithium-Ion Batteries. AB - Embedded Si/graphene composite was fabricated by a novel method, which was in situ generated SiO2 particles on graphene sheets followed by magnesium-thermal reduction. The tetraethyl orthosilicate (TEOS) and flake graphite was used as original materials. On the one hand, the unique structure of as-obtained composite accommodated the large volume change to some extent. Simultaneously, it enhanced electronic conductivity during Li-ion insertion/extraction. The MR-Si/G composite is used as the anode material for lithium ion batteries, which shows high reversible capacity and ascendant cycling stability reach to 950 mAh.g-1 at a current density of 50 mA.g-1 after 60 cycles. These may be conducive to the further advancement of Si-based composite anode design. PMID- 29247262 TI - Organic acid pretreatment of oil palm trunk: effect on enzymatic saccharification and ethanol production. AB - Effective lignocellulosic biomass saccharification is one of the crucial requirements of biofuel production via fermentation process. Organic acid pretreatments have been gained much interests as one of the high potential methods for promoting enzymatic saccharification of lignocellulosic materials due to their lower hazardous properties and lower production of inhibitory by products of fermentation than typical chemical pretreatment methods. In this study, three organic acids, including acetic acid, oxalic acid, and citric acid, were examined for improvement of enzymatic saccharification and bioethanol production from oil palm trunk biomass. Based on response surface methodology, oxalic acid pretreated biomass released the maximum reducing sugar of 144 mg/g pretreated biomass at the optimum condition, which was higher than untreated samples for 2.30 times. The released sugar yield of oil palm trunk also corresponded to the results of FT-IR analysis, which revealed the physical modification of cellulose and hemicellulose surface structures of pretreated biomass. Nevertheless, citric acid pretreatment is the most efficient pretreatment method to improve bioethanol fermentation of Saccharomyces cerevisiae TISTR 5606 at 1.94 times higher than untreated biomass. These results highlighted the selection of organic acid pretreatment as a potential method for biofuel production from oil palm trunk feedstocks. PMID- 29247263 TI - Pretreatment identification of patients likely to have pathologic complete response after neoadjuvant chemoradiotherapy for rectal cancer. AB - PURPOSE: In selected patients, a wait-and-see strategy after chemoradiotherapy for rectal cancer might be feasible provided that the probability of pathologic complete response (pCR) is high. This study aimed to identify clinical parameters associated with pCR. Furthermore, we attempted to identify subgroups with increased probability of pCR that might aid in clinical decision making. METHODS: A total of 6444 patients that underwent surgical resection of a single primary carcinoma of the rectum after neoadjuvant chemoradiotherapy (nCRT) between January 2009 and December 2016 in the Netherlands were included in the study. Data on the outcome variable, pCR, and potential covariates were retrieved from a nationwide database. The variables included in the analysis were selected based on previous studies and were analyzed using univariate and multivariate logistic regression analyses. RESULTS: pCR was observed in 1010 patients (15.7%). Pretreatment clinical tumor stage and signs of obstruction were independently associated with pCR. Nodal stage and presence of metastatic disease decreased chances of pCR significantly. The best response rate was observed in patients diagnosed with a non-obstructive, well-/moderately differentiated adenocarcinoma of the lower rectum with no clinical apparent nodal or distant metastatic disease (pCR ratio 18.8%). The percentage of patients demonstrating pCR decreased in case of symptoms of pretreatment obstruction or poorly differentiated tumors (pCR ratio of 11.8 and 6.7%, respectively). CONCLUSION: This nationwide study confirms several of the previously reported clinical predictors of pCR. PMID- 29247264 TI - Functional identification of glutamate cysteine ligase and glutathione synthetase in the marine yeast Rhodosporidium diobovatum. AB - Glutathione (GSH) fulfills a variety of metabolic functions, participates in oxidative stress response, and defends against toxic actions of heavy metals and xenobiotics. In this study, GSH was detected in Rhodosporidium diobovatum by high performance liquid chromatography (HPLC). Then, two novel enzymes from R. diobovatum were characterized that convert glutamate, cysteine, and glycine into GSH. Based on reverse transcription PCR, we obtained the glutathione synthetase gene (GSH2), 1866 bp, coding for a 56.6-kDa protein, and the glutamate cysteine ligase gene (GSH1), 2469 bp, coding for a 90.5-kDa protein. The role of GSH1 and GSH2 for the biosynthesis of GSH in the marine yeast R. diobovatum was determined by deletions using the CRISPR-Cas9 nuclease system and enzymatic activity. These results also showed that GSH1 and GSH2 were involved in the production of GSH and are thus being potentially useful to engineer GSH pathways. Alternatively, pET GSH constructed using vitro recombination could be used to detect the function of genes related to GSH biosynthesis. Finally, the fermentation parameters determined in the present study provide a reference for industrial GSH production in R. diobovatum. PMID- 29247265 TI - End-of-life care pathway of head and neck cancer patients: single-institution experience. AB - BACKGROUND: Studies on palliative care of head and neck cancer (HNC) patients are scarce although the affected patient population is quite large. OBJECTIVE: To evaluate the role of a specialised palliative-care pathway of HNC patients. PATIENTS AND METHODS: Data on all HNC patients who were treated at the Helsinki University Hospital Palliative Care Center during 1 year were retrospectively reviewed. The analysis comprised 60 patients (49 males; mean age 67 years; range 28-88). All patients had a minimum follow-up of 1 year or until death. RESULTS: Fifty-nine (98%) out of the 60 patients died during the follow-up period. Median survival after diagnosis was 11 months (range 3 weeks-11.9 years) and after withholding disease-specific therapies 3 months (range 0-16). Thirty-three (55%) patients received palliative radiotherapy, 27 (45%) had PEG tube and 17 (28%) tracheostomy. Thirty-seven (66%) patients visited an emergency department (ED) (median 1.3 visits; range 0-6) and 21 (35%) were hospitalised at the university hospital during the palliative period. The most common severe complications were infection (also the most common reason for ED visits and hospitalisation), bleeding (four massive airway bleedings with one death), delirium and airway obstruction (one emergency tracheostomy). Twelve (35%) out of the 34 patients who were referred to specialised home care died at home as compared with three (12%) out of the 26 patients not supported by a specialised home-care team. CONCLUSIONS: Severe complications leading to an emergency unit visit and hospitalisation are common among HNC patients in their relatively short palliative period reflecting the need for early-integrated palliative care. Collaboration with a specialised palliative home-care team seems to increase end of-life care at home. PMID- 29247266 TI - A Systematic Review of Behavioral Interventions to Reduce Condomless Sex and Increase HIV Testing for Latino MSM. AB - Latino men who have sex with men (MSM) in the United States are disproportionately affected by HIV, and there have been calls to improve availability of culturally sensitive HIV prevention programs for this population. This article provides a systematic review of intervention programs to reduce condomless sex and/or increase HIV testing among Latino MSM. We searched four electronic databases using a systematic review protocol, screened 1777 unique records, and identified ten interventions analyzing data from 2871 Latino MSM. Four studies reported reductions in condomless anal intercourse, and one reported reductions in number of sexual partners. All studies incorporated surface structure cultural features such as bilingual study recruitment, but the incorporation of deep structure cultural features, such as machismo and sexual silence, was lacking. There is a need for rigorously designed interventions that incorporate deep structure cultural features in order to reduce HIV among Latino MSM. PMID- 29247267 TI - Diagnostic approaches for pericardial effusions : Beyond mere cytopathology. PMID- 29247268 TI - [Anticoagulation strategies in patients with deep vein thrombosis and pulmonary artery embolisms]. AB - Deep vein thrombosis and pulmonary artery embolisms share pathophysiological features and are therefore collectively referred to as venous thromboembolisms (VTE). While the incidence of VTE has been increasing for years as a result of demographic changes and improved diagnostics, the morbidity and mortality are decreasing. This is particularly due to more sensitive diagnostics, improvements in risk stratification and more effective anticoagulation strategies. The aim of effective anticoagulation therapy is the avoidance of early events up to death and prevention of recurrent events. Anticoagulation treatment should be started with either heparins (unfractionated or low molecular weight), the pentasaccharide fondaparinux or direct oral anticoagulants. Patients with recurrent events qualify for indefinite anticoagulation treatment. For a first episode of VTE anticoagulation treatment for at least 3 months is recommended (maintenance therapy). Subsequently, prolonged maintenance therapy for secondary prevention can be meaningful, depending on the individual patient risk (provoked event, risk for recurrence or bleeding). The non-vitamin K antagonist oral anticoagulants (NOACs) have now also been approved for this indication. As a result of a probably permanently high risk for recurrent events of up to 10% per year after cessation of anticoagulation, insufficient scores for estimation of the risk of bleeding and recent data documenting the safety and efficacy of NOACs for secondary prevention, a shift towards prolonged anticoagulation of 3-6 months or even indefinite (>1 year) treatment can be anticipated for patients after thromboembolic diseases. PMID- 29247270 TI - Surface Nanostructures Formed by Phase Separation of Metal Salt-Polymer Nanocomposite Film for Anti-reflection and Super-hydrophobic Applications. AB - This paper describes a simple and low-cost fabrication method for multi functional nanostructures with outstanding anti-reflective and super-hydrophobic properties. Our method employed phase separation of a metal salt-polymer nanocomposite film that leads to nanoisland formation after etching away the polymer matrix, and the metal salt island can then be utilized as a hard mask for dry etching the substrate or sublayer. Compared to many other methods for patterning metallic hard mask structures, such as the popular lift-off method, our approach involves only spin coating and thermal annealing, thus is more cost efficient. Metal salts including aluminum nitrate nonahydrate (ANN) and chromium nitrate nonahydrate (CNN) can both be used, and high aspect ratio (1:30) and high resolution (sub-50 nm) pillars etched into silicon can be achieved readily. With further control of the etching profile by adjusting the dry etching parameters, cone-like silicon structure with reflectivity in the visible region down to a remarkably low value of 2% was achieved. Lastly, by coating a hydrophobic surfactant layer, the pillar array demonstrated a super-hydrophobic property with an exceptionally high water contact angle of up to 165.7 degrees . PMID- 29247269 TI - Late esophageal wall injury after mesh repair for large esophageal hiatal hernia: a case report. AB - BACKGROUND: Plication of an esophageal hiatus during surgery for esophageal hiatal hernia is a common practice; however, a mesh may be used if the hiatus is markedly enlarged. Recently, various late complications occurring as a result of mesh-induced esophageal and/or gastric wall injuries have been reported. CASE PRESENTATION: A 71-year-old woman presented at a neighborhood clinic in November 2010 with chief complaints of respiratory distress on exertion and heartburn. She was diagnosed as having a large esophageal hiatal hernia and was treated at our hospital using a laparoscopic Toupet fundoplication with mesh repair of the esophageal hiatus. Two years and 1 month after the operation, the patient complained of a bowel obstruction. An upper gastrointestinal endoscopy revealed that part of the mesh had extruded into the esophageal lumen, resulting in ulceration and stricture of the esophageal wall. Endoscopic balloon dilatation failed to improve the esophageal stricture. In July 2012, the patient underwent a lower esophagectomy with proximal gastrectomy and was discharged on the 25th hospital day. CONCLUSIONS: We experienced a rare case requiring surgical treatment for a mesh-induced esophageal wall injury after surgery for a giant esophageal hiatal hernia. The selection of a soft, durable mash and its firm securement at a position distant from the gastrointestinal wall may be important to avoid late esophageal wall injury. PMID- 29247271 TI - A Cost-Effectiveness Analysis to Evaluate a System Change in Mental Healthcare in the Netherlands for Patients with Depression or Anxiety. AB - Over the last decade, the Dutch mental healthcare system has been subject to profound policy reforms, in order to achieve affordable, accessible, and high quality care. One of the adjustments was to substitute part of the specialized care for general mental healthcare. Using a quasi-experimental design, we compared the cost-effectiveness of patients in the new setting with comparable patients from specialized mental healthcare in the old setting. Results showed that for this group of patients the average cost of treatment was significantly reduced by, on average, ?2132 (p < 0.001), with similar health outcomes as in the old system. PMID- 29247272 TI - Interferonregulatoryfactor-8(IRF-8) regulates the expression of matrix metalloproteinase-13 (MMP-13) in chondrocytes. AB - Low levels of inflammation-induced expression of matrix metalloproteinase (MMP) play a crucial role in articular cartilage matrix destruction in osteoarthritis (OA) patients. Interferon regulatory factor-8 (IRF-8), an important member in the IRF family, plays a key role in regulating the inflammation-related signaling pathway. The aim of this study is to investigate the physiological roles of IRF-8 in the pathological progression of OA. We found that IRF-8 was expressed in human primary chondrocytes. Interestingly, the expression of IRF-8 was upregulated in OA chondrocytes. In addition, IRF-8 was increased in response to interleukin 1beta (IL-1beta) treatment, mediated by the Janus kinase 2 (JAK2) pathway. Overexpression of IRF-8 in human chondrocytes by transduction with lentiviral-IRF 8 exacerbated IL-1beta-induced expression of matrix metalloproteinase-13 (MMP-13) in human chondrocytes. In contrast, knockdown of IRF-8 inhibited IL-1beta-induced expression of MMP-13. Importantly, IRF-8 could bind to the promoter of MMP-13 and stimulate its activity. Additionally, overexpression of IRF-8 exacerbated IL 1beta-induced degradation of type II collagen. However, silencing IRF-8 abrogated the degradation of type II collagen. Taken together, our findings identified a novel function of IRF-8 in regulating articular cartilage matrix destruction by promoting the expression of MMP-13. PMID- 29247274 TI - Procedural sedation and analgesia practices by emergency physicians in the Netherlands: a nationwide survey. AB - BACKGROUND: Several efforts have been made to assure and to improve the quality of procedural sedation and analgesia (PSA) performed by emergency physicians (EPs) in The Netherlands. This study investigated the current PSA practice and competences of EPs in both adult and paediatric patients. In particular, if residency and current training, awareness of guidelines is sufficient for registered EPs to adequately perform PSA and if the availability of both adult and paediatric PSA in the ED is adequate. METHODS: A cross-sectional nationwide survey was performed amongst Dutch EPs (n = 463) in June 2016. We collected data on background, training, practice, and competencies of both adult and paediatric PSA. We investigated guideline adherence, reasons for not performing PSA, and desired improvements. RESULTS: The respondents (n = 191) represented 84.6% hospitals with EPs and 41.3% of all EPs in The Netherlands. Nearly all EPs (97.8%) performed PSA in adult patients compared to only 59.1% who performed PSA in paediatric patients (p < 0.001). The major reason for not performing paediatric PSA was caused by a lack of exposure during the training-program (74.1%). PSA-guideline knowledge (98.3%) and PSA related adverse event registration (98.3%) were excellent. Lack of 24/7-availability of both adult and paediatric emergency department PSA was mainly caused by a shortage of EPs. Self reflection indicated that EPs feel less competent in performing paediatric PSA when compared to adult PSA. CONCLUSION: This nationwide survey demonstrates that there is still a significant gap between the performance of adult and paediatric PSA even though guideline adherence and registration of PSA-related adverse events appear to be adequate. Enhancement of paediatric PSA training in combination with an increase of EP-staffing can help improve the availability of adult and paediatric PSA in the emergency department. PMID- 29247273 TI - Live high-train low guided by daily heart rate variability in elite Nordic skiers. AB - PURPOSE: To analyze if live high-train low (LHTL) effectiveness is improved when daily training is guided by heart rate variability (HRV). METHODS: Twenty-four elite Nordic skiers took part in a 15-day LHTL study and were randomized into a HRV-guided training hypoxic group (H-HRV, n = 9, sleeping in normobaric hypoxia, FiO2 = 15.0%) and two predefined training groups sleeping either in hypoxia (H, n = 9, FiO2 = 15.0%) or normoxia (N, n = 6). HRV and training loads (TL) were recorded daily. Prior (Pre), one (Post-1), and 21 days (Post-21) following LHTL, athletes performed a 10-km roller-ski test, and a treadmill test for determination of [Formula: see text] was performed at Pre and Post-1. RESULTS: Some HRV parameters measured in supine position were different between H-HRV and H: low and high (HF) frequency power in absolute (ms2) (16.0 +/- 35.1 vs. 137.0 +/- 54.9%, p = 0.05) and normalized units (- 3.8 +/- 10.1 vs. 53.0 +/- 19.5%, p = 0.02), HF(nu) (6.3 +/- 6.8 vs. - 13.7 +/- 8.0%, p = 0.03) as well as heart rate (3.7 +/- 6.3 vs. 12.3 +/- 4.1%, p = 0.008). At Post-1, [Formula: see text] was improved in H-HRV and H (3.8 +/- 3.1%; p = 0.02 vs. 3.0 +/- 4.4%; p = 0.08) but not in N (0.9 +/- 5.1%; p = 0.7). Only H-HRV improved the roller-ski performance at Post-21 (- 2.7 +/- 3.6%, p = 0.05). CONCLUSION: The daily individualization of TL reduced the decrease in autonomic nervous system parasympathetic activity commonly associated with LHTL. The improved performance and oxygen consumption in the two LHTL groups confirm the effectiveness of LHTL even in elite endurance athletes. PMID- 29247275 TI - Protective Effect of miR-374a on Chemical Hypoxia-Induced Damage of PC12 Cells In Vitro via the GADD45alpha/JNK Signaling Pathway. AB - To explore the effect of microRNA-374a (miR-374a) on chemical hypoxia-induced pheochromocytoma (PC12) cell damage by mediating growth arrest and the DNA damage 45 alpha (GADD45alpha)/c-Jun N-terminal kinase (JNK) signaling pathway. PC12 cells were divided into a Control group (no treatment), Model group (treated with CoCl2 for 24 h), negative control (NC) group (transfected with miR-374a negative control sequence and treated with CoCl2 for 24 h), and miR-374a mimic group (transfected with miR-374a mimics and treated with CoCl2 for 24 h). The viability and apoptosis of PC12 cells were determined by the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry, while the mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) content were assessed by Rh123 and dichloro-dihydro-fluorescein diacetate (DCFH-DA) methods. The expression of miR-374a and GADD45alpha/JNK proteins was detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. A significant decrease was found in the survival rate, MMP and miR 374a expression, while an increase was shown in the ROS content and GADD45alpha and p-JNK expression in hypoxic PC12 cells (all P < 0.05). A luciferase reporter gene assay demonstrated that GADD45alpha is the target gene of miR-374a. When transfected with miR-374a mimics, hypoxic PC12 cells showed an obvious elevation in survival rate and MMP but a great reduction in cell apoptosis and ROS content, as well as in the expression of GADD45alpha and p-JNK proteins (all P < 0.05). MiR-374a can protect PC12 cells against hypoxia-induced injury by inhibiting the GADD45alpha/JNK pathway, enhancing cell viability, suppressing oxidative stress, and inhibiting cell apoptosis, thereby becoming a potential therapeutic target for hypoxic damage. PMID- 29247276 TI - Long non-coding RNA BDNF-AS modulates osteogenic differentiation of bone marrow derived mesenchymal stem cells. AB - For patients with osteoporosis, the inability of osteogenic differentiation is the key reason for bone loss. In this study, we investigated the expression and function of long non-coding RNA BDNF-AS in mesenchymal stem cell-derived osteogenic differentiation. Mouse bone marrow-derived mesenchymal stem cells (BMMSCs) were cultured in vitro and induced toward osteogenic differentiation. Quantitative real-time PCR (qRT-PCR) was used to evaluate gene expressions of BDNF-AS and BDNF during osteogenic differentiation. BMMSCs were also extracted from ovariectomized (OVX) mice. The dynamic change of BDNF-AS in OVX-derived BMMSCs during osteogenic differentiation was also evaluated. Lentivirus was used to upregulate BDNF-AS in BMMSCs. The effects of BDNF-AS upregulation on BMMSCs' proliferation and osteogenic differentiation were then evaluated. In addition, qRT-PCR and western blot were applied to further examine the effect of BDNF-AS upregulation on osteogenesis-associated signaling pathways, including BDNF, OPN, and Runx2, in osteogenic differentiation. BDNF-AS was downregulated, whereas BDNF was upregulated in osteogenic differentiation of BMMSCs. Among OVX-derived BMMSCs, BDNF-AS expression was upregulated during osteogenic differentiation. Lentivirus-induced BDNF-AS upregulation promoted BMMSCs self-proliferation but inhibited osteogenic differentiation, as demonstrated by proliferation, alizarin red staining, and alkaline phosphatase activity assays, respectively. QRT-PCR and western blot demonstrated that BDNF, OPN, and Runx2 were downregulated by BDNF-AS upregulation in the differentiated BMMSCs. BDNF-AS is dynamically regulated in osteogenic differentiation. Upregulating BDNF-AS inhibits osteogenesis, possibly through inverse regulation on BDNF and osteogenic signaling pathways. PMID- 29247277 TI - Surface pH changes suggest a role for H+/OH- channels in salinity response of Chara australis. AB - To understand salt stress, the full impact of salinity on plant cell physiology has to be resolved. Electrical measurements suggest that salinity inhibits the proton pump and opens putative H+/OH- channels all over the cell surface of salt sensitive Chara australis (Beilby and Al Khazaaly 2009; Al Khazaaly and Beilby 2012). The channels open transiently at first, causing a characteristic noise in membrane potential difference (PD), and after longer exposure remain open with a typical current-voltage (I/V) profile, both abolished by the addition of 1 mM ZnCl2, the main known blocker of animal H+ channels. The cells were imaged with confocal microscopy, using fluorescein isothiocyanate (FITC) coupled to dextran 70 to illuminate the pH changes outside the cell wall in artificial fresh water (AFW) and in saline medium. In the early saline exposure, we observed alkaline patches (bright fluorescent spots) appearing transiently in random spatial distribution. After longer exposure, some of the spots became fixed in space. Saline also abolished or diminished the pH banding pattern observed in the untreated control cells. ZnCl2 suppressed the alkaline spot formation in saline and the pH banding pattern in AFW. The osmotic component of the saline stress did not produce transient bright spots or affect banding. The displacement of H+ from the cell wall charges, the H+/OH- channel conductance/density, and self organization are discussed. No homologies to animal H+ channels were found. Salinity activation of the H+/OH- channels might contribute to saline response in roots of land plants and leaves of aquatic angiosperms. PMID- 29247278 TI - Analysis of chloroplast differences in leaves of rice isonuclear alloplasmic lines. AB - The chloroplast being an important organelle of plant cells could possibly be associated with plant cytoplasmic male sterility (CMS). To better understand the correlation between (CMS) and chloroplast, we presented a comprehensive analysis based on the changes of photosynthetic parameters, chloroplasts ultrastructure, soluble sugar and starch content, the relative expression of sugar and starch metabolism genes, and chloroplast genome in rice isonuclear alloplasmic CMS lines at the flowering stage. Leaf gas exchange parameters did not affect by CMS lines (M2BS and M2A), although intercellular CO2 concentration (C i) was influenced in both M2BS and M2A. Ultrastructural observation results indicated that many starch granules were observed in the chloroplast of CMS lines, especially bigger size in M2BS, while few ones in M2B. Only the chloroplasts of M2A contained some additional number of lipoids compared with those of the other two lines (M2B and M2BS). Soluble sugar and starch contents in CMS lines (M2BS and M2A) were significantly higher than those in maintainer line (M2B) (p < 0.01). The relative expression of sugar and starch metabolism genes indicated the imbalance of starch and sugar synthesis and decomposition may lead to accumulation of starch granules and demonstrated the presence of cytoplasmic effects. Moreover, chloroplast genome sequencing results showed similarity in both CMS lines, which revealed different single nucleotide polymorphisms (SNPs) and insertion/deletion (InDels) models compared with their maintainer line. Those models were located in psbD, rpoC2, rpl33, psbB, ndhA, ndhH, and intergenic regions. These findings, aligned with the possible association of CMS characteristics with cpDNA and genetically close relationship among both CMS lines, may contribute for future research. PMID- 29247279 TI - Greater Curvature Plication with Duodenal-Jejunal Bypass: a Novel Metabolic Surgery for Type 2 Diabetes Mellitus. AB - OBJECTIVE: The study investigated the use of great curvature plication with duodenal-jejunal bypass (GCP-DJB) in a type 2 diabetic with obesity rat model. METHODS: Twenty-two Sprague-Dawley rats were given a high fat and sugar diet with subsequent intraperitoneal injection of a small dosage of streptozotocin (30 mg/kg) and randomly assigned to either GCP-DJB (n = 12) or Sham surgery (n = 10). Body weight, peripheral blood glucose, and fasting serum insulin were assayed, and insulin resistance index (IRI) was calculated, before and at 1, 2, 4, and 8 weeks after surgery. RESULTS: No differences were found in the preoperative characteristics of the two groups (P > 0.05). At week 1, the body weights decreased significantly, but there was no significant difference between the two groups (P > 0.05).The fasting blood glucose was significantly lower in the GCP DJB than in the Sham group (P < 0.05), serum insulin levels were higher (P < 0.05), and IRI began to decline (P < 0.05). From 2 to 8 weeks, the body weight of Sham group gradually recovered and continued to rise, while the GCP-DJB group remained at a relatively lower state. Compared to the Sham group, the body weight, fasting blood glucose as well as IRI of GCP-DJB rats had significantly decreased (P < 0.05). But, the fasting insulin concentrations had significantly increased (P < 0.05). CONCLUSION: This novel GCP-DJB procedure established a stable animal model for the study of metabolic surgery to treat type 2 diabetes mellitus (T2DM). PMID- 29247280 TI - Rothia dentocariosa endophthalmitis following intravitreal injection-a case report. AB - PURPOSE: This report describes the first recognised case of Rothia dentocariosa endophthalmitis following intravitreal injection. CASE REPORT: A 57-year-old indigenous Australian diabetic female developed pain, redness and decreased vision 3 days after intravitreal aflibercept injection to the right eye administered for diabetic vitreous haemorrhage with suspected macular oedema and proliferative diabetic retinopathy. Examination revealed best corrected visual acuity (BCVA) of hand movements, ocular hypertension and marked anterior chamber inflammation. The left eye was unaffected but had a BCVA of 6/24 due to pre existing diabetic retinopathy. Vitreous culture isolated Rothia dentocariosa as the organism responsible for the endophthalmitis. The following treatment with intraocular cephazolin, vancomycin and ceftazidime, topical ciprofloxacin and gentamicin and systemic ciprofloxacin, the patient underwent vitrectomy. Nine weeks after onset, the patient's BCVA had improved to 6/36, and fundal examination revealed extensive retinal necrosis. CONCLUSION: Rothia dentocariosa is presented as a rare cause of endophthalmitis following intravitreal injection and reports the appearance of 'pink hypopyon' previously observed with other organisms. Its identification also demonstrates the risk of oral bacterial contamination during intraocular injections. Vigilance with strategies to minimise bacterial contamination in the peri-injection period are important. Further research to identify additional techniques to prevent contamination with oral bacteria would be beneficial, including whether a role exists for patients wearing surgical masks during intravitreal injections. PMID- 29247281 TI - St. Rene Goupil: the patron saint of anesthesia. PMID- 29247282 TI - Camellia euphlebia exerts its antidepressant-like effect via modulation of the hypothalamic-pituitary-adrenal axis and brain monoaminergic systems. AB - Camellia euphlebia (family, Theaceae) is a Chinese folk medicine, known for its multiple pharmacological properties. The present study aimed to provide further insights into the therapeutic basis of C. euphlebia using several animal behavioral tests and physiological indexes. Tail suspension test, forced swimming test, open-field test, chronic unpredictable mild stress (CUMS), reversal of reserpine-induced hypothermia and palpebral ptosis, and 5-hydroxytryptophane induced head-twitch response were used to evaluate the antidepressant effect of aqueous extract of Camellia euphlebia (AEC) on mice. The possible underlying mechanism was explored by investigating the changes associated with several parameters of animal behavior, as well as the changes in monoamine neurotransmitter and stress hormone levels in these animals during the tests. Mice administered AEC at 100 and 200 mg/kg/day doses for 7 days showed significantly reduced immobility duration in forced swimming test and tail suspension test, whilst exhibiting no apparent changes in locomotor activity. Additionally, administration of AEC also effectively antagonized reserpine induced palpebral ptosis and hypothermia and enhanced 5-hydroxytryptophane induced head-twitch response. AEC significantly elevated the levels of serotonin, noradrenaline and dopamine in the blood and brain compared to non-treated mice. After 28 days of administration, the maximum AEC dose (100 mg/kg/day) significantly reversed CUMS-induced inhibition of weight gain and sucrose intake, while decreasing the levels of plasma adrenocorticotropic hormone and serum corticosterone. The antidepressant effect of AEC appeared to involve the alteration of hypothalamic-pituitary-adrenal axis and monoaminergic systems. PMID- 29247283 TI - Reply to 'Single high dose versus repeated bone-targeted radionuclide therapy'. PMID- 29247285 TI - Antioxidant-Based Eutectics of Irbesartan: Viable Multicomponent Forms for the Management of Hypertension. AB - The present research work highlights the development of multicomponent solid form of the antihypertensive drug irbesartan (IRB) to improve its biopharmaceutical attributes. Mechanochemical synthesis of a new solid form of IRB with coformers having antioxidant properties (syringic acid, nicotinic acid, and ascorbic acid) resulted into three eutectic mixtures (EMs). Formation of eutectic was ascertained by differential scanning calorimetry whereas exact stoichiometry (50/50% w/w) was established by phase diagram and Tamman's triangle. The strong homomeric interaction between individual components and steric hindrances is responsible for the eutectic formation. EMs exhibited superior apparent solubility (five- to nine fold) and significant enhancement in intrinsic dissolution rate (two- to three fold) as compared to the plain drug. In vivo pharmacokinetic and in vivo pharmacodynamic studies revealed a significant improvement in the biopharmaceutical performance of EMs. Marked protection against oxidative stress was observed in EMs over plain drug by controlling the level/activity of plasma H2O2 and antioxidant enzymes (superoxide dismutase and catalase) in the kidney matrix of dexamethasone (Dexa)-induced hypertensive rats. Thus, these solid forms of IRB can serve as viable multicomponent forms to be translated into product development for better therapeutic efficacy in the management of hypertension. PMID- 29247286 TI - Social relationship and hair cortisol level in captive male chimpanzees (Pan troglodytes). AB - Understanding how social relationships affect long-term stress is important because stress has a profound impact on the welfare of animals and social relationships often exert a strong influence on their stress responses. The purpose of this study was to investigate the relationship between social behaviors and long-term stress levels as assessed by hair cortisol (HC) concentration. The subjects were 11 chimpanzees living in an all-male group (divided into two sub-groups) in Kumamoto Sanctuary, Kyoto University, Japan. Behavioral data were collected between December 2014 and March 2015. The total observation time was 129 h. Hair samples were collected in late March and early April 2015, and cortisol was extracted from the hair and measured with enzyme immunoassay. The hair growth rate was estimated to be 1.33 +/- 0.06 cm/month. The results revealed that there was a positive correlation between the rate of receiving aggression and HC levels. We also found a significant negative correlation between the balance between giving and receiving grooming (grooming balance index: GBI), which was calculated by subtracting the rate with which grooming is given from that with which it is received, and the rate of receiving aggression and between the GBI and HC levels. Thus, individuals receiving higher levels of aggression also tended to give grooming for relatively long periods compared to the time they were being groomed. In contrast, the rate of initiating aggression did not have a relationship with either HC levels or any measure of social grooming. We did not find social buffering effects, as there was no correlation between mutual social grooming and HC levels. These results show that not only aggressive interactions but also overall social situations in which animals do not have balanced relationships with others might result in the long term elevation of cortisol levels in captive male chimpanzees. PMID- 29247284 TI - Third-line treatment and 177Lu-PSMA radioligand therapy of metastatic castration resistant prostate cancer: a systematic review. AB - AIMS: There is a controversy as to the relative efficacy of 177Lu prostate specific membrane antigen (PSMA) radioligand therapy (RLT) and third-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). The aim of our systematic review was to elucidate whether 177Lu-PSMA RLT and third-line treatment have similar effects and adverse effects (PROSPERO ID CRD42017067743). METHODS: The review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Searches in Pubmed and Embase selected articles up to September 2017. A search in ClinicalTrials.gov indicated ongoing studies. The meta-analysis used the random-effects model. RESULTS: Twelve studies including 669 patients reported 177Lu-PSMA RLT. Overall, 43% of the patients had a maximum decline of PSA of >=50% following treatment with 177Lu-PSMA RLT. The treatment with 177Lu-PSMA-617 and 177Lu-PSMA for imaging and therapy (I&T) had mainly transient adverse effects. Sixteen studies including 1338 patients reported third-line treatment. Overall, 21% of the patients had a best decline of PSA of >=50% following third-line treatment. After third-line treatment with enzalutamide and cabazitaxel, adverse effects caused discontinuation of treatment for 10% to 23% of the patients. 177Lu-PSMA RLT gave a best PSA decline >=50% more often than third-line treatment (mean 44% versus 22%, p = 0.0002, t test). 177Lu-PSMA RLT gave objective remission more often than third-line treatment (overall 31 of 109 patients versus 43 of 275 patients, p = 0.004, chi2 test). Median survival was longer after 177Lu-PSMA RLT than after third-line treatment, but the difference was not statistically significant (mean 14 months versus 12 months, p = 0.32, t test). Adverse effects caused discontinuation of treatment more often for third-line treatment than for 177Lu PSMA RLT (22 of 66 patients versus 0 of 469 patients, p < 0.001, chi2 test). CONCLUSIONS: As for patients with mCRPC, treatment with 177Lu-PSMA-617 RTL and 177Lu-PSMA I&T gave better effects and caused fewer adverse effects than third line treatment. PMID- 29247287 TI - [The role of psychopharmacotherapy in the development of social psychiatry in Germany]. AB - Early experiences and indications are reported that psychopharmacotherapy, particularly as prophylactic long-term medication for prevention of relapses, has led to an increased recognition of social determinants of the course of illness, especially in schizophrenic patients. As a result, institutions combining both social and psychopharmacological treatment have developed, e. g., in Berlin beginning with "Phonix" a transition home ("Ubergangsheim") in 1956 to a catamnesis for long-term outpatient treatment of schizophrenic patients in 1957, a social service in 1960, a day and night hospital in 1962 up to a university department of social psychiatry in 1972 with a rich spectrum of facilities for a step by step rehabilitation of mentally ill patients. In comparison with well known humanistic sources of German psychiatric reform, some less well-known sources based on psychopharmacotherapeutic experiences that need further historical elaboration are considered. Questions include: 1. how psychiatric pharmacotherapy has influenced the development of social psychiatry in Germany, 2. whether the pioneering spirit of the 1950s, initiated by new treatment with psychotropic drugs has influenced or fostered the development of social psychiatry in Germany, 3. whether retardation of the development of social psychiatry in Germany (as opposed to England, France, and Canada and possibly related to its post-war international isolation) has been overcome not least by the new scientific development of psychopharmacology that has encouraged renewal of international contacts. In any case the possible influence of psychopharmacotherapy should not be missing in an overall view of the development of social psychiatry in Germany. PMID- 29247288 TI - Characterization of genome-wide microsatellite markers in rabbitfishes, an important resource for artisanal fisheries in the Indo-West Pacific. AB - Rabbitfishes are reef-associated fishes that support local fisheries throughout the Indo-West Pacific region. Sound management of the resource requires the development of molecular tools for appropriate stock delimitation of the different species in the family. Microsatellite markers were developed for the cordonnier, Siganus sutor, and their potential for cross-amplification was investigated in 12 congeneric species. A library of 792 repeat-containing sequences was built. Nineteen sets of newly developed primers, and 14 universal finfish microsatellites were tested in S. sutor. Amplification success of the 19 Siganus-specific markers ranged from 32 to 79% in the 12 other Siganus species, slightly decreasing when the genetic distance of the target species to S. sutor increased. Seventeen of these markers were polymorphic in S. sutor and were further assayed in S. luridus, S. rivulatus, and S. spinus, of which respectively 9, 10 and 8 were polymorphic. Statistical power analysis and an analysis of molecular variance showed that subtle genetic differentiation can be detected using these markers, highlighting their utility for the study of genetic diversity and population genetic structure in rabbitfishes. PMID- 29247289 TI - Explaining the singlet complexes detected for the reaction Zr(3F) + CH3CH3 through a non-spin flip scheme. AB - Energy profiles for the lowest lying triplet and singlet electronic pathways that link the reactants Zr + CH3CH3 with the products observed under matrix-isolation conditions were obtained from DFT and CASSCF-MRMP2 calculations. The insertion of the metal into the C-H bond of the organic molecule to yield the oxidative addition product is not favorable for any of the investigated channels. However, the inserted structure H-Zr-CH2CH3 can be obtained from two sequential reactions involving the radical species ZrH and CH2CH3. According to this scheme, a first reaction produces the radical fragments from the ground state of the reactants. Then, the radicals can recombine themselves in a second reaction to form the inserted species H-Zr-CH2CH3. As the triplet and singlet radical asymptotes ZrH + CH2CH3 that vary only in spin of the non-metallic fragment are degenerate, the rebounding of the radicals can occur through both multiplicity channels. It is shown that the low spin channel leads to the most stable structures of the dihydride ZrH2-(CH2)2 and the vinyl metal trihydride complexes ZrH3-CH=CH2 experimentally determined for this reaction under matrix-isolation conditions. The description attained for this interaction does not invoke interactions between the triplet and singlet electronic states emerging from the reactants, as proposed by other authors. PMID- 29247290 TI - Indirect effects of mutualism: ant-treehopper associations deter pollinators and reduce reproduction in a tropical shrub. AB - Animal-pollinated plants can be susceptible to changes in pollinator availability. Honeydew-producing treehoppers frequently occur on inflorescences, potentially enhancing ant-mediated negative effects on pollination services. However, the effect of ant-attended, honeydew-producing insects on plant reproduction remains uncertain. We recorded the abundance of treehoppers and ants on Byrsonima intermedia (Malpighiaceae), and monitored floral visitors in a Brazilian cerrado savanna. We manipulated the presence of ants and ant-treehopper associations on inflorescences to assess their effect on pollination and fruit formation. We used dried ants pinned to inflorescences to evaluate the effect of ant presence and ant identity on potential pollinators. Results show that the presence of treehoppers increases ant abundance on flowers and disrupts pollination by oil-collecting bees, decreasing the frequency and duration of floral visits and reducing fruit and seed set. Treehopper herbivory has no direct effect on fruit or seed production, which are independent of treehopper density. Pinned ants promote avoidance by floral visitors, reducing the number of visits. Ant identity mediates visitation decisions, with Ectatomma brunneum causing greater avoidance by floral visitors than Camponotus rufipes. Field videos show that pollinating bees are harassed by ants near flowers, prompting avoidance behavior by the bees. This is the first demonstration of indirect effects by honeydew-gathering ants, via disrupted pollination, on plant reproduction in tropical cerrado savanna. Our results highlight the importance of studying other interactions near flowers, in addition to just observing pollinators, for a proper understanding of plant reproduction. PMID- 29247292 TI - Enhanced multiple stress tolerance in Arabidopsis by overexpression of the polar moss peptidyl prolyl isomerase FKBP12 gene. AB - KEY MESSAGE: PaFKBP12 overexpression in Arabidopsis resulted in stress tolerance to heat, ABA, drought, and salt stress, in addition to growth promotion under normal conditions. Polytrichastrum alpinum (alpine haircap moss) is one of polar organisms that can withstand the severe conditions of the Antarctic. In this study, we report the isolation of a peptidyl prolyl isomerase FKBP12 gene (PaFKBP12) from P. alpinum collected in the Antarctic and its functional implications in development and stress responses in plants. In P. alpinum, PaFKBP12 expression was induced by heat and ABA. Overexpression of PaFKBP12 in Arabidopsis increased the plant size, which appeared to result from increased rates of cell cycle. Under heat stress conditions, PaFKBP12-overexpressing lines (PaFKBP12-OE) showed better growth and survival than the wild type. PaFKBP12-OE also showed higher root elongation rates, better shoot growth and enhanced survival at higher concentrations of ABA in comparison to the wild type. In addition, PaFKBP12-OE were more tolerant to drought and salt stress than the wild type. All these phenotypes were accompanied with higher induction of the stress responsive genes in PaFKBP12-OE than in the wild type. Taken together, our findings revealed important functions of PaFKBP12 in plant development and abiotic stress responses. PMID- 29247293 TI - Work-related social support modulates effects of early life stress on limbic reactivity during stress. AB - Early life stress (ELS) affects stress- reactivity via limbic brain regions implicated such as hippocampus and amygdala. Social support is a major protective factor against ELS effects, while subjects with ELS experience reportedly perceive less of it in their daily life. The workplace, where most adults spend a substantial amount of time in their daily lives, might serve as a major resource for social support. Since previous data demonstrated that social support attenuates stress reactivity, we here used a psychosocial stress task to test the hypothesis that work-related social support modulates the effects of ELS. Results show decreased amygdala reactivity during stress in ELS subjects who report high levels of work- related social support, thereby indicating a signature for reduced stress reactivity. However, this effect was only observable on the neural, but not on the behavioral level, since social support had no buffering effect regarding the subjective experience of stress in daily life as well as regarding feelings of uncontrollability induced by the stress task. Accordingly, our data suggest that subjects with ELS experiences might benefit from interventions targeted at lowering their subjective stress levels by helping them to better perceive the availability of social support in their daily lives. PMID- 29247291 TI - Multidisciplinary European Low Dose Initiative (MELODI): strategic research agenda for low dose radiation risk research. AB - MELODI (Multidisciplinary European Low Dose Initiative) is a European radiation protection research platform with focus on research on health risks after exposure to low-dose ionising radiation. It was founded in 2010 and currently includes 44 members from 18 countries. A major activity of MELODI is the continuous development of a long-term European Strategic Research Agenda (SRA) on low-dose risk for radiation protection. The SRA is intended to identify priorities for national and European radiation protection research programs as a basis for the preparation of competitive calls at the European level. Among those key priorities is the improvement of health risk estimates for exposures close to the dose limits for workers and to reference levels for the population in emergency situations. Another activity of MELODI is to ensure the availability of European key infrastructures for research activities, and the long-term maintenance of competences in radiation research via an integrated European approach for training and education. The MELODI SRA identifies three key research topics in low dose or low dose-rate radiation risk research: (1) dose and dose rate dependence of cancer risk, (2) radiation-induced non-cancer effects and (3) individual radiation sensitivity. The research required to improve the evidence base for each of the three key topics relates to three research lines: (1) research to improve understanding of the mechanisms contributing to radiogenic diseases, (2) epidemiological research to improve health risk evaluation of radiation exposure and (3) research to address the effects and risks associated with internal exposures, differing radiation qualities and inhomogeneous exposures. The full SRA and associated documents can be downloaded from the MELODI website ( http://www.melodi-online.eu/sra.html ). PMID- 29247294 TI - rCBF and cognitive impairment changes assessed by SPECT and ADAS-cog in late onset Alzheimer's disease after 18 months of treatment with the cholinesterase inhibitors donepezil or galantamine. AB - Late-onset Alzheimer's disease (AD) differs substantially from early-onset AD. In this cross sectional study we investigated brain perfusion changes after 18 months of treatment with cholinesterase inhibitors (ChEIs) donepezil or galantamine. Twenty-five drug-naive late-onset AD patients were recruited from outpatient clinics. We examined brain perfusion using single photon emission computed tomography (SPECT) and used three-dimensional stereotactic surface projection (3D-SSP) and the stereotactic extraction estimation method (SEE) level 3 to analyze classified gyrus level segments. We assessed cognitive function using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) grouped into three subgroup domains, language, memory, and praxis. In the follow up data, some regions were further hypoperfused, reflecting worsening of the disease, while other regions showed alleviated hypoperfusion, potentially related to the ChEIs treatment. Regional cerebral blood flow (rCBF) decreased in the parietal cortex and increased in the frontal and the limbic cortices. Increased hypoperfusion significantly correlated with ADAS-cog scores changes were seen in the superior parietal lobule, inferior parietal lobule, angular gyrus, and supramarginal gyrus of the parietal cortex. Alleviated hypoperfusion significantly related to recovery of ADAS-cog scores were seen in the rectal and paracentral lobule of the frontal cortex, and the anterior cingulate of the limbic cortex. These regions showed significant relationships with total ADAS-cog and language, memory and praxis subscales scores. The current longitudinal study indicates prominent rCBF changes and their relationships with changes in ADAS-cog scores in late-onset AD patients. PMID- 29247295 TI - The predictive value of drug-induced sleep endoscopy for CPAP titration in OSA patients. AB - PURPOSE: The aim of this study was to identify possible upper airway obstructions causing a higher continuous positive airway pressure (CPAP) titration level, utilizing drug-induced sleep endoscopy (DISE). METHODS: A total of 76 patients with obstructive sleep apnea (OSA) underwent CPAP titration and DISE. DISE findings were recorded using the VOTE classification system. Polysomnographic (PSG) data, anthropometric variables, and patterns of airway collapse during DISE were analyzed with CPAP titration levels. RESULTS: A significant association was found between the CPAP titration level and BMI, oxygen desaturation index (ODI), apnea-hypopnea index (AHI), and neck circumference (NC) (P < 0.001, P < 0.001, P < 0.001, and P < 0.001, respectively, by Spearman correlation). Patients with concentric collapse of the velum or lateral oropharyngeal collapse were associated with a significantly higher CPAP titration level (P < 0.001 and P = 0.043, respectively, by nonparametric Mann-Whitney U test; P < 0.001 and P = 0.004, respectively, by Spearman correlation). No significant association was found between the CPAP titration level and any other collapse at the tongue base or epiglottis. CONCLUSIONS: By analyzing PSG data, anthropometric variables, and DISE results with CPAP titration levels, we can better understand possible mechanisms resulting in a higher CPAP titration level. We believe that the role of DISE can be expanded as a tool to identify the possible anatomical structures that may be corrected by oral appliance therapy or surgical intervention to improve CPAP compliance. PMID- 29247297 TI - Assessment of coronary artery disease based on coronary flow velocity reserve by transthoracic Doppler echocardiography and coronary computed tomography angiography in a patient with dextrocardia: a case report. PMID- 29247296 TI - Decrease of perforin positive CD3+gammadelta-T cells in patients with obstructive sleep disordered breathing. AB - INTRODUCTION: Sleep related breathing disorders (SRBD) cause sleep fragmentation, intermittent hypoxia or a combination of both leading to homeostasis perturbations, including in the immune system. We investigated whether SRBD patients with or without intermittent hypoxia show substantial differences in perforin and granzyme-B positive peripheral blood lymphocytes. METHODS: A total of 87 subjects were included and distributed as follows: 24 controls (C), 19 patients with respiratory effort related arousals due to increased upper airway resistance (UAR) without hypoxic events, 24 obese patients with obstructive sleep apnea (OSA) (oOSA), and 20 without obesity (noOSA). After polysomnographic recording, we analyzed in fasting blood samples routine hematologic and biochemical parameters and the percentage of lymphocytes containing the proteins perforin and granzyme-B (GrB). Kruskal-Wallis tests and a posteriori multiple comparisons were applied for statistical analysis of results. RESULTS: Perforin positive gammadelta-cells revealed significant differences between groups (p = 0.017), especially between the Control group and the oOSA (p-value = 0.04); the remaining SRBD groups also showed differences from the control (C vs UAR: p = 0.08; C vs noOSA = 0.09), but they did not raise to statistical significance. There were no differences among the SRBD groups. Granzyme-B cells were decreased in SRBD patients, but the differences were not statistically significant. No additional statistical significant result was found in the other investigated lymphocyte subsets. CONCLUSIONS: Obstructive sleep-disordered breathing is associated with a decrease in perforin-positive CD3+gammadelta-T cells. Although this finding was detected in lean patients without intermittent hypoxia, the reduction was only statistically significant in obese patients with severe OSA. Because CD3+gammadelta-T cells play an important role in the control of tumor cells, our findings are directly relevant for the study of the association of OSA and cancer. PMID- 29247298 TI - Worsening of soft tissue dystrophic calcification in an osteoporotic patient treated with teriparatide. AB - Teriparatide, used for treatment of osteoporosis in patients at high risk of fracture risk, sometimes results in mild and transient hypercalcemia. There have been two recent reports of worsening dystrophic calcification in patients with autoimmune disorders following teriparatide treatment. We report a patient with severe osteoporosis and without a pre-existing autoimmune disorder, who developed symptomatic worsening of dystrophic calcification 4 months after teriparatide was initiated. Symptoms resolved within 1 week of teriparatide cessation. PMID- 29247299 TI - Influence of Body Odors and Gender on Perceived Genital Arousal. AB - Olfaction is often linked to mating behavior in nonhumans. Additionally, studies in mating behavior have shown that women seem to be more affected by odor cues than men. However, the relationship between odor cues and sexual response specifically, sexual arousal-has not been studied yet. The aim of this study was to evaluate the impact of the exposure to human body odors (from individuals of the opposite gender) on perceived genital arousal, while these were presented concomitantly to sexually explicit video clips. Eighty university students (40 women) rated their perceived genital arousal (perceived degree of erection/genital lubrication) in response to an audiovisual sexual stimulus, while simultaneously exposed to a body odor from an opposite-gender donor or no odor. Participants also rated each odor sample's (body odor and no odor) perceived pleasantness, intensity, and familiarity. Findings indicated that odor condition had an effect on women's (but not men's) perceived genital arousal, with women showing higher levels of perceived genital arousal in the no odor condition. Also, results showed that women rated body odors as less pleasant than no odor. Notwithstanding, the odor ratings do not seem to explain the association between body odor and perceived genital arousal. The current results support the hypothesis that women, rather than men, are sensitive to odors in the context of sexual response. The findings of this study have relevance for the understanding of human sexuality with respect to chemosensory communication. PMID- 29247300 TI - Monte Carlo-based quantitative pinhole SPECT reconstruction using a ray-tracing back-projector. AB - BACKGROUND: Monte Carlo simulations provide accurate models of nuclear medicine imaging systems as they can properly account for the full physics of photon transport. The accuracy of the model included in the maximum-likelihood expectation-maximization (ML-EM) reconstruction limits the overall accuracy of the reconstruction results. In this paper, we present a Monte Carlo-based ML-EM reconstruction method for pinhole single-photon emission computed tomography (SPECT) that has been incorporated into the SIMIND Monte Carlo program. The Monte Carlo-based model, which accounts for all of the physical and geometrical characteristics of the camera system, is used in the forward-projection step of the reconstruction, while a simpler model based on ray-tracing is used for back projection. The aim of this work was to investigate the quantitative accuracy of this combination of forward- and back-projectors in the clinical pinhole camera GE Discovery NM 530c. RESULTS: The total activity was estimated in 99mTc-filled spheres with volumes between 0.5 and 16 mL. The total sphere activity was generally overestimated but remained within 10% of the reference activity defined by the phantom preparation. The recovered activity converged towards the reference activity as the number of iterations increased. Furthermore, the recovery of the activity concentrations within the physical boundaries of the spheres increased with increasing sphere volume. Additionally, the Monte Carlo based reconstruction enabled recovery of the true activity concentration in the myocardium of a cardiac phantom mounted in a torso phantom regardless of whether the torso was empty or water-filled. A qualitative comparison to data reconstructed using the clinical reconstruction algorithm showed that the two methods performed similarly, although the images reconstructed using the clinical software were more uniform due to the incorporation of noise regularization and post-filtration in that reconstruction technique. CONCLUSIONS: We developed a Monte Carlo-based reconstruction method for pinhole SPECT and evaluated it using phantom measurements. The combination of a Monte Carlo-based forward-projector and a simplified analytical ray-tracing back-projector produced quantitative images of acceptable image quality. No explicit calibration is necessary in this method since the forward-projector model maintains a relationship between the number of counts and activity. PMID- 29247301 TI - An Investigation on a Crystalline-Silicon Solar Cell with Black Silicon Layer at the Rear. AB - Crystalline-Si (c-Si) solar cell with black Si (b-Si) layer at the rear was studied in order to develop c-Si solar cell with sub-band gap photovoltaic response. The b-Si was made by chemical etching. The c-Si solar cell with b-Si at the rear was found to perform far better than that of similar structure but with no b-Si at the rear, with the efficiency being increased relatively by 27.7%. This finding was interesting as b-Si had a large specific surface area, which could cause high surface recombination and degradation of solar cell performance. A graded band gap was found to form at the rear of the c-Si solar cell with b-Si layer at the rear. This graded band gap tended to expel free electrons away from the rear, thus reducing the probability of electron-hole recombination at b-Si and improving the performance of c-Si solar cell. PMID- 29247302 TI - Purification of Target Proteins from Native Tissues: CCT Complex from Bovine Testes and PP2Ac from Porcine Brains. AB - Proteomics is a powerful approach for systematic identification and quantification of the entire proteome of a biological system (cell, tissue, organ, biological fluid, or organism) at specific time points ( http://www.nature.com ). Extracting and purifying target proteins from native tissues are essential steps for many aspects of proteomic studies. In this chapter, we will introduce the experimental procedures to obtain soluble proteins from two different tissues: (1) the CCT (cpn-containing TCP-1) complex from bovine testes and (2) the protein phosphatase 2A (PP2A) catalytic subunit (PP2Ac or C) from porcine brains. With these two examples, we would like to provide some general guidelines for researchers on how to extract and purify target proteins from specific tissues and extend these approaches to other proteins of interest. PMID- 29247303 TI - Root cone angle is enlarged in docs1 LRR-RLK mutants in rice. AB - BACKGROUND: The DEFECTIVE IN OUTER CELL LAYER SPECIFICATION 1 (DOCS1) gene belongs to the Leucine-Rich Repeat Receptor-Like Kinase (LRR-RLK) subfamily. It has been discovered few years ago in Oryza sativa (rice) in a screen to isolate mutants with defects in sensitivity to aluminum. The c68 (docs1-1) mutant possessed a nonsense mutation in the C-terminal part of the DOCS1 kinase domain. FINDINGS: We have generated a new loss-of-function mutation in the DOCS1 gene (docs1-2) using the CRISPR-Cas9 technology. This new loss-of-function mutant and docs1-1 present similar phenotypes suggesting the original docs1-1 was a null allele. Besides the aluminum sensitivity phenotype, both docs1 mutants shared also several root phenotypes described previously: less root hairs and mixed identities of the outer cell layers. Moreover, our new results suggest that DOCS1 could also play a role in root cap development. We hypothesized these docs1 root phenotypes may affect gravity responses. As expected, in seedlings, the early gravitropic response was delayed. Furthermore, at adult stage, the root gravitropic set angle of docs1 mutants was also affected since docs1 mutant plants displayed larger root cone angles. CONCLUSIONS: All these observations add new insights into the DOCS1 gene function in gravitropic responses at several stages of plant development. PMID- 29247304 TI - Reversible Electrochemical Control over Photoexcited Luminescence of Core/Shell CdSe/ZnS Quantum Dot Film. AB - Semiconductor quantum dots (QDs) are widely used in light-emitting diodes and solar cells. Electrochemical modulation is a good way to understand the electrical and optical properties of QDs. In this work, the effects of electrochemical control on photoluminescence (PL) spectra in core/shell CdSe/ZnS QD films are studied. The results show different spectral responses for surface emission and core emission when a negative electrochemical potential is applied: the core emission is redshifted while the surface emission is blueshifted. The former is attributed to the electrostatic expansion of the excitonic wave function, due to the asymmetric distribution of adsorbed cations on the surface of the dots. The latter is attributed to the occupation of lower surface states by the injected electrons, i.e., the photoexcited electrons are more likely to be trapped onto higher surface states, leading to a blueshift of the surface emission. Both the spectral shift and the accompanying PL-quenching processes are reversible by resetting the potential. PMID- 29247306 TI - Identifying Criteria for the Evaluation of the Implications of Brain Reading for Mental Privacy. AB - Contemporary brain reading technologies promise to provide the possibility to decode and interpret mental states and processes. Brain reading could have numerous societally relevant implications. In particular, the private character of mind might be affected, generating ethical and legal concerns. This paper aims at equipping ethicists and policy makers with conceptual tools to support an evaluation of the potential applicability and the implications of current and near future brain reading technology. We start with clarifying the concepts of mind reading and brain reading, and the different kinds of mental states that could in principle be read. Subsequently, we devise an evaluative framework that is composed of five criteria-accuracy, reliability, informativity, concealability and enforceability-aimed at enabling a clearer estimation of the degree to which brain reading might be realistically deployed in contexts where mental privacy could be at stake. While accuracy and reliability capture how well a certain method can access mental content, informativity indicates the relevance the obtainable data have for practical purposes. Concealability and enforceability are particularly important for the evaluation of concerns about potential violations of mental privacy and civil rights. The former concerns the degree with which a brain reading method can be concealed from an individual's perception or awareness. The latter regards the extent to which a method can be used against somebody's will. With the help of these criteria, stakeholders can orient themselves in the rapidly developing field of brain reading. PMID- 29247305 TI - Neurologic disease in feline immunodeficiency virus infection: disease mechanisms and therapeutic interventions for NeuroAIDS. AB - Feline immunodeficiency virus (FIV) is a lentivirus that causes immunosuppression through virus-mediated CD4+ T cell depletion in feline species. FIV infection is complicated by virus-induced disease in the nervous system. FIV enters the brain soon after primary infection and is detected as FIV-encoded RNA, DNA, and proteins in microglia, macrophages, and astrocytes. FIV infection activates neuroinflammatory pathways including cytokines, chemokines, proteases, and ROS with accompanying neuronal injury and loss. Neurobehavioral deficits during FIV infection are manifested as impaired motor and cognitive functions. Several treatment strategies have emerged from studies of FIV neuropathogenesis including the therapeutic benefits of antiretroviral therapies, other protease inhibitors, anti-inflammatory, and neurotrophic compounds. Recently, insulin's antiviral, anti-inflammatory, and neuroprotective effects were investigated in models of lentivirus brain infection. Insulin suppressed HIV-1 replication in human microglia as well as FIV replication of lymphocytes. Insulin treatment diminished cytokine and chemokine activation in HIV-infected microglia while also protecting neurons from HIV-1 Vpr protein-mediated neurotoxicity. Intranasal (IN) insulin delivery for 6 weeks suppressed FIV expression in the brains of treated cats. IN insulin also reduced neuroinflammation and protected neurons in the hippocampus, striatum, and neocortex of FIV-infected animals. These morphological and molecular effects of IN insulin were confirmed by neurobehavioral studies that showed IN insulin-treated FIV-infected animals displayed improved motor and cognitive performance compared to sham-treated FIV-infected animals. Thus, FIV infection of the nervous system provides a valuable comparative in vivo model for discovering and evaluating disease mechanisms as well as developing therapeutic strategies for NeuroAIDS in humans. PMID- 29247307 TI - Attitudes towards end-of-life issues in intensive care unit among Italian anesthesiologists: a nation-wide survey. AB - BACKGROUND: The aim of this paper is to collect data on the practice of palliative care, withholding and withdrawal of life-sustaining therapies, and management of end of life (EOL) in Italian intensive care units (ICUs). METHODS: Web-based survey among Italian anesthesiologists endorsed by the Italian Society of Anesthesiology Analgesia Reanimation and Intensive Care (SIAARTI). The survey consists of 27 close-ended and 2 open-ended questions. RESULTS: Eight hundred and five persons responded to the full list of questions. The highest proportion of respondents was of 36-45 years of age (34%) and catholic (66%). Almost 70% of responders declared that palliative/supportive care are applied in their ICU in case of futility of intensive treatments. Decision on withdrawing/withholding of life-sustaining treatments resulted from team consensus in most cases (58%). In more than 70% of responders' ICUs, there is no collaboration with palliative/supportive care experts. Systematic recording of most frequent symptoms experienced by critically ill patients (e.g., pain, dyspnea, thirst) was not common. Vasopressors, extracorporeal therapies, blood component transfusions and invasive monitoring were the most commonly modified/interrupted measures in case of futility. Almost 85% of respondents have not received training in palliative/supportive care. The proportion of respondents whose institution has a palliative care team and who had training in palliative care was not homogenous across the country. CONCLUSIONS: These data suggest that training in palliative care and its clinical application should be implemented in Italy. Efforts should be made to improve and homogenize the management of dying patients in ICU. PMID- 29247308 TI - Severe sarcopenia might be associated with a decline of physical independence in older patients undergoing chemotherapeutic treatment. AB - PURPOSE: Assessing physical reserve in older cancer patients before treatment decision-making remains challenging. The maintenance of physical independence during therapy is sometimes just as important for these patients as oncological outcomes. Recently, sarcopenia has been recognized as a possible important prognostic factor for outcome in cancer patients. We investigated the association between different levels of sarcopenia and the decline of physical independence during chemotherapy in older cancer patients (>= 65 years). METHODS: Sarcopenia was divided into presarcopenia, sarcopenia, and severe sarcopenia according to an international consensus and was related to physical independence determined by measuring instrumental activities of daily living (IADL), using binary logistic regression models. CT-based muscle mass is necessary to diagnose sarcopenia and was related to five functional tests, in order to investigate whether these easy to-perform tests could replace the more invasive CT-based muscle measurement. RESULTS: A total of 131 patients were included (median age 72 years). The prevalence of presarcopenia, sarcopenia, and severe sarcopenia was 47.7, 18.5, and 7.7%, respectively. Compared to no sarcopenia, only severe sarcopenia seemed associated with a decline of physical independence after chemotherapy (OR 5.95, 95% CI 0.76-46.48). Muscle mass was only significantly associated with muscle strength, but not with tests measuring physical function. CONCLUSION: The level of sarcopenia might be a useful tool in addition to routine oncological assessment to identify older cancer patients with increased risk of physical decline after chemotherapy. PMID- 29247309 TI - Pathological upstaging of clinical T1 renal cell carcinoma: an analysis of 115,835 patients from National Cancer Data Base, 2004-2013. AB - PURPOSE: Clinical staging is vital for treatment decision-making by renal cell carcinoma (RCC) patients. Some RCCs clinically appear T1 on CT, but are actually T3a due to extension into fat or renal vein, causing the tumor to be pathologically upstaged. The objective of this study to determine the rate, survival, and predictors of RCC upstaging, for patients with cT1 disease treated surgically. METHODS: Using the National Cancer Data Base Participant User File for RCC from 2004 to 2013, we selected AJCC cT1 patients, who underwent surgical resection and whose AJCC pathological T stage (pT) was available. Upstaging was characterized dichotomously-overall (any pT > T1) and pT3a-specific upstaging. Patient and tumor characteristics of those upstaged and not were compared using Chi-squared analyses. Multivariable logistic regression was used to analyze predictors of upstaging, and Cox proportional hazards regression was used to estimate overall survival hazards ratios. RESULTS: Overall upstaging (pT > T1) was observed in 8252 (7.1%) patients, and T3a-specific upstaging was observed in 3380 (5.4%) patients. Patients who were older, male, and had comorbidities, and tumors that were cT1b, underwent RN, and had high Fuhrman grade were at a higher risk of pathological upstaging. Upstaging led to a 40% increased risk of death compared to patients who were not upstaged. CONCLUSION: The rate of upstaging is not negligible (5-7% of the time), negatively impacts survival, and various patient and tumor characteristics can be used to predict upstaging. PMID- 29247310 TI - Identifying Autism with a Brief and Low-Cost Screening Instrument-OERA: Construct Validity, Invariance Testing, and Agreement Between Judges. AB - Simple and low-cost observational-tools to detect symptoms of Autism Spectrum Disorder (ASD) are still necessary. The OERA is a new assessment tool to screen children eliciting observable behaviors with no substantial knowledge on ASD required. The sample was 99 children aged 3-10: 76 with ASD and 23 without ASD (11/23 had intellectual disability). The 13 remained items exhibited high interrater agreement and high reliability loaded onto a single latent trait. Such model showed excellent fit indices evaluated via confirmatory factor analysis and no item showed differential function in terms of age/sex/IQ. A cutoff of five points or higher resulted in the highest sensitivity (92.75) and specificity (90.91) percentages. OERA is a brief, stable, low-cost standardized observational screening to identify ASD children. PMID- 29247311 TI - Implementing Group Prenatal Counseling for Expanded Noninvasive Screening Options. AB - Recently, practices have begun integrating cell-free DNA-based noninvasive prenatal screening as a screening option for a variety of genetic conditions. According to the National Society of Genetic Counselors, the integration of cfDNA screening into clinical prenatal practice may "significantly shift the paradigm of prenatal testing and screening for all women." The purpose of this study was to determine whether group information sessions can feasibly serve as an alternative to extended one-on-one genetic counseling for the increasing number of women making decisions about prenatal testing and screening. This study assessed the effect of group genetic information sessions coupled with abbreviated counseling on pregnant women's knowledge about and attitudes toward prenatal testing and screening. PMID- 29247312 TI - Evaluation of Breast Cancer Patients with Genetic Risk in a University Hospital: Before and After the Implementation of a Heredofamilial Cancer Unit. AB - The identification of patients at risk for breast cancer by genetic testing has proven to reduce breast cancer mortality. In 2010, due to a lack of systematization in hereditary cancer assistance in our center, we implemented a multidisciplinary Heredofamilial Cancer Unit (HFCU). We analyze if the HFCU improved the rates of referrals and preventive management of breast cancer patients with genetic risk. We retrospectively compared family history records, referrals of high-risk patients to genetic counseling, and detection and management of patients with BRCA1/2 mutations in two cohorts of breast cancer patients diagnosed before (first period: 2007-2010) and after the creation of the HFCU (second period: 2010-2013). In the first period, 893 patients were included, and 902 were included in the second. Due to the inability to establish their genetic risk, 142 patients (15.9%) vs. 70 (7.8%) were excluded from analysis (p < 0.001). Among the evaluable patients, 194 (25.8%) vs. 223 (26.8%) fulfilled one or more risk criteria (p = 0.65). Family history documentation in patient's medical records (92.4 vs. 97.8%, p < 0.001) and referral rate (26.3 vs. 52%, p < 0.0001) significantly increased in the second period. Eight BRCA1/2 mutations were detected among patients referred in the first period and 17 among those referred to the HFCU. The rate of preventive surgeries in patients with BRCA mutations significantly increased in the second period (25 vs. 76.5%, p = 0.03). In conclusion, there was a clear improvement in family history records, referrals, and preventive surgeries in breast cancer patients with genetic risk after the implementation of the HFCU. PMID- 29247313 TI - Rethinking moral distress: conceptual demands for a troubling phenomenon affecting health care professionals. AB - Recent medical and bioethics literature shows a growing concern for practitioners' emotional experience and the ethical environment in the workplace. Moral distress, in particular, is often said to result from the difficult decisions made and the troubling situations regularly encountered in health care contexts. It has been identified as a leading cause of professional dissatisfaction and burnout, which, in turn, contribute to inadequate attention and increased pain for patients. Given the natural desire to avoid these negative effects, it seems to most authors that systematic efforts should be made to drastically reduce moral distress, if not altogether eliminate it from the lives of vulnerable practitioners. Such efforts, however, may be problematic, as moral distress is not adequately understood, nor is there agreement among the leading accounts regarding how to conceptualize the experience. With this article I make clear what a robust account of moral distress should be able to explain and how the most common notions in the existing literature leave significant explanatory gaps. I present several cases of interest and, with careful reflection upon their distinguishing features, I establish important desiderata for an explanatorily satisfying account. With these fundamental demands left unsatisfied by the leading accounts, we see the persisting need for a conception of moral distress that can capture and delimit the range of cases of interest. PMID- 29247314 TI - Long-term outcomes of daily oral vs. pulsed intravenous cyclophosphamide in a non trial setting in ANCA-associated vasculitis. AB - We aimed to compare risk of death, relapse, neutropenia and infection requiring hospital admission between unselected ANCA-associated vasculitis (AAV) patients according to whether cyclophosphamide induction was by daily oral (PO) or pulse intravenous (IV) route. We identified all newly diagnosed AAV patients treated with PO or IV cyclophosphamide between March 2007 and June 2013. We used Cox and logistic regression models to compare mortality, relapse and adverse events and adjusted these for age, renal function and other significant confounders. Fifty seven patients received PO and 57 received IV cyclophosphamide. One-year survival was 86.0% in PO and 98.2% in IV patients; all-time adjusted hazard ratio (HR) for PO compared to that of IV cyclophosphamide was 1.8 (95% CI 0.3-10.6, P = 0.54). One-year relapse-free survival was 80.7% in PO compared to 87.3% in IV patients, all-time adjusted HR 3.8 (0.2-846, P = 0.37). During the first 12 months, neutropenia of <= 0.5 * 109/L occurred in 9 (16%) PO and 0 (0%) IV cyclophosphamide patients (P = 0.003). The number of patients admitted with one or more infections was 16 (28%) in the PO group and 9 (16%) in the IV group, adjusted OR 2.2 (0.6-8.6, P = 0.23). We observed an increased risk of neutropenia, a trend towards increased risk of death and an admission with infection with PO cyclophosphamide. This adds certainty to previous studies, indicating that PO administration induces greater marrow toxicity. Infection related admissions within 12 months of starting cyclophosphamide were higher than those in clinical trials, possibly reflecting the unselected nature of this cohort. PMID- 29247315 TI - Development of a copper-clioquinol formulation suitable for intravenous use. AB - Clioquinol (CQ) is an FDA-approved topical antifungal agent known to kill cancer cells. This facilitated the initiation of clinical trials in patients with refractory hematologic malignancies. These repurposing efforts were not successful; this was likely due to low intracellular levels of the drug owing to poor absorption and rapid metabolism upon oral administration. CQ forms a sparingly soluble copper complex (Cu(CQ)2) that exhibits enhanced anticancer activity in some cell lines. We have utilized a novel method to synthesize Cu(CQ)2 inside liposomes, an approach that maintains the complex suspended in solution and in a format suitable for intravenous administration. The complex was prepared inside 100-nm liposomes composed of 1,2-distearoyl-sn-glycero-3 phosphocholine/cholesterol (55:45). The therapeutic activity of the resultant formulation was evaluated in two subcutaneous tumor models (glioblastoma and ovarian cancers) but was not active. We also assessed the ability of the Cu(CQ)2 formulation to increase copper delivery to cancer cells in vitro and its potential to be used in combination with disulfiram (DSF). The results suggested that addition of Cu(CQ)2 enhanced cellular copper levels and the activity of DSF in vitro; however, this combination did not result in a statistically significant reduction in tumor growth in vivo. These studies demonstrate that a Cu(CQ)2 formulation suitable for intravenous use can be prepared, but this formulation used alone or in combination with DSF was not efficacious. The methods described are suitable for development formulations of other analogues of 8 hydroxyquinoline which could prove to be more potent. PMID- 29247316 TI - Development of transdermal vitamin D3 (VD3) delivery system using combinations of PLGA nanoparticles and microneedles. AB - Although vitamin D3 (VD3), which is the main form of vitamin D, can be produced in human skin under the sunlight, vitamin D deficiency emerged as a major public health problem worldwide. Mainly, oral supplements or vitamin D-fortified foods are distributed to help supplementation of vitamin D. However, those oral methods are limitedly supplied in the Middle East countries, and oral absorption has low efficiency due to many barriers and various changes of conditions along the route. Then, it is recommended to take them every day in order to maintain the adequate serum level of vitamin D. Alternatively, transdermal delivery system could provide a convenient way to get sustained supplement of vitamin D by its advantages like avoiding first-pass effect of the liver and providing release for long periods of time. In this study, we introduced transdermal delivery system for sustained vitamin D release using coating microneedles that easily pierce the skin layer with enough mechanical strength and allow the localization of drugs within the dermal region. According to the experimental results, poly (lactic-co glycolic acid) (PLGA) successfully encapsulated VD3 as a nanoparticle form with appropriate properties for transdermal delivery such as size distribution, skin compatibility, and effective release of encapsulated compound. Finally, PVD3 layers coated on solid microneedles were completely dissolved into intradermal region in porcine skin model and revealed better performance for VD3 release into plasma compared to ointment base transdermal method. PMID- 29247317 TI - Bilayer Amniotic Membrane/Nano-fibrous Fibroin Scaffold Promotes Differentiation Capability of Menstrual Blood Stem Cells into Keratinocyte-Like Cells. AB - The skin provides a dynamic barrier separating and protecting human body from the exterior world, and then immediate repair and rebuilding of the epidermal barrier is crucial after wound and injury. Wound healing without scars and complete regeneration of skin tissue still remain as a clinical challenge. The demand to engineer scaffolds that actively promote regeneration of damaged areas of the skin has been increased. In this study, menstrual blood-derived stem cells (MenSCs) have been induced to differentiate into keratinocytes-like cells in the presence of human foreskin-derived keratinocytes on a bilayer scaffold based on amniotic membrane and silk fibroin. Based on the findings, newly differentiated keratinocytes from MenSCs successfully expressed the keratinocytes specific markers at both mRNA and protein levels judged by real-time PCR and immunostaining techniques, respectively. We could show that the differentiated cells over bilayer composite scaffolds express the keratinocytes specific markers at higher levels when compared with those cultured in conventional 2D culture system. Based on these findings, bilayer amniotic membrane/nano-fibrous fibroin scaffold represents an efficient natural construct with broad applicability to generate keratinocytes from MenSCs for stem cell-based skin wounds healing and regeneration. PMID- 29247319 TI - [Management of severe sepsis using a Cytokin-adsorber]. AB - Based on a representative case, which was treated in our center for severe burn injuries, the severity of the Waterhouse-Friderichsen syndrome and the complexity of the prolonged course of treatment are illustrated. Special attention is focused on the new treatment paradigm using the CytoSorb(r) adsorber. PMID- 29247320 TI - Time-dependent propagators for stochastic models of gene expression: an analytical method. AB - The inherent stochasticity of gene expression in the context of regulatory networks profoundly influences the dynamics of the involved species. Mathematically speaking, the propagators which describe the evolution of such networks in time are typically defined as solutions of the corresponding chemical master equation (CME). However, it is not possible in general to obtain exact solutions to the CME in closed form, which is due largely to its high dimensionality. In the present article, we propose an analytical method for the efficient approximation of these propagators. We illustrate our method on the basis of two categories of stochastic models for gene expression that have been discussed in the literature. The requisite procedure consists of three steps: a probability-generating function is introduced which transforms the CME into (a system of) partial differential equations (PDEs); application of the method of characteristics then yields (a system of) ordinary differential equations (ODEs) which can be solved using dynamical systems techniques, giving closed-form expressions for the generating function; finally, propagator probabilities can be reconstructed numerically from these expressions via the Cauchy integral formula. The resulting 'library' of propagators lends itself naturally to implementation in a Bayesian parameter inference scheme, and can be generalised systematically to related categories of stochastic models beyond the ones considered here. PMID- 29247321 TI - A Global Picture of the Gamma-Ricker Map: A Flexible Discrete-Time Model with Factors of Positive and Negative Density Dependence. AB - The gamma-Ricker model is one of the more flexible and general discrete-time population models. It is defined on the basis of the Ricker model, introducing an additional parameter [Formula: see text]. For some values of this parameter ([Formula: see text], population is overcompensatory, and the introduction of an additional parameter gives more flexibility to fit the stock-recruitment curve to field data. For other parameter values ([Formula: see text]), the gamma-Ricker model represents populations whose per-capita growth rate combines both negative density dependence and positive density dependence. The former can lead to overcompensation and dynamic instability, and the latter can lead to a strong Allee effect. We study the impact of the cooperation factor in the dynamics and provide rigorous conditions under which increasing the Allee effect strength stabilizes or destabilizes population dynamics, promotes or prevents population extinction, and increases or decreases population size. Our theoretical results also include new global stability criteria and a description of the possible bifurcations. PMID- 29247318 TI - Super-Resolution Track-Density Imaging Reveals Fine Anatomical Features in Tree Shrew Primary Visual Cortex and Hippocampus. AB - Diffusion-weighted magnetic resonance imaging (dMRI) is widely used to study white and gray matter (GM) micro-organization and structural connectivity in the brain. Super-resolution track-density imaging (TDI) is an image reconstruction method for dMRI data, which is capable of providing spatial resolution beyond the acquired data, as well as novel and meaningful anatomical contrast that cannot be obtained with conventional reconstruction methods. TDI has been used to reveal anatomical features in human and animal brains. In this study, we used short track TDI (stTDI), a variation of TDI with enhanced contrast for GM structures, to reconstruct direction-encoded color maps of fixed tree shrew brain. The results were compared with those obtained with the traditional diffusion tensor imaging (DTI) method. We demonstrated that fine microstructures in the tree shrew brain, such as Baillarger bands in the primary visual cortex and the longitudinal component of the mossy fibers within the hippocampal CA3 subfield, were observable with stTDI, but not with DTI reconstructions from the same dMRI data. The possible mechanisms underlying the enhanced GM contrast are discussed. PMID- 29247322 TI - A biomechanical study of sacroiliac rod fixation for unstable pelvic ring injuries: verification of the "within ring" concept. AB - PURPOSE: The aim of this study was to compare the fixation power of sacroiliac rod fixation (SIRF), which was developed based on our original "within ring" concept to exclude the lumbar vertebra from the fixation range, and spinopelvic fixation (SPF) in a biomechanical experiment. METHODS: SPF and SIRF were applied to the posterior element in four bones each with the pelvic ring fracture model (AO/OTA classification 61-C1.3). A 300-N axial force was loaded on the fifth lumbar vertebra of the simulated pelvis. Then the stiffness (N/m) and deformation (mm) of SPF and SIRF were determined, and the final displacement (mm) of the fracture region and angular deformity (degrees) were measured. Displacements were measured using the markers at two sites of the sacral fracture [upper margin of the sacral ala (Ala) and second sacral vertebra level (S2)] and one site of the pubic symphysis (PS), and angular deformity was measured at Ala and PS. RESULTS: In SPF and SIRF, the mean stiffnesses and deformations showed no statistically significant difference. Only the vertical displacement at Ala differed significantly between SPF and SIRF (p = 0. 045), and the fixing force of SPF was higher. There was no other significant difference in vertical and horizontal displacement. The mean angular deformities also showed no significant difference between the two methods. CONCLUSIONS: In biomechanics experiments, vertical resistance was stronger in SPF-treated than SIRF-treated bone, but stiffness and deformation, horizontal resistance, and angular deformity did not differ significantly. PMID- 29247323 TI - A Two-Step Methodology to Study the Influence of Aggregation/Agglomeration of Nanoparticles on Young's Modulus of Polymer Nanocomposites. AB - A two-step technique based on micromechanical models is suggested to determine the influence of aggregated/agglomerated nanoparticles on Young's modulus of polymer nanocomposites. The nanocomposite is assumed to include nanoparticle aggregation/agglomeration and effective matrix phases. This method is examined for different samples, and the effects of important parameters on the modulus are investigated. Moreover, the highest and the lowest levels of predicted modulus are calculated based on the current methodology. The suggested technique can correctly predict Young's modulus for the samples assuming the aggregation/agglomeration of nanoparticles. Additionally, the aggregation/agglomeration of nanoparticles decreases Young's modulus of polymer nanocomposites. It is demonstrated that the high modulus of nanoparticles is not sufficient to obtain a high modulus in nanocomposites, and the surface chemistry of components should be adjusted to prevent aggregation/agglomeration and to disperse nano-sized particles in the polymer matrix. PMID- 29247324 TI - Neutrophils in critical illness. AB - During critical illness, dramatic alterations in neutrophil biology are observed including abnormalities of granulopoeisis and lifespan, cell trafficking and antimicrobial effector functions. As a result, neutrophils transition from powerful antimicrobial protectors into dangerous mediators of tissue injury and organ dysfunction. In this article, the role of neutrophils in the pathogenesis of critical illness (sepsis, trauma, burns and others) will be explored, including pathological changes to neutrophil function during critical illness and the utility of monitoring aspects of the neutrophil phenotype as biomarkers for diagnosis and prognostication. Lastly, we review findings from clinical trials of therapies that target the harmful effects of neutrophils, providing a bench-to bedside perspective on neutrophils in critical illness. PMID- 29247325 TI - TGF-beta signaling inhibits canonical BMP signaling pathway during palate development. AB - During early palate development, gene expression and regulation exhibit heterogeneity along the anterior-posterior axis. Transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signaling pathways play essential roles in secondary palatal formation but the exact relationship between the TGF beta and BMP pathways in palate development remains unknown. Here, we demonstrate that, during early secondary palate development, phospho-(p)Smad1/5/8 is highly expressed in the anterior palate but relatively lowly expressed in the posterior palate. Conversely, pSmad2/3 has a lower expression level in the anterior palate than in the posterior palate. With the BRE-Gal reporter, we found that the canonical BMP signaling pathway was not activated in the anterior palate but exhibited a moderate level in the posterior palate. Co-immunoprecipitation revealed that Smad4 bound to pSmad1/5/8 only in the posterior palate and not in the anterior palate. Knocking-out of Tgfbr2 (Wnt1-Cre;Tgfbr2 f/f;BRE) in the palatal mesenchyme enhanced canonical BMP activity in the posterior palate but not in the anterior palate, because of decreased pSmad2/3. pSmad1/5/8-Smad4 complexes were found to be dramatically increased in posterior palatal mesenchymal cells at embryonic day 13.5 cultured in the presence of SB525334. Proximity ligation assay also showed pSmad1/5/8-Smad4 complexes were increased in the posterior palate of Wnt1-Cre;Tgfbr2 f/f mice. Therefore, the reduction of pSmad2/3 level in the palatal mesenchyme of Wnt1-Cre;Tgfbr2 f/f;BRE mice contributes primarily to the increase of pSmad1/5/8-Smad4 complexes leading to enhanced canonical BMP activity in the posterior palate. Moreover, during early development, canonical BMP signaling operates in the posterior palate but is completely absent in the anterior palate. Canonical TGF-beta signaling suppresses canonical BMP signaling activity in the posterior palate by competing limited Smad4. PMID- 29247326 TI - Geoelectrical assessment of polluted zone by sewage effluent in University of Ibadan campus southwestern Nigeria. AB - Sewage effluent was discharged through leaking sewer into the agricultural training farms, University of Ibadan which is used for cultivation of vegetables and cereals, thus constituting threat to human health. This study examined the reliability of the electrical resistivity technique in delineating sewage polluted zones and possible pathways into the groundwater network. The area investigated is underlain by banded gneisses. Ten resistivity Wenner-imaging lines (N-S) were established and inverted section generated using RES2DINV. Thirty VES stations were occupied using Schlumberger array, the current electrode spacing (AB/2) expanded from 1 to 75 m and data analysed using WinResist. 2-D inverted section depicted the top soil and clay unit. Resistivity in the top soil (36-70 Omega-m) showed a decrease of 57 to 78% while the clayey unit (6-18 Omega m) showed a reduction of 63 to 88% relative to the control units. Plunge in resistivity within the top soil and clay units suggests the presence of pollutants. VES-derived geoelectric section recorded three varying sequences, with a fall in resistivity in the top soil (22-58 Omega-m) and the clay unit (6 15 Omega-m) compared with the reference layers having 233 and 34 Omega-m, respectively; the fractured sections in some parts of the bedrock could serve as a conduit for the seepage of the pollutants into the groundwater system. Drop in resistivity suggests the presence of pollutants within the top soil and clay units. These techniques have helped in mapping out unnatural zones around the farm. PMID- 29247327 TI - IL-21 Enhances the Degradation of Cartilage Through the JAK-STAT Signaling Pathway During Osteonecrosis of Femoral Head Cartilage. AB - This study aims to investigate the role of interleukin-21 (IL-21) in the mechanism of osteonecrosis of the femoral head. The serum content of IL-21 in patients with osteonecrosis of the femoral head (ONFH) and with femoral neck fracture (FNF) was examined by an enzyme-linked immunosorbent assay (ELISA). The cartilage specimens were stained with safranin-O. The expression of IL-21, tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase (COX-2), a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4), matrix metalloproteinase-13(MMP-13), and aggrecan in the cartilage was detected, by immunohistochemistry and western blot analysis. Moreover, chondrocytes were treated with IL-21 (100 ng/mL) or PBS to examine the mRNA content of TNF-alpha, COX-2, IL-1beta and NOS-2 by RT-PCR, and the protein levels of ADAMTS-4, MMP-13, and aggrecan by western blot analysis. The activity of the JAK-STAT pathway was determined in vitro after stimulation with IL-21. IL-21 serum levels were obviously higher in the ONFH patients and positively correlated with the severity of ONFH. There were more cells positive for inflammatory cytokines, including IL 21, TNF-alpha, and COX-2, in the cartilage of the ONFH patients than the FNF patients. The level of certain relative biomarkers, such as ADAMTS-4 and MMP-13, was higher and aggrecan was lower in the ONFH patients. The mRNA contents of TNF alpha, COX-2, IL-1beta, and NOS-2, as well as the levels of ADAMTS-4, MMP-13, were enhanced, and aggrecan decreased after stimulation with IL-21. The protein content of p-STAT-1, as well as p-STAT-3, also increased after IL-21 stimulation, and the highest level appeared at 30 min. Furthermore, the protein level of ADAMTS-4 and MMP-13 and the mRNA level of TNF-alpha, COX-2, IL-1beta, and NOS-2 significantly decreased after stimulation with AG-490. IL-21 enhances cartilage inflammation to promote cartilage degradation through the JAK-STAT signaling pathway in the cartilage of ONFH patients. PMID- 29247328 TI - Identification and cytochemical immunolocalization of acetyl-CoA acetyltransferase involved in the terpenoid mevalonate pathway in Euphorbia helioscopia laticifers. AB - BACKGROUND: Terpenoids, the largest class of natural products in the plant kingdom, have been widely used in medicine. The precursors of terpenoids, isoprene phosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), were synthesized from a mevalonate (MVA) pathway and a 2-C-methyl-D-erythritol-4 phosphate (MEP) pathway respectively. The acetyl-CoA acetyltransferase (AACT) is the initial enzyme in MVA pathway and is considered presently to be essential for terpenoid backbone biosynthesis. The basic research on cytochemistry of terpenoid metabolic enzymes is important for understanding the mechanisms underlying major metabolic processes. However, compartmentalization of AACT in plants is in controversy. Euphorbia helioscopia L. containing laticifers in the whole plant is a famous ancient folk medicine for tumor treatment, and the terpenoid is an active ingredient. Furthermore, the laticifer cell is the main synthesizing and storing site for terpenoids. RESULTS: The gene of AACT was cloned successfully from E. helioscopia, and named as EhAACT. The EhAACT expression has no significant difference among roots, stems and leaves. However, compared with the roots and stems, the EhAACT expression level is slightly higher in leaves. In addition, EhAACT recombinant protein was expressed by procaryotic expression system and anti-EhAACT antibody was prepared, the molecular weight is about 43 kDa. Western blotting results illustrated that the EhAACT antibodies specifically recognized the endogenous proteins in E. helioscopia laticifers. At last, the subcellular localization of EhAACT in E. helioscopia laticifers was observed by using colloidal gold immune-electron microscopy. EhAACT was found to mainly distribute in the endoplasmic reticulum (ER), vacuoles originated from ER and cytosol aound vacuoles originated from ER. CONCLUSIONS: As a result, we speculated that in E. helioscopia laticifers, EhAACT located in cytosol would be transferred to small vacuoles dilated from ER, and the precursors of terpenoids were synthesized in these small vacuoles, then terpenoids were further synthesized into latex particles. This result would provide theoretical basis for regulating and controlling of terpenoid biosynthesis in laticifers. PMID- 29247329 TI - Understanding childhood diabetes mellitus: new pathophysiological aspects. AB - Diabetes mellitus (DM) is not a single disease, but several pathophysiological conditions where synthesis, release, and/or action of insulin are disturbed. A progressive autoimmune/autoinflammatory destruction of islet cells is still considered the main pathophysiological event in the development of T1DM, but there is evidence that T1DM itself is a heterogeneous disease. More than 50 gene regions are closely associated with T1DM and a variety of epigenetic factors and metabolic patterns have been characterized, which may play a role in the development of T1DM. The pathogenesis and genetics of type 2 DM (T2DM) are distinct from T1DM. Genes associated with T2DM are distinct from those in T1DM. Characteristic metabolic patterns, different from those in T1DM were reported in T2DM, and some children with T2DM also express islet-antibodies. Huge progress has been made in the characterization of other specific types of DM, which had been considered very rare before. The molecular clarification of maturity-onset diabetes of the young (MODY) has greatly improved our understanding of the pathophysiology of DM. There are genetic overlaps between T2DM and monogenetic DM. Neonatal DM has been shown to be monogenetic in most cases, and genetic elucidation leads to more precise and individualized therapies. Cystic fibrosis related DM (CFRDM) should be considered a genuine part of cystic fibrosis, and not a complication, since pancreatic fibrosis does not sufficiently explain the pathophysiology of CFRDM. Disturbances of cystic fibrosis transmembrane conductance regulator (CFTR) as well as autoimmunity are involved in the pathogenesis of CFRDM. PMID- 29247330 TI - Alteration of flower colour in Ipomoea nil through CRISPR/Cas9-mediated mutagenesis of carotenoid cleavage dioxygenase 4. AB - Japanese morning glory, Ipomoea nil, exhibits a variety of flower colours, except yellow, reflecting the accumulation of only trace amounts of carotenoids in the petals. In a previous study, we attributed this effect to the low expression levels of carotenogenic genes in the petals, but there may be other contributing factors. In the present study, we investigated the possible involvement of carotenoid cleavage dioxygenase (CCD), which cleaves specific double bonds of the polyene chains of carotenoids, in the regulation of carotenoid accumulation in the petals of I. nil. Using bioinformatics analysis, seven InCCD genes were identified in the I. nil genome. Sequencing and expression analyses indicated potential involvement of InCCD4 in carotenoid degradation in the petals. Successful knockout of InCCD4 using the CRISPR/Cas9 system in the white-flowered cultivar I. nil cv. AK77 caused the white petals to turn pale yellow. The total amount of carotenoids in the petals of ccd4 plants was increased 20-fold relative to non-transgenic plants. This result indicates that in the petals of I. nil, not only low carotenogenic gene expression but also carotenoid degradation leads to extremely low levels of carotenoids. PMID- 29247331 TI - Polymorphisms in inflammation-related genes and the risk of primary varicose veins in ethnic Russians. AB - Inflammation was shown to be activated in varicose veins, although its role in the development of vein wall transformation remains inconclusive. We aimed to investigate the influence of 13 inflammation-related single nucleotide polymorphisms (SNPs) TNF rs1800629 and rs3093661, IL1A rs1800587, IL1RN rs4251961, IL6 rs1800795 and rs1800796, IFNG rs2430561, IL10 rs1800896, TGFB1 rs1800469, HIF1A rs11549465, NFKB1 rs28362491, and rs4648068 on the risk of primary varicose veins (PVVs) in ethnic Russians. We genotyped 709 patients with PVVs and 278 individuals without a history of chronic venous disease and performed a single SNP and a haplotype analysis. Several associations with P < 0.05 were revealed in our study. Variant allele HIF1A rs11549465 T, TNF rs3093661 A, and NFKB1 rs28362491 ATTG deletion showed the reverse association with PVV risk, and allele IL6 rs1800795 C was associated with the increased risk of the studied pathology. Haplotype analysis revealed associations of TNF haplotypes rs3093661 A-rs1800629 G and IL6 rs1800795 C-rs1800796 G with the decreased and the increased risk of PVVs, correspondingly. However, all the observed associations failed to reach statistical significance after the correction for multiple testing, which was set at a level of 10-3 due to many tests performed. Our study therefore provides evidence that investigated polymorphisms do not play a major role in susceptibility to PVVs. PMID- 29247332 TI - Pharmacokinetics, Safety, and Tolerability of Single-Dose Elbasvir in Participants with Hepatic Impairment. AB - BACKGROUND: The combination of elbasvir and grazoprevir is approved for the treatment of hepatitis C virus genotype 1 or 4 infection. OBJECTIVE: To evaluate the pharmacokinetics and safety of single-dose elbasvir 50 mg in participants with hepatic impairment. METHODS: Participants with mild, moderate, or severe hepatic impairment and age-, sex-, and weight-matched healthy controls were enrolled in a 3-part, open-label, sequential-panel, single-dose pharmacokinetic study. Blood samples were collected to assess pharmacokinetics. Safety and tolerability were assessed throughout the study. RESULTS: Thirty-four participants were enrolled: eight with mild hepatic impairment, 11 with moderate hepatic impairment, seven with severe hepatic impairment, and eight healthy matched controls. Participants with mild, moderate, and severe hepatic impairment demonstrated a numeric, but not statistically significant, decrease in elbasvir exposure compared with controls, with a mean 39, 28, and 12% decrease in area under the concentration-time curve from time 0 extrapolated to infinity, as well as a 42, 31, and 42% decrease in maximum plasma concentration (C max), respectively. The observed median time to C max was similar in participants with hepatic impairment and controls. Single-dose administration of elbasvir was well tolerated. CONCLUSIONS: The pharmacokinetics of elbasvir after a single, oral 50 mg dose were not clinically meaningfully altered in non-HCV-infected participants with mild, moderate, or severe hepatic dysfunction. However, since elbasvir is currently available only as part of a fixed-dose combination with grazoprevir, the fixed-dose combination should not be administered to patients with moderate or severe hepatic impairment, due to the significantly increased plasma grazoprevir exposures in those populations. PMID- 29247333 TI - Medium-Chain Fatty Acids (MCFA) Production Through Anaerobic Fermentation Using Clostridium kluyveri: Effect of Ethanol and Acetate. AB - Medium-chain fatty acids (MCFA) are saturated monocarboxylic acids and can be used as antimicrobials, corrosion inhibitors, precursors in biodiesel, and bioplastic production. In the present study, MCFA production was evaluated with acetate and ethanol using the bacteria Clostridium kluyveri. Effects of substrate, electron donor, and methane inhibitor on MCFA production were evaluated. Bacteria successfully converted the ethanol and acetate to butyrate (C4), caproate (C6), and caprylate (C8) by chain elongation process. The highest concentrations of butyrate (4.6 g/l), caproate (3.2 g/l), and caprylate (0.5 g/l) were obtained under methane inhibition conditions than other conditions. The productions of butyrate and caproate were 1.6 and 1.48 times higher under methane inhibition conditions, respectively. Results denoted that the bacteria C. kluyveri can be used for conversion of acetate and ethanol into useful products like butyrate and caproate. PMID- 29247334 TI - Response to Letter to the Editor. PMID- 29247335 TI - Biomarkers of Cardiac Disease in Duchenne Muscular Dystrophy are Insufficient in the Absence of Clinical Cardiologic and Neurologic Assessment. PMID- 29247336 TI - Effects of Phenolic Compounds on Growth of Colletotrichum spp. In Vitro. AB - Colletotrichum acutatum is responsible for anthracnose fruit rot, one of the most devastating diseases in strawberry. Phenolic compounds have been described as contributors to anthracnose resistance in strawberry (Fragaria x ananassa, Duch.). Six isolates of Colletotrichum acutatum and four isolates of three other Colletotrichum species, C. gloeosporioides, C. fragariae, and C. graminicola, associated with disease symptoms were investigated in this study. The potential inhibitory effect of phenolic acids (gallic acid, caffeic acid, chlorogenic acid, ferulic acid, trans-cinnamic acid, p-coumaric acid, salicylic acid), flavonoids (catechin, quercetin, naringenin), and ellagic acid, which are naturally found in strawberry, were screened against two different spore suspension concentrations of the Colletotrichum isolates at 5, 10, 50 mM in vitro. Among the phenolic acids and flavonoids tested in this study, only trans-cinnamic acid, ferulic acid, and p-coumaric acid inhibited fungal growth. The inhibitory effects were concentration-dependent but also varied with the spore suspension concentration of the isolates. The results demonstrated that trans-cinnamic acid had the greatest inhibitory effect on all Colletotrichum spp. isolates tested. PMID- 29247337 TI - Microbial Contamination of Smartphone Touchscreens of Italian University Students. AB - In this study, the microbial contamination of smartphones from Italian University students was analyzed. A total of 100 smartphones classified as low, medium, and high emission were examined. Bacteria were isolated on elective and selective media and identified by biochemical tests. The mean values of cfu/cm2 were 0.79 +/- 0.01; in particular, a mean of 1.21 +/- 0.12, 0.77 +/- 0.1 and 0.40 +/- 0.10 cfu/cm2 was present on smartphones at low, medium, and high emission, respectively. The vast majority of identified microorganisms came from human skin, mainly Staphylococci, together with Gram-negative and positive bacilli and yeasts. Moreover, the main isolated species and their mixture were exposed for 3 h to turned on and off smartphones to evaluate the effect of the electromagnetic wave emission on the bacterial cultivability, viability, morphology, and genotypic profile in respect to the unexposed broth cultures. A reduction rate of bacterial growth of 79 and 46% was observed in Staphylococcus aureus and Staphylococcus epidermidis broth cultures, respectively, in the presence of turned on smartphone. No differences in viability were observed in all detected conditions. Small colony variants and some differences in DNA fingerprinting were detected on bacteria when the smartphones were turned on in respect to the other conditions. The colonization of smartphones was limited to human skin microorganisms that can acquire phenotype and genotypic modifications when exposed to microwave emissions. PMID- 29247338 TI - Diverse replication-associated protein encoding circular DNA viruses in guano samples of Central-Eastern European bats. AB - Circular replication-associated protein encoding single-stranded DNA (CRESS DNA) viruses are increasingly recognized worldwide in a variety of samples. Representative members include well-described veterinary pathogens with worldwide distribution, such as porcine circoviruses or beak and feather disease virus. In addition, numerous novel viruses belonging to the family Circoviridae with unverified pathogenic roles have been discovered in different human samples. Viruses of the family Genomoviridae have also been described as being highly abundant in different faecal and environmental samples, with case reports showing them to be suspected pathogens in human infections. In order to investigate the genetic diversity of these viruses in European bat populations, we tested guano samples from Georgia, Hungary, Romania, Serbia and Ukraine. This resulted in the detection of six novel members of the family Circoviridae and two novel members of the family Genomoviridae. Interestingly, a gemini-like virus, namely niminivirus, which was originally found in raw sewage samples in Nigeria, was also detected in our samples. We analyzed the nucleotide composition of members of the family Circoviridae to determine the possible host origins of these viruses. This study provides the first dataset on CRESS DNA viruses of European bats, and members of several novel viral species were discovered. PMID- 29247340 TI - Assessing the opportunity costs of patients with multidrug-resistant organisms in hospitals. AB - OBJECTIVES: The concept of opportunity cost can be applied to the utilization of hospital beds with special focus on patients colonized or infected with multidrug resistant organisms. Blocked beds due to isolation measures or increased length of stay may result in opportunity costs if newly arriving patients have to be rejected and the hospital is confronted with revenue foregone. However, the amount of these costs is unclear, since different approaches are used in the literature to determine the respective costs. Our paper develops a concept to assess opportunity costs from the perspective of a hospital. METHODS: The analysis is two-stage. In a first step, the probability of rejecting a patient due to over-occupancy in a hospital is calculated with a queuing model and a Monte Carlo simulation taking various assumptions into account. In a second step, the amount of the opportunity costs is calculated as an expected value applying a stochastic approach based on a potential patient pool. RESULTS: Opportunity costs will occur only with a probability that is influenced, among others, by current bed occupancy rates. They have to be measured by average net revenue foregone, i.e., by the difference between average revenue foregone and average costs avoided. CONCLUSIONS: Previous studies have a tendency of overestimating the occurrence or the size of opportunity costs with regard to the use of hospital beds. Nonetheless, its influence on the hospital budget is crucial and should be determined exactly. PMID- 29247341 TI - From biomarkers to therapeutic targets-the promises and perils of long non-coding RNAs in cancer. AB - Biomarker-driven personalized cancer therapy is a field of growing interest, and several molecular tests have been developed to detect biomarkers that predict, e.g., response of cancers to particular therapies. Identification of these molecules and understanding their molecular mechanisms is important for cancer prognosis and the development of therapeutics for late stage diseases. In the past, significant efforts have been placed on the discovery of protein or DNA based biomarkers while only recently the class of long non-coding RNA (lncRNA) has emerged as a new category of biomarker. The mammalian genome is pervasively transcribed yielding a vast amount of non-protein-coding RNAs including lncRNAs. Hence, these transcripts represent a rich source of information that has the potential to significantly contribute to precision medicine in the future. Importantly, many lncRNAs are differentially expressed in carcinomas and they are emerging as potent regulators of tumor progression and metastasis. Here, we will highlight prime examples of lncRNAs that serve as marker for cancer progression or therapy response and which might represent promising therapeutic targets. Furthermore, we will introduce lncRNA targeting tools and strategies, and we will discuss potential pitfalls in translating these into clinical trials. PMID- 29247343 TI - A caffeine-maltodextrin mouth rinse counters mental fatigue. AB - INTRODUCTION: Mental fatigue is a psychobiological state caused by prolonged periods of demanding cognitive activity that has negative implications on many aspects in daily life. Caffeine and carbohydrate ingestion have been shown to be able to reduce these negative effects of mental fatigue. Intake of these substances might however be less desirable in some situations (e.g., restricted caloric intake, Ramadan). Rinsing caffeine or glucose within the mouth has already been shown to improve exercise performance. Therefore, we sought to evaluate the effect of frequent caffeine-maltodextrin (CAF-MALT) mouth rinsing on mental fatigue induced by a prolonged cognitive task. METHODS: Ten males (age 23 +/- 2 years, physical activity 7.3 +/- 4.3 h/week, low CAF users) performed two trials. Participants first completed a Flanker task (3 min), then performed a 90 min mentally fatiguing task (Stroop task), followed by another Flanker task. Before the start and after each 12.5% of the Stroop task (eight blocks), subjects received a CAF-MALT mouth rinse (MR: 0.3 g/25 ml CAF: 1.6g/25 ml MALT) or placebo (PLAC: 25 ml artificial saliva). RESULTS: Self-reported mental fatigue was lower in MR (p = 0.017) compared to PLAC. Normalized accuracy (accuracy first block = 100%) was higher in the last block of the Stroop in MR (p = 0.032) compared to PLAC. P2 amplitude in the dorsolateral prefrontal cortex (DLPFC) decreased over time only in PLAC (p = 0.017). CONCLUSION: Frequent mouth rinsing during a prolonged and demanding cognitive task reduces mental fatigue compared to mouth rinsing with artificial saliva. PMID- 29247342 TI - Effects of Banxia Xiexin Decoction () on Cisplatin-Induced Apoptosis of Human A549 Lung Cancer Cells. AB - OBJECTIVE: To examinie the synergistic effects of Banxia Xiexin Decoction (, Known as Banhasasim-tang in Korean) extract (BXDE) on cisplatin-induced cytotoxicity in the A549 human lung cancer cell lines. METHODS: A549 cells were treated with varying concentrations (50-200 MUg/mL) of cisplatin and BXDE alone or in combination for 96 h. We used 1-(4,5-dimethylthiazol-2-yl)-3,5 diphenylformazan assay and flow cytometry to analyze cell viability and apoptosis, respectively. RESULTS: The exposure of cells to cisplatin and BXDE alone or in combination decreased cell viability dose- and time-dependently (P<0.05), which was found to be mediated by the apoptotic pathway as confirmed by the increase in the annexin V+/propidium iodide- stained cell population and a ladder pattern of discontinuous DNA fragments. Furthermore, the apoptosis was inhibited by the pan-caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (z-VAD-FMK). CONCLUSIONS: BXDE significantly potentiated apoptotic effects of cisplatin in A549 cells. Moreover, apoptosis induced by BXDE might be the pivotal mechanism mediating its chemopreventative action against cancer. PMID- 29247344 TI - Molecular study of human sperm RNA: Ropporin and CABYR in asthenozoospermia. AB - BACKGROUND: Sperm motility is an essential aspect of human fertility. Sperm contain an abundance of transcripts, thought to be remnants of mRNA, which comprise a genetic fingerprint and can be considered a historic record of gene expression during spermatogenesis. The aberrant expression of numerous genes has been found to contribute to impaired sperm motility; these include ROPN1 (rhophilin associated tail protein 1), which encodes a component of the fibrous sheath of the mammalian sperm flagella, and CABYR (calcium-binding tyrosine-(Y) phosphorylation-regulated protein), which plays an important role in calcium activation and modulation. The aim of this study was to investigate ROPN1 and CABYR gene co-expression in asthenozoospermic semen samples in comparison with normozoospermic samples. METHODS: We studied 120 semen samples (60 normozoospermic and 60 asthenozoospermic) from Caucasian patients attending our centre for an andrological check-up. Total RNA was extracted from purified spermatozoa with RNeasy mini kit. ROPN1 and CABYR mRNA expression was analysed using RT-qPCR. Continuous variables were described as means +/- standard deviations. RESULTS: ROPN1 and CABYR mRNA were simultaneously downregulated in asthenozoospermic in comparison with normozoospermic samples. There was also a positive correlation between total progressive motility and ROPN1 and CABYR gene expression and between total motile sperm number and ROPN1 and CABYR gene expression. CONCLUSIONS: The results demonstrated downregulation of both ROPN1 and CABYR in asthenozoospermic samples and importantly, a positive correlation between the expression of the two genes, suggesting that ROPN1 and CABYR co expression is a prerequisite for normal flagellar function and sperm motility. PMID- 29247345 TI - Bone Marrow Mesenchymal Stem Cells Carrying FANCD2 Mutation Differ from the Other Fanconi Anemia Complementation Groups in Terms of TGF-beta1 Production. AB - Transforming growth factor beta (TGF-beta) secretion from cells in the bone marrow (BM) niche affects hematopoietic stem cell (HSC) fate and has a cardinal role in HSC quiescence. BM mesenchymal stem cells (BM-MSCs), a component of the BM niche, may produce abnormal levels of TGF-beta in Fanconi anemia (FA) and may play a role in bone marrow failure. Here, we molecularly and cellularly characterized FA BM-MSCs by addressing their immunophenotype, proliferation- and differentiation- capacity, reactive oxygen species (ROS) production, senescence activity as well as expression and secretion levels of TGF-beta isoforms. In ten FA patients, mutations were detected in FANCA (n = 7), FANCG (n = 1) and FANCD2 (n = 2) genes. The immunophenotype, with the exception of CD29, and differentiation capacity of FA BM-MSCs were similar to healthy donors. FA BM-MSCs showed decreased proliferation, increased ROS level and an arrest in G2 following DEB treatment. beta-galactosidase staining indicated elevated senescence of FANCD2-deficient cells. FA BM-MSCs displayed TGF-beta1 mRNA levels similar to donor BM-MSCs, and was not affected by DEB treatment. However, secretion of TGF beta was absent in FA-D2 BM-MSCs. Absence of TGF-beta secretion may be related to early onset of senescence of the FANCD2-deficient BM-MSCs. The proliferative response of FA-D2 BM-MSCs to rTGF-beta1 was not different from FANCA-deficient and donor cells and raises the possibility that rTGF-beta1 may reverse the senescence of the FANCD2-deficient BM-MSCs which needs to be investigated further. PMID- 29247346 TI - The TT genotype of the rs6860 polymorphism of the charged multivesicular body protein 1A gene is associated with susceptibility to fibromyalgia in southern Spanish women. PMID- 29247349 TI - Are Lead Exposures a Risk in European Fresh Waters? A Regulatory Assessment Accounting for Bioavailability. AB - An indicative compliance assessment of the Europe-wide bioavailable lead Environmental Quality Standard of 1.2 ug L-1 (EQS) was undertaken against regulatory freshwater monitoring data from six European member states and FOREGS database. Bio-met, a user-friendly tool based upon Biotic Ligand Models (BLMs) was used to account for bioavailability, along with the current European Water Framework Directive lead dissolved organic carbon correction approach. The outputs from both approaches were compared to the BLM. Of the 9054 freshwater samples assessed only 0.6% exceeded the EQS of 1.2 ug L-1 after accounting for bioavailability. The data showed that ambient background concentrations of lead across Europe are unlikely to influence general compliance with the EQS, although there may be isolated local issues. The waters showing the greatest sensitivity to potential lead exposures are characterized by relatively low DOC (< 0.5 mg L 1), regardless of the pH and calcium concentrations. PMID- 29247347 TI - Patient and physician perspectives on the impact of health-related quality of life in Mexican patients with ANCA-associated vasculitis. AB - The objective of this study is to describe aspects of health-related quality of life (HRQOL) in Mexican patients with antineutrophil cytoplasmic-associated vasculitis (AAV). Cross-sectional comparison study includes patients with established AAV and a comparison group with rheumatoid arthritis (RA), chronic kidney disease (CKD), and healthy subjects. Variables considered were: socio demographic data, comorbidities, laboratory, disease activity, damage, and Physician's and Patient's Global Assessment (PhGA and PtGA). The following measurements were done: Pittsburg sleep quality index, Multidimesional Fatigue Inventory (MFI-20), Hospital Anxiety and Depression Scale, Short Form 36 questionnaire (SF-36), and Health Assessment Questionnaire. 60 patients with AAV were included, median age 54 years, and 60% female. Significant differences were found only in the bodily pain domain of the SF-36 (p = 0.01). Aspects of disease relevant for AAV patients were: fatigue and lack of energy; visual abnormalities; neuropathy; renal impairment; arthritis, and sinusitis. Greater total score on MFI-20 (p < 0.001) and worse PtGA (p = 0.01) were associated with worse physical health. Higher PhGA values were associated with worse physical quality of life (p = 0.01). Greater fatigue score (p = 0.002), greater anxiety-depression score (p = 0.005), and worse PtGA (p = 0.01) were associated with worse mental health quality of life. No differences were found in prevalence of sleep impairment, anxiety, depression, or disability between groups. AAV patients experienced more general and physical fatigue (p < 0.0001), and reduced activity (p = 0.01) than healthy subjects, but similar to RA and CKD patients. Vasculitis has negative effects on patients' physical and mental HRQOL. PMID- 29247348 TI - Eosinophilic fasciitis during pregnancy: case report and review of literature. AB - The authors describe the case of a 23-year-old woman who was referred to the rheumatologist due to symmetrical and progressive stiffness, induration, and swelling of arms and thighs at the 12th week of her first gestation. The characteristic clinical aspect of 'peau d'orange', associated to the histopathologic results of the deep biopsy of the skin confirmed the diagnosis of eosinophilic fasciitis. Treatment with oral prednisone, at an initial dose of 1 mg/kg/day, was effective and rapidly tapered to 10 mg/day till the birth of a healthy newborn. A literature review showed only one previous description of pregnancy and eosinophilic fasciitis. PMID- 29247350 TI - Development of pumping emulsification device with glass membrane to form ideal lipiodol emulsion in transarterial chemoembolization. AB - PURPOSE: To evaluate a pumping emulsification device that can improve the physiochemical properties and stability of lipiodol emulsion for conventional transarterial chemoembolization. MATERIALS AND METHODS: A pumping emulsification device constructed of a glass membrane with a hydrophobic surface with pore size of 50 MUm in diameter was placed between two syringe adaptors. Epirubicin solutions were mixed with lipiodol with pumping exchanges using the emulsification device or a three-way cock. The ratios of epirubicin solution to lipiodol were 1:2 or 1:1. A total of 120 emulsions were created. RESULTS: The emulsification device showed significantly higher percentages of water-in-oil when compared with the three-way cock (97.9 % vs. 68.9 % in 1:2 ratio, and 82.1 % vs. 17.8 % in 1:1 ratio, p < .001). Droplet sizes in the emulsification device were more homogenous. Mean droplet sizes and viscosities in the emulsification device did not show any significant changes for 30 min after pumping, whereas in the three-way cock, the droplet sizes significantly enlarged and viscosities significantly decreased (p=.023 and p=.002). CONCLUSION: The emulsification device can form a high percentage of water-in-oil emulsion with stable droplets sizes and viscosities. This developed device is promising to increase therapeutic effects in conventional transarterial chemoembolization. KEY POINTS: * We developed new device for transarterial chemoembolization for liver cancer. * The device can improve the physiochemical properties of lipiodol emulsion. * The device can increase the therapeutic effects in conventional transarterial chemoembolization. PMID- 29247351 TI - Round-the-clock performance of coronary CT angiography for suspected acute coronary syndrome: Results from the BEACON trial. AB - OBJECTIVE: To assess the image quality of coronary CT angiography (CCTA) for suspected acute coronary syndrome (ACS) outside office hours. METHODS: Patients with symptoms suggestive of an ACS underwent CCTA at the emergency department 24 hours, 7 days a week. A total of 118 patients, of whom 89 (75 %) presented during office hours (weekdays between 07:00 and 17:00) and 29 (25 %) outside office hours (weekdays between 17:00 and 07:00, weekends and holidays) underwent CCTA. Image quality was evaluated per coronary segment by two experienced readers and graded on an ordinal scale ranging from 1 to 3. RESULTS: There were no significant differences in acquisition parameters, beta-blocker administration or heart rate between patients presenting during office hours and outside office hours. The median quality score per patient was 30.5 [interquartile range 26.0 33.5] for patients presenting during office hours in comparison to 27.5 [19.75 32.0] for patients presenting outside office hours (p=0.043). The number of non evaluable segments was lower for patients presenting during office hours (0 [0 1.0] vs. 1.0 [0-4.0], p=0.009). CONCLUSION: Image quality of CCTA outside office hours in the diagnosis of suspected ACS is diminished. KEY POINTS: * Quality scores were higher for coronary-CTA during office hours. * There were no differences in acquisition parameters. * There was a non-significant trend towards higher heart rates outside office hours. * Coronary-CTA on the ED requires state-of-the-art scanner technology and sufficiently trained staff. * Coronary-CTA on the ED needs preparation time and optimisation of the procedure. PMID- 29247353 TI - Structured vs narrative reporting of pelvic MRI for fibroids: clarity and impact on treatment planning. AB - OBJECTIVES: To evaluate clarity and usefulness of MRI reporting of uterine fibroids using a structured disease-specific template vs. narrative reporting for planning of fibroid treatment by gynaecologists and interventional radiologists. METHODS: This is a HIPAA-compliant, IRB-approved study with waiver of informed consent. A structured reporting template for fibroid MRIs was developed in collaboration between gynaecologists, interventional and diagnostic radiologists. The study population included 29 consecutive women who underwent myomectomy for fibroids and pelvic MRI prior to implementation of structured reporting, and 42 consecutive women with MRI after implementation of structured reporting. Subjective evaluation (on a scale of 1-10, 0 not helpful; 10 extremely helpful) and objective evaluation for the presence of 19 key features were performed. RESULTS: More key features were absent in the narrative reports 7.3 +/- 2.5 (range 3-12) than in structured reports 1.2 +/- 1.5 (range 1-7), (p < 0.0001). Compared to narrative reports, gynaecologists and radiologists deemed structured reports both more helpful for surgical planning (p < 0.0001) (gynaecologists: 8.5 +/- 1.2 vs. 5.7 +/- 2.2; radiologists: 9.6 +/- 0.6 vs. 6.0 +/- 2.9) and easier to understand (p < 0.0001) (gynaecologists: 8.9 +/- 1.1 vs. 5.8 +/- 1.9; radiologists: 9.4 +/- 1.3 vs. 6.3 +/- 1.8). CONCLUSION: Structured fibroid MRI reports miss fewer key features than narrative reports. Moreover, structured reports were described as more helpful for treatment planning and easier to understand. KEY POINTS: * Structured reports missed only 1.2 +/- 1.5 out of 19 key features, as compared to narrative reports that missed 7.3 +/- 2.5 key features for planning of fibroid treatment. * Structured reports were more helpful and easier to understand by clinicians. * Structured template can provide essential information for fibroids treatment planning. PMID- 29247352 TI - Imaging putative foetal cerebral blood oxygenation using susceptibility weighted imaging (SWI). AB - OBJECTIVE: To evaluate the magnetic susceptibility, ?chi v , as a surrogate marker of venous blood oxygen saturation, S v O 2, in second- and third-trimester normal human foetuses. METHODS: Thirty-six pregnant women, having a mean gestational age (GA) of 31 2/7 weeks, underwent magnetic resonance imaging (MRI). Susceptibility-weighted imaging (SWI) data from the foetal brain were acquired. ?chi v of the superior sagittal sinus (SSS) was quantified using MR susceptometry from the intra-vascular phase measurements. Assuming the magnetic property of foetal blood, ?chi do , is the same as that of adult blood, S v O 2 was derived from the measured Deltachi v . The variation of ?chi v and S v O 2, as a function of GA, was statistically evaluated. RESULTS: The mean ?chi v in the SSS in the second-trimester (n = 8) and third-trimester foetuses (n = 28) was found to be 0.34+/- 0.06 ppm and 0.49 +/-0.05 ppm, respectively. Correspondingly, the derived S v O 2 values were 69.4% +/-3.27% and 62.6% +/-3.25%. Although not statistically significant, an increasing trend (p = 0.08) in Deltachi v and a decreasing trend (p = 0.22) in S v O 2 with respect to advancing gestation was observed. CONCLUSION: We report cerebral venous blood magnetic susceptibility and putative oxygen saturation in healthy human foetuses. Cerebral oxygen saturation in healthy human foetuses, despite a slight decreasing trend, does not change significantly with advancing gestation. KEY POINTS: * Cerebral venous magnetic susceptibility and oxygenation in human foetuses can be quantified. * Cerebral venous oxygenation was not different between second- and third-trimester foetuses. * Foetal cerebral venous oxygenation does not change significantly with advancing gestation. PMID- 29247354 TI - Preoperative short hookwire placement for small pulmonary lesions: evaluation of technical success and risk factors for initial placement failure. AB - OBJECTIVES: To retrospectively evaluate the technical success of computed tomography fluoroscopy-guided short hookwire placement before video-assisted thoracoscopic surgery and to identify the risk factors for initial placement failure. METHODS: In total, 401 short hookwire placements for 401 lesions (mean diameter 9.3 mm) were reviewed. Technical success was defined as correct positioning of the hookwire. Possible risk factors for initial placement failure (i.e., requirement for placement of an additional hookwire or to abort the attempt) were evaluated using logistic regression analysis for all procedures, and for procedures performed via the conventional route separately. RESULTS: Of the 401 initial placements, 383 were successful and 18 failed. Short hookwires were finally placed for 399 of 401 lesions (99.5%). Univariate logistic regression analyses revealed that in all 401 procedures only the transfissural approach was a significant independent predictor of initial placement failure (odds ratio, OR, 15.326; 95% confidence interval, CI, 5.429-43.267; p < 0.001) and for the 374 procedures performed via the conventional route only lesion size was a significant independent predictor of failure (OR 0.793, 95% CI 0.631-0.996; p = 0.046). CONCLUSIONS: The technical success of preoperative short hookwire placement was extremely high. The transfissural approach was a predictor initial placement failure for all procedures and small lesion size was a predictor of initial placement failure for procedures performed via the conventional route. KEY POINTS: * Technical success of preoperative short hookwire placement was extremely high. * The transfissural approach was a significant independent predictor of initial placement failure for all procedures. * Small lesion size was a significant independent predictor of initial placement failure for procedures performed via the conventional route. PMID- 29247355 TI - Optimisation of sonourethrography: the clamp method. AB - PURPOSE: To describe the clamp method for performing retrograde sonourethrography (RSUG) and contrast-enhanced voiding sonourethrography (CE-VSUG) via the transperineal approach in male adults. MATERIALS AND METHODS: Prospective study of 113 males (14-86 years) with urethral strictures confirmed by urethrography who received sonourethrography via the clamp method between 2011 and 2015. The characteristic parameters of the quantitative variables were calculated and a comparative analysis of the qualitative variables was conducted using the McNemar test. RESULTS: RSUG was performed successfully in all the cases (n = 113) and detected 49 cases with anterior urethral strictures; the strictures in the proximal bulbar cone in five of them (10.2%) were not visualised on retrograde urethrography (RUG) (p < 0.05). CE-VSUG was performed successfully in 97 cases and observed posterior urethral strictures in 82; the bladder neck strictures in 6 of them (7.3%) were not observed on voiding cystourethrography (VCUG) (p < 0.05). Retrograde bladder filling was achieved in approximately 6 min. CONCLUSION: The clamp method enables RSUG and CE-VSUG to be performed simply, effectively and painlessly by a single operator. It also allows the evaluation of cases with urethromeatal alterations (stricture, hypospadias and meatotomy). KEY POINTS: * The clamp method enables RSUG to be performed simply and painlessly. * The clamp method requires only one operator and allows assessing urethromeatal alterations. * RSUG shows greater capacity for detecting anterior urethral strictures than RUG. * The clamp method achieves retrograde bladder filling in approximately 6 min. * CE-VSUG shows greater capacity for detecting strictures than VCUG. PMID- 29247358 TI - Single infusion of low-dose ofatumumab in a child with complicated nephrotic syndrome with anti-rituximab antibodies. PMID- 29247357 TI - Tibial internal rotation negatively affects clinical outcomes in total knee arthroplasty: a systematic review. AB - PURPOSE: The aim of this systematic review is to analyze the effect of tibial rotational alignment after total knee arthroplasty (TKA) on clinical outcomes and assess the eventual cut-off values for tibial TKA rotation leading to poor outcomes. METHODS: A detailed and systematic search from 1997 to 2017 of the Pubmed, Medline, Cochrane Reviews, and the Google Scholar databases was performed using the keyword terms "total knee arthroplasty", "total knee replacement", "tibial alignment", "tibial malalignement", "tibial rotation", "rotational error", "axis", "angle", "tibial malrotation", "clinical outcome", in several combinations. The modified Coleman scoring methodology (mCMS) was used. All the primary TKAs studies analyzing correlation between clinical results and tibial rotation were included. RESULTS: Five articles met the inclusion criteria. A total of 333 arthroplasties were included in this review; 139 had tibial component malalignment, while 194 were in control groups. The mean age of patients was 67.3 (SD 0.57) years. The mean average postoperative follow-up delay was 34.7 months (range 21-70). The mean mCMS score was 59.2 points indicating good methodological quality in the included studies. Functional outcomes were assessed through KSS, OKS, KOOS and VAS, negatively related to tibial internal rotation. CONCLUSIONS: Our review confirmed that excessive internal rotation of the tibial TKA component represents a significant risk factor for pain and inferior functional outcomes after TKA (> 10 degrees of internal rotation demonstrated the common value), since external rotation does not affect the results. However, a universal precise cut-off value has not been found in the available literature and there remains a debate about CT rotation assessment and surgical intra-operative landmarks. LEVEL OF EVIDENCE: III. PMID- 29247356 TI - Current and future pharmacological therapies for NAFLD/NASH. AB - Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and there is no approved pharmacotherapy. The efficacy of vitamin E and pioglitazone has been established in nonalcoholic steatohepatitis (NASH), a progressive form of NAFLD. GLP-1RA and SGLT2 inhibitors, which are currently approved for use in diabetes, have shown early efficacy in NASH, and also have beneficial cardiovascular or renal effects. Innovative NASH therapies include four main pathways. The first approach is targeting hepatic fat accumulation. Medications in this approach include modulation of peroxisome proliferator activator receptors (e.g., pemafibrate, elafibranor), medications targeting farnesoid X receptor axis [obeticholic acid; OCA)], inhibitors of de novo lipogenesis (aramchol, ACC inhibitor), and fibroblast growth factor-21 analogues. A second target is oxidative stress, inflammation, and apoptosis. This class of drug includes apoptosis signaling kinase 1 (ASK1) inhibitor and emricasan (an irreversible caspase inhibitor). A third target is intestinal microbiomes and metabolic endotoxemia. Several agents are in ongoing trials, including IMMe124, TLR4 antagonist, and solithromycin (macrolide antibiotics). The final target is hepatic fibrosis, which is strongly associated with all-cause or liver-related mortality in NASH. Antifibrotic agents are a cysteine-cysteine motif chemokine receptor-2/5 antagonist (cenicriviroc; CVC) and galectin 3 antagonist. Among a variety of medications in development, four agents such as OCA, elafibranor, ASK1 inhibitor, and CVC are currently being evaluated in an international phase 3 trial for the treatment of NASH. Within the next few years, the availability of therapeutic options for NASH will hopefully curb the rising trend of NASH-related diseases. PMID- 29247359 TI - Preparation and Thermoelectric Characteristics of ITO/PtRh:PtRh Thin Film Thermocouple. AB - Thin film thermocouples (TFTCs) can provide more precise in situ temperature measurement for aerospace propulsion systems without disturbance of gas flow and surface temperature distribution of the hot components. ITO/PtRh:PtRh TFTC with multilayer structure was deposited on alumina ceramic substrate by magnetron sputtering. After annealing, the TFTC was statically calibrated for multiple cycles with temperature up to 1000 degrees C. The TFTC with excellent stability and repeatability was realized for the negligible variation of EMF in different calibration cycles. It is believed that owing to oxygen diffusion barriers by the oxidation of top PtRh layer and Schottky barriers formed at the grain boundaries of ITO, the variation of the carrier concentration of ITO film is minimized. Meanwhile, the life time of TFTC is more than 30 h in harsh environment. This makes ITO/PtRh:PtRh TFTC a promising candidate for precise surface temperature measurement of hot components of aeroengines. PMID- 29247360 TI - Cervical vestibular-evoked myogenic potentials in patients with multiple sclerosis: sensitive in detecting brainstem involvement? AB - Cervical vestibular-evoked myogenic potentials (cVEMPs) are accepted to demonstrate the vestibulo-collic reflex. However, the brainstem pathway is still not fully understood. The aim of the study was to evaluate the contribution of cVEMPs to detection of brainstem involvement in multiple sclerosis (MS). Thirty patients fulfilling the criteria for definite MS were included in the study. All were newly diagnosed cases, admitted due to an attack with active lesions on MRI. Thirty-one age- and sex-matched healthy controls constituted the control group. The latencies of peaks p13 and n23 and peak-to-peak amplitude of p13-n23 were measured. Brainstem lesions on MRI were present in 13 of the patients (43.4%). Comparison of the overall results recorded from patients with the healthy controls did not reveal a statistically significant difference in any of the parameters studied (p > 0.05). A significant inter-side difference was not also present between groups (p > 0.05). When p13 and n23 latencies exceeding 2.5 standard deviations (SD) were taken into consideration, it was seen that there were seven patients (23.3%) with prolonged latencies mainly involving the p13 peak. Five of them had brainstem signs on examination and had brainstem lesions on MRI. In the other eight patients with abnormal MRI, normal results were recorded indicating that in only 38% of patients with brainstem lesions, cVEMPs were altered. Absence of a correlation between cVEMPs and brainstem clinical or MRI lesions defies their role in identifying lower brainstem involvement. PMID- 29247361 TI - Biocompatible 5-Aminolevulinic Acid/Au Nanoparticle-Loaded Ethosomal Vesicles for In Vitro Transdermal Synergistic Photodynamic/Photothermal Therapy of Hypertrophic Scars. AB - Biocompatible 5-aminolevulinic acid/Au nanoparticle-loaded ethosomal vesicle (A/A ES) is prepared via ultrasonication for synergistic transdermal photodynamic/photothermal therapy (PDT/PTT) of hypertrophic scar (HS). Utilizing ultrasonication, Au nanoparticles (AuNPs) are synthesized and simultaneously loaded in ethosomal vesicles (ES) without any toxic agents, and 5-aminolevulinic acid (ALA) is also loaded in ES with 20% of the entrapment efficiency (EE). The prepared A/A-ES displays strong absorbance in 600-650 nm due to the plasmonic coupling effect between neighboring AuNPs in the same A/A-ES, which can simultaneously stimulate A/A-ES to produce heat and enhance quantum yields of reactive oxygen species (ROS) by using 632 nm laser. In vitro transdermal penetrability study demonstrates that A/A-ES acts as a highly efficient drug carrier to enhance both ALA and AuNPs penetration into HS tissue. Taking human hypertrophic scar fibroblasts (HSF) as therapeutic targets, synergistic PDT/PTT of HS indicates that A/A-ES could enhance quantum yields of ROS by photothermal effect and localized surface plasmon resonance (LSPR) of AuNPs, resulting in a high level of apoptosis or necrosis. In a word, the prepared A/A-ES shows a better synergistic PDT/PTT efficiency for HSF than the individual PDT and PTT, encouraging perspective for treatment of HS. PMID- 29247363 TI - Promises and pitfalls of electronic health record analysis. AB - Routinely collected electronic health records (EHRs) are increasingly used for research. With their use comes the opportunity for large-scale, high-quality studies that can address questions not easily answered by randomised clinical trials or classical cohort studies involving bespoke data collection. However, the use of EHRs generates challenges in terms of ensuring methodological rigour, a potential problem when studying complex chronic diseases such as diabetes. This review describes the promises and potential of EHRs in the context of diabetes research and outlines key areas for caution with examples. We consider the difficulties in identifying and classifying diabetes patients, in distinguishing between prevalent and incident cases and in dealing with the complexities of diabetes progression and treatment. We also discuss the dangers of introducing time-related biases and describe the problems of inconsistent data recording, missing data and confounding. Throughout, we provide practical recommendations for good practice in conducting EHR studies and interpreting their results. PMID- 29247364 TI - Laparoscopic repair of traumatic flank hernias. AB - INTRODUCTION: Traumatic flank hernias (TFH) are caused by a blunt abdominal trauma with resultant detachment of the oblique musculofascial complex at the iliac crest and/or costal margin. Given such proximity to the bony structures and essential absence of healthy fascia to anchor the mesh, TFH represent a challenging surgical problem. Although laparoscopic repair of ventral hernias has become very common, no series of laparoscopic repairs of TFH has been reported to date. We present a series of patients undergoing laparoscopic repair of TFH. METHODS: After retrospective review of prospective hernia database at two Hernia centers, patients undergoing laparoscopic TFH repair were identified and analyzed. Main outcome measures included patient demographics, surgical technique, intraoperative data, and post-operative outcomes. RESULTS: From December 2007 to December 2013, 14 patients underwent laparoscopic repair of a TFH. Eleven patients had chronically incarcerated viscera within the defect. Operative steps included complete reduction of the hernia sac, pre/retroperitoneal dissection to expose the entire lateral edge of a psoas muscle, defect closure with transabdominal sutures, wide mesh overlap, and transabdominal suture fixation with selective use of bone anchors. The mean operative time was 174 min (range 125-230). Mean estimated blood loss was 65 cc. Mean mesh size was 295 cm2. There were no peri-operative complications. Mean hospital stay was 3.1 days and all patients returned to full activities by 6 weeks. At a mean follow-up of 35 months, there have been no recurrences. CONCLUSION: Laparoscopic approach to TFH is feasible and safe. It is associated with minimal hospital stay and fast functional recovery. The key components of our approach include wide pre/retroperitoneal with defect closure and subsequent wide mesh underlay coverage with fixation to bony structures using anchors/screws. We believe that the laparoscopic approach should safely considered for the majority of patients with TFH. PMID- 29247365 TI - Full-thickness skin graft vs. synthetic mesh in the repair of giant incisional hernia: a randomized controlled multicenter study. AB - PURPOSE: Repair of large incisional hernias includes the implantation of a synthetic mesh, but this may lead to pain, stiffness, infection and enterocutaneous fistulae. Autologous full-thickness skin graft as on-lay reinforcement has been tested in eight high-risk patients in a proof-of-concept study, with satisfactory results. In this multicenter randomized study, the use of skin graft was compared to synthetic mesh in giant ventral hernia repair. METHODS: Non-smoking patients with a ventral hernia > 10 cm wide were randomized to repair using an on-lay autologous full-thickness skin graft or a synthetic mesh. The primary endpoint was surgical site complications during the first 3 months. A secondary endpoint was patient comfort. Fifty-three patients were included. Clinical evaluation was performed at a 3-month follow-up appointment. RESULTS: There were fewer patients in the skin graft group reporting discomfort: 3 (13%) vs. 12 (43%) (p = 0.016). Skin graft patients had less pain and a better general improvement. No difference was seen regarding seroma; 13 (54%) vs. 13 (46%), or subcutaneous wound infection; 5 (20%) vs. 7 (25%). One recurrence appeared in each group. Three patients in the skin graft group and two in the synthetic mesh group were admitted to the intensive care unit. CONCLUSION: No difference was seen for the primary endpoint short-term surgical complication. Full-thickness skin graft appears to be a reliable material for ventral hernia repair producing no more complications than when using synthetic mesh. Patients repaired with a skin graft have less subjective abdominal wall symptoms. PMID- 29247367 TI - Mucoralean fungi for sustainable production of bioethanol and biologically active molecules. AB - Mucoralean fungi are suitable microorganisms for the sustainable production of food, fodder, and fuels from inexpensive natural resources. Ethanol-producing Mucorales are particularly advantageous for second-generation ethanol production in comparison to the conventional ethanolic yeasts and bacteria. They are able to ferment a wide range of sugars to a range of valuable products, while they are typically resistance against the inhibitors available in different substrates, including untreated lignocellulosic hydrolysates. In addition to a high ethanol yield, the fungi produce several commercially valuable by-products, including chitosan, microbial oil (mainly polyunsaturated fatty acids), and protein. Moreover, the fungal extracts can replace the expensive nutrients required in fermentation. Besides, their morphologies can be altered from filamentous to yeast like and are adjustable based on the process requirement. The focus of this review is on applying Mucorales in producing ethanol and the biomass by-products thereof. PMID- 29247366 TI - Human thyroid-stimulating hormone synthesis in human embryonic kidney cells and related N-glycoprofiling analysis for carbohydrate composition determination. AB - A strain of embryonic human kidney cells (HEK293) was transiently co-transfected with the expression vectors coding for the alpha- and beta-subunits of human thyroid-stimulating hormone (hTSH), and, for the first time, a human cell-derived recombinant hTSH was synthesized and extensively characterized. The purification strategy involving two steps provided an overall yield of 55% and a purity level > 90%. The purified material (hTSH-HEK) was analyzed and compared to a CHO derived recombinant preparation (hTSH-CHO) and to a pituitary-derived (hTSH-Pit) preparation. The three preparations showed an equivalent purity (> 95%) with a hTSH-HEK molecular mass 2.1% lower than that of hTSH-CHO and 2.7% higher than that of hTSH-Pit. Remarkable differences were found in the carbohydrate moiety, the lowest sialic acid content and highest fucose content being observed in hTSH HEK. In vivo biological activity was confirmed for the three preparations, the hTSH-HEK bioactivity being 39 and 16% lower than those of hTSH-CHO and hTSH-Pit, respectively. The hTSH-HEK circulatory half-life (t 1/2) was also shorter than those of hTSH-CHO (1.5-fold) and hTSH-Pit (1.2-fold). According to these findings, HEK-293-derived hTSH can be considered to be useful for clinical applications, in view as well of its human origin and particular carbohydrate composition. PMID- 29247368 TI - N-Acyl-homoserine lactones and autoinducer-2-mediated quorum sensing during wastewater treatment. AB - Bacteria can coordinate and synchronize activities through a cell density dependent regulatory mechanism called quorum sensing (QS). Bacteria can measure their population by the synthesis, secretion, and perception of QS signal molecules to regulate specific gene expression when the population reaches a critical threshold. QS participates in various microbial processes such as marine organism bioluminescence, bacterial biofilm formation, and virulence factor expression. The use of QS systems mediated by N-acyl-homoserine lactones and autoinducer-2 has been recently recognized as a promising regulatory approach in environmental science and technology that can intrinsically promote the profound comprehension of wastewater treatment from a microbiology perspective. This article reviewed the study of QS in several environmental systems in wastewater treatment, including systems of aerobic granular sludge, biological nitrogen removal, and bioaugmentation, while several future prospects and suggestions are proposed on the basis of current studies. PMID- 29247369 TI - Past crops yield dynamics reconstruction from tree-ring chronologies in the forest-steppe zone based on low- and high-frequency components. AB - Interrelations of the yield variability of the main crops (wheat, barley, and oats) with hydrothermal regime and growth of conifer trees (Pinus sylvestris and Larix sibirica) in forest-steppes were investigated in Khakassia, South Siberia. An attempt has been made to understand the role and mechanisms of climatic impact on plants productivity. It was found that amongst variables describing moisture supply, wetness index had maximum impact. Strength of climatic response and correlations with tree growth are different for rain-fed and irrigated crops yield. Separated high-frequency variability components of yield and tree-ring width have more pronounced relationships between each other and with climatic variables than their chronologies per se. Corresponding low-frequency variability components are strongly correlated with maxima observed after 1- to 5-year time shift of tree-ring width. Results of analysis allowed us to develop original approach of crops yield dynamics reconstruction on the base of high-frequency variability component of the growth of pine and low-frequency one of larch. PMID- 29247370 TI - Trans-gastric pancreaticogastrostomy reconstruction after pylorus-preserving robotic Whipple: a proposal for a standardized technique. AB - BACKGROUND: A number of technical improvements regarding the pancreatic anastomosis have decreased the morbidity and mortality after pancreaticoduodenectomy. However, postoperative pancreatic fistula (POPF) remains is the most feared complication, and the ideal technique for pancreatic reconstruction is undetermined. MATERIALS AND METHODS: This study is a retrospective review of a prospectively maintained database. Data were collected from all consecutive robot-assisted pancreaticoduodenectomies (RAPD), performed by a single surgeon, at the University of Illinois Hospital & Health Sciences System, between September 2007 and January 2016. RESULTS: A total of 28 consecutive patients (16 male and 12 female) who underwent a RAPD were included in this study. Patients had a mean age and mean BMI of 61.5 years (SD = 12.3) and 27 kg/m2 (SD = 4.9), respectively. The mean operative time was 468.2 min (SD = 73.7) and the average estimated blood loss was 216.1 ml (SD = 113.1). The mean length of hospitalization was 13.1 days (SD = 5.4). There was no clinically significant POPF registered. CONCLUSION: Trans-gastric pancreaticogastrostomy (TPG) represents a valid and feasible option as a pancreatic digestive reconstruction during RAPD. Initial results showed decreased incidence of POPF with an increased risk of postoperative bleeding. Our experience suggests that TPG might be safer than pancreaticojejunostomy (PJ); further studies are needed in order to confirm. PMID- 29247371 TI - Impact of Using Different Response Criteria for Pneumococcal Polysaccharide Vaccination for Assessment of Humoral Immune Status. PMID- 29247372 TI - Smoking-related lung abnormalities on computed tomography images: comparison with pathological findings. AB - Smoking-related lung abnormalities are now an increasing public health concern. According to the findings of large-cohort studies, approximately 8% of smokers have interstitial lung abnormalities, which are associated with a relatively high risk of all-cause mortality. We reviewed the radiological and pathological findings of smoking-related interstitial lung diseases, such as respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, and airspace enlargement with fibrosis. We have also discussed the histological basis of unclassifiable interstitial pneumonia in smokers, which exhibits airway centered cystic lesions with fibrosis. A variety of radiological findings coexist in the lungs of a smoker. This overlapping of multiple pathological conditions might cause the radiological patterns of diseases to become unclassifiable. Therefore, diagnosis should be performed not on the basis of a single radiological finding, but in a comprehensive manner, by including clinical symptoms and disease behavior. Among interstitial abnormalities in smokers, the usual interstitial pneumonia (UIP) pattern is correlated with a worse prognosis than others. Basal-predominant subpleural reticulation is a clue for accurate diagnosis of UIP, which can be achieved by computer-aided quantitative analysis. PMID- 29247374 TI - Inter-Agency Strategies Used by State Mental Health Agencies to Assist with Federal Behavioral Health Parity Implementation. PMID- 29247373 TI - (-)-Epigallocatechin-3-gallate, the major green tea catechin, regulates the desensitization of beta1 adrenoceptor via GRK2 in experimental heart failure. AB - OBJECTIVE: We investigated the effect of (-)-epigallocatechin-3-gallate (EGCG) on cardiac function and its mechanism, which focused on the desensitization of beta1 AR and GRK2 in heart failure (HF) rats. METHODS: HF was induced by abdominal aortic coarctation. Four weeks after HF induction, the rats were given EGCG (25, 50, 100 mg/kg/day). Cardiac function was assessed by measuring haemodynamic parameters. Histological changes were analyzed by HE and Masson's trichrome staining. The expression of beta1-AR was detected by immunohistochemistry and immunofluorescence. The membrane expression of beta1-AR and GRK2 was detected by western blot. The expression levels of beta1-AR mRNA and GRK2 mRNA were evaluated by Q-PCR. RESULT: Compared to the control group, the left ventricular end diastolic pressure, mean blood pressure, heart weight/body weight, and posterior wall thickness in the HF group were significantly increased, whereas the left ventricular systolic pressure, maximum rate of left ventricular pressure rise (+ dP/dt max) and maximum rate of left ventricular pressure fall (- dP/dt max) were clearly decreased. EGCG could improve cardiac function by regulating these parameters. Inflammatory cell infiltration, irregularly arranged cardiomyocytes, swelling of cardiomyocytes and myocardial fibrosis were observed in HF rats' myocardial morphology, and EGCG obviously improved the morphological signs. The expression of beta1-AR was significantly decreased in the left ventricle tissue of HF rats by immunohistochemistry and immunofluorescence. The membrane expression of beta1-AR decreased, whereas GRK2 increased in vivo and in vitro by western blot. EGCG could down-regulate the membrane expression of GRK2 and up regulate the expression of beta1-AR. There were no significant differences in the total expression of beta1-AR mRNA and GRK2 mRNA. CONCLUSIONS: EGCG has therapeutic effects on the heart function of HF rats. The mechanism might be related to the inhibition of the transfer membrane of GRK2 and to the reduction of the desensitization of beta1-AR. PMID- 29247375 TI - A novel mutation in LAMC3 associated with generalized polymicrogyria of the cortex and epilepsy. AB - Occipital cortical malformation is a rare neurodevelopmental disorder characterized by pachygyria and polymicrogyria of the occipital lobes as well as global developmental delays and seizures. This condition is due to biallelic, loss-of-function mutations in LAMC3 and has been reported in four unrelated families to date. We report an individual with global delays, seizures, and polymicrogyria that extends beyond the occipital lobes and includes the frontal, parietal, temporal, and occipital lobes. Next-generation sequencing identified a homozygous nonsense mutation in LAMC3: c.3190C>T (p.Gln1064*). This finding extends the cortical phenotype associated with LAMC3 mutations. PMID- 29247376 TI - Neurotrophin Expression in Lymphocytes: a Powerful Indicator of Degeneration in Parkinson's Disease, Amyotrophic Lateral Sclerosis and Ataxia. AB - Deregulated neurotrophin is an etiological factor in the pathology of neurodegenerative diseases (ND) that are clinically different entities but characterised by similar limb dysfunction. Earlier validation of peripheral biomarkers can provide significant translational benefit to ND patients. We analysed brain-derived neurotrophic factor (BDNF)-tropomyosin possessing tyrosine related kinase (Trk B) and its key downstream proteins which are implicated in ND such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and ataxia. Blood from ND patients with PD, ALS and Ataxia with movement dysfunctions were obtained to analyse mRNA and protein expressions of the above mentioned factors in lymphocytes. The mRNA and protein expression of BDNF-Trk B and its key downstream molecules showed a significant variation when compared to control and among NDs. The study intends to show that on identifying the variation of these key molecules in the blood samples of patients with ND can serve as early diagnostic candidates. Thus by intervening, the neurotrophins and their pathways can help in early diagnosis and optimising levels of diagnostic certainty. PMID- 29247379 TI - Label-free electrochemical immunosensor for ultrasensitive detection of neuron specific enolase based on enzyme-free catalytic amplification. AB - Enzyme-free catalytic amplification is of great significance for sensitive label free electrochemical immunosensors. In this study, an enzyme-free catalytic amplification based label-free amperometric immunosensor was developed for sensitive detection of neuron-specific enolase (NSE) by use of a AuPd nanoparticle-multiwalled carbon nanotube (AuPd-MWCNT) composite, ferrocenecarboxaldehyde (Fc-CHO), and chitosan hybrid hydrogel. The intrinsic virtues of chitosan not only resulted in bioactivity of the attached antibodies and made the other component of the immunosensor easier to fix on the electrode, but also imparted abundant binding sites to the hydrogel to condense Fc-CHO to achieve the initial signal amplification. Fc-CHO, which served as an electroactive species to generate a redox response, also exhibits excellent electrocatalytic activity toward H2O2. AuPd-MWCNT composite, with enhanced peroxidase-like catalytic activity, could catalyze H2O2 to accelerate electron transfer. When H2O2 was present in the detection solution, synergetic catalysis of Fc-CHO and AuPd-MWCNT composite toward H2O2 was achieved, thus realizing enzyme-free signal amplification. On the basis of this enzyme-free signal amplification, the electrochemical immunosensing platform provided a wide linear range from 1 pg mL-1 to 100 ng mL-1, a low detection limit of 0.483 pg mL-1, and high sensitivity of 7.22 MUA (log10 C NSE)-1. Moreover, the immunosensor showed enormous potential in clinical application. Graphical abstract An enzyme-free catalytic amplification based label-free amperometric immunosensor was developed for sensitive detection of neuron-specific enolase (NSE) by use of a AuPd nanoparticle-multiwalled carbon nanotube (MWCNT) composite, ferrocenecarboxaldehyde (Fc-CHO), and chitosan (CS) hybrid hydrogel. BSA bovine serum albumin, GA glutaraldehyde, SWV square wave voltammetry. PMID- 29247377 TI - CCN5/WISP2 and metabolic diseases. AB - Obesity and type 2 diabetes increase worldwide at an epidemic rate. It is expected that by the year 2030 around 500 million people will have diabetes; predominantly type 2 diabetes. The CCN family of proteins has become of interest in both metabolic and other common human diseases because of their effects on mesenchymal stem cell (MSCs) proliferation and differentiation as well as being important regulators of fibrosis. We here review current knowledge of the WNT1 inducible signaling pathway protein 2 (CCN5/WISP2). It has been shown to be an important regulator of both these processes through effects on both the canonical WNT and the TGFbeta pathways. It is also under normal regulation by the adipogenic commitment factor BMP4, in contrast to conventional canonical WNT ligands, and allows MSCs to undergo normal adipose cell differentiation. CCN5/WISP2 is highly expressed in, and secreted by, MSCs and is an important regulator of MSCs growth. In a transgenic mouse model overexpressing CCN5/WISP2 in the adipose tissue, we have shown that it is secreted and circulating in the blood, the mice develop hypercellular white and brown adipose tissue, have increased lean body mass and enlarged hypercellular hearts. Obese transgenic mice had improved insulin sensitivity. Interestingly, the anti-fibrotic effect of CCN5/WISP2 is protective against heart failure by inhibition of the TGFbeta pathway. Understanding how CCN5/WISP2 is regulated and signals is important and may be useful for developing new treatment strategies in obesity and metabolic diseases and it can also be a target in regenerative medicine. PMID- 29247380 TI - Utilizing mass spectrometry imaging to map the thyroid hormones triiodothyronine and thyroxine in Xenopus tropicalis tadpoles. AB - Thyroid hormones are not only responsible for thermogenesis and energy metabolism in animals, but also have an important role in cell differentiation and development. Amphibian metamorphosis provides an excellent model for studying the remodeling of the body. This metamorphic organ remodeling is induced by thyroid hormones, and a larval body is thus converted into an adult one. The matrix assisted laser desorption/ionization (MALDI)-mass spectrometry (MS) imaging technology is expected to be a suitable tool for investigating small bioreactive molecules. The present study describes the distribution of the thyroid hormones, i.e., triiodothyronine (T3) and thyroxine (T4) and their inactive form reverse T3 (rT3) in Xenopus tropicalis tadpoles using two different types of imaging techniques, MS/MS and Fourier transform (FT)-MS imaging. As a result of MS/MS imaging, we demonstrated that T3 was mainly distributed in the gills. T4 was faintly localized in the eyes, inner gills, and intestine during metamorphosis. The intensity of T3 in the gills and the intensity of T4 in the body fluids were increased during metamorphosis. Moreover, the localization of the inactive form rT3 was demonstrated to be separate from T3, namely in the intestine and muscles. In addition, FT-MS imaging could utilize simultaneous imaging including thyroid hormone. This is the first report to demonstrate the molecular distribution of thyroid hormones themselves and to discriminate T3, T4, and rT3 in animal tissues. PMID- 29247381 TI - Development of a light-initiated chemiluminescent assay for the quantitation of sIgE against egg white allergens based on component-resolved diagnosis. AB - The determination of specific IgE (sIgE) level is of great importance in IgE mediated food allergies. Our aim was to develop a homogeneous immunoassay-light initiated chemiluminescent assay (LICA)-for measuring allergen sIgE of a single component in egg white, thus evaluating the LICA-sIgE assay as a useful tool in the diagnosis of food allergy. The LICA-sIgE assay was performed by incubating serum sample with anti-human IgE antibody coated with chemiluminescer beads, streptavidin-coated sensitizer beads, and biotinylated antigens, which consist of four components in egg white. Serum samples from egg allergic patients (n = 70) and healthy volunteers (n = 30) were collected. For calibration, purified human IgE was used as the calibrator. Working conditions of this homogeneous immunoassay were optimized, analytical performance was determined, and correlation of the results between LICA and ImmunoCAP was evaluated. The assays were performed in 8-well plates with a sample volume diluted to 1:10 of 25 MUl. Intra-assay precision (% coefficient of variation) ranged from 1.83 to 4.13%, and inter-assay precision ranged from 2.70 to 8.70%. It exhibited excellent sensitivity, which could distinguish between positive samples and negative samples even at a large dilution level. The sIgE-LICA and ImmunoCAP correlated well in patients allergic to single component (r 2 = 0.929). Also, the components ovomucoid and ovalbumin were best at predicting ImmunoCAP results, with the same area under the ROC curve (AUC) of 0.81, and a specificity of 90.0 and 93.3%, respectively. Our data show effective performance characteristics of LICA to detect sIgE in human serum based on component-resolved diagnostic tests (CRD). The homogeneous sIgE-LICA assay has the following key advantages: requires no washing, simplicity and rapidity, reproducibility, high-throughput, good performance in a liquid phase assay, and good suitability for sIgE diagnosis in food allergy based on CRD. Graphical abstract A light-initiated chemiluminescent assay was developed for the quantitation of sIgE against egg white allergens based on component-resolved diagnosis. Components Gal d 1 and Gal d 2 with the highest AUC values of 0.81 were considered the best at predicting egg allergy. PMID- 29247382 TI - Effects of Phytophthora ramorum on volatile organic compound emissions of Rhododendron using gas chromatography-mass spectrometry. AB - Phytophthora ramorum is an invasive and devastating plant pathogen that causes sudden oak death in coastal forests in the western United States and ramorum blight in nursery ornamentals and native plants in various landscapes. As a broad host-range quarantine pest that can be asymptomatic in some hosts, P. ramorum presents significant challenges for regulatory efforts to detect and contain it, particularly in commercial nurseries. As part of a program to develop new detection methods for cryptic infections in nursery stock, we compared volatile emissions of P. ramorum-inoculated and noninoculated Rhododendron plants using three gas chromatography-mass spectrometry methods. The first used a branch enclosure combined with headspace sorptive extraction to measure plant volatiles in situ. Seventy-eight compounds were found in the general Rhododendron profile. The volatile profile of inoculated but asymptomatic plants (121 days post inoculation) was distinguishable from the profile of the noninoculated controls. Three compounds were less abundant in inoculated Rhododendron plants relative to noninoculated and mock-inoculated control plants. A second method employed stir bar sorptive extraction to measure volatiles in vitro from leaf extractions in methanol; 114 volatiles were found in the overall profile with 30 compounds less abundant and one compound more abundant in inoculated Rhododendron plants relative to mock-inoculated plants. At 128 days post-inoculation, plants were asymptomatic and similar in appearance to the noninoculated controls, but their chemical profiles were different. In a third technique, volatiles from water runoff from the soil of potted healthy and inoculated Rhododendron plants were compared. Runoff from the inoculated plants contained four unique volatile compounds that never appeared in the runoff from mock-inoculated plants. These three volatile detection techniques could lead to innovative approaches that augment detection and diagnosis of P. ramorum and oomycete pathogens in nurseries and other settings. Graphical abstract Detection of volatile signatures may aid in discriminating healthy vs. infected but asymptomatic plants in nursery and greenhouse facilities. PMID- 29247384 TI - Gastric lipomatosis treated by total gastrectomy: a case report. AB - BACKGROUND: Gastric lipomatosis is characterized by multiple gastric lipomas or a diffuse gastric infiltration of the submucosal or subserosal layer by the adipose tissue; diffuse-type gastric lipomatosis is an extremely rare condition. Here, we present the case of a patient with gastric lipomatosis treated by total gastrectomy. CASE PRESENTATION: A 54-year-old man diagnosed with gastric submucosal tumor in 2008 was referred to our hospital for further examination and treatment in September 2016. Upper gastrointestinal endoscopy revealed a submucosal tumor with an associated ulcer on the anterior wall of the lower body of the stomach. A compressing mass was observed on the anterior wall of the greater curvature and the posterior wall of the stomach. Following a biopsy of the submucosal tumor and ulcer, lipoma without malignancy was diagnosed by microscopy. A giant gastric lipoma was suspected because endoscopic ultrasound revealed a high-echoic lesion on the antral wall that extended to the stomach. Therefore, total gastrectomy was performed, and gastric lipomatosis was confirmed by a histological examination of the resected specimen. CONCLUSIONS: Surgical treatment is a highly effective treatment for symptomatic gastric lipomatosis with extensive involvement or multiple lipomas and can be used for patient diagnosis. PMID- 29247385 TI - Within-subject mediation analysis for experimental data in cognitive psychology and neuroscience. AB - Statistical mediation allows researchers to investigate potential causal effects of experimental manipulations through intervening variables. It is a powerful tool for assessing the presence and strength of postulated causal mechanisms. Although mediation is used in certain areas of psychology, it is rarely applied in cognitive psychology and neuroscience. One reason for the scarcity of applications is that these areas of psychology commonly employ within-subjects designs, and mediation models for within-subjects data are considerably more complicated than for between-subjects data. Here, we draw attention to the importance and ubiquity of mediational hypotheses in within-subjects designs, and we present a general and flexible software package for conducting Bayesian within subjects mediation analyses in the R programming environment. We use experimental data from cognitive psychology to illustrate the benefits of within-subject mediation for theory testing and comparison. PMID- 29247383 TI - Adjusted Indirect Comparison Using Propensity Score Matching of Osimertinib to Platinum-Based Doublet Chemotherapy in Patients with EGFRm T790M NSCLC Who Have Progressed after EGFR-TKI. AB - BACKGROUND AND OBJECTIVE: An adjusted indirect comparison was conducted to assess efficacy outcomes, particularly overall survival (OS), of osimertinib versus platinum-based doublet chemotherapy in patients with epidermal growth factor receptor-mutated (EGFRm) T790M mutation-positive non-small-cell lung cancer (NSCLC) who had progressed following an EGFR tyrosine kinase inhibitor (TKI). Analysis of treatment effect from two separate trials had the potential to more accurately estimate the magnitude of OS benefit due to absence of confounding due to treatment switching from the control arm to the osimertinib arm of the ongoing randomized control trial, AURA3. METHODS: Two non-randomized individual datasets were compared: pooled patients from the AURA extension and AURA2 trials (osimertinib 80 mg, n = 405, with a confirmed T790M mutation using tissue samples), and patients from the control arm of the IMPRESS study (platinum-based doublet chemotherapy, n = 61, with a confirmed T790M mutation using plasma circulating tumour DNA [ctDNA]). A propensity score-based approach was used to account for differences in baseline demographics and disease characteristics. RESULTS: After adjustment for baseline differences between the two groups, osimertinib demonstrated a statistically significant improvement in progression free survival (PFS) versus platinum-based doublet chemotherapy (hazard ratio [HR] = 0.278, 95% confidence interval [CI] 0.188-0.409, p < 0.0001; median PFS 10.9 vs. 5.3 months). Improvements were also observed for objective response rate (ORR) and disease control rate (DCR) (ORR: 64.3 vs. 33.3%; odds ratio [OR] = 5.31, 95% CI 2.47-11.40, p < 0.001; DCR: 92.1 vs. 75.0%; OR = 4.72, 95% CI 1.92 11.58, p < 0.001). Similar results were obtained for patients who received osimertinib as second-line treatment only. A statistically significant improvement in OS was observed for the osimertinib group (HR = 0.412, 95% CI 0.273-0.622, p < 0.0001). Median OS for osimertinib was not reached. CONCLUSIONS: In this indirect comparison, osimertinib showed a statistically significant improvement in efficacy outcomes versus platinum-based doublet chemotherapy in patients with EGFRm T790M NSCLC who had progressed after EGFR-TKI therapy. PMID- 29247386 TI - All for one or some for all? Evaluating informative hypotheses using multiple N = 1 studies. AB - Analyses are mostly executed at the population level, whereas in many applications the interest is on the individual level instead of the population level. In this paper, multiple N = 1 experiments are considered, where participants perform multiple trials with a dichotomous outcome in various conditions. Expectations with respect to the performance of participants can be translated into so-called informative hypotheses. These hypotheses can be evaluated for each participant separately using Bayes factors. A Bayes factor expresses the relative evidence for two hypotheses based on the data of one individual. This paper proposes to "average" these individual Bayes factors in the gP-BF, the average relative evidence. The gP-BF can be used to determine whether one hypothesis is preferred over another for all individuals under investigation. This measure provides insight into whether the relative preference of a hypothesis from a pre-defined set is homogeneous over individuals. Two additional measures are proposed to support the interpretation of the gP-BF: the evidence rate (ER), the proportion of individual Bayes factors that support the same hypothesis as the gP-BF, and the stability rate (SR), the proportion of individual Bayes factors that express a stronger support than the gP-BF. These three statistics can be used to determine the relative support in the data for the informative hypotheses entertained. Software is available that can be used to execute the approach proposed in this paper and to determine the sensitivity of the outcomes with respect to the number of participants and within condition replications. PMID- 29247387 TI - Modeling and development of screen-printed impedance biosensor for cytotoxicity studies of lung carcinoma cells. AB - Electrical cell-substrate impedance sensing (ECIS) is a powerful technique to monitor real-time cell behavior. In this study, an ECIS biosensor formed using two interdigitated electrode structures (IDEs) was used to monitor cell behavior and its response to toxicants. Three different sensors with varied electrode spacing were first modeled using COMSOL Multiphysics and then fabricated and tested. The silver/silver chloride IDEs were fabricated using a screen-printing technique and incorporated with polydimethylsiloxane (PDMS) cell culture wells. To study the effectiveness of the biosensor, A549 lung carcinoma cells were seeded in the culture wells together with collagen as an extracellular matrix (ECM) to promote cell attachment on electrodes. A549 cells were cultured in the chambers and impedance measurements were taken at 12-h intervals for 120 h. Cell index (CI) for both designs were calculated from the impedance measurement and plotted in comparison with the growth profile of the cells in T-flasks. To verify that the ECIS biosensor can also be used to study cell response to toxicants, the A549 cells were also treated with anti-cancer drug, paclitaxel, and its responses were monitored over 5 days. Both simulation and experimental results show better sensitivity for smaller spacing between electrodes. Graphical abstract The fabricated impedance biosensor used screen-printed silver/silver chloride IDEs. Simulation and experimental results show better sensitivity for smaller between electrodes. PMID- 29247388 TI - Transfer of the Active Ingredients of Some Plant Protection Products from Raspberry Plants to Beehives. AB - Plant protection products (PPPs) have been found increasingly in the environment. They pose a huge threat to bees, contributing to honeybee colony losses and consequently to enormous economic losses. Therefore, this field investigation was designed to determine whether their active ingredients (AIs) were transferred from raspberry plants to beehives located in the immediate neighbourhood of the crop and to what extent they were transferred. Every week for 2 months, samples of soil, raspberry leaves, flowers and fruits, worker bees, honeybee brood, and honey were collected and analysed for the presence of propyzamide, chlorpyrifos, iprodione, pyraclostrobin, boscalid, cypermethrin, difenoconazole, azoxystrobin, and pyrimethanil residues. Five of these substances were found in the worker bee bodies. Chlorpyrifos, applied to only the soil through the irrigation system, also was detected in the brood. A small amount of boscalid was noted in the honey, but its residues did not exceed the maximum residue level. For chlorpyrifos, boscalid, and pyrimethanil, a positive correlation between the occurrence of PPPs in the crops and the beehives was found. Statistical methods confirmed that the application of PPPs on a raspberry plantation, as an example of nectar-secreting plants, was linked to the transfer of their AIs to beehives. PMID- 29247389 TI - Degree of prescriber's knowledge about variability in biological drugs "innovators" in manufacturing process. AB - PURPOSE: The purpose of the study is to analyse the degree of prescribers' knowledge about the regulation and variability in manufacturing processes (MP) in bio-drugs "innovators" (BI). METHODS: For each selected drugs, the date of authorization by the European Medicines Agency, time elapsed until the first change, total number of changes and annual rate of change (ARC) were recorded. A survey was designed with 4 parts: (a) identifying the BI prescribed; (b) knowledge of the number and ARC of each BI during its MP; (c) knowledge of comparability requirement of BI before or after the MP; (d) evaluating the utility of the information in the survey. RESULTS: Drugs selected and total number of changes: infliximab (41), adalimumab (20), abatacept (13), golimumab (7), etanercept (18), tocilizumab (6) and certolizumab. All BI had been changed in the MP after their authorisation. The survey was answered by 35 professionals from rheumatology, digestive and dermatology area. They had prescribed one or more drugs included in the survey at least once. Sixty-three percent of prescribers did not know the existence of changes relative to the MP. Thirty seven percent of prescribers knew of their existence, but not about number or frequency. Fifty-seven percent of prescribers did not know the regulation about the comparability among BI. The rest of them knew it, but 29% related it only to biosimilar drugs. Ninety-four percent of prescribers identified information as useful. CONCLUSION: BI present a high ARC during their MP after their commercialization, without any efficacy or safety difficulties. Knowledge of this might increase confidence for biosimilars. PMID- 29247390 TI - Cognitive impairment in celiac disease and non-celiac gluten sensitivity: review of literature on the main cognitive impairments, the imaging and the effect of gluten free diet. AB - Celiac disease (CD) and non celiac gluten sensitivity (NCGS) can be responsible for neurological complications such as ataxia and peripheral neuropathies but also cognitive impairment. This cognitive involvement is variable in its expression, its duration and its prognosis ranging from transient and reversible subtle involvement to dementia itself. Through this article, we tried to achieve a review of the literature to better understand this topic. Several mechanisms were proposed to explain the deleterious influence of gluten-related pathologies on cognitive functions: nutritional deficiencies, elevation of circulating cytokine levels due to systemic inflammation, low brain serotonin levels... Several types of dementia such as Alzheimer dementia, vascular dementia, frontotemporal dementia were reported in association with CD. Memory disorder, acalculia, inattention, visuospatial deficits and executive dysfunction must be sought systematically by a neuropsychological assessment in patients with CD or NCGS. As far as the cognitive impairment is concerned, there is no pathognomonic radiological lesion. Concerning therapeutic management; although its effect is controversial, gluten free diet should be introduced, as early as possible, because of its potentially protective effect. PMID- 29247391 TI - Trazodone alleviates both dyskinesia and psychosis in the parkinsonian marmoset model of Parkinson's disease. AB - Trazodone is a clinically available anti-depressant that exhibits affinity for serotonin 1A and 2A receptors, as well as for alpha-adrenoceptors, suggesting that it may be useful to treat L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis that are encountered in advanced Parkinson's disease (PD). Here, we investigated the anti-dyskinetic and anti-psychotic effects of trazodone in the parkinsonian non-human primate. 6 common marmosets were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following repeated administration of L-DOPA to induce stable dyskinesia and psychosis-like behaviours (PLBs), trazodone (0.1, 1 and 10 mg/kg) or vehicle was administered in combination with L-DOPA and its effects on dyskinesia, PLBs and parkinsonism were determined. The addition of trazodone 10 mg/kg to L-DOPA reduced peak dose dyskinesia by ~ 39% (P < 0.01) and peak dose PLBs by ~ 17% (P < 0.01). However, parkinsonian disability was significantly worsened by trazodone 10 mg/kg (P < 0.05) and duration of anti-parkinsonian action was diminished by ~ 21% (P < 0.05). Our results suggest that trazodone may be effective in alleviating L-DOPA-induced dyskinesia and psychosis in PD, but its deleterious effect on motor function is a concern and may limit its tolerability and usefulness in clinical settings. PMID- 29247392 TI - Spontaneous healing of a shredded esophagus after ACDF without direct repair. AB - Esophageal perforation is a catastrophic complication of anterior cervical discectomy and fusion (ACDF). While direct surgical repair has been reported as optimal for restoration of upper gut function, we present the case of a 58-year old woman who achieved complete resolution when treated only with debridement and drainage. We find that a supportive approach, surgical management without direct repair, may play a vital role in select patient populations in order to avoid potentially long-term consequences or radical treatments, like esophageal diversion. Decisions regarding direct repair versus debridement and inspection only should be made on a case-by-case basis through a multidisciplinary approach. PMID- 29247393 TI - Probing the Structural, Electronic, and Magnetic Properties of Ag n V (n = 1-12) Clusters. AB - The structural, electronic, and magnetic properties of Ag n V (n = 1-12) clusters have been studied using density functional theory and CALYPSO structure searching method. Geometry optimizations manifest that a vanadium atom in low-energy AgnV clusters favors the most highly coordinated location. The substitution of one V atom for an Ag atom in Ag n + 1 (n >= 5) cluster modifies the lowest energy structure of the host cluster. The infrared spectra, Raman spectra, and photoelectron spectra of Ag n V (n = 1-12) clusters are simulated and can be used to determine the most stable structure in the future. The relative stability, dissociation channel, and chemical activity of the ground states are analyzed through atomic averaged binding energy, dissociation energy, and energy gap. It is found that V atom can improve the stability of the host cluster, Ag2 excepted. The most possible dissociation channels are Ag n V = Ag + Ag n - 1V for n = 1 and 4-12 and Ag n V = Ag2 + Ag n - 2V for n = 2 and 3. The energy gap of Ag n V cluster with odd n is much smaller than that of Ag n + 1 cluster. Analyses of magnetic property indicate that the total magnetic moment of Ag n V cluster mostly comes from V atom and varies from 1 to 5 MU B. The charge transfer between V and Ag atoms should be responsible for the change of magnetic moment. PMID- 29247395 TI - The challenge of exploring organ function: knowledge is not care, but care needs knowledge! PMID- 29247394 TI - Dose monitoring in pediatric and young adult head and cervical spine CT studies at two emergency duty departments. AB - PURPOSE: As the number of pediatric computed tomography (CT) imaging is increasing, there is a need for real-time radiation dose monitoring and evaluation of the imaging protocols. The aim of this study was to present the imaging data, patient doses, and observations of pediatric and young adult trauma and routine head CT and cervical spine CT collected by a dose monitoring software. METHODS: Patient age, study date, imaging parameters, and patient dose as volume CT dose index (CTDIvol) and dose length product (DLP) were collected from two emergency departments' CT scanners for 2-year period. The patients were divided into four age groups (0-5, 6-10, 11-15, and 16-20 years) for statistical analysis and effective dose determination. The 75th percentile doses were evaluated to be used as local diagnostic reference levels (DRLs). RESULTS: Six hundred fifteen trauma head, 318 routine head, and 592 trauma cervical spine CT studies were assessed. All mean CTDIvol values were statistically lower in hospital B (40.3 +/- 12.3, 30.03 +/- 11.1, and 6.9 +/- 3.1 mGy, respectively) than in hospital A (53.0 +/- 12.9, 43.2 +/- 8.7, and 18.3 +/- 7.3 mGy, respectively). Statistically significant differences were observed on scanning length between hospitals and between CTDIvol values when protocol was updated. The 75th percentiles of trauma cervical spine in hospital B can be used as local DRL. Non-optimized protocols were also revealed in hospital A. CONCLUSION: Dose monitoring software offers a valuable tool for evaluating the imaging practices and finding non-optimized protocols. PMID- 29247396 TI - The mechanism in junctional failure of thoraco-lumbar fusions. Part II: Analysis of a series of PJK after thoraco-lumbar fusion to determine parameters allowing to predict the risk of junctional breakdown. AB - PURPOSE: To identify risk factors, in 12 patients with junctional breakdown (JBD) after thoraco-sacral fusions and to test a software locating maximal bending moment on full spine EOS images. METHODS: Twelve patients underwent long fusions for lumbar degenerative pathologies. Preop EOS images were compared to first postop EOS showing JBD. Parameters analyzed were: spinopelvic parameters [pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), sagittal vertical axis (SVA), spinosacral angle (SSA), lordosis, and kyphosis], proximal junctional angle (PJA), odontoid-hip axis angle (ODHA), and CIA. A new software estimated the location of maximum bending moment (M max) before and after JBD. RESULTS: All patients except one had a JBD located between T10 and L1, diagnosed at average follow-up of 18.58 months. JBD was a fracture in six patients, severe adjacent disc degeneration in the remaining. Average PI was 52 degrees . PT increased, SS decreased after JBD versus preop (p > 0.05). Average PJA was 34.5 degrees . Global lordosis (GLL), upper lordosis (ULL), L4-S1 lordosis, and thoracic kyphosis (TK) were increased (p < 0.05). Lower lumbar lordosis (LLL), was not increased postJBD (p = 0.6). SVA, SSA, ODHA, and C7 slope were not modified (p > 0.05). CIA average value decreased by 7.5% after JBD. T1-T5 alignment was correlated to C7 slope before (R 2 = 0.77075) and after JBD (R 2 = 0.85409). ODHA decreased after JBD (p > 0.05). Most JBD occurred at or one level away from preoperative M max location. CONCLUSION: This study confirms the importance of harmonious distribution of lumbar (GLL, ULL, and ILL) and thoracic curves (TK, T1 T5 segment) in thoraco-sacral fusions. All patients showed an exaggerated ULL, resulting in a posterior shift and increased lever arm at the thoraco-lumbar junction, leading to JBD. PMID- 29247397 TI - Minimally invasive transpedicular approach for the treatment of central calcified thoracic disc disease: a technical note. AB - PURPOSE: To assess the utility of stereotactic navigation for the surgical treatment of ossified, paracentral thoracic discs via a minimally invasive (MI) transpedicular approach. METHODS: The authors performed a retrospective review of cases with paracentral thoracic disc herniation resulting in myelopathy where a traditional MI approach would be difficult, who underwent a stereotactic assisted MI transpedicular approach via a tubular retractor system between 2011 and 2016. Five cases of patients over the age of 18 were selected. Collected data included patient age at surgery, sex, preoperative Nurick grade, number of levels treated, calcified disc presence, length of surgery, estimated blood loss (EBL), length of stay (LOS), complication rate, postoperative Nurick grade, and length of follow up. RESULTS: Five patients had a stereotaxic assisted MI transpedicular thoracic discectomy for paracentrally located calcified disc herniation. Intraoperative navigational images were acquired using intraoperative CT scans (O-arm) to plan and guide the surgical procedure, and real-time navigation was used for precise navigation around the cord to access and remove all fragments. MIS surgery was successfully performed in these otherwise contraindicated cases due to the use of intraoperative real-time stereotactic navigation. All patients had a successful decompression around the anterior aspect of the cord. CONCLUSION: The traditional MI transpedicular thoracic discectomy approach can be further refined and enhanced by stereotactic navigation to expand the limitations of the MIS technique allowing for an increased number and types of patients eligible for minimally invasive surgery. Therefore, MIS via a tubular retractor system with stereotactic navigation is a novel, safe, and effective improvement in feasibility from the traditional minimally invasive transpedicular thoracic discectomy technique. PMID- 29247398 TI - The impact of low back pain on health-related quality of life in old age: results from a survey of a large sample of Swiss elders living in the community. AB - PURPOSE: The present study aims at investigating the effects of low back pain (LBP), i.e., type of symptoms, activity limitations, frequency, duration, and severity on health-related quality of life (HRQoL) in a sample of 707 community dwelling men and women aged >= 65 years living in Switzerland. METHODS: The study is part of a larger survey conducted in Switzerland on a sample of older adults selected randomly from population records, stratified by age and sex. The Standardized Back Pain Definition was used to investigate LBP, and HRQoL was assessed by means of the EQ-5D, including Health Utility Index (HUI) measures. RESULTS: For more than half of the sufferers, pain was chronic, occurred most days or every day and induced activity limitations. One-third of the sufferers reported sciatica symptoms. Individuals reporting every day pain, severe pain and more than 3 years since the last episode without pain lost nearly 10 points of HRQoL. Amongst the dimension of HRQoL, Mobility was the most affected by LBP. CONCLUSIONS: These results provide further insight into the impact of qualitative aspects of LBP and in particular the importance of radiating leg pain and pain frequency and duration. While LBP-related activity limitations had little impact on both self-rated overall health and HUI, radiating leg pain and pain frequency and duration were associated with significantly decreased scores on both dimensions. PMID- 29247399 TI - BMP7 plays a critical role in TMEM100-inhibited cell proliferation and apoptosis in mouse metanephric mesenchymal cells in vitro. AB - Kidney mainly arises from the induction of metanephric mesenchymal cells (MM cells) and the ureteric bud (UB). Transmembrane protein-100 (Tmem100) consists of two transmembrane regions with strong temporal and spatial expression characteristics during renal development. However, the function of Tmem100 in mouse embryonic kidney-derived cells remained unclear. We provided qPCR to verify the relationship between Tmem100 and the BMP signal pathway. To clarify the role of Tmem100 in cell proliferation and apoptosis, we carry out EdU incorporation, annexin V- fluorescein isothiocyanate (FITC) apoptosis assay. Here, we find that the knockdown of Tmem100 increases the proliferation and apoptosis of mouse embryonic kidney-derived cells, and this promotion can be inhibited by knockdown of BMP7 at the same time; these results suggest that BMP7 plays a crucial role in Tmem100-regulated cell proliferation and apoptosis. qRT-PCR results further demonstrate that the deficiency of Tmem100 leads to BMP7 upregulation and overexpression could get opposite results. In BMP7-depleted MK3 cells, Tmem100 is highly upregulated and BMPR-II is downregulated. And in BMP7-overexpressed MK3 cells, the expression of Tmem100 is decreased. In BMPR-II-depleted MK3 cells, Tmem100 is downregulated and BMP7 expression remains still. These findings indicate that both BMP7 and BMPR-II can regulate Tmem100 and vice versa, and BMPR II expression is regulated by BMP7. However, BMP7 has no association with BMPR-II in MK3 cells. Our data demonstrated the significant role of BMP7 in Tmem100 regulated cell proliferation and apoptosis and revealed the complicated regulation network among Tmem100, BMP7, and BMPR-II in mouse embryonic kidney derived cells. PMID- 29247401 TI - HCV load as a possible prognostic factor in patients with HCV-related DLBCL. PMID- 29247400 TI - Immune thrombocytopenia induced by vonoprazan fumarate: a single center retrospective study. PMID- 29247402 TI - Efficacy of antithymocyte globulin as first-line treatment for aplastic anemia-a single-center experience. PMID- 29247403 TI - Personal reflections on Cletus P. Kurtzman (July 19 1938-November 27 2017). PMID- 29247404 TI - Evaluation of the Copan Myco-TB kit for the decontamination of respiratory samples for the detection of Mycobacteria. AB - The purpose of this study was to test a newly developed decontamination and fluidization kit for processing respiratory specimens for the detection of mycobacteria: the Myco-TB procedure (developed by Copan (Brescia, Italy)). This technique was compared with the Zephiran decontamination method in use in our hospital. Respiratory specimens (n = 387: 130 endotracheal/bronchial aspirates, 172 bronchoalveolar lavages and 55 sputa) submitted to the University Hospital of Brussels between January 2016 and March 2017 were included. All samples were divided into two aliquots: one was subjected to the Myco-TB method and one to the Zephiran technique prior to culture. The sensitivities for culture for the Zephiran technique on solid media, the Myco-TB method on solid media and Myco-TB combined with the MGITTM system were respectively 67%, 87% and 89%. The contamination rates were 22% with both the Zephiran and Myco-TB method on solid media and only 4% with the Myco-TB kit combined with the MGITTM system. For direct microscopy, the sensitivities of the Zephiran method and the Myco-TB method were equal (40%) when the centrifugation time was 20 min. The Myco-TB decontamination method is easy and rapid to perform. It is more sensitive for culture as compared to the Zephiran method and gives lower contamination levels when combined with the MGITTM technique. When increasing the centrifugation step to 20 min, the sensitivity of direct microscopy is equal to the Zephiran method. PMID- 29247405 TI - Impact of Depression and Demoralization on Blood Pressure Control in African Americans with Hypertension: Findings from the TRIUMPH Trial. AB - BACKGROUND: African Americans develop hypertension earlier and have worse cardiovascular outcomes than Caucasians. Accumulating evidence suggests that psychological distress may play a role in the observed racial differences in hypertension. Several studies have investigated the relationship between depression and hypertension while little is still known about the role of demoralization. METHODS: Using data from the Trial Using Motivational Interviewing, Positive Affect, and Self-affirmation in African Americans with Hypertension (TRIUMPH), logistic regression models were used to estimate differences in blood pressure control at 12 months among participants with demoralization, depression, and both conditions. RESULTS: Our logistic models showed that reported psychosocial symptoms significantly differed in predicting success in blood pressure control at 12 months. Contrast analyses showed that, after adjusting for sociodemographic, clinical, and psychosocial variables, demoralized patients were less likely to achieve blood pressure control than participants without affective conditions (p = 0.020). Similar results emerged for patients with depression (p = 0.042) and both conditions (p = 0.022). CONCLUSIONS: Depression can be extremely debilitating and has serious health consequence. Our findings confirm this result and show that, even though depression and demoralization share common features, they are two distinct clinical phenomena with similar negative impact on blood pressure control in African Americans. PMID- 29247406 TI - Is the soil quality monitoring an effective tool in consumers' protection of agricultural crops from cadmium soil contamination?-a case of the Silesia region (Poland). AB - The monitoring of soil quality should be a control tool used to reduce the adverse health effects arising from exposure to toxic chemicals in soil through cultivated crop absorption. The aim of the study was to evaluate the effectiveness of the monitoring and control system of soil quality in Poland, in terms of consumer safety, for agricultural plants cultivated in areas with known serious cadmium contamination, such as Silesia Province. To achieve the objective, the contents of cadmium in soils and vegetables in the Silesia administrative area were examined. The obtained results were compared with the results of soil contamination from the quality monitoring of arable soil in Poland. The studies show a significant exceedance of the permissible values of cadmium in soil samples and the vegetables cultivated on that soil. The threat to consumer health is a valid concern, although this threat was not indicated by the results of the national monitoring of soil quality. The results indicated an unequal distribution of risk to consumers resulting from contaminated soil. Moreover, the monitoring systems should be designed at the local or regional scale to guarantee the safety of consumers of edible plants cultivated in the areas contaminated with cadmium. PMID- 29247407 TI - Zfyve16 regulates the proliferation of B-lymphoid cells. AB - Zfyve16 (a.k.a. endofin or endosome-associated FYVE-domain protein), a member of the FYVE-domain protein family, is involved in endosomal trafficking and in TGF beta, BMP, and EGFR signaling. The FYVE protein SARA regulates the TGF-beta signaling pathway by recruiting Smad2/3 and accelerating their phosphorylation, thereby altering their susceptibility to TGF-beta-mediated T cell suppression. Zfyve16 binds to Smad4 and their binding affects the formation of Smad2/3-Smad4 complex in TGF-beta signaling. However, the in vivo function of Zfyve16 remains unknown. In this study, we generated a Zfyve16 knockout mouse strain (Zfyve16 KO ) and examined its hematopoietic phenotypes and hematopoietic reconstruction ability. The proportion of Tcells in the peripheral blood of Zfyve16 KO mice increases compared with that in wild-type mice. This finding is consistent with the role of Zfyve16 in facilitating TGF-beta signaling. Unpredictably, B cell proliferation is inhibited in Zfyve16 KO mice. The proliferation potential of Zfyve16 KO B-lymphoid cells also significantly decreases in vitro. These results suggest that Zfyve16 inhibits the proliferation of T cells, possibly through the TGF-beta signaling, but upregulates the proliferation of B-lymphoid cells. PMID- 29247408 TI - Associations between total mercury and methyl mercury exposure and cardiovascular risk factors in US adolescents. AB - Low levels of chronic heavy metal exposure are associated with a range of adverse health effects. However, whether total blood mercury (Hg) and methyl mercury (MeHg) exposure affect risk factors for cardiovascular disease (CVD) in adolescents remains unclear. The associations between CVD risk factors and total blood Hg and MeHg in adolescents were evaluated using data from the National Health and Nutrition Examination Survey (NHANES), 2011-2012. Data for 1129 adolescents (age 12-19 years) who participated in the US NHANES 2011-2012 were analyzed. A multivariate linear regression was performed to investigate the associations between CVD risk factors and blood Hg and MeHg concentrations. We identified a strong positive association between blood Hg and MeHg and total cholesterol in adolescents in adjusted model. No associations with other CVD risk factors were found in the overall population. In the gender-stratified generalized linear models, girls with the highest MeHg levels demonstrated a 4.22% (95% CI 0.80%, 7.76%) greater increase in serum total cholesterol (P for trend = 0.029) when compared with girls with the lowest MeHg levels. Our findings suggest that blood MeHg may be positively associated with total cholesterol in adolescent girls. More research is needed to verify this association and to elucidate its underlying mechanisms. PMID- 29247409 TI - Organochlorine pesticides in placenta in Kyrgyzstan and the effect on pregnancy, childbirth, and newborn health. AB - Organochlorine pesticides (OCPs) were determined by gas chromatography in 241 placentas from cotton-growing regions, 121 placentas from an urban area (city of Osh), and 146 placentas from unpolluted mountain regions of Kyrgyzstan. Manifestations of disease were recorded in the mothers during pregnancy and parturition and in their newborns during the first 6 days of life. OCPs were detected in 240 out of 508 placentas (47.2%), with increased incidence in the two polluted regions (65%), particularly in placentas from women living near former pesticide storehouses and agro air-strips (99%), but only in 2.7% of placentas from the unpolluted region. alpha-, beta-, and gamma-hexachlorocyclohexane (HCH); DDT; DDE; aldrin; and heptachlor were detected. The sum of concentrations of all OCPs (total OCPs) was calculated for each of the 240 placentas with detectable OCPs (median 9.5 MUg/kg placenta, mean 88.3 MUg/kg, range 0.1-3070 MUg/kg). The incidence of health problems in four subgroups of this data set, with increasing levels of total OCPs, was compared with the incidence of health problems in the group of 268 placentas, where OCPs were undetectable. Relative risk of health problems in both, mothers and newborns, increased significantly, in a concentration-dependent manner, with increasing levels of total OCPs (p < 0.0001). Health complications with increased incidence in OCP-exposed newborns included, i.a., low birth weight, congenital malformations, infections, and stillbirths, in OCP-exposed mothers preterm delivery, (pre-)eclampsia/gestosis, and frequency of hospitalizations after delivery (infections). Women living near former pesticide storehouses and agro airstrips should be considered as being at risk. Reduction of exposure is urgently needed. PMID- 29247410 TI - Contrasted effects of an anti-cyanobacterial ultrasound device on the non-target freshwater invertebrate species Gammarus roeseli. AB - The aim of this work was to investigate the effects of an anti-cyanobacterial ultrasound device (supplied by an electrical power of 15 W and emitting at 23 and 46 kHz) on the widespread freshwater amphipod species Gammarus roeseli. First, laboratory scale experiments in 8-L glass tanks showed that an ultrasound exposure of 2 h and 40 min was sufficient to produce 50% mortality, along with a 6.5 degrees C water temperature increase. Avoiding excessive heating by using a water-cooling and recirculation system permitted an exposure time of 29 h for the same mortality rate. A potential relationship between temperature's rise and amphipod mortality was hence highlighted. Moreover, the use of plastic mesh bag (0.5 mm mesh size) as a physical barrier has not shown any lethal effects of ultrasound exposure. Furthermore, the induction of GPx or GST activity as oxidative stress biomarkers was not observed. This could be explained by reduced ultrasound intensity inside the mesh bags. Thus, according to these results, the tested ultrasound system is not expected to be acutely harmful in the field. PMID- 29247411 TI - The association of windmills with conservation of pollinating insects and wild plants in homogeneous farmland of western Poland. AB - Loss of suitable seminatural habitats and homogenization of crop types have led to the population decline of pollinating insects in farmland. As these insects support crop production, many practical efforts aim to sustain pollinator diversity which is especially challenging in intensively managed and homogeneous farmland. However, there are ongoing changes of the farmland toward its multifunctionality that includes, for example, wind farm development. Windmills are often built within crops; thus, we examined if the noncropped area around windmills can be valuable habitats for wild plants and pollinating insects: bees, butterflies, and flies. Species richness, abundances, and species diversity index of plants and pollinators around windmills were similar to those found in grassland patches (a typical habitat for these insects) and higher than in the adjacent crops. Pollinator diversity index and species richness at windmills increased with the distance to the nearest grassland patch and windmill. The population sizes of pollinating insects were also positively associated with plant diversity. Particular groups of pollinators showed specific habitat associations: bees occurred mostly at windmills, butterflies were highly associated with grasslands, while flies occurred in a similar number at windmill and on grasslands. Since windmills are frequently built within extensive homogeneous fields, thus, they introduce pollination services into the interior of cropped areas, contrary to field margins, road verges, or seminatural grasslands. Thus, although the development of wind farms has various negative environmental consequences, they can be alleviated by the increase of the local population size and diversity of wild plants and pollinating insects at windmills. PMID- 29247412 TI - Surface properties of PM2.5 calcite fine particulate matter in the presence of same size bacterial cells and exocellular polymeric substances (EPS) of Bacillus mucitaginosus. AB - Microorganism cells and spores are the main components of PM2.5 (fine particulate matter) as well as fine mineral particles. In the microscopic system, the microorganisms will affect the minerals through attachment, charge neutralization, and dissolution related to the cell surface structure and metabolite. To explore the process and the results of microbial cells and their extracellular polymeric substances (EPS) acting on the surface properties of minerals of PM2.5 through the metabolism, a common native soil bacterium Bacillus mucitaginosus with abundant extracellular polymers was chosen as the tested strain. Meanwhile, as one of the PM2.5 common minerals, calcite fine particles were taken as the research object to explore the influence of microbial cells and extracellular polymers on its surface properties. High performance liquid chromatography (HPLC), inductively coupled plasma spectrometry (ICP), Zeta potential analysis, Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction spectroscopy (XRD), and scanning electron microscopy (SEM) were used to characterize the composition of EPS, the soluble ions, surface charge, surface groups, crystal form, and surface morphology of calcite residual solid after being treated by the bacterial cells and EPS. The results revealed the EPS of B. mucitaginosus mainly consisted of protein and polysaccharides. Both the whole cell and its EPS could promote the dissolution of calcite particles into calcium ions. Due to the adhesion of organic groups on the calcite surface, the surface potential shifted significantly in the negative direction and the solution pH was clearly increased. The morphology of calcite surface was significantly changed after dissolution and re-crystallization. Experimental results also showed that the existence of the bacteria cells and EPS significantly affected the surface properties of calcite and provide a theoretical basis for the mechanism of PM fine particulate matter on human health impact for further study. PMID- 29247413 TI - Combination of in situ spectroscopy and chemometric techniques to discriminate different types of Roman bricks and the influence of microclimate environment. AB - Red and yellow bricks are the wall-building materials generally used in Roman masonries. The reasons for the different coloration are not always understood, causing loss of crucial information both for the conservation and for the archaeological knowledge of the cultural sites. In this work, a combination of in situ analyses, employing portable Raman spectroscopy and handheld energy dispersive X-ray fluorescence (HH-ED-XRF) spectroscopy along with chemometric analysis, was carried out on ancient Roman bricks of the "Casa di Diana" building (Ostia Antica, Italy-130 CE). Specifically, the compounds and the characteristic elements, which describe each type of brick (red and yellow), were studied avoiding destructive or invasive sampling. The molecular analysis allowed us to identify the major and minor compounds that characterise the bricks (anatase, hematite, quartz, calcite and silicates). However, the elemental analysis gave more useful information. Thus, the complex HH-ED-XRF data matrix generated was treated by a specific principal component analysis (PCA) to identify behavioural differences of the coloured bricks. The results revealed that Ca and Fe are the discriminatory elements for the two types of bricks. The PCA outcomes suggest that the contribution of certain elements is different in the bricks (mainly Ca, P, Sr, As and S, for yellow bricks), which could indicate different raw materials. Even among bricks with the same red colour (Al, Si, Ti, K, Fe, Cr, Mn, Ni, Zn, Cu, Rb and Zr, seemed to be the elements linked to raw materials), as a function of the surface impacts (orientation and microclimate affect the salts' formation), a distinction was made. Furthermore, the PCA pointed out that the yellow bricks are those more affected by decaying processes (related with Ca, P and S), complying with the Raman spectroscopy results in which the efflorescences (gypsum) affect especially the surface of these types of bricks. PMID- 29247414 TI - Seasonal and spatial variations of microcystins in Poyang Lake, the largest freshwater lake in China. AB - Poyang Lake is the largest freshwater lake in China and an important drinking water source. Since the year 2000, toxic cyanobacteria have been observed frequently in Poyang Lake. In the present study, spatial and seasonal variations of microcystins (MCs; MC-RR, MC-YR, and MC-LR) in water column were examined monthly from January to December (except the months of March, May, and November) in 2013, by using ultra-high-performance liquid chromatography-electrospray ionization tandem triple quadrupole/mass spectrometry (UPLC-MS/MS). MC-RR was the most dominant variant, followed by MC-LR, while MC-YR was detected in low concentration. Total MC concentrations (intracellular + extracellular MCs) ranged from 1.26 to 9916.05 ng/L, with an average of 469.99 ng/L, and only 3.14% (6 out of 192 samples) of the water samples contained MC concentrations that exceeded the drinking water guideline level of 1 MUg/L for MC-LR proposed by the World Health Organization (WHO). MC concentrations in water column showed obvious seasonal variations in Poyang Lake. Intracellular and extracellular MCs were both at a low level from January to April but increased quickly from June to August and decreased dramatically thereafter. Intracellular MCs exhibited similar spatial distribution pattern with extracellular MCs. Both intracellular and extracellular MC concentrations in eastern bays and around Songmen Mountain of Poyang Lake were higher than other regions. Intracellular MC concentrations were positively correlated with Chl a (r = 046, P < 0.01), pH (r = 0.25, P < 0.01), cyanobacterial biomass (r = 0.40, P < 0.01), and temperature (r = 0.36, P < 0.01) but negatively correlated with TN (r = - 0.28, P < 0.01), suggesting that TN, cyanobacteria biomass, pH, and temperature might be regulating factors for MC production in Poyang Lake. PMID- 29247415 TI - Financial development, income inequality, and CO2 emissions in Asian countries using STIRPAT model. AB - The main purpose of this paper is to find the effects of financial development, income inequality, energy usage, and per capita GDP on carbon dioxide (CO2) emissions as well the environmental Kuznets curve (EKC) for the three developing Asian countries-Bangladesh, India, and Pakistan. Panel data during the period 1980-2014 and the Stochastic Impacts by Regression on Population, Affluence, and Technology model with fully modified ordinary least squares (FMOLS) are employed for empirical investigation. The results show that financial development has a significant negative relationship with CO2 emission in the three selected Asian countries with the exception of India. The results further reveal that income inequality in Pakistan and India reduce CO2 emission, while the result for Bangladesh is opposite. Likewise, energy usage has a significant positive effect on CO2 emission in Bangladesh, Pakistan, and India. Our empirical analysis based on long-run and short-run elasticity appraisal suggests the validation of the EKC in Pakistan and India. The study findings recommend an important policy insinuation. The study suggests introducing a motivational campaign for the inhabitant towards utilization of high-efficiency electrical appliances, constructing mutual cooperation for economic development rather involve in winning development race, and introducing effective pollution absorption measures along with big projects. PMID- 29247416 TI - beta-carotene and retinol reduce benzo[a]pyrene-induced mutagenicity and oxidative stress via transcriptional modulation of xenobiotic metabolizing enzymes in human HepG2 cell line. AB - Benzo[a]pyrene (B[a]P) is one of the polycyclic aromatic hydrocarbons which is formed due to smoking of foods, incomplete combustion of woods, vehicle exhausts, and cigarettes smokes. B[a]P gets entry into human and animal bodies mainly through their diets. Metabolic activation of B[a]P is required to induce mutagenesis and carcinogenesis in animal and human studies. Carotenoids and retinoids are phytochemicals that if ingested have multiple physiological interferences in the human and animal bodies. In this study, we firstly investigated the protective effects of beta-carotene, beta-apo-8-carotenal, retinol, and retinoic acid against B[a]P-induced mutagenicity and oxidative stress in human HepG2 cells. Secondly, we tested the hypothesis of modulating xenobiotic metabolizing enzymes (XMEs) by carotenoids and retinoids as a possible mechanism of protection by these micronutrients against B[a]P adverse effects. The obtained results declared that beta-carotene and retinol significantly reduced B[a]P-induced mutagenicity and oxidative stress. Tested carotenoids and retinoids reduced B[a]P-induced phase I XMEs and induced B[a]P reduced phase II and III XMEs. Thus, the protective effects of these micronutrients are probably due to their ability of induction of phase II and III enzymes and interference with the induction of phase I enzymes by the promutagen, B[a]P. It is highly recommended to consume foods rich in these micronutrients in the areas of high PAH pollution. PMID- 29247417 TI - Technology acceptance perception for promotion of sustainable consumption. AB - Economic growth in the past decades has resulted in change in consumption pattern and emergence of tech-savvy generation with unprecedented increase in the usage of social network technology. In this paper, the technology acceptance value gap adapted from the technology acceptance model has been applied as a tool supporting social network technology usage and subsequent promotion of sustainable consumption. The data generated through the use of structured questionnaires have been analyzed using structural equation modeling. The validity of the model and path estimates signifies the robustness of Technology Acceptance value gap in adjudicating the efficiency of social network technology usage in augmentation of sustainable consumption and awareness. The results indicate that subjective norm gap, ease-of-operation gap, and quality of green information gap have the most adversarial impact on social network technology usage. Eventually social networking technology usage has been identified as a significant antecedent of sustainable consumption. PMID- 29247418 TI - Elemental composition in rainbow trout tissues from a fish farm from Patagonia, Argentina. AB - Rainbow trout is a salmonid specie of commercial importance raised in hatcheries in many countries. Studies over mineral requirements have being perform to guarantee the fulfillment of the nutritional needs and therefore improving the fish farm productions. The aim of this work was to investigate the performance of the elements like Ag, As, Br, Ca, Cr, Cs, Fe, Hg, K, Na, Rb, Se, and Zn, in rainbow trout from a Patagonian fish farming. Body burden of each element in relation to weight were analyzed for identifying potential bioaccumulation or dilution processes. Our results indicated that water and food were the sources for most of the elements, except Se and Ag. Selenium showed the highest value in unfertilized eggs, and Ag was detected in larvae newly after feeding. Toxic elements as Ag, Cr, and Hg were below the regulation standards for human consumption but tend to bioconcentrate in the juvenile state, and the As was during all the growth studied. The macro and micro nutrients assemble the daily requirements for the humans consume, excepting the K. PMID- 29247420 TI - Shifts from methyl chloride sink to source functions within a coastal salt marsh in eastern China: an examination of the effects of biomass burning prohibition policies. AB - Our previous study found that a salt marsh in eastern China can act as a large CH3Cl sink. One striking finding of this previous study was a strong relationship between high-ambient CH3Cl concentrations and fluxes during the growing season. Moreover, the high-ambient CH3Cl concentration was likely to be related to local biomass burning. However, implementation of biomass burning prohibition policies has effectively reduced biomass burning. Therefore, we predicted that the prohibition of biomass burning would alter CH3Cl concentration and flux within the eastern Chinese coastal salt marsh. In this study, we used static flux chambers to measure CH3Cl fluxes in the early (July of 2004 and January of 2005) and middle-late stages (August and December of 2013) of biomass burning prohibition of along a creek and vegetation transects of the salt marsh. After implementation of the biomass burning prohibition, the concentration and flux of CH3Cl directly related to biomass burning changed remarkably. During the middle late stage of prohibition, the initial CH3Cl concentration was significantly reduced compared to during the early stage of prohibition. Reductions in atmospheric CH3Cl concentration were especially apparent during the growing season, when biomass burning was prohibited and atmospheric CH3Cl concentration dropped to levels nearly as low as the Northern Hemisphere background concentration. Atmospheric CH3Cl concentration significantly varied throughout the salt marsh, with the highest concentrations appearing over the inland areas and mudflat and lower values occurring over the middle locations. This spatial distribution of CH3Cl may have been directly related to the existence and distribution of potential CH3Cl sources, such as coastal seawater, terrestrial biomass burning, and senescent and decaying aboveground biomass. These changes in initial CH3Cl concentration caused by the biomass burning prohibition may eventually lead to shift in the salt marsh from the tendency to act as a CH3Cl sink to the tendency to act as a CH3Cl source. When the initial atmospheric CH3Cl concentration was high, the vegetation stands acted as CH3Cl sinks. Conversely, they became CH3Cl sources. Therefore, we conclude that the biomass burning prohibition altered the ecosystem-atmosphere exchange of CH3Cl within the studied eastern Chinese coastal salt marsh. PMID- 29247422 TI - Colorectal Kaposi Sarcoma in an Immunosuppressed Ulcerative Colitis Patient. PMID- 29247419 TI - Heavy metal pollution in immobile and mobile components of lentic ecosystems-a review. AB - With growing population and urbanization, there is an increasing exploitation of natural resources, and this often results to environmental pollution. In this review, the levels of heavy metal in lentic compartments (water, sediment, fishes, and aquatic plants) over the past two decades (1997-2017) have been summarized to evaluate the current pollution status of this ecosystem. In all the compartments, the heavy metals dominated are zinc followed by iron. The major reason could be area mineralogy and lithogenic sources. Enormous quantity of metals like iron in estuarine sediment is a very natural incident due to the permanently reducing condition of organic substances. Contamination of cadmium, lead, and chromium was closely associated with anthropogenic origin. In addition, surrounding land use and atmospheric deposition could have been responsible for substantial pollution. The accumulation of heavy metals in fishes and aquatic plants is the result of time-dependent deposition in lentic ecosystems. Moreover, various potential risk assessment methods for heavy metals were discussed. This review concludes that natural phenomena dominate the accumulation of essential heavy metals in lentic ecosystems compared to anthropogenic sources. Amongst other recent reviews on heavy metals from other parts of the world, the present review is executed in such a way that it explains the presence of heavy metals not only in water environment, but also in the whole of the lentic system comprising sediment, fishes, and aquatic plants. PMID- 29247421 TI - Clinical Factors and Postoperative Impact of Bile Leak After Liver Resection. AB - BACKGROUND: Despite technical advances, bile leak remains a significant complication after hepatectomy. The current study uses a targeted multi institutional dataset to characterize perioperative factors that are associated with bile leakage after hepatectomy to better understand the impact of bile leak on morbidity and mortality. METHODS: Adult patients in the 2014-2015 ACS NSQIP targeted hepatectomy dataset were linked to the ACS NSQIP PUF dataset. Bivariable and multivariable regression analyses were used to assess the associations between clinical factors and post-hepatectomy bile leak. RESULTS: Of 6859 patients, 530 (7.7%) had a postoperative bile leak. Proportion of bile leaks was significantly greater in patients after major compared to minor hepatectomy (12.6 vs. 5.1%, p < 0.001). The proportion of patients with bile leak was significantly greater in patients after major hepatectomy who had concomitant enterohepatic reconstruction (31.8 vs. 10.1%, p < 0.001). Postoperative mortality was significantly greater in patients with bile leaks (6.0 vs. 1.7%, p < 0.001). After adjusting for significant covariates, bile leak was independently associated with increased risk of postoperative morbidity (OR = 4.55; 95% CI 3.72 5.56; p < 0.001). After adjusting for significant effects of postoperative complications, liver failure, and reoperation (all p<0.001), bile leak was not independently associated with increased risk of postoperative mortality (p = 0.262). CONCLUSION: Major hepatectomy and enterohepatic biliary reconstruction are associated with significantly greater rates of bile leak after liver resection. Bile leak is independently associated with significant postoperative morbidity. Mitigation of bile leak is critical in reducing morbidity and mortality after liver resection. PMID- 29247423 TI - Inhibition of return revisited: Localized inhibition on top of a pervasive bias. AB - An inhibitory after-effect of attention, frequently referred to as inhibition of return (IOR), operates at a previously attended location to discourage perseverative orienting. Using the classic cueing task, previous work has shown that IOR is not restricted to a previously attended location, but rather spreads to adjacent visual space in a graded manner. The present study expands on this earlier work by exploring a wider visual region and a broader range of cue-target onset asynchronies (CTOAs) to characterize the temporal dynamics of the IOR gradient. The results reveal that the magnitude of IOR generated by cueing decreases exponentially as the CTOA increases. The width of the IOR gradient first increases and then decreases, with a temporal profile that is well captured by an alpha function. Importantly, the present study reveals that in addition to its rapidly decaying local properties, cue-induced IOR can include a pervasive inhibitory bias, which remains relatively stable across IOR's lifetime. PMID- 29247424 TI - Method Development for Clinical Comprehensive Evaluation of Pediatric Drugs Based on Multi-Criteria Decision Analysis: Application to Inhaled Corticosteroids for Children with Asthma. AB - BACKGROUND: Establishing a comprehensive clinical evaluation system is critical in enacting national drug policy and promoting rational drug use. In China, the 'Clinical Comprehensive Evaluation System for Pediatric Drugs' (CCES-P) project, which aims to compare drugs based on clinical efficacy and cost effectiveness to help decision makers, was recently proposed; therefore, a systematic and objective method is required to guide the process. METHODS: An evidence-based multi-criteria decision analysis model that involved an analytic hierarchy process (AHP) was developed, consisting of nine steps: (1) select the drugs to be reviewed; (2) establish the evaluation criterion system; (3) determine the criterion weight based on the AHP; (4) construct the evidence body for each drug under evaluation; (5) select comparative measures and calculate the original utility score; (6) place a common utility scale and calculate the standardized utility score; (7) calculate the comprehensive utility score; (8) rank the drugs; and (9) perform a sensitivity analysis. The model was applied to the evaluation of three different inhaled corticosteroids (ICSs) used for asthma management in children (a total of 16 drugs with different dosage forms and strengths or different manufacturers). RESULTS: By applying the drug analysis model, the 16 ICSs under review were successfully scored and evaluated. Budesonide suspension for inhalation (drug ID number: 7) ranked the highest, with comprehensive utility score of 80.23, followed by fluticasone propionate inhaled aerosol (drug ID number: 16), with a score of 79.59, and budesonide inhalation powder (drug ID number: 6), with a score of 78.98. In the sensitivity analysis, the ranking of the top five and lowest five drugs remains unchanged, suggesting this model is generally robust. CONCLUSIONS: An evidence-based drug evaluation model based on AHP was successfully developed. The model incorporates sufficient utility and flexibility for aiding the decision-making process, and can be a useful tool for the CCES-P. PMID- 29247425 TI - Asthma Mimickers: Approach to Differential Diagnosis. AB - The airway of a child can be easily obstructed because of its small size and there are myriad conditions that may obstruct it. Though asthma is the most common condition causing reversible obstruction of the airway; there are a large number of conditions which can obstruct the airway both reversibly and irreversibly. These asthma mimics can present as clinical problems from the neonatal period through adolescence. This article presents an overview of the clinical situations that must be kept in mind when the child presents with subtly unusual clinical features or a deviant course. This is followed by a brief description of the common mimickers along with clinical clues to their diagnosis. Clinicians will need a high index of suspicion for diagnosing these conditions. Prompt recognition and optimal case management and referral will ensure the best outcomes in these children. PMID- 29247426 TI - Asthma - A Disease of How We Breathe: Role of Breathing Exercises and Pranayam. AB - To describe the role of breathing exercises or yoga and/or pranayama in the management of childhood asthma. We conducted an updated literature search and retrieved relevant literature on the role of breathing exercises or yoga and/or pranayama in the management of childhood asthma. We found that the breathing exercises or yoga and/or pranayama are generally multi-component packaged interventions, and are described as follows: Papworth technique, Buteyko technique, Yoga and/or Pranayam. These techniques primarily modify the pattern of breathing to reduce hyperventilation resulting in normalisation of CO2 level, reduction of bronchospasm and resulting breathlessness. In addition they also change the behaviour, decrease anxiety, improve immunological parameters, and improve endurance of the respiratory muscles that may ultimately help asthmatic children. We found 10 clinical trials conducted in children with asthma of varying severity, and found to benefit children with chronic (mild and moderate) and uncontrolled asthma, but not acute severe asthma. Breathing exercises or yoga and/or pranayama may benefit children with chronic (mild and moderate) and uncontrolled asthma, but not acute severe asthma. Before these techniques can be incorporated into the standard care of asthmatic children, important outcomes like quality of life, medication use, and patient reported outcomes need to be evaluated in future clinical trials. PMID- 29247427 TI - Clinical Spectrum and Outcome of Pediatric Drug Induced Liver Injury. AB - Limited literature is available in pediatric population regarding drug-induced liver injury (DILI) making it a diagnostic challenge. This study was thus planned to determine the clinical spectrum and the outcome of DILI in children. All patients with DILI under 18 y of age were retrospectively reviewed and details regarding clinical presentation, Roussel Uclaf Causality Assessment Method (RUCAM) scale, drugs implicated, biochemical abnormalities and outcome were noted. DILI constituted 3.7% of all children with liver disease. Cases were divided into the hepatocellular (18, 50%), cholestatic (10, 27.8%), and mixed pattern (8, 22.2%). Complementary and alternative medicines (CAM) and antitubercular (ATT) drugs accounted for three-fourth cases of total DILI (39% and 33% cases respectively). Overall, 4 (11%) patients died and 5 (14%) patients progressed to chronic DILI. Presence of ascites, non-hepatocellular injury pattern and high serum total IgG levels were significantly associated with unfavourable outcome (death or chronicity). PMID- 29247428 TI - Newer Vaccines against Mosquito-borne Diseases: Correspondence. PMID- 29247429 TI - Prevalence of Hypocalcemia in Seizures in Infancy. AB - A one-year prospective study on developmentally normal children between 1-mo to 2 y with seizures was done to study the prevalence of hypocalcemia. The contribution of hypovitaminosis-D to hypocalcemia was also studied. Of 78 infants (51 boys) enrolled, 18 (23.1%) had hypocalcemia. Fifteen (19.2%) had hypocalcemia secondary to hypovitaminosis-D and 3 (3.8%) had hypomagnesemia. In infants aged less than 6 mo who were exclusively breastfed, 15 (41.67%) had hypocalcemia in comparison to other two age groups [2 (10.53%) in 6-12 mo age-group and 1 (4.35%) in 1-2 y age-group]. This association was statistically significant (p = 0.001). PMID- 29247430 TI - Early Life Origins of Obesity and Related Complications. AB - The idea that nutrition in early life (such as before conception, during pregnancy and in infancy) can influence, or programme, long-term health, known as the 'Developmental Origins of Health and Disease Hypothesis', has generated great scientific interest. This concept is particularly relevant for the development of obesity and its complications, arguably the most important public health issue of the twenty-first century worldwide. The concept is strongly supported by evidence from animal studies, both observational and experimental (randomised) studies in humans, and is highly relevant for population health in both low-income and high incomes countries. For instance, optimising nutrition in pregnancy (both in terms of under-nutrition and over-nutrition) and preventing too fast infant weight gain have been shown to reduce the risk of future obesity. Proposed mechanisms have included effects of early nutrition on the epigenome, hormones such as insulin, and regulation of appetite, that effect long-term risk of obesity. Although further data from experimental studies is required to support a causal link between early nutrition and future adiposity, the developmental origins hypothesis is already changing health policy and practice globally. The present review considers the evidence for the developmental origins of obesity, the mechanisms involved, and the implications for public health. PMID- 29247431 TI - Infrared photobiomodulation (PBM) therapy improves glucose metabolism and intracellular insulin pathway in adipose tissue of high-fat fed mice. AB - Obesity represents a continuously growing global epidemic and is associated with the development of type 2 diabetes mellitus. The etiology of type 2 diabetes is related to the resistance of insulin-sensitive tissues to its action leading to impaired blood glucose regulation. Photobiomodulation (PBM) therapy might be a non-pharmacological, non-invasive strategy to improve insulin resistance. It has been reported that PBM therapy in combination with physical exercise reduces insulin resistance. Therefore, the aim of this study was to investigate the effects of PBM therapy on insulin resistance in obese mice. Male Swiss albino mice received low-fat control diet (n = 16, LFC) or high-fat diet (n = 18, HFD) for 12 weeks. From 9th to 12th week, the mice received PBM therapy (LASER) or Sham (light off) treatment and were allocated into four groups: LFC Sham (n = 8), LFC PBM (n = 8), HFD Sham (n = 9), and HFD PBM (n = 9). The PBM therapy was applied in five locations: to the left and right quadriceps muscle, upper limbs and center of the abdomen, during 40 s at each point, once a day, 5 days a week, for 4 weeks (780 nm, 250 mW/cm2, 10 J/cm2, 0.4 J per site; 2 J total dose per day). Insulin signaling pathway was evaluated in the epididymal adipose tissue. PBM therapy improved glucose tolerance and phosphorylation of Akt (Ser473) and reversed the HFD-induced reduction of GLUT4 content and phosphorylation of AS160 (Ser588). Also, PBM therapy reversed the increased area of epididymal and mesenteric adipocytes. The results showed that chronic PBM therapy improved parameters related to obesity and insulin resistance in HFD-induced obesity in mice. PMID- 29247432 TI - Antimicrobial photodynamic therapy-a promising treatment for prosthetic joint infections. AB - Periprosthetic joint infection (PJI) is associated with high patient morbidity and a large financial cost. This study investigated Photodynamic Therapy (PDT) as a means of eradicating bacteria that cause PJI, using a laser with a 665-nm wavelength and methylene blue (MB) as the photosensitizer. The effectiveness of MB concentration on the growth inhibition of methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Pseudomonas aeruginosa and Acinetobacter baumannii was investigated. The effect of laser dose was also investigated and the optimized PDT method was used to investigate its bactericidal effect on species within planktonic culture and following the formation of a biofilm on polished titanium and hydroxyapatite coated titanium discs. Results showed that Staphylococci were eradicated at the lowest concentration of 0.1 mM methylene blue (MB). With P. aeruginosa and A. baumannii, increasing the MB concentration improved the bactericidal effect. When the laser dose was increased, results showed that the higher the power of the laser the more bacteria were eradicated with a laser power >= 35 J/cm2 and an irradiance of 35 mW/cm2, eradicating all S. epidermidis. The optimized PDT method had a significant bactericidal effect against planktonic MRSA and S. epidermidis compared to MB alone, laser alone, or control (no treatment). When biofilms were formed, PDT treatment had a significantly higher bactericidal effect than MB alone and laser alone for all species of bacteria investigated on the polished disc surfaces. P. aeruginosa grown in a biofilm was shown to be less sensitive to PDT when compared to Staphylococci, and a HA-coated surface reduced the effectiveness of PDT. This study demonstrated that PDT is effective for killing bacteria that cause PJI. PMID- 29247434 TI - Comment on "Low-level laser therapy with 940 nm diode laser on stability of dental implants: a randomized controlled clinical trial". PMID- 29247433 TI - EMLA cream does not influence efficacy and pain reduction during pulsed-dye laser treatment of port-wine stain: a prospective side-by-side comparison. AB - EMLA cream was developed to reduce pain during pulsed-dye laser (PDL) treatment; however, no standard assessment for the therapeutic outcomes of PDL with EMLA creams thus far available. This comparative, prospective clinical trial evaluates laser efficacy and pain reduction during PDL treatment with EMLA cream for local topical anesthesia. Nineteen patients with untreated port-wine stain (PWS) were treated using PDL and examined in this study. Treatment specifications included Vbeam(r) PDL (Candela Corp.), 595-nm wavelength, 9 J/cm2 radiant exposure, 0.45 ms pulse duration, 10 mm spot size, and cryogen spray cooling (40 ms cooling plus a 20 ms delay). A topical anesthetic (EMLA cream: 2.5% lidocaine and 2.5% prilocaine) and a placebo were applied to two respective testing areas on all patients prior to treatment. The visual analog scale (VAS) was used for pain assessment. Clinical therapeutic outcomes were evaluated by visual evaluation and with the use of a chromameter 2 months after 3PDL treatments. The average VAS scores were 3.15 +/- 0.95 and 8 +/- 0.57 for the EMLA cream site and the placebo site, respectively, at a significance level p < 0.001. The EMLA cream site and the placebo site had clearance or fading rates of 45.08 and 44.12%, respectively (p < 0.05). No serious side effects were reported. Patients reported a consistent decrease in pain during PDL treatment when the topical anesthetic EMLA cream was administered. Treatment of PWS by PDL with EMLA cream does not lead to a decrease in efficacy or an increase in side effects; instead, it significantly reduces pain during treatment. EMLA cream is a safe and effective local topical anesthetic for PWS treatment by PDL. PMID- 29247436 TI - Capsule Commentary on Belson et al., Effects of Discontinuation of Urate-Lowering Therapy: A Systematic Review. PMID- 29247435 TI - Trends for Reported Discrimination in Health Care in a National Sample of Older Adults with Chronic Conditions. AB - BACKGROUND: Discrimination in health care settings is associated with poor health outcomes and may be especially harmful to individuals with chronic conditions, who need ongoing clinical care. Although efforts to reduce discrimination are growing, little is known about national trends in discrimination in health care settings. METHODS: For Black, White, and Hispanic respondents with chronic disease in the 2008-2014 Health and Retirement Study (N = 13,897 individuals and 21,078 reports), we evaluated trends in patient-reported discrimination, defined based on frequency of receiving poorer service or treatment than other people from doctors or hospitals ("never" vs. all other). Respondents also reported the perceived reason for the discrimination. In addition, we evaluated whether wealth predicted lower prevalence of discrimination for Blacks or Whites. We used generalized estimating equation models to account for dependency of repeated measures on individuals and wave-specific weights to represent the US non institutionalized population aged 54+ . RESULTS: The estimated prevalence of experiencing discrimination in health care among Blacks with a major chronic condition was 27% (95% CI: 23, 30) in 2008 and declined to 20% (95% CI: 17, 22) in 2014. Reports of receiving poorer service or treatment were stable for Whites (17%, 95% CI: 16, 19 in 2014). The Black-White difference in reporting any health care discrimination declined from 8.2% (95% CI: 4.5, 12.0) in 2008 to 2.5% (95% CI: -1.1, 6.0) in 2014. There was no clear trend for Hispanics. Blacks reported race and Whites reported age as the most common reason for discrimination. CONCLUSIONS: Findings suggest national declines in patient-reported discrimination in health care among Blacks with chronic conditions from 2008 to 2014, although reports of discrimination remain common for all racial/ethnic groups. Our results highlight the critical importance of monitoring trends in reports of discrimination in health care to advance equity in health care. PMID- 29247437 TI - The French National Authority for Health (HAS) Guidelines for Conducting Budget Impact Analyses (BIA). AB - BACKGROUND: Budget impact analysis (BIA) provides short- and medium-term estimates on changes in budgets and health outcomes resulting from the adoption of new health interventions. OBJECTIVE: The purpose of this study is to present the newly developed French National Authority for Health (HAS) guidelines on budget impact analysis as follows: process, literature review, recommendations and comparisons with other guidelines. METHODS: The development process of the HAS guidelines included a literature review (search dates: January 2000 to June 2016), a retrospective investigation of BIA previously submitted to HAS, a public consultation, international expert reviews and approval from the HAS Board and the Economic and Public Health Evaluation Committee of HAS. RESULTS: Documents identified in the literature review included 12 national guidelines, 5 recommendations for good practices developed by national and international society of health economics and 14 methodological publications including recommendations for conducting BIA. Based on its research findings, HAS developed its first BIA guidelines, which include recommendations on the following topics: BIA definition, perspective, populations, time horizon, compared scenarios, budget impact models, costing, discounting, choice of clinical data, reporting of results and uncertainty exploration. CONCLUSION: It is expected that the HAS BIA guidelines will enhance the usefulness, quality and transparency of BIA submitted by drug manufacturers to HAS. BIA is becoming an essential part of a comprehensive economic assessment of healthcare interventions in France, which also includes cost-effectiveness analysis and equity of access to healthcare. PMID- 29247438 TI - [Impact of functional mass lesions in professional female singers : Biomechanics of vocal fold oscillation in the register transition regions]. AB - BACKGROUND: The influence of functional mass lesions on vocal fold oscillation patterns in vocally challenging tasks is not yet understood in detail. MATERIALS UND METHODS: Glissandi on the vowel [a:] from 220 to 440 Hz and 440 to 880 Hz were analyzed in three groups of four professional female singers: without a mass lesion or dysphony (group A), with a functional mass lesion (swellings without a great impact on oscillation patterns during stroboscopy; group B), and with organic dysphony (group C). High-speed digital imaging (HSDI; 20,000 fps), and acoustic and electroglottographic (EGG) signals were used for analysis. Based on the EGG sample entropy, time windows for analysis of register transition phenomena were constructed. The voice signals (glottal area waveform, GAW; acoustic and EGG signals) were perceptually rated in terms of the noticeability of registration events. RESULTS: The absolute sample entropy revealed maxima in fundamental frequency regions where register transitions typically occur. Groups A and B could be distinguished neither by perceptual rating nor based on sample entropy values. In comparison to the other two groups, the absolute sample entropy values of group C were greater in the lower glissando. However, the larger vocal fold oscillatory irregularities were observable for the upper glissando in this group. CONCLUSION: Functional mass lesions do not influence biomechanics adversely in vocally challenging tasks such as register transitions. The use of sample entropy as a criterion for detection of register transitions is promising, but needs further validation. PMID- 29247439 TI - [Intracranial hemorrhage after sinus venous thrombosis during cochlear implantation : A case report]. AB - Cochlear implantation is a safe surgical procedure with low complication rates. In particular, intracranial complications are rare. We present the case of a patient with difficult anatomical relations, which led to injury of the sigmoid sinus during cochlear implantation. Thrombosis and intracerebral hemorrhage followed. The diagnostic steps and treatment of these complications are explained in this case report. PMID- 29247440 TI - Analysis of breast cancer in young women in the Department of Defense (DOD) database. AB - PURPOSE: Breast tumors from young women under the age of 40 account for approximately 7% of cases and have a poor prognosis independent of established prognostic factors. We evaluated the patient population served by the Military Health System, where a disproportionate number of breast cancer cases in young women are seen and treated in a single universal coverage healthcare system. METHODS: The Military Health System Repository and the DoD Central Registration databases were used to identify female breast cancer patients diagnosed or treated at military treatment facilities from 1998 to 2007. RESULTS: 10,066 women were diagnosed with invasive breast cancer at DoD facilities from 1998 to 2007, of which 11.3% (1139), 23.4% (2355) and 65.2% (6572) were < 40, 40-49 and > 50 years old (yo), respectively, at diagnosis. 53% in the < 40 yo cohort were white, 25% were African American (AA) and 8% were Hispanic, with 14% undisclosed. Breast cancer in women diagnosed < 40 yo was more high grade (p < 0.0001), Stage II (p < 0.0001) and ER negative (p < 0.0001). There was a higher rate of bilateral mastectomies among the women < 40 compared to those 40-49 and > 50 (18.4% vs. 9.1% and 5.0%, respectively). Independent of disease stage, chemotherapy was given more frequently to < 40 yo (90.43%) and 40-49 yo (81.44%) than >= 50 yo (53.71%). The 10-year overall survival of younger women was similar to the >= 50 yo cohort. Outcomes in the African American and Hispanic subpopulations were comparable to the overall cohort. CONCLUSION: Younger women had a similar overall survival rate to older women despite receiving more aggressive treatment. PMID- 29247441 TI - Predictors of survival for breast cancer patients with a BRCA1 mutation. AB - PURPOSE: To evaluate in a contemporary cohort the impacts of chemotherapy and oophorectomy on survival for breast cancer patients with a BRCA1 mutation. EXPERIMENTAL DESIGN: We reviewed the pathology reports and medical records of 372 women with breast cancer and a BRCA1 mutation, diagnosed from 2005 to 2017, between the ages of 25 and 65 and followed them for death from all causes and death from breast cancer. Death was ascertained through the Poland vital statistics registry. We performed survival analysis to evaluate the impacts of chemotherapy (including neoadjuvant cisplatinum) and of oophorectomy on survival. RESULTS: After a mean follow-up of 5.6 years (median 5.2), 66 of the 372 women died; 56 of the deaths were from breast cancer and 6 were from ovarian cancer. 127 women received neoadjuvant cisplatinum and 245 women received other chemotherapies. Cisplatinum (versus all other therapies) was associated with a hazard ratio of 0.42 (95%CI 0.20-0.87) on breast cancer-specific survival. The 10 year actuarial all-cause survival for women who had both cisplatinum and an oophorectomy was 94.4%. The 10-year all-cause survival for women who had neither cisplatinum nor an oophorectomy was 65.4% (p < 0.01). CONCLUSIONS: Cisplatinum and oophorectomy are effective therapies for women with breast cancer and a BRCA1 mutation. PMID- 29247442 TI - Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor positive metastatic breast cancer. AB - BACKGROUND: Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. METHODS: From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed. RESULTS: 60 patients were treated accordingly; median age was 61 years; 50 patients (83.3%) had visceral metastasis, and 10 (16.7%) had bone-only disease. Patients had previously received a median of 5 (1-14) lines of treatment, including ET (median 3) and chemotherapy (median 2); 28 (46.7%) received previously fulvestrant and all everolimus. With a median follow-up of 10.3 months, median progression-free survival (mPFS) was 5.8 months (95% CI 3.9-7.3). Patients pretreated with fulvestrant had a similar PFS of 6.4 months (HR 1.00; 95% CI 0.55-1.83; P = 1.00). The most common AEs (adverse events) were neutropenia (93%), anemia (65%), and thrombocytopenia (55%). CONCLUSION: In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8 months with the same magnitude of benefit for fulvestrant-pretreated patients. PMID- 29247443 TI - Ichthyophthirius multifiliis impairs splenic enzymes of the phosphoryl transfer network in naturally infected Rhamdia quelen: effects on energetic homeostasis. AB - Its integrated energetic and metabolic signaling roles place the phosphoryl transfer network, through the enzymes creatine kinase (CK), adenylate kinase (AK), and pyruvate kinase (PK), as a regulatory system coordinating components of the cellular bioenergetics network. Analysis of these enzymes provides new information and perspectives with which to understand disturbances in energetic metabolism between sites of adenosine triphosphate (ATP) generation and utilization. Thus, the aim of this study was to evaluate the involvement of the phosphoryl transfer network in splenic tissue linked with the pathogenesis of silver catfish naturally infected with Ichthyophthirius multifiliis. Splenic cytosolic and mitochondrial CK activities decreased in infected animals compared to uninfected animals, as was also observed for splenic PK activity and splenic ATP levels. In contrast, splenic AK activity increased in infected animals compared to uninfected animals. Based on this evidence, the inhibition and absence of efficient communication between CK isoenzymes cause the impairment of splenic bioenergetics, which is in turn compensated by the augmentation of splenic AK activity in an attempt to restore energy homeostasis. The inhibition of splenic PK activity impairs communication between sites of ATP generation and ATP utilization, as corroborated by splenic ATP depletion. In summary, these alterations contribute to disease pathogenesis linked to spleen tissue in animals infected with white spot disease. PMID- 29247445 TI - Effects of Zinc Supplementation During In Vitro Maturation on Meiotic Maturation of Oocytes and Developmental Capacity in Yak. AB - Zinc (Zn) is an essential trace element that is required during mammalian developmental processes. The objective of this study was to investigate the effects of Zn supplementation during in vitro maturation (IVM) on the developmental capacity of yak (Bos grunniens) oocytes. Cumulus expansion, nuclear maturation, intracellular glutathione (GSH), reactive oxygen species (ROS) levels, superoxide dismutase (SOD) activity, subsequent embryonic development, and the expression of Zn transporters (ZnTs) and Zrt and Irt-like proteins (ZiPs) were evaluated. The Zn concentrations in yak plasma and follicular fluid were 0.740 +/- 0.012 and 0.382 +/- 0.009 MUg/mL, respectively. The cumulus expansion did not show significant differences in COCs after matured with or without Zn supplementation (P > 0.05). The intracellular GSH was higher in oocytes matured with 1 or 2 mg/L Zn than in control group (0 mg/L) (P < 0.05). However, ROS levels of oocytes matured with 1 or 2 mg/L Zn were reduced significantly compared with the control and 0.5 mg/L groups (P < 0.05). The SOD activity was increased significantly after Zn supplementation. The cleavage rate was not significantly different after Zn supplementation (P > 0.05). Percentages of matured oocytes that developed into the blastocyst stage after IVF were 47.9, 50.5, 60.4, and 58.9% for 0, 0.5, 1, and 2 mg/L Zn groups, respectively. Gene expression analysis revealed that the expression patterns associated with Zn were changed after Zn supplementation. In conclusion, Zn supplementation to IVM improved yak oocyte maturation and subsequent development by increasing GSH and SOD activity, decreasing ROS in oocytes. PMID- 29247444 TI - Effect of Arsenic Exposure on NRF2-KEAP1 Pathway and Epigenetic Modification. AB - Arsenic (As) is a known toxic element and carcinogen. Transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) controls cellular adaptation to oxidants and electrophiles by inducing antioxidant genes in response to redox stress. To explore associations between As level and NRF2-regulated cytoprotective genes expression, an observational study was conducted in a population of 61 occupationally exposed men with median (Me) age 50 years (interquartile range (IQR) 42-54) and in a control group of 52 men aged 40 (IQR 31-51.5) without occupational exposure. NRF2, KEAP1, GSTP1, HMOX1, NQO1, PRDX1, and TXNRD1 transcript levels were determined by means of quantitative real-time PCR along with the gene expression, methylation of NRF2 and KEAP1, as well as global DNA methylation were assessed. The median urine As tot. level in the exposed and control group was found to be 21.8 MUg/g creat. (IQR 15.5-39.8 MUg/g creat.) and 3.8 MUg/g creat. (IQR 2.5-9.3) (p < 0.001). Global DNA methylation was significantly higher in occupationally exposed workers than in controls (Me 14.1 (IQR 9.5-18.1) vs Me 8.5 (IQR 5.9-12.6) p < 0.0001). NRF2 mRNA level was positively correlated with expression of all investigated NRF2-target genes in both groups (0.37 > R < 0.76, all p values < 0.0001). The multivariate linear regression adjusting for global methylation showed that As(III) level was significantly associated with expression of TXNRD1, GSTP1, HMOX1, and PRDX1. The results of this study indicate that arsenic occupational exposure is positively associated with global DNA methylation. The findings provide evidence for rather inactivation of NRF2-KEAP1 pathway in response to chronic arsenic exposure. PMID- 29247446 TI - Correction to: The relationship between endogenous thymidine concentrations and [18F]FLT uptake in a range of preclinical tumour models. AB - CORRECTION: Unfortunately, the original version of Figs. 4, 5 and 6b in the article [1] contained errors in the n numbers as indicated on the columns. Please note that column heights and error bars in the original figures and data in the ESM tables are correct and statistical tests are valid. These corrections do not affect any results or conclusions in this article. PMID- 29247447 TI - Relationships of oxidized HDL with blood coagulation and fibrinolysis in patients with type 2 diabetes mellitus. AB - Although oxidization of LDL is known to be a crucial step for atherosclerotic progression, the significance of oxidized HDL remains to be clarified. The purpose of this study was to determine the relationships of oxidized HDL with blood coagulation and fibrinolysis in patients with diabetes. The subjects were outpatients with type 2 diabetes (n = 163; median hemoglobin A1c, 6.9%). Activities of blood coagulation and fibrinolysis were evaluated by levels of thrombin-anti-thrombin complex (TAT) and plasmin-alpha2 plasmin inhibitor complex (PIC), respectively. Relationships of oxidized HDL with TAT and PIC were investigated by using linear regression analysis and logistic regression analysis. Oxidized HDL showed a significant inverse correlation with TAT and a marginally significant correlation with PIC (Spearman's rank correlation coefficient: TAT, - 0.205 [p < 0.01]; PIC, - 0.135 [p = 0.087]). Prevalence of high TAT was significantly lower in the 3rd tertile group for oxidized HDL than in its 1st tertile (20.4 vs. 5.6%, p < 0.05), and prevalence of high PIC was marginally significantly lower in the 3rd tertile group for oxidized HDL than in its 1st tertile (40.7 vs. 24.1%, p = 0.099). In multivariate logistic regression analysis using age, gender, smoking, alcohol drinking, BMI, hemoglobin A1c, therapy for dyslipidemia, therapy for diabetes and anti-coagulation therapy as explanatory variables, odds ratios for high TAT and high PIC in the 3rd tertile group for oxidized HDL versus its 1st tertile group were significantly lower than the reference level of 1.00 (high TAT: 0.19 [0.04-0.99], p < 0.05; high PIC: 0.33 [0.12-0.95], p < 0.05). The frequency of high TAT or high PIC was lower in the higher tertile group for oxidized HDL than in its lower tertile group. Thus, oxidized HDL is thought to be inversely associated with both blood coagulation and fibrinolysis in patients with type 2 diabetes. PMID- 29247449 TI - Psoriasis and risk of malignant lymphoma: a population-based cohort study. PMID- 29247448 TI - iTRAQ-Based Quantitative Proteomics Reveals the New Evidence Base for Traumatic Brain Injury Treated with Targeted Temperature Management. AB - This study aimed to investigate the effects of targeted temperature management (TTM) modulation on traumatic brain injury (TBI) and the involved mechanisms using quantitative proteomics technology. SH-SY5Y and HT-22 cells were subjected to moderate stretch injury using the cell injury controller (CIC), followed by incubation at TTM (mild hypothermia, 32 degrees C), or normothermia (37 degrees C). The real-time morphological changes, cell cycle phase distribution, death, and cell viability were evaluated. Moderate TBI was produced by the controlled cortical impactor (CCI), and the effects of TTM on the neurological damage, neurodegeneration, cerebrovascular histopathology, and behavioral outcome were determined in vivo. Results showed that TTM treatment prevented TBI-induced neuronal necrosis in the brain, achieved a substantial reduction in neuronal death both in vitro and in vivo, reduced cortical lesion volume and neuronal loss, attenuated cerebrovascular histopathological damage, brain edema, and improved behavioral outcome. Using an iTRAQ proteomics approach, proteins that were significantly associated with TTM in experimental TBI were identified. Importantly, changes in four candidate molecules (plasminogen [PLG], antithrombin III [AT III], fibrinogen gamma chain [FGG], transthyretin [TTR]) were verified using TBI rat brain tissues and TBI human cerebrospinal fluid (CSF) samples. This study is one of the first to investigate the neuroprotective effects of TTM on the proteome of human and experimental models of TBI, providing an overall landscape of the TBI brain proteome and a scientific foundation for further assessment of candidate molecules associated with TTM for the promotion of reparative strategies post-TBI. PMID- 29247450 TI - A comprehensive approach to assigning periodontal prognosis. AB - AIM: The purpose of this retrospective case series study was to evaluate the usefulness and performance of a comprehensive approach to assigning periodontal prognosis by assessing the risk of tooth loss due to periodontal disease (TLPD) and estimate the survival time (ST) of periodontally compromised teeth (PCT). MATERIAL AND METHODS: The Long-Term Outcome (LTO) index was utilized to assess the risk of TLPD, at baseline, in 100 patients following periodontal maintenance for a mean 24.7 year (+/-2.4). A TLPD prediction model was utilized to assign ST to PCT. The performance of the TLPD prediction based on both parameters was assessed. RESULTS: The mean TLPD rate increased as the LTO index increased (Kruskal-Wallis p < .001). The percentage of TLPD increased as the ST decreased, with significantly differences between the LTO categories <4 and >=4 for all ST intervals (Mann-Whitney p < .001 to p .021). Only 21% of PCT were lost. This percentage was 58% for teeth assigned the shortest ST and increased to 71% and 88% for these teeth in LTO >=4 patients. CONCLUSIONS: This approach might be useful to predict TLPD in patients with an initial higher risk of TLPD while it was not useful in patients with lower risk of TLPD. PMID- 29247451 TI - Pharmacokinetics of dexmedetomidine administered to patients with end-stage renal failure and secondary hyperparathyroidism undergoing general anaesthesia. AB - WHAT IS KNOWN AND OBJECTIVE: The primary objective of this study was to compare the pharmacokinetics of dexmedetomidine in patients with end-stage renal failure and secondary hyperparathyroidism with those in normal individuals. METHOD: Fifteen patients with end-stage renal failure and secondary hyperparathyroidism (Renal-failure Group) and 8 patients with normal renal and parathyroid gland function (Control Group) received intravenous 0.6 MUg/kg dexmedetomidine for 10 minutes before anaesthesia induction. Arterial blood samples for plasma dexmedetomidine concentration analysis were drawn at regular intervals after the infusion was stopped. The pharmacokinetics were analysed using a nonlinear mixed effect model with NONMEM software. The statistical significance of covariates was examined using the objective function (-2 log likelihood). In the forward inclusion and backward deletion, covariates (age, weight, sex, height, lean body mass [LBM], body surface area [BSA], body mass index [BMI], plasma albumin and grouping factor [renal failure or not]) were tested for significant effects on pharmacokinetic parameters. The validity of our population model was also evaluated using bootstrap simulations. RESULTS AND DISCUSSION: The dexmedetomidine concentration-time curves fitted best with the principles of a two-compartmental pharmacokinetic model. No covariate of systemic clearance further improved the model. The final pharmacokinetic parameter values were as follows: V1 = 60.6 L, V2 = 222 L, Cl1 = 0.825 L/min and Cl2 = 4.48 L/min. There was no influence of age, weight, sex, height, LBM, BSA, BMI, plasma albumin and grouping factor (renal failure or not) on pharmacokinetic parameters. Although the plasma albumin concentrations (35.46 +/- 4.13 vs 44.10 +/- 1.12 mmol/L, respectively, P < .05) and dosage of propofol were significantly lower in the Renal-failure Group than in the Control Group (81.68 +/- 18.08 vs 63.07 +/- 13.45 MUg/kg/min, respectively, P < .05), there were no differences in the context-sensitive half-life and the revival time of anaesthesia between the 2 groups. WHAT IS NEW AND CONCLUSION: The pharmacokinetics of dexmedetomidine were best described by a two-compartment model in our study. The pharmacokinetic parameters of dexmedetomidine in patients with end-stage renal failure and hyperparathyroidism were similar to those in patients with normal renal function. Further studies of dexmedetomidine pharmacokinetics are recommended to optimize its clinical use. PMID- 29247452 TI - Influence of autogenous platelet concentrate on combined GTR/graft therapy in intra-bony defects: A 13-year follow-up of a randomized controlled clinical split mouth study. AB - AIM: To investigate the clinical long-term outcomes 13 years following guided tissue regeneration (GTR) in deep intra-bony defects with and without additional application of autogenous platelet concentrate (APC). METHODS: In 25 patients, two deep contra-lateral intra-bony defects were treated according to GTR using beta-TCP and bio-resorbable membranes. In test defects, APC was applied additionally. After 13 years, clinical healing results were assessed and compared to results at baseline and after 1 year. Furthermore, a tooth survival analysis was carried out. RESULTS: After 13 years, 22 patients were available for tooth survival analysis showing 81.8% of test and 86.4% of control teeth still in situ. Based on the 15 patients still available for split-mouth analysis, median CAL was 10.0 mm in test and 12.0 mm in control sites at baseline. After 1 year, both groups revealed significant CAL gains of 5.0 mm, followed by a new CAL loss of 1.0 mm in the following 12 years. There were no significant differences between test and control sites. CONCLUSION: Within the limits of this study, the data show that most of the CAL gain following GTR can be maintained over 13 years. The additional use of APC had no positive influence on the long-term stability. PMID- 29247453 TI - Plasma adrenocorticotropic hormone (ACTH) concentrations in ponies measured by two different assays suggests seasonal cross-reactivity or interference. AB - BACKGROUND: Analysis of plasma adrenocorticotropic hormone concentration [ACTH] aids diagnosis of pituitary pars intermedia dysfunction (PPID). Comparisons of the validated chemiluminescent-immunoassay (CI) and immunofluorescent (IF) assays are limited. OBJECTIVES: To compare the results of [ACTH] analysis by CI and IF methods of samples collected in autumn and spring and assess cross-reactivity. STUDY DESIGN: Method comparison. METHODS: Plasma from nonlaminitic ponies was analysed concurrently using the IF and CI methods in autumn and the following spring. Diagnostic thresholds for the IF method were derived using ROC curves and Youden indices to correspond with CI thresholds. Assay specificity was assessed using commercially available ACTH fragments and degradation products of endogenous ACTH. RESULTS: CI and IF methods yielded different results (P<0.001); mean differences (CI-IF), (95% confidence intervals): Autumn (n=99) 38.6 (30.6 46.5) pg/ml, Spring (n=88) 5.1 (3.9-6.3) pg/ml. The association between CI and IF results differed in autumn and spring, consistent with seasonally dependent cross reactivity or interference. Good (kappa=0.66-0.74) agreement was obtained for binary interpretation in spring between IF and CI using thresholds of >24 and >29 pg/ml respectively and in autumn between IF and CI using thresholds of >27 and >47 pg/ml respectively or >33 and >77 pg/ml respectively. Of 88 ponies with both spring and autumn samples, 56 (64%) exceeded a published autumn CI threshold (>47 pg/ml), of which 39 (70%) were below the equivalent threshold (<29 pg/ml) the following spring without treatment. The CI assay showed apparent increases in [ACTH] following addition of CLIP (ACTH 18-39). Degradation of ACTH during storage affected the assays differently. MAIN LIMITATIONS: Limited numbers of PPID cases were included. Immunoreactivity of commercially available peptides may differ from their endogenous equivalents. CONCLUSIONS: The methods yielded different absolute values but the agreement for binary classification was good. An altered pituitary secretome in autumn that affects apparent [ACTH] values is likely. The Summary is available in Spanish - see Supporting information. PMID- 29247455 TI - Synthesis and evaluation of an 18 F-labeled trifluoroborate derivative of 2 nitroimidazole for imaging tumor hypoxia with positron emission tomography. AB - 2-Nitroimidazole-based hypoxia imaging tracers such as 18 F-FMISO are normally imaged at late time points (several hours post-injection) due to their slow clearance from background tissues. Here, we investigated if a hydrophilic zwitterion-based ammoniomethyl-trifluoroborate derivative of 2-nitroimidazole, 18 F-AmBF3 -Bu-2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF3 -Bu-2NI was prepared in 4 steps. 18 F labeling was conducted via 18 F-19 F isotope exchange reaction, and 18 F-AmBF3 -Bu-2NI was obtained in 14.8 +/- 0.4% (n = 3) decay-corrected radiochemical yield with 24.5 +/- 5.2 GBq/MUmol specific activity and >99% radiochemical purity. Imaging and biodistribution studies in HT-29 tumor-bearing mice showed that 18 F-AmBF3 -Bu-2NI cleared quickly from blood and was excreted via the hepatobiliary and renal pathways. However, the tumor was not visualized in PET images until 3 hours post-injection due to low tumor uptake (0.54 +/- 0.13 and 0.19 +/- 0.04%ID/g at 1 and 3 hours post-injection, respectively). The low tumor uptake is likely due to the highly hydrophilic motif of ammoniomethyl-trifluoroborate that prevents free diffusion of 18 F-AmBF3 -Bu-2NI across the cell membrane. Our results suggest that highly hydrophilic 18 F-labeled ammoniomethyl-trifluoroborate derivatives might not be suitable for imaging intracellular targets including nitroreductase, a common tumor hypoxia imaging target. PMID- 29247454 TI - Dermatologists across Europe underestimate depression and anxiety: results from 3635 dermatological consultations. AB - BACKGROUND: It was recently demonstrated that a significant number of patients with common skin diseases across Europe are clinically depressed and anxious. Studies have shown that physicians not trained as psychiatrists underdiagnose depression. This has not been explored among dermatologists. OBJECTIVES: To estimate the concordance between clinical assessment of depression and anxiety by a dermatologist and assessment with the Hospital Anxiety and Depression Scale (HADS). METHODS: The study was an observational cross-sectional multicentre study of prevalent cases of skin diseases in 13 countries in Europe. Consecutive patients were recruited in outpatient clinics and filled in questionnaires prior to clinical examination by a dermatologist who reported any diagnosis of skin disease and signs of mood disorders. RESULTS: Analysis of the 3635 consultations showed that the agreement between dermatologist and HADS was poor to fair (lower than 0.4) for all diagnosis categories. The true-positive rate (represented by the percentage of dermatologists recognizing signs of depression or anxiety in patients with depression or anxiety as defined by a HADS value >= 11) was 44.0% for depression and 35.6% for anxiety. The true negative rate (represented by the percentage of dermatologists not detecting signs of depression or anxiety in non depressed or non-anxious patients defined by HADS-value < 11) was 88.8% for depression and 85.7% for anxiety. CONCLUSIONS: Dermatologists in Europe tend to underestimate mood disorders. The results suggest that further training for dermatologists to improve their skills in diagnosing depression and anxiety might be appropriate. When present, the psychological suffering of patients with dermatological conditions needs to be addressed. PMID- 29247456 TI - Audit of operative hysteroscopies among infertile women in a resource-poor setting. AB - OBJECTIVE: To evaluate the operative hysteroscopy procedures performed among infertile women at two hospitals in Nigeria. METHODS: A prospective case series was undertaken among all patients with infertility who underwent operative hysteroscopy between November 2015 and April 2017. The outcome measures included the frequency and type of operative hysteroscopy and the reproductive outcome. RESULTS: The series included 159 women, 70.4% (n=112) of whom had abnormal findings at hysteroscopy. A total of 162 operative hysteroscopic procedures were performed; the most common procedures were adhesiolysis (76 [46.9%]), polypectomy (28 [17.3%]), and septum resection/incision (17 [10.5%]). The instruments used were mainly scissors (65 [40.1%]) and a resectoscope (52 [32.1%]). Complete removal of the lesions was achieved in 86.4% (n=140) of the procedures and a normal cavity in 87.0% (n=141). The complication rate was 6.8% (n=11); the most common complication was minor hemorrhage (5 [3.1%]). The main challenges included poor distention (10 [6.2%]) and poor vision (8 [4.9%]). Menstrual normalization was achieved in 64 (40.3%) of the patients, the cumulative pregnancy rate was 19.5% (n=31), and the live birth rate was 3.8% (n=6). CONCLUSION: Operative hysteroscopy was feasible and safe in the present resource-poor region. There is a need to build capacity for the performance of hysteroscopy to facilitate the management of infertility in the region. PMID- 29247457 TI - Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing in vitro fertilization/intracytoplasmic sperm injection: A prospective randomized controlled trial. AB - OBJECTIVE: To compare the endocrinological profiles, cycle characteristics and pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) with or without clomiphene citrate (CC) supplementation in normal ovulatory women undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). DESIGN: Prospective randomized controlled study. PATIENT(S): A total of 320 infertile women undergoing IVF/ICSI. Medroxyprogesterone acetate (MPA) and human menopausal gonadotropin (hMG) were simultaneously administered on menstrual cycle day 3. The women were randomized into 2 equal groups with or without CC supplementation. MEASURES: The primary outcome measure was the percentage of women with profound pituitary suppression (luteinizing hormone [LH] <1.0 IU/L on the trigger day). The secondary outcomes were endocrinological profiles, cycle characteristics and pregnancy outcomes. RESULTS: The percentage of women with profound pituitary suppression was significantly lower in the study group (hMG + MPA + CC) than in the control group (hMG + MPA) (1.9% vs 33.1%, P < .001). The mean LH level during controlled ovarian stimulation (COS) was higher in the study group than in the control group (P < .001), but none of the patients in either group exhibited a premature LH surge. The doses of Gn in the study group were significantly lower than those in the control group (1334.06 +/- 212.53 IU vs 1488.28 +/- 325.08 IU, P < .001). The number of oocytes retrieved was similar between the 2 groups (10.03 +/- 5.97 vs 10.34 +/- 7.52, P > .05). No significant differences were observed in either the number of viable embryos or the pregnancy outcomes between the 2 groups. CONCLUSION(S): Clomiphene citrate is an effective adjuvant to alleviate pituitary suppression in the PPOS protocol; however, it has no impact on clinical outcomes. PMID- 29247459 TI - 131 I radiolabeled immune albumin nanospheres loaded with doxorubicin for in vivo combinatorial therapy. AB - For the purpose of providing new insights for high-efficiency radiochemotherapy of hepatoma, a radioimmunotherapy and chemotherapy combinatorial therapy albumin nanospheres 131 I-antiAFPMcAb-DOX-BSA-NPs was designed and prepared. It was obtained in a high radiolabeling yield approximately 65% with the radiochemical purity of over 98%. The transmission electron microscope showed that the nanospheres obtained in good monodispersion with a diameter of approximately 230 nm. The doxorubicin (DOX) loading capacity of the DOX-BSA-NPs nanoparticles was determined to be approximately 180 MUg/mg and 95.79 +/- 3.89%. DOX was released gradually in 6 days. In vivo tumor-growth inhibition experiments showed that after treating with 131 I-antiAFPMcAb-DOX-BSA-NPs for 14 days, the tumor volume decreased more obvious than that of other 2 time points and the control groups. All the results indicated that the radiolabeled immune albumin nanospheres 131 I antiAFPMcAb-DOX-BSA-NPs could significantly inhibit the hepatoma tumor growth with the strategy of combinatorial radioimmunotherapy and chemotherapy. PMID- 29247458 TI - The Tyneside Pegboard Test: development, validation, and observations in unilateral cerebral palsy. AB - AIM: The aims of this study were twofold: first, to develop and validate a timed test of unimanual and bimanual dexterity suitable for those with disability affecting hand function; second, to explore relationships between unimanual and bimanual completion times. METHOD: We developed the Tyneside Pegboard Test (TPT), an electronically timed test with three peg sizes, incorporating an asymmetrical bimanual task. Nine hundred and seventy-four participants (455 males, 519 females; age range 4-80y) provided normative data. Test-retest reliability and construct validity were assessed (50 adults: 14 males, 36 females; 15-73y) on two occasions 2 weeks apart. Bimanual and unimanual completion times were measured in 87 children (51 males, 36 females) with unilateral cerebral palsy (CP) and 498 individuals in a comparison group (238 males, 260 females; 5-15y). RESULTS: The comparison group showed an asymmetrical U-shaped relationship between completion times and age. Intraclass correlation coefficients ranged from 0.74 to 0.91, indicating moderate test-retest reliability. There was a negative relationship between average TPT bimanual times and Purdue pegboard bimanual scores (Spearman's rho -0.611, degrees of freedom 44, p<0.001). Children with unilateral CP had greater prolongation of bimanual than unimanual completion times compared with the comparison group (mean difference 20.31s, 95% confidence interval 18.13 22.49, p<0.001). INTERPRETATION: The TPT is accessible for those with impaired hand function. Children with unilateral CP demonstrated disproportionate bimanual deficits, even allowing for unimanual dexterity: this has implications for therapy. WHAT THIS PAPER ADDS: We developed an adapted, electronically timed 9 hole pegboard test. Our modifications facilitate use by those with disability affecting hand function. The test incorporates an asymmetrical bimanual task. Children with unilateral cerebral palsy showed disproportionate bimanual dexterity deficits even allowing for unimanual dexterity. PMID- 29247461 TI - Biradicaloid and Zwitterion Reactivity of Dicarbondiphosphide Stabilized with N Heterocyclic Carbenes. AB - Organic biradicals are usually very short lived species under standard laboratory conditions, which makes their experimental studies difficult. In contrast, heteroatom-substituted analogues of these biradicals show enhanced stability due to pi-electron delocalization, which is why main group biradicals (or biradicaloids) of archetypical heterocyclobutanediyls have been thoroughly investigated. Herein, N-heterocyclic carbene (NHC)-stabilized dicarbondiphosphide compounds of the type (L2 )C2 P2 (L=NHC) were utilized to activate both single and multiple bonds in small molecules with a feasible concerted mechanism. This reactivity is explicable by considerable biradicaloid character of the dicarbondiphosphide compounds, which is further corroborated by theoretical studies. Furthermore, the dicarbondiphosphide compounds also exhibited Lewis base properties towards Lewis acids, such as borane and metal halides. PMID- 29247460 TI - Identification of an (-)-englerin A analogue, which antagonizes (-)-englerin A at TRPC1/4/5 channels. AB - BACKGROUND AND PURPOSE: (-)-Englerin A (EA) is a potent cytotoxic agent against renal carcinoma cells. It achieves its effects by activation of transient receptor potential canonical (TRPC)4/TRPC1 heteromeric channels. It is also an agonist at channels formed by the related protein, TRPC5. Here, we sought an EA analogue, which might enable a better understanding of these effects of EA. EXPERIMENTAL APPROACH: An EA analogue, A54, was synthesized by chemical elaboration of EA. The effects of EA and A54 on the activity of human TRPC4 or TRPC5 channels overexpressed on A498 and HEK 293 cells were investigated, firstly, by measuring intracellular Ca2+ and, secondly, current using whole-cell patch clamp recordings. KEY RESULTS: A54 had weak or no agonist activity at endogenous TRPC4/TRPC1 channels in A498 cells or TRPC4 or TRPC5 homomeric channels overexpressed in HEK 293 cells. A54 strongly inhibited EA-mediated activation of TRPC4/TRPC1 or TRPC5 and weakly inhibited activation of TRPC4. Studies of TRPC5 showed that A54 shifted the EA concentration-response curve to the right without changing its slope, consistent with competitive antagonism. In contrast, Gd3+ -activated TRPC5 or sphingosine-1-phosphate-activated TRPC4 channels were not inhibited but potentiated by A54. A54 did not activate TRPC3 channels or affect the activation of these channels by the agonist 1-oleoyl-2 acetyl-sn-glycerol. CONCLUSIONS AND IMPLICATIONS: This study has revealed a new tool compound for EA and TRPC1/4/5 channel research, which could be useful for characterizing endogenous TRPC1/4/5 channels and understanding EA-binding sites and their physiological relevance. PMID- 29247462 TI - Cross-modal refinement of visual performance after brief somatosensory deprivation in adult mice. AB - It is well established that the congenital lack of one sensory modality enhances functionality in the spared senses. However, whether a late onset deprivation of one sense leads to such alterations is largely unknown. Here, we investigated whether a somatosensory deprivation induced by bilateral whisker removal affects visual acuity and contrast sensitivity in fully adult mice. Using the visual cortex-dependent visual water task, we found that a brief somatosensory deprivation markedly improved behavioral visual acuity and contrast sensitivity by about 40%. Determining these attributes of vision using periodic optical imaging of intrinsic signals in the same mice revealed that visual cortex responses elicited by weak visual stimuli were massively increased after somatosensory deprivation. Strikingly, comparison of visual acuity and contrast sensitivity values determined by the visual water task and intrinsic signal imaging revealed that these measurements were almost identical, even at the level of individual animals. In summary, our results suggest that a brief manipulation of somatosensory experience profoundly boosts visual cortex-dependent vision in adults. PMID- 29247463 TI - Primary Cutaneous Rhabdomyosarcoma: an illustrative case of an uncommon neoplasm. PMID- 29247464 TI - No-call non-invasive prenatal testing gives important information. PMID- 29247465 TI - Cannabinoid-glutamate interactions and neural oscillations: implications for psychosis. AB - Preclinical and clinical data suggest that the cannabinoid and glutamatergic systems are implicated in the pathophysiology of schizophrenia (SZ), the prototypical psychotic disorder. This has led to distinct "cannabis" and "ketamine" models of SZ, respectively. However, these two models need not be mutually exclusive. Indeed, in several brain regions implicated in the putative neural circuitry of SZ (e.g., hippocampus, frontal cortex, cerebellum), cannabinoid receptor type 1 (CB1Rs) and glutamate N-methyl-D-aspartate receptors (NMDARs) have direct and indirect interactions. CB1R agonists and NMDAR antagonists act upon gamma-aminobutyric acid (GABA) interneurons to reduce GABAergic neurotransmission. This would be predicted to result in the unsynchronized activity of pyramidal neurons, disrupting neural network oscillations involved in information processing, thus leading to psychotomimetic effects. Hence, the overarching aim of the current review is to synthesize the known literature on cannabinoids and glutamate in the context of neural oscillations in SZ. First, discussion of SZ and the basic mechanisms of neural oscillations are discussed, including a summary of the role of theta (4-7 Hz) and gamma (30-80 Hz) oscillations in neurocognition. Next, a brief review of the role of the cannabinoid and glutamatergic systems in SZ is outlined, followed by discussion of the known synaptic interactions between these two systems. Finally, the potential role of CB1Rs and NMDARs, both independently and in combination, on neural oscillations in relation to psychotic symptoms is considered. It is hoped that this review will yield a series of testable hypotheses that may be used to further elucidate the pathophysiology of SZ. PMID- 29247466 TI - Disease implications of animal social network structure: A synthesis across social systems. AB - The disease costs of sociality have largely been understood through the link between group size and transmission. However, infectious disease spread is driven primarily by the social organization of interactions in a group and not its size. We used statistical models to review the social network organization of 47 species, including mammals, birds, reptiles, fish and insects by categorizing each species into one of three social systems, relatively solitary, gregarious and socially hierarchical. Additionally, using computational experiments of infection spread, we determined the disease costs of each social system. We find that relatively solitary species have large variation in number of social partners, that socially hierarchical species are the least clustered in their interactions, and that social networks of gregarious species tend to be the most fragmented. However, these structural differences are primarily driven by weak connections, which suggest that different social systems have evolved unique strategies to organize weak ties. Our synthetic disease experiments reveal that social network organization can mitigate the disease costs of group living for socially hierarchical species when the pathogen is highly transmissible. In contrast, highly transmissible pathogens cause frequent and prolonged epidemic outbreaks in gregarious species. We evaluate the implications of network organization across social systems despite methodological challenges, and our findings offer new perspective on the debate about the disease costs of group living. Additionally, our study demonstrates the potential of meta-analytic methods in social network analysis to test ecological and evolutionary hypotheses on cooperation, group living, communication and resilience to extrinsic pressures. PMID- 29247467 TI - Release from informational masking by auditory stream segregation: perception and its neural correlate. AB - In the analysis of acoustic scenes, we easily miss sounds or are insensitive to sound features that are salient if presented in isolation. This insensitivity that is not due to interference in the inner ear is termed informational masking (IM). So far, the cellular mechanisms underlying IM remained elusive. Here, we apply a sequential IM paradigm to humans and gerbils using a sound level increment detection task determining the sensitivity to target tones in a background of standard (same frequency) and distracting tones (varying in level and frequency). The amount of IM that was indicated by the level increment thresholds depended on the frequency separation between the distracting and the standard and target tones. In humans and gerbils, we observed similar perceptual thresholds. A release from IM of more than 20 dB was observed in both species if the distracting tones were well segregated in frequency from the other tones. Neuronal rate responses elicited by similar sequences in gerbil inferior colliculus and auditory cortex were recorded. At both levels of the auditory pathway, the neuronal thresholds obtained with a signal-detection-theoretic approach deducing the sensitivity from the analysis of the neurons' receiver operating characteristics matched the psychophysical thresholds revealing that IM already emerges at midbrain level. By applying objective response measures in physiology and psychophysics, we demonstrated that the population of neurons has a sufficient sensitivity for explaining the perceptual level increment thresholds indicating IM. There was a good correspondence between the neuronal and perceptual release from IM being related to auditory stream segregation. PMID- 29247468 TI - The F1 -ATPase from Trypanosoma brucei is elaborated by three copies of an additional p18-subunit. AB - The F-ATPases (also called the F1 Fo -ATPases or ATP synthases) are multi-subunit membrane-bound molecular machines that produce ATP in bacteria and in eukaryotic mitochondria and chloroplasts. The structures and enzymic mechanisms of their F1 catalytic domains are highly conserved in all species investigated hitherto. However, there is evidence that the F-ATPases from the group of protozoa known as Euglenozoa have novel features. Therefore, we have isolated pure and active F1 ATPase from the euglenozoan parasite, Trypanosoma brucei, and characterized it. All of the usual eukaryotic subunits (alpha, beta, gamma, delta, and epsilon) were present in the enzyme, and, in addition, two unique features were detected. First, each of the three alpha-subunits in the F1 -domain has been cleaved by proteolysis in vivo at two sites eight residues apart, producing two assembled fragments. Second, the T. brucei F1 -ATPase has an additional subunit, called p18, present in three copies per complex. Suppression of expression of p18 affected in vitro growth of both the insect and infectious mammalian forms of T. brucei. It also reduced the levels of monomeric and multimeric F-ATPase complexes and diminished the in vivo hydrolytic activity of the enzyme significantly. These observations imply that p18 plays a role in the assembly of the F1 domain. These unique features of the F1 -ATPase extend the list of special characteristics of the F-ATPase from T. brucei, and also, demonstrate that the architecture of the F1 -ATPase complex is not strictly conserved in eukaryotes. PMID- 29247469 TI - Long-term outcome of liver transplantation in childhood: A study of 20-year survivors. AB - We report the results of a study of survival, liver and kidney functions, and growth with a median follow-up of 24 years following liver transplantation in childhood. From 1988 to 1993, 128 children underwent deceased donor liver transplantation (median age: 2.5 years). Twenty-year patient and graft survival rates were 79% and 64%, respectively. Raised serum aminotransferase and/or gamma glutamyl transferase activities were present in 42% of survivors after a single transplantation. Graft histology (35 patients) showed signs of chronic rejection in 11 and biliary obstruction in 5. Mean total fibrosis scores were 4.5/9 and 3/9 in patients with abnormal and normal serum liver tests, respectively. Glomerular filtration rate was <90 mL.min-1 in 35 survivors, including 4 in end-stage renal disease who were undergoing dialysis or had undergone renal transplantation. Median final heights were 159 cm for women and 172 cm for men; final height was below the target height in 37 patients. Twenty-year survival after childhood liver transplantation may be close to 80%, and final height is within the normal range for most patients. However, chronic kidney disease or altered liver biochemistries are present in over one third of patients, which is a matter of concern for the future. PMID- 29247471 TI - Hypothesis: does exposure to sperm lead to pregnancy? PMID- 29247470 TI - Acute effect of multiple ozone metrics on mortality by season in 34 Chinese counties in 2013-2015. AB - BACKGROUND: Although numerous multicentre studies have estimated the association between ozone exposure and mortality, there are currently no nationally representative multicentre studies of the ozone-mortality relationship in China. OBJECTIVE: To investigate the effect on total (nonaccidental) and cause-specific mortality of short-term exposure to ambient ozone, and examine different exposure metrics. METHODS: The effects of short-term exposure to ozone were analysed using various metrics (daily 1-h maximum, daily 8-h maximum and daily average) on total (nonaccidental) and cause-specific (circulatory and respiratory) mortality from 2013 to 2015 in 34 counties in 10 cities across China. We used distributed lag nonlinear models for estimating county-specific relative risk of mortality and combined the county-specific relative rates by conducting a random-effects meta analysis. RESULTS: In all-year analyses, a 10 MUg m-3 increase in daily average, daily 1-h maximum and daily 8-h maximum ozone at lag02 corresponded to an increase of 0.6% (95% CI: 0.33, 0.88), 0.26% (95% CI: 0.12, 0.39) and 0.37% (95% CI: 0.2, 0.55) in total (nonaccidental) mortality, 0.66% (95% CI: 0.28, 1.04), 0.31% (95% CI: 0.11, 0.51) and 0.39% (95% CI: 0.16, 0.62) in circulatory mortality, and 0.57% (95% CI: -0.09, 1.23), 0.11% (95% CI: -0.22, 0.44) and 0.22% (95% CI: -0.28, 0.72) in respiratory mortality, respectively. These estimates had a different seasonal pattern by cause of death. In general, the seasonal patterns were consistent with the times of year when ozone concentrations are highest. CONCLUSIONS: Our findings suggest that in China, the acute effects of ozone are more closely related to daily average exposure than any other metric. PMID- 29247472 TI - Short-term adverse effects of early subclinical allograft inflammation in kidney transplant recipients with a rapid steroid withdrawal protocol. AB - The impact of subclinical inflammation (SCI) noted on early kidney allograft biopsies remains unclear. This study evaluated the outcome of SCI noted on 3 month biopsy. A total of 273/363 (75%) kidney transplant recipients with a functioning kidney underwent allograft biopsies 3-months posttransplant. Among those with stable allograft function at 3 months, 200 biopsies that did not meet the Banff criteria for acute rejection were identified. These were Group I: No Inflammation (NI, n = 71) and Group II: Subclinical Inflammation (SCI, n = 129). We evaluated differences in kidney function at 24-months and allograft histology score at 12-month biopsy. SCI patients had a higher serum creatinine (1.6 +/- 0.7 vs 1.38 +/- 0.45; P = .02) at 24-months posttransplant, and at last follow-up at a mean of 42.5 months (1.69 +/- 0.9 vs 1.46 +/- 0.5 mg/dL; P = .027). The allograft chronicity score (ci + ct + cg + cv) at 12-months posttransplant was higher in the SCI group (2.4 +/- 1.35 vs 1.9 +/- 1.2; P = .02). The incidence of subsequent rejections within the first year in SCI and NI groups was 24% vs 10%, respectively (P = .015). De novo donor-specific antibody within 12 months was more prevalent in the SCI group (12/129 vs 1/71, P = .03). SCI is likely not a benign finding and may have long-term implications for kidney allograft function. PMID- 29247474 TI - Towards the Shell Biorefinery: Sustainable Synthesis of the Anticancer Alkaloid Proximicin A from Chitin. AB - A shell biorefinery would involve fractionation of crustacean shells and incorporation of the components into value-added products, particularly those that contain nitrogen. In a proof-of-concept study that validates this concept, the anticancer alkaloid proximicin A has been synthesized from the chitin-derived platform chemical 3-acetamido-5-acetylfuran (3A5AF). This study accentuates the leading role chitin is likely to play in the sustainable production of nitrogen containing fine chemicals that are not directly attainable from lignocellulose. PMID- 29247475 TI - Nanosized Metal Phosphides Embedded in Nitrogen-Doped Porous Carbon Nanofibers for Enhanced Hydrogen Evolution at All pH Values. AB - Transition-metal phosphides (TMPs) have emerged as promising catalyst candidates for the hydrogen evolution reaction (HER). Although numerous methods have been investigated to obtain TMPs, most rely on traditional synthetic methods that produce materials that are inherently deficient with respect to electrical conductivity. An electrospinning-based reduction approach is presented, which generates nickel phosphide nanoparticles in N-doped porous carbon nanofibers (Ni2 P@NPCNFs) in situ. Ni2 P nanoparticles are protected from irreversible fusion and aggregation in subsequent high-temperature pyrolysis. The resistivity of Ni2 P@NPCNFs (5.34 Omega cm) is greatly decreased by 104 times compared to Ni2 P (>104 Omega cm) because N-doped carbon NFs are incorporated. As an electrocatalyst for HER, Ni2 P@NPCNFs reveal remarkable performance compared to other previously reported catalysts in acidic media. Additionally, it offers excellent catalytic ability and durability in both neutral and basic media. Encouraged by the excellent electrocatalytic performance of Ni2 P@NPCNFs, a series of pea-like Mx P@NPCNFs, including Fe2 P@NPCNFs, Co2 P@NPCNFs, and Cu3 P@NPCNFs, were synthesized by the same method. Detailed characterization suggests that the newly developed method could render combinations of ultrafine metal phosphides with porous carbon accessible; thereby, extending opportunities in electrocatalytic applications. PMID- 29247476 TI - Robotic D4 lymphadenectomy for the treatment of rectal cancer with metastasis to N3-N4 lymph nodes - a video vignette. PMID- 29247473 TI - The Movember Foundation's GAP3 cohort: a profile of the largest global prostate cancer active surveillance database to date. AB - OBJECTIVES: The Movember Foundation launched the Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative to create a global consensus on the selection and monitoring of men with low-risk prostate cancer (PCa) on active surveillance (AS). The aim of this study is to present data on inclusion and follow-up for AS in this unique global AS database. PATIENTS AND METHODS: Between 2014 and 2016, the database was created by combining patient data from 25 established AS cohorts worldwide (USA, Canada, Australasia, UK and Europe). Data on a total of 15 101 patients were included. Descriptive statistics were used to report patients' clinical and demographic characteristics at the time of PCa diagnosis, clinical follow-up, discontinuation of AS and subsequent treatment. Cumulative incidence curves were used to report discontinuation rates over time. RESULTS: At diagnosis, the median (interquartile range [IQR]) patient age was 65 (60-70) years and the median prostate-specific antigen level was 5.4 (4.0-7.3) ng/mL. Most patients had clinical stage T1 disease (71.8%), a biopsy Gleason score of 6 (88.8%) and one tumour-positive biopsy core (60.3%). Patients on AS had a median follow-up time of 2.2 (1.0-5.0) years. After 5, 10 and 15 years of follow-up, respectively, 58%, 39% and 23% of patients were still on AS. The current version of GAP3 has limited data on magnetic resonance imaging (MRI), quality of life and genomic testing. CONCLUSIONS: GAP3 is the largest worldwide collaboration integrating patient data from men with PCa on AS. The results will allow individual patients and clinicians to have greater confidence in the personalized decision to either delay or proceed with active treatment. Longer follow-up and the evaluation of MRI, new genomic markers and patient-related outcomes will result in even more valuable data and eventually in better patient outcomes. PMID- 29247477 TI - Finding politically feasible conservation policies: the case of wildlife trafficking. AB - Conservation management is of increasing importance in ecology as most ecosystems nowadays are essentially managed ecosystems. Conservation managers work within a political-ecological system when they develop and attempt to implement a conservation plan that is designed to meet particular conservation goals. In this article, we develop a decision support tool that can identify a conservation policy for a managed wildlife population that is both sustainable and politically feasible. Part of our tool consists of a simulation model composed of interacting influence diagrams. We build, fit, and use our tool on the case of rhino horn trafficking between South Africa and Asia. Using these diagrams, we show how a rhino poacher's belief system can be modified by such a policy and locate it in a perceived risks-benefits space before and after policy implementation. We statistically fit our model to observations on group actions and rhino abundance. We then use this fitted model to compute a politically feasible conservation policy. PMID- 29247478 TI - Chinese medicine Tongxinluo capsule alleviates cerebral microcirculatory disturbances in ischemic stroke by modulating vascular endothelial function and inhibiting leukocyte-endothelial cell interactions in mice: A two-photon laser scanning microscopy study. AB - OBJECTIVE: The aim of this study was to examine the effect of TXL, a Chinese medicine prescription, on cerebral microcirculatory disturbances after pMCAO in mice using TPLSM and further explore the underlying mechanisms. METHODS: Adlut male C57BL/6J mice were subjected to pMCAO and orally administered with TXL (3.0, 1.5 and 0.75 g/kg/d) at 1, 3, and 21 hours after pMCAO. The following parameters were examined at 6 and 24 hours after pMCAO: neurological deficits, infarct volume, BBB permeability, cerebral microvessel structure, brain microcirculation (TPLSM imaging), vasoactive factors, and adhesion molecules. RESULTS: TXL improved neurological deficits, reduced infarct volume, attenuated BBB disruption, protected cerebral microvessel structure, increased cerebral capillary flow velocity and volume flux, and inhibited leukocyte-endothelial cell interactions at 6 or 24 hours after pMCAO. The therapeutic efficacy was exerted in a dose-dependent manner. Further study revealed that TXL (high dose) regulated the expression of PGI2, TXA2, and ET-1, and suppressed ICAM-1 and P-selectin. CONCLUSIONS: TXL alleviates cerebral microcirculatory disturbances against ischemic injury by modulating endothelial function and inhibiting leukocyte endothelial cell interactions. These effects are associated with regulating the expression of PGI2, TXA2, and ET-1, and suppressing ICAM-1 and P-selectin expression. PMID- 29247479 TI - The many faces of tuberculosis of the oral mucosa - three cases with distinct pathomechanisms. PMID- 29247480 TI - Fluorescence angiography during transanal trans-stomal proctectomy and ileal pouch anal anastomosis: a video vignette. AB - Indocanine green (ICG) fluorescence is able to assess in vivo tissue perfusion. This technique has been validated in colorectal surgery and provides, by real time angiography, the evaluation of bowel perfusion before anastomosis[1]. This video shows the usefulness of ICG fluorescence application in ileal pouch anal surgery. This article is protected by copyright. All rights reserved. PMID- 29247481 TI - Pityriasis rubra pilaris: algorithms for diagnosis and treatment. AB - Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease that affects men and women of all ages and also children. The clinical appearance of PRP is highly variable, as is the individual prognosis. Therefore, stratifying PRP into six disease subtypes represents a first step to personalized medicine for this rare inflammatory skin disease. The next step should be to associate specific therapeutic strategies with these subtypes of PRP. However, no randomized, controlled trials on the treatment of PRP have been performed. Consequently, the actual treatment algorithm for PRP will be based on clinical experience, small case series and case reports. The majority of published evidence is on type I PRP, whereas the treatment experience for other clinical types of PRP is still sparse and has to be gained. Nevertheless, it is now time to start developing valid algorithms as a basis for the diagnosis and treatment of PRP based on the data available. This review makes use of algorithms developed in psoriasis and atopic eczema and puts together recent insights into the pathogenesis, diagnosis and treatment experience of PRP. The innovative intention of this appraisal is to develop a structured algorithm for PRP treatment that should be further developed going forward. PMID- 29247484 TI - Accurate Ionization Energies for Mononuclear Copper Complexes Remain a Challenge for Density Functional Theory. AB - Copper is ubiquitous and its one-electron redox chemistry is central to many catalytic processes. Modeling such chemistry requires electronic structure methods capable of the accurate prediction of ionization energies (IEs) for compounds including copper in different oxidation states and supported by various ligands. Herein, we estimate IEs for 12 mononuclear Cu species previously reported in the literature by using 21 modern density functionals and the DLPNO CCSD(T) wave function theory model; we consider extrapolated values of the latter to provide reference values of acceptable accuracy. Our results reveal a considerable diversity in functional performance. Although there is nearly always at least one functional that performs well for any given species, there are none that do so for every member of the test set, and certain cases are particularly pathological. Over the entire test set, the SOGGA11-X functional performs best with a mean unsigned error (MUE) of 0.22 eV. PBE0, omegaB97X-D, CAM-B3LYP, M11-L, B3LYP, and M11 exhibit MUEs ranging between 0.23 and 0.34 eV. When including relativistic effects with the zero-order regular approximation, omegaB97X-D, CAM B3LYP, and PBE0 are found to provide the best accuracy. PMID- 29247483 TI - Peptidoglycan synthesis in Tannerella forsythia: Scavenging is the modus operandi. AB - Tannerella forsythia is a Gram-negative oral pathogen strongly associated with periodontitis. This bacterium has an absolute requirement for exogenous N acetylmuramic acid (MurNAc), an amino sugar that forms the repeating disaccharide unit with amino sugar N-acetylglucosamine (GlcNAc) of the peptidoglycan backbone. In silico genome analysis indicates that T. forsythia lacks the key biosynthetic enzymes needed for the de novo synthesis of MurNAc, and so relies on alternative ways to meet its requirement for peptidoglycan biosynthesis. In the subgingival niche, the bacterium can acquire MurNAc and peptidoglycan fragments (muropeptides) released by the cohabiting bacteria during their cell wall breakdown associated with cell division. Tannerella forsythia is able to also use host sialic acid (Neu5Ac) in lieu of MurNAc or muropeptides for its survival during the biofilm growth. Evidence suggests that the bacterium might be able to shunt sialic acid into a metabolic pathway leading to peptidoglycan synthesis. In this review, we explore the mechanisms by which T. forsythia is able to scavenge MurNAc, muropeptide and sialic acid for its peptidoglycan synthesis, and the impact of these scavenging activities on pathogenesis. PMID- 29247485 TI - An EEG index of sensorimotor interhemispheric coupling after unilateral stroke: clinical and neurophysiological study. AB - Brain connectivity has been employed to investigate on post-stroke recovery mechanisms and assess the effect of specific rehabilitation interventions. Changes in interhemispheric coupling after stroke have been related to the extent of damage in the corticospinal tract (CST) and thus, to motor impairment. In this study, we aimed at defining an index of interhemispheric connectivity derived from electroencephalography (EEG), correlated with CST integrity and clinical impairment. Thirty sub-acute stroke patients underwent clinical and neurophysiological evaluation: CST integrity was assessed by Transcranial Magnetic Stimulation and high-density EEG was recorded at rest. Connectivity was assessed by means of Partial Directed Coherence and the normalized Inter Hemispheric Strength (nIHS) was calculated for each patient and frequency band on the whole network and in three sub-networks relative to the frontal, central (sensorimotor) and occipital areas. Interhemipheric coupling as expressed by nIHS on the whole network was significantly higher in patients with preserved CST integrity in beta and gamma bands. The same index estimated for the three sub networks showed significant differences only in the sensorimotor area in lower beta, with higher values in patients with preserved CST integrity. The sensorimotor lower beta nIHS showed a significant positive correlation with clinical impairment. We propose an EEG-based connectivity index which is a measure of the interhemispheric cross-talking and correlates with functional motor impairment in subacute stroke patients. Such index could be employed to evaluate the effects of training aimed at re-establishing interhemispheric balance and eventually drive the design of future connectivity-driven rehabilitation interventions. PMID- 29247486 TI - High-fat diet exacerbates imiquimod-induced psoriasis-like dermatitis in mice. AB - Psoriasis, a chronic inflammatory skin disease, is closely related to systemic metabolism. An elevated body mass index (BMI) is a risk factor for psoriasis; inflammasomes are activated by adipose tissue macrophages in obese subjects. We hypothesized that hyperlipidaemia is involved in the pathogenesis of psoriasis and examined the role of a high-fat diet (HFD) in the development of psoriasis in imiquimod (IMQ)-treated mice. The body weight and serum level of cholesterol were significantly higher in mice fed an HFD than in a regular diet (RD). HFD mice had higher psoriasis skin scores, and the number of neutrophils infiltrating into the lesional skin was elevated. IL-17A mRNA expression was significantly increased in the skin of IMQ-treated HFD mice; the expression of IL-22, IL-23 and TNF-alpha mRNA was not enhanced. Caspase-1 and IL-1beta were activated in the skin of IMQ treated HFD mice, and their serum level of IL-17A, TNF-alpha and IL-1beta was significantly upregulated. Our findings strongly suggest that hyperlipidaemia is involved in the development and progression of psoriasis via systemic inflammation and inflammasome activation. PMID- 29247487 TI - The locus coeruleus-norepinephrine system as pacemaker of attention - a developmental mechanism of derailed attentional function in autism spectrum disorder. AB - Children with autism spectrum disorder (ASD) exhibit diminished visual engagement to environmental stimuli. Aberrant attentional function provides an explanation by reduced phasic alerting and orienting to exogenous stimuli. We review aberrant attentional function (alerting, orienting and attentional control) in children with ASD as studied by neurocognitive and neurophysiological tasks as well as magnetic resonance imaging studies. The locus coeruleus-norepinephrine (LC-NE) system is outlined as a pacemaker of attentional function. The LC-NE system regulates adaptive gain in synaptic signal transmission, which moderates phasic alerting ('promoting') and the activation of the ventral frontoparietal attention network within orienting ('permitting'). In children with ASD, atypical LC-NE activity is proposed as underlying mechanism of aberrant attentional function. It may manifest as (i) increased tonic activity with reduced phasic reactivity to exogenous stimuli, (ii) attenuated bottom-up signalling mitigating salience and predictive reward attribution during phasic alerting, and (iii) reduced activation of the ventral frontoparietal attention system attenuating orienting to exogenous stimuli. Increased tonic pupil dilation and aberrant pupil reactivity are discussed as indicators of atypical LC-NE activity. Pupillometry is outlined as feasible method to assess alerting, orienting and attentional control that can be dissected from the pupil dilation time course. In children with ASD, aberrant attentional function through atypical LC-NE activity is proposed as developmental mechanism leading to reduced social attention as well as social interaction and communication impairments. PMID- 29247488 TI - Oxaliplatin resistance in colorectal cancer cells is mediated via activation of ABCG2 to alleviate ER stress induced apoptosis. AB - Oxaliplatin (OXA), is a third generation platinum drug used as first-line chemotherapy in colorectal cancer (CRC). Cancer cells acquires resistance to anti cancer drug and develops resistance. ATP-binding cassette (ABC) drug transporter ABCG2, one of multidrug resistance (MDR) protein which can effectively discharge a wide spectrum of chemotherapeutic agents out of cancer cells and subsequently reduce the intracellular concentration of these drugs. Role of ABCG2 and plausible molecular signaling pathways involved in Oxaliplatin-Resistant (OXA-R) colon cancer cells was evaluated in the present study. OXA resistant LoVo cells was developed by exposing the colon cells to OXA in a dose-dependent manner. Development of multi drug resistance in OXA-R cells was confirmed by exposing the resistance cells to oxaliplatin, 5-FU, and doxorubicin. OXA treatment resulted in G2 phase arrest in parental LoVo cells, which was overcome by OXA-R LoVo cells. mRNA and protein expression of ABCG2 and phosphorylation of NF-kappaB was significantly higher in OXA-R than parental cells. Levels of ER stress markers were downregulated in OXA-R than parental cells. OXA-R LoVo cells exposed to NF kappaB inhibitor QNZ effectively reduced the ABCG2 and p-NF-kappaB expression and increased ER stress marker expression. On other hand, invasion and migratory effect of OXA-R cells were found to be decreased, when compared to parental cells. Metastasis marker proteins also downregulated in OXA-R cells. ABCG2 inhibitor verapamil, downregulate ABCG2, induce ER stress markers and induces apoptosis. In vivo studies in nude mice also confirms the same. PMID- 29247489 TI - Revisiting Rectosacral and Waldeyer's Fascia by Laparoscopic or Robotic Approach Video Vignette. AB - During the clinical practice of total mesorectal excision (TME) for the treatment of middle and low rectal cancer, posterior mobilisation of the rectum is along the holy plane, which consists of loose areolar connective tissues [1]. With further posterior downward mobilisation, a thick tough fascia will be encountered, generally known as rectosacral fascia, and failure to recognise and divide the rectosacral fascia can perforate the mesorectum or lead to severe presacral haemorrhage. This article is protected by copyright. All rights reserved. PMID- 29247490 TI - Neuronal oscillations: unavoidable and useful? AB - Neuronal systems have a high propensity to engage in oscillatory activity because both the properties of individual neurons and canonical circuit motifs favour rhythmic activity. In addition, coupled oscillators can engage in a large variety of dynamical regimes, ranging from synchronization with different phase offsets to chaotic behaviour. Which regime prevails depends on differences between preferred oscillation frequencies, coupling strength and coupling delays. The ability of delay coupled oscillator networks to generate a rich repertoire of temporally structured activation sequences is exploited by central pattern generator networks for the control of movements. However, it is less clear whether temporal patterning of neuronal discharges also plays a role in cognitive processes. Here, it will be argued that the temporal patterning of neuronal discharges emerging from delay coupled oscillator networks plays a pivotal role in all instances in which selective relations have to be established between the responses of distributed assemblies of neurons. Examples are the dynamic formation of functional networks, the selective routing of activity in densely interconnected networks, the attention-dependent selection of sensory signals, the fast and context-dependent binding of responses for further joint processing in pattern recognition and the formation of associations by learning. Special consideration is given to arguments that challenge a functional role of oscillations and synchrony in cognition because of the volatile nature of these phenomena and recent evidence will be reviewed suggesting that this volatility is functionally advantageous. PMID- 29247491 TI - The roles of TRPV1, TRPA1 and TRPM8 channels in chemical and thermal sensitivity of the mouse oral mucosa. AB - Spices in food and beverages and compounds in tobacco smoke interact with sensory irritant receptors of the transient receptor potential (TRP) cation channel family. TRPV1 (vanilloid type 1), TRPA1 (ankyrin 1) and TRPM8 (melastatin 8) not only elicit action potential signaling through trigeminal nerves, eventually evoking pungent or cooling sensations, but by their calcium conductance they also stimulate the release of calcitonin gene-related peptide (CGRP). This is measured as an index of neuronal activation to elucidate the chemo- and thermosensory transduction in the isolated mouse buccal mucosa of wild types and pertinent knockouts. We found that the lipophilic capsaicin, mustard oil and menthol effectively get access to the nerve endings below the multilayered squamous epithelium, while cigarette smoke and its gaseous phase were weakly effective releasing CGRP. The hydrophilic nicotine was ineffective unless applied unprotonated in alkaline (pH9) solution, activating TRPA1 and TRPV1. Also, mustard oil activated both these irritant receptors in millimolar but only TRPA1 in micromolar concentrations; in combination (1 mm) with heat (45 degrees C), it showed supraadditive, that is heat sensitizing, effects in TRPV1 and TRPA1 knockouts, suggesting action on an unknown heat-activated channel and mustard oil receptor. Menthol caused little CGRP release by itself, but in subliminal concentration (2 mm), it enabled a robust cold response that was absent in TRPM8 /- but retained in TRPA1-/- and strongly reduced by TRPM8 inhibitors. In conclusion, all three relevant irritant receptors are functionally expressed in the oral mucosa and play their specific roles in inducing neurogenic inflammation and sensitization to heat and cold. PMID- 29247482 TI - Commonalities in epileptogenic processes from different acute brain insults: Do they translate? AB - The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCgamma1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL 1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention. PMID- 29247492 TI - New evidence of connections between increased O-GlcNAcylation and inflammasome in the oral mucosa of patients with oral lichen planus. AB - Oral lichen planus (OLP) is considered a chronic inflammatory immune-mediated disease of the oral mucosa. Immunopathogenesis of OLP is thought to be associated with cell-mediated immune dysregulation. O-GlcNAcylation is a form of reversible glycosylation. It has been demonstrated that O-GlcNAcylation promoted nuclear factor kappa B (NF-kappaB) signalling. Activation of NF-kB can induce expression of nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is a large intracellular multi-protein complex involving an immune response. Dysregulated expression of the NLRP3 inflammasome was reported to be associated with autoinflammatory diseases. No integrative studies between O-GlcNAcylation and NLRP3 inflammasome in OLP patients have been reported. The present study aimed to determine the immunohistochemical expression of O-GlcNAcylation, NF-kappaB signalling molecules and NLRP3 inflammasome in oral mucosae of OLP patients. Oral tissue samples were collected from 30 OLP patients and 30 healthy individuals. Immunohistochemical staining and analyses of immunostaining scores were performed to evaluate expression of O-GlcNAcylation, NF-kappaB signalling molecules and NLRP3 inflammasome. According to observations in this study, significantly higher levels of O-GlcNAcylation, NF-kappaB signalling molecules and NLRP3 inflammasome were demonstrated in OLP patients compared with control subjects (P < 0.001). Positive correlations among O GlcNAcylation, NF-kappaB signalling molecules and NLRP3 inflammasome were also observed in OLP samples (P < 0.01). In conclusion, the present study provides supportive evidence that increased O-GlcNAcylation is associated with increased expression of NLRP3 inflammasome via the NF-kappaB signalling pathway. These findings provide a new perspective on immunopathogenesis of OLP in relation to autoinflammation. PMID- 29247494 TI - Podocyte and endothelial cell injury lead to nephrotic syndrome in proliferative lupus nephritis. AB - AIMS: Nephrotic syndrome (NS) is a major manifestation of lupus nephritis (LN). The dysregulation of podocytes, the glomerular basement membrane (GBM) and endothelial cells (ECs) results in proteinuria in glomerular diseases. The aim of our study was to clarify whether the dysregulation of these barriers is associated with NS in proliferative LN and membranous LN. METHODS AND RESULTS: Fifty-six patients with NS, including minimal change NS in 15, primary membranous nephropathy (PMN) in 13, class III/IV LN in 15, and class V LN in 13, were enrolled in this study. Subjects with idiopathic haematuria were assigned as controls. Glomerular expression of Wilms tumour protein 1 (WT1), nephrin, synaptopodin and podocalyxin was evaluated by immunohistochemistry (IHC) and real time quantitative reverse transcription polymerase chain reaction. EC injury was evaluated by CD31 immunostaining and electron microscopy (EM). Reduced expression of WT1, nephrin and synaptopodin was found in PMN, class III/IV LN and class V LN as compared with controls by IHC and mRNA analysis. Reduced expression of these molecules was not different between class III/IV LN and class V LN. Reduced numbers of CD31-positive ECs were found in class III/IV LN as compared with class V LN. EC injury showing subendothelial widening on EM was apparent in class III/IV LN as compared with class V LN. Foot process effacement was found only along the GBM showing EC injury in class III/IV LN. CONCLUSIONS: Our study suggests that coexistence of podocyte and EC injury may lead to NS in proliferative LN. Podocyte damage alone leads to NS in membranous LN. PMID- 29247495 TI - Presenting symptoms and long-term survival in head and neck cancer. AB - OBJECTIVES: To assess how type and number of symptoms are related to survival in patients with head and neck cancer. DESIGN: Patients were followed up for over 10 years from the Scottish Audit of Head and Neck Cancer (national cohort of head and neck cancer patients in Scotland 1999-2001). September 2013, cohort was linked to national mortality data. First, second and third presenting symptoms were recorded at diagnosis. SETTING: National prospective audit-Scotland. PARTICIPANTS: A subset of 1589 patients, from the original cohort of 1895, who had cancer arising from one of the four main subsites; larynx, oropharynx, oral cavity and hypopharynx. MAIN OUTCOME MEASURES: Median survival in relation to patients' presenting symptoms. RESULTS: A total of 1146 (72%) males and 443 (28%) females, mean age at diagnosis 64 years (13-95). There was a significant difference in survival in relation to the number of the patient's presenting symptoms; one symptom had a median survival of 5.3 years compared with 1.1 years for three symptoms. Patients who presented with weight loss had a median survival of 0.8 years, compared to 4.2 years if they did not (P < .001). Patients who presented with hoarseness had a median survival of 5.9 years compared to 2.6 years without (P < .001). There was no significant difference in long-term survival for patients who presented with an ulcer, compared to those that did not (P = .105). CONCLUSIONS: This study highlights the importance of patients' presenting symptoms, giving valuable information in highlighting appropriate "red flag" symptoms and subsequent treatment planning and prognosis. PMID- 29247493 TI - The yin and yang of KV channels in cerebral small vessel pathologies. AB - Cerebral SVDs encompass a group of genetic and sporadic pathological processes leading to brain lesions, cognitive decline, and stroke. There is no specific treatment for SVDs, which progress silently for years before becoming clinically symptomatic. Here, we examine parallels in the functional defects of PAs in CADASIL, a monogenic form of SVD, and in response to SAH, a common type of hemorrhagic stroke that also targets the brain microvasculature. Both animal models exhibit dysregulation of the voltage-gated potassium channel, KV 1, in arteriolar myocytes, an impairment that compromises responses to vasoactive stimuli and impacts CBF autoregulation and local dilatory responses to neuronal activity (NVC). However, the extent to which this channelopathy-like defect ultimately contributes to these pathologies is unknown. Combining experimental data with computational modeling, we describe the role of KV 1 channels in the regulation of myocyte membrane potential at rest and during the modest increase in extracellular potassium associated with NVC. We conclude that PA resting membrane potential and myogenic tone depend strongly on KV 1.2/1.5 channel density, and that reciprocal changes in KV channel density in CADASIL and SAH produce opposite effects on extracellular potassium-mediated dilation during NVC. PMID- 29247496 TI - Ametropia, retinal anatomy, and OCT abnormality patterns in glaucoma. 1. Impacts of refractive error and interartery angle. AB - Retinal nerve fiber layer thickness (RNFLT) measured by optical coherence tomography (OCT) is widely used in clinical practice to support glaucoma diagnosis. Clinicians frequently interpret peripapillary RNFLT areas marked as abnormal by OCT machines. However, presently, clinical OCT machines do not take individual retinal anatomy variation into account, and according diagnostic biases have been shown particularly for patients with ametropia. The angle between the two major temporal retinal arteries (interartery angle, IAA) is considered a fundamental retinal ametropia marker. Here, we analyze peripapillary spectral domain OCT RNFLT scans of 691 glaucoma patients and apply multivariate logistic regression to quantitatively compare the diagnostic bias of spherical equivalent (SE) of refractive error and IAA and to identify the precise retinal locations of false-positive/negative abnormality marks. Independent of glaucoma severity (visual field mean deviation), IAA/SE variations biased abnormality marks on OCT RNFLT printouts at 36.7%/22.9% of the peripapillary area, respectively. 17.2% of the biases due to SE are not explained by IAA variation, particularly in inferonasal areas. To conclude, the inclusion of SE and IAA in OCT RNFLT norms would help to increase diagnostic accuracy. Our detailed location maps may help clinicians to reduce diagnostic bias while interpreting retinal OCT scans. PMID- 29247497 TI - The prevalence of antibody responses against Staphylococcus aureus antigens in patients with atopic dermatitis: a systematic review and meta-analysis. AB - BACKGROUND: Staphylococcus aureus plays a role in the pathogenesis of atopic dermatitis (AD), possibly via the expression of various virulence antigens. An altered antibody response towards these antigens might contribute to inflammation. OBJECTIVES: To provide an overview of the varying prevalences and odds of antibody responses against S. aureus antigens in patients with AD. METHODS: Data were systematically obtained from Embase, MEDLINE, Web of Science, Scopus, Cochrane, PubMed and Google Scholar up to 12 February 2016. We selected all original observational and experimental studies assessing antistaphylococcal antibodies in serum of patients with AD. Prevalences and odds ratios (ORs) of IgE, IgG, IgM and IgA against S. aureus in patients with AD vs. healthy controls were pooled using the random-effects model. We calculated I2 statistics to assess heterogeneity and rated study quality using the Newcastle-Ottawa Scale. RESULTS: Twenty-six articles (2369 patients) were included, of which 10 were controlled studies. Study quality was fair to poor. Patients with AD had higher prevalences of IgE against staphylococcal enterotoxin (SE)A (OR 8.37, 95% confidence interval 2.93-23.92) and SEB (OR 9.34, 95% confidence interval 3.54-24.93) compared with controls. Prevalences of antistaphylococcal IgE were 33% for SEA, 35% for SEB and 16% for toxic shock syndrome toxin-1. However, study heterogeneity and imprecision should be taken into consideration when interpreting the results. Data on IgG, IgM and IgA, as well as other antigens, are limited. CONCLUSIONS: Patients with AD more often show an IgE antibody response directed against S. aureus superantigens than healthy controls, supporting a role for S. aureus in AD pathogenesis. PMID- 29247498 TI - Impact of high-intensity interval training and moderate-intensity continuous training on resting and postexercise cardiac troponin T concentration. AB - NEW FINDINGS: What is the central question of this study? Does exercise training impact resting and postexercise cardiac troponin T (cTnT) concentration? What is the main finding and its importance? This randomized controlled intervention study demonstrated that 12 weeks of either high-intensity interval training or moderate-intensity continuous training largely abolished the exercise-induced elevation in cTnT when exercise was performed at the same absolute intensity. There was no impact of training on resting cTnT or postexercise appearance of cTnT when exercise was performed at the same relative intensity. These findings provide new information that might help clinicians with decision-making in relationship to basal and postexercise values of cTnT in individuals with different training status. ABSTRACT: We evaluated the influence of 12 weeks of high-intensity interval training [HIIT; repeated 4 min cycling at 90% of maximal oxygen uptake (VO2max) interspersed with 3 min rest, 200-300 kJ per session, 3 or 4 days each week] and work-equivalent moderate-intensity continuous training (MICT; continuous cycling at 60% VO2max) on resting cardiac troponin T (cTnT) and the appearance of exercise-induced cTnT. Forty-eight sedentary obese young women were randomly assigned to HIIT, MICT or a control group. The VO2max and body composition were measured before and after training. At baseline, cTnT was assessed using a high-sensitivity assay at rest and immediately, 2 and 4 h after 45 min cycling at 60% VO2max. After a 12 week training period, cTnT was assessed before and after 45 min cycling at the same relative and absolute intensities as before training. Training led to higher VO2max and lower fat mass in both HIIT and MICT groups (all P < 0.05). Before training, cTnT was significantly elevated in all three groups (by 35-118%, all P < 0.05) with acute exercise. After training, both resting and postexercise cTnT concentrations (same relative intensity) were similar to pretraining values. In contrast, postexercise cTnT (same absolute intensity, which represented a smaller exercise stimulus) was not elevated from rest in both HIIT and MICT groups. In conclusion, 12 weeks of either HIIT or MICT largely abolished the postexercise elevation of cTnT concentration when exercise was performed at the same absolute intensity. There was, however, no impact of training on resting cTnT or postexercise appearance of cTnT for exercise performed at the same relative intensity. PMID- 29247500 TI - Biologic treatment sequences for plaque psoriasis: a cost-utility analysis based on 10 years of Dutch real-world evidence from BioCAPTURE. AB - BACKGROUND: Treatment with biologics may be indicated for patients with moderate to-severe plaque psoriasis, but comparative evidence on cost-effectiveness is limited. Switching of biologics is common, but it is unclear what the effect is of differences in sequences of biologics. OBJECTIVES: To evaluate the cost effectiveness of different biologic treatment sequences for psoriasis based on real-world evidence. PATIENTS AND METHODS: A sequence model was developed to evaluate the costs and health effects of three consecutive lines of biologic treatments [for example adalimumab-etanercept-ustekinumab (Ada-Eta-Ust) vs. Eta Ust-Ada] over a 10-year time horizon in the Netherlands. The model was populated with data from the Dutch BioCAPTURE registry and scientific literature. Analyses were conducted of cost per quality-adjusted life year (QALY) and uncertainty was addressed by probabilistic as well as scenario analyses. RESULTS: Treatment of psoriasis with biologics for a 10-year period was estimated to be associated with a cost of ?141 962 to ?148 442 per patient depending on the treatment sequence used. Cumulative health effects ranged from 7.79 to 8.03 QALYs. Starting with Ada or Ust seems favourable concerning cost and utilities compared with strategies starting with Eta, although credible intervals were partly overlapping. CONCLUSIONS: The order in which biologics are used influences treatment cost effectiveness, both in terms of costs and health effects. Initiation of a biologic treatment sequence for psoriasis might best be done with Ada or Ust; Eta seems less optimal from a health-economic perspective. PMID- 29247501 TI - Shift work and the risk of cardiovascular disease. A systematic review and meta analysis including dose-response relationship. AB - Objectives The aim of this review was to assess the risk of cardiovascular disease (CVD) events associated with shift work and determine if there is a dose response relationship in this association. Method Electronic databases (PubMed, Scopus, and Web of Science) were searched for cohort or case-control control study designs in any population, reporting exposure to shift work as the main contributing factor to estimate CVD risk. For each study, adjusted relative risk (RR) ratios and 95% confidence intervals (CI) were extracted, and used to calculate the pooled RR using random-effect models. Meta-regression analysis was conducted to explore potential heterogeneity sources. Potential non-linear dose response relationships were examined using fractional polynomial models. Results We included 21 studies with a total of 173 010 unique participants. The majority of the studies were ranked low-to-moderate risk of bias. The risk of any CVD event was 17% higher among shift workers than day workers. The risk of coronary heart disease (CHD) morbidity was 26% higher (1.26, 95% CI 1.10-1.43, I 2= 48.0%). Sub-group analysis showed an almost 20% higher risk of CVD and CHD mortality among shift workers than those who did not work shifts (1.22, 95% CI 1.09-1.37, I 2= 0% and 1.18, 95% CI 1.06-1.32 I 2=0%; respectively). After the first five years of shift work, there was a 7.1% increase in risk of CVD events for every additional five years of exposure (95% CI 1.05-1.10). Heterogeneity of the pooled effect size (ES) estimates was high (I 2=67%), and meta-regression analysis showed that sample size explained 7.7% of this. Conclusions The association between shift work and CVD risk is non-linear and seems to appear only after the first five years of exposure. As shift work remains crucial for meeting production and service demands across many industries, policies and initiatives are needed to reduce shift workers' CVD risk. PMID- 29247499 TI - Cardiac output changes after osmotic therapy in neurosurgical and neurocritical care patients: a systematic review of the clinical literature. AB - AIM: Osmotherapy constitutes a first-line intervention for intracranial hypertension management. However, hyperosmolar solutes exert various systematic effects, among which their impact on systemic haemodynamics is poorly clarified. This review aims to appraise the clinical evidence of the effect of mannitol and hypertonic saline (HTS) on cardiac performance in neurosurgical and neurocritical care patients. METHOD: A database search was conducted to identify randomized clinical trials and observational studies reporting HTS or mannitol use in acute brain injury setting. The primary end-points were alterations of cardiac output (CO) and other haemodynamic variables, while the impact of osmotic agents on intracranial pressure, brain relaxation, plasma osmolality, electrolyte levels and urinary output constituted secondary outcomes. RESULTS: Eight studies, enrolling 182 patients in total, were included. HTS exerted a more profound cardiac output augmentation than mannitol, but no distinct difference between groups occurred. Central venous pressure, stroke volume and stroke volume variation were favourably affected by both osmotic agents, whilst the reported changes in blood pressure were inconclusive. HTS infusion yielded a larger intracranial pressure reduction than mannitol but had an equivalent effect on brain relaxation. Mannitol presented a more potent diuretic effect than HTS. Effect on serum osmolality was alike in both osmotic agents, but contrary to HTS promoted hypernatraemia, mannitol use induced transient hyponatraemia. CONCLUSIONS: Mannitol or HTS administration seems to induce an enhancement of cardiac performance; being more prominent after HTS infusion. This effect combined with mannitol-induced enhancement of diuresis and HTS-promoted increase of plasma sodium concentration could partially explain the effects of osmotherapy on cerebral haemodynamics. PMID- 29247502 TI - Immunotherapy (excluding checkpoint inhibitors) for stage I to III non-small cell lung cancer treated with surgery or radiotherapy with curative intent. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is the most common lung cancer, accounting for approximately 80% to 85% of all cases. For patients with localised NSCLC (stages I to III), it has been speculated that immunotherapy may be helpful for reducing postoperative recurrence rates, or improving the clinical outcomes of current treatment for unresectable tumours. While several new agents have now entered phase III clinical trials, we felt a systematic review was needed to address the question of the effectiveness and safety of immunotherapy in patients with stages I to III NSCLC. OBJECTIVES: To evaluate the effectiveness and safety of immunotherapy (excluding checkpoint inhibitors) in patients with localised NSCLC (stages I to III) who received surgery or radiotherapy with curative intent. SEARCH METHODS: We searched the following databases (from inception to 20 January 2017): CENTRAL, MEDLINE, Embase, and CINAHL, and five trial registers. We also manually checked abstracts or reports from relevant conference proceedings and the reference lists of included trials. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) in adults (>= 18 years) with histologically confirmed early-stage (stages I to III) NSCLC after surgical resection, and those with unresectable locally advanced stage III NSCLC who had received radiotherapy with curative intent. For patients who had received primary surgical treatment, postoperative radiotherapy or chemoradiotherapy was allowed if it was used for both experimental and control groups. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible trials, assessed risk of bias, and extracted data. We used survival analysis to pool time-to-event data, expressing the intervention effect as a hazard ratio (HR). We calculated risk ratios (RR) for dichotomous data, and mean differences for continuous data, with 95% confidence intervals (CI). Due to clinical heterogeneity (immunotherapeutic agents with different underlying mechanisms), we used random-effects models for our meta-analyses. MAIN RESULTS: We identified nine eligible trials that randomised 4940 participants, who had received surgical resection or curative radiotherapy, to either an immunotherapy group or a control group. Included immunological interventions were active immunotherapy (i.e. Bacillus Calmette Guerin (BCG)), adoptive cell transfer (i.e. transfer factor (TF), tumour infiltrating lymphocytes (TIL), dendritic cell-cytokine induced killer (DC-CIK), and antigen-specific cancer vaccines (melanoma-associated antigen 3 (MAGE-A3) and L-BLP25). Except for one small trial, which provided insufficient information for risk assessment, we assessed five studies at high risk of bias for at least one of the seven biases studied; we considered the risk of bias in the other three trials to be low. We included data from seven of the nine trials in the meta analyses (4695 participants). We pooled data from 3693 participants from the three high quality RCTs to evaluate overall survival (OS) and progression-free survival (PFS). We found a small, but not statistically significant, improvement in OS (HR 0.94, 95% CI 0.83 to 1.06; P = 0.35), and PFS (HR 0.93, 95% CI 0.81 to 1.07; P = 0.19; high-quality evidence). The addition of immunotherapy resulted in a small, but not statistically significant, increased risk of having any adverse event (RR 1.15, 95% CI 0.97 to 1.37; P = 0.11, three trials, 3955 evaluated participants, moderate-quality evidence), or severe adverse events (RR 1.10, 95% CI 0.88 to 1.39; four trials, 4362 evaluated participants; low-quality evidence).We analysed data from six studies for one-, two-, and three-year survival rates (4265 participants), and from six studies for five-year survival rates (4234 participants). We observed no clear between-group differences (low quality evidence for one- and two-year survival rates, and moderate-quality evidence for three- and five-year survival rate).No trial reported the overall response rates; only one trial provided health-related quality of life results. AUTHORS' CONCLUSIONS: The current literature does not provide evidence that suggests a survival benefit from adding immunotherapy (excluding checkpoint inhibitors) to conventional curative surgery or radiotherapy, for patients with localised NSCLC (stages I to III). The addition of vaccine-based immunotherapy might increase the risk of adverse events. Several ongoing trials with immune checkpoints inhibitors (PD-1/PD-L1) might bring new insights for role of immunotherapy for patients with stages I to III NSCLC. PMID- 29247503 TI - Comparison of Accuracy of Pedicle Screw Insertion Among 4 Guided Technologies in Spine Surgery. AB - BACKGROUND As an available new tool for spinal surgery, robotic technology holds great potential and has been demonstrated to have better clinical outcomes compared with traditional techniques. However, it has not been compared with other assisted tools for the treatment of lumbar degenerative disease. This article focused on studying such variances. MATERIAL AND METHODS A total of 176 pedicle screws were inserted in 39 patients using a spine robot (group 1), 134 screws were implanted in 28 patients using navigational template (group 2), 234 screws were implanted in 51 patients by O-arm-based navigation (group 3), and 346 screws were implanted in 72 patients by fluoroscopy-guided assistance (group 4). The screw position was evaluated using postoperative scans according to Rampersaud A to D classification, and other secondary data were also collected. RESULTS "Perfect" pedicle screw insertion (Grade A) was 90.34%, 91.79%, 84.19%, and 65.03% of groups 1-4, respectively. "Clinically acceptable" screw implantation (Grade A+B) was 94.32%, 95.52, 90.60%, and 78.03% in groups 1-4, respectively. Deviation sagittal ( degrees ) respectively was 3+/-9, 2+/-10, 4+/ 7, and 10+/-8 degrees in groups 1-4, respectively. Deviation transversal ( degrees ) screw insertion was 3+/-8, 3+/-7, 4+/-9, and 8+/-13 degrees in groups 1-4, respectively. Statistical analysis showed group 1 had no significant difference in the accuracy of "Perfect and Clinical acceptable" as well as deviation sagittal or transversal, respectively, compared with groups 2 and 3 but not group 4. CONCLUSIONS Robotic-assistance technology no clear advantage in terms of accuracy compared to the navigation template or O-arm systems for screw implantation, but it significantly reduced adverse events, fluoroscopy time per screw, postoperative stay, and blood loss. PMID- 29247504 TI - Molecular recognition of glyconanoparticles by RCA and E. coli K88 - designing transports for targeted therapy. AB - The targeted drug delivery has been studied as one of the main methods in medicine to ensure successful treatments of diseases. Pharmaceutical sciences are using micro or nano carriers to obtain a controlled delivery of drugs, able to selectively interact with pathogens, cells or tissues. In this work, we modified bovine serum albumin (BSA) with lactose, obtaining a neoglycan (BSA-Lac). Subsequently, we synthesized glyconanoparticles (NPBSA-Lac) with the premise that it would be recognized by microbial galactose specific lectins. NPBSA-Lac were tested for bio-recognition with adhesins of E. coli K88 and Ricinus communis agglutinin I (RCA). Glycation of BSA with lactose was analyzed by electrophoresis, infrared spectroscopy and fluorescence. Approximately 41 lactoses per BSA molecule were estimated. Nanoparticles were obtained using water in oil emulsion method and spheroid morphology with a range size of 300-500 nm was observed. Specific recognition of NPBSA-Lac by RCA and E. coli K88 was displayed by aggregation of nanoparticles analyzed by dynamic light scattering and atomic force microscopy. The results indicate that the lactosylated nanovectors could be targeted at the E. coli K88 adhesin and potentially could be used as a transporter for an antibacterial drug. PMID- 29247505 TI - First insight into microbial community composition in a phosphogypsum waste heap soil. AB - The aim of this study was to investigate the soil microbial communities of a phosphogypsum waste heap. The soil microbial community structures can differ over time, as they are affected by the changing environmental conditions caused by a long-term exposure to different kinds of pollutions, like is the case of soil in the post-production waste area in Wislinka (in the northern part of Poland) currently undergoing restoration. Our analyses indicated that the most abundant phyla were Proteobacteria, Acidobacteria, and Actinobacteria, and generally such an abundance is common for most of the studied soils. The most dominant class were Alphaproteobacteria, with their participation in 33.46% of the total reads. Among this class, the most numbered order was Sphingomonadales, whereas among this order the Sphingomonadaceae family was the most abundant one. The Sphingomonadaceae family is currently in the center of interest of many researchers, due to the ability of some of its members to utilize a wide range of naturally occurring organic compounds and many types of environmental contaminants. This kind of knowledge about microbial populations can support efforts in bioremediation and can improve monitoring changes in the contaminated environments. PMID- 29247506 TI - Suboptimal Antituberculosis Drug Concentrations and Outcomes in Small and HIV Coinfected Children in India: Recommendations for Dose Modifications. AB - This work aimed to evaluate the once-daily antituberculosis treatment as recommended by the new Indian pediatric guidelines. Isoniazid, rifampin, and pyrazinamide concentration-time profiles and treatment outcome were obtained from 161 Indian children with drug-sensitive tuberculosis undergoing thrice-weekly dosing as per previous Indian pediatric guidelines. The exposure-response relationships were established using a population pharmacokinetic-pharmacodynamic approach. Rifampin exposure was identified as the unique predictor of treatment outcome. Consequently, children with low body weight (4-7 kg) and/or HIV infection, who displayed the lowest rifampin exposure, were associated with the highest probability of unfavorable treatment (therapy failure, death) outcome (Punfavorable ). Model-based simulation of optimized (Punfavorable <= 5%) rifampin once-daily doses were suggested per treatment weight band and HIV coinfection status (33% and 190% dose increase, respectively, from the new Indian guidelines). The established dose-exposure-response relationship could be pivotal in the development of future pediatric tuberculosis treatment guidelines. PMID- 29247507 TI - Clinicopathological characteristics of cutaneous malignant melanoma in patients at a tertiary hospital in Macaronesia. Survival as a function of locoregional prognostic factors per the American Joint Committee on Cancer. AB - BACKGROUND: Despite suffering high ultraviolet radiation levels, few data on malignant melanoma (MM) in Macaronesia are available. METHODS: Observational study of cutaneous MM cases diagnosed during a period of 12 years at a tertiary hospital in Canary Islands. RESULTS: A total of 532 patients (female/male = 1.4) with an average age of 56 years were included; 5% developed more than one MM, and 7% reported family history of MM. Phototype II (43%), dark eyes (41%), and dark hair (41%) predominated. There was a lower frequency of light-colored hair and eyes in those born in the Canary Islands. The most frequent locations of MM were on the back for men (37%) and on the lower extremities for women (35%). Among the infiltrating tumors (83%), the (median) thickness was 1.07 mm (women, 0.90 mm; men, 1.21 mm). Anatomopathological ulceration (AU) and a mitotic rate >=1 mitosis/mm2 (HMR) were recorded in 27% of patients. Patients with regional disease constituted 12% of the population. The most common stage was IA (34%). Melanoma-specific survival (MSSV) decreased significantly with thickness, presence of AU, HMR, and sentinel lymph node disease. These four variables were independent prognostic factors. The five-year MSSV varied between 100% (stage IA) and 39% (stage IIIC). CONCLUSIONS: The characteristics of the patients were similar to those published in datasets from continental Europe, although the pigmentary features were darker in those originating from Macaronesia. The prognostic parameters described in the 7th edition of the American Joint Committee on Cancer (AJCC) independently predict MSSV in our patients. PMID- 29247508 TI - Understanding sunscreen SPF performance using cross-polarized UVA reflectance photography. AB - OBJECTIVES: Objective methods for understanding sunscreen behaviour in vitro before they are applied to the skin have failed to keep pace with the ever increasing demands for higher SPF scores where the products are absorbing more and more similar levels of UV. A novel method for visualizing the spreading and location of SPF ingredients based on cross-polarized UVA reflectance photography is described here which gives new insights into the formation of final film morphology and how it correlates with in vivo SPF efficacy for a set of test products. METHODS: High-resolution UVA-based images of sunscreen films spread onto PMMA plates were captured using a modified commercial SLR camera in a custom imaging system. Visual grading and image analysis were used to describe the overall UVA absorbance and streakiness of the resultant films, and the data compared with both in vivo and calculated in vitro SPF scores for the products. RESULTS: Differences were observed between the products in terms of how they spread during application. A strong correlation was observed between the evenness of the resultant film as determined from the photographs and final in vivo SPF scores. CONCLUSIONS: Cross-polarized UVA reflectance photography has been demonstrated to be a valuable new method for assessing sunscreen distribution after spreading and to differentiate product based on film morphology, as well as strongly correlating with final in vivo behaviour. PMID- 29247509 TI - Prevalence of skin disease in a population-based sample of adults from five European countries. AB - BACKGROUND: There is a lack of prevalence data on skin diseases in the general adult population; most studies have been carried out in small, national or consecutive clinical samples. OBJECTIVES: To determine the prevalence of common skin disease in the general European population and to assess differences in the characteristics of treatment between countries. METHODS: A random sample consisting of 12 377 participants aged 18-74 years was drawn from the general population of five European countries (Germany, Italy, the Netherlands, Portugal and Sweden). This was a cross-sectional study and all participants were interviewed using a standardized questionnaire that assessed the occurrence of 10 common skin diseases during lifetime, past year and past month. If a skin disease was reported, we additionally assessed who performed the diagnosis and treatment, and whether drugs had been prescribed. RESULTS: The most common skin disease was warts (41.3%), followed by acne (19.2%) and contact dermatitis (15.0%). In general, women were more often affected by skin diseases compared with men; only skin cancer had a slightly higher prevalence in men. The prevalence of skin diseases in northern countries (Germany, the Netherlands and Sweden) was generally higher than in the southern countries (Italy and Portugal). In the Netherlands the treatment of skin diseases was less often performed by a dermatologist compared with the other countries. CONCLUSIONS: The prevalence estimates reported in this study are derived from a representative sample of the general population. Data assessment was performed comprehensively across countries, thus country-specific prevalence estimates are comparable. PMID- 29247510 TI - Culprit plaque characteristics in women vs men with a first ST-segment elevation myocardial infarction: In vivo optical coherence tomography insights. AB - BACKGROUND: It is unclear whether more severe coronary atherosclerosis is a prerequisite to an initial acute coronary event in women vs men. HYPOTHESIS: Women may have more severe coronary atherosclerosis than men in patients with acute coronary event. METHODS: We used intravascular optical coherence tomography (OCT) to evaluate gender differences in culprit-plaque morphology in patients with a first ST-segment elevation myocardial infarction (STEMI).We retrospectively enrolled 211 consecutive patients who experienced a first STEMI and underwent an OCT examination of their infarct-related artery before primary percutaneous coronary intervention. RESULTS: Of the 211 patients enrolled, 162 (76.7%) were men and 49 (23.2%) were women. The women were significantly older than the men (mean age, 60.2 +/- 8.2 vs 55.7 +/- 11.2 years; P = 0.01) and less likely to be current smokers (P = 0.02). Moreover, the delay from symptom onset to reperfusion was longer in women than in men (7.6 +/- 6.1 vs 5.5 +/- 4.4 hours; P = 0.01). The OCT data indicated that there were no gender differences in culprit-plaque morphology, including lipid length, lipid arc, minimum fibrous cap thickness, or minimum lumen area. Additionally, no gender differences were found in the prevalence of plaque rupture, thin-cap fibroatheroma, residual thrombus, microvessels, macrophages, cholesterol crystals, or calcification. CONCLUSIONS: Among patients presenting with a first STEMI, there were no differences in culprit plaque features between women and men. PMID- 29247511 TI - Isometric handgrip echocardiography: A noninvasive stress test to assess left ventricular diastolic function. AB - BACKGROUND: Cycle exercise echocardiography is a useful tool to "unmask" diastolic dysfunction; however, this approach can be limited by respiratory and movement artifacts. Isometric handgrip avoids these issues while reproducibly increasing afterload and myocardial oxygen demand. HYPOTHESIS: Isometric handgrip echocardiography (IHE) can differentiate normal from abnormal diastolic function. METHODS: First recruited 19 young healthy individuals (mean age, 24 +/- 4 years) to establish the "normal" response. To extend these observations to a more at risk population, we performed IHE on 17 elderly individuals (mean age, 72 +/- 6 years) with age-related diastolic dysfunction. The change in the ratio of mitral valve inflow velocity to lateral wall tissue velocity (E/e'), a surrogate for left ventricular filling pressure, was used to assess the diastolic stress response in each group. RESULTS: In the young subjects, isometric handgrip increased heart rate and mean arterial pressure (25 +/- 12 bpm and 26 +/- 17 mmHg, respectively), whereas E/e' changed minimally (0.6 +/- 0.9). In the elderly subjects, heart rate and mean arterial pressure were similarly increased with isometric handgrip (19 +/- 16 bpm and 25 +/- 11 mmHg, respectively), whereas E/e' increased more dramatically (2.3 +/- 1.7). Remarkably, 11 of the 17 elderly subjects had an abnormal diastolic response (DeltaE/e': 3.4 +/- 1.1), whereas the remaining 6 elderly subjects showed very little change (DeltaE/e': 0.3 +/- 0.7), independent of age or the change in myocardial oxygen demand. CONCLUSIONS: IHE is a simple, effective tool for evaluating diastolic function during simulated activities of daily living. PMID- 29247512 TI - Alemtuzumab depletion failure can occur in multiple sclerosis. AB - Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Although these anti-drug responses have been reported to be of no significance, we hypothesized that they will affect the depleting capacity and treatment response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population level there was lack of influence of 'ever-positive' alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and adverse effects during the 2-year trial. This was not surprising as no one before the first infusion, and only 0.6% of people before the second-infusion, had pre-infusion, neutralizing antibodies (NAbs). However, at the individual level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, which suggests that problems may occur in people requiring additional alemtuzumab cycles. In addition, we also identified individuals, following 'post-marketing' alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Hence, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete poorly, probably due to biological-response variation and NAbs, and this may lead to treatment failure. Monitoring depletion following infusion and assessment of the neutralizing response before re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure. PMID- 29247513 TI - Clinical efficacy of irrigated catheter application of amiodarone during ablation of persistent atrial fibrillation. AB - BACKGROUND: Pharmacological treatment during ablation of persistent atrial fibrillation (AF) is common, but utility of irrigated catheter application of amiodarone during ablation of persistent AF remains unclear. HYPOTHESIS: Irrigated catheter application of amiodarone improves quality of ablation and long-term outcomes. METHODS: We enrolled 90 persistent AF patients who underwent catheter ablation. Patients were randomized to the amiodarone group (n = 45) or control group (n = 45). All patients underwent stepwise ablation beginning with isolation of the pulmonary veins. Next, we performed ablation of linear lesions and focal triggers until sinus rhythm (SR) was achieved. The primary endpoint was documented atrial arrhythmia during follow-up. The secondary endpoint was cardioversion to SR during ablation. RESULTS: All pulmonary veins were successfully isolated. Conversion of AF to SR occurred more frequently in the amiodarone group than in the control group (33 vs 23 [73.3% vs 51.1%]; P = 0.03). The amiodarone group had lower procedure, radiofrequency, and fluoroscopy times than the control group (167.4 +/- 22.5 min vs 186.7 +/- 25.3 min; 78.3 +/- 14.2 min vs 90.4 +/- 15.5 min; and 6.5 +/- 1.9 min vs 8.6 +/- 2.4 min, respectively; P < 0.05). More importantly, the atrial arrhythmia recurrence-free survival rates were 80% in the amiodarone group and 60% in the control group during the 14.7 +/- 7.5-month follow-up (P = 0.043). CONCLUSIONS: Irrigated catheter application of amiodarone during ablation for persistent AF resulted in higher cardioversion rates and lower procedure times and significantly reduced rates of atrial arrhythmia recurrence. PMID- 29247514 TI - Treatment-related psychological stress in different in vitro fertilization therapies with and without gonadotropin stimulation. AB - INTRODUCTION: Infertility treatments such as in vitro fertilization (IVF) impose substantial distress. However, the specific role of individual contributory factors remains unclear. We therefore compared treatment-related psychological stress in IVF treatments with (cIVF) and without (NC-IVF) gonadotropin stimulation, as cIVF includes potentially stressful factors such as ovarian stimulation, anesthesia, embryo selection and cryopreservation, whereas NC-IVF does not. MATERIAL AND METHODS: Women were offered to have cIVF or NC-IVF. Validated psychological questionnaires filled in online before, during and after completed treatment cycle(s) at home were used to analyze psychological distress and treatment-related satisfaction and quality of life. To avoid different pregnancy rates in the two treatment groups, one cIVF was compared with three NC IVF therapies, resulting in the same cumulative pregnancy rate. RESULTS: Data from 57 NC-IVF and 62 cIVF patients were evaluated. NC-IVF resulted in a similar overall clinical pregnancy rate than one cIVF. NC-IVF patients had a significantly lower level of depression (CES-D, 13.4 vs. 15.7, p < 0.05) and a higher satisfaction with the treatment (Treatment FertiQoL, 67.9 vs. 62.9, p < 0.05) compared with cIVF patients. The level of psychological distress increased during c-IVF treatment and decreased during NC-IVF treatment. In contrast, during NC-IVF treatment there was a significant increase in satisfaction with the treatment, whereas satisfaction with treatment in the cIVF patients decreased. CONCLUSIONS: Factors other than just pregnancy rate seem to have an impact on psychological stress in IVF treatment. Due to reduced psychological stress in NC IVF, this treatment could be especially considered in psychologically stressed women. PMID- 29247515 TI - Intrahepatic and peripheral blood phenotypes of natural killer and T cells: differential surface expression of killer cell immunoglobulin-like receptors. AB - Deep characterization of the frequencies, phenotypes and functionalities of liver and peripheral blood natural killer (NK), natural killer T (NKT) and T cells from healthy individuals is an essential step to further interpret changes in liver diseases. These data indicate that CCR7, a chemokine essential for cell migration through lymphoid organs, is almost absent in liver NK and T cells. CD56bright NK cells, which represent half of liver NK cells, showed lower expression of the inhibitory molecule NKG2A and an increased frequency of the activation marker NKp44. By contrast, a decrease of CD16 expression with a potential decreased capacity to perform antibody-dependent cellular cytotoxicity was the main difference between liver and peripheral blood CD56dim NK cells. Liver T cells with an effector memory or terminally differentiated phenotype showed an increased frequency of MAIT cells,T-cell receptor-gammadelta (TCR-gammadelta) T cells and TCR-alphabeta CD8+ cells, with few naive T cells. Most liver NK and T cells expressed the homing markers CD161 and CD244. Liver T cells revealed a unique expression pattern of killer cell immunoglobulin-like receptors (KIR) receptors, with increased degranulation ability and higher secretion of interferon-gamma. Hence, the liver possesses a large amount of memory and terminally differentiated CD8+ cells with a unique expression pattern of KIR activating receptors that have a potent functional capacity as well as a reduced amount of CCR7, which are unable to migrate to regional lymph nodes. These results are consistent with previous studies showing that liver T (and also NK) cells likely remain and die in the liver. PMID- 29247516 TI - Impact of coronary artery disease in patients undergoing transcatheter aortic valve replacement: Insights from the FRANCE-2 registry. AB - BACKGROUND: Coronary artery disease (CAD) is common in patients undergoing transcatheter aortic valve replacement (TAVR). However, the impact of CAD distribution before TAVR on short- and long-term prognosis remains unclear. HYPOTHESIS: We hypothesized that the long-term clinical impact differs according to CAD distribution in patients undergoing TAVR using the FRench Aortic National CoreValve and Edwards (FRANCE-2) registry. METHODS: FRANCE-2 is a national French registry including all consecutive TAVR performed between 2010 and 2012 in 34 centers. Three-year mortality was assessed in relation to CAD status. CAD was defined as at least 1 coronary stenosis >50%. RESULTS: A total of 4201 patients were enrolled in the registry. For the present analysis, we excluded patients with a history of coronary artery bypass. CAD was reported in 1252 patients (30%). Half of the patients presented with coronary multivessel disease. CAD extent was associated with an increase in cardiovascular risk profile and in logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (from 19.3% +/- 12.8% to 21.9% +/- 13.5%, P < 0.001). Mortality at 30 days and 3 years was 9% and 44%, respectively, in the overall population. In multivariate analyses, neither the presence nor the extent of CAD was associated with mortality at 3 years (presence of CAD, hazard ratio [HR]: 0.90; 95% confidence interval [CI]: 0.78-1.07). A significant lesion of the left anterior descending (LAD) was associated with higher 3-year mortality (HR: 1.42; 95% CI: 1.10-1.87). CONCLUSIONS: CAD is not associated with decreased short- and long-term survival in patients undergoing TAVR. The potential deleterious effect of LAD disease on long-term survival and the need for revascularization before or at the time of TAVR should be validated in a randomized control trial. PMID- 29247517 TI - Left atrial function and mortality in the oldest old. AB - BACKGROUND: Previous studies demonstrated that left atrium (LA) size is associated with mortality in an elderly population. It remains unclear whether indices of LA function including reservoir, conduit, or booster elements of LA function provide incremental prognostic information. HYPOTHESIS: Echocardiographic measures of the various parameters of LA function would predict 5-year mortality in a community-dwelling population of 85 to 86 year olds independently of LA volume. METHODS: Subjects ages 85 to 86 years old underwent home echocardiography. LA volumes were assessed by the biplane Simpson's method from apical views using measurements of phasic volumes and functions of the LA, including LA expansion index. LA passive and active emptying fractions were assessed. Survival status at 5-year follow-up was assessed. RESULTS: Two hundred eighty-two subjects were included, of whom 87 (31%) had died at follow-up. Survival of the subjects in the lowest quartile of the LA expansion index as well as LA active filling index was significantly lower. When measurements of LA volume index were added to the model, the relationship between survival and indices of LA function remained significant. CONCLUSIONS: This study demonstrated that elderly subjects aged 85 to 86 years with significantly impaired LA function had increased 5-year mortality independently of indices of LA volume. PMID- 29247518 TI - Cardiovascular safety of NSAIDs: Additional insights after PRECISION and point of view. AB - Increasing numbers of patients with arthritis use nonsteroidal anti-inflammatory drugs (NSAIDs), some for long periods. The relative cardiovascular safety of NSAID use is of considerable concern, particularly among patients with or at risk of cardiovascular disease. Until recently, the evidence base was limited to older trials with small sample sizes. The large-scale Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen (PRECISION) trial and a recent Bayesian meta-analysis of individual patient data in nearly a half-million patients were undertaken to address some of the existing gaps in knowledge relative to the cardiovascular safety of NSAID use. We reviewed the results, strengths, and limitations of PRECISION. We believe that the results of the meta analysis will further assist clinicians in decision-making for management of patients with osteoarthritis. The totality of evidence would support avoidance of NSAID use, if possible, in patients with or at high risk for cardiovascular disease. If used, the shortest-duration and lowest effective NSAID doses should be chosen, given the evidence that risk is duration- and dose-dependent. We also provide a brief discussion of the mechanism of action of NSAIDs, along with discussion of existing guidelines and the recent meta-analysis. PMID- 29247519 TI - Real-world incidence of efficacy and safety outcomes in patients on direct oral anticoagulants with left ventricular systolic dysfunction at a tertiary referral center. AB - BACKGROUND: Patients with heart failure (HF) have increased risk for thromboembolic events. Real-world incidences of efficacy and safety outcomes of direct oral anticoagulants (DOACs) in patients with left ventricular systolic dysfunction (LVSD) are of growing clinical interest. HYPOTHESIS: Real-world efficacy and safety outcomes of DOACs in patients with LVSD will be similar to those of LVSD or HF subgroups in the RE-LY, ROCKET-AF, and ARISTOTLE trials. METHODS: We performed a retrospective review of adult patients with LVSD (left ventricular ejection fraction <=40%) on DOAC therapy between 2010 and 2016. Incidences of safety and efficacy outcomes of anticoagulation with DOACs were extracted from primary and secondary hospital discharge diagnoses. RESULTS: DOACs were prescribed to 287 patients with LVSD over a mean follow-up of 313.3 +/- 52.3 days. Many patients had moderate and severe chronic kidney disease (28.9% and 10.1%, respectively) and indications for anticoagulation therapy other than atrial fibrillation (19.9%). For efficacy outcomes, the calculated incidence rates of ischemic stroke and systemic embolism were 1.2 (95% confidence interval [CI]: 0.25-3.56) and 0.81 (95% CI: 0.10-2.94) events per 100 person-years, respectively. For the safety outcomes, incidence rates of GI bleeding and intracranial hemorrhage were 2.4 (95% CI: 0.8-5.3) and 0.41 (95% CI: 0.1-2.2) events per 100 patient-years, respectively. CONCLUSIONS: Our findings are largely compatible with the results of LVSD or HF subgroups in RE-LY, ROCKET-AF, and ARISTOTLE trials and add to increasing confidence that DOACs can be safely used for stroke and systemic embolism prevention in patients with LVSD. PMID- 29247520 TI - Lithium-induced electrocardiographic changes: A complete review. AB - Lithium has been used for the treatment of bipolar disorder for more than 6 decades. Reports of cardiac side effects resulting in both benign electrocardiographic (ECG) changes and near fatal arrhythmias have been reported in the literature. A systematic literature search was conducted on 2 electronic databases-PubMed and Medline-for the time period between January 1970 and March 2016 using the key word "lithium," along with "electrocardiography" or "ECG." All articles and their references were then screened by title for relevance by 2 authors and a librarian. A total of 406 articles were found on literature search, of which 56 met the screening criteria. T wave inversion was the most frequently reported ECG finding. Other findings include sinus node dysfunction, sinoatrial blocks, PR prolongation, QT prolongation/dispersion, and ventricular tachyarrhythmias. Some cases have shown lithium-treated patients experiencing serious cardiac outcomes, such as ST elevation myocardial infarction, heart blocks, and the Brugada pattern. Electrical changes from lithium were found to be dependent on both duration of treatment and the serum lithium level. Although there are no standardized ECG guidelines, frequent monitoring of patients on lithium therapy can ensure the medication's safe use. PMID- 29247521 TI - Comparative outcomes between ameroid ring constrictor and cellophane banding for treatment of single congenital extrahepatic portosystemic shunts in 49 dogs (1998 2012). AB - OBJECTIVE: To compare outcomes and identify prognostic factors in dogs with single congenital extrahepatic portosystemic shunt (CEHPSS) gradually attenuated with an ameroid ring constrictor (ARC) or cellophane banding (CB). STUDY DESIGN: Retrospective, multi-institutional study. ANIMALS: Forty-nine dogs with CEHPSS (n = 23 for ARC; n = 26 for CB). METHODS: Medical records of dogs with CEHPSS treated by ARC or CB were reviewed for postoperative (<1 month), midterm (1-6 months), and long-term (> 6 months) outcomes. Data were evaluated to detect factors associated with postoperative complications, residual shunting, and long term outcome. RESULTS: Postoperative complication rates did not differ between ARC (26.1%) and CB (23.1%, P = .89) and were negatively associated with body weight (P = .03). Overall, postoperative mortality was low (2.0%). Clinical long term outcome was excellent in 45.0% and 39.1% and good in 55.0% and 60.9% of dogs after ARC and CB, respectively. Suspected residual shunting rate upon abdominal ultrasonography was greater after CB (31.6%) than after ARC (0%). CONCLUSION: ARC and CB were both effective for attenuation of CEHPSS, resulting in good to excellent outcomes with low morbidity and mortality. Residual shunting was suspected in a higher proportion of dogs treated with CB on the basis of abdominal ultrasonography results. However, further prospective randomized studies must be conducted with validated evaluation methods to verify this assumption. PMID- 29247522 TI - Pharmacokinetics and Pharmacodynamics of Treosulfan in Patients With Thalassemia Major Undergoing Allogeneic Hematopoietic Stem Cell Transplantation. AB - A treosulfan (Treo)-based conditioning regimen prior to hematopoietic stem cell transplantation (HSCT) has been successfully used in treating hematological malignant and nonmalignant diseases. We report Treo pharmacokinetics (PK) in patients with thalassemia major undergoing HSCT (n = 87), receiving Treo at a dose of 14 g/m2 /day. Median Treo AUC and clearance (CL) was 1,326 mg*h/L and 10.8 L/h/m2 , respectively. There was wide interindividual variability in Treo AUC and CL (64 and 68%) which was not explained by any of the variables tested. None of the Treo PK parameters were significantly associated with graft rejection or toxicity; however, Treo CL <7.97 L/h/m2 was significantly associated with poor overall (hazard ratio (HR) 2.7, confidence interval (CI) (1.09-6.76), P = 0.032) and event-free survival (HR 2.4, CI (0.98-5.73), P = 0.055). Further studies in a larger cohort are warranted to identify the factors explaining the variation in Treo PK as well as to establish a therapeutic range of Treo for targeted dose adjustment to improve HSCT outcome. PMID- 29247523 TI - Impact of obstructive sleep apnea on cardiovascular outcomes in patients with acute symptomatic pulmonary embolism: Rationale and methodology for the POPE study. AB - In normotensive patients with acute symptomatic pulmonary embolism (PE), the effect of undiagnosed obstructive sleep apnea (OSA) on cardiovascular (CV) outcomes lacks clarity. The Prognostic Significance of Obstructive Sleep Apnea in Patients With Acute Symptomatic Pulmonary Embolism (POPE) study is a multicenter, observational study designed to prospectively assess the prognostic significance of concomitant OSA in hemodynamically stable outpatients with acute symptomatic PE. Adult patients with acute stable PE are eligible. Recruited patients undergo an overnight sleep study using a level III portable diagnostic device within 7 days (and preferably within 48 hours) of diagnosis of PE. The sleep tracings are analyzed by a certified sleep technologist and audited by a sleep physician, both of whom are blinded to other study data. The patients are divided into 2 groups based on apnea-hypopnea index (AHI): OSA (AHI >=15) and non-OSA (AHI <15) groups. The study uses a composite of PE-related death, CV death, clinical deterioration requiring an escalation of treatment, or nonfatal CV events (recurrent venous thromboembolism, acute myocardial infarction, or stroke) within 30 days after the diagnosis of PE as the primary outcome. The projected sample size of 225 patients will provide 80% power to test the hypothesis that OSA will increase the primary outcome from 7% in the non-OSA group to 20% in the OSA group, with alpha <=0.05. The trial results will be important to understand the burden and CV effects of OSA in PE patients. PMID- 29247524 TI - Rationale and design of the long-Term rIsk, clinical manaGement, and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients (TIGRIS) study. AB - The long-term progression of coronary artery disease as defined by the natural disease course years after a myocardial infarction (MI) is an important but poorly studied area of clinical research. The long-Term rIsk, clinical manaGement, and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients (TIGRIS) study was designed to address this knowledge gap by evaluating patient management and clinical outcomes following MI in different regions worldwide. TIGRIS (ClinicalTrials.gov Identifier: NCT01866904) is a multicenter, observational, prospective, longitudinal study enrolling patients with history of MI 1 to 3 years previously and high risk of developing atherothrombotic events in a general-practice setting. The primary objective of TIGRIS is to evaluate clinical events (time to first occurrence of any event from the composite cardiovascular endpoint of MI, unstable angina with urgent revascularization, stroke, or death from any cause), and healthcare resource utilization associated with hospitalization for these events (hospitalization duration and procedures) during follow-up. Overall, 9225 patients were enrolled between June 2013 and November 2014 and are being followed in 369 different centers worldwide. This will allow for the description of regional differences in patient characteristics, risk profiles, medical treatment patterns, clinical outcomes, and healthcare resource utilization. Patients will be followed for up to 3 years. Here we report the rationale, design, patient distribution, and selected baseline characteristics of the TIGRIS study. TIGRIS will describe real-world management, quality of life (self-reported health), and healthcare resource utilization for patients with stable coronary artery disease >=1 year post-MI. PMID- 29247525 TI - QTc dispersion and Cornell duration product can predict 10-year outcomes in hypertensive patients with left ventricular hypertrophy. AB - BACKGROUND: Persistent and adequate treatment of patients with arterial hypertension leads to more favorable disease outcome. HYPOTHESIS: Aside for the present left ventricular hypertrophy (LVH), there are other non-invasive parameters which can represent additional predictors of unfavorable prognosis in patients with essential arterial hypertension during the 10-year follow-up. METHODS: A hypertensive group with LVH (124 patients; age 57.0 +/- 8.0; 84 males and 40 females) was included in the study and examined noninvasively. Patients used regular medication therapy during the follow-up period. RESULTS: During the 10-year follow-up period, unfavorable outcome was recorded for 40 (32.3%) patients. Patients with unfavorable outcome had higher baseline values of left ventricular mass index (178.9 +/- 29.5 g/m2 vs 165.5 +/- 29.5 g/m2 ; P < 0.05) and QTc dispersion (64.1 +/- 24.7 ms vs 54.8 +/- 19.4 ms; P < 0.05). Frequency of positive Cornell product was higher in the group of patients with unfavorable outcome (35% vs 22.2%; P < 0.01). Positive Lyon-Sokolow score did not show statistical significance (25% vs 11.9%; P = 0.06). Cornell product (beta = 0.234; P < 0.01) and QTc dispersion >65 ms (beta = 0.184; P < 0.05) had prognostic significance in LVH (multiple regression analysis: R = 0.314, R = 0.099, adjusted R = 0.084, standard error of the estimate = 0.449, P < 0.05). CONCLUSIONS: Patients with a positive Cornell product and larger QTc dispersion had more unfavorable 10-year outcomes compared with other patients with LVH. PMID- 29247526 TI - Effects of shRNA-mediated Silencing of PSMA7 on Cell Proliferation and Vascular Endothelial Growth Factor Expression via the Ubiquitin-Proteasome Pathway in Cervical Cancer. AB - This study aims to evaluate the effects of PSMA7 silencing on cervical cancer (CC) cell proliferation and vascular endothelial growth factor (VEGF) expression through the ubiquitin-proteasome (UPP) pathway. CC tissue (n = 43) and normal tissues (n = 27) were first collected from patients. Human CC cell line (SiHa) and human normal cervical epithelial cells (H8) were obtained and classified into the normal, blank, negative control (NC), PSMA7-shRNA1 and PSMA7-shRNA2 groups. Hybridization in situ was used to detect the expressions of wild-type and mutant p53 proteins. Immunofluorescence assay was carried out to test the activity of 20S proteasomes. RT-qPCR and Western blotting were both performed to determine the expressions of PSMA7, ubiquitin, P27, P53 and VEGF in sample tissues and cells. MTT assay was used analyze cell proliferation rates, and flow cytometry to analyze cell cycle and apoptotic rate. Compared with normal tissue, CC tissues had increased expression levels of PSMA7, ubiquitin, p53, VEGF as well as increased the activity of 20S proteasomes, but exhibited a decrease in p27 expression. Compared with the blank and NC groups, the PSMA7-shRNA1 and PSMA7 shRNA2 groups all had decreased expression levels of PSMA7, ubiquitin, p53 and VEGF as well as decreased cell proliferation, 20S proteasomes activity and cell number in the S phase, increased p27 expression, cell apoptosis and cell number in the G0/G1 phase. Our study demonstrates that PSMA7 silencing can suppress CC cell proliferation and VEGF expression in addition to promoting cell apoptosis through inhibition of the UPP signaling pathway. This article is protected by copyright. All rights reserved. PMID- 29247527 TI - High-volume forced diuresis with matched hydration using the RenalGuard System to prevent contrast-induced nephropathy: A meta-analysis of randomized trials. AB - BACKGROUND: Contrast-induced nephropathy (CIN) is a well-recognized complication of coronary angiography that is associated with poor outcomes. Several small randomized controlled trials (RCTs) have recently shown that in patients with chronic kidney disease (CKD), furosemide-induced forced diuresis with matched hydration using the RenalGuard system can prevent its occurrence. However, individual studies have been underpowered and thus cannot show significant differences in major clinical endpoints. HYPOTHESIS: Forced diuresis with matched hydration using the RenalGuard system improves clinical outcomes in patients undergoing coronary angiography. METHODS: Scientific databases and websites were searched for relevant RCTs. The pooled risk ratios were calculated using random effects models. The primary endpoint was CIN, and the secondary endpoints were major adverse clinical events (MACEs) and the need for renal replacement therapy. RESULTS: Data from 3 trials including 586 patients were analyzed. High-volume forced diuresis with matched hydration using the RenalGuard system decreased risk of CIN by 60% (risk ratio: 0.40, 95% confidence interval: 0.25 to 0.65, P < 0.001), MACE rate by 59%, and the need for renal replacement therapy by 78%, compared with the standard of care. CONCLUSIONS: In patients with CKD undergoing coronary angiography, high-volume forced diuresis with matched hydration using the RenalGuard system significantly reduces the risk of CIN, MACE rate, and the need for renal replacement therapy. Larger RCTs with sufficient power are needed to confirm these findings. PMID- 29247528 TI - Prevalence and predictors of elevated high-sensitivity C-reactive protein in post myocardial infarction patients: Insights from the VIRGO and TRIUMPH registries. AB - Elevated high-sensitivity C-reactive protein (hs-CRP) is associated with worse cardiovascular outcomes in patients with acute myocardial infarction (AMI), but little is known about the distribution of hs-CRP levels and predictors of elevated hs-CRP after AMI in the real world. Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status (TRIUMPH) and Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) are prospective AMI registries in the United States that assessed hs-CRP levels 30 days after AMI. TRIUMPH additionally assessed hs-CRP levels at the time of AMI and at 6 months. Hierarchical models were built to examine predictors of elevated hs-CRP (>=2.0 mg/L) at 30 days in both registries and at 6 months after AMI in TRIUMPH. Of 3410 patients in both registries, 58.6% had elevated hs-CRP 30 days after AMI. Patients with elevated hs-CRP at 30 days were more likely to be older, female, obese, smokers, report financial difficulties, and have higher low-density lipoprotein cholesterol levels on admission, diabetes, and hypertension. In TRIUMPH, baseline hs-CRP >=2 mg/L (n = 1301) was significantly associated with elevated hs-CRP at follow-up (P < 0.001). Similar associations were found in TRIUMPH patients with elevated hs-CRP at 6 months. Our study identified a high prevalence and several patient characteristics associated with elevated hs-CRP at 1 and 6 months after discharge. Further studies to test routine screening after AMI may be warranted to identify higher-risk patients for more aggressive secondary prevention. PMID- 29247529 TI - Serum M2BPGi level is a novel predictive biomarker for the responses to pegylated interferon-alpha treatment in HBeAg-positive chronic hepatitis B patients. AB - Serum Mac-2-binding protein glycosylation isomer (M2BPGi) level was found to be a useful prognostic marker for hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients treated with nucleoside/nucleotide analogs (NUCs) therapy, and the aim of our study is to evaluate the clinical implementation of M2BPGi level in the prediction of antiviral responses to pegylated-interferon alpha (PEG-IFN-alpha) treatment in HBeAg-positive CHB patients. Ninety-six CHB patients who received PEG-IFN-alpha treatment for at least 48 weeks were recruited. The serum M2BPGi, alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), HBeAg, and HBV DNA levels at baseline, weeks 4, 12, and 24 after PEG-IFN-alpha treatment were determined and their associations with antiviral responses were evaluated and the virological response (VR) rate and serological response (SR) rate after 48 weeks of treatment were 65.6% and 35.4%, respectively. Baseline serum M2BPGi level was significantly different between VR and non-VR (P = 0.002) or SR and non-SR groups (P = 0.012). Multivariate analyses suggested that baseline serum M2BPGi level was independently associated with VR and SR of PEG-IFN-alpha treatment at week 48. The area under the ROC curve (AUC) of baseline M2BPGi was 0.682 in predicting VR, which was superior to HBsAg (AUC = 0.566) or HBV DNA (AUC = 0.567). The AUC of baseline M2BPGi in predicting SR was 0.655, which was also higher than that of HBsAg (AUC = 0.548) or HBV DNA (AUC = 0.583). These results suggested that baseline serum M2BPGi level was a novel predictor of VR and SR for PEG-IFN-alpha treatment in HBeAg-positive CHB patients. PMID- 29247530 TI - Appropriateness vs value: Echocardiography in primary care. AB - BACKGROUND: Despite efforts targeting the growth of healthcare spending within the United States, the current increase in expenditures remains a widespread systemic issue. The overuse of healthcare testing has previously been identified as a modifiable contributing factor. One such test, echocardiography, has seen a continuous increase in its rate of use. This test is frequently ordered by primary-care physicians. HYPOTHESIS: In the setting of a low likelihood of disease, echocardiography does not substantially change cardiac therapy, even if appropriately ordered. METHODS: We randomly identified 500 patients who received an echocardiogram ordered by a primary-care physician between January 1, 2014, and December 31, 2014. Of these, 239 patient charts were reviewed and the following extracted: primary indication for the test, echocardiogram results, and changes in patient medical management. In addition, appropriateness of the test was assessed using the appropriate use criteria guidelines for echocardiography. RESULTS: Nearly 97% of the studies within the ambulatory primary-care setting were appropriately ordered according to the appropriate use criteria. Among the 239 patients studied, only 52 had abnormalities and only 6 (2.5%) experienced a change in management that corresponded with the initial suspected diagnosis and echocardiographic findings. CONCLUSIONS: To ensure the greatest value and optimize use of diagnostic testing, it may be necessary to develop a more comprehensive set of guidelines to assist clinicians to readily identify patient populations at low, moderate, and high risk for the presence of disease and provide educational interventions, including feedback regarding individual ordering behaviors. PMID- 29247531 TI - Effects of Acute Phase Intensive Electrical Muscle Stimulation in Frail Elderly Patients With Acute Heart Failure (ACTIVE-EMS): Rationale and protocol for a multicenter randomized controlled trial. AB - In elderly patients with acute heart failure (AHF), clinical outcome is adversely affected by frailty. Although a number of potentially effective interventions for frailty have been reported, little is known about the effects of rehabilitation programs in frail elderly AHF patients. We postulated that addition of electrical muscle stimulation (EMS), which induces muscle contraction without requiring patient volition, to early rehabilitation would be efficacious in frail elderly AHF patients. The ACTIVE-EMS (Effects of Acute Phase Intensive Electrical Muscle Stimulation in Frail Elderly Patients With AHF; UMIN000019551) trial is a multicenter, randomized controlled trial that will enroll 80 patients from 3 hospitals in Japan. AHF patients age >= 75 years positive for frailty, defined as Short Physical Performance Battery score 4 to 9, will be randomly assigned to receive early rehabilitation program only or EMS add-on therapy for 2 weeks. The primary endpoint of the trial is the change in quadriceps isometric strength between baseline and 2 weeks, with changes in physical function and cognitive function, and clinical safety and feasibility of EMS therapy as secondary outcomes. ACTIVE-EMS is the first randomized trial to evaluate the clinical effectiveness of adding EMS therapy to early rehabilitation in frail elderly AHF patients. The results of this study will provide insight for the development of appropriate rehabilitation programs for this high-risk population. PMID- 29247533 TI - Development of an oesophageal stimulation method to elicit swallowing reflex in humans. AB - Swallowing reflex is known to be evoked by gastroesophageal regurgitation or oesophageal stimulation in animal studies. However, details regarding the stimulating material, bolus size and stimulation area remain unclear for the stimulation-induced type of swallowing reflex in humans. Here, we evaluated the effects of different kinds of stimulation via water and air injection of the oesophagus on the initiation of the swallowing reflex. Nine healthy individuals participated in this study. A fibre-optic endoscope was passed transnasally, and a thin catheter for injection was passed through the other side. The tip of the catheter was placed at the upper, upper middle, lower middle or lower region of the oesophagus, and the rate of injection was controlled at 0.2 mL/s. Swallowing reflex latency was calculated as the time from injection via air or thin/thick fluid until the onset of white-out in endoscopic images. Reflex latency was significantly shorter when injection occurred at the upper region of the oesophagus than at the lower region, for both thin and thick fluids (P < .01). At the upper region of the oesophagus, the latency was significantly shorter after injection of thin fluid than with thick fluid (P < .05). Injection of air did not induce the swallowing reflex at all sites. These findings suggest that while the swallowing reflex is evoked by stimulation via fluid injection of the oesophagus in humans, sensitivity is greatest in the upper region of the oesophagus compared with the lower region and can vary depending on the injecting material. PMID- 29247532 TI - Gender differences in the association between discharge hemoglobin and 12-month mortality after acute myocardial infarction. AB - BACKGROUND: Anemia at discharge in patients with acute myocardial infarction is associated with poor prognosis; whether this differs in women and men or if there is a threshold value at which these relationships change is unknown. HYPOTHESIS: Women have a lower discharge hemoglobin (Hb) at which outcomes worsen. METHODS: We identified patients with acute myocardial infarction in the TRIUMPH registry between 2005 and 2008. In multivariable models, we evaluated the relationship between discharge Hb and 12-month mortality and tested whether this relationship varied by gender. We assessed whether the relationship with discharge Hb values was nonlinear using a restricted cubic spline term. RESULTS: Of 4243 patients with AMI, 32.9% were female. Mean admission Hb was 12.9 +/- 1.9 g/dL in women and 14.5 +/- 2.0 g/dL in men, with mean discharge Hb 11.4 +/- 1.8 g/dL and 12.9 +/- 1.9 g/dL, respectively. Lower discharge Hb was independently associated with increased mortality (P < 0.05). In multivariable models, discharge Hb decline was similarly associated with increased 12-month mortality in women and men (per 1 g/dL decrease Hb; women HR: 1.24, 95% CI: 1.09-1.42, P < 0.01; and men HR: 1.25, 95% CI: 1.13-1.37, P < 0.01; P for gender interaction = 0.99). The relationship between discharge Hb and 12-month mortality was linear (P for nonlinear spline term = 0.12). CONCLUSIONS: Lower discharge Hb levels were similarly associated with increased 12-month mortality in women and men. These relationships are linear without a clear threshold, suggesting any decline in discharge Hb is associated with poor outcomes. PMID- 29247534 TI - Effect of patient rotation on ovary observation during laparoscopic ovariectomy in dogs. AB - OBJECTIVE: To describe the optimal recumbency for laparoscopic ovariectomy (LapOVE) in dogs. STUDY DESIGN: Prospective clinical trial. ANIMALS: Sixteen healthy client-owned female dogs undergoing routine single-port LapOVE. METHODS: Anesthetized dogs were placed in dorsal recumbency on a tilting operation table. The operating laparoscope was introduced and, after inspection of abdominal organs, directed toward the randomly assigned ovary. Fifteen-second video recordings were taken at each table rotation of 0 degrees , 22.5 degrees , and 45 degrees . LapOVE was performed using the single-port technique. The procedure was repeated on the contralateral side. Blinded observers (3 inexperienced [IO], 3 experienced [EO], 1 expert [EE]) evaluated the recordings postoperatively for visibility of ovary/ovarian bursa, ovario-uterine transition, and other organs. RESULTS: In the 0 degrees position, ovarian structures were rarely visualized (IO, 13/96 [13.5%]; EO, 7/96 [7.3%]; EE, 5/32 [15.6%]). In the 22.5 degrees position, visualization improved significantly for EO (26/96 [27.1%], P < .001). There was a marked improvement in visualization for all groups when the positioning angle was altered to 45 degrees (IO, 62/96 [64.6%]; EO, 67/96 [69.8%]; EE, 25/32 [78.1%]). The differences between 0 degrees and 45 degrees and between 22.5 degrees and 45 degrees were significant for all groups of observers (all P < .001). There was an advantage for ovary visualization when procedures were started with left ovariectomy. CONCLUSION: The 45 degrees table rotation provided the best ovary visualization, regardless of body side or observer experience. There is evidence that procedures should be started with the left ovary when body side declination is used for organ retraction from the ovaries. PMID- 29247536 TI - Three-dimensional liver-derived extracellular matrix hydrogel promotes liver organoids function. AB - An important advantage of employing extracellular matrix (ECM)-derived biomaterials in tissue engineering is the ability to tailor the biochemical and biophysical microenvironment of the cells. This study aims to assess whether three-dimensional (3D) liver-derived ECM hydrogel (LEMgel) promotes physiological function of liver organoids generated by self-organization of human hepatocarcinoma cells together with human mesenchymal and endothelial cells. We have optimized the decellularization method to fabricate liver ECM derived from sheep to preserve the greatest content of glycosaminoglycans, collagen, laminin, and fibronectin in produced LEMgel. During gelation, complex viscoelasticity modulus of the LEMgel (3 mg/mL) increased from 186.7 to 1570.5 Pa and Tan Delta decreased from 0.27 to 0.18. Scanning electron microscopy (SEM) determined that the LEMgel had a pore size of 382 +/- 71 um. Hepatocarcinoma cells in the self organized liver organoids in 3D LEMgel (LEMgel organoids) showed an epithelial phenotype and expressed ALB, CYP3A4, E-cadherin, and ASGPR. The LEMgel organoid had significant upregulation of transcripts of ALB, CYP3A4, CYP3A7, and TAT as well as downregulation of AFP compared to collagen type I- and hydrogel-free organoids or organoids in solubilized LEM and 2D culture of hepatocarcinoma cells. Generated 3D LEMgel organoids had significantly more ALB and AAT secretion, urea production, CYP3A4 enzyme activity, and inducibility. In conclusion, 3D LEMgel enhanced the functional activity of self-organized liver organoids compared to traditional 2D, 3D, and collagen gel cultures. Our novel 3D LEMgel organoid could potentially be used in liver tissue engineering, drug discovery, toxicology studies, or bio-artificial liver fabrication. PMID- 29247537 TI - GATA1 activated lncRNA (Galont) promotes anoxia/reoxygenation-induced autophagy and cell death in cardiomyocytes by sponging miR-338. AB - The hypernomic autophagy is associated with various cardiovascular diseases. Long noncoding RNAs (lncRNAs) are emerging as important regulators in gene expression, which have been involved in multiple physiological and pathological processes. However, the function of lncRNAs and how they functioned in the autophagy in cardiomyocytes were rarely reported. In this study, we report that a lncRNA, named GATA1 activated lncRNA (Galont), can directly interact with miR-338 and promote ATG5-mediated autophagic cell death in murine cardiomyocytes. First, we found that Galont was upregulated by anoxia/reoxygenation (A/R) stimulus, and it was able to promote autophagy and cell death in cardiomyocytes exposure to A/R. Then, miR-338 was identified as a novel suppressor in autophagy and autophagic cell death. Our results from bioinformatic analysis and luciferase reporter gene assay indicated that ATG5 is a target gene of miR-338. Furthermore, RNA pull-down assays demonstrated that Galont directly interacted with miR-338, and thus promoted ATG5 expression and autophagic cell death. Our findings reveal a novel regulatory circuit in the autophagy in cardiomyocytes, which consists of Galont, miR-338 and ATG5. PMID- 29247538 TI - Narrative review shows that the short-term use of ketorolac is safe and effective in the management of moderate-to-severe pain in children. AB - : In June 2013, the European Medicine Agency recommended limiting codeine use in paediatric patients, creating a void in managing moderate pain. We reviewed the literature published in English (1985-June 2017) on the pharmacokinetic, pharmacodynamic and safety profile of ketorolac, a possible substitute for codeine and opioids, for treating moderate-to-severe pain. We found that gastrointestinal side effects were mainly reported with prolonged use, significant bleeding was reported in adenotonsillectomy, and adverse renal effects appeared to be limited to patients with specific coexisting risk factors. CONCLUSION: The short-term use of ketorolac appears to be safe for children in many situations. PMID- 29247539 TI - Fluorescein sodium-guided resection of intracranial lesions in 22 dogs. AB - OBJECTIVE: To evaluate the safety of an intraoperative fluorescein sodium (FS) injection and elucidate the relationships between the MRI findings, pathological diagnoses, and intraoperative staining characteristics of intracranial lesions in 22 dogs. STUDY DESIGN: Prospective case series. ANIMALS: Twenty-two dogs with intracranial lesions. METHODS: FS was intravenously administered to 22 dogs undergoing craniotomy for suspected intracranial tumors to evaluate perioperative and postoperative adverse effects. The intensities and patterns of gadolinium (Gd) enhancement on preoperative magnetic resonance imaging and intraoperative FS staining were graded, and their relationship was evaluated. Intraoperative FS staining characteristics and pathological diagnoses were compared. RESULTS: The only adverse effect noted was repetitive vomiting in 2 dogs. The intensities and patterns between preoperative Gd enhancement and intraoperative FS staining appeared to agree. High-grade glioma and histiocytic sarcoma had more intense FS staining. Lesions with strong Gd enhancement, including meningiomas and choroid plexus tumors, also had intense FS staining. CONCLUSION: The intraoperative use of FS is a simple and safe technique to guide the resection of intracranial lesions in dogs. The findings on Gd enhancement, FS staining, and histopathology appeared to agree but require validation in a larger set of cases. CLINICAL SIGNIFICANCE: The intraoperative use of FS may improve the prognosis of dogs with brain tumors by guiding the resection of lesions. PMID- 29247535 TI - The role of extracellular matrix stiffness in megakaryocyte and platelet development and function. AB - The extracellular matrix (ECM) is a key acellular structure in constant remodeling to provide tissue cohesion and rigidity. Deregulation of the balance between matrix deposition, degradation, and crosslinking results in fibrosis. Bone marrow fibrosis (BMF) is associated with several malignant and nonmalignant pathologies severely affecting blood cell production. BMF results from abnormal deposition of collagen fibers and enhanced lysyl oxidase-mediated ECM crosslinking within the marrow, thereby increasing marrow stiffness. Bone marrow stiffness has been recently recognized as an important regulator of blood cell development, notably by modifying the fate and differentiation process of hematopoietic or mesenchymal stem cells. This review surveys the different components of the ECM and their influence on stem cell development, with a focus on the impact of the ECM composition and stiffness on the megakaryocytic lineage in health and disease. Megakaryocyte maturation and the biogenesis of their progeny, the platelets, are thought to respond to environmental mechanical forces through a number of mechanosensors, including integrins and mechanosensitive ion channels, reviewed here. PMID- 29247540 TI - Efficacy and safety of rituximab for systemic lupus erythematosus-associated immune cytopenias: A multicenter retrospective cohort study of 71 adults. AB - The aim of the study was to assess the efficacy and safety of rituximab (RTX) for treating systemic lupus erythematosus (SLE)-associated immune cytopenias. This multicenter retrospective cohort study of adults from French referral centers and networks for adult immune cytopenias and SLE involved patients >=18 years old with a definite diagnosis of SLE treated with RTX specifically for SLE-associated immune cytopenia from 2005 to 2015. Response assessment was based on standard definitions. In total, 71 patients, 61 women (85.9%), with median age 36 years [interquartile range 31-48], were included. The median duration of SLE at the time of the first RTX administration was 6.1 years [2.6-11.6] and the reason for using RTX was immune thrombocytopenia (ITP) for 44 patients (62.0%), autoimmune hemolytic anemia (AIHA) for 16 (22.5%), Evans syndrome for 10 (14.1%), and pure red cell aplasia for one patient. Before receiving RTX, patients had received a mean of 3.1 +/- 1.3 treatments that included corticosteroids (100%), and hydroxychloroquine (88.5%). The overall initial response rate to RTX was 86% (91% with ITP, 87.5% with AIHA, and 60% with Evans syndrome), including 60.5% with complete response. Median follow-up after the first injection of RTX was 26.4 months [14.3-71.2]. Among 61 initial responders, relapse occurred in 24 (39.3%); for 18, RTX retreatment was successful in 16 (88.8%). Severe infections occurred after RTX in three patients, with no fatal outcome. No cases of RTX-induced neutropenia were observed. In conclusion, RTX seems effective and relatively safe for treating SLE-associated immune cytopenias. PMID- 29247542 TI - Intravenous immunoglobulin as salvage therapy for refractory thrombotic thrombocytopenic purpura. PMID- 29247541 TI - Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI3K activity. AB - Recent genetic studies have highlighted the potential involvement of melatonin receptor 1 (MT1 ) and melatonin receptor 2 (MT2 ) in the pathogenesis of type 2 diabetes. Here, we report that mice lacking MT1 (MT1 KO) tend to accumulate more fat mass than WT mice and exhibit marked systemic insulin resistance. Additional experiments revealed that the main insulin signaling pathway affected by the loss of MT1 was the activation of phosphatidylinositol-3-kinase (PI3K). Transcripts of both catalytic and regulatory subunits of PI3K were strongly downregulated within MT1 KO mice. Moreover, the suppression of nocturnal melatonin levels within WT mice, by exposing mice to constant light, resulted in impaired PI3K activity and insulin resistance during the day, similar to what was observed in MT1 KO mice. Inversely, administration of melatonin to WT mice exposed to constant light was sufficient and necessary to restore insulin-mediated PI3K activity and insulin sensitivity. Hence, our data demonstrate that the activation of MT1 signaling at night modulates insulin sensitivity during the day via the regulation of the PI3K transcription and activity. Lastly, we provide evidence that decreased expression of MTNR1A (MT1 ) in the liver of diabetic individuals is associated with poorly controlled diabetes. PMID- 29247543 TI - Side effects during subcutaneous immunotherapy in children with allergic diseases. AB - BACKGROUND: Allergen-specific immunotherapy is the only causal form of therapy for IgE-mediated allergic diseases. Subcutaneous immunotherapy (SCIT) is considered safe and well tolerated in adults, yet there is less evidence of safety in the pediatric population. METHODS: A non-interventional prospective observing longitudinal study was carried out to determine the incidence of local and systemic side effects by SCIT, routinely performed in pediatric patients. A total of 581 pediatric patients were observed in 18 study centers between March 2012 and October 2014, recording 8640 treatments and 10 015 injections. RESULTS: A total of 54.6% of the patients experienced immediate local side effects at least once; delayed local side effects were seen in 56.1%. Immediate systemic adverse reactions occurred in 2.2% of patients; 7.4% experienced delayed systemic side effects. However, severe systemic side effects (grade III in the classification of Ring and Messmer) were seen in 0.03% of all treatments, all appearing within 30 minutes after the injections. No grade IV reactions were observed. In addition, many potential risk factors were investigated, yet only a few were found to be associated with the occurrence of side effects. CONCLUSIONS: Subcutaneous immunotherapy is a safe form of therapy in pediatric patients, with similar rates of local side effects compared to adult patients and low rates of severe systemic side effects. However, local and systemic reactions occurring later than 30 minutes after injection were observed more often than expected, which makes it essential to be attentive on behalf of pediatricians, patients, and parents. PMID- 29247544 TI - Removal of hemangiosarcoma cells from canine blood with a cell salvage system and leukocyte reduction filter. AB - OBJECTIVE: To determine the ability of an intraoperative cell salvage (IOCS) system and a leukocyte reduction filter (LRF) to remove hemangiosarcoma (HSA) cells from canine blood. STUDY DESIGN: Cultured HSA cells were added to canine blood to simulate intraoperative hemorrhage and address hemoabdomen from ruptured splenic HSA. The blood/HSA cell mixture was processed through an IOCS, followed by LRF processing. SAMPLE POPULATION: Whole blood from 3 healthy dogs combined with cultured HSA cells. METHODS: The ability of quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), multiparameter flow cytometry, and cytologic examination to detect 50 HSA cells per milliliter of culture media was confirmed. RT-PCR, multiparameter flow cytometry, and cytologic examination were used to determine the presence of cultured HSA cells at 4 points during processing. RESULTS: HSA cells were found in all control samples and in all samples after IOCS but prior to LRF processing with all 3 cell detection methods. HSA cells were not found after IOCS/LRF processing with all 3 cell detection methods. CONCLUSION: IOCS combined with LRF processing is able to remove cultured HSA cells from canine blood. The addition of LRF to IOCS may allow application of IOCS in dogs with HSA. CLINICAL SIGNIFICANCE: A combination of IOCS and LRF processing may provide an alternative to allogeneic blood transfusion in dogs with hemoabdomen due to HSA. PMID- 29247545 TI - Neurally adjusted ventilatory assist can be used to wean infants with congenital diaphragmatic hernias off respiratory support. PMID- 29247546 TI - Japan Gastroenterological Endoscopy Society guidelines for endoscopic sphincterotomy. AB - The Japan Gastroenterological Endoscopy Society (JGES) has recently compiled guidelines for endoscopic sphincterotomy (EST) using evidence-based methods. Content regarding actual clinical practice, including detailed endoscopic procedures, instruments, device types and usage, has already been published by the JGES postgraduate education committee in May 2015 and, thus, in these guidelines we avoided duplicating such content as much as possible. The guidelines do not address pancreatic sphincterotomy, endoscopic papillary balloon dilation (EPBD), and endoscopic papillary large balloon dilation (EPLBD). The guidelines for EPLBD are planned to be developed separately. The evidence level in this field is often low and, in many instances, strong recommendation has to be determined on the basis of expert consensus. At this point in time, the guidelines are divided into six items including indications, techniques, specific cases, adverse events, outcomes, and postoperative follow up. PMID- 29247547 TI - Psychosocial impacts of hybrid closed-loop systems in the management of diabetes: a review. AB - There is a pressing need for new treatment regimens that enable improved glycaemic control and reduced diabetes self-management burdens. Closed-loop, or artificial pancreas, systems represent one of the most promising avenues in this regard. Closed-loop systems connect wearable continuous glucose monitor (CGM) sensors to smartphone- or tablet-mounted algorithms that process and model CGM data to deliver precise and frequently updated doses of fast-acting insulin (and glucagon in dual-hormone systems) to users via wearable pumps. Recent studies have demonstrated that closed-loop systems offer significant benefit in terms of improved glycaemic control. However, less attention has been paid to the psychosocial impact on users of closed-loop systems. This article reviews recent research on psychosocial aspects of closed-loop usage in light of preceding research on user experience of currently available technologies such as insulin pumps and CGM sensors. The small, but growing body of research in this field reports generally positive user experience and a number of experienced benefits including: reassurance and reduced anxiety, improved sleep and confidence, and 'time off' from diabetes demands. However, these benefits are counterbalanced by important challenges, ranging from variable levels of trust to concerns about physical bulk, technical glitches and difficulties incorporating closed-loop systems into everyday life. Future research should explore psychosocial aspects of closed-loop usage in more diverse groups and with regard to clinicians, as well as users, to ensure that the clinical benefits of closed-loop systems are realized at scale in routine medical care. PMID- 29247548 TI - Extracellular vesicles as drivers of epithelial-mesenchymal transition and carcinogenic characteristics in normal prostate cells. AB - There is increasing evidence that cancer dissemination and metastasis establishment may not only be due to the movement of tumor cells. Content of extracellular vesicles (EVs) secreted by tumor cells may also reflect the origin of these cells. Some molecules that constitute these EVs have already been used as targets for detection of specific tumors. However, to the best of our knowledge, EVs from biopsies and plasma have not yet been compared nor thoroughly investigated as triggers of malignant transformation and metastatic niche formation. To evaluate the role of EVs in the cellular microenvironment, we have treated the normal epithelial prostate cell lines, RWPE-1 and PNT-2, with a pool of EVs from biopsies of prostate primary tumors (bEVs), biopsies of benign prostate hyperplasia (hEVs), plasma of prostate cancer (PCa) patients (pEVs) or plasma of healthy individuals (pnEVs). Each of the four pools consisted of isolated EVs from several subjects, of which PCa patients were in different stages of cancer. Migration and proliferation profiles, cytokine release, and a panel of PCa-associated genes' expression of epithelial-mesenchymal transition in the cell lines were evaluated after 24 h incubation with EVs. When compared to the control groups, cells treated with the pool of EVs isolated from tumor biopsies and plasma of PCa patients showed greater migration and proliferation, significant alterations in gene expression, and high levels of IL-8, factors that are associated with cancer development. Specifically, isolated bEVs and pEVs may induce malignant features in non-tumor cells by activating several cellular events associated with cancer progression, suggesting that future PCa therapy may target multiple elements found in tumor-derived EVs. PMID- 29247549 TI - A training program of a new simplified classification of magnified narrow band imaging for superficial esophageal squamous cell carcinoma. AB - BACKGROUND AND AIM: Optimal staging of the invasion depth of superficial esophageal squamous cell carcinoma is vital before endoscopic treatment. A new simplified magnified narrow-band imaging (M-NBI) classification system based on vascular architecture has recently been developed by the Japan Esophageal Society; however, its validity remains uncertain. METHODS: A total of 11 experienced and 11 inexperienced endoscopists were invited to join an endoscopic training program, which was composed of pretest, educational section, and post test. The pretest and post-test sections included a set of endoscopic photos from 40 subjects with superficial esophageal squamous cell carcinoma with various invasion depths. Each subject appeared twice in the test, one with white-light imaging (WLI) only and the other with both WLI and M-NBI. The educational section included lectures and video demonstrations. RESULTS: The accuracy of WLI alone and combined with M-NBI at baseline were 0.53, 0.57 and 0.43, 0.41 for the experienced and inexperienced endoscopists, respectively, which then improved to 0.57, 0.63 and 0.49, 0.52 after training. Inter-observer agreement (k-value) of WLI alone and combined WLI and M-NBI for the experienced and inexperienced endoscopists also improved from 0.61, 0.61, and 0.61, 0.53 to 0.68, 0.71, and 0.71, 0.59, respectively. Multivariate analysis revealed that the educational course but not experience in endoscopy, NBI, or magnification significantly improved the diagnostic accuracy. M-NBI had a significant additional benefit to WLI, with an improvement in accuracy from 36% to 56% for the cases with m3/sm1 cancers (P < 0.05). CONCLUSIONS: A well-designed training program can improve the diagnostic accuracy in evaluating cancer invasion depth, with substantial agreement. PMID- 29247551 TI - Occipital blood-brain barrier permeability is an independent predictor of visual outcome in type 2 diabetes, irrespective of the retinal barrier: A longitudinal study. AB - Blood-brain barrier (BBB) permeability in type 2 diabetic patients has been previously shown to be altered in certain brain regions such as the basal ganglia and the hippocampus. Because of the histological and functional similarities between the BBB) and the blood-retinal barrier (BRB), we aimed to investigate how the permeability of both barriers predicts visual outcome. We included 2 control groups (acute unilateral stroke patients, n = 9; type 2 diabetics without BRB leakage n = 10) and a case study group of type 2 diabetics with established BRB leakage (n = 17). We evaluated sex, age, disease duration, metabolic impairment, retinopathy grade and BBB permeability as predictors of visual acuity at baseline, 12 and 24 months in the type 2 diabetics without BRB leakage group and the case study group. We have also explored differences in BBB permeability in the occipital lobe and frontal lobe in the 3 different groups. Ktrans (volume transfer coefficient) and Vp (fractional plasma volume) were estimated. The BBB permeability parameter Vp was higher in the case study group compared to the unaffected hemisphere of the stroke patient control group, suggesting vascular dynamics were changed in the occipital lobe of type 2 diabetics with established BRB leakage. These patients showed a significant correlation between glycated hemoglobin (HbA1C) levels and occipital and frontal Ktrans . We report for the first time that occipital BBB permeability is an independent predictor of visual acuity at baseline, as well as at 12 and 24 months, in type 2 diabetics with established BRB leakage. Our results suggest that occipital BBB permeability might be an independent biomarker for visual impairment in patients with established BRB leakage. PMID- 29247552 TI - Ehlers-Danlos syndrome in a young woman with anorexia nervosa and complex somatic symptoms. AB - The Ehler-Danlos syndromes (EDS) are a group of clinically heterogeneous connective tissue disorders characterized by joint hypermobility, hyperextensibility of the skin, and a general connective tissue fragility that can induce symptoms from multiple organ systems. We present a case of comorbid anorexia nervosa and EDS in a 23-year old woman with a multitude of somatic symptoms that were initially attributed to the eating disorder but that were likely caused by the underlying EDS. Various EDS symptoms, such as gastrointestinal complaints, smell and taste abnormalities, and altered somatosensory awareness may resemble or mask an underlying eating disorder, and vice versa. Because of the large clinical heterogeneity, correctly identifying symptoms of EDS presents a challenge for clinicians, who should be aware of this group of underdiagnosed and potentially serious syndromes. The Beighton Hypermobility Score is an easily applicable screening instrument in assessing potential EDS in patients with joint hypermobility. PMID- 29247550 TI - Melatonin prevents hypochlorous acid-mediated cyanocobalamin destruction and cyanogen chloride generation. AB - Hypochlorous acid (HOCl) is a potent cytotoxic oxidant generated by the enzyme myeloperoxidase (MPO) in the presence of hydrogen peroxide (H2 O2 ) and chloride (Cl- ). Elevated levels of HOCl play an important role in various pathological conditions through oxidative modification of several biomolecules. Recently, we have highlighted the ability of HOCl to mediate the destruction of the metal-ion derivatives of tetrapyrrole macrocyclic rings such as hemoproteins and vitamin B12 (VB12 ) derivatives. Destruction of cyanocobalamin, a common pharmacological form of VB12 mediated by HOCl, results in the generation of toxic molecular products such as chlorinated derivatives, corrin ring cleavage products, the toxic blood agents cyanide (CN- ) and cyanogen chloride (CNCl), and redox-active free cobalt. Here, we show that melatonin prevents HOCl-mediated cyanocobalamin destruction, using a combination of UV-Vis spectrophotometry, high-performance liquid chromatography analysis, and colorimetric CNCl assay. Identification of several melatonin oxidation products suggests that the protective role of melatonin against HOCl-mediated cyanocobalamin destruction and subsequent CNCl generation is at the expense of melatonin oxidation. Collectively, this work highlights that, in addition to acting as an antioxidant and as a MPO inhibitor, melatonin can also prevent VB12 deficiency in inflammatory conditions such as cardiovascular and neurodegenerative diseases, among many others. PMID- 29247553 TI - Prediction models for progression of non-muscle-invasive bladder cancer: A review. AB - An accurate prediction of progression is critically important in the management of non-muscle-invasive bladder cancer. At present, three risk models are widely known for prediction of the risk of tumor recurrence and progression of non muscle-invasive bladder cancer: the European Organization for Research and Treatment of Cancer, Club Urologico Espanol de Tratamiento Oncologico, and new European Organization for Research and Treatment of Cancer models. Bladder neck involvement has been shown to be one of the significant predictors for progression in non-muscle-invasive bladder cancer, and a new scoring model (Tokyo Medical and Dental University model) consisting of bladder neck involvement, tumor grade, and stage has been developed and externally validated. However, the predictive abilities of these models are still unsatisfactory, and more precise models are necessary for accurate individual prediction of prognosis. Until now, time-fixed analysis has been used for most studies predicting the prognosis and outcome of non-muscle-invasive bladder cancer patients. In order to predict progression more precisely, time-dependent models should be developed using multiple-event analytical techniques, as non-muscle-invasive bladder cancer often progresses to muscle-invasive bladder cancer after multiple recurrences and changes in tumor characteristics over a long natural history. Integration of molecular markers is also a promising approach. A validated model that accurately predicts the risk of progression would help urologists and patients decide whether and when to choose radical cystectomy on an individual basis. PMID- 29247554 TI - Diabetes and chronic kidney disease: an increasingly common multi-morbid disease in need of a paradigm shift in care. AB - Diabetes is considered the commonest cause of end-stage renal disease. The increasing incidence of obesity and an ageing population, together, will lead to a greater number of people with diabetes associated with chronic kidney disease that could either be secondary to diabetic nephropathy or of different aetiology. Ageing and obesity influence approaches to the management of diabetes and accurate assessment of kidney disease. People with diabetes and chronic kidney disease consume a disproportionate component of expenditure on medical care. Guidelines on managing diabetes and kidney disease do not recognize the complex multi-morbid nature of the process. In addition to managing glycaemia and monitoring renal function, the assessment and management of cardiovascular disease risk factors and cardiovascular disease itself need to be factored into care. People with diabetes and diabetic nephropathy are more vulnerable to retinopathy and foot complications requiring coordinated care. People with diabetes and chronic kidney disease are more prone to anaemia and metabolic bone disease than those without diabetes at similar stages of chronic kidney disease, further increasing their vulnerability to acute complications from cardiovascular disease, foot emergencies and fractures. People with diabetes and chronic kidney disease are also more prone to hospitalization with infections and acute kidney injury. Given the 30-40% prevalence of kidney disease amongst people with diabetes, potentially >2% of the adult population would fit into this category, making it vital that new surveillance models of supported care are provided for those living with diabetes and kidney disease and for primary care teams who manage the vast majority of such people. PMID- 29247556 TI - Best friend or spy: a qualitative meta-synthesis on the impact of continuous glucose monitoring on life with Type 1 diabetes. AB - AIMS: This is a meta-synthesis of extant qualitative literature related to impact of continuous glucose monitoring (CGM). CGM has been available for a decade for the management of Type 1 diabetes and is the lynchpin of future artificial pancreas technologies. Clinical uptake of CGM is an important area of inquiry. The purpose of this meta-synthesis is to understand the impact of CGM on individuals with Type 1 diabetes and others (parents, significant others, providers) in order to design appropriate clinical interventions for adherence. METHODS: Studies published in English between 2007 and 2017 were included, reflecting commercial CGM availability. PubMed, PsychINFO, CINALH, Web of Science and EMBASE databases were queried using search terms related to CGM, qualitative, experience and Type 1 diabetes. Included articles contained original qualitative or mixed-method research on CGM, sensor-augmented pump or closed-loop therapies. Articles underwent quality appraisal and thematic interpretive integration by a multidisciplinary team. RESULTS: Nine articles (343 participants) met the inclusion criteria and were included in the synthesis. Six novel themes emerged: interacting with CGM, burden of living with CGM, feeling different from others, feeling empowered, interacting with glucose information and impact on relationships. CONCLUSION: CGM affects physical, emotional and relational aspects of life. Clinicians can help minimize the burden of CGM with carefully delivered education and expectation-setting with individuals. Empowerment and relational partnerships in diabetes care can be explored to maximize satisfaction with CGM. Systematic interpretive synthesis of qualitative studies provides a comprehensive, contextual understanding of the impact of CGM on daily life and relationships. PMID- 29247555 TI - The triterpenoid corosolic acid blocks transformation and epigenetically reactivates Nrf2 in TRAMP-C1 prostate cells. AB - Corosolic acid (CRA) is found in various plants and has been used as a health food supplement worldwide. Although it has been reported that CRA exhibits significant anticancer activity, the effect of this compound on prostate cancer remains unknown. In this study, we investigated the effect of CRA on cellular transformation and the reactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) through epigenetic regulation in TRAMP-C1 prostate cells. Specifically, we found that CRA inhibited anchorage-independent growth of prostate cancer TRAMP C1 cells but not Nrf2 knockout prostate cancer TRAMP-C1 cells. Moreover, CRA induced mRNA and protein expression of Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H Quinone Oxidoreductase 1 (NQO1). Bisulfite genomic sequencing and methylated DNA immunoprecipitation results revealed that CRA treatment decreased the level of methylation of the first five CpG sites of the Nrf2 promoter. Histone modification was analyzed using a chromatin immunoprecipitation (ChIP) assay, which revealed that CRA treatment increased the acetylation of histone H3 lysine 27 (H3K27ac) while decreasing the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter region of Nrf2. Furthermore, CRA treatment attenuated the protein expression of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). These findings indicate that CRA has a significant anticancer effect in TRAMP-C1 cells, which could be partly attributed to epigenetics including its ability to epigenetically restore the expression of Nrf2. PMID- 29247557 TI - Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation. AB - Head and neck squamous cell carcinoma (HNSCC) clearly involves activation of the Akt mammalian target of rapamycin (mTOR) signalling pathway. However, the effectiveness of treatment with the mTOR inhibitor rapamycin is often limited by chemoresistance. Melatonin suppresses neoplastic growth via different mechanisms in a variety of tumours. In this study, we aimed to elucidate the effects of melatonin on rapamycin-induced HNSCC cell death and to identify potential cross talk pathways. We analysed the dose-dependent effects of melatonin in rapamycin treated HNSCC cell lines (Cal-27 and SCC-9). These cells were treated with 0.1, 0.5 or 1 mmol/L melatonin combined with 20 nM rapamycin. We further examined the potential synergistic effects of melatonin with rapamycin in Cal-27 xenograft mice. Relationships between inhibition of the mTOR pathway, reactive oxygen species (ROS), and apoptosis and mitophagy reportedly increased the cytotoxic effects of rapamycin in HNSCC. Our results demonstrated that combined treatment with rapamycin and melatonin blocked the negative feedback loop from the specific downstream effector of mTOR activation S6K1 to Akt signalling, which decreased cell viability, proliferation and clonogenic capacity. Interestingly, combined treatment with rapamycin and melatonin-induced changes in mitochondrial function, which were associated with increased ROS production, increasing apoptosis and mitophagy. This led to increase cell death and cellular differentiation. Our data further indicated that melatonin administration reduced rapamycin-associated toxicity to healthy cells. Overall, our findings suggested that melatonin could be used as an adjuvant agent with rapamycin, improving effectiveness while minimizing its side effects. PMID- 29247558 TI - European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) clinical practice recommendations for the management of non-alcoholic fatty liver disease: evaluation of their application in people with Type 2 diabetes. AB - AIMS: To evaluate the application of the recently proposed recommendations by the European Association for the Study of the Liver, European Association for the Study of Diabetes and European Association for the Study of Obesity for the diagnosis, treatment and follow-up of non-alcoholic fatty liver disease in people with Type 2 diabetes. METHODS: A total of 179 people with Type 2 diabetes were included in this study. Liver fat content (assessed using proton magnetic resonance spectroscopy), fatty liver index score, non-alcoholic fatty liver disease fibrosis score, and SteatoTest and FibroTest scores were determined. RESULTS: According to proton magnetic resonance spectroscopy, 68.7% of participants had steatosis (liver fat content >5.5%). The application of the guidelines using several combinations (fatty liver index + non-alcoholic fatty liver disease fibrosis scores, Steatotest + FibroTest scores, proton magnetic resonance spectroscopy + non-alcoholic fatty liver disease fibrosis score, proton magnetic resonance spectroscopy + FibroTest) resulted in a referral to a liver clinic for 33.5-84.9% people with Type 2 diabetes. CONCLUSIONS: The application of these new algorithms for the diagnosis, and follow-up of non-alcoholic fatty liver disease would lead to an excessive number of people with Type 2 diabetes being referred to a liver clinic. We suggest that new clinical and/or biological biomarkers of steatosis and fibrosis be specifically validated in people with Type 2 diabetes. PMID- 29247559 TI - Rice histone deacetylase 10 and Arabidopsis histone deacetylase 14 genes encode N acetylserotonin deacetylase, which catalyzes conversion of N-acetylserotonin into serotonin, a reverse reaction for melatonin biosynthesis in plants. AB - In plants, melatonin production is strictly regulated, unlike the production of its precursor, serotonin, which is highly inducible in response to stimuli, such as senescence and pathogen exposure. Exogenous serotonin treatment does not greatly induce the production of N-acetylserotonin (NAS) and melatonin in plants, which suggests the possible existence of one or more regulatory genes in the pathway for the biosynthesis of melatonin from serotonin. In this report, we found that NAS was rapidly and abundantly converted into serotonin in rice seedlings, indicating the presence of an N-acetylserotonin deacetylase (ASDAC). To clone the putative ASDAC gene, we screened 4 genes that were known as histone deacetylase (HDAC) genes, but encoded proteins targeted into chloroplasts or mitochondria rather than nuclei. Of 4 recombinant Escherichia coli strains expressing these genes, one E. coli strain expressing the rice HDAC10 gene was found to be capable of producing serotonin in response to treatment with NAS. The recombinant purified rice HDAC10 (OsHDAC10) protein exhibited ASDAC enzyme activity toward NAS, N-acetyltyramine (NAT), N-acetyltryptamine, and melatonin, with the highest ASDAC activity for NAT. In addition, its Arabidopsis ortholog, AtHDAC14, showed similar ASDAC activity to that of OsHDAC10. Both OsHDAC10 and AtHDAC14 were found to be expressed in chloroplasts. Phylogenetic analysis indicated that ASDAC homologs were present in archaea, but not in cyanobacteria, which differs from the distribution of serotonin N-acetyltransferase (SNAT). This suggests that SNAT and ASDAC may have evolved differently from ancestral eukaryotic cells. PMID- 29247560 TI - New protocol for compound-specific radiocarbon analysis of archaeological bones. AB - RATIONALE: For radiocarbon results to be accurate, samples must be free of contaminating carbon. Sample pre-treatment using a high-performance liquid chromatography (HPLC) approach has been developed at the Oxford Radiocarbon Accelerator Unit (ORAU) as an alternative to conventional methods for dating heavily contaminated bones. This approach isolates hydroxyproline from bone collagen, enabling a purified bone-specific fraction to then be radiocarbon dated by accelerator mass spectrometry (AMS). METHODS: Using semi-preparative chromatography and non-carbon-based eluents, this technique enables the separation of underivatised amino acids liberated by hydrolysis of extracted bone collagen. A particular focus has been the isolation of hydroxyproline for single compound AMS dating since this amino acid is one of the main contributors to the total amount of carbon in mammalian collagen. Our previous approach, involving a carbon-free aqueous mobile phase, required a two-step separation using two different chromatographic columns. RESULTS: This paper reports significant improvements that have been recently made to the method to enable faster semi preparative separation of hydroxyproline from bone collagen, making the method more suitable for routine radiocarbon dating of contaminated and/or poorly preserved bone samples by AMS. All steps of the procedure, from the collagen extraction to the correction of the AMS data, are described. CONCLUSIONS: The modifications to the hardware and to the method itself have reduced significantly the time required for the preparation of each sample. This makes it easier for other radiocarbon facilities to implement and use this approach as a routine method for preparing contaminated bone samples. PMID- 29247561 TI - Protein-altering variants of PTPN2 in childhood-onset Type 1A diabetes. AB - AIM: To examine the contribution of PTPN2 coding variants to the risk of childhood-onset Type 1A diabetes. METHODS: PTPN2 mutation analysis was carried out for 169 unrelated Japanese people with childhood-onset Type 1A diabetes. We searched for coding variants that were absent or extremely rare in the general population and were scored as damaging by multiple in silico programs. We performed mRNA analysis and three-dimensional structural prediction of the detected variants, when possible. We also examined possible physical links between these variants and previously reported risk SNPs as well as clinical information from variant-positive children. RESULTS: One frameshift variant (p.Q286Yfs*24) and two probably damaging missense substitutions (p.C232W and p.R350Q) were identified in one child each. Of these, p.Q286Yfs*24 and p.C232W were hitherto unreported, while p.R350Q accounted for 2/121,122 alleles of the exome datasets. The p.Q286Yfs*24 variant did not encode stable mRNA, and p.C232W appeared to affect the structure of the tyrosine-protein phosphatase domain. The three variants were physically unrelated to known risk SNPs. The variant-positive children manifested Type 1A diabetes without additional clinical features and invariably carried risk human leukocyte antigen alleles. CONCLUSIONS: The results provide the first indication that PTPN2 variants contribute to the risk of Type 1A diabetes, independently of known risk SNPs. PTPN2 coding variants possibly induce non-specific Type 1A diabetes phenotypes in individuals with human leukocyte antigen-mediated disease susceptibility. Our findings warrant further validation. PMID- 29247562 TI - A history of genome editing in Saccharomyces cerevisiae. AB - Genome editing is a form of highly precise genetic engineering which produces alterations to an organism's genome as small as a single base pair with no incidental or auxiliary modifications; this technique is crucial to the field of synthetic biology, which requires such precision in the installation of novel genetic circuits into host genomes. While a new methodology for most organisms, genome editing capabilities have been used in the budding yeast Saccharomyces cerevisiae for decades. In this review, I will present a brief history of genome editing in S. cerevisiae, discuss the current gold standard method of Cas9 mediated genome editing, and speculate on future directions of the field. PMID- 29247563 TI - Acetylcholine precursor, citicoline (cytidine 5'-diphosphocholine), reduces hypoglycaemia-induced neuronal death in rats. AB - Citicoline (cytidine 5'-diphosphocholine) is an important precursor for the synthesis of neuronal plasma membrane phospholipids, mainly phosphatidylcholine. The administration of citicoline serves as a choline donor for the synthesis of acetylcholine. Citicoline has been shown to reduce the neuronal injury in animal models with cerebral ischaemia and in clinical trials of stroke patients. Citicoline is currently being investigated in a multicentre clinical trial. However, citicoline has not yet been examined the context of hypoglycaemia induced neuronal death. To clarify the therapeutic impact of citicoline in hypoglycaemia-induced neuronal death, we used a rat model with insulin-induced hypoglycaemia. Acute hypoglycaemia was induced by i.p. injection of regular insulin (10 U kg-1 ) after overnight fasting, after which iso-electricity was maintained for 30 minutes. Citicoline injections (500 mg/kg, i.p.) were started immediately after glucose reperfusion. We found that post-treatment of citicoline resulted in significantly reduced neuronal death, oxidative injury and microglial activation in the hippocampus compared to vehicle-treated control groups at 7 days after induced hypoglycaemia. Citicoline administration after hypoglycaemia decreased immunoglobulin leakage via blood-brain barrier disruption in the hippocampus compared to the vehicle group. Citicoline increased choline acetyltransferase expression for phosphatidylcholine synthesis after hypoglycaemia. Altogether, the present findings suggest that neuronal membrane stabilisation by citicoline administration can save neurones from the degeneration process after hypoglycaemia, as seen in several studies of ischaemia. Therefore, the results suggest that citicoline may have therapeutic potential to reduce hypoglycaemia-induced neuronal death. PMID- 29247565 TI - Oocyte oxidative DNA damage may be involved in minimal/mild endometriosis-related infertility. AB - Early endometriosis is associated with infertility, and oxidative stress may play a role in the pathogenesis of disease-related infertility. This prospective case control study aimed to compare the presence of oxidative stress markers in the follicular microenvironment and systemic circulation of infertile women with minimal/mild endometriosis (EI/II) versus individuals undergoing controlled ovarian stimulation for intracytoplasmic sperm injection (ICSI). Seventy-one blood samples (27 from infertile women with EI/II and 44 controls with tubal and/or male infertility factor) and 51 follicular fluid samples (19 EI/II and 32 controls) were obtained on the day of oocyte retrieval. Total hydroperoxides (FOX1 ), reduced glutathione, vitamin E, Superoxide dismutase, total antioxidant capacity, malondialdehyde, advanced oxidation protein products, and 8-hydroxy-2' deoxyguanosine (8OHdG) concentrations were measured in both fluids. Women with EI/II showed higher FOX1 (8.48 +/- 1.72 vs. 7.69 +/- 1.71 MUmol/g protein) and lower total antioxidant capacity (0.38 +/- 0.18 vs. 0.46 +/- 0.15 mEq Trolox/L) concentrations in serum, and higher 8OHdG concentrations (24.21 +/- 8.56 vs. 17.22 +/- 5.6 ng/ml) in follicular fluid compared with controls. These data implicate both systemic and follicular oxidative stress may in infertile women with EI/II undergoing controlled ovarian stimulation for ICSI. Furthermore, the elevated 8OHdG concentrations in follicular fluid of women with EI/II may be related to compromised oocyte quality. PMID- 29247564 TI - Secondary structure of cell-penetrating peptides during interaction with fungal cells. AB - Cell-penetrating peptides (CPPs) are peptides that cross cell membranes, either alone or while carrying molecular cargo. Although their interactions with mammalian cells have been widely studied, much less is known about their interactions with fungal cells, particularly at the biophysical level. We analyzed the interactions of seven CPPs (penetratin, Pep-1, MPG, pVEC, TP-10, MAP, and cecropin B) with the fungal pathogen Candida albicans using experiments and molecular simulations. Circular dichroism (CD) of the peptides revealed a structural transition from a random coil or weak helix to an alpha-helix occurs for all peptides when the solvent is changed from aqueous to hydrophobic. However, CD performed in the presence of C. albicans cells showed that proximity to the cell membrane is not necessarily sufficient to induce this structural transition, as penetratin, Pep-1, and MPG did not display a structural shift in the presence of cells. Monte Carlo simulations were performed to further probe the molecular-level interaction with the cell membrane, and these simulations suggested that pVEC, TP-10, MAP, and cecropin B strongly penetrate into the hydrophobic domain of the membrane lipid bilayer, inducing a transition to an alpha-helical conformation. In contrast, penetratin, Pep-1 and MPG remained in the hydrophilic region without a shift in conformation. The experimental data and MC simulations combine to explain how peptide structure affects their interaction with cells and their mechanism of translocation into cells (direct translocation vs. endocytosis). Our work also highlights the utility of combining biophysical experiments, biological experiments, and molecular modeling to understand biological phenomena. PMID- 29247566 TI - Application of the BACs-on-BeadsTM assay for rapid prenatal detection application of BoBsTM for PND of aneuploidies and microdeletions. AB - Prenatal diagnosis focuses on the detection of anatomic and physiologic problems with a foetus before birth. Karyotyping is currently considered the gold standard for prenatal diagnosis of chromosomal abnormalities, but this method can be time consuming. This study evaluated the diagnostic accuracy of the BACs-on-BeadsTM (BoBsTM) assay for the rapid diagnosis of aneuploidies and microdeletions. A total of 625 samples from pregnant women in Fujian province, in southeastern China-including three chorionic villus biopsies, 523 amniotic fluid samples, and 99 umbilical-cord centesis samples-were assessed for chromosomal abnormalities by karyotyping and by the BoBsTM assay. A diagnosis was successfully achieved by karyotyping for 98.8% (618/625) and by the BoBsTM assay for 100% (625/625) of the samples. Both assays were concordant for trisomy 21 (2.72%, 17/625), trisomy 18 (1.12%, 7/625), trisomy 13 (0.48%, 3/625), and sex chromosome aneuploidies (0.8%, 5/625). Unlike karyotyping, the BoBsTM assay detected 22q11.2 microdeletion (0.64%, 4/625), 22q11.2 microduplication (0.16%, 1/625), Smith-Magenis syndrome microdeletion (0.16%, 1/625), and Miller-Dieker syndrome microdeletion (0.16%, 1/625). Thus, the BoBsTM assay is a reliable and rapid test for detecting common aneuploidies and microdeletions for prenatal diagnosis, and could be used instead of karyotyping for detection of common aneuploidies as well as to provide additional information regarding microdeletions. PMID- 29247568 TI - Oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma involving the cervical lymph nodes of unknown primary origin. AB - BACKGROUND: The purpose of this study was to present our findings on the use of limited-field, oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma of unknown primary origin. METHODS: Between April 2011 and January 2016, 25 patients with a histological diagnosis of p16-positive squamous cell carcinoma were selectively irradiated to the ipsilateral oropharynx and cervical neck for tumors of unknown primary origin. The dose to the oropharynx ranged from 54-60 Gy (median 60 Gy) in 30-33 fractions. Concurrent cisplatin-based chemotherapy was administered to 8 patients (32%). RESULTS: The actuarial 2-year estimates of locoregional control, progression-free survival, and overall survival were 91%, 87%, and 92%, respectively. One patient failed in the contralateral neck. There was no grade 3 + toxicity in either the acute or late setting. CONCLUSION: Oropharynx-directed, ipsilateral radiation results in disease control that compares favorably with historical controls treated by comprehensive mucosal and bilateral neck radiation. PMID- 29247567 TI - ADAM9 is over-expressed in human ovarian clear cell carcinomas and suppresses cisplatin-induced cell death. AB - ADAMs (a disintegrin and metalloproteinases) are involved in various biological events such as cell adhesion, migration and invasion, membrane protein shedding and proteolysis. However, there have been no systematic studies on the expression of ADAMs in human ovarian carcinomas. We therefore examined mRNA expression of all the proteolytic ADAM species including ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, 33 and ADAMDEC1 in human ovarian carcinomas, and found that prototype membrane-anchored ADAM9m, but not secreted isoform ADAM9s, is significantly over expressed in carcinomas than in control non-neoplastic ovarian tissue. Among the histological subtypes of serous, endometrioid, mucinous and clear cell carcinomas, ADAM9m expression was highest in clear cell carcinomas. Immunohistochemistry showed that all the clear cell carcinoma samples displayed ADAM9m primarily on the carcinoma cell membrane. By immunoblotting, ADAM9m was detected mainly in an active form in the clear cell carcinoma tissues. When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, viability was significantly reduced and apoptosis increased in ADAM9m knockdown cells compared with mock transfectants. In addition, treatment of the cells with neutralizing anti-ADAM9m antibody significantly decreased viability compared with non-immune IgG, whereas ADAM9m over-expression significantly increased viability compared with mock transfectants. Our data show, to the best of our knowledge, for the first time, that ADAM9m is over-expressed in an activated form in human ovarian clear cell carcinomas, and suggest that ADAM9m plays a key role in cisplatin resistance. PMID- 29247569 TI - Penetration into membrane of amino-terminal region of SecA when associated with SecYEG in active complexes. AB - The general secretory (Sec) system of Escherichia coli translocates both periplasmic and outer membrane proteins through the cytoplasmic membrane. The pathway through the membrane is provided by a highly conserved translocon, which in E. coli comprises two heterotrimeric integral membrane complexes, SecY, SecE, and SecG (SecYEG), and SecD, SecF, and YajC (SecDF/YajC). SecA is an associated ATPase that is essential to the function of the Sec system. SecA plays two roles, it targets precursors to the translocon with the help of SecB and it provides energy via hydrolysis of ATP. SecA exists both free in the cytoplasm and integrally membrane associated. Here we describe details of association of the amino-terminal region of SecA with membrane. We use site-directed spin labelling and electron paramagnetic resonance spectroscopy to show that when SecA is co assembled into lipids with SecYEG to yield highly active translocons, the N terminal region of SecA penetrates the membrane and lies at the interface between the polar and the hydrophobic regions, parallel to the plane of the membrane at a depth of approximately 5 A. When SecA is bound to SecYEG, preassembled into proteoliposomes, or nonspecifically bound to lipids in the absence of SecYEG, the N-terminal region penetrates more deeply (8 A). Implications of partitioning of the SecA N-terminal region into lipids on the complex between SecB carrying a precursor and SecA are discussed. PMID- 29247570 TI - MicroRNA-155 promotes gastric cancer growth and invasion by negatively regulating transforming growth factor-beta receptor 2. AB - Gastric cancer (GC) is one of the most common malignancies worldwide and has high morbidity and mortality rates. It is essential to elucidate the molecular events of GC proliferation and invasion, which will provide new therapeutic targets for GC. The inactivation of transforming growth factor-beta receptor 2 (TGFbetaR2) correlates with cancer cell growth and metastasis, but the mechanisms underlying the downregulation of TGFbetaR2 expression remain unknown. MicroRNAs (miRNAs) act as post-transcriptional regulators and play a key role in the development of cancers. Bioinformatics analysis and luciferase reporter assays have shown that miR-155 directly binds to the 3'-UTR of TGFbetaR2 mRNA. In this study, we found that the TGFbetaR2 protein levels, but not mRNA levels, were downregulated in GC tissues, and the levels of miR-155 were significantly increased in GC tissues. We deduced that miR-155 was inversely correlated with TGFbetaR2 in GC cells. In vitro studies showed that overexpression of miR-155 in SGC7901 inhibited the expression of TGFbetaR2 and then promoted GC cell proliferation and migration, whereas miR-155 inhibitor showed opposite effects. In addition, the tumor suppressing function of TGFbetaR2 was verified by using siRNA and TGFbetaR2 overexpressing plasmids. The results showed that miR-155 promotes cell growth and migration by negatively regulating TGFbetaR2. Thus, miR-155-regulated TGFbetaR2 as a potential therapeutic target in GC. PMID- 29247571 TI - Testis-specific Lypd9 is dispensable for spermatogenesis in mouse. PMID- 29247572 TI - Identifying potential molecular factors involved in Bacillus amyloliquefaciens 5113 mediated abiotic stress tolerance in wheat. AB - Abiotic stressors are main limiting factors for agricultural production around the world. Plant growth-promoting bacteria have been successfully used to improve abiotic stress tolerance in several crops including wheat. However, the molecular changes involved in the improvement of stress management are poorly understood. The present investigation addressed some molecular factors involved in bacterially induced plant abiotic stress responses by identifying differentially expressed genes in wheat (Triticum aestivum) seedlings treated with the beneficial bacterium Bacillus amyloliquefaciens subsp. plantarum UCMB5113 prior to challenge with abiotic stress conditions such as heat, cold or drought. cDNA AFLP analysis revealed differential expression of more than 200 transcript derived fragments (TDFs) in wheat leaves. Expression of selected TDFs was confirmed using RT-PCR. DNA sequencing of 31 differentially expressed TDFs revealed significant homology with both known and unknown genes in database searches. Virus-induced gene silencing of two abscisic acid-related TDFs showed different effects upon heat and drought stress. We conclude that treatment with B. amyloliquefaciens 5113 caused molecular modifications in wheat in order to induce tolerance against heat, cold and drought stress. Bacillus treatment provides systemic effects that involve metabolic and regulatory functions supporting both growth and stress management. PMID- 29247573 TI - Modulation of the tumor microenvironment by Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma. AB - Latent membrane protein 1 (LMP1) is a primary oncogene encoded by the Epstein Barr virus, and various portions of LMP1 are detected in nasopharyngeal carcinoma (NPC) tumor cells. LMP1 has been extensively studied since the discovery of its transforming property in 1985. LMP1 promotes cancer cell growth during NPC development and facilitates the interaction of cancer cells with surrounding stromal cells for invasion, angiogenesis, and immune modulation. LMP1 is detected in 100% of pre-invasive NPC tumors and in approximately 50% of advanced NPC tumors. Moreover, a small population of LMP1-expressing cells in advanced NPC tumor tissue is proposed to orchestrate NPC tumor tissue maintenance and development through cancer stem cells and progenitor cells. Recent studies suggest that LMP1 activity shifts according to tumor development stage, but it still has a pivotal role during all stages of NPC development. PMID- 29247574 TI - IgE promotes type 2 innate lymphoid cells in murine food allergy. AB - BACKGROUND: Mast cells serve an important sentinel function at mucosal barriers and have been implicated as key early inducers of type 2 immune responses in food allergy. The generation of Th2 and IgE following food allergen ingestion is inhibited in the absence of mast cells. Group 2 innate lymphoid cells are also thought to play an important early role in nascent allergic responses. OBJECTIVE: To test whether IgE-mediated mast cell activation promotes intestinal ILC2 responses following ingestion of food allergens and whether ILC2 amplify food allergy. METHODS: Two different mouse models of food allergy, one using intraperitoneally ovalbumin (OVA)-primed BALB/c animals and the other using enterally peanut-sensitized inherently atopic IL4raF709 mice, were applied to test the contributions of IgE antibodies and mast cells to ILC2 responses. The effect of ILC2 on mast cell activation and on anaphylaxis was tested. RESULTS: ILC2 responses were significantly impaired in both models of food allergy in Igh7 /- mice harbouring a targeted deletion of the gene encoding IgE. A similar reduction in food allergen-induced ILC2 was observed in mast cell-deficient Il4raF709 KitW-sh mice, and this was partially corrected by reconstituting these animals using cultured bone marrow mast cells. Mast cells activated ILC2 for IL 13 production in an IL-4Ralpha-dependent manner. Activated ILC2 amplified systemic anaphylaxis by increasing target tissue sensitivity to mast cell mediators. CONCLUSIONS AND CLINICAL RELEVANCE: These findings support an important role for IgE-activated mast cells in driving intestinal ILC2 expansion in food allergy and reveal that ILC2, in turn, can enhance responsiveness to the mediators of anaphylaxis produced by mast cells. Strategies designed to inhibit IgE signalling or mast cell activation are likely to inhibit both type 2 immunity and immediate hypersensitivity in food allergy. PMID- 29247575 TI - Local differentiation of cell wall matrix polysaccharides in sinuous pavement cells: its possible involvement in the flexibility of cell shape. AB - The distribution of homogalacturonans (HGAs) displaying different degrees of esterification as well as of callose was examined in cell walls of mature pavement cells in two angiosperm and two fern species. We investigated whether local cell wall matrix differentiation may enable pavement cells to respond to mechanical tension forces by transiently altering their shape. HGA epitopes, identified with 2F4, JIM5 and JIM7 antibodies, and callose were immunolocalised in hand-made or semithin leaf sections. Callose was also stained with aniline blue. The structure of pavement cells was studied with light and transmission electron microscopy (TEM). In all species examined, pavement cells displayed wavy anticlinal cell walls, but the waviness pattern differed between angiosperms and ferns. The angiosperm pavement cells were tightly interconnected throughout their whole depth, while in ferns they were interconnected only close to the external periclinal cell wall and intercellular spaces were developed between them close to the mesophyll. Although the HGA epitopes examined were located along the whole cell wall surface, the 2F4- and JIM5- epitopes were especially localised at cell lobe tips. In fern pavement cells, the contact sites were impregnated with callose and JIM5-HGA epitopes. When tension forces were applied on leaf regions, the pavement cells elongated along the stretching axis, due to a decrease in waviness of anticlinal cell walls. After removal of tension forces, the original cell shape was resumed. The presented data support that HGA epitopes make the anticlinal pavement cell walls flexible, in order to reversibly alter their shape. Furthermore, callose seems to offer stability to cell contacts between pavement cells, as already suggested in photosynthetic mesophyll cells. PMID- 29247576 TI - Effect of non-beta-lactams on stable variants of inhibitor-resistant TEM beta lactamase in uropathogenic Escherichia coli: implication for alternative therapy. AB - AIMS: beta-lactamase inhibitor resistance (BLIR) among the uropathogenic Escherichia coli (UPEC) minimizes treatment options. This study aimed to identify inhibitor-resistant TEM (IRT) beta-lactamase that impart BLIR phenotype and explore non-beta-lactams as alternative therapeutics. METHODS AND RESULTS: Thirty BLIR UPEC isolates were detected by Kirby-Bauer disc diffusion technique using beta-lactam-beta-lactamase inhibitor combination. Conjugal transfer of BLIR was successful from 17 isolates. PCR and sequencing of the TEM beta-lactamases from the transconjugants indicated 14 TEM-84 (IRT) and three novel IRT variants (pUE184TEM, pUE203TEM, pUE210TEM). Three-dimensional models of the latter were predicted and validated. Molecular docking of selected non-beta-lactams (morin, catechin, naringenin triacetate) with the variants using AutoDock 4.2 showed comparable docking scores with significant hydrogen bond and hydrophobic interactions. Molecular dynamics simulation study confirmed stability of the non beta-lactams inside the catalytic pocket of the enzymes. Moreover, all three non beta-lactams were found to inhibit the purified TEM beta-lactamase variants in vitro. Microbroth dilution method indicated naringenin triacetate 64 MUg ml-1 in combination with ceftazidime (CAZ) 30 MUg ml-1 to be most effective against the BLIR transconjugants. CONCLUSIONS: BLIR phenotypes were primarily attributed to the production of IRT beta-lactamases. Administration of the non-beta-lactams with CAZ demonstrated an alternative therapeutic strategy against the IRT beta lactamase producers. SIGNIFICANCE AND IMPACT OF THE STUDY: This study indicates high risk of transmission of IRT beta-lactamases and suggests beta-lactam-non beta-lactam combination therapy to combat BLIR. PMID- 29247578 TI - Interventions developed with the Intervention Mapping protocol in the field of cancer: A systematic review. AB - OBJECTIVES: The Intervention Mapping (IM) protocol provides a structured framework to develop, implement, and evaluate complex interventions. The main objective of this review was to identify and describe the content of the interventions developed in the field of cancer with the IM protocol. Secondary objectives were to assess their fidelity to the IM protocol and to review their theoretical frameworks. METHODS: Medline, Web of Science, PsycINFO, PASCAL, FRANCIS, and BDSP databases were searched. All titles and abstracts were reviewed. A standardized extraction form was developed. All included studies were reviewed by 2 reviewers blinded to each other. RESULTS: Sixteen studies were identified, and these reported 15 interventions. The objectives were to increase cancer screening participation (n = 7), early consultation (n = 1), and aftercare/quality of life among cancer survivors (n = 7). Six reported a complete participatory planning group, and 7 described a complete logic model of the problem. Ten studies described a complete logic model of change. The main theoretical frameworks used were the theory of planned behaviour (n = 8), the transtheoretical model (n = 6), the health belief model (n = 6), and the social cognitive theory (n = 6). The environment was rarely integrated in the interventions (n = 4). Five interventions were reported as effective. CONCLUSIONS: Culturally relevant interventions were developed with the IM protocol that were effective to increase cancer screening and reduce social disparities, particularly when they were developed through a participative approach and integrated the environment. Stakeholders' involvement and the role of the environment were heterogeneously integrated in the interventions. PMID- 29247577 TI - Ovarian cancer risk, ALDH2 polymorphism and alcohol drinking: Asian data from the Ovarian Cancer Association Consortium. AB - The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians. We conducted a pooled analysis of Asian ancestry participants in the Ovarian Cancer Association Consortium. We included seven case-control studies and one cohort study comprising 460 invasive OvCa cases, 37 borderline mucinous OvCa and 1274 controls of Asian descent with information on recent alcohol consumption. Pooled odds ratios (OR) with 95% confidence intervals (CI) for OvCa risk associated with alcohol consumption, rs671 and their interaction were estimated using logistic regression models adjusted for potential confounders. No significant association was observed for daily alcohol intake with invasive OvCa (OR comparing any consumption to none = 0.83; 95% CI = 0.58 1.18) or with individual histotypes. A significant decreased risk was seen for carriers of one or both Lys alleles of rs671 for invasive mucinous OvCa (OR = 0.44; 95% CI = 0.20-0.97) and for invasive and borderline mucinous tumors combined (OR = 0.48; 95% CI = 0.26-0.89). No significant interaction was observed between alcohol consumption and rs671 genotypes. In conclusion, self-reported alcohol consumption at the quantities estimated was not associated with OvCa risk among Asians. Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype. This association will require replication in a larger sample. PMID- 29247579 TI - Peg-interferon and ribavirin treatment in HIV/HCV co-infected patients in Thailand: efficacy, safety and pharmacokinetics. AB - OBJECTIVE: In Thailand, 7.2% of HIV patients are co-infected with hepatitis C virus (HCV), and these patients are treated with peg-interferon + ribavirin (PR) for their HCV infection. This study evaluates efficacy and safety of PR treatment and pharmacokinetics of ribavirin in this population. METHODS: HIV/HCV co infected Thai patients were treated with PR for 24 or 48 weeks. Sustained virological response 24 weeks after the end of treatment (SVR24) was used to describe efficacy. (laboratory) safety parameters and ribavirin plasma concentrations were evaluated during study visits. Ribavirin concentrations were compared with t-tests for patients with and without anaemia (haemoglobin <10 g/dl) and SVR24. RESULTS: A total of 101 HIV/HCV co-infected patients were included; 88% were male (n = 88), and 46% were infected with genotype 3. The median (IQR) start dose was 14.28 mg/kg/day. SVR24 rate was 56%. All patients reported at least one (serious) adverse event, of which 28% of patients developed anaemia. Seven patients discontinued treatment due to toxicity issues. Geometric mean (IQR) ribavirin concentration was 1.81 (1.42-2.32) mg/l at week 8 of treatment. At week 8, patients with and without anaemia and SVR had ribavirin concentrations of 2.29 and 1.63 mg/l and 1.91 and 1.74 mg/l, respectively. CONCLUSIONS: PR treatment has comparable response rates and toxicity profile in Thai HIV/HCV co-infected patients as in Western HIV/HCV patients. However, ribavirin plasma concentrations were comparable with previously published studies in HIV/HCV co-infected patients, but both, just as SVR rate, were lower than in mono-infected patients. PMID- 29247580 TI - Successful refolding and NMR structure of rMagi3: A disulfide-rich insecticidal spider toxin. AB - The need for molecules with high specificity against noxious insects leads the search towards spider venoms that have evolved highly selective toxins for insect preys. In this respect, spiders as a highly diversified group of almost exclusive insect predators appear to possess infinite potential for the discovery of novel insect-selective toxins. In 2003, a group of toxins was isolated from the spider Macrothele gigas and the amino acid sequence was reported. We obtained, by molecular biology techniques in a heterologous system, one of these toxins. Purification process was optimized by chromatographic methods to determine the three-dimensional structure by nuclear magnetic resonance in solution, and, finally, their biological activity was tested. rMagi3 resulted to be a specific insect toxin with no effect on mice. PMID- 29247581 TI - Life-history trade-offs vary with resource availability across the geographic range of a widespread plant. AB - Trade-offs between reproduction, growth and survival arise from limited resource availability in plants. Environmental stress is expected to exacerbate these negative correlations, but no studies have evaluated variation in life-history trade-offs throughout species geographic ranges. Here we analyse the costs of growth and reproduction across the latitudinal range of the widespread herb Plantago coronopus in Europe. We monitored the performance of thousands of individuals in 11 populations of P. coronopus, and tested whether the effects of growth and reproduction on a set of vital rates (growth, probability of survival, probability of reproduction and fecundity) varied with local precipitation and soil fertility. To account for variation in internal resources among individuals, we analysed trade-offs correcting for differences in size. Growth was negatively affected by previous growth and reproduction. We also found costs of growth and reproduction on survival, reproduction probability and fecundity, but only in populations with low soil fertility. Costs also increased with precipitation, possibly due to flooding-related stress. In contrast, growth was positively correlated with subsequent survival, and there was a positive covariation in reproduction between consecutive years under certain environments, a potential strategy to exploit temporary benign conditions. Overall, we found both negative and positive correlations among vital rates across P. coronopus geographic range. Trade-offs predominated under stressful conditions, and positive correlations arose particularly between related traits like reproduction investment across years. By analysing multiple and diverse fitness components along stress gradients, we can better understand life-history evolution across species' ranges, and their responses to environmental change. PMID- 29247582 TI - American Thyroid Association ultrasound system for the initial assessment of thyroid nodules: Use in stratifying the risk of malignancy of indeterminate lesions. AB - BACKGROUND: The ultrasound risk stratification system of the American Thyroid Association (ATA) is frequently adopted in clinical practice. Here, we evaluated its performance in a series of nodules with indeterminate fine-needle aspiration cytology (FNAC) report. METHODS: Indeterminate thyroid nodules diagnosed at 2 medical centers were retrospectively screened, ultrasound images were reevaluated, and lesions were classified according to the ATA. Single ultrasound parameters were also analyzed. RESULTS: One hundred seventy-three indeterminate lesions were included with 24.8% of malignancy. The high suspicion class showed a cancer rate (75%) significantly (P < .001) higher than that recorded in the other categories (16.8%). Between ultrasound parameters, halo and microcalcifications were the most sensitive and specific ones. The most accurate receiver operating characteristic (ROC)-derived cutoff of nodule's diameter was >4.1 cm. At multivariate analysis, only the ATA class of high suspicion and size >4.1 cm were significantly associated with cancer (odds ratios [ORs] 19.4 and 5.4, respectively). CONCLUSION: The ATA ultrasound system is reliable in the risk stratification of indeterminate thyroid lesions. PMID- 29247583 TI - Tough Gel Electrolyte Using Double Polymer Network Design for the Safe, Stable Cycling of Lithium Metal Anode. AB - The growth of lithium dendrites and low coulombic efficiency restrict the development of Li metal anodes. Polymer electrolytes are expected to be promising candidates to solve the issue, but ways to obtain a polymer electrolyte that integrates high ionic conductivity and high mechanical toughness is still challenging. By introducing a double polymer network into the electrolyte design to reshape it, a tough polymer electrolyte was developed with high conductivity, and stable operation of lithium metal anodes was further realized. The double network (DNW) gel electrolyte has high modulus of 44.3 MPa and high fracture energy of 69.5 kJ m-2 . The conductivity of DNW gel is 0.81 mS cm-1 at 30 degrees C. By using this gel electrolyte design, the lithium metal electrode could be cycled more than 400 times with a coulombic efficiency (CE) as high as 96.3 % with carbonate-based electrolytes. PMID- 29247584 TI - Predictors of adherence to exercise interventions during and after cancer treatment: A systematic review. AB - OBJECTIVE: Exercise interventions benefit cancer patients. However, only low numbers of patients adhere to these interventions. This review aimed to identify predictors of exercise intervention adherence in patients with cancer, during and after multimodality cancer treatment. METHODS: A literature search was performed using electronic databases (PubMed, Embase, and Cochrane) to identify relevant papers published before February 1, 2017. Papers reporting randomized controlled trials, conducted in adult cancer patients who participated in an exercise intervention during and/or after multimodality cancer treatment, and providing outcome of factors predicting exercise adherence were included. Papers were assessed for methodological quality by using the Physiotherapy Evidence Database scale. RESULTS: The search identified 720 potentially relevant papers, of which 15 fulfilled the eligibility criteria. In these 15 studies, 2279 patients were included and 1383 of these patients were randomized to an exercise intervention. During cancer treatment, the factors predicting exercise adherence were as follows: location of the rehabilitation center, extensive exercise history, high motivation for exercise, and fewer exercise limitations. After cancer treatment, factors that predicted adherence were as follows: less extensive surgery, low alcohol consumption, high previous exercise adherence, family support, feedback by trainers, and knowledge and skills of exercise. Methodological quality of the included papers was rated "high". CONCLUSIONS: The most prominent predictors of adherence to exercise interventions were location of the rehabilitation center, extensive exercise history, high motivation for exercise, and fewer exercise limitations. To increase the number of cancer patients who will benefit, these results should be considered into the development and implementation of future exercise interventions. PMID- 29247586 TI - Gas-phase fragmentation reactions of protonated cocaine: New details to an old story. PMID- 29247585 TI - Simultaneous acquisition of MR angiography and diagnostic images of abdomen at view-sharing multiarterial phases and comparing the effect of two different contrast agents. AB - BACKGROUND: Simultaneous acquisition of magnetic resonance angiography (MRA) and diagnostic images is challenging in contrast-enhanced upper abdominal MRI. PURPOSE: To evaluate the image quality of MRA of the abdomen acquired simultaneously with diagnostic MR images, and to compare the contrast effect, conspicuity of aortic branches, and pancreatic lesions in MRA between gadobutrol and gadoterate meglumine. STUDY TYPE: Prospective. POPULATION: Eighty-eight patients with known and suspected upper abdominal disease. FIELD STRENGTH/SEQUENCES: 3T/4D-eTHRIVE (T1 -weighted fat-suppressed 3D fast gradient echo) for multiarterial phase imaging. ASSESSMENT: The artery-to-muscle signal intensity ratio (SIR), conspicuity of aortic branches on the axial, maximum intensity projection (MIP), and volume-rendered (VR) images, and conspicuity of focal pancreatic lesions were compared between gadobutrol and gadoterate meglumine. The diameters of aortic branches were measured on axial MRA and computed tomography angiography (CTA) images and then compared. STATISTICAL TESTS: Quantitative and qualitative data were assessed with the Mann-Whitney U test. The diameters of aortic branches between MRA and CTA were compared with a Spearman rank correlation test. RESULTS: View-sharing multiarterial phase imaging was successfully performed in all patients. The SIRs of common hepatic artery (P = 0.0051) and left renal artery (RA) (P = 0.045), vascular conspicuities of right and left hepatic arteries (P = 0.010 and 0.030) and right and left RAs on axial (P = 0.0065 and 0.036), and that of gastroduodenal artery on MIP (P = 0.039) with gadobutrol were significantly higher than those with gadoterate meglumine. The conspicuity of focal pancreatic lesions were comparable between the gadobutrol and gadoterate meglumine (P = 0.73). The vascular diameters on MRA and CTA were strongly correlated in all aortic branches (r = 0.842-0.942, P < 0.0001). DATA CONCLUSION: High-quality MRA of the abdomen was obtained simultaneously with the diagnostic MR images using view-sharing multiarterial phase imaging that also demonstrated comparable image quality between gadobutrol and gadoterate meglumine. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 1 J. Magn. Reson. Imaging 2017. PMID- 29247587 TI - Factors associated with possible complicated grief and major depressive disorders. AB - OBJECTIVE: Complicated grief (CG) is considered a distinctive symptom from other bereavement-related mental impairments such as major depressive disorder (MDD). CG and MDD may appear independently or co-morbidly; however, the factors associated with each situation are unclear. METHODS: We conducted a nationwide cross-sectional questionnaire survey involving bereaved family members of cancer patients in 175 institutions. The following items were included in the questionnaires to assess the prevalence of CG and MDD, and the following associated factors: demographic characteristics; bereaved family depression (Patient Health Questionnaire-9) and grief status (Brief Grief Questionnaire); structure and process of care (Care Evaluation Scale); overall care satisfaction; and achievement of a good death (Good Death Inventory). RESULTS: A total of 9123 questionnaires were returned. The prevalence of CG and MDD was 14% and 17%, respectively. Additionally, 58% of the possible CG participants showed co-morbid symptoms. Common factors that showed significant association with either independent or co-morbid symptoms of CG and MDD were pre-existing mental impairment; belief in the survival of the soul after physical death; unpreparedness for the death; poor physical or psychological health status; and the belief that the deceased felt themselves as a burden to others (all P < 0.05). The duration of bereavement did not remain significant after multivariate analysis. CONCLUSIONS: While there were many common factors associated with both CG and MDD independently, few participants exhibited associations to both CG and MDD. Therefore, CG and MDD can be considered as distinctive symptoms, which frequently appear co-morbidly. PMID- 29247588 TI - Oocyte maturation in the toad Rhinella arenarum (Amphibia, Anura): Evidence of cAMP involvement in steroid production and action. AB - In this work, we describe the participation of the adenylate cyclase/3'-5'-cyclic adenonsine monophosphate (cAMP) pathway in the seasonal follicular secretion of progesterone (P4 ) and testosterone (T), and its relationship with the maturation of Rhinella arenarum oocytes. Under gonadotropin stimulation, P4 secretion was the dominant steroid produced during the reproductive period, resulting in 100% germinal vesicle breakdown (GVBD) in oocytes in vitro; in contrast, T and estradiol (E2 ) secretion increased (~16 nM/20 follicles and ~80 pM/20 follicles, respectively) during the non-reproductive period, but only yielded 50% GVBD. Treatment of the follicles with dibutyryl-cAMP or forskolin induced a significant increase in T secretion during both periods, but P4 secretion did not significantly change and GVBD did not occur. These results suggest that high cAMP levels in the oocyte maintain meiotic arrest and prevent the induction effect of follicular steroids. An increase in cAMP levels in denuded oocytes, however, negatively regulated T-induced maturation since treatment with increasing db-cAMP or forskolin inhibited their maturation. Therefore, we hypothesize that an elevation in T during the non-reproductive period favors its aromatization to E2 , leading to follicle growth. During the reproductive period, P4 production might promote oocyte maturation when environmental conditions are favorable for reproduction. Together, the results indicate that steroidogenesis is seasonal and depends on gonadotropic activity in R. arenarum. PMID- 29247591 TI - Hydrogen peroxide bleaching induces changes in the physical properties of dental restorative materials: Effects of study protocols. AB - OBJECTIVE: The purpose of this study was to evaluate the influence of study protocols on the effects of bleaching on the surface roughness, substance loss, flexural strength (FS), flexural modulus (FM), Weibull parameters, and color of 7 restorative materials. MATERIALS AND METHODS: The test materials included 4 composite resins, 1 glass-ionomer cement, 1 dental ceramic, and 1 polyacid modified composite. The specimens were randomly divided into 4 groups (n = 20) according to different study protocols: a bleaching group at 25 degrees C (group 25B), a bleaching group at 37 degrees C (group 37B), a control group at 25 degrees C (group 25C), and a control group at 37 degrees C (group 37C). The specimens in the bleaching group were treated with 40% hydrogen peroxide for 80 min at the respective environmental temperatures. The surface roughness, substance loss, FS, FM, and color of the specimens were measured before and after treatment. FS data were also subjected to Weibull analysis, which was used to estimate of the Weibull modulus (m) and the characteristic strength (sigma0 ). RESULTS: Surface roughness increased and significant color changes were observed for all tested specimens after bleaching treatment, except for the ceramic. After bleaching at 37 degrees C, the polyacid-modified composite showed significantly reduced FS, FM, m, and sigma0 values in comparison to the control specimens stored at 37 degrees C in whole saliva. Significant differences were also found between the 37B and 25B polyacid-modified composite groups in terms of surface roughness, FS, m, sigma0 , and color changes. CONCLUSIONS: Varying effects of bleaching on the physical properties of dental restorative materials were observed, and the influences of the study protocols on bleaching effects were found to be material-dependent. CLINICAL SIGNIFICANCE: The influence of study protocols on the effects of bleaching on the surface roughness, flexural properties, and color of dental restorative materials are material-dependent and should be considered when evaluating the effects of bleaching on dental restorative materials. PMID- 29247589 TI - Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity. AB - Although trastuzumab-induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify genetic variants determining the risk of trastuzumab induced cardiotoxicity, we carried out whole exome sequencing of germline DNA samples from 9 patients with trastuzumab-induced cardiotoxicity, and conducted a case-control association study of 2258 genetic variants between 9 cases (with trastuzumab-induced cardiotoxicity) and general Japanese population controls registered in the Human Genetic Variation Database (HGVD). The top variant which showed the lowest P-value in the screening study was rs139503277 in PHD Finger Protein 3 (Pmin = .00012, odds ratio [OR] = 51.23). To further validate the result of screening study, we carried out a replication study of 10 variants showing Pmin < .001 in the screening study using 234 independent patients treated with trastuzumab, including 10 cases and 224 controls (without trastuzumab induced cardiotoxicity). In the replication study, we observed that three variants had an effect in the same direction as in the screening study (rs78272919 in exon 2 of Keratin 15, rs5762940 in exon 2 of zinc and ring finger 3, and rs139944387 in exon 44 of Eyes shut homologs [EYS]). A combined result of the screening and the replication studies suggested an association of a locus on chromosome 6q12 with trastuzumab-induced cardiotoxicity (rs139944387 in EYS, combined Pmin = .00056, OR = 13.73). This finding provides new insights into personalized trastuzumab therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive cancer. PMID- 29247590 TI - Transient phenotypic changes in endothelial cells and pericytes in neonatal mouse retina following short-term blockade of vascular endothelial growth factor receptors. AB - BACKGROUND: A short-term interruption of vascular development causes structural abnormalities in retinal vasculature. However, the detailed changes in vascular components (endothelial cells, pericytes, and basement membranes) remain to be fully determined. The present study aimed to provide a detailed description of morphological changes in vascular components following a short-term interruption of retinal vascular development in mice. RESULTS: Two-day treatment of neonatal mice with the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg, subcutaneously) on postnatal day (P)0 and P1 (P0/1) and P4 and P5 (P4/5) induced different degrees and patterns of impairment of retinal vascular development. Three days after completion of the treatment, the delayed radial vascular growth occurred in P0/1 group mice, whereas in P4/5 group mice, revascularization preferentially occurred in the central avascular area, and radial vascular growth remained suppressed by P10. Differences in alpha smooth muscle actin expression in pericytes were noted in the processes between normal vascular formation and vascular regrowth. The changes in vascular cells were associated with the hypoxia-induced enhancement of VEGF expression in the superficial retinal layer. CONCLUSIONS: These findings suggest that the phenotype of vascular cells is altered following a short-term interruption of vascular development in the retina. Developmental Dynamics 247:699-711, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29247592 TI - Relationship between smoking and total antioxidant status, total oxidant status, oxidative stress index, vit C, vit E. AB - BACKGROUND: Tobacco smoking contains many toxic, carcinogenic and mutagenic chemicals, as well as stable and unstable free radicals. In this study, we aimed to assess the vitamin E, vitamin C and total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI) in smoking and non-smoking men. MATERIALS AND METHODS: This case-control analytical study was conducted on 78 smoking and 82 non-smoking men. Fagerstrom nicotine-dependence test was used to assess the participants' addiction status. Low-density lipoprotein-c, high density lipoprotein-c, total cholesterol, triglyceride, fasting blood glucose, vitamin E, vitamin C, TAS and TOS levels were determined. RESULTS: The mean age of 160 men who participated in our study was 33.0 +/- 10.6 years. The comparison of smoker and non-smoker groups was made in terms of the parameters of TAS, TOS, OSI, vitamin C and vitamin E; it was seen that TAS (P = .003), vitamin C (P < .001) and vitamin E (P < .001) values in non-smokers' group were found significantly higher than smokers. In non-smokers, vitamin C level was 4.3 times more than the smokers. In non-smokers, vitamin E level was 6.9 times more than the smokers. The values of TOS (P < .001) and OSI (P < .001) in smokers were significantly higher than the control group. CONCLUSIONS: The parameters of TAS, vitamin C and vitamin E were significantly higher in the non-smoker group than in the smoker group. The levels of TOS and OSI were higher in the smoker group. It is known that cigarette smoking leads to various diseases because of the free radicals it contains. PMID- 29247593 TI - Solid-Phase Enzymatic Remodeling Produces High Yields of Single Glycoform Antibodies. AB - Antibodies are synthesized in mammalian cell culture as heterogeneous mixtures of glycoforms. Production of single glycoforms remains a challenge despite their value as therapeutics. The authors report a method of sequential enzymatic-based changes to antibodies while immobilized on an affinity column. Various antibodies (monoclonal and polyclonal) are isolated on Protein A or G columns and their glycans modified by sequential addition of enzymes for a desired transformation. Galactosylated antibodies (>90% yield) are produced by a one stage reaction process with sialidase to remove any sialic acid residues and addition of galactose with galactosyltransferase and UDP-Gal. Sialylated antibodies (>90%) are produced by a 2 stage conversion involving alpha(2,3) sialidase and galactosyltransferase followed by treatment with alpha(2,6) sialyltransferase in the presence of CMP-NANA. By this method, >90% of a disialylated human-llama antibody (EG2-hFc) and equimolar quantities of monosialylated and disialylated forms of human antibodies (alphaIL8-hFc and human polyclonal) are produced. Such high levels of sialylation are very difficult to obtain by typical cell culture methods. This method of transformation while the antibody is held on a solid phase column is superior to previous methods because it allows a series of enzymatic steps without the need for intermediate purification. This is an efficient and rapid method to generate therapeutic antibodies with predefined glycosylation profiles. This should also assist in investigating the structure function relationship of antibody glycans to find the desired glycosylation profile for high functional activity. With further optimization the method can be used to modify antibodies in large-scale manufacturing. PMID- 29247594 TI - Genes associated with venous thromboembolism in colorectal cancer patients. AB - : Essentials The underlying pathophysiological mechanisms behind cancer associated thrombosis are unknown. We compared expression profiles in tumor cells from patients with and without thrombosis. Tumors from patients with thrombosis showed significant differential gene expression profiles. Patients with thrombosis had a proinflammatory status and increased fibrin levels in the tumor. SUMMARY: Background Venous thromboembolism (VTE) is a frequent complication in patients with cancer, and is associated with significant morbidity and mortality. However, the mechanisms behind cancer-associated thrombosis are still incompletely understood. Objectives To identify novel genes that are associated with VTE in patients with colorectal cancer (CRC). Methods Twelve CRC patients with VTE were age-matched and sex-matched to 12 CRC patients without VTE. Tumor cells were isolated from surgical samples with laser capture microdissection approaches, and mRNA profiles were measured with next-generation RNA sequencing. Results This approach led to the identification of new genes and pathways that might contribute to VTE in CRC patients. Application of ingenuity pathway analysis indicated significant links with inflammation, the methionine degradation pathway, and increased platelet function, which are all key processes in thrombus formation. Tumor samples of patients with VTE had a proinflammatory status and contained higher levels of fibrin and fibrin degradation products than samples of those without VTE. Conclusion This case-control study provides a proof of-principle that tumor gene expression can discriminate between cancer patients with low and high risks of VTE. These findings may help to further unravel the pathogenesis of cancer-related VTE. The identified genes could potentially be used as candidate biomarkers to select high-risk CRC patients for thromboprophylaxis. PMID- 29247595 TI - Method for hull-less barley transformation and manipulation of grain mixed linkage beta-glucan. AB - Hull-less barley is increasingly offering scope for breeding grains with improved characteristics for human nutrition; however, recalcitrance of hull-less cultivars to transformation has limited the use of these varieties. To overcome this limitation, we sought to develop an effective transformation system for hull less barley using the cultivar Torrens. Torrens yielded a transformation efficiency of 1.8%, using a modified Agrobacterium transformation method. This method was used to over-express genes encoding synthases for the important dietary fiber component, (1,3;1,4)-beta-glucan (mixed-linkage glucan), primarily present in starchy endosperm cell walls. Over-expression of the HvCslF6 gene, driven by an endosperm-specific promoter, produced lines where mixed-linkage glucan content increased on average by 45%, peaking at 70% in some lines, with smaller increases in transgenic HvCslH1 grain. Transgenic HvCslF6 lines displayed alterations where grain had a darker color, were more easily crushed than wild type and were smaller. This was associated with an enlarged cavity in the central endosperm and changes in cell morphology, including aleurone and sub-aleurone cells. This work provides proof-of-concept evidence that mixed-linkage glucan content in hull-less barley grain can be increased by over-expression of the HvCslF6 gene, but also indicates that hull-less cultivars may be more sensitive to attempts to modify cell wall composition. PMID- 29247596 TI - miR-191/DAB2 axis regulates the tumorigenicity of estrogen receptor-positive breast cancer. AB - Disabled-2 (DAB2) has been shown to be downregulated in a variety of human cancer types including breast tumors. However, the role of DAB2 in estrogen receptor positive (ER+) breast cancer cells has not been reported. In this context, we demonstrated that DAB2 expression was significantly decreased in ER+ breast cancer cell lines and ER+ clinical specimens, compared with ER- breast cancer cell lines and ER- tissues, respectively. Depletion of estrogen significantly elevated DAB2 expression in ER+ MCF7 and T-47D cells. Treatment with estradiol (E2) reduced the expression of DAB2 and administration of tamoxifen upregulated DAB2 expression in a dose-dependent manner. Functionally, silencing of DAB2 in hormone-starved MCF7 and T-47D cells promoted cellular proliferation and enforced expression of DAB2 in normal-cultured or E2-treated cells suppressed cellular proliferation. Mechanistically, estrogen-induced miR-191 was identified as a direct upstream regulator of DAB2 in ER+ cells. Luciferase reporter assay indicated that miR-191 inhibited DAB2 expression by directly targeting the 3'-UTR of DAB2. Importantly, the expression and function of miR-191 showed the opposite tendency with DAB2 in ER+ cells. In vivo, inhibition of miR-191 significantly suppressed the xenograft growth induced by E2, and silencing of DAB2 could restored the growth arrest induced by miR-191 inhibition. Taken together, our data unveil that the miR-191-DAB2 axis seems to be an important pathway associated with estrogen signaling in breast cancer and may serve as a potential diagnostic biomarker and a powerful therapeutic target for ER+ breast cancer patients. (c) 2017 IUBMB Life, 70(1):71-80, 2018. PMID- 29247597 TI - Metabolic responses of Eucalyptus species to different temperature regimes. AB - Species and hybrids of Eucalyptus are the world's most widely planted hardwood trees. They are cultivated across a wide range of latitudes and therefore environmental conditions. In this context, comprehensive metabolomics approaches have been used to assess how different temperature regimes may affect the metabolism of three species of Eucalyptus, E. dunnii, E. grandis and E. pellita. Young plants were grown for 53 d in the greenhouse and then transferred to growth chambers at 10 degrees C, 20 degrees C or 30 degrees C for another 7 d. In all three species the leaf chlorophyll content was positively correlated to temperature, and in E. pellita the highest temperature also resulted in a significant increase in stem biomass. Comprehensive metabolomics was performed using untargeted gas chromatography mass spectrometry (GC-MS) and liquid chromatography (LC)-MS. This approach enabled the comparison of the relative abundance of 88 polar primary metabolites from GC-MS and 625 semi-polar secondary metabolites from LC-MS. Using principal components analysis, a major effect of temperature was observed in each species which was larger than that resulting from the genetic background. Compounds mostly affected by temperature treatment were subsequently selected using partial least squares discriminant analysis and were further identified. These putative annotations indicated that soluble sugars and several polyphenols, including tannins, triterpenes and alkaloids were mostly influenced. PMID- 29247598 TI - Ligustrazine suppresses neuron apoptosis via the Bax/Bcl-2 and caspase-3 pathway in PC12 cells and in rats with vascular dementia. AB - The aim of this study was to examine the comprehensive neuroprotective mechanism of ligustrazine, which is extracted from Ligusticum Chuanxiong Hort., against vascular dementia (VD) in rats and apoptosis in oxygen and glucose deprivation (OGD) PC12 cells. Rats were subjected to bilateral common carotid artery occlusion (BCCAO) surgery and administered ligustrazine intragastrically for 6 weeks. At the end of the experiments, the hippocampal biomarkers brain-derived neurotrophic factor (BDNF), monocyte chemotactic protein 1 (MCP-1), and homocysteine (Hcy) were examined. In experiments in vitro, OGD PC12 cells were treated with ligustrazine for 0.5, 1, 3, 6, 12, or 24 h. The cell-released biomarkers BDNF, MCP-1, and Hcy were examined. Microscopy, acridine orange ethidium bromide (AO/EB) staining, and flow cytometry assays were performed to investigate apoptosis. Cleaved caspase-3, Bcl-2 associated X protein (Bax), and B cell lymphoma 2 (Bcl-2) expression was examined using Western blot assays. The results showed that biomarkers, including MCP-1 and Hcy, were significantly increased in both the in vivo and in vitro models, while the BDNF level was significantly decreased compared with the sham or vehicle models. Microscopy, AO/EB staining, and flow cytometry analysis showed that severe cell damage occurred in OGD PC12 cells, and apoptosis played a major role in this environment. Further Western blot studies showed that the apoptosis-related Bax/Bcl-2 protein ratio and cleaved caspase-3 were significantly increased in the experiment. However, ligustrazine profoundly suppressed the imbalance of these biomarkers, reduced cell damage, decreased the Bax/Bcl-2, and downregulated cleaved caspase-3. Pro- and anti-apoptotic biomarkers of multiple pathways including BDNF, MCP-1, and Hcy played a joint role in triggering the activation of the mitochondria-related Bax/Bcl-2 and caspase-3 apoptosis pathway in VD. Ligustrazine attenuated VD by comprehensively regulating BDNF, MCP-1, and Hcy and inactivating the Bax/Bcl-2 and caspase-3 apoptosis pathway. Our data provide novel insight into ligustrazine, which is a promising neuroprotective agent for VD disease treatment strategies. (c) IUBMB Life, 70(1):60-70, 2018. PMID- 29247599 TI - Sterilization of hydrogels for biomedical applications: A review. AB - Despite the beneficial properties and outstanding potential of hydrogels for biomedical applications, several unmet challenges must be overcome, especially regarding to their known sensitivity to conventional sterilization methods. It is crucial for any biomaterial to withstand an efficient sterilization to obtain approval from regulatory organizations and to safely proceed to clinical trials. Sterility assurance minimizes the incidence of medical device-related infections, which still constitute a major concern in health care. In this review, we provide a detailed and comprehensive description of the published work from the past decade regarding the effects of sterilization on different types of hydrogels for biomedical applications. Advances in hydrogel production methods with simultaneous sterilization are also reported. Terminal sterilization methods can induce negative or positive effects on several material properties (e.g., aspect, size, color, chemical structure, mechanical integrity, and biocompatibility). Due to the complexity of factors involved (e.g., material properties, drug stability, sterilization conditions, and parameters), it is important to note the virtual impossibility of predicting the outcome of sterilization methods to determine a set of universal rules. Each system requires case-by-case testing to select the most suitable, effective method that allows for the main properties to remain unaltered. The impact of sterilization methods on the intrinsic properties of these systems is understudied, and further research is needed. (c) 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2472-2492, 2018. PMID- 29247600 TI - SaCas9 Requires 5'-NNGRRT-3' PAM for Sufficient Cleavage and Possesses Higher Cleavage Activity than SpCas9 or FnCpf1 in Human Cells. AB - CRISPR/Cas9-mediated gene therapy holds great promise for the treatment of human diseases. The protospacer adjacent motif (PAM), the sequence adjacent to the target sequence, is an essential targeting component for the design of CRISPR/Cas9-mediated gene editing. However, currently, very few studies have attempted to directly study the PAM sequence in human cells. To address this issue, the authors develop a dual fluorescence reporter system that could be harnessed for identifying functional PAMs for genome editing endonuclease, including Cas9. With this system, the authors investigate the effects of different PAM sequences for SaCas9, which is small and has the advantage of allowing in vivo genome editing, and found only 5'-NNGRRT-3' PAM could induced sufficient target cleavage with multi-sites. The authors also found SaCas9 possesses higher activity than SpCas9 or FnCpf1 via plasmids (episomal) and chromosomes with integrated eGFP-based comparison. Taken together, the authors show that a dual fluorescence reporter system is a means to identifying a functional PAM and quantitatively comparing the efficiency of different genome editing endonucleases with the similar or identical target sequence in human cells. PMID- 29247601 TI - Designing an Autonomous Integrated Downstream Sequence From a Batch Separation Process - An Industrial Case Study. AB - This work is a proof of concept of how a sequence of industrial batch separation steps together are used to form an integrated autonomous downstream process. The sequence in this case study consisted of an anion chromatography step, virus inactivation and finally a hydrophobic chromatography step. Moving from batch to integrated separation minimizes hold-up times, storage tanks, and required equipment. The conversion from batch to integrated mode is achieved by extracting operating points and separation data from batch chromatograms. The integrated separation process is realized on an AKTA Pure controlled by an open research software called Orbit, making it possible to operate complex process configurations including multiple steps. The results from this case study is the principle and method of the steps taken to automation, achieving a more continuous and efficient downstream process. PMID- 29247602 TI - A systematic review of validated sinus surgery simulators. AB - BACKGROUND: Simulation provides a safe and effective opportunity to develop surgical skills. A variety of endoscopic sinus surgery (ESS) simulators has been described in the literature. Validation of these simulators allows for effective utilisation in training. OBJECTIVE OF REVIEW: To conduct a systematic review of the published literature to analyse the evidence for validated ESS simulation. SEARCH STRATEGY: Pubmed, Embase, Cochrane and Cinahl were searched from inception of the databases to 11 January 2017. EVALUATION METHOD: Twelve thousand five hundred and sixteen articles were retrieved of which 10 112 were screened following the removal of duplicates. Thirty-eight full-text articles were reviewed after meeting search criteria. Evidence of face, content, construct, discriminant and predictive validity was extracted. RESULTS: Twenty articles were included in the analysis describing 12 ESS simulators. Eleven of these simulators had undergone validation: 3 virtual reality, 7 physical bench models and 1 cadaveric simulator. Seven of the simulators were shown to have face validity, 7 had construct validity and 1 had predictive validity. None of the simulators demonstrated discriminate validity. CONCLUSION: This systematic review demonstrates that a number of ESS simulators have been comprehensively validated. Many of the validation processes, however, lack standardisation in outcome reporting, thus limiting a meta-analysis comparison between simulators. PMID- 29247603 TI - On-Line Control of Glucose Concentration in High-Yielding Mammalian Cell Cultures Enabled Through Oxygen Transfer Rate Measurements. AB - Glucose control is vital to ensure consistent growth and protein production in mammalian cell cultures. The typical fed-batch glucose control strategy involving bolus glucose additions based on infrequent off-line daily samples results in cells experiencing significant glucose concentration fluctuations that can influence product quality and growth. This study proposes an on-line method to control and manipulate glucose utilizing readily available process measurements. The method generates a correlation between the cumulative oxygen transfer rate and the cumulative glucose consumed. This correlation generates an on-line prediction of glucose that has been successfully incorporated into a control algorithm manipulating the glucose feed-rate. This advanced process control (APC) strategy enables the glucose concentration to be maintained at an adjustable set point and has been found to significantly reduce the deviation in glucose concentration in comparison to conventional operation. This method has been validated to produce various therapeutic proteins across cell lines with different glucose consumption demands and is successfully demonstrated on micro (15 mL), laboratory (7 L), and pilot (50 L) scale systems. This novel APC strategy is simple to implement and offers the potential to significantly enhance the glucose control strategy for scales spanning micro-scale systems through to full scale industrial bioreactors. PMID- 29247605 TI - Chronic Lead Intoxication From Eating Wild-Harvested Game. AB - BACKGROUND: The purpose of this article is to determine if conversion from eating wild game harvested with lead-based ammunition to nonlead-based ammunition results in lower blood lead levels. Supersonic injection of toxin-leeching frangible projectiles into food is intuitively bad. As much as 95% of the ~13.7 million hunters in the United States choose shrapnel-inducing lead bullets to kill game; in addition, not harvesting meat is an incarcerable crime. A lead ammunition ban on certain federal lands was recently rescinded and the National Rifle Association refutes any risk from eating lead bullet-harvested game. METHODS: A patient subsisting solely on lead-shot meat was converted to non-lead ammunition and his blood lead level tracked. Concomitant with his conversion to nonlead ammunition, a controlled experiment was performed using the patient's bullets to determine his daily lead intake from lead-shot meat. RESULTS: While eating lead-shot meat, the patient was consuming 259.3 +/- 235.6 ug of lead daily and his blood lead level was 74.7 ug/dL. Conversion to nonlead ammunition was associated with a reduced blood lead level. CONCLUSIONS: Unsafe blood lead levels can occur from eating game harvested with lead ammunition. Physicians should warn hunting patients of this potential risk and counsel them about the availability of nonlead ammunition alternatives. PMID- 29247604 TI - Biosynthesis of the Nylon 12 Monomer, omega-Aminododecanoic Acid with Novel CYP153A, AlkJ, and omega-TA Enzymes. AB - Bioplastics are derived from renewable biomass sources, such as vegetable oils, cellulose, and starches. An important and high-performance member of the bioplastic family is Nylon 12. The biosynthesis of omega-amino dodecanoic acid (omega-AmDDA), the monomer of Nylon 12 from vegetable oil derivatives is considered as an alternative to petroleum-based monomer synthesis. In this study, for the production of omega-AmDDA from dodecanoic acid (DDA), the cascade of novel P450 (CYP153A), alcohol dehydrogenase (AlkJ), and omega-transaminase (omega TA) is developed. The regioselective omega-hydroxylation of 1 mM DDA with near complete conversion (>99%) is achieved using a whole-cell biocatalyst co expressing CYP153A, ferredoxin reductase and ferredoxin. When the consecutive biotransformation of omega-hydroxy dodecanoic acid (omega-OHDDA) is carried out using a whole-cell biocatalyst co-expressing AlkJ and omega-TA, 1.8 mM omega OHDDA is converted into omega-AmDDA with 87% conversion in 3 h. Finally, when a one-pot reaction is carried out with 2 mM DDA using both whole-cell systems, 0.6 mM omega-AmDDA is produced after a 5 h reaction. The results demonstrated the scope of the potential cascade reaction of novel CYP153A, AlkJ, and omega-TA for the production of industrially important bioplastic monomers, amino fatty acids, from FFAs. PMID- 29247606 TI - Light-harvesting chlorophyll protein (LHCII) drives electron transfer in semiconductor nanocrystals. AB - Type-II quantum dots (QDs) are capable of light-driven charge separation between their core and the shell structures; however, their light absorption is limited in the longer-wavelength range. Biological light-harvesting complex II (LHCII) efficiently absorbs in the blue and red spectral domains. Therefore, hybrid complexes of these two structures may be promising candidates for photovoltaic applications. Previous measurements had shown that LHCII bound to QD can transfer its excitation energy to the latter, as indicated by the fluorescence emissions of LHCII and QD being quenched and sensitized, respectively. In the presence of methyl viologen (MV), both fluorescence emissions are quenched, indicating an additional electron transfer process from QDs to MV. Transient absorption spectroscopy confirmed this notion and showed that electron transfer from QDs to MV is much faster than fluorescence energy transfer between LHCII and QD. The action spectrum of MV reduction by LHCII-QD complexes reflected the LHCII absorption spectrum, showing that light absorbed by LHCII and transferred to QDs increased the efficiency of MV reduction by QDs. Under continuous illumination, at least 28 turnovers were observed for the MV reduction. Presumably, the holes in QD cores were filled by a reducing agent in the reaction solution or by the dihydrolipoic-acid coating of the QDs. The LHCII-QD construct can be viewed as a simple model of a photosystem with the QD component acting as reaction center. PMID- 29247607 TI - Modifications in routine protocol of RNA isolation can improve quality of RNA purified from adipocytes. AB - Adipose tissue is of interest in the context of its role in the pathogenesis of cardiovascular diseases. Modern experimental techniques require a well-purified RNA, but all the routine protocols for RNA extraction have a number of limitations in case of fatty tissues. Here we described a modified protocol for RNA extraction from human adipocytes based on routine column method. Suggested modifications optimized the sample preparation, lysis and washing lead to enhance RNA purity. We conclude that the current protocol for total RNA purification from adipocytes allows extracting a high-quality RNA devoid of fatty acids, organic solvents and salts contamination. PMID- 29247609 TI - Improved HPLC-method for estimation and correction of amino acid losses during hydrolysis of unknown samples. AB - Amino acid analysis, commonly done by acid hydrolysis of proteins and HPLC analysis, faces one major problem: incomplete hydrolysis of stable amino acids and degradation of unstable amino acids are causing amino acid losses. As a result, amino acid recovery of unknown samples cannot be estimated. Some methods have been reported for correction of these factors in the past. This paper shows an improved and integrated method to overcome this problem by using stillage as an exemplary unknown sample material. Amino acid recovery from an unknown sample can be estimated by standard addition of a known protein. If the sample does not cause matrix effects during amino acid hydrolysis, recoveries of the standard protein are transferable to the sample. If the sample does cause matrix effects correction of amino acid losses can instead be done by determination of hydrolysis kinetics. Therefore, first order kinetics were used for amino acids that undergo degradation during hydrolysis. For all stable amino acids higher order kinetics were used, a novel approach to determine hydrolysis kinetics. The presented method can be a helpful tool for scientists who want to optimize amino acid analysis of a particular biomass substrate. PMID- 29247608 TI - A macrodomain-linked immunosorbent assay (MLISA) for mono-ADP ribosyltransferases. AB - ADP-ribosyltransferases (ARTs) catalyze reversible additions of mono- and poly ADP-ribose onto diverse types of proteins by using nicotinamide adenine dinucleotide (NAD+) as a cosubstrate. In the human ART superfamily, 14 out of 20 members are shown to catalyze endogenous protein mono-ADP-ribosylation and play important roles in regulating various physiological and pathophysiological processes. Identification of new modulators of mono-ARTs can thus potentially lead to discovery of novel therapeutics. In this study, we developed a macrodomain-linked immunosorbent assay (MLISA) for characterizing mono-ARTs. Recombinant macrodomain 2 from poly-ADP-ribose polymerase 14 (PARP14) was generated with a C-terminal human influenza hemagglutinin (HA) tag for detecting mono-ADP-ribosylated proteins. Coupled with an anti-HA secondary antibody, the generated HA-tagged macrodomain 2 reveals high specificity for mono-ADP ribosylation catalyzed by distinct mono-ARTs. Kinetic parameters of PARP15 catalyzed automodification were determined by MLISA and are in good agreement with previous studies. Eight commonly used chemical tools for PARPs were examined by MLISA with PARP15 and PARP14 in 96-well plates and exhibited moderate inhibitory activities for PARP15, consistent with published reports. These results demonstrate that MLISA provides a new and convenient method for quantitative characterization of mono-ART enzymes and may allow identification of potent mono-ART inhibitors in a high-throughput-compatible manner. PMID- 29247610 TI - New limits of sensitivity of site-directed spin labeling electron paramagnetic resonance for membrane proteins. PMID- 29247611 TI - Cobalt and nickel affect the fluidity of negatively-charged biomimetic membranes. AB - Elevated levels of the essential trace metals cobalt and nickel are associated with a variety of toxic effects, which are not well-understood, and may involve interactions with the lipid membrane. Fluidity changes of biomimetic lipid membranes upon exposure to CoCl2 and NiCl2 were studied using the fluorescent probe Laurdan, which senses changes in environment polarity. Liposomes were prepared by extrusion in 20 mM HEPES + 100 mM NaCl at pH 7.4. Additionally, dynamic light scattering was used to monitor metal induced size changes of liposomes composed of: phosphatidic acid (PA), cardiolipin (CL), phosphatidylglycerol (PG), phosphatidylserine (PS), and phosphatidylcholine (PC), with saturated and unsaturated acyl chains. Micromolar concentrations of both metals significantly rigidify negatively-charged liposomes and generally increase the melting temperature. Saturated acyl chains showed stronger metal effects in PS and PG, while no clear acyl chain preference was observed in CL and PA systems. The strength of the effect appears to be influenced greatly by both the head group and acyl chain. The rigidifying effects of cobalt were almost always much larger than those of nickel. In addition, size changes and aggregation by both metals was detected in PS or PA liposomes at molar metal/lipid ratios as low as 1/10. PMID- 29247612 TI - Intestinal alkaline phosphatase ameliorates experimental colitis via toll-like receptor 4-dependent pathway. AB - Intestinal alkaline phosphatase (IAP) is an intestinal brush border enzyme which plays an important role in gut homeostasis and mucosal inflammation. However, the mechanism of the protective effect of IAP is not fully elucidated. The aim of the present study was to evaluate whether the protective effect of IAP on colitis is mediated via the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-kappaB) pathway. For in vitro analysis, peritoneal macrophages from the wild-type (WT) and TLR4-deficient (TLR4-/-) C57BL/6 mice were used. IAP strongly inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) by suppressing the LPS-induced phosphorylation of IkappaBalpha and the DNA-binding activity of NF-kappaB in WT macrophages; however, the inhibitory effects mediated by IAP were reduced in the TLR4-/- macrophages. For in vivo analysis, the protective mechanisms of IAP on dextran sulfate sodium (DSS)-induced colitis were evaluated using WT and TLR4-/- mice. Although oral administration of IAP significantly attenuated the severity of colitis in both preventive and therapeutic models of WT mice, these protective effects were not significant in TLR4-/- mice. When immunohistochemical analysis of IkappaBalpha was performed in the colitic tissues, the inhibitory effects of IAP on IkappaBalpha phosphorylation were also observed in the colon of WT mice, but these effects decreased in the colon of TLR4-/- mice. In conclusion, the protective effects of IAP on colitis were mediated via the TLR4/NF-kappaB pathway. These results of this study shall be helpful in tailoring treatment against colitis using IAP. PMID- 29247613 TI - Lariciresinol induces apoptosis in HepG2 cells via mitochondrial-mediated apoptosis pathway. AB - Lariciresinol (LA) is one of the main active ingredients in many traditional medicinal plants such as Patrinia, and has the role of anti-liver cancer. However, the precise mechanisms are unclear. This study investigated the molecular mechanisms of LA against HepG2 cells. LA anti-tumor activity was assessed with the CCK-8, Ki-67, and immunofluorescence staining. Cells apoptotic ratio was evaluated by Annexin V/PI double-staining assay. A proteomic approach was used to identify differentially expressed proteins after LA treatment. JC-1 staining was carried out to detect the mitochondrial membrane potential (DeltaPsim), and the Western blot analysis was used to analyse the apoptosis associated proteins. Our results suggested that LA significantly suppressed the viability of HepG2 cells. The CCK-8 and Ki-67 expression indicated dose-dependent decreases in cell proliferation. Flow cytometry analysis showed that LA exhibited a apoptosis-inducing effect. The proteomic study observed the presence of apoptosis-associated proteins and mitochondrial dysfunction in HepG2 cells after LA-treatment. Further analysis showed that LA could trigger the mitochondrial mediated apoptosis pathway, based on a decrease in DeltaPsim; deliver of cytochrome c; activation of caspase-9/-3 and poly(ADP-ribose) polymerase; and decrease of the proportion of Bcl-2/Bax. Collectively, our studies found that LA exhibits significant cytotoxic effects by inhibiting cell proliferation, inducing apoptosis, possibly via activation of the mitochondrial-mediated apoptosis pathway. PMID- 29247614 TI - Mechanism implicated in the anti-allodynic and anti-hyperalgesic effects induced by the activation of heme oxygenase 1/carbon monoxide signaling pathway in the central nervous system of mice with neuropathic pain. AB - The administration of a carbon monoxide-releasing compound (tricarbonyldichlororuthenium(II)dimer, CORM-2) or an heme oxygenase 1 (HO-1) inductor (cobalt protoporphyrin IX, CoPP) exerts potent antinociceptive effects during chronic pain, but their actions in the central nervous system of animals with neuropathic pain have not been evaluated. Our objective is to investigate the effects of these treatments on the oxidative, inflammatory and molecular changes induced by sciatic nerve injury in several brain areas. In male C57BL6 mice with neuropathic pain induced by the chronic constriction of sciatic nerve (CCI), we evaluated the effects of CORM-2 and CoPP on the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1 and NAD(P)H:quinone oxidoreductase-1 (NQO1), the microglial marker (CD11b/c), and the mitogen activated protein kinases (MAPK) (JNK, ERK1/2 and P38) in the amygdala, prefrontal cortex, hippocampus, hypothalamus and spinal cord, by using western blot assay. Our results showed that, although CORM-2 and CoPP did not alter the protein levels of Nrf2 and NQO1in none of the areas evaluated, both treatments increased the HO-1 expression and inhibited the overexpression of CD11b/c and/or MAPK phosphorylation caused by nerve injury in the spinal cord, hippocampus and amygdala and/or prefrontal cortex. This study demonstrates that treatment with CORM-2 and/or CoPP further to exert potent anti-allodynic and anti-hyperalgesic actions also produce anti-oxidative and anti-inflammatory effects and inhibit MAPK activated by sciatic nerve injury in specific brain areas. In conclusion, these data reveal new mechanism of action of CORM-2 and CoPP in the central nervous system of animals with persistent neuropathic pain. PMID- 29247615 TI - How to Adjust Neochordae Length Accurately in Degenerative Mitral Regurgitation. AB - We describe a simple technique for the accurate adjustment of polytetrafluoroethylene neochordae length in degenerative mitral regurgitation using the annuloplasty ring's own suture as a reference instead of using sophisticated or less precise maneuvers. Two threads of the annuloplasty ring suture are placed at the level of the mitral valve annulus plane to be used as a reference to tie the neochordae. PMID- 29247616 TI - The BRICS (Bronchiectasis Radiologically Indexed CT Score): A Multicenter Study Score for Use in Idiopathic and Postinfective Bronchiectasis. AB - OBJECTIVES: The goal of this study was to develop a simplified radiological score that could assess clinical disease severity in bronchiectasis. METHODS: The Bronchiectasis Radiologically Indexed CT Score (BRICS) was devised based on a multivariable analysis of the Bhalla score and its ability in predicting clinical parameters of severity. The score was then externally validated in six centers in 302 patients. RESULTS: A total of 184 high-resolution CT scans were scored for the validation cohort. In a multiple logistic regression model, disease severity markers significantly associated with the Bhalla score were percent predicted FEV1, sputum purulence, and exacerbations requiring hospital admission. Components of the Bhalla score that were significantly associated with the disease severity markers were bronchial dilatation and number of bronchopulmonary segments with emphysema. The BRICS was developed with these two parameters. The receiver operating-characteristic curve values for BRICS in the derivation cohort were 0.79 for percent predicted FEV1, 0.71 for sputum purulence, and 0.75 for hospital admissions per year; these values were 0.81, 0.70, and 0.70, respectively, in the validation cohort. Sputum free neutrophil elastase activity was significantly elevated in the group with emphysema on CT imaging. CONCLUSIONS: A simplified CT scoring system can be used as an adjunct to clinical parameters to predict disease severity in patients with idiopathic and postinfective bronchiectasis. PMID- 29247617 TI - Tinea capitis-like infection caused by Rhodotorula mucilaginosa in a shelter for African Refugee Children in Northern Israel. AB - Rhodotorula is a genus of unicellular pigmented yeasts, part of the division Basidiomycota. In this article, we report three cases of refugee children in a day care shelter in northern Israel who were clinically diagnosed and treated empirically as with ringworm infection but with clean and exclusive growth of Rhodotorula mucilaginosa in repeated cultures of several skin samples. Skin infections caused by this yeast are rare and there are few reports in the literature, mainly in patients who are immunocompromised. Here we report an infectious process of the scalp in immunocompetent children, caused by Rhodotorula mucilaginosa mimicking tinea capitis. PMID- 29247618 TI - Malaria control in a tribal area of central India using existing tools. AB - Malaria is difficult to control in central India because of geographical terrain, efficient vectors, and perennial transmission of Plasmodium falciparum and socio cultural practices of ethnic tribes. The objective was to develop a model to prevent and control malaria in hard to reach areas using existing tools. Baigachak (Tribe population 31,900) situated in Dindori district was undertaken for this study. Intervention measures used are indoor residual spray (IRS), long lasting insecticide treated bed nets (LLINs), prompt diagnosis and treatment along with intensive Information, Education and Communication (IEC) involving school children as agent of change. Door to door rapid fever surveys were carried out in the study area from 2009 to 14 and finger prick blood smears were made from all fever cases and examined under microscope. Mosquitoes were assayed for the presence of sporozoites by enzyme-linked immunosorbent assay (ELISA) technique and sibling species by polymerase chain reaction (PCR). There are two highly efficient vectors i.e. Anopheles culicifacies and An. fluviatilis. In monsoon season of 2009, the man hour density for An. culicifacies was 36.2 which declined to 10.9 during monsoon season of 2010-14 (t = 6.52; p < 0.0001). Epidemiological results revealed that malaria positivity was declined from 27% in 2009-3% in 2014 (Trend chi2 = 57.21; p < 0.0001) and P. falciparum declined from 23.6 to 2.4% (Trend chi2 = 48.33; p < 0.0001). Spleen rate was declined from 47% in 2009-5% in 2014 (chi2 for trend = 6.1; p = 0.0135). Baigachak has achieved a remarkable 89% reduction in malaria. This study confirms that the control strategies undertaken in this study are useful and should be extended at multiple sites for further validation. PMID- 29247619 TI - A new Drosophila model of Ubiquilin knockdown shows the effect of impaired proteostasis on locomotive and learning abilities. AB - Ubiquilin (UBQLN) plays a crucial role in cellular proteostasis through its involvement in the ubiquitin proteasome system and autophagy. Mutations in the UBQLN2 gene have been implicated in amyotrophic lateral sclerosis (ALS) and ALS with frontotemporal lobar dementia (ALS/FTLD). Previous studies reported a key role for UBQLN in Alzheimer's disease (AD); however, the mechanistic involvement of UBQLN in other neurodegenerative diseases remains unclear. The genome of Drosophila contains a single UBQLN homolog (dUbqn) that shows high similarity to UBQLN1 and UBQLN2; therefore, the fly is a useful model for characterizing the role of UBQLN in vivo in neurological disorders affecting locomotion and learning abilities. We herein performed a phenotypic and molecular characterization of diverse dUbqn RNAi lines. We found that the depletion of dUbqn induced the accumulation of polyubiquitinated proteins and caused morphological defects in various tissues. Our results showed that structural defects in larval neuromuscular junctions, abdominal neuromeres, and mushroom bodies correlated with limited abilities in locomotion, learning, and memory. These results contribute to our understanding of the impact of impaired proteostasis in neurodegenerative diseases and provide a useful Drosophila model for the development of promising therapies for ALS and FTLD. PMID- 29247620 TI - Protein kinase D regulates metabolism and growth by controlling secretion of insulin like peptide. AB - Mechanisms coupling growth and metabolism are conserved in Drosophila and mammals. In metazoans, such coupling is achieved across tissue scales through the regulated secretion of chemical messengers such as insulin that control the metabolism and growth of cells. Although the regulated secretion of Insulin like peptide (dILP) is key to normal growth and metabolism in Drosophila, the sub cellular mechanisms that regulate dILP release remain poorly understood. We find that reduced function of the only protein kinase D in Drosophila (dPKDH) results in delayed larval growth and development associated with abnormal sugar and lipid metabolism, reduced insulin signalling and accumulation of dILP2 in the neurosecretory IPCs of the larval brain. These phenotypes are rescued by tissue selective reconstitution of dPKD in the neurosecretory cells of dPKDH. Selective downregulation of dPKD activity in the neurosecretory IPCs phenocopies the growth defects, metabolic abnormalities and dILP2 accumulation seen in dPKDH. Thus, dPKD mediated secretion of dILP2 from neurosecretory cells during development is necessary for normal larval growth. PMID- 29247621 TI - Peripheral Ameloblastoma: A Study of 18 Cases and Usage of Ber-EP4 Immunohistochemistry to Rule out a Diagnosis of Intraoral Basal Cell Carcinoma. AB - PURPOSE: Peripheral ameloblastoma (PA) is a rare odontogenic tumor arising in the mucosa of tooth-bearing areas of the jaws that typically shows no radiographic evidence of bone involvement. It bears close histologic resemblance to intraoral basal cell carcinoma (IOBCC), an extremely rare entity. In our experience from previous published data, 3 cases of IOBCC were initially misdiagnosed as PA and were later differentiated from PA on the basis of Ber-EP4 protein expression. This unusual but significant experience set the premise for us to rule out a diagnosis of IOBCC by evaluating Ber-EP4 expression in all previously diagnosed cases of PA from the University of Florida Oral Pathology (UFOP) biopsy service archives. MATERIALS AND METHODS: With institutional review board approval, 18 cases of PA were retrieved from the UFOP biopsy service archives. We describe the clinicopathologic features of these cases and discuss the Ber-EP4 immunohistochemical staining performed to rule out a potential diagnosis of IOBCC. In addition, we conducted calretinin and epithelial membrane antigen staining for 1 case of PA. RESULTS: Most PAs presented in the lingual gingiva of the posterior mandible. Men were affected twice as often as women, and the average age at the diagnosis was 59 +/- 21.5 years. Of the 18 lesions, 13 showed no reactivity to Ber-EP4, 4 displayed patchy membranous immunoreactivity, and 1 demonstrated nonspecific reactivity. CONCLUSIONS: We have concluded that all cases of PA that present with histologic overlap with basal cell carcinoma, especially those from incisional biopsies, those that appear significantly infiltrative, and those that appear ulcerated and/or demonstrate recurrence should be evaluated with Ber-EP4 to rule out IOBCC. PMID- 29247622 TI - Discontinuous Versus In-Continuity Neck Dissection in Squamous Cell Carcinoma of the Tongue and Floor of the Mouth: Comparing the Rates of Locoregional Recurrence. AB - PURPOSE: To date, consensus has not been reached on which treatment modality, that is, in-continuity neck dissection or discontinuous neck dissection, is more appropriate for managing patients with squamous cell carcinoma (SCC) of the tongue and floor of the mouth. This study aimed to perform a meta-analysis to compare discontinuous neck dissection with in-continuity neck dissection as a treatment modality for SCC of the tongue and floor of the mouth. MATERIALS AND METHODS: The PubMed, Web of Science, China National Knowledge Infrastructure, and Wanfang databases were searched for articles that compared discontinuous neck dissection with in-continuity neck dissection in SCC of the tongue and floor of the mouth until March 1, 2017. The predictor variable was whether discontinuous neck dissection or in-continuity neck dissection was performed in each group. The primary outcome variable was the incidence of locoregional recurrence. Two authors individually extracted the data and assessed the study quality. The meta analysis was performed using Stata (version 13.0; StataCorp, College Station, TX). RESULTS: We included 8 studies with 796 patients in our meta-analysis. The results showed that in-continuity neck dissection had a statistically significantly lower incidence of locoregional recurrence than discontinuous neck dissection (random-effects model: relative risk, 0.459; 95% confidence interval, 0.240 to 0.877; P = .019). Because significant heterogeneity among studies (I2 = 74.5%, P < .001) was found in the heterogeneity evaluation, a separate analysis was performed. However, the results still showed that in-continuity neck dissection had a statistically significantly lower rate of locoregional recurrence than discontinuous neck dissection in patients with T2 and T3 SCC of the tongue and floor of the mouth (fixed-effects model: relative risk, 0.281; 95% confidence interval, 0.183 to 0.433; P < .001). CONCLUSIONS: Compared with discontinuous neck dissection, in-continuity neck dissection can significantly reduce the rate of locoregional recurrence in patients with SCC of the tongue and floor of the mouth. PMID- 29247623 TI - Effect of Alendronate on Bone Microarchitecture in Irradiated Rats With Osteoporosis: Micro-CT and Histomorphometric Analysis. AB - PURPOSE: The aim of the present study was to evaluate the effect of alendronate (ALN) on the bone microarchitecture of irradiated rats with estrogen deficiency, using microcomputed tomography (micro-CT) and histomorphometric analysis. MATERIALS AND METHODS: Forty adult Wistar rats were subjected to ovariectomy and randomly divided into the following groups: control (CON), ALN, irradiated (IRR), and ALN/irradiated (ALN/IRR). Approximately 50 days after ovariectomy, the hind limbs of the rats in the IRR and ALN/IRR groups were irradiated with 15 Gy of x radiation. The rats were euthanized 7 and 30 days after irradiation. The bone microarchitecture was analyzed using micro-CT and histomorphometry. The bone microarchitecture was evaluated using the Mann-Whitney U test, analysis of variance, and the post hoc Tukey test, with statistical significance set at 5%. RESULTS: Irradiation had increased the thickness of the cortical bone at 7 days (P < .05) and also decreased the number of trabeculae per unit length and increased the average distance between the trabeculae (P < .05) at 30 days. ALN inhibited the deleterious effect of x-radiation, preventing the distance between the trabeculae from increasing and the number of trabeculae per unit length from decreasing (P < .05). CONCLUSIONS: The present results have demonstrated that the initial effect of ALN could be positive, because it checked the deleterious action in the bone tissue submitted to x-radiation. PMID- 29247624 TI - Juxta-Apical Radiolucency: Prevalence, Characterization, and Association With the Third Molar Status. AB - PURPOSE: This study aimed to investigate the prevalence of juxta-apical radiolucency (JAR), assessing its association with third molar status and describing its radiologic features through panoramic radiography. MATERIALS AND METHODS: We evaluated 1,050 radiographs (1,830 third molars) for the presence of JAR. The JAR and control groups were classified according to the third molar's angulation, impaction, and root development. The presence of radiographic signs of proximity between the mandibular canal and third molar and the imaging features of JAR also were recorded. RESULTS: JAR was identified in 116 patients (11%) and 130 third molars (7.1%), being significantly associated with female patients and with the second and third decades of life. There also was an association with teeth with a vertical angulation and complete root formation. Radiographic signs of proximity to the mandibular canal were absent in 66.2% of JAR cases. In most cases, there was lamina dura in the juxta-apical area that appeared to overlap the mandibular canal and to have a cortical outline. CONCLUSIONS: JAR is not a rare imaging finding. Given its possible relationship with nerve injuries and its differential diagnostic possibilities, knowing the characteristics of JAR is important to assist professionals in treatment planning and making the correct diagnosis. PMID- 29247625 TI - Preliminary Psychometric Evaluation of the Brachial Assessment Tool Part 2: Construct Validity and Responsiveness. AB - OBJECTIVES: To evaluate construct validity and responsiveness of the Brachial Assessment Tool (BrAT), a new patient-reported outcome measure for people with traumatic brachial plexus injury (BPI), and to compare it to the Disabilities of the Arm, Shoulder and Hand (DASH) and the Upper Extremity Functional Index (UEFI). DESIGN: Cross-sectional study. SETTING: Outpatient clinics. PARTICIPANTS: Adults (N=29; age range, 20-69y) with confirmed traumatic BPI. INTERVENTIONS: Participants completed the BrAT 3 times over an 18-month period together with 16 DASH activity items and the UEFI. Evaluations were undertaken of construct validity, known-groups validity, 1-way repeated analysis of variance, and effect size. MAIN OUTCOME MEASURES: BrAT, DASH, and UEFI. RESULTS: The BrAT demonstrated a moderate to low correlation with the DASH activity items (<0.7) and a large correlation with the UEFI (>0.7). According to known-groups validity, only the BrAT was able to discriminate between people who stated they could use their hand versus those who were unable to use their hand to perform activities. All measures indicated a significant effect for time with the exception of BrAT subscale 1. The effect size was highest for the BrAT but lower than expected (BrAT, .52-.40; DASH, .15; UEFI, .36). CONCLUSIONS: These preliminary findings support the BrAT as a valid and responsive patient-reported outcome measure for adults with traumatic BPI. The BrAT activity items appear to be more targeted than the DASH or UEFI particularly for people with more severe BPI. The BrAT also appears to be measuring a different activity construct than the DASH and the UEFI. Further work is required to confirm these results with larger sample sizes. PMID- 29247626 TI - Low-Frequency Pulsed Current Versus Kilohertz-Frequency Alternating Current: A Scoping Literature Review. AB - OBJECTIVES: To compare the effectiveness of low-frequency pulsed current versus kilohertz-frequency alternating current in terms of evoked force, discomfort level, current intensity, and muscle fatigability; to discuss the physiological mechanisms of each neuromuscular electrical stimulation type; and to determine if kilohertz-frequency alternating current is better than low-frequency pulsed current for clinical treatment. DATA SOURCES: Articles were obtained from PubMed, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, MEDLINE, and SPORTSDiscus databases using the terms Russian current or kilohertz current or alternating current or pulsed current or Aussie current and torque or discomfort or fatigue or current intensity, and through citation tracking up to July 2017. STUDY SELECTION: Two independent reviewers selected studies comparing the use of the 2 neuromuscular electrical stimulation currents. Studies describing maximal current intensity tolerated and the main effects of the 2 different current types on discomfort, muscle force, and fatigability were independently reviewed. DATA EXTRACTION: Data were systematized according to (1) methodology; (2) electrical current characteristics; and (3) outcomes on discomfort level, evoked force, current intensity, and muscle fatigability. DATA SYNTHESIS: The search revealed 15 articles comparing the 2 current types. Kilohertz-frequency alternated current generated equal or less force, similar discomfort, similar current intensity for maximal tolerated neuromuscular electrical stimulation, and more fatigue compared with low-frequency pulsed current. Similar submaximal levels of evoked force revealed higher discomfort and current intensity for kilohertz-frequency alternated current compared with low-frequency pulsed current. CONCLUSIONS: Available evidence does not support the idea that kilohertz-frequency alternated current is better than low-frequency pulsed current for strength training and rehabilitation. PMID- 29247627 TI - Evaluation of Cognitive Behavioral Interventions and Psychoeducation Implemented by Rehabilitation Specialists to Treat Fear-Avoidance Beliefs in Patients With Low Back Pain: A Systematic Review. AB - OBJECTIVES: To systematically locate, critically appraise, and synthesize the available evidence regarding the effectiveness of cognitive behavioral therapies (CBTs) and psychoeducation that can be implemented by rehabilitation specialists to treat fear-avoidance beliefs in patients with acute, subacute, and chronic low back pain (LBP). DATA SOURCES: Electronic databases (CINAHL, PubMed, Psychology and Behavior Sciences Collection, SPORTDiscus, PsycINFO) were searched from inception to September 2017. STUDY SELECTION: Assessment of methodological quality was completed using the Physiotherapy Evidence Database (PEDro) scale. The Strength of Recommendation Taxonomy was used to evaluate the quality of evidence. DATA EXTRACTION: Study sample, subject demographics, CBT and/or psychoeducation intervention details, data collection time points, outcome assessments, statistical analysis, results, and conclusions were extracted from each study. In addition, effect sizes were calculated. DATA SYNTHESIS: Five high quality studies (PEDro >=6) were included. All included studies evaluated fear avoidance beliefs. CBTs and psychoeducation strategies designed to target patient specific fears demonstrated clinically meaningful results, while psychoeducation methodologies were not as effective. CONCLUSIONS: There is inconsistent, patient oriented evidence (grade B) to support the use of CBTs and/or psychoeducation strategies by rehabilitation specialists to treat fear-avoidance beliefs. Patient centered and personalized CBTs were most effective to treat these psychosocial factors in patients with LBP when compared with a control treatment. PMID- 29247628 TI - Racial Differences in Weight Gain: A 5-Year Longitudinal Study of Persons With Spinal Cord Injury. AB - OBJECTIVE: To assess racial differences in body mass index (BMI) change over 5 years among people with spinal cord injury (SCI). DESIGN: Multicenter longitudinal study. SETTING: Spinal Cord Injury Model Systems centers. PARTICIPANTS: Individuals (N=437; 313 non-Hispanic white, 81 non-Hispanic black, and 43 Hispanic; 335 men; mean age, 41.3+/-13.5y) who incurred an SCI from 1974 to 2010 and completed 2 follow-up assessments within 5 years between October 1, 2006 and September 18, 2015 (mean duration of injury, 9.1+/-9.6y at the start of the 5-year follow-up). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: BMI (in kilograms per meters squared). RESULTS: The mean BMI of 437 participants increased from 26.4+/-6.3 to 27.0+/-6.4kg/m2 over 5 years (P=.002). The greatest increase was noted for Hispanics (2.0+/-5.7kg/m2; P=.02), followed by non Hispanic whites (0.6+/-3.9kg/m2; P=.01) and non-Hispanic blacks (0.01+/-3.7kg/m2; P>.99). The differences in BMI increase across racial groups were significant (P=.03) in those with paraplegia (American Spinal Injury Association Impairment Scale A, B or C), those who were underweight or of normal weight at baseline, and those within 10 years of their injury. Such racial differences remained significant after taking into account demographic and injury characteristics. CONCLUSIONS: Our study findings provide a foundation for future research to explore risk and protective factors that contribute to racial differences in weight gain after SCI, which help alert health care professionals to a high-risk group for obesity prevention and management. PMID- 29247629 TI - Anxiolytic- and antidepressant-like actions of Urocortin 2 and its fragments in mice. AB - The aim of the present study was to investigate the potential anxiolytic- and antidepressant-like actions of Urocortin 2 (Ucn2) and its two fragments, Ucn2 (1 21) and Ucn2 (22-38), in mice, in an attempt to identify the biologically active sequence of this 38 amino acid neuropeptide. In this purpose, male C57BL/6 mice were treated intracerebroventricularly (icv) with 0.125, 0.25, 0.5 and 1 ug/2 ul of Ucn2, Ucn2 (1-21) or Ucn2 (22-38). After 30 min, the mice were evaluated in an elevated plus-maze test and a forced swim test for anxiety- and depression-like behavior, respectively. Each test lasted 5 min. Ucn2 at dose of 0.25 ug/2 ul and Ucn2 (1-21) at dose of 0.125 ug/2 ul, but not Ucn2 (22-38), increased significantly the number of entries into and the time spent in the open-arms, without influencing the total number of entries. In parallel, the same doses of Ucn2 and Ucn2 (1-21), but not Ucn2 (22-38), increased significantly the climbing and the swimming activity, while decreasing significantly the time of immobility. In addition, Ucn2 at doses of 0.125 ug/2 ul and 0.5 ug/2 ul decreased significantly the time of immobility, but they did not change the other parameters. The present study demonstrates that Ucn2 exerts anxiolytic- and antidepressant-like effects in C57BL/6 mice, which are mediated by the N terminal, but not the C-terminal fragment of the peptide. The establishment of the smallest active sequence by further fragmentation of Ucn2 (1-21) may allow the synthesis of new anxiolytic and antidepressant drugs. PMID- 29247631 TI - The effects of trait impulsivity on proactive and reactive interference control. AB - The current study used event-related brain potentials (ERPs) to explore whether self-reported trait impulsivity in healthy individuals might be differentially related to proactive and reactive interference control. Participants with high and low impulsivity (HI and LI, respectively) performed a modified version of the prime-target interference task. Proactive interference control was induced in the mostly incongruent (MI) context and reactive interference control was induced in the mostly congruent (MC) context. Although the behavioral data revealed no difference between HI and LI individuals in terms of the interference effects (incongruent - congruent) under both contexts, the ERP results showed that impulsivity has a different influence on the interference effects under different task contexts. In the MC context, the interference effects on the medial frontal negativity (MFN) and the negative sustained potential (N-SP) were greater, while that on the positive sustained potential (P-SP) were smaller in the HI compared to those in the LI group. This suggests that high levels of impulsivity might be associated with a reduced efficiency of the processes supporting reactive control to resolve interference when interference is not expected. In contrast, the three ERP indices (MFN, P-SP, and N-SP) of interference processing in the MI context were insensitive to variations in impulsivity. This suggests that HI individuals might be as effective as LI individuals in recruiting proactive control for sustained active maintenance of task goals to anticipate and prevent interference throughout the experimental blocks where interference occurs frequently. In conclusion, these results indicate that impulsivity has a more negative influence on reactive interference control than on proactive interference control. PMID- 29247630 TI - Effects of repetitive transcranial magnetic stimulation (rTMS) on attribution of movement to ambiguous stimuli and EEG mu suppression. AB - Recent research suggests that attributing human movement to ambiguous and static Rorschach stimuli (M responses) is associated with EEG mu suppression, and that disrupting the left inferior gyrus (LIFG; a putative area implicated in mirroring activity) decreases the tendency to see human movement when exposed to the Rorschach ambiguous stimuli. The current study aimed to test whether disrupting the LIFG via repetitive transcranial stimulation (rTMS) would decrease both the number of human movement attributions and EEG mu suppression. Each participant was exposed to the Rorschach stimuli twice, i.e., during a baseline condition (without rTMS but with EEG recording) and soon after rTMS (TMS condition with EEG recording). Experimental group (N = 15) was stimulated over the LIFG, while the control group (N = 13) was stimulated over the Vertex. As expected, disrupting the LIFG but not Vertex, decreased the number of M attributions provided by the participants exposed to the Rorschach stimuli, with a significant interaction effect. Unexpectedly, however, rTMS did not significantly influence EEG mu suppression. PMID- 29247632 TI - A nomogram for predicting prognostic value of inflammatory biomarkers in patients with acute-on-chronic liver failure. AB - BACKGROUND: Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) in china is a critical clinical syndrome with a high short-term mortality. This study aimed to construct and validate a model for neutrophil to lymphocyte ratio (NLR)-based nomogram for 3-month mortality estimation for patients with ACLF. METHODS: The nomogram was based on a retrospectively study of 96 patients with ACLF. The predictive accuracy and discriminative ability of nomogram were evaluated by a concordance index (C-index), and calibration curve, comparing with model for end-stage liver disease (MELD) score. The results were validated using bootstrap resampling and an external cohort of 88 patients. RESULTS: A total of 184 patients with ACLF were enrolled, with 3-month mortality of 40.76%. The cut off value for NLR was 5.7 using X-tile program. Patients with NLR>5.7 had significantly higher mortality (p<0.001). On multivariate analysis of the training cohort, independent factors for survival were age, NLR and total bilirubin, which were all selected into the nomogram. The calibration curve for probability of survival showed optimal agreement between prediction by nomogram and actual observation. The C-index of nomogram was higher than that of MELD score for predicting survival (0.72 vs 0.56). The results were confirmed in validation cohort. CONCLUSIONS: The proposed nomogram with NLR resulted in more accurate prognostic prediction for patients with HBV-related ACLF. PMID- 29247633 TI - Relationships of kidney injury molecule-1 with renal function and cardiovascular risk factors in the general population. AB - BACKGROUND: Kidney injury molecule-1 (KIM-1) has been associated with kidney damage in patients with preexisting renal disease. However, little is known about the relationships of KIM-1 with renal function and cardiovascular risk factors in healthy individuals from the general population. METHODS: Healthy individuals aged 25-41years were enrolled in a population-based study. Main exclusion criteria were a BMI >35kg/m2, preexisting kidney disease or established cardiovascular disease. KIM-1 was measured from frozen plasma samples using a high-sensitivity assay. Multivariable linear regression models were constructed to assess the relationships of KIM-1 with renal function and various cardiovascular risk factors. RESULTS: We included 2060 individuals (47% men, median (interquartile range) age: 37 (31-40) years) in this analysis. Median KIM 1 levels were 82.5 (IQR 59.4-112.7) pg/ml. We found no significant relationship of KIM-1 with creatinine (adjusted beta-coefficient (95% confidence interval) 0.0005 (-0.002; 0.003), p=0.61) and cystatin C (-0.02 (-0.21; 0.17), p=0.84). There were significant linear relationships of log-transformed KIM-1 with systolic blood pressure (adjusted beta-coefficient (95% confidence interval) 0.07 (0.04; 0.09), p<0.0001), diastolic blood pressure (0.04 (0.02; 0.07), p=0.001), low-density lipoprotein cholesterol (0.09 (0.06; 0.11), p<0.0001), high-density lipoprotein cholesterol (0.07 (0.05; 0.1), p<0.0001), high-sensitivity C-reactive protein (0.05 (0.03; 0.07), p<0.0001), age (0.09 (0.07; 0.11), p<0.0001), BMI (0.04 (0.01; 0.06), p=0.005) and current smoking (0.12 (0.07; 0.17), p<0.0001). CONCLUSION: Among healthy adults from the general population, plasma levels of KIM-1 were not associated with renal function but were independently related to multiple cardiovascular risk factors. PMID- 29247634 TI - Comparison of Single Nucleotide Polymorphism genotyping of CYP2C19 by Loop mediated isothermal amplification and real-time PCR melting curve analysis. AB - BACKGROUND: CYP2C19, a member of cytochrome P450 enzymes, is involved in various drug metabolisms, such as Clopidogrel. Common Single Nucleotide Polymorphisms (SNPs) of CYP2C19 gene, CYP2C19*2 and CYP2C19*3, are liable for the poor metabolism of Clopidogrel. It is crucial to identify poor metabolizers for alternative treatment as poor metabolism of Clopidogrel has been shown to correlate with worse clinical outcome in acute coronary syndrome (ACS) patients. METHOD: A genotyping method, Loop-mediated isothermal amplification (LAMP) was employed in this study. CYP2C19*2 and CYP2C19*3 were adapted from Iwasaki M. et al. with modifications in the reaction mixtures and end-point detection method where simpler visual detection using SYBR(r) Safe was employed instead of a more technical and equipment demanding real-time PCR. Real-time PCR melting curve analysis is a common method for SNPs analysis and hence chosen as a reference for results obtained from the LAMP assay. RESULTS: The CYP2C19-LAMP assay successfully detected CYP2C19*2 and CYPC19*3 mutants. The typing results of CYP2C19-LAMP assay, performed in triplicates, were concordant with the real-time PCR melting curve analysis results. CONCLUSION: CYP2C19-LAMP assay using SYBR(r) Safe dye for visual detection of end-point result is a simple, rapid and cost effective method for CYP2C19 genotyping. PMID- 29247635 TI - Trichomonas vaginalis is most frequently detected in women at the age of peri /premenopause: an unusual pattern for a sexually transmitted pathogen. AB - BACKGROUND: Trichomonas vaginalis is the most common nonviral sexually transmitted infection. However, because it is not a reportable disease in the United States, there is limited information on the age of infected individuals and their geographic distribution. OBJECTIVE: The purpose of this study was to evaluate the detection rates of T vaginalis infection compared with Chlamydia trachomatis by age and state in a commercial laboratory setting. STUDY DESIGN: Quantitative real-time polymerase chain reactions were used to detect the presence of T vaginalis and C trachomatis in cervicovaginal samples that were obtained during gynecologic examinations. A total of 1,554,966 and 1,999,077 samples from females 10-79 years old were analyzed retrospectively for the presence of T vaginalis and C trachomatis, respectively. RESULTS: The highest detection rate of an infection with T vaginalis was ages 47-53 years. For C trachomatis, the highest detection rate was ages 14-20 years. T vaginalis detection rate distribution by age shows a bimodal pattern with first peak at ages 21-22 years (4.0-4.1%) and a higher second peak at ages 48-51 years (5.4 5.8%). C trachomatis prevalence distribution by age shows a maximum peak of 8.6% at age 17 years and a rapid decline thereafter. In general, the detection rates of both pathogens were higher in the southeast and in states along the Mississippi River Valley than in other parts of the country. A nucleotide polymorphism associated with T vaginalis metronidazole resistance (ntr6TVK80STOP) was not associated with age and was found most frequently in specimens from New Mexico and Vermont. CONCLUSIONS: The detection rate of T vaginalis does not appear to decrease with age as observed for C trachomatis and reaches maximum rates in women 48-51 years old. The geographic distribution of T vaginalis appears to be broadly similar to that of other sexually transmitted diseases. The ntr6TVK80STOP polymorphism did not have a specific association with age or geography. PMID- 29247636 TI - A randomized controlled trial of screening and brief interventions for substance misuse in reproductive health. AB - BACKGROUND: Screening, brief intervention, and referral to treatment may reduce substance misuse but has received minimal study among women who are treated in reproductive health settings. OBJECTIVE: The purpose of this study was to determine whether "screening, brief intervention and referral to treatment" that is delivered either electronically or by clinician are more effective than enhanced usual care in decreasing days of primary substance use. STUDY DESIGN: Women from 2 reproductive centers who smoked cigarettes or misused alcohol, illicit drugs, or prescription medication were allocated randomly to "screening, brief intervention and referral to treatment" delivered electronically or by clinician or to enhanced usual care. Assessments were completed at baseline and at 1-, 3-, and 6-months after a baseline has been established. Coprimary outcomes were days/months of primary substance use and postintervention treatment use. A sample size of 660 women was planned; randomization was stratified by primary substance use and pregnancy status. "Screening, brief intervention and referral to treatment" groups were compared with enhanced usual care groups with the use of generalized estimation equations, and effect sizes were calculated with the use of Cohen's d. RESULTS: Between September 2011 and January 2015, women were assigned randomly to a group: 143 women (16.8% pregnant) in the electronic delivered "screening, brief intervention and referral to treatment" group, 145 women (18.6% pregnant) in the clinician-delivered "screening, brief intervention and referral to treatment" group, and 151 women (19.2% pregnant) in the enhanced usual care group; the retention was >84%. Based on the generalized estimating equations model, predicted mean days per month of use at baseline for primary substance were 23.9 days (95% confidence interval, 22.4-25.5) for the electronic delivered group, 22.8 days (95% confidence interval, 21.4-24.3) for the clinician delivered group, and 23.5 days (95% confidence interval, 22.2, 24.9) for enhanced usual care, which respectively declined to 20.5 days (95% confidence interval, 19.0-22.2), 19.8 days (95% confidence interval,18.5-21.3), and 21.9 days (95% confidence interval, 20.7-23.1) at 1 month; 16.9 days (95% confidence interval, 15.0-19.0), 16.6 days (95% confidence interval, 14.8-18.6), and 19.5 days (95% confidence interval, 18.1-21.1) at 3 months; and 16.3 days (95% confidence interval, 14.3-18.7), 16.3 days (95% confidence interval, 14.4-18.5), and 17.9 days (95% confidence interval, 16.1-19.9) at 6 months. Estimated declines were greater in the electronic-delivered group (beta [standard error]=-0.090[0.034]; P=.008; Cohen's d, 0.19 at 1 month, 0.30 at 3 months, and 0.17 at 6 months) and the clinician-delivered group (beta [standard error]=-0.078[0.037]; P=.038; Cohen's d, 0.17 at 1 month, 0.22 at 3 months, and 0.06 at 6 months) compared with enhanced usual care. Treatment use did not differ between groups. CONCLUSION: "Screening, brief intervention and referral to treatment" significantly decreased days of primary substance use among women in reproductive healthcare centers; neither resulted in more treatment use than enhanced usual care. PMID- 29247637 TI - Spectrum of symptoms in women diagnosed with endometriosis during adolescence vs adulthood. AB - BACKGROUND: Endometriosis symptoms often start at a young age, and the time between symptom onset and endometriosis diagnosis can be several years. It is not clear whether the symptoms that are experienced by adolescents differ from adults. Better understanding may shorten the often lengthy delay in diagnosis. OBJECTIVE: The purpose of the study was to further elucidate the symptom presentation of adolescents as compared with adults to determine whether differences existed, based on age at surgical diagnosis that could impact time to diagnosis. STUDY DESIGN: This investigation was a cross-sectional study at enrollment within a longitudinal cohort of adolescents and women with endometriosis. The population-based cohort was recruited from 2 tertiary care centers and the surrounding communities. Participants included adolescents (diagnosed at <=18 years old; n=295) and adults (diagnosed at >18 years old; n=107) with surgically confirmed endometriosis who were enrolled into The Women's Health Study: From Adolescence to Adulthood. Participants completed an expanded version of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project standard clinical questionnaire that included items regarding menstrual history, associated symptoms, and pain. Chi-square or Fisher's exact tests were applied to categoric data; Wilcoxon rank sum tests were applied to continuous data. RESULTS: Most participants (90%) experienced moderate severe menstrual pain. On average, 3 doctors were seen before diagnosis, regardless of age at presentation (range, 0-25 years). Time from symptoms to diagnosis averaged 2 years for adolescents and 5 years for adults (P<.001). More adolescents (50%) than adults (33%) reported pain starting at menarche (P=.002) and nausea accompanying pain (69% vs 53%; P=.01). Noncyclic, general pelvic pain was prevalent. One-half of the participants reported relief of their general pelvic pain after a bowel movement. Pain interfered with work/school, daily activities, exercise, and sleep to a moderate-extreme degree; difficulties were similar by age at diagnosis. CONCLUSIONS: Pelvic pain was severe and noncyclic and negatively impacted quality of life. At our tertiary care centers, symptoms of endometriosis did not differ between women surgically diagnosed during adolescence compared with those diagnosed as adults. Adolescents had more nausea and symptom onset at menarche. Multi-year delays in diagnosis were common. Clinicians should be aware of these alternate symptom patterns and include endometriosis in their differential diagnosis for both adolescent and young adult women who experience noncyclic pelvic pain and nausea. PMID- 29247638 TI - Editorial Comment. PMID- 29247639 TI - Editorial Comment. PMID- 29247641 TI - Molecular mechanism for miR-350 in regulating of titanium dioxide nanoparticles in macrophage RAW264.7 cells. AB - This study investigated the role of microRNA(miRNA) in regulating the cytotoxicity of TiO2 nanoparticles (nano-TiO2) to RAW264.7 cells. RAW264.7 cells were treated with 0 and 100 MUg/ml nano-TiO2 for 24 h (for miRNA analysis). The differentially expressed miRNAs were detected using Illumina HiSeqTM 2000 sequencing. Through the bio-informatics analysis, miR-350 was found to play an important role in multiple signaling pathways, including MAPK signaling pathway, NF-kappa B signaling pathway and Apoptosis. To characterize the miR-350 function, miR-350 mimic was transfected into RAW264.7 cells for 24 h. MTT and Flow Cytometry were performed to detect cell proliferation, apoptosis and cell cycle (repetition), respectively. QRT-PCR, Western Blot methods and Luciferase assays were applied to detect expression of putative target gene PIK3R3. The results showed that miRNA profiles were differentially dysregulated. The apoptosis rate of miR-350 mimic group was significantly higher than negative control group (p < .05). Cell proliferation and cell cycle had no significant differences between treatment and negative control group. Compared with negative control, the level of protein of PIK3R3 was significantly decreased (p < .05), and the expression of 3'UTR constructs of PIK3R3 was significantly decreased (p < .05) in miR-350 mimic group. The expression of miRNAs was changed after exposed to nano-TiO2, and biological function and target gene results showed miR-350 may promote RAW264.7 cell apoptosis through the negative regulation of PIK3R3 gene. Our results could provide a basis for further understanding of toxicity and possible mechanisms of nano-TiO2 exposure. PMID- 29247640 TI - Effects of a novel microtubule-depolymerizer on pro-inflammatory signaling in RAW264.7 macrophages. AB - The Nuclear Factor-kappa B (NF-kappaB) pathway is vital for immune system regulation and pro-inflammatory signaling. Many inflammatory disorders and diseases, including cancer, are linked to dysregulation of NF-kappaB signaling. When macrophages recognize the presence of a pathogen, the signaling pathway is activated, resulting in the nuclear translocation of the transcription factor, NF kappaB, to turn on pro-inflammatory genes. Here, we demonstrate the effects of a novel microtubule depolymerizer, NT-07-16, a polysubstituted pyrrole compound, on this process. Treatment with NT-07-16 decreased the production of pro inflammatory cytokines in RAW264.7 mouse macrophages. It appears that the reduction in pro-inflammatory mediators produced by the macrophages after exposure to NT-07-16 may be due to activities upstream of the translocation of NF kappaB into the nucleus. NF-kappaB translocation occurs after its inhibitory protein, IkappaB-alpha is phosphorylated which signals for its degradation releasing NF-kappaB so it is free to move into the nucleus. Previous studies from other laboratories indicate that these processes are associated with the microtubule network. Our results show that exposure to the microtubule depolymerizer, NT-07-16 reduces the phosphorylation of IkappaB-alpha and also decreases the association of NF-kappaB with tubulin which may affect the ability of NF-kappaB to translocate into the nucleus. Therefore, the anti-inflammatory activity of NT-07-16 may be explained, at least in part, by alterations in these steps in the NF-kappaB signaling pathway leading to less NF-kappaB entering the nucleus and reducing the production of pro-inflammatory mediators by the activated macrophages. PMID- 29247642 TI - Nature to the natural rescue: Silencing microbial chats. AB - Communication is the sole means by which effective networking and co-existence is accomplished amongst living beings. Microbes have their own chit-chats. Science has overheard these microbial gossips and have concluded that these aren't just informal communications, but carefully coordinated signals that plan their effective strategies. Tracking one such signal molecule, N-acyl homoserine lactone (AHL), led to a fundamental understanding to microbial quorum sensing (QS). Furtherance of research sought for ways to cut off communication between these virulent forms, so as to hinder their combinatorial attacks through quorum sensing inhibitors (QSIs). A clear understanding of the inhibitors of these microbial communication systems is vital to destroy their networking and co working. The current review, consolidates the solutions for QSIs offered from natural sources against these micro components, that are capable of slaughtering even nature's most fit entity-man. The applications of effective out sourcing of this QSI technologies and the need for development are discussed. The importance of silencing this microbial chatter to various aspects of human life and their implications are discussed and elaborated. PMID- 29247643 TI - Traditional herbal medicine-derived sulforaphene promotes mitophagic cell death in lymphoma cells through CRM1-mediated p62/SQSTM1 accumulation and AMPK activation. AB - Sulforaphene (LFS-01) is the major chemical constituent of Raphanus sativus, a medicinal herb used for over a thousand years in traditional Chinese medicine. Here we identified that LFS-01 can selectively eradicate lymphoma cells while sparing normal lymphocytes by triggering concomitant mitophagy and apoptosis. We demonstrated that LFS-01 can retain Nrf2 in the nucleus by covalently modulating CRM1 and consequently upregulate p62/SQSTM1, an essential structural component of the autophagosomes during mitophagic process. We found that LFS-01 treatment also stimulated AMPK and thereby inhibited the mTOR pathway. On the contrary, we revealed that AMPK inhibition can severely impair the LFS-01-mediated mitophagy. Transcriptomic studies confirmed that 15 autophagy-associated genes such as p62/SQSTM1, VCP and BCL2 were differentially expressed after LFS-01 treatment. Furthermore, protein interactome network analysis revealed that the events of apoptosis and the assembly of autophagy vacuole were significant upon LFS-01 exposure. Lastly, we found that LFS-01 exhibited strong efficacy in xenograft mouse model yet with the lack of apparent toxicity to animals. We concluded that LFS-01 triggered mitophagic cell death via CRM1-mediated p62 overexpression and AMPK activation. Our findings provide new insights into the mechanism of action for LFS-01 and highlight its potential applications in treating major human diseases. PMID- 29247644 TI - Angiotensin II type 1 receptor-associated protein regulates carotid intimal hyperplasia through controlling apoptosis of vascular smooth muscle cells. AB - Intimal hyperplasia is the main cause of restenosis after carotid artery injury, and the underlying mechanism involves the proliferation and migration of vascular smooth muscle cells (VSMCs). Angiotensin II Type 1 Receptor-Associated Protein (ATRAP) has been reported to withstand intimal hyperplasia by inhibiting VSMCs proliferation and migration; however, whether the beneficial effect of ATRAP associates with VSMCs apoptosis remains unclarified. We demonstrated that the adenoviral-mediated overexpression of ATRAP induced VSMC apoptosis, alleviating the balloon injury-induced neointima formation in rats. Under the condition of Angiotensin-II stimulation, ATRAP overexpression induced the apoptosis of rat VSMCs by depressing the PI3K-Akt signaling; whereas up-regulation of Akt by PTEN inhibitor abolished the apoptotic death. Thus, ATRAP regulates carotid intimal hyperplasia through controlling the PI3K-Akt signal-mediated VSMCs apoptosis. PMID- 29247645 TI - Effects of dietary glucose and sodium chloride on intestinal glucose absorption of common carp (Cyprinus carpio L.). AB - The co-transport of sodium and glucose is the first step for intestinal glucose absorption. Dietary glucose and sodium chloride (NaCl) may facilitate this physiological process in common carp (Cyprinus carpio L.). To test this hypothesis, we first investigated the feeding rhythm of intestinal glucose absorption. Carps were fed to satiety once a day (09:00 a.m.) for 1 month. Intestinal samples were collected at 01:00, 05:00, 09:00, 13:00, 17:00 and 21:00. Result showed that food intake greatly enhanced sodium/glucose cotransporter 1 (SGLT1) and glucose transporter type 2 (GLUT2) expressions, and improved glucose absorption, with highest levels at 09:00 a.m.. Then we designed iso-nitrogenous and iso-energetic diets with graded levels of glucose (10%, 20%, 30%, 40% and 50%) and NaCl (0%, 1%, 3% and 5%), and submitted to feeding trial for 10 weeks. The expressions of SGLT1 and GLUT2, brush border membrane vesicles (BBMVs) glucose transport and intestinal villus height were determined after the feeding trial. Increasing levels of dietary glucose and NaCl up-regulated mRNA and protein levels of SGLT1 and GLUT2, enhanced BBMVs glucose transport in the proximal, mid and distal intestine. As for histological adaptive response, however, high-glucose diet prolonged while high-NaCl diet shrank intestinal villus height. Furthermore, we also found that higher mRNA levels of SGLT1 and GLUT2, higher glucose transport capacity of BBMVs, and higher intestinal villus were detected in the proximal and mid intestine, compared to the distal part. Taken together, our study indicated that intestinal glucose absorption in carp was primarily occurred in the proximal and mid intestine, and increasing levels of dietary glucose and NaCl enhanced intestinal glucose absorption in carp. PMID- 29247646 TI - Incomplete clearance of apoptotic cells by core 1-derived O-glycan-deficient resident peritoneal macrophages. AB - The core 1 beta1,3-galactosyltransferase-specific molecular chaperon (Cosmc) is essential for the synthesis of the core 1 structure of mucin-type O-glycans. To clarify the physiological role of core 1-derived O-glycans in macrophages, we exploited the LysM-Cre transgene to generate a conditional Cosmc mutant allele (conditional Cosmc knockout; cKO) in myeloid cells. cKO mice developed normally with no gross phenotypic abnormalities or abnormal peripheral blood counts. Resident peritoneal macrophages (rpMacs) of cKO mice exhibited impaired engulfment of apoptotic cells but showed normal macrophage differentiation and counts. T-cell immunoglobulin and mucin domain-containing molecule 4 (Tim4) is a phosphatidylserine (PS) receptor expressed on rpMacs and possesses a heavily O glycosylated domain. Tim4 tethers apoptotic cells through PS binding. Expression of the Tim4 transcript was unchanged in cKO rpMacs, whereas flow cytometric, Western and dot blot analyses revealed that Tim4 protein expression in cKO rpMacs was significantly lower than that in wild-type (WT) rpMacs. Moreover, the expression levels of other efferocytosis-related molecules, Mertk, Itgav and Itgb3, were normal in rpMacs. In addition, hypoglycosylated Tim4-FLAG fusion protein sufficiently recognized PS. These results demonstrated that core 1 derived O-glycan is required for Tim4-dependent normal efferocytosis and may contribute to the stable expression of the Tim4 glycoprotein. PMID- 29247647 TI - Moesin and myosin IIA modulate phagolysosomal biogenesis in macrophages. AB - Biogenesis of phagolysosomes is central to the elimination of pathogens by macrophages. We previously showed that Src homology region 2 domain-containing phosphatase 1 (SHP-1) participates in the regulation of phagosome maturation. Through proteomics, we identified moesin and the non-muscle myosin-IIA as proteins interacting with SHP-1 during phagocytosis. Silencing of either moesin or myosin IIA with small interfering RNA inhibited phagosomal acidification and recruitment of LAMP-1. Moreover, the intraphagosomal oxidative burst was impaired in the absence of either SHP-1 or myosin IIA but not moesin. Finally, absence of either SHP-1, moesin, or myosin IIA ablated the capacity of macrophages to clear bacterial infection. Collectively, these results implicate both moesin and myosin IIA in the regulation of phagolysosome biogenesis and in host defense against infections. PMID- 29247648 TI - PKC and Rab13 mediate Ca2+ signal-regulated GLUT4 traffic. AB - Exercise/muscle contraction increases cell surface glucose transporter 4 (GLUT4), leading to glucose uptake to regulate blood glucose level. Elevating cytosolic Ca2+ mediates this effect, but the detailed mechanism is not clear yet. We used calcium ionophore ionomycin to raise intracellular cytosolic Ca2+ level to explore the underlying mechanism. We showed that in L6 myoblast muscle cells stably expressing GLUT4myc, ionomycin increased cell surface GLUT4myc levels and the phosphorylation of AS160, TBC1D1. siPKCalpha and siPKCtheta but not siPKCdelta and siPKCepsilon inhibited the ionomycin-increased cell surface GLUT4myc level. siPKCalpha, siPKCtheta inhibited the phosphorylation of AS160 and TBC1D1 induced by ionomycin. siPKCalpha and siPKCtheta prevented ionomycin inhibited endocytosis of GLUT4myc. siPKCtheta, but not siPKCalpha inhibited ionomycin-stimulated exocytosis of GLUT4myc. siRab13 but not siRab8a, siRab10 and siRab14 inhibited the exocytosis of GLUT4myc promoted by ionomycin. In summary, ionomycin-promoted exocytosis of GLUT4 is partly reversed by siPKCtheta, whereas ionomycin-inhibited endocytosis of GLUT4 requires both siPKCalpha and siPKCtheta. PKCalpha and PKCtheta contribute to ionomycin-induced phosphorylation of AS160 and TBC1D1. Rab13 is required for ionomycin-regulated GLUT4 exocytosis. PMID- 29247649 TI - The proper localization of RESPONSIVE TO DESICCATION 20 in lipid droplets depends on their biogenesis induced by STRESS-RELATED PROTEINS in vegetative tissues. AB - Arabidopsis LD surface proteins, SRPs are found only in higher plants and are important for LD biogenesis and abiotic stress signaling. However, the cellular mechanism of SRPs is still unclear. To investigate molecular functions of SRPs, we used tobacco transient expression system. Transient expression of SRPs was sufficient and synergistic for LD biogenesis, and SRPs participated in the formation step of LD in tobacco leaves. RESPONSIVE TO DESICCATION 20 (RD20), a known LD-localizing peroxygenase, localized to LD in the presence of an SRP, and its peroxygenase activity correlated with proper localization of RD20 to LD. Our data suggest that Arabidopsis SRPs play roles as positive factors for LD biogenesis to provide a proper localization of LD-localizing proteins in vegetative tissues. PMID- 29247650 TI - Increased circulating trimethylamine N-oxide contributes to endothelial dysfunction in a rat model of chronic kidney disease. AB - Chronic kidney disease (CKD) is strongly associated with increased cardiovascular risk. Impaired endothelial function, a key initiating step in the pathogenesis of cardiovascular disease, has been reported in patients with CKD, but the mechanisms responsible for endothelial dysfunction in CKD remain elusive. Emerging evidence reveals that trimethylamine-N-oxide (TMAO), a gut microbiota generated metabolite, is involved in the pathogenesis of many cardiovascular diseases. Circulating TMAO is elevated in CKD. Here we tested the hypothesis that elevated TMAO plays a contributory role in the pathogenesis of endothelial dysfunction in CKD. Rats underwent 5/6 nephrectomy to induce CKD or sham operation, and were treated with 1.0% 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) or vehicle. Eight weeks after nephrectomy and DMB treatment, circulating TMAO levels were markedly elevated in CKD-vehicle rats compared with sham-vehicle rats, but were reduced in CKD-DMB rats. Acetylcholine induced endothelium-dependent vasodilation was impaired in CKD-vehicle rats compared with sham-vehicle rats as indicated by reduced maximal relaxation (Emax) and decreased area under the curve (AUC). Emax and AUC were both normalized in CKD-DMB rats. No difference in sodium nitroprusside-induced endothelial independent vasodilation was observed across groups. Molecular studies revealed that endothelial nitric-oxide synthase activity was decreased, while superoxide production and proinflammatory cytokine expression were increased in the aorta of CKD-vehicle rats compared with sham-vehicle rats. Of note, the abnormalities in above molecular parameters were completely restored in CKD-DMB rats. These results suggest that CKD elevates circulating TMAO levels, which may reduce eNOS derived NO production by increasing vascular oxidative stress and inflammation, contributing to CKD-associated endothelial dysfunction and cardiovascular disease. PMID- 29247651 TI - Berberine-induced activation of AMPK increases hepatic FGF21 expression via NUR77. AB - Fibroblast growth factor 21 (FGF21), a hormone-like protein mainly derived from liver, exhibits multiple beneficial effect on energy metabolism. Similar to FGF21, berberine exerts anti-hyperglycemic and anti-dyslipidemic properties. Previous studies revealed that the beneficial metabolic effect of berberine was attributed to the activation of AMP-activated protein kinase (AMPK). Here we investigated the effect of berberine on FGF21 expression in primary mouse hepatocytes. As expected, berberine induced hepatic FGF21 expression in a dose dependent and time-dependent manner, along with the increased expression of NUR77, a proved transcription factor of FGF21. Berberine stimulated the phosphorylations of AMPK and acetyl-CoA carboxylase in primary mouse hepatocytes. Adenovirus-mediated overexpression of constitutively active AMPK triggered hepatic FGF21 and NUR77 expressions. The inhibition of AMPK by compound C abolished berberine-stimulated FGF21 and NUR77 expressions. These results suggest that berberine-induced activation of AMPK may contribute to hepatic FGF21 expression via NUR77. PMID- 29247652 TI - Aberrant alternative splicing of RHOA is associated with loss of its expression and activity in diffuse-type gastric carcinoma cells. AB - RhoA is a member of Rho family small GTPases that regulates diverse cellular functions. Recent large-scale sequencing studies have identified recurrent somatic mutations of RHOA in diffuse-type gastric carcinoma (DGC), indicating that RHOA is a driver of DGC. In this study, we investigated the possible abnormalities of RHOA in a panel of gastric carcinoma (GC) cell lines. Pulldown assay and immunoblot analysis showed that the activity and expression of RhoA were detectable in all GC cell lines tested, except for two DGC cell lines, HSC 59 and GSU. RHOA coding region sequencing revealed that aberrant alternative splicing of RHOA occurred in these cell lines. Quantitative real-time PCR analysis showed that the expression of wild-type RHOA was nearly undetectable, whereas splicing variants were almost exclusively expressed in HSC-59 and GSU cell lines. However, the expression levels of RHOA splicing variants were very low and the corresponding proteins were not detected by immunoblotting. Moreover, the splicing isoforms of RhoA protein were neither efficiently expressed nor activated even if ectopically expressed in cells. These results indicate that aberrant alternative splicing of RHOA results in the loss of its activity and expression in DGC cells. PMID- 29247653 TI - Taurine and beta-alanine intraperitoneal injection in lactating mice modifies the growth and behavior of offspring. AB - Taurine, one of the sulfur-containing amino acids, has several functions in vivo. It has been reported that taurine acts on gamma-aminobutyric acid receptors as an agonist and to promote inhibitory neurotransmission. Milk, especially colostrum, contains taurine and it is known that milk taurine is essential for the normal development of offspring. beta-Alanine is transported via a taurine transporter and a protein-assisted amino acid transporter, the same ones that transport taurine. The present study aimed to investigate whether the growth and behavior of offspring could be altered by modification of the taurine concentration in milk. Pregnant ICR mice were separated into 3 groups: 1) a control group, 2) a taurine group, and 3) a beta-alanine group. During the lactation periods, dams were administered, respectively, with 0.9% saline (10 ml/kg, i.p.), taurine dissolved in 0.9% saline (43 mg/10 ml/kg, i.p.), or beta-alanine dissolved in 0.9% saline (31 mg/10 ml/kg, i.p.). Interestingly, the taurine concentration in milk was significantly decreased by the administration of beta-alanine, but not altered by the taurine treatment. The body weight of offspring was significantly lower in the beta-alanine group. beta-Alanine treatment caused a significant decline in taurine concentration in the brains of offspring, and it was negatively correlated with total distance traveled in the open field test at postnatal day 15. Thus, decreased taurine concentration in the brain induced hyperactivity in offspring. These results suggested that milk taurine may have important role of regulating the growth and behavior of offspring. PMID- 29247654 TI - Mechanisms and Consequences of Inflammasome Activation. PMID- 29247655 TI - Behavioral thermoregulation in a small herbivore avoids direct UVB damage. AB - Direct damage of increased solar ultraviolet-B (UVB) on organism fitness has attracted attention due to stratospheric ozone depletion. Although most ectotherms are not capable of detecting and avoiding solar UVB, they may avoid direct exposure to solar UVB via thermoregulation behavior. However, it is still not clear whether organisms are harmed by ambient UVB radiation before escaping to shaded microhabitats. In this study we used the English grain aphid, Sitobion avenae (Hemiptera: Aphididae), to test whether sunlight-avoidance behavior was caused by heat stress rather than UVB, and whether behavioral thermoregulation in shaded microhabitats contributes to avoidance or reduction of direct UVB damage. Our results showed that S. avenae tended to inhabit exposed adaxial leaf surfaces in mid-May in Mongolia, but inhabited shaded leaf surfaces in mid-June, thereby avoiding strong sunlight. Heat exposure rather than solar UVB was the primary reason for such avoidance behavior. The average and extreme temperatures of shaded leaf surfaces were several degrees lower than sunlight-exposed surfaces at midday, suggesting that movement to shaded leaf surfaces represents a form of behavioral thermoregulation. Such responses occurred before UVB radiation reached harmful levels, and contributed to avoiding direct UVB damage. As future climate warming is expected to lead to harmful UVB radiation as well as increasing temperatures, this may represent a case where responses to one stressor inadvertently protect against the harmful effects of a different stressor. PMID- 29247656 TI - mRNA expression of platelet activating factor receptor (PAFR) in peripheral blood mononuclear cells is associated with albuminuria and vascular dysfunction in patients with type 2 diabetes. AB - AIMS: Renal dysfunction in addition to diabetes is a serious risk factor for cardiovascular events. We hypothesized that some of the changes in gene expression in blood cells cause renal dysfunction and macrovascular disease through impaired endothelial function. This study aimed to define which changes in gene expression in peripheral blood mononuclear cells (PBMCs) are related to renal function parameters and endothelial function of large arteries in patients with type 2 diabetes mellitus (T2DM). METHODS: We recruited 95 patients with T2DM. After matching for gender, age, BMI and HbA1c levels, the patient cohort included 42 with normoalbuminuria, 28 with microalbuminuria, and 25 with macroalbuminuria. All patients in the three groups were assessed for urinary albumin to creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), flow-mediated dilatation (FMD), and mRNA expression in PBMCs. RESULTS: The mRNA expression of platelet activating factor receptor (PAFR) differed most markedly between the three groups and was significantly higher in the macroalbuminuric group (p < 0.001 vs. normoalbuminuric group; p < 0.05 vs. microalbuminuric group). PAFR mRNA expression significantly correlated with log transformed ACR (rho = 0.424, p < 0.001) but not eGFR. PAFR mRNA expression also had a significant negative correlation with FMD (rho = -0.379, p < 0.001). Furthermore, the prevalence of macrovascular complications, particularly stroke, was significantly higher in patients with elevated PAFR mRNA expression in PBMCs. CONCLUSIONS: PAFR overexpression in PBMCs may link diabetic nephropathy to macroangiopathy through impairment of endothelial function in patients with T2DM. PMID- 29247657 TI - Spironolactone voltammetric determination on renewable amalgam film electrode. AB - In this study a new high sensitive method of spironolactone (SP) determination is proposed using voltammetric technique. As the working electrode amalgam film silver based electrode (Hg(Ag)FE) was applied, that resulted in obtaining low limit of spironolactone detection, ex. for the preconcentration time 45 s obtained detection limit was 4.7.10-9 mol L-1 (1.96.10-6 g L-1). The linear response of spironolactone signal on mercury film electrode was obtained in the range of concentration from 15.10-9 to 3.0.10-6 mol L-1 and the obtained repeatability measured as RSD was very good, with the value of 2.0% (n = 5; concentration 0.5.10-6 mol L-1). The proposed method was successfully applied and validated by studying the recovery in commercially available pharmaceutical formulations containing known amount of spironolactone. PMID- 29247658 TI - Is the recent increase in cervical cancer in women aged 20-24years in England a cause for concern? AB - The rates of cervical cancer (CxCa) in England among women aged 20-24yrs increased from 2.7 in 2012 to 4.6 per 100,000 in 2014 (p=0.0006). There was concern that the sudden increase was linked to the withdrawal of cervical screening in women aged 20-24 (a policy that affected women born since 1984). We analyse granular data on age and FIGO stage at diagnosis using a generalised linear model to see whether the unprecedented increase in CxCa in young women in 2014 was linked to the change in 2012 to the age at which the first invitation to screening was sent (from 25.0 to 24.5). Annual rates of CxCa per 100,000 women aged 20.0-24.5yrs decreased gradually over time, whereas at age 24.5-25.0yrs they increased from an average of 16 pre-2013 to 49 in 2015. An increase of 20.3 per 100,000 women aged 24.5-25.0yrs (95% CI: 15.2-25.4) was associated with inviting women for screening at age 24.5yrs instead of at age 25.0. At age 25.0-25.5yrs, rates decreased by 23.7 per 100,000 after women were invited at age 24.5yrs (p<0.001). All these changes were limited to stage I CxCa. There was a dramatic increase in diagnoses at age 25yrs in 2009-2011 associated with changing the age at first invitation from 20yrs to 25yrs. No changes were observed at age 26.0 27.0yrs. The increase in CxCa aged 20-24 is attributable to an increase in the proportion of women first screened aged 24.5yrs. The increase was limited to stage I CxCa. There is no evidence of a lack of screening leading to increasing rates. PMID- 29247659 TI - Variability in the Expression of Immunohistochemical Markers: Implications for Biomarker Interpretation in Cutaneous T-Cell Lymphoma. PMID- 29247660 TI - Genome-Wide DNA Methylation Profiling Identifies Differential Methylation in Uninvolved Psoriatic Epidermis. AB - Psoriasis is a chronic inflammatory skin disease with both local and systemic components. Genome-wide approaches have identified more than 60 psoriasis susceptibility loci, but genes are estimated to explain only one-third of the heritability in psoriasis, suggesting additional, yet unidentified, sources of heritability. Epigenetic modifications have been linked to psoriasis and altered DNA methylation patterns in psoriatic versus healthy skin have been reported in whole-skin biopsies. In this study, focusing on epigenetic modifications in the psoriatic uninvolved skin, we compared the lesional and non-lesional epidermis from psoriasis patients with epidermis from healthy controls. We performed an exhaustive genome-wide DNA methylation profiling using reduced representation bisulfite sequencing, which interrogates the methylation status of approximately 3-4 million CpG sites. More than 2,000 strongly differentially methylated sites were identified and a striking overrepresentation of the Wnt and cadherin pathways among the differentially methylated sites was found. In particular, we observe a strong differential methylation in several psoriasis candidate genes. A substantial number of differentially methylated sites present in the uninvolved versus healthy epidermis suggests the presence of a pre-psoriatic state in the clinically healthy skin type. Our exploratory study represents a starting point for identifying biomarkers for psoriasis-prone skin before disease onset. PMID- 29247661 TI - Identification of Atorvastatin for Moderate to Severe Hidradenitis through Drug Repositioning Using Public Gene Expression Datasets. PMID- 29247662 TI - Cryptosporidium spp. in caged exotic psittacines from Brazil: Evaluation of diagnostic methods and molecular characterization. AB - The aim of this study was to evaluate the prevalence of and diagnostic methods for Cryptosporidium spp. in caged adult exotic parrots from Southern and Southeastern Brazil. Oocysts were purified from fecal samples from 463 psittacines by centrifugal-flotation in Sheather's sugar solution. Cryptosporidium spp. were detected by malachite green negative staining and nested PCR targeting the 18S rRNA gene. Cryptosporidium species were identified by sequencing nested PCR amplicons. Samples were also tested by duplex real-time PCR targeting the 18S rRNA gene of Cryptosporidium galli and Cryptosporidium avian genotype III. The prevalence rates of Cryptosporidium spp. determined by microscopy and nested PCR were 3.0% (14/463) and 5.0% (23/463), respectively. The nested PCR/sequencing identified avian genotype III (1.7%; 8/463), Cryptosporidium parvum (0.9%; 4/463) and Cryptosporidium canis (0.2%; 1/463). Duplex real-time PCR was positive for gastric Cryptosporidium in 9.5% (44/463) of the samples. Among them, 1.9% (9/463) were positive for C. galli, 5.8% (27/463) were positive for avian genotype III and 1.7% (8/463) showed mixed infections with C. galli and avian genotype III. With regards to the positive detection of Cryptosporidium spp., there was no statistically significant difference between nested PCR and microscopic analysis (p = .1237), and a fair agreement existed between them (Kappa = 0.242). A statistically significant difference (p < .0001) and fair agreement (Kappa = 0.317) were obtained between nested PCR/sequencing and duplex real-time PCR for the detection of gastric Cryptosporidium. We determined that nested PCR and duplex real-time PCR are the best options for the detection of Cryptosporidium spp. and gastric Cryptosporidium, respectively, and that avian genotype III is the most common Cryptosporidium genotype/species in psittacines. PMID- 29247663 TI - Specificity of research antibodies: "trust is good, validation is better". PMID- 29247664 TI - Fate of PEGylated antibody fragments following delivery to the lungs: Influence of delivery site, PEG size and lung inflammation. AB - Pulmonary administration of anti-cytokine antibodies offers a targeted therapy in asthma. However, the rapid elimination of proteins from the lungs limits the efficacy of inhaled medications. PEGylation has been shown to increase the residence time of anti-interleukin (IL)-17A and anti-IL-13 antibody fragments in the lungs and to improve their therapeutic efficacy. Yet, little is known about the factors that affect the residence time of PEGylated antibody fragments in the lungs following pulmonary delivery. In this study, we showed that the molecular weight of polyethylene glycol (PEG), 20kDa or 40kDa, had a moderate effect on the residence time of an anti-IL-17A Fab' fragment in the lungs of mice. By contrast, the site of delivery of the anti-IL-17A and anti-IL-13 Fab' fragments within the lungs had a major impact on their residence time, with the deeper the delivery, the more prolonged the residence time. The nature of the Fab' fragment had an influence on its residence time as well and the anti-IL-17A Fab' benefited more from PEGylation than the anti-IL-13 Fab' did. Acute lung inflammation slightly shortened the residence time of the anti-IL-17A and anti-IL-13 Fab' fragments in the lungs but PEGylation was able to prolong their presence in both the healthy and inflamed lungs. Antibody fragments were predominately located within the airway lumen rather than the lung parenchyma. Transport experiments on monolayers of Calu-3 cells and studies of fluorescence recovery after photobleaching in respiratory mucus showed that mechanisms involved in the prolonged presence of PEGylated Fab' in the airway lumen might include binding to the mucus, reduced uptake by respiratory cells and reduced transport across lung epithelia. Finally, using I125-labeled anti-IL-17A Fab', we showed that the protein fragment hardly penetrated into the lungs following subcutaneous injection, as opposed to pulmonary delivery. PMID- 29247665 TI - Photodynamic and photothermal tumor therapy using phase-change material nanoparticles containing chlorin e6 and nanodiamonds. AB - This paper describes the fabrication and evaluation of phase-change material (PCM) nanoparticles containing chlorin e6 (Ce6) and nanodiamonds (NDs) for photodynamic and photothermal approaches for tumor therapy, respectively. The temperature of the PCM nanoparticles containing NDs (ND/PCM, 0.5mg/mL in water) is increased to 45 degrees C during laser exposure for 5min. The singlet oxygen generation intensity of PCM nanoparticles containing Ce6 and NDs (Ce6/ND/PCM) is gradually increased with respect to the laser exposure time. Also, the release of Ce6 from Ce6/ND/PCM can be controlled in an on-and-off manner using laser. Cell ablation tests reveal that Ce6/ND/PCM greatly ablates KB cells upon laser exposure, which is attributed to both the temperature increase in the media and singlet oxygen generation by the released Ce6. In an animal model, tumor volume is notably reduced over time after the intratumoral injection of Ce6/ND/PCM and subsequent laser exposure with a higher efficiency compared to ND/PCM. The Ce6/ND/PCM can be a promising nanomedicine for tumor therapy. PMID- 29247666 TI - Getting a handle on virtual tools: An examination of the neuronal activity associated with virtual tool use. AB - Tool use is associated with three visual streams-dorso-dorsal, ventro-dorsal, and ventral visual streams. These streams are involved in processing online motor planning, action semantics, and tool semantics features, respectively. Little is known about the way in which the brain represents virtual tools. To directly assess this question, a virtual tool paradigm was created that provided the ability to manipulate tool components in isolation of one another. During functional magnetic resonance imaging (fMRI), adult participants performed a series of virtual tool manipulation tasks in which vision and movement kinematics of the tool were manipulated. Reaction time and hand movement direction were monitored while the tasks were performed. Functional imaging revealed that activity within all three visual streams was present, in a similar pattern to what would be expected with physical tool use. However, a previously unreported network of right-hemisphere activity was found including right inferior parietal lobule, middle and superior temporal gyri and supramarginal gyrus - regions well known to be associated with tool processing within the left hemisphere. These results provide evidence that both virtual and physical tools are processed within the same brain regions, though virtual tools recruit bilateral tool processing regions to a greater extent than physical tools. PMID- 29247667 TI - Making predictable unpredictable with style - Behavioral and electrophysiological evidence for the critical role of prosodic expectations in the perception of prominence in speech. AB - Perceptual prominence of linguistic units such as words has been earlier connected to the concepts of predictability and attentional orientation. One hypothesis is that low-probability prosodic or lexical content is perceived as prominent due to the surprisal and high information value associated with the stimulus. However, the existing behavioral studies have used stimulus manipulations that follow or violate typical linguistic patterns present in the listeners' native language, i.e., assuming that the listeners have already established a model for acceptable prosodic patterns in the language. In the present study, we investigated whether prosodic expectations and the resulting subjective impression of prominence is affected by brief statistical adaptation to suprasegmental acoustic features in speech, also in the case where the prosodic patterns do not necessarily follow language-typical marking for prominence. We first exposed listeners to five minutes of speech with uneven distributions of falling and rising fundamental frequency (F0) trajectories on sentence-final words, and then tested their judgments of prominence on a set of new utterances. The results show that the probability of the F0 trajectory affects the perception of prominence, a less frequent F0 trajectory making a word more prominent independently of the absolute direction of F0 change. In the second part of the study, we conducted EEG-measurements on a set of new subjects listening to similar utterances with predominantly rising or falling F0 on sentence-final words. Analysis of the resulting event-related potentials (ERP) reveals a significant difference in N200 and N400 ERP-component amplitudes between standard and deviant prosody, again independently of the F0 direction and the underlying lexical content. Since N400 has earlier been associated with semantic processing of stimuli, this suggests that listeners implicitly track probabilities at the suprasegmental level and that predictability of a prosodic pattern during a word has an impact to the semantic processing of the word. Overall, the study suggests that prosodic markers for prominence are at least partially driven by the statistical structure of recently perceived speech, and therefore prominence perception could be based on statistical learning mechanisms similar to those observed in early word learning, but in this case operating at the level of suprasegmental acoustic features. PMID- 29247668 TI - Calmodulin as a protein linker and a regulator of adaptor/scaffold proteins. AB - Calmodulin (CaM) is a universal regulator for a huge number of proteins in all eukaryotic cells. Best known is its function as a calcium-dependent modulator of the activity of enzymes, such as protein kinases and phosphatases, as well as other signaling proteins including membrane receptors, channels and structural proteins. However, less well known is the fact that CaM can also function as a Ca2+-dependent adaptor protein, either by bridging between different domains of the same protein or by linking two identical or different target proteins together. These activities are possible due to the fact that CaM contains two independently-folded Ca2+ binding lobes that are able to interact differentially and to some degree separately with targets proteins. In addition, CaM can interact with and regulates several proteins that function exclusively as adaptors. This review provides an overview over our present knowledge concerning the structural and functional aspects of the role of CaM as an adaptor protein and as a regulator of known adaptor/scaffold proteins. PMID- 29247670 TI - Sleep on a high heat capacity mattress increases conductive body heat loss and slow wave sleep. AB - Environmental temperature can strongly affect sleep. The habitual sleep phase is usually located between evening decline and morning rise of the circadian rhythm of core body temperature (CBT). However, the thermophysiological mechanisms promoting or disturbing sleep are not yet fully understood. The purpose of this study was to examine the effects of a high heat capacity mattress (HHCM) on CBT, skin temperatures and sleep in comparison to a conventional low heat capacity mattress (LHCM). Based on the higher heat capacity of HHCM an increase in conductive body heat loss enhances the nocturnal decline in CBT can be expected. Based on previous findings this may then be accompanied by an increase in slow wave sleep (SWS). The mattresses were studied in a randomized single-blind crossover design in fifteen healthy young men (Age: 26.9+/-2.1yr, BMI: 22.2+/ 0.4kg/m2) by overnight in laboratory standard video-polysomnography in a temperature stabilized setting. CBT, room temperature, and skin and mattress surface temperatures were continuously recorded in order to get information about inner and outer body heat flow. Additionally, subjective sleep quality was estimated by visual analogue scale. In comparison to LHCM sleep on HHCM exhibited a selective increase in SWS (16%, p<0.05), increased subjective sleep quality and sleep stability [reduced cyclic alternating pattern (CAP) rate; 5.3%, p<0.01]. Additionally, analyses of the sleep stages showed in the second part of the night a significant increase in SWS and a decrease in REMS. In addition, HHCM induced a greater reduction in CBT (maximally by -0.28 degrees C), reduced the increase in proximal skin temperatures on the back (PROBA; maximally by -0.98 degrees C), and delayed the increase in mattress surface temperature (maximal difference LHCM HHCM: 6.12 degrees C). Thus, the CBT reduction can be explained by an increase in conductive heat loss to the mattress via proximal back skin regions. Regression analysis identified PROBA as the critical variable to predict inner conductive heat transfer from core to shell and SWS. In conclusion, the study expands the previous findings that a steeper nocturnal decline in CBT increases SWS and subjective sleep quality, whereas inner conductive heat transfer could be identified as the crucial thermophysiological variable, and not CBT. PMID- 29247669 TI - Elevation of sensitivity to anticancer agents of human lung adenocarcinoma A549 cells by knockdown of claudin-2 expression in monolayer and spheroid culture models. AB - Claudins, tight junctional proteins, regulate the paracellular permeability of ions and small molecules. Claudin-2 is highly expressed in human lung adenocarcinoma cells and is involved in the up-regulation of cell proliferation. However, the effect of claudin-2 on cellular sensitivity to anticancer agents has not been clarified. The cytotoxicity of anticancer agents such as cisplatin, gefitinib and doxorubicin (DXR) was increased by claudin-2 knockdown in A549 cells. Claudin-2 knockdown also significantly decreased the expression level of multidrug resistance-associated protein/ABCC2. The expression levels of other drug efflux transporters were unchanged. The intracellular accumulation of 5 chloromethylfluorescein diacetate (CMFDA) and DXR, substrates of ABCC2, was increased by claudin-2 knockdown, whereas the efflux was decreased. MK-571, an inhibitor of ABCC2, enhanced the cytotoxicity of anticancer agents. Claudin-2 knockdown decreased the levels of p-c-Jun and nuclear Sp1. SP600125, an inhibitor of c-Jun, and mithramycin, an inhibitor of Sp1, decreased the level of ABCC2. The promoter activity of ABCC2 was decreased by claudin-2 knockdown, SP600125 and mithramycin treatments, suggesting that claudin-2 is involved in the up regulation of ABCC2 expression at the transcriptional level. Claudin-2 knockdown increased the paracellular permeability of DXR in a 2D monolayer culture model. In addition, the accumulation of DXR into spheroids was enhanced by claudin-2 knockdown, resulting in a reduction in cell viability. We suggest that claudin-2 may be a novel therapeutic target in lung adenocarcinoma, because claudin-2 knockdown increased the accumulation of anticancer agents in cancer cells and spheroids. PMID- 29247671 TI - Efficient expression of cyclodextrin glycosyltransferase from Geobacillus stearothermophilus in Escherichia coli by promoter engineering and downstream box evolution. AB - Cyclodextrin glycosyltransferase (CGTase) catalyzes hydrolysis, cyclization, coupling, and disproportionation reactions and is widely used in the starch processing industry. In this work, the expression of CGTase from Geobacillus stearothermophilus in Escherichia coli BL21 (DE3) was significantly improved by promoter engineering and downstream box evolution. Firstly, the effects of the promoter type (PT7, Ptrp, PlacUV5, and the hybrid promoters PtacI and PtacII) and spacer sequence on the expression of CGTase were examined. PtacI demonstrated the highest rate of transcriptional activity, which was 4.4-, 7.1-, 3.3-, and 1.5 fold greater than that of PT7, Ptrp, PlacUV5, and PtacII, respectively. The spacer sequence of the promoter was optimized using a degenerate base library, and the GC content of the spacer was found to be inversely proportional to CGTase expression. In addition, CGTase expression was higher when TG:CA and TA:TA dimers were present in the spacer sequence. Under the control of the PtacI promoter with an optimized spacer sequence, extracellular CGTase activity reached 170.6 U/mL, which was seven times higher than that of the original strain (25.2 U/mL). Directed evolution of the downstream box sequence was then performed by randomization of the sequence using degenerate codons, similarly as for the optimization of the spacer sequence. After optimizing the downstream box sequence, CGTase activity increased from 170.6 to 214 U/mL. The results obtained here indicate that in addition to promoter type, the spacer sequence of the promoter and the downstream box are important target elements for improved gene expression. PMID- 29247672 TI - Prospects and progress in the production of valuable carotenoids: Insights from metabolic engineering, synthetic biology, and computational approaches. AB - Carotenoids are isoprenoid pigments synthesized exclusively by plants and microorganisms and play critical roles in light harvesting, photoprotection, attracting pollinators and phytohormone production. In recent years, carotenoids have been used for their health benefits due to their high antioxidant activity and are extensively utilized in food, pharmaceutical, and nutraceutical industries. Regulation of carotenoid biosynthesis occurs throughout the life cycle of plants, with vibrant changes in composition based on developmental needs and responses to external environmental stimuli. With advancements in metabolic engineering techniques, there has been tremendous progress in the production of industrially valuable secondary metabolites such as carotenoids. Application of metabolic engineering and synthetic biology has become essential for the successful and improved production of carotenoids. Synthetic biology is an emerging discipline; metabolic engineering approaches may provide insights into novel ideas for biosynthetic pathways. In this review, we discuss the current knowledge on carotenoid biosynthetic pathways and genetic engineering of carotenoids to improve their nutritional value. In addition, we investigated synthetic biological approaches for the production of carotenoids. Theoretical biology approaches that may aid in understanding the biological sciences are discussed in this review. A combination of theoretical knowledge and experimental strategies may improve the production of industrially relevant secondary metabolites. PMID- 29247673 TI - Tat-enhanced delivery of the C terminus of HDAg-L inhibits assembly and secretion of hepatitis D virus. AB - Hepatitis D virus (HDV) contains a single-stranded circular RNA genome that encodes two forms of hepatitis delta antigen (HDAg), the small delta antigen (HDAg-S) and the large delta antigen (HDAg-L). The two proteins have an identical amino acid sequence, except that HDAg-L has a 19-amino-acid extension at the C terminus. The domain spanning amino acid residues 198-210 of the HDAg-L (HDAg L(198-210)) contains a nuclear export signal (NES), which is important for the nuclear export of HDV ribonucleoprotein to the cytoplasm. In this study, we established a cell permeable TAT-HA-HDAg-L(198-210) fusion protein using an E. coli protein expression system, to determine its function during HDV infection. The cytotoxicity of the TAT-HA-HDAg-L(198-210) fusion protein was investigated using an MTT assay, while a GST pull-down assay revealed that the TAT-HA-HDAg L(198-210) fusion protein interfered with the interaction between HDAg-L and clathrin heavy chain (CHC). In addition, the cellular distribution of HDAg-L, in the presence of HBsAg, was observed by immunofluorescence staining and the TAT-HA HDAg-L(198-210) fusion protein was found to impede the nuclear export of HDAg-L. Furthermore, assembly of HDV virus-like particles (VLPs) was decreased by the expression of the TAT-HDAg-L(198-210) fusion protein. The TAT-HA-HDAg-L(198-210) fusion protein also inhibited virus particle assembly and HDV secretion in a mouse model. These results suggest that the TAT-HA-HDAg-L(198-210) fusion protein inhibits the nuclear export of HDAg-L and competes with the C terminus of HDAg-L for interaction with CHC, and may have potential as a therapeutic agent for HDV infection. PMID- 29247674 TI - Developmental exposure to low level ambient ultrafine particle air pollution and cognitive dysfunction. AB - Developmental exposures to ambient ultrafine particles (UFPs) can produce multiple neuropathological and neurochemical changes that might contribute to persistent alterations in cognitive-type functions. The objective of the current study was to test the hypothesis that developmental UFP exposure produced impairments in learning, memory and impulsive-like behaviors and to determine whether these were selective and thus independent of deficits in other behavioral domains such as motor activity or motivation. Performance on measures of learning (repeated learning), memory (novel object recognition, NOR), impulsive-like behavior (differential reinforcement of low rate (DRL), schedule of reward and delay of reward (DOR)), motor activity (locomotor behavior) and motivation (progressive ratio schedule) were examined in adult mice that had been exposed to concentrated (10-20x) ambient ultrafine particles (CAPS) averaging approximately 45 ug/m3 particle mass concentrations from postnatal day (PND) 4-7 and 10-13 for 4 h/day. Given the number of behavioral tests, animals were tested in different groups. Results showed male-specific alterations in learning and memory functions (repeated learning, NOR and DRL) specifically during transitions in reinforcement contingencies (changes in rules governing behavior) that did not appear to be related to alterations in locomotor function or motivation. Females did not exhibit cognitive-like deficits at these exposure concentrations, but displayed behaviors consistent with altered motivation, including increases in response rates during repeated learning, significantly increased latencies to respond on the delay of reward paradigm, and reductions in the progressive ratio break point. Consistent with our prior findings, male-specific learning and memory related deficits were seen and occurred even at relatively low level developmental UFP exposures, while females show alterations in motivational behaviors but not final performance. These findings add to the evidence suggesting the need to regulate UFP levels. PMID- 29247676 TI - Cosine similarity as a sample size-free measure to quantify phase clustering within a single neurophysiological signal. AB - BACKGROUND: Phase clustering within a single neurophysiological signal plays a significant role in a wide array of cognitive functions. Inter-trial phase coherence (ITC) is commonly used to assess to what extent phases are clustered in a similar direction over samples. However, this measure is especially dependent on sample size. Although ITC was transformed into ITCz, namely, Rayleigh's Z, to "correct" for the sample-size effect in previous research, the validity of this strategy has not been formally tested. New method This study introduced cosine similarity (CS) as an alternative solution, as this measure is an unbiased and consistent estimator for finite sample size and is considered less sensitive to the sample-size effect. RESULTS: In a series of studies using either artificial or real datasets, CS was robust against sample size variation even with small sample sizes. Moreover, several different aspects of examinations confirmed that CS could successfully detect phase-clustering differences between datasets with different sample sizes. Comparison with existing methods Existing measures suffer from sample-size effects. ITCz produced a mixed pattern of bias in assessing phase clustering according to sample size, whereas ITC overestimated the degree of phase clustering with small sample sizes. CONCLUSIONS: The current study not only reveals the incompetence of the previous "correction" measure, ITCz, but also provides converging evidence showing that CS may serve as an optimal measure to quantify phase clustering. PMID- 29247675 TI - Adrenergic and glucocorticoid receptor antagonists reduce ozone-induced lung injury and inflammation. AB - Recent studies showed that the circulating stress hormones, epinephrine and corticosterone/cortisol, are involved in mediating ozone-induced pulmonary effects through the activation of the sympathetic-adrenal-medullary (SAM) and hypothalamus-pituitary-adrenal (HPA) axes. Hence, we examined the role of adrenergic and glucocorticoid receptor inhibition in ozone-induced pulmonary injury and inflammation. Male 12-week old Wistar-Kyoto rats were pretreated daily for 7days with propranolol (PROP; a non-selective beta adrenergic receptor [AR] antagonist, 10mg/kg, i.p.), mifepristone (MIFE; a glucocorticoid receptor [GR] antagonist, 30mg/kg, s.c.), both drugs (PROP+MIFE), or respective vehicles, and then exposed to air or ozone (0.8ppm), 4h/d for 1 or 2 consecutive days while continuing drug treatment. Ozone exposure alone led to increased peak expiratory flow rates and enhanced pause (Penh); with greater increases by day 2. Receptors blockade minimally affected ventilation in either air- or ozone-exposed rats. Ozone exposure alone was also associated with marked increases in pulmonary vascular leakage, macrophage activation, neutrophilic inflammation and lymphopenia. Notably, PROP, MIFE and PROP+MIFE pretreatments significantly reduced ozone-induced pulmonary vascular leakage; whereas PROP or PROP+MIFE reduced neutrophilic inflammation. PROP also reduced ozone-induced increases in bronchoalveolar lavage fluid (BALF) IL-6 and TNF-alpha proteins and/or lung Il6 and Tnfalpha mRNA. MIFE and PROP+MIFE pretreatments reduced ozone-induced increases in BALF N-acetyl glucosaminidase activity, and lymphopenia. We conclude that stress hormones released after ozone exposure modulate pulmonary injury and inflammatory effects through AR and GR in a receptor-specific manner. Individuals with pulmonary diseases receiving AR and GR-related therapy might experience changed sensitivity to air pollution. PMID- 29247677 TI - Brainstem GLP-1 signalling contributes to cancer anorexia-cachexia syndrome in the rat. AB - The cancer anorexia-cachexia syndrome (CACS) is a frequent and severe condition in cancer patients. Currently, no pharmacological treatment is approved for the therapy of CACS. Centrally, glucagon-like peptide-1 (GLP-1) is expressed in the nucleus tractus solitarii (NTS) and is implicated in malaise, nausea and food aversion. The NTS is reciprocally connected to brain sites implicated in the control of energy balance including the area postrema (AP), which mediates CACS in certain tumour models. Given the role of GLP-1 as a mediator of anorexia under acute sickness conditions, we hypothesized that brainstem GLP-1 signalling might play a role in the mediation of CACS. Using hepatoma tumour-bearing (TB) rats, we first tested whether the chronic delivery of the GLP-1R antagonist exendin-9 (Ex 9) into the fourth ventricle attenuates CACS. Second, we investigated whether a genetic knockdown of GLP-1 expression in the NTS ameliorates CACS. Ex-9 attenuated anorexia, body weight loss, muscle and fat depletion compared to TB controls. Similarly, TB animals with a knockdown of GLP-1 expression in the NTS had higher food intake, reduced body weight loss, and higher lean and fat mass compared to TB controls. Our study identifies brainstem GLP-1 as crucial mediator of CACS in hepatoma TB rats. The GLP-1R represents a promising target against CACS and possibly other forms of disease-related anorexia/cachexia. PMID- 29247680 TI - Changes in steroid profiles of the blue mussel Mytilus trossulus as a function of season, stage of gametogenesis, sex, tissue and mussel bed depth. AB - This paper describes changes in the content of free steroid hormones e.g. testosterone (T), estradiol-17beta (E2), estrone (E1) and estriol (E3) of Mytilus trossulus from the southern Baltic Sea as a function of season, stage of gametogenesis, sex, tissue (gonadal and somatic) and depth. The highest levels of T, E2, E1 and E3 were found in mussels sampled in spring and summer while the lowest levels were found in winter. This pattern was stable and was seen in both sexes and tissues in mussels from both mussel beds. The spring and summer peaks in steroid levels (SL) coincided with advanced levels of gametogenesis (the highest gonadal index, GI) of our model species. But, the lowest GI (autumn) and the lowest steroids content (winter) did not overlap. Instead, water temperature increase was followed by increase of SL and vice versa. This suggests that steroids may not be actively involved in the early stages of gamete development and does not preclude them from potentially being involved as endogenous modulators in the final stages of reproduction (e.g. spawning). Hence, observed fluctuations in SL in our model species are unlikely to be caused by reproductive cycle but are rather of unknown nature, likely linked with environmental conditions. Sex-related differences in steroid content included estrogen domination in females and androgen domination in males. A trend towards higher level of steroids in gills than in gonads was found, supporting the hypothesis about an exogenous origin of steroids in bivalves. However, based on the present results, we cannot exclude the possibility that these steroids have both an endogenous and exogenous origin. PMID- 29247679 TI - Anti-leptin receptor antibodies strengthen leptin biofunction in growing chickens. AB - Antibodies against the extracellular domains of the chicken leptin receptor were used to study the biological function of leptin in growing chickens. Both polyclonal and monoclonal anti-LEPR antibodies were administered intramuscularly to 30-d-old Chinese indigenous Gushi pullets. Both antibody preparations increased feed intake for 6 h after injection and reduced plasma concentrations of glucose, triglycerides, and both high- and low-density lipoproteins. The antibody treatments also upregulated agouti-related peptide and neuropeptide Y in the hypothalamus and downregulated proopiomelanocortin, melanocortin 4 receptor, and leptin receptor. The treatments also upregulated leptin receptor, acetyl CoA carboxylase beta, and acyl-CoA oxidase in the liver, abdominal fat, and breast muscle and downregulated sterol regulatory element-binding protein-1 and fatty acid synthase. Furthermore, even though the anti-leptin receptor antibodies failed to affect leptin receptor signaling transduction when administered alone, they did augment the induction of leptin receptor signaling transduction by leptin. These results demonstrate that antibodies against the extracellular domains of leptin-specific receptor enhance, but do not mimic, the ability of leptin to activate receptors. Furthermore, the enhanced leptin bioactivity observed after the intramuscular injection of anti-LEPR antibodies confirmed the occurrence of de novo leptin in the peripheral tissues and blood of treated chickens. PMID- 29247681 TI - Chemokines in systemic sclerosis. PMID- 29247678 TI - Absence of synemin in mice causes structural and functional abnormalities in heart. AB - Cardiomyopathies have been linked to changes in structural proteins, including intermediate filament (IF) proteins located in the cytoskeleton. IFs associate with the contractile machinery and costameres of striated muscle and with intercalated disks in the heart. Synemin is a large IF protein that mediates the association of desmin with Z-disks and stabilizes intercalated disks. It also acts as an A-kinase anchoring protein (AKAP). In murine skeletal muscle, the absence of synemin causes a mild myopathy. Here, we report that the genetic silencing of synemin in mice (synm -/-) causes left ventricular systolic dysfunction at 3months and 12-16months of age, and left ventricular hypertrophy and dilatation at 12-16months of age. Isolated cardiomyocytes showed alterations in calcium handling that indicate defects intrinsic to the heart. Although contractile and costameric proteins remained unchanged in the old synm -/- hearts, we identified alterations in several signaling proteins (PKA-RII, ERK and p70S6K) critical to cardiomyocyte function. Our data suggest that synemin plays an important regulatory role in the heart and that the consequences of its absence are profound. PMID- 29247683 TI - Functional dissection of astrocyte-secreted proteins: Implications in brain health and diseases. AB - Astrocytes, which are homeostatic cells of the central nervous system (CNS), display remarkable heterogeneity in their morphology and function. Besides their physical and metabolic support to neurons, astrocytes modulate the blood-brain barrier, regulate CNS synaptogenesis, guide axon pathfinding, maintain brain homeostasis, affect neuronal development and plasticity, and contribute to diverse neuropathologies via secreted proteins. The identification of astrocytic proteome and secretome profiles has provided new insights into the maintenance of neuronal health and survival, the pathogenesis of brain injury, and neurodegeneration. Recent advances in proteomics research have provided an excellent catalog of astrocyte-secreted proteins. This review categorizes astrocyte-secreted proteins and discusses evidence that astrocytes play a crucial role in neuronal activity and brain function. An in-depth understanding of astrocyte-secreted proteins and their pathways is pivotal for the development of novel strategies for restoring brain homeostasis, limiting brain injury/inflammation, counteracting neurodegeneration, and obtaining functional recovery. PMID- 29247684 TI - Reply to: Comment on "Serious infections among a large cohort of subjects with systemically treated psoriasis". PMID- 29247682 TI - Collection and storage of HLA NGS genotyping data for the 17th International HLA and Immunogenetics Workshop. AB - For over 50 years, the International HLA and Immunogenetics Workshops (IHIW) have advanced the fields of histocompatibility and immunogenetics (H&I) via community sharing of technology, experience and reagents, and the establishment of ongoing collaborative projects. Held in the fall of 2017, the 17th IHIW focused on the application of next generation sequencing (NGS) technologies for clinical and research goals in the H&I fields. NGS technologies have the potential to allow dramatic insights and advances in these fields, but the scope and sheer quantity of data associated with NGS raise challenges for their analysis, collection, exchange and storage. The 17th IHIW adopted a centralized approach to these issues, and we developed the tools, services and systems to create an effective system for capturing and managing these NGS data. We worked with NGS platform and software developers to define a set of distinct but equivalent NGS typing reports that record NGS data in a uniform fashion. The 17th IHIW database applied our standards, tools and services to collect, validate and store those structured, multi-platform data in an automated fashion. We have created community resources to enable exploration of the vast store of curated sequence and allele-name data in the IPD-IMGT/HLA Database, with the goal of creating a long-term community resource that integrates these curated data with new NGS sequence and polymorphism data, for advanced analyses and applications. PMID- 29247685 TI - Comparison among different "revealers" in the study of accelerated blood clearance phenomenon. AB - The markers are the "revealers" of accelerated blood clearance (ABC) phenomenon. PEGylated nanocarriers labeled with various markers have been used to explore the mechanism of ABC. However, different markers were labeled on different nanocarriers, and the influence of different markers on ABC phenomenon is questionable. In this study, tocopheryl nicotinate (TN), N-(7-nitrobenz-2-oxa-1,3 diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine, triethylammonium salt (NBD-DPPE), and 1,1'-dioctadecyl-3,3,3',3'-tetra methylindotricarbocyanine iodide (DiR) were selected as markers. ABC index(0 30min) was used as an evaluation indicator to reveal ABC phenomenon after repeated injections of PEGylated emulsions (PEs) in Wistar rats. No significant difference was observed in ABC index(0-30min) of PE labeled with the three markers (P>0.05), suggesting that the results of previous studies using these markers were comparable and interchangeable. Of the three markers, TN required tedious analytical method and showed proliferative effect on liver cells, while NBD-DPPE fluorescence was easily interfered by tissues and its phospholipid composition affected ABC analysis. On the contrary, DiR was deemed superior due to its near-infrared fluorescence, high-sensitivity, and convenient analytical detection. PMID- 29247686 TI - Folic acid-modified liposomal drug delivery strategy for tumor targeting of 5 fluorouracil. AB - The aim of this study was to develop a liposomal formulation to selectively target cancer cells. Liposomes were prepared using thin layer method and folic acid (FA) was applied for targeted delivery of 5FU to cancer cells. Liposomes prepared were characterized for encapsulation efficiency (EE%), morphology and their particle size. Cellular uptake, cytotoxicity study and ROS production were evaluated using CT26 cell line. Hemolysis test was performed on rat red blood cells (RBCs). Moreover, the efficacy of targeted liposomes were investigated by in vivo antitumor activity and tissue toxicities were studied by histological examination. The EE% and average particle size of liposomes were 67.88+/-1.84% and 114.00+/-4.58nm, respectively. TEM image revealed that liposomes were spherical in shape. Targeted liposomes showed higher cellular uptake, lower IC50 (12.02MUM compared to 39.81MUM for liposomal 5FU and 39.81MUM for free 5FU) and higher ROS production than free drug (62,271.28 vs 2369.55 fluorescence intensity) on cancer cells. Results of hemolysis assay confirmed the blood biocompatibility of the liposomes. Moreover, folate targeted liposomes showed better tumor inhibition than free drug (88.75mm3 tumor volume vs 210.00mm3) and no tissue abnormalities were found in histological examination. It can be concluded that folate targeted liposomes provide an effective and safe strategy for colon cancer targeted chemotherapy. PMID- 29247688 TI - Caffeic acid and resveratrol ameliorate cellular damage in cell and Drosophila models of spinocerebellar ataxia type 3 through upregulation of Nrf2 pathway. AB - Polyglutamine (polyQ)-expanded mutant ataxin-3 protein, which is prone to misfolding and aggregation, leads to cerebellar neurotoxicity in spinocerebellar ataxia type 3 (SCA3), an inherited PolyQ neurodegenerative disease. Although the exact mechanism is unknown, the pathogenic effects of mutant ataxin-3 are associated with dysregulation of transcription, protein degradation, mitochondrial function, apoptosis, and antioxidant potency. In the present study we explored the protective role and possible mechanism of caffeic acid (CA) and resveratrol (Res) in cells and Drosophila expressing mutant ataxin-3. Treatment with CA and Res increased the levels of antioxidant and autophagy protein expression with consequently corrected levels of reactive oxygen species, mitochondrial membrane potential, mutant ataxin-3, and the aggregation of mutant ataxin-3 in SK-N-SH-MJD78 cells. Moreover, in SK-N-SH-MJD78 cells, CA and Res enhanced the transcriptional activity of nuclear factor erythroid-derived-2-like 2 (Nrf2), a master transcription factor that upregulates the expression of antioxidant defense genes and the autophagy gene p62. CA and Res improved survival and motor performance in SCA3 Drosophila. Additionally, the above mentioned protective effects of CA were also observed in CA-supplemented SCA3 Drosophila. Notably, blockade of the Nrf2 pathway by use of small interfering RNA annulled the health effects of CA and Res on SCA3, which affirmed the importance of the increase in Nrf2 activation by CA and Res. Additional studies are need to dissect the protective role of CA and Res in modulating neurodegenerative progression in SCA3 and other polyQ diseases. PMID- 29247687 TI - Genotypic variations between wild-type and small colony variant of Staphylococcus aureus in prosthetic valve infectious endocarditis: a comparative genomic and transcriptomic analysis. AB - Staphylococcus aureus small colony variants (SCVs) can cause persistent infections. However, the genomes and transcriptomes of S. aureus SCVs remain poorly understood. A pair of isogenic wild-type and SCV methicillin-resistant S. aureus (MRSA) strains (IE1 and IE2, respectively) were isolated from a patient with prosthetic valve infectious endocarditis. The SCV strain IE2 grew more slowly than the wild-type strain, and serum killing and mouse lethality assays revealed that the virulence of SCV strain IE2 was decreased. Whole-genome sequencing of the SCV and wild-type strains revealed 15 mutations in nine genes associated with metabolism, virulence and DNA repair, including serine/threonine protein kinase PrkC (prkC), glycerol-3-phosphate acyltransferase (plsY), 2 deoxyribose-5-phosphate aldolase (deoC), extracellular adherence protein (eap), iron compound ABC uptake transporter substrate-binding protein (sstD), RecU Holliday junction resolvase (recU), excinuclease ABC subunit B (uvrB), type I restriction-modification system, M subunit (hsdM) and smooth muscle caldesmon. Sequencing of RNA transcripts revealed that expression levels of 321 genes were upregulated and 582 genes were downregulated in SCV strain IE2 compared with IE1. Most of the differentially expressed genes were involved in metabolism. Expression levels of several genes involved in the pathways to which plsY, deoC, eap and sstD belonged were changed, associated with the metabolism and virulence of S. aureus. In conclusion, the reduced growth rate and decreased virulence of MRSA SCV strains may be related to mutations in and downregulation of genes associated with metabolism and virulence, especially plsY, deoC, eap and sstD. PMID- 29247689 TI - Molecular characterization, RNA interference and recombinant protein approach to study the function of the putative Molt Inhibiting Hormone (FmMIH1) gene from the shrimp Fenneropenaeus merguiensis. AB - The Molt Inhibiting Hormone gene and cDNA of the banana shrimp Fenneropenaeus merguiensis (FmMIH1) has been cloned and characterized. FmMIH1 possesses most of the characteristics of the eyestalk CHH/MIH/GIH family subtype-II neuropeptides. FmMIH1 open reading frame consists of 315 bp encoding for 105 amino acid residues. The mature peptide of FmMIH1 consists of 76 amino acid residues, a glycine residue at position 11 of the mature peptide and 6 cysteine residues located in the conserved position. In addition to eyestalk, high levels of FmMIH1 transcript could also be detected in the intestine. FmMIH1 transcript level is low throughout the post-molt, early to mid-intermolt and premolt. However, a sharp increase could be observed in late intermolt (C3 stage). Both alignment and phylogenetic analysis reveal that FmMIH1 is most similar to the MIH1 of other shrimps. For functional assay, RNA interference results show that a significant 2.3 days (P < 0.05) reduction in molt cycle duration could be observed in shrimp receiving dsFmMIH1 injection. Surprisingly, injection of recombinant FmMIH1 could also cause a significant reduction of the molt cycle (average 1.9 days, P < 0.05). We hypothesize that the recombinant protein is biological inactive but it competes with the endogenous MIH for carrier protein binding and consequently reduces the amount of biological MIH that could reach the targets. In conclusion, the result of this study will provide us new insight in molting/growth control in crustacean. PMID- 29247690 TI - Dermal peptide delivery using enhancer moleculs and colloidal carrier systems. Part II: Tetrapeptide PKEK. AB - Due to the lipophilic properties of the uppermost skin layer of the stratum corneum (SC) it is highly challenging to reach therapeutic concentrations of cosmetic actives and drugs. Particularly, the hydrophilic ones penetrate poorly across the SC. The purpose of this study was to improve the topical bioavailability of the hydrophilic, polar tetrapeptide PKEK (amino acid sequence in one-letter notation). A nano-sized carrier system (microemulsion, ME) was therefore developed since MEs provide excellent penetration enhancing properties. The penetration of PKEK from the ME was compared to the penetration from a standard formulation. For the two preparations the penetration of the tetrapeptide in ex vivo human skin was investigated. This allows to make statements regarding dermal penetration, localization and distribution of the active substances in each skin layer as well as the influence of vehicle variations, in this case the incorporation of PKEK into a ME system. Relatively high amounts between 40 and 58% of the tetrapeptide PKEK penetrated from the standard cream into the skin. The major proportion of PKEK, which penetrated from the standard cream, remained in the SC and did not reach the target compartment within the skin. Penetration of PKEK from the ME was comparable with the cream for the shortest test time. However, very high PKEK amounts penetrated form the nano-sized carrier system (ME) into the human skin after 100 min (94%) and after 300 min (88%). The largest proportion did not remain in the skin, but permeated into the acceptor compartment. Therefore, the relative peptide content in the viable skin layers was predominantly comparable for the cream and the ME. For some samples a tendency could be observed that slightly higher amounts of PKEK were detected after the application of the standard cream. The absolute peptide concentrations gave a similar conclusion. The results indicate that liquid nano sized systems are very effective carriers for extremely hydrophilic peptides used in cosmetics and also in therapeutics. PMID- 29247691 TI - Single dose HBsAg CS-gamma-PGA nanogels induce potent protective immune responses against HBV infection. AB - Hepatitis B virus (HBV) infection is a severe threat to public health, which can be prevented by prophylactic vaccination. Here, we tested nanogels carriers in the prophylactic effect of hepatitis B surface antigen (HBsAg) vaccine. HBsAg nanogels (Ng) were prepared using chitosan (CS) and poly-gamma-glutamic acid (gamma-PGA). Positively charged Ng (+) and negatively charged Ng (-) were prepared by adjusting the CS and gamma-PGA proportion. Dendritic cells (DCs) maturation in mice immunized with HBsAg Ng (+) and HBsAg Ng (-) could be augmented in response to pAAV/HBV1.2 plasmid challenge. Single-dose immunization with HBsAg Ng (+) induced HBsAg specific-antibodies. HBsAg Ng (+) immunized mice cleared HBsAg and restored anti-HBs production after pAAV/HBV1.2 plasmid challenge. Single-dose HBsAg Ng (+) induced humoral and cellular immunity, and could induce effector memory T cells. Single-dose HBsAg Ng (-) favored the induction of cellular immunity, and induced central memory T cells and effector memory T cells. However, HBsAg elimination was similar between HBsAg Ng (+)- and HBsAg Ng (+) plus HBsAg Ng (-)-immunized mice. Zeta potential measurements showed that HBsAg Ng (+) were more stable than HBsAg Ng (-). Therefore, Ng (+) are desirable HBsAg prophylactic vaccine carriers, providing long-term protection against HBV, and are a good choice to study and apply weakly immunostimulatory antigens. PMID- 29247692 TI - Granzyme B in skin inflammation and disease. AB - Granzyme B (GzmB) is a serine protease emerging as an important mediator of skin injury, inflammation and repair. Found at low levels in healthy skin, GzmB is dramatically elevated in chronic disease and inflammatory skin disorders, including diabetic ulcers, hypertrophic scarring, autoimmune skin disorders, cutaneous leishmaniasis and aging skin. Traditionally known for its pro-apoptotic function, the role of GzmB in disease has been redefined due to the discovery of additional activities involving the cleavage of extracellular matrix proteins, epithelial barrier disruption, fibrosis, vascular permeability, anoikis, inflammation and autoimmunity. In addition to the accumulation of GzmB+ cells in diseased tissue, and critical to the mechanistic redefinition, is the realization that GzmB often accumulates in the extracellular milieu, retains its activity in plasma, and is expressed by both immune and non-immune cells that may or may not express perforin, the pore-forming protein required for GzmB internalization into target cells. As GzmB is not normally found in the extracellular milieu, and does not appear to be regulated, GzmB-mediated proteolysis can impact processes such as tissue remodelling, barrier function, autoantigen generation and angiogenesis. The present review will summarize and critically examine the current knowledge regarding GzmB in inflammatory skin disease, providing an overview of both apoptotic and extracellular mechanisms, but with a focus on the extracellular roles of GzmB in skin health and disease. PMID- 29247694 TI - The selective cleaning behaviour of juvenile blue-headed wrasse (Thalassoma bifasciatum) in the Caribbean. AB - Through the removal of parasites, dead skin and mucus from the bodies of visiting reef fish (clients), cleaner fish have a significant ecosystem function in the ecology of coral reefs. Cleaners gain nutrition from these interactions and through offering a 'service' are afforded protection from predators. Given these benefits, it is unclear why more fish do not engage in cleaning, and why part time cleaning strategies exist. On coral reefs, dedicated species clean throughout their life, whereas some species are facultative, employing opportunistic and/or temporary cleaning strategies. Here, we investigate the cleaning behaviour of a facultative species to assess the relative importance of this interaction to the cleaner. Using a combination of focal and event sampling from a coral reef in Tobago, we show that cleaning is not an essential food source for facultative juvenile blue-headed wrasse (Thalassoma bifasciatum), as cleaning rate was unrelated to their foraging rate on the substrate. These wrasse displayed two cleaning strategies: stationary versus wandering cleaning, with cleaning frequency being highest for stationary cleaners. A specific cleaning location facilitated increased cleaning frequency, and wrasse cleaning rate decreased as cleaner or client abundance increased. We also compared juvenile blue-headed wrasse cleaning behaviour to a resident dedicated cleaner, the sharknose goby (Elacatinus evelynae), and showed that, in comparison, juvenile wrasse clean a narrower client range, predominately cleaning three species of gregarious free-ranging surgeonfish (Acanthurus spp.). The wrasse, however, frequently approached these clients without cleaning, which suggests that their selective cleaning strategy may be driven by the acquisition of a particular parasitic food source. Juvenile blue-headed wrasse are generalist foragers, and may thus be limited in their cleaning behaviour by their nutritional requirements, the availability of a suitable cleaning site, and fish density, which ultimately means that they do not adopt more dedicated cleaning roles within the reef community. PMID- 29247693 TI - Understanding cardiac extracellular matrix remodeling to develop biomarkers of myocardial infarction outcomes. AB - Cardiovascular Disease (CVD) is the most common cause of death in industrialized countries, and myocardial infarction (MI) is a major CVD with significant morbidity and mortality. Following MI, the left ventricle (LV) undergoes a wound healing response to ischemia that results in extracellular matrix (ECM) scar formation to replace necrotic myocytes. While ECM accumulation following MI is termed cardiac fibrosis, this is a generic term that does not differentiate between ECM accumulation that occurs in the infarct region to form a scar that is structurally necessary to preserve left ventricle (LV) wall integrity and ECM accumulation that increases LV wall stiffness to exacerbate dilation and stimulate the progression to heart failure. This review focuses on post-MI LV ECM remodeling, targeting the discussion on ECM biomarkers that could be useful for predicting MI outcomes. PMID- 29247696 TI - Is state-dependent valuation more adaptive than simpler rules? AB - McNamara et al. (2012) claim to provide an explanation of certain systematic deviations from rational behavior using a mechanism that could arise through natural selection. We provide an arguably much simpler mechanism in terms of computational limitations, that performs better in the environment described by McNamara et al. (2012). To argue convincingly that animals' use of state dependent valuation is adaptive and is likely to be selected for by natural selection, one must argue that, in some sense, it is a better approach than the simple strategies that we propose. PMID- 29247695 TI - Neural activity associated with rhythmicity of song in juvenile male and female zebra finches. AB - Rhythm is an important aspect of both human speech and birdsong. Adult zebra finches show increased neural activity following exposure to arrhythmic compared to rhythmic song in regions similar to the mammalian auditory association cortex and amygdala. This pattern may indicate that birds are detecting errors in the arrhythmic song relative to their learned song template or to more general expectations of song structure. Here we exposed juvenile zebra finches to natural conspecific song (rhythmic) or song with altered inter-syllable intervals (arrhythmic) prior to or during template formation, or afterward as males are matching vocal production to a memorized song template (sensorimotor integration). Before template formation, expression of the immediate early gene ZENK was increased in the caudomedial nidopallium (NCM) of birds exposed to rhythmic relative to arrhythmic song. During template formation, ZENK expression was increased in the caudomedial mesopallium (CMM) of birds exposed to arrhythmic relative to rhythmic song. These results suggest that the youngest birds may be predisposed to respond to a more natural stimulus, and a template may be required for arrhythmic song to elicit increased neural activity. It also appears that functional development across the brain regions investigated continues to maturity. PMID- 29247697 TI - Antiallergic and antihistaminic actions of Ceasalpinia bonducella seeds: Possible role in treatment of asthma. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Seed kernel of the plant Ceasalpinia bonducella Linn (Caesalpiniacaeae) are used for the treatment of asthma in folk medicine and ancient books. AIM OF STUDY: To assess the pharmacological efficacy of the plant in asthma and to confine and describe the synthetic constituents from the seeds that are in charge of the action. MATERIAL AND METHODS: The viability of petroleum ether, ethanol extract and ethyl acetate fraction from ethanol extract of C. bonducella seeds were screened for the treatment of asthma by various methods viz. effect of test drug on clonidine and haloperidol induced catalepsy, milk-induced leukocytosis and eosinophilia, mast cell stabilizing activity in mice and studies on smooth muscle preparation of guinea pig ileum (in-vitro). Column chromatography of active extract was done to pinpoint the active compound followed by structure elucidation by FTIR, GCMS and NMR spectroscopic methods. RESULTS: Ethyl acetate fraction from ethanol extract of C. bonducella seeds exhibited antihistaminic activity at the dose of 50 and 100 mg/kg, inhibited clonidine-induced catalepsy but not haloperidol-induced catalepsy. Ethyl acetate fraction from ethanol extract significantly inhibited increased leukocyte and eosinophil count due to milk allergen and showed maximum protection against mast cell degranulation by clonidine. The results of guinea pig ileum indicated that the compound 2 methyl, 1 hexadecanol isolated from ethyl acetate fraction of ethanol extract relaxed significantly the ileum muscle strips pre-contracted by which suggests the involvement of beta2-agonists on the relaxation of the tissue. All the results are dose dependent. Active ethyl acetate fraction from ethanol extract showed presence of anti-asthmatic compound, 2-methyl, 1-hexadecanol. CONCLUSION: The ethyl acetate fraction from ethanol extract of seeds of the plant C. bonducella can inhibit parameters linked to asthma disease. PMID- 29247698 TI - Pathway analysis of global gene expression change in dendritic cells induced by the polysaccharide from the roots of Actinidia eriantha. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The roots of Actinidia eriantha Benth have been used clinically to treat a variety of cancers in traditional Chinese medicine. The polysaccharide from this drug (AEPS) was previously reported to be a potential antitumor agent with immunomodulatory activity. However, the mechanisms of its antitumor action in immunomodulation have not yet been well-defined. AIM OF THE STUDY: To investigate the effects of AEPS on the phenotypic and functional maturation of dendritic cells and to explore the intracellular signaling mechanisms of its antitumor action in the immunomodulation. MATERIALS AND METHODS: The effects of AEPS on the phagocytic activity, expression of surface molecules, mRNA and protein expression levels of cytokines and chemokines in mouse bone-marrow derived dendritic cells (BMDCs) were determined by flow cytometry, qRT-PCR and ELISA, respectively. The transcriptional profile induced by AEPS was established using oligonucleotide microarray, and Ingenuity Pathway Analysis (IPA) was used to identify potential signaling pathways. Western blotting, neutralization experiments and inhibition assay were performed to confirm signaling pathway involved in maturation of DCs induced by AEPS. Furthermore, we discussed the downstream effects of the action of AEPS using clustering, network and pathway mapping approaches. RESULTS: AEPS could significantly reduced phagocytic activity, promoted expression of accessory and co-stimulatory molecules, and up-regulated the mRNA and protein expression levels of cytokines and chemokines in BMDCs. Microarray assay revealed that AEPS induced significantly differential expression of 452 genes including up-regulated cytokines (IL-6, IL-1beta, TNF-alpha, IL-10, IL-12p40, IFN-beta and IFN-gamma), chemokines (MIP-1alpha, MIP-1beta, CCL5, MDC and MCP-1), transcription factors (STAT1, STAT2, STAT5b, IRF1 and IRF7) and pattern recognition receptors (TLR3, DDX58, DHX58 and IFIH1) in the BMDCs. AEPS-induced production of TNF-alpha and IL 12p40 from BMDCs was inhibited by antibodies against TLR2 and TLR4. Furthermore, AEPS induced the phosphorylation of NF-kappaB p65 in a time-dependent manner, and BAY 11-7082, an inhibitor of NF-kappaB, remarkably suppressed the production of cytokines induced by AEPS. CONCLUSION: AEPS triggers the phenotypic and functional maturation of DCs via TLR2/4 and NF-kappaB signaling pathway, resulting in augmented antitumor immune responses. Our results suggested that AEPS might be helpful in potentiating the efficiency of DC-based cancer immunotherapy. This study further expanded current knowledge on the mechanisms of antitumor action of AEPS. PMID- 29247700 TI - Cochrane Qualitative and Implementation Methods Group guidance series-paper 3: methods for assessing methodological limitations, data extraction and synthesis, and confidence in synthesized qualitative findings. AB - The Cochrane Qualitative and Implementation Methods Group develops and publishes guidance on the synthesis of qualitative and mixed-method implementation evidence. Choice of appropriate methodologies, methods, and tools is essential when developing a rigorous protocol and conducting the synthesis. Cochrane authors who conduct qualitative evidence syntheses have thus far used a small number of relatively simple methods to address similarly written questions. Cochrane has invested in methodological work to develop new tools and to encourage the production of exemplar reviews to show the value of more innovative methods that address a wider range of questions. In this paper, in the series, we report updated guidance on the selection of tools to assess methodological limitations in qualitative studies and methods to extract and synthesize qualitative evidence. We recommend application of Grades of Recommendation, Assessment, Development, and Evaluation-Confidence in the Evidence from Qualitative Reviews to assess confidence in qualitative synthesized findings. This guidance aims to support review authors to undertake a qualitative evidence synthesis that is intended to be integrated subsequently with the findings of one or more Cochrane reviews of the effects of similar interventions. The review of intervention effects may be undertaken concurrently with or separate to the qualitative evidence synthesis. We encourage further development through reflection and formal testing. PMID- 29247699 TI - Fast and non-destructive pore structure analysis using terahertz time-domain spectroscopy. AB - Pharmaceutical tablets are typically manufactured by the uni-axial compaction of powder that is confined radially by a rigid die. The directional nature of the compaction process yields not only anisotropic mechanical properties (e.g. tensile strength) but also directional properties of the pore structure in the porous compact. This study derives a new quantitative parameter, Sa, to describe the anisotropy in pore structure of pharmaceutical tablets based on terahertz time-domain spectroscopy measurements. The Sa parameter analysis was applied to three different data sets including tablets with only one excipient (functionalised calcium carbonate), samples with one excipient (microcrystalline cellulose) and one drug (indomethacin), and a complex formulation (granulated product comprising several excipients and one drug). The overall porosity, tablet thickness, initial particle size distribution as well as the granule density were all found to affect the significant structural anisotropies that were observed in all investigated tablets. The Sa parameter provides new insights into the microstructure of a tablet and its potential was particularly demonstrated for the analysis of formulations comprising several components. The results clearly indicate that material attributes, such as particle size and granule density, cause a change of the pore structure, which, therefore, directly impacts the liquid imbibition that is part of the disintegration process. We show, for the first time, how the granule density impacts the pore structure, which will also affect the performance of the tablet. It is thus of great importance to gain a better understanding of the relationship of the physical properties of material attributes (e.g. intragranular porosity, particle shape), the compaction process and the microstructure of the finished product. PMID- 29247701 TI - Adaptation or pathology? The role of prenatal stressor type and intensity in the developmental programing of adult phenotype. AB - The mother is the major interface between the offspring and its prenatal environment. Prenatal toxins and stress-inducing physical agents are important factors programming the developmental trajectory of mammals that likely involve epigenetic modifications. However, prenatal stressors commonly-used in the laboratory (e.g. prenatal restraint stress and prenatal chronic variable stress) are typically administered at high intensities. These exposures typically lead to pathological phenotypes supporting the development origin of health and disease hypothesis. In this review, we compare the phenotypic outcomes of these commonly used prenatal stressors to an ecologically-relevant, psychogenic stressor that has been present over evolutionary times, predator or predator cues presence. Prenatal stress by predator threat results in behavioral, physiological, endocrine, transcript abundance and epigenetic (DNA methylation) modifications. These phenotypic modifications are consistent with developmental forecasting according to the Predictive Adaptive Response hypothesis, yielding adaptive responses in environments where such predation stress is present. The evidence described in this review suggests that the type of prenatal stress agent and its intensity modifies the phenotype expressed, which can range from adaptive to pathological. Prenatal Bisphenol A exposure studies are presented as an example where graded intensities (concentrations) of prenatal toxin exposure can be compared directly. Finally, we emphasize the importance of studying both sexes in these studies, as sex differences appear to be a common feature of the response to prenatal stress. PMID- 29247702 TI - Developmental dynamics of the epigenome: A longitudinal study of three toddlers. AB - Epigenetic regulation plays an important role in development, at the embryonic stages and later during the lifespan. Some epigenetic marks are highly conserved throughout the lifespan whereas others are closely associated with specific age periods and/or particular environmental factors. Little is known about the dynamics of epigenetic regulation during childhood, especially during the period of rapid early development. Our study was aimed to determine whether the developmental program at the early stages of human development is accompanied by significant changes in the systems of genome regulation, specifically, by genome wide changes in DNA methylation. Using a sequencing approach (MBD-seq) we investigated genome-wide DNA methylation patterns in the T-lymphocytes of three healthy toddlers at two timepoints within the second year of life. Pairwise comparison of the methylation patterns across the individuals and time points was conducted to determine common longitudinal changes in the DNA methylation patterns. Despite relatively high interindividual variability in their epigenetic profiles and the dynamics of these profiles during the second year of life, all children showed consistent changes in the DNA methylation patterns of genes involved in the control of the immune system and genes related to the development of the CNS. Thereby, we provide evidence that early development might be accompanied by epigenetic changes in specific functional groups of genes; many such epigenetic changes appear to be related to the rapid development of the CNS. PMID- 29247703 TI - Effects of tiotropium bromide on airway hyperresponsiveness and inflammation in mice exposed to organic dust. AB - INTRODUCTION: Acute exposure to organic dust (OD) in pig barns induces intense airway inflammation with neutrophilia and hyperresponsiveness. This reaction is likely associated with increased cholinergic activity. Therefore, the involvement of cholinergic mechanisms in the reaction to acute exposure of OD was investigated in mice using the long-acting muscarinic antagonist tiotropium. METHODS: BALB/c mice received tiotropium (2-200 ng) intranasally on day 1 of the study. On days 2-4, mice received vehicle or OD (25 MUg) intranasally. Airway hyperresponsiveness to methacholine was assessed 24 h following the last OD exposure. Bronchoalveolar lavage (BAL) fluid, lung tissue and blood were collected for analyses. RESULTS: Organic dust elevated airway responsiveness to methacholine compared with controls (PBS) assessed as Newtonian resistance (1.5 +/- 0.1 vs 0.9 +/- 0.1 cm H2O x s/mL), tissue damping (12.4 +/- 1.4 vs 8.9 +/- 0.9 cm H2O?s/mL) and tissue elastance (41.1 +/- 5.3 vs 27.2 +/- 2.5 cm H2O?s/mL). Tiotropium (200 ng) decreased the Newtonian resistance and tissue damping after exposure to PBS or OD. Organic dust exposure increased inflammatory cells in BAL fluid by almost 400%, mainly due to neutrophil influx, which was unaffected by tiotropium. Organic dust increased levels of mainly Th1 mediators. Tiotropium treatment attenuated OD-induced release of IL-2, IL-4 and IL-6. CONCLUSIONS: Tiotropium decreased the OD-induced increase of specific cytokines without influencing the OD-induced increase of airway responsiveness and neutrophil infiltration into the lungs. We conclude that the cholinergic pathway contributes to the pro-inflammatory effects caused by inhalation of OD from pig barns. PMID- 29247704 TI - Increased anti-biofilm efficacy of toluidine blue on Staphylococcus species after nano-encapsulation. AB - BACKGROUND: Photodynamic therapy has been studied as a method for inactivating bacterial growth. Workers have used planktonic bacterial as well as biofilm bacterial cultures to evaluate the potential of photodynamic therapy in inactivating bacteria. However, almost all the studies use a photosensitiser in aqueous solution, which could be detrimental to the efficiency of photodynamic therapy. METHODS: In this study, the photodynamic killing effect of toluidine blue O (TBO) has been investigated on Staphylococcal biofilms in-vitro. The sensitivity of the in-vitro biofilms to photodynamic killing action was compared using different formulations of TBO, different dosages of photosensitiser and different light irradiation strengths. Effect of TBO formulations on bacterial quorum sensing system was evaluated using a colorimetric assay. Finally, dual staining using hoechst and propidium iodide stains was carried out on the photodynamically treated biofilms to visualise and compare the effects of photodynamic therapy. Scanning electron microscope imagery was also carried out to evaluate the photodynamic killing effect on the in-vitro biofilms. RESULTS: The sensitivity of biofilms to the photodynamic killing effect increased proportionally with the photosensitiser dosage and the light irradiation duration. TBO encapsulated in microemulsion was more effective in killing the biofilm bacteria than only TBO in water. The combination of TBO in microemulsion with EDTA was another effective way of increasing the photodynamic killing effect on the bacterial biofilms. Effect of encapsulated TBO on the quorum sensing system of bacteria was greater than the effect of aqueous solution of TBO. The in vitro Staphylococcal biofilms could thus be inhibited by the photodynamic effect, and TBO encapsulated in microemulsion was much more effective than only TBO in water. CONCLUSIONS: The encapsulation of a photosensitiser is an effective way of increasing the likelihood of the complete and successful inactivation of the biofilm growth. The encapsulated photosensitiser achieves higher inactivation of the bacterial biofilm than that of the aqueous solution of a photosensitiser. PMID- 29247705 TI - Transcriptome and Metabolic Profiling Provides Insights into Betalain Biosynthesis and Evolution in Mirabilis jalapa. AB - Betalains are tyrosine-derived pigments that occur solely in one plant order, the Caryophyllales, where they largely replace the anthocyanins in a mutually exclusive manner. In this study, we conducted multi-species transcriptome and metabolic profiling in Mirabilis jalapa and additional betalain-producing species to identify candidate genes possibly involved in betalain biosynthesis. Among the candidates identified, betalain-related cytochrome P450 and glucosyltransferase type genes, which catalyze tyrosine hydroxylation or (hydroxy)cinnamoyl-glucose formation, respectively, were further functionally characterized. We detected the expression of genes in the flavonoid/anthocyanin biosynthetic pathways as well as their metabolite intermediates in betalain-accumulating M. jalapa flowers, and found that the anthocyanin-related gene ANTHOCYANIDIN SYNTHASE (MjANS) is highly expressed in the betalain-accumulating petals. However, it appears that MjANS contains a significant deletion in a region spanning the corresponding enzyme active site. These findings provide novel insights into betalain biosynthesis and a possible explanation for how anthocyanins have been lost in this plant species. Our study also implies a complex, non-uniform history for the loss of anthocyanin production across betalain producers, previously assumed to be strictly due to diminished expression of anthocyanin-related genes. PMID- 29247706 TI - Episodes of the epidemiological factors correlated with prevailing viral infections with dengue virus and molecular characterization of serotype-specific dengue virus circulation in eastern India. AB - BACKGROUND: Dengue is one of the most important and widespread viral infection comprises 4 related serotypes (DEN-1, 2, 3, and 4). Infection with one serotype does not protect against the others, and sequential infections put people at greater risk for dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). This study determines the epidemiology of prevailing viral infections with dengue and molecular characterization of serotype-specific DENV circulation in Odisha of eastern India. METHODS: During the year 2013, 1980 blood samples with suspected dengue cases were obtained between days 1-10 of illness and analyzed by NS1 Ag RDT, NS1 Ag-ELISA, and RT-PCR. The differential detection of dengue infections and DENV serotyping were carried out by IgM/IgG Ab-ELISA and RT-PCR, respectively. RESULTS: Of the 1980 samples, 733 (37.0%) were positive for dengue RNA by RT-PCR. The confirmed cases of dengue were more in males (73.6%) in comparing to females (26.4%). The age group of 15-44years (527 cases, 71.9%) were more susceptible to dengue infections. 656 (89.5%) cases had infected with monotypic infection by different DENV serotype and 77 (10.5%) cases had multitypic infections by multiple serotypes of DENV. Of the total multitypic infections, there were 74 (10.1%) cases had infected with DENV-2 and DENV-3 serotypes at a time; and only 3 (0.4%) cases had the concurrent infections of all three serotypes that were, DENV-1, DENV-2, and DENV-3. Of the 28 DHF cases, there were 17 (2.3%) cases had infected with multitypic infections and 11 (1.5%) cases had infected with monotypic infection. CONCLUSION: Dengue infections have prevailed from the month of July and grasped it's the peak in September. Rain, temperature and relative humidity have favored the dengue infections. Young adults and males are more susceptible to dengue infections. Serotypes DEN-2 followed by DEN-3 was dominant among the confirmed dengue cases. Co-circulation of multitypic infections with multiple DENV serotypes and the emergence of DHF cases suggested that eastern Indian state Odisha was becoming a hyper-endemic province for dengue; therefore, continuous surveillance is suggested for understanding the epidemiology of the diseases and monitoring the changes in the characteristics of circulating DENV strains. PMID- 29247707 TI - The Nitrate-Nitrite-NO Pathway as a Novel Therapeutic Target in Heart Failure with Reduced Ejection Fraction. PMID- 29247708 TI - Modulation the expression of natural killer cell activating receptor (NKp44) in the peripheral blood of diffuse large B-cell lymphoma patients and the correlation with clinic pathological features. AB - NK cell activation is one strategy to improve the immunotherapy of non-Hodgkin's lymphoma. So, we aimed to investigate expression of Natural killer cell activating receptor NKp44 in patients with diffuse large B-cell lymphoma (DLBCL) and its correlation with clinic pathological data. In this study, 30 new cases with DLBCL in addition to 20 healthy control were involved. All were submitted to full history, clinical examination, histopathology, Routine laboratory investigations including CBC, LDH, beta2microgloubine and bone marrow examination. Cell culture of peripheral blood mononuclear cells and expression of CD56 and NKp44 by flowcytometry was done. We demonstrated increased NK cell populations (CD 56 +ve NKp44 -ve, CD 56 -veNKp44 +ve, total CD 56 +ve) and NKp44 MFI after in-vitro activation in both healthy control and DLBCL cases except for CD 56 +ve NKp44 +ve which significantly increased in patients not in healthy control (p=0.005, 0.601) respectively. No significant difference between the DLBCL and healthy control regarding all NK cell populations without PHA stimulation. However, the culture with PHA in DLBCL showed significant increase in NK cell populations than the healthy control (CD 56 +ve NKp44 +ve 12.37+/ 7.52vs 6.80+/-4.07, p=0.008), (Total CD 56 +ve 18.80+/-8.74vs 12.66+/-5.17, p=0.017), (MFI of NKp44 10.95+/-6.18vs 5.58+/-1.70, p=0.001). Regarding the association with clinic pathologic features, increased expression of NKp44 was associated with lower values of LDH and earlier stages of DLBCL (p<0.05). So, activating receptor NKp44 can be modulated by in-vitro activation, hence improvement of its function as an approach of immunotherapy of DLBCL. PMID- 29247709 TI - Single nucleotide polymorphism rs1800872 in the promoter region of the IL10 gene is associated with predisposition to chronic hepatitis C in Russian population. AB - Previously, we studied an association of two IL28B gene single nucleotide polymorphisms (SNPs) and three IL10 gene SNPs with predisposition to tick-borne encephalitis in a Russian population. In this study, a possible involvement of these SNPs in the development of predisposition to chronic hepatitis C (caused by structurally similar, related virus from the Flaviviridae family) was investigated in the same population. Only the IL10 promoter rs1800872 SNP was associated with predisposition to chronic hepatitis C. This SNP seems to be a common genetic marker of predisposition to two diseases caused by hepatitis C and tick-borne encephalitis viruses in Russian population. PMID- 29247710 TI - Oropouche fever, an emergent disease from the Americas. AB - Oropouche virus is the aetiological agent of Oropouche fever, a zoonotic disease mainly transmitted by midges of the species Culicoides paraensis. Although the virus was discovered in 1955, more attention has been given recently to both the virus and the disease due to outbreaks of Oropouche fever in different areas of Brazil and Peru. Serological studies in human and wild mammals have also found Oropouche virus in Argentina, Bolivia, Colombia, and Ecuador. Several mammals act as reservoirs of the disease, although the sylvatic cycle of Oropouche virus remains to be assessed properly. Oropouche fever lacks key symptoms to be differentiated from other arboviral febrile illnesses from the Americas. Sporadic cases of aseptic meningitis have also been described with good prognosis. Habitat loss can increase the likelihood of Oropouche virus emergence in the short-term in South America. PMID- 29247712 TI - Effects of normobaric hypoxia on upper body critical power and anaerobic working capacity. AB - PURPOSE: To evaluate the effects of moderate normobaric hypoxia on the parameters of the work-time relationship in the upper body. METHODS: Twenty-one recreationally active men completed a graded exercise test in both normobaric hypoxia (H) and normoxia (N) to exhaustion on an arm ergometer to determine VO2peak and peak power output (PPO). Each participant completed four constant work-rate (CWR) arm-cranking tests at 90-120% PPO in both environmental conditions. Linear regression was used to estimate critical power (CP) and anaerobic working capacity (AWC) via work-time relationship during the CWR tests. RESULTS: H significantly reduced VO2peak (N: 2.34 +/- 0.34 L vs. H: 2.27 +/- 0.34 L, p = 0.041), PPO (N: 125.29 +/- 17.98 W vs. H: 121.11 +/- 17.98 W, p = 0.001), and CP (N: 90.22 +/- 12.88 W vs. H: 85.26 +/- 9.64 W, p = 0.042), but had no effect on AWC (N: 9.16 +/- 2.81 kJ vs. H: 8.75 +/- 3.23 kJ, p = 0.600). DISCUSSION: Moderate normobaric hypoxia appears to reduce CP in the upper body but has a variable effect on AWC. PMID- 29247713 TI - Role of microglia-neuron interactions in diabetic encephalopathy. AB - In the central nervous system, the primary immune cells, the microglia, prevent pathogenic invasion as the first line of defense. Microglial energy consumption is dependent on their degree of activity. Microglia express transporters for the three primary energy substrates (glucose, fatty acids, glutamine) and regulate diabetic encephalopathy via microglia-neuron interactions. Microglia may play a sentry role for rapid protection or even ablation of impaired neurons. Neurons exhibit hyperactivity in response to hyperglycemia, hyperlipidemia, and neurotoxic factors and release potential microglial activators. Microglial activation is also regulated by proinflammatory factors, caspase-3 activity, P2X7 receptor, interferon regulatory factor-8, and glucocorticoids. Modulation of microglia in diabetic encephalopathy may involve CX3CL1, p38 MAPK, purinergic, and CD200/CD200R signaling pathways, and pattern recognition receptors. The microglia-neuron interactions play an important role in diabetic encephalopathy, and modulation of microglial activation may be a therapeutic target for diabetic encephalopathy. PMID- 29247711 TI - Hexokinase 2 confers resistance to cisplatin in ovarian cancer cells by enhancing cisplatin-induced autophagy. AB - The high mortality rate of ovarian cancer is connected with the development of acquired resistance to multiple cancer drugs, especially cisplatin. Activation of cytoprotective autophagy has been implicated as a contributing mechanism for acquired cisplatin resistance in ovarian cancer cells. Hexokinase 2 (HK2) phosphorylates glucose to generate glucose-6-phosphate, the rate-limiting step in glycolysis. Higher HK2 expression has been associated with chemoresistance in ovarian cancer. However, whether HK2 functionally contributes to cisplatin resistance in ovarian cancer is unclear. In this study, we investigated the role of HK2 in regulating ovarian cancer cisplatin resistance. Increased HK2 levels were detected in drug-resistant human ovarian cancer cells and tissues. Cisplatin downregulated HK2 in cisplatin-sensitive but not in resistant ovarian cancer cells. HK2 knockdown sensitized resistant ovarian cancer cells to cisplatin induced cell death and apoptosis. Conversely, HK2 overexpression in cisplatin sensitive cells induced cisplatin resistance. Mechanistically, cisplatin increased ERK1/2 phosphorylation as well as autophagic activity. Blocking autophagy with the autophagy inhibitor 3-MA sensitized resistant ovarian cancer cells to cisplatin. HK2 overexpression enhanced cisplatin-induced ERK1/2 phosphorylation and autophagy while HK2 knockdown showed the opposite effects. Blocking the MEK/ERK pathway using the MEK inhibitor U0126 prevented cisplatin induced autophagy enhanced by HK2 overexpression. Furthermore, HK2 knockdown sensitized resistance ovarian tumor xenografts to cisplatin in vivo. In conclusion, our data supported that HK2 promotes cisplatin resistance in ovarian cancer by enhancing drug-induced, ERK-mediated autophagy. Therefore, targeting HK2 may be a new therapeutic strategy to combat chemoresistance in ovarian cancer. PMID- 29247714 TI - Multifaceted roles of basophils in health and disease. AB - Until recently, basophils had often been neglected in immunologic studies because of their minority status among immune cells or confused with tissue-resident mast cells because of some phenotypic similarities between them in spite of different anatomic localization. It is now appreciated that basophils and mast cells are distinct cell lineages and that basophils play important and nonredundant roles distinct from those played by mast cells. On the one hand, basophils contribute beneficially to protective immunity, particularly against parasitic infections. On the other hand, basophils are involved in the development of various disorders, including allergy and autoimmune disease. Basophils interact with other immune cells and nonhematopoietic cells through cell-to-cell contact or basophil-derived factors, such as cytokines and proteases, contributing to the regulation of immune and allergic responses. In this review article we highlight recent advances in our understanding of basophil pathophysiology in human subjects and animal models by consolidating research findings reported during the past 5 years. Further studies on basophils and their products will help identify suitable targets for novel therapeutics in allergy and effective vaccines against parasitic infection. PMID- 29247715 TI - The neonatal window of opportunity-early priming for life. PMID- 29247717 TI - Higher order thalamic nuclei resting network connectivity in early schizophrenia and major depressive disorder. AB - The pulvinar and the mediodorsal (MDN) nuclei of the thalamus are higher order nuclei which have been implicated in directed effort and corollary discharge systems. We used seed-based resting fMRI to examine functional connectivity to bilateral pulvinar and MDN in 24 schizophrenic patients (SZ), 24 major depressive disorder patients (MDD), and 24 age-matched healthy controls. SZ had less connectivity than controls between the left pulvinar and precuneus, left ventral lateral prefrontal cortex (vlPFC), and superior and medial-frontal regions, between the right pulvinar and right frontal pole, and greater connectivity between the right MDN and left dorsolateral prefrontal cortex (dlPFC). SZ had less connectivity than MDD between the left pulvinar and ventral anterior cingulate (vACC), left vlPFC, anterior insula, posterior cingulate cortex (PCC), and right hippocampus, between the right pulvinar and right PCC, and between the right MDN and right dorsal anterior cingulate (dACC). This is the first study to measure the functional connectivity to the higher order nuclei of the thalamus in both SZ and MDD. We observed less connectivity in SZ than MDD between pulvinar and emotional encoding regions, a directed effort region, and a region involved in representation and salience, and between MDN and a directed effort region. PMID- 29247718 TI - Important signals regulating coronary artery angiogenesis. AB - Angiogenesis is a complex process of budding, the formation of new blood vessels from pre-existing microvessels, via migration, proliferation and survival. Vascular angiogenesis factors include different classes of molecules that have a fundamental role in blood vessel formation. Numerous inducers of angiogenesis, such as the members of the vascular endothelial growth factor (VEGF) family, basic fibroblast growth factor (bFGF), angiopoietin (Ang), hepatocyte growth factor (HGF), and hypoxia inducible factor-1 (HIF-1), have an important role in angiogenesis. However, VEGF, platelet-derived growth factor (PDGF), and transforming growth factor beta (TGF-beta) expression appear to be important in intraplaque angiogenesis. Interaction and combined effects between growth factors is essential in endothelial cell migration, proliferation, differentiation, and endothelial cell-cell communication that ultimately lead to the microvessel formation. Since VEGF has a key role during angiogenesis; it may be considered as a good therapeutic target in the clinic. The essential function of several angiogenic factors involved in coronary angiogenesis and intraplaque angiogenesis in atherosclerosis are carefully considered along with the use of angiogenic factors in clinical practice. PMID- 29247716 TI - Airway exposure initiates peanut allergy by involving the IL-1 pathway and T follicular helper cells in mice. AB - BACKGROUND: Little is currently known regarding the immunologic mechanism(s) that initiate peanut allergy. Notably, peanut proteins have been detected in house dust, and their levels correlate with peanut allergy prevalence. OBJECTIVE: This study aimed to develop a new mouse model for peanut allergy and to investigate the immunologic mechanisms involved in peanut allergen sensitization. METHODS: To mimic environmental exposure, naive mice were exposed to peanut flour by inhalation for up to 4 weeks. We then analyzed serum levels of IgE antibody and challenged mice with peanut proteins. Immunological mechanisms involved in sensitization were analyzed using cytokine reporter mice, an adoptive cell transfer model, and gene knockout mice. RESULTS: When exposed to peanut flour by inhalation, both BALB/c and C57BL/6 mice developed peanut allergy, as demonstrated by the presence of peanut-specific IgE antibodies and manifestation of acute anaphylaxis on challenge. A large number of follicular helper T (Tfh) cells were also detected in draining lymph nodes of allergic mice. These cells produced IL-4 and IL-21, and they more robustly promoted peanut-specific IgE production than Th2 cells did. Genetic depletion of Tfh cells decreased IgE antibody levels and protected mice from anaphylaxis, without affecting Th2 cells. Furthermore, peanut flour exposure increased lung levels of IL-1alpha and IL 1beta, and mice deficient in the receptor for these cytokines showed a significant decrease in Tfh cells compared with in wild-type mice. CONCLUSIONS: Tfh cells play a key role in peanut allergy, and the IL-1 pathway is involved in the Tfh response to peanut allergen exposure. PMID- 29247719 TI - Developmental changes of l-arginine transport at the blood-brain barrier in rats. AB - l-Arginine is required for regulating synapse formation/patterning and angiogenesis in the developing brain. We hypothesized that this requirement would be met by increased transporter-mediated supply across the blood-brain barrier (BBB). Thus, the purpose of this work was to test the idea that elevation of blood-to-brain l-arginine transport across the BBB in the postnatal period coincides with up-regulation of cationic acid transporter 1 (CAT1) expression in developing brain capillaries. We found that the apparent brain-to-plasma concentration ratio (Kp, app) of l-arginine after intravenous administration during the first and second postnatal weeks was 2-fold greater than that at the adult stage. Kp, app of l-serine was also increased at the first postnatal week. In contrast, Kp, app of d-mannitol, a passively BBB-permeable molecule, did not change, indicating that increased transport of l-arginine and l-serine is not due to BBB immaturity. Double immunohistochemical staining of CAT1 and a marker protein, glucose transporter 1, revealed that CAT1 was localized on both luminal and abluminal membranes of brain capillary endothelial cells during the developmental and adult stages. A dramatic increase in CAT1 expression in the brain was seen at postnatal day 7 (P7) and day 14 (P14) and the expression subsequently decreased as the brain matured. In accordance with this, intense immunostaining of CAT1 was observed in brain capillaries at P7 and P14. These findings strongly support our hypothesis and suggest that the supply of blood born l-arginine to the brain via CAT1 at the BBB plays a key role in meeting the elevated demand for l-arginine in postnatal brain. PMID- 29247720 TI - Voltage-gated potassium channels and NOS contribute to a sustained cutaneous vasodilation elicited by local heating in an interactive manner in young adults. AB - Local skin heating to 42 degrees C causes rapid increases in cutaneous perfusion (initial peak), followed by a brief nadir and subsequent sustained elevation (plateau). Several studies have demonstrated that nitric oxide synthase (NOS) largely contributes to the plateau response during local heating. In this study, we tested the hypothesis that voltage-gated potassium (Kv) channels contribute to the plateau of the cutaneous vasodilation during local heating through NOS dependent mechanisms. Eleven young males (25+/-4years) participated in this study wherein cutaneous vascular conductance (CVC) was measured at four intradermal microdialysis sites that were continuously perfused with either 1) lactated Ringer (Control), 2) 10mM 4-aminopyridine (Kv channel blocker), 3) 10mM Nomega Nitro-L-arginine (NOS inhibitor), or 4) a combination of 4-aminopyridine and Nomega-Nitro-L-arginine. In comparison to the Control site, the inhibition of Kv channels alone attenuated the increase in CVC observed at the initial peak, nadir, and plateau phases measured during local heating; in contrast, the inhibition of NOS alone attenuated the increase in CVC at the nadir and plateau phases only (e.g., plateau response: Control site: 59+/-5%max, Kv channel blockade site: 49+/-8%max, NOS inhibition site: 35+/-11%max, combined inhibition site: 40+/-12%max). Further, no effect of Kv channel blockade on CVC was measured at any phase of the local heating response when the modulating influence of NOS was simultaneously removed. We show that Kv channels and NOS contribute to the local heating mediated sustained increase (i.e., plateau) in cutaneous vasodilation in an interactive manner. (243/250 words). PMID- 29247721 TI - Polymorphisms in the canine IL7R 3'UTR are associated with thymic output in Labrador retriever dogs and influence post-transcriptional regulation by microRNA 185. AB - Interleukin-7 (IL-7) and its receptor (IL-7R) are essential for T cell development in the thymus, and changes in the IL-7/IL-7R pathway have been implicated in age-associated thymic involution which results in a reduction of naive T cell output. The aim of this study was to investigate the relationship between IL7 and IL7R genetic variation and thymic output in dogs. No single nucleotide polymorphisms (SNPs) were identified in the canine IL7 gene, but a number were present in the canine IL7R gene. Polymorphisms in the IL7R exon 8 and 3'UTR were found to be associated with signal joint T cell receptor excision circle (sj-TREC) values (a biomarker of thymic output) in young and geriatric Labrador retrievers. Additionally, one of the SNPs in the IL7R 3'UTR (SNP 14 c.1371 + 446 A > C) was found to cause a change in the seed-binding site for microRNA 185 which, a luciferase reporter assay demonstrated, caused changes in post-transcriptional regulation, and therefore might be capable of influencing IL 7R expression. The research findings suggest a genetic link between IL7R genotype and thymic output in dogs, which might impact on immune function as these animals age and provide further evidence of the involvement of IL-7/IL-7R pathway in age associated thymic involution. PMID- 29247722 TI - Two types of lysozymes from the whitefly Bemisia tabaci: Molecular characterization and functional diversification. AB - Lysozyme is well-known as an immune effector in the immune system. Here we identified three genes including one c-type lysozyme, Btlysc, and two i-type lysozymes, Btlysi1 and Btlysi2, from the whitefly Bemisia tabaci. All three lysozymes were constitutively expressed in different tissues and developmental stages, but the two types of lysozymes showed different expression patterns. The expression levels of Btlysi1 and Btlysi2 were dramatically induced after the whitefly fed with different host plants while the expression level of Btlysc kept unchanged. After fungal infection and begomovirus acquisition, Btlysc expression was significantly upregulated while Btlysi1 and Btlysi2 expression were basically not induced. Furthermore, we found that Btlysc showed muramidase and antibacterial activities. Altogether, our results suggest that the two types of lysozymes act in two different ways in B. tabaci, that is, Btlysc is involved in the whitefly immune system while Btlysi1 and Btlysi2 may play a role in digestion or nutrition absorption. PMID- 29247723 TI - Molecular features and the transcriptional and functional delineation of complement system activators C1r and C1s from Sebastes schlegelii. AB - C1r and C1s are serine proteases responsible for activating the classical complement pathway to initiate the complement cascade, which plays a crucial role in eliminating invading pathogenic microbes. In this study, cDNA sequences of C1r and C1s were identified from black rockfish and designated as SsC1r and SsC1s, respectively. In both sequences, two CUB domains, an EGF-like domain, two CCP domains, and a trypsin-like serine protease domain were identified. Multiple sequence alignments with known vertebrate homologs demonstrated that both sequences were highly conserved and, especially, the catalytic and substrate binding residues were completely conserved. In the constructed phylogenetic tree, C1r and C1s formed two separate clusters, which further branched into groups of related organisms. SsC1r and SsC1s joined with their respective teleostean clusters. Transcriptional analysis showed that the highest mRNA expression level was in the liver under normal physiological conditions. Significantly upregulated expression of both mRNAs in spleen and liver after pathologic stress, by intraperitoneal injection with different stimuli, suggested their vital role in immunity. The serine protease domains of SsC1r and SsC1s were cloned and the recombinant proteins were expressed and purified. A protease assay, conducted to confirm their functionality, indicated that both recombinant proteins had proteolytic activity. Taken together, these results indicate that SsC1r and SsC1s have significant properties to aid in the immunity of black rockfish by activating the complement system by proteolytic cleavage. PMID- 29247724 TI - Anti-HBV response to toll-like receptor 7 agonist GS-9620 is associated with intrahepatic aggregates of T cells and B cells. AB - BACKGROUND & AIMS: GS-9620, an oral agonist of toll-like receptor 7, is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the chimpanzee and woodchuck models of CHB. Herein, we investigated the immunomodulatory mechanisms underlying these antiviral effects. METHODS: Archived liver biopsies and paired peripheral blood mononuclear cell samples from a previous chimpanzee study were analyzed by RNA sequencing, quantitative reverse transcription PCR, immunohistochemistry (IHC) and in situ hybridization (ISH). RESULTS: GS-9620 treatment of CHB chimpanzees induced an intrahepatic transcriptional profile significantly enriched with genes associated with hepatitis B virus (HBV) clearance in acutely infected chimpanzees. Type I and II interferon, CD8+ T cell and B cell transcriptional signatures were associated with treatment response, together with evidence of hepatocyte death and liver regeneration. IHC and ISH confirmed an increase in intrahepatic CD8+ T cell and B cell numbers during treatment, and revealed that GS-9620 transiently induced aggregates predominantly comprised of CD8+ T cells and B cells in portal regions. There were no follicular dendritic cells or IgG-positive cells in these lymphoid aggregates and very few CD11b+ myeloid cells. There was no change in intrahepatic natural killer cell number during GS-9620 treatment. CONCLUSION: The antiviral response to GS-9620 treatment in CHB chimpanzees was associated with an intrahepatic interferon response and formation of lymphoid aggregates in the liver. Our data indicate these intrahepatic structures are not fully differentiated follicles containing germinal center reactions. However, the temporal correlation between development of these T and B cell aggregates and the antiviral response to treatment suggests they play a role in promoting an effective immune response against HBV. LAY SUMMARY: New therapies to treat chronic hepatitis B (CHB) are urgently needed. In this study we performed a retrospective analysis of liver and blood samples from a chimpanzee model of CHB to help understand how GS-9620, a drug in clinical trials, suppressed hepatitis B virus (HBV). We found that the antiviral response to GS-9620 was associated with accumulation of immune cells in the liver that can either kill cells infected with HBV or can produce antibodies that may prevent HBV from infecting new liver cells. These findings have important implications for how GS-9620 may be used in patients and may also help guide the development of new therapies to treat chronic HBV infection. PMID- 29247725 TI - Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism. AB - BACKGROUND & AIMS: GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the woodchuck and chimpanzee models of CHB. Herein, we investigated the molecular mechanisms that contribute to the antiviral response to GS-9620 using in vitro models of hepatitis B virus (HBV) infection. METHODS: Cryopreserved primary human hepatocytes (PHH) and differentiated HepaRG (dHepaRG) cells were infected with HBV and treated with GS-9620, conditioned media from human peripheral blood mononuclear cells treated with GS-9620 (GS-9620 conditioned media [GS-9620-CM]), or other innate immune stimuli. The antiviral and transcriptional response to these agents was determined. RESULTS: GS-9620 had no antiviral activity in HBV-infected PHH, consistent with low level TLR7 mRNA expression in human hepatocytes. In contrast, GS-9620-CM induced prolonged reduction of HBV DNA, RNA, and antigen levels in PHH and dHepaRG cells via a type I interferon (IFN)-dependent mechanism. GS-9620-CM did not reduce covalently closed circular DNA (cccDNA) levels in either cell type. Transcriptional profiling demonstrated that GS-9620-CM strongly induced various HBV restriction factors - although not APOBEC3A or the Smc5/6 complex - and indicated that established HBV infection does not modulate innate immune sensing or signaling in cryopreserved PHH. GS-9620-CM also induced expression of immunoproteasome subunits and enhanced presentation of an immunodominant viral peptide in HBV infected PHH. CONCLUSIONS: Type I IFN induced by GS-9620 durably suppressed HBV in human hepatocytes without reducing cccDNA levels. Moreover, HBV antigen presentation was enhanced, suggesting additional components of the TLR7-induced immune response played a role in the antiviral response to GS-9620 in animal models of CHB. LAY SUMMARY: GS-9620 is a drug currently being tested in clinical trials for the treatment of chronic hepatitis B virus (HBV) infection. GS-9620 has previously been shown to suppress HBV in various animal models, but the underlying antiviral mechanisms were not completely understood. In this study, we determined that GS-9620 does not directly activate antiviral pathways in human liver cells, but can induce prolonged suppression of HBV via induction of an antiviral cytokine called interferon. However, interferon did not destroy the HBV genome, suggesting that other parts of the immune response (e.g. activation of immune cells that kill infected cells) also play an important role in the antiviral response to GS-9620. PMID- 29247726 TI - Cryptogenic vs. NASH-cirrhosis: The rose exists well before its name.... PMID- 29247727 TI - Comparative investigation for hypoglycemic effects of polysaccharides from four substitutes of Lonicera japonica in Chinese medicine. AB - The polysaccharide fractions were obtained from flower buds of the four substitutes of Lonicera japonica, L. macranthoides (LMPB), L. hypoglauca (LHPB), L. fulvotomentosa (LFPB) and L. confuse (LCPB), and their hypoglycemic effects were investigated. In study, streptozocin (STZ)-induced diabetic rats were orally administrated once daily with LMPB, LHPB, LFPB and LCPB (each 800 mg/kg) for 42 days. Reduction for food and water intake (p < 0.05, p < 0.01) and levels of sugar and insulin (p < 0.01, p < 0.05) in blood, as well as elevation for contents of liver and skeletal muscle glycogen (p < 0.05) and concentrations of hepatic pyruvate kinase and hexokinase (p < 0.01, p < 0.05) were observed. Together with significant decline of total cholesterol (TC, 45.8 51.0%, p < 0.05), total triglyceride (TG, 50.6-53.8%, p < 0.01), low-density lipoprotein cholesterin (LDL-C, 71.2-76.3%, p < 0.01) and very-low-density lipoprotein cholesterin (VLDL-C, 45.2-50.0%, p < 0.01), the significant rise of high-density lipoprotein-cholesterin (HDL-C, 21.6-24.3%, p < 0.05) were also demonstrated. Consequently, the four polysaccharide fractions displayed notable hypoglycemic effects, similar to that of the polysaccharide fraction from L. japonica (LJP), so that they can be also considered as ingredients of functional foods for type-2 diabetes mellitus (T2DM). PMID- 29247728 TI - Glycine-rich loop encompassing active site at interface of hexameric M. tuberculosis Eis protein contributes to its structural stability and activity. AB - RvEis is a crucial thermostable hexameric aminoglycoside acetyltransferase of Mycobacterium tuberculosis, overexpression of which confers Kanamycin resistance in clinical strains. The thermostability associated with hexameric RvEis is important for the enhanced intracellular survival of mycobacteria. However, the structural determinants responsible for its thermal stability remain unexplored. In this study, we have assessed the role of glycines of conserved glycine-rich motif (G123GIYG127) present at the oligomeric interface in the hydrophobic core of RvEis in sustenance of its structural stability, oligomerization and functional activity. Substitution of glycines to alanine (G123A/G127A) result in significant decrease in melting temperature (Tm), reduction in the oligomerization with concomitant increase in the monomeric form and higher susceptibility towards the denaturants like GdmCl and urea relative to wild type. G123A/G127A mutant displayed lower catalytic efficiency (kcat/Km) and is completely inactive at 60 degrees C. ANS binding assay and the complete dissociation of hexameric complex into monomers at lower concentration of urea in G123A/G127A relative to wtRvEis suggests that altered hydrophobic environment could be the reason for its instability. In sum, these results demonstrate the role of G123GIYG127 motif in structural stability and activity of RvEis. PMID- 29247729 TI - Pramipexole dihydrochloride loaded chitosan nanoparticles for nose to brain delivery: Development, characterization and in vivo anti-Parkinson activity. AB - In the current study, Pramipexole dihydrochloride loaded chitosan nanoparticles (P-CNs) were prepared for Parkinson's disease via nose to brain pathway by ionic gelation method. Optimized P-CNs with chitosan and sodium tripolyphosphate (6:1 v/v) exhibited particle size and entrapment efficiency of 292.5 nm +/- 8.80 and 91.25% +/- 0.95 respectively and its diffusion across the artificial membrane and goat nasal mucosa was found to be 93.32% +/- 2.56 and 83.03% +/- 3.48 correspondingly after 24 h. Transmission electron microscopy displayed the spherical nature of the P-CNs particles and rough surface morphology was observed in scanning electron microphotographs. In pharmacodynamic studies, the comparative results of behavioral testing revealed improved score of photoactometer and reduced motor deficit in the form of catalepsy in P-CN treatment group as compare to its nasal solution or oral marketed tablets. Similarly, P-CNs enhanced antioxidant status in the form of increased superoxide dismutase and catalase activities, along with increased dopamine level in the brain significantly. Therefore, it can be concluded that intranasal delivery of Pramipexole loaded chitosan nanoparticles exhibited essential in vitro characteristics and superior in vivo activity than other formulations for brain targeted delivery in Parkinson disease. PMID- 29247730 TI - Collapse of DNA in packaging and cellular transport. AB - The dawn of molecular biology and recombinant DNA technology arose from our ability to manipulate DNA, including the process of collapse of long extended DNA molecules into nanoparticles of approximately 100 nm diameter. This condensation process is important for the packaging of DNA in the cell and for transporting DNA through the cell membrane for gene therapy. Multivalent cations, such as natural polyamines (spermidine and spermine), were initially recognized for their ability to provoke DNA condensation. Current research is targeted on molecules such as linear and branched polymers, oligopeptides, polypeptides and dendrimers that promote collapse of DNA to nanometric particles for gene therapy and on the energetics of DNA packaging. PMID- 29247731 TI - Engineering poly(hydroxy butyrate-co-hydroxy valerate) based vascular scaffolds to mimic native artery. AB - Electrospun tri-layered fibrous scaffold incorporating VEGF and Platelet Factor Concentrate (PFC) in multiple layers having different layer architectures was designed to mimic native artery. The scaffold consisted of longitudinally aligned poly(hydroxy butyrate-co-hydroxy valerate) (PHBV) and poly(vinyl alcohol) (PVA) nanofibers (inner layer), radially aligned PHBV-elastin nanofibers (middle layer) to provide the bi-directional alignment and combination of longitudinally aligned PHBV-elastin and random PHBV/PVA multiscale fibers (peripheral layer). Tubular constructs of diameter <6 mm were developed. The developed electrospun fibers were characterised by Scanning Electron Microscope (SEM), Fourier Transform Infrared Spectroscopy and Tensile tests. Further the burst strength, compliance and stiffness index of tri-layered tubular scaffold was evaluated. SEM images of fibrous layers showed the typical longitudinal and radial alignment of fibers in the tubular construct. SEM images showed that the prepared PHBV nanofibers were in the range of 500-800 nm and PHBV microfibers were of 1-2 MUm in diameter in the tri-layered electrospun membrane. PVA nanofibers were of size 200-250 nm. The tensile strength, percentage compliance and stiffness index of tri-layered membrane was in accordance with that of native small blood vessels. The developed tri-layered membrane was blood compatible, with hemolysis degree 0.85 +/- 0.21% and did not activate platelets. Controlled release of VEGF and PFC was observed from the scaffold. The biocompatibility of the tri-layered scaffold was evaluated using HUVECs, SMCs and MSCs and SMCs infiltration from the outer layer was also evaluated. Specific protein expression for the HUVECs and SMCs was evaluated by flow cytometry and immunocytochemistry. HUVECs and SMCs exhibited good elongation and alignment along the direction of fibers and was found to maintain its CD31, VE-Cadherin and alphaSMA expression respectively. The results highlight the importance of bi-directional fiber alignment on the tri-layered electrospun scaffold as a suitable architectural prototype for vascular scaffolds to mimic the native arteries. PMID- 29247732 TI - Amaranth, quinoa and chia protein isolates: Physicochemical and structural properties. AB - An increasing use of vegetable protein is required to support the production of protein-rich foods which can replace animal proteins in the human diet. Amaranth, chia and quinoa seeds contain proteins which have biological and functional properties that provide nutritional benefits due to their reasonably well balanced aminoacid content. This review analyses these vegetable proteins and focuses on recent research on protein classification and isolation as well as structural characterization by means of fluorescence spectroscopy, surface hydrophobicity and differential scanning calorimetry. Isolation procedures have a profound influence on the structural properties of the proteins and, therefore, on their in vitro digestibility. The present article provides a comprehensive overview of the properties and characterization of these proteins. PMID- 29247733 TI - Specific and highly efficient condensation of GC and IC DNA by polyaza pyridinophane derivatives. AB - Two bis-polyaza pyridinophane derivatives and their monomeric reference compounds revealed strong interactions with ds-DNA and RNA. The bis-derivatives show a specific condensation of GC- and IC-DNA, which is almost two orders of magnitude more efficient than the well-known condensation agent spermine. The type of condensed DNA was identified as psi-DNA, characterized by the exceptionally strong CD signals. At variance to the almost silent AT(U) polynucleotides, these strong CD signals allow the determination of GC-condensates at nanomolar nucleobase concentrations. Detailed thermodynamic characterisation by ITC reveals significant differences between the DNA binding of the bis-derivative compounds (enthalpy driven) and that of spermine and of their monomeric counterparts (entropy driven). Atomic force microscopy confirmed GC-DNA compaction by the bis derivatives and the formation of toroid- and rod-like structures responsible for the psi-type pattern in the CD spectra. PMID- 29247734 TI - Human Chitotriosidase Does Not Catabolize Hyaluronan. AB - Humans express an enzyme that degrades chitin, called chitotriosidase, despite the fact that we do not produce chitin. One possible explanation for this is that chitinase also degrades hyaluronan, a polysaccharide that is abundant in human tissues and shares structural attributes in common with chitinase. The objective of this study was to determine whether human chitotriosidase is capable of hydrolyzing hyaluronan. Hyaluronan of various sizes under a range of pH conditions displayed no degradation when incubated with various chitinases over a period of 5 days, while commercial hyaluronidase readily digested the hyaluronan. Under the same conditions, recombinant chitinase but not our negative control chitinase, was able to digest chitosan. We conclude that human chitinase does not digest hyaluronan. Because chitin is a prominent component of certain fungi and insects, it seems likely that human chitinase evolved for roles in host defense rather than serving to catabolize the endogenous polymer hyaluronan. PMID- 29247735 TI - A prospective study of adolescents' body dysmorphic symptoms: Peer victimization and the direct and protective roles of emotion regulation and mindfulness. AB - In this study, we examined whether peer appearance-related victimization was associated with adolescents' increasing body dysmorphic disorder (BDD) symptoms over 12 months. Also, given emotion regulation and mindfulness have been associated with less body dissatisfaction, we expected that they would protect against the negative impact of peer victimization on BDD symptoms. Participants were 367 Australian adolescents (Mage=13years). In multiple regressions, two aspects of emotion regulation, strategies and clarity, and two components of mindfulness, acting with awareness and being non-judgmental, were uniquely associated with fewer BDD symptoms at T2 relative to T1. There was evidence that one mindfulness component, observing, was a risk factor for more BDD symptoms. Further, acting with awareness and observing moderated the prospective relationship between victimization and BDD symptoms; low acting with awareness and high observing were risks for symptoms regardless of victimization, whereas high acting with awareness and low observing appeared protective of BDD symptoms, but only for adolescents who reported lower victimization. PMID- 29247736 TI - Metabolic Pathway of Icotinib In Vitro: The Differential Roles of CYP3A4, CYP3A5, and CYP1A2 on Potential Pharmacokinetic Drug-Drug Interaction. AB - Icotinib is the first self-developed small molecule drug in China for targeted therapy of non-small cell lung cancer. To date, systematic studies on the pharmacokinetic drug-drug interaction of icotinib were limited. By identifying metabolite generated in human liver microsomes and revealing the contributions of major cytochromes P450 (CYPs) in the formation of major metabolites, the aim of the present work was to understand the mechanisms underlying pharmacokinetic and pharmacological variability in clinic. A liquid chromatography/UV/high-resolution mass spectrometer method was developed to characterize the icotinib metabolites. The formation of 6 major metabolites was studied in recombinant CYP isozymes and human liver microsomes with specific inhibitors to identify the CYPs responsible for icotinib metabolism. The metabolic pathways observed in vitro are consistent with those observed in human. Results demonstrated that the metabolites are predominantly catalyzed by CYP3A4 (77%~87%), with a moderate contribution from CYP3A5 (5%~15%) and CYP1A2 (3.7%~7.5%). The contribution of CYP2C8, 2C9, 2C19, and 2D6 is insignificant. Based on our observations, to minimize drug-drug interaction risk in clinic, coprescription of icotinib with strong CYP3A inhibitors or inducers must be weighed. CYP1A2, a highly inducible enzyme in the smoking population, may also represent a determinant of pharmacokinetic and pharmacological variability of icotinib, especially in lung cancer patients with smoking history. PMID- 29247737 TI - Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression. AB - Continuous manufacturing of tablets has many advantages, including batch size flexibility, demand-adaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process. PMID- 29247738 TI - Fatty Acid-Binding Protein 5 Mediates the Uptake of Fatty Acids, but not Drugs, Into Human Brain Endothelial Cells. AB - The purpose of this study was to examine the involvement of fatty acid-binding protein 5 (FABP5), a lipid-binding protein expressed at the blood-brain barrier (BBB), in fatty acid and drug uptake into human brain endothelial cells. Following transfection with siRNA against hFABP5, human brain endothelial cell (hCMEC/D3) uptake of lipophilic ligands with varying affinity to FABP5 was assessed with intracellular concentrations quantified by liquid scintillation counting, HPLC, or LCMS/MS. The in situ BBB transport of [3H]-diazepam was also assessed in wild type and FABP5-deficient mice. hFABP5 siRNA reduced FABP5 expression in hCMEC/D3 cells by 39.9 +/- 3.8% (mRNA) and 38.8 +/- 6.6% (protein; mean +/- SEM), leading to a reduction in uptake of [14C]-lauric acid, [3H]-oleic acid, and [14C]-stearic acid by 37.5 +/- 8.8%, 41.7 +/- 11.6%, and 50.7 +/- 13.6%, respectively, over 1 min. No significant changes in [14C]-diazepam, pioglitazone, and troglitazone uptake were detected following FABP5 knockdown in hCMEC/D3 cells. Similarly, no difference in BBB transport of [3H]-diazepam was observed between wild type and FABP5-deficient mice. Therefore, although FABP5 facilitates brain endothelial cell uptake of fatty acids, it has limited effects on brain endothelial cell uptake and BBB transport of drugs with lower affinity for FABP5. PMID- 29247739 TI - Roll Compaction/Dry Granulation of Dibasic Calcium Phosphate Anhydrous-Does the Morphology of the Raw Material Influence the Tabletability of Dry Granules? AB - The influence of raw material particle morphology on the tabletabilty of dry granules was investigated. Therefore, dibasic calcium phosphate anhydrous was used as a model material. One milled grade, 2 agglomerated grades with different porosities, and a functionalized structure, that is, an agglomerate formed by very small primary particles, were included. Particle size, density, and specific surface area of raw materials were measured. The starting materials and 2 fractions of dry granules were compressed to tablets. The tabletability of granules was compared to that of the powders and the influence of specific compaction force, granule size, and lubrication on tablet tensile strength was evaluated. All materials showed a loss in tabletability induced by a previous compaction step but to a varying extent. Only in case of the functionalized calcium phosphate morphology, this effect depended on the specific compaction force. In contrast to the other materials, the tabletability of functionalized calcium phosphate was influenced by the granule size. This effect was not related to an overlubrication as internal and external lubrication resulted in similar tensile strengths. A clear influence of the particle morphology on tablet strength was demonstrated by the study. The functionalized structure showed aspects of a more plastic deformation behavior. The functionalized dibasic calcium phosphate and the more porous agglomerate performed as potential filler/binder in the field of roll compaction/dry granulation. PMID- 29247740 TI - Role of Solvent Selection on Crystal Habit of 5-Aminosalicylic Acid-Combined Experimental and Computational Approach. AB - Many active pharmaceutical ingredients exhibit a needle-like (acicular) crystal habit, which can significantly complicate their downstream processing. In this study, the acicular crystal habit of a model active pharmaceutical ingredient, 5 aminosalicylic acid (5-ASA), was modified by addition of selected organic solvents to the typical aqueous crystallization process. 5-ASA was crystallized by a pH shift from 7.5-8 to 4 in the presence of methanol, acetonitrile, acetone, tetramethylurea, tetrahydrofuran or dimethyl sulfoxide at 25% v/v, or butanol at 9% v/v. Changes to the experimentally observed crystal habit are rationalized by considering adsorption energy calculations for the solvent molecules onto the morphologically important crystal faces. The crystal habit was influenced most significantly by organic solvents containing a good H-bond acceptor atom, particularly oxygen in acetone, tetramethylurea, tetrahydrofuran, and dimethyl sulfoxide. Such solvents have strongly stabilizing adsorption energies onto the fast-growing crystal faces, and their presence in solution thereby serves to modify the acicular habit of 5-ASA. The developed knowledge base on crystal interface-solvent interactions can form a basis for further engineering of an optimal crystal habit for 5-ASA. PMID- 29247741 TI - Investigations on the Mechanism of Magnesium Stearate to Modify Aerosol Performance in Dry Powder Inhaled Formulations. AB - The potential of the force control agent magnesium stearate (MgSt) to enhance the aerosol performance of lactose-based dry powder inhaled (DPI) formulations was investigated in this study. The excipient-blends were investigated with analytical techniques including time-of-flight secondary ion mass spectrometry and single particle aerosol mass spectrometry (SPAMS), and particle size, morphology, and surface properties were evaluated. Excipient-blends were manufactured either by high-shear or low-shear blending lactose carrier with different amounts of MgSt in the range from 0% to 10% (w/w). Fluticasone propionate (FP) and salmeterol xinafoate (SX) used as model active pharmaceutical ingredients were added by low-shear mixing. The in vitro aerosol performance in terms of aerodynamic particle size distribution and fine particle fraction (FPF) of the FP and SX DPI formulations was evaluated with the Next Generation Impactor and also with SPAMS using a Breezhaler(r) inhalation device. The distribution of MgSt on the lactose carrier in the blends was visualized and found to depend strongly on the blending method. This affected drug particle detachment from the carrier and thus impacted aerosol performance for FP and SX. Compared with blends without force control agent, low-shear blending of MgSt increases the FPF of the model drug SX, whereas high-shear blending significantly increased FPF of both SX and FP. The interactions between drug and carrier particles were substantially affected by the choice of blending technique of MgSt with lactose. This allows detailed control of aerosol performance of a DPI by an adequate choice of the blending technique. SPAMS successfully demonstrated that it is capable to distinguish changes in DPI formulations blended with different amounts of MgSt, and additional information in terms of dispersibility of fine particles could be generated. PMID- 29247742 TI - Cellular Pharmacokinetic Model-Based Analysis of Genistein, Glyceollin, and MK 571 Effects on 5 (and 6)-Carboxy-2',7'-Dichloroflourescein Disposition in Caco-2 Cells. AB - Pharmacokinetic modeling was used to describe 5 (and 6)-carboxy-2',7' dichloroflourescein (CDF) disposition in Caco-2 cells following CDF or CDFDA (CDF diacetate) dosing. CDF transcellular flux was modeled by simple passive diffusion. CDFDA dosing models were based on simultaneous fitting of CDF levels in apical, basolateral, and intracellular compartments. Predicted CDF efflux was 50% higher across the apical versus the basolateral membrane. This difference was similar following apical and basolateral CDFDA dosing, despite intracellular levels being 3-fold higher following basolateral dosing, thus supporting nonsaturable CDF efflux kinetics. A 3-compartment catenary model with intracellular CDFDA hydrolysis described CDF disposition. This model predicted that apical CDF efflux was not altered in the presence of MK-571, and that basolateral membrane clearance was enhanced to account for reduced intracellular CDF in the presence of this multidrug resistance-associated protein (MRP) inhibitor. Similar effects were predicted for glyceollin, while genistein exposure had no predicted effects on CDF efflux. These modulator effects are discussed in the context of model predicted intracellular CDF concentrations relative to reports of CDF affinity (measured by Km) for MRP2 and MRP3. This model-based analysis confirms the complexity of efflux kinetics and suggests that other transporters may have contributed to CDF efflux. PMID- 29247743 TI - The global role for Cdc13 and Yku70 in preventing telomere resection across the genome. AB - Yeast Cdc13 protein (related to human CTC1) maintains telomere stability by preventing 5'-3' end resection. While Cdc13 and Yku70/Yku80 proteins appear to prevent excessive resection, their combined contribution to maintenance of telomere ends across the genome and their relative roles at specific ends of different chromosomes have not been addressable because Cdc13 and Yku70/Yku80 double mutants are sickly. Using our PFGE-shift approach where large resected molecules have slower pulse field gel electrophoresis mobilities, along with methods for maintaining viable double mutants, we address end-resection on most chromosomes as well as telomere end differences. In this global approach to looking at ends of most chromosomes, we identify chromosomes with 1-end resections and end-preferences. We also identify chromosomes with resection at both ends, previously not possible. 10-20% of chromosomes exhibit PFGE-shift when cdc13-1 cells are switched to restrictive temperature (37 degrees C). In yku70Delta cdc13-1 mutants, there is a telomere resection "storm" with approximately half the chromosomes experiencing at least 1-end resection, ~10 kb/telomere, due to exonuclease1 and many exhibiting 2-end resection. Unlike for random internal chromosome breaks, resection of telomere ends is not coordinated. Telomere restitution at permissive temperature is rapid (<1 h) in yku70Delta cdc13-1 cells. Surprisingly, survival can be high although strain background dependent. Given large amount of resected telomeres, we examined associated proteins. Up to 90% of cells have >=1 Rfa1 (RPA) focus and 60% have multiple foci when ~30-40 telomeres/cell are resected. The ends are dispersed in the nucleus suggesting wide distribution of resected telomeres across nuclear space. The previously reported Rad52 nuclear centers of repair for random DSBs also appear in cells with many resected telomere ends, suggesting a Rad52 commonality to the organization of single strand ends and/or limitation on interactions of single strand ends with Rad52. PMID- 29247744 TI - Disruption of Ssp411 causes impaired sperm head formation and male sterility in mice. AB - BACKGROUND: We previously cloned the Ssp411 gene. We found that the Ssp411 protein is predominantly expressed in elongated spermatids in the rat testis in a stage-dependent manner. Although our findings strongly suggested that Ssp411 might play an important role in mammalian spermatogenesis, this hypothesis has not been studied. METHODS: We first used real-time PCR, Western blotting and immunohistochemistry to confirm that the expression pattern of Ssp411 in several murine tissues is similar to its expression pattern in corresponding rat tissues. To better understand the roles of Ssp411 in male reproduction in vivo, we identified and characterized an Ssp411 expression-disrupted murine strain (Ssp411PB/PB) that was generated by piggyBac (PB) transposon insertion. We studied Ssp411-interacting proteins using proteome microarray, co-IP and GST pull down assay. RESULTS: Both Ssp411 mRNA and protein were detected exclusively in spermatids after step 9 during spermiogenesis in testis. Phenotypic analysis suggested that only Ssp411PB/PB males are sterile. These males have smaller testes, reduced sperm counts, decreased sperm motility and deformed spermatozoa. Microscopy analysis indicated that the manchette, a structurally reshaped sperm head, is aberrant in Ssp411PB/PB spermatids. The results of proteome microarray analysis and GST pull-down assays suggested that Ssp411 participates the ubiquitin-proteasome system by interacting with PSMC3. This has been reported to be manchette-associated and important for the head shaping of spermatids. CONCLUSIONS: Our study suggested that Ssp411 is required for spermiogenesis. It seems to play a role in sperm head shaping. The lack of Ssp411 causes sperm deformation and results in male infertility. GENERAL SIGNIFICANCE: Ssp411PB/PB mouse strain is an animal model of idiopathic oligoasthenoteratozoospermia (iOAT), and the gene may represent a therapeutic target for iOAT patients. PMID- 29247745 TI - Thymidine kinase 1 combined with CEA, CYFRA21-1 and NSE improved its diagnostic value for lung cancer. AB - AIMS: Thymidine kinase 1 (TK1) is a tumor biomarker in human malignancies. The purpose of this study was to evaluate the diagnostic efficiency of this marker for lung cancer using the combined analysis of carcinoembryonic antigen (CEA), cytokeratin-19 fragment (CYFRA21-1), neuron specific enolase (NSE) and TK1. MAIN METHODS: From 2013 to 2014, 147 patients with lung cancer and 228 patients with lung benign diseases who were admitted to our hospital were reviewed. Peripheral blood samples were collected for the detection of TK1, CEA, CYFRA21-1 and NSE. The diagnostic value of each marker was analyzed using receiver operating characteristic (ROC) curves and logistic regression equations. KEY FINDINGS: The serum levels of TK1, CEA, CYFRA21-1 and NSE were significantly higher than those in patients with lung benign diseases (all P<0.05). The TK1 concentration was dependent on TNM stage (P=0.005). The ROC curve analyses showed that the diagnostic value of TK1 combined with CEA, CYFRA21-1 and NSE in lung cancer was significantly higher than that of each biomarker alone (all P<0.0001). In addition, TK1 combined with CEA, CYFRA21-1, or NSE could also improve the diagnosis of the squamous cell carcinoma, adenocarcinoma and small cell lung cancer subtypes, respectively. SIGNIFICANCE: The combined detection of TK1 and the other three markers significantly improved the diagnosis of lung cancer. Furthermore, the detection of TK1 combined with that of CYFRA21-1, CEA or NSE increased the diagnostic value of TK1 for lung squamous cell carcinoma, adenocarcinoma and SCLC, respectively. PMID- 29247746 TI - Calcimimetic R568 inhibits tetrodotoxin-sensitive colonic electrolyte secretion and reduces c-fos expression in myenteric neurons. AB - AIMS: Calcium-sensing receptor (CaSR) is expressed on neurons of both submucosal and myenteric plexuses of the enteric nervous system (ENS) and the CaSR agonist R568 inhibited Cl- secretion in intestine. The purpose of this study was to localize the primary site of action of R568 in the ENS and to explore how CaSR regulates secretion through the ENS. MATERIALS AND METHODS: Two preparations of rat proximal and distal colon were used. The full-thickness preparation contained both the submucosal and myenteric plexuses, whereas for the "stripped" preparation the myenteric plexus with the muscle layers was removed. Both preparations were mounted onto Ussing chambers and Cl- secretory responses were compared by measuring changes in short circuit current (Isc). Two tissue-specific CaSR knockouts (i.e., neuron-specific vs. enterocyte-specific) were generated to compare the effect of R568 on expression of c-fos protein in myenteric neurons by immunocytochemistry. KEY FINDINGS: In full-thickness colons, tetrodotoxin (TTX) inhibited Isc, both in proximal and distal colons. A nearly identical inhibition was produced by R568. However, in stripped preparations, while the effect of TTX on Isc largely remained, the effect of R568 was nearly completely eliminated. In keeping with this, R568 reduced c-fos protein expression only in myenteric neurons of wild type mice and mutant mice that contained CaSR in neurons (i.e., villinCre/Casrflox/flox mice), but not in myenteric neurons of nestinCre/Casrflox/flox mice in which neuronal cell CaSR was eliminated. SIGNIFICANCE: These results indicate that R568 exerts its anti-secretory effects predominantly via CaSR-mediated inhibition of neuronal activity in the myenteric plexus. PMID- 29247747 TI - Prognostic values of excision repair cross-complementing genes mRNA expression in ovarian cancer patients. AB - Excision repair cross-complementing (ERCC) genes, key components of the nucleotide excision repair pathway, are regarded as crucial factors for DNA repair capacity. Previous studies have investigated prognostic values of ERCC genes in a number of malignancies. However, the relationship between ERCC genes and prognosis of ovarian cancer patients remains controversial. Therefore, in the current study, we systematically analyze the prognostic values of ERCC genes in ovarian cancer by the Kaplan-Meier plotter, which includes updated gene expression data and survival information of 1656 ovarian cancer patients. Our results showed that high expression of ERCC1 and ERCC8 mRNA was related to a worse overall survival among ovarian cancer patients, especially in late stage and poor differentiation serous ovarian patients. Increased ERCC4 mRNA expression indicated a better overall survival among serous ovarian cancer patients. The other ERCC genes were uncorrelated with prognosis in ovarian cancer. These results indicate that some ERCC genes have critical prognostic values in ovarian cancer. PMID- 29247749 TI - Regional and long-range neural synchronization abnormality during passive hyperthermia. AB - Passive hyperthermia would impair wide-domain cognitive performances (e.g. attention, working memory), which may involve abnormal regional and long-range neural activity. Combining the regional homogeneity (ReHo) and seed-based functional connectivity analysis, this study investigated the regional and long range neural synchronization abnormality during passive hyperthermia. We acquired the resting-state blood oxygenation level dependent (BOLD) data from twenty-three healthy male participants in two simulated thermal conditions: normothermic condition (NC) with temperature at 25 degrees C for 1 h and hyperthermic condition (HC) with temperature at 50 degrees C for 1 h. After scanning, participants were asked to perform an attention network test (ANT). Relative to NC participants, the participants in HC group exhibited decreased regional neural synchronization in the frontal-occipital cortex, specifically in the left opercular part of inferior frontal gyrus/insula, bilateral middle occipital gyrus, and posterior cingulate cortex/precuneus, but increased one in the left dorsal superior/middle frontal gyrus. Using these significantly differed ReHo clusters as seeds, we further performed functional connectivity analysis and found aberrant long-range neural synchronization in the orbital medial frontal cortex, temporal-parietal junction areas. Further neurobehavioral correlation analysis showed significant positive correlation between the regional ReHo alteration in left dorsolateral superior/middle frontal gyrus and executive control effect. Additionally, the functional connectivity of the orbital medial frontal cortex with the seeds "left superior/middle frontal gyrus" and "posterior cingulate cortex/precuneus" were negatively correlated with the increase of rectal temperature. In current study, the participants showed hyperthermia induced brain activity disruptions, appearing as altered local ReHo and long range functional connectivity, which might help understand the relationship between neuronal and circuit activities and physiological thermal sensation and regulation as well as behavioral changes. PMID- 29247748 TI - Action simulation and mirroring in children with autism spectrum disorders. AB - Mental imitation, perhaps a precursor to motor imitation, involves visual perspective-taking and motor imagery. Research on mental imitation in autism spectrum disorders (ASD) has been rather limited compared to that on motor imitation. The main objective of this fMRI study is to determine the differences in brain responses underlying mirroring and mentalizing networks during mental imitation in children and adolescents with ASD. Thirteen high-functioning children and adolescents with ASD and 15 age-and- IQ-matched typically developing (TD) control participants took part in this fMRI study. In the MRI scanner, participants were shown cartoon pictures of people performing everyday actions (Transitive actions: e.g., ironing clothes but with the hand missing; and Intransitive actions: e.g., clapping hands with the palms missing) and were asked to identify which hand or palm orientation would best fit the gap. The main findings are: 1) both groups performed equally while processing transitive and intransitive actions; 2) both tasks yielded activation in the bilateral inferior frontal gyrus (IFG) and inferior parietal lobule (IPL) in ASD and TD groups; 3) Increased activation was seen in ASD children, relative to TD, in left ventral premotor and right middle temporal gyrus during intransitive actions; and 4) ASD symptom severity positively correlated with activation in left parietal, right middle temporal, and right premotor regions across all subjects. Overall, our findings suggest that regions mediating mirroring may be recruiting more brain resources in ASD and may have implications for understanding social movement through modeling. PMID- 29247750 TI - Attentional responses to stimuli associated with a reward can occur in the absence of knowledge of their predictive values. AB - Classical conditioning theories of addiction suggest that stimuli associated with rewards acquire incentive salience, inducing emotional and attentional conditioned responses. It is not clear whether those responses occur without contingency awareness (CA), i.e. are based on explicit or implicit learning processes. Examining implicit aspects of stimulus-reward associations can improve our understanding of addictive behaviours, supporting treatment and prevention strategies. However, the acquisition of conditioned responses without CA has yet to be rigorously demonstrated, as the existing literature shows a lack of methodological agreement regarding the measurement of implicit and explicit processes. The purpose of two experiments presented here was to study the emotional value acquired by CS through implicit emotional and attentional processes, trying to overcome critical methodological issues. Experiment 1 (n = 48) paired two stimuli categories (houses/buildings) with high (HR) or low (LR) probabilities of monetary reward. An Emotional Attentional Blink revealed preferential attention for HR over LR regardless of CA; while pleasantness ratings were unaffected, probably due to the intrinsic nature of CS. Experiment 2 (n = 60) replicated the effect of conditioning on the Emotional Attentional Blink utilising abstract CS (octagons/squares). In addition increased pleasantness for HR over LR was found significant overall, and marginally significant for Aware but not for Unaware participants. Here CA was rigorously determined using a signal-detection analysis and metacognitive-awareness measurements. Bayesian analyses verified the unconscious nature of the learning. These findings demonstrate that attentional conditioned responses can occur without CA and advance our understanding of the mechanisms by which implicit conditioning can occur and becomes observable. Furthermore, these results can highlight how addictive behaviours might develop. PMID- 29247751 TI - Performance of the odour span task is not impaired following inactivations of parietal cortex in rats. AB - Working memory (WM) is the ability to temporarily store information for use and manipulation. Working memory is thought to depend on a distributed set of higher cortical areas including the prefrontal and parietal cortex in primates while relatively little research has been conducted in rodents to elucidate the exact role of the parietal cortex (PC) in WM, particularly in relation to the construct of WM capacity. Previous work in our lab demonstrates that performance of the odour span task (OST), an olfactory incremental delayed nonmatching-to-sample task, relies on the medial prefrontal cortex (mPFC). However, the effects of inactivating the PC on the OST have not been studied. Therefore, the present experiment assessed the effects of inactivating the PC with the GABA receptor agonists muscimol/baclofen on performance of the OST. Infusions of muscimol/baclofen did not disrupt working memory performance, assessed by the mean number of odours each rat could remember before making an error on each day of testing. In contrast, performance of a positive control task, spontaneous cross-modal object recognition, was impaired by inactivating the PC. These results suggest that performance of the OST does not depend on the PC in rats. Our results are notable given past research demonstrating the importance of the parietal cortex for attentional processes and working memory in other tasks. PMID- 29247752 TI - Insight into the dynamic of gadolinium based contrast agent (GBCA) hypersensitivity: Acquisition, persistence and disappearance. AB - Anaphylaxis against gadolinium based contrast agents (GBCAs) has been reported in all severity grades but is less frequent than hypersensitivity/allergy against iodinated contrast materials. Once a patient acquires such an adverse reaction a life-long premedication is usually the consequence in concert with GBCA-enhanced MR-imaging procedures. The usefulness of this prophylaxis has been questioned, and discussed controversially during the past. The herein presented case may shed some light into the dynamic of contrast-medium-induced hypersensitivity reactions. PMID- 29247753 TI - Effects of Exercise Training on Restless Legs Syndrome, Depression, Sleep Quality, and Fatigue Among Hemodialysis Patients: A Systematic Review and Meta analysis. AB - CONTEXT: Hemodialysis (HD) patients experience a heavy symptom burden that leads to a decreased quality of life. Pharmacological treatment is effective but costly and has adverse effects. Exercise is a promising approach for symptom management, but the effect of exercise on restless legs syndrome (RLS), depression, sleep quality, and fatigue in HD patients is still uncertain. OBJECTIVES: This meta analysis was conducted to identify whether exercise training is beneficial in the treatment of the symptoms of RLS, depression, poor sleep quality, and fatigue in patients receiving HD. METHODS: A systematic search of PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science was conducted to identify randomized controlled trials (RCTs) comparing exercise training with routine care on RLS, depression, sleep quality, and fatigue among HD patients. Quality assessment was conducted using the Cochrane risk of bias tool, and RevMan 5.3 was used to analyze the data. RESULTS: Fifteen RCTs that met our inclusion criteria were included. The pooled effect size showed that exercise training was effective on RLS (P < 0.001), depression (P < 0.001), and fatigue (P < 0.001). However, effect size combinations for sleep quality were not performed owing to the sensitivity analysis results. CONCLUSION: Exercise training may help HD patients to reduce the severity of RLS, depression, and fatigue. More high-quality RCTs with larger samples and comparative RCTs focused on different exercise regimens are needed. PMID- 29247754 TI - Advance Care Planning in Community-Dwelling Patients With Dementia. AB - CONTEXT: Little is known about advance care planning (ACP) among community dwelling patients with dementia. OBJECTIVES: To describe aspects of ACP among patients with dementia and examine the association between ACP and health care proxy (HCP) acceptance of patients' illness. METHODS: Cross-sectional observational survey of 62 HCPs of patients with dementia (N = 14 mild, N = 48 moderate/severe), from seven outpatient geriatric and memory disorder clinics in Boston. Aspects of ACP included HCP's report of patients' preferences for level of future care, communication with HCP and physician regarding care preferences, and proxy preparedness for shared decision making. The association between ACP and HCP acceptance with patients' illness was examined using the Peace, Equanimity, and Acceptance subscale of the Cancer Experience Scale. RESULTS: Eleven percent of proxies believed that the patient would want life-prolonging treatment, 31% a time-limited trial of curative treatment, and 47% comfort focused care. Thirty-one percent reported that the patient had communicated with their physician regarding preferences for care, and 77% had communicated with the HCP. Forty-four percent of HCPs wanted more discussion with the patient regarding care preferences. The HCP having discussed care preferences with the patient was associated with greater acceptance of the patient's illness (P = 0.004). CONCLUSION: Our findings support need for greater ACP discussions between patients and proxies. Discussions regarding goals of care are likely to benefit patients through delivery of care congruent with their wishes and HCPs in terms of greater acceptance of patients' illness. PMID- 29247755 TI - Variations in Hospice Utilization and Length of Stay for Medicare Patients With Melanoma. AB - CONTEXT: Timely hospice referral is an indicator of high-quality end-of-life care for cancer patients. Variations in patient characteristics associated with hospice utilization and length of stay have been demonstrated in studies of other malignancies but not melanoma. OBJECTIVES: We sought to understand hospice utilization and patient characteristics associated with variability in use for the older melanoma population. METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify 13,393 melanoma patients aged 65+ years at time of diagnosis between 2000 and 2009, who died by 12/31/10. The primary outcome was enrollment in hospice with secondary outcome of hospice duration. Patient characteristics associated with variations in hospice enrollment were examined. RESULTS: Among 13,393 patients who died with melanoma, 5298 (40%) received hospice care. Of these, 17% were enrolled in hospice for three days or less, while 13% had >=90 days of hospice care. Despite improvements over time in the proportion of patients who received hospice and those who received at least 90 days of hospice care, late hospice enrollments did not change. Multivariable analysis revealed that patients of older age, with distant disease at time of diagnosis, and residing in rural areas or in census tracts with higher rates of high school completion were more likely to enroll in hospice. CONCLUSION: Rates of hospice enrollment increased over time but remained under accepted quality benchmarks with variations evident in those who receive hospice services. Efforts to increase access to earlier hospice care for all patients dying with melanoma are essential. PMID- 29247756 TI - Determining mRNA half-lives on a transcriptome-wide scale. AB - Every step in the life cycle of an RNA transcript provides opportunity for regulation. One important aspect of post-transcriptional control is the regulation of RNA stability. Of the many strategies for determining mRNA stability, transcription inhibition and metabolic labeling have proved the most amenable to high-throughput analysis and have opened the door to dissecting mRNA decay transcriptome-wide. Here, we describe experimental and computational methods to determine transcriptome-wide RNA stabilities using both pharmacological inhibition of transcription and metabolic labeling. To aid in the analysis of these experiments, we discuss key characteristics of high-quality experiments and address other experimental and computational considerations for the analysis of mRNA stability. Broader application of these approaches will further our understanding of mRNA decay and illuminate its contribution to different biological processes. PMID- 29247757 TI - Structural dynamics of protein S1 on the 70S ribosome visualized by ensemble cryo EM. AB - Bacterial ribosomal protein S1 is the largest and highly flexible protein of the 30S subunit, and one of a few core ribosomal proteins for which a complete structure is lacking. S1 is thought to participate in transcription and translation. Best understood is the role of S1 in facilitating translation of mRNAs with structured 5' UTRs. Here, we present cryo-EM analyses of the 70S ribosome that reveal multiple conformations of S1. Based on comparison of several 3D maximum likelihood classification approaches in Frealign, we propose a streamlined strategy for visualizing a highly dynamic component of a large macromolecular assembly that itself exhibits high compositional and conformational heterogeneity. The resulting maps show how S1 docks at the ribosomal protein S2 near the mRNA exit channel. The globular OB-fold domains sample a wide area around the mRNA exit channel and interact with mobile tails of proteins S6 and S18. S1 also interacts with the mRNA entrance channel, where an OB-fold domain can be localized near S3 and S5. Our analyses suggest that S1 cooperates with other ribosomal proteins to form a dynamic mesh near the mRNA exit and entrance channels to modulate the binding, folding and movement of mRNA. PMID- 29247759 TI - Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA methylation profiles in the mouse medial prefrontal cortex. AB - Methamphetamine (METH) and modafinil are psychostimulants with different long term cognitive profiles: METH is addictive and leads to cognitive decline, whereas modafinil has little abuse liability and is a cognitive enhancer. Increasing evidence implicates epigenetic mechanisms of gene regulation behind the lasting changes that drugs of abuse and other psychotropic compounds induce in the brain, like the control of gene expression by histones 3 and 4 tails acetylation (H3ac and H4ac) and DNA cytosine methylation (5-mC). Mice were treated with a seven-day repeated METH, modafinil or vehicle protocol and evaluated in the novel object recognition (NOR) test or sacrificed 4days after last injection for molecular assays. We evaluated total H3ac, H4ac and 5-mC levels in the medial prefrontal cortex (mPFC), H3ac and H4ac promotor enrichment (ChIP) and mRNA expression (RT-PCR) of neurotransmitter systems involved in arousal, wakefulness and cognitive control, like dopaminergic (Drd1 and Drd2), alpha-adrenergic (Adra1a and Adra1b), orexinergic (Hcrtr1 and Hcrtr2), histaminergic (Hrh1 and Hrh3) and glutamatergic (AMPA Gria1 and NMDA Grin1) receptors. Repeated METH and modafinil treatment elicited different cognitive outcomes in the NOR test, where modafinil-treated mice performed as controls and METH-treated mice showed impaired recognition memory. METH-treated mice also showed i) decreased levels of total H3ac and H4ac, and increased levels of 5-mC, ii) decreased H3ac enrichment at promoters of Drd2, Hcrtr1/2, Hrh1 and Grin1, and increased H4ac enrichment at Drd1, Hrh1 and Grin1, iii) increased mRNA of Drd1a, Grin1 and Gria1. Modafinil-treated mice shared none of these effects and showed increased H3ac enrichment and mRNA expression at Adra1b. Modafinil and METH showed similar effects linked to decreased H3ac in Hrh3, increased H4ac in Hcrtr1, and decreased mRNA expression of Hcrtr2. The specific METH-induced epigenetic and transcriptional changes described here may be related to the long term cognitive decline effects of the drug and its detrimental effects on mPFC function. The lack of similar epigenetic effects of chronic modafinil administration supports this notion. PMID- 29247760 TI - Common variation in ZNF804A (rs1344706) is not associated with brain morphometry in schizophrenia or healthy participants. AB - BACKGROUND: The single nucleotide polymorphism (SNP) rs1344706 [A>C] within intron 2 of the zinc finger protein 804A gene (ZNF804A) is associated with schizophrenia at the genome-wide level, but its function in relation to the development of psychotic disorders, including its influence on brain morphology remains unclear. METHODS: Using both univariate (voxel-based morphometry, VBM; cortical thickness) and multivariate (source-based morphometry, SBM) approaches, we examined the effects of variation of the rs1344706 polymorphism on grey matter integrity in 214 Caucasian schizophrenia cases and 94 Caucasian healthy individuals selected from the Australian Schizophrenia Research Bank. RESULTS: Neither univariate nor multivariate analyses showed any associations between indices of grey matter and rs1344706 variation in schizophrenia or healthy participants. This was revealed in the context of the typical pattern of decreased grey matter integrity in schizophrenia compared to healthy individuals, including: (1) large grey matter volume reductions in the orbitofrontal and anterior cingulate cortices and the left fusiform/inferior temporal gyri; (2) decreased cortical thickness in the left inferior temporal and fusiform gyri, the left orbitofrontal gyrus, as well as in the right pars opercularis/precentral gyrus; and (3) decreased covariation of grey matter concentration in frontal and limbic brain regions emerging from the SBM analyses. CONCLUSIONS: Contrary to some - but not all - previous findings, this study of a large sample of schizophrenia cases and healthy controls reveals no evidence for association between grey matter alterations and variation in rs1344706 (ZNF804A). Differences in sample sizes and ethnicities may account for discrepant findings between the present and previous studies. PMID- 29247758 TI - Ensemble and single-molecule FRET studies of protein synthesis. AB - Protein synthesis is a complex, multi-step process that involves large conformational changes of the ribosome and protein factors of translation. Over the last decade, Forster resonance energy transfer (FRET) has become instrumental for studying structural rearrangements of the translational apparatus. Here, we discuss the design of ensemble and single-molecule (sm) FRET assays of translation. We describe a number of experimental strategies that can be used to introduce fluorophores into the ribosome, tRNA, mRNA and protein factors of translation. Alternative approaches to tethering of translation components to the microscope slide in smFRET experiments are also reviewed. Finally, we discuss possible challenges in the interpretation of FRET data and ways to address these challenges. PMID- 29247761 TI - Genotoxicity assessment of biphasic calcium phosphate of modified porosity on human dental pulp cells using Ames and Comet assays. AB - Biphasic Calcium Phosphate (BCP) with a ratio of 20/80 Hydroxyapatite (HA)/Beta tricalcium phosphate (beta-TCP) promotes the differentiation of human dental pulp cells (HDPCs). In the current study, the genotoxicity of locally produced BCP of modified porosity (65%) with a mean pore size of 300micrometer (MUm) was assessed using Comet and Ames assays. HDPCs were treated with BCP extract at three different inhibitory concentrations which were obtained based on cytotoxicity test conducted with concurrent negative and positive controls. The tail moment of HDPCs treated with BCP extract at all three concentrations showed no significant difference compared to negative control (p>0.05), indicating that BCP did not induce DNA damage to HDPCs. The BCP was evaluated using five tester strains of Salmonella typhimurium TA98, TA100, TA102, TA1537 and TA1538. Each strain was incubated with BCP extract with five different concentrations in the presence and absence of metabolic activation system (S9) mix. Concurrently, negative and positive controls were included. The average number of revertant colonies per plate treated with the BCP extract was less than double as compared to the number of revertant colonies in negative control plate and no dose-related increase was observed. Results from both assays suggested that the BCP of modified porosity did not exhibit any genotoxic effect under the present test conditions. PMID- 29247762 TI - Prenatal antidepressant exposure and the risk of attention-deficit hyperactivity disorder in children: A systematic review and meta-analysis. AB - This systematic review assesses the association between prenatal antidepressant exposure and risk of ADHD in children. Electronic databases were searched up to 25 July 2017. Observational studies examining this association were included in the review and meta-analysis was conducted where appropriate. Eight relevant studies were identified. The seven studies included in the meta-analysis comprised a total of 2,886,502 children. The pooled estimates comparing prenatal exposure to non-exposure showed an adjusted rate ratio (aRR) of 1.39 (95%CI 1.21 1.61). Similarly, an increased risk was found comparing previous antidepressant users and non-users: aRR = 1.56 (95%CI 1.25-1.95). The relationship between maternal psychiatric conditions and ADHD in children yielded an aRR of 1.90 (95%CI 1.47-2.45). Three studies conducted sibling-matched analyses with aRR of 0.94 (95%CI 0.75-1.16). These data suggest that the observed association between prenatal use of antidepressants and risk of ADHD in offspring can be partially explained by confounding by indication because the results from sibling-matched analyses do not support an increased risk of ADHD in discordant exposed siblings. PMID- 29247763 TI - Nanoplasmonic sensors for detecting circulating cancer biomarkers. AB - The detection of cancer biomarkers represents an important aspect of cancer diagnosis and prognosis. Recently, the concept of liquid biopsy has been introduced whereby diagnosis and prognosis are performed by means of analyzing biological fluids obtained from patients to detect and quantify circulating cancer biomarkers. Unlike conventional biopsy whereby primary tumor cells are analyzed, liquid biopsy enables the detection of a wide variety of circulating cancer biomarkers, including microRNA (miRNA), circulating tumor DNA (ctDNA), proteins, exosomes and circulating tumor cells (CTCs). Among the various techniques that have been developed to detect circulating cancer biomarkers, nanoplasmonic sensors represent a promising measurement approach due to high sensitivity and specificity as well as ease of instrumentation and operation. In this review, we discuss the relevance and applicability of three different categories of nanoplasmonic sensing techniques, namely surface plasmon resonance (SPR), localized surface plasmon resonance (LSPR) and surface-enhanced Raman scattering (SERS), for the detection of different classes of circulating cancer biomarkers. PMID- 29247764 TI - Efficacy and safety concerns over the use of mucus modulating agents for drug delivery using nanoscale systems. AB - Drug delivery to the mucus covered mucosae is fraught with difficulties and many different approaches have been developed to permeate the mucus barrier. Generally by modifying the delivery system to avoid interaction with the mucus. These modifications are reviewed here in terms of efficacy and safety. These are particular problems for oral delivery the pharmaceutical industry's favoured route for drug administration. For effective delivery through the gastrointestinal tract a drug must pass through three barriers in sufficient amounts to yield a biological effect. These barriers are the digestive barrier in the lumen, the mucus barrier, and the epithelial barrier. Other approaches involve mucolytic agents added with or prior to the delivery system or agents regulating mucus production and are reviewed here. In terms of safety, a key property of a mucus modulating delivery system is that it must not damage the protective function of the mucus layer. PMID- 29247765 TI - Integration of biomimicry and nanotechnology for significantly improved detection of circulating tumor cells (CTCs). AB - Circulating tumor cells (CTCs) have received a great deal of scientific and clinical attention as a biomarker for diagnosis and prognosis of many types of cancer. Given their potential significance in clinics, a variety of detection methods, utilizing the recent advances in nanotechnology and microfluidics, have been introduced in an effort of achieving clinically significant detection of CTCs. However, effective detection and isolation of CTCs still remain a tremendous challenge due to their extreme rarity and phenotypic heterogeneity. Among many approaches that are currently under development, this review paper focuses on a unique, promising approach that takes advantages of naturally occurring processes achievable through application of nanotechnology to realize significant improvement in sensitivity and specificity of CTC capture. We provide an overview of successful outcome of this biomimetic CTC capture system in detection of tumor cells from in vitro, in vivo, and clinical pilot studies. We also emphasize the clinical impact of CTCs as biomarkers in cancer diagnosis and predictive prognosis, which provides a cost-effective, minimally invasive method that potentially replaces or supplements existing methods such as imaging technologies and solid tissue biopsy. In addition, their potential prognostic values as treatment guidelines and that ultimately help to realize personalized therapy are discussed. PMID- 29247766 TI - Fibrin-based delivery strategies for acute and chronic wound healing. AB - Fibrin, a natural hydrogel, is the end product of the physiological blood coagulation cascade and naturally involved in wound healing. Beyond its role in hemostasis, it acts as a local reservoir for growth factors and as a provisional matrix for invading cells that drive the regenerative process. Its unique intrinsic features do not only promote wound healing directly via modulation of cell behavior but it can also be fine-tuned to evolve into a delivery system for sustained release of therapeutic biomolecules, cells and gene vectors. To further augment tissue regeneration potential, current strategies exploit and modify the chemical and physical characteristics of fibrin to employ combined incorporation of several factors and their timed release. In this work we show advanced therapeutic approaches employing fibrin matrices in wound healing and cover the many possibilities fibrin offers to the field of regenerative medicine. PMID- 29247767 TI - Implications of melanin binding in ocular drug delivery. AB - Pigmented ocular tissues contain melanin within the intracellular melanosomes. Drugs bind to melanin at varying extent that ranges from no binding to extensive binding. Binding may lead to drug accumulation to the pigmented tissues and prolonged drug retention in the melanin containing cells. Therefore, melanin binding is an important feature that affects ocular drug delivery and biodistribution, but this topic has not been reviewed since 1998. In this review, we present current knowledge on ocular melanin, melanosomes and binding of drugs to pigmented cells and tissues. In vitro, in vivo and in silico methods in the field were critically evaluated, because the literature in this field can be confusing if the reader does not properly understand the methodological aspects. Literature analysis includes a comprehensive table of literature data on melanin binding of drugs. Furthermore, we aimed to give some insights beyond the current literature by making a chemical structure based classification model for melanin binding of drugs and kinetic simulations that revealed significant interplay between melanin binding and drug permeability across the melanosomal and plasma membranes. Overall, more mechanistic and systematic research is needed before the impact of melanin binding on ocular drug delivery can be properly understood and predicted. PMID- 29247768 TI - The role of introns in the conservation of the metabolic genes of Arabidopsis thaliana. AB - In Arabidopsis thaliana, primary metabolic genes (PMGs) are more evolutionarily conserved and intron-rich than secondary metabolic genes. We observed that PMGs are more primitive and pan-taxonomically persistent as compared to secondary (SMGs) and non-metabolic genes (NMGs). This difference in primitiveness and persistence is primarily correlated with intron number and is independent of gene expression level. We propose a twofold explanation behind higher intron enrichment in PMGs. Firstly, introns might increase protein versatility amongst PMGs through alternative splicing, providing selective advantage of PMGs and making them more persistent across diverse plant taxa. Also, multifunctional PMGs may acquire functional domains by increasing the intronic burden. Additionally, single nucleotide polymorphisms (SNPs) accumulate at a higher rate in introns as compared to exons. Moreover, a strong negative correlation between cumulative exonic SNPs density and intron number indicates that introns may protect the exonic regions against the deleterious effect of these mutations, making them more conserved. PMID- 29247769 TI - Genetic diversity and natural selection in wild fruit flies revealed by whole genome resequencing. AB - We characterized 26 wild fruit flies comparative population genomics from six different altitude and latitude locations by whole genome resequencing. Genetic diversity was relatively higher in Ganzi and Chongqing populations. We also found 13 genes showing selection signature between different altitude flies and variants related to hypoxia and temperature stimulus, were preferentially selected during the flies evolution. One of the most striking selective sweeps found in all high altitude flies occurred in the region harboring Hsp70Aa and Hsp70Ab on chromosome 3R. Interestingly, these two genes are involved in GO terms including response to hypoxia, unfolded protein, temperature stimulus, heat, oxygen levels. Mutation in HPH gene, a candidate gene in the hypoxia inducible factor pathway, might contributes to hypoxic high-altitude adaptation. Intriguingly, some of the selected genes, primarily utilized in humans, were involved in the response to hypoxia, which could imply a conserved molecular mechanisms underlying high-altitude adaptation between insects and humans. PMID- 29247770 TI - Apigenin promotes TRAIL-mediated apoptosis regardless of ROS generation. AB - Apigenin is a bioactive flavone in several herbs including parsley, thyme, and peppermint. Apigenin possesses anti-cancer and anti-inflammatory properties; however, whether apigenin enhances TRAIL-mediated apoptosis in cancer cells is unknown. In the current study, we found that apigenin enhanced TRAIL-induced apoptosis by promoting caspase activation and death receptor 5 (DR5) expression and a chimeric antibody against DR5 completely blocked the apoptosis. Apigenin also upregulated reactive oxygen species (ROS) generation; however, intriguingly, ROS inhibitors, glutathione (GSH) or N-acetyl-l-cysteine (NAC), moderately increased apigenin/TRAIL-induced apoptosis. Additional results showed that an autophagy inducer, rapamycin, enhanced apigenin/TRAIL-mediated apoptosis by a slight increase of ROS generation. Accordingly, NAC and GSH rather decreased apigenin-induced autophagy formation, suggesting that apigenin-induced ROS generation increased autophagy formation. However, autophagy inhibitors, bafilomycin (BAF) and 3-methyladenine (3-MA), showed different result in apigenin/TRAIL-mediated apoptosis without ROS generation. 3-MA upregulated the apoptosis but remained ROS levels; however, no changes on apoptosis and ROS generation were observed by BAF treatment. Taken together, these findings reveal that apigenin enhances TRAIL-induced apoptosis by activating apoptotic caspases by upregulating DR5 expression regardless of ROS generation, which may be a promising strategy for an adjuvant of TRAIL. PMID- 29247771 TI - In vitro/in vivo antioxidant and hepatoprotective potential of defatted extract and flavonoids isolated from Astragalus spruneri Boiss. (Fabaceae). AB - The aim of the current study was to evaluate the effect of a defatted extract (EAS) and three flavonoids, isolated from Astragalus spruneri Boiss. (Fabaceae) using in vitro/in vivo models of liver injury. The EAS was characterized by HPLC and flavonoids (14 mg/g dw) and saponins (8 mg/g dw) were proved. The flavonoids (ASF1, ASF3 and ASF5) were isolated from the same extract and partially identified by LC-MS. In in vitro models of non-enzyme induced (Fe2+/AA) lipid peroxidation in isolated liver microsomes and CCl4-induced metabolic bioactivation and t-BuOOH-induced oxidative stress in isolated rat hepatocytes, both EAS and the flavonoids exerted similar to silybin (positive control) an antioxidant and cytoprotective activity, discerned by decreased MDA production in the microsomes and by preserved cell viability and GSH levels as well as by decreased LDH activity and MDA quantity in isolated rat hepatocytes. The antioxidant and hepatoprotective effect of EAS has been confirmed in vivo against CCl4-induced liver injury in rats. EAS restored the GSH levels and the activity of the antioxidant enzymes CAT and SOD, affected by CCl4 administration, as well as decreased the production of MDA. The effect of EAS was commensurable with those of silymarin. PMID- 29247772 TI - Chrysin attenuates testosterone-induced benign prostate hyperplasia in rats. AB - Benign prostate hyperplasia (BPH) is a common age-related health problem affecting almost 3 out of 4 men in their sixties. Chrysin is a dietary phytoestrogen found naturally in bee propolis and various plant extracts. It possesses antioxidant, anti-inflammatory and anti-proliferative properties. The current study was conducted to explore the role chrysin plays in protection against testosterone-induced BPH in rats. On grounds of a preliminary experiment, a dose of chrysin (50 mg/kg) was chosen for further investigation. Testosterone significantly depleted glutathione, suppressed superoxide dismutase and catalase activities, and elevated lipid peroxidation. Moreover, it markedly scaled down the level of cleaved caspase-3 enzyme, reduced Bax/Bcl-2 ratio and mRNA expression of p53 and p21; conversely, protein expression of proliferating cell nuclear antigen was enhanced. Chrysin alleviated testosterone-induced oxidative stress and restored cleaved caspase-3 level, Bax/Bcl-2 ratio and mRNA expression of p53 and p21 to almost control levels. Chrysin prevented the increase in binding activity of nuclear factor kappa B (NF-kappaB) p65 subunit, mRNA expression of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 1 receptor (IGF-1R). These data highlight the protective role of chrysin against experimentally-induced BPH. This is attributed - at least partly - to its antioxidant, antiproliferative and proapoptotic properties. PMID- 29247774 TI - Regulation of Microglia Identity from an Epigenetic and Transcriptomic Point of View. AB - Microglia have long been recognized as the endogenous innate immune elements in the central nervous system (CNS) parenchyma. Besides fulfilling local immune related functions, they provide cross-talk between the CNS and the immune system at large. In the adult CNS, microglia are involved in maintaining brain homeostasis, modulating synaptic transmission and clearance of apoptotic cells. During embryonic development, microglia are responsible for the removal of supernumerary synapses and neurons, and neuronal network formation. The full scale of their potential abilities has been highlighted by improvements in microglia isolation methods, the development of genetically tagged mouse models, advanced imaging technologies and the application of next-generation sequencing in recent years. Genome-wide expression analysis of relatively pure microglia populations from both mouse and human CNS tissues has thereby greatly contributed to our knowledge of their biology; what defines them under homeostatic conditions and how microglia respond to processes like aging and CNS disease? How and to what degree beneficial functions of microglia can be restored in the aged or diseased brain will be the key issue to be addressed in future research. PMID- 29247773 TI - Molecular determinants of PPARgamma partial agonism and related in silico/in vivo studies of natural saponins as potential type 2 diabetes modulators. AB - The metabolic syndrome, which includes hypertension, type 2 diabetes (T2D) and obesity, has reached an epidemic-like scale. Saponins and sapogenins are considered as valuable natural products for ameliorating this pathology, possibly through the nuclear receptor PPARgamma activation. The aims of this study were: to look for in vivo antidiabetic effects of a purified saponins' mixture (PSM) from Astragalus corniculatus Bieb; to reveal by in silico methods the molecular determinants of PPARgamma partial agonism, and to investigate the potential PPARgamma participation in the PSM effects. In the in vivo experiments spontaneously hypertensive rats (SHRs) with induced T2D were treated with PSM or pioglitazone as a referent PPARgamma full agonist, and pathology-relevant biochemical markers were analysed. The results provided details on the PSM modulation of the glucose homeostasis and its potential mechanism. The in silico studies focused on analysis of the protein-ligand interactions in crystal structures of human PPARgamma-partial agonist complexes, pharmacophore modelling and molecular docking. They outlined key pharmacophoric features, typical for the PPARgamma partial agonists, which were used for pharmacophore-based docking of the main PSM sapogenin. The in silico studies, strongly suggest possible involvement of PPARgamma-mediated mechanisms in the in vivo antidiabetic and antioxidant effects of PSM from A. corniculatus. PMID- 29247775 TI - Temporal and Spatial Patterns of Neural Activity Associated with Information Selection in Open-ended Creativity. AB - Novel information selection is a crucial process in creativity and was found to be associated with frontal-temporal functional connectivity in the right brain in closed-ended creativity. Since it has distinct cognitive processing from closed ended creativity, the information selection in open-ended creativity might be underlain by different neural activity. To address this issue, a creative generation task of Chinese two-part allegorical sayings was adopted, and the trials were classified into novel and normal solutions according to participants' self-ratings. The results showed that (1) novel solutions induced a higher lower alpha power in the temporal area, which might be associated with the automatic, unconscious mental process of retrieving extensive semantic information, and (2) upper alpha power in both frontal and temporal areas and frontal-temporal alpha coherence were higher in novel solutions than in normal solutions, which might reflect the selective inhibition of semantic information. Furthermore, lower alpha power in the temporal area showed a reduction with time, while the frontal temporal and temporal-temporal coherence in the upper alpha band appeared to increase from the early to the middle phase. These dynamic changes in neural activity might reflect the transformation from divergent thinking to convergent thinking in the creative progress. The advantage of the right brain in frontal temporal connectivity was not found in the present work, which might result from the diversity of solutions in open-ended creativity. PMID- 29247776 TI - Necrostatin-1 Improves Long-term Functional Recovery Through Protecting Oligodendrocyte Precursor Cells After Transient Focal Cerebral Ischemia in Mice. AB - Ischemic stroke often results in severe injury to white matter structures including the axons, oligodendroglia, and other glial cells. Immature stages of oligodendroglia, such as oligodendrocyte precursor cells (OPCs) and premature oligodendroglia, are more vulnerable to ischemia than mature oligodendroglia. Extensive studies have been performed on the necroptosis of neurons following cerebral ischemia. The present study aimed to investigate the effect of necrostatin-1 (Nec-1), a necroptosis inhibitor, on the survival of OPCs and long term functional recovery following transient cerebral ischemia. Male adult ICR mice (25-30 g) were subjected to 60-min middle cerebral artery occlusion (MCAO) and 24 h of reperfusion. Nec-1 (0.04 mg/kg) was injected intracerebroventricularly 1 h before the onset of MCAO. Cognitive functions were evaluated <=30 days after MCAO. Necroptosis-related proteins, receptor interacting protein kinase 1 (RIPK1), RIPK3, MLKL, and P-MLKL, were assessed by western blot analyses. The cultured primary mouse OPCs were used to confirm the effects of Nec-1 on the viability of OPCs following oxygen-glucose deprivation (OGD). This study demonstrated that pretreatment with Nec-1 significantly promoted OPCs survival, alleviated white matter injury, and improved cognitive function after transient cerebral ischemia. Nec-1 also inhibited the activation of RIPK1, RIPK3, MLKL, and P-MLKL in the subventricular zone (SVZ) and corpus callosum regions after MCAO. OPCs' culture experiments confirmed that Nec-1 significantly reduced the necroptosis of OPCs, perhaps by inhibiting the expression of RIPK1, RIPK3, MLKL, and P-MLKL. Nec-1, an inhibitor of RIPK1, may reduce ischemic white matter damage and improve recovery of long-term neurological function following cerebral ischemia. PMID- 29247778 TI - Heart and lymphoma: An unusual case of secondary cardiac lymphoma manifested through presyncope and syncope episodes and atrial flutter. PMID- 29247779 TI - Allogeneic Stem Cell Transplantation versus Tyrosine Kinase Inhibitors Combined with Chemotherapy in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. AB - Here we compare outcomes between the tyrosine kinase inhibitors (TKIs) plus chemotherapy regimen and allogeneic hematopoietic stem cell transplantation (transplantation cohort) in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and explore factors associated with prognosis. Data from 145 Ph+ ALL patients were analyzed retrospectively. Patients were treated with imatinib plus chemotherapy and then transplantation or continuous TKIs with chemotherapy based on patient preference. A total of 145 Ph+ ALL patients were recruited for this study (median age, 37 years; range, 14 to 65). Among these patients, 81 were men (55.9%) and 86 underwent IKZF1 detection, which identified 59 patients (68.6%) with IKZF1 deletions. After treatment 136 patients (95.8%) achieved complete remission (CR) eventually. With a median follow-up of 33 months (range, 4 to 114) for CR patients, 77 patients (57.9%) underwent transplantation and 56 (42.1%) received continuous TKIs with chemotherapy. At the 4-year follow-up the cumulative incidence of relapse (CIR), disease-free survival (DFS), and overall survival (OS) were 29.4% (95% confidence interval [CI], 24.9% to 34.4%), 60.9% (95% CI, 56.5% to 65.3%), and 69.2% (95% CI, 65.1% to 73.3%), respectively. Multivariate analysis showed that WBC counts < 30 * 109/L at diagnosis (hazard ratio [HR], 4.2; 95% CI, 1.9 to 9.2; P < .001; HR, 2.6; 95% CI, 1.4 to 4.9; P = .003; HR, 2.7; 95% CI, 1.4 to 5.4; P = .003), 3-log reduction of BCR-ABL levels from baseline after 2 consolidation cycles (HR, 4.4; 95% CI, 1.9 to 9.9; P < .001; HR, 3.1; 95% CI, 1.7 to 5.9; P < .001; HR, 3.5; 95% CI, 1.9 to 8.7; P = .001; defined as "minimal residual disease low level"), and transplantation (HR, 5.0; 95% CI, 2.2 to 11.2; P < .001; HR, 3.3; 95% CI, 1.7 to 6.4; P < .001; HR, 4.1; 95% CI, 1.9 to 8.7; P < .001) were the favorable factors of CIR, DFS, and OS. According to the first 2 risk factors, CR patients were divided into 3 groups: low risk (no factor, n = 42, 31.6%), intermediate risk (1 factor, n = 73, 54.9%), and high risk (2 factors, n = 18, 13.5%). In the low-risk group at the 4-year follow up no significant difference existed between the transplant and nontransplant arms for the probabilities of CIR (8.5% versus 7.7%, P = .671), DFS (88.2% versus 83.9%, P = .426), and OS (96.6% versus 83.3%, P = .128). In the intermediate- and high-risk groups at the 4-year follow-up, CIR (23.6% versus 36.9%, P = .017; 37.5% versus 100.0%, P <.001), DFS (62.4% versus 43.8%, P = .048; 56.2% versus 0%, P <.001), and OS (76.1% versus 47.7%, P = .037; 51.4% versus 6.3%, P = .001) rates were significantly better in the transplant arm than in the nontransplant arm. In surviving patients of the low risk group, no difference in complete molecular response (CMR) rates (85.7% versus 72.7%, P = .379) between the transplant and nontransplant arms was found. However, in the intermediate-risk group the proportion of CMR was significantly higher in the transplant arm than in the nontransplant arm (82.8% versus 42.9%, P = .006). In the high-risk group 4 of 7 transplant patients (57.1%) were in CMR, and no patients survived in the nontransplant arm. Allogeneic hematopoietic stem cell transplantation confers significant survival advantages for Ph+ ALL patients compared with TKIs plus chemotherapy, especially in intermediate- and high-risk patients. PMID- 29247780 TI - Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation. AB - Dose intensity of the conditioning regimen has significant impact on the outcomes after stem cell transplantation (SCT) for acute myeloid leukemia. Most studies have shown more relapse, less nonrelapse mortality (NRM), and similar overall survival after reduced-intensity and myeloablative conditioning. There are limited data on the dose equivalence and expected outcomes of treosulfan-based compared with busulfan-based conditioning. We compared SCT outcomes after fludarabine with either intravenous busulfan at a myeloablative dose (FB4, 12.8 mg/kg, n = 1265) or a reduced dose (FB2, 6.4 mg/kg, n = 1456) or treosulfan at 42 g/m2 (FT14, n = 403) or 36 g/m2 (FT12, n = 168). Median patient age was 48, 60, 57, and 60 years in the FB4, FB2, FT14, and FT12 groups, respectively (P < .0001). Two-year overall survival was 58%, 53%, 53%, and 51%, respectively (P = .25). Multivariate analysis identified advanced age, advanced disease status, and secondary leukemia to be associated with worse survival. Relapse rate was 30%, 35%, 34%, and 40%, respectively. Relapse was more common after FB2, advanced age and disease status, secondary leukemia, and sibling donors. NRM was 17%, 18%, 21%, and 16%, respectively. NRM was least common after FT12 and more common with advanced age and disease status and unrelated donors. Treosulfan-based regimens were associated with lower rates of graft-versus-host disease. There was no difference in any outcome among patients in first complete remission at transplantation. However, there was better survival with treosulfan-based conditioning in advanced leukemia. In conclusion, survival is determined mostly by disease biology and is similar after various regimens. Treosulfan-based conditioning is more similar to myeloablative than to reduced-intensity conditioning but can be administered safely in older patients, with lower rates of graft-versus-host disease and possibly better outcomes in patients with active leukemia. PMID- 29247777 TI - Determining Risk of Barrett's Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants. AB - BACKGROUND & AIMS: We developed comprehensive models to determine risk of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors. METHODS: We used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett's and EAC consortium as well as the United Kingdom's BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis. RESULTS: Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89-2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07-2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%. CONCLUSIONS: We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use. PMID- 29247781 TI - Killer Cell Immunoglobulin-Like Receptor-Ligand Mismatch in Donor versus Recipient Direction Provides Better Graft-versus-Tumor Effect in Patients with Hematologic Malignancies Undergoing Allogeneic T Cell-Replete Haploidentical Transplantation Followed by Post-Transplant Cyclophosphamide. AB - We evaluated the impact of unidirectional donor versus recipient killer cell immunoglobulin-like receptor (KIR)-ligand mismatch (KIR-Lmm) on the outcomes of T cell-replete haploidentical stem cell transplantation (Haplo-SCT) with post transplant cyclophosphamide (PT-Cy) in a cohort of 144 patients treated for various hematologi diseases. We separately analyzed 81 patients in complete remission (CR group) and 63 with active disease (no CR group) at the time of Haplo-SCT. One-third of patients in each group had KIR-Lmm. In the no CR group, KIR-Lmm was associated with a significantly lower incidence of relapse (hazard ratio, .21; P = .013) and better progression-free survival (hazard ratio, .42; P = .028), with no significant increase in graft-versus-host disease incidence or nonrelapse mortality. In contrast, in the CR group no benefit of KIR-Lmm was observed. Our results encourage considering KIR-Lmm as an additional tool to improve donor selection for T cell-replete Haplo-SCT with PT-Cy, especially in patients with high-risk diseases. PMID- 29247782 TI - Response of serum 25(OH)D to Vitamin D and calcium supplementation in school children from a semi-rural setting in India. AB - The objectives of this study were to: 1) Determine the impact of varying baseline serum 25OHD on increase in vitamin D concentrations after daily supplementation with vitamin D and calcium (1000 IU + 500 mg respectively) for six months in school-children from a semi-rural setting 2) Test the efficacy of daily vitamin D calcium supplementation on improvement in serum vitamin D concentrations to >=75 nmol/L. Data collected from 106 subjects (58 boys, 48 girls), aged 6-12 years, included anthropometric measures like height and weight, body composition analysis, three one-day dietary recalls and sunlight exposure (by questionnaire). Blood was collected at baseline and endline and estimated for serum vitamin D by ELISA technique using standard kits. Classification of Vitamin D status was performed according to the 2011 Endocrine Society Practice Guidelines: vitamin D deficiency - <50 nmol/L; insufficiency - 50.0-74.9 nmol/L; sufficiency - >=75 nmol/L. Statistical analysis was performed using SPSS software. Mean baseline serum vitamin D concentration was 59.7 +/- 11.2 nmol/L; this rose to 79.8 +/- 23.3 nmol/L with no significant differences between genders at the two time points. Inverse relationship was obtained between baseline serum 25(OH)D concentrations and change in serum concentrations after supplementation, implying that with increasing baseline serum concentrations of 25(OH)D, increase in vitamin D levels post supplementation were significantly lower (r = - 0.96, p < 0.0001). Greatest benefit of change in serum vitamin D concentrations after supplementation was experienced by children with basal concentrations of <45 nmol/L. Daily vitamin D supplementation was effective in improving serum 25(OH)D to >=75 nmol/L in 44% of children. Significantly higher percentage of children who were deficient at baseline (64%) were able to attain serum concentrations of >=75 nmol/L as compared to children who were vitamin D insufficient (43%) (p < 0.001). Thus, daily supplementation with 1000 IU of vitamin D along with 500 mg of calcium helped in improving serum vitamin D concentrations to >=75 nmol/L. Children who were vitamin D deficient particularly experienced these benefits. PMID- 29247783 TI - Sex-specific expression of apolipoprotein levels following replenishment of vitamin D. AB - Numerous studies have been done to establish the relationship between vitamin D and lipids, yet a definitive causal link is not found. This interventional study aims to evaluate and compare levels of apolipoproteins among vitamin D deficient subjects at baseline and after they achieved full vitamin D status correction.120 Saudi adults with vitamin D deficiency [25(OH)D < 50nmol/l] were recruited and given 50,000IU cholecalciferol weekly for first 2 months, then twice a month for next 2 months, followed by daily 1000IU until month 6. Blood samples were taken at baseline and after 6 months. Serum 25(OH)D, lipid profile and apolipoproteins (A1, A2, B, C1, C2, C3, E and H) were analyzed using commercially available kits. Overall, serum 25(OH)D increased significantly(63.3 +/- 16.5nmol/l at end of study vs. 32.5 +/- 10.8 at baseline; p < 0.0001). In parallel, a significant increase in apolipoproteins C1, C2, C3 and E (all p-values < 0.01) and a significant decrease in apolipoprotein B (p = 0.02) was observed. Following, stratification according to sex, apolipoproteins C2 and C3 significantly increased only in males (p-values < 0.01) while apolipoprotein C1 significantly increased only in females (p < 0.01). In addition, apolipoprotein B significantly decreased only in females (p = 0.002). These results suggests role of vitamin D in modulation of circulating levels of lipoproteins. The sexual dimorphism observed in circulating levels of measured apolipoproteins following vitamin D correction may explain, in part, known sexual disparity in the events of cardiometabolic health. PMID- 29247784 TI - Efficacy of Vitamin D interventional strategies in saudi children and adults. AB - Despite the amount of sunshine in Saudi Arabia, vitamin D (25(OH)D) deficiency is highly prevalent among Saudis. Several strategies are known to improve 25(OH)D status. The aim of this study was to evaluate the efficacy of different interventional strategies in improving 25(OH)D status in Saudi children and adults. This interventional study was undertaken among 593 out of 1152 Saudi subjects [530 students (aged 13-17 years) and 63 teachers (aged 26-46 years)] over a 6-month period from different secondary schools in Riyadh, Saudi Arabia. 25(OH)D status was taken at baseline and after 6 months post interventions. Subjects were divided into 3 groups and requested to implement different vitamin D correction schemes: sun-exposure, vitamin D-fortified milk consumption, and oral vitamin D supplementation (1000IU/day). Follow-up results revealed that all correction strategies used could decrease the deficiency of serum 25(OH)D with different potencies, with the highest positive percentage change observed in oral supplementation in both adults and children (11% men, 17% women, 16% boys and 8% girls). The oral vitamin D supplementation strategy also showed significant positive associations between delta (Delta) changes and HDL-cholesterol in both adults and children. In conclusion, oral vitamin D supplementation was the most effective strategy in improving vitamin D status in Saudi adults and children than sunlight exposure or consumption of vitamin D-fortified dairy products. PMID- 29247785 TI - Ecdysteroid and juvenile hormone biosynthesis, receptors and their signaling in the freshwater microcrustacean Daphnia. AB - The two essential insect hormones, ecdysteroids and juvenile hormones, are possessed not only by insects, but also widely by arthropods, and regulate various developmental and physiological processes. In contrast to the abundant information about molecular endocrine mechanisms in insects, the knowledge of non insect arthropod endocrinology is still limited. In this review, we summarize recent reports about the molecular basis of these two major insect hormones in the freshwater microcrustacean Daphnia, a keystone taxon in limnetic ecology and a bioindicator in environmental studies. Comprehensive comparisons of endocrine signaling pathways between insects and daphnids may shed light on the regulatory mechanisms of various biological phenomena and, moreover, evolutionary processes of arthropod species. PMID- 29247786 TI - Periadventitial local drug delivery to target restenosis. AB - The adventitia functions as a dynamic compartment for cell trafficking into and out of the artery wall, and communicates with medial and intimal cells. The resident cells in the tunica adventitia play an integral role in the regulation of vessel wall structure, repair, tone, and remodeling. Following injury to the vascular wall, adventitial fibroblasts are activated, which proliferate and differentiate into migratory myofibroblasts, and initiate inflammation through the secretion of soluble factors such as chemokines, cytokines, and adhesion molecules. The secreted factors subsequently promote leukocyte recruitment and extravasation into the media and intima. The adventitia generates reactive oxygen species and growth factors that participate in cell proliferation, migration, and hypertrophy, resulting in intimal thickening. The adventitial vasa vasorum undergoes neovascularization and serves as a port of entry for the delivery of inflammatory cells and resident stem/progenitor cells into the intima, and thus facilitates vascular remodeling. This review highlights the contribution of multilineage cells in the adventitia along with de-differentiated smooth muscle like cells to the formation of neointimal hyperplasia, and discusses the potential of periadventitial local drug delivery for the prevention of vascular restenosis. PMID- 29247787 TI - Therapeutic opportunities based on caspase modulation. AB - Caspases are a family of proteolytic enzymes that play a critical role in the regulation of programmed cell death via apoptosis. Activation of caspases is frequently impaired in human cancers, contributing to cancer formation, progression and therapy resistance. A better understanding of the molecular mechanisms regulating caspase activation in cancer cells is therefore highly important. Thus, targeted modulation of caspase activation and apoptosis represents a promising approach for the development of new therapeutic options to elucidate cancer cell death. PMID- 29247788 TI - Vector representations of multi-word terms for semantic relatedness. AB - This paper presents a comparison between several multi-word term aggregation methods of distributional context vectors applied to the task of semantic similarity and relatedness in the biomedical domain. We compare the multi-word term aggregation methods of summation of component word vectors, mean of component word vectors, direct construction of compound term vectors using the compoundify tool, and direct construction of concept vectors using the MetaMap tool. Dimensionality reduction is critical when constructing high quality distributional context vectors, so these baseline co-occurrence vectors are compared against dimensionality reduced vectors created using singular value decomposition (SVD), and word2vec word embeddings using continuous bag of words (CBOW), and skip-gram models. We also find optimal vector dimensionalities for the vectors produced by these techniques. Our results show that none of the tested multi-word term aggregation methods is statistically significantly better than any other. This allows flexibility when choosing a multi-word term aggregation method, and means expensive corpora preprocessing may be avoided. Results are shown with several standard evaluation datasets, and state of the results are achieved. PMID- 29247789 TI - Explosive type of contractions should not be avoided during resistance training in elderly. PMID- 29247790 TI - Age-related reduction in single muscle fiber calcium sensitivity is associated with decreased muscle power in men and women. AB - Age-related declines in human skeletal muscle performance may be caused, in part, by decreased responsivity of muscle fibers to calcium (Ca2+). This study examined the contractile properties of single vastus lateralis muscle fibers with various myosin heavy chain (MHC) isoforms (I, I/IIA, IIA and IIAX) across a range of Ca2+ concentrations in 11 young (24.1+/-1.1years) and 10 older (68.8+/-0.8years) men and women. The normalized pCa-force curve shifted rightward with age, leading to decreased activation threshold (pCa10) and/or Ca2+ sensitivity (pCa50) for all MHC isoforms examined. In older adults, the slope of the pCa-force curve was unchanged in MHC I-containing fibers (I, I/IIA), but was steeper in MHC II containing fibers (IIA, IIAX), indicating greater cooperativity compared to young adults. At sub-maximal [Ca2+], specific force was reduced in MHC I-containing fibers, but was minimally decreased in MHC IIA fibers as older adults produced greater specific forces at high [Ca2+] in these fibers. Lessor pCa50 in MHC I fibers independently predicted reduced isokinetic knee extensor power across a range of contractile velocities, suggesting that the Ca2+ response of slow-twitch fibers contributes to whole muscle dysfunction. Our findings show that aging attenuates Ca2+ responsiveness across fiber types and that these cellular alterations may lead to age-related reductions in whole muscle power output. PMID- 29247791 TI - Immune senescence and biomarkers profile of Bambui aged population-based cohort. AB - During immunosenescence many proinflammatory markers such as cytokines and chemokines are increased. This process called by Franceschi and colleagues as inflammaging is associated with chronic inflammation and the ethiology and pathophysiolgy of many ageing diseases as Alzheimer's and atherosclerosis. The knowledge of immune profile during ageing may provide some interventions that would improve the immune function in elderly and quality of life for old people. However, the identification of a group of potential biomarkers to monitor the ageing process is very difficult. In addition, most of the evidence evaluating immune biomarkers profile is based on data from older Caucasian adults. To our knowledge, no previous Latin American old population-based cohort has evaluated immunological parameters along the ageing process. The present work evaluated CXCL8, CXCL9, CXCL10, CCL2, CCL5, IL-1, IL-6, IL-12, TNF and IL-10 serum levels in 1494 older adults aged 60 to 95 from a population based ageing cohort in Brazil. Our data suggest that there is an increased positive predicted probability of participants to be a high producer of IL-6, CXCL8 and CXCL9. Moreover, results did not differ between men and women, except for CXCL10 that increased only in men. Results were not different in the adjusted model by many potential confounders, including African genomic ancestry. Together, these findings add novel insights about the immunologic aspects of ageing supported by a large population-based cohort study that provides evidences that corroborate with the inflammaging proposal and subsidize the establishment of biomarkers for monitoring the health status of aged population. PMID- 29247792 TI - Narrative Derived From Medical Student Reflection in Action: Lessons Learned and Implications for Assessment. AB - A process and tool that prompts learners to think about and reflect on their clinical performance was implemented. Learner narrative reflections about their work and faculty feedback, both captured in the moment, provided data for decisions about level of performance in a competency-based assessment system. PMID- 29247793 TI - A Case of Olmesartan-associated Sprue-like Enteropathy. PMID- 29247794 TI - A single WAP domain (SWD)-containing protein with antiviral activity from Pacific white shrimp Litopenaeus vannamei. AB - The single whey acidic protein (WAP) domain (SWD)-containing proteins, also called type III crustins, are a group of antimicrobial peptides (AMPs) in crustaceans. At present, a number of SWDs have been identified in shrimp, which showed essential antibacterial activities. However, the roles of SWDs in antiviral immune responses have not been reported up to now. In this study, a novel SWD (LvSWD3) was identified from Pacific white shrimp, Litopenaeus vannamei, which contained a typical single WAP domain homologous to those of other crustacean SWDs. Although lacking the pro and arg-rich region between the signal peptide and the WAP domain, LvSWD3 was closely clustered with other shrimp SWDs in the phylogenetic tree. Similar to many shrimp SWDs, the highest expression of LvSWD3 was detected in hemocytes. The LvSWD3 expression exhibited only limited changes after challenges with Vibrio parahaemolyticus, Poly (I:C) and lipopolysaccharide, but was significantly up-regulated after white spot syndrome virus (WSSV) infection. Silencing of LvSWDs significantly accelerated the death of the WSSV-infected but not the V. parahaemolyticus-infected shrimp. The recombinant LvSWD3 protein did not show proteinase inhibitory and antibacterial activities but could significantly postpone the death of WSSV infected shrimp and reduce the viral load in tissues. These suggested that LvSWD3 was a novel SWD with antiviral activity. PMID- 29247795 TI - Patient demographic and microbiology trends in bacterial conjunctivitis in children. AB - The management of bacterial conjunctivitis has a significant economic impact, despite the relatively benign nature of the disease. We reviewed the medical records for children diagnosed with conjunctivitis at inpatient and outpatient facilities of a tertiary university center over a 5-year period to examine the microbial trends and physician practice patterns and found that most cases of conjunctivitis were treated empirically. When cultures were performed and an organism was recovered, there were significant differences in the organism based on age. Although bacterial conjunctivitis accounted for only 10% of cases, antibiotics were dispensed in more than half of the cases. Pediatricians prescribed antibiotics for conjunctivitis more than twice as often as ophthalmologists. Less than 5% of patients who did not receive antibiotics returned to clinic within 1 month for persistent symptoms. PMID- 29247796 TI - Theta-burst modulation of mid-ventrolateral prefrontal cortex affects salience coding in the human ventral tegmental area. AB - In the context of hedonic (over-)eating the ventral tegmental area (VTA) as a core part of the dopaminergic reward system plays a central role in coding incentive salience of high-caloric food. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate whether transcranial magnetic theta-burst stimulation (TBS) over the right mid-ventrolateral prefrontal cortex (mid-VLPFC) can induce modulation of calorie-sensitive brain activation in the VTA. The prefrontal location for TBS had been predetermined by seed-based resting state fMRI with a functionally defined portion of the VTA serving as seed region obtained from an independent second fMRI experiment. In a sample of 15 healthy male participants, modulation of calorie-sensitive VTA activation did not significantly differ between the two TBS protocols. Comparisons with baseline revealed that both TBS protocols significantly affected calorie-sensitive neural processing of the mid-VLPFC in a rather similar way. In the VTA significant modulation of calorie-sensitive activation was observed after continuous TBS, whereas the modulatory effect of intermittent TBS was less reliable but also associated with a decrease of activation for high-caloric food images. Neurostimulation of right mid-VLPFC is suggestive as a main entry point of downstream signal changes for high- and low-caloric food cues that could enforce a shift in valuating stimuli of initially different incentive salience. PMID- 29247797 TI - Effect of price and information on the food choices of women university students in Saudi Arabia: An experimental study. AB - OBJECTIVE: To explore the impact of price manipulation and healthy eating information on intended food choices. DESIGN: Health information was provided to a random half of subjects (vs. information on Saudi agriculture). Each subject chose from the same lunch menu, containing two healthy and two unhealthy entrees, deserts and beverages, on five occasions. Reference case prices were 5, 3 and 2 Saudi Arabian Reals (SARs). Prices of healthy and unhealthy items were manipulated up (taxed) and down (subsidized) by 1 SAR in four menu variations (random order); subjects were given a budget enabling full choice within any menu. The number of healthy food choices were compared with different price combinations, and between information groups. Linear regression modelling explored the effect of relative prices of healthy/unhealthy options and information on number of healthy choices controlling for dietary behaviours and hunger levels. SETTING: University campus, Saudi Arabia, 2013. SUBJECTS: 99 women students. RESULTS: In the reference case, 49.5% of choices were for healthy items. When the price of healthy items was reduced, 58.5% of selections were healthy; 57.2% when the price of unhealthy items rose. In regression modelling, reducing the price of healthy items and increasing the price of unhealthy items increased the number of healthy choices by 5% and 6% respectively. Students reporting a less healthy usual diet selected significantly fewer healthy items. Providing healthy eating information was not a significant influence. CONCLUSION: Price manipulation offers potential for altering behaviours to combat rising youth obesity in Saudi Arabia. PMID- 29247798 TI - Circular RNA expression profile of articular chondrocytes in an IL-1beta-induced mouse model of osteoarthritis. AB - Osteoarthritis (OA) is a widely prevalent degenerative joint disease characterized by articular cartilage degradation and joint inflammation. The pathogenesis of OA remains unclear, leading to a lack of effective treatment. Previous studies have reported that circular RNAs (circRNAs) are involved in the development of various diseases. However, the function of circRNAs and their roles in OA is largely unknown. Therefore, we aimed to investigate changes in circRNA expression and predict their functions in OA by using bioinformatics analysis. An OA model was established in mouse articular chondrocytes (MACs) treated by interleukin-1beta (IL-1beta), and then the circRNA profile was screened by Next Generation Sequencing. By comparing circRNA expression in IL 1beta- treated MACs and normal controls, differentially expressed circRNAs were identified during OA pathogenesis, and differential expression levels of selected circRNAs were validated by qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were employed to predict the functions of these circRNAs. Because circRNAs can act as "miRNA sponges", we also constructed a circRNA-miRNA network to predict their functions. A total of 255 circRNAs were found to be differentially expressed in IL-1beta-treated MACs (p<=0.05; fold-change>=2) from the expression of the normal controls. Among them, 119 circRNAs were significantly up-regulated, and the other 136 were down regulated. Seven circRNAs were randomly selected to verify the reliability of these profiles by quantitative qRT-PCR. After obtaining the parental genes of differentially expressed circRNA, the top 30 enrichment GO entries and KEGG pathways were annotated. Then, two significantly differentially expressed circRNAs (mmu-circRNA-30365 and mmu-circRNA-36866) were identified and selected for further analysis, meanwhile a circRNA-miRNA regulation network was created and the top five most likely functional-related target miRNAs of the circRNAs were collected. Although the exact mechanisms and biological functions of these circRNAs in the development of OA need further exploration, our findings do suggest that the differentially expressed circRNAs were involved in the pathogenesis of OA. Thus, our study brings us closer to understanding the pathogenic mechanisms and finding new molecular targets for the clinical treatment of osteoarthritis. PMID- 29247799 TI - Identification of an alternatively spliced nuclear isoform of human N-terminal acetyltransferase Naa30. AB - N-terminal acetylation is a highly abundant and important protein modification in eukaryotes catalyzed by N-terminal acetyltransferases (NATs). In humans, six different NATs have been identified (NatA-NatF), each composed of individual subunits and acetylating a distinct set of substrates. Along with most NATs, NatC acts co-translationally at the ribosome. The NatC complex consists of the catalytic subunit Naa30 and the auxiliary subunits Naa35 and Naa38, and can potentially Nt-acetylate cytoplasmic proteins when the initiator methionine is followed by a bulky hydrophobic/amphipathic residue at position 2. Here, we have identified a splice variant of human NAA30, which encodes a truncated protein named Naa30288. The splice variant was abundantly present in thyroid cancer tissues and in several different human cancer cell lines. Surprisingly, Naa30288 localized predominantly to the nucleus, as opposed to annotated Naa30 which has a cytoplasmic localization. Full-length Naa30 acetylated a classical NatC substrate peptide in vitro, whereas no significant NAT activity was detected for Naa30288. Due to the nuclear localization, we also examined acetyltransferase activity towards lysine residues. Neither full-length Naa30 nor Naa30288 displayed any lysine acetyltransferase activity. Overexpression of full-length Naa30 increased cell viability via inhibition of apoptosis. In contrast, Naa30288 did not exert an anti-apoptotic effect. In sum, we identified a novel and widely expressed Naa30 isoform with a potential non-catalytic role in the nucleus. PMID- 29247800 TI - De novo RNA-Seq based transcriptome analysis of Papiliotrema laurentii strain RY1 under nitrogen starvation. AB - Nitrogen is a key nutrient for all cell forms. Most organisms respond to nitrogen scarcity by slowing down their growth rate. On the contrary, our previous studies have shown that Papiliotrema laurentii strain RY1 has a robust growth under nitrogen starvation. To understand the global regulation that leads to such an extraordinary response, we undertook a de novo approach for transcriptome analysis of the yeast. Close to 33 million sequence reads of high quality for nitrogen limited and enriched condition were generated using Illumina NextSeq500. Trinity analysis and clustered transcripts annotation of the reads produced 17,611 unigenes, out of which 14,157 could be annotated. Gene Ontology term analysis generated 44.92% cellular component terms, 39.81% molecular function terms and 15.24% biological process terms. The most over represented pathways in general were translation, carbohydrate metabolism, amino acid metabolism, general metabolism, folding, sorting, degradation followed by transport and catabolism, nucleotide metabolism, replication and repair, transcription and lipid metabolism. A total of 4256 Single Sequence Repeats were identified. Differential gene expression analysis detected 996 P-significant transcripts to reveal transmembrane transport, lipid homeostasis, fatty acid catabolism and translation as the enriched terms which could be essential for Papiliotrema laurentii strain RY1 to adapt during nitrogen deprivation. Transcriptome data was validated by quantitative real-time PCR analysis of twelve transcripts. To the best of our knowledge, this is the first report of Papiliotrema laurentii strain RY1 transcriptome which would play a pivotal role in understanding the biochemistry of the yeast under acute nitrogen stress and this study would be encouraging to initiate extensive investigations into this Papiliotrema system. PMID- 29247801 TI - Optimization of cranial computed tomography in patients with AIDS and clinical suspicion of a neural opportunistic pathology. AB - Cranial computed tomography (CT) remains valuable for the identification of opportunistic pathologies in AIDS patients in low-income countries. Delayed iodinated contrast medium CT images have the potential to better demonstrate inflammatory-infectious or neoplastic opportunistic pathologies. The main objective of this study was to optimize the protocol for cranial CT in patients with AIDS and clinical signs of opportunistic pathologies at the authors' institution. It was hypothesized that 20-min delayed contrast-enhanced CT images would be sufficient to optimize the detection of brain pathologies and that no additional delayed images would be necessary. Twenty-six adult patients with AIDS and brain pathologies were enrolled and had their cranial CT images analyzed by three evaluators. The numbers of lesions identified at two predetermined delayed time-points were compared. There was no variation in the number of lesions depicted by each evaluator, between the 20-min delayed contrast-enhanced CT image and the image obtained at the other predetermined delayed time-point. PMID- 29247802 TI - Corrigendum to "The plant heat stress transcription factor (Hsf) family: Structure, function and evolution" [BBAGRM 1819 (2) 104-119]. PMID- 29247803 TI - Staphylococcus aureus controls interleukin-5 release in upper airway inflammation. AB - : Staphylococcus aureus is a frequent colonizer of the upper airways in chronic rhinosinusitis with nasal polyps, but also resides intramucosally; it has been shown that secreted staphylococcal proteins such as enterotoxins and serine proteases induce the release of cytokines such as IL-5. We have analyzed nasal polyp tissue freshly obtained during routine surgery, which did or did not contain cultivatable S. aureus, to study spontaneous IL-5 production by nasal polyp tissue over 24 and 72h in tissue culture. In S. aureus-positive samples we interfered by killing the bacteria using antibiotics or S. aureus specific intravenous staphylococcal phages (ISP), active or heat-inactivated. Phage neutralizing antibodies were used to demonstrate the specificity of the phage mediated effects. We monitored S. aureus colony forming units, and identified S. aureus proteins by mass spectrometry. We demonstrate that cultivatable S. aureus may be found in type-2 inflamed nasal polyps; the pathogen is replicating within 24h and secretes proteins, including enterotoxins and serine proteases. The presence of S. aureus was associated with a significantly higher release of IL-5. Killing of S. aureus by antibiotics or specific ISP significantly reduced the IL 5 release. The suppressive activity of the bacteriophage on IL-5 be abolished by heat inactivation or anti-phage antibodies. BIOLOGICAL SIGNIFICANCE: In this study, we used high resolution mass spectrometry to identify S. aureus proteins directly in infected nasal polyp tissue and nasal polyp tissue incubated over 24 and 72h in culture. We discovered bacterial proteins including enterotoxins and serine proteases like proteins. These experiments indicate a direct role of S. aureus in the regulation of IL-5 production in nasal polyps and may suggest the involvement of bacterial proteins detected in the tissues. PMID- 29247804 TI - Infection and adaption-based proteomic changes of Streptococcus suis serotype 2 in a pig model. AB - : Streptococcus suis (S. suis) is an emerging zoonotic agent that is responsible for significant economic losses to the porcine industry worldwide. However, most research regarding the pathogenic mechanisms has used in vitro cultures of S. suis, which may not provide an accurate representation of the in vivo biological activities. In this study, 188 differential abundance S. suis proteins were identified in in vivo samples obtained from the blood of the infected pigs. These were compared with in vitro samples by a Tandem Mass Tags (TMT) experiment. Thus, a virulence associated network was established using the enriched differential abundance proteins (obtained via bioinformatics analysis in this study) and the previously reported putative virulence factors associated with in vivo infection. One of the most important up-regulated hubs in this network, adhE (an acetaldehyde-CoA/alcohol dehydrogenase) was found. Furthermore, knocking out adhE in S. suis serotype 2 strain ZY05719 decreased virulence. Cell culture experiments and far-western blot analysis showed that adhE is involved in adhesion to Caco-2 cells; Hsp60 could be one of the receptors for this protein. SIGNIFICANCE: This study is a systematical research to identify in vivo regulated virulence associated proteins of S. suis in pigs. It constructs a network consisting of in vivo infection related factors for the first time to get to know the coordinated actions of a multitude of factors that lead to host pathogenicity and filter the most important hubs. The individual factors that contribute to infection is also identified. A novel differential protein adhE which is one of the most important hubs of this network and is up-regulated in abundance in vivo is found to moonlight as an important adhesion by binding Hsp60 and finally contributes to virulence. PMID- 29247805 TI - Evidence for spatiotemporally distinct effects of image repetition and perceptual expectations as measured by event-related potentials. AB - Repeated stimulus presentation leads to reductions in responses of cortical neurons, known as repetition suppression or stimulus-specific adaptation. Circuit based models of repetition suppression provide a framework for investigating patterns of repetition effects that propagate through cortical hierarchies. To further develop such models it is critical to determine whether (and if so, when) repetition effects are modulated by factors such as expectation and attention. We investigated whether repetition effects are influenced by perceptual expectations, and whether the time courses of each effect are similar or distinct, by presenting pairs of repeated and alternating face images and orthogonally manipulating expectations regarding the likelihood of stimulus repetition. Event-related potentials (ERPs) were recorded from n = 39 healthy adults, to map the spatiotemporal progression of stimulus repetition and stimulus expectation effects, and interactions between these, using mass univariate analyses. We also tested for another expectation effect that may contribute to repetition effects in many previous experiments: that repeated stimulus identities are predictable after seeing the first stimulus in a trial, but unrepeated stimulus identities cannot be predicted. Separate blocks were presented with predictable and unpredictable alternating face identities. Multiple repetition and expectation effects were identified between 99 and 800ms from stimulus onset, which did not statistically interact at any point and exhibited distinct spatiotemporal patterns of effects. Repetition effects in blocks with predictable alternating faces were smaller than in unpredictable alternating face blocks between 117-179 ms and 506-652ms, and larger between 246 and 428ms. The distinct spatiotemporal patterns of repetition and expectation effects support separable mechanisms underlying these phenomena. However, previous studies of repetition effects, in which the repeated (but not unrepeated) stimulus was predictable, are likely to have conflated repetition and stimulus predictability effects. PMID- 29247806 TI - Contrasting functional imaging parametric maps: The mislocation problem and alternative solutions. AB - In the field of neuroimaging, researchers often resort to contrasting parametric maps to identify differences between conditions or populations. Unfortunately, contrast patterns mix effects related to amplitude and location differences and tend to peak away from sources of genuine brain activity to an extent that scales with the smoothness of the maps. Here, we illustrate this mislocation problem on source maps reconstructed from magnetoencephalographic recordings and propose a novel, dedicated location-comparison method. In realistic simulations, contrast mislocation was on average ~10 mm when genuine sources were placed at the same location, and was still above 5 mm when sources were 20 mm apart. The dedicated location-comparison method achieved a sensitivity of ~90% when inter-source distance was 12 mm. Its benefit is also illustrated on real brain-speech entrainment data. In conclusion, contrasts of parametric maps provide precarious information for source location. To specifically address the question of location difference, one should turn to dedicated methods as the one proposed here. PMID- 29247808 TI - Affective value, intensity and quality of liquid tastants/food discernment in the human brain: An activation likelihood estimation meta-analysis. AB - The primary dimensions of taste are affective value, intensity and quality. Numerous studies have reported the role of the insula in evaluating these dimensions of taste; however, the results were inconsistent. Therefore, in the current study, we performed meta-analyses of published data to identify locations consistently activated across studies and evaluate whether different regions of the human brain could be responsible for processing different dimensions of taste. Meta-analyses were performed on 39 experiments, with 846 total healthy subjects (without psychiatric/neurological disorders) in 34 studies reporting whole-brain results. The aim was to establish the activation likelihood estimation (ALE) of taste-mediated regional activation across the whole brain. Apart from one meta-analysis for all studies in general, three analyses were performed to reveal the clusters of activation that were attributable to processing the affective value (data from 323 foci), intensity (data from 43 foci) and quality (data from 45 foci) of taste. The ALE revealed eight clusters of activation outside the insula for processing affective value, covering the middle and posterior cingulate, pre-/post-central gyrus, caudate and thalamus. The affective value had four clusters of activation (two in each hemisphere) in the insula. The intensity and quality activated only the insula, each with one cluster on the right. The concurrence between studies was moderate; at best, 53% of the experiments contributed to the significant clusters attributable to the affective value, 60% to intensity and 50% to quality. The affective value was processed bilaterally in the anterior to middle insula, whereas intensity was processed in the right antero-middle insula, and quality was processed in the right middle insula. The right middle dorsal insula was responsible for processing both the affective value and quality of taste. The exploratory analysis on taste quality did not have a significant result if the studies using liquid food stimuli were excluded. Results from the meta-analyses on studies involving the oral delivery of liquid tastants or liquid food stimuli confirmed that the insula is involved in processing all three dimensions of taste. More experimental studies are required to investigate whether brain activations differ between liquid tastants and food. The coordinates of activated brain areas and brain maps are provided to serve as references for future taste/food studies. PMID- 29247807 TI - Real-time decoding of covert attention in higher-order visual areas. AB - Brain-computer-interfaces (BCI) provide a means of using human brain activations to control devices for communication. Until now this has only been demonstrated in primary motor and sensory brain regions, using surgical implants or non invasive neuroimaging techniques. Here, we provide proof-of-principle for the use of higher-order brain regions involved in complex cognitive processes such as attention. Using realtime fMRI, we implemented an online 'winner-takes-all approach' with quadrant-specific parameter estimates, to achieve single-block classification of brain activations. These were linked to the covert allocation of attention to real-world images presented at 4-quadrant locations. Accuracies in three target regions were significantly above chance, with individual decoding accuracies reaching upto 70%. By utilising higher order mental processes, 'cognitive BCIs' access varied and therefore more versatile information, potentially providing a platform for communication in patients who are unable to speak or move due to brain injury. PMID- 29247809 TI - Diclofenac for reversal of right ventricular dysfunction in acute normotensive pulmonary embolism: A pilot study. AB - BACKGROUND: The inflammatory response associated with acute pulmonary embolism (PE) contributes to the development of right ventricular (RV) dysfunction. Nonsteroidal anti-inflammatory drugs (NSAIDs) may facilitate the reversal of PE associated RV dysfunction. METHODS: We randomly assigned normotensive patients who had acute PE associated with echocardiographic RV dysfunction and normal systemic blood pressure to receive intravenous (IV) diclofenac (two doses of 75mg in the first 24h after diagnosis) or IV placebo. All patients received standard anticoagulation with subcutaneous low-molecular-weight heparin (LMWH) and an oral vitamin K antagonist. RV dysfunction was defined by the presence of, at least, two of the following criteria: i) RV diastolic diameter>30mm in the parasternal window; ii) RV diameter>left ventricle diameter in the apical or subcostal space; iii) RV free wall hypokinesis; and iv) estimated pulmonary artery systolic pressure>30mmHg. Persistence of RV dysfunction at 48h and 7days after randomization were the primary and secondary efficacy outcomes, respectively. The primary safety outcome was major bleeding within 7days after randomization. RESULTS: Of the 34 patients randomly assigned to diclofenac or placebo, the intention-to-treat analysis showed persistent RV dysfunction at 48h in 59% (95% confidence interval [CI], 33-82%) of the diclofenac group and in 76% (95% CI, 50 93%) of the placebo group (difference in risk [diclofenac minus standard anticoagulation], -17 percentage points; 95% CI, -47 to 17). Similar proportions (35%) of patients in the diclofenac and placebo groups had persistent RV dysfunction at 7days. Major bleeding occurred in none of patients in the diclofenac group and in 5.9% (95% CI, 0.2-29%) of patient in the placebo group. CONCLUSIONS: Due to slow recruitment, our study is inconclusive as to a potential benefit of diclofenac over placebo to reverse RV dysfunction in normotensive patients with acute PE. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01590342. PMID- 29247810 TI - Surgical revascularization of the celiac artery for persistent intestinal ischemia in short bowel syndrome. AB - BACKGROUND AND OBJECTIVES: Without prompt superior mesenteric artery (SMA) revascularization, acute mesenteric ischemia (AMI) frequently leads to death or short bowel syndrome (SBS). In SBS patients, persistent or chronic intestinal ischemia (PII) of the remnant bowel can lead to recurrences of AMI. Since SMA revascularization is sometimes unfeasible, celiac artery (CA) revascularization may improve blood supply to the remnant bowel. The aim of this study was to describe and to assess our experience of the CA revascularization in case of SMA occlusion unsuitable for revascularization in the setting of PII in SBS patients. METHODS: All consecutive patients with i) SBS consecutive to AMI, ii) persistent intestinal ischemia (PII), iii) irreversible SMA occlusion, i.e unsuitable for radiological or surgical revascularization and iv) occlusion or severe stenosis of the CA were included. RESULTS: Thirteen patients (7 males/6 females, mean age = 47.2 +/- 12.1 years) were included. The mean length of remnant small bowel was 47 +/- 39 cm and 77% of patients had a stoma. The types of revascularization included anterograde aorto-hepatic bypass n = 11 (84%), ilio-hepatic bypass n = 1 (8%) and endarterectomy n = 1 (8%). Major adverse events were observed in 5 cases: bypass graft infection (n = 2), hemorrhagic pericarditis (n = 2), hemorrhagic shock (n = 2) and aortic false aneurysm (n = 1). After a mean follow up of 27.0 +/- 25.2 months, symptoms of PII relieved in 12 cases (92%) allowing for digestive surgical rehabilitation with continuity restoration in 7 patients (54%). PN was weaned for 2 patients. One-year and 3-year survival rates were 73.8% and 73.8% respectively. No recurrence of AMI or further need for bowel resection was noticed. CONCLUSION: For patients with SBS suffering from PII with CA occlusion or stenosis without possibility of SMA revascularization, the surgical revascularization of the CA allowed digestive rehabilitation with acceptable morbidity and mortality rates. PMID- 29247811 TI - Irradiated allograft versus autograft for anterior cruciate ligament reconstruction: A meta-analysis and systematic review of prospective studies. AB - BACKGROUND: Irradiated allografts and autografts are commonly used for anterior cruciate ligament (ACL) reconstruction. The outcomes between these two grafts are controversial. This meta-analysis and systematic review of prospective comparative studies was performed to compare the clinical outcomes, including knee functionality, stability, subjective evaluation, complications, and failure, of irradiated allografts and autografts in primary ACL reconstruction. MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Library were searched from database inception to 12 August 2017 to identify prospective studies that compared irradiated allografts with autografts for primary ACL reconstruction. Randomized controlled trials were included in the meta-analysis. Prospective cohort studies were included in the systematic reviews. Two reviewers independently assessed the study quality and extracted relevant data. Statistical heterogeneity among the trials was evaluated by the chi-square and I-square tests. RESULTS: Four randomized controlled trials and two prospective cohort studies involving 18,835 patients met the inclusion criteria. In the meta-analysis, significant differences were observed in knee stability and subjective evaluation with respect to the KT-2000 score (p < .0001), pivot shift test (p = .001), anterior drawer test (p = .0001), Lachman test (p = .0002), subjective International Knee Documentation Committee (IKDC) score (p < .0001), Cincinnati knee score (p = .04), Lysholm score (p = .01), and Tegner score (p = .03). However, the differences in functional assessment in terms of the overall IKDC score (p = .21), range of motion (p = .94), Harner's vertical jump test (p = .09), Daniel's one-leg hop test (p = .50), and complication rate (p = .34) were not significant between the two groups. Failure was reported in two prospective cohort studies in 302 of 14,829 (2%) patients in the autograft group and 157 of 3941 (4%) patients in the irradiated allograft group. CONCLUSION: Irradiated allografts are inferior to autografts for patients undergoing primary ACL reconstruction with respect to knee stability and subjective evaluation. However, no significant differences were found between the two groups in terms of function and complication. The robustness of the findings might need to be further validated because of the limited number of randomized controlled trials. More randomized controlled trials with longer follow-ups are required to further evaluate the failure rate in the two groups. PMID- 29247812 TI - Reply letter to: "Inspiring surgeons of the future: A school outreach event and possible solution to the imminent recruitment crisis. PMID- 29247813 TI - Letter to the editor - Response to: Inspiring surgeons of the future: A school outreach event and possible solution to the imminent recruitment crisis. PMID- 29247814 TI - Clinical application of different operative approach of total knee replacement in knee valgus patients. Retrospective cohort study. AB - PURPOSE: According to the severity of knee valgus, different operative approaches were applied in total knee replacement. Hence, we assessed the safety and efficacy of different operative approaches in the level IV study. METHODS: From May 2011 to March 2014, a retrospectively analysis was conducted among 31 patients with knee valgus (mild in 10 cases, moderate in 8 cases and severe in 13 cases based on Keblish grade). Medial approach trip knee replacement was performed in mild and moderate patients, which were assigned as medial approach group. Lateral approach was performed in severe patients, which was assigned as lateral approach group. Relevant results were compared between medial approach group and lateral approach group, including valgus corrected angle, postoperative knee joint activity and Kss score. Furthermore, operative time, postoperative blood loss, patellar trajectory and anterior knee pain were also compared between the two groups. RESULTS: All operations were successful without obvious complications. In medial approach group, postoperative knee valgus angle was (7 +/- 1) degrees . Three months after operation, degree of knee joint activity was (85.2 +/- 5.2) degrees , and KSS score of knee joint was (80.1 +/- 5.2). Significant differences were detected in these compared with preoperative data (all P < .05). Moreover, similar results were found in lateral approach group with postoperative knee valgus angle as (8.2 +/- 2.3) degrees , degree of knee joint activity three months after operation as (85.2 +/- 5.3) degrees , and KSS score of knee joint as (80.3 +/- 3.2). However, no significant differences were found among these three groups in operative time, postoperative blood loss, patellar trajectory or anterior knee pain. CONCLUSIONS: Different operative approaches in total knee replacement according to the severity of knee valgus were proved as effective and safe procedures, which deserved further application. PMID- 29247815 TI - Over the hill and falling down: Can the NEXUS criteria be applied to the elderly? AB - INTRODUCTION: The National Emergency X-Radiography Utilization Study (NEXUS) criteria have been criticized due to the presumed unreliability of the clinical exam in elderly patients. The objective of this study was to determine if the NEXUS criteria can be safely applied to this vulnerable group of patients. METHODS: 596 trauma patients over the age of 65 were enrolled in a prospectively designed study between April 1, 2015 and October 1, 2016. The study was designed to encourage the use of the NEXUS criteria for all trauma patients including the elderly. NEXUS-negative patients (n = 226) were defined as individuals fulfilling none of the low risk criteria. The specificity and sensitivity of the NEXUS criteria were calculated based on any cervical spine injuries which were missed in NEXUS-positive patients (n = 129) who met one or more criteria. RESULTS: Out of the 596 included elderly patients, 355 patients underwent computed tomography (CT) of the cervical spine. 129 patients were NEXUS-positive and in this group ten nonoperative cervical spine injuries were detected. There were no NEXUS positive patients who did not undergo CT scans of the cervical spine. No cervical spine injuries were detected in the 226 NEXUS-negative patients. In elderly patients, the NEXUS criteria had a sensitivity of 100% and specificity of 100%. CONCLUSION: The NEXUS criteria have been criticized in prior literature as less sensitive in elderly patients. Based on the current study, the use of the NEXUS criteria may lead to decreased radiation exposure and healthcare costs allowing for better allocation of resources for patients who warrant imaging of the cervical spine. PMID- 29247816 TI - Generation of an ASS1 heterozygous knockout human embryonic stem cell line, WAe001-A-13, using CRISPR/Cas9. AB - The ASS1 gene encodes argininosuccinate synthetase-1, a cytosolic enzyme with a critical role in the urea cycle. Mutations are found in all ASS1 exons and cause the autosomal recessive disorder citrullinemia. Using CRISPR/Cas9-editing, we established the WAe001-A-13 cell line, which was heterozygous for an ASS1 mutation, from the human embryonic stem cell line H1. The WAe001-A-13 cell line maintained the pluripotent phenotype, the ability to differentiate into all three germ layers and a normal karyotype. PMID- 29247817 TI - Generation of a PXR reporter human induced pluripotent stem cell line (PXR mCherry hiPSC) using the CRISPR/Cas9 system. AB - Pregnane X receptor (PXR) is a key nuclear receptor that mediates drug metabolism and stimulates hepatocyte proliferation. However, the lack of PXR expression in human pluripotent stem cell-derived hepatocytes limits their application for drug screening and toxicity testing. Here, we generated a PXR-mCherry reporter human induced pluripotent stem cell (hiPSC) line using the CRISPR/Cas9 system. PXR mCherry hiPSCs were pluripotent and had differentiation potential and a normal karyotype. This cell line is an important tool for identifying factors that increase PXR-mediated drug metabolism and hepatocyte proliferation. PMID- 29247818 TI - Epidemiology of malpractice claims in the orthopedic and trauma surgery department of a French teaching hospital: A 10-year retrospective study. AB - INTRODUCTION: Orthopedic and trauma surgery is the specialty for which claims for compensation are most often filed. Little data exists on the subject in France, especially in a teaching hospital. We conducted a retrospective study aimed at (1) identifying the epidemiological characteristics of patients filing claims against the orthopedic surgery and traumatology department of a teaching hospital in France, (2) analyzing the surgical procedures involved, the type of legal proceedings, and the financial consequences. HYPOTHESIS: The epidemiological profile of proceedings seeking damages in France is consistent with the data from European and American studies. MATERIALS AND METHODS: An observational, retrospective, single-center study of all claims for damages between 2007 and 2016 involving the orthopedic and trauma surgery department of a teaching hospital was carried out. Patients' epidemiological data, the surgical procedure, type of legal proceeding, and financial consequences were analyzed. RESULTS: Of the 51,582 surgical procedures performed, 71 claims (0.0014%) were analyzed (i.e., 1/726 procedures). A significant increase in the number of cases (p=0.040) was found over a 10-year period. Of these, 36/71 (53.7%) were submitted to the French regional conciliation and compensation commission (CRCI), 23/71 (32.8%) were filed with the administrative court, and 12/71 (13.4%) were submitted for an amicable settlement. The most common reason for which patients filed claims was hospital-acquired infections, with 36/71 (50.7%) cases. Twenty-nine complaints (40.8%) resulted in monetary damages being awarded to the patient, with an average award of ? 28,301 (? 2,400-299,508). Damage awards were significantly higher (p<0.05) for cases involving surgery on a lower limb than those involving an upper limb. CONCLUSION: Claims against orthopedic surgeons have been increasing significantly over the last 10 years. Although rare, they represent a significant cost to society. Hospital-acquired infections are the main reason for disputes in our specialization. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 29247819 TI - Diagnostic uncertainty and clinical decision-making strategies. PMID- 29247820 TI - A study of salivary opiorphin levels using different anesthetic drugs and techniques - A randomized controlled clinical study. AB - PURPOSE: This study aimed at assessing the change in salivary opiorphin levels before and after administration of local anesthesia, with the use of three different local anesthetic agents, and different anaesthetic techniques. METHODS: The investigators implemented a randomized controlled clinical study in 144 patients who required tooth extraction after administration of local anaesthesia. A total of 288 samples were collected in sterile containers before and after administration of local anesthetics. The salivary samples were centrifuged and salivary opiorphin levels were estimated using ELISA testing and spectrophotometric analysis. Statistical analysis was done using one way ANOVA and unpaired t test. RESULTS: There was a mean decrease in salivary opiorphin levels after administration of local anesthesia. There was no significant difference in the change in salivary opiorphin levels across different anesthetic techniques and different drug subgroups. CONCLUSION: The present study did not show much association between various local anesthetic agents and techniques and change in salivary opiorphin levels. The role of opiorphin as a biomarker for pain control and its effect on various pain control methods including local anesthesia must be evaluated in detail. Institutional review board number SRMDC/IRB/2014/MDS/No. 405. PMID- 29247822 TI - Treatment for patients with recurrent intractable epilepsy after primary hemispherectomy. AB - BACKGROUND: Hemispherectomy is useful for treating patients with intractable epilepsy caused by diffuse unilateral hemispheric disease. Few patients develop recurrent seizures after hemispherectomy, but managing epilepsy by medical means alone is challenging for these patients, and it is also difficult to determine the treatment options and assess the need for reoperation. OBJECTIVE: To present the treatment strategies and outcomes of patients who developed recurrent intractable epilepsy after initial hemispherectomies that were performed at a single institution by a single surgeon between 2004 and 2014. METHOD: The preoperative medical records, operative reports, imaging findings, and follow-up data for patients with recurrent epilepsy who underwent hemispherectomy for intractable epilepsy between 2004 and 2014 at Sanbo Brain Hospital Capital Medical University were retrospectively reviewed. The baseline characteristics, cause of seizures, imaging findings, electrophysiological findings, primary surgery-related complications, treatments for recurrent epilepsy and long-term seizure outcomes were evaluated. A reduction of seizure frequency greater than 90% was considered a favorable outcome. RESULTS: In the cohort of 17 patients who suffered recurrent epilepsy after primary hemispherectomy, 11 had undergone reoperative surgery, whereas 6 patients took medication alone. No major complications occurred in this series. At the last follow-up, favorable outcome was noted in 10 (91%) patients who underwent reoperative surgery and in 1 (17%) patient who received only medication for treatment (Table 1, p = 0.005). Patients with malformation of cortical development tended to have worse seizure outcomes. CONCLUSIONS: Reoperative hemispherectomy is an effective and safe treatment for patients who still have seizures after primary hemispherectomy for epilepsy caused by unilateral cortical lesion. PMID- 29247821 TI - Lipase-inorganic hybrid nanoflower constructed through biomimetic mineralization: A new support for biodiesel synthesis. AB - We reported a facile, economic and green method based on biomimetic mineralization to acquire lipase-inorganic hybrid nanoflower, which was then employed as a biocatalyst for biodiesel production. In the hybrid nanoflower, enzyme molecules and Cu2+ ions were utilized as the organic and inorganic components, respectively. The morphology of nanoflower and the distribution and loading of proteins were systematically characterized by scanning electron microscopy, confocal laser scanning microscopy and ultraviolet-visible spectroscopy, which indicated the successful encapsulation of lipase in the hybrid nanoflower. Using the hydrolysis of p-nitrophenyl caprylate as a model, lipase-inorganic hybrid nanoflower was observed to possess favorable catalytic activity and stability in the ester hydrolysis. Further, the hybrid nanoflower was used as a catalyst for biodiesel production, in which it could convert sunflower oil to biodiesel with 96.5% conversion and remain 72.5% conversion after being used for 5 cycles. Thus, the lipase-inorganic hybrid nanoflower is potential to be used as an economically viable biocatalyst for the production of biofuel as the future petrol-fuel replacement. PMID- 29247823 TI - The long noncoding RNA LUCAT1 promotes tumorigenesis by controlling ubiquitination and stability of DNA methyltransferase 1 in esophageal squamous cell carcinoma. AB - Available targeted therapies for esophageal squamous cell carcinoma (ESCC) are limited; thus, further genetic and epigenetic studies are needed. Recently, many long noncoding RNAs (lncRNAs) have been reported to be involved in various cancers. Here, we investigated whether the lncRNA LUCAT1 was related to the carcinogenesis of ESCC based on previous studies in lung cancer. LUCAT1 was significantly upregulated in ESCC cell lines and cancer tissue compared with normal cells and adjacent normal tissues. LUCAT1 knockdown reduced cell proliferation, induced apoptosis, and upregulated tumor-suppressor genes by reducing DNA methylation in KYSE-30 cells. Moreover, LUCAT1 siRNA reduced DNA methyltransferase 1 (DNMT1) protein levels without affecting transcription. Patients with high LUCAT1 expression had significantly lower survival rates than patients with low LUCAT1 expression. Our results thus suggest that LUCAT1 regulates the stability of DNMT1 and inhibits the expression of tumor suppressors through DNA methylation, leading to the formation and metastasis of ESCC. We identified LUCAT1 as a potential target for drug development and as a biomarker for ESCC. PMID- 29247824 TI - High-throughput sequencing of the immune repertoire in oncology: Applications for clinical diagnosis, monitoring, and immunotherapies. AB - The diagnostic, monitoring and therapeutic options for cancers currently remain limited. These limitations represent a large threat to human health. Adaptive immunity, which is dependent on diverse repertoires of B cell receptors (BCRs) and T cell receptors (TCRs), plays a critical role in the anti-tumor immune response. Modulation and surveillance of adaptive immunity has become a powerful weapon to combat cancers. Recently, the high-throughput sequencing of immune repertoire (HTS-IR) technology, which provides a robust tool for deep sequencing repertoires of BCRs or TCRs, has been applied in the development of tumor biomarkers and immunotherapeutics for cancers. This review will first provide an overview of the advancement of HTS-IR technology at the population-cell and single-cell levels. It will then provide a current summary of the applications of HTS-IR technology in the diagnosis and monitoring of minimal residual disease (MRD), focusing on immune reconstitution after the treatment of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in B/T-cell malignancies, and the precise detection of tumor-infiltrating lymphocytes (TILs) in non-B/T-cell malignancies. Finally, current advances of HTS-IR technology in cancer immunotherapeutic applications, such as therapeutic antibodies, CAR-T cell based adoptive immunotherapies, and neoantigen-specific TCR-T cell-based adoptive immunotherapies, will be introduced. PMID- 29247825 TI - Hypoxia-induced microRNA-590-5p promotes colorectal cancer progression by modulating matrix metalloproteinase activity. AB - Hypoxia leads to cancer progression and promotes the metastatic potential of cancer cells. MicroRNAs (miRNAs) are small non-coding RNA that have emerged as key players involved in cancer development and progression. Hypoxia alters a set of hypoxia-mediated miRNAs expression during tumor development and it may function as oncogenes or tumor-suppressors. However, the roles and molecular mechanisms of hypoxia-regulatory miRNAs in colorectal cancer (CRC) progression remain poorly understood. Here we firstly identified miR-590-5p as hypoxia sensitive miRNAs which was upregulated in colon cancer cells under hypoxia. Hypoxia-induced miR-590-5p suppressed the expression of RECK, in turn, promoting cell invasiveness and migratory abilities via activation of matrix metalloproteinases (MMPs) and filopodia protrusion in vitro. Inhibition of miR 590-5p suppressed tumor growth and metastasis in mouse xenograft and CRC liver metastasis models via inhibition of MMPs activity. Clinical analysis revealed higher miR-590-5p expression in CRC, compared to normal specimens. Furthermore, miR-590-5p expression was significantly increased in liver metastasis as compared to their matched primary CRC. Taken together, our findings provide the first evidence that miR-590-5p may have potential as a therapeutic target for CRC patients with metastasis. PMID- 29247826 TI - Cytostatic hydroxycoumarin OT52 induces ER/Golgi stress and STAT3 inhibition triggering non-canonical cell death and synergy with BH3 mimetics in lung cancer. AB - Coumarins are natural compounds with antioxidant, anti-inflammatory and anti cancer potential known to modulate inflammatory pathways. Here, non-toxic biscoumarin OT52 strongly inhibited proliferation of non-small cell lung cancer cells with KRAS mutations, inhibited stem-like characteristics by reducing aldehyde dehydrogenase expression and abrogated spheroid formation capacity. This cytostatic effect was characterized by cell cycle arrest and onset of senescence concomitant with endoplasmic reticulum and Golgi stress, leading to metabolic alterations. Mechanistically, this cellular response was associated with the novel capacity of biscoumarin OT52 to inhibit STAT3 transactivation and expression of its target genes linked to proliferation. These results were validated by computational docking of OT52 to the STAT3 DNA-binding domain. Combination treatments of OT52 with subtoxic concentrations of Bcl-xL and Mcl-1 targeting BH3 protein inhibitors triggered synergistic immunogenic cell death validated in colony formation assays as well as in vivo by zebrafish xenografts. PMID- 29247827 TI - SEC-induced activation of ANXA7 GTPase suppresses prostate cancer metastasis. AB - Annexin A7 (ANXA7) is a suppressor of tumorigenesis and metastasis in prostate cancer. Activated ANXA7 GTPase promotes prostate cancer cell apoptosis. However, the role and underlying mechanism of ANXA7 GTPase in prostate cancer metastasis have not been established. RKIP is a metastatic suppressor and downregulated in prostate cancer metastases. The binding of RKIP and its target proteins could inhibit the activation of its interactive partners. However, the effect of RKIP on ANXA7 GTPase activation is not clear. Here, we report that activation of ANXA7 GTPase by a small molecule SEC ((S)-ethyl 1-(3-(4-chlorophenoxy)-2-hydroxypropyl) 3- (4-methoxyphenyl)-1H-pyrazole-5-carboxylate) effectively inhibited prostate cancer metastasis. Mechanistically, activated ANXA7 promoted AMPK phosphorylation, leading to decreased mTORC1 activity, suppressed STAT3 nuclear translocation, and downregulation of pro-metastatic genes, including CCL2, APLN, and IL6ST. Conversely, RKIP interacted with ANXA7 and impaired activation of ANXA7 GTPase by SEC and its downstream signaling pathway. Notably, SEC treatment suppressed metastasis of prostate cancer cells in in vivo orthotopic analysis. Together, our findings provide a novel insight into how metastasis of prostate cancer with low RKIP expression is suppressed by SEC-induced activation of ANXA7 GTPase via the AMPK/mTORC1/STAT3 signaling pathway. PMID- 29247829 TI - PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes. AB - INTRODUCTION: Combined immune checkpoint blockade has led to rare autoimmune complications, such as fatal myocarditis. Recent approvals of several anti programmed death 1 (anti-PD-1) drugs for lung cancer treatment prompted ongoing clinical trials that directly combine PD-1 inhibitors with thoracic radiotherapy for locally advanced lung cancer. Overlapping toxicities from either modality have the potential to increase the risk for radiation-induced cardiotoxicity (RICT), which is well documented among patients with Hodgkin's disease and breast cancer. METHODS: To investigate cardiotoxicity without the compounding pulmonary toxicity from thoracic radiotherapy, we developed a technique to deliver cardiac irradiation (CIR) in a mouse model concurrently with PD-1 blockade to determine the presence of cardiac toxicity by using physiological testing and mortality as end points along with histological analysis. RESULTS: We observed an acute mortality of 30% within 2 weeks after CIR plus anti-PD-1 antibody compared with 0% from CIR plus immunoglobulin G (p = 0.023). Physiological testing demonstrated a reduced left ventricular ejection fraction (p < 0.01) by echocardiogram. Tissue analyses revealed increased immune cell infiltrates within cardiac tissue. Depletion of CD8-positive lymphocytes with anti-CD8 antibody reversed the acute mortality, suggesting that the toxicity is CD8-positive cell-mediated. To validate these findings using a clinically relevant fractionated radiotherapy regimen, we repeated the study by delivering five daily fractions of 6 Gy. Similar mortality, cardiac dysfunction, and histological changes were observed in mice receiving fractionated radiotherapy with concurrent anti-PD-1 therapy. CONCLUSIONS: This study provides strong preclinical evidence that radiation induced cardiotoxicity is modulated by the PD-1 axis and that PD-1 blockade should be administered with careful radiotherapy planning with an effort of reducing cardiac dose. PMID- 29247828 TI - Hypersensitivity of mouse embryonic fibroblast cells defective for DNA polymerases eta, iota and kappa to various genotoxic compounds: Its potential for application in chemical genotoxic screening. AB - Genotoxic agents cause modifications of genomic DNA, such as alkylation, oxidation, bulky adduct formation, and strand breaks, which potentially induce mutations and changes to the structure or number of genes. Majority of point mutations are generated during error-prone bypass of modified nucleotides (translesion DNA synthesis, TLS); however, when TLS fails, replication forks stalled at lesions eventually result in more lethal effects, formation of double stranded breaks (DSBs). Here we compared sensitivities to various compounds among mouse embryonic fibroblasts derived from wild-type and knock-out mice lacking one of the three Y-family TLS DNA polymerases (Poleta, Poliota, and Polkappa) or all of them (TKO). The compounds tested in this study include genotoxins such as methyl methanesulfonate (MMS) and nongenotoxins such as ammonium chloride. We found that TKO cells exhibited the highest sensitivities to most of the tested genotoxins, but not to the non-genotoxins. In order to quantitatively evaluate the hypersensitivity of TKO cells to different chemicals, we calculated ratios of half-maximal inhibitory concentration for WT and TKO cells. The ratios for 9 out of 10 genotoxins ranged from 2.29 to 5.73, while those for 5 nongenotoxins ranged from 0.81 to 1.63. Additionally, the two markers for DNA damage, ubiquitylated proliferating cell nuclear antigen and gamma-H2AX after MMS treatment, were accumulated in TKO cells more greatly than in WT cells. Furthermore, following MMS treatment, TKO cells exhibited increased frequency of sister chromatid exchange compared with WT cells. These results indicated that the hypersensitivity of TKO cells to genotoxins resulted from replication fork stalling and subsequent DNA double-strand breaks, thus demonstrating that TKO cells should be useful for evaluating chemical genotoxicity. PMID- 29247830 TI - Phase 2 Study of the HSP-90 Inhibitor AUY922 in Previously Treated and Molecularly Defined Patients with Advanced Non-Small Cell Lung Cancer. AB - INTRODUCTION: In this phase 2 study, we evaluated the activity of AUY922 in pretreated patients with stage IV NSCLC. METHODS: Patients with advanced NSCLC were divided into molecularly defined strata based on mutations in the EGFR gene, the ALK receptor tyrosine kinase gene (ALK), the KRAS gene, or the wild type of all three. All patients must have received more than two prior lines of therapy, except for those in a fifth stratum for a less pretreated EGFR cohort (EGFR<2). In the EGFR-mutant and ALK-rearranged strata, prior platinum therapy was not required. Patients with EGFR mutation must have received an EGFR tyrosine kinase inhibitor unless they had de novo resistance (e.g., T790M or exon 20 insertions). Eligible patients received weekly intravenous AUY922, 70 mg/m2. The primary objective was to estimate efficacy (complete or partial response, or in the absence of complete or partial response, stable disease) at 18 weeks, by the Response Criteria in Solid Tumors. RESULTS: A total of 153 patients from 21 global centers were enrolled from October 2010 to November 2014. The investigator assessed overall response rate and stable disease rate at 18 weeks were 31.8% and 9.1% in the ALK-rearranged stratum, 17.1% and 8.6% in EGFR-mutant stratum, 9.7% and 22.6% in the EGFR<2 stratum, 0% and 7.1% in KRAS-mutant stratum, and 8.8% and 8.8% in wild-type stratum. Biomarker data showed activity of AUY922 in EGFR mutant patients with exon 19 deletion, T790M mutation, and exon 20 insertion. The most common (>=40%) all-causality adverse events were diarrhea, nausea, and decreased appetite. Visual-related disorders were reported in 79.7% of patients (most were grade 1/2). Thirty-five patients (22.9%) reported night blindness. CONCLUSION: AUY922 is active in patients with NSCLC, particularly among patients with ALK rearrangements and EGFR mutations. PMID- 29247831 TI - Persuasion strategies and sexual solicitations and interactions in online sexual grooming of adolescents: Modeling direct and indirect pathways. AB - Online sexual grooming and exploitation of adolescents is receiving increasing social attention. Drawing on a social influence framework, the aim of this study was to test a model of the direct and mediated relationships between an adult's use of persuasion strategies and online sexual grooming of early adolescents. The initial sample of the study consisted of 2731 early Spanish adolescents between 12 and 15 years old (50.6% female). Of these, 196 adolescents (7.17% of the total; 53% girls) were involved in online grooming (mean age = 14.93, SD = 0.90). Persuasion strategies by the adult through internet increased the probability of using deceit, bribery, and the minor's nonsexual involvement. In addition, deceit and bribery were associated with higher rates of sexual solicitation, which in turn increased abusive sexual interactions. Understanding strategies used by adults to groom minors contributes to the prevention of and intervention in this crucial societal problem. PMID- 29247832 TI - A novel ultrasonic precise bonding with non-constant amplitude control for thermalplastic polymer MEMS. AB - Ultrasonic bonding has been emerging paving the way in micro assembly, with the high demand in fusion quality control. Under this background a novel ultrasonic precise bonding method based on non-constant amplitude control is proposed. A two step bonding process, including frictional heating and viscoelastic heating, divided by the vibration propagation is designed. In step I, initial melting of the contacting surfaces is achieved at the amplitude bigger than the critical value. In step II, the whole interfacial fusion is realized at smaller amplitude to weaken the ultrasonic cavitation effect. The primary parameters in this method, including the amplitudes for the two steps and the conversion point, are studied. Results indicate that whole fusion bonding can be achieved with the flaws restrained. The proportion of cavity reduces to less than 2% when the amplitude for step II is set at a smaller value. PMID- 29247833 TI - Inferring anatomical therapeutic chemical (ATC) class of drugs using shortest path and random walk with restart algorithms. AB - The anatomical therapeutic chemical (ATC) classification system is a widely accepted drug classification scheme. This system comprises five levels and includes several classes in each level. Drugs are classified into classes according to their therapeutic effects and characteristics. The first level includes 14 main classes. In this study, we proposed two network-based models to infer novel potential chemicals deemed to belong in the first level of ATC classification. To build these models, two large chemical networks were constructed using the chemical-chemical interaction information retrieved from the Search Tool for Interactions of Chemicals (STITCH). Two classic network algorithms, shortest path (SP) and random walk with restart (RWR) algorithms, were executed on the corresponding network to mine novel chemicals for each ATC class using the validated drugs in a class as seed nodes. Then, the obtained chemicals yielded by these two algorithms were further evaluated by a permutation test and an association test. The former can exclude chemicals produced by the structure of the network, i.e., false positive discoveries. By contrast, the latter identifies the most important chemicals that have strong associations with the ATC class. Comparisons indicated that the two models can provide quite dissimilar results, suggesting that the results yielded by one model can be essential supplements for those obtained by the other model. In addition, several representative inferred chemicals were analyzed to confirm the reliability of the results generated by the two models. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. PMID- 29247834 TI - The KL-VS polymorphism of KLOTHO gene is protective against retinopathy incidence in patients with type 1 diabetes. AB - BACKGROUND AND AIMS: KLOTHO is an anti-ageing circulating hormone involved in insulin signaling, inflammation and vascular homeostasis through its protective effects on the endothelium and antioxidant actions. The common functional "KL-VS" variant of the KLOTHO gene is reproducibly associated with longevity in humans. Large number of studies have evaluated close relationship between KLOTHO protein and diabetes but the association between KL-VS variant and retinopathy in type 1 diabetes mellitus (T1D) is unknown. Therefore, in the present study we examined the association between the KL-VS polymorphism and the risk of diabetic retinopathy (DR) in patients with T1D. METHODS: We examined 400 patients with T1D and 350 healthy age-matched controls. The analysis concerned KL-VS polymorphism along with the levels of serum inflammatory (CRP, TNF-alpha) and anti inflammatory (IL-10) markers, pro-angiogenic (angiogenin) and anti-angiogenic interferon gamma-induced protein 10 (IP-10) factors as well as adhesion molecules (ICAM-1, ICAM-3). RESULTS: We did not find significant association between T1D and KL-VS alleles. However, we observed that the incidence of KL-VS genotype is lower in a group with retinopathy in comparison to diabetic patients without this complication. Moreover, we established that KL-VS carriers had the lowest levels of inflammatory markers, pro-angiogenic factors and adhesion molecules. Simultaneously, the KL-VS carriers had increased serum levels of anti inflammatory and anti-angiogenic cytokines than holders bearing wild type genotype. CONCLUSIONS: In conclusion, the findings of our studies suggest that the functional KL-VS variant of the KLOTHO gene protects against the development of retinopathy in patients with T1D. PMID- 29247835 TI - Amlexanox provides a potential therapy for nonsense mutations in the lysosomal storage disorder Aspartylglucosaminuria. AB - Aspartylglucosaminuria (AGU) is a lysosomal storage disorder caused by mutations in the gene for aspartylglucosaminidase (AGA). This enzyme participates in glycoprotein degradation in lysosomes. AGU results in progressive mental retardation, and no curative therapy is currently available. We have here characterized the consequences of AGA gene mutations in a compound heterozygous patient who exhibits a missense mutation producing a Ser72Pro substitution in one allele, and a nonsense mutation Trp168X in the other. Ser72 is not a catalytic residue, but is required for the stabilization of the active site conformation. Thus, Ser72Pro exchange impairs the autocatalytic activation of the AGA precursor, and results in a considerable reduction of the enzyme activity and in altered AGA precursor processing. Betaine, which can partially rescue the AGA activity in AGU patients carrying certain missense mutations, turned out to be ineffective in the case of Ser72Pro substitution. The Trp168X nonsense allele results in complete lack of AGA polypeptide due to nonsense-mediated decay (NMD) of the mRNA. Amlexanox, which inhibits NMD and causes a translational read through, facilitated the synthesis of a full-length, functional AGA protein from the nonsense allele. This could be demonstrated as presence of the AGA polypeptide and increased enzyme activity upon Amlexanox treatment. Furthermore, in the Ser72Pro/Trp168X expressing cells, Amlexanox induced a synergistic increase in AGA activity and polypeptide processing due to enhanced processing of the Ser72Pro polypeptide. Our data show for the first time that Amlexanox might provide a valid therapy for AGU. PMID- 29247836 TI - Coexpression network analysis identifies transcriptional modules associated with genomic alterations in neuroblastoma. AB - Neuroblastoma is a highly complex and heterogeneous cancer in children. Acquired genomic alterations including MYCN amplification, 1p deletion and 11q deletion are important risk factors and biomarkers in neuroblastoma. Here, we performed a co-expression-based gene network analysis to study the intrinsic association between specific genomic changes and transcriptome organization. We identified multiple gene coexpression modules which are recurrent in two independent datasets and associated with functional pathways including nervous system development, cell cycle, immune system process and extracellular matrix/space. Our results also indicated that modules involved in nervous system development and cell cycle are highly associated with MYCN amplification and 1p deletion, while modules responding to immune system process are associated with MYCN amplification only. In summary, this integrated analysis provides novel insights into molecular heterogeneity and pathogenesis of neuroblastoma. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. PMID- 29247837 TI - Cholesterol ester hydrolase inhibitors reduce the production of synaptotoxic amyloid-beta oligomers. AB - The production of amyloid-beta (Abeta) is the key factor driving pathogenesis in Alzheimer's disease (AD). Increasing concentrations of Abeta within the brain cause synapse degeneration and the dementia that is characteristic of AD. Here the factors that affect the release of disease-relevant forms Abeta were studied in a cell model. 7PA2 cells expressing the human amyloid precursor protein released soluble Abeta oligomers that caused synapse damage in cultured neurons. Supernatants from 7PA2 cells treated with the cholesterol synthesis inhibitor squalestatin contained similar concentrations of Abeta42 to control cells but did not cause synapse damage in neuronal cultures. These supernatants contained reduced concentrations of Abeta42 oligomers and increased concentrations of Abeta42 monomers. Treatment of 7PA2 cells with platelet-activating factor (PAF) antagonists had similar effects; it reduced concentrations of Abeta42 oligomers and increased concentrations of Abeta42 monomers in cell supernatants. PAF activated cholesterol ester hydrolases (CEH), enzymes that released cholesterol from stores of cholesterol esters. Inhibition of CEH also reduced concentrations of Abeta42 oligomers and increased concentrations of Abeta42 monomers in cell supernatants. The Abeta monomers produced by treated cells protected neurons against Abeta oligomer-induced synapse damage. These studies indicate that pharmacological manipulation of cells can alter the ratio of Abeta monomer:oligomer released and consequently their effects on synapses. PMID- 29247838 TI - A retrospective analysis of adverse effects of an in vivo fluoroquinolone antibiotic enrofloxacin treatment on oocyte quality in the common marmoset. AB - Here we report a retrospective analysis of negative effects of routine enrofloxacin treatment of recurrent diarrhea on the ovary and the developing oocytes of the common marmoset, a small New World primate. The most deleterious effect on oocytes was observed about two months post treatment suggesting that the enrofloxacin effect is on early growing follicles. Manifestations of toxicity included decreased numbers of growing follicles and recovered culturable oocytes, as well as signs of early atresia of granulosa cells. In addition, increased amounts of holed stroma after treatment strongly suggested increased death of the early growing follicles. Of the oocytes judged to be of adequate quality for culture, maturation rates were not affected but fertilization of in vitro matured MII oocytes and subsequent cleavage rates were severely reduced in the enrofloxacin treated animals. Further, the arrested oocytes, which failed to mature or fertilize, showed obvious meiotic spindle abnormalities. PMID- 29247839 TI - alpha-Solanine impairs oocyte maturation and quality by inducing autophagy and apoptosis and changing histone modifications in a pig model. AB - In this study, we used a pig model to investigate the effects of alpha-solanine (a natural toxin found mainly in potato sprouts) on oocyte maturation, quality and subsequent embryonic development. We found that alpha-solanine (10 MUM) disturbed meiotic resumption and increased abnormal spindle formation and altered the cortical granule (CG) distribution compared with the untreated group. alpha Solanine triggered autophagy and apoptosis by increasing the expressions of autophagy-related genes (LC3, ATG7, and LAMP2) and apoptotic related genes (BAX and CASP3). Exposure of porcine oocytes to alpha-solanine significantly increased the levels of H3K36me3 and H3K27me3. Moreover, alpha-solanine significantly reduced the cleavage and blastocyst formation rates, decreased the total and inner cell mass cells numbers, and increased apoptosis in these porcine embryos. Taken together, our data indicate that alpha-solanine toxically impairs oocyte maturation and quality by triggering autophagy/apoptosis and facilitating epigenetic modifications. Furthermore, alpha-solanine suppressed subsequent embryonic development and reduced embryo quality. PMID- 29247840 TI - Bisphenol A reduces testosterone production in TM3 Leydig cells independently of its effects on cell death and mitochondrial membrane potential. AB - Leydig cells are the major testosterone-producing cells of the male reproductive system, and damage to these cells can impair fertility of men. Bisphenol A (BPA) is one of the chemicals with the highest volume of production worldwide. The aim of this study was to evaluate the effects of BPA on the growth, viability, and testosterone production of TM3 murine Leydig cells after exposure to BPA for 24 or 48 h. BPA reduced testosterone production, cell viability and cell growth in a concentration-dependent manner. The highest tested concentration of BPA (100 MUM) increased cellular death, as indicated by an increased sub-G1 phase population and a larger number of cells labeled with Hoechst 3342. This concentration of BPA also decreased the number of metabolically active mitochondria as revealed by rhodamine staining. Therefore, our data show that BPA is toxic to Leydig TM3 cells and impairs their steroidogenic function. PMID- 29247841 TI - Time of the day dictates the variability of biomarkers of exposure to disinfection byproducts. AB - Non-persistent environmental chemicals (NOPEC) are xenobiotics with short half lives of elimination (<7h). Similar to chronopharmacokinetics, NOPEC metabolism may follow diurnal patterns of cytochrome P450 activity. The role of circadian liver clock in shaping NOPEC metabolism and their concomitant measurements of biomarkers of exposure and effect remains poorly understood in real-life human settings. Metabolic activation (toxication) by CYP2E1 converts trihalomethanes (THM) to harmful metabolites. We investigated the diurnal variation of urinary THM exposures and their metabolism patterns as catalyzed by CYP2E1 redox activity, using the surrogate marker of 4-hydroxynonenal (4HNE). We implemented three time-series trials with adult volunteers conducting specific household cleaning activities at predefined times of a day. Circadia variation of 4HNE was assessed with a cosinor model and its mesor levels increased with THM exposure. The time of exposure within the day dictated the magnitude of urinary THM levels and their toxication effect; in all three trials and relative to urinary THM levels before the activity, lower and higher median THM were measured right after the activity in morning and afternoon/night, respectively. This is consistent with higher reported CYP2E1 redox activity in light/active phase. Population health studies should incorporate time-stamped biomarker data to improve the understanding of chronic disease processes. PMID- 29247842 TI - Organophosphate flame retardants in dust collected from United States fire stations. AB - Firefighters are exposed to chemicals during fire events and we previously demonstrated that fire station dust has high levels of polybrominated diphenyl ethers (PBDEs). In conducting the Fire Station Dust Study, we sought to further characterize the chemicals to which firefighters could be exposed - measuring the emerging class of phosphorous-containing flame retardants (PFRs) in fire stations, for the first time, as well as PBDEs. Dust samples from 26 fire stations in five states were collected from vacuum-cleaner bags and analyzed for PFRs and PBDEs. PFR concentrations were found to be on the same order of magnitude as PBDE concentrations (maximum PFR: 218,000ng/g; maximum PBDE: 351,000ng/g). Median concentrations of tri-n-butyl phosphate (TNBP), tris (2 chloroisopropyl) phosphate (TCIPP), and tris(1,3-dichloroisopropyl)phosphate (TDCIPP) in dust from fire stations were higher than those previously reported in homes and other occupational settings around the world. Total PFR levels did not vary significantly among states. Levels of TDCIPP were higher in stations where vacuum cleaners were used to clean surfaces other than the floor. PBDE levels were comparable to those found in our previous study of 20 California fire stations and much higher than levels in California residences. PFR and PBDE levels in fire station dust are higher than in other occupational and residential settings, underscoring the need to identify and control sources of this contamination. PMID- 29247843 TI - Dietary betaine supplementation in hens modulates hypothalamic expression of cholesterol metabolic genes in F1 cockerels through modification of DNA methylation. AB - Betaine is widely used in animal nutrition to promote growth, development and methyl donor during methionine metabolism through nutritional reprogramming via regulation of gene expression. Prenatal betaine exposure is reported to modulate hypothalamic cholesterol metabolism in chickens, yet it remains unknown whether feeding hens with betaine-supplemented diet may affect hypothalamic cholesterol metabolism in F1 offspring. In this study, hens were fed with basal or betaine supplemented (0.5%) for 30days, and the eggs were collected for incubation. The hatchlings were raised under the same condition up to 56days of age. Betaine treated group showed significantly (P<0.05) higher plasma concentration of total cholesterol and HDL-cholesterol, together with increased hypothalamic content of total cholesterol and cholesterol ester. Concordantly, hypothalamic gene expression of SREBP2, HMGCR, and LDLR was significantly up regulated (P<0.05). Also, mRNA abundances of SREBP1, ACAT1 and APO-A1 were up-regulated, while that of CYP46A1 was significantly down-regulated (P<0.05). These changes coincided with a significant down-regulation of BDNF and CRH, and a significant up regulation of NPY mRNA expression. Moreover, genes involved in methyl transfer cycle were also modulated. DNMT1 and BHMT were up-regulated (P<0.05) at both mRNA and protein levels, which was associated with significant modifications of CpG methylation on the promoter of SREBP-1, SREBP-2 and APO-A1 genes as detected by bisulfate sequencing. These results indicate that feeding betaine to hens modulates hypothalamic expression of genes involved in cholesterol metabolism and brain functions in F1 cockerels with modification of promoter DNA methylation. PMID- 29247844 TI - Strategies of biochemical adaptation for hibernation in a South American marsupial, Dromiciops gliroides: 4. Regulation of pyruvate dehydrogenase complex and metabolic fuel selection. AB - Mammalian hibernation is characterized by extensive adjustments to metabolism that typically include suppression of carbohydrate catabolism and a switch to triglycerides as the primary fuel during torpor. A crucial locus of control in this process is the pyruvate dehydrogenase complex that gates carbohydrate entry into the tricarboxylic acid cycle. Within the complex, the E1 enzyme pyruvate dehydrogenase (PDH) is the main regulatory site and is subject to inhibitory phosphorylation at three serine residues (S232, S293, S300). To determine if marsupial hibernators show a comparable focus on PDH to regulate fuel metabolism, the current study explored PDH control by site-specific phosphorylation in the South American marsupial, monito del monte (Dromiciops gliroides). Luminex multiplex technology was used to analyze PDH responses in six tissues comparing control and hibernating (4days continuous torpor) animals. Total PDH content did not change significantly during hibernation in any tissue but phospho-PDH content increased in all. Heart PDH showed increased phosphorylation at all three sites by 8.1-, 10.6- and 2.1-fold for S232, S293 and S300, respectively. Liver also showed elevated p-S300 (2.5-fold) and p-S293 (4.7-fold) content. Phosphorylation of S232 and S293 increased significantly in brain and lung but only S232 phosphorylation increased in kidney and skeletal muscle. The results show that PDH suppression via enzyme phosphorylation during torpor is a conserved mechanism for inhibiting carbohydrate catabolism in both marsupial and eutherian mammals, an action that would also promote the switch to fatty acid oxidation instead. PMID- 29247845 TI - Strategies of biochemical adaptation for hibernation in a South American marsupial Dromiciops gliroides: 1. Mitogen-activated protein kinases and the cell stress response. AB - Hibernation is a period of torpor and heterothermy that is typically associated with a strong reduction in metabolic rate, global suppression of transcription and translation, and upregulation of various genes/proteins that are central to the cellular stress response such as protein kinases, antioxidants, and heat shock proteins. The current study examined cell signaling cascades in hibernating monito del monte, Dromiciops gliroides, a South American marsupial of the Order Microbiotheria. Responses to hibernation by members of the mitogen-activated protein kinase (MAPK) pathways, and their roles in coordinating hibernator metabolism were examined in liver, kidney, heart and brain of control and versus hibernating (4days continuous torpor) D. gliroides. The targets evaluated included key protein kinases in their activated phosphorylated forms (p-ERK/MAPK 1/2, p-MEK1, p-MSK1, p-p38, p-JNK) and related target proteins (p-CREB 2, p-ATF2, p-c-Jun and p-p53). Liver exhibited a strong coordinated response by MAPK members to hibernation with significant increases in protein phosphorylation levels of p MEK1, p-ERK/MAPK1/2, p-MSK1, p-JNK and target proteins c-Jun, and p-ATF2, all combining to signify a strong activation of MAPK signaling during hibernation. Kidney also showed activation of MAPK cascades with significant increases in p MEK1, p-ERK/MAPK1/2, p-p38, and p-c-Jun levels in hibernating animals. By contrast, responses by heart and brain indicated reduced MAPK pathway function during torpor with reduced phosphorylation of targets including p-ERK/MAPK 1/2 in both tissues as well as lower p-p38 and p-JNK content in heart. Overall, the data indicate a vital role for MAPK signaling in regulating the cell stress response during marsupial hibernation. PMID- 29247846 TI - Strategies of biochemical adaptation for hibernation in a South American marsupial, Dromiciops gliroides: 2. Control of the Akt pathway and protein translation machinery. AB - When faced with harsh environmental conditions, the South American marsupial, monito del monte (Dromiciops gliroides), reduces its body temperature and uses either daily torpor or multiday hibernation to survive. This study used ELISA and multiplex assays to characterize the responses to hibernation by three regulatory components of protein translation machinery [p-eIF2alpha(S51), p-eIF4E(S209), p 4EBP(Thr37/46)] and eight targets involved in upstream signaling control of translation [p-IGF-1R(Tyr1135/1136), PTEN(S380), p-Akt(S473), p-GSK-3alpha(S21), p-GSK-3beta(S9), p-TSC2(S939), p-mTOR(S2448), and p70S6K(T412)]. Liver, brain and kidney were analyzed comparing control and hibernation (4days continuous torpor) conditions. In the liver, increased phosphorylation of IGF-1R, Akt, GSK-3beta, TSC2, mTOR, eIF2alpha, and 4EBP (1.60-1.98 fold compared to control) occurred during torpor suggesting that the regulatory phosphorylation cascade and protein synthesis remained active during torpor. However, responses by brain and kidney differed; torpor resulted in increased phosphorylation of GSK-3beta (2.15-4.17 fold) and TSC2 (2.03-3.65 fold), but phosphorylated Akt decreased (to 34-62% of control levels). Torpor also led to an increase in phosphorylated eIF2alpha (1.4 fold) content in the brain. These patterns of differential protein phosphorylation in brain and kidney were indicative of suppression of protein translation but also could suggest an increase in antioxidant and anti-apoptotic signaling during torpor. Previous studies of liver metabolism in hibernating eutherian mammals have shown that Akt kinase and its downstream signaling components play roles in facilitating hypometabolism by suppressing energy expensive anabolic processes during torpor. However, the results in this study reveal differences between eutherian and marsupial hibernators, suggesting alternative actions of liver Akt during torpor. PMID- 29247847 TI - Transcriptome sequence-based phylogeny of chalcidoid wasps (Hymenoptera: Chalcidoidea) reveals a history of rapid radiations, convergence, and evolutionary success. AB - Chalcidoidea are a megadiverse group of mostly parasitoid wasps of major ecological and economical importance that are omnipresent in almost all extant terrestrial habitats. The timing and pattern of chalcidoid diversification is so far poorly understood and has left many important questions on the evolutionary history of Chalcidoidea unanswered. In this study, we infer the early divergence events within Chalcidoidea and address the question of whether or not ancestral chalcidoids were small egg parasitoids. We also trace the evolution of some key traits: jumping ability, development of enlarged hind femora, and associations with figs. Our phylogenetic inference is based on the analysis of 3,239 single copy genes across 48 chalcidoid wasps and outgroups representatives. We applied an innovative a posteriori evaluation approach to molecular clock-dating based on nine carefully validated fossils, resulting in the first molecular clock-based estimation of deep Chalcidoidea divergence times. Our results suggest a late Jurassic origin of Chalcidoidea, with a first divergence of morphologically and biologically distinct groups in the early to mid Cretaceous, between 129 and 81 million years ago (mya). Diversification of most extant lineages happened rapidly after the Cretaceous in the early Paleogene, between 75 and 53 mya. The inferred Chalcidoidea tree suggests a transition from ancestral minute egg parasitoids to larger-bodied parasitoids of other host stages during the early history of chalcidoid evolution. The ability to jump evolved independently at least three times, namely in Eupelmidae, Encyrtidae, and Tanaostigmatidae. Furthermore, the large-bodied strongly sclerotized species with enlarged hind femora in Chalcididae and Leucospidae are not closely related. Finally, the close association of some chalcidoid wasps with figs, either as pollinators, or as inquilines/gallers or as parasitoids, likely evolved at least twice independently: in the Eocene, giving rise to fig pollinators, and in the Oligocene or Miocene, resulting in non-pollinating fig-wasps, including gallers and parasitoids. The origins of very speciose lineages (e.g., Mymaridae, Eulophidae, Pteromalinae) are evenly spread across the period of chalcidoid evolution from early Cretaceous to the late Eocene. Several shifts in biology and morphology (e.g., in host exploitation, body shape and size, life history), each followed by rapid radiations, have likely enabled the evolutionary success of Chalcidoidea. PMID- 29247848 TI - Refining the biogeographical scenario of the land snail Cornu aspersum aspersum: Natural spatial expansion and human-mediated dispersal in the Mediterranean basin. AB - The land snail Cornu aspersum aspersum, native to the Mediterranean region, has been the subject of several anatomical and molecular studies leading to recognize two divergent lineages, named "East" and "West" according to their geographical distribution in North Africa. The first biogeographical scenario proposed the role of Oligocene paleogeographic events and Quaternary glacial refugia to explain spatial patterns of genetic variation. The aim of this study was to refine this scenario using molecular and morphometric data from 169 populations sampled across Mediterranean islands and continents. The two previously described lineages no longer correspond to distinct biogeographical entities. Phylogenetic relationships reveal the existence of seven clades, do not support the Tyrrhenian vicariance hypothesis, and suggest that C. a. aspersum most likely originates from North Africa. We found two contrasted patterns with the seven clades defining spatially well-structured populations in the southern Mediterranean whereas one clade is distributed across the basin. High genetic diversities and rates of endemism in North Africa support the role of this region for the diversification of C. a. aspersum. In referring to divergence times previously estimated, we suggest allopatric differentiation due to geological changes of the Atlas system and multiple refugial areas during Pleistocene glaciations. The new biogeographical scenario implies an initial range expansion from North Africa to the Iberian Peninsula and the peri-Tyrrhenian regions through land bridges connections during the Messinian Salinity Crisis and Pleistocene glaciations. Historical events appear to have also structured morphometric variation but recent dispersal events favored the emergence of secondary contacts between clades. Southern Mediterranean clades are limited to their initial distribution and populations of the recent clade would have rapidly recolonized the whole Mediterranean in the Holocene due to greater adaptive potential and the influence of human transportations. PMID- 29247849 TI - Mitogenomics supports an unexpected taxonomic relationship for the extinct diving duck Chendytes lawi and definitively places the extinct Labrador Duck. AB - Chendytes lawi, an extinct flightless diving anseriform from coastal California, was traditionally classified as a sea duck, tribe Mergini, based on similarities in osteological characters. We recover and analyze mitochondrial genomes of C. lawi and five additional Mergini species, including the extinct Labrador Duck, Camptorhynchus labradorius. Despite its diving morphology, C. lawi is reconstructed as an ancient relictual lineage basal to the dabbling ducks (tribe Anatini), revealing an additional example of convergent evolution of characters related to feeding behavior among ducks. The Labrador Duck is sister to Steller's Eider which may provide insights into the evolution and ecology of this poorly known extinct species. Our results demonstrate that inclusion of full length mitogenomes, from taxonomically distributed ancient and modern sources can improve phylogeny reconstruction of groups previously assessed with shorter single-gene mitochondrial sequences. PMID- 29247850 TI - Tissue specific expression and in-silico characterization of a putative cysteine synthase gene from Lathyrus sativus L. AB - Grass pea (Lathyrus sativus L.) is a worldwide popular pulse crop especially for its protein rich seeds with least production cost. However, the use of the crop became controversial due to the presence of non-protein amino acid, beta-N-oxalyl L-alpha, beta-diaminopropionic acid (beta-ODAP) in its seed and leaf, which is known as the principle neurotoxin to cause neurolathyrism (a motor neurodegenerative disease of humans and animals) during prolonged consumption as regular diet. Till date, the knowledge on beta-ODAP biosynthesis in Lathyrus sp. is limited only to a small part of the complex bio-chemical steps involved including a few known sulfur-containing enzymes (viz. cysteine synthase, ODAP synthase etc.). In Lathyrus sativus, biosynthesis of beta-ODAP varies differentially in a tissue-specific manner as well as in response to several environmental stresses viz. zinc deficiency, iron over-exposure, moisture stress etc. In the present study, a novel cysteine synthase gene (LsCSase) from Lathyrus sativus L was identified and characterized through bioinformatics approaches. The bioinformatic analysis revealed that LsCSase showed maximum similarity with the O acetyl serine (thiol) lyase of Medicago truncatula with respect to several significant sequence-specific conserved motifs (cysK, CBS like, ADH_zinc_N, PALP), sub-cellular localization (chloroplast or cytoplasm) etc., similar to other members of cysteine synthase protein family. Moreover, the tissue-specific regulation of the LsCSase as well as its transcriptional activation under certain previously reported stressed conditions (low Zn+2-high Fe+2, PEG induced osmotic stress) were also documented through quantitative real-time PCR analyses, suggesting a possible link between the LsCSase gene activation and beta-ODAP biosynthesis to manage external stresses in grass pea. This preliminary study offers a probable way towards the development of less toxic consumer-safe grass pea by down-regulation or deactivation of such gene/s (cysteine synthase) through genetic manipulations. PMID- 29247851 TI - The Involvement of the Endocannabinoid System in the Peripheral Antinociceptive Action of Ketamine. AB - : Ketamine has been widely used as an analgesic and produces dissociative anesthetic effects. The antinociceptive effects of ketamine have been studied, but the involvement of endocannabinoids in these effects has not yet been investigated. In this study, we evaluated the involvement of the endocannabinoid system in the peripheral antinociceptive effects induced by ketamine. All drugs were administered via the intraplantar route. To induce hyperalgesia, rat paws were injected with prostaglandin E2 (2 ug per paw). The nociceptive threshold for mechanical stimulation was measured in the right hind paw of Wistar rats using the Randall-Selitto test. The tissue levels of anandamide (AEA), 2 arachidonoylglycerol, palmitoylethanolamide, and oleoylethanolamide were measured using liquid chromatography coupled to single quadrupole mass spectrometry. The administration of the cannabinoid receptor type 1 (CB1) antagonist, N(piperidine 1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl 1 pyrazolcarboxamide (20, 40, and 80 ug per paw), but not the cannabinoid receptor type 2 antagonist, 6 iodo-2-methyl-1-(2-morpholinoethyl)-1H-indol-3-yl) (4-methoxyphenyl) methanone (100 ug per paw), antagonized the ketamine-induced peripheral antinociception in a dose-dependent manner. Additionally, the administration of the endocannabinoid metabolizing enzyme inhibitor (.5 ug per paw) or an AEA reuptake inhibitor, (5Z,8Z,11Z,14Z)N(4Hydroxy2methylphenyl)5,8,11,14 eicosatetraenamide (2.5 ug per paw) significantly enhanced low-dose ketamine-induced peripheral antinociception. AEA paw levels were increased only after ketamine administration to prostaglandin E2-injected paws. These data suggest that ketamine, in the presence of a nociceptive stimulus, induces a selective release of AEA levels and subsequent CB1 cannabinoid activation at the peripheral level. PERSPECTIVE: This study suggests that ketamine antinociception depends at least in part on AEA release and CB1 cannabinoid receptor activation in inflammatory conditions. This study could potentially help clinicians in the use of ketamine as a peripheral analgesic for inflammatory pain. PMID- 29247852 TI - Developmental control of macrophage function. AB - The combination between novel fate-mapping tools and single-cell RNA-sequencing technology has revealed the presence of multiple macrophage progenitors. This raises the fascinating possibility that what was once perceived as immense functional plasticity of macrophages could in fact come down to separate macrophage subsets performing distinct functions because of their differential cellular origin. The question of macrophage plasticity versus macrophage heterogeneity is broader than the difference between macrophages of embryonic or adult hematopoietic origin and is particularly relevant in the context of inflammation. In this manuscript, we review the potential impact of cellular origin on the function of macrophages. We also highlight the need for novel 'functional fate-mapping' tools that would reveal the history of the functional state of macrophages, rather than their cellular origin, in order to finally study their true plasticity in vivo. PMID- 29247853 TI - Cytosolic sensing of immuno-stimulatory DNA, the enemy within. AB - In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2'-5'-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I). Activation of the pro-inflammatory cGAS-STING-IRF3 response is triggered by direct recognition of the DNA genomes of bacteria and viruses, but also during RNA virus infection, neoplastic transformation, tumor immunotherapy and systemic auto-inflammatory diseases. In these circumstances, the source of immuno stimulatory DNA has often represented a fundamental yet poorly understood aspect of the response. This review focuses on recent findings related to cGAS activation by an array of self-derived DNA substrates, including endogenous retroviral elements, mitochondrial DNA (mtDNA) and micronuclei generated as a result of genotoxic stress and DNA damage. These findings emphasize the role of the cGAS axis as a cell-intrinsic innate immune response to a wide variety of genomic insults. PMID- 29247854 TI - Combined attention controls complex behavior by suppressing unlikely events. AB - Attention enables behavior by modulating both sensory inputs and task goals. Combining attentional resources from both of those sources exerts qualitatively large effects on manual performance. Here we tested how combined attention was represented in sensory processing, as reflected by the P1 component and associated activity in the alpha band. We measured performance and recorded EEG while participants' attention was engaged in an automated, endogenous, and combined (i.e., automated and endogenous) manner. Behavioral results replicated past reports with reliable effects of isolated automated and endogenous attention, as well as their qualitatively unique combined effect. ERP analyses indicated expected increases in P1 amplitude for validly relative to invalidly cued targets in automated and endogenous conditions. However, in the combined case, the P1 difference between validly relative to invalidly cued targets decreased. Analyses of target-locked alpha-band further revealed that this condition was associated with an increased synchrony in the alpha frequency for invalidly cued targets. This suggests that the large performance benefit observed when attentional systems combine is partly driven by suppressed processing of unexpected targets, dovetailing with the notion that in addition to increasing sensory gain of attended targets, attention may also modulate complex behavior by increasing suppression of unattended ones. PMID- 29247855 TI - "Omics" in oral cancer: New approaches for biomarker discovery. AB - OBJECTIVES: In this review paper, we explored the application of "omics" approaches in the study of oral cancer (OC). It will provide a better understanding of how "omics" approaches may lead to novel biomarker molecules or molecular signatures with potential value in clinical practice. A future direction of "omics"-driven research in OC is also discussed. METHODS: Studies on "omics"-based approaches [genomics/proteomics/transcriptomics/metabolomics] were investigated for differentiating oral squamous cell carcinoma,oral sub-mucous fibrosis, oral leukoplakia, oral lichen planus, oral erythroplakia from normal cases. Electronic databases viz., PubMed, Springer, and Google Scholar were searched. RESULTS: One eighty-one studies were included in this review. The review shows that the fields of genomics, transcriptomics, proteomics, and metabolomics-based marker identification have implemented advanced tools to screen early changes in DNA, RNA, protein, and metabolite expression in OC population. CONCLUSIONS: It may be concluded that despite advances in OC therapy, symptomatic presentation occurs at an advanced stage, where various curative treatment options become very limited. A molecular level study is essential for detecting an OC biomarker at an early stage. Modern "Omics" strategies can potentially make a major contribution to meet this need. PMID- 29247856 TI - Effects of Rhodomyrtus tomentosa extract on virulence factors of Candida albicans and human neutrophil function. AB - OBJECTIVE: Candida albicans has become a major problem of oral candidiasis due to increase in antibiotic resistance. Rhodomyrtus tomentosa, a medicinal plant possessing several phytochemical constituents, has been considered as a potential source of antimicrobial and immunomodulatory agents. The aim of this study was to investigate anti-virulence and immunostimulatory activity of R. tomentosa ethanolic leaf extract against C. albicans. METHODS: The effects of the extract on C. albicans were assessed on germ tube production, adherence of the organisms to surfaces, and biofilm. In addition, the effects of the extract on phagocytosis and killing activity of neutrophils against the pathogen were investigated. RESULTS: Suppression of germ tube production following 30 min exposure to the extract at 256 MUg/mL was significantly increased in comparison with that of the unexposed cells (p < 0.05). The pathogens demonstrated a significant reduction in adherence ability to surfaces in a dose dependent manner, compared with the control (p < 0.05). At 48 h, the extract at 512-1024 MUg/mL significantly reduced biofilm forming ability of the organisms up to 42.31-64.58% (p < 0.05). Compared with the control group, a significant inhibition of mature biofilm after treated with the extract at 256 MUg/mL was observed (p < 0.05). The extract at 50 MUg/mL significantly enhanced phagocytosis and killing activity of neutrophils against the organism, compared with the control (p < 0.05). CONCLUSIONS: The findings suggest that R. tomentosa extract displayed a dual mode of action, inhibiting virulence factors of C. albicans and enhancing neutrophil functions. Further pharmaceutical development of the extract might be useful as an alternative therapeutic agent against oral candidiasis. PMID- 29247857 TI - A highly potent CDK4/6 inhibitor was rationally designed to overcome blood brain barrier in gliobastoma therapy. AB - Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system. Here, we designed and synthesized a series of novel CDK4/6 inhibitors with favorable BBB permeability for the treatment of GBM. Compound 11 exhibited a favorable pharmacological profile and significant penetration of the BBB with the Kp value of 4.10 and the Kp,uu value of 0.23 in mice after an oral dose of 10 mg/kg. IC50 values for CDK4/cyclin D1 and CDK6/cyclin D3 were 3 nM and 1 nM, respectively. In vivo studies with an orthotopic xenograft mouse model of GBM showed that 11 had tumor growth inhibition values ranging from 62% to 99% for doses ranging from 3.125 to 50 mg/kg, and no significant body weight loss was observed. The increase in life span based on the median survival time of vehicle-treated animals in mice administered a dose of 50 mg/kg was significant at 162% (p < 0.0001). These results suggest that compound 11 is a promising candidate for further investigation as an effective drug for the treatment of GBM. PMID- 29247858 TI - Investigating the structure-activity relationships of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds. AB - Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected chronic tropical infection endemic in Latin America. New and effective treatments are urgently needed because the two available drugs - benznidazole (BZD) and nifurtimox (NFX) - have limited curative power in the chronic phase of the disease. We have previously reported the design and synthesis of N'-[(5 nitrofuran-2-yl) methylene] substituted hydrazides that showed high trypanocidal activity against axenic epimastigote forms of three T. cruzi strains. Here we show that these compounds are also active against a BZD- and NFX-resistant strain. Herein, multivariate approaches (hierarchical cluster analysis and principal component analysis) were applied to a set of thirty-six formerly characterized compounds. Based on the findings from exploratory data analysis, novel compounds were designed and synthesized. These compounds showed two-to three-fold higher trypanocidal activity against epimastigote forms than the previous set and were 25-30-fold more active than BZD. Their activity was also evaluated against intracellular amastigotes by high content screening (HCS). The most active compounds (BSF-38 to BSF-40) showed a selective index (SI') greater than 200, in contrast to the SI' values of reference drugs (NFX, 16.45; BZD, > 3), and a 70-fold greater activity than BZD. These findings indicate that nitrofuran compounds designed based on the activity against epimastigote forms show promising trypanocidal activity against intracellular amastigotes, which correspond to the predominant parasite stage in the chronic phase of Chagas disease. PMID- 29247859 TI - Synthesis and biological evaluation of novel 1-(aryl-aldehyde-oxime)uracil derivatives as a new class of thymidine phosphorylase inhibitors. AB - A novel series of 1-(aryl aldehyd oxime) uracil derivatives were synthesized, characterized and evaluated for its inhibitory activity against thymidine phosphorylase. Among them, the compound 8d, 8e, 8f, 8g and 8l displayed potent thymidine phosphorylase inhibitory activities with the IC50 values ranging between 0.12 +/- 0.05 and 7.2 +/- 1.4 MUM. And the compounds 8a, 8h, 8i, 8j, 8m, 8n, 8o, 8q, 8s, 8t and 8u (IC50 is from 10.7 to 39.9 MUM) showed a good thymidine phosphorylase inhibition when compared to the standard 7DX and TPI. The most biologically active compound 8l was demonstrated to be a competition mode of enzyme inhibition. The Molecular docking analysis showed the interaction of these newly synthesized compounds at the active binding site of thymidine phosphorylase based on the experimental results. In general, these results indicated these compounds are promising inhibitors of thymidine phosphorylase for the potential treatment of anti-angiogenesis. PMID- 29247861 TI - Prototype apparatus for the measurement of tritium in expired air using plastic scintillator pellets. AB - A new apparatus for measuring tritiated water in expired air was developed using plastic scintillator (PS) pellets and a low-background liquid scintillation counter. The sensitivity of the apparatus was sufficient when a large adapted Teflon vial was used. The measurement method generated low amounts of organic waste because the PS pellets were reusable by rinsing, and had adequate detection limits. The apparatus is useful for the safety management of workers that are exposed to radioactive materials. PMID- 29247860 TI - Structure-activity studies on N-Substituted tranylcypromine derivatives lead to selective inhibitors of lysine specific demethylase 1 (LSD1) and potent inducers of leukemic cell differentiation. AB - FAD-dependent lysine-specific demethylase 1 (LSD1) is overexpressed or deregulated in many cancers such as AML and prostate cancer and hence is a promising anticancer target with first inhibitors in clinical trials. Clinical candidates are N-substituted derivatives of the dual LSD1-/monoamine oxidase inhibitor tranylcypromine (2-PCPA) with a basic amine function in the N substituent. These derivatives are selective over monoamine oxidases. So far, only very limited information on structure-activity studies about this important class of LSD1 inhibitors is published in peer reviewed journals. Here, we show that N-substituted 2-PCPA derivatives without a basic function or even a polar group are still potent inhibitors of LSD1 in vitro and effectively inhibit colony formation of leukemic cells in culture. Yet, these lipophilic inhibitors also block the structurally related monoamine oxidases (MAO-A and MAO-B), which may be of interest for the treatment of neurodegenerative disorders, but this property is undesired for applications in cancer treatment. The introduction of a polar, non-basic function led to optimized structures that retain potent LSD1 inhibitors but exhibit selectivity over MAOs and are highly potent in the suppression of colony formation of cultured leukemic cells. Cellular target engagement is shown via a Cellular Thermal Shift Assay (CETSA) for LSD1. PMID- 29247862 TI - The application of U-isotopes to assess weathering in contrasted soil-water regime in Brazil. AB - This paper presents the use of U-series radionuclides 238U and 234U to evaluate the biogeochemical disequilibrium in soil cover under a contrasted soil-water regime. The approach was applied in three profiles located in distinct topographical positions, from upslope ferralitic to downslope hydromorphic domain. The U fractionation data was obtained in the samples representing the saprolite and the superficial and subsuperficial soil horizons. The results showed a significant and positive correlation between U and the Total Organic Carbon (TOC). Soil organic matter has accumulated in soil due to hydromorphy. There is no evidence of positive correlation between U and Fe, as expected in lateritic soils. The advance of the hydromorphy on Ferralsol changes the weathering rates, and the ages of weathering are discussed as a function of the advance of waterlogged soil conditions from downslope. Also, the bioturbation could represent the other factor responsible to construct a more recent soil horizon. PMID- 29247864 TI - Microbial synthesis of pyrogallol using genetically engineered Escherichia coli. AB - Pyrogallol is a simple phenolic compound that serves as an attractive chemical with broad applications in food, agricultural, dyeing, printing, cosmetic, photography, chemical and pharmaceutical industries owing to its antioxidant, antibacterial, antiseptic, anticancer, oxygen-absorbing and strong reducing properties. Currently, pyrogallol is commercially produced by thermal decarboxylation of gallic acid under high temperature and pressure. However, this process is limited by the inaccessible raw material, the strict reaction conditions and the relatively low product yield. Here, we report establishment of a novel and efficient biosynthetic pathway for the synthesis of pyrogallol. First, we identified and characterized an efficient 2,3-dihydroxybenzoic acid (2,3-DHBA) 1-monoxygenase from a series of oxygenases and hydroxylases based on the structural similarity in the substrates and products, which enabled non natural production of pyrogallol from 2,3-DHBA. Then, over-expression of 2,3-DHBA synthase and 2,3-DHBA 1-monoxygenase achieved synthesis of pyrogallol in Escherichia coli, with a titer of 201.52mg/L at 24h. Further optimizations by enhancement of the carbon flux through the shikimate pathway, modular optimization of the pathway and alleviation of the pyrogallol autoxidation boosted pyrogallol titer to 1035.75mg/L in shake flask experiments. This work constructed an efficient microbial platform for gram per liter level production of pyrogallol, indicating the great potential for industrial biomanufacturing of pyrogallol. PMID- 29247863 TI - Becoming a medical marijuana user. AB - BACKGROUND: Since marijuana became legal for medical use in California in 1996, reasons for medical use among medical marijuana patients (MMP) have become increasingly well described in qualitative studies. However, few studies have detailed how the use of marijuana for medical purposes fits into the broader career trajectories of either becoming a marijuana user or becoming a MMP, including the social influences on medical use. METHODS: Young adult MMP (N=40) aged 18 to 26 years old were recruited in Los Angeles, CA in 2014-15 and administered a semi-structured interview that included questions focusing on marijuana use practices before and after becoming MMP. RESULTS: MMP were categorized into three trajectory groups: primarily medical users (n=30); primarily non-medical users (n=3); and medical users who transitioned to non medical users (n=7). Most medical users discovered medicinal effects from marijuana in the context of non-medical use as adolescents prior to becoming MMP. Becoming a mature MMP followed interactions with dispensary staff or further self exploration of medical uses and often involved a social process that helped confirm the legitimacy of medical use and identity as a medical user. In some cases, MMP transitioned back to non-medical users as health conditions improved or remained primarily non-medical users even after becoming MMP for reasons unrelated to health, e.g., protection against arrest. CONCLUSION: Becoming a medical marijuana user was an important career trajectory that was influenced by early discoveries of effective medicinal use, interaction with proponents of medical use at dispensaries, experiences with new kinds of medical use, and the demands of particular health condition requiring more or less treatment with marijuana. PMID- 29247865 TI - Bioproduction of a betalain color palette in Saccharomyces cerevisiae. AB - Betalains are a family of natural pigments found exclusively in the plant order Caryophyllales. All members of this chemical family are biosynthesized through the common intermediate betalamic acid, which is capable of spontaneously condensing with various primary and secondary amines to produce betalains. Of particular interest is the red-violet betanin, most commonly obtained from Beta vulgaris (beet) as a natural food dye. We demonstrate the first complete microbial production of betanin in Saccharomyces cerevisiae from glucose, an early step towards a fermentation process enabling rapid, on-demand production of this natural dye. A titer of 17mg/L was achieved, corresponding to a color intensity obtained from 10g/L of beetroot extract. Further, we expanded the spectrum of betalain colors by condensing betalamic acid with various amines fed to an engineered strain of S. cerevisiae. Our work establishes a platform for microbial production of betalains of various colors as a potential alternative to land- and resource-intensive agricultural production. PMID- 29247866 TI - High-titer production of lathyrane diterpenoids from sugar by engineered Saccharomyces cerevisiae. AB - Euphorbiaceae are an important source of medically important diterpenoids, such as the anticancer drug ingenol-3-angelate and the antiretroviral drug prostratin. However, extraction from the genetically intractable natural producers is often limited by the small quantities produced, while the organic synthesis of terpene derived drugs is challenging and similarly low-yielding. While transplanting the biosynthetic pathway into a heterologous host has proven successful for some drugs, it has been largely unsuccessful for diterpenoids due to their elaborate biosynthetic pathways and lack of genetic resources and tools for gene discovery. We engineered casbene precursor production in S. cerevisiae, verified the ability of six Euphorbia lathyris and Jatropha curcas cytochrome P450s to oxidize casbene, and optimized the expression of these P450s and an alcohol dehydrogenase to generate jolkinol C, achieving ~800mg/L of jolkinol C and over 1g/L total oxidized casbanes in millititer plates, the highest titer of oxidized diterpenes in yeast reported to date. This strain enables the semisynthesis of biologically active jolkinol C derivatives and will be an important tool in the elucidation of the biosynthetic pathways for ingenanes, tiglianes, and lathyranes. These findings demonstrate the ability of S. cerevisiae to produce oxidized drug precursors in quantities that are sufficient for drug development and pathway discovery. PMID- 29247867 TI - Physicochemical, antioxidant, DNA cleaving properties and antimicrobial activity of fisetin-copper chelates. AB - Fisetin (3,3',4',7-tetrahydroxyflavone) metal chelates are of interest as this plant polyphenol has revealed broad prospects for its use as natural medicine in the treatment of various diseases. Metal interactions may change or enhance fisetin biological properties so understanding fisetin metal chelation is important for its application not only in medicine but also as a food additive in nutritional supplements. This work was aimed to determine and characterize copper complexes formed in different pH range at applying various metal/ligand ratios. Fisetin and Cu(II)-fisetin complexes were characterized by potentiometric titrations, UV-Vis (Ultraviolet-visible spectroscopy), EPR, ESI-MS, FTIR and cyclic voltammetry. Their effects on DNA were investigated by using circular dichroism, spectrofluorimetry and gel electrophoresis methods. The copper complex with the ratio of Cu(II)/fisetin 1/2 exhibited significant DNA cleavage activity, followed by complete degradation of DNA. The influence of copper(II) ions on antioxidant activity of fisetin in vitro has been studied using DPPH, ABTS and mitochondrial assays. The results have pointed out that fisetin or copper complexes can behave both as antioxidants or pro-oxidants. Antimicrobial activity of the compounds has been investigated towards several bacteria and fungi. The copper complex of Cu(II)/fisetin 1/2 ratio showed higher antagonistic activity against bacteria comparing to the ligand and it revealed a promising antifungal activity. PMID- 29247868 TI - The cytotoxicity of some phenanthroline-based antimicrobial copper(II) and ruthenium(II) complexes. AB - The in vitro cytotoxic properties of antimicrobial copper(II) complexes with 3,4,7,8-tetramethyl-1,10-phenanthroline (TMP) or 4,7-dipyridyl-1,10 phenanthroline (DIP) ligands and ruthenium(II) complexes coordinated with TMP or 2,9-dimethyl-1,10-phenanthroline ligands were investigated. Both copper(II) complexes were found to have similar inhibitory concentrations (IC50~2-2.5MUM). Their cytotoxicity was found to be necrotic, associated with cytoplasmic vacuolisation, rounding, detachment and lack of apoptosis-associated DNA fragmentation, in comparison to the apoptotic effects of cisplatin which demonstrate adherent cell enlargement or detachment, membrane blebbing and condensation. Antimicrobial ruthenium(II) complexes demonstrated a lower renal cytotoxicity than copper(II) complexes or cisplatin (IC50>60MUM). [Cu(DIP)(dach)](ClO4)2 and [Cu(TMP)(dach)](ClO4)2 (where dach=1,2 diaminocyclohexane) induced dihydroethidium-sensitive ROS and the cytotoxicity of both TMP and DIP coordinated copper(II) complexes was mitigated by catalase, highlighting a role of H2O2 generation in their mode of action. The cytotoxicity of either copper(II) complex was not affected by coincubation with organic cation transporter (OCT) inhibitors cimetidine or disopyramide, in contrast to cisplatin, suggesting a non-OCT dependent mode of uptake for the copper(II) complexes in human cells. Coincubation with copper sulfate reduced the cytotoxicity of [Cu(TMP)(dach)](ClO4)2 (3-6*). The TMP complex induced a greater degree of G2/M accumulation and micronuclei generation than the DIP complex, possibly attributable to its greater DNA binding affinity. These results highlight the potentially low genotoxicity of copper(II) complexes coordinated with TMP or DIP and polypyridyl ruthenium(II) complexes as potential antimicrobial agents. PMID- 29247869 TI - Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines. AB - Thiosemicarbazones (TSCs), and their copper derivatives, have been extensively studied mainly due to the potential applications as antitumor compounds. A part of the biological activity of the TSC-CuII complexes rests on their reactivity against cell reductants, as glutathione (GSH). The present paper describes the structure of the [Cu(PTSC)(ONO2)]n compound (1) (HPTSC=pyridine-2-carbaldehyde thiosemicarbazone) and its spectroscopic and magnetic properties. ESI studies performed on the reaction of GSH with 1 and the analogous [{Cu(PTSC*)(ONO2)}2] derivative (2, HPTSC*=pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) show the absence of peaks related with TSC-Cu-GSH species. However GSH-Cu ones are detected, in good agreement with the release of CuI ions after reduction in the experimental conditions. The reactivity of 1 and 2 with cytochrome c and myoglobin and their activities against HT-29 and SW-480 colon carcinoma cell lines are compared with those shown by the free HPTSC and HPTSC* ligands. PMID- 29247870 TI - Synthesis and evaluation of the antibiotic and adjuvant antibiotic potential of organotin(IV) derivatives. AB - A series of organotin(IV) derivatives was investigated in vitro for their antibiotic and adjuvant antibiotic properties (efflux pump inhibitors) against Staphylococcus aureus strains that overexpress efflux pump proteins for norfloxacin (SA-1199B), erythromycin (RN-4220) and tetracycline (IS-58). Most organotin(IV) compounds showed significant antibacterial activity with small Minimum Inhibitory Concentration (MIC) values, some of which were close to 1.0MUg/mL (3.1MUM), but this feature was also associated with substantial cytotoxicity. Nevertheless, the cytotoxicity of these organotin(IV) compounds can be overcome when they are used as antibiotic adjuvants. Their remarkable adjuvant antibiotic properties allow potentiation of the action of tetracycline (against IS-58 strain) by up to 128-fold. This likely indicates that they can act as putative inhibitors of bacterial efflux pumps. These results reinforce organotin(IV) complexes as promising antibacterial agents, and many of these complexes, if associated with antibiotics, can act as potential adjuvant antibiotic candidates. PMID- 29247871 TI - Simple and mixed complexes of copper(II) with 8-hydroxyquinoline derivatives and amino acids: Characterization in solution and potential biological implications. AB - Copper(II) complexes with 8-hydroxyquinoline (8-HQ) and two 8-HQ derivatives, namely clioquinol (CQ) and 5,7-dichloro-2-[(dimethylamino)methyl]quinolin-8-ol (PBT2), were investigated in organic and, where feasible, in aqueous solutions. This class of compounds is of particular interest in neurological disorders since they may act as metal-protein attenuating compounds and may help redistributing metal ions and restoring intracellular metal reserves, which are often perturbed in neurological patients. Several techniques, like potentiometry, UV-Vis absorption, electron paramagnetic resonance (EPR), cyclic voltammetry and electrospray ionisation-mass spectrometry (ESI-MS), were used to obtain information on both the formation of copper(II) complexes in solution as well as on the structure of their species. Multi-wavelength treatment of UV-Vis data clearly indicated the formation of both [Cu(PBT2)]+ and [Cu(PBT2)2] species; the speciation was also supported by ESI-MS data. The EPR results showed that the mono- and bis-copper(II) complexes with PBT2 have square-based pyramidal structures while the bis-copper (II) complexes with CQ or 8-HQ have square-planar o pseudo-octahedral geometries. The formation of copper(II) ternary complexes with 8-HQ, CQ and PBT2 and some selected neurotransmitters (glycine, glutamate and histidine) is also reported. Except for the copper(II) ternary complex with PBT2 and His, almost all ternary complexes have molecular geometries, which are not different from those of the bis-complexes. Interestingly the ternary copper(II) complexes, containing CQ, 8-HQ and PBT2 and glycine, glutamate or histidine turned out to be more soluble in aqueous solution than their binary complexes with parent 8-HQ derivatives; the copper(II) complexes can also be reduced more easily than their parent bis-complexes. PMID- 29247873 TI - The Ability of Different Imputation Methods to Preserve the Significant Genes and Pathways in Cancer. AB - Deciphering important genes and pathways from incomplete gene expression data could facilitate a better understanding of cancer. Different imputation methods can be applied to estimate the missing values. In our study, we evaluated various imputation methods for their performance in preserving significant genes and pathways. In the first step, 5% genes are considered in random for two types of ignorable and non-ignorable missingness mechanisms with various missing rates. Next, 10 well-known imputation methods were applied to the complete datasets. The significance analysis of microarrays (SAM) method was applied to detect the significant genes in rectal and lung cancers to showcase the utility of imputation approaches in preserving significant genes. To determine the impact of different imputation methods on the identification of important genes, the chi squared test was used to compare the proportions of overlaps between significant genes detected from original data and those detected from the imputed datasets. Additionally, the significant genes are tested for their enrichment in important pathways, using the ConsensusPathDB. Our results showed that almost all the significant genes and pathways of the original dataset can be detected in all imputed datasets, indicating that there is no significant difference in the performance of various imputation methods tested. The source code and selected datasets are available on http://profiles.bs.ipm.ir/softwares/imputation_methods/. PMID- 29247872 TI - Proteomic Analysis Shows Constitutive Secretion of MIF and p53-associated Activity of COX-2-/- Lung Fibroblasts. AB - The differential expression of two closelyassociated cyclooxygenase isozymes, COX 1 and COX-2, exhibited functions beyond eicosanoid metabolism. We hypothesized that COX-1 or COX-2 knockout lung fibroblasts may display altered protein profiles which may allow us to further differentiate the functional roles of these isozymes at the molecular level. Proteomic analysis shows constitutive production of macrophage migration inhibitory factor (MIF) in lung fibroblasts derived from COX-2-/- but not wild-type (WT) or COX-1-/- mice. MIF was spontaneously released in high levels into the extracellular milieu of COX2-/- fibroblasts seemingly from the preformed intracellular stores, with no change in the basal gene expression of MIF. The secretion and regulation of MIF in COX-2-/- was "prostaglandin-independent." GO analysis showed that concurrent with upregulation of MIF, there is a significant surge in expression of genes related to fibroblast growth, FK506 binding proteins, and isomerase activity in COX-2-/- cells. Furthermore, COX-2-/- fibroblasts also exhibit a significant increase in transcriptional activity of various regulators, antagonists, and co-modulators of p53, as well as in the expression of oncogenes and related transcripts. Integrative Oncogenomics Cancer Browser (IntroGen) analysis shows downregulation of COX-2 and amplification of MIF and/or p53 activity during development of glioblastomas, ependymoma, and colon adenomas. These data indicate the functional role of the MIF-COX-p53 axis in inflammation and cancer at the genomic and proteomic levels in COX-2-ablated cells. This systematic analysis not only shows the proinflammatory state but also unveils a molecular signature of a pro oncogenic state of COX-1 in COX-2 ablated cells. PMID- 29247874 TI - A Novel Nonlinear Parameter Estimation Method of Soft Tissues. AB - The elastic parameters of soft tissues are important for medical diagnosis and virtual surgery simulation. In this study, we propose a novel nonlinear parameter estimation method for soft tissues. Firstly, an in-house data acquisition platform was used to obtain external forces and their corresponding deformation values. To provide highly precise data for estimating nonlinear parameters, the measured forces were corrected using the constructed weighted combination forecasting model based on a support vector machine (WCFM_SVM). Secondly, a tetrahedral finite element parameter estimation model was established to describe the physical characteristics of soft tissues, using the substitution parameters of Young's modulus and Poisson's ratio to avoid solving complicated nonlinear problems. To improve the robustness of our model and avoid poor local minima, the initial parameters solved by a linear finite element model were introduced into the parameter estimation model. Finally, a self-adapting Levenberg-Marquardt (LM) algorithm was presented, which is capable of adaptively adjusting iterative parameters to solve the established parameter estimation model. The maximum absolute error of our WCFM_SVM model was less than 0.03 Newton, resulting in more accurate forces in comparison with other correction models tested. The maximum absolute error between the calculated and measured nodal displacements was less than 1.5 mm, demonstrating that our nonlinear parameters are precise. PMID- 29247875 TI - Autocalibration method for non-stationary CT bias correction. AB - Computed tomography (CT) is a widely used imaging modality for screening and diagnosis. However, the deleterious effects of radiation exposure inherent in CT imaging require the development of image reconstruction methods which can reduce exposure levels. The development of iterative reconstruction techniques is now enabling the acquisition of low-dose CT images whose quality is comparable to that of CT images acquired with much higher radiation dosages. However, the characterization and calibration of the CT signal due to changes in dosage and reconstruction approaches is crucial to provide clinically relevant data. Although CT scanners are calibrated as part of the imaging workflow, the calibration is limited to select global reference values and does not consider other inherent factors of the acquisition that depend on the subject scanned (e.g. photon starvation, partial volume effect, beam hardening) and result in a non-stationary noise response. In this work, we analyze the effect of reconstruction biases caused by non-stationary noise and propose an autocalibration methodology to compensate it. Our contributions are: 1) the derivation of a functional relationship between observed bias and non-stationary noise, 2) a robust and accurate method to estimate the local variance, 3) an autocalibration methodology that does not necessarily rely on a calibration phantom, attenuates the bias caused by noise and removes the systematic bias observed in devices from different vendors. The validation of the proposed methodology was performed with a physical phantom and clinical CT scans acquired with different configurations (kernels, doses, algorithms including iterative reconstruction). The results confirmed the suitability of the proposed methods for removing the intra-device and inter-device reconstruction biases. PMID- 29247876 TI - Robust MR elastography stiffness quantification using a localized divergence free finite element reconstruction. AB - As disease often alters structural and functional properties in tissue, the noninvasive measurement of material stiffness in vivo is desirable. Magnetic resonance elastography provides an approach to in vivo tissue characterization, using images of wave motion in tissue and biomechanical principles to reconstruct and quantify stiffness. Successful clinical translation of this technology requires stiffness reconstruction algorithms that are robust, easy to manage, and fast. In this paper, a reconstruction method is presented which addresses these issues by using a local compact divergence-free reconstruction kernel coupled with non-physical constraint elimination and inverse residual weighting to reliably reconstruct stiffness. The proposed technique is compared with local curl reconstructions and global stiffness-pressure reconstructions across two ground-truth phantoms as well as in vivo data sets. Sensitivity analysis is also performed, assessing the variability of reconstruction results and robustness to noise. It is shown that the proposed method can be robustly applied across data sets, is less sensitive to noise, attains comparable (or improved) accuracy, provides better correlation to anatomical features, and can be completed in short timescales. PMID- 29247878 TI - Cognitive capacity limitations and Need for Cognition differentially predict reward-induced cognitive effort expenditure. AB - While psychological, economic, and neuroscientific accounts of behavior broadly maintain that people minimize expenditure of cognitive effort, empirical work reveals how reward incentives can mobilize increased cognitive effort expenditure. Recent theories posit that the decision to expend effort is governed, in part, by a cost-benefit tradeoff whereby the potential benefits of mental effort can offset the perceived costs of effort exertion. Taking an individual differences approach, the present study examined whether one's executive function capacity, as measured by Stroop interference, predicts the extent to which reward incentives reduce switch costs in a task-switching paradigm, which indexes additional expenditure of cognitive effort. In accordance with the predictions of a cost-benefit account of effort, we found that a low executive function capacity-and, relatedly, a low intrinsic motivation to expend effort (measured by Need for Cognition)-predicted larger increase in cognitive effort expenditure in response to monetary reward incentives, while individuals with greater executive function capacity-and greater intrinsic motivation to expend effort-were less responsive to reward incentives. These findings suggest that an individual's cost-benefit tradeoff is constrained by the perceived costs of exerting cognitive effort. PMID- 29247879 TI - The determinants of response time in a repeated constant-sum game: A robust Bayesian hierarchical dual-process model. AB - The investigation of response time and behavior has a long tradition in cognitive psychology, particularly for non-strategic decision-making. Recently, experimental economists have also studied response time in strategic interactions, but with an emphasis on either one-shot games or repeated social dilemmas. I investigate the determinants of response time in a repeated (pure conflict) game, admitting a unique mixed strategy Nash equilibrium, with fixed partner matching. Response times depend upon the interaction of two decision models embedded in a dual-process framework (Achtziger and Alos-Ferrer, 2014; Alos-Ferrer, 2016). The first decision model is the commonly used win-stay/lose shift heuristic and the second the pattern-detecting reinforcement learning model in Spiliopoulos (2013b). The former is less complex and can be executed more quickly than the latter. As predicted, conflict between these two models (i.e., each one recommending a different course of action) led to longer response times than cases without conflict. The dual-process framework makes other qualitative response time predictions arising from the interaction between the existence (or not) of conflict and which one of the two decision models the chosen action is consistent with-these were broadly verified by the data. Other determinants of RT were hypothesized on the basis of existing theory and tested empirically. Response times were strongly dependent on the actions chosen by both players in the previous rounds and the resulting outcomes. Specifically, response time was shortest after a win in the previous round where the maximum possible payoff was obtained; response time after losses was significantly longer. Strongly auto correlated behavior (regardless of its sign) was also associated with longer response times. I conclude that, similar to other tasks, there is a strong coupling in repeated games between behavior and RT, which can be exploited to further our understanding of decision making. PMID- 29247877 TI - Learning non-linear patch embeddings with neural networks for label fusion. AB - In brain structural segmentation, multi-atlas strategies are increasingly being used over single-atlas strategies because of their ability to fit a wider anatomical variability. Patch-based label fusion (PBLF) is a type of such multi atlas approaches that labels each target point as a weighted combination of neighboring atlas labels, where atlas points with higher local similarity to the target contribute more strongly to label fusion. PBLF can be potentially improved by increasing the discriminative capabilities of the local image similarity measurements. We propose a framework to compute patch embeddings using neural networks so as to increase discriminative abilities of similarity-based weighted voting in PBLF. As particular cases, our framework includes embeddings with different complexities, namely, a simple scaling, an affine transformation, and non-linear transformations. We compare our method with state-of-the-art alternatives in whole hippocampus and hippocampal subfields segmentation experiments using publicly available datasets. Results show that even the simplest versions of our method outperform standard PBLF, thus evidencing the benefits of discriminative learning. More complex transformation models tended to achieve better results than simpler ones, obtaining a considerable increase in average Dice score compared to standard PBLF. PMID- 29247880 TI - Entrainment for attentional selection in Parkinson's disease. AB - Neural entrainment plays a crucial role in perception and action, especially when stimuli possess a certain temporal regularity, and is also suggested to serve as a neural process to select and attend the relevant stream in situations where there are competing stimulus streams. Beneficial effects of entrainment have led to the suggestion that rhythmic stimuli can improve motor function in patients with Parkinson's disease (PD). Behavioural studies support this suggestion, but neurophysiological studies have shown reduced entrainment of motor areas in PD. However, oscillatory entrainment in PD has only been tested in paradigms with a single isochronous stimulus stream, whereas entrainment has an enhanced benefit in situations where one rhythmic stimulus stream has to be segregated from distractor stimuli. Therefore, we here used an intermodal selective attention task with concurrent auditory and visual stimulus streams while recording oscillatory brain activity with Magnetoencephalography (MEG). We aimed to (i) replicate earlier findings of deficient motor entrainment in PD patients in conditions where there is a single stimulus stream, and (ii) to evaluate whether increasing the benefit of entrainment by introducing a distractor stream would lead to entrainment in PD patients not seen otherwise. Contrary to this hypothesis, PD patients showed reduced motor entrainment compared to controls during both conditions, as indexed by beta oscillatory activity. These results suggest that entrainment in PD patients is deficient, even under conditions that encourage entrainment. PMID- 29247881 TI - College students' perceived benefit-to-risk tradeoffs for nonmedical use of prescription stimulants: Implications for intervention designs. AB - OBJECTIVES: Few studies have examined the benefit-to-risk tradeoffs undergraduate students perceive when engaging in the nonmedical use of prescription stimulants (NPS). This study examined the variation in college students' perceived risks and benefits for NPS. METHODS: An online survey was administered to 259 college students (ages 18-25) at six public universities who had engaged in NPS in the past year. A best-worst scaling (BWS) instrument assessed the relative importance of 12 perceived benefits and risks of NPS. Probabilities of selection of each factor and 95% confidence intervals were estimated for the aggregate sample and latent preference subgroups were derived using latent class analysis (LCA). RESULTS: For the aggregate sample, the strongest motivators for NPS were better grades (m=2.33, p<0.05) and meeting deadlines (m=1.62, p<0.05). The LCA generated four subgroups: 1) assuredly performance-driven (n=64; 25%), who prioritized academic performance and nonacademic responsibilities; 2) cautiously grade/career oriented (n=117; 45%), who balanced academic improvements with expulsion and limiting future career opportunities; 3) risk-averse (n=64; 25%), who prioritized expulsion above academic improvements; and 4) recreational (n=14; 5%), who most valued having fun partying. CONCLUSIONS: These findings identify subgroups of college NPS users that could have vastly different trajectories in terms of future drug use and college performance. Given this heterogeneity among students regarding perceived risks and benefits of NPS, interventions should be designed to assess motives and provide personalized feedback. Further research is needed with larger, more diverse samples and to assess the prospective stability of perceived risks and benefits. PMID- 29247882 TI - Canopy of advantage: Who benefits most from city trees? AB - Urban tree canopy provides a suite of ecological, social, and economic benefits to the residents of urban areas. With an expanding recognition of these benefits among city residents, there is growing concern that access to these benefits is not distributed equally and may represent the presence of an environmental injustice. This study examines the spatial relationship between median household income and tree canopy variables, specifically realized tree canopy cover and potential tree canopy cover, for Toronto, Canada. Toronto provides a strong empirical focus as it is a densely populated urban setting reported to be exhibiting an increase in the geographic polarization of residents based upon household income. Spatial relationships between median household income and tree canopy variables are evaluated using the bivariate Moran's I statistic, a specialized local indicator of spatial autocorrelation (LISA). This method explicitly identified where statistically significant spatial clusters of high and low household income coincide with significant clusters of high and low urban tree canopy, providing the basis for an examination of the policies and management decisions that led to this temporal snapshot. The importance of these spatial clusters is examined from the perspective of understanding the impact of urban change (both socio-demographic and built form), and from the standpoint of improving equality of access to city trees and their benefits resulting from future tree planting decisions. PMID- 29247883 TI - Novel ecosystems: Governance and conservation in the age of the Anthropocene. AB - Meeting conservation objectives in an era of global environmental change has precipitated debate about where and how to intervene. Ecological and social values of novel ecosystems are particularly contested. Governance has a role to play, but this role is underexplored. Here, we critically review the novel ecosystems literature to identify challenges that fall within the realm of governance. Using a conceptual framework for analysing adaptive governance, we consider how governance could help address five challenges. Specifically, we argue that reforming governance can support the re-framing of policy objectives for ecosystems where transformation is likely, and in doing so, it could highlight the tensions between the emergence of novel ecosystems on the one hand and cultural expectations about how ecosystems should look on the other. We discuss the influence of power, authority and administrative competence on conservation efforts in times of environmental change. We consider how buffering can address translational mismatch between conventional conservation policy and modern ecological reality. This review provides insights into how governance reform could enable more adaptive responses to transformative changes, such as novel ecosystems, while remaining committed to achieving conservation outcomes. Indeed, at their best, adaptive responses would encompass the reality of ecological transformation while being sympathetic to concerns about undesirable outcomes. Connections between researchers in the fields of governance, ecology and conservation could help to achieve these twin aims. We provide examples of governance and policy-making techniques that can support context-specific governance reform that supports more effective conservation in the Anthropocene. PMID- 29247884 TI - A Low-Toxicity DNA-Alkylating N-Mustard-Quinoline Conjugate with Preferential Sequence Specificity Exerts Potent Antitumor Activity Against Colorectal Cancer. AB - Efficacy and safety are fundamental prerequisites for anticancer drug development. In the present study, we explored the anti-colorectal cancer (CRC) activity of SL-1, a DNA-directed N-mustard-quinoline conjugate. The N-mustard moiety in SL-1 induced DNA strand breaks, interstrand cross-links (ICLs), G2/M arrest, and apoptosis, whereas its quinoline moiety preferentially directed SL-1 to target the selective guanine sequence 5'-G-G/C-N-G-C/T-3'. Notably, SL-1 was highly cytotoxic to various CRC cell lines. Experiments using xenograft models revealed that SL-1 was more potent than 5-fluorouracil (5-FU) and oxaliplatin for suppressing the growth of RKO and RKO-E6 (oxaliplatin-resistant subline) cells as well as metastatic SW620 cells. In addition, SL-1 combined with 5-FU was more effective than oxaliplatin and 5-FU for suppressing RKO or SW620 cell growth in mice. Significantly, compared with cisplatin, oxaliplatin, or 5-FU, SL-1 alone or in combination with 5-FU did not cause obvious kidney or liver toxicity in ICR mice. In summary, SL-1, a DNA-directed alkylating agent, is established as an anti-CRC agent with high efficacy and low toxicity and thus warrants further development for the treatment of CRC patients. PMID- 29247885 TI - Hypoxia Inducible Factors Modify Collagen I Fibers in MDA-MB-231 Triple Negative Breast Cancer Xenografts. AB - Hypoxia inducible factors (HIFs) are transcription factors that mediate the response of cells to hypoxia. HIFs have wide-ranging effects on metabolism, the tumor microenvironment (TME) and the extracellular matrix (ECM). Here we investigated the silencing effects of two of the three known isoforms, HIF-1alpha and HIF-2alpha, on collagen 1 (Col1) fibers, which form a major component of the ECM of tumors. Using a loss-of-function approach for HIF-1alpha or 2alpha or both HIF-1alpha and 2alpha, we identified a relationship between HIFs and Col1 fibers in MDA-MB-231 tumors. Tumors derived from MDA-MB-231 cells with HIF-1alpha or 2alpha or both HIF-1alpha and 2alpha silenced contained higher percent fiber volume and lower inter-fiber distance compared to tumors derived from empty vector MDA-MB-231 cells. Depending upon the type of silencing, we observed changes in Col1 degrading enzymes, and enzymes involved in Col1 synthesis and deposition. Additionally, a reduction in lysyl oxidase protein expression in HIF down-regulated tumors suggests that more non-cross-linked fibers were present. Collectively these results identify the role of HIFs in modifying the ECM and the TME and provide new insights into the effects of hypoxia on the tumor ECM. PMID- 29247886 TI - Microcalcification morphological descriptors and parenchyma fractal dimension hierarchically interact in breast cancer: A diagnostic perspective. AB - INTRODUCTION: Herein, we propose a Systems Biology approach aimed at identifying quantitative morphological parameters useful in discriminating benign from malignant breast microcalcifications at digital mammography. MATERIALS AND METHODS: The study includes 31 patients in which microcalcifications had been detected during XR mammography and were further confirmed by stereotactic (XR guided) biopsies. Patients were classified according to the BIRADS (Breast Imaging-Reporting and Data System), along with their parenchyma fractal dimension and biopsy size. A geometrical-topological characterization of microcalcifications was obtained as well. RESULTS: The 'size of biopsy' was the parameter endowed with the highest discriminant power between malignant and benign lesions thus confirming the reliability of surgeon judgment. The quantitative shape evaluation of both lesions and parenchyma allowed for a promising prediction of the BIRADS score. The area of lesions and parenchyma fractal dimension show a complex distribution for malignant breast calcifications that are consistent with their qualitative morphological pattern. Fractal dimension analysis enables the user to obtain reliable results as proved by its efficiency in the prediction of the morphology of breast cancer. CONCLUSION: By reconstructing a phase-space distribution of biophysical parameters, different patterns of aggregation are recognized corresponding to different calcium deposition patterns, while the combination of tissue and microcalcification morphological descriptors provide a statistically significant prediction of tumour grade. CLINICAL RELEVANCE: The development of an automated morphology evaluation system can help during clinical evaluation while also sketching mechanistic hypotheses of microcalcification generation. PMID- 29247887 TI - Protective role of exogenous phytohormones on redox status in pea seedlings under copper stress. AB - The present work aims to provide insight on the role of phytohormone application in developing efficient practical defense strategies to improve plants tolerance under heavy metal contamination. For this purpose, pea (Pisum sativum L.) seeds were germinated in an aqueous solution of 200MUM CuCl2 up to the 3rd day and then continued to germinate in the presence of distilled water (stress cessation) or were subjected to following combinations: Cu+1MUM IAA and Cu+1MUM GA3 for 3 additional days. The results showed that copper excess induced oxidative stress in germinating seeds, which resulted in changes of the redox state of glutathione and cysteine, and proteomics revealed Cu-induced modifications of thiols (SH) and carbonyls (CO) (indicators of protein oxidation). However, application of IAA or GA3 in the germination medium after 3days of Cu exposure alleviated toxicity on seedlings, despite the persistence of Cu up to 6th day. This improving effect seems to be mediated by a cell Cu accumulation decrease and a protein reduced status recovery, since phytohormones modulate thioredoxin/ferredoxin systems in favor of protecting proteins against oxidation. In addition, an IAA and GA3 protective effect was evidenced by a cellular homeostasis amelioration resulting from the balance conservation between the regeneration and consumption processes of glutathione and cysteine reduced forms. The exogenous effectors also induced modifications of profiles of SH and CO, suggesting changes in the regulation and expression of proteins that could be involved in defense mechanism against Cu stress. PMID- 29247888 TI - Possible involvement of glutathione S-transferases in imazamox detoxification in an imidazolinone-resistant sunflower hybrid. AB - The resistance of crops to herbicides can be due to target site based resistance or non-target site based resistance mechanisms or a combination of both. In non target site resistance, the detoxification efficiency plays a major role by involvement of enzymes such as P450s, GTs, GSTs and ABC transporters. The resistance of the first commercial Clearfield sunflower hybrids (Imisun trait) to herbicides of imidazolinone group is based on a combination of both types of resistance. The target site resistance consists of a mutation in Ahasl1 gene, encoding the synthesis of the AHAS enzyme. The non-target site resistance is supposed to be due to intensified herbicide disposal and is not fully understood. The objective of this study was to detect the fast response of the glutathione mediated detoxification system in IMI-R and IMI-S sunflower hybrids to the herbicide imazamox and to study the possible participation of GSTs in the enhancement of the hybrids' tolerance. The obtained results allow to presume that GSTs are involved in imazamox detoxification in the sunflower Imisun trait and thus contributing to its non-target site resistance. PMID- 29247889 TI - Salicylaldehyde synthase activity from Venturia inaequalis elicitor-treated cell culture of apple. AB - Salicylic acid (SA) is known to trigger a number of plant defense responses upon pathogen attack. It is well known that apple (Malus domestica) plants respond to pathogen invasion by synthesizing SA, but its biosynthesis is not well understood. In this study, we report salicylaldehyde synthase (SAS) activity from Venturia inaequalis elicitor (VIE)-treated cell suspension cultures of apple (Malus domestica 'Florina'). SAS catalyzes non-oxidative C2-side chain cleavage of 2-coumaric acid to form salicylaldehyde (SALD) in the presence of a reducing agent such as cysteine. The side chain cleavage mechanism was found to be very similar to that of salicylaldehyde synthase activity from tobacco and 4 hydroxybenzaldehyde synthase activity from Vanilla planifolia and Daucus carota. A basal SAS activity was observed in the non-elicited cell cultures, and a 7-fold increase in SAS activity was observed upon elicitation. In parallel to SAS activity, the level of total SA accumulation increased by 5.6-fold after elicitation compared to the untreated control cells. Elicitor treatment further resulted in an 8.7-fold increase in the activity of the phenylalanine ammonia lyase (PAL) enzyme that preceded the peak of SAS activity and total SA accumulation, suggesting the involvement of the phenylpropanoid pathway in SA metabolism. The preferred substrate for SAS was 2-coumaric acid (Km = 0.35 mM), with cysteine being the preferred reducing agent. In addition, a 1.8-fold enhancement in the SA content and 0.7-fold enhancement in the SALD content was observed when elicited cell cultures were fed with 2-coumaric acid. These observations suggest the involvement of SAS in SALD biosynthesis. PMID- 29247890 TI - Automated localization and segmentation techniques for B-mode ultrasound images: A review. AB - B-mode ultrasound imaging is used extensively in medicine. Hence, there is a need to have efficient segmentation tools to aid in computer-aided diagnosis, image guided interventions, and therapy. This paper presents a comprehensive review on automated localization and segmentation techniques for B-mode ultrasound images. The paper first describes the general characteristics of B-mode ultrasound images. Then insight on the localization and segmentation of tissues is provided, both in the case in which the organ/tissue localization provides the final segmentation and in the case in which a two-step segmentation process is needed, due to the desired boundaries being too fine to locate from within the entire ultrasound frame. Subsequenly, examples of some main techniques found in literature are shown, including but not limited to shape priors, superpixel and classification, local pixel statistics, active contours, edge-tracking, dynamic programming, and data mining. Ten selected applications (abdomen/kidney, breast, cardiology, thyroid, liver, vascular, musculoskeletal, obstetrics, gynecology, prostate) are then investigated in depth, and the performances of a few specific applications are compared. In conclusion, future perspectives for B-mode based segmentation, such as the integration of RF information, the employment of higher frequency probes when possible, the focus on completely automatic algorithms, and the increase in available data are discussed. PMID- 29247891 TI - Study of lipid peroxidation and ascorbic acid protective role in large unilamellar vesicles from a new electrochemical performance. AB - In this contribution an electrochemical study is described for the first time of lipid peroxidation and the role of antioxidant on lipid protection using large unilamellar vesicles (LUVs). In order to simulate the cell membrane, LUVs composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) were used. A vesicle modified electrode was constructed by immobilizing DOPC LUVs onto carbon paste electrodes (CPEs). Lipid peroxidation was studied electrochemically by incubating the vesicle-modified electrodes with hydroxyl (HO) radicals generated via the Fenton reaction. Oxidative damage induced by HO was verified by using square wave voltammetry (SWV) and was indirectly measured by the increase of electrochemical peak current to [Fe(CN)6]4- which was used as the electrochemical label. Ascorbic acid (AA) was used as the antioxidant model in order to study its efficacy on free radical scavenging. The decrease of the electrochemical signal confirms the protective key role promoted by AA in the prevention of lipid peroxidation in vesicles. Through microscopy, it was possible to observe morphologic modification on vesicle structures after lipid peroxidation in the presence or absence of AA. PMID- 29247892 TI - Halimane-type diterpenoids from Vitex rotundifolia and their anti-hyperlipidemia activities. AB - Vitex rotundifolia is the variant of the traditional Chinese medicine (TCM) Vitex trifolia. Diterpenoids from V. trifolia have shown anti-hyperlipidemia activity. As part of a continuous research program of searching for anti-hyperlipidemia constituents from TCM, 95% alcohol extract of the fruits of V. rotundifolia was fully studied, and 18 diterpenoids were isolated, including eight previously undescribed compounds (viterofolins A-H). Among them, viterofolins A-B were previously undescribed rearranged halimane-type diterpenoids, viterofolins CH were previously undescribed halimane-type diterpenoids. These compounds were then firstly evaluated in lipid (Dil-LDL) uptake assay in HepG2 cells. Viterofolin H, (5S, 6R, 8R, 9R, 10S)-6-acetoxy-9-hydroxy-13 (14)-labden-16,15-olide and previtexilactone showed moderate activities in promoting LDL uptake (1.27-1.35 fold). This work laid the foundation for searching anti-hyperlipidemia natural products. PMID- 29247893 TI - Polycyclic polyprenylated acylphloroglucinols and biphenyl derivatives from the roots of Garcinia nuntasaenii Ngerns. & Suddee. AB - Seven previously undescribed compounds, including three polycyclic polyprenylated acylphloroglucinols (garcinuntins A-C), three biphenyl derivatives (garcinuntabiphenyls A-C) and a lanostane triterpene (garcinuntine), along with thirteen known compounds were isolated from the root of Garcinia nuntasaenii Ngerns. & Suddee. Their structures were elucidated on the basis of spectroscopic techniques. For garcinuntins A-C, the absolute configurations were confirmed by the combination of single X-ray crystallography and ECD calculations. Anti-HIV activity using anti-HIV-1 reverse transcriptase and syncytium inhibition assays, and cytotoxic activity against a panel of cultured mammalian cancer cell lines of isolated compounds were investigated. PMID- 29247894 TI - Unusual phenethylamine-containing alkaloids from Elaeocarpus tectorius. AB - From the leaves of Elaeocarpus tectorius (Lour.) Poir. four previously undescribed phenethylamine-containing alkaloids were isolated, namely, tectoricine, possessing an unprecedented isoquinuclidinone ring system incorporating a phenethylamine moiety, tectoraline, representing a rare alkamide incorporating two phenethylamine moieties, and tectoramidines A and B, representing the first naturally occurring trimeric and dimeric phenethylamine alkaloids incorporating an amidine function. The structures of these alkaloids were established by detailed spectroscopic analysis. The absolute configuration of tectoricine was determined by comparison of the experimental and calculated ECD spectra. Plausible biosynthetic pathways to the four alkaloids are proposed. PMID- 29247895 TI - Therapists' self-reported drift from dialectical behavior therapy techniques for eating disorders. AB - OBJECTIVE: Research has shown that clinicians underuse or omit techniques that constitute an essential part of evidence-based therapies. However, it is not known whether this is the case in DBT for eating disorders. The aims of this study were; 1) exploring the extent to which DBT techniques were used by self identified DBT clinicians treating eating disorders; 2) determining whether therapists fell into distinct groups, based on their usage of DBT techniques; and 3) examining whether clinician characteristics were related to the use of such techniques. METHOD: Seventy-three clinicians offering DBT for eating disorders completed an online survey about their use of specific DBT techniques. They also completed measures of personality and intolerance of uncertainty. RESULTS: In relation to the first aim, the pattern of use of DBT techniques showed a bimodal distribution - most were used either a lot or a little. Considering the second aim, clinicians fell into two groups according to the techniques that they delivered - one characterized by a higher use of DBT techniques and the other by a higher use of techniques that were specific to the treatment of eating disorders, rather than DBT methods. Finally, more experienced clinicians were more likely to be in the 'DBT technique-focused' group. DISCUSSION: DBT clinicians are encouraged to implement both sets of techniques (DBT techniques and standard techniques for the treatment of eating disorders) in an integrated way. Training, supervision and the use of manuals are recommended to decrease therapist drift in DBT. PMID- 29247896 TI - An ART score to note objectively the quality of an ART procedure. AB - OBJECTIVE: To construct an ART score to evaluate an ART procedure before the result (pregnancy or not), and to provide objective data in discussions with couples in the decision to discontinue further attempts. STUDY DESIGN: A retrospective multicentrique study was performed. The ART score was constructed using data from the MediFirst(c) database used in our center. The development of the score was conducted on a sample of 507 in vitro fertilization cycles carried out between January 2011 and July 2011. Model calibration and determination of the discrimination capacity of the ART score were performed with 4463 cycles in our center and 1369 cycles from an external ART center. The ART score was validated temporally and geographically with clinical pregnancy and take home baby rate. RESULTS: The ART score was obtained from data from both partners and ART procedure. The ART score was segmented into four classes depending on the clinical pregnancy rate. There was a linear relationship between the ART score and clinical pregnancy rate (r = 1.0, p < 0.001). The ART score was validated temporally and geographically. CONCLUSION: An objective ART score has been constructed and validated. It will be of help to ART teams and it is an objective tool to explain to a couple the choices for the next ART attempt. PMID- 29247898 TI - "I'm a normal autistic person, not an abnormal neurotypical": Autism Spectrum Disorder diagnosis as biographical illumination. AB - Building on Michael Bury's "biographical disruption" and Kathy Charmaz's "loss of self," which describe the deteriorative impacts of chronic illness on perceptions of selfhood, I propose "biographical illumination"-a transformed conceptualization of self and identity that is facilitated by but extends beyond medical meaning, enriching personal biography and social relationships. The concept is perhaps most applicable to experiences with neurological and neurodevelopmental conditions in which brain difference and personhood are perceived to be closely intertwined. In this study, biographical illumination is used to describe the experiences of autistic adults who learned of their Autism Spectrum Disorder (ASD) diagnosis during teen years or adulthood. Through an ASD lens, participants found explanation for their atypicality and developed a more valued self-concept. Learning of the condition did not disrupt their biography; rather, it became integral to and constitutive of it. With a new self-concept, participants re-gauged personal expectations for normalization and accessed communities of alike others, forging relationships that affirmed identity. PMID- 29247899 TI - Self-rated health and endogenous selection into primary care. AB - This study assesses the causal effects of primary care utilization on subjective health status in Turkey using individual-level data from the 2012 Health Research Survey. Employing recursive bivariate ordered models that take into account the possibility that selection into healthcare might be correlated with the respondent's self-reported health status, we find that selection into primary care is endogenously determined and that the utilization of primary care significantly improves self-rated health after controlling for sociodemographics, socioeconomic status, health behaviors and risk factors, and access to healthcare. We show that the causal association between healthcare utilization and health status is robust to the use of objective measures of health and specific types of care, suggesting that the use of a single-item question on self rated health and binary measures of preventive care utilization is valid. PMID- 29247897 TI - Post-translational regulation of macrophage migration inhibitory factor: Basis for functional fine-tuning. AB - Macrophage migration inhibitory factor (MIF) is a chemokine-like protein and an important mediator in the inflammatory response. Unlike most other pro inflammatory cytokines, a number of cell types constitutively express MIF and secretion occurs from preformed stores. MIF is an evolutionarily conserved protein that shows a remarkable functional diversity, including specific binding to surface CD74 and chemokine receptors and the presence of two intrinsic tautomerase and oxidoreductase activities. Several studies have shown that MIF is subject to post-translational modification, particularly redox-dependent modification of the catalytic proline and cysteine residues. In this review, we summarize and discuss MIF post-translational modifications and their effects on the biological properties of this protein. We propose that the redox-sensitive residues in MIF will be modified at sites of inflammation and that this will add further depth to the functional diversity of this intriguing cytokine. PMID- 29247900 TI - Risk factors for recurrence in depression in the Lundby population, 1947-1997. AB - BACKGROUND: Depression is a common disorder in both men and women, and the recurrence rate is high. The aim of this study was to identify risk factors for recurrence in depression in the Lundby Study. METHODS: The Lundby Study is a community-based longitudinal study with focus on mental health. The study started in 1947 and three follow-ups have been carried out since, the last one in 1997. The population consists of 3563 subjects. Data from 508 subjects afflicted by depression was gathered. Premorbid factors (gender, socioeconomic status, marital status, personality and heredity) and factors related to the first depressive episode (age, degree of impairment and melancholic depression) were investigated regarding their influence on the risk for recurrence in depression. Multiple logistic regression was used in the calculations. RESULTS: Risk factors associated with recurrent depression were melancholic depression at first onset (OR 3.52 [95% CI 1.62-7.66, p < 0.001]), young age as compared to old age at first onset (OR 0.51 [95% CI 0.28-0.92, p = 0.03]) and a premorbid nervous/tense personality (OR 1.77 [95% CI 1.22-2.56, p < 0.01]). Demographic factors, including gender, had no effect on the odds of recurrence. LIMITATIONS: The Lundby Study spans over 50 years, making the results vulnerable to changes in diagnostic regimes and recall bias. CONCLUSION: Melancholia at onset, regardless of severity of symptoms, had the greatest impact on the risk of recurrence in depression in the Lundby Study. Information about risk factors for recurrence in depression are useful in offering effective preventive measures in the form of psychotropic drugs and psychotherapy, and deciding the length of follow-up. PMID- 29247901 TI - Temporal distribution of suicide mortality: A systematic review. AB - BACKGROUND: suicide is a problem with world impact and the leading cause of premature deaths. The study of its distribution over time can bring a changed understanding of parameters attributed to, and the prevention of, suicide. AIM: to identify the temporal pattern of suicide by systematic review. METHODS: Pubmed (Medline), LILACS, Virtual Health Library (VHL), Science Direct and Scopus (Elsevier), Web of Science (Thomson Reuters) and PsyNET (APA) were searched, using suicide-related descriptors and terms, for observational epidemiological studies of the temporal distribution of suicide. The review protocol was registered in PROSPERO (CRD42016038470). LIMITATIONS: The lack of uniformity in reporting or standardisation of methodology in the studies selected, hindered comparison of populations with similar socioeconomic and cultural profiles, considerably limiting the scope of the results of this review. RESULTS: forty five studies from 26 different countries were included in this review. Clear seasonal patterns were observed by day of the week, month, season and age-period cohort effects. Few studies studied by trend, time of day or day of the month. CONCLUSION: the review findings provide further evidence of substantial temporal patterns influenced by geographic, climatic and social conditions. PMID- 29247902 TI - Ultrasound to facilitate thoracic paravertebral catheter in severe scoliosis. PMID- 29247903 TI - Polychlorinated naphthalenes (PCNs) in seafood: Estimation of dietary intake in Korean population. AB - Polychlorinated naphthalenes (PCNs) were measured in 33 seafood species including fish, mollusks and crustaceans purchased from local markets in five Korean cities between 2012 and 2013. Five samples were collected from each species for the measurements. Thirty-seven PCN congeners from tetra-CN to octa-CN were measured. Octa-CN (octachloronaphthalene) was not detected in any of the samples. Tetra-CN and penta-CN were the predominant homologues of PCNs in seafood samples with PCN 51 and PCN 52/60 being the most abundant congeners in the samples. Total PCNs concentrations and their corresponding dioxin-like toxic equivalent (TEQ) values ranged from non-detection (ND) to 110pg/g on a wet weight (ww) basis and from ND to 0.14pg-TEQ/g ww, respectively. The estimated daily intake of total PCNs based on an absolute content and TEQ potency were estimated for the Koreans to be 570pg/day and 0.44pg-TEQ/day, respectively. However, the estimated TEQ value of PCNs intake from seafood, represented only a small fraction (3.0%) of the total TEQ intake from consumption of seafood in Korean population. This is the first report to exhibit the presence of PCNs in seafood samples collected from local markets in Korea and their intake by general population. PMID- 29247904 TI - Microplastic-associated bacterial assemblages in the intertidal zone of the Yangtze Estuary. AB - Plastic trash is common in oceans. Terrestrial and marine ecosystem interactions occur in the intertidal zone where accumulation of plastic frequently occurs. However, knowledge of the plastic-associated microbial community (the plastisphere) in the intertidal zone is scanty. We used high-throughput sequencing to profile the bacterial communities attached to microplastic samples from intertidal locations around the Yangtze estuary in China. The structure and composition of plastisphere communities varied significantly among the locations. We found the taxonomic composition on microplastic samples was related to their sedimentary and aquatic origins. Correlation network analysis was used to identify keystone bacterial genera (e.g. Rhodobacterales, Sphingomonadales and Rhizobiales), which represented important microbial associations within the plastisphere community. Other species (i.e. potential pathogens) were considered as hitchhikers in the plastic attached microbial communities. Metabolic pathway analysis suggested adaptations of these bacterial assemblages to the plastic surface-colonization lifestyle. These adaptations included reduced "cell motility" and greater "xenobiotics biodegradation and metabolism." The findings illustrate the diverse microbial assemblages that occur on microplastic and increase our understanding of plastisphere ecology. PMID- 29247905 TI - The development of a pregnancy PBPK Model for Bisphenol A and its evaluation with the available biomonitoring data. AB - Recent studies suggest universal fetal exposure to Bisphenol A (BPA) and its association with the adverse birth outcomes. Estimation of the fetal plasma BPA concentration from the maternal plasma BPA would be highly useful to predict its associated risk to this specific population. The objective of current work is to develop a pregnancy-physiologically based pharmacokinetic (P-PBPK) model to predict the toxicokinetic profile of BPA in the fetus during gestational growth, and to evaluate the developed model using biomonitoring data obtained from different pregnancy cohort studies. To achieve this objective, first, the adult PBPK model was developed and validated with the human BPA toxicokinetic data. This validated human PBPK model was extended to develop a P-PBPK model, which included the physiological changes during pregnancy and the fetus sub-model. The developed model would be able to predict the BPA pharmacokinetics (PKs) in both mother and fetus. Transplacental BPA kinetics parameters for this study were taken from the previous pregnant mice study. Both oral and dermal exposure routes were included into the model to simulate total BPA internal exposure. The impact of conjugation and deconjugation of the BPA and its metabolites on fetal PKs was investigated. The developed P-PBPK model was evaluated against the observed BPA concentrations in cord blood, fetus liver and amniotic fluid considering maternal blood concentration as an exposure source. A range of maternal exposure dose for the oral and dermal routes was estimated, so that simulation concentration matched the observed highest and lowest mother plasma concentration in different cohorts' studies. The developed model could be used to address the concerns regarding possible adverse health effects in the fetus being exposed to BPA and might be useful in identifying critical windows of exposure during pregnancy. PMID- 29247906 TI - Long-term monitoring of breath methane. AB - In recent years, methane as a component of exhaled human breath has been considered as a potential bioindicator providing information on microbial activity in the intestinal tract. Several studies indicated a relationship between breath methane status and specific gastrointestinal disease. So far, almost no attention has been given to the temporal variability of breath methane production by individual persons. Thus here, for the first time, long-term monitoring was carried out measuring breath methane of three volunteers over periods between 196 and 1002days. Results were evaluated taking into consideration the health status and specific medical intervention events for each individual during the monitoring period, and included a gastroscopy procedure, a vaccination, a dietary change, and chelate therapy. As a major outcome, breath methane mixing ratios show considerable variability within a person-specific range of values. Interestingly, decreased breath methane production often coincided with gastrointestinal complaints whereas influenza infections were mostly accompanied by increased breath methane production. A gastroscopic examination as well as a change to a low-fructose diet led to a dramatic shift of methane mixing ratios from high to low methane production. In contrast, a typhus vaccination as well as single chelate injections resulted in significant short term methane peaks. Thus, this study clearly shows that humans can change from high to low methane emitters and vice versa within relatively short time periods. In the case of low to medium methane emitters the increase observed in methane mixing ratios, likely resulting from immune reactions and inflammatory processes, might indicate non-microbial methane formation under aerobic conditions. Although detailed reaction pathways are not yet known, aerobic methane formation might be related to cellular oxidative-reductive stress reactions. However, a detailed understanding of the pathways involved in human methane formation is necessary to enable comprehensive interpretation of methane breath levels. PMID- 29247907 TI - Sorption, bioavailability and ecotoxic effects of hydrophobic organic compounds in biochar amended soils. AB - This work addresses the effect of biochar amendment to soil on contaminant sorption, bioavailability, and ecotoxicity. A distinction between positive primary amendment effects caused by reduced toxicity resulting from contaminant sorption, and negative secondary amendment effects of the biochars themselves was seen. Two biochars (one from high technology and one from low technology production processes) representing real world biochars were tested for the adsorption of pyrene, polychlorinated biphenyl (PCB) 52), and dichlorodiphenyldichloroethylene (p,p'-DDE). Sorption by both biochars was similar, both for compounds in single and mixed isotherms, in the presence and absence of soil. p,p'-DDE natively contaminated and spiked soils were amended with biochar (0, 1, 5, and 10%) and bioavailability, operationally defined bioaccessibility and ecotoxicity were assessed using polyethylene (PE), polymeric resin (XAD) and Folsomia candida, respectively. At the highest biochar dose (10%), bioavailability and bioaccessibility decreased by >37% and >41%, respectively, compared to unamended soils. Mortality of F. candida was not observed at any biochar dose, while reproductive effects were dose dependent. F. candida benefited from the reduction of p,p'-DDE bioavailability upon 1% and 5% biochar addition to contaminated soils while at 10% dose, these positive effects were nullified by biochar-induced toxicity. p,p'-DDE toxicity corrected for such secondary effects was predicted well by both PE uptake and XAD extraction. PMID- 29247908 TI - Multimodality treatment of intradural extramedullary Ewing's sarcomas. A systematic review. AB - Ewing's sarcoma (ES) is an aggressive bone and soft tissue sarcoma that usually affects adolescents and young adults. ES occasionally presents as an intradural extramedullary lesion of the spine. Our aim was to study the role of the multimodality treatment on the survival (overall survival, recurrence-free survival, and metastasis-free survival) of patients with intradural extramedullary Ewing's sarcoma. Pubmed, EMBASE, Scopus, Web of Science, Cochrane Reviews were searched up to January 2017, using as mesh terms "intradural extramedullary", "Ewing's sarcoma", AND "treatment". The multidisciplinary treatment was recorded in binary variables under the headings of "surgery", "chemotherapy" and "radiotherapy". We also recorded three time-to-event variables, including death, recurrence, and metastasis. We performed survival analysis for all potential combinations. Twenty articles with twenty-three patients were eligible for the current review. The survival curves of GTR did not differ from the equivalent of STR regarding survival (p=0.098), recurrence-free survival (p=0.318), and metastasis-free survival (p=0.089). Patients who received chemotherapy enjoyed longer survival regarding overall survival (p<0.05), recurrence-free survival (p<0.05), and metastasis-free survival (p<0.05), when compared to those who did not receive chemotherapy. Their overall survival of patients who had radiotherapy was marginally superior to those who did not receive (p=0.0653). However, their recurrence-free survival (p<0.05), and metastasis-free survival (p<0.05) were significantly improved in comparison to the latter. In conclusion, the multimodality treatment is mandatory for the management of patients with intradural extramedullary Ewing's sarcomas, with surgery assisting in the diagnosis and decompression the neural elements. However, it is chemotherapy that improves survival, recurrence-free survival, and metastasis-free survival. Radiotherapy is reserved as an adjuvant therapy in the local control, especially in cases with subtotal tumour resection. PMID- 29247909 TI - Structural and immunological characterization of a glycoconjugate based on the delipidated lipopolysaccharide from a nontypeable Helicobacter pylori strain PJ1 containing an extended d-glycero-d-manno-heptan. AB - Structural characterization of the lipopolysaccharide (LPS) from a nontypeable Helicobacter pylori strain PJ1 and two corresponding mutants, PJ1 HP1283:cam and PJ1 HP1284:cam, was performed using a combination of NMR and mass spectrometric techniques. It resulted in the core structure that differed significantly from the one proposed previously. Overall architecture of PJ1 LPS was found to be consistent with a structural model described for several other H. pylori strains. It contained a polymer of d-glycero-d-manno-heptose (dd-Hep) as the O-chain component, linked to alpha-1,6-glucan through a dd-Hep oligosaccharide. H. pylori PJ1 HP1283:cam LPS was missing dd-heptan, terminating with an alpha-1,6-glucan chain containing 5-13 glucose residues. LPS of strain PJ1 HP1284:cam was missing dd-Hep from the core and had beta-GlcNAc attached directly to O-3 of the inner core ld-Hep residue. To investigate the role of dd-heptan in protective immunity, delipidated LPS (dLPS) from strain PJ1 was conjugated to tetanus toxoid (TT) and immunological properties of the resultant glycoconjugate dLPS(PJ1)-TT determined. The dLPS(PJ1)-TT conjugate was immunogenic in mice and rabbits and induced specific and cross-reactive functional antibodies against homologous and heterologous strains of H. pylori. Whole cell indirect ELISA performed on a selected number of H. pylori isolates confirmed that the immune response correlated with the presence of alpha-1,6-glucan and was not augmented by the dd Hep content of these strains. PMID- 29247910 TI - Conjugation of carbohydrates to proteins using di(triethylene glycol monomethyl ether) squaric acid ester revisited. AB - Properties of di(triethylene glycol monomethyl ether) squarate relevant to conjugation of carbohydrates to proteins have been reinvestigated and compared with those of dimethyl squarate. It is concluded that the commercially available, crystalline dimethyl squarate remains the most convenient and efficient reagent for conjugation of amine-containing carbohydrates to proteins by a two-step or one-pot conjugation protocol. PMID- 29247911 TI - Degradation of perfluorinated compounds by sulfate radicals - New mechanistic aspects and economical considerations. AB - Perfluorinated organic compounds (PFC) are an important group of pollutants, which are difficult to be degraded in conventional water treatment. Even hydroxyl radical based processes are not capable to degrade these compounds. Sulfate radicals can oxidize a group of PFC, i.e., perfluorinated carboxylic (PFCAs) acids. However, information in literature on kinetics and reaction mechanism is largely based on model simulations which are prone to errors. The present study provides mechanistic insights based on product formation, material balances, competition kinetics experiments and quantum chemical calculations. Furthermore, energy requirements for sulfate radical based degradation of PFCA is evaluated in the present study. PFCAs can be partly mineralized in chain reactions initiated by sulfate radicals (SO4?). The perfluorinated acetic acid (TFA), propionic acid, and butanoic acid are largely degraded in a primary reaction with sulfate radicals. In case of PFCA with a chain length of > 4 carbons low yields of PFCA products were observed. Regarding reaction kinetics sulfate radicals react very slow with PFCAs (~ 104 M-1 s-1). Thus, the energy demand required for generation of SO4? by photolysis of S2O82? (UV/S2O82-) is very high. A 90% degradation of a PFCA by UV/S2O82- was estimated to be 55 kW h m-3 in pure water. PMID- 29247912 TI - A small pericardial effusion is a marker of complicated hospitalization in patients with community-acquired pneumonia. AB - OBJECTIVE: Although often asymptomatic, presence of small pericardial effusion (SPE) is shown to be associated with adverse events and increased mortality in various conditions. This study aimed to evaluate the frequency and prognostic importance of SPE in a cohort of patients hospitalized for community-acquired pneumonia (CAP). METHODS: We prospectively followed 154 consecutive adult patients hospitalized with CAP. The severity of CAP was evaluated with the pneumonia severity index (PSI) and the CURB-65 (confusion, urea, respiratory rate, arterial blood pressure and age) score. All patients underwent transthoracic echocardiography within the first 48h of admission. Patients were followed-up until hospital discharge or death. The outcomes of interest were length of stay in hospital and complicated hospitalization (CH) which is defined as intensive care unit admission, need for mechanical ventilation or in-hospital mortality. This study was registered with ClinicalTrials.gov, number NCT02441855. RESULTS: A total 34 episodes of CHs occurred in 21 (13.6%) patients. Older patients and those with more co-morbid conditions such as diabetes, coronary artery diseases, cerebrovascular diseases, and chronic obstructive pulmonary diseases tended to have a higher rate of CH. Patients with CH had higher N terminal pro-brain natriuretic peptide, troponin and creatinine levels on admission compared to patients without CH. Patients with CH had also higher CURB 65 and PSI scores and had longer durations of stay compared to patients with uncomplicated course. SPE was noted in 24 (15.6%) of the patients in our study cohort. Incidence of CH was greater for patients with a SPE (26 CHs occurred in 14 of the 24 patients) compared to those without an effusion (8 CHs occurred in 7 of the 130 patients, p<0.001). Logistic multivariate analysis revealed that the presence of SPE was an independent predictor of CH (OR: 3.26; 95% CI: 2.19-8.71; p=0.008). CONCLUSION: This study is the first to demonstrate that the presence of SPE is associated with increased adverse events in patients with CAP. PMID- 29247914 TI - Visual detection of trace lead ion based on aptamer and silver staining nano metal composite. AB - In this paper, visual detection of trace lead ion was established by aptamer and silver staining. The basic strategy was that aminated PS2.M aptamer was immobilized onto slide and formed stable G-quadruplex structure. PbS was generated by adding S2-, and it catalyzed subsequent silver staining reaction, through the silver staining amplification effect, the slide presented visible ash black. The gray value of slide after silver staining was analyzed and the semi quantitative detection of Pb2+ in solution was realized. The results showed that optical darkness ratio (ODR) and logarithmic value of Pb2+ concentration had a good linear relationship (R2 = 0.951) over the range of 0.5-10 MUM. In addition, there was no obvious interference of other common metal ions for the detection, indicating that this method presented outstanding selectivity. And it was also used for qualitative and semi-quantitative determination of Pb2+ in soil sample successfully. PMID- 29247913 TI - Polycation-telodendrimer nanocomplexes for intracellular protein delivery. AB - Intracellular delivery of protein therapeutics by cationic polymer vehicles is an emerging technique that is, however, encountering poor stability, high cytotoxicity and non-specific cell uptake. Herein, we present a facile strategy to optimize the protein-polycation complexes by encapsulating with linear dendritic telodendrimers. The telodendrimers with well-defined structures enable the rational design and integration of multiple functionalities for efficient encapsulation of the protein-polycation complexes by multivalent and hybrid supramolecular interactions to produce sub-20 nm nanoparticles. This strategy not only reduces the polycation-associated cytotoxicity and hemolytic activity, but also eliminates the aggregation and non-specific binding of polycations to other biomacromolecules. Moreover, the telodendrimers dissociate readily from the complexes during the cellular uptake process, which restores the capability of polycations for intracellular protein delivery. This strategy overcomes the limitations of polycationic vectors for intracellular delivery of protein therapeutics. PMID- 29247916 TI - Studies on influence of process parameters on simultaneous biodegradation of atrazine and nutrients in aquatic environments by a membrane photobioreactor. AB - A Lab scale algal-bacterial membrane photobioreactor (MPBR) was designed and operated under 12-h light and 12-h dark conditions with a light intensity of 8000lx, in order to investigate the effects of initial concentrations of atrazine, carbon concentration, and hydraulic retention time on the ability of this photobioreactor in simultaneous removal of atrazine and nutrients in the continuous mode. The removal efficiencies of atrazine (ATZ), chemical oxygen demand (COD), phosphorus (PO43--P) and nitrogen (NOx) in optimum condition was more than 95%, 99%, 98% and 97% when the maximum removal rates were 9.5 * 10-3, 99.231, 11.773 and 7.762mg/L-day, respectively. Results showed that the quality of the effluent was reduced by the increase of atrazine concentration. The outcomes on the hydraulic and toxic shocks indicated that the system has a relatively good resistance to the shocks and can return to the stable conditions. Microalgae showed a great deal of interest and capability in cultivating and attaching to the surface of the membrane and bioreactor, and the total biomass accumulated in the system was greater than 6g/L. The kinetic coefficients of atrazine removal were also studied using various kinetic models. The maximum atrazine removal rate was determined by the modified Stover-Kincannon model. The results approved the ability of the MPBR reactor in wastewater treatment and microalgae cultivation and growth. The decline of atrazine concentration in this system could be attributed to the algal-bacterial symbiosis and co-metabolism process. Accordingly, the MPBR reactor is a practical, simple, economical and therefore suitable process for simultaneous biodegradation of chlorinated organic compounds and nutrients removal from aquatic environments. PMID- 29247915 TI - Uncovering neurodevelopmental windows of susceptibility to manganese exposure using dentine microspatial analyses. AB - BACKGROUND: Associations between manganese (Mn) and neurodevelopment may depend on dose and exposure timing, but most studies cannot measure exposure variability over time well. OBJECTIVE: We apply temporally informative tooth-matrix biomarkers to uncover windows of susceptibility in early life when Mn is associated with visual motor ability in childhood. We also explore effect modification by lead (Pb) and child sex. METHODS: Participants were drawn from the ELEMENT (Early Life Exposures in MExico and NeuroToxicology) longitudinal birth cohort studies. We reconstructed dose and timing of prenatal and early postnatal Mn and Pb exposures for 138 children by analyzing deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. Neurodevelopment was assessed between 6 and 16 years of age using the Wide Range Assessment of Visual Motor Abilities (WRAVMA). Mn associations with total WRAVMA scores and subscales were estimated with multivariable generalized additive mixed models. We examined Mn interactions with Pb and child sex in stratified models. RESULTS: Levels of dentine Mn were highest in the second trimester and declined steeply over the prenatal period, with a slower rate of decline after birth. Mn was positively associated with visual spatial and total WRAVMA scores in the second trimester, among children with lower (< median) tooth Pb levels: one standard deviation (SD) increase in ln-transformed dentine Mn at 150 days before birth was associated with a 0.15 [95% CI: 0.04, 0.26] SD increase in total score. This positive association was not observed at high Pb levels. In contrast to the prenatal period, significant negative associations were found in the postnatal period from ~ 6 to 12 months of age, among boys only: one SD increase in ln-transformed dentine Mn was associated with a 0.11 [95% CI: - 0.001, - 0.22] to 0.16 [95% CI: 0.04, - 0.28] SD decrease in visual spatial score. CONCLUSIONS: Using tooth matrix biomarkers with fine scale temporal profiles of exposure, we found discrete developmental windows in which Mn was associated with visual-spatial abilities. Our results suggest that Mn associations are driven in large part by exposure timing, with beneficial effects found for prenatal levels and toxic effects found for postnatal levels. PMID- 29247917 TI - Evaluation of TeO2 content on the optical and spectroscopic properties of Yb3+ doped calcium borotellurite glasses. AB - This paper reports the synthesis and the characterization of Yb3+-doped calcium borotellurite (CaBTeX) glasses with composition 10CaF2-(29.5-0.4x)CaO-(60 0.6x)B2O3-xTeO2-0.5Yb2O3 (x=10, 16, 22, 31 and 54mol%). The results of XRD confirm the amorphous character of all the samples. The density, molar volume, refractive index and electronic polarizability values show an increase with TeO2 content. Otherwise, the optical band gap energy shows a decrease with the increase of TeO2 content. The replacement of CaO and B2O3 by TeO2 changes the glass structure, which decreases the excited Yb3+/cm3 and, consequently, the luminescence intensity. The temperature dependence of luminescence was studied for all the samples up to 420K. The fluorescence lifetime does not change significantly due to TeO2 addition. In addition, absorption and emission cross section were calculated and present high values as compared to other tellurite and phosphate glasses. PMID- 29247918 TI - Time-resolved laser fluorescence spectroscopy of organic ligands by europium: Fluorescence quenching and lifetime properties. AB - Time-resolved Laser Fluorescence Spectroscopy (TRLFS) has proved its usefulness in the fields of biophysics, life science and geochemistry to characterize the fluorescence probe molecule with its chemical environment. The purpose of this study is to demonstrate the applicability of this powerful technique combined with Steady-State (S-S) measurements. A multi-mode factor analysis, in particular CP/PARAFAC, was used to analyze the interaction between Europium (Eu) and Humic substances (HSs) extracted from Saint Lawrence Estuary in Canada. The Saint Lawrence system is a semi-enclosed water stream with connections to the Atlantic Ocean and is an excellent natural laboratory. CP/PARAFAC applied to fluorescence S-S data allows introspecting ligands-metal interactions and the one-site 1:1 modeling gives information about the stability constants. From the spectral signatures and decay lifetimes data given by TRLFS, one can deduce the fluorescence quenching which modifies the fluorescence and discuss its mechanisms. Results indicated a relatively strong binding ability between europium and humic substances samples (LogK value varies from 3.38 to 5.08 at pH 7.00). Using the Stern-Volmer plot, it has been concluded that static and dynamic quenching takes places in the case of salicylic acid and europium interaction while for HSs interaction only a static quenching is observed. PMID- 29247919 TI - Two sugar-rhodamine "turn-on" fluorescent probes for the selective detection of Fe3. AB - Two new sugar-rhodamine fluorescent probes (RDG1 and RDG2) have been synthesized and characterized by 1H NMR, 13C NMR and HRMS. Their UV-Vis, fluorescence spectra and fluorescence-response to Fe3+ are investigated and discussed. RDG1 had a very nice linear relationship between UV absorbance and Fe3+ concentration with the correlation coefficient as high as 0.997 and the detection limit is 3.46*10-6M. Upon the addition of Fe3+, the spirolactam ring of RDG1 was opened and a 1:1 metal ligand complex was formed from Job's plot. The results showed that RDG1 can be used as an effective fluorescent probe for selective detection of Fe3+ in water. RDG2 was incorporated the well-known rhodamine group and a water-soluble d glucose group within one molecule and can be used for detecting Fe3+ in natural water as a selective fluorescent sensor. The addition of Fe3+ into RDG2 resulted in a strongly enhanced fluorescence as well as color change of solution from colorless to pink. Job's plot of RDG2 indicated 1:1 stoichiometry of RDG2-Fe3+. RDG2 can serve as a probe for Fe3+ between pH=4.0 to 7.0 and it's detection limit is 2.09*10-6M. The OFF-ON fluorescent mechanisms of RDG1-Fe3+ and RDG2-Fe3+ are proposed. PMID- 29247920 TI - Aggregation and metal-complexation behaviour of THPP porphyrin in ethanol/water solutions as function of pH. AB - The effect of pH change on 5,10,15,20-Tetrakis(4-hydroxyphenyl)-21H,23H-porphine (THPP) with its aggregation as function of water-ethanol mixture was studied with UV-vis, fluorescence, Raman and computational analysis. In neutral pH, THPP was present as free-base and, increasing the water amount, aggregation occurred with the formation of H- and J-aggregates. The aggregation constant and the concentration of dimers were calculated, other information about the dimer aggregation were evaluated by computational study. In acidic pH, by the insertions of two hydrogens in the porphyrin rings, the porphyrin changed its geometry with a ring deformation confirmed by red-shifted spectrum and quenching in fluorescence; at this low pH, increasing the water amount, the acidic form (THPPH2)2+ resulted more stable due to a polar environment with stronger interaction by hydrogen bonding. In basic pH, reached by NH4OH, THPP porphyrin was able to react with alkali metals in order to form sitting-atop complex (M2THPP) confirmed by the typical absorption spectrum of metallo-porphyrin, Raman spectroscopy and by computational analysis. PMID- 29247921 TI - Oral health-related quality of life in Brazilian child abuse victims: A comparative study. AB - This study aims to assess and compare Oral Health-Related Quality of Life (OHRQoL) in child abuse victims and non-abused children in a Southern Brazilian city. The study compared two independent samples of children aged 8-10 years: 48 child abuse victims recruited from a centre for Child and Adolescent Psychological Support (NACA) for abused children, and 144 public and private school students. Data collection consisted of administration of the Child Perceptions Questionnaire 8-10 (CPQ8-10) to measure OHRQoL (dependent variable), clinical examination (dental caries), and collection of socioeconomic and demographic information (age, sex, skin colour, family income, and type of school). Multiple linear regression models were used to assess the association between presence of abuse and OHRQoL and subscales. After adjustment for clinical and sociodemographic variables, child abuse victims were found to exhibit higher CPQ scores on the overall scale and on the oral symptoms and functional limitations subscales. In conclusion, child abuse victims have a higher impact on OHRQoL. Based on the results, it is possible to suggest that greater care should be taken of these children, not only in providing treatment for oral disorders, but also in providing interdisciplinary care. PMID- 29247922 TI - Analysis of meat quality traits and gene expression profiling of pigs divergent in residual feed intake. AB - Residual feed intake (RFI), the difference between actual feed intake and predicted feed requirements, is suggested to impact various aspects of meat quality. The objective of this study was to investigate the molecular mechanisms underpinning the relationship between RFI and meat quality. Technological, sensory and nutritional analysis as well as transcriptome profiling were carried out in Longissimus thoracis et lumborum muscle of pigs divergent in RFI (n=20). Significant differences in sensory profile and texture suggest a minor impairment of meat quality in more efficient pigs. Low RFI animals had leaner carcasses, greater muscle content and altered fatty acid profiles compared to high RFI animals. Accordingly, differentially expressed genes were enriched in muscle growth and lipid & connective tissue metabolism. Differences in protein synthesis and degradation suggest a greater turnover of low RFI muscle, while divergence in connective tissue adhesion may impact tenderness. Fatty acid oxidation tending towards decrease could possibly contribute to reduced mitochondrial activity in low RFI muscle. PMID- 29247923 TI - Distinct pathological profiles of inmates showcasing cluster B personality traits, mental disorders and substance use regarding violent behaviors. AB - High rates of violence are found amid offenders with severe mental illnesses (SMI), substance use disorders (SUDs) and Cluster B personality disorders. Elevated rates of comorbidity lead to inconsistencies when it comes to this relationship. Furthermore, overlapping Cluster B personality traits have been associated with violence. Using multiple correspondence analysis and cluster analysis, this study was designed to differentiate profiles of 728 male inmates from penitentiary and psychiatric settings marked by personality traits, SMI and SUDs following different violent patterns. Six significantly differing clusters emerged. Cluster 1, "Sensation seekers", presented recklessness with SUDs and low prevalence's of SMI and auto-aggression. Two clusters committed more sexual offenses. While Cluster 2, "Opportunistic-sexual offenders", had more antisocial lifestyles and SUDs, Cluster 6, "Emotional-sexual offenders", displayed more emotional disturbances with SMI and violence. Clusters 3 and 4, representing "Life-course-persistent offenders", shared early signs of persistent antisocial conduct and severe violence. Cluster 3, "Early-onset violent delinquents", emerged as more severely antisocial with SUDs. Cluster 4, "Early-onset unstable mentally ill delinquents", were more emotionally driven, with SMI and auto aggression. Cluster 5, "Late-start offenders", was less severely violent, and emotionally driven with antisocial behavior beginning later. This study suggests the presence of specific psychopathological organizations in violent inmates. PMID- 29247924 TI - The role of emotion dysregulation: A longitudinal investigation of the interpersonal theory of suicide. AB - Emotion dysregulation is considered to be transdiagnostic in nature, given its association with a variety of problem behaviors. Of concern, emotion dysregulation also may be associated with key components of the Interpersonal Theory of Suicide (ITS), namely suicidal desire and acquired capability for suicide (ACS; heightened fearlessness toward death and pain tolerance). ITS suggests that experiencing suicidal desire in conjunction with ACS leads to greater risk for suicide attempts. The present 4-wave longitudinal study tested bidirectional associations among emotion dysregulation, NSSI, ACS, and suicidal desire. Emotion dysregulation was associated with both desire and capability for suicide over time. Specifically, emotion dysregulation was associated with (1) higher levels of suicidal desire, (2) higher levels of NSSI, which in turn predicted higher ACS, and (3) lower ACS, suggesting that individuals with emotion dysregulation may find thoughts of death and pain more aversive. Thus, there are two separate paths for how emotion regulation leads to ACS, one path in which emotion dysregulation indirectly leads to ACS through NSSI, and one path in which emotion dysregulation protects against the development of ACS (note that higher levels of ACS alone are not sufficient to lead to a suicide attempt - suicidal desire also is required). PMID- 29247925 TI - Comparison of various methods to analyse toxic effects in human skin explants: Rediscovery of TTC assay. AB - Skin explants are a suitable model which can replace dermatological experiments on animals or human volunteers. In this study, we searched for a fast, cheap and reproducible method for screening skin explant viability after treatment with UVA radiation or/and chemical agents. We compared frequently used methods: 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), neutral red (NR) and lactate dehydrogenase (LDH) activity assay with a rarely used 2,3,5-triphenyl-2H tetrazolium chloride (TTC) assay for the evaluation of UVA radiation and/or chlorpromazine and 8-methoxypsoralen effect as model agents. Histological analysis of skin explants was also performed by a simple haematoxylin-eosin method. Only the TTC assay was able to show the toxicity of model agents in a dose- and concentration-dependent manner. LDH assay was partially able to demonstrate results comparable to the TTC method, however, the agents' effect was less pronounced. The MTT and NR assays completely failed in the evaluation. Haematoxylin-eosin staining showed discrete structural changes in samples treated with UVA alone and CPZ+UVA, but only after 48h. Therefore, the method is not useful for screening of toxic or phototoxic effects either. In conclusion, the TTC assay was the most suitable for the evaluation of toxicity or phototoxicity in ex vivo skin. PMID- 29247926 TI - Non-invasive quantification of foliar pigments: Possibilities and limitations of reflectance- and absorbance-based approaches. AB - Established reflectance-based approaches for estimation of foliar pigment contents assume close relationship between leaf absorbance and reflectance. Complex organization and high pigment content of leaves may lead to violation of the essential assumptions under Kubleka-Munk theory relating reflectance and absorbance. We compared relationships of absorbance and reciprocal reflectance vs. pigment content in leaves collected across species, developmental stages and physiological states. As a result, limitations of reflectance-based spectroscopy for pigment quantification were revealed. We deduced in situ absorbance of foliar chlorophylls, carotenoids, and flavonoids (including red-colored anthocyanins) and introduced a concept of specific spectral response of the optical properties to each pigment group. Quantitative criteria of spectral range selection for the absorbance- and reflectance-based techniques yielding effect of each pigment on the background of other pigment absorption were suggested and validated. We argue that absorbance- and reflectance-based approaches to pigment estimation complement each other and can be used synergistically in advanced models for accurate estimating foliar pigments. The study provides a deeper insight into interception of light by photosynthetic and photoprotective pigments as function of physiological condition and developmental stage, which is important for plant biology as well as knowledge-driven selection of spectral bands for noninvasive pigment estimation models. PMID- 29247927 TI - Comparison of salting-out and sugaring-out liquid-liquid extraction methods for the partition of 10-hydroxy-2-decenoic acid in royal jelly and their co-extracted protein content. AB - Homogeneous liquid-liquid extraction (h-LLE) has been receiving considerable attention as a sample preparation method due to its simple and fast partition of compounds with a wide range of polarities. To better understand the differences between the two h-LLE extraction approaches, salting-out assisted liquid-liquid extraction (SALLE) and sugaring-out assisted liquid-liquid extraction (SULLE), have been compared for the partition of 10-hydroxy-2-decenoic acid (10-HDA) from royal jelly, and for the co-extraction of proteins. Effects of the amount of phase partition agents and the concentration of acetonitrile (ACN) on the h-LLE were discussed. Results showed that partition efficiency of 10-HDA depends on the phase ratio in both SALLE and SULLE. Though the partition triggered by NaCl and glucose is less efficient than MgSO4 in the 50% (v/v) ACN-water mixture, their extraction yields can be improved to be similar with that in MgSO4 SALLE by increasing the initial concentration of ACN in the ACN-water mixture. The content of co-extracted protein was correlated with water concentration in the obtained upper phase. MgSO4 showed the largest protein co-extraction at the low concentration of salt. Glucose exhibited a large protein co-extraction in the high phase ratio condition. Furthermore, NaCl with high initial ACN concentration is recommended because it produced high extraction yield for 10-HDA and the lowest amount of co-extracted protein. These observations would be valuable for the sample preparation of royal jelly. PMID- 29247928 TI - A review of bioinformatic methods for forensic DNA analyses. AB - Short tandem repeats, single nucleotide polymorphisms, and whole mitochondrial analyses are three classes of markers which will play an important role in the future of forensic DNA typing. The arrival of massively parallel sequencing platforms in forensic science reveals new information such as insights into the complexity and variability of the markers that were previously unseen, along with amounts of data too immense for analyses by manual means. Along with the sequencing chemistries employed, bioinformatic methods are required to process and interpret this new and extensive data. As more is learnt about the use of these new technologies for forensic applications, development and standardization of efficient, favourable tools for each stage of data processing is being carried out, and faster, more accurate methods that improve on the original approaches have been developed. As forensic laboratories search for the optimal pipeline of tools, sequencer manufacturers have incorporated pipelines into sequencer software to make analyses convenient. This review explores the current state of bioinformatic methods and tools used for the analyses of forensic markers sequenced on the massively parallel sequencing (MPS) platforms currently most widely used. PMID- 29247929 TI - Role of dissolved oxygen on the degradation mechanism of Reactive Green 19 and electricity generation in photocatalytic fuel cell. AB - In this study, a membraneless photocatalytic fuel cell with zinc oxide loaded carbon photoanode and platinum loaded carbon cathode was constructed to investigate the impact of dissolved oxygen on the mechanism of dye degradation and electricity generation of photocatalytic fuel cell. The photocatalytic fuel cell with high and low aeration rate, no aeration and nitrogen purged were investigated, respectively. The degradation rate of diazo dye Reactive Green 19 and the electricity generation was enhanced in photocatalytic fuel cell with higher dissolved oxygen concentration. However, the photocatalytic fuel cell was still able to perform 37% of decolorization in a slow rate (k = 0.033 h-1) under extremely low dissolved oxygen concentration (approximately 0.2 mg L-1) when nitrogen gas was introduced into the fuel cell throughout the 8 h. However, the change of the UV-Vis spectrum indicates that the intermediates of the dye could not be mineralized under insufficient dissolved oxygen level. In the aspect of electricity generation, the maximum short circuit current (0.0041 mA cm-2) and power density (0.00028 mW cm-2) of the air purged photocatalytic fuel cell was obviously higher than that with nitrogen purging (0.0015 mA cm-2 and 0.00008 mW cm-2). PMID- 29247930 TI - Variability of biological indices, biomarkers, and organochlorine contaminants in flounder (Platichthys flesus) in the Gulf of Gdansk, southern Baltic Sea. AB - Biological indices, biomarkers (EROD activity, DNA SB, 1-OH pyrene), and organochlorine contaminants were investigated in flounder collected in the Gulf of Gdansk during March-December 2011 to describe their seasonal variability and interrelations. Univariate and multivariate statistics were used to evaluate the relations. The EROD activity positively correlated with DNA SB, both negatively correlated with CF, GSI, and HSI, and there was a moderate positive correlation for EROD and DNA SB with 1-OH pyrene. EROD highest activity corresponded to a resting stage of gonad development. DNA SB, highest during spawning, gradually decreased until late autumn. The PCBs, DDTs, HCB, HCHs, dieldrin, and heptachlor levels in muscle tissue were quantified on a wet and lipid basis. In each case, their levels decreased after spawning, fluctuated over the study period indicating that their accumulation was pronouncedly controlled by chemical specific properties, their levels in prey, and lipid dynamics. PMID- 29247931 TI - Contact with a glyphosate-based herbicide has long-term effects on the activity and foraging of an agrobiont wolf spider. AB - Animals that live in conventional agroecosystems must cope with a variety of anthropogenic chemicals. Most of the focus of toxicology is on lethality, deformities, or short-term shifts in behavior. However, for animals that succeed in spite of their exposure, it is important to determine if long-term changes are brought on by their experience. We tested the hypothesis that contact with a commercial formulation of a glyphosate-based herbicide would affect the behavior of subsequent instars in the wolf spider, Pardosa milvina, a species that thrives in the agroecosystems of eastern United States. In one experiment, we housed females carrying egg sacs on a surface treated with the herbicide for 7 h. Then we monitored their activity and foraging of the offspring 4 weeks after emergence. We repeated the same tests on adults that had been housed with herbicide during their penultimate stage. In both studies, exposed spiders displayed higher levels of activity and greater capture success than their unexposed counterparts. Exposure of penultimate instar to herbicide had larger effects on the behavior of adult males than adult females. These results suggest that herbicides have the potential to adjust the behavior of individuals in the predator community. Thus, impact on the food web and their positive or negative potential for biological control may extend beyond their role in controlling weeds. PMID- 29247932 TI - Phytoremediation potential of poplar and willow species in small scale constructed wetland for boron removal. AB - Boron (B) pollution is an expanding environmental problem throughout the world due to intensive mining practices and extensive usage of B in agricultural chemicals and industrial products in recent years. The purpose of this study was to investigate B removal performance of four poplar and four willow species in small scale Constructed Wetland (CW). Rooted cuttings of tested species were treated with simulated wastewater having five elevated B concentrations (0.5, 5, 10, 20 and 40 ppm). All the tested species could resist up to 20 ppm wastewater B supply and could regrow from their roots in the soil having maximum 15 mg/kg B content. The result of the study indicated that 65% +/- 5.3 of B was removed from the wastewater in 5 ppm B treatment while the same efficiency decreased to 45% +/ 4.6 at 40 ppm B supply. The average effect of sediment on B removal was found to be approximately 20% for all B treatments while the remaining part of the loaded B was removed from the CW within effluent (35-54%). Therefore, actual effects of plant species on B removal was ranged from 45% to 25% between 5 and 40 ppm B treatments. Mass B removal within plant body (phytextraction) comprised the 13 10% of total loaded B in CW while the remaining part of the loaded B (31-15%) was stabilized into the sediment with the effects of poplar and willow roots. These results presented clear understanding of effective B purification mechanisms in CWs. Boron phytextraction capacity of a plant species was less effective than its phytstabilization efficiency which increase filtering capacity of the sediment and stabilization of more B around the rhizosphere. In terms of their B removal ability, P.nigra and S.anatolica had the highest B removal capacities with phytextraction (20-11%) while S.alba, P.alba and S.babylonica had more phytstabilizaiton performance (40-15%) in CW. Disposal of B loaded plant material create another environmental costs for CW applications. Therefore, B loaded wood and leaf tissues were mixed and used for production of wooden panels in the study. Then a combustion test was applied on these panels to test their fire resistance. The results of the tests revealed much higher burning tolerance of the B loaded panels (5-20%) compared to controls. Annual harvesting, fast growing and deep rooting ability of the poplar and willow species with their high phytstabilization and phytextraction efficiencies make these species excellent tools to remove B from the polluted waters. Utilization of these species for B removal in large scale CWs is quite possible which should be also investigated in further studies. PMID- 29247933 TI - Remediation of Arsenic contaminated soil using malposed intercropping of Pteris vittata L. and maize. AB - Intercropping of arsenic (As) hyperaccumulator and cash crops during remediation of contaminated soil has been applied in farmland remediation project. However, little is known about the fate of As fractions in the soil profile and As uptake within the intercropping plants under field condition. In this study, As removal, uptake, and translocation were investigated within an intercropping system of Pteris vittata L. (P. vittata) and maize (Zea mays). Results indicated that the concentration of As associated with amorphous Fe (hydr)oxides in the 10-20 cm soil layer was significantly lower under malposed intercropping of P. vittata and maize, and As accumulation in P. vittata and biomass of P. vittata were simultaneously higher under malposed intercropping than under coordinate intercropping, leading to a 2.4 times higher rate of As removal. Although maize roots absorbed over 13.4 mg kg-1 As and maize leaves and flowers accumulated over 21.5 mg kg-1 As (translocation factor higher than 1), grains produced in all intercropping modes accumulated lower levels of As, satisfying the standard for human consumption. Our results suggested that malposed intercropping of a hyperaccumulator and a low-accumulation cash crop was an ideal planting pattern for As remediation in soil. Furthermore, timely harvest of P. vittata, agronomic strategies during remediation, and appropriate management of the above ground parts of P. vittata and high-As tissues of cash crops may further improve remediation efficiency. PMID- 29247934 TI - Comparison of gene expression profiles in the aquatic midge (Chironomus tentans) larvae exposed to two major agricultural pesticides. AB - We developed a high-resolution expression microarray based on 2456 unique transcripts from a cDNA library of the aquatic midge (Chironomus tentans). By using the microarray, we detected that 146, 434 and 243 genes were differentially expressed after C. tentans larvae were exposed to chlorpyrifos (organophosphate insecticide) at 0.1 and 0.5 MUg/L, and atrazine (triazine herbicide) at 1000 MUg/L, respectively, for 48 h. The number of differentially expressed genes in the larvae exposed to chlorpyrifos at 0.5 MUg/L was three times of that in the larvae exposed to chlorpyrifos at 0.1 MUg/L. Among the differentially expressed genes in response to chlorpyrifos exposures, 76 genes showed significant Blast hits, and among them 42 were in common between the chlorpyrifos and atrazine exposures. In 19 differentially expressed xenobiotic detoxification genes, 16 were significantly up-regulated in the larvae exposed to chlorpyrifos and/or atrazine. Two cytochrome P450 genes (CtCYP6EV1 and CtCYP4DG2) were specifically up-regulated by chlorpyrifos, whereas three cytochrome P450 genes (CtCYP4DG1, CtCYP6EX3 and CtCYP6EV3) were specifically up-regulated by atrazine. Our results showed that chlorpyrifos exposures even at low concentrations can lead to significant changes in gene expression. The significant transcriptional responses are likely attributed to larval intoxication by the insecticide. These results not only support our previous studies in which candidate gene approaches were used, but also can potentially help develop specific molecular markers for monitoring pesticide exposures in non-target organisms in aquatic systems. PMID- 29247935 TI - Provenance, prevalence and health perspective of co-occurrences of arsenic, fluoride and uranium in the aquifers of the Brahmaputra River floodplain. AB - The present work focuses on understanding the provenance, prevalence and health perspective of As and F- along with possible co-occurrence of uranium (U) in the aquifers of the Brahmaputra floodplains (BFP), India. Groundwater (n = 164) and sediment samples (n = 5) were obtained from the upper, middle and lower BFP. Energy dispersive spectroscopy (EDX) revealed the presence of As, U and Fe in the sediment matrix. Regression analysis showed a weaker relationship between As and F- co-occurrence. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) suggested reductive dissolution of Fe (hydr)oxides responsible for As release in the BFP, especially in the upper and lower BFP. Bicarbonate appeared to compete with As oxyanions for adsorption on positively charged surfaces leading to As release. Arsenic desorption in presence of PO43-, F- and HCO3- at elevated pH appeared greatest in the upper BFP, suggesting the highest potential for co-occurrence. Co-occurrence, were mainly in isolated aquifers of the upper BFP owing to desorption of adsorbed As and F- from Fe (hydr)oxides at higher pH. Weathering and dissolution of clay minerals in the upper BFP, and competitive desorption in presence of HCO3- and PO43- in the middle and lower BFP, respectively, explain variabilities in F- release. Amorphous Fe (hydr)oxides like ferrihydrite act as sinks of U. Concentrations of As and F- will likely increase in the future as projected from the saturated levels of goethite and ferrihydrite. Hazard indices (HI) revealed that children (3-8 years) were at greater health risk than adults. PMID- 29247936 TI - Primary carbon metabolism-related changes in cucumber exposed to single and sequential treatments with salt stress and bacterial infection. AB - This study examines how salt stress interacts with bacterial infection at the metabolic level. We measured chlorophyll a fluorescence as well as profiles of phosphoenolpyruvate carboxylase (PEPC), NADP-malic enzyme (NADP-ME), NADP isocitrate dehydrogenase (NADP-ICDH) and fumarase activities, malic and citric acids contents and the expression of NADP-ICDH and NADP-ME in the organ-dependent (root vs leaves) response of cucumber plants exposed to individual or sequential action of salt stress (50 mM or 100 mM NaCl) and Pseudomonas syringae pv lachrymans (Psl). NaCl treatment, Psl infection and the combination of these stresses caused disturbances in the activity of photosystem II which were suggested to specifically transmit the stress signals. PEPC and NADP-ME were induced in cucumber plants under stress, confirming that in C3 plants they function in defence responses. The profiles of malate and citrate contents, PEPC as well as NADP-ICDH and NADP-ME activities and gene expression in response to a combination of salt and pathogen stresses differed from those provoked by individual stress with respect to the direction, intensity and timing. The results indicated that the most pronounced defence response related to the readjustment of the carbon metabolism was observed in the leaves of plants exposed to combined stress. Intense activity changes of NADPH-generating enzymes, NADP-ICDH and NADP-ME, characterized the tailored response to combined stress and could be important for the integration of defence mechanisms between organs. PMID- 29247937 TI - Eucalypt plants are physiologically and metabolically affected by infection with Ceratocystis fimbriata. AB - Ceratocystis wilt, caused by Ceratocystis fimbriata, is currently one of the most important disease in eucalypt plantations. Plants infected by C. fimbriata have lower volumetric growth, lower pulp yields and reduced timber values. The physiological bases of infection induced by this pathogen in eucalypt plant are not known. Therefore, this study aims to assess the physiological and metabolic changes in eucalypt clones that are resistant and susceptible to C. fimbriata. Once, we evaluated in detail their leaf gas exchange, chlorophyll a fluorescence, water potential, metabolite profiling and growth-related parameters. When inoculated, the susceptible clone displayed reduced water potential, CO2 assimilation rate, stomatal conductance, transpiration rate, photochemical quenching coefficient, electron transport rate, and root biomass. Inoculated resistant and susceptible clones both presented higher respiration rates than healthy plants. Many compounds of primary and secondary metabolism were significantly altered after fungal infection in both clones. These results suggest that, C. fimbriata interferes in the primary and secondary metabolism of plants that may be linked to the induction of defense mechanisms and that, due to water restrictions caused by the fungus in susceptible plants, there is a partial closure of the stomata to prevent water loss and a consequent reduction in photosynthesis and the transpiration rate, which in turn, leads to a decrease in the plant's growth-related. These results combined, allowed for a better understanding of the physiological and metabolic changes following the infectious process of C. fimbriata, which limit eucalypt plant growth. PMID- 29247938 TI - Physiological and antioxidant responses of the sabkha biotope halophyte Limonium delicatulum to seasonal changes in environmental conditions. AB - In saline biotopes, different mechanisms may contribute to the tolerance of halophytes to high soil salinity and temperature, drought and other abiotic stresses, but their relative responses and their ecological plasticity for a given species remain unknown. In this study, we examined the responses of the salt marsh halophyte Limonium delicatulum to changing environmental conditions of its natural habitats (Sabkha "El Kalbia", Tunisia). The specific aim of the work was to check whether statistically significant correlations could be established between particular stress response mechanisms (ion uptake, activation of antioxidant systems) and soil parameters and climatic data associated with environmental stress. The results showed that the salinity of the soil increased during the months of June, July and August (dry period), concomitantly with a strong accumulation of salt ions in the aerial parts of the plant. Moreover, the highest antioxidant capacity of this halophyte (enzymes and antioxidant molecules) was reached during the same period of the year. The remaining periods (corresponding to the rainy season) did not show a significant difference in enzymes activities and level of antioxidants, with a minimum observed in the months of January and February. These results show a remarkable effect of salinity in the natural habitat on the activity of enzymes and antioxidant molecules. Other edaphic and climatic factors could also be involved to increase antioxidant capacity, such as nutrient deficiency, temperature and precipitation. PMID- 29247939 TI - Opportunistic disease in yellow perch in response to decadal changes in the chemistry of oil sands-affected waters. AB - Oil sands-affected water from mining must eventually be incorporated into the reclaimed landscape or treated and released. However, this material contains petrogenic organic compounds, such as naphthenic acids and traces of polycyclic aromatic hydrocarbons. This has raised concerns for impacts of oil sands process affected waters on the heath of wildlife and humans downstream of receiving environments. The objective of this study was to evaluate the temporal association of disease states in fish with water chemistry of oil sands-affected waters over more than a decade and determine the pathogens associated with disease pathologies. Yellow perch (Perca flavescens) captured from nearby lakes were stocked into two experimental ponds during 1995-1997 and 2008-2010. South Bison Pond is a drainage basin that has received unextracted oil sands contaminated material. Demonstration Pond is a constructed pond containing mature fine tailings capped with fresh water. Two disease pathologies, fin erosion for which a suspected bacterial pathogen (Acinetobacter Iwoffi) is identified, and lymphocystis (confirmed using a real-time PCR) were associated with oil sands affected water exposure. From 1995 to 1997 pathologies were most prevalent in the South Bison Pond; however, from 2008 to 2009, disease was more frequently observed in the Demonstration Pond. CYP1A activity was 3-16 fold higher in fish from experimental ponds as compared to reference populations and this pattern was consistent across all sampling years. Bile fluorescence displayed a gradient of exposure with experimental ponds being elevated over local perch populations. Naphthenic acids decreased in the Bison Pond from approximately 12 mg/L to <4 mg/L while naphthenic acids increased in the Demonstration Pond from 6 mg/L to 12 mg/L due to tailings densification. Temporal changes in naphthenic acid levels, CYP1A activity and bile fluorescent metabolites correlate positively with incidence of disease pathologies whereas all inorganic water quality changes (major ions, pH, metals) were not associated with disease responses. PMID- 29247940 TI - Cyanotoxins as the "common suspects" for the Dalmatian pelican (Pelecanus crispus) deaths in a Mediterranean reconstructed reservoir. AB - Toxic cyanobacterial blooms have been implicated for their negative consequences on many terrestrial and aquatic organisms. Water birds belong to the most common members of the freshwater food chains and are most likely to be affected by the consumption of toxic cyanobacteria as food. However, the contribution of cyanotoxins in bird mortalities is under-studied. The aim of the study was to investigate the likely role of cyanotoxins in a mass mortality event of the Dalmatian pelican (Pelecanus crispus) in the Karla Reservoir, in Greece. Water, scum, tissues and stomach content of dead birds were examined for the presence of microcystins, cylindrospermopsins and saxitoxins by an enzyme-linked immunosorbent assay. High abundances of potential toxic cyanobacterial species and significant concentrations of cyanotoxins were recorded in the reservoir water. All examined tissues and stomach content of the Dalmatian pelicans contained significant concentrations of microcystins and saxitoxins. Cylindrospermopsin concentrations were detected in all tissues except from the brain. Our results suggest that cyanotoxins are a plausible cause for this bird mass mortality episode in the Karla Reservoir. PMID- 29247941 TI - Transgenic Bt cotton expressing Cry1Ac/Cry2Ab or Cry1Ac/EPSPS does not affect the plant bug Adelphocoris suturalis or the pollinating beetle Haptoncus luteolus. AB - The widespread cultivation of transgenic Bt cotton makes assessing the potential effects of this recombinant crop on non-target organisms a priority. However, the effect of Bt cotton on many insects is currently virtually unknown. The plant bug Adelphocoris suturalis is now a major pest of cotton in southern China and the beetle Haptoncus luteolus is one of the most ancient cotton pollinators. We conducted laboratory experiments to evaluate the toxicity of the Bt cotton varieties ZMSJ, which expresses the toxins Cry1Ac and Cry2Ab, and ZMKCKC, which expresses Cry1Ac and EPSPS, on adult A. suturalis and H. luteolus. No significant increase in the mortality of either species was detected after feeding on Bt cotton leaves or pollen for 7 days. Trace amounts of Cry1Ac and Cry2Ab proteins could be detected in both species but in vitro binding experiments found no evidence of Cry1Ac and Cry2Ab binding proteins. These results demonstrate that feeding on the leaves or pollen of these two Bt cotton varieties has no toxic effects on adult A. suturalis or H. luteolus. PMID- 29247942 TI - Spatiotemporal characterization and mapping of PM2.5 concentrations in southern Jiangsu Province, China. AB - As a result of rapid industrialization and urbanization, China is experiencing severe air pollution problems. Understanding the spatiotemporal variation and trends of air pollution is a key element of an improved understanding of the underlying physical mechanisms and the implementation of the most effective risk assessment and environmental policy in the region. The motivation behind the present work is that the study region of southern Jiangsu province of China is one of the most populated and developed regions in China. The daily concentrations of particulate matter with particle diameter smaller than 2.5 MUm (PM2.5) in southern Jiangsu province obtained during the year 2014 were used to derive the variogram model that provided a quantitative characterization of the spatiotemporal (ST) variation of PM2.5 concentrations in the study region. A spatiotemporal ordinary kriging (STOK) technique was subsequently employed to generate informative maps of the ST pollutant distribution in southern Jiangsu province. The results generated by STOK showed that during 2014 about 29.3% of the area was PM2.5 polluted (at various severity levels, according to the criteria established by the Chinese government), and that the number of days characterized as polluted varied from 59 to 164 at different parts of the study region. Nanjing, the capital of Jiangsu province, was the place with the highest PM2.5 pollution (including 3 days of serious pollution). The PM2.5 pollution exhibited a decreasing spatial trend from the western to the eastern part of southern Jiangsu. A similar temporal PM2.5 pattern was found from the western to the eastern part of southern Jiangsu, which was characterized by 4 peaks and 3 troughs linked to different meteorological conditions and human factors. PMID- 29247943 TI - Integration of behavioral tests and biochemical biomarkers of terrestrial isopod Porcellio scaber (Isopoda, Crustacea) is a promising methodology for testing environmental safety of chars. AB - We investigated how different carbonized materials, or chars (olive mill pomace biochar (BC) and urban greens pruning residues hydrochar (HC)) affect an important member of soil fauna, the terrestrial isopod Porcellio scaber. The selection behavior of isopods towards chars after a 48 h exposure was studied in (i) soil-char amended tests with single and multiple choices, and (ii) tests with chars offered as pure material. Finally, we exposed the isopods to char-amended soils for a period of 14 days to follow the effect on food consumption, body mass and activities of enzymes that are commonly altered upon stressor exposure (acetylcholinesterase, AChE, and glutathione S-transferase, GST). We showed that isopods are able to select between char amended and un-amended soil and different forms of char amendments: a clear preference for BC, and avoidance of HC were evidenced. The preferences remained the same when the chars were sterilized leading to the conclusion that initial microorganism composition was not the reason for selection, but selection was governed by other chars' physico-chemical properties. It remains to be elucidated which of these properties were the dominant reason for the selection. We also showed that isopods intentionally use BC as food at a similar rate to alder leaves. Medium-term exposure to HC resulted in adverse effects on isopods because it led to reduced feeding and growth, in addition to increasing GST activity, although no alterations in AChE activity were found. We suggest that behavioral tests with P. scaber could be used as a fast, reliable and economically feasible screening method for determining the safety of chars for the soil environment. Results represent significant contribution in the field of char toxicity testing, highlighting the importance of tests with isopods as important members of soil meso fauna, with the aim of influencing environmental policies and quality standards. PMID- 29247944 TI - Sorption mechanisms of neonicotinoids on biochars and the impact of deashing treatments on biochar structure and neonicotinoids sorption. AB - To elucidate the sorption affinity of biochars for neonicotinoid pesticides and the influence of biochar structure on sorption mechanisms therein, 24 biochar samples were obtained by pyrolyzing maize straw and pig manure at pyrolyzing temperatures (PTs) of 200-700 degrees C and by further deashing them using acids, and the sorption of three typical neonicotinoids, imidacloprid, clothianidin and thiacloprid on untreated and acid-deashed biochars were evaluated. All the biochar samples could efficiently adsorb the three neonicotinoids and multiple mechanisms were involved in sorption. With the increasing PTs, hydrophobic partition sorption increased, but had a declined contribution to the total sorption as revealed by a dual-mode model. Besides hydrophobic partition, specific interactions like cation-pi electron donor acceptor (EDA) interactions (only for protonated IMI and CLO) and hydrogen bond and contributed much to the sorption on low-PT (<=500 degrees C) biochars, while the sorption on those high-PT (>500 degrees C) biochars mainly depended on pore filling strengthened by cation-pi and p/pi-pi EDA interactions. Thiacloprid showed stronger sorption on untreated biochars compared to imidacloprid and clothianidin, due to its greater ability to form hydrogen bond and hydrophobic interactions. Acid-deashing treatments increased the relative percentage contents of organic carbon, bulk O, aromaticity and O-containing functional groups, surface area and pore volume of biochars. The ash can bind neonicotinoids by specific interactions but played a negative role in the whole sorption on high-PT biochars by covering the inner sorption sites of organic moieties and blocking the micropores in biochars. The results acquired in the present study will help us to get deep insight in the comprehensive sorption mechanisms of polar pesticides on biochar and the effects of biochar structure. PMID- 29247945 TI - Simultaneous determination of (N-ethyl perfluorooctanesulfonamido ethanol)-based phosphate diester and triester and their biotransformation to perfluorooctanesulfonate in freshwater sediments. AB - While (N-ethyl perfluorooctanesulfonamido ethanol)-based phosphates (SAmPAPs) have been proposed as a group of perfluorooctanesulfonate (PFOS) precursors, investigation of their occurrence and fate has been limited to SAmPAP diester. In this study, SAmPAP diester and triester were simultaneously determined in freshwater sediment from Taihu Lake using a newly developed UPLC-MS/MS method, and their biotransformation to PFOS in lake sediment was investigated. SAmPAP diester and triester were detected in sediments with a detection frequency of 56% and 88%, and their mean concentrations were 0.24 +/- 0.11 ng/g dry weight (dw) and 0.12 +/- 0.03 ng/g dw, respectively. The SAmPAP diester/triester ratio in sediment was 1.1 +/- 4.2, much lower than that (6.7) observed in the technical product, and the positive correlation was found between the concentrations of SAmPAP diester and PFOS in sediments (r2 = 0.45, p = 0.01), suggesting that SAmPAP diester would be biotransformed to PFOS in the lake sediment. The microbial degradation test in the lake sediments further clarified that SAmPAP diester was biodegraded to PFOS, but SAmPAP triester was highly recalcitrant to microbial degradation. This study suggests that the occurrence of SAmPAP diester in freshwater lake sediments may be an important precursor of PFOS. PMID- 29247946 TI - Effective teaching behaviors in the emergency department: A qualitative study with Millennial nursing students in Shanghai. AB - BACKGROUND: Millennial nursing students are different from generations before especially with the rapid development of China's economy, their varieties of characteristics affect the clinical teaching and learning. But how their learning preference impact their learning outcomes remain unclear. OBJECTIVES: The aim of this study is to explore effective teaching methods in the emergency department from the perspective of Millennial nursing students in Shanghai, China. One of the main objectives is to provide valuable information to help nursing programs in China to effectively educate Millennial students to deliver patient-centered care and to meet medical changes according to Chinese healthcare reform. METHODS AND PARTICIPANTS: Qualitative study design was used and semistructured interviews were conducted in a purposive sample of 16 nursing students from six colleges of nursing and five nursing high schools in Shanghai. They are from eight geographical areas across China and have a clinical practice in the teaching hospital. Colaizzi seven-step framework was applied for data analysis. RESULTS: Three themes were emerged including: demonstrating harmonious faculty-student relationship, possessing professional competence and being empathetic for teaching. CONCLUSIONS: The findings of this study provide valuable information for promoting the clinical teaching quality in China. It is crucial to put more emphasis on demonstrating harmonious faculty-student relationship, rendering Millennial students more caring behavior, possessing sufficient competence in both knowledge and skills, and taking full advantage of technology in clinical teaching. The results of this study are relevant to envision the future training of clinical nursing teachers. PMID- 29247947 TI - Stream transport of iron and phosphorus by authigenic nanoparticles in the Southern Piedmont of the U.S. AB - Authigenic nanoparticles containing iron (Fe) and phosphorus (P) have been identified at the anoxic/oxic interface of various aquatic ecosystems, forming upon the oxidation of reduced Fe. Little is known about the prevalence of these authigenic nanoparticles in streams, their impact on biogeochemical fluxes, or the bioavailability of P associated with them. In this paper we used transmission electron microscopy to document the presence of authigenic (amorphous) nanoparticles, rich in Fe and P, in baseflow of streams in the Southern Piedmont region of the U.S. We used a simple centrifugation and ultrafiltration technique to separate authigenic nanoparticles from truly dissolved (<1 kDa) and crystalline mineral/coarse organic fractions in baseflow, employing three different quality control methods to verify a successful separation: X-ray diffraction, electron microscopy, and stoichiometry of Fe and aluminum. This allowed us to quantify the amount of Fe and P in three different fractions of baseflow: truly dissolved, authigenic nanoparticles, and crystalline mineral/coarse organic particles. For the rural and urban stream in our study, on average, authigenic nanoparticles in baseflow transport 66% of Fe, with baseflow concentrations ranging from 80 MUg/L to 650 MUg/L. Authigenic nanoparticles also transport an average of 38% of reactive P, depending upon seasonality and time elapsed since the last storm event. PMID- 29247948 TI - Effects of conventional ozonation and electro-peroxone pretreatment of surface water on disinfection by-product formation during subsequent chlorination. AB - The electro-peroxone (E-peroxone) process is an emerging ozone-based electrochemical advanced oxidation process that combines conventional ozonation with in-situ cathodic hydrogen peroxide (H2O2) production for oxidative water treatment. In this study, the effects of the E-peroxone pretreatment on disinfection by-product (DBP) formation from chlorination of a synthetic surface water were investigated and compared to conventional ozonation. Results show that due to the enhanced transformation of ozone (O3) to hydroxyl radicals (OH) by electro-generated H2O2, the E-peroxone process considerably enhanced dissolved organic carbon (DOC) abatement and significantly reduced bromate (BrO3-) formation compared to conventional ozonation. However, natural organic matter (NOM) with high UV254 absorbance, which is the major precursors of chlorination DBPs, was less efficiently abated during the E-peroxone process than conventional ozonation. Consequently, while both conventional ozonation and the E-peroxone process substantially reduced the formation of DBPs (trihalomethanes and haloacetic acids) during post-chlorination, higher DBP concentrations were generally observed during chlorination of the E-peroxone pretreated waters than conventional ozonation treated. In addition, because of conventional ozonation or the E-peroxone treatment, DBPs formed during post-chlorination shifted to more brominated species. The overall yields of brominated DBPs exhibited strong correlations with the bromide concentrations in water. Therefore, while the E peroxone process can effectively suppress bromide transformation to bromate, it may lead to higher formation of brominated DBPs during post-chlorination compared to conventional ozonation. These results suggest that the E-peroxone process can lead to different DBP formation and speciation during water treatment trains compared to conventional ozonation. PMID- 29247949 TI - Long non-coding RNA OIP5-AS1 functions as an oncogene in lung adenocarcinoma through targeting miR-448/Bcl-2. AB - LncRNAs are increasingly verified to be aberrantly expressed in cancers. The abnormal expression of lncRNAs has turned out to be closely related to tumorigenesis or tumor progression. It has been reported that lncRNA OPI5-AS1 serves as a crucial regulator in tumors. However, the specific function of OIP5 AS1 on the progression of lung adenocarcinoma is still uncertain. In this paper, we mainly elucidated that OIP5-AS1 exerts oncogenic functions in human lung adenocarcinoma through targeting miR-448. We inspected that the expression of OIP5-AS1 was definitely high in lung adenocarcinoma tissues and cells, while miR 448 was sluggishly expressed in lung adenocarcinoma. OIP5-AS1 and miR-448 was negatively related to each other, the result was obtained from Pearson correlation analysis. We discovered a fact that OIP5-AS1 could directly sponge miR-448 through using dual luciferase reporter assay, RIP assay and RNA pull-down assay. Cell proliferation, migration and invasion were restrained after we disrupted the expression of OIP5-AS1 in lung adenocarcinoma. We also certified that OIP5-AS1 could sponge and regulate miR-448 to affect cell function in lung adenocarcinoma. MiR-448 could target Bcl-2 and affect the expression of Bcl-2. Then, we discovered that the expression of OIP5-AS1 and Bcl-2 was positively related. So we affirmed that lncRNA OIP5-AS1 modulated the expression of Bcl-2 by targeting miR-448 in lung adenocarcinoma cells. PMID- 29247950 TI - Baicalin attenuates diet induced nonalcoholic steatohepatitis by inhibiting inflammation and oxidative stress via suppressing JNK signaling pathways. AB - Nonalcoholic steatohepatitis may develop into hepatic cirrhosis. The therapeutic drugs for NASH are absent. Baicalin (BC) has hepatoprotective effect, while whether BC could prevent the development of NASH is unknown. This study aimed to investigate the effect of BC on the development of diet induced NASH and the possible mechanisms involved. Mice were fed with high fat and high cholesterol (HFC) diet to establish a NASH model, BC (0.5% w/w) was added into the diet to evaluate its effect on NASH. Mice fed an HFC diet developed NASH in 12 weeks. BC administration attenuated hepatic steatosis, inflammation and fibrosis induced by HFC diet. The NALFD activity score (NAS) was sharply decreased by BC. Mice serum ALT and AST were decreased in the BC group. BC decreased hepatic inflammatory cell infiltration, inflammatory genes (MCP-1, TNFalpha) and fibrosis genes (COL1, alpha-SMA, TGFbeta) mRNA expression. BC has antioxidant function evidenced by upregulated hepatic GSH and SOD levels and downregulated MDA levels. BC restored some oxidative stress markers including 4-HNE, 8-OHdG in liver. Western blot analysis stated that BC suppressed pro-inflammatory COX-2 levels, pro-oxidative CYP2E1 levels and phosphorylation of JNK in mice liver. Collectively, BC can attenuate diet induced NASH and the mechanism in which possibly due to its anti inflammatory and anti-oxidant effects via blockade of the activation of JNK. PMID- 29247951 TI - Long non-coding RNA XLOC_008466 acts as an oncogenic molecular in cervical cancer tumorigenesis. AB - Cervical cancer is one of the most common malignant carcinomas in the female reproductive system. Long non-coding RNAs (lncRNAs) have been verified to participate in the tumorigenesis of cervical cancer. In present study, we investigate the role of lncRNA XLOC_008466 in the occurrence and progression of cervical cancer. Results showed that XLOC_008466 expression was up-regulated in cervical cancer tissue and cells compared to normal controls. In vitro functional experiments, CCK-8 assay and colony formation assay showed that XLOC_008466 knockdown suppressed the proliferation of cervical cancer cells. Flow cytometry and transwell assay showed that XLOC_008466 knockdown induced G0/G1 phase arrest and aggravated the apoptosis. In vivo, XLOC_008466 knockdown inhibited the tumor growth. Bioinformatics analysis revealed that XLOC_008466 sponged miR-216b with the complementary binding sites at 3'-UTR. Overall, our study reveals the tumor promoting role of XLOC_008466 in cervical cancer carcinogenesis, providing a novel molecular mechanism and therapeutic target for cervical cancer. PMID- 29247953 TI - Efficient decolorization of typical azo dyes using low-frequency ultrasound in presence of carbonate and hydrogen peroxide. AB - The aims of this study as to evaluate and understand the decolorization of azo dyes using carbonate and hydrogen peroxide under low-frequency ultrasonic irradiation. Under optimal conditions, the decolorization ratio of acid orange 8 (AO 8), a typical azo dye, was > 90% after 2 h of irradiation. The decolorization rate of AO 8 was 0.023 min-1 under ultrasonic irradiation, which was about two times that without ultrasound. Different from the results of other published studies, OH played a minor role, while CO3- played the most important role in AO 8 ultrasonic decolorization in the presence of CO32- and H2O2, with a contribution of 56.52%, followed by CO42- (32.61%) and 1O2 (10.87%). Another difference is that CO3- formed through the cleavage of peroxymonocarbonate or peroxydicarbonate under ultrasonic irradiation rather than through reaction between hydroxyl radical and carbonate. Investigations for different azo dyes revealed that the decolorization rate decreased in the order AO 8 ~ orange II > acid red 9 > acid yellow 11, probably because of molecular differences among the azo dyes. PMID- 29247952 TI - Overexpressed miR-195 attenuated immune escape of diffuse large B-cell lymphoma by targeting PD-L1. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) seriously threatens patients life with the morbidity increases at a high rate. Immune response disorder is the potential factor that induces DLBCL, while the potential mechanism still not fully understand. METHODS: Real-time PCR and western blot were performed to determine genes expression. Flow cytometry was employed to detect the expression of PD-1 and the ratio of PD-1+T cells. Enzyme-linked immune sorbent assay (ELISA) was used to determine the cytokines secretion. RESULTS: MiR-195 was down regulated, while PD-L1 was up-regulated in DLBCL tissues, and the rate of PD-1+T cells was increased in T cells of peripheral blood in DLBCL. Overexpressed miR 195 suppressed the expression of PD-L1. Moreover, miR-195 overexpression significantly promoted the secretion of IFN-gamma and TNF-alpha, but decreased IL 10 and PD-1+T cells rate in the co-culture model of T cells and OCI-Ly-10 cells. MiR-195 targets PD-L1 to regulate the expression of IFN-gamma, TNF-alpha, IL-10 and the rate of PD-1+T cells. CONCLUSION: MiR-195 regulated immune response of DLBCL through targeting PD-L1. PMID- 29247954 TI - TiO2@Pt@CeO2 nanocomposite as a bifunctional catalyst for enhancing photo reduction of Cr (VI) and photo-oxidation of benzyl alcohol. AB - An solar-light-driven and bifunctional photocatalyst was designed for photo reduction of Cr(VI) and selective photo-oxidation of benzyl alcohol into benzaldehyde in the presence of water under ambient conditions. Double-shelled and sandwiched TiO2@Pt@CeO2 hollow spheres were prepared by using functionalized polystyrene spheres, sol-gel, hydrothermal reaction, and calcination. The Pt nanoparticles (NPs) were controllably loaded between the TiO2 shell and CeO2 shell. Under solar-light irradiation, the photo-reduction rate of Cr(VI) (MUmol h 1) was in the order of TiO2@Pt@CeO2 (1.901) > TiO2@CeO2 (1.424) > TiO2 (1.040) > CeO2 (0.992). Among the above-mentioned photocatalysts, the conversion rate of benzyl alcohol for TiO2@Pt@CeO2 was also the best. These results were attributed to the combination of TiO2 and CeO2 as photocatalyst and oxygen buffer, the double-shelled and sandwiched nanostructure, and the addition of Pt NPs as cocatalyst and electron trap site, which could store and shuttle photo-generated electrons, reduce the recombination of the electron-hole, and then enhance photo generation of active radicals. This conclusion was verified by the electron paramagnetic resonance (EPR) spectroscopy. Considering the versatile combination of photocatalyst, oxygen buffer and cocatalyst, this work could provide new insights into the design of high-performance bifunctional photocatalysts for heavy metal removal and selective synthesis. PMID- 29247955 TI - Plant extract-mediated green silver nanoparticles: Efficacy as soil conditioner and plant growth promoter. AB - Recently, concerns have been raised regarding the ultimate fate of silver nanoparticles (SNPs) after their release into the environment. In this study, the environmental feasibility of plant leaf (Thuja occidentalis) extract-mediated green SNPs (GSNPs) was assessed in terms of their effects on soil physicochemical properties and crop growth in comparison to conventionally synthesized silver nanoparticles (CSNPs). Upon application of GSNPs, soil pH shifted toward neutrality, and substantial increments were observed in water holding capacity (WHC), cation exchange capacity (CEC), and N/P availability. The mechanism behind the enhanced availability of N was verified through lab-scale experiments in which GSNP-treated soils efficiently resisted nitrate leaching, thereby sustaining N availability in root zone soil layers. However, retardation in nutrient availability and enzyme activity was apparent in soils treated with 100 mg kg-1 of either CSNPs or GSNPs. Remarkable improvements in leaf area index (LAI), leaf number, chlorophyll content, nitrate reductase (NR) activity, and Phaseolus vulgaris pod yield were observed after the application of low doses of GSNPs (25-50 mg kg-1). The true benefit of GSNP application to soil was substantiated through experiments on plant uptake of nutrients, NR expression, and ferredoxin gene expression in P. vulgaris leaves. PMID- 29247956 TI - Electrochemical inactivation of Microcystis aeruginosa using BDD electrodes: Kinetic modeling of microcystins release and degradation. AB - Electrochemical inactivation of cyanobacteria using boron-doped diamond (BDD) electrode were comprehensively investigated in this study. The pulse amplitude modulated (PAM) fluorometry, flow cytometry, and confocal laser scanning microscopy (CLSM) were used to characterize the photosynthetic capacity and cell integrity of Microcystis aeruginosa. Persulfate is in-situ generated and activated during the process and responsible for the inactivation of M. aeruginosa. The inactivation efficiency increases along with the increase of applied currents. Additionally, a kinetic model based on a sequence of two consecutive irreversible first-order processes was developed to simulate the release and degradation of microcystins (MCLR). The model was able to successfully predict the concentration of extracellular, intracellular and total MCLR under different applied currents and extended exposure time. PMID- 29247957 TI - Characterization and adsorption mechanism of ZrO2 mesoporous fibers for health hazardous fluoride removal. AB - One-dimension ZrO2 mesoporous fibers were successfully synthesized by utilizing the electrospinning device combining with the soft-template method. The morphology and composite of the fibers were characterized by XRD, SEM, TEM, FT IR, TGA/DSC and XPS, and the pore structure and surface area were calculated according the BET measured results. The fluoride adsorption performance of the fibers was investigated and the adsorption capacity was upto 297.70 mg g-1. Moreover, the equilibrium concentration could be reached to 1.41 mg L-1 with the initial of 30 mg L-1, and the removal rate could be reached to 95.3%. The adsorption data were well fitted with the Freundlich isotherm model and pseudo second-order kinetic model. The fibers had a good reusability and long-term utilization for fluoride adsorption. All the results suggested that the as prepared ZrO2 mesoporous fibers with high surface area could be an excellent adsorbent for the wastewater defluoridation treatment. PMID- 29247958 TI - Inductive and deductive reasoning in obsessive-compulsive disorder. AB - BACKGROUND AND OBJECTIVES: This study examined the hypothesis that participants diagnosed with obsessive-compulsive disorder (OCD) show a selective deficit in inductive reasoning but are equivalent to controls in deductive reasoning. METHODS: Twenty-five participants with OCD and 25 non-clinical controls made inductive and deductive judgments about a common set of arguments that varied in logical validity and the amount of positive evidence provided (premise sample size). A second inductive reasoning task required participants to make forced choice decisions and rate the usefulness of diverse evidence or non-diverse evidence for evaluating arguments. RESULTS: No differences in deductive reasoning were found between participants diagnosed with OCD and control participants. Both groups saw that the amount of positive evidence supporting a conclusion was an important guide for evaluating inductive arguments. However, those with OCD showed less sensitivity to premise diversity in inductive reasoning than controls. The findings were similar for both emotionally neutral and OCD-relevant stimuli. LIMITATIONS: The absence of a clinical control group means that it is difficult to know whether the deficit in diversity-based reasoning is specific to those with OCD. CONCLUSIONS: People with OCD are impaired in some forms of inductive reasoning (using diverse evidence) but not others (use of sample size). Deductive reasoning appears intact in those with OCD. Difficulties using evidence diversity when reasoning inductively may maintain OCD symptoms through reduced generalization of learned safety information. PMID- 29247959 TI - Triacylglycerol "hand-shape profile" of Argan oil. Rapid and simple UHPLC-PDA-ESI TOF/MS and HPTLC methods to detect counterfeit Argan oil and Argan-oil-based products. AB - The marketing of new argan-based products is greatly increased in the last few years and consequently, it has enhanced the number of control analysis aimed at detecting counterfeit products claiming argan oil as a major ingredient. Argan oil is produced in Morocco and it is quite expensive. Two simple methods for the rapid screening of pure oil and argan-oil based products, focused on the analysis of the triacylglycerol profile, have been developed. A three-minute-run by UHPLC PDA allows the identification of a pure argan oil, while the same run with the MS detector allows also the analysis of products containing the oil down to 0.03%. On the other hand, by HPTLC the simultaneous analysis of twenty samples, containing argan oil down to 0.5%, can be carried out in a forty-five-minute run. The triglyceride profile of the most common vegetable fats such as almond, coconut, linseed, wheat germ, sunflower, peanut, olive, soybean, rapeseed, hemp oils as well as shea butter used either in cosmetics or commonly added for the counterfeiting of argan oil, has been also investigated. Over sixty products with different formulations and use have been successfully analyzed and argan oil in the 2.4-0.06% concentration range has been quantified. The methods are suitable either for a rapid screening or for quantifying argan oil in different formulations. PMID- 29247961 TI - Comprehensive quality evaluation of medical Cannabis sativa L. inflorescence and macerated oils based on HS-SPME coupled to GC-MS and LC-HRMS (q-exactive orbitrap(r)) approach. AB - There are at least 554 identified compounds in C. sativa L., among them 113 phytocannabinoids and 120 terpenes. Phytocomplex composition differences between the pharmaceutical properties of different medical cannabis chemotype have been attributed to strict interactions, defined as 'entourage effect', between cannabinoids and terpenes as a result of synergic action. The chemical complexity of its bioactive constituents highlight the need for standardised and well defined analytical approaches able to characterise the plant chemotype, the herbal drug quality as well as to monitor the quality of pharmaceutical cannabis extracts and preparations. Hence, in the first part of this study an analytical procedures involving the combination of headspace-solid-phase microextraction (HS SPME) coupled to GC-MS and High Resolution Mass-Spectrometry LC-HRMS (Orbitrap(r)) were set up, validated and applied for the in-depth profiling and fingerprinting of cannabinoids and terpenes in two authorised medical grade varieties of Cannabis sativa L. inflorescences (Bedrocan(r) and Bediol(r)) and in obtained macerated oils. To better understand the trend of all volatile compounds and cannabinoids during oil storage a new procedure for cannabis macerated oil preparation without any thermal step was tested and compared with the existing conventional methods to assess the potentially detrimental effect of heating on overall product quality. PMID- 29247960 TI - Application of miniaturized near-infrared spectroscopy for quality control of extemporaneous orodispersible films. AB - Extemporaneous oral preparations are routinely compounded in the pharmacy due to a lack of suitable formulations for special populations. Such small-scale pharmacy preparations also present an avenue for individualized pharmacotherapy. Orodispersible films (ODF) have increasingly been evaluated as a suitable dosage form for extemporaneous oral preparations. Nevertheless, as with all other extemporaneous preparations, safety and quality remain a concern. Although the United States Pharmacopeia (USP) recommends analytical testing of compounded preparations for quality assurance, pharmaceutical assays are typically not routinely performed for such non-sterile pharmacy preparations, due to the complexity and high cost of conventional assay methods such as high performance liquid chromatography (HPLC). Spectroscopic methods including Raman, infrared and near-infrared spectroscopy have been successfully applied as quality control tools in the industry. The state-of-art benchtop spectrometers used in those studies have the advantage of superior resolution and performance, but are not suitable for use in a small-scale pharmacy setting. In this study, we investigated the application of a miniaturized near infrared (NIR) spectrometer as a quality control tool for identification and quantification of drug content in extemporaneous ODFs. Miniaturized near infrared (NIR) spectroscopy is suitable for small-scale pharmacy applications in view of its small size, portability, simple user interface, rapid measurement and real-time prediction results. Nevertheless, the challenge with miniaturized NIR spectroscopy is its lower resolution compared to state-of-art benchtop equipment. We have successfully developed NIR spectroscopy calibration models for identification of ODFs containing five different drugs, and quantification of drug content in ODFs containing 2-10mg ondansetron (OND). The qualitative model for drug identification produced 100% prediction accuracy. The quantitative model to predict OND drug content in ODFs was divided into two calibrations for improved accuracy: Calibration I and II covered the 2-4mg and 4-10mg ranges respectively. Validation was performed for method accuracy, linearity and precision. In conclusion, this study demonstrates the feasibility of miniaturized NIR spectroscopy as a quality control tool for small-scale, pharmacy preparations. Due to its non-destructive nature, every dosage unit can be tested thus affording positive impact on patient safety. PMID- 29247962 TI - Vulnerability to exercise addiction, socio-demographic, behavioral and psychological characteristics of runners at risk for eating disorders. AB - BACKGROUND: Excessive exercise is frequently associated with eating disorders and may degenerate into exercise addiction. We still don't know whether runners at risk for eating disorders are at risk for exercise addiction. Our aim is to assess: 1) risk for exercise addiction in runners at risk for eating disorders and 2) socio-demographic, behavioral and psychological characteristics distinguishing runners at-risk from not-at-risk for eating disorders. METHODS: We assessed risk for eating disorders and exercise addiction using the SCOFF questionnaire and the Exercise Addiction Inventory personality traits with the Big-Five Inventory Test, socio-demographic data, eating and training habits in a sample of 154 healthy runners. RESULTS: Twenty five subjects had a score of >=2 at the SCOFF and were included in the group "at risk for eating disorders". In this group, we found a higher percentage of subjects at risk for exercise addiction (p=0.01) and higher average scores at the Exercise Addiction Inventory (p=0.01) than runners not at risk (N=136). Runners at risk were statistically younger (p=0.03), women (p=0.001), started running to lose weight more often (p=0.03), lost more kilos since affiliation in their running club (p=0.04), and were characterized by neurotic traits using the Big-Five-Inventory Test (p=3.10 6). CONCLUSIONS: Screening for exercise addiction and mood disorders could lead to a more accurate management of runners at risk for eating disorders. Identifying vulnerable individuals will facilitate the prevention of eating disorders and preserve the benefits of sport practice. PMID- 29247963 TI - ECoG high-gamma modulation versus electrical stimulation for presurgical language mapping. AB - OBJECTIVE: This meta-analysis compared diagnostic validity of electrocorticographic (ECoG) high-gamma modulation (HGM) with electrical stimulation mapping (ESM) for presurgical language localization. METHODS: From a structured literature search, studies with electrode level data comparing ECoG HGM and ESM for language localization were included in the meta-analysis. Outcomes included global measures of diagnostic validity: area under the summary receiver operating characteristic (SROC) curve (AUC), and diagnostic odds ratio (DOR); as well as pooled estimates of sensitivity and specificity. Clinical and technical determinants of sensitivity/specificity were explored. RESULTS: Fifteen studies were included in qualitative synthesis, and 10 studies included in the meta-analysis (number of patients 1-17, mean age 10.3-53.6years). Overt picture naming was the most commonly used task for language mapping with either method. Electrocorticographic high-gamma modulation was analyzed at 50-400Hz with different bandwidths in individual studies. For ESM, pulse duration, train duration, and maximum current varied greatly among studies. Sensitivity (0.23 0.99), specificity (0.48-0.96), and DOR (1.45-376.28) varied widely across studies. The pooled estimates are: sensitivity 0.61 (95% CI 0.44, 0.76), specificity 0.79 (95% CI 0.68, 0.88), and DOR 6.44 (95% CI 3.47, 11.94). Area under the SROC curve was 0.77. Results of bivariate meta-regression were limited by small samples for individual variables. CONCLUSION: Electrocorticographic high gamma modulation is a specific but not sensitive method for language localization compared with gold-standard ESM. Given the pooled DOR of 6.44 and AUC of 0.77, ECoG HGM can fairly reliably ascertain electrodes overlying ESM cortical language sites. PMID- 29247964 TI - Intraindividual variability in attentional vigilance in children with epilepsy. AB - Attentional vigilance, the ability to maintain focus over time, is frequently impaired in childhood epilepsy. Typically, indices of Omissions (failure to detect a target) and Commissions (responding to a nontarget) are considered primary indices of attentional vigilance. Recently, the concept of intraindividual variability (IIV) has been identified as an important measure of attentional vigilance in several pediatric and adult clinical populations, but has not yet been systematically examined in childhood epilepsy. Here, we examined IIV on the Connors Continuous Performance Task-II (CCPT-II) for 144 newly diagnosed children with epilepsy (age 8-18years) and a matched age group of healthy children (n=82). Intraindividual variability showed a large effect size difference (d=0.68) between groups. In addition, IIV significantly predicted both intellectual functioning and academic achievement. These findings support the utility of examining IIV in the assessment of attentional ability in childhood epilepsy. PMID- 29247965 TI - Predictive value of preoperative statistical parametric mapping of regional glucose metabolism in mesial temporal lobe epilepsy with hippocampal sclerosis. AB - OBJECTIVE: This study was designed to use statistical parametric mapping of interictal positron-emission tomography using [18F]Fluorodeoxyglucose (FDG-PET) to compare the brain metabolisms of patients with mesial temporal lobe epilepsy (MTLE)/hippocampal sclerosis and controls. Another aim of this study was to analyze the potential differences among patients in terms of epilepsy duration, side of hippocampal sclerosis, histopathological findings, insult in their history, and postoperative outcomes. METHODS: We analyzed FDG-PET scans from 49 patients with MTLE/hippocampal sclerosis and 24 control subjects. We analyzed the differences in regional glucose metabolism between the patients and the control group and within the patient group using multiple variables. RESULTS: We observed widespread hypometabolism in the patient group in comparison with the control group in temporal and extratemporal areas on the epileptogenic side (ES). On the nonepileptogenic side (NES), we observed the most hypometabolism in the thalamus and the anterior and middle cingulate gyrus. In the group of patients with more severe hippocampal sclerosis, we observed statistically significant hypometabolism in the insula on the ES. In patients with poor postoperative outcomes, we found statistically significant hypometabolism in the insula on the ES and the temporal pole (TP) on the NES. Patients with any insult in their history showed hypermetabolism in the TP on both sides. CONCLUSION: Our study showed that there are widespread changes in metabolism in patients with MTLE in comparison to controls, either inside or outside the temporal lobe. There are significant differences among these patients in terms of postoperative outcomes, degree of hippocampal sclerosis, and insults in their history. PMID- 29247966 TI - Post cholecystectomy syndrome need to redo laparoscopic completion surgery: A case report. AB - INTRODUCTION: Cholecystectomy is the standard treatment for symptomatic gallbladder stone disease. However, symptoms such as abdominal pain and dyspepsia may persist even after surgery, if the gallbladder is incompletely removed known as postcholecystectomy syndrome. CASE PRESENTATION: A 55-year-old man with a history of open cholecystectomy presented with a complaint of recurrent pain on his upper abdomen. Abdominal ultrasonography and magnetic resonance cholangiopancreatography revealed a cystic structure in the gallbladder fossa, with a filling defect at the midpoint of the cystic duct, suggesting a retained stone in the cystic duct and residual gallbladder. Therefore, he underwent completion laparoscopic cholecystectomy. He had an uneventful postoperative period with relief of the recurrent pain. DISCUSSION: Proper dissection and identification of the gallbladder and cystic duct junction is necessary for complete removal of the gallbladder and preventing postcholecystectomy syndrome. Patients with a retained stone in the residual gallbladder should undergo surgery, and the laparoscopic method can be performed by a surgeon with expertise in this revision surgery. CONCLUSION: In post-cholecystectomy syndrome, symptomatic Patients with retained stone in partially removed gall bladder by open method needs laparoscopic cholecystectomy by an expert surgeon to relieve their symptoms. PMID- 29247967 TI - Early stage malignant phyllodes tumor case report. AB - INTRODUCTION: Malignant phyllodes tumor of the breast is an extremely rare entity usually presenting with similar clinical features with those of benign fibroadenoma. Due to its scarcity and clinical presentation, it is quite difficult for clinicians to suspect and diagnose the disease at its early stage. There is currently no consensus regarding adjunctive radiotherapy, hormonal therapy and systemic chemotherapy recommended for malignant phyllodes tumors. PRESENTATION OF CASE: This report presents a case of early-stage malignant phyllodes tumor treated by lumpectomy only without adjunctive chemoradiation therapy, but with an excellent outcome. DISCUSSION: Early diagnosis and staging with high suspicion are crucial in malignant phyllodes tumor patients since they do not only improve the overall outcome of the disease after lumpectomy only but they also decrease morbidity and mortality with adjunctive chemoradiation therapy. This case report has been reported in line with the SCARE criteria (Agha et al., 2016 [1]). PMID- 29247968 TI - An alternative approach for addressing mediastinal tumours through mini-invasive surgery. AB - INTRODUCTION: The treatment of choice for mediastinal tumours is surgical, with the standard approach being sternotomy. Because of the invasive nature of this procedure, the management of these masses through mini-invasive surgery has become an alternative method. PRESENTATION OF CASE: We report the case of a woman with a mediastinum tumour and a new technique used for resection, through an inframammary left incision, using a Thoratrak rib spreader and Rultract Skyhook retractor assisted by a video. DISCUSSION/CONCLUSION: This approach allows a complete visualization of the mediastinum and total dissection of the tumour safely around vascular and nervous structures. The pain is minimal because there is no real rib spread but instead an anterior displacement of the upper rib. This is the first reported case of resection of a mediastinum tumour by inframammary approach using a Thoratrak rib spreader and Rultract Skyhook. PMID- 29247969 TI - Studies of x-ray localization and thickness dependence in atomic-scale elemental mapping by STEM energy-dispersive x-ray spectroscopy using single-frame scanning method. AB - The delocalization of x-ray signals limits the spatial resolution in atomic-scale elemental mapping by scanning transmission electron microscopy (STEM) using energy-dispersive x-ray spectroscopy (EDS). In this study, using a SrTiO3 [001] single crystal, we show that the x-ray localization to atomic columns is strongly dependent on crystal thickness, and a thin crystal is critical for improving the spatial resolution in atomic-scale EDS mapping. A single-frame scanning technique is used in this study instead of the multiple-frame technique to avoid peak broadening due to tracking error. The strong thickness dependence is realized by measuring the full width at half maxima (FWHM) as well as the peak-to-valley (P/V) ratio of the EDS profiles for Ti K and Sr K + L, obtained at several crystal thicknesses. A FWHM of about 0.16 nm and a P/V ratio of greater than 7.0 are obtained for Ti K for a crystal thickness of less than 20 nm. With increasing crystal thickness, the FWHM and P/V ratio increases and decreases, respectively, indicating the advantage of using a thin crystal for high-resolution EDS mapping. PMID- 29247970 TI - Comprehensive biomechanical characterization of feet in USMA cadets: Comparison across race, gender, arch flexibility, and foot types. AB - Lower extremity musculoskeletal injuries are common, complex, and costly problems. Literature supports associations between static foot structure and dynamic foot function, as well as between overuse injury and demographic characteristics. Previous studies failed to provide a comprehensive biomechanical foot characteristics of at-risk military personnel. In this study, foot structure, function, and arch height flexibility (AHF) were objectively measured in 1090 incoming cadets (16.3% female, mean age of 18.5years and BMI of 24.5kg/m2) of the United States Military Academy at the start of their training. A Generalized Linear Model with an identity link function was used to examine the effects of race, gender, foot types, and AHF while accounting for potential dependence in bilateral data. Planus and flexible feet independently demonstrated over-pronation, as measured by reduced Center of Pressure Excursion Index (CPEI). When comparing across race, Black participants showed a significantly lower arch height index (AHI), a larger malleolar valgus index (MVI), and a higher prevalence of pes planus (91.7% versus 73.3% overall). However, Asian participants with flexible arches, rather than Black with low arch, displayed over-pronation in gait. Females showed no significant difference in standing AHI and MVI but demonstrated a significantly greater AHF and a reduced CPEI than male participants. This was the first large scale investigation that comprehensively characterized biomechanical foot in a cohort of young at-risk individuals with lower limb musculoskeletal injuries. Long-term goal is to examine the relationship between these biomechanical features and injuries, ultimately to develop effective preventive measures. PMID- 29247971 TI - Refolding of autodisplayed anti-NEF scFv through oxidation with glutathione for immunosensors. AB - In this study, a single-domain antibody against negative regulatory factor (anti NEF scFv) was autodisplayed on the outer membrane of Escherichia coli and used to detect NEF in an immunoassay based on fluorescence-activated cell sorting, enzyme linked immunosorbent assay, and surface plasmon resonance biosensors. Next, the autodisplayed single-domain antibody was oxidized to form disulfide bonds by using glutathione, and the change in NEF-binding activity of anti-NEF scFv was analyzed by fluorescence-activated cell sorting-based immunoassay, chromogenic immunoassay, and surface plasmon resonance biosensor. For each type of immunoassays the anti-NEF scFv on the isolated outer membrane showed more NEF binding activity after the disulfide bond formation by glutathione. To determine the role of cysteines in anti-NEF scFv, three mutants were prepared, and the NEF binding activity of mutants was compared with that of wild-type anti-NEF scFv in a competitive immunoassay based on FACS. In these mutant studies, the refolding process of autodisplayed anti-NEF scFv by following oxidation via GSH/GSSG revealed that disulfide bonds formed and increased NEF binding activity. PMID- 29247972 TI - Electrochemical detection of carcinoembryonic antigen. AB - In this work, a sandwich-type electrochemical immunosensor for carcinoembryonic antigen (CEA) detection has been constructed and tested. Unlike many other sensors using external electrochemical species in the electrolyte to generate an electrochemical signal, a ferrocene derivative has been integrated into the design of the sensor to provide an internal reporting system, allowing detection of CEA in buffers and biological samples. Gold nanoparticles, which have been used to increase the conductivity of sensing surfaces, also carry immobilized secondary anti-CEA and a ferrocene derivative. The shelf life testing of the sensor shows good performance after storage for 4 weeks. The sensor has been calibrated against different concentration of the target protein using square wave voltammetry. The calibration curve has been obtained in the range of 0.05 20ngmL-1, and the detection limit for CEA is ~ 0.01ngmL-1. The capability of the immunosensor has been verified by performing detection of CEA in human serum samples. PMID- 29247973 TI - Excess mortality in children born to opioid-addicted parents: A national register study in Taiwan. AB - BACKGROUND: Young offspring of individuals with opioid use disorders have great exposure to a wide array of social disadvantages and stressors. This study aimed to investigate excess mortality before the age of six and predictors of premature death in children born to opioid-involved parents. METHODS: A total of 3210 children born between 2004 and 2009 to parents with opioid use disorders (roughly a quarter of whom were born after parental methadone treatment enrollment) were identified in Taiwan. Information concerning sociodemographic characteristics, history of medical condition, and survival status was obtained through data linkage with the National Health Insurance Database and death registration. The age-, birth year-, and sex-adjusted standardized mortality ratios (SMRs) and survival analyses were used to assess risk estimates and evaluate predictors. RESULTS: The overall SMR for children with opioid-involved parents was 2.31 (95% confidence interval [CI] = 1.68-3.10), with the estimate reaching 4.23 (95% CI = 2.37-6.97) when the causes of death were unnatural (e.g., injury and accident). The most salient predictors of premature death were low birth weight and paternal opioid problem severity, which increased risk of premature death 2.5--5.2-fold (all P < 0.05). Being born after parents enrolled in methadone treatment was slightly associated with a reduced risk of death in those mothered by opioid users (adjusted hazard ratio = 0.30). CONCLUSION: The elevated risk of premature death in the offspring of opioid-addicted parents suggests the need to prioritize resource allocation to safeguard this marginalized and vulnerable segment of the pediatric population. PMID- 29247975 TI - 6:2 fluorotelomer sulfonamide alkylbetaine (6:2 FTAB), a novel perfluorooctane sulfonate alternative, induced developmental toxicity in zebrafish embryos. AB - 6:2 fluorotelomer sulfonamide alkylbetaine (6:2 FTAB) is a major component of Forafac(r)1157, a novel perfluorooctane sulfonate (PFOS) alternative used globally in aqueous film forming foams (AFFFs). Although 6:2 FTAB has been recently detected in the aquatic environment, its toxic effects on aquatic organisms remain unclear. Here, zebrafish embryos were exposed to various concentrations of 6:2 FTAB (0, 5, 10, 20, 40, 60, 80, and 100 mg/L) from 6 to 120 h post-fertilization (hpf) to investigate its developmental toxicity and possible mechanism of action. Results showed that exposure to 40 mg/L or higher concentrations of 6:2 FTAB significantly decreased the survival percentage and increased the malformation percentage. The median lethal concentration (LC50) at 120 hpf was 43.73 +/- 3.24 mg/L, and the corresponding benchmark dose lower limit (BMDL) of lethal effect was 33.79 mg/L. These values were both higher than those for PFOS, supporting the notion that 6:2 FTAB is less toxic than PFOS to zebrafish embryos. The most common developmental defect in 6:2 FTAB-treated embryos was rough-edged skin/fins. TUNEL assay showed that 6:2 FTAB exposure induced cell apoptosis in the tail region compared with that of the control, which might explain the rough-edged skin/fins. The increased transcriptional levels of p53, bax, and apaf1 and the increased activities of caspase-3, -8, and 9 provided further evidence of 6:2 FTAB-induced apoptosis. We also analyzed the effects of 6:2 FTAB on oxidative stress and the immune system. Results showed that reactive oxygen species and malondialdehyde accumulated in concentration dependent manners after exposure to 6:2 FTAB, and antioxidant enzyme activities (catalase and glutathione peroxidase) also changed. Exposure to 6:2 FTAB also altered the transcriptional levels of ccl1, il-1beta, il-8, tnfalpha, ifn, and cxcl-c1c, which play important roles in the innate immune system. Collectively, our data suggest that 6:2 FTAB exposure can induce cell apoptosis, oxidative stress, and immunotoxicity, thus highlighting the developmental toxicity of 6:2 FTAB in zebrafish embryos. PMID- 29247974 TI - Evidence of validity and reliability of the Opiate Dosage Adequacy Scale (ODAS) in a sample of heroin addicted patients in buprenorphine/naloxone maintenance treatment. AB - OBJECTIVE: The Opiate Dosage Adequacy Scale (ODAS) is a clinical tool to individually measure the "adequacy" of opioid doses in patients on maintenance treatment. The aim of this paper is to provide evidence for the validity and reliability of the ODAS in a sample of patients in buprenorphine/naloxone (B/N) maintenance treatment. METHOD: Cross-sectional study of a convenience sample of B/N-treated patients (n = 316) from four Autonomous Communities in Spain. Participants completed a battery of instruments to assess the following: buprenorphine dose adequacy; heroin dependence severity; psychological adjustment; and patient-desired adjustment of buprenorphine dose. RESULTS: Exploratory Factor Analysis identified four factors from the ODAS that together account for 85.4% of the total variance: "Heroin craving and use"; "Overmedication"; "Objective opiate withdrawal symptoms (OWS)" and 'Subjective OWS'. Compared to patients with an "inadequate" B/N dose (ODAS), patients with "adequate" doses had less heroin use in the last week (0.01 vs. 0.40; t = -2.73; p < 0.01, 95% CI: -0.67, -0.10), less severe heroin dependence (2.20 vs. 5.26, t = -5.14, p < 0.001; 95% CI: -4.23, -1.88), less psychological distress (3.00 vs. 6.31, t = -4.37, p < 0.001; 95% CI: -4.80, -1.81), and greater satisfaction with their doses (42.1% vs. 13.6%, chi2 = 14.44, p < 0.01). Cronbach's alpha coefficient was 0.76 (0.81, 0.92, 0.94, and 0.93, respectively, for the four factor dimensions). CONCLUSION: These findings support the validity and reliability of the ODAS as a tool to measure and assess buprenorphine dose adequacy in the context of an opioid dependency treatment program. PMID- 29247976 TI - Coronary calcification as a mechanism of plaque/media shrinkage in vessels treated with bioresorbable vascular scaffold: A multimodality intracoronary imaging study. AB - BACKGROUND AND AIMS: Whether coronary calcification is correlated with plaque/media shrinkage (PS) remains unclear. The aim of this study was to assess the relationship between the calcification process and PS, combining serial optical coherence tomography (OCT) and intravascular ultrasound (IVUS) in vessels treated with bioresorbable vascular scaffolds (BVS). METHODS: In 15 patients (16 vessels), OCT and IVUS images were matched using anatomic landmarks at post procedure and five years. PS was defined as relative decrease in plaque/media area >5%. The association between the calcification process and PS was investigated. Mixed effect models were used to assess correlations and changes over time. RESULTS: Seventy-two OCT and IVUS paired cross sections in- and out scaffolded segments were matched at baseline and follow-up (432 images). In total, 35 out of the 72 cross sections showed PS, and 37 cross sections showed no PS (non-PS) at 5-year follow-up. Delta (Delta) plaque/media area showed negative correlation with Delta OCT calcium area (r = -0.29, p = 0.004), Delta OCT calcium arc (r = -0.42, p < 0.001), Delta OCT calcium length (r = -0.5, p < 0.001), and Delta IVUS calcium arc (r = -0.31, p = 0.024), respectively. On echogenicity analysis, Delta plaque/media area was positively associated with Delta hypoechogenic area (r = 0.47, p = 0.002). An increase in calcium area was negatively correlated to Delta hypoechogenicity (r = -0.29, p < 0.016). The increase in calcium area was positively correlated with Delta lumen area (r = 0.24, p = 0.044). CONCLUSIONS: In segments treated with BVS, the calcification process was associated with PS, decrease in the hypoechogenic tissue and late luminal enlargement. Combining IVUS and OCT provides a unique method to assess the correlation between the calcification process and plaque/media shrinkage. PMID- 29247977 TI - Temporally extended self-awareness and affective engagement in three-year-olds. AB - The aim of the current study was to analyze the role of affective engagement during social interaction on the emergence of a temporally extended self (TES). A Delayed Self Recognition task was administered in two different social contexts: in presence of the mother ("Mother condition") or in presence of an unfamiliar person ("Experimenter condition"). The same sample of 71 tree-year-olds was tested twice in these two treatment conditions. Results showed higher self recognition scores in the "Mother condition". These findings are consistent with developing-self theories that emphasize the impact of reciprocal social interaction on the emergence of self-awareness, and support a conception of the Self as a dialogic entity. We interpreted this link as a evidence that, when completing the procedure with their mother, children are aware of her attention, which corresponds to a familiar mode of self-perception, as well as to a peculiar affective consciousness of Self. PMID- 29247978 TI - Advances in chromosomal translocations and fusion genes in sarcomas and potential therapeutic applications. AB - Chromosomal translocations and fusion genes are very common in human cancer especially in subtypes of sarcomas, such as rhabdomyosarcoma, Ewing's sarcoma, synovial sarcoma and liposarcoma. The discovery of novel chromosomal translocations and fusion genes in different tumors are due to the advancement of next-generation sequencing (NGS) technologies such as whole genome sequencing. Recently, many novel chromosomal translocations and gene fusions have been identified in different types of sarcoma through NGS approaches. In addition to previously known sarcoma fusion genes, these novel specific fusion genes and associated molecular events represent important targets for novel therapeutic approaches in the treatment of sarcomas. This review focuses on recent advances in chromosomal translocations and fusion genes in sarcomas and their potential therapeutic applications in the treatment of sarcomas. PMID- 29247979 TI - Porous architected biomaterial for a tibial-knee implant with minimum bone resorption and bone-implant interface micromotion. AB - This investigation presents the numerical development of a fully porous tibial knee implant that is suggested to alleviate the clinical problems associated with current prostheses that are fully solid. A scheme combining multiscale mechanics and topology optimization is proposed to handle the homogenized analysis and property tailoring of the porous architecture with the aim of reducing the stiffness mismatch between the implant and surrounding bone. The outcome of applying this scheme is a graded lattice microarchitecture that can potentially offer the implant an improved degree of load bearing capacity while reducing concurrently bone resorption and interface micromotion. Asymptotic Homogenization theory is used to characterize the mechanics of its building block, a tetrahedron based unit cell, and the Soderberg fatigue criterion to represent the implant fatigue resistance under multiaxial physiological loadings. The numerical results suggest that the overall amount of bone resorption around the graded porous tibial stem is 26% lower than that around a conventional, commercially available, fully dense titanium implant of identical shape and size. In addition, an improved interface micromotion is observed along the tibial stem, with values at the tip of the stem as low as 17um during gait cycle and 22um for deep bend compared to a fully dense implant. This decrease in micromotion compared to that of an identical solid implant made of titanium can reasonably be expected to alleviate post-operative end of stem pain suffered by some patients undergoing surgery at the present time. PMID- 29247980 TI - Influence of alcohol containing and alcohol free cosmetics on FAEE concentrations in hair. A performance evaluation of ethyl palmitate as sole marker, versus the sum of four FAEEs. AB - Fatty acid ethyl esters (FAEE) are direct metabolites of ethanol and have been shown to be suitable markers for the evaluation of alcohol consumption. Previous research has suggested that the regular use of alcohol containing cosmetic products can influence the concentration of FAEE detected in hair. In this study we investigated the influence of alcohol containing and alcohol free hair cosmetics (hairspray and waxes) on the FAEE concentrations in hair. The effect of cosmetic treatment was measured against the impact on ethyl palmitate in isolation as compared to the sum of four esters. 10 volunteers treated part of their scalp with cosmetic products every day during a 2 month period (alcohol free hairspray n=2, hairspray containing alcohol (42% by volume) n=3, alcohol free wax n=2, wax containing alcohol (11% by volume) n=3). After the 2 month period of cosmetic application hair samples from volunteers were collected from both sides of the scalp. Hair samples were washed with n-heptane, and then cut finely into small pieces. All samples were subjected to clean-up by HS-SPME and then GC PCI-MS/MS for analysis of FAEEs. Comparison of FAEE concentrations between treated and untreated hair showed in some instances that application of hair spray or wax products caused an increase in FAEE levels. Products containing alcohol caused a more substantial increase in alcohol metabolite concentrations in hair when compared to alcohol free products. Three volunteers using an alcohol based hairspray in the study experienced a significant increase in FAEE levels (+27.4%, +205.5%, and +1287.5%), with one of the volunteers showing levels below the cut off for 'abstinence' in the untreated scalp portion, and levels above the cut off for 'chronic excessive consumption' in the treated scalp portion. Performance evaluation of ethyl palmitate as sole marker, compared to the sum of four esters approach suggested that the two quantification approaches react in a very similar manner to the application of hair sprays and waxes. We would suggest that the interpretative value of FAEE hair measurements from people reporting the use of alcohol based hairsprays are treated with caution. PMID- 29247981 TI - Exploring the clinical use of ultrasound imaging: A survey of physiotherapists in New Zealand. AB - BACKGROUND: In New Zealand ultrasound imaging (USI) is being used increasingly by physiotherapists. To fully understand the extent to which physiotherapists in New Zealand are using USI, it is necessary to evaluate not only the context of its clinical use but also the barriers preventing its uptake. OBJECTIVES: To examine the field and scope of use of USI, the type and content of training and the barriers restricting physiotherapists from using the technique. DESIGN: Cross sectional observational design utilising an Internet-based electronic survey. METHOD: An electronic survey built on the design of previous research with guidance from an expert review panel. Participants were included if they were New Zealand registered physiotherapists. RESULTS: Of the 465 participants who responded, 433 were eligible to complete the survey. There were 415 participants who completed the survey, 24% who said they used USI whilst 76% did not. For those using USI, the uses were varied including those within a rehabilitative paradigm (i.e. biofeedback; 52%) and also diagnostic (49%). USI training was also varied ranging from formal to informal. The main barriers preventing physiotherapists from using USI were lack of training, access to equipment, and equipment expense. CONCLUSIONS: The participants reported a variety of clinical uses of USI and levels of training. A better understanding of the clinical uses and benefits of USI would enhance both training and clinical uptake. With the identification of barriers limiting physiotherapists' use of USI, ways to overcome these in New Zealand can now be explored further. PMID- 29247982 TI - Ultrasound surveillance for cholangiocarcinoma in an endemic area: A prove of survival benefits. AB - BACKGROUND AND AIM: Cholangiocarcinoma (CCA) is an aggressive malignancy with rapid progression and poor prognosis. Abdominal ultrasound surveillance may detect early-stage malignancy and improve surgical outcome. However, little data exist on the benefits of abdominal ultrasound surveillance in populations at high risk for CCA development in an endemic area. This study compared survival outcomes of CCA patients recruited through abdominal ultrasound surveillance program and those presented to the hospital independent of surveillance. METHODS: The surveillance population-based cohort was 4225 villagers in Northern Thailand, aged 30-60 years, who consented to a 5-year abdominal ultrasound surveillance program, which included interval ultrasound examinations every 6 months. The non surveillance cohort was hospital-based CCA patients diagnosed during April 2007 to November 2015. Numbers of operable tumors, percentages of R0 resection, and survival analyses were compared between the two cohorts. RESULTS: There were 48 and 192 CCA patients in the surveillance and the non-surveillance cohorts, respectively. Of these, 37/48 (77.1%) and 22/192 (11.5%) were in an operable stage and R0 resections performed in 36/48 (97.3%) and 14/192 (63.6%), respectively. The median survival in each group was 31.8 and 6.7 months, respectively (with correction of lead time bias) (P < 0.0001). By multivariate analysis, abdominal ultrasound surveillance (hazard ratio [HR] = 0.41; P = 0.012), operable stage (HR = 0.11; P < 0.001), and serum albumin >= 3.5 g/dL (HR = 0.42; P < 0.001) were significantly associated with decreased mortality, whereas size of CCA (HR = 1.11; P < 0.001), serum alanine aminotransferase > 40 IU/L (HR = 1.71; P = 0.017), and tumor recurrence (HR = 4.86; P = 0.017) were associated with increased mortality. CONCLUSION: Abdominal ultrasound surveillance provided survival benefits and should be considered in areas highly endemic for CCA to reduce mortality. PMID- 29247983 TI - Relative abundance of mature myostatin rather than total myostatin is negatively associated with bone mineral density in Chinese. AB - Myostatin is mainly secreted by skeletal muscle and negatively regulates skeletal muscle growth. However, the roles of myostatin on bone metabolism are still largely unknown. Here, we recruited two large populations containing 6308 elderly Chinese and conducted comprehensive statistical analyses to evaluate the associations among lean body mass (LBM), plasma myostatin, and bone mineral density (BMD). Our data revealed that total myostatin in plasma was mainly determined by LBM. The relative abundance of mature myostatin (mature/total) was significantly lower in high versus low BMD subjects. Moreover, the relative abundance of mature myostatin was positively correlated with bone resorption marker. Finally, we carried out in vitro experiments and found that myostatin has inhibitory effects on the proliferation and differentiation of human osteoprogenitor cells. Taken together, our results have demonstrated that the relative abundance of mature myostatin in plasma is negatively associated with BMD, and the underlying functional mechanism for the association is most likely through inhibiting osteoblastogenesis and promoting osteoclastogenesis. PMID- 29247984 TI - High serum total cholesterol is associated with suicide mortality in Japanese women independently of menopause. PMID- 29247985 TI - Slow movement resistance training using body weight improves muscle mass in the elderly: A randomized controlled trial. AB - To examine the effect of a 12-week slow movement resistance training using body weight as a load (SRT-BW) on muscle mass, strength, and fat distribution in healthy elderly people. Fifty-three men and 35 women aged 70 years old or older without experience in resistance training participated, and they were randomly assigned to a SRT-BW group or control group. The control group did not receive any intervention, but participants in this group underwent a repeat measurement 12 weeks later. The SRT-BW program consisted of 3 different exercises (squat, tabletop push-up, and sit-up), which were designed to stimulate anterior major muscles. Initially, these exercises were performed by 2 sets of 10 repetitions, and subsequently, the number of repetitions was increased progressively by 2 repetitions every 4 weeks. Participants were instructed to perform each eccentric and concentric phase of movement slowly (spending 4 seconds on each movement), covering the full range of motion. We evaluated muscle mass, strength, and fat distribution at baseline and after 12 weeks of training. Changes over 12 weeks were significantly greater in the SRT-BW group than in the control group, with a decrease in waist circumference, hip circumference, and abdominal preperitoneal and subcutaneous fat thickness, and an increase in thigh muscle thickness, knee extension strength, and hip flexion strength. In conclusion, relatively short term SRT-BW was effective in improving muscle mass, strength, and fat distribution in healthy elderly people. PMID- 29247986 TI - Biology of IL-38 and its role in disease. AB - IL-38 belongs to the IL-36 cytokines, which in turn are part of the IL-1 family. The first biological function of IL-38 described was blocking the activation of the IL-36R signaling similar to IL-36Ra. Since IL-36 cytokines require processing in order to become fully active, it is likely that IL-38 also must be processed to become maximally active. However, the protease(s) responsible for this is currently not known. In addition of IL-38 binding IL-36R, it has been proposed it can also interact with the co-receptor TIGIRR2. IL-38 is expressed in several tissues including tonsils, placenta, heart and brain, and IL-38 has been implicated in a wide variety of diseases including cardiovascular and autoimmune disease. Here, we discuss the discovery and biological function of IL-38, and its role in the pathogenesis of a wide variety of diseases. PMID- 29247987 TI - Suppression of inflammation and acquired immunity by IL-37. AB - IL-37 is a unique member of the IL-1 family of cytokines, which functions as a natural suppressor of inflammatory and immune responses. Immune and non-immune cells produce IL-37 precursor following pro-inflammatory stimuli. Following activating cleavage by caspase-1, mature IL-37 translocates to the nucleus, where it suppresses transcription of pro-inflammatory genes. Both precursor and mature IL-37 are also secreted in the extracellular space, where they bind IL-18Ralpha and recruit the IL-1R8 (formerly TIR8 or SIGIRR), which transduces anti inflammatory signals by suppressing NF-kB and MAPK and by activating Mer-PTEN-DOK pathways. During inflammation, IL-37 restores the metabolism of the cell by reducing succinate, inhibiting mTOR, and activating AMPK. Transgenic mice expressing human IL-37 and wild type mice treated with recombinant human IL-37 are protected from several experimental models of inflammation, including endotoxin shock, colitis, lung and spinal cord injury, coronary artery disease, arthritis and inflammation-induced fatigue, while also exhibiting reduced adaptive immune responses. In humans, IL-37 likely functions to limit excessive inflammation: accordingly, IL-37 levels are abnormal in patients with inflammatory and autoimmune diseases. In this review, we provide an overview of the discovery and biology of IL-37, and discuss the potential for development of this cytokine as a therapeutic agent. PMID- 29247988 TI - Interleukin-18: Biological properties and role in disease pathogenesis. AB - Initially described as an interferon (IFN)gamma-inducing factor, interleukin (IL) 18 is indeed involved in Th1 and NK cell activation, but also in Th2, IL-17 producing gammadelta T cells and macrophage activation. IL-18, a member of the IL 1 family, is similar to IL-1beta for being processed by caspase 1 to an 18 kDa biologically active mature form. IL-18 binds to its specific receptor (IL 18Ralpha, also known as IL-1R7) forming a low affinity ligand chain. This is followed by recruitment of the IL-18Rbeta chain. IL-18 then uses the same signaling pathway as IL-1 to activate NF-kB and induce inflammatory mediators such as adhesion molecules, chemokines and Fas ligand. IL-18 also binds to the circulating high affinity IL-18 binding protein (BP), such as only unbound free IL-18 is active. IL-18Ralpha may also bind IL-37, another member of the IL-1 family, but in association with the negative signaling chain termed IL-1R8, which transduces an anti-inflammatory signal. IL-18BP also binds IL-37 and this acts as a sink for the anti-inflammatory properties of IL-37. There is now ample evidence for a role of IL-18 in various infectious, metabolic or inflammatory diseases such as influenza virus infection, atheroma, myocardial infarction, chronic obstructive pulmonary disease, or Crohn's disease. However, IL-18 plays a very specific role in the pathogenesis of hemophagocytic syndromes (HS) also termed Macrophage Activation Syndrome. In children affected by NLRC4 gain-of-function mutations, IL-18 circulates in the range of tens of nanograms/mL. HS is treated with the IL-1 Receptor antagonist (anakinra) but also specifically with IL-18BP. Systemic juvenile idiopathic arthritis or adult-onset Still's disease are also characterized by high serum IL-18 concentrations and are treated by IL-18BP. PMID- 29247990 TI - The intra- and extracellular functions of ASC specks. AB - Inflammasomes are the central signaling hubs of the inflammatory response. They process cytosolic evidence of infection, cell damage, or metabolic disturbances, and elicit a pro-inflammatory response mediated by members of the interleukin-1 family of cytokines and pyroptotoic cell death. On the molecular level, this is accomplished by the sensor-nucleated recruitment and oligomerization of the adapter protein ASC. Once a tunable threshold is reached, cooperative assembly of ASC into linear filaments and their condensation into macromolecular ASC specks promotes an all-or-none response. These structures are highly regulated and provide a unique signaling platform or compartment to control the activity of caspase-1 and likely other effectors. Emerging evidence indicates that ASC specks are also released from inflammasome-activated cells and accumulate in inflamed tissues, where they can continue to mature cytokines or be internalized by surrounding cells to further nucleate ASC specks in their cytosol. Little is known about the mechanisms governing ASC speck release, uptake, and endosomal escape, as well as its contribution to inflammation and disease. Here, we describe the different outcomes of inflammasome activation and discuss the potential function of extracellular ASC specks. We highlight gaps in our understanding of this central process of inflammation, which may have direct consequences on the modulation of host responses and chronic inflammation. PMID- 29247989 TI - Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8. AB - Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) are key players in immunity and inflammation and are tightly regulated at different levels. Most cell types, including cells of the innate and adaptive immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R2 and IL-1R8 (also known as TIR8 or SIGIRR) are members of the ILR family acting as negative regulators of the IL-1 system. IL-1R2 binds IL-1 and the accessory protein IL-1RAcP without activating signaling and can be released as a soluble form (sIL-1R2), thus modulating IL-1 availability for the signaling receptor. IL-1R8 dampens ILR- and TLR-mediated cell activation and it is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R2 and IL-1R8, focusing on their role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation. We also address the emerging evidence regarding the role of IL-1R8 as a crucial checkpoint molecule in NK cells in anti-cancer and antiviral activity and the potential therapeutic implications of IL-1R8 blockade in specific pathological contexts. PMID- 29247992 TI - Metabolic regulation of NLRP3. AB - A shift in our understanding of macrophage biology has come about as a result of recent discoveries in the area of metabolic reprogramming of macrophages. The NLRP3 inflammasome drives the activation of caspase-1, leading to the production of IL-1beta, IL-18, and a type of cell death termed pyroptosis. The NLRP3 inflammasome has been shown to sense metabolites such as palmitate, uric acid, and cholesterol crystals and is inhibited by ketone bodies produced during metabolic flux. The NLRP3 inflammasome has also been shown to be regulated by mitochondrial reactive oxygen species and components of glycolysis, such as Hexokinase. Here, we review these findings and discuss their importance for inflammation and furthermore discuss potential therapeutic benefits of targeting NLRP3. PMID- 29247993 TI - Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family. AB - Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8+ T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells. PMID- 29247994 TI - Regulation and function of interleukin-36 cytokines. AB - The interleukin (IL)-36 cytokines include 3 agonists, IL-36alpha, IL-36beta, and IL-36gamma that bind to a common receptor composed of IL-36R and IL-1RAcP to stimulate inflammatory responses. IL-36Ra is a natural antagonist that binds to IL-36R, but does not recruit the co-receptor IL-1RAcP and does not stimulate any intracellular responses. The IL-36 cytokines are expressed predominantly by epithelial cells and act on a number of cells including immune cells, epithelial cells, and fibroblasts. Processing of the N-terminus is required for full agonist or antagonist activity for all IL-36 members. The role of IL-36 has been extensively demonstrated in the skin where it can act on keratinocytes and immune cells to induce a robust inflammatory response that has been implicated in psoriatic disorders. Emerging data also suggest a role for this cytokine family in pulmonary and intestinal physiology and pathology. PMID- 29247991 TI - Function and regulation of IL-1alpha in inflammatory diseases and cancer. AB - The interleukin (IL)-1 family of cytokines is currently comprised of 11 members that have pleiotropic functions in inflammation and cancer. IL-1alpha and IL 1beta were the first members of the IL-1 family to be described, and both signal via the same receptor, IL-1R. Over the last decade, much progress has been made in our understanding of biogenesis of IL-1beta and its functions in human diseases. Studies from our laboratory and others have highlighted the critical role of nod-like receptors (NLRs) and multi-protein complexes known as inflammasomes in the regulation of IL-1beta maturation. Recent studies have increased our appreciation of the role played by IL-1alpha in inflammatory diseases and cancer. However, the mechanisms that regulate the production of IL 1alpha and its bioavailability are relatively understudied. In this review, we summarize the distinctive roles played by IL-1alpha in inflammatory diseases and cancer. We also discuss our current knowledge about the mechanisms that control IL-1alpha biogenesis and activity, and the major unanswered questions in its biology. PMID- 29247996 TI - IL-1 and IL-1 regulatory pathways in cancer progression and therapy. AB - Inflammation is an important component of the tumor microenvironment. IL-1 is an inflammatory cytokine which plays a key role in carcinogenesis and tumor progression. IL-1 is subject to regulation by components of the IL-1 and IL-1 receptor (ILR) families. Negative regulators include a decoy receptor (IL-1R2), receptor antagonists (IL-1Ra), IL-1R8, and anti-inflammatory IL-37. IL-1 acts at different levels in tumor initiation and progression, including driving chronic non-resolving inflammation, tumor angiogenesis, activation of the IL-17 pathway, induction of myeloid-derived suppressor cells (MDSC) and macrophage recruitment, invasion and metastasis. Based on initial clinical results, the translation potential of IL-1 targeting deserves extensive analysis. PMID- 29247998 TI - The AIM2 inflammasome: Sensor of pathogens and cellular perturbations. AB - Recognition of pathogens and altered self must be efficient and highly specific to orchestrate appropriate responses while limiting excessive inflammation and autoimmune reaction to normal self. AIM2 is a member of innate immune sensors that detects the presence of DNA, arguably the most conserved molecules in living organisms. However, AIM2 achieves specificity by detecting altered or mislocalized DNA molecules. It can detect damaged DNA, and the aberrant presence of DNA within the cytosolic compartment such as genomic DNA released into the cytosol upon loss of nuclear envelope integrity. AIM2 is also a key sensor of pathogens that detects the presence of foreign DNA accumulating in the cytosol during the life cycle of intracellular pathogens including viruses, bacteria, and parasites. AIM2 activation initiates the assembly of the inflammasome, an innate immune complex that leads to the activation of inflammatory caspases. This triggers the maturation and secretion of the cytokines IL-1beta and IL-18. It can also initiate pyroptosis, a proinflammatory form of cell death. The AIM2 inflammasome contributes to physiological responses and diseases. It is a key player in host defenses, but its deregulation can contribute immune-linked diseases, such as autoinflammatory and autoimmune pathologies. Moreover, AIM2 may play a role in cancer development. Recent studies have shown that the detection of self-DNA species by AIM2 is an important factor that contributes to diseases associated with perturbation of cellular homeostasis. Thus, in addition of being a sensor of pathogen associated molecular patterns (PAMPs), the AIM2 inflammasome is emerging as a key guardian of cellular integrity. PMID- 29247997 TI - The NLRC4 Inflammasome. AB - 15 years ago, the fundamental biology of an inflammatory signaling complex eventually dubbed "the inflammasome" began to unravel in chronologic parallel with the discovery that many inflammatory diseases were associated with its hyperactivity. Though the genetic origins of Familial Mediterranean Fever (FMF, caused my mutations in MEFV) were discovered first, it would take nearly two decades before the mechanistic connections to a PYRIN inflammasome were made. In the interim, the intensive study of the NLRP3 inflammasome, and the diseases associated with its hyperactivation, have largely dictated the paradigm of inflammasome composition and function. Despite impressive gains, focusing on NLRP3 left gaps in our understanding of inflammasome biology. Foremost among these gaps were how inflammasomes become activated and the connections between inflammasome structure and function. Fortunately, work in another inflammasome inducer, NLRC4, grew to fill those gaps. The current understanding of the NLRC4 inflammasome is perhaps the most comprehensive illustration of the inflammasome paradigm: trigger (e.g. cytosolic flagellin), sensor (NAIP), nucleator (NLRC4), adaptor (ASC), and effector (CASP1). Detailed work has also identified observations that challenge this paradigm. Simultaneously, the features unique to each inflammasome offer a lesson in contrast, providing perspectives on inflammasome activation, regulation, and function. In this review, we endeavor to highlight recent breakthroughs related to NLRC4 inflammasome structure and activation, important in vivo work in infection and systemic inflammation, and the characterization of a spectrum of human NLRC4-associated autoinflammatory diseases. PMID- 29247995 TI - Overview of the IL-1 family in innate inflammation and acquired immunity. AB - The interleukin-1 (IL-1) family of cytokines and receptors is unique in immunology because the IL-1 family and Toll-like receptor (TLR) families share similar functions. More than any other cytokine family, the IL-1 family is primarily associated with innate immunity. More than 95% of living organisms use innate immune mechanisms for survival whereas less than 5% depend on T- and B cell functions. Innate immunity is manifested by inflammation, which can function as a mechanism of host defense but when uncontrolled is detrimental to survival. Each member of the IL-1 receptor and TLR family contains the cytoplasmic Toll-IL 1-Receptor (TIR) domain. The 50 amino acid TIR domains are highly homologous with the Toll protein in Drosophila. The TIR domain is nearly the same and present in each TLR and each IL-1 receptor family. Whereas IL-1 family cytokine members trigger innate inflammation via IL-1 family of receptors, TLRs trigger inflammation via bacteria, microbial products, viruses, nucleic acids, and damage associated molecular patterns (DAMPs). In fact, IL-1 family member IL-1a and IL 33 also function as DAMPs. Although the inflammatory properties of the IL-1 family dominate in innate immunity, IL-1 family member can play a role in acquired immunity. This overview is a condensed update of the IL-1 family of cytokines and receptors. PMID- 29247999 TI - Interleukin 1 gene polymorphism and susceptibility to disease. AB - The Interleukin 1 (IL-1) family plays a central role in the generation and regulation of inflammatory responses, in both innate and adaptive immunity. Although the IL-1 molecules are traditionally considered to be classical proinflammatory cytokines, their functions are not restricted to inflammation, and they have also been shown to play a key role in a wide range of additional physiological and pathological functions, including learning modulation, sleep, pregnancy, depression, appetite, hematopoiesis, metabolism, and many others. Since their effect as cytokines and regulators of inflammation is so pleiotropic, any shift of the biological balance between agonistic and antagonistic signals has the potential to cause disease. Here, we consider the genetic influence of interleukin-1 gene polymorphism in the context of susceptibility to human diseases. We review known single nucleotide polymorphisms (SNP) of IL-1 genes linked to human diseases, and suggest how exploring biological effects of IL-1 gene cluster polymorphism may lead to new directions in understanding and diagnostic of disease and effective treatment. PMID- 29248000 TI - Autophagy limits activation of the inflammasomes. AB - Inflammasomes are multiprotein complexes that control the maturation and production of interleukin-1 family members and play crucial roles in host defense against pathogens. However, dysregulated activation of inflammasomes is associated with intense inflammation, leading to the development of inflammatory diseases. Therefore, inflammasomes must be activated at a proper strength to protect against infection and avoid tissue damage. Recent studies have highlighted the cross-talk between inflammasome activation and autophagy, the cellular machinery associated with the degradation of intracellular components and maintenance of cellular homeostasis. Notably, deficiencies in autophagy related proteins induce the aberrant activation of inflammasomes, causing severe tissue damage. In contrast, autophagy inducers ameliorate symptoms of inflammasome-related diseases. In this review, we discuss recent advances in the involvement of autophagy in regulating inflammasomes activation and in the development of inflammatory diseases. PMID- 29248001 TI - Introduction to the interleukin-1 family of cytokines and receptors: Drivers of innate inflammation and acquired immunity. PMID- 29248002 TI - The family of the interleukin-1 receptors. AB - The extracellular forms of the IL-1 cytokines are active through binding to specific receptors on the surface of target cells. IL-1 ligands bind to the extracellular portion of their ligand-binding receptor chain. For signaling to take place, a non-binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll-IL-1-receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL 1 receptors (IL-1R) includes 10 structurally related members, and the distantly related soluble protein IL-18BP that acts as inhibitor of the cytokine IL-18. Over the years the receptors of the IL-1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand-binding chains (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), 2 types of accessory chains (IL 1R3, IL-1R7), molecules that act as inhibitors of signaling (IL-1R2, IL-1R8, IL 18BP), and 2 orphan receptors (IL-1R9, IL-1R10). In this review, we will examine how the receptors of the IL-1 family regulate the inflammatory and anti inflammatory functions of the IL-1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL-1/IL-1R system in the brain will be also described, as an example of the peculiarities of organ-specific modulation of inflammation. PMID- 29248003 TI - The role of the interleukin-1 family in trained immunity. AB - Immunological memory was long considered a trait exclusive to cells of the adaptive immune system. However, recent studies have shown that after activation of the innate immune system, innate immune cells may undergo long-term functional reprogramming characterized by the ability to mount either a stronger or attenuated inflammatory response upon reactivation. This phenomenon, which has been termed trained immunity and is a de facto innate immune memory, is regulated by a network of integrated metabolic and epigenetic rewiring. The endogenous mediators that modulate trained immunity in the host are only partially understood, but increasing evidence supports the concept that the interleukin (IL)-1 family of cytokines plays an important role. In this review, we will highlight key findings from studies that provide insight into the multifaceted roles of members of the IL-1 family for trained immunity. Finally, we will discuss how the recent advances of our understanding on the role of IL-1 cytokines in this field may lead to new therapeutic strategies for treatment of common conditions, such as IL-1-driven autoinflammatory diseases. PMID- 29248004 TI - Intact Cell Mass Spectrometry as a Quality Control Tool for Revealing Minute Phenotypic Changes of Cultured Human Embryonic Stem Cells. AB - The stability of in vitro cell cultures is an important issue for any clinical, bio-industrial, or pharmacological use. Embryonic stem cells are pluripotent; consequently, they possess the ability to differentiate into all three germ layers and are inherently prone to respond to differentiation stimuli. However, long-term culture inevitably yields clones that are best adapted to the culture conditions, passaging regimes, or differentiation sensitivity. This cellular plasticity is a major obstacle in the development of bio-industrial or clinical grade cultures. At present, the quality control of cell cultures is limited by the lack of reliable (epi)genetic or molecular markers or by the focus on a particular type of instability such as karyotype abnormalities or adverse phenotypic traits. Therefore, there is an ongoing need for robust, feasible, and sensitive methods of determining or confirming cell status and for revealing potential divergences from the optimal state. We modeled both intrinsic and extrinsic changes in human embryonic stem cell (hESC) states using different experimental strategies and addressed the changes in cell status by intact cell mass spectrometry fingerprinting. The analysis of spectral fingerprints by methods routinely used in analytical chemistry clearly distinguished the morphologically and biochemically similar populations of hESCs and provided a biomarker-independent tool for the quality control of cell culture. Stem Cells Translational Medicine 2018;7:109-114. PMID- 29248006 TI - Editorial. PMID- 29248007 TI - YET ANOTHER ATTACK ON WAGES AND CONDITIONS. AB - An unobjectionable-sounding title obscures the real intent of the latest in a series of Bills which the federal Coalition government is attempting to legislate in its ongoing attempts to undermine employee wages and conditions and attack unions. PMID- 29248005 TI - Short-term disuse promotes fatty acid infiltration into skeletal muscle. AB - BACKGROUND: Many physiological and/or pathological conditions lead to muscle deconditioning, a well-described phenomenon characterized by a loss of strength and muscle power mainly due to the loss of muscle mass. Fatty infiltrations, or intermuscular adipose tissue (IMAT), are currently well-recognized components of muscle deconditioning. Despite the fact that IMAT is present in healthy human skeletal muscle, its increase and accumulation are linked to muscle dysfunction. Although IMAT development has been largely attributable to inactivity, the precise mechanisms of its establishment are still poorly understood. Because the sedentary lifestyle that accompanies age-related sarcopenia may favour IMAT development, deciphering the early processes of muscle disuse is of great importance before implementing strategies to limit IMAT deposition. METHODS: In our study, we took advantage of the dry immersion (DI) model of severe muscle inactivity to induce rapid muscle deconditioning during a short period. During the DI, healthy adult men (n = 12; age: 32 +/- 5) remained strictly immersed, in a supine position, in a controlled thermo-neutral water bath. Skeletal muscle biopsies were obtained from the vastus lateralis before and after 3 days of DI. RESULTS: We showed that DI for only 3 days was able to decrease myofiber cross sectional areas (-10.6%). Moreover, protein expression levels of two key markers commonly used to assess IMAT, perilipin, and fatty acid binding protein 4, were upregulated. We also observed an increase in the C/EBPalpha and PPARgamma protein expression levels, indicating an increase in late adipogenic processes leading to IMAT development. While many stem cells in the muscle environment can adopt the capacity to differentiate into adipocytes, fibro-adipogenic progenitors (FAPs) represent the population that appears to play a major role in IMAT development. In our study, we showed an increase in the protein expression of PDGFRalpha, the specific cell surface marker of FAPs, in response to 3 days of DI. It is well recognized that an unfavourable muscle environment drives FAPs to ectopic adiposity and/or fibrosis. CONCLUSIONS: This study is the first to emphasize that during a short period of severe inactivity, muscle deconditioning is associated with IMAT development. Our study also reveals that FAPs could be the main resident muscle stem cell population implicated in ectopic adiposity development in human skeletal muscle. PMID- 29248008 TI - CHRONIC DISEASE CRISIS. WHY PREVENTION IS BETTER THAN CURE. AB - A health check-up shows the burden of chronic disease is crippling our nation. About half of all Australians now have a chronic disease while 20% have multiple chronic diseases. It's time we changed course to prioritise prevention, health promotion and early detection, while recognizing the valuable contribution of nurses and midwives, to combat the skyrocketing incidence of chronic illnesses, writes Karen Keast. PMID- 29248009 TI - THE HARMS OF HATE SPEECH. AB - In 2009, Andrew Bolt, an Australian journalist and right wing columnist, published two articles in the Herald-Sun in which he impugned the identity and authenticity of 'fair skinned' Aboriginal people. His articles conveyed the offensive messages that fair-skinned Aboriginal people 'were not genuinely Aboriginal and were pretending to be Aboriginal so they could access benefits that are available to Aboriginal people' (http://www.austlii.edu.au/cgibin/sinodisp/au/cases/cth/FCA/2011/1103.html). PMID- 29248010 TI - USING ADENOSINETRIPHOSPHATE BIOLUMINESCENCE TO VALIDATE DECONTAMINATION FOR DUODENOSCOPES. AB - Reports of outbreaks involving Carbapenemase resistant Enterobacteriaceae have been associated with gastrointestinal endoscopy. We used Adenosinetriphosphate (ATP) bioluminescence to demonstrate cleanliness prior to Endoscopic Retrograde Cholangiopancreatography (ERCP). We compared ATP testing with microbiological monitoring for 40 duodenoscopes. ATP testing of duodenoscopes prior to ERCP procedures provided a timely marker of safety and quality. PMID- 29248011 TI - What are they thinking? Facilitating clinical reasoning through longitudinal patient exposure in rural practice. AB - INTRODUCTION: This article reports the findings from an international research workshop, held over 2 days in October 2014 in Bairnsdale, Australia, which brought together 19 clinician teachers and medical educators who work in rural primary care. The objectives of the workshop were to clarify and identify the key aspects of the development of clinical reasoning in students and junior doctors, particularly as a result of longitudinal immersion in rural community practice. METHODS: Delegates were asked to prepare a 55-word vignette related to their experience of teaching clinical reasoning, and these case studies formed the basis of identification of key issues, further refined via a modified Delphi process. RESULTS: The workshop identified four key themes: the patient’s story, the learner’s reasoning, the context of learning, and the role of the supervisor. Exposure to undifferentiated patient presentations is increasingly common in medical education, particularly in longitudinal integrated placements. CONCLUSIONS: This research explored clinicians’ perspectives of how students develop their clinical reasoning: by learning from patients, from their supervisors and by understanding the context of their clinical interactions.  . PMID- 29248012 TI - Correction to: Novel phenotypic variant in the MYH7 spectrum due to a stop-loss mutation in the C-terminal region: a case report. AB - Following publication of the original article [1], the authors requested a correction to the details of one of the co-authors. PMID- 29248013 TI - Fertility-sparing surgery in advanced stage malignant ovarian germ cell tumor: a case report. AB - BACKGROUND: Malignant ovarian germ cell tumor is a rare type of disease, which generally has a good prognosis due to the high chemosensitivity of this type of tumor. Fertility preservation is an important issue because malignant ovarian germ cell tumor commonly affects young women. Although conservation is the standard for early stage, it becomes more debatable as the disease progresses to more advanced stages. AIM: Report the case of a patient with an International Federation of Gynecology and Obstetrics Stage IIIc malignant ovarian germ cell tumor, who had conservative surgery and chemotherapy with a good fertility outcome. CASE PRESENTATION: A 23-year-old North African woman with a left malignant ovarian germ cell tumor stage IIIc was treated by left adnexectomy and omentectomy followed by chemotherapy. A 15-year follow-up showed no signs of relapse, and she completed three full-term natural pregnancies. CONCLUSIONS: Malignant ovarian germ cell tumor is a rare ovarian tumor with a good prognosis. It is usually associated with a good fertility outcome in early stages. However, due to the rarity of the disease in advanced stages, the fertility outcome for this group of patients is not clear. This lack of data surrounding advanced stages points to the need for a meta-analysis of all published cases. PMID- 29248015 TI - Plant extracts as a natural treatment against the fish ectoparasite Neobenedenia sp. (Monogenea: Capsalidae). AB - The toxicity of water-ethanol extracts of garlic (Allium sativum), ginger (Zingiber officinale), basil (Ocimum basilicum), bitter chaparro (Castela tortuousa), onion (Allium cepa) and papaya (Carica papaya) against adults, eggs and oncomiracidia of Neobenedenia spp. parasites was examined. Parasites were exposed to continuous immersion and treated as follows: extracts were tested at three dilutions: 1:10, 1:50 and 1:100 made with filtered seawater (35 g l-1); ethanol (70%) was evaluated at the same dilutions of 1:10 (7% ethanol), 1:50 (1.4% ethanol) and 1:100 (0.07% ethanol) and a seawater (35 g l-1) control. The antiparasitic effect was measured on: (1) adult survival, egg production and time to detachment from the culture vessel; (2) egg development and cumulative egg hatching; and (3) oncomiracidia survival. All three dilutions of ginger and dilutions 1:100 and 1:50 of basil extract reduced adult survival in vitro, time to detachment from the surface of the culture vessel, egg production and oncomiracidia survival. Bitter chaparro extract reduced adult egg production and oncomiracidia survival. Hatching success was significantly reduced (P < 0.05) in basil extract (1:100) to 86.6% compared to the seawater control (100%). Dilutions 1:10 of ginger and basil exhibited the highest impact on the biological parameters of Neobenedenia sp. Our study demonstrates that water-ethanol extracts of ginger, basil and bitter chaparro are toxic against Neobenedenia sp. life stages. PMID- 29248014 TI - A cluster randomized controlled trial of lay health worker support for prevention of mother to child transmission of HIV (PMTCT) in South Africa. AB - BACKGROUND: We evaluate the impact of clinic-based PMTCT community support by trained lay health workers in addition to standard clinical care on PMTCT infant outcomes. METHODS: In a cluster randomized controlled trial, twelve community health centers (CHCs) in Mpumalanga Province, South Africa, were randomized to have pregnant women living with HIV receive either: a standard care (SC) condition plus time-equivalent attention-control on disease prevention (SC; 6 CHCs; n = 357), or an enhanced intervention (EI) condition of SC PMTCT plus the "Protect Your Family" intervention (EI; 6 CHCs; n = 342). HIV-infected pregnant women in the SC attended four antenatal and two postnatal video sessions and those in the EI, four antenatal and two postnatal PMTCT plus "Protect Your Family" sessions led by trained lay health workers. Maternal PMTCT and HIV knowledge were assessed. Infant HIV status at 6 weeks postnatal was drawn from clinic PCR records; at 12 months, HIV status was assessed by study administered DNA PCR. Maternal adherence was assessed by dried blood spot at 32 weeks, and infant adherence was assessed by maternal report at 6 weeks. The impact of the EI was ascertained on primary outcomes (infant HIV status at 6 weeks and 12 months and ART adherence for mothers and infants), and secondary outcomes (HIV and PMTCT knowledge and HIV transmission related behaviours). A series of logistic regression and latent growth curve models were developed to test the impact of the intervention on study outcomes. RESULTS: In all, 699 women living with HIV were recruited during pregnancy (8-24 weeks), and assessments were completed at baseline, at 32 weeks pregnant (61.7%), and at 6 weeks (47.6%), 6 months (50.6%) and 12 months (59.5%) postnatally. Infants were tested for HIV at 6 weeks and 12 months, 73.5% living infants were tested at 6 weeks and 56.7% at 12 months. There were no significant differences between SC and EI on infant HIV status at 6 weeks and at 12 months, and no differences in maternal adherence at 32 weeks, reported infant adherence at 6 weeks, or PMTCT and HIV knowledge by study condition over time. CONCLUSION: The enhanced intervention administered by trained lay health workers did not have any salutary impact on HIV infant status, ART adherence, HIV and PMTCT knowledge. Trial registration clinicaltrials.gov: number NCT02085356. PMID- 29248017 TI - An analysis of true- and false-positive results of vocal fold uptake in positron emission tomography-computed tomography imaging. AB - OBJECTIVES: Positron emission tomography-computed tomography with fluorine-18 fluorodeoxy-D-glucose has a major role in the investigation of head and neck cancers. Fluorine-18 fluorodeoxy-D-glucose is not a tumour-specific tracer and can also accumulate in benign pathology. Therefore, positron emission tomography computed tomography scan interpretation difficulties are common in the head and neck, which can produce false-positive results. This study aimed to investigate patients detected as having abnormal vocal fold uptake on fluorine-18 fluorodeoxy D-glucose positron emission tomography-computed tomography. METHODS: Positron emission tomography-computed tomography scans were identified over a 15-month period where reports contained evidence of unilateral vocal fold uptake or vocal fold pathology. Patients' notes and laryngoscopy results were analysed. RESULTS: Forty-six patients were identified as having abnormal vocal fold uptake on positron emission tomography-computed tomography. Twenty-three patients underwent positron emission tomography-computed tomography and flexible laryngoscopy: 61 per cent of patients had true-positive positron emission tomography-computed tomography scans and 39 per cent had false-positive scan results. CONCLUSION: Most patients referred to ENT for abnormal findings on positron emission tomography-computed tomography scans had true-positive findings. Asymmetrical fluorine-18 fluorodeoxy-D-glucose uptake should raise suspicion of vocal fold pathology, accepting a false-positive rate of approximately 40 per cent. PMID- 29248016 TI - New generation cut-and-seal devices in oral and oropharyngeal cancer resection: clinical and cost-effectiveness study. AB - OBJECTIVES: To evaluate the clinical efficacy and cost-effectiveness of ultrasonic shears and the electrothermal bipolar vessel sealing system, in comparison to the traditional cold knife and bipolar forceps, in oral and oropharyngeal cancer surgery. METHODS: Patients who underwent oral or oropharyngeal cancer resection and neck dissection with either ultrasonic shears (n = 36) or electrothermal bipolar vessel sealing (n = 32) were enrolled. Surgical time, intra-operative bleeding, blood drainage, post-operative pain, neck oedema, complications and hospitalisation duration were compared to those of an historical cohort of 36 patients treated using a cold knife and bipolar forceps. Additionally, a cost-effectiveness evaluation was performed. RESULTS: Ultrasonic shears and, in particular, electrothermal bipolar vessel sealing, were advantageous compared to the traditional techniques. The cost of ultrasonic shears and electrothermal bipolar vessel sealing was completely offset by declining time-driven costs for the surgical team and operating theatre. CONCLUSION: Ultrasonic shears and, in particular, electrothermal bipolar vessel sealing, are more advantageous compared to the traditional techniques, from both a clinical and economic point of view. PMID- 29248019 TI - Refining the assessment of disrupted maternal communication: Using item response models to identify central indicators of disrupted behavior. AB - The Atypical Maternal Behavior Instrument for Assessment and Classification (AMBIANCE; Bronfman, Madigan, & Lyons-Ruth, 2009-2014; Bronfman, Parsons, & Lyons Ruth, 1992-2004) is a widely used and well-validated measure for assessing disrupted forms of caregiver responsiveness within parent-child interactions. However, it requires evaluating approximately 150 behavioral items from videotape and extensive training to code, thus making its use impractical in most clinical contexts. Accordingly, the primary aim of the current study was to identify a reduced set of behavioral indicators most central to the AMBIANCE coding system using latent-trait item response theory (IRT) models. Observed mother-infant interaction data previously coded with the AMBIANCE was pooled from laboratories in both North America and Europe (N = 343). Using 2-parameter logistic IRT models, a reduced set of 45 AMBIANCE items was identified. Preliminary convergent and discriminant validity was evaluated in relation to classifications of maternal disrupted communication assigned using the full set of AMBIANCE indicators, to infant attachment disorganization, and to maternal sensitivity. The results supported the construct validity of the refined item set, opening the way for development of a brief screening measure for disrupted maternal communication. IRT models in clinical scale refinement and their potential for bridging clinical and research objectives in developmental psychopathology are discussed. PMID- 29248020 TI - Gene * Environment contributions to autonomic stress reactivity in youth. AB - Dysregulated physiological stress reactivity has been suggested to impact the development of children and adolescents with important health consequences throughout the life span. Both environmental adversity and genetic predispositions can lead to physiological imbalances in stress systems, which in turn lead to developmental differences. We investigated genetic and environmental contributions to autonomic nervous system reactivity to a psychosocial stressor. Furthermore, we tested whether these effects were consistent with the differential susceptibility framework. Composite measures of adverse life events combined with socioeconomic status were constructed. Effects of these adversity scores in interaction with a polygenic score summarizing six genetic variants, which were hypothesized to work as susceptibility factors, were tested on autonomic nervous system measures as indexed by heart rate and heart rate variability. Results showed that carriers of more genetic variants and exposed to high adversity manifested enhanced heart rate variability reactivity to a psychosocial stressor compared to carriers of fewer genetic variants. Conversely, the stress procedure elicited a more moderate response in these individuals compared to carriers of fewer variants when adversity was low. PMID- 29248018 TI - An outbreak of Shiga toxin-producing Escherichia coli O157:H7 associated with contaminated salad leaves: epidemiological, genomic and food trace back investigations. AB - In August 2015, Public Health England detected an outbreak of Shiga toxin producing Escherichia coli (STEC) serotype O157:H7 caused by contaminated salad leaves in a mixed leaf prepacked salad product from a national retailer. The implicated leaves were cultivated at five different farms and the zoonotic source of the outbreak strain was not determined. In March 2016, additional isolates from new cases were identified that shared a recent common ancestor with the outbreak strain. A case-case study involving the cases identified in 2016 revealed that ovine exposures were associated with illness (n = 16; AOR 8.24; 95% CI 1.55-39.74). By mapping the recent movement of sheep and lambs across the United Kingdom, epidemiological links were established between the cases reporting ovine exposures. Given the close phylogenetic relationship between the outbreak strain and the isolates from cases with ovine exposures, it is plausible that ovine faeces may have contaminated the salad leaves via untreated irrigation water or run-off from fields nearby. Timely and targeted veterinary and environmental sampling should be considered during foodborne outbreaks of STEC, particularly where ready to eat vegetables and salads are implicated. PMID- 29248021 TI - Heightened connectivity between the ventral striatum and medial prefrontal cortex as a biomarker for stress-related psychopathology: understanding interactive effects of early and more recent stress. AB - BACKGROUND: The experience of childhood maltreatment is a significant risk factor for the development of depression. This risk is particularly heightened after exposure to additional, more contemporaneous stress. While behavioral evidence exists for this relation, little is known about biological correlates of these stress interactions. Identifying such correlates may provide biomarkers of risk for later depression. METHODS: Here, we leverage behavioral, experiential, and neuroimaging data from the Duke Neurogenetics Study to identify potential biomarkers of stress exposure. Based on the past research, we were specifically interested in reward-related connectivity and the interaction of early and more recent stress. We examined psychophysiological interactions between the ventral striatum and other brain regions in relation to these stress variables, as well as measures of internalizing symptomatology (n = 926, participant age range = 18 22 years of age). RESULTS: We found relatively increased reward-related functional connectivity between the left ventral striatum and the medial prefrontal cortex in individuals exposed to greater levels of childhood maltreatment who also experienced greater levels of recent life stress (beta = 0.199, p < 0.005). This pattern of functional connectivity was further associated with elevated symptoms of depression (beta = 0.089, p = 0.006). Furthermore, using a moderated mediation framework, we demonstrate that this functional connectivity provides a biological link between cumulative stress exposure and internalizing symptomatology. CONCLUSIONS: These findings suggest a novel biomarker linking cumulative stress exposure with the later experience of depressive symptoms. Our results are discussed in the context of past research examining stress exposure in relation to depression. PMID- 29248022 TI - Analysis of sexual healthcare provided by school nurses. AB - : AimThe aim of this study was to explore the role and activities of the school nursing service in sexual health within a large inner London borough. BACKGROUND: School nurses (SNs) are specialist community public health nurses working with the school age population to promote their health and well-being and therefore are arguably in a prime position to promote the sexual health of children and young people. This is particularly pertinent in inner city boroughs where the rates of sexually transmitted infections and under-18 conceptions are a significant problem. METHODS: Following a review of the literature, a mixed methods study was undertaken which included an audit of documentary data to identify the referrals received in relation to sexual health and also included questionnaire surveys of school staff and SNs on their views of the role of the SN in sexual health.FindingsSNs and school staff identified that SNs have a role in sexual health, which was reflected in the referrals received during the audit of documentary data. There appeared to be inconsistencies across the service and evidence suggested that the school nursing service may be underutilised in comparison to the number of students who require sexual health support. The current service appears to be predominantly reactive, particularly for males and those less than 12 years old. However, both SNs and school staff would like to see a more preventative approach; including greater sexual health promotion, condom distribution and school health clinics. PMID- 29248023 TI - Readmissions With Multidrug-Resistant Infection in Patients With Prior Multidrug Resistant Infection. AB - OBJECTIVE To determine incidence of and risk factors for readmissions with multidrug-resistant organism (MDRO) infections among patients with previous MDRO infection. DESIGN Retrospective cohort of patients admitted between January 1, 2006, and October 1, 2015. SETTING Barnes-Jewish Hospital, a 1,250-bed academic tertiary referral center in St Louis, Missouri. METHODS We identified patients with MDROs obtained from the bloodstream, bronchoalveolar lavage (BAL)/bronchial wash, or other sterile sites. Centers for Disease Control and prevention (CDC) and European CDC definitions of MDROs were utilized. All readmissions <=1 year from discharge from the index MDRO hospitalization were evaluated for bloodstream, BAL/bronchial wash, or other sterile site cultures positive for the same or different MDROs. RESULTS In total, 4,429 unique patients had a positive culture for an MDRO; 3,453 of these (78.0%) survived the index hospitalization. Moreover, 2,127 patients (61.6%) were readmitted >=1 time within a year, for a total of 5,849 readmissions. Furthermore, 512 patients (24.1%) had the same or a different MDRO isolated from blood, BAL/bronchial wash, or another sterile site during a readmission. Bone marrow transplant, end-stage renal disease, lymphoma, methicillin-resistant Staphylococcus aureus, or carbapenem-resistant Pseudomonas aeruginosa during index hospitalization were factors associated with increased risk of having an MDRO isolated during a readmission. MDROs isolated during readmissions were in the same class of MDRO as the index hospitalization 9%-78% of the time, with variation by index pathogen. CONCLUSIONS Readmissions among patients with MDRO infections are frequent. Various patient and organism factors predispose to readmission. When readmitted patients had an MDRO, it was often a pathogen in the same class as that isolated during the index admission, with the exception of Acinetobacter (~9%). Infect Control Hosp Epidemiol 2018;39:12-19. PMID- 29248025 TI - Post-cooling survival, growth and deformity rates in zebrafish embryos (Danio rerio). AB - This study investigated and analysed survival, growth and macro- and microscopic damage during the development of zebrafish embryos up to the adult stage after undergoing cooling. The embryos at 50% epiboly stage were selected, submerged in cryoprotectant solution of methanol and sucrose, cooled gradually to 0 +/- 2 degrees C temperature, and divided into two groups with different storage times (6 and 18 h). Subsequently, the embryos were reheated, rehydrated and incubated normally. The experiment lasted 5 months and, from hatching onward, the larvae were examined, collected and processed at pre-established time intervals. The hatching rate was significantly higher for the larvae stored for 18 h compared with the 6-h group. However, embryos from this group gave rise to a larger number of malformations, and these were much more severe compared with those in the 6 h group, which led to a higher mortality in the long term. Regarding larval length, the animals of the 6 h group had higher mean total length compared with the 18 h group, but both treatments were inferior to the control. Numerous macro- and microscopic malformations were observed and, in both treatments, only the morphologically normal individuals were able to develop to the adult stage, with organ development similar to the control, except for the gonads that were still undifferentiated in treated animals. PMID- 29248024 TI - Association between malaria incidence and meteorological factors: a multi location study in China, 2005-2012. AB - This study aims to investigate the climate-malaria associations in nine cities selected from malaria high-risk areas in China. Daily reports of malaria cases in Anhui, Henan, and Yunnan Provinces for 2005-2012 were obtained from the Chinese Center for Disease Control and Prevention. Generalized estimating equation models were used to quantify the city-specific climate-malaria associations. Multivariate random-effects meta-regression analyses were used to pool the city specific effects. An inverted-U-shaped curve relationship was observed between temperatures, average relative humidity, and malaria. A 1 degrees C increase of maximum temperature (T max) resulted in 6.7% (95% CI 4.6-8.8%) to 15.8% (95% CI 14.1-17.4%) increase of malaria, with corresponding lags ranging from 7 to 45 days. For minimum temperature (T min), the effect estimates peaked at lag 0 to 40 days, ranging from 5.3% (95% CI 4.4-6.2%) to 17.9% (95% CI 15.6-20.1%). Malaria is more sensitive to T min in cool climates and T max in warm climates. The duration of lag effect in a cool climate zone is longer than that in a warm climate zone. Lagged effects did not vanish after an epidemic season but waned gradually in the following 2-3 warm seasons. A warming climate may potentially increase the risk of malaria resurgence in China. PMID- 29248026 TI - Prevalence of food neophobia in pre-school children from southern Poland and its association with eating habits, dietary intake and anthropometric parameters: a cross-sectional study. AB - OBJECTIVES: The present study aimed to assess the prevalence of food neophobia in pre-school children and its association with eating habits, dietary intake and anthropometric parameters. DESIGN: Cross-sectional survey performed in 2012-2013. The Child Food Neophobia Scale (CFNS) adapted by Wardle, Carnell and Cooke was used to assess the level of food neophobia. Dietary intake was measured using an FFQ and dietary records from three days. Anthropometric measurements were taken to determine children's nutritional status and BMI was computed based on Polish growth charts. Wilcoxon's rank test and Pearson's rank-correlation coefficient were applied to compare the level of food neophobia and frequency of consumption of food products and nutrient intakes. SETTING: Kindergartens in southern Poland located in or near Cracow. SUBJECTS: Three hundred and twenty-five pre-school children and their parents. RESULTS: Low neophobia was observed in 12.3 % and high neophobia in 10.8 % of the children examined. Children with a high level of neophobia were significantly less likely (P<0.05) to eat eggs, raw or cooked vegetables and legumes, whereas they tended to eat sweets and snacks more frequently; these foodstuffs were also eaten more often between meals. Because the neophobic children ate vegetables very rarely, their intakes of vitamin C (36 % of RDA) and thiamin (84 % of RDA) were far below the norms. No differences in anthropometric parameters according to level of food neophobia were observed. CONCLUSIONS: High levels of neophobia are associated with diet variation and may enhance the risk of nutritional deficiencies in children. PMID- 29248027 TI - Peripheral levels of superoxide dismutase and glutathione peroxidase in youths in ultra-high risk for psychosis: a pilot study. AB - : Introduction Oxidative stress has been documented in chronic schizophrenia and in the first episode of psychosis, but there are very little data on oxidative stress prior to the disease onset. OBJECTIVE: This work aimed to compare serum levels of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in young individuals at ultra-high risk (UHR) of developing psychosis with a comparison healthy control group (HC). METHODS: Thirteen UHR subjects and 29 age- and sex matched healthy controls (HC) were enrolled in this study. Clinical assessment included the Comprehensive Assessment of At-Risk Mental States (CAARMS), the Semi Structured Clinical Interview for DSM-IV Axis-I (SCID-I) or the Kiddie-SADS Present and Lifetime Version (K-SADS-PL), and the Global Assessment of Functioning (GAF) scale. Activities of SOD and GPx were measured in serum by the spectrophotometric method using enzyme-linked immunosorbent assay kits. RESULTS: After adjusting for age and years of education, there was a significant lower activity of SOD and lower GPX activity in the UHR group compared to the healthy control group (rate ratio [RR]=0.330, 95% CI 0.187; 0.584, p<0.001 and RR=0.509, 95% CI 0.323; 0.803, p=0.004, respectively). There were also positive correlations between GAF functioning scores and GPx and SOD activities. CONCLUSION: Our results suggest that oxidative imbalances could be present prior to the onset of full-blown psychosis, including in at-risk stages. Future studies should replicate and expand these results. PMID- 29248028 TI - Why do patients with minor complaints choose emergency departments and does satisfaction with primary care services influence their decisions? AB - : AimTo identify the reasons why patients with minor complaints choose emergency departments (EDs) as a first contact of care and whether dissatisfaction with primary care services influences their decisions. METHODS: In this study, a self completed survey called EUROPEP was given to 535 outpatients who were admitted to the XXXXX Hospital in Bursa and examined in the green zone in July 2015. Patients were asked about their complaints and why they preferred EDs as a first contact of care. RESULTS: EDs were the first contact of care in 87.8% of cases. In all, 9% of patients registered to family physicians who were working outside the city of Bursa. There was no relationship between patient satisfaction and the number of previous visits to EDs in last 12 months (P=0.09). The main reasons for admitting to the emergency services were feeling excessive pain (20.4%), perception of urgency (14.5%) and that the family doctor services were closed outside working hours (13.2%). The mean patient satisfaction with family practice offices was calculated to be 68.1%. CONCLUSIONS: The frequency of admission to EDs as a first contact of care was extremely high in the absence of a referral system. Patients who did not have family doctors in the settlement where they live put an extra burden on the EDs. Overall, patient satisfaction with their GPs did not influence the number of visits to EDs but accessibility remains a big challenge. PMID- 29248029 TI - The value of the twinkling artefact for the diagnosis of sialolithiasis of the large salivary glands. AB - OBJECTIVE: The imaging of stones in the salivary glands and ducts poses a challenge, even to experienced ultrasound examiners. This study investigated whether the 'twinkling artefact', which occurs at internal calcific foci during Doppler ultrasound examinations, is useful for detecting salivary gland stones. METHODS: In a model test, 20 salivary stones were analysed in vitro, via Doppler ultrasound, with regard to their representability and the triggering of the twinkling artefact. In a follow-up study, 28 patients with sialolithiasis and food-related large salivary gland swellings were examined, using both power and colour Doppler modes, with regard to the twinkling artefact. All ultrasound examinations were performed by an experienced examiner and retrospectively graded by two experienced sonographers. RESULTS: All stones could reliably be detected using the twinkling artefact in the model test. Twenty-seven of 28 salivary stones (96 per cent) also showed twinkling in vivo, during patient assessment. The power Doppler mode showed a significantly higher intensity level of twinkling than the colour Doppler mode (p < 0.0001). CONCLUSION: The twinkling artefact is a very reliable sign for the diagnosis of sialolithiasis. Power Doppler is superior to colour Doppler for detection of the twinkling artefact. PMID- 29248030 TI - Social determinants of household food expenditure in Australia: the role of education, income, geography and time. AB - OBJECTIVE: To examine socio-economic status (SES) and time-related factors associated with less healthy food purchases in Australia. DESIGN: Data were from the 2009/10 Household Expenditure Survey (HES) conducted by the Australian Bureau of Statistics. Regression analysis was used to examine the associations between the proportion of the household food budget spent on various food types (processed and unprocessed foods, foods purchased from takeaways and restaurants) and SES and time constraint variables. SETTING: Australia, 2009-2010. SUBJECTS: Nationally representative sample of Australian households. RESULTS: Household income seems to be the most important correlate with food expenditure patterns once other SES indicators are controlled for. Time constraints appear to explain some, but not all, of the adjusted SES gradients in food expenditure. Comparing home food consumption categories (processed and unprocessed foods) with foods purchased away from home (takeaway and restaurant foods) shows that wealthier, more highly educated and least disadvantaged households spend relatively less of their total food budget on processed and unprocessed foods prepared at home and more on foods purchased away from home at restaurants. CONCLUSIONS: Simple SES gradients in dietary behaviour are influenced by correlations between different SES indicators and between SES and time constraints. Examining these factors separately obscures some of the possible causal effects of disadvantage on healthy eating. When formulating policy responses to unhealthy diets, policy makers should consider alternative sources of disadvantage, including time pressure. PMID- 29248031 TI - Double aortic arch presenting as neonatal respiratory failure in the delivery room. AB - Respiratory symptoms are prevalent in vascular ring anomalies, including double aortic arch, which is considered the most common type of vascular ring. However, respiratory failure owing to critical airway obstruction in the neonatal period is rare with few reported cases in the literature. We report a case of a newborn patient who required emergent intubation within the first few hours of life and was later discovered to have a double aortic arch. PMID- 29248032 TI - Birth weight influences the kidney size and function of Bangladeshi children. AB - Early-life conditions influence organ growth patterns and their functions, as well as subsequent risk for non-communicable chronic diseases in later life. A limited number of studies have determined that in Bangladesh, kidney size relates to its function among children as a consequence of the maternal and postnatal conditions. The present study objectives were to determine early-life conditions in relation to childhood kidney size and to compare their influences on kidney function. The study was embedded in a population-based prospective cohort of 1067 full-term singleton live births followed from fetal life onward. Kidney volume was measured by ultrasound in children at the age of 4.5 years (range 45-64 months), and the estimated glomerular filtration rate (eGFR) was assessed at the age of 9 years (range 96-116 months). The mean (s.d.) kidney volume of children at 4.5 years was 64.2 (11.3) cm3, with a significant mean difference observed between low birth weight and normal birth weight children (P<0.001). The multivariable model showed, changes in status from low birth weight to normal birth weight children, with kidney volume increases of 2.92 cm3/m2, after adjusting for the child's age, sex, maternal age and early pregnancy body mass index, and socio-economic index variables. One-unit change in kidney volume (cm3/m2) improved the eGFR to 0.18 ml/min/1.73 m2. The eGFR in low birth weight children was 5.44 ml/min/1.73 m2 less than that in normal birth weight children after adjustments. Low birth weight leads to adverse effects on kidney size and function in children. PMID- 29248033 TI - Practicing safety: a quality improvement intervention to test tools to enhance pediatric psychosocial care for children 0-3 years. AB - BACKGROUND: Child maltreatment is a significant public health issue in the United States. Yet, fewer than half of pediatricians discuss behavioral, developmental, or parenting issues with parents. OBJECTIVE: This paper describes the testing of bundles of tools and processes, part of a larger intervention, Practicing Safety, targeted at changing physician and staff behavior to identify families at risk for child maltreatment, provide anticipatory guidance, refer to community resources, and follow-up and track at-risk families. The intervention was implemented with 14 pediatric primary care practices throughout the United States; the study was completed in 2011. METHODS: A within-subjects repeated measures pre-post follow-up design was used to evaluate the intervention. Baseline and repeated measurements of pediatric practices' processes were collected using qualitative and quantitative methods. In total, 14 core improvement teams from across the country tested three bundles of tools (maternal, infant, toddler) within a quality improvement framework over seven months. RESULTS: Quantitative results showed statistically significant adoption of tools and processes and enhancement of practice behaviors and office environmental supports. The increase in tool use was immediate and was sustained for six months after implementation. Qualitative data provided insight as to how meaningful the intervention was to the core improvement teams, especially with more complicated behaviors (eg, engaging social workers or community agencies for referrals). Barriers included lack of community resources. Findings showed unanticipated outcomes such as helping practices to become medical homes. CONCLUSION: Lessons learned included that practices appreciate and can adopt brief interventions that have meaningful and useful tools and process to enhance psychosocial care for children 0-3 and that do not place a burden on pediatric practice. An innovative, quality improvement strategy, intuitive to pediatricians, with a brief intervention may help prevent child maltreatment. PMID- 29248034 TI - Health Outcomes for Children in Haiti Since the 2010 Earthquake: A Systematic Review. AB - BACKGROUND: Haiti remains the poorest country in the Americas and one of the poorest in the world. Children in Haiti face many health concerns, some of which were exacerbated by the 2010 earthquake. This systematic review summarizes published research conducted since the 2010 earthquake, focusing on health outcomes for children in Haiti, including physical, psychological, and socioeconomic well-being. METHODS: A literature search was conducted identifying articles published from January 2010 through May 2016 related to pediatric health outcomes in Haiti. Two reviewers screened articles independently. Included research articles described at least one physical health, psychological health, or socioeconomic outcome among children less than 18 years of age in Haiti since the January 2010 earthquake. RESULTS: Fifty-eight full-length research articles were reviewed, covering infectious diseases (non-cholera [N=12] and cholera [N=7]), nutrition (N=11), traumatic injuries (N=11), mental health (N=9), anemia (N=4), abuse and violence (N=5), and other topics (N=3). Many children were injured in the 2010 earthquake, and care of their injuries is described in the literature. Infectious diseases were a significant cause of morbidity and mortality among children following the earthquake, with cholera being one of the most important etiologies. The literature also revealed that large numbers of children in Haiti have significant symptoms of posttraumatic stress disorder (PTSD), peri-traumatic stress, depression, and anxiety, and that food insecurity and malnutrition continue to be important issues. CONCLUSIONS: Future health programs in Haiti should focus on provision of clean water, sanitation, and other measures to prevent infectious diseases. Mental health programming and services for children also appear to be greatly needed, and food insecurity/malnutrition must be addressed if children are to lead healthy, productive lives. Given the burden of injury after the 2010 earthquake, further research on long-term disabilities among children in Haiti is needed. Dube A , Moffatt M , Davison C , Bartels S . Health outcomes for children in Haiti since the 2010 earthquake: a systematic review. Prehosp Disaster Med. 2018;33(1):77-88. PMID- 29248042 TI - Positioning health promotion as a policy priority in Australia. PMID- 29248041 TI - System reform in the human services: what role can health promotion play? PMID- 29248043 TI - Consumer evaluation of 'Veggycation(r)', a website promoting the health benefits of vegetables. AB - Issue addressed Whether the website Veggycation(r) appeals to particular groups of consumers significantly more than other groups. Methods Australian adults aged >=18 years (n = 1000) completed an online survey. The website evaluation instrument used was tested for validity and reliability. Associations between demographic variables and website evaluation dimensions of attractiveness, content, user-friendliness and loyalty intentions were examined using a general linear model (GLM). The appraisal of the website was further investigated based on the respondents' daily consumption level of vegetables and the importance they attach to vegetable consumption in their diet, using GLM and a Tukey's all-pair comparison. Results Veggycation(r) has a high level of acceptance among the Australian community with certain groups evaluating the website more favourably. These include women, people aged<=29 years, higher income respondents, non-metro respondents and those who viewed vegetables as extremely important in their daily diet. Conclusions Customisation of the website for consumer groups with low vegetable consumption is recommended. Designing tailored communication tools will assist in enhancing the knowledge base of vegetable-related health benefits and may promote vegetable consumption among the Australian population. So what? The promotion of higher vegetable consumption is aided by tailored, well-designed web communication. This study adds to the existing body of knowledge for the education of organisations developing e-tools for promoting health education and literacy. PMID- 29248044 TI - Handbook on Gender and Health, edited by Jasmine Gideon. PMID- 29248047 TI - Health Promotion Futures. PMID- 29248048 TI - Achieving equity in Crunch&Sip(r): a pilot intervention of supplementary free fruit and vegetables in NSW classrooms. AB - Issue addressed Anecdotal evidence from teachers in Western Sydney Local Health District (WSLHD) indicated that many primary school children are regularly unable to participate in the Crunch&Sip(r) (C&S) program (breaks during class time to eat fruit and/or vegetables and drink water) as they do not bring produce from home. Actual reach of the program may therefore be currently overestimated, and inequitable. This study examined the feasibility, acceptability and efficacy of providing school children supplementary, fresh free produce in supporting equitable participation in C&S. Methods Free fruit and vegetables were provided for 10 weeks to four schools in a socioeconomically-disadvantaged area in Western Sydney. WSLHD sourced the produce at a discounted rate and storage and distribution was arranged in partnership with industry. Schools determined methods of allocation to children who did not have fruit or vegetables for the C&S break. Pre- and late-intervention (Week 9) classroom surveys provided quantitative data of intervention efficacy. Qualitative methods were used with key school persons to explore barriers and enablers to implementation. Results Participation of children in C&S increased significantly from 46.7% pre intervention to 92.0% in Week 9. The proportion of children bringing fruit or vegetables from home also increased significantly, from 46.7% to 54.0%. Schools perceived the supplementary strategy to be highly feasible and acceptable. Conclusion Expansion of this equity strategy warrants consideration, although issues of sustainability would need to be addressed. The criteria for 'full implementation' should include high proportional participation by students in participating classes. So what? Establishing a system by which schools in disadvantaged areas can supplement their C&S program would effectively increase access to fruit and vegetables among those children most at need. PMID- 29248049 TI - Corrigendum to: Changes in smoking, drinking, overweight and physical inactivity in young Australian women 1996-2013. AB - Issue addressed: Smoking, risky drinking, overweight and obesity, and physical inactivity are health-risk factors (HRFs) that contribute significantly to morbidity worldwide. Several initiatives have been introduced over the past two decades to reduce these HRFs. This paper examines changes in the prevalence of HRFs in young women (aged 18-23 years) between 1996 and 2013, overall and within demographic groups.Methods: Data from two cohorts of the Australian Longitudinal Study on Women's Health, born in 1973-78 (n=14247) and 1989-95 (n=17012) were weighted to provide national estimates. Prevalence ratios were used to compare HRFs in 2013 relative to 1996.Results: In 1996, 32% were current smokers, 38% were risky drinkers, 22% were overweight or obese and 7% were physically inactive. In 2013, corresponding estimates were 19%, 35%, 33% and 6%. Between 1996 and 2013, overall smoking prevalence decreased, but remained over 43% among least educated women. Overweight and obesity increased in all demographic groups.Conclusions: The findings suggest that only smoking, which has been the subject of changes in taxation, legislation and regulation, declined significantly, in all except the least educated women. In contrast, the prevalence of overweight and obesity, which has largely been addressed through awareness campaigns and voluntary actions by the food industry, increased markedly in all demographic sub-groups.So what?: The findings show that comprehensive health promotion interventions, such as those for tobacco control, are successful (but may still be ineffective among less educated women). In contrast the measures to control population weight gain among young women have been futile so far. PMID- 29248051 TI - Health Promotion leads the way in 'knowledge translation': but just a new coat? PMID- 29248053 TI - HOW MIDWIVES ARE REDUCING FEAR OF CHILDBIRTH. AB - Whether it's dramatic childbirth scenes on the screen, the effects of sex abuse, or women sharing their birth horror stories, fear is having a major impact on the way some women give birth. Researchers are now working to conquer women's fears through midwifery-led counselling. PMID- 29248052 TI - Spanish Clinical Guidelines on Vascular Access for Haemodialysis. AB - Vascular access for haemodialysis is key in renal patients both due to its associated morbidity and mortality and due to its impact on quality of life. The process, from the creation and maintenance of vascular access to the treatment of its complications, represents a challenge when it comes to decision-making, due to the complexity of the existing disease and the diversity of the specialities involved. With a view to finding a common approach, the Spanish Multidisciplinary Group on Vascular Access (GEMAV), which includes experts from the five scientific societies involved (nephrology [S.E.N.], vascular surgery [SEACV], vascular and interventional radiology [SERAM-SERVEI], infectious diseases [SEIMC] and nephrology nursing [SEDEN]), along with the methodological support of the Cochrane Center, has updated the Guidelines on Vascular Access for Haemodialysis, published in 2005. These guidelines maintain a similar structure, in that they review the evidence without compromising the educational aspects. However, on one hand, they provide an update to methodology development following the guidelines of the GRADE system in order to translate this systematic review of evidence into recommendations that facilitate decision-making in routine clinical practice, and, on the other hand, the guidelines establish quality indicators which make it possible to monitor the quality of healthcare. PMID- 29248054 TI - Measuring efficiency of health plan payment systems in managed competition health insurance markets. AB - Adverse selection in health insurance markets leads to two types of inefficiency. On the demand side, adverse selection leads to plan price distortions resulting in inefficient sorting of consumers across health plans. On the supply side, adverse selection creates incentives for plans to inefficiently distort benefits to attract profitable enrollees. Reinsurance, risk adjustment, and premium categories address these problems. Building on prior research on health plan payment system evaluation, we develop measures of the efficiency consequences of price and benefit distortions under a given payment system. Our measures are based on explicit economic models of insurer behavior under adverse selection, incorporate multiple features of plan payment systems, and can be calculated prior to observing actual insurer and consumer behavior. We illustrate the use of these measures with data from a simulated market for individual health insurance. PMID- 29248055 TI - Risk adjustment with an outside option. AB - Much of the risk adjustment literature has focused on how persons should be classified and given weights. It has given less attention to the amount of funds in the risk adjustment pool. If, however, there is an outside option, as there is in the principal American risk adjustment systems, there can be favorable or adverse selection in the risk pool. To address any such selection requires that the risk adjustment system not be zero sum; the main American risk adjustment systems differ in this respect. PMID- 29248056 TI - Imperfect risk adjustment, risk preferences, and sorting in competitive health insurance markets. AB - I develop a model of insurer price-setting and consumer welfare under risk adjustment, a policy commonly used to combat inefficient sorting due to adverse selection in health insurance markets. I use the model to illustrate graphically that risk-adjustment causes health plan prices to be based on costs not predicted by the risk-adjustment model ("residual costs") rather than total costs, either weakening or exacerbating selection problems depending on the correlation between demand and costs predicted by the risk-adjustment model. I then use a structural model to estimate the welfare consequences of risk-adjustment, finding a welfare gain of over $600 per person-year. PMID- 29248057 TI - Medicaid program choice, inertia and adverse selection. AB - In 2012, Kentucky implemented Medicaid managed care statewide, auto-assigned enrollees to three plans, and allowed switching. Using administrative data, we find that the state's auto-assignment algorithm most heavily weighted cost minimization and plan balancing, and placed little weight on the quality of the enrollee-plan match. Immobility - apparently driven by health plan inertia - contributed to the success of the cost-minimization strategy, as more than half of enrollees auto-assigned to even the lowest quality plans did not opt-out. High cost enrollees were more likely to opt-out of their auto-assigned plan, creating adverse selection. The plan with arguably the highest quality incurred the largest initial profit margin reduction due to adverse selection prior to risk adjustment, as it attracted a disproportionate share of high-cost enrollees. The presence of such selection, caused by differential degrees of mobility, raises concerns about the long run viability of the Medicaid managed care market without such risk adjustment. PMID- 29248058 TI - Supplemental health insurance in the Colombian managed care system: Adverse or advantageous selection? AB - The aim of this article is to estimate the type of selection that exists in the supplemental health insurance market in Colombia where compulsory coverage is implemented through managed care competition. We build a panel database that combines individuals' information from the Ministry of Health and a database provided by two private health insurers. We perform the correlation test for consumption of health services frequency and supplemental coverage. Following Fang et al. (2008), we condition the estimation on health controls that are available to the econometrician but not to insurers. In both cases we obtain a positive correlation, suggesting that adverse selection predominates. In order to rule out some moral hazard effects, we estimate the correlation between previous frequency of healthcare service consumption and supplemental insurance purchase. The positive correlation obtained is robust to the inclusion of controls for diagnosis implemented by health insurers, suggesting that despite some risk selection strategies, they are not protected from adverse selection. We conclude that some subsidies to supplemental coverage purchase would lower public expenditure in Colombia. PMID- 29248059 TI - Introducing risk adjustment and free health plan choice in employer-based health insurance: Evidence from Germany. AB - To equalize differences in health plan premiums due to differences in risk pools, the German legislature introduced a simple Risk Adjustment Scheme (RAS) based on age, gender and disability status in 1994. In addition, effective 1996, consumers gained the freedom to choose among hundreds of existing health plans, across employers and state-borders. This paper (a) estimates RAS pass-through rates on premiums, financial reserves, and expenditures and assesses the overall RAS impact on market price dispersion. Moreover, it (b) characterizes health plan switchers and investigates their annual and cumulative switching rates over time. Our main findings are based on representative enrollee panel data linked to administrative RAS and health plan data. We show that sickness funds with bad risk pools and high pre-RAS premiums lowered their total premiums by 42 cents per additional euro allocated by the RAS. Consequently, post-RAS, health plan prices converged but not fully. Because switchers are more likely to be white collar, young and healthy, the new consumer choice resulted in more risk segregation and the amount of money redistributed by the RAS increased over time. PMID- 29248060 TI - Demand elasticities and service selection incentives among competing private health plans. AB - We examine selection incentives by health plans while refining the selection index of McGuire et al. (2014) to reflect not only service predictability and predictiveness but also variation in cost sharing, risk-adjusted profits, profit margins, and newly-refined demand elasticities across 26 disaggregated types of service. We contrast selection incentives, measured by service selection elasticities, across six plan types using privately-insured claims data from 73 large employers from 2008 to 2014. Compared to flat capitation, concurrent risk adjustment reduces the elasticity by 47%, prospective risk adjustment by 43%, simple reinsurance system by 32%, and combined concurrent risk adjustment with reinsurance by 60%. Reinsurance significantly reduces the variability of individual-level profits, but increases the correlation of expected spending with profits, which strengthens selection incentives. PMID- 29248061 TI - Does Part D abet advantageous selection in Medicare Advantage? AB - The use of risk-adjustment formulae in setting payments to Medicare Advantage (MA) plans reduces the potential for advantageous selection on factors included in the formulae, but can theoretically worsen overall selection if plans are able to target beneficiaries based on excluded factors. Since MA medical risk adjustment excludes prescription drug utilization, demand for drugs can be exploited by plans to induce advantageous selection. We show evidence that the introduction of Medicare Part D provided a mechanism for MA plans to increase selection, and that consumers responded, increasing MA market shares among beneficiaries taking drugs associated with the strongest advantageous selection incentives. For the average Medicare beneficiary in our sample, we estimate that this change in advantageous selection following the introduction of Medicare Part D increased the probability of enrolling in an MA plan by about 7.1%. PMID- 29248062 TI - Insurers' response to selection risk: Evidence from Medicare enrollment reforms. AB - Evidence on insurers' behavior in environments with both risk selection and market power is largely missing. We fill this gap by providing one of the first empirical accounts of how insurers adjust plan features when faced with potential changes in selection. Our strategy exploits a 2012 reform allowing Medicare enrollees to switch to 5-star contracts at anytime. This policy increased enrollment into 5-star contracts, but without risk selection worsening. Our findings show that this is due to 5-star plans lowering both premiums and generosity, thus becoming more appealing for most beneficiaries, but less so for those in worse health conditions. PMID- 29248063 TI - Plan responses to diagnosis-based payment: Evidence from Germany's morbidity based risk adjustment. AB - Many competitive health insurance markets adjust payments to participating health plans according to their enrollees' risk - including based on diagnostic information. We investigate responses of German health plans to the introduction of morbidity-based risk adjustment in the Statutory Health Insurance in 2009, which triggers payments based on "validated" diagnoses by providers. Using the regulator's data from office-based physicians, we estimate a difference-in difference analysis of the change in the share and number of validated diagnoses for ICD codes that are inside or outside the risk adjustment but are otherwise similar. We find a differential increase in the share of validated diagnoses of 2.6 and 3.6 percentage points (3-4%) between 2008 and 2013. This increase appears to originate from both a shift from not-validated toward validated diagnoses and an increase in the number of such diagnoses. Overall, our results indicate that plans were successful in influencing physicians' coding practices in a way that could lead to higher payments. PMID- 29248064 TI - Peer review: A critical cog in the scholarship wheel. PMID- 29248065 TI - It's no debate, debates are great. AB - INTRODUCTION: A debate can be a pedagogical method used to instill essential functions in pharmacy students. This non-traditional teaching method may help to further develop a number of skills that are highlighted in the current Accreditation Council for Pharmacy Education Standards 2016 and Center for the Advancement of Pharmacy Education Educational Outcomes 2013. COMMENTARY: Debates have also been used as an educational tool in other health disciplines. Current pharmacy literature does illustrate the use of debates in various areas within the pharmacy curriculum in both required and elective courses; however, the current body of literature would suggest that debates are an underutilized teaching tool in pharmacy experiential education. IMPLICATIONS: With all potential benefits of debates as a teaching tool, pharmacy experiential preceptors should further explore their use in the experiential setting. PMID- 29248066 TI - Comparison of a medication adherence simulation in professional pharmacy students versus undergraduate students. AB - BACKGROUND AND PURPOSE: Previous research at colleges and schools of pharmacy showed that simulation learning is an effective method to teach pharmacy students about the issues patients face when prescribed complicated medication regimens. The purpose of this analysis was to compare reported medication adherence rates, perceived barriers, and methods used to increase adherence between undergraduate students and pharmacy students based on a medication-taking simulation course activity. EDUCATIONAL ACTIVITY AND SETTING: In spring semesters 2014 and 2015, students in both a pharmacy course and an undergraduate seminar course participated in a short simulation involving a complicated medication regimen. Within one week of participating in the simulation activity, the students answered survey questions about the assignment through an online course sharing platform. FINDINGS: Almost all students enrolled in the courses (237/246 pharmacy students and 34/36 undergraduate students) completed the assignment (> 96% response rate). A large percentage of each group reported some non-adherence; 95% (225/237) of first-year pharmacy students and 82% (28/34) of undergraduate students. The top two barriers reported were 1) simply forgetting and 2) difficulty following the food- and/or alcohol-related restrictions associated with some of the simulated medications. The top two methods used to increase adherence were phone/electronic reminders and paper/spreadsheet reminders. DISCUSSION: A limitation to this study was the small sample size of undergraduate students. Even though the response rate was over 96%, the course was a small seminar-type course. Although it might be expected that pharmacy students would be more adherent since they may have had experience with non-adherence issues while working in a pharmacy, opposite results were found. Since the students were relatively young, most had not personally dealt with a complicated medication regimen. SUMMARY: Pharmacy students reported lower adherence to a complicated medication regimen than undergraduate students. The most common reasons for non adherence and most common methods used to increase adherence were similar between the two cohorts. The use of electronic reminders was common for both groups of students, and should be included in discussions about methods to improve adherence rates. PMID- 29248067 TI - Active methodology and blended learning: An experience in pharmaceutical care. AB - BACKGROUND AND PURPOSE: The aim of this study was to analyze the implementation of an active methodology in a blended model of education in the teaching-learning processes of students enrolled in two disciplines: Pharmaceutical Care I and Pharmaceutical Care II, both part of the undergraduate Bachelor of Pharmacy program at the Federal University of Parana. EDUCATIONAL ACTIVITY AND SETTING: The study design was quasi-experimental, prospective, comparative, following a pre/posttest format, where Pharmaceutical Care classes were the intervention. Identical pre- and post-intervention tests were designed based on Anderson and Krathwohl's (2001) revision of Bloom's taxonomy, and according to the three levels of the cognitive domain: remember and understand; apply and analyze; evaluate and create. FINDINGS: Participants were 133 students enrolled in the two Pharmaceutical Care classes. A significant difference between pre- and posttest results was observed, showing an increase in students' performance in the applied tests at all cognitive levels. This is the first study of its kind involving Pharmaceutical Care and Blended Learning. DISCUSSION AND SUMMARY: By comparing the results of the diagnostic and summative assessments based on Bloom's taxonomy at all levels of the cognitive domain, positive results were observed regarding the students' performance in the two disciplines (Pharmaceutical Care I and II). PMID- 29248068 TI - Measuring social science concepts in pharmacy education research: From definition to item analysis of self-report instruments. AB - MY ISSUE: Interpreting results from quantitative research can be difficult when measures of concepts are constructed poorly, something that can limit measurement validity. METHODS: Social science steps for defining concepts, guidelines for limiting construct-irrelevant variance when writing self-report questions, and techniques for conducting basic item analysis are reviewed to inform the design of instruments to measure social science concepts in pharmacy education research. MY RECOMMENDATIONS AND THEIR APPLICATIONS: Based on a review of the literature, four main recommendations emerge: These include: (1) employ a systematic process of conceptualization to derive nominal definitions; (2) write exact and detailed operational definitions for each concept, (3) when creating self-report questionnaires, write statements and select scales to avoid introducing construct irrelevant variance (CIV); and (4) use basic item analysis results to inform instrument revision. POTENTIAL IMPACT: Employing recommendations that emerge from this review will strengthen arguments to support measurement validity which in turn will support the defensibility of study finding interpretations. An example from pharmacy education research is used to contextualize the concepts introduced. PMID- 29248069 TI - A compliance assessment of midpoint formative assessments completed by APPE preceptors. AB - INTRODUCTION: Experiential pharmacy preceptors should provide formative and summative feedback during a learning experience. Preceptors are required to provide colleges and schools of pharmacy with assessments or evaluations of students' performance. Students and experiential programs value on-time completion of midpoint evaluations by preceptors. The objective of this study was to determine the number of on-time electronically documented formative midpoint evaluations completed by preceptors during advanced pharmacy practice experiences (APPEs). METHODS: Compliance rates of on-time electronically documented formative midpoint evaluations were reviewed by the Office of Experiential Education of a five-member consortium during the two-year study period prior to the adoption of Standards 2016. Pearson chi-square test and generalized linear models were used to determine if statistically significant differences were present. RESULTS: Average midpoint compliance rates for the two-year research period were 40.7% and 41% respectively. No statistical significance was noted comparing compliance rates for year one versus year two. However, statistical significance was present when comparing compliance rates between schools during year two. Feedback from students and preceptors pointed to the need for brief formal midpoint evaluations that require minimal time to complete, user friendly experiential management software, and methods for documenting verbal feedback through student self reflection. CONCLUSIONS: Additional education and training to both affiliate and faculty preceptors on the importance of written formative feedback at midpoint is critical to remaining in compliance with Standards 2016. PMID- 29248070 TI - Residents as preceptors and educators: What we can learn from a national survey to improve our residency programs. AB - INTRODUCTION: Developing pharmacy residents into effective preceptors is essential to meet the demands of pharmacy education. A survey was created to assess the availability of resident precepting educational opportunities, identify common barriers associated with developing preceptors' skills, and discover strategies to optimize programming. METHODS: An online survey focused on the development of residents as preceptors was e-mailed to all residency program directors (RPD) for American Society of Health-System Pharmacists accredited residencies in the United States. Information was collected on program demographics, level of support and precepting activities offered and resident employment outcomes. RESULTS: Five hundred thirty-eight responses were received. The majority were postgraduate year one RPDs and had less than six residents. Sixty-one percent of programs were affiliated with a college of pharmacy. Seventy eight percent devoted 10hours or less per month in developing residents as preceptors with 33% providing less than five hours. Seventy-one percent of the residency programs did not offer a formal precepting rotation. However, 59% of respondents indicated that their residency graduates frequently accepted positions, which required teaching/precepting. The most common barriers to developing residents as preceptors included: lack of time for residents to precept within the residency structure (41%), availability of preceptors to mentor residents throughout experience (33%) and lack of preceptors' availability to mentor residents' precepting abilities over time (30%). DISCUSSION AND CONCLUSIONS: RPDs should prioritize training of residents as preceptors. Requiring residents to serve as primary preceptors in rotations dedicated to teaching is important to prepare for future job responsibilities. PMID- 29248071 TI - Factors influencing professional state association membership decisions among recent pharmacy graduates. AB - INTRODUCTION: State pharmacy association membership levels have remained stagnant in recent years despite active student organization involvement among student pharmacists and an increased number of pharmacy schools producing new pharmacy graduates in the United States. The objective of this project was to examine factors considered by recent pharmacy graduates when deciding to join state pharmacy associations. METHODS: A 16-item cross sectional survey of recent pharmacy graduates collected respondents' demographic profile, professional student organization involvement, association memberships, and membership decision factors. RESULTS: The most influential factors in membership decisions included continuing education (62.8%), opportunity to advance pharmacy practice (51.1%), email updates (39.4%), and networking opportunities (37.2%). State pharmacy association meeting attendance (p = 0.004 and p = 0.028 for the Kentucky Society of Health-System Pharmacists and the Kentucky Pharmacists Association respectively), student organization membership (p = 0.038), committee service (p = 0.025), and state association board participation (p = 0.021) during pharmacy education increases the likelihood of membership in state associations. CONCLUSIONS: Early engagement in state pharmacy associations during pharmacy school improves the likelihood of new practitioner membership. Pharmacy schools should engage with state association leaders to promote student committee participation, association board participation, and attendance at state meetings to ensure the continued success of state pharmacy associations. PMID- 29248072 TI - Perceptions of pharmacy faculty need for development in educational research. AB - INTRODUCTION: Pharmacy educators have identified that pharmacy faculty need a better understanding of educational research to facilitate improvement of teaching, curricula, and related outcomes. However, the specific faculty development needs have not been assessed. The purpose of this study was to investigate self-reported confidence among clinical doctor of pharmacy faculty in skills essential for conducting educational research. METHODS: Faculty members with primary responsibilities in teaching at the University of Florida College of Pharmacy were invited to the take the Adapted Self-Efficacy in Research Measure (ASERM). Descriptive analysis and independent samples t-tests were used to compare the self-efficacy items by faculty rank, gender, and years of experience. RESULTS: Twenty-two of the 37 faculty members answered the 30-item survey that identified their self-efficacy in items and categories of skills, including writing skills, statistical skills, research design, research management and dissemination in education research. Senior faculty had significantly higher confidence than junior faculty on seven items. Participants who worked more than ten years had statistically higher confidence in preparing and submitting grant proposals to obtain funding for educational research. Skills where both junior and senior faculty had low confidence were related to using non-traditional methods such as qualitative methods and identifying funding resources for educational research. DISCUSSION AND CONCLUSIONS: Findings from the ASERM provided insights among pharmacy educators regarding self-efficacy related to skills needed for educational research, options for faculty development opportunities and actions for improving educational research knowledge and skills among them. PMID- 29248073 TI - Pharmacy student involvement in student-run free clinics in the United States. AB - INTRODUCTION: The role of pharmacy students in student-run free clinics (SRFCs) across the United States has not been well-defined. This study sought to assess the level of involvement and roles of pharmacy students in SRFCs as well as their interprofessional collaboration. METHODS: An online survey was sent to each pharmacy school registered with the American Association of Colleges of Pharmacy (AACP). The survey addressed the following concepts within SRFCs: pharmacy student roles, precepting and school of pharmacy involvement, interprofessional experience, leadership positions held by pharmacy students, and dissemination of feedback in this service-learning experience. RESULTS: The survey was sent to 139 schools; 45 pharmacy schools responded (32%); of those that responded, 29 schools were not connected to a SRFC (64%) and 16 schools were affiliated with at least one SRFC and completed the survey (36%). The most common disciplines pharmacy students work with in SRFCs included: dental, medical, mental health, nutrition, nursing, physical therapy, public health, and social work. Pharmacy students find their volunteer experience with SRFCs to be valuable, noting that they are able to apply their knowledge in a practice setting to benefit patients, improve their patient interviewing and health screening skills, become involved in the community, work as a team with other health professional students, formulate treatment plans, and obtain leadership positions. DISCUSSION AND CONCLUSIONS: SRFCs offer interprofessional and leadership activities that pharmacy students find valuable, but many pharmacy schools are not associated with SRFCs. PMID- 29248074 TI - Assessing the evidence based medicine educational needs of community pharmacy preceptors within an experiential program in Qatar. AB - INTRODUCTION: Observations have shown a lack of evidence-based medicine (EBM) knowledge and skills among community pharmacy preceptors in Qatar. These skills are important when delivering evidence-based recommendations to healthcare providers and patients. The aim of this study was to explore the community pharmacy preceptors' knowledge and understanding of EBM and to identify challenges in applying this approach to community practice. METHODS: A survey instrument was developed to assess the knowledge of community pharmacy preceptors related to EBM. Knowledge-based questions were mapped according to National Association of Pharmacy Regulatory Authorities professional competencies for practicing pharmacists. The survey tool was administered to community pharmacy preceptors involved in mentoring Qatar University College of Pharmacy students. RESULTS: Twenty-six community pharmacy preceptors completed the survey with a response rate of 65%. The knowledge-based questions linked to drug information resulted in 18%, 36%, and 46% of correct, incorrect, and unsure responses respectively while the critical appraisal questions showed 18%, 27%, 55% of correct, incorrect, and unsure responses respectively. Major barriers to practicing EBM included lack of EBM training (81%) and interpreting study results (80%). CONCLUSIONS: Community pharmacy preceptors showed poor knowledge and understanding of EBM. These results and expressed needs by pharmacists support the development of a supplementary course to improve EBM skills. PMID- 29248075 TI - Pharmacy education in Saudi Arabia: The past, the present, and the future. AB - INTRODUCTION: Saudi Arabia has a population of approximately 31 million people. The amount of literature published regarding pharmacy education in Saudi Arabia, however, is insignificant in number. The objective of this study is to describe the condition of pharmacy education in Saudi Arabia. METHODS: PubMed, Saudi Arabian government's publications and websites of pharmacy colleges have been searched. Descriptive content analysis has been used to draw a complete picture of pharmacy education in Saudi Arabia. RESULTS: From 1959 to 2001, Saudi Arabia had only one college of pharmacy. However, from 2001 to 2014, with the government initiative to train more national pharmacists, the nation witnessed the establishment of 23 government colleges and seven private colleges. No new colleges have been established since 2014. By the end of 2014, there were 30 pharmacy colleges offering more than 37 undergraduate programs. Only three colleges offer postgraduate programs, however. None of the colleges are accredited nationally or internationally. CONCLUSION: There is no evidence that this increase in the number of pharmacy colleges will meet the demand for nationally-born pharmacists. More research needs to be conducted concerning Saudi Arabia's need. There are very few opportunities for advanced degrees. The program names should be a normalized as all of them lead to registration as a pharmacist. The dramatic increase may have affected program quality as no colleges are nationally or internationally accredited. Colleges should seek accreditation to ensure they are within accepted international standards. PMID- 29248076 TI - StrengthsFinder(r) signature themes of talent in pharmacy residents at four midwestern pharmacy schools. AB - BACKGROUND AND PURPOSE: StrengthsFinder(r) is a widely-used assessment that can be used to help student pharmacists discover their talents (i.e., signature themes [STs]) and develop their leadership skills. The assessment has also been used in pharmacy residents, but the prevalence of various STs in that group has not been compared to those in student pharmacists. EDUCATIONAL ACTIVITY AND SETTING: Residents from four midwestern pharmacy institutions completed StrengthsFinder(r) 2.0 and received their top five STs. STs were organized and examined by domains (executing, influencing, relationship building, and strategic thinking). StrengthsFinder(r) data on student pharmacists were obtained from a previously published study. The distribution of the themes and domains was compared between residents and student pharmacists. FINDINGS: Responses from 31 residency program cohorts, including 290 pharmacy residents from a pool of 304 (95.4%) possible respondents, were included in the study. The learner ST was more frequently reported in the top five in pharmacy residents versus student pharmacists (42.8% versus 35.5%, p = 0.022). The woo and communication STs were also more frequently reported in the top five, while the consistency ST was reported less frequently in the top five in pharmacy residents versus student pharmacists (p < 0.05). The executing and relationship building domains had the highest average number of STs (1.58 and 1.56, respectively). DISCUSSION AND SUMMARY: The ST profile of pharmacy residents at residency programs affiliated with four midwestern schools of pharmacy is generally similar to that of pharmacy graduates. However, several STs were more or less prevalent in pharmacy residents. Recognition of these differences may assist residency program directors in marketing and design of programs and ranking of candidates. PMID- 29248077 TI - Impact of debates on student perceptions and competency scores in the advanced pharmacy practice setting. AB - BACKGROUND AND PURPOSE: Advanced pharmacy practice experience (APPE) students are faced with the difficult reality that there is rarely one correct answer to a patient care question. Faculty preceptors developed a clinical debate activity to provide students with an opportunity to explore pharmacy topics with competing viewpoints. EDUCATIONAL ACTIVITY AND SETTING: The clinical debate activity was implemented in the APPE setting as a collaboration between three faculty preceptors from Drake University and University of Iowa. Student pre-debate and post-debate survey data was collected to assess the perceived impact of clinical debates on student confidence in skills related to the debate. Students were also asked to provide which skills were developed through the debate, whether participation in the debate changed their opinion on the issue, and if debates should be used as a teaching tool. Faculty preceptor scores on midpoint and final evaluations for applicable APPE competencies were also evaluated. FINDINGS: Forty two students participated in a clinical debate over a 12-month period. Students demonstrated improved confidence in almost all areas assessed, and 90.5% of students felt debates should be used as a teaching tool. Assessment of faculty midpoint (pre-debate) and final (post-debate) evaluation scores revealed statistically significant improvements in competencies related to literature evaluation and communication skills. DISCUSSION AND CONCLUSIONS: Clinical debates have had a positive impact on both subjective and objective results in this APPE setting. Preceptors are encouraged to consider implementing a similar activity. Debates are a useful teaching tool in developing confidence and skills. PMID- 29248078 TI - A naloxone and harm reduction educational program across four years of a doctor of pharmacy program. AB - BACKGROUND AND PURPOSE: Naloxone distribution is an increasing service provided by pharmacists as more states enact laws enabling pharmacists to dispense naloxone without a prescription or per protocol to individuals in the wake of an opioid overdose epidemic. Education and training programs are necessary to ensure students and practicing pharmacists are able to effectively provide the service. EDUCATIONAL ACTIVITY AND SETTING: All first, second, and third year students in the doctor of pharmacy (PharmD) program at The Ohio State University College of Pharmacy (OSUCOP) participated in a pilot naloxone and harm reduction educational program. The program consisted of a three-part recorded lecture and a hands-on interactive workshop. Fourth-year students had the opportunity to participate. Students completed a ten-question assessment based on the content of the recorded lecture. Following the workshop, self-reflection and feedback were solicited. FINDINGS: Qualitative data indicated students felt the naloxone educational program was beneficial. Inclusion of harm reduction strategies, a mock counseling session, hands-on practice with naloxone delivery devices, and patient case discussions were valued. DISCUSSION AND SUMMARY: OSUCOP was able to develop and deliver a naloxone and harm reduction educational program across all four years of the PharmD curriculum within one year of passage of laws increasing pharmacist dispensing of naloxone. PMID- 29248079 TI - Preliminary findings from a student pharmacist operated transitions of care pilot service. AB - BACKGROUND AND PURPOSE: Student pharmacists are well equipped to complete transitions of care (TOC) activities. This communication describes the implementation of a student-operated TOC pilot service at a community hospital and explores the clinical and educational findings of such a service. EDUCATIONAL ACTIVITY AND SETTING: Patients admitted to the hospital were included in the service if they had a primary care provider from an affiliated ambulatory care office. The TOC student pharmacist verified the medication history upon admission, reviewed the inpatient chart during the hospitalization, assessed medication adherence, provided discharge counseling, and prepared a TOC document to share with the patient's ambulatory care office. FINDINGS: Forty-one patients were followed in the TOC pilot service. Student pharmacists identified 208 medication discrepancies between hospital and ambulatory care medication lists upon admission for 35 of the patients. Review of the discharge medication reconciliation was performed for 31 (75.6%) of the patients prior to discharge. The Adherence Estimator(r) was performed for 32 (78%) of the patients, with a mean score of 2.2. Student pharmacists anecdotally reported satisfaction with their involvement, and preceptors felt confident that the students were able to serve as an extension of the TOC service. DISCUSSION AND SUMMARY: Implementation of a student pharmacist-operated TOC service broadened student involvement on advanced pharmacy practice experience (APPE) and improved patient care through resolution of medication discrepancies, reinforcement of adherence, and communication with primary care providers. PMID- 29248081 TI - An innovative addition to team-based-learning pedagogy to enhance teaching and learning: Students' perceptions of team exams. AB - BACKGROUND AND PURPOSE: The study investigates students' perceptions of the value of implementing a team exam to enhance learning prior to a summative assessment. Team exams are similar to midterm exams, except that answering questions is a team effort. EDUCATIONAL ACTIVITY AND SETTING: Data was collected from second year pharmacy students at California Northstate University College of Pharmacy (CNUCOP) through a self-administered online survey. The survey questions included closed-ended questions to evaluate students' perception on preparedness for a summative assessment and to rank advantages and disadvantages of the team exams. FINDINGS: Of the 40 students who completed the survey (38% response rate), 100% of participants agreed that having a team exam prior to a major exam made them feel more prepared for a major summative exam. Ninety-seven percent of students believed that the team exam helped them to identify gaps in their knowledge and 85% agreed that taking a team exam reinforced their knowledge by teaching other students. The survey results did not identify any major disadvantages to holding a team exam. SUMMARY: Students perceived that taking a team exam prior to a midterm exam is an effective approach to review the course contents and identify areas of improvement. PMID- 29248080 TI - Case-based studies in teaching medicinal chemistry in PharmD curriculum: Perspectives of students, faculty, and pharmacists from academia. AB - BACKGROUND AND PURPOSE: Pharmacy practice has evolved tremendously over the years to meet the demands of the growing healthcare system. Foundational sciences like, medicinal chemistry can enhance the critical-thinking and therapeutic decision making skills of today's professional pharmacists. The importance of medicinal chemistry for the doctor of pharmacy (PharmD) curriculum has been discussed from the perspectives of medicinal chemistry and practicing clinical faculty whose focused practices vary from infectious diseases to geriatrics. EDUCATIONAL ACTIVITY AND SETTING: An Institutional Review Board (IRB)-approved perception survey and a year-end course evaluation were given to the second and third professional year students. FINDINGS: Eighty-eight percent of the participating second-year students and 92% of the participating third-year students thought that the introduction of case studies in the medicinal chemistry curriculum enhanced their learning and appreciation for the subject. DISCUSSION AND SUMMARY: The Pharmacy Curriculum Outcomes Assessment (PCOA) exams, given at the University of Houston College of Pharmacy during the years of 2013-2015, were briefly discussed. Since the requirement to administer the PCOA went into effect in early 2016, the authors felt that not enough time existed to establish meaningful controls to conduct a correlation study with the student perspective survey results obtained and PCOA data provided in 2015. This study, therefore, highlights the importance of integrated approaches to pharmacy teaching at the University of Houston. PMID- 29248082 TI - Evaluation of pharmacy students' knowledge and perceptions of pharmacogenetics before and after a simulation activity. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate students' knowledge and perceptions of the clinical application of pharmacogenetics through a simulation activity and to assess communication of pharmacogenetic-guided treatment recommendations utilizing standardized patients. EDUCATIONAL ACTIVITY AND SETTING: Third-year students in the four-year doctor of pharmacy (PharmD) program at University of South Florida College of Pharmacy completed a pharmacogenetics simulation involving a patient case review, interpretation of pharmacogenetic test results, completion of a situation, background, assessment, recommendation (SBAR) note with drug therapy recommendations, and patient counseling. Voluntary assessments were completed before and after the simulation, which included demographics, knowledge, and perceptions of students' ability to interpret and communicate pharmacogenetic results. FINDINGS: Response rates for the pre- and post-simulation assessments were 109 (98%) and 104 (94%), respectively. Correct responses in application-type questions improved after the simulation (74%) compared to before the simulation (44%, p < 0.01). Responses to perception questions shifted towards "strongly agree" or "agree" after the simulation (p < 0.01). DISCUSSION AND SUMMARY: The simulation gave students an opportunity to apply pharmacogenetics knowledge and allowed them to gain an appreciation of pharmacists' roles within the pharmacogenetics field. PMID- 29248083 TI - The Importance of Research and Clinical Care for Adolescent and Young Adult Health and Well-Being. PMID- 29248084 TI - Adolescents' Right to Participate: Opportunities and Challenges for Health Care Professionals. AB - BACKGROUND: Health care professionals and patients are partners in health care delivery, and this partnership is critical in the treatment of adolescents. International children's rights law establishes that all children have a right to participate in decisions that affect their lives. Fulfillment of that right is as critical in health care settings as any other area of children's lives. OBJECTIVES: In this article we examine the right to participate under international children's rights law, its relevance to health care settings, and how health care professionals can foster adolescents' participation to fulfill children's rights and improve health care outcomes. FINDINGS: The Convention on the Rights of the Child establishes a legal mandate-where ratified-that adolescents have the right to express their views in health care settings and that such views must be given due consideration. In many health care settings, adolescents are not adequately consulted or have limited opportunities to express their views. A review of research finds that both processes and outcomes can improve when youth participation is cultivated. CONCLUSIONS: Health care providers and organizations have numerous opportunities to cultivate adolescent's participation rights and in doing so improve health care delivery and outcomes. Health care providers and organizations should further develop structures and processes to ensure opportunities for children and adolescents to be heard on matters relevant to their health care and health status. Creating opportunities for adolescents to realize their right to participate means engaging youth at every stage in the process, beginning with the design of such opportunities. It also means addressing all aspects of health care, from the built environment to patient-provider communication to follow-up services, so that the entire process fosters an environment conductive to meaningful participation by adolescents. PMID- 29248086 TI - Broadening the Frontiers of Adolescent Health Through Telemedicine and Online Networks. PMID- 29248085 TI - Recommendations on Arresting Global Health Challenges Facing Adolescents and Young Adults. AB - BACKGROUND: The health challenges faced by young people are more complex than adults and can compromise their full growth and development. Attention must be paid to the health of this age group, yet adolescents and youth remain largely invisible and often disappear from the major global datasets. OBJECTIVE: The aim of this paper is to discuss the global health challenges faced by adolescents and youth, global legislations and guidelines pertaining to this particular age group, recommendations to arrest these challenges, and research priorities. RESULTS: Major direct and indirect global health risks faced by adolescents include early pregnancy and childbirth, femicide, honor killing, female genital mutilation, nutritional habits and choices, social media, and peer pressure. There are no standard legal age cut-offs for adulthood; rather, the age varies for different activities, such as age of consent or the minimum age that young people can legally work, leave school, drive, buy alcohol, marry, be held accountable for criminal action, and make medical decisions. This reflects the fact that the existing systems and structures are focused on either children or adults, with very few investments and interventions directed specifically to young people. Existing legislation and guidelines need transformation to bring about a specific focus on adolescents in the domains of substance use and sexual behaviors, and the capacity for adolescent learning should be exploited through graduated legal and policy frameworks. CONCLUSION: Sustainable development goals provide an opportunity to target this neglected and vulnerable age group. A multisectoral approach is needed to bring about healthy change and address the challenges faced by adolescents and youth, from modifications at a broader legislative and policy level to ground-level (community-level) implementations. PMID- 29248087 TI - Administration of Childhood Physical and Childhood Sexual Abuse Screens in Adolescents and Young Adults: a Literature Review. AB - BACKGROUND: Childhood physical and sexual abuse can have a negative impact on adolescents and young adults. Although effective interventions that can ameliorate both the short- and long-term negative impacts are available, many adolescent and young adult victims remain without help: They rarely self-identify as victims, and health care providers generally fail to inquire about a history of childhood abuse, especially in the absence of physical signs. The health care field lacks an understanding of effective methods for the identification of childhood abuse. OBJECTIVES: To address this knowledge gap, this paper focuses on a systematic review of the literature for studies comparing modes of administration of measures to identify a history of childhood physical and sexual abuse in adolescents and young adults. METHODS: A systematic review of the literature published in English in peer-reviewed journals between January 1, 1994, and December 31, 2014 was conducted to identify studies that compared 2 or more modes of administration using the same measure to identify a history of childhood physical and sexual abuse in adolescent and young adult populations. Studies that compared 2 or more different measures for identifying abuse were not included in this review because the focus of the review was to isolate the effects of the mode of administration. FINDINGS: Only 1 study that met review criteria was found. It was conducted among female college students in a university setting. No studies were identified that compared modes of administration used to elicit disclosure of a history of childhood abuse among adolescents. CONCLUSIONS: There remains an urgent need to conduct evaluations of methods to identify childhood physical and sexual abuse including the mode of administration of screens in young people. It is recommended that future studies include diverse populations and randomized and quasi-experimental approaches. PMID- 29248088 TI - Comparison of Modes of Administration of Screens to Identify a History of Childhood Physical Abuse in an Adolescent and Young Adult Population. AB - BACKGROUND: Childhood physical abuse is a major public health issue with negative consequences to health and well-being manifested in childhood and adolescence, and persisting into adulthood. Yet much childhood physical abuse is not identified when it occurs and little is known about how to screen for it. METHODS: To address this gap, the effectiveness of 4 modes of administration of screens to identify childhood physical abuse were compared in a sample of 506 adolescents and young adults aged 12-24 years seeking general health services at a primary care clinic. Comparisons were made between paper and pencil screen, audio computer-assisted self-interview screen, face-to-face structured screen (all 3 using the same measure), and face-to-face unstructured interview. FINDINGS: Overall, 44.5% of the sample disclosed that they had been physically abused. Compared to paper and pencil screen, the odds of reporting physical abuse were 1.5 (95% confidence interval [CI]: 0.92, 2.58) and 4.3 (95% CI: 2.49, 7.43) higher among participants using face-to-face structured screen and face-to-face unstructured interview methods, respectively. The face-to-face unstructured interview identified significantly more reports than the paper and pencil screen. CONCLUSIONS: Although the unstructured interview was the most effective mode for screening for childhood physical abuse, additional research is needed to confirm whether this holds true in other health care settings. Further research should examine how a health provider's training, experience, and comfort level might influence the identification of physical abuse disclosure in primary care settings using face-to-face unstructured interview. PMID- 29248089 TI - Health Care Use and Status Among Abused Young People. AB - BACKGROUND: Childhood abuse negatively affects young people's health. Little is known about its effect on health care usage patterns or on perception of health status during a life stage when learning to use care independently is a key developmental task. OBJECTIVES: In nonclinical study settings, abuse has been found to be associated with disorganized use of care and perceived poorer health. Our objective was to determine whether abused youth receiving health care had similar outcomes. METHODS: This observational study, conducted between December 5, 2005 and April 13, 2007, screened for childhood abuse in 532 young people seeking services at a primary care clinic. The setting was a New York City young people's free health clinic. Participants were aged 12-24 years, recruited during a visit, mostly female (86%), Latino or black (94%), and currently in school or college (79%). Exclusions included not being fluent in English or having difficulty understanding the study/consent process. RESULTS: Health care use (routine vs urgent care) in the prior 12 months and perceived health status were measured using the Health Service Utilization Scale. Potential demographic covariates were controlled for, as was depression (using the Beck Depression Inventory for Primary Care-Fast Screen). A total of 54% disclosed abuse. Compared with those who were not abused, those reporting sexual abuse had 1.4 times greater odds of choosing both urgent and routine care over routine care only. Those reporting any type of abuse had lower odds of selecting urgent care only over routine care. No association was found between childhood abuse and perceived health status. CONCLUSIONS: In contrast to studies conducted among youth in nonclinic settings, in this study childhood abuse was not associated with health care usage patterns or with poorer perception of health. Further research is needed regarding the impact receiving health care has on perceived health and health care use in abused youth. Annals of Global Health 2017;0:000-000. PMID- 29248091 TI - Autism Spectrum Disorder in Lower Socioeconomic Communities. PMID- 29248090 TI - Cumulative Psychosocial Risk is a Salient Predictor of Depressive Symptoms among Vertically HIV-Infected and HIV-Affected Adolescents at the Kenyan Coast. AB - BACKGROUND: Little is known of mental health outcomes among vertically HIV infected or HIV-affected adolescents in Africa. OBJECTIVES: The current study set out to describe depressive symptoms and their correlates among vertically HIV infected and HIV-affected adolescents at the Kenyan Coast. METHODS: 130 adolescents (vertically HIV-infected [n = 44], HIV-affected [n = 53], and unexposed [n = 33]) and their caregivers participated in this cross-sectional study. An adapted version of the Beck Depression Inventory-11 (BDI) was administered to examine depressive symptoms in both adolescents and caregivers, together with measures of sociodemographic, medical, and anthropometric characteristics. FINDINGS: Our analysis indicated a main effect of HIV status on mean BDI scores in HIV-infected (18.4 [SD = 8.3) and HIV-affected (16.8 [SD = 7.3]) adolescents compared to the community controls (12.0 [SD = 7.9]), F (2, 127) = 6.704, P = .002, eta2 = .095. Post hoc analysis showed that BDI scores of HIV-infected adolescents were higher than those of community controls (P < .001). Similarly, HIV-affected adolescents had BDI scores that were higher than those of community controls (P = .007). However, there was no difference in BDI scores between HIV-infected and HIV-affected adolescents (P = .304). A path analytic model indicated that cumulative psychosocial risk (orphanhood, family poverty, and caregiver depressive symptoms) were positive predictors of BDI scores among adolescents, while nutritional status had a limited role. CONCLUSIONS: Both HIV infected and HIV-affected adolescents are at a high risk of experiencing depressive symptoms, largely due to the multiple psychosocial risk factors in their environment. The provision of adequate psychosocial support and counseling needs to become an integral part of the care program for adolescents from families living with HIV/AIDS at the Kenyan coast and other similar settings. PMID- 29248092 TI - Exploring Drivers of Infant Deaths in Rural Rwanda Through Verbal Social Autopsy. AB - BACKGROUND: Rwanda has been a leader in the global effort to reduce infant mortality, particularly in regions of sub-Saharan Africa. Although rates have dropped, deaths still occur. OBJECTIVE: To explore the care pathways and barriers taken by infant caregivers before the death of their infant through a verbal social autopsy study in 2 districts in eastern Rwanda. METHODS: We adapted the World Health Organization verbal socialautopsy tools to reflect local context and priorities. Caregivers of infants in the 2 districts were interviewed using the adapted quantitative survey and semistructured interview guide. Interviews were recorded and thematic analysis employed on a subsample (n = 133) to extract the content relevant to understanding the drivers of infant death and inform results of the quantitative data until saturation was reached (66). Results were interpreted through a driver diagram framework to explore caregiver-reported challenges in knowledge and experiences with care access and delivery. FINDINGS: Most study participants (82%) reported accessing the formal health system at some point before the infant's death. The primary caregiver-reported drivers for infant death included challenges in accessing care in a timely manner, concerns about the technical quality of care received, and poor responsiveness of the system and providers. The 2 most commonly discussed drivers were gaps in communication between providers and patients and challenges obtaining and using the community-based health insurance. The framework of the driver diagram was modified to identify the factors where change was needed to further reduce mortality. CONCLUSION: This study provides important information on the experiential quality of care received by infants and their caregivers within the current health care space in rural Rwanda. By listening to the individual stories of so many caregivers regarding the gaps and challenges they faced, appropriate action may be taken to bolster the existing health care system. PMID- 29248094 TI - Optimizing Adolescent LARC: an Answer to Pregnancy Prevention. PMID- 29248093 TI - "It Has Changed": Understanding Change in a Parenting Program in South Africa. AB - BACKGROUND: Poor parenting that leads to child maltreatment during adolescence presents a major public health burden. Research from high-income countries indicates that evidence-based parenting program interventions can reduce child maltreatment. Much less is known, however, about how beneficiaries of these programs experience this process of change. Understanding the process that brings about change in child maltreatment practices is essential to understanding intervention mechanisms of change. This is particularly important given the current scale-up of parenting programs across low- and middle-income countries. OBJECTIVES: This study aimed to provide insight into how caregivers and adolescents attending a parenting program in South Africa perceived changes associated with abuse reduction. METHODS: Semi-structured interviews were conducted with caregivers and adolescents (n = 42) after the intervention, as well as observations of sessions (n = 9) and focus group discussions (n = 240 people). Participants were adolescents between the ages of 10-18 and their primary caregiver residing in peri-urban and rural program clusters in the Eastern Cape Province of South Africa. Data were coded in Atlas.ti, and thematic content analysis was conducted. FINDINGS: Based on participant perceptions, the Sinovuyo Teen parenting program workshops catalyzed change into practice by creating an environment that was conducive to learning alternatives. It did so through prioritizing a process of mutual respect, openness, and being valued by others, giving legitimacy to a respectful reciprocity and new ways of spending time together that enabled caregivers and teenagers to shift and normalize more positive behaviors. This in turn led to reductions in physical and verbal abuse. CONCLUSIONS: This study's findings may be of use to policymakers and practitioners who need to understand how parenting programs support parents and teenagers in increasing positive parenting approaches and changing potentially harmful practices. It additionally highlights the importance of assessing the experiences of both parents and teenagers attending such programs. PMID- 29248095 TI - New Findings on Child Marriage in Sub-Saharan Africa. AB - Despite increasing global attention and commitments by countries to end the harmful practice of child marriage, each year some 15 million girls marry before the age of 18. The preponderance of the evidence produced historically on child marriage comes from South Asia, where the vast majority of child brides live. Far less attention has been paid to child marriage in sub-Saharan Africa, where prevalence rates remain high. The International Center for Research on Women (ICRW) recently conducted research in Kenya, Senegal, Uganda, and Zambia to contribute to greater understanding of the drivers of child marriage in each of these contexts. Synthesizing findings from 4 diverse countries provides a useful opportunity to identify similarities and differences, as well as understandings that may be applicable to and helpful for preventing child marriage across these and other settings. Across the 4 countries, ICRW's research echoes the existing literature base in affirming that child marriage is rooted in inequitable gender norms that prioritize women's roles as wives, mothers, and household caretakers, resulting in inadequate investments by families in girls' education. These discriminatory norms interact closely with poverty and a lack of employment opportunities for girls and young women to perpetuate marriage as a seemingly viable alternative for girls. We found in the African study sites that sexual relations, unplanned pregnancy, and school dropout often precede child marriage, which differs from much of the existing evidence on child marriage from South Asia. Further, unlike in South Asia, where family members typically determine the spouse a girl will marry, most girls in the Africa study settings have greater autonomy in partner choice selection. In Senegal, increasing educational attainment and labor migration, particularly by young women, has contributed to reduced rates of child marriage for girls. Our findings suggest that improving gender equitable norms and providing more-and more equitable-opportunities for girls, particularly with regard to education and employment, are likely to improve child marriage outcomes. Providing comprehensive sexuality education and youth-friendly reproductive health services can reduce rates of early pregnancy that contribute to child marriage. Finally, identifying ways in which to improve communication between parents and adolescent daughters could go far in ensuring that girls feel valued and that parents feel heard as they make decisions together regarding the lives and opportunities of these adolescent girls. PMID- 29248096 TI - Adolescent and Young Adult Injuries in Developing Economies: A Comparative Analysis from Oman and Kenya. AB - BACKGROUND: Adolescence is a distinct period of rapid and dramatic biological, cognitive, psychological, and social development. The burden of injuries among young people (aged 10-24) is both substantial and maldistributed across regions and levels of economic development. OBJECTIVES: Our objective was to compare sociodemographic correlates of injury cause, intentionality, and mortality between Kenya and Oman, 2 countries with different levels of economic development and position in the demographic and epidemiologic transitions. METHODS: Data on 566 patients in Oman and 5859 in Kenya between 10 and 24 years old were extracted from 2 separate multicenter trauma registries. Multivariable log binomial and Poisson regressions were used to evaluate social and demographic factors associated with injury cause, intentionality, and mortality. Literature on adolescent development was used to parameterize variables, and Akaike information criteria were used in the final model selections. FINDINGS: The trauma registry data indicated a substantial burden of adolescent and young adult injury in both Oman and Kenya, particularly among males. The data indicated significant differences between countries (P < .001) in age category, gender distributions, level of education, occupation, cause of injury, and place where injury occurred. Consistent with other literature, road traffic injuries emerged as the most common type of injury as well as the most severe and fatal, with interpersonal violence also resulting in severe injury across contexts. Both road traffic injuries and interpersonal violence were more common among older adolescents and young adults. Education and being in school were protective against injury, after controlling for gender, age category, occupation, and country. CONCLUSIONS: A rising burden of injuries among young people has been documented in every region of the world, irrespective on income status or level of development. Cost effective injury control measures targeting this age group exist, including involvement in educational, vocational, and other prosocial activities; environmental alterations; and road safety measures. PMID- 29248098 TI - The Donald L. D. Caspar Structural Biology Symposium at Florida State University. PMID- 29248099 TI - The journey goes on. PMID- 29248097 TI - Applying a Global Perspective to School-Based Health Centers in New York City. AB - BACKGROUND: Since the 1960s, school-based health centers (SBHC) in the United States have emerged and grown with the mission of providing primary medical, reproductive, and mental health services, as well as comprehensive health education, to all students who are enrolled in the participating school. SBHCs have demonstrated a unique ability to reduce barriers to medical care for underserved populations in New York City, including undocumented immigrants and those who are of lower income status. METHODS: The Mount Sinai Adolescent Health Center School-Based Health Program (MSAHC SBHP) was established in 1985 in order to increase access to care for New York City teens. After a change of physical location, one particular site of the MSAHC SBHP had a significant decrease in clinic visits and enrollment. Traditional outreach strategies were utilized, but the results of the efforts were disappointing. Applying the Community Health Worker model, as defined by the World Health Organization (WHO), the MSAHC SBHP developed the Student Ambassador Program, a student-organized community engagement initiative. The program is based on the premise that youth can be effective at outreach and serving as community liaisons to increase awareness and use of the SBHC. The SBH staff provided recruitment, training, and support. The student ambassadors initiated peer-informed outreach projects to appeal to the student body. Upon completion of the Student Ambassador projects, clinic enrollment increased 4.3% and visits increased 32% over the prior year. CONCLUSIONS: School-based health centers in the United States have helped to provide comprehensive, multidisciplinary care to many children who would otherwise not be able to access care, but community engagement is critical to their success. Applying the WHO Community Health Worker Model to utilize school students for outreach to their school community is an effective way to increase utilization. PMID- 29248100 TI - Complex iliocaval endovascular recanalization combined with thrombolysis for extensive acute deep venous thrombosis. PMID- 29248101 TI - Design and rationale of a randomized trial comparing standard versus ultrasound assisted thrombolysis for submassive pulmonary embolism. AB - BACKGROUND: Catheter-directed interventions for the treatment of patients with submassive pulmonary embolism (sPE) have shown promise in rapidly improving right sided heart strain and preventing decompensation to massive pulmonary embolism. Among various catheter interventions, ultrasound-assisted thrombolysis (USAT) has attracted interest as potentially having more efficient lytic effect that could achieve thrombolysis faster and with a reduced lytic dose. However, based on clinical evidence, it is unclear whether USAT is superior to standard catheter directed thrombolysis (SCDT). We herein describe the study design of the Standard vs UltrasouNd-assiSted CathEter Thrombolysis for Submassive Pulmonary Embolism (SUNSET sPE) trial, an ongoing randomized clinical trial designed to address this question. METHODS: Adults with sPE presenting or referred to our institution are considered for enrollment in the trial. At the discretion of the treatment team, all patients undergo a catheter-directed intervention plus concomitant therapeutic anticoagulation. Participants are randomized 1:1 to a USAT catheter or an SCDT catheter. Study assessors are blinded to treatment group. The primary outcome is clearance of pulmonary thrombus burden, assessed by postprocedure computed tomography angiography. Secondary outcomes include resolution of right ventricular strain by echocardiography; improvement in pulmonary artery pressures; and 3- and 12-month improvement in echocardiographic, functional capacity, and quality of life measures. The study is powered to detect a 50% improvement in pulmonary artery thrombus clearance. Our enrollment target is 40 patients per treatment arm. CONCLUSIONS: SUNSET sPE is an ongoing randomized, head-to-head, single-blinded clinical trial with the goal of assessing whether USAT results in superior thrombus clearance compared with SCDT in patients with sPE. We expect the results of our study to inform future guidelines on choice of thrombolysis modality in this population of challenging patients. PMID- 29248102 TI - The Center for Vein Restoration Study on presenting symptoms, treatment modalities, and outcomes in Medicare-eligible patients with chronic venous disorders. AB - BACKGROUND: Chronic venous disorders (CVDs) have been estimated to affect up to 20 million Americans. Despite this huge prevalence, the signs, symptoms, and treatment outcomes in patients 65 years of age and older are not well defined. Our goal was to determine the presentation and treatment outcomes in elderly patients compared with a cohort of patients younger than 65 years. METHODS: From January 2015 to December 2016, we retrospectively reviewed prospectively collected data from 38,750 patients with CVD from the Center for Vein Restoration's electronic medical record (NextGen Healthcare Information Systems, Irvine, Calif). We divided patients into two groups; group A patients were younger than 65 years, and group B patients were 65 years of age or older. Medical and surgical history, presenting symptoms, treatment modalities, and revised Venous Clinical Severity Score before and after intervention were evaluated. A multivariate logistic regression analysis was performed to determine the predictive value of presenting and associated symptoms. Groups A and B were subdivided by Clinical, Etiology, Anatomy, and Pathophysiology class for subgroup analysis. Data were analyzed with GraphPad Prism (GraphPad Software Inc, La Jolla, Calif) or SAS version 9.4 statistical software package (SAS Institute, Cary, NC). RESULTS: There were 27,536 patients in group A and 11,214 in group B. Women constituted 78% of all patients. Group B demonstrated a higher incidence of chronic diseases compared with group A (P <= .003). As initial presenting symptoms, pain, heaviness, fatigue, and aching were more common in group A than in group B (61% vs 55%, 30% vs 27%, 27% vs 24%, and 17% vs 12%, respectively; P <= .001). Swelling, skin discoloration, and venous ulceration were more common in group B than in group A (29% vs 23%, 12% vs 6%, and 5% vs 2%; P <= .001). Ablations were more commonly performed in group B patients with C4 to C6 disease (P <= .004). The revised Venous Clinical Severity Scores before and 1 month after intervention were similar between groups. Treatment improvement was statistically significant in both groups (P <= .001). Multivariate logistic regression analysis indicated that varices, bleeding, swelling, skin changes, venous ulceration, aching, heaviness, pain, fatigue, cramping, and restless legs were associated with the presence of CVD (P <= .001). CONCLUSIONS: Medicare beneficiaries presented with more chronic diseases and more severe disease. Initial and associated symptoms were highly associated with the presence of CVD. Despite requiring more interventions than patients younger than 65 years, Medicare beneficiaries demonstrated the same degree of clinical improvement. Medicare should not develop coverage policy decisions that prevent access to therapies that alleviate CVD-induced symptoms. PMID- 29248103 TI - Preparing for the outpatient treatment of venous disease under MACRA. PMID- 29248104 TI - Regarding "Catheter-directed, ultrasound-assisted thrombolysis is a safe and effective treatment for pulmonary embolism, even in high-risk patients". PMID- 29248105 TI - Reply. PMID- 29248106 TI - Clinical correlation of success and acute thrombotic complications of lower extremity endovenous thermal ablation. AB - OBJECTIVE: Endovenous thermal ablation has become the primary modality of treatment for patients with venous insufficiency. Previous literature has provided reviews of radiofrequency ablation (RFA) or endovenous laser ablation (EVLA) that mostly focus on the great saphenous vein (GSV) and small saphenous vein (SSV). Data with an extended review including the anterior accessory saphenous vein (ASV) and perforator veins (PVs) have been limited. This study examines the treatment of venous insufficiency with RFA and EVLA of these multiple veins to identify clinical and demographic predictors of both the early success and thrombotic complications of endovenous thermal ablation. METHODS: A retrospective analysis of patients who underwent either RFA or EVLA of the GSV, SSV, ASV, or PVs was performed from March 2012 through February 2014. The PVs were treated only using RFA. The success and complication rates of each method were compared. Procedure results were determined by duplex ultrasound examination at the next office visit. Obliteration of the target vein was defined as a success. A complication was defined as thrombosis of any vein proximal to the target vein or acute thrombosis of any tributaries. RESULTS: A total of 808 patients were treated with either RFA or EVLA (2057 procedures); 47 patients were excluded because of incomplete records. In total, 1811 procedures were included with an average of 2.4 procedures per patient. Excluding the PVs, the success rate of RFA was 98.4%, equivalent to EVLA at 98.1% (P = .66). The success rates of thermal ablation for each vein were as follows: GSV, 98.5%; SSV, 98.2%; ASV, 97.2%; and PVs, 82.4%. The overall thrombotic complication rate was 10.5%. The thrombotic complications include endovenous heat-induced thrombosis (EHIT; 5.9%) and acute superficial venous thrombosis (4.6%). However, when EHIT class 1 was excluded, the true EHIT rate was 1.16%. The rate of a thrombotic complication for each vein was as follows: GSV, 11.8%; SSV, 5.5%; ASV, 6.5%; and PVs, 2.4%. The thrombotic complication rate was 7.7% for RFA and 11.4% for EVLA (P = .007). Age, gender, laterality, presenting symptoms (based on Clinical, Etiology, Anatomy, and Pathophysiology class), and vein type and diameter have no effect on successful ablation. Increased vein diameter (P < .001) and type of vein (P < .0001) were significant predictors of acute thrombotic complications; however, on multivariable analysis, only type of vein was an independent statistically significant predictor when nested for within-person correlation. CONCLUSIONS: There were no statistical difference in successful closure rates between RFA and EVLA. The type of procedure (EVLA), larger vein diameters, and treatment of the GSV were associated with a greater thrombotic complication rate, but type of vein was the most significant independent predictor. PMID- 29248107 TI - Prospective comparative cohort study evaluating incompetent great saphenous vein closure using radiofrequency-powered segmental ablation or 1470-nm endovenous laser ablation with radial-tip fibers (Varico 2 study). AB - BACKGROUND: Endovenous laser ablation (EVLA) and radiofrequency-powered segmental ablation (RPSA) of the incompetent great saphenous vein (GSV) are both known for their excellent technical and clinical outcomes for the treatment of varicose veins. RPSA has reduced postprocedural pain and morbidity with shorter recovery time for the patient compared with EVLA using bare-tip fibers. However, new generation EVLA devices with less traumatic radial-tip fibers (RTFs) operating at longer wavelengths up to 1470 nm also reduce postprocedural pain. The objective of this study was to compare long-term effectiveness of GSV thermal ablation and postprocedural recovery using RPSA or 1470-nm EVLA with RTF (EVLA-RTF). METHODS: In a comparative prospective monthly altering-treatment cohort study of 311 patients (346 treated legs), each leg with incompetence of the GSV was treated with either RPSA (158 patients, 175 legs) or EVLA-RTF (153 patients, 171 legs). The primary outcome was anatomic occlusion of the GSV, assessed at 12, 24, 36, 48, and 60 months using Kaplan-Meier statistics and compared using the log-rank test. Secondary outcomes included freedom of varicose vein recurrence, clinical success measured by Venous Clinical Severity Score (VCSS), disease-specific quality of life determined using the Aberdeen Varicose Vein Questionnaire (AVVQ), postoperative pain scores, and time to return to work. RESULTS: The total primary obliteration rate after 36 and 60 months was 96.2% with RPSA and 96.7% with EVLA RTF (P = .81). Freedom of symptomatic anterior accessory vein recurrence after 5 years was 85% after RPSA and 87% after EVLA-RTF (P = .50). VCSS and AVVQ score presented similar and durable improvements in both groups between 6 weeks and 60 months. There was no difference in postoperative pain scores after both treatments during the first 14 days (mean visual analog scale score, 0.54-2.19). The median time for return to work was 1 day after both treatments. No severe adverse events were observed. CONCLUSIONS: RPSA and EVLA-RTF have similarly high GSV obliteration rates in the long term, and the treatments are equally effective clinically. Both treatments are associated with similar minimal postprocedural pain scores and short recovery times. PMID- 29248108 TI - Results of the ATTRACT trial do not change the management of acute deep vein thrombosis. PMID- 29248109 TI - Venous stent placement ameliorates cutaneous microvascular function in iliocaval venous obstruction. AB - BACKGROUND: The role of cutaneous microvascular dysfunction is well known in the development of chronic venous disease. However, the effects of venous obstruction on microcirculation have not been well investigated. The aim of this study was to assess cutaneous microvascular function in patients with iliocaval venous obstruction (ICVO) before and after venous stent placement. METHODS: Endothelium dependent and endothelium-independent vasodilator responses to iontophoretic administration of incremental doses of acetylcholine (ACh) and sodium nitroprusside (SNP) were evaluated using a laser Doppler scanner in the perimalleolar region in the supine and sitting positions in patients with ICVO (n = 11) and in healthy control subjects (n = 15). Cutaneous microvascular function, the Venous Clinical Severity Score (VCSS), and the Clinical, Etiology, Anatomy, and Pathophysiology (CEAP) clinical class were re-evaluated 3 months after stent placement in patients with ICVO. RESULTS: The vasodilatory responses to ACh and SNP in the cutaneous microcirculation were lower in patients with ICVO than in healthy subjects in the sitting position (P < .05). Recanalization and stent placement were successful in all patients in the evaluation of VCSS and clinical class, and a significant decrease was determined in the signs and symptoms of the venous disease (P < .01). Stent placement resulted in a significant increase in vasodilation response to both ACh and SNP in the supine position and no improvement in the sitting position in patients with ICVO. CONCLUSIONS: ICVO impairs endothelium-dependent and endothelium-independent vasodilation in the perimalleolar region. Iliocaval venous stent placement may recover microvascular dysfunction at different levels. PMID- 29248110 TI - Quantitative comparison between the laser scanner three-dimensional method and the circumferential method for evaluation of arm volume in patients with lymphedema. AB - OBJECTIVE: Several methods are used to evaluate arm volumes. The most commonly used methods are water displacement and the circumferential method (CM), but these techniques have some limitation in application in clinical settings and accuracy. Recently, the laser scanner three-dimensional (LS3D) method was successfully proposed as a valid method for volume measurements of the upper limb in healthy individuals. The aim of the study was to compare, in terms of intraobserver and interobserver reliability, the CM and LS3D method to measure the upper limb in a group of women with upper limb lymphedema. METHODS: There were 200 women with upper limb lymphedema (mean age, 64 +/- 9 years; body mass index, 24.72 +/- 2.94 kg/m2) involved in this study. Arm measurements were obtained with both the CM and LS3D method. Statistical analysis was conducted to compare the CM and LS3D method. RESULTS: Both the CM and LS3D method have a satisfactory level of agreement, but we found some statistically significant differences in terms of some measurements (both circumferential and volume measurements). CONCLUSIONS: The data obtained in this study indicate that the LS3D method could represent a reliable, valid method to measure arm circumferences and volumes in arms with lymphedema, suitable for daily clinical use. It combines precision, reproducibility, and ease of use with the possibility of measuring geometric parameters and shape information of scanned limbs. PMID- 29248111 TI - When the ribosomal DNA does not tell the truth: The case of the taxonomic position of Kurtia argillacea, an ericoid mycorrhizal fungus residing among Hymenochaetales. AB - The nuclear ribosomal DNA (nuc-rDNA) is widely used for the identification and phylogenetic reconstruction of Agaricomycetes. However, nuc-rDNA-based phylogenies may sometimes be in conflict with phylogenetic relationships derived from protein coding genes. In this study, the taxonomic position of the basidiomycetous mycobiont that forms the recently discovered sheathed ericoid mycorrhiza was investigated, because its nuc-rDNA is highly dissimilar to any other available fungal sequences in terms of nucleotide composition and length, and its nuc-rDNA-based phylogeny is inconclusive and significantly disagrees with protein coding sequences and morphological data. In the present work, this mycobiont was identified as Kurtia argillacea (= Hyphoderma argillaceum) residing in the order Hymenochaetales (Basidiomycota). Bioinformatic screening of the Kurtia ribosomal DNA sequence indicates that it represents a gene with a non standard substitution rate or nucleotide composition heterogeneity rather than a deep paralogue or a pseudogene. Such a phenomenon probably also occurs in other lineages of the Fungi and should be taken into consideration when nuc-rDNA (especially that with unusual nucleotide composition) is used as a sole marker for phylogenetic reconstructions. Kurtia argillacea so far represents the only confirmed non-sebacinoid ericoid mycorrhizal fungus in the Basidiomycota and its intriguing placement among mostly saprobic and parasitic Hymenochaetales begs further investigation of its eco-physiology. PMID- 29248112 TI - Cooperation between ER stress and calcineurin signaling contributes to the maintenance of cell wall integrity in Candida glabrata. AB - Candida glabrata is the second most common source of Candida infections in humans. In this pathogen, the maintenance of cell wall integrity (CWI) frequently precludes effective pharmacological treatment by antifungal agents. In numerous fungi, cell wall modulation is reported to be controlled by endoplasmic reticulum (ER) stress, but how the latter affects CWI maintenance in C. glabrata is not clearly understood. Here, we characterized a C. glabrata strain harboring a mutation in the CNE1 gene, which encodes a molecular chaperone associated with nascent glycoprotein maturation in the ER. Disruption of cne1 induced ER stress and caused changes in the normal cell wall structure, specifically a reduction in the beta-1,6-glucan content and accumulation of chitin. Conversely, a treatment with the typical ER stress inducer tunicamycin up-regulated the production of cell wall chitin but did not affect beta-1,6-glucan content. Our results also indicated that C. glabrata features a uniquely evolved ER stress-mediated CWI pathway, which differs from that in the closely related species Saccharomyces cerevisiae. Furthermore, we demonstrated that ER stress-mediated CWI pathway in C. glabrata is also induced by the disruption of other genes encoding proteins that function in a correlated manner in the quality control of N-linked glycoproteins in the ER. These results suggest that calcineurin and ER quality control system act as a platform for maintaining CWI in C. glabrata. PMID- 29248113 TI - A phylogenetic and morphological overview of sections Bohusia, Sanguinolenti, and allied sections within Agaricus subg. Pseudochitonia with three new species from France, Iran, and Portugal. AB - The genus Agaricus was recently rearranged to accommodate numerous tropical taxa. Accordingly, the genus was split into six subgenera and 22 sections of which 12 are included in A. subg. Pseudochitonia. Preliminary data indicated that three putative new species belong to this subgenus. Our objectives were to describe these species, to determine to which sections they belong, and to experience the interest of some traditional traits in this new context. We morphologically described Agaricus coniferarum from France and Portugal, Agaricus iranicus from Iran, and Agaricus lusitanicus from Portugal. Multi-gene phylogenetic analyses based on ITS, LSU, and tef1 sequence data of representatives of the 12 sections clearly indicated that A. coniferarum and A. lusitanicus are placed in Agaricus sect. Bohusia, while A. iranicus is in A. sect. Sanguinolenti. Incidentally, we replaced the illegitimate name Agaricus magnivelaris by Agaricus fiardianus. In a phylogenetic tree, based on all available ITS sequence data and focussing on six related sections, we examined the phylogenetic distribution of various characters. The intensity of red discolouration when the sporocarp is rubbed or cut appeared as a phylogenetically weak informative trait. We propose a determination key leading to a group of three hardly distinguishable sections (Bohusia, Nigrobrunnescentes, and Sanguinolenti). PMID- 29248114 TI - Inactivation of bacterial quorum sensing signals N-acyl homoserine lactones is widespread in yeasts. AB - The inactivation of quorum sensing signals, a phenomenon known as quorum quenching, has been described in diverse microorganisms, though it remains almost unexplored in yeasts. Beyond the well-known properties of these microorganisms for the industry or as eukaryotic models, the role of yeasts in soil or in the inner tissues of a plant is largely unknown. In this report, the wider survey of quorum quenching activities in yeasts isolated from Antarctic soil and the inner tissues of sugarcane, a tropical crop, is presented. Results show that, independently of their niche, quorum quenching activities are broadly present in unicellular fungi. Although yeasts showing a broad range of quorum quenching activity are present in the two niches, at the same time specific AHL inactivation profiles can also be found. Furthermore, yeasts from both sampling sites show quorum quenching activities compatible with lactonase-like and acylase like inactivations of AHLs. Interestingly, the characterization of Rhodotorula mucilaginosa 7Apo1 showed that the presence of a particular AHL does not interfere with the quenching of a second molecule. Evidence suggests that yeasts could play a role in the modulation of the quorum sensing activity of bacteria. The relationship among phylogeny, sampling sites and yeast quorum quenching activities of the isolates is analyzed. PMID- 29248115 TI - Glycerol metabolism genes in Aureobasidium pullulans and Aureobasidium subglaciale. AB - Intracellular glycerol accumulation is one of the main fungal adaptations to osmotic and also cold stress. We investigated the management of glycerol metabolism in polyextremotolerant black yeasts Aureobasidium pullulans and Aureobasidium subglaciale. We show that increased salinity (5 % and 10 %; w/v), but not cold (10 degrees C) trigger intracellular glycerol accumulation. The transcriptional response of the genes involved in glycerol synthesis, degradation and import, to increased salinity, low temperature or a combination of both was analysed with real-time PCR. Each of the two species contains an NAD+-dependent glycerol-3-phosphate dehydrogenase, a glycerol-3-phosphate phosphatase, a mitochondrial glycerol-3-phosphate dehydrogenase, two copies of a glycerol kinase, and more than ten copies of major facilitator superfamily transporters similar to glycerol proton symporters. Similarly to glycerol accumulation itself, transcriptional response to hypersaline stress was larger compared to low temperature stress and was more consistent in A. pullulans compared to A. subglaciale, reflecting the different stress tolerance and ecological strategy of each species. PMID- 29248116 TI - Molecular diversity and allergenic profiles of Alternaria spp. from desert environments in Arizona. AB - This study examined the genetic diversity of small-spored Alternaria species in the southwest desert of the USA by sampling 552 isolates from different habitats (soil and plant debris) in different locations (urban and an undisturbed desert). To estimate the genetic diversity, Amplified Fragment Length Polymorphism (AFLP) fingerprinting analysis was performed for all isolates. Strains representative of the sampled genotypic diversity (n = 125) were further characterized according their sporulation pattern and the capability to produce allergens. Morphological characterization assigned the majority of the strains to the Alternaria alternata and Alternaria tenuissima morpho-groups with only two isolates assigned to the Alternaria arborescens morpho-group. AFLP fingerprinting differentiated the A. arborescens morpho-groups, but could not distinguish between the A. alternata and A. tenuissima morpho-groups. Western blot analysis showed that a large number of allergenic proteins were produced by strains. These proteins were not specific for any morpho-group nor source of isolation. A hierarchical analysis of molecular variance was performed on the AFLP data to quantify molecular variation and partition this variation among sampled locations and habitat. No statistically significant differentiation among locations and habitat was detected indicating a lack of population structure across environments. PMID- 29248117 TI - Editorial overview: Host-microbe interactions: fungi. PMID- 29248118 TI - Editorial overview: Host-microbe interactions: parasites. PMID- 29248119 TI - [Hyponatremia associated with SSRI/NRSI: Descriptive and comparative epidemiological study of the incidence rates of the notified cases from the data of the French National Pharmacovigilance Database and the French National Health Insurance]. AB - INTRODUCTION: Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) are frequently prescribed. These antidepressants can potentially induce serious hyponatremia through the SIADH syndrome. That seems to concern all molecules of these classes but the individual risk of each molecule is not well known. The aims of the study were to compare the incidence rate of each molecule in order to identify the existence of molecules more at risk of inducing hyponatremia and to characterize a profile of patients at risk for hyponatremia during a treatment with a SSRI or a SNRI. METHOD: The cases of hyponatremia under SSRI/SNRI were extracted from the French pharmacovigilance database (BPNV). The exposition to the different SSRIs/SNRIs in the French population was estimated from the French National Health Insurance database (SNIIRAM) using a sampled database (Echantillon Generalistes des Beneficiaires). The study ran from 01/01/2011 to 31/12/2013. The primary study endpoint was the incidence rate of notifications of the hyponatremia cases in patients treated by SSRI/SNRI and recorded into the BNPV database, related to the average annual number of corresponding treatments initiated during the same period. RESULTS: The number of cases of hyponatremia included in the study was 169 for 3 749 800 adult patients initiating treatment. The incidence rate of cases was 1.64 for 100 000 persons per year (PY). The standardized incidence rates between the different molecules showed no difference except for duloxetine (2.79/100 000 PY p > 0.03). Identified risk factors were age, with a large increase of incidence rate from 75 years old (incidence 12.5 higher) and female gender. CONCLUSIONS: Comparison of the incidence rates from spontaneous reports indicates a greater risk of hyponatremia for duloxetine for 2011-2013. This result needs to be confirmed by other studies. The advanced age and female sex are risk factors, irrespective of the molecule. PMID- 29248120 TI - Infection of hematopoietic stem cells by Leishmania infantum increases erythropoiesis and alters the phenotypic and functional profiles of progeny. AB - Immunosuppression is a well-established risk factor for Visceral Leishmaniasis. Post-immunosuppression leishmaniasis is characterized by an increase of parasite burden, hematopoietic disorders and unusual clinical manifestations. Although there are many reports on bone marrow findings in VL, less is known about the relationship between parasite dynamics in this organ and the function of either hematopoietic stem cells and progenitor cells themselves. In the present study, we tackle these issues using a new approach of infecting human stem cells derived from bone marrow with L. infantum. Using this strategy, we show that human hematopoietic stem cells (hHSC) are able to phagocytize L. infantum promastigotes and release modulatory and pro-inflammatory cytokines, mainly TNF-alpha. Our results demonstrated that L. infantum infection in vitro enhances hematopoiesis, favoring the development of erythrocitic lineage through a mechanism yet unknown. Moreover, we found that L. infantum infection alters the phenotypic profile of the hematopoietic progeny; modifying the surface markers expression of differentiated cells. Thus, our study represents a rare opportunity to monitor the in vitro differentiation of human stem cells experimentally infected by L. infantum to better understand the consequences of the infection on phenotypic and functional profile of the cell progeny. PMID- 29248121 TI - Percutaneous drug-eluting balloon angioplasty to treat dialysis access stenosis. AB - A common complication of arteriovenous fistula for hemodialysis is development of conduit stenosis, which compromises function and can result in access thrombosis. Possible treatment options include open repair and endovascular therapy, with the latter preferred due to lower morbidity and similar outcomes. Recurrence of conduit stenosis is common and, based on the pathophysiology of this lesion, the application of drug-coated balloon angioplasty is attractive. In this report, the application of drug-eluting balloon angioplasty for dialysis access stenosis in 18 consecutive patients is detailed and primary patency rates of 82% at 1 year and 68% at 2 years were calculated. PMID- 29248122 TI - Pathology of graft and stent-graft infections: Lessons learned from examination of explant materials. AB - Due to the aging population, the number of patients treated with aortic grafts or endografts continues to increase. Although infection after these procedures is uncommon, aortic graft infection is a life-threatening condition, and refinement of management guidelines based on implant pathophysiology is appropriate. In the early 1990s, our European collaborative retrieval program, European Group for Research on Prostheses Applied for Vascular Surgery (GEPROVAS) was commissioned to analyze the degenerative phenomenon occurring on explanted grafts or endografts. In this review, our observations from the examination of explanted aortic grafts and endografts found that both fabric and structural degradation is present and is greater in the setting of inflammation produced by infection. PMID- 29248123 TI - Current management of infected aortic grafts in patients with connective tissue disorders. AB - Patients with connective tissue disorder present a particular clinical challenge in the treatment of aortic graft infections. Specific complexities arise in patients with connective tissue disorders when reoperation for aortic graft infection is required. Herein we describe current management of infected aortic grafts in patients with connective tissue disorders using homograft and rifampin coated graft replacements using in situ replacement therapy, which is associated with improved outcome compared to graft excision and extra-anatomic bypass. PMID- 29248124 TI - Current status of endovascular treatment of aortoenteric fistula. AB - Aortoenteric fistula (AEF) is one of the most challenging diagnostic and therapeutic entities in vascular surgery. AEF can occur either primarily involving the aorta and the gastrointestinal tract or, more commonly, secondary to previous aortic reconstructive surgery. Traditionally, the treatment of AEF includes graft excision and extra-anatomic bypass surgery or in situ graft replacement. However, recently endovascular repair has emerged as an alternative therapeutic option. In this article, we present published and current evidence for endovascular repair of primary and secondary AEF. When endovascular treatment is applied where appropriate, early outcomes seem to be superior compared to open surgery. This benefit may be lost during long-term follow-up, implying that a staged approach with early conversion to in situ grafting may realize the best patient survival and morbidity. Lifelong administration of antibiotics is associated with a reduction in re-infection. An endovascular approach used as a bridging procedure in unstable patients is recommended, followed by definitive open therapy, if feasible, in patients with good life expectancy. PMID- 29248125 TI - Aortobronchial and aortoenteric fistula. AB - Pathologic communication between the thoracic aorta and esophagus or tracheobronchial tree is a rare vascular condition and most commonly develops after open or endovascular aortic repair complicated by infection. Patients with aortoesophageal or tracheobronchial fistula often present with systemic infection and are at risk for major hemorrhage. Medical management is uniformly fatal. Expeditious definitive management requires operative repair by open repair or a combination of endovascular and open procedures. Appropriate antibiotic regimens are important for preventing graft reinfection. PMID- 29248126 TI - Management of the infected aortic endograft. AB - Although the incidence of abdominal and thoracic aortic endograft infection is infrequent, ranging between 0.2% and 5%, stent-graft infection carries significant morbidity and mortality and exemplifies a formidable therapeutic challenge. The treatment goal is to eradicate the infectious process by endograft explantation, regional tissue debridement, and arterial reconstruction by either an extra-anatomic or in situ grafting procedure using autologous vein, cryopreserved allograft, or antibiotic-soaked prosthetic grafts. Successful treatment should maintain normal arterial perfusion to the visceral arteries and lower extremities. Important treatment adjuncts included antibiotic therapy based on cultures, specific bacterial isolates, and coverage of the repair or aortic stump using an omental wrap. Nonoperative treatment in patients with severe comorbidities that preclude endograft explantation may be appropriate in the setting of low-grade biofilm infection. Percutaneous drainage of the perigraft abscess followed by continuous antibacterial irrigation of the cavity can be utilized, but is associated with a high clinical failure rate. PMID- 29248127 TI - How to best treat infectious complications of open and endovascular thoracic aortic repairs. AB - Infectious complications of open and endovascular procedures for descending thoracic aortic disease are relatively rare, affecting 1% to 6% of treated patients. However, the number of thoracic aortic procedures, especially endovascular, is increasing continuously, and infectious complications involving the graft or endograft have been observed more frequently in recent years. Several causative factors may play a role in thoracic aortic prosthetic infections, including hematogenous seeding, local bacterial translocation, and iatrogenous contamination. In addition, the development of a fistula between the aortic graft and the esophagus or the bronchial tree is a common associated finding, representing a dramatic event that further increases mortality rates and requires multidisciplinary management. Treatment of these conditions is demanding, often including a number of pharmacological, surgical, and endovascular options. Because there are several different surgical strategies and timing modalities that are chosen according to the surgeon's experience, the results of different treatment options are difficult to summarize, and no consensus exists on a standardized paradigm of treatment. In this review, published reports regarding clinical outcomes related to thoracic graft and endograft infections are discussed, including our personal experience with surgical and endovascular management of this condition. PMID- 29248128 TI - Management of stage III non-small cell lung cancer. AB - Optimal management of patients with locally advanced non-small cell lung cancer remains challenging in the context of this heterogeneous disease. Despite aggressive therapeutic approaches, survival benefits are still unsatisfactory for what might be viewed as a localized malignancy. A combined modality approach offers patients superior outcomes, especially because technological advances and refined surgical procedures now provide better results with fewer complications. Nevertheless, several features of therapy remain controversial and lack formal prospective data. Traditional cytotoxic chemoradiation therapy may have reached a plateau and future perspectives opting to integrate molecularly targeted agents and immunotherapy might be the way to improve outcomes in this disease subset. PMID- 29248129 TI - The distribution of cancer cases in Somalia. AB - OBJECTIVE: The aim of this study was to investigate the frequency and distribution of cancer cases in a defined time period in Somalia. MATERIALS AND METHODS: A total of 403 cancer cases were diagnosed between January 01, 2016 and March 01, 2017 in the Department of Pathology at the Somalia Mogadishu-Turkey Education and Research Hospital or the Department of Oncology at Uniso Hospital, Somalia University. Data on cancer type, patient age, and gender were obtained from pathology reports and hospital records. RESULTS: Female patients totaled 49.6% (n = 200) and 50.4% of patients were male (n = 203). The youngest patient was 18 years of age, the oldest was 97, and the average age was 53.4 years. The 10 most common types of cancer were esophageal (n = 130, 32.3%), non-Hodgkin lymphoma (n = 35, 8.7%), liver (n = 26, 6.5%), breast (n = 24, 6.0%), skin (n = 17, 4.2%), thyroid (n = 13, 3.2%), brain (n = 12, 3.0%), bone (n = 11, 2.7%), colorectal (n = 11, 2.7%), and soft tissue (n = 11, 2.7%). The most common site of cancer in both males and females was the esophagus. CONCLUSION: These results show a high incidence of esophageal cancer in Somalia, and strongly suggest that environmental risk factors and nutritional habits have a strong impact in this population. Serious and extensive research on the etiology of esophageal cancer is required. PMID- 29248130 TI - Guidance Statement On BRCA1/2 Tumor Testing in Ovarian Cancer Patients. AB - The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3%-9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin-fixed, paraffin-embedded specimens. The current manuscript reviews some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements. PMID- 29248132 TI - Mitochondrial and glycolytic metabolic compartmentalization in diffuse large B cell lymphoma. AB - Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as 18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas non neoplastic lymphocytes in the control samples did not express these markers. Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic tissue. Furthermore, the differential expression of lactate exporters (MCT4) on tumor-associated stroma and lactate importers (MCT1) on neoplastic lymphocytes support the hypothesis that neoplastic cells are metabolically linked to the stroma likely via mutually beneficial reprogramming. MCT4 is a marker of tumor associated stroma in neoplastic tissue. Our findings suggest that disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and MCT4 blockade should be studied to determine if it could represent a novel treatment target in DLBCL. PMID- 29248131 TI - Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development. AB - Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis, or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation. Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize oxidative phosphorylation. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation, and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate, and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB), and is highly expressed in cancer associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism, are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers. PMID- 29248135 TI - Metabolic symbiosis in cancer and its therapeutic implication. PMID- 29248134 TI - Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-Acetylcysteine in Breast Cancer. AB - BACKGROUND: High oxidative stress as defined by hydroxyl and peroxyl activity is often found in the stroma of human breast cancers. Oxidative stress induces stromal catabolism, which promotes cancer aggressiveness. Stromal cells exposed to oxidative stress release catabolites such as lactate, which are up-taken by cancer cells to support mitochondrial oxidative phosphorylation. The transfer of catabolites between stromal and cancer cells leads to metabolic heterogeneity between these cells and increased cancer cell proliferation and reduced apoptosis in preclinical models. N-Acetylcysteine (NAC) is an antioxidant that reduces oxidative stress and reverses stromal catabolism and stromal-carcinoma cell metabolic heterogeneity, resulting in reduced proliferation and increased apoptosis of cancer cells in experimental models of breast cancer. The purpose of this clinical trial was to determine if NAC could reduce markers of stromal cancer metabolic heterogeneity and markers of cancer cell aggressiveness in human breast cancer. METHODS: Subjects with newly diagnosed stage 0 and I breast cancer who were not going to receive neoadjuvant therapy prior to surgical resection were treated with NAC before definitive surgery to assess intra-tumoral metabolic markers. NAC was administered once a week intravenously at a dose of 150 mg/kg and 600 mg twice daily orally on the days not receiving intravenous NAC. Histochemistry for the stromal metabolic markers monocarboxylate transporter 4 (MCT4) and caveolin-1 (CAV1) and the Ki67 proliferation assay and TUNEL apoptosis assay in carcinoma cells were performed in pre- and post-NAC specimens. RESULTS: The range of days on NAC was 14-27 and the mean was 19 days. Post-treatment biopsies showed significant decrease in stromal MCT4 and reduced Ki67 in carcinoma cells. NAC did not significantly change stromal CAV1 and carcinoma TUNEL staining. NAC was well tolerated. CONCLUSIONS: NAC as a single agent reduces MCT4 stromal expression, which is a marker of glycolysis in breast cancer with reduced carcinoma cell proliferation. This study suggests that modulating metabolism in the tumor microenvironment has the potential to impact breast cancer proliferation. PMID- 29248136 TI - Uncoupling tumor-stroma interactions in breast cancer patients. PMID- 29248133 TI - Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment. AB - BACKGROUND: Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells, such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes. METHODS: A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from four subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1), and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1, and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in > 50% of cells. RESULTS: TOMM20, MCT1, and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared with TAMs and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1, while TAMs have absent expression of TOMM20 and MCT1 in all but two cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but one case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1, and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenvironment. A high metabolic heterogeneity signature was associated with relapsed or refractory cHL with a hazard ratio of 5.87 (1.16-29.71; two-sided P < .05) compared with the low metabolic heterogeneity signature. CONCLUSION: Aggressive cHL exhibits features of metabolic heterogeneity with high mitochondrial metabolism in cancer cells and high glycolysis in TAMs, which is not seen in reactive lymph nodes. Future studies will need to confirm the value of these markers as prognostic and predictive biomarkers in clinical practice. Treatment intensity may be tailored in the future to the metabolic profile of the tumor microenvironment and drugs that target metabolic heterogeneity may be valuable in this disease. PMID- 29248137 TI - Epidemiology of cardiac surgery-associated acute kidney injury. AB - Acute kidney injury (AKI) is defined by the KDIGO definition into 3 stages on basis of an increase in serum creatinine or a period of oliguria. AKI is defined as rapid reversal when the episode is 48 h or less. When AKI persists for 7 days or longer, the term acute kidney disease is used. Subclinical AKI is defined by increased concentration of an AKI biomarker, without meeting the KDIGO definition for AKI. In contrast to this, functional AKI is defined by the KDIGO definition, wherein the AKI biomarker concentration is not increased. AKI is multifactorial and heterogeneous and occurs in half of ICU patients as defined by the current KDIGO definition for AKI. In this review, we specifically describe the epidemiology of cardiac surgery-associated AKI and describe the role of scoring systems and specific AKI biomarkers. PMID- 29248138 TI - Pathophysiology of AKI. AB - Acute kidney injury (AKI) is common in the perioperative and intensive care setting. Although AKI is usually multifactorial, haemodynamic instability, sepsis and drug toxicity are commonly implicated. Independent of the exact aetiology, several different pathophysiologic processes occur simultaneously and in sequence, including endothelial dysfunction, alteration of the microcirculation, tubular injury, venous congestion and intrarenal inflammation. A multitude of different immune cells from within the kidney and the systemic circulation play a role in the development, maintenance and recovery phase of AKI. In this review, we describe the common processes involved in AKI and their connections, with particular emphasis on the perioperative and critical care setting. PMID- 29248139 TI - The macro- and microcirculation of the kidney. AB - Acute kidney injury (AKI) remains one of the main causes of morbidity and mortality in the intensive care medicine today. Its pathophysiology and progress to chronic kidney disease is still under investigation. In addition, the lack of techniques to adequately monitor renal function and microcirculation at the bedside makes its therapeutic resolution challenging. In this article, we review current concepts related to renal hemodynamics compromise as being the event underlying AKI. In doing so, we discuss the physiology of the renal circulation and the effects of alterations in systemic hemodynamics that lead to renal injury specifically in the context of reperfusion injury and sepsis. The ultimate key culprit of AKI leading to failure is the dysfunction of the renal microcirculation. The cellular and subcellular components of the renal microcirculation are discussed and how their injury contributes to AKI is described. PMID- 29248140 TI - Biomarkers in acute kidney injury (AKI). AB - Acute kidney injury is common in critically ill patients and portends a significant impact on mortality, progressive chronic kidney disease, and cardiovascular disease and mortality. Though most physicians alter therapy depending on changes in serum creatinine, this often represents delayed intervention. Various AKI biomarkers have been discovered and validated to improve timely detection, differentiation and stratification into risk groups for progressive renal decline, need for renal replacement therapy or death. This chapter will review AKI biomarkers validated over the past decade. We also describe the clinical performance of the biomarkers. We suggest that using AKI biomarkers to complement serum creatinine (or cystatin C) and urine output will better integrate patient care through earlier recognition and clinical outcome prediction after AKI. PMID- 29248141 TI - Impact of volume status and volume therapy on the kidney. AB - Volume resuscitation to correct hypotension in surgical and critically ill patients is a common practice. Available evidence suggests that iatrogenic volume overload is associated with worse outcomes in established acute kidney injury. Intraoperative arterial hypotension is associated with postoperative renal dysfunction, and prompt correction with fluid management protocols that combine inotrope infusions with volume therapy targeted to indices of volume responsiveness should be considered. From the perspective of renal function, the minimum amount of intravenous fluid required to maintain perfusion and oxygen delivery is desirable. Available evidence and expert opinion suggest that balanced crystalloid solutions are preferable to isotonic saline for volume resuscitation. Moreover, albumin has a similar safety profile as crystalloids. Hetastarch-containing colloids have a clear association with acute kidney injury. PMID- 29248142 TI - Impact of e-alert systems on the care of patients with acute kidney injury. AB - With the recent advancement in electronic health record systems and meaningful use of information technology incentive programs (i.e., the American Recovery and Reinvestment Act, the Health Information Technology for Economic and Clinical Health Act, and the Centers for Medicare & Medicaid Services), interest in clinical decision support systems has risen. These systems have been used to examine a variety of different syndromes with variable reported effects. In recent years, electronic alerts (e-alerts) have been implemented at various institutions to decrease the morbidity associated with acute kidney injury (AKI). AKI is common, accounting for 1 in 7 hospital admissions, and is associated with increased length of hospital stay and mortality. AKI is often underrecognized, causing delayed intervention. The use of e-alerts may result in earlier recognition and intervention, as well as decreased morbidity and mortality. This must be balanced with the possibility of increased resource utilization that e alerts may cause. Before widespread implementation, the ethical and legal consequences of not following e-alert recommendations must be established, and the optimal algorithm for AKI e-alert detection must be determined. PMID- 29248143 TI - Prevention of acute kidney injury. AB - Acute kidney injury is a prevalent but underdiagnosed complication that is associated with increased in-hospital morbidity and mortality. The importance of this complication is being increasingly recognized. The lack of timely diagnostic methods and effective preemptive and therapeutic strategies make its perioperative management challenging. To reduce the incidence of acute kidney injury, it is crucial to focus the resources on high-risk patients who can be identified by clinical scoring systems with a high predictive value and newly developed renal biomarkers. The 'Kidney Disease: Improving Global Outcomes' guidelines recommend the implementation of preventive strategies that include a bundle of supportive measures. However, clear evidence to support such an approach is lacking. Previous studies demonstrated improved patients' outcome following remote ischemic preconditioning in high-risk patients. Other studies reached an opposite result. To date, renal replacement therapy is the "gold standard" for the treatment of severe acute kidney injury, although the ideal timing, technique, and application of this therapy remain under debate. PMID- 29248144 TI - Renal replacement therapy for AKI: When? How much? When to stop? AB - Severe acute kidney injury (AKI) requiring renal replacement therapy (RRT) is a serious clinical disorder in the intensive care unit (ICU), occurring in a significant proportion of critically ill patients. However, many questions remain about the optimal administration of RRT with regard to several important considerations, including treatment dose, timing of treatment initiation and cessation, therapy mode, type of anticoagulation, and management of fluid overload. While Level 1 evidence exists for RRT dosing in AKI, all the studies contributing to this evidence base employed fixed-dose regimens throughout a patient's continuous RRT (CRRT) course, without regard for the possibility of individualizing treatment dose according to the clinical status of a given patient at a specific time. As opposed to CRRT dose, no consensus about the timing of RRT in critically ill AKI patients exists currently. While numerous clinical trials over the past 40 years have attempted to assess "early" versus "late" initiation of RRT, they have been plagued by a myriad of methodological problems, including their largely observational nature and the widely varying definitions of early and late initiation. Although questions about the appropriate timing of CRRT discontinuation arise very frequently in clinical practice, even less information is available in the literature to guide this important decision. The aim of this review is to provide a comprehensive update on RRT delivery to critically ill AKI patients, with specific attention paid to treatment dose and timing and emphasis on addressing the practical questions that arise in daily clinical practice. PMID- 29248145 TI - Renal replacement therapy and anticoagulation. AB - Today, up to 20% of all intensive care unit patients require renal replacement therapy (RRT), and continuous renal replacement therapies (CRRT) are the preferred technique. In CRRT, effective anticoagulation of the extracorporeal circuit is mandatory to prevent clotting of the circuit or filter and to maintain filter performance. At present, a variety of systemic and regional anticoagulation modes for CRRT are available. Worldwide, unfractionated heparin is the most widely used anticoagulant. All systemic techniques are associated with significant adverse effects. Most important are bleeding complications and heparin-induced thrombocytopenia (HIT-II). Regional citrate anticoagulation (RCA) is a safe and effective technique. Compared to systemic anticoagulation, RCA prolongs filter running times, reduces bleeding complications, allows effective control of acid-base status, and reduces adverse events like HIT-II. In this review, we will discuss systemic and regional anticoagulation techniques for CRRT including anticoagulation for patients with HIT-II. Today, RCA can be recommended as the therapy of choice for the majority of critically ill patients requiring CRRT. PMID- 29248146 TI - Renal recovery. AB - Recovery patterns after acute kidney injury (AKI) have increasingly become the focus of research, because currently available preventive measures and specific therapeutic intervention are limited. Moreover, changes in renal functional reserve are recognized as a "hidden" indicator of kidney susceptibility to either acute kidney injury or chronic kidney disease. Understanding these phenomena and their association with outcome may enable the initiation of strategies that facilitate fast and sustained recovery during the time course of AKI and limit AKI progression towards chronic kidney disease. Different interventions may be required during various phases of AKI continuum. Early recognition and prevention of second hit by kidney stress, treatment of cause and prevention of aggravation in the early phase of AKI and facilitation of recovery in the phase of acute kidney disease may together represent the key aspects of modern AKI management. PMID- 29248147 TI - Sequelae of AKI. AB - Large epidemiologic studies in a variety of patient populations reveal increased morbidity and mortality that occur months to years after an episode of acute kidney injury (AKI). Even milder forms of AKI have increased associated morbidity and mortality. Residual confounding may account for these findings, but considering the huge number of individuals afflicted with AKI, the sequelae of AKI may be a very large public health burden. AKI may simply be a marker for increased risk, but there is increasing evidence that it is part of the causal pathway to chronic kidney disease. These studies have upended the traditional view that AKI survivors who returned to baseline, or near baseline renal function, do not suffer additional long-term consequences. Recovery of renal function after AKI, short of independence from renal replacement therapy, is yet to be clearly defined but may be of significant importance in the management of AKI survivors. The association between AKI in patients who undergo cardiac surgery and clinical outcomes is of considerable importance to clinicians, surgeons, and anesthesiologists alike and is a major focus of this review. PMID- 29248148 TI - Acute kidney injury in pediatric patients. AB - Acute kidney injury (AKI) is highly prevalent among hospitalized children, especially those who are critically ill. The incorporation of pediatric elements into consensus definitions has led to a greater understanding of pediatric AKI epidemiology, risk factors, and outcomes. The best available data suggest that AKI occurs in 5% and 27% of non-critically ill and critically ill children, respectively. Additionally, AKI and fluid overload are independently associated with worse outcomes including mortality. Currently, the diagnosis of AKI relies upon urine output and creatinine measurements, both of which pose unique problems in children. However, novel biomarker discovery and new risk stratification techniques have led to enhanced detection and diagnostic strategies. Although no specific treatments exist, strategies designed to prevent AKI are being developed and there is growing evidence that early detection may improve outcomes. We hope that advances in AKI management will follow the diagnostic innovations seen in the past decade. PMID- 29248149 TI - Morphea in Childhood: An Update. AB - Morphea is an inflammatory, fibrosing skin disorder. When it occurs in childhood, it is also known as localized juvenile scleroderma. It is more common in girls and typically appears around the age of 5 to 7 years. According to a recent classification system, morphea is divided into 5 types: circumscribed (plaque), linear, generalized, pansclerotic, and mixed. Approximately 40% of patients present extracutaneous manifestations. Childhood morphea is treated with phototherapy, oral or topical calcitriol, topical tacrolimus 0.1%, methotrexate, topical or systemic corticosteroids, mycophenolate mofetil, bosentan, and topical imiquimod 5%. A variety of measuring tools are used to monitor response to treatment. Few prognostic studies have been conducted, but findings to date suggest that the disease tends to run a chronic or intermittent-recurrent course and frequently causes sequelae. PMID- 29248152 TI - Editorial introduction to the special issue: Aqua species immunity. PMID- 29248150 TI - Multimodal Measurements of Single-Molecule Dynamics Using FluoRBT. AB - Single-molecule methods provide direct measurements of macromolecular dynamics, but are limited by the number of degrees of freedom that can be followed at one time. High-resolution rotor bead tracking (RBT) measures DNA torque, twist, and extension, and can be used to characterize the structural dynamics of DNA and diverse nucleoprotein complexes. Here, we extend RBT to enable simultaneous monitoring of additional degrees of freedom. Fluorescence-RBT (FluoRBT) combines magnetic tweezers, infrared evanescent scattering, and single-molecule FRET imaging, providing real-time multiparameter measurements of complex molecular processes. We demonstrate the capabilities of FluoRBT by conducting simultaneous measurements of extension and FRET during opening and closing of a DNA hairpin under tension, and by observing simultaneous changes in FRET and torque during a transition between right-handed B-form and left-handed Z-form DNA under controlled supercoiling. We discover unanticipated continuous changes in FRET with applied torque, and also show how FluoRBT can facilitate high-resolution FRET measurements of molecular states, by using a mechanical signal as an independent temporal reference for aligning and averaging noisy fluorescence data. By combining mechanical measurements of global DNA deformations with FRET measurements of local conformational changes, FluoRBT will enable multidimensional investigations of systems ranging from DNA structures to large macromolecular machines. PMID- 29248151 TI - Protein Flexibility and Synergy of HMG Domains Underlie U-Turn Bending of DNA by TFAM in Solution. AB - Human mitochondrial transcription factor A (TFAM) distorts DNA into a U-turn, as shown by crystallographic studies. The relevance of this U-turn is associated with transcription initiation at the mitochondrial light strand promoter (LSP). However, it has not been yet discerned whether a tight U-turn or an alternative conformation, such as a V-shape, is formed in solution. Here, single-molecule FRET experiments on freely diffusing TFAM/LSP complexes containing different DNA lengths show that a DNA U-turn is induced by progressive and cooperative binding of the two TFAM HMG-box domains and the linker between them. SAXS studies further show compaction of the protein upon complex formation. Finally, molecular dynamics simulations reveal that TFAM/LSP complexes are dynamic entities, and the HMG boxes induce the U-turn against the tendency of the DNA to adopt a straighter conformation. This tension is resolved by reversible unfolding of the linker, which is a singular mechanism that allows a flexible protein to stabilize a tight bending of DNA. PMID- 29248153 TI - Impact of Pectus Excavatum on Cardiopulmonary Function. AB - BACKGROUND: Pectus excavatum is classified using the Haller Index (HI) or the Correction Index. However, no correlation between the HI and CI and cardiopulmonary impairment has been described in detail. METHODS: This prospective cohort study included 99 otherwise healthy patients with pectus excavatum who underwent cardiopulmonary exercise testing and magnetic resonance imaging at inspiration and expiration to correlate cardiopulmonary function with the grade of thoracic dysmorphia. RESULTS: Probands with an HI exceeding 3.25 had first an increase in heart rate at anaerobic threshold (from 148.0 +/- 16.0 beats/min to 155.9 +/- 15.0 beats/min, p = 0.036), with an HI of more than 3.6 a reduction in oxygen pulse at anaerobic threshold (from 10.7 +/- 2.6 mL/beat to 9.3 +/- 2.9 mL/beat, p = 0.017), with an HI exceeding 3.8 a reduction of maximum oxygen pulse (from 13.9 +/- 3.4 mL/beat to 11.9 +/- 3.7 mL/beat, p = 0.010), and with an HI of exceeding 4.0 a decline in maximum oxygen uptake (from 43.7 +/- 6.5 mL . kg-1 . min-1 to 40.4 +/- 7.4 mL . kg-1 . min-1, p = 0.025). The CI of more 27% reflects cardiopulmonary changes earlier than the corresponding HI exceeding 3.25 (p = 0.01 for maximum oxygen pulse; p = 0.017 for oxygen pulse at anaerobic threshold; p = 0.015 for heart rate at anaerobic threshold). CONCLUSIONS: The inspiratory HI and CI reflect the effect of pectus excavatum on cardiopulmonary function. The cardiopulmonary system reacts first with an increase in heart rate at anaerobic threshold, followed by a decrease in stroke volume at anaerobic threshold and maximum stroke volume. Increased severity of the deformity then leads to a decrease in cardiac output. PMID- 29248154 TI - Improving emulsion formation, stability and performance using mixed emulsifiers: A review. AB - The formation, stability, and performance of oil-in-water emulsions may be improved by using combinations of two or more different emulsifiers, rather than an individual type. This article provides a review of the physicochemical basis for the ability of mixed emulsifiers to enhance emulsion properties. Initially, an overview of the most important physicochemical properties of emulsifiers is given, and then the nature of emulsifier interactions in solution and at interfaces is discussed. The impact of using mixed emulsifiers on the formation and stability of emulsions is then reviewed. Finally, the impact of using mixed emulsifiers on the functional performance of emulsifiers is given, including gastrointestinal fate, oxidative stability, antimicrobial activity, and release characteristics. This information should facilitate the selection of combinations of emulsifiers that will have improved performance in emulsion-based products. PMID- 29248155 TI - Validation of Predictive Score of 30-Day Hospital Readmission or Death in Patients With Heart Failure. AB - Existing prediction algorithms for the identification of patients with heart failure (HF) at high risk of readmission or death after hospital discharge are only modestly effective. We sought to validate a recently developed predictive model of 30-day readmission or death in HF using an Australia-wide sample of patients. This study used data from 1,046 patients with HF at teaching hospitals in 5 Australian capital cities to validate a predictive model of 30-day readmission or death in HF. Besides standard clinical and administrative data, we collected data on individual sociodemographic and socioeconomic status, mental health (Patient Health Questionnaire [PHQ]-9 and Generalized Anxiety Disorder [GAD]-7 scale score), cognitive function (Montreal Cognitive Assessment [MoCA] score), and 2-dimensional echocardiograms. The original sample used to develop the predictive model and the validation sample had similar proportions of patients with an adverse event within 30 days (30% vs 29%, p = 0.35) and 90 days (52% vs 49%, p = 0.36). Applying the predicted risk score to the validation sample provided very good discriminatory power (C-statistic = 0.77) in the prediction of 30-day readmission or death. This discrimination was greater for predicting 30-day death (C-statistic = 0.85) than for predicting 30-day readmission (C-statistic = 0.73). There was a small difference in the performance of the predictive model among patients with either a left ventricular ejection fraction of <40% or a left ventricular ejection fraction of >=40%, but an attenuation in discrimination when used to predict longer-term adverse outcomes. In conclusion, our findings confirm the generalizability of the predictive model that may be a powerful tool for targeting high-risk patients with HF for intensive management. PMID- 29248156 TI - Factors associated with inter-arm blood pressure differences in patients admitted to critical care units. AB - BACKGROUND: Experts recommend obtaining one-time dual- (inter)-arm blood pressure (BP) measurements to predict cardiovascular morbidity risk. OBJECTIVES: To determine differences in inter-arm systolic (S)/diastolic (D) BPs obtained simultaneously and sequentially and examine associations between patient factors and clinical outcomes and inter-arm BP differences. METHOD: A comparative study of adults treated in intensive care; multivariable logistic models were created to determine the extent that inter-arm BP differences predicted outcomes. RESULTS: Of 427 adults in intensive care units, 31.8% had differences of >10 mmHg on simultaneous measurement and 35.1% had differences of >10 mmHg on sequential measurement; differences >15 mmHg were 17.9% and 19.8%, respectively. After controlling for patient factors, simultaneous inter-arm DBP differences >15 mmHg were associated with shorter hospital and longer intensive care length of stay (p = 0.031 and 0.029, respectively) and a 79% reduction in the likelihood of discharge to home (p = 0.009). CONCLUSIONS: Simultaneous inter-arm DBP differences >15 mmHg were associated with clinical outcomes. PMID- 29248157 TI - Relative position control design of receiver UAV in flying-boom aerial refueling phase. AB - This paper proposes the design of the relative position-keeping control of the receiver unmanned aerial vehicle (UAV) with the time-varying mass in the refueling phase utilizing an inner-outer loop structure. Firstly, the model of the receiver in the refueling phase is established. And then tank model is set up to analyze the influence of fuel transfer on the receiver. Subsequently, double power reaching law based sliding mode controller is designed to control receiver translational motion relative to tanker aircraft in the outer loop while active disturbance rejection control technique is applied to the inner loop to stabilize the receiver. In addition, the closed-loop stabilities of the subsystems are established, respectively. Finally, an aerial refueling model under various refueling strategies is utilized. Simulations and comparative analysis demonstrate the effectiveness and robustness of the proposed controllers. PMID- 29248159 TI - An effort to improve the accuracy of documented surgical wound classifications. AB - BACKGROUND: Discordance between circulating nurse- and surgeon diagnosis-based wound classifications may lead to erroneous risk-adjusted rates of surgical site infections with effects on inter-hospital rating, reimbursement, and public perceptions regarding quality of care. METHODS: After an initial two-month audit, we placed a wound class reference algorithm in each operating room and educated staff. An audit was repeated for a two-month period after this intervention. Statistical analysis of the whole and subgroup was performed. RESULTS: Pre intervention, the wound classifications for 70 of 300 cases were discordant. In the post-intervention group, 79 of 483 cases were discordant (p = 0.016). Subgroup analysis of colectomy and appendectomy cases demonstrated dramatically improved concordance. For colectomies, discordance dropped from 84.6% to 15% post intervention (p = <0.001). Appendectomy discordance went from 80% of cases to 30.4% post-intervention (p = 0.001). Wound class discordance increased for the cholecystectomy subgroup (20.4%-37%) but this was not statistically significant (p = 0.066). CONCLUSIONS: As we trend towards a pay-for-performance model, health care systems should review their internal controls on documenting surgical wound classes. PMID- 29248158 TI - The role of left insula in executive set-switching: Lesion evidence from an acute stroke cohort. AB - Impairments in executive functions are common in stroke survivors, both in the acute and in the chronic phase. However, little is known about the underlying lesion neuroanatomy of these deficits. This study aimed to elucidate the pattern of brain damage underlying executive dysfunction in a large and acute stroke cohort. Executive set-switching deficits were evaluated by a shape-based analogue of the Trail Making Test (from the Oxford Cognitive Screen) in a consecutive sample of 144 stroke patients (age: 70 +/- 15 years, examination: 5 +/- 4 days post-stroke; brain imaging: 1.7 +/- 2.9 days post-stroke). A voxelwise lesion symptom mapping analysis was performed by combining executive set-switching accuracy scores with manually delineated lesions on computerized tomography or magnetic resonance imaging scans. The analysis showed that lesions within the left insular cortex and adjacent white matter predicted poorer executive set switching. Further analyses confirmed that the lesion effect in the left insula survived correction for the low-level visuospatial and motor component processes of executive set-switching. In conclusion, the study provides lesion-based evidence for the role of the left insular cortex in flexible switching of attention. The findings are consistent with emergent models of insular function postulating the role of this region in regulatory aspects of goal-directed behaviour. PMID- 29248160 TI - A rare cause of dyspnea: radiotherapy-induced angiosarcoma. PMID- 29248161 TI - Liver elastography: what it is, how it is done, and how it is interpreted. AB - Liver elastography is a noninvasive method for diagnosing fibrosis that has been developed over the last decade in response to the limitations of liver biopsies, blood markers, and traditional imaging modalities. There are different methods of measuring tissue stiffness through ultrasound; thus far, shear wave elastography has proven superior for diagnosing clinically significant liver fibrosis, where early detection modifies the approach to treatment and improves prognosis. This article aims to provide a brief review of the different methods for performing elastography with ultrasound, focusing especially on shear wave elastography and on technical aspects for carrying out the procedure and key points for interpreting the findings. PMID- 29248162 TI - Surgery for hypoplastic left heart syndrome. Taking the long view. PMID- 29248163 TI - Estimated absolute effects on efficacy and safety outcomes of using non-vitamin K antagonist oral anticoagulants in 'real-world' atrial fibrillation patients: A comparison with optimally acenocoumarol anticoagulated patients. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) have been proposed as an alternative to vitamin K antagonists (VKA) for atrial fibrillation (AF) patients. Some studies have proposed that well-managed warfarin therapy is still a valid alternative as efficacious as NOACs but the potential impact and absolute effect of NOACs in "real world" optimally management of VKA AF patients is unknown. PURPOSE: To estimate the potential absolute benefit in clinical outcome rates if the optimally anticoagulated "real-world" AF patients with acenocoumarol had been treated with NOACs. METHODS: We included 1361 patients stable on acenocoumarol with a time in therapeutic range of 100% for the previous 6months and 6.5years of follow-up. The estimation of clinical events avoided was calculated applying absolute risk reductions, relative risk reductions and hazard ratios from the pivotal clinical trials, relative to acenocoumarol. RESULTS: Compared to acenocoumarol, the highest estimated event reduction for stroke was seen with dabigatran 150mg, with an estimated reduction of 0.53%/year. For major bleeding, the highest estimated reduction was seen with apixaban (0.88%/year). For mortality, the largest estimated reduction was with dabigatran 150mg (0.75%/year). In net clinical outcome, apixaban had the estimated highest reduction (1.23%/year). All NOACs showed significantly lower rates for intracranial haemorrhage. CONCLUSION: In optimally acenocoumarol anticoagulated AF patients, estimated reductions in stroke, bleeding and net clinical outcomes with various NOACs are evident. NOACs would potentially show an improvement even among optimally VKA AF patients. PMID- 29248165 TI - Long-term efficacy of a tongue tie service in improving breast feeding rates: A prospective study. AB - BACKGROUND: Breast feeding rates in England at 3months of age are approximately 17% for exclusive breast-feeding and 55% for breast-feeds supplemented with formula. Tongue-tie (TT) in infants is cited as a significant cause of difficulty with maintaining breast-feeding. Early treatment and support can improve breast feeding and allow infants to benefit from the many long-term benefits of breast feeding. Our aim was to determine BF rates in infants 3months after attending our tongue-tie clinic (TTC). METHODS: Institutional ethical approval and study approval were obtained. Patients attending the TTC from May to July 2016 were included. Telephone contact was made 3months postprocedure to establish current behaviour. Symptom resolution was recorded as complete resolution (CR), moderate resolution (MoR), or minimal resolution (MiR). Feeding pattern was either exclusively BF or combined breast and formula feeds or exclusively formula fed. RESULTS: 100 infants were included with complete follow-up data on 87 (87% response rate). Median age at release of TT was 17 (2-88) days without any recurrence. Status at 3months was CR (n=70, 80%); MoR (n=13, 15%), and MiR (n=4, 5%). 43 (49%) were exclusively BF, 36 (41%) were supplementing BF with some formula (2/3 by choice and 1/3 owing to insufficient milk production), and 8 (10%) were using only formula milk (7 by choice and 2 owing to ongoing feeding difficulties). Of the 17 mothers still experiencing symptoms, 5 were exclusively breast-feeding, and 8 were persisting with combined feeds. CONCLUSION: Infants attending our tongue-tie clinic achieved both higher exclusive breastfeeding and combined breast and bottle-feeding when compared to national breast-feeding data at 3months of age. This can facilitate the achievement of long-term breastfeeding, exposing infants and mothers to many of the associated benefits. LEVEL OF EVIDENCE: 4. PMID- 29248164 TI - Deficiency of receptor-interacting protein kinase 3 (RIPK3) attenuates inflammation and organ injury in neonatal sepsis. AB - INTRODUCTION: Sepsis is the third leading cause of morbidity and mortality in neonates. Sepsis in neonates is characterized as the systemic inflammation owing to infection within the first 28days after birth. The molecular mechanism causing the exaggerated inflammation phenotype in neonates has not been completely elucidated. Receptor interacting protein kinase 3 (RIPK3) is a protein identified as a mediator in programmed necrosis or necroptosis. We hypothesize that RIPK3 could be responsible for the inflammatory response in neonates and that deficiency in the RIPK3 protein attenuates inflammation and organ injury in neonatal sepsis. METHODS: Male and female C57BL6 wild-type (WT) and RIPK3 knock out (KO) newborn mice aged 5-7days (3-4g body weight) were injected intraperitoneally with 0.9mg/g cecal slurry (CS). At 10h after injection, the newborns were euthanized and blood, the lungs and gut tissues were collected. RESULTS: At 10h after CS injection, serum cytokines IL-6 and IL-1beta in the WT mice were increased by 511- and 43-fold whereas in KO mice, these levels were increased by 166-fold and 22-fold, respectively. Lung IL-1beta in the WT mice increased by 7-fold after CS injection whereas only a 4-fold increase was seen in the KO mice. In the lungs of CS injected KO mice, the injury score, MIP-2 mRNA, myeloperoxidase (MPO) activity and TUNEL staining were significantly reduced by 76%, 70%, 26% and 74%, respectively compared to the CS WT mice. Gut TUNEL staining was also reduced by 80%. CONCLUSION: The deficiency in RIPK3 attenuated serum and lung cytokines, lung injury and neutrophil infiltration and lung and gut apoptosis. These data suggest that RIPK3, in part, is responsible for the systemic inflammatory response in neonatal sepsis. PMID- 29248166 TI - High temporal resolution modeling of the impact of rain, tides, and sea level rise on water table flooding in the Arch Creek basin, Miami-Dade County Florida USA. AB - Modeling of groundwater levels in a portion of the low-lying coastal Arch Creek basin in northern Miami-Dade County in Southeast Florida USA, which is subject to repetitive flooding, reveals that rain-induced short-term water table rises can be viewed as a primary driver of flooding events under current conditions. Areas below 0.9m North American Vertical Datum (NAVD) elevation are particularly vulnerable and areas below 1.5m NAVD are vulnerable to exceptionally large rainfall events. Long-term water table rise is evident in the groundwater data, and the rate appears to be consistent with local rates of sea level rise. Linear extrapolation of long-term observed groundwater levels to 2060 suggest roughly a doubling of the number of days when groundwater levels exceed 0.9m NAVD and a threefold increase in the number of days when levels exceed 1.5m NAVD. Projected sea level rise of 0.61m by 2060 together with increased rainfall lead to a model prediction of frequent groundwater-related flooding in areas<0.9m NAVD. However, current simulations do not consider the range of rainfall events that have led to water table elevations>1.5m NAVD and widespread flooding of the area in the past. Tidal fluctuations in the water table are predicted to be more pronounced within 600m of a tidally influenced water control structure that is hydrodynamically connected to Biscayne Bay. The inland influence of tidal fluctuations appears to increase with increased sea level, but the principal driver of high groundwater levels under the 2060 scenario conditions remains groundwater recharge due to rainfall events. PMID- 29248167 TI - The intersection of physician wellbeing and clinical application of diabetes guidelines. AB - OBJECTIVES: Prediabetes (preDM) and diabetes are complex conditions that place significant strain on medical providers. This can have a negative impact on providers' wellbeing and could impact clinical decisions. We investigated the interplay of caring for patients with prediabetes, physician mental wellbeing, and clinical care. METHODS: Using the theory of planned behavior, we conducted a secondary analysis to evaluate physicians' self-reported provision of care to patients with preDM. We evaluated the effect of mental wellbeing and perceived barriers to caring for patients with preDM. RESULTS: Among 1015 academic physicians, a greater perception of barriers to care and a higher percentage of patients seen with preDM were both significantly associated with a less positive physician state of mind. Physician state of mind was not associated with self reported clinical behavior. Physician perception of patient barriers has a positive correlation with their likelihood of prescribing metformin for preDM. CONCLUSIONS: Caring for a larger proportion of patients with preDM is associated with worse mental wellbeing. Physician attitudes and subjective norms may predict adherence to guidelines, while physician attitudes and wellbeing affect self reported prescribing behavior. PRACTICE IMPLICATIONS: Future research should evaluate ways to lessen the psychological burden of caring for patients with diabetes and preDM. PMID- 29248168 TI - Low-Dose Hypersensitive Response for Residual pATM and gammaH2AX Foci in Normal Fibroblasts of Cancer Patients. AB - PURPOSE: To define the dose-response relationship for initial and residual pATM and gammaH2AX foci and temporal response of pATM foci in fibroblasts of 4 hyper radiosensitivity (HRS)-positive cancer patients and 8 HRS-negative cancer patients and answer the question regarding the role of DNA double-strand break (DSB) recognition and repair in the mechanism of HRS. METHODS AND MATERIALS: The cells were irradiated with single doses (0.1-4 Gy) of 6-MV X rays. The number of initial and residual pATM and gammaH2AX foci was assessed 1 hour and 24 hours after irradiation, respectively. Kinetics of DSB recognition and repair was estimated by pATM foci assay after irradiation with 0.2 and 2 Gy. RESULTS: Hyper radiosensitivity response (confirmed by the induced-repair model) was clearly evident for residual pATM and gammaH2AX foci in fibroblasts of HRS-positive patients but not in fibroblasts of HRS-negative patients. Significantly less DSB was recognized by pATM early (10-30 minutes) after irradiation with 0.2 Gy in HRS positive compared with HRS-negative fibroblasts. CONCLUSIONS: The present results provide evidence for the role of DSB recognition by pATM and repair in the mechanism of HRS and seem to support the idea of nucleo-shuttling of the pATM protein to be involved in HRS response. PMID- 29248169 TI - Simultaneous Integrated Boost for Radiation Dose Escalation to the Gross Tumor Volume With Intensity Modulated (Photon) Radiation Therapy or Intensity Modulated Proton Therapy and Concurrent Chemotherapy for Stage II to III Non-Small Cell Lung Cancer: A Phase 1 Study. AB - PURPOSE: To establish, in the phase 1 portion of a prospective phase 1/2 study, the maximum tolerated dose of image guided intensity modulated radiation therapy (IMRT) or proton therapy (IMPT), both with a simultaneous integrated boost (SIB), for patients with stage II to IIIB non-small cell lung cancer receiving concurrent chemoradiation therapy. METHODS AND MATERIALS: Patients had pathologically proven non-small cell lung cancer, either unresectable stage II to IIIB disease or recurrent disease after surgical resection, and could tolerate concurrent chemoradiation. Radiation doses were selectively escalated to the SIB volume (internal gross tumor volume + 5-mm margin), and the dose to the planning target volume (internal gross tumor volume + 8-mm margin for clinical target volume + 5 mm) was kept at 60 Gy [cobalt gray equivalent (CGE)] over 30 fractions. Patients were randomized between the IMRT and IMPT groups if slots were available on the treatment machines for both groups. Otherwise, patients were allocated to IMRT or IMPT, whichever had an open treatment slot on the machine without randomization. RESULTS: Fifteen patients (6 IMRT, 9 IMPT) were enrolled. The highest doses to the SIB were 72 Gy in the IMRT group and 78 Gy(CGE) in the IMPT group. Nine patients (6 IMRT, 3 IMPT) received an SIB dose of 72 Gy(CGE) [biologically effective dose = 89.3 Gy(CGE)], and 6 patients (IMPT) received an SIB dose of 78 Gy(CGE) [biologically effective dose = 98.3 Gy(CGE)]. Dose-limiting (grade >=3) toxicity (esophagitis) developed in 1 of the 9 patients given 72 Gy(CGE) SIB. Grade >=3 pneumonitis developed in 2 of the 6 patients treated to 78 Gy(CGE) IMPT SIB: 1 (grade 3) at 3 months after treatment and the other (grade 5, possibly related to treatment) at 2 months after treatment. Only 1 patient developed a marginal tumor recurrence with a median follow-up of 25 months (range, 4.3-47.4 months). CONCLUSIONS: We recommend that an SIB dose of 72 Gy(CGE) be used as the highest SIB dose for the planned randomized phase 2 study. PMID- 29248170 TI - Severe lymphopenia during neoadjuvant chemoradiation for esophageal cancer: A propensity matched analysis of the relative risk of proton versus photon-based radiation therapy. AB - BACKGROUND AND PURPOSE: Circulating lymphocytes are exquisitely sensitive to radiation exposure, even to low scattered doses which can vary drastically between radiation modalities. We compared the relative risk of radiation-induced lymphopenia between intensity modulated radiation therapy (IMRT) or proton beam therapy (PBT) in esophageal cancer (EC) patients undergoing neoadjuvant chemoradiation therapy (nCRT). MATERIAL AND METHODS: EC patients treated with IMRT and PBT were propensity matched based on key clinical variables. Treatment associated lymphopenia was graded using CTCAE v.4.0. Using matched cohorts, univariate and multivariable multiple logistic regression was used to identify factors associated with increased risk of grade 4 lymphopenia as well as characterize their relative contributions. RESULTS: Among the 480 patients treated with nCRT, 136 IMRT patients were propensity score matched with 136 PBT patients. In the matched groups, a greater proportion of the IMRT patients (55/136, 40.4%) developed grade 4 lymphopenia during nCRT compared with the PBT patients (24/136, 17.6%, P < 0.0001). On multivariable analysis, PBT was significantly associated with a reduction in grade 4 lymphopenia risk (odds ratio, 0.29; 95% confidence interval, 0.16-0.52; P < 0.0001). CONCLUSION: PBT is associated with significant risk reduction in grade 4 lymphopenia during nCRT in esophageal cancer. PMID- 29248171 TI - Local recurrences after curative IMRT for HNSCC: Effect of different GTV to high dose CTV margins. AB - INTRODUCTION: The aim was to analyze position of CT-verified local recurrences (LR) and local control (LC) among three centers that used different GTV to CTV1 margins. MATERIALS AND METHODS: In total, 1576 patients completing radical primary IMRT for larynx, pharynx, oral cavity HNSCC in three centers in Denmark between 2006 and 2012 were included. CT-verified LRs were analyzed as possible points of recurrence origin and compared between groups of small (0-2.5 mm), larger (>2.5 mm), and anatomical GTV-CTV1 margins. The recurrence point's position relative to the GTV and 95% prescription dose was evaluated. Overall local control rate was evaluated using Cox uni- and multi-variate analysis. RESULTS: After a median follow-up of 41 months, 272 patients had local failure. Median GTV-CTV1 margin in Center1, 2 and 3 was 0.0, 3.7 and 9.7 mm, respectively. 51% of local recurrences were inside the GTV. No difference in distribution of LRs in relation to GTV surface (p = 0.4) or the dose to LRs (p = 0.2) was detected between the groups. A difference in LC was found univariate between the centers (p = 0.03), but not in multivariate analysis (p = 0.4). CONCLUSIONS: No relation was found between the recurrences' distributions as function of the margins used at three centers. In multivariate analysis, local control was not influenced by the centers. PMID- 29248172 TI - The Effects of Forward Head Posture on Neck Extensor Muscle Thickness: An Ultrasonographic Study. AB - OBJECTIVE: This study aimed to compare neck extensor muscle thickness, thickness changes, and strength between participants with forward head posture (FHP) and controls with normal head posture (NHP). METHODS: Twenty college students with FHP (mean age 21.30 +/- 2.36 years) and 20 students with NHP (mean age 21.85 +/- 2.78 years) participated in this case-control study. The thickness of neck extensor muscles was measured at rest and at maximal voluntary isometric contraction (MVIC). In addition, the craniovertebral angle (CVA) was calculated. To compare thickness changes between the 2 groups and among 5 muscles, a 2-way repeated measures analysis of variance was applied. In addition, Pearson's correlation test was performed to investigate the relationship between neck extensor MVIC and CVA. RESULTS: The FHP group demonstrated lower MVIC compared with the NHP group (P = .03). Semispinalis capitis showed the smallest thickness changes during neck extensor MVIC in FHP compared with the controls (P < .001). However, no significant difference in terms of muscle thickness was observed between the 2 groups at the state of rest (P = .16-.99). A positive association was also found between the MVIC and CVA (P = .02). CONCLUSIONS: Semispinalis capitis had less thickness changes during MVIC of neck extensors in individuals with FHP compared with those with NHP. This indirectly implies lower activity of this muscle in FHP condition. This study finding may help researchers develop therapeutic exercise protocols to manage FHP. PMID- 29248173 TI - The Primary Tube Versus Trabeculectomy Study: Methodology of a Multicenter Randomized Clinical Trial Comparing Tube Shunt Surgery and Trabeculectomy with Mitomycin C. AB - PURPOSE: To describe the methodology of the Primary Tube Versus Trabeculectomy (PTVT) Study. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Patients with medically uncontrolled glaucoma and no prior incisional ocular surgery. METHODS: Patients are being enrolled at 16 clinical centers and randomly assigned to treatment with a tube shunt (350-mm2 Baerveldt glaucoma implant) or trabeculectomy with mitomycin C (0.4 mg/ml for 2 minutes). MAIN OUTCOME MEASURES: The primary outcome measure is the rate of surgical failure, defined as intraocular pressure (IOP) more than 21 mmHg or reduced by less than 20% from baseline, IOP of 5 mmHg or less, reoperation for glaucoma, or loss of light perception vision. Secondary outcome measures include IOP, glaucoma medical therapy, visual acuity, visual fields, and surgical complications. CONCLUSIONS: Practice patterns vary in the surgical management of glaucoma, and opinions differ among surgeons regarding the preferred primary operation for glaucoma. The PTVT Study will provide valuable information comparing the 2 most commonly performed glaucoma surgical procedures. PMID- 29248174 TI - Synthesis and Anticancer Activity of Novel Ureas and Sulfamides Incorporating 1 Aminotetralins. AB - BACKGROUND AND AIMS: In the present study, a series of ureas and sulfamides derived from 1-aminotetralins were synthesized. For this purpose, urea and sulfamide analogues were synthesized from the reactions of substituted 1 aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride. The anticancer activity of newly synthesized compounds was tested against human U-87MG glioblastoma and PC-3 prostate cancer cell lines. Cytotoxicity was examined using MTT and LDH release assays. RESULTS: The obtained data revealed that tested compounds showed a variable degree of cytotoxic activity against the tested cell lines. 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen 1-yl)-1,1-dimethylurea (9) and 3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl) 1,1-dimethylurea (10) proved to be the most active cytotoxic members in this study. CONCLUSIONS: These two compounds could be considered as possible anticancer agents. PMID- 29248175 TI - Calvarium mass as the first presentation of glioblastoma multiforme: A very rare manifestation of high-grade glioma. AB - Glioblastoma multiforme (GBM) is a high grade glial tumor, primarily located in cerebral hemispheres. The most common clinical presentations are slowly progressive neurological deficit such as motor weakness, seizure, and headaches that last less than three months. Calvarium and extra-axial invasion are very rare and generally occur after a brain biopsy or surgery, or secondary to radiotherapy of primary intra-axial glial tumors. We report a case of GBM with calvarium involvement in a 60-year-old man who presented with a frontal bump and left-sided clumsiness. Imaging studies revealed a tumoral lesion that destroyed the frontal bone with white matter involvement of the frontal lobe and extension into the corpus callosum. Histopathological examination of intra-axial and extra axial lesions revealed pleomorphic high-grade tumor with large areas of necrosis and hemorrhage. Immunohistochemical (IHC) studies confirmed GBM that spread directly into the dura, galea, and calvarium (positive reaction for GFAP, S-100, CD68, OLIG2, and p53). The patient was treated with radiotherapy (60Gy/30 fractions) and concomitant temozolomide. Unfortunately, the patient died seven months after the initial diagnosis. PMID- 29248176 TI - Pondering Publishing Reflections on a decade of privilege. PMID- 29248177 TI - A Peek into Parkinson's Disease Progression through Human Dopamine Neurons in a Dish. AB - Using induced human dopamine (DA) neurons, a study by Burbulla and colleagues demonstrated a toxic cascade of cellular dysfunctions which may underlie Parkinson's disease (PD) progression. Their findings reveal what could be the causal relationship between multiple pathogenic pathways in human neurons obtained from idiopathic and familial cases, and suggest novel targets for therapeutic intervention. PMID- 29248178 TI - Pseudoaneurysm of an ileal mesenteric artery after a stapled anastomosis. PMID- 29248179 TI - Association of time-to-surgery with outcomes in clinical stage I-II pancreatic adenocarcinoma treated with upfront surgery. AB - BACKGROUND: Time-to-surgery from cancer diagnosis has increased in the United States. We aimed to determine the association between time-to-surgery and oncologic outcomes in patients with resectable pancreatic ductal adenocarcinoma undergoing upfront surgery. METHODS: The 2004-2012 National Cancer Database was reviewed for patients undergoing curative-intent surgery without neoadjuvant therapy for clinical stage I-II pancreatic ductal adenocarcinoma. A multivariable Cox model with restricted cubic splines was used to define time-to-surgery as short (1-14 days), medium (15-42), and long (43-120). Overall survival was examined using Cox shared frailty models. Secondary outcomes were examined using mixed-effects logistic regression models. RESULTS: Of 16,763 patients, time-to surgery was short in 34.4%, medium in 51.6%, and long in 14.0%. More short time to-surgery patients were young, privately insured, healthy, and treated at low volume hospitals. Adjusted hazards of mortality were lower for medium (hazard ratio 0.94, 95% confidence interval, .90, 0.97) and long time-to-surgery (hazard ratio 0.91, 95% confidence interval, 0.86, 0.96) than short. There were no differences in adjusted odds of node positivity, clinical to pathologic upstaging, being unresectable or stage IV at exploration, and positive margins. Medium time-to-surgery patients had higher adjusted odds (odds ratio 1.11, 95% confidence interval, 1.03, 1.20) of receiving an adequate lymphadenectomy than short. Ninety-day mortality was lower in medium (odds ratio 0.75, 95% confidence interval, 0.65, 0.85) and long time-to-surgery (odds ratio 0.72, 95% confidence interval, 0.60, 0.88) than short. CONCLUSION: In this observational analysis, short time-to-surgery was associated with slightly shorter OS and higher perioperative mortality. These results may suggest that delays for medical optimization and referral to high volume surgeons are safe. PMID- 29248180 TI - Impact of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) on growth of colorectal liver metastases. AB - BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy induces an unprecedented liver hypertrophy and enables resection of otherwise unresectable liver tumors. The effect of associating liver partition and portal vein ligation for staged hepatectomy on tumor proliferation, however, remains a concern. This study investigated the impact of associating liver partition and portal vein ligation for staged hepatectomy on growth of colorectal metastases in mice and in humans. METHODS: The effect of associating liver partition and portal vein ligation for staged hepatectomy and 90% portal vein ligation on colorectal liver and lung metastases was investigated in mice. In vivo tumor progression was assessed by magnetic resonance imaging, histology, and survival experiments. The effects of associating liver partition and portal vein ligation for staged hepatectomy, portal vein ligation, and control sera on cultures of several colorectal cancer cell lines (MC38 and CT26) were tested in vitro. Additionally, the international associating liver partition and portal vein ligation for staged hepatectomy registry enabled us to identify patients with remaining tumor in the future liver remnant after associating liver partition and portal vein ligation for staged hepatectomy stage 1. RESULTS: Two and 3 weeks after associating liver partition and portal vein ligation for staged hepatectomy stage 1, portal vein ligation, or sham surgery, liver magnetic resonance images showed similar numbers (P=.14/0.82), sizes (P=.45/0.98), and growth kinetics (P=.58/0.68) of intrahepatic tumor. Tumor growth was not different between the associating liver partition and portal vein ligation for staged hepatectomy and portal vein ligation groups after completion of stage 2. Median survival after tumor cell injection was similar after sham surgery (36 days; 95% confidence interval; 27-57 days), completion of associating liver partition and portal vein ligation for staged hepatectomy (42 days; 95% confidence interval; 35-49 days), and portal vein ligation (39 days; 95% confidence interval; 34-43 days, P=.237). Progression of pulmonary metastases and in vitro cell proliferation were comparable among groups. Observations in humans failed to identify any accelerated tumor growth in the future liver remnant within the regenerative phase after associating liver partition and portal vein ligation for staged hepatectomy stage 1. CONCLUSION: The accelerated regeneration process associated with associating liver partition and portal vein ligation for staged hepatectomy does not appear to enhance growth of colorectal metastases. PMID- 29248182 TI - Deciphering extubation failure in extremely preterm infants: Time to embrace complexity and move forward. PMID- 29248181 TI - Principal component analysis of coagulation assays in severely injured children. AB - BACKGROUND: Trauma-induced coagulopathy is common and associated with poor outcome in injured children. Our aim is to identify patterns of coagulation dysregulation after injury and associate these phenotypes with relevant clinical outcomes. METHODS: We performed principal components analysis on prospectively collected data from children with the highest-level trauma activation June 2015 June 2016. Parameters included admission international normalized ratio, platelet count and thromboelastograms. Variables were reduced to principal components; principal component scores were generated for each subject and used in logistic regression with outcomes including mortality, disability, venous thromboembolism, and blood transfusion in the first 24 hours. RESULTS: We included 133 subjects with median interquartile range age =10 (5-13 years), median interquartile range Injury Severity Score =17 (9-25), 73.5% boys, 70.8% blunt trauma. principal component analysis identified 3 significant principal components accounting for 75.0% of overall variance. Principal component 1 reflected clot strength; principal component 2 reflected abnormal fibrinolysis, both hyperfibrinolysis and fibrinolysis shutdown; principal component 3 reflected global clotting factor depletion. High principal component 1 score was associated with increased mortality (odds ratio =1.63) and blood transfusion (odds ratio 1.36). Principal component 2 score was correlated with Injury Severity Score (rho 0.4) and associated with venous thromboembolism (odds ratio 1.84), functional disability (odds ratio 1.66), mortality (odds ratio 2.07) and blood transfusion (odds ratio 2.79). PC3 score was associated with increased mortality (odds ratio 1.92) and blood transfusion (odds ratio 1.25). CONCLUSION: Principal component analysis detects 3 patterns of coagulation dysregulation using widely available laboratory parameters: (1) abnormalities in clot strength; (2) abnormalities in fibrinolysis, and (3) clotting factor depletion. While all were associated with mortality and transfusion, fibrinolytic dysregulation was associated with injury severity and portends particularly poor outcome including venous thromboembolism and disability. PMID- 29248183 TI - Is Extracorporeal Membrane Oxygenation for a Neonate Ever Ethically Obligatory? AB - Certain interventions in the neonatal intensive care unit are considered ethically obligatory, and should be provided over parental objections. After reviewing a case, comparative outcome data, and relevant ethical principles, we propose that extracorporeal membrane oxygenation for meconium aspiration syndrome may, in some cases, be an ethically obligatory treatment. PMID- 29248184 TI - Coronary Stenosis after Kawasaki Disease: Size Matters. PMID- 29248185 TI - Soft tissue complications and timing of surgery in patients with a tongue-type displaced intra-articular calcaneal fracture: An international retrospective cohort study. AB - INTRODUCTION: Tongue-type displaced intra-articular calcaneal fractures (DIACF) are associated with a specific pattern of fracture displacement in contrast to joint depression fractures. This may result in tension of soft tissue in the posterior part of the heel. Tension-induced ischemia can result in skin necrosis. The objectives of this study were to investigate whether patients with tongue type calcaneal fractures exert a higher risk of complications, especially of the posterior soft tissues, than joint depression type fractures. Also, late interventions (e.g., antibiotics, debridements, and amputations) and the effect of timing of surgery on the complication rate was assessed. METHODS: In this international retrospective cohort study, data of adult patients with a DIACF in the period January 1, 2005-December 31, 2015 were extracted from patients' medical files. Descriptive, univariate, and multivariable analyses were performed in SPSS. RESULTS: A total of 560 patients with 632 DIACF were included (295 tongue-type and 337 non-tongue-type fractures). At hospital presentation, 20.3% of the patients with a tongue-type fracture had compromised posterior soft tissue versus 12.8% with non-tongue-type fractures (p = 0.032). However, corrected for potential confounders the risk was no longer statistically significant (OR 1.497; 95% CI 0.831-2.696). Patients with a TT-DIACF had a 1.2-3.4-fold higher rate of any local wound complication (deep infections, and full thickness lesions, p < 0.03). In addition they had 2.0-8.0-fold more intravenous antibiotics, debridements, soft tissue coverage procedures and amputations (p < 0.03). Patients who underwent surgery within two days after trauma had a higher risk to develop any complication, in particular superficial infections, when compared to surgery between 3-7 days, but no significant difference between 3 and 7 and >=8 days could be demonstrated. CONCLUSION: Despite the fact that patients with a tongue-type fracture developed posterior skin and soft tissue compromise nearly twice as often, this difference disappeared after correction for confounders. The overall complication risk was increased in patients with tongue-type calcaneal fractures as compared to patients with a non-tongue-type fracture. Whether or not patients with tongue-type fractures require immediate surgery cannot be concluded from the data. PMID- 29248186 TI - Emotional responses to unintentional and intentional traumatic injuries among urban black men: A qualitative study. AB - PURPOSE: The burden of injuries is disproportionately concentrated among Black men in the United States. Previous studies suggest that the mental health effects of trauma may vary by the intentionality of the injury (intentional vs. unintentional), yet little is known about this experience among Black men. We explored the emotional responses to traumatic injuries in the context of injury intentionality among Black men in an urban area. METHODS: We conducted semi structured, qualitative interviews with 74 Black men who were traumatically injured. The interviews took place three months after discharge from the hospital and they were audiotaped, transcribed, and de-identified. We used systematic thematic analysis to identify themes about post-trauma emotional responses to intentional and unintentional injuries. RESULTS: The narratives of intentionally injured men revealed persistent exposure to neighborhood violence and their distrust of others including the people they knew and to whom they felt close. Survivors of unintentional injuries did not express a similar distrust of others. Our findings suggest that survivors of intentional injuries experience loss of social support following their injuries. CONCLUSIONS: Emotional responses can differ by intentionality of traumatic injury among urban Black men. Intentional injuries may be a marker for chronic exposure to violence and limited social support for recovery. Additional resources should be targeted to survivors of intentional injury who return to disadvantaged communities after medical treatment to decrease risk of re-traumatization and adverse emotional responses. PMID- 29248188 TI - [Aspiration of prosthetic material. A case report]. PMID- 29248187 TI - Early transfusion on battlefield before admission to role 2: A preliminary observational study during "Barkhane" operation in Sahel. AB - INTRODUCTION: Haemorrage is the leading cause of death after combat related injuries and bleeding management is the cornerstone of management of these casualties. French armed forces are deployed in Barkhane operation in the Sahel Saharan Strip who represents an immense area. Since this constraint implies evacuation times beyond doctrinal timelines, an institutional decision has been made to deploy blood products on the battlefield and transfuse casualties before role 2 admission if indicated. The purpose of this study was to evaluate the transfusion practices on battlefield during the first year following the implementation of this policy. MATERIALS AND METHODS: Prospective collection of data about combat related casualties categorized alpha evacuated to a role 2. Battlefield transfusion was defined as any transfusion of blood product (red blood cells, plasma, whole blood) performed by role 1 or Medevac team before admission at a role 2. Patients' characteristics, battlefield transfusions' characteristics and complications were analysed. RESULTS: During the one year study, a total of 29 alpha casualties were included during the period study. Twenty-eight could be analysed, 7/28 (25%) being transfused on battlefield, representing a total of 22 transfusion episodes. The most frequently blood product transfused was French lyophilized plasma (FLYP). Most of transfusion episodes occurred during medevac. Compared to non-battlefield transfused casualties, battlefield transfused casualties suffered more wounded anatomical regions (median number of 3 versus 2, p = 0.04), had a higher injury severity score (median ISS of 45 versus 25, p = 0,01) and were more often transfused at role 2, received more plasma units and whole blood units. There was no difference in evacuation time to role 2 between patients transfused on battlefield and non transfused patients. There was no complication related to battlefield transfusions. Blood products transfusion onset on battlefield ranged from 75 min to 192 min after injury. CONCLUSION: Battlefield transfusion for combat-related casualties is a logistical challenge. Our study showed that such a program is feasible even in an extended area as Sahel-Saharan Strip operation theatre and reduces time to first blood product transfusion for alpha casualties. FLYP is the first line blood product on the battlefield. PMID- 29248189 TI - [DRESS and viruses: The way forward]. PMID- 29248190 TI - Thigh-calf contact parameters for six high knee flexion postures: Onset, maximum angle, total force, contact area, and center of force. AB - In high knee flexion, contact between the posterior thigh and calf is expected to decrease forces on tibiofemoral contact surfaces, therefore, thigh-calf contact needs to be thoroughly characterized to model its effect. This study measured knee angles and intersegmental contact parameters in fifty-eight young healthy participants for six common high flexion postures using motion tracking and a pressure sensor attached to the right thigh. Additionally, we introduced and assessed the reliability of a method for reducing noise in pressure sensor output. Five repetitions of two squatting, two kneeling, and two unilateral kneeling movements were completed. Interactions of posture by sex occurred for thigh-calf and heel-gluteal center of force, and thigh-calf contact area. Center of force in thigh-calf regions was farther from the knee joint center in females, compared to males, during unilateral kneeling (82 and 67 mm respectively) with an inverted relationship in the heel-gluteal region (331 and 345 mm respectively), although caution is advised when generalizing these findings from a young, relatively fit sample to a population level. Contact area was larger in females when compared to males (mean of 155.61 and 137.33 cm2 across postures). A posture main effect was observed in contact force and sex main effects were present in onset and max angle. Males had earlier onset (121.0 degrees ) and lower max angle (147.4 degrees ) with onset and max angles having a range between movements of 8 degrees and 3 degrees respectively. There was a substantial total force difference of 139 N between the largest and smallest activity means. Force parameters measured in this study suggest that knee joint contact models need to incorporate activity-specific parameters when estimating loading. PMID- 29248191 TI - Manipulating post-stroke gait: Exploiting aberrant kinematics. AB - Post-stroke individuals often exhibit abnormal kinematics, including increased pelvic obliquity and hip abduction coupled with reduced knee flexion. Prior examinations suggest these behaviors are expressions of abnormal cross-planar coupling of muscle activity. However, few studies have detailed the impact of gait-retraining paradigms on three-dimensional joint kinematics. In this study, a cross-tilt walking surface was examined as a novel gait-retraining construct. We hypothesized that relative to baseline walking kinematics, exposure to cross-tilt would generate significant changes in subsequent flat-walking joint kinematics during affected limb swing. Twelve post-stroke participants walked on a motorized treadmill platform during a flat-walking condition and during a 10-degree cross tilt with affected limb up-slope, increasing toe clearance demand. Individuals completed 15 min of cross-tilt walking with intermittent flat-walking catch trials and a final washout period (5 min). For flat-walking conditions, we examined changes in pelvic obliquity, hip abduction/adduction and knee flexion kinematics at the spatiotemporal events of swing initiation and toe-off, and the kinematic event of maximum angle during swing. Pelvic obliquity significantly reduced at swing initiation and maximum obliquity in the final catch trial and late washout. Knee flexion significantly increased at swing initiation, toe-off, and maximum flexion across catch trials and late washout. Hip abduction/adduction was not significantly influenced following cross-tilt walking. Significant decrease in the rectus femoris and medial hamstrings muscle activity across catch trials and late washout was observed. Exploiting the abnormal features of post stroke gait during retraining yielded desirable changes in muscular and kinematic patterns post-training. PMID- 29248192 TI - Thoracolumbar spine loading associated with kinematics of the young and the elderly during activities of daily living. AB - Excessive mechanical loading of the spine is a critical factor in vertebral fracture initiation. Most vertebral fractures develop spontaneously or due to mild trauma, as physiological loads during activities of daily living might exceed the failure load of osteoporotic vertebra. Spinal loading patterns are affected by vertebral kinematics, which differ between elderly and young individuals. In this study, the effects of age-related changes in spine kinematics on thoracolumbar spinal segmental loading during dynamic activities of daily living were investigated using combined experimental and modeling approach. Forty-four healthy volunteers were recruited into two age groups: young (N = 23, age = 27.1 +/- 3.8) and elderly (N = 21, age = 70.1 +/- 3.9). The spinal curvature was assessed with a skin-surface device and the kinematics of the spine and lower extremities were recorded during daily living tasks (flexion-extension and stand-sit-stand) with a motion capture system. The obtained data were used as input for a musculoskeletal model with a detailed thoracolumbar spine representation. To isolate the effect of kinematics on predicted loads, other model properties were kept constant. Inverse dynamics simulations were performed in the AnyBody Modeling System to estimate corresponding spinal loads. The maximum compressive loads predicted for the elderly motion patterns were lower than those of the young for L2/L3 and L3/L4 lumbar levels during flexion and for upper thoracic levels during stand-to-sit (T1/T2-T8/T9) and sit-to-stand (T3/T4 T6/T7). However, the maximum loads predicted for the lower thoracic levels (T9/T10-L1/L2), a common site of vertebral fractures, were similar compared to the young. Nevertheless, these loads acting on the vertebrae of reduced bone quality might contribute to a higher fracture risk for the elderly. PMID- 29248193 TI - Effects of mechanical stretch on the functions of BK and L-type Ca2+ channels in vascular smooth muscle cells. AB - It is well recognized that pathologically increased mechanical stretch plays a critical role in vascular remodeling during hypertension. However, how the stretch modulates the functions of ion channels of vascular smooth muscle cells (VSMCs) remains to be elucidated. Here, we demonstrated the effects of mechanical stretch on the activity of large conductance calcium, voltage-activated potassium (BK) and L-type Ca2+ channels. In comparison with 5% stretch (physiological), 15% stretch (pathological) upregulated the current density of L-type Ca2+ and BK channels as well as the frequency and amplitude of calcium oscillation in VSMCs. 15% stretch also increased the open probability and mean open time of the BK channel compared with 5% stretch. BK and L-type Ca2+ channels participated in the mechanical stretch-modulated calcium oscillation. Our results suggested that during hypertension, pathological stretch altered the activity of BK and L-type Ca2+ channels and manipulated the calcium oscillation of VSMCs. PMID- 29248194 TI - Novel image analysis methods for quantification of in situ 3-D tendon cell and matrix strain. AB - Macroscopic tendon loads modulate the cellular microenvironment leading to biological outcomes such as degeneration or repair. Previous studies have shown that damage accumulation and the phases of tendon healing are marked by significant changes in the extracellular matrix, but it remains unknown how mechanical forces of the extracellular matrix are translated to mechanotransduction pathways that ultimately drive the biological response. Our overarching hypothesis is that the unique relationship between extracellular matrix strain and cell deformation will dictate biological outcomes, prompting the need for quantitative methods to characterize the local strain environment. While 2-D methods have successfully calculated matrix strain and cell deformation, 3-D methods are necessary to capture the increased complexity that can arise due to high levels of anisotropy and out-of-plane motion, particularly in the disorganized, highly cellular, injured state. In this study, we validated the use of digital volume correlation methods to quantify 3-D matrix strain using images of naive tendon cells, the collagen fiber matrix, and injured tendon cells. Additionally, naive tendon cell images were used to develop novel methods for 3-D cell deformation and 3-D cell-matrix strain, which is defined as a quantitative measure of the relationship between matrix strain and cell deformation. The results support that these methods can be used to detect strains with high accuracy and can be further extended to an in vivo setting for observing temporal changes in cell and matrix mechanics during degeneration and healing. PMID- 29248196 TI - A systematic review and meta-analysis on the attribution of human papillomavirus (HPV) in neuroendocrine cancers of the cervix. AB - BACKGROUND: There remains uncertainty about the role of human papillomavirus (HPV) infection in causing small-cell neuroendocrine carcinoma (SCNC) and large cell neuroendocrine carcinoma (LCNC) of the cervix. To clarify the role of HPV in the development of SCNC and LCNC, we conducted a systematic review and meta analyses. METHODS: PubMed and Embase were searched to initially identify 143 articles published on or before June 1, 2017. Studies were limited to methods that tested for HPV in the cancer tissue directly to minimize misattribution. Thirty-two studies with 403 SCNC and 9 studies of 45 LCNC were included in the analysis. RESULTS: For SCNC, 85% (95% confidence interval [95%CI]=71%-94%) were HPV positive, 78% (95%CI=64%-90%) were HPV16 and/or HPV18 positive, 51% (95%CI=39%-64%) were singly HPV18 positive, and 10% (95%CI=4%-19%) were singly HPV16 positive. In a subset of 5 SCNC studies (75 cases), 93% were positive for p16INK4a by immunohistochemistry and 100% were HPV positive. For LCNC, 88% (95%CI=72%-99%) were HPV positive, 86% (95%CI=70%-98%) were positive for HPV16 or HPV18, 30% were singly HPV18 positive (95%CI=4%-60%), and 29% (95%CI=2%-64%) were singly HPV16 positive. CONCLUSIONS: In conclusion, most SCNC and LCNC are caused by HPV, primarily HPV18 and HPV16. Therefore, most if not all SCNC and LCNC will be prevented by currently available prophylactic HPV vaccines. PMID- 29248195 TI - Is chemotherapy always necessary for patients with nonmetastatic gestational trophoblastic neoplasia with histopathological diagnosis of choriocarcinoma? AB - OBJECTIVE: To evaluate expectant management versus immediate chemotherapy following pathological diagnosis of gestational choriocarcinoma (GCC) in patients with nonmetastatic disease. METHODS: Multicenter retrospective cohort that included patients with histological diagnosis of GCC with nonmetastatic disease followed at one of thirteen Brazilian referral centers for gestational trophoblastic disease from January 2000 to December 2016. RESULTS: Among 3191 patients with gestational trophoblastic neoplasia, 199 patients with nonmetastatic GCC were identified. Chemotherapy was initiated immediately in 152 (76.4%) patients per FIGO 2000 guideline, while 47 (23.6%) were managed expectantly. Both groups presented with similar characteristics and outcomes. All patients (n=12) who had normal human chorionic gonadotropin (hCG) in the first 2 3weeks of expectant management achieved complete sustained remission with no chemotherapy. Only 44.7% (21 patients) of patients who were expectantly managed needed to receive chemotherapy due to plateauing or rising hCG level in the first 2-3weeks of follow up. The outcome of patients receiving chemotherapy after initial expectant management was similar to those who received chemotherapy immediately after the diagnosis in terms of need for multi-agent chemotherapy or number of cycles of chemotherapy. There was no case of relapse or death in either group. Logistic regression analysis showed that age>=40years and hCG>=92,428IU/L at GCC diagnosis were risk factors for needing chemotherapy after initial expectant management of nonmetastatic GCC. CONCLUSION: In order to avoid exposing patients unnecessarily to chemotherapy, close surveillance of women with pathological diagnosis of nonmetastatic GCC seems to be a safe practice, particularly for those who have a normal hCG at the time of diagnosis. If confirmed by other studies, the FIGO guidelines may need to be revised. PMID- 29248197 TI - Significance of venous thromboembolism in women with uterine carcinosarcoma. AB - OBJECTIVE: To identify risk factors for venous thromboembolism (VTE) and to examine the association of VTE and survival in women with uterine carcinosarcoma. METHODS: This multicenter retrospective study examined 906 women who underwent primary surgical treatment for stage I-IV uterine carcinosarcoma. Time-dependent analyses were performed for cumulative incidence of VTE after surgery on multivariate models. RESULTS: There were 72 (7.9%) women who developed VTE after surgery with 1-, 2-, and 5-year cumulative incidences being 5.1%, 7.3%, and 10.2%, respectively. On multivariate analysis, older age (hazard ratio [HR] per year 1.03, P=0.012), non-Asian race (HR 6.28, P<0.001), large body habitus (HR per kg/m2 1.04, P=0.014), residual disease at surgery (HR 3.04, P=0.003), tumor size >=5cm (HR 2.73, P=0.003), and stage IV disease (HR 2.12, P=0.025) were independently associated with increased risk of developing VTE. A risk pattern analysis identified that obese Non-Asian women with large tumors (13.7% of population) had the highest incidence of VTE (2-year cumulative rate, 26.1%) whereas Asian women with no residual disease (47.1% of population) had the lowest (2-year cumulative rate, 1.6%) (P<0.001). Presence of carcinoma/sarcoma in metastatic sites was significantly associated with increased risk of VTE compared to carcinoma alone (2-year rates, 31.2% versus 8.4%, P=0.049). VTE was independently associated with decreased progression-free survival on multivariate models (5-year rates, 24.9% versus 47.2%, HR 1.46, 95%CI 1.05-2.04, P=0.026). CONCLUSION: Our study suggests that VTE represents a surrogate marker of aggressive tumor behavior and diminished patient condition in uterine carcinosarcoma; obese Non-Asian women with large tumors carry a disproportionally high risk of VTE, suggesting that long-term prophylaxis may benefit this population. PMID- 29248198 TI - A phase II study of apatinib in patients with recurrent epithelial ovarian cancer. AB - OBJECTIVE: Antiangiogenic treatments have been implicated to play a major role in epithelial ovarian cancer (EOC). Apatinib, a novel oral antiangiogenic agent targeting vascular endothelial growth factor receptor (VEGFR2), is currently being studied in different tumor types and is already used in gastric adenocarcinoma. This study was performed to assess the efficacy and safety of apatinib in patients with recurrent, pretreated EOC. PATIENTS AND METHODS: Patients with recurrent, platinum-resistant, pre-treated EOC who failed available standard chemotherapy were enrolled. Apatinib was administered as 500mg daily. Primary objective is the overall response rate (ORR) according to MASS criteria. Secondary objectives are progression free survival (PFS), overall survival (OS), disease control rate (DCR), safety and tolerability. The treatment duration is until disease progression or intolerability of apatinib. RESULTS: 29 eligible patients were enrolled in this multicenter, open-label, single arm study and received apatinib for a median of 36.8weeks (range 13-64.8weeks). Median follow up time was 12months. 28 patients were eligible for efficacy analysis. ORR is 41.4% (95% confidence interval (CI), 23.3%-59.4%). DCR is 68.9% (95% CI, 52.1% 85.8%). Median PFS is 5.1months (95% CI, 3.8m-6.5m). Median OS is 14.5months (95% CI, 12.4m-16.4m). The most common treatment-related adverse events (AEs) were hand-foot syndrome (51.7%), hypertension (34.6%), nausea and vomiting (31.0%). 3 patients had no significant toxicity. 9 patients experienced grade 3 treatment related AEs. CONCLUSIONS: Apatinib 500mg daily p.o. is a feasible treatment in patients with recurrent, platinum-resistant, pretreated EOC. Multi-center prospective studies enrolling more patients are needed. PMID- 29248199 TI - Reply. PMID- 29248200 TI - Diagnosis and Treatment of Infectious Enteritis in Adult Ruminants. AB - Infectious enteritis in adult ruminants is often a result of 1 or more viral, bacterial, or parasitic pathogens. Diagnosis of etiologic agents causing enteritis is important when considering herd implications and zoonotic potential of some etiologies. Differential diagnoses for enteritis in adult ruminants is not simple based on clinical signs alone. Diagnostic samples include feces, blood, and antemortem and postmortem tissues. Treatment of infectious enteritis is aimed at correcting dehydration and electrolyte imbalances secondary to diarrhea. In cases of some bacterial and parasitic pathogens, additional targeted treatment and control are recommended. Management of enteritis may be instituted while awaiting laboratory test results. PMID- 29248201 TI - Safety and effects on motor cortex excitability of five cathodal transcranial direct current stimulation sessions in 25hours. AB - OBJECTIVE: To assess the safety and effects on motor cortex excitability of five cathodal-tDCS sessions (charge density 342.9C/m2) delivered over the dominant motor cortex with a return electrode over the ipsilateral shoulder at increasing time intervals in 25hours. METHODS: Safety was operatively defined as absence of serious adverse events related to tDCS including brain tissue alterations documentable by magnetic resonance imaging and spectroscopy. Effects on motor cortex excitability were evaluated by motor evoked potential (MEP) amplitude. RESULTS: Thirty-two healthy subjects were enrolled. No serious adverse events occurred. Magnetic resonance imaging and spectroscopy did not show alterations. Inter-individual MEP variability was assessed by the standard error of mean at baseline and subjects were classified on the basis of the ratio between normalized MEPs after the first stimulation compared to baseline. Fifty-six percent of subjects responded with reduction of MEP amplitude, 25% were non responders and 19% were inverse responders. In responders, MEP suppression was 32% one hour after the end of first cathodal-tDCS, 21% three hours after the second, no longer present with increasing stimulation intervals and 38% two and half hours after the fifth stimulation. Intra-individual inter-sessional reliability in response was high (88-92%). CONCLUSIONS: Five cathodal-tDCS sessions in 25hours are safe. Inter-individual variability in MEP suppression is considerable but response to one cathodal-tDCS highly predicts the response to other sessions. Duration of MEP suppression is limited to three hours. These findings should be considered in trials utilizing repeated cathodal-tDCS. PMID- 29248202 TI - Clonidine administration during intraoperative monitoring for pediatric scoliosis surgery: Effects on central and peripheral motor responses. AB - OBJECTIVE: To study the effect of clonidine administrated as a co-analgesic during scoliosis surgery, on the neuromonitoring of spinal motor pathways. METHODS: Using standardized intraoperative monitoring, we compared the time course of peripherally and transcranially electrically evoked motor potentials (TcEMEPs) before and after injection of a single bolus of clonidine in children under total intravenous anesthesia (TIVA). MEP data were obtained from 9 patients and somatosensory evoked potentials (SSEPs) were obtained from 2 patients. The potential effect of clonidine on mean blood pressure (BP) was controlled. RESULTS: TcEMEPs from upper and lower limbs rapidly showed significant drops in amplitude after the injection of clonidine. Amplitudes reached minimal values within five minutes and remained very weak for at least 10-20minutes during which monitoring of the central motor pathways was severely compromised. SSEPs were not altered during maximal amplitude depression of the TcEMEPS. CONCLUSIONS: This is the first report showing that clonidine severely interferes with neuromonitoring of the spinal cord motor pathways. The results are discussed in light of the literature describing the effects of dexmedetomidine, another alpha-2 adrenergic agonist. The experimental and literature data point to central mechanisms taking place at both the spinal and cerebral levels. Therefore, clonidine as well as other alpha-2 adrenergic agonists should be used with extreme caution in patients for whom neuromonitoring of the motor pathways is required during surgery. PMID- 29248203 TI - In response to Letter to the Editor entitled 'Is an endoscopic or a microscopic approach optimal for management of attic cholesteatoma?' PMID- 29248204 TI - Intestinal permeability and Meniere's disease. AB - PURPOSE: Meniere disease (MD) is a multifactorial chronic disabling condition characterized by episodic vertigo, ear fullness, and hearing loss. MD patients often complain of aspecific gastrointestinal symptoms associated with autonomic dysregulation, frequently outweighed by the otological manifestations. Dietary modifications have been reported to improve the typical MD symptoms in some cases. Our purpose was to test the urinary levels of lactulose and mannitol (double sugar test) and the fecal calprotectin, both markers of altered intestinal permeability, in subjects with definite MD in an active and inactive stage. MATERIALS AND METHODS: Twenty-six with definite unilateral MD were studied: 14 patients were symptomatic for at least 3months with moderate to severe vertigo spells and a functional level >=4; 12 patients had been asymptomatic (no vertigo spells) for at least 3months and had a functional level=1 at the time of testing. Twenty healthy volunteers were recruited as "control group". RESULTS: Lactulose and mannitol absorption was significantly increased in the symptomatic M patients compared to the asymptomatic group (p<0.02 and p<0.004, respectively) and to the controls. FC were also higher than normal only in the symptomatic group. (p<0.01). CONCLUSIONS: An altered intestinal permeability, according to the two assays, was found only in symptomatic MD patients. The rationale for a possible relationship between MD and intestinal permeability is forwarded. The double-sugar test and FC quantification might be implemented in the MD diagnostic workup. PMID- 29248206 TI - Current and Newly Emerging Autoimmune Diseases. AB - There are many autoimmune diseases that are recognized in domestic animals. The descriptions of diseases provide examples of the magnitude of immune targets and the variable nature of autoimmune diseases. Other autoimmune diseases that are recognized in dogs, cats, and horses include immune-mediated thrombocytopenia, VKH (Vogt-Koyanagi-Harada) ocular disease (dogs), and Evans syndrome (which includes both immune-mediated anemia and immune-mediated thrombocytopenia). PMID- 29248207 TI - Sudden unexpected death in epilepsy: Incidence at a Spanish epilepsy unit. AB - INTRODUCTION: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with epilepsy. Most studies concerning this issue have been conducted in central and northern European countries and the United States. We conducted an epidemiologic study of SUDEP at our hospital's epilepsy unit. METHODS: This retrospective cohort study included all epileptic patients aged >=14 years, regardless of epilepsy severity, who were treated at the outpatient epilepsy unit of our hospital between 2000 and 2013. The study included 2,309 patients. Deceased patients were identified using civil records. The cause of death was obtained from death certificates, autopsy reports, hospital reports, general practitioner records, and witnesses of the event. We calculated the incidence and proportional mortality of SUDEP based on our data. RESULTS: We identified 7 cases of definite SUDEP (2 patients with SUDEP plus), one case of probable SUDEP, and one case of possible SUDEP. Considering only cases of definite SUDEP, incidence was estimated at 0.44 cases per 1,000 patient-years and proportional mortality at 4.6%. Mean age of patients with definite SUDEP was 38.14 years; 4 were men and 3 were women. Most deaths occurred while patients were in bed and were therefore unwitnessed. Epilepsy in these patients was either remote symptomatic or cryptogenic. All patients but one had generalised seizures. None of the patients was in remission. CONCLUSIONS: SUDEP incidence and proportional mortality rates in our study are similar to those reported by population studies. This may be due to the fact that we did not select patients by severity. Risk factors for SUDEP in our sample are therefore consistent with those reported in the literature. PMID- 29248208 TI - Trends in the treatment of cerebral aneurysms: Analysis of a hospital series. PMID- 29248205 TI - A guided tour of selected issues pertaining to metastatic carcinomas involving or originating from the gynecologic tract. PMID- 29248209 TI - Horner syndrome secondary to cephalic paravertebral migration of local anaesthetic. PMID- 29248212 TI - Influence of conjugated linoleic acids and vitamin E on biochemical, hematological, and immunological variables of dairy cows during the transition period. AB - The objective of this experiment was to determine the effects of conjugated linoleic acid (CLA) and vitamin E as well as their interaction on biochemical and hematological variables and on leukocyte populations and their functionality. We assigned 59 German Holstein cows between the 2nd and 9th lactation to 4 dietary groups in a 2 * 2 factorial design with the factors CLA and vitamin E. Six weeks before calving the cows had a BCS of 3.7 to provoke a higher risk of developing ketosis, which might impair their immune function. Blood samples for analyses were taken on d -42, -14, -7, -3, 1, 3, 7, 10, 14, 21, 28, 35, 42, 56, and 70 relative to parturition. Furthermore, peripheral blood mononuclear cells were cultured on d -42, -7, 1, 7, 14, 28, and 70 relative to calving. Most variables were characterized by a high variation between d 7 antepartum and d 7 postpartum. Treatments did not elicit any effect, with the exception of vitamin E, which increased serum urea concentrations and decreased monocyte percentages. Haptoglobin, aspartate-aminotransferase, red blood cell count, leukocyte percentage and populations, as well as peripheral blood mononuclear cells were influenced by parity. In conclusion, the impairment of immune function caused by calving was more severe in cows in >=3rd parity than in younger cows. However, neither vitamin E nor CLA supplementation was successful to stabilize parity or parturition related variance in hematological and immunological traits. PMID- 29248211 TI - Influence of ad libitum milk replacer feeding and butyrate supplementation on the systemic and hepatic insulin-like growth factor I and its binding proteins in Holstein calves. AB - Ad libitum milk feeding and butyrate (B) supplementation have the potential to stimulate postnatal growth and development in calves. The somatotropic axis is the main endocrine regulator of postnatal growth and may be affected by both ad libitum milk replacer (MR) feeding and B supplementation in calves. We hypothesized that ad libitum MR feeding and B supplementation stimulate systemic and hepatic insulin-like growth factor (IGF)-I and IGF binding proteins (IGFBP) in preweaning calves. Sixty-four (32 male, 32 female) Holstein calves were examined from birth until wk 11 of life. Calves received MR either ad libitum (Adl) or restrictively (6 L/d; Res). In each feeding group half of the calves received a MR with 0.24% butyrate and the other half received same MR without butyrate. Ad libitum MR feeding was performed from d 4 until wk 8 of age. From wk 9 to 10, Adl and Res calves were gradually weaned and were fed 2 L/d until the end of the trial. Concentrate, hay, and water were freely available. Feed intake was measured daily and body weight weekly. Blood samples for analyzing plasma concentrations of glucose, insulin, IGF-I, and IGFBP-2, -3, and -4 were taken on d 1, 2, 4, and 7, then weekly or every other week (IGFBP) until wk 11 of life. Liver samples were taken on d 50 and at the end of the study (d 80) to measure gene expression of the growth hormone receptor 1A (GHR1A), IGF1, IGFBP1 to 4, and of the IGF Type 1 and insulin receptor in the liver. Intake of MR and body weight were greater, but concentrate intake was lower in Adl than in Res. Plasma concentrations of IGF-I and IGFBP-3 were greater and plasma concentration of IGFBP-2 was lower in Adl than in Res during the ad libitum milk feeding period. After reduction of MR in both groups to 2 L/d plasma concentrations of IGF-I and IGFBP-4 were lower and plasma concentration of IGFBP-2 was higher in Adl than in Res. Supplementation of B depressed plasma IGF-I from wk 1 to 4 and in wk 9. On d 50, mRNA abundance of the GHR1A and IGF1 was greater and of IGFBP2 mRNA was lower in Adl than in Res. At d 80, IGFBP2 mRNA was greater in Adl than in Res, and IGFBP2 mRNA increased with B supplementation. Ad libitum MR feeding stimulated the systemic and hepatic IGF system and mirrored the greater growth rate during the ad libitum MR feeding, whereas butyrate supplementation partly reduced the systemic and hepatic IGF system. PMID- 29248210 TI - Results of an international comparison of activity measurements of 68Ge. AB - An international key comparison, identifier CCRI(II)-K2.Ge-68, has been performed. The National Institute of Standards and Technology (NIST) served as the pilot laboratory, distributing aliquots of a 68Ge/68Ga solution. Results for the activity concentration, CA, of 68Ge at a reference date of 12h00 UTC 14 November 2014 were submitted by 17 laboratories, encompassing many variants of coincidence methods and liquid-scintillation counting methods. The first use of 4pi(Cherenkov)beta-gamma coincidence and anticoincidence methods in an international comparison is reported. One participant reported results by secondary methods only. Two results, both utilizing pure liquid-scintillation methods, were identified as outliers. Evaluation using the Power-Moderated Mean method results in a proposed Comparison Reference Value (CRV) of 621.7(11)kBqg-1, based on 14 results. The degrees of equivalence and their associated uncertainties are evaluated for each participant. Several participants submitted 3.6mL ampoules to the BIPM to link the comparison to the International Reference System (SIR) which may lead to the evaluation of a Key Comparison Reference Value and associated degrees of equivalence. PMID- 29248213 TI - Effect of leaving milk trucks empty and idle for 6 h between raw milk loads. AB - The US Pasteurized Milk Ordinance (PMO) allows milk tanker trucks to be used repeatedly for 24 h before mandatory clean-in-place cleaning, but no specifications are given for the length of time a tanker can be empty between loads. We defined a worst-case hauling scenario as a hauling vessel left empty and dirty (idle) for extended periods between loads, especially in warm weather. Initial studies were conducted using 5-gallon milk cans (pilot-scale) as a proof of-concept and to demonstrate that extended idle time intervals could contribute to compromised raw milk quality. Based on pilot-scale results, a commercial hauling study was conducted through partnership with a Pacific Northwest dairy co op to verify that extended idle times of 6 h between loads have minimal influence on the microbiological populations and enzyme activity in subsequent loads of milk. Milk cans were used to haul raw milk (load 1), emptied, incubated at 30 degrees C for 3, 6, 10, and 20 h, and refilled with commercially pasteurized whole milk (load 2) to measure cross-contamination. For the commercial-scale study, a single tanker was filled with milk from a farm known to have poorer quality milk (farm A, load 1), emptied, and refilled immediately (0 h) or after a delay (6 h) with milk from a farm known to have superior quality milk (farm B, load 2). In both experiments, milk samples were obtained from each farm's bulk tank and from the milk can or tanker before unloading. Each sample was microbiologically assessed for standard plate count (SPC), lactic acid bacteria (LAB), and coliform counts. Selected isolates were assessed for lipolytic and proteolytic activity using spirit blue agar and skim milk agar, respectively. The pilot-scale experiment effectively demonstrated that extended periods of idle (>3 h) of soiled hauling vessels can significantly affect the microbiological quality of raw milk in subsequent loads; however, extended idle times of 6 h or less would not measurably compromise milk quality in subsequent loads in commercial tankers. Current tanker sanitation practices appear to be sufficient for maintaining raw milk SPC, LAB, and coliform levels, which are important measures of milk quality. PMID- 29248214 TI - Multi-year evaluation of stocking rate and animal genotype on milk production per hectare within intensive pasture-based production systems. AB - The objective of this experiment was to evaluate the effect of stocking rate (SR) and animal genotype (BR) on milk production, body weight (BW), and body condition score (BCS) within intensive pasture-based systems. A total of 533 lactation records, from 246 elite genetic merit dairy cows were available for analysis; 68 Holstein-Friesian (HF) and 71 Jersey * Holstein-Friesian (JxHF) crossbred cows in each of 4 consecutive years (2013-2016, inclusive). Cows from each BR were randomly allocated to 1 of 3 whole-farm comparative SR treatments, low (LSR; 1,200 kg of BW/ha), medium (MSR; 1,400 kg of BW/ha), and high (HSR; 1,600 kg of BW/ha), and remained in the same SR treatments for the duration of the experiment. The effects of SR, BR, and their interaction on milk production/cow and per hectare, BW, BCS, and grazing characteristics were analyzed. Total pasture utilization per hectare consumed in the form of grazed pasture increased linearly as SR increased: least in LSR (10,237 kg of dry matter/ha), intermediate in MSR (11,016 kg of dry matter/ha), and greatest in HSR (11,809 kg of dry matter/ha). Milk and milk solids (MS) yield per hectare was greatest for HSR (15,942 and 1,354 kg, respectively), intermediate for MSR (14,191 and 1,220 kg, respectively), and least for LSR (13,186 and 1,139 kg, respectively) with similar trends evident for fat, protein, and lactose yield/ha. At higher SR (MSR and HSR), MS yield per kg of BW per ha was reduced (0.85 and 0.82 kg of MS/kg of BW, respectively) compared with LSR (0.93 kg of MS/kg of BW/ha). Holstein-Friesian cows achieved fewer grazing days per hectare (-37 d), and produced more milk (+561 kg/ha) but less fat plus protein (-57 kg/ha) compared with JxHF cows; the JxHF cows were lighter. At similar BW per hectare, JxHF cows produced more fat plus protein/ha during the grazing season at low (1,164 vs. 1,113 kg), medium (1,254 vs. 1,185 kg), and high (1,327 vs. 1,380 kg) SR. In addition, JxHF cows produced more fat plus protein per kg of BW/ha (0.90 kg) compared with HF cows (0.84 kg). The results highlight the superior productive efficiency of high genetic potential crossbred dairy cows within intensive pasture-based production systems. PMID- 29248215 TI - Computed tomography study of the fetal development of the dairy cow stomach complex. AB - In the fetal development of animals, critical physiological and anatomical events influence the long-term health and performance of the offspring. To identify the critical growth phases of the fetal bovine stomach, we used computed tomography imaging on 30 German Holstein fetuses to examine the fetal bovine stomach in situ. Computed tomography allows the study of diverse parameters such as the volume of the stomach chambers in situ without the need for sophisticated filling preparation techniques. The absolute volume, relative volume, and monthly volume increase of each stomach chamber were determined. Computed tomography was a reliable method for in situ examination of the fetal bovine stomach complex from the third month of gestation onward. It was able to detect an abnormal position of the abomasum in 2 fetuses. The crown-rump length of the fetuses studied ranged from 9.5 to 89 cm (from 2.2 to 8.3 mo of gestation). Over this timeline, the changes in the relative volumes of the ruminoreticulum and abomasum were inversely related. Until mo 5 of gestation, the relative volume of the ruminoreticulum increased steadily, whereas that of the abomasum decreased. Thereafter, the relative volume of the ruminoreticulum became gradually smaller, and that of the abomasum became larger; by mo 8, the abomasum was larger than the ruminoreticulum. All stomach chambers had large increases in volume over the gestation period and we observed differences in development patterns and volume changes of the individual stomach chambers over this period. The largest monthly volume increase of the stomach complex was between mo 4 and 5 of gestation. In this period, the volume of the ruminoreticulum increased 43.8 times, that of the omasum 38.9 times, and that of the abomasum 30.03 times. Between mo 5 and 6 of gestation, the abomasum had another growth spurt, with a monthly volume increase of 10.4 times. These 2 time points in the gestation period may be critical phases of fetal development that should be considered in the management of pregnant cattle. PMID- 29248216 TI - Inclusion of calcium hydroxide-treated corn stover as a partial forage replacement in diets for lactating dairy cows. AB - Chemical treatment may improve the nutritional value of corn crop residues, commonly referred to as corn stover, and the potential use of this feed resource for ruminants, including lactating dairy cows. The objective of this study was to determine the effect of prestorage chopping, hydration, and treatment of corn stover with Ca(OH)2 on the feeding value for milk production, milk composition, and dry matter intake (DMI). Multiparous mid-lactation Holstein cows (n = 30) were stratified by parity and milk production and randomly assigned to 1 of 3 diets. Corn stover was chopped, hydrated, and treated with 6% Ca(OH)2 (as-fed basis) and stored in horizontal silo bags. Cows received a control (CON) total mixed ration (TMR) or a TMR in which a mixture of treated corn stover and distillers grains replaced either alfalfa haylage (AHsub) or alfalfa haylage and an additional portion of corn silage (AH+CSsub). Treated corn stover was fed in a TMR at 0, 15, and 30% of the diet DM for the CON, AHsub, and AH+CSsub diets, respectively. Cows were individually fed in tiestalls for 10 wk. Milk production was not altered by treatment. Compared with the CON diet, DMI was reduced when the AHsub diet was fed and tended to be reduced when cows were fed the AH+CSsub diet (25.9, 22.7, and 23.1 +/- 0.88 kg/d for CON, AHsub, and AH+CSsub diets, respectively). Energy-corrected milk production per unit of DMI (kg/kg) tended to increase with treated corn stover feeding. Milk composition, energy-corrected milk production, and energy-corrected milk per unit of DMI (kg/kg) were not different among treatments for the 10-wk feeding period. Cows fed the AHsub and AH+CSsub diets had consistent DMI over the 10-wk treatment period, whereas DMI for cows fed the CON diet increased slightly over time. Milk production was not affected by the duration of feeding. These data indicate that corn stover processing, prestorage hydration, and treatment with calcium hydroxide can serve as an alternative to traditional haycrop and corn silage in diets fed to mid lactation dairy cows. PMID- 29248217 TI - Effect of aluminized reflective hutch covers on calf health and performance. AB - The effect of polyethylene hutches wrapped in aluminized reflective covers (ARC) on health and performance of pre-weaned Holstein heifers during summer was evaluated. Ambient and hutch temperature and temperature-humidity index (THI) were also assessed. The study was conducted from June to October 2016 where temperature, humidity, and THI ranged from -1.3 to 38.4 degrees C, 9.8 to 99.7%, and 33.6 to 81.1 units, respectively. Heifers enrolled at 1 d of life and housed in individual polyethylene hutches with (covered) or without (control) ARC were monitored until 60 d of life in 2 study groups (SG1, n = 94, monitored from June to September; and SG2, n = 101, monitored from August to October 2016). Calves were assessed twice per week for health status, behavior, rectal temperature, and respiratory rate. Similarly, hutch inner wall and sand bedding temperatures were determined for comparison between covered and control hutches housing calves. Four empty hutches per treatment group were continuously monitored for temperature and THI. The odds (95% confidence interval) of presenting diarrhea were 1.30 (1.01-1.60) times greater for calves housed in covered hutches than for those in the control group. Similarly, the odds of an abnormal ear score were 1.40 (1.03-2.00) times greater for calves in covered hutches compared with calves in control hutches. The odds of nasal discharge, eye discharge, and clinical dehydration did not differ between treatment groups. Rectal temperatures and respiratory rates were also similar in both groups. No differences were found in average daily gain between calves housed in covered and control hutches. Calf location determined at a fixed time during the day (starting at 1200 h) was associated with the use of ARC. The odds of remaining inside the hutch were 1.33 (1.03-1.70) times greater for calves housed in control compared with covered hutches. Overall, the average of hutch interior temperature was higher in covered compared with control hutches in both studies (SG1, 23.2 +/- 0.06 vs. 22.8 +/- 0.06 degrees C; SG2, 17.1 +/- 0.07 vs. 16.9 +/- 0.07 degrees C). Hutch THI was higher in covered empty hutches compared with control hutches in both study groups (SG1: 68.6 +/- 0.06 vs. 67.6 +/- 0.06 degrees C; SG2: 60.2 +/- 0.08 vs. 59.6 +/- 0.08 degrees C). Average temperature (measured at 1200 h) of the inner surface of the hutch wall was lower in covered compared with control hutches by 1 degrees C (24.4 +/- 0.13 vs. 25.4 +/- 0.13 degrees C), whereas the temperature of the sand bedding did not differ between groups. Our results suggest that the use of ARC did not generate a hutch microclimate that resulted in significant improvements on health and performance of pre-weaned dairy calves under these specific study settings. PMID- 29248218 TI - Diagnostic performance of cytology for assessment of hepatic lipid content in dairy cattle. AB - The objective of our study was to characterize the diagnostic performance of cytology for assessing hepatic lipid content (HLC) in dairy cows by comparing microscopic evaluation of lipid vacuolation in touch imprint slide preparations of liver biopsies with quantitative measurement of triglyceride concentration ([TG]; mg/mg of wet weight) in paired biopsy samples. Our study also sought to compare the diagnostic performance of liver cytology, plasma nonesterified fatty acid concentration ([NEFA]), and plasma beta-hydroxybutyrate concentration ([BHB]) derived from a measurement performed on whole blood, for assessing HLC. Chemical extraction of TG from liver tissue remains the gold standard for quantifying HLC, largely because available blood tests, although useful for detecting some types of pathology, such as increased lipid mobilization, ketosis, or hepatocellular injury, are nonspecific as to etiology. Veterinary practitioners can sample bovine liver for cytological evaluation in a fast, minimally invasive, and inexpensive manner. Thus, if highly predictive of HLC, cytology would be a practical diagnostic tool for dairy veterinarians. In our study, liver biopsy samples from Holstein cows (219 samples from 105 cows: 52 from cows 2 to 20 d prepartum, 105 from cows 0 to 10 d in milk, 62 from cows 18 to 25 d in milk) were used to prepare cytology slides and to quantify [TG] using the Folch extraction method followed by the Hantzch condensation reaction and spectrophotometric measurement. An ordinal scale (0-4) based on amount of hepatocellular cytoplasm occupied by discrete clear vacuoles was used by 3 blinded, independent observers to rank HLC in Wright-Giemsa-stained slides. Interobserver agreement in cytology scoring was good. Corresponding plasma [NEFA] and [BHB] measurements were available for 187 and 195 of the 219 samples, respectively. Liver [TG] correlated more strongly with cytology score than with NEFA or BHB, and receiver operating characteristic curve analysis showed that cytology had better diagnostic performance than either NEFA or BHB for correctly categorizing [TG] at thresholds of 5, 10, and 15%. Hepatic lipidosis in high producing dairy cows is of major clinical and economic importance, and this study demonstrates that cytology is an accurate means of assessing HLC. Additional work is indicated to evaluate the diagnostic utility of liver cytology. PMID- 29248219 TI - Temperature modulates the production and activity of a metalloprotease from Pseudomonas fluorescens 07A in milk. AB - This work evaluated the expression and activity of a metalloprotease released by Pseudomonas fluorescens 07A in milk. Low relative expression of the protease by the strain was observed after incubation for 12 h at 25 degrees C while the strain was in the logarithmic growth phase. After 24 h, protease production significantly increased and remained constant for up to 48 h, a time range during which the strain remained in the stationary phase. Conversely, at refrigeration temperatures, at 12 h the strain was still in the lag phase and expressed the protease at higher levels than when the logarithmic phase was reached. Casein fractions were highly degraded by P. fluorescens 07A, the purified protease, and the bacterial pellet on d 7 of incubation at 25 degrees C and to a lesser extent at 10 degrees C for the sample incubated with the bacterium. Heat treatment at 90 degrees C for 5 min completely inactivated the proteolytic activity of the purified protease and the bacterial pellet. This work contributes to the knowledge about the conditions of milk storage that influence the production and activity of this extracellular metalloprotease. The results demonstrate the need to find alternative strategies to control the synthesis and activity of proteolytic enzymes in the dairy industry to ensure the quality of processed products. PMID- 29248220 TI - Economic costs of recorded reasons for cow mortality and culling in a pasture based dairy industry. AB - The objective of this study was to determine the economic costs associated with different reasons for cow culling or on-farm mortality in a pasture-based seasonal system. A bioeconomic model was developed to quantify costs associated with the different farmer-recorded reasons and timing of cow wastage. The model accounted for the parity and stage of lactation at which the cows were removed as well as the consequent effect on the replacement rate and average age structure of the herd. The costs and benefits associated with the change were quantified, including animal replacement cost, cull salvage value, milk production loss, and the profitability of altered genetic merit based on industry genetic trends for each parity. The total cost of cow wastage was estimated to be NZ$23,628/100 cows per year (NZ$1 = US$0.69) in a pasture-based system. Of this total cost, NZ$14,300/100 cows worth of removals were for nonpregnancy and unknown reasons, and another NZ$3,631/100 cows was attributed to low milk production, mastitis, and udder problems. The total cost for cow removals due to farmer-recorded biological reasons (excluding unknown, production, and management-related causes) was estimated to be NZ$13,632/100 cows per year. Of this cost, an estimated NZ$10,286/100 cows was attributed to nonpregnancy, mastitis, udder problems, calving trouble, and injury or accident. There is a strong economic case for the pasture-based dairy industries to invest in genetic, herd health, and production management research focused on reducing animal wastage due to reproductive failure, mastitis, udder problems, injuries or accidents, and calving difficulties. PMID- 29248221 TI - Method comparison and validation of a prototype device for measurement of ionized calcium concentrations cow-side against a point-of-care instrument and a benchtop blood-gas analyzer reference method. AB - The objective of this study was to assess an optimized ion-selective electrode Ca module prototype as a potential cow-side device for ionized Ca (iCa) measurements in bovine blood. A linearity experiment showed no deviation from linearity over a range of iCa concentrations compared with a commercial point-of-care (POC) device commonly used in the field (POCVS; VetScan i-STAT, Abaxis North America, Union City, CA) and a laboratory gold standard benchtop blood-gas analyzer [reference analyzer (RA); ABL-800 FLEX, Radiometer Medical, Copenhagen, Denmark]. Coefficient of variation on 3 samples with high, within-range, and low iCa concentrations ranged from 1.0 to 3.9% for the prototype. A follow-up validation experiment was performed, in which our objectives were to (1) assess the performance of the prototype cow-side against the POCVS (farm gold-standard) using fresh non-anticoagulated whole-blood samples; (2) assess the performance of the prototype and the POCVS against the RA in a diagnostic laboratory using blood collected in a heparin-balanced syringe; and (3) assess the agreement of the prototype and POCVS on-farm (fresh non-anticoagulated whole blood) against the RA on heparin-balanced blood. Finally, sensitivity and specificity of the results obtained by the prototype and the POCVS cow-side compared with the results obtained by the laboratory RA using 3 different iCa cut points for classification of subclinical hypocalcemia were calculated. A total of 101 periparturient Holstein cows from 3 dairy farms in New York State were used for the second experiment. Ionized Ca results from the prototype cow-side were, on average, 0.06 mmol/L higher than the POCVS. With heparin-balanced samples under laboratory conditions, the prototype and POCVS measured an average 0.04 mmol/L higher and lower, respectively, compared with the RA. Results from the prototype and POCVS cow-side were 0.01 mmol/L higher and 0.05 mmol/L lower, respectively, compared with results from the laboratory RA on heparinized blood. Sensitivity and specificity for the prototype and the POCVS under farm conditions at 3 potential subclinical hypocalcemia cut points were 100 and >=93.5%, respectively. This novel ion-selective electrode Ca-module could become a rapid low-cost tool for assessing iCa cow-side, while qualitatively allowing classification of subclinical hypocalcemia on-farm. PMID- 29248222 TI - Dynamics of methanogenesis, ruminal fermentation, and alfalfa degradation during adaptation to monensin supplementation in goats. AB - This study aimed to examine the temporal (hourly within a day and daily over the long term) effects of monensin on CH4 emissions, ruminal fermentation, and in situ alfalfa degradation in dairy goats during dietary monensin supplementation by controlling the confounding effects of feed intake and ambient temperature. Six ruminally cannulated dairy goats were used, and they were housed in environmental chambers and fed a restricted amount of ration throughout the experiment. The experiment included a baseline period of 20 d followed by a treatment period of 55 d with 32 mg of monensin/d. During the whole experiment, CH4 production was measured every 5 d, whereas fermentation characteristics and in situ alfalfa degradation were analyzed every 10 d. The CH4-depressing effect of monensin was time dependent on the duration of treatment, highly effective at d 5 but thereafter decreased gradually until d 55 even though CH4-suppressing effect still remained significant. The decreasing effects of monensin on ruminal acetate proportion and acetate to propionate ratio also faded over days of treatment, and the acetate proportion returned up to the pre-supplementation level on d 50. Monensin supplementation elevated ruminal propionate proportion and decreased the effective ruminal degradability of alfalfa NDF, but both measurements tended to recover over time. The postprandial increase rate of hourly CH4 emissions was reduced, whereas that of propionate proportion was enhanced by monensin supplementation. However, the postprandial responses to monensin in CH4 emission rates, ruminal VFA profiles, and in situ degradation kinetics declined with both hours after feeding and days of treatment. Our results suggest that the CH4-suppressing effect of monensin supplementation in goats was attributed to reductions in both ruminal feed degradation and acetate to propionate ratio, but those reductions faded with time, hours after feeding, and days of treatment. PMID- 29248223 TI - Reliability of sampling strategies for measuring dairy cattle welfare on commercial farms. AB - Our objective was to evaluate how the proportion of high-producing lactating cows sampled on each farm and the selection method affect prevalence estimates for animal-based measures. We assessed the entire high-producing pen (days in milk <100; range = 81-241 cows) on 10 California farms using measures from the Welfare Quality Protocol for Cattle. Cows were restrained in head locks and visually evaluated for body condition, dirtiness, skin alterations (hair loss, lesions, or swelling), discharge (ocular, nasal, vulvar), diarrhea, and impaired respiration. Lameness was scored upon release. Prevalence was calculated as a percentage of assessed cows. The most common conditions were dirty hindquarters (33.5 +/- 10.7%, mean +/- standard deviation) and lesions or swelling on the carpal joint (34.4 +/- 7.0%) and hock (26.4 +/- 16.7%). Diarrhea (8.0 +/- 5.8%), lameness (moderate = 7.3 +/- 4.7%, severe = 2.2 +/- 2.2%), and neck (5.8 +/- 12.6%), flank (4.5 +/- 5.0%), or hindquarter alterations (5.5 +/- 3.9%) were less common. Very fat cows, vulvar discharge, and impaired respiration were rare (<=1%) and were excluded from further analysis. Four sampling strategies were used to generate 20 estimates for each animal-based measure. The strategies were (1) selecting every 10th, 5th, 4th, 3rd, 2nd, 2 of 3, or 3 of 4 cows at the feed bunk (7 estimates/measure); (2) randomly selecting 7 matching proportions of the pen; (3) randomly selecting cows using 3 sample size calculations from the Welfare Quality Protocol; and (4) selecting the first, middle, or final third of cows exiting the milking parlor. Estimates were compared with true values using regression analysis and were considered accurate if they met 3 criteria: the coefficient of determination was >=0.9 and the slope and intercept did not differ significantly from 1 and 0, respectively. All estimates met the slope and intercept criteria, whereas the coefficient of determination increased when more cows were sampled. All estimates were accurate for neck alterations, ocular discharge (22.2 +/- 27.4%), and carpal joint hair loss (14.1 +/- 17.4%). Selecting a third of the milking order or using the Welfare Quality sample size calculations failed to accurately estimate all measures simultaneously. However, all estimates were accurate when selecting at least 2 of every 3 cows locked at the feed bunk. Using restraint position at the feed bunk did not differ systematically from computer selecting the same proportion of cows randomly, and the former may be a simpler approach for welfare assessments. PMID- 29248224 TI - Varying the ratio of Lys:Met while maintaining the ratios of Thr:Phe, Lys:Thr, Lys:His, and Lys:Val alters mammary cellular metabolites, mammalian target of rapamycin signaling, and gene transcription. AB - Amino acids are not only precursors for but also signaling molecules regulating protein synthesis. Regulation of protein synthesis via AA occurs at least in part by alterations in the phosphorylation status of mammalian target of rapamycin (mTOR) pathway proteins. Although the ideal profile of Lys:Met to promote milk protein synthesis during established lactation in dairy cows has been proposed to be 3:1, aside from being the most-limiting AA for milk protein synthesis, the role of Met in other key biologic pathways such as methylation is not well characterized in the bovine. The objective of this study was to determine the influence of increasing supplemental Met, based on the ideal 3:1 ratio of Lys to Met, on intracellular metabolism related to protein synthesis and mTOR pathway phosphorylation status. MAC-T cells, an immortalized bovine mammary epithelial cell line, were incubated (n = 5 replicates/treatment) for 12 h with 3 incremental doses of Met while holding Lys concentration constant to achieve the following: Lys:Met 2.9:1 (ideal AA ratio; IPAA), Lys:Met 2.5:1 (LM2.5), and Lys:Met 2.0:1 (LM2.0). The ratios of Thr:Phe (1.05:1), Lys:Thr (1.8:1), Lys:His (2.38:1), and Lys:Val (1.23:1) were the same across the 3 treatments. Applying gas chromatography-mass spectrometry metabolomics revealed distinct clusters of differentially concentrated metabolites in response to Lys:Met. Lower Phe, branched-chain AA, and putrescine concentrations were observed with LM2.5 compared with IPAA. Apart from greater intracellular Met concentrations, further elevations in Met level (LM2.0) led to greater intracellular concentrations of nonessential AA (Pro, Glu, Gln, and Gly) compared with IPAA and greater essential AA (EAA; Met, Ile, and Leu) and nonessential AA (Pro, Gly, Ala, Gln, and Glu) compared with LM2.5. However, compared with IPAA, mRNA expression of beta-casein and AA transporters (SLC7A5, SLC36A1, SLC38A2, SLC38A9, and SLC43A1) and mTOR phosphorylation were lower in response to LM2.5 and LM2.0. Overall, the results of this study provide evidence that increasing Met while Lys and the ratios of Phe, Thr, His, and Val relative to Lys were held constant could increase the concentration and utilization of intracellular EAA, in particular branched-chain AA, potentially through improving the activity of AA transporters partly controlled by mTOR signaling. Because EAA likely are metabolized by other tissues upon absorption, a question for future in vivo studies is whether formulating diets for optimal ratios of EAA in the metabolizable protein is sufficient to provide the desired levels of these AA to the mammary cells. PMID- 29248225 TI - Reproductive performance and herd exit dynamics of lactating dairy cows managed for first service with the Presynch-Ovsynch or Double-Ovsynch protocol and different duration of the voluntary waiting period. AB - The objective of this experiment was to evaluate the reproductive performance and herd exit dynamics of dairy cows managed for first service with programs varying in method of submission for insemination and voluntary waiting period (VWP) duration. Holstein cows from a commercial farm in New York were randomly allocated to receive timed artificial insemination (TAI) after the Double-Ovsynch protocol (GnRH, 7 d later PGF2alpha, 3 d later GnRH, 7 d later GnRH, 7 d later PGF2alpha, 56 h later GnRH, and 16 to 18 h later TAI) at 60 +/- 3 d in milk (DIM) (DO60 = 458), TAI after Double-Ovsynch at 88 +/- 3 DIM (DO88 = 462), or a combination of AI at detected estrus (starting at 50 +/- 3 d in milk) and TAI with the Presynch-Ovsynch protocol (PGF2alpha, 14 d later PGF2alpha, 12 d later GnRH, 7 d later PGF2alpha, 56 h later GnRH, and 16 to 18 h later TAI; PSOv = 450). Subsequent artificial insemination (AI) services were conducted at detected estrus or the Ovsynch protocol (32 +/- 3 d after AI GnRH, 7 d later PGF2alpha, 56 h later GnRH, and 16 to 18 h later TAI) for cows not reinseminated at detected estrus. In a subgroup of cows, cyclicity (based on progesterone concentration), uterine health (vaginal discharge and uterine cytology), and BCS were evaluated at baseline (DO60 and DO88 = 33 +/- 3 DIM; PSOv = 34 +/- 3 DIM), beginning of the synchronization protocol (DO60 = 33 +/- 3 DIM; DO88 = 61 +/- 3 DIM; PSOv = 34 +/- 3 DIM), and within -5 (PSOv) or -10 d (DO) of the VWP end (DO60 = 50 +/- 3 DIM; DO88 = 78 +/- 3 DIM; PSOv = 45 +/- 3 DIM). Effects of treatments were assessed with multivariable statistical methods relevant for each outcome variable. Cows in the DO88 treatment had delayed time to pregnancy during lactation (DO60 vs. DO88 hazard ratio = 1.53, 95% confidence interval = 1.32 to 1.78; PSOv vs. DO88 hazard ratio = 1.37, 95% confidence interval = 1.19 to 1.61) and, within multiparous cows, the DO88 and PSOv treatments had greater risk of leaving the herd than cows in the DO60 treatment (DO88 vs. DO60 hazard ratio = 1.49, 95% confidence interval = 1.11 to 2.00; PSOv vs. DO60 hazard ratio = 1.39, 95% confidence interval = 1.03 to 1.85). Cows in the DO88 treatment had improved uterine health, greater BCS, and reduced incidence of anovulation than cows in DO60 and PSOv; however, overall pregnancy per AI 39 +/- 3 d after AI was similar for the 3 treatment groups. In summary, reproductive management strategies that led to similar average DIM to the first service (~60 d) through a combination of AI at estrus with TAI (PSOv) or all TAI (DO60) resulted in reduced time to pregnancy after calving when compared with an all TAI program (DO88) with a VWP of 88 d. Within the multiparous cow group, those that received all TAI with a VWP duration of 60 d were less likely to leave the herd than cows in the other treatments. PMID- 29248226 TI - Genetic analysis of predicted fatty acid profiles of milk from Danish Holstein and Danish Jersey cattle populations. AB - The objective of this study was to assess the genetic variability of the detailed fatty acid (FA) profiles of Danish Holstein (DH) and Danish Jersey (DJ) cattle populations. We estimated genetic parameters for 11 FA or groups of FA in milk samples from the Danish milk control system between May 2015 and October 2016. Concentrations of different FA and FA groups in milk samples were measured by mid infrared spectroscopy. Data used for parameter estimation were from 132,732 first parity DH cows and 21,966 first-parity DJ cows. We found the highest heritabilities for test day measurements in both populations for short-chain FA (DH = 0.16; DJ = 0.16) and C16:0 (DH = 0.14; DJ = 0.16). In DH, the highest heritabilities were also found for saturated FA and monounsaturated FA (both populations: 0.15). Genetic correlations between the fatty acid traits showed large differences between DH and DJ for especially short-chain FA with the other FA traits measured. Furthermore, genetic correlations of total fat with monounsaturated FA, polyunsaturated FA, short-chain FA, and C16:0 differed markedly between DH and DJ populations. In conclusion, we found genetic variation in the mid-infrared spectroscopy-predicted FA and FA groups of the DH and DJ cattle populations. This finding opens the possibility of using genetic selection to change the FA profiles of dairy cattle. PMID- 29248227 TI - d-Glucose and amino acid deficiency inhibits casein synthesis through JAK2/STAT5 and AMPK/mTOR signaling pathways in mammary epithelial cells of dairy cows. AB - Amino acids and energy deficiency lead to lower milk protein content in dairy cows. However, the known mechanisms involved in this process do not adequately explain the variability of milk protein concentration in the mammary gland. We hypothesized that a deficiency in d-glucose (d-Glc) or AA would inhibit casein synthesis by regulating signaling pathways in mammary epithelial cells. Cow mammary epithelial cells (CMEC) were subjected to combinations of 1 of 3 concentrations of d-Glc (0, 2.50, or 17.5 mM) and 1 of 3 concentrations of AA (0, 1.03, or 7.20 mM). The effect of each mixture on cell cycle stage was assessed by flow cytometry. The expression levels of beta-casein and kappa-casein (encoded by CSN2 and CSN3) were measured by quantitative real-time PCR and Western blotting. Phosphorylation of Janus kinase 2 (Jak2), signal transducer and activator of transcription 5a (Stat5a), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase 1 (S6K1), and eukaryotic factor 4E-binding protein 1 (4EBP1) were analyzed by Western blotting. The percentages of cells in the DNA postsynthetic (G2) and DNA synthesis (S) phases would decrease, with the level of d-Glc or AA declining individually, but no interaction was observed between the d-Glc and AA effects. The CSN2 and CSN3 mRNA and protein were downregulated when d-Glc or AA decreased individually from 17.5 to 2.50 mM or from 7.20 to 1.03 mM, but d-Glc deficiency had a greater effect according to the regression analysis. The phosphorylation ratio of Jak2 (Tyr1007/1008), Stat5a (Tyr694), mTOR (Ser2448), S6K1 (Thr389), and 4EBP1 (Thr37) was downregulated with the level of d-Glc or AA decline, whereas the phosphorylation ratio of AMPK (Thr183/172) was upregulated. And the change of d Glc level had a more marked effect than AA in regulating the activity of these signaling protein above according to the regression analysis. Thus, d-Glc or AA deficiency likely reduced casein transcription via inhibition of the Jak2/Stat5 pathway, and reduced translation via suppression of the mTOR pathway by activation of AMPK, but d-Glc deficiency had a more marked effect. These indicated that deficiency of AA, and especially Glc, suppressed proliferation of CMEC and casein gene and protein expression, associated with inhibition of JAK2/STAT5 and AMPK/mTOR signaling pathways. PMID- 29248228 TI - Effects of magnesium source and monensin on nutrient digestibility and mineral balance in lactating dairy cows. AB - The interaction of monensin and 2 supplemental Mg sources (MgO and MgSO4) on total-tract digestion of minerals and organic nutrients and milk production was evaluated in lactating dairy cattle. Eighteen multiparous Holstein cows (139 +/- 35 DIM) were used in a split-plot experiment with 0 or 14 mg/kg diet DM of monensin as the whole-plot treatments and Mg source as split-plot treatments. During the entire experiment (42 d), cows remained on the same monensin treatment but received a different Mg source in each period (21 d) of the Latin square. Diets were formulated to contain 0.35% Mg with about 40% of that provided by MgO or MgSO4. Diets were formulated to have similar concentrations of major nutrients and K concentrations were elevated (2.1% of DM) with K2CO3 to create antagonism to Mg absorption. Apparent digestibility was measured by total collection of urine and feces. Supplemental MgSO4 decreased DMI (26.9 vs. 25.7 kg/d) and tended to decrease milk yield (40.2 vs. 39.3 kg/d), but increased the digestibility of OM (68.3 vs. 69.2%) and starch (91.9 vs. 94.4%) compared with MgO. Feeding MgSO4 with monensin decreased NDF digestibility compared with other treatments (46.7 vs. 50.2%). That diet also had decreased apparent absorption of Mg compared with diets without monensin (15.6 vs. 19.2%), whereas MgO with monensin had greater apparent absorption of Mg (23.0%) than other treatments. Cows consuming MgSO4 had increased apparent Ca absorption (32.2 vs. 28.1%) and balance. A diet with MgSO4 without monensin increased the concentration of long-chain fatty acids in milk, suggesting increased mobilization of body fat or decreased de novo fatty acid synthesis in the mammary gland. Overall, when dietary Mg was similar, MgO was the superior Mg source for lactating dairy cattle, but inclusion of monensin in diets should be considered when evaluating Mg sources. PMID- 29248229 TI - Breastfeeding-associated microbiota in human milk following supplementation with Lactobacillus rhamnosus GG, Lactobacillus acidophilus La-5, and Bifidobacterium animalis ssp. lactis Bb-12. AB - Breastfeeding is one of the major factors affecting the early development of the infant gut microbiota, and weaning is associated with a shift in the gut microbiota toward a more adult composition. Through breastfeeding, infants receive bioactive components that shape their microbiota while also being exposed to the breast milk and breast surface microbial communities. Recent studies have suggested the possibility of an entero-mammary route of microbial transfer, opening the possibility of infant gut microbiota modulation through maternal probiotic supplementation. In this study, we have analyzed breast milk samples collected at 10 d and 3 mo postpartum from women participating in the Probiotics in the Prevention of Allergy among Children in Trondheim placebo controlled trial. Women who were randomized to the probiotic arm of the Probiotics in the Prevention of Allergy among Children in Trondheim trial received a fermented milk supplemented with Lactobacillus rhamnosus GG, Lactobacillus acidophilus La-5, and Bifidobacterium animalis ssp. lactis Bb-12, consuming this daily from 4 wk before their expected due date until 3 mo after birth. In total, 472 breast milk samples were assessed for the administered bacteria using quantitative real-time PCR and the microbiota transferred during breastfeeding was analyzed using 16S ribosomal RNA gene sequencing of 142 samples. We found that breastfeeding is unlikely to be a significant source of L. rhamnosus GG, L. acidophilus La-5, and B. animalis ssp. lactis Bb-12 for infants in the probiotic arm of the trial. Furthermore, maternal supplementation did not significantly affect the overall composition of the breast milk microbiota transferred during breastfeeding. We also present a descriptive analysis of this microbiota, which was largely dominated by Streptococcus and Staphylococcus genera at both 10 d and 3 mo postpartum. Samples collected at 3 mo postpartum had a statistically significant lower presence and relative abundance of the Staphylococcus genus. These samples also had a greater number of observed species and diversity, including more operational taxonomic units from the Rothia, Veillonella, Granulicatella, and Methylbacterium genera. PMID- 29248230 TI - Calf management risk factors on dairy farms associated with male calf mortality on veal farms. AB - The objective of this cross-sectional herd-level study was to assess the association of calf management practices on source dairy farms with mortality risk on veal farms. From April to October 2016, 52 source dairy farms supplying male calves to 2 veal operations were visited once. A questionnaire was administered that covered all areas of calf management, calves between 1 and 10 d of age were examined using a standardized health scoring system, and blood was taken to evaluate passive transfer of immunoglobulins. The mortality risk for calves from each dairy farm was calculated based on the number of male calves sold from the dairy farm and that died during 2016 at the veal operations. The mean mortality risk was calculated for both veal farms and, based on the veal facility-adjusted mortality risk, dairy farms were classified as high- or low mortality source farms. Using the information gathered at the 52 source dairy farms, a logistic regression model was used to assess factors associated with being a high-mortality source farm. Suppliers to veal farm 1 had a mean mortality risk of 9.6% and suppliers to veal farm 2 had a mean mortality risk of 4.2%. The lower mortality risk at veal farm 2 was partially influenced by a shorter period of observation. Of the 182 calves examined during the single visit to the source dairy farms, 41% of male calves and 29% of female calves had at least one identifiable health abnormality. The risk of failure of passive transfer on source dairy farms was low, with only 13% of calves tested having <10 mg of IgG/mL of serum. The subset of calves examined at the source dairy farm was not followed prospectively to the veal farms. Using a tube feeder or pail to feed colostrum, bedding male calves on wood shavings or chopped straw at the source dairy farm, and the herd veterinarian not routinely and actively inquiring about the health and performance of calves during regular herd visits were significantly associated with the farm being classified as a high-mortality source dairy farm. Checking the calving pen at an interval of every 3 h or more during the day was associated with a lower probability of being classified as a high-mortality source dairy farm. The results of this study suggest that there are management practices on the source farm that contribute to the risk of mortality on veal farms. PMID- 29248231 TI - Heritabilities and genetic correlations in the same traits across different strata of herds created according to continuous genomic, genetic, and phenotypic descriptors. AB - The most common approach in dairy cattle to prove genotype by environment interactions is a multiple-trait model application, and considering the same traits in different environments as different traits. We enhanced such concepts by defining continuous phenotypic, genetic, and genomic herd descriptors, and applying random regression sire models. Traits of interest were test-day traits for milk yield, fat percentage, protein percentage, and somatic cell score, considering 267,393 records from 32,707 first-lactation Holstein cows. Cows were born in the years 2010 to 2013, and kept in 52 large-scale herds from 2 federal states of north-east Germany. The average number of genotyped cows per herd (45,613 single nucleotide polymorphism markers per cow) was 133.5 (range: 45 to 415 genotyped cows). Genomic herd descriptors were (1) the level of linkage disequilibrium (r2) within specific chromosome segments, and (2) the average allele frequency for single nucleotide polymorphisms in close distance to a functional mutation. Genetic herd descriptors were the (1) intra-herd inbreeding coefficient, and (2) the percentage of daughters from foreign sires. Phenotypic herd descriptors were (1) herd size, and (2) the herd mean for nonreturn rate. Most correlations among herd descriptors were close to 0, indicating independence of genomic, genetic, and phenotypic characteristics. Heritabilities for milk yield increased with increasing intra-herd linkage disequilibrium, inbreeding, and herd size. Genetic correlations in same traits between adjacent levels of herd descriptors were close to 1, but declined for descriptor levels in greater distance. Genetic correlation declines were more obvious for somatic cell score, compared with test-day traits with larger heritabilities (fat percentage and protein percentage). Also, for milk yield, alterations of herd descriptor levels had an obvious effect on heritabilities and genetic correlations. By trend, multiple trait model results (based on created discrete herd classes) confirmed the random regression estimates. Identified alterations of breeding values in dependency of herd descriptors suggest utilization of specific sires for specific herd structures, offering new possibilities to improve sire selection strategies. Regarding genomic selection designs and genetic gain transfer into commercial herds, cow herds for the utilization in cow training sets should reflect the genomic, genetic, and phenotypic pattern of the broad population. PMID- 29248232 TI - Replacing maize silage plus soybean meal with red clover silage plus wheat in diets for lactating dairy cows. AB - The objectives of this study were to evaluate the effects of replacing maize silage plus soybean meal with red clover silage (RCS) plus wheat on feed intake, diet digestibility, N partitioning, urinary excretion of purine derivatives, and milk production in dairy cows. Forty-four lactating German Holstein cows were used in a 4 * 4 Latin square design with 21-d periods composed of a 13-d adaptation phase followed by an 8-d sampling phase. Experimental diets offered as total mixed ration consisted of a constant forage-to-concentrate ratio (75:25) with targeted proportions of RCS-to-maize silage of 15:60 (RCS15), 30:45 (RCS30), 45:30 (RCS45), and 60:15 (RCS60) on a dry matter (DM) basis. Increasing the proportion of RCS plus wheat in the diet decreased linearly the intake of DM from 22.4 to 19.8 kg/d, and of organic matter from 21.1 to 18.1 kg/d. The apparent total tract digestibility (ATTD) of DM and organic matter did not differ across diets and averaged 68.4 and 70.5%, respectively. However, ATTD of N decreased linearly from 68.5 to 63.2%, whereas ATTD of neutral detergent fiber and acid detergent fiber increased linearly from 50.4 to 59.6% and from 48.4 to 57.7%, respectively, when increasing the proportion of RCS plus wheat. Fecal N excretion increased from 31.6 (RCS15) to 37.2% (RCS60) of N intake, whereas urinary N excretion was the lowest (32.8% of N intake) with RCS45. Hence, N efficiency (milk N/N intake) decreased linearly with incremental levels of RCS plus wheat, being the lowest when feeding RCS60 (25.4%), probably due to increased nonprotein N proportion in total dietary N. Urinary excretion of purine derivatives decreased linearly from 378 to 339 mmol/d, which suggests that increasing levels of RCS plus wheat reduced the microbial crude protein flow at the duodenum. Milk yield and milk protein concentration declined linearly from 35.9 to 30.2 kg/d and from 3.20 to 3.01%, respectively, when increasing the proportion of RCS plus wheat. In conclusion, caution should be taken before introducing high levels of RCS plus wheat in diets of high-yielding dairy cows. However, RCS plus wheat can be included up to 30% of the dairy cow diet (DM basis) without a reduction in lactation performance. PMID- 29248233 TI - Lactobacillus casei asp23 gene contributes to gentamycin resistance via regulating specific membrane-associated proteins. AB - Lactobacillus casei Zhang is a probiotic strain originally isolated from koumiss. Previously, we showed that an alkaline shock protein (encoded by asp23) was involved in the adaptation of L. casei Zhang to gentamycin. In the present study, we compared the proteomes of the asp23 mutant and its parent strain grown in the presence of gentamycin. The results showed that 22 and 21 proteins were significantly up- and downregulated, respectively (>1.5-fold difference). By parallel reaction monitoring analysis, we further validated that specific membrane-associated proteins were important in regulating the antibiotics-induced cell wall stress. The findings provide insight into the physiological role of the asp23 gene in the growth response of L. casei when exposed to antibiotic stress. PMID- 29248234 TI - Technical note: Near infrared reflectance spectroscopy to predict fecal indigestible neutral detergent fiber for dairy cows. AB - In vitro and in situ procedures performed to estimate indigestible neutral detergent fiber (iNDF) in forage or fecal samples are time consuming, costly, and limited by intrinsic factors. In contrast, near infrared reflectance spectroscopy (NIRS) has become widely recognized as a valuable tool for accurately determining chemical composition and digestibility parameters of forages. The aim of this study was to build NIRS calibrations and equations for fecal iNDF. In total, 1,281 fecal samples were collected to build a calibration data set, but only 301 were used to develop equations. Once dried, samples were ground and chemically analyzed for crude protein, ash, amylase and sodium sulfite-treated NDF corrected for ash residue (aNDFom), acid detergent fiber, acid detergent lignin, and in vitro digestion at 240 h to estimate iNDF (uNDF240). Each fecal sample was scanned using a NIRSystem 6500 instrument (Perstorp Analytical Inc., Silver Spring, MD). Spectra selection was performed, resulting in 301 sample spectra used to develop regression equations with good accuracy and low standard error of prediction. The standard error of calibration (SEC), cross validation (SECV), and coefficients of determination for calibration (R2) and for cross validation (1 - VR, where VR = variance ratio) were used to evaluate calibration and validation results. Moreover, the ratio performance deviation (RPD) and ratio of the range of the original data to SECV (range/SECV; range error ratio, RER) were also used to evaluate calibration and equation performance. Calibration data obtained on fiber fractions aNDFom (R2 = 0.92, 1 - VR = 0.87, SEC = 1.48, SECV = 1.89, RPD = 2.80, and RER = 20.19), uNDF240 (R2 = 0.92, 1 - VR = 0.86, SEC = 1.65, SECV = 2.24, RPD = 2.57, and RER = 14.30), and in vitro rumen aNDFom digestibility at 240 h (R2 = 0.90, 1 - VR = 0.85, SEC = 2.68, SECV = 3.43, RPD = 2.53, and RER = 14.0) indicated the predictive equations had good predictive value. PMID- 29248235 TI - Bipolar androgen therapy: an intriguing paradox. PMID- 29248237 TI - The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system correlates with cost of care for diabetic foot ulcers treated in a multidisciplinary setting. AB - OBJECTIVE: We have previously demonstrated that the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification correlates with wound healing time in patients with diabetic foot ulcers (DFUs) treated in a multidisciplinary setting. Our aim was to assess whether the charges and costs associated with DFU care increase with higher WIfI stages. METHODS: All patients presenting to our multidisciplinary diabetic limb preservation service from June 2012 to June 2016 were enrolled in a prospective database. Inpatient and outpatient charges, costs, and total revenue from initial visit until complete wound healing were compared for wounds stratified by WIfI classification. RESULTS: A total of 319 wound episodes in 248 patients were captured, including 31% WIfI stage 1, 16% stage 2, 30% stage 3, and 24% stage 4 wounds. Limb salvage at 1 year was 95% +/- 2%, and wound healing was achieved in 85% +/- 2%. The mean number of overall inpatient admissions (stage 1, 2.07 +/- 0.48 vs stage 4, 3.40 +/- 0.27; P < .001), procedure-related admissions (stage 1, 1.86 +/- 0.45 vs stage 4, 2.28 +/- 0.24; P < .001), and inpatient vascular interventions (stage 1, 0.14 +/- 0.10 vs stage 4, 0.80 +/- 0.12; P < .001) increased significantly with increasing WIfI stage. There were no significant differences in mean number of inpatient podiatric interventions or outpatient procedures between groups (P >= .10). The total cost of care per wound episode increased progressively from stage 1 ($3995 +/- $1047) to stage 4 ($50,546 +/- $4887) wounds (P < .001). Inpatient costs were significantly higher for advanced stage wounds (stage 1, $21,296 +/- $4445 vs stage 4, $54,513 +/- $5001; P < .001), whereas outpatient procedure costs were not significantly different between groups (P = .72). Overall, hospital total revenue increased with increasing WIfI stage (stage 1, $4182 +/- $1185 vs stage 4, $55,790 +/- $5540; P < .002). CONCLUSIONS: Increasing WIfI stage is associated with a prolonged wound healing time, a higher number of surgical procedures, and an increased cost of care. While limb salvage outcomes are excellent, the overall cost of DFU care from presentation to healing is substantial, especially for patients with advanced (WIfI stage 3/4) disease treated in a multidisciplinary setting. PMID- 29248236 TI - Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. AB - BACKGROUND: Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses. We aimed to evaluate BAT in patients with metastatic castration-resistant prostate cancer that progressed after enzalutamide. METHODS: We did this single-centre, open label, phase 2, multicohort study in the USA. We included patients aged 18 years or older who had histologically confirmed and radiographically documented metastatic castration-resistant prostate cancer, with no more than two previous second-line hormonal therapies, and a castrate concentration of testosterone. Patients were asymptomatic, with Eastern Cooperative Oncology Group performance status of 0-2, and did not have high-risk lesions for tumour flare (eg, >5 sites of visceral disease or bone lesions with impending fracture). For the cohort reported here, we required patients to have had progression on enzalutamide with a continued prostate-specific antigen (PSA) rise after enzalutamide treatment discontinuation. Patients received BAT, which consisted of intramuscular testosterone cipionate 400 mg every 28 days until progression and continued luteinising hormone-releasing hormone agonist therapy. Upon progression after BAT, men were rechallenged with oral enzalutamide 160 mg daily. The co-primary endpoints were investigator-assessed 50% decline in PSA concentration from baseline (PSA50) for BAT (for all patients who received at least one dose) and for enzalutamide rechallenge (based on intention-to-treat analysis). These data represent the final analysis for the post-enzalutamide cohort, while two additional cohorts (post-abiraterone and newly castration-resistant prostate cancer) are ongoing. The trial is registered with ClinicalTrials.gov, number NCT02090114. FINDINGS: Between Aug 28, 2014, and May 18, 2016, we accrued 30 eligible patients and treated them with BAT. Nine (30%; 95% CI 15-49; p<0.0001) of 30 patients achieved a PSA50 to BAT. 29 patients completed BAT and 21 proceeded to enzalutamide rechallenge, of whom 15 (52%; 95% CI 33-71; p<0.0001) achieved a PSA50 response. During BAT, the only grade 3-4 adverse event occurring in more than one patient was hypertension (three [10%] patients). Other grade 3 or worse adverse events occurring during BAT in one [3%] patient each were pulmonary embolism, myocardial infarction, urinary obstruction, gallstone, and sepsis. During enzalutamide retreatment, no grade 3-4 toxicities occurred in more than one patient. No treatment-related deaths were reported during either BAT or enzalutamide retreatment. INTERPRETATION: BAT is a safe therapy that resulted in responses in asymptomatic men with metastatic castration-resistant prostate cancer and also resensitisation to enzalutamide in most patients undergoing rechallenge. Further studies with BAT are needed to define the potential clinical role for BAT in the management of metastatic castration-resistant prostate cancer and the optimal strategy for sequencing between androgen and antiandrogen therapies in metastatic castration-resistant prostate cancer to maximise therapeutic benefit to patients. FUNDING: National Institutes of Health and National Cancer Institute. PMID- 29248238 TI - Contemporary outcomes for ruptured abdominal aortic aneurysms using endovascular balloon control for hypotension. AB - OBJECTIVE: Ruptured abdominal aortic aneurysm (rAAA) continues to portend significant mortality, despite ruptured endovascular aneurysm repair (rEVAR), enhanced perioperative care, and endovascular balloon control (EBC) for hypotension. We review our academic institution's experience using a protocol of EBC for all hypotensive patients, irrespective of type of repair. METHODS: A retrospective review was conducted of 66 cases of rAAA treated at a single academic institution from 2007 to 2016 using EBC for hypotensive patients. Demographics, comorbidities, intraoperative parameters, and clinical outcomes were recorded. Patients were studied with respect to hemodynamic status, rEVAR, or ruptured open aortic repair in the setting of EBC for hypotension. RESULTS: rEVAR was performed in 43 patients (65%) and ruptured open aortic repair in 23 patients (35%). rAAA was treated in 51 men (77%). Mean rAAA size was 7.6 mm, and mean age of the patients was 73 years. Perioperative survival was 82%. Overall survival at 30 days, 1 year, and 5 years was 71%, 65%, and 52%. Blood transfusion and severe hypotension were significant predictors of mortality at 30 days on multivariable analysis (odds ratio of 1.2 [P = .08] and 39 [P = .03], respectively). Severe hypotension was defined as a mean arterial blood pressure <65 mm Hg and vasopressor use and was present in 59% of the cohort. Normotension was defined as an absence of these conditions and was present in 12%, with 29% of patients exhibiting moderate hypotension. There was no difference in 30-day survival between normotensive and moderately hypotensive patients. The 30-day survival for severely hypotensive patients was 61% vs 85% for moderately hypotensive patients (P = .003), with a significant difference between groups that persisted at 1 year (85% vs 51%; P = .008) and 5 years (66% vs 51%; P = .017). CONCLUSIONS: Good midterm outcomes for moderately hypotensive and normotensive patients can be obtained using an EBC protocol for hypotension with a regionalized transport system directly to the operating room. Severely hemodynamically unstable rAAA patients still pose a significant challenge despite mitigation of hypotension by EBC, suggesting that survival may be compromised by factors other than hypotension alone. We still advocate for the use of EBC for all hypotensive patients as part of a defined rAAA protocol before definitive repair. PMID- 29248239 TI - Magnetic resonance imaging characteristics of lesions relate to the difficulty of peripheral arterial endovascular procedures. AB - OBJECTIVE: Limitations with current peripheral arterial imaging modalities make selection of patients for percutaneous vascular interventions difficult. The purpose of this study was to determine whether a novel preprocedural magnetic resonance imaging (MRI) method can identify lesions that would be more challenging to cross during percutaneous vascular intervention. METHODS: Fourteen patients with peripheral arterial disease underwent MRI before their intervention. A novel steady-state free precession flow-independent magnetic resonance (MR) angiogram was used to locate lesions, and an ultrashort echo time image was used to characterize hard lesion components including calcium and dense collagen. Lesions were characterized as hard if >=50% of the lumen was occluded with calcium or collagen (as determined by MR image characteristics) in the hardest cross section within the lesion. The primary outcome was the time it took to cross a guidewire through the target lesion. The secondary outcome was the need for stenting. RESULTS: Of 14 lesions, 8 (57%) were defined as hard and 6 (43%) were soft on the basis of MR image characteristics. Hard lesions took significantly longer to cross than soft lesions (average, 14 minutes 49 seconds vs 2 minutes 17 seconds; P = .003). Hard lesions also required stenting more often than soft lesions (Fisher exact test, P = .008). Of 14 lesions, 2 (14%) could not be crossed with a guidewire, and both lesions were hard. MR images also detected occult patencies and noncalcified hard lesions that could not be seen on X-ray angiography. CONCLUSIONS: MRI can be used to determine which peripheral arterial lesions are more difficult to cross with a guidewire. Future work will determine whether MRI lesion characterization can predict long-term endovascular outcomes to aid in procedure planning. PMID- 29248240 TI - Higher surgeon annual volume, but not years of experience, is associated with reduced rates of postoperative complications and reoperations after open abdominal aortic aneurysm repair. AB - OBJECTIVE: Volume-outcome relationships for open abdominal aortic aneurysm (AAA) repair have received less attention in publicly funded health systems. Furthermore, the roles of surgeon seniority (years of experience) and composite volume (encompassing all major arterial cases) on outcomes after open AAA repair are less well known. We sought to determine the effects of surgeon volume, surgeon years of experience, and composite volume on outcomes after elective open AAA repairs performed in Ontario, Canada. METHODS: Using a population-based, prospectively collected health administrative database, all elective open AAA repairs occurring in the province of Ontario from 2005 to 2014 were identified. Surgeon annual volume was classified by quintiles, with the highest volume quintile acting as the reference category. Multivariable logistic regression modeling was used, adjusting for patient factors (age, sex, comorbidities, year of procedure, income) to investigate the relationship between surgeon annual volume and 30-day mortality, 30-day major complications, 30-day reoperations, 1 year mortality, and 1-year reoperations (related to index procedure). The potential effects of annual surgeon composite volume and surgeon years of experience on postoperative outcomes were also explored. RESULTS: A total of 7211 elective open AAA repairs performed by 101 surgeons were identified between 2005 and 2014. Most of the operations were performed by vascular surgeons (81.5%), followed by cardiac (12.1%) and general surgeons (6.1%). Median number of procedures in the lowest quintile group was 3 repairs/y, whereas the highest quintile group performed 54 repairs/y. Overall 30-day mortality was 3%. No difference in mortality was detected in comparing the lowest with the highest volume groups (1.89% vs 3.01%; adjusted odds ratio [OR], 0.60; 95% confidence interval [CI], 0.27-1.33). The lowest volume group exhibited a higher 30-day complication rate (28.0% vs 20.4%; OR, 1.54; 95% CI, 1.15-2.06) and 30-day reoperation rate (10.53% vs 6.73%; OR, 1.64; 95% CI, 1.13-2.38) compared with the highest volume group. No effect of surgeon volume on 1-year mortality or 1-year reoperation was observed. Similarly, composite volume and surgeon years of experience were not associated with postoperative outcomes. CONCLUSIONS: In a single-payer system with a relatively high number of open AAA repairs/surgeon per year, surgeon annual volume had no effect on postoperative mortality but was associated with lower postoperative complication and reoperation rates. PMID- 29248241 TI - Matched cohort comparison of endovascular abdominal aortic aneurysm repair with and without EndoAnchors. AB - OBJECTIVE: The objective of this study was to examine whether prophylactic use of EndoAnchors (Medtronic, Santa Rosa, Calif) contributes to improved outcomes after endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms through 2 years. METHODS: The Aneurysm Treatment Using the Heli-FX Aortic Securement System Global Registry (ANCHOR) subjects who received prophylactic EndoAnchors during EVAR were considered for this analysis. Imaging data of retrospective subjects who underwent EVAR at ANCHOR enrolling institutions were obtained to create a control sample. Nineteen baseline anatomic measurements were used to perform propensity score matching, yielding 99 matched pairs. Follow-up imaging of the ANCHOR and control cohorts was then compared to examine outcomes through 2 years, using Kaplan-Meier survival analysis. RESULTS: Freedom from type Ia endoleak was 97.0% +/- 2.1% in the ANCHOR cohort and 94.1% +/- 2.5% in the control cohort through 2 years (P = .34). The 2-year freedom from neck dilation in the ANCHOR and control cohorts was 90.4% +/- 5.6% and 87.3% +/- 4.3%, respectively (P = .46); 2-year freedom from sac enlargement was 97.0% +/- 2.1% and 94.0% +/- 3.0%, respectively (P = .67). No device migration was observed. Aneurysm sac regression was observed in 81.1% +/- 9.5% of ANCHOR subjects through 2 years compared with 48.7% +/- 5.9% of control subjects (P = .01). Cox regression analysis found an inverse correlation between number of hostile neck criteria met and later sac regression (P = .05). Preoperative neck thrombus circumference and infrarenal diameter were also variables associated with later sac regression, although not to a significant degree (P = .10 and P = .06, respectively). Control subjects with thrombus were significantly less likely to experience later sac regression than those without thrombus (6% and 43%, respectively; P = .001). In ANCHOR subjects, rate of regression was not significantly different in subjects with or without thrombus (33% and 36%, respectively; P = .82). Control subjects with wide aortic necks (>28 mm) were observed to experience sac regression at a lower rate than subjects with smaller diameter necks (10% and 44%, respectively; P = .004). Wide neck and normal neck subjects implanted with EndoAnchors experienced later sac regression at roughly equivalent rates (44% and 33%, respectively; P = .50). CONCLUSIONS: In propensity-matched cohorts of subjects undergoing EVAR, the rate of sac regression in subjects treated with EndoAnchors was significantly higher. EndoAnchors may mitigate the adverse effect of wide infrarenal necks and neck thrombus on sac regression, although further studies are needed to evaluate the long-term effect of EndoAnchors. PMID- 29248242 TI - Plasma microbiome-modulated indole- and phenyl-derived metabolites associate with advanced atherosclerosis and postoperative outcomes. AB - OBJECTIVE: Multiple studies have shown that gut microbes contribute to atherosclerosis, and there is mounting evidence that microbial metabolism of dietary nutrients influences pathophysiology. We hypothesized that indole- and phenyl-derived metabolites that originate solely or in part from bacterial sources would differ between patients with advanced atherosclerosis and age- and sex-matched controls without clinically apparent atherosclerosis. METHODS: Plasma from the advanced atherosclerosis cohort (n = 100) was from patients who underwent carotid endarterectomy, open infrainguinal leg revascularization, or major leg amputation for critical limb ischemia. The controls (n = 22) were age- and sex-matched participants who had no peripheral arterial disease or history of stroke or myocardial infarction. Patients with chronic kidney disease were excluded. Metabolites and internal standards were measured using high-performance liquid chromatography and tandem mass spectrometry. RESULTS: Plasma metabolite concentrations differed significantly between the advanced atherosclerosis and control cohorts. After adjustment for traditional atherosclerosis risk factors, indole (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.75-0.95; P = .004), tryptophan (OR, <0.001; 95% CI, <0.001-0.003; P < .001), indole-3 propionic acid (OR, 0.27; 95% CI, 0.019-0.91; P = .02), and indole-3-aldehyde (OR, 0.12; 95% CI, 0.014-0.92; P = .04) concentrations negatively associated with advanced atherosclerosis, whereas the kynurenine/tryptophan ratio (OR, 61.7; 95% CI, 1.9->999; P = .02) was positively associated. Furthermore, tryptophan and indole-3-propionic acid concentrations (Spearman coefficients of 0.63 and 0.56, respectively; P < .001) correlated with the ankle-brachial index, a surrogate for overall atherosclerotic disease burden. Fourteen patients experienced a major postoperative cardiac complication within 30 days in the advanced atherosclerosis cohort, which was associated with baseline kynurenine/tryptophan ratio (P = .001) and hippuric acid (P = .03). In a multivariate analysis, only the kynurenine/tryptophan ratio remained significantly associated with a postoperative cardiac complication (OR, 44.1; 95% CI, 3.3-587.1; P = .004). Twenty patients in the advanced atherosclerosis cohort experienced a major adverse cardiac event during the follow-up period, which was associated with hippuric acid (P = .002) and the kynurenine/tryptophan ratio (P < .001) at baseline. Both hippuric acid and the kynurenine/tryptophan ratio were independently associated with a major adverse cardiac event in multivariate analyses that included diabetes mellitus. CONCLUSIONS: Specific microbe-derived metabolite signatures associate with advanced human atherosclerosis and postoperative cardiac complications. We suggest that these metabolites are potential novel biomarkers for atherosclerotic disease burden and that further investigation into mechanistic links between defined microbial metabolic pathways and cardiovascular disease is warranted. PMID- 29248243 TI - Systemic hypersensitivity reaction to endovascular stainless steel stent. AB - Endovascular intervention has become the mainstay for treatment of most patients suffering from peripheral vascular disease. We describe a patient with a known nickel allergy who underwent placement of a stainless steel stent for aortoiliac occlusive disease. Despite our attempt to avoid a nickel-containing stent, the patient developed a diffuse rash consistent with a nickel or metal allergy. A review of stainless steel metallurgy revealed that nickel, cobalt, and titanium are frequently used to provide anticorrosive properties to stainless steel. The clinical significance of the use of nickel-alloy stents in the setting of patients with a nickel allergy is discussed. PMID- 29248244 TI - Patency and in vivo compatibility of bacterial nanocellulose grafts as small diameter vascular substitute. AB - OBJECTIVE: Despite the clinical success of large-diameter vascular grafts, synthetic grafts in small-diameter vessels are of limited use because of their poor patency rates. Previous experiments of our group provided evidence for good biocompatibility of bacterial nanocellulose (BNC) as a small-vessel graft in the carotid artery in sheep. However, the patency rate of our first-generation tubes after 3 months was only 50%. To advance our concept, we now used modified second generation tubes with diminished wall thickness and a smoother inner surface to reduce the thrombogenic potential. The aim was to investigate mechanical characteristics of modified second-generation BNC tubes, to evaluate in vivo performance and biocompatibility, and to analyze patency rates. METHODS: We replaced the right carotid artery of 23 sheep with second-generation BNC tubes. Compared with our first-generation tubes, tubes were modified with different surface properties and diminished wall thickness (inner diameter, 4.0-5.0 mm; wall thickness, 1.0-2.5 mm; length, 100 mm) to generate a smoother inner surface with reduced thrombogenic potential and a more porous outer zone, allowing easier cell immigration. RESULTS: At the end of the investigational period, BNC tubes were explanted and grafts were processed for histopathologic analysis. Histologic analysis revealed no acute signs of foreign body reaction such as immigration of giant cells or other acute inflammatory reaction and therefore provided evidence for good biocompatibility of the second-generation tubes. However, all grafts of the sheep without antiplatelet therapy were occluded after 9 months, whereas grafts in sheep receiving dual platelet inhibition showed a patency rate of 67% (six of nine grafts). Further modified grafts revealed a patency rate of 80% (four of five grafts remained open). CONCLUSIONS: Patency rates of the second generation tubes could be substantially improved compared with our first generation tubes. However, poor patency rates of tissue-engineered blood vessels still limit their use in clinical studies. Further efforts in terms of in vitro and in vivo studies are essential to improve grafts of BNC. PMID- 29248245 TI - Outcomes of tibial endovascular intervention in patients with poor pedal runoff. AB - OBJECTIVE: Tibial interventions for critical limb ischemia are now commonplace. The aim of this study was to examine the impact of pedal runoff on patient centered outcomes after tibial endovascular intervention. METHODS: A database of patients undergoing lower extremity endovascular interventions at a single urban academic medical center between 2006 and 2016 was retrospectively queried. Patients with critical ischemia (Rutherford 5 and 6) were identified. Preintervention angiograms were reviewed in all cases to assess pedal runoff. Each dorsalis pedis, lateral plantar, and medial plantar artery was assigned a score according to the reporting standards of the Society for Vascular Surgery (0, no stenosis >20%; 1, 21%-49% stenosis; 2, 50%-99% stenosis; 2.5, half or less of the vessel length occluded; 3, more than half the vessel length occluded). A foot score (dorsalis pedis + medial plantar + lateral plantar + 1) was calculated for each foot (1-10). Two runoff score groups were identified: good vs poor, <7 and >=7, respectively. Patient-oriented outcomes of clinical efficacy (absence of recurrent symptoms, maintenance of ambulation, and absence of major amputation), amputation-free survival (survival without major amputation), and freedom from major adverse limb events (above-ankle amputation of the index limb or major reintervention [new bypass graft, jump/interposition graft revision]) were evaluated. RESULTS: There were 1134 patients (56% male; average age, 59 years) who underwent tibial intervention for critical ischemia, with a mean of two vessels treated per patient and a mean pedal runoff score of 6 (47% had a runoff score >=7). Overall major adverse cardiac events were equivalent at 30 days after the procedure in both groups. At 5 years, vessels with compromised runoff (score >=7) had significantly lower ulcer healing (25% +/- 3% vs 73% +/- 4%, mean +/- standard error of the mean [SEM]) and a lower 5-year limb salvage rate (45% +/- 6% vs 69% +/- 4%, mean +/- SEM) compared with those with good runoff (score <7). Patients with poor pedal runoff (score >=7) had significantly lower clinical efficacy (23% +/- 8% vs 38% +/- 4%, mean +/- SEM), amputation-free survival (32% +/- 6% vs 48% +/- 5%, mean +/- SEM), and freedom from major adverse limb events (23% +/- 9% vs 41% +/- 8%, mean +/- SEM) at 5 years compared with patients with good runoff (score <7). CONCLUSIONS: Pedal runoff score can identify those patients who will not achieve ulcer healing and patient-centered outcomes after tibial intervention. Defining such subgroups will allow stratification of the patients and appropriate application of interventions. PMID- 29248246 TI - [Children exposure to PM10 on the way to school: Regulatory impact of speed regulation under 30km/h]. AB - BACKGROUND: In Paris, air pollution is now a persistent environmental problem, especially linked to diesel cars in circulation. Exposure of children to air pollution during the journey from home to school, which takes place during peak hours of traffic, is poorly documented. METHODS: The purpose of this work was to identify spaces less exposed to PM10 pollution. We identified spatial recurrences in the relative distribution of air pollution levels using PM10 geolocated measures taken along a fixed circuit, crossing, among others, a speed regulation zone (<30km/h). Measurements were made eight mornings between 8 and 9 a.m., in April and September 2016 in the 14th district of Paris. We obtained a hierarchical classification of spaces in terms of recurrence of relative levels of PM10 concentration. RESULTS: The cartography of the results revealed that the spaces more exposed to high concentrations were found similarly along main roads, side streets and speed regulation<30km/h) zones. These findings suggest speed regulation is insufficient to reduce individual exposure in city streets. CONCLUSION: Elements linked to the functional aspects of the street (commercial/residential) were apparently as important as traffic speed. PMID- 29248248 TI - Skin: Uncovering Our Covering. PMID- 29248247 TI - Infralittoral-sublittoral (submerged zone) macroinfauna community structure of high-impact, medium-impact and non-impact beaches on the Gulf of Cadiz coast (SW Spain). Evaluation of anthropogenic alterations: Nourishments, human impact and urbanization. AB - Beaches are dynamic transitional environments subject to numerous natural and anthropic alterations. In these ecosystems, the infralittoral-sublittoral macrofauna communities play a key role in the food web. The objective of this study was to compare macrofauna communities on six beaches on the Gulf of Cadiz coast, which were classified according to the anthropic alterations they support, and evaluate the influence of abiotic factors on the species distribution. Sampling was done in the infralittoral-sublittoral zone of each beach using a modified manual dredge. Five perpendicular transects of 25 m, each separated by 10 m, were performed per beach, with a total sample area of 43.75 m2 per beach. A total of 27 species were found, of which Donax trunculus, Diogenes pugilator, and Tritia grana were the most abundant. Anthropogenic effects are appreciable in the infralittoral-sublittoral although they are areas that are permanently submerged and less exposed than the intertidal. Beach nourishments carried out with large volumes of sand can alter the grain size, the most influential parameter on the distribution of the species, and consequently, affect the macrofauna community that inhabits these beaches. PMID- 29248249 TI - New technique to contour the paramedian forehead flap in nasal reconstruction. PMID- 29248250 TI - Effect of meal timing on postprandial glucose responses to a low glycemic index meal: A crossover trial in healthy volunteers. AB - BACKGROUND & AIMS: Glucose metabolism is, in part, regulated by the circadian rhythm. Postprandial glucose response is exaggerated and insulin sensitivity is reduced at night compared with the morning. Sustained poor glucose tolerance may be related to the increased risk of type-2 diabetes mellitus and cardiovascular disease experienced by shift workers. Manipulation of meal type may be able to dampen such postprandial excursions. Therefore, the study's aim was to investigate postprandial glucose and insulin responses to a low glycemic index (GI) meal in the morning compared to night in healthy volunteers. METHODS: An oral glucose tolerance test (OGTT), was undertaken to confirm diurnal glucose response. Participants consumed a glucose solution at 0800h (morning) and 2000h (evening). In a separate trial, participants consumed a low GI meal (3.3 MJ, 48% energy (E) from carbohydrate, 40%E from fat and 11%E from protein, 22 g fiber) at 0800h, 2000h and 0000h (midnight). Postprandial glucose and insulin were collected over 3 h. Incremental area under the curve (iAUC) was calculated and significance tested using Wilcoxon-signed rank. A p-value <0.05 was taken as significant. RESULTS: In the OGTT (n = 10), postprandial glucose iAUC was higher in the evening compared to morning (p = 0.007). In the low GI meal trial (n = 9), postprandial glucose iAUC at evening and midnight were higher than the morning (p = 0.008, p = 0.021) but not significantly different between evening and midnight (p = 0.594). Postprandial insulin iAUC was also higher in the evening and at midnight compared to the morning (p = 0.008 for both). CONCLUSIONS: The current study confirms that meal intake at night, even when comprised of low glycemic ingredients, contributes to higher glucose excursions and concomitantly greater insulin levels, compared with an equivalent meal in the morning. This demonstrates that meal timing has an effect on glucose metabolism, which can be observed from as early as 8pm and persists throughout the night. This identifies meal timing as an important modifiable risk factor for metabolic-related disease, which may have implications for high risk populations such as shift workers but also the general population. TRIAL REGISTRATION: Study ID number: ACTRN12616000164493; Website of trial registry: http://www.anzctr.org.au/. PMID- 29248251 TI - Dietary n-3 polyunsaturated fatty acid intake and all-cause and cardiovascular mortality in adults on hemodialysis: The DIET-HD multinational cohort study. AB - BACKGROUND & AIMS: Patients on hemodialysis suffer from high risk of premature death, which is largely attributed to cardiovascular disease, but interventions targeting traditional cardiovascular risk factors have made little or no difference. Long chain n-3 polyunsaturated fatty acids (n-3 PUFA) are putative candidates to reduce cardiovascular disease. Diets rich in n-3 PUFA are recommended in the general population, although their role in the hemodialysis setting is uncertain. We evaluated the association between the dietary intake of n-3 PUFA and mortality for hemodialysis patients. METHODS: The DIET-HD study is a prospective cohort study (January 2014-June 2017) in 9757 adults treated with hemodialysis in Europe and South America. Dietary n-3 PUFA intake was measured at baseline using the GA2LEN Food Frequency Questionnaire. Adjusted Cox regression analyses clustered by country were conducted to evaluate the association of dietary n-3 PUFA intake with cardiovascular and all-cause mortality. RESULTS: During a median follow up of 2.7 years (18,666 person-years), 2087 deaths were recorded, including 829 attributable to cardiovascular causes. One third of the study participants consumed sufficient (at least 1.75 g/week) n-3 PUFA recommended for primary cardiovascular prevention, and less than 10% recommended for secondary prevention (7-14 g/week). Compared to patients with the lowest tertile of dietary n-3 PUFA intake (<0.37 g/week), the adjusted hazard ratios (95% confidence interval) for cardiovascular mortality for patients in the middle (0.37 to <1.8 g/week) and highest (>=1.8 g/week) tertiles of n-3 PUFA were 0.82 (0.69-0.98) and 1.03 (0.84-1.26), respectively. Corresponding adjusted hazard ratios for all-cause mortality were 0.96 (0.86-1.08) and 1.00 (0.88-1.13), respectively. CONCLUSIONS: Dietary n-3 PUFA intake was not associated with cardiovascular or all-cause mortality in patients on hemodialysis. As dietary n-3 PUFA intake was low, the possibility that n-3 PUFA supplementation might mitigate cardiovascular risk has not been excluded. PMID- 29248252 TI - A rare case of tibial hemimelia, surgical technique and clinical results. AB - We report a nine-year-old boy with a type IIIa tibial hemimelia, according to the new Paley classification. We describe the x-ray findings, the surgical treatment technique, and the prognostic course of the patient. Descriptions of such cases are very infrequent in the literature and type of treatment is still object of debate. PMID- 29248253 TI - [Accessory left atrial chordae: an unusual cause of mitral regurgitation in children]. PMID- 29248254 TI - [Myocardial tumour infiltration mimicking myocardial ischaemia in electrocardiogram]. PMID- 29248256 TI - Challenges in reducing influenza-associated mortality. PMID- 29248257 TI - Forearm as a valuable source of vascularized bone graft for the distal humerus. AB - BACKGROUND: The nonunion of a distal humeral fracture is a challenging complication. Our aim was to assess the results of the application of pedicled bone flap to treat this problem. METHODS: There were 6 men and 3 women with delayed union or nonunion of the distal humerus treated by 10 procedures of rigid fixation plus radial bone forearm or posterior interosseous bone flaps. A locking plate was applied for fixation in 4 patients and a pin and plate for 5 patients. The olecranon osteotomy was performed in 6 elbows. RESULTS: Patients were a mean age of 49.2 years (range, 31-70 years). The average interval between the trauma and the index operation was 19.2 months (range, 3-49 months). Eight elbows showed union within an average of 3.75 months (range, 3-6 months) in the column where the bony flap was placed. The radial forearm bone flap failed to unite the nonunion of the lateral column of 1 elbow, and additional tension banding was required. Two elbows did not heal at the medial column when the radial forearm bone flap was located on the lateral column. For 1 elbow, another posterior interosseous bone flap was applied on the medial side in another session. By a mean follow-up of 37.3 months (range, 24-79 months), the mean of the visual analog scale demonstrated significant improvement from 6.44 postoperatively to 2.22 (P < .001). The Mayo Elbow Performance Score and 11-Item version of the Disabilities of the Arm, Shoulder and Hand score also showed clinically and statistically significant improvements. CONCLUSION: Vascularized bone flaps could be considered as an option to facilitate healing of distal humerus delayed union or nonunion. PMID- 29248258 TI - Selection, implementation, and interpretation of patient-centered shoulder and elbow outcomes. AB - The movement toward a value-based health care market requires comparison of physicians, hospitals, and health systems. Traditionally, process-based measures such as infection and readmission rates have been used. However, these events are uncommon in shoulder and elbow surgery, thus limiting their utility. Patient reported outcomes (PROs) are a promising measure of quality and have been proposed as a potential metric to compare surgeon performance. However, there are over 25 different PROs for shoulder and elbow conditions. Therefore, the American Shoulder and Elbow Surgeons Value Committee was established to recommend shoulder and elbow PROs in an effort to align their implementation for quality assessment. The committee developed criteria for assessing the outcome measures including that each measure should be patient reported, not requiring clinician input; have published validation and psychometrics; and be standardized and demonstrate ease of use for the patient and clinician. Two sets were suggested: one set for clinical implementation and a more robust set for research purposes. The final recommendation was that all patients should complete the Veterans Rand 12 for general health and the Single Assessment Numeric Evaluation for the specified body region. For patients with shoulder complaints, the American Shoulder and Elbow Surgeons score was recommended, and for those with elbow complaints, the Quick Disabilities of the Arm, Shoulder and Hand score was recommended. More robust disease-specific measures were provided for research purposes. Continued efforts should be made to align these measures across orthopedics to facilitate use of patient outcome measures as a component of value-based health care assessment. PMID- 29248259 TI - Congenital Pulmonary Malformations Diagnosed Over a Period of 10 Years. PMID- 29248260 TI - Secondary Organizing Pneumonia Mimicking Pulmonary Metastasis of a Diffuse Large Cell Lymphoma. PMID- 29248261 TI - Walking Program for Copd Patients: Clinical Impact After Two Years of Follow-up. PMID- 29248262 TI - Does The Impact Of Cough On Quality Of Life In Bronchiectasis Depend On Prognosis? PMID- 29248263 TI - Impact of rotavirus vaccination on the burden of acute gastroenteritis in Nagoya city, Japan. AB - BACKGROUND: In Nagoya city, Japan, rotavirus (RV) vaccination has been available since 2011 with estimated coverage reaching 92% by 2015 after the introduction of a public subsidy in 2012. This study assessed the impact of vaccination on the RV gastroenteritis (RVGE) burden in children aged <5 years old (y) by comparing RVGE hospitalizations and outpatient visits during pre-vaccination (2007-2011), transition (2011-2012) and subsidization (2012-2016) periods. METHODS: All hospitalizations and outpatient visits in children aged <5 y from 2 administrative districts of Nagoya city were identified from the hospital-based electronic databases of 4 hospitals. RVGE cases were identified by diagnostic code and/or positive results of diagnostic kits. RESULTS: Compared to the pre vaccination period, there was a decrease in RVGE hospitalizations for children <5 y from 5.59 per 1000 person-year (kPY) to 3.65/kPY in the subsidization period (i.e. 34.69%). In children <1 y, the incidence of RVGE hospitalizations decreased continuously from 6.62/kPY in the pre-vaccination period to 1.84/kPY in the subsidization period (i.e. 72.19%). The highest decrease was observed in the subsidization season i.e. when high coverage was reached: 69% and 75.57% in the 2013/2014 season for 2-3 y and 3-4 y, and 74.03% in the 2014/2015 season for 4-5 y, respectively. Proportion of RVGE outpatient visits decreased by 87.44% for children <1 y and 57.05% for <5 y from the pre-vaccination to the subsidization period. This decrease started the first year of subsidization for children <1 y, 1-2 y and 2-3 y (78.89%, 18.86% and 5.80%) and the second year (2013/2014 season) for children 3-4 y and 4-5 y (87.73% and 51.78%). CONCLUSIONS: Although yearly fluctuations have been observed, the introduction of vaccination significantly decreased pediatric RVGE hospitalizations and outpatient visits, especially in the age group eligible for vaccination. During the second and third year of subsidization, we observed a herd protection effect on other age groups <5 y who were not eligible for vaccination. Clinicaltrial.gov.registered#:NCT01733862. PMID- 29248255 TI - Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. AB - BACKGROUND: Estimates of influenza-associated mortality are important for national and international decision making on public health priorities. Previous estimates of 250 000-500 000 annual influenza deaths are outdated. We updated the estimated number of global annual influenza-associated respiratory deaths using country-specific influenza-associated excess respiratory mortality estimates from 1999-2015. METHODS: We estimated country-specific influenza-associated respiratory excess mortality rates (EMR) for 33 countries using time series log linear regression models with vital death records and influenza surveillance data. To extrapolate estimates to countries without data, we divided countries into three analytic divisions for three age groups (<65 years, 65-74 years, and >=75 years) using WHO Global Health Estimate (GHE) respiratory infection mortality rates. We calculated mortality rate ratios (MRR) to account for differences in risk of influenza death across countries by comparing GHE respiratory infection mortality rates from countries without EMR estimates with those with estimates. To calculate death estimates for individual countries within each age-specific analytic division, we multiplied randomly selected mean annual EMRs by the country's MRR and population. Global 95% credible interval (CrI) estimates were obtained from the posterior distribution of the sum of country-specific estimates to represent the range of possible influenza associated deaths in a season or year. We calculated influenza-associated deaths for children younger than 5 years for 92 countries with high rates of mortality due to respiratory infection using the same methods. FINDINGS: EMR-contributing countries represented 57% of the global population. The estimated mean annual influenza-associated respiratory EMR ranged from 0.1 to 6.4 per 100 000 individuals for people younger than 65 years, 2.9 to 44.0 per 100 000 individuals for people aged between 65 and 74 years, and 17.9 to 223.5 per 100 000 for people older than 75 years. We estimated that 291 243-645 832 seasonal influenza associated respiratory deaths (4.0-8.8 per 100 000 individuals) occur annually. The highest mortality rates were estimated in sub-Saharan Africa (2.8-16.5 per 100 000 individuals), southeast Asia (3.5-9.2 per 100 000 individuals), and among people aged 75 years or older (51.3-99.4 per 100 000 individuals). For 92 countries, we estimated that among children younger than 5 years, 9243-105 690 influenza-associated respiratory deaths occur annually. INTERPRETATION: These global influenza-associated respiratory mortality estimates are higher than previously reported, suggesting that previous estimates might have underestimated disease burden. The contribution of non-respiratory causes of death to global influenza-associated mortality should be investigated. FUNDING: None. PMID- 29248264 TI - Safety of vaccines that have been kept outside of recommended temperatures: Reports to the Vaccine Adverse Event Reporting System (VAERS), 2008-2012. AB - BACKGROUND: Vaccines should be stored and handled according to manufacturer specifications. Inadequate cold chain management can affect potency; but, limited data exist on adverse events (AE) following administration of vaccines kept outside of recommended temperatures. OBJECTIVE: To describe reports to the Vaccine Adverse Event Reporting System (VAERS) involving vaccines inappropriately stored outside of recommended temperatures and/or exposed to temperatures outside of manufacturer specifications for inappropriate amounts of time. METHODS: We searched the VAERS database (analytic period 2008-2012) for reports describing vaccines kept outside of recommended temperatures. We analyzed reports by vaccine type, length outside of recommended temperature and type of temperature excursion, AE following receipt of potentially compromised vaccine, and reasons for cold chain breakdown. RESULTS: We identified 476 reports of vaccines kept outside of recommended temperatures; 77% described cluster incidents involving multiple patients. The most commonly reported vaccines were quadrivalent human papillomavirus (n = 146, 30%), 23-valent pneumococcal polysaccharide (n = 51, 11%), and measles, mumps, and rubella (n = 45, 9%). Length of time vaccines were kept outside of recommended temperatures ranged from 15 mins to 6 months (median 51 h). Most (n = 458, 96%) reports involved patients who were administered potentially compromised vaccines; AE were reported in 32 (7%), with local reactions (n = 21) most frequent. Two reports described multiple patients contracting diseases they were vaccinated against, indicating possible influenza vaccine failure. Lack of vigilance, inadequate training, and equipment failure were reasons cited for cold chain management breakdowns. CONCLUSIONS: Our review does not indicate any substantial direct health risk from administration of vaccines kept outside of recommended temperatures. However, there are potential costs and risks, including vaccine wastage, possible decreased protection, and patient and parent inconvenience related to revaccination. Maintaining high vigilance, proper staff training, regular equipment maintenance, and having adequate auxiliary power are important components of comprehensive vaccine cold chain management. PMID- 29248265 TI - Predictors of measles vaccination coverage among children 6-59 months of age in the Democratic Republic of the Congo. AB - BACKGROUND: Measles is a significant contributor to child mortality in the Democratic Republic of the Congo (DRC), despite routine immunization programs and supplementary immunization activities (SIA). Further, national immunization coverage levels may hide disparities among certain groups of children, making effective measles control even more challenging. This study describes measles vaccination coverage and reporting methods and identifies predictors of vaccination among children participating in the 2013-2014 DRC Demographic and Health Survey (DHS). METHODS: We examined vaccination coverage of 6947 children aged 6-59 months. A multivariate logistic regression model was used to identify predictors of vaccination among children reporting vaccination via dated card in order to identify least reached children. We also assessed spatial distribution of vaccination report type by rural versus urban residence. RESULTS: Urban children with educated mothers were more likely to be vaccinated (OR = 4.1, 95% CI: 1.6, 10.7) versus children of mothers with no education, as were children in wealthier rural families (OR = 2.9, 95% CI: 1.9, 4.4). At the provincial level, urban areas more frequently reported vaccination via dated card than rural areas. CONCLUSIONS: Results indicate that, while the overall coverage level of 70% is too low, socioeconomic and geographic disparities also exist which could make some children even less likely to be vaccinated. Dated records of measles vaccination must be increased, and groups of children with the greatest need should be targeted. As access to routine vaccination services is limited in DRC, identifying and targeting under-reached children should be a strategic means of increasing country-wide effective measles control. PMID- 29248266 TI - Serotype-specific immune responses to pneumococcal conjugate vaccine among children are significantly correlated by individual: Analysis of randomized controlled trial data. AB - BACKGROUND: The magnitude of an individual's serotype-specific immunoglobulin G (IgG) response to a pneumococcal conjugate vaccine (PCV) has been associated with the vaccine's protective efficacy against carriage of pneumococci of that serotype, though the relationship with other serotypes needs to be understood. METHODS: Using immunogenicity data collected during a trial comparing the 7 valent (PCV7) and 13-valent (PCV13) vaccines, we measured associations between serotype-specific IgG levels, and used multiple regressions to identify demographic predictors of response. RESULTS: Vaccine-induced IgG levels were moderately positively correlated with one another, with pairwise correlation coefficients of 0.40-0.70. Principal component analysis of vaccine-serotype responses yielded one principal component indicating general immune responsiveness, and a second principal component mainly describing responses to serotype 14, which was the least correlated with the other responses. Overall, demographic variables explained only 17.0 and 20.4% of the geometric mean PCV7 and PCV13 responses, respectively. In both groups, older age at the first vaccine dose and shorter time from vaccination to antibody measurement were independently associated with stronger geometric mean responses. DISCUSSION: Improved understanding of the nature and causes of variation in immune response may aid in optimizing vaccination schedules and identifying robust correlates of protection. PMID- 29248267 TI - A combined carrier-adjuvant system of peptide nanofibers and toll-like receptor agonists potentiates robust CD8+ T cell responses. AB - Improving CD8+ T cell responses activated by subunit vaccination is crucial for improving vaccine efficacy and safety. Here we report a carrier-adjuvant system composed of self-assembling peptide nanofibers presenting an immunodominant antigen from herpes simplex virus (HSV) and toll-like receptor (TLR) agonists that induces robust effector and memory CD8+ T cell responses in mice. The effector function of vaccine-induced CD8+ T cells was influenced by the type of TLR agonist. The use of CpG (TLR9 agonist) resulted in significantly greater specific in vivo cytotoxicity and trended towards more cells producing both IFN gamma and TNF-alpha compared to gardiquimod (TLR7 agonist). Prime-boost immunization with peptide nanofibers combined with either adjuvant resulted in development of HSV-specific CD8+ memory T cells further demonstrating the capability of the carrier-adjuvant system to induce strong HSV-specific CD8+ T cell responses. Inclusion of peptide epitope-nanofibers in protein-based subunit vaccines should increase the functional spectrum of the vaccine-elicited immune response and protection. PMID- 29248268 TI - Trifluoroacetic acid: Three times the fluoride, three times the toxicity? AB - Trifluoroacetic acid (TFAA) is a carboxylic acid, similar to acetic acid, used industrially and in laboratories. There is a paucity of data regarding exposure and the concern is that toxicity may mimic that of hydrofluoric acid (HF), causing electrolyte abnormalities, dysrhythmia, and cardiac arrest. We report a case of a 27-year-old male that presents with a dermal exposure to TFAA. His exam was remarkable for a 4% body surface area partial thickness burn to the right forearm. There were no initial electrolyte abnormalities or dysrhythmias and the patient was admitted to telemetry monitoring overnight. Serial laboratories were normal, dysrhythmias did not occur, and patient was ultimately discharged with routine burn care of the wound. Previously reported TFAA exposures are uncommon and tend to be very small body surface area chemical burns without clear systemic toxicity. HF as well as sodium and ammonium bifluorides have been shown to cause clinically significant electrolyte disturbances that can lead to dysrhythmias and fatalities. While TFAA may be structurally similar, it does not appear to have similar toxicity. This is an important difference in presentation and treatment that emergency physicians should be aware of as occupational exposures are likely to present to the emergency department. PMID- 29248269 TI - Uremic pericarditis in patients with End Stage Renal Disease: Prevalence, symptoms and outcome in 2017. AB - : The prevalence of uremic pericarditis (UP) used to range from 3% to 41%. More recently, it has decreased to about 5%-20% and to <5% in the last decades, as hemodialysis techniques have become widely used and dialysis quality improved. The objective of this work is to determine the initial clinical picture and the prognosis of patients presenting End Stage Renal Disease (ESRD) with UP. MATERIALS: This is a retrospective study (May 2015-September 2017). Inclusion criteria targeted patients who had uremic pericarditis defined as pericarditis occurring in a patient with ESRD before initiation of renal replacement therapy, or within eight weeks of its initiation. RESULTS: 16 patients met the inclusion criteria. The median age of patients was 54 [24, 71] years and 56.2% were male. Pericardial effusion was small, moderate and large in 31.2%, 37.6% and 31.2% of cases respectively. One pericardiocentesis was performed in view of a clinical picture of impending cardiac tamponade and three pericardial drainages were performed given presentation of tamponade. Hemodialysis was initiated for all the patients and continued for 2 to 3weeks until complete regression of the pericardial effusion. The mean number of dialysis sessions was 11+/-3.5. One patient died of septic shock that developed three weeks after diagnosis of uremic pericarditis. CONCLUSION: UP is considered a rare but fatal complication of ESRD because of the risk of tamponade and its prognosis remains dependent on early diagnosis and adequate treatment of ESRD. PMID- 29248270 TI - Acute myocardial infarction due to simultaneous spasm of 3 coronary arteries that worsened over time. AB - Coronary artery spasm (CAS) rarely worsens from single-vessel to simultaneous multivessel CAS naturally, and simultaneous multivessel CAS leads to serious conditions such as cardiopulmonary arrest (CPA). A 77-year-old Japanese man who took medications for CAS was transferred to our hospital due to persistent chest pain. On arrival, his vital signs were stable, but his electrocardiogram (ECG) showed ST-segment elevation in leads II, III and aVF. Ventricular fibrillation developed suddenly. Although routine cardiopulmonary resuscitation (CPR) including intravenous administration of epinephrine was performed immediately, he could not be resuscitated. After initiation of percutaneous cardiopulmonary support (PCPS), there was a return of spontaneous circulation. His ECG showed exacerbation of myocardial ischemia with ST-segment elevation in leads I, II, III, aVL, aVF and V3-V6. Emergency coronary angiography revealed severe CAS of the right and left coronary arteries, which was relieved completely by intracoronary administration of nitrates. He was diagnosed with acute myocardial infarction due to simultaneous 3-vessel CAS that progressed over time. About 6h after arrival, he developed hemodynamic instability and died. CAS worsened from single-vessel to simultaneous 3-vessel spasm, and intracoronary administration of nitrates was effective in relieving CAS, which was documented by the ECG and coronary angiogram. Since CAS can progress over time, nitrates must be administered immediately. When CAS leads to CPA, epinephrine may be ineffective in CPR because of its vasoconstrictive effect on coronary arteries; therefore, PCPS should be initiated, and intracoronary nitrates should be administered. PMID- 29248271 TI - In reply: Trauma patients presenting with a King laryngeal tube in place can be safely intubated in the emergency department. PMID- 29248272 TI - Editorial. PMID- 29248273 TI - "1 Voice": Learn urinary tract dilation (UTD) classification to assess fetal & newborn urological ultrasound findings. PMID- 29248274 TI - Expert opinion: "1 Voice": Learn Urinary Tract Dilation (UTD) classification to assess fetal & newborn urological ultrasound findings. PMID- 29248275 TI - Featuring: Comparing inpatient versus outpatient bowel preparation in children and adolescents undergoing appendicovesicostomy. PMID- 29248276 TI - Pre-operative risk factors for stomal stenosis with Malone antegrade continence enema procedures. AB - INTRODUCTION: The Malone antegrade continence enema (MACE) procedure remains an effective tool in providing independence to patients with refractory constipation. Appendiceal, ileal and colonic segments are all used depending upon the patient's individual anatomy and surgeon's preference. Unfortunately, MACE stomal stenosis (SS) remains a frustrating complication. It was hypothesized that SS is associated with the type of efferent limb used for MACE construction. OBJECTIVE: To perform a retrospective risk analysis of the pre-operative factors that correlated with postoperative stomal stenosis. MATERIALS AND METHODS: The study reviewed 39 consecutive patients treated with MACE by a single surgeon at the present institution. Collected data included: the type of channel construction, stoma site, pre-operative body mass index (BMI) z-score, pre operative diagnosis, and development of SS. Stomal stenosis was defined as a documented inability to catheterize, requirement of a Chait tube, or a subsequent stomal revision. An odds ratio (OR) analysis was performed to evaluate the association with the development of SS. RESULTS: Stomal stenosis developed in 19 patients (49%) with an average follow-up of 4.7 years. The majority of patients had a diagnosis of myelomeningocele (90%), and there was no significant difference in gender distribution (54% males, 46% females). The distribution types of MACE efferent limbs consisted of appendicocecostomy in 20 (51%), cecal wall flap in 16 (41%) and ileocecostomy in three patients (8%). Neither type of efferent limb, nor stomal location were significant predictors of postoperative SS. Pre-operative obesity (BMI >=95%), however, demonstrated a significant risk of SS compared to non-obese patients (OR 4.44, 95% CI 1.08-18.4, P = 0.04). DISCUSSION: This was a single-institution study of a relatively small number of patients. However, examining consecutive patients with a common surgeon can minimize technique variability. Also, the rates of stenosis in this cohort were higher than most. This may have been due to a more broad definition (unable to catheterize). These findings complement recent literature showing an increased complication rate for the obese pediatric patient. CONCLUSION: Stomal stenosis remains a frustrating complication following creation of the MACE stoma. In the present series, neither a cecal wall flap, nor the stomal site location contributed to SS. Obesity was the only identified statistically significant risk factor that led to SS. PMID- 29248277 TI - Interactions between surfactants and hydrolytic enzymes. AB - Hydrolytic enzymes are combined with surfactants in many types of formulations, for instance detergents and personal care products. If the surfactant interacts with the enzyme there may be conformational changes that eventually lead to loss of the enzymatic activity. From a practical point of view it is important to understand the nature and magnitude of these interactions. After an introduction of the topic the review briefly discusses enzyme catalyzed reactions where surfactants are substrates for the enzyme. The rest of the review relates to associations between surfactants and hydrolytic enzymes without the surfactant being a substrate in the reaction. A discussion about general principles for such interactions is followed by a survey of the relevant literature related to four important types of hydrolytic enzymes: lipases, proteases, amylases and cellulases. It is shown in the review that the effect exerted by the surfactant differs between the different types of enzymes; it is therefore difficult to make general statements about which surfactants are most detrimental to the activity of hydrolytic enzymes. However, as a general rule nonionic surfactants can be regarded as more benign to an enzyme than anionic and cationic surfactants. This difference can be ascribed to the difference in binding mode. Whereas a nonionic surfactant only binds to the enzyme through hydrophobic interactions, an ionic surfactant can bind by a combination of electrostatic attraction and hydrophobic interaction. This latter type of binding can be strong and lead to conformational changes already at very low surfactant concentration, often far below its critical micelle concentration. PMID- 29248279 TI - Does a third arterial conduit to the right coronary circulation improve survival? AB - BACKGROUND: The long-term benefits of a third arterial conduit to the right circulation in triple-vessel disease remain debatable. This retrospective, single center, propensity-matched study investigates the impact of a third arterial conduit to the right circulation on early and intermediate survival after coronary artery bypass grafting. METHODS: Data were retrospectively collected from 2004 to 2014 for all surgical revascularizations for triple-vessel disease with at least 2 arterial conduits to the left circulation and a third arterial or venous conduit to the right circulation. A total of 167 pairs were propensity matched to arterial versus venous third conduit to right circulation. Hazard functions were obtained with Cox multivariate regression and Kaplan-Meier survival curves were compared between the matched cohorts. RESULTS: Extracardiac arteriopathy, logistic euroSCORE, and left main stem disease were significant predictors of adverse survival. A third arterial conduit to the right circulation was not a significant predictor of improved survival in multivariate analysis (HR, 0.72; 95% CI, 0.34-1.55; P = .411). 30-day mortality was 0.6% in both groups. There was no significant difference in early or intermediate survival in the propensity-matched groups (venous vs arterial, 99.2% vs 99.2%; P = 1.000 at 1 year; 85.2% vs 88.8%; P = .248 at 5 years and 69.2% vs 88.8%; P = .297 at 7 years) CONCLUSIONS: The use of a third arterial versus a venous conduit to the right circulation does not improve early or intermediate survival up to 7 years in triple-vessel coronary artery disease in this study. Longer follow-up and larger cohorts may be needed for differences to emerge. PMID- 29248278 TI - Hospital Emergency Department Lethal Means Counseling for Suicidal Patients. AB - INTRODUCTION: Lethal means counseling of suicidal individuals in emergency departments has the potential to reduce suicide. This study examines the provision of lethal means counseling and the presence of written protocols in a region with high rates of both firearm ownership and suicide. METHODS: In 2015 2016, emergency department nurse managers in hospital-based emergency departments throughout eight states were surveyed using an 80-item survey developed through qualitative interviews and pilot testing. Questions focused on discharge counseling with suicidal patients and the presence of written protocols. Using survey weights to adjust for nonresponse, relationships of protocols with counseling practices were examined. RESULTS: Data were obtained from 52.3% of all 363 eligible hospital emergency departments in the region. Among facilities that discharge suicidal patients, 79.7% (95% CI=75.0%, 84.4%) reported asking about access to firearms and 68.9% (95% CI=62.9%, 74.8%) counsel about safe storage when patients reported access. Forty-four percent of emergency departments reported having written protocols for lethal means counseling. Presence of written protocols was associated with a higher rate of counseling for all suicidal patients even if they were not planning to use a gun (45.0% [95% CI=33.4%, 56.7%] in hospitals with protocols vs 21.5% [95% CI=14.9%, 29.0%] in facilities without protocols). CONCLUSIONS: There are significant gaps in attention to lethal means counseling in emergency departments. This signals an opportunity to increase consistency and thoroughness of care for suicidal patients in the emergency department and for leadership from key professional organizations to advocate for protocols. PMID- 29248280 TI - Finding value in a common medical misnomer: The importance of identifying a bovine arch in patients with aortic coarctation. PMID- 29248281 TI - Repair of a quadricuspid truncal valve by tricuspidization and reconstruction of right ventricular outflow tract with the excised truncal cusp. AB - OBJECTIVE: Quadricuspid truncal valves are susceptible to regurgitation, and tricuspid configuration is considered more durable after repairing the truncal valve. We report a new method by excising the excessive truncal cuspid to reconstruct a new competent aortic valve. METHODS: Bilateral pulmonary banding failed to stabilize a 4-month-old baby with type I truncus arteriosus and quadricuspid truncal valve with severe regurgitation, so surgery was performed. The aorta was transected, and the pulmonary arteries was separated from the aorta. There was an excessive cusp between the right coronary and left coronary cusp. A transannular incision was carried into the right ventricular outflow tract through the left border of the right coronary cusp. We performed truncal valve repair by translocating the excessive cusp, its annulus, and its wall to the right ventricular outflow tract side and reconstructing the neoaortic valve to tricuspid. Ventricular septal defect was repair through a right ventricular outflow tract approach. The floor of the right ventricular outflow tract was made from the excised cusp, including its wall and the resected posterior aortic wall. Then the anterior wall was reconstructed with bovine pericardial patch with a 19 mm porcine valve. RESULTS: Postoperative echocardiography confirmed a tricuspid neo-aortic valve with trivial aortic regurgitation, no residual ventricular septal defect, and a patent right ventricular outflow tract. CONCLUSIONS: We present the surgical technique to repair a quadricuspid truncal valve insufficiency by using the excessive anterior cusp and its pedicled flap for reconstruction of the pulmonary pathway and restoration of the tricuspid truncal valve. PMID- 29248283 TI - Discussion. PMID- 29248282 TI - Extracorporeal life support as a bridge to lung transplantation-experience of a high-volume transplant center. AB - OBJECTIVES: Extracorporeal life support (ECLS) is increasingly used to bridge deteriorating patients awaiting lung transplantation (LTx), however, few systematic descriptions of this practice exist. We therefore aimed to review our institutional experience over the past 10 years. METHODS: In this case series, we included all adults who received ECLS with the intent to bridge to LTx. Data were retrieved from patient charts and our institutional ECLS and transplant databases. RESULTS: Between January 2006 and September 2016, 1111 LTx were performed in our institution. ECLS was used in 71 adults with the intention to bridge to LTx; of these, 11 (16%) were bridged to retransplantation. The median duration of ECLS before LTx was 10 days (range, 0-95). We used a single dual lumen venous cannula in 23 patients (32%). Nine of 13 patients (69%) with pulmonary hypertension were bridged by central pulmonary artery to left atrium Novalung. Twenty-five patients (35%) were extubated while on ECLS and 26 patients (37%) were mobilized. Sixty-three patients (89%) survived to LTx. Survival by intention to treat was 66% (1 year), 58% (3 years) and 48% (5 years). Survival was significantly shorter in patients undergoing ECLS bridge to retransplantation compared with first LTx (median survival, 15 months (95% CI, 0-31) versus 60 months (95% CI, 37-83); P = .041). CONCLUSIONS: In our center experience, ECLS bridge to first lung transplant leads to good short-term and long-term outcomes in carefully selected patients. In contrast, our data suggest that ECLS as a bridge to retransplantation should be used with caution. PMID- 29248284 TI - Cost of individual complications following coronary artery bypass grafting. AB - OBJECTIVE: The financial implications of postoperative complications in cardiac surgery remain poorly understood. The purpose of this study was to define the cost of surgery without complications and demonstrate the incremental cost of each complication. METHODS: All patients undergoing isolated coronary artery bypass grafting (CABG) were evaluated (2006-2015) from a statewide Society of Thoracic Surgeons database collaborative (N = 36,588). Patients were stratified by presence of postoperative complications, including major morbidities as defined by the Society of Thoracic Surgeons (ie, prolonged ventilation, renal failure, reoperation, stroke, and deep sternal wound infection). Hierarchical modeling was used to identify the independent inflation-adjusted cost of each complication while controlling for hospital variation and time. RESULTS: The median age was 64 years, 74.3% were men, and average predicted risk of mortality was 1.9%. A total of 24,738 (67.7%) patients experienced no complications at an average cost of $36,580. Each complication independently increases the cost of care and resulted in an exponential increase in cost. After accounting for incidence and incremental costs, institutions in our collaborative have spent an estimated $59.1 million on prolonged ventilation, $8.3 million on renal failure, $7.6 million on reoperation, $3.3 million on stroke, and $256,000 on deep sternal wound infections over the past 10 years. CONCLUSIONS: The average cost of CABG without complication was $36,580. Each additional major complication resulted in an exponential increase in cost. Over the past 10 years, the total cost of complications after isolated CABG was $78.6 million, emphasizing the importance of quality improvement projects to contain costs. PMID- 29248285 TI - Discussion. PMID- 29248287 TI - Bicuspid aortic valve with aortic aneurysms. PMID- 29248286 TI - Perioperative evaluation of regional aortic wall shear stress patterns in patients undergoing aortic valve and/or proximal thoracic aortic replacement. AB - OBJECTIVES: To assess in patients with aortopathy perioperative changes in thoracic aortic wall shear stress (WSS), which is known to affect arterial remodeling, and the effects of specific surgical interventions. METHODS: Presurgical and postsurgical aortic 4D flow MRI were performed in 33 patients with aortopathy (54 +/- 14 years; 5 women; sinus of Valsalva (d_SOV)/midascending aortic (d_MAA) diameters = 44 +/- 5/45 +/- 6 mm) scheduled for aortic valve (AVR) and/or root (ARR) replacement. Control patients with aortopathy who did not have surgery were matched for age, sex, body size, and d_MAA (n = 20: 52 +/- 14 years; 3 women; d_SOV/d_MAA = 42 +/- 4/42 +/- 4 mm). Regional aortic 3D systolic peak WSS was calculated. An atlas of WSS normal values was used to quantify the percentage of at-risk tissue area with abnormally high WSS, excluding the area to be resected/graft. RESULTS: Peak WSS and at-risk area showed low interobserver variability (<=0.09 [-0.3; 0.5] Pa and 1.1% [-7%; 9%], respectively). In control patients, WSS was stable over time (follow-up-baseline differences <=0.02 Pa and 0.0%, respectively). Proximal aortic WSS decreased after AVR (n = 5; peak WSS difference <=-0.41 Pa and at-risk area <=-10%, P < .05 vs controls). WSS was increased after ARR in regions distal to the graft (peak WSS difference >=0.16 Pa and at-risk area >=4%, P < .05 vs AVR). Follow-up duration had no significant effects on these WSS changes, except when comparing ascending aortic peak WSS between ARR and AVR (P = .006). CONCLUSIONS: Serial perioperative 4D flow MRI investigations showed distinct patterns of postsurgical changes in aortic WSS, which included both reductions and translocations. Larger longitudinal studies are warranted to validate these findings with clinical outcomes and prediction of risk of future aortic events. PMID- 29248288 TI - Two incisions are better than one. PMID- 29248289 TI - Is hemodynamic transesophageal echocardiography needed for patients with left ventricular assist device? AB - BACKGROUND: Interventions in patients with a left ventricular assist device (LVAD) in the intensive care unit (ICU) are typically performed based on the results of conventional monitoring, such as vital signs and Swan-Ganz catheter (SGC) and LVAD parameters. These variables might not always accurately reflect a patient's cardiac function, volume status, and interventricular septal configuration, however. To assess the accuracy of standard monitoring, we performed routine continuous hemodynamic transesophageal echocardiography (hTEE) to evaluate cardiac function, volume status, and septal position. METHODS: Between 2011 and 2015, 93 HeartMate II LVADs were implanted. The study group comprised 30 patients with an SGC in place who were monitored routinely by hTEE in the ICU every 1 to 3 hours until extubation. A total of 147 hTEE studies were analyzed retrospectively to observe differences between conventional monitoring and hTEE. RESULTS: Among the 30 patients studied, 26 (87%) had at least 1 disagreement between conventional monitoring and hTEE findings. In 22 patients (73%), at least 1 of the hTEE studies was abnormal whereas conventional parameters were normal. Abnormal hTEE findings included a shift in the interventricular septum in 19 patients (63%), abnormal ventricular volume status in 22 patients (73%), and right ventricular failure in 9 patients (30%). Based on conventional monitoring, none of the patients required an LVAD speed change, whereas hTEE showed that 14 patients (47%) needed an LVAD speed adjustment. CONCLUSIONS: Conventional monitoring in the ICU might not provide an accurate representation of cardiac function, ventricular volume status, or septal position in patients with LVAD. Continuous monitoring with hTEE in patients with an LVAD may help guide optimal intervention in the ICU setting during the early postoperative period. PMID- 29248290 TI - Discussion. PMID- 29248291 TI - Be less invasive: Please, turn right! PMID- 29248293 TI - A heartfelt goodbye and a continuing mission. PMID- 29248292 TI - Long-term outcomes after near-infrared sentinel lymph node mapping in non-small cell lung cancer. AB - OBJECTIVE: To report the first analysis of long-term outcomes using near-infrared (NIR) image-guided sentinel lymph node (SLN) mapping in non-small cell lung cancer (NSCLC). METHODS: Retrospective analysis of patients with NSCLC enrolled in 2 prospective phase 1 NIR-guided SLN mapping trials, including an indocyanine green (ICG) dose-escalation trial, was performed. All patients underwent NIR imaging for SLN identification followed by multistation mediastinal lymph node sampling (MLNS) and pathologic assessment. Disease-free (DFS) and overall survival (OS) were compared between patients with NIR+ SLN (SLN group) and those without (non-SLN group). RESULTS: SLN detection, recurrence, DFS, and OS were assessed in 42 patients with NSCLC who underwent intraoperative peritumoral ICG injection, NIR imaging, and MLNS. NIR+ SLNs were identified in 23 patients (SLN group), whereas SLNs were not identified in 19 patients enrolled before ICG dose and camera optimization (non-SLN group). Median follow-up was 44.5 months. Pathology from NIR+ SLNs was concordant with overall nodal status in all 23 patients. Sixteen patients with SLN were deemed pN0 and no recurrences were, whereas 4 of 15 pN0 non-SLN patients developed nodal or distant recurrent disease. Comparing SLN versus non-SLN pN0 patients, the probability of 5-year OS is 100% versus 70.0% (P = .062) and 5-year DFS is statistically significantly improved at 100% versus 66.1% (P = .036), respectively. Among the 11 pN+ patients, 7 were in the SLN group, with >40% showing metastases in the SLN alone. CONCLUSIONS: Patients with pN0 SLNs showed favorable disease-free and overall survival. This preliminary review of NIR SLN mapping in NSCLC suggests that pN0 SLNs may better represent true N0 status. A larger clinical trial is planned to validate these findings. PMID- 29248294 TI - Phenotyping of PER3 variants reveals widespread effects on circadian preference, sleep regulation, and health. AB - Period3 (Per3) is one of the most robustly rhythmic genes in humans and animals. It plays a significant role in temporal organisation in peripheral tissues. The effects of PER3 variants on many phenotypes have been investigated in targeted and genome-wide studies. PER3 variants, especially the human variable number tandem repeat (VNTR), associate with diurnal preference, mental disorders, non visual responses to light, brain and cognitive responses to sleep loss/circadian misalignment. Introducing the VNTR into mice alters responses to sleep loss and expression of sleep homeostasis-related genes. Several studies were limited in size and some findings were not replicated. Nevertheless, the data indicate a significant contribution of PER3 to sleep and circadian phenotypes and diseases, which may be connected by common pathways. Thus, PER3-dependent altered light sensitivity could relate to high retinal PER3 expression and may contribute to altered brain response to light, diurnal preference and seasonal mood. Altered cognitive responses during sleep loss/circadian misalignment and changes to slow wave sleep may relate to changes in wake/activity-dependent patterns of hypothalamic gene expression involved in sleep homeostasis and neural network plasticity. Comprehensive characterisation of effects of clock gene variants may provide new insights into the role of circadian processes in health and disease. PMID- 29248296 TI - Synthesis and biological evaluation of 4beta-(thiazol-2-yl)amino-4'-O-demethyl-4 deoxypodophyllotoxins as topoisomerase-II inhibitors. AB - A series of 4beta-(thiazol-2-yl)amino-4'-O-demethyl-4-deoxypodophyllotoxins were synthesized, and their cytotoxicities were evaluated against four human cancer cell lines (A549, HepG2, HeLa, and LOVO cells) and normal human diploid fibroblast line WI-38. Some of the compounds exhibited promising antitumor activity and less toxicity than the anticancer drug etoposide. Among them, compounds 15 and 17 were found to be the most potent synthetic derivatives as topo-II inhibitors, and induced DNA double-strand breaks via the p73/ATM pathway as well as the H2AX phosphorylation in A549 cells. These compounds also arrested A549 cells cycle in G2/M phase by regulating cyclinB1/cdc2(p34). Taken together, these results show that a series of compounds are potential anticancer agents. PMID- 29248295 TI - NOTA analogue: A first dithiocarbamate inhibitor of metallo-beta-lactamases. AB - The emergence of antibiotic drug (like carbapenem) resistance is being a global crisis. Among those resistance factors of the beta-lactam antibiotics, the metallo-beta-lactamases (MBLs) is one of the most important reasons. In this paper, a series of cyclic dithiocarbamate compounds were synthesized and their inhibition activities against MBLs were initially tested combined with meropenem (MEM) by in vitro antibacterial efficacy tests. Sodium 1,4,7-triazonane-1,4,7 tris(carboxylodithioate) (compound 5) was identified as the most active molecule to restore the activity of MEM. Further anti-bacterial effectiveness assessment, compound 5 restored the activity of MEM against Escherichia coli, Citrobacter freundii, Proteus mirabilis and Klebsiella pneumonia, which carried resistance genes of blaNDM-1. The compound 5 was non-hemolytic, even at a concentration of 1000 ug/mL. This compound was low toxic toward mammalian cells, which was confirmed by fluorescence microscopy image and the inhibition rate of HeLa cells. The Ki value of compounds 5 against NDM-1 MBL was 5.63 +/- 1.27 MUM. Zinc ion sensitivity experiments showed that the inhibitory effect of compound 5 as a MBLs inhibitor was influenced by zinc ion. The results of the bactericidal kinetics displayed that compound 5 as an adjuvant assisted MEM to kill all bacteria. These data validated that this NOTA dithiocarbamate analogue is a good inhibitor of MBLs. PMID- 29248297 TI - Facile conversion of ATP-binding RNA aptamer to quencher-free molecular aptamer beacon. AB - We have developed RNA-based quencher-free molecular aptamer beacons (RNA-based QF MABs) for the detection of ATP, taking advantage of the conformational changes associated with ATP binding to the ATP-binding RNA aptamer. The RNA aptamer, with its well-defined structure, was readily converted to the fluorescence sensors by incorporating a fluorophore into the loop region of the hairpin structure. These RNA-based QF-MABs exhibited fluorescence signals in the presence of ATP relative to their low background signals in the absence of ATP. The fluorescence emission intensity increased upon formation of a RNA-based QF-MAB.ATP complex. PMID- 29248298 TI - Investigation of copper-free alkyne/azide 1,3-dipolar cycloadditions using microwave irradiation. AB - The prevalence of 1,3-dipolar cycloadditions of azides and alkynes within both biology and chemistry highlights the utility of these reactions. However, the use of a copper catalyst can be prohibitive to some applications. Consequently, we have optimized a copper-free microwave-assisted reaction to alleviate the necessity for the copper catalyst. A small array of triazoles was prepared to examine the scope of this approach, and the methodology was translated to a protein context through the use of unnatural amino acids to demonstrate one of the first microwave-mediated bioconjugations involving a full length protein. PMID- 29248299 TI - Discovery of 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5 (trifluoromethyl)pyridin-2(1H)-one, an orally active multi-target agent for the treatment of diabetic nephropathy. AB - Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC50 of 90MUM in NIH3T3 cell lines, t1/2 of 4.89+/-1.33h in male rats and LD50>2000mg/kg in mice, has been advanced to preclinical studies as an oral treatment for DN. PMID- 29248301 TI - A prognostic model based on lymph node metastatic ratio for predicting survival outcome in gastric cancer patients with N3b subclassification. AB - BACKGROUND: Determining the survival outcome for gastric cancer patients with metastases to more than 15 regional lymph nodes is difficult. This study aims to develop a lymph node metastatic ratio (LNR)-based prognostic model to predict the survival outcome after D2 surgery in such patient groups. METHODS: Our study retrospectively enrolled 139 gastric cancer patients with metastases to more than 15 regional lymph nodes who underwent D2 surgery between 2007 and 2014. Clinicopathologic variables to predict overall survival (OS) using multivariate Cox regression were selected to create a prognostic model. RESULTS: The prognostic model for predicting OS was developed based on five independent factors, namely, T-classification (T2 or T3 vs. T4), LNR (<0.80 vs. >=0.80), carcinoembryonic antigen level (<5 vs. >=5 ng/ml), Eastern Cooperative Oncology Group performance scale (scale 0-1 vs. >=2), and adjuvant chemotherapy (yes vs. no). Using the prognostic score, patients were stratified into good, intermediate, and poor prognostic groups. The median OS in the good, intermediate, and poor prognostic risk groups was 32.0 months (95% confidence interval [CI]: 22.3-41.7), 12.4 months (95% CI: 8.5-16.3), and 5.4 months (95% CI: 2.1-8.7), respectively. The c-index of the prognostic model was 0.79 (95% CI: 0.71-0.87). CONCLUSION: This study developed an accurate LNR-based prognostic model for predicting the survival outcome after D2 surgery in gastric cancer patients with metastasis to more than 15 regional lymph nodes. This model might assist clinicians in prognostic stratification of such patients and convince eligible patients to receive adjuvant chemotherapy. PMID- 29248300 TI - Review of four major distinct types of human phospholipase A2. AB - The phospholipase A2 superfamily of enzymes plays a significant role in the development and progression of numerous inflammatory diseases. Through their catalytic action on membrane phospholipids, phospholipases are the upstream regulators of the eicosanoid pathway releasing free fatty acids for cyclooxygenases, lipoxygenases, and cytochrome P450 enzymes which produce various well-known inflammatory mediators including leukotrienes, thromboxanes and prostaglandins. Elucidating the association of phospholipases A2 with the membrane, the extraction and binding of phospholipid substrates, and their interactions with small-molecule inhibitors is crucial for the development of new anti-inflammatory therapeutics. Studying phospholipases has been challenging because they act on the surface of cellular membranes and micelles. Multidisciplinary approaches including hydrogen/deuterium exchange mass spectrometry, molecular dynamics simulations, and other computer-aided drug design techniques have been successfully employed by our laboratory to study interactions of phospholipases with membranes, phospholipid substrates and inhibitors. This review summarizes the application of these techniques to study four human recombinant phospholipases A2. PMID- 29248303 TI - Why Is a Psychologist Interested in the Kidneys? PMID- 29248302 TI - Nursing Diagnosis of Neonatal Jaundice: Study of Clinical Indicators. AB - PURPOSE: This study aimed to identify the defining characteristics of, and examine their association with, the nursing diagnosis (ND) of Neonatal Jaundice (00194) in sample of hospitalized newborns. DESIGN AND METHODS: A cross-sectional study developed with 100 newborns aged between 24h and ten days. Data collection was performed in a public hospital of tertiary health care between March and June of 2016. RESULTS: The ND of Neonatal jaundice was present in 31% of the sample. The most frequent defining characteristics were yellow-orange skin color (65%) and abnormal blood profile (75%). Yellow mucous membranes, yellow-orange skin color and bruised skin showed statistically significant sensitivity and specificity. Yellow mucous membranes, yellow sclera and yellow-orange skin color were statistically associated with Neonatal jaundice. Yellow mucous membranes showed the best diagnostic accuracy measurements. CONCLUSIONS: The clinical indicators that best predicted and increased the probability of developing jaundice were identified. PRACTICE IMPLICATIONS: These clinical indicators increase the ability of nurses to clinically infer nursing diagnoses. This allows nurses to identify signs and symptoms of health conditions in a sensible and definitive manner, decreasing the possibility of errors. PMID- 29248304 TI - Glucose-6-Phosphate Dehydrogenase Deficiency Mimicking Atypical Hemolytic Uremic Syndrome. AB - A 4-year-old boy presented with nonimmune hemolysis, thrombocytopenia, and acute kidney injury. Investigations for an underlying cause failed to identify a definitive cause and a putative diagnosis of complement-mediated atypical hemolytic uremic syndrome (aHUS) was made. The patient was started initially on plasma exchange and subsequently eculizumab therapy, after which his kidney function rapidly improved. While on eculizumab therapy, despite adequate complement blockade, he presented 2 more times with hemolytic anemia and thrombocytopenia, but without renal involvement. Genetic analysis did not uncover a mutation in any known aHUS gene (CFH, CFI, CFB, C3, CD46, THBD, INF2, and DGKE) and anti-factor H antibodies were undetectable. Whole-exome sequencing was undertaken to identify a cause for the eculizumab resistance. This revealed a pathogenic variant in G6PD (glucose-6-phosphate dehydrogenase), which was confirmed by functional analysis demonstrating decreased erythrocyte G6PD activity. Eculizumab therapy was withdrawn. Complement-mediated aHUS is a diagnosis of exclusion and this case highlights the diagnostic difficulty that remains without an immediately available biomarker for confirmation. This case of G6PD deficiency presented with a phenotype clinically indistinguishable from complement-mediated aHUS. We recommend that G6PD deficiency be included in the differential diagnosis of patients presenting with aHUS and suggest measuring erythrocyte G6PD concentrations in these patients. PMID- 29248305 TI - State-of-the-art transforaminal percutaneous endoscopic lumbar surgery under local anesthesia: Discectomy, foraminoplasty, and ventral facetectomy. AB - Transforaminal (TF) percutaneous endoscopic surgery for the lumbar spine under the local anesthesia was initiated in 2003 in Japan. Since it requires only an 8 mm skin incision and damage of the paravertebral muscles would be minimum, it would be the least invasive spinal surgery at present. At the beginning, the technique was used for discectomy; thus, the procedure was called PELD (percutaneous endoscopic lumbar discectomy). TF approach can be done under the local anesthesia, there are great benefits. During the surgery patients would be in awake and aware condition; thus, severe nerve root damage can be avoided. Furthermore, the procedure is possible for the elderly patients with poor general condition, which does not allow the general anesthesia. Historically, the technique was first applied for the herniated nucleus pulposus. Then, foraminoplasty, which is the enlargement surgery of the narrow foramen, became possible thanks to the development of the high speed drill. It was called the percutaneous endoscopic lumbar foraminoplasty (PELF). More recently, this technique was applied to decompress the lateral recess stenosis, and the technique was named percutaneous endoscopic ventral facetectomy (PEVF). In this review article, we explain in detail the development of the surgical technique of with time with showing our typical cases. PMID- 29248306 TI - Mental toughness and behavioural perseverance: A conceptual replication and extension. AB - OBJECTIVES: The purpose of this study was to conduct a conceptual replication of the proposition that mental toughness is associated positively with behavioural perseverance. DESIGN: Repeated-measures design. METHODS: In total, 38 male Australian rules footballers took part in this study (age, 21+/-3 y; mass, 82.7+/ 11.0kg; height, 1.84+/-.07m; football experience, 13+/-4 y). Participants self reported mental toughness approximately one week prior to their first testing session where we assessed their aerobic capacity via the measurement of peak oxygen consumption (VO2peak). Approximately one week later, participants completed a 20m shuttle run test (MST). The final testing session took place approximately one week later, where participants completed a simulated team game circuit (STGC; 60min) to simulate game-relevant level of fatigue, which was followed immediately by a 20m MST. RESULTS: Mental toughness was a salient determinant of the variation in behavioural perseverance under typical circumstances, when prior knowledge from past research was incorporated directly into the estimation process. However, the positive association between mental toughness and behavioural perseverance did not generalise to a performance context in which participants were fatigued. CONCLUSIONS: The results of the current study suggest that mental toughness represents a salient psychological correlate of behavioural perseverance in a discrete physical task that taxes the aerobic energy system in some but not all situations. When fatigued, the effect of mental toughness is outweighed by greater underlying fitness. PMID- 29248307 TI - Relative dearth of 'sex differences' research in sports medicine. PMID- 29248308 TI - Testosterone prior to hypospadias repair: No clear-cut benefit or reassurance regarding long-term safety. PMID- 29248311 TI - A Cost-Effectiveness Analysis of Contact X-ray Brachytherapy for the Treatment of Patients with Rectal Cancer Following a Partial Response to Chemoradiotherapy. AB - AIMS: Following chemoradiotherapy in patients with rectal cancer, the addition of contact X-ray brachytherapy (CXB) in partial responders might increase the proportion of patients with a clinical complete response (cCR) and who are thus suitable for watch and wait management. However, the long-term cost-effectiveness of this approach has not been evaluated. MATERIALS AND METHODS: Decision analytical modelling and a Markov simulation were used to compare long-term costs, quality-adjusted life years (QALYs) and cost-effectiveness from a third party payer (National Health Service) perspective for treatment strategies after chemoradiotherapy; watch and wait with CXB when a cCR was not initially achieved after external beam radiotherapy (EBRT) (WWCXB), watch and wait with EBRT alone (WWEBRT) and radical surgery for all patients. The effect of uncertainty in model parameters and patient demographics was investigated. RESULTS: WWCXB had a higher QALY payoff than both radical surgery and WWEBRT and was less costly in most scenarios and demographic cohorts. In all plausible scenarios, WWCXB was the most cost-effective, at a threshold of L20 000/QALY. This finding was insensitive to uncertainty associated with model parameters. CONCLUSIONS: WWCXB is likely to be cost-effective compared with both WWEBRT alone and radical surgery. These findings support the use of CXB boost as an adjunct to a watch and wait strategy. PMID- 29248312 TI - Stress prevalence and stressors among anaesthesiology and intensive care unit workers: A multicentre survey study. AB - BACKGROUND: High stress levels have been commonly reported among ICU workers. Currently, anaesthesiology is safer for the patient but more stressful for the staff working in this branch of medicine. ICU and anaesthesiology personnel are prone to stress because of the specific character of their work. OBJECTIVES: Our objectives were to assess stress prevalence among anaesthesiology and ICU workers to compare this stress prevalence in relation to professional groups, sex, job seniority, and type of hospital and describe the importance of major stressors at work. METHODS: The ICU and anaesthesiology workers of 15 randomly selected Polish hospitals were surveyed. To assess stress prevalence, the Perceived Stress Scale (PSS-10) was used. The analysis included 544 surveys. RESULTS: The examined population was divided into two groups. Group N consisted of 406 nurses (74.60%) and group P of 138 physicians (25.40%). The mean result in the PSS-10 scale for the N group was 19.00 and for the P group 17.00. Both group results were related to a 6 sten score, which implied a medium level of stress. In the N group, the PSS-10 results were significantly higher than in the P group. Women showed higher levels of stress than men. CONCLUSIONS: Stress levels among ICU and anaesthesiology personnel were of a medium range. Nurses showed significantly higher levels of stress than physicians. Female personnel showed higher levels of stress than male personnel. Age, job seniority and type of hospital did not have an influence on stress levels. The most stressful circumstances for anaesthesiology and ICU personnel included night shifts and duty overload. PMID- 29248310 TI - When Clarity Is Crucial: Regulating Ocular Surface Immunity. AB - The ocular surface is a unique mucosal immune compartment in which anatomical, physiological, and immunological features act in concert to foster a particularly tolerant microenvironment. These mechanisms are vital to the functional competence of the eye, a fact underscored by the devastating toll of excessive inflammation at the cornea - blindness. Recent data have elucidated the contributions of specific anatomical components, immune cells, and soluble immunoregulatory factors in promoting homeostasis at the ocular surface. We highlight research trends at this distinctive mucosal barrier and identify crucial gaps in our current knowledge. PMID- 29248309 TI - Corrigendum to "A European randomised controlled trial of the addition of etoposide to standard vincristine and carboplatin induction as part of an 18 month treatment programme for childhood (<=16 years) low grade glioma - A final report" [Eur J of Canc (2017) 206-225]. PMID- 29248314 TI - The effect of rebamipide ophthalmic suspension on ocular surface mucins in soft contact lens wearers. AB - PURPOSE: To evaluate the changes in ocular surface mucins with 2%rebamipide ophthalmic suspension treatment in soft contact lens (SCL) wearers. Rebamipide suspension is a mucin secretagogue approved for the treatment of dry eye syndrome in Japan. In this study, the fluorescence intensity of wheat germ agglutinin conjugate of fluorescein (F-WGA) was used as a marker of membrane-associated mucins, and sialic acid concentration in tear fluids as a marker of secreted mucins. METHODS: Thirty-two eyes of 16 SCL wearers with discomfort were treated with rebamipide suspension at a dose of one drop in each eye four times daily for two weeks. The parameters of clinical efficacy were tear break-up time, fluorescein staining scores for the cornea and conjunctiva, and Schirmer test values. Fluorescence intensities in the central cornea were measured by fluorophotometry after the application of 5% F-WGA solution. Tears collected by Schirmer test strips were analyzed by high-performance liquid chromatography, and the concentrations of sialic acid, total protein, and the four major tear proteins, namely secretory IgA, lactoferrin, lipocalin-1, and lysozyme were measured. RESULTS: Significant increases in F-WGA fluorescence intensities (p < 0.005) were seen in the corneal surfaces. Sialic acid concentrations increased over time; however, the differences were not statistically significant. Except for a slight increase in kerato-conjunctival staining scores (p < 0.05) and secretory IgA (p < 0.05), no other significant differences were seen among clinical parameters or tear proteins. CONCLUSIONS: Topical application of rebamipide suspension significantly increased F-WGA intensity, a marker of membrane-associated mucins in SCL wearers. PMID- 29248313 TI - Healthcare-associated respiratory infections in intensive care unit can be reduced by a hand hygiene program: A multicenter study. AB - PURPOSE: Healthcare-associated respiratory tract infections are common and markedly affect the quality of life and mortality, as well as increasing costs for health systems due to prolonged hospitalisation. This study aimed to assess the change in both level and trend of respiratory tract infections after a specific hand hygiene program for intensive care unit (ICU) staff. MATERIALS AND METHODS: The infection data collection was carried out from January 2013 to August 2014. The hand hygiene program started in December 2013. To analyse the change in level and trend of infections after the intervention, the Interrupted Time Series method was used. Chi-square test was used to compare the incidence of respiratory tract infections before and after the intervention. RESULTS: A total of 825 patients were hospitalised in three Italian ICUs. The infection level was significantly decreased by 36.3 infections per 1000 device-days after the intervention. The infection trend was also decreased of about 1 infection per month. CONCLUSIONS: After the hand hygiene program a decreased level of infection was found. Continuous performance feedback should be provided to promote a long term adherence to the guidelines. Organisational and individual risk factors must be individuated and correctly managed to increase quality of practice. PMID- 29248315 TI - On-eye breakage and recovery of mini-scleral contact lens without compromise for the ocular surface. AB - PURPOSE: To report the on-eye breakage of a mini-scleral contact lens in a healthy cornea after being hit by a speeding object, without causing any severe corneal damage. CASE REPORT: A 24-year-old Caucasian male involved in a clinical study reported the in situ breakage of a mini-scleral contact lens during motorbike maintenance. The patient reported eye redness and irritation that significantly decreased after all the pieces of the lens were recovered from the eye. Ocular examinations within 48 h showed absence of corneal damage other than superficial punctate keratitis inferiorly and no fragments of the lens were found in the conjunctival sac. The patient was wearing a 15.2 mm mini-scleral lens in a high Dk material. The evolution of rigid materials towards higher Dk values has resulted in a decreased hardness and modulus values, so these materials are more elastic when subjected to mechanical stress, which could be a beneficial aspect in absorbing the energy of an impact before breaking in pieces. CONCLUSION: This case report shows that ScCL could have a protective effect to the corneal surface from the direct impact of a high-speed object. Mechanical material properties, wide supporting area and post-lens tear volume acted as protective factors helping to absorb and distribute the kinetic energy of the impacting object. PMID- 29248316 TI - Cytotoxic and inflammatory effects of contact lens solutions on human corneal epithelial cells in vitro. AB - PURPOSE: To ascertain the effect that four contact lens (CL) multipurpose solutions (MPS) have on the viability and release of pro-inflammatory cytokines from human corneal epithelial cells (HCEC). METHODS: HCEC were exposed to four different MPS at various concentrations for 18 hours. The cells were also exposed to phosphate buffer, borate buffer, and PHMB. The cell viability was evaluated using the alamarBlue assay. The release of pro-inflammatory cytokines was measured using a Multiplex electrochemiluminescent assay. RESULTS: MPS-A, MPS-B and MPS-C all reduced cell metabolic activity p < 0.05 from control with MPS-A showing the greatest cytotoxic effect (maximum reduction, 90.6%). In contrast, MPS-D showed no significant reductions in cytotoxicity except at the highest concentration tested (19% reduction at 20% MPS concentration). Of the four cytokines evaluated MPS-C showed a substantial increase in the release of IL 1beta, IL-6, IL-8, and TNF-alpha at higher concentrations when compared to control p < 0.05. At the 20% concentration of MPS-A and MPS-B the release of IL-1 beta increased p < 0.05 but the release of IL-6, IL-8, and TNF-alpha decreased. MPS-D did not cause a change in the release of cytokines IL-1beta, IL-6, IL-8 and TNF-alpha p > 0.05. Exposing the cells to borate buffer and PHMB caused an increase in the release of TNF-alpha p < 0.05. CONCLUSIONS: This investigation demonstrates that at different concentration levels, several of the MPS tested showed a decrease in viability and an increase in the release of inflammatory cytokines from HCEC. The borate buffer component as well as PHMB appears to contribute to this pro-inflammatory reaction. PMID- 29248317 TI - Volumetric MRI in Neurofibromatosis Type 1 (NF1) Comes of Age to Help Determine Initiation and Monitoring of Targeted Therapies for Plexiform Neurofibromas. PMID- 29248318 TI - Unusual location of developmental venous anomaly within fourth ventricle causing obstructive hydrocephalus - A case report. AB - Developmental venous anomaly (DVA) is now considered common and benign disease within the field of cerebral vascular malformation. Though symptomatic DVA is uncommon, further management is necessary to alleviate the symptoms and signs induced by symptomatic DVA, such as parenchymal hemorrhage, venous infarction, brain edema, obstructive hydrocephalus, and nerve root compression. From the viewpoint of obstructive hydrocephalus, mostly resulted from obstruction of aqueduct of Sylvius. Herein, we reported a case with presentation of obstructive hydrocephalus caused by DVA induced fourth ventricle outlet obstruction. PMID- 29248320 TI - Intrathecal baclofen in progressive neurological disease: To be considered before all other options fail. PMID- 29248319 TI - Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes. AB - BACKGROUND: Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored. OBJECTIVE: To determine the safety, efficacy, and immunomodulatory effects of gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic DNA damage response gene alterations on antitumor activity. DESIGN, SETTING, AND PARTICIPANTS: Multicenter single arm phase 2 study enrolling 36 chemotherapy naive patients with metastatic urothelial cancer. Peripheral blood flow cytometry was performed serially on all patients and whole exome sequencing of archival tumor tissue was performed on 28/36 patients. INTERVENTION: Two cycles of GC followed by four cycles of GC plus ipilimumab. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 1-yr overall survival (OS). Secondary endpoints included safety, objective response rate, and progression free survival. RESULTS AND LIMITATIONS: Grade >=3 adverse events occurred in 81% of patients, the majority of which were hematologic. The objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence interval: 51%). On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after GC alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity=47.6%, specificity=100%, positive predictive value=100%, and negative predictive value=38.9%). Limitations are related to the sample size and single-arm design. CONCLUSIONS: GC+ipilimumab did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones, and potential predictive biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov NCT01524991. PATIENT SUMMARY: Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is feasible. Further studies are needed to refine optimal combinations and evaluate tests that might identify patients most likely to benefit. PMID- 29248321 TI - [Evaluation of knowledge and practices regarding heterozygous familial hypercholesterolemia in children]. AB - INTRODUCTION: Dominant heterozygous familial hypercholesterolemia (FH) is frequent (prevalence, 1/500 to 1/250) and leads to severe and premature cardiovascular complications. It is easily detected, and its treatment is effective. However, recommendations for screening are not followed worldwide. OBJECTIVES: The aim of this study was to evaluate the knowledge and practices of doctors in the Isere department, France, regarding screening and treatment of FH in children. METHODS: A questionnaire was distributed by email or during training sessions to general practitioners, doctors working in Infant and Mother Protection (IMP) services, and pediatricians in private practice in Isere. RESULTS: Fifty-nine doctors completed the questionnaire (overall response rate, 61%). Respondents were general practitioners (36%), IMP doctors (36%), and pediatricians in private practice (28%). Generalized screening for all children was done by only 8% of the respondents, while cascade screening, in case of familial cardiovascular medical history, was done by only 36%, of which 5% were general practitioners while 53% were doctors with a clinical practice focused on children. The most recent French recommendations by the Societe francaise de pediatrie and the Nouvelle Societe francaise d'atherosclerose, which were published in 2010, had been read by only nine doctors (15%). Having read them led to a better policy of generalized screening, either generalized to all children (OR=12.0 [2.3-64.0], P=0.004) or in cascade (OR=22.8 [4.2-123.2], P<0.001). DISCUSSION: The number of questionnaires collected was small, with possible selection and declaration bias, but the different types of pediatric practice were equally represented. CONCLUSION: Screening of FH in children is not very well organized and recommendations are not followed by doctors in Isere, France. Children with FH are probably underdiagnosed and undertreated. PMID- 29248322 TI - [Can a simple lung ultrasound score predict length of ventilation for infants with severe acute viral bronchiolitis?] AB - BACKGROUND: Lung ultrasound (LU) is a bedside point-of-care technique in critical care and emergency medicine. LU is quick and non-irradiating, and provides accurate diagnostic information when compared with chest radiographs. Specific LU signs have been described for bronchiolitis. This study aimed to evaluate the correlation between severity of LU-diagnosed lung lesions, using a quantitative LU score, and the length of non-invasive ventilation (LOV) for infants diagnosed with severe viral bronchiolitis. METHODS: This was a prospective observational single-center study conducted at a level 3 pediatric intensive care unit. A LU score was calculated for 47 infants under 6 months of age with severe acute viral bronchiolitis during the 2015-2016 epidemic, and the number of intercostal spaces with consolidation or interstitial syndrome was counted for each lung. The LU score is based on the presence of A lines or B-line artifacts and consolidation (0-2 points). The modified Wood score (mWCAS) was used to define clinical severity. Other parameters such as gestational age at birth, age, supplemental oxygen (LOS), and length of stay were recorded. All LU scans were later reviewed by two trained ultrasonographers to assess the score's inter-rater reproducibility. RESULTS: The LU score on admission (3.5+/-2.6) did not correlate with LOV (69+/-68.6), mWCAS score (4+/-1.6), LOS (3+/-3.4), or length of stay (4+/-3.4). However, there was a significant correlation between the number of affected intercostal spaces on the right and LOS (Spearman's Rho 0.318; P=0.037). CONCLUSION: This is the first study to evaluate the use of LU in infants needing PICU admission for severe acute bronchiolitis. The LU score does not correlate with LOV, mWCAS, LOS, or length of stay, but the number of pathological intercostal spaces on the right side correlates significantly with LOS. Although LU scores have been validated for the newborn and the adult, this has been in the setting of restrictive lung diseases. Bronchiolitis is a predominantly obstructive lung disease and this may explain the lack of performance observed. PMID- 29248323 TI - Staphylococcal scalded skin syndrome: An uncommon symptomatology revealing an immune deficiency. AB - Primary immune deficiencies associated with hyper-IgE syndrome are rare diseases with clinical features dominated by recurring cutaneous and visceral bacterial infections, particularly infections due to Staphylococcus species. Most of these infections are associated with milder inflammation compared to normal. We report a primary immune deficiency associated with a hyper-IgE syndrome revealed by a staphylococcal scalded skin syndrome in a 5-year-old girl. The patient presented with a severe staphylococcal infection with extensive skin lesions and disseminated intravascular coagulation. She received intravenous fluids to compensate for fluid losses and anti-staphylococcal antibiotics. Coagulopathy was also corrected. However, the progression was rapidly fatal. PMID- 29248324 TI - Lethal form of spinocerebellar ataxia type 7 with early onset in childhood. AB - Progressive cerebellar ataxias are well-known hereditary neurological disorders. Among them, spinocerebellar ataxia type 7 (SCA7) is inherited as an autosomal dominant trait and is ascribed to the expansion of a CAG trinucleotide repeat within the ATXN7 gene. An anticipation phenomenon can occur during paternal transmission and sometimes is responsible for a severe infantile form. The specificity of SCA7 is the retinal involvement with retinitis pigmentosa and cone rod dystrophy. We describe a familial form with two siblings who died of a severe infantile form. Diagnosis was made in their father, who had a recent history of macular atrophy and presented with gait disturbance thereafter. Retrospectively, substantial triplet repeat expansion was confirmed in the two affected infants. These infantile forms are rare and difficult to diagnose in the absence of suggestive family symptoms. PMID- 29248325 TI - Spontaneous pneumothorax: Diagnosis may be a click away. AB - We report the case of a 14-year-old boy presenting to our unit because of a spontaneous left pneumothorax. Over the 3 preceding weeks, he described a rhythmic precordial click and the sensation of bubbles floating inside his chest. This noise, audible to the patient and his family without a medical device, proved to be the Hamman sign, a rare although typical sound formerly related to pneumomediastinum that can be exceptionally encountered in isolated left pneumothorax. Its pathophysiology remains unclear. Small pockets of air close to the heart may be pushed inside pleura and amplified by the chest wall, hence provoking a recurrent rhythmic sound. A small left pneumothorax must be suspected whenever the Hamman sign is elicited in the absence of pneumomediastinum. Chest tomography must be precociously considered if plain x-rays are not contributive. PMID- 29248326 TI - Peripheral Nerve Injury in Cardiac Surgery. PMID- 29248327 TI - The Diagnostic Accuracy of Video Electroencephalography Without Event Capture. AB - OBJECTIVE: The aim of this study was to quantify the accuracy of 24-hour video electroencephalography (vEEG) for the diagnosis of epilepsy when a patient's typical paroxysmal event was not captured (no-event vEEG). METHODS: We performed a retrospective chart review of all first-time 24 hour no-event vEEG studies at Cincinnati Children's Hospital Medical Center. Clinician diagnosis of epilepsy with a minimum of one year follow-up was used as the reference standard to calculate diagnostic accuracy. Sensitivity and specificity of routine EEG (rEEG) and vEEG were compared in patients with both studies, and factors affecting the accuracy of vEEG were explored with a multivariable analysis. RESULTS: No-event vEEG showed sensitivity of 0.54 (95% confidence interval [CI] 0.44 to 0.64) and specificity of 0.88 (95% CI 0.84 to 0.92) respectively, with a diagnostic odds ratio of 7.53 (95% CI 4.45 to 12.76). The sensitivity of vEEG was statistically superior to that of rEEG, whereas specificity was comparable. Age emerged as the only factor that affected the diagnostic accuracy of no-event vEEG. CONCLUSION: Even in the absence of a typical seizure or spell, video EEG is a useful test for predicting or excluding epilepsy, with diagnostic accuracy that is superior to rEEG and unaffected by the presence of a chronic neurological condition. PMID- 29248329 TI - Vascular endothelial growth factors and placenta growth factor in retinal vasculopathies: Current research and future perspectives. AB - Vision loss due to disease or degeneration of the eye (retina, choroid, retinal veins, or macula) is a leading cause of blindness worldwide. In most cases, vision-threatening ocular diseases are accompanied by abnormal changes in the vasculature of the eye, especially the retina, and these conditions are collectively referred to as retinal vasculopathies. Impaired blood supply or hypoxia stimulates angiogenesis in the vascular and non-vascular sections of the eye, which results in neovascularization, leading to conditions such as diabetic retinopathy or age-related macular degeneration. Studies show that vascular endothelial growth factors: VEGF-A, VEGF-B, and placental growth factor (PlGF) are elevated in these diseases, and hence, these factors could be used as markers for disease prognosis and therapy. In this review, we discuss the function of these growth factors in normal development and disease, with focus on ocular disorders and emphasize the importance of accurately determining their levels in the vitreous and serum of patients for correct diagnosis and therapy. PMID- 29248328 TI - Global Carbon Cycling on a Heterogeneous Seafloor. AB - Diverse biological communities mediate the transformation, transport, and storage of elements fundamental to life on Earth, including carbon, nitrogen, and oxygen. However, global biogeochemical model outcomes can vary by orders of magnitude, compromising capacity to project realistic ecosystem responses to planetary changes, including ocean productivity and climate. Here, we compare global carbon turnover rates estimated using models grounded in biological versus geochemical theory and argue that the turnover estimates based on each perspective yield divergent outcomes. Importantly, empirical studies that include sedimentary biological activity vary less than those that ignore it. Improving the relevance of model projections and reducing uncertainty associated with the anticipated consequences of global change requires reconciliation of these perspectives, enabling better societal decisions on mitigation and adaptation. PMID- 29248330 TI - SECT Clinical practice guideline on the management of patients with spontaneous pneumothorax. AB - This clinical practice guideline (CPG) emerges as an initiative of the scientific committee of the Spanish Society of Thoracic Surgery. We formulated PICO (patient, intervention, comparison, and outcome) questions on various aspects of spontaneous pneumothorax. For the evaluation of the quality of evidence and preparation of recommendations we followed the guidelines of the Grading of recommendations, Assessment, Development and Evaluation (GRADE) working group. PMID- 29248331 TI - Evaluating the Usefulness of MP-3 Microperimetry in Glaucoma Patients. AB - PURPOSE: The purpose of the current study was to evaluate the test-retest reproducibility and structure-function relationship of the MP-3 microperimeter, compared against the Humphrey Field Analyzer (HFA). METHODS: Design: Reliability and validity study. SETTING: Institutional, or clinical practice. STUDY POPULATION: Thirty eyes of 30 primary open-angle glaucoma patients were enrolled. OBSERVATION PROCEDURES: Visual fields (VF) were measured twice with the MP-3 and HFA instruments, using the 10-2 test grid pattern in both perimeters. Ganglion cell complex (GCC) thickness was measured using optical coherence tomography (OCT). Test-retest reproducibility was assessed using the mean absolute deviation (MAD) measure at all 68 VF test points, and also the intraclass correlation coefficient (ICC) of the repeated VF sensitivities. The structure-function relationship between VF sensitivities (measured with MP-3 or HFA) and GCC thickness (adjusted for the retinal ganglion cell displacement) was analyzed using linear mixed modeling. MAIN OUTCOME MEASURE: Reproducibility and structure function relationship. RESULTS: The average measurement duration with the HFA 10 2 was 7 minutes and 6 seconds (7m06s) +/- 0m49s (mean +/- standard deviation). A significantly (P < .001, paired Wilcoxon test) longer measurement duration was observed for the MP-3 test: 10m29s +/- 2m55s. There were no significant differences in MAD and ICC values between HFA (MAD; 0.83 +/- 0.69 dB and ICC: 0.89 +/- 0.69, mean +/- standard deviation) and MP-3 (MAD: 0.65 +/- 0.67 dB and ICC: 0.89 +/- 0.69). MP-3 VF sensitivities had a stronger structure-function relationship with GCC thickness compared to HFA. CONCLUSIONS: The MP-3 microperimeter has a similar test-retest reproducibility to the HFA but a better structure-function relationship. PMID- 29248332 TI - Manual Uterine Aspiration: Adding to the Emergency Physician Stabilization Toolkit. PMID- 29248333 TI - Effect of Automated Prescription Drug Monitoring Program Queries on Emergency Department Opioid Prescribing. AB - STUDY OBJECTIVE: We assess whether an automated prescription drug monitoring program intervention in emergency department (ED) settings is associated with reductions in opioid prescribing and quantities. METHODS: We performed a retrospective cohort study of ED visits by Medicaid beneficiaries. We assessed the staggered implementation (pre-post) of automated prescription drug monitoring program queries at 86 EDs in Washington State from January 1, 2013, to September 30, 2015. The outcomes included any opioid prescribed within 1 day of the index ED visit and total dispensed morphine milligram equivalents. The exposure was the automated prescription drug monitoring program query intervention. We assessed program effects stratified by previous high-risk opioid use. We performed multiple sensitivity analyses, including restriction to pain-related visits, restriction to visits with a confirmed prescription drug monitoring program query, and assessment of 6 specific opioid high-risk indicators. RESULTS: The study included 1,187,237 qualifying ED visits (898,162 preintervention; 289,075 postintervention). Compared with the preintervention period, automated prescription drug monitoring program queries were not significantly associated with reductions in the proportion of visits with opioid prescribing (5.8 per 1,000 encounters; 95% confidence interval [CI] -0.11 to 11.8) or the amount of prescribed morphine milligram equivalents (difference 2.66; 95% CI -0.15 to 5.48). There was no evidence of selective reduction in patients with previous high-risk opioid use (1.2 per 1,000 encounters, 95% CI -9.5 to 12.0; morphine milligram equivalents 1.22, 95% CI -3.39 to 5.82). The lack of a selective reduction in high-risk patients was robust to all sensitivity analyses. CONCLUSION: An automated prescription drug monitoring program query intervention was not associated with reductions in ED opioid prescribing or quantities, even in patients with previous high-risk opioid use. PMID- 29248334 TI - Diagnostic Accuracy of a New High-Sensitivity Troponin I Assay and Five Accelerated Diagnostic Pathways for Ruling Out Acute Myocardial Infarction and Acute Coronary Syndrome. AB - STUDY OBJECTIVE: This diagnostic accuracy study describes the performance of 5 accelerated chest pain pathways, calculated with the new Beckman's Access high sensitivity troponin I assay. METHODS: High-sensitivity troponin I was measured with presentation and 2-hour blood samples in 1,811 patients who presented to an emergency department (ED) in Australia. Patients were classified as being at low risk according to 5 rules: modified accelerated diagnostic protocol to assess patients with chest pain symptoms using troponin as the only biomarker (m-ADAPT), the Emergency Department Assessment of Chest Pain Score (EDACS) pathway, the History, ECG, Age, Risk Factors, and Troponin (HEART) pathway, the No Objective Testing Rule, and the new Vancouver Chest Pain Rule. Endpoints were 30-day acute myocardial infarction and acute coronary syndrome. Measures of diagnostic accuracy for each rule were calculated. RESULTS: Data included 96 patients (5.3%) with acute myocardial infarction and 139 (7.7%) with acute coronary syndrome. The new Vancouver Chest Pain Rule and No Objective Testing Rule had high sensitivity for acute myocardial infarction (100%; 95% confidence interval [CI] 96.2% to 100% for both) and acute coronary syndrome (98.6% [95% CI 94.9% to 99.8%] and 99.3% [95% CI 96.1% to 100%]). The m-ADAPT, EDACS, and HEART pathways also yielded high sensitivity for acute myocardial infarction (96.9% [95% CI 91.1% to 99.4%] for m ADAPT and 97.9% [95% CI 92.7% to 99.7%] for EDACS and HEART), but lower sensitivity for acute coronary syndrome (<=95.0% for all). The m-ADAPT, EDACS, and HEART rules classified more patients as being at low risk (64.3%, 62.5%, and 49.8%, respectively) than the new Vancouver Chest Pain Rule and No Objective Testing Rule (28.2% and 34.5%, respectively). CONCLUSION: In this cohort with a low prevalence of acute myocardial infarction and acute coronary syndrome, using the Beckman's Access high-sensitivity troponin I assay with the new Vancouver Chest Pain Rule or No Objective Testing Rule enabled approximately one third of patients to be safely discharged after 2-hour risk stratification with no further testing. The EDACS, m-ADAPT, or HEART pathway enabled half of ED patients to be rapidly referred for objective testing. PMID- 29248336 TI - Erratum. PMID- 29248335 TI - Outpatient Management of Emergency Department Patients With Acute Pulmonary Embolism: Variation, Patient Characteristics, and Outcomes. AB - STUDY OBJECTIVE: Outpatient management of emergency department (ED) patients with acute pulmonary embolism is uncommon. We seek to evaluate the facility-level variation of outpatient pulmonary embolism management and to describe patient characteristics and outcomes associated with home discharge. METHODS: The Management of Acute Pulmonary Embolism (MAPLE) study is a retrospective cohort study of patients with acute pulmonary embolism undertaken in 21 community EDs from January 2013 to April 2015. We gathered demographic and clinical variables from comprehensive electronic health records and structured manual chart review. We used multivariable logistic regression to assess the association between patient characteristics and home discharge. We report ED length of stay, consultations, 5-day pulmonary embolism-related return visits and 30-day major hemorrhage, recurrent venous thromboembolism, and all-cause mortality. RESULTS: Of 2,387 patients, 179 were discharged home (7.5%). Home discharge varied significantly between EDs, from 0% to 14.3% (median 7.0%; interquartile range 4.2% to 10.9%). Median length of stay for home discharge patients (excluding those who arrived with a new pulmonary embolism diagnosis) was 6.0 hours (interquartile range 4.6 to 7.2 hours) and 81% received consultations. On adjusted analysis, ambulance arrival, abnormal vital signs, syncope or presyncope, deep venous thrombosis, elevated cardiac biomarker levels, and more proximal emboli were inversely associated with home discharge. Thirteen patients (7.2%) who were discharged home had a 5-day pulmonary embolism-related return visit. Thirty-day major hemorrhage and recurrent venous thromboembolism were uncommon and similar between patients hospitalized and those discharged home. All cause 30-day mortality was lower in the home discharge group (1.1% versus 4.4%). CONCLUSION: Home discharge of ED patients with acute pulmonary embolism was uncommon and varied significantly between facilities. Patients selected for outpatient management had a low incidence of adverse outcomes. PMID- 29248337 TI - Clinical efficacy of the novel thiazolidinedione lobeglitazone in patients with type 2 diabetes. PMID- 29248338 TI - Efficacy of hypopressive abdominal gymnastics in rehabilitating the pelvic floor of women: A systematic review. AB - BACKGROUND: Hypopressive abdominal gymnastics has been proposed as a new paradigm in rehabilitating the pelvic floor. Its claims contraindicate the recommendation for pelvic floor muscle training during the postpartum period. OBJECTIVE: To determine whether hypopressive abdominal gymnastics is more effective than pelvic floor muscle training or other alternative conservative treatments for rehabilitating the pelvic floor. METHODS: We consulted the databases of the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, Latin American and Caribbean Health Sciences Literature (LILACS), Physiotherapy Evidence Database (PEDro), PubMed, Scopus, Trip Database and Web of Science. We selected systematic reviews, clinical trials and analytical studies that assessed the efficacy of hypopressive abdominal gymnastics in women. The measured outcomes were the strengthening of the pelvic floor muscles, the incidence of urine incontinence or prolapse and symptom remission. We included 4 clinical trials, whose quality was measured with the PEDro scale. RESULTS: Hypopressive gymnastics is less effective than pelvic floor muscle training for activating pelvic floor muscles, achieving closure of the levator hiatus of the anus and increasing pelvic floor muscle thickness, strength and resistance. PRACTICAL IMPLICATION: The evidence reviewed does not support the recommendation for hypopressive abdominal gymnastics for strengthening the pelvic floor either during the postpartum period or outside that period. Pelvic floor muscle training remains the first-line treatment for pelvic floor dysfunction. CONCLUSION: There is a lack of quality clinical trials that have evaluated the efficacy of hypopressive abdominal gymnastics. PMID- 29248339 TI - A new CHCHD2 mutation identified in a southern italy patient with multiple system atrophy. PMID- 29248340 TI - Role of LRRK2 and SNCA in autosomal dominant Parkinson's disease in Turkey. AB - INTRODUCTION: Mutations in the LRRK2 and alpha-synuclein (SNCA) genes are well established causes of autosomal dominant Parkinson's disease (PD). However, their frequency differs widely between ethnic groups. Only three studies have screened all coding regions of LRRK2 and SNCA in European samples so far. In Turkey, the role of LRRK2 in Parkinson's disease has been studied fragmentarily, and the incidence of SNCA copy number variations is unknown. The purpose of this study is to determine the frequency of LRRK2 and SNCA mutations in autosomal dominant PD in Turkey. METHODS: We performed Sanger sequencing of all coding LRRK2 and SNCA exons in a sample of 91 patients with Parkinsonism. Copy number variations in SNCA, PRKN, PINK1, DJ1 and ATP13A2 were assessed using the MLPA method. All patients had a positive family history compatible with autosomal dominant inheritance. RESULTS: Known mutations in LRRK2 and SNCA were found in 3.3% of cases: one patient harbored the LRRK2 G2019S mutation, and two patients carried a SNCA gene duplication. Furthermore, we found a heterozygous deletion of PRKN exon 2 in one patient, and four rare coding variants of unknown significance (LRRK2: A211V, R1067Q, T2494I; SNCA: T72T). Genetic testing in one affected family identified the LRRK2 R1067Q variant as a possibly pathogenic substitution. CONCLUSION: Point mutations in LRRK2 and SNCA are a rare cause of autosomal dominant PD in Turkey. However, copy number variations should be considered. The unclassified variants, especially LRRK2 R1067Q, demand further investigation. PMID- 29248341 TI - Targeting gait and life quality in persons with Parkinson's disease: Potential benefits of Equine-Assisted Interventions. PMID- 29248342 TI - Evaluation of ionic liquid gas chromatography stationary phases for the separation of polychlorinated biphenyls. AB - The feasibility of six ionic liquid- (IL-) based stationary phases for the analysis of environmentally important polychlorinated biphenyls (PCBs) by gas chromatography combined with either electron capture micro-detector (GC-micro ECD) or quadrupole mass spectrometry (GC-MS, for confirmation) have been evaluated. These IL-based columns showed a separation mechanism different from that observed for other commercial phases, such a low bleed high temperature 8% phenyl (equiv.) polycarborane-siloxane suggested shape-selective phase for non ortho and mono-ortho-CBs, HT-8, or a polar poly(ethylene glycol), resulting in a different elution order of the 69 investigated PCBs. However, no all phases provided equality satisfactory resolutions for the most environmentally relevant congeners, the 12 toxic and the 7 priority PCBs. From this point of view, the best results were obtained with the SLB-IL76 and SLB-IL59 phases, which showed a number of coelutions for these specific congeners only slightly higher to that observed on HT-8. Interestingly, the SLB-IL59 phase was the only one among the evaluated phases allowing a complete resolution of the most toxic non-ortho substituted congeners # 77, 126 and 169 from all other PCBs investigated. SLB IL76 and SLB-IL59 also demonstrated a superior chromatographic performance concerning peak symetry, retention time stability and column bleeding, compared to the other four IL-based columns evaluated. Altogether, results obtained for the analysis of pure standards illustrated the potential of, in particular, SLB IL 59 as an alternative phase for confirmation of the identity of PCBs typically detected in environmental matrices that coeluted on conventional non-polar phases in use for this type of determination. However, the long-term stability and quantitative behaviour of these stationary phases during the analysis of real samples still need to be addressed. PMID- 29248343 TI - Corrigendum to "Mechanism of protein desorption from 4-mercaptoethylpyridine resins by arginine solutions" [J. Chromatogr. A 1373 (2014) 141-148]. PMID- 29248344 TI - Use of an online extraction liquid chromatography quadrupole time-of-flight tandem mass spectrometry method for the characterization of polyphenols in Citrus paradisi cv. Changshanhuyu peel. AB - Chemical profiling of natural products by high performance liquid chromatography (HPLC) was critical for understanding of their clinical bioactivities, and sample pretreatment steps have been considered as a bottleneck for analysis. Currently, concerted efforts have been made to develop sample pretreatment methods with high efficiency, low solvent and time consumptions. Here, a simple and efficient online extraction (OLE) strategy coupled with HPLC-diode array detector quadrupole time-of-flight tandem mass spectrometry (HPLC-DAD-QTOF-MS/MS) was developed for rapid chemical profiling. For OLE strategy, guard column inserted with ground sample (2 mg) instead of sample loop was connected with manual injection valve, in which components were directly extracted and transferred to HPLC-DAD-QTOF-MS/MS system only by mobile phase without any extra time, solvent, instrument and operation. By comparison with offline heat-reflux extraction of Citrus paradisi cv. Changshanhuyu (Changshanhuyu) peel, OLE strategy presented higher extraction efficiency perhaps because of the high pressure and gradient elution mode. A total of twenty-two secondary metabolites were detected according to their retention times, UV spectra, exact mass, and fragmentation ions in MS/MS spectra, and nine of them were discovered in Changshanhuyu peel for the first time to our knowledge. It is concluded that the developed OLE-HPLC-DAD-QTOF-MS/MS system offers new perspectives for rapid chemical profiling of natural products. PMID- 29248345 TI - Aqueous size-exclusion chromatography of polyelectrolytes on reversed-phase and hydrophilic interaction chromatography columns. AB - The size-exclusion separation of a water-soluble polyelectrolyte polymer, sodium polystyrene sulfonate (NaPSS), was demonstrated on common reversed-phase (C18, C4, phenyl, and cyano) and hydrophilic interaction chromatography (HILIC) columns. The effect of common solvents - acetonitrile (ACN), tetrahydrofuran (THF), and methanol (MeOH), used as mobile phase modifiers - on the elution of NaPSS and the effect of column temperature (within a relatively narrow range corresponding to typical chromatographic conditions, i.e., 10 degrees C-60 degrees C) on the partition coefficient, KSEC, were also investigated. Non-size exclusion chromatography (non-SEC) effects can be minimized by the addition of an electrolyte and an organic modifier to the mobile phase, and by increasing the column temperature (e.g., to 50 degrees C or 60 degrees C). Strong solvents such as THF and ACN are more successful in the reduction of such effects than is the weaker solvent MeOH. The best performance is seen on medium polarity and polar stationary phases, such as cyanopropyl- and diol-modified silica (HILIC), where the elution of the NaPSS polyelectrolyte is by a near-ideal SEC mechanism. Hydrophobic stationary phases, such as C18, C4, and phenyl, require a higher concentration of a strong solvent modifier (THF) in the mobile phase to reduce non-SEC interactions of the solute with the stationary phase. PMID- 29248346 TI - Metal-organic framework-derived three-dimensional porous graphitic octahedron carbon cages-encapsulated copper nanoparticles hybrids as highly efficient enrichment material for simultaneous determination of four fluoroquinolones. AB - A unique 3D porous Cu@graphitic octahedron carbon cages were constructed by rapid room-temperature synthesis of a Cu-based metal-organic framework (MOF) with further pyrolysis in N2, which exhibited good enrichment ability for four fluoroquinolones (FQs) due to their superior chemical affinities to the target analytes. Applied Cu@graphitic octahedron carbon cages as adsorbent, a dispersive solid phase extraction (DSPE) method combined with HPLC was developed for detecting four FQs in real samples. Various parameters affecting residues FQs extraction efficiency were inquired in more detail. Under optimal conditions, the extraction recoveries of four FQs in chicken muscle, fish tissue, seawater and river water samples were in the range of 81.3~104.3% and the RSDs (n = 5) were less than 5.2%. This method was successfully used to the determination of FQs in real samples. PMID- 29248347 TI - Thin-layer chromatography combined with diode laser thermal vaporization inductively coupled plasma mass spectrometry for the determination of selenomethionine and selenocysteine in algae and yeast. AB - In this work we present a simple and cost-effective approach for the determination of selenium species in algae and yeast biomass, based on a combination of thin-layer chromatography (TLC) with diode laser thermal vaporization inductively coupled plasma mass spectrometry (DLTV ICP MS). Extraction of freeze-dried biomass was performed in 4M methanesulphonic acid and the selenium species were vaporized from cellulose TLC plates employing a continuous-wave infrared diode laser with power up to 4 W using a simple laboratory-built apparatus. Selenomethionine and selenocysteine were quantified with limits of detection 3 MUg L-1 in a Se-enriched microalgae Chlorella vulgaris and yeast certified reference material SELM-1. Results delivered by TLC-DLTV ICP MS were consistent with those obtained by a routine coupling of high-performance liquid chromatography (HPLC) to ICP MS. In addition, the TLC approach is capable of analyzing extract containing even undiluted crude hydrolysates that could damage HPLC columns. PMID- 29248348 TI - An alternative method for calibration of flow field flow fractionation channels for hydrodynamic radius determination: The nanoemulsion method (featuring multi angle light scattering). AB - This study suggests a novel method for determination of the channel height in asymmetrical flow field-flow fractionation (AF4), which can be used for calibration of the channel for hydrodynamic radius determinations. The novel method uses an oil-in-water nanoemulsion together with multi angle light scattering (MALS) and elution theory to determine channel height from an AF4 experiment. The method is validated using two orthogonal methods; first, by using standard particle elution experiments and, secondly, by imaging an assembled and carrier liquid filled channel by x-ray computed tomography (XCT). It is concluded that the channel height can be determined with approximately the same accuracy as with the traditional channel height determination technique. However, the nanoemulsion method can be used under more challenging conditions than standard particles, as the nanoemulsion remains stable in a wider pH range than the previously used standard particles. Moreover, the novel method is also more cost effective. PMID- 29248349 TI - The forgotten organ. PMID- 29248350 TI - Effectiveness of kinesiology tape on sports performance abilities in athletes: A systematic review. AB - OBJECTIVE: Establish the effectiveness of kinesiology tape (KT) on sports performance abilities compared to that of other tapes or no tape with consideration to the application methodology, timeframe, and outcome measurement. METHODS: PubMed, Embase, and PEDro databases were systematically searched. The following inclusion criteria were applied: 1) participants were healthy athletes, 2) compared any brand of dynamic KT to other types of tape (sham or therapeutic) and/or no tape, 3) measured some construct of functional sports performance, 4) involved randomization. The PEDro scale was used to grade the risk of bias. RESULTS: Fifteen studies met the inclusion criteria with PEDro scores ranging from 3 to 8 of 10 points. The sports performance abilities included: ball skills; power squats; cycling; dynamic balance; jumping (vertical and horizontal); agility; sprint speed; and distance running with 193 comparisons between KT and other tapes or no tape at a variety of timeframes after application. In total, eleven comparisons demonstrated significant effects: 2 in favor of KT, 8 in favor of Mulligan's tape, and one in favor of no tape. CONCLUSION: There is a lack of compelling evidence to support the use of KT to enhance the sports performance abilities based on this review. LEVEL OF EVIDENCE: 1a-. PMID- 29248351 TI - Weight loss after bariatric surgery in obese adolescents: a systematic review and meta-analysis. AB - Of adolescents in the United States, 20% have obesity and current treatment options prioritize intensive lifestyle interventions that are largely ineffective. Bariatric surgery is increasingly being offered to obese adolescent patients; however, large-scale effectiveness data is lacking. We used MEDLINE, Embase, and Cochrane databases, and a manual search of references to conduct a systematic review and meta-analysis on overall weight loss after gastric band, gastric sleeve, and gastric bypass in obese adolescent patients (age <=19) and young adults (age <=21) in separate analyses. We provided estimates of absolute change in body mass index (BMI, kg/m2) and percent excess weight loss across 4 postoperative time points (6, 12, 24, and 36 mo) for each surgical subgroup. Study quality was assessed using a 10 category scoring system. Data were extracted from 24 studies with 4 having multiple surgical subgroups (1 with 3, and 3 with 2 subgroups), totaling 29 surgical subgroup populations (gastric band: 16, gastric sleeve: 5, gastric bypass: 8), and 1928 patients (gastric band: 1010, gastric sleeve: 139, gastric bypass: 779). Mean preoperative BMI (kg/m2) was 45.5 (95% confidence interval [CI]: 44.7, 46.3) in gastric band, 48.8 (95%CI: 44.9, 52.8) in gastric sleeve, and 53.3 (95%CI: 50.2, 56.4) in gastric bypass patients. The short-term weight loss, measured as mean (95%CI) absolute change in BMI (kg/m2) at 6 months, was -5.4 (-3.0, -7.8) after gastric band, -11.5 (-8.8, 14.2) after gastric sleeve, and -18.8 (-10.9, -26.6) after gastric bypass. Weight loss at 36 months, measured as mean (95%CI) absolute change in BMI (kg/m2) was 10.3 (-7.0, -13.7) after gastric band, -13.0 (-11.0, -15.0) after gastric sleeve, and -15.0 (-13.5, -16.5) after gastric bypass. Bariatric surgery in obese adolescent patients is effective in achieving short-term and sustained weight loss at 36 months; however, long-term data remains necessary to better understand its long-term efficacy. PMID- 29248352 TI - Natural products as sources of new fungicides (IV): Synthesis and biological evaluation of isobutyrophenone analogs as potential inhibitors of class-II fructose-1,6-bisphosphate aldolase. AB - Several recently identified antifungal compounds share the backbone structure of acetophenones. The aim of the present study was to develop new isobutyrophenone analogs as new antifungal agents. A series of new 2,4-dihydroxy-5-methyl isobutyrophenone derivatives were prepared and characterized by 1H, 13C NMR and MS spectroscopic data. These products were evaluated for in vitro antifungal activities against seven plant fungal pathogens by the mycelial growth inhibitory rate assay. Compounds 3, 4a, 5a, 5b, 5e, 5f and 5g showed a broad-spectrum high antifungal activity. On the other hand, for the first time, these compounds were also assayed as potential inhibitors against Class II fructose-1,6-bisphosphate aldolase (Fba) from the rice blast fungus, Magnaporthe grisea. Compounds 5e and 5g were found to exhibit the inhibition constants (Ki) for 15.12 and 14.27 MUM, respectively, as the strongest competitive inhibitors against Fba activity. The possible binding-modes of compounds 5e and 5g were further analyzed by molecular docking algorithms. The results strongly suggested that compound 5g could be a promising lead for the discovery of new fungicides via targeting Class II Fba. PMID- 29248353 TI - alpha-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors. AB - Disruption of protein geranylgeranylation via inhibition of geranylgeranyl diphosphate synthase (GGDPS) represents a novel therapeutic strategy for a variety of malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the alpha carbon. These studies reveal that incorporation of an alpha-methyl substituent enhances the potency of these compounds as GGDPS inhibitors, and, in the case of the homogeranyl/homoneryl series, abrogates the effects of olefin stereochemistry on inhibitory activity. The incorporation of the methyl group allowed preparation of a POM-prodrug, which displayed a 10-fold increase in cellular activity compared to the corresponding salt. These studies form the basis for future preclinical studies investigating the anti-myeloma activity of these novel alpha methyl triazole bisphosphonates. PMID- 29248354 TI - Sleep and other correlates of high-level health in older adults. AB - A large sample (N = 1139) of adults >=75 years from the 2011-2014 NHANES cohorts was used to examine predictors of high-level health. Analyses were done with SAS to control for sample weights and allow results to be reported as population parameters. The majority of participants described their health as high-level (73.6%). Logistic regression found a longer sleep duration, minority status, decreased income, multiple medications, low physical activity, and late stage memory impairment were significant predictors of low-level health (p < .05) while sex, education level, marital status, body mass index, and depression symptoms were not. The assessment of sleep should be expanded to cover dimensions such as sleep quality and sleep disorders to help maintain wellness in older adults. This study supports that the majority of older adults have high-level health and identifies several modifiable factors to maintain wellness. PMID- 29248355 TI - Pilot testing of the effectiveness of nurse-guided, patient-centered heart failure education for older adults. AB - Heart failure (HF) is the most common cause of hospitalization and rehospitalization among those 65 years and older. Effective HF self-management is recommended for reducing readmissions. This pilot study, through a one-group, pretest-posttest design, examines the effects of nurse-guided, patient-centered HF education on readmissions among older adults (n = 26) in a post-acute care unit. All selected participants received 3 sessions of tailored patient education. Their knowledge and self-care skills were measured pre- and post intervention with the Atlanta Heart Failure Knowledge Test (A-HFKT) and the Self Care of Heart Failure Index (SCHFI). Patients' HF-related knowledge and self-care skills showed statistically significant improvements, and only 1 patient was rehospitalized for any HF-related reason within 30 days post-discharge. These results suggest that HF rehabilitation teams could support better patient outcomes by assigning nursing staff to provide individualized patient education, as this can help ensure that patients understand discharge instructions for effective self-care. PMID- 29248356 TI - Corrigendum to "Docking assay of small molecule antivirals to p7 of HCV" [Comput. Biol. Chem. 53 (2014) 308-317]. PMID- 29248357 TI - Placentophagia: Revolution in Postpartum Medicine, or Just a Trend? PMID- 29248358 TI - Risk Factors for Methicillin-Resistant Staphylococcus aureus (MRSA) Colonization Among Patients Admitted to Obstetrical Units: A Nested Case-Control Study. AB - OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) among obstetrical patients can increase birth complications for both mothers and infants, but little is known about the risk factors for MRSA in this population. The objective of this study was to determine the prevalence of MRSA among obstetrical patients and identify risk factors associated with MRSA colonization. METHODS: This nested case-control study used obstetrical patients with MRSA colonization identified through a universal screening program at The Ottawa Hospital (February 2008 January 2010). Cases and three matched controls were compared using chi-square tests for categorical variables, median and interquartile range (IQR), and Wilcoxon rank-sum tests for continuous variables. Conditional logistic regression using ORs and 95% CIs was used to identify risk factors. Standard microbiologic techniques and pulsed-field gel electrophoresis of the MRSA isolates from case patients were performed. RESULTS: Out of 11 478 obstetrical patients, 39 (0.34%) were MRSA colonized; 117 patients were selected as matched controls. The median age was 30 (IQR 27.5-35.00) and median length of stay was 2.55 days (IQR 1.95 3.24). Only MRSA cases had a previous MRSA infection (4 vs. 0). MRSA cases had significantly higher parity (median 3; IQR 2-5) compared with controls (median 2; IQR 1-3) (OR 1.52; 95% CI 1.22-1.90) CONCLUSION: This study identified a low prevalence of MRSA among obstetrical patients. Risk factors associated with MRSA colonization were previous MRSA infection and multiparity. Obstetrical patients who previously tested positive for MRSA should be placed on contact precautions at the time of hospital admission because this is a risk factor for future colonization. PMID- 29248359 TI - Impact of long-term elosulfase alfa on activities of daily living in patients with Morquio A syndrome in an open-label, multi-center, phase 3 extension study. AB - BACKGROUND: Long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) were assessed in 173 patients with Morquio A syndrome (mucopolysaccharidosis IVA) in a 96-week, open-label, multi-center, phase 3 extension study (MOR-005) of the pivotal 24-week, placebo-controlled study (MOR 004). Changes in efficacy endpoints were evaluated over 120weeks, from MOR-004 baseline to MOR-005 week 96. We report the impact of ERT on activities of daily living (ADL) across three domains (mobility, self-care, and caregiver assistance), as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ) after 72 and 120weeks or approximately 1 and 2years. RESULTS: Mean baseline MPS-HAQ domain scores showed impairments in mobility, self care, and independence. The MOR-005 intent-to-treat population (ITT; N=169, including 158 with 2years follow-up) showed sustained significant reductions (representing improvements) in mobility and self-care domain least square (LS) mean scores vs. baseline at 1 and 2years and a non-significant decrease in the caregiver-assistance domain at 2years. At week 120, LS mean (SE) changes from baseline were -0.5 (0.1) for mobility (P=0.002), -0.4 (0.1) for self-care (P=0.001), and -1.0 (0.5) for caregiver-assistance (P=0.06) (ITT population). Improvements in MPS-HAQ domain scores vs. baseline at 1 and 2years were greater in patients continuously treated with the weekly dosing regimen than in the total MOR-005 population and statistically significant across domains. A comparable untreated cohort of patients from the Morquio A Clinical Assessment Program (MorCAP) natural history study (ITT population, N=94, including 37 with 2years follow-up) showed no improvement over 2years, with two of the three domains worsening (LS mean (SE) changes from baseline: 0.3 (0.3) for mobility, 0.4 (0.2) for self-care, -0.5 (0.8) for caregiver-assistance). Changes in LS mean scores vs. baseline were statistically significantly different between MOR-005 and MorCAP for the mobility domain (-0.7 (SE 0.4), P=0.0490) and the self-care domain (-0.7 (SE 0.3), P=0.0146) at 2years. CONCLUSIONS: Together, these findings suggest that long-term elosulfase alfa ERT is associated with partial recovery of functional abilities, improving Morquio A patients' abilities to perform ADL. TRIAL REGISTRATION: ClinicalTrials.govNCT01415427. Registered 8 August 2011, retrospectively registered. PMID- 29248360 TI - Balancing training and outcomes in total knee replacement: A ten-year review. AB - INTRODUCTION: 10-year study examining differences in total knee arthroplasty (TKA) functional outcomes and survivorship in patients operated on by consultant and trainee orthopaedic surgeons. METHOD: Data was prospectively collected from all elective TKAs performed at our three linked institutions. Patient demographics, surgeon grade, and length of hospital stay were recorded. Outcomes pre-operatively and at 1, 3, 5, 7 and 10 years included mortality, need for revision surgery and function as documented by the patients' Knee Society Score. RESULTS: 686 patients were included in the study. 450 (65.5%) patients were operated by consultant surgeons and 236 (34.4%) by trainees. On multivariate analysis no significant differences were observed between groups in length of hospital stay (p = 0.695), implant survival (p = 0.422), and function (p = 0.507) at 10 years. On Cox regression analysis no significant difference was observed in mortality (p = 0.209) at 10 years. 4 patients over this time period were lost to formal follow up. CONCLUSION: No significant difference was observed in the TKA outcomes between consultants and trainees 10 years post-operatively. PMID- 29248361 TI - Leptin, An Adipokine With Central Importance in the Global Obesity Problem. AB - Leptin has central importance in the global obesity and cardiovascular disease problem. Leptin is principally secreted by adipocytes and acts in the hypothalamus to suppress appetite and food intake, increase energy expenditure, and regulate body weight. Based on clinical translation of specific and networked actions, leptin affects the cardiovascular system and may be a marker and driver of cardiometabolic risk factors with interventions that are actionable by cardiologists. Leptin subnetwork analysis demonstrates a statistically significant role for ethnoculturally and socioeconomically appropriate lifestyle intervention in cardiovascular disease. Emergent mechanistic components and potential diagnostic or therapeutic targets include hexokinase 3, urocortins, clusterin, sialic acid-binding immunoglobulin-like lectin 6, C-reactive protein, platelet glycoprotein VI, albumin, pentraxin 3, ghrelin, obestatin prepropeptide, leptin receptor, neuropeptide Y, and corticotropin-releasing factor receptor 1. Emergent associated symptoms include weight change, eating disorders, vascular necrosis, chronic fatigue, and chest pain. Leptin-targeted therapies are reported for lipodystrophy and leptin deficiency, but they are investigational for leptin resistance, obesity, and other chronic diseases. PMID- 29248362 TI - Large-Scale Epidemiologic Studies of Cardiovascular Diseases in China: Need for Improved Data Collection, Methods, Transparency, and Documentation. AB - With the advent of international precision medicine initiatives, it is important to evaluate existing large-scale studies to inform future investigation. This study sought to review, describe, and evaluate all large-scale cardiovascular disease (CVD) studies completed in China. We undertook a review of all large scale CVD studies completed in China to describe and evaluate their design, implementation, and dissemination in published medical reports. Seventeen studies met the inclusion criteria. There were substantial variations in study design, geographic location, and data collection. Most studies lacked standard study names, did not publish their methods, and provided no publicly available data. Few studies included underdeveloped regions or minority groups. Most published articles contained only descriptions of the average population at risk of CVD, and no study predicted individual CVD risk or identified people at high risk. Future CVD studies in China may need to incorporate stronger systematic data collection methods, increased data transparency, clearer documentation, and standard study names to most gain from China's burgeoning field of CVD research. PMID- 29248363 TI - Global Coalition for the Fight Against Heart Disease and Stroke: A Global Coalition for WHF Second Global Summit on Circulatory Health. PMID- 29248364 TI - CV Risk Factors in Rural-to-Urban Migrants Versus the Urban-Born in South India. PMID- 29248365 TI - Monitoring universal health coverage within the Sustainable Development Goals: development and baseline data for an index of essential health services. AB - BACKGROUND: Achieving universal health coverage, including quality essential service coverage and financial protection for all, is target 3.8 of the Sustainable Development Goals (SDG). As a result, an index of essential health service coverage indicators was selected by the UN as SDG indicator 3.8.1. We have developed an index for measuring SDG 3.8.1, describe methods for compiling the index, and report baseline results for 2015. METHODS: 16 tracer indicators were selected for the index, which included four from within each of the categories of reproductive, maternal, newborn, and child health; infectious disease; non-communicable diseases; and service capacity and access. Indicator data for 183 countries were taken from UN agency estimates or databases, supplemented with submissions from national focal points during a WHO country consultation. The index was computed using geometric means, and a subset of tracer indicators were used to summarise inequalities. FINDINGS: On average, countries had primary data since 2010 for 72% of the final set of indicators. The median national value for the service coverage index was 65 out of 100 (range 22 86). The index was highly correlated with other summary measures of health, and after controlling for gross national income and mean years of adult education, was associated with 21 additional years of life expectancy over the observed range of country values. Across 52 countries with sufficient data, coverage was 1% to 66% lower among the poorest quintile as compared with the national population. Sensitivity analyses suggested ranks implied by the index are fairly stable across alternative calculation methods. INTERPRETATION: Service coverage within universal health coverage can be measured with an index of tracer indicators. Our universal health coverage service coverage index is simple to compute by use of available country data and can be refined to incorporate relevant indicators as they become available through SDG monitoring. FUNDING: Ministry of Health, Japan, and the Rockefeller Foundation. PMID- 29248366 TI - Progress on impoverishing health spending in 122 countries: a retrospective observational study. AB - BACKGROUND: The goal of universal health coverage (UHC) requires that families who get needed health care do not suffer financial hardship as a result. This can be measured by instances of impoverishment, when a household's consumption including out-of-pocket spending on health is more than the poverty line but its consumption, excluding out-of-pocket spending, is less than the poverty line. This links UHC directly to the policy goal of reducing poverty. METHODS: We measure the incidence and depth of impoverishment as the difference in the poverty head count and poverty gap with and without out-of-pocket spending included in household total consumption. We use three poverty lines: the US$1.90 per day and $3.10 per day international poverty lines and a relative poverty line of 50% of median consumption per capita. We estimate impoverishment in 122 countries using 516 surveys between 1984 and 2015. We estimate the global incidence of impoverishment due to out-of-pocket payments by aggregating up from each country, using a survey for the year in question when available, and interpolation and model-based estimates otherwise. We do not derive global estimates to measure the depth of impoverishment but focus on the median depth for the 122 countries in our sample, accounting for 90% of the world's population. FINDINGS: We find impoverishment due to out-of-pocket spending even in countries where the entire population is officially covered by a health insurance scheme or by national or subnational health services. Incidence is negatively correlated with the share of total health spending channelled through social security funds and other government agencies. Across countries, the population-weighted median annual rate of change of impoverishment is negative at the $1.90 per day poverty line but positive at the $3.10 per day and relative poverty lines. We estimate that at the $1.90 per day poverty line, the worldwide incidence of impoverishment decreased between 2000 and 2010, from 131 million people (2.1% of the world's population) to 97 million people (1.4%). The population-weighted median of the poverty gap increase attributable to out-of pocket health expenditures among the 122 countries in our sample are c1.22 per capita at the $1.90 per day poverty line and c3.74 per capita at the $3.10 per day poverty line. In all countries, out-of-pocket spending can be both catastrophic and impoverishing at all income levels, but this partly depends on the choice of the poverty line. INTERPRETATION: Out-of-pocket spending on health can add to the poverty head count and the depth of poverty by diverting household spending from non-health budget items. The scale of such impoverishment varies between countries and depends on the poverty line but might in some low-income countries account for as much as four percentage points of the poverty head count. Increasing the share of total health expenditure that is prepaid, especially through taxes and mandatory contributions, can help reduce impoverishment. FUNDING: Rockefeller Foundation, Ministry of Health of Japan, and UK Department for International Development. PMID- 29248367 TI - Progress on catastrophic health spending in 133 countries: a retrospective observational study. AB - BACKGROUND: The goal of universal health coverage (UHC) requires inter alia that families who get needed health care do not suffer undue financial hardship as a result. This can be measured by the percentage of people in households whose out of-pocket health expenditures are large relative to their income or consumption. We aimed to estimate the global incidence of catastrophic health spending, trends between 2000 and 2010, and associations between catastrophic health spending and macroeconomic and health system variables at the country level. METHODS: We did a retrospective observational study of health spending using data obtained from household surveys. Of 1566 potentially suitable household surveys, 553 passed quality checks, covering 133 countries between 1984 and 2015. We defined health spending as catastrophic when it exceeded 10% or 25% of household consumption. We estimated global incidence by aggregating up from every country, using a survey for the year in question when available, and interpolation and model-based estimates otherwise. We used multiple regression to explore the relation between a country's incidence of catastrophic spending and gross domestic product (GDP) per person, the Gini coefficient for income inequality, and the share of total health expenditure spent by social security funds, other government agencies, private insurance schemes, and non-profit institutions. FINDINGS: The global incidence of catastrophic spending at the 10% threshold was estimated as 9.7% in 2000, 11.4% in 2005, and 11.7% in 2010. Globally, 808 million people in 2010 incurred catastrophic health spending. Across 94 countries with two or more survey datapoints, the population-weighted median annual rate of change of catastrophic payment incidence was positive whatever catastrophic payment incidence measure was used. Incidence of catastrophic payments was correlated positively with GDP per person and the share of GDP spent on health, and incidence correlated negatively with the share of total health spending channelled through social security funds and other government agencies. INTERPRETATION: The proportion of the population that is supposed to be covered by health insurance schemes or by national or subnational health services is a poor indicator of financial protection. Increasing the share of GDP spent on health is not sufficient to reduce catastrophic payment incidence; rather, what is required is increasing the share of total health expenditure that is prepaid, particularly through taxes and mandatory contributions. FUNDING: Rockefeller Foundation, Ministry of Health of Japan, UK Department for International Development (DFID). PMID- 29248368 TI - Towards a meaningful measure of universal health coverage for the next billion. PMID- 29248369 TI - Mercury removal from MSW incineration flue gas by mineral-based sorbents. AB - Three samples of commercially available mineral-based sorbents (zeolite, bentonite and diatomaceous earth) were selected and evaluated for Hg capture under conditions of simulated dry flue gas atmosphere typical in Municipal Solid Waste Incineration (MSWI). The experiments were carried out in a lab-scale fixed bed device at temperatures between 120 and 200 degrees C. Two samples of activated carbons (AC) (raw-AC and sulphur impregnated AC) were tested under the same conditions. The mineral-based sorbents were chemically promoted by sulphur, FeCl3 and CaBr2, achieving an improvement in the overall reduction percentage of Hg0out (g) up to 85%, which was comparable to that obtained using a commercial activated carbon for Hg capture (sulphur impregnated AC). The study demonstrates that sorbents with a matrix relatively richer in TiO2, Fe2O3 and Al2O3, as bentonite, favour Hg heterogeneous oxidation. The best Hg capture capacity was achieved with a zeolite sorbent sample characterized by high specific surface (132 m2/g) and impregnated with elemental sulphur. The final form of mercury retained in this sorbent was HgS with proved long-term stability in disposal and landfilling. The higher the temperature, the lower the efficiency of Hg capture being the optimum temperature for Hg-capture in the range of 120-150 degrees C. This study provides a basis for the development of new efficient non-carbon sorbents for mercury removal in the air pollution control lines of MSWI facilities considering the non-hazardous final form of mercury and its long-term landfilling/sequestration. PMID- 29248370 TI - Improvement of home composting process of food waste using different minerals. AB - This article presents the experimental study of the process of composting in a prototype home-scale system with a special focus on process improvement by using different additives (i.e. woodchips, perlite, vermiculite and zeolite). The interventions with different bulking agents were realized through composting cycles using substrates with 10% additives in specific mixtures of kitchen waste materials. The pre-selected proportion of the mixtures examined was 3:1:1 in cellulosic:proteins:carbohydrates, in order to achieve an initial C/N ratio equal to 30. The control of the initial properties of the examined substrates aimed at the consequent improvement of the properties of the final product (compost). The results indicated that composting process was enhanced with the use of additives and especially the case of zeolite and perlite provided the best results, in terms of efficient temperature evolution (>55 degrees C for 4 consecutive days). Carbon to nitrogen ratios decreased by 40% from the initial values for the reactors were minerals were added, while for the bioreactor tested with woodchips the reduction was slight, showing slowest degradation rate. Moisture content of produced compost varied within the range of 55-64% d.m., while nutrient content (K, Na, Ca, Mg) was in accordance with the limit values reported in literature. Finally, the composts obtained, exhibited a satisfactory degree of maturity, fulfilling the criterion related to the absence of phytotoxic compounds. PMID- 29248371 TI - Valorization of vitreous China waste to EMT/FAU, FAU and Na-P zeotype materials. AB - In this study, Na-X, Na-P, SOD and EMT/FAU zeotype materials have been prepared from vitreous China waste by conventional hydrothermal route and alkaline fusion prior to hydrothermal synthesis. The conventional route has shown its limits in the activation of the waste in the chosen experimental conditions, [NaOH] = 3.5 M and T = 60 degrees C. The amorphous phase of vitreous China waste plays an important role during the zeolitization process because it easily dissolves into the alkaline solution compared to crystalline phases like quartz and mullite. By the conventional route, Na-X and Na-P1 and SOD zeolites were obtained. The alkaline fusion step using NaOH as mineralizer at 550 degrees C converted the waste to highly active soluble aluminate and silicate salts. The fused material was mixed with distilled water to have liquid to solid ratio L/S = 5, under vigorous stirring at room temperature for 1 day. The obtained gel with molar composition of 7.0 Na2O: 1.0 Al2O3: 4.8 SiO2: 209.4 H2O was converted by hydrothermal crystallization at 60 degrees C to nanosized EMT/FAU zeotype and geopolymeric amorphous aluminosilicate material. With the increase of fusion time, there is a decrease of the amount of EMT-type zeolite. PMID- 29248372 TI - Food waste co-digestion with slaughterhouse waste and sewage sludge: Digestate conditioning and supernatant quality. AB - In this study, the anaerobic mesophilic co-digestion of food waste (FW) with municipal sewage sludge (MSS) and slaughterhouse waste (SHW) was undertaken in 3 dm3 laboratory reactors as well as in 50-dm3 reactors operated in semi-continuous conditions. The highest methane yield of around 0.63 m3 CH4/kgVSfed was achieved for the mixture of FW and SHW treated in the laboratory digester operated at solids retention time (SRT) of 30 days, whereas the co-digestion of FW with MSS under similar operating conditions produced 0.46 m3 of methane from 1 kgVSfed. No significant differences between methane yields from laboratory digesters and large-scale reactors were reported. The conditioning tests with the digestates from reactor experiments revealed the highest efficiency of inorganic coagulants among all investigated chemicals, which applied in a dose of 10 g/kg allowed to reduce capiliary suction time (CST) of the digestate below 20 s. The combined conditioning with coagulants and bentonite did not further reduce the CST value but improved the quality of the digestate supernatant. In particular, the concentrations of suspended solids, COD as well as metals in the supernatant were considerably lowered. PMID- 29248373 TI - Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression. AB - Upon stimulation of cells with transforming growth factor beta (TGF-beta), Smad proteins form trimeric complexes and activate a broad spectrum of target genes. It remains unresolved which of the possible Smad complexes are formed in cellular contexts and how these contribute to gene expression. By combining quantitative mass spectrometry with a computational selection strategy, we predict and provide experimental evidence for the three most relevant Smad complexes in the mouse hepatoma cell line Hepa1-6. Utilizing dynamic pathway modeling, we specify the contribution of each Smad complex to the expression of representative Smad target genes, and show that these contributions are conserved in human hepatoma cell lines and primary hepatocytes. We predict, based on gene expression data of patient samples, increased amounts of Smad2/3/4 proteins and Smad2 phosphorylation as hallmarks of hepatocellular carcinoma and experimentally verify this prediction. Our findings demonstrate that modeling approaches can disentangle the complexity of transcription factor complex formation and its impact on gene expression. PMID- 29248375 TI - Chaotic Dynamics Mediate Brain State Transitions, Driven by Changes in Extracellular Ion Concentrations. AB - Previous studies have suggested that changes in extracellular ion concentrations initiate the transition from an activity state that characterizes sleep in cortical neurons to states that characterize wakefulness. However, because neuronal activity and extracellular ion concentrations are interdependent, isolating their unique roles during sleep-wake transitions is not possible in vivo. Here, we extend the Averaged-Neuron model and demonstrate that, although changes in extracellular ion concentrations occur concurrently, decreasing the conductance of calcium-dependent potassium channels initiates the transition from sleep to wakefulness. We find that sleep is governed by stable, self-sustained oscillations in neuronal firing patterns, whereas the quiet awake state and active awake state are both governed by irregular oscillations and chaotic dynamics; transitions between these separable awake states are prompted by ionic changes. Although waking is indicative of a shift from stable to chaotic neuronal firing patterns, we illustrate that the properties of chaotic dynamics ensure that the transition between states is smooth and robust to noise. PMID- 29248374 TI - Multi-omics Reveal Specific Targets of the RNA-Binding Protein Puf3p and Its Orchestration of Mitochondrial Biogenesis. AB - Coenzyme Q (CoQ) is a redox-active lipid required for mitochondrial oxidative phosphorylation (OxPhos). How CoQ biosynthesis is coordinated with the biogenesis of OxPhos protein complexes is unclear. Here, we show that the Saccharomyces cerevisiae RNA-binding protein (RBP) Puf3p regulates CoQ biosynthesis. To establish the mechanism for this regulation, we employed a multi-omic strategy to identify mRNAs that not only bind Puf3p but also are regulated by Puf3p in vivo. The CoQ biosynthesis enzyme Coq5p is a critical Puf3p target: Puf3p regulates the abundance of Coq5p and prevents its detrimental hyperaccumulation, thereby enabling efficient CoQ production. More broadly, Puf3p represses a specific set of proteins involved in mitochondrial protein import, translation, and OxPhos complex assembly (pathways essential to prime mitochondrial biogenesis). Our data reveal a mechanism for post-transcriptionally coordinating CoQ production with OxPhos biogenesis, and they demonstrate the power of multi-omics for defining genuine targets of RBPs. PMID- 29248377 TI - Management of a complex intracranial arteriovenous malformation with gamma knife radiosurgery: A case report with review of literature. AB - The risks and benefits of arteriovenous malformation (AVM) treatment should be considered cautiously in each patient since management strategy of it depends on various factors including age of the patient, location and volume of AVM and presence of other vascular abnormalities. Current management options of AVM include observation, endovascular embolization, radiosurgery and microsurgical resection or in combination of any two of the above procedures. Here, we have discussed a case of intracranial AVM with radiation induced early cyst formation, and performed a literature review to determine the optimum treatment of complex intracranial AVM. Standard search strategies were performed in PubMed/Medline using appropriate terms such as "intracranial arteriovenous malformation" radiosurgery, embolization and microsurgical resection as well as medical subject headings. The particular case in this study was retrospectively reviewed. Literature review revealed that the mean marginal radiation dose used by the different authors was 19 Gy, cysts were developed in 3.6% patients, the average time to form cyst was 6.6 years, average volume of cyst was 6.7 ml and maximum cysts were removed by resection. In our case, the cyst was developed 2.5 years after radiosurgery. Radiation induced cyst formation is a delayed complication of AVM management. However, cyst formation in this case was comparatively earlier in our case. Therefore, continuous follow-up after radiosurgery is required for early detection of cyst formation. In addition, the review revealed that embolization before radiosurgery was a poor strategy. PMID- 29248376 TI - Postoperative radiosurgery for the treatment of metastatic brain tumor: Evaluation of local failure and leptomeningeal disease. AB - In patients undergoing surgical resection of a metastatic brain tumor, whole brain radiation therapy reduces the risk of recurrence and neurologic death. Focal radiation has the potential to mitigate neurocognitive side effects. We present an institutional experience of postoperative radiosurgery for the treatment of brain metastases. A retrospective review of a prospectively maintained institutional radiosurgery database was performed for the years 2005 2015 identifying all adult patients treated with postoperative radiosurgery to the tumor bed. Primary endpoints include local recurrence and postoperative LMD. Kaplan-Meier curves and Cox regression were used to evaluate time to local recurrence and postoperative LMD. Ninety-one patients received adjuvant focal radiation for a brain metastasis. Median radiographic follow-up among patients who had not developed a local failure was 9 months. Of the 91 patients, 20 (22%) developed local recurrence and 32 (35%) experienced postoperative LMD. Freedom from local recurrence and LMD at 1 year was 84% and 69%, respectively. In multivariable models, predictors of local failure included the presence of more than one brain metastasis (HR = 2.65, p = .04) with a preoperative tumor diameter of >3 cm (HR = 4.16, p = .06) trending toward significance. There was a trend to a higher risk of LMD with >1 tumor (HR 2.07, p = .06) and breast cancer (HR 2.37, p = .07). More than one metastasis is an independent predictor of local and leptomeningeal failure following postoperative radiosurgery. The high rate of LMD was likely related to the liberal definition of LMD to include focal dural recurrences. PMID- 29248378 TI - Atypical teratoid/rhabdoid tumor of the sellar region in adult women: Is it a sex related disease? AB - Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal tumor in children and a rare entity. Although adult AT/RT is extremely rare, some cases of adult-onset AT/RT in the sellar region have been described. Here, we report an adult patient with AT/RT of the sellar region in whom it was difficult to make a definitive diagnosis and the clinical course was aggressive. This is the first report of autopsy findings that could confirm the clinical characteristics of this rare unresolved pathology, and will contribute to the improvement of prognosis. In addition, a literature review was performed to clarify this exceptionally rare condition. Interestingly, all reported adult patients with sellar AT/RT, along with the present case, were female. This raises the possibility of its being a sex-related disease. However, further studies are required to come to a definitive conclusion. PMID- 29248379 TI - Intramedullary spinal cord metastasis from thyroid carcinoma: Case report and a systematic pooled analysis of the literature. AB - Intramedullary spinal cord metastasis (ISCM) is rare and occurs most commonly in the setting of advanced malignancy. The optimal management pathways are not well defined and treatment outcomes from contemporary therapies remain variable. We report a case of a 49-year-old woman with known primary papillary thyroid carcinoma, who presented with rapidly progressive clinical features of Brown Sequard syndrome. A detailed pooled analysis of the literature was conducted to characterise the clinical and demographic features, management options, and expected survival outcomes for cases of ISCM. We secondarily performed a subgroup analysis on the incidence, clinical and management characteristics of thyroid carcinoma ISCM. PMID- 29248380 TI - Clinical pathologic case report: A 70-year-old man with inflammatory cerebral amyloid angiopathy causing headache, cognitive impairment, and aphasia. AB - A 70-year-old man presented with two months of worsening cognitive impairment, hallucinations, and difficulty speaking, with superimposed headaches. Cerebrospinal fluid analysis was notable for lymphocytic pleocytosis and elevated protein. Imaging studies revealed multiple acute and subacute infarcts with cortical microhemorrhages. The patient underwent a stereotactic brain biopsy. In this article, we discuss the patient's differential diagnosis, pathologic findings, ultimate diagnosis, and clinical outcome. PMID- 29248382 TI - Risk factors for nosocomial infections after cardiac surgery in newborns with congenital heart disease. AB - BACKGROUND: Congenital heart diseases are among the most common congenital malformations. Approximately 50% of the patients with congenital heart disease undergo cardiac surgery. Nosocomial infections (NIs) are the main complications and an important cause of increased morbidity and mortality associated with congenital heart diseases. This study's objective was to identify the risk factors associated with the development of NIs after cardiac surgery in newborns with congenital heart disease. METHODS: This was a nested case-control study that included 112 newborns, including 56 cases (with NI) and 56 controls (without NI). Variables analyzed included perinatal history, associated congenital malformations, Risk-Adjusted Congenital Heart Surgery (RACHS-1) score, perioperative and postoperative factors, transfusions, length of central venous catheter, nutritional support, and mechanical ventilation. STATISTICAL ANALYSIS: Differences were calculated with the Mann-Whitney-U test, Pearson X2, or Fisher's exact test. A multivariate logistic regression was used to determine the independent risk factors. RESULTS: Sepsis was the most common NI (37.5%), and the main causative microorganisms were gram-positive cocci. The independent risk factors associated with NI were non-cardiac congenital malformations (OR 6.1, CI 95% 1.3-29.4), central venous catheter indwelling time > 14 days (OR 3.7, CI 95% 1.3-11.0), duration of mechanical ventilation > 7 days (OR 6.6, CI 95% 2.1-20.1), and >=5 transfusions of blood products (OR 3.1, CI 95% 1.3-8.5). Mortality attributed to NI was 17.8%. CONCLUSION: Newborns with non-cardiac congenital malformations and with >7 days of mechanical ventilation were at higher risk for a postoperative NI. Efforts must focus on preventable infections, especially in bloodstream catheter-related infections, which account for 20.5% of all NIs. PMID- 29248381 TI - High-grade thalamic gliomas: Microsurgical treatment and prognosis analysis. AB - This retrospective study is aimed to investigate the efficacy of microsurgical treatment for high-grade thalamic gliomas, and to analyze the relevant prognosis. From May 2011 to Aug 2015, 49 patients with thalamic gliomas underwent microsurgical resection, and received chemotherapy and radiotherapy postoperatively. The postoperative symptoms and complications were documented, and the overall survival (OS) and the progression-free survival (PFS) data were collected. The prognostic factors were evaluated by univariate and multivariate analyses. Finally, there was no perioperative death. Twenty cases, 24 cases and 5 cases were achieved subtotal resection (>90%), partial resection (70-90%) and less than partial resection (<70%) respectively. All patients' pathological diagnosis was confirmed. The symptoms were improved in 32 cases, unchanged in 11 cases, and worsen in 6 cases. Postoperative complications were absent in 9 cases. The 6-month, 12-month, and 24-month OS were 71.4%, 38.9%, and 12.1% respectively; corresponding PFS were 66.6%, 27.1%, and 10.2% respectively. The median OS time and PFS time were 9.0 months (95% CI 6.9-11.1) and 9.0 months (95% CI 6.6-11.4) respectively. Multivariate analysis revealed extent of resection were independent prognostic factors for OS (p < .05), patients with postoperative adjuvant chemotherapy and radiotherapy had a significant prolonged OS (p < .001) and PFS (p < .001). The study shows that the short-term efficacy of microsurgery for high grade thalamic gliomas is satisfactory. Microsurgery can effectively alleviate patients' symptoms and improve life quality. Postoperative adjuvant chemotherapy and radiotherapy are helpful for prolonging the survival time. PMID- 29248383 TI - The effect of nesting positions on pain, stress and comfort during heel lance in premature infants. AB - BACKGROUND: Nesting positions are commonly used in procedural analgesic administration in premature neonates. The effectiveness of nesting positions is questioned. The aim of the this study was to assess the pain, stress, comfort and salivary cortisol and melatonin values in nesting positions during the heel lance procedure in premature infants at the NICU. METHODS: Experimental research; repeated measurement design. The sample comprised 33 premature neonates with gestational age of 31-35 weeks who had been hospitalized in the NICU. Nesting positions were given using linen or towels. The procedure of heel lance was recorded on camera. The camera recordings were evaluated according to the NIPS and the COMFORTneo scale. Saliva samples were obtained five minutes prior to and 30 min after the heel lance procedure. Salivary Cortisol and Melatonin were measured using the Salimetrics Cortisol Elisa Kit and the Salimetrics Melatonin Elisa Kit. RESULTS: The crying time, the mean NIPS score, the COMFORTneo score, the COMFORTneo NRS-pain scores and the COMFORTneo NRS-distress scores for premature neonates who were in the prone position during the procedure were significantly lower than the scores in the supine position (p < 0.000). Furthermore, the level of salivary cortisol five minutes prior to and 30 min after the heel lance procedure had significantly decreased in the prone position; however, there were insignificant differences in the mean levels of salivary melatonin between the positions. CONCLUSIONS: Nesting in the prone position has a pain reducing effect, enhancing comfort and reducing stress in premature infants. PMID- 29248385 TI - A cytosolic sensor, PmDDX41, mediates antiviral immune response in black tiger shrimp Penaeus monodon. AB - DEAD (Asp-Glu-Ala-Asp)-box polypeptide 41 (DDX41), a receptor belonging to the DExD family, has recently been identified as an intracellular DNA sensor in vertebrates. Here, we report on the identification and functional characterization of PmDDX41, the first cytosolic DNA sensor in shrimp. By searching a Penaeus monodon expressed sequence tag (EST) database (http://pmonodon.biotec.or.th), three cDNA fragments exhibiting similarity to DDX41 in various species were identified and assembled, resulting in a complete open reading frame of PmDDX41 that contains 1863-bp and encodes a putative protein of 620 amino acids. PmDDX41 shares 83% and 79% similarity to DDX41 homolog from the bee Apis florea and fruit fly Drosophila melanogaster, respectively and contains three conserved domains in the protein: DEADc domain, HELICc domain, and zinc finger domain. The transcript of PmDDX41 was detected in all tested tissues and was up-regulated upon infection with a DNA virus, white spot syndrome virus (WSSV). However, PmDDX41 mRNA expression was not significantly changed and down-regulated in response to a bacterium, Vibrio harveyi, or an RNA virus, yellow head virus (YHV), respectively, compared with the control phosphate-buffered saline-injected shrimp. Furthermore, the suppression of PmDDX41 by dsRNA-mediated gene silencing resulted in more rapid death of WSSV-infected shrimp and a significant decrease in the mRNA expression levels of several immune-related genes (PmIKKbeta, PmIKKE, PmRelish, PmCactus, PmDorsal, PmPEN3, PmPEN5, and ALFPm6). These results suggest that PmDDX41 is involved in the antiviral response, probably via a DNA-sensing pathway that is triggered through the IkappaB kinase complex and leads to the activation of several immune-related genes. PMID- 29248384 TI - Efficacy and Tolerability of Telmisartan/Amlodipine + Hydrochlorothiazide Versus Telmisartan/Amlodipine Combination Therapy for Essential Hypertension Uncontrolled With Telmisartan/Amlodipine: The Phase III, Multicenter, Randomized, Double-blind TAHYTI Study. AB - PURPOSE: This 8-week study in Korea aimed to evaluate the efficacy and tolerability of a telmisartan/amlodipine + hydrochlorothiazide (TAH) combination versus telmisartan/amlodipine (TA) combination in patients with essential hypertension that did not respond appropriately to 4-week treatment with TA. METHODS: All patients who met the inclusion criteria received TA (40/5 mg) during a 4-week run-in period (period 1). Patients who met the criteria for essential hypertension (mean sitting systolic blood pressure [MSSBP], >=140 and <200 mm Hg, or >=130 and<200 mm Hg in those with diabetes mellitus or chronic kidney disease) after period 1 were randomly assigned to receive TA 40/5 mg + hydrochlorothiazide 12.5 mg (test group) or TA only (control group). The test and control drugs were administered in each group for 2 weeks (period 2). Patients who completed period 2 underwent 6-week treatment (period 3) with a TAH and TA dose twice that in period 2. The primary end point was the change in MSSBP at week 8 of treatment. Secondary end points were the change in MSSBP at week 2 and MS diastolic BP, BP control rate, and BP response rate at weeks 2 and 8. Treatment tolerability was assessed based on adverse events (AEs), laboratory evaluations (chemistry, hematology, and urinalysis), 12-lead ECG, and physical examination including vital sign measurements. FINDINGS: We randomized 310 patients to the treatment groups. The mean (SD) ages of the TAH and TA groups were 62.0 (10.8) and 63.4 (10.4) years, respectively. The least squares mean change in MSSBP was significantly greater in the TAH group than in the TA group after 8 weeks (-18.7 vs -12.2 mm Hg; P < 0.001). Similar results were obtained on changes in MSSBP after 2 weeks and changes in sitting diastolic BP, BP control rate, and BP response rate at weeks 2 and 8 compared with the respective baseline values. The prevalences of treatment-emergent AEs (29.0% vs 16.3%; P = 0.008) and adverse drug reactions (20.0% vs 10.5%; P = 0.020) were significantly greater in the TAH group than in the TA group. Most treatment-emergent AEs were mild or moderate; none were severe. The most frequently reported AEs were dizziness and headache. IMPLICATION: TAH triple therapy was more effective than was TA double therapy in reducing BP in these patients in Korea with essential hypertension that did not adequately respond to TA. ClinicalTrials.gov identifier: NCT02738632. PMID- 29248386 TI - Assessment of Antihistamines and Corticosteroids as Premedication in Rapid Drug Desensitization to Paclitaxel: Outcomes in 155 Procedures. AB - BACKGROUND: In early clinical trials, infusion reactions during the administration of taxanes were managed using systematic premedication with antihistamines and corticosteroids before standard infusions. Consequently, these premedications are also administered before rapid drug desensitization (RDD) with taxanes. However, their role in RDD has not been studied. OBJECTIVE: To assess the need for premedication with antihistamines and corticosteroids to prevent hypersensitivity reactions in RDD to paclitaxel. METHODS: Over a 4-year period, we selected patients with confirmed hypersensitivity to paclitaxel (positive skin testing and/or drug provocation testing results) who had received paclitaxel through RDD. These patients were assigned to 2 prospective noninception cohorts: one cohort premedicated with antihistamine and corticosteroids and another cohort that was not. RESULTS: We assessed 66 paclitaxel-reactive patients, of whom 22 met the inclusion criteria. A total of 155 RDDs to paclitaxel were performed. There were no significant differences in tolerance to RDD between the cohorts. CONCLUSIONS: Administering systematic premedication with corticosteroids and antihistamines had no significant effect on the effectiveness or safety of RDD in patients with confirmed hypersensitivity to paclitaxel in the study population. Moreover, these premedications can mask early signs of hypersensitivity and delay treatment. We believe that systematic premedication with these drugs for patients undergoing RDD should be carefully and individually assessed if their only purpose is to prevent breakthrough reactions during RDD. PMID- 29248387 TI - The Prevalence of Food Sensitization Appears Not to Have Changed between 2 Melbourne Cohorts of High-Risk Infants Recruited 15 Years Apart. AB - BACKGROUND: Although food allergy has probably risen over recent decades, recent reports suggest that the prevalence of food sensitization in the general population has not changed. However, this has not been analyzed in infants at high risk of food allergy. OBJECTIVE: The objective of this study was to compare the prevalence of food sensitization in high-risk infants from 2 cohorts recruited 15 years apart in the same region. METHODS: This study includes 620 high-risk infants with a family history of allergy (Melbourne Atopy Cohort Study [MACS]) born 1990-1994, and a subgroup of high-risk infants from the population based HealthNuts study (n = 3,661/5,276), born 2006-2010. Both studies undertook skin prick tests (SPT) to peanut, egg, and milk at age 12 months. A logistic regression model generated adjusted prevalences to account for differences in sampling frame. SPT >= 95% positive predictive values (PPVs) for food allergy were used as proxies for food allergy. RESULTS: The adjusted prevalence of sensitization in MACS was similar to the observed prevalence of sensitization in the high-risk subgroup of HealthNuts: 7.9% (95% confidence interval 6.8-8.9) and 7.9% (7.0-8.8) respectively for peanut, 15.0% (13.4-16.6) and 14.5% (13.4-15.7) respectively for egg, and 2.4% (1.6-3.1) and 2.6% (2.0-3.4) respectively for cow's milk. The prevalence of SPT >= 95% PPVs was similar between the 2 studies. CONCLUSIONS: The prevalence of food sensitization among high-risk infants has remained stable in Australia since the 1990s, despite the reported increase in food-related anaphylaxis in the same period. This discrepancy could be due to increased food allergy in the low-risk population, increased conversion of food sensitization to allergy, or increased number of high-risk infants. Alternatively, increased awareness or severity of reactions may have led to an apparent increase in food allergy. PMID- 29248388 TI - Voice Range Change After Injection Laryngoplasty for Unilateral Vocal Fold Paralysis. AB - OBJECTIVES: Patients with unilateral vocal fold paralysis (UVFP) caused by nerve injury manifest with voice changes. This study investigated vocal performance measured by voice range profile (VRP) in patients with UVFP and changes in VRP in response to intracordal hyaluronate injection. METHODS: Eighty-five patients with UVFP were enrolled prospectively, among whom 68 received intracordal hyaluronate injections. The outcome measurements included VRP, acoustic and aerodynamic analyses, peak turn frequency of thyroarytenoid-lateral cricoarytenoid muscle complex (TA-LCA) measured by laryngeal electromyography, and normalized glottal gap area by videolaryngostroboscopy. RESULTS: The peak turn frequency of the paralyzed TA-LCA showed a modest correlation with max fundamental frequency (F0) and F0 range. Closed-phase normalized glottal gap area showed modest negative correlations with max F0 and F0 semitone range. Regarding conventional acoustic and aerodynamic analyses, the paralyzed TA-LCA peak turn frequency was only correlated with maximal phonation time. Intracordal hyaluronate injection improved VRP performance by increasing max F0, decreasing min F0, increasing F0 range, and increasing semitone range (all P <0.01) with small or medium strength of effect size (Cohen d, 0.39-0.76). CONCLUSIONS: Change in voice pitch in patients with UVFP can partly predict impairment of neuromuscular functions and glottal gap. VRP provides a more sensitive reflection of the severity of neuromuscular impairment, compared with conventional voice analysis. The validity of VRP is further supported by a robust response to voice improvements following injection laryngoplasty. PMID- 29248389 TI - Ethnic Differences in Cigarette Use Trajectories and Health, Psychosocial, and Academic Outcomes. AB - PURPOSE: Cigarette smoking among youth is associated with poorer health and psychosocial outcomes. However, few studies address how smoking may differentially relate to the emergence of disparities in functioning across races/ethnicities over adolescence. METHODS: Youth (n = 2,509) were surveyed eight times from ages 11 to 18. We measured cigarette use, academic and social functioning, mental and physical health, and delinquency. Sequelae of change models controlled for sociodemographic factors, and tested whether intercept and slope for smoking trajectories were associated with outcomes at the end of high school, and examined racial/ethnic differences in outcomes assuming similar smoking trajectories across groups. RESULTS: Youth were 45% Hispanic, 20% Asian, 20% white, 10% multiethnic, 2% black, and 1% other ethnicities. Higher average probability of smoking and steeper slopes of smoking trajectories were associated with poorer outcomes in multiple domains. Controlling for smoking trajectories, we observed the following disparities (vs. white youth; all p's < .05): black, Hispanic, and multiethnic youth reported lower academic performance; Asian, black, and multiethnic youth reported higher academic unpreparedness; Asian and multiethnic youth reported poorer mental health; Asian, Hispanic, and multiethnic youth reported poorer physical health; and Asian youth reported higher delinquency and poorer social functioning. CONCLUSIONS: Statistically adjusting for similar smoking trajectories, racial/ethnic minority youth demonstrated poorer outcomes in multiple domains compared with white peers. Smoking may be a particularly robust marker for risk of negative outcomes in racial/ethnic minority youth. Screening for cigarette use and intervening on smoking and associated risk behaviors among minority youth may help reduce disparities in functioning. PMID- 29248390 TI - School-located Influenza Vaccinations for Adolescents: A Randomized Controlled Trial. AB - PURPOSE: We aimed to evaluate the effect of school-located influenza vaccination (SLIV) on adolescents' influenza vaccination rates. METHODS: In 2015-2016, we performed a cluster-randomized trial of adolescent SLIV in middle/high schools. We selected 10 pairs of schools (identical grades within pairs) and randomly allocated schools within pairs to SLIV or usual care control. At eight suburban SLIV schools, we sent parents e-mail notifications about upcoming SLIV clinics and promoted online immunization consent. At two urban SLIV schools, we sent parents (via student backpack fliers) paper immunization consent forms and information about SLIV. E-mails were unavailable at these schools. Local health department nurses administered nasal or injectable influenza vaccine at dedicated SLIV clinics and billed insurers. We compared influenza vaccination rates at SLIV versus control schools using school directories to identify the student sample in each school. We used the state immunization registry to determine receipt of influenza vaccination. RESULTS: The final sample comprised 17,650 students enrolled in the 20 schools. Adolescents at suburban SLIV schools had higher overall influenza vaccination rates than did adolescents at control schools (51% vs. 46%, p < .001; adjusted odds ratio = 1.27, 95% confidence interval 1.18-1.38, controlling for vaccination during the prior two seasons). No effect of SLIV was noted among urbanschools on multivariate analysis. SLIV did not substitute for vaccinations in primary care or other settings; in suburban settings, SLIV was associated with increased vaccinations in primary care or other settings (adjusted odds ratio = 1.10, 95% confidence interval 1.02-1.19). CONCLUSIONS: SLIV in this community increased influenza vaccination rates among adolescents attending suburban schools. PMID- 29248391 TI - The Impact of a Parental Notification Requirement on Illinois Minors' Access to and Decision-Making Around Abortion. AB - PURPOSE: This study aims to examine the impact of a parental notification (PN) requirement on the frequency, timing, and out-of-state travel of minors seeking abortion, as well as changes in who minors involve in their decision, support received, and decision certainty. METHODS: We analyzed administrative and medical records of 1,577 women obtaining an abortion before and after implementation of a PN requirement at one Illinois facility. Using multivariate regression within a difference-in-differences framework, we quantified changes in the number and timing of women seeking care, frequency of parental awareness and support, travel from out-of-state, decision certainty, and anticipated coping among minors 17 years and below compared with young adults (YAs) aged 18-20 years. RESULTS: A smaller proportion of abortions to women ages 20 years and under post-law were among minors (39%-33%, p = .017). Compared with YAs, minors experienced a larger increase in parental awareness (71%-93% [minors] vs. 53%-58% [YAs], p < .000]; however, parents' support for the decision was unchanged. The proportion of minors certain of their decision went from 77% pre-law to 71% post-law (p = .099) compared with 82% pre- and post-law among YAs (p = .798). Compared with YAs, a larger proportion of minors obtained second trimester care post-law if coming from another state (21%-31% [minors] vs. 23%-16% [YAs], p = .022). CONCLUSIONS: Illinois' PN requirement was associated with a decrease in the number of abortions among minors, delayed care for those from out-of-state, increased parental awareness of the pregnancy, and no change in parents' support. PMID- 29248392 TI - Targeting Human Immunodeficiency Virus Pre-Exposure Prophylaxis to Adolescent Sexual Minority Males in Higher Prevalence Areas of the United States: A Modeling Study. AB - PURPOSE: Pre-exposure prophylaxis (PrEP) is an effective and safe intervention to prevent human immunodeficiency virus (HIV) transmission in men who have sex with men; current Centers for Disease Control and Prevention guidelines indicate its use among high-risk adults. Adolescent sexual minority males (ASMM) also have significant HIV risk, but implementation strategies are likely to differ for this population. We aimed to estimate impact and efficiency of PrEP for ASMM in higher prevalence US settings, using a variety of implementation strategies and assumptions about coverage, adherence, and background prevalence. METHODS: We develop a stochastic, dynamic, network-based model, parametrized using numerous ASMM behavioral and clinical data sources. We simulate 10 years with and without PrEP, comparing percent of incident infections averted (impact) and number of person-years on PrEP per infection averted (efficiency). RESULTS: Our main scenario (PrEP for 16- to 18-year-old ASMM, initiating PrEP 6 months after first anal intercourse, 40% coverage, adherence profiles from the ATN 113 trial; 2.9% background HIV prevalence among ASMM) prevents 27.8% of infections, with 38 person-years on PrEP per infection averted. Expanding implementation to cover younger ages or earlier initiation has small effects on impact and efficiency. Targeting highest risk ASMM increases efficiency, but requires querying sexual histories. Across levels examined, coverage and adherence do not have major impacts on efficiency, whereas background prevalence does. CONCLUSIONS: PrEP can have a large impact on HIV incidence among ASMM in the United States, especially in settings with high prevalence. However, willingness of, and support for, providers will be central to achieving the coverage needed to make this a success. PMID- 29248394 TI - Reverse lymphatic mapping without radioisotope in the surgical treatment of lymphedema. PMID- 29248393 TI - Primary Care Physicians' Decision Making Regarding Initial Oncology Referral for Adolescents and Young Adults With Cancer. AB - PURPOSE: The objectives of this study were to determine whether pediatricians are more likely than other primary care physicians (PCPs) to refer newly diagnosed adolescent and young adult patients with cancer to pediatric oncological specialists, and to assess the physician and patient characteristics that affect patterns of referral. METHODS: A cross-sectional vignette survey was mailed to PCPs to examine hypothetical referral decisions as a function of physician characteristics and patient characteristics, including diagnosis, age, gender, race/ethnicity, family support, transportation, insurance, and patient preference for site of care. Pediatrician PCPs and nonpediatrician PCPs (family medicine, internal medicine, and emergency medicine physicians) practicing in North Carolina and in Washington State participated in the study. RESULTS: A total of 406 surveys were completed (35.8% response rate). Sixty percent of pediatric PCPs referred their hypothetical patients with cancer to pediatric specialists (PSs), compared with only 37% of nonpediatric PCPs. Patient age also influenced referral patterns; 89% of 13-year-olds, 74% of 16-year-olds, 25% of 19-year-olds, and only 9% of 22-year-old patients were referred to a PS. Multivariate logistic regression demonstrated that diagnosis and physician practice setting also were associated with referral patterns. CONCLUSIONS: Both patient age and PCP specialty were significant predictors of referral patterns in hypothetical vignettes of newly diagnosed adolescent and young adult patients with cancer. Pediatricians were more likely than nonpediatrician PCPs to refer patients to a PS. Referrals to PSs decreased dramatically between ages 16 and 19. Because the site of oncological care can impact outcomes, these data have the potential to inform awareness and education initiatives directed at PCPs. PMID- 29248395 TI - Accessory extensor pollicis longus: A rare tendon anomaly. AB - This report provides a complete review of a rare anatomical variation, the accessory extensor pollicis longus (EPL) tendon and its clinical significance. We will describe a case of an asymptomatic accessory EPL that was found incidentally during surgery with a tendon located in the fourth extensor compartment. Pulling on it induced extension of the thumb interphalangeal joint. Very few cases of accessory EPL have been previously reported with various muscle origins and tendon insertions. In the literature, three symptomatic cases of accessory EPL were reported with a tendon running in a compartment other than the fourth. Although this variation is asymptomatic in most cases, knowledge of its existence might be useful in routine procedures to avoid inadvertent tendon damage, or during tendon repair. PMID- 29248396 TI - Biomechanical study comparing Pulvertaft suture to step-cut suture. AB - Tendon grafts are a component of the therapeutic arsenal for managing chronic flexor tendons injuries in the hand, especially during two-stage Hunter reconstruction. The purpose of this anatomical study was to compare the strength of the Pulvertaft weave versus the step-cut suture used for flexor tendon reconstruction to determine their role in early active mobilization. We performed a biomechanical study with cadaver specimens. Thirty-four hands were randomized and the tendons from both hands were equally assigned to each group. A comparison of the Pulvertaft weave (group 1) versus the step-cut suture (group 2) using the flexor digitorum profundus from the fourth finger and the longus palmaris was carried out. The main variable was the failure load in both repair groups. We also evaluated the cross-sectional area (CSA) and the tensile strength of the repairs. Thirty hands were included in our study. There was no significant difference in the failure load between the two groups (116N for group 1 versus 103N for group 2, P=0.2). The CSA was significantly smaller in the step-cut group compared to Pulvertaft group (19.8mm2 versus 35mm2, P<0.01). The tensile strength was significantly higher in the step-cut group than in the Pulvertaft group (5.3N/mm2 versus 3.4N/mm2, P<0.01). Early active mobilization requires a minimum repair strength of 75N. In our study, the step-cut suture appears strong enough and thin enough to decrease the fibrosis, which would lead to better functional results. No other study of this type has been published. The specimens in which the repair strength was less than 75N all involved a thin, weak longus palmaris. Other biomechanical studies should be done to define the anatomical criteria required for use of the palmaris longus tendon. The step-cut suture seems to be strong enough and thin enough to provide sufficient proximal attachment during flexor tendon reconstruction to allow early active mobilization. PMID- 29248397 TI - Comparison of low back mobility and stability exercises from Pilates in non specific low back pain: A study protocol of a randomized controlled trial. AB - BACKGROUND: There is some evidence in the literature about the effectiveness of the Pilates methods in the low back pain. Moreover, Pilates focus on exercises that empathizes the stability and/or mobility of the spine. Therefore, it is discussed in the literature whether higher levels of stability or mobility of the lumbar spine generates better results, both in performance and rehabilitation for low back pain. OBJECTIVES: Compare the effects of the low back mobility and stability exercises from Pilates Method on low back pain, disability and movement functionality in individuals with non-specific chronic low back pain. METHODS: 28 participants will be randomized into two exercise protocol from Pilates methods, one focusing on low back stability and other on low back mobility. Low back pain (visual analogic scale), low back disability (Oswestry) and movement functionality (7 functional movement tasks) will be evaluated before and after 10 sessions of Pilates exercise by the same trained assessor. A mixed designed ANOVA with two factors will be used. This study is the first to compare these outcomes for chronic low back pain participants with two exercises protocol focusing on low back mobility and stability and the results will evaluate what to prioritize with Pilates exercises to give better results for that population. PMID- 29248398 TI - Challenging disease, challenging trial, challenging interpretation. PMID- 29248400 TI - The risk of incidental gallbladder cancer is negligible in macroscopically normal cholecystectomy specimens. AB - BACKGROUND: Cholecystectomy is usually carried out for benign indications. Most perform routine histopathologic examination to detect incidental gallbladder cancer (GBC). METHODS: Cholecystectomies performed at four hospitals in the Helsinki Metropolitan Area during 2010-2012 were analyzed retrospectively. Patients with preoperative suspicion of neoplasia, active malignancy, or in whom cholecystectomy was performed as a secondary procedure were excluded. RESULTS: A total of 2034 cholecystectomies were included. In ten patients (0.5%), GBC was identified, each with an associated macroscopic finding, including local hardness (n = 1), a thickened wall (n = 5), acute inflammation and necrosis (n = 1), or suspected neoplasia (n = 3). No GBC was found in macroscopically normal gallbladders (n = 1464). Of the ten patients with GBC, five underwent subsequent liver resection, four had metastatic disease, and one had locally advanced inoperable disease. Three of the five patients who underwent liver resection were alive and disease-free at final follow-up (median 48 months). The remaining seven patients with GBC died of the disease, with a median survival of 14 months (range 10-48 months). CONCLUSIONS: Routine histopathologic examination of a macroscopically normal gallbladder does not improve diagnosis of GBC. A histopathological examination is, however, mandatory when a macroscopic abnormality is present. PMID- 29248399 TI - Palliative chemoradiotherapy versus radiotherapy alone for dysphagia in advanced oesophageal cancer: a multicentre randomised controlled trial (TROG 03.01). AB - BACKGROUND: A short course of radiotherapy is commonly prescribed for palliative relief of malignant dysphagia in patients with incurable oesophageal cancer. We compared chemoradiotherapy with radiotherapy alone for dysphagia relief in the palliative setting. METHODS: This multicentre randomised controlled trial included patients with advanced or metastatic oesophageal cancer who were randomly assigned (1:1) through a computer-generated adaptive biased coin design to either palliative chemoradiotherapy or radiotherapy alone for treatment of malignant dysphagia at 22 hospitals in Australia, Canada, New Zealand, and the UK. Eligible patients had biopsy-proven oesophageal cancer that was unsuitable for curative treatment, symptomatic dysphagia, Eastern Cooperative Oncology Group performance status 0-2, and adequate haematological and renal function. Patients were stratified by hospital, dysphagia score (Mellow scale 1-4), and presence of metastases. The radiotherapy dose was 35 Gy in 15 fractions over 3 weeks for patients in Australia and New Zealand and 30 Gy in ten fractions over 2 weeks for patients in Canada and the UK. Chemotherapy consisted of one cycle of intravenous cisplatin (either 80 mg/m2 on day 1 or 20 mg/m2 per day on days 1-4 of radiotherapy at clinician's discretion) and intravenous fluorouracil 800 mg/m2 per day on days 1-4 of radiotherapy in week 1. Patients were assessed weekly during treatment. The primary endpoint was dysphagia relief (defined as >=1 point reduction on the Mellow scale at 9 weeks and maintained 4 weeks later), and key secondary endpoints were dysphagia progression-free survival (defined as a worsening of at least 1 point on the Mellow scale from baseline or best response) and overall survival. These endpoints were analysed in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00193882. This trial is closed. FINDINGS: Between July 7, 2003, and March 21, 2012, 111 patients were randomly assigned to chemoradiotherapy and 109 patients to radiotherapy. One patient in the chemoradiotherapy group was omitted from analysis because of ineligibility. 50 (45%, 95% CI 36-55) patients in the chemoradiotherapy group and 38 (35%, 26-44) in the radiotherapy group obtained dysphagia relief (difference 10.6%, 95% CI -2 to 23; p=0.13). Median dysphagia progression-free survival was 4.1 months (95% CI 3.5-4.8) versus 3.4 months (3.1 4.3) in the chemoradiotherapy and radiotherapy groups, respectively (p=0.58), and median overall survival was 6.9 months (95% CI 5.1-8.3) versus 6.7 months (4.9 8.0), respectively (p=0.88). Of the 211 patients who commenced radiotherapy, grade 3-4 acute toxicity occurred in 38 (36%) patients in the chemoradiotherapy group and in 17 (16%) patients in the radiotherapy group (p=0.0017). Anaemia, thrombocytopenia, neutropenia, oesophagitis, diarrhoea, nausea and vomiting, and mucositis were significantly worse in patients who had chemoradiotherapy than in patients who had radiotherapy. INTERPRETATION: Palliative chemoradiotherapy showed a modest, but not statistically significant, increase in dysphagia relief compared with radiotherapy alone, with minimal improvement in dysphagia progression-free survival and overall survival with chemoradiotherapy but at a cost of increased toxicity. A short course of radiotherapy alone should be considered a safe and well tolerated treatment for malignant dysphagia in the palliative setting. FUNDING: National Health and Medical Research Council, Canadian Cancer Society Research Institute, Canadian Cancer Trials Group, Trans Tasman Radiation Oncology Group, and Cancer Australia. PMID- 29248401 TI - Health economic implications of complications associated with pancreaticoduodenectomy at a University Hospital: a retrospective cohort cost study. AB - BACKGROUND: A cost analyses of complications following pancreaticoduodenectomy (PD) was performed in a high volume hepato-biliary-pancreatic service. We hypothesised that costs are increased with both severity and number of complications; we investigated the relationship between complications and specific cost centres. METHODS: 100 patients from 2011 to 2016 were included. Data relating to their perioperative course were collected. Complications were documented by the Clavien-Dindo classification and costs were inflated and converted to 2017 USD. RESULTS: Mean hospital costs in complicated patients more than doubled those of uncomplicated patients ($28 330 vs. $57 150, p < 0.0001). Total hospital costs significantly increased with both severity and number of complications. This cost increase was influenced by medical consult, pathology, pharmacy, radiology, ward, intensive care, and allied health costs, but not operating theatre or anaesthesia costs. Postoperative pancreatic fistula, postoperative haemorrhage, delayed gastric emptying and infection were associated with cost differentials of $65 438, $74 079, $35 620 and $46 316 respectively over uncomplicated patients. CONCLUSION: The development of complications following PD is common, costly and associated with increased length of stay. Costs increased with greater complication severity, and specific complications. The in-depth breakdown of hospital costs suggests specific targets for cost containment. PMID- 29248402 TI - Association of HLA class I and class II alleles with bullous pemphigoid in Chinese Hans. AB - BACKGROUND: Bullous pemphigoid (BP) is one of the most common autoimmune skin diseases. Associations of genes, especially human leukocyte antigen (HLA)-DQ alleles, with BP indicate that genetic predisposition contributes to the disease. OBJECTIVES: To evaluate the association of HLA class I and HLA class II alleles with susceptibility to BP in the northern Chinese Han population. METHODS: We performed genotype for HLA-A, -B, -C, -G, -DPA1, -DPB1, -DQA1, -DQB1 and -DRB1 loci in 105 patients with BP by Sanger sequence-based typing (SBT) method. These data were compared with a local control cohort of 420 age- and sex-matched cases. RESULTS: Among the HLA alleles described herein, the susceptibility alleles associated with a high prevalence of BP were A*11:01 (OR = 1.9 Pc = 0.017); B*37:01 (OR = 8, Pc = 1.811 * 10-6); G*01:01 (OR = 3.61, Pc = 2.839 * 10-15) and G*01:06 (OR = 2.22, Pc = 0.025); DQA1*01:05 (OR = 4.87, Pc = 5.822 * 10-5), DQA1*05:05 (OR = 2.64, Pc = 9.114 * 10-4), and DQA1*05:08 (OR = 10.2, Pc = 0.016); DQB1*03:01 (OR = 1.69, Pc = 0.048) and DQB1*05:01 (OR = 3.42, Pc = 7.28 * 10-6); and DRB1*10:01 (OR = 6.85, Pc = 2.63 * 10-6). To the contrary, HLA DQA1*01:02 (OR = 0.46, Pc = 8.603 * 10-4) and DQA1*01:03 (OR = 0.38, Pc = 0.048); DQB1*02:02 (OR = 0.28, Pc = 0.016); and DRB1*07:01 (OR = 0.26, Pc = 0.004) had significant associations with protection against BP. In addition, the frequency of haplotype HLA-DRB1*13-DQA1*05-DQB1*03 (OR = 12.32, Pc = 0.026) in BP patients was significantly higher than those in controls. CONCLUSION: Our data demonstrated that the alleles and haplotypes found in this study may be important differential genetic markers for susceptibility to or protection against BP in individuals of northern Chinese Han population. PMID- 29248404 TI - What can treatment research offer general practice? PMID- 29248403 TI - Reconstructed human epidermis for in vitro studies on atopic dermatitis: A review. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease causing a strong impact on quality of life. Its pathophysiology is the result of complex interactions involving immunological, genetic and environmental factors. Although there are several published in vitro three-dimensional models mimicking AD, none of them have taken all these pathophysiological features into account; thus, finding the right model may be complicated. This paper reviews the literature on the different reconstructed epidermis models of AD as well as their relevance. We focused our attention on both the defect of the epidermal barrier and the inflammation linked to the immune system. PMID- 29248405 TI - Laser-Assisted Transcaval Access for Transcatheter Aortic Valve Replacement. PMID- 29248406 TI - Percutaneous Coronary Intervention and the Obesity Paradox: Fat Chance. PMID- 29248407 TI - Multimodality Imaging of Rare Adult Presentation of ALCAPA Treated With Takeuchi Repair. PMID- 29248408 TI - Spontaneous Coronary Artery Dissection: Reflections on an Uncommon Etiology of Acute Myocardial Infarction. PMID- 29248409 TI - Trends of Incidence, Clinical Presentation, and In-Hospital Mortality Among Women With Acute Myocardial Infarction With or Without Spontaneous Coronary Artery Dissection: A Population-Based Analysis. AB - OBJECTIVES: The authors sought to determine the clinical characteristics and in hospital survival of women presenting with acute myocardial infarction (AMI) and spontaneous coronary artery dissection (SCAD). BACKGROUND: The clinical presentation and in-hospital survival of women with AMI and SCAD remains unclear. METHODS: The National Inpatient Sample (2009 to 2014) was queried for all women with a primary diagnosis of AMI and concomitant SCAD. Iatrogenic coronary dissection was excluded. The main outcome was in-hospital mortality. Propensity score matching and multivariable logistic regression analyses were performed. RESULTS: Among 752,352 eligible women with AMI, 7,347 had a SCAD diagnosis. Women with SCAD were younger (61.7 vs. 67.1 years of age) with less comorbidity. SCAD was associated with higher incidence of in-hospital mortality (6.8% vs. 3.4%). In SCAD patients, a decrease in in-hospital mortality was evident with time (11.4% in 2009 vs. 5.0% in 2014) and concurred with less percutaneous coronary intervention (PCI) (82.5% vs. 69.1%). Propensity score yielded 7,332 SCAD and 14,352 patients without SCAD. The odds ratio (OR) of in-hospital mortality remained higher with SCAD after propensity matching (OR: 1.87, 95% confidence interval [CI]: 1.65 to 2.11) and on multivariable regression analyses (OR: 2.41, 95% CI: 2.07 to 2.80). PCI was associated with higher mortality in SCAD patients presenting with non-ST-segment elevation myocardial infarction (OR: 2.01; 95% CI: 1.00 to 4.47), but not with STEMI (OR: 0.62; 95% CI: 0.41 to 0.96). CONCLUSIONS: Women presenting with AMI and SCAD appear to be at higher risk of in-hospital mortality. Lower rates of PCI were associated with improved survival, with evidence of worse outcomes when PCI was performed for SCAD in the setting of non with ST-segment elevation myocardial infarction. PMID- 29248410 TI - Infective Endocarditis Diagnosed With Aspiration Thrombectomy. PMID- 29248411 TI - Fate of Different Types of Intrastent Tissue Protrusion: Optical Coherence Tomography and Angioscopic Serial Observations at Baseline and 9-Day and 3-Month Follow-Up. PMID- 29248413 TI - Type I Endoleak Post-Endovascular Aneurysm Repair, Successfully Treated With Excluder Cuff and Fixation Screws. PMID- 29248412 TI - Effects of Body Mass Index on Clinical Outcomes in Female Patients Undergoing Percutaneous Coronary Intervention With Drug-Eluting Stents: Results From a Patient-Level Pooled Analysis of Randomized Controlled Trials. AB - OBJECTIVES: This study sought to investigate the effect of different body mass index (BMI) categories on clinical outcomes in female patients treated with percutaneous coronary intervention (PCI) and drug-eluting stents. BACKGROUND: Patients with higher BMI might, paradoxically, have better long-term clinical outcomes after acute coronary syndrome treated with PCI. METHODS: We pooled patient-level data for female participants from 26 randomized trials on PCI with drug-eluting stents. Patients were stratified into underweight (BMI, <18.5), normoweight (BMI, 18.5 to 24.9), overweight (BMI, 25 to 29.9), obese (BMI, 30 to 34.9), or morbidly obese (BMI, >=35). The primary endpoint was major adverse cardiac events, a composite of death, myocardial infarction, or target lesion revascularization at 3 years. RESULTS: Among 11,557 female patients included in the pooled database, 9,420 were treated with a drug-eluting stent and had BMI data available. Patients with higher BMI were significantly younger and with more cardiovascular risk factors. Only 139 patients were underweight and had significantly higher adjusted rates of cardiac mortality and all-cause mortality than the rest of the population (hazard ratio: 2.20 [1.31 to 3.71] compared with normoweight). There was a significantly lower frequency of unadjusted 3-year all cause mortality in overweight, obese, and severely obese patients compared with normoweight. However, following multivariable analysis, a trend toward increased risk of death in severely obese patients was observed, describing an inverse "J" shaped relation between BMI and 3-year mortality. Conversely, the relationship between BMI and other outcomes, such as major adverse cardiac events, was flat for normoweight and higher BMI. CONCLUSIONS: The risk of 3-year adjusted cardiac events did not differ across BMI groups, whereas the risk of all-cause mortality compared with normoweight was significantly higher in underweight patients and lower in overweight patients with a trend toward increased risk in the severely obese population. PMID- 29248414 TI - Effects of vector control on the population structure of tsetse (Glossina fuscipes fuscipes) in western Kenya. AB - Displacement rates of tsetse affect performance of targets during vector control. Fly size, one of the indicators of population structure usually obtained from wing measurement, is among the determinants of displacement rates. Although recovery of tsetse in previous intervention areas has been widely reported, the population structure of tsetse that recover is rarely evaluated despite being associated with displacements rates. Previously, intervention trials had reduced tsetse densities by over 90% from >3 flies/trap/day to <1fly/trap/day on Big Chamaunga and Manga islands of Lake Victoria in western Kenya. In this study, we assessed the recovery in densities of Glossina fuscipes fuscipes on the two islands and evaluated the effects vector control might have on the population structure. A before and after intervention study was undertaken on four islands of Lake Victoria in western Kenya; Small and Big Chamaunga, Manga and Rusinga Islands, two of which tsetse control intervention had previously been undertaken. Three years after intervention average G. f. fuscipes catches in biconical traps were estimated on each island. Wing centroid size (CS) (a measurement of fly size) and shape, indicators of the population structure of flies from the four islands were compared using geometric morphometric analyses. CS and shape of available female but not male tsetse wings obtained before the intervention trial on Big and Small Chamaunga islands were compared with those from the same islands after the intervention trial. G. f. fuscipes apparent density on the previous intervention islands were>9 flies/trap/day. Irrespective of sex, wing shape did not isolate tsetse based on their islands of origin. The fly size from Big and Small Chamaunga did not differ significantly before intervention trials (P = 0.728). However, three years after the intervention flies from Big Chamaunga were significantly smaller than those from Small Chamaunga (P < 0.003). Further, there was an increase in the divergence of wing morphology between flies collected from Big Chamaunga and those from Small Chamaunga after tsetse control. In conclusion, even though populations are not isolated, vector control could influence the population structure of tsetse by exerting size and wing morphology differential selection pressures. Therefore, we recommend further studies to understand the mechanism behind this as it may guide future vector control strategies. PMID- 29248415 TI - Ultrastructure of male genitalia of blow flies (Diptera: Calliphoridae) of forensic importance. AB - Male genitalia of blow flies (Diptera: Calliphoridae) are distinctive in their morphological features and are often used for species identification. The aim of this work was to investigate the male genitalia of blow flies of medical and forensic importance from Thailand at the ultrastructural level, using scanning electron microscopy (SEM). Flies in two subfamilies were examined: Chrysomyinae [Chrysomya bezziana Villeneuve, Chrysomya chani Kurahashi, Chrysomya nigripes Aubertin, Chrysomya pinguis (Walker), Chrysomya rufifacies (Macquart), Chrysomya thanomthini Kurahashi & Tumrasvin, and Chrysomya villeneuvi Patton] and Luciliinae [Hemipyrellia ligurriens (Wiedemann), Hypopygiopsis infumata (Bigot), Hypopygiopsis tumrasvini Kurahashi, Lucilia cuprina (Wiedemann), Lucilia papuensis Macquart, Lucilia porphyrina (Walker), and Lucilia sinensis Aubertin]. Particular attention was paid to the main distinguishing features such as the shapes of the cercus and the surstylus, and the complex structure of the distiphallus. The differentiation of the male genitalia of these species at the SEM level is discussed and compared to the conditions in closely related species such as Chrysomya megacephala (Fabricius). A key for the identification of 14 blow fly species based on male genitalia is provided. PMID- 29248416 TI - Simulation-Based Skill Training for Trainees in Cardiac Surgery: A Systematic Review. AB - BACKGROUND: Simulation-based training has been an important part of the solution to address the shortfalls in cardiac surgery training. This review was conducted to identify and systematically summarize existing evidence on outcomes and methodological quality of simulation-based skills training for cardiac surgery trainees. METHODS: MEDLINE, Embase, and ERIC (Education Resources Information Center) databases were searched. Studies included peer-reviewed publications with simulation-based skill training in cardiac surgery programs with outcome measures of performance. Data extraction covered the type of skills training, simulator type and fidelity, the level of trainees, assessment tools, assessors, study design and its components, strengths and limitations, and elements required for the Medical Education Research Study Quality Instrument score. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 16 studies that met the criteria, only four (25%) randomized controlled trials were identified, and the remaining were observational studies. Seven observational studies (43.7%) were single-group pre post tests. The mean number of trainees was 20.4 (SD, 14.1). Low-fidelity simulators were used in 13 studies (81.2%). Most of the studies (81.3%) were high quality based on a Medical Education Research Study Quality Instrument score of 12 or more. Evidence of assessment tool validation was absent among all studies. No study outcome measures were directed to skills transfer to the operating room or patient outcomes. Overall learning outcomes' effect sizes were consistently high (2.2; SD, 1.6), with junior residents benefitting most (effect size, 2.8; SD, 2.2) CONCLUSIONS: Simulation-based skill training is associated with improved learning outcomes for cardiac surgery trainees with large effect sizes, but more behavior-level outcomes are required to fully assess its value. PMID- 29248417 TI - Altered ADAMTS5 Expression and Versican Proteolysis: A Possible Molecular Mechanism in Barlow's Disease. AB - BACKGROUND: We hypothesized that gene expression profiles of mitral valve (MV) leaflets from patients with Barlow's disease (BD) are distinct from those with fibroelastic deficiency (FED). METHODS: MVs were obtained from patients with BD (7 men, 3 women; 61.4 +/- 12.7 years old) or FED (6 men, 5 women; 54.5 +/- 6.0 years old) undergoing operations for severe mitral regurgitation (MR). Normal MVs were obtained from 6 donor hearts unmatched for transplant (3 men, 3 women; 58.3 +/- 7.5 years old), and gene expression was assessed using cDNA microarrays. Select transcripts were validated by quantitative reverse-transcription polymerase chain reaction, followed by an assessment of protein levels by immunostaining. RESULTS: The global gene expression profile for BD was clearly distinct from normal and FED groups. A total of 4,684 genes were significantly differential (fold-difference >1.5, p < 0.05) among the three groups, 1,363 of which were commonly altered in BD and FED compared with healthy individuals (eg TGFbeta2 [transforming growth factor beta2] and TGFbeta3 were equally upregulated in BD and FED). Most interesting were 329 BD-specific genes, including ADAMTS5 (a disintegrin-like and metalloprotease domain with thrombospondin-type 5), which was uniquely downregulated in BD based on microarrays and quantitative reverse transcription polymerase chain reaction. Consistent with this finding, the ADAMTS5 substrate versican was increased in BD and conversely lower in FED. CONCLUSIONS: MV leaflets in BD and FED exhibit distinct gene expression patterns, suggesting different pathophysiologic mechanisms are involved in leaflet remodeling. Moreover, downregulation of ADAMTS5 in BD, along with the accumulation of its substrate versican in the valvular extracellular matrix, might contribute to leaflet thickening and enlargement. PMID- 29248418 TI - Evaluation of the modified carbapenem inactivation method for the detection of carbapenemase-producing Enterobacteriaceae. AB - Carbapenemase-producing Enterobacteriaceae (CPE) are increasing worldwide. Rapid and accurate detection of CPE is necessary for appropriate antimicrobial treatment and hospital infection control. However, CPE contains some strains that are difficult to detect depending on genotype and MIC value of carbapenem, and a detection method has not been established. The recently reported modified carbapenem inactivation method (mCIM) has been developed in CLSI M100-S27 as a phenotypic technique for detecting carbapenemase activity. In the present study, we examined mCIM as a new CPE detection method using 207 Enterobacteriaceae isolates in comparison with the three existing screening methods of modified Hodge test, Carba NP test and carbapenem inactivation method and evaluated its performance. Consequently, both the sensitivity and specificity of mCIM were 100%, indicating better results than the conventional screening methods. The mCIM is a useful tool for microbiology laboratories due to its simplicity, clear criteria, cost-effectiveness and availability at any laboratory. PMID- 29248419 TI - MAPping Kinase Regulation of ICE1 in Freezing Tolerance. AB - Mitogen-activated protein kinase (MAPK) signaling has important roles in plant stress responses. Two recent reports showed how MAPK signaling regulates the response to cold stress through the Inducer of CBF expression 1 (ICE1)-CBF-cold responsive (COR) transcriptional pathway in Arabidopsis thaliana, expanding our understanding of cold stress signaling and regulation in plants. PMID- 29248420 TI - Understanding Health Literacy for People Living With HIV: Locations of Learning. AB - Health literacy, including people's abilities to access, process, and comprehend health-related information, has become an important component in the management of complex and chronic diseases such as HIV infection. Clinical measures of health literacy that focus on patients' abilities to follow plans of care ignore the multidimensionality of health literacy. Our thematic analysis of 28 focus groups from a qualitative, multisite, multinational study exploring information practices of people living with HIV (PLWH) demonstrated the importance of location as a dimension of health literacy. Clinical care and conceptual/virtual locations (media/Internet and research studies) were used by PLWH to learn about HIV and how to live successfully with HIV. Nonclinical spaces where PLWH could safely discuss issues such as disclosure and life problems were noted. Expanding clinical perspectives of health literacy to include location, assessing the what and where of learning, and trusted purveyors of knowledge could help providers improve patient engagement in care. PMID- 29248421 TI - Monckeberg medial calcinosis of the infraorbital arteries: a first case report. AB - Monckeberg medial calcinosis describes calcifications affecting only the tunica media of medium-sized arteries. The entity is strongly associated with chronic kidney disease and diabetes mellitus. Radiographically, medial calcinosis presents as areas of linear calcifications in soft tissue; the linear calcifications are referred to as "tram tracks," "pipe stem," "rail tracking," or "tram line" when the affected vessel is viewed longitudinally. In oral and maxillofacial radiology, it is generally an incidental finding of the facial artery. In this article, we review the literature of Monckeberg medial calcinosis and its clinical significance related to systemic diseases; we also present a case of Monckeberg medial calcinosis of the head and neck that affects the facial arteries, internal carotid arteries, and infraorbital arteries. We believe this is the first presentation in the literature of Monckeberg medial calcinosis visualized in the infraorbital arteries. PMID- 29248422 TI - A symptomatic swelling of the upper lip. PMID- 29248423 TI - Use of Integra in oral reconstruction: a case series. AB - OBJECTIVE: Small intraoral defects are usually reconstructed using skin autografts. However, the goal of this research was to describe an alternative to classic techniques using artificial dermis (Integra) in the reconstruction of these types of injuries. MATERIALS AND METHODS: Four patients with small intraoral lesions in different locations underwent resection. The created defects were covered with a bilayer of Integra; then, a chlorhexidine stent cure (Laboratorios Salvat, Barcelona, Spain) was applied. The patients were followed up daily during the first week to detect any signs of infection, dehiscence, or loss of the lamina. Thereafter, they were followed up once a week for 1 month. RESULTS: None of the patients presented with infections or loss of the dermis. When the silicon sheet was detached, granulation tissue was detected, with complete re-epithelialization of the lesion in the postoperative weeks 3 to 4. CONCLUSIONS: The use of the Integra allowed for the rapid reconstruction of slight intraoral defects while preventing the morbidity associated with classic techniques. In this study, no complications were observed. PMID- 29248424 TI - Hyperbaric oxygen treatment did not significantly affect radiation injury in the mandibular area of rats. AB - OBJECTIVE: Hyperbaric oxygen therapy (HBOT) has been used to enhance microcirculation and thereby oxygen tension in tissues. The present study aimed to investigate the effect of HBOT on radiation injury in the mandibular area of rats. STUDY DESIGN: The left mandibles of rats were irradiated by external radiotherapy (15 Gy every other week for a total of 75 Gy). Four HBOT strategies were used: 2 prophylactic groups receiving HBOT either between each radiation treatment or immediately following terminated radiation treatment, and 2 therapeutic groups receiving HBOT after the latent period of 6 weeks after irradiation either every day (standard HBOT protocol) or 3 days a week for 6 weeks. Tissue samples of the irradiated area were taken from skin, the salivary gland, and the mandible. All tissues were stained with hematoxylin and eosin for morphologic examination. Furthermore, skin samples were stained with CD31 for blood vessel analysis. RESULTS: There was no change in blood vessel density or morphology between controls and HBOT tissues after radiation. The dentin of 2 of the 5 rats that received HBOT either normalized or was not affected by irradiation. CONCLUSIONS: HBOT did not affect radiation injury of the mandibular area in rats within 12 weeks after irradiation. PMID- 29248425 TI - Ameliorative effect of panaxynol on the reduction in high-molecular-weight adiponectin secretion from 3T3-L1 adipocytes treated with palmitic acids. AB - Reduced plasma levels of the high-molecular weight (HMW) form of adiponectin, rather than total adiponectin levels, have been shown to be closely associated with various metabolic diseases including insulin resistance, type 2 diabetes, and cardiovascular disease. Therefore, we sought to explore active, naturally occurring compounds that promote the recovery of HMW adiponectin secretion suppressed by palmitic acid in our model. A total of 90 crude drug extracts were screened for the ability to augment HMW adiponectin secretion from 3T3-L1 adipocytes treated with palmitic acid. Panaxynol was isolated from Saposhnikovia divaricata as an active compound with HMW adiponectin promoting properties. Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists are reported to increase the secretion of HMW adiponectin, although the effects of panaxynol were found to be independent of PPARgamma activation. When the underlying mechanisms were further examined, panaxynol was found to inhibit the palmitic-acid-induced downregulation of forkhead box O1 (FoxO1) protein, and the anti-lipotoxic effects were abolished by a FoxO1 inhibitor. Furthermore, CCAAT/enhancer-binding protein-alpha (C/EBPalpha) mRNA levels were also increased by panaxynol. Reactive oxygen species have critical roles in the reduction in HMW adiponection secretion by palmitic acid; however, panaxynol reduced this increase in reactive oxygen species generation, followed by reductions in markers of endoplasmic reticulum stress and inflammation. Taken together, these findings suggest that panaxynol ameliorates the impaired HMW adiponection secretion in adipocytes treated with palmitic acid by restoring FoxO1 expression, owing to inhibition of reactive oxygen species generation, in a PPARgamma-independent manner. PMID- 29248426 TI - Pharmacological evidence that metformin blocks the vasopressor responses mediated by stimulation of alpha1- and alpha2-adrenoceptors in pithed rats. AB - It has been reported that metformin reduces blood pressure although the mechanisms have not been described. Indeed, several mechanisms could be implicated including the interaction with alpha-adrenoceptors or inhibition of sympathetic outflow. Therefore, this study was designed to determine the capability of metformin to block the vasopressor responses induced by alpha1/2 adrenoceptor agonists or selective electrical stimulation of sympathetic outflow. For this purpose, Wistar male rats were anesthetized, pithed and cannulated for selective preganglionic stimulation of the vasopressor sympathetic outflow or drugs administration. The effect of i.v. bolus injection of metformin (180 and 310mg/kg) or its vehicle (bidistilled water) was studied on the vasopressor responses induced by: (1) selective sympathetic stimulation (0.03-3Hz); (2) exogenous noradrenaline (0.03-3MUg/kg); (3) methoxamine (1-100MUg/kg); and (4) UK 14,304 (0.1-30MUg/kg). The tachycardic responses to noradrenaline were also investigated in presence of metformin. The vasopressor responses induced by selective electrical stimulation of sympathetic outflow were diminished by metformin (180 and 310mg/kg) and remained unchanged in presence of vehicle. Moreover, the vasopressor responses induced by exogenous noradrenaline, methoxamine and UK 14,304 were dose-dependently inhibited by i.v. bolus injections of metformin (180 and 310mg/kg) and were not affected by vehicle. Metformin practically did not block the tachycardic responses to noradrenaline except at the dose of 3MUg/kg. Taken together, these results demonstrate that metformin is capable to block vascular alpha1/2-adrenoceptors but not cardiac beta-adrenoceptors. Thus, this mechanism could contribute, at least in part, on the hypotensive responses induced by metformin. PMID- 29248427 TI - CAR-T Cells: A Systematic Review and Mixed Methods Analysis of the Clinical Trial Landscape. AB - CAR-T cells are a promising new therapy that offer significant advantages compared with conventional immunotherapies. This systematic review and clinical trial landscape identifies and critiques published CAR-T cell clinical trials and examines the critical factors required to enable CAR-T cells to become a standard therapy. A review of the literature was conducted to identify suitable studies from the MEDLINE and Ovid bibliographic databases. The literature and database searches identified 20 studies for inclusion. The average number of participants per clinical trial examined was 11 patients. All studies included in this systematic review investigated CAR-T cells and were prospective, uncontrolled clinical studies. Leukemia is the most common cancer subtype and accounts for 57.4% (n = 120) of disease indications. The majority of studies used an autologous cell source (85%, n = 17) rather than an allogeneic cell source. Translational challenges encompass technical considerations relating to CAR-T cell development, manufacturing practicability, clinical trial approaches, CAR-T cell quality and persistence, and patient management. PMID- 29248428 TI - Irradiation Enhances Abscopal Anti-tumor Effects of Antigen-Specific Immunotherapy through Regulating Tumor Microenvironment. AB - Ionizing radiation therapy is a well-established method of eradicating locally advanced tumors. Here, we examined whether local RT enhanced the potency of an antigen-specific DNA vaccine, and we investigated the possible underlying mechanism. Using the HPV16 E6/E7+ syngeneic TC-1 tumor, we evaluated the combination of CTGF/E7 vaccination with local irradiation with regard to synergistic antigen-specific immunity and anti-tumor effects. Tumor-bearing mice treated with local RT (6 Gy twice weekly) and CTGF/E7 DNA vaccination exhibited dramatically increased numbers of E7-specific CD8+ cytotoxic T cell precursors, higher titers of anti-E7 Abs, and significantly reduced tumor size. The combination of local RT and CTGF/E7 vaccination also elicited abscopal effects on non-irradiated local subcutaneous and distant pulmonary metastatic tumors. Local irradiation induced the expression of high-mobility group box 1 protein (HMGB-1) in apoptotic tumor cells and stimulated dendritic cell (DC) maturation, consequently inducing antigen-specific immune responses. Additionally, local irradiation eventually increased the effector-to-suppressor cell ratio in the tumor microenvironment. Overall, local irradiation enhanced the antigen-specific immunity and anti-tumor effects on local and distant metastatic tumors generated by an antigen-specific DNA vaccine. These findings suggest that the combination of irradiation with antigen-specific immunotherapy is a promising new clinical strategy for cancer therapy. PMID- 29248429 TI - Predicting therapy response and resistance in metastatic prostate cancer with circulating tumor DNA. AB - The treatment of metastatic castration-resistant prostate cancer (mCRPC) is empirical, with progress to a more precision medicine approach hampered by lack of predictive biomarkers. This is due in large part to the historical difficulty of molecularly profiling a bone-predominant metastatic disease. Focus has turned to minimally invasive sources of tumor material to better understand the molecular drivers of therapy resistance. Circulating cell-free tumor DNA (ctDNA) is highly abundant in the bloodstream of mCRPC patients and appears to provide an accurate snapshot of real-time tumor genomics. Already, the analysis of androgen receptor gene alterations in the ctDNA of mCRPC patient cohorts has suggested significant potential for guiding the use of androgen receptor-directed therapy. Furthermore, the monitoring of patient ctDNA burden in the wake of systemic therapy may offer a powerful surrogate for tracking tumor responses and emerging resistant subclones. This seminar covers recent advances in mCRPC patient ctDNA profiling, emerging associations of distinct molecular subtypes with clinical outcomes, and the potential for ctDNA to augment precision oncology. PMID- 29248431 TI - Tezacaftor-ivacaftor is safe and efficacious in patients with cystic fibrosis with Phe508del mutations. PMID- 29248430 TI - Adherence to pelvic lymph node dissection recommendations according to the National Comprehensive Cancer Network pelvic lymph node dissection guideline and the D'Amico lymph node invasion risk stratification. AB - PURPOSE: To assess adherence rates to pelvic lymph node dissection (PLND) according to National Comprehensive Cancer Network (NCCN) PLND guideline (2% or higher risk) and D'Amico lymph node invasion (LNI) risk stratification (intermediate/high risk) in contemporary North American patients with prostate cancer treated with radical prostatectomy (RP). MATERIAL AND METHODS: We relied on 49,358 patients treated with RP and PLND (2010-2013) in SEER database. Adherence rates were quantified and multivariable (MVA) logistic regression analyses tested for independent predictors. RESULTS: According to NCCN PLND guideline and D'Amico LNI classification, PLND was recommended in 63.3% and 64.9% of patients, respectively. Corresponding adherence rates were 68.8% and 69.1%. Adherence rates improved from 67.3% to 71.6% and from 67.6% to 72.0%, respectively, over time. In MVA, more advanced clinical stage, higher biopsy Gleason score and higher number of positive biopsy cores predicted PLNDs that were performed below NCCN LNI nomogram risk threshold. Conversely, lower clinical stage, lower PSA and lower biopsy Gleason score predicted PLND omission in individuals with risk level above NCCN LNI nomogram risk threshold. MVA results for D'Amico classification were virtually identical. CONCLUSIONS: Adherence to NCCN PLND guideline and D'Amico LNI classification for purpose of PLND is suboptimal in SEER population-based patients treated with RP. However, adherence rates have improved over time. Patients, who did not undergo PLND despite elevated LNI risk, had more favorable PCa characteristics than the average. Conversely, patients, who underwent PLND despite low-risk, had worse PCa characteristics than the average. PMID- 29248432 TI - Remote or in-person breathing retraining for uncontrolled asthma symptoms. PMID- 29248434 TI - Does my older cancer patient have cognitive impairment? AB - Cancer and impaired cognition are both frequent conditions in old age and consequently coexist to certain degree. The prevalence of impaired cognition increases sharply after the age of 65 and the more advanced form of cognitive impairment; dementia, is exceeding 30% by the age of 85years. Adequate cognition is crucial for understanding important facts and for giving consent for intervention. There are many different stages of cognitive impairment, ranging from subjective cognitive impairment to severe dementia. The mildest stages of cognitive impairment are sometimes reversible but in more severe stages, there is brain damage of some kind, most frequently caused by neurodegenerative disorder such as Alzheimer's disease. Therefore, some kind of evaluation of cognition should be offered to all older individuals with cancer and in need for intervention. In this evaluation, information should also be sought from a close relative. In the earlier stages of cognitive impairment, the individual usually retains ability to give consent and understands information given but in later stages of dementia, a surrogate decision maker is needed. In milder stages of dementia, an individual evaluation is needed for decision of capability for consent. A specific diagnosis of a disorder such as Alzheimer's disease does not in itself preclude the individual from giving consent, the degree of cognitive impairment, impaired judgement and poor insight are more decisive in this regard. It is also important to know the difference of delirium, most often a time limited condition and dementia that usually is progressive. PMID- 29248435 TI - Delphi consensus of an expert committee in oncogeriatrics regarding comprehensive geriatric assessment in seniors with cancer in Spain. AB - OBJECTIVES: The aim of this work was to reach a national consensus in Spain regarding the Comprehensive Geriatric Assessment (CGA) domains in older oncological patients and the CGA scales to be used as a foundation for widespread use. MATERIAL AND METHODS: The Delphi method was implemented to attain consensus. Representatives of the panel were chosen from among the members of the Oncogeriatric Working Group of the Spanish Society of Medical Oncology (SEOM). Consensus was defined as >=66.7% coincidence in responses and by the stability of said coincidence (changes <=15% between rounds). The study was conducted between July and December 2016. RESULTS: Of the 17 people invited to participate, 16 agreed. The panel concluded by consensus that the following domains should be included in the CGA:(and the scales to evaluate them): functional (Barthel Index, Lawton-Brody scale, gait speed), cognitive (Pfeiffer questionnaire), nutritional (Mini Nutritional Assessment - MNA), psychological/mood (Yesavage scale), social familial (Gijon scale), comorbidity (Charlson index), medications, and geriatric syndromes (urinary and/or fecal incontinence, low auditory and/or visual acuity, presence of falls, pressure sores, insomnia, and abuse). Also by consensus, the CGA should be administered to older patients with cancer for whom there is a subsequent therapeutic intent and who scored positive on a previous frailty screening questionnaire. CONCLUSION: After 3 rounds, consensus was reached regarding CGA domains to be used in older patients with cancer, the scales to be administered for each of these domains, as well as the timeline to be followed during consultation. PMID- 29248433 TI - Physiotherapy breathing retraining for asthma: a randomised controlled trial. AB - BACKGROUND: Despite effective pharmacotherapy, asthma continues to impair quality of life for most patients. Non-pharmacological approaches, including breathing retraining, are therefore of great interest to patients. However, clinicians rarely advocate breathing retraining and access to this intervention is restricted for most patients due to the limited availability of suitable physiotherapists and poor integration of breathing retraining into standard care. We aimed to assess the effectiveness of a digital self-guided breathing retraining intervention. METHODS: In this randomised controlled trial, we recruited patients from 34 general practices in the UK. Eligibility criteria for patients with asthma were broad, comprising a physician diagnosis of asthma, age of 16-70 years, receipt of at least one anti-asthma medication in the previous year, and impaired asthma-related quality of life (Asthma Quality of Life Questionnaire [AQLQ] score of <5.5). We developed a self-guided intervention, which was delivered as a DVD plus a printed booklet (DVDB). Participants were randomly assigned to receive either the DVDB intervention, three face-to-face breathing retraining sessions, or standard care, in a 2:1:2 ratio, for 12 months. Randomisation was achieved using the Southampton Clinical Trials Unit telephone randomisation service by use of random number generators. The primary outcome was the AQLQ score in the intention-to-treat population at 12 months. The trial was powered to show equivalence between the two active intervention groups, and superiority of both intervention groups over usual care. Secondary outcomes included patient-reported and physiological measures of asthma control, patient acceptability, and health-care costs. This trial was registered with International Standard Randomised Controlled Trial Number registry, number ISRCTN88318003. FINDINGS: Between Nov 5, 2012 and Jan 28, 2014, invitations to participate in the study were sent to 15 203 patients with general practitioner diagnosed asthma, of whom 655 were recruited into the study. AQLQ scores at 12 months were significantly higher in the DVDB group (mean 5.40, SD 1.14) than in the usual care group (5.12, SD 1.17; adjusted mean difference 0.28, 95% CI 0.11 to 0.44), and in the face-to-face group (5.33, SD 1.06) than in the usual care group (adjusted mean difference 0.24, 95% CI 0.04 to 0.44); AQLQ scores were similar between the DVDB group and the face-to-face group (0.04, 95% CI -0.16 to 0.24). There were no significant differences between the randomisation groups in FEV1 or fraction of exhaled nitric oxide. 744 adverse events occurred in 272 patients: 101 (39%) of 261 patients in the DVDB group, 55 (42%) of 132 patients in the face-to-face group, and 132 (50%) of 262 in the usual care group, with patients reporting one or more event. 11 (4%) patients in the DVDB group, four (3%) patients in the face-to-face group, and 20 (8%) patients in the usual care group had a serious adverse event. INTERPRETATION: Breathing retraining programmes improve quality of life in patients with incompletely controlled asthma despite having little effect on lung function or airway inflammation. Such programmes can be delivered conveniently and cost-effectively as a self-guided digital audiovisual programme, so might also reduce health-care costs. FUNDING: UK National Institute of Health Research. PMID- 29248436 TI - Estrogen signaling in the medial amygdala decreases emotional stress responses and obesity in ovariectomized rats. AB - Declining estradiol (E2), as occurs during menopause, increases risk for obesity and psychopathology (i.e., depression, anxiety). E2 modulates mood and energy homeostasis via binding to estrogen receptors (ER) in the brain. The often comorbid and bidirectional relationship between mood and metabolic disorders suggests shared hormonal and/or brain networks. The medial amygdala (MeA) is abundant in ERs and regulates mood, endocrine, and metabolic stress responses; therefore we tested the hypothesis that E2 in the MeA mitigates emotional and metabolic dysfunction in a rodent model of surgical menopause. Adult female rats were ovariectomized (OVX) and received bilateral implants of E2 or cholesterol micropellets aimed at the MeA. E2-MeA decreased anxiety-like (center entries, center time) and depression-like (immobility) behaviors in the open field and forced swim tests (FST), respectively in ovariectomized rats. E2-MeA also prevented hyperphagia, body weight gain, increased visceral adiposity, and glucose intolerance in ovariectomized rats. E2-MeA decreased caloric efficiency, suggestive of increased energy expenditure. E2-MeA also modulated c-Fos neural activity in amygdalar (central and medial) and hypothalamic (paraventricular and arcuate) brain regions that regulate mood and energy homeostasis in response to the FST, a physically demanding task. Given the shared neural circuitry between mood and body weight regulation, c-Fos expression in discrete brain regions in response to the FST may be due to the psychologically stressful and/or metabolic demands of the task. Together, these findings suggest that the MeA is a critical node for mediating estrogenic effects on mood and energy homeostasis. PMID- 29248437 TI - Mortality risk of serum potassium on admission in patients with type A acute aortic dissection. PMID- 29248438 TI - Response to Letter to the Editor. PMID- 29248439 TI - Letter to Editor. PMID- 29248440 TI - JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice. AB - BACKGROUND & AIMS: Maintenance of acid-base homeostasis is required for normal physiology, metabolism, and development. It is not clear how cell death is activated in response to changes in pH. We performed a screen to identify agents that induce cell death in a pH-dependent manner (we call this alkaliptosis) in pancreatic ductal adenocarcinoma cancer (PDAC) cells and tested their effects in mice. METHODS: We screened a library of 254 compounds that interact with G protein-coupled receptors (GPCRs) to identify those with cytotoxic activity against a human PDAC cell line (PANC1). We evaluated the ability of JTC801, which binds the opiod receptor and has analgesic effects, to stimulate cell death in human PDAC cell lines (PANC1, MiaPaCa2, CFPAC1, PANC2.03, BxPc3, and CAPAN2), mouse pancreatic cancer-associated stellate cell lines, primary human pancreatic ductal epithelial cells, and 60 cancer cell lines (the NCI-60 panel). Genes encoding proteins in cell death and GPCR signaling pathways, as well as those that regulate nuclear factor-kappaB (NF-kappaB) activity, were knocked out, knocked down, or expressed from transgenes in cancer cell lines. JTC801 was administered by gavage to mice with xenograft tumors, C57BL/6 mice with orthographic pancreatic tumors grown from Pdx1-Cre;KRasG12D/+;Tp53R172H/+ (KPC) cells, mice with metastases following tail-vein injection of KPC cells, and Pdx-1 Cre;KrasG12D/+ mice crossed with Hmgb1flox/flox mice (KCH mice). Pancreata were collected from mice and analyzed for tumor growth and by histology and immunohistochemistry. We compared gene and protein expression levels between human pancreatic cancer tissues and patient survival times using online R2 genomic or immunohistochemistry analyses. RESULTS: Exposure of human PDAC cell lines (PANC1 and MiaPaCa2) to JTC801 did not induce molecular markers of apoptosis (cleavage of caspase 3 or poly [ADP ribose] polymerase [PARP]), necroptosis (interaction between receptor-interacting serine-threonine kinase 3 [RIPK3] and mixed lineage kinase domain like pseudokinase [MLKL]), or ferroptosis (degradation of glutathione peroxidase 4 [GPX4]). Inhibitors of apoptosis (Z-VAD FMK), necroptosis (necrosulfonamide), ferroptosis (ferrostatin-1), or autophagy (hydroxychloroquine) did not prevent JTC801-induced death of PANC1 or MiaPaCa2 cells. The cytotoxic effects of JTC801 in immortalized fibroblast cell lines was not affected by disruption of genes that promote apoptosis (Bax-/-/Bak-/- cells), necroptosis (Ripk1-/-, Ripk3-/-, or Mlkl-/- cells), ferroptosis (Gpx4-/- cells), or autophagy (Atg3-/-, Atg5-/-, Atg7-/-, or Sqstm1-/- cells). We found JTC801 to induce a pH-dependent form cell death (alkaliptosis) in cancer cells but not normal cells (hepatocytes, bone marrow CD34+ progenitor cells, peripheral blood mononuclear cells, or dermal fibroblasts) or healthy tissues of C57BL/6 mice. JTC801 induced alkaliptosis in cancer cells by activating NF-kappaB, which repressed expression of the carbonic anhydrase 9 gene (CA9), whose product regulates pH balance in cells. In analyses of Cancer Genome Atlas data and tissue microarrays, we associated increased tumor level of CA9 mRNA or protein with shorter survival times of patients with pancreatic, kidney, or lung cancers. Knockdown of CA9 reduced the protective effects of NF-kappaB inhibition on JTC801 induced cell death and intracellular alkalinization in PANC1 and MiaPaCa2 cell lines. Oral administration of JTC801 inhibited growth of xenograft tumors (from PANC1, MiaPaCa2, SK-MEL-28, PC-3, 786-0, SF-295, HCT116, OV-CAR3, and HuH7 cells), orthotropic tumors (from KPC cells), lung metastases (from KPC cells) of mice, and slowed growth of tumors in KCH mice. CONCLUSIONS: In a screen of agents that interact with GPCR pathways, we found JTC801 to induce pH-dependent cell death (alkaliptosis) specifically in cancer cells such as PDAC cells, by reducing expression of CA9. Levels of CA9 are increased in human cancer tissues. JTC801 might be developed for treatment of pancreatic cancer. PMID- 29248441 TI - Kruppel-like Factor 5, Increased in Pancreatic Ductal Adenocarcinoma, Promotes Proliferation, Acinar-to-Ductal Metaplasia, Pancreatic Intraepithelial Neoplasia, and Tumor Growth in Mice. AB - BACKGROUND & AIMS: Activating mutations in KRAS are detected in most pancreatic ductal adenocarcinomas (PDACs). Expression of an activated form of KRAS (KrasG12D) in pancreata of mice is sufficient to induce formation of pancreatic intraepithelial neoplasia (PanINs)-a precursor of PDAC. Pancreatitis increases formation of PanINs in mice that express KrasG12D by promoting acinar-to-ductal metaplasia (ADM). We investigated the role of the transcription factor Kruppel like factor 5 (KLF5) in ADM and KRAS-mediated formation of PanINs. METHODS: We performed studies in adult mice with conditional disruption of Klf5 (Klf5fl/fl) and/or expression of KrasG12D (LSL-KrasG12D) via CreERTM recombinase regulated by an acinar cell-specific promoter (Ptf1a). Activation of KrasG12D and loss of KLF5 was achieved by administration of tamoxifen. Pancreatitis was induced in mice by administration of cerulein; pancreatic tissues were collected, analyzed by histology and immunohistochemistry, and transcriptomes were compared between mice that did or did not express KLF5. We performed immunohistochemical analyses of human tissue microarrays, comparing levels of KLF5 among 96 human samples of PDAC. UN-KC-6141 cells (pancreatic cancer cells derived from Pdx1-Cre;LSL KrasG12D mice) were incubated with inhibitors of different kinases and analyzed in proliferation assays and by immunoblots. Expression of KLF5 was knocked down with small hairpin RNAs or CRISPR/Cas9 strategies; cells were analyzed in proliferation and gene expression assays, and compared with cells expressing control vectors. Cells were subcutaneously injected into flanks of syngeneic mice and tumor growth was assessed. RESULTS: Of the 96 PDAC samples analyzed, 73% were positive for KLF5 (defined as nuclear staining in more than 5% of tumor cells). Pancreata from Ptf1a-CreERTM;LSL-KrasG12D mice contained ADM and PanIN lesions, which contained high levels of nuclear KLF5 within these structures. In contrast, Ptf1a-CreERTM;LSL-KrasG12D;Klf5fl/fl mice formed fewer PanINs. After cerulein administration, Ptf1a-CreERTM;LSL-KrasG12D mice formed more extensive ADM than Ptf1a-CreERTM;LSL-KrasG12D;Klf5fl/fl mice. Pancreata from Ptf1a-CreERTM;LSL KrasG12D;Klf5fl/fl mice had increased expression of the tumor suppressor NDRG2 and reduced phosphorylation (activation) of STAT3, compared with Ptf1a CreERTM;LSL-KrasG12D mice. In UN-KC-6141 cells, PI3K and MEK signaling increased expression of KLF5; a high level of KLF5 increased proliferation. Cells with knockdown of Klf5 had reduced proliferation, compared with control cells, had reduced expression of ductal markers, and formed smaller tumors (71.61 +/- 30.79 mm3 vs 121.44 +/- 34.90 mm3 from control cells) in flanks of mice. CONCLUSION: Levels of KLF5 are increased in human PDAC samples and in PanINs of Ptf1a CreERTM;LSL-KrasG12D mice, compared with controls. KLF5 disruption increases expression of NDRG2 and reduces activation of STAT3 and reduces ADM and PanINs formation in mice. Strategies to reduce KLF5 activity might reduce progression of acinar cells from ADM to PanIN and pancreatic tumorigenesis. PMID- 29248442 TI - Metaplastic Cells in the Stomach Arise, Independently of Stem Cells, via Dedifferentiation or Transdifferentiation of Chief Cells. AB - Spasmolytic polypeptide-expressing metaplasia (SPEM) develops in patients with chronic atrophic gastritis due to infection with Helicobacter pylori; it might be a precursor to intestinal metaplasia and gastric adenocarcinoma. Lineage tracing experiments of the gastric corpus in mice have not established whether SPEM derives from proliferating stem cells or differentiated, post-mitotic zymogenic chief cells in the gland base. We investigated whether differentiated cells can give rise to SPEM using a nongenetic approach in mice. Mice were given intraperitoneal injections of 5-fluorouracil, which blocked gastric cell proliferation, plus tamoxifen to induce SPEM. Based on analyses of molecular and histologic markers, we found SPEM developed even in the absence of cell proliferation. SPEM therefore did not arise from stem cells. In histologic analyses of gastric resection specimens from 10 patients with adenocarcinoma, we found normal zymogenic chief cells that were transitioning into SPEM cells only in gland bases, rather than the proliferative stem cell zone. Our findings indicate that SPEM can arise by direct reprogramming of existing cells-mainly of chief cells. PMID- 29248443 TI - Molecular cloning and functional characterization of three terpene synthases from unripe fruit of black pepper (Piper nigrum). AB - To identify terpene synthases (TPS) responsible for the biosynthesis of the sesquiterpenes that contribute to the characteristic flavors of black pepper (Piper nigrum), unripe peppercorn was subjected to the Illumina transcriptome sequencing. The BLAST analysis using amorpha-4,11-diene synthase as a query identified 19 sesquiterpene synthases (sesqui-TPSs), of which three full-length cDNAs (PnTPS1 through 3) were cloned. These sesqui-TPS cDNAs were expressed in E. coli to produce recombinant enzymes for in vitro assays, and also expressed in the engineered yeast strain to assess their catalytic activities in vivo. PnTPS1 produced beta-caryophyllene as a main product and humulene as a minor compound, and thus was named caryophyllene synthase (PnCPS). Likewise, PnTPS2 and PnTPS3 were, respectively, named cadinol/cadinene synthase (PnCO/CDS) and germacrene D synthase (PnGDS). PnGDS expression in yeast yielded beta-cadinene and alpha copaene, the rearrangement products of germacrene D. Their kcat/Km values (20 37.7 s-1 mM-1) were comparable to those of other sesqui-TPSs. Among three PnTPSs, the transcript level of PnCPS was the highest, correlating with the predominant beta-caryophyllene biosynthesis in the peppercorn. The products and rearranged products of three PnTPSs could account for about a half of the sesquiterpenes in number found in unripe peppercorn. PMID- 29248444 TI - Excitotoxicity in encephalopathy associated with STEC O-157 infection. AB - Cytokines play an important role in the pathogenesis of the severe complications of Shiga toxin-producing Escherichia coli (STEC) infection, such as hemolytic uremic syndrome (HUS) and acute encephalopathy. A 3-year-old boy with acute encephalopathy associated with STEC O-157 HUS showed increased levels of IL-6 and IL-10, which normalized after methylprednisolone pulse therapy, and additionally exhibited a transient increase of glutamine on MR spectroscopy. This finding suggests that excitotoxicity, in addition to hypercytokinemia, may play an important role in the pathogenesis of HUS encephalopathy. PMID- 29248445 TI - Intracellular manganese enhanced MRI signals reflect the frequency of action potentials in Aplysia neurons. AB - BACKGROUND: Manganese-enhanced magnetic resonance imaging (MEMRI) is an increasingly popular alternative to standard functional MRI methods in animal studies. The contrast in MEMRI images is based on the accumulation of Mn2+ ions inside neurons, and, since manganese can serve as calcium analogue, this accumulation reflects calcium dynamics providing versatile information about brain neuroarchitecture and functionality. However, despite its use as a functional imaging tool, the exact relationship between the MEMRI signal and neuronal activity remains elusive. NEW METHOD: In order to better understand the mechanisms underlying Mn2+ accumulation resulting in MEMRI signal enhancement we investigated single neuron responses of isolated Aplysia buccal ganglia subjected to chemical (dopamine) or electrical stimulation of an input nerve (oesophageal nerve). The elicited electrical activity that represents a fictive feeding was recorded with electrophysiological methods and the Mn2+ uptake in individual neurons was evaluated with MEMRI at 17.2T. RESULTS & COMPARISON WITH EXISTING METHOD(S): We show a positive correlation between bursts of electrical activity and MEMRI signal intensity in identified neurons and demonstrate that the MEMRI signal reflects mainly fast and high membrane depolarization processes such as action potentials, and it is not sensitive to slow and small membrane depolarizations, such as post-synaptic potentials. PMID- 29248446 TI - Cellular accumulation and lipid binding of perfluorinated alkylated substances (PFASs) - A comparison with lysosomotropic drugs. AB - Many chemicals accumulate in organisms through a variety of different mechanisms. Cationic amphiphilic drugs (CADs) accumulate in lysosomes and bind to membranes causing phospholipidosis, whereas many lipophilic chemicals target adipose tissue. Perfluoroalkyl substances (PFASs) are widely used as surfactants, but many of them are highly bioaccumulating and persistent in the environment, making them notorious environmental toxicants. Understanding the mechanisms of their bioaccumulation is, therefore, important for their regulation and substitution with new, less harmful chemicals. We compared the highly bioaccumulative perfluorooctanesulfonic acid PFOS to its three less bioaccumulative alternatives perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA) and perfluorobutane sulfonic acid (PFBS), in their ability to accumulate and remain in lung epithelial cells (NCI-H292) and adipocytes (3T3-L1K) in vitro. As a reference point we tested a set of cationic amphiphilic drugs (CADs), known to highly accumulate in cells and strongly bind to phospholipids, together with their respective non-CAD controls. Finally, all compounds were examined for their ability to bind to neutral lipids and phospholipids in cell-free systems. Cellular accumulation and retention of the test compounds were highly correlated between the lung epithelial cells and adipocytes. Interestingly, although an anion itself, intensities of PFOS accumulation and retention in cells were comparable to those of CAD compounds, but PFOS failed to induce phospholipidosis or alter lysosomal volume. Compared to other lipophilicity measures, phospholipophilicity shows the highest correlation (R^2 = 0.75) to cellular accumulation data in both cell types and best distinguishes between high and low accumulating compounds. This indicates that binding to phospholipids may be the most important component in driving high cellular accumulation in lung epithelial cells, as well as in adipocytes, and for both CADs and bioaccumulating PFASs. Obtained continuous PLS models based on compound's affinity for phospholipids and neutral lipids can be used as good prediction models of cellular accumulation and retention of PFASs and CADs. PMID- 29248447 TI - Evaluation of pro-inflammatory events induced by Bothrops alternatus snake venom. AB - Inflammation is a major local feature of envenomation by bothropic snakes being characterized by a prominent local edema, pain, and extensive swelling. There are reports demonstrating that whole Bothrops snake venoms and toxins isolated from them are able to activate macrophages functions, such as phagocytosis, production of reactive oxygen, cytokines and eicosanoids, however, little is known about the effects of Bothrops alternatus (B.a.) venom on macrophages. In this work, we evaluated the proinflammatory effects of B.a. venom with in vivo and in vitro experiments using the Raw 264.7 cell line and mouse peritoneal macrophages. We detected that B.a. venom augments cell permeability (2-fold), and cellular extravasation (mainly neutrophils), increase proinflammatory cytokines IL1 (~300 fold), IL12 (~200-fold), and TNFalpha (~80-fold) liberation and induce the expression of enzymes related to lipid signaling, such as cPLA2alpha and COX-2. Additionally, using lipidomic techniques we detected that this venom produces a release of arachidonic acid (~10 nMol/mg. Protein) and other fatty acids (16:0 and 18:1 n-9c). Although much of these findings were described in inflammatory processes induced by other bothropic venoms, here we demonstrate that B.a. venom also stimulates pro-inflammatory pathways involving lipid mediators of cell signaling. In this sense, lipidomics analysis of macrophages stimulated with B.a. venom evidenced that the main free fatty acids are implicated in the inflammatory response, and also demonstrated that this venom, is able to activate lipid metabolism even with a low content of PLA2. PMID- 29248448 TI - Zhen-wu-tang ameliorates adenine-induced chronic renal failure in rats: regulation of the canonical Wnt4/beta-catenin signaling in the kidneys. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zhen-wu-tang (ZWT), composed of Radix Aconiti lateralis, Rhizoma Atractylodis macrocephalae, Poria, Radix Paeoniae alba and ginger, is a classic Chinese herbal formula for the treatment of chronic kidney diseases that may cause chronic renal failure (CRF). AIM OF THE STUDY: To better understand its clinical use, this study investigated the effects and underlying mechanisms of action of ZWT on CRF. MATERIALS AND METHODS: CRF was induced by adenine. ZWT was given via an oral gavage method. The serum biochemical parameters were measured enzymatically or by ELISA. The kidneys were examined pathohistologically. The gene expression was analyzed by real time PCR and Western blot. RESULTS: Similar to the positive control losartan, ZWT extract inhibited adenine-induced increase in serum concentrations of creatinine, BUN and advanced oxidation protein products in rats. These effects were accompanied by attenuation of proteinuria and renal pathological changes and suppression of renal mRNA and protein overexpression of Collagen IV and fibronectin, two of the key components of fibrosis. Mechanistically, renal mRNA and protein expression of Wnt4, a Wnt signaling ligand, was increased in the adenine-treated group, compared to the vehicle-treated control. Consistently, Wnt4 downstream genes beta catenin and Axin were also overexpressed. Treatment with ZWT extract and losartan suppressed adenine-stimulated overexpression of these mRNAs and proteins. CONCLUSIONS: The present results demonstrate that ZWT extract ameliorates adenine induced CRF in rats by regulation of the canonical Wnt4/beta-catenin signaling in the kidneys. Our findings provide new insight into the underlying renoprotective mechanisms of the ancient formula. PMID- 29248449 TI - Interactions between crude drug extracts used in Japanese traditional Kampo medicines and organic anion-transporting polypeptide 2B1. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The use of herbal medicines has become popular worldwide, and the information on drug interactions between herbal medicines and chemical drugs is needed. AIM OF THE STUDY: We screened the inhibitory effects of crude drugs used in Kampo medicines used in Japan on organic anion-transporting polypeptide (OATP) 2B1 to predict potential interactions between Kampo medicines and chemical drugs used together. MATERIALS AND METHODS: We chose 98 kinds of crude drugs frequently used as ingredients of Kampo formulations in Japan and prepared their boiling water extracts. We then screened their inhibitory effects on OATP2B1 by measuring the uptake of estrone 3-sulphate (E3S) by HEK293 cells stably expressing OATP2B1. RESULTS: At the concentration of 100ug/ml, the extracts prepared from 12 kinds of crude drugs, Scuteralliae Radix, Arecae Semen, Aurantii Fructus Immaturus, Perillae Herba, Panacis Japonici Rhizoma, Moutan Cortex, Polygalae Radix, Rhei Rhizoma, Cannabis Fructus, Chrysanthemi Flos, Eriobotryae Folium, and Querci Cortex, suppressed the function of OATP2B1 by less than 20%. The extract of bofutsushosan, a representative Kampo formulation, inhibited OATP2B1 function with sufficient levels to suppress absorption of OATP2B1 substrates in clinics. We further evaluated the inhibitory effects of several ingredients containing Rhei Rhizoma, Perillae Herba, and Moutan Cortex on OATP2B1. CONCLUSIONS: Because of crude drugs used in Kampo medicines might suppress absorption of OATP2B1 substrates, these results may contribute to the safe and effective use of Kampo medicine in clinics. A list of abbreviations: EC, (-)-epicatechin; ECG, epicatechin gallate; EGC, epigallocatechin; EGCG, Epigallocatechin gallate; FBS, fetal bovine serum; grapefruit juice; HEK293, Human embryonic kidney; IC50, The half inhibitory concentration; OATP, organic anion-transporting polypeptide; beta-PGG, penta-O-galloyl-beta-D-glucose; t.i.d, 3 times a day. PMID- 29248450 TI - Evaluating the hematological and clinical-chemistry parameters of kratom (Mitragyna speciosa) users in Malaysia. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Kratom (Mitragyna speciosa Korth.) from the Rubiaceae family is an indigenous tropical medicinal tree of Southeast Asia. Kratom leaves have been used for decades in Malaysia and Thailand in traditional context for its perceived vast medicinal value, and as a mild stimulant among manual labourers. Kratom consumption has been reported to cause side-effects in kratom users. AIM OF THE STUDY: To evaluate kratom's effects towards hematological and clinical-chemistry parameters among regular kratom users in Malaysia. METHODS: A total of 77 subjects (n=58 regular kratom users, and n=19 healthy controls) participated in this cross-sectional study. All the surveys were conducted through face-to-face interview to elicit subject's socio demographic characteristics and kratom use history. A full-blood test was also administered. Laboratory analysis was conducted using GC-MS to determine mitragynine content in the acquired kratom samples in order to relate mitragynine consumption with possible alterations in the blood parameters of kratom users. RESULTS: Findings showed that there were no significant differences in the hematological and clinical-chemistry parameters of traditional kratom users and healthy controls, except for HDL and LDL cholesterol values; these were found to be above the normal reference range for the former. Similarly, long-term kratom consumption (>5 years), and quantity of daily kratom use (>=3 1/2 glasses; mitragynine content 76.3-114.8mg) did not appear to alter the hematological and biochemical parameters of kratom users. CONCLUSION: These data suggest that even long-term and heavy kratom consumption did not significantly alter the hematological and clinical-chemistry parameters of kratom users in a traditional setting. PMID- 29248451 TI - Features and outcomes of drugs for combination therapy as multi-targets strategy to combat Alzheimer's disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer's disease (AD), a deleterious neurodegenerative disorder that impairs memory, cognitive functions and may lead to dementia in late stage of life. The pathogenic cause of AD remains incompletely understood and FDA approved drugs are partial inhibitors rather than curative. Most of drugs are synthetic or natural products as galanthamine is an alkaloid obtained from Galanthus spp. Huperzine A, an alkaloid found in Huperzia spp., gingkolides a diterpenoids from Gingko biloba and many ethnobotanicals like Withania somnifera (L.) Dunal., Physostigma venenosum Balf., Bacopa monnieri (L.) Wettst., Centella asiatica (L.) Urb. have been used by traditional Indian, Chinese, and European system of medicines in AD. Clinical significance opioid alkaloid in Papaver somniferum has shown another dimension to this study. Over exploitation of medicinal plants with limited bioactive principles has provided templates to design synthetic drugs in AD e.g. rivastigmine, phenserine, eptastigmine based on chemical structure of physostigmine of Physostigma venenosum Balf. Even ZT-1 a prodrug of Hup A and memogain a prodrug of galantamine has achieved new direction in drug development in AD. All these first line cholinesterase-inhibitors are used as symptomatic treatments in AD. Single modality of "One-molecule-one-target" strategy for treating AD has failed and so future therapies on "Combination-drugs-multi-targets" strategy (CDMT) will need to address multiple aspects to block the progression of pathogenesis of AD. Besides, cholinergic and amyloid drugs, in this article we summarize proteinopathy-based drugs as AD therapeutics from a variety of biological sources. In this review, an attempt has been made to elucidate the molecular mode of action of various plant products, and synthetic drugs investigated in various preclinical and clinical tests in AD. It also discusses current attempts to formulate a comprehensive CDMT strategy to counter complex pathogenesis in AD. MATERIALS AND METHODS: Information were collected from classical books on medicinal plants, pharmacopoeias and scientific databases like PubMed, Scopus, GoogleScholar, Web of Science and electronic searches were performed using Cochrane Library, Medline and EMBASE. Also published scientific literatures from Elsevier, Taylor and Francis, Springer, ACS, Wiley publishers and reports by government bodies and documentations were assessed. RESULTS: 60 no. of natural and synthetic drugs have been studied with their significant bioactivities. A decision matrix designed for evaluation of drugs for considering to the hypothetic "CDMT" strategy in AD. We have introduced the scoring pattern of individual drugs and based on scoring pattern, drugs that fall within the scoring range of 18-25 are considered in the proposed CDMT. It also highlights the importance of available natural products and in future those drugs may be considered in CDMT along with the qualified synthetic drugs. CONCLUSION: A successful validation of the CDMT strategy may open up a debate on health care reform to explore other possibilities of combination therapy. In doing so, it should focus on clinical and molecular relationships between AD and CDMT. A better understanding of these relationships could inform and impact future development of AD-directed treatment strategies. This strategy also involves in reducing costs in treatment phases which will be affordable to a common man suffering from AD. PMID- 29248452 TI - Protective effect of Terminalia chebula against seizures, seizure-induced cognitive impairment and oxidative stress in experimental models of seizures in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Teminalia chebula (TC) has been traditionally used in the Ayurvedic system of medicine primarily for gastrointestinal disorders. Its fruit extract has also been used to treat epilepsy and other CNS disorders. AIM OF THE STUDY: To evaluate the effect of hydroalcoholic fruit extract of Terminalia chebula (HETC) on experimental models of seizures, seizure induced cognitive impairment and oxidative stress in rats. MATERIALS AND METHODS: In vitro antioxidant activity of HETC was evaluated by using ABTS, NO and DPPH radical scavenging assay. For in-vivo study, seizures were induced in Wistar rats (200-225g) by pentylenetetrazole (PTZ) and maximal-electroshock. (MES). The anticonvulsant effect of the HETC (250, 500, and 1000mg/kg, orally) was evaluated in seizure models. The therapeutic and sub-therapeutic dose of valproate and phenytoin were also assayed. The potential effect of co-administration of HETC (500mg/kg) with sub-therapeutic dose of valproate and phenytoin were also evaluated in PTZ and MES seizures model respectively. Effect on cognition was assessed using elevated plus maze (EPM) and passive avoidance test (PA). The in- vivo oxidative stress parameters (malondialdehyde and glutathione) were assessed in the cerebral cortex and hippocampus part of rat brain. RESULTS: The IC50 value of HETC in in vitro antioxidant assays i.e. ABTS, DPPH and NO radical scavenging assay was found to be 2.27MUg/ml, 6.04MUg/ml and 4.37MUg/ml respectively. In experimental study, PTZ and MES treated groups exhibited 100% seizures with increased oxidative stress (p < 0.001) and cognitive deficits (p < 0.01) as compared to control group. HETC at highest dose (1000mg/kg) showed 83.33% (5/6) protection in MES induced seizures while 66.66% (4/6) protection in PTZ induced seizures. However, HETC (1000mg/kg) and co-administration of sub-therapeutic dose of HETC with valproate and phenytoin showed complete protection. In addition, it also attenuated the seizure induced oxidative stress and cognitive impairment as indicated by significant (p < 0.01) improvement in the transfer latencies in EPM and PA as compared to PTZ and MES treated group. CONCLUSIONS: The findings suggest that HETC exhibited significant anticonvulsant activity and also potentiated the subtherapeutic dose of phenytoin and valproate indicate its usefulness as an adjuvant to antiepileptic drugs with an advantage of preventing cognitive impairment and oxidative stress. PMID- 29248453 TI - Reishi mushroom Ganoderma lucidum Modulates IgA production and alpha-defensin expression in the rat small intestine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Immunoglobulin A (IgA) secretion and alpha defensins play a role in the innate immune system to protect against infection. Ganoderma lucidum (W.Curt.: Fr.) P. Karst. (Reishi) is a well-known mushroom in traditional Chinese medicine. This study aimed to determine the effects of Reishi on IgA secretion from Peyer's patch (PP) cells and alpha-defensin-5 (RD-5) and RD 6 expression in the rat small intestine. MATERIALS AND METHODS: The rats received an oral injection of 0.5-5mg/kg of Reishi powder (1mL/kg) by sonde. All animals were euthanized 24h after Reishi administration. We examined RD-5, RD-6, and Toll like receptor (TLR) 4 mRNA levels in the jejunum, ileum, and in Peyer's patches (PP) through quantitative real-time PCR analysis. IgA secretion from PP was measured through enzyme-linked immunosorbent assay of the supernatant after primary culture. RESULTS: Reishi increased IgA secretion in the presence of lipopolysaccharide (LPS) and increased TLR4 mRNA levels, but had no effect on the viability of PP cells. Moreover, Reishi increased RD-5, RD-6, and TLR4 mRNA levels significantly in the ileum in a concentration-dependent manner. CONCLUSIONS: Reishi can induce IgA secretion and increase the mRNA levels of RD-5 and RD-6 in the rat small intestine, through a TLR4-dependent pathway. The present results indicate that Reishi might reduce the risk of intestinal infection. PMID- 29248455 TI - A Large Set of miRNAs Is Dysregulated from the Earliest Steps of Human Hepatocellular Carcinoma Development. AB - Hepatocellular carcinoma (HCC) typically results from a stepwise process characterized by the development of premalignant lesions, such as low- or high grade dysplastic nodules (LGDNs and HGDNs, respectively), in a cirrhotic setting. MicroRNAs (miRNAs) are small noncoding RNAs involved in post-transcriptional regulation of gene expression that can act as oncogenes or tumor suppressors. Whether and which miRNAs are involved in the early stages of HCC development remains elusive. Here, small-RNA sequencing was applied to profile miRNA expression in 55 samples (cirrhotic nodules; CNs), LGDNs, HGDNs, early HCCs, and small progressed HCCs, obtained from 17 patients bearing HCCs of different etiologies. An miRNA expression signature of 62 miRNAs distinguishing small progressed HCCs from matched CNs was identified. Interestingly, 52 of these miRNAs discriminated CNs from LGDNs/HGDNs, regardless of etiology, and remained modified along the tumorigenic process. Functional analysis of the predicted mRNA targets of deregulated miRNAs identified common modifications between the early and late stages of HCC development likely involved in the stepwise process of HCC development. Our results demonstrate that miRNA deregulation happens very early in HCC in humans, implying their crucial role in the tumorigenic process. The identification of miRNAs discriminating CNs from neoplastic nodules may have relevant translational implications in early diagnosis. PMID- 29248454 TI - Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice. AB - Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection. PMID- 29248456 TI - Endothelin-2 Injures the Blood-Retinal Barrier and Macroglial Muller Cells: Interactions with Angiotensin II, Aldosterone, and NADPH Oxidase. AB - Although increasing evidence indicates that endothelin-2 (Edn2) has distinct roles in tissue pathology, including inflammation, glial cell dysfunction, and angiogenesis, its role in the retina and the factors that regulate its actions are not fully understood. We hypothesized that Edn2 damages the blood-retinal barrier (BRB) and that this is mediated by interactions with the renin angiotensin-aldosterone system and reactive oxygen species derived from NADPH oxidase (Nox). C57BL/6J mice received an intravitreal injection of Edn2 or control vehicle to examine the blood pressure-independent effects of Edn2. Mice administered Edn2 were randomized to receive by intraperitoneal injection treatments that inhibited the Edn type a receptor, Edn type b receptor, angiotensin type 1 receptor, mineralocorticoid receptor, or Nox isoforms 1 to 4. One month later, mice administered Edn2 exhibited breakdown of the BRB with increased vascular leakage, vascular endothelial growth factor expression, and infiltrating macrophages (Ly6C+CD45highCD11b+). Further, macroglial Muller cells, which influence the integrity of the BRB and prevent retinal edema, became gliotic and expressed increased levels of water (aquaporin-4) and ion (Kir4.1) channels. This Edn2-mediated retinopathy was reduced by all treatments. Complementary in vitro studies in cultured Muller cells supported these findings and demonstrated the importance of reactive oxygen species in mediating these events. In conclusion, Edn2 has detrimental effects on the BRB and Muller cells that involve interactions with the renin-angiotensin aldosterone system and Nox1/4. PMID- 29248457 TI - Malnutrition in Pancreatic Ductal Adenocarcinoma (PDA): Dietary Pancreatic Enzymes Improve Short-Term Health but Stimulate Tumor Growth. AB - Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that resists efforts to identify better chemotherapeutics. PDA is associated with chronic pancreatitis and acinar cell dedifferentiation. This reduces enzyme production by the exocrine pancreas, resulting in digestive insufficiencies. Malabsorption of partially digested food causes bloating, overfilled intestines, abdominal pain, excessive feces, steatorrhea, and malnutrition. These maladies affect quality of life and restrict treatment options for pancreatitis and PDA. Here, we characterize health benefits and risks of dietary pancreatic enzymes in three mouse models of PDA-KC, KCR8-16, and KIC. KC expresses oncogenic KrasG12D in pancreatic tissue whereas KCR8-16 also has deletions of the Rgs8 and Rgs16 genes. Rgs proteins inhibit the release of digestive enzymes evoked by G-protein-coupled-receptor agonists. KC and KCR8-16 mice developed dedifferentiated exocrine pancreata within 2 months of age and became malnourished, underweight, hypoglycemic, and hypothermic. KC mice adapted but KCR8-16 mice rapidly transitioned to starvation after mild metabolic challenges. Dietary pancreatic enzyme supplements reversed these symptoms in KC and KCR8-16 animals, and extended survival. Therefore, we tested the benefits of pancreatic enzymes in an aggressive mouse model of PDA (KIC). Median survival improved with dietary pancreatic enzyme supplements and was extended further when combined with warfarin and gemcitabine chemotherapy. However, dietary pancreatic enzymes stimulated tumor growth in the terminal stages of disease progression in KIC mice. PMID- 29248458 TI - Hepatic Stem/Progenitor Cell Activation Differs between Primary Sclerosing and Primary Biliary Cholangitis. AB - Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are human primary cholangiopathies characterized by the damage of mature cholangiocytes and by the appearance of ductular reaction (DR) as the results of hepatic progenitor cell activation. This study evaluated the differences in progenitor cell niche activation between these two cholangiopathies. Liver tissue was obtained from healthy liver donors (n = 5) and from patients with PSC (n = 20) or PBC (n = 20). DR, progenitor cell phenotype, and signaling pathways were investigated by IHC analysis and immunofluorescence. Our results indicated that DR was more extended, appeared earlier, and had a higher proliferation index in PBC compared with PSC. In PBC, DR was strongly correlated with clinical prognostic scores. A higher percentage of sex determining region Y-box (SOX)9+ and cytokeratin 19+ cells but fewer features of hepatocyte fate characterized progenitor cell activation in PBC versus PSC. Lower levels of laminin and neurogenic locus notch homolog protein 1 but higher expression of wingless related integration site (WNT) family pathway components characterize progenitor cell niche in PSC compared with PBC. In conclusion, progenitor cell activation differs between PSC and PBC and is characterized by a divergent fate commitment and different signaling pathway predominance. In PBC, DR represents a relevant histologic prognostic marker. PMID- 29248459 TI - Discrete Pools of Oligomeric Amyloid-beta Track with Spatial Learning Deficits in a Mouse Model of Alzheimer Amyloidosis. AB - Despite increasing appreciation that oligomeric amyloid-beta (Abeta) may contribute to cognitive decline of Alzheimer disease, defining the most critical forms has been thwarted by the changeable nature of these aggregates and the varying methods used for detection. Herein, using a broad approach, we quantified Abeta oligomers during the evolution of cognitive deficits in an aggressive model of Abeta amyloidosis. Amyloid precursor protein/tetracycline transactivator mice underwent behavioral testing at 3, 6, 9, and 12 months of age to evaluate spatial learning and memory, followed by histologic assessment of amyloid burden and biochemical characterization of oligomeric Abeta species. Transgenic mice displayed progressive impairments in acquisition and immediate recall of the trained platform location. Biochemical analysis of cortical extracts from behaviorally tested mice revealed distinct age-dependent patterns of accumulation in multiple oligomeric species. Dot blot analysis demonstrated that nonfibrillar Abeta oligomers were highly soluble and extracted into a fraction enriched for extracellular proteins, whereas prefibrillar species required high-detergent conditions to retrieve, consistent with membrane localization. Low-detergent extracts tested by 82E1 enzyme-linked immunosorbent assay confirmed the presence of bona fide Abeta oligomers, whereas immunoprecipitation-Western blotting using high-detergent extracts revealed a variety of SDS-stable low-n species. These findings show that different Abeta oligomers vary in solubility, consistent with distinct localization, and identify nonfibrillar Abeta oligomer-positive aggregates as tracking most closely with cognitive decline in this model. PMID- 29248460 TI - gammadelta T Cells Contribute to Injury in the Developing Brain. AB - Brain injury in premature infants, especially periventricular leukomalacia, is an important cause of neurologic disabilities. Inflammation contributes to perinatal brain injury development, but the essential mediators that lead to early-life brain injury remain largely unknown. Neonates have reduced capacity for mounting conventional alphabetaT-cell responses. However, gammadeltaT cells are already functionally competent during early development and are important in early-life immunity. We investigated the potential contribution of gammadeltaT cells to preterm brain injury using postmortem brains from human preterm infants with periventricular leukomalacia and two animal models of preterm brain injury-the hypoxic-ischemic mouse model and a fetal sheep asphyxia model. Large numbers of gammadeltaT cells were observed in the brains of mice, sheep, and postmortem preterm infants after injury, and depletion of gammadeltaT cells provided protection in the mouse model. The common gammadeltaT-cell-associated cytokines interferon-gamma and IL-17A were not detectable in the brain. Although there were increased mRNA levels of Il17f and Il22 in the mouse brains after injury, neither IL-17F nor IL-22 cytokines contributed to preterm brain injury. These findings highlight unique features of injury in the developing brain, where, unlike injury in the mature brain, gammadeltaT cells function as initiators of injury independently of common gammadeltaT-cell-associated cytokines. This finding will help to identify therapeutic targets for preventing or treating preterm infants with brain injury. PMID- 29248461 TI - Knockout of l-Histidine Decarboxylase Prevents Cholangiocyte Damage and Hepatic Fibrosis in Mice Subjected to High-Fat Diet Feeding via Disrupted Histamine/Leptin Signaling. AB - Feeding a high-fat diet (HFD) coupled with sugar, mimicking a Western diet, causes fatty liver disease in mice. Histamine induces biliary proliferation and fibrosis and regulates leptin signaling. Wild-type (WT) and l-histidine decarboxylase (Hdc-/-) mice were fed a control diet or an HFD coupled with a high fructose corn syrup equivalent. Hematoxylin and eosin and Oil Red O staining were performed to determine steatosis. Biliary mass and cholangiocyte proliferation were evaluated by immunohistochemistry. Senescence and fibrosis were measured by quantitative PCR and immunohistochemistry. Hepatic stellate cell activation was detected by immunofluorescence. Histamine and leptin levels were measured by enzyme immunoassay. Leptin receptor (Ob-R) was evaluated by quantitative PCR. The HDC/histamine/histamine receptor axis, ductular reaction, and biliary senescence were evaluated in patients with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, or end-stage liver disease. Hdc-/- HFD mice had increased steatosis compared with WT HFD mice. WT HFD mice had increased biliary mass, biliary proliferation, senescence, fibrosis, and hepatic stellate cell activation, which were reduced in Hdc-/- HFD mice. In Hdc-/- HFD mice, serum leptin levels increased, whereas biliary Ob-R expression decreased. Nonalcoholic steatohepatitis patients had increased HDC/histamine/histamine receptor signaling. Hdc-/- HFD mice are susceptible to obesity via dysregulated leptin/Ob R signaling, whereas the lack of HDC protects from HFD-induced fibrosis and cholangiocyte damage. HDC/histamine/leptin signaling may be important in managing obesity-induced biliary damage. PMID- 29248463 TI - Predictors of outcomes and refractoriness in status epilepticus: A prospective study; Methodological issues. PMID- 29248462 TI - Fibroblasts Promote Inflammation and Pain via IL-1alpha Induction of the Monocyte Chemoattractant Chemokine (C-C Motif) Ligand 2. AB - Fibroblasts persist within fibrotic scar tissue and exhibit considerable phenotypic and functional plasticity. Herein, we hypothesized that scar associated fibroblasts may be a source of stress-induced inflammatory exacerbations and pain. To test this idea, we used a human model of surgery induced fibrosis, total knee arthroplasty (TKA). Using a combination of tissue protein expression profiling and bioinformatics, we discovered that many months after TKA, the fibrotic joint exists in a state of unresolved chronic inflammation. Moreover, the infrapatellar fat pad, a soft tissue that becomes highly fibrotic in the post-TKA joint, expresses multiple inflammatory mediators, including the monocyte chemoattractant, chemokine (C-C motif) ligand (CCL) 2, and the innate immune trigger, IL-1alpha. Fibroblasts isolated from the post-TKA fibrotic infrapatellar fat pad express the IL-1 receptor and on exposure to IL 1alpha polarize to a highly inflammatory state that enables them to stimulate the recruitment of monocytes. Blockade of fibroblast CCL2 or its transcriptional regulator NF-kappaB prevented IL-1alpha-induced monocyte recruitment. Clinical investigations discovered that levels of patient-reported pain in the post-TKA joint correlated with concentrations of CCL2 in the joint tissue, such that the chemokine is effectively a pain biomarker in the TKA patient. We propose that an IL-1alpha-NF-kappaB-CCL2 signaling pathway, operating within scar-associated fibroblasts, may be therapeutically manipulated for alleviating inflammation and pain in fibrotic joints and other tissues. PMID- 29248464 TI - Decanoic acid suppresses proliferation and invasiveness of human trophoblast cells by disrupting mitochondrial function. AB - Decanoic acid (DA) is a medium-chain fatty acid used in the manufacture of various products including plastics, cosmetics, and lubricants. In addition to antiviral and antibacterial effects, DA's, reported biological activities include regulation of signaling pathways and redox homeostasis in various human cell types. The influence of DA on functional properties of human trophoblasts, including proliferation, invasion and apoptosis is currently unknown. In the present study, we evaluated the anti-proliferative and anti-invasive effects of DA on the human trophoblast cell line HTR8/SVneo. In addition, DA induced oxidative stress, as evidenced by generation of reactive oxygen species (ROS) and induction of lipid peroxidation (LPO). This oxidative stress was accompanied by activation of the mitochondria-dependent apoptotic pathway in HTR8/SVneo cells. We also observed elevated mitochondrial Ca2+, and loss of mitochondrial membrane potential in response to DA treatment. Chelation of mitochondrial Ca2+ using BAPTA-AM rescued cellular proliferation suppressed by DA. We also verified that signaling proteins including AKT, P70S6K, S6, and ERK1/2 and their targets were significantly reduced in HTR8/SVneo cells by DA treatment. Pre-treatment of cells with selective inhibitors of AKT (LY294002) and ERK1/2 (U0126) revealed that the AKT and ERK1/2 signaling pathways regulated by DA displayed cross-talk in HTR8/SVneo cells. Collectively, these results suggest that personal products containing DA will have harmful effects on human trophoblasts, and could cause implantation and placentation failure during early pregnancy. PMID- 29248465 TI - Disposition of beta-N-methylamino-l-alanine (L-BMAA), a neurotoxin, in rodents following a single or repeated oral exposure. AB - beta-N-methylamino-l-alanine (L-BMAA) is produced by cyanobacteria (blue-green algae). Human exposure to L-BMAA occurs via consumption of L-BMAA-contaminated water and food. It is speculated that exposure to L-BMAA, and subsequent brain accumulation, may contribute to an increased incidence of neurodegenerative diseases indicating the need to evaluate risk of L-BMAA exposure to humans. As an initial step in this process, we have evaluated disposition following a single or repeated gavage administration of 1, 10 or 100mg/kg [14C]L-BMAA in rats and mice. L-BMAA was well absorbed following a single gavage administration with minimal dose, species, or sex-related effect. In both species, the main excretion route was as exhaled CO2 (46-61%) with 7-13% and 1.4-8% of the administered dose excreted in the urine and feces, respectively. L-BMAA was distributed to all tissues examined; the total radioactivity in tissues increased with the dose and was significant in both species (8-20%). In male rats, L-BMAA was slowly eliminated from blood and tissues (half-lives >=48h). Following 1, 5 and 10days of dosing in male rats, levels in tissues increased with the number of doses demonstrating potential for accumulation of BMAA-derived equivalents. There was no greater affinity for accumulation in the brain compared to other organs and tissues. Following repeated exposure in rats, amino acid mass shifts associated with L-BMAA were detected in brain peptides. However, the low frequency of occurrence suggests that the substitution of an amino acid with L-BMAA is not significant relative to substitutions and/or modifications by other L-BMAA derived equivalents. PMID- 29248466 TI - Leptin suppresses microRNA-122 promoter activity by phosphorylation of foxO1 in hepatic stellate cell contributing to leptin promotion of mouse liver fibrosis. AB - Adipocytokine leptin promotes hepatic stellate cell (HSC) activation (a key step in liver fibrogenesis) and liver fibrosis. microRNA-122 (miR-122) is the most abundant liver-specific miRNA and was demonstrated to inhibit liver fibrosis and reduced HSC proliferation. Our previous study revealed that leptin reduced miR 122 level in HSCs. This study was aimed to investigate whether leptin affected miR-122 promoter and the underlying mechanisms in HSCs. Results showed that leptin inhibited miR-122 promoter activity. Forkhead box protein O1(FoxO1) bound to miR-122 promoter at a site around - 56 and thus promoted miR-122 promoter activity, which could be suppressed by leptin-induced phosphorylation of FoxO1 at serine 256. The PI3K/Akt signaling pathway was involved in leptin-induced phosphorylation of FoxO1 and the effect of leptin on miR-122 expression. Furthermore, FoxO1 increased miR-122 and pri-miR-122 (primary miR-122) levels in HSCs in vivo, and reduced leptin-induced HSC activation and liver fibrosis in ob/ob mouse (leptin deficient) model. In conclusion, leptin suppressed microRNA 122 expression by PI3K/Akt/foxO1 axis in HSCs. These results have potential implications for clarifying the mechanisms for liver fibrogenesis in obese patients with hyperleptinaemia. PMID- 29248467 TI - Protective capabilities of silymarin and inulin nanoparticles against hepatic oxidative stress, genotoxicity and cytotoxicity of Deoxynivalenol in rats. AB - Deoxynivalenol (DON) is a Fusarium mycotoxin that frequently contaminates cereal and cereal-based food and induces liver injury. This study evaluated the protective role of silymarin nanoparticles (SILNPs) and inulin nanoparticles (INNPs) against DON-induced liver injury in rats. Eleven groups of rats were treated orally for 3 weeks as follows: the control group, DON-treated group (5 mg/kg b.w.); INNPs-treated groups at low (LD) or high (HD) dose (100 or 200 mg/kg b.w.); SILPNs-treated group (50 mg/kg b.w.); SILNPs plus INNPs(LD) or INNPs(HD) treated groups; INNPs(LD) or INNPs(HD) plus DON-treated groups and DON plus SILNPs and INNPs(LD) or INNPs(HD)-treated groups. Blood and tissue samples were collected for different analyses. The results revealed that the practical sizes were 200 and 98 nm for SILNPs and INNPs respectively. DON increased liver enzymes activity, lipid profile, serum cytokines, number and percentage of chromosomal aberration, DNA fragmentation and comet score. It disturbed the oxidative stress markers, down regulated gene expression and induced histological changes in the liver tissue. Treatment with DON and SILNPs and/or INNPs at the two tested doses improved all the tested parameters and SILNPs plus INNPs(HD) normalized most of these parameters in DON-treated animals. SILNPs and INNPs could be promising candidates as hepatoprotective against DON or other hepatotoxins. PMID- 29248468 TI - Suspected anaphylaxis and lack of clinical protection associated with envenomation in two dogs previously vaccinated with Crotalus atrox toxoid. AB - OBJECTIVE: to describe the clinical presentation of two canines present in anaphylactic shock secondary to rattlesnake envenomation. In both cases, there was no previous documented previous envenomation event and the initial sensitization required for anaphylactic response is believed to be secondary to Crotalus atrox toxoid vaccine. CASE DESCRIPTION: In the first case, a 12-year-old golden retriever present for collapse, severe hematochezia, and vomiting after first time envenomation from a suspected western diamondback rattlesnake. The patient presented in severe hypovolemic shock and required aggressive fluid therapy, antivenom, anti-emetics, and pain management. The patient made a full recovery within 24 hours. In the second case, an 8-year old English setter presented for acute collapse, vomiting, and facial swelling after suspected first time envenomation from a suspected Prairie rattlesnake. The patient presented in severe hypovolemic shock with cardiac arrhythmias and required aggressive fluid therapy, antivenom, pain control, anti-emetics, and antibiotics. The patient made a full recovery after three days of hospitalization. Both patients had been previously vaccinated with the C. atrox vaccine. CONCLUSION: This case report documents suspected anaphylaxis in two canine patients after first time envenomation by a rattlesnake. Both patients were previously vaccinated by the Crotalus atrox toxoid, which is hypothesized to be the initial inciting trigger. PMID- 29248469 TI - Venom-gland transcriptomics and venom proteomics of the Hentz striped scorpion (Centruroides hentzi; Buthidae) reveal high toxin diversity in a harmless member of a lethal family. AB - Of the 14 extant scorpion families, Buthidae has the most thoroughly characterized venoms. Most of this characterization, however, has been limited to species with medically significant stings, including members of the Centruroides genus, which have caused human deaths (e.g., Centruroides sculpturatus). To understand the origin and evolution of highly toxic venoms, we should also characterize the more harmless venoms of close relatives. We used Illumina sequencing to separately characterize the venom-gland transcriptomes of a male and female Hentz striped scorpion (Centruroides hentzi) and performed independent quantitative mass-spectrometry analysis of the venom from each individual, providing the first full venom characterization of a Centruroides species that poses no serious threat to humans. We identified 59 venom proteins that were proteomically confirmed, 63 additional transcripts that were identified on the basis of homology to known toxins, and 355 nontoxins expressed in the venom glands. The most abundant toxins belonged to the Na+ and K+-channel toxin classes. Antimicrobial peptides and peptidases were also identified, along with a large group of venom proteins that could not be classified based on homology, suggesting C. hentzi is a source of previously untapped toxin diversity. PMID- 29248472 TI - Evolution and development of the cartilaginous skull: From a lancelet towards a human face. AB - Chrondrocranium, the cartilaginous skull, is one of the major innovations that underlie evolution of the vertebrate head. Control of the induction and shaping of the cartilage is a key for the formation of the facial bones and largely defines facial shape. The appearance of cartilage in the head enabled many new functions such as protection of central nervous system and sensory structures, support of the feeding apparatus and formation of muscle attachment points ensuring faster and coordinated jaw movements. Here we review the evolution of cartilage in the cranial region and discuss shaping of the chondrocranium in different groups of vertebrates. PMID- 29248473 TI - Editorial Comment. PMID- 29248474 TI - Reply by Authors. PMID- 29248471 TI - Evolvability of the vertebrate craniofacial skeleton. AB - The skull is a vertebrate novelty. Morphological adaptations of the skull are associated with major evolutionary transitions, including the shift to a predatory lifestyle and the ability to masticate while breathing. These adaptations include the chondrocranium, dermatocranium, articulated jaws, primary and secondary palates, internal choanae, the middle ear, and temporomandibular joint. The incredible adaptive diversity of the vertebrate skull indicates an underlying bauplan that promotes evolvability. Comparative studies in craniofacial development suggest that the craniofacial bauplan includes three secondary organizers, two that are bilaterally placed at the Hinge of the developing jaw, and one situated in the midline of the developing face (the FEZ). These organizers regulate tissue interactions between the cranial neural crest, the neuroepithelium, and facial and pharyngeal epithelia that regulate the development and evolvability of the craniofacial skeleton. PMID- 29248475 TI - Alleviating the hepatotoxicity of trazodone via supramolecular encapsulation. AB - In order to develop a novel strategy to alleviate the inherent hepatotoxicity of antidepressant trazodone (TZ), Cucurbit[7]uril (CB[7]) was adopted as pharmaceutical excipients and was studied for its capability to reduce the hepatotoxicity of TZ via supramolecular encapsulation. CB[7] was found to form strong 1:1 host-guest complexes with TZ and its metabolite m-chlorophenyl piperazine (mCPP), with binding constants of 1.50 (+/-0.13) * 106 M-1 and 6.90 (+/-0.49) * 105 M-1, respectively. The supramolecular complexations were examined by 1H NMR and UV-visible spectroscopic titrations, ESI-MS and ITC. In the presence of 0.5 mM CB[7], the IC50 values of TZ and mCPP on a human normal liver cell line L02 were increased from 215.5 +/- 3.3 MUM to 544.1 +/- 51.2 MUM, and from 166.8 +/- 3.8 MUM to 241.7 +/- 6.8 MUM, respectively. Evaluation on a zebrafish model demonstrated that CB[7] (0.1 mM) significantly alleviated the TZ induced liver toxicity, as shown by the level of liver degeneration, liver size and yolk sac retention. Our study may provide a supramolecular strategy to alleviate the hepatotoxicity induced by TZ and its metabolite mCPP, and this strategy may be extendable to other drugs that have inherent hepatotoxicity or other adverse effects. PMID- 29248476 TI - Survey on the effects of electron beam irradiation on chemical quality and sensory properties on quail meat. AB - INTRODUCTION: Irradiation is one of the intervention strategies for effective control of food-borne pathogen microorganisms, which reduces microbial load and extends the meat shelf life. MATERIALS AND METHODS: This experimental study was carried out on quail meat. Quail meat samples were treated with electron beam irradiation at doses of 0.5, 1, and 3 kGy and stored at 4 +/- 1 degrees C for 15 days. Five days after irradiation, the chemical and organoleptic changes in the quail meat were evaluated for 15 days. Total volatile basic nitrogen and TBA were also measured to investigate chemical changes. RESULTS: Irradiation significantly reduced the amount of total volatile basic nitrogen in irradiated samples. Furthermore, the increase of TBA level was significant in irradiated samples, which had a direct correlation with irradiation dose and storage/shelf life duration. Despite the increase of thiobarbituric acid, irradiation had no significant effect on the sensory properties of quail meat. CONCLUSION: Irradiation of quilt meat resulted in extension of the meat shelf life to at least two weeks at refrigeration temperature by decreasing the corrosion-causing microorganisms and improving microbial quality, while the sensory properties of meat were preserved. Regarding the increase in the oxidation level at high doses of the electron beam and the absence of significant differences in the studied dosages in reducing the total amount of total volatile basic nitrogen, it is recommended to apply electron beam irradiation at doses of 1.5 and 3 kGy to extend the meat shelf life and preserve the quality/health of the quail meat. PMID- 29248477 TI - Temperature induced lipid membrane restructuring and changes in nanomechanics. AB - The naturally occurring milk sphingomyelin is of particular interest owing to its complex composition and involvement in the formation of the milk fat globule membrane (MFGM). Knowledge of membrane organization and nanomechanical stability has proved to be crucial in understanding their properties and functions. In this work, two model membrane systems composed of 1, 2 dioleoyl-sn-glycero-3 phosphocholine (DOPC), egg sphingomyelin (egg-SM) and cholesterol, and DOPC, milk sphingomyelin (milk-SM) and cholesterol were exposed to both RT and 10 degrees C. The morphological and nanomechanical changes were investigated using atomic force microscopy (AFM) imaging and force mapping below RT using a designed liquid cell with temperature-control. In both systems, the size and shape of SM/Chol-enriched liquid ordered domains (Lo) and DOPC-enriched liquid disordered phase (Ld) were monitored at controlled temperatures. AFM based force-mapping showed that rupture forces were consistently higher for Lo domains than Ld phases and were decreased for Ld with decreasing temperature while an increase in breakthrough force was observed in Lo domains. More interestingly, dynamic changes and defect formations in the hydrated lipid bilayers were mostly detected at low temperature, suggesting a rearrangement of lipid molecules to relieve additional tension introduced upon cooling. Noteworthy, in these model membrane systems, tension driven defects generally heal on reheating the sample. The results of this work bring new insights to low temperature induced membrane structural reorganization and mechanical stability changes which will bring us one step closer to understand more complex systems such as the MFGM. PMID- 29248478 TI - Expression, activity and pharmacokinetic impact of ocular transporters. AB - The eye is protected by several tissues that limit the permeability and entry of potentially harmful substances, but also hamper the delivery of drugs in the treatment of ocular diseases. Active transport across the ocular barriers may affect drug distribution, but the impact of drug transporters on ocular drug delivery is not well known. We have collected and critically reviewed the literature for ocular expression and activity of known drug transporters. The review concentrates on drug transporters that have been functionally characterized in ocular tissues or primary cells and on transporters for which there is available expression data at the protein level. Species differences are highlighted, since these may explain observed inconsistencies in the influence of specific transporters on drug disposition. There is variable evidence about the pharmacokinetic role of transporters in ocular tissues. The strongest evidence for the role of active transport is available for the blood-retinal barrier. We explored the role of active transport in the cornea and blood retinal barrier with pharmacokinetic simulations. The simulations show that the active transport is important only in the case of specific parameter combinations. PMID- 29248479 TI - Nanomaterials and molecular transporters to overcome the bacterial envelope barrier: Towards advanced delivery of antibiotics. AB - With the dramatic consequences of bacterial resistance to antibiotics, nanomaterials and molecular transporters have started to be investigated as alternative antibacterials or anti-infective carrier systems to improve the internalization of bactericidal drugs. However, the capability of nanomaterials/molecular transporters to overcome the bacterial cell envelope is poorly understood. It is critical to consider the sophisticated architecture of bacterial envelopes and reflect how nanomaterials/molecular transporters can interact with these envelopes, being the major aim of this review. The first part of this manuscript overviews the permeability of bacterial envelopes and how it limits the internalization of common antibiotic and novel oligonucleotide drugs. Subsequently we critically discuss the mechanisms that allow nanomaterials/molecular transporters to overcome the bacterial envelopes, focusing on the most promising ones to this end - siderophores, cyclodextrins, metal nanoparticles, antimicrobial/cell-penetrating peptides and fusogenic liposomes. This review may stimulate drug delivery and microbiology scientists in designing effective nanomaterials/molecular transporters against bacterial infections. PMID- 29248480 TI - Functional therapies for cutaneous wound repair in epidermolysis bullosa. AB - Chronic wounding as a result of recurrent skin blistering in the painful genetic skin disease epidermolysis bullosa, may lead to life-threatening infections, increased risk of tumor formation, and other serious medical complications. Therefore, epidermolysis bullosa patients have an urgent need for optimal wound care and tissue regeneration. Therapeutic strategies using gene-, protein-, and cell-therapies are being developed to improve clinical symptoms, and some of them have already been investigated in early clinical trials. The most favorable options of functional therapies include gene replacement, gene editing, RNA targeting, and harnessing natural gene therapy. This review describes the current progress of the different approaches targeting autologous skin cells, and will discuss the benefits and challenges of their application. PMID- 29248481 TI - Leptin and ghrelin: Sewing metabolism onto neurodegeneration. AB - Life expectancy has considerably increased over the last decades. The negative consequence of this augmented longevity has been a dramatic increase of age related chronic neurodegenerative diseases, such as Alzheimer's, Parkinson's and multiple sclerosis. Epidemiology is telling us there exists a strong correlation between the neuronal loss characterizing these disorders and metabolic dysfunction. This review aims at presenting the evidence supporting the existence of a molecular system linking metabolism with neurodegeneration, with a specific focus on the role of two hormones with a key role in the regulatory cross talk between metabolic imbalance and the damage of nervous system: leptin and ghrelin. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.' PMID- 29248470 TI - Spontaneous preterm birth: advances toward the discovery of genetic predisposition. AB - Evidence from family and twin-based studies provide strong support for a significant contribution of maternal and fetal genetics to the timing of parturition and spontaneous preterm birth. However, there has been only modest success in the discovery of genes predisposing to preterm birth, despite increasing sophistication of genetic and genomic technology. In contrast, DNA variants associated with other traits/diseases have been identified. For example, there is overwhelming evidence that suggests that the nature and intensity of an inflammatory response in adults and children are under genetic control. Because inflammation is often invoked as an etiologic factor in spontaneous preterm birth, the question of whether spontaneous preterm birth has a genetic predisposition in the case of pathologic inflammation has been of long-standing interest to investigators. Here, we review various genetic approaches used for the discovery of preterm birth genetic variants in the context of inflammation associated spontaneous preterm birth. Candidate gene studies have sought genetic variants that regulate inflammation in the mother and fetus; however, the promising findings have often not been replicated. Genome-wide association studies, an approach to the identification of chromosomal loci responsible for complex traits, have also not yielded compelling evidence for DNA variants predisposing to preterm birth. A recent genome-wide association study that included a large number of White women (>40,000) revealed that maternal loci contribute to preterm birth. Although none of these loci harbored genes directly related to innate immunity, the results were replicated. Another approach to identify DNA variants predisposing to preterm birth is whole exome sequencing, which examines the DNA sequence of protein-coding regions of the genome. A recent whole exome sequencing study identified rare mutations in genes encoding for proteins involved in the negative regulation (dampening) of the innate immune response (eg, CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and antimicrobial peptide/proteins (eg, DEFB1, MBL2). These findings support the concept that preterm labor, at least in part, has an inflammatory etiology, which can be induced by pathogens (ie, intraamniotic infection) or "danger signals" (alarmins) released during cellular stress or necrosis (ie, sterile intraamniotic inflammation). These findings support the notion that preterm birth has a polygenic basis that involves rare mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. An overlap among the whole exome sequencing identified genes and other inflammatory conditions associated with preterm birth, such as periodontal disease and inflammatory bowel disease, was observed, which suggests a shared genetic substrate for these conditions. We propose that whole exome sequencing, as well as whole genome sequencing, is the most promising approach for the identification of functionally significant genetic variants responsible for spontaneous preterm birth, at least in the context of pathologic inflammation. The identification of genes that contribute to preterm birth by whole exome sequencing, or whole genome sequencing, promises to yield valuable population-specific biomarkers to identify the risk for spontaneous preterm birth and potential strategies to mitigate such a risk. PMID- 29248483 TI - Dose-Dependent Resorption of Allograft by rhBMP-2 Uncompensated by New Bone Formation-A Canine Study With Implants and Zoledronate. AB - BACKGROUND: Impacted bone allograft is used to restore lost bone in total joint arthroplasties. Bone morphogenetic proteins (BMPs) can induce new bone formation to improve allograft incorporation, but they simultaneously invoke a seemingly dose-dependent allograft resorption mediated by osteoclasts. Bisphosphonates effectively inhibit osteoclast activity. Predicting allograft resorption when augmented with bone morphogenetic protein 2 (BMP-2), we intended to investigate whether a balanced bone metabolism was achievable within a range of BMP-2 doses with systemic zoledronate treatment. METHODS: Implants were coated with 1 of 3 BMP-2 doses (15 MUg, 60 MUg, and 240 MUg) or left untreated. Implants were surrounded by a 2.5-mm gap filled with impacted morselized allograft. Each of the 12 dogs included received 1 of each implant (15 MUg, 60 MUg, 240 MUg, and untreated), 2 in each proximal humerus. During the 4-week observation period, zoledronate intravenous (0.1 mg/kg) was administered to all animals 10 days after surgery as anticatabolic treatment. Implant osseointegration was evaluated by histomorphometry and mechanical push-out tests. RESULTS: Untreated implants had the best mechanical fixation and superior retention of allograft as compared to any of the BMP-2 implants. Both mechanical implant fixation and retention of allograft decreased significantly with BMP-2 dose increments. Surprisingly, there was no difference among the treatment groups in the amount of new bone. CONCLUSION: The use of BMP-2 to augment impaction-grafted implants cannot be recommended even when combined with systemic zoledronate. PMID- 29248482 TI - Targeted inhibition of RAGE reduces amyloid-beta influx across the blood-brain barrier and improves cognitive deficits in db/db mice. AB - AIMS: To investigate restorative effects of the receptor for advanced glycation end products (RAGE)-specific inhibitor FPS-ZM1 on abnormal amyloid beta (Abeta) influx across the blood brain-barrier (BBB) and cognitive deficits in db/db mice. METHODS: Abeta influx across the BBB was determined by intra-arterial infusion of 125I-Abeta1-40. Receptor for advanced glycation end products (RAGE), Abeta, NF kappaB p65, caspase-3, Bax, Bcl-2, PSD-95 and synaptophysin were assayed by Western blot, immunohistochemistry or RT-PCR. Apoptosis was quantified by TUNEL assay. In vivo hippocampal long term potentiation (LTP) recording, Golgi Staining, Morris water maze (MWM) task and Y-maze test were performed. RESULTS: FPS-ZM1 (1.0 mg/kg i.p.) inhibited Abeta influx across the BBB and expression of RAGE participating in Abeta influx, consequently decreased hippocampal Abeta1-40 and Abeta1-42 in db/db mice. After FPS-ZM1 treatment, NF-kappaB signaling was inhibited, and neuronal apoptosis was reduced, which revealed by less TUNEL + cells, reduced caspase-3 activity and higher ratio of Bcl-2/Bax. In addition, FPS ZM1 improved hippocampal plasticity evidenced by enhanced in vivo LTP and the restoration of spine deficit and increased PSD-95 expression in hippocampal neuron. Further studies found that FPS-ZM1 treatment alleviated cognitive deficits shown by better performance in behavioral tests, without significant metabolic effects on blood glucose, insulin and cerebral AGEs. CONCLUSION: Downregulation of abnormal Abeta influx across the BBB by FPS-ZM1 at higher dosage contributes to reduced neuronal apoptosis, improved hippocampal plasticity and cognitive impairment in db/db mice. PMID- 29248484 TI - Is There Any Role for Direct Repair of Extensor Mechanism Disruption Following Total Knee Arthroplasty? AB - BACKGROUND: Extensor mechanism disruption remains a challenging problem in total knee arthroplasty (TKA) with historically poor outcomes. The purpose of our study is to determine if patients undergoing acute extensor mechanism repair had different outcomes than patients undergoing allograft reconstruction. METHODS: We reviewed a series of 126 total knee arthroplasty patients requiring surgical repair or reconstruction of an extensor mechanism injury from 2005 to 2014 with a minimum of 24 months of follow-up. Demographics, comorbidities, Knee Society Scores, time from injury, and reoperations were all recorded from the medical record. A poor outcome was defined as an extensor lag >30 degrees , postoperative Knee Society Scores <60, or a reoperation. A multivariate analysis was then performed to identify independent risk factors for a poor outcome. RESULTS: Of the 126 patients, there were 58 patients who underwent direct extensor repair (46%) and 68 patients who underwent allograft reconstruction (54%) at a mean postsurgical follow-up of 81.2 months. Rates of poor outcomes were comparably high in both groups (33% vs 44%, P = .192). Patella tendon repair had the highest rate of poor outcomes compared to quadriceps repair and patella fixation (63% vs 22% vs 8%, P = .002). Independent risk factors for poor outcomes included patients with a history of infection (odds ratio 4.559, P = .002) and injury greater than 2 weeks duration (odds ratio 4.237, P = .031). CONCLUSION: Outcomes following direct extensor mechanism are comparable to extensor mechanism allograft reconstruction; however, patients should be counseled regarding poor outcomes. Direct repair of patellar tendon injuries should likely be avoided due to prohibitively high complication rate. PMID- 29248485 TI - Uncemented vs Cemented Cruciate Retaining Total Knee Arthroplasty in Patients With Body Mass Index Greater Than 30. AB - BACKGROUND: Aseptic loosening of cemented and uncemented tibial components continues to be a source of implant failure after total knee arthroplasty (TKA) in the obese population. There is limited literature reviewing uncemented cruciate retaining (CR) components in the obese population. METHODS: A clinical and radiographic review was performed on 325 patients who underwent a cemented or uncemented TKA with a CR knee prosthesis and body mass index >=30 kg/m2 between January 2010 and June 2013. Charts were reviewed for the incidence of revision due to aseptic loosening of the tibial baseplate, revision for any reason, incidence of radiolucent lines around the tibial baseplate, range of motion, and patient reported outcomes. RESULTS: There was no statistically significant difference between groups in survivorship for aseptic loosening of the tibial component (99.4% uncemented, 99.3% cemented, P = .94) and overall survivorship (98.1% uncemented, 98.3% cemented, P = .90). The Lower Extremity Activity Scale and Forgotten Joint Score-12 clinical outcome measures were similar between groups (10.2 +/- 3.7 vs 9.7 +/- 3.4 and 66.1 +/- 28.2 vs 64.9 +/- 24.3, P = .33, P = .78, respectively). Postoperative knee flexion was similar between groups (114.6 +/- 9.3 vs 114.1 +/- 9.3, P = .67). CONCLUSION: Our study demonstrated similar survivorship of this CR design for aseptic loosening of the tibial baseplate and overall revision rates in obese patients undergoing either an uncemented or cemented TKA. The uncemented and cemented groups had comparable clinical and radiographic short to mid-term outcomes when implanted in good alignment when treating end-stage knee osteoarthritis. PMID- 29248486 TI - Rate and Risk Factors for Periprosthetic Joint Infection Among 36,494 Primary Total Hip Arthroplasties. AB - BACKGROUND: As periprosthetic joint infections (PJIs) can have tremendous health and socioeconomic implications, recognizing patients at risk before surgery is of great importance. Therefore, we sought to determine the rate of and risk factors for deep PJI in patients undergoing primary total hip arthroplasty (THA). METHODS: Clinical characteristics of patients treated with primary THA between January 1999 and December 2013 were retrospectively reviewed. These included patient demographics, comorbidities (including the Charlson/Deyo comorbidity index), length of stay, primary diagnosis, total/allogeneic transfusion rate, and in-hospital complications, which were grouped into local and systemic (minor and major). We determined the overall deep PJI rate, as well as the rates for early onset (occurring within 2 years after index surgery) and late-onset PJI (occurring more than 2 years after surgery). A Cox proportional hazards regression model was constructed to identify risk factors for developing deep PJI. Significance level was set at 0.05. RESULTS: A deep PJI developed in 154 of 36,494 primary THAs (0.4%) during the study period. Early onset PJI was found in 122 patients (0.3%), whereas late PJI occurred in 32 patients (0.1%). Obesity, coronary artery disease, and pulmonary hypertension were identified as independent risk factors for deep PJI after primary THA. CONCLUSION: The rate of deep PJIs of the hip is relatively low, with the majority occurring within 2 years after THA. If the optimization of modifiable risk factors before THA can reduce the rate of this complication remains unknown, but should be attempted as part of good practice. PMID- 29248487 TI - Evaluation of the safety profile of an electronic vapour product used for two years by smokers in a real-life setting. AB - The safety profile of PuritaneTM, a closed system electronic vapour product (EVP), was evaluated when used by smokers of conventional cigarettes (CCs) for 24 months in a real-life setting. The study was a two-centre ambulatory clinical study with 209 healthy volunteers. Outcome measures included adverse events (AEs), vital signs, electrocardiogram, lung function tests, exposure to nicotine and selected smoke constituents, nicotine withdrawal effects and smoking desire. No serious AEs related to EVP use were observed. The most frequently reported AEs were headache, nasopharyngitis, sore throat and cough, reported by 28.7%, 28.7%, 19.6% and 16.7% of subjects, respectively, which dissipated over time. Small decreases in lung function were not considered clinically relevant. No clinically relevant findings were observed in the other safety parameters. From Month 2, nicotine withdrawal symptoms decreased. Smoking desire and CC consumption steadily decreased over time in all subjects. EVP use was associated with reduced exposure to cigarette smoke constituents, whereas urinary nicotine levels remained close to baseline. Body weight did not increase in CC subjects switching to the EVP. In conclusion, the aerosol of the EVP at study was well tolerated and not associated with any clinically relevant health concerns after usage for up to 24 months. PMID- 29248488 TI - Safety assessment of propylparaben in juvenile rats. AB - There are conflicting literature reports that parabens, useful antimicrobial additives in pharmaceuticals, may have estrogenic activity. We conducted a comprehensive study to determine whether propylparaben (PP) administration to juvenile rats is associated with adverse effects on reproductive development and function. PP was administered orally once daily to groups of Crl:CD(SD) rats at doses of 0 (vehicle), 10, 100, or 1,000 mg/kg on Postnatal Days (PNDs) 4-90. In life observations, clinical pathology, reproductive organ weights and histopathology, landmarks of sexual maturation, estrous cyclicity and functional reproductive competence were assessed. A conventional uterotrophic assay was conducted separately using the same doses. Systemic exposures to PP and 3 metabolites were evaluated on PND 7, 21 and 83. These studies demonstrated that PP was well tolerated when administered from PND 4-90 at all doses (AUC[0-T] on PND 83 = 69.9 ng*h/mL). Para-hydroxybenzoic acid, a non-estrogenic compound, was the predominant metabolite contributing to 95% of the total exposure at 1,000 mg/kg/day on PND 7. There was no evidence of estrogenic activity at any dose, and no effects on reproductive organs or function. The No-Observed-Adverse-Effect Level (NOAEL) was 1,000 mg/kg/day. PMID- 29248489 TI - "In vitro" studies on galectin-3 in human natural killer cells. AB - Galectin-3 (Gal-3) is a beta-galactoside binding protein able to modulate both innate and adaptive immune responses. First identified in macrophages, Gal-3 has been studied widely in many mammalian immune cells, but scarcely in natural killer (NK) cells. The aim of this study was to analyze Gal-3 in human NK cells, isolated from peripheral blood mononuclear cells. Both PCR and RT-PCR analysis showed that resting human NK cells express Gal-3 mRNA, which can be modulated upon cytokine stimulation (100 U/ml IL-2 + 20 ng/ml IL-15) for different period of time (1-24 h). Western blot, cytofluorimetry, and confocal microscopy analysis clearly demonstrated that the Gal-3 gene can translate into the corresponding protein. From our results, resting NK cells, isolated from different healthy donors, can express high or low basal levels of Gal-3. In NK cells, Gal-3 was always intracellularly detected at both cytoplasm and nucleus levels, while never at the membrane surface, and its localization resulted independent from the cellular activation status. In addition, the intracellular Gal-3 can co-localize with perforin in exocytic vesicles. Cell treatment with a thiodigalactoside-based Gal-3 inhibitor (1-30 MUM) slightly increased the number of degranulating NK cells, while it significantly increased the percentage of cells releasing high amounts of cytotoxic granules (+ 36 +/- 3% vs. inhibitor-untreated cells at 30 MUM Gal-3). In conclusion, our results demonstrate that human resting NK cells express Gal-3 at both gene and protein levels and that the Gal-3 expression can be modulated upon cytokine stimulation. In the same cells, Gal-3 always localizes intracellularly and functionally correlates with the degree of NK cell degranulation. PMID- 29248490 TI - Acetylation regulates the MKK4-JNK pathway in T cell receptor signaling. AB - T cell functions are regulated by multiple signaling cascades, including the MKK4 JNK (c-Jun NH2 terminal kinase) pathway. However, the mechanism regulating the MKK4-JNK axis in T cells remains unclear. Herein, we demonstrated that protein acetylation modulates JNK activity induced by T cell receptor (TCR) activation. The acetyltransferase, CREB-binding protein (CBP), is transported from the nucleus to the cytoplasm in response to TCR cross-linking. To investigate the role of CBP in TCR signaling, we overexpressed CBP in the cytoplasm of Jurkat cells, a human T lymphocyte line. Enforced expression of cytoplasmic CBP led to MKK4 acetylation and interfered with MKK4-mediated JNK phosphorylation. Insufficient JNK activity decreased the activity of the transcription factor, AP 1. In contrast, other transcription factors, NF-kappaB and NFAT, stimulated with anti-CD3 and anti-CD28 antibodies were activated normally in the presence of cytoplasmic-CBP. These results provide valuable insights into the role of acetylation in MKK4-JNK signaling in T cells. PMID- 29248491 TI - Atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats through a mechanism involving down-regulation of miR-21-5p/203a-3p. AB - Statins are reported to exert benefits on endothelial function through a mechanism involving in prevention of endothelial senescence. This study aims to explore whether atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats or ox-LDL-treated HUVECs through a mechanism involving suppress of miR-21-5p/203a-3p expression and their downstream pathway. The rats were fed with high-fat diet to establish a hyperlipidemic model, which showed an increase in plasma lipids and endothelial senescence, accompanied by the elevation in plasma levels of miR-21-5p/203a-3p, down-regulation of Drp1 and up regulation of p53 in the aorta of hyperlipidemic rats; these phenomena were reversed by atorvastatin. Next, HUVECs were incubated with ox-LDL to establish a senescent model in vitro. Consistent with the finding in vivo, atorvastatin treatment decreased the level of miR-21-5p and miR-203a-3p in the ox-LDL-treated HUVECs, restored Drp1 expression and mitochondrial function, as well as suppressed p53 and p16 expression and endothelial senescence. Based on these observations, we conclude that atorvastatin exerts inhibitory effect on endothelial senescence in hyperlipidemic rats through a mechanism involving down regulation of miR-21-5p/203a-3p, which leads to the restoration of Drp1 level and recovery of mitochondrial function. Our findings highlight a novel non-lipid effect for atorvastatin besides its function in modulation of lipids. PMID- 29248493 TI - TNF-alpha-induced protein 3 (TNFAIP3)/A20 acts as a master switch in TNF-alpha blockade-driven IL-17A expression. AB - BACKGROUND: Anti-TNF inhibitors successfully improve the quality of life of patients with inflammatory disease. Unfortunately, not all patients respond to anti-TNF therapy, and some patients show paradoxical immune side effects, which are poorly understood. Surprisingly, anti-TNF agents were shown to promote IL-17A production with as yet unknown clinical implications. OBJECTIVE: We sought to investigate the molecular mechanism underlying anti-TNF-driven IL-17A expression and the clinical implications of this phenomenon. METHODS: Fluorescence-activated cell sorting, RNA sequencing, quantitative real-time PCR, Western blotting, small interfering RNA interference, and kinase inhibitors were used to study the molecular mechanisms in isolated human CD4+ T cells from healthy donors. The clinical implication was studied in blood samples of patients with inflammatory bowel disease (IBD) receiving anti-TNF therapy. RESULTS: Here we show that anti TNF treatment results in inhibition of the anti-inflammatory molecule TNF-alpha induced protein 3 (TNFAIP3)/A20 in memory CD4+ T cells. We found an inverse relationship between TNFAIP3/A20 expression levels and IL-17A production. Inhibition of TNFAIP3/A20 promotes kinase activity of p38 mitogen-activated protein kinase and protein kinase C, which drives IL-17A expression. Regulation of TNFAIP3/A20 expression and cognate IL-17A production in T cells are specifically mediated through TNF receptor 2 signaling. Ex vivo, in patients with IBD treated with anti-TNF, we found further evidence for an inverse relationship between TNFAIP3/A20 expression levels and IL-17A-producing T cells. CONCLUSION: Anti-TNF treatment interferes in the TNFAIP3/A20-mediated anti-inflammatory feedback loop in CD4+ T cells and promotes kinase activity. This puts TNFAIP3/A20, combined with IL-17A expression, on the map as a potential tool for predicting therapy responsiveness or side effects of anti-TNF therapy. Moreover, it provides novel targets related to TNFAIP3/A20 activity for superior therapeutic regimens in patients with IBD. PMID- 29248492 TI - R-loops cause genomic instability in T helper lymphocytes from patients with Wiskott-Aldrich syndrome. AB - BACKGROUND: Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia, which are caused by WAS mutations affecting Wiskott-Aldrich syndrome protein (WASp) expression or activity, manifest in immunodeficiency, autoimmunity, genomic instability, and lymphoid and other cancers. WASp supports filamentous actin formation in the cytoplasm and gene transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined. OBJECTIVE: We sought to define how dysfunctional gene transcription is causally linked to the degree of TH cell deficiency and genomic instability in the XLT/WAS clinical spectrum. METHODS: In human TH1- or TH2-skewing cell culture systems, cotranscriptional R-loops (RNA/DNA duplex and displaced single-stranded DNA) and DNA double-strand breaks (DSBs) were monitored in multiple samples from patients with XLT and WAS and in normal T cells depleted of WASp. RESULTS: WASp deficiency provokes increased R-loops and R-loop-mediated DSBs in TH1 cells relative to TH2 cells. Mechanistically, chromatin occupancy of serine 2-unphosphorylated RNA polymerase II is increased, and that of topoisomerase 1, an R-loop preventing factor, is decreased at R-loop-enriched regions of IFNG and TBX21 (TH1 genes) in TH1 cells. These aberrations accompany increased unspliced (intron-retained) and decreased spliced mRNA of IFNG and TBX21 but not IL13 (TH2 gene). Significantly, increased cellular load of R-loops and DSBs, which are normalized on RNaseH1-mediated suppression of ectopic R loops, inversely correlates with disease severity scores. CONCLUSION: Transcriptional R-loop imbalance is a novel molecular defect causative in TH1 immunodeficiency and genomic instability in patients with WAS. The study proposes that cellular R-loop load could be used as a potential biomarker for monitoring symptom severity and prognostic outcome in the XLT-WAS clinical spectrum and could be targeted therapeutically. PMID- 29248494 TI - S1PR5 is essential for human natural killer cell migration toward sphingosine-1 phosphate. PMID- 29248495 TI - Isotype-specific agglutination-PCR (ISAP): A sensitive and multiplex method for measuring allergen-specific IgE. PMID- 29248496 TI - Clinical and histopathological features of nasopalatine duct cyst: A 47-year retrospective study and review of current concepts. AB - PURPOSE: To evaluate the clinical and histopathological features of nasopalatine duct cysts (NDCs) stored in the archives of a referred Oral Pathology Service over a 47-year-period, and to review current concepts about these cysts. MATERIAL AND METHODS: All NDCs were reviewed, and clinical data were obtained from the patient records. Thirty cases were re-evaluated microscopically by 2 oral pathologists. RESULTS: Among 14,564 cases, 30 (0.20%) were NDCs. Fifteen (50.0%) of the patients were female, and the mean age was 42.7 years. The lesions measured on average 2.37 +/- 1.69 cm. Histologically, stratified squamous epithelium, alone or in combination with other epithelia, was present in 13 (46.6%) cases. Goblet cells and subepithelial hyalinization were common. Fourteen (46.6%) cases exhibited a slight degree of inflammation. Nerves were observed in 15 (50%) cases and mucous glands in 7 (23.3%). Hyaline ring granulomas (which is described here for the first time in NDC) and cholesterol crystals were not common. CONCLUSION: Knowledge of clinical-histopathological aspects of NDCs provides more accurate data about their nature and behavior. Our results suggest that the predominant epithelial lining of these cystic lesions is exclusively stratified squamous epithelium or combined with another type. Vessels, nerves, mucous glands and inflammatory infiltrate are frequently observed. PMID- 29248497 TI - Electrophysiological evidence for Audio-visuo-lingual speech integration. AB - Recent neurophysiological studies demonstrate that audio-visual speech integration partly operates through temporal expectations and speech-specific predictions. From these results, one common view is that the binding of auditory and visual, lipread, speech cues relies on their joint probability and prior associative audio-visual experience. The present EEG study examined whether visual tongue movements integrate with relevant speech sounds, despite little associative audio-visual experience between the two modalities. A second objective was to determine possible similarities and differences of audio-visual speech integration between unusual audio-visuo-lingual and classical audio-visuo labial modalities. To this aim, participants were presented with auditory, visual, and audio-visual isolated syllables, with the visual presentation related to either a sagittal view of the tongue movements or a facial view of the lip movements of a speaker, with lingual and facial movements previously recorded by an ultrasound imaging system and a video camera. In line with previous EEG studies, our results revealed an amplitude decrease and a latency facilitation of P2 auditory evoked potentials in both audio-visual-lingual and audio-visuo-labial conditions compared to the sum of unimodal conditions. These results argue against the view that auditory and visual speech cues solely integrate based on prior associative audio-visual perceptual experience. Rather, they suggest that dynamic and phonetic informational cues are sharable across sensory modalities, possibly through a cross-modal transfer of implicit articulatory motor knowledge. PMID- 29248500 TI - Selective recognition of creatinine - Development of a colorimetric sensor. AB - The present report describes a simple and cost effective protocol for colourimetric determination of creatinine (CR), L-cysteine stabilized copper nanoparticles (L-cys-CuNPs) exhibited selective and sensitive interaction with CR. Utilizing this interaction, a colourimetric sensor has been developed based on the reduction in LSPR intensity as monitored by a UV-visible spectrophotometer. The developed sensor exhibited a linear dynamic range of 5.33 * 10-6 to 3.33 * 10-7 M. Proposed sensor is simple and cost - effective compared to methods based on noble metal nanoparticles and the sensitivity to determine CR was as low as 4.54 * 10-10 M. The sensor was successfully applied for quantification of CR in artificial serum and urine samples. Sensor developed in this work has a high potential for rapid and on-site determination of CR in physiological and clinical samples. PMID- 29248499 TI - Gp41, a superfamily SF2 helicase from bacteriophage BFK20. AB - Gp41 is one of two helicases encoded by the genome of bacteriophage BFK20. The gp41 sequence contains conserved motifs from the SF2 family of helicases. We prepared and studied three recombinant proteins: gp41HN, a wild type-like protein with an N-terminal His-Tag; gp41HC, with an S2A mutation and a C-terminal His Tag; and gp41dC, a mutant protein with a deleted C-terminal region and His-Tags on both N- and C-termini. We tested the enzymatic activities and DNA binding abilities of these isolated proteins. We found that both gp41HN and gp41HC had strong DNA-dependent ATPase activities, but that the ATPase activity of gp41dC was significantly lower regardless of the presence of DNA. The preferred substrates for the NTP hydrolysis reactions were ATP and dATP. gp41HC and gp41HN exhibited a low helicase activity in a fluorescence-based assay using dsDNA substrates with a 3' overhang and with a forked end in the presence of ATP. We infer that the C-terminal region of gp41 may be involved in DNA binding, since removing this region in gp41dC reduced the protein's DNA binding ability. PMID- 29248498 TI - Towards a neuro-computational account of prism adaptation. AB - Prism adaptation has a long history as an experimental paradigm used to investigate the functional and neural processes that underlie sensorimotor control. In the neuropsychology literature, prism adaptation behaviour is typically explained by reference to a traditional cognitive psychology framework that distinguishes putative functions, such as 'strategic control' versus 'spatial realignment'. This theoretical framework lacks conceptual clarity, quantitative precision and explanatory power. Here, we advocate for an alternative computational framework that offers several advantages: 1) an algorithmic explanatory account of the computations and operations that drive behaviour; 2) expressed in quantitative mathematical terms; 3) embedded within a principled theoretical framework (Bayesian decision theory, state-space modelling); 4) that offers a means to generate and test quantitative behavioural predictions. This computational framework offers a route towards mechanistic neurocognitive explanations of prism adaptation behaviour. Thus it constitutes a conceptual advance compared to the traditional theoretical framework. In this paper, we illustrate how Bayesian decision theory and state-space models offer principled explanations for a range of behavioural phenomena in the field of prism adaptation (e.g. visual capture, magnitude of visual versus proprioceptive realignment, spontaneous recovery and dynamics of adaptation memory). We argue that this explanatory framework can advance understanding of the functional and neural mechanisms that implement prism adaptation behaviour, by enabling quantitative tests of hypotheses that go beyond merely descriptive mapping claims that 'brain area X is (somehow) involved in psychological process Y'. PMID- 29248501 TI - Blocked recombinase polymerase amplification for mutation analysis of PIK3CA gene. AB - A blocked recombinase polymerase amplification (blocked-RPA) approach has been developed for the enrichment of mutated templates in heterogeneous specimens as tumor tissues. This isothermal amplification technique opens alternative solutions for meeting the technological demand of physician office laboratories. Herein, the detection of mutations in PIK3CA gene, such as p.E545K, and p.H1047L, is presented. The main element was an oligonucleotide (dideoxycytidine functionalized at 3'-end) which matched with wild-type sequence in the target locus. The amplification was performed operating at 37 degrees C during 40 min. The results demonstrated that the competition between the upstream primer and the blocker reduced the percentage of amplified wild-type allele, making the detection of the present mutation easier. For mutation discrimination, a fast hybridization assay was performed in microarray format on plastic chip and colorimetric detection. This approach enabled the reliable discrimination of specific mutations against a background of up to 95% wild-type DNA. The applicability of the method, based on the combination of blocked-RPA and low-cost chip hybridization, was successfully proven for the genotyping of various cancer cell lines as well as tumor tissues. The assignations agreed with those provided by next-generation sequencing. Therefore, these investigations would support a personalized approach to patient care based on the molecular signature of human cancers. PMID- 29248502 TI - A continuous assay for l-talarate/galactarate dehydratase using circular dichroism. AB - l-Talarate/galactarate dehydratase (TGD) is a member of the enolase superfamily of enzymes and catalyzes the dehydration of either meso-galactarate or l-talarate to form 5-keto-4-deoxy-d-glucarate (5-KDG). To facilitate study of this enzyme and other galactarate dehydratases, a continuous circular dichroism-based assay has been developed. Using recombinant enzyme from Salmonella typhimurium (StTGD), the rates of StTGD-catalyzed conversion of m-galactarate to 5-KDG were determined by following the change in ellipticity at 323 nm. The apparent molar ellipticity ([theta]323) for the 5-KDG formed was determined to be 202 +/- 2 deg cm2 dmol-1, which was used to convert observed rates (Deltatheta/Deltat) into concentration dependent rates (Deltac/Deltat). The kinetic parameters Km, kcat, and kcat/Km were 0.38 +/- 0.05 mM, 4.8 +/- 0.1 s-1, and 1.3 (+/-0.2) * 104 M-1s-1, respectively. These values are in excellent agreement with those published previously [Yew, W.S. et al. (2007) Biochemistry46, 9564-9577] using a coupled assay system. To demonstrate the utility of the assay, the inhibition constant (Ki = 10.7 +/- 0.4 mM) was determined for the competitive inhibitor tartronate. The continuous CD-based assay offers a practical and efficient alternative method to the coupled assay that requires access to 5-KDG aldolase, and to the labor intensive, fixed-time assays. PMID- 29248503 TI - Method validation in quantitative analysis of phase I and phase II metabolites of mitragynine in human urine using liquid chromatography-tandem mass spectrometry. AB - A method using solid phase extraction and liquid chromatography-tandem mass spectrometry to quantitatively detect mitragynine, 16-carboxy mitragynine, and 9 O-demethyl mitragynine in human urine samples was developed and validated. The relevant metabolites were identified using multiple reaction monitoring in positive ionization mode using nalorphine as an internal standard. The method was validated for accuracy, precision, recovery, linearity, and lower limit of quantitation. The intra- and inter-day accuracy and precision were found in the range of 83.6-117.5% with coefficient of variation less than 13%. The percentage of recovery for mitragynine, 16-carboxy mitragynine, and 9-O-demethyl mitragynine was within the range of 80.1-118.9%. The lower limit of quantification was 1 ng/mL for mitragynine, 2 ng/mL for 16-carboxy mitragynine, and 50 ng/mL for 9-O demethyl mitragynine. The developed method was reproducible, high precision and accuracy with good linearity and recovery for mitragynine, 16-carboxy mitragynine, and 9-O-demethyl mitragynine in human urine. PMID- 29248505 TI - Fear and hierarchy: critical influences on antibiotic decision-making in the operating theatre. PMID- 29248504 TI - Rapid emergence of colistin resistance and its impact on fatality among healthcare-associated infections. AB - This article describes the emergence of resistance and predictors of fatality for 1556 cases of healthcare-associated Gram-negative bloodstream infection in 2014 and 2015. The colistin resistance rate in Klebsiella pneumoniae was 16.1%, compared with 6% in 2013. In total, 660 (42.4%) cases were fatal. The highest fatality rate was among patients with Acinetobacter baumannii bacteraemia (58%), followed by Pseudomonas aeruginosa (45%), Klebsiella pneumoniae (41%), Enterobacter cloacae (32%) and Escherichia coli (28%). On multi-variate analysis, the minimum inhibitory concentrations for carbapenems [odds ratio (OR) 1.02, 95% confidence interval (CI) 1.01-1.04; P = 0.002] and colistin (OR 1.1, 95% CI 1.03 1.17; P = 0.001) were found to be significantly associated with fatality. PMID- 29248506 TI - Evaluating the appropriateness of antimicrobial treatment in hospitalized patients: a comparison of three methods. AB - BACKGROUND: Approximately 20-50% of antimicrobial therapy in hospitalized patients is considered inappropriate, which may be associated with increased morbidity and mortality. The best method for evaluation of appropriateness is not well defined. AIM: To evaluate the rate of appropriate antimicrobial therapy in a secondary hospital using three different methods, and determine the rate of agreement between the different methods. METHODS: A point prevalence study included all adult hospitalized patients receiving systemic antimicrobial therapy during 2016, screened on a single day. Clinical, laboratory and therapeutic data were collected from patient files, and appropriateness was rated with a qualitative evaluation by expert opinion. In addition, a quantitative evaluation was performed according to 11 quality indicators (QIs) rated for each patient. A strict definition of appropriateness was fulfilled if six essential QIs were met, and a lenient definition was fulfilled if at least five QIs were met. Agreement between methods was analysed using kappa statistic. FINDINGS: Among 106 patients included, rates of appropriateness of antimicrobial therapy ranged from 20% to 75%, depending on the method of evaluation. Very low agreement was found between the strict definition and expert opinion (kappa=0.068), and medium agreement was found between the lenient definition and expert opinion (kappa=0.45). CONCLUSIONS: Rates of appropriateness of antimicrobial therapy varied between evaluation methods, with low to moderate agreement between the different methods. PMID- 29248509 TI - Costello Syndrome: The Challenge of Hypoglycemia and Failure to Thrive. PMID- 29248510 TI - Feeling the Pressure to Be Perfect: Effect on Pain-Related Distress and Dysfunction in Youth With Chronic Pain. AB - : Despite clinical observation of perfectionistic tendencies among youth with chronic pain and their parents as well as established relationships between perfectionism and functional somatic symptoms in adults and youth, no research in the pediatric pain literature has examined perfectionism. This study explored the role of various types of youth and parent perfectionism on youth and parent pain related distress and behavior and youth pain-related dysfunction. At admission, 239 parent-child pairs from outpatient and day-treatment rehabilitation settings completed several questionnaires assessing perfectionism, pain-related distress, and pain-related dysfunction. Bivariate correlations indicated that socially prescribed perfectionism in youth and parents was linked to youth pain duration, parent and youth pain-related distress and behavior, and youth somatization. Indirect relations showed that youth socially prescribed perfectionism was the only form of perfectionism directly associated with youth somatization whereas all forms of youth perfectionism were indirectly associated with somatization and functional disability through increases in youth pain-related fear and catastrophizing. Additionally, socially prescribed perfectionism was the only type of parent perfectionism linked to youth pain-related dysfunction (somatization, functional disability) through its association with youth pain related fear. Findings support clinical observations that parent and youth perfectionism is a psychosocial factor that should be targeted in pediatric chronic pain treatment. PERSPECTIVE: Perfectionism in youth with chronic pain and their parents was indirectly linked to youth pain-related dysfunction through its effect on youth pain-related catastrophizing and fear. Findings support clinical observations that parent and youth perfectionism is a psychosocial factor that should be targeted in pediatric chronic pain treatment. PMID- 29248508 TI - Extracellular Lactate Dehydrogenase A Release From Damaged Neurons Drives Central Nervous System Angiogenesis. AB - Angiogenesis, a prominent feature of pathology, is known to be guided by factors secreted by living cells around a lesion. Although many cells are disrupted in a response to injury, the relevance of degenerating cells in pathological angiogenesis is unclear. Here, we show that the release of lactate dehydrogenase A (LDHA) from degenerating neurons drives central nervous system (CNS) angiogenesis. Silencing neuronal LDHA expression suppressed angiogenesis around experimental autoimmune encephalomyelitis (EAE)- and controlled cortical impact induced lesions. Extracellular LDHA-mediated angiogenesis was dependent on surface vimentin expression and vascular endothelial growth factor receptor (VEGFR) phosphorylation in vascular endothelial cells. Silencing vimentin expression in vascular endothelial cells prevented angiogenesis around EAE lesions and improved survival in a mouse model of glioblastoma. These results elucidate novel mechanisms that may mediate pathologic angiogenesis and identify a potential molecular target for the treatment of CNS diseases involving angiogenesis. PMID- 29248507 TI - Potential Diagnostic Power of Blood Circular RNA Expression in Active Pulmonary Tuberculosis. AB - BACKGROUND: Circular RNAs (circRNAs) are a class of novel RNAs with important biological functions, and aberrant expression of circRNAs has been implicated in human diseases. However, the feasibility of using blood circRNAs as disease biomarkers is largely unknown. METHODS: We explored the potential of using human peripheral blood mononuclear cell (PBMC) circRNAs as marker molecules to diagnose active pulmonary tuberculosis (TB). FINDINGS: First, we demonstrated that circRNAs are widely expressed in human PBMCs and that many are abundant enough to be detected. Second, we found that the magnitude of PBMC circRNAs in TB patients was higher than that in the paired healthy controls. Compared with host linear transcripts, the circRNAs within several pathways are disproportionately upregulated in active TB patients, including "Cytokine-cytokine receptor interaction", "Chemokine signaling pathway", "Neurotrophin signaling pathway", and "Bacterial invasion of epithelial cells". Based on the differentially expressed circRNAs within these pathways, we developed a PBMC circRNA-based molecular signature differentiating active TB patients from healthy controls. We validated the classification power of the PBMC circRNA signature in an independent cohort with the area under the receiver operating characteristic curve (AUC) at 0.946. INTERPRETATION: Our results suggest that PBMC circRNAs are potentially reliable marker molecules in TB diagnosis. PMID- 29248511 TI - Daily Fluctuations of Progesterone and Testosterone Are Associated With Fibromyalgia Pain Severity. AB - : The purpose of this longitudinal blood sampling study was to examine relationships between sex hormones and fibromyalgia pain. Eight women meeting case definition criteria for fibromyalgia provided venous blood samples and reported their fibromyalgia pain severity over 25 consecutive days. All women exhibited normal menstrual cycles and were not taking oral contraceptives. Cortisol, and the sex hormones estradiol, progesterone, and testosterone, were assayed from serum. A linear mixed model was used to determine if fluctuations of sex hormones were associated with changes in pain severity. In the entire sample, day to day changes in progesterone (P = .002) as well as testosterone (P = .015) were significantly and inversely correlated with pain severity. There was no relationship between estradiol and pain (P = .551) or cortisol and pain (P = .633). These results suggest that progesterone and testosterone play a protective role in fibromyalgia pain severity. Sex and other hormones may serve to increase as well as decrease fibromyalgia pain severity. PERSPECTIVE: Sex hormones fluctuate normally in women with fibromyalgia, but may still contribute to pain severity. PMID- 29248512 TI - The brains of bats foraging at wastewater treatment works accumulate arsenic, and have low non-enzymatic antioxidant capacities. AB - Increasing rates of urbanisation cause ubiquitous infrastructures that remove anthropogenic contaminants - particularly Wastewater Treatment Works (WWTWs) - to become stressed, and hence pollute surrounding water systems. Neoromicia nana bats are suitable models to study the effects of pollution in these environments because they exploit abundant pollutant-tolerant chironomid midges that breed at WWTWs, and consequently accumulate metals such as iron, copper and zinc in their livers and kidneys. If these metals persist in their circulatory systems, and cross the blood brain barrier (BBB) they can have adverse effects on critical functions such as flight and echolocation. The aim of this study was to investigate the potential neurological effects on N. nana foraging at WWTWs versus bats at reference sites in Durban, South Africa. Our objectives were to 1) compare trace metal levels in brain and hair samples (as a proxy for circulating metals) between N. nana foraging at WWTWs and reference sites to determine if excess metals pass through the BBB via the circulatory system; and 2) compare biomarkers of neuron function (acetylcholinesterase activity), protection (antioxidant capacity), DNA integrity (DNA fragmentation), lipid integrity (lipid peroxidation) and cell viability (caspase-3 activity) between N. nana foraging at WWTW and reference sites. We found a significantly higher concentration of arsenic in hair (p < 0.05) and brain tissue (p < 0.1) of WWTW bats compared to bats at reference sites. By contrast, acetylcholinesterase activity did not differ in bats among sites and there was no evidence of significant differences in lipid peroxidation, compromised DNA integrity or apoptosis in the brains between WWTW bats and reference site bats. However, total antioxidant capacity was significantly lower in brains of WWTW bats than bats at reference sites suggesting that antioxidant protection may be compromised. Long-term exposure to environmental pollutants at WWTWs may therefore affect cellular processes and protection mechanisms in brains of N. nana bats. It may also affect other mechanisms and functions in the brain such as mitochondrial efficiency and other neurotransmitters but that remains to be tested. PMID- 29248513 TI - Detection of VIM-1 and IMP-1 genes in Klebsiella pneumoniae and relationship with biofilm formation. AB - Klebsiella pneumoniae is an important human pathogen that is considered in recent years due to nosocomial infections resistant to treatment as well as the ability to form biofilms particularly in patients with urinary tract infection in ICU or hospital. The aim of this study was to evaluate the prevalence of VIM1, IMP1 genes and their ability to form biofilm in K. pneumoniae strains isolated from patients with urinary tract infection. In the study, using culture and biochemical methods, 1807 K. pneumoniae samples were isolated from patients with urinary tract infection hospitalized or referred to hospitals in Qom in 2013 2014. For isolation of MBL producing isolates, Double Disk Synergy Test (DDST) was used. Then MBL positive isolates were examined for the presence of VIM1, IMP1 genes using PCR method. Furthermore, all strains were investigated for biofilm formation by phenotypic microplate method. From 3165 urine samples cultured, 1807 isolates of K. pneumoniae were isolated and 109 strains (93.2%) were positive for MBL enzymes production. PCR results showed that the prevalence of VIM1 and IMP1 genes are 15.6 and 6.4%, respectively. The Phenotypic method indicated that 91.2% of isolates formed biofilm. Biofilm formation in K. pneumoniae isolates is high and there is a significant relationship between strong biofilm formation and prevalence of VIM1 and IMP1 genes. Also due to the presence of MBL genes in K. pneumoniae and horizontal transfer of genes to other bacteria, and to control the indiscriminate use of antibiotics, the hospital infection control methods must be considered. PMID- 29248514 TI - Green synthesis of anisotropic zinc oxide nanoparticles with antibacterial and cytofriendly properties. AB - Zinc oxide nanoparticles (ZnONPs) exhibit abundant biomedical applications. Anisotropic ZnONPs with a defined shape and size were synthesized using Bacillus megaterium (NCIM 2326) cell free extract as a bio-reductant. The study investigated the multidimensional effect of ZnONPs on Helicobacter pylori strains and assessed its biosafety in normal human mesenchymal stem cells (hMSc). The highly stable ZnONPs were produced using B. megaterium and Zinc nitrate as a precursor. The phase of ZnONPs formation and structural characterization were performed by UV- visible (UV-Vis), Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and Field Emission Scanning electron microscopy (FESEM) analysis. Furthermore, the ZnONPs exhibited higher biocompatibility against human mesenchymal stem cells (hMSC) and proved to be potentially safe in mammalian cells. Corroborating the current investigation, we described the anti-H. Pylori dosage of ZnONPs was safe to hMSC and could efficiently use as nano-antibiotic. PMID- 29248515 TI - Limonia acidissima L. leaf mediated synthesis of silver and zinc oxide nanoparticles and their antibacterial activities. AB - Green chemistry is a novel method for the synthesis of silver and zinc oxide nanoparticles. The present investigation focused on synthesis of biogenic silver and zinc oxide nanoparticles. They were assayed for their antibacterial activities against test bacterial species. The results revealed that the silver nanoparticles showed the maximum zone of inhibition 15.16, 15.5 and 13.33 mm at 400 MUg/mL to S. aureus, S. typhi and P. aeruginosa respectively, when compared to the Erythromycin. While zinc oxide nanoparticles showed less activity in comparison to silver nanoparticles owing to the agglomeration of nanoparticles. It is evident from our investigation that silver nanoparticles could be used as an antimicrobial due to their intrinsic properties in biomedical application and food packing industries. PMID- 29248516 TI - Salmonella as an endophytic colonizer of plants - A risk for health safety vegetable production. AB - Contamination of vegetables and fruits is the result of presence of human pathogen bacteria which can contaminate products in any part of production chain. There is an evidence of presence of: Salmonella spp. on the fresh vegetables and Salmonellosis is connected with tomato, sprouts, cantaloupe etc. The goal of this research is transmission of pathogen bacteria from irrigation water to plants and studying/monitoring the ability of the Salmonella spp. to colonize the surface and interior (endophytic colonization) of root at different vegetable species. Transmission of three Salmonella spp. strains from irrigation water to plants, as well as colonization of plants by these bacteria was investigated by using Fluorescence In Situ Hybridization (FISH) in combination with confocal laser scanning microscopy (CLSM). All tested Salmonella spp. strains showed ability to more or less colonize the surface and interior niches of the root, stem and leaf of the investigated plant species. These bacteria also were found in plant cells cytoplasm, although the mechanism of their entrance has not been clarified yet. PMID- 29248517 TI - The future is finally here: Advances in the treatment of atopic dermatitis. PMID- 29248518 TI - Emerging therapies for atopic dermatitis: JAK inhibitors. AB - The Janus kinase-signal transducer and activator of transcription pathway is a conserved master regulator of immunity and myeloproliferation. Advanced understanding of this pathway has led to development of targeted inhibitors of Janus kinases (Jakinibs). As a class, JAK inhibitors effectively treat a multitude of hematologic and inflammatory diseases. Given such success, use of JAK inhibitors for mitigation of atopic dermatitis is under active investigation. Herein, we review the evolving data on the safety and efficacy of JAK inhibitors in treatment of atopic dermatitis. Although it is still early in the study of JAK inhibitors for atopic dermatitis, evidence identifies JAK inhibitors as effective alternatives to conventional therapies. Nonetheless, multiple large safety and efficacy trials are needed before widespread use of JAK inhibitors can be advocated for atopic dermatitis. PMID- 29248519 TI - T-cell inhibitors for atopic dermatitis. AB - The management of atopic dermatitis is changing with the development of novel biologic agents to target specific molecules in the inflammatory cascade. Following the ability of dupilumab has proved its ability to act on the interleukin 4 receptor in treating atopic dermatitis. Thymic stromal lymphopoietin monoclonal antibody (AMG157/MEDI9929) and OX40 blocking antibody (GBR 830) were developed by targeting the same pathway as dupilumab further upstream. The clinical data on the efficacy for these drugs are not yet known. There is some early evidence that AMG157/MEDI9929 attenuates most measures of allergen-induced asthmatic responses. However, there are no public data on its ability to treat atopic dermatitis. In a phase 2a study, GBR 830 showed at least a 50% reduction in the Eczema Area and Severity Index scores of 17 of 23 patients, but it was not sufficiently powered for identification of statistical differences between GBR 830 versus placebo. Although there is potential for these 2 drugs to greatly improve the management of severe atopic dermatitis, significant clinical trials have not yet been completed to prove efficacy, and there are not yet any available phase 3 clinical trials, which are needed to truly evaluate their efficacy in affecting T-cells. PMID- 29248520 TI - New therapies for atopic dermatitis: Additional treatment classes. AB - BACKGROUND: A wide array of miscellaneous agents is being studied for the treatment of atopic dermatitis (AD), including targeted topical, oral systemic, and biologic agents. OBJECTIVE: To review the known efficacy and safety to date for such agents being studied for the treatment of AD. METHODS: A nonsystematic review of the literature was performed. PubMed and ClinicalTrials.gov were searched for studies assessing agents not described previously for the treatment of AD. Randomized controlled trials were primarily sought, but other study types were also included if they contained pertinent data. Agents are presented by mechanism of action, with analysis of mechanism of action and data regarding efficacy and safety in patients with AD. RESULTS: Data regarding the following agents are presented: omiganan (an antimicrobial peptide), tapinarof (a nonsteroidal anti-inflammatory agent), PR022 (hypochlorous acid), asimadoline (a kappa-opioid agonist), DS107 (dihomo-gamma-linolenic acid), ZPL-389 (a histamine H4 receptor antagonist), secukinumab (an interleukin 17A inhibitor), and fezakinumab (interleukin 22 inhibitor). LIMITATIONS: Limited clinical data exist for many of the described agents. CONCLUSIONS: As recent research has improved our understanding of AD pathogenesis, various agents with unique mechanisms of action have been studied for the treatment of AD. Many of these hold great therapeutic promise for AD, and continued research and development is warranted. PMID- 29248521 TI - Monoclonal antibodies against interleukin 13 and interleukin 31RA in development for atopic dermatitis. AB - The interleukin 13 (IL-13) and IL-31 cytokines and inflammatory pathways have been identified as important for the pathophysiology of atopic dermatitis (AD). Monoclonal antibodies against IL-13 have been studied for the treatment of asthma since 2011. More recently, 2 phase 2 trials have been completed with these antibodies in AD treatment. In both trials, significant reductions of Eczema Area and Severity Index scores were seen. IL-31 is thought to play a role transmitting itch sensation to the central nervous system, and blocking IL-31 activity reduces itch in patients with AD. One phase 2 trial has been completed for a humanized antibody against IL-31 receptor alpha, which is 1 subunit of the IL-31 receptor complex. This study showed significant dose-dependent reductions in pruritus, Eczema Area and Severity Index scores, and markers of sleep quality. Initial clinical trials for monoclonal antibodies against IL-13 and IL-31 receptor A all show promise, although long-term safety and efficacy data are lacking. Nevertheless, these medications will likely play a role in the treatment of moderate-to-severe AD. PMID- 29248522 TI - Phosphodiesterase 4 inhibitors. AB - Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety. PMID- 29248523 TI - Emerging therapies for atopic dermatitis: The prostaglandin/leukotriene pathway. AB - The role of leukotrienes and prostaglandins in development of atopy has been prototypically established in studies of asthma pathogenesis. Likewise, both in vitro and in vivo studies of atopic dermatitis have demonstrated that these molecules maintain important pathophysiologic roles. Thus, it follows that targeted therapies against these molecules may be promising in management of atopic dermatitis. Montelukast has had questionable efficacy in patients with atopic dermatitis, whereas small pilots using zileuton did have some clinically significant improvement. There are several agents in development that target leukotrienes and/or prostaglandins as well, including OC000459, Q301, and ZPL 521. In atopic dermatitis, OC000459 did not demonstrate efficacy in clinical trials, and the efficacy of the other 2 agents remains to be seen. Should these medications prove promising, these topical agents may play a future role in chronic maintenance therapy and flare prophylaxis in atopic dermatitis, as antileukotriene therapy does in asthma. PMID- 29248524 TI - Emerging therapies for atopic dermatitis: TRPV1 antagonists. AB - Transient receptor potential (TRP) ion channels are important mediators of somatosensory signaling throughout the body. Our understanding of the contribution of TRPs to a multitude of cutaneous physiologic processes has grown substantially in the past decade. TRP cation channel subfamily V member 1 (TRPV1), one of the better-understood members of this large family of ion channels, affects multiple pathways involved in pruritus. Further, TRPV1 appears to play a role in maintaining skin barrier function. Together, these properties make TRPV1 a ripe target for new therapies in atopic dermatitis. Neurokinin antagonists may affect similar pathways and have been studied to this effect. Early trials data suggest that these therapies are safe, but assessment of their efficacy in atopic dermatitis is pending as we await publication of phase II and III clinical trials data. PMID- 29248525 TI - Assessing the efficiency of Wolbachia driven Aedes mosquito suppression by delay differential equations. AB - To suppress wild population of Aedes mosquitoes, the primary transmission vector of life-threatening diseases such as dengue, malaria, and Zika, an innovative strategy is to release male mosquitoes carrying the bacterium Wolbachia into natural areas to drive female sterility by cytoplasmic incompatibility. We develop a model of delay differential equations, incorporating the strong density restriction in the larval stage, to assess the delicate impact of life table parameters on suppression efficiency. Through mathematical analysis, we find the sufficient and necessary condition for global stability of the complete suppression state. This condition, combined with the experimental data for Aedes albopictus population in Guangzhou, helps us predict a large range of releasing intensities for suppression success. In particular, we find that if the number of released infected males is no less than four times the number of mosquitoes in wild areas, then the mosquito density in the peak season can be reduced by 95%. We introduce an index to quantify the dependence of suppression efficiency on parameters. The invariance of some quantitative properties of the index values under various perturbations of the same parameter justifies the applicability of this index, and the robustness of our modeling approach. The index yields a ranking of the sensitivity of all parameters, among which the adult mortality has the highest sensitivity and is considerably more sensitive than the natural larvae mortality. PMID- 29248526 TI - Significant alterations of the novel 15 gene signature identified from macrophage tumor interactions in breast cancer. AB - BACKGROUND: Tumor microenvironment is composed of a largely altered extracellular matrix with different cell types. The complex interplay between macrophages and tumor cells through several soluble factors and signaling is an important factor in breast cancer progression. METHODS: We have extended our earlier studies on monocyte and macrophage conditioned medium (MphiCM) and have carried out proteomic analysis to identify its constituents as well as validation. The 8-gene signature identified through macrophage-breast cancer cell interactions was queried in cBioportal for bioinformatic analyses. RESULTS: Proteomic analysis (MALDI-TOF and LC-MS/MS) revealed integrin and matrix metalloproteinases in MphiCM which activated TGF-beta1, IL-6, TGF- betaRII and EGFR as well as its downstream STAT and SMAD signaling in breast cancer cells. Neutralization of pro inflammatory cytokines (TNF-alpha. Il-1beta, IL-6) abrogated the MphiCM induced migration but invasion to lesser extent. The 8- gene signature identified by macrophage-tumor interactions (TNF-alpha, IL-1beta, IL-6, MMP1, MMP9, TGF-beta1, TGF-betaRII, EGFR) significantly co-occurred with TP53 mutation, WTAPP1 deletion and SLC12A5 amplification along with differential expression of PSAT1 and ESR1 at the mRNA level and TPD52and PRKCD at the protein level in TCGA (cBioportal). Together these genes form a novel 15 gene signature which is altered in 63.6% of TCGA (1105 samples) data and was associated with high risk and poor survival (p<0.05) in many breast cancer datasets (SurvExpress). CONCLUSIONS: These results highlight the importance of macrophage signaling in breast cancer and the prognostic role of the15-gene signature. GENERAL SIGNIFICANCE: Our study may facilitate novel prognostic markers based on tumor-macrophage interaction. PMID- 29248528 TI - Feasibility, Safety, and Efficacy of Subcutaneous Peripheral Nerve Field Stimulation for the Treatment of Refractory Low Back Pain: A Two-year Single center Study. AB - Chronic low back pain (CLBP) is challenging to treat. Minimal invasive neurostimulation therapies, such as subcutaneous peripheral nerve field stimulation (SPNS), improve pain relief and quality of life. The goal of the present study was to assess the usefulness, safety, and efficacy of SPNS in patients with CLBP. Twenty-six consecutive patients with CLBP were prospectively included in the study. For trial neurostimulation, two electrodes were implanted vertically at a depth of 1 cm into the subcutaneous tissue, <=10 cm from the region of maximum pain. Trial neurostimulation was performed in all patients for 14 days. A successful outcome was defined as at least 50% pain relief. To monitor the effects of permanent neurostimulation, the Visual Analog Scale (VAS), the Oswestry Disability Index (ODI), and quality of life (EQ-5D-3L) were scored preoperatively and at 6-month and 24-month follow-ups. Thirteen patients responded to trial stimulation and had a permanent neurostimulator implanted. The use of pain medication, including opioid analgesics, was reduced in 92% of patients after 24 months. VAS, ODI, and EQ-5D-3L scores were significantly improved in these patients at the 24-month follow-up. The complication rate was 23% (3/13 patients). In non-responders, VAS and ODI at 24 months dropped significantly as well but the decrease was less pronounced compared to responders and had not led to a decrease in pain medication. SPNS is a novel, safe, and effective treatment for CLBP and may have advantages over interventional treatments including intrathecal therapy and spinal cord stimulation. PMID- 29248527 TI - Inhibiting Mesolimbic Dopamine Neurons Reduces the Initiation and Maintenance of Instrumental Responding. AB - Mesolimbic dopamine perturbations modulate performance of reward-seeking behavior, with tasks requiring high effort being especially vulnerable to disruption of dopamine signaling. Previous work primarily investigated long-term perturbations such as receptor antagonism and dopamine depletion, which constrain the ability to assess dopamine contributions to effort expenditure in isolation from other behavior events, such as reward consumption. Also unclear is if dopamine is required for both initiation and maintenance when a sequence of multiple instrumental responses is required. Here we used optogenetic inhibition of midbrain TH+ neurons to probe the role of dopamine neuron activity during instrumental responding for reward by varying the time epoch of neural inhibition relative to the time of response initiation. Within a fixed-ratio procedure, requiring eight nosepoke responses per reinforcer delivery, or a progressive ratio (PR) procedure, in which within-session response requirements increased exponentially, inhibiting dopamine neurons while mice were engaged in response bouts decreased the probability of continued responding. If inhibition occurred during each attempted bout, the effect was to decrease total responses, and thus amount of rewards earned, over a session. In contrast, if inhibition was applied only during some bouts, mice increased the number of bouts initiated to earn control levels of reward. Inhibiting dopamine neurons while mice were not responding decreased the probability of initiating an instrumental response but had no effect on the amount of effort exerted over the entire session. We conclude that midbrain dopamine signaling promotes initiation of instrumental responding and maintains motivation to continue ongoing bouts of effortful responses. PMID- 29248529 TI - High avidity anti-integrase antibodies discriminate recent and non-recent HIV infection: Implications for HIV incidence assay. AB - Estimation of HIV incidence provides real-time information of HIV transmission trends for decision makers. Anti-integrase antibodies are the last ones produced during seroconversion and presence of high-avidity anti-integrase antibodies indicates the chronicity of HIV infection. This study aimed to evaluate the performance of these antibodies in discriminating of recent from non-recent HIV infection. For this purpose, different ELISA formats were developed to detect high-avidity anti-integrase antibodies in a commercially available performance panel, and the best assay was selected for further evaluation. The false recent rate of the selected assay was evaluated in a panel of Iranian patients and compared to two commercial assays, BED-EIA and LAg-Avidity. While the false recent rate of the developed assay was 3.8%, it was 14.1% and 1.3% for BED-EIA and LAg-Avidity, respectively. To our knowledge, this is the first report to study the performance of high-avidity anti-integrase antibodies for classification of HIV infection. The preliminary results showed that the specificity of the newly developed assay is markedly higher than BED-EIA and is comparable with LAg-Avidity. The promising results point to the potential use of anti-integrase antibodies as a biomarker in HIV incidence laboratory tests or algorithms. The developed assay needs further evaluation in future. PMID- 29248530 TI - Stability of hepatitis C virus RNA and anti-HCV antibody in air-dried and freeze dried human plasma samples. AB - Diagnosis of hepatitis C virus (HCV) infection is based on testing for antibodies to HCV (anti-HCV), hepatitis C core antigen (HCV cAg) and HCV RNA. To ensure quality control (QC) and quality assurance (QA), proficiency panels are provided by reference laboratories and various international organizations, requiring costly dry ice shipments to maintain specimen integrity. Alternative methods of specimen preservation and transport can save on shipping and handling and help in improving diagnostics by facilitating QA/QC of various laboratories especially in resource limited countries. Plasma samples positive for anti-HCV and HCV RNA were either dried using dried tube specimens (DTS) method or lyophilization for varying durations of time and temperature. Preservation of samples using DTS method resulted in loss of anti-HCV reactivity for low-positive samples and did not generate enough volume for HCV RNA testing. Lyophilized samples tested positive for anti-HCV even after storage at 4 degrees C and 25 degrees C for 12 weeks. Further, HCV RNA was detectable in 5 of 5 (100%) samples over the course of 12 week storage at 4, 25, 37 and 45 degrees C. In conclusion, lyophilization of specimens maintains integrity of plasma samples for testing for markers of HCV infection and can be a potent mode of sharing proficiency samples without incurring huge shipping costs and avoids challenges with dry ice shipments between donor and recipient laboratories. PMID- 29248531 TI - Tregs that express the Foxp3 transcription factor can influence oxygen-induced retinopathy. PMID- 29248532 TI - Elusively reaching the apex. AB - A 64-year-old man presented with a 3-month history of diplopia and left-sided proptosis. Examination was significant for impairment of his left second, third, fourth, fifth, sixth, and seventh cranial nerves. Magnetic resonance imaging revealed a left orbital apex and cavernous sinus lesion. However, subtle thickening of his left frontal and supraorbital nerve was not identified until later. A trial of steroids provided minimal effect. Biopsy of the lesion showed a well-differentiated squamous cell carcinoma. The patient was subsequently managed with palliative radiotherapy. PMID- 29248533 TI - Gene therapy for RPE65-mediated retinal dystrophies. PMID- 29248534 TI - New antibody-based therapies for thyroid-associated ophthalmopathy. PMID- 29248535 TI - Deep learning algorithm. PMID- 29248536 TI - Orbital cellulitis. AB - Orbital cellulitis (OC) is an inflammatory process that involves the tissues located posterior to the orbital septum within the bony orbit, but the term generally is used to describe infectious inflammation. It manifests with erythema and edema of the eyelids, vision loss, fever, headache, proptosis, chemosis, and diplopia. OC usually originates from sinus infection, infection of the eyelids or face, and even hematogenous spread from distant locations. OC is an uncommon condition that can affect all age groups but is more frequent in the pediatric population. Morbidity and mortality associated with the condition have declined with advances in diagnostic and therapeutic options; however, OC can still lead to serious sight- and life-threatening complications in the modern antibiotics era. Therefore, prompt diagnosis and treatment remain crucial. Antibiotic coverage, computed tomography imaging, and surgical intervention when needed have benefitted patients and changed the disease prognosis. We review the worldwide characteristics of OC, predisposing factors, current evaluation strategies, and management of the disease. PMID- 29248538 TI - Enzyme targeting strategies for prevention and treatment of cancer: Implications for cancer therapy. AB - Extensive growth of cancer in humans is a major cause of death. Numerous studies are being conducted to improve the early diagnosis, prevention, and treatment of cancer. Recent technological advancements in medical science and research indicate molecular target therapy holds much promise in cancer treatment. In the past, therapeutic and diagnostic targeting of non-glycolytic and glycolytic enzymes in cancer have been successful, and discoveries of biomarker enzymes in cancer hold promise for therapeutic treatments. In this review, we discuss the roles of several cancer-associated enzymes that could potentially act as therapeutic targets, and place special focus on non-glycolytic and glycolytic enzymes. This review indicates that the targeting of metabolic signaling offers a promising means of developing novel anti-cancer therapies. PMID- 29248539 TI - Modeling of decision-making process for moving straight using inverse Bayesian inference. AB - Humans sometimes make unreasonable decisions when viewed in objective terms. Even in the real world, we may lose sense of direction by turning around the corner several times or mistaking the estimation of travel distance. We experimented in virtual space how we lose sense of direction under what circumstances. In the experiment, subjects viewed a three-dimensional space displayed on a computer display in the first person's perspective and were instructed to go straight from the start to the goal position. Results showed that unreasonable selections that strayed from the centerline connecting the start and goal positions were frequently made. The change in the direction is more influential than the change in the distance, and the angle of turning also affects. Furthermore, the subject's decision - making process was modeled using Bayesian inference and inverse Bayesian inference. Comparing the two models, when the decision-making pattern suddenly changed, the model by inverse Bayesian inference could follow up faster than the Bayesian inference. PMID- 29248537 TI - Direct inhibition of RAS: Quest for the Holy Grail? AB - RAS GTPases (H-, K-, and N-RAS) are the most frequently mutated oncoprotein family in human cancer. However, the relatively smooth surface architecture of RAS and its picomolar affinity for nucleotide have given rise to the assumption that RAS is an "undruggable" target. Recent advancements in drug screening, molecular modeling, and a greater understanding of RAS function have led to a resurgence in efforts to pharmacologically target this challenging foe. This review focuses on the state of the art of RAS inhibition, the approaches taken to achieve this goal, and the challenges of translating these discoveries into viable therapeutics. PMID- 29248540 TI - Sodium butyrate triggers a functional elongation of microglial process via Akt small RhoGTPase activation and HDACs inhibition. AB - Microglia, a type of immune cell in the brain, are in a ramified status with branched processes in normal conditions. Upon pathological stimulation, microglia retract their processes and become activated. Searching methods to make the activated microglia return to ramified status would help cope with injuries induced by neuroinflammation. Here, we investigated the influence of sodium butyrate (SB), a sodium salt form of butyrate produced by fermentation of dietary fibers in the gut on microglial process. Results showed that SB induced reversible elongations of microglial process in both normal and inflammatory conditions, and these elongations were accompanied with significant changes in markers reflecting the pro-inflammatory and anti-inflammatory status of microglia. The protein kinase B (Akt)-RhoGTPase signal was considered to mediate the effect of SB on microglial process, as: i) SB activated the small RhoGTPases Rac1 and Cdc42; ii) SB promotes Akt phosphorylation; iii) Rac1, Cdc42, and Akt inhibition abrogated the pro-elongation effect of SB on microglial process. Further analysis showed that incubation of microglia with two other histone deacetylases (HDACs) inhibitors trichostatin A (TSA) and valproic acid (VPA) also promoted microglial process elongation and Akt phosphorylation, suggesting that the SB-triggered microglial process elongation may be mediated by HDACs inhibition. Furthermore, Akt inhibition prevented the anti-inflammatory effect of SB in primary cultured microglia, and abrogated the inhibitory effects of SB on microglial process retraction and behavioral abnormalities induced by lipopolysaccharide (LPS). These results for the first time identify an anti inflammatory role of SB from the aspect of microglial process elongation. PMID- 29248541 TI - Chicken GRIFIN: Structural characterization in crystals and in solution. AB - Despite its natural abundance in lenses of vertebrates the physiological function(s) of the galectin-related inter-fiber protein (GRIFIN) is (are) still unclear. The same holds true for the significance of the unique interspecies (fish/birds vs mammals) variability in the capacity to bind lactose. In solution, ultracentrifugation and small angle X-ray scattering (at concentrations up to 9 mg/mL) characterize the protein as compact and stable homodimer without evidence for aggregation. The crystal structure of chicken (C-)GRIFIN at seven pH values from 4.2 to 8.5 is reported, revealing compelling stability. Binding of lactose despite the Arg71Val deviation from the sequence signature of galectins matched the otherwise canonical contact pattern with thermodynamics of an enthalpically driven process. Upon lactose accommodation, the side chain of Arg50 is shifted for hydrogen bonding to the 3-hydroxyl of glucose. No evidence for a further ligand-dependent structural alteration was obtained in solution by measuring hydrogen/deuterium exchange mass spectrometrically in peptic fingerprints. The introduction of the Asn48Lys mutation, characteristic for mammalian GRIFINs that have lost lectin activity, lets labeled C-GRIFIN maintain capacity to stain tissue sections. Binding is no longer inhibitable by lactose, as seen for the wild-type protein. These results establish the basis for detailed structure activity considerations and are a step to complete the structural description of all seven members of the galectin network in chicken. PMID- 29248543 TI - Plasma ghrelin suppression as an early predictor for postoperative complications after pancreatoduodenectomy. AB - BACKGROUND/OBJECTIVES: The gut peptide hormone ghrelin induces appetite and exhibits an anti-inflammatory effect. Serial perioperative changes in ghrelin have been examined in several surgical procedures, but few in pancreatectomy. The present study analyzed perioperative changes in plasma ghrelin levels after pancreaduodenectomy (PD). METHODS: The study included 24 patients undergoing PD between May 2015 and January 2016 at Osaka University Hospital. Plasma ghrelin and interleukin-6 (IL-6) levels, as well as white blood cells (WBCs) and C reactive protein (CRP), were measured preoperatively and on postoperative day (POD) 1, 3, 7, and 14 by enzyme-linked immunosorbent assay. The relationship between the individual ghrelin ratio relative to preoperative value (IGR) and the development of grade IIIa-V Clavien-Dindo (CD) complications was examined. RESULTS: Twelve patients (50%) developed grade IIIa CD complications (n = 6 [25%] pancreatic fistula, n = 7 [29%] intraabdominal abscess, n = 3 [13%] post pancreatectomy hemorrhage, n = 5 [21%] wound infection, and n = 1 [4%] lymphorrhea). The IGR on POD 1 was significantly lower (p = 0.014) in patients who developed the complications compared to those who did not, but no significant differences were found in terms of WBC, CRP, or IL-6 on POD 1. When the IGR cut off was set to 82% by receiver operative curve analysis, the sensitivity was 83%, specificity 75% and area under the curve 0.80. The lower IGR group (<=82%) had more postoperative complications and longer hospital stay. CONCLUSIONS: The IGR on POD 1 after PD is a useful marker for predicting postoperative complications. PMID- 29248542 TI - Toluidine blue O modifies hippocampal amyloid pathology in a transgenic mouse model of Alzheimer's disease. AB - Recently, we have demonstrated that toluidine blue O (TBO), a phenothiazine dye, shows inhibitory effects on both cholinesterases and amyloid pathology in Alzheimer's disease (AD) cellular model. In the present study, we aimed to determine the effects of TBO (in a purity of 85%) on amyloid and tau pathologies in a triple transgenic mouse model of AD (3xTg-AD). Beginning at 7.5 (mild pathology) or 13 (severe pathology) months of age, 3xTg-AD mice were treated intraperitoneally with 4 mg/kg TBO or vehicle daily for 30 days. TBO treatment significantly reduced the levels of insoluble Abeta40 and Abeta42 in the hippocampi of mild and severe pathology groups compared to vehicle-treated counterparts. When the levels of full-length amyloid precursor protein (APP) and beta-site APP-cleaving enzyme 1 (BACE1) were assessed in 3xTg-AD mice at late pathological stage, no significant changes were observed after TBO treatment. Similarly, TBO did not recover hyperphosphorylation of tau at residues Thr181 and Ser202/Thr205 significantly in soluble and insoluble hippocampal fractions of 3xTg-AD mice. Taken together, the current study is the first in vivo report, to our knowledge, demonstrating that TBO mitigates amyloid pathology in 3xTg-AD mice with no apparent change on tau phosphorylation. Overall, the preliminary data presented here support the possible use of TBO as a disease-modifying drug for AD treatment. PMID- 29248544 TI - Genome-Wide DNA Methylation Analysis in Systemic Sclerosis Reveals Hypomethylation of IFN-Associated Genes in CD4+ and CD8+ T Cells. AB - Epigenetic modifications, including DNA methylation, play an important role in the pathogenesis of autoimmune diseases. In this study, we characterized the DNA methylome in primary T cells of patients with systemic sclerosis. Genome-wide DNA methylation assays of CD4+ and CD8+ T cells from 24 systemic sclerosis patients and 24 matched controls were conducted and differentially methylated regions were validated. In the discovery stage, we found that hypomethylation of genes involved in the type I IFN signaling pathway was significantly enriched in both CD4+ (P = 7.59 * 10-6) and CD8+ (P = 2.10 * 10-8) differentially methylated regions. In the validation stage, we confirmed these changes for five type I IFN associated genes. In addition, protein levels of both type I IFN-alpha (P < 0.0001) and beta (P = 0.002) were significantly elevated in the sera of systemic sclerosis patients. Moreover, significant associations between type I IFN alpha/beta protein levels with the DNA methylation status as well as the expression profiles of these IFN-associated genes were confirmed. In conclusion, the type I IFN pathway is dysfunctional at the epigenetic level in systemic sclerosis patients, indicating that hypomethylation and upregulation of type I IFN-associated genes might be critical in systemic sclerosis pathogenesis. PMID- 29248545 TI - Dietary Control of Skin Lipid Composition and Microbiome. PMID- 29248546 TI - Accelerated Endothelial to Mesenchymal Transition Increased Fibrosis via Deleting Notch Signaling in Wound Vasculature. AB - Skin wound healing in adults is characterized by a peak of angiogenesis followed by regression of the excessive vasculature in parallel with collagen deposition and fibrosis in the wound. We hypothesized that regressing vessels in healing wounds were in fact entering an endothelial to mesenchymal transition contributing to scarring. Using vascular-specific fate tracking (Cdh5 creERt2/ROSA-YFP mice), full-thickness excisional wounds were analyzed to reveal a time-dependent transition from endothelial phenotype characterized by vascular endothelial-cadherin, CD31, and CD34 toward a mesenchymal phenotype characterized by alpha-smooth muscle actin and fibroblast-specific protein 1 expression. We next conditionally ablated RBPJ in the vasculature (Rbpjfl/fl/Cdh5-creERt2ROSA YFP) to evaluate the role of canonical Notch signaling in this process. Endothelial to mesenchymal transition was clearly accelerated after the loss of Notch signaling within the vasculature. The acceleration of endothelial to mesenchymal transition resulted in delayed wound healing, increased fibrosis, and extensive scar tissue formation, with the rapid loss of key endothelial genes and proteins and upregulation of mesenchymal protein expression (alpha-smooth muscle actin and fibroblast-specific protein 1) in vessels. Our findings here uncover a cellular contributor to skin wound scarring through the process of endothelial to mesenchymal transition in skin wounds and demonstrate the importance of Notch signaling in regulating this critical process during healing. PMID- 29248547 TI - Dual Role of EZH2 in Cutaneous Anaplastic Large Cell Lymphoma: Promoting Tumor Cell Survival and Regulating Tumor Microenvironment. AB - Primary cutaneous anaplastic T-cell lymphoma, characterized by the CD30+ anaplastic large T cells, comprises the second most common group of cutaneous T cell lymphoma. Little is known about the mechanisms of disease progression. Here we report that enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 that mediates histone H3 lysine 27 trimethylation, is overexpressed in CD30+ anaplastic cells in primary cutaneous anaplastic T-cell lymphoma and large-cell transformed cutaneous T-cell lymphoma. Silencing EZH2 or inhibiting its histone methyltransferase activity conferred increased apoptosis and G1 cell-cycle arrest in primary cutaneous anaplastic T-cell lymphoma cells in vitro and a xenograft model in vivo. This was mediated by the de-repression of thioredoxin-interacting protein, a major redox control molecule, and consequent formation of reactive oxygen species. Silencing thioredoxin-interacting protein abrogated reactive oxygen species accumulation in EZH2 suppressed cells and rescued cell growth disadvantage. Moreover, EZH2 suppression de-repressed C-X-C motif chemokine ligand 10 and facilitated the recruitment of effector CD4+ and CD8+ T cells into the tumor microenvironment via a C-X-C motif chemokine ligand 10/receptor 3 interaction. These results demonstrate a dual role for polycomb repressive complex 2-mediated epigenetic silencing in tumor progression and antitumor immunity in primary cutaneous anaplastic T-cell lymphoma, and provide a rationale for the pharmacologic inhibition of EZH2 activity in large-cell transformed cutaneous T-cell lymphoma. PMID- 29248548 TI - Epigenetic regulation of mammalian sex determination. AB - Regulation of gene expression without changing the DNA sequence is governed by epigenetic mechanisms. Epigenetic regulation is important for changing chromatin structure in response to environmental cues as well as maintaining chromatin structure after cell division. The epigenetic machinery can reversibly change chromatin function, allowing a wide variety of biological processes in multicellular organisms to be controlled. Epigenetic regulation ensures spatial and temporal accuracy of the expression of developmentally regulated genes. So far, few studies have focused on the relationship between epigenetic regulation and mammalian sex development, despite this being an interesting area of research. Sex development consists of three sequential stages: the undifferentiated stage, gonadal differentiation into testes or ovaries, and differentiation of internal and external genitalia. Some genetic studies have revealed that epigenetic regulation is required for proper gonadal differentiation in mice. Particularly, the epigenetic machinery plays an integral part in sex determination, which is the first step of gonadal differentiation. Mammalian sex determination is triggered by activation of the mammalian sex determining gene, Sry, in a spatially and temporally accurate manner. Several studies have demonstrated that expression of Sry is controlled not only by specific transcription factors but also by the epigenetic machinery. Here, we focus on the epigenetic regulation of Sry expression. PMID- 29248549 TI - A role of SIPL1/SHARPIN in promoting resistance to hormone therapy in breast cancer. AB - SIPL1 inhibits PTEN function and stimulates NF-kappaB signaling; both processes contribute to resistance to hormone therapy in estrogen receptor positive breast cancer (ER+ BC). However, whether SIPL1 promotes tamoxifen resistance in BC remains unclear. We report here that SIPL1 enhances tamoxifen resistance in ER+ BC. Overexpression of SIPL1 in MCF7 and TD47 cells conferred tamoxifen resistance. In MCF7 cell-derived tamoxifen resistant (TAM-R) cells, SIPL1 expression was upregulated and knockdown of SIPL1 in TAM-R cells re-sensitized the cells to tamoxifen. Furthermore, xenograft tumors produced by MCF7 SIPL1 cells but not by MCF7 empty vector cells resisted tamoxifen treatment. Collectively, we demonstrated a role of SIPL1 in promoting tamoxifen resistance in BC. Increases in AKT activation and NF-kappaB signaling were detected in both MCF7 SIPL1 and TAM-R cells; using specific inhibitors and unique SIPL1 mutants to inhibit either pathway significantly reduced tamoxifen resistance. A SIPL1 mutant defective in activating both pathways was incapable of conferring resistance to tamoxifen, showing that both pathways contributed to SIPL1-derived resistance to tamoxifen in ER+ BCs. Using the Curtis dataset of breast cancer (n=1980) within the cBioPortal database, we examined a correlation of SIPL1 expression with ER+ BC and resistance to hormone therapy. SIPL1 upregulation strongly associates with reductions in overall survival in BC patients, particularly in patients with hormone naive ER+ BCs. Taken together, we provide data suggesting that SIPL1 contributes to promote resistance to tamoxifen in BC cells through both AKT and NF-kappaB actions. PMID- 29248550 TI - Crowded milieu tuning the stability and activity of stem bromelain. AB - Proteins in vivo are under an extremely crowded environment because of the presence of bulky and large biological macromolecules (known as crowders). These crowders affect the proper functioning and structure of proteins in a cell. During in vitro studies, we often ignore the effect of macromolecular crowding on protein stability. However, if a large concentration of crowder is used to examine protein stability, its effects on the functioning of protein inside the cell in a confined environment, as stated, can be understood. Keeping this in context, we investigated the effects of macromolecular crowding on stem bromelain (BM) with the help of different crowding agents of varying molecular weights such as dextran (40 kDa and 6 kDa) and ficoll (70 kDa). Activity and stability of BM was examined using UV-vis, fluorescence and circular dichroism (CD) spectroscopy. Furthermore, docking methods are used to complement the crowding effects on the stability of BM. We found that stability and activity of BM are dependent on the surrounding crowder molecules. Thermal flouresence results showed that, thermal stability of BM decreses with incresing concentration of crowder except dextran40. It was observed that the decrese in stability and activity can be related to the presence of soft interactions between crowder and BM. Thus,crowding does not always stabilize the native structure, instead, it depends on degree of disorder of protein structure and on two competing effects: the excluded volume, which favors compact states, and soft interactions, which favor extended conformers. PMID- 29248551 TI - Structure characterization and biological activities of a pectic polysaccharide from cupule of Castanea henryi. AB - A pectic polysaccharide (CHIP3) was fractionated from the natural cupule of Castanea henryi. It contained mannose (10.70%), rhamnose (8.70%), galacturonic acid (38.21%), galactose (13.75%) and arabinose (28.63%) with a molecular weight of 2.44 * 104 g/mol by multi-laser light scattering. The structure was elucidated by using FT-IR spectroscopy, methylation analysis and NMR analysis. Results showed that the backbone of CHIP3 consisted of 1, 4-alpha-linked d-GalpA residues containing the non-methyl-esterified carboxyl groups, interspersed with a few 1,2 alpha-l-Rhap units. Its side chains were attached by two branches to O-4 of Rhap with 1,4-beta-linked d-Galp units and 1,5-alpha-l-linked Araf units bearing 3,5 substituted alpha-l-linked Araf residues as branching points. AFM data revealed it existed as a flexible chain in 0.1 M NaNO3 aqueous solution. Furthermore, CHIP3 was demonstrated to have notable antioxidant activity of FRAP, ABTS+ radical scavenging and reducing power. Cytotoxicity assay showed it displayed inhibitory activity against HepG2 cells with IC50 values of 242.6 MUg/mL. PMID- 29248552 TI - Fully biodegradable Poly(lactic acid)/Starch blends: A review of toughening strategies. AB - Polylactic acid (PLA) and Starch are both bio-based biodegradable polymers that have properties that are complementary to each other. PLA/starch blend exploits the good mechanical property of PLA and the low cost of Starch. However, PLA/Starch blend is intrinsically brittle. This paper reviews the current state of arts in toughening of PLA/Starch blend, which are categorized as: Additive Plasticization, Mixture Softening, Elastomer Toughening and Interphase Compatibilization. These strategies are not mutually exclusive and can be applied jointly in a single blend, opening up a wide range of toughening techniques that can be employed in PLA/Starch blend. Even though significant progress has been made in this area, there is still much room for research, in order to achieve easy to process, fully bio-based and completely biodegradable PLA/Starch blends that have mechanical properties suitable for a wide range of applications. PMID- 29248553 TI - Can any "non-specific charge modification within microtubule binding domains of Tau" be a prerequisite of the protein amyloid aggregation? An in vitro study on the 1N4R isoform. AB - The aggregation of Tau into amyloid fibrils is a hallmark of neurodegenerative diseases such as Alzheimer's disease (AD). Compared to the Abeta peptide, tau pathology more closely tracks changes in brain function that are responsible for the onset of early symptoms in AD. Tau belongs to the class of intrinsically disordered protein and folds into an ordered beta-structure during aggregation, a process that appears in many cases to be preceded by hyperphosphorylation of Tau monomers. Although Tau fibrils can be formed by heparin-induced aggregation of un phosphorylated recombinant Tau, it is important to understanding the paradox of Tau's random-like conformations and aggregation propensity. In this study, to look into the effect of charge neutralization on Tau aggregation propensity, solvent accessible lysine residues were chemically acetylated/pseudo phosphorylated. All Tau variants did not aggregate in the absence of the polyanionic factor; however, in contrast to the wild-type protein, acetylated and pseudo-phosphorylated variants were not able to aggregate even in the presence of the polyanionic cofactor. These aggregation incompetent Tau variants may be good analogs for the phosphorylated Tau, to explore more about the exact role of the phosphorylated Tau monomers in AD progress. PMID- 29248554 TI - Induced mutation analysis with biochemical and molecular characterization of high yielding lentil mutant lines. AB - Induced mutagenesis generates macromolecular variations which ultimately alters the bio-physiological and morphological nature of the crop genotypes. In the present study, molecular characterization of six high yielding lentil mutant lines, developed from hydrazine hydrates (HZ) and gamma rays mutagenesis, was carried out with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) and random amplified polymorphic DNA (RAPD) markers. Activity of nitrate reductase (NR) and content of chlorophyll and carotenoid were found to be significantly high in the mutant lines. Protein and mineral (Fe, Zn & Cu) contents were also increased considerably in the mutant lines compared to their respective parent genotypes. SDS-PAGE profile of seed storage proteins showed 35 unique bands with 97.14% polymorphism. Genetic divergence analysis generated total 41 reproducible RAPD bands with average calculated polymorphic percentage of 63.06%. Among the primers, OPA-10 showed the highest polymorphism with significant PIC value. Genetic divergent analysis revealed that genome of cultivar DPL 62 mutated relatively more than the cultivar Pant L 406 due to the mutagen treatments, while DPL 62-B and Pant L406-A were the most divergent mutants induced in the present study. Biochemical and molecular profile of the induced mutant lines facilitates a basis for future conservation and utilization strategies to widen the genetic base of the current lentil breeding population. PMID- 29248555 TI - A review on chitosan and its nanocomposites in drug delivery. AB - Chitosan the second most abundant next to cellulose, naturally occurring amino polysaccharide, derived as a deacetylated form of chitin. Its nontoxic, biocompatible, antibacterial and biodegradable properties have led to significant research towards biomedical and pharmaceutical applications, such as drug delivery, tissue engineering, wound-healing dressing etc. The primary amine group in chitosan are responsible for its various properties such as cationic nature, controlled drug release, muco-adhesion, in situ gelation, antimicrobial, permeation enhancement etc. This review discusses the various forms of chitosan materials such as beads, films, microspheres, nanoparticles, nanofibers, hydrogels, nanocomposites, etc. as drug delivery device and attempted to report the vast literature available on chitosan based materials in drug delivery applications. Moreover, chitosan derivatives and chitosan nanocomposites with different nanofillers and its application in drug delivery have also been reviewed. PMID- 29248557 TI - Differences in Survival Associated with Performance of Lymph Node Dissection in Patients with Invasive Penile Cancer: Results from the National Cancer Database. AB - PURPOSE: Inguinal lymphadenectomy remains under performed in patients with invasive penile cancer. Using a large national cancer registry we assessed temporal trends in inguinal lymphadenectomy performance and evaluated the impact of the procedure on survival in patients in whom inguinal lymphadenectomy was an absolute indication (T1b-4 N0/x-1) according to NCCN(r) (National Comprehensive Cancer Network(r)) Guidelines(r). MATERIALS AND METHODS: We queried the National Cancer Database for all cases of nonmetastatic, T1b-4 N0/x-1 squamous cell carcinoma of the penis from 2004 to 2014. Multivariable logistic regression models adjusting for patient, demographic, and clinicopathological characteristics were used to examine the association between available covariates and receipt of inguinal lymphadenectomy. Cox proportional hazards regression analysis was then done to assess the impact of clinical and pathological variables on overall survival. Propensity score weighted analysis was performed to assess the effect of inguinal lymphadenectomy on overall survival. RESULTS: A total of 2,224 patients met analysis criteria, of whom 606 (27.2%) underwent inguinal lymphadenectomy. Following adjustment the procedure was more likely in younger patients, those who presented with palpable adenopathy (cN1), those treated at an academic facility and those with a more contemporary diagnosis. On survival analysis controlling for all known and measured confounders inguinal lymphadenectomy was associated with improved overall survival (HR 0.79, 95% CI 0.74-0.84, p <0.001). CONCLUSIONS: At hospitals that report to the National Cancer Database the overall rate of inguinal lymphadenectomy in patients with invasive penile cancer was only 27.2%. Inguinal lymphadenectomy was associated with increased overall survival, justifying the procedure as an important quality metric for performance reporting in patients with invasive penile cancer. PMID- 29248556 TI - Extracellular matrix directs phenotypic heterogeneity of activated fibroblasts. AB - Activated fibroblasts are key players in the injury response, tumorigenesis, fibrosis, and inflammation. Dichotomous outcomes in response to varied stroma targeted therapies in cancer emphasize the need to disentangle the roles of heterogeneous fibroblast subsets in physiological and pathophysiological settings. In wound healing, fibrosis, and myriad tumor types, fibroblast activation protein (FAP) and alpha-smooth muscle actin (alphaSMA) identify distinct, yet overlapping, activated fibroblast subsets. Prior studies established that FAPHi reactive fibroblasts and alphaSMAHi myofibroblasts can exert opposing influences in tumorigenesis. However, the factors that drive this phenotypic heterogeneity and the unique functional roles of these subsets have not been defined. We demonstrate that a convergence of ECM composition, elasticity, and transforming growth factor beta (TGF-beta) signaling governs activated fibroblast phenotypic heterogeneity. Furthermore, FAPHi reactive fibroblasts and alphaSMAHi myofibroblasts exhibited distinct gene expression signatures and functionality in vitro, illuminating potentially unique roles of activated fibroblast subsets in tissue remodeling. These insights into activated fibroblast heterogeneity will inform the rational design of stroma-targeted therapies for cancer and fibrosis. PMID- 29248558 TI - Curcumin-lipoic acid conjugate as a promising anticancer agent on the surface of gold-iron oxide nanocomposites: A pH-sensitive targeted drug delivery system for brain cancer theranostics. AB - Brain tumor is a lethal, fast growing cancer and a difficult case for treatment. Receptor-mediated endocytosis has been recognized as one of the most effective methods for drug delivery to brain tissue by overcoming obstacles associated with conventional therapeutics. In this work, a targeted theranostic drug delivery system (DDS) was prepared based on gold-iron oxide nanocomposites (Fe3O4@Au NCs). Lipoic acid-curcumin (LA-CUR) was synthesized and introduced as a novel anticancer drug, and glutathione (GSH) was exploited as the targeting ligand. Both LA-CUR and GSH were easily attached to Fe3O4@Au NCs via Au-S interaction. As a negatively charged nanocarrier, the prepared DDS showed relatively less protein adsorption. Accordingly, hemocompatibility assays (complement, platelet, and leucocyte activation) revealed its hemocompatible virtue, especially in respect of free LA-CUR. GSH functionalization led to 2-fold increase of cellular uptake in GSH receptor-positive astrocyte cells which could primarily indicate the probable ability of the DDS to bypass BBB. Cytotoxicity and apoptosis assays together showed the noticeably enhanced cytotoxicity of LA-CUR against cancerous U87MG cells (IC50=2.69MUg/ml) in comparison with curcumin (IC50=21.31MUg/ml); moreover, the DDS demonstrated relatively higher cytotoxicity against cancerous U87MG cells than normal astrocyte cells which was in accordance with pH sensitive mechanism of LA-CUR release. Besides, the results of in vitro magnetic resonance imaging (MRI) (relaxation rate (r2)=80.73 (s-1.mM-1)) primarily revealed that the DDS can be applied as a negative MRI contrast agent. In sum, the prepared DDS appeared to be a promising candidate for brain cancer treatment and a favorable MRI contrast agent. PMID- 29248559 TI - PLGA nanoparticles are effective to control the colonic release and absorption on ibuprofen. AB - The oral controlled release (CR) formulations have become more important in recent years. Among them, the polymeric nanoparticles have been thoroughly studied during the last decades, consequently they are extensively employed for a broad range of applications and drugs. The objective of this research was to develop polymeric nanoparticles (NPs) of ibuprofen with poly(lactic-co-glycolic) acid (PLGA) as polymer, and to test their applicability for oral CR formulations development. Different proportions of drug/polymer were employed to develop the ibuprofen NPs and their in vitro release profiles were analysed. The in situ segmental permeability of ibuprofen was tested in Wistar rat and demonstrated the high permeability of ibuprofen in rat colon. In addition, in vivo assays were performed to study the plasma concentration-time profiles of encapsulated versus non-encapsulated ibuprofen. The results showed that ibuprofen release from the NPs was pH-dependent and consequently higher at colonic pH. Moreover, the plasma concentration-time profiles reveal a controlled release from the ibuprofen NP. Therefore, the ibuprofen PLGA-NPs will be a good CR formulation to achieve a controlled release targeted to the colon, where the release rate of the drug from the NPs will be the limiting factor for the absorption process. PMID- 29248560 TI - VEGF attenuates 2-VO induced cognitive impairment and neuronal injury associated with the activation of PI3K/Akt and Notch1 pathway. AB - Vascular endothelial growth factor (VEGF) has been identified as a potential treatment for effectively improving cognitive function in several neuropathological conditions. However, the underlying mechanism and the relevant downstream protective pathways that are activated in neurons by VEGF remain elusive, especially in chronic global cerebral ischemia. In this study, we intended to investigate the signaling mechanisms of VEGF in cognitive protection and anti-apoptosis in a rat model of chronic global cerebral ischemia induced by permanent bilateral common carotid artery occlusion (2-VO). The results showed that intranasal administration of VEGF (72h post-ischemia for 6 successive days) caused a significant improvement in the cognitive deficits induced by 2-VO, accompanied by a reversal of oxidative stress and VEGF depletion in the hippocampus. In addition, VEGF-treatment decreased the expression of Bax and Caspase-3, increased the expression of anti-apoptotic Bcl-xl and the main protein involved in energy homeostasis AMP-activated protein kinase (AMPK), which may account for the anti-apoptotic effects of VEGF. Importantly, VEGF administration upregulated the phosphorylation levels of Akt (pAkt) and PI3K, activated Notch1 pathway in 2-VO hippocampus. These findings suggested that intranasal administration of VEGF alleviated cognitive impairment induced by 2-VO injury, and attenuated oxidative damage and neuronal injury in hippocampus associated with the regulation of PI3K/Akt and Notch1 signaling pathway, which might be the underlying mechanisms of VEGF on global chronic cerebral ischemia. PMID- 29248561 TI - Downstream processing from melt granulation towards tablets: In-depth analysis of a continuous twin-screw melt granulation process using polymeric binders. AB - The concept of twin-screw melt granulation (TSMG) has steadily (re)-gained interest in pharmaceutical formulation development as an intermediate step during tablet manufacturing. However, to be considered as a viable processing option for solid oral dosage forms there is a need to understand all critical sources of variability which could affect this granulation technique. The purpose of this study was to provide an in-depth analysis of the continuous TSMG process in order to expose the critical process parameters (CPP) and elucidate the impact of process and formulation parameters on the critical quality attributes (CQA) of granules and tablets during continuous TSMG. A first part of the study dealt with the screening of various amorphous polymers as binder for producing high-dosed melt granules of two model drug (i.e. acetaminophen and hydrochlorothiazide). The second part of this study described a quality-by-design (QbD) approach for melt granulation of hydrochlorothiazide in order to thoroughly evaluate TSMG, milling and tableting stage of the continuous TSMG line. Using amorphous polymeric binders resulted in melt granules with high milling efficiency due to their brittle behaviour without producing excessive amounts of fines, providing high granule yields with low friability. Therefore, it makes them extremely suitable for further downstream processing. One of the most important CPP during TSMG with polymeric binders was the granulation-torque, which - in case of polymers with high Tg - increased during longer granulation runs to critical levels endangering the continuous process flow. However, by optimizing both screw speed and throughput or changing to polymeric binders with lower Tg it was possible to significantly reduce this risk. This research paper highlighted that TSMG must be considered as a viable option during formulation development of solid oral dosage forms based on the robustness of the CQA of both melt granules and tablets. PMID- 29248562 TI - High-density mapping of a single-loop biatrial macroreentrant tachycardia. PMID- 29248563 TI - Exercise participation and shared decision-making in patients with inherited channelopathies and cardiomyopathies. AB - Sports eligibility and disqualification of patients with cardiac diseases are important considerations for adult and pediatric cardiologists. The 2005 guidelines that addressed this issue have recently been revised and updated, and the new guidelines advocate for a shared decision-making approach in which the well-informed athlete and family participate in the discussion. In this review, we focus on the benefits of sports participation and review the revised guidelines related to sports participation in patients with channelopathies and cardiomyopathies. PMID- 29248564 TI - EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic disorder caused by mutations in the cardiac ryanodine receptor RyR2 that increase diastolic calcium cation (Ca2+) leak from the sarcoplasmic reticulum (SR). Calmodulin (CaM) dissociation from RyR2 has been associated with diastolic Ca2+ leak in heart failure. OBJECTIVE: Determine whether the tetracaine derivative compound EL20 inhibits abnormal Ca2+ release from RyR2 in a CPVT model and investigate the underlying mechanism of inhibition. METHODS: Spontaneous Ca2+ sparks in cardiomyocytes and inducible ventricular tachycardia were assessed in a CPVT mouse model, which is heterozygous for the R176Q mutation in RyR2 (R176Q/+ mice) in the presence of EL20 or vehicle. Single-channel studies using sheep cardiac SR or purified RyR2 reconstituted into proteoliposomes with and without exogenous CaM were used to assess mechanisms of inhibition. RESULTS: EL20 potently inhibits abnormal Ca2+ release in R176Q/+ myocytes (half-maximal inhibitory concentration = 35.4 nM) and diminishes arrhythmia in R176Q/+ mice. EL20 inhibition of single-channel activity of purified RyR2 occurs in a similar range as seen in R176Q/+ myocytes (half-maximal inhibitory concentration = 8.2 nM). Inhibition of single-channel activity for cardiac SR or purified RyR2 supplemented with 100-nM or 1-MUM CaM shows a 200- to 1000-fold reduction in potency. CONCLUSION: This work provides a potential therapeutic mechanism for the development of antiarrhythmic compounds that inhibit leaky RyR2 resulting from CaM dissociation, which is often associated with failing hearts. Our data also suggest that CaM dissociation may contribute to the pathogenesis of arrhythmias with the CPVT-linked R176Q mutation. PMID- 29248565 TI - Person-centered examination of salivary cortisol and alpha-amylase responses to psychosocial stress: Links to preadolescent behavioral functioning and coping. AB - This study adopted a person-centered approach to identify preadolescent salivary cortisol (sC) and alpha-amylase (sAA) co-activation response patterns and examine links to behavioral functioning and coping. Children (N = 151, 51.7% male) were exposed to the Trier Social Stress Test (TSST) and one of two randomly-assigned, post-TSST coping conditions: distraction or avoidance. Multi-trajectory modeling yielded four child subgroups. Child internalizing and externalizing positively predicted High sC-High sAA relative to Low sC-Low sAA and Low sC-High sAA relative to High sC-Low sAA subgroup membership, respectively. Low sC-Low sAA children demonstrated more efficient sC recovery when primed with distraction and more protracted sC recovery when primed with avoidance. For High sC-High sAA, internalizing children, the opposite was true. Findings illustrate adjustment linked variability in preadolescent sC-sAA co-activation response patterns that further articulates for whom effortful coping works to effectively manage stressor-induced neuroendocrine activation. PMID- 29248566 TI - Opioids in the Treatment of Pain. Beliefs, Knowledge, and Attitudes of the General Spanish Population. Identification of Subgroups Through Cluster Analysis. AB - CONTEXT: A lack of information has been found related to patients' perception toward pain management. OBJECTIVES: To analyze the point of view of the general Spanish population regarding the use of opioids in pain treatment. To identify groups of individuals based on this information. METHODS: Nationwide cross sectional study on a representative sample of 1299 Spanish adults. Data were collected on beliefs, knowledge, fears, opinions, and attitudes toward the use of opioids. A cluster analysis to identify groups of people based on these parameters and a multinomial logistic regression model to analyze the variables related to the clusters were performed. RESULTS: Three groups of subjects were identified based on their perspective toward opioids: a first group with a positive point of view (N = 448) composed of people older than 65 years who would accept a treatment if prescribed and who were less fearful of these drugs; a second group with a moderate point of view (N = 337) formed by younger subjects with university education, better informed about opioids, afraid of these drugs (odds ratio [OR] 2.67), and more frequently associated them with drowsiness (OR 2.58), nausea (OR 3.04), and tolerance (OR 2.16); and a third group with a negative point of view (N = 468), with lower educational level who would more often reject treatment with opioids, more afraid of them (OR 3.95), considering that they may not be able to stop the treatment (OR 3.04) and may produce tolerance (OR 3.03). CONCLUSION: The different perspectives of patients regarding the use of opioids to treat pain should be taken into consideration by the physician when designing strategies to inform patients about the treatment of pain with opioids. This should promote their correct use, specially preventing their misuse. PMID- 29248567 TI - When Less Is More: Optimizing Care for Elderly Patients Failing to Thrive on Dialysis. PMID- 29248568 TI - Comparison of Indicators for Achievement of Pain Control With a Personalized Pain Goal in a Comprehensive Cancer Center. AB - CONTEXT: The achievement of a personalized pain goal (PPG) is advocated as an individualized pain relief indicator. OBJECTIVES: Pain relief indicators, including PPG, pain intensity (PI), and interference with daily activities (interference), were compared herein. METHODS: This was a single-center cross sectional study. Adult patients with cancer on opioid medications who visited the outpatient clinic at the National Cancer Center Hospital East between March and September 2015 were consecutively enrolled. Patients conducted a self-report questionnaire, including reports of average PI, interference, PPG, and the need for further analgesic treatment. We compared the proportion of patients achieving PPG (PI <= PPG) and other pain relief indicators including PI <=3 or interference <=3 and the percentage of patients who did not need further analgesic treatment among those who fulfilled each pain relief indicator. RESULTS: A total of 347 patients (median age 64; 38% females) were analyzed. Median (interquartile range [IQR]) of PPG, PI, and interference was 2 (IQR 1-3), 2 (IQR 1-4), and 2 (IQR 0 5), respectively. The proportion of patients achieving PPG was 45.3% and significantly lower than those with PI <=3 (69.0%; P < 0.001) and interference <=3 (70.2%; P < 0.001). Eighty percent of patients achieving PPG did not need further analgesic treatment, whereas 70.8% of patients with PI <=3 (P < 0.001) and 73.3% with interference <=3 did need further analgesic treatment (P < 0.001). CONCLUSION: The achievement of PPG was a stricter pain relief indicator than PI and interference and may reflect a real need for pain control. PMID- 29248569 TI - Molecular characterization and gene expression of synaptosome-associated protein 25 (SNAP-25) in the brain during both seaward and homeward migrations of chum salmon Oncorhynchus keta. AB - It is generally accepted that information about some of the odorants in the natal streams of anadromous Pacific salmon (Genus Oncorhynchus) is imprinted during their seaward migration, and that anadromous Pacific salmon use olfaction to identify their natal streams during the homeward migration. However, little is known about the molecular mechanisms of the various pre-synaptic functions that are important for olfactory imprinting and memory retrieval in the salmon brain. Synaptosome-associated protein-25 (SNAP-25) mediates pre-synaptic vesicle exocytosis and regulates synaptic transmission and neuronal plasticity. Despite the importance of synaptic plasticity for memorization, the expression of SNAP-25 in the salmon brain is not well understood. In this study, snap25 expression was detected in chum salmon (O. keta) brains using molecular biological techniques. Two cDNAs encoding salmon SNAP-25 were isolated and sequenced (SNAP-25a and SNAP 25b). These cDNAs encoded proteins with 204 amino acid residues, which showed marked homology with each other (97%). The protein and nucleotide sequences demonstrated a high level of homology between salmon SNAP-25s and those of other teleost species. By quantitative PCR, the expression of snap25a and snap25b was detected in all regions of the salmon brain, especially in the telencephalon. The expression levels of snap25a in the olfactory blub were higher during seaward migration than in upriver and post-upriver migrations, reflecting synaptogenesis in the olfactory nervous system, and snap25b in the telencephalon was increased during upriver period. Our results indicated that snap25s gene is involved in synaptic plasticity for olfactory imprinting and/or olfactory memory retrieval in Pacific salmon. PMID- 29248570 TI - Synthetic capacity does not predict elasmobranchs' ability to maintain trimethylamine oxide without a dietary contribution. AB - Trimethylamine oxide (TMAO) is an organic osmolyte and universal protein stabilizer. Its role as a cytoprotectant is particularly important in ureosmotic elasmobranchs that accumulate high levels of urea, a macromolecular perturbant. Feeding is a key component in the turnover and maintenance of these nitrogenous compounds. However, previous studies examining TMAO regulation have been largely completed using starved individuals, when nitrogen balance is altered. Here, under fed conditions, we test the importance of dietary TMAO on long-term maintenance in three elasmobranch species with differing endogenous synthetic capacities. Smoothhounds (Mustelus canis), spiny dogfish (Squalus acanthias), and little skates (Leucoraja erinacea) exhibited species- and tissue-specific differences in their ability to conserve TMAO when fed a low TMAO diet for 56days. Smoothhounds, a species with the capacity for endogenous production, exhibited a decrease in muscle TMAO. Spiny dogfish and little skates, species with no reported ability for synthesis, exhibited decreases in plasma and liver TMAO, respectively. Our findings are contrary to previous starvation studies demonstrating constant levels of TMAO for up to 56days in elasmobranchs. Further, the previously reported synthetic capacity of these species did not correlate with their ability to conserve TMAO and cannot be used to predict a species reliance on dietary contributions for prolonged maintenance. It is possible that all species rely to a degree on absorption of TMAO from the diet or that alternate synthetic or regulatory pathways play a larger role than previously thought. PMID- 29248571 TI - The secondary Fusarium metabolite aurofusarin induces oxidative stress, cytotoxicity and genotoxicity in human colon cells. AB - Aurofusarin (AURO), a dimeric naphthoquinone, is produced by Fusarium fungi. Although frequently found in food and feed, toxicological studies are limited. Hence, the in vitro toxicity of AURO was investigated in the colon adenocarcinoma cell line HT29 and the non-tumorigenic colon cells HCEC-1CT. Cytotoxic effects were found at concentrations >=1 MUM by evaluating mitochondrial activity (WST-1) and cellular proliferation (sulforhodamine B assay). 10 MUM of AURO induced a decrease of cells in the S-phase, measured by flow cytometry. Confocal microscopy revealed AURO-mediated increase of intracellular p53 protein. In accordance, DNA damage was seen in the comet assay (>=1 MUM) together with enhanced levels of formamidopyrimidine-DNA-glycosylase (fpg)-sensitive sites, indicative for oxidative stress. An increase of intracellular reactive oxygen species was observed in the dichlorofluorescein (DCF) assay (>=5 MUM). The GSSG/GSH ratio was elevated, but no impact on redox-sensitive Nrf2-dependent genes (Nrf2, gamma-GCL, NQO1) was found at the gene expression level. However, induction of cytochrome P450 monooxygenase (CYP) 1A1 was measured at the gene expression and protein level. In conclusion, these in vitro data suggest that, when co-occurring, AURO might be considered as a potential contributor to the overall toxicity of respective Fusarium mycotoxin mixtures. PMID- 29248572 TI - 1,3-Dichloro-2-propanol evokes inflammation and apoptosis in BV-2 microglia via MAPKs and NF-kappaB signaling pathways mediated by reactive oxygen species. AB - 1,3-dichloro-2-propanol (1,3-DCP) is a widely concerned food processing contaminant which has been investigated for decades. While the neurotoxicity of 1,3-DCP and related mechanisms are still elusive. Herein, the effect of 1,3-DCP on neurotoxicity was investigated using BV-2 microglia cells. 1,3-DCP significantly decreased cell viability from 78.6% to 59.2% at doses between 2 and 20 mM. AO/EB and JC-1 staining indicated that 1,3-DCP induced apoptosis by means of the decrease of mitochondrial membrane potential. Meanwhile, western blot showed that 1,3-DCP stimulated inflammation of BV-2 cells through phosphorylation of MAPKs and activation of NF-kappaB pathways mediated by reactive oxygen species (ROS). Furthermore, the degree of inflammation and apoptosis has eased through MAPKs and NF-kappaB pathways with cells pretreated by N-acetylcysteine (NAC). Overall, these results presented here suggested that 1,3-DCP has neurotoxic effect on BV-2 microglia mainly via MAPKs and NF-kappaB pathways mediated by ROS. PMID- 29248573 TI - Bisphenol A exposure induces increased microglia and microglial related factors in the murine embryonic dorsal telencephalon and hypothalamus. AB - Bisphenol A (BPA) is a widely used compound in the food packaging industry. Prenatal exposure to BPA induces histological abnormalities in the neocortex and hypothalamus in association with abnormal behaviors. Yet, the molecular and cellular neurodevelopmental toxicological mechanisms of BPA are incompletely characterized on neuroinflammatory-related endopoints. To evaluate the neurodevelopmental effects of BPA exposure in mouse embryos, we examined microglial numbers as well as the expression of microglial-related factors in the E15.5 embryonic brain. BPA-exposed embryos exhibited significant increases in Iba1-immunoreactive microglial numbers in the dorsal telencephalon and the hypothalamus compared to control embryos. Further, the expression levels of microglial markers (Iba1, CD16, iNOS, and CD206), inflammatory factors (TNFalpha and IL4), signal transducing molecules (Cx3Cr1 and Cx3Cl1), and neurotrophic factor (IGF1) were altered in BPA-exposed embryos. These findings suggest that BPA exposure increases microglial numbers in the brain and alters the neuroinflammatory status at a transcriptional level. Together, these changes may represent a novel target for neurodevelopmental toxicity assessment after BPA exposure. PMID- 29248574 TI - LncRNA UCA1 attenuates autophagy-dependent cell death through blocking autophagic flux under arsenic stress. AB - Arsenic (As) is a naturally toxin which exists ubiquitously in foods and various environment media, incurring diverse toxicities and health problems. Previous studies have shown that oxidative stress, genotoxic damage and pro-apoptotic pathways are ascribed to As-associated detrimental effects. Meanwhile, epigenetic regulations (such as miRNAs and histone modifications) were also reported to contribute to As-induced adverse effects. Nonetheless, whether long non-coding RNAs (LncRNAs) are indispensable for the regulation of As-induced biological outcomes are nearly unknown. In this study, we identified that a lncRNA UCA1 was markedly induced by As treatment in human hepatocytes. Functional assessments revealed that UCA1 played a critical role in protecting hepatocytes from As induced autophagy inhibition. Furthermore, through RNA-seq assay, oxidative stress induced growth inhibitor 1 (OSGIN1) was uncovered to be the most responsive target downstream of UCA1, and miR-184 acted as an intermediate for the regulation of UCA1 on the level of OSGIN1 through a competing endogenous RNAs (ceRNAs) mechanism. Further mechanistic investigations demonstrated that UCA1/OSGIN1 signaling contributed to As-induced autophagic flux blockage through activating mTOR/p70S6 K cascade, resulting in compromised cell death. Collectively, our study deciphered a lncRNA-dictated molecular mechanism responsible for As toxicity: UCA1 leads a protective role against As-induced cell death through blocking autophagic flux. PMID- 29248576 TI - Counteracting desensitization of human alpha7-nicotinic acetylcholine receptors with bispyridinium compounds as an approach against organophosphorus poisoning. AB - Irreversible inhibition of acetylcholinesterase (AChE) resulting in accumulation of acetylcholine and overstimulation of muscarinic and nicotinic receptors accounts for the acute toxicity of organophosphorus compounds (OP). Accordingly, the mainstay pharmacotherapy against poisoning by OP comprises the competitive muscarinic acetylcholine receptor antagonist atropine to treat muscarinic effects and, in addition, oximes to reactivate inhibited AChE. A therapeutic gap still remains in the treatment of desensitized nicotinic acetylcholine receptors following OP exposure. Hereby, nicotinic effects result in paralysis of the central and peripheral respiratory system if untreated. Thus, these receptors pose an essential target for therapeutic indication to address these life threatening nicotinic symptoms of the cholinergic crisis. Identification of ligands regulating dynamic transitions between functional states by binding to modulatory sites appears to be a promising strategy for therapeutic intervention. In this patch clamp study, the ability of differently substituted bispyridinium non-oximes to "resensitize" i.e. to recover the activity of desensitized human homomeric alpha7-type nAChRs stably transfected in CHO cells was investigated and compared to the already described alpha7-specific positive allosteric modulator PNU-120596. The structures of these bispyridinium analogues were based on the lead structure of the tert-butyl-substituted bispyridinium propane MB327, which has been shown to have a positive therapeutic effect due to a non-competitive antagonistic action at muscle-type nAChRs in vivo and has been found to have a positive allosteric activity at neuronal receptors in vitro. Prior to test compounds, desensitization of halpha7-nAChRs was verified by applying an excess of nicotine revealing activation at low, and desensitization at high concentrations. Thereby, desensitization could be reduced by modulation with PNU 120596. Desensitization was further verified by dose-response profiles of agonists, carbamoylcholine and epibatidine in the absence and presence of PNU 120596. Although less pronounced than PNU-120596 and the lead structure MB327, bispyridinium compounds, particularly those substituted at position 3 and 4, resensitized the nicotine desensitized halpha7-nAChRs in a concentration dependent manner and prolonged the mean channel open time. In summary, identification of more potent compounds able to restore nAChR function in OP intoxication is needed for development of a putative efficient antidote. PMID- 29248575 TI - Hepatic cells derived from human skin progenitors show a typical phospholipidotic response upon exposure to amiodarone. AB - Phospholipidosis is a metabolic disorder characterized by intracellular accumulation of phospholipids. It can be caused by short-term or chronic exposure to cationic amphiphilic drugs (CADs). These compounds bind to phospholipids, leading to inhibition of their degradation and consequently to their accumulation in lysosomes. Drug-induced phospholipidosis (DIPL) is frequently at the basis of discontinuation of drug development and post-market drug withdrawal. Therefore, reliable human-relevant in vitro models must be developed to speed up the identification of compounds that are potential inducers of phospholipidosis. Here, hepatic cells derived from human skin (hSKP-HPC) were evaluated as an in vitro model for DIPL. These cells were exposed over time to amiodarone, a CAD known to induce phospholipidosis in humans. Transmission electron microscopy revealed the formation of the typical lamellar inclusions in the cell cytoplasm. Increase of phospholipids was already detected after 24 h exposure to amiodarone, whereas a significant increase of neutral lipid vesicles could be observed after 72 h. At the transcriptional level, the modulation of genes involved in DIPL was detected. These results provide a valuable indication of the applicability of hSKP-HPC for the quick assessment of drug-induced phospholipidosis in vitro, early in the drug development process. PMID- 29248577 TI - Long non-coding RNA FOXD2-AS1 aggravates nasopharyngeal carcinoma carcinogenesis by modulating miR-363-5p/S100A1 pathway. AB - Long non-coding RNAs (lncRNAs) have been wildly verified to modulate multiple tumorigenesis, especially nasopharyngeal carcinoma (NPC). In present study, we aim to investigate the role of lncRNA FOXD2-AS1 in the NPC carcinogenesis. It was indicated that FOXD2-AS1 was markedly increased in NPC tissues and cells in comparison to their corresponding controls. Moreover, the aberrant overexpression of FOXD2-AS1 indicated the poor prognosis of NPC patients. Silence of FOXD2-AS1 was able to repress NPC cell growth in vitro while overexpression of FOXD2-AS1 inversed this process. Moreover, in vivo tumor xenografts were established using CNE-1/SUNE-1 cells to investigate the function of FOXD2-AS1 in NSCLC tumorigenesis. Rescue assay was performed to further confirm that FOXD2-AS1 contributed to NPC progression by regulating miR-363-5p/S100A1 signal pathway. Taken together, our study discovered the oncogenic role of FOXD2-AS1 in clinical specimens and cellular experiments, showing the potential FOXD2-AS1/miR-363 5p/S100A1 pathway. This results and findings provide a novel insight for NPC tumorigenesis. PMID- 29248578 TI - Identification of a fish short-chain dehydrogenase/reductase associated with bone metabolism. AB - Although human and mouse genetics have largely contributed to the better understanding of the mechanisms underlying skeletogenesis, much more remains to be uncovered. In this regard alternative and complementary systems have been sought and cell systems capable of in vitro calcification have been developed to study the mechanisms underlying bone formation. In gilthead seabream (Sparus aurata), a gene coding for an unknown protein that is strongly up-regulated during extracellular matrix (ECM) mineralization of a pre-osteoblast cell line was recently identified as a potentially important player in bone formation. In silico analysis of the deduced protein revealed the presence of domains typical of short-chain dehydrogenase/reductases (SDR). Closely related to carbonyl reductase 1, seabream protein belongs to a novel subfamily of SDR proteins with no orthologs in mammals. Analysis of gene expression by qPCR confirmed the strong up-regulation of sdr-like expression during in vitro mineralization but also revealed high expression levels in calcified tissues. A possible role for Sdr like in osteoblast and bone metabolism was further evidenced through (i) the localization by in situ hybridization of sdr-like transcript in pre-osteoblasts of the operculum and (ii) the regulation of sdr-like gene transcription by Runx2 and retinoic acid receptor, two regulators of osteoblast differentiation and mineralization. Expression data also indicated a role for Sdr-like in gastrointestinal tract homeostasis and during gilthead seabream development at gastrulation and metamorphosis. This study reports a new subfamily of short-chain dehydrogenases/reductases in vertebrates and, for the first time, provides evidence of a role for SDRs in bone metabolism, osteoblast differentiation and/or tissue mineralization. PMID- 29248579 TI - Genetic profile of patients with early onset inflammatory bowel disease. AB - Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract. The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway. We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate "in silico" analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range. The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD). PMID- 29248580 TI - MiR-564 is down-regulated in osteosarcoma and inhibits the proliferation of osteosarcoma cells via targeting Akt. AB - Aberrant expression of miRNAs has been observed in a variety of human cancers. In this study, we reported that miR-564 was down-regulated in human osteosarcoma (OS) cell lines and patients. Overexpression of miR-564 in OS cells suppressed the cell proliferation and induced cell apoptosis. Mechanistically, we identified Akt as a direct target of miR-564. Highly expressed miR-564 decreased the expression of Akt at both mRNA and protein level and consequently, inhibited the essential role of Akt in the glycolysis of OS cells. Notably, restoring the expression of Akt in miR-564 overexpressing cells recovered the glucose metabolism and cell growth. These results suggested that miR-564 inhibited the glycolysis and cell proliferation through directly targeting Akt, which highlighted the potential application of miR-564-Akt axis in the treatment of osteosarcoma. PMID- 29248581 TI - Exome sequencing of a large family identifies potential candidate genes contributing risk to bipolar disorder. AB - Bipolar disorder is a mental illness with lifetime prevalence of about 1%. Previous genetic studies have identified multiple chromosomal linkage regions and candidate genes that might be associated with bipolar disorder. The present study aimed to identify potential susceptibility variants for bipolar disorder using 6 related case samples from a four-generation family. A combination of exome sequencing and linkage analysis was performed to identify potential susceptibility variants for bipolar disorder. Our study identified a list of five potential candidate genes for bipolar disorder. Among these five genes, GRID1(Glutamate Receptor Delta-1 Subunit), which was previously reported to be associated with several psychiatric disorders and brain related traits, is particularly interesting. Variants with functional significance in this gene were identified from two cousins in our bipolar disorder pedigree. Our findings suggest a potential role for these genes and the related rare variants in the onset and development of bipolar disorder in this one family. Additional research is needed to replicate these findings and evaluate their patho-biological significance. PMID- 29248582 TI - Association between vitamin D receptor polymorphisms and hepatitis B virus infection susceptibility: A meta-analysis study. AB - BACKGROUND: Hepatitis B virus (HBV) infection is still a serious public health problem. Understanding risk factors associated with development of HBV is greatly important. Numerous studies focus on relationship between vitamin D receptor (VDR) polymorphisms (TaqI, FokI, ApaI, BsmI) and the risk of HBV infection in different ethnic groups. However the results published so far are inconsistent. The aim of this study is to quantify the association between VDR polymorphisms with HBV infection by meta-analysis approach. METHODS: A systematic search was performed in Pubmed, Embase, China National Knowledge Infrastructure (CNKI), Database of Chinese Scientific and Technical Periodicals (VIP), and WANFANG. All the relevant studies were published up to October 2016. RESULTS: Finally, 15 published studies included 4218 cases and 2298 controls were included in this meta-analysis. It is interesting to note that FokI FF tends to be a risk factor for HBV infection [FF vs. ff: P<0.01, OR (95%CI)=1.54 (1.19-2.00), I2=0.0%], with no heterogeneity. In addition, genotype Ff and allele F could increase HBV infection risk [Ff vs. ff: P<0.01, OR (95%CI)=1.39 (1.13-1.72); F vs. f: P=0.02, OR (95%CI)=1.23(1.04-1.45)]. However, no associations were found about VDR TaqI, ApaI and BsmI polymorphisms with HBV infection based on each comparison model. CONCLUSION: This meta-analysis indicates that FokI genotype FF, Ff and allele F increase the risk of HBV infection. All these results support the notion that VDR FokI genotype might has potential role in HBV susceptibility. PMID- 29248583 TI - GmPLP1, a PAS/LOV protein, functions as a possible new type of blue light photoreceptor in soybean. AB - Light is one of the most important environmental factors for the growth and development of plants. To adapt to changes in day length, the photoreception and transmission of the light signals in plants mainly depend on the various light receptor proteins. The PAS/LOV protein (PLP) has a PAS domain in the N-terminal and LOV domain in the C-terminal and has been confirmed as a new type of blue light receptor in Arabidopsis thaliana. However, the role of its counterpart in soybean remains largely unclear. In this study, the expression pattern of the GmPLP1 under different light qualities was determined by real-time RT-PCR analysis using the cultivar 'DongNong 42', a photosensitive soybean cultivar, suggesting that GmPLP1 was affected by the circadian clock and was a dark-induced gene. Moreover, the mRNA abundance increased significantly under blue light. Further analysis revealed that overexpression of GmPLP1 displayed the inhibition of hypocotyl elongation under blue light, and the expression of CRY1, CRY2, CKL3, CKL4, BIT1, and HY5 were simultaneously increased in GmPLP1-transgenic Arabidopsis, suggesting that the shortened hypocotyl was associated with the up regulation of these genes. Taken together, our results suggest that GmPLP1, which is a new possible type of blue light photoreceptor in soybean, plays an important role in the blue light signaling pathway. PMID- 29248584 TI - Dexamethasone inhibits inflammatory response via down regulation of AP-1 transcription factor in human lung epithelial cells. AB - The production of inflammatory mediators by epithelial cells in inflammatory lung diseases may represent an important target for the anti-inflammatory effects of glucocorticoids. Activator protein-1 is a major activator of inflammatory genes and has been proposed as a target for inhibition by glucocorticoids. We have used human pulmonary type-II A549 cells to examine the effect of dexamethasone on the phorbol ester (PMA)/Lipopolysaccharide (LPS) induced pro-inflammatory cytokines and AP-1 factors. A549 cells were treated with and without PMA or LPS or dexamethasone and the cell viability and nitric oxide production was measured by MTT assay and Griess reagent respectively. Expression of pro-inflammatory cytokines and AP-1 factors mRNA were measured using semi quantitative RT-PCR. The PMA/LPS treated cells show significant 2-3 fold increase in the mRNA levels of pro-inflammatory cytokines (IL-1beta, IL-2, IL-6, IL-8 and TNF-alpha), cyclo oxygenase-2 (COX-2) and specific AP-1 factors (c-Jun, c-Fos and Jun-D). Whereas, pretreatment of cells with dexamethasone significantly inhibited the LPS induced nitric oxide production and PMA/LPS induced mRNAs expression of above pro inflammatory cytokines, COX-2 and AP-1 factors. Cells treated with dexamethasone alone at both the concentrations inhibit the mRNAs expression of IL-1beta, IL-6 and TNF-alpha compared to control. Our study reveals that dexamethasone decreased the mRNAs expression of c-Jun and c-Fos available for AP-1 formation suggested that AP-1 is the probable key transcription factor involved in the anti inflammatory activity of dexamethasone. This may be an important molecular mechanism of steroid action in asthma and other chronic inflammatory lung diseases which may be useful for treatment of lung inflammatory diseases. PMID- 29248585 TI - Human protective monoclonal antibodies against the HA stem of group 2 HAs derived from an H3N2 virus-infected human. AB - OBJECTIVES: Broadly reactive human monoclonal antibodies against the HA stem of influenza A virus are being developed as therapeutic agents as well as to understand the epitopes that are essential for a universal influenza virus vaccine. METHODS: We isolated and characterized two hetero-reactive human monoclonal antibodies from an H3N2 virus-infected human. RESULTS: These antibodies, which are predominantly bound to the HA stem of group 2 HAs, used IGHV3-66 and IGHV4-38-2 germline genes, respectively. They possessed in vitro neutralizing ability, and in vivo protective efficacy against lethal infection with H3N2 or H7N9 virus. Escape mutations revealed that one of the protective antibodies recognized the alpha-helix A of HA2, and the other recognized the C terminal portion of the fusion peptide and the beta-sheet that precedes the alpha helix A of HA2. CONCLUSIONS: Of many human protective monoclonal antibodies against the HA stem, two human protective monoclonal antibodies were isolated in this study that predominantly recognize epitopes on the HA stem of group 2 and use unique IGHV3-66 and IGHV4-38-2 germline genes. PMID- 29248586 TI - Improving the diagnosis of invasive aspergillosis by the detection of Aspergillus in broncho-alveolar lavage fluid: Comparison of non-culture-based assays. AB - OBJECTIVES: This study aimed to evaluate new tools to diagnose invasive aspergillosis (IA) directly from broncho-alveolar lavage (BAL) samples. METHODS: All consecutive patients with suspected IA who underwent bronchoscopy with BAL were prospectively included. Mycological culture and ELISA detection of galactomannan (GM) were performed on BAL. Two in-house and two marketed PCR assays were used on BAL DNA extracts to detect Aspergillus species. Susceptibility testing was performed after culture; marketed PCR assays detected mutations in the CYP51A gene associated to resistance. RESULTS: Within 3 years, 1555 BAL samples were processed, including 413 samples from 387 immunosuppressed patients. IA diagnosis was no-IA, possible, probable or proven IA in 326, 23, 37 and 1 patients, respectively. PCR assays sensitivity for Aspergillus detection ranged from 61% to 74%, below GM (87%), but contrasting with 47% for cultures. Combining PCR to EORTC/MSG criteria increased the sensitivity to 100%. Interestingly, tests performance in non-hematological patients ranged from 60% to 75%, and were higher than in hematological patients, and those with prior exposure to antifungals. All 16 isolates of Aspergillus fumigatus were susceptible; PCR did not detect any resistance marker in the 37 A. fumigatus PCR positive samples. CONCLUSION: The molecular detection of Aspergillus directly in BAL samples greatly improved the diagnosis of IA, particularly in non hematological patients. PMID- 29248588 TI - Asian journals are doin' it for themselves. PMID- 29248587 TI - Enhanced case management can be delivered for patients with EVD in Africa: Experience from a UK military Ebola treatment centre in Sierra Leone. AB - BACKGROUND: Limited data exist describing supportive care management, laboratory abnormalities and outcomes in patients with Ebola virus disease (EVD) in West Africa. We report data which constitute the first description of the provision of enhanced EVD case management protocols in a West African setting. METHODS: Demographic, clinical and laboratory data were collected by retrospective review of clinical and laboratory records of patients with confirmed EVD admitted between 5 November 2014 and 30 June 2015. RESULTS: A total of 44 EVD patients were admitted (median age 37 years (range 17-63), 32/44 healthcare workers), and excluding those evacuated, the case fatality rate was 49% (95% CI 33%-65%). No pregnant women were admitted. At admission 9/44 had stage 1 disease (fever and constitutional symptoms only), 12/44 had stage 2 disease (presence of diarrhoea and/or vomiting) and 23/44 had stage 3 disease (presence of diarrhoea and/or vomiting with organ failure), with case fatality rates of 11% (95% CI 1%-58%), 27% (95% CI 6%-61%), and 70% (95% CI 47%-87%) respectively (p = 0.009). Haemorrhage occurred in 17/41 (41%) patients. The majority (21/40) of patients had hypokalaemia with hyperkalaemia occurring in 12/40 patients. Acute kidney injury (AKI) occurred in 20/40 patients, with 14/20 (70%, 95% CI 46%-88%) dying, compared to 5/20 (25%, 95% CI 9%-49%) dying who did not have AKI (p = 0.01). Ebola virus (EBOV) PCR cycle threshold value at baseline was mean 20.3 (SD 4.3) in fatal cases and 24.8 (SD 5.5) in survivors (p = 0.007). Mean national early warning score (NEWS) at admission was 5.5 (SD 4.4) in fatal cases and 3.0 (SD 1.9) in survivors (p = 0.02). Central venous catheters were placed in 37/41 patients and intravenous fluid administered to 40/41 patients (median duration of 5 days). Faecal management systems were inserted in 21/41 patients, urinary catheters placed in 27/41 and blood component therapy administered to 20/41 patients. CONCLUSIONS: EVD is commonly associated life-threatening electrolyte imbalance and organ dysfunction. We believe that the enhanced levels of protocolized care, scale and range of medical interventions we report, offer a blueprint for the future management of EVD in resource-limited settings. PMID- 29248590 TI - Amniotic fluid embolism complicated with pulmonary embolism during cesarean section: Management with TEE and ROTEM(r). PMID- 29248589 TI - A comparison of the dose of anesthetic agents and the effective interval from the block procedure to skin incision for ultrasound-guided supraclavicular brachial plexus block in upper extremity surgery. AB - OBJECTIVE: The aim of this study was to review and evaluate the selection and dose of anesthetic agents and the interval from the block procedure to skin incision for supraclavicular brachial plexus block in upper extremity surgery. METHODS: We reviewed our cases that underwent upper extremity surgery using only ultrasound-guided supraclavicular brachial plexus block in our hospital between 2011 and 2016. Adverse events during surgery were evaluated. Receiver operating characteristic (ROC) curves were constructed to investigate the relationship between the time from the end of the block procedure to skin incision and the use of local anesthesia on the surgical site. RESULTS: There were 255 patients who were divided into three groups according to the anesthetic agents used: group 1, 1% lidocaine (L) 10 ml + 0.75% ropivacaine (R) 20 ml (n = 62); group 2, L 20 ml + R 10 ml (n = 93); and group 3, L 10 ml + R 15 ml (n = 100). The rate of use of local anesthesia on the surgical site was significantly higher in group 3 than in the other two groups. There were no significant differences in the other evaluated items among the three groups. ROC curve analysis indicated that >=24 min from the end of the block procedure to skin incision might reduce the use of local anesthesia. CONCLUSION: The total volume of anesthetic agents had an important influence on the rate of the addition of local anesthesia for surgical pain; however, the combined dose of agents did not influence the evaluation items. For effective analgesia, >=24 min should elapse from the end of the block procedure to skin incision. PMID- 29248591 TI - Strategies of biochemical adaptation for hibernation in a South American marsupial, Dromiciops gliroides: 3. Activation of pro-survival response pathways. AB - The South American marsupial, monito del monte (Dromiciops gliroides) uses both daily torpor and multi-day hibernation to survive in its southern Chile native environment. The present study leverages multiplex technology to assess the contributions of key stress-inducible cell cycle regulators and heat shock proteins to hibernation in liver, heart, and brain of monito del monte in a comparison of control versus 4day hibernating conditions. The data indicate that MDM2, a stress-responsive ubiquitin ligase, plays a crucial role in marsupial hibernation since all three tissues showed statistically significant increases in MDM2 levels during torpor (1.6-1.8 fold). MDM2 may have a cytoprotective action to deal with ischemia/reperfusion stress and is also involved in a nutrient sensing pathway where it could help regulate the metabolic switch to fatty acid oxidation during torpor. Elevated levels of stress-sensitive cell cycle regulators including ATR (2.32-3.91 fold), and the phosphorylated forms of p-Chk1 (Ser345) (1.92 fold), p-Chk2 (Thr68) (2.20 fold) and p21 (1.64 fold) were observed in heart and liver during hibernation suggesting that the cell cycle is likely suppressed to conserve energy while animals are in torpor. Upregulation of heat shock proteins also occurred as a cytoprotective strategy with increased levels of hsp27 (2.00 fold) and hsp60 (1.72-2.76 fold) during hibernation. The results suggest that cell cycle control and selective chaperone action are significant components of hibernation in D. gliroides and reveal common molecular responses to those seen in eutherian hibernators. PMID- 29248592 TI - Fluorochloridone induces primary cultured Sertoli cells apoptosis: Involvement of ROS and intracellular calcium ions-mediated ERK1/2 activation. AB - Fluorochloridone (FLC) is a widely used pyrrolidone selective herbicide and reported to induce testis injuries in male rats, but the underlying mechanism is largely unknown. In the present study, primary-cultured Sertoli cells were exposed to FLC at the concentration of 0-10.00MUM to study the mechanism of FLC induced apoptosis. The roles of ROS, intracellular calcium, endoplasmic reticulum (ER), and ERK1/2 were looked at with ROS scavenger N-acetyl-cysteine (NAC), intracellular calcium chelator BAPTA-AM, ER calcium depleting agent thapsigargin (TG), and ERK1/2 inhibitor U0126, respectively. FLC induced dose-dependent apoptosis increase as well as the elevation in levels of ROS, intracellular calcium, and ERK1/2 activation. FLC treatment led to constantly increasing apoptotic rates and ERK1/2 activation over time, while inversed-V shaped change tendencies of ROS and intracellular calcium levels were observed. FLC-induced ROS generation disrupted the intracellular calcium homeostasis by attacking the ER, and the elevated intracellular calcium levels resulted in ERK1/2 over phosphorylation and consequently promoted Sertoli cell apoptosis. Taken together, ROS and intracellular calcium-mediated ERK1/2 activation led to FLC-induced Sertoli cell apoptosis. PMID- 29248593 TI - Phototoxic effect of oxytetracycline on normal human melanocytes. AB - Oxytetracycline is a broad-spectrum antibiotic, used in dermatology and veterinary medicine. Like other tetracyclines, it may evoke skin phototoxic reactions related to generation of reactive oxygen species (ROS). Melanins are biopolymers synthesised in melanocytes - highly specialised cells, localised in the basal layer of epidermis. Production of melanin is a defence mechanism against harmful effects of UV radiation, ROS and many chemical substances, including drugs. In the present study the influence of oxytetracycline and UVA radiation on darkly pigmented melanocytes viability, the melanogenesis process and the activity of antioxidant enzymes were analysed. The obtained results show that oxytetracycline decreases cell viability in a dose-dependent manner. It has also been stated that UVA radiation as well as simultaneous exposure to oxytetracycline and UVA radiation reduce melanocytes viability. The tested drug alone exhibits little effect on antioxidant enzymes activity and has no influence on the synthesis of melanin. However, simultaneous exposure of the cells to oxytetracycline and UVA radiation causes an increase of SOD and GPx activity, a decrease of CAT activity as well as stimulates melanogenesis. The obtained results suggest that phototoxicity of oxytetracycline towards normal human melanocytes depends on both time of UVA exposure and the drug concentration. PMID- 29248594 TI - LST-3TM12 is a member of the OATP1B family and a functional transporter. AB - Organic anion transporting polypeptides (OATPs) and particularly the two members of the OATP1B family are known for their role in pharmacokinetics. Both SLCO1B3 and SLCO1B1 are located on chromosome 12 encompassing the gene locus SLCO1B7. Hitherto, this particular gene has been assumed to be a pseudogene, even though there are published mRNA sequences linked to this chromosomal area. It was aim of this study to further investigate SLCO1B7 and the associated mRNA LST-3TM12. In a first step, we aligned all mRNAs linked to the chromosomal region of SLCO1B transporters. This in silico analysis revealed that LST-3TM12 is a product of splicing of SLCO1B3 and SLCO1B7, and encodes for a protein with twelve transmembrane domains. The existence of LST-3TM12 mRNA was verified by polymerase chain reaction showing liver enriched expression. In addition, immunohistological staining showed that LST-3TM12 protein was expressed in the endoplasmic reticulum (ER) of hepatocytes. Localization in the ER was further verified by immunoblot analysis showing high amounts of LST-3TM12 in liver microsomes. Function of LST 3TM12 was assessed by transport studies after heterologous expression in HeLa cells, where the transporter was shown to be expressed not only in the ER but also in the plasma membrane. Overexpression of LST-3TM12 was associated with enhanced cellular accumulation of dehydroepiandrosterone sulfate (Vmax 300.2 pmol mg-1 min-1; Km 34.2 um) and estradiol 17beta-glucuronide (Vmax 29.9 mol mg-1 min 1 and Km 32.8 uM). In conclusion, LST-3TM12 is a functional splice variant of SLCO1B3 and SLCO1B7 expressed in the ER of human liver. PMID- 29248595 TI - Quantification of 11beta-hydroxysteroid dehydrogenase 1 kinetics and pharmacodynamic effects of inhibitors in brain using mass spectrometry imaging and stable-isotope tracers in mice. AB - 11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1; EC 1.1.1.146) generates active glucocorticoid hormones. Small molecule inhibitors have been developed to target 11beta-HSD1 for the treatment of dementia; these must enter brain subregions, such as the hippocampus, to be effective. We previously reported mass spectrometry imaging measurement of murine tissue steroids, and deuterated steroid tracer infusion quantification of 11beta-HSD1 turnover in humans. Here, these tools are combined to assess tissue pharmacokinetics and pharmacodynamics of an 11beta-HSD1 inhibitor that accesses the brain. [9,11,12,12-2H]4-Cortisol was infused (1.75 mg/day) by minipump for 2 days into C57Bl6 mice (male, age 12 weeks, n = 3/group) after which an 11beta-HSD1 inhibitor (UE2316) was administered (25 mg/kg oral gavage) and animals culled immediately or 1, 2 and 4 h post-dosing. Mice with global genetic disruption of Hsd11B1 were studied similarly. Turnover of d4-cortisol to d3-cortisone (by loss of the 11-deuterium) and regeneration of d3-cortisol (by 11beta-HSD1-mediated reduction) were assessed in plasma, liver and brain using matrix assisted laser desorption ionization coupled to Fourier transform cyclotron resonance mass spectrometry. The tracer d4 cortisol was detected in liver and brain following a two day infusion. Turnover to d3-cortisone and on to d3-cortisol was slower in brain than liver. In contrast, d3-cortisol was not detected in mice lacking 11beta-HSD1. UE2316 impaired d3-cortisol generation measured in whole body (assessed in plasma; 53.1% suppression in rate of appearance in d3-cortisol), liver and brain. Differential inhibition in brain regions was observed; active glucocorticoids were suppressed to a greater in extent hippocampus or cortex than in amygdala. These data confirm that the contribution of 11beta-HSD1 to the tissue glucocorticoid pool, and the consequences of enzyme inhibition on active glucocorticoid concentrations, are substantial, including in the brain. They further demonstrate the value of mass spectrometry imaging in pharmacokinetic and pharmacodynamic studies. PMID- 29248596 TI - The wonderland of neuronal nicotinic acetylcholine receptors. AB - Nearly 30 years of experimental evidence supports the argument that ligands of nicotinic acetylcholine receptors (nAChRs) have potential as therapeutic agents. However, as in the famous Lewis Carroll novel "Alice in Wonderland", there have been many unexpected adventures along the pathway of development, and few nAChR ligands have been approved for any clinical condition to date with the exception of nicotine dependence. The recent failures of nAChR ligands in AD and schizophrenia clinical trials have reduced enthusiasm for this therapeutic strategy and many pharmaceutical companies have now abandoned this field of research. As with other clinical failures, multiple questions arise as to the basis for the failure. More generic questions focus on a potential translational gap between the animal models used and the human clinical condition they are meant to simulate, or the clinical trial mindset that large Ns have to be achieved for statistical power (often requiring multiple trial sites) as opposed to smaller patient cohorts at limited sites where conditions can be better controlled and replicated. More specific to the nAChR field are questions about subtype selectivity, dose selection, whether an agonist, antagonist, or allosteric modulator strategy is best, etc. The purpose of this review is to discuss each of these questions, but also to provide a brief overview of the remarkable progress that has been made over the last three decades in our understanding of this unique ligand-gated ion channel and how this new knowledge may help us improve drug development successes in the future. PMID- 29248597 TI - H2S and polysulfide metabolism: Conventional and unconventional pathways. AB - It is now well established that hydrogen sulfide (H2S) is an effector of a wide variety of physiological processes. It is also clear that many of the effects of H2S are mediated through reactions with cysteine sulfur on regulatory proteins and most of these are not mediated directly by H2S but require prior oxidation of H2S and the formation of per- and polysulfides (H2Sn, n = 2-8). Attendant with understanding the regulatory functions of H2S and H2Sn is an appreciation of the mechanisms that control, i.e., both increase and decrease, their production and catabolism. Although a number of standard "conventional" pathways have been described and well characterized, novel "unconventional" pathways are continuously being identified. This review summarizes our current knowledge of both the conventional and unconventional. PMID- 29248598 TI - The interaction of IGF-1/IGF-1R and hydrogen sulfide on the proliferation of mouse primary vascular smooth muscle cells. AB - Hydrogen sulfide (H2S) is mostly produced by cystathionine-gamma-lyase (CSE) in vascular system and it inhibits the proliferation of vascular smooth muscle cells (SMCs). Insulin-like growth factor-1 (IGF-1), via its receptor (IGF-1R), exerts multiple physiological and pathophysiological effects on the vasculature, including stimulating SMC proliferation and migration, and inhibiting SMC apoptosis. Since H2S and IGF-1/IGF-1R have opposite effects on SMC proliferation, it becomes imperative to better understand the interaction of these two signaling mechanisms on SMC proliferation. SMCs isolated from small mesenteric arteries of CSE knockout (KO) and wild-type (WT) mice were used in the present study. The effects of IGF-1 and H2S on SMC proliferation were evaluated with 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and bromodeoxyuridine (BrdU) assays. Protein expression was determined by western blot, and H2S-induced protein S-sulfhydration was assessed with a modified biotin switch assay. We found that IGF-1 dose-dependently increased the proliferation of both WT-SMCs and KO-SMCs, and this effect was more significant in KO-SMCs. Supplement of sodium hydrosulfide (NaHS) inhibited IGF-1-induced cell proliferation, while this effect was abolished by blocking IGF-1/IGF-1R signaling with picropodophyllin (PPP) or knocking out of the expression of IGF-1R. H2S significantly down-regulates the expression of IGF-1R, stimulates IGF-1R S-sulfhydration, and attenuates the binding of IGF-1 with IGF-1R. This study provides novel insight on the involvement of IGF-1/IGF-1R in H2S-inhibited SMC proliferation and suggests H2S based innovative treatment strategies for proliferative cardiovascular diseases such as atherosclerosis. PMID- 29248599 TI - How often should we expect to be wrong? Statistical power, P values, and the expected prevalence of false discoveries. AB - There is a clear perception in the literature that there is a crisis in reproducibility in the biomedical sciences. Many underlying factors contributing to the prevalence of irreproducible results have been highlighted with a focus on poor design and execution of experiments along with the misuse of statistics. While these factors certainly contribute to irreproducibility, relatively little attention outside of the specialized statistical literature has focused on the expected prevalence of false discoveries under idealized circumstances. In other words, when everything is done correctly, how often should we expect to be wrong? Using a simple simulation of an idealized experiment, it is possible to show the central role of sample size and the related quantity of statistical power in determining the false discovery rate, and in accurate estimation of effect size. According to our calculations, based on current practice many subfields of biomedical science may expect their discoveries to be false at least 25% of the time, and the only viable course to correct this is to require the reporting of statistical power and a minimum of 80% power (1 - beta = 0.80) for all studies. PMID- 29248600 TI - STEM tomography analysis of the trypanosome transition zone. AB - The protist Trypanosoma brucei is an emerging model for the study of cilia and flagella. Here, we used scanning transmission electron microscopy (STEM) tomography to describe the structure of the trypanosome transition zone (TZ). At the base of the TZ, nine transition fibres irradiate from the B microtubule of each doublet towards the membrane. The TZ adopts a 9 + 0 structure throughout its length of ~300 nm and its lumen contains an electron-dense structure. The proximal portion of the TZ has an invariant length of 150 nm and is characterised by a collarette surrounding the membrane and the presence of electron-dense material between the membrane and the doublets. The distal portion exhibits more length variation (from 55 to 235 nm) and contains typical Y-links. STEM analysis revealed a more complex organisation of the Y-links compared to what was reported by conventional transmission electron microscopy. Observation of the very early phase of flagellum assembly demonstrated that the proximal portion and the collarette are assembled early during construction. The presence of the flagella connector that maintains the tip of the new flagellum to the side of the old was confirmed and additional filamentous structures making contact with the membrane of the flagellar pocket were also detected. The structure and potential functions of the TZ in trypanosomes are discussed, as well as its mode of assembly. PMID- 29248601 TI - Isolation of Acinetobacter junii strain carrying blaOXA-58 from a rectal swab, Marseille, France. PMID- 29248602 TI - Taking off the training wheels: Measuring auditory P3 during outdoor cycling using an active wet EEG system. AB - Mobile EEG allows the investigation of brain activity in increasingly complex environments. In this study, EEG equipment was adapted for use and transportation in a backpack while cycling. Participants performed an auditory oddball task while cycling outside and sitting in an isolated chamber inside the lab. Cycling increased EEG noise and marginally diminished alpha amplitude. However, this increased noise did not influence the ability to measure reliable event related potentials (ERP). The P3 was similar in topography, and morphology when outside on the bike, with a lower amplitude in the outside cycling condition. There was only a minor decrease in the statistical power to measure reliable ERP effects. Unexpectedly, when biking outside significantly decreased P2 and increased N1 amplitude were observed when evoked by both standards and targets compared with sitting in the lab. This may be due to attentional processes filtering the overlapping sounds between the tones used and similar environmental frequencies. This study established methods for mobile recording of ERP signals. Future directions include investigating auditory P2 filtering inside the laboratory. PMID- 29248603 TI - Mixed metaphors: Electrophysiological brain responses to (un)expected concrete and abstract prepositional phrases. AB - Languages around the world use spatial terminology, like prepositions, to describe non-spatial, abstract concepts, including time (e.g., in the moment). The Metaphoric Mapping Theory explains this pattern by positing that a universal human cognitive process underlies it, whereby abstract concepts are conceptualized via the application of concrete, three-dimensional space onto abstract domains. The alternative view is that the use of spatial propositions in abstract phrases is idiomatic, and thus does not trigger metaphoric mapping. In the current study, event-related potentials (ERPs) were used to examine the time course of neural processing of concrete and abstract phrases consisting of the prepositions in or on followed by congruent and incongruent nouns (e.g., in the bowl/plate and in the moment/mend). ERPs were recorded from the onset of reference nouns in 28 adult participants using a 128-channel electrode net. Results show that congruency has differential effects on neural measures, depending on whether the noun is concrete or abstract. Incongruent reference nouns in concrete phrases (e.g., on the bowl) elicited a significant central negativity (an N400 effect), while incongruent reference nouns in abstract phrases (e.g., on the moment) did not. These results suggest that spatially incongruent concrete nouns are semantically unexpected (N400 effect). A P600 effect, which might indicate rechecking, reanalysis and/or reconstruction, was predicted for incongruent abstract nouns, but was not observed, possibly due to the variability in abstract stimuli. Findings cast doubt on accounts claiming that abstract uses of prepositions are cognitively and metaphorically linked to their spatial sense during natural, on-line processing. PMID- 29248604 TI - Comparison of Two Different Distraction Methods Affecting the Level of Pain and Anxiety during Extracorporeal Shock Wave Lithotripsy: A Randomized Controlled Trial. AB - BACKGROUND: Extracorporeal shock wave lithotripsy can cause pain and anxiety for patients. Despite the use of many distraction methods to reduce pain and anxiety, there is no study on the use of stress balls during lithotripsy. AIM: The aim of the study was to investigate the efficacy of use of stress balls and music therapy to reduce pain and anxiety during lithotripsy. DESIGN: This was a single center, parallel randomized controlled trial. SETTINGS: The study involved the lithotripsy unit in a training and research hospital in Turkey. PARTICIPANTS: The study included 120 patients who had kidney or ureter stones. METHODS: The patients were randomly divided into three groups. The control group (group 1) received no interference, whereas experimental groups received stress ball (group 2) and music (group 3) interventions during lithotripsy, respectively. Data were collected using the Patient Information Form, visual analog scale, and State Trait Anxiety Inventory. RESULTS: There was no statistically significant difference among the three groups in regard to anxiety and pain mean scores (p > .05). No statistically significant difference was found between anxiety scores before and after lithotripsy in each group (p > .05), whereas there was a statistically significant difference between pain scores during and after lithotripsy (p < .05). CONCLUSION: Based on the present study, no statistically significant difference was found between the use of stress balls and music in reducing pain and anxiety during lithotripsy. Further studies are needed to evaluate the effectiveness of stress balls used during lithotripsy. PMID- 29248605 TI - Pain Treatment Practices of Community-Dwelling Black Older Adults. AB - Black older adults often experience disparities in pain treatment that results in unmet pain needs. The aims of this study were to assess the pain management experiences of a group of community dwelling Black older adults and identify gaps in clinical practice. A qualitative, descriptive design was employed using the methodology of ethnography. The setting was an urban, low-income, community elderly housing high-rise facility. Participants included facility residents (n = 106); of these, 20 completed structured qualitative interviews. The Brief Pain Inventory and qualitative interviews were used to determine pain prevalence, treatment practices, and barriers. Eighty-six percent of the participants had severe pain with a mean worst pain rating of 7 on a 0 to 10 scale. Pain interfered moderately with general activity (5.59), walking (5.73) and normal work (5.70), also measured on 0 to 10 scales. Participants preferred non-opioid analgesics, topical over-the-counter treatments, and nonpharmacological interventions such as prayer/meditation, and exercise for treatment. Medications most commonly used by participants for pain management included, hydrocodone with acetaminophen (28.6%), nonsteroidal anti-inflammatory drugs (13.2%), acetaminophen with codeine (12%), and tramadol (9.9). Qualitative interviews revealed that pain management barriers were centered around communication concerns about side effects, fears of addiction, and provider mistrust. A communication gap exists between patients and providers. Discussing patient treatment preferences, providing balanced treatment information, and following-up with patients on treatment plan effectiveness by phone can improve how pain is managed for Black older adults. PMID- 29248606 TI - Comparison of a revaprazan-loaded solid dispersion, solid SNEDDS and inclusion compound: Physicochemical characterisation and pharmacokinetics. AB - The aim of this research was to compare three strategies for enhancing the solubility of poorly water-soluble revaprazan hydrochloride: solid dispersion, solid SNEDDS and inclusion compound. The influence of polymers, surfactants and oils on the drug solubility was assessed, and via the chosen carriers, the three types of formulations were prepared utilising spray drying technique. Their physicochemical properties, solubility, dissolution and pharmacokinetics in rats were performed compared with revaprazan powder. Among the liquid SNEDDS formulations assessed, the compositions of revaprazan, peceol, Tween 80 and Labrasol (10:15:55:30, weight ratio) provided the smallest emulsion size. Moreover, this liquid SNEDDS and dextran were suspended/dissolved in distilled water, and spray-dried, producing an optimal revaprazan-loaded solid SNEDDS. The appropriate solid dispersion and inclusion compound were composed of revaprazan, hydroxypropylmethylcellulose and cremophor A25 (5:1.4:5.6) and drug and hydroxyl beta-cyclodextrin (2.5:8.77), respectively. The crystalline drug was converted to an amorphous state in all formulations. In the solid dispersion, the drug was attached to the hydrophilic carrier. The solid SNEDDS and inclusion compound contained aggregate microspheres and separate microspheres, respectively. All formulations significantly increased the drug solubility, dissolution, plasma concentration and AUC compared with revaprazan powder. These properties were ranked in the order solid dispersion >= solid SNEDDS > inclusion compound. Particularly, the solid dispersion improved about 9500-fold drug solubility and 10-fold oral bioavailability. Thus, the improved properties were considerably dependent upon these techniques, although all of the techniques employed similar mechanisms. Among the strategies checked, the solid dispersion system would be recommended as an oral revaprazan-loaded pharmaceutical product. PMID- 29248607 TI - Involvement of mitogen activated kinase kinase 7 intracellular signalling pathway in Sunitinib-induced cardiotoxicity. AB - The tyrosine kinase inhibitor Sunitinib is used to treat cancer and is linked to severe adverse cardiovascular events. Mitogen activated kinase kinase 7 (MKK7) is involved in the development of cardiac injury and is a component of the c-Jun N terminal kinase (JNK) signal transduction pathway. Apoptosis signal-regulating kinase 1 (ASK1) is the upstream activator of MKK7 and is specifically inhibited by 2,7-dihydro-2,7-dioxo-3H-naphtho[1,2,3-de]quinoline-1-carboxylic acid ethyl ester (NQDI-1). This study investigates the role of ASK1, MKK7 and JNK during Sunitinib-induced cardiotoxicity. Infarct size were measured in isolated male Sprague-Dawley rat Langendorff perfused hearts treated for 125 min with Sunitinib in the presence and absence of NQDI-1. Left ventricular cardiac tissue samples were analysed by qRT-PCR for MKK7 mRNA expression and cardiotoxicity associated microRNAs (miR-1, miR-27a, miR-133a and miR-133b) or Western blot analysis to measure ASK1/MKK7/JNK phosphorylation. Administration of Sunitinib (1 MUM) during Langendorff perfusion resulted in increased infarct size, increased miR-133a expression, and decreased phosphorylation of the ASK1/MKK7/JNK pathway compared to control. Co-administration of NQDI-1 (2.5 MUM) attenuated the increased Sunitinib-induced infarct size, reversed miR-133a expression and restored phosphorylated levels of ASK1/MKK7/JNK. These findings suggest that the ASK1/MKK7/JNK intracellular signalling pathway is important in Sunitinib-induced cardiotoxicity. The anti-cancer properties of Sunitinib were also assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay. Sunitinib significantly decreased the cell viability of human acute myeloid leukemia 60 cell line (HL60). The combination of Sunitinib (1 nM-10 MUM) with NQDI-1 (2.5 MUM) enhanced the cancer-fighting properties of Sunitinib. Investigations into the ASK1/MKK7/JNK transduction pathway could lead to development of cardioprotective adjunct therapy, which could prevent Sunitinib induced cardiac injury. PMID- 29248608 TI - Assessment of Blood Flow Patterns Distal to Aortic Occlusion Using CT in Patients with Resuscitative Endovascular Balloon Occlusion of the Aorta. AB - BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is used to decrease hemorrhage below the level of aortic occlusion (AO); however, the amount of collateral blood flow below the level of occlusion is unknown. Our aim was to investigate blood flow patterns during complete AO in patients who underwent CT scan after REBOA. STUDY DESIGN: Between February 2013 and January 2017, patients who received REBOA and underwent CT scan with intravenous contrast during full AO were included. Patients were excluded if they had a CT scan performed with the balloon partially or fully deflated. RESULTS: Nine patients (8 men) were included; all had blunt trauma. Mean Injury Severity Score (+/-SD) was 48 +/- 8 and mean age was 45 +/- 19 years. Four had supra-celiac AO, and 5 had infra-renal AO. Arterial contrast enhancement was noted below the level of AO in all patients, and distal to REBOA sheath placement in 5. Collateralization from arteries above and below the AO was identified in all patients. Contrast extravasation distal to AO was identified in 4 patients, and hematomas in 8. Distal vascular enhancement patterns varied by level of AO and contrast administration site. CONCLUSIONS: Aortic occlusion appears to dramatically decrease, but does not completely impede, distal perfusion during REBOA due to multiple pathways of collateralization. Active extravasation and hematomas can still be detected in the setting of full AO, with purposefully timed contrast and image acquisition. Blood flow persists below the level of both the AO and in dwelling sheath. Dynamic flow studies are needed to determine the contribution of AO and sheath placement to distal tissue ischemia. PMID- 29248609 TI - Size characterization of lipid-based self-emulsifying pharmaceutical excipients during lipolysis using Taylor dispersion analysis with fluorescence detection. AB - Self-emulsifying drug delivery systems based on lipids have gained in interest in recent years due to their capacity to enhance the bioavailability of poorly water soluble drugs. Their oral intake suggests that they will be in contact with gastric and pancreatic enzymes during their passage through the gastrointestinal tract. The study of the evolution of such systems in the presence of enzymes is thus essential to develop better drug delivery vehicles. In this work, the lipolysis of two lipid based self-emulsifying drug delivery systems, Labrasol(r) and Gelucire(r) 44/14 by pancreatic enzymes and under conditions mimicking the gastrointestinal tract are presented. The following of the digestion is realized by Taylor dispersion analysis using fluorescent detection. A hydrophobic marker was used to tag the microdroplets. Results have shown that, Labrasol(r) droplets decrease exponentially in size with lipolysis time, from 11.8 nm to 3.5 nm in 20 min. On the contrary, Gelucire(r) 44/14 droplets increased sigmoidally in size from 5.6 to 24.7 nm. Even after 120 min lipolysis, both systems maintained a solubilizing capacity of the hydrophobic marker. PMID- 29248610 TI - Cross Talk: Evaluation of a Curriculum to Teach Medical Students How to Use Telephone Interpreter Services. AB - PURPOSE: Telephone interpretation and recent technology advances assist patients with more timely access to rare languages, but no one has examined the role of this technology in the medical setting and how medical students can be prepared for their use. We sought to determine if structured curriculum on interpretation would promote learners self-reported competency in these encounters and if proficiency would be demonstrated in actual patient encounters. METHODS: Training on the principles of interpreter use with a focus on communication technology was added to medical student education. The students later voluntarily completed a retrospective pre/post training competency self-assessment. A cohort of students rotating at a clinical site had a blinded review of their telephone interpretation encounters scored on a modified validated scale and compared to scored encounters with preintervention learners. Nested ANOVA models were used for audio file analysis. RESULTS: A total of 176 students who completed the training reported a statistically significant improvement in all 4 interpretation competency domains. Eighty-three audio files were analyzed from students before and after intervention. These scored encounters showed no statistical difference between the scores of the 2 groups. However, plotting the mean scores over time from each encounter suggests that those who received the curriculum started their rotation with higher scores and maintained those scores. CONCLUSIONS: In an evaluation of learners' ability to use interpreters in actual patient encounters, focused education led to earlier proficiency of using interpreters compared to peers who received no training. PMID- 29248611 TI - A vicious interplay between genetic and environmental insults in the etiology of blood cancers. AB - Over the years, the etiology of cancer has been attributed alternatively to genetic and environmental insults. According to the genetic hypothesis, cancer cells arise from the acquisition of mutations that dysregulate the intrinsic mechanisms controlling normal cell growth and survival. In contrast, the environmental hypothesis holds that cancer can be caused by multiple extrinsic challenges that alter normal tissue homeostasis, but may not necessarily involve mutations. It is, however, quite possible that these two mechanisms are not mutually exclusive. According to this third hypothesis, environmental challenges, by mechanisms still poorly understood, may act by imposing a selection pressure that confers a proliferative advantage on cells carrying specific driver mutations, leading to disease initiation. The authors of a brief report published in this journal (Exp Hematol. 2017;56:1-6) tested this third hypothesis experimentally and provide new evidence that chronic inflammation, by increasing tumor necrosis factor (TNF)-alpha, may positively select malignant hematopoietic stem cells (HSCs) carrying loss-of-function TET2 mutations that switch the TNF alpha signaling responses to activate proliferation rather than inducing quiescence. Furthermore, these mutations skew hematopoietic differentiation toward the myelomonocytic lineage and the output of macrophages producing TNF alpha constitutively, promoting further environment-independent expansion of the malignant HSCs. These findings support a model in which the formation of a malignant population is triggered by a vicious interplay between genetic (TET2 mutations) and environmental (inflammation) insults, suggesting the need for strategies that target both the malignant cells and their environment. PMID- 29248612 TI - Hematopoietic development: a gap in our understanding of inherited bone marrow failure. AB - Inherited bone marrow failure syndromes (IBMFS) represent a heterogeneous group of multisystem disorders that typically present with cytopenia in early childhood. Efforts to understand the underlying hematopoietic stem cell (HSC) losses have generally focused on postnatal hematopoiesis. However, reflecting the role of many of the involved genes in core cellular functions and the diverse nonhematologic abnormalities seen in patients at birth, studies have begun to explore IBMFS manifestations during fetal development. Here, I consider the current evidence for fetal deficits in the HSC pool and highlight emerging concepts regarding the origins and unique pathophysiology of hematopoietic failure in IBMFS. PMID- 29248613 TI - High frequency stimulation induces LTD of AMPA receptor-mediated postsynaptic responses and LTP of synaptically-evoked firing in the dorsolateral striatum. AB - In the striatum, long term potentiation (LTP) and long-term depression (LTD) of glutamatergic transmission are believed to underlie motor learning and are impaired in animal models of Parkinson's disease. High frequency stimulation (HFS) is often used to induce synaptic plasticity in the brain. In the striatum, the polarity of HFS-induced plasticity is influenced by the recording conditions, which can differ between various studies. Here, we examined the ability of HFS to induce synaptic plasticity in the dorsolateral striatum in the presence of extracellular Mg2+ ions, with no GABAA receptor blocker, and without membrane depolarization during HFS. We found that HFS induced a LTD of excitatory postsynaptic currents (EPSCs) mediated by AMPA receptors (AMPARs) in medium spiny neurons (MSNs) recorded with whole-cell voltage-clamp. However, HFS induced a LTP of field excitatory postsynaptic potentials/population spikes (fEPSP/PSs), which was dependent on the stimulation intensity applied. The rate of synaptically evoked spiking in MSNs, measured with cell-attached recordings, showed LTP following HFS. LTD and LTP were impaired in the dopamine-depleted striatum of 6 hydroxydopamine (6-OHDA) lesioned mice, a model of Parkinson's disease. This study shows that HFS induces opposing forms of dopamine-dependent synaptic plasticity in the striatum, i.e. LTD of AMPAR-EPSCs and LTP of both fEPSP/PS and synaptically-evoked firing in MSNs. PMID- 29248614 TI - Significant association between catechol-O-methyltransferase (COMT) Val158/108Met polymorphism and cognitive function in veterans with PTSD. AB - Core features of posttraumatic stress disorder (PTSD) are cognitive disturbances. Enzyme catechol-O-methyltransferase (COMT) degrades dopamine primarily in prefrontal cortex. Its functional polymorphism, COMT Val158/108Met, affects COMT activity and dopamine availability and is associated with disturbances in cognition. The hypothesis was that PTSD subjects will have worse working memory than healthy controls and that the carriers of the COMT Met allele will show better cognitive performance compared to Val/Val carriers in PTSD and controls subjects. The aim of this study was to assess the differences in cognitive functioning between PTSD and control subjects and to evaluate the association between COMT Val158/108Met polymorphism and cognitive function determined using the Rey-Osterrieth complex figure (ROCF) copy, immediate and delayed test. The study included 323 male Caucasian participants of Croatian origin: 205 male combat veterans with PTSD and 118 control subjects. A significant association between the COMT Val158/108Met and the ROCF immediate and delayed scores in veterans with PTSD was found. We confirmed, on ethnically homogenous groups of veterans with matched combat experience, that controls had higher ROCF immediate and delayed test scores than veterans with PTSD. In PTSD subjects, the Met carriers of the COMT Val158/108Met performed better (i.e. had higher ROCF scores) than Val/Val homozygotes on both ROCF immediate recall and delayed recall test. Our results provide the first evidence that the presence of one or two Met alleles of the COMT Val158/108Met might act as a protective variant in working memory tasks in combat exposed veterans with PTSD. PMID- 29248615 TI - Exploring the neural correlates of lexical stress perception in english among Chinese-English bilingual children with autism spectrum disorder: An ERP study. AB - Previous studies found that individuals with autism spectrum disorder (ASD) were less sensitive to the variations of lexical stress in their native language than typically developing controls. However, no study has been conducted to explore the perception of lexical stress in the second language among individuals with ASD. Using ERPs (event-related potentials) measurement with an oddball paradigm, the current study examined and compared the neural responses by Chinese-English bilingual children with ASD and typically developing controls in the processing of English lexical stress. The results showed that when compared with typically developing controls, children with ASD manifested reduced MMN (mismatch negativity) amplitude at the left temporal-parietal and parietal sites, indicating that they were less sensitive to lexical stress. However, a more negative MMN response was found for ASD group than for typically developing group at the right central-parietal, temporal-parietal, and temporal sites. In addition, the right hemisphere was more activated than the left hemisphere for ASD group, which might be derived from the reversed asymmetry of brain activation for individuals with ASD when processing language-related stimuli. PMID- 29248616 TI - Long-lasting ameliorating effects of the oligodeoxynucleotide IMT504 on mechanical allodynia and hindpaw edema in rats with chronic hindpaw inflammation. AB - PURPOSE: Previously we showed that systemic administration of IMT504 prevents or ameliorates mechanical and thermal allodynia in rats with sciatic nerve crush. Here we analyzed if IMT504 is also effective in reducing mechanical allodynia and inflammation in rats undergoing hindpaw inflammation. MATERIALS AND METHODS: Male Sprague-Dawley rats received unilateral intraplantar injection of complete Freunds adjuvant (CFA), and were grouped into: 1) untreated CFA, 2) vehicle treated CFA, 3) IMT504-treated CFA (5 daily (5*) doses of 20, 2 or 0.2 mg/kg, or 3*2 mg/kg). Naive groups were also included. Finally, early (immediately after intraplantar CFA) and late (7 days after intraplantar CFA) IMT504 treatment protocols were also tested. Hindpaw mechanical allodynia, dorsoventral thickness, edema and cellular infiltration of ipsilateral hindpaws were evaluated in all groups. RESULTS: Untreated CFA rats exhibited mechanical allodynia of quick onset (day 1) and long duration (7 weeks inclusive). Early and late treatments with 5*20 mg/kg IMT504 to CFA rats resulted in both quick and long-lasting antiallodynic effects, as compared to untreated CFA rats. This was also the case in CFA rats undergoing late IMT504 treatment at lower doses (3* and 5*2 mg/kg). Very low doses of IMT504 (5*0.2 mg/kg) only showed a mild improvement in withdrawal threshold, never reaching basal levels. Finally, rats treated with 3* or 5*2 mg/kg or 5*0.2 mg/kg exhibited significant decreases in dorsoventral thickness, edema, and inflammatory cell infiltration of the inflamed hindpaw. CONCLUSION: Early and late administration of IMT504 results in quick and long lasting reductions in mechanical allodynia and hindpaw edema. While the mechanisms behind these effects remain to be established, data suggests that IMT504 administration could be a promising strategy in the control of inflammatory pain. PMID- 29248617 TI - Modelling how drivers respond to a bicyclist crossing their path at an intersection: How do test track and driving simulator compare? AB - Bicyclist fatalities are a great concern in the European Union. Most of them are due to crashes between motorized vehicles and bicyclists at unsignalised intersections. Different countermeasures are currently being developed and implemented in order to save lives. One type of countermeasure, active safety systems, requires a deep understanding of driver behaviour to be effective without being annoying. The current study provides new knowledge about driver behaviour which can inform assessment programmes for active safety systems such as Euro NCAP. This study investigated how drivers responded to bicyclists crossing their path at an intersection. The influences of car speed and cyclist speed on the driver response process were assessed for three different crossing configurations. The same experimental protocol was tested in a fixed-base driving simulator and on a test track. A virtual model of the test track was used in the driving simulator to keep the protocol as consistent as possible across testing environments. Results show that neither car speed nor bicycle speed directly influenced the response process. The crossing configuration did not directly influence the braking response process either, but it did influence the strategy chosen by the drivers to approach the intersection. The point in time when the bicycle became visible (which depended on the car speed, the bicycle speed, and the crossing configuration) and the crossing configuration alone had the largest effects on the driver response process. Dissimilarities between test-track and driving-simulator studies were found; however, there were also interesting similarities, especially in relation to the driver braking behaviour. Drivers followed the same strategy to initiate braking, independent of the test environment. On the other hand, the test environment affected participants' strategies for releasing the gas pedal and regulating deceleration. Finally, a mathematical model, based on both experiments, is proposed to characterize driver braking behaviour in response to bicyclists crossing at intersections. This model has direct implications on what variables an in-vehicle safety system should consider and how tests in evaluation programs should be designed. PMID- 29248618 TI - Understanding international road safety disparities: Why is Australia so much safer than the United States? AB - Despite similarities to the US in terms of transportation, land use, and culture, Australia kills 5.3 people per 100,000 population on the roads each year, as compared to the US rate of 12.4. Similar trends hold when accounting for distance driven and the number of registered cars. This paper seeks to understand what is behind the road safety disparities between these two countries. The results suggest that a number of inter-related factors seem to play a role in the better road safety outcomes of Australia as compared to the US. This includes Australia's strategies related to seat belt usage and impaired driving as well as their efforts to help curb vehicle speeds and reduce exposure. Design-related differences include a much greater reliance on roundabouts and narrower street cross-sections as well as guidelines that encourage self-enforcing roads. Policy related differences include stronger and more extensive enforcement programs, restrictive licensing programs, and higher driving costs. Combined with a more urban population and multimodal infrastructure, Australia tends to discourage driving mileage and exposure while encouraging safer modes of transportation such as transit, at least more so than in most of the US. Australia also enacted their version of Vision Zero - called the Safe System Approach - more than a decade before similar policies began cropping up in US cities. While it is difficult to attribute recent road safety successes to any specific policy, Australia continues to expand their lead on the US in terms of safety outcomes and is a road safety example worthy of consideration. PMID- 29248619 TI - A new approach for assessing and training drivers' speed management. AB - Motor vehicle crashes are the leading cause of death and injury for teens and speeding is a major contributor, particularly driving too fast for conditions (CDC, 2015, 2013; NHTSA, 2012; Lam, 2003; McKnight & McKnight, 2003). Speed management is a type of tacit knowledge learned through experience that combines speed perception with decisions about safety. Effective training and assessment of speed management requires a safe method for accumulating practice that includes realistic perceptual cues. This study investigated whether speed can be manipulated in an online environment using special effects technology without distorting speed perception. A forced-choice experiment revealed that drivers' perception of speed was not influenced by the special effects technology, indicating that critical perceptual information was not altered by the speed manipulation of the videos. The experiment also looked at the role of experience in detecting speed differences and found that experienced drivers were able to make judgments about speed more quickly than inexperienced drivers. Implications of these findings for training and assessment are discussed. PMID- 29248620 TI - Interobserver Reliability of the Berlin ARDS Definition and Strategies to Improve the Reliability of ARDS Diagnosis. AB - BACKGROUND: Failure to reliably diagnose ARDS may be a major driver of negative clinical trials and underrecognition and treatment in clinical practice. We sought to examine the interobserver reliability of the Berlin ARDS definition and examine strategies for improving the reliability of ARDS diagnosis. METHODS: Two hundred five patients with hypoxic respiratory failure from four ICUs were reviewed independently by three clinicians, who evaluated whether patients had ARDS, the diagnostic confidence of the reviewers, whether patients met individual ARDS criteria, and the time when criteria were met. RESULTS: Interobserver reliability of an ARDS diagnosis was "moderate" (kappa = 0.50; 95% CI, 0.40 0.59). Sixty-seven percent of diagnostic disagreements between clinicians reviewing the same patient was explained by differences in how chest imaging studies were interpreted, with other ARDS criteria contributing less (identification of ARDS risk factor, 15%; cardiac edema/volume overload exclusion, 7%). Combining the independent reviews of three clinicians can increase reliability to "substantial" (kappa = 0.75; 95% CI, 0.68-0.80). When a clinician diagnosed ARDS with "high confidence," all other clinicians agreed with the diagnosis in 72% of reviews. There was close agreement between clinicians about the time when a patient met all ARDS criteria if ARDS developed within the first 48 hours of hospitalization (median difference, 5 hours). CONCLUSIONS: The reliability of the Berlin ARDS definition is moderate, driven primarily by differences in chest imaging interpretation. Combining independent reviews by multiple clinicians or improving methods to identify bilateral infiltrates on chest imaging are important strategies for improving the reliability of ARDS diagnosis. PMID- 29248622 TI - Partial enteral nutrition increases intestinal sIgA levels in mice undergoing parenteral nutrition in a dose-dependent manner. AB - BACKGROUND AND AIMS: Partial enteral nutrition (PEN) protects parenteral nutrition (PN) induced gut mucosal immunity impairment. However, the gastrointestinal function of most patients with PN is too poor to tolerate full dosage of PEN and no guidelines recommend PEN dose. We aimed to identify an optimal PEN dose and to understand the protective mechanism. METHODS: Mice were assigned to groups with total parenteral nutrition (TPN), total enteral nutrition (TEN), or various degrees of PEN with PN. Additionally, AS1517499 was used to inhibit STAT6. Five days after treatment, secretory immunoglobulin A (sIgA) levels of luminal washing fluid and JAK1-STAT6 signalling in ileum tissue of different groups were assessed. RESULTS: We found that TPN lowered luminal sIgA and down-regulated pIgR, phosphorylated JAK1 and STAT6, IL-4 and IL-13 as well relative to TEN. Moreover, 40% EN were lowest dose that reversed these detrimental consequences of PN to an equivalent level as TEN. The rescue of pIgR and luminal sIgA expression was decreased when the JAK1-STAT6 pathway was inhibited. CONCLUSION: We conclude that 40% EN is the optimal PEN dose that reverses PN-induced impairment of gut mucosal immunity. Additionally, we hypothesise that this benefit involves activation of the JAK1-STAT6 pathway. PMID- 29248623 TI - Surgical site infection following open reduction and internal fixation of a closed ankle fractures: A retrospective multicenter cohort study. PMID- 29248621 TI - Asthma Is a Risk Factor for Respiratory Exacerbations Without Increased Rate of Lung Function Decline: Five-Year Follow-up in Adult Smokers From the COPDGene Study. AB - BACKGROUND: Previous investigations in adult smokers from the COPDGene Study have shown that early-life respiratory disease is associated with reduced lung function, COPD, and airway thickening. Using 5-year follow-up data, we assessed disease progression in subjects who had experienced early-life respiratory disease. We hypothesized that there are alternative pathways to reaching reduced FEV1 and that subjects who had childhood pneumonia, childhood asthma, or asthma COPD overlap (ACO) would have less lung function decline than subjects without these conditions. METHODS: Subjects returning for 5-year follow-up were assessed. Childhood pneumonia was defined by self-reported pneumonia at < 16 years. Childhood asthma was defined as self-reported asthma diagnosed by a health professional at < 16 years. ACO was defined as subjects with COPD who self reported asthma diagnosed by a health-professional at <= 40 years. Smokers with and those without these early-life respiratory diseases were compared on measures of disease progression. RESULTS: Follow-up data from 4,915 subjects were examined, including 407 subjects who had childhood pneumonia, 323 subjects who had childhood asthma, and 242 subjects with ACO. History of childhood asthma or ACO was associated with an increased exacerbation frequency (childhood asthma, P < .001; ACO, P = .006) and odds of severe exacerbations (childhood asthma, OR, 1.41; ACO, OR, 1.42). History of childhood pneumonia was associated with increased exacerbations in subjects with COPD (absolute difference [beta], 0.17; P = .04). None of these early-life respiratory diseases were associated with an increased rate of lung function decline or progression on CT scans. CONCLUSIONS: Subjects who had early-life asthma are at increased risk of developing COPD and of having more active disease with more frequent and severe respiratory exacerbations without an increased rate of lung function decline over a 5-year period. TRIAL REGISTRY: ClinicalTrials.gov; No. NCT00608764; https://clinicaltrials.gov. PMID- 29248624 TI - Association of Surgeons in Training conference: Bournemouth 2017. AB - The Association of Surgeons in Training (ASiT) is a professional body and registered charity working to promote excellence in surgical training for the benefit of junior doctors and patients alike. The Association provides support at both regional and national levels throughout the United Kingdom and Republic of Ireland. Originally founded in 1976, ASiT is independent of the National Health Service (NHS), Surgical Royal Colleges, and specialty associations. The 2017 Annual Conference in Bournemouth brought together over 700 delegates for a diverse educational weekend with numerous expert guest speakers. With a theme of '#AdvancesIn,' we looked to celebrate cutting edge progress in training, clinical management, medical technology, leadership and entrepreneurialism. These updates were complimented by debates on current training in surgery and an array of focussed parallel sessions. For the first time, delegates were also able to interact with the conference digitally, with the debut of our conference smartphone App. The weekend started with 9 pre-conference courses covering a diverse range of topics including core laparoscopic, vascular, orthopaedics, neurosurgical skills, leadership and global surgery. Over 1000 abstract submissions were received and those successful competed for over 30 awards, representing nearly L4000 in trainee prizes and bursaries. As the only national surgical trainee meeting for all specialties, ASiT continues to grow and we look forward to an even larger and more successful international conference next year in Edinburgh 6-8th April 2018 with the theme of #nurturingexcellence. PMID- 29248625 TI - Updated molecular phylogeny of the squid family Ommastrephidae: Insights into the evolution of spawning strategies. AB - Two types of spawning strategy have been described for ommastrephid squids: coastal and oceanic. It has been suggested that ancestral ommastrephids inhabited coastal waters and expanded their distribution into the open ocean during global changes in ocean circulation in the Oligocene. This hypothesis could explain the different reproductive strategies in oceanic squids, but has never been tested in a phylogenetic context. In the present study, we assess the coastal-to-open-ocean hypothesis through inferring the evolution of reproductive traits (spawning type) of ommastrephid squids using the phylogenetic comparative method to estimate ancestral states and divergence times. This analysis was performed using a robust molecular phylogeny with three mitochondrial genes (COI, CYTB and 16S) and two nuclear genes (RHO and 18S) for nearly all species of ommastrephid squid. Our results support dividing the Ommastrephidae into the three traditional subfamilies, plus the monotypic subfamily Todaropsinae as proposed previously. Divergence times were found to be older than those suggested. Our analyses strongly suggest that early ommastrephid squids spawned in coastal areas, with some species subsequently switching to spawn in oceanic areas, supporting previous non-tested hypotheses. We found evidence of gradual evolution change of spawning type in ommastrephid squids estimated to have occurred since the Cretaceous. PMID- 29248626 TI - Vectors of diversity: Genome wide diversity across the geographic range of the Chagas disease vector Triatoma dimidiata sensu lato (Hemiptera: Reduviidae). AB - To date, the phylogeny of Triatoma dimidiata sensu lato (s. l.) (Hemiptera: Reduviidae: Triatominae), the epidemiologically most important Chagas disease vector in Central America and a secondary vector in Mexico and northern South America, has only been investigated by one multi-copy nuclear gene (Internal Transcribed Spacer - 2) and a few mitochondrial genes. We examined 450 specimens sampled across most of its native range from Mexico to Ecuador using reduced representation next-generation sequencing encompassing over 16,000 single nucleotide polymorphisms (SNPs). Using a combined phylogenetic and species delimitation approach we uncovered two distinct species, as well as a well defined third group that may contain multiple species. The findings are discussed with respect to possible drivers of diversification and the epidemiological importance of the distinct species and groups. PMID- 29248627 TI - Species diversity in the marine microturbellarian Astrotorhynchus bifidus sensu lato (Platyhelminthes: Rhabdocoela) from the Northeast Pacific Ocean. AB - Increasing evidence suggests that many widespread species of meiofauna are in fact regional complexes of (pseudo-)cryptic species. This knowledge has challenged the 'Everything is Everywhere' hypothesis and also partly explains the meiofauna paradox of widespread nominal species with limited dispersal abilities. Here, we investigated species diversity within the marine microturbellarian Astrotorhynchus bifidus sensu lato in the Northeast Pacific Ocean. We used a multiple-evidence approach combining multi-gene (18S, 28S, COI) phylogenetic analyses, several single-gene and multi-gene species delimitation methods, haplotype networks and conventional taxonomy to designate Primary Species Hypotheses (PSHs). This included the development of rhabdocoel-specific COI barcode primers, which also have the potential to aid in species identification and delimitation in other rhabdocoels. Secondary Species Hypotheses (SSHs) corresponding to morphospecies and pseudo-cryptic species were then proposed based on the minimum consensus of different PSHs. Our results showed that (a) there are at least five species in the A. bifidus complex in the Northeast Pacific Ocean, four of which can be diagnosed based on stylet morphology, (b) the A. bifidus complex is a mixture of sympatric and allopatric species with regional and/or subglobal distributions, (c) sympatry occurs on local (sample sites), regional (Northeastern Pacific) and subglobal (Northern Atlantic, Arctic, Northeastern Pacific) scales. Mechanisms for this co-occurrence are still poorly understood, but we hypothesize they could include habitat differentiation (spatial and/or seasonal) and life history characteristics such as sexual selection and dispersal abilities. Our results also suggest the need for improved sampling and exploration of molecular markers to accurately map gene flow and broaden our understanding of species diversity and distribution of microturbellarians in particular and meiofauna in general. PMID- 29248628 TI - Systematic review of smartphone-based passive sensing for health and wellbeing. AB - OBJECTIVE: To review published empirical literature on the use of smartphone based passive sensing for health and wellbeing. MATERIAL AND METHODS: A systematic review of the English language literature was performed following PRISMA guidelines. Papers indexed in computing, technology, and medical databases were included if they were empirical, focused on health and/or wellbeing, involved the collection of data via smartphones, and described the utilized technology as passive or requiring minimal user interaction. RESULTS: Thirty-five papers were included in the review. Studies were performed around the world, with samples of up to 171 (median n = 15) representing individuals with bipolar disorder, schizophrenia, depression, older adults, and the general population. The majority of studies used the Android operating system and an array of smartphone sensors, most frequently capturing accelerometry, location, audio, and usage data. Captured data were usually sent to a remote server for processing but were shared with participants in only 40% of studies. Reported benefits of passive sensing included accurately detecting changes in status, behavior change through feedback, and increased accountability in participants. Studies reported facing technical, methodological, and privacy challenges. DISCUSSION: Studies in the nascent area of smartphone-based passive sensing for health and wellbeing demonstrate promise and invite continued research and investment. Existing studies suffer from weaknesses in research design, lack of feedback and clinical integration, and inadequate attention to privacy issues. Key recommendations relate to developing passive sensing strategies matching the problem at hand, using personalized interventions, and addressing methodological and privacy challenges. CONCLUSION: As evolving passive sensing technology presents new possibilities for health and wellbeing, additional research must address methodological, clinical integration, and privacy issues. Doing so depends on interdisciplinary collaboration between informatics and clinical experts. PMID- 29248629 TI - Polymeric immunoglobulin receptor in dojo loach (Misgurnus anguillicaudatus): Molecular characterization and expression analysis in response to bacterial and parasitic challenge. AB - The polymeric immunoglobulin receptor (pIgR) is an essential component of the mucosal immune system in jawed vertebrates including teleost fish, which mediate transepithelial transport of secretory immunoglobulins (sIgs) to protect organisms against environmental pathogens. In this study, we firstly cloned and identified the pIgR from dojo loach (Misgurnus anguillicaudatus). The full-length cDNA of Ma-pIgR was of 1145 bp, containing an open reading frame (ORF) of 1101 bp encoded a predicted protein of 336 amino acids. The structure of Ma-pIgR is comprised of a signal peptide, a transmembrane region, an intracellular region and an extracellular region with two Ig-like domains (ILDs), which are similar to their counterparts described in other teleosts. Multiple sequence alignment and phylogenetic analysis showed the dojo loach is closely related to the fish family Cyprinidae. The transcriptional level of Ma-pIgR was detected by quantitative real-time PCR (qRT-PCR) in different tissues and high expression was found in liver, skin, kidney, eye, fin and gills. Two infection models of the loach with bacteria (Aeromonas hydrophila) and parasite (Ichthyophthirius multifiliis) were constructed for the first time. Histological studies showed the goblet cells in skin significantly increased and the ratio of gill length to width also significantly changed after challenged with A.hydrophila. Both challenge experiments resulted in the significant up-regulated expression of Ma-pIgR not only in kidney and spleen, but also in skin and gills. Our results suggest that pIgR may play an important role in skin and gill mucosal immunity to protect the loach against bacteria and parasite. PMID- 29248630 TI - Cortical slow wave activity correlates with striatal synaptic strength in normal but not in Parkinsonian rats. AB - Urethane-induced cortical slow wave activity (SWA) spreads into the basal ganglia in dopamine (DA)-depleted rat models of Parkinson's disease (PD). During physiological sleep, SWA is powerfully expressed at the beginning of night and progressively reduced during sleep-time reflecting the sleep need. However, its underlying slow oscillations may contribute directly to modulate cortical plasticity. In order to determine the impact of the SWA on synaptic strength and its interplay with DA, we simultaneously recorded the electrocorticogram (ECoG) and the corticocortical- and corticostriatal-evoked potentials (CC-EPs, CS-EPs) during eight hours of robust urethane-induced SWA in both normal and PD animals. A subgroup of PD rats was assessed with repetitive apomorphine (APO) administrations. Normal animals showed a progressive reduction of SWA power during urethane-induced SWA. Compared to normal animals, PD animals showed lower SWA power at the start of anesthesia without a significant reduction over time. Accordingly, synaptic strength measured by CC- and CS-EP amplitudes decreased in normal but not in Parkinsonian rats. The PD animals treated with APO showed a CS EP amplitude reduction comparable to normal animals. Interestingly, SWA power directly correlated with CS-EP amplitude in normal animals. These data support the hypothesis that cortical SWA is directly associated with the regulation of synaptic efficacy in which DA exerts a crucial role. PMID- 29248631 TI - An integrative perspective of the anaerobic threshold. AB - The concept of anaerobic threshold (AT) was introduced during the nineteen sixties. Since then, several methods to identify the anaerobic threshold (AT) have been studied and suggested as novel 'thresholds' based upon the variable used for its detection (i.e. lactate threshold, ventilatory threshold, glucose threshold). These different techniques have brought some confusion about how we should name this parameter, for instance, anaerobic threshold or the physiological measure used (i.e. lactate, ventilation). On the other hand, the modernization of scientific methods and apparatus to detect AT, as well as the body of literature formed in the past decades, could provide a more cohesive understanding over the AT and the multiple physiological systems involved. Thus, the purpose of this review was to provide an integrative perspective of the methods to determine AT. PMID- 29248632 TI - Measuring physiological stress in the common marmoset (Callithrix jacchus): Validation of a salivary cortisol collection and assay technique. AB - Cortisol levels are often used as a physiological measure of the stress response in captive primates, with non-invasive measures of this being an important step in welfare assessment. We report a method of collecting saliva samples voluntarily from unrestrained captive common marmosets (Callithrix jacchus), and validate an enzyme-linked immunosorbent assay (ELISA) technique previously unused in this species. Saliva samples were collected from marmosets housed in pairs in a UK laboratory. The assay showed parallelism, precision, accuracy and sensitivity, meeting the criteria typically used to investigate the effectiveness of new analytical techniques. Use of Salimetrics(r) Oral Swabs considerably increased the amount of cortisol recovered in comparison with previous studies using cotton buds. However, while use of banana on the swabs can encourage chewing, it may influence results. Although increases in cortisol levels have traditionally been interpreted as an indicator of stress in primates, there are many factors that affect the hypothalamic-pituitary-adrenal axis, with some studies showing decreases in cortisol levels post-stressor. Following a likely stressful event (capture for weighing), we also found cortisol levels significantly decreased, possibly due to social buffering or 'blunting' of the HPA axis. Order of weighing also had an effect. The method therefore provided an effective non-invasive means of assessing acute changes in cortisol level that may be more useful than previous methods, improving our ability to study physiological aspects of welfare in primates. We discuss methodological considerations, as well as implications of using cortisol as a measure of stress. PMID- 29248633 TI - Effects of non-contingent cocaine on 3alpha-androstanediol. I. Disruption of male sexual behavior. AB - One of the hallmarks of drug abuse is a reduction in the salience of, and motivation for, natural rewards, such as mating. The effects of psychostimulants on male sexual interest and performance are conflicting; use of psychostimulants can produce increases in risky sexual behaviors but have detrimental effects on sexual ability. We hypothesize that these conflicting effects on sexual behavior are due to interactions between cocaine and androgens, such as testosterone and its neuroactive metabolite, 3alpha-androstanediol (3alpha-diol). Male rats were administered saline or cocaine (5, 10, or 20mg/kg, i.p.). Motor behavior was observed in the first 30min following drug-administration, and then sexual responding was assessed for 15min. Levels of androgens (testosterone, 3alpha diol, and testosterone's aromatized metabolite, estradiol) were measured in circulation and brain regions (frontal cortex, hippocampus, hypothalamus/striatum (hypo/str), and midbrain). Cocaine had no effect on measures of sexual interest (i.e. anogenital investigation). However, cocaine had substantial effects on consummatory sexual behaviors, such as the latency to mount/intromit and the number of sexual contacts. Frontal cortex and hypo/str 3alpha-diol levels were strongly correlated with consummatory behaviors in saline administered rats; however, this relationship was disrupted by cocaine at all dosages, concomitant with impaired sexual behaviors. Additionally, there was a shift in metabolism at low dosages of cocaine to push testosterone metabolism in the midbrain towards 3alpha-diol. On the contrary, moderate and high dosages of cocaine shifted testosterone metabolism towards estradiol. These data demonstrate that the association between cortical and hypo/str 3alpha-diol levels and sexual behavior of male rats is disrupted by non-contingent cocaine and that there may be dose dependent effects of acute cocaine on androgen metabolism. PMID- 29248634 TI - New concepts in Chlamydia induced inflammasome responses. AB - Since the concept of the inflammasome was introduced by Martinon, Burns and Tschopp in 2002, there has been an exponential increase in our understanding of how inflammasomes (caspase activating molecular platforms) regulate innate inflammatory responses to infectious microorganisms. Advances in understanding inflammasome biology have been developed using a range of bacterial pathogens. Recent studies investigating inflammasome responses during Chlamydia infection have provided interesting mechanistic insights in to inflammasome activation during intracellular bacterial infection. This review highlights new concepts regulating inflammasome activation to bacterial infections including: interferon regulated loss of compartmentalisation, mechanisms of canonical and non-canonical inflammasome activation and their relevance to Chlamydia infections are discussed. PMID- 29248636 TI - I love you Toxoplasma gondii. PMID- 29248635 TI - Immunological bases of increased susceptibility to invasive nontyphoidal Salmonella infection in children with malaria and anaemia. AB - Malaria and anaemia are key underlying factors for iNTS disease in African children. Knowledge of clinical and epidemiological risk-factors for iNTS disease has not been paralleled by an in-depth knowledge of the immunobiology of the disease. Herein, we review human and animal studies on mechanisms of increased susceptibility to iNTS in children. PMID- 29248637 TI - Size matters - how the immune system deals with fungal hyphae. AB - Fungal hyphae constitute a special challenge for the immune system, since they are too large to be phagocytosed. This review summarizes our current knowledge on those immune cells that are able to attack and eliminate hyphae and we discuss the different means that are employed by these cells in order to kill hyphae. PMID- 29248638 TI - Peptide and peptide-carbon nanotube hydrogels as scaffolds for tissue & 3D tumor engineering. AB - : The use of hybrid self-assembling peptide (EFK8)-carbon nanotube (SWNT) hydrogels for tissue engineering and in vitro 3D cancer spheroid formation is reported. These hybrid hydrogels are shown to enhance the attachment, spreading, proliferation and movement of NIH-3T3 cells relative to that observed using EFK8 only hydrogels. After five days, ~30% more cells are counted when the hydrogel contains SWNTs. Also, 3D encapsulation of these cells when injected in hydrogels does not adversely affect their behavior. Compressive modulus measurements and microscopic examination suggest that SWNTs have this beneficial effect by providing sites for cell anchorage, spreading and movement rather than by increasing hydrogel stiffness. This shows that the cells have a particular interaction with SWNTs not shared with EFK8 nanofibers despite a similar morphology. The effect of EFK8 and EFK8-SWNT hydrogels on A549 lung cancer cell behavior is also investigated. Increasing stiffness of EFK8-only hydrogels from about 44 Pa to 104 Pa promotes a change in A549 morphology from spheroidal to a stretched one similar to migratory phenotype. EFK8-SWNT hydrogels also promote a stretched morphology, but at lower stiffness. These results are discussed in terms of the roles of both microenvironment stiffness and cell-scaffold adhesion in cancer cell invasion. Overall, this study demonstrates that applications of peptide hydrogels in vitro can be expanded by incorporating SWNTs into their structure which further provides insight into cell-biomaterial interactions. STATEMENT OF SIGNIFICANCE: For the first time we used hybrid self-assembling peptide-carbon nanotube hybrid hydrogels (that we have recently introduced briefly in the "Carbon" journal in 2014) for tissue engineering and 3D tumor engineering. We showed the potential of these hybrid hydrogels to enhance the efficiency of the peptide hydrogels for tissue engineering application in terms of cell behavior (cell attachment, spreading and migration). This opens up new rooms for the peptide hydrogels and can expand their applications. Also our system (peptide and peptide-CNT hydrogels) was used for cancer cell spheroid formation showing the effect of both tumor microenvironment stiffness and cell scaffold adhesion on cancer cell invasion. This was only possible based on the presence of CNTs in the hydrogel while the stiffness kept constant. Finally it should be noted that these hybrid hydrogels expand applications of peptide hydrogels through enhancing their capabilities and/or adding new properties to them. PMID- 29248639 TI - The limiting layer of fish scales: Structure and properties. AB - : Fish scales serve as a flexible natural armor that have received increasing attention across the materials community. Most efforts in this area have focused on the composite structure of the predominately organic elasmodine, and limited work addresses the highly mineralized external portion known as the Limiting Layer (LL). This coating serves as the first barrier to external threats and plays an important role in resisting puncture. In this investigation the structure, composition and mechanical behavior of the LL were explored for three different fish, including the arapaima (Arapaima gigas), the tarpon (Megalops atlanticus) and the carp (Cyprinus carpio). The scales of these three fish have received the most attention within the materials community. Features of the LL were evaluated with respect to anatomical position to distinguish site-specific functional differences. Results show that there are significant differences in the surface morphology of the LL from posterior and anterior regions in the scales, and between the three fish species. The calcium to phosphorus ratio and the mineral to collagen ratios of the LL are not equivalent among the three fish. Results from nanoindentation showed that the LL of tarpon scales is the hardest, followed by the carp and the arapaima and the differences in hardness are related to the apatite structure, possibly induced by the growth rate and environment of each fish. STATEMENT OF SIGNIFICANCE: The natural armor of fish, turtles and other animals, has become a topic of substantial scientific interest. The majority of investigations have focused on the more highly organic layer known as the elasmodine. The present study addresses the highly mineralized external portion known as the Limiting Layer (LL). Specifically, the structure, composition and mechanical behavior of the LL were explored for three different fish, including the arapaima (Arapaima gigas), the tarpon (Megalops atlanticus) and the carp (Cyprinus carpio). Results show that there are significant differences in the surface morphology of the LL from posterior and anterior regions in the scales, and between the three species. In addition, the composition of the LL is also unique among the three fish. Results from nanoindentation showed that the LL of tarpon scales is the hardest, followed by the carp and the arapaima and the differences in hardness are related to the apatite structure, possibly induced by the growth rate and environment of each fish. In addition, a new feature was indentified in the LL, which has not been discussed before. As such, we feel this work is unique and makes a significant contribution to the field. PMID- 29248640 TI - Association of Active and Passive Components of LV Diastolic Filling With Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Mechanistic Insights From Spironolactone Response. AB - OBJECTIVES: This study sought to investigate the association of left ventricular (LV) untwisting rate (UT) and E/e' ratio with the response of exercise capacity to spironolactone in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: In most patients with HFpEF, LV filling abnormalities represent a central component in the development of dyspnea. LV diastolic filling is determined by the interplay of passive (LV stiffness and myocardial collagen content, reflected by E/e' ratio) and active myocardial properties (UT, a precursor to isovolumic pressure decay and contributor to diastolic suction). METHODS: In 194 patients with HFpEF (64 +/- 8 years), a complete echocardiogram (including assessment of myocardial deformation and rotational mechanics) was performed. Echocardiography following maximal exercise was undertaken to assess LV systolic and diastolic responses to stress. A subset of 105 patients with an exercise-induced increase in estimated LV filling pressure were randomly assigned to spironolactone 25 mg (n = 51) or placebo (n = 54) for 6 months. RESULTS: Baseline peak Vo2 was associated with UT (beta = 0.19; p = 0.01) and E/e' (beta = -0.16; p = 0.03), independent of clinical data and exercise reserve in longitudinal deformation and ventricular-arterial coupling. An increase in peak Vo2 with treatment was independently associated with changes in UT (beta = 0.28; p = 0.003) and exertional increase in E/e' (beta = -0.23; p = 0.01) from baseline to follow-up. A significant interaction with the use of spironolactone on peak Vo2 was found for E/e' (p = 0.02) but not for UT (p = 0.62). CONCLUSIONS: Both active and passive determinants of LV filling, as reflected by UT and E/e', contribute to reduced exercise capacity in HFpEF. Improvement in functional capacity with a 6-month therapy with spironolactone is associated with improvements in both indices. However, the possible mediating effect of this medication is observed only on E/e'. PMID- 29248641 TI - Improving Plaque Classification With Optical Coherence Tomography. PMID- 29248642 TI - Dark-Blood Late-Enhancement Imaging Improves Detection of Myocardial Infarction. PMID- 29248643 TI - The Shape of Imaging in the Future: Lessons Learned From the CRESCENT II Trial. PMID- 29248644 TI - Muller Maneuver as a Tool for Stress Echocardiography: Evaluation of Exercise Capacity in Patients With Dilated Cardiomyopathy. PMID- 29248645 TI - Diagnostic Value of Transluminal Attenuation Gradient for the Presence of Ischemia as Defined by Fractional Flow Reserve and Quantitative Positron Emission Tomography. AB - OBJECTIVES: The aim of this study was to investigate the incremental diagnostic value of transluminal attenuation gradient (TAG), TAG with corrected contrast opacification (TAG-CCO), and transluminal diameter gradient (TDG) over coronary computed tomography angiography (CTA)-derived diameter stenosis alone for the identification of ischemia as defined by both the invasive reference standard fractional flow reserve (FFR) and the noninvasive reference standard quantitative positron emission tomography (PET). BACKGROUND: In addition to anatomic information obtained by coronary CTA, several functional CT parameters have been proposed to identify hemodynamically significant lesions more accurately, such as TAG, TAG-CCO, and more recently TDG. However, clinical validation studies have reported conflicting results, and a recent study has suggested that TAG may be affected by changes in vessel diameter. METHODS: Patients with suspected coronary artery disease underwent coronary CTA and [15O]H2O PET followed by invasive coronary angiography with FFR of all major coronary arteries. TAG, TAG-CCO, and TDG were assessed, and the incremental diagnostic value of these parameters over coronary CTA-derived diameter stenosis alone for ischemia as defined by PET (hyperemic myocardial blood flow <=2.30 ml/min/g) and FFR (<=0.80) was determined. RESULTS: A total of 557 (91.9%) coronary arteries of 201 patients were included for analysis. TAG, TAG-CCO, and TDG did not discriminate between vessels with or without ischemia as defined by either PET or FFR. Furthermore, these parameters did not have incremental diagnostic accuracy over coronary CTA alone for the presence of ischemia as defined by PET and FFR. There was a significant correlation between TDG and TAG (r = 0.47; p < 0.001) and between TDG and TAG-CCO (r = 0.37; p < 0.001). CONCLUSIONS: TAG, TAG-CCO, and TDG do not provide incremental diagnostic value over coronary CTA alone for the presence of ischemia as defined by [15O]H2O PET and/or FFR. The lack of diagnostic value of contrast enhancement-based flow estimations appears related to coronary luminal dimension variability. PMID- 29248647 TI - Emerging Sex Differences in Aortic Stenosis. PMID- 29248646 TI - Symptom Onset in Aortic Stenosis: Relation to Sex Differences in Left Ventricular Remodeling. AB - OBJECTIVES: The aim of this study was to establish sex differences in remodeling and outcome in aortic stenosis (AS) and their associations with biomarkers of myocardial fibrosis. BACKGROUND: The remodeling response and timing of symptoms is highly variable in AS, and sex plays an important role. METHODS: A total of 174 patients (133 men, mean age 66.2 +/- 13.3 years) with asymptomatic moderate to severe AS underwent comprehensive stress cardiac magnetic resonance imaging, transthoracic echocardiography, and biomarker analysis (matrix metalloproteinase [MMP]-2, -3, -7, -8, and -9; tissue inhibitor matrix metalloproteinases-1 and -4; syndecan-1 and -4; and N-terminal pro-B-type natriuretic peptide), and were followed up at 6-month intervals. A primary endpoint was a composite of typical AS symptoms necessitating referral for aortic valve replacement, cardiovascular death, or major adverse cardiovascular events. RESULTS: For a similar severity of AS, male patients demonstrated higher indexed left ventricular (LV) volumes and mass, more concentric remodeling (higher LV mass/volume), a trend to more late gadolinium enhancement (present in 51.1% men vs. 34.1% women; p = 0.057), and higher extracellular volume index than female patients (13.27 [interquartile range (IQR): 11.5 to 17.0] vs. 11.53 [IQR: 10.5 to 13.5] ml/m2, p = 0.017), with worse systolic and diastolic function and higher MMP-3 and syndecan-4 levels, whereas female patients had higher septal E/e'. Male sex was independently associated with indexed LV mass (beta = 13.32 [IQR: 9.59 to 17.05]; p < 0.001). During median follow-up of 374 (IQR: 351 to 498) days, a primary outcome, driven by spontaneous symptom onset, occurred in 21.8% of male and 43.9% of female patients (relative risk: 0.50 [95% confidence interval: 0.31 to 0.80]; p = 0.004). Measures of AS severity were associated with the primary outcome in both sexes, whereas N-terminal pro-B-type natriuretic peptide, MMP-3, and mass/volume were only associated in men. CONCLUSIONS: In AS, women tolerate pressure overload with less concentric remodeling and myocardial fibrosis but are more likely to develop symptoms. This may be related to higher wall stress and filling pressures in women. PMID- 29248648 TI - Atrial Fibrillation Begets Mitral Regurgitation, or Is it Vice Versa? PMID- 29248650 TI - Is Global Longitudinal Strain a Superior Parameter for Predicting Outcome After Myocardial Infarction? PMID- 29248649 TI - Prognostic Value of Strain by Tissue Tracking Cardiac Magnetic Resonance After ST Segment Elevation Myocardial Infarction. AB - OBJECTIVES: The aim of this study was to evaluate the prognostic value of strain as assessed by tissue tracking (TT) cardiac magnetic resonance (CMR) soon after ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The prognostic value of myocardial strain as assessed post-STEMI by TT-CMR is unknown. METHODS: The authors studied the prognostic value of TT-CMR in 323 patients who underwent CMR 1 week post-STEMI. Global (average of peak segmental values [%]) and segmental (number of altered segments) longitudinal (LS), circumferential, and radial strain were assessed using TT-CMR. Global and segmental strain cutoff values were derived from 32 control patients. CMR-derived left ventricular ejection fraction, microvascular obstruction, and infarct size were determined. Results were validated in an external cohort of 190 STEMI patients. RESULTS: During a median follow-up of 1,085 days, 54 first major adverse cardiac events (MACE), which included 10 cardiac deaths, 25 readmissions for heart failure, and 19 readmissions for reinfarction were documented. MACE was associated with more severe abnormalities in all strain indexes (p < 0.001), although only global LS was an independent predictor (p < 0.001). The MACE rate was higher in patients with a global LS of >=-11% (22% vs. 9%; p = 0.001). After adjustment for baseline and CMR variables, global LS (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.11 to 1.32; p < 0.001) was associated with MACE. In the external validation cohort, a global LS >=-11% was seen in a higher proportion of patients with MACE (34% vs. 9%; p < 0.001). Global LS predicted MACE after adjustment for baseline and CMR variables (HR: 1.18; 95% CI: 1.04 to 1.33; p = 0.008). The addition of global LS to the multivariate models, including baseline and CMR variables, did not significantly improve the categorical net reclassification improvement index in either the study group (-0.015; p = 0.7) or in the external validation cohort (-0.019; p = 0.9). CONCLUSIONS: TT-CMR provided prognostic information soon after STEMI. However, it did not substantially improve risk reclassification beyond traditional CMR indexes. PMID- 29248651 TI - From Lab to Life: Cardiac Biomarker Measurement in the Intact Heart by Means of Hyperpolarized 13C-Carbon CMR. PMID- 29248652 TI - High Frame-Rate Contrast Echocardiography: In-Human Demonstration. PMID- 29248654 TI - Value of Myocardial Perfusion Assessment With Coronary Computed Tomography Angiography in Patients With Recent Acute-Onset Chest Pain. AB - OBJECTIVES: The authors sought to perform a randomized controlled trial to evaluate the clinical efficacy of combined examination with coronary computed tomography angiography (CTA) and computed tomography perfusion imaging (CTP) compared to coronary CTA alone. BACKGROUND: Stress myocardial CTP may increase diagnostic specificity when added to coronary CTA in patients suspected of having ischemic heart disease. METHODS: Patients recently hospitalized for acute-onset chest pain, who had acute coronary syndrome had been ruled out by normal electrocardiograms, normal troponin levels, and relief of symptoms, and who had a clinical indication for outpatient noninvasive testing, were screened for inclusion in the CATCH-2 (CArdiac cT in the treatment of acute CHest pain 2) trial (NCT02014311). Patients were randomized 1:1 to examination with coronary CTA or coronary CTA+CTP. The primary endpoint was the frequency of coronary revascularization among patients referred for invasive coronary angiography (ICA) based on index computed tomography evaluation. Secondary endpoints were invasive procedural complications at index-related ICA, post-index cardiac death, hospital admittance because of recurrence of chest pain, unstable angina pectoris, or acute myocardial infarction, ICA, and revascularization. RESULTS: Among 300 patients allocated to the coronary CTA+CTP group, 41 (14%) were referred for ICA compared with 89 (30%) allocated to coronary CTA (p < 0.0001). The primary endpoint occurred in 50% of coronary CTA+CTP patients versus 48% of invasively examined patients (p = 0.85). The total number of revascularizations was significantly lower in the coronary CTA+CTP group compared to the coronary CTA group (n = 20 [7%] vs. n = 42 [14%]; p = 0.0045). At median follow-up of 1.5 years, the occurrence of secondary endpoints was similar in the 2 groups. CONCLUSIONS: A post-discharge diagnostic strategy of coronary CTA+CTP safely reduces the need for invasive examination and treatment in patients suspected of having ischemic heart disease. (CArdiac cT in the treatment of acute CHest pain 2 Myocardial CT Perfusion [CATCH2]; NCT02014311). PMID- 29248653 TI - Hyperpolarized [1,4-13C2]Fumarate Enables Magnetic Resonance-Based Imaging of Myocardial Necrosis. AB - OBJECTIVES: The aim of this study was to determine if hyperpolarized [1,4 13C2]malate imaging could measure cardiomyocyte necrosis after myocardial infarction (MI). BACKGROUND: MI is defined by an acute burst of cellular necrosis and the subsequent cascade of structural and functional adaptations. Quantifying necrosis in the clinic after MI remains challenging. Magnetic resonance-based detection of the conversion of hyperpolarized [1,4-13C2]fumarate to [1,4 13C2]malate, enabled by disrupted cell membrane integrity, has measured cellular necrosis in vivo in other tissue types. Our aim was to determine whether hyperpolarized [1,4-13C2]malate imaging could measure necrosis after MI. METHODS: Isolated perfused hearts were given hyperpolarized [1,4-13C2]fumarate at baseline, immediately after 20 min of ischemia, and after 45 min of reperfusion. Magnetic resonance spectroscopy measured conversion into [1,4-13C2]malate. Left ventricular function and energetics were monitored throughout the protocol, buffer samples were collected and hearts were preserved for further analyses. For in vivo studies, magnetic resonance spectroscopy and a novel spatial-spectral magnetic resonance imaging sequence were implemented to assess cardiomyocyte necrosis in rats, 1 day and 1 week after cryo-induced MI. RESULTS: In isolated hearts, [1,4-13C2]malate production became apparent after 45 min of reperfusion, and increased 2.7-fold compared with baseline. Expression of dicarboxylic acid transporter genes were negligible in healthy and reperfused hearts, and lactate dehydrogenase release and infarct size were significantly increased in reperfused hearts. Nonlinear regression revealed that [1,4-13C2]malate production was induced when adenosine triphosphate was depleted by >50%, below 5.3 mmol/l (R2 = 0.904). In vivo, the quantity of [1,4-13C2]malate visible increased 82-fold over controls 1 day after infarction, maintaining a 31-fold increase 7 days post infarct. [1,4-13C2]Malate could be resolved using hyperpolarized magnetic resonance imaging in the infarct region one day after MI; [1,4-13C2]malate was not visible in control hearts. CONCLUSIONS: Malate production in the infarcted heart appears to provide a specific probe of necrosis acutely after MI, and for at least 1 week afterward. This technique could offer an alternative noninvasive method to measure cellular necrosis in heart disease, and warrants further investigation in patients. PMID- 29248655 TI - Dark-Blood Delayed Enhancement Cardiac Magnetic Resonance of Myocardial Infarction. AB - OBJECTIVES: This study introduced and validated a novel flow-independent delayed enhancement technique that shows hyperenhanced myocardium while simultaneously suppressing blood-pool signal. BACKGROUND: The diagnosis and assessment of myocardial infarction (MI) is crucial in determining clinical management and prognosis. Although delayed enhancement cardiac magnetic resonance (DE-CMR) is an in vivo reference standard for imaging MI, an important limitation is poor delineation between hyperenhanced myocardium and bright LV cavity blood-pool, which may cause many infarcts to become invisible. METHODS: A canine model with pathology as the reference standard was used for validation (n = 22). Patients with MI and normal controls were studied to ascertain clinical performance (n = 31). RESULTS: In canines, the flow-independent dark-blood delayed enhancement (FIDDLE) technique was superior to conventional DE-CMR for the detection of MI, with higher sensitivity (96% vs. 85%, respectively; p = 0.002) and accuracy (95% vs. 87%, respectively; p = 0.01) and with similar specificity (92% vs, 92%, respectively; p = 1.0). In infarcts that were identified by both techniques, the entire length of the endocardial border between infarcted myocardium and adjacent blood-pool was visualized in 33% for DE-CMR compared with 100% for FIDDLE. There was better agreement for FIDDLE-measured infarct size than for DE-CMR infarct size (95% limits-of-agreement, 2.1% vs. 5.5%, respectively; p < 0.0001). In patients, findings were similar. FIDDLE demonstrated higher accuracy for diagnosis of MI than DE-CMR (100% [95% confidence interval [CI]: 89% to 100%] vs. 84% [95% CI: 66% to 95%], respectively; p = 0.03). CONCLUSIONS: The study introduced and validated a novel CMR technique that improves the discrimination of the border between infarcted myocardium and adjacent blood-pool. This dark blood technique provides diagnostic performance that is superior to that of the current in vivo reference standard for the imaging diagnosis of MI. PMID- 29248656 TI - Myocardial Fibrosis in Competitive Triathletes Detected by Contrast-Enhanced CMR Correlates With Exercise-Induced Hypertension and Competition History. AB - OBJECTIVES: This study analyzed the presence of myocardial fibrosis detected by late gadolinium-enhancement (LGE) cardiac magnetic resonance (CMR) in correlation with the performance of competitive triathletes objectified by an exercise test and individual competition history. BACKGROUND: Myocardial fibrosis detected by LGE CMR has been reported to occur in 0% to 50% of asymptomatic athletes. However, the cause and mechanisms of myocardial fibrosis are unclear. METHODS: Eighty-three asymptomatic triathletes undergoing >10 training h per week (43 +/- 10 years of age; 65% male) and 36 sedentary controls were studied by using LGE and extracellular volume (ECV) CMR. Parameters of physical fitness were measured by spiroergometry. Triathletes reported their lifetime competition results. RESULTS: LGE CMR revealed focal nonischemic myocardial fibrosis in 9 of 54 (17%) male triathletes (LGE+) but in none of the female triathletes (p < 0.05). LGE+ triathletes had higher peak exercise systolic blood pressure (213 +/- 24 mm Hg) than LGE- triathletes (194 +/- 26 mm Hg; p < 0.05). Furthermore, left ventricular mass index was higher in LGE+ triathletes (93 +/- 7 g/m2) than in LGE- triathletes (84 +/- 11 g/m2; p < 0.05). ECV in LGE- myocardium was higher in LGE+ triathletes (26.3 +/- 1.8%) than in LGE- triathletes (24.4 +/- 2.2%; p < 0.05). LGE+ triathletes completed longer cumulative distances in swimming and cycling races and participated more often in middle and Iron Man distances than LGE- triathletes. A cycling race distance of >1,880 km completed during competition had the highest accuracy to predict LGE, with an area under the curve value of 0.876 (p < 0.0001), resulting in high sensitivity (89%) and specificity (79%). Multivariate analysis identified peak exercise systolic blood pressure (p < 0.05) and the swimming race distance (p < 0.01) as independent predictors of LGE presence. CONCLUSIONS: Myocardial fibrosis in asymptomatic triathletes seems to be associated with exercise-induced hypertension and the race distances. There appears to be a safe upper limit, beyond which exercise may result in myocardial fibrosis. PMID- 29248657 TI - Comprehensive Cardiac CT With Myocardial Perfusion Imaging Versus Functional Testing in Suspected Coronary Artery Disease: The Multicenter, Randomized CRESCENT-II Trial. AB - OBJECTIVES: This study sought to assess the effectiveness, efficiency, and safety of a tiered, comprehensive cardiac computed tomography (CT) protocol in comparison with functional testing. BACKGROUND: Although CT angiography accurately rules out coronary artery disease (CAD), incorporation of CT myocardial perfusion imaging as part of a tiered diagnostic approach could improve the clinical value and efficiency of cardiac CT in the diagnostic work-up of patients with angina pectoris. METHODS: Between July 2013 and November 2015, 268 patients (mean age 58 years; 49% female) with stable angina (mean pre-test probability 54%) were prospectively randomized between cardiac CT and standard guideline-directed functional testing (95% exercise electrocardiography). The tiered cardiac CT protocol included a calcium scan, followed by CT angiography if calcium was detected. Patients with >=50% stenosis on CT angiography underwent CT myocardial perfusion imaging. RESULTS: By 6 months, the primary endpoint, the rate of invasive coronary angiograms without a European Society of Cardiology class I indication for revascularization, was lower in the CT group than in the functional testing group (2 of 130 [1.5%] vs. 10 of 138 [7.2%]; p = 0.035), whereas the proportion of invasive angiograms with a revascularization indication was higher (88% vs. 50%; p = 0.017). The median duration until the final diagnosis was 0 (0 of 0) days in the CT group and 0 (0 of 17) in the functional testing group (p < 0.001). Overall, 13% of patients randomized to CT required further testing, compared with 37% in the functional testing group (p < 0.001). The adverse event rate was similar (3% vs. 3%; p = 1.000), although the median cumulative radiation dose was higher for the CT group (3.1 mSv [interquartile range: 1.6 to 7.8] vs. 0 mSv [interquartile range: 0.0 to 7.1]; p < 0.001). CONCLUSIONS: In patients with suspected stable CAD, a tiered cardiac CT protocol with dynamic perfusion imaging offers a fast and efficient alternative to functional testing. (Comprehensive Cardiac CT Versus Exercise Testing in Suspected Coronary Artery Disease 2 [CRESCENT2]; NCT02291484). PMID- 29248658 TI - Topographic Pattern of Valve Calcification: A New Determinant of Disease Severity in Aortic Valve Stenosis. PMID- 29248659 TI - Intraluminal Assessment of Coronary Arteries With Ferumoxytol-Enhanced Magnetic Resonance Angiography. PMID- 29248660 TI - Myocardial Metabolism in Endurance Exercise-Induced Left Ventricular Hypertrophy. PMID- 29248661 TI - Mitral Valve Adaptation to Isolated Annular Dilation: Insights Into the Mechanism of Atrial Functional Mitral Regurgitation. AB - OBJECTIVES: This study hypothesized that compensatory mitral leaflet area (MLA) adaptation occurs in patients with persistent atrial fibrillation (AF) without left ventricular (LV) dysfunction but has limitations that augment mitral regurgitation (MR). The study also explored whether asymmetrical annular dilation is matched by relative leaflet enlargement. BACKGROUND: Functional MR occurs in patients with AF and isolated annular dilation, but the relationship of MLA adaptation with annular area (AA) is unknown. METHODS: Three-dimensional echocardiographic images were acquired from 86 patients with quantified MR: 53 with nonvalvular persistent AF (23 MR+ with moderate or greater MR, 30 MR-) without LV dysfunction or dilation and 33 normal controls. Comprehensive 3 dimensional analysis included total diastolic MLA, adaptation ratios of MLA to annular area and MLA to leaflet closure area, and annular and tenting geometry. RESULTS: Total MLA was 22% larger in patients with AF than in controls, thus paralleling the increased AA. However, as AA increased, adaptive indices (MLA/AA ratio and ratio of MLA to closure area) plateaued, becoming lowest in MR+ patients (ratio of MLA to closure area = 1.63 +/- 0.17 controls, 1.60 +/- 0.11 MR , 1.32 +/- 0.10 MR+; p < 0.001). MR increased as the ratio of MLA to closure area decreased (R2 = 0.68; p < 0.001). The posterior-to-anterior MLA ratio remained constant, whereas the posterior-to-anterior mitral annulus perimeter increased (1.21 +/- 0.16 controls, 1.32 +/- 0.20 MR-, 1.46 +/- 0.19 MR+; p < 0.001). Multivariate MR determinants were annular area, total MLA to closure area, and posterior-to-anterior perimeter ratios. CONCLUSIONS: MLA adaptively increases in AF with isolated annular dilation and normal LV function. This compensatory enlargement becomes insufficient with greater annular dilation, and the leaflets fail to match asymmetrical annular remodeling, thereby increasing MR. These findings can potentially help optimize therapeutic options and motivate basic studies of adaptive growth processes. PMID- 29248663 TI - Definition of Left Ventricular Segments for Cardiac Magnetic Resonance Imaging. PMID- 29248662 TI - Coronary Plaque Microstructure and Composition Modify Optical Polarization: A New Endogenous Contrast Mechanism for Optical Frequency Domain Imaging. AB - OBJECTIVES: This study aimed to evaluate whether polarimetry, performed using a modified optical frequency domain imaging (OFDI) system, can improve the assessment of histological features relevant to characterizing human coronary atherosclerosis. BACKGROUND: The microscopic structure and organization of the arterial wall influence the polarization of the infrared light used by OFDI. Modification of the OFDI apparatus, along with recently developed image reconstruction methods, permits polarimetric measurements simultaneously with conventional OFDI cross-sectional imaging through standard intravascular imaging catheters. METHODS: The main coronary arteries of 5 cadaveric human hearts were imaged with an OFDI system capable of providing polarimetric assessment. Cross sectional views of tissue birefringence, measured in refractive index units, and depolarization, expressed as the ratio of depolarized signal to total intensity, were reconstructed, together with conventional OFDI images. Following imaging, the vessels underwent histological evaluation to enable interpretation of the observed polarization features of individual tissue components. RESULTS: Birefringence in fibrous tissue was significantly higher than in intimal tissue with minimal abnormality (0.44 * 10-3 vs. 0.33 * 10-3; p < 0.0001). Birefringence was highest in the tunica media (p < 0.0001), consistent with its high smooth muscle cell content, cells known to associate with birefringence. In fibrous areas, birefringence showed fine spatial features and close correspondence with the histological appearance of collagen. In contrast, necrotic cores and regions rich in lipid elicited significant depolarization (p < 0.0001). Depolarization was also evident in locations of cholesterol crystals and macrophages. CONCLUSIONS: Intravascular measurements of birefringence and depolarization can be obtained using conventional OFDI catheters in conjunction with a modified console and signal processing algorithms. Polarimetric measurements enhance conventional OFDI by providing additional information related to the tissue composition and offer quantitative metrics enabling characterization of plaque features. PMID- 29248664 TI - Focal Fibrosis in the Endurance Athlete's Heart: Running Scarred or Running Scared? PMID- 29248665 TI - A case of a primary lung cancer comprised of adenocarcinoma and atypical carcinoid tumor with both components harboring BRAF p.V600E mutation. AB - Mixed morphology lung tumors are rare; this is the second report of a combined NSCLC and atypical carcinoid tumor. Next generation sequencing was performed on both histologically distinct patterns which identified that both components harbored a BRAF p.V600E mutation. Molecular studies inform our knowledge of the biology and aid in treatment decisions for mixed morphology lung cancers. PMID- 29248666 TI - Hydrosalpinx Sclerotherapy Before In Vitro Fertilization: Systematic Review and Meta-analysis. AB - The presence of a hydrosalpinx has been shown to impair the outcome of in vitro fertilization (IVF) treatment. This outcome can be improved by removing the hydrosalpinx; however, there are some concerns regarding its feasibility and safety, especially in women with previous surgeries and dense adhesions. The purpose of our meta-analysis was to evaluate the efficacy of hydrosalpinx aspiration with or without sclerotherapy on the risk of recurrence and the IVF outcome compared with salpingectomy or no intervention. We performed an electronic-based search using PubMed, Embase, Ovid MEDLINE, Google Scholar, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials. Our main outcome measures were the recurrence rate, fertility outcome, and adverse events. Ten studies were included in our review. The overall recurrence rates of hydrosalpinx aspiration with or without sclerotherapy were 21.7% to 30.5% and 21.8% to 32.5%, respectively. There was no difference in the clinical pregnancy or miscarriage rate between hydrosalpinx sclerotherapy and salpingectomy. When compared with salpingectomy, hydrosalpinx aspiration only was associated with a significantly lower clinical pregnancy rate and higher miscarriage rate. Compared with no intervention, hydrosalpinx aspiration resulted in significantly higher clinical pregnancies rates but a similar miscarriage rate. We conclude that hydrosalpinx sclerotherapy before IVF improves the fertility outcome and can be used as an alternative to salpingectomy. PMID- 29248667 TI - The lateral habenula interacts with the hypothalamo-pituitary adrenal axis response upon stressful cognitive demand in rats. AB - The lateral habenula (LHb) is involved in emotional and cognitive behaviors. Recently, we have shown in rats that blockade of excitatory inputs to the LHb not only induced deficits of memory retrieval in the water maze, but also altered swim strategies (i.e., induced excessive thigmotaxis). The latter observation, although consistent with the occurrence of memory deficits, could also possibly be the consequence of an excessive level of stress, further suggesting a role for the LHb in the stress response in our behavioral paradigm. To test this hypothesis we performed in rats intra-LHb infusion of 6-cyano-7-nitroquinoxaline 2,3-dione (CNQX, 267 ng/side in 0.3 MUL), or vehicle, and assessed the responsiveness of the hypothalamo-pituitary adrenal (HPA) axis to environmental stressful or non-stressful situations. We have measured plasma corticosterone (CORT) concentrations at different time points before and following intra-LHb infusion of CNQX - or of the same volume of vehicle - in three conditions: during the probe test of a water maze experiment; in an anxiety test, the elevated plus maze; and in a home cage condition. Whereas there were no differences in the home cage condition and in the elevated plus maze, in the water maze experiment we observed that CNQX-treated rats presented, along with memory deficits, a higher level of blood CORT than vehicle-treated rats. These results suggest that perturbations of the modulation of the HPA axis are consecutive to the alteration of LHb function, whether it is the result of a defective direct control of the LHb over the HPA axis, or the consequence of memory deficits. PMID- 29248668 TI - Comparison for younger and older adults: Stimulus temporal asynchrony modulates audiovisual integration. AB - Recent research has shown that the magnitudes of responses to multisensory information are highly dependent on the stimulus structure. The temporal proximity of multiple signal inputs is a critical determinant for cross-modal integration. Here, we investigated the influence that temporal asynchrony has on audiovisual integration in both younger and older adults using event-related potentials (ERP). Our results showed that in the simultaneous audiovisual condition, except for the earliest integration (80-110ms), which occurred in the occipital region for older adults was absent for younger adults, early integration was similar for the younger and older groups. Additionally, late integration was delayed in older adults (280-300ms) compared to younger adults (210-240ms). In audition-leading vision conditions, the earliest integration (80 110ms) was absent in younger adults but did occur in older adults. Additionally, after increasing the temporal disparity from 50ms to 100ms, late integration was delayed in both younger (from 230 to 290ms to 280-300ms) and older (from 210 to 240ms to 280-300ms) adults. In the audition-lagging vision conditions, integration only occurred in the A100V condition for younger adults and in the A50V condition for older adults. The current results suggested that the audiovisual temporal integration pattern differed between the audition-leading and audition-lagging vision conditions and further revealed the varying effect of temporal asynchrony on audiovisual integration in younger and older adults. PMID- 29248669 TI - Imaging of subclinical haemopoiesis after stem-cell transplantation in patients with haematological malignancies: a prospective pilot study. AB - BACKGROUND: Haemopoietic stem-cell transplantation (HSCT) eradicates host haemopoiesis before venous infusion of haemopoietic stem cells (HSCs). The pathway to cellular recovery has been difficult to study in human beings because of risks associated with interventions during aplasia. We investigated whether 18F-fluorothymidine (18F-FLT) imaging was safe during allogenic HSCT and allowed visualisation of early cellular proliferation and detection of patterns of cellular engraftment after HSCT. METHODS: Eligible patients were aged 18-55 years, had high-risk haematological malignancies. All patients underwent myeloablation followed by HSCT. The imaging primary endpoint was detection of early subclinical engraftment after HSCT with 18F-FLT PET or CT. Imaging was done 1 day before and 5 or 9, and 28 days, and 1 year after HSCT. This study is registered with ClinicalTrials.gov, number NCT01338987. FINDINGS: Between April 1, 2014, and Dec 31, 2015, 23 patients were enrolled and assessable for toxic effects after completing accrual. 18F-FLT was not associated with any adverse events or delayed engraftment. 18F-FLT imaging objectively identified subclinical bone-marrow recovery within 5 days of HSC infusion, which was up to 20 days before engraftment became clinically evident. Quantitatively, 18F-FLT intensity differed significantly between myeloablative infusion before HSCT and subclinical HSC recovery (p=0.00031). 18F-FLT biodistribution over time revealed a previously unknown path of cellular recovery of haemopoiesis in vivo that mirrored fetal ontogeny. INTERPRETATION: 18F-FLT allowed quantification and tracking of subclinical bone-marrow repopulation in human beings and revealed new insights into the biology of HSC recovery after HSCT. FUNDING: National Institutes of Health, Ben's Run/Ben's Gift, Albert and Elizabeth Tucker Foundation, Mex Frates Leukemia Fund, Jones Family fund, and Oklahoma Center for Adult Stem Cell Research. PMID- 29248671 TI - Chromatin in nervous system development and disease. AB - Epigenetic regulation of gene expression is critical during development of the central nervous system. Pathogenic variants in genes encoding epigenetic factors have been found to cause a wide variety of neurodevelopmental disorders including Autism spectrum disorder, intellectual disability, and epilepsy. Cancers affecting neuronal and glial cells in the brain have also been shown to exhibit somatic mutations in epigenetic regulators, suggesting chromatin-based links between regulated and dysregulated cellular proliferation and differentiation. In this special issue, six articles review recent discoveries implicating epigenetic modifiers in normal and disease states affecting the nervous system, and the underlying mechanisms by which these modifiers function. Two articles present new information about roles for chromatin regulators in nervous system development and cancer. Together, these manuscripts provide a concise overview of this rapidly growing field. In this introduction, we briefly summarize themes presented in the issue, and pose questions for ongoing research and discovery. PMID- 29248670 TI - Imaging bone-marrow activity with 18F-fluorothymidine PET. PMID- 29248672 TI - NURSE PRACTITIONER LEADERSHIP IN PATIENT-CENTRED COLLABORATIVE CARE. AB - Important changes are underway for the Australian health system. National health reform and the Healthier Medicare Review are creating new opportunities to lead innovation in primary healthcare, in particular, chronic disease management. PMID- 29248673 TI - Drinking with a very long proboscis: Functional morphology of orchid bee mouthparts (Euglossini, Apidae, Hymenoptera). AB - Neotropical orchid bees (Euglossini) possess the longest proboscides among bees. In this study, we compared the feeding behavior and functional morphology of mouthparts in two similarly large-sized species of Euglossa that differ greatly in proboscis length. Feeding observations and experiments conducted under semi natural conditions were combined with micro-morphological examination using LM, SEM and micro CT techniques. The morphometric comparison showed that only the components of the mouthparts that form the food tube differ in length, while the proximal components, which are responsible for proboscis movements, are similar in size. This study represents the first documentation of lapping behaviour in Euglossini. We demonstrate that Euglossa bees use a lapping-sucking mode of feeding to take up small amounts of fluid, and a purely suctorial technique for larger fluid quantities. The mouthpart movements are largely similar to that in other long-tongued bees, except that the postmentum in Euglossa can be extended, greatly enhancing the protraction of the glossa. This results in a maximal functional length that is about 50% longer than the length of the food canal composing parts of the proboscis. The nectar uptake and the sensory equipment of the proboscis are discussed in context to flower probing. PMID- 29248674 TI - Nanodesign of new self-assembling core-shell gellan-transfersomes loading baicalin and in vivo evaluation of repair response in skin. AB - Gellan nanohydrogel and phospholipid vesicles were combined to incorporate baicalin in new self-assembling core-shell gellan-transfersomes obtained by an easy, scalable method. The vesicles were small in size (~107 nm) and monodispersed (P.I. <= 0.24), forming a viscous system (~24 mPa/s) as compared to transfersomes (~1.6 mPa/s), as confirmed by rheological studies. Gellan was anchored to the bilayer domains through cholesterol, and the polymer chains were distributed onto the outer surface of the bilayer, thus forming a core-shell structure, as suggested by SAXS analyses. The optimal carrier ability of core shell gellan-transfersomes was established by the high deposition of baicalin in the skin (~11% in the whole skin), especially in the deeper tissue (~8% in the dermis). Moreover, their ability to improve baicalin efficacy in anti inflammatory and skin repair tests was confirmed in vivo in mice, providing the complete skin restoration and inhibiting all the studied inflammatory markers. PMID- 29248675 TI - PEGylated hyaluronic acid-coated liposome for enhanced in vivo efficacy of sorafenib via active tumor cell targeting and prolonged systemic exposure. AB - This study aimed to design an effective formulation for enhancing the tumor targeted delivery of sorafenib. Three sorafenib-loaded liposomal formulations including uncoated liposome (SF-Lip), hyaluronic acid-coated liposome (HA-SF Lip), and PEGylated hyaluronic acid-coated liposome (PEG-HA-SF-Lip) were developed with narrow size distribution and high encapsulation efficiency. The cellular uptake and cytotoxicity of HA-SF-Lip and PEG-HA-SF-Lip were greater than those of SF-Lip in MDA-MB-231 cells overexpressing CD44, whereas there were no significant differences in MCF-7 cells with low CD44 expression, indicating the CD44-mediated cellular uptake of coated liposomes. In comparison with sorafenib solution, PEG-HA-SF-Lip increased the systemic exposure and plasma half-life in rats by 3-fold and 2-fold, respectively. Consistently, PEG-HA-SF-Lip was the most effective for tumor growth inhibition through CD44 targeting in the MDA-MB-231 tumor xenograft mouse model. Taken together, the present study suggests that PEG HA-SF-Lip might be effective for the tumor-targeted delivery of sorafenib with enhanced systemic exposure and longer blood circulation. PMID- 29248676 TI - Antibody-functionalized polymer nanoparticle leading to memory recovery in Alzheimer's disease-like transgenic mouse model. AB - Alzheimer's disease (AD) is a neurodegenerative disorder related, in part, to the accumulation of amyloid-beta peptide (Abeta) and especially the Abeta peptide 1 42 (Abeta1-42). The aim of this study was to design nanocarriers able to: (i) interact with the Abeta1-42 in the blood and promote its elimination through the "sink effect" and (ii) correct the memory defect observed in AD-like transgenic mice. To do so, biodegradable, PEGylated nanoparticles were surface functionalized with an antibody directed against Abeta1-42. Treatment of AD-like transgenic mice with anti-Abeta1-42-functionalized nanoparticles led to: (i) complete correction of the memory defect; (ii) significant reduction of the Abeta soluble peptide and its oligomer level in the brain and (iii) significant increase of the Abeta levels in plasma. This study represents the first example of Abeta1-42 monoclonal antibody-decorated nanoparticle-based therapy against AD leading to complete correction of the memory defect in an experimental model of AD. PMID- 29248677 TI - Influence of natural and synthetic vitamin C (ascorbic acid) on primary and secondary metabolites and associated metabolism in quinoa (Chenopodium quinoa Willd.) plants under water deficit regimes. AB - Phytoextracts are being widely used these days as a source of bioactive compounds for mitigating the harmful effects of abiotic stresses including drought stress. In this study, it was assessed how far foliar applied pure synthetic ascorbic acid (AsA) or natural sweet orange juice (OJ) enriched with AsA could mitigate the drought stress induced adverse effects on growth and some key metabolic processes in quinoa (Chenopodium quinoa Willd.; cultivar V9) plants. Two weeks old quinoa seedlings were subjected to varying irrigation regimes as control [100% field capacity (FC)] and drought stress (60% FC, 40% FC and 20% FC). After one month of water deficit treatments, various levels of ascorbic acid (150 mg L 1 AsA or 25% OJ) besides control [distilled water (DW) and no spray (NS)] were applied as a foliar spray. After 15 days of AsA application, different physio biochemical attributes were measured. The results showed that water deficit markedly decreased plant growth, relative water content (RWC), photosynthetic rate, total carotenoids (CAR) and total flavonoids, while it increased relative membrane permeability (RMP), intrinsic AsA content, hydrogen peroxide (H2O2), malondialdehyde (MDA), glycinebetaine (GB), total phenolics, total soluble proteins (TSP), total free amino acids, activities of key antioxidant enzymes [superoxide dismutase (SOD), peroxidase (POD)], total soluble sugars (TSS), reducing (RS) and non-reducing sugars (NRS). Most obvious results of most of these parameters were observed at 40% and 20% FC. Foliar-applied pure 150 mg L-1 AsA and 25% OJ were found to be very effective in improving plant growth, RMP, photosynthetic rate, CAR, proline, AsA, MDA, GB, TSP, free amino acids, SOD, POD, TSS, RS, NRS and total flavonoids. It was noticed that 25% OJ enriched with AsA and other essential nutrients and biomolecules was as efficient as 150 mg L-1 AsA in reducing the adverse effects of drought stress on quinoa plants. So, it was concluded that OJ, a cheaper source of vitamin C, can be used as a mitigating agent for improving drought tolerance in plants under drought-prone environments. PMID- 29248678 TI - Nitric oxide promotes light-initiated seed germination by repressing PIF1 expression and stabilizing HFR1. AB - Seed germination is a crucial stage in the life cycle of plants and is tightly controlled by internal and external signals. Phytochrome photoreceptors perceive light stimulation to promote seed germination. Previous studies have shown that PHYTOCHROME-INTERACTION FACTOR 1 (PIF1) is a negative regulatory factor and represses seed germination, while LONG HYPOCOTYL IN FAR-RED (HFR1) sequesters PIF1 by forming a heterodimer to relieve the inhibitory effect of seed germination during the initial phase. Nitric oxide (NO) has been reported to break seed dormancy, but the underlying mechanism is not well understood. Here, we report that NO signal enhances phytochrome B (PHYB)-dependent seed germination, and PHYB perceives red light stimulation to activate NR activity and NO accumulation. NO signal not only downregulates the transcription of PIF1, but also stabilize HFR1 proteins to intensify the interaction of the HFR1-PIF1 heterodimer, and compensate for the inhibitory effect of PIF1 on its target genes associated with hormone metabolism and cell wall loosening, consequently initiating seed germination. Thus, our results reveal a new mechanism for NO signals in modulating PHYB-mediated seed germination by repressing PIF1 expression at the transcriptional level as well as preventing PIF1 activity by stabilizing HFR1 protein. PMID- 29248679 TI - Abscisic acid mediated differential growth responses of root and shoot of Vigna radiata (L.) Wilczek seedlings under water stress. AB - Water stress is a common problem in Indian agriculture and recent global climate change has aggravated this problem further. Plants have an adaptive response to water scarcity as reflected in differential root and shoot growth. In case of Vigna radiata seedlings we have observed earlier promotion of root growth while inhibition of shoot (hypocotyl) growth under mild water stress, which is probably mediated by ABA. However, the exact mechanism of ABA action is far from clear. The present study attempts to elucidate the action of ABA through apoplastic reactive oxygen species (ROS) and its impact upon antioxidant defence system during the growth of root and shoot under water stress. Thus promotion of root growth by application of exogenous ABA (10 MUM) and mild water stress (psi -0.5 MPa) may be correlated with enhanced apoplastic ROS production possibly by activating plasma membrane located NADPH oxidase (NOX) enzyme. On the contrary, in hypocotyls where growth was rather inhibited by application of water stress or ABA, neither NOX activity nor ROS accumulation was significantly detected upon these treatments. Overall activity of antioxidant enzymes [superoxide dismutase (SOD, EC 1.15.1.1), peroxidase (POX, EC 1.11.1.7), ascorbate peroxidase (APX, EC 1.11.1.1) and catalase (CAT, EC 1.11.1.6)] was high and somewhat promoted by ABA and water stress treatment in roots compared to hypocotyls. A possible ROS mediated role of ABA in promoting growth and antioxidant activity in roots under water stress has been proposed. PMID- 29248681 TI - Characteristics and application of S1-P1 nucleases in biotechnology and medicine. AB - 3'-nucleases/nucleotidases of the S1-P1 family (EC 3.1.30.1) are single-strand specific or non-specific zinc-dependent phosphoesterases present in plants, fungi, protozoan parasites, and in some bacteria. They participate in a wide variety of biological processes and their current biotechnological applications rely on their single-strand preference, nucleotide non-specificity, a broad range of catalytic conditions and high stability. We summarize the present and potential utilization of these enzymes in biotechnology and medicine in the context of their biochemical and structure-function properties. Explanation of unanswered questions for bacterial and trypanosomatid representatives could facilitate development of emerging applications in medicine. PMID- 29248680 TI - Exosome biogenesis, bioactivities and functions as new delivery systems of natural compounds. AB - A rapidly growing body of experimental evidence has begun to shed light on the wide ranging molecular mechanisms which modulate intra- and inter-cellular communications. A substantial quantity of the available knowledge has only been uncovered in recent years, and we are learning that donor cells release nanovesicles, known as exosomes, which regulate the cellular behavior of recipient cells following uptake. Based on the impressive capacity of exosomes in delivering their "payload", different therapeutic agents, are currently being tested using this delivery method for more effective therapy. This review summarizes the most recent developments in exosome bioactivities and discusses the biochemical nature of exosomes and their biogenesis. It also summarizes the use of exosomes as delivery vehicles for drugs and natural compounds to the targeted site. PMID- 29248682 TI - Synthetic biology of modular endolysins. AB - Endolysins and their derivatives have emerged in recent years as a novel class of antibacterials, which have now entered the clinical phases. Their rapid mode-of action and proteinaceous nature differentiates them from any other class of antibiotics. A key feature of endolysins is their modularity and the opportunities that emerge thereof to customize properties such as specificity, activity, stability and solubility. Extensive protein engineering efforts have expanded the activity spectrum to (pan)drug-resistant Gram-negative bacteria or have improved the activity against Gram-positive pathogens. In addition, specific cell wall binding domains derived from endolysins are exploited for the development of diagnostics. PMID- 29248683 TI - Importance of microbial defence systems to bile salts and mechanisms of serum cholesterol reduction. AB - An important feature of the intestinal microbiota, particularly in the case of administered probiotic microorganisms, is their resistance to conditions in the gastrointestinal tract, particularly tolerance to and growth in the presence of bile salts. Bacteria can use several defence mechanisms against bile, including special transport mechanisms, the synthesis of various types of surface proteins and fatty acids or the production of exopolysaccharides. The ability to enzymatically hydrolyse bile salts occurs in a variety of bacteria. Choloylglycine hydrolase (EC 3.5.1.24), a bile salt hydrolase, is a constitutive intracellular enzyme responsible for the hydrolysis of an amide bond between glycine or taurine and the steroid nucleus of bile acids. Its presence was demonstrated in specific microorganisms from several bacterial genera (Lactobacillus spp., Bifidobacterium spp., Clostridium spp., Bacteroides spp.). Occurrence and gene arrangement encoding this enzyme are highly variable in probiotic microorganisms. Bile salt hydrolase activity may provide the possibility to use the released amino acids by bacteria as sources of carbon and nitrogen, to facilitate detoxification of bile or to support the incorporation of cholesterol into the cell wall. Deconjugation of bile salts may be directly related to a lowering of serum cholesterol levels, from which conjugated bile salts are synthesized de novo. Furthermore, the ability of microorganisms to assimilate or to bind ingested cholesterol to the cell wall or to eliminate it by co-precipitation with released cholic acid was also documented. Some intestinal microflora produce cholesterol reductase that catalyses the conversion of cholesterol to insoluble coprostanol, which is subsequently excreted in faeces, thereby also reducing the amount of exogenous cholesterol. PMID- 29248684 TI - Involvement of polyhydroxyalkanoates in stress resistance of microbial cells: Biotechnological consequences and applications. AB - Polyhydroxyalkanoates (PHA) are polyesters accumulated by numerous prokaryotes as storage materials; they attract attention as "green" alternatives to petrochemical plastics. Recent research has demonstrated that their biological role goes beyong their storage function, since they presence in cytoplasm enhances stress resistance of microorganisms. To address these complex functions, this review summarizes the protective effects of PHA for microrganisms; the involvement of PHA in stress resistance is discussed also from a praxis-oriented perspective. The review discourses the controlled application of stress to improve PHA productivity. Also the manifold advantages of using stress adapted microbes - extremophiles as PHA producers are discussed. PMID- 29248685 TI - Bioconversion of carbon dioxide to methane using hydrogen and hydrogenotrophic methanogens. AB - Biogas produced from organic wastes contains energetically usable methane and unavoidable amount of carbon dioxide. The exploitation of whole biogas energy is locally limited and utilization of the natural gas transport system requires CO2 removal or its conversion to methane. The biological conversion of CO2 and hydrogen to methane is well known reaction without the demand of high pressure and temperature and is carried out by hydrogenotrophic methanogens. Reducing equivalents to the biotransformation of carbon dioxide from biogas or other resources to biomethane can be supplied by external hydrogen. Discontinuous electricity production from wind and solar energy combined with fluctuating utilization cause serious storage problems that can be solved by power-to-gas strategy representing the production of storable hydrogen via the electrolysis of water. The possibility of subsequent repowering of the energy of hydrogen to the easily utilizable and transportable form is a biological conversion with CO2 to biomethane. Biomethanization of CO2 can take place directly in anaerobic digesters fed with organic substrates or in separate bioreactors. The major bottleneck in the process is gas-liquid mass transfer of H2 and the method of the effective input of hydrogen into the system. There are many studies with different bioreactors arrangements and a way of enrichment of hydrogenotrophic methanogens, but the system still has to be optimized for a higher efficiency. The aim of the paper is to gather and critically assess the state of a research and experience from laboratory, pilot and operational applications of carbon dioxide bioconversion and highlight further perspective fields of research. PMID- 29248686 TI - Augmented reality for personalized nanomedicines. AB - As our understanding of onset and progress of diseases at the genetic and molecular level rapidly progresses, the potential of advanced technologies, such as 3D-printing, Socially-Assistive Robots (SARs) or augmented reality (AR), that are applied to personalized nanomedicines (PNMs) to alleviate pathological conditions, has become more prominent. Among advanced technologies, AR in particular has the greatest potential to address those challenges and facilitate the translation of PNMs into formidable clinical application of personalized therapy. As AR is about to adapt additional new methods, such as speech, voice recognition, eye tracing and motion tracking, to enable interaction with host response or biological systems in 3-D space, a combination of multiple approaches to accommodate varying environmental conditions, such as public noise and atmosphere brightness, will be explored to improve its therapeutic outcomes in clinical applications. For instance, AR glasses still being developed by Facebook or Microsoft will serve as new platform that can provide people with the health information they are interested in or various measures through which they can interact with medical services. This review has addressed the current progress and impact of AR on PNMs and its application to the biomedical field. Special emphasis is placed on the application of AR based PNMs to the treatment strategies against senior care, drug addiction and medication adherence. PMID- 29248687 TI - Nitric oxide promotes epidermal stem cell proliferation via FOXG1-c-Myc signalling. AB - OBJECTIVE: Epidermal stem cells (ESCs) play a critical role in wound repair, but the mechanism underlying ESC proliferation is unclear. Here, we explored the effects of nitric oxide (NO) on ESC proliferation and the possible underlying mechanism. METHODS: The effect of NO (two NO donors, SNAP and spermine NONOate, were used) on cell proliferation was detected using cell proliferation and DNA synthesis assays. Thereafter, expression of FOXG1 and c-Myc induced by NO was determined by immunoblot analysis. pAdEasy-FOXG1 adenovirus and c-Myc siRNA plasmids were infected or transfected, respectively, into human ESCs to detect the effect of FOXG1 and c-Myc on NO-induced cell proliferation. Additionally, NO induced ESC proliferation in vivo was detected by BrdU incorporation and a superficial second-degree mouse burn model. Moreover, the relationships among NO, FOXG1 and c-Myc were detected by western blotting, real-time PCR and dual luciferase assay. RESULTS: NO exerted a biphasic effect on ESC proliferation, and 100 MUM SNAP and 10 MUM spermine NONOate were the optimal concentrations to promote cell proliferation. Additionally, NO-promoted human ESC proliferation was mediated by FOXG1 and c-Myc in vitro and vivo. Furthermore, NO regulated FOXG1 expression through cGMP signalling, and NO-induced transcription of c-Myc was regulated by FOXG1-mediated c-Myc promoter activity. CONCLUSION: This study showed that the biphasic effect of NO on ESC proliferation as well as NO induced ESC proliferation were regulated by the cGMP/FOXG1/c-Myc signalling pathway, suggesting that NO may serve as a new disparate target for wound healing. PMID- 29248688 TI - Application of silica coated magnetite nanoparticles modified with Cu(I) neocuproine as nanosorbent to simultaneous separation-preconcentration of trace amounts of nitrate and nitrite. AB - A novel, inexpensive and sensitive type of magnetic nanosorbent based on the functionalized silica-coated Fe3O4 nanoparticles was prepared and used for the adsorption of trace amounts of nitrite and nitrate ions. The work is based on selective ion-pairing complex formation of nitrate and nitrite with Cu(I) neocuproine which are covalently bounded on nanoparticles. Nitrite was determined according to its reaction with barbituric acid to give violuric acid and determination of nitrate was based on its reduction to nitrite in the presence of Zn/NaCl. After formation of violuric acid, the absorbance was measured spectrophotometrically at 310 nm. The quantitative recoveries were obtained at pH 5.5 for the analytes. Under optimum conditions, the limits of detection in the original solutions were 0.49 MUg L-1 and 0.40 MUg L-1 for nitrate and nitrite, respectively. The linearity ranges were found to be 1.5 to 2.8 * 103 MUg L-1(NO3 ) and 1.2 to 1.9 * 103 MUg L-1 (NO2-). The preconcentration factor was 120 for nitrate and 150 for nitrite. This method has been successfully applied to the determination of trace amounts of nitrite and nitrate in various water and food samples and also accuracy was confirmed by the analysis of the spiked recovery test. PMID- 29248690 TI - Application of the Health Belief Model to customers' use of menu labels in restaurants. AB - Some countries require the provision of menu labels on restaurant menus to fight the increasing prevalence of obesity and related chronic diseases. This study views customers' use of menu labels as a preventive health behavior and applies the Health Belief Model (HBM) with the aim of determining the health belief factors that influence customers' use of menu labels. A self-administered survey was distributed for data collection. Responses were collected from 335 restaurant customers who experienced menu labels in restaurants within three months prior to the survey. The results of a structural equation model showed that all the HBM variables (perceived threats, perceived benefits, and perceived barriers of using menu labels) positively affected the customers' use of menu labels. Perceived threats were influenced by cues to action and cues to action had an indirect influence on menu label use through perceived threats. In conclusion, health beliefs were good predictors of menu label use on restaurant menus. This study validated the application of the HBM to menu labeling in restaurants, and its findings could offer guidelines for the industry and government in developing strategies to expand the use of menu labels among the public. PMID- 29248691 TI - Kratom use and mental health: A systematic review. AB - BACKGROUND: Kratom (Mitragyna speciosa) is a psychoactive plant native to Southeastern Asia that is receiving increased international attention as a potential therapeutic agent. While much of the limited scientific research on kratom is focused on its analgesic potential, kratom use also has important risks and benefits in the domain of mental health. METHODS: We conducted a comprehensive systematic review of all studies on kratom use and mental health published between January 1960 and July 2017. RESULTS: Findings indicate kratom's potential as a harm reduction tool, most notably as a substitute for opioids among people who are addicted. Kratom also enhances mood and relieves anxiety among many users. For many, kratom's negative mental health effects - primarily withdrawal symptoms - appear to be mild relative to those of opioids. For some users, however, withdrawal is highly uncomfortable and maintaining abstinence becomes difficult. CONCLUSION: Results inform clinicians working in the mental health and substance use fields, policy-makers, and researchers about the mental health effects of this plant. PMID- 29248689 TI - Pattern of access determines influence of junk food diet on cue sensitivity and palatability. AB - AIMS: Like drug addiction, cues associated with palatable foods can trigger food seeking, even when sated. However, whether susceptibility to the motivating influence of food-related cues is a predisposing factor in overeating or a consequence of poor diet is difficult to determine in humans. Using a rodent model, we explored whether a highly palatable 'junk food' diet impacts responses to reward-paired cues in a Pavlovian-to-instrumental transfer test, using sweetened condensed milk (SCM) as the reward. The hedonic impact of SCM consumption was also assessed by analyzing licking microstructure. METHODS: To probe the effects of pattern and duration of junk food exposure, we provided rats with either regular chow ad libitum (controls) or chow plus access to junk food for either 2 or 24 h per day for 1, 3, or 6 weeks. We also examined how individual susceptibility to weight gain related to these measures. RESULTS: Rats provided 24 h access to the junk food diet were insensitive to the motivational effects of a SCM-paired cue when tested sated even though their hedonic experience upon reward consumption was similar to controls. In contrast, rats provided restricted, 2 h access to junk food exhibited a cue generalization phenotype under sated conditions, lever-pressing with increased vigor in response to both a SCM-paired cue, and a cue not previously paired with reward. Hedonic response was also significantly higher in these animals relative to controls. CONCLUSIONS: These data demonstrate that the pattern of junk food exposure differentially alters the hedonic impact of palatable foods and susceptibility to the motivating influence of cues in the environment to promote food-seeking actions when sated, which may be consequential for understanding overeating and obesity. PMID- 29248692 TI - When parents supply alcohol to their children: Exploring associations with drinking frequency, alcohol-related harms, and the role of parental monitoring. AB - BACKGROUND: Youth obtain alcohol from many sources, including friends, siblings, parents and other adults. Whether parental supply, relative to other sources, is associated with experiencing a negative alcohol-related outcome is an area of considerable debate. Less well understood is whether the observed association is further contextualized by level of parental monitoring of the child. OBJECTIVES: This study has two main objectives: 1) determine if there is a relationship between parental supply, drinking frequency, and alcohol-related harms among youth; and 2) assess whether parental monitoring moderates this relationship. METHODS: Participants were drawn from the 2012 Student Drug Use Survey in Canada's Atlantic Provinces, an anonymous cross-sectional survey of high school students (ages 15-19 years). Adjusted regression models assessed the association between drinking frequency, experiencing alcohol-related harms, and four different sources of supply. Additional analyses stratified on levels of parental monitoring. RESULTS: Relative to receiving alcohol from friends, parental supply was associated with lower odds of experiencing any alcohol-related harm (AOR 0.42; 95% CI 0.28-0.61) and loss of control (AOR = 0.42; 95% CI 0.29-0.62). Drinking frequency did not differ by source of supply. Associations between parental supply and harm were absent among youth reporting low levels of parental monitoring. CONCLUSIONS: Youth who receive alcohol from parents' report fewer alcohol-related harms relative to those who obtain their alcohol from friends, despite no observed differences in drinking frequency. Understanding how parents may help to minimize experiences of alcohol-related harm among youth beyond the simple promotion of abstinence from drinking is warranted. PMID- 29248693 TI - Neuropathic pain inhibitor, RAP-103, is a potent inhibitor of microglial CCL1/CCR8. AB - Chemokine signaling is important in neuropathic pain, with microglial cells expressing chemokine (C-C motif) receptor CCR2, CCR5 and CCR8, all playing key roles. In the previous report (Padi et al., 2012), oral administration of a short peptide, RAP-103, for 7 days fully prevents mechanical allodynia and inhibits the development of thermal hyperalgesia after partial ligation of the sciatic nerve in rodents. As for the mechanism of the inhibiting effect of RAP-103, it was speculated to be due to dual blockade of CCR2 and CCR5. We report here that RAP 103 exhibits stronger antagonism for CCR8 (half maximal inhibitory concentration [IC50] 7.7 fM) compared to CCR5 (IC50 < 100 pM) in chemotaxis using primary cultured mouse microglia. In addition, RAP-103 at a concentration of 0.1 pM completely inhibits membrane ruffling and phagocytosis induced by chemokine (C-C motif) ligand 1 (CCL1), an agonist for CCR8. It has been shown that CCL1/CCR8 signaling is important in tactile allodynia induced by nerve ligation. Therefore, CCR8, among other chemokine receptors such as CCR2/CCR5, could be the most potent target for RAP-103. Inhibitory effects of RAP-103 on plural chemokine receptors may play important roles for broad clinical use in neuropathic pain treatment. PMID- 29248694 TI - Sirt3 confers protection against acrolein-induced oxidative stress in cochlear nucleus neurons. AB - Acrolein is a ubiquitous dietary and environmental pollutant, which can also be generated endogenously during cellular stress. However, the molecular mechanisms underlying acrolein-induced neurotoxicity, especially in ototoxicity conditions, have not been fully determined. In this study, we investigated the mechanisms on acrolein-induced toxicity in primary cultured cochlear nucleus neurons with focus on Sirt3, a mitochondrial deacetylase. We found that acrolein treatment induced neuronal injury and programmed cell death (PCD) in a dose dependent manner in cochlear nucleus neurons, which was accompanied by increased intracellular reactive oxygen species (ROS) generation and lipid peroxidation. Acrolein exposure also significantly reduced the mitochondrial membrane potential (MMP) levels, promoted cytochrome c release and decreased mitochondrial ATP production. In addition, increased ER tracker fluorescence and activation of ER stress factors were observed after acrolein treatment, and the ER stress inhibitors were shown to attenuate acrolein-induced toxicity in cochlear nucleus neurons. The results of western blot and RT-PCR showed that acrolein markedly decreased the expression of Sirt3 at both mRNA and protein levels, and reduced the activity of downstream mitochondrial enzymes. Furthermore, overexpression of Sirt3 by lentivirus transfection partially prevented acrolein-induced neuronal injury in cochlear nucleus neurons. These results demonstrated that acrolein induces mitochondrial dysfunction and ER stress in cochlear nucleus neurons, and Sirt3 acts as an endogenous protective factor in acrolein-induced ototoxicity. PMID- 29248695 TI - Considerations in setting up and planning a graft processing facility. AB - The graft processing facility forms one of the core components of a clinical haematopoietic stem cell transplant program. The quality of a graft is instrumental in leading to consistent and reproducible outcomes of engraftment and other parameters. As such, meticulous planning and consideration is required and will include core elements including physical design and clinical correlates. The successful running of such a facility depends on an overarching quality program and adherence to local and international regulatory guidelines. PMID- 29248696 TI - Vasodilator and hypotensive effects of the spider peptide Lycosin-I in vitro and in vivo. AB - Lycosin-I, a spider peptide isolated from the venom of the spider Lycosa singoriensis, has anti-bacteria and anti-cancer properties in organisms. However, cardiovascular effects of Lycosin-I have not been studied. In this study, we investigated for the first time the vasodilator and hypotensive effects of Lycosin-I and the possible mechanisms, in order to develop a promising treatment for hypertension-related diseases. For in vitro experiments, thoracic aortas were isolated, and divided into two groups, endothelium-intact and endothelium-denuded aortic rings. Lycosin-I induced a remarkable dose-dependent relaxation in endothelium-intact aortic rings pre-treated with phenylephrine (p < 0.05), while it showed no obvious vasodilator effects in endothelium-denuded aortic rings (p > 0.05). The vasodilator effects of Lycosin-I were significantly weakened by a nitric oxide synthase (NOS) inhibitor, L-NAME (p < 0.001) and a selective inhibitor of nitric oxide (NO)-sensitive soluble guanylate cyclase (sGC), ODQ (p < 0.05), respectively. The levels of endothelial nitric oxide synthase (eNOS) phosphorylation and the NO production were significantly higher in human umbilical vascular endothelial cells pre-cultured with Lycosin-I than the control (p < 0.001), determined via western blot analysis and ozone-chemiluminescence technology. For in vivo experiments, arterial and venous catheters were inserted for mean arterial pressure (MAP) recording and drug administration in anaesthetized spontaneously hypertensive rats. Lycosin-I caused a transient drop of MAP 2 min after the administration compared with the control (p < 0.001). In conclusion, Lycosin-I has the potential to be an anti-hypertensive drug by endothelium-dependent vasodilatation, in which eNOS and NO-sensitive sGC are two main involved factors. PMID- 29248697 TI - 3D spatially-adaptive canonical correlation analysis: Local and global methods. AB - Local spatially-adaptive canonical correlation analysis (local CCA) with spatial constraints has been introduced to fMRI multivariate analysis for improved modeling of activation patterns. However, current algorithms require complicated spatial constraints that have only been applied to 2D local neighborhoods because the computational time would be exponentially increased if the same method is applied to 3D spatial neighborhoods. In this study, an efficient and accurate line search sequential quadratic programming (SQP) algorithm has been developed to efficiently solve the 3D local CCA problem with spatial constraints. In addition, a spatially-adaptive kernel CCA (KCCA) method is proposed to increase accuracy of fMRI activation maps. With oriented 3D spatial filters anisotropic shapes can be estimated during the KCCA analysis of fMRI time courses. These filters are orientation-adaptive leading to rotational invariance to better match arbitrary oriented fMRI activation patterns, resulting in improved sensitivity of activation detection while significantly reducing spatial blurring artifacts. The kernel method in its basic form does not require any spatial constraints and analyzes the whole-brain fMRI time series to construct an activation map. Finally, we have developed a penalized kernel CCA model that involves spatial low pass filter constraints to increase the specificity of the method. The kernel CCA methods are compared with the standard univariate method and with two different local CCA methods that were solved by the SQP algorithm. Results show that SQP is the most efficient algorithm to solve the local constrained CCA problem, and the proposed kernel CCA methods outperformed univariate and local CCA methods in detecting activations for both simulated and real fMRI episodic memory data. PMID- 29248699 TI - Machine learning ensemble modelling to classify caesarean section and vaginal delivery types using Cardiotocography traces. AB - Human visual inspection of Cardiotocography traces is used to monitor the foetus during labour and avoid neonatal mortality and morbidity. The problem, however, is that visual interpretation of Cardiotocography traces is subject to high inter and intra observer variability. Incorrect decisions, caused by miss interpretation, can lead to adverse perinatal outcomes and in severe cases death. This study presents a review of human Cardiotocography trace interpretation and argues that machine learning, used as a decision support system by obstetricians and midwives, may provide an objective measure alongside normal practices. This will help to increase predictive capacity and reduce negative outcomes. A robust methodology is presented for feature set engineering using an open database comprising 552 intrapartum recordings. State-of-the-art in signal processing techniques is applied to raw Cardiotocography foetal heart rate traces to extract 13 features. Those with low discriminative capacity are removed using Recursive Feature Elimination. The dataset is imbalanced with significant differences between the prior probabilities of both normal deliveries and those delivered by caesarean section. This issue is addressed by oversampling the training instances using a synthetic minority oversampling technique to provide a balanced class distribution. Several simple, yet powerful, machine-learning algorithms are trained, using the feature set, and their performance is evaluated with real test data. The results are encouraging using an ensemble classifier comprising Fishers Linear Discriminant Analysis, Random Forest and Support Vector Machine classifiers, with 87% (95% Confidence Interval: 86%, 88%) for Sensitivity, 90% (95% CI: 89%, 91%) for Specificity, and 96% (95% CI: 96%, 97%) for the Area Under the Curve, with a 9% (95% CI: 9%, 10%) Mean Square Error. PMID- 29248698 TI - Multiple time courses of somatosensory responses in human cortex. AB - Here we show how anatomical and functional data recorded from patients undergoing stereo-EEG can be used to decompose the cortical processing following nerve stimulation in different stages characterized by specific topography and time course. Tibial, median and trigeminal nerves were stimulated in 96 patients, and the increase in gamma power was evaluated over 11878 cortical sites. All three nerve datasets exhibited similar clusters of time courses: phasic, delayed/prolonged and tonic, which differed in topography, temporal organization and degree of spatial overlap. Strong phasic responses of the three nerves followed the classical somatotopic organization of SI, with no overlap in either time or space. Delayed responses presented overlaps between pairs of body parts in both time and space, and were confined to the dorsal motor cortices. Finally, tonic responses occurred in the perisylvian region including posterior insular cortex and were evoked by the stimulation of all three nerves, lacking any spatial and temporal specificity. These data indicate that the somatosensory processing following nerve stimulation is a multi-stage hierarchical process common to all three nerves, with the different stages likely subserving different functions. While phasic responses represent the neural basis of tactile perception, multi-nerve tonic responses may represent the neural signature of processes sustaining the capacity to become aware of tactile stimuli. PMID- 29248700 TI - Matrix metalloproteinase-8 analysis in patients with periodontal disease with prediabetes or type 2 diabetes mellitus: A systematic review. AB - OBJECTIVES: The objective of this systematic review was to evaluate information on the levels of MMP-8 in patients diagnosed with prediabetes or type 2 diabetes mellitus with periodontal disease, analyzing its validity as a possible biomarker for the diagnosis and progression of periodontal disease (PD). METHODS: A systematic search of the following databases was performed: PubMed/Medline, CENTRAL (The Cochrane Library), EMBASE and Web of Science. Studies involving the evaluation of MMP-8 in patients with prediabetes or patients presenting type 2 diabetes mellitus concomitantly with PD were selected. The evaluation of the methodological quality of the selected studies was based on the methodological bias risk analysis (QUADAS-2). RESULTS: Eight of the initially identified 2683 articles were selected. In all the selected studies, evaluator calibration and the use of clear methods for patient diagnosis with periodontal disease were present. Studies have demonstrated significantly higher MMP-8 concentrations in PD patients compared to controls, as well as in patients presenting more advanced stages of PD. However, controversies regarding MMP-8 levels in prediabetes/diabetes type 2 patients with PD. CONCLUSIONS: Higher MMP-8 levels in patients with PD compared to controls imply the potential use of MMP-8 in the diagnosis of PD. The influence of patient glycemic state, as well as medications these patients make use of, are factors that possibly contribute to the modulation of MMP-8 concentrations in patients with diabetes and should be analyzed, aiming at a better understanding of the relationship between glycemic state and MMP-8 levels in patients with PD. PMID- 29248701 TI - The association of Salmonella enterica from aquatic environmental and clinical samples in Taiwan. AB - Salmonella is one of the most common pathogens of waterborne and foodborne disease-causing pathogens. In this study, we collected 172 surface water samples from Puzih River and Kaoping River between the years 2010 and 2011. Salmonella was detected in 31.7% (32/101) and 42.2% (30/71) of the samples from the two rivers, respectively. From these positive samples, 44 Salmonella isolates were obtained from these positive samples and were characterized using serotyping and pulsed-field gel electrophoresis (PFGE) genotyping. The isolates were found with 17 serovars and 32 PFGE patterns. Salmonella enterica Newport, Bareilly, Kedougou, Albany and subspecies IIIb 50:k:z were the five most common serovars in aquatic environmental Salmonella isolates. In addition, of the total clinical samples from Chiayi and Kaohsiung, 33.7% (60/178) Newport serovars were isolated. After conducting categorical analysis, we found that the serovar Newport was not uniformly distributed cross the cities. The serovar Newport was over-represented (p<0.001) among human isolates in Chiayi and Kaohsiung. To investigate the association between Salmonella isolates from aquatic environment and human samples, we compared the environmental PFGE patterns of the test samples with those of 2438 clinical isolates, obtained from 51 hospitals across the country between 2010 and 2011. Of the 32 PFGE genotypes of environmental isolates, 8 genotypes were identical to those of clinical samples. Serovar Newport isolates with PFGE patterns SNX.119 and SNX.183 obtained from Puzih River samples were also identified in human samples at a local hospital. These suggest that there is a link between environmental and human clinical Salmonella. Identification of Salmonella serovars and genotypes present in surface water provides an indication of the specific S. enterica serovars and genotypes present in humans. This is the first study to investigate the Salmonella serovars and genotypes present in aquatic environment and humans in Taiwan. PMID- 29248702 TI - Groundwater origin and recharge in the hyperarid Cordillera de la Costa, Atacama Desert, northern Chile. AB - The Cordillera de la Costa is located along the coastline of northern Chile, in the hyperarid Atacama Desert area. Chemical and isotopic analyses of several small coastal springs and groundwater reservoirs between 22.5 degrees S and 25.5 degrees S allow understanding groundwater origin, renewal time and the probable timing of recharge. The aquifers are mostly in old volcanic rocks and alluvial deposits. All spring waters are brackish, of the sodium chloride type due to intensive concentration of precipitation due aridity and for deep groundwater to additional water-rock interaction in slowly renewed groundwater and mixing with deep seated brines. The heavy delta18O and delta2H values in spring water are explained by recharge by the arrival of moist air masses from the Pacific Ocean and the originally lighter values in the deep wells can be associated to past recharge by air masses coming from the Atlantic Ocean. Current recharge is assumed almost nil but it was significant in past wetter-than-present periods, increasing groundwater reserves, which are not yet exhausted. To explain the observed chloride content and radiocarbon (14C) activity, a well-mixed (exponential) flow model has been considered for aquifer recharge. The average residence time of groundwater feeding the springs has been estimated between 1 and 2kyr, up to 5kyr and between 7 and 13kyr for deep well water, assuming that current recharge is much less than during the previous wetter period. The recharge period feeding the coastal springs could have been produced 1 to 5kyr BP, when the area was already inhabited, and recharge in the Michilla mine was produced during the 10 to 14.5kyr BP CAPE (Central Andean Pluvial Event) pluvial events of the central Andes. The approximate coincidence of turnover time with the past wet periods, as revealed by paleoclimate data, points to significant recharge during them. PMID- 29248703 TI - Sequential samples reveal significant variation of mercury isotope ratios during single rainfall events. AB - Although the investigation of mercury (Hg) isotopes in precipitation has largely improved our knowledge of the source and transformation of Hg in the atmosphere, rainwater investigated in previous studies were integrated samples collected over an event and could obscure key information about the physiochemical transformation and deposition dynamics of Hg (and its isotopes) in short precipitation events. In this study, we investigated Hg isotopic composition of filtered (HgF) and particulate Hg (HgPM) in sequential rain samples from three single rainfall events in Guiyang, China. All samples showed a decrease of total Hg concentration, as well as HgF and HgPM with time in each rainfall event, and large variation of both mass-dependent fractionation (MDF) and mass-independent fractionation of odd Hg isotopes (odd-MIF) for both phases. Isotopic data indicated variable contributions of different sources triggered by the instant change of meteorological conditions, rather than internal atmospheric processes. The rapid response of MDF and odd-MIF of precipitation samples to the incense burning on the Tomb Sweeping Day implied that Hg isotopic composition was very sensitive to the momentary anthropogenic emission, which could have at least a regional short-lived effect and should be taken into account in future studies. Hg isotopes are a powerful tool for investigating both atmospheric transformation and instant deposition dynamic of Hg, and like stable H and O isotopes, could provide useful information about local or regional meteorological changes. PMID- 29248704 TI - Transcriptomic responses of the freshwater snail (Parafossarulus striatulus) following dietary exposure to cyanobacteria. AB - Freshwater snails are promising bioindicators that can be used in ecotoxicological testing and ecological risk assessments. To screen molecular responses following mollusk exposure to algal blooms, whole transcriptome sequencing was performed with the freshwater snail (Parafossarulus striatulus) fed with blue algae (Microcystis aeruginosa). A total of 86,848 unigenes were assembled, and 10,413 unigenes were annotated in the TrEMBL, Pfam, KEGG, and SwissProt databases. In snails fed with both green and blue algae, a total of 276 differentially expressed unigenes were identified, though there were limited differences in snails fed with only green algae. In addition, ten randomly selected differentially expressed unigenes were analyzed in snails collected from Taihu Lake, China. The expression of four unigenes exhibited a trend consistent with that observed in transcriptome profiling of laboratory snails. The results of this study provide an invaluable resource for enhancing our understanding of ecotoxicology following the occurrence of algal blooms in lakes. PMID- 29248705 TI - A linear regression approach to evaluate the green supply chain management impact on industrial organizational performance. AB - The increase in the environmental pollution is one of the most important topic in today's world. In this context, the industrial activities can pose a significant threat to the environment. To manage problems associate to industrial activities several methods, techniques and approaches have been developed. Green supply chain management (GSCM) is considered one of the most important "environmental management approach". In developing countries such as Pakistan the implementation of GSCM practices is still in its initial stages. Lack of knowledge about its effects on economic performance is the reason because of industries fear to implement these practices. The aim of this research is to perceive the effects of GSCM practices on organizational performance in Pakistan. In this research the GSCM practices considered are: internal practices, external practices, investment recovery and eco-design. While, the performance parameters considered are: environmental pollution, operational cost and organizational flexibility. A set of hypothesis propose the effect of each GSCM practice on the performance parameters. Factor analysis and linear regression are used to analyze the survey data of Pakistani industries, in order to authenticate these hypotheses. The findings of this research indicate a decrease in environmental pollution and operational cost with the implementation of GSCM practices, whereas organizational flexibility has not improved for Pakistani industries. These results aim to help managers regarding their decision of implementing GSCM practices in the industrial sector of Pakistan. PMID- 29248706 TI - Gas/particle partitioning and particle size distribution of PCDD/Fs and PCBs in urban ambient air. AB - Urban ambient air samples, including gas-phase (PUF), total suspended particulates (TSP), PM10, PM2.5 and PM1 airborne particle fractions were collected to evaluate gas-particle partitioning and size particle distribution of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs). Clausius-Clapeyron equation, regressions of logKp vs logPL and logKOA, and human respiratory risk assessment were used to evaluate local or long distance transport sources, gas-particle partitioning sorption mechanisms, and implications for health. Total ambient air levels (gas phase+particulate phase) of TPCBs and TPCDD/Fs, were 437 and 0.07pgm-3 (median), respectively. Levels of PCDD/F in the gas phase (0.004-0.14pgm-3, range) were significantly (p<0.05) lower than those found in the particulate phase (0.02-0.34pgm-3). The concentrations of PCDD/Fs were higher in winter. In contrast, PCBs were mainly associated to the gas phase, and displayed maximum levels in warm seasons, probably due to an increase in evaporation rates, supported by significant and strong positive dependence on temperature observed for several congeners. No significant differences in PCDD/Fs and PCBs concentrations were detected between the different particle size fractions considered (TSP, PM10, PM2.5 and PM1), reflecting that these chemicals are mainly bounded to PM1. The toxic content of samples was also evaluated. Total toxicity (PUF+TSP) attributable to dl-PCBs (13.4fg-TEQ05 m-3, median) was higher than those reported for PCDD/Fs (6.26fg TEQ05 m-3). The inhalation risk assessment concluded that the inhalation of PCDD/Fs and dl-PCBs pose a low cancer risk in the studied area. PMID- 29248707 TI - Optimizing accuracy of protocols for measuring dry matter and nutrient yield of forage crops. AB - Farmers around the world must precisely manage nutrients applied to and removed from crop fields to maintain production and without causing nutrient pollution. This study is the first to quantify the baseline accuracy of current industry measurement protocols and achievable accuracy from intensifying protocols for measuring dry matter (DM), nitrogen (N), potassium (K), and phosphorus (P) yields from forage crops harvested for silage. The 'true' DM and nutrient yields of three fields each of corn, sorghum, and small grain were intensively measured by weighing and sampling every truckload of harvested forage. Simulations quantified the accuracy of practical sampling protocols by repeatedly subsampling the complete dataset for each field to measure average truckload weight and average DM and nutrient concentrations. Then uncertainty was propagated to DM, N, P, and K yield calculations using standard error equations. Yields measured using current industry protocols diverged from the true yields of some fields by more than +/-40%, emphasizing the need for improved protocols. This study shows that improving average DM and nutrient concentration measurements is unlikely to improve accuracy of yield measurements if average load weight is not precisely measured. Accuracy did not come within 27% of true yields without weighing all truckloads on some fields even when DM and nutrient concentration measurements were perfectly accurate. Once all truckloads were weighed, the timing of forage sample collection to measure average DM concentration had the greatest impact on accuracy; precision improved by an average of 6.2% when >3 samples were evenly spaced throughout the harvest compared to the same number of consecutive samples. All crop fields are affected by within field variation in growing conditions that results in heterogeneity in DM and nutrient yield. Globally, this study provides foundational methodology to quantitatively evaluate and improve yield measurement protocols that ultimately support sustainable crop production. PMID- 29248708 TI - Air quality modelling in Catalonia from a combination of solar radiation, surface reflectance and elevation. PMID- 29248709 TI - Stimulating ammonia oxidizing bacteria (AOB) activity drives the ammonium oxidation rate in a constructed wetland (CW). AB - An integrated approach to document high ammonium oxidation rate in Guanjinggang constructed wetland (GJG-CW) was performed and the results showed that the substantial ammonium oxidation rate could be obtained by enhancing Ammonia Oxidizing Bacteria (AOB) activity rather than Ammonia Oxidizing Archaea (AOA) activity. In the plant-bed/ditch system, ditch center and plant-bed fringe were two active zones for NH4+-N removal with ammonium oxidation rate peaking at 2.98+/-0.04 and 2.15+/-0.02mgNkg-1d-1, respectively. The enhanced AOB activity were achieved by increasing water level fluctuations, extending hydraulic retention time (HRT) and stimulating substrate availability, which subsequently enhanced NH4+-N removal by 34.06% in GJG-CW. However, the high AOB activity was not correlated with high AOB abundance, but was instead mostly determined by specific AOB taxa, particularly Nitrosomonas, which dominated in the active AOB. The increased cell-specific AOA activity and high AOA diversity were also achieved using those engineering measures. Although the AOA activity decreased overall with extended HRT and increased NH4+-N contents in GJG-CW, AOA still played a major role on ammonium oxidation in plant-bed soil. The study illustrated that artificially enhancing AOB activity and certain species in anthropogenically polluted water ecosystems would be an effective strategy to improve NH4+-N removal. PMID- 29248710 TI - Influence of solid-liquid separation method parameters employed in soil leaching tests on apparent metal concentration. AB - Soil leaching tests are commonly used to evaluate the leachability of hazardous materials, such as heavy metals, from the soil. Batch leaching tests often enhance soil colloidal mobility and may require solid-liquid separation procedures to remove excess soil particles. However, batch leaching test results depend on particles that can pass through a 0.45MUm membrane filter and are influenced by test parameters such as centrifugal intensity and filtration volume per filter. To evaluate these parameters, we conducted batch leaching experiments using metal-contaminated soils and focused on the centrifugal intensity and filtration volume per filter used in solid-liquid separation methods currently employed in standard leaching tests. Our experiments showed that both centrifugal intensity and filtration volume per filter affected the reproducibility of batch leaching tests for some soil types. The results demonstrated that metal concentrations in the filtrates significantly differed according to the centrifugal intensity when it was 3000 g for 2h or less. Increased filtration volume per filter led to significant decreases in filtrate metal concentrations when filter cakes formed during filtration. Comparison of the filtration tests using 0.10 and 0.45MUm membrane filters showed statistically significant differences in turbidity and metal concentration. These findings suggest that colloidal particles were not adequately removed from the extract and contributed substantially to the apparent metal concentrations in the leaching test of soil containing colloidal metals. PMID- 29248711 TI - Ultrasound assessment of soft tissue augmentation around implants in the aesthetic zone using a connective tissue graft and xenogeneic collagen matrix - 1 year randomised follow-up. AB - PURPOSE: A comparative, ultrasound evaluation of the thickness of keratinized mucosa (TKT) around implants one year after gingival augmentation (GA) by means of a connective tissue graft (CTG) and the xenogeneic collagen matrix (CMX). MATERIALS AND METHODS: A total of 75 bone level tapered implants (Conelog(r) Camlog) were inserted in 57 patients in the aesthetic area of both jaws. The patients were divided into 3 groups: control group I- without GA; group II- GA 3 months before implantation, and group III- GA 3 months after implantation. Groups II and III were divided into two subgroups depends on type of material used for GA: (a) CMX (Mucograft(r), Geistlich Pharma AG) and (b) CTG. The patients underwent a clinical and ultrasound examination before, then after 3 and 12 months following GA respectively to evaluate TKT at two points using ultrasound equipment (Pirop(r), Echoson). Point 1 was considered to be in the middle of the line connecting the cemento-enamel junction (CEJ) to the adjacent teeth, and point 2 on the mucogingival junction (MGJ). RESULTS: Three months after GA, the highest increase in gingival thickness was noted in group IIIb (point 1 - 0.95mm, 2 - 1.01mm). However, 12 months after GA the highest gingival thickness was observed in group IIb (point 1 - 1.76mm, 2 - 1.36m) and next IIIb (point 1 - 1.52mm, 2 - 1.15mm). CONCLUSIONS: Both CTG and Geistlich Mucograft(r) increased TKT, but higher values were noted using CTG augmentation before implantation. An ultrasonic device can be used as a non-invasive, reliable, and reproducible method for evaluating TKT. PMID- 29248712 TI - Genetic variant repressing ADH1A expression confers susceptibility to esophageal squamous-cell carcinoma. AB - Genome-wide association studies (GWAS) have discovered numerous genetic susceptibility loci including a cluster of alcohol dehydrogenase (ADH) gene family for esophageal squamous-cell carcinoma (ESCC). However, the underlying mechanism has not fully been elucidated. In this study, we integrated the GWAS data, gene-drinking interaction, expression quantitative trait locus (eQTL) analysis and biochemical experiments to clarify the specific mechanism of the polymorphisms in ADH loci. By imputation and eQTL analysis, we identified rs1154402C>G in intron 1 of ADH5 substantially associated with the expression levels of ADH1A. Association analysis showed that the rs1154402[G] allele was significantly associated with ESCC risk in drinkers (OR = 1.44, 95% CI = 1.20 1.73; P = 7.74 * 10-5) but not in nondrinkers (OR = 1.14, 95% CI = 0.93-1.37; P = .220). Furthermore, the ADH5 variant showed a significant interaction with drinking and the genetic variant near ALDH2 encoding the enzyme oxidizing acetaldehyde, a carcinogenic product resulted from alcohol oxidation catalyzed by ADHs. We demonstrated for the first time that rs1154402C>G change might create a silencer, repressing ADH1A transcription via long-range interaction with ADH1A promoter. These results suggest that genetic variant in ADH5 might confer alcohol drinkers susceptible to ESCC by down-regulation of ADH1A, which weakens alcohol catabolism. PMID- 29248713 TI - New microtubulin inhibitor MT189 suppresses angiogenesis via the JNK-VEGF/VEGFR2 signaling axis. AB - The microtubulin inhibitor MT189 possesses anticancer activity and has been shown to overcome multidrug resistance. Here, we report that MT189 also inhibits angiogenesis. MT189 inhibited the proliferation, migration and differentiation of endothelial cells, with or without VEGF stimulation, and suppressed microvessel formation ex vivo and in vivo. MT189 reduced VEGF expression and secretion in both tumor and endothelial cells, under either hypoxic or normoxic conditions. The activation of VEGFR2 and downstream Src was thus abrogated in the MT189 treated endothelial cells. MT189 subsequently stabilized endothelial cell-cell junctions consist of VE-cadherin, beta-catenin, vinculin, and actin. MT189 also disrupted endothelial cell-matrix junctions by inhibiting the turnover of focal adhesions containing FAK, paxillin, vinculin, and actin. Inhibition of JNK reversed MT189-mediated inhibition of endothelial migration and differentiation, JNK activation, the reduction of VEGF expression and secretion, and the decrease of Src and FAK phosphorylation. These results indicate that MT189 suppresses angiogenesis by reducing endothelial proliferation, migration, and differentiation via the JNK-VEGF/VEGFR2 signaling axis. Together with our previous report showing that MT189 exhibited anticancer activity via the JNK-MCL 1 pathway, these new findings further support MT189-based drug development for cancer therapy. PMID- 29248714 TI - FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells. AB - Cancer associated fibroblast (CAF) is a well-known microenvironment contributor for the development of hepatocellular carcinoma (HCC), while forkhead box (FOX) proteins are also critical to exacerbate HCC malignancy. However, whether FOX proteins are involved in the crosstalk between CAFs and HCC cells remains unclear. In the present study, we reveal that CAFs induce forkhead box Q1 (FOXQ1) expression, and N-myc downstream-regulated gene 1 (NDRG1) is therefore trans activated to enhance HCC initiation. Intriguingly, pSTAT6/C-C motif chemokine ligand 26 (CCL26) signaling is induced by FOXQ1/NDRG1 axis, thus recruiting hepatic stellate cells (HSCs), the main cellular source of CAFs, to the tumor microenvironment. Thereby, tumor initiating properties are enhanced at least partly through a positive feedback loop between CAFs and HCC cells. Importantly, leflunomide, a pSTAT6 inhibitor that has been approved for the treatment of rheumatoid arthritis, significantly blocks the loop and HCC progression. High expression of CAF marker, ACTA2, and induced FOXQ1/NDRG1 axis in HCC tissues predict unfavorable prognosis. Collectively, our findings uncover a positive feedback loop between CAFs and FOXQ1/NDRG1 axis in neoplastic cells to drive HCC initiation, thus providing new potential therapeutic targets for HCC. PMID- 29248715 TI - A highly permselective electrochemical glucose sensor using red blood cell membrane. AB - We developed an electrochemical enzymatic biosensor coated with red blood cell membrane (RBCM) for highly selective glucose measurement. The RBCM containing its membrane proteins (glucose transporter-1) was extracted from a human red blood cell (RBC), and then placed on an established enzymatic glucose sensor by the vesicle fusion method. In the newly fabricated glucose sensor, the RBCM plays the role in the diffusion barrier of preventing the penetration of interfering molecules, while in contrast making glucose molecules permeable. We employed scanning electron microscopy and atomic force microscopy to analyze the RBCM diffusion barriers. The performance of our glucose sensors with diffusion barriers was tested regarding selectivity to glucose against other interfering molecules, such as ascorbic acid, uric acid, and galactose. Remarkably, employing the RBCM significantly improved the selectivity and accuracy of the glucose measurement, even under human serum, compared to the uncoated sensors. This result implies that the RBCM serves well as a highly permselective layer to glucose molecules, and a diffusion barrier to other molecules. PMID- 29248716 TI - Visual electrochemiluminescence ratiometry on bipolar electrode for bioanalysis. AB - In this work, we developed a visual ECL ratiometry on a closed bipolar electrode (BPE) for the detection of prostate specific antigen (PSA), prostate cancer biomarker. High efficient CdTe QDs was synthesized which emitted visualized red light at BPE cathode. Integrating with the anodic ECL emitters, luminol, visual emission of red-blue ratiometric ECL was achieved in BPE array chips. As a sensing probe, Au NRs nanocomposite was assembled on the surface of the cathode and acted as both the quencher of the CdTe QDs ECL and the promoter of the luminol ECL. After incubated with PSA, the Au NRs nanocomposite was peeled off from the electrode surface due to the specific recognition between PSA and aptamer. Consequently, the cathode ECL partly recovered and the anode ECL turned off. By measuring the ratio of visual ECL intensity at two poles of BPE, sensitive detection of PSA was achieved with a linear range from 1.0ng/mL to 1.0MUg/mL and detection limit of 0.5ng/mL (S/N=3). This strategy combining the BPE-ECL and visual ratiometry provided an accurate and intrinsic way for the sensing of PSA and showed good perspective in the clinical diagnosis. PMID- 29248717 TI - Cd-doped Sb2O4 nanostructures modified glassy carbon electrode for efficient detection of melamine by electrochemical approach. AB - Cadmium doped antimony oxide (Cd-doped Sb2O4) nanostructures (CAO-NSs) were synthesized by a facile hydrothermal method in alkaline phase at low temperature to detect the melamine from aqueous solution. The calcined CAO-NSs were characterized systematically by FE-SEM, EDS, UV/Vis., FTIR spectroscopy, powder XRD, and XPS techniques. The glassy carbon electrode (GCE) was modified with the CAO-NSs and sensing performance towards the selective melamine was explored by the electrochemical approach in phosphate buffer solution. The melamine undergoes a reduction reaction in the presence of CAO-NSs/GCE in PBS. The CAO-NSs/GCE attained the higher sensitivity (3.153MUAMUM-1cm-2) for a wide ranges of concentration (LDR: 0.05nM-0.5mM), an ultra-low limit of detection (LOD: 14.0 +/- 0.05p.M.; S/N = 3), long-term stability, excellent repeatability, and reproducibility. This method might represent an efficient way of sensitive sensor development for the toxic melamine and their derivatives for the safety of biomedical and health care fields in broad scales. PMID- 29248718 TI - Proteomic Characterization of Prostate Cancer to Distinguish Nonmetastasizing and Metastasizing Primary Tumors and Lymph Node Metastases. AB - Patients with metastatic prostate cancer (PCa) have a poorer prognosis than patients with organ-confined tumors. We strove to uncover the proteome signature of primary PCa and associated lymph node metastases (LNMs) in order to identify proteins that may indicate or potentially promote metastases formation. We performed a proteomic comparative profiling of PCa tissue from radical prostatectomy (RPE) of patients without nodal metastases or relapse at the time of surgical resection (n=5) to PCa tissue from RPE of patients who suffered from nodal relapse (n=5). For the latter group, we also included patient-matched tissue of the nodal metastases. All samples were formalin fixed and paraffin embedded. We identified and quantified more than 1200 proteins by liquid chromatography tandem mass spectrometry with subsequent label-free quantification. An increase of ribosomal or proteasomal proteins in LNM (compared to corresponding PCa) became apparent, while extracellular matrix components rather decreased. Immunohistochemistry (IHC) corroborated accumulation of poly (ADP-ribose)-polymerase 1 and N-myc-downstream-regulated-gene 3, alpha/beta hydrolase domain-containing protein 11, and protein phosphatase slingshot homolog 3 in LNM. These findings strengthen the present interest in examining PARP inhibitors for the treatment of aggressive PCa. IHC also corroborated increased abundance of retinol dehydrogenase 11 in metastasized primary PCa compared to organ-confined PCa. Generally, metastasizing primary tumors were characterized by an enrichment of proteins involved in cellular lipid metabolic processes with concomitant decrease of cell adhesion proteins. This study highlights the usefulness of a combined proteomic-IHC approach to explore novel aspects in tumor biology. Our initial results open novel opportunities for follow-up studies. PMID- 29248719 TI - Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth. AB - Usp9x has emerged as a potential therapeutic target in some hematologic malignancies and a broad range of solid tumors including brain, breast, and prostate. To examine Usp9x tumorigenicity and consequence of Usp9x inhibition in human pancreatic tumor models, we carried out gain- and loss-of-function studies using established human pancreatic tumor cell lines (PANC1 and MIAPACA2) and four spontaneously immortalized human pancreatic patient-derived tumor (PDX) cell lines. The effect of Usp9x activity inhibition by small molecule deubiquitinase inhibitor G9 was assessed in 2D and 3D culture, and its efficacy was tested in human tumor xenografts. Overexpression of Usp9x increased 3D growth and invasion in PANC1 cells and up-regulated the expression of known Usp9x substrates Mcl-1 and ITCH. Usp9x inhibition by shRNA-knockdown or by G9 treatment reduced 3D colony formation in PANC1 and PDX cell lines, induced rapid apoptosis in MIAPACA2 cells, and associated with reduced Mcl-1 and ITCH protein levels. Although G9 treatment reduced human MIAPACA2 tumor burden in vivo, in mouse pancreatic cancer cell lines established from constitutive (8041) and doxycycline-inducible (4668) KrasG12D/Tp53R172H mouse pancreatic tumors, Usp9x inhibition increased and sustained the 3D colony growth and showed no significant effect on tumor growth in 8041-xenografts. Thus, Usp9x inhibition may be therapeutically active in human PDAC, but this activity was not predicted from studies of genetically engineered mouse pancreatic tumor models. PMID- 29248720 TI - CKIP-1 affects the polyubiquitination of Nrf2 and Keap1 via mediating Smurf1 to resist HG-induced renal fibrosis in GMCs and diabetic mice kidneys. AB - Our previous study indicated that Casein kinase 2 interacting protein-1 (CKIP-1) could promote the activation of the nuclear factor E2-related factor 2 (Nrf2)/ antioxidant response element (ARE) pathway, playing a significant role in inhibiting the fibrosis of diabetic nephropathy (DN). However, the underlying mechanism is still unknown. Here, we investigated whether CKIP-1 affects the polyubiquitination of Nrf2 and its cytosolic inhibitor kelch like ECH-associated protein 1 (Keap1) via mediating Smad ubiquitylation regulatory factor-1 (Smurf1) to promote the activation of the Nrf2/ARE signaling and resist high glucose (HG) induced renal fibrosis in glomerular mesangial cells (GMCs) and diabetic mice kidneys. Results showed that the expression of Smurf1 increased in HG-induced GMCs, with a paramount upregulation at 1h. Overexpression of wild-type Smurf1 plasmid further promoted the HG-induced the over-production of fibronectin (FN) and intercellular adhesionmolecule-1 (ICAM-1), and depletion of Smurf1 dramatically reduced the expression of FN and ICAM-1. Overexpression of CKIP-1 decreased the K48-linked polyubiquitination and increased the K63-linked polyubiquitination of Nrf2 as well as enhanced the K48-linked polyubiquitination and reduced K63-linked polyubiquitination of Keap1, promoting the activation of the Nrf2/ARE pathway. Overexpression of Smurf1 increased the K48-linked polyubiquitination and decreased the K63-linked polyubiquitination of Nrf2, and down-regulated the K48-linked polyubiquitination and up-regulated the K63-linked polyubiquitination of Keap1, inhibiting the activation of the Nrf2/ARE pathway. CKIP-1 promoted the degradation of Smurf1 by increasing the ubiquitination of Smurf1. Treatment of CKIP-1 adenovirus infection reduced the Smurf1 levels, promoted the activation of the Nrf2/ARE pathway as well as suppressed the production of reactive oxygen species (ROS), and then improved the failure of renal function of diabetic mice. Experiments above suggested that CKIP-1 affects the polyubiquitination of Nrf2 and Keap1 and promotes the Nrf2-ARE pathway through down-regulating Smurf1 to resist HG-induced up-regulation of FN and ICAM 1 in GMCs and diabetic mice kidneys. PMID- 29248721 TI - The 3-phenylcoumarin derivative 6,7-dihydroxy-3-[3',4'-methylenedioxyphenyl] coumarin downmodulates the FcgammaR- and CR-mediated oxidative metabolism and elastase release in human neutrophils: Possible mechanisms underlying inhibition of the formation and release of neutrophil extracellular traps. AB - In this study, we report the ability of a set of eight 3-phenylcoumarin derivatives bearing 6,7- or 5,7-dihydroxyl groups, free or acetylated, bound to the benzopyrone moiety, to modulate the effector functions of human neutrophils. In general, (i) 6,7-disubstituted compounds (5, 6, 19, 20) downmodulated the Fcgamma receptor-mediated neutrophil oxidative metabolism more strongly than 5,7 disubstituted compounds (21, 22, 23, 24), and (ii) hydroxylated compounds (5, 19, 21, 23) downmodulated this neutrophil function more effectively than their acetylated counterparts (6, 20, 22, 24, respectively). Compounds 5 (6,7-dihydroxy 3-[3',4'-methylenedioxyphenyl]-coumarin) and 19 (6,7-dihydroxy-3-[3',4' dihydroxyphenyl]-coumarin) effectively downmodulated the neutrophil oxidative metabolism elicited via Fcgamma and/or complement receptors. Compound 5 also downmodulated the immune complex-stimulated phagocytosis, degranulation of elastase, and production and release of neutrophil extracellular traps, as well as the human neutrophil chemotaxis towards n-formyl-methionyl-leucyl phenylalanine, without altering the expression level of formyl peptide receptor type 1. Both compounds 5 and 19 did not impair the neutrophil capacity to recognize and kill Candida albicans. Docking calculations revealed that compounds 5 and 19 directly interacted with three catalytic residues - Gln-91, His-95, and Arg-239 - inside the myeloperoxidase active site. Together, these findings indicate that (i) inhibition of reactive oxygen species generation and degranulation of elastase are closely associated with downmodulation of release of neutrophil extracellular traps; and (ii) compound 5 can be a prototype for the development of novel immunomodulating drugs to treat immune complex-mediated inflammatory diseases. PMID- 29248722 TI - Crosstalk between Nrf2 and YAP contributes to maintaining the antioxidant potential and chemoresistance in bladder cancer. AB - Redox adaptation plays an important role in cancer cells drug resistance. The antioxidant response is principally mediated by the transcription factor Nrf2, that induces the transcriptional activation of several genes involved in GSH synthesis, chemoresistance, and cytoprotection. YAP is emerging as a key mediator of chemoresistance in a variety of cancers, but its role in controlling the antioxidant status of the cells is yet elusive. Here, we show that impairing YAP protein expression reduced GSH content and Nrf2 protein and mRNA expression in bladder cancer cells. Moreover, in YAP knocked down cells the expression of FOXM1, a transcription factor involved in Nrf2 transcription, was down-regulated and the silencing of FOXM1 reduced Nrf2 expression. On the other hand, the silencing of Nrf2, as well as the depletion of GSH by BSO treatment, inhibited YAP expression, suggesting that cross-talk exists between YAP and Nrf2 proteins. Importantly, we found that silencing either YAP or Nrf2 enhanced sensitivity of bladder cancer cells to cytotoxic agents and reduced their migration. Furthermore, the inhibition of both YAP and Nrf2 expressions significantly increased cytotoxic drug sensitivity and synergistically reduced the migration of chemoresistant bladder cancer cells. These findings provide a rationale for targeting these transcriptional regulators in patients with chemoresistant bladder cancer, expressing high YAP and bearing a proficient antioxidant system. PMID- 29248723 TI - Iodine prevents the increase of testosterone-induced oxidative stress in a model of rat prostatic hyperplasia. AB - Oxidative stress and inflammation are involved in the development and/or progression of benign prostatic hyperplasia (BPH). Molecular iodine (I2) induces antiproliferative and apoptotic effects in prostate cancer cells, but it is unknown if I2 regulates oxidative stress in the normal and/or tumoral prostate. The purpose of this study was to analyze the effects of I2 and celecoxib (Cxb) on oxidative stress and inflammation in a model of prostatic hyperplasia. Cxb was used as positive control of cyclooxygenase-2 (COX-2) inhibition. Prostatic hyperplasia was induced in male Wistar rats (170g) with testosterone (5mg/kg/week, for three weeks). One week before hyperplasia induction, I2 (25mg/day/rat) or Cxb (1.25mg/day/rat) was supplied for four weeks in the drinking water. Prostatic hyperplasia was evaluated by histological analysis, DNA content, and/or proliferating cell nuclear antigen (PCNA) expression. Lipoperoxidation (malondialdehyde) and nitrite (NO2-) levels were analyzed by colorimetric methods, while nitric oxide synthase (NOS), COX, and myeloperoxidase (MPO) enzymes were analyzed using RT-PCR, immunoblotting, and/or enzymatic assays. Levels of 15-F2t-isoprostanes, prostaglandins (PGE2), leukotrienes (LTB4), and tumor necrosis factor alpha (TNFalpha) were measured by ELISA. Control testosterone-treated animals exhibited hyperplasia in the dorsolateral prostate, as well as increments in almost all oxidative parameters except for COX 1, TNFalpha, or MPO. I2 and Cxb prevented epithelial hyperplasia (DNA content) and oxidative stress induction generated by testosterone in almost the same intensity, and the minimum I2 dose required was 2.5mg/rat. The antioxidant capacity of I2 was also analyzed in a cell-free system, showing that this element inhibited the conversion of nitrate (NO3-) to NO2-. I2 did not modify the prostatic oxidative state in testosterone untreated rats. In summary, our data showed that antiproliferative and antioxidant effects of I2 involve the inhibition of NOS and the COX-2 pathway. Further studies are necessary to analyze the therapeutic and/or adjuvant effects of I2 with first-line medications used to treat BPH. PMID- 29248724 TI - Recommendations for assessing the risk of bias in systematic reviews of health care interventions. AB - OBJECTIVES: Risk-of-bias assessment is a central component of systematic reviews, but little conclusive empirical evidence exists on the validity of such assessments. In the context of such uncertainty, we present pragmatic recommendations that promote transparency and reproducibility in processes, address methodological advances in the risk-of-bias assessment, and can be applied consistently across review topics. STUDY DESIGN AND SETTING: Epidemiological study design principles; available empirical evidence, risk-of bias tools, and guidance; and workgroup consensus. RESULTS: We developed recommendations for assessing the risk of bias of studies of health-care interventions specific to framing the focus and scope of risk-of-bias assessment; selecting the risk-of-bias categories; choosing assessment instruments; and conducting, analyzing, and presenting results of risk-of-bias assessments. Key recommendations include transparency and reproducibility of judgments, separating risk of bias from other constructs such as applicability and precision, and evaluating the risk of bias per outcome. We recommend against certain past practices, such as focusing on reporting quality, relying solely on study design or numerical quality scores, and automatically downgrading for industry sponsorship. CONCLUSION: Risk-of-bias assessment remains a challenging but essential step in systematic reviews. We presented standards to promote transparency of judgments. PMID- 29248725 TI - Cochrane Qualitative and Implementation Methods Group guidance series-paper 2: methods for question formulation, searching, and protocol development for qualitative evidence synthesis. AB - This paper updates previous Cochrane guidance on question formulation, searching, and protocol development, reflecting recent developments in methods for conducting qualitative evidence syntheses to inform Cochrane intervention reviews. Examples are used to illustrate how decisions about boundaries for a review are formed via an iterative process of constructing lines of inquiry and mapping the available information to ascertain whether evidence exists to answer questions related to effectiveness, implementation, feasibility, appropriateness, economic evidence, and equity. The process of question formulation allows reviewers to situate the topic in relation to how it informs and explains effectiveness, using the criterion of meaningfulness, appropriateness, feasibility, and implementation. Questions related to complex questions and interventions can be structured by drawing on an increasingly wide range of question frameworks. Logic models and theoretical frameworks are useful tools for conceptually mapping the literature to illustrate the complexity of the phenomenon of interest. Furthermore, protocol development may require iterative question formulation and searching. Consequently, the final protocol may function as a guide rather than a prescriptive route map, particularly in qualitative reviews that ask more exploratory and open-ended questions. PMID- 29248726 TI - Integrative analysis of rewired central metabolism in temozolomide resistant cells. AB - An authenticated U87MG clonal glioblastoma cell line was investigated to identify a sub-population of neurospheroidal (NSP) cells within the main epithelial population (U87MG). The NSP cells sorted using Fluorescence Assisted Cell Sorting (FACS) showed varied morphology, 30% lower growth rates, 40% higher IC50 values for temozolomide drug and could differentiate into the glial cell type (NDx). Metabolite profiling using HR-LCMS identified glucose, glutamine and serine in both populations and tryptophan only in U87MG as growth limiting substrates. Glycine, alanine, glutamate and proline were secreted by U87MG, however proline and glycine were re-utilized in NSP. Exo-metabolite profiling and phenotypic microarrays identified differential metabolism of primary carbon sources glucose and derived pyruvate for U87MG; glutamine and derived glutamate metabolism in NSP. Differential mRNA abundance of AKT1, PTEN, PIK3CA controlling metabolism, drug efflux, nutrient transport and epigenetic control MDM2 are potentially critical in shaping DNA methylation effects of temozolomide. Our study provides a new insight into the combined effect of these factors leading to temozolomide resistance in NSP. PMID- 29248727 TI - Measurement of enzymatic and motile activities of Arabidopsis myosins by using Arabidopsis actins. AB - There are two classes of myosin, XI and VIII, in higher plants. Myosin XI moves actin filaments at high speed and its enzyme activity is also very high. In contrast, myosin VIII moves actin filaments very slowly with very low enzyme activity. Because most of these enzymatic and motile activities were measured using animal skeletal muscle alpha-actin, but not plant actin, they would not accurately reflect the actual activities in plant cells. We thus measured enzymatic and motile activities of the motor domains of two Arabidopsis myosin XI isoforms (MYA2, XI-B), and one Arabidopsis myosin VIII isoform (ATM1), by using three Arabidopsis actin isoforms (ACT1, ACT2, and ACT7). The measured activities were different from those measured by using muscle actin. Moreover, Arabidopsis myosins showed different enzymatic and motile activities when using different Arabidopsis actin isoforms. Our results suggest that plant actin should be used for measuring enzymatic and motile activities of plant myosins and that different actin isoforms in plant cells might function as different tracks along which affinities and velocities of each myosin isoform are modulated. PMID- 29248728 TI - Effects and limitations of a nucleobase-driven backmapping procedure for nucleic acids using steered molecular dynamics. AB - Coarse-grained models can be of great help to address the problem of structure prediction in nucleic acids. On one hand they can make the prediction more efficient, while on the other hand they can also help to identify the essential degrees of freedom and interactions for the description of a number of structures. With the aim to provide an all-atom representation in an explicit solvent to the predictions of our SPlit and conQueR (SPQR) coarse-grained model of RNA, we recently introduced a backmapping procedure which enforces the predicted structure into an atomistic one by means of steered molecular dynamics. These simulations minimize the ERMSD, a particular metric which deals exclusively with the relative arrangement of nucleobases, between the atomistic representation and the target structure. In this paper, we explore the effects of this approach on the resulting interaction networks and backbone conformations by applying it on a set of fragments using as a target their native structure. We find that the geometry of the target structures can be reliably recovered, with limitations in the regions with unpaired bases such as bulges. In addition, we observe that the folding pathway can also change depending on the parameters used in the definition of the ERMSD and the use of other metrics such as the RMSD. PMID- 29248729 TI - A novel 3D heterotypic spheroid model for studying extracellular vesicle-mediated tumour and immune cell communication. AB - Cancer-derived extracellular vesicles (EVs) have emerged as important mediators of tumour-host interactions, and they have been shown to exert various functional effects in immune cells. In most of the studies on human immune cells, EVs have been isolated from cancer cell culture medium or patients' body fluids and added to the immune cell cultures. In such a setting, the physiological relevance of the chosen EV concentration is unknown and the EV isolation method and the timing of EV administration may bias the results. In the current study we aimed to develop an experimental cell culture model to study EV-mediated effects in human T and B cells at conditions mimicking the tumour microenvironment. We constructed a human prostate cancer cell line PC3 producing GFP-tagged EVs (PC3-CD63-GFP cells) and developed a 3D heterotypic spheroid model composed of PC3-CD63-GFP cells and human peripheral blood mononuclear cells (PBMCs). The transfer of GFP tagged EVs from PC3-CD63-GFP cells to the lymphocytes was analysed by flow cytometry and fluorescence imaging. The endocytic pathway was investigated using three endocytosis inhibitors. Our results showed that GFP-tagged EVs interacted with a large fraction of B cells, however, the majority of EVs were not internalised by B cells but rather remained bound at the cell surface. T cell subsets differed in their ability to interact with the EVs - 15.7-24.1% of the total CD3+ T cell population interacted with GFP-tagged EVs, while only 0.3-5.8% of CD8+ T were GFP positive. Furthermore, a fraction of EVs were internalised in CD3+ T cells via macropinocytosis. Taken together, the heterotypic PC3-CD63-GFP and PBMC spheroid model provides the opportunity to study the interactions and functional effects of cancer-derived EVs in human immune cells at conditions mimicking the tumour microenvironment. PMID- 29248731 TI - Pharmacokinetic profile of PBRM in rodents, a first selective covalent inhibitor of 17beta-HSD1 for breast cancer and endometriosis treatments. AB - The development of a covalent inhibitor of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a promising approach for the treatment of hormone dependent breast cancer and endometriosis. After reporting the steroid derivative PBRM as a first potent covalent inhibitor of 17beta-HSD1 without estrogenic activity, we are now interested in studying its pharmaceutical behavior. The metabolism study in a human liver microsomal preparation showed a gradual transformation of PBRM into PBRM-O, an oxidized ketonic form of PBRM at position C17. Interestingly, PBRM-O also inhibits 17beta-HSD1 and is not estrogenic in estrogen-sensitive T-47D cells. However, when PBRM was injected subcutaneously (sc) in mice, a very small proportion of PBRM-O was measured in a 24 h-time course experiment. A pharmacokinetic study in mice revealed suitable values for half-life (T1/2 = 3.4 h), clearance (CL = 2088 mL/h kg), distribution volume (Vz = 10.3 L/kg) and absolute bioavailability (F = 65%) when PBRM was injected sc at 14.7 mg/kg. A good F value of 33% was also obtained when PBRM was given orally. A tritiated version of PBRM, 3H-PBRM, was synthesized and used for an in vivo biodistribution study that showed its gradual accumulation in various mouse tissues (peak at 6 h) followed by elimination until complete disappearance after 72 h. Elimination was found to occur in feces (93%) and urine (7%) as revealed by a mass balance experiment. PBRM was also evaluated for its toxicity in mice and it was found to be very well tolerated after weekly sc administration (30-405 mg/kg for 8 weeks) or by po administration (300-900 mg/kg for 4 weeks). Overall, these experiments represent important steps in the preclinical characterization of the pharmaceutical behavior of PBRM, as well as for its translation to clinical trials. PMID- 29248732 TI - Simple, Low-Cost Educational Interventions Can Reduce Radiation Exposure. PMID- 29248730 TI - Perceptual mechanisms underlying amodal surface integration of 3-D stereoscopic stimuli. AB - The visual system can represent a partially occluded 3-D surface from images of separated surface segments. The underlying amodal surface integration process accomplishes this by amodally extending each surface segment behind the occluder (amodal surface extension) and integrating the extended surfaces to form a whole surface representation. We conducted five experiments to investigate how depth cues, such as binocular disparity, half-occlusion, and monocular depth cues (T junctions and L-junctions), contribute to amodal surface extension, and how the geometrical relationship and image similarity among the surface segments affect surface integration. This was achieved by having observers adjust the stereoscopic depth and slant of a comparison stimulus to match those of the tested 3-D stimulus. We found that both binocular disparity and half-occlusion cues are used to determine border-ownership assignment of surface segments and for amodal surface extension. We also found that separated surface segments need to have the same luminance contrast-polarity for them to be integrated as a whole surface. Finally, we found that having the same motion direction, minimum misalignment between boundary contours, and proximity among separated segments facilitate their integration. Overall, our findings reveal a set of "perceptual factors" for amodal surface integration, which arguably reflects our visual system's built-in knowledge of the regularities in natural scenes. PMID- 29248733 TI - Esophageal Mucosal Impedance Patterns Discriminate Patients With Eosinophilic Esophagitis From Patients With GERD. AB - BACKGROUND & AIMS: It is a challenge to make a diagnosis of eosinophilic esophagitis (EoE) because its symptoms and histologic features overlap with those of gastroesophageal reflux disease (GERD). A minimally invasive device was recently developed to detect mucosal impedance (MI) that measures epithelial integrity during upper endoscopy. We aimed to quantify MI along the esophagus and identify patterns that differentiated patients with and without GERD from those with EoE, and determine whether MI values and patterns are sufficient to identify patients with EoE using histologic findings as a reference. METHODS: We performed a retrospective analysis of 91 patients with upper gastrointestinal symptoms referred for diagnostic testing for GERD and EoE from 2012 through 2014 (discovery set). During the first endoscopy, MI measurements were obtained at 2, 5, and 10 cm from the squamocolumnar junction. GERD was confirmed by ambulatory pH tests, and histologic analyses of biopsies were used to confirm EoE. We then used statistical modeling to identify MI patterns along the esophagus (at 10 cm, 5 cm, and 2 cm) that associated with GERD vs EoE. We validated our findings in a prospective cohort of 49 patients undergoing elective upper endoscopy for dysphagia, from 2015 through 2016, testing the ability of MI patterns to identify patients with vs. without EoE. RESULTS: We found patients with EoE to have a unique MI pattern, with low values along the esophageal axis. MI measurements at 5 cm could discern patients with normal vs abnormal mucosa with 83% sensitivity and 79% specificity, and patients with EoE vs GERD with 84% sensitivity and 70% specificity; these measurements differentiated the patient populations with the highest level of accuracy of any of the 6 measurements tested. In the validation study, a rater using the esophageal MI pattern identified patients with EoE with 100% sensitivity and 96% specificity. CONCLUSION: We identified and validated a pattern of MI along the esophagus that can identify patients with EoE vs normal mucosa or GERD with high levels of sensitivity. PMID- 29248734 TI - Eosinophilic Esophagitis Reference Score Accurately Identifies Disease Activity and Treatment Effects in Children. AB - BACKGROUND & AIMS: The endoscopic reference score (EREFS) is used to determine severity of 5 endoscopic findings: edema, rings, exudates, furrows, and strictures. Little is known about the relationship between EREFSs and histologic markers of disease activity in children with eosinophilic esophagitis (EoE). We aimed to determine whether the EREFS can be used to identify children with EoE and how it changes with treatment. METHODS: We performed a prospective study of consecutive children (ages 2-17 years) undergoing diagnostic or post-treatment endoscopy scored real-time with EREFS from December 2012 through 2016. Findings from 192 diagnostic endoscopies and 229 post-treatment endoscopies were evaluated, from 371 children. Incident EoE cases were diagnosed based on 2011 consensus guidelines. Patients were treated with either elimination diet or topical steroids. Subjects who underwent endoscopy for symptoms of esophageal dysfunction but had normal esophageal findings from histology analysis were used as controls. EREFS and receiver operating characteristic curves were determined for incident EoE cases (n = 77) vs controls (n = 115), patients with active EoE (n = 101) vs inactive EoE after treatment (n = 128), and paired pre- and post treatment cases of EoE (n = 85). Component and composite scores were correlated with eosinophilia. RESULTS: Visual detection of more than 1 esophageal abnormality during the diagnostic endoscopy identified children with EoE with 89.6% sensitivity and 87.9% specificity. EREFS correlated with peak level of eosinophilia (P < .001) at all esophageal levels. Children who responded to therapy had mean EREFSs of 0.5 compared to 2.4 in non-responders. In comparing pre-treatment vs post-treatment data from 85 patients, we found a significant reduction in the composite EREFS (from 2.4 to 0.7) (P < .001) among patients who responded to treatment; 92% of responders had a reduced EREFSs after treatment. EREFSs identified children with EoE with an area under the curve value (AUC) of 0.93. EREFSs identified children with active EoE following treatment with an AUC of 0.81 before treatment and an AUC of 0.79 after treatment. CONCLUSIONS: In a prospective study of children undergoing diagnostic or post-treatment endoscopy, we found the EREFS to accurately identify those with EoE. Children who responded to therapy had lower EREFS scores than non-responders. EREFSs can be used to measure outcomes of pediatric patients, in conjunction with histology findings, and assess treatments for children with EoE. PMID- 29248735 TI - Hepatic Steatosis and its Effects on Fibrosis in Patients With Chronic Hepatitis B Virus Infection. PMID- 29248736 TI - Contemporary glycomic approaches using ion mobility-mass spectrometry. AB - Characterization of complex oligosaccharides has historically required extensive sample handling and separations before analysis using nuclear magnetic resonance spectroscopy and electron impact mass spectra following hydrolysis, derivatization, and gas chromatographic separation. Advances in liquid chromatography separations and tandem mass spectrometry have expanded the range of intact glycan analysis, but carbohydrate structure and conformation-integral chemical characteristics-are often difficult to assess with minimal amounts of sample in a rapid fashion. Because ion mobility spectrometry (IMS) separates analytes based upon an effective 'size-to-charge' ratio, IMS is, by extension, highly applicable to glycomics. Furthermore, the speed of IMS, its growing levels of separation efficiency, and direct compatibility with all forms of mass spectrometry, illustrates is core role in the future of glycomics efforts. This review assesses the current state of ion mobility-mass spectrometry applied to glycan, glycoprotein, and glycoconjugate analysis. Currently, assessing optimal ion polarity and adduct type for a glycan class along with the appropriate tandem mass spectrometry technique underpin many of the current glycan analysis efforts using ion mobility-mass spectrometry (IMMS). Once determined, these parameters have enabled a growing and impressive range of glycomics campaigns employing this technique. Additionally, the combination of IMS with tandem mass spectrometry, and even spectroscopic methods, further expands the dimensionality of hybrid instrumentation to provide a more comprehensive assessment of glycan structure across a wide dynamic range. Continued computational efforts to complement experimental and instrumental advancements also serve as a core component of IMMS workflows applied to glycomics and promise to maximize the information gained from mobility separations. PMID- 29248737 TI - Environmental and hormonal control of body color polyphenism in late-instar desert locust nymphs: Role of the yellow protein. AB - Locusts show body color polyphenism that is considered to be an adaptation to various biotic and abiotic environmental changes. In Schistocerca gregaria, wild type late-instar nymphs growing under crowded conditions (gregarious form) develop yellow and black body coloration, whereas they assume various body colors under isolated conditions (solitarious form). Black and green body colorations are induced by the neuropeptide corazonin (Crz) and juvenile hormone (JH), respectively. To characterize the molecular mechanisms controlling body color polyphenism, we investigated factors influencing body coloration in S. gregaria. We report here that yellow body coloration in the last nymphal instar is caused by the yellow protein of the takeout family (YPT) in this locust. YPT transcription was enhanced under high-temperature conditions during which the nymphs turned bright yellow and had little black patterning. RNAi-mediated YPT knockdown suppressed the appearance of yellow individuals and yellow staining in the exuviae. In albino nymphs, injection of JH induced yellow and green coloration and enhanced the YPT expression levels in both yellow and green individuals. YPT knockdown also suppressed yellow staining in the exuviae but did not prevent the appearance of yellow individuals. Therefore, another factor or pigment may contribute to the observed yellow body color. Injection of Crz into wild-type nymphs caused darkening and suppressed yellowing and YPT expression at high temperatures. Thus, Crz signaling could inhibit yellowing by suppressing YPT expression. Rearing cup substrate color significantly influenced YPT expression in albino nymphs both under isolated and crowded conditions. In contrast, substrate color affected YPT expression in wild-type nymphs only under isolated conditions. From these results, we conclude that YPT is an important factor in the control of body color polyphenism in S. gregaria, and its expression is influenced by temperature, JH, Crz, and substrate color of the growing environment. PMID- 29248738 TI - Identification of immature stages of phlebotomine sand flies using MALDI-TOF MS and mapping of mass spectra during sand fly life cycle. AB - The aim of the study was to evaluate the potential of matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) for the species identification of sand flies at different developmental stages and map changes in their protein profiles during the course of whole life cycle. Specimens of six different species from laboratory colonies at larval and pupal stages were examined using MALDI-TOF MS. The protein profiles of larvae were stable from the L2 to L4 developmental stages and clearly distinguishable at the species level. In a validation study, 123 larvae of the six species were queried against reference database resulting in 93% correct species identification (log score values higher than 2.0). The spectra generated from sand fly pupae allow species identification as well and surprisingly, in contrast to biting midges and mosquitoes, they did not change during this developmental stage. For adults, thorax was revealed as the optimal body part for sample preparation yielding reproducible spectra regardless age and diet. Only variations were uncovered for freshly engorged females profiles of which were affected by blood signals first two days post bloodmeal. The findings demonstrate that in addition to adult species differentiation MALDI-TOF MS may also serve as a rapid and effective tool for species identification of juvenile stages of phlebotomine sand flies. PMID- 29248740 TI - Allogeneic Transplantation for Acute Myelogenous Leukemia in CR1. PMID- 29248741 TI - Downward migration of radiocesium in an abandoned paddy soil after the Fukushima Dai-ichi Nuclear Power Plant accident. AB - After the Fukushima Dai-ichi Nuclear Power Plant accident on March 2011, continuous monitoring of the detailed vertical distribution of radiocesium in soil is required to evaluate the fate of radiocesium and establish strategies for remediation and management of the contaminated land. It is especially important to investigate paddy soil because little knowledge has been accumulated for paddy soil and wetland rice is a major staple in Japan. Therefore, we monitored the vertical distribution of 137Cs in abandoned paddy soil in a planned evacuation zone from June 2011 to March 2016. The decontamination works (i.e., 5 cm of surface soil removal and re-covering with uncontaminated soil) were conducted by the government in 2015. As a result of monitoring, the 137Cs gradually migrated downward with time and the 137Cs concentration in the 0-10 cm soil was almost homogenous in October 2014, although it was non-cultivated. The liner relationship was obtained between the median depth, which is the thickness of a soil layer containing half of the total 137Cs inventory, and the time after the accident, indicating the migration rate was constant (1.3 cm y-1) before the decontamination works. After the decontamination works, the 137Cs concentration in the uppermost surface layer was reduced by 90%, however the total 137Cs inventory was reduced by only 50-70%. It was shown that the efficiency of 137Cs removal by the decontamination works decrease linearly over time in fields like the studied paddy, in which the homogenization of 137Cs concentration occurred. Conversely, the downward migration of 137Cs to subsurface layers deeper than 10 cm (i.e., plowpan layer) with low permeability rarely occurred. It is expected that these unique trends in distribution and migration of 137Cs would be found in abandoned paddy soils with properties similar to the studied soil, sandy loam but poorly drained because of the low permeable plowpan layer, although further validation is necessary. PMID- 29248739 TI - Maf1 phenotypes and cell physiology. AB - As a master regulator of transcription by RNA polymerase (Pol) III, Maf1 represses the synthesis of highly abundant non-coding RNAs as anabolic signals dissipate, as the quality or quantity of nutrients decreases, and under a wide range of cellular and environmental stress conditions. Thus, Maf1 responds to changes in cell physiology to conserve metabolic energy and to help maintain appropriate levels of tRNAs and other essential non-coding RNAs. Studies in different model organisms and cell-based systems show that perturbations of Maf1 can also impact cell physiology and metabolism. These effects are mediated by changes in Pol III transcription and/or by effects of Maf1 on the expression of select Pol II-transcribed genes. Maf1 phenotypes can vary between different systems and are sometimes conflicting as in comparisons between Maf1 KO mice and cultured mammalian cells. These studies are reviewed in an effort to better appreciate the relationship between Maf1 function and cell physiology. This article is part of a Special Issue entitled: SI: Regulation of tRNA synthesis and modification in physiological conditions and disease edited by Dr. Boguta Magdalena. PMID- 29248742 TI - Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors. AB - The ability of a number of nitrogen-containing compounds that simultaneously carry the adamantane and monoterpene moieties to inhibit Tdp1, an important enzyme of the DNA repair system, is studied. Inhibition of this enzyme has the potential to overcome chemotherapeutic resistance of some tumor types. Compound (+)-3c synthesized from 1-aminoadamantane and (+)-myrtenal, and compound 4a produced from 2-aminoadamantane and citronellal were found to be most potent as they inhibited Tdp1 with IC50 values of 6 and 3.5 uM, respectively. These compounds proved to have low cytotoxicity in colon HCT-116 and lung A-549 human tumor cell lines (CC50 > 50 uM). It was demonstrated that compound 4a at 10 uM enhanced cytotoxicity of topotecan, a topoisomerase 1 poison in clinical use, against HCT-116 more than fivefold and to a lesser extent of 1.5 increase in potency for A-549. PMID- 29248743 TI - Acellular dermal matrix collagen responds to strain by intermolecular spacing contraction with fibril extension and rearrangement. AB - Acellular dermal matrix (ADM) materials are used as scaffold materials in reconstructive surgery. The internal structural response of these materials in load-bearing clinical applications is not well understood. Bovine ADM is characterized by small-angle X-ray scattering while subjected to strain. Changes in collagen fibril orientation (O), degree of orientation as an orientation index (OI) (measured both edge-on and flat-on to the ADM), extension (from d-spacing changes) and changes to intermolecular spacing are measured as a result of the strain and stress in conjunction with mechanical measurements. As is already well established in similar systems, when strained, collagen fibrils in ADM can accommodate the strain by reorienting by up to 50 degrees (as an average of all the fibrils). This reorientation corresponds to the OI increasing from 0.3 to 0.7. Here it is shown that concurrently, the intermolecular spacing between tropocollagen decreases by 10% from 15.8 to 14.3A, with the fibril diameter decreasing from 400 to 375A, and the individual fibrils extending by an average of 3.1% (D-spacing from 63.9 to 65.9nm). ADM materials can withstand large strain and high stress due to the combined mechanisms of collagen reorientation, individual fibril extension, sliding and changes in the molecular packing density. PMID- 29248744 TI - Underbody blast effect on the pelvis and lumbar spine: A computational study. AB - Explosion from an anti-tank landmine under a military vehicle, known as underbody blast (UBB), may cause severe injury or even death for the occupants inside the vehicle. Severity and patterns of lower extremity, pelvis and lumbar spine injuries subjected to UBB have been found highly related to loading conditions, i.e. the vertical acceleration pulse. A computational human model has been developed and successfully simulated the tibia fracture under UBB in the previous study. In the present study, it was further improved by building a detailed lumbar spine and pelvis model with high biofidelity. The newly developed pelvis and lumbar spine were validated against component level test data in the literature. Then, the whole body model was validated with the published cadaver sled test data. Using the validated whole body model, parametric studies were conducted by adjusting the peak acceleration and time duration of pulses produced in the UBB to investigate the effect of waveform on the injury response. The critical values of these two parameters for pelvis and lumbar spine fracture were determined, and the relationship between injury pattern and loading conditions was established. PMID- 29248745 TI - To Bring Flowers or Do a Runner: Gibberellins Make the Decision. PMID- 29248746 TI - Research priorities for the discovery of a cure for chronic hepatitis B: Report of a workshop. AB - In early 2017, the Hepatitis B Foundation invited 30 experts in the fields of hepatitis B and liver cancer research to identify projects they deemed important to the goal of finding a cure for chronic hepatitis B and D and the diseases with which these viral infections are associated. They were also asked to identify general categories of research and to prioritize sub-project topics within those areas. The experts generally agreed on broadly defined areas of research, but there was usually little difference between the highest and lowest scoring projects; for the most part, all programs described in this document were considered valuable and necessary. An executive summary of this discussion was recently published (Alter et al., Hepatology 2017). The present manuscript reports the areas of research identified by the workshop participants, provides a brief rationale for their selection, and attempts to express differences among the priorities assigned to each area of research, when such distinctions were expressed. PMID- 29248747 TI - Brain size does not impact shoaling dynamics in unfamiliar groups of guppies (Poecilia reticulata). AB - Collective movement is achieved when individuals adopt local rules to interact with their neighbours. How the brain processes information about neighbours' positions and movements may affect how individuals interact in groups. As brain size can determine such information processing it should impact collective animal movement. Here we investigate whether brain size affects the structure and organisation of newly forming fish shoals by quantifying the collective movement of guppies (Poecilia reticulata) from large- and small-brained selection lines, with known differences in learning and memory. We used automated tracking software to determine shoaling behaviour of single-sex groups of eight or two fish and found no evidence that brain size affected the speed, group size, or spatial and directional organisation of fish shoals. Our results suggest that brain size does not play an important role in how fish interact with each other in these types of moving groups of unfamiliar individuals. Based on these results, we propose that shoal dynamics are likely to be governed by relatively basic cognitive processes that do not differ in these brain size selected lines of guppies. PMID- 29248748 TI - Occurrence of polybrominated dibenzo-p-dioxins, dibenzofurans (PBDD/Fs) and polybrominated diphenyl ethers (PBDEs) in pilot whales (Globicephala melas) caught around the Faroe Islands. AB - Blubber from Faroese pilot whales (Globicephala melas) was analysed for brominated dioxins PBDD/Fs, with a subset also analysed for chlorinated dioxins, PCDD/Fs. The studied individuals were restricted to juvenile male whales sampled in the Faroe Islands during the period 1997-2013. Among the PBDD/Fs, the furans were predominant, although the relative abundance of various congeners differed between samples. Furans accounted for, on average, 79% of the ?PBDD/Fs in the samples, with 1,2,3,4,6,7,8-HpBDF the most abundant congener, found in half of the analysed pilot whales. The concentration range for ?PBDD/Fs among the samples was 0.080-71 pg/g l.w. (lipid weight), and the sum of toxic equivalents ranged from 0.0039 to 4.7 pg TEQ/g l.w. No relationship was found between PBDD/Fs and PCDD/Fs. In addition, 20 pilot whale samples from the period 2010-2013 were analysed for PBDEs. Several PBDE congeners were found in all of the sampled pilot whales, and at noticeably higher levels than PBDD/Fs and PCDD/Fs. The ?PBDEs ranged from 140 to 1900 ng/g l.w., with BDE #47 the most abundant congener detected in the samples. Results from the present study were then compared with data from previous studies on pilot wales to investigate temporal trends between 1986 and 2013. The comparison indicated that PBDE concentrations in juvenile males have decreased from 1996 to the latest observations in 2013. No relationship between the concentration levels of PBDD/Fs and PBDEs in the sampled pilot whales could be identified, which indicates possible differences in the metabolism of, or exposure to, PBDEs and PBDD/Fs. PMID- 29248749 TI - Study of the antimicrobial activity of cyclic cation-based ionic liquids via experimental and group contribution QSAR model. AB - Over the past decades, Ionic liquids (ILs) have gained considerable attention from the scientific community in reason of their versatility and performance in many fields. However, they nowadays remain mainly for laboratory scale use. The main barrier hampering their use in a larger scale is their questionable ecological toxicity. This study investigated the effect of hydrophobic and hydrophilic cyclic cation-based ILs against four pathogenic bacteria that infect humans. For that, cations, either of aromatic character (imidazolium or pyridinium) or of non-aromatic nature, (pyrrolidinium or piperidinium), were selected with different alkyl chain lengths and combined with both hydrophilic and hydrophobic anionic moieties. The results clearly demonstrated that introducing of hydrophobic anion namely bis((trifluoromethyl)sulfonyl)amide, [NTF2] and the elongation of the cations substitutions dramatically affect ILs toxicity behaviour. The established toxicity data [50% effective concentration (EC50)] along with similar endpoint collected from previous work against Aeromonas hydrophila were combined to developed quantitative structure-activity relationship (QSAR) model for toxicity prediction. The model was developed and validated in the light of Organization for Economic Co-operation and Development (OECD) guidelines strategy, producing good correlation coefficient R2 of 0.904 and small mean square error (MSE) of 0.095. The reliability of the QSAR model was further determined using k-fold cross validation. PMID- 29248750 TI - Waste-water treatment plants are implicated as an important source of flame retardants in insectivorous tree swallows (Tachicyneta bicolor). AB - Wastewater treatment plants (WWTPs) are an important source of anthropogenic chemicals, including organic flame retardants (FRs). Limited studies indicate birds can be exposed to FRs by feeding from waters receiving WWTP effluent or in fields receiving biosolids. Expanding on our earlier study, 47 legacy and 18 new FR contaminants were characterized in the eggs of insectivorous tree swallows (Tachycineta bicolor) feeding in water bodies receiving effluent from two WWTPs and compared to those from a reference site 19 km downstream of the nearest WWTP. Of the FRs measured, polybrominated diphenyl ethers (PBDEs) dominated the FR profile, specifically BDE-47, -99, -100, -153, -154, with considerably lower concentrations of hexabromocyclododecane (HBCDD), BDE-183 and BDE-209; each detected in 96-100% of the eggs overall except HBCDD (83%). FR concentrations were usually significantly greater in eggs from the secondary WWTP versus the tertiary WWTP and/or reference site. Despite low detection rates, concentrations of new FRs, specifically pentabromobenzyl acrylate (PBBA), 1,2,-bis-(2,4,6 tribromophenoxy)ethane (BTBPE), bis(2-ethylhexyl)-tetrabromophthalate (BEHTBP), tetrabromo-o-chlorotoluene (TBCT), hexabromobenzene (HBB), alpha- and beta-1,2 dibromo-4-(1,2-dibromoethyl)-cyclohexane (DBE-DBCH), were greater than HBCDD or BDE-209. Additional evidence that WWTPs are an important source of exposure to new FR contaminants for birds utilizing associated water bodies is that only the WTTP eggs, not the reference eggs, had measureable concentrations of PBBA, TBCT, BEHTBP, HBB, alpha-DBE-DBCH, 2,2',4,5,5'-pentabromobiphenyl (BB-101), pentabromoethyl benzene (PBEB), 2,4,6-tribromophenyl allyl ether (TBPAE), and tetrabromo-p-xylene (pTBX). Our study suggests that WWTPs are an important source of legacy and new FR contaminants for birds consuming prey that are associated with WWTP out-flows. PMID- 29248751 TI - Design, synthesis and biological assessment of new thiazolylhydrazine derivatives as selective and reversible hMAO-A inhibitors. AB - In the recent works, it was shown that numerous thiazolylhydrazine derivatives display hMAO inhibitory activity in the range of micromolar concentration. Hence, in the present study a new series of new thiazole-hydrazines (3a-3n) were designed, synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro flurometric method. The enzyme inhibition assay revealed that most of the synthesized compounds have selective inhibition potency against hMAO-A. The compounds 3f and 3h showed promising hMAO-A inhibition with an IC50 values of 0.012 MUM and 0.011 MUM and significant selectivity indexes of 1214 and 1601 towards hMAO-A, respectively. The mechanism of hMAO-A inhibition of compounds 3f and 3h was investigated by Lineweaver-Burk graphics and reversible-competitive inhibition of hMAO-A was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 3h was found as non-cytotoxic and non-genotoxic. Theoretical calculation of ADME properties suggested that synthesized compounds may have a good pharmacokinetic profile. The docking study of compound 3f and 3h revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound. PMID- 29248752 TI - Inhibition of neddylation pathway represses influenza virus replication and pro inflammatory responses. AB - The neddylation pathway belongs post-translational modifications and plays important roles in regulating viral infection and replication. To address the relationship of influenza A virus with the neddylation modification pathway, we demonstrate that IAV infection in A549 cells can activate the neddylation modification pathway to increase virus growth and enhance the expression of pro inflammatory cytokines to increase pathogenicity. The pre-treatment of Nedd8 activating enzyme subunit 1 (NAE1)-specific inhibitor, MLN4924, interferes with Nedd8 conjugation and NF-kappaB activity. MLN4924 exhibited pronounced antiviral activity against different subtypes of influenza A virus, including classical H1N1 (PR8), H9N2 subtype, and pandemic H1N1 2009 (pdmH1N1) viruses. Through the inhibition of the CRL/NF-kappaB pathway, MLN4924 could significantly suppress the expression levels of pro-inflammatory cytokines induced by IAVs. These findings suggest that MLN4924 can be developed as a novel antiviral therapy for influenza infection for anti-viral efficacy and anti-inflammation activity. PMID- 29248753 TI - The study of vitamin D administration effect on CRP and Interleukin-6 as prognostic biomarkers of ventilator associated pneumonia. AB - PURPOSE: In regard with the effect of immune-stimulants in the treatment of infectious diseases, the effect of vitamin D administration on the outcome of patients with Ventilator-Associated Pneumonia (VAP) with a high rate of mortality, was studied. MATERIAL AND METHOD: In this trial, 46 adult patients suffering from VAP and vitamin D deficiency were enrolled. The first group of patients received single intramuscular injection of vitamin D (300000Unit), while the other group were given the placebo. RESULTS: Administration of vitamin D significantly enhanced its levels (P<0.0001) in the treated patients (12.28+/ 8.26) in comparison with placebo group (1.15+/-1.50). Serum Interleukin-6 levels were significantly reduced in the treated group compared to placebo (P=0.01). Although C-Reactive protein (CRP) levels showed an improving trend in the vitamin D group, no significant difference between groups (P=0.12) was found. Interestingly, the mortality rate of patients that treated with vitamin D (5/24) was significantly lower (p=0.04) than that of the placebo group (11/22). CONCLUSION: Our results indicate that vitamin D administration can significantly reduce the IL-6 as prognostic marker in VAP patients, and must be considered as adjunct option in the treatment of VAP patients. PMID- 29248754 TI - NMR interaction tensors of 51V and 207Pb in vanadinite, Pb5(VO4)3Cl, determined from DFT calculations and single-crystal NMR measurements, using only one general rotation axis. AB - Orientation-dependent NMR spectra of a single crystal of the mineral vanadinite, Pb5(VO4)3Cl, were acquired using only one rotation axis with a general orientation in the hexagonal crystal lattice (space group P63/m). The chemical shift (CS) tensors for the 207Pb on Wyckoff positions 6h and 4f, and both CS and quadrupole coupling tensor Q for 51V at the positions 6h were determined by including the NMR response of symmetry-related atoms in the unit cell (and in case of 207Pb at 4f, also the isotropic shift from MAS NMR spectra). This previously suggested 'single rotation method' greatly reduces the necessary amount of data acquisition and analysis. The precise orientation of the rotation axis could not be found by X-ray diffraction experiments because of the high linear absorption coefficient of vanadinite, which is chiefly due to its high lead content. The axis orientation was therefore included into the multi parameter data fit routine. This NMR-based approach is widely applicable, and offers an alternative way of orienting single crystals. The NMR parameters derived from the tensor eigenvalues are deltaiso=(-1729+/-9) ppm, Deltadelta=( 1071+/-5) ppm, etaCS=0.362+/-0.008 for 207Pb at positions 6h, and deltaiso=( 1619+/-2) ppm, Deltadelta=(-780+/-58) ppm, etaCS=0.06+/-0.08 for positions 4f. For 51V, deltaiso=(-509+/-3) ppm, Deltadelta=(-37+/-2) ppm, etaCS=0.78+/-0.09, with the quadrupolar coupling described by chi=(2.52+/-0.01) MHz and etaQ=0.047+/ 0.003. In contrast to the precisely determined tensor eigenvalues, the orientation of the eigenvectors in the crystal ab -plane of the vanadinite system could only be resolved by resorting to data obtained from density functional theory (DFT) calculations. PMID- 29248755 TI - Construction of a synthetic metabolic pathway for the production of 2,4 dihydroxybutyric acid from homoserine. AB - 2,4-dihydroxybutyrate (DHB) is a precursor for the chemical synthesis of the methionine analogue 2-hydroxy-4-(methylthio)butyrate. Since no annotated metabolic pathway exists for its microbial production from sugar, we have conceived a two-step synthetic metabolic pathway which converts the natural amino acid homoserine to DHB. The pathway proceeds through the homoserine transaminase catalyzed deamination of homoserine to obtain 2-oxo-4-hydroxybutyrate (OHB), and continues with the reduction of OHB to DHB, which is catalyzed by an OHB reductase enzyme. We identified homoserine transaminase and OHB reductase activity in several candidate enzymes which act on sterically cognate substrates, and improved OHB reductase activity of lactate dehydrogenase A of Lactococcus lactis by structure-based enzyme engineering. Fed-batch cultivation of a homoserine-overproducing Escherichia coli strain which expressed homoserine transaminase and OHB reductase enzymes resulted in the production of 5.3g/L DHB at a yield of 0.1g/g. PMID- 29248756 TI - Changes in the element concentration of the dorsal hippocampus CA1 region during memory consolidation and reconsolidation. AB - The concentration and distribution of Mg, P, Cl, K, Cu and Zn in the dorsal hippocampus CA1 region of rat brains were studied during memory consolidation and reconsolidation processes stimulated with inhibitory avoidance (IA) tests. Experimental rats were divided into four groups: i) group not submitted to inhibitory avoidance task (IA-N); ii) group submitted to inhibitory avoidance training session (IA-Y); iii) group submitted to inhibitory avoidance reactivation session but did not step down from the platform (IAR-N); and iv) group submitted to avoidance reactivation session and stepped down from the platform (IAR-Y). Elemental concentration and distribution in the CA1 hippocampus region were obtained through the Particle-Induced X-ray Emission (PIXE) technique. The results indicate that the concentration of Mg, P, Cl, K and Cu increased during memory consolidation. During the memory reconsolidation process, the concentrations of Mg, P, Cl and K increased, while Cu and Zn had no significant changes with respect to their basal condition. These results show that the major part of these elements may be engaged in memory consolidation could be also participating in memory reconsolidation. For all elements, the general trend related to their concentration did not change during reconsolidation regardless the presence of a novelty event, i.e. stepping down from the platform. PMID- 29248757 TI - Envelope glycoproteins sampling states 2/3 are susceptible to ADCC by sera from HIV-1-infected individuals. AB - Recent analysis of HIV-1 envelope glycoproteins (Env) dynamics showed that the unliganded Env trimer can potentially sample three conformations: a metastable "closed" conformation (State 1), an "open" CD4-bound conformation (State 3), and an intermediate "partially open" conformation (State 2). HIV-1 evolved several mechanisms to avoid "opening" its Env in order to evade immune responses such as antibody-dependent cellular cytotoxicity (ADCC), which preferentially targets Envs in the CD4-bound conformation on the surface of infected cells. Here we took advantage of a well-characterized single-residue change in the gp120 trimer association domain to modify Env conformation and evaluate its impact on ADCC responses. We found that cells infected with viruses expressing Env stabilized in States 2/3 become highly susceptible to ADCC responses by sera from HIV-1 infected individuals. Our results indicate that the conformations spontaneously sampled by the Env trimer at the surface of infected cells has a significant impact on ADCC responses. PMID- 29248758 TI - Poor cognitive ageing: Vulnerabilities, mechanisms and the impact of nutritional interventions. AB - BACKGROUND: Ageing is a highly complex process marked by a temporal cascade of events, which promote alterations in the normal functioning of an individual organism. The triggers of normal brain ageing are not well understood, even less so the factors which initiate and steer the neuronal degeneration, which underpin disorders such as dementia. A wealth of data on how nutrients and diets may support cognitive function and preserve brain health are available, yet the molecular mechanisms underlying their biological action in both normal ageing, age-related cognitive decline, and in the development of neurodegenerative disorders have not been clearly elucidated. OBJECTIVES: This review aims to summarise the current state of knowledge of vulnerabilities that predispose towards dysfunctional brain ageing, highlight potential protective mechanisms, and discuss dietary interventions that may be used as therapies. A special focus of this paper is on the impact of nutrition on neuroprotection and the underlying molecular mechanisms, and this focus reflects the discussions held during the 2nd workshop 'Nutrition for the Ageing Brain: Functional Aspects and Mechanisms' in Copenhagen in June 2016. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). CONCLUSION: Coupling studies of cognitive ageing with studies investigating the effect of nutrition and dietary interventions as strategies targeting specific mechanisms, such as neurogenesis, protein clearance, inflammation, and non-coding and microRNAs is of high value. Future research on the impact of nutrition on cognitive ageing will need to adopt a longitudinal approach and multimodal nutritional interventions will likely need to be imposed in early-life to observe significant impact in older age. PMID- 29248759 TI - Asbestos fibre burden in gallbladder: A case study. AB - The methods conventionally used to determine the burden of asbestos fibres inhaled/incorporated in lung require chemical digestion of the biological matrix before counting/characterising the inorganic fibrous phases under scanning electron microscopy and energy dispersive spectroscopy (SEM/EDS). Asbestos fibres can also be present in extra-pulmonary organs, and we set out to quantify the fibres in gallbladder. Although the standardised procedure requires approximately 5 * 10-1 g of wet tissue, this amount of tissue is not always available. We applied the procedure on about 9 * 10-4 g of gallbladder from a patient with known environmental and workplace exposure to asbestos. The patient died of malignant pleural mesothelioma and was also affected by severe bile-tract problems. The traditional procedure of digesting tissue samples in NaClO and filtering the resulting suspension was carried out. The filter was then examined under SEM/EDS using two methods 1. following the standardised procedure to assess the fibre burden in lung by investigating only 2 mm2 of the filter (660 microscopic fields), and 2. analysing all the microscopic fields in one-quarter of the filter (about 82 mm2). In parallel, histological sections (prepared in the usual way for medical diagnosis) were analysed without digestion or manipulation of the sample using variable pressure SEM/EDS. The fibre counts obtained using the two methods were of the same order of magnitude, i.e., ~105 fibres/g of wet tissue. We showed that the counting of fibres in human tissue may be successfully carried out even when a limited amount of tissue is available. We also found that, when exposure to asbestos is considerable, the number of asbestos fibres accumulating in the gallbladder may be significant. PMID- 29248761 TI - Low-dose metformin exposure causes changes in expression of endocrine disruption associated genes. AB - The presence of intersex fish in watersheds around the world is a warning of the presence of anthropogenic endocrine-disrupting compounds (EDCs) being deposited into the aquatic environment. The anti-diabetic drug metformin is among the most prevalent and ubiquitous of the myriad pharmaceuticals found in wastewater effluent and watersheds worldwide. In addition to its prescription for type-2 diabetes, metformin is indicated as a treatment in cancers and the endocrine disorder polycystic ovarian syndrome (PCOS). Our previous research found evidence of endocrine-disruption following Pimephales promelas (fathead minnow) exposure to metformin at an environmentally relevant concentration. However, the mechanism of action leading to these impacts is unknown. Although metformin does not structurally resemble classical EDCs, there's an increasing recognition that endocrine disruption may occur by mechanisms other than classical endocrine receptor binding, and metformin's off-label use for treating endocrine-related disorders such as PCOS indicates its potential interaction with the endocrine system. To further explore metformin's mechanism of action as an EDC, we measured expression of numerous endocrine-related genes in male fathead minnows exposed to metformin at a low-dose similar to that found in wastewater effluent and the environment (40 MUg L-1) for a full year (early development to adulthood) and discovered significant upregulation of the AR (3.6 +/- 0.9-fold), 3beta-HSD (3.9 +/- 0.8-fold), 17beta-HSD (17 +/- 4-fold), CYP19A1 (40 +/- 20-fold), and SULT2A1 (2.3 +/- 0.4-fold) genes in exposed male gonad. We also found a significant correlation between expression of 3beta-HSD, 17beta-HSD, and CYP19A1 in testis of metformin-treated male fish and the degree of intersex occurring in their gonads. These results provide additional evidence of the endocrine disrupting impact of the drug metformin and insight into the potential mechanisms by which metformin may influence the endocrine system in aquatic organisms. PMID- 29248760 TI - Individuals with Borderline Personality Disorder show larger preferred social distance in live dyadic interactions. AB - Personal space regulation is a key component of effective social engagement. Personal space varies among individuals and with some mental health conditions. Simulated personal space intrusions in Borderline Personality Disorder (BPD) reveal larger preferred interpersonal distance in that setting. These findings led us to conduct the first test of live interpersonal distance preferences in symptoms in BPD. With direct observation of subjects' personal space behavior in the stop-distance paradigm, we found a 2-fold larger preferred interpersonal distance in BPD than control (n = 30, n = 23). We discuss this result in context of known biology and etiology of BPD. Future work is needed to identify neural circuits underlying personal space regulation in BPD, individual differences in preferred interpersonal distance in relation to specific symptoms and relationship to recovery status. PMID- 29248762 TI - Serum persistent organic pollutants levels and stroke risk. AB - Knowledge of environmental risk factors for stroke and their role are limited. We performed a case-cohort study to evaluate the association between serum persistent organic pollutants (POPs) level and stroke risk. 526 subcohort members and 111 stroke incidence cases were identified from the Korean Cancer Prevention Study-II. Serum levels of POPs were measured using gas chromatography/high resolution mass spectrometry. The hazard ratios (HRs) for stroke (ischemic, hemorrhagic, and all stroke types) were estimated using the weighted Cox regression model. Age, sex, body mass index, smoking status, physical activity, family history of cardiovascular disease, and hypertension were adjusted in the weighted Cox regression model. After adjusting for potential confounding factors, increased risk for stroke was observed among participants with serum concentration of p,p'-DDE in the highest tertile compared to those in the lowest tertile (HR = 4.10, 95% CI: 1.58, 10.59). A similar association was estimated for PCB118 (HR = 2.33, 95% CI: 1.04, 5.22), PCB156 (HR = 3.42, 95% CI: 1.42, 8.23), and PCB138 (HR = 3.80, 95% CI: 1.48, 9.76). For TEQ, stroke was three times as likely to occur among subjects with TEQ in the highest tertile compared to those in the lowest tertile (HR = 3.12, 95% CI: 1.27, 7.65). PCBs were positively associated with ischemic stroke, but not with hemorrhagic stroke. Elevated serum POPs levels were associated with an increased risk of stroke, especially ischemic stroke. PMID- 29248763 TI - Surgical treatment of osteoporotic degenerative spinal deformity with expandable pedicle screw fixation: 2-year follow-up clinical study. AB - BACKGROUND: Osteoporotic bone offers poor purchase for the instrumentation in patients with degenerative spinal deformity (DSD), which could lead to several complications. Recently, augmentation methods to improve pedicle screw fixation have been proposed. This retrospective study was to investigate the clinical and radiographic outcomes of expandable pedicle screws (EPS) in patients with osteoporotic DSD. HYPOTHESIS: Expandable pedicle screws (EPS) provide excellent instrument fixation in patients with osteoporotic DSD, improving radiographic and clinical outcomes. MATERIALS AND METHODS: A total of 27 (6 males and 21 females) DSD patients who underwent orthopedics operation with EPS were retrospectively studied. Full-length standing spinal radiographs were obtained in all patients pre- and postoperatively and again at the two-year follow-up. The functional evaluations before operation and at two-year follow-up were graded with Scoliosis Research Society outcomes instrument-22 (SRS-22) and Oswestry Disability Index (ODI) scoring system. RESULTS: All patients obtained good corrective outcomes on spinal deformity. The preoperative ODI score was 36.7% and reduced to 11.9% at two-year follow-up (p=0.0000). Before operation, the SRS-22 function, pain, appearance and mental scores were 2.7+/-0.4, 3+/-0.6, 2.7+/-0.5 and 2.9+/-0.6, respectively. The scores at two-year follow-up were significantly improved to 3.8+/-0.7, 4.2+/-0.6, 4.3+/-0.6 and 4.4+/-0.7, respectively (p=0.0000). The SRS 22 satisfaction score was 4.6+/-0.4 at two-year follow-up. No instances of screw breakage, loosening or pullout in any patient at follow-up. DISCUSSION: EPS provides excellent instrument fixation in patients with osteoporotic DSD, improving radiographic and clinical outcomes at two years' follow-up. TYPE OF STUDY: Retrospective case series study. LEVEL OF EVIDENCE: IV. PMID- 29248764 TI - Application of 3D-printing technology in the treatment of humeral intercondylar fractures. AB - PURPOSE OF THE STUDY: This study was aimed to compare conventional surgery and surgery assisted by 3D-printing technology in the treatment of humeral intercondylar fractures. In addition, we also investigated the effect of 3D printing technology on the communication between doctors and patients. MATERIAL AND METHODS: A total of 91 patients with humeral intercondylar fracture were enrolled in the study from March 2013 to August 2015. They were divided into two groups: 43 cases of 3D-printing group, 48 cases of conventional group. The individual models were used to simulate the surgical procedures and carry out the surgery according to plan. Operation duration, blood loss volume, fluoroscopy times and time to fracture union were recorded. The final functional outcomes, including the motion of the elbow, MEPS and DASH were also evaluated. Besides, we made a simple questionnaire to verify the effectiveness of the 3D-printed model for both doctors and patients. RESULTS: The operation duration, blood loss volume and fluoroscopy times for 3D-printing group was 76.6+/-7.9minutes, 231.1+/-18.1mL and 5.3+/-1.9 times, and for conventional group was 92.0+/-10.5minutes, 278.6+/ 23.0mL and 8.7+/-2.7 times respectively. There was statistically significant difference between the conventional group and 3D-printing group (p<0.05). However, No significant difference was noted in the final functional outcomes between the two groups. Furthermore, the questionnaire showed that both doctors and patients exhibited high scores of overall satisfaction with the use of a 3D printing model. DISCUSSIONS: This study suggested the clinical feasibility of 3D printing technology in treatment of humeral intercondylar fractures. LEVEL OF EVIDENCE: Level II prospective randomized study. PMID- 29248765 TI - Chronic anterior shoulder instability with significant Hill-Sachs lesion: Arthroscopic Bankart with remplissage versus open Latarjet procedure. AB - BACKGROUND: The objective of this study was to compare short-term shoulder stability after arthroscopic Bankart repair with remplissage versus the open Latarjet procedure in patients who had chronic anterior shoulder instability with a significant Hill-Sachs lesion. HYPOTHESIS: The dislocation recurrence rate is higher after Bankart repair with remplissage than after open Latarjet. PATIENTS AND METHODS: An observational non-randomised retrospective cohort study was conducted at two surgical centres in patients treated for chronic anterior shoulder instability with a significant Hill-Sachs defect between January 2009 and July 2014. The study compared 43 patients managed by arthroscopic Bankart repair and remplissage and 43 patients managed with open Latarjet. The two groups were matched on age at surgery and on follow-up duration. All patients were evaluated by independent observers based on a questionnaire including recurrences, range of motion, and functional outcomes (Shoulder Subjective Value [SSV], Walch-Duplay score, and Rowe score). RESULTS: Mean follow-up was 47.3 months (range, 24-67 months). The recurrence rate at last follow-up was not significantly different between the two groups (9.3% versus 11.2%; P=0.67). The Bankart group had significantly greater loss of external rotation and a significantly higher proportion of patients with residual pain (21% versus 9%, P=0.023). The SSV, Walch-Duplay score, and Rowe score values were similar between groups. DISCUSSION: In patients who had chronic anterior shoulder instability with a significant Hill-Sachs lesion, arthroscopic Bankart repair with remplissage and open Latarjet were reliable and safe procedures associated with low and similar recurrence rates. However, loss of external rotation and residual pain were significantly more common with the combined Bankart-remplissage procedure. LEVEL OF EVIDENCE: III; comparative retrospective study. PMID- 29248766 TI - Management of metastatic humeral fractures: Variations according to orthopedic subspecialty, tumor characteristics. AB - HYPOTHESIS: This study assessed, if there was a difference in surgical decision making for metastatic humeral lesions based on; orthopaedic subspecialty, tumor characteristics. STUDY TYPE: Cross sectional survey study. MATERIALS AND METHODS: Twenty-four case scenarios were created by combining: tumor type, life expectancy, fracture type, and anatomical location. Participants were asked for every case: what treatment would you recommend? Participants were 78 (48%) orthopaedic oncologists and 83 (52%) orthopaedic surgeons that were not regularly involved in the treatment of bone tumors. RESULTS: There was a difference between orthopaedic oncologists and other subspecialty surgeons in recommendation for specific treatments: intramedullary nailing was less often recommended by orthopaedic oncologists (53%, 95%CI: 47-59) compared to other surgeons (62%, 95%CI: 57-67) (p=0.023); while endoprosthetic reconstruction (orthopaedic oncologists: 8.8% [95%CI: 6.6-11], other surgeons: 3.6%[95%CI: 2.3-4.8], p<0.001) and plate-screw fixation (orthopaedic oncologists: 19%[95%CI: 14-25], other surgeons: 9.5%[95%CI: 5.9-13], p=0.003) were more often recommended by orthopaedic oncologists. There was no difference in recommendation for nonoperative management. There were differences in recommendation for specific treatments based on tumor type, life expectancy, and anatomical location, but not fracture type. DISCUSSION: Subspecialty training and patient and tumor characteristics influence the decision for operative management and the decision for a specific implant in metastatic humeral fractures. LEVEL OF EVIDENCE: Level 3. PMID- 29248767 TI - Efficient purification of Apolipoprotein A1 (ApoA1) from plasma by HEA HyperCelTM: An alternative approach. AB - HDL-ApoA1 plays a pivotal role in the prevention of atherosclerosis and cardiovascular diseases. ApoA1 purification from blood plasma has always remained tedious, involving multiple steps, large volumes of plasma and substantial loss in the final yield of pure ApoA1. In this study, a two-step method has been developed and optimized for the purification of ApoA1 from plasma. Plasma was first subjected to 60% ammonium sulphate (NH4)2SO4 precipitation and subsequently, ApoA1 was recovered using mixed mode chromatographic sorbent, HEA HyperCelTM. ApoA1 was found to be enriched in 60% (NH4)2SO4 supernatant that was dialyzed and injected onto HEA sorbent with 50 mM phosphate buffer pH 7.4. The bound proteins were eluted by decreasing the pH in step-gradient from pH 7.4 to pH 4.0 and subsequently to pH 3.5 using 50 mM sodium acetate buffer. Gel electrophoresis showed elution of homogeneous apoA1 at pH 3.5, with purity and yield of 63%. An interesting feature of this approach is that the purified ApoA1 was monomeric with a mass of 28,079.30 Da as confirmed by MS analysis. This simple and efficient method of purification of apoA1 serves as an alternative method which can be combined with traditional approaches and has a great potential for biochemical and clinical studies. PMID- 29248768 TI - Measurement of 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydro guanosine in cerebrospinal fluid by ultra performance liquid chromatography tandem mass spectrometry. AB - Increased levels of nucleosides modified by oxidation in human cerebrospinal fluid (CSF) have several times been reported in Alzheimer patients and patients suffering from Parkinson's disease. The focus has especially been on nucleosides containing the 8-hydroxylation of guanine. Only few reports on quantification of the ribonucleoside 8-oxo-7,8-dihydro-guanosine (8oxoGuo) in CSF have been published, whereas more have been published on the quantification of the deoxy ribonucleoside 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodGuo). The reports on the quantification of 8oxodGuo concentrations in CSF report absolute concentrations varying by a factor >105 in healthy humans. This could indicate that there is a serious specificity problem in some of the methods. In this paper an isotope dilution UPLC-MS/MS method with high specificity and sensitivity for the quantification of 8oxoGuo and 8oxodGuo in CSF is presented. LLOQ for the two analytes is determined to 4pM and 2pM, respectively. The calibration curves has been tested to be linear in the range from 4 to 3,000pM for 8oxoGuo and between 2 and 3,000pM for 8oxodGuo. Using a weighting factor of 1/x the correlation coefficient "r" for both analytes is >0.999. PMID- 29248769 TI - An improved liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of dexmedetomidine concentrations in samples of human plasma. AB - Dexmedetomidine (DMET) is a sedative, analgesic and anxiolytic with minimum adverse respiratory effects. An LC-MS/MS bioanalytical method has been developed and validated to accurately measure DMET concentrations in samples of human plasma. The method overcomes difficulties in the extraction and quantification of DMET due to the fact that it binds strongly to glass and plastic tubes, as well as solid phase extraction (SPE) cartridges. Human plasma (50 MUL) was mixed with the internal standard (IS) (DMET-d4) solution (100 MUL) and 0.1% formic acid (50 MUL) and extracted using Oasis HLB 1 CC (30 mg) solid phase extraction (SPE) cartridges (Waters(r)). The glass tubes were coated with bovine serum albumin (BSA) 0.5% (20 MUL) before eluting DMET and the IS. After evaporation under nitrogen at room temperature, the analytes were reconstituted in 20% acetonitrile in 0.1% formic acid in water and transferred to silanized glass vials. An electrospray ionisation (ESI) mass spectrometry method in positive mode was created and the precursor/product transitions (m/z) were 201.1 -> 95.0 (DMET) and 204.9 -> 99.0 (IS). The method was robust and fully validated based on the 2012 EMEA guideline for bioanalytical method validation in the concentration range of 0.5-20 ng/mL. Using this assay, we showed that DMET binds strongly to Extracorporeal Membrane Oxygenation (ECMO) circuits, consistent with expectations for small lipophilic compounds. PMID- 29248770 TI - Development and validation of an UHPLC-ESI-QTOF-MS method for quantification of the highly hydrophilic amyloid-beta oligomer eliminating all-D-enantiomeric peptide RD2 in mouse plasma. AB - During preclinical drug development, a method for quantification of unlabeled compounds in blood plasma samples from treatment or pharmacokinetic studies in mice is required. In the current work, a rapid, specific, sensitive and validated liquid chromatography mass-spectrometric UHPLC-ESI-QTOF-MS method was developed for the quantification of the therapeutic compound RD2 in mouse plasma. RD2 is an all-D-enantiomeric peptide developed for the treatment of Alzheimer's disease, a progressive neurodegenerative disease finally leading to dementia. Due to RD2's highly hydrophilic properties, the sample preparation and the chromatographic separation and quantification were very challenging. The chromatographic separation of RD2 and its internal standard were accomplished on an Acquity UPLC BEH C18 column (2.1 * 100 mm, 1.7 MUm particle size) within 6.5 min at 50 degrees C with a flow rate of 0.5 mL/min. Mobile phases consisted of water and acetonitrile with 1% formic acid and 0.025% heptafluorobutyric acid, respectively. Ions were generated by electrospray ionization (ESI) in the positive mode and the peptide was quantified by QTOF-MS. The developed extraction method for RD2 from mouse plasma revealed complete recovery. The linearity of the calibration curve was in the range of 5.3 ng/mL to 265 ng/mL (r2 > 0.999) with a lower limit of detection (LLOD) of 2.65 ng/mL and a lower limit of quantification (LLOQ) of 5.3 ng/mL. The intra-day and inter-day accuracy and precision of RD2 in plasma ranged from -0.54% to 2.21% and from 1.97% to 8.18%, respectively. Moreover, no matrix effects were observed and RD2 remained stable in extracted mouse plasma at different conditions. Using this validated bioanalytical method, plasma samples of unlabeled RD2 or placebo treated mice were analyzed. The herein developed UHPLC-ESI-QTOF-MS method is a suitable tool for the quantitative analysis of unlabeled RD2 in plasma samples of treated mice. PMID- 29248771 TI - The application of dispersive liquid-liquid microextraction in the analyses of the fatty acid profile in bovine milk in response to changes in body condition score. AB - Dispersive liquid-liquid microextraction (DLLME) was used prior to gas chromatography flame ionization detection (GC-FID) for the extraction of five fatty acids from milk taken from cows with different body condition scores. Optimum extraction conditions were: 300 MUL of chloroform (extraction solvent), and 1 mL methanol (dispersive solvent). The procedure was optimised using Design of Experiments (DoE). The analytes were separated on a GC capillary column containing a polyethylene glycol stationary phase (15 m * 0.53 mm * 1.2 MUm). Enrichment factors were in the range of 8-15 and limit of detection (LOD) was 0.04 MUg/mL. Calibration graphs showed good linearity with coefficients of determination higher than 0.994% and relative standard deviations lower than 7%. This method provided a simple and rapid derivatisation and extraction method for the determination of fatty acids in bovine milk. It showed that there was a significant difference in the palmitic acid content of milk from cows that had an optimum body condition score (10.85 mg/mL) compared to cows that had a high body condition score (5.73 mg/mL). PMID- 29248772 TI - Studies on polar high-speed counter-current chromatographic systems in separation of amaranthine-type betacyanins from Celosia species. AB - Betacyanins, natural plant pigments exhibiting antioxidant and chemopreventive properties, were extracted from Celosia spicata (Thouars) Spreng. inflorescences and separated by high-speed counter-current chromatography (HSCCC) in two polar solvent systems composed of: TBME - 1-BuOH - ACN - H2O (0.7% HFBA, 2:2:1:5, v/v/v/v) (system I) and EtOH - ACN - 1-PrOH - (NH4)2SO4satd.soln - H2O (0.5:0.5:0.5:1.2:1, v/v/v/v/v) (system II). The systems were used in the head-to tail (system I) and tail-to-head (system II) mode. The flow rate of the mobile phase was 2.0 ml/min and the column rotation speed was 860 rpm. The retention of the stationary phase was 73.5% (system I) and 80.0% (system II). For the identification of separated betacyanins in the crude extract as well as in the HSCCC fractions, LC-DAD-ESI-MS/MS analyses were performed. Depending on the target compounds, each of the systems exhibit meaningfully different selectivity and applicability. For the pairs of amaranthines (1/1') and betanins (2/2'), the best choice is the system II, but the acylated amaranthine pairs (3/3' and 4/4') can be resolved only in the ion-pair system I. For the indication of the most suitable solvent system for Celosia plumosa hort., Celosia cristata L. and Celosia spicata (Thouars) Spreng. species, the profiles of betacyanins in different plant parts were studied. PMID- 29248773 TI - Spine Surgery Complicated by an Engorged Lumbar Epidural Venous Plexus from Cerebrospinal Fluid Overshunting: A Case Report and Review of the Literature. AB - BACKGROUND: Overshunting of cerebrospinal fluid may lead to intracranial hypotension and dilation of spinal epidural veins. Radiculopathy may rarely occur secondary to engorged spinal epidural veins. In addition, the cause of radiculopathy may be obscured by concomitant spinal degenerative changes. We present a case and review the pathogenesis as well as the current clinical literature. CASE DESCRIPTION: A 29-year-old woman presented with positional headaches from intracranial hypotension in the setting of cerebrospinal fluid overshunting. The patient also had back pain and lumbar radiculopathy, which became more severe after lumboperitoneal shunt placement. On radiographic work up, there was evidence of right L5 nerve root impingement secondary to a disc bulge and an engorged lumbar epidural venous plexus secondary to overshunting. The patient underwent surgery for a planned L4-5 decompression with a transforaminal lumbar interbody fusion. The operation was complicated by rapid blood loss originating from the epidural venous plexus, and we were unable to safely place the interbody graft. CONCLUSIONS: Spinal surgeons need to be aware of the rare diagnosis of radiculopathy secondary to epidural venous plexus engorgement, as it may change the treatment approach or lead to deleterious intraoperative consequences, such as hemorrhage. PMID- 29248774 TI - Presenting Symptoms and Prognostic Factors for Symptomatic Outcomes Following Resection of Meningioma. AB - BACKGROUND: Meningioma is the most common primary intracranial tumor and patients present with diverse neurologic symptoms related to meningioma location. This study aimed to systematically quantify the presenting symptoms of meningioma and identify prognostic factors for symptomatic outcome following resection. METHODS: Two-hundred and eighty-three patients who underwent resection of a total of 313 meningiomas at a single institution were retrospectively identified, including 161 World Health Organization grade I (52.6%), 108 grade II (35.5%), and 37 grade III meningiomas (12.1%). Patient-reported symptoms were extracted from the medical record and dichotomized into acute (<3 months) and long-term (3-12 months) categories. The chi2 test and multivariate regression were used to compare groups. RESULTS: Patients presented primarily with headaches (48.2%) and either cerebral dysfunctions (48.5%) with convexity meningiomas or cranial nerve deficits (38.9%) with skull base meningiomas. Symptomatic improvement in the acute postoperative period was significantly correlated with long term symptomatic improvement (P <= 0.01). Headaches and seizures had the greatest rates of symptomatic improvement after surgery (78%), and the vast majority of patients with symptom improvement experienced complete resolution (86%). In contrast, symptoms persisted in >60% of patients with anosmia, sensory changes, or frontal, temporal, or cerebellar symptoms. Multivariate regression identified subtotal resection as a prognostic factor for persistent symptoms (odds ratio, 0.62; 95% confidence interval, 0.03-1.21; P = 0.041). CONCLUSIONS: Symptoms improve in the majority of patients after resection of meningioma, with the rate of improvement varying according to symptom type and extent of resection. These data may be a useful when counseling patients about symptoms after resection of meningiomas. PMID- 29248775 TI - Pre-Intracerebral Hemorrhage and In-Hospital Statin Use in Intracerebral Hemorrhage: A Systematic Review and Meta-analysis. AB - BACKGROUND: The association between pre-intracerebral hemorrhage (ICH) statin use and clinical outcomes after intracerebral hemorrhage (ICH) is still conflicting. Recently, some studies investigating the effects of in-hospital statin use after the onset of ICH have been published. To provide a more complete picture of the clinical effects of statin use in ICH, we performed a systematic review to examine whether statin use influences clinical outcomes. METHODS: We conducted a systematic review of literature in the Cochrane Library, MEDLINE, EMBASE, and the China National Knowledge Infrastructure database. RESULTS: Twenty-one studies were included in our systematic review. Meta-analysis of 12 studies suggested that pre-ICH statins use did not significantly decrease mortality when aggregated across all time points tested-that is, in-hospital or at 30 or 90 days (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.70-1.03). Meta-analysis of 7 studies suggested that pre-ICH statins use did not significantly affect poor functional outcomes, defined as a modified Rankin Scale (mRS) score of 3-6 (OR, 0.93; 95% CI, 0.72-1.18) or mRS score of 4-6 (OR, 0.92; 95% CI, 0.60-1.40). Meta analysis of 7 studies suggested that in-hospital statin use significantly decreased mortality when aggregated across all time points tested (OR, 0.37; 95% CI, 0.28-0.50). Statin discontinuation was independently associated with poor clinical outcome. CONCLUSIONS: The patients with pre-ICH statin use did not improve clinical outcomes. However, in-hospital statin use can significantly decrease mortality after ICH. In-hospital statin therapy might be beneficial for patients with ICH. PMID- 29248776 TI - Spinal Epidural Cavernous Hemangioma: A Clinical Series of 7 Patients. AB - OBJECTIVE: To investigate imaging characteristics of spinal epidural cavernous hemangiomas (ECHs) and improve understanding of this rare disease. METHODS: This retrospective study included 7 cases of ECH, confirmed with surgical pathology and imaging. All patients underwent computed tomography and conventional magnetic resonance imaging. One patient underwent diffusion-weighted imaging. RESULTS: ECH originated from vertebrae with coarsened trabeculae in 5 patients. Among these, 1 tumor was mainly in the intervertebral foramen and paravertebral space, 2 extended to the intraspinal and paravertebral spaces and appeared dumbbell shaped, and 2 were located in the intraspinal space. Purely epidural hemangiomas were present in 2 patients; 1 of these patients had adjacent bony erosion. Epidural hemangiomas were isointense in 6 patients and hyperintense in 1 patient on T1-weighted images; lesions were hyperintense on T2-weighted images in all 7 patients. Peripheral fat was present in 4 ECHs; 2 were of vertebral origin, and 2 were of epidural space origin. In the patient who underwent diffusion-weighted imaging, the lesion showed restricted diffusion. The affected vertebra had coarsened trabeculae, which may be a critical finding for differentiating ECHs of vertebral origin from foraminal nerve sheath tumors. Peripheral fat around hemangiomas of vertebral origin and primary epidural space hemangiomas indicates chronicity. CONCLUSIONS: ECHs are classified either as epidural hemangiomas of vertebral origin or as primary epidural hemangiomas. Awareness of imaging characteristics of ECHs may facilitate diagnosis and treatment of these lesions. PMID- 29248777 TI - Atlantoaxial Joint Distraction for the Treatment of Basilar Invagination: Clinical Outcomes and Radiographic Evaluation. AB - OBJECTIVE: To investigate the causes of partial remission in patients with basilar invagination (BI) and irreducible atlantoaxial dislocation (IAAD) treated with transoral atlantoaxial reduction plate (TARP) without odontoidectomy and quantify the distance of odontoid descent. METHODS: Between August 2010 and July 2012, 22 consecutive patients with BI with IAAD who underwent TARP surgery were reviewed. The preoperative and postoperative radiographic parameters were evaluated. Follow-up data and the symptom treatment interval (STI), defined as the interval between the onset of symptoms and surgical treatment, were assessed. Neurological function was evaluated as neurologic improvement, defined as ([Postoperative Japanese Orthopedic Association (JOA) score] - [Preoperative JOA score])/(17 - [Preoperative JOA score]). The patients were assigned to group A (<50%) or group B (>=50%) based on their level of neurologic improvement. RESULTS: All 22 patients improved clinically to varying degrees. The mean preoperative STI was 105.6 +/- 67.6 months for group A and 45.3 +/- 46.7 months for group B (P < 0.05). There were no significant between-group differences in follow-up (P > 0.05) or with respect to radiographic parameters (P > 0.05). Persistent brainstem compression was observed in 1 patient, whose symptoms were not adequately relieved after revision surgery (transoral odontoidectomy and posterior decompression and fusion). No fixation failure was observed. CONCLUSIONS: Descent of the odontoid process is useful for treating basilar invagination. TARP surgery without odontoidectomy may pull the dens caudally and ventrally to achieve sufficient decompression of the spinal cord. Neurologic improvement may be associated with STI. PMID- 29248778 TI - Radiologic Factors Predicting Deterioration of Mental Status in Patients with Acute Traumatic Subdural Hematoma. AB - OBJECTIVE: To evaluate whether subdural hematoma (SDH) volume and other radiologic factors predict deterioration of mental status in patients with acute traumatic SDH. METHODS: SDH volumes were measured with a semiautomated tool. The area under the receiver operating characteristic curve was used to determine optimal cutoff values for mental deterioration, including the variables midline shift, SDH volume, hematoma thickness, and Sylvian fissure ratio. Multivariate logistic regression was used to calculate the odds ratio for mental deterioration based on several predictive factors. RESULTS: We enrolled 103 consecutive patients admitted to our hospital with acute traumatic SDH over an 8-year period. We observed an increase in SDH volume of approximately 7.2 mL as SDH thickness increased by 1 mm. A steeper slope for midline shift was observed in patients with SDH volumes of approximately 75 mL in the younger age group compared with patients in the older age group. When comparing cutoff values used to predict poor mental status at time of admission between the 2 age groups, we observed smaller midline shifts in the older patients. CONCLUSIONS: Among younger patients, an overall tendency for more rapid midline shift progression was observed in patients with relatively low SDH volumes compared with older patients. Older patients seem to tolerate larger hematoma volumes owing to brain atrophy compared with younger patients. When there is a midline shift, older patients seem to be more vulnerable to mental deterioration than younger patients. PMID- 29248779 TI - Decompression Alone Versus Decompression and Fusion for Lumbar Degenerative Spondylolisthesis: A Meta-Analysis. AB - OBJECTIVE: To compare the effectiveness and safety of decompression alone (D group) with decompression and fusion (DF group) for patients who were diagnosed with lumbar degenerative spondylolisthesis (LDS). METHODS: Electronic databases were searched for relevant studies that compared decompression alone with decompression and fusion for LDS. Then, data extraction and quality assessment were conducted, and the extracted data were analyzed by using RevMan 5.3. We used the random effects model for studies that had heterogeneity between them, and for those without heterogeneity, the fixed model was used. RESULTS: Four randomized controlled trials and 14 nonrandomized controlled studies involving 77,994 patients were included for this meta-analysis. Although the DF group was associated with a higher postoperative change score on a visual analog scale compared with the D group in terms of back (P = 0.02) and leg (P = 0.04), they failed to reach the minimum clinically important difference. Moreover, no significant differences were found in Oswestry Disability Index, European Quality of Life-5 Dimensions, Short-Form 36 physical and mental component summaries score, and patients' satisfaction (P > 0.05) between treatment groups. Complication rate and reoperation rate (P > 0.05) were similar in both groups. Data analysis also showed that the DF group was associated with longer operation time (P < 0.00001), more intraoperative blood loss (P < 0.00001), and longer length of hospital stay (P < 0.00001). CONCLUSIONS: Among patients with LDS, decompression and fusion surgery did not yield better clinical outcomes than decompression alone surgery. Also, the complication rate and reoperation rate were comparable between treatment groups. However, patients who had undergone decompression alone had shorter operation time, less intraoperative blood loss, and shorter hospital stay. PMID- 29248780 TI - Correlation of Lactate Concentration in Peripheral Plasma and Cerebrospinal Fluid with Glasgow Outcome Scale for Patients with Tuberculous Meningitis Complicated by Acute Hydrocephalus Treated with Fluid Diversions. AB - BACKGROUND: Tuberculous meningitis (TBM) is an endemic infectious disease in developing countries, and it can become a serious illness in children. Treatment of TBM is more difficult and prone to failure than treatment of pulmonary tuberculosis. TBM causes hydrocephalus, cerebral edema, increased intracranial pressure, global ischemia, and neurologic deficits, which disturb cellular metabolism and increase lactate levels. A reliable, widely available clinical indicator of TBM severity is needed. Successful treatment of TBM is assessed using the Glasgow Outcome Scale (GOS). METHODS: This prospective cohort study included 34 patients with TBM and acute hydrocephalus who had undergone fluid diversions and were admitted to Dr. Hasan Sadikin Hospital in Bandung from 2014 to 2015. A portable machine for blood glucose measurement was used to measure lactate concentrations. Statistical significance was defined as P <= 0.05. RESULTS: Average levels of plasma and cerebrospinal fluid (CSF) lactate were 1.99 +/- 0.70 mmol/L and 3.04 +/- 1.05 mmol/L, respectively. A significantly higher level of lactate was observed in CSF compared with plasma. Preoperative plasma lactate was negatively correlated to GOS (r = -0.539; P = 0.013), and CSF lactate was negatively correlated to GOS (r = -0.412; P = 0.027). Average lactate levels in CSF (central) were higher than plasma (peripheral) levels. GOS scale of patients decreased with increased plasma and CSF lactate levels. CONCLUSIONS: Examination of plasma and CSF lactate levels should be included in routine examinations to determine extent of cellular damage and GOS score in patients with TBM and acute hydrocephalus who have undergone fluid diversions. PMID- 29248781 TI - Drivers of Cervical Deformity Have a Strong Influence on Achieving Optimal Radiographic and Clinical Outcomes at 1 Year After Cervical Deformity Surgery. AB - OBJECTIVE: The primary driver (PD) of cervical malalignment is important in characterizing cervical deformity (CD) and should be included in fusion to achieve alignment and quality-of-life goals. This study aims to define how PDs improve understanding of the mechanisms of CD and assesses the impact of driver region on realignment/outcomes. METHODS: Inclusion: radiographic CD, age >18 years, 1 year follow-up. PD apex was classified by spinal region: cervical, cervicothoracic junction (CTJ), thoracic, or spinopelvic by a panel of spine deformity surgeons. Primary analysis evaluated PD groups meeting alignment goals (by Ames modifiers cervical sagittal vertical axis/T1 slope minus cervical lordosis/chin-brow vergical angle/modified Japanese Orthopaedics Association questionnaire) and health-related quality of life (HRQL) goals (EuroQol-5 Dimensions questionnaire/Neck Disability Index/modified Japanese Orthopaedics Association questionnaire) using t tests. Secondary analysis grouped interventions by fusion constructs including the primary or secondary apex based on lowest instrumented vertebra: cervical, lowest instrumented vertebra (LIV) <=C7; CTJ, LIV <=T3; and thoracic, LIV <=T12. RESULTS: A total of 73 patients (mean age, 61.8 years; 59% female) were evaluated with the following PDs of their sagittal cervical deformity: cervical, 49.3%; CTJ, 31.5%; thoracic, 13.7%; and spinopelvic, 2.7%. Cervical drivers (n = 36) showed the greatest 1-year postoperative cervical and global alignment changes (improvement in T1S, CL, C0 C2, C1 slope). Thoracic drivers were more likely to have persistent severe T1 slope minus cervical lordosis modifier grade at 1 year (0, 20.0%; +, 0.0%; ++, 80.0%). Cervical deformity modifiers tended to improve in cervical patients whose construct included the PD apex (included, 26%; not, 0%; P = 0.068). Thoracic and cervicothoracic PD apex patients did not improve in HRQL goals when PD apex was not treated. CONCLUSIONS: CD structural drivers have an important effect on treatment and 1-year postoperative outcomes. Cervical or thoracic drivers not included in the construct result in residual deformity and inferior HRQL goals. These factors should be considered when discussing treatment plans for patients with CD. PMID- 29248782 TI - The effect of laterite density on radon diffusion behavior. AB - Radon generated in porous media such as soils and rocks migrates into indoor and outdoor air mainly by diffusion, possessing significant hazards to human health. In order to reduce these hazards of radon, it is of great importance to study the diffusion behavior of radon. In this study, we systematically measured the radon diffusion coefficient of laterite with the density ranging from 0.917gcm-3 to 2.238gcm-3, and studied the effect of laterite density on the radon diffusion. The results show that the radon diffusion coefficient of the laterite generally decreases with the increasing laterite density. In addition, three possible relationships between the radon diffusion coefficient and the laterite density are found out as follows: (1) the linear correlation with a slope of -4.48 * 10-6 for laterite with density ranging from 0.917 to 1.095gcm-3, (2) the exponential correlation for laterite with density from 1.095 to 1.63gcm-3, (3) linear correlation with a slope of -3.1 * 10-7 for laterite with density from 1.63 to 2.238gcm-3. The complex relationship between the radon diffusion coefficient and density is caused by the change of porosity and tortuosity of the laterite. Therefore, we suggest that a suitable density should be adopted while using the laterite to effectively cover uranium tailings or economically produce building materials that can curb the radon exhalation. PMID- 29248783 TI - Investigation of a high-pressure pressed powder pellet technique for the analysis of coal by wavelength dispersive X-ray fluorescence spectroscopy. AB - Using the proposed high-pressure pressed powder pellet technique, a coal sample was pressed into an ideal pellet without binders, which provides a solution to the poor self-binding quality of coal for the determination by X-ray fluorescence spectroscopy (XRF). The pellet produced by this method was more compact and smoother, which was particularly meaningful for spectrometer, where the sample is placed over the tube window. Additionally, the high-pressure sample preparation technique effectively eliminated the effect of falling powder and contamination in the Measuring chamber of the spectrometer. Wavelength Dispersive X-ray Fluorescence Spectroscopy (WDXRF) was applied successfully to the determination of carbon, nitrogen and ash content in coal samples. This could provide an alternative method for the rapid analysis of carbon, nitrogen and ash content in the coal rather than the combustion method or the high-frequency infrared absorption with a slow ashing method. Furthermore, WDXRF could provide simultaneous determination of other major, minor and trace elements by X-ray fluorescence spectroscopy. The XRF results indicated that the sensitivity, precision, and limit of detection for most components were improved when the coal sample was pressed at 1600kN compared with preparation at 400kN. PMID- 29248784 TI - Diaphragm correction factors for the FAC-IR-300 free-air ionization chamber. AB - A free-air ionization chamber FAC-IR-300, designed by the Atomic Energy Organization of Iran, is used as the primary Iranian national standard for the photon air kerma. For accurate air kerma measurements, the contribution from the scattered photons to the total energy released in the collecting volume must be eliminated. One of the sources of scattered photons is the chamber's diaphragm. In this paper, the diaphragm scattering correction factor, kdia, and the diaphragm transmission correction factor, ktr, were introduced. These factors represent corrections to the measured charge (or current) for the photons scattered from the diaphragm surface and the photons penetrated through the diaphragm volume, respectively. The kdia and ktr values were estimated by Monte Carlo simulations. The simulations were performed for the mono-energetic photons in the energy range of 20 - 300keV. According to the simulation results, in this energy range, the kdia values vary between 0.9997 and 0.9948, and ktr values decrease from 1.0000 to 0.9965. The corrections grow in significance with increasing energy of the primary photons. PMID- 29248785 TI - Nuclear model analysis of excitation functions of alpha-particle induced reactions on In and Cd up to 60MeV with relevance to the production of high specific activity 117mSn. AB - Excitation functions were calculated for the alpha-particle induced reactions 115In(alpha,x)117mSn, 114Cd(alpha,n)117mSn, 116Cd(alpha,3n)117mSn and natCd(alpha,x)117mSn to analyse the production of the medically important 117mSn (T1/2 = 13.6 d). For calculations three nuclear model codes (i.e. TALYS, EMPIRE and ALICE-IPPE) were used and the results were compared with the available experimental data. For the most important reaction, 116Cd(alpha,3n)117mSn, evaluated data are presented. The yield and radionuclidic purity of 117mSn from each reaction are discussed. PMID- 29248786 TI - Biophysical risks to carbon sequestration and storage in Australian drylands. AB - Carbon abatement schemes that reduce land clearing and promote revegetation are now an important component of climate change policy globally. There is considerable potential for these schemes to operate in drylands which are spatially extensive. However, projects in these environments risk failure through unplanned release of stored carbon to the atmosphere. In this review, we identify factors that may adversely affect the success of vegetation-based carbon abatement projects in dryland ecosystems, evaluate their likelihood of occurrence, and estimate the potential consequences for carbon storage and sequestration. We also evaluate management strategies to reduce risks posed to these carbon abatement projects. Identified risks were primarily disturbances, including unplanned fire, drought, and grazing. Revegetation projects also risk recruitment failure, thereby failing to reach projected rates of sequestration. Many of these risks are dependent on rainfall, which is highly variable in drylands and susceptible to further variation under climate change. Resprouting vegetation is likely to be less vulnerable to disturbance and have faster recovery rates upon release from disturbance. We conclude that there is a strong impetus for identifying management strategies and risk reduction mechanisms for carbon abatement projects. Risk mitigation would be enhanced by effective co ordination of mitigation strategies at scales larger than individual abatement project boundaries, and by implementing risk assessment throughout project planning and implementation stages. Reduction of risk is vital for maximising carbon sequestration of individual projects and for reducing barriers to the establishment of new projects entering the market. PMID- 29248787 TI - Bamboo-Leaf Prickly Ash extract: A potential bio-pesticide against oriental leaf worm, Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae). AB - Bamboo-Leaf Prickly Ash, Zanthoxylum armatum (Rutaceae) is a versatile and widely distributed plant species in nature. It is an edible plant species, commonly used in daily life for condiments and therapeutic remedies. Besides its bioactive and medicinal properties, different plant parts of the Z. armatum also have insecticidal potential. However, this potential has not been yet determined against many agricultural pests, including leaf worm, Spodoptera litura (Lepidoptera: Noctuidae). In this study, we demonstrated for the first time the contact and oral toxicity and sub-lethal effects (including antifeedent and ovicidal action) of various fractions of pericarp, leaf and seeds of Z. armatum against S. litura. Overall findings revealed that the n-hexane pericarp extract of Z. armatum has strong antifeedent, ovicidal and larvicidal properties against S. litura. Sub-lethal doses of pericarp extract can negatively alter the biology of S. litura. Since n-hexane extract of leaves also has better larvicidal properties, it could also be utilized for the S. litura management during period of unavailability of fruits (or pericarp). Accordingly, the Z. armatum pericarp and leaf extract has tremendous commercial utilization potential for the management of polyphagus pests like S. litura and other related species, which are quite difficult to manage even by chemical pesticides. PMID- 29248788 TI - Advanced oxidation processes for the removal of natural organic matter from drinking water sources: A comprehensive review. AB - Natural organic matter (NOM), a key component in aquatic environments, is a complex matrix of organic substances characterized by its fluctuating amounts in water and variable molecular and chemical properties, leading to various interaction schemes with the biogeosphere and hydrologic cycle. These factors, along with the increasing amounts of NOM in surface and ground waters, make the effort of removing naturally-occurring organics from drinking water supplies, and also from municipal wastewater effluents, a challenging task requiring the development of highly efficient and versatile water treatment technologies. Advanced oxidation processes (AOPs) received an increasing amount of attention from researchers around the world, especially during the last decade. The related processes were frequently reported to be among the most suitable water treatment technologies to remove NOM from drinking water supplies and mitigate the formation of disinfection by products (DBPs). Thus, the present work overviews recent research and development studies conducted on the application of AOPs to degrade NOM including UV and/or ozone-based applications, different Fenton processes and various heterogeneous catalytic and photocatalytic oxidative processes. Other non-conventional AOPs such as ultrasonication, ionizing radiation and plasma technologies were also reported. Furthermore, since AOPs are unlikely to achieve complete oxidation of NOM, integration schemes with other water treatment technologies were presented including membrane filtration, adsorption and others processes. PMID- 29248789 TI - Spatially differentiated strategies for reducing nitrate loads from agriculture in two Danish catchments. AB - Nutrient loss from agriculture is the largest source of diffuse water pollution in Denmark. To reduce nutrient loads a number of solutions have been implemented, but this has been insufficient to achieve the environmental objectives without unacceptable repercussions for agricultural production. This has substantiated the need to develop a new approach to achieve nitrogen (N) load reduction to the aquatic environments with lower costs to farmers. The new approach imply targeting N leaching mitigation to those parts of the landscape which contribute most to the N-loadings. This would involve either reducing the source loading or enhancing the natural reduction (denitrification) of N after it is leached from the root zone of agricultural crops. In this study, a new method of spatially differentiated analysis for two Danish catchments (Odense and Norsminde) was conducted that reach across the individual farms to achieve selected N-load reduction targets. It includes application of cover crops within current crop rotations, set-a-side application on high N-load areas, and changes in agricultural management based on maps of N-reduction available for two different spatial scales, considering soil type and farm boundaries as spatial constraints. In summary, the results revealed that considering spatial constraints for changes in agricultural management will affect the effectiveness of N-load reduction, and the highest N-load reduction was achieved where less constraints were considered. The results also showed that the range of variation in land use, soil types, and N-reduction potential influence the reduction of N-loadings that can originate from critical source areas. The greater the spatial variation the greater the potential for N load reduction through targeting of measures. Therefore, the effectiveness of spatially differentiated measures in term of set-a-side area in Odense catchment were relatively greater compared to Norsminde catchment. The results also showed that using a fine spatial N-reduction map provides greater potential for N load reductions compared to using sub-catchment scale N-reduction maps. PMID- 29248790 TI - Rewetting in Mediterranean reclaimed peaty soils and its potential for phyto treatment use. AB - A pilot experimental field combining rewetting of reclaimed peaty soils and water phyto-treatment was set up in the Massaciuccoli Lake basin (Tuscany, Italy) to reduce the water eutrophication and peat degradation caused by almost a century of drainage-based agricultural use. In this paper, we investigated the restoration process occurring consequently to the conversion of a drained area in a natural wetland system (NWS) (the partial top soil removal, the realization of a perimeter levee to contain the waters, the rewetting with the drainage waters coming from the of surrounding cultivated areas) and the capability of the spontaneous vegetation to catch nutrients acting as a vegetation filter. To follow the restoration process over time (2012-2016), we used a mixed approach merging phytosociological surveys with ortophotos taken by an Unmanned Aerial Vehicle (UAV). During the last year of observation (2016), we performed destructive sampling on the most widespread plant communities in the area (Phragmites australis and Myriophyllum aquaticum community) to quantify the biomass production and the uptake of nitrogen and phosphorus. Stands of Phragmites australis (Cav.) Trin. ex Steud. yielded more than Myriophyllum aquaticum (Vell.) Verdc. (4.94 kg m-2 vs 1.08 kg m-2). M. aquaticum showed higher nutrient contents (2.04% of N and 0.35% of P), however P. australis was able to take up more nutrients within the NWS because of its larger cover and productivity. In the perspective of maximizing the plant development and consequently the amount of nutrients extracted from treated waters, the authors suggest 4-5 year-long-harvesting turns, better occurring in spring-summer. PMID- 29248791 TI - Pleural and pericardial effusions in patient on tyrosine kinase inhibitor. PMID- 29248793 TI - An efficient subarray average delay multiply and sum beamformer algorithm in ultrasound imaging. AB - Beamformer plays an important role in medical ultrasound imaging systems. The delay multiply and sum (DMAS) beamformer achieves better performance in contrast and resolution compared with the delay and sum (DAS) beamformer, but suffers from higher computational complexity and partial energy loss. The higher computational complexity mainly arises from the multiply and geometric average operation, which needs (N2-N)/2 computations at every point, where N denotes the number of array elements. The partial energy loss, mainly due to the autocorrelation component of the echo signals, has been neglected in the DMAS beamformer. In this paper, we propose a subarray average delay multiply and sum (SA-DMAS) beamformer which is combined with subarray average technique of covariance matrix and DMAS beamformer. This will lower the computational complexity, while keeping the side lobe suppressing property of DMAS. The main idea of the proposed method is adding autocorrelation component of the echo signals to DMAS, and converting the expression in covariance matrix form. The subarray average technique is used to estimate the covariance matrix of the echo signals. The field II simulation of point targets and cyst phantoms was used to prove the performance of the proposed method. An RF data experiment was applied to support the feasibility and validity of our method. The simulation and experimental results show that our method has a lower computational complexity as O(9/2L2) , where L denotes the sub-array size, and has equivalent performance like the MV and DMAS beamformer. PMID- 29248792 TI - Crocin alleviates coronary atherosclerosis via inhibiting lipid synthesis and inducing M2 macrophage polarization. AB - Atherosclerosis is a chronic inflammatory disease arising from an imbalance in lipid levels and the accumulation of cholesterol-laden macrophages in the artery wall. Crocin is an active ingredient of Crocus sativus L. This study established a rat coronary atherosclerosis model induced by vitamin D3 (VD3), to explore the effect of Crocin on lipid metabolism, macrophage polarization and the activity of inflammatory proteins. The results revealed that Crocin decreased blood lipid levels by decreasing the levels of endothelin (ET), total cholesterol (TC), triglyceridelow (TG) and low-density lipoprotein cholesterol (LDL-c), elevating the level of high-density lipoprotein cholesterin (HDL-c). Crocin also inhibited lipogenesis by suppressing the expression of lipogenesis-related proteins and elevating lipid catabolism-related proteins. Moreover, Crocin effectively alleviated inflammation by suppressing the expression of pro-inflammatory cytokines and increasing levels of anti-inflammatory cytokines. We further found that Crocin promoted macrophage polarization to the M2 phenotype by reducing M1 markers (CD40+ and CD11c+) and elevating M2 markers (CD68+ and CD206+). Finally, Crocin strongly inhibited the expression of NF-kappaB p65 and its translocation into the nucleus. Crocin partially counteracted nuclear factor kappa-light-chain enhancer of activated B cells (NF-kappaB) p65 expression and the nuclei accumulation caused by NF-kappaB p65 overexpression. Taken together, our research indicated that Crocin inhibited lipogenesis and alleviated the inflammation in a VD3-induced rat coronary atherosclerosis model by promoting M2 macrophage polarization and maybe by inhibiting NF-kappaB p65 nuclear translocation. This study implicates Crocin as a potential therapeutic strategy for coronary atherosclerosis. PMID- 29248794 TI - Quantitative imaging performance of frequency-tunable capacitive micromachined ultrasonic transducer array designed for intracardiac application: Phantom study. AB - Commercially available intracardiac echo (ICE) catheters face a trade-off between viewing depth and resolution. Frequency-tunable ICE probes would offer versatility of choice between penetration or resolution imaging within a single device. In this phantom study, the imaging performance of a novel, frequency tunable, 32-element, 1-D CMUT array integrated with front-end electronics is evaluated. Phased-array ultrasound imaging with a forward-looking CMUT probe prototype operated beyond collapse mode at voltages up to three times higher than the collapse voltage (-65 V) is demonstrated. Imaging performance as a function of bias voltage (-70 V to -160 V), transmit pulse frequency (5-25 MHz), and number of transmit pulse cycles (1-3) is quantified, based on which penetration, resolution, and generic imaging modes are identified. It is shown that by utilizing the concept of frequency tuning, images with different characteristics can be generated trading-off the resolution and penetration depth. The penetration mode provides imaging up to 71 mm in the tissue-mimicking phantom, axial resolution of 0.44 mm, and lateral resolution of 0.12 rad. In the resolution mode, axial resolution of 0.055 mm, lateral resolution of 0.035 rad, and penetration depth of 16 mm are measured. These results show what this CMUT array has the potential versatile characteristics needed for intracardiac imaging, despite its relatively small transducer aperture size of 2 mm * 2 mm imposed by the clinical application. PMID- 29248795 TI - Increased mutability to fosfomycin resistance in Proteus mirabilis clinical isolates. AB - In the present study, we screened a collection of 77 Proteus mirabilis clinical isolates for the presence of mutators, using the frequency of both rifampicin and fosfomycin resistance mutants as markers of spontaneous mutagenesis. We found that none of the strains in our collection are mutators for the rifampicin resistance (RifR) marker. Nevertheless, a significant fraction of the isolates (17%) show high frequencies of fosfomycin resistant mutants (FosR). We show that this increased mutability to FosR correlates with a low level of resistance to Fosfomycin (MICs 8-64MUg/ml). These strains also show high frequencies of single step mutants with clinically relevant FosR resistance levels (MIC >=256MUg/ml). Our findings point out to the risk of fosfomycin resistance emergence in P. mirabilis. PMID- 29248796 TI - Multiple introductions of reassorted highly pathogenic avian influenza viruses (H5N8) clade 2.3.4.4b causing outbreaks in wild birds and poultry in Egypt. AB - Recently, an increased incidence of outbreaks of highly pathogenic avian influenza (HPAI) H5N8 in poultry linked to infected migratory birds has been reported from different European, Asian and African countries. In Egypt, incursion of HPAI H5N8 virus of clade 2.3.4.4b has been recently registered. Full genomic characterization of 3 virus isolates from wild birds and poultry (backyard and commercial farm sectors) showed high nucleotide similarity among the HA, NA, M, and NS gene segments of the three Egyptian HPAI H5N8 viruses, indicating that they are descendants of a common ancestral virus. However, the analyzed Egyptian H5N8 viruses revealed distinct genotypes involving different origins of the PB2, PB1, PA and/or NP segments. In genotype-1 represented by strain A/common-coot/Egypt/CA285/2016 the PB2 and NP segments showed closest relationship to H5N6 and H6N2 viruses, recently detected in Italy. The second is replacement of PB1 and NP genes A novel reassortant, represented by strain A/duck/Egypt/SS19/2017, showed an exchange of PB1 and NP genes which might have originated from H6N8 or H1N1 and H6N2 viruses. Finally, replacement of PA and NP genes characterized strain A/duck/Egypt/F446/2017. Bayesian phylogeographic analyses revealed that Egyptian H5N8 viruses are highly likely derived from Russian 2016 HPAI H5N8 virus (A/great_crested_grebe/Uvs-Nuur_Lake/341/2016 (H5N8)) and the reassortment likely occurred before incursion to Egypt. PMID- 29248797 TI - Molecular epidemiology of Mycobacterium tuberculosis strains from prison populations in Santa Catarina, Southern Brazil. AB - The Tuberculosis (TB) notification rates are 5 to 81 times higher in prisons worldwide when compared to the general population. The state of Santa Catarina (SC) has few epidemiological data regarding TB in prisons. The aim of this study was to evaluate the molecular epidemiology of circulating strains in prisons of SC. The study comprised 95 clinical samples from six prisons. Among the cases included, all subjects were male, predominantly caucasians, and young adults, with low education level. The positive smear in the TB diagnosis comprised 62.0% of cases. About 50% of subjects had some condition associated with TB. The Spoligotyping results showed that the most frequent lineages were LAM (50.7%), T (22.2%) and S (11.6%). The 12-loci MIRU generated 62 different genotypes. The MSTs showed evolutionary relationships between Mycobacterium tuberculosis spoligotypes from SC and evolutionary relationships between the prison isolates and studied parameters. This first study on TB in prison units of SC highlighted the predominance of SIT216/LAM5, and SIT34/S. Interestingly, his profile was found to be different from that observed in a previous study performed with the state's general population. This data shows the need for continued surveillance of episodes of TB occurring among prison inmates in an emerging country like Brazil. PMID- 29248798 TI - Fear, an unpleasant experience among undergraduate midwifery students: A qualitative study. AB - : Fear is a normal emotion that can evoke an appropriate response when facing threat. However, sometimes the consequences of fear can lead to responses that are maladaptive. Fear can have negative effects on learning. Research has focused on the experience of fear and its consequences among midwifery students during their undergraduate program. A qualitative analysis was conducted of interviews with ten midwifery students in different years of an undergraduate program. The data was analyzed through a content analysis approach. Two main categories and five subcategories emerged. The first category, areas of fear in midwifery students, consisted of the following subcategories: fear of doing harm, fear of encountering their first childbirth, and fear of penalties. The second category, consequences of fear, consisted of the following subcategories: general physical and psychological consequences and interference in adopting the professional role. In this study, fear not only raised the students' stress levels thereby, leading to physical and psychological issues but also hindered their adoption of their professional role. These findings will potentially inform support and retention strategies within midwifery undergraduate programs in the future. BACKGROUND: Maternity care in Iran is provided mainly within a medical model of care. The majority of women give birth in hospital, where care is provided by midwives who work under the direction and supervision of an obstetrician. Midwives within the medically dominated system lack autonomy and have very little opportunity to gain experience in providing continuity of care for women as midwife-led models of care are rare. This practice context means that midwifery students have very little opportunity to gain experience in autonomous midwifery practice. Midwifery undergraduate program in Iran is for four years. Admission to the undergraduate program is implemented via a direct entry route. Nearly all of the midwifery students are school leavers with their first exposure to university and hospital systems. Most of the midwifery students have chosen this career without sufficient understanding about midwifery and the work that it involves (Arfaee et al., 2008). The midwifery undergraduate program comprises theoretical and clinical elements. After the first semester, students enter clinical settings under the supervision of their clinical instructors. PMID- 29248799 TI - Early withdrawal of non-anesthetic antiepileptic drugs after successful termination of nonconvulsive seizures and nonconvulsive status epilepticus. AB - PURPOSE: Multiple antiepileptic drugs (AEDs) are often necessary to treat nonconvulsive seizures (NCS) and nonconvulsive status epilepticus (NCSE). AED polypharmacy places patients at risk for adverse side effects and drug-drug interactions. Identifying the likelihood of seizure relapse when weaning non anesthetic AEDs may provide guidance in the critical care unit. METHOD: Ninety nine adult patients with successful treatment of electrographic-proven NCS or NCSE on continuous critical care EEG (CCEEG) monitoring were identified retrospectively. Patients were determined to undergo an AED wean if the number of non-anesthetic AEDs was reduced at the time of discharge compared to the number of non-anesthetic AEDs at primary seizure cessation. Primary outcome was recurrent seizures either clinically or by CCEEG during hospitalization. Secondary outcome measures included hospital length of stay and discharge disposition. RESULTS: The rate of recurrent seizures in the wean group was not statistically different when compared to the group that did not undergo an AED wean (17% vs. 13%, respectively; p = 0.77). The wean group had a median value of 4 (IQR: 3-4) non-anesthetic AEDs at the time of primary seizure cessation compared with 3 (IQR: 2-3) in the non-wean group (p < 0.0001). However, both groups had similar values of AEDs at discharge (median of 2 (IQR: 2-3) vs. 3 (IQR: 2-3) for wean and non-wean groups respectively; p = 0.40). Discharge disposition (favorable, acceptable, or unfavorable) was similar between groups (p = 0.32). CONCLUSIONS: Early weaning of non-anesthetic AEDs does not increase the risk of recurrent seizures in patients treated for NCS or NCSE during their hospitalization. PMID- 29248800 TI - Effects of silver-graphene oxide nanocomposites on soil microbial communities. AB - Due to the application of silver-graphene oxide (Ag-GO) in diverse fields, it is important to investigate its potential impacts on the environment including soils. In this study, the response of microbial communities in soils treated with Ag-GO synthesized by glucose reduction was determined by analyzing enzyme activities, biomass, and inorganic N concentrations and by pyrosequencing. In soils treated with 0.1-1 mg Ag-GO g-1 soil, the activities of beta-glucosidase, cellobiohydrolase, and xylosidase decreased up to 80% and NO3- concentration decreased up to 82% indicating inhibited nitrification. Within the bacterial community, the relative abundance of Acidobacteria and Cyanobacteria in soils treated with Ag-GO were lower than that in control soil. Meanwhile, the relative abundance of AD3 and Firmicutes tended to increase under Ag-GO treatments. These changes in bacterial community composition reflected lowered activities associated with C and N cycling. On the other hand, microbial biomass showed no distinct change in response to Ag-GO treatment. Our study can serve as important basis in establishing guidelines for regulating the release of nanocomposites such as Ag-GO to the soil environment. PMID- 29248802 TI - eEF1A1 Overexpression Enhances Tumor Progression and Indicates Poor Prognosis in Hepatocellular Carcinoma. AB - Liver is a major contributor of protein production physiologically. The aberrant state of protein synthesis leads to tumor progression. Eukaryotic elongation factor 1 alpha 1 (eEF1A1) is a major member of the eukaryotic elongation factor family that regulates protein synthesis. Although eEF1A1 plays an essential role in controlling the cell fate, its clinical significance in tumor development and progression has not been reported. Here, we aimed to uncover the expression and prognostic significance of eEF1A1 in hepatocellular carcinoma (HCC). Our data indicated that eEF1A1 expression was elevated in HCC cell lines and clinical samples at both the mRNA and protein levels. Immunohistochemistry revealed that eEF1A1 expression was upregulated in HCC samples compared with corresponding non tumorous tissues. In 50 HCC cases with portal vein embolus, higher eEF1A1 immunoreactivity was detected in tumor metastases compared with the primary lesions. Kaplan-Meier analysis indicated that increased eEF1A1 expression was closely associated with unfavorable post-surgical overall and disease-free survival in 453 HCC patients. Moreover, multivariate analysis indicated eEF1A1 as an independent predictor for overall and disease-free survival. Collectively, our study suggests eEF1A1 as a novel prognostic biomarker and potential therapeutic target for HCC patients. PMID- 29248801 TI - Plasma magnesium is inversely associated with Epstein-Barr virus load in peripheral blood and Burkitt lymphoma in Uganda. AB - BACKGROUND: Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma (eBL). EBV control was improved by magnesium (Mg2+) supplementation in XMEN, an X-linked genetic disease associated with Mg2+ deficiency, high circulating EBV levels (viral loads), and EBV-related lymphomas. We, therefore, investigated the relationship between Mg2+ levels and EBV levels and eBL in Uganda. METHODS: Plasma Mg2+ was measured in 45 women with low or high circulating EBV levels, 40 pediatric eBL cases, and 79 healthy children. Mg2+ uptake by T-lymphocytes was evaluated in samples from healthy donors. RESULTS: Plasma Mg2+ deficiency (plasma level <1.8 mg/dl) was more likely in women with high- vs. low-EBV levels (76.0% vs. 35%; odds ratio [OR] 11.3, 95% CI 2.14-60.2), controlling for age, and in eBL cases than controls (42.0% vs. 13.9%; OR 3.61, 95% CI 1.32-9.88), controlling for sex, age group, and malaria status. Mg2+ uptake by T-lymphocytes was related to extracellular Mg2+ concentration. INTERPRETATION: Plasma Mg2+ deficiency is associated with high EBV levels and eBL. PMID- 29248804 TI - Comparison of colloidal silica involved fouling behavior in three membrane distillation configurations using PTFE membrane. AB - Colloidal silica involved fouling behaviors in direct contact membrane distillation (DCMD), vacuum membrane distillation (VMD) and sweeping gas membrane distillation (SGMD) were studied. Three foulants were used in the experiments, including colloidal silica as representative of particulate foulants, calcium bicarbonate as dissolved inorganic foulant, and NOM (humic acid + alginate + BSA) as the dissolved organic foulant. The three types of fouants were combined to produce four different feed waters: silica alone; silica + calcium bicarbonate; silica + NOM; and silica + calcium bicarbonate + NOM. With 25% feed recovery, it was found that VMD showed the worst performance for most of the foulant combinations due to turbulence dead zones caused by the membrane deformation that increased foulant deposition. For the silica + calcium bicarbonate + NOM feed DCMD had the greatest fouling rate, although DCMD also had the highest flux of all configurations. SGMD showed the best fouling resistance of all configurations, although it was inclined to calcium carbonate fouling because carbon dioxide was removed in the permeate leading to calcium carbonate precipitation and could be alleviated by using air as sweeping gas. For feeds containing high-concentration calcium bicarbonate or carbonate foulants, VMD should be avoided to lower the formation of carbonate precipitants on the membrane surface if scale inhibitors are not used. PMID- 29248803 TI - Calcium addition to increase the production of phosphate granules in anaerobic treatment of black water. AB - Simultaneous recovery of calcium phosphate granules (CaP granules) and methane from vacuum collected black water (BW), using an upflow anaerobic sludge blanket (UASB) reactor was previously investigated. It was calculated that only 2% of the total phosphorus (P) fed was present as CaP granules whereas 51% of the P accumulated dispersed in the reactor, limiting the applicability of this process for recovery of phosphate. This study proposes adding calcium to increase the P accumulation in the reactor and the production of CaP granules. Calcium was added in a lab-scale UASB reactor fed with BW. An identical UASB reactor was used as reference, to which no calcium was added. The treatment performance was evaluated by weekly monitoring of influent, effluent and produced biogas. Sludge bed development and CaP granulation were assessed through particle size analysis. The composition and structure of CaP granules were chemically and optically assessed. Calcium addition increased accumulation of P in the reactor and formation and growth of granules with size > 0.4 mm diameter (CaP granules). Moreover, with calcium addition, CaP granules contained 5.6 +/- 1.5 wt% of P, while without calcium a lower P content was observed (3.7 +/- 0.3 wt%). By adding Ca, 89% of the incoming P from BW accumulated in the reactor and 31% was sampled as CaP granules (> 0.4 mm diameter). Addition of 250 mgCa L-1 of BW was the optimum loading found in this study. Furthermore, no significant reduction in CODTotal removal (> 80%) and CH4 production (0.47 +/- 0.10 gCOD-CH4 g-1CODTotal-BW) was observed. Therefore, adding calcium can significantly increase the CaP granulation without inhibiting the simultaneous CH4 recovery. This further indicates the potential of this process for phosphate recovery. PMID- 29248805 TI - Water quality assessment with emphasis in parameter optimisation using pattern recognition methods and genetic algorithm. AB - A non-supervised (k-means) and a supervised (k-Nearest Neighbour in combination with genetic algorithm optimisation, k-NN/GA) pattern recognition algorithms were applied for evaluating and interpreting a large complex matrix of water quality (WQ) data collected during five years (2008, 2010-2013) in the Paute river basin (southern Ecuador). 21 physical, chemical and microbiological parameters collected at 80 different WQ sampling stations were examined. At first, the k means algorithm was carried out to identify classes of sampling stations regarding their associated WQ status by considering three internal validation indexes, i.e., Silhouette coefficient, Davies-Bouldin and Calinski-Harabasz. As a result, two WQ classes were identified, representing low (C1) and high (C2) pollution. The k-NN/GA algorithm was applied on the available data to construct a classification model with the two WQ classes, previously defined by the k-means algorithm, as the dependent variables and the 21 physical, chemical and microbiological parameters being the independent ones. This algorithm led to a significant reduction of the multidimensional space of independent variables to only nine, which are likely to explain most of the structure of the two identified WQ classes. These parameters are, namely, electric conductivity, faecal coliforms, dissolved oxygen, chlorides, total hardness, nitrate, total alkalinity, biochemical oxygen demand and turbidity. Further, the land use cover of the study basin revealed a very good agreement with the WQ spatial distribution suggested by the k-means algorithm, confirming the credibility of the main results of the used WQ data mining approach. PMID- 29248806 TI - Magnesium alloy based interference screw developed for ACL reconstruction attenuates peri-tunnel bone loss in rabbits. AB - Peri-tunnel bone loss after anterior cruciate ligament (ACL) reconstruction is often observed clinically, which may detrimentally affect tendon graft integration with surrounding bone tissue. Biodegradable magnesium (Mg) based fixators in terms of interference screws may be suitable for fixation of the tendon graft due to their favorable effects on promotion of new bone formation. However, the poor mechanical strength of Mg is still one of the major challenges for its clinical applications. The addition of alloying elements into Mg is one of the strategies to improve their mechanical properties. Here, we prepared magnesium (Mg)-(4 and 6 wt%) zinc (Zn)-(0.2, 0.5, 1 and 2 wt%) strontium(Sr) alloys and tested their potential for attenuating peri-tunnel bone loss in ACL reconstruction. The optimal (6 wt%) Zn and (0.5 wt%) Sr contents were screened with respect to the microstructures, mechanical properties and corrosion behavior of these alloys. As compared to pure Mg, Mg-6Zn-0.5Sr rods and screws showed significantly higher torque and torsional stiffness in both numerical and experimental analysis. The in vitro cyto-compatibility of Mg-6Zn-0.5Sr alloy was assessed with MTT test and fluorescence assay. The Mg-6Zn-0.5Sr interference screw was designed for fixation of the tendon graft to the femoral tunnel in a rabbit model of ACL reconstruction, with a commercially available poly-lactide (PLA) screw for comparison. In vivo high resolution peripheral quantitative computed tomography (HR-pQCT) scanning was performed to measure the degradation behavior of Mg-6Zn-0.5Sr interference screws and peri-tunnel bone quality at 0, 6, 12 and 16 weeks post-surgically. Mg-6Zn-0.5Sr interference screw was completely degraded within 12 weeks after surgery. The peri-tunnel bone loss was significantly attenuated in the Mg-6Zn-0.5Sr group when compared to the PLA group. Importantly, the bony ingrowth rapidly filled the cavity left by the complete degradation of Mg-6Zn-0.5Sr screws at 16 weeks. In histological analysis, more bone formation was observed in peri-tunnel region in the Mg-6Zn 0.5Sr group in comparison to the PLA group at 6 and 16 weeks after surgery. The femur-tendon graft-tibia complex was harvested at the end of week 6 and 16 post operation for tensile testing. The maximum load to failure was significantly improved in the Mg-6Zn-0.5Sr group at week 16 post-operation. Therefore, our results indicate the potential clinical application of MgZnSr based interference screws in ACL reconstruction. PMID- 29248807 TI - Parental perceptions of facilitators and barriers to physical activity for children with intellectual disabilities: A mixed methods systematic review. AB - BACKGROUND: There is a need increase our understanding of what factors affect physical activity participation in children with intellectual disabilities (ID) and develop effective methods to overcome barriers and increase activity levels. AIM: This study aimed to systematically review parental perceptions of facilitators and barriers to physical activity for children with ID. METHODS: A systematic search of Embase, Medline, ERIC, Web of Science, and PsycINFO was conducted (up to and including August, 2017) to identify relevant papers. A meta ethnography approach was used to synthesise qualitative and quantitative results through the generation of third-order themes and a theoretical model. RESULTS: Ten studies were included, which ranged from weak to strong quality. Seventy-one second-order themes and 12 quantitative results were extracted. Five third-order themes were developed: family, child factors, inclusive programmes and facilities, social motivation, and child's experiences of physical activity. It is theorised that these factors can be facilitators or barriers to physical activity, depending on the information and education of relevant others, e.g. parents and coaches. CONCLUSIONS: Parents have an important role in supporting activity in children with ID. Increasing the information and education given to relevant others could be an important method of turning barriers into facilitators. PMID- 29248808 TI - Mixed urinary incontinence: A prospective study on the effect of trans-obturator mid-urethral sling. AB - OBJECTIVES: It is hypothesized that urethral dysfunction is central in mixed urinary incontinence (MUI) in women, since urine entering the proximal urethra under increased intra-abdominal pressure provokes a urethro-detrusorial reflex and involuntary detrusor contraction. Mid-urethral slings have been proposed as a solution. Our primary objective was to evaluate the long-term subjective and objective outcomes on continence and other urinary symptoms of a trans-obturator mid-urethral sling (TOT) procedure. Our secondary objectives were to determine its impact on quality of life (QoL), and to investigate which factors influence outcomes. STUDY DESIGN: This is a single-centre prospective study on a consecutive series of 86 women who underwent TOT for MUI as defined by ICS/IUGA. Since the definition of MUI that we used is symptom-based, we included patients both with and without associated detrusor overactivity. All patients underwent placement of Monarc(r) Subfascial Hammocks. STATISTICAL ANALYSIS: We used the McNemar chi-square test, the paired t-test and Fisher's exact test. A logistic regression model and odds ratios were used to assess age, parity, body mass index, menopausal status, preoperative detrusor over-activity, and detrusor pressure at maximum flow as possible factors for treatment failure. Only those that were statistically significant in the univariate analysis were included in the multivariate analysis. RESULTS: With a mean follow-up of 59 months, SUI was cured objectively in 83.7% of patients and subjectively in 87.2%. Three patients underwent further anti-incontinence surgery. The continence rates were 74.4% for urgency urinary incontinence (UUI) and 66.3% for SUI-UUI. The patient-reported success rate was 87.2% ('much better' or 'very much better' on Patient Global Impression of Improvement scale). There were statistically significant improvements in all domains except general health. The univariate analysis found no significant risk factor for persistence of SUI. Median age >60 years and menopause were predictive for persistence of UUI. Median and mean age >60 years were predictive of persistence of overall incontinence. In the multivariate model, all variables lost their statistical significance. CONCLUSION: Our study demonstrates TOT surgery can be performed for patients with MUI following unsuccessful conservative therapy. We also demonstrate that menopause and age >60 are risk factors for failure. This should be considered when counselling preoperatively. PMID- 29248809 TI - The identification of high potential archers based on fitness and motor ability variables: A Support Vector Machine approach. AB - Support Vector Machine (SVM) has been shown to be an effective learning algorithm for classification and prediction. However, the application of SVM for prediction and classification in specific sport has rarely been used to quantify/discriminate low and high-performance athletes. The present study classified and predicted high and low-potential archers from a set of fitness and motor ability variables trained on different SVMs kernel algorithms. 50 youth archers with the mean age and standard deviation of 17.0 +/- 0.6 years drawn from various archery programmes completed a six arrows shooting score test. Standard fitness and ability measurements namely hand grip, vertical jump, standing broad jump, static balance, upper muscle strength and the core muscle strength were also recorded. Hierarchical agglomerative cluster analysis (HACA) was used to cluster the archers based on the performance variables tested. SVM models with linear, quadratic, cubic, fine RBF, medium RBF, as well as the coarse RBF kernel functions, were trained based on the measured performance variables. The HACA clustered the archers into high-potential archers (HPA) and low-potential archers (LPA), respectively. The linear, quadratic, cubic, as well as the medium RBF kernel functions models, demonstrated reasonably excellent classification accuracy of 97.5% and 2.5% error rate for the prediction of the HPA and the LPA. The findings of this investigation can be valuable to coaches and sports managers to recognise high potential athletes from a combination of the selected few measured fitness and motor ability performance variables examined which would consequently save cost, time and effort during talent identification programme. PMID- 29248810 TI - Fast screening tests for the simultaneous detection of 11 drugs of abuse in urine specimens. A forensic epidemiology study of 28,298 cases in Tunisia. AB - Forensic investigation performed on people suspected to be drug abusers covering all Tunisian cities was conducted by monitoring an epidemiological study of human urine samples surveying positive rates of consumption for drugs of abuse. The forensic investigations were conducted on a total of 28,298 arrested individuals suspected to be drug addicts during five years (January 2010-December 2015). An immunoassay screening tests to detect elevated levels of drugs classes in urine samples was performed. These screening assays provide a preliminary qualitative test result. Only positives urine specimens were analyzed with GC-MS for confirmation. Except for cannabis, the results showed insignificant number of positive cases for cocaine, ecstasy (MDMA) and amphetamine consumptions (<1%). PMID- 29248811 TI - Assessment of the stability of DNA in specimens collected under conditions for drug testing-A pilot study. AB - For forensic biological sample collections, the specimen donor is linked solidly to his or her specimen through a chain of custody (CoC) sometimes referenced as a chain of evidence. Rarely, a donor may deny that a urine or oral fluid (OF) specimen is his or her specimen even with a patent CoC. The goal of this pilot study was to determine the potential effects of short-term storage on the quality and quantity of DNA in both types of specimen under conditions that may be encountered with employment-related drug testing specimens. Fresh urine and freshly collected oral fluid all produced complete STR profiles. For the "pad" type OF collectors, acceptable DNA was extractable both from the buffer/preservative and the pad. Although fresh urine and OF produced complete STR profiles, partial profiles were obtained after storage for most samples. An exception was the DNA in the Quantisal OF collector, from which a complete profile was obtained for both freshly collected OF and stored OF. PMID- 29248812 TI - N/S/B-doped graphitized carbon encased Fe species as a highly active and durable catalyst towards oxygen reduction reaction. AB - Exploring cost-effective, high-performance and durable non-precious metal catalysts is of great significance for the acceleration of sluggish oxygen reduction reaction (ORR). Here, we report an intriguing heteroatom-doped graphitized carbon encased Fe species composite by introducing N, S and B sequentially. The experimental approach was designed ingeniously for that the FeCl3.6H2O could catalyze thiourea to synthesize N, S co-doped carbon materials which would further react with H3BO3 and NH3 (emerged at the heat-treatment process) to prepare N, S and B co-doped carbon materials (Fe-N/S/B-C). The Fe N/S/B-C exhibits an impressive ORR activity for its half-wave potential of -0.1 V, which is 36 mV or 19 mV higher than that of the corresponding single or dual doped counterparts (Fe-N-C or Fe-N/S-C) and 31 mV positive than that of Pt/C catalyst, respectively. Further chronoamperometric measurement and accelerated aging test confirm the excellent electrochemical durability of Fe-N/S/B-C with the stable core-shell structure. The remarkable ORR performance and facile preparation method enable Fe-N/S/B-C as a potential candidate in electrochemical energy devices. PMID- 29248813 TI - In-situ deposition of sodium titanate thin film as anode for sodium-ion micro batteries developed by pulsed laser deposition. AB - Sodium-ion thin-film micro-batteries form a niche sector of energy storage devices. Sodium titanate, Na2Ti6O13 (NTO) thin films were deposited by pulsed laser deposition (PLD) using solid-state synthesized polycrystalline Na2Ti6O13 compound. The phase-purity and crystallinity of NTO in bulk and thin-film forms were confirmed by Rietveld refinement. Electron microscopy and atomic force microscopy revealed the formation of uniform ~100 nm thin film with roughness of ~4 nm consisting of homogeneous nanoscale grains. These PLD-deposited NTO thin films, when tested in Na-half cell architecture, delivered a near theoretical reversible capacity close to 42 mA h g-1 involving Ti4+/Ti3+ redox activity along with good cycling stability and rate kinetics. Na2Ti6O13 can work as an efficient and safe anode in designing sodium-ion thin-film micro-batteries. PMID- 29248815 TI - Electrokinetic investigation of deposition of cationic fabric softener vesicles on anionic porous cotton fabrics. AB - HYPOTHESIS: Colloidal deposition on porous substrates is a complex process influenced by both, (i) characteristics of colloidal permeation into porous substrates, and (ii) mechanism of colloidal deposition on solid surfaces. Such processes are quintessential to action of products such as hair conditioners and fabric softeners where the substrates to be treated are porous. The performance of these formulations is linked with the distribution of deposited colloids across porous substrates i.e. whether deposition is localized near substrate periphery, or deposition is homogeneously distributed. EXPERIMENTS: In this work, we investigate the deposition of cationic vesicles, commonly used in fabric softeners, on anionic porous cotton yarns via spectrophotometric measurement of adsorption density of vesicles on yarns and electrokinetic measurement of cotton yarn apparent zeta potentials. Under the employed conditions, cotton yarn apparent zeta potentials are sensitive predominantly to external yarn surfaces. Therefore, these measurements can distinguish between deposition on external and internal yarn surfaces. FINDINGS: The phase behavior of lipid bilayers constituting the vesicles is identified as an important governing factor with solid-gel vesicles depositing more near yarn periphery, and liquid-crystalline vesicles depositing more uniformly throughout the yarns. Bulk electrical conductivity also influences the distribution of deposited vesicles. The results are explained with the help of a newly proposed theory. PMID- 29248814 TI - Fabrication of supramolecular star-shaped amphiphilic copolymers for ROS triggered drug release. AB - Star-shaped copolymers with branched structures can form unimolecular micelles with better stability than the micelles self-assembled from conventional linear copolymers. However, the synthesis of star-shaped copolymers with precisely controlled degree of branching (DB) suffers from complicated sequential polymerizations and multi-step purification procedures, as well as repeated optimizations of polymer compositions. The use of a supramolecular host-guest pair as the block junction would significantly simplify the preparation. Moreover, the star-shaped copolymer-based unimolecular micelle provides an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficacy if the association/dissociation of the supramolecular host-guest joint can be triggered by the biologically relevant stimuli. For this purpose, in this study, a panel of supramolecular star-shaped amphiphilic block copolymers with 9, 12, and 18 arms were designed and fabricated by host-guest complexations between the ring-opening polymerization (ROP) synthesized star-shaped poly(epsilon-caprolactone) (PCL) with 3, 4, and 6 arms end-capped with ferrocene (Fc) (PCL-Fc) and the atom transfer radical polymerization (ATRP)-produced 3-arm poly(oligo ethylene glycol) methacrylates (POEGMA) with different degrees of polymerization (DPs) of 24, 30, 47 initiated by beta-cyclodextrin (beta-CD) (3Br-beta-CD-POEGMA). The effect of DB and polymer composition on the self-assembled properties of the five star-shaped copolymers was investigated by dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescence spectrometery. Interestingly, the micelles self-assembled from 12-arm star-shaped copolymers exhibited greater stability than the 9- and 18-arm formulations. The potential of the resulting supramolecular star-shaped amphiphilic copolymers as drug carriers was evaluated by an in vitro drug release study, which confirmed the ROS-triggered accelerated drug release from the doxorubicin (DOX)-loaded supramolecular star-shaped micelles due to the oxidation-induced dissociation of beta-CD/Fc pair and the consequent loss of the colloidal stability of the star-shaped micelles. Studies of the delivery efficacy by an in vitro cytotoxicity study further indicated that higher DBs and longer hydrophilic arm compromised the therapeutic efficacy of the DOX-loaded supramolecular star-shaped micelles, resulting in significantly reduced cytotoxicity, as measured by increased IC50 value. Overall, our results revealed that the screening of hydrophilic block by DB and MW for an optimized star-shaped copolymer should balance the stability versus therapeutic efficacy tradeoff for a comprehensive consideration. Therefore, the 12-arm star-shaped copolymer with POEGMA30 is the best formulation tested. PMID- 29248816 TI - A novel multi-reaction model for kinetics of Zn release from soils: Roles of soil binding sites. AB - The kinetics of Zn release from soil is a key process affecting the fate and bioavailability of Zn in soil, which may be complicated by multiple soil binding sites and reactions during the Zn release process. In this study, we developed a novel quantitative model for the dynamic Zn speciation in soil during the Zn release process, by integrating the mechanistic equilibrium model WHAM 7 and molecular level investigation of Zn speciation with X-ray absorption spectroscopy (XAS). The kinetics model specifically considered Zn reactions with soil organic matter (SOM), iron (hydr)oxides, and clay minerals, and dissolution of Zn precipitates. Batch and replenishment experiments were conducted to study kinetics of Zn release from laboratory-spiked soils and XAS was employed to identify soil Zn speciation. Overall, the model described the experimental data reasonably well with minimal model fitting parameters. We quantitatively assessed the dynamic changes of Zn speciation in different soil components and SOM binding sites at various time scales and reaction conditions. Our kinetics model provides a quantitative framework for predicting the dynamic behavior of Zn in soil environments. PMID- 29248817 TI - Structure and properties of hybrid biopolymer particles fabricated by co precipitation cross-linking dissolution procedure. AB - The Co-precipitation Crosslinking Dissolution technique (CCD-technique) allows a few-steps fabrication of particles composed of different biopolymers and bioactive agents under mild conditions. Morphology and properties of the fabricated biopolymer particles depend on the fabrication conditions, the nature of the biopolymers and additives, but also on the choice of the inorganic templates for co-precipitation. Here, we investigate the influence of an acidic biopolymer, hyaluronic acid (HA), on the formation of particles from bovine hemoglobin and bovine serum albumin applying co-precipitation with CaCO3 and MnCO3. CaCO3 templated biopolymer particles are almost spherical with particle size from 2 to 20 um and protein entrapment efficiency from 13 to 77%. Presence of HA causes significant structural changes of the particles and decreasing protein entrapment efficiency. In contrast, MnCO3 templated particles exhibit uniform peanut shape and submicron size with remarkably high protein entrapment efficiency of nearly 100%. Addition of HA has no influence on the protein entrapment efficiency or on morphology and size of the particles. These effects can be attributed to the strong interaction of Mn2+ with proteins and much weaker interaction with HA. Therefore, entrapment efficiency, size and structure of biopolymer particles can be optimized by varying the mineral templates and additives. PMID- 29248818 TI - Barriers, facilitators, and potential strategies for increasing HPV vaccination: A statewide assessment to inform action. AB - OBJECTIVE: The objective was to investigate how state level strategies in South Carolina could maximize HPV vaccine uptake. DESIGN: An environmental scan identified barriers, facilitators, and strategies for improving HPV vaccination in South Carolina. Interviews were conducted with state leaders from relevant organizations such as public health agencies, medical associations, K-12 schools, universities, insurers, and cancer advocacy organizations. A thematic content analysis design was used. Digital interview files were transcribed, a data dictionary was created and data were coded using the data dictionary. RESULTS: Thirty four interviews were conducted with state leaders. Barriers to HPV vaccination included lack of HPV awareness, lack of provider recommendation, HPV vaccine concerns, lack of access and practice-level barriers. Facilitators included momentum for improving HPV vaccination, school-entry Tdap requirement, pharmacy-based HPV vaccination, state immunization registry, HEDIS measures and HPV vaccine funding. Strategies for improving HPV vaccination fell into three categories: 1) addressing lack of awareness about the importance of HPV vaccination among the public and providers; 2) advocating for policy changes around HPV vaccine coverage, vaccine education, and pharmacy-based vaccination; and 3) coordination of efforts. DISCUSSION: A statewide environmental scan generated a blueprint for action to be used to improve HPV vaccination in the state. PMID- 29248819 TI - Elemental sulfur reduction to H2S by Tetrahymena thermophila. AB - Eukaryotic nucleocytoplasm is believed to be descended from ancient Archaea that respired on elemental sulfur. If so, a vestige of sulfur reduction might persist in modern eukaryotic cells. That was tested in Tetrahymena thermophila, chosen as a model organism. When oxygenated, the cells consumed H2S rapidly, but when made anoxic they produced H2S mostly by amino acid catabolism. That could be inhibited by adding aminooxyacetic acid, and then H2S production from elemental sulfur became more evident. Anoxic cell lysates produced H2S when provided with sulfur and NADH, but not with either substrate alone. When lysates were fractionated by centrifugation, NADH-dependent H2S production was 83% in the soluble fraction. When intact cells that had just previously oxidized H2S were shifted to anoxia, the cells produced H2S evidently by re-using the oxidized sulfur. After aerobic H2S oxidation was stopped, the oxidation product remained available for H2S production for about 10 min. The observed H2S production is consistent with an evolutionary relationship of nucleocytoplasm to sulfur-reducing Archaea. Mitochondria often are the cellular site of H2S oxidation, suggesting that eukaryotic cells might have evolved from an ancient symbiosis that was based upon sulfur exchange. PMID- 29248820 TI - Effect of maternal postpartum depression on offspring's growth. AB - BACKGROUND: Previous studies have linked maternal depression to different child offspring's growth outcomes. However, its effect has not been well established. The aim of this review was to evaluate the available evidence on the effect of maternal postpartum depression on offspring weight and height growth outcomes. METHODS: A systematic review of longitudinal studies that evaluated the effect of maternal depression on child's growth outcomes was conducted in PubMed, LILACs, Web of Science, Science Direct and PsyInfo databases, using maternal postpartum depression related keywords, according to each database searching tool. RESULTS: A total of 9608 articles were screened and 20 met the final inclusion criteria. The child's first-year growth was the most affected by the exposure to maternal depression. Children of depressed mothers had a higher chance of being underweight and stunted in the first year of life. Maternal depression was also associated with child's linear growth impairment after the first year. LIMITATIONS: As a literature review, a publication bias could not be ruled out. The diversity of the published data made it unfeasible for a pooled effect to be estimated. CONCLUSIONS: Considering the results observed on child's first year of life growth, physicians should engage in assessing maternal depression, as it is a treatable and manageable disease, thus avoiding unnecessary harm on child's physical development. PMID- 29248821 TI - Psychometric properties of the well-being index (WHO-5) spanish version in a sample of euthymic patients with bipolar disorder. AB - BACKGROUND: The concept of well-being which focuses on positive emotions has received increased research attention. However, a consensus definition of this term is lacking. The Well-Being Index scale (WHO-5) is a generic, self-report scale that contains five Likert-type items to evaluate psychological well-being. This construct may provide a relevant outcome in bipolar disorder (BD) research and care beyond the rating of mood symptoms. Thus, in the current study, the psychometric properties of the WHO-5 Spanish version were assessed in a sample of euthymic patients with BD. METHODS: Patients with BD- I and BD-II and healthy controls completed the Well-Being Index (WHO-5) together with an assessment of depressive (Hamilton Depression Rating Scale-17; HAM-D) and manic symptoms (Young Mania Rating Scale; YMRS); and a measure of psychosocial functioning (Functioning Assessment Short Test; FAST). Internal consistency reliability was measured through Cronbach's alpha. Test-retest reliability was calculated comparing the WHO-5 total score at baseline and after 10 days of the first administration. To assess the structure of the scale, a principal component analysis (PCA) was carried out. Correlations between the WHO-5, HAM-D, YMRS and FAST were calculated. Finally, a t-test for independent samples was applied to compare the WHO-5 total score in the patient and control groups. RESULTS: A total of 104 patients with BD and 40 healthy controls were included in this study. A Chronbach's alpha of 0.83 indicated acceptable internal consistency. A paired sample t-test revealed no significant differences between WHO-5 total score at baseline and at follow-up (tn = - 0.72; df = 15; p = 0.48). The PCA provided a single factor solution that accounted for 59.74% of the variation in WHO-5. Test retest reliability was high (r = 0.83; p < 0.001). Moderate negative correlations were observed between the WHO-5 total score, the FAST (r = - 0.46.; p < 0.001) and the HAM-D (r = - 0.68; p < 0.001), but not with the YMRS (r = - 0.07; p = 0.42). Finally, significant differences were found when comparing the WHO-5 total score between patient and healthy controls (t = 5.1; df = 147; p < 0.001). LIMITATIONS: some limitations include the lack of a comparator scale to test for validity construct and the small sample size in the test-retest reliability CONCLUSIONS: The WHO-5 shows an acceptable reliability index and measures a unitary construct in a Spanish population of euthymic patients with BD. PMID- 29248822 TI - 'Taking back the reins' - A qualitative study of the meaning and experience of self-management in bipolar disorder. AB - BACKGROUND: Self-management (SM) is increasingly emphasised as a key aspect of bipolar disorder (BD) treatment. However, little is known about the subjective experience of SM, which might have both positive and negative impacts. The present study aimed to advance this literature through qualitative investigation of the experiences of people with BD who participated in an SM intervention targeting quality of life (QoL). METHODS: Forty-three individuals with BD engaged with an SM intervention and were later questioned about personal experiences of engagement with the intervention, including attempts to enact self-management strategies. Thematic analysis was used to identify important aspects of the experience of SM in BD. RESULTS: Four themes describing people's experiences of SM were identified: 1) SM for BD is empowering, 2) individual responsibility to self-manage BD, 3) SM strategies lack power to control BD, and 4) the relationship of SM to the healthcare system. LIMITATIONS: Potential limitations to generalisability may occur from self-selection bias in favour of SM and the QoL-focused nature of the present intervention. CONCLUSIONS: The findings of this research generate novel insights into ways in which individuals with BD engage with SM interventions. For most people with BD, SM invokes a sense of empowerment and responsibility, although some feel symptoms remain beyond their control. A sense of partnership between consumers and clinicians may emerge from attention to SM, but traditional medical approaches were perceived as neglecting this aspect of care. Considerations from consumer perspectives are presented to assist clinicians and researchers utilising SM interventions in BD. PMID- 29248823 TI - Negative affect is related to reduced differential neural responses to social and non-social stimuli in 5-to-8-month-old infants: A functional near-infrared spectroscopy-study. AB - Both social perception and temperament in young infants have been related to social functioning later in life. Previous functional Near-Infrared Spectroscopy (fNIRS) data (Lloyd-Fox et al., 2009) showed larger blood-oxygenation changes for social compared to non-social stimuli in the posterior temporal cortex of five month-old infants. We sought to replicate and extend these findings by using fNIRS to study the neural basis of social perception in relation to infant temperament (Negative Affect) in 37 five-to-eight-month-old infants. Infants watched short videos displaying either hand and facial movements of female actors (social dynamic condition) or moving toys and machinery (non-social dynamic condition), while fNIRS data were collected over temporal brain regions. Negative Affect was measured using the Infant Behavior Questionnaire. Results showed significantly larger blood-oxygenation changes in the right posterior-temporal region in the social compared to the non-social condition. Furthermore, this differential activation was smaller in infants showing higher Negative Affect. Our results replicate those of Lloyd-Fox et al. and confirmed that five-to-eight month-old infants show cortical specialization for social perception. Furthermore, the decreased cortical sensitivity to social stimuli in infants showing high Negative Affect may be an early biomarker for later difficulties in social interaction. PMID- 29248824 TI - Contextualizing public stigma: Endorsed mental health treatment stigma on college and university campuses. AB - Scholars suggest that public mental health stigma operates at a meso-level and is associated with severity of symptoms, disclosure, self-esteem, and treatment seeking behavior. However, the operationalization of public stigma nearly always comes from an individual-level generalization of what others believe. Using data from over 60,000 students on 75 U.S. college and university campuses between 2009 and 2015, we contextualize public stigma by creating a school-level measure of students' individual-level endorsed mental health treatment stigma. We present multilevel logistic regression models for 21 different dependent variables. We find that even after controlling for individual-level stigma scores, school-level stigma is negatively associated with self-reports of suicidal ideation and self injury, although not associated with screens for depression or anxiety. Moreover, school-level stigma is negatively associated with medication use, counseling and therapy visits, and to a lesser degree, informal support. We suggest that future research should continue to examine the contextual environment of public stigma, while policymakers may be able to implement changes to significantly reduce stigma at this level. PMID- 29248825 TI - Predictors of seasonal influenza vaccination behaviour among nurses and implications for interventions to increase vaccination uptake: A cross-sectional survey. AB - BACKGROUND: Vaccination has been proven the most effective method to prevent seasonal influenza. Nurses' vaccination can provide protection against influenza not only for themselves but also for patients they take care of. However, vaccination coverage of nurses is suboptimal worldwide, especially in China. The influencing factors need to be explored so as to develop specific, workable strategies to improve nurses' vaccination behaviour. OBJECTIVES: To explore predictors of their vaccination behaviour, identify the motivators and barriers of vaccination, and provide implications for future interventions. DESIGN: A cross-sectional convenience sampling questionnaire survey. SETTINGS: Nine hospitals including five tertiary hospitals, two secondary hospitals, and two primary hospitals in Shanghai, China. PARTICIPANTS: A total of 1000 nurses from the nine hospitals were invited to participate in this survey. Among them, 921 nurses responded and 895 returned valid questionnaires that were used in data analysis. METHODS: The Chinese version of the King's Nurses' Influenza Vaccination Questionnaire was used as the survey instrument and distributed to the participants during February-November 2012. Descriptive statistics, univariate analyses, and multivariate analyses were conducted to explore the predictors of nurses' vaccination behaviour. RESULTS: Overall, 8.8% of the respondents received seasonal influenza vaccination in the past influenza season (2011/2012 season). Nurses had averagely received 0.38 +/- 0.71 influenza vaccines during the past five influenza seasons (2007/2008 to 2011/2012 season). Predictors of nurses' vaccination status were clinical specialty, knowledge about influenza vaccination [1.331 (1.102, 1.608), p = 0.003], internal health locus of control [0.910 (0.845, 0.980), p = 0.013], chance health locus of control [1.075 (1.023, 1.130), p = 0.004]and powerful others health of locus control [1.166 (1.083, 1.255), p < 0.001]. Predictors of their vaccination times were hospital level, clinical specialty, and knowledge about influenza vaccination [1.458 (1.242, 1.711), p < 0.001]. Self-protection was the most common cited reason for getting vaccinated, and "no need" was cited as the most common refusal reason. CONCLUSIONS: This is the first well-designed study conducted in mainland China to explore nurses' vaccination behaviour against seasonal influenza. Vaccination coverage in this population was suboptimal. Mandatory vaccination policy should be implemented and attempts of multi-faceted interventions including specific education might also be needed. PMID- 29248826 TI - The Royal Free Hospital 'hub-and-spoke network model' delivers effective care and increased access to liver transplantation. AB - OBJECTIVES: 'Hub-and-spoke' networks may be one solution to reduce the geographical inequality in access to liver transplantation (LT) and the growing demands on, and saturation of, LT centres. It is not clear if such networks improve equity of access, deliver comparable patient outcomes or effect patient satisfaction. STUDY DESIGN: Retrospective evaluation of outcomes and patient satisfaction within the Royal Free liver transplant 'hub-and-spoke' network. METHODS: Patient outcomes in those assessed for LT between September 2011 and 2014 at spoke centres (n = 4) were compared retrospectively with those assessed at the LT hub centre. Patient satisfaction questionnaires were completed and changes in LT referral patterns were explored with data obtained directly from NHS Blood and Transplant (NHSBT). RESULTS: A total of 655 patients (180 spoke; 475 hub) were assessed for LT. Patients referred from spoke centres were more likely to have viral hepatitis as an underlying aetiology (72/180 vs 110/475; P < 0.001), or hepatocellular carcinoma (48/180 vs 60/475; P < 0.001) as an indication for LT and were more likely to be listed for LT when compared with hub patients (139/180 vs 312/475, P = 0.005). Mortality on the waiting list (9/123 vs 25/269, P = 0.57), waiting time to LT (64-days vs 78-days, P = 0.91) and Model for End-Stage liver disease (MELD)/United Kingdom End-Stage Liver Disease (UKELD) score (P = 0.24/0.26) in listed patients were equivalent as were 1- and 3-year patient and graft survival rates. Patient satisfaction rates were high at both types of centre, with significantly more patients preferring 'locally delivered care' at spoke vs hub (11/50 vs 70/73, P<=0.0001). Since the development of formal hub-and-spoke networks data from NHSBT based on postcode confirmed a significant increase in patients undergoing LT (153%) from spoke centres, whereas numbers assessed and transplanted from the hub centre have remained static. CONCLUSION: Hub-and-spoke LT networks are effective in offering equivalent clinical outcomes, high patient satisfaction and alleviate clinical pressure on the hub centre. They have to potential to help eliminate the geographical disparity in mortality rates from chronic liver disease. PMID- 29248827 TI - Effect of dietary counseling on preventing excessive weight gain during pregnancy. AB - OBJECTIVES: Excessive gestational weight gain (EGWG) is associated with short- and long-term health problems among mothers and their offspring. The aim of this study was to assess the effect of dietary counseling on EGWG. STUDY DESIGN: Randomized controlled intervention trial. METHODS: The study was conducted at the antenatal care (ANC) clinic, Center for Social and Preventive Medicine, Pediatrics Hospital, Cairo University, during the period from July 2015 to April 2016. A total of 200 primigravidae aged between 20 and 30 years were included and randomized into intervention and control groups. Based on data analysis from phase 1, nutritional practices of the studied participants were identified and tailored nutrition counseling sessions designed. Follow-up of the studied participants throughout ANC visits was done to enforce the healthy dietary intake and encourage weight gain according to the recommendations to avoid EGWG. RESULTS: The intervention resulted in a significantly higher proportion of women in the intervention group who gained gestational weight within the Institute of Medicine recommendations compared to women in the control group (42.7% vs 13.9%, respectively) (P-value <0.001); this was detected between the 25th and 35th weeks of gestation. Dietary counseling had significantly improved the frequency of consumption of different food items and knowledge, attitude, and practice mean scores of the intervention group in comparison with the control group (P-value <0.001). CONCLUSIONS: The results of the present study demonstrated that dietary counseling given to pregnant women reduced the proportion of EGWG and improved dietary practices. There is a strong need for effective intervention strategies targeting EGWG to prevent adverse pregnancy outcomes. PMID- 29248828 TI - Mechanisms of phloem unloading: shaped by cellular pathways, their conductances and sink function. AB - Phloem unloading represents a series of cell-to-cell transport steps transferring phloem-mobile constituents from phloem to sink tissues/organs to fuel their development or resource storage. Our analysis focuses on unloading of two major phloem-mobile constituents, sugars and water. Their unloading can occur across phloem plasma membranes (apoplasmic unloading), through plasmodesmata interconnecting phloem and sink cells (symplasmic unloading) or predominately symplasmically with an intervening post-phloem apoplasmic step. In planta studies of phloem unloading encounter substantial technical challenges in accessing phloem within a meshwork of vascular/ground tissues. Thus, current understanding of phloem-unloading mechanisms largely has been deduced from indirect experimental measures or modelling. Here we highlight recent advances in understanding phloem unloading mechanisms and identify where important knowledge gaps remain. PMID- 29248829 TI - Iron-loaded transferrin (Tf) is detrimental whereas iron-free Tf confers protection against brain ischemia by modifying blood Tf saturation and subsequent neuronal damage. AB - Despite transferrin being the main circulating carrier of iron in body fluids, and iron overload conditions being known to worsen stroke outcome through reactive oxygen species (ROS)-induced damage, the contribution of blood transferrin saturation (TSAT) to stroke brain damage is unknown. The objective of this study was to obtain evidence on whether TSAT determines the impact of experimental ischemic stroke on brain damage and whether iron-free transferrin (apotransferrin, ATf)-induced reduction of TSAT is neuroprotective. We found that experimental ischemic stroke promoted an early extravasation of circulating iron loaded transferrin (holotransferrin, HTf) to the ischemic brain parenchyma. In vitro, HTf was found to boost ROS production and to be harmful to primary neuronal cultures exposed to oxygen and glucose deprivation. In stroked rats, whereas increasing TSAT with exogenous HTf was detrimental, administration of exogenous ATf and the subsequent reduction of TSAT was neuroprotective. Mechanistically, ATf did not prevent extravasation of HTf to the brain parenchyma in rats exposed to ischemic stroke. However, ATf in vitro reduced NMDA-induced neuronal uptake of HTf and also both the NMDA-mediated lipid peroxidation derived 4-HNE and the resulting neuronal death without altering Ca2+-calcineurin signaling downstream the NMDA receptor. Removal of transferrin from the culture media or blockade of transferrin receptors reduced neuronal death. Together, our data establish that blood TSAT exerts a critical role in experimental stroke induced brain damage. In addition, our findings suggest that the protective effect of ATf at the neuronal level resides in preventing NMDA-induced HTf uptake and ROS production, which in turn reduces neuronal damage. PMID- 29248831 TI - Essential oil of Cymbopogon citratus (lemongrass) and geraniol, but not citral, promote gastric healing activity in mice. AB - Cymbopogon citratus, popularly known as lemongrass, is used for the treatment of gastric, nervous and hypertensive disorders, in addition to its use in the food and pharmaceutical industries. This study evaluated the gastroprotective and gastric healing effect of essential oil of C. citratus (EOCC), citral and geraniol at doses of 1-100 mg/kg (p.o) on acute ethanol-induced ulcer and chronic acetic acid-induced ulcer. Histological and histochemical evaluation was also performed, as well as the in vitro evaluation of the effects of these phytochemicals on H+/K+-ATPase activity. In the ethanol-induced gastric ulcer, the minimum effective oral dose of EOCC, citral and geraniol were 10, 100 and 3 mg/kg, reducing the ulcer area by 51.67%, 96.57% and 55.74%, respectively, compared to vehicle group (25.82 +/- 3.59 mm2). Moreover, EOCC (10 mg/kg, p.o) and geraniol (3 mg/kg), but not citral (100 mg/kg), accelerated the gastric healing process by 34.52 and 80.57%, compared to acetic-acid ulcerated group treated with vehicle (36.04 +/- 1.03 mm2). These healing effects were confirmed histologically by the contraction of the ulcer base and by the enhancement on mucin staining in slices of ulcer site from mice treated with EOCC or geraniol. Interestingly, EOCC and citral at 100 MUg/ml inhibited the H+/ K+-ATPase activity by 28.26% and 44.36%, whereas geraniol did not change this parameter. Together, these findings confirm the gastroprotective and healing gastric ulcer effects of essential oil from aerial parts of C. citratus and added the information that geraniol, but not citral, promotes healing effects on installed ulcers. PMID- 29248830 TI - miR-200a-5p regulates myocardial necroptosis induced by Se deficiency via targeting RNF11. AB - Necroptosis has been discovered as a new paradigm of cell death and may play a key role in heart disease and selenium (Se) deficiency. Hence, we detected the specific microRNA (miRNA) in response to Se-deficient heart using microRNAome analysis. For high-throughput sequencing using Se-deficient chicken cardiac tissue, we selected miR-200a-5p and its target gene ring finger protein 11 (RNF11) based on differential expression in cardiac tissue and confirmed the relationship between miR-200a-5p and RNF11 by dual luciferase reporter assay and real-time quantitative PCR (qRT-PCR) in cardiomyocytes. We further explored the function of miR-200a-5p and observed that overexpression of miR-200a-5p spark the receptor interacting serine/threonine kinase 3 (RIP3)-dependent necroptosis in vivo and in vitro. To understand whether miR-200a-5p and RNF11 are involved in the RIP3-dependent necroptosis pathway, we presumed that oxidative stress, inflammation response and the mitogen-activated protein kinase (MAPK) pathway might trigger necroptosis. Interestingly, necroptosis trigger, z-VAD-fmk, failed to induce necroptosis but enhanced cell survival against necrosis in cardiomyocytes with knockdown of miR-200a-5p. Our present study provides a new insight that the modulation of miR-200a-5p and its target gene might block necroptosis in the heart, revealing a novel myocardial necrosis regulation model in heart disease. PMID- 29248832 TI - Polyphenol-rich ethyl acetate fraction isolated from Molineria latifolia ameliorates insulin resistance in experimental diabetic rats via IRS1/AKT activation. AB - This study aimed to evaluate the effect of ethyl acetate fraction (EAF) isolated from Molineria latifolia rhizome as dietary interventions for type 2 diabetes mellitus (T2DM) and its underlying molecular mechanisms in vivo. Experimental rats were induced by high fat diet feeding coupled with combined exposure to streptozotocin and nicotinamide. Treatment with EAF improved glucose tolerance and lipid profiles, but the insulin secretion was unaltered. Gene expression analyses on insulin/adipocytokine signalling-related genes demonstrated tissue specific transcriptional responses. In skeletal muscle and liver tissues, Socs1, Tnf and Mapk8 showed consistent transcript regulation. Furthermore, hepatic translational analyses revealed sensitization on proximal insulin signalling, with reduced expression of IRS1 serine phosphorylation, increased IRS1 tyrosine phosphorylation and increased phospho-AKT (Ser473). The present findings suggested that EAF exerted its effect by modulating insulin signalling, potentially via IRS1/AKT activation. The pharmacological attributes of EAF may implicate its potential therapeutic applications for diabetes management. PMID- 29248833 TI - Endoscopic management of Atypical sellar cavernous hemangioma: A case report and review of the literature. AB - INTRODUCTION: supratentorial cavernous hemangiomas, particularly those found in the sellar region, are extremely rare. We present a case of sellar cavernous hemangioma with radiological characteristics that have never been reported. Due to the difficulty diagnosing these lesions, misdiagnosis might occur. Thus, briefing surgeons about the clinico-radiological features of such rare lesions is crucial for better understanding the enigmatic features of such rare lesions and to develop early management approaches that could result in better surgical excision with a lower tendency for complications. PRESENTATION OF CASE: A 43-year old male presented with headache, blurred vision, and impotence for the last 2 years. Brain magnetic resonance imaging showed an atypical sellar mass displaying signals of heterogeneous intensity on T1- and T2-weighted imaging. The mass exhibited heterogeneous enhancement after gadolinium injection. Endoscopic endonasal surgery was subsequently performed, during which an uneventful subtotal resection of the mass was achieved. Histopathological analysis confirmed the diagnosis of intrasellar cavernous hemangioma. DISCUSSION: Many questions regarding how best to manage such lesions remain unanswered. Hence, we summarize the relevant surgical techniques and discuss misconceptions. CONCLUSION: Seller cavernous hemangioma (SCH) is an extremely rare lesion that can be misdiagnosed. It is characterized by clinico-radiological features similar to those of other lesions such as pituitary macroadenoma and should be included in the differential diagnosis. The endoscopic endonasal transsphenoidal (EET) approach with subtotal/total resection appears to be a feasible option for debulking, with less surgical complications. Nonetheless, combining stereotactic radiosurgery will reduce postsurgical morbidities. PMID- 29248834 TI - Cerebellar metastasis of gastrointestinal stromal tumor: A case report and review of the literature. AB - INTRODUCTION: Intracranial metastases of gastro intestinal tumors are very rare. To the best of our knowledge only few cases were reported on the literature. CASE DESCRIPTION: We describe the case of 66-year-old male that presented with headache and vomiting. Physical examination found a kinetic cerebellar syndrome. Brain CT scan and MRI showed a right cerebellar tumor. Sub-occipital craniotomy was performed and the tumor was completely resected. Surgical outcomes were marked by the occurrence of an abdominal pain two days after brain surgery. Peritonitis was diagnosed and the patient underwent surgery. Per-operatively, a hemorrhagic tumor perforating the intestines was found and resected. Pathologic examination of the cerebral tumor's resection piece and the intestinal resection piece concluded to a metastasis of a stromal gastro-intestinal tumor. DISCUSSION: Gastro-intestinal stromal tumors are frequent neoplasms, but intracranial metastases of these neoplasms are extremely rare. Abdominal symptomatology frequently reveals the pathology. However, extra digestive symptoms may in rare cases disclose intestinal tumors. Intracranial metastases of gastro-intestinal stromal tumors are generally solitary mainly supratentorial. Infratentorial metastases are very uncommon. Management of gastro-intestinal stromal tumors is based on surgical removal of the tumor. Adjuvant treatment consisting on chemotherapy and radiotherapy is subject of debate. CONCLUSIONS: Gastro intestinal stromal tumors are frequent neoplasms with a high metastasizing potential on liver and peritoneum. Brain metastases are extremely rare and the prognosis is worse when they are present. Surgery remains the main treatment for the primitive and the secondary lesions. PMID- 29248835 TI - A successful management of sever gummy smile using gingivectomy and botulinum toxin injection: A case report. AB - INTRODUCTION: A gummy smile (GS) affects the esthetic and the psychological status as it usually decreases the self-confidence leading to hidden or controlling the smile. A smile with more than 2 mm exposed gingiva is called gummy smile. It may be due to one or more of the following etiologies; altered passive eruption of teeth, dentoalveolar extrusion, vertical maxillary excess, and short or hyperactive lip muscles. The treatment of gummy smile should be planned according to its cause/causes. The purpose of this case report was to highlight the ability of combined treatment of gingivectomy and Botox injection technique in managing a severe gummy smile. Also, techniques, advantages, disadvantages, indication and contraindications of Botulinum toxin (BT) are discussed at the literacy. PRESENTATION OF THE CASE: A 24 year old female patient with a severe gummy smile was refereed to the periodontal clinics of our institution. Clinical examination revealed that she has a GS of an 11-12 mm gingival exposed area that was indicated for orthognathic surgery. The GS was treated by a gingivectomy surgery to increase the clinical crowns of upper anterior teeth and the use of Botox injections. The treatment showed remarkable and satisfactory results instead of doing extensive surgery. DISCUSSION AND CONCLUSION: It is important to assess the patients' esthetic expectations and show the possible therapeutic solutions that fit him. We revealed that BT is considered as one of the minimally invasive, quick and affordable modalities that can replace extensive surgical procedures for corrections of sever GS. PMID- 29248836 TI - A case report: Primary hydatid cyst of uterus. AB - INTRODUCTION: Echinococcus granulosus is a parasitic tape worm. The definitive host is the dog and humans are one of its intermediate hosts. It involves organs such as liver and lungs. Uterus involvement is very rare. PRESENTATION OF CASE: We here report a case of primary uterus hydatid cyst that we had to remove her uterine on left ovary and fallopian tube. Generalized toxic shock and infection due to cyst rupture or organ dysfunction due to invasion (like our patient) or pressure of cyst are complications of this cyst. DISCUSSION: Because of low incidence of hydatid cysts in uterus it can be misdiagnosed by mimicking other conditions such as multi-cystic ovarian tumor, hemorrhagic ovarian cyst, endometrioma, cystadenoma, leiomyoma and etc. CONCLUSION: Especially in endemic area for this parasite, one of differential diagnoses of pelvic cyst must be echinococcosis. PMID- 29248837 TI - Isolated and mixed effects of diuron and its metabolites on biotransformation enzymes and oxidative stress response of Nile tilapia (Oreochromis niloticus). AB - Diuron is one of the most used herbicide in the world, and its field application has been particularly increased in Brazil due to the expansion of sugarcane crops. Diuron has often been detected in freshwater ecosystems and it can be biodegraded into three main metabolites in the environment, the 3,4 dichloroaniline (DCA), 3,4-dichlorophenylurea (DCPU) and 3,4-dichlorophenyl-N methylurea (DCPMU). Negative effects under aquatic biota are still not well established for diuron, especially when considering its presence in mixture with its different metabolites. In this study, we evaluated the effects of diuron alone or in combination with its metabolites, DCPMU, DCPU and 3,4-DCA on biochemical stress responses and biotransformation activity of the fish Oreochromis niloticus. Results showed that diuron and its metabolites caused significant but dispersed alterations in oxidative stress markers and biotransformation enzymes, except for ethoxyresorufin-O-deethylase (EROD) activity, that presented a dose-dependent increase after exposure to either diuron or its metabolites. Glutathione S-transferase (GST) activity was significant lower in gills after exposure to diuron metabolites, but not diuron. Diuron, DCPMU and DCA also decreased the multixenobiotic resistance (MXR) activity. Lipid peroxidation levels were increased in gill after exposure to all compounds, indicating that the original compound and diuron metabolites can induce oxidative stress in fish. The integration of all biochemical responses by the Integrated Biomarker Response (IBR) model indicated that all compounds caused significant alterations in O. niloticus, but DCPMU caused the higher alterations in both liver and gill. Our findings imply that diuron and its metabolites may impair the physiological response related to biotransformation and antioxidant activity in fish at field concentrations. Such alterations could interfere with the ability of aquatic animals to adapt to environments contaminated by agriculture. PMID- 29248838 TI - Removal of emerging pharmaceutical contaminants by adsorption in a fixed-bed column: A review. AB - Pharmaceutical pollutants substantially affect the environment; thus, their treatments have been the focus of many studies. In this article, the fixed-bed adsorption of pharmaceuticals on various adsorbents was reviewed. The experimental breakthrough curves of these pollutants under various flow rates, inlet concentrations, and bed heights were examined. Fixed-bed data in terms of saturation uptakes, breakthrough time, and the length of the mass transfer zone were included. The three most popular breakthrough models, namely, Adams-Bohart, Thomas, and Yoon-Nelson, were also reviewed for the correlation of breakthrough curve data along with the evaluation of model parameters. Compared with the Adams Bohart model, the Thomas and Yoon-Nelson more effectively predicted the breakthrough data for the studied pollutants. PMID- 29248839 TI - Infrared and Raman spectroscopy study of AsS chalcogenide films prepared by plasma-enhanced chemical vapor deposition. AB - AsS chalcogenide films, where As content is 60-40at.%, have been prepared via a RF non-equilibrium low-temperature argon plasma discharge, using volatile As and S as the precursors. Optical properties of the films were studied in UV-visible NIR region in the range from 0.2 to 2.5MUm. Infrared and Raman spectroscopy have been employed for the elucidation of the molecular structure of the newly developed material. It was established that PECVD films possess a higher degree of transparency (up to 80%) and a wider transparency window (>20MUm) in comparison with the "usual" AsS thin films, prepared by different thermal methods, which is highly advantageous for certain applications. PMID- 29248840 TI - Introducing a design exigency to promote student learning through assessment: A case study. AB - BACKGROUND: Assessment technologies are often used to classify student and newly qualified nurse performance as 'pass' or 'fail', with little attention to how these decisions are achieved. Examining the design exigencies of classification technologies, such as performance assessment technologies, provides opportunities to explore flexibility and change in the process of using those technologies. OBJECTIVE: Evaluate an established assessment technology for nursing performance as a classification system. METHODS: A case study analysis that is focused on the assessment approach and a priori design exigencies of performance assessment technology, in this case the Australian Nursing Standards Assessment Tool 2016. FINDINGS: Nurse assessors are required to draw upon their expertise to judge performance, but that judgement is described as a source of bias, creating confusion. The definition of satisfactory performance is 'ready to enter practice'. To pass, the performance on each criterion must be at least satisfactory, indicating to the student that no further improvement is required. The Australian Nursing Standards Assessment Tool 2016 does not have a third 'other' category, which is usually found in classification systems. DISCUSSION: Introducing a 'not yet competent' category and creating a two-part, mixed methods assessment process can improve the Australian Nursing Standards Assessment Tool 2016 assessment technology. Using a standards approach in the first part, judgement is valued and can generate learning opportunities across a program. Using a measurement approach in the second part, student performance can be 'not yet competent' but still meet criteria for year level performance and a graded pass. CONCLUSION: Subjecting the Australian Nursing Standards Assessment Tool 2016 assessment technology to analysis as a classification system provides opportunities for innovation in design. This design innovation has the potential to support students who move between programs and clinicians who assess students from different universities. PMID- 29248841 TI - Readiness for self-directed learning: How bridging and traditional nursing students differs? AB - BACKGROUND: The dean of the nursing college has an initiative to reform the BSN program in the college to minimize the use of lecturing and maximize interactive and lifelong learning. Appropriate assessment of how our students are prepared to be self-directed learners is crucial. OBJECTIVE: To compare traditional and bridging students in regard to their SDLR scores in the nursing college in Saudi Arabia. DESIGN: This was a comparative study to compare traditional and bridging students in regard to their self-directed learning readiness scores (SDLR). SETTINGS: The data was collected at the Nursing College, King Saud University, Riyadh, Saudi Arabia. PARTICIPANTS: A convenient sample of undergraduate nursing students at the sixth and eighth levels in both regular and bridging programs were recruited in this study to indicate their SDLR scores. METHODS: The study used Fisher et al.'s (2001) Self-Directed Learning Readiness Scale to measure the self-directed learning readiness among undergraduate nursing students. RESULTS: The total mean score of SDLR was 144 out of 200, which indicated a low level of readiness for SDL. There were significant variations between the included academic levels among participants. Students in the sixth academic level scored higher in the total SDLR scores compared to eighth-level students. There were no significant variations with gender and program types in the total SDLR scores. CONCLUSIONS: A comprehensive plan is needed to prepare both faculty members and students to improve the SDL skills. PMID- 29248842 TI - Group-wise similarity registration of point sets using Student's t-mixture model for statistical shape models. AB - A probabilistic group-wise similarity registration technique based on Student's t mixture model (TMM) and a multi-resolution extension of the same (mr-TMM) are proposed in this study, to robustly align shapes and establish valid correspondences, for the purpose of training statistical shape models (SSMs). Shape analysis across large cohorts requires automatic generation of the requisite training sets. Automated segmentation and landmarking of medical images often result in shapes with varying proportions of outliers and consequently require a robust method of alignment and correspondence estimation. Both TMM and mrTMM are validated by comparison with state-of-the-art registration algorithms based on Gaussian mixture models (GMMs), using both synthetic and clinical data. Four clinical data sets are used for validation: (a) 2D femoral heads (K= 1000 samples generated from DXA images of healthy subjects); (b) control-hippocampi (K= 50 samples generated from T1-weighted magnetic resonance (MR) images of healthy subjects); (c) MCI-hippocampi (K= 28 samples generated from MR images of patients diagnosed with mild cognitive impairment); and (d) heart shapes comprising left and right ventricular endocardium and epicardium (K= 30 samples generated from short-axis MR images of: 10 healthy subjects, 10 patients diagnosed with pulmonary hypertension and 10 diagnosed with hypertrophic cardiomyopathy). The proposed methods significantly outperformed the state-of-the art in terms of registration accuracy in the experiments involving synthetic data, with mrTMM offering significant improvement over TMM. With the clinical data, both methods performed comparably to the state-of-the-art for the hippocampi and heart data sets, which contained few outliers. They outperformed the state-of-the-art for the femur data set, containing large proportions of outliers, in terms of alignment accuracy, and the quality of SSMs trained, quantified in terms of generalization, compactness and specificity. PMID- 29248843 TI - Modulation of voltage-gated sodium channels induces capacitation in bull spermatozoa through phosphorylation of tyrosine containing proteins. AB - In our previous study, we have reported the molecular presence of Nav 1.8 in bull spermatozoa and its potential involvement in regulation of sperm functions. With the selective blocking of Nav 1.8 using A-803467, alterations in sperm functions were observed, therefore, we envisaged of investigating the involvement of Nav in regulating sperm function and the mechanism(s) involved in it using veratridine, a selective opener of Nav channels. Forty ejaculates were collected from four Hariana bulls and semen samples were pooled in view of the non-significant variations between the different ejaculates. Treatment of sperm cells with veratridine (6, 8, and 10 MUM) resulted in concentration- and time-dependent increase in forward progressive sperm motility and it persisted up to 6 h. However, hyperactive motility was induced by veratridine at higher concentrations (8 and 10 MUM) and after 2 h of incubation, which was confirmed by subjective assessment followed by chlortetracycline staining showing the increased B-pattern spermatozoa, and thereby suggesting the involvement of Nav in regulation of capacitation in spermatozoa. To substantiate the functional study observations especially veratridine-induced capacitation, immunoblotting and indirect immune fluorescence assays were performed for detection of the tyrosine-phosphorylated proteins. The immune blot study revealed the presence of five tyrosine phosphorylated proteins, namely-p17, p30, p54, p90 and p100. The p17 protein showed the highest band intensity compared to other protein bands indicating its potential involvement in the process of capacitation. Immunolocalization study revealed positive immunoreactivity for tyrosine phosphorylated proteins in the middle piece, post acrosomal region (high fluorescence) and tail of the spermatozoa (low fluorescence). From the results of present study, it is evident that activation of NaV by veratridine, especially at higher concentrations, induced capacitation which is evidently mediated through phosphorylation of the tyrosine containing proteins localized in the post acrosomal regions, middle piece and tail of the spermatozoa. However, further studies will help in unraveling the involvement of Nav and other ion channels regulating different physiological functions of sperm. PMID- 29248844 TI - Effect of increasing equilibration time of diluted bull semen up to 72 h prior to freezing on sperm quality parameters and calving rate following artificial insemination. AB - An equilibration period of approximately 3-4 h prior to semen cryopreservation is standard practice for maintaining membrane integrity and motility of bull sperm. However, a number of studies indicate that an overnight equilibration period prior to freezing results in improved post-thaw semen quality thus optimising pregnancy rates. The aim of this study was to assess the effect of increasing the equilibration time of bull semen up to 72 h before freezing on sperm quality parameters and calving rate (CR) following artificial insemination (AI) with frozen-thawed semen. The effect of holding semen at 4 degrees C for 6, 24, 48 or 72 h post dilution before freezing on subsequent post-thaw total and progressive motility (Experiment 1) and field fertility (n = 1640 inseminations, Experiment 2) of frozen-thawed semen was assessed. Equilibration time did not affect post thaw total and progressive motility (P > 0.05). In addition, there was no effect (P > 0.05) of equilibration time on field fertility with a CR of 53.3, 50.5, 51.3 and 47.3 for the 6, 24, 48 and 72 h treatments, respectively. In conclusion, increasing the equilibration time of diluted bull semen from 6 to 72 h had no significant effect on CR, within the expected range of fertility outcomes, thus providing semen processing centres with flexibility in the time which semen can be held prior to freezing. PMID- 29248845 TI - Bioinspired microneedle insertion for deep and precise skin penetration with low force: Why the application of mechanophysical stimuli should be considered. AB - A mosquito is known to precisely and easily insert its proboscis to the human skin by pressing down a labium and vibrating a fascicle bundle. Its advanced skin piercing mechanisms indicate that skin resistance to the insertion of needle-like objects can be changed by the application of mechanophysical stimuli. Here, we characterize the effect of the application of mechanophysical stimuli on skin resistance to microneedle insertion to find clues for inserting a microneedle in a deep and precise fashion with low force. Microneedles with a diameter of 60 140um are inserted at a velocity of 0.1-2.0mm/s to full-thickness porcine skins while either uniaxial/equibiaxial stretch of 0-20% or mechanical vibration at a frequency of 1 to 1000Hz and an amplitude of 1-10um is applied to the skins as static or dynamic mechanophysical stimulus, respectively. The values of force and depth at two events of skin puncture and maximum penetration are measured to explore changes in skin resistance induced by the application of external stimuli. The static mechanophysical stimulus applied to the skin mainly affects the precision of microneedle insertion; the application of dynamic mechanophysical stimulus controls the value and deviation of skin resistance to microneedle insertion. The application of mechanophysical stimuli, inspired from a mosquito, therefore allows a microneedle to be deeply and easily inserted to the skin in a controlled way. The findings will have broad impacts on microneedle mediated applications and lead to an in-depth understanding of skin biomechanics. PMID- 29248846 TI - Impact of strain rate on the hardness and elastic modulus of human tooth enamel. AB - Human tooth enamel is a natural biocomposite consisting of mineral units surrounded by a soft protein shell. The mechanical behaviors of enamel are closely associated with its structure. In this paper, the strain-rate dependent mechanical properties of enamel were investigated with nanoindentation techniques. Five constant strain rates (0.01s-1, 0.03s-1, 0.05s-1, 0.1s-1, 0.3s 1) were used in this study. Results showed that the hardness and elastic modulus of enamel increased with increasing strain rate. These results indicate that the variation of hardness under different stain rates is associated with creep behavior of organic matrix in enamel. And indentation creep rate sensitivity of human enamel was measured with a value of 0.062. Moreover, the elastic module of enamel is dependent upon strain rate. Such rate dependence originates from the organic matrix which is sensitive to the strain rate. This behavior may be important in explaining the excellent toughness and energy absorption abilities of natural tooth structure. PMID- 29248847 TI - Investigation of micromechanical properties of hard sphere filled composite hydrogels by atomic force microscopy and finite element simulations. AB - Atomic force microscopy (AFM) indentation is the most suitable way to characterize micromechanical properties of soft materials such as bio tissues. However, the mechanical data obtained from force-indentation measurement are still not well understood due to complex geometry of the bio tissue, nonlinearity of indentation contact, and constitutive relation of hyperelastic soft material. Poly-N-isopropyl acrylamide (PNIPAM) filled with 5wt% polystyrene (PS) sphere particles material system can be utilized as a simplified model for mimicking a whole host of soft materials. Finite element model has been constructed to simulate indentation as in AFM experiments using colloidal probes for a parametric study, with the main purpose of understanding the effect of particles on overall behavior of mechanical data and local deformation field under indentation contact. Direct comparison between finite element simulation and indentation data from AFM experiments provides a powerful method to characterize soft materials properties quantitatively, addressing the lack of analytical solutions for hard-soft composites, both biological and synthetic ones. In this framework, quantitative relations are found between the depth, at which the particle was embedded, the particle size and the elastic modulus of the overall composite. Comprehensive characterizations were established to distinguish indentation on a particle residing on top of the hydrogel from a particle embedded inside the hydrogel matrix. Finally, different assumptions of interface friction at the boundary between the particle and the hydrogel have been tested and directly compared with experimental measurements. PMID- 29248848 TI - The coupled effects of crouch gait and patella alta on tibiofemoral and patellofemoral cartilage loading in children. AB - BACKGROUND: Elevated tibiofemoral and patellofemoral loading in children who exhibit crouch gait may contribute to skeletal deformities, pain, and cessation of walking ability. Surgical procedures used to treat crouch frequently correct knee extensor insufficiency by advancing the patella. However, there is little quantitative understanding of how the magnitudes of crouch and patellofemoral correction affect cartilage loading in gait. METHODS: We used a computational musculoskeletal model to simulate the gait of twenty typically developing children and fifteen cerebral palsy patients who exhibited mild, moderate, and severe crouch. For each walking posture, we assessed the influence of patella alta and baja on tibiofemoral and patellofemoral cartilage contact. RESULTS: Tibiofemoral and patellofemoral contact pressures during the stance phase of normal gait averaged 2.2 and 1.0 MPa. Crouch gait increased pressure in both the tibofemoral (2.6-4.3 MPa) and patellofemoral (1.8-3.3 MPa) joints, while also shifting tibiofemoral contact to the posterior tibial plateau. For extended-knee postures, normal patellar positions (Insall-Salvatti ratio 0.8-1.2) concentrated contact on the middle third of the patellar cartilage. However, in flexed knee postures, both normal and baja patellar positions shifted pressure toward the superior edge of the patella. Moving the patella into alta restored pressure to the middle region of the patellar cartilage as crouch increased. CONCLUSIONS: This work illustrates the potential to dramatically reduce tibiofemoral and patellofemoral cartilage loading by surgically correcting crouch gait, and highlights the interaction between patella position and knee posture in modulating the location of patellar contact during functional activities. PMID- 29248849 TI - How do walkers behave when crossing the way of a mobile robot that replicates human interaction rules? AB - Previous studies showed the existence of implicit interaction rules shared by human walkers when crossing each other. Especially, each walker contributes to the collision avoidance task and the crossing order, as set at the beginning, is preserved along the interaction. This order determines the adaptation strategy: the first arrived increases his/her advance by slightly accelerating and changing his/her heading, whereas the second one slows down and moves in the opposite direction. In this study, we analyzed the behavior of human walkers crossing the trajectory of a mobile robot that was programmed to reproduce this human avoidance strategy. In contrast with a previous study, which showed that humans mostly prefer to give the way to a non-reactive robot, we observed similar behaviors between human-human avoidance and human-robot avoidance when the robot replicates the human interaction rules. We discuss this result in relation with the importance of controlling robots in a human-like way in order to ease their cohabitation with humans. PMID- 29248850 TI - Aberrations of the peripheral erythrocytes and its recovery patterns in a freshwater teleost, silver barb exposed to profenofos. AB - The present experiment was conducted to explicate the genotoxic effects of profenofos, an organophosphate insecticide, on the erythrocytes of silver barb (Barbonymus gonionotus). Silver barb were exposed to a solution of 10% and 50% of lethal concentrations (LC50) of profenofos as sub-lethal concentrations at different days (1, 7, 15, and 30 d), along with a control (0% profenofos). Subsequent recovery patterns were assessed allowing the fish exposed to profenofos free water for the same period that they were exposed to profenofos. Our results revealed that with the progression of time and concentration, fish exposed to profenofos showed significantly (p < .05) higher level of erythrocytic nuclear abnormalities (ENA) such as micronuclei, bi-nuclei, degenerated nuclei, notched nuclei, nuclear bridge and nuclear buds, as well as erythrocytic cellular abnormalities (ECA) such as echinocytic, elongated, fusion, spindle, tear-drop and twin shaped cells. After exposure, the silver barb recovered spontaneously, and the abnormal erythrocytic parameters were normalized with a concentration- and duration-dependent fashion. Therefore, these abnormalities and their recovery can be used to assess the toxic levels of pesticides on aquatic organisms. There is great potential to use this technique as in vivo to predict susceptibility of aquatic animals to environmental pollution. PMID- 29248851 TI - Traffic-related air pollution associated with chronic kidney disease among elderly residents in Taipei City. AB - The associations of air pollution with chronic kidney disease (CKD) have not yet been fully studied. We enrolled 8,497 Taipei City residents older than 65 years and calculated the estimated glomerular filtration rate (eGFR) using the Taiwanese Chronic Kidney Disease Epidemiology Collaboration equation. Proteinuria was assessed via dipstick on voided urine. CKD prevalence and risk of progression were defined according to the KDIGO 2012 guidelines. Land-use regression models were used to estimate the participants' one-year exposures to PM of different sizes and traffic-related exhaust, PM2.5 absorbance, nitrogen dioxide (NO2), and NOx. Generalized linear regressions and logistic regressions were used to examine the associations of one-year air pollution exposures with eGFR, proteinuria, CKD prevalence and risk of progression. The results showed that the interquartile range (IQR) increments of PM2.5 absorbance (0.4 * 10-5/m) and NO2 (7.0 MUg/m3) were associated with a 1.07% [95% confidence interval (CI): 0.54-1.57] and 0.84% (95% CI: 0.37-1.32) lower eGFR, respectively; such relationships were magnified in subjects who had an eGFR >60 ml/min/1.73 m2 or who were non-diabetic. Similar associations were also observed for PM10 and PM2.5-10. Two-pollutant models showed that PM10 and PM2.5 absorbance were associated with a lower eGFR. The odd ratios (ORs) of CKD prevalence and risk of progression also increased with exposures to PM2.5 absorbance and NO2. In summary, one-year exposures to traffic related air pollution were associated with lower eGFR, higher CKD prevalence, and increased risk of CKD progression among the elderly population. Air pollution related impaired renal function was stronger in non-CKD and non-diabetic subjects. PMID- 29248852 TI - Determination of endocrine-disrupting potencies of agricultural soils in China via a battery of steroid receptor bioassays. AB - Pollution of agricultural soils by pesticides, such as organochlorine pesticides (OCPs), can be a significant issue since high detection rates of these compounds were reported in our previous studies. However, more uncertain kinds, quantities and density of pollutants remained in soil samples were unidentified. In this study, the total hormonal activities of complex mixtures of both known and unknown contaminants in agricultural soils in mainland China were measured by applying highly sensitive reporter gene assays for detecting agonists/antagonists for estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR), glucocorticoid receptor (GR) and mineralocorticoid receptor (MR). High detection rates of estrogenic activities and anti-progestogenic activities were observed among the 123 soil samples, reaching 79% and 73%, respectively. More than half of the soil samples showed obvious antagonistic effects against AR and GR. Approximately a third of tested samples exhibited androgenic, progestogenic and glucocorticoidic effects. A total of 72% and 78% soil extracts had mineralocorticoid-like and anti-mineralocorticoid activities, respectively. Significant positive correlations were observed between estrogenic activity and the concentrations of Sigmadichlorodiphenyltrichloroethanes (DDTs), Sigmaendosulfans, Sigmachlordanes, heptachlor and Sigmadrins, respectively, but not other receptors. As a rapid and convenient pre-caution method, determination of endocrine-disrupting potencies of contaminated soils via bioassay could help to identify and define sites that required further attention for ecological risk assessments. PMID- 29248853 TI - Parental exposure to gamma radiation causes progressively altered transcriptomes linked to adverse effects in zebrafish offspring. AB - Ionizing radiation causes a variety of effects, including DNA damage associated to cancers. However, the effects in progeny from irradiated parents is not well documented. Using zebrafish as a model, we previously found that parental exposure to ionizing radiation is associated with effects in offspring, such as increased hatching rates, deformities, increased DNA damage and reactive oxygen species. Here, we assessed short (one month) and long term effects (one year) on gene expression in embryonic offspring (5.5 h post fertilization) from zebrafish exposed during gametogenesis to gamma radiation (8.7 or 53 mGy/h for 27 days, total dose 5.2 or 31 Gy) using mRNA sequencing. One month after exposure, a global change in gene expression was observed in offspring from the 53 mGy/h group, followed by embryonic death at late gastrula, whereas offspring from the 8.7 mGy/h group was unaffected. Interestingly, one year after exposure newly derived embryos from the 8.7 mGy/h group exhibited 2390 (67.7% downregulated) differentially expressed genes. Overlaps in differentially expressed genes and enriched biological pathways were evident between the 53 mGy/h group one month and 8.7 mGy/h one year after exposure, but were oppositely regulated. Pathways could be linked to effects in adults and offspring, such as DNA damage (via Atm signaling) and reproduction (via Gnrh signaling). Comparison with gene expression analysis in directly exposed embryos indicate transferrin a and cytochrome P450 2x6 as possible biomarkers for radiation response in zebrafish. Our results indicate latent effects following ionizing radiation exposure from the lower dose in parents that can be transmitted to offspring and warrants monitoring effects over subsequent generations. PMID- 29248854 TI - Spatial (bio)accumulation of pharmaceuticals, illicit drugs, plasticisers, perfluorinated compounds and metabolites in river sediment, aquatic plants and benthic organisms. AB - Organic contaminants such as pharmaceuticals, personal care products (PPCPs) and other emerging contaminants (ECs) are known to persist in the aquatic environment and many are indicated as endocrine, epigenetic, or other toxicants. Typically, the study of PPCPs/ECs in the aquatic environment is limited to their occurrence dissolved in river water. In this study, accumulation and spatial distribution of thirteen PPCPs/ECs were assessed in aquatic sediment (n = 23), periphyton (biofilm, n = 8), plants Callitriche sp. (n = 8) and Potamogeton sp. (n = 7) as well as amphipod crustaceans (Gammarus pulex, n = 10) and aquatic snails (Bithynia tentaculata, n = 9). All samples (n = 65) were collected from the Hogsmill, Blackwater and Bourne Rivers in southern England. Targeted PPCPs/ECs included pharmaceuticals, plasticisers, perfluorinated compounds, illicit drugs and metabolites. Extraction from solid matrices occurred using ultrasonic assisted extraction followed by an in-house validated method for solid-phase extraction and subsequent liquid-chromatography tandem mass-spectrometry. Field derived bioconcentration-factors and biota-sediment accumulation-factors were determined for all studied biota. Residues of studied contaminants were found in all sediment and biota. Concentrations of contaminants were generally higher in biota than sediment. Evidence suggests that the studied aquatic plants may effectively degrade bisphenol-A into its main transformation product hydroxyacetophenone, potentially mediated by cytochrome p450 and internalisation of contaminants into the cellular vacuole. A positive association between both hydrophobicity and PFC chain length and contaminant accumulation was observed in this work. Only PFCs, plasticisers and HAP were classified as either 'bioaccumulative' or 'very bioaccumulative' using BCF criteria established by guidelines of four governments. Contaminants appeared to be differentially bioaccumulative in biota, indicating there may be a need for a species-specific BCF/BSAF classification system. These data form a detailed accounting of PPCP/EC fate and distribution in the aquatic environment highlighting accumulation at lower trophic levels, a potential source for higher organisms. PMID- 29248855 TI - Concentrations and trophic magnification of polychlorinated naphthalenes (PCNs) in marine fish from the Bohai coastal area, China. AB - Polychlorinated naphthalenes (PCNs) have been found widely in the aquatic environment and can be transferred through food chains, which can magnify or dilute their toxic effects on humans. In this study, PCNs were analyzed in samples of 17 species of fish with different dietary habits collected in the Bohai coastal area in China. Dichloronaphthalenes, which have rarely been quantified in previous studies, were determined. The total PCN concentrations were from 7.3 to 214 pg/g wet weight, and the highest concentration was found in ditrema. The trichloronaphthalenes were the most abundant PCNs, followed by the dichloronaphthalenes and pentachloronaphthalenes. The relatively high contributions of the less-chlorinated homologs to the total PCN concentrations indicated that the main PCN sources around the Bohai were industrial thermal process emissions rather than technical PCN formulations. The trophic magnification factors of the PCN homologs were from 3.1 to 9.9, indicating that PCNs were biomagnified by fish. The trophic magnification factor of dichloronaphthalene and trichloronaphthalenes was 5.8 and 6.4, respectively, indicating for the first time that dichloronaphthalene and trichloronaphthalenes can undergo trophic magnification by fish. The two highest trophic magnification factors were for the pentachloronaphthalenes and hexachloronaphthalenes, probably because these PCNs having fewer vicinal carbon atoms without chlorine atoms attached are less easily biotransformed than the other homologs. The dioxin-like toxicities of the PCNs in the samples, expressed as potential toxic equivalences (TEQs), were assessed. The highest total TEQ was 0.0090 pg/g ww, in Pacific herring, and the hexachloronaphthalenes were the dominant contributors to the total TEQs in the fish samples. The PCN TEQs were much lower than the polychlorinated dibenzo-p-dioxin and dibenzofuran and dioxin-like polychlorinated biphenyl TEQs found in fish from the Bohai in previous studies, and made marginal contributions to overall human exposure to dioxin-like TEQs, suggesting that PCNs pose no toxicological concerns. PMID- 29248856 TI - Efficacy of dust aerosol forecasts for East Asia using the adjoint of GEOS-Chem with ground-based observations. AB - Asian dust storms occur often and have a great impact on East Asia and the western Pacific in spring. Early warnings based on reliable forecasts of dust storms thus are crucial for protecting human health and industry. Here we explore the efficacy of 4-D variational method-based data assimilation in a chemical transport model for dust storm forecasts in East Asia. We use a 3-D global chemical transport model (GEOS-Chem) and its adjoint model with surface PM10 mass concentration observations. We evaluate the model for several severe dust storm events, which occurred in May 2007 and March 2011 in East Asia. First of all, simulated the PM10 mass concentrations with the forward model showed large discrepancies compared with PM10 mass concentrations observed in China, Korea, and Japan, implying large uncertainties of simulated dust emission fluxes in the source regions. Based on our adjoint model constrained by observations for the whole period of each event, the reproduction of the spatial and temporal distributions of observations over East Asia was substantially improved (regression slopes from 0.15 to 2.81 to 0.85-1.02 and normalized mean biases from -74%-151% to -34%-1%). We then examine the efficacy of the data assimilation system for daily dust storm forecasts based on the adjoint model including previous day observations to update the initial condition of the forward model simulation for the next day. The forecast results successfully captured the spatial and temporal variations of ground-based observations in downwind regions, indicating that the data assimilation system with ground-based observations effectively forecasts dust storms, especially in downwind regions. However, the efficacy is limited in nearby the dust source regions, including Mongolia and North China, due to the lack of observations for constraining the model. PMID- 29248858 TI - Cathodal electrical stimulation of frontoparietal cortex disrupts statistical learning of visual configural information. AB - Attentional performance is facilitated by exploiting regularities and redundancies in the environment by way of incidental statistical learning. For example, during visual search, response times to a target are reduced by repeating distractor configurations-a phenomenon known as contextual cueing (Chun & Jiang, 1998). A range of neuroscientific methods have provided evidence that incidental statistical learning relies on subcortical neural structures associated with long-term memory, such as the hippocampus. Functional neuroimaging studies have also implicated the prefrontal cortex (PFC) and posterior parietal cortex (PPC) in contextual cueing. However, the extent to which these cortical regions are causally involved in statistical learning remains unclear. Here, we delivered anodal, cathodal, or sham transcranial direct current stimulation (tDCS) to the left PFC and left PPC online while participants performed a contextual cueing task. Cathodal stimulation of both PFC and PPC disrupted the early cuing effect, relative to sham and anodal stimulation. These findings causally implicate frontoparietal regions in incidental statistical learning that acts on visual configural information. We speculate that contextual cueing may rely on the availability of cognitive control resources in frontal and parietal regions. PMID- 29248857 TI - Catechol-O-methyltransferase (COMT) genotype affects cognitive control during total sleep deprivation. AB - Adaptive decision making is profoundly impaired by total sleep deprivation (TSD). This suggests that TSD impacts fronto-striatal pathways involved in cognitive control, where dopamine is a key neuromodulator. In the prefrontal cortex (PFC), dopamine is catabolized by the enzyme catechol-O-methyltransferase (COMT). A functional polymorphism (Val158Met) influences COMT's enzymatic activity, resulting in markedly different levels of prefrontal dopamine. We investigated the effect of this polymorphism on adaptive decision making during TSD. Sixty-six healthy young adults participated in one of two in-laboratory studies. After a baseline day, subjects were randomized to either a TSD group (n = 32) with 38 h or 62 h of extended wakefulness or a well-rested control group (n = 34) with 10 h nighttime sleep opportunities. Subjects performed a go/no-go reversal learning (GNGr) task at well-rested baseline and again during TSD or equivalent control. During the task, subjects were required to learn stimulus-response relationships from accuracy feedback. The stimulus-response relationships were reversed halfway through the task, which required subjects to learn the new stimulus-response relationships from accuracy feedback. Performance on the GNGr task was quantified by discriminability (d') between go and no-go stimuli before and after the stimulus-response reversal. GNGr performance did not differ between COMT genotypes when subjects were well-rested. However, TSD exposed a significant vulnerability to adaptive decision making impairment in subjects with the Val allele. Our results indicate that sleep deprivation degrades cognitive control through a fronto-striatal, dopaminergic mechanism. PMID- 29248859 TI - Impact of age, comorbidity, and polypharmacy on the efficacy and safety of edoxaban for the treatment of venous thromboembolism: An analysis of the randomized, double-blind Hokusai-VTE trial. AB - BACKGROUND: Many patients with venous thromboembolism (VTE) are elderly, have multiple comorbidities and take several concomitant medications. Physicians may prefer warfarin over direct oral anticoagulants (DOACs) in such patients because comparative data are lacking. This analysis was designed to determine the effects of advanced age, comorbidities, and polypharmacy on the efficacy and safety of edoxaban and warfarin in patients with VTE. METHODS: Using data from the Hokusai VTE study, we report rates of recurrent VTE and of clinically relevant bleeding by age category (<65, 65-75, and >=75; <80 versus >=80years), and by number of comorbidities (0, 1-2, >2) and concomitant medications (<3, 3-5, >5). Hazard ratios (HR) and corresponding 95% confidence intervals (CI) for edoxaban versus warfarin were determined and Kaplan-Meier methodology was used to construct time to-event curves. At 3months, pre- and postdose levels of edoxaban were measured using mass spectrometry. For warfarin-treated patients, the time in therapeutic range was calculated. The study was approved by institutional review boards; informed consent was obtained. RESULTS: Recurrent VTE increased with advanced age, multiple comorbidities, and polypharmacy in warfarin-treated patients but not with edoxaban. Edoxaban was more effective than warfarin in patients >=75years of age and in those with multiple comorbidities. In the 517 patients over 80years of age, recurrent VTE occurred in 2.8% given edoxaban and in 5.7% given warfarin (HR 0.51, 95% CI 0.21-1.24). Bleeding increased with age, comorbidity, and polypharmacy regardless of treatment, but the relative safety of edoxaban versus well-managed warfarin was maintained. Age, comorbidity, and polypharmacy did not impact edoxaban concentrations. CONCLUSIONS: These data suggest that a once-daily fixed dose of edoxaban is more effective and at least as safe as warfarin in high-risk VTE patients identified by older age, more comorbidities, and polypharmacy. CLINICAL TRIAL REGISTRATION: NCT00986154. PMID- 29248860 TI - Microbial fuel cells in saline and hypersaline environments: Advancements, challenges and future perspectives. AB - This review is aimed to report the possibility to utilize microbial fuel cells for the treatment of saline and hypersaline solutions. An introduction to the issues related with the biological treatment of saline and hypersaline wastewater is reported, discussing the limitation that characterizes classical aerobic and anaerobic digestions. The microbial fuel cell (MFC) technology, and the possibility to be applied in the presence of high salinity, is discussed before reviewing the most recent advancements in the development of MFCs operating in saline and hypersaline conditions, with their different and interesting applications. Specifically, the research performed in the last 5years will be the main focus of this review. Finally, the future perspectives for this technology, together with the most urgent research needs, are presented. PMID- 29248861 TI - Viability of sublethally injured coliform bacteria on fresh-cut cabbage stored in high CO2 atmospheres following rinsing with electrolyzed water. AB - The extent of sublethally injured coliform bacteria on shredded cabbage, either rinsed or not rinsed with electrolyzed water, was evaluated during storage in air and high CO2 controlled atmospheres (5%, 10%, and 15%) at 5 degrees C and 10 degrees C using the thin agar layer (TAL) method. Sublethally injured coliform bacteria on nonrinsed shredded cabbage were either absent or they were injured at a 64-65% level when present. Rinsing of shredded cabbage with electrolyzed water containing 25ppm available chlorine reduced the coliform counts by 0.4 to 1.1 log and caused sublethal injury ranging from 42 to 77%. Pantoea ananatis was one of the species injured by chlorine stress. When shredded cabbage, nonrinsed or rinsed with electrolyzed water, was stored in air and high CO2 atmospheres at 5 degrees C for 7days and 10 degrees C for 5days, coliform counts on TAL plates increased from 3.3-4.5 to 6.5-9.0 log CFU/g during storage, with the increase being greater at 10 degrees C than at 5 degrees C. High CO2 of 10% and 15% reduced the bacterial growth on shredded cabbage during storage at 5 degrees C. Although injured coliform bacteria were not found on nonrinsed shredded cabbage on the initial day, injured coliforms at a range of 49-84% were detected on samples stored in air and high CO2 atmospheres at 5 degrees C and 10 degrees C. Injured cells were detected more frequently during storage at both temperatures irrespective of the CO2 atmosphere when shredded cabbage was rinsed with electrolyzed water. These results indicated that injured coliform bacteria on shredded cabbage, either rinsed or not rinsed with electrolyzed water, exhibited different degrees of injury during storage regardless of the CO2 atmosphere and temperature tested. PMID- 29248862 TI - Occurrence of Aspergillus section Flavi and aflatoxins in Brazilian rice: From field to market. AB - The guarantee of the high quality of rice is of utmost importance because any toxic contaminant may affect consumer health, especially in countries such as Brazil where rice is part of the daily diet. A total of 187 rice samples, from field, processing and market from two different production systems, wetland from the state of Rio Grande do Sul, dryland, from the state of Maranhao and market samples from the state of Sao Paulo, were analyzed for fungi belonging to Aspergillus section Flavi and the presence of aflatoxins. Twenty-three soil samples from wetland and dryland were also analyzed. A total of 383 Aspergillus section Flavi strains were isolated from rice and soil samples. Using a polyphasic approach, with phenotypic (morphology and extrolite profiles) and molecular data (beta-tubulin gene sequences), five species were identified: A. flavus, A. caelatus, A. novoparasiticus, A. arachidicola and A. pseudocaelatus. This is the first report of these last three species from rice and rice plantation soil. Only seven (17%) of the A. flavus isolates produced type B aflatoxins, but 95% produced kojic acid and 69% cyclopiazonic acid. Less than 14% of the rice samples were contaminated with aflatoxins, but two of the market samples were well above the maximum tolerable limit (5MUg/kg), established by the Brazilian National Health Surveillance Agency. PMID- 29248863 TI - The efficacy of computerized interventions to reduce cannabis use: A systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Cannabis is the most widely consumed illicit drug. Although it is too early to confirm the impact of legalization, the use of cannabis appears to be on the rise in some countries due to its authorization for medical/recreational purposes. Among different types of therapeutic approaches to reduce cannabis use, computerized interventions are becoming a new treatment option. To assess their efficacy, a systematic review and meta-analysis was conducted. METHODS: A systematic review and meta-analysis was performed employing randomized controlled clinical trials indexed in MEDLINE and PsycINFO. The principal outcome measure was cannabis use, and the secondary one was the use of other substances during interventions. A subgroup analysis was conducted by length of follow-up, number of sessions, age group, type of analysis, and type of control condition. RESULTS: The meta-analysis included nine studies with 2963 participants. Computerized interventions resulted in significant reductions in the use of cannabis (standardized mean difference [SMD]: -0.19; 95% CI: -0.26, 0.11) and other substances (SMD: -0.27; 95% CI: -0.46, -0.08). CONCLUSIONS: Computerized interventions examined in the present study reduced the frequency of cannabis and other substance use. Limitations included the recalculation of dichotomous and continuous data as SMD and the lower number of studies included in the secondary outcome. Computerized interventions could be a viable option to reduce cannabis use. PMID- 29248864 TI - Examination of approach and avoidance inclinations on the reinforcing value of alcohol. AB - Although behavioral economics tends to focus on environmental factors (i.e., price, availability) that act to influence valuation of alcohol, recent research has begun to address how motivational and cognitive factors influence an individual's demand for alcohol. Motivational states, including craving, are one possible mechanism underlying the value based decision making that demand represents. Using a multidimensional model of craving (Ambivalence Model of Craving), the current study examined the relationships between indices of alcohol demand (i.e., reinforcing value of alcohol) and craving (i.e., approach inclinations), and the ways in which competing desires moderate that relationship (i.e., avoidance inclinations). Individuals who reported consuming alcohol in the past month were recruited for the study using Amazon's Mechanical Turk. A total of 529 participants (mean age=33.03years, SD=8.85) completed a series of surveys assessing their drinking behavior and other alcohol-related measures. Multiple regression analyses indicated that while approach significantly predicted intensity (i.e., consumption at zero cost), Omax (i.e., the maximum alcohol expenditure) and breakpoint (i.e., the first price that seizes consumption), avoidance moderated the relationship between approach and Omax and breakpoint. Specifically, follow up analyses demonstrated that higher avoidance inclinations attenuated the effect of approach inclinations on these demand indices. Finally, despite conceptual overlap between approach, avoidance, and alcohol demand, regression analyses indicated that these constructs account for unique variance in alcohol outcomes. These results illustrate the importance of considering the effects of both approach and avoidance inclinations on an individual's valuation of alcohol. PMID- 29248866 TI - A discrete-choice experiment to elicit preferences of patients with epilepsy for self-management programs. AB - BACKGROUND: There is an increasing number of self-management programs developed for patients with epilepsy, with the goal of supporting treatment management and improving their quality of life. With the aim of increasing medication adherence and effectiveness of self-management programs, it is important to design programs that are engaging to, and align with the preferences of patients with epilepsy. This study aimed to evaluate and compare the preferences of patients with epilepsy for self-management programs in three European countries. This is the first cross-border evaluation of the preferences of patients with epilepsy in Europe for such programs. METHODS: Using a discrete-choice experiment, patients with epilepsy from Germany, France, and the Netherlands were surveyed, and chose repetitively between two hypothetical self-management programs. These differed in the following six characteristics: i) the thematic area which would be the main focus of the program, ii) the method of interaction, iii) the source of information or provider of the program, iv) the amount of time spent on the program per week, v) the cost, and vi) whether the program would start immediately, or if there would be a delay of 3weeks before its initiation. A Bayesian efficient design was used to construct 15 choice sets, and a mixed panel logit model was used to estimate patients' preferences. Subgroup analyses were conducted according to socioeconomic status, burden of disease, and previous activation in self-management. RESULTS: A total of 299 people with epilepsy were included in the study, with a mean age of 45.5years. Only 15% had previously made use of a self-management program, although 44.5% reported having previously heard of them. In all three countries, all attributes barring the content were significant at 10%. The cost attribute - i.e., an out-of-pocket expenditure for a program - was reported as the most important feature in each country and across subgroups (significant at 1%). This was followed by the length of program sessions per week, which ranged from 20 to 90min per week. Although there was some heterogeneity between countries and subgroups, the patients, overall, had a preference for a face-to-face meeting with a doctor. In the Netherlands, a preference for online programs and physician assistants was observed when compared with the other countries. Other attributes, including the information source - whether a program was led by a physician, another patient with epilepsy, or another combination - was also important to patients, who appear willing to trade preferences in order to gain their favored attribute level. However, 20% of the population chose consistently to not participate in any self-management program. CONCLUSION: Given the heterogeneity of the epilepsies, preferences, and dispreferences across subgroups, our study highlights that if full account is not taken of different segmentation strategies when designing a self-management program, a large proportion of the population may not be attracted to it. PMID- 29248865 TI - Prenatal particulate matter exposure and mitochondrial dysfunction at the maternal-fetal interface: Effect modification by maternal lifetime trauma and child sex. AB - BACKGROUND: Prenatal ambient fine particulate matter (PM2.5) and maternal chronic psychosocial stress have independently been linked to changes in mithochondrial DNA copy number (mtDNAcn), a marker of mitochondrial response and dysfunction. Further, overlapping research shows sex-specific effects of PM2.5 and stress on developmental outcomes. Interactions among PM2.5, maternal stress, and child sex have not been examined in this context. METHODS: We examined associations among exposure to prenatal PM2.5, maternal lifetime traumatic stressors, and mtDNAcn at birth in a sociodemographically diverse pregnancy cohort (N=167). Mothers' daily exposure to PM2.5 over gestation was estimated using a satellite-based spatio temporally resolved prediction model. Lifetime exposure to traumatic stressors was ascertained using the Life Stressor Checklist-Revised; exposure was categorized as high vs. low based on a median split. Quantitative real-time polymerase chain reaction (qPCR) was used to determine mtDNAcn in placenta and cord blood leukocytes. Bayesian Distributed Lag Interaction regression models (BDLIMs) were used to statistically model and visualize the PM2.5 timing dependent pattern of associations with mtDNAcn and explore effect modification by maternal lifetime trauma and child sex. RESULTS: Increased PM2.5 exposure across pregnancy was associated with decreased mtDNAcn in cord blood (cumulative effect estimate=-0.78; 95%CI -1.41, -0.16). Higher maternal lifetime trauma was associated with reduced mtDNAcn in placenta (beta=-0.33; 95%CI -0.63, -0.02). Among women reporting low trauma, increased PM2.5 exposure late in pregnancy (30 38weeks gestation) was significantly associated with decreased mtDNAcn in placenta; no significant association was found in the high trauma group. BDLIMs identified a significant 3-way interaction between PM2.5, maternal trauma, and child sex. Specifically, PM2.5 exposure between 25 and 40weeks gestation was significantly associated with increased placental mtDNAcn among boys of mothers reporting high trauma. In contrast, PM2.5 exposure in this same window was significantly associated with decreased placental mtDNAcn among girls of mothers reporting low trauma. Similar 3-way interactive effects were observed in cord blood. CONCLUSIONS: These results indicate that joint exposure to PM2.5 in late pregnancy and maternal lifetime trauma influence mtDNAcn at the maternal-fetal interface in a sex-specific manner. Additional studies will assist in understanding if the sex-specific patterns reflect distinct pathophysiological processes in addition to mitochondrial dysfunction. PMID- 29248868 TI - Sleep architecture and EEG power spectra in recently detoxified alcohol dependent patients. AB - OBJECTIVES: Persistent sleep abnormalities during abstinence are a harbinger for relapse in patients with chronic alcohol dependence. The present study aimed to compare polysomnography (PSG) data between 'recently detoxified' patients with chronic alcohol dependence and healthy controls. METHODS: Both conventional sleep architectural and power spectral analyses were conducted. Twenty subjects in each of the groups were enrolled. A 2 nights' sleep (first-habituation and second experimental) PSG data was collected. Computer assisted scoring supplemented by manual method using the Rechtschaffen and Kales criteria were used for sleep staging. Twenty eight channels were used for the EEG recording. Spectral power across early NREM (Non-rapid-eye-movement), Slow Wave Sleep and REM was computed using the Welch's averaged periodogram method. RESULTS: Results on conventional sleep staging showed that patients had significantly lesser total sleep time, sleep efficiency and stage shifts and longer sleep onset latency; while duration of each NREM stages were significantly lower, and latency of stage 2 NREM was significantly longer in patients. After controlling for multiple comparisons, spectral power analysis revealed significant differences only during REM sleep and specifically in high frequency (beta and gamma) bands. CONCLUSIONS: Stating the mutually complementary role of conventional and spectral analyses of polysomnography EEG data, we conclude that sleep abnormalities are fairly evident in recently detoxified alcohol dependent patients. PMID- 29248867 TI - The impact of depressive symptoms on the clinical presentation of Persistent Delusional Disorder. AB - BACKGROUND: Our aim was to investigate the influence of depressive symptoms on the clinical presentation of Persistent Delusional Disorder (PDD). METHODS: We have previously conducted a retrospective review of patients diagnosed with PDD (n = 455). We divided this sample into two groups according to the presence or absence of co-morbid depressive symptoms - a subsample of PDD with depressive co morbidity (PDD + D; n = 187) and a subsample of PDD without depressive co morbidity (PDD only; n = 268). RESULTS: PDD + D group had a significantly younger age at onset of PDD. The PDD + D group received significantly more antidepressants but had similar response and adherence rates. CONCLUSIONS: The presence of depressive symptoms in 41% of the study population did not appear to influence the clinical presentation or response to treatment. PMID- 29248869 TI - Ion beam heating of kinetically constrained nanomaterials. AB - The gallium ion beam heating on electron transparent transmission electron microscopy (TEM) samples of Au/Ni bilayer films supported by SiO2 substrates was studied by in-situ TEM combined with energy dispersive X-ray spectroscopy. Brief Ga+ ion beam irradiation during sample transfer inside the focused ion beam instrument was found to induce dewetting of bilayer films. The observed morphological changes of the metal films are complemented by considerable Au diffusion through the underlying polycrystalline Ni film and adsorption at the Ni/substrate interface. In-situ heating experiments confirm that alterations of the metal bilayer films caused by ion beam irradiation are consistent with thermal annealing at 400 degrees C for several minutes in the absence of any ion bombardment. Ion beam damage effects equivalent to prolonged heating may pose considerable limitations to ion beam microscopy of samples with reduced dimensions. Ex-situ lift-out procedures of electron transparent samples in the absence of any ion beam irradiation lead to successful conservation of sample morphologies. PMID- 29248870 TI - Preventing damage and redeposition during focused ion beam milling: The "umbrella" method. AB - Focused ion beam (FIB) milling has enabled the development of key microstructure characterization techniques (e.g. 3D electron backscatter diffraction (EBSD), 3D scanning electron microscopy imaging, site-specific sample preparation for transmission electron microscopy, site-specific atom probe tomography), and micro mechanical testing techniques (e.g. micro-pillar compression, micro-beam bending, in-situ TEM nanoindentation). Yet, in most milling conditions, some degree of FIB damage is introduced via material redeposition, Ga+ ion implantation or another mechanism. The level of damage and its influence vary strongly with milling conditions and materials characteristics, and cannot always be minimized. Here, a masking technique is introduced, that employs standard FIB-SEM equipment to protect specific surfaces from redeposition and ion implantation. To investigate the efficiency of this technique, high angular resolution EBSD (HR-EBSD) has been used to monitor the quality of the top surface of several micro-pillars, as they were created by milling a ringcore hole in a stress-free silicon wafer, with or without protection due to an "umbrella". HR-EBSD provides a high-sensitivity estimation of the amount of FIB damage on the surface. Without the umbrella, EBSD patterns are severely influenced, especially within 5 um of the milled region. With an optimized umbrella, sharp diffraction patterns are obtained near the hole, as revealed by average cross correlation factors greater than 0.9 and equivalent phantom strains of the order 2 * 10-4. Thus, the umbrella method is an efficient and versatile tool to support a variety of FIB based techniques. PMID- 29248871 TI - Selective production of hydrogen ion species at atomically designed nanotips. AB - Hydrogen scanning ion microscopy systems rely on nanotip gas field ion sources to generate the hydrogen ion beam. The exact structure of the nanotip and the applied electric field are shown to be important. It is demonstrated that hydrogen ion beams are found to occur as mixtures of H+, H2+ and H3+ depending on the electric field strength and the nanotip structure. Various nanotips were prepared, including single atom tips (SATs), trimers and other nano-structured tips to compare the contents of hydrogen ion beams. It was found that single atom tips produce primarily H2+ at low operating voltages, but as the voltage is increased, H3+ dominates. For the trimer case, H2+ becomes a significant species and equals the H3+ current but H3+ can be isolated at higher voltages. For the hexamer tip structure, H2+ almost completely dominates with little H3+ being produced. H+ is only observed in small quantities for all tip structures until a high voltage regime, where apex atom resolution is not observed. Comparisons W SATs and Ir SATs showed similar H3+/H2+ product ratios indicating the nanotip structure plays a key role in the catalytic formation of H3+. Temperature affects are also discussed and operating parameters for single species ion beams are discussed. PMID- 29248872 TI - The long tail of a demon drug: The 'bath salts' risk environment. AB - Using the case of synthetic cathinones (commonly referred to as 'bath salts' in the US context), this paper analyses structural factors surrounding novel psychoactive substances (NPS) as contributing to the unique risk environment surrounding their use. Drawing on interviews with 39 people who use bath salts from four U.S. cities and analysis of the infrastructural, social, economic, and policy contexts, we document the unique harms related to changing contexts for illicit drug regulation, manufacture, and consumption. Findings suggest that NPS and designer drug markets, which are highly reliant upon the internet, share characteristics of the entertainment industry which has come to rely more heavily upon profits derived from the 'long tail' of myriad lesser-known products and the diminished centrality of 'superstars' and 'hits'. Findings point toward increased theoretical and policy attention to changing drug market structures, more rigorous evaluations of drug 'analogues' legislation and greater involvement with NPS education and testing by harm reduction agencies. PMID- 29248873 TI - Soil contamination from lead battery manufacturing and recycling in seven African countries. AB - Lead battery recycling is a growing hazardous industry throughout Africa. We investigated potential soil contamination inside and outside formal sector recycling plants in seven countries. We collected 118 soil samples at 15 recycling plants and one battery manufacturing site and analyzed them for total lead. Lead levels in soils ranged from < 40-140,000mg/kg. Overall mean lead concentrations were ~23,200mg/kg but, average lead levels were 22-fold greater for soil samples from inside plant sites than from those collected outside these facilities. Arithmetic mean lead concentrations in soil samples from communities surrounding these plants were ~2600mg/kg. As the lead battery industry in Africa continues to expand, it is expected that the number and size of lead battery recycling plants will grow to meet the forecasted demand. There is an immediate need to address ongoing exposures in surrounding communities, emissions from this industry and to regulate site closure financing procedures to ensure that we do not leave behind a legacy of lead contamination that will impact millions in communities throughout Africa. PMID- 29248874 TI - Oxidative stress-mediated p53/p21WAF1/CIP1 pathway may be involved in microcystin LR-induced cytotoxicity in HepG2 cells. AB - A previous study showed that microcystin-LR (MC-LR) exerted cytotoxicity and induced apoptosis in HepG2 cells. In the present study, we investigated whether oxidative stress-mediated p53/p21WAF1/CIP1 is involved in this process to further elucidate the mechanism of cytotoxicity induced by MC-LR. Morphological evaluation showed that MC-LR induced time- and dose-dependent cytotoxicity in HepG2 cells. Biochemical assays revealed that MC-LR exposure altered the protein levels of HSP70 and HSP90, generally inhibited superoxide dismutase and catalase, reduced glutathione content, and increased the cellular malondialdehyde level of HepG2 cells, suggesting that MC-LR may induce biochemical disturbance and oxidative stress in HepG2 cells. The protein levels of p-p53 and p21 were markedly increased by MC-LR exposure in a concentration-dependent manner, suggesting that p53 and p21 may be involved in the process. Moreover, we also found that the proto-oncogene c-myc was significantly activated in HepG2 cells following MC-LR exposure, indicating that c-myc in HepG2 cells was potentially involved in response to MC-LR-induced apoptosis. These findings may contribute to further understanding the in vitro molecular mechanism of MC-LR hepatotoxicity. PMID- 29248875 TI - Development and psychometric validation of a shorter version of the Breast Cancer Treatment Outcome Scale (BCTOS-12). AB - OBJECTIVES: Aesthetic and functional outcomes after oncoplastic breast-conserving surgery (BCS) are directly related to the patients' quality of life (QoL). The Breast Cancer Treatment Outcome Scale (BCTOS) is a validated but burdensome questionnaire for the assessment of these outcomes. The aim of the study was to strengthen and focus the BCTOS instrument by reducing the number of items and subscales without loss of information and validity. METHODS: This study used a dataset of 871 patients with stage 0 - III breast cancer, from a prospective cohort study, who underwent BCS. We investigated correlations and other criteria of homogeneity of the BCTOS items to identify redundancies. An exploratory factor analysis was used to remodel the item-factor structure. Correlation and linear regression analysis with validated QoL subscales assessed the convergent and discriminant validity of the modified BCTOS structure. RESULTS: The factor analysis revealed two distinct subscales for aesthetic and functional outcomes. It was possible to reduce the 22 items of the original BCTOS to 12 items, thus the "BCTOS-12". The two new scales had very good internal consistency: Cronbach's alpha = 0.86 for the new Aesthetic Status subscale and alpha = 0.81 for the new Functional Status subscale. Bootstrapping confirmed the item-factor structure for all 10,000 samples, remarkably. CONCLUSION: The modified BCTOS questionnaire with only 12 items (BCTOS-12) is shorter, easier to interpret, and shows good validity. PMID- 29248876 TI - Associations between adjuvant radiotherapy and different causes of death in a German breast cancer cohort. AB - BACKGROUND: Studies of cohorts of breast cancer (BC) patients diagnosed before 1990 showed radiotherapy (RT) to be associated with increased cardiovascular (CVD) and lung cancer mortality many years after diagnosis. In the late 1990s, improvements in RT planning techniques reduced radiation doses to normal tissues. Recent studies did not consistently report higher RT-related mortality for CVD and second cancers. Aim of the study was to analyze specific causes of death after 3D-conformal RT in a recent BC cohort. METHODS: Stage I-III BC patients diagnosed 2001-2005 and enrolled in the population based MARIEplus study were followed-up for 11.9 years (median). Associations between adjuvant RT and cause specific mortality were analyzed by using competing risks models, yielding subdistribution hazard ratios (SHR) for RT directly related to cumulative incidences. Models were adjusted for differences in baseline characteristics applying inverse-probability-of-treatment-weighting (IPTW). RESULTS: Of the 2951 patients, 2439 (83.0%) received RT. No significant association of RT with lung cancer mortality (SHRIPTW 0.88, 0.35-2.12), other cancer mortality (SHRIPTW 1.04, 95% CI 0.62-1.73) or cardiac mortality was observed (SHRIPTW 1.57, 0.75-3.29). Mortality from lung and other diseases were significantly lower in irradiated women (SHRIPTW 0.39, 95% CI 0.17-0.90 and SHRIPTW 0.58, 95% CI 0.34-0.97, respectively). CONCLUSION: In line with recent studies, 3D-conformal RT did not significantly increase mortality from non-BC causes in the German MARIEplus cohort. Since long-term data are still sparse and event rates low in BC-cohorts, who received modern RT, investigation of possible late RT effects on mortality beyond 14 years of follow-up is warranted. PMID- 29248877 TI - Fatty acid oxidation contributes to IL-1beta secretion in M2 macrophages and promotes macrophage-mediated tumor cell migration. AB - Tumor-associated macrophages (TAMs) are predominantly M2 phenotype in solid cancers including hepatocellular carcinoma (HCC). Though differentiation of M2 macrophages has been recently linked to fatty acid oxidation (FAO), whether FAO plays a role in functional maintenance of M2 macrophages is still unclear. Here, we used an in vitro model to mimic TAM-HCC interaction in tumor microenvironment. We found that M2 monocyte-derived macrophages (MDMs) enhanced the proliferation, migration, and invasion of HCC cells through an FAO-dependent way. Further investigations identified that IL-1beta mediated the pro-migratory effect of M2 MDM. Using etomoxir and siRNA to inhibit FAO and palmitate to enhance FAO, we showed that FAO was responsible for the up-regulated secretion of IL-1beta and, thus, the pro-migratory effect in M2 MDMs. In addition, we proved that IL-1beta induction was reactive oxygen species and NLRP3-dependent. Our study demonstrates that FAO plays a key role in functional human M2 macrophages by enhancing IL 1beta secretion to promote HCC cell migration. These findings provide evidence for different dependency of energy sources in macrophages with distinct phenotypes and functions, and suggest a novel strategy to treat HCC by reprogramming cell metabolism or modulating tumor microenvironment. PMID- 29248878 TI - Systematic review and meta-analysis of the effectiveness of pharmacist-led medication reconciliation in the community after hospital discharge. AB - BACKGROUND: Pharmacists' completion of medication reconciliation in the community after hospital discharge is intended to reduce harm due to prescribed or omitted medication and increase healthcare efficiency, but the effectiveness of this approach is not clear. We systematically review the literature to evaluate intervention effectiveness in terms of discrepancy identification and resolution, clinical relevance of resolved discrepancies and healthcare utilisation, including readmission rates, emergency department attendance and primary care workload. METHODS: This is a systematic literature review and meta-analysis of extracted data. Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, Allied and Complementary Medicine Database (AMED),Education Resources Information Center (ERIC), Scopus, NHS Evidence and the Cochrane databases were searched using a combination of medical subject heading terms and free-text search terms. Controlled studies evaluating pharmacist-led medication reconciliation in the community after hospital discharge were included. Study quality was appraised using the Critical Appraisal Skills Programme. Evidence was assessed through meta-analysis of readmission rates. Discrepancy identification rates, emergency department attendance and primary care workload were assessed narratively. RESULTS: Fourteen studies were included, comprising five randomised controlled trials, six cohort studies and three pre-post intervention studies. Twelve studies had a moderate or high risk of bias. Increased identification and resolution of discrepancies was demonstrated in the four studies where this was evaluated. Reduction in clinically relevant discrepancies was reported in two studies. Meta-analysis did not demonstrate a significant reduction in readmission rate. There was no consistent evidence of reduction in emergency department attendance or primary care workload. CONCLUSIONS: Pharmacists can identify and resolve discrepancies when completing medication reconciliation after hospital discharge, but patient outcome or care workload improvements were not consistently seen. Future research should examine the clinical relevance of discrepancies and potential benefits on reducing healthcare team workload. PMID- 29248879 TI - Enlarging hypermetabolic nodule: benign non-functional adrenocortical adenoma. PMID- 29248880 TI - Constrictive bronchiolitis presenting with a mixed obstructive and restrictive pattern, associated with acid reflux. AB - A previously healthy 55-year-old woman presented with worsening dyspnoea on exertion. The patient lived at altitude, did not smoke and had no exposure to occupational or environmental toxins. Her physical examination, including pulmonary, was unremarkable. Pulmonary function tests showed forced expiratory volume in 1 s/forced vital capacity ratio 74% predicted, diffusing capacity for carbon monoxide (DLCO) 92% predicted and residual volume 213% predicted. Rheumatological workup was negative. Chest radiograph showed hyperinflation without consolidation, and high-resolution chest CT showed mosaic attenuation with air trapping on expiratory imaging. A decreasing DLCO lead to transbronchial biopsies that were inconclusive. A video-assisted thoracic surgery lung biopsy showed small airway disease suggestive of constrictive bronchiolitis. Oesophagram and a barium swallow showed a hiatal hernia with large volume gastro-oesophageal reflux to the level of the clavicles. The development of constrictive bronchiolitis in this patient was possibly secondary to hiatal hernia and silent gastroesophageal reflux disease (GERD). In the face of presumably idiopathic lung disease, clinicians should perform a GERD workup even in the absence of GERD symptoms. PMID- 29248881 TI - Three-vessel coronary artery aneurysmal disease complicated by multivessel thrombosis and cardiogenic shock: the saving role of intracoronary thrombolysis. AB - The benefit of intracoronary thrombolytics in ST-elevation myocardial infarction (STEMI) is not well established. Mainstays of STEMI management include intravenous thrombolytics, percutaneous coronary interventions and surgical revascularisation. However, in cases of STEMI secondary to coronary artery aneurysmal disease (CAAD), standard treatment options may not be suitable due to high thrombus burden, perioperative risk and factors unique to each patient. Thus, STEMI management in CAAD can represent a therapeutically challenging clinical scenario. Here, we describe a patient with severe three-vessel CAAD complicated by multivessel thrombosis and cardiogenic shock for whom traditional management options including placement of haemodynamic support devices were not feasible. As an alternative measure, the patient was treated with intracoronary thrombolysis with remarkable clinical stabilisation and angiographic resolution of thrombosis. He remains clinically stable several years later without recurrent events. This case serves to demonstrate the potential lifesaving benefit of intracoronary thrombolysis in complicated multivessel CAAD. PMID- 29248882 TI - 'Mutiny on the crown': two cases of rare cephalic malformations. AB - The presentation and management of two bizarre congenital cephalic curiosities at the two extremes of the clinical spectrum are discussed herewith. Case 1: presented to us as a neonate with a scalp swelling mirror-imaging her head and face. The journey from clinics to wards and to the operation theatre and to her home is introspected. Case 2: presented to us as dicephalous dibrachius dipus parapagus conjoined twins. The detailed work-up of individual organ systems, the multidisciplinary approach to management and the final outcome are discussed. This is an unsolved mystery for the anatomists, paediatric surgeons, radiologists and the medical fraternity at large. PMID- 29248883 TI - Necrotising soft tissue infection without systemic toxicity in a patient with rheumatoid arthritis treated with tocilizumab. AB - A Japanese woman aged 76 years with rheumatoid arthritis treated with prednisolone and tocilizumab presented with a 2-day history of redness and pain in her right thigh. She was hospitalised with a primary diagnosis of cellulitis and antimicrobial therapy was initiated. She had been stable until the fourth day of admission, when the swelling of her right thigh rapidly worsened and demonstrated purpura; she was subsequently unable to walk because of the pain. A diagnosis of necrotising soft tissue infection (NSTI) was made and extensive debridement was performed. Over the next 4 months, additional debridement was performed four times. Her condition improved significantly and she was able to walk later. Physicians should recognise that tocilizumab can mask systemic toxicities and inflammatory findings even in severe infections. To avoid delays in diagnosis and surgical intervention, clinicians should consider NSTIs when they encounter patients treated with tocilizumab, even if it mimics cellulitis. PMID- 29248884 TI - Use of general practice before and after mild traumatic brain injury: a nationwide population-based cohort study in Denmark. AB - OBJECTIVES: Traumatic brain injury (TBI) is commonly seen in the emergency department (ED). Approximately 85%-90% of TBIs are mild (mTBI). Some cause symptoms such as headache, dizziness, anxiety, blurred vision, insomnia and concentration difficulties, collectively known as postconcussion syndrome (PCS). Some studies suggest that recovery from mTBI is complete. Others find that symptoms persist for months, even years. The aim of this study was to describe the use of general practice, before and after mTBI, as a proxy for symptoms in a large cohort. DESIGN: Nationwide population-based matched cohort study. SETTING: Danish EDs and general practice. PARTICIPANTS: All patients (aged >=18 years), first-time diagnosed with mTBI in a Danish ED between 1 January 1998 and 31 December 2010 (n=93 517). Ten reference persons per patient with mTBI were randomly matched on gender, age and general practice (n=935 170). PRIMARY OUTCOME: Overall use of general practice; consultations relating to mental and physical health. RESULTS: We found higher use of general practice during the first year after mTBI for all ages, both genders and all types of contacts. Age 18-40 years: women, incidence rate ratio (IRR) 1.59 (95% CI 1.57 to 1.61); men, IRR 1.82 (95% CI 1.80 to 1.85). Age 41-65 years: women, IRR 1.75 (95% CI 1.72 to 1.78); men, IRR 1.85(95% CI 1.82 to 1.89). Age 66+ years: women, IRR 1.55 (95% CI 1.52 to 1.58); men, IRR 1.55 (95% CI 1.51 to 1.59). After the first year, the use decreased to the level before mTBI. Individuals with mTBI and higher use of general practice before mTBI had lower socioeconomic status and more comorbidities (P<0.001). CONCLUSIONS: The use of general practice was higher in the first year after mTBI, specifically in the first 3 months. Patients with mTBI had different healthcare-seeking behaviour several years before diagnosis than their matched reference persons. Pretraumatic morbidity should be considered in the evaluation of PCS. PMID- 29248885 TI - Occupational radiation exposure and its health effects on interventional medical workers: study protocol for a prospective cohort study. AB - INTRODUCTION: Although fluoroscopically guided procedures involve a considerably high dose of radiation, few studies have investigated the effects of radiation on medical workers involved in interventional fluoroscopy procedures. Previous research remains in the early stages and has not reached a level comparable with other occupational studies thus far. Furthermore, the study of radiation workers provides an opportunity to estimate health risks at low doses and dose rates of ionising radiation. Therefore, the objectives of this study are (1) to initiate a prospective cohort study by conducting a baseline survey among medical radiation workers who involve interventional fluoroscopy procedures and (2) to assess the effect of occupational radiation exposure and on the overall health status through an in-depth cross-sectional study. METHODS AND ANALYSIS: Intervention medical workers in Korea will be enrolled by using a self-administered questionnaire survey, and the survey data will be linked with radiation dosimetry data, National Health Insurance claims data, cancer registry and mortality data. After merging these data, the radiation organ dose, lifetime attributable risk due to cancer and the risk per unit dose will be estimated. For the cross sectional study, approximately 100 intervention radiology department workers will be investigated for blood tests, clinical examinations such as ultrasonography (thyroid and carotid artery scan) and lens opacity, the validation of badge dose and biodosimetry. ETHICS AND DISSEMINATION: This study was reviewed and approved by the institutional review board of Korea University (KU-IRB-12-12-A-1). All participants will provide written informed consent prior to enrolment. The findings of the study will be disseminated through peer-reviewed scientific journals, conference presentations, and a report will be submitted to the relevant public health authorities in the Korea Centers for Disease Control and Prevention to help with the development of appropriate research and management policies. PMID- 29248886 TI - Impact of birth characteristics, breast feeding and vital statistics on the eruption of primary teeth among healthy infants in Saudi Arabia: an observational study. AB - OBJECTIVES: This study aimed to explore the impact of gender, birth weight, maternal age, type of delivery, gestational age and feeding practices on the eruption of teeth in children with no underlying medical conditions or developmental defects in their first year of life. DESIGN: A cross-sectional observational study design was used. SETTING: A primary healthcare setting in Riyadh, Saudi Arabia. PARTICIPANTS: All children in their first year of life attending a vaccination clinic (n=422) were included in the study. Infants with chronic childhood illnesses, those who were below the 5th percentile in height or weight, infants with congenital birth defects and chronic illnesses, infants who were born preterm and low birth weight infants were excluded from the study. OUTCOME MEASURES: The type of delivery, birth weight, age of mother, height and weight percentile for age (as plotted on the WHO growth chart for infants) and feeding practices were recorded by the examiner, and this was followed by a clinical examination to determine the presence or absence of each tooth. Regression models were developed to determine the effect of the different variables on the presence of primary teeth. RESULTS: There was a significant association between the weight percentile of the child (adjusted for age) and the number of erupted primary teeth, suggesting that heavier children have an earlier eruption of teeth. No association was observed between birth weight, height percentile for age or maternal age at the time of birth and the number of erupted primary teeth. Children who were exclusively breast fed were significantly more likely to have an erupted first primary tooth earlier than non-breastfed group. CONCLUSIONS: Breast feeding and the weight of the child may have an influence on the eruption of primary teeth in the first year of life. PMID- 29248887 TI - The lived experience of chronic headache: a systematic review and synthesis of the qualitative literature. AB - OBJECTIVE: To systematically review the qualitative literature of the lived experience of people with a chronic headache disorder. BACKGROUND: Chronic headaches affect 3%-4% of the population. The most common chronic headache disorders are chronic migraine, chronic tension-type headache and medication overuse headache. We present a systematic review and meta-ethnographic synthesis of the lived experience of people with chronic headache. METHODS: We searched seven electronic databases, hand-searched nine journals and used a modified Critical Appraisal Skills Programme checklist to appraise study quality. Following thematic analysis we synthesised the data using a meta-ethnographic approach. RESULTS: We identified 3586 unique citations; full texts were examined for 86 studies and 4 were included in the review. Included studies differed in their foci: exploring, patient-centred outcomes, chronic headache as a socially invisible disease, psychological processes mediating impaired quality of life, and the process of medication overuse. Initial thematic analysis and subsequent synthesis gave three overarching themes: 'headache as a driver of behaviour' (directly and indirectly), 'the spectre of headache' and 'strained relationships'. CONCLUSION: This meta-synthesis of published qualitative evidence demonstrates that chronic headaches have a profound effect on people's lives, showing similarities with other pain conditions. There were insufficient data to explore the similarities and differences between different chronic headache disorders. PMID- 29248888 TI - Genetics and genomics of breast fibroadenomas. AB - Fibroadenomas of the breast are benign fibroepithelial tumours most frequently encountered in women of reproductive age, although they may be diagnosed at any age. The fibroadenoma comprises a proliferation of both stromal and epithelial components. The mechanisms underlying fibroadenoma pathogenesis remain incompletely understood. In the clinical setting, distinguishing cellular fibroadenomas from benign phyllodes tumours is a common diagnostic challenge due to subjective histopathological criteria and interobserver differences. Recent sequencing studies have demonstrated the presence of highly recurrent mutations in fibroadenomas, and also delineated the genomic landscapes of fibroadenomas and the closely related phyllodes tumours, revealing differences at the gene level, which may be of potential adjunctive diagnostic use. The present article provides an overview of key studies uncovering genetic and genomic abnormalities in fibroadenomas, from initial karyotype reports revealing myriad cytogenetic aberrations to next-generation sequencing-based approaches that led to the discovery of highly recurrent MED12 mutations. A thorough understanding of these abnormalities is important to further elucidate the mechanisms by which fibroadenomas arise and to refine diagnostic assessment of this very common tumour. PMID- 29248890 TI - Thromboembolism peaking 3 months after starting testosterone therapy: testosterone-thrombophilia interactions. AB - We assessed time of thrombotic events (venous thromboembolism (VTE)) after starting testosterone therapy (TT) in 21 men who sustained 23 VTE. The density of thrombotic events was greatest at 3 months after starting TT, with a rapid decline in events by 10 months. The 21 cases with VTE on TT differed from 110 patient controls with unprovoked VTE, not taking TT (VTE-no TT) for Factor V Leiden heterozygosity (FVL) (33 per cent vs 13 per cent, P=0.037), for high lipoprotein (a) (Lp(a)) (55 per cent vs 17 per cent, P=0.012), and for the lupus anticoagulant (33 per cent vs 4 per cent, P=0.003). These differences between cases and VTE-no TT controls were independent of age and gender. TT can interact with underlying thrombophilia-hypofibrinolysis promoting VTE. We suggest that TT should not be started in subjects with known thrombophilia. Coagulation screening, particularly for the FVL , Lp(a), and the lupus anticoagulant should be considered before starting TT, to identify men at high VTE risk who have an adverse risk/benefit ratio for TT. PMID- 29248889 TI - An integrated tool for determining the primary origin site of metastatic tumours. AB - AIMS: Cancers of unknown primary sites account for 3%-5% of all malignant neoplasms. Current diagnostic workflows based on immunohistochemistry and imaging tests have low accuracy and are highly subjective. We aim to develop and validate a gene-expression classifier to identify potential primary sites for metastatic cancers more accurately. METHODS: We built the largest Reference Database (RefDB) reported to date, composed of microarray data from 4429 known tumour samples obtained from 100 different sources and divided into 25 cancer superclasses formed by 58 cancer subclass. Based on specific profiles generated by 95 genes, we developed a gene-expression classifier which was first trained and tested by a cross-validation. Then, we performed a double-blinded retrospective validation study using a real-time PCR-based assay on a set of 105 metastatic formalin fixed, paraffin-embedded (FFPE) samples. A histopathological review performed by two independent pathologists served as a reference diagnosis. RESULTS: The gene expression classifier correctly identified, by a cross-validation, 86.6% of the expected cancer superclasses of 4429 samples from the RefDB, with a specificity of 99.43%. Next, the performance of the algorithm for classifying the validation set of metastatic FFPE samples was 83.81%, with 99.04% specificity. The overall reproducibility of our gene-expression-classifier system was 97.22% of precision, with a coefficient of variation for inter-assays and intra-assays and intra-lots <4.1%. CONCLUSION: We developed a complete integrated workflow for the classification of metastatic tumour samples which may help on tumour primary site definition. PMID- 29248892 TI - Peripheral inflammation in prodromal Alzheimer's and Lewy body dementias. AB - OBJECTIVES: There is growing evidence for the role of systemic inflammation in Alzheimer's disease (AD) and other neurodegenerative diseases; however the systemic inflammatory profile in dementia with Lewy bodies (DLB) has never before been investigated. This study aimed to characterise systemic inflammatory mediators in established DLB and AD, as well as in their prodromal, mild cognitive impairment (MCI) phases. METHODS: We obtained plasma samples from patients with DLB (n=37), AD (n=20), MCI with DLB profile (n=38), MCI with AD profile (n=20) and healthy control subjects (n=20). The following inflammatory biomarkers were measured using Roche cobas c702 and Meso Scale Discovery V-Plex Plus: high-sensitivity C-reactive protein, interferon-gamma, interleukin (IL)-10, IL-12p70, IL-13, IL-1beta, IL-2, IL-4, IL-6, IL-8 and tumour necrosis factor alpha. RESULTS: We found significantly higher levels of IL-10, IL-1beta, IL-4 and IL-2 in both MCI groups (P<0.001), while there was no significant difference in inflammatory markers between dementia groups and controls. Furthermore, increased disease severity was associated with lower levels of IL-1beta, IL-2 and IL-4 (P<0.05). INTERPRETATION: We have shown for the first time that in both DLB and AD, increased peripheral inflammation occurs early at the MCI disease stages. These data support a role for inflammation early in the disease process, and have important implications for the stage of disease where trials of anti-inflammatory medication should be focused. PMID- 29248893 TI - Autoimmune nodo-paranodopathies of peripheral nerve: the concept is gaining ground. AB - Peripheral neuropathies are classified as primarily demyelinating or axonal. Microstructural alterations of the nodal region are the key to understand the pathophysiology of neuropathies with antibodies to gangliosides and the new category of nodo-paranodopathy has been proposed to better characterise these disorders and overcome some inadequacies of the dichotomous classification. Recently, the research in autoimmune neuropathies has been boosted by reports of patients carrying immunoglobulin G4 antibodies against paranodal axo-glial proteins with distinct phenotypes and showing loss of transverse bands, terminal myelin loop detachment, nodal widening and axonal loss. These patients have been classified up to now as chronic inflammatory demyelinating polyradiculoneuropathy but, in our opinion, better fit into the nodo-paranodopathy category because nerve injury is due to dismantling of the paranode, segmental de-remyelination is absent and the pathogenic mechanism is not inflammatory. Evidence from nerve conductions and electron microscopy studies in patients and mutant animal models can reconcile the apparent contrast between the electrophysiological 'demyelinating' features, explainable just by the paranodal involvement and the axonal pathology. These patients broaden the autoimmune nodo-paranodopathy category and re-emphasise the usage of the term that pointing to the site of nerve injury reminds specific pathophysiological mechanisms, reconciles contrasting electrophysiological and pathological findings, and avoids misdiagnosis and taxonomic confusion. In our opinion, the nodo-paranodopathy term more adequately classifies the peripheral nerve disorders due to an autoimmune attack directed and limited to the nodal region integrating the traditional classification of peripheral neuropathies. PMID- 29248894 TI - A standardised frankincense extract reduces disease activity in relapsing remitting multiple sclerosis (the SABA phase IIa trial). AB - OBJECTIVE: To investigate whether oral administration of a standardised frankincense extract (SFE) is safe and reduces disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We performed an investigator-initiated, bicentric phase IIa, open-label, baseline-to-treatment pilot study with an oral SFE in patients with RRMS (NCT01450124). After a 4-month baseline observation phase, patients were treated for 8 months with an option to extend treatment for up to 36 months. The primary outcome measures were the number and volume of contrast-enhancing lesions (CEL) measured in MRI during the 4-month treatment period compared with the 4-month baseline period. Eighty patients were screened at two centres, 38 patients were included in the trial, 28 completed the 8-month treatment period and 18 of these participated in the extension period. RESULTS: The SFE significantly reduced the median number of monthly CELs from 1.00 (IQR 0.75-3.38) to 0.50 (IQR 0.00-1.13; difference -0.625, 95% CI -1.25 to -0.50; P<0.0001) at months 5-8. We observed significantly less brain atrophy as assessed by parenchymal brain volume change (P=0.0081). Adverse events were generally mild (57.7%) or moderate (38.6%) and comprised mainly gastrointestinal symptoms and minor infections. Mechanistic studies showed a significant increase in regulatory CD4+ T cell markers and a significant decrease in interleukin-17A-producing CD8+ T cells indicating a distinct mechanism of action of the study drug. INTERPRETATION: The oral SFE was safe, tolerated well and exhibited beneficial effects on RRMS disease activity warranting further investigation in a controlled phase IIb or III trial. CLINICAL TRIAL REGISTRATION: NCT01450124; Results. PMID- 29248895 TI - CSF beta-amyloid and white matter damage: unravelling the neuropathology of Alzheimer's disease. PMID- 29248896 TI - Heat-not-burn tobacco product use in Japan: its prevalence, predictors and perceived symptoms from exposure to secondhand heat-not-burn tobacco aerosol. AB - OBJECTIVES: A heat-not-burn (HNB) tobacco product, IQOS, was first launched in Japan and Italy as test markets and is currently in commerce in 30 countries. Using two data sources, we examined interest in HNB tobacco (IQOS, Ploom and glo), its prevalence, predictors of its use and symptoms from exposure to secondhand HNB tobacco aerosol in Japan, where HNB tobacco has been sold since 2014. METHODS: Population interest in HNB tobacco was explored using Google search query data. Prevalence of HNB tobacco current use (ie, use in the previous 30 days) was calculated using a longitudinal internet survey of 8240 individuals (15-69 years old in 2015) followed up to 2017. Rates of perceived symptoms from exposure to exhaled aerosol of others' HNB tobacco were also calculated. RESULTS: The largest internet search volume for IQOS occurred in April 2016 in the week after a popular national entertainment TV show introduced IQOS. For Ploom and glo, search volumes have remained limited since their launch. Prevalence of IQOS users increased from 0.3% in January-February 2015 to 0.6% in January-February 2016 and up to 3.6% in January-February 2017, while estimated rates of use of other HNB tobacco products remained low in 2017. Respondents who had seen the TV programme in 2016 were more likely to have used IQOS than those who had not seen it (10.3% vs 2.7%). Among never-smokers who had been exposed to secondhand HNB tobacco aerosol, nearly half reported at least one acute symptom, although these symptoms were not serious. CONCLUSIONS: A popular TV programme triggered IQOS diffusion in Japan. Extrapolating from survey results to the general population, around 3.1 million people currently use IQOS in Japan. Tobacco control organisations and governments should closely monitor HNB tobacco and consider how to regulate it. PMID- 29248897 TI - Negative affect, message reactance and perceived risk: how do pictorial cigarette pack warnings change quit intentions? AB - OBJECTIVE: Pictorial warnings on cigarette packs increase motivation to quit smoking. We sought to examine the potential mediating role of negative affect, message reactance (ie, an oppositional reaction to a message) and perceived risk in shaping quit intentions. METHODS: In 2014 and 2015, we randomly assigned 2149 adult US smokers to receive either pictorial warnings or text-only warnings applied to their cigarette packs for 4 weeks. Analyses used structural equation modelling with bootstrapped SEs to test our theorised mediational model. FINDINGS: Pictorial warnings increased negative affect, message reactance and quit intentions (all P<0.001), but not perceived risk (ie, perceived likelihood and severity of harms of smoking). Negative affect mediated the impact of pictorial warnings on quit intentions (mediated effect=0.16, P<0.001). Message reactance weakened the impact of pictorial warnings on quit intentions, although the effect was small (mediated effect=-0.04, P<0.001). Although pictorial warnings did not directly influence perceived risk, the model showed additional small mediation effects on quit intentions through negative affect and its positive association with perceived risk (mediated effect=0.02, P<0.001), as well as reactance and its negative association with perceived risk (mediated effect= 0.01, P<0.001). CONCLUSIONS: Pictorial cigarette pack warnings increased quit intentions by increasing negative affect. Message reactance partially attenuated this increase in intentions. The opposing associations of negative affect and reactance on perceived risk may explain why pictorial warnings did not lead to observable changes in perceived risk. PMID- 29248898 TI - Confidence in palliative care issues by medical students and internal medicine residents. AB - BACKGROUND: Palliative care (PC) is a relatively new field in Brazil, but this knowledge is of great importance in medical practice. OBJECTIVE: To evaluate the degree of confidence among medical students and first-year and second-year internal medicine residents in addressing issues of death and terminal illness with patients and their families. METHOD: A modified version of the Self-Efficacy in Palliative Care Scale was applied to 293 students in their first year to sixth year at the School of Medicine of Sao Jose do Rio Preto and to 43 residents in their first year or second year of medical practice at the same institution in Brazil, in 2015. The questionnaire evaluated students' opinions on the need to include theoretical and practical classes on PC in the medical school. RESULTS: Students in their fifth year of medical school were more confident than the students in their first, second, third and fourth years; there were no statistically significant differences between fifth-year students, sixth-year students and the internal medicine residents. CONCLUSION: Residents were more confident than all of the medical school students except those in their fifth year (P<0.05) because they have more contact with terminally ill patients than other students do; fifth-year medical students are likely overestimating their abilities. PMID- 29248899 TI - Factors associated with condom use among men and women living with HIV in Lilongwe, Malawi: a cross-sectional study. AB - BACKGROUND: Understanding the influences on condom use among men and women living with HIV is critical to tailoring sexually transmitted infection/HIV prevention efforts. METHODS: This is a sub-analysis of a cross-sectional survey including 255 women and 220 men who were sexually active, HIV-positive, and attending HIV care visits in Lilongwe, Malawi. We estimated adjusted prevalence ratios (aPRs) to evaluate for factors associated with consistent condom use (always using condoms in the past month) and use at last coitus for men and women in separate models. RESULTS: Among women: 38% and 55% reported consistent condom use and condom use at last coitus, respectively. For women, consistent use and use at last coitus were positively associated with the ability to refuse sex without condoms and shared decision-making compared with making the decision alone regarding condom use, and negatively associated with desire for children in the future. Consistent use also increased with longer antiretroviral therapy (ART) use (>=1 year compared with no ART use). Among men: 51% and 69% reported consistent condom use and condom use at last coitus, respectively. For men, the ability to refuse sex without condoms was associated with consistent use and use at last coitus, and believing that condoms should be used with other contraception was associated with consistent use. CONCLUSIONS: Our findings demonstrate ongoing low condom utilisation among HIV-positive individuals, and highlight that ART and contraceptive use do not deter condom use. Efforts to increase condom utilisation must recognise individual-level factors that influence use and should focus on relationship dynamics and promotion of empowerment and self-efficacy. PMID- 29248900 TI - Karl Jaspers: The Icon of Modern Psychiatry. AB - December 2015 and March 2016 issues of the American Journal of Psychiatry contain a debate focusing on the legacy of Emil Kraepelin, widely considered one of the founders if not the iconic founder of modern scientific psychiatry. The authors, Eric J. Engstrom and Kenneth S. Kendler, challenge the so-called neo-Kraepelinian view of Kraepelin and argue that the true, historical Kraepelin was far more inclined towards scientific psychology, less reductionist and brain-centric, and more skeptical nosologically than his later followers apparently believe. Commenting upon this paper, Rael D. Strous, Annette A. Opler, and Lewis A. Opler do not question these claims per se, but rather recall and emphasize historical facts that the paper regrettably omitted: Kraepelin's avid promotion of degeneration theory, eugenics, racism, and anti-Semitism as well as his mentoring of several of the most prominent Nazi-collaborating psychiatrists. Strous, Opler and Opler go on to suggest that it is now time for psychiatry to unburden itself of any iconic indebtedness to Kraepelin. The authors of the current paper agree, and propose to replace Kraepelin with the psychiatrist Karl Jaspers, MD (1883 1969) as the proper iconic founder of present-day and future psychiatry. Acknowledging our debt to Jaspers can usher in a fully humanistic and scientific psychiatric practice that can flourish as a medical discipline that is respectful of and of service to patients, beneficial for research, multiperspectival and methodologically pluralistic. PMID- 29248901 TI - Can Living in the Shadow of Terror Leave no Marks? Long-Term Effects of Traumatic Environments of Varying Intensity. AB - INTRODUCTION: This study investigated the long-term effects of different traumatic environments on adolescents. Environments were characterized by different threats that varied in predictability, duration, and the extent to which the threat can be defended against. The research examined: 1) Jerusalem during the Second Intifada (2001-2004), 2) Israel's northern cities during the Second Lebanon War (2006), and 3) cities that suffered neither the suicide bombings (that occurred in Jerusalem) nor the rocket bombardments (that occurred in the north). METHOD: Data was collected from surveys administered to 115 subjects aged 19-28 who were adolescents in the aforementioned cities at the relevant times but were not directly affected by terror. Participants were administered the Beck Depression Inventory (BDI), the Post-Traumatic Growth Inventory (PTGI) and the Impact of Event Scale - Revised (IES-R). RESULTS: No significant differences were found between subjects who lived in different traumatic environments as adolescents in levels of depression, posttraumatic symptoms (PTS) or posttraumatic growth (PTG). In fact, a pattern in the data indicates that adolescents in Jerusalem were less negatively impacted by their environment than were the other groups, even though Jerusalem experienced an unpredictable threat that could not be defended against, a chronic chaotic environment. CONCLUSIONS: These findings suggest that the effects of a chronic chaotic environment did not produce significantly more symptoms than other environments when examined several years later. Reactions to terror, including parental attitude towards adolescents' daily routine, are also discussed. PMID- 29248902 TI - Are "Sense of Coherence" and "Hope" Related Constructs? Examining These Concepts in Three Cultural Groups in Israel. AB - INTRODUCTION: The aim of this study was to evaluate the relationships between two coping factors which facilitate adoptive adjustment when facing stressful situations. We have examined links between sense of coherence (SOC) and the concept of hope as well as its wish and expectation components and its collective and individual dimensions. We have studied three cultural groups in Israel: secular Jews, religious Jews and Bedouin Arabs. METHOD: Data were collected during two military operations (Pillar of Clouds and Protective Edge) from 385 adolescents aged 12-18; 76 secular Jews, 110 religious Jews and 199 Bedouin Arabs. Adolescents filled out selfreported questionnaires which were comprised of items determining demographics, sense of coherence and hope. RESULTS: Results show that while religious Jews reported the strongest SOC, Bedouin Arabs reported the strongest hope. As for the links, major differences were revealed between the Jewish groups and the Bedouin Arab group. In both Jewish groups significant correlations were found between the expectation component and/or the global hope and SOC; however, no links were found between the global hope or its components or dimensions and SOC among the Bedouin Arab group. CONCLUSION: Overall, in spite of some overlap between these concepts in the Jewish groups it seems that SOC and hope have their own unique characteristics and, thus, stand as separate resources when facing stress situation. The discussion highlights cultural differences and similarities among these groups with regard to the main concepts of this article. Finally, some psychoeducational suggestions are offered, focusing on cultural sensitivity. PMID- 29248903 TI - A Cross-Sectional Analysis of the Relationship among Adolescents' Perceived Social Support, Psychological State and Future Expectations among Turkish Students. AB - INTRODUCTION: Due to social and emotional changes alongside the cognitive and logical changes in adolescence, alterations occur in the adolescent's communication with family and friends in this period, and social support assumes greater importance. METHODS: From each of the two middle and high schools in the Ilkadim district of Samsun, a total 688 students were employed by a two-stage sampling method in this cross-sectional study. The data were collected from sociodemographic information, Multidimensional Scale of Perceived Social Support (MSPSS), Brief Symptom Inventory (BSI) and Future Expectations Scale for Adolescents (FESA) questionnaires distributed under the supervision of guidance counselors in these schools between December 2014 and February 2015. The Mann- Whitney U test and Spearman's Rank Correlation were used for statistical analysis. The significance level was accepted as p<0.05 for all tests. RESULTS: In the study group, MSPSS Family subscale had a stronger correlational relationship with all the BSI subscales including global indices and also with total score of FESA and subscales with the exception of the Marriage and Family subscale than the other two MSPSS subscales. There were moderate negative correlation between scores of MSPSS and BSI, and a low-moderate positive correlation was observed between total MSPSS and FESA scores of adolescents. The results demonstrated that adolescents who exercise regularly and avoid smoking and alcohol have higher perceptions of social support. CONCLUSION: Perceived social support from family may be more effective than perceived social support from friends or a significant other in the development of psychological well being and positive future expectations of Turkish adolescents. PMID- 29248904 TI - Depression and Somatic Symptoms Among Two Ethnic Groups in Israel: Testing Three Theoretical Models. AB - INTRODUCTION: This study examined three theoretical models of the relationship between depressive symptoms and somatic complaints among Bedouin Arab and Jewish college/university students in Israel. The functional model suggests that somatic complaints may precede depressive symptoms; the affect-dysregulation model suggests that depressive symptoms may precede somatic complaints; and the sociocultural model suggests that depressive symptoms are strongly linked to somatic complaints mainly in Western cultural contexts. METHOD: One hundred and ninety individuals participated in the study, including 89 Bedouin Arab students and 101 Jewish students. Two assessment waves, one year apart, were employed. Participants completed measures regarding depression, somatic complaints and demographics. RESULTS: Bedouin Arabs reported higher levels of both depression (Time 1 and Time 2) and somatization (only Time 1) as compared to Jewish students. A multiple-group, cross-lagged SEM analysis provided support for the functional model among the Bedouin Arab and Jewish student: Somatic complaints prospectively predicted depression in both groups. However, support for the affect-dysregulation model was found only among the Bedouin Arab students, among whom depression prospectively predicted somatic complaints. CONCLUSIONS: This study highlights cultural/ethnic similarities concerning the functional model and the cross-sectional associations between depression and somatization. However, these findings also underscore ethnic differences concerning the affect dysregulation model. PMID- 29248905 TI - Primary Addictive Substances Used among Patients Treated in a Hospital-Based Addiction Medicine Service. AB - INTRODUCTION: This study sought to explore the differences in primary addictive substances used among individuals referred to an ambulatory hospital-based addiction service in Israel according to sex, age and source of referral. METHOD: Data were drawn from all referral forms received during a two-year period (N=140). Categories of primary addictive substances included alcohol, drugs (cannabis, synthetic cannabinoids, illicit stimulants and heroin) and medications (prescription opioids, prescription stimulants and benzodiazepines). Sources of referral included physicians, non-medical health professionals and self-referral. RESULTS: Among individuals referred to treatment, the most frequent categories of addictive substances were drugs (39%), followed by medications (38%) and alcohol (23%). Among those referred by a physician, the most common category of addictive substances was medications (45%), whereas among those referred by non-medical health professionals the most common category was drugs (61%). Significant (p<0.05) sex differences were found in primary addictive substances: men most commonly reported using drugs while women most commonly reported using medications. Individuals seeking treatment for drug use disorders were significantly younger (mean age = 34.3+/-12.4) than those seeking treatment for alcohol or prescription-medication use disorders (41.2+/-13.4 and 43.6+/-13.5, respectively). CONCLUSIONS: Age, sex and source of referral should be taken into consideration when screening for primary addictive substances. PMID- 29248906 TI - The Vividness of Movement Imagery Questionnaire (VMIQ-2) - Translation and Reliability of a Hebrew Version. AB - INTRODUCTION: The Vividness of Movement Imagery Questionnaire 2 (VMIQ-2) assesses individuals' ability to imagine themselves performing 12 simple motor tasks, from three perspectives: internal visual imagery, external visual imagery and kinesthetic imagery. The purpose of the current study was twofold: (a) to describe the translation process of the VMIQ-2 into a Hebrew version, and (b) to test the reliability of the Hebrew version. METHOD: Eighty-eight physical education students completed the questionnaire twice (test, re-test), with two weeks in-between the tests. RESULTS: Correlational analyses on the scores of the questionnaires given in the two phases - test and re-test - yielded two main findings: (a) there were no differences in mean scores of the questionnaires administered in the test phase and re-test phase; (b) significant moderate correlations between the questionnaires' score in the test and re-test phases were observed. CONCLUSIONS: The Hebrew version of the VMIQ-2 was found to be reliable. A number of implications are discussed concerning the use of the questionnaire in the fields of psychiatry and psychology. Address. PMID- 29248907 TI - Is Bacterial Meningitis a Risk Factor for Developing Attention Deficit Hyperactivity Disorder. AB - INTRODUCTION: Bacterial meningitis is a severe disease with high morbidity. Many medical conditions are known to be associated with meningitis including Attention Deficit Hyperactivity Disorder (ADHD). The goal of the present study was to examine the frequency of ADHD in children who had had bacterial meningitis. An additional goal was to assess the odds ratio for ADHD in children who had had meningitis and children who had not had it. METHODS: The sample comprised 60 children who had had meningitis in the first year of their lives and 60 control children who had not had the disease. ADHD was assessed through the structural clinical interviews with parents according to the criteria set in DSM-IV. RESULTS: The total frequency of ADHD in children who had had meningitis was 62%, as compared to 5% in children who had not had the disease. The odds ratio for developing ADHD was 30.5 (95% CI = 8.5 to 109) in favor of children in the meningitis group. CONCLUSION: Meningitis is a significant risk factor for developing ADHD later in childhood. Children who had meningitis need to be monitored for timely detecting and treating ADHD symptoms. PMID- 29248908 TI - International Survey of Speech-Language Pathologists' Practices in Working with Children with Autism Spectrum Disorder. AB - OBJECTIVE: Autism spectrum disorder (ASD) is a complex neurodevelopmental impairment. To better understand the role of speech-language pathologists (SLPs) in different countries in supporting children with ASD, the International Association of Logopedics and Phoniatrics (IALP) Child Language Committee developed a survey for SLPs working with children or adolescents with ASD. Method and Participants: The survey comprised 58 questions about background information of respondents, characteristics of children with ASD, and the role of SLPs in diagnosis, assessment, and intervention practices. The survey was available in English, French, Russian, and Portuguese, and distributed online. RESULTS: This paper provides a descriptive summary of the main findings from the quantitative data from the 1,114 SLPs (representing 35 countries) who were supporting children with ASD. Most of the respondents (91%) were experienced in working with children with ASD, and the majority (75%) worked in schools or early childhood settings. SLPs reported that the children's typical age at diagnosis of ASD on their caseload was 3-4 years, completed mostly by a professional team. CONCLUSIONS: The results support positive global trends for SLPs using effective practices in assessment and intervention for children with ASD. Two areas where SLPs may need further support are involving parents in assessment practices, and supporting literacy development in children with ASD. PMID- 29248910 TI - Dedication to Dr. Carol Westby. PMID- 29248909 TI - Stimulation of Executive Functions as Part of the Language Intervention Process in Children with Autism Spectrum Disorder. AB - AIMS: Identifying effective methods for stimulating language and communication of children with autism spectrum disorder (ASD) is fundamental to the effective use of available resources to support these children. This pilot study was designed to explore the potential benefits of a program of stimulation of executive functions (SEF) on the functional aspects of language and communication through the assessment of the functional communicative profile and social-cognitive performance. METHODS: Twenty children, aged 5-12 years, with a diagnosis of ASD participated in the study. Two stimulation programs were offered over a 10- to 12 week period as part of the regular services offered to these children through a University's speech and language therapy outpatient clinic in Sao Paulo, Brazil. Children either received SEF intervention in their home implemented by their parent/s, with close monitoring by the speech-language pathologist (SLP) (group 1), or they received SEF by the SLP during regular speech-language therapy individual sessions (group 2). RESULTS: The findings suggested that there were differences between the children's pre- and posttest performance. Significantly different performances were observed in the areas of occupation of communication space, proportion of communicative interactivity, and social-cognitive performance. CONCLUSION: The inclusion of activities to stimulate executive function abilities in language intervention for children with ASD warrants further investigation. PMID- 29248911 TI - Irisin and Volume Overload are Associated with Protein Energy Wasting in Peritoneal Dialysis Patients. AB - BACKGROUND/AIMS: Protein energy wasting (PEW) is a common medical phenomenon that is observed in maintenance dialysis patients. PEW also increases morbidity and mortality of these patients. Its pathogenesis is unclear. We hypothesize that serum irisin levels and volume overload may induce PEW in peritoneal dialysis (PD) patients. The aim of this study is to measure serum irisin levels, evaluate volume status of PD patients, and study their correlations with PEW in PD patients. METHODS: This study is a cross-sectional study with 160 PD patients from the PD center of Peking University Third Hospital and 35 healthy control subjects. PD patients were divided into PEW group and non-PEW group according to PEW diagnosis criteria. Serum irisin concentrations were measured by ELISA. Volume overload status (volume overload is defined as overhydration value >=2 liters) of PD patients was analyzed by bioelectrical impedance. RESULTS: The serum irisin levels were significantly lower in PD patients compared with those of the controls (113.2+/-11.8 ng/ml vs. 464.2+/-37.4 ng/ml, P<0.01). The serum irisin levels were lower in PD patients with PEW than those of the patients without PEW (106.5+/-15.2 ng/ml vs. 117.4+/-17.6 ng/ml, P<0.01). PEW is more prevalent in patients with volume overload than patients without volume overload (62.5% vs. 43.1%, x2=5.756, P=0.016); however, no direct relationship was found between irisin levels and volume overload status. The independent influencing factors of PEW were serum irisin, serum albumin, and volume overload. CONCLUSION: Our results are the first to provide clinical evidence of the association between serum irisin, volume overload, and PEW in PD patients. PEW may inhibit the release or synthesis of irisin from skeletal muscles, and volume overload may aggravate PEW in PD patients. PMID- 29248912 TI - Screening for Fabry Disease in Kidney Disease: a Cross-Sectional Study in Males and Females. AB - BACKGROUND/AIMS: Evaluate the prevalence of Fabry disease in men and women with kidney disease; and observe the presence and importance of the main signs and symptoms in patients with kidney disease. METHODS: A cross-sectional analysis of secondary data from a multicenter project of Clinical and Epidemiological Analysis of Fabry Disease in 854 Dialysis Centers. A total of 36,442 patients underwent the questionnaire and algorithm; of them, 28,284 were discarded for not presenting signs and symptoms of Fabry disease, while the other 8,087 submitted to blood collection and analysis. All participants signed a Free and Informed Consent Form and a questionnaire was applied. The questionnaire data were analyzed using a computerized algorithm. This program/algorithm analyzes and separates patients into: discarded, patients unlikely to have Fabry disease; suspect, patients who submitted to blood collection. The blood of suspect patients was collected on filter paper for enzyme measurement and genetic testing. A descriptive data analysis was performed and the likelihood ratio was determined. RESULTS: The general prevalence was 0.19% and after use of algorithm was 0.87%. Although more men were screened (59.3%), the prevalence was higher in women (65.1%). The most prevalent signs and symptoms were: heart disease (60.6%), decreased or lack of sweating (42.3%), heat and cold intolerance (28.2%), and pain crises spreading throughout the body (26.8%). CONCLUSION: The prevalence was higher in women, and the most prevalent symptom was heart diseases. PMID- 29248913 TI - Fluocinolone Acetonide Intravitreal Implant 190 MUg (ILUVIEN(r)) in Vitrectomized versus Nonvitrectomized Eyes for the Treatment of Chronic Diabetic Macular Edema. AB - PURPOSE: To compare the functional and anatomical outcomes after a 0.2 ug/day fluocinolone acetonide (FAc) implant between vitrectomized and nonvitrectomized eyes with chronic diabetic macular edema (DME). METHODS: This is a retrospective, comparative analysis of 43 eyes with chronic DME. All eyes were treated with a single 0.2 ug/day FAc implant and followed up for a mean period of 8.5 months (median, 6.0 months; range, 1-21 months). The patients with a 0.2 ug/day FAc implant were divided into 2 groups: 24 eyes which had undergone pars plana vitrectomy prior to 0.2 ug/day FAc (group 1) and 19 eyes which had not been vitrectomized (group 2). Outcome measures included mean changes in best corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study letters, central subfield foveal thickness (CSFT), and intraocular pressure (IOP), and were measured prior to administration of the 0.2 ug FAc implant, in the first week, at month 1, and quarterly thereafter. RESULTS: Following the 0.2 MUg/day FAc implant, the mean change in BCVA at the last observation point, from baseline, was +16.9 +/- 3.39 (mean +/- SE) letters (p <= 0.001) in group 1 and +8.2 +/- 4.62 letters (p = 0.092) in group 2. From baseline, a gain of >=15 letters was achieved in 37.5 and 36.8% of the eyes in group 1 and group 2, respectively. Additionally, an improvement in vision >=20/40 in 29.2% of group 1 and 15.8% of group 2 was observed. The mean change in CSFT was -217.7 +/- 40.8 um and -155.6 +/- 43.4 um in group 1 and group 2, respectively. The mean change in IOP was +1.6 +/- 0.7 mm Hg in group 1 and +0.8 +/- 1.3 mm Hg in group 2, relative to baseline. At the last observation point, there were no significant differences between groups 1 and 2 (p > 0.05) in terms of their changes in BCVA, CSFT, and IOP. CONCLUSION: The results from the real-life practice study demonstrate that the 0.2 MUg/day FAc implant is effective and well tolerated in vitrectomized and nonvitrectomized eyes of patients with chronic DME. Our results support the use of a 0.2 MUg/day FAc implant to obtain long-term functional and anatomical improvements (mean, 8.5 months; median, 6.0 months) in vitrectomized and nonvitrectomized eyes. PMID- 29248916 TI - Foreword. PMID- 29248915 TI - Using Controlled Substance Receipt Patterns to Predict Prescription Overdose Death. AB - BACKGROUND: This study evaluates complete state data from controlled substance prescribing trends in the prescription monitoring program (PMP) database and their association with the risk of prescription drug overdose death. SUMMARY: Maine PMP records of individuals who died of prescription overdose deaths between 2006 and 2010 were selected (n = 690). For each subject, an age, gender, and residence matched cohort of PMP users in a 50: 1 ratio was identified (n = 34,500). Key Messages: Prescription opioids contributed to 480 of 690 prescription deaths, many co-ingestions were noted, and OR for overdose death increased with milligram of morphine equivalent (MME)/day >100. The majority who were prescribed MME >100 per day received a prescription within 90 days of overdose matching the toxicology cause of death. CONCLUSIONS: Medication profiles available through state PMP can identify dosing of prescriptions associated with drug overdose death. PMID- 29248914 TI - Whole-Genome Analysis of an Extensive Drug-Resistant Acinetobacter Baumannii ST195 Isolate from a Recipient After DCD Renal Transplantation in China. AB - BACKGROUND/AIMS: Infection with Acinetobacter baumannii was emerging as one of the leading causes of mortality after donation after cardiac death transpalantion. METHODS: We reported a case of a recipient who underwent DCD renal transplantation and later got infected by A.baumannii. Etests were done to verify the susceptibility test results in clinic. Whole-genome analysis was applied to investigate the resistant mechanism at gene level. RESULTS: The pathogen was isolated from his draining liquid the day after the surgery, and susceptibility test reavealed that it was sensitive to tigecycline. However, the isolate obtained from the draining liquid became tigecycline-resistant after fifteen-day administration of tigecycline. The Susceptibility tests showed that the pathogen recovered from tigecycline resistance and became intermediated to tigecycline. Whole-Genome analysis revealed the genetic level change leading to tigecycline resistance and we identified the location of mutation by comparing the whole genome sequence of the isolates. Three loci were figured out which may contribute to drug resistance, including genes encoding HTH domain protein, MFS transporter and AdeS. CONCLUSION: Understanding the genetic characteristics associated with drug resistance mechanism and antimicrobial profiles of pathogen is important in controlling infection outbreak and preventing serious complications and gives a new insight into the development of antimicrobial agents. PMID- 29248917 TI - The Home Literacy Environment of Preschool-Age Children with Autism or Down Syndrome. AB - AIMS: This exploratory study investigated if there were differences in the home literacy environment of preschool children on the autism spectrum and preschool children with Down syndrome to determine if the home literacy environment may potentially be associated with strengths or weaknesses in children's social communication skills. METHODS: A total of 111 parents of preschoolers with identified disabilities completed a home literacy questionnaire. RESULTS: Results indicated that both groups of parents started reading to their children at an early age and owned at least 25 children's books. However, parents of children with Down syndrome read to their child more often, reported higher child interest in reading, and more frequently played rhyming games with their child. No group differences were found in teaching of letter names, although parents of children with autism reported a higher frequency of pointing out signs/words in the environment and reported their children knew more letter names. Group differences were also found in the relationship between parent behaviours, child interest, and children's print-related skills. CONCLUSION: This study highlights the influence both parent behaviours and child interest may have on shared book reading practices of parents with their preschool children with disabilities. PMID- 29248918 TI - Issues in Identification and Assessment of Children with Autism and a Proposed Resource Toolkit for Speech-Language Pathologists. AB - BACKGROUND: The prevalence of autism spectrum disorder (ASD) has increased significantly in the last decade as have treatment choices. Nonetheless, the vastly diverse autism topic includes issues related to naming, description, iden tification, assessment, and differentiation from other neu-rodevelopmental conditions. ASD issues directly impact speech-language pathologists (SLPs) who often see these children as the second contact, after pediatric medical practitioners. Because of shared symptomology, differentiation among neurodevelopmental disorders is crucial as it impacts treatment, educational choices, and the performance trajectory of affected children. OBJECTIVES: To highlight issues in: identification and differentiation of ASD from other communication and language challenges, the prevalence differences between ASD gender phenotypes, and the insufficient consideration of cultural factors in evaluating ASD in children. A second objective was to propose a tool to assist SLPs in the management of autism in children. SUMMARY: A universal resource toolkit development project for SLP communities at large is proposed. The resource is comprised of research-based observation and screening tools for caregivers and educators, as well as parent questionnaires for portraying the children's function in the family, cultural com-munity, and educational setting. PMID- 29248919 TI - Tiermedizinische Publikationen in Complementary Medicine Research. PMID- 29248920 TI - Association Between Comprehensive Nutritional Scoring System (CNSS) and Outcomes of Continuous Ambulatory Peritoneal Dialysis Patients. AB - BACKGROUND/AIMS: The presence of protein-energy wasting (PEW) among dialysis patients is a crucial risk factor for outcomes. The complicated pathogenesis of PEW makes it difficult to assess and treat. This single-center retrospective study focuses on the association between nutritional markers and the outcomes of continuous ambulatory peritoneal dialysis(CAPD) patients, aiming to establish a practical comprehensive nutritional scoring system for CAPD patients. METHODS: 924 patients who initiated peritoneal dialysis in our center from January 1st,2005 to December 31st,2015 were enrolled. Comprehensive nutritional scoring system(CNSS) was based on items including SGA, BMI, ALB, TC, MAC and TSF. We divide patients into 3 groups according to their CNSS score. Outcomes including mortality, hospitalization days and hospitalization frequency were compared between 3 grades. RESULTS: The CNSS grade correlated significantly with hospitalization days (P<0.05). Both categorized CNSS grade (HR:0.56; 95% CI:0.41 0.78; P = 0.001) and continuous CNSS score (HR:0.87; 95% CI: 0.80-0.94; P = 0.001) independently protect PD patients from all-cause mortality. CONCLUSION: CNSS provides an integrated scoring system with significant associations with hospitalization and mortality in PD patients. The CNSS grade differentiates patients with malnutritional risk and independently predicts high risk of morbidity and mortality. PMID- 29248921 TI - Impact of Kidney Transplantation on Reproductive Hormone Levels in Males: A Longitudinal Study. AB - BACKGROUND/AIMS: Male patients with end-stage renal disease suffer from sexual disturbances and infertility. Disturbances in the hypothalamic-pituitary-gonadal axis are one of the causes of this. Decreased testosterone synthesis in Leydig cells of the testes and hyperprolactinemia are common. Kidney transplantation, unlike hemodialysis, normalizes these changes. However, how kidney transplantation affects Sertoli cell function is poorly understood. This study is aimed at investigating the changes in fertility-related hormones in men before, during, and after renal transplantation. METHODS: This longitudinal and prospective single center study enrolled 12 men undergoing living donor kidney transplantation. Plasma levels of creatinine, cystatin C, and serum levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, sex hormone-binding globulin, inhibin B, and anti-Mullerian hormone (AMH) were assayed at 10 different time points before, during, and after kidney transplantation. RESULTS: A rapid decrease in creatinine and cystatin C levels indicated successful renal transplantation. High pre-transplantation plasma levels of prolactin (mean 516 +/- 306 mIE/L) and LH (9.4 +/- 4.7 IU/L) were normalized after 7 days (248 +/- 161 mIE/L and 6.1 +/- 3.1 IU/L, respectively). Testosterone decreased rapidly during transplantation and increased again one week post-transplantation. Sertoli cell-derived hormone inhibin B decreased after transplantation, and there was a small non-significant trend of increased AMH after 12 months. CONCLUSION: Sertoli cell function, based on AMH and inhibin B levels, does not improve to the same extent or as fast as Leydig cell function after kidney transplantation, as determined by testosterone and LH levels. PMID- 29248922 TI - Association between Dental Caries and Delayed Growth in Korean Children. AB - The purpose of this study was to assess the relationship of dental caries with anthropometric outcomes in 4- to 6-year-old children participating in the Korean National Health and Nutrition Examination Survey (KNHANES). The sample size was 1,910 children from the 4th and 5th KNHANES. The caries status was assessed with the decayed and filled teeth index in primary dentition (dft score). We employed height for age, body weight for age, and body mass index for age as outcome variables. Age, gender, region, and income were confounders. Nutritional deficiency as a mediator in the association between dental caries and delayed growth was also examined. A series of logistic regression analyses estimated the magnitude of association between dental caries and unfavorable growth after adjustment of the confounders and the mediator. Those with a high dft score were more likely to be deficient in nutrition (OR 1.77, 95% CI 1.14-2.74). After adjusting for sociodemographic factors and nutritional deficiency, we also found that a high dft score was associated with low weight (OR 1.70, 95% CI 1.15-2.51). The influence of dental caries on delayed growth was found in Korean representative children. PMID- 29248923 TI - Risk Factors and Outcomes of Early-Onset Peritonitis in Chinese Peritoneal Dialysis Patients. AB - BACKGROUND/AIMS: Studies on the risk factors and outcomes of peritonitis within the first 6 months in peritoneal dialysis patients are sparse. This study aims to investigate the risk factors associated with early-onset peritonitis (EOP) and its influence on patients' technique survival and mortality. METHODS: This is a retrospective observational cohort study. A total of 483 patients who had at least one episode of peritonitis were enrolled and followed from March 1, 2002, to August 31, 2016, at our center. According to the time to first peritonitis, we divided patients into two groups: EOP (<= 6 months, n=167) and late-onset peritonitis (LOP, >6 months, n=316). Logistic regression was used to analyze the factors associated with EOP. A Cox proportional hazards model was constructed to examine the influence of EOP on clinical outcomes. RESULTS: Of the 483 patients, 167 (34.6%) patients developed their first episode of peritonitis within the first 6 months. The EOP patient group had more male patients, a shorter time on peritoneal dialysis (PD), lower serum albumin levels at the time of PD initiation and a higher peritonitis rate (P<0.05). The EOP patient group had fewer infections with Gram-negative organisms (P=0.013) and more culture-negative peritonitis (P=0.014) than the LOP patient group for the first episode of peritonitis. The multivariate logistic regression analysis showed that factors associated with EOP included male gender (odds ratio (OR) 1.920, 95% confidence interval (CI) 1.272-2.897, P=0.002) and a low serum albumin level at the start of PD (OR 0.950, 95% CI 0.914-0.986, P=0.007). In the Cox proportional hazards model, EOP was a significant predictor of all-cause mortality (hazard ratio (HR) 2.766, 95% CI 1.561-4.900, P<0.001). There were no differences between EOP and LOP for technique failure. However, in continuous analyses, a negative correlation was observed between the time to first peritonitis and technique failure (HR 0.988, 95% CI 0.980-0.997, P=0.006). In the Spearman analysis, the time to first peritonitis was negatively correlated with the peritonitis rate (r= 0.573, P<0.001). CONCLUSION: Male gender and a low serum albumin level before PD were strongly associated with EOP. Additionally, EOP patients had a higher risk of poor clinical outcomes. More importantly, an early peritonitis onset was associated with a high peritonitis rate. PMID- 29248924 TI - Is There More to Zika? Complex Cardiac Disease in a Case of Congenital Zika Syndrome. AB - The epidemic of Zika virus (ZIKV) has resulted in a surge of newborns with microcephaly and brain abnormalities. In this report, we describe the first case, to our knowledge, of congenital Zika syndrome with concomitant critical congenital heart disease. The mother had a confirmed ZIKV infection in the first trimester of pregnancy. Fetal ultrasonography at 31 weeks of gestation revealed cerebral cortical calcifications and hypoplastic left heart syndrome. The severity of brain involvement was assessed by postnatal magnetic resonance imaging and echocardiogram, and palliative surgery was performed. The ethical dimensions of this infant's clinical management are discussed. ZIKV is known to affect neural progenitor cells, but whether it could have a tropism for other tissues remains unclear. PMID- 29248925 TI - Morpho-Orthographic Processing in Children with Autism Spectrum Disorder: The Case of Hebrew Orthography. AB - OBJECTIVE: Most studies on word reading in children with autism spectrum disorder (ASD) focus on graphemic-phonemic decoding and the direct orthographic route. To extend the scope, we investigated morpho-orthographic identification beyond graphemic-phonemic abilities. PATIENTS AND METHODS: The original study included 31 sixth-grade children with ASD and comparison groups of typically developing (TD) children: 23 age-matched children, 15 third-graders, and 17 second-graders. The groups were compared regarding reading of morphologically based Hebrew pointed pseudowords to examine graphemic-phonemic decoding, and unpointed pseudowords to test morpho-orthographic identification. To better focus on morpho orthographic identification processes, we eventually included only children with a minimum threshold of >=65% correct in reading pointed pseudowords, thereby excluding 11 children with ASD, 1 TD age-matched child, and 1 TD third-grader. RESULTS: About half of the children with ASD eventually included were as accurate as the TD second-graders in reading unpointed pseudowords, and slow in reading both pointed and unpointed pseudowords. The other half were as accurate as their typical peers in reading unpointed pseudowords, but slightly slower. CONCLUSION: The results highlight the difficulties many Hebrew-reading children with ASD experience in using morpho-orthographic processes beyond their difficulties in using graphemic-phonemic processes, demonstrating effortful (slow) reading. While this study can be considered a pilot investigation, further studies are needed. PMID- 29248926 TI - Comprehension of "Narrow Focus" by Adolescents in the Autism Spectrum. AB - OBJECTIVE: The study compared the performance of adolescents with autistic spectrum disorder (ASD) to that of age-matched peers with typical development (TD) and cognitive language-matched peers with TD on measures of identification and comprehension of "narrow focus." PARTICIPANTS: Forty-nine participants, 17 autistic, 17 TD peers matched for age and sex, and 15 TD children matched for expressive vocabulary participated in the study. METHOD: The Hebrew Narrow Focus Test (HNFT) was used. The HNFT includes 3 subtests. The first subtest (A) required identification of the stressed word in the sentence based on psychoacoustic abilities alone. The second (B) and third (C) subtests required understanding the meaning of focused stress in different contexts. In subtest B, the meaning of "narrow focus" was to contrast other possibilities related to the lexical-grammatical role of the stressed word in the sentence, whereas in subtest C, the meaning was to indicate a mistake. RESULTS: ASD participants showed reduced performance compared to peers across all the subtests of the HNFT, but similar performance compared to TD children in subtests A and B and better performance on subtest C. A significant correlation was found between the Raven test for assessing nonverbal intelligence and subtests B and C of the HNFT in the group of adolescents with ASD. CONCLUSIONS: Comprehension of narrow focus in adolescents with ASD who study in a special educational system is related to their cognitive-linguistic abilities and not to the autistic condition by itself or to its severity. PMID- 29248927 TI - Differentiating Autism from Typical Development: Preliminary Findings of Greek Versions of a Pragmatic Language and Social Communication Questionnaire. AB - OBJECTIVE: A social pragmatic communication disorder is one of the primary characteristics of children with autism. Although several measures of pragmatics and social communication exist, many are not comprehensive, do not examine the quality of interactions across contexts and interlocutors, and cannot be easily administered and interpreted. The aim of this article is to report on preliminary data collected using the Greek version of comprehensive social communication and pragmatic language questionnaires completed by parents and teachers interacting with young children in different contexts. METHODS: A Greek translation of the social communication and pragmatic language questionnaires was administered to parents and teachers of 31 children diagnosed with autism and of 51 typically developing children aged 3.0-6.0 years. Analysis and Results: The performance on the Greek versions of the social communication and pragmatic language questionnaires of typically developing children was compared with the performance of the children with autism using a series of independent t tests. Descriptive statistics were used to summarize participant characteristics and performances on the measure. Preliminary results showed that significant differences with moderate effect sizes were found between groups on 63% of the 30 test items. CONCLUSIONS: The performance of children on questionnaires may lead to the development of easily administered and interpretable assessments for differentiating children with pragmatics and social communication impairments, such as children with autism, from typically developing children. PMID- 29248928 TI - Differential Kinetics of Aspergillus nidulans and Aspergillus fumigatus Phagocytosis. AB - Invasive aspergillosis mainly occurs in immunocompromised patients and is commonly caused by Aspergillus fumigatus, while A.nidulans is rarely the causative agent. However, in chronic granulomatous disease (CGD) patients, A. nidulans is a frequent cause of invasive aspergillosis and is associated with higher mortality. Immune recognition of A. nidulans was compared to A. fumigatus to offer an insight into why A. nidulans infections are prevalent in CGD. Live cell imaging with J774A.1 macrophage-like cells and LC3-GFP-mCherry bone marrow derived macrophages (BMDMs) revealed that phagocytosis of A. nidulans was slower compared to A. fumigatus. This difference could be attributed to slower migration of J774A.1 cells and a lower percentage of migrating BMDMs. In addition, delayed phagosome acidification and LC3-associated phagocytosis was observed with A. nidulans. Cytokine and oxidative burst measurements in human peripheral blood mononuclear cells revealed a lower oxidative burst upon challenge with A. nidulans. In contrast, A. nidulans induced significantly higher concentrations of cytokines. Collectively, our data demonstrate that A. nidulans is phagocytosed and processed at a slower rate compared to A. fumigatus, resulting in reduced fungal killing and increased germination of conidia. This slower rate of A. nidulans clearance may be permissive for overgrowth within certain immune settings. PMID- 29248929 TI - Familial X/Y Translocation Encompassing ARSE in Two Moroccan Siblings with Sensorineural Deafness. AB - Unbalanced translocations involving X and Y chromosomes are rare and associated with a contiguous gene syndrome. The clinical phenotype is heterogeneous including mainly short stature, chondrodysplasia punctata, ichthyosis, hypogonadism, and intellectual disability. Here, we report 2 brothers with peculiar gestalt, short stature, and hearing loss, who harbor an X/Y translocation. Physical examination, brainstem acoustic potential evaluation, bone age, hormonal assessment, and X-ray investigations were performed. Because of their dysmorphic features, karyotyping, FISH, and aCGH were carried out. The probands had short stature, hypertelorism, midface hypoplasia, sensorineural hearing loss, normal intelligence as well as slight radial and ulnar bowing with brachytelephalangy. R-banding identified a derivative X chromosome with an abnormally expanded short arm. The mother was detected as a carrier of the same aberrant X chromosome. aCGH disclosed a 3.1-Mb distal deletion of chromosome region Xp22.33pter. This interval encompasses several genes, especially the short stature homeobox (SHOX) and arylsulfatase (ARSE) genes. The final karyotype of the probands was: 46,Y,der(X),t(X;Y)(p22;q12).ish der(X)(DXYS129-,DXYS153 )mat.arr[hg19] Xp22.33(61091_2689408)*1mat,Xp22.33(2701273_3258404)*0mat,Yq11.222q12 (21412851_59310245)*2. Herein, we describe a Moroccan family with a maternally inherited X/Y translocation and discuss the genotype-phenotype correlations according to the deleted genes. PMID- 29248930 TI - Sesamin Protects Against Cardiac Remodeling Via Sirt3/ROS Pathway. AB - BACKGROUND/AIMS: Cardiac remodeling is associated with oxidative stress. Sesamin, a well-known antioxidant from sesamin seeds, have been used extensively as traditional health foods. However, there is little known about the effect of sesamin on cardiac remodeling. Therefore, the present study aimed to determine whether sesamin could protect against cardiac remodeling and to clarify potential molecular mechanisms. METHODS: The mice were subjected to either transverse aortic constriction (TAC) or sham surgery (control group). Beginning one week after surgery, the mice were oral gavage treated with sesamin (100mg.kg-1.day-1) or vehicle for 3 weeks. Cardiac hypertrophy was assessed by echocardiographic parameters, histological analyses and hypertrophic markers. RESULTS: Sesamin alleviated cardiac hypertrophy, inhibited fibrosis and attenuated the inflammatory response. The increased production of reactive oxygen species, the activation of ERK1/2-dependent nuclear factor-kappaB and the increased level of Smad2 phosphorylation were observed in cardiac remolding model that were treated with sesamin. Furthermore, TAC induced alteration of Sirt3 and SOD2 was normalized by sesamin treatment. Finally, a selective Sirt3 inhibitor 3-TYP blocks all the protective role of sesamin, suggesting that a Sirt3-dependent effect of sesamin on cardiac remodeling. CONCLUSION: Sesamin improves cardiac function and prevents the development of cardiac hypertrophy via Sirt3/ROS pathway. Our results suggest the protective effect of sesamin on cardiac remolding. PMID- 29248931 TI - Molecular Detection and Incidence of Y Chromosomal Material in Patients with Turner Syndrome. AB - The presence of a Y chromosome in patients with Turner syndrome (TS) is a risk factor for the development of gonadal tumor and/or virilization. With conventional cytogenetic analysis, some cells containing a Y chromosome can be missed. The aim of this study was to determine the presence and incidence of Y chromosome-derived material in TS patients using PCR and the markers SRY, DYZ1, DYZ3, DYS132, ZFY, and TSPY. Fifty-five TS patients (aged 5.5-26.75 years) were analyzed. A total of 17/55 (30.9%) were Y-positive, but only 7/17 had a Y chromosome in their karyotype and underwent gonadectomy. In 2 of these patients (28.6%), histopathologic examination revealed gonadoblastoma and dysgerminoma, respectively. In 8 patients in the studied group (8/55; 14.5%), the TSPY gene was detected, and the SRY gene (or a fragment) was identified in 9(3)/55 patients. No coding region mutations were observed in these SRY-positive patients. In conclusion, we have shown a high prevalence of Y chromosomal material in TS. Y markers were also observed in patients who had no Y chromosome in their karyotype, and PCR is very precise in detecting the presence of genetic material from the Y chromosome. Further follow-up of these Y-positive TS patients is mandatory. PMID- 29248932 TI - Neurobiological Bases of Autism Spectrum Disorders and Implications for Early Intervention: A Brief Overview. AB - OBJECTIVES: To better understand the pathogenesis of autism spectrum disorder (ASD) and implications for intervention, the current paper reports on research related to the neurobiological underpinnings of ASD and the implication for early intervention with a focus on the importance of joint attention and eye gaze behaviors. PARTICIPANTS AND METHODS: An overview is provided on the available research findings from the fields of social neuroscience and experimental psychology specific to brain development, brain pathology, eye gaze, and joint attention behaviors. RESULTS: The results of the review converge towards the existence of aberrant brain connections and atypical brain morphology areas, which in complex and dynamic ways hinder the prioritization of social information. Consequently, the atypical social interaction skills exhibited by infants at risk for developing ASD are traced in the malformation of respective brain connections. CONCLUSIONS: Given the importance of neurobiological findings and their mapping onto early social pragmatic skills, early intervention goals need to focus on increasing appropriate eye gaze skills and joint attention. Such goals could potentially improve intervention outcomes in terms of improving social communication skills in youngsters with ASD. PMID- 29248933 TI - Relationship Between Short-Term Blood Pressure Variability and Incidence of Acute Kidney Injury in Critically Ill Patients. AB - BACKGROUND/AIMS: Blood pressure (BP) variability is associated with cardiovascular events, and cerebral and renal damage. The aim of this study was to investigate any potential relationship between short-term BP variability and incidence of acute onset conditions, such as acute kidney injury (AKI), in critically ill patients. METHODS: BP was monitored to analyze its variability in critically ill patients in present study. Short-term BP variability was assessed as average real variability (ARV), standard deviation (SD) and coefficient of variation (CV) of 24-hour BP. RESULTS: A total of 565 patients were included, 41.2% (n=233) of which presented with AKI after admission (AKI stage I, n = 94; stage II, n = 37; stage III, n = 102). The mean APACHE II score was 21.5 for all patients. ARV of 24 h systolic BP was significantly higher in patients with AKI (p<0.001). This association remained (p=0.006) after adjustment for potential confounders. The incidence of AKI increased with the ARV from 14.0% (ARV <=6 mmHg) to 73.9% (ARV >14 mmHg). A weak association was also found between BP variability and hospital mortality in critically ill patients. CONCLUSION: BP variability is correlated with the incidence of AKI in critically ill patients. PMID- 29248934 TI - Proteomic Mapping of Dental Enamel Matrix from Inbred Mouse Strains: Unraveling Potential New Players in Enamel. AB - Enamel formation is a complex 2-step process by which proteins are secreted to form an extracellular matrix, followed by massive protein degradation and subsequent mineralization. Excessive systemic exposure to fluoride can disrupt this process and lead to a condition known as dental fluorosis. The genetic background influences the responses of mineralized tissues to fluoride, such as dental fluorosis, observed in A/J and 129P3/J mice. The aim of the present study was to map the protein profile of enamel matrix from A/J and 129P3/J strains. Enamel matrix samples were obtained from A/J and 129P3/J mice and analyzed by 2 dimensional electrophoresis and liquid chromatography coupled with mass spectrometry. A total of 120 proteins were identified, and 7 of them were classified as putative uncharacterized proteins and analyzed in silico for structural and functional characterization. An interesting finding was the possibility of the uncharacterized sequence Q8BIS2 being an enzyme involved in the degradation of matrix proteins. Thus, the results provide a comprehensive view of the structure and function for putative uncharacterized proteins found in the enamel matrix that could help to elucidate the mechanisms involved in enamel biomineralization and genetic susceptibility to dental fluorosis. PMID- 29248935 TI - Potential of Moringa oleifera in the Treatment of Benign Prostate Hyperplasia: Role of Antioxidant Defence Systems. AB - OBJECTIVE: This study sought to evaluate the protective effect of ethanolic leaf extract of Moringa oleifera on testosterone-induced benign prostatic hyperplasia (BPH) in male Sprague-Dawley rats. MATERIALS AND METHODS: BPH was induced in rats by the administration of testosterone propionate (3 mg/kg, s.c., in olive oil) for 4 weeks. M. oleifera (50, 100, or 200 mg/kg), celecoxib (20 mg/kg), or M. oleifera (50 mg/kg) + celecoxib (20 mg/kg) were orally administered daily 15 min before testosterone. On day 29, blood was collected to measure the levels of serum testosterone and prostate-specific antigen before the animals were sacrificed. The prostates were weighed, assayed, and histologically examined. RESULTS: M. oleifera significantly reduced the testosterone-induced increase in prostate weight (20.16%), prostate index (65.85%), serum testosterone (72.86%), and prostate-specific antigen (48.49%). Testosterone caused a significant increase in malondialdehyde (73%) as well as a reduction in glutathione (62.5%), superoxide dismutase (50%), and catalase (64%) activities which were attenuated by M. oleifera with a peak effect obtained at 100 mg/kg. The disruption of prostate histoarchitecture by testosterone was also ameliorated by M. oleifera. CONCLUSION: M. oleifera prevented testosterone-induced BPH through enhancement of antioxidant defence mechanisms, and hence could be used as an adjunct in the treatment of BPH. PMID- 29248937 TI - Resilience and Quality of Life: Exploring the Mediator Role of Social Support in Patients with Breast Cancer. AB - BACKGROUND The diagnosis and treatment of breast cancer can provoke a series of negative emotional changes in patients, further affecting their quality of life. It has been shown that patients with higher resilience have better quality of life. Social support systems are important protective factors that are necessary for the process of resilience to occur. Hence, this study aimed to investigate the role of social support in the relationship between resilience and quality of life among Chinese patients with breast cancer. MATERIAL AND METHODS A demographic-disease survey, the Chinese version of the Connor-Davidson Resilience Scale 25, Medical Outcomes Study Social Support Survey, and Functional Assessment of Cancer Therapy Breast Cancer Version 3 were used to interview 98 patients with breast cancer from a teaching hospital in Chongqing, China. Data analysis was performed by descriptive statistics, independent-sample t test, one-way ANOVA, and regression analyses. RESULTS The mean scores of resilience, social support, and quality of life were 54.68, 61.73, and 80.74 respectively, which were in the moderate range. Participants with stronger social support had higher resilience and better quality of life. Social support played a partial mediator role in the relationship between resilience and quality of life. The mediation effect ratio was 28.0%. CONCLUSIONS Social support is essential for the development of resilience and the improvement of quality of life in Chinese patients with breast cancer. Health professionals should provide appropriate guidelines to help patients seek effective support and enhance their resilience to improve their quality of life after breast cancer. PMID- 29248936 TI - Patients with Coexistence of Circulating Hepatitis B Surface Antigen and Its Antibody May Have a Strong Predisposition to Virus Reactivation During Immunosuppressive Therapy: A Hypothesis. AB - Hepatitis B virus (HBV) reactivation is a well-recognized complication in patients who undergo immunosuppressive drug therapy. Although the recommendation of antiviral prophylaxis made by the American Gastroenterological Association in 2015 focuses on the risk stratification of different immunosuppressive drugs, risk factors for HBV reactivation are also worth identifying in clinical practice. Recent studies have shown that the uncommon serological pattern of coexistent circulating HBV surface antigen (HBsAg) and its antibody (anti-HBs) was associated with double mutations (A1762T/G1764A) in the basal core promoter (BCP) region of the HBV genome, which is critical for HBV replication. Here, we depicted rheumatoid arthritis (RA) patients with coexistent HBsAg and anti-HBs in our medical center, who developed HBV reactivation during immunosuppressive drug therapy. DNA sequencing analysis of the HBV genome revealed triple mutations (A1762T, G1764A, and T1753V) in the BCP region, which could further enhance the ability of HBV replication. Hence, a novel hypothesis is advanced for the first time that patients with coexistent HBsAg and anti-HBs may have a strong predisposition to HBV reactivation due to specific BCP mutations. This hypothesis would, if correct, justify the concurrent detection of HBsAg and anti-HBs in HBV screening in patients with rheumatic diseases and quickly recognize patients with high risk of HBV reactivation. Further controlled studies are needed to confirm this hypothesis. PMID- 29248938 TI - Morphological characteristics of the facial bone wall related to the tooth position in the alveolar crest in the maxillary anterior. AB - The purpose of this study was to analyze whether the position of the tooth in the alveolar ridge influences the thickness of the facial bone wall and the distance between the cemento-enamel junction (CEJ) and osseous zenith (OZ). Cone-beam computed tomography (CBCT) scans from fifty four dentate patients were included in the study (22 male and 32 female, mean age 41. 5 years). The measurements taken included: (1). The Facial bone thickness at 7 different equidistant levels measuring levels (ML 1-7) - between OZ and the root apex (A). (2) The CEJ -OZ distance. (3) Facial position of the tooth (FPT) relative to a straight line traced from mesial to distal interproximal depressions of the alveolar plate at the level of the CEJ. The Facial bone wall thickness ranged between 0 mm and 3. 8 mm, with greater values at more apical levels. Mean values were smaller than 1 mm at every level except ML7. The CEJ-OZ distance varied between 0. 5 mm and 6. 9 mm (mean 2. 9 mm). The Mean of FPT value was 0. 6 mm. No statistically significant correlation was found between FPT and the CEJ-OZ distance. Weak negative statistically significant correlations were found between FPT and the thickness of the facial bone wall at MP1 and MP3. Within the limits of this study, no clinically relevant correlation between FPT and facial bone thickness - CEJ-OZ distance was found. More studies should be conducted to evaluate a greater number of teeth, especially those that may present misalignment with greater FPT values. PMID- 29248939 TI - Postural alterations as a risk factor for temporomandibular disorders. AB - The aims of this study were to estimate frequency and assess postural alterations as a risk factor for temporomandibular disorders (TMD). Patients aged 10 to 15years (N=243, mean age 12. 6) seeking comprehensive dental care were analyzed according to RDC/ TMD. For static postural assessment, photographs were taken and analyzed by a physiotherapist following Kendall's model. Patients were divided into: A: without TMD (n=133); B: with muscle disorders (n=61); C: with disk displacement (N=49). No difference in age wasobserved between groups (p=0. 95). Significant association was observed between muscular TMD and alterations in spinal curves, head posture, and lower limbs: OR: 3. 40, 2. 44 and 2. 22 respectively. The most frequent types were hyperlordosis 23. 30 and 32. 78%; forward head posture 39. 85 and 52. 45%; and genu valgum 33. 08 and 45. 90% in A and B respectively. Alterations in head posture, vertebral curves and lower limbs could be considered risk factors for muscular TMD. The most frequent postural alterations were lumbar hyperlordosis, forward head posture and genu valgus. PMID- 29248940 TI - The impact of oral health on quality of life in individuals with head and neck cancer after radiotherapy: the importance of dentistry in psychosocial issues. AB - The aim of this study was to assess the impact of oral health on the quality of life of patients with head and neck cancer after radiotherapy, combined or not with chemotherapy, and to compare it with that ofpatients with no history of neoplasia. A total 75 individuals were evaluated, including 30 with head and neck cancer after radiotherapy (study group) and 45 with no history of cancer (control group). All patients were evaluated according to World Health Organization criteria: caries activity by DMTF index, presence of periodontal disease by CPI index, edentulism index and impact of oral condition on quality of life through the OHIP-14 questionnaire. Statistically significant differences were found between the study group (SG) and the control group (CG)for caries activity conditions (p <0. 001), periodontal disease (p <0. 001) and missing teeth (p <0. 001). These conditions had an average impact on the quality of life of cancer patients. The oral health condition of individuals with head and neck cancer deteriorates after radiotherapy, with direct impact on their quality of life. PMID- 29248941 TI - Evaluation of an experimental remineralizing agent for repairing enamel surfaces. AB - The best material for repairing enamel surface defects is one very similar to the original enamel and which interacts with natural remineralization mechanisms. It does not repair extensive damage, so in order to fill large defects, external help is required using phosphocalcic ceramic composites that activate salivary remineralization efficiently though on smaller in scale. Effective adhesion of the repair may depend on the amount of aqueous fluids present in the enamel, which apparently enable nucleation and growth of new minerals to ensure adhesion and stability. The amount of fluids is governed by osmotic pressure. This study evaluated the influence of two osmotic pressure values of isotonic and hypotonic saliva and two modified remineralizing agent compositions: combinations of "conditioner" and "remineralizing agent" in proportions of 90%: 10% (A) and 50%: 50%(B), on filling artificial cracks. Results were evaluated by profilometer, stereomicroscope and confocal laser microscope. A 22 factorial design and a logistic model for statistical analysis were used. Only the composition of the mineralizing agent had a significant effect on efficiency in repairing defects. Compositions A and B both repaired dental enamel defects, but composition B presented higher levels of repair and more compact deposits as observed under stereomicroscope. PMID- 29248942 TI - Dental skeletal effects of the metallic splinted Herbst appliance after growth spurt: a lateral oblique cephalometric assessment. AB - The aim of this study was to evaluate dental and skeletal changes induced by the use of Herbst appliance compared to natural growth in young adults with Class II division I malocclusion with mandibular retrusion, by means of lateral oblique radiographs. Forty-six subjects, I4 -18 years old, after pubertal growth peak, with Class II division I malocclusion were assessed. Subjects were divided into two groups: the Experimental group included 23 subjects treated with Metallic Splinted Herbst and the Control group included 23 subjects followed without treatment. The Experimental and Control groups were paired by sex and chronological age. Oblique lateral cephalometric radiographs of the left and the right side of the mandible before treatment (TI) and after 8 months' treatment (T2) were used to evaluate dental and skeletal changes. Statistical analysis was performed with Intra Class Correlation and Student t-test, according to the study hypothesis. The results showed that the appliance corrected the Class II relationship in an 8-month period by mesial tipping movement of lower permanent first molars. It had little influence on mandibular structure and mandibular length and no influence on maxillary structure and upper molar. To conclude, late treatment of Class II malocclusion with the Herbst appliance was accomplished by means of dentoalveolar changes. These findings suggest that this type of treatment can be used in patients after growth has ceased because the results do not depend upon skeletal changes. PMID- 29248943 TI - Edentulism and its relationship with self-rated health: secondary analysis of the SABE Ecuador 2009 Study. AB - Edentulism is related to a number of conditions in older adults, impacting their overall health status and thus their quality of life and relationship with the environment. At the same time, self-rated health has been shown to be an accurate marker of overall health status. However there is little information on how edentulism relates to self-rated health in older adults of Hispanic origin. The aim of this study was to evaluate the impact of edentulism on self-rated health in older adults. We analyzed data from SABE Ecuador 2009, a cross-sectional study that included a probabilistic representative sample of 5, 235 community-dwelling older adults aged 60 years or older. The dependent variable was self-rated health and the independent variable was edentulism, with age, sex and comorbidities as confounding variables. In order to test the independent association of edentulism with self-rated health, a logistic regression model was fitted. Out of the whole sample, 77. 13% of older adults reported having fair/poor self-rated health. We found an independent association between edentulism and self-rated health with incremental risk according to number of missingteeth, ranging from OR 1. 35 (CI 95% 0. 75 - 2. 43) p 0. 32 for less than 4 missing teeth to OR 1. 88(1. 06 - 3. 32) p 0. 029for more than half of teeth missing. Even though oral health has long been considered separately from the rest of the body and mind, it is clear from our results that oral health is a very important component of global health status in the elderly. PMID- 29248944 TI - Surface wear of resin composites used for Invisalign(r) attachments. AB - Orthodontic treatments with Invisalign(r) require the use of attachments, which are composite resin buttons attached to tooth surfaces. Attachments constitute one of the most powerful tools for improving the efficiency of orthodontic tooth movement. The main purpose of this study was to evaluate surface wear over six months in two resin composites (Filtek Z350 XT, 3MESPE and Amelogen Plus TW, Ultradent Products Inc. ) used for making Invisalign(r) attachments. These composites were selected for their esthetic and mechanical properties. Forty attachments were bonded to the buccal surface of maxillary teeth. Materials were randomized and assigned in a double blind manner. Impressions were taken of the attachments using a preestablished technique immediately after bonding and following 6 months of clinical use. The impressions were examined by Scanning Electron Microscopy (SEM) at 12-fold magnification to identify changes in surface texture and attachment shape. Data were analyzed using Mann-Whitney's test on the overall ranking of detected changes in those variables. Statistically significant differences (P<0. 001) were found for surface wear, with greater changes in Amelogen Plus. Attachment shape did not change significantly in either material (P>0. 05). According to the results of this study, the alteration of the attachment surface during the first six months of treatment depends on the composite used, while attachment shape does not appear to be affected, so the clinical performance of the materials evaluated could be considered acceptable. PMID- 29248946 TI - Elastic Multi-scale Mechanisms: Computation and Biological Evolution. AB - Explanations based on low-level interacting elements are valuable and powerful since they contribute to identify the key mechanisms of biological functions. However, many dynamic systems based on low-level interacting elements with unambiguous, finite, and complete information of initial states generate future states that cannot be predicted, implying an increase of complexity and open ended evolution. Such systems are like Turing machines, that overlap with dynamical systems that cannot halt. We argue that organisms find halting conditions by distorting these mechanisms, creating conditions for a constant creativity that drives evolution. We introduce a modulus of elasticity to measure the changes in these mechanisms in response to changes in the computed environment. We test this concept in a population of predators and predated cells with chemotactic mechanisms and demonstrate how the selection of a given mechanism depends on the entire population. We finally explore this concept in different frameworks and postulate that the identification of predictive mechanisms is only successful with small elasticity modulus. PMID- 29248945 TI - (+/-)-MDMA and its enantiomers: potential therapeutic advantages of R(-)-MDMA. AB - The use of (+/-)-3,4-methylenedioxymethamphetamine ((+/-)-MDMA) as an adjunct to psychotherapy in the treatment of psychiatric and behavioral disorders dates back over 50 years. Only in recent years have controlled and peer-reviewed preclinical and clinical studies lent support to (+/-)-MDMA's hypothesized clinical utility. However, the clinical utility of (+/-)-MDMA is potentially mitigated by a range of demonstrated adverse effects. One potential solution could lie in the individual S(+) and R(-) enantiomers that comprise (+/-)-MDMA. Individual enantiomers of racemic compounds have been employed in psychiatry to improve a drug's therapeutic index. Although no research has explored the individual effects of either S(+)-MDMA or R(-)-MDMA in humans in a controlled manner, preclinical research has examined similarities and differences between the two molecules and the racemic compound. This review addresses information related to the pharmacodynamics, neurotoxicity, physiological effects, and behavioral effects of S(+)-MDMA and R(-)-MDMA that might guide preclinical and clinical research. The current preclinical evidence suggests that R(-)-MDMA may provide an improved therapeutic index, maintaining the therapeutic effects of (+/-)-MDMA with a reduced side effect profile, and that future investigations should investigate the therapeutic potential of R(-)-MDMA. PMID- 29248947 TI - Variation of Metallothionein I and II Gene Expression in the Bank Vole (Clethrionomys glareolus) Under Environmental Zinc and Cadmium Exposure. AB - The main idea of the study was to assess how environmental metal pollution activates defence responses at transcription levels in the tissues of bank voles (Clethrionomys glareolus). For this purpose, the metallothioneine (MT) genes expression (a well known biomarker of exposure and response to various metals) was measured. The real-time PCR method was used for relative quantification of metallothionein I and metallothionein II expressions in the livers, kidneys and testes of bank voles from six populations exposed to different contaminants, mainly zinc, cadmium and iron. The assessment of Zn, Cu and Fe concentrations in the tissues allowed to study the MTs gene expression responses to these metals. ANOVA analysis showed differences between populations in terms of metal concentration in tissues, livers and kidneys. Student T test showed significant differences in metal concentration between unpolluted and polluted sites only for the liver tissue: significantly lower Zn levels and significantly higher Fe levels in the unpolluted sites. Kruskal-Wallis test performed on C T data shows differences in the gene expressions between populations for both MT genes for liver and testes. In the liver metallothionein I gene expression was upregulated in populations considered as more polluted (up to 7.5 higher expression in Miasteczko Slaskie comparing to Mikolajki). Expression of metallothionein II revealed a similar pattern. In kidneys, differences in expression of both MT genes were not that evident. In testes, MT upregulation in polluted sites was noted for metallothionein II. For metallothionein however, we found downregulation in populations from more contaminated sites. The expressions of both MTs were positively influenced by cadmium in kidney (concentration data from the previous study) and zinc and copper in liver, while cadmium had effects only on the liver MT II gene expression. Positive relationship was obtained for lead and metallothionein II expression in the liver. PMID- 29248948 TI - Secondary Metabolites and Their Biological Activity from Aspergillus aculeatus KKU-CT2. AB - The bioactive compounds of the fungus Aspergillus aculeatus strain KKU-CT2, have been studied. The crude extracts from this fungus showed good antimicrobial activity against human pathogens, including Gram-positive and Gram-negative bacteria and yeast-like fungi. Its chemical components were isolated and purified by chromatographic methods. The structures of the secondary metabolites were elucidated by spectroscopic methods (IR, 1H, and 13C NMR). They were identified as ergosterol peroxide (1), secalonic acid D (2), secalonic acid F (3), variecolin (4), variecolactone (5), and ergosterol (6). Compounds 1 and 4-6 are reported for the first time as fungal metabolites from this species. Compound 1 displayed inhibitory effects on HSV-1 with an IC50 of 11.01 MUg/ml. Compounds 3, 4, and 6 exhibited antimalarial activity against Plasmodium falciparum with IC50 of 1.03, 1.47, and 5.31 ug/ml, respectively. Additionally, all compounds from A. aculeatus KKU-CT2 showed unprecedented anticancer activities against human epidermoid carcinoma in the mouth (KB) (compounds 1-6), human breast cancer (MCF 7) (compounds 2, 4, and 5), and human lung cancer cells (NCI-H187) (compounds 1-4 and 6). These results suggest that secondary metabolites from A. aculeatus KKU CT2 might be interesting for further derivatization, targeting diseases such as cancer. PMID- 29248949 TI - Robot-assisted extravesical ureteral reimplantation (revur) for unilateral vesico ureteral reflux in children: results of a multicentric international survey. AB - PURPOSE: This multicentric international retrospective study aimed to report the outcome of robot-assisted extravesical ureteral reimplantation (REVUR) in patients with unilateral vesico-ureteral reflux (VUR). METHODS: The medical records of 55 patients (35 girls, 20 boys) underwent REVUR in four international centers of pediatric robotic surgery for primary unilateral VUR were retrospectively reviewed. Patients' average age was 4.9 years. The preoperative grade of reflux was III in 12.7%, IV in 47.3% and V in 40%. Twenty-six patients (47.3%) presented a loss of renal function preoperatively and 10 (18.1%) had a duplex system. RESULTS: Average robot docking time was 16.2 min (range 5-30). Average total operative time was 92.2 min (range 50-170). No conversions or intra operative complications were recorded. All patients had a bladder Foley catheter for 24 h post-operatively. Average hospital stay was 2 days (range 1-3). Average follow-up length was 28 months (range 9-60). We recorded three (5.4%) postoperative complications: 1 small urinoma resolved spontaneously (II Clavien) and 2 persistent reflux, only one requiring redo-surgery using endoscopic injection (IIIb Clavien). CONCLUSION: REVUR is a safe and effective technique for treatment of primary unilateral VUR. The procedure is easy and fast to perform thanks to the 6 degrees of freedom of robotic arms. The learning curve is short and it is useful to begin the robotics experience with a surgeon expert in robotic surgery as proctor on the 2nd robot console. The high cost and the diameter of instruments remain the main challenges of robotics applications in pediatric urology. PMID- 29248950 TI - A single mitochondrial DNA deletion accurately detects significant prostate cancer in men in the PSA 'grey zone'. AB - PURPOSE: To determine the clinical performance of a blood-based test for clinically significant (CS) prostate cancer (PCa) (grade group >= 2) intended for use in men with prostate serum antigen levels in the 'grey zone' (PSA < 10 ng/ml). The test quantifies a previously described 3.4 kb mitochondrial DNA (mtDNA) deletion. METHODS: In a first prospective study of an MRI-guided re biopsy population (n = 126), the 3.4 kb deletion and 18S rRNA gene were amplified from plasma. A diagnostic threshold was selected from the coordinates of the receiver operating characteristic curve and tested in a second population of men who were (n = 92) biopsy naive when the mtDNA deletion was assayed and for whom those diagnosed with cancer on initial biopsy were treated with radical prostatectomy. RESULTS: The 3.4 kb deletion was a good predictor of CS PCa in the image-guided re-biopsy population [AUC 0.84, (95% CI 0.73-0.95)] and the selected threshold corresponded to a sensitivity of 87% [95% CI, 70-96%], specificity of 68% [95% CI, 47-85%] and negative predictive value (NPV) of 97%. Applying this threshold to the second population showed this deletion to be a strong predictor of CS cancer [AUC 0.98, (95% CI 0.94-1.02)], independent of PSA or age [sensitivity 100% (95% CI, 93-100%), specificity 90% (95%CI 73-98%) and NPV 100%]. CONCLUSION: The 3.4 kb deletion in plasma is an accurate predictor of CS cancer for men in the PSA 'grey zone'. Used in advance of biopsy for improved patient selection, this deletion may reduce the number of biopsies needed to diagnose CS prostate cancers. PMID- 29248951 TI - Early prelingual auditory development in Italian infants and toddlers analysed through the Italian version of the Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS). AB - PURPOSE: To evaluate the reliability and validity of the Italian version of the Infant-Toddler Meaningful Auditory Integration Scale (I-IT-MAIS), and to assess the normal trajectory of early prelingual auditory (EPLAD) development from birth to 24 months in a group of normal-hearing Italian children using the I-IT-MAIS. METHODS: The study consisted of four phases: item generation, reliability analysis, assessment of the normal trajectory for EPLAD, and validity analysis. A group of 120 normal-hearing children and a group of 31 deaf children wearing hearing aids and on a waiting list for cochlear implantation were enrolled. All the parents completed the I-IT-MAIS. Sixty of them completed the I-IT-MAIS twice, 2 weeks apart, for test-retest reliability analysis. The I-IT-MAIS scores were used to assess the normal trajectory of EPLAD development from birth to 24 months in normal-hearing children. For criterion validity analysis, the I-IT-MAIS scores were correlated with production of infant scale evaluation (PRISE) scores in 60 normal-hearing children. For discriminant validity analysis, the I-IT-MAIS scores obtained in normal and deaf children were compared. RESULTS: Internal consistency of I-IT-MAIS was satisfactory as well as individual item reliability, test-retest reliability, and discriminant validity. EPLAD development in normal-hearing Italian-speaking children was evaluated. As far as the criterion validity of the I-IT-MAIS is concerned, a strong correlation between I-IT-MAIS and PRISE scores was found. CONCLUSION: I-IT-MAIS is reliable and valid. Its application is recommended for clinical practice and outcome research. PMID- 29248952 TI - A comprehensive care program achieves high remission rates in rheumatoid arthritis in a middle-income setting. Experience of a Center of Excellence in Colombia. AB - Management of rheumatoid arthritis (RA) in many Latin-American countries is impaired by fragmentation and scarce healthcare provision, resulting in obstacles to access, diagnosis, and treatment, and consequently in poor health outcomes. The aim of this study is to propose a comprehensive care program as a model to provide healthcare to RA patients receiving synthetic DMARDs in a Colombian setting by describing the model and its results. Health outcomes were prospectively collected in all patients entering the program. By protocol, patients are followed up during 24 months using a treat-to-target strategy with a patient-centered care (PCC) model, meaning that a patient should be seen by rheumatologist, physical and occupational therapist, physiatrist, nutritionist and psychologist, at least three times a year according to disease activity by DAS28. Otherwise, patients receive standard therapy. The incidence of remission and low disease activity (LDA) was calculated by periods of follow-up. A total of 968 patients entered the program from January 2015 to December 2016; 80.2% were women. At baseline, 41% of patients were in remission, 17% in LDA and 42% in MDS/SDA. At 24 months of follow-up, 66% were in remission, 18% in LDA and only 16% in MDS/SDA. Regarding DAS28, the mean at the beginning of the time analysis was 3.1 (SD 1.0) and after 24 months it was 2.4 (SD 0.7), showing a statistically significant improvement (p < 0.001). In all patients, the reduction of disease activity was 65% (95% CI, 58-71). Patients entering the PCC program benefited from a global improvement in disease activity in terms of DAS28. PMID- 29248953 TI - Inability of DNAzymes to cleave RNA in vivo is due to limited Mg[Formula: see text] concentration in cells. AB - Sequence specific cleavage of RNA can be achieved by hammerhead ribozymes as well as DNAzymes. They comprise a catalytic core sequence flanked by regions that form double strands with complementary RNA. While different types of ribozymes have been discovered in natural organisms, DNAzymes derive from in vitro selection. Both have been used for therapeutic down-regulation of harmful proteins by reducing drastically the corresponding mRNA concentration. A priori DNAzymes appear advantageous because of the higher haemolytic stability and better cost effectiveness when compared to RNA. In the present work the 10-23 DNAzyme was applied to knockdown expression of the prion protein (PrP), the sole causative agent of transmissible spongiform encephalopathies. We selected accessible target sequences on the PrP mRNA based on a sequential folding algorithm. Very high effectivity of DNAzymes was found for cleavage of RNA in vitro, but activity in neuroblastoma cells was very low. However, siRNA directed to the identical target sequences reduced expression of PrP in the same cell type. According to our analysis, three Mg[Formula: see text] bind cooperatively to the DNAzyme to exert full activity. However, free ATP binds the Mg[Formula: see text] ions more strongly and already stoichiometric amounts of Mg[Formula: see text] and ATP inhibited the activity of DNAzymes drastically. In contrast, natural ribozymes form three-dimensional structures close to the cleavage site that stabilize the active conformation at much lower Mg[Formula: see text] concentrations. For DNAzymes, however, a similar stabilization is not known and therefore DNAzymes need higher free Mg[Formula: see text] concentrations than that available inside the cell. PMID- 29248954 TI - Methylmercury Biogeochemistry in Freshwater Ecosystems: A Review Focusing on DOM and Photodemethylation. AB - Mercury contamination is a growing concern for freshwater food webs in ecosystems without point sources of mercury. Methylmercury (MeHg) is of particular concern, as this is the form of mercury that crosses the blood-brain barrier and is neurotoxic to organisms. Wetlands and benthic sediments have high organic content and low oxygen availability. Anaerobic bacteria drive the metabolic function in these ecosystems and subsequently can methylate mercury. The bioavailability of MeHg is controlled by physicochemical characteristics such as pH, binding affinities, and dissolved organic matter (DOM). Similarly, photodemethylation is influenced by similar characteristics and thereby the two processes should be studied in tandem. The degradation of MeHg through photochemistry is an effective destruction mechanism in freshwater lakes. This review will highlight the uncertainties and known effects of DOM on subsequent photoreactions that lead to the occurrence of mercury photodemethylation and reduction in mercury bioavailability in freshwater ecosystems. PMID- 29248955 TI - Lead Concentrations in Soils and Some Wild Plant Species Along Two Busy Roads in Pakistan. AB - This study assessed the level of Pb in soil and five wild plant species (Calotropis procera, Datura alba, Parthenium hysterophorus, Cenchrus ciliaris and Ricinus communis) during all the four seasons. Two busy roads varying in age and traffic volume were selected i.e., Faisalabad-Sargodha road (FSR) and Pindi Bhattian to Lillah (M-2) in the Punjab, Pakistan. Results showed raised levels of Pb in both plants and soil samples along both roads. The range of Pb concentration in plants was 0.08-3.98 and 1.95-4.74 mg kg- 1 for soil. Higher Pb contamination was recorded along FSR road as compared to M-2. Among seasons, the higher Pb concentration was found during summer, probably due to very high temperature. Among all the plants studied, Calotropis procera accumulated the highest level (3.98 mg kg- 1 dry wt.) of Pb; Thus, it can be used as good biomonitor/phytoremediator at Pb contaminated areas. PMID- 29248956 TI - Human c-SRC kinase (CSK) overexpression makes T cells dummy. AB - Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide-MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the majority of the adverse events are due to TCR recognition of the wrong target, we tested if blocking the signalling would affect the binding. By over-expressing the c-SRC kinase (CSK), a negative regulator of LCK, in redirected T cells, we showed that peripheral blood T cells inhibited anti-CD3/anti-CD28-induced phosphorylation of ERK, whereas TCR proximal signalling was not affected. Similarly, overexpression of CSK together with a therapeutic TCR prevented pMHC-induced ERK phosphorylation. Downstream effector functions were also almost completely blocked, including pMHC-induced IL-2 release, degranulation and, most importantly, target cell killing. The lack of effector functions contrasted with the unaffected TCR expression, pMHC recognition, and membrane exchange activity (trogocytosis). Therefore, co-expression of CSK with a therapeutic TCR did not compromise target recognition and binding, but rendered T cells incapable of executing their effector functions. Consequently, we named these redirected T cells "dummy T cells" and propose to use them for safety validation of new TCRs prior to therapy. PMID- 29248957 TI - Ancestry inference of 96 population samples using microhaplotypes. AB - Microhaplotypes have become a new type of forensic marker with a great ability to identify and deconvolute mixtures because massively parallel sequencing (MPS) allows the alleles (haplotypes) of the multi-SNP loci to be determined directly for an individual. As originally defined, a microhaplotype locus is a short segment of DNA with two or more SNPs defining three or more haplotypes. The length is short enough, less than about 300 bp, that the read length of current MPS technology can produce a phase-known sequence of each chromosome of an individual. As part of the discovery phase of our studies, data on 130 microhaplotype loci with estimates of haplotype frequency data on 83 populations have been published. To provide a better picture of global allele frequency variation, we have now tested 13 more populations for 65 of the microhaplotype loci from among those with higher levels of inter-population gene frequency variation, including 8 loci not previously published. These loci provide clear distinctions among 6 biogeographic regions and provide some information distinguishing up to 10 clusters of populations. PMID- 29248958 TI - Reliability of the Greulich and Pyle method for chronological age estimation and age majority prediction in a Spanish sample. AB - Estimating the forensic age of living individuals is ever more important in forensic practice, due to the ongoing increase of migratory flows, amongst other causes. Using the Greulich and Pyle method on a sample of 1150 individuals of the Spanish population (n = 560, 0-18 years for girls, and n = 590, 0-19 years for boys), the mean difference between the bone and chronological ages was obtained: 0.01 years (- 0.81, + 0.92) for girls and 0.33 years (- 1.15, + 0.34) for boys. For a same class of age and sex, the inherent variability was also evaluated: [Formula: see text] (0.41-1.25) for girls and [Formula: see text]years (0.36 1.76) for boys. To minimise systematic errors with regard to the reference population, adjustment factors are proposed for each age and sex. A sequential classification criterion based on decision trees is postulated to improve reliability in the prediction of maturity. Implementation of the decision criterion in three categories enables the doubtful individuals to be separated into the category of "undetermined" and to satisfactorily classify in the categories of "mature" and "under age": 0.96 (0.86-0.99) specificity; 1.00 (0.92 1.00) specificity; and 1.00 (0.92-1.00) predictive value. PMID- 29248959 TI - The third molar maturity index in indicating the legal adult age in Kosovar population. AB - The third molar tooth, known as the "wisdom tooth," is the only tooth that can be used to determine legal adult age. This study aimed to test the accuracy of Cameriere's third molar maturity index (I3M) in assessing the legal adult age of 18 years in the Kosovar population. Orthopantomographs (OPTs) of 1221 healthy living Kosovar individuals, aged between 12 and 23 years and with no congenital or developmental anomalies, were analyzed. Intra-class correlation coefficients were 0.858 (95% CI, 0.786 to 0.906) and 0.852 (95% CI, 0.779 to 0.903) for intra rater and for inter-rater agreement, respectively. The sample was divided into training dataset (800 OPTs) and test dataset (421 OPTs). The training dataset was used to generate the logistic regression model, while the test dataset was used to study the performance of the model. I3M and gender as independent variables and adult age (>= 18 years) or minor age (< 18 years) as the dependent variable were used for logistic regression analysis. The receiver operating curve (ROC) analysis was used to determine the specific cut-off value of I3M for predicting adult age. The results showed that only I3M statistically significantly contributed to discriminating adults and minors. ROC analysis showed that the cut off value of I3M < 0.08 was the best in discriminating adults and minors. An analysis of the test dataset (421 OPTs) showed that as I3M decreased the age gradually increased. The performance of the cut-off value of I3M < 0.08, to discriminate between adults and minors, was analyzed by contingency tables for both sexes. In males, the accurate classification (Acc) was 0.968 (95% CI, 0.926 to 0.985), the sensitivity (Se) was 0.962 (95% CI, 0.925 to 0.978), and the specificity (Sp) was 0.976 (95% CI, 0.929 to 0.995). The Bayes post-test probability (Bayes PTP) was 0.975 (95% CI, 0.905 to 1.00). In females, Acc was 0.909 (95% CI, 0.870 to 0.917), Se and Sp were 0.826 (95% CI, 0.787 to 0.834) and 0.991 (95% CI, 0.953 to 1.00) respectively, while Bayes PTP was 0.989 (95% CI, 0.926 to 1.00). Our data support the usefulness of I3M < 0.08 to indicate legal adult age in a Kosovar population. PMID- 29248960 TI - Predictors of the need for pacemaker implantation after the Cox maze IV procedure for atrial fibrillation. AB - PURPOSE: The Cox maze IV (CMIV) procedure is being used increasingly frequently for surgical ablation of atrial fibrillation (AF). This study aimed to identify the risk factors of the need for postoperative pacemaker implantation (PMI) after CMIV. METHODS: Preoperative, intraoperative, and postoperative data were retrospectively collected from 67 consecutive patients who underwent CMIV at our institution; 7 (10.4%) required PMI (as a treatment of brady AF or sick sinus syndrome). RESULTS: Patients who needed PMI tended to have lower preoperative heart rates than those who did not on a 12-lead electrocardiogram (ECG; 68.7 +/- 11.6 vs. 79.1 +/- 18.5 bpm, p = 0.07) and a 24-h ECG (94,772 +/- 9800 vs. 109,854 +/- 19,078 beats/day, p = 0.03). A multivariate analysis identified a low amplitude of the fibrillatory wave on preoperative ECG as a risk factor of PMI necessity after CMIV [odds ratio = 14.7; 95% confidence interval (CI) 1.9-324.7; p = 0.007] and internal use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs/ARBs) as a negative risk factor (odds ratio = 0.16; 95% CI 0.02-0.99; p = 0.049). CONCLUSIONS: A low amplitude of the fibrillatory wave was identified as a risk factor of PMI necessity, whereas the internal use of ACEIs/ARBs diminished the need for PMI. These factors should be considered before CMIV is performed. PMID- 29248962 TI - Effects of bilateral pallidal deep brain stimulation on chorea after pulmonary thromboendarterectomy with deep hypothermia and circulatory arrest: a case report. AB - A 41-year-old man was diagnosed with chronic pulmonary thromboembolism and underwent pulmonary thromboendarterectomy (PTE) with deep hypothermia and circulatory arrest. Five days after the operation, chorea emerged in the lower extremities. The patient was referred to our hospital for disabling chorea 16 years after PTE. Neurological examination revealed choreatic movements in the four extremities. Brain magnetic resonance images indicated atrophy in the bilateral head of the caudate nuclei. The patient underwent deep brain stimulation (DBS) of the bilateral globus pallidus interna (GPi). Continuous GPi DBS diminished the choreatic movements. GPi-DBS may be a treatment option for sustained choreatic movements after PTE. PMID- 29248961 TI - Multilayered dominance hierarchy in plant self-incompatibility. AB - KEY MESSAGE: Epigenetic dominance modifier. In polymorphic loci, complex genetic dominance relationships between alleles are often observed. In plants, control of self-incompatibility (SI) expression via allelic interactions in the Brassicaceae is the best-known example of such mechanisms. Here, with emphasis on two recently published papers, we review the progress toward understanding the dominance regulatory mechanism of SI in the Brassicaceae. Multiple small RNA genes linked to the Self-incompatibility (S) locus were found in both Brassica and Arabidopsis genera. Mono-allelic gene expression of the male determinant of SI, SP11/SCR, from a dominant S-allele is under epigenetic control by such small RNA genes. Possible evolutionary trajectories leading to the formation of multilayered dominance hierarchy in Brassicaceae are discussed. We also identify some remaining questions for future studies. PMID- 29248963 TI - Effects of occlusal cavity configuration on 3D shrinkage vectors in a flowable composite. AB - OBJECTIVE: The objective of this study was to investigate the effects of cavity configuration on the shrinkage vectors of a flowable resin-based composite (RBC) placed in occlusal cavities. MATERIALS AND METHODS: Twenty-seven human molars were divided into three groups (n = 9) according to cavity configuration: "adhesive," "diverging," and "cylindrical." The "adhesive" cavity represented beveled enamel margins and occlusally converging walls, the "diverging" cavity had occlusally diverging walls, and the "cylindrical" cavity had parallel walls (diameter = 6 mm); all cavities were 3 mm deep. Each prepared cavity was treated with a self-etch adhesive (Adper Easy Bond, 3 M ESPE) and filled with a flowable RBC (Tetric EvoFlow, Ivoclar Vivadent) to which had been added 2 wt% traceable glass beads. Two micro-CT scans were performed on each sample (uncured and cured). The scans were then subjected to medical image registration for shrinkage vector calculation. Shrinkage vectors were evaluated three-dimensionally (3D) and in the axial direction. RESULTS: The "adhesive" group had the greatest mean 3D shrinkage vector lengths and upward movement (31.1 +/- 10.9 MUm; - 13.7 +/- 12.1 MUm), followed by the "diverging" (27.4 +/- 12.1 MUm; - 5.7 +/- 17.2 MUm) and "cylindrical" groups (23.3 +/- 11.1 MUm; - 3.7 +/- 13.6 MUm); all groups differed significantly (p < 0.001 for each comparison, one-way ANOVA, Tamhane's T2). CONCLUSION: The values and direction of the shrinkage vectors as well as interfacial debonding varied according to the cavity configuration. CLINICAL RELEVANCE: Cavity configuration in terms of wall orientation and beveling of enamel margin influences the shrinkage pattern of composites. PMID- 29248964 TI - Prevention of hospital infections by intervention and training (PROHIBIT): results of a pan-European cluster-randomized multicentre study to reduce central venous catheter-related bloodstream infections. AB - PURPOSE: To test the effectiveness of a central venous catheter (CVC) insertion strategy and a hand hygiene (HH) improvement strategy to prevent central venous catheter-related bloodstream infections (CRBSI) in European intensive care units (ICUs), measuring both process and outcome indicators. METHODS: Adult ICUs from 14 hospitals in 11 European countries participated in this stepped-wedge cluster randomised controlled multicentre intervention study. After a 6 month baseline, three hospitals were randomised to one of three interventions every quarter: (1) CVC insertion strategy (CVCi); (2) HH promotion strategy (HHi); and (3) both interventions combined (COMBi). Primary outcome was prospective CRBSI incidence density. Secondary outcomes were a CVC insertion score and HH compliance. RESULTS: Overall 25,348 patients with 35,831 CVCs were included. CRBSI incidence density decreased from 2.4/1000 CVC-days at baseline to 0.9/1000 (p < 0.0001). When adjusted for patient and CVC characteristics all three interventions significantly reduced CRBSI incidence density. When additionally adjusted for the baseline decreasing trend, the HHi and COMBi arms were still effective. CVC insertion scores and HH compliance increased significantly with all three interventions. CONCLUSIONS: This study demonstrates that multimodal prevention strategies aiming at improving CVC insertion practice and HH reduce CRBSI in diverse European ICUs. Compliance explained CRBSI reduction and future quality improvement studies should encourage measuring process indicators. PMID- 29248965 TI - Effectiveness of olanzapine in patients who fail therapy with aprepitant while receiving highly emetogenic chemotherapy. AB - Chemotherapy-induced nausea-vomiting (CINV) compromises the quality of life of patients with cancer. We present data on the effectiveness of olanzapine after failure of aprepitant in patients receiving highly emetogenic chemotherapy (HEC). A single-center prospective study was conducted, where patients >= 18 years who failed aprepitant, palonosetron, dexamethasone (APD) received olanzapine, palonosetron and dexamethasone (OPD) in the subsequent cycle of HEC. Failure of APD was defined as occurrence of >= grade 2 acute and/or delayed nausea +/- vomiting. Response rates were compared with what was achieved in their previous cycle with the use of APD in the acute (0-24 h), delayed (24-120 h) and overall (0-120 h) periods after the start of HEC. Impact on life was assessed using the MD Anderson Symptom Inventory (MDASI). Fifty-five patients failed APD and received OPD in the subsequent cycle; 54 were evaluable for response. Complete response rate for OPD versus APD is 80 versus 20% (acute period), 90 versus 18% (delayed period) and 74 versus 5% (overall period), and no nausea rate for OPD versus APD is 57 versus 13% (acute), 59 versus 15% (delayed) and 48 versus 0% (overall period), p < 0.001 for all comparisons. MDASI scores showed significant improvement after switching to OPD. A mild increase in drowsiness noted in patients receiving OPD did not affect daily life in most patients. In patients receiving HEC and failing CINV prophylaxis with APD, switching to OPD regimen in the subsequent cycle greatly improves control of vomiting, increases "no nausea" rates and significantly reduces symptom severity scores. PMID- 29248966 TI - Comparison of superb micro-vascular imaging (SMI) and conventional Doppler imaging techniques for evaluating testicular blood flow. AB - PURPOSE: Superb micro-vascular imaging (SMI) is a new blood flow (BF) technique recently developed to outface the limitations of conventional Doppler imaging techniques (CDIT). SMI can observe micro-vascular BF and low-velocity BF. SMI is available in two modes as color SMI (cSMI) and monochrome SMI (mSMI). To evaluate testicular BF, we have compared color Doppler (CD), power Doppler (PD), cSMI, and mSMI techniques. PATIENTS AND METHODS: A total of 156 patients (310 testes) were included in the study. We evaluated BF in the testes via CD, PD, cSMI, and mSMI techniques in a heterogenous patient group. Doppler examination was performed by observing the whole testis parenchyma within the examination area at the testicular hilus level at all examinations. Spot and linear flow color encoding determined in testis parenchyma were separately counted for every examination. RESULTS: SMI was found to be superior in all age groups and testis volumes for showing the BF. When we sequenced the examinations to show the BF in testis according to their priorities, it was found that mSMI > cSMI > PD > CD. As the testis volume decreases, a significant increase is observed in mSMI when compared to other examinations in showing vascularity in pediatric age groups, in cases diagnosed with undescended testis, and in cases that underwent surgery for undescended testis. CONCLUSIONS: SMI renders more detailed vascular information on BF in the testes than CDIT. In particular, as the testis volume decreases, the priority of SMI showing BF increases. SMI should be a part of vascular examination in pediatric patients with small testis volume. PMID- 29248967 TI - Species A rotaviruses isolated from hospitalized patients over 5 years of age in Kolkata, India, in 2012/13. AB - In hospital-based diarrhoeal disease surveillance at Infectious Diseases & Beliaghata-General Hospital (May-2012 to April-2013), Kolkata, India, stool samples were collected from patients < 5 years (n = 830) and > 5 years of age (n = 728) hospitalized with diarrhea. Group-A rotavirus (GARV) was identified by ELISA followed by multiplex RT-PCR. In children < 5 years of age, 53.4% of the samples were positive for GARV. In patients > 5 years to 90 years old, only 6.04% (n = 44) tested positive for GARV. G2P[4] strains (n = 16 [36.36%]) were the most prevalent, followed by G9P[4] strains (n = 13 [29.54%]), while P[4]-(n = 30 [68.18%]) was most prevalent among the P genotypes. The GARV strains G2, G9 and P[4] detected in adults clustered together in the phylogenetic tree with the GARV strains identified in children (< 5 years) during the same period. Rotavirus positivity was high among female patients (75%), suggesting that caregivers (mother/grandmother/older-siblings) may get infected through young children or may act as carriers for transmission. PMID- 29248968 TI - Contradictory intrahepatic immune responses activated in high-load hepatitis C virus livers compared with low-load livers. AB - We found a HLA class II histocompatibility antigen gene, DQ alpha 1 chain (HLA DQA1), that was expressed more than 9-fold higher in high-load hepatitis C virus (HCV) livers than low-load HCV livers using transcriptomics of chronic HCV infected livers. To further investigate this finding, we examined which cells were positive for HLA-DQA1 and what liver immune responses were different between HCV-high and -low livers. HLA-DQA1-positive cells were significantly increased in the HCV-high group, and most positive cells were identified as non-parenchymal sinusoid cells and lymphocytic infiltrates in the portal area. Parenchymal hepatocytes were negative for HLA-DQA1. HLA-DQA1-positive cells in the liver sinusoid were positive for CD68 (macrophages or Kupffer cells); those in the lymphocytic infiltrates were positive for CD20 (B cells) or CD3 (T cells). mRNA levels of antigen-presenting cell (APC) markers such as CD68 and CD11c were significantly upregulated in the HCV-high group and were correlated with HLA-DQA mRNA levels. CD8B mRNA (CD8+ T cells) was upregulated in both HCV-positive livers compared with HCV-negative livers, whereas CD154 mRNA (CD4+ T helper cell) was upregulated in the HCV-high group compared with the HCV-low group. The immune regulatory molecules FOXP3 mRNA (regulatory T cell, T reg) and programmed cell death ligand-1 (PD-L1) mRNA were significantly increased in the HCV-high group. HCV-high livers had two molecular immune responses: increased APC numbers and adaptive immunity and the induction of immune tolerance. The local hepatic imbalance of contradictory immune responses might be responsible for high HCV loads. PMID- 29248970 TI - A Study of the Longitudinal Patterns of Stimulant and Amyl Nitrite Use and Sexual Behavior Pre- and Post-HIV Seroconversion Among MSM. AB - The use of stimulant drugs alone or in combination with amyl nitrites (stimulant/nitrites) has been associated with higher rates of risky sexual behavior and predictive of HIV infection among men who have sex with men. However, the temporal pattern of stimulant/nitrite use pre- and post seroconversion has not been well established. This study assessed changes in stimulant/nitrite use and risky sexual behavior among seroconverting MSM over time. Data were collected in the Baltimore-Washington, DC; Pittsburgh; Chicago; and Los Angeles sites of the Multicenter AIDS Cohort Study (MACS), a longitudinal study of the natural history of HIV infection among MSM. We used propensity scores to select 1044 MSM from 7087 MACS participants composed of 348 seroconverting, 348 seronegative, and 348 seroprevalent participants matched on demographics, recruitment cohort, and study visits. We centered up to four-years of semi-annual data around the seroconversion visit of the seroconverting case within each matched group of participants. Mixed effects regressions estimated the effects of serostatus, recruitment cohort, and time on self-reported stimulant/nitrite use, numbers of male intercourse partners, and numbers of unprotected receptive anal intercourse (URAI) partners. Covariates included demographics, binge drinking, and marijuana use. Seroconverters had the highest odds of stimulant/inhaled nitrite use (AOR 10.3, CI 4.8-22.0), incident rates of intercourse (IRR 1.6, CI 1.3-2.1), and URAI partners (IRR 5.1, CI 3.5-7.3). All participants decreased drug use and sexual risk behavior over time. However, the decreases were largest for seroconverters who nevertheless maintained the highest rates of stimulant/nitrite use and sexual risk. Cohort-related effects were associated with sharp reductions in stimulant/nitrite use and URAI in the early 1990s that rebounded considerably within the first decade of the 2000s. Although all participants decreased risky sexual behavior and stimulant and/or nitrite use over time, seroconverters had the largest decreases. There was no evidence for abrupt or substantial increases in drug use or risky sex post-seroconversion. However, there was substantial variation at the individual level, with the factors underlying this variation not well understood and worth further study. Moreover, stimulant/nitrite use and risky sexual behavior appear to have been strongly influenced by contextual historical and socio-cultural effects. The manner in which contextual factors influence individual behavior is also not well understood and also warrants further study. PMID- 29248969 TI - Somatic embryogenesis of muskmelon (Cucumis melo L.) and genetic stability assessment of regenerants using flow cytometry and ISSR markers. AB - A new protocol for in vitro regeneration through direct somatic embryogenesis for two muskmelon cultivars (Cucumis melo L., "Mashhadi" and "Eivanaki") is reported. Somatic embryos were obtained culturing 4- and 8-day-old cotyledons, seeds, and hypocotyls on Murashige and Skoog medium supplemented with three different hormonal combinations never tested so far for melon (naphthoxyacetic acid (NOA) + thidiazuron (TDZ), NOA + 6-banzylaminopurine (BAP), and 2,4-dichlorophenoxyacetic acid (2,4-D) + N-(2-chloro-4-pyridyl)-N'-phenylurea (4-CPPU)). Results were compared with those obtained when explants were cultivated in the presence of 2,4 D + BAP, previously used on melon. Embryogenesis occurred more successfully in 4 day-old cotyledons and seeds than hypocotyls and 8-day-old cotyledons. The best result was achieved with NOA + BAP. Genotypes significantly affected embryogenesis. The number of embryos in "Eivanaki" was significantly higher than that in "Mashhadi." Embryo proliferation when explants were maintained in jars (9.3%) was found to be higher compared to that in petri dishes. For the first time, genetic stability of regenerated melon plants was evaluated using inter simple sequence repeat markers. Polymerase chain reaction (PCR) products demonstrated a total of 102 well-resolved bands, and regenerants were 93% similar compared to the mother plant. Somaclonal changes during embryogenesis were evaluated by flow cytometry, showing 91% of the same patterns in regenerated plants. The results suggest that the new hormone components are effective when applied for in vitro embryogenesis of muskmelon as they show a high frequency in regeneration and genetic homogeneity. PMID- 29248971 TI - Connecting Corrections and HIV Care: Building a Care Coordination Program for Recently Incarcerated Persons Living with HIV in Virginia. AB - Incarcerated individuals are disproportionately affected by HIV and often experience risk factors associated with poor maintenance of HIV care upon release. Therefore, the transition period from incarceration to the community is a particularly critical time for persons living with HIV to ensure continuity of care and treatment. By building relationships with Department of Corrections staff and community partners, the Virginia Department of Health developed a program to link recently incarcerated persons living with HIV to care and treatment immediately upon release from correctional facilities across Virginia. Findings show that clients served by the program have better outcomes along the HIV continuum of care than the overall population living with HIV in Virginia. This paper describes the development, implementation and health outcomes of the Care Coordination program for recently incarcerated persons living with HIV in Virginia. PMID- 29248973 TI - Alteration of serum immunoglobins, C-reactive protein, vitamin D, and electrolyte by atenolol and amlodipine in stress-induced hypertensive rats. AB - The present study is designed for the assessment of various pathological changes like immunoglobins, C-reactive protein, vitamin D, sodium, potassium, calcium in stress-induced hypertensive rats. Albino Wistar rats of sex male were grouped into six. Each group consists of six animals. Groups were Group I (normal control), Group II (disease control), Group III (amlodipine control), Group IV (atenolol control), Group V (amlodipine treatment), and Group VI (atenolol treatment). Group II, V, and VI animals exposed to regular stress by placing them in cages individually and giving foot electric shocks (1 mA, 50 ms duration with 0.5-1 min of intervals regulated randomly by a computer) along with forced swimming (30 min) in order to induce hypertension in rats. This stress was given two times daily (morning and evening) for regular 15 days. Induction of hypertension was confirmed by measuring the tail arterial pressure of blood and angiotensin II. For next 1 month, Group III and V animals are treated with amlodipine with 1 mg/kg, s.c. dose while Group IV and VI animals were given 10 mg/kg, s.c. the dose of atenolol once daily. At the end of the experimental work, blood collected, rats sacrificed, and serum separated. Serum sodium, potassium, immunoglobins, C-reactive protein, vitamin D, and calcium were measured by semi auto-analyzer. Stress-induced hypertension in rats produced altered serum sodium, potassium, immunoglobins, C-reactive protein, vitamin D, and calcium level which is restored by atenolol. Administration of amlodipine in animals without hypertension shows alteration in the level of immunoglobins, calcium, vitamin D, and electrolytes. PMID- 29248972 TI - Pharmacological targeting of HSP90 with 17-AAG induces apoptosis of myogenic cells through activation of the intrinsic pathway. AB - We have shown that pharmacological inhibition of HSP90 ATPase activity induces apoptosis of myoblasts during their differentiation. However, the signaling pathways remain not fully characterized. We report that pharmacological targeting of HSP90 with 17-AAG activates the intrinsic pathway including caspase-dependent and caspase-independent pathways. 17-AAG induces the typical apoptotic phenotypes including PARP cleavage, chromatin condensation, and nuclear fragmentation with mitochondrial release of cytochrome c, Smac/DIABLO, procaspase-9 processing, and caspase-3 activation. AIF and EndoG redistribute from the mitochondria into the cytosol and are partially translocated to the nucleus in 17-AAG-treated cells. These results suggest that caspase-dependent and caspase-independent pathways should be considered in apoptosis of myogenic cells induced by inhibition of HSP90 ATPase activity. PMID- 29248974 TI - Management and outcome of children and adolescents with non-medulloblastoma CNS embryonal tumors in Spain: room for improvement in standards of care. AB - Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0-21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0-14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0-12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7 9.3). 3-year PFS was 31.9% (95% CI 17-47%) and OS 35.1% (95% CI 20-50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients. PMID- 29248976 TI - Hoopoe males experience intra-seasonal while females experience inter-seasonal reproductive costs. AB - Reproductive and survival costs due to reproductive investment are a central element for the evolution of life histories. Both intra- (reduction of reproductive performance of second brood due to investment in first brood) and inter-seasonal costs (reduction of reproductive performance or annual survival due to reproductive investment in preceding year) may appear in multiple breeding species. Knowledge about how trade-offs within and between seasons shape individual trajectories and influence fitness are crucial in life-history evolution, yet intra- and inter-seasonal reproductive costs are rarely analysed simultaneously. We investigated sex-specific differences in intra- and inter seasonal reproductive and survival costs in response to previous reproductive effort in a monogamous, double-brooding bird, the hoopoe (Upupa epops), accounting for heterogeneity in individual and annual quality. Intra-seasonal reproductive costs were detected in males and inter-seasonal reproductive and survival costs were detected in females. In males, the probability of being a successful double breeder was negatively correlated with the number of hatchlings produced in the first brood. In females, the number of fledglings raised in the first brood was negatively correlated with the reproductive effort in the preceding season. Female annual survival was also negatively influenced by the number of broods produced in the previous reproductive season. Most of these reproductive costs were detected only in years with low productivity, suggesting that costs become evident when environmental conditions are harsh. Our results illustrate how different investment in current vs. future reproduction and survival shape different life-history strategies in males and females of a monogamous bird species. PMID- 29248977 TI - Treatment of extraarticular knee extension contracture secondary to prolonged external fixation by a modified Judet quadricepsplasty technique. AB - : The goal of this study is to evaluate the functional results of the modified Judet quadricepsplasty for a knee extension contracture secondary to prolonged external fixation. This is a retrospective study of 31 patients with the diagnosis of an extraarticular knee extension contracture who had prolonged external fixation of the femur. Functional assessment was conducted after a minimum follow-up of 1 year. After performing the functional assessment, according to the Judet scale, 51% of the 31 patients had good results and 19.35% (6 cases) showed excellent results. The improvement in mobility from pre operative to post-operative range of motion was significant. The performance of the technique, following the authors' described steps and making the subsequent modifications, allowed for partial knee mobility restoration, which significantly improved the patients' functional status. LEVEL OF EVIDENCE: IV. Series of cases. PMID- 29248975 TI - A meta-analysis of obstructive sleep apnea in patients with cerebrovascular disease. AB - BACKGROUND: There is increasing evidence that there is a direct relationship between obstructive sleep apnea (OSA) and cerebrovascular (CV) disease. This meta analysis includes prospective cohorts and cross-sectional studies. It determines the prevalence of OSA among patients with CV disease and also looks for the risk o f cerebrovascular events among patients with OSA. METHOD: We conducted a computerized literature search in the databases of Medline, Embase, Wanfang, CNKI, Wiley Online Library, and CINAHL (date till April 2017). The random effects model was used to pool the hazard ratio (HR) and effect sizes (ES). Heterogeneity, subgroup, sensitivity analyses, and publication bias were performed. RESULT: Fifty-eight studies involving 3 million patients/participants were included. The pooled HR of 15 prospective cohort studies indicated a significant association between OSA and the risk of CV disease after adjustment confounding factors (HR 1.94; 95% CI 1.31-2.89; P = 0.001), and OSA is present in up to 58.8% of patients with CV disease after pooling the remaining 43 studies. CONCLUSIONS: OSA is very common in patients with CV disease. Similarly, patients with OSA are prone to have CV disease. PMID- 29248978 TI - Antileishmanial activity of a naphthoquinone derivate against promastigote and amastigote stages of Leishmania infantum and Leishmania amazonensis and its mechanism of action against L. amazonensis species. AB - Leishmaniasis has become a significant public health issue in several countries in the world. New products have been identified to treat against the disease; however, toxicity and/or high cost is a limitation. The present work evaluated the antileishmanial activity of a new naphthoquinone derivate, Flau-A [2-(2,3,4 tri-O-acetyl-6-deoxy-beta-L-galactopyranosyloxy)-1,4-naphthoquinone], against promastigote and amastigote-like stages of Leishmania amazonensis and L. infantum. In addition, the cytotoxicity in murine macrophages and human red cells was also investigated. The mechanism of action of Flau-A was assessed in L. amazonensis as well as its efficacy in treating infected macrophages and inhibiting infection of pretreated parasites. Results showed that Flau-A was effective against promastigotes and amastigote-like forms of both parasite species, as well as showed low toxicity in mammalian cells. Results also highlighted the morphological and biochemical alterations induced by Flau-A in L. amazonensis, including loss of mitochondrial membrane potential, as well as increased reactive oxygen species production, cell shrinkage, and alteration of the plasma membrane integrity. The present study demonstrates for the first time the antileishmanial activity of Flau-A against two Leishmania species and suggests that the mitochondria of the parasites may be the main target organelle. Data shown here encourages the use of this molecule in new studies concerning treatment against Leishmania infection in mammalian hosts. PMID- 29248980 TI - Delayed Intra Splenic Abscess: a Specific Complication Following Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Delayed intra splenic abscess after laparoscopic sleeve gastrectomy (LSG) is a very rare complication with poor manifestations. METHODS: We present three cases of delayed intrasplenic abscess which were managed in our departmentof minimal invasive surgery. DISCUSSION: Splenic abscess may occur in the early post-operative period following LSG; it is usually an extra splenic event after the gastric leak or an infected hematoma. In our cases, two patients had an asymptomatic ischemic demarcation in the upper part of the spleen. This underlines the possible role of ischemia as a factor in abscess formation of late intrasplenic abscesses that enhanced by a state of transient immune suppression. CONCLUSION: Intrasplenic abscess complicating laparoscopic sleeve gastrectomy is different from early extra splenic abscesses. The exact causes are still unclear; the role of partial splenic ischemia has to be rolled out. PMID- 29248979 TI - Application of modified JDP-DGGE-based molecular genotyping method to predict Acanthamoeba genotype and to analyse community diversity in aquatic environments. AB - Acanthamoeba spp. are ubiquitous, opportunistic potential human pathogens, causing granulomatous amoebic encephalitis and keratitis. They are classified as protozoa, and they include at least 20 different genotypes (T1-T20) based on variation in the 18S rRNA gene. Acanthamoeba spp. are diverse in their production of toxins and in their ability to resist environmental factors. Therefore, it is necessary to develop a rapid genotyping method for Acanthamoeba spp. in aquatic environments. Although the denaturing gradient gel electrophoresis (DGGE) method for analysing microbial genotypes is potentially useful for rapid identification of aquatic environmental species, the technique has been compromised by artificial DGGE profiles in which many DNA fragments of identical sequences are segregated and displayed as different bands. The results indicate that PCR-DGGE genotyping with a GC clamp results in many segregated weaker bands of identical DNA sequences. In contrast, PCR-DGGE genotyping without a GC clamp displays genotype-dependent patterns in the major bands. Thus, DGGE without a GC clamp was performed to compare genotyping efficiency for Acanthamoeba in 21 water samples from rivers and reservoirs in Taiwan. Among them, four samples were found to demonstrate a banding pattern with more than one major band, and these band profiles of major bands were identical to those of positive controls. DNA cloning further confirmed that the sequences of the major bands were identical. In conclusion, more than two genotypes of Acanthamoeba in the four samples were identified by this method, suggesting that PCR-DGGE genotyping without a GC clamp is a useful approach for studying the diversity of Acanthamoeba communities. Graphical abstract. PMID- 29248981 TI - Remission of Sjogren's Syndrome after Roux-en-Y Gastric Bypass for Morbid Obesity. PMID- 29248982 TI - A case series of atypical features of patients with biopsy-proven isolated IgG4 related hypophysitis and normal serum IgG4 levels. AB - BACKGROUND: IgG4-related hypophysitis is a rare clinical entity that forms part of an emerging group of multi-organ IgG4-related fibrosclerotic systemic diseases. The rare prevalence of the disease, presenting features that overlap with other sellar pathologies, and variable imaging features can make preoperative identification challenging. PURPOSE AND METHODS: We report three cases of isolated IgG4-related hypophysitis with atypical clinical and imaging features that mimicked those of pituitary apoplexy and other sellar lesions. Additionally, we review the literature of IgG4-related hypophysitis to provide context for individual patient data described herein. RESULTS: All patients presented with symptoms that mimicked those of pituitary apoplexy and visual disturbance, and MRI findings suggestive of pituitary macroadenoma, Rathke's cleft cyst and craniopharyngioma. The clinical presentation warranted surgical decompression, resulting in rapid symptomatic improvement. Preoperative high-dose followed by postoperative low-dose glucocorticoid replacement therapy was administered in all cases. Histopathology showed dense infiltrate of IgG4 cells. Post-operative follow-up monitoring for 12-26 months revealed normal serum IgG4 levels with no other organ involvement, while endocrinological testing revealed persistent pituitary hormone deficiencies. CONCLUSIONS: Our cases highlight the importance of considering IgG4-related hypophysitis in the differential diagnosis of solid and cystic sellar lesions presenting acutely with pituitary apoplexy symptoms. Existing diagnostic criteria may not be sufficiently precise to permit rapid and reliable identification, or avoidance of surgery in the acute setting. In contrast to other reports of the natural history of this condition, despite the severity of presenting features, the disease in our cases was pituitary restricted with normal serum IgG4 levels. PMID- 29248983 TI - Are Covert Saccade Functionally Relevant in Vestibular Hypofunction? AB - The vestibulo-ocular reflex maintains gaze stabilization during angular or linear head accelerations, allowing adequate dynamic visual acuity. In case of bilateral vestibular hypofunction, patients use saccades to compensate for the reduced vestibulo-ocular reflex function, with covert saccades occurring even during the head displacement. In this study, we questioned whether covert saccades help maintain dynamic visual acuity, and evaluated which characteristic of these saccades are the most relevant to improve visual function. We prospectively included 18 patients with chronic bilateral vestibular hypofunction. Subjects underwent evaluation of dynamic visual acuity in the horizontal plane as well as video recording of their head and eye positions during horizontal head impulse tests in both directions (36 ears tested). Frequency, latency, consistency of covert saccade initiation, and gain of covert saccades as well as residual vestibulo-ocular reflex gain were calculated. We found no correlation between residual vestibulo-ocular reflex gain and dynamic visual acuity. Dynamic visual acuity performance was however positively correlated with the frequency and gain of covert saccades and negatively correlated with covert saccade latency. There was no correlation between consistency of covert saccade initiation and dynamic visual acuity. Even though gaze stabilization in space during covert saccades might be of very short duration, these refixation saccades seem to improve vision in patients with bilateral vestibular hypofunction during angular head impulses. These findings emphasize the need for specific rehabilitation technics that favor the triggering of covert saccades. The physiological origin of covert saccades is discussed. PMID- 29248984 TI - Different Cerebellar Ataxia Phenotypes Associated with Mutations of the PNPLA6 Gene in Brazilian Patients with Recessive Ataxias. AB - Autosomal recessive cerebellar ataxias (ARCAs) represent a heterogeneous group of inherited disorders. The association of early-onset cerebellar ataxia with hypogonadotropic hypogonadism is related to two syndromes, known as Gordon Holmes syndrome (GHS-ataxia and pyramidal signs with hypogonadotropic hypogonadism) and Boucher-Neuhauser syndrome (BNS-ataxia with chorioretinal dystrophy). Mutations in the PNPLA6 gene have been identified as the cause of hereditary spastic paraplegia and complex forms of ataxia associated with retinal and endocrine manifestations. We reported two Brazilian patients with sporadic, progressive cerebellar ataxia, associated with hypogonadotropic hypogonadism, in whom the GHS and BNS were confirmed by the demonstration of compound heterozygote mutations in the PNPLA6 gene. Genetic analysis of the patient 1 revealed compound heterozygous mutations, one allele in exon 34 and the other allele in exon 29. Genetic exam of the patient 2 also demonstrated compound heterozygous mutations. Three were novel mutations. The missense mutation c.3373G> A, found in the BNS patient, was previously related to Oliver-McFarlane syndrome. These different mutations in this gene suggest a complex phenotype associated disease spectrum. PMID- 29248985 TI - On the information content of discrete phylogenetic characters. AB - Phylogenetic inference aims to reconstruct the evolutionary relationships of different species based on genetic (or other) data. Discrete characters are a particular type of data, which contain information on how the species should be grouped together. However, it has long been known that some characters contain more information than others. For instance, a character that assigns the same state to each species groups all of them together and so provides no insight into the relationships of the species considered. At the other extreme, a character that assigns a different state to each species also conveys no phylogenetic signal. In this manuscript, we study a natural combinatorial measure of the information content of an individual character and analyse properties of characters that provide the maximum phylogenetic information, particularly, the number of states such a character uses and how the different states have to be distributed among the species or taxa of the phylogenetic tree. PMID- 29248986 TI - The impact of pharmacist-led medication reconciliation during admission at tertiary care hospital. AB - Background Medication errors represent the most common type of error that compromises patient safety, with approximately 20% believed to result in harm. Over 40% of these errors are believed to result from inadequate medication reconciliation during admission, transfer, and discharge of patients and many of these errors could be prevented if adequate medication reconciliation processes were in place. In an effort to minimize adverse events caused during these care transitions, the Joint Commission has stated medication reconciliation as one of its National Patient Safety Goals and health care providers and organizations are encouraged to perform the process at various patient care transitions. Objective Identify the types of medication discrepancy that occurred during medication reconciliation performed by a pharmacist gathering the best possible medication history (BPMH). Estimate the potential for harm with each medication discrepancy using the severity rating methods developed by Cornish et al. (Arch Intern Med 165(4):424-429, 2005). Setting Tertiary care hospital in Jeddah, Saudi Arabia. Method Prospective 3-month study on 286 adult patients, admitted for at least 24 h and regularly taking at least four chronic prescription medications. Medication histories taken by physicians and by a pharmacist gathering the BPMH were compared. Identified discrepancies were reviewed by a panel of clinical pharmacists to assess the potential to cause patient harm with these errors. Main Outcome measure Number and types of medication discrepancies recorded by the pharmacist. Results Total number of medications recorded by physicians was 2548, versus 3085 by the pharmacist. 48.3% of patients had at least one unintended medication discrepancy by physicians. 537 medication discrepancies were reported (17.4% of number of medication discrepancies recorded by pharmacist). Types of medication discrepancies included, omissions (77% of discrepancies), commissions (13%), dosing errors (7%), and frequency errors (3%). 52% of the identified medication discrepancies had the potential to cause moderate to severe patient discomfort. Conclusion Patient medication histories are frequently recorded inaccurately by physicians during admission of patients which results in medication-related errors and compromises patient safety. Medication reconciliation is crucial in reducing these errors. Pharmacists can help in reducing these medication-related errors and the associated risks and complications. PMID- 29248987 TI - Healthcare professionals' agreement on clinical relevance of drug-related problems among elderly patients. AB - Background Disagreement among healthcare professionals on the clinical relevance of drug-related problems can lead to suboptimal treatment and increased healthcare costs. Elderly patients with chronic non-cancer pain and comorbidity are at increased risk of drug related problems compared to other patient groups due to complex medication regimes and transition of care. Objective To investigate the agreement among healthcare professionals on their classification of clinical relevance of drug-related problems in elderly patients with chronic non-cancer pain and comorbidity. Setting Multidisciplinary Pain Centre, Rigshospitalet, Copenhagen, Denmark. Method A pharmacist performed medication review on elderly patients with chronic non-cancer pain and comorbidity, identified their drug-related problems and classified these problems in accordance with an existing categorization system. A five-member clinical panel rated the drug-related problems' clinical relevance in accordance with a five level rating scale, and their agreement was compared using Fleiss' kappa. Main outcome measure Healthcare professionals' agreement on clinical relevance of drug related problems, using Fleiss' kappa. Results Thirty patients were included in the study. A total of 162 drug related problems were identified, out of which 54% were of lower clinical relevance (level 0-2) and 46% of higher clinical relevance (level 3-4). Only slight agreement (kappa = 0.12) was found between the panellists' classifications of clinical relevance using a five-level rating scale. Conclusion The clinical pharmacist identified drug related problems of lower and higher clinical relevance. Poor overall agreement on the severity of the drug related problems was found among the panelists. PMID- 29248988 TI - Pharmacovigilance in developing countries (part I): importance and challenges. AB - The thalidomide disaster was the significant historical event that acted as a catalyst for pharmacovigilance activity. Following this event developed countries initiated drug monitoring systems that evolved and now extend their scope to broader drug-related safety issues; however, this was not the case in developing countries. Pharmacovigilance is still a relatively new concept with low priority in developing countries although various issues are raising concerns that magnify the need for systems to monitor post marketing drug safety in these countries. This article analyzes the barriers to introducing robust pharmacovigilance systems in developing countries. PMID- 29248989 TI - Stratified prevention: opportunities and limitations. Report on the 1st interdisciplinary cardiovascular workshop in Augsburg. AB - Sufficient exercise and sleep, a balanced diet, moderate alcohol consumption and a good approach to handle stress have been known as lifestyles that protect health and longevity since the Middle Age. This traditional prevention quintet, turned into a sextet by smoking cessation, has been the basis of the "preventive personality" that formed in the twentieth century. Recent analyses of big data sets including genomic and physiological measurements have unleashed novel opportunities to estimate individual health risks with unprecedented accuracy, allowing to target preventive interventions to persons at high risk and at the same time to spare those in whom preventive measures may not be needed or even be harmful. To fully grasp these opportunities for modern preventive medicine, the established healthy life styles require supplementation by stratified prevention. The opportunities of these developments for life and health contrast with justified concerns: A "surveillance society", able to predict individual behaviour based on big data, threatens individual freedom and jeopardises equality. Social insurance law and the new German Disease Prevention Act (Praventionsgesetz) rightly stress the need for research to underpin stratified prevention which is accessible to all, ethical, effective, and evidence based. An ethical and acceptable development of stratified prevention needs to start with autonomous individuals who control and understand all information pertaining to their health. This creates a mandate for lifelong health education, enabled in an individualised form by digital technology. Stratified prevention furthermore requires the evidence-based development of a new taxonomy of cardiovascular diseases that reflects disease mechanisms. Such interdisciplinary research needs broad support from society and a better use of biosamples and data sets within an updated research governance framework. PMID- 29248990 TI - Large-Scale Survey of Human Enteroviruses in Wastewater Treatment Plants of a Metropolitan Area of Southern Italy. AB - Human enteroviruses (HEVs) occur in high concentrations in wastewater and can contaminate receiving environmental waters, constituting a major cause of acute waterborne disease worldwide. In this study, we investigated the relative abundance, occurrence, and seasonal distribution of polio and other enteroviruses at three wastewater treatment plants (WWTPs) in Naples, Southern Italy, from January 2010 to December 2014. Influent and effluent samples from the three WWTPs were collected monthly. One hundred and sixty-one of the 731 wastewater samples collected (22.0%) before and after water treatment were CPE positive on RD cells; while no samples were positive on L20B cells from any WWTPs. Among the 140 non polio enterovirus isolated from inlet sewage, 69.3% were Coxsackieviruses type B and 30.7% were Echoviruses. Among these, CVB3 and CVB5 were most prevalent, followed by CVB4 and Echo6. The twenty-one samples tested after treatment contained 6 CVB4, 5 CVB3, 3 Echo11, and 2 Echo6; while other serotypes were isolated less frequently. Data on viral detection in treated effluents of WWTPs confirmed the potential environmental contamination by HEVs and could be useful to establish standards for policies on wastewater management. PMID- 29248991 TI - Longitudinal Associations between Maternal Involvement, Cultural Orientations, and Prosocial Behaviors Among Recent Immigrant Latino Adolescents. AB - Prosocial behaviors (i.e., actions that benefit others) are important markers of healthy social functioning, and understanding the factors that predict such outcomes among recent immigrant Latino adolescents is important. The current study examines the longitudinal associations between maternal involvement and prosocial behaviors via collectivism values. Data comes from a longitudinal project (Construyendo Oportunidades Para los Adolescentes Latinos) of 302 recently immigrated U.S. Latina/o adolescents (53.3% male, average age = 14.51 years old). The current study uses data from three times points across 2 years. The results demonstrated that maternal involvement was positively associated with collectivism values. Collectivism was positively associated with changes in prosocial behaviors. There was also partial support for a reverse-causal model. Discussion focuses on the links among parenting, cultural values, and prosocial behaviors among immigrant U.S. Latina/o adolescents. PMID- 29248992 TI - Antibiotics and open fractures of the lower extremity: less is more. AB - PURPOSE: Infectious complications in open lower extremity fractures contribute to significant morbidity. Historically, orthopedic guidelines have recommended Grade III fractures receive a first generation cephalosporin and an aminoglycoside. Despite these guidelines, few studies have evaluated the utility of adding an aminoglycoside in this patient population. At our trauma center, we have a unique trauma service where half of our surgeons treat Grade III open fractures with a cephalosporin alone and half use a cephalosporin + aminoglycoside. We hypothesized that our outcomes were the same between the two groups. METHODS: We identified all Grade III fractures of the lower extremity admitted to our urban Level I Trauma Center over the 5-year study period. Charts were retrospectively reviewed to identify demographic information, injury severity score (ISS), fracture location, grade of fracture, type of antibiotic administered, incidence of acute kidney injury (AKI), surgical site infection (SSI), hardware removal, hospital length of stay (HLOS), and disposition. Patients were classified into two groups: those treated with a cephalosporin alone (CEPH) or cephalosporin + an aminoglycoside (CEPH + AG). RESULTS: A total of 126 grade III fractures of the lower extremity were admitted our Trauma Center during the 5-year study period. There were 65 (52%) patients in the CEPH group and 61 (48%) in the CEPH + AG group. Demographics, ISS, fracture location, grade of fracture, rate of SSI, need for hardware removal, and disposition were not different between the two groups. In contrast, patients in the CEPH group had a 4% incidence of AKI, while the incidence was 10% of patients in the CEPH + AG group (p < 0.05). CONCLUSION: The addition of an AG to antibiotic prophylaxis in open lower extremity fractures was associated with a significant increase in AKI with no change in the incidence of wound infection or hardware removal. Cephalosporins alone may be sufficient for prophylaxis in Grade III open fractures of the lower extremity. A large-scale prospective randomized trial is needed to confirm these findings and inform clinical practice. PMID- 29248993 TI - Challenges, Dilemmas and Factors Involved in PGD Decision-Making: Providers' and Patients' Views, Experiences and Decisions. AB - Providers and patients are considering and pursuing PGD for ever-more conditions, but questions arise concerning how they make, view and experience these decisions, and what challenges they may face. Thirty-seven in-depth semi structured interviews were conducted (with 27 IVF providers and 10 patients). Patients and providers struggled with challenges and dilemmas about whether to pursue PGD in specific cases, and how to decide. Respondents varied in how they viewed, experienced and made these choices, and for which conditions to pursue PGD (from lethal, childhood-onset conditions to milder, treatable, or adult-onset disorders). Several factors were involved, including differences in gene penetrance, predictability, and phenotypic expression, and disease severity, age of onset, treatability, stigma and degree of disability. Providers and patients face questions regarding possibilities of screening for more than one condition in one set of embryos, and limitations of PGD (e.g., inaccurate results). Characteristics of providers (e.g., amount of PGD experience, understandings of genetics, and use of genetic counselors), and of patients (e.g., related to broader moral and social attitudes) can also affect these decisions. These data, the first to examine several key questions concerning PGD, suggest that providers and patients confront several dilemmas. These findings have critical implications for future practice, guidelines, education and research. PMID- 29248994 TI - The phosphorelay signal transduction system in Candida glabrata: an in silico analysis. AB - Signaling systems allow microorganisms to sense and respond to different stimuli through the modification of gene expression. The phosphorelay signal transduction system in eukaryotes involves three proteins: a sensor protein, an intermediate protein and a response regulator, and requires the transfer of a phosphate group between two histidine-aspartic residues. The SLN1-YPD1-SSK1 system enables yeast to adapt to hyperosmotic stress through the activation of the HOG1-MAPK pathway. The genetic sequences available from Saccharomyces cerevisiae were used to identify orthologous sequences in Candida glabrata, and putative genes were identified and characterized by in silico assays. An interactome analysis was carried out with the complete genome of C. glabrata and the putative proteins of the phosphorelay signal transduction system. Next, we modeled the complex formed between the sensor protein CgSln1p and the intermediate CgYpd1p. Finally, phosphate transfer was examined by a molecular dynamic assay. Our in silico analysis showed that the putative proteins of the C. glabrata phosphorelay signal transduction system present the functional domains of histidine kinase, a downstream response regulator protein, and an intermediate histidine phosphotransfer protein. All the sequences are phylogenetically more related to S. cerevisiae than to C. albicans. The interactome suggests that the C. glabrata phosphorelay signal transduction system interacts with different proteins that regulate cell wall biosynthesis and responds to oxidative and osmotic stress the same way as similar systems in S. cerevisiae and C. albicans. Molecular dynamics simulations showed complex formation between the response regulator domain of histidine kinase CgSln1 and intermediate protein CgYpd1 in the presence of a phosphate group and interactions between the aspartic residue and the histidine residue. Overall, our research showed that C. glabrata harbors a functional SLN1 YPD1-SSK1 phosphorelay system. PMID- 29248995 TI - A (five-)level playing field for mental health conditions?: exploratory analysis of EQ-5D-5L-derived utility values. AB - PURPOSE: Economic evaluations of mental health interventions often measure health benefit in terms of utility values derived from the EQ-5D. For the five-level version of the EQ-5D, there are two methods of estimating utility [crosswalk and stated preference (5L-SP)]. This paper explores potential impacts for researchers and decision-makers when comparing utility values derived from either method in the specific context of mental health. METHODS: Baseline EQ-5D-5L data from three large randomised controlled trials of interventions for mental health conditions were analysed. Utility values were generated using each method. Mean utility values were compared using a series of t tests on pooled data and subgroups. Scenario analyses explored potential impacts on cost-effectiveness decisions. RESULTS: EQ-5D data were available for 1399 participants. The mean utility value for each trial was approximately 0.08 higher when estimated using the 5L-SP approach compared to crosswalk (p < 0.0001). The difference was greatest among people reporting extreme anxiety/depression (mean utility 5L-SP 0.309, crosswalk 0.084; difference = 0.225; p < 0.0001). Identical improvements in health status were associated with higher costs to gain one QALY with the 5L-SP approach; this is more pronounced when improvements are across all domains compared to improvements on the anxiety/depression domain only. CONCLUSIONS: The two approaches produce significantly different utility values in people with mental health conditions. Resulting differences in cost per QALY estimates suggest that thresholds of cost-effectiveness may also need to be reviewed. Researchers and decision-makers should exercise caution when comparing or synthesising data from trials of mental health interventions using different utility estimation approaches. PMID- 29248996 TI - Careless responding in internet-based quality of life assessments. AB - PURPOSE: Quality of life (QoL) measurement relies upon participants providing meaningful responses, but not all respondents may pay sufficient attention when completing self-reported QoL measures. This study examined the impact of careless responding on the reliability and validity of Internet-based QoL assessments. METHODS: Internet panelists (n = 2000) completed Patient-Reported Outcomes Measurement Information System (PROMIS(r)) short-forms (depression, fatigue, pain impact, applied cognitive abilities) and single-item QoL measures (global health, pain intensity) as part of a larger survey that included multiple checks of whether participants paid attention to the items. Latent class analysis was used to identify groups of non-careless and careless responders from the attentiveness checks. Analyses compared psychometric properties of the QoL measures (reliability of PROMIS short-forms, correlations among QoL scores, "known-groups" validity) between non-careless and careless responder groups. Whether person-fit statistics derived from PROMIS measures accurately discriminated careless and non careless responders was also examined. RESULTS: About 7.4% of participants were classified as careless responders. No substantial differences in the reliability of PROMIS measures between non-careless and careless responder groups were observed. However, careless responding meaningfully and significantly affected the correlations among QoL domains, as well as the magnitude of differences in QoL between medical and disability groups (presence or absence of disability, depression diagnosis, chronic pain diagnosis). Person-fit statistics significantly and moderately distinguished between non-careless and careless responders. CONCLUSIONS: The results support the importance of identifying and screening out careless responders to ensure high-quality self-report data in Internet-based QoL research. PMID- 29248997 TI - Quality of life among parents of preterm infants: a scoping review. AB - PURPOSE: To synthesize the body of knowledge on the factors influencing the QoL of mothers and fathers of preterm infants. METHODS: A scoping review was performed. Publications indexed in PubMed(r), Web of ScienceTM, CINAHL(r) and PsycINFO(r) were searched, targeting studies presenting original empirical data that examined parental perception on QoL after a preterm delivery. Eligibility and data extraction were conducted by two independent researchers. The main quantitative findings were synthesized and qualitative data were explored by content analysis. RESULTS: The studies, 11 quantitative and 1 mixed methods, were derived mainly from the USA (n = 6). Heterogeneity across the studies was observed regarding the operationalization of QoL and the use of units of analysis (mothers, parents, families and caregivers). In a context where 40 out of 45 covariates were analysed by only one or two studies, results suggested that parental QoL after a preterm delivery is influenced by factors related with mother's characteristics, family issues and health care environment rather than infants' variables. Factors regarding fathers' characteristics and structural levels were not addressed. CONCLUSIONS: Standardizing the operationalization of the QoL when analysing mothers and fathers of preterm infants calls for a structured questionnaire adapted to their specific needs. Further research should include both mothers and fathers, invest in mixed methods approaches and be performed in different countries and settings for allowing integration and comparison of findings. PMID- 29248998 TI - Measuring what matters MOST: validation of the Measure of Ovarian Symptoms and Treatment, a patient-reported outcome measure of symptom burden and impact of chemotherapy in recurrent ovarian cancer. AB - PURPOSE: Gynecologic Cancer Intergroup Symptom Benefit Study (GCIG-SBS) Stage 2 aimed to review, revise, and validate a patient-reported outcome measure (PROM), the Measure of Ovarian Symptoms and Treatment concerns (MOST), developed in GCIG SBS Stage 1 (MOSTv1, 35 items), and document recurrent ovarian cancer (ROC) symptom burden and benefit. METHODS: GCIG-SBS Stage 2 recruited patients with platinum-resistant/refractory ROC (PRR-ROC) or potentially platinum-sensitive ROC with >= 3 lines of prior chemotherapy (PPS-ROC >= 3). Patients completed MOSTv1, QLQ-C30, QLQ-OV28, and FACT-O/FOSI at baseline and before cycle 3 of chemotherapy (pre-C3), and global assessments of change (MOST-Change) pre-C3. Clinicians rated patients' cancer-related symptoms, performance status, and adverse events. Convergent and divergent validity (Spearman's correlations), discriminative validity (effect sizes between groups classified by clinician-rated characteristics), and responsiveness (paired t tests in patients expected to experience clinically meaningful change) were assessed. RESULTS: Of 948 recruits, 903 completed PROMs at baseline and 685 pre-C3. Baseline symptom burden was substantial for PRR-ROC and PPS-ROC >= 3. MOSTv2 has 24 items and five multi-item scales: abdominal symptoms (MOST-Abdo), disease or treatment-related symptoms (MOST-DorT), chemotherapy-related symptoms (MOST-Chemo), psychological symptoms (MOST-Psych), and MOST-Well-being. Correlations confirmed concurrent and divergent validity. Discriminative validity was confirmed by effect sizes that conformed with a priori hypotheses. MOST-Abdo was responsive to improvements in abdominal symptoms and MOST-Chemo detected the adverse effects of chemotherapy. CONCLUSIONS: The MOSTv2 validly quantifies patient-reported symptom burden, adverse effects, and symptom benefit in ROC, and as such is fit-for-purpose for clinical trials of palliative chemotherapy in ROC. Further research is required to assess test-retest reliability. PMID- 29249000 TI - Uveo-meningo-cerebral syndrome. PMID- 29248999 TI - Safety and efficacy of Cerebrolysin in early post-stroke recovery: a meta analysis of nine randomized clinical trials. AB - This meta-analysis combines the results of nine ischemic stroke trials, assessing efficacy of Cerebrolysin on global neurological improvement during early post stroke period. Cerebrolysin is a parenterally administered neuropeptide preparation approved for treatment of stroke. All included studies had a prospective, randomized, double-blind, placebo-controlled design. The patients were treated with 30-50 ml Cerebrolysin once daily for 10-21 days, with treatment initiation within 72 h after onset of ischemic stroke. For five studies, original analysis data were available for meta-analysis (individual patient data analysis); for four studies, aggregate data were used. The combination by meta analytic procedures was pre-planned and the methods of synthesis were pre-defined under blinded conditions. Search deadline for the present meta-analysis was December 31, 2016. The nonparametric Mann-Whitney (MW) effect size for National Institutes of Health Stroke Scale (NIHSS) on day 30 (or 21), combining the results of nine randomized, controlled trials by means of the robust Wei-Lachin pooling procedure (maximin-efficient robust test), indicated superiority of Cerebrolysin as compared with placebo (MW 0.60, P < 0.0001, N = 1879). The combined number needed to treat for clinically relevant changes in early NIHSS was 7.7 (95% CI 5.2 to 15.0). The additional full-scale ordinal analysis of modified Rankin Scale at day 90 in moderate to severe patients resulted in MW 0.61 with statistical significance in favor of Cerebrolysin (95% CI 0.52 to 0.69, P = 0.0118, N = 314). Safety aspects were comparable to placebo. Our meta analysis confirms previous evidence that Cerebrolysin has a beneficial effect on early global neurological deficits in patients with acute ischemic stroke. PMID- 29249001 TI - Distinguishing features of microglia- and monocyte-derived macrophages after stroke. AB - After stroke, macrophages in the ischemic brain may be derived from either resident microglia or infiltrating monocytes. Using bone marrow (BM)-chimerism and dual-reporter transgenic fate mapping, we here set out to delimit the responses of either cell type to mild brain ischemia in a mouse model of 30 min transient middle cerebral artery occlusion (MCAo). A discriminatory analysis of gene expression at 7 days post-event yielded 472 transcripts predominantly or exclusively expressed in blood-derived macrophages as well as 970 transcripts for microglia. The differentially regulated genes were further collated with oligodendrocyte, astrocyte, and neuron transcriptomes, resulting in a dataset of microglia- and monocyte-specific genes in the ischemic brain. Functional categories significantly enriched in monocytes included migration, proliferation, and calcium signaling, indicative of strong activation. Whole-cell patch-clamp analysis further confirmed this highly activated state by demonstrating delayed outward K+ currents selectively in invading cells. Although both cell types displayed a mixture of known phenotypes pointing to the significance of 'intermediate states' in vivo, blood-derived macrophages were generally more skewed toward an M2 neuroprotective phenotype. Finally, we found that decreased engraftment of blood-borne cells in the ischemic brain of chimeras reconstituted with BM from Selplg-/- mice resulted in increased lesions at 7 days and worse post-stroke sensorimotor performance. In aggregate, our study establishes crucial differences in activation state between resident microglia and invading macrophages after stroke and identifies unique genomic signatures for either cell type. PMID- 29249003 TI - Mitochondrial Disease in Children: The Nephrologist's Perspective. AB - : Mitochondrial diseases (MD) are a heterogeneous group of clinical syndromes characterized by the involvement of different organ systems. They constitute the most prevalent hereditary metabolic disease group. OBJECTIVE: To review the importance of the kidney in MD from the nephrologist's perspective within the setting of a pediatric tertiary reference center. STUDY DESIGN: Retrospective study of children (<18 years) with MD followed between 2000 and 2016 at a tertiary Spanish center. RESULTS: 52 patients were included. The mean age at the time of the study was 10 years (SD +/- 5.1). The mean follow-up time was 6.1 years (SD +/- 4.7). The median age at diagnosis was 2.5 years (0.3-13.5).The median number of affected systems was two (range 1-6). The nervous system was the most affected system, with 51 patients (~98%) presenting with neurological involvement. 20 patients (~40%) presented with endocrinological manifestations, 18 (~35%) with vision problems, 16 (~30%) with gastrointestinal symptoms, 5 (~10%) patients developed hearing impairment, and 6 (~10%) cardiac disease.We detected renal involvement in 13 patients (25%). Eight patients had tubular disease, most frequently hypercalciuria with hypouricemia and five patients had glomerular involvement, with proteinuria and/or decreased glomerular filtration rate as the most frequent symptoms. Only 21 patients (~40%) had been seen by a pediatric nephrologist. CONCLUSIONS: Renal disease was a common occurrence in patients with mitochondrial disease, present in our study in 25% of patients. A regular screening of renal function parameters and the involvement of a nephrologist as part of the multidisciplinary approach to mitochondrial disease appears warranted. PMID- 29249002 TI - Notch-mediated lateral inhibition is an evolutionarily conserved mechanism patterning the ectoderm in echinoids. AB - Notch signaling is a crucial cog in early development of euechinoid sea urchins, specifying both non-skeletogenic mesodermal lineages and serotonergic neurons in the apical neuroectoderm. Here, the spatial distributions and function of delta, gcm, and hesc, three genes critical to these processes in euechinoids, are examined in the distantly related cidaroid sea urchin Eucidaris tribuloides. Spatial distribution and experimental perturbation of delta and hesc suggest that the function of Notch signaling in ectodermal patterning in early development of E. tr ibuloides is consistent with canonical lateral inhibition. Delta transcripts were observed in t he archenteron, apical ectoderm, and lateral ectoderm in gastrulating e mbryos of E. tribuloides. Perturbation of Notch signaling by either delta morpholino or treatment of DAPT downregulated hesc and upregulated delta and gcm, resulting in ectopic expression of delta and gcm. Similarly, hesc perturbation mirrored the effects of delta perturbation. Interestingly, perturbation of delta or hesc resulted in more cells expressing gcm and supernumerary pigment cells, suggesting that pigment cell proliferation is regulated by Notch in E. tribuloides. These results are consistent with an evolutionary scenario whereby, in the echinoid ancestor, Notch signaling was deployed in the ectoderm to specify neurogenic progenitors and controlled pigment cell proliferation in the dorsal ectoderm. PMID- 29249004 TI - Leber Hereditary Optic Neuropathy and Longitudinally Extensive Transverse Myelitis. AB - Leber Hereditary Optic Neuropathy is an inherited optic neuropathy caused by mitochondrial DNA point mutations leading to sudden, painless loss of vision. We report a case of an 8-year-old boy presenting with a radiological phenotype of longitudinally extensive transverse myelitis on a background of severe visual impairment secondary to Leber Hereditary Optic Neuropathy (LHON). He was found to have dual mitochondrial DNA mutations at 14484 (MTND6 gene) and 4160 (MTND1 gene) in a family with a severe form of LHON characterised by not only an unusually high penetrance of optic neuropathy, but also severe extra-ocular neurological complications. The m.14484T>C mutation is a common LHON mutation, but the m.4160T>C mutation is to our knowledge not reported outside this family and appears to drive the neurological manifestations. To our knowledge there have been no previous reports of spinal cord lesions in children with LHON. PMID- 29249005 TI - Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation. AB - PURPOSE: Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). METHODS: 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. RESULTS: Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5 11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. CONCLUSIONS: MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression. PMID- 29249006 TI - Quantified frequency-domain optical coherence tomography analysis for the thin high signals on restenotic tissue after paclitaxel-coated balloon angioplasty. AB - Thin-high signals (THS), detectable by optical coherence tomography (OCT), represent the paclitaxel coverage of in-stent restenotic tissue. This study was conducted to assess the relationship between THS and angiographic outcomes by means of quantified post-procedural frequency-domain OCT (FD-OCT) analysis. From January 2014 to July 2016, 41 patients underwent FD-OCT-guided percutaneous coronary intervention using paclitaxel-coated balloon (PCB) to prevent in-stent restenosis. Of these, we retrospectively enrolled 32 patients (38 lesions) who underwent a 6- to 9-month follow-up angiogram. THS were assessed quantitatively, as THS length and lumen perimeter length were measured using semi-automated software; %THS was calculated by the following formula; total THS area/lumen perimeter area * 100. THS were detected in all 38 lesions that had undergone PCB angioplasty. THS and %THS were significantly higher in lesions without binary restenosis (3.34 +/- 2.11 vs. 11.48 +/- 8.53 mm2, p = 0.001 and 1.49 +/- 0.73 vs. 4.42 +/- 2.71%, p = 0.001, respectively). Values for THS, which indicates the paclitaxel coverage on restenotic tissue, are associated with reducing restenosis after PCB for in-stent restenosis. PMID- 29249007 TI - Human Umbilical Cord Blood CD45+ Pan-Hematopoietic Cells Induced a Neurotherapeutic Effect in Mice with Traumatic Brain Injury: Immunophenotyping, Comparison of Maternal and Neonatal Parameters, and Immunomodulation. AB - Human umbilical cord blood (HUCB) transplantation has become an alternative cell therapy for hematological and oncological malignancies in the clinic and is considered for neurological disorders. The heterogeneity in the content of the different stem and progenitor cells composing HUCB mononuclear cells (MNC) may influence their engraftment and neurotherapeutic effect. We hypothesized that CD45 pan-hematopoietic marker expression is heterogeneous in MNC, and therefore, CD45+ subpopulation enrichment for neurotherapy may provide a tool to overcome cellular variance in different HUCB units. We employed an immunomagnetic separation method to isolate and characterize HUCB CD45+ pan-hematopoietic subpopulation and to investigate whether the vaginal or cesarean deliveries influence their neurotherapeutic effect in a traumatic brain injury (TBI) mouse model. Adult C57BL/6J male mice were subjected to moderate TBI and intravenously xenotransplanted with 1 * 106 CD45+ cells derived from either vaginal or cesarean HUCB units. A large heterogeneity in the expression of CD45 marker in MNC, both in vaginal and cesarean HUCB units, was found, regardless of the number of live births. A higher expression of hematopoietic markers was found in the CD45+ subpopulation while low expressional levels of typical mesenchymal markers were detected. Neurotherapeutic effects, evaluated with an established neurological severity score and novel object recognition test, indicated improved functional motor and memory recovery and found independent of delivery type. Cytokine analysis in extracts of TBI brain cortices indicated an acute immunomodulatory effect by HUCB CD45+ subpopulation upon xenotransplantation. These results may provide insights to CD45 marker as a predictor of HUCB units' quality for neurotherapy in TBI. PMID- 29249008 TI - Secondary imaging for suspected appendicitis after equivocal ultrasound: time to disposition of MRI compared to CT. AB - PURPOSE: The purpose of this study was to compare MRI to CT as a secondary imaging modality for children age 5 years and older with suspected appendicitis after an equivocal abdominal ultrasound in terms of (1) the time to ED disposition decision, (2) surgery consultation rate, and (3) imaging test accuracy. METHODS: We retrospectively studied children with suspected appendicitis and equivocal ultrasound results who underwent MR or CT as secondary imaging in a pediatric emergency department over two-consecutive 9-month periods. No oral or intravenous contrast was utilized for MRI. No sedation was utilized for any modality. Time of disposition is the time to admission or discharge order. RESULTS: Twenty-five patients underwent CT and 30 underwent MRI, with no significant difference in the median time from ultrasound to disposition between the CT (5.9 h, IQR 4.5, 8.4) and the MRI (5.9 h, IQR 4.6, 6.9) groups (p = 0.65). Fifteen patients had appendicitis. Of the 40 negative or equivocal studies, surgery was consulted for 79% in the CT and 48% in the MRI group (odds ratio 4.12, 95% CI 1.02-16.67). Diagnostic accuracy was as follows: MRI: sensitivity of 90%, specificity of 97.1%, positive predictive value of 90%, and negative predictive value of 97.1%. Abdominal CT: sensitivity of 88%, specificity of 98.6%, positive predictive value of 95.7%, and negative predictive value of 95.8%. CONCLUSION: MRI is a feasible alternative to CT for secondary imaging in acute appendicitis for showing comparable ED throughput metrics and diagnostic accuracy, with added benefits of reduced radiation and avoidance of intravenous contrast. PMID- 29249009 TI - Health-related quality of life in patients with polycystic ovary syndrome: validation of the German PCOSQ-G. AB - PURPOSE: Patients with polycystic ovary syndrome (PCOS) report a decreased health related quality of life (HRQOL) and higher levels of psychological distress. Validated questionnaires are necessary to assess the impact of PCOS on patients' lives. The aim of the present study was to evaluate the German "Polycystic Ovary Syndrome Questionnaire" (PCOSQ-G). METHODS: The psychometric properties of the PCOSQ-G were investigated in PCOS patients with item-total correlation, internal consistency and test-retest reliability. Correlations with the Short-Form-36 Health Survey (SF-36) and the Hospital Anxiety and Depression Scale (HADS-D) were calculated to evaluate the validity of the PCOSQ-G. Discriminatory validity was investigated through a receiver operating characteristic curve and independent sample t tests compared with healthy controls. RESULTS: Good psychometric properties were found for most items. Acceptable to high internal consistency was found for the total score (alpha = 0.94-0.95) and all subscales (alpha = 0.70 0.97). High test-retest reliability was found for the total score (0.86) and all subscales (0.81-0.90). The validity analyses showed that the PCOSQ-G total score was positively correlated with both SF-36 summary scales and was negatively correlated with both HADS subscales. Patients reported significantly lower values for the PCOSQ-G total score (p < 0.001) and all subscales, and the PCOSQ-G discriminated well between patients and healthy controls (AUC = 0.81, p < 0.001). CONCLUSIONS: PCOSQ-G is a reliable and valid tool to assess the HRQOL in patients with PCOS and can be used in future clinical research. Patients with PCOS exhibited an impaired HRQOL, which indicates the need for psychosomatic counseling. PMID- 29249010 TI - Evaluating the main sources of groundwater pollution in the southern Tehran aquifer using principal component factor analysis. AB - Determining the main sources of pollution (MSP) in groundwater is crucial to improve water quality (WQ) status. Field studies were conducted in this research, where five sampling campaigns were carried out from 36 wells in the southern Tehran aquifer. In all samples, WQ parameters were measured and evaluated regarding the Iranian drinking water standard (IDWS). Finally, by using the principal component factor analysis (PCFA), the probable MSP in the aquifer were determined. The results showed that all ions, total hardness, and total dissolved solids were above the IDWS. To analyze the PCFA results, only the first four of twenty rotated principal factors (RPFs) that conserved a high percentage of the variance of the data (about 90%) were considered. The results of the first PRF revealed that the geological structure was the MSP in the aquifer. Furthermore, the second RPF was mainly affected by nutrients (nitrate and orthophosphate) and microbial parameters (fecal and total coliforms), indicating the importance of agricultural activities and sewage effluents as another MSP in the aquifer. Finally, the remarkable share of heavy metals and pH in formation of the third and fourth RPFs, respectively, reflected the role of industrial activities as a probable MSP of groundwater. PMID- 29249011 TI - Development of Emotion Self-Regulation Among Young Children with Autism Spectrum Disorders: The Role of Parents. AB - Emotional self-regulation (ESR) challenges are well-documented in the diagnostic profiles of children with Autism; however, less is known about the development of ESR and the role of parents in ESR development for this population. Thirty-seven young children with autism and one of their parents participated in a home-based, observational study exploring the associations between the children's social communication and sensory processing characteristics and their parents' behaviors associated with ESR development. Findings revealed that parent use of physical and language behaviors were associated with child social communication abilities. No associations between child sensory processing and parent behaviors were found. Understanding the interactive processes between parents and children with ASD has implications for the development of parent-based interventions that increase child ESR. PMID- 29249012 TI - What Works for College Students with Autism Spectrum Disorder. AB - This article reports the results of a systematic review of the emerging research on programs and services designed to meet the needs of students with ASD. For the purposes of this review, only articles that included data on program outcomes were included. A total of eight studies that met this criterion were identified. These studies included three that examined the effects of cognitive-behavioral interventions, three that reported the results of methods to enhance social communication skills, one study of a transition to college program, and one evaluation of a variety of widely used accommodations. This review identifies methods that have been found to be effective supporting students with ASD in higher education settings as well as needs for future research. PMID- 29249013 TI - Results with nine years mean follow up on one hundred and three KAPS(r) uni knee arthroplasties: eighty six medial and seventeen lateral. AB - PURPOSE: The purpose of this study was to present the results of the KAPS(r) uni knee arthroplasty system, both mobile and fixed bearing with reference to function, alignment and complications in 103 implants with a mean follow-up of nine years. METHODS: This was a retrospective study of 103 unicompartimental knee arthroplasties in 89 patients operated on between March 2005 and March 2010. The population was composed of 50 males and 39 females, with a mean age of 70.5 +/- 7.5 years (41 - 90). Eighty-seven patients had a genu varum deformity (84.5%), one of whom had an osteoid osteoma of the lateral tibial plateau and 16 patients had a genu valgum (15.5%). Eighty-six medial prostheses were implanted (82 mobile bearings and 4 fixed bearings) and 17 lateral prostheses (all fixed bearings) including the osteoid osteoma. RESULTS: At a mean follow-up of 107.5 months (73 138), 72 knees (58 patients) were reviewed (70%). The mean IKS score was of 173 +/- 31 points (58 - 200). The mean Oxford knee score was 21 +/- 8 points (12 - 50). The cumulated survival rate at a follow up of 132 months was 98.2%. CONCLUSION: The KAPS(r) unicompartmental knee arthroplasty gives efficacious and safe outcomes in the majority of cases at a mean follow-up of nine years. The availability of both fixed and mobile bearings with the same instrumentation, allowing to choose the right implant intra-operatively, is a great advantage in order to avoid the occurrence of some complications, specific to mobile bearing prostheses (dislocation and over-correction). PMID- 29249014 TI - Distinct mortality profile in systemic sclerosis: a death certificate study in Rio de Janeiro, Brazil (2006-2015) using a multiple causes of death analysis. AB - The objective of this study was to assess the mortality profile related to SSc in the state of Rio de Janeiro, Brazil. We retrospectively examined all registered deaths in the region (2006-2015 period) in which the diagnosis of SSc was mentioned on any line of the death certificates (underlying cause of death [UCD], n = 223; non-UCD, n = 151). Besides the analysis of gender, age, and the causes of death, we also compared the mortality from UCDs between individuals whose death causes included SSc (cases) and those whose death causes did not include SSc (deceased controls). For the latter comparison, we used the mortality odds ratio to approximate the cause-specific standardized mortality ratio. We identified 1495 death causes among the 374 SSc cases. The mean age at death of the SSc cases (85% women) was significantly lower than that of the controls (n = 1,294,117) (58.7 vs. 65.5 years, respectively). The main death causes were circulatory system diseases, infections, and respiratory diseases (36%, 34%, and 21% of SSc cases, respectively). Compared to the deceased controls, there were proportionally more deaths among the SSc cases from pulmonary arterial hypertension, lung fibrosis, septicemia, gastrointestinal hemorrhage, other systemic connective tissue diseases, and heart failure (for death age < 50 years). We confirmed the high burden of cardiovascular, respiratory, and infectious causes in this predominantly non-Caucasian sample of SSc patients. Of interest, the percentage of infection-related deaths in our report was about three times higher than that in SSc studies with predominantly Caucasian populations. PMID- 29249015 TI - Cost-effectiveness of cell-free DNA in maternal blood testing for prenatal detection of trisomy 21, 18 and 13: a systematic review. AB - The aim of this paper was to conduct a systematic review of the cost effectiveness of the analysis of cell-free DNA in maternal blood, often called the non-invasive prenatal test (NIPT), in the prenatal screening of trisomy in chromosomes 21, 18 and 13. MEDLINE, MEDLINE in process, EMBASE, and Cochrane Library were searched in April 2017. We selected: (1) economic evaluations that estimated the costs and detected cases of trisomy 21, 18 or 13; (2) comparisons of prenatal screening with NIPT (universal or contingent strategies) and the usual screening without NIPT, (3) in pregnant women with any risk of foetal anomalies. Studies were reviewed by two researchers. Data were extracted, the methodological quality was assessed and a narrative synthesis was prepared. In total, 12 studies were included, four of them performed in Europe. Three studies evaluated NIPT as a contingent test, three studies evaluated a universal NIPT, and six studies evaluated both. The results are heterogeneous, especially for the contingent NIPT where the results range from NIPT being dominant to a dominated strategy. Universal NIPT was found to be more effective but also costlier than the usual screening, with very high incremental cost-effectiveness ratios. One advantage of screening with NIPT is lower invasive procedure-related foetal losses than with usual screening. In conclusion, the cost-effectiveness of contingent NIPT is uncertain according to several studies, while the universal NIPT is not cost-effective currently. PMID- 29249017 TI - Teriparatide therapy for severe, refractory osteoradionecrosis of the jaw. AB - Although osteoradionecrosis (ORN) is a serious complication of craniofacial radiotherapy, the current management methods remain suboptimal. Teriparatide (TPTD), a recombinant human parathyroid hormone (1-34), has shown beneficial effects on osseous regeneration in medication-related osteonecrosis of the jaw or periodontitis. However, TPTD therapy in irradiated bones has not been indicated yet because of the theoretical risk of osteosarcoma seen in rat models. Hence, we first report here two patients with tongue cancer with late-emerging ORN who were successfully treated with TPTD for 4-6 months with serum calcium and vitamin D supplementation. In contrast to the usual progress of ORN, the bone defect regenerated well and bone turnover markers including serum C-terminal telopeptide of type 1 collagen and osteocalcin were restored with TPTD therapy. Our experience might suggest that TPTD therapy with careful monitoring can provide an effective treatment option for patients with ORN in select refractory cases, with the benefits outweighing the potential risks. PMID- 29249016 TI - Therapeutic activity of plant-derived alkaloid conophylline on metabolic syndrome and neurodegenerative disease models. AB - Increasing metabolic syndromes including type-2 diabetes mellitus, obesity, and steatohepatitis are serious problems in most countries in the world. Neurodegenerative diseases such as Alzheimer, Parkinson's, and Huntington's diseases are increasing in many countries. However, therapy for these diseases is not sufficient yet. Thus, effective chemotherapy for these diseases is being expected. Conophylline is an alkaloid isolated from the leaves of Ervatamia microphylla and related plants. It was found to induce beta-cell differentiation in the precursor pancreatic cells. Oral administration of this compound ameliorated type-2 diabetes mellitus model in mice and rats. Later, fibrosis of the pancreatic islets was found to be greatly reduced by conophylline in the pancreatic islets. It also inhibited chemically induced liver cirrhosis. Further study indicated that conophylline inhibited non-alcoholic steatohepatitis in the model mice. On the one hand, loss of autophagy often causes protein aggregation to give neural cell death. Conophylline was found to activate autophagy in cultured neural cells. Activation of autophagy ameliorated cellular models of Parkinson's and Huntington's diseases. Thus, conophylline is likely to be useful for the development of chemotherapy for metabolic and neurodegenerative diseases. PMID- 29249018 TI - One-hour post-load plasma glucose level is associated with a worse metabolic profile in children with GH deficiency. AB - PURPOSE: In children, the plasma glucose value at 1 h (1hPG) during OGTT higher than 132.5 mg/dl is a predictor of alterations in glucose metabolism. We aimed to metabolically characterize GHD children according to 1hPG levels. METHODS: Fifty one GHD children (35 M, 16 F; mean age 8.6 years), grouped according to 1hPG, were evaluated at diagnosis and after 12 months of GH treatment (GHT) and compared with 50 matched controls at baseline. Auxological parameters, insulin like growth factor-1 (IGF-1), glucose and insulin during OGTT, lipid profile, the oral disposition index (DIo), the homeostasis model assessment estimate of insulin resistance (Homa-IR), and the insulin sensitivity index (ISI) were evaluated. RESULTS: At baseline, 31.4% of GHD children and 12% of controls (p = 0.016) showed 1hPG >= 132.5 mg/dl. The first ones showed higher mean 1hPG (p = 0.025) and LDL cholesterol (p = 0.029) and lower HDL cholesterol (p = 0.014) than controls. GHD with higher 1hPG showed a significant decrease in DIo (p < 0.001) without improvement in lipid profile after GHT, compared with children with lower 1hPG. After 12 months, the higher 1hPG group showed lower ISI Matsuda (p = 0.047) and DIo (p < 0.001) than the lower 1hPG group. 1hPG levels proved to be positively correlated with Homa-IR (p = 0.010) and LDL cholesterol (p = 0.032) and negatively with ISI Matsuda (p = 0.001) and DIo (p = 0.019). The 1hPG value at baseline was the only independent variable significantly associated with DIo at 12 months (p = 0.041). CONCLUSIONS: 1hPG level at baseline may be a useful tool to identify and properly follow up children with enhanced metabolic risk who probably need more surveillance during GHT. PMID- 29249019 TI - Acrolein toxicity at advanced age: present and future. AB - It is thought that tissue damage at advanced age is mainly caused by ROS (reactive oxygen species, O2-, H2O2, and .OH). However, it was found that acrolein (CH2=CH-CHO) is more toxic than ROS, and is mainly produced from spermine (SPM), one of the polyamines, rather than from unsaturated fatty acids. Significant amounts of SPM are present normally as SPM-ribosome complexes, and contribute to protein synthesis. However, SPM was released from ribosomes due to the degradation of ribosomal RNA by .OH or the binding of Ca2+ to ribosomes, and acrolein was produced from free SPM by polyamine oxidases, particularly by SPM oxidase. Acrolein inactivated several proteins such as GAPDH (glycelaldehyde-3 phosphate dehydrogenase), and also stimulated MMP-9 (matrix metalloproteinase-9) activity. Acrolein-conjugated GAPDH translocated to nucleus, and caused apoptosis like nitrosylated GAPDH. Through acrolein conjugation with several proteins, acrolein causes tissue damage during brain stroke, dementia, renal failure, and primary Sjogren's syndrome. Thus, development of acrolein scavengers with less side effects is very important to maintain QOL (quality of life) of elderly people. PMID- 29249020 TI - Multi-omic approach decodes paradoxes of the triple-negative breast cancer: lessons for predictive, preventive and personalised medicine. AB - Breast cancer epidemic in the early twenty-first century results in around two million new cases and half-a-million of the disease-related deaths registered annually worldwide. A particularly dramatic situation is attributed to some specific patient subgroups such as the triple-negative breast cancer (TNBC). TNBC is a particularly aggressive type of breast cancer lacking clear diagnostic approach and targeted therapies. Consequently, more than 50% of the TNBC patients die of the metastatic BC within the first 6 months of the diagnosis. In the current study we have hypothesised that multi-omic approach utilising blood samples may lead to discovery of a unique molecular signature of the TNBC subtype. The results achieved demonstrate, indeed, multi-omics as highly promising approach that could be of great clinical utility for development of predictive diagnosis, targeted prevention and treatments tailored to the person overall advancing the management of the TNBC. PMID- 29249021 TI - In Their Own Words: Research Misconduct from the Perspective of Researchers in Malaysian Universities. AB - Published data and studies on research misconduct, which focuses on researchers in Malaysia, is still lacking, therefore, we decided that this was an area for investigation. This study provides qualitative results for the examined issues through series of in-depth interviews with 21 researchers and lecturers in various universities in Malaysia. The aims of this study were to investigate the researchers' opinions and perceptions regarding what they considered to be research misconduct, their experience with such misconduct, and the factors that contribute to research misconduct. Our findings suggest that the most common research misconducts that are currently being witnessed in Malaysian universities are plagiarism and authorship disputes, however, researchers seldom report incidents of research misconduct because it takes too much time, effort and work to report them, and some are just afraid of repercussions when they do report it. This suggests possible loopholes in the monitoring system, which may allow some researchers to bypass it and engage in misconduct. This study also highlights the structural and individual factors as the most influential factors when it comes to research misconduct besides organizational, situational and cultural factors. Finally, this study highlights the concerns of all participants regarding the 'publish or perish' pressure that they believe would lead to a hostile working environment, thus enhancing research misconduct, as researchers tend to think about their own performance rather than that of whole team or faculty. Consequently this weakens the interpersonal relationships among researchers, which may compromise the teaching and supervision of junior researchers and research students. PMID- 29249022 TI - Google Search as an Additional Source in Systematic Reviews. PMID- 29249023 TI - Cortical Fractal Analysis and Collagen Crosslinks Content in Femoral Neck After Osteoporotic Fracture in Postmenopausal Women: Comparison with Osteoarthritis. AB - The femoral neck (FN) has been previously characterized by thinner cortices in osteoporotic fracture (HF) when compared to hip osteoarthritis (HOA). The purposes of this study were to complete the previous investigations on FNs from HF and HOA by analyzing the complexity of the cortical structure and to approach the intrinsic properties of cortical bone by assessing the collagen crosslink contents. FN samples were obtained during arthroplasty in 35 postmenopausal women (HF; n = 17; mean age 79 +/- 2 years; HOA; n = 18; mean age 66 +/- 2 years). The cortical fractal dimension (Ct.FD) and lacunarity (Ct.Lac) derived from high resolution peripheral quantitative tomography (isotropic voxel size: 82 MUm) images of FN by using Ctan software and Fraclac running in ImageJ were analyzed. The collagen crosslinks content [pyridinoline, deoxypyridinoline, pentosidine (PEN)] were assessed in cortical bone. Ct.FD was significantly lower (p < 0.0001) in HF than HOA reflecting a decreased complexity and was correlated to the age and BMD. In two sub-groups, BMD- and age-matched, respectively, Ct.FD remained significantly lower in HF than HOA (p < 0.001). Ct.Lac was not different between HF and HOA. PEN content was two times higher in HF than HOA (p < 0.0001) independently of age. In conclusion, FN with HF was characterized by a less complex cortical texture and higher PEN content than HOA. In addition to the decreased bone mass and BMD previously reported, these modifications contribute to the lower bone quality in HF than HOA in postmenopausal women. PMID- 29249024 TI - Investigations of microbial degradation of polycyclic aromatic hydrocarbons based on 13C-labeled phenanthrene in a soil co-contaminated with trace elements using a plant assisted approach. AB - Co-contaminations of soils with organic and inorganic pollutants are a frequent environmental problem. Due to their toxicity and recalcitrance, the heterogeneous pollutants may persist in soil. The hypothesis of this study was that degradation of polycyclic aromatic hydrocarbons (PAHs) is enhanced if heavy metals in soil are immobilized and their bioavailability reduced. For metal immobilization and enhanced biodegradation, distinct mineral and organic soil amendments (iron oxides, gravel sludge, biochar) were deployed in an incubation batch experiment. The second part of the experiment consisted of a greenhouse pot experiment applying fast-growing and pollution-tolerant woody plants (willow and black locust). Soil amendments initially immobilized NH4NO3-extractable zinc, cadmium, and lead; after 100 days of incubation, soil amendments showed reductions only for cadmium and a tendency to enhance arsenic mobility. In order to monitor the remediation success, a 13C-phenanthrene (PHE) label was applied. 13C-phospholipid fatty acid analysis (13C-PLFA) further enabled the identification of PHE degrading soil microorganisms. Both experiments exhibited a similar PLFA profile. Gram-negative bacteria (esp. cy17:0, 16:1omega7 + 6, 18:1omega7c) were the most significant microbial group taking up 13C-PHE. Plants effectively increased the label uptake by gram-positive bacteria and increased the biomass of the fungal biomarker, although their contribution to the degradation process was minor. Plants tended to prolong PAH dissipation in soil; at the end of the experiment, however, all treatments showed equally low total PAH concentrations in soil. While black locust plants tended not to take up potentially toxic trace elements, willows accumulated them in their leaves. The results of this study show that the chosen treatments did not enhance the remediation of the experimental soil. PMID- 29249025 TI - Monitoring of heavy metal burden in wild birds at eastern/north-eastern part of Hungary. AB - Concentrations of different heavy metals (As, Cd, Cr, Cu, Hg, Pb, Zn) were examined in the contour feathers of long-eared owl (Asio otus), little owl (Athene noctua), tawny owl (Strix aluco), barn owl (Tyto alba), Eurasian sparrowhawk (Accipiter nisus), rook (Corvus frugilegus), hooded crow (Corvus cornix), carrion crow (Corvus corone), common buzzard (Buteo buteo) and barn swallow (Hirundo rustica). The samples were collected from the Hortobagyi Madarpark (Bird Hospital Foundation) in Hungary. The bird species were classified into six groups based on their nourishment. Feathers were analysed by inductively coupled plasma optical emission spectroscopy (ICP-OES). The aim of our study was to determine the concentration of the above-mentioned heavy metals in the six different groups and to compare them by the groups, to find a possible connection between the concentrations and the age of birds and to get some information about the heavy metal burden of the environment. The highest As concentration was measured in little owl (0.65 +/- 0.56 mg/kg). The highest Cd, Cr and Pb concentration was found in the feathers of barn swallow (0.13 +/- 0.06 mg/kg; 1.69 +/- 0.44 mg/kg; 5.36 +/- 1.46 mg/kg), while the highest Cu and Hg concentration (65.45 +/- 17.66 mg/kg; 2.72 +/- 1.08 mg/kg) in sparrowhawk feathers and the highest Zn concentration in owls (157.21 +/- 57.3 mg/kg). Statistically significant difference has been determined between the juvenile and adult crows in the case of Cd (p = 0.011). The higher concentration was measured in adults (0.14 +/- 0.04 mg/kg) than that in juveniles (0.08 +/- 0.02 mg/kg). Based on our results, the examined area is not contaminated by these heavy metals on that level, which can cause any adverse effect or poisoning in birds, so this region is safe to wildlife. PMID- 29249026 TI - Efficiency of biogas slurry and Burkholderia phytofirmans PsJN to improve growth, physiology, and antioxidant activity of Brassica napus L. in chromium contaminated soil. AB - Contamination of soil is a major problem globally with colligated danger for ecosystem and human health. Chromium (Cr) is a toxic heavy metal and caused harmful effect on growth and development of plants. Phytostabilization reduced the mobility of heavy metals with addition of amendments which can significantly decrease metal solubility in soil. Phytostabilization can be achieved by application of biogas slurry (BGS) and endophytic bacteria as amendments in the contaminated soils. The present study revealed that the Burkholderia phytofirmans PsJN and BGS improved the growth, physiology, and antioxidant activity and reduced Cr uptake under a pot experiment spiked with Cr (20 mg kg-1 soil). The experiment was designed under completely randomized design, four treatments with three replications in normal and Cr-contaminated soil. The inoculation of endophytic bacteria improved the growth and physiology of Brassica. This study showed that the inoculation of endophytic bacteria stabilized the Cr levels in soil and minimized the uptake by the plant shoots and roots in BGS-amended soil. Similarly, activity of antioxidants such as catalase (CAT), reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and glutathione s-transferase (GST) was decreased to normal with combined treatment of BGS and endophytic bacteria in Cr stressed soil. Overall, the best results were analyzed by combined treatment of BGS and endophytic bacteria to improve growth, physiology, and antioxidant activity of Brassica and immobilize Cr in soil. Moreover, results emphasized the need to use BGS alone or in combination with endophytic bacteria to optimize crop performance, stabilize Cr concentration, and improve environmental efficiency. PMID- 29249027 TI - Treatment of produced water originated from oil and gas production wells: a pilot study and cost analysis. AB - Produced water originated from oil and gas production wells was treated by a pilot-scale system including pre-treatment (chemical precipitation), pre filtration, and post-filtration units. Pre-filtration unit consisted of sand filter, granulated activated carbon (GAC) filter, and ultrafiltration (UF) membrane. Post-filtration unit included reverse osmosis (RO) membrane unit. In this study, two different RO membranes including sea water (SW) and brackish water (BW) membranes were comparatively evaluated in terms of treatment and filtration performance. Besides, a cost analysis was conducted for a real scale RO membrane unit by using the data obtained from the pilot plant study. Average fluxes of 12.7 and 9.4 L/m2 h were obtained by SW and BW membrane units, respectively. Higher COD and conductivity removal efficiencies were obtained by SW membrane in comparison to BW membrane. Total cost of 0.88 ?/m3 was estimated for a RO plant treating produced water with a flowrate capacity of 300 m3/d. PMID- 29249028 TI - Effects of rice straw mulching on N2O emissions and maize productivity in a rain fed upland. AB - In the hilly areas of southern China, uplands and paddies are located adjacent to each other. Using rice straw as mulch for upland soil may improve crop production and partially replace chemical fertilizers, which may mitigate N2O emissions. A field experiment was conducted to investigate the potential of rice straw mulching for mitigating N2O emissions and increasing crop production. The treatments included no mulching (CK), 5000 kg ha-1 of straw mulching (SM5), and 10,000 kg ha-1 of straw mulching (SM10). Moreover, all the treatments received equivalent amounts of nitrogen, phosphorus, and potassium from chemical fertilizers plus rice straw. Relative to CK, cumulative N2O emissions decreased by 23.1 and 33.5% with SM5 and SM10, respectively. Significant positive correlations were observed between N2O fluxes and soil water-filled pore space (WPFS) (r 2 = 0.495, P < 0.05) and between seasonal cumulative N2O fluxes and the chemical N fertilization rate (r 2 = 0.814, P < 0.05). These findings indicate that soil WPFS was the key environmental factor in N2O emissions and that the substitution of chemical nitrogen fertilizer with rice straw was the main driver of N2O mitigation. Relative to CK, the maize yield increased by 16.5 and 29.6% with SM5 and SM10, respectively, which can be attributed primarily to the increases in soil moisture. The chemical fertilizer input could be decreased and N2O emissions could be mitigated through straw mulching, while achieving improved crop yield. This management strategy has great potential, and this study provides an important reference for low-carbon agriculture. PMID- 29249029 TI - Efficient fluoride removal using Al-Cu oxide nanoparticles supported on steel slag industrial waste solid. AB - A SSW/Al-Cu formed from an industrial solid waste and Al-Cu Nps are utilized for the removal of fluoride from aqueous solutions. The SSW/Al-Cu was obtained by a chemical reduction method. The SSW/Al-Cu was characterized by TEM, SEM, FT-IR, XRD, BET, and pHzpc techniques. The Nps were formed as bimetallic oxides and deposited in the form of spheroidal particles forming agglomerations. The sizes of these particles range from 1 to 3 nm. The surface area and average pore width of SSW/Al-Cu were 2.99 m2/g and 17.09 nm, respectively. The adsorption kinetics were better described using the second-order model, pointing to chemical adsorption with an equilibrium time of 540 min. The thermodynamic parameters obtained here confirm the spontaneous and endothermic nature of the process. The percentage of fluoride removal was 89.5% using the four-bladed disk turbine, and computational fluid dynamics (CFD) modeling demonstrated that using the four bladed disk turbine helped improve the fluoride removal process. The maximum adsorption capacity was 3.99 mg/g. The Langmuir-Freundlich model best describes the adsorption process, which occurred by a combination of mechanisms, such as electrostatic interactions between the ions involved in the process. This study proves that the chemical modification of this waste solid created an efficient bimetallic nanomaterial for fluoride removal. Furthermore, the method of preparation of these nanocomposites is quite scalable. PMID- 29249030 TI - Removal of Procion Red dye from colored effluents using H2SO4-/HNO3-treated avocado shells (Persea americana) as adsorbent. AB - The treatment of colored effluents containing Procion Red dye (PR) was investigated using H2SO4 and HNO3 modified avocado shells (Persea americana) as adsorbents. The adsorbent materials (AS-H2SO4 and AS-HNO3) were properly characterized. The adsorption study was carried out considering the effects of adsorbent dosage and pH. Kinetic, equilibrium, and thermodynamic aspects were also evaluated. Finally, the adsorbents were tested to treat simulated dye house effluents. For both materials, the adsorption was favored using 0.300 g L-1 of adsorbent at pH 6.5, where, more than 90% of PR was removed from the solution. General order model was able to explain the adsorption kinetics for both adsorbents. The Sips model was adequate to represent the isotherm data, being the maximum adsorption capacities of 167.0 and 212.6 mg g-1 for AS-H2SO4 and AS-HNO3, respectively. The adsorption processes were thermodynamically spontaneous, favorable (- 17.0 < DeltaG 0 < - 13.2 kJ mol-1), and exothermic (DeltaH 0 values of - 29 and - 55 kJ mol-1). AS-H2SO4 and AS-HNO3 were adequate to treat dye house effluents, attaining color removal percentages of 82 and 75%. Avocado shells, after a simple acid treatment, can be a low-cost option to treat colored effluents. PMID- 29249031 TI - Application of protein typing in molecular epidemiological investigation of nosocomial infection outbreak of aminoglycoside-resistant Pseudomonas aeruginosa. AB - Pseudomonas aeruginosan has emerged as an important pathogen elated to serious infections and nosocomial outbreaks worldwide. This study was conducted to understand the prevalence of aminoglycoside (AMG)-resistant P. aeruginosa in our hospital and to provide a scientific basis for control measures against nosocomial infections. Eighty-two strains of P. aeruginosa were isolated from clinical departments and divided into AMG-resistant strains and AMG-sensitive strains based on susceptibility test results. AMG-resistant strains were typed by drug resistance gene typing (DRGT) and protein typing. Five kinds of aminoglycoside-modifying enzyme (AME) genes were detected in the AMG-resistant group. AMG-resistant P. aeruginosa strains were classified into three types and six subtypes by DRGT. Four protein peaks, namely, 9900.02, 7600.04, 9101.25 and 10,372.87 Da, were significantly and differentially expressed between the two groups. AMG-resistant P. aeruginosa strains were also categorised into three types and six subtypes at the distance level of 10 by protein typing. AMG resistant P. aeruginosa was cloned spread in our hospital; the timely implementation of nosocomial infection prevention and control strategies were needed in preventing outbreaks and epidemic of AMG-resistant P. aeruginosa. SELDI TOF MS technology can be used for bacterial typing, which provides a new method of clinical epidemiological survey and nosocomial infection control. PMID- 29249032 TI - Cistus monspeliensis L. as a potential species for rehabilitation of soils with multielemental contamination under Mediterranean conditions. AB - The Iberian Pyrite Belt (IPB; SW of the Iberian Peninsula) is one of the most important volcanogenic massive sulphide ore deposits in the world. Cistus monspeliensis L. is a native woody shrub that grows spontaneously in non contaminated soils as well as in soils with multielemental contamination from the IPB. In this study, different ecophysiological parameters of C. monspeliensis growing in soils with different levels of metal(loid)s were evaluated to assess the potential of this species for revegetation of degraded areas. Composite samples of plants and rhizosphere soils were sampled in Sao Domingos and Lousal mines and in a reference area without soil contamination (Pomarao, Portugal) (Portuguese sector of IPB). Classical characterisation of the soils and quantification of their total and available metal(loid) concentrations were done. Multielemental concentration was determined in plants (shoots and roots). Ecophysiological parameters were also determined in shoots: concentrations of pigments (chlorophylls, anthocyanins and carotenoids), antioxidants (glutathione and ascorbate) and hydrogen peroxide as well as activities of several antioxidative enzymes. Although mining soils present high total concentrations of potentially hazardous elements, their available fractions were low and similar among studied areas. Soil pH as well as concentrations of extractable P, total concentrations of As, Cd and Ni and concentrations of Cu, Cr, Ni, Pb and Sb in the soil available fraction differentiate the studied areas. Only concentrations of Cd, Pb and Sb in roots and shoots were explained by the concentrations of the same elements in the soil available fraction. Although the majority of elements were translocated from roots to shoots, the shoots concentrations were below the toxic values for domestic animals and only As, Mn and Zn reached phytotoxic concentrations. Ecophysiological parameters were similar independently of the studied area. Due to its adaptability, tolerance and standard plant features, C. monspeliensis is a good choice for rehabilitation of soils with multielemental contamination under similar climatic characteristics. PMID- 29249033 TI - Simultaneous purifying of Hg0, SO2, and NOx from flue gas by Fe3+/H2O2: the performance and purifying mechanism. AB - Hg0, SO2, and NOx result in heavily global environmental pollution and serious health hazards. Up to now, how to efficiently remove mercury with SO2 and NOx from flue gas is still a tough task. In this study, series of high oxidizing Fenton systems were employed to purify the pollutants. The experimental results showed that Fe3+/H2O2 was more suitable to purify Hg0 than Fe2+/H2O2 and Cu2+/H2O2. The optimal condition includes Fe3+ concentration of 0.008 mol/L, Hg0 inlet concentration of 40 MUg/m3, solution temperature of 50 degrees C, pH of 3, H2O2 concentration of 0.7 mol/L, and O2 percentage of 6%. When SO2 and NOx were taken into account under the optimal condition, Hg0 removal efficiency could be enhanced to 91.11% while the removal efficiency of both NOx and SO2 was slightly declined, which was consistent to the analysis of purifying mechanism. The removal efficiency of Hg0 was stimulated by accelerating the conversion of Fe2+ to Fe3+, which resulted from the existence of SO2 and NOx. The results of this study suggested that simultaneously purifying Hg0, SO2, and NOx from flue gas is feasible. PMID- 29249034 TI - Risk exposure assessment of per- and polyfluoroalkyl substances (PFASs) in drinking water and atmosphere in central eastern China. AB - We examined per- and polyfluoroalkyl substances (PFASs) in air from eight cities, and in water from six drinking-water treatment plants (DWTPs), in central eastern China. We analyzed raw and treated water samples from the DWTPs for 17 ionic PFASs with high-performance liquid chromatography/negative-electrospray ionization tandem mass spectrometry (HPLC/(-)ESI-MS/MS), and analyzed the gas and particle phases of atmospheric samples for 12 neutral PFASs by gas chromatography mass spectrometry (GC-MS). Perfluorooctanoic acid (PFOA) and perfluorohexanoic acid (PFHxA) were the dominant compounds in drinking water, and fluorotelomer alcohols (FTOHs) dominated in atmospheric samples. Of all the compounds in the treated water samples, the concentration of PFOA, at 51.0 ng L-1, was the highest. Conventional treatments such as coagulation (COA), flocculation (FOC), sedimentation (SED), and sand filtration (SAF) did not remove PFASs. Advanced treatments, however, including ultrafiltration (UF) and activated carbon (AC), removed the majority of PFASs except for shorter-chain PFASs such as perfluorobutanoic acid (PFBA) and perfluoropentanoic acid (PFPA). We also investigated human exposure to PFASs via drinking water and the atmosphere and found that the mean daily intake of PFASs was 0.43 ng kg-1 day-1. PMID- 29249035 TI - Clinicopathologic and Immunohistochemical Study of Combined Small Cell Carcinoma and Urothelial Carcinoma Molecular Subtype. AB - Muscle invasive bladder cancer, an aggressive disease with heterogeneous molecular profiles, has recently been subclassified into three major molecular subtypes -basal, luminal and "p53-like" urothelial carcinomas (UCas), which bear prognostic and therapeutic implication. Similar to breast cancer, basal and luminal subtype UCas are designated by basal (CK5/14) and luminal (CK20) markers. The "p53-like" subtype presents with wild-type p53 gene with upregulated p53 pathways and is implicated in chemoresistance. Urinary bladder is one of the most common primary sites of extrapulmonary small cell carcinoma (SmCC). Bladder SmCC frequently coexists with UCa; however, the relation of SmCC with specific UCa molecular subtypes has not been studied. The aim of this study is to investigate the clinicopathology and immunophenotypes of the combined SmCC and UCa molecular subtypes. A total of 22 combined SmCC and UCa cases were studied for the clinicopathology and immunohistochemical (IHC) profiles by luminal and basal cell markers as well as Her2/Neu and p53. Our results demonstrated that all the urinary bladder SmCCs were associated with high grade UCas. They were more commonly seen in older male patients with a smoking history and had a poor prognosis. Based on the reported molecular subtyping, the UCas could be immunohistochemically subclassified into luminal, basal, dual and null types, which showed different clinicopathologic and IHC features. Compared to non-SmCC associated UCa, the subtypes of UCa in the combined SmCCs and UCas were characterized by: 1) Although overall luminal type was still relatively more common in men, basal marker-expressing subtypes were significantly increased in incidence and were more common in women. 2) Her2/Neu overexpression was more commonly observed in luminal than basal cell marker-expressing UCas. 3) IHC overexpression of p53 was common in all the subtypes, with UCas and SmCCs sharing the same p53 expression pattern. Although limited by relatively a small number of cases, the results of this study will enhance our understanding of the combined SmCC and UCa entity and potentially lead to a future therapeutic management. PMID- 29249036 TI - Impact of diet restriction in the management of diabetes: evidences from preclinical studies. AB - The inappropriate dietary habits lead to the onset of age-related pathologies which include diabetes and cardiovascular ailments. Dietary restriction and nutritional therapy play an important role in the prevention of these chronic ailments. Preclinical research provides a basis for the therapeutic exploration of new dietary interventions for the clinical trials to potentiate the scientific management of diabetes and its related complications which further help in translating these nutritional improvements from bench to bedside. Within the same context, numerous therapeutically proved preclinical dietary interventions like high-fiber diet, caloric restriction, soy isoflavone-containing diets, etc., have shown the promising results for the management of diabetes and the associated complications. The focus of the present review is to highlight the various preclinical evidences of diet restriction for the management of diabetes and which will be helpful for enlightening the new ideas of nutritional therapy for future research exploration. In addition, some potential approaches are also discussed which are associated with various nutritional interventions to combat progressive diabetes and the associated disorders. Graphical abstract ?. PMID- 29249037 TI - Transient receptor potential vanilloid-3 (TRPV3) activation plays a central role in cardiac fibrosis induced by pressure overload in rats via TGF-beta1 pathway. AB - Cardiac fibrosis is a common pathologic change along with pressure overload. Recent studies indicated that transient receptor potential (TRP) channels played multiple roles in heart. However, the functional role of transient receptor potential vanilloid-3 (TRPV3) in cardiac fibrosis remained unclear. The present study was designed to investigate the relationship between TRPV3 activation and pressure overload-induced cardiac fibrosis. Pressure overload rats were successfully established by abdominal aortic constriction (AAC), and cardiac fibrosis was simulated by 100 nM angiotensin II (Ang II) in neonatal cardiac fibroblasts. Echocardiographic parameters, cardiac fibroblast proliferation, cell cycle, intracellular calcium concentration ([Ca2+] i ), and the protein expressions of collagen I, collagen III, transforming growth factor beta 1 (TGF beta1), cyclin E, and cyclin-dependent kinase 2 (CDK2) were measured. Echocardiographic and histological measurements suggested that the activation of TRPV3 exacerbated the cardiac dysfunction and increased interstitial fibrosis in pressure overload rats. Further results showed that TRPV3 activation upregulated the expressions of collagen I, collagen III, TGF-beta1, cyclin E, and CDK2 in vivo and in vitro. At the same time, blocking TGF-beta1 pathway could partially reverse the effect of TRPV3 activation. These results suggested that TRPV3 activation exacerbated cardiac fibrosis by promoting cardiac fibroblast proliferation through TGF-beta1/CDK2/cyclin E pathway in the pressure-overloaded rat hearts. PMID- 29249038 TI - Nitrate removal in a combined bioelectrochemical and sulfur autotrophic denitrification system under high nitrate concentration: effects of pH. AB - A combined bioelectrochemical and sulfur autotrophic denitrification (CBSAD) system was established to treat high concentration nitrate under different pH conditions in this study. The microbial communities and structures were evaluated to deeply reveal the nitrate removal mechanisms in this combined system. When initial pH was adjusted to 6.5, the CBSAD system obtained 66.45% denitrification efficiency. The combined system achieved highest nitrate removal efficiency of 96.84% at pH 7.5. However, nitrate removal efficiency decreased to 87.05% when initial pH increased to 8.5. Microbial analyses demonstrated that pH value slightly influenced the bacterial abundances and bacterial species in this CBSAD system under high nitrate concentration condition. Proteobacteria was the most dominant phylum in this system, which accounted for more than 90% of the total phyla. Epsilonproteobacteria, Betaproteobacteria, and Gammaproteobacteria were the most important classes for denitrification process. Genus Sulfurimonas was primarily responsible for high nitrate removal in this CBSAD system. PMID- 29249040 TI - Correction to: Generation and characterization of tissue-type plasminogen activator transgenic rats. AB - In the original publication of the article, the sentence in "Result" section have been incorrectly published as: "Three lines of tPA Tg rats were generated and analyzed by Southern blotting to confirm the presence of the transgene in genomic DNA. When rat DNA was digested with EcoRI and hybridized to the tPA probe described in "Materials and methods", a 1.0 kb band was detected (Fig. 1a, b). One founder line was selected because of its high copy number (about ten copies) of tPA gene and itansgene) and 4.4 kb (endogenous gene) reding appearance, body weight, hematology, and systematization." The corrected sentence should read as: "Three lines of tPA Tg rats were generated and analyzed by Southern blotting to confirm the presence of the transgene in genomic DNA. When rat DNA was digested with EcoRI and hybridized to the tPA probe described in "Materials and methods", a 1.0 kb band was detected (Fig. 1a, b). One founder line was selected because of its high copy number (about ten copies) of tPA gene and its lack of detectable abnormal findings, including appearance, body weight, hematology, and systematization." The original article has been corrected. PMID- 29249042 TI - Variations in the temperature sensitivity of spring leaf phenology from 1978 to 2014 in Mudanjiang, China. AB - Continuous long-term temperature sensitivity (ST) of leaf unfolding date (LUD) and main impacting factors in spring in the period 1978-2014 for 40 plant species in Mudanjiang, Heilongjiang Province, Northeast China, were analyzed by using observation data from the China Phenological Observation Network (CPON), together with the corresponding meteorological data from the China Meteorological Data Service Center. Temperature sensitivities, slopes of the regression between LUD and mean temperature during the optimum preseason (OP), were analyzed using 15 year moving window to determine their temporal trends. Major factors impacting ST were then chosen and evaluated by applying a random sampling method. The results showed that LUD was sensitive to mean temperature in a defined period before phenophase onset for all plant species analyzed. Over the period 1978-2014, the mean ST of LUD for all plant species was - 3.2 +/- 0.49 days degrees C-1. The moving window analysis revealed that 75% of species displayed increasing ST of LUD, with 55% showing significant increases (P < 0.05). ST for the other 25% exhibited a decreasing trend, with 17% showing significant decreases (P < 0.05). On average, ST increased by 16%, from - 2.8 +/- 0.83 days degrees C-1 during 1980-1994 to - 3.30 +/- 0.65 days degrees C-1 during 2000-2014. For species with later LUD and longer OP, ST tended to increase more, while species with earlier LUD and shorter OP tended to display a decreasing ST. The standard deviation of preseason temperature impacted the temporal variation in ST. Chilling conditions influenced ST for some species, but photoperiod limitation did not have significant or coherent effects on changes in ST. PMID- 29249039 TI - Advances in ovarian cancer therapy. AB - Epithelial ovarian cancer is typically diagnosed at an advanced stage. Current state-of-the-art surgery and chemotherapy result in the high incidence of complete remissions; however, the recurrence rate is also high. For most patients, the disease eventually becomes a continuum of symptom-free periods and recurrence episodes. Different targeted treatment approaches and biological drugs, currently under development, bring the promise of turning ovarian cancer into a manageable chronic disease. In this review, we discuss the current standard in the therapy for ovarian cancer, major recent studies on the new variants of conventional therapies, and new therapeutic approaches, recently approved and/or in clinical trials. The latter include anti-angiogenic therapies, polyADP-ribose polymerase (PARP) inhibitors, inhibitors of growth factor signaling, or folate receptor inhibitors, as well as several immunotherapeutic approaches. We also discuss cost-effectiveness of some novel therapies and the issue of better selection of patients for personalized treatment. PMID- 29249041 TI - Comparison of TIVA with different combinations of ketamine-propofol mixtures in pediatric patients. AB - PURPOSE: Adding ketamine to propofol has been suggested to be useful for sedation and general anesthesia. This study aimed to determine the effect of TIVA with different ratios of ketofol on recovery in children. METHODS: Seventy-five children aged 3-12 years and undergoing adenoidectomy and/or tonsillectomy surgery were randomized into three groups. Ratios of 1:5, 1:6.7 and 1:10 ketamine propofol mixture (ketofol) were prepared in the same syringe for groups I, II and III, respectively. Induction and maintenance of anesthesia were performed with 1:5, 1:6.7 and 1:10 ratios of ketofol in groups I, II and III, respectively. A McFarlan infusion dose regimen was used (15 mg/kg/h for 15 min, 13 mg/kg/h for 15 min, 11 mg/kg/h for 30 min) and infusion rates were decreased for the different ratios. Infusion rates were reduced to 67, 80 and 90% of the McFarlan dose regimen for groups I, II and III, respectively. Extubating time, length of stay in PACU, postoperative PAED and FLACC scores were recorded. RESULTS: Extubating time was significantly lower [mean 254.3 +/- 92.7 s (95% CI 216.6-292.6, p = 0.001)] in group III than in groups I and II [371.3 +/- 153 s (308.1-434.48) and 343.2 +/- 123.7 s (292.2-394.3), respectively]. Length of stay in the PACU was lower in group III [median 15 min (interquartile range 15-20, p = 0.001)] than in groups I and II: 20 (15-27.5) and 20 min (20-27.5), respectively. CONCLUSION: TIVA with a 1:10 ratio of ketofol admixture with a 90% reduction of McFarlan regimen can provide improved recovery conditions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02848963. PMID- 29249043 TI - Consensus on the assessment of disordered eating in pregnancy: an international Delphi study. AB - This study aimed to assess and develop consensus on the assessment of disordered eating in pregnancy. A three-round modified Delphi approach was used. Participants were international clinicians and researchers (N = 26) with extensive knowledge on and/or clinical experience with eating disorders, particularly in relation to pregnancy and/or women's health. Clear consensus among the panel, defined as 75% agreement, was reached regarding the assessment of disordered eating in pregnancy, in addition to potential assessment methods. Antenatal assessment of disordered eating was perceived to be crucial and ideally occur in a routine manner. Despite agreement that various assessment methods would be relevant in assessing disordered eating in pregnancy, psychometrically sound brief screening instruments were perceived to be most feasible for practitioners and women accessing antenatal care; however, these instruments must be pregnancy-specific and delivered in an authentic and caring manner to be beneficial. PMID- 29249044 TI - Endogenous Fusarium Endophthalmitis During Treatment for Acute Myeloid Leukemia, Successfully Treated with 25-Gauge Vitrectomy and Antifungal Medications. AB - Endogenous fungal endophthalmitis (EFE) caused by disseminated fusariosis is a rare condition that generally has a poor outcome, even with intensive therapy. Here, we describe a case in which this type of EFE was diagnosed with vitreous sampling and was successfully treated with 25-gauge vitrectomy and antifungals, including liposomal amphotericin B and voriconazole. A 16-year-old male patient undergoing treatment for acute myeloid leukemia complained of eye pain and blurred vision in his right eye. Treatment was initiated for a vitreous opacity, possibly associated with herpetic retinitis, but the patient worsened and he was referred to us. Right-eye visual acuity was limited to light perception. We suspected endogenous endophthalmitis and performed 25-gauge vitrectomy with antibiotic perfusion of ceftazidime, vancomycin, and voriconazole. Vitreous culturing revealed the presence of Fusarium solani species complex, and enhanced computed tomography revealed disseminated fusariosis lesions in the lung, spleen, and the soft tissue of the left upper arm. The patient received antifungal treatment with liposomal amphotericin B and voriconazole, and these conditions were eliminated. Visual acuity recovered to 20/400 after additional vitrectomy for tractional retinal detachment and was maintained at this level during the 6 month follow-up period. The success of our treatment allowed the capture of optical coherence tomography images of the retina during fusarium-associated endogenous endophthalmitis and the follow-up period. Furthermore, this case showed that immediate vitrectomy for suspected EFE and intensive treatment can lead to a good clinical outcome. PMID- 29249045 TI - Longitudinal patterning in roots: a GATA2-auxin interaction underlies and maintains the root transition domain. AB - MAIN CONCLUSION: In Arabidopsis thaliana root meristems the GATA2 transcription factor is a marker for the root transition domain, is auxin regulated, and functions to restrict cell division activity. The growing part of roots is comprised of three discrete regions; the proliferative domain (PD), an elongation zone, and interposed between these two, the transition domain (TD), which is the focus of this investigation. Within the TD, it is hypothesized that cells are reprogrammed, losing the capacity to divide and begin to differentiate. In recently germinated Arabidopsis thaliana seedlings, a TD is not anatomically evident, but subsequently forms in a region of the root in which there has occurred prior expression of both AUX1/PIN2 proteins and of transcripts of the GATA transcription factor family (pGATA2:H2B-YFP or pGATA2:GUS). pGATA2:GUS expression is regulated by auxin and is reduced in seedlings in which either auxin transport or auxin sensitivity is perturbed. Application of cytokinin results in a reduction in both pGATA2:GUS expression and in TD cell number, via a pathway involving ARR1 and ARR12. Overexpression of GATA2 is accompanied by a reduction in cell number in the PD, but has no effect on cell number in the TD, whereas in knockdowns of GATA transcription factors, cell number is reduced in both the PD and TD. We conclude: (1) that GATA2 expression is localized to (a marker for) the TD; (2) that development and maintenance of the TD are associated with an auxin-regulation of GATA2 expression; (3) that GATA transcription factors function to restrict cell division activity. PMID- 29249046 TI - Generation of transgenic goats by pronuclear microinjection: a retrospective analysis of a commercial operation (1995-2012). AB - Production of transgenic founder goats involves introducing and stably integrating an engineered piece of DNA into the genome of the animal. At LFB USA, the ultimate use of these transgenic goats is for the production of recombinant human protein therapeutics in the milk of these dairy animals. The transgene or construct typically links a milk protein specific promoter sequence, the coding sequence for the gene of interest, and the necessary downstream regulatory sequences thereby directing expression of the recombinant protein in the milk during the lactation period. Over the time period indicated (1995-2012), pronuclear microinjection was used in a number of programs to insert transgenes into 18,120, 1- or 2- cell stage fertilized embryos. These embryos were transferred into 4180 synchronized recipient females with 1934 (47%) recipients becoming pregnant, 2594 offspring generated, and a 109 (4.2%) of those offspring determined to be transgenic. Even with new and improving genome editing tools now available, pronuclear microinjection is still the predominant and proven technology used in this commercial setting supporting regulatory filings and market authorizations when producing founder transgenic animals with large transgenes (> 10 kb) such as those necessary for directing monoclonal antibody production in milk. PMID- 29249047 TI - Electrolytic post-training lesions of the bed nucleus of the stria terminalis block startle potentiation in a cued fear conditioning procedure. AB - Existing neuroanatomical models argue that the bed nucleus of the stria terminalis (BST) principally mediates sustained, long-lasting fear or anxiety responses, but not shorter, phasic fear responses, although recent studies paint a more complex picture. In the current study, we evaluated the effect of post training electrolytic BST lesions in a cued fear conditioning protocol with relatively short (10 s) tones. We hypothesized that the BST would not play a crucial role in the expression of fear upon re-exposure to the conditioned tones. Tone fear memory was primarily assessed through fear-potentiated startle. In addition, freezing measurements were obtained throughout the test sessions. In a series of three experiments, we explored the effects of BST lesions, taking into consideration contextual influences on cued fear expression (using (dis)similar training and test contexts) and temporal involvement of the BST in the consolidation of fear learning (lesion induction 3 or 27 h after fear conditioning). In all three experiments, we found that post-training electrolytic lesions of the BST significantly reduced fear-potentiated startle, implying a deficit in differentiation between tone and context. These results are surprising and challenge the general consensus on the lack of BST involvement in cued fear. We discuss several alternative explanations that may account for these unexpected findings. PMID- 29249048 TI - A 14-Year Study of 398 Esophageal Adenocarcinomas Diagnosed Among 156,256 EGDs Performed at Two Large Hospitals: An Inlet Patch Is Proposed as a Significant Risk Factor for Proximal Esophageal Adenocarcinoma. AB - BACKGROUND: An association between inlet patches and proximal esophageal adenocarcinomas is currently suspected because of numerous case reports of simultaneous occurrence of both diseases. AIMS: To analyze whether inlet patches are significantly associated with proximal esophageal adenocarcinomas in a large population. METHODS: Computerized search of pathology and EGD reports revealed 398 cases of esophageal adenocarcinomas among 156,236 EGDs (performed on 106,510 patients) diagnosed by histopathology performed at Royal Oak/Troy, William Beaumont Hospitals, 2003-2016. Adenocarcinomas localized as distal, middle, or proximal; and characterized as associated versus unassociated with inlet patches. Medical records were reviewed. Endoscopic photographs, radiologic images, and pathologic slides were re-reviewed. Two researchers independently performed systematic computerized literature searches; cases of simultaneous diseases identified by consensus. RESULTS: Adenocarcinoma locations included: distal-381, middle-14, and proximal esophagus-3. Five patients had inlet patches with esophageal adenocarcinomas located at: distal-2, middle-0, and proximal esophagus 3 (relative frequency of inlet patches with cancers of distal/middle esophagus = 2/395 [.5%] vs. proximal esophagus = 3/3 [100%], p < .000001, 95% OR CI > 50.1, Fisher's exact test). Cases of proximal esophageal adenocarcinomas within inlet patches included: (1) Seventy-eight-year-old man presented with dysphagia. Neck CT showed proximal esophageal mass. EGD revealed semi-circumferential, multinodular, 3.0 * 1.5 cm mass within inlet patch. Histopathology of biopsies revealed moderately-to-poorly differentiated adenocarcinoma. Patient received chemoradiotherapy and expired 2 years later. (2) Seventy-nine-year-old man presented with anorexia and weight loss. EGD demonstrated proximal esophageal mass within inlet patch. Histopathology of biopsies revealed poorly differentiated, signet ring cell adenocarcinoma. Chest CT revealed 3.4 * 2.1-cm proximal esophageal mass. Patient expired 4 months later. (3) Sixty-year-old man presented with dysphagia. EGD revealed 4-cm-long, semi-circumferential, proximal esophageal mass within inlet patch. Histopathology of biopsies revealed poorly differentiated adenocarcinoma. Patient underwent emergency esophagectomy for esophageal perforation 2 weeks after initiating chemoradiotherapy, and died shortly thereafter. Literature review revealed 39 cases of simultaneous disease. STUDY LIMITATIONS: Potential underreporting by endoscopists of inlet patches at EGD. CONCLUSIONS: Study supplements 39 previously reported cases of simultaneous disease, by adding three new cases, and by novel report of statistically significant association between these two entities, which has important implications in the pathophysiology of proximal esophageal adenocarcinoma. PMID- 29249049 TI - Tramadol ameliorates behavioural, biochemical, mitochondrial and histological alterations in ICV-STZ-induced sporadic dementia of Alzheimer's type in rats. AB - Alzheimer disease represents a major public health issue with limited therapeutic interventions. We explored the possibility of therapeutic approach by repurposing of tramadol in a sporadic animal model of Alzheimer's type. Streptozocin (STZ 3 mg/kg; bilaterally) was injected to male SD rats through intracerebroventricular (ICV) route. Drug treatment was started just after streptozocin administration and continued for 3 weeks. The rats were killed on the 21st day following the last behavioral test, and cytoplasmic fractions of the hippocampus and pre frontal cortex were prepared for the quantification of acetylcholinesterase, oxidative stress parameter, mitochondrial enzymes activity and histological examination. Tramadol (5, 10 and 20 mg/kg, i.p.) was used as a treatment drug, and memantine (10 mg/kg, i.p.) was used as a standard. Tramadol significantly attenuated behavioral, biochemical, mitochondrial and histological alterations at low (5 mg/kg) and intermediate (10 mg/kg) dose, suggesting its neuroprotective potential in ICV-STZ-treated rats. Further, the neuroprotective effect of tramadol (10 mg/kg) was comparable to memantine (10 mg/kg). In conclusion, our results indicate the effectiveness of tramadol in preventing ICV-STZ-induced cognitive impairment as well as mito-oxidative stress. Further, these findings reveal the possibility of MOR agonist as a therapeutic approach for sporadic Alzheimer disease. PMID- 29249050 TI - A fuzzy logic expert system for evaluating policy progress towards sustainability goals. AB - Evaluating progress towards environmental sustainability goals can be difficult due to a lack of measurable benchmarks and insufficient or uncertain data. Marine settings are particularly challenging, as stakeholders and objectives tend to be less well defined and ecosystem components have high natural variability and are difficult to observe directly. Fuzzy logic expert systems are useful analytical frameworks to evaluate such systems, and we develop such a model here to formally evaluate progress towards sustainability targets based on diverse sets of indicators. Evaluation criteria include recent (since policy enactment) and historical (from earliest known state) change, type of indicators (state, benefit, pressure, response), time span and spatial scope, and the suitability of an indicator in reflecting progress toward a specific objective. A key aspect of the framework is that all assumptions are transparent and modifiable to fit different social and ecological contexts. We test the method by evaluating progress towards four Aichi Biodiversity Targets in Canadian oceans, including quantitative progress scores, information gaps, and the sensitivity of results to model and data assumptions. For Canadian marine systems, national protection plans and biodiversity awareness show good progress, but species and ecosystem states overall do not show strong improvement. Well-defined goals are vital for successful policy implementation, as ambiguity allows for conflicting potential indicators, which in natural systems increases uncertainty in progress evaluations. Importantly, our framework can be easily adapted to assess progress towards policy goals with different themes, globally or in specific regions. PMID- 29249051 TI - Interference of action perception on action production increases across the adult life span. AB - Action perception and action production are assumed to be based on an internal simulation process that involves the sensorimotor system. This system undergoes changes across the life span and is assumed to become less precise with age. In the current study, we investigated how increasing age affects the magnitude of interference in action production during simultaneous action perception. In a task adapted from Brass et al. (Brain Cogn 44(2):124-143, 2000), we asked participants (aged 20-80 years) to respond to a visually presented finger movement and/or symbolic cue by executing a previously defined finger movement. Action production was assessed via participants' reaction times. Results show that participants were slower in trials in which they were asked to ignore an incongruent finger movement compared to trials in which they had to ignore an incongruent symbolic cue. Moreover, advancing age was shown to accentuate this effect. We suggest that the internal simulation of the action becomes less precise with age making the sensorimotor system more susceptible to perturbations such as the interference of a concurrent action perception. PMID- 29249053 TI - A Review of Switching Biologic Agents in the Treatment of Moderate-to-Severe Plaque Psoriasis. AB - Psoriasis is an immune-mediated polygenic inherited skin disease. Many biologic agents have been approved for the treatment of moderate-to-severe plaque psoriasis. The most commonly utilized biologics include TNF-alpha antagonists (etanercept, infliximab, and adalimumab), IL-12/23P40 antagonist (ustekinumab), IL-23P19 antagonist (guselkumab), IL-17A antagonist (secukinumab and ixekizumab), and IL-17RA antagonist (brodalumab). However, some patients may fail to respond well to their first biologic agent. Reasons for failure include primary failure (lack of initial efficacy), secondary failure (loss of efficacy over time) or the development of adverse effects. For patients desiring maximum skin clearance and better quality of life, switching to a second biologic agent might be a worthwhile option. This review discusses recent clinical studies on switching therapies in treating psoriasis, and found that switching biologic agents can significantly improve outcomes for patients. Some clinical guidelines are also discussed. This research provides some advice on establishing individualized treatment regimens based on clinical needs and pharmacologic characteristics. PMID- 29249052 TI - Progressive loss of hybrid histidine kinase genes during the evolution of budding yeasts (Saccharomycotina). AB - Two-component systems (TCSs) are widely distributed cell signaling pathways used by both prokaryotic and eukaryotic organisms to cope with a wide range of environmental cues. In fungi, TCS signaling routes, that mediate perception of stimuli, correspond to a multi-step phosphorelay between three protein families including hybrid histidine kinases (HHK), histidine phosphotransfer proteins (HPt) and response regulators (RR). The best known of these fungal transduction pathways remains the Sln1(HHK)-Ypd1(HPt)-Ssk1(RR) system that governs the high osmolarity glycerol (HOG) mitogen-activated protein kinase (MAPK) pathway for osmo-adaptation in Saccharomyces cerevisiae. Although recent advances have provided a preliminary overview of the distribution of TCS proteins in the kingdom Fungi, underlying mechanisms that drive the remarkable diversity among HHKs and other TCS proteins in different fungal lineages remain unclear. More precisely, evolutionary paths that led to the appearance, transfer, duplication, and loss of the corresponding TCS genes in fungi have never been hitherto addressed. In the present study, we were particularly interested in studying the distribution of TCS modules across the so-called "budding yeasts clade" (Saccharomycotina) by interrogating the genome of 82 species. With the exception of the emergence of an additional RR (named Srr1) in the fungal CTG clade, TCS proteins Ypd1 (HPt), Ssk1 (RR), Skn7 (RR), and Rim15 (RR) are well conserved within the Saccharomycotina. Surprisingly, some species from the basal lineages, especially Lipomyces starkeyi, harbor several filamentous-type HHKs that appear as relict genes that have been likely retained from a common ancestor of Saccharomycotina. Overall, this analysis revealed a progressive diminution of the initial pool of HHK-encoding genes during Saccharomycotina yeast evolution. PMID- 29249054 TI - Transthyretin familial amyloid polyneuropathy: an update. AB - Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a progressive, fatal, inherited disorder first identified in Portugal and now recognized in all continents. Over the past decade, thanks to the availability of the genetic test, our knowledge on the range of clinical expressions of this disorder has expanded, including different patterns and progression rates of the neuropathy, as well as aspects of the cardiomyopathy, which can be prominent. In the mean time, new tools are being developed to detect earlier TTR amyloid deposition such as cardiac scintigraphy with technetium-labelled pyrophosphate tracers or small nerve fiber alterations from skin biopsies, or using neurophysiological approaches as well as magnetic resonance neurography (MRN). Such refinements, along with an increased awareness of the disease, should reduce the diagnostic delay and facilitate early treatment. In this regard, thanks to a better understanding of the TTR amyloid formation, major advances have been made, allowing for therapeutic developments which are less invasive than liver transplantation (LT). TTR stabilizer drugs are safe and seem to delay the disease progression in some groups of patients. Indeed, positive results have just been released from 2 phase III trials on TTR gene modifiers, namely silencing RNA and antisense oligonucleotide therapies. These recent advances open a new area in the field with the hope that we can safely bring about long-term stabilization of the disease. Furthermore, immunotherapies targeting the amyloid deposits are being explored. PMID- 29249055 TI - Brain magnetic resonance-imaging findings of anti-N-methyl-D-aspartate receptor encephalitis: a cohort follow-up study in Chinese patients. AB - The aim of this report was to assess routine clinical brain magnetic resonance imaging (MRI) and its relation to clinical characteristics and disease prognosis. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patients were consecutively recruited from West China Hospital between October 1, 2011 and April 1, 2016. Brain MRI findings of 106 patients were analysed, and outcomes were assessed at 4, 8, and 12 months after discharge from the hospital using the modified Rankin scale (mRS). An MRI of the brain was normal in 52/106 (49.1%) patients and abnormal or atypical in 54/106 (50.9%) patients. The initial MRI was abnormal with T2 or fluid-attenuated inversion recovery (FLAIR) hyper-intensity signals in 20/106 (18.9%) patients. There were no statistically significant differences between the MRI findings and clinical presentations (seizure, hypoventilation, loss of consciousness, and tumour) (P > 0.05). Patients with normal MRIs were younger than patients with abnormal MRIs (P < 0.05). The mean mRS score at the 4-month follow-up was significantly higher in patients with abnormal MRIs than in patients with normal MRIs (P < 0.05). Brain MRI abnormalities are typically mild or unrelated to clinical symptoms, which is a clinico-radiological paradox of this type of immune encephalitis. Abnormal MRIs did not affect prognosis evaluated by mRS. PMID- 29249056 TI - Adam Opalski (1897-1963). PMID- 29249057 TI - Stroke-associated infection independently predicts 3-month poor functional outcome and mortality. AB - Stroke-associated infection (SAI) is a common and serious complication of stroke. This study aimed to assess the effects of SAI on patient mortality and functional outcome at 3 months after stroke onset. We retrospectively analyzed 809 consecutive patients with acute stroke (517 men and 292 women; median age, 72 years) who were admitted to our department between September 2014 and June 2016. SAI was defined as an infection diagnosed during the hospitalization period. Poor outcome was defined as a modified Rankin Scale (mRS) score of 3-5 or death (mRS score of 6). The effect of SAI on functional outcome was evaluated using a multivariate logistic regression analysis. SAI occurred in 169 patients (20.9%); of these, 106 (62.7%) had pneumonia, 23 (13.6%) had a urinary-tract infection, and 40 (23.7%) had other types of infection. Patients with SAI were older, more likely to be female, had lower body mass indices, had higher stroke severity, and were more likely to have atrial fibrillation and a history of ischemic heart disease than patients without SAI. Poor functional outcome and mortality were more common in patients with SAI than in patients without SAI (poor functional outcome 41.8 vs. 4.8%, mortality 24.3 vs. 3.9%, respectively). After adjusting for age, sex, stroke severity, and various comorbidities, SAI was independently associated with poor functional outcome [odds ratio (OR) 6.88; 95% confidence interval (CI) 3.72-12.73] and mortality (OR 4.45, 95% CI 2.27-8.72) at 3 months after stroke onset. Our results suggest that SAI during the hospitalization period is independently associated with 3-month poor functional outcome and mortality. PMID- 29249058 TI - Changes in bone mineral density in women with breast cancer receiving aromatase inhibitor therapy. AB - PURPOSE: We assessed bone mineral density (BMD) change with aromatase inhibitor (AI) treatment in a contemporary cohort of women with breast cancer treated in Kaiser Permanente Northern California. METHODS: Percent and estimated annual percent changes in BMD at the total hip and lumbar spine were examined in 676 women receiving AI therapy who had two serial BMD reports available (at least 1 year apart) before and after AI initiation (N = 317) or during continued AI therapy (N = 359). BMD changes were examined at the total hip and lumbar spine and compared by age and clinical subgroups. RESULTS: Women experienced BMD declines after AI initiation or continued therapy, with median annual percent change - 1.2% (interquartile range, IQR - 2.4 to - 0.1%) at the hip and - 1.0% (IQR - 2.3 to 0.1%) at the spine after AI initiation, and - 1.1% (IQR - 2.4 to 0.1%) at the hip and - 0.9% (IQR - 2.4 to 0.5%) at the spine during continued therapy. Higher levels of bone loss were observed among younger (< 55 years) compared with older (>= 75 years) women at the hip (- 1.6% vs. - 0.8%) and at the spine (- 1.5% vs. - 0.5%) after AI initiation, and at the hip (- 1.4% vs. - 1.2%) and at the spine (- 2.4% vs. - 0.001%) during continued therapy. CONCLUSIONS: Small but consistent declines in total hip and lumbar spine BMD were present in breast cancer patients following AI therapy initiation or continued AI therapy. Although the overall rates of osteoporosis were low, greater estimated levels of annual bone loss were evident among women < 55 years. PMID- 29249059 TI - Convergent priorities and tensions: a qualitative study of the integration of complementary and alternative therapies with conventional cancer treatment. AB - PURPOSE: Demand for complementary and alternative medicine (CAM) is high among cancer patients. This, alongside growing evidence for the efficacy of some CAM therapies, is driving change within cancer centres, where evidence-based CAM therapies are increasingly provided alongside standard cancer treatments. In Australia, commitment to equitable access to healthcare is strong, and some cancer centres are now providing integrative services at no cost to the patient. This represents a significant shift in healthcare provision. This study aimed to examine health professional and patient dynamics in an integrated cancer service where CAM is provided at no cost to patients alongside standard cancer treatments. It specifically sought to understand what might drive or hinder further integration of CAM with standard treatment in the cancer context. METHODS: Qualitative interviews were undertaken with twenty key stakeholders cancer patients, cancer nurses, and oncologists-who were delivering or receiving care in an Australian public hospital where acupuncture services are provided at no cost to patients alongside standard chemotherapy and radiation treatments. RESULTS: Findings point to key areas where the concerns and priorities of cancer patients, cancer nurses, and oncologists converge and diverge in ways that reflect core personal and professional interests regarding patient care needs, the evidence base for CAM efficacy and safety, and rising healthcare costs. CONCLUSIONS: Understanding points of convergence and divergence could assist clinicians and service providers in negotiating ways forward for integrative cancer services. PMID- 29249060 TI - Genetics in palliative oncology: a missing agenda? A review of the literature and future directions. AB - PURPOSE: In the palliative oncology setting, genetic assessment may not impact on the patient's management but can be of vital importance to their surviving relatives. Despite care of the family being central to the ethos of palliative care, little is known about how hereditary aspects of cancer are addressed in this setting. This review aims to examine current practices, identify practice barriers and determine the genetic information and support needs of patients, family members and health providers. METHODS: Key databases were systematically searched to identify both quantitative and qualitative studies that addressed these aims. Data was extracted and coded using thematic analysis. RESULTS: Eight studies were included for review. Suboptimal genetic practices were identified, with lack of knowledge and poor confidence amongst providers reported as barriers in both qualitative and quantitative studies. Providers expressed concern about the emotional impact of initiating these discussions late in the disease trajectory; however, qualitative interviews amongst palliative patients suggested there may be emotional benefits. CONCLUSIONS: All lines of evidence suggest that genetics is currently missing from the palliative agenda, signifying lost opportunities for mutation detection, genetic counselling and appropriate risk management for surviving relatives. There is an urgent need for interventions to improve provider knowledge and awareness of genetic referral pathways and for research into the genetic information and support needs of palliative care patients. PMID- 29249061 TI - Combining an experimental study and ANFIS modeling to predict landfill leachate transport in underlying soil-a case study in north of Iran. AB - In the contemporary world, urbanization and progressive industrial activities increase the rate of waste material generated in many developed countries. Municipal solid waste landfills (MSWs) are designed to dispose the waste from urban areas. However, discharged landfill leachate, the soluble water mixture that filters through solid waste landfills, can potentially migrate into the soil and affect living organisms by making harmful biological changes in the ecosystem. Due to well-documented landfill problems involving contamination, it is necessary to investigate the long-term influence of discharged leachate on the consistency of the soil beds beneath MSW landfills. To do so, the current study collected vertical deep core samples from different locations in the same unlined landfill. The impacts of effluent leachate on physical and chemical properties of the soil and its propagation depth were studied, and the leachate-transport pattern between successive boreholes was predicted by a developed mathematical model using an adaptive neuro-fuzzy inference system (ANFIS). The decomposition of organic leachate admixtures in the landfill yield is to produce organic acids as well as carbon dioxide, which diminishes the pH level of the landfill soil. The chemical analysis of discharged leachate in the soil samples showed that the concentrations of heavy metals are much lower than those of chloride, COD, BOD5, and bicarbonate. Using linear regression and mean square errors between the measured and predicted data, the accuracy of the proposed ANFIS model has been validated. Results show a high correlation between observed and predicated data. PMID- 29249062 TI - Knockout of CTNNB1 by CRISPR-Cas9 technology inhibits cell proliferation through the Wnt/beta-catenin signaling pathway. AB - OBJECTIVE: To study the effects of CTNNB1 gene knockout by CRISPR-Cas9 technology on cell adhesion, proliferation, apoptosis, and Wnt/beta-catenin signaling pathway. RESULTS: CTNNB1 gene of HEK 293T cells was knocked out by CRISPR-Cas9. This was confirmed by sequencing and western blotting. Methylthiazolyl tetrazolium bromide assays indicated that deletion of beta-catenin significantly weakened adhesion ability and inhibited proliferation rate (P < 0.01) of HEK 293T cells. Nevertheless, deletion of beta-catenin did not affect apoptosis of HEK 293T cells, which was analyzed by flow cytometry with Annexin V-fluorescein isothiocyanate/propidium iodide double staining. In addition, expression level of GSK-3beta, CCND1, and CCNE1 detected by qPCR and expression level of N-Cadherin and cyclin D1 detected by western blotting were significantly decreased (P < 0.01) while expression of gamma-catenin detected by western blotting was significantly increased (P < 0.001). CONCLUSIONS: Knockout of CTNNB1 disturbed Wnt/beta-catenin signaling pathway and significantly inhibited adhesion and proliferation of HEK 293T cells. PMID- 29249063 TI - The application of plant in vitro cultures in cannabinoid production. AB - Cannabinoids have considerable interest in the pharmaceutical industry. However, the production of medicines from hemp (Cannabis sativa L.) in most countries is restricted by law. Large-scale, field cultivation of hemp is difficult to control. Cannabinoid content in plants is variable and depends on multiple factors. Therefore, alternative methods of production have been investigated. The development of micropropagation techniques is a necessary step for genetic modification. Promising results have been obtained for certain narcotic genotypes. However, micropropagation of fibre types requires further research. Hemp can be genetically modified which may contribute to the breeding of new varieties in the future. Cell suspension cultures and hairy root cultures of hemp have been used to produce cannabinoids but obtaining cannabinoids from callus and cell suspension cultures has proved impossible. Adventitious roots can, however, deliver small amounts of these metabolites but production ceases over time and is too low for industrial applications. PMID- 29249064 TI - Reduced deep regional cerebral venous oxygen saturation in hemodialysis patients using quantitative susceptibility mapping. AB - Cerebral venous oxygen saturation (SvO2) is an important indicator of brain function. There was debate about lower cerebral oxygen metabolism in hemodialysis patients and there were no reports about the changes of deep regional cerebral SvO2 in hemodialysis patients. In this study, we aim to explore the deep regional cerebral SvO2 from straight sinus using quantitative susceptibility mapping (QSM) and the correlation with clinical risk factors and neuropsychiatric testing. 52 hemodialysis patients and 54 age-and gender-matched healthy controls were enrolled. QSM reconstructed from original phase data of 3.0 T susceptibility weighted imaging was used to measure the susceptibility of straight sinus. The susceptibility was used to calculate the deep regional cerebral SvO2 and compare with healthy individuals. Correlation analysis was performed to investigate the correlation between deep regional cerebral SvO2, clinical risk factors and neuropsychiatric testing. The deep regional cerebral SvO2 of hemodialysis patients (72.5 +/- 3.7%) was significantly lower than healthy controls (76.0 +/- 2.1%) (P < 0.001). There was no significant difference in the measured volume of interests of straight sinus between hemodialysis patients (250.92 +/- 46.65) and healthy controls (249.68 +/- 49.68) (P = 0.859). There were no significant correlations between the measured susceptibility and volume of interests in hemodialysis patients (P = 0.204) and healthy controls (P = 0.562), respectively. Hematocrit (r = 0.480, P < 0.001, FDR corrected), hemoglobin (r = 0.440, P < 0.001, FDR corrected), red blood cell (r = 0.446, P = 0.003, FDR corrected), dialysis duration (r = 0.505, P = 0.002, FDR corrected) and parathyroid hormone (r = -0.451, P = 0.007, FDR corrected) were risk factors for decreased deep regional cerebral SvO2 in patients. The Mini-Mental State Examination (MMSE) scores of hemodialysis patients were significantly lower than healthy controls (P < 0.001). However, the deep regional cerebral SvO2 did not correlate with MMSE scores (P = 0.630). In summary, the decreased deep regional cerebral SvO2 occurred in hemodialysis patients and dialysis duration, parathyroid hormone, hematocrit, hemoglobin and red blood cell may be clinical risk factors. PMID- 29249066 TI - Bacillus amyloliquefaciens Spore Production Under Solid-State Fermentation of Lignocellulosic Residues. AB - This study was conducted to elucidate cultivation conditions determining Bacillus amyloliquefaciens B-1895 growth and enhanced spore formation during the solid state fermentation (SSF) of agro-industrial lignocellulosic biomasses. Among the tested growth substrates, corncobs provided the highest yield of spores (47 * 1010 spores g-1 biomass) while the mushroom spent substrate and sunflower oil mill appeared to be poor growth substrates for spore formation. Maximum spore yield (82 * 1010 spores g-1 biomass) was achieved when 15 g corncobs were moistened with 60 ml of the optimized nutrient medium containing 10 g peptone, 2 g KH2PO4, 1 g MgSO4.7H2O, and 1 g NaCl per 1 l of distilled water. The cheese whey usage for wetting of lignocellulosic substrate instead water promoted spore formation and increased the spore number to 105 * 1010 spores g-1. Addition to the cheese whey of optimized medium components favored sporulation process. The feasibility of developed medium and strategy was shown in scaled up SSF of corncobs in polypropylene bags since yield of 10 * 1011 spores per gram of dry biomass was achieved. In the SSF of lignocellulose, B. amyloliquefaciens B-1895 secreted comparatively high cellulase and xylanase activities to ensure good growth of the bacterial culture. PMID- 29249065 TI - Methods to Assess the Antioxidative Properties of Probiotics. AB - Probiotics prove useful in correcting and preventing numerous health conditions, including those having severe impact on society, e.g., obesity and cancer. Notably, these capabilities of probiotics appear to be associated with their antioxidant properties. The mechanisms of antioxidant action of probiotics range from immediate biochemical scavenging of reactive substances to induction of signaling events leading to increased capacity of the host's cytoprotective systems. Since the antioxidant effects of probiotics significantly vary in types and details, a broad selection of methods of assessment of these properties is required in order to identify, characterize, and develop novel probiotics for medical purposes, as well as to explain the mechanisms of action of probiotics already in use in healthcare. This review revises the versatile toolbox, which can be used to assess the antioxidant properties of probiotics. PMID- 29249067 TI - Detection of angiographically significant coronary obstruction using resting transthoracic coronary Doppler echocardiography. AB - BACKGROUND: Transesophageal Doppler echocardiography has shown that significant stenosis can be detected based on the presence of aliasing with color Doppler in the stenotic area. The study aimed to assess the detection of angiographically significant coronary stenosis (ASCS) by analyzing the characteristics and velocities of resting coronary artery flow (RCF) using transthoracic coronary Doppler echocardiography (TCDE). METHODS: TCDE was performed before diagnostic coronary angiography (CA). The following velocities were measured: peak systolic velocity (PSV), peak diastolic velocity (PDV), mean diastolic velocity (MDV), end diastolic velocity (EDV), and distal to proximal velocity ratios. RESULTS: Twenty five patients were included, and CA revealed ASCS in 14 patients. With TCDE, the proximal and distal portions of the left anterior descending artery (LAD) could be measured in 84% of cases. Among 12 patients with ASCS in the distal left main coronary artery (LMCA) or proximal or mid LAD, proximal and distal flow could be measured in ten patients. Proximal diastolic velocities were higher in patients with ASCS in the LAD, and a distal MDV/proximal MDV ratio < 0.5 had a 60% sensitivity and a 92% specificity for the detection of ASCS (AUC 0.77, 95% CI 0.56-0.92). For the detection of ASCS limited to the LMCA and/or proximal LAD, the distal MDV/proximal MDV ratio had a sensitivity of 100% and a specificity of 89% (AUC 0.98, 95% CI 0.81-0.99). CONCLUSIONS: Resting TCDE can detect ASCS in the LAD, particularly at the proximal level, analyzing the ratio between distal and proximal flow velocities. These results could not be demonstrated in the RCA and CX arteries. PMID- 29249068 TI - Melatonin as an alternative sedation method during magnetic resonance imaging in preschool children with musculoskeletal problems. AB - : Magnetic resonance imaging (MRI) in preschool children is often challenging due to excessive motion artifacts. Sedation or general anesthesia (GA) is commonly used to prevent children from moving in the MRI scanner, with increased risk for cardiopulmonary complications and requirement for skilled personnel. Herein, we investigated whether oral melatonin, a natural hormone implicated in circadian rhythm regulation, could be used as an alternative sedation method prior to the MRI in preschool children with musculoskeletal problems. Fifteen children with suspected juvenile idiopathic arthritis underwent a total of 16 MRI examinations following administration of 10 mg of oral melatonin; satisfactory images were obtained in all but one case, with no adverse events. CONCLUSION: The use of melatonin before the musculoskeletal MRI in preschool children is an effective, safe, and inexpensive alternative to standard sedation and general anesthesia in preventing motion artifacts. What is Known: * Magnetic resonance imaging (MRI) is a well-recognized diagnostic method to visualize synovial inflammation and changes of cartilage and bone in juvenile idiopathic arthritis. * MRI examination requires sedation or general anesthesia to ensure immobility in children who are uncooperative. What is New: * Melatonin without sleep deprivation is efficacious and safe alternative to conventional sedation and general anesthesia before the musculoskeletal contrast-enhanced MRI in preschool children with JIA with timely insertion of intravenous cannula. PMID- 29249069 TI - Circumpapillary microperimetry to detect glaucoma: a pilot study for sector-based comparison to circumpapillary retinal nerve fiber layer measurement. AB - PURPOSE: To evaluate and compare the diagnostic performance of circumpapillary microperimetry (MP) sensitivity and circumpapillary retinal nerve fiber layer thickness (cpRNFLT) measured with optical coherence tomography (OCT) for detection of early to moderate open-angle glaucoma. METHODS: Eleven eyes (11 patients) with early or moderate open-angle glaucoma and seven normal eyes (7 subjects) underwent MP (MP-3 microperimeter, NIDEK, Japan) and cpRNFLT measurement (RS-3000 Advance OCT, NIDEK, Japan) using an identical circumpapillary circle and similar measurement sectors. The structure-function relationship and the area under the receiver-operating characteristics curve (AUROC) were investigated for each sector, respectively. RESULTS: Significant differences (P < 0.05) between glaucoma and normal eyes were found for five of the 12 OCT sectors and seven of the 24 MP sectors. High correlation between cpRNFLT and MP sensitivity was found in the inferotemporal area (OCT sector 5) and superotemporal area (OCT sector 1) (r = 0.818, P < 0.001, and r = 0.796, P < 0.001, respectively). The AUROC values in these sectors ranged 0.890-1.000 for cpRNFLT and 0.825-0.981 for MP sensitivity. Overall, the AUROC ranged 0.506-1.000 for sector cpRNFLT and 0.591-0.981 for sector MP sensitivity. CONCLUSIONS: In this pilot study, circumpapillary MP sensitivity and cpRNFLT showed similar diagnostic power. The structure-function relationship was strong for the superotemporal and inferotemporal circumpapillary areas. Our results suggest that circumpapillary MP represents a new aspect of microperimetry in glaucoma. Further studies on larger populations are necessary to clarify whether the current results are confirmed in clinical practice. PMID- 29249070 TI - Vascular stenosis in a child with visual pathway glioma treated with bevacizumab: a case report and review of literature. AB - BACKGROUND: Bevacizumab (BVZ) is a vascular endothelial growth factor inhibitor that has been widely accepted since its introduction into the cancer pharmacopoeia. Anecdotal reports suggested improvements in vision in children with visual pathway glioma. CASE PRESENTATION: We report a boy with visual pathway glioma whose vision had deteriorated significantly on vincristine and carboplatin, to the point that he was registered blind. Following bevacizumab therapy, there was a dramatic improvement in vision with reduction in tumour volume. However, following 20 doses of BVZ given over 19 months, he developed a significant cerebrovascular stenosis. CONCLUSION: The BVZ-induced cerebrovascular diseases in children are extremely rare but potentially serious. Importantly, stenosis has not been previously described in literature. PMID- 29249071 TI - Can fetus feel pain in the second trimester? Lessons learned from a sentinel event. PMID- 29249072 TI - Surgical approaches to upper thoracic Pott's disease with spinal instability during childhood: two cases. AB - PURPOSE: Tuberculosis is a common disease worldwide that is caused by Mycobacterium tuberculosis. Tuberculosis is primarily a pulmonary disease, but extrapulmonary manifestations are not uncommon, especially in children and adolescents. METHODS: We present two pediatric patients who underwent surgery in our clinic for Pott's disease in the upper thoracic region. The patients were investigated to describe their age, complaints, neurological examination results, disease location, surgical procedure, and complications. RESULTS: The patients were 2 and 14 years old and exhibited disease located in the upper thoracic region (T2-T3 and T1-T2). Both patients displayed severe neurological deficits (Frankel B and C). The kyphotic angles were 82.2 degrees and 43.2 degrees . The patients were stabilized by applying fusion using transpedicular screws via a posterior approach. They also underwent anti-tuberculosis treatment for approximately 1 year. One year later, neither patient exhibited any neurological deficit, and their kyphotic angles were measured as 11 degrees and 1 degrees , respectively. CONCLUSIONS: The recommended treatment approach for unstable cases of Pott's disease located in the upper thoracic region who exhibit neurological deficit and severe kyphotic angling or the development of kyphosis on the thoracic vertebrae is surgical. Decompression, stabilization, and fusion and kyphotic correction can be safely performed via a posterior approach. One of the present cases is the youngest patient described in the literature to undergo transpedicular surgery as a result of Pott's disease. Our other case is the first described in the literature who developed ptosis as a result of tuberculosis and underwent a procedure via posterior transpedicular screw. PMID- 29249073 TI - Medical and socioeconomic predictors of quality of life in myelomeningocele patients with shunted hydrocephalus. AB - INTRODUCTION: Children with myelomeningocele (MMC) often develop hydrocephalus, and the combination of these conditions can lead to psychosocial, cognitive, and physical health issues that decrease their health-related quality of life (HRQOL). The goal of the present study was to understand the QOL in patients with MMC and shunted hydrocephalus. METHODS: Data from the Toronto Hydrocephalus QOL Database was acquired between 2004 and 2009 using parent-completed questionnaires and, when appropriate, child-completed questionnaires: Hydrocephalus Outcome Questionnaire (HOQ) and the Health Utilities Index. We identified several medical and socioeconomic factors potentially relevant to the outcome measure (e.g., level of myelomeningocele, length of stay in hospital, and shunt-related hospital admissions; family functioning, income, parental education, employment status, etc.). Linear regression models were used to examine associations between potential predictor variables and HRQOL, with P < 0.05 in the multivariate model suggesting significance. RESULTS: The analysis consisted of 131 patients (mean age = 12.6, SD = 3.7). The mean HUI score was 0.51, and the mean HOQ overall health score was 0.67. There was a significant association between lower age and higher HOQ social-emotional health (P = 0.03) and HUI scores (P = 0.03), lower anatomical level of myelomeningocele and higher HUI scores (P = 0.01), better family functioning and higher HOQ overall health scores (P = 0.004), and higher family income and higher HOQ overall health, physical health, and HUI scores (P = 0.001, P = 0.003, and P = 0.02, respectively). CONCLUSION: Myelomeningocele patients with shunted hydrocephalus can have a poor health-related quality of life. Our results indicate a strong association of income and family functioning on quality of life, along with younger age and lower level of myelomeningocele. PMID- 29249074 TI - Prognostic factors of acute neurological outcomes in infants with traumatic brain injury. AB - PURPOSE: The purpose of this study is to clarify risk factors for poor neurological outcomes and distinctive characteristics in infants with traumatic brain injury. METHODS: The study retrospectively reviewed data of 166 infants with traumatic intracranial hemorrhage from three tertiary institutions in Japan between 2002 and 2013. Univariate and multivariate analyses were used to identify clinical symptoms, vital signs, physical findings, and computed tomography findings associated with poor neurological outcomes at discharge from the intensive care unit. RESULTS: In univariate analysis, bradypnea, tachycardia, hypotension, dyscoria, retinal hemorrhage, subdural hematoma, cerebral edema, and a Glasgow Coma Scale (GCS) score of <= 12 were significantly associated with poor neurological outcomes (P < 0.05). In multivariate analysis, a GCS score of <= 12 (OR = 130.7; 95% CI, 7.3-2323.2; P < 0.001), cerebral edema (OR = 109.1; 95% CI, 7.2-1664.1; P < 0.001), retinal hemorrhage (OR = 7.2; 95% CI, 1.2-42.1; P = 0.027), and Pediatric Index of Mortality 2 score (OR = 1.6; 95% CI, 1.1-2.3; P = 0.018) were independently associated with poor neurological outcomes. Incidence of bradypnea in infants with a GCS score of <= 12 (25/42) was significantly higher than that in infants with GCS score of > 12 (27/90) (P = 0.001). CONCLUSIONS: Infants with a GCS score of <= 12 are likely to have respiratory disorders associated with traumatic brain injury. Physiological disorders may easily lead to secondary brain injury, resulting in poor neurological outcomes. Secondary brain injury should be prevented through early interventions based on vital signs and the GCS score. PMID- 29249075 TI - The characteristics of transcranial color-coded duplex sonography in children with cerebral arteriovenous malformation presenting with headache. AB - PURPOSE: Cerebral arteriovenous malformations (AVM) are uncommon lesions. They are most often presented in childhood as intracranial hemorrhage. The aim of this report is to present the use of transcranial color-coded duplex sonography (TCCS) in detection of AVMs in children suffering headache. METHODS: This report describes five pediatric patients with headache and cerebral AVM which were initially discovered by TCCS. Diagnosis was confirmed by magnetic resonance imaging and digital subtraction angiography. RESULTS: In all patients, TCCS showed saccular enlargement of the vessels with a multicolored pattern corresponding to the different directions of blood flow. Spectral analysis showed significantly high flow systolic and diastolic velocities and low resistance index. CONCLUSIONS: In this report, we describe TCCS as a valuable non-invasive, harmless, low-cost, widely available method for the detection and follow-up of hemodynamic changes of AVMs in children with headache, before and after treatment. PMID- 29249076 TI - Endoscopic third ventriculostomy in children with a fiber optic neuroendoscopy. AB - OBJECTIVE: Endoscopic third ventriculostomy (ETV) provides a shunt-free treatment for obstructive hydrocephalus children. With rapidly evolving technology, the semi-rigid fiber optic neuroendoscopy shows a potential application in ETV by blunt fenestration. A retrospective analysis of our experience is reviewed. METHODS: The authors review infants and children who underwent ETV using this technique from June 2004 to June 2016 with radiological and clinical follow-up done by a single surgeon. Patients who underwent ETV with channel scope were excluded. Demographic variables and operative reports were collected. Improvement of preoperative symptoms and avoidance of additional cerebrospinal fluid (CSF) diversion procedures were considered a success. The ETV success score (ETVSS) was used to correlate with clinical outcomes. RESULTS: A total of 79 patients were included with a mean age of 8.3 +/- 5.5 years, and 40.5% were female. The mean clinical and radiographic follow-up was 38.6 +/- 40.9 months. The overall complication rate was 6.3%, while 73.4% were considered successful. The ETV failure cases received conversion to ventriculoperitoneal shunt or redo of ETV with a median time of 2 months. The mean ETV success score was 74.3 +/- 11.8 with positive correlation between success rate (P < 0.05). Kaplan-Meier failure-free survival rates of 30-day, 90-day, 6-month, 1-year, and 2-year were 89.9, 83.5, 78.5, 75.9, and 74.6%. Eight patients required redo ETV, and five of these patients required eventual shunt placements. Approximately 61.9% of failure occurred within 3 months. Patients with post-intraventricular hemorrhage (IVH) /infection, and age younger than 12 months had the poorest outcome (P < 0.05). CONCLUSIONS: Blunt dissection of the third ventricle floor under endoscopic vision with the stylet tip of a fiber optic neuroendoscopy is safe and requires less equipment in the pediatric population. This technique is successful with an optimistic long-term outcome except for infants and the post-IVH and infectious subgroups. PMID- 29249077 TI - Distinguishing benign from malignant thyroid nodules using thyroid ultrasonography: utility of adding superb microvascular imaging and elastography. AB - OBJECTIVE: Thyroid nodules are common; however, malignancy is less than 7%. Therefore, additional techniques such as Doppler ultrasonography or elastography are used to improve diagnostic performance of conventional ultrasonography. We want to prospectively investigate the use of additional superb microvascular imaging (SMI) and strain elastography to B-mode ultrasound in thyroid nodules in distinguishing benign from malignant thyroid nodules. METHODS: We analyzed 52 thyroid nodules (malignant = 26, benign = 26) and reviewers scored the likelihood of malignancy for three data sets (i.e., B-mode ultrasonography alone, B-mode ultrasonography + SMI, and B-mode ultrasonography + strain elastography). The area under the receiver-operating characteristic curve (Az) values, sensitivities, and specificities were compared. RESULTS: A comparison of the data sets revealed that area under the receiver-operating characteristic curve values were similar without statistical difference. However, on comparing sensitivity and specificity based on the management decision of whether to conduct fine needle aspiration (FNA) after combining information from all three types of imaging (B-mode ultrasonography + SMI + strain elastography), specificity was significantly higher for the combined technique (34.6%) than for B-mode ultrasonography alone (11.5%), without decrease in sensitivity (P = 0.032). CONCLUSION: Additional use of SMI and strain elastography could potentially lead to increase in specificity in thyroid ultrasonography. PMID- 29249078 TI - Concordance between fine-needle aspiration and core biopsies for osseous lesions by lesion imaging appearance and CT attenuation. AB - OBJECTIVES: To compare the concordance between fine-needle aspiration and core biopsies for osseous lesions by lesion imaging appearance and CT attenuation. MATERIALS AND METHODS: Retrospective review of 215 FNAs of osseous lesions performed in conjunction with core biopsy at our institution over a 6-year period (2011-2016). FNAs were interpreted independently of core biopsies. We assessed if FNA in conjunction with core biopsy increased diagnostic accuracy compared to core biopsy alone. We also calculated the concordance between FNA and core biopsy by lesion appearance, lesion CT attenuation, lesion histology, lesion location and FNA needle gauge size. RESULTS: Core biopsy alone provided the diagnosis in 207/215 cases (96.3%), however, the FNA provided the diagnosis in the remaining 8/215 cases (3.7%) where the core biopsy was non-diagnostic. There were 154 (71.6%) lytic lesions, 21 (9.8%) blastic lesions, 25 (11.6%) mixed lytic and blastic lesions and 15 (7.0%) lesions that were neither lytic nor blastic. The concordance between FNA and core biopsy for lytic osseous lesions (136/154 cases, 88.3%) was statistically significantly higher than that for blastic osseous lesions (13/21 cases, 61.9%) [P = 4.2 * 10-3; 95% CI (0.02, 0.50)]. The concordance between FNA and core biopsy was higher for low-attenuation- (110/126) than high-attenuation (58/77) lesions (P = 0.028). The concordance between FNA and core biopsy was also higher for metastases (102/119 cases, 85.7%) than non metastases (78/96, 81.3%) [P = 0.487; 95% CI (- 0.15, 0.065)]. There was no difference in the rate of concordance between FNA and core biopsy by lesion location or FNA needle gauge size (P > 0.05). CONCLUSION: FNA with core biopsy increases diagnostic rate compared to core biopsy alone or FNA alone. The concordance between FNA and core biopsy is higher for lytic lesions than for blastic lesions; and higher for low-attenuation lesions than for high-attenuation lesions. PMID- 29249079 TI - Interventional therapeutic procedures in the musculoskeletal system: an Italian Survey by the Italian College of Musculoskeletal Radiology. AB - PURPOSE: To perform an online survey among all members of the Italian College of Musculoskeletal Radiology to understand how therapeutic musculoskeletal procedures are performed in daily practice in Italy. METHODS: We administered an online survey to all 2405 members about the use of therapeutic musculoskeletal procedures in their institutions asking 16 different questions. Subgroup analysis was performed between general and orthopaedic hospitals with Mann-Whitney U and chi 2 statistics. RESULTS: A total of 129/2405 answers (5.4% of members) were included in our analysis. A median of 142.5 (25th-75th percentiles: 50-535.5; range 10-5000) therapeutic musculoskeletal procedures per single institution was performed in 2016. Arthropathic pain was the main indication. The most common procedures were joint injection, bursal/tendon injection, and irrigation of calcific tendinopathy. Ultrasound-guided procedures were mainly performed in ultrasonography rooms (77.4%) rather than in dedicated interventional rooms (22.6%). Conversely, fluoroscopic procedures were performed almost with the same frequency in interventional radiology suites (52.4%) and in general radiology rooms (47.6%). In most institutions (72%), autologous blood or components were not used. The median number of therapeutic musculoskeletal procedures performed in orthopaedic hospitals was significantly higher than in general hospitals (P = 0.002), as well as for the use of autologous preparations (P = 0.004). CONCLUSION: Joint injection, bursal/tendon injection, and irrigation of calcific tendinopathy were the most common therapeutic musculoskeletal procedures, being arthropathic pain the main indication. The percentage of procedures and the use of autologous preparations were significantly higher in orthopaedic hospitals than in general hospitals. PMID- 29249080 TI - Duration of extinction trials as a determinant of instrumental extinction in terrestrial toads (Rhinella arenarum). AB - Instrumental learning guides behavior toward resources. When such resources are no longer available, approach to previously reinforced locations is reduced, a process called extinction. The present experiments are concerned with factors affecting the extinction of acquired behaviors in toads. In previous experiments, total reward magnitude in acquisition and duration of extinction trials were confounded. The present experiments were designed to test the effects of these factors in factorial designs. Experiment 1 varied reward magnitude (900, 300, or 100 s of water access per trial) and amount of acquisition training (5 or 15 daily trials). With total amount of water access equated in acquisition, extinction with large rewards was faster (longer latencies in 900/5 than 300/15), but with total amount of training equated, extinction with small rewards was faster (longer latencies in 100/15 than 300/15). Experiment 2 varied reward magnitude (1200 or 120 s of water access per trial) while holding constant the number of acquisition trials (5 daily trials) and the duration of extinction trials (300 s). Extinction performance was lower with small, rather than large reward magnitude (longer latencies in 120/300 than in 1200/300). Thus, instrumental extinction depends upon the amount of time toads are exposed to the empty goal compartment during extinction trials. PMID- 29249081 TI - Immobilization of Lipase by Ionic Liquid-Modified Mesoporous SiO2 Adsorption and Calcium Alginate-Embedding Method. AB - Porcine pancreatic lipase (PPL) was immobilized onto functionalized ionic liquid modified silica carrier using gelatinization and physical adsorption. The immobilized lipase was characterized with N2 adsorption-desorption, X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FT-IR) before and after modification and immobilization. The results showed that the modification of the ionic liquid and the introduction of lipase had been successfully approved. The rate of enzymatic reaction and its influencing factors was primarily studied by enzymatic reaction kinetics. K m values of PPL-SiO2@CA and PPL-IM/BF4-SiO2@CA were 4.9 and 3.7 mg/ml, respectively. It indicated that the modification of the functionalized ionic liquid enhanced the affinity between the immobilized enzyme and the substrate. The immobilization efficiency, specific activity, optimum temperature, optimum pH, thermal stability, reusability, and storage stability of the immobilized enzyme were investigated. We found that the stability of the immobilized enzyme was significantly higher than that of the unmodified immobilized enzyme. Specially, PPL-IM/BF4-SiO2@CA maintained good thermal stability and retained more than 92% of its activity at 65 degrees C after preheating 3 h. Graphical Abstract Above, the immobilized lipase maintained more than 92% of its initial activity after incubating at 65 degrees C for 3 h. PMID- 29249082 TI - Epidemiology of Injuries in Women Playing Competitive Team Bat-or-Stick Sports: A Systematic Review and a Meta-Analysis. AB - BACKGROUND: Team bat-or-stick sports, including cricket, softball and hockey, are popular among women. However, little is known about the injury profile in this population. OBJECTIVE: The aim was to describe the incidence, nature and anatomical location of injuries in bat-or-stick sports played by women in a competitive league. METHODS: This review was prospectively registered (PROSPERO CRD42015026715). CINAHL, MEDLINE, PsycINFO, PubMed, SPORTDiscus were systematically searched from January 2000 to September 2016, inclusive. Peer reviewed original research articles reporting the incidence, nature and anatomical location of injuries sustained by women aged 18 + years in competitive bat-or-stick sports were included. Two meta-analyses based on injury incidence proportions (injury IP) and injury rates per 1000 person-days of athletic exposure (AE) were performed. RESULTS: A total of 37 studies satisfied the inclusion criteria, and five had low risk of bias. The weighted injury IP was 0.42 [95% confidence interval (CI) 0.39-0.45]. The weighted injury rate was 6.12 (95% CI 6.05-6.18) overall, and greater in games [15.79 (95% CI 15.65-15.93)] than in practice [3.07 (95% CI 2.99-3.15)]. The ankle was the most commonly injured anatomical location, followed by the hand (including wrist and fingers), knee and head. Soft tissue and ligament injuries were most common types of injuries. CONCLUSION: Injury prevention in women's sports is a novel and emerging field of research interest. This review highlights that injury incidence is high among female bat-or-stick players, but little information is known about direct causal mechanisms. This review clearly establishes the need for enhancements to injury data collection. Without this information, it will not be possible to develop evidence-based injury prevention interventions. PMID- 29249084 TI - Return to Sport in Athletes with Midportion Achilles Tendinopathy: A Qualitative Systematic Review Regarding Definitions and Criteria. AB - BACKGROUND: Midportion Achilles tendinopathy (AT) can cause long-term absence from sports participation, and shows high recurrence rates. It is important that the decision to return to sport (RTS) is made carefully, based on sharply delimited criteria. Lack of a well-defined definition and criteria hampers the decision to RTS among athletes with AT, and impedes comparison of RTS rates between different studies. OBJECTIVE: The aim of this study was to systematically review the literature for definitions of, and criteria for, RTS in AT research. STUDY DESIGN: Qualitative systematic review. METHODS: The PubMed, EMBASE, Cochrane, CINAHL, PEDro, and Scopus electronic databases were searched for articles that reported on the effect of a physiotherapeutic intervention for midportion AT. Article selection was independently performed by two researchers. Qualitative content analysis was used to analyze the included studies and extract definitions of, and criteria for, RTS. RESULTS: Thirty-five studies were included in the content analysis, showing large variety in both the definitions and criteria. Thirty-two studies reported a definition of RTS, but only 19 studies described the criteria for RTS. The content analysis revealed that 'reaching pre injury activity/sports level, with the ability to perform training and matches without limitations', 'absence of pain', and 'recovery' were the main content categories used to define RTS. Regarding the criteria for RTS, eight different content categories were defined: (1) 'level of pain'; (2) 'level of functional recovery'; (3) 'recovery of muscle strength'; (4) 'recovery of range of motion'; (5) 'level of endurance of the involved limb'; (6) 'medical advice'; (7) 'psychosocial factors'; and (8) 'anatomical/physiological properties of the musculotendinous complex'. Many criteria were not clearly operationalized and lacked specific information. CONCLUSIONS: This systematic review shows that RTS may be defined according to the pre-injury level of sports (including both training and matches), but also with terms related to the absence of pain and recovery. Multiple criteria for RTS were found, which were all related to level of pain, level of functional recovery, muscular strength, range of motion, endurance, medical advice, psychosocial factors, or anatomical/physiological properties of the Achilles tendon. For most of the criteria we identified, no clear operationalization was given, which limits their validity and practical usability. Further research on how RTS after midportion AT should be defined, and which criteria should be used, is warranted. PROSPERO REGISTRATION NUMBER: CRD42017062518. PMID- 29249085 TI - Correction to: A Comparison of the Energetic Cost of Running in Marathon Racing Shoes. AB - An Online First version of this article was made available online at https://link.springer.com/article/10.1007/s40279-017-0811-2 on 16 November 2017. An error was subsequently identified in the article, and the following correction should be noted. PMID- 29249087 TI - A complex ventricular septal defect following transcatheter aortic valve implantation evaluated by 3D transthoracic echocardiography. AB - Transcatheter aortic valve implantation (TAVI) has revolutionized the treatment of elderly patients with symptomatic severe aortic valve stenosis. Among the possible TAVI complications, a rare one is the annular/left ventricular outflow tract rupture. We report a rare case of a late complex ventricular septal defect (VSD) following TAVI with a balloon-expandable prosthesis, conservatively managed. Our case demonstrates the role of 3D transthoracic echocardiography (3DTTE) in the accurate diagnosis of this TAVI complication and suggests that, in some cases, it can be used as an alternative to other diagnostic tools, such as transesophageal echocardiography, cardiac catheterization, and computed tomography. PMID- 29249088 TI - CLINICAL ENGAGEMENT MODEL: PROVIDING THE SUPPORT BETWEEN STUDENTS AND THE CLINICAL ENVIRONMENT. AB - Clinical placement is an essential component to undergraduate nursing students' development and provides an invaluable opportunity to develop skills, tacit knowledge, demonstrate conceptual understanding, and professional competency. PMID- 29249086 TI - Reassessing Ethnic Differences in Mean BMI and Changes Between 2007 and 2013 in English Children. AB - OBJECTIVE: National body fatness (BF) data for English South Asian and Black children use BMI, which provides inaccurate ethnic comparisons. BF levels and time trends in the English National Child Measurement Programme (NCMP) between 2007 and 2013 were assessed by using ethnic-specific adjusted BMI (aBMI) for South Asian and Black children. METHODS: Analyses were based on 3,195,323 children aged 4 to 5 years and 2,962,673 children aged 10 to 11 years. aBMI values for South Asian and Black children (relating to BF as in White children) were derived independently. Mean aBMI levels and 5-year aBMI changes were obtained by using linear regression. RESULTS: In the 2007-2008 NCMP, mean aBMIs in 10- to 11-year-old children (boys, girls) were higher in South Asian children (20.1, 19.9 kg/m2 ) and Black girls, but not in Black boys (18.4, 19.2 kg/m2 ) when compared with White children (18.6, 19.0 kg/m2 ; all P < 0.001). Mean 5-year changes (boys, girls) were higher in South Asian children (0.16, 0.32 kg/m2 per 5 y; both P < 0.001) and Black boys but not girls (0.13, 0.15 kg/m2 per 5 y; P = 0.01, P = 0.41) compared with White children (0.02, 0.11 kg/m2 per 5 y). Ethnic differences at 4 to 5 years were similar. Unadjusted BMI showed similar 5-year changes but different mean BMI patterns. CONCLUSIONS: BF levels were higher in South Asian children than in other groups in 2007 and diverged from those in White children until 2013, a pattern not apparent from unadjusted BMI data. PMID- 29249089 TI - PALLIATIVE CARE. WORKFORCE DEVELOPMENT. AB - Palliative care is delivered in almost all settings where healthcare is provided, including neonatal units, paediatric services, acute hospitals, general practices, community settings and aged care services. People who are dying have needs which require that nurses are able to deliver high quality evidence based and compassionate care no matter what their setting of practice. PMID- 29249083 TI - Effects of Strength Training on the Physiological Determinants of Middle- and Long-Distance Running Performance: A Systematic Review. AB - BACKGROUND: Middle- and long-distance running performance is constrained by several important aerobic and anaerobic parameters. The efficacy of strength training (ST) for distance runners has received considerable attention in the literature. However, to date, the results of these studies have not been fully synthesized in a review on the topic. OBJECTIVES: This systematic review aimed to provide a comprehensive critical commentary on the current literature that has examined the effects of ST modalities on the physiological determinants and performance of middle- and long-distance runners, and offer recommendations for best practice. METHODS: Electronic databases were searched using a variety of key words relating to ST exercise and distance running. This search was supplemented with citation tracking. To be eligible for inclusion, a study was required to meet the following criteria: participants were middle- or long-distance runners with >= 6 months experience, a ST intervention (heavy resistance training, explosive resistance training, or plyometric training) lasting >= 4 weeks was applied, a running only control group was used, data on one or more physiological variables was reported. Two independent assessors deemed that 24 studies fully met the criteria for inclusion. Methodological rigor was assessed for each study using the PEDro scale. RESULTS: PEDro scores revealed internal validity of 4, 5, or 6 for the studies reviewed. Running economy (RE) was measured in 20 of the studies and generally showed improvements (2-8%) compared to a control group, although this was not always the case. Time trial (TT) performance (1.5-10 km) and anaerobic speed qualities also tended to improve following ST. Other parameters [maximal oxygen uptake ([Formula: see text]), velocity at [Formula: see text], blood lactate, body composition] were typically unaffected by ST. CONCLUSION: Whilst there was good evidence that ST improves RE, TT, and sprint performance, this was not a consistent finding across all works that were reviewed. Several important methodological differences and limitations are highlighted, which may explain the discrepancies in findings and should be considered in future investigations in this area. Importantly for the distance runner, measures relating to body composition are not negatively impacted by a ST intervention. The addition of two to three ST sessions per week, which include a variety of ST modalities are likely to provide benefits to the performance of middle- and long-distance runners. PMID- 29249090 TI - RE-DO STATIONS AFTER HIGH-FIDELITY SIMULATION DEBRIEF IN NURSING EDUCATION. AB - While use of simulation in nursing education is both complex and well established, learning by re-doing is a scaffolded learning strategy neglected in simulation and minimal research has been conducted with it. PMID- 29249091 TI - SUPPORTING CLINICAL FACILITATORS THROUGH PEER REVIEW OF TEACHING. AB - The QUT School of Nursing is currently trialling peer review of teaching (PRoT) as one strategy to support clinical facilitators working with undergraduate students. Work integrated learning (WIL) relies on collaborative partnerships and clinical facilitators need specific skills and knowledge. PMID- 29249092 TI - NURSES REPORT FORMAL EDUCATION IMPROVES PRACTICE. AB - Increased demand for colonoscopy procedures has led to the introduction of nurse endoscopist in Australia. Evidence suggests that nurse endoscopy is safe and effective (Williams et al. 2009). PMID- 29249093 TI - EDUCATION IN PRE AND POSTOPERATIVE SURGICAL NURSING: CAN GUIDED PERIOPERATIVE EXPERIENCE ASSIST? AB - It is reported that surgical adverse events occurred in 3.6% of patient admissions representing 64.5% of reported events (Zegers et al. 2011). These were severe and 41% were considered to be preventable (Zegers et al. 2011). PMID- 29249094 TI - EDUCATION INITIATIVES IN GRADUATE TRANSITION. PMID- 29249095 TI - GOLD COAST SIMULATION SERVICE. AB - There is plenty of evidence about how effective simulation education is in healthcare despite all the challenges it brings. The literature reflects improvement of not only technical and nontechnical skills in clinicians, but ultimately patient outcomes. PMID- 29249096 TI - THE NATIONAL CANCER NURSING EDUCATION PROJECT -- TEN YEARS ON. AB - The National Cancer Nursing Education Project (EdCaN) suite of resources support integration of a nationally consistent approach to cancer care education and professional development of nurses at all levels of practice in a range of settings. PMID- 29249097 TI - A PROFESSIONAL PORTFOLIO OF LEARNING FOR UNDERGRADUATE NURSING STUDENTS. AB - Traditionally, the assessment of clinical competence has been completed using 'paper based' systems which is still the predominant approach in Undergraduate Nursing Programs. PMID- 29249098 TI - A PROFESSIONAL PORTFOLIO OF LEARNING FOR UNDERGRADUATE NURSING STUDENTS. AB - Traditionally, the assessment of clinical competence has been completed using 'paper based' systems which is still the predominant approach in Undergraduate Nursing Programs. PMID- 29249099 TI - STRATEGIES FOR FUTURE NURSING AND MIDWIFERY EDUCATION. AB - Major challenges can be expected for nurse education in the near future in response to changes in healthcare practice, technology, regulation and funding. The advancement of nursing and midwifery professions is largely dependent upon what occurs at the teaching-research-practice nexus. PMID- 29249100 TI - ENGAGING STUDENTS IN ACUTE MENTAL HEALTHCARE. AB - Mental health is an increasing component of the burden of disease worldwide, providing challenges in healthcare and health systems (World Health Organization, 2013); it is widespread, and not limited to dedicated mental health facilities. PMID- 29249101 TI - REIMAGINING A FUTURE FOCUSED BACHELOR OF NURSING CURRICULA. AB - Higher education providers of nursing education programs are charged with the responsibility to produce 'work ready' graduates to meet the changing demands of healthcare including a shift from acute care to home and community based chronic care (Primary health Care Advisory Group, 2015. PMID- 29249102 TI - [Relation between Helicobacter pylori infection and chronic urticaria]. AB - BACKGROUND: Chronic spontaneous urticaria is a frequent disease that affects the quality of life of patients. Helicobacter pylori infection has increased in the world, linking current studies with a link between both entities. OBJECTIVE: To determine the relationship between chronic urticaria and Helicobacter pylori infection. METHODS: An observational cohort study was conducted with the objective of demonstrating the relationship between chronic urticaria and Helicobacter pylori infection in the allergology clinic of the Hospital Universitario "Manuel Ascunce Domenech" in the province of Camaguey, Cuba, in the period from January 2015 to December of 2016. A universe composed of 93 patients with spontaneous chronic urticaria and the sample by the 43 who met the criteria and formed the case and control group were the 35 apparently healthy patients who gave informed consent for the study. RESULTS: 76.6 % of the women had urticaria and the mean age was 36.10 years. The serological study was positive in 100 % of the cases. CONCLUSIONS: In the present study, the relationship between chronic urticaria and Helicobacter pylori infection was demonstrated. Apparently, the eradicating treatment for Helicobacter pylori was effective as the patients had no symptoms after treatment. Specific immunoglobulin G and urease test together constitute a suitable diagnostic module for the diagnosis of Helicobacter pylori conditions. PMID- 29249103 TI - [Does Ecuadorians with asthma has preferences in the use of information and communication technologies? Pilot study]. AB - BACKGROUND: Inadequate communication between asthmatic patients and their physicians may interfere directly with asthma control. In the last years, the use of information and communication technologies (ICTs) it has increased in Latin America. This technology seems to be a good tool to improve communication and management of the asthmatic patient. OBJECTIVE: We evaluated the frequency and preference patterns of communication and information technologies in Ecuadorian patients with bronchial asthma. METHODS: We conducted a pilot cross-sectional study to identify the frequency and preferences of ICT in patients with asthma. The Spanish version of the Michigan questionnaire was used. Age and educational level were categorized into 3 groups. We used logistic regression between these groups regarding the frequency of use, interest in seeking and receiving information related to their asthma for the age and educational level of the patients. RESULTS: A total of 222 patients participated in our study. The mean age was 45.6 years (SD 17.4), the most common sex was female with 89.25 %. Almost all patients had a cell phone (87.5 %) and internet access (62.7 %). The three ICTs most likely to be used to search for or receive information about their illness were WhatsApp, Facebook and email (p <0.05). CONCLUSION: Information and communication technologies improve the care of asthmatic patients. In our pilot study email and text messages are the most preferred ICT among patients however WhatsApp and Facebook may be appropriate for certain ages especially young asthmatic. Knowledge of preferences can help the development of ICT in a personalized way and improve the outcomes in patients with asthma. PMID- 29249104 TI - [Evaluation of functional capacity by 6-minute walk test in children with asthma]. AB - BACKGROUND: Asthma patients show lower exercise tolerance. OBJECTIVE: Assessment of functional capacity in children with asthma. METHODS: Girls and boys from 6 to 17 years old were included in two groups: asthmatic patients and healthy subjects. PSPQ was applied and vital signs, peak expiratory flow and Modified Borg Dyspnea Scale were measured at the beginning and the end of 6MWD. RESULTS: Participants included 58 subjects, including 32 asthmatic patients, and 55.2 % male subjects. Mean age: 10.6 years +/- 3.1. Asthmatic group: mean distance covered in meters 456.04 +/- 54.05, meters covered by gender 456.31 +/- 48.73 male and 455.74 +/- 61.29 female (p = 0.28). Control group: the mean was 468.28 +/- 54.52 meters, meters covered by gender 465.98 +/- 58.04 male, 471.44 +/- 51.95 female (p = 0.35). The difference between asthmatic group and control group was 12.24 meters in favor of control group (p = 0.378). There was no association between body mass index (BMI) and distance covered (p = 0.53), but a Pearson correlation p = -0.445. In the male gender, CF was positively associated with self-perception in CAF variables: physical condition, physical attractiveness, strength (p = 0.04) and physical self-concept in general (p = 0.02). CONCLUSIONS: There was no significant difference in the distance covered between the two groups. The main impact factor was the body mass index with an inverse relation to the distance. Males had better physical self-perception, which is positively associated with CF. PMID- 29249105 TI - [Self-reported prevalence of latex allergy and associated factors in healthcare workers]. AB - BACKGROUND: In our country, the prevalence of latex allergy in health personnel has rarely been studied. OBJECTIVE: To determine the prevalence and associated factors to self-reported latex allergy in health care workers. METHODS: A cross sectional study was conducted among 1,292 health care workers of a second level hospital. All workers were included and they were required to answer a structured questionnaire aimed at identifying latex allergy, atopic personal and family history, exposure to latex gloves and surgical background. Odds ratio (OR) and 95 % confidence interval (95 % CI) were estimated using regression logistic to investigate factors associated to latex allergy. RESULTS: The female to male ratio was 2.4:1. The men age 38.4 +/- 11.6 years. The prevalence of latex allergy auto-reported was 9.7 %, with a confidence interval of 95 % (95 % CI) 8.1 %-11.3 %. There was no statistical difference by workplace (p = 0.508). Factors associated with latex allergy included female gender (OR = 1.68; 95 % CI: 1.03 2.73, p = 0.037), personal history of atopy (OR = 4.82; 95 % CI: 3.19-7.26, p < 0.0001), family history of atopic dermatitis (OR = 4.33, 95 % CI: 1.20-4.41) and history of allergy to fruits (OR = 4.33; 95 % CI: 2.62-7.14, p < 0.0001). CONCLUSIONS: Up to 10 out to 100 health workers may have latex allergy. The main factors associated with latex allergy in this study were: being a female, personal or familiar atopy and allergy to fruits. PMID- 29249106 TI - [IgE sensitization and sociodemographic conditions as determinant factors in asthma severity]. AB - BACKGROUND: In Latin America there are few data about the factors that influence the control and severity of asthma. OBJECTIVE: To describe the association between IgE sensitization to intra-home allergens and housing conditions in the severity of asthma. METHODS: Sensitization to aero-allergens was evaluated by skin prick test and socio-demographic data by a questionnaire in a population between 6 and 14 years of age with diagnosis of asthma. Asthma control was measured according to spirometric results and to the application of the ACT (Asthma Control Test); the severity and symptom control was evaluated according to the GINA guideline. RESULTS: A total of 150 resident patients from the Aburra Valley (Colombia) were included. The median age of participants was 11 years, 95 (63.3 %) male. 92 % of the patients resided in the urban area. Mite sensitization was the most prevalent in controlled and uncontrolled patients. Sensitization to cockroach and some poverty conditions were risk factors for asthma severity. CONCLUSION: Poverty conditions appear to favor the development of severe asthma and in turn IgE sensitization to cockroaches. This sensitization could serve as a biomarker of severity. PMID- 29249107 TI - [Common immunodeficiency variable in adults]. AB - Primary immunodeficiencies (PIDs) are low-incidence diseases caused by defects in genes involved in the development, maintenance, and regulation of the immune system. Common variable immunodeficiency (CVID) is the most common symptomatic immunodeficiency of adulthood. It has an approximate prevalence of 1 in 25 000-50 000 in the general population, with a delay in diagnosis between 6-7 years. The clinical manifestations of CVID constitute six main categories: infections, pulmonary complications, granulomatous or polyclonal lymphocytic disease, autoimmunity, gastrointestinal diseases and malignancy Most patients must have at least one of the following clinical manifestations (infection, autoimmunity, lymphoproliferation). However, the diagnosis of CVID can be conferred in asymptomatic patients, especially in familial cases. Secondary causes of hypogammaglobulinemia should be ruled out in any patient meeting the diagnostic criteria for CVID, as the treatment may be totally different from that required for CVID. Because CVID comprises a heterogeneous group of syndromes with poor primary antibody production, the potential number of entities within this group is unknown. Patients with CVID suffer from various complications that are considered prognostic. In the absence of clear guidelines for their search, it is recommended that lymphoproliferative disease, lung disease, liver disease and autoimmunity be investigated intentionally during the initial evaluation. The intervals in which they should be performed are not clear, but several evaluations may be required per year, according to the clinical evolution of the patient. PMID- 29249108 TI - [Regulation of immune responses by exosomes derived from antigen presenting cells]. AB - Cells release several biomolecules to the extracellular environment using them as a communication alternative with neighbor cells. Besides these molecules, cells also release more complex elements, like vesicles; structures composed of a lipidic bilayer with transmembrane proteins that protect a hydrophilic content. Exosomes are a small subtype of vesicles (30-150 nm), produced by many cell types, such as tumor cells, neurons, epithelial cells and immune cells. Included in this last group, antigen presenting cells produce exosomes that contain different types of molecules depending on their activation and/or maturation state. In recent years there has been an exponential interest in exosomes due to the recent evidences that show the immunomodulatory properties of these vesicles and therefore, their great potential in diagnostic approaches and development of therapies for different inflammation-associated pathologies. PMID- 29249109 TI - [Clinical significance vs statistical significance. How to interpret the confidence interval at 95]. AB - The validity of a study depends on its proper planning, execution and analysis. If these are sufficiently correct, the decision to apply the recommendations issued depends on the expected clinical effect. This effect may have random variations, hence the need to use statistical inference. For years the p-value has been used to determine this statistical significance and the confidence intervals to measure the magnitude of the effect. In this review we present a proposal of how to interpret the 95 % confidence intervals (CI 95 %) as estimators of the expected effect variability based on considering the threshold or value of clinical significance and the null value of the difference or rejection of statistical significance. Thus, an association or effect where the CI 95 % includes the null value (no effect or difference) is interpreted as inconclusive; one between the null value and the clinical threshold (without including them) as possibly inconsequential; one that does not include the null value but the clinical threshold as yet not conclusive and one beyond the clinical threshold as conclusive. PMID- 29249110 TI - [Severe atopic dermatitis and hiper-IgE]. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory and complex skin disease, typically occurring in individuals with a personal or family history of atopy. It is characterized by lesions of dermatitis, pruritus and dry skin (xerosis) that evolve with chronic course and intermittent outbreaks alternating with remission phases. AD appears from 5-15 % of the general population, 10-20 % of the pediatric population, and 1-3 % of the adult population. CLINICAL REPORT: A 19-year-old male patient with a severe AD (SCORAD of 84.3), and hyper-IgE (34 400 UI/mL), who was treated with deflazacort, Healing creams and emollients, as well as detergent-free gel. With which did not progress favorably, so a combinated therapy with deflazacort, methotrexate, tacrolimus, and transfer factor was prescribed, obtaining excellent results. CONCLUSION: There are many algorithms reported in the literature for the treatment of AD, but the evolution of the disease is the only one that will give us the guidelines for the treatment to be followed. PMID- 29249111 TI - [Hereditary angioedema by C1 inhibitor-deficit: Diagnostic and therapeutic challenges. Case report]. AB - BACKGROUND: Hereditary angioedema is a disease which manifests itself with episodes of spontaneous edema on skin, mucosal and airway. Treatment includes acute and prophylactic approach to minimize the attacks and severity. In many parts of the world, androgen derivatives, antifibrinolytic and fresh frozen plasma are the therapies available for prophylaxis. CLINICAL REPORT: 16 years old teenager of without history of immune decease, has in the course of 1-year repetitive episodes of painless, non-pruritic angioedema, does not respond to antihistamine therapy, corticosteroids or adrenaline; fresh frozen plasma is applied in 1 occasion exacerbating episode with severity. The diagnosis is delayed because of the unavailability of the study in the country, so it is shipped abroad confirming the deficit of C1 Inhibitor (7.1 MUg/mL). Initiating prophylactic therapy with Danazol, with subsequent episodes decreased. CONCLUSION: The delay diagnosis involves considerable risk in these patients; the importance of long-term prophylactic treatment is ratified in the use of androgens, being as an available option in developing countries. PMID- 29249112 TI - [Disseminated infection by M. tuberculosis complex in patient with IFN-gamma receptor 1 complete deficiency]. AB - BACKGROUND: Several mutations have been described leading to impaired immunity in the IL-12/IFN-gamma axis and, they confer susceptibility to mycobacterial infections. One of the more serious clinical phenotypes is secondary to mutations at IFN-gamma receptor 1 gene, characterized by an early onset and more severe disease. CLINICAL REPORT: We present a 3-month-old female patient with systemic M. tuberculosis complex who has a homozygous mutation, it affects the splicing site at IFNGR1 c.201-1G> T. At time of this report, she is with antimycobacterial treatment in the protocol of pluripotent hematopoietic cell transplantation (TCHP). CONCLUSION: It has been reported that antiphimic treatment should be maintained until the immune system is restored by the TCHP. If patients receive THCP before the age of 1 year old, they have a better prognosis. Diminish the levels of IFN-gamma in plasma before the procedure is associated to better results. PMID- 29249113 TI - [Delayed allergic reaction to amlodipine with a positive lymphocyte transformation test]. AB - BACKGROUND: Amlodipine is one of the third generation dihydropyridine calcium channel blockers used for hypertension. Mild, moderate and severe reactions have been reported with calcium channel blockers. Cross-reactivity among these drugs has not been established. CLINICAL REPORT: We have presented the case of a patient who developed a delayed pruritic, and erythematous maculopapular skin exanthema after the intake of amlodipine. A positive lymphocyte transformation test (LTT) confirmed the implication of amlodipine in the reaction and showed positivity to another calcium channel blocker, nifedipine, demonstrating cross reactivity. CONCLUSION: This is the first reported case of hypersensitivity to amlodipine in which the involvement of the drug is confirmed by a positive TTL. TTL could become a good diagnostic alternative for patients who experience late reactions to amlodipine and possibly cross-reactivity with nifedipine. PMID- 29249114 TI - Fragments of immunological memory: An interview with Dr. Berron. PMID- 29249115 TI - READY TO TRY SOME NEW CPD? thinking OUTSIDE THE BOX FOR ONGOING MIDWIFERY EDUCATION. AB - As registered midwives in Australia, there is a need to maintain an ongoing involvement in education, to complete Continuing Professional Development (CPD) activities. This responsibility is not only to be able to tick the box on your registration renewal, but also a professional responsibility to maintain and grow our knowledge, skills and practice. PMID- 29249116 TI - Rare Manifestation of Churg-Strauss Syndrome with Mediastinal Lymphadenopathies: Report of an Autopsy Case. PMID- 29249117 TI - Patterns of initial failure after resection for gallbladder cancer: implications for adjuvant radiotherapy. AB - PURPOSE: This study sought to identify potential candidates for adjuvant radiotherapy and patterns of regional failure in patients who underwent curative intent surgery for gallbladder cancer. MATERIALS AND METHODS: Records for 70 patients with gallbladder cancer who underwent curative resection at a single institution between 2000 and 2016 were analysed retrospectively. No patients received adjuvant radiotherapy. Initial patterns of failure were evaluated. Regional recurrence was categorized according to the definitions of lymph node stations suggested by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. RESULTS: Median follow-up was 23 months. Locoregional recurrence as any component of first failure occurred in 29 patients (41.4%), with isolated locoregional recurrence in 13 (18.6%). Regional recurrence occurred in 23 patients, and 77 regional recurrences were identified. Commonly involved regional stations were #13, #12a2, #12p2, #12b2, #16a2, #16b1, #9, and #8. Independent prognostic factors for locoregional recurrence were >=pT2 disease (hazard ratio [HR], 5.510; 95% confidence interval [CI], 1.260-24.094; p = 0.023) and R1 resection (HR, 6.981; 95% CI, 2.378-20.491; p < 0.001). CONCLUSION: Patients with pT2 disease or R1 resection after curative surgery for gallbladder cancer may benefit from adjuvant radiotherapy. Our findings on regional recurrence may help physicians construct a target volume for adjuvant radiotherapy. PMID- 29249119 TI - Expression of miRNA 155, FOXP3 and ROR gamma, in children with moderate and severe atopic dermatitis. AB - BACKGROUND: Atopic dermatitis is a disease characterized by a chronic inflammatory process in the skin, but its link to miRNA 155 is less known. The aim of the study was to evaluate the expression of microRNA155, and T helper type 17 cells and Treg cells in children with atopic dermatitis. METHODS: The study population consisted of: children seen for atopic dermatitis at the outpatient ambulatory of Dermatology at the Children Hospital Regina Margherita, Torino, Italy,( n = 23); healthy control subjects ( n =23). Blood samples were taken during routine control analysis and the expression of miRNA 155 and the production of FOXP3 and ROR? was determined using PCR real time. RESULTS: The analysis of miR-155 shows that the over-expression of miR-155 is statistically significant (p = 0.0040) in the group of patients with atopic dermatitis compared to the healthy control group. Analysis of mRNAs of FOXP3 and ROR? shows a FOXP3 mRNA expression statistically higher in the group of patients (p = 0.0057). The Th17 / Treg ratio is significantly smaller in patients with atopic dermatitis (p = 0.0012). Also the ratio miR-155/Th17/Treg is larger in the group of patients with atopic dermatitis (p = 0.0002). CONCLUSIONS: Our results suggest that increased miR-155 and FOXP3 and ROR? responses may provide a link to immune dysregulation associated with atopic dermatitis. Although a point-by-point correlation between miR-155 and the ratio Th17/Treg is not demonstrated, our findings shows that these two elements do not appear to be completely unrelated to each other. PMID- 29249118 TI - Endovascular thoracic aortic transection repair has equivalent survival to open repair after blunt thoracic aortic injury. AB - BACKGROUND: Blunt thoracic aortic injury (BTAI) is highly lethal and its management has evolved with the advent of endovascular approaches. We hypothesized that endovascular repair (ER) would have equivalent/improved survival compared to open repair (OR). The aim of our study was to review our center's morbidity and mortality after BTAI. METHODS: Our Level I trauma center registry was queried for BTAI between 2002-2015. This cohort was stratified into three groups: ER, OR and those patients managed non-operatively (NOP). Primary endpoint was mortality and secondary endpoints included complications after repair and freedom from re-intervention at follow-up. RESULTS: Among 81 patients with BTAI, there was a 58% mortality at presentation with a mean Injury Severity Score (ISS) of 65. From the remaining 34 patients alive after initial resuscitation, 12 (35%) patients were managed via OR, 12 (35%) via ER and 10 (30%) NOP. The mean ISS among these groups was 31, 44, and 30 respectively (P=0.6). 42% of patients in ER underwent coverage of the left subclavian artery without sequelae. There was one death in the OR and ER groups. Postoperative complications included one paraplegia after ER and one lower extremity weakness and vocal cord paralysis after OR. There was a shift in the year 2007 in the treatment of BTAI for ER instead of OR. Mean follow-up was 59.7+/-48.5months. None of the patients on follow-up required re-interventions. CONCLUSIONS: Although BTAI still carries a high mortality rate, data from our trauma center suggest that ER has equivalent survival when compared to OR. PMID- 29249120 TI - The variegated histopathological features of atypical lentiginous melanocytic nevi (ALMNs): a single institution experience. AB - BACKGROUND: Atypical lentiginous melanocytic nevi (ALMNs) are atypical pigmented lesions with histopathological features similar to those of dysplastic nevi, with a lentiginous pattern. Variable histopathological features of ALMNs were observed in our practice. METHODS: We described the histopathological features of ALMNs diagnosed in the period 2009- 2015. Our cases were divided into 2 groups: Group 1: ALMNs showing the same histopathological features as previously described in the literature; Group 2: ALMNs with different features. RESULTS: 29 ALMNs were diagnosed. 2 groups of ALMNs were identified. Group 1 ALMNs showed a constant, mild epidermal acanthosis; frequently, an inflammatory infiltrate and dermal fibrosis, cytological atypia and mild architectural atypia. Group 2 ALMNs showed a constant psoriasis-like acanthosis with a hypercellularity of the rete ridges; cytological atypia was rare, whereas architectural atypia was constantly observed. Immunohistochemistry (MART-1 staining) revealed that the melanocytes were localized at the dermo-epidermal junction in both groups. ALMNs showed a broad spectrum of histopathological features. CONCLUSIONS: Our main finding was a constant architectural atypia in all lesions of Group 2. The identification of a unique type of ALMN seems no longer possible. The correct recognition of such benign, though atypical, melanocytic lesions is important in order to avoid an overdiagnosis of cutaneous melanoma and to prevent their potential evolution to the latter. PMID- 29249121 TI - Matrix metalloproteinase 1: a better biomarker for squamous cell carcinoma by multiple microarray analyses. AB - BACKGROUND: The present study aimed to validate MMP1 role in the development of squamous cell carcinoma (SCC) by bioinformatics methods. METHODS: Gene expression data of 10 GSE series (5 HNSCCs and 5 cSCCs) were obtained from the Gene Expression Omnibus (GEO) database and used to identify differentially expressed genes (DEGs). RESULTS: Higher expression of MMP1 was found rank number one in 9/10 GSE series of SCC. MMP1 was mainly focused on Gene Ontology (GO) terms of collagen catabolic process, extracellular matrix disassembly. The analysis results of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways mainly involved Rheumatoid arthritis, Bladder cancer and Pathways in cancer. Also, MMP1 was identified as a hub protein in the PPI network by using Cytoscape software. In addition, others MMPs members of family were analysed. CONCLUSIONS: These results suggested that MMP1 may be pivotal to the transition from normal skin to premalignant lesions to SCC, thus representing a potential therapeutic target gene of diagnosis and prevention in SCC. PMID- 29249122 TI - Vitamin D and melanoma: state of the art and possible therapeutic uses. AB - Despite the presence of several studies in literature, the real connection between vitamin D serological levels, vitamin D receptor and melanoma remains unclear, probably because of the complex correlation between vitamin D and melanoma. Indeed, UV radiations are not reported as the main risk factor for melanoma in non-sun-exposed, while systemic immunosuppression, anatomical and physiological features may contribute to malignancy. Therefore, the correlation between melanoma cells in sun- exposed areas and vitamin D, as well as vitamin D receptor could be different from the one in melanoma of sun-shielded sites. These differences may also explain the controversial results reported in the literature regarding the correlation between melanoma and vitamin D, as well as the different outcomes in melanoma patients treated with vitamin D as adjuvant therapy. The aim of this review is to highlight the most recent findings about vitamin D and melanoma, focusing on the anatomic site of the primary tumor as well as on the possible therapeutic uses of vitamin D in melanoma patients. PMID- 29249123 TI - Lichen planus as paradoxical side effect of TNF-alpha inhibitors treatment in one patient with many psoriasis comorbidities. PMID- 29249124 TI - Histopathological aspects of psoriasis and its uncommon variants. AB - Psoriasis is a chronic complex multisystem, inflammatory, skin disorder that causes vasodilatation and hyperproliferation of keratinocytes, whose clinical expression includes a thickened, erythematous skin, often covered with silver gray scales. Psoriasis is a unique disease where both autoimmune and autoinflammatory responses coexist and the balance between the two components is essential in determining its clinical and histopathological presentation. Adaptive immune responses prevail in chronic plaque psoriasis while innate and autoinflammatory responses predominate in pustular psoriasis. The histopathology of psoriasis is easily recognizable when the disease involves the typical sites such as the extensor surfaces. Although a biopsy is rarely required in case of classic psoriasis, in atypical and controversial conditions, histopathological examination remains the main diagnostic tool that can help in differentiating psoriasis from other dermatoses. In this review, we will discuss the histopathological pictures of the different clinical variants of psoriasis giving some clues to drive the correct diagnosis when the clinical aspects are not enough indicative of the disease. PMID- 29249125 TI - Panniculitis in the setting of dermato/rheumatologic diseases. AB - Panniculitides represent a heterogeneous group of inflammatory diseases that are traditionally considered one of the most difficult challenge for clinicians and pathologists. They may occur in a variety of dermato/rheumatologic diseases and are of particular relevance for clinicians dealing with such pathologies, including immune-mediated/autoimmune and autoinflammatory disorders. In fact, panniculitides can be the initial sign of presentation of a dermato/rheumatologic disease, thereby providing the physician with important clues to the correct diagnosis. Then, panniculitides may serve as an easy-to-access indicator of both systemic involvement and prognostic outcome in dermato/rheumatologic disorders. This review will focus on clinical and histopathological findings of panniculitides in the setting of dermato/rheumatologic disorders and discusses the value of skin biopsies and consequent histopathological examination in the diagnosis of these disorders with the help of a logarithmic table. PMID- 29249126 TI - Dyspareunia in vulvar lichen sclerosus: an overview of a distressing symptom. AB - BACKGROUND: Dyspareunia is a symptom of vulvar lichen sclerosus (VLS). This study specifically addressed prevalence and severity of dyspareunia in patients affected with VLS as well as the factors that can influence its occurrence. Changes in the severity of dyspareunia with treatment were also explored. METHODS: In this retrospective, cohort study we included VLS patients who had undergone any topical treatment for 12 weeks, between January 2011 and March 2016, at our Vulva Unit; demographics, history and clinical features recorded at baseline and at treatment completion were elaborated. RESULTS: 177 patients were included; among the 90 patients who reported having sexual activity 56.7% complained of dyspareunia; the frequency and severity of dyspareunia was higher among the patients who had not previously been treated with topical corticosteroids than among those who had undergone previous treatments; the patients complaining of dyspareunia reported significantly higher scores for itching and burning compared with those who did not have painful intercourses; after the treatment, 52.5%, 78.4% and 64.3% of the patients reported an improvement >=75% compared with baseline in dyspareunia, itching and burning scores, respectively. CONCLUSIONS: Dyspareunia occurred in more than half VLS patients. The patients who complained of dyspareunia had a more severe overall symptom profile than those who did not report having painful intercourses. The objective severity of VLS did not seem to significantly affect dyspareunia occurrence and severity. Dyspareunia was found to be the symptom most resistant to treatment, however early treatment can be expected to reduce its occurrence and severity. PMID- 29249127 TI - Liver transplantation for non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome, and it is defined by the presence of steatosis in >5% of hepatocytes, according to histological analysis or detected by specific proton density fat fraction obtained magnetic resonance imaging. The term NAFLD covers two pathologically distinct conditions: non-alcoholic fatty liver and non alcoholic steatohepatitis (NASH), which can have similar clinical presentation, but with different prognosis. Both conditions can lastly lead to the development of cirrhosis. End stage liver-disease and hepatocellular carcinoma represent the two standard indications for liver transplantation (LT) in patients affected by NAFLD. Despite the evolution to end stage liver disease occur in 15-20% of NASH cases, the absolute number of LT performed for NAFLD is dramatically increased in the last decade. Between 2004 and 2013 new waitlist registrants for NAFLD as indication increased from 804 to 2174, becoming rapidly the second most common indication for liver transplantation in the USA. During the same period, indications to LT such as hepatitis C virus-related and alcohol-related cirrhosis increased only by 14% and 45% respectively. This review will focus on the management before and after LT for patients with NAFLD, with particular interest to comorbidities and outcomes. PMID- 29249129 TI - Epidemiology of liver cancer in South Korea. AB - Liver cancer is the sixth most common cancer (fourth in men and sixth in women) and the second largest cause of cancer mortality in South Korea. The crude incidence rate of liver cancer was 31.9/100,000 (47.5/100,000 in men and 16.2/100,000 in women) and the age-standardized incidence rate was 19.9/100,000 (32.4/100,000 in men and 8.8/100,000 in women) in 2014. The crude incidence rate increased from 1999 to 2011 and thereafter showed a subtle decreasing tendency. The crude prevalence rate was 113.6/100,000 (170.2/100,000 in men and 57.1/100,000 in women) and the age-standardized prevalence rate was 72.6/100,000 (115.7/100,000 in men and 33.7/100,000 in women) in 2014, which increased from 2010 to 2014. Survival from liver cancer has improved over the last two decades. The 5-year relative survival rate was markedly increased from 10.7% in those diagnosed with liver cancer between 1993 and 1995 to 32.8% in those diagnosed between 2010 and 2014. The epidemiology of liver cancer is influenced by that of underlying liver diseases such as viral hepatitis. Substantial progress has been made in the prevention and treatment of viral hepatitis; however, uncontrolled alcoholic liver disease, obesity and diabetes appears to have the potential to emerge as major causes for liver cancer. Depending on the success of the control of risk factors, the epidemiology of liver cancer in Korea may change. PMID- 29249130 TI - Case analysis of short stature complicated with neurofibromatosis type 1. PMID- 29249132 TI - Shrimp allergy: beyond avoidance diet. AB - Summary: Currently, the management of people diagnosed with shellfish allergy relies on the avoidance of those foods. HDM immunotherapy has been reported to induce both shrimp allergy in non-allergic patients, and shrimp tolerance in shrimp-allergic patients. This article summarizes therapeutic options other than avoidance diet for shrimp allergic patients available once the diagnostic is established, such as production of hypoallergenic shrimp, use of immunotherapy with modified allergens, probiotics and Chinese herbal formulations. PMID- 29249131 TI - Medicinal bioactivites and allergenic properties of pumpkin seeds: review upon a pediatric food anaphylaxis case report. AB - Summary: Food allergy to pumpkin seed is considered very rare, and only some isolated case reports have so far been published. We report here a case of food anaphylaxis to pumpkin seed in an eight-year-old boy, who tolerated all other edible seeds, peanut and tree nuts, as well as pulp of different kinds of pumpkins and other fruits of the Cucurbitaceae family. From this observation, a review of the botanical, historical, medicinal and allergenic aspects of pumpkin and its seeds is proposed. With the advent of diets rich in omega-3 and omega-6 polyunsaturated fatty acids, edible seeds like pumpkin seed have been incorporated in the modern diet. Their incremental use in the food-processing industry might contribute to an increase in food allergy to pumpkin seed in the future. PMID- 29249133 TI - Serum 25-hydroxyvitamin D levels in children with recurrent wheezing and relation to the phenotypes and frequency of wheezing. AB - Summary: Background. Recurrent wheezing may be related to various reasons. There is a lack of knowledge about the effect of vitamin D status in the children with recurrent wheezing. The aim of this study is to compare the level of vitamin D between recurrent wheezing children and healthy controls, and to investigate the relationship between vitamin D status and the clinical parameters of recurrent wheezing in preschool children. Methods. One hundred-ten children followed up in our hospital with recurrent wheezing were included in the study. The control group included fifty children without wheezing episodes. The serum 25 hydroxyvitamin D (25OHD) level was measured. The patients with recurrent wheezing were grouped according to their vitamin D status as "deficient group" and "non deficient group (Vitamin D level is insufficient and normal)". We investigated the relationship between vitamin D status and the clinical and laboratory parameters of children with recurrent wheezing. Results. Mean 25OHD level was 21.66 +/- 8.13 ng/mL (5.6-53) in the study group and 25.36 +/- 10.17 ng/mL (6-59) in the control group. The difference was statistically significant (p = 0.015). When the patients with recurrent wheezing were compared according to their vitamin D status, number of hospitalizations, number of positive sensitivity, percentage of eosinophil, serum IgE levels, Asthma Predictive Index positivity and wheezing phenotypes were not found to be different between groups. However, the duration of wheezing, the number of wheezing episodes and systemic glucocorticoid need in the previous year, and the total number of wheezing episodes were significantly higher in the deficient group (p < 0.05). The serum 25OHD level was negatively correlated with the duration of wheezing (r: -0.238; p: 0.012), total number of wheezing episodes (r: -0.436; p: 0.001), number of wheezing episodes in the previous year (r: -0.395; p: 0.001), and systemic glucocorticoid need in the previous year (r: -0.324; p: 0.001). Conclusions. Mean 25OHD levels were lower in patients with recurrent wheezing than in healthy controls. The duration of illness and number of wheezing episodes were correlated with vitamin D levels. An evaluation of the serum levels of vitamin D and supplementation if needed should be recommended in patients with recurrent wheezing, especially in those with long-term and frequent wheezing episodes. PMID- 29249128 TI - Prevention and management of gastroesophageal varices. AB - Bleeding from gastroesophageal varices is a serious complication in patients with liver cirrhosis and portal hypertension. Although there has been significance improvement in the prognosis of variceal bleeding with advancement in diagnostic and therapeutic modalities for its management, mortality rate still remains high. Therefore, appropriate prevention and rapid, effective management of bleeding from gastroesophageal varices is very important. Recently, various studies about management of gastoesophageal varices, including prevention of development and aggravation of varices, prevention of first variceal bleeding, management of acute variceal bleeding, and prevention of variceal rebleeding, have been published. The present article reviews published articles and practice guidelines to present the most optimal management of patients with gastroesophageal varices. PMID- 29249134 TI - Galactose-alpha-1,3-galactose syndrome: an Italian survey. AB - Summary: Background. The term of alpha-Gal syndrome, which includes the delayed allergy to red meat and the allergic reactions following the administration of cetuximab, is associated to the presence of specific IgE to alpha-Gal. In Italy, only anecdotal cases were reported so far. The Association of Italian Allergists (AAITO) carried out a survey with the aim of evaluating presence, characteristics, clinical features, and distribution of the syndrome in Italy. Methods. A web structured questionnaire was made available on the website of AAIITO from July 2016 to January 2017. It included 31 multiple-choice questions concerning different items, including the site of physicians, the number of patients diagnosed as having cetuximab allergy and/or delayed red meat allergy, recall of tick bites, symptoms, time to reactions, elicitor foods, reactions with foods other than meat, and in-vivo and in-vitro tests used for the diagnosis. Results. Seventy-nine physicians completed the questionnaire. Nine cases of allergy to cetuximab and 40 cases of delayed red meat allergy were recorded across Italy. 22.5% of patients with cetuximab allergy and 62.5% of those with delayed red meat allergy recalled a tick bite. 75% of patients with delayed red meat allergy experienced symptoms after eating beef (butcher's cut in 72.5%). Urticaria was the most frequent clinical manifestation (65% of cases). In 60.6% of cases symptoms appeared 2 - 4 hours after meat ingestion, while in 7.9% symptoms appeared after > 4 hours. The most used diagnostic methods were the intradermal test for cetuximab allergy (88.9%) and the detection of IgE to alpha Gal (55.5%) for red meat allergy. Most case reports came from Northern Italy. Conclusions. alpha-Gal syndrome is present in Italy and beef is the most frequent offending food. In most cases symptoms were not severe. PMID- 29249135 TI - Prevalence, molecular characterization, and clinical relevance of sensitization to Anisakis simplex in children with sensitization and/or allergy to Dermatophagoides pteronyssinus. AB - Summary: Prevalence of the Anisakis Simplex's (AS) sensitization in children sensitized to Dermatophagoides pteronissynus (DP) is not known, neither it is to which percentage it might be due to cross-reactivity. The primary objective of the present retrospective cross-sectional study is to evaluate the prevalence of sensitization to AS in children sensitized or allergic to DP. Secondary outcomes were the prevalence of cross-reactivity and clinical relevance of the condition. The prevalence of sensitization to AS differs significantly among patients sensitized and not to DP (13.43% vs. 3.80%; p=0.019). The higher prevalence is mainly due to cross-reactivity with Der p10 (OR=8.86; 95% CI=4.33-40.74; p=0.0001). Currently, the sensitization to AS seems to have no clinical relevance in the pediatric population. PMID- 29249136 TI - Pattern of inpatient referrals to a drug allergy unit in Kuwait. AB - Summary: Introduction. There is no information regarding the pattern of inpatient referrals to drug allergy units in Kuwait. Objectives. The main goal of this study is to clarify the pattern of inpatient referrals to a drug allergy unit in terms of incidence, drugs implicated and allergy evaluation outcomes in comparison with studies in other countries. Patients and Methods. A retrospective chart review of inpatient drug allergy consultations at Al-Rashed Allergy Center over a 3-year period was performed. Results. A total of 51 patients were referred for drug allergy consultations, with an estimated incidence of reported drug allergy among inpatients of 0.008%. There is an increasing trend of referrals from public health centres located in proximity to Al-Rashed Allergy Center. Beta lactams, contrast media, and general anaesthetics were the most common drugs leading to referrals. In total, 30% of patients were diagnosed with an allergy to the offending drug after a full allergy evaluation. Conclusion. Inpatient drug allergy referrals are highly underreported in Kuwait. PMID- 29249137 TI - Occupational allergy to Spagulax(r)(Plantago ovata seed). AB - Summary: We report the case of a 36-year-old male pharmaceutical laboratory worker. On handling Spagulax(r) sachets whose content is a laxative called Plantago ovata, he immediately presented rhinoconjunctivitis. Methods. Specific allergy study included SDS-PAGE with Western Blot and specific nasal challenge to Plantago ovata extract. Results. Prick by prick for Spagulax(r) was negative. Total IgE: 126.5 U/mL. Western Blot recognized two proteins of 15 and 20 kDa in the extract of Plantago ovata and three proteins of 15, 18 and 50 kDa in the extract of Plantago lanceolata. Conclusions. We present a case of occupational allergy due to inhalation of and/or contact with Plantago ovata seeds. PMID- 29249138 TI - Transient hair loss in patients with chronic spontaneous urticaria treated with omalizumab. AB - Summary: Omalizumab (anti-IgE) is used as add-on therapy for antihistamine refractory chronic urticaria patients. The most commonly reported adverse effects were headache, arthralgia, upper respiratory infections, fatigue, nausea and injection-site reactions. However, lately a few cases of hair loss have been reported. We describe a case of transient hair loss in a young female patient after initiating treatment with omalizumab. Despite this side effect, the patient continued with omalizumab treatment for 10 months with good effect. PMID- 29249139 TI - Omalizumab for refractory chronic spontaneous urticaria during concurrent immunomodulatory therapy for multiple sclerosis. AB - Summary: Data derived from previous clinical trials and real-life studies have shown that omalizumab may represent an effective third-line treatment option for patients with chronic spontaneous urticaria (CSU) refractory to standard antihistamine treatment. Nevertheless, the safety and efficacy of omalizumab treatment for CSU, when administered concurrently with other immunomodulatory agents remains largely unknown. We herein present the case of a female patient with relapsing-remitting multiple sclerosis (RRMS), under treatment with interferon beta-1a, azathioprine and gabapentin, who was successfully treated with omalizumab for refractory CSU. To the best of our knowledge, this is the first reported case attesting to the safety and efficacy of omalizumab for CSU when administered concurrently with other immunomodulatory agents. PMID- 29249140 TI - Impact of two hydrogymnastics class methodologies on the functional capacity and flexibility of elderly women. AB - BACKGROUND: Activities in the aquatic environment can be an interesting alternative of physical exercise for the elderly, due to several properties of water, which can favor the physiological, metabolic, perceptive, and musculoskeletal effects. OBJECTIVE: To compare the effects of performing two hydrogymnastic class methodologies on the functional capacity and flexibility in elderly women. METHODS: 90 women, aged 55-70 years, were divided into three groups, the Control Group (CG; n= 30) who did not exercise during the 12 weeks, Experimental Group 1 (EG1; n= 30), who performed water gymnastics classes with emphasis on lower limb exercises for 12 weeks, and Experimental Group 2 (EG2; n= 30), who performed conventional hydrogymnastics classes for 12 weeks. The volunteers were evaluated through the 30-second chair stand (30CST), 2-minute step test (2MST), timed up and go (TUG), static balance (SB) and chair sit-and reach (CSR) tests. RESULTS: In the intragroup comparison, there were significant improvements in the performance of 30CST tests (F=5.5, p=0.022), TUG (F=19.3, p<0.001), SB (F=5.3, p=0.025), and CSR (F=12.0, p=0.001) in EG1 and EG2. For intergroup comparisons, the EG1 presented better results than CG in CST (p<0.05). The EG2, presented better results than CG in CST, TUG, SB and CSR (p<0.05).There were no significant differences for the comparison between EG1 and EG2. CONCLUSIONS: It was concluded that 12 weeks of hydrogymnastics practice improved the functional capacity and flexibility of the elderly women evaluated, and no differences were found between the two types of methodologies used. PMID- 29249141 TI - Effect of textured insoles on postural control during static upright posture following lower limb muscle fatigue. AB - BACKGROUND: The purpose of this study was to assess the effects of textured insoles on static upright posture before and after lower limb muscle fatigue. Textured insoles used contained small and non-deformable pebbles of various sizes that are able to stimulate a major number of mechanoreceptors. It was inserted inside footwear. METHODS: Ten healthy young adults participated in the study (mean age 26.1 +/- 3.07 years). They were asked to stand on a force platform in four sensory states: vision, no vision, with and without natural plantar stimulation. For each sensory state the subjects underwent a single 30-second trial in pre-fatigue and post-fatigue conditions. Muscle fatigue was induced by 60 seconds of continuous jumping. Centre of Pressure displacement, sway velocity, antero-posterior and medio- lateral sway velocity were measured using force platform. RESULTS: Textured insoles had a stabilizing effect on balance compared to control insoles. Textured insoles significantly reduced CoPDISP and VA/P levels in closed eyes pre-fatigue condition. Post-fatigue all postural parameters improved in both vision and no vision conditions. CONCLUSIONS: Textured insoles with rigid stimulation significantly improved CoPDISP, independently of vision, supplying relevant and complete sensory information and improving balance in fatigue conditions. PMID- 29249142 TI - Electrochemical Cutting in Weak Aqueous Electrolytes: The Strategy for Efficient and Controllable Preparation of Graphene Quantum Dots. AB - The controllable and efficient electrochemical preparation of highly crystalline graphene quantum dots (GQDs) in an aqueous system is still challenging. Here, we developed a weak electrolyte-based (typically an ammonia solution) electrochemical method to enhance the oxidation and cutting process and therefore achieve a high yield of GQDs. The yield of GQDs (3-8 nm) is 28%, approximately 28 times higher than the yield of GQDs prepared by other strong electrolytes. The whole preparation process can be accomplished within 2 h because of the effective free radical oxidation process and the suppressed intercalation-induced exfoliation in weakly ionized aqueous electrolytes. The GQDs also showed excellent crystallinity which is obviously better than the crystallinity of GQDs obtained via bottom-up approaches. Moreover, amino-functionalization of GQDs can be realized by manipulating the electrolyte concentration. We further demonstrate that the proposed method can also be expanded to other weak electrolytes (such as HF and H2S) and different anode precursor materials (such as graphene/graphite papers, carbon fibers, and carbon nanotubes). PMID- 29249143 TI - Iodine-Mediated Difunctionalization of Imidazopyridines with Sodium Sulfinates: Synthesis of Sulfones and Sulfides. AB - Novel iodine-induced sulfonylation and sulfenylation of imidazopyridines have been described using sodium sulfinates as the sulfur source. This strategy enables highly selective difunctionalization of imidazo[1,2-a]pyridine to access sulfones and sulfides in good yields. A wide range of substrates and functional groups were well-tolerated under optimized conditions. Moreover, control experiments have been conducted, indicating a radical pathway involved in the reaction mechanisms. PMID- 29249145 TI - Carboxylic Acid Group-Induced Oxygen Vacancy Migration on an Anatase (101) Surface. AB - Dye-sensitized solar cells (DSSCs) have aroused intensive interest for the replacement of conventional crystalline silicon solar cells. Through carboxylic acid groups, the dyes attach to the TiO2 anatase (101) surface, on which the subsurface oxygen vacancies (Vosubs) are predominant. The performance of DSSCs can be affected by the presence and positions of oxygen vacancies (Vos). By applying density functional theory calculations, we found that the adsorption of a carboxylic acid group-decorated dye molecule reverses the relative stability between the surface oxygen vacancy (Vosurf) and Vosub on the anatase (101) surface, which facilitates the migration of the Vo from the subsurface to the surface by overcoming an energy barrier of less than 0.16 eV, which is significantly lower than the 1.01 eV energy barrier on the clean surface. Further, ab initio molecular dynamics simulations indicate that the Vosub can easily migrate to the surface at room temperature. This dynamic interplay between the Vo of the anatase (101) surface and the carboxylic acid group would be important for future studies concerning the stability and photovoltaic efficiency of the solar cells. PMID- 29249146 TI - Catalytic Performance of a Dicopper-Oxo Complex for Methane Hydroxylation. AB - A dicopper(II) complex, [Cu2(MU-OH)(6-hpa)]3+, where 6-hpa is 1,2-bis[2-[bis(2 pyridylmethyl)aminomethyl]-6-pyridyl]ethane, generates an oxyl radical of CuIIO* and catalyzes the selective hydroxylation of benzene to phenol. From the structural similarity to methane activation catalysts (e.g., bare CuO+ ion, Cu ZSM-5, and particulate methane monooxygenase), it is expected to catalyze methane hydroxylation. The catalytic performance for the hydroxylation of methane to methanol by this dicopper complex is investigated by using density functional theory (DFT) calculations. The whole reaction of the methane conversion involves two steps without radical species: (1) C-H bond dissociation of methane by the CuIIO* moiety and (2) C-O bond formation with methyl migration. In the first step, the activation barrier is calculated to be 10.2 kcal/mol, which is low enough for reactions taking place under normal conditions. The activation barrier by the other CuIIO2* moiety is higher than that by the CuIIO* moiety, which should work to turn the next catalytic cycle. DFT calculations show that the dicopper complex has a precondition to hydroxylate methane to methanol. Experimental verification is required to look in detail at the reactivity of this dicopper complex. PMID- 29249144 TI - BioSITe: A Method for Direct Detection and Quantitation of Site-Specific Biotinylation. AB - Biotin-based labeling strategies are widely employed to study protein-protein interactions, subcellular proteomes and post-translational modifications, as well as, used in drug discovery. While the high affinity of streptavidin for biotin greatly facilitates the capture of biotinylated proteins, it still presents a challenge, as currently employed, for the recovery of biotinylated peptides. Here we describe a strategy designated Biotinylation Site Identification Technology (BioSITe) for the capture of biotinylated peptides for LC-MS/MS analyses. We demonstrate the utility of BioSITe when applied to proximity-dependent labeling methods, APEX and BioID, as well as biotin-based click chemistry strategies for identifying O-GlcNAc-modified sites. We demonstrate the use of isotopically labeled biotin for quantitative BioSITe experiments that simplify differential interactome analysis and obviate the need for metabolic labeling strategies such as SILAC. Our data also highlight the potential value of site-specific biotinylation in providing spatial and topological information about proteins and protein complexes. Overall, we anticipate that BioSITe will replace the conventional methods in studies where detection of biotinylation sites is important. PMID- 29249147 TI - Semisynthesis of Complex-Type Biantennary Oligosaccharides Containing Lactosamine Repeating Units from a Biantennary Oligosaccharide Isolated from a Natural Source. AB - Poly-N-acetyllactosamine (poly-LacNAc) structures on glycoproteins play important roles in essential biological events such as cell-cell adhesion. Here, we report a new strategy for the semisynthesis of LacNAc-extended complex-type biantennary oligosaccharides. We found an efficient isopropylidenation reaction that selectively protects the terminal Gal-3,4-OH of a biantennary complex-type nonasaccharide isolated from a natural source. This finding enabled the conversion of the nonasaccharide into the two types of oligosaccharides containing di-LacNAc units at one or two antennae via ten-step chemical sequences. PMID- 29249148 TI - Growth of Sub-5 nm Metal Nanoclusters in Polymer Melt Aerosol Droplets. AB - Ultrasmall metal nanoparticles are inherently unstable because of their high specific surface area. This work investigates how growth and aggregation of these nanostructures can be circumvented by incorporating them into a polymer matrix in an on-the-fly growth process. We demonstrate the formation of sub-5 nm particles of Ni, Co, and Cu nanoparticles in a polymer matrix using an aerosol single-drop reactor approach. The rapid thermal pulse given to the aerosol particles enables the formation of nuclei and growth, with subsequent rapid quenching to freeze in the structure. The role of the temperature as well as the precursor concentration of the resulting size and morphology is discussed. A characteristic time analysis and an analysis of the particle size distributions lead to the conclusion that growth is governed by nucleation and surface growth, with little coagulation or Ostwald ripening. Finally, we note that this aerosol route is amenable to scale up for large-scale production of nanoclusters that can either be used as is within the polymer or released by solvent extraction, depending on the application. PMID- 29249149 TI - Strong Dual-Compartment Microcapsules Loaded with High Cargo Contents. AB - Compartmentalized microcapsules are useful for the release of multiple cargos in medicine, agriculture, and advanced responsive materials. Although several encapsulation strategies that involve more than one cargo have been proposed, dual- or multicompartment capsules with high cargo loadings and sufficient mechanical stability are rarely reported. Here, we propose a single-step emulsification route for the preparation of strong dual-compartment capsules that can host the main cargo in their core in combination with another liquid cargo stored within their thick shell. Capsules are produced through the polymerization of the middle oil phase of water-oil-water double emulsions made by microfluidics. Compartmentalization results from the phase separation of monomers within the middle phase of the double emulsion. We investigate the effect of such phase separation process on the microstructure and mechanical properties of the capsules and eventually illustrate the potential of this approach by creating thermosensitive capsules with programmable bursting temperature. The large variety of possible mixtures of monomers and cargos that can be added in the oil and aqueous phases of the double emulsion templates makes this encapsulation approach a promising route for the fabrication of robust microcapsules for on demand release of multiple cargos. PMID- 29249150 TI - Design of Nanofibrous and Microfibrous Channels for Fast Capillary Flow. AB - The speed of capillary flow is a key bottleneck in improving the performance of nanofluidic and microfluidic devices for various applications including microfluidic diagnostics, thermal management heat pipes, micromolding devices, functional fabrics, and oil-water separators. Here, we present a novel nanofibrous or microfibrous hollow-wedged channel (named as W-Channel), which can significantly speed up the capillary flow. The capillary flow in the initial 100 s in the nanofibrous W-Channel was shown to be 8 times faster than that in the single-layer strip of the same material when placed vertically and over 20 times faster when placed horizontally. The enhanced flow under gravity is attributed to the adaptive interplay of capillary pressure and flow resistance within the triangular hollow wedge between the fibrous layers. The W-Channel can be fabricated following a simple procedure using inexpensive materials such as electrospun nanofibers or microfibrous filter papers. PMID- 29249151 TI - Oriented Films of Conjugated 2D Covalent Organic Frameworks as Photocathodes for Water Splitting. AB - Light-driven water electrolysis at a semiconductor surface is a promising way to generate hydrogen from sustainable energy sources, but its efficiency is limited by the performance of available photoabsorbers. Here we report the first time investigation of covalent organic frameworks (COFs) as a new class of photoelectrodes. The presented 2D-COF structure is assembled from aromatic amine functionalized tetraphenylethylene and thiophene-based dialdehyde building blocks to form conjugated polyimine sheets, which pi-stack in the third dimension to create photoactive porous frameworks. Highly oriented COF films absorb light in the visible range to generate photoexcited electrons that diffuse to the surface and are transferred to the electrolyte, resulting in proton reduction and hydrogen evolution. The observed photoelectrochemical activity of the 2D-COF films and their photocorrosion stability in water pave the way for a novel class of photoabsorber materials with versatile optical and electronic properties that are tunable through the selection of appropriate building blocks and their three dimensional stacking. PMID- 29249152 TI - Age-Corrected Trends and Toxic Equivalence of PCDD/F and CP-PCBs in Lake Trout and Walleye from the Great Lakes: 2004-2014. AB - Our research reports polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (CP-PCBs) concentrations and age-corrected trends for lake trout and walleye in the Great Lakes over the 2004-2014 period. We determined that age-contaminant corrections are required to accurately report contaminant trends due to significant lake trout age structure changes. The age-trend model (ATM) described here uses a lake specific age-contaminant regression to mitigate the effect of a fluctuating lake trout age structure to directly improve the log-linear regression model. ATM results indicate that half-life (t1/2) and percent decreases for PCDD/Fs, CP PCBs, and toxic equivalence (TEQ) (average -56 to 70%) were fairly uniform and consistent across the Great Lakes over the 2004-2014 period. The vast majority of TEQ associated with all Great Lakes lake trout and walleye samples is due to the nonortho CP-PCBs (average = 79%) as compared with PCDD/Fs (average = 21%). On average, CP-PCB_126 individually accounted for over 95% of the total CP-PCB TEQ. A retrospective analysis (1977-2014) of 2378-TCDF and 2378-TCDD raw concentrations in Lake Ontario lake trout revealed decreases of 94% and 96%, respectively. Tissue residue guidelines for wildlife protection based on lake trout and walleye total TEQ were uniformly exceeded in all the Great Lakes. PMID- 29249153 TI - Native and Engineered Clifednamide Biosynthesis in Multiple Streptomyces spp. AB - Polycyclic tetramate macrolactam (PTM) natural products are produced by actinomycetes and other bacteria. PTMs are often bioactive, and the simplicity of their biosynthetic clusters make them attractive for bioengineering. Clifednamide type PTMs from Streptomyces sp. strain JV178 contain a distinctive ketone group, suggesting the existence of a novel PTM oxidizing enzyme. Here, we report the new cytochrome P450 enzyme (CftA) is required for clifednamide production. Genome mining was used to identify several new clifednamide producers, some having improved clifednamide yields. Using a parallel synthetic biology approach, CftA isozymes were used to engineer the ikarugamycin pathway of Streptomyces sp. strain NRRL F-2890 to yield clifednamides. Further, we observed that strong CftA expression leads to the production of a new PTM, clifednamide C. We demonstrate the utility of both genome mining and synthetic biology to rapidly increase clifednamide production. PMID- 29249154 TI - Identifying Sources of Environmental Contamination in European Honey Bees (Apis mellifera) Using Trace Elements and Lead Isotopic Compositions. AB - Trace element concentrations (As, Mn, Pb, and Zn) and Pb isotopic compositions were analyzed in honey bees, wax, and honey along with co-located soil and dust samples from Sydney metropolitan and Broken Hill, Australia. Compared with the other trace elements, Pearson correlations show that Pb concentrations in soil and dust had the strongest relationship to corresponding values in honey bees and their products. Dust Pb was not only highly correlated to corresponding soil values (r = 0.806, p = 0.005), it was the strongest predictor of Pb concentrations in honey bees, wax, and honey (p = 0.001, 0.007, 0.017, respectively). Lead isotopic compositions (206Pb/207Pb and 208Pb/207Pb) showed that honey bees and their products from Broken Hill were nearly identical (95 98%) to the composition of the local ore body. Samples of honey bees and their products collected from background sites adjacent to national parks in Sydney had Pb isotopic compositions (206Pb/207Pb = 1.138-1.159, 208Pb/207Pb = 2.417-2.435) corresponding to local geogenic values (206Pb/207Pb = 1.123-1.176, 208Pb/207Pb = 2.413-2.500). By contrast, honey bees and their products from Sydney metropolitan (206Pb/207Pb = 1.081-1.126, 208Pb/207Pb = 2.352-2.408) were similar to aerosols measured during the period of leaded petrol use (206Pb/207Pb = 1.067-1.148, 208Pb/207Pb = 2.341-2.410). These measurements show Pb concentrations and its isotopic compositions of honey bees, and their products can be used to trace both legacy and contemporary environmental contamination, particularly where sources are well documented. Moreover, this study demonstrates that legacy Pb emissions continue to be remobilized in dust, contaminating both food and ecological systems. PMID- 29249155 TI - Exploring ECD on a Benchtop Q Exactive Orbitrap Mass Spectrometer. AB - As the application of mass spectrometry intensifies in scope and diversity, the need for advanced instrumentation addressing a wide variety of analytical needs also increases. To this end, many modern, top-end mass spectrometers are designed or modified to include a wider range of fragmentation technologies, for example, ECD, ETD, EThcD, and UVPD. Still, the majority of instrument platforms are limited to more conventional methods, such as CID and HCD. While these latter methods have performed well, the less conventional fragmentation methods have been shown to lead to increased information in many applications including middle down proteomics, top-down proteomics, glycoproteomics, and disulfide bond mapping. We describe the modification of the popular Q Exactive Orbitrap mass spectrometer to extend its fragmentation capabilities to include ECD. We show that this modification allows >=85% matched ion intensity to originate from ECD fragment ion types as well as provides high sequence coverage (>=60%) of intact proteins and high fragment identification rates with ~70% of ion signals matched. Finally, the ECD implementation promotes selective disulfide bond dissociation, facilitating the identification of disulfide-linked peptide conjugates. Collectively, this modification extends the capabilities of the Q Exactive Orbitrap mass spectrometer to a range of new applications. PMID- 29249156 TI - Antiobesity Efficacy of Quercetin-Rich Supplement on Diet-Induced Obese Rats: Effects on Body Composition, Serum Lipid Profile, and Gene Expression. AB - The antiobesity effects of quercetin-rich supplement (QRS), which contain quercetin, lycopene, taurine, and litchi flower extract, on a high-fat diet (HFD) induced obese rats were investigated. The rats that consume HFD with QRS (185 mg/kg rat) have significantly modulated the final body weights [490 +/- 11 (HFD) > 441 +/- 11 (HFD+QRS) g], total body fat [112.9 +/- 4.5 (HFD) -> 86.6 +/- 5.7 (HFD+QRS) g], liver weights [14.8 +/- 0.4 (HFD) -> 12.6 +/- 0.4 (HFD+QRS) g/rat], and the serum TG [102.5 +/- 7.3 (HFD) -> 90.7 +/- 6.5 (HFD+QRS) mg/dL] to a level that resembled the regular diet-consumed rats (p < 0.05). The excretion of lipid in the faeces augmented in QRS groups as compared with the nonsupplemented HFD group [faecal total lipid: 62.43 +/- 2.80 (HFD) -> 73.15 +/- 0.88 (HFD+QRS) mg/g dried faeces, p < 0.05]. In the histological analysis, quercetin-rich formulation supplemented groups presented a much less lipid accumulation and smaller size of adipocytes. Moreover, a decreased serum thiobarbituric acid reactive substances [1.55 +/- 0.17 (HFD) -> 0.78 +/- 0.04 (HFD+QRS) nmol MDA eq/mL serum] increased levels of serum Trolox equivalent antioxidant capacity [3.89 +/- 0.08 (HFD) -> 6.46 +/- 0.20 (HFD+QRS) MUmol/mL serum], and more active hepatic antioxidant enzymes were observed in the supplemented groups (p < 0.05). The result of this work is a good demonstration of how a combination of bioactive compounds could work synergistically and become very effective in disease prevention. PMID- 29249158 TI - Multiscale Spatial Modeling of Human Exposure from Local Sources to Global Intake. AB - Exposure studies, used in human health risk and impact assessments of chemicals, are largely performed locally or regionally. It is usually not known how global impacts resulting from exposure to point source emissions compare to local impacts. To address this problem, we introduce Pangea, an innovative multiscale, spatial multimedia fate and exposure assessment model. We study local to global population exposure associated with emissions from 126 point sources matching locations of waste-to-energy plants across France. Results for three chemicals with distinct physicochemical properties are expressed as the evolution of the population intake fraction through inhalation and ingestion as a function of the distance from sources. For substances with atmospheric half-lives longer than a week, less than 20% of the global population intake through inhalation (median of 126 emission scenarios) can occur within a 100 km radius from the source. This suggests that, by neglecting distant low-level exposure, local assessments might only account for fractions of global cumulative intakes. We also study ~10 000 emission locations covering France more densely to determine per chemical and exposure route which locations minimize global intakes. Maps of global intake fractions associated with each emission location show clear patterns associated with population and agriculture production densities. PMID- 29249159 TI - Bidentate Ligand-Passivated CsPbI3 Perovskite Nanocrystals for Stable Near-Unity Photoluminescence Quantum Yield and Efficient Red Light-Emitting Diodes. AB - Although halide perovskite nanocrystals (NCs) are promising materials for optoelectronic devices, they suffer severely from chemical and phase instabilities. Moreover, the common capping ligands like oleic acid and oleylamine that encapsulate the NCs will form an insulating layer, precluding their utility in optoelectronic devices. To overcome these limitations, we develop a postsynthesis passivation process for CsPbI3 NCs by using a bidentate ligand, namely 2,2'-iminodibenzoic acid. Our passivated NCs exhibit narrow red photoluminescence with exceptional quantum yield (close to unity) and substantially improved stability. The passivated NCs enabled us to realize red light-emitting diodes (LEDs) with 5.02% external quantum efficiency and 748 cd/m2 luminance, surpassing by far LEDs made from the nonpassivated NCs. PMID- 29249160 TI - Photoconductance from Exciton Binding in Molecular Junctions. AB - We report on a theoretical analysis and experimental verification of a mechanism for photoconductance, the change in conductance upon illumination, in symmetric single-molecule junctions. We demonstrate that photoconductance at resonant illumination arises due to the Coulomb interaction between the electrons and holes in the molecular bridge, so-called exciton-binding. Using a scanning tunneling microscopy break junction technique, we measure the conductance histograms of perylene tetracarboxylic diimide (PTCDI) molecules attached to Au electrodes, in the dark and under illumination, and show a significant and reversible change in conductance, as expected from the theory. Finally, we show how our description of the photoconductance leads to a simple design principle for enhancing the performance of molecular switches. PMID- 29249157 TI - De Novo Design of Tetranuclear Transition Metal Clusters Stabilized by Hydrogen Bonded Networks in Helical Bundles. AB - De novo design provides an attractive approach to test the mechanism by which metalloproteins define the geometry and reactivity of their metal ion cofactors. While there has been considerable progress in designing proteins that bind transition metal ions including iron-sulfur clusters, the design of tetranuclear clusters with oxygen-rich environments has not been accomplished. Here, we describe the design of tetranuclear clusters, consisting of four Zn2+ and four carboxylate oxygens situated at the vertices of a distorted cube-like structure. The tetra-Zn2+ clusters are bound at a buried site within a four-helix bundle, with each helix donating a single carboxylate (Glu or Asp) and imidazole (His) ligand, as well as second- and third-shell ligands. Overall, the designed site consists of four Zn2+ and 16 polar side chains in a fully connected hydrogen bonded network. The designed proteins have apolar cores at the top and bottom of the bundle, which drive the assembly of the liganding residues near the center of the bundle. The steric bulk of the apolar residues surrounding the binding site was varied to determine how subtle changes in helix-helix packing affect the binding site. The crystal structures of two of four proteins synthesized were in good agreement with the overall design; both formed a distorted cuboidal site stabilized by flanking second- and third-shell interactions that stabilize the primary ligands. A third structure bound a single Zn2+ in an unanticipated geometry, and the fourth bound multiple Zn2+ at multiple sites at partial occupancy. The metal-binding and conformational properties of the helical bundles in solution, probed by circular dichroism spectroscopy, analytical ultracentrifugation, and NMR, were consistent with the crystal structures. PMID- 29249161 TI - Surface-Active Hollow Titanosilicate Particles as a Pickering Interfacial Catalyst for Liquid-Phase Alkene Epoxidation Reactions. AB - The design of catalyst particles bearing excellent catalytic activity and suitable surface wettability is the key to successful application of Pickering interfacial catalysis. In this study, the epoxidation of 1-hexene and cyclohexene with aqueous hydrogen peroxide over hollow TS-1 (HTS-1) zeolite was studied as a probe reaction to investigate the influence of catalyst surface wettability on catalytic activity. Hydrophobized HTS-1 particles were fabricated via a postsynthesis desilication treatment with tetrapropylammonium hydroxide and a postsynthesis silylation treatment with hexamethyldisiloxane (HMDSO). The successful preparation of HTS-1 particles was verified by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy, and Fourier-transform infrared spectroscopy. X-ray diffraction patterns and ultraviolet-visible spectra confirmed that the hydrophobic modification had no effect on the zeolite structure of HTS-1 particles. Stable Pickering emulsions of aqueous hydrogen peroxide in either 1-hexene or cyclohexene could be prepared using HTS-1 particles as emulsifiers and confirmed by cryo-SEM images. The catalytic behavior in the obtained Pickering emulsions revealed a parabolic distribution of turnover frequency values with respect to the hydrophobization degrees with 0.2-HMDSO/HTS 1 particles possessing the maximum values of 20.6 h-1 for 1-hexene epoxidation and 8.1 h-1 for cyclohexene epoxidation. In addition, these 0.2-HMDSO/HTS-1 particles showed good reusability for more than five cycles. PMID- 29249162 TI - Dietary Apostichopus japonicus Alleviates Diabetes Symptoms and Modulates Genes Expression in Kidney Tissues of db/db Mice. AB - The effects of Apostichopus japonicus enzymatic hydrolysate on the regulation of dyslipidemia, pathoglycemia, and transcription changes in kidney tissues of db/db mice were evaluated. In this study, the symptoms of diabetes in db/db mice were alleviated after 10 weeks of treatments with low (db/db + LD group) and high dose (db/db + HD group) of Apostichopus japonicus enzymatic hydrolysate, and the high dose treatment showed a better antidiabetic effect. Compared with the db/db group, the fasting blood glucose levels (36.84 +/- 7.82 vs 25.18 +/- 6.84 mmol/L, P < 0.01), the urine glucose levels (45.44 +/- 3.93 vs 22.66 +/- 5.58 mmol/L, P < 0.01), and the serum insulin sensitivity index (-4.65 +/- 0.43 vs -4.74 +/- 0.75, P > 0.05) in the db/db + HD group were decreased, whereas the fasting plasma insulin (3.12 +/- 1.08 vs 5.54 +/- 1.82 MUg/L, P < 0.01) and the serum insulin resistance index (5.01 +/- 2.02 vs 5.96 +/- 2.49, P < 0.05) were increased. Subsequently, the kidney transcription profiles were measured in the db/db group and db/db + HD group via microarray, and the results show that Apostichopus japonicus hydrolysate induced differential expression of 77 genes. Among these genes, the down-regulation of genes ntrK1 and ptpN5 played vital roles, as this effect induced the further down-regulation of neurotrophin tyrosine kinase, protein tyrosine phosphatase, and other transcription factors, which are involved in the classical mitogen-activated protein kinases (MAPK) and p38MAPK signaling pathways. The inhibited MAPK and p38MAPK signaling pathways are involved in glycometabolism and the control of lipid metabolism, and they regulate the occurrence and development of diabetic nephropathy. PMID- 29249164 TI - Effect of river water exposition on adhesion and invasion abilities of Salmonella Oranienburg and Saintpaul. AB - This study was performed to evaluate in vitro the adherence and invasiveness capacity of Salmonella Oranienburg and Saintpaul (isolated from river water) exposed to laboratory and river water growth conditions and inoculated into epithelial HEp-2 cell. Results showed that Salmonella Oranienburg and Salmonella Saintpaul showed lower ability to adhere and invade epithelial HEp-2 cells under both growth conditions as compared to Salmonella Typhimurium reference strain. S. Oranienburg adhesion capacity was not affected by the growth conditions, while S. Saintpaul exposed to river water significantly (p < 0.05) decreased its adhesion capacity by 75.7 %. On the contrary, S. Oranienburg exposed to river water reduced its invasion efficiency by 80 %, whereas S. Saintpaul showed no differences between growth conditions. In conclusion, this study suggests that the exposure to non-host conditions, such as river water, adversely affects the adhesion and invasiveness of Salmonella serotypes differently, impacting on their ability to re-enter a new host. PMID- 29249165 TI - Diabetes is associated with decreased migraine risk: A nationwide cohort study. AB - Background Results from studies on diabetes and migraine risk are conflicting, which may be due to methodological limitations. Prospective studies with long follow-up could increase our understanding of the relationship between the two diseases. Method We performed a cohort study including the whole Norwegian population alive on 01.01.2004, using prescriptions registered in the Norwegian prescription database to identify individuals developing type 1 diabetes, type 2 diabetes and migraine during follow-up (10 years). We used Cox proportional hazards regression to estimate rate ratios with corresponding 95% confidence intervals for the effect of diabetes on migraine risk, adjusting for age, sex, and educational level. Result We identified 7,883 type 1 diabetes patients and 93,600 type 2 patients during the study period. Type 1 diabetes was significantly associated with a subsequent decreased migraine risk during follow-up in the age- and sex-adjusted analyses (0.74; 0.61-0.89). Type 2 diabetes was also associated with a significantly lower migraine risk (0.89; 0.83-0.95). Further adjustment for educational level yielded similar results for both diabetes. Conclusion Both type 1 and type 2 diabetes were significantly associated with a decreased risk of migraine. This suggests that diabetes or diabetes treatment may have a protective effect on the development of migraine. PMID- 29249166 TI - Safety and efficacy of rivaroxaban for the secondary prevention following acute coronary syndromes among biomarker-positive patients: Insights from the ATLAS ACS 2-TIMI 51 trial. AB - BACKGROUND: Despite dual antiplatelet therapy, persistent thrombin generation and thrombin-mediated platelet activation account in part for the residual risk of atherothrombotic disease among patients with prior acute coronary syndrome (ACS). Inhibition of thrombin generation among high-risk ACS patients (biomarker positive ACS) with the factor Xa inhibitor rivaroxaban may limit ongoing thrombus formation and myocardial necrosis and thereby improve clinical outcomes. OBJECTIVES AND METHODS: ATLAS ACS 2-TIMI 51 was a double-blind, placebo controlled clinical trial that randomized ACS patients to either rivaroxaban 2.5 mg b.i.d., rivaroxaban 5 mg b.i.d., or placebo plus standard-of-care antiplatelet therapy for a mean of 13.1 months and up to 31 months ( N=15,526). This post-hoc analysis evaluates the safety and efficacy of rivaroxaban among biomarker positive ACS patients with and without a history of prior stroke of transient ischemic attack in the ATLAS ACS 2-TIMI 51 trial. RESULTS: A total of 12,626 biomarker-positive ACS patients were included in this analysis. Among biomarker positive patients without a prior history of stroke or transient ischemic attack, rivaroxaban 2.5 b.i.d. was associated with a reduction in the primary efficacy endpoint (composite of cardiovascular death, myocardial infarction, or stroke) as compared with placebo (hazard ratio=0.80, 95% confidence interval (0.68-0.94), p=0.007) at the expense of an increase in non-coronary-artery-bypass-graft related Thrombolysis in Myocardial Infarction major bleeding (1.9% vs. 0.7%, p<0.0001), but not a significant increase in either intracranial hemorrhage (0.4% vs. 0.2%, p=0.11) or fatal bleeding (0.1% vs. 0.3%, p=0.16). CONCLUSION: Rivaroxaban 2.5 mg b.i.d. was associated with a significant reduction in the composite of cardiovascular death, myocardial infarction, or stroke with no increase in fatal bleeding. Biomarker-positive patients with no prior history of stroke or transient ischemic attack may be a optimal target population to receive "dual pathway" therapy with rivaroxaban plus dual antiplatelet therapy for secondary prevention following ACS. PMID- 29249167 TI - Comparison of ultrasound shear wave elastography with magnetic resonance elastography and renal microvascular flow in the assessment of chronic renal allograft dysfunction. AB - Background Monitoring of renal allograft function is essential for early identification of dysfunction and improvement of kidney transplant (KTX) outcome. Purpose To non-invasively assess renal stiffness in KTX recipients using ultrasound shear wave elastography (USE) in correlation with multifrequency magnetic resonance elastography (MRE), renal allograft function, and renal microvascular flow determined using a novel ultrasound microvascular imaging technique. Material and Methods This prospective study investigated 25 KTXs (functional KTX [FCT], n = 14; chronic KTX insufficiency [DYS], n = 11) in 20 KTX recipients (mean age = 43 +/- 14 years). USE was performed using a high-frequency broadband linear transducer and compared with MRE. Shear wave velocity (SWV) was correlated with the estimated glomerular filtration rate (eGFR). Qualitative differences in renal microvascular flow were obtained using SMI. Results FCT had higher SWV than DYS in both cortex and pyramids (cortex, FCT: 3.75 +/- 0.82 m/s vs. DYS: 2.79 +/- 0.73 m/s, P = 0.0002; pyramid, FCT: 2.89 +/- 0.46 m/s vs. DYS: 2.39 +/- 0.34 m/s, P = 0.044). Cutoff values of 3.265 m/s for cortex, 2.535 m/s for pyramids, and 2.985 m/s for combined non-hilar parenchyma provided sensitivities of 72.7%, 77.8%, and 90.9% and specificities of 71.4%, 78.6%, and 85.7% for detecting renal allograft dysfunction with area under the receiver operating characteristic curve (AUC) values of 0.831, 0.841, 0.925 (95% confidence interval [CI] = 0.67-0.99, 0.66-1.02, 0.83-1.03). USE correlated positively with eGFR ( r = 0.741, P = 0.0004) and with MRE-derived SWV ( r = 0.562, P = 0.004). Renal microvascular flow was decreased in DYS. Conclusion USE is sensitive to renal allograft dysfunction, which is characterized by reduced SWV and renal perfusion. USE has higher image resolution than MRE, while MRE has slightly better diagnostic accuracy. PMID- 29249168 TI - Professor Arnulf Skjennald steps down as Chief Editor. PMID- 29249169 TI - Beliefs and knowledge of cardiovascular-related disease among uninsured primary care patients: A cross-sectional study. AB - Objective The purpose of this study was to examine cardiovascular disease-related health beliefs and how they are influenced by knowledge and a sense of community among uninsured primary care patients. Method This study was a cross-sectional study using a self-administered paper survey (January to April 2016). The study population included medically uninsured US-born English speakers, non-US-born English speakers, and Spanish speakers. Results Medically uninsured adults utilizing a free clinic (N = 374) participated in the survey. Increasing knowledge about major risk factors for developing cardiovascular disease helped enhance levels of perceived severity of cardiovascular disease and benefits of healthy diet and physical activity. Spanish speakers reported higher levels of perceived severity of cardiovascular disease but lower levels of knowledge compared to US-born or non-US-born English speakers. Conclusion Spanish speakers may need different approaches to promote cardiovascular disease prevention due to their higher levels of perceived severity of cardiovascular disease but lower levels of cardiovascular disease-related knowledge compared to English speakers. Developing a healthy "community" in a clinic setting may be effective to promote cardiovascular disease-related health for underserved populations. PMID- 29249170 TI - Occult catheter rupture causing episodic symptoms in a patient treated with epoprostenol. AB - Infection, thrombosis, and catheter dislodgment are well-recognized potential complications of chronic intravenous prostanoid therapy for pulmonary arterial hypertension. As long-term outcomes of pulmonary hypertension patients improve, novel adverse events are likely to arise. We describe the sudden development of unexplained hypotension and lightheadedness in a patient receiving intravenous epoprostenol for several years, ultimately determined to be due to an unusual catheter complication, not previously described in this population. PMID- 29249171 TI - Celebrities' Memorial Afterlives: Obituaries, Tributes, and Posthumous Gossip in the Romanian Media Deathscape. AB - Cross-culturally, dead are protected from posthumous negative evaluations by the universal "nil nisi bonum" precept that governs the ethics within the community of mourners. In this study, we set out to test the observance of this injunction against posthumous gossiping in the Romanian public deathscape. Obituaries and other posthumous articles ( N = 1,148) were collected that covered the deaths of 63 celebrities who passed away between 2013 and 2016. Materials were gathered from the digital archives of three Romanian news sources (a news agency, a "quality" newspaper, and a tabloid), published one week after the moment of death. The findings show that 22% of the articles do contain negative evaluations of the deceased. The percentage rises to 36.4% if we restrict the sample to only those celebrities with a controversial anthumous reputation (19 of 63). These results indicate that celebrities are not spared from critical assessments after they pass away. PMID- 29249172 TI - Influence of Training on First-Year Nursing Department Students' Attitudes on Death and Caring for Dying Patients: A Single-Group Pretest-Posttest Experimental Study. AB - The study examined the influence of training on first-year nursing department students' attitudes on death and caring for dying patients. Utilizing the experimental model, the study sample consisted of 81 first-year students attending the nursing department of a university. Death Attitude Profile-Revised and Frommelt Attitude toward Care of the Dying Scale were used for data collection. Data analysis included means, standard deviation, and t test for related samples. Student attitudes toward death were measured as 146.43 (16.741) and 152.75 (15.132) for pre- and posttraining, respectively. Student attitudes toward caring for dying patients were established to be 103.02 (7.655) during pretraining period and 111.02 (10.359) at posttraining period. The difference between pre- and posttests for mean attitudes toward death and caring for the dying patient was statistically significant. Study results determined that training was effective in forming positive student attitudes toward death and caring for dying patients. PMID- 29249173 TI - Long-term prospective memory impairment following mild traumatic brain injury with loss of consciousness: findings from the Canadian Longitudinal Study on Aging. AB - OBJECTIVE: We aimed to examine the extent to which loss of consciousness (LOC) following mild traumatic brain injury (mTBI) may be associated with impairments in time- and event-based prospective memory (PM). PM is thought to involve executive processes and be subserved by prefrontal regions. Neuroimaging research suggests alterations to these areas of the brain several years after mTBI, particularly if LOC was experienced. However, it remains unclear whether impairments in time- or event-based functioning may persist more than a year after mTBI, and what the link with duration of LOC may be. METHOD: Analyses were run on data from the Canadian Longitudinal Study on Aging, a nationwide study on health and aging involving individuals between the ages of 45-85. The present study consisted of 1937 participants who experienced mTBI more than 12 months prior, of whom 1146 reported spending less than 1 min unconscious, and 791 had LOC between 1 and 20 min, and 13,525 cognitively healthy adults. Participants were administered the Miami Prospective Memory Test, and tests of retrospective memory and executive functioning. RESULTS: Both mTBI groups were impaired in time based PM relative to people with no history of TBI. Time- and event-based impairments were predicted by older age, and executive dysfunction among those who spent more time unconscious. CONCLUSIONS: Those with mTBI with LOC may experience impairments in PM, particularly in conditions of high demand on executive processes (time-based PM). Implications for interventions aimed at ameliorating PM among those who have experienced mTBI are discussed. PMID- 29249174 TI - Biomechanical insights into the determinants of speed in the fencing lunge. AB - For fencing, speed of the lunge is considered critical to success. The aim of this study is to investigate determinants of lunge speed based on biomechanics. Ground reaction force (GRF) and three-dimensional kinematic data were collected from 7 elite fencers and 12 intermediate-level fencers performing maximum-effort lunges. The results showed that elite fencers acquired a higher horizontal peak velocity of the centre of gravity (HPV) and concomitantly a higher horizontal peak GRF exerted by rear leg (PGRF) than intermediate-level fencers (P < .01). Studying the affecting factors, elite fencers obtained higher joint peak power, joint peak moment, and range of motion of rear knee than intermediate-level fencers (P < .05) during the lunge, and these parameters were significantly correlated with both HPV and PGRF (P < .05). Both elite and intermediate-level fencers had joint flexion before the extension in forward knee; however, the latter showed greater flexion, higher peak angular velocity and less time for extension compared to the former (P <= .05). Our findings suggest that training aimed at enhancing strength and power of rear knee extensors is important for fencers to improve speed of the lunge. Also, increasing the extension of rear knee during the lunge, at the same time decreasing the flexion of the forward knee before extension are positive for lunge performance. PMID- 29249176 TI - Neural mechanisms of strength increase after one-week motor imagery training. AB - The neural mechanisms explaining strength increase following mental training by motor imagery (MI) are not clearly understood. While gains are mostly attributed to cortical reorganization, the sub-cortical adaptations have never been investigated. The present study investigated the effects of MI training on muscle force capacity and the related spinal and supraspinal mechanisms. Eighteen young healthy participants (mean age: 22.5 +/- 2.6) took part in the experiment. They were distributed into two groups: a control group (n = 9) and an MI training group (n = 9). The MI group performed seven consecutive sessions (one per day) of imagined maximal isometric plantar flexion (4 blocks of 25 trials per session). The control group did not engage in any physical or mental training. Both groups were tested for the isometric maximal plantar flexion torque (MVC) and the rate of torque development (RTD) before and after the training session. In addition, soleus and medial gastrocnemius spinal and supraspinal adaptations were assessed through the recording of H-reflexes and V-waves, with electrical stimulations of the posterior tibial nerve evoked at rest and during MVC, respectively. After one week, only the MI training group increased both plantar flexion MVC and RTD. The enhancement of muscle torque capacity was accompanied by significant increase of electromyographic activity and V-wave during MVC and of H-reflex at rest. The increased cortical descending neural drive and the excitability of spinal networks at rest could explain the greater RTD and MVC after one week of MI training. PMID- 29249175 TI - A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFbeta in leukemic cells. AB - The core binding factor (CBF) gene RUNX1 is a target of chromosomal translocations in leukemia, including t(8;21) in acute myeloid leukemia (AML). Normal CBF function is essential for activity of AML1-ETO, product of the t(8;21), and for survival of several leukemias lacking RUNX1 mutations. Using virtual screening and optimization, we developed Runt domain inhibitors which bind to the Runt domain and disrupt its interaction with CBFbeta. On-target activity was demonstrated by the Runt domain inhibitors' ability to depress hematopoietic cell formation in zebrafish embryos, reduce growth and induce apoptosis of t(8;21) AML cell lines, and reduce progenitor activity of mouse and human leukemia cells harboring the t(8;21), but not normal bone marrow cells. Runt domain inhibitors had similar effects on murine and human T cell acute lymphocytic leukemia (T-ALL) cell lines. Our results confirmed that Runt domain inhibitors might prove efficacious in various AMLs and in T-ALL. PMID- 29249177 TI - Active recovery intervals restore initial performance after repeated sprints in swimming. AB - The purpose of this study was to examine the effects of active recovery (AR) and passive recovery (PR) using short (2-min) and long (4-min) intervals on swimming performance. Twelve male competitive swimmers completed a progressively increasing speed test of 7 * 200-m swimming repetitions to locate the speed before the onset of curvilinear increase in blood lactate concentration (LT1). Subsequently, performance time of 6 * 50-m sprints was recorded during four different conditions: (i) 2-min PR (PR-2), (ii) 4-min PR (PR-4), (iii) 2-min AR (AR-2) and (iv) 4-min AR (AR-4) intervals. Blood lactate concentration was measured before the first and after the last 50-m repetition. AR was applied at an intensity corresponding to LT1. Performance as indicated by the time needed to complete 6 * 50-m sprints was impaired after AR-4 compared to PR-4 (AR-4: 28.65 +/- 1.04, PR-4: 28.17 +/- 0.72 s; mean% difference: MD% +/-s; +/-90% confidence limits: 90%CL, 1.71 +/- 3.01%; +/-1.43%, p = .01) but was not different between AR-2 compared to PR-2 conditions (AR-2: 28.68 +/- 0.85, PR-2: 28.69 +/- 0.82 s; MD%: 0.03 +/- 1.61%; 90%CL +/- 0.77%, p = .99). Performance in sprint-6 was improved after AR compared to PR independent of interval duration (AR: 28.55 +/- 0.81, PR: 29.01 +/- 1.03 s; MD%: 1.52 +/- 2.61%; 90%CL +/- 1.2%; p = .03). Blood lactate concentration was lower after AR-4 compared to PR-4 but did not differ between AR-2 and PR-2 conditions. In conclusion, AR impaired performance after a 4-min but not after a 2-min interval. A better performance during sprint-6 after AR could be attributed to a faster metabolic recovery or anticipatory regulatory mechanisms towards the end of the series especially when adequate 4-min active recovery interval is applied. PMID- 29249178 TI - Biomarkers of cardiometabolic health and nutritional status in individuals with positive celiac disease serology. AB - BACKGROUND: Celiac disease (CD) is an autoimmune disorder characterized by damage to the intestinal mucosa and nutrient malabsorption in severe cases. However, it remains unclear whether nutrient deficiencies and other adverse health effects are prevalent in individuals with positive CD serology identified through screening studies. OBJECTIVE: The objective was to determine whether biomarkers of cardiometabolic health and nutritional status differ between those with positive and negative CD serology identified in a screening study of Canadian adults. METHODS: Participants ( n=2832) were from the Toronto Nutrigenomics and Health Study and the Toronto Healthy Diet Study. Individuals were screened for CD specific anti-tissue transglutaminase autoantibodies. Lipid profiles as well as concentrations of six carotenoids (alpha-carotene, beta-carotene, beta cryptoxanthin, lutein, lycopene, and zeaxanthin), three tocopherols (alpha tocopherol, delta-tocopherol, and gamma-tocopherol), retinol, ascorbic acid, and 25-hydroxyvitamin D were cross-sectionally compared between those with positive and negative CD serology using general linear mixed models. RESULTS: Individuals with positive CD serology ( n=23) had significantly lower levels of HDL cholesterol ( p=0.008) and apolipoprotein-AI ( p=0.02), a higher ratio of total cholesterol to HDL-cholesterol ( p=0.006), and a higher apolipoprotein-B/AI ratio ( p=0.03) than those with negative CD serology. Positive CD serology was also associated with significantly lower concentrations of retinol ( p=0.006) in fully adjusted models. Those with positive CD serology had lower serum 25 hydroxyvitamin D in unadjusted models ( p=0.01), but not in fully adjusted models ( p=0.08). CONCLUSIONS: Individuals with undiagnosed CD may have unfavorable lipid profiles and be at elevated risk for inadequacy of certain fat-soluble vitamins, but not widespread nutrient deficiencies. PMID- 29249179 TI - Real-life use of diagnostic biopsies before treatment of kidney cancer: results from a Norwegian population-based study. AB - OBJECTIVE: Interest in renal mass biopsies (RMBs) has increased in recent years. However, most publications are low-volume and/or single-center studies, so their generalizability is questionable. The aim of this study was to describe population-based, real-life use of diagnostic RMBs for localized and advanced kidney cancer (KC). MATERIALS AND METHODS: All KC patients diagnosed during 2008 2013 extracted from the database at the Cancer Registry of Norway were included. Relationships with outcome were analyzed using multivariate logistic regression and competing risks analyses. RESULTS: Of patients treated radically for localized KC, a pretreatment RMB was used in 8.4%. For similar patients treated by observation only, the rate increased from 29.3% to 60.7% during the study period. Tumor size <=4 cm, another malignancy, multiple tumors, old age (>= 80 years) and second study half were independent RMB predictors. Competing risks analysis showed that among radically treated patients with localized KC, those who had undergone an RMB had a higher risk of dying of other diseases. In patients with advanced KC, biopsy was used in 54.5%, and is increasing. Study limitations include a lack of data on benign tumors, comorbidity and performance status. CONCLUSIONS: For localized KC, the use of RMBs in Norway is in line with current guidelines. Because real-world data on RMB use are scarce, this study is useful for benchmarking in future studies. Furthermore, the study shows that fewer patients with advanced KC are treated without histopathological verification, and biopsies seem to have an increasing role in tailoring treatment. PMID- 29249182 TI - ACP 31st Annual Congress Abstracts November 2-5, 2017. PMID- 29249180 TI - The effects of transdermal rotigotine on non-motor symptoms of Parkinson's disease: a multicentre, observational, retrospective, post-marketing study. AB - AIM: This study evaluated the effect of >=6 months of transdermal rotigotine on non-motor and motor symptoms of patients with advanced Parkinson's disease. MATERIALS AND METHODS: The study was conducted in Spain between September 2011 and December 2012 (ClinicalTrials.gov: NCT01504529). The primary efficacy variable was the change from baseline in non-motor symptoms, as assessed by changes in Parkinson's Disease Non-Motor Symptoms Questionnaire total scores at 6 months. Secondary endpoints included the assessment of motor symptoms by Unified Parkinson's Disease Rating Scale III scores. RESULTS: Data from 378 patients (mean age: 70.2 years; 56.9% male) with Parkinson's disease receiving rotigotine from were collected. Mean disease duration was 6.1 years, and mean rotigotine treatment duration was 45.6 months. Rotigotine reduced non-motor symptoms by 14.6% (mean change from baseline in Parkinson's Disease Non-Motor Symptoms Questionnaire: -1.5 +/- 3.4; p < 0.0001). The majority of patients (58.2%) had improved non-motor symptoms at 6 months. Comparing the baseline versus study end, fewer patients experienced events in the urinary (78.6% vs. 73.3%; p = 0.0066), sleep (82.8% vs. 72.8%; p < 0.0001) and mood/cognition (77.3% vs. 66.4%; p < 0.0001) domains of the Parkinson's Disease Non-Motor Symptoms Questionnaire. Mean motor symptoms were reduced from baseline by 8.0% (mean change from baseline in Unified Parkinson's Disease Rating Scale III: -2.6 +/- 8.0; p < 0.0001). CONCLUSIONS: In clinical practice in Spain, rotigotine may be an effective treatment to reduce the non-motor and motor symptoms in patients with advanced Parkinson's disease. PMID- 29249183 TI - AAV gene delivery to the spinal cord: serotypes, methods, candidate diseases, and clinical trials. AB - INTRODUCTION: Adeno-associated viral (AAV) vector-mediated gene delivery to the spinal cord has finally entered the pathway towards regulatory approval. Phase 1 clinical trials using AAV gene therapy for pediatric disorders - spinal muscular atrophy (SMA) and giant axonal neuropathy (GAN) - are now underway. Areas covered: This review addresses the latest progress in the field of AAV gene delivery to the spinal cord, particularly focusing on the most prominent AAV serotypes and delivery methodologies to the spinal cord. Candidate diseases and scaling up experiments in large animals are also discussed. Expert opinion: Intravenous (IV) and intrathecal (IT) deliveries seem to undoubtedly be the preferred routes of administration for diffuse spinal cord delivery of therapeutic AAV vectors that can cross the blood-brain barrier (BBB) and correct inherited genetic disorders. Conversely, intraparenchymal delivery is still an undervalued but very viable approach for segmental therapy in afflictions such as ALS or Pompe Disease as a means to prevent respiratory dysfunction. PMID- 29249184 TI - Caffeine affects HFD-induced hepatic steatosis by multifactorial intervention. AB - The incidence of nonalcoholic fatty liver disease (NAFLD) is considered a risk factor for hepatic fibrosis. Therefore, there is critical need to develop novel cheap and effective therapeutic approaches to prevent and reverse NAFLD. Caffeine is commonly consumed beverage and has antioxidant and anti-inflammatory activities. This study examined whether caffeine can ameliorate liver injury induced by high-fat diet (HFD) feeding. Four groups of rats were used and treated for 16 weeks as follows: control group, rats were fed a standard diet; HFD group, rats were fed HFD; and caffeine 20 and caffeine 30 groups, rats were fed HFD for 16 weeks in addition to different doses of caffeine (20 or 30 mg/kg, respectively) for last 8 weeks. The HFD-induced liver injury is determined biochemically by evaluating serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, bilirubin, triglycerides, cholesterol, and high density lipoprotein-cholesterol and by histopathological examination. Tissue malondialdehyde, total nitrate/nitrite, and glutathione concentration were also measured. Real-time reverse transcription polymerase chain reaction technique was used to determine the expression of lipogenic enzyme genes. Caffeine treatment significantly decreased the elevated serum ALT, AST, and bilirubin and increased the reduced albumin level. Interestingly, the hepatic mRNA expression of Fatty acid synthase and acetyl CoA carboxylase was decreased by caffeine, while the protein expression of hepatic carnitine palmitoyltransferase 1 and proliferation activated receptor alpha was increased. Furthermore, caffeine reduced tissue lipid peroxidation and oxidative stress. These effects suggest that caffeine could improve HFD-induced hepatic injury by suppressing inflammatory response and oxidative stress and regulating hepatic de novo lipogenesis and beta-oxidation. PMID- 29249186 TI - Obinutuzumab monotherapy in previously untreated chronic lymphocytic leukemia. PMID- 29249187 TI - An update on the management of aspirin-exacerbated respiratory disease. AB - INTRODUCTION: Clinical features of aspirin-exacerbated respiratory disease (AERD) consist of moderate to severe asthma associated with chronic rhinosinusitis (CRS), which are derived from overproduction of cysteinyl leukotrienes along with chronic type 2 mediated inflammation in the upper and lower airway mucosa. Area covered: This review provides recent up-to-date information regarding phenotypes of AERD and encompasses comprehensive diagnostic methods and treatment options. To confirm the diagnosis of AERD, provocation testing via nasal, inhalation or the oral route of aspirin remains the gold standard; in vitro diagnostic methods are still not available. Essential management is to avoid cross-reacting cyclooxygenase 1 (COX-1) inhibitors along with use of highly selective COX-2 inhibitors and to maintain pharmacologic treatment depending on the severity of asthma and chronic rhinosinusitis. Recent biologics, including anti-IgE and anti IL5 antibodies, are required in severe AERD patients with CRS. Aspirin desensitization can be recommended when indicated. Expert commentary: AERD is a heterogeneous disease in terms of severity and associated allergic disease. When performing diagnosis and treatment for AERD, such disease characteristics need to be kept in mind. PMID- 29249185 TI - MiR-145 regulates osteogenic differentiation of human adipose-derived mesenchymal stem cells through targeting FoxO1. AB - In this study, we aimed to investigate the expression of miR-145 before and after hASCs osteogenic differentiation. We also intended to explore the influence of the target relationship between miR-145 and FoxO1 on osteogenic differentiation. Dual-luciferase reporter gene assay and real-time PCR were used to confirm the target relationship between miR-145 and FoxO1. Furthermore, the modulatory effects of miR-145 and FoxO1 on hASCs osteoinductive differentiation were measured by real-time PCR , Western blot, ALP staining, ARS staining, and cell immunofluorescence assay. After osteogenic differentiation, miR-145 was gradually down-regulated, while FoxO1 was up-regulated in hASCs. MiR-145 could directly target FoxO1 3'UTR. FoxO1 was negatively regulated by miR-145. After osteoinductive differentiation, BSP, Ocn, and OPN expression was lowered with the overexpression of miR-145 or the knockdown of FoxO1. Furthermore, ALP and ARS staining assay results showed weakened ALP activity and extracellular matrix calcification. When overexpressing miR-145 and FoxO1 simultaneously, no obvious change in ALP activity and extracellular matrix calcification was seen. MiR-145 could suppress hASCs osteoinductive differentiation by suppressing FoxO1 directly. Impact statement Researching on ASCs was a promising strategy to study osteogenic differentiation. The regulatory role of miR-145 on hASCs osteogenic differentiation remained partially explored. Our study revealed a novel mechanism of the osteogenic differentiation process and suggested that miR-145 and its target gene FoxO1 may be potential targets for the therapy of human osteogenic related disorders. PMID- 29249188 TI - Negotiating the Lack of Intimacy in Assisted Living: Resident Desires, Barriers, and Strategies. AB - Despite continuity in the desire for sex and partnership, many older adults experience a lack of intimacy in late life. The use of assisted living is a complicating factor for understanding issues of partnership, sex, and intimacy for older adults. Using in-depth interviews with 23 assisted living residents and grounded theory methods, we examined how residents negotiate a lack of intimacy in assisted living. The process of negotiation entailed three factors: desire, barriers, and strategies. Although some residents continued to desire intimacy, there was a marked absence of dating or intimacy in our study sites. Findings highlight unique barriers to acting on desire and the strategies residents used as aligning actions between desire and barriers. This research expands previous studies of sexuality and older adults by examining the complex ways in which they balanced desire and barriers through the use of strategies within the assisted living environment. PMID- 29249189 TI - Medical Care Avoidance Among Older Adults. AB - OBJECTIVE: To examine factors and reasons associated with medical care avoidance among older adults in the United States. METHOD: Analysis of data on 2,155 adults aged 65 and older, who completed the 2008 Health Information National Trends Survey. RESULTS: Nearly one fourth of older adults reported medical care avoidance ( n = 449; weighted % = 22.5%). Of these, more than one third reported doing so because of feeling uncomfortable when their body is examined (34.5%) or fearing a serious illness (35.9%) and with fewer reporting avoiding care because it made them think of dying (14.3%). Likelihood of avoidance was higher among those with worse self-reported health status, severe psychological distress, lower health self-efficacy, lower confidence in obtaining health information, lower trust in doctors, less patient-centered communication, lower perceived health care quality, and those who were current smokers. Qualitative reasons for avoidance corroborated quantitative results. CONCLUSION: Avoidance by older adults appears to be largely associated with evaluations of the quality of care and provider communication. PMID- 29249190 TI - Barriers to Nursing Home Care for Nonelderly Rural Residents. AB - Rural residents experience higher disability, mortality, and poverty rates than their urban counterparts; they also have more barriers to accessing care, including nursing home care. Meanwhile, the proportion of nonelderly adult nursing home residents (<65 years old) is growing, yet little is known about this population and barriers they face trying to access care, especially in rural areas. This qualitative study uses data from 23 semistructured interviews with rural hospital discharge planners in five states to identify specific barriers to finding nursing home care for nonelderly rural residents. We grouped those barriers into three primary themes-payment status, fit, and medical complexity-as well as two minor themes-caregivers and bureaucratic processes-and discuss each in the article, along with potential policy and programmatic interventions to improve access to nursing home care for nonelderly rural residents. PMID- 29249191 TI - Burst and high frequency stimulation: underlying mechanism of action. AB - INTRODUCTION: Paresthesia-free spinal cord stimulation (SCS) techniques, such as burst and high-frequency (HF) SCS, have been developed and demonstrated to be successful for treating chronic pain, albeit via different mechanisms of action. The goal of this review is to discuss the mechanisms of action for pain suppression at both the cellular and systems levels for burst and HF SCS. In addition, we also discuss the neuromodulation devices that mimic these paradigms. Areas covered: The authors performed a literature review to unravel the mechanisms of action for burst and HF SCS coupled with booklets and user manuals from neuromodulation companies to understand the programmable parameters and operating ranges. Burst SCS modulates the medial pathway to suppress pain. On cellular level, burst SCS is independent on activation of gamma-aminobutyric acid (GABA) receptors to inhibit neuronal firing. HF SCS blocks large-diameter fibers from producing action potentials with little influence on smaller fibers, increasing pain suppression as frequency increases. Expert commentary: The neuromodulation industry is in a phase of intense innovation characterized by adaptive stimulation to improve patients' experience and experiment with alternative frequencies and novel stimulation targets. PMID- 29249192 TI - DNA damage response-initiated cytokine secretion in bone marrow stromal cells promotes chemoresistance of myeloma cells. AB - Acquisition of chemoresistance accounts for a major cause of chemotherapy failure for multiple myeloma (MM). Bone marrow stromal cells (BMSCs) are considered to play a pivotal role in modulating drug resistance of MM cells. However, the underlying mechanism whereby BMSCs, particularly damaged stromal cells, affects chemoresistance has not been identified yet. Here, we show exposure to doxorubicin doxorubicin (Dox) induced dramatic ATM (ataxia-telangiectasia mutated)-dependent DNA damage response (DDR) and increased secretion of interleukin (IL)-6 in HS-5 cell line and primary BMSCs derived from healthy donors. Specifically, IL-6-containing conditioned media (CM) derived from Dox pretreated stromal cells displayed significant protective effect on Dox-induced apoptosis of MM cells. Also, treatment of BMSCs with ATM kinase inhibitor markedly reduced IL-6 secretion and concurrently, partially reversed CM-mediated chemoresistance in myeloma cells. These data indicate that DNA-damaging drug triggers an ATM-dependent DDR in BMSCs, leading to increased cytokine secretion and resistance of myeloma cells to chemotherapy-induced apoptosis. PMID- 29249193 TI - Embodied Clocks. PMID- 29249194 TI - Multi-functional magnetic nanoparticles as an effective drug carrier for the controlled anti-tumor treatment. AB - Because of the complications and mutability of cancers, combination of chemotherapy and other therapy with multi-mechanisms would be a bright future for the treatment of cancer. Thus, development of multi-functional tumor-targeted drug delivery systems with two or more than two functions should be of great significance. In the study, the Fe3O4@C nanoparticles linked with thermoresponsive copolymer (MTC-NPs) were synthesized, after that, the magnetic properties and photothermal effects of MTC NPs were evaluated. Compared to the pure water, MTC-NPs absorbed more energy and transform it into heat under the 808 nm laser irradiation, and the temperature could increase over 60C. In addition, the grafted copolymer with coil-to-globule transition acts as a gatekeeper for the temperature-controlled release of mitoxantrone molecules. The super paramagnetic behavior of MTC-NPs certified by the hysteresis loop gives a negligible coercivity at room temperature. Both in vitro and in vivo studies confirmed that the synergistic combination of magnetic targeting, drug controlled release, and thermochemotherapy improve the anti-tumor efficacy with lower side effects. This nanoparticle is a great potential drug carrier in anti-tumor drugs, which can improve the effect of hyperthermia, increase target distribution in tumor, and enhance curative effect for tumor while reducing normal tissue toxicity. PMID- 29249195 TI - Surface nanotopography-induced favorable modulation of bioactivity and osteoconductive potential of anodized 3D printed Ti-6Al-4V alloy mesh structure. AB - The objective of the study described here is to fundamentally elucidate the biological response of 3D printed Ti-6Al-4V alloy mesh structures that were surface modified to introduce titania nanotubes with an average pore size of ~80 nm via an electrochemical anodization process from the perspective of enhancing bioactivity. The bioactivity of the mesh structures were analyzed through immersion test in simulated body fluid, which confirmed the nucleation and growth of fine globular nanoscale apatite on the nanoporous titania-modified (anodized) mesh structure surface, and agglomerated apatite with fine flakes of apatite crystals on as-fabricated mesh structure surface, that were rich in calcium and phosphorous. The cellular activity of bioactive anodized mesh structure was explored in terms of cell-material interactions involving adhesion, proliferation, synthesis of extracellular and intracellular proteins, differentiation, and mineralization. Cells adhered with a sheet-like morphology on as-fabricated mesh structure, whereas, on anodized mesh structure, numerous filopodia-like cellular extensions interacting with nanotube pores were observed. The formation of a bioactive nanoscale apatite, cell-nanotube interactions as imaged via electron microscopy, higher expression of proteins (actin, vinculin, fibronectin, and alkaline phosphatase (ALP)), and calcium content points toward the determining role of anodized mesh structure in modulating osteoblasts functions. The unique combination of nanoporous bioactive titania and interconnected porous architecture of anodized titanium alloy mesh structure provided a multimodal roughness surface ranging from nano to micro to macroscale, which helps in attaining strong primary and secondary fixation of the implant device along with the pathway for supply of nutrients and oxygen to cells and tissue. PMID- 29249196 TI - Nanosized strontium substituted hydroxyapatite prepared from egg shell for enhanced biological properties. AB - The fabrication and application of bioactive hydroxyapatite has always been a research hot spot in the fields of orthopaedics. Now it is common to use calcium (Ca) salt as Ca2+ source to synthesise hydroxyapatite. And egg shell could be another promising raw material as Ca2+ source, which is not only economical but also biogenic. In this study, egg shell (ES)-hydroxyapatite was prepared by using egg shells via hydrothermal method. Furthermore, ES-Sr hydroxyapatite was synthesized by incorporation of bioactive element strontium (Sr2+) into ES hydroxyapatite. The in vitro experiment showed that compared with hydroxyapatite, ES-hydroxyapatite showed better biological performances, which could be attributed to the trace elements in egg shell, such as magnesium (Mg). And the incorporation of Sr2+ could further enhance the bioactivity. These results indicated that apatite with high biological activity, which had great application prospects in orthopedics, could be produced by egg shells and the incorporation of Sr2+. PMID- 29249197 TI - Evaluation of the hemocompatibility of RADA 16-I peptide. AB - RADA 16-I is an ionic self-assembling peptide that can form macroscopic scaffolds through beta-sheet structures which are used in favor of cell growth and tissue engineering. This peptide has also the ability to stop bleeding effectively and quickly (~20 seconds) when applied directly to the injuries. This study is focused on coagulation process, platelet aggregation, C3 and C4 concentrations, CBC counting, hemolysis, and white blood cell morphology tests to analyze hemocompatibility of RADA 16-I at different concentrations - 0.1, 0.2, 0.3 and 0.5%. According to the results, RADA 16-I hydrogel decreased the number of blood cells, slightly increased clot formation time and platelet aggregation, and yielded negligible hemolysis and only small changes in C3 and C4 concentrations and white blood cell morphology. All by all, the in vitro tests of hemocompatibility showed no perturbation in the blood composition when the peptides were in contact with the blood. The observed rapid hemostasis might be a result of increasing local concentrations of molecules involved in the formation of clot near the peptide hydrogel, thereby making a barrier which ended up with complete hemostasis. In conclusion, our experiments strongly supported further development of biomaterials based on RADA 16-I peptide. PMID- 29249198 TI - Beyond Competence: Perspectives From Two Centuries. AB - A sense of failure and guilt can often be associated with the death of a patient. Using the Serenity Prayer as a framework, we present autobiographical narratives describing encounters that happened in Vellore, India over a hundred years apart. Powerlessness in the face of death, we suggest, is not the same as ignorance or incompetence. It could well be the breakthrough to a deeper wisdom and lasting empowerment. PMID- 29249199 TI - A new species of Xenoturbella from the western Pacific Ocean and the evolution of Xenoturbella. AB - BACKGROUND: Xenoturbella is a group of marine benthic animals lacking an anus and a centralized nervous system. Molecular phylogenetic analyses group the animal together with the Acoelomorpha, forming the Xenacoelomorpha. This group has been suggested to be either a sister group to the Nephrozoa or a deuterostome, and therefore it may provide important insights into origins of bilaterian traits such as an anus, the nephron, feeding larvae and centralized nervous systems. However, only five Xenoturbella species have been reported and the evolutionary history of xenoturbellids and Xenacoelomorpha remains obscure. RESULTS: Here we describe a new Xenoturbella species from the western Pacific Ocean, and report a new xenoturbellid structure - the frontal pore. Non-destructive microCT was used to investigate the internal morphology of this soft-bodied animal. This revealed the presence of a frontal pore that is continuous with the ventral glandular network and which exhibits similarities with the frontal organ in acoelomorphs. CONCLUSIONS: Our results suggest that large size, oval mouth, frontal pore and ventral glandular network may be ancestral features for Xenoturbella. Further studies will clarify the evolutionary relationship of the frontal pore and ventral glandular network of xenoturbellids and the acoelomorph frontal organ. One of the habitats of the newly identified species is easily accessible from a marine station and so this species promises to be valuable for research on bilaterian and deuterostome evolution. PMID- 29249200 TI - Anatomical variant of the meniscus related to posterior junction: a case report. AB - BACKGROUND: There are several reports on anatomical differences of the meniscus. However, there are only a few reports on abnormalities in both menisci and anatomical differences in anterior cruciate ligament insertions. CASE PRESENTATION: This is a case report of a 36-year-old Hispanic man presenting symptoms, including knee pain, locking, and effusion, with an anatomical abnormality of the menisci corresponding to the fusion of the posterior horns of the menisci in tandem with the insertion of the posterior meniscus fibers in the anterior cruciate ligament. CONCLUSIONS: This is the first study describing a meniscus anatomical variant with isolated posterior junction of the posterior horn with an anomalous insertion to the anterior cruciate ligament. The recognition of meniscus variants is important as they can be misinterpreted for more significant pathology on magnetic resonance images. PMID- 29249201 TI - The monetary value of human lives lost due to neglected tropical diseases in Africa. AB - BACKGROUND: Neglected tropical diseases (NTDs) are an important cause of death and disability in Africa. This study estimates the monetary value of human lives lost due to NTDs in the continent in 2015. METHODS: The lost output or human capital approach was used to evaluate the years of life lost due to premature deaths from NTDs among 10 high/upper-middle-income (Group 1), 17 middle-income (Group 2) and 27 low-income (Group 3) countries in Africa. The future losses were discounted to their present values at a 3% discount rate. The model was re analysed using 5% and 10% discount rates to assess the impact on the estimated total value of human lives lost. RESULTS: The estimated value of 67 860 human lives lost in 2015 due to NTDs was Int$ 5 112 472 607. Out of that, 14.6% was borne by Group 1, 57.7% by Group 2 and 27.7% by Group 3 countries. The mean value of human life lost per NTD death was Int$ 231 278, Int$ 109 771 and Int$ 37 489 for Group 1, Group 2 and Group 3 countries, respectively. The estimated value of human lives lost in 2015 due to NTDs was equivalent to 0.1% of the cumulative gross domestic product of the 53 continental African countries. CONCLUSIONS: Even though NTDs are not a major cause of death, they impact negatively on the productivity of those affected throughout their life-course. Thus, the case for investing in NTDs control should also be influenced by the value of NTD morbidity, availability of effective donated medicines, human rights arguments, and need to achieve the NTD-related target 3.3 of the United Nations Sustainable Development Goal 3 (on health) by 2030. PMID- 29249204 TI - Evidence for trophic transfer of Inodosporus octospora and Ovipleistophora arlo n. sp. (Microsporidia) between crustacean and fish hosts. AB - Within aquatic habitats, the hyper-abundant Order Crustacea appear to be the predominant host group for members of the Phylum Microsporidia. The musculature, a common site of infection, provides access to biochemical (carbohydrate-rich) and physiological (mitochondria-rich) conditions conducive to prolific parasite replication and maturation. The significant proportion of body plan devoted to skeletal musculature in Crustacea provides the location for a highly efficient intracellular parasite factory. In this study, we utilize histological, ultrastructural and phylogenetic evidence to describe a previously known (Inodosporus octospora) and novel (Ovipleistophora arlo n. sp.) microsporidian parasites infecting the musculature of the common prawn (Palaemon serratus) from the same site, at the same time of year. Despite similar clinical signs of infection, both parasites are otherwise distinct in terms of pathogenesis, morphology and phylogeny. Based upon partial subunit ribosomal RNA (SSU rDNA) sequence, we show that that I. octospora may be identical to a Kabatana sp. previously described infecting two-spot goby (Gobiusculus flavescens) in Europe, or at least that Inodosporus and Kabatana genera are synonyms. In addition, SSU rDNA sequence for O. arlo places it within a distinct clade containing Ovipleistophora mirandellae and Ovipleistophora ovariae, both infecting the oocytes of freshwater fish in Europe. Taken together, our data provide strong evidence for trophic-transfer between crustacean and fish hosts for two different microsporidians within clade 5 of the phylum. Furthermore, it demonstrates that morphologically and phylogenetically distinct microsporidians can infect the same tissues of the same host species to impart clinical signs which mimic infection with the other. PMID- 29249203 TI - Characterization of excitatory synaptic transmission in the anterior cingulate cortex of adult tree shrew. AB - The tree shrew, as a primate-like animal model, has been used for studying high brain functions such as social emotion and spatial learning memory. However, little is known about the excitatory synaptic transmission in cortical brain areas of the tree shrew. In the present study, we have characterized the excitatory synaptic transmission and intrinsic properties of pyramidal neurons in the anterior cingulate cortex (ACC) of the adult tree shrew, a key cortical region for pain perception and emotion. We found that glutamate is the major excitatory transmitter for fast synaptic transmission. Excitatory synaptic responses induced by local stimulation were mediated by AMPA and kainate (KA) receptors. As compared with mice, AMPA and KA receptor mediated responses were significantly greater. Interestingly, the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in tree shrews was significantly less than that of mice. Moreover, both the ratio of paired-pulse facilitation (PPF) and the time of 50% decay for fast blockade of NMDA receptor mediated EPSCs were greater in the tree shrew. Finally, tree shrew neurons showed higher initial firing frequency and neuronal excitability with a cell type-specific manner in the ACC. Our studies provide the first report of the basal synaptic transmission in the ACC of adult tree shrew. PMID- 29249202 TI - Modeling HIV-HCV coinfection epidemiology in the direct-acting antiviral era: the road to elimination. AB - BACKGROUND: HCV treatment uptake has drastically increased in HIV-HCV coinfected patients in France since direct-acting antiviral (DAA) treatment approval, resulting in HCV cure in 63% of all HIV-HCV patients by the end of 2015. We investigated the impact of scaling-up DAA on HCV prevalence in the whole HIV population and in various risk groups over the next 10 years in France using a transmission dynamic compartmental model. METHODS: The model was based on epidemiological data from the French Dat'AIDS cohort. Eight risk groups were considered, including high-risk (HR) and low-risk (LR) men who have sex with men (MSM) and male/female heterosexuals, intra-venous drug users, or patients from other risk groups. The model was calibrated on prevalence and incidence data observed in the cohort between 2012 and 2015. RESULTS: On January 1, 2016, 156,811 patients were registered as infected with HIV in France (24,900 undiagnosed patients) of whom 7938 (5.1%) had detectable HCV-RNA (722 undiagnosed patients). Assuming a treatment coverage (TC) rate of 30%/year (i.e., the observed rate in 2015), model projections showed that HCV prevalence among HIV patients is expected to drop to 0.81% in 2026. Sub-analyses showed a similar decrease of HIV-HCV prevalence in most risk groups, including LR MSM. Due to higher infection and reinfection rates, predicted prevalence in HR MSM remained stable from 6.96% in 2016 to 6.34% in 2026. Increasing annual TC rate in HR MSM to 50/70% would decrease HCV prevalence in this group to 2.35/1.25% in 2026. With a 30% TC rate, undiagnosed patients would account for 34% of HCV infections in 2026. CONCLUSIONS: Our model suggests that DAA could nearly eliminate coinfection in France within 10 years for most risk groups, including LR MSM. Elimination in HR MSM will require increased TC. PMID- 29249205 TI - Attention, vigilance, and visuospatial function in hospitalized elderly medical patients: relationship to delirium syndromal status and motor subtype profile. AB - : ABSTRACTBackground:The early and effective detection of neurocognitive disorders poses a key diagnostic challenge. We examined performance on common cognitive bedside tests according to differing delirium syndromal status and clinical (motor) subtypes in hospitalized elderly medical inpatients. METHODS: A battery of nine bedside cognitive tests was performed on elderly medical inpatients with DSM-IV delirium, subsyndromal delirium (SSD), and no delirium (ND). Patients with delirium were compared according to clinical (motor) subtypes. RESULTS: A total of 198 patients (mean age 79.14 +/- 8.26) were assessed with full syndromal delirium (FSD: n = 110), SSD (n = 45), and ND (n = 43). Delirium status was not associated with differences in terms of gender distribution, age, or overall medication use. Dementia burden increased with greater delirium status. Overall, the ability to meaningfully engage with the tests varied from 59% for the Vigilance B test to 85% for Spatial Span Forward test and was lowest in patients with FSD, where engagement ranged from 32% for the Vigilance B test to 77% for the Spatial Span Forwards test. The ND group was distinguished from SSD group for the Months of the year backwards, Vigilance B, global VSP, Clock Drawing test, and Interlocking Pentagons test. The SSD group was distinguished from the FSD group by Vigilance A, Spatial Span Forward, and Spatial Span Backwards. Regarding differences among motor subtypes in terms of percentage engagement and performance, the No subtype group had higher ratings across all tests. Delirious patients with no subtype had significantly lower scores on the DRS-R98 than for the other three subtype categories. CONCLUSIONS: Simple bedside tests of attention, vigilance, and visuospatial ability are useful in distinguishing neurocognitive disorders, including SSD from other presentations. PMID- 29249206 TI - Early health technology assessment of future clinical decision rule aided triage of patients presenting with acute chest pain in primary care. AB - The objective of the paper is to estimate the number of patients presenting with chest pain suspected of acute coronary syndrome (ACS) in primary care and to calculate possible cost effects of a future clinical decision rule (CDR) incorporating a point-of-care test (PoCT) as compared with current practice. The annual incidence of chest pain, referrals and ACS in primary care was estimated based on a literature review and on a Dutch and Belgian registration study. A health economic model was developed to calculate the potential impact of a future CDR on costs and effects (ie, correct referral decisions), in several scenarios with varying correct referral decisions. One-way, two-way, and probabilistic sensitivity analyses were performed to test robustness of the model outcome to changes in input parameters. Annually, over one million patient contacts in primary care in the Netherlands concern chest pain. Currently, referral of eventual ACS negative patients (false positives, FPs) is estimated to cost ?1,448 per FP patient, with total annual cost exceeding 165 million Euros in the Netherlands. Based on 'international data', at least a 29% reduction in FPs is required for the addition of a PoCT as part of a CDR to become cost-saving, and an additional ?16 per chest pain patient (ie, 16.4 million Euros annually in the Netherlands) is saved for every further 10% relative decrease in FPs. Sensitivity analyses revealed that the model outcome was robust to changes in model inputs, with costs outcomes mainly driven by costs of FPs and costs of PoCT. If PoCT aided triage of patients with chest pain in primary care could improve exclusion of ACS, this CDR could lead to a considerable reduction in annual healthcare costs as compared with current practice. PMID- 29249207 TI - Mechanism of action of vesicular monoamine transporter 2 (VMAT2) inhibitors in tardive dyskinesia: reducing dopamine leads to less "go" and more "stop" from the motor striatum for robust therapeutic effects. AB - Tardive dyskinesia can now be successfully treated by inhibiting the vesicular monoamine transporter type 2 (VMAT2). PMID- 29249208 TI - Suicide risk of old adults with special reference to aging. AB - Koo et al. (2017) compared differences in sociodemographic variables, recent life events, and mental and physical illnesses between three age groups (65-74 years, 75-84 years, and 85 years and over) who died by suicide. Psychiatric problems, suicidal behavior, legal and financial stressors, and relationship problems decreased with age. In contrast, physical conditions and bereavement increased with age. Suicide rates were increasing with age for males, but not for females. In addition, significant differences in the prevalence of potential risk factors within the three different age groups existed. I have some concerns about their study. PMID- 29249209 TI - Passive smoking as a risk factor for dementia and cognitive impairment: systematic review of observational studies. AB - : ABSTRACTBackground:Smoking is a well-established risk factor for dementia, but the effects of passive smoking are unclear. We aimed to examine links between passive smoking and dementia or cognitive impairment. METHODS: We searched seven medical research databases: MEDLINE, Web of Science (Core Collection), Cochrane, EMBASE, PsycINFO, Scopus, and CINAHL Plus. Studies were included if they examined measures of passive smoking and either cognitive impairment or dementia. RESULTS: Of 1,425 records found, nine papers of varying methodologies were included after screening against inclusion criteria. Eight papers reported weak associations between passive smoking and either cognitive impairment or dementia. One paper only found this association alongside carotid artery stenosis. The papers' quality was variable, with only two deemed high quality. CONCLUSION: There is limited weak observational evidence linking passive smoking with an increased risk of cognitive impairment or dementia. However, the studies were methodologically diverse and of inconsistent quality, preventing firm conclusions. PMID- 29249210 TI - Management and Outcomes in the Oldest-Old Population with Glioblastoma. AB - OBJECTIVES: Glioblastoma is a lethal disease in the elderly population. We aimed to evaluate disease and treatment outcomes in the oldest-old patients. METHODS: Patients >80 years old with histologically confirmed glioblastoma treated between 2004 and 2009 were identified. We included patients managed with best supportive care (BSC), temozolomide (TMZ) alone, radiotherapy (RT) alone, or concomitantly with TMZ (CRT). Survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: Ultimately, 48 patients were analyzed. Median age and Eastern Cooperative Oncology Group (ECOG) Performance Status were 82 years and 2, respectively. The median Age-Adjusted Charlson Index (AAC) was 6. Gross total and subtotal resections were performed in 16.7% and 18.8% of patients, respectively. Biopsy followed by RT alone was the treatment modality for 23/48 (47.9%), while 17/48 (35.4%) received surgery followed by RT alone or CRT. A total of 8 (16.7%) were managed with BSC after biopsy. Median overall survival (OS) and progression free survival (PFS) were 4.1 (95% confidence interval [95% CI] 3.3-4.9) and 2.7 (95% CI 1.5-3.9) months, respectively. Improved median OS was observed in those treated with surgical resection followed by RT alone or CRT (7.1 months), compared to biopsy followed by RT alone (4.2 months) or BSC (2.0 months; p=0.002). Surgical resection, age<=85, and AAC<6 were associated with better OS (p=0.032, p=0.031, and p=0.02, respectively). Cause of death was neurological progression in 56% of cases. RT was well-tolerated. CONCLUSIONS: PFS and OS outcomes remain poor in the oldest-old patients (>80 years old). Younger age, lower AAC, surgical resection, and adjuvant treatment were associated with improved OS. PMID- 29249212 TI - Reducing Inappropriate Urinary Catheter Use in the Emergency Department: Comparing Two Collaborative Structures. AB - BACKGROUND Urinary catheters, many of which are placed in the emergency department (ED) setting, are often inappropriate, and they are associated with infectious and noninfectious complications. Although several studies evaluating the effect of interventions have focused on reducing catheter use in the ED setting, the organizational contexts within which these interventions were implemented have not been compared. METHODS A total of 18 hospitals in the Ascension health system (ie, system-based hospitals) and 16 hospitals in the state of Michigan (ie, state-based hospitals led by the Michigan Health and Hospital Association) implemented ED interventions focused on reducing urinary catheter use. Data on urinary catheter placement in the ED, indications for catheter use, and presence of physician order for catheter placement were collected for interventions in both hospital types. Multilevel negative binomial regression was used to compare the system-based versus state-based interventions. RESULTS A total of 13,215 patients (889 with catheters) from the system-based intervention were compared to 12,104 patients (718 with catheters) from the state based intervention. Statistically significant and sustainable reductions in urinary catheter placement (incidence rate ratio, 0.79; P=.02) and improvements in appropriate use of urinary catheters (odds ratio [OR], 1.86; P=.004) in the ED were observed in the system-based intervention, compared to the state-based intervention. Differences by collaborative structure in changes in presence of physician order for urinary catheter placement (OR, 1.14; P=.60) were not observed. CONCLUSIONS An ED intervention consisting of establishing institutional guidelines for appropriate catheter placement and identifying clinical champions to promote adherence was associated with reducing unnecessary urinary catheter use under a system-based collaborative structure. Infect Control Hosp Epidemiol 2018;39:77-84. PMID- 29249213 TI - Vitrification of bovine embryos followed by in vitro hatching and expansion. AB - The objective of this study was to assess the effects of bovine embryo vitrification by applying three different vitrification solutions containing ethylene glycol (EG) and dimethylsulphoxide (DMSO) at different concentrations (10, 20 or 25% each) combined with 1.0 M glucose or 1.0 M sucrose, on the in vitro hatching and expansion rates. Healthy oocytes were selected for in vitro maturation and fertilization from 200 bovine ovaries, and subsequently cultured up to the blastocyst stage (n = 800). Control (n = 200) and vitrified cells (n = 100 per treatment; 600 in total) were cultured for an extra 24 or 48 h to evaluate hatching and expansion, respectively. Vitrification significantly decreased embryonic re-expansion and hatching rates independently of the tested solution when compared with control embryos, but solutions with 25% EG + 25% DMSO resulted in the highest re-expansion (75%) and hatching (70%) rates, independently of the added sugar. The addition of sucrose resulted in higher rates of re-expanded and hatched embryos when compared with glucose addition. We concluded that the combination of 25% EG + 25% DMSO and 1.0 M sucrose allowed hatching and expansion of vitrified-warmed bovine embryos produced in vitro. PMID- 29249211 TI - Remodelling of primary human CD4+ T cell plasma membrane order by n-3 PUFA. AB - Cell membrane fatty acids influence fundamental properties of the plasma membrane, including membrane fluidity, protein functionality, and lipid raft signalling. Evidence suggests that dietary n-3 PUFA may target the plasma membrane of immune cells by altering plasma membrane lipid dynamics, thereby regulating the attenuation of immune cell activation and suppression of inflammation. As lipid-based immunotherapy might be a promising new clinical strategy for the treatment of inflammatory disorders, we conducted in vitro and in vivo experiments to examine the effects of n-3 PUFA on CD4+ T cell membrane order, mitochondrial bioenergetics and lymphoproliferation. n-3 PUFA were incorporated into human primary CD4+ T cells phospholipids in vitro in a dose dependent manner, resulting in a reduction in whole cell membrane order, oxidative phosphorylation and proliferation. At higher doses, n-3 PUFA induced unique phase separation in T cell-derived giant plasma membrane vesicles. Similarly, in a short-term human pilot study, supplementation of fish oil (4 g n 3 PUFA/d) for 6 weeks in healthy subjects significantly elevated EPA (20 : 5n-3) levels in CD4+ T cell membrane phospholipids, and reduced membrane lipid order. These results demonstrate that the dynamic reshaping of human CD4+ T cell plasma membrane organisation by n-3 PUFA may modulate down-stream clonal expansion. PMID- 29249214 TI - Hitting a triple in the non-alcoholic fatty liver disease field: sucrose intake in adulthood increases fat content in the female but not in the male rat offspring of dams fed a gestational low-protein diet. AB - The excessive consumption of carbohydrates is related to non-alcoholic fatty liver disease (NAFLD) in infants and adults. The effect of combining maternal malnutrition and a high carbohydrate intake on the development of NAFLD in adulthood remains unknown. We therefore hypothesized that consumption of 5% sucrose by the offspring of dams fed a low-protein diet during pregnancy promotes liver fat accumulation and oxidative damage differently in females and males. To test this, 12-month-old female and male offspring of mothers fed a Control (C) or low-protein diet (Restricted, R) were provided with either tap water or 5% sucrose for a period of 10 weeks. Livers were excised to measure the fat content and 3-nitrotyrosine (3-NTyr) immunostaining; serum samples were also obtained to measure the concentration of malondialdehyde (MDA). Data were analyzed using a non-repeated measures three-way analysis of variance to determine significant differences (P<0.05) regarding to the interaction among maternal diet, sucrose consumption and sex. Results showed that the liver fat content of females from R mothers was higher than that of their male counterpart. Hepatic 3-NTyr immunostaining and serum MDA concentrations were not affected by the interaction involving maternal diet, sucrose consumption and sex. Otherwise, liver fat content was correlated with the hepatic 3-NTyr immunostaining and serum MDA concentrations only in females. Thus, sucrose intake in adulthood increases fat content in the female but not in the male rat offspring of dams fed with a low protein diet during pregnancy. This research emphasizes the importance of a balanced diet during pregnancy and the influence of the diet on the adult offspring. PMID- 29249215 TI - Adult-Onset Anti-N-methyl-D-aspartate-receptor Encephalitis Presenting as a Non Fluent Aphasia. PMID- 29249216 TI - Pathogen Distribution and Antimicrobial Resistance Among Pediatric Healthcare Associated Infections Reported to the National Healthcare Safety Network, 2011 2014. AB - OBJECTIVE To describe pathogen distribution and antimicrobial resistance patterns for healthcare-associated infections (HAIs) reported to the National Healthcare Safety Network (NHSN) from pediatric locations during 2011-2014. METHODS Device associated infection data were analyzed for central line-associated bloodstream infection (CLABSI), catheter-associated urinary tract infections (CAUTI), ventilator-associated pneumonia (VAP), and surgical site infection (SSI). Pooled mean percentage resistance was calculated for a variety of pathogen-antimicrobial resistance pattern combinations and was stratified by location for device associated infections (neonatal intensive care units [NICUs], pediatric intensive care units [PICUs], pediatric oncology and pediatric wards) and by surgery type for SSIs. RESULTS From 2011 to 2014, 1,003 hospitals reported 20,390 pediatric HAIs and 22,323 associated pathogens to the NHSN. Among all HAIs, the following pathogens accounted for more than 60% of those reported: Staphylococcus aureus (17%), coagulase-negative staphylococci (17%), Escherichia coli (11%), Klebsiella pneumoniae and/or oxytoca (9%), and Enterococcus faecalis (8%). Among device associated infections, resistance was generally lower in NICUs than in other locations. For several pathogens, resistance was greater in pediatric wards than in PICUs. The proportion of organisms resistant to carbapenems was low overall but reached approximately 20% for Pseudomonas aeruginosa from CLABSIs and CAUTIs in some locations. Among SSIs, antimicrobial resistance patterns were similar across surgical procedure types for most pathogens. CONCLUSION This report is the first pediatric-specific description of antimicrobial resistance data reported to the NHSN. Reporting of pediatric-specific HAIs and antimicrobial resistance data will help identify priority targets for infection control and antimicrobial stewardship activities in facilities that provide care for children. Infect Control Hosp Epidemiol 2018;39:1-11. PMID- 29249217 TI - Palatal Tremor Revisited: Disorder with Nosological Diversity and Etiological Heterogeneity. AB - This case series aimed to describe clinicoradiological, electromyographic, and etiological spectra in palatal tremor (essential=1; symptomatic=26). Patients with symptomatic palatal tremor had 2 to 10 Hz arrhythmic electromyographic bursts, a spectrum of changes in inferior olivary nucleus, with/without lesions in Guillain Mollaret triangle, and varied etiologies (genetic=9, vascular=6, trauma=3, infections=3). Exome sequencing showed variations in POLG, WDR81, NDUFS8, TENM4, and EEF2. Clinical phenotypes of patients with POLG, WDR81, and NDUFS8 variations were consistent with that described in literature. We highlight salient magnetic resonance imaging features, electrophysiological observations, and diverse etiologies in a large cohort of palatal tremor. PMID- 29249218 TI - Direct Costs of a Contact Isolation Day: A Prospective Cost Analysis at a Swiss University Hospital. AB - We prospectively evaluated direct costs of contact precautions using on-site observation. Additional mean costs per patient day were calculated for extra materials used, increased workload, and one-off isolation activities. The cost of contact precautions was $158.90 (95% confidence interval, $124.90-$192.80) per patient day. Infect Control Hosp Epidemiol 2018;39:101-103. PMID- 29249219 TI - The role of the tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) in offspring exposed to prenatal hypoxia. AB - Exposure to prenatal hypoxia in rats leads to intrauterine growth restriction (IUGR), decreases fetal cardiomyocyte proliferation and increases the risk to develop cardiovascular diseases (CVD) later in life. The tumor necrosis factor related weak inducer of apoptosis (TWEAK) induces cardiomyocyte proliferation through activation of the fibroblast growth factor-inducible molecule 14 (Fn-14) receptor. The TWEAK/Fn-14 pathway becomes quiescent shortly after birth, however, it becomes upregulated with CVD; suggesting that it could be a link between the increased susceptibility to CVD in pregnancies complicated by hypoxia/IUGR. We hypothesized that offspring exposed to prenatal hypoxia will exhibit reduced cardiomyocyte proliferation due to reduced Fn-14 expression and that the TWEAK/Fn 14 pathway will be expressed in those adult offspring. We exposed pregnant Sprague Dawley rats to control (21% oxygen) or hypoxic (11% oxygen) conditions from gestational days 15 to 21. Ventricular cardiomyocytes were isolated from male and female, control and hypoxic offspring at postnatal day 1. Proliferation was assessed in the presence or absence of r-TWEAK (72 h, 100 ng/ml). Prenatal hypoxia was not associated with differences in Fn-14 protein expression in either male or female offspring. Cardiomyocytes from prenatal hypoxic male, but not female, offspring had decreased proliferation compared with controls. Addition of r-TWEAK increased cardiomyocyte proliferation in all offspring. In adult offspring of all groups, the TWEAK/Fn-14 pathway was not detectable. Cardiomyocyte proliferation was reduced in only male offspring exposed to prenatal hypoxia but this was not due to changes in the Fn-14 pathway. Studies addressing other pathways associated with CVD and prenatal hypoxia are needed. PMID- 29249220 TI - DRD3 Ser9Gly Polymorphism and Its Influence on Risperidone Response in Autistic Children. AB - PURPOSE: Autism, a neuropsychiatric illness, is a complex ailment of mainly indefinite cause. Although precise pathophysiological mechanism is unclear but the role of genetics is undeniable therefore pharmacogenetics may assist to a better management of symptoms. Risperidone is widely used in autism. Considering the significance of dopaminergic system in psychological and neurological diseases and its association with autism, the hypothesis that genetic variant of dopamine receptor (DRD3), Ser9Gly (rs6280), may influence treatment of autism may be assumed. METHOD: In the present study, 56 autistic Persian children within the age range of 2.5 to 14 years were included. Diagnosis of autism was based on DSM V criteria and the severity degree was measured by ABC-C checklists at base line and after 8 weeks of treatment with risperidone. Based on their scores patients were categorized as responsive and non-responsive groups. DRD3 Ser9Gly (rs6280) was determined by PCR-RFLP. RESULTS: Carriers of Gly allele as well as carriers of Gly/Gly and Ser/Gly genotypes showed significantly better response to risperidone compared with carriers of Ser allele and Ser/Ser genotype (P=0.027; OR= 4.18; 95%CI=1.16-15.03 and P=0.014; OR=6.825; 95%CI=1.36-34.13). CONCLUSION: Our results advocate the possible influence of genetic variation of DRD3 in clinical response to antipsychotics like risperidone in autistic individuals. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29249221 TI - Sex Hormones Regulate Rat Hepatic Monocarboxylate Transporter Expression and Membrane Trafficking. AB - PURPOSE: Monocarboxylate transporters (MCTs) are involved in the transport of monocarboxylates such as ketone bodies, lactate, and pharmaceutical agents. CD147 functions as an ancillary protein for MCT1 and MCT4 for plasma membrane trafficking. Sex differences in MCT1 and MCT4 have been observed in muscle and reproductive tissues; however, there is a paucity of information on MCT sex differences in tissues involved in drug disposition. The objective of the present study was to quantify hepatic MCT1, MCT4 and CD147 mRNA, total cellular and membrane protein expression in males, over the estrous cycle in females and in ovariectomized (OVX) females. METHOD: Liver samples were collected from females at the four estrous cycle stages (proestrus, estrus, metestrus, diestrus), OVX females and male Sprague-Dawley rats (N = 3 - 5). Estrus cycle stage of females was determined by vaginal lavage. mRNA and protein (total and membrane) expression of MCT1, MCT4 and CD147 was evaluated by qPCR and western blot analysis. RESULTS: MCT1 mRNA and membrane protein expression varied with estrous cycle stage, with OVX females having higher expression than males, indicating that female sex hormones may play a role in MCT1 regulation. MCT4 membrane expression varied with estrous cycle stage with expression significantly lower than males. MCT4 membrane expression in OVX females was also lower than males, suggesting that androgens play a role in membrane expression of MCT4. Males had higher membrane CD147 expression, whereas there was no difference in whole cell protein and mRNA levels suggesting that androgens are involved in regulating CD147 membrane localization. CONCLUSIONS: This study demonstrates hepatic expression and membrane localization of MCT1, MCT4 and CD147 are regulated by sex hormones. Sex differences in hepatic MCT expression may lead to altered drug disposition, so it is critical to elucidate the underlying mechanisms in the sex hormone-dependent regulation of MCT expression. This article is open to POST PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29249222 TI - The New Modesty. PMID- 29249223 TI - Occult Focus of Septic Shock. PMID- 29249224 TI - Non-Pharmacological Treatment in People With Cognitive Impairment. AB - BACKGROUND: A number of non-pharmacological methods are available to help elderly people with cognitive impairment. Unstructured and non-evidencebased interventions are commonly used. The multicomponent therapy MAKS (a German acronym for Motor, Activities of daily living, Cognitive, Social) has already been evaluated in nursing homes; in this study, we investigated its use in day care centers (DCCs). METHODS: A cluster-randomized, controlled, single-blinded trial involving a 6-month intervention phase was performed. 362 cognitively impaired persons in 32 DCCs took part in the trial. Multiple regression analyses were used to determine whether MAKS therapy led to any statistically significant and clinically relevant improvement over time (compared to membership in the control group) in these persons' cognitive abilities and activities of daily living (ADL) abilities, as assessed, respectively, with the Mini-Mental State Examination (MMSE) and the Erlangen Test of Activities of Daily Living in Persons with Mild Dementia or Mild Cognitive Impairment (ETAM). A primary per-protocol analysis was supplemented by an intention-to-treat analysis. Two secondary outcomes (social behavior and neuropsychiatric symptoms) were analyzed exploratively as well. Study registration: ISRCTN16412551. RESULTS: In the primary per-protocol analysis at 6 months, the intervention group had significantly better MMSE and ETAM scores than the control group (Cohen's d, 0.26 and 0.21, respectively; p = 0.012 for both). The same was found in the ITT analysis at 6 months (Cohen's d = 0.21, p = 0.033; and Cohen's d = 0.20, p = 0.019, respectively). Neuropsychiatric symptoms, one of the secondary outcomes, also evolved more favorably in the intervention group (Cohen's d = 0.23, p = 0.055). CONCLUSION: MAKS therapy is effective for persons with cognitive impairment ranging from mild cognitive impairment (MCI) to moderate dementia who live at home and regularly visit a day care center. The fact that 32 day care facilities from all over Germany participated in this study gives its findings high external validity. PMID- 29249225 TI - Tranexamic Acid in Endoprosthesis. PMID- 29249226 TI - Tranexamic Acid Prophylaxis in Hip and Knee Joint Replacement. AB - BACKGROUND: The antifibrinolytic agent tranexamic acid (TXA) is widely used for the prevention and treatment of hyperfibrinolytic states, such as in severe polytrauma. It can also be used for the systemic prevention of hemorrhage in elective orthopedic procedures. In this review, we assess the efficacy and risks of the prophylactic administration of tranexamic acid before major endoprosthetic surgery of the hip and knee. METHODS: This review is based on pertinent articles retrieved by a selective literature search in the PubMed and Cochrane Library databases. RESULTS: Endoprosthetic surgery of the hip and knee is often associated with perioperative blood losses exceeding 500 mL. The prophylactic administration of tranexamic acid immediately before such procedures has been shown in randomized, controlled trials to lessen the quantity of intra- and postoperative bleeding and to reduce the likelihood of blood transfusion (number needed to treat [NNT] 3.7-5.7 for knee replacement and 4.1-8.2 for hip replacement). The rate of thromboembolic events did not differ significantly from the rate in the placebo groups. No reliable data are available on the frequency of epileptic seizures as a complication of TXA use in knee and hip endoprosthetic surgery. On the basis of data from other types of surgery, one may reasonably conclude that the doses of TXA used for knee and hip endoprosthetic procedures are unlikely to cause this problem. CONCLUSION: The prophylactic intravenous administration of tranexamic acid lessens the amount of bleeding in endoprosthetic knee and hip procedures and reduces the likelihood of blood transfusion. According to the current state of the evidence, complications are rare. Nonetheless, consideration of the risks and benefits implies that tranexamic acid should not be given for this purpose to patients who have recently had urogenital bleeding, pulmonary embolism, or a myocardial infarction, who have recently undergone percutaneous transluminal coronary angioplasty or stenting, or who are known to have epilepsy. PMID- 29249227 TI - Clinical Neuropathology image 1-2018: Golgi silver staining, the black reaction. PMID- 29249228 TI - Adult nephrotic syndrome complicated by spontaneous pneumococcal peritonitis: A case report. PMID- 29249229 TI - Thrombotic microangiopathy in patients with diabetic nephropathy is associated with low VEGF expression and end-stage renal disease?. AB - BACKGROUND: Thrombotic microangiopathy (TMA) has been associated with diabetic nephropathy, but its pathogenesis is unknown. OBJECTIVES: To determine the role of vascular endothelial growth factor (VEGF) expression in patients with TMA and diabetes mellitus. MATERIALS AND METHODS: Retrospective cohort study, patients were divided into diabetic nephropathy patients either without thrombotic microangiopathy (DN-TMA) or with thrombotic microangiopathy (DN+TMA). VEGF levels were analyzed using immunohistochemistry. Statistical analysis was performed with SPSS 20.0 software. RESULTS: There were 36 patients included in this study with a mean age of 47.6 +/- 9.3 years. The average time since the diagnosis of diabetes mellitus was 6.8 +/- 4.1 years. There were 21 patients (58.3%) with DN+TMA and 15 patients (41.7%) with DN-TMA. Patients with DN+TMA had a higher systolic blood pressure (p = 0.014) and diastolic blood pressure (p < 0.001) as well as proteinuria (p = 0.006), and a lower rate of glomerular filtration at baseline (p = 0.01). VEGF assessment showed lower arteriolar and glomerular expression in patients with DN+TMA (p < 0.001). The VEGF expression levels had an inverse relationship with proteinuria (r = -0.373; p = 0.03) and were directly proportional with glomerular filtration (r = 0.712; p < 0.01). Kaplan-Meier curves showed a higher probability of end-stage renal disease in patients with DN+TMA (log-rank p < 0.012). CONCLUSION: TMA is associated with low VEGF expression and end-stage renal disease in patients with diabetic nephropathy.?. PMID- 29249230 TI - Full age spectrum equation may be an alternative method to estimate the glomerular filtration rate in Chinese patients with chronic kidney disease?. AB - OBJECTIVE: To assess the performance of the full age spectrum (FAS) equation in comparison to other equations in subjects with chronic kidney disease (CKD) for the first time in China. MATERIALS AND METHODS: The measured glomerular filtration rate (mGFR) obtained by the 99mTc-diethylenetriamine pentaacetic acid renogram was used as the reference standard. Bias, precision, and accuracy were analyzed to identify which of these four equations performed better: FAS equation, the Modification of Diet in Renal Disease (MDRD) equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the Berlin Initiative Study-1 (BIS-1) equation. kappa-test and the Bland-Altman method were applied to evaluate the classification and the agreement between the estimated glomerular filtration rate (eGFR) and mGFR, respectively. RESULTS: 396 subjects were enrolled in this study. The precision (root mean square error, RMSE) of the FAS equation was 19.49 (95% CI 17.98, 21.27) in adults (18 - 70 years) and 14.06 (95% CI 12.50, 16.07) in older adults (>= 70 years), better than the corresponding values of MDRD equation 22.32 (95% CI 20.59, 24.36) and 20.76 (95% CI 18.46, 23.72)(p < 0.05), superior to 17.59 (15.64, 20.10) for CKD-EPI equation in older adults, respectively. The FAS equation showed the least bias (1.28 (95% CI -1.38, 4.03)) in older adults and the highest percentage (63.64%) of accuracy (30%) in all participants. The FAS correctly classified subjects into GFR categories. CONCLUSION: The FAS equation improved the precision and accuracy of eGFR, especially in older adults. It also decreased the bias of the estimated GFR. The FAS equation is applicable to adults and may be an alternative to measuring eGFR in China.?. PMID- 29249231 TI - Hemoglobinuric acute kidney injury in a patient with a kinked prosthetic aortic graft?. AB - Acute kidney injury (AKI) due to intravascular hemolysis has been well described in paroxysmal nocturnal hemoglobinuria (PNH) and in cardiac valvular dysfunction. However, reported cases of hemoglobinuric AKI from prosthetic aortic grafts are sparse. We present a case of microangiopathic hemolytic anemia and hemoglobinuric AKI presenting 9 days after repair of an ascending aortic dissection with a prosthetic graft. After an unremarkable recovery following the initial procedure, the patient presented on postoperative day 9 with dyspnea, fatigue, and cola colored urine. Attempts to manage conservatively with intravenous fluids, blood pressure control, and erythrocyte transfusion were unsuccessful. A magnetic resonance angiography revealed narrowing of the ascending aorta with a kink, causing turbulent blood flow. Surgical intervention was indicated due to persistent hemolysis, transfusion-refractory anemia, and worsening renal function. After surgical release of the kinked graft, his AKI and hemolysis labs improved immediately. On follow-up, his anemia resolved, and renal function returned to baseline, although he continues to have subclinical hemolysis.?. PMID- 29249233 TI - Abatacept efficacy in steroid-resistant minimal-change disease revealed by the speed of proteinuria reduction after the start of abatacept?. AB - A unique characteristic of the response of minimal-change disease (MCD) or focal and segmental glomerulosclerosis (FSGS) to steroid therapy is that the remission of proteinuria occurs quickly, for example, within 4 - 6 weeks of the onset of steroid therapy, even in those with severe nephrotic syndrome. Remission of proteinuria in MCD and FSGS can also occur spontaneously (not steroid induced). However, spontaneous remission usually proceeds over several months or longer. Recently, there have been several reports that abatacept can induce proteinuria remission in MCD and FSGS. These claims, however, are dubious because either the remission occurred slowly over several months of abatacept therapy, or remission occurred within a few weeks of abatacept therapy, but the patient was also receiving therapies that could have accounted for the remission of proteinuria. Our case is unique in that his severe steroid- and cyclosporine-resistant MCD remitted acutely while receiving abatacept, and there was no other plausible explanation for the acute remission of his MCD.?. PMID- 29249232 TI - An integrated pathology and ultrasonography-based simulation for training in performing kidney biopsy?. AB - BACKGROUND: Medical practice trends and limitations in trainees' duty hours have diminished the interest and exposure of nephrology fellows to percutaneous kidney biopsy (PKB). We hypothesized that an integrated nephrology-pathology-led simulation may be an effective educational tool. MATERIALS AND METHODS: A 4-hour PKB simulation workshop (KBSW), led by two ultrasonography (US)-trained nephrologists and two nephropathologists, consisted of 6 stations: 1) diagnostic kidney US with live patients, 2) kidney pathology with plasticine models of embedded torso cross-sections, 3) US-based PKB with mannequin (Blue PhantomTM), 4) kidney pathology with dissected cadavers, 5) US-based PKB in lightly-embalmed cadavers, and 6) tissue retrieval adequacy examination by microscope. A 10 question survey assessing knowledge acquisition and procedural confidence gain was administered pre- and post-KBSW. RESULTS: 21 participants attended the KBSW and completed the surveys. The overall percentage of correct answers to knowledge questions increased from 55 to 83% (p = 0.016). The number of "extremely confident" answers increased from 0 - 5% to 19 - 28% in all 4 questions (p = 0.02 - 0.04), and the number of "not at all confident" answers significantly decreased from 14 - 62% to 0 - 5% in 3 out of 4 questions (p = 0.0001 - 0.03). Impact of the imparted training on subsequent practice pattern was not assessed. CONCLUSION: A novel KBSW is an effective educational tool to acquire proficiency in PKB performance and could help regain interest among trainees in performing PKBs.?. PMID- 29249234 TI - High-dose melphalan and autologous hematopoietic stem cell transplant in patient with C3 glomerulonephritis associated with monoclonal gammopathy?. AB - There is currently no standard treatment for monoclonal immunoglobulin (MIg) associated C3 glomerulopathy, and treatment is often dictated by the extent of the monoclonal gammopathy. Although chemotherapy treatment for MIg-associated C3 glomerulopathy may stabilize renal function, the overall renal prognosis of MIg associated C3 glomerulopathy is still poor with frequent progression to end-stage renal disease. We present a case of a 55-year-old man with IgG-kappa gammopathy associated C3 glomerulonephritis (C3GN) with bone marrow biopsy demonstrating 5 - 10 kappa-restricted plasma cells. Following chemotherapy treatment unfortunately, the patient encountered relapsing courses of the disease. The patient subsequently received high-dose melphalan treatment followed by autologous hematopoietic stem cell transplant (ASCT). At 8 months follow-up, the patient remained hematologic response with stable kidney function. Since ASCT can offer durable hematologic remission, ASCT can potentially be a curative treatment option for patients with MIg-associated C3GN.?. PMID- 29249235 TI - Kidney stone composition in the Kingdom of Saudi Arabia?. AB - INTRODUCTION: Urolithiasis is a globally-distributed disease; however, its prevalence varies across countries and regions. Countries in the Middle East have been reported to have particularly high nephrolithiasis prevalence rates. To date, however, we have an incomplete understanding of the composition of stones seen in this region. Therefore, we performed a study to characterize stone composition over a 14-year period in the Eastern Province of the Kingdom of Saudi Arabia (KSA). MATERIALS AND METHODS: A retrospective review of all adult patients who had the composition of their upper urinary tract calculi analyzed at Johns Hopkins Aramco Healthcare (JHAH) between 1999 and 2013 was performed. Patient demographics and pathology results were obtained from the electronic medical record. RESULTS: A total of 1,747 stones were analyzed in the study period. The results are presented in the Table. Male patients predominated (79%). For both men and women, the majority of stones were calcium oxalate: 85.2% male, 85.9% female. Uric acid stones were the next most common: 10.1% male; 9.0% female. Overall, there were no significant differences between gender with regards to the distribution of stone types. CONCLUSION: This study represents one of the largest characterizations of stone composition in the Middle East. There remains a significant gender disparity in stone prevalence in the Eastern Province of KSA, with males affected to a significantly greater extent. Calcium oxalate is the most common type of stone, and this is true for both men and women. Future investigations of dietary and environmental factors can build on these initial epidemiologic findings.?. PMID- 29249236 TI - Editorial for the special issue on "constrained peptides". PMID- 29249237 TI - Enzyme-catalyzed peptide cyclization. AB - The recent advancement of peptide macrocycles as promising therapeutics creates a need for novel methodologies for their efficient synthesis and (large scale) production. Within this context, due to the favorable properties of biocatalysts, enzyme-mediated methodologies have gained great interest. Enzymes such as sortase A, butelase 1, peptiligase and omniligase-1 represent extremely powerful and valuable enzymatic tools for peptide ligation, since they can be applied to generate complex cyclic peptides with exquisite biological activity. Therefore, the use of enzymatic strategies will effectively supplement the scope of existing chemical methodologies and will accelerate the development of future cyclic peptide therapeutics. The advantages and disadvantages of the different enzymatic methodologies will be discussed in this review. PMID- 29249238 TI - Identification of nonstandard macrocyclic peptide ligands through display screening. AB - Techniques facilitating the synthesis and screening of very high diversity nonstandard macrocyclic peptide libraries have led to such compounds receiving increasing attention as potential drug candidates. Specifically, approaches which allow the use of non-proteinogenic amino acids are proving to be particularly effective, since they expand the accessible chemical space of the starting library and thus allow the identification of compounds with structural similarity to known drugs. This review focuses on mRNA display screening platforms for drug discovery and their combined use with genetic code reprogramming to identify novel macrocyclic peptides with high affinities for disease-related targets of interest. PMID- 29249239 TI - Tools to investigate the ubiquitin proteasome system. AB - Ubiquitin is a 76-amino acid regulatory protein involved in many important cellular processes. Ubiquitin can be attached to other proteins at either a lysine residue or to the N-terminus by the consecutive actions of E1, E2, and E3 enzymes. Ubiquitin can also be attached to itself, resulting in poly-ubiquitin chains. Ubiquitination affects substrate proteins in different ways, for example by resulting in degradation of the substrate protein by the 26S proteasome. Ubiquitination can be reversed by deubiquitinating enzymes, which either trim or remove ubiquitin chains from proteins. Many proteins involved in either the ubiquitination, deubiquitination or degradation of proteins are implicated in human diseases and are currently under investigation as potential drug targets. PMID- 29249240 TI - Recent advances in the synthesis of cyclic pseudopeptides. AB - Constrained peptides pose tremendous value in drug discovery. For example, owing to their large surface areas, they offer novel ways at inhibiting protein-protein interactions. As this field has grown, it has become desirable to introduce non peptidic functionality into these rings to enable differentiated structure activity relationships and improved pharmacokinetic properties. Recent advances in the synthesis of cyclic pseudopeptides include macrocyclization through cysteine alkylation, multicomponent reactions, decarboxylative couplings, and novel stapling chemistry. PMID- 29249241 TI - Constrained cell penetrating peptides. AB - In this review we provide an overview of recent developments in the field of cell penetrating peptides (CPPs) on research that aims to achieve better control over their transduction properties - one of the big challenges - by means of restraining them. Three different constraining strategies are presented: triggerable activation, backbone rigidification and macrocyclization. Each of these methods have their opportunities in gaining control over CPP activity and selectivity. PMID- 29249242 TI - Navigating the Peer Review Process. AB - This editorial provides insights and guidelines for publishing in The Journal of Molecular Diagnostics. PMID- 29249243 TI - Identification of Germline Variants in Tumor Genomic Sequencing Analysis. AB - This Correspondence relates to the article by Li et al (Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and the College of American Pathologists. J Mol Diagn 2017, 19:4-23). PMID- 29249244 TI - Authors' Reply. AB - Authors' Reply to the Letter to the Editor by Montgomery et al (Identification of Germline Variants in Tumor Genomic Sequencing Analysis. J Mol Diagn 2017, 19:XXXX XXXX). PMID- 29249245 TI - Relationship between sleep-disordered breathing and renal dysfunction in acute coronary syndrome. AB - BACKGROUND: Sleep-disordered breathing (SDB) is associated with cardiovascular complications. However, the effect of SDB on renal function in patients with acute coronary syndrome (ACS) treated by percutaneous coronary intervention (PCI) remains unclear. METHODS: We enrolled 154 consecutive ACS patients without heart failure. A sleep study was performed immediately after PCI. RESULTS: The mean apnea-hypopnea index (AHI) was 16.4+/-13.1, and 33 patients (21%) had severe SDB, defined as AHI>=25. Estimated glomerular filtration rate (eGFR) values on admission (60+/-12mL/min/1.73m2 vs. 67+/-17mL/min/1.73m2, p=0.046) and at discharge (54+/-15mL/min/1.73m2 vs. 63+/-15mL/min/1.73m2, p=0.002) were lower in patients with severe SDB than in those patients without severe SDB. Multiple linear regression analysis showed that AHIs were significantly correlated with absolute changes in eGFR values from admission to discharge (beta=0.201, p=0.004). Median 24-h urinary noradrenaline excretion measured on the same day of the sleep study was higher [297 (interquartile range {IQR}: 232-472) vs. 174 (IQR: 107-318)MUg/day, p=0.021] in patients with severe SDB. On multivariate logistic regression analysis, the presence of severe SDB was a significant predictor (adjusted odds ratio 3.76, 95% confidence interval 1.06-13.9, p=0.047) for eGFR of less than 45mL/min/1.73m2 at discharge. This association was independent of age, eGFR on admission, and a presentation of ST-segment elevation myocardial infarction. CONCLUSION: In patients with ACS who undergo PCI, severe SDB is associated with impaired renal function on admission and its deterioration during hospitalization. Further studies will be needed to conclude that SDB would be a therapeutic target in ACS. PMID- 29249246 TI - [What's new in clinical dermatology?] AB - In addition to continuous medical education, medical journals offer to dermatologists a huge variety of news that differ by their content, validity, originality and clinical relevance. I collected here various articles relative to clinical dermatology that have been published between September, 2016 and September, 2017. These papers have been chosen in the aim of reflecting such diversity. I just excluded, as far as possible, articles dealing with other issues that the reader will find further in this booklet (such as research, pediatric, instrumental, oncologic or therapeutic dermatology, or dermatology and internal medicine). Space restriction required to skip some commentaries while keeping the references to the selected papers, which the reader will be able to read carefully in its original form. PMID- 29249247 TI - [What's new in instrumental dermatology?] AB - This "What's new in instrumental dermatology" dedicated skin surgeryis based upon a 2015-2017 literature analysis. The excision of skin cancers is an important part of surgical dermatology. Will artificial intelligence and new drug be able to face the increasing need for therapy? Wrong-site surgery is due to multiple factors. Photographs of biopsy site and short time between biopsy and surgery decrease postponement of surgery and wrong-site surgery. Noninvasive imaging technologies are improving and help to delineate skin tumors and increase the probability of complete tumor removal. They are beginning to be an essential tool for skin surgery. The 2005 recommendations for the management of melanoma stages I to III have been updated in 2016. The Slow-Mohs technique is the better way to treat dermatofibrosarcoma protuberans whose sub-clinical invasion is often asymmetric and unpredictable. Wide local excision for the treatment of severe hidradenitis suppurativa improves the quality of life and decreases recurrence rate. Cutaneous surgery is considered as safe procedures with a low risk of complications. Postoperative bleedings are the most frequent. Anti-thrombotics enhance the risk, but must not be stopped or bridged, except the novel oral anticoagulants which can be interrupted 24h before surgery and started again a few hours after. The risk of surgical site infections is low in dermatologic surgery. Most recommended measures to prevent them have been extrapolated from other types of surgery and the level of evidence is low. The reconstruction of skin defect must be adapted on size and location. A birhombic transposition flap is reliable in case of a defect too large to be repaired by a single flap. Full thickness skin graft is a safe option to repair defect on the external ear. PMID- 29249248 TI - [What's new in dermatological research?] AB - This manuscript provides a selection of dermatological research manuscripts published from September 2016 to August 2017. It is not an exhaustive review but rather a selection of manuscripts susceptible to modify the dermatological practice or affording new pathophysiologic mechanisms and new therapeutic approaches. The following areas of interest are concerned: recognition of dermatological images by artificial intelligence, new concepts in atopic dermatitis, wound repair and hair growth cycle. New data concerning melanomagenesis, epidermolysis bullosa simplex and drug eruption are also highlighted. PMID- 29249249 TI - [What's new in internal medicine?] AB - As it is practiced in France, internal medicine meets the Anglo-Saxon definition of the specialty, ie doctors "equipped to handle the broad and comprehensive spectrum of illnesses that affect adults, and are recognized as experts in diagnosis, in treatment of chronic illness, and in health promotion and disease prevention - they are not limited to one type of medical problem or organ system". This 2017 "What's new in internal medicine" will consist of 2 parts, a first part on significant publications in the field of systemic and autoimmune diseases and a second part on more diverse publications (HIV, cancer, pregnancy, well-being...) important for medicine in general and its different specialties. PMID- 29249250 TI - [What's new in pediatric dermatology?] AB - The year 2017 in pediatric dermatology was marked by several consensus recommendations and meta analyzes on childhood psoriasis, atopic dermatitis or PHACE syndrome, case series on the role of anti-JAK treatment in adolescent with alopecia areata, sirolimus for vascular malformations, ivermectine for rosacea, inhibitors of MEK for type 1 neurofibromatosis or on the side effects of the oral isotretinoin for acne or propranolol for immature hemangioma. Only few randomized controlled studies have been published on the interest of adalimumab in the treatment of psoriasis or topical sirolimus for angiofibroma in tuberous sclerosis complex for example. There were also clinical articles on various affections such as the sign of the scalp hair collar sign, childhood prurigo, ichthyosis, atopic dermatitis, warts or Zika virus infection. Finally, numerous publications reported new genes responsible for dermatosis in mosaics with new questionings and perspectives. PMID- 29249251 TI - [What's new in oncodermatology?] AB - This 'What's new in oncodermatology?' addresses the developments in 2017 on the epidemiology and management of skin cancers. We observe a constant increase in carcinomas, risk factors for squamous cell carcinoma, especially in transplant recipients where skin cancer mortality is important. Among epidemiological developments in melanoma are increased mortality despite screening, occupational exposure to UV, second melanoma and higher risk after carcinoma. New classifications that should be considered are AJCC8 for melanoma and carcinoma. In a near future artificial intelligence could change skin cancer screening practices through deep learning. For the sentinel lymph node, there is no interest in systematic lymphadenectomy that does not improve survival. Radiation therapy is essential for the prognosis of Merkel's carcinoma, and Mohs' surgery can be of interest. In metastatic melanoma, results on immunotherapy and targeted treatments include duration, dose, combinations, and the study of resistance mechanisms. The great novelty is immunotherapy or targeted therapy as an adjuvant treatment, giving an improvement in survival without relapse. PMID- 29249253 TI - Correction. PMID- 29249252 TI - [What's new in dermatological treatment?] AB - On a therapeutic point of view, 2017 in dermatology could be summarized in one disease, one pathway and in one number : atopic dermatitis, JAK inhibitors and 23. 2017 will be the year of the first registration of a biologic treatment in atopic dermatitis, dupilumab, with numerous other drugs currently in development. JAK inhibitors show promising results in several difficult-to-treat conditions, such as alopecia areata, vitiligo or atopic dermatitis, but still warrant confirmation in upcoming controlled trials. Monoclonal antibodies targeting IL-23 have confirmed in phase III studies their great efficacy in controlling psoriasis and will be soon available in practice, illustrating well the optimal link between bench side and bed in this emblematic inflammatory dermatological condition. PMID- 29249254 TI - Note of Concern. PMID- 29249256 TI - ? PMID- 29249255 TI - Reduced Expression of Hydrogen Sulfide-Generating Enzymes Down-Regulates 15 Hydroxyprostaglandin Dehydrogenase in Chorion during Term and Preterm Labor. AB - Chorionic NAD-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) plays a pivotal role in controlling the amount of prostaglandins in the uterus and has been implicated in the process of labor. Prior studies identified hydrogen sulfide-generating enzymes cystathionine-beta-synthetase (CBS) and cystathionine gamma-lyase (CSE) in fetal membranes. We investigated whether hydrogen sulfide is involved in the regulation of PGDH expression in the chorion during labor. The chorionic tissues were obtained from pregnant women at preterm in labor and at term in labor or not in labor at term. Levels of CSE and CBS and hydrogen sulfide production rate were down-regulated in term in labor and preterm in labor groups compared with not in labor at term group. The CBS level correlated to PGDH expression in the chorion. Hydrogen sulfide donor NaHS and precursor l-cysteine dose-dependently stimulated PGDH expression and activity in cultured chorionic trophoblasts. The effect of l-cysteine was blocked by CBS inhibitor and CBS siRNA but not by CSE inhibitor and CSE siRNA. Hydrogen sulfide treatment suppressed miR 26b and miR-199a expression in chorionic trophoblasts. miR-26b and miR-199a mimics blocked hydrogen sulfide upregulation of PGDH expression. Our results indicate that hydrogen sulfide plays pivotal roles in maintenance of PGDH expression in the chorion during human pregnancy. Reduced expression of hydrogen sulfide-generating enzymes contributes to an increased amount of prostaglandins in the uterus during labor. PMID- 29249257 TI - ? PMID- 29249258 TI - ? PMID- 29249259 TI - ? PMID- 29249260 TI - ? PMID- 29249261 TI - Atrophying Pityriasis Versicolor. PMID- 29249262 TI - Clinical Research at the Heart of the Spanish Academy of Dermatology and Venereology. PMID- 29249263 TI - Reconstructive methods in Mohs micrographic surgery in Uruguay: A bidirectional descriptive cohort analysis. AB - BACKGROUND AND OBJECTIVES: The primary goal of Mohs micrographic surgery (MMS) is to completely excise a cancerous lesion and a wide range of reconstructive techniques of varying complexity are used to close the resulting wound. In this study, we performed a descriptive analysis of patients who underwent MMS, with a focus on wound closure methods. MATERIAL AND METHODS: We conducted a bidirectional descriptive cohort analysis of all MMS procedures performed by a single surgeon between November 2013 and April 2016. Cosmetic outcomes were photographically assessed by a dermatologist after a minimum follow-up of 90 days. RESULTS: We analyzed 100 MMS procedures in 71 patients with a median age of 73 years. The tumors were basal cell carcinoma (70%), squamous cell carcinoma (29%), and dermatofibrosarcoma protuberans (1%); 75% were located on the head and neck. The reconstructive techniques used were flap closure (48%), simple closure (36%), closure by second intention (11%), and other (5%). Cosmetic outcomes were assessed for 70 procedures (47 patients) and the results were rated as excellent in 20% of cases, very good in 40%, good in 20%, moderate in 17%, and bad/very bad in 2.9%. No significant associations were observed between cosmetic outcome and sex, Fitzpatrick skin type, hypertension, diabetes mellitus, or smoking. Worse outcomes, however, were significantly associated with larger tumor areas and defects, location on the trunk, and flap and second-intention closure. CONCLUSIONS: Although there was a tendency to use simple wound closure for lesions located on the trunk and surgical defects of under 4.4cm2, the choice of reconstructive technique should be determined by individual circumstances with contemplation of clinical and tumor-related factors and the preference and experience of the surgeon. PMID- 29249264 TI - Editorial for "Experimental Approaches to Advance Therapies for Tumors of the Central and Peripheral Nervous System". PMID- 29249265 TI - Topical Cidofovir for Treatment-Refractory Ocular Surface Squamous Neoplasia. PMID- 29249266 TI - Differential gene modulation of pattern-recognition receptor TLR and RIG-I-like and downstream mediators on intestinal mucosa of pigs infected with PEDV non S INDEL and PEDV S-INDEL strains. AB - Porcine epidemic diarrhea virus (PEDV) strains can be divided into non-S-INDEL and S-INDEL strains. PEDV pathogenesis is strain-specific, and studies in neonatal pigs have demonstrated that the PEDV non-S-INDEL strains are more pathogenic than the PEDV S-INDEL strains. RNA viruses, including PEDV, can interact with a large number of pattern recognition receptors (PRRs) in the intestinal mucosa, including toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). We investigated the differential gene modulation of TLRs, RIG-I, and downstream mediators on the intestinal mucosa of neonatal pigs infected with PEDV S-INDEL and non-S-INDEL strains. Ten five-day-old piglets were inoculated orally with 10ml of 104 TCDI50/ml of either PEDV non-S-INDEL or S-INDEL strains. PEDV S INDEL infection induced pro-inflammatory cytokines through the non-canonical NF kappaB signaling pathway by activating RIG-I. In contrast, PEDV non-S-INDEL infection suppressed the induction of pro-inflammatory cytokines and type 1 interferon production by down-regulation of TLRs and downstream signaling molecules. PMID- 29249267 TI - Coronaviruses and arteriviruses display striking differences in their cyclophilin A-dependence during replication in cell culture. AB - Cyclophilin A (CypA) is an important host factor in the replication of a variety of RNA viruses. Also the replication of several nidoviruses was reported to depend on CypA, although possibly not to the same extent. These prior studies are difficult to compare, since different nidoviruses, cell lines and experimental set-ups were used. Here, we investigated the CypA dependence of three distantly related nidoviruses that can all replicate in Huh7 cells: the arterivirus equine arteritis virus (EAV), the alphacoronavirus human coronavirus 229E (HCoV-229E), and the betacoronavirus Middle East respiratory syndrome coronavirus (MERS-CoV). The replication of these viruses was compared in the same parental Huh7 cells and in CypA-knockout Huh7 cells generated using CRISPR/Cas9-technology. CypA depletion reduced EAV yields by ~ 3-log, whereas MERS-CoV progeny titers were modestly reduced (3-fold) and HCoV-229E replication was unchanged. This study reveals that the replication of nidoviruses can differ strikingly in its dependence on cellular CypA. PMID- 29249268 TI - Treatment Outcomes of 4-Corner Arthrodesis for Patients With Advanced Carpal Collapse: An Average of 4 Years' Follow-Up Comparing 2 Different Plate Types. AB - PURPOSE: The objective was to investigate the clinical and subjective outcomes of patients after 4-corner arthrodesis (FCA) for scapholunate advanced collapse (SLAC) or scaphoid nonunion advanced collapse (SNAC) and to analyze complications. Furthermore, we compared the long-term results of a first generation nonlocking plate (Spider) and a plate with a locking screw design (Flower plate). METHODS: In a retrospective cohort study, we included 39 patients with stage II or III SLAC or SNAC who underwent FCA. Twenty wrists were treated with a nonlocking plate and 19 with a locking plate. Patients completed the Patient-Rated Wrist Evaluation (PRWE) and the Michigan Hand Outcomes Questionnaire (MHQ). Active range of wrist motion, radiological signs such as impingement, and signs of implant loosening and nonunion, as well as postoperative complications, were assessed. RESULTS: After a median postoperative follow-up time of 4.1 years, the PRWE score was 18 and the total MHQ score 79. Patient-reported and clinical outcomes were similar for the 2 plate types. Wrists fixed with the nonlocking plate had more dorsal impingements and loosening than wrists fixed with a locking plate. One nonunion was noted in the nonlocking plate group, and a single case of implant failure was seen for each plate type. A total of 5 patients with a nonlocking plate incurred postoperative complications that required further medical treatment. CONCLUSIONS: FCA for patients with stage II or III SLAC or SNAC yields positive clinical and subjective outcomes. Based on the high complication rate following FCA with a nonlocking plate, we no longer use this implant and recommend fixation with a locking screw plate. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29249269 TI - Historical review of our knowledge of acute pancreatitis. AB - Acute pancreatitis is one of most common causes of consultation due to abdominal pain in medical emergency units and it requires hospital admission. Although the majority of cases are mild and patients tend to recover quickly, a small percentage of cases is severe, with mortality in the region of 5-10%. This historical review considers how our understanding of this disease has changed since it was first described in 1579 thanks to the contributions of renowned experts such as Nicolaes Tulp, Reginald Fitz, Nicholas Senn and many others who, through their expertise and dedication, have improved the survival of patients with this disease. PMID- 29249270 TI - Black bowel: An unexpected cause of abdominal pain. PMID- 29249271 TI - Evaluation and comparison of capsule endoscopy scores for assessment of inflammatory activity of small-bowel in Crohn's disease. AB - INTRODUCTION: Capsule endoscopy (CE) has the highest sensitivity in the evaluation of small-bowel mucosa in Crohn's disease (CD). Recent guidelines recommend the use of validated CE scores to assess small-bowel inflammatory activity in CD. Lewis score (LS) and Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) are the currently available validated scores, but comparative studies are scarce. Moreover, correlation of these endoscopic scores with biomarkers and clinical activity is lacking. This study aims to compare LS with CECDAI, to determine cutoff values for CECDAI similar to those of LS (135-790), and to correlate LS and CECDAI with biomarkers and symptoms. STUDY: All patients with CD who underwent CE between March/2010 and February/2016 were included. LS and CECDAI were determined after analysis of each CE. In patients with small bowel CD, C-reactive protein (CRP) and Harvey-Bradshaw index (HBI) were evaluated. STATISTICAL ANALYSIS: descriptive statistics, Spearman's correlation coefficient and linear regression analysis. SIGNIFICANCE: p<0.05. RESULTS: Fifty three patients were included and the mean values obtained for LS were 1147+/ 1453, CECDAI 11.3+/-6.9, CRP 0.92+/-1.5mg/dL and HBI 2.4+/-2.8. There was a very strong correlation between LS and CECDAI (rs=0.878; p<0.0001) and thresholds values of 135-790 in LS corresponded to 7.7-10.3 cutoff values in CECDAI, respectively. Neither CRP correlated with LS (rs=0.068; p=0.72) or CECDAI (rs= 0.004; p=0.98), nor HBI with LS (rs=-0.15; p=0.40) or CECDAI (rs=-0.10; p=0.23). CONCLUSION: Correlation between the two CE activity scores was very strong, with LS thresholds of 135-790 corresponding to CECDAI values of 7.7-10.3. HBI and CRP had no correlation with CECDAI and LS. PMID- 29249272 TI - Successful spinal anaesthesia in a patient with a Tarlov cyst. AB - Perineural (Tarlov) cysts are cerebrospinal fluid-containing perineural sacs that are usually located in the sacral spine. While often asymptomatic, they can cause progressive neurological symptoms including pain, paraesthesia and weakness. We present a case of a 24-year-old patient who had uneventful spinal anaesthesia at the L3-4 level for an elective caesarean section. Prior to her procedure, she had reported a two-year history of intermittent back pain and lower-limb paraesthesia, secondary to an S1 segment perineural cyst. Recurrent cyst-related symptoms were managed using serial radiologically-guided injection and cerebrospinal fluid aspiration, rather than a more invasive neurosurgical approach. Successful neuraxial anaesthesia for caesarean section, in the context of Tarlov cysts, is described; and the management options are discussed. PMID- 29249273 TI - 30-day all-cause hospital readmission after cystectomy: no worse for rural Medicare residents. AB - OBJECTIVE: To evaluate rural/urban disparities in 30-day all-cause hospital admission after cystectomy. MATERIALS AND METHODS: We used the SEER-Medicare database to identify all Medicare beneficiaries who underwent radical cystectomy (ICD-9 codes 57.7, 57.71, 57.79, and 68.8) between the years 1991 and 2009, yielding a total sample size of 15,572. Our primary outcome was 30-day hospital readmission rate. Rural Urban Continuum Codes were used to designate county-level rural status based on patient residence. Location of surgery was not a variable considered in this analysis. A multivariable regression model was constructed with demographic and clinical variables as covariates. RESULTS: A total of 2,003 rural and 2,904 urban patients (31.1% vs. 31.8%, P = 0.33) were readmitted within 30 days of discharge. In the multivariable model, older age, unmarried status, lower socioeconomic status, higher Charlson comorbidity score, shorter index admission hospital stay, and discharge to a skilled nursing facility were associated with higher odds of readmission. The variables for gender, race, cancer stage, tumor grade, and type of urinary diversion were not significant. The odds ratio for readmission was not significant for patients from rural counties in the final model. CONCLUSIONS: Rural Medicare residents were not at higher risk for 30-day all-cause hospital readmission after cystectomy after accounting for various demographic and clinical variables. PMID- 29249274 TI - Evaluation of the diagnostic value of preoperative sentinel lymph node (SLN) imaging in penile carcinoma patients without palpable inguinal lymph nodes via single photon emission computed tomography/computed tomography (SPECT/CT) as compared to planar scintigraphy. AB - BACKGROUND: Sentinel lymph node (SLN) biopsy represents a well-established diagnostic tool for the assessment of lymphatic metastasis. Correct pre- and intraoperative visualization of SLN is of the utmost importance to ensure the safety and feasibility of the procedure. Aim of this study was to evaluate the diagnostic value of preoperative SLN imaging via single photon emission computed tomography/computed tomography (SPECT/CT) and planar scintigraphy in patients with penile carcinoma with nonpalpable inguinal lymph nodes. MATERIALS AND METHODS: After peritumoral intradermal tracer injection (150MBq/4.05mCi Tc-99m nanocolloid), we acquired planar scintigraphies including indirect body contouring using a twin head gamma camera. Subsequently we acquired SPECT/CT images of the abdomen via a hybrid system. Prospective evaluation of 52 groins in 26 examined patients was done for all image files obtained with both techniques by 2 trained experts in consensual assessment. RESULTS: A total of 71 SLNs in 37 groins were identified by means of planar scintigraphy. In these images, no radiolabeled lymph nodes were visualized in 15 out of 52 groins (28.8%). The SPECT/CT images showed a total of 82 SLNs in 42 groins. In 19.2% (10 of the 52 groins), there was no visualization of lymph nodes in SPECT/CT. 8 SLNs in 7 groins that were visualized in the planar technique were found to be false positive by SPECT/CT. In total, 19 SLNs in 16 groins that were overlooked by planar imaging could only be detected by SPECT/CT. In contrast to planar scintigraphy, SPECT/CT imaging enabled clear and precise anatomical localization of SLNs in all 42 groins where radiolabeled SLNs were visible. Even under consideration of all lymphatic drainage regions, statistical evaluation showed a significantly higher number of detected SLNs with SPECT/CT in comparison to the planar technique (P = 0.0022). CONCLUSION: In these patients SPECT/CT is capable of visualizing SLNs that cannot be detected with planar imaging. The SPECT/CT technique reduces the number of false positive findings from planar SLN imaging and is able to show anatomic SLN localization more precisely. If possible, preoperative SLN imaging should be performed by means of the SPECT/CT technique in patients with this tumor entity. PMID- 29249275 TI - Fibrin opens the "gate" for leukocytes in the endothelium. PMID- 29249277 TI - Rifampicin for Staphylococcus aureus bacteraemia: give it ARREST. PMID- 29249278 TI - Incisional hernia prevention using a cyanoacrilate-fixed retrofascial mesh. AB - INTRODUCTION: The rate of incisional hernia in high-risk patients (obesity, cancer, etc.) is high, even in laparoscopic surgery. The aim of this study is to evaluate the safety of the use of cyanoacrylate fixed prophylactic meshes in the assistance incision in overweight or obese patients undergoing laparoscopic colorectal surgery. METHODS: A prospective, non-randomized cohort study of patients undergoing elective laparoscopic resection for colorectal cancer between January 2013 and March 2016 was performed. Those with a body mass index greater than 25kg / m2 were evaluated to implant a prophylactic meshes fixed with cyanoacrylate (Histoacryl(r)) as reinforcement of the assistance incision. RESULTS: 52 patients were analyzed (mean body mass index: 28.4+/-2kg / m 2). Prophylactic meshes was implanted in 15 patients. The time to put the mesh in place was always less than 5minutes. There was no significant difference in wound infection rate (12% vs. 10%). No mesh had to be explanted. Although the mean follow-up was shorter (14.1+/-4 vs. 22.3+/-9 months), there were no incisional hernia in the mesh group. On the other hand, in the non-mesh group, 1 acute evisceration (2.7%) and 4 incisional hernia of the assistance incision were observed (10.8%). There were no significant differences between groups regarding trocar incisional hernia (6.6 vs. 5.4%). CONCLUSIONS: The implantation of a reinforcement prophylactic mesh in overweight or obese patients undergoing laparoscopic colorectal surgery is safe and seems to reduce the short-term rate of incisional hernia. Fixation with cyanoacrylate is a rapid method that facilitates the procedure without additional complications. PMID- 29249279 TI - To Prevent Parastomal Hernia After Stomal Surgery, a Prophylactic Mesh does Work. PMID- 29249280 TI - Social and situational characteristics associated with adolescents' drinking at party and non-party events. AB - We investigated social and situational characteristics associated with adolescents' drinking at party and non-party events and whether these associations vary by party location (homes versus other locations). Ecological momentary assessment data were obtained over two weekends from 149 adolescents in California (46% female, M age=16.4years), using smartphone surveys administered early and late in the evening and the following morning. We assessed whether, where, and with whom adolescents drank alcohol. Social contexts with more people (RRR=1.05, p<=0.005) and with mixed gender composition (RRR=3.15, p<=0.05) were positively associated with increased risks of alcohol use at parties, but not at non-party events. Conversely, social contexts with friends were positively associated with alcohol use at non-party events (RRR=4.32, p<=0.005), but not at parties. Perceived access to alcohol was associated with increased risks for alcohol use at both party and non-party events, but the association was stronger for alcohol use at parties than non-parties (RRR=1.85, p<0.005 versus 4.01, p<=0.005). Additional analyses showed that contexts with mixed gender composition were positively associated with alcohol use at parties not in homes (RRR=11.29, p<=0.05), and perceptions of getting caught by parents or police were negatively associated with non-party alcohol use in homes (RRR=0.57, p<=0.005). This study identified social-ecological contexts of underage drinking parties, which are high risk settings for heavier drinking and other alcohol-related problems. Findings can inform context-based interventions to target these high-risk settings, whether at homes or other locations. PMID- 29249281 TI - Psychosocial resilience and vulnerability in Western Australian aboriginal youth. AB - Resilience is defined as a dynamic and contextually embedded process of positive development despite exposure to significant adversity. The Australian Aboriginal and Torres Strait Islander population experience significant disadvantage and adversity relative to the non-Aboriginal population, with disproportionate and increasing rates of Aboriginal children in out-of-home care and substantiated child maltreatment seven times the rates for non-Aboriginal children. Despite decades of resilience research there remains a gap in our understanding of the extent to which specific mechanisms and processes support resilient outcomes. This discussion paper synthesizes findings from our four previously published studies which together illustrate the application of a person-based resilience framework of analysis in the context of Western Australian Aboriginal youth. We discuss the implications of this approach for better understanding processes differentially impacting psychosocial functioning of youth depending on level of family-risk exposure. Data for these studies were available for 1021 Aboriginal youth, 12-17 years, drawn from the 2000-2002 Western Australian Aboriginal Child Health Survey (WAACHS), a population representative survey of 5289 Aboriginal children (0-17 years) living in 1999 families. Multivariate logistic regression analyses were used to model the differential influence of individual, family, cultural and community factors on psychosocial outcomes depending on family-risk context. Key findings revealed 56% of high-risk youth as psychosocially resilient; prosocial friendship and living in low SES neighborhoods uniquely protected psychosocial functioning; and exposure to racism was an additional risk factor for low-risk exposed youth. We conclude that a resilience perspective holds potential for exploring diversity within disadvantaged populations, identifying processes uniquely beneficial for those at greatest risk, and provides crucial insights for communities, practitioners and policy-makers. PMID- 29249282 TI - Spatial Information in a Non-retinotopic Visual Cortex. AB - Turtle dorsal cortex (dCx), a three-layered cortical area of the reptilian telencephalon, receives inputs from the retina via the thalamic lateral geniculate nucleus and constitutes the first cortical stage of visual processing. The receptive fields of dCx neurons usually occupy the entire contralateral visual field. Electrophysiological recordings in awake and anesthetized animals reveal that dCx is sensitive to the spatial structure of natural images, that dCx receptive fields are not entirely uniform across space, and that adaptation to repeated stimulation is position specific. Hence, spatial information can be found both at the single-neuron and population scales. Anatomical data are consistent with the absence of a clear retinotopic mapping of thalamocortical projections. The mapping and representation of visual space in this three-layered cortex thus differ from those found in mammalian primary visual cortex. Our results support the notion that dCx performs a global, rather than local, analysis of the visual scene. PMID- 29249283 TI - Single-Neuron Representation of Memory Strength and Recognition Confidence in Left Human Posterior Parietal Cortex. AB - The human posterior parietal cortex (PPC) is thought to contribute to memory retrieval, but little is known about its specific role. We recorded single PPC neurons of two human tetraplegic subjects implanted with microelectrode arrays, who performed a recognition memory task. We found two groups of neurons that signaled memory-based choices. Memory-selective neurons preferred either novel or familiar stimuli, scaled their response as a function of confidence, and signaled subjective choices regardless of truth. Confidence-selective neurons signaled confidence regardless of stimulus familiarity. Memory-selective signals appeared 553 ms after stimulus onset, but before action onset. Neurons also encoded spoken numbers, but these number-tuned neurons did not carry recognition signals. Together, this functional separation reveals action-independent coding of declarative memory-based familiarity and confidence of choices in human PPC. These data suggest that, in addition to sensory-motor integration, a function of human PPC is to utilize memory signals to make choices. PMID- 29249284 TI - The M5 Cell: A Color-Opponent Intrinsically Photosensitive Retinal Ganglion Cell. AB - Intrinsically photosensitive retinal ganglion cells (ipRGCs) combine direct photosensitivity through melanopsin with synaptically mediated drive from classical photoreceptors through bipolar-cell input. Here, we sought to provide a fuller description of the least understood ipRGC type, the M5 cell, and discovered a distinctive functional characteristic-chromatic opponency (ultraviolet excitatory, green inhibitory). Serial electron microscopic reconstructions revealed that M5 cells receive selective UV-opsin drive from Type 9 cone bipolar cells but also mixed cone signals from bipolar Types 6, 7, and 8. Recordings suggest that both excitation and inhibition are driven by the ON channel and that chromatic opponency results from M-cone-driven surround inhibition mediated by wide-field spiking GABAergic amacrine cells. We show that M5 cells send axons to the dLGN and are thus positioned to provide chromatic signals to visual cortex. These findings underscore that melanopsin's influence extends beyond unconscious reflex functions to encompass cortical vision, perhaps including the perception of color. PMID- 29249285 TI - alpha-synuclein Induces Mitochondrial Dysfunction through Spectrin and the Actin Cytoskeleton. AB - Genetics and neuropathology strongly link alpha-synuclein aggregation and neurotoxicity to the pathogenesis of Parkinson's disease and related alpha synucleinopathies. Here we describe a new Drosophila model of alpha synucleinopathy based on widespread expression of wild-type human alpha synuclein, which shows robust neurodegeneration, early-onset locomotor deficits, and abundant alpha-synuclein aggregation. We use results of forward genetic screening and genetic analysis in our new model to demonstrate that alpha synuclein expression promotes reorganization of the actin filament network and consequent mitochondrial dysfunction through altered Drp1 localization. Similar changes are present in a mouse alpha-synucleinopathy model and in postmortem brain tissue from patients with alpha-synucleinopathy. Importantly, we provide evidence that the interaction of alpha-synuclein with spectrin initiates pathological alteration of the actin cytoskeleton and downstream neurotoxicity. These findings suggest new therapeutic approaches for alpha-synuclein induced neurodegeneration. PMID- 29249286 TI - Neurotransmitter Funneling Optimizes Glutamate Receptor Kinetics. AB - Ionotropic glutamate receptors (iGluRs) mediate neurotransmission at the majority of excitatory synapses in the brain. Little is known, however, about how glutamate reaches the recessed binding pocket in iGluR ligand-binding domains (LBDs). Here we report the process of glutamate binding to a prototypical iGluR, GluA2, in atomistic detail using unbiased molecular simulations. Charged residues on the LBD surface form pathways that facilitate glutamate binding by effectively reducing a three-dimensional diffusion process to a spatially constrained, two dimensional one. Free energy calculations identify residues that metastably bind glutamate and help guide it into the binding pocket. These simulations also reveal that glutamate can bind in an inverted conformation and also reorient while in its pocket. Electrophysiological recordings demonstrate that eliminating these transient binding sites slows activation and deactivation, consistent with slower glutamate binding and unbinding. These results suggest that binding pathways have evolved to optimize rapid responses of AMPA-type iGluRs at synapses. PMID- 29249288 TI - Dendritic Spines Prevent Synaptic Voltage Clamp. AB - Synapses are the fundamental units of information processing in the mammalian brain. Much of our understanding of their functional properties comes from voltage-clamp analysis, the predominant approach for investigating synaptic physiology. Here, we reveal that voltage clamp is completely ineffective for most excitatory synapses due to spine electrical compartmentalization. Under local dendritic voltage clamp, single-spine activation produced large spine head depolarizations that severely distorted measurements and recruited voltage dependent channels. To overcome these voltage-clamp errors, we developed an approach to provide new, accurate measurements of synaptic conductance. Single synapse AMPA conductance was much larger than previously appreciated, producing saturation effects on synaptic currents. We conclude that electrical compartmentalization profoundly shapes both synaptic function and how that function can be assessed with electrophysiological methods. PMID- 29249287 TI - Reward-Based Learning Drives Rapid Sensory Signals in Medial Prefrontal Cortex and Dorsal Hippocampus Necessary for Goal-Directed Behavior. AB - The neural circuits underlying learning and execution of goal-directed behaviors remain to be determined. Here, through electrophysiological recordings, we investigated fast sensory processing across multiple cortical areas as mice learned to lick a reward spout in response to a brief deflection of a single whisker. Sensory-evoked signals were absent from medial prefrontal cortex and dorsal hippocampus in naive mice, but developed with task learning and correlated with behavioral performance in mice trained in the detection task. The sensory responses in medial prefrontal cortex and dorsal hippocampus occurred with short latencies of less than 50 ms after whisker deflection. Pharmacological and optogenetic inactivation of medial prefrontal cortex or dorsal hippocampus impaired behavioral performance. Neuronal activity in medial prefrontal cortex and dorsal hippocampus thus appears to contribute directly to task performance, perhaps providing top-down control of learned, context-dependent transformation of sensory input into goal-directed motor output. PMID- 29249276 TI - Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (>=18 years) with S aureus bacteraemia who had received <=96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1.4%, 95% CI -7.0 to 4.3; hazard ratio 0.96, 0.68-1.35, p=0.81). From randomisation to 12 weeks, no evidence of differences in serious (p=0.17) or grade 3-4 (p=0.36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0.004), and 24 (6%) versus six (2%) had drug interactions (p=0.0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment. PMID- 29249290 TI - Re: Association Between Lymph Node Yield and Survival Among Patients Undergoing Radical Nephroureterectomy for Urothelial Carcinoma of the Upper Tract. PMID- 29249289 TI - Old Brains Come Uncoupled in Sleep: Slow Wave-Spindle Synchrony, Brain Atrophy, and Forgetting. AB - The coupled interaction between slow-wave oscillations and sleep spindles during non-rapid-eye-movement (NREM) sleep has been proposed to support memory consolidation. However, little evidence in humans supports this theory. Moreover, whether such dynamic coupling is impaired as a consequence of brain aging in later life, contributing to cognitive and memory decline, is unknown. Combining electroencephalography (EEG), structural MRI, and sleep-dependent memory assessment, we addressed these questions in cognitively normal young and older adults. Directional cross-frequency coupling analyses demonstrated that the slow wave governs a precise temporal coordination of sleep spindles, the quality of which predicts overnight memory retention. Moreover, selective atrophy within the medial frontal cortex in older adults predicted a temporal dispersion of this slow wave-spindle coupling, impairing overnight memory consolidation and leading to forgetting. Prefrontal-dependent deficits in the spatiotemporal coordination of NREM sleep oscillations therefore represent one pathway explaining age-related memory decline. PMID- 29249291 TI - A Multigene Signature Based on Cell Cycle Proliferation Improves Prediction of Mortality Within 5 Yr of Radical Nephrectomy for Renal Cell Carcinoma. AB - BACKGROUND: There is a critical need for improved prognostic discrimination in patients with renal cell carcinoma (RCC) given the increasing awareness that some patients may be managed with active surveillance, while others with higher-risk disease might benefit from adjuvant therapy following surgery. OBJECTIVE: To determine whether a multigene proliferation signature predicts long-term oncologic outcomes in surgically resected RCC. DESIGN, SETTING, AND PARTICIPANTS: The cell cycle proliferation (CCP) score was determined after radical nephrectomy for localized clear cell, papillary, or chromophobe RCC in 565 patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was disease-specific mortality (DSM), and disease recurrence was a secondary end point. Association with outcomes was evaluated by Cox proportional hazards survival analysis. The CCP score was compared with the Karakiewicz nomogram, and a composite (R-CCP) score was developed. RESULTS AND LIMITATIONS: A total of 68 patients (12%) recurred and 32 (6%) died of disease within 5 yr of nephrectomy. The CCP score was an independent predictor of recurrence (hazard ratio [HR] 1.50, 95% confidence interval [CI] 1.07-2.09) and DSM (HR 2.49, 95% CI 1.53-4.04) after adjusting for clinical variables using the baseline nomogram. The composite R-CCP score gave a Harrell's concordance index of 0.87 and stratified patients into low (n=338) and high-risk (n=202) categories with 99% and 84% cancer-specific survival probabilities, respectively (p<0.001). CONCLUSIONS: The CCP score is a significant, independent predictor of long-term oncologic outcomes in patients who have undergone nephrectomy for RCC. Combining the molecular classifier with baseline clinical variables allows for accurate, patient-specific risk assessment for use in guiding clinical management. PATIENT SUMMARY: In this study, we sought to understand how well gene expression information from individual kidney tumors can predict cancer recurrence and death following surgical removal. We found that the combination of the gene expression test and clinical characteristics provides an accurate prognostic assessment to help inform clinical decisions. PMID- 29249292 TI - The role of ISWI chromatin remodeling complexes in brain development and neurodevelopmental disorders. AB - The mammalian ISWI (Imitation Switch) genes SMARCA1 and SMARCA5 encode the ATP dependent chromatin remodeling proteins SNF2L and SNF2H. The ISWI proteins interact with BAZ (bromodomain adjacent to PHD zinc finger) domain containing proteins to generate eight distinct remodeling complexes. ISWI complex-mediated nucleosome positioning within genes and gene regulatory elements is proving important for the transition from a committed progenitor state to a differentiated cell state. Genetic studies have implicated the involvement of many ATP-dependent chromatin remodeling proteins in neurodevelopmental disorders (NDDs), including SMARCA1. Here we review the characterization of mice inactivated for ISWI and their interacting proteins, as it pertains to brain development and disease. A better understanding of chromatin dynamics during neural development is a prerequisite to understanding disease pathologies and the development of therapeutics for these complex disorders. PMID- 29249293 TI - Epigenetic crosstalk: Pharmacological inhibition of HDACs can rescue defective synaptic morphology and neurotransmission phenotypes associated with loss of the chromatin reader Kismet. AB - We are beginning to appreciate the complex mechanisms by which epigenetic proteins control chromatin dynamics to tightly regulate normal development. However, the interaction between these proteins, particularly in the context of neuronal function, remains poorly understood. Here, we demonstrate that the activity of histone deacetylases (HDACs) opposes that of a chromatin remodeling enzyme at the Drosophila neuromuscular junction (NMJ). Pharmacological inhibition of HDAC function reverses loss of function phenotypes associated with Kismet, a chromodomain helicase DNA-binding (CHD) protein. Inhibition of HDACs suppresses motor deficits, overgrowth of the NMJ, and defective neurotransmission associated with loss of Kismet. We hypothesize that Kismet and HDACs may converge on a similar set of target genes in the nervous system. Our results provide further understanding into the complex interactions between epigenetic protein function in vivo. PMID- 29249294 TI - Gut Endothelial Leakage of Endotoxin May Be the Source of Vascular Inflammation and Injury in CKD. How Can This Be Targeted? PMID- 29249296 TI - Happy New Year. PMID- 29249295 TI - Eating During Hemodialysis Treatment: A Consensus Statement From the International Society of Renal Nutrition and Metabolism. AB - Poor nutritional status and protein-energy wasting are common among maintenance dialysis patients and associated with unfavorable outcomes. Providing foods, meal trays, snack boxes, and/or oral nutritional supplements during hemodialysis can improve nutritional status and might also reduce inflammation, enhance health related quality of life, boost patient satisfaction, and improve survival. Potential challenges include postprandial hypotension and other hemodynamic instabilities, aspiration risk, gastrointestinal symptoms, hygiene issues, staff burden, reduced solute removal, and increased costs. Differing in-center nutrition policies exist within organizations and countries around the world. Recent studies have demonstrated clinical benefits and highlight the need to work toward clear guidelines. Meals or supplements during hemodialysis may be an effective strategy to improve nutritional status with limited reports of complications in real-world scenarios. Whereas larger multicenter randomized trials are needed, meals and supplements during hemodialysis should be considered as a part of the standard-of-care practice for patients without contraindications. PMID- 29249297 TI - Kidney-Friendly Label Reading for Chronic Kidney Disease Shoppers. PMID- 29249298 TI - The tumor microenvironment: Thousand obstacles for effector T cells. AB - The immune system is endowed with the capability to recognize and destroy transformed cells, but even in the presence of an immune infiltrate many tumors do progress. In the last decades new discoveries have shed light into (some of) the underlying mechanisms. Immune effector cells are not only under the influence of immune suppressive cell subsets, but also intrinsically regulated by immune check point molecules that under physiological condition avoid attach of healthy tissue. Moreover, tumor cells are modifying the surrounding microenvironment through secretion of immune modulators as well as via their own metabolism, thus further impairing the development of immune effector functions. Different approaches are currently being evaluated in the clinic to overcome those regulatory mechanisms and to unleash effector T cells. PMID- 29249299 TI - A kind of peace: Tracking the reflexive and resilient drug war. PMID- 29249301 TI - NG2 and GFAP co-expression after differentiation in cells transfected with mutant GFAP and in undifferentiated glioma cells. AB - INTRODUCTION: Alexander disease is a rare disorder caused by mutations in the gene coding for glial fibrillary acidic protein (GFAP). In a previous study, differentiation of neurospheres transfected with these mutations resulted in a cell type that expresses both GFAP and NG2. OBJECTIVE: To determine the effect of molecular marker mutations in comparison to undifferentiated glioma cells simultaneously expressing GFAP and NG2. METHODS: We used samples of human glioblastoma (GBM) and rat neurospheres transfected with GFAP mutations to analyse GFAP and NG2 expression after differentiation. We also performed an immunocytochemical analysis of neuronal differentiation for both cell types and detection of GFAP, NG2, vimentin, Olig2, and caspase-3 at 3 and 7 days from differentiation. RESULTS: Both the cells transfected with GFAP mutations and GBM cells showed increased NG2 and GFAP expression. However, expression of caspase-3 positive cells was found to be considerably higher in transfected cells than in GBM cells. CONCLUSIONS: Our results suggest that GFAP expression is not the only factor associated with cell death in Alexander disease. Caspase-3 expression and the potential role of NG2 in increasing resistance to apoptosis in cells co expressing GFAP and NG2 should be considered in the search for new therapeutic strategies for the disease. PMID- 29249300 TI - Incidence and etiological mechanism of stroke in cardiac surgery. AB - OBJECTIVE: We studied patients who had experienced a stroke in the postoperative period of cardiac surgery, aiming to analyse their progression and determine the factors that may influence prognosis and treatment. METHODS: We established a protocol for early detection of stroke after cardiac surgery and collected data on stroke onset and a number of clinical, surgical, and prognostic variables in order to perform a descriptive analysis. RESULTS: Over the 15-month study period we recorded 16 strokes, which represent 2.5% of the patients who underwent cardiac surgery. Mean age in our sample was 69 +/- 8 years; 63% of patients were men. The incidence of stroke in patients aged 80 and older was 5.1%. Five patients (31%) underwent emergency surgery. By type of cardiac surgery, 7% of patients underwent mitral valve surgery, 6.5% combined surgery, 3% aortic valve surgery, and 2.24% coronary surgery. Most cases of stroke (44%) were due to embolism, followed by hypoperfusion (25%). Stroke occurred within 2 days of surgery in 69% of cases. The mean NIHSS score in our sample of stroke patients was 9; code stroke was activated in 10 cases (62%); one patient (14%) underwent thrombectomy. Most patients progressed favourably: 13 (80%) scored<=2 on the modified Rankin Scale at 3 months. None of the patients died during the postoperative hospital stay. CONCLUSION: In our setting, strokes occurring after cardiac surgery are usually small and have a good long-term prognosis. Most of them occur within 2 days, and they are mostly embolic in origin. The incidence of stroke in patients aged 80 and older and undergoing cardiac surgery is twice as high as that of the general population. PMID- 29249302 TI - Motor learning induces plastic changes in Purkinje cell dendritic spines in the rat cerebellum. AB - INTRODUCTION: The paramedian lobule of the cerebellum is involved in learning to correctly perform motor skills through practice. Dendritic spines are dynamic structures that regulate excitatory synaptic stimulation. We studied plastic changes occurring in the dendritic spines of Purkinje cells from the paramedian lobule of rats during motor learning. METHODS: Adult male rats were trained over a 6-day period using an acrobatic motor learning paradigm; the density and type of dendritic spines were determined every day during the study period using a modified version of the Golgi method. RESULTS: The learning curve reflected a considerable decrease in the number of errors made by rats as the training period progressed. We observed more dendritic spines on days 2 and 6, particularly more thin spines on days 1, 3, and 6, fewer mushroom spines on day 3, fewer stubby spines on day 1, and more thick spines on days 4 and 6. CONCLUSION: The initial stage of motor learning may be associated with fast processing of the underlying synaptic information combined with an apparent "silencing" of memory consolidation processes, based on the regulation of the neuronal excitability. PMID- 29249303 TI - Report by the Spanish Foundation of the Brain on the social impact of Alzheimer disease and other types of dementia. AB - INTRODUCTION: Knowledge of the socioeconomic impact of dementia-related disorders is essential for appropriate management of healthcare resources and for raising social awareness. METHODS: We performed a literature review of the published evidence on the epidemiology, morbidity, mortality, associated disability and dependence, and economic impact of dementia and Alzheimer disease (AD) in Spain. CONCLUSIONS: Most population studies of patients older than 65 report prevalence rates ranging from 4% to 9%. Prevalence of dementia and AD is higher in women for nearly every age group. AD is the most common cause of dementia (50%-70% of all cases). Dementia is associated with increased morbidity, mortality, disability, and dependence, and results in a considerable decrease in quality of life and survival. Around 80% of all patients with dementia are cared for by their families, which cover a mean of 87% of the total economic cost, resulting in considerable economic and health burden on caregivers and loss of quality of life. The economic impact of dementia is huge and difficult to evaluate due to the combination of direct and indirect costs. More comprehensive programmes should be developed and resources dedicated to research, prevention, early diagnosis, multidimensional treatment, and multidisciplinary management of these patients in order to reduce the health, social, and economic burden of dementia. PMID- 29249304 TI - CAR T-cell therapy in refractory large B-cell lymphoma. PMID- 29249305 TI - San Antonio Breast Cancer Symposium 2017. PMID- 29249306 TI - TAS-102 in metastatic colorectal cancer. PMID- 29249307 TI - 2017 ASH Meeting. PMID- 29249308 TI - Impact of SRT on the performance of MBRs for the treatment of high strength landfill leachate. AB - This study examines the performance and fouling potential of flat sheet (FS) and hollow fiber (HF) membrane bioreactors (MBRs) during the treatment of high strength landfill leachate under varying solid retention times (SRT = 5-20 days). Mixed-liquor bacterial communities were examined over time using 16S rRNA gene sequence analysis in an attempt to define linkages between the system performance and the microbial community composition. Similarly, biofilm samples were collected at the end of each SRT to characterize the microbial communities that evolved on the surface of the FS and HF membranes. In general, both systems exhibited comparable removal efficiencies that dropped significantly as SRT was decreased down to 5 days. Noticeably, ammonia and nitrite oxidizing bacteria were not detected at the tested SRTs. This suggests that the nitrifiers were not enriched, possibly due to the high organic and ammonium content of the leachate that led to low TN and NH3 removal efficiency. The steady-state fouling rate of both membranes increased linearly with the decrease in SRT at an estimated factor of 1.1 and 1.2 for the FS- and HF-MBR, respectively, when the SRT was reduced from 15 to 10 days and from 10 to 5 days. Similar dominant genera were detected in both MBRs, including Pseudomonas, Aequorivita, Ulvibacter, Taibaiella, and Thermus. Aequorivita, Taibaiella; Thermus were the dominant genera in the biofilms. Hierarchical clustering and non-metric multidimensional scaling revealed that while the mixed liquor communities in the FS-MBR and HF-MBRs were dynamic, they clustered separately. Similarly, biofilm communities on the FS and HF membranes differed in the dynamic bacterial community structure, especially for the FS-MBR; however this was less dynamic than the mixed liquor community. PMID- 29249309 TI - Triboelectrostatic separation of polypropylene, polyurethane, and polyvinylchloride used in passenger vehicles. AB - Recycling and reuse of automotive plastics have elicited global attention due to the increasing number of end-of-life vehicles. Through the single-factor experiment, a high-voltage triboelectrostatic sorting device was developed to separate polypropylene (PP), polyurethane (PU), and polyvinylchloride (PVC) in a plastic mixture commonly used in exterior and interior parts of passenger vehicles. Products of PP, PU, and PVC were obtained after two-stage separation; their purity exceeded 95%, and their productivities were 74%, 94%, and 41%, respectively. The appropriate experimental parameters for high voltage level and rotational speed of the friction drum and cylinder electrode for the first stage of separation were 35 kV, 30 rpm, and 35 rpm, respectively, and the parameters for the second stage of separation were 35 kV, 30 rpm, and 25 rpm, respectively. Results showed that hybrid materials should be selected based on the triboelectric series to separate three-component plastic mixtures feasibly. PMID- 29249310 TI - Pre-treatment and inoculum affect the microbial community structure and enhance the biogas reactor performance in a pilot-scale biodigestion of municipal solid waste. AB - During anaerobic digestion of municipal solid waste, organic matter is converted to methane, carbon dioxide, and other organic and inorganic compounds through a complex cooperation among different microbial groups with different metabolic activities. Here, culture-dependent and independent approaches provided evidence for examining the relationship between bacterial and archaeal communities and methane production in a pilot-scale anaerobic digestion. The abundance of aerobic and anaerobic functional groups of C and N cycles, such as cellulolytic, pectinolytic, amylolytic and proteolytic bacteria, was high at the beginning of the experiment and was drastically decreased after anaerobic digestion. In contrast, the ammonifiers increased in the biogas producing reactors in a higher pH environment. The methanogenic archaeal genera recovered were Methanobrevibacter, Methanobacterium, Methanoculleus and Methanocorpusculum, thus indicating that methane was formed primarily by the hydrogenotrophic pathway in the reactors. Moreover, the mechanical pretreatment effects, as well as the effect of pelleted manure as inoculum, were considered. The highest methane production was detected in the biodigesters with minced organic waste, thus indicating that pre-treatment of a heterogeneous starting matrix was essential for improving biogas production and stabilizing the process. PMID- 29249311 TI - Determination of gas recovery efficiency at two Danish landfills by performing downwind methane measurements and stable carbon isotopic analysis. AB - In this study, the total methane (CH4) generation rate and gas recovery efficiency at two Danish landfills were determined by field measurements. The landfills are located close to each other and are connected to the same gas collection system. The tracer gas dispersion method was used for quantification of CH4 emissions from the landfills, while the CH4 oxidation efficiency in the landfill cover layers was determined by stable carbon isotopic technique. The total CH4 generation rate was estimated by a first-order decay model (Afvalzorg) and was compared with the total CH4 generation rate determined by field measurements. CH4 emissions from the two landfills combined ranged from 29.1 to 49.6 kg CH4/h. The CH4 oxidation efficiency was 6-37%, with an average of 18% corresponding to an average CH4 oxidation rate of 8.1 kg CH4/h. The calculated gas recovery efficiency was 59-76%, indicating a high potential for optimization of the gas collection system. Higher gas recovery efficiencies (73-76%) were observed after the commencement of gas extraction from a new section of one of the landfills. A good agreement was observed between the average total CH4 generation rates determined by field measurements (147 kg CH4/h) and those estimated by the Afvalzorg model (154 kg CH4/h). PMID- 29249312 TI - Decreased plasma amino acid concentrations in cats with chronic gastrointestinal diseases and their possible contribution in the inflammatory response. AB - In humans, plasma amino acids (AAs) levels are used as dynamic nutritional markers. Moreover, some AAs are associated with chronic inflammation. In this study, we analyzed plasma AA profiles in cats with chronic gastrointestinal (GI) diseases. Eight healthy controls (HCs) and 12 client-owned cats with chronic GI diseases including chronic enteritis (n=8) and neoplasms (n=4) were recruited. Plasma albumin, total protein, and 22 AAs (11 essential and 11 non-essential AAs) levels were estimated. There was no significant difference in plasma albumin and total protein concentrations between the cats with chronic GI diseases and HCs. The plasma concentrations of 7 essential AAs (arginine, histidine, lysine, methionine, phenylalanine, taurine, and tryptophan) and 7 non-essential AAs (asparagine, aspartic acid, glutamic acid, glycine, hydroxyproline, proline, and serine) were significantly decreased in the cats with chronic GI diseases (P<0.05). Moreover, plasma histidine and tryptophan levels were inversely correlated with severity of symptoms (histidine: rs=-0.7781, P<0.005; tryptophan: rs=-0.6040, P<0.05). To examine the contribution of altered AAs levels in the inflammatory response, feline macrophages were stimulated by lipopolysaccharides (LPS) with or without histidine, and the expression of interleukin-8 (IL-8) mRNA was quantified. The expression of IL-8 mRNA was significantly increased in the LPS-stimulated feline macrophages (P<0.05). Histidine almost suppressed the LPS induced IL-8 expression in the feline macrophages (P<0.05). Our findings suggest that plasma AAs levels are more sensitive nutritional markers than albumin and total protein levels in cats with chronic GI diseases. There is a possibility that the decrease of histidine levels in cats with GI diseases is associated with chronic inflammation. PMID- 29249313 TI - In silico identification and high throughput screening of antigenic proteins as candidates for a Mannheimia haemolytica vaccine. AB - This study examined the use of comparative genomic analysis for vaccine design against Mannheimia haemolytica, a respiratory pathogen of ruminants. A total of 2,341genes were identified in at least half of the 23 genomes. Of these, a total of 240 were identified to code for N-terminal signal peptides with diverse sub cellular localizations (78 periplasmic, 52 outer membrane, 15 extracellular, 13 cytoplasmic membrane and 82 unknown) and were examined in an ELISA assay using a coupled-cell free transcription/translation system for protein expressionwith antisera from cattle challenged with serovars 1, 2 or 6 of M. haemolytica. In total, 186 proteins were immunoreactive to at least one sera type and of these, 105 were immunoreactive to all sera screened. The top ten antigens based on immunoreactivity were serine protease Ssa-1 (AC570_10970), an ABC dipeptid transporter substrate-binding protein (AC570_04010), a ribonucleotide reductase (AC570_10780), competence protein ComE (AC570_11510), a filamentous hemagglutinin (AC570_01600), a molybdenum ABC transporter solute-binding protein (AC570_10275), a conserved hypothetical protein (AC570_07570), a porin protein (AC569_05045), an outer membrane assembly protein YeaT (AC570_03060), and an ABC transporter maltose binding protein MalE (AC570_00140). The framework generated from this research can be further applied towards rapid vaccine design against other pathogens involved in complex respiratory infections in cattle. PMID- 29249315 TI - The immunomodulatory function of equine MSCs is enhanced by priming through an inflammatory microenvironment or TLR3 ligand. AB - Mesenchymal stem cells (MSCs) have the therapeutic potential to treat a variety of inflammatory and degenerative disease processes, however the effects of the tissue environment on MSCs have been overlooked. Our hypothesis was that the immunomodulatory function of MSCs would be impaired by TLR4 stimulation or exposure to inflammatory macrophages, whereas their immunosuppressive properties would be enhanced by TLR3 stimulation. MSCs were exposed to polyinosinic:polycytidylic acid (poly I:C) to stimulate TLR3 receptors or lipopolysaccharide (LPS) to stimulate TLR4 receptors. MSC1 proinflammatory phenotype in human MSCs was associated with increased IL-6 and IL-8 and MSC2 regenerative phenotype was associated with increased CCL2 and CXCL10. MSC immunomodulatory function was assessed by measuring the ability of primed MSCs to suppress mitogen-stimulated T cell proliferation. Peripheral blood monocytes were isolated using CD14 MACs positive selection, differentiated into macrophages, and polarized using interferon-gamma (IFN-gamma). Polarization was confirmed by increased gene expression of TNFalpha, CCL2, and CXCL10. Inflammatory macrophages were co-cultured with MSCs for 6h, and the resultant MSC phenotype was analyzed as described above. Both TLR3 and TLR4 priming and co-culture of MSCs with inflammatory macrophages resulted in increased expression of IL-6, CCL2, and CXCL10 in MSCs. Both TLR3 and TLR4 priming or exposure of MSCs to inflammatory macrophages significantly (p<0.05) enhanced their immunomodulatory function, demonstrated by a decrease in T cell proliferation in the presence of poly I:C primed MSCs (11%), LPS primed MSCs (7%), or MSCs exposed to inflammatory macrophages (12%), compared to unstimulated MSCs. Additionally, MHC class II positive MSCs tended to have a greater magnitude of response to priming compared to MHC class II negative MSCs. These results suggest that MSCs can be activated by a variety of inflammatory stimuli, but the recipient injured tissue bed in chronic injuries may not contain sufficient inflammatory signals to activate MSC immunomodulatory function. Enhancement of MSCs immunomodulatory function through inflammatory priming prior to clinical application might improve the therapeutic effect of MSC treatments. PMID- 29249314 TI - Protective effect of a polyvalent influenza DNA vaccine in pigs. AB - BACKGROUND: Influenza A virus in swine herds represents a major problem for the swine industry and poses a constant threat for the emergence of novel pandemic viruses and the development of more effective influenza vaccines for pigs is desired. By optimizing the vector backbone and using a needle-free delivery method, we have recently demonstrated a polyvalent influenza DNA vaccine that induces a broad immune response, including both humoral and cellular immunity. OBJECTIVES: To investigate the protection of our polyvalent influenza DNA vaccine approach in a pig challenge study. METHODS: By intradermal needle-free delivery to the skin, we immunized pigs with two different doses (500MUg and 800MUg) of an influenza DNA vaccine based on six genes of pandemic origin, including internally expressed matrix and nucleoprotein and externally expressed hemagglutinin and neuraminidase as previously demonstrated. Two weeks following immunization, the pigs were challenged with the 2009 pandemic H1N1 virus. RESULTS: When challenged with 2009 pandemic H1N1, 0/5 vaccinated pigs (800MUg DNA) became infected whereas 5/5 unvaccinated control pigs were infected. The pigs vaccinated with the low dose (500MUg DNA) were only partially protected. The DNA vaccine elicited binding , hemagglutination inhibitory (HI) - as well as cross-reactive neutralizing antibody activity and neuraminidase inhibiting antibodies in the immunized pigs, in a dose-dependent manner. CONCLUSION: The present data, together with the previously demonstrated immunogenicity of our influenza DNA vaccine, indicate that naked DNA vaccine technology provides a strong approach for the development of improved pig vaccines, applying realistic low doses of DNA and a convenient delivery method for mass vaccination. PMID- 29249316 TI - Immunization of guinea pigs with Salmonella delivered anti-Brucella formulation reduces organs bacterial load and mitigates histopathological consequences of Brucella abortus 544 challenge. AB - With an objective to generate safe and effective anti-Brucella vaccine, an attenuated live Salmonella Typhimurium vector delivering heterologous Brucella immunogenic proteins SOD, Omp19, BLS, and PrpA formulated with purified Brucella abortus lipopolysaccharide was evaluated on a guinea pig model. This model represents high susceptibility to Brucella infections and showed similarities in reproducing human pathologies. On safety perspectives, the vaccine formulation induced no observable alterations on general health and histology of the vaccinated guinea pigs. Upon virulent strain 544 challenge, a protective index of 1.52 was observed based on differential splenic counts. Post-challenge histopathology revealed that Brucella induced microgranulomas and fatty degenerations were prominent in the organs of non-immunized animals as compared to immunized animals. With these findings, it is suggestive that this live Brucella-free vaccine formulation is safe and protective on a sensitive guinea pig model and may be suitable for further human-related vaccine trials. PMID- 29249317 TI - Chicken macrophages infected with Salmonella (S.) Enteritidis or S. Heidelberg produce differential responses in immune and metabolic signaling pathways. AB - Protein kinases act in coordination with phosphatases to control protein phosphorylation and regulate signaling pathways and cellular processes involved in nearly every functions of cell life. Salmonella are known to manipulate the host kinase network to gain entrance and survive inside host cells. The effect of Salmonella infection on the host kinase network has been studied in mammalian cells, but information is largely lacking in chicken immune cells. Our previous study indicated that chicken macrophage cells respond differentially to different Salmonella strains. In order to better understand the interaction between chicken macrophages and Salmonella, we used a peptide array-based kinome analysis to identify cellular process and signaling pathways that may play a critical role in the outcome of Salmonella infection. The kinome assay was performed on chicken HD11 macrophages collected at 1.5, 3, and 7h post-infection (hpi) with either S. Heidelberg or S. Enteritidis. A large number of peptides show significantly changed phosphorylation (p<=0.05) during the infection: 390, 449, and 575 peptides for S. Enteritidis and 185, 470, and 442 for S. Heidelberg at 1.5, 3, and 7 hpi, respectively. Many pathways involved in immunity, signal transduction, cellular process, and metabolism were significantly altered, in some case differentially, during the infection by the two Salmonella strains. Particularly, effects on lysosome process, iNOS, CARD9, NLRP3, and MAPK pathway provide significant insight to the inter play between pathogens and chicken macrophage cells during the infection. PMID- 29249318 TI - Defining resilience to mycobacterial disease: Characteristics of survivors of ovine paratuberculosis. AB - Paratuberculosis is an insidious, chronic disease of ruminants that has significant animal welfare implications and reduces on-farm profitability globally. Not all animals exposed to the causative pathogen, Mycobacterium avium subspecies paratuberculosis (MAP), succumb to disease and this unique, long-term trial was designed to track animals that were resilient. The advantages of understanding immune protection include the management option to retain resilient individuals in a herd/flock and the potential for deliberate manipulation of the host immune response using novel vaccines. Twenty sheep experimentally exposed to MAP and 10 controls were monitored for 2.5 years during which the condition progressed, resembling natural disease development. Cellular and humoral immune parameters and faecal MAP shedding were examined regularly and disease outcomes were classified at necropsy, based on the presence of viable MAP and histopathological lesions in intestinal tissues, either at the termination of the trial or when animals were culled due to weight loss. There were distinct characteristics, such as an early strong IFNgamma response, that differentiated resilient sheep from susceptible individuals prior to the onset of clinical disease. Faecal MAP shedding and serum antibody level, commonly used to diagnose disease, were more ambiguous. The former was transient in the majority of resilient animals and therefore should not be used for diagnosis of MAP infection in younger animals. Remarkably, the serum antibody level in some resilient animals was higher than the usual positive-negative cut-off for disease diagnosis at multiple samplings throughout the trial. Consequently the antibody response in resistance to paratuberculosis requires further investigation. PMID- 29249319 TI - Innate immune responses of equine monocytes cultured in equine platelet lysate. AB - Platelet lysate (PL) has been extensively used for the laboratory expansion of human mesenchymal stem cells (MSC) in order to avoid fetal bovine serum (FBS) which has been associated with immune-mediated host reactions and transmission of bovine-origin microbial contaminants. Before suggesting the routine use of PL for MSC culture, we wanted to further investigate whether PL alone might trigger inflammatory responses when exposed to reactive white blood cells such as monocytes. Our objectives were to evaluate the inflammatory profile of equine monocytes cultured with equine PL (ePL) and to determine if ePL can modulate the expression of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated monocytes. In a first experiment, equine monocytes were isolated and incubated with donor horse serum (DHS), FBS, six individual donors ePL or pooled ePL from all horses. In a second experiment, monocytes were stimulated with E. coli LPS in the presence of 1, 5 or 10% DHS and/or pooled ePL. After 6h of incubation, cell culture supernatants were assayed via ELISA for production of the pro inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and Interleukin 1beta (IL-1beta) as well as for the anti-inflammatory Interleukin 10 (IL-10). Equine monocytes incubated with pooled ePL produced significantly less TNF-alpha and significantly more IL-10 than monocytes incubated in FBS. A statistically significant difference was not identified for the production of IL-1beta. The second experiment showed that pooled ePL added to LPS-stimulated equine monocytes resulted in a significant reduction in TNF-alpha and IL-1beta production. IL-10 production was not significantly upregulated by the addition of ePL to LPS stimulated monocytes. Finally, the addition of ePL to LPS-stimulated monocytes in the presence of various concentrations of DHS resulted to statistically significant decrease of TNF-alpha and IL-1beta compared to the control groups. This is the first study to demonstrate that ePL suppresses the release of pro inflammatory cytokines from stimulated equine monocytes. These results encourage further exploration of PL as a homologous media substitute for FBS but also opens the possibility of investigating its use as means to suppress cell-mediated inflammation. PMID- 29249320 TI - The expression profile of sterile alpha motif and histidine-aspartate domain containing protein 1 (SAMHD1) in feline tissues. AB - SAMHD1 restricts lentiviruses by limiting availability of deoxynucleoside triphosphates for reverse transcription. HIV-2 and SIV have virion-associated proteins to counteract SAMHD1. Cats have an ortholog to human SAMHD1 and the FIV is restricted by human SAMHD1, but expression of feline SAMHD1 is unknown. Using a whole-body tissue microarray consisting of 24 tissues for immunohistochemistry, SAMHD1 expression was identified in a wide range of cat tissues. SAMHD1 was most strongly expressed in skin and mucosal epithelium, and in hemolymphatic and spermatogenic tissues. Both nuclear and cytoplasmic expression was detected. Feline cell lines susceptible to FIV infection also highly expressed SAMHD1. Preferential expression of SAMHD1 at sites of viral entry and replication supports a role for feline SAMHD1 in restricting FIV. PMID- 29249321 TI - Immune function in arctic mammals: Natural killer (NK) cell-like activity in polar bear, muskox and reindeer. AB - Natural killer (NK) cells are a vital part of the rapid and non-specific immune defense against invading pathogens and tumor cells. This study evaluated NK cell like activity by flow cytometry for the first time in three ecologically and culturally important Arctic mammal species: polar bear (Ursus maritimus), muskox (Ovibos moschatus) and reindeer (Rangifer tarandus). NK cell-like activity for all three species was most effective against the mouse lymphoma cell line YAC-1, compared to the human leukemia cell line K562; NK cell response displayed the characteristic increase in cytotoxic activity when the effector:target cell ratio increased. Comparing NK activity between fresh and cryopreserved mouse lymphocytes revealed little to no difference in function, highlighting the applicability of cryopreserving cells in field studies. The evaluation of this important innate immune function in Arctic mammals can contribute to future population health assessments, especially as pollution-induced suppression of immune function may increase infectious disease susceptibility. PMID- 29249322 TI - Saponin Quil A up-regulates type I interferon-regulated gene and type I and II interferon expressions which are suppressed by porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses innate immune response following infection of myeloid antigen-presenting cells. Poor innate immune response results in weak and delayed PRRSV-specific adaptive immunity, and facilitates PRRSV replication, pathogenesis, and persistent infection. Numerous efforts have been made to enhance the effective innate and adaptive immune defenses to PRRSV, however, only a few attempts have so far elicited satisfactory results. The present study aims to evaluate in vitro the potential of saponin quil A to enhance the expression of type I interferon (IFN) regulated gene, type I and II IFNs, and pro-inflammatory cytokines in PRRSV inoculated peripheral blood mononuclear cells (PBMC). Naive PBMC from four PRRSV seronegative pigs were inoculated with PRRSV and subsequently stimulated with quil A in the absence or presence of either polyinosinic:polycytidylic acid (poly IC) or lipopolysaccharide (LPS). The mRNA expression levels of myxovirus resistance 1 (Mx1), interferon regulatory factor 3 (IRF3), IRF7, 2'-5' oligoadenylatesynthetase 1 (OAS1), stimulator of interferon genes (STING), osteopontin (OPN), IFNalpha, IFNbeta, IFNgamma, interleukin-2 (IL-2), IL-10, IL 13, tumor necrosis factor alpha (TNFalpha), and transforming growth factor beta (TGFbeta) were evaluated by real-time PCR. Compared with uninoculated PBMC, PRRSV significantly suppressed expression of all immune parameters except IL-2, IL-10, IL-13, and TGFbeta. When compared with PRRSV-inoculated PBMC, stimulation with quil A significantly enhanced Mx1, IRF3, IRF7, OAS1, STING, IFNbeta, and IFNgamma mRNA expressions, and significantly reduced TGFbeta mRNA expression. Our findings thus suggest that quil A has a potential to up-regulate the expression of type I IFN-regulated gene and type I and II IFNs which are suppressed by PRRSV. Therefore, it may serve as an effective immunostimulator for potentiating the innate immune defense to PRRSV. PMID- 29249323 TI - Characterization and comparative analysis of immunoglobulin lambda chain diversity in a neonatal porcine model. AB - To elucidate how antigen exposure and selection shape the porcine antibody repertoires, we investigated the immunoglobulin lambda light chain (IGL) gene repertoires of the binary cross-bred (Yorkshire*Landrace) pig at different developmental stages, pre-suckle neonate (0days), wean piglet (35days) and growing pig (75days) under normal farming conditions. Immunoglobulin lambda light transcript (IGLV-J-C) clones of the peripheral blood mononuclear cells (PBMCs) from these different developmental stages were assessed for IGL combination, junction and sequence diversity. Previous research has revealed that IGLV8 plays a major role in immunity during the early fetus stage and that IGLV3 accounts for 30% of the neonatal IGLV repertoires. Here, we found that the antibody profile exhibited salient features at different stages. The usage of the IGLV3-3 subclass gradually decreased during development, in contrast, the utilization of IGLV8 (IGLV8-10, IGLV8-13 and IGLV8-18), which started in the fetal stage, has increased in the growing stage. Moreover, the junction diversity, as measured by the IGLV hypervariable complementarity determining region 3 (CDR3L) lengths, was constant during the different stages. The complete junction mutation ratio clearly increased in the growing pig compared to that in the younger pig. Our data provide new insights into the postnatal porcine IGLV repertoires maturation which can lay the foundation for porcine antibody gene research. PMID- 29249324 TI - DNA shedding in non-small-cell lung cancer: useful to assess? PMID- 29249325 TI - Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: a genomic study. AB - BACKGROUND: Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs. METHODS: Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR-activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma. Patients took 20-240 mg osimertinib per day until disease progression or development of intolerable side effects. Plasma samples were collected every 6 weeks and tumour tissue biopsy was done at study entry and was optional after disease progression. We tested samples for resistance mechanisms, including EGFR-activating, Thr790Met, and Cys797Ser mutations, and assessed associations with overall survival, progression-free survival, and survival after disease progression. FINDINGS: Of 71 patients enrolled in AURA, 53 were eligible for this analysis. Median progression-free survival was 11.1 months (95% CI 8.4-13.9) and overall survival was 16.9 months (11.7-29.1). 47 patients had disease progression. Median overall survival after osimertinib progression was 5.4 months (95% CI 4.1-10.0). Plasma samples were available for 40 patients after disease progression. 12 (30%) of these had the Thr790Met mutation (four of whom also had Cys797Ser mutations). Patients without detectable EGFR-activating mutations in plasma before treatment had the best overall and post-progression survival (22.4 months, 95% CI 15.6-not reached, and 10.8 months, 7.2-not reached, respectively). Loss of the Thr790Met mutation but presence of EGFR-activating mutations in plasma were associated with the shortest progression-free survival (median 2.6 months, 95% CI 1.3-not reached). In 22 post progression tumour samples, we found one squamous cell and two small-cell transformations. We detected Thr790Met in nine (50%) of 18 samples, Cys797Ser in two (17%) of 12, cMET amplification in five (50%) of ten, BRAF mutation in one (8%) of 13, and KRAS mutation in one (8%) of 13. INTERPRETATION: Heterogeneous resistance mechanisms developed in patients receiving osimertinib. Differences in resistance mechanisms might dictate future development strategies for osimertinib in clinical trials. FUNDING: AstraZeneca, Taiwan Ministry of Science and Technology. PMID- 29249326 TI - Patient-Related Risk Factors for Periprosthetic Ankle Joint Infection: An Analysis of 6977 Total Ankle Arthroplasties. AB - Periprosthetic joint infection (PJI) after total ankle arthroplasty (TAA) is a devastating complication that often results in explantation to resolve the infection. The purpose of the present investigation was to determine the patient related risk factors for PJI after TAA. A national insurance database was queried for patients undergoing TAA using the Current Procedural Terminology and International Classification of Diseases, ninth revision, procedure codes from 2005 to 2012. Patients undergoing TAA with concomitant fusion procedures or more complex forefoot procedures were excluded. PJI within 6 months was then assessed using the International Classification of Diseases, ninth revision, codes for diagnosis or treatment of postoperative PJI. Multivariate binomial logistic regression analysis was performed to evaluate the patient-related risk factors for PJI. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each risk factor, with p < .05 considered statistically significant. A total of 6977 patients were included in the present study. Of these 6977 patients, 294 (4%) had a diagnosis of, or had undergone a procedure for, PJI. The independent risk factors for PJI included age <65 years (OR 1.44; p = .036), body mass index <19 kg/m2 (OR 3.35; p = .013), body mass index >30 kg/m2 (OR 1.49; p = .034), tobacco use (OR 1.59; p = .002), diabetes mellitus (OR 1.36; p = .017), inflammatory arthritis (OR 2.38; p < .0001), peripheral vascular disease (OR 1.64; p < .0001), chronic lung disease (OR 1.37; p = .022), and hypothyroidism (OR 1.32; p = .022). The independent patient-related risk factors identified in the present study should help guide physicians and patients considering elective TAA and develop risk stratification algorithms that could decrease the risk of deep, postoperative infection. PMID- 29249327 TI - Monitoring and controlling ovarian function in the rhinoceros. AB - Despite their size and potentially dangerous demeanor, the rhinoceros has been a preferred subject of wildlife reproductive scientists. Several factors contribute to this taxon's popularity including the ability to utilize insightful tools like non-invasive hormone metabolite monitoring and transrectal ultrasonography, the necessity for mate introductions to coincide with the female's estrus when breeding certain species or individuals, and the desire to develop assisted reproductive technologies to facilitate the genetic management and ultimate sustainability of small, managed populations in human care. The resulting profusion of rhinoceros reproductive studies has revealed significant species specific characteristics and exposed the prevalence of aberrant reproductive activity within this taxon. Of equal importance, it has guided necessary intervention and enhanced our success in overcoming challenges associated with breeding rhinoceroses. PMID- 29249328 TI - Monitoring and controlling follicular activity in camelids. AB - This paper reviews that state of our knowledge concerning follicular wave dynamics, monitoring and manipulation. All camelids have overlapping follicular waves in absence of ovulation which is induced by a seminal plasma factor (betaNGF). The interval between follicular waves varies. The size of the ovulatory follicle varies between 11 and 25 mm in camels and between in 6 and 13 mm in South American Camelids. The interval between induction of ovulation and next ovulatory follicle is 15 +/- 1 day for all camelids. Follicular activity is best monitored by transrectal ultrasonography. Progesterone therapy for 7-15 days seems to suppress follicular dominance but does not completely inhibit follicular recruitment. Combination of estradiol and progesterone seems to provide better control of follicular activity. Both methods have provided variable results in the synchronization of follicular waves. Combination of induction of ovulation with GnRH and luteolysis at predetermined times shows some promise in synchronization of follicular dominance. These synchronization protocols require further investigation in order to provide practical approaches for fixed-time breeding. Ovarian superstimulation with FSH and eCG alone or in combination is somewhat successful. The best results are obtained when treatment is initiated at the emergence of a new follicular wave after induction of ovulation or following treatment with progesterone for 7-14 days. However, response remains extremely variable particularly in terms of ovulation rate and number of recovered embryos. Sources of this variability need to be studied including the effects of season, nutrition, doses and frequency of administration of gonadotropin. PMID- 29249330 TI - Is there a crystal ball for predicting the outcome of cardiomyopathy surgery? Preload recruitable stroke work, may be a possible candidate. PMID- 29249329 TI - Comparative ovarian function and reproductive monitoring of endangered mammals. AB - The ability to track gonadal function is facilitated by the use of endocrine and ultrasound techniques, both of which are important tools for optimizing reproduction and ensuring sustainability of fragile populations. With so many species now endangered, captive breeding is increasingly viewed as a means to sustain important insurance populations. As reproduction is key to species survival, understanding how to control and monitor ovarian function is vital. Through decades of study, we now have a greater understanding of the diversity, and plasticity, of reproductive mechanisms across taxa. Even within related species, there are marked differences in seasonal, environmental and social influences on ovarian cycle dynamics, ovulatory mechanisms, and responses to assisted reproductive/ovulation induction protocols. For most wildlife species, endocrine function is assessed noninvasively through analyses of hormones or their metabolites excreted in urine or feces. Perhaps it should not be surprising then, that major differences in metabolism and routes of excretion exist, not only between species, but also among hormone types within a species. This means that a species by species, and sometimes hormone by hormone, approach is essential for developing effective reproductive monitoring and control strategies. Over the past 30 years, our laboratory has developed and validated a number of reproductive assay techniques, which has led to our amassing a database of ovarian cycle dynamics on over 100 species. This paper presents an overview of ovarian physiology, and summarizes comparative ovarian function research on some of our most well-studied species: felids, elephants, rhinos, tapirs and the giant panda, and how that information has been used to aid ex situ management. Each of these species represents a range of reproductive strategies, from the highly seasonal, monestrus giant panda to the aseasonal, polyestrus elephant. Some species exhibit spontaneous ovulations, while others are induced ovulators or both, with variations in ovarian cycle lengths that range from a few days to several months. These differences reinforce the need for studies of species basic biology to optimize breeding strategies. PMID- 29249331 TI - Exploring the Fear of Birth Scale in a mixed population of women of childbearing age-A Swedish pilot study. AB - AIM: The aim of this pilot study was to explore the Fear of Birth Scale in a mixed sample of women of childbearing age, by investigating the levels of childbirth fear and the content of women's thoughts when completing the scale. METHODS: A cross-sectional mixed method study of 179 women who completed a short questionnaire and a think aloud interview. RESULTS: The mean score of the Fear of Birth Scale was 40.80 (SD 27.59) and 28.5% were classified as having fear of childbirth (>=60). The internal consistency showed a Cronbach's alpha>0.92, and a mean inter-item correlation of 0.85.The highest scores were found in women younger than 25 years (mean 60.10), foreign-born women (mean 54.30) and women who did not have any previous children (48.72). The lowest scores were found in women who had recently given birth (mean 34.82) and women older than 35 years (mean 34.85). The content analysis categorization matrix clearly accommodated all 436 statements into the five pre-existing categories. The largest categories were: the content of fear and worry with 138 statements and strategies to cope with fear or worry (122 statements). CONCLUSION: The Fear of Birth Scale seems to be a useful instrument for different subgroups of women. The construct of fear of childbirth may be universally understood and experienced by women of childbearing age irrespective of whether they are currently pregnant, have recently given birth or do not have children. Identifying fear of birth is important in clinical practice in order to support women's reproductive needs. PMID- 29249333 TI - Beyond Hemoglobin: Screening for Malaria Host Factors. AB - Severe malaria is caused by the Apicomplexan parasite Plasmodium falciparum, and results in significant global morbidity and mortality, particularly among young children and pregnant women. P. falciparum exclusively infects human erythrocytes during clinical illness, and several natural erythrocyte polymorphisms are protective against severe malaria. Since erythrocytes are enucleated and lack DNA, genetic approaches to understand erythrocyte determinants of malaria infection have historically been limited. This review highlights recent advances in the use of hematopoietic stem cells to facilitate genetic screening for malaria host factors. While challenges still exist, this approach holds promise for gaining new insights into host-pathogen interactions in malaria. PMID- 29249334 TI - Advancing Sex- and Gender-Informed Approaches to Health in an Academic Medical Center. PMID- 29249335 TI - An automated dose tracking system for adaptive radiation therapy. AB - BACKGROUND AND OBJECTIVE: The implementation of adaptive radiation therapy (ART) into routine clinical practice is technically challenging and requires significant resources to perform and validate each process step. The objective of this report is to identify the key components of ART, to illustrate how a specific automated procedure improves efficiency, and to facilitate the routine clinical application of ART. METHODS: Data was used from patient images, exported from a clinical database and converted to an intermediate format for point-wise dose tracking and accumulation. The process was automated using in-house developed software containing three modularized components: an ART engine, user interactive tools, and integration tools. The ART engine conducts computing tasks using the following modules: data importing, image pre-processing, dose mapping, dose accumulation, and reporting. In addition, custom graphical user interfaces (GUIs) were developed to allow user interaction with select processes such as deformable image registration (DIR). A commercial scripting application programming interface was used to incorporate automated dose calculation for application in routine treatment planning. Each module was considered an independent program, written in C++or C#, running in a distributed Windows environment, scheduled and monitored by integration tools. RESULTS: The automated tracking system was retrospectively evaluated for 20 patients with prostate cancer and 96 patients with head and neck cancer, under institutional review board (IRB) approval. In addition, the system was evaluated prospectively using 4 patients with head and neck cancer. Altogether 780 prostate dose fractions and 2586 head and neck cancer dose fractions went processed, including DIR and dose mapping. On average, daily cumulative dose was computed in 3 h and the manual work was limited to 13 min per case with approximately 10% of cases requiring an additional 10 min for image registration refinement. CONCLUSIONS: An efficient and convenient dose tracking system for ART in the clinical setting is presented. The software and automated processes were rigorously evaluated and validated using patient image datasets. Automation of the various procedures has improved efficiency significantly, allowing for the routine clinical application of ART for improving radiation therapy effectiveness. PMID- 29249332 TI - Nuclear Long Noncoding RNAs: Key Regulators of Gene Expression. AB - A significant portion of the human genome encodes genes that transcribe long nonprotein-coding RNAs (lncRNAs). A large number of lncRNAs localize in the nucleus, either enriched on the chromatin or localized to specific subnuclear compartments. Nuclear lncRNAs participate in several biological processes, including chromatin organization, and transcriptional and post-transcriptional gene expression, and also act as structural scaffolds of nuclear domains. Here, we highlight recent studies demonstrating the role of lncRNAs in regulating gene expression and nuclear organization in mammalian cells. In addition, we update current knowledge about the involvement of the most-abundant and conserved lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), in gene expression control. PMID- 29249336 TI - Pulsatile flow of non-Newtonian blood fluid inside stenosed arteries: Investigating the effects of viscoelastic and elastic walls, arteriosclerosis, and polycythemia diseases. AB - BACKGROUND AND OBJECTIVE: In this study, the interaction of pulsatile blood flow with the viscoelastic walls of the axisymmetric artery is numerically investigated for different severities of stenosis. The geometry of artery is modeled by an axisymmetric cylindrical tube with a symmetric stenosis in a two dimensional case. The effects of stenosis severity on the axial velocity profile, pressure distribution, streamlines, wall shear stress, and wall radial displacement for the viscoelastic artery are also compared to the elastics artery. Furthermore, the effects of atherosclerosis and polycythemia diseases on the hemodynamics and the mechanical behavior of arterial walls are investigated. METHODS: The pulsatile flow of non-Newtonian blood is simulated inside the viscoelastic artery using the COMSOL Multiphysics software (version 5) and by employing the fluid-structure interaction (FSI) method and the arbitrary Lagrangian-Eulerian (ALE) method. Moreover, finite element method (FEM) is used to solve the governing equations on the unstructured grids. For modeling the non Newtonian blood fluid and the viscoelastic arterial wall, the modified Casson model, and generalized Maxwell model are used, respectively. RESULTS: According to the results, with stenosis severity increasing from 25% to 75% at the time of maximum volumetric flow rate, the maximum value of axial velocity and its gradient increase 7.9 and 19.6 times, and the maximum wall shear stress of viscoelastic wall increases 24.2 times in the constriction zone. With the progression of the atherosclerosis disease (fivefold growth of arterial elastic modulus), the wall radial displacement of viscoelastic arterial walls decreases nearly 40%. CONCLUSIONS: In this study, axial velocity profile, pressure distribution, streamlines, wall radial displacement, and wall shear stress were examined for different percentages of stenosis (25%, 50%, and 75%). The atherosclerosis disease was investigated by the fivefold growth of viscoelastic arterial elastic modulus and polycythemia disease was examined by the 21-fold increase in the yield stress of the blood fluid. Furthermore, the comparison of results between the elastic and viscoelastic arterial walls shows that the wall radial displacement for viscoelastic artery is lower than that for the elastic artery as much as 21.7% for the severe stenosis of 75%. PMID- 29249337 TI - Arteriovenous ratio and papilledema based hybrid decision support system for detection and grading of hypertensive retinopathy. AB - BACKGROUND AND OBJECTIVES: Hypertensive Retinopathy (HR) is a retinal disease which happened due to consistent high blood pressure (hypertension). In this paper, an automated system is presented that detects the HR at various stages using arteriovenous ratio and papilledema signs through fundus retinal images. METHODS: The proposed system consists of two modules i.e. vascular analysis for calculation of arteriovenous ratio and optic nerve head (ONH) region analysis for papilledema. First module uses a set of hybrid features in Artery or Vein (A/V) classification using support vector machine (SVM) along with its radial basis function (RBF) kernel for arteriovenous ratio. In second module, proposed system performs analysis of ONH region for possible signs of papilledema. This stage utilizes different features along with SVM and RBF for classification of papilledema. RESULTS: The first module of proposed method shows average accuracies of 95.10%, 95.64% and 98.09%for images of INSPIRE-AVR, VICAVR, and local dataset respectively. The second module of proposed method achieves average accuracies of 95.93% and 97.50% on STARE and local dataset respectively. CONCLUSIONS: The system finally utilizes results from both modules to grade HR with good results. The presented system is a novel step towards automated detection and grading of HR disease and can be used as clinical decision support system. PMID- 29249338 TI - Wavelet coherence-based classifier: A resting-state functional MRI study on neurodynamics in adolescents with high-functioning autism. AB - BACKGROUND AND OBJECTIVE: The autism spectrum disorder (ASD) diagnosis requires a long and elaborate procedure. Due to the lack of a biomarker, the procedure is subjective and is restricted to evaluating behavior. Several attempts to use functional MRI as an assisting tool (as classifier) have been reported, but they barely reach an accuracy of 80%, and have not usually been replicated or validated with independent datasets. Those attempts have used functional connectivity and structural measurements. There is, nevertheless, evidence that not the topology of networks, but their temporal dynamics is a key feature in ASD. We therefore propose a novel MRI-based ASD biomarker by analyzing temporal brain dynamics in resting-state fMRI. METHODS: We investigate resting-state fMRI data from 2 independent datasets of adolescents: our in-house data (12 ADS, 12 controls), and the Leuven dataset (12 ASD, 18 controls, from Leuven university). Using independent component analysis we obtain relevant socio-executive resting state networks (RSNs) and their associated time series. Upon these time series we extract wavelet coherence maps. Using these maps, we calculate our dynamics metric: time of in-phase coherence. This novel metric is then used to train classifiers for autism diagnosis. Leave-one-out cross validation is applied for performance evaluation. To assess inter-site robustness, we also train our classifiers on the in-house data, and test them on the Leuven dataset. RESULTS: We distinguished ASD from non-ASD adolescents at 86.7% accuracy (91.7% sensitivity, 83.3% specificity). In the second experiment, using Leuven dataset, we also obtained the classification performance at 86.7% (83.3% sensitivity, and 88.9% specificity). Finally we classified the Leuven dataset, with classifiers trained with our in-house data, resulting in 80% accuracy (100% sensitivity, 66.7% specificity). CONCLUSIONS: This study shows that change in the coherence of temporal neurodynamics is a biomarker of ASD, and wavelet coherence-based classifiers lead to robust and replicable results and could be used as an objective diagnostic tool for ASD. PMID- 29249339 TI - Leveraging hospital big data to monitor flu epidemics. AB - BACKGROUND AND OBJECTIVE: Influenza epidemics are a major public health concern and require a costly and time-consuming surveillance system at different geographical scales. The main challenge is being able to predict epidemics. Besides traditional surveillance systems, such as the French Sentinel network, several studies proposed prediction models based on internet-user activity. Here, we assessed the potential of hospital big data to monitor influenza epidemics. METHODS: We used the clinical data warehouse of the Academic Hospital of Rennes (France) and then built different queries to retrieve relevant information from electronic health records to gather weekly influenza-like illness activity. RESULTS: We found that the query most highly correlated with Sentinel network estimates was based on emergency reports concerning discharged patients with a final diagnosis of influenza (Pearson's correlation coefficient (PCC) of 0.931). The other tested queries were based on structured data (ICD-10 codes of influenza in Diagnosis-related Groups, and influenza PCR tests) and performed best (PCC of 0.981 and 0.953, respectively) during the flu season 2014-15. This suggests that both ICD-10 codes and PCR results are associated with severe epidemics. Finally, our approach allowed us to obtain additional patients' characteristics, such as the sex ratio or age groups, comparable with those from the Sentinel network. CONCLUSIONS: Conclusions: Hospital big data seem to have a great potential for monitoring influenza epidemics in near real-time. Such a method could constitute a complementary tool to standard surveillance systems by providing additional characteristics on the concerned population or by providing information earlier. This system could also be easily extended to other diseases with possible activity changes. Additional work is needed to assess the real efficacy of predictive models based on hospital big data to predict flu epidemics. PMID- 29249340 TI - Fully automated segmentation of a hip joint using the patient-specific optimal thresholding and watershed algorithm. AB - BACKGROUND AND OBJECTIVE: Automated segmentation with high accuracy and speed is a prerequisite for FEA-based quantitative assessment with a large population. However, hip joint segmentation has remained challenging due to a narrow articular cartilage and thin cortical bone with a marked interindividual variance. To overcome this challenge, this paper proposes a fully automated segmentation method for a hip joint that uses the complementary characteristics between the thresholding technique and the watershed algorithm. METHODS: Using the golden section method and load path algorithm, the proposed method first determines the patient-specific optimal threshold value that enables reliably separating a femur from a pelvis while removing cortical and trabecular bone in the femur at the minimum. This provides regional information on the femur. The watershed algorithm is then used to obtain boundary information on the femur. The proximal femur can be extracted by merging the complementary information on a target image. RESULTS: For eight CT images, compared with the manual segmentation and other segmentation methods, the proposed method offers a high accuracy in terms of the dice overlap coefficient (97.24 +/- 0.44%) and average surface distance (0.36 +/- 0.07 mm) within a fast timeframe in terms of processing time per slice (1.25 +/- 0.27 s). The proposed method also delivers structural behavior which is close to that of the manual segmentation with a small mean of average relative errors of the risk factor (4.99%). CONCLUSION: The segmentation results show that, without the aid of a prerequisite dataset and users' manual intervention, the proposed method can segment a hip joint as fast as the simplified Kang (SK)-based automated segmentation, while maintaining the segmentation accuracy at a similar level of the snake-based semi-automated segmentation. PMID- 29249341 TI - Modified histogram-based segmentation and adaptive distance tracking of sperm cells image sequences. AB - Proper recognition and tracking of microscopic sperm cells in video images are vital steps of male infertility diagnosis and treatment. The segmentation and detection of sperms in microscopic image analysis is a complicate process as a result of their small sizes, fast movements, and considerable collisions. Histogram-based thresholding schemes are very popular for this purpose, since they are quite fast and provide almost acceptable results. This paper proposes a combined method for sperm cells detection, which consists of a non-linear pre processing stage, a histogram-based thresholding algorithm, and a tracking method based on an adaptive distance scheme. The results of conducted experiments verify the superiority of the proposed scheme with incorporated Kittler algorithm compared to the other competitive methods in the majority of cases. PMID- 29249342 TI - Predictions of ocular changes caused by diabetes in glaucoma patients. AB - BACKGROUND AND OBJECTIVE: This paper builds different neural network models with simple topologies, having one or two hidden layers which were subsequently employed in the prediction of ocular changes progression in patients with diabetes associated with primer open-angle glaucoma. MATERIAL AND METHODS: For attempting to indicate whether there is a relationship between glaucoma and diabetes, a simulation method, based on artificial neural networks (ANN), Jordan Elman networks (JEN) type, in particular, was applied in conjunction with clinical observation. The study was conducted on a sample of 101 eyes with open angle glaucoma included and, in each case, the patients had associated diabetes mellitus. A high degree of accuracy was exhibited by the models, demonstrating the potential effectiveness of this artificial intelligence technique for predicting ocular changes associated with diabetes. The parameters considered in this study for modelling purpose were: glaucoma age, diabetes age, C/D ratio (cup/disk size), glycated haemoglobin level (HbA1c), intraocular pressure (IOP), patient age, mean deviation (MD) and LENS appearance. RESULTS: Relatively simple models, feed-forward neural networks with one or two intermediate layers, provided clinically meaningful data in direct modelling, the probability of correct answers being of 95%. Inverse modelling was also performed, in which MD depreciation was the output parameter. High accuracy was exhibited, in this case, with Jordan Elman networks, with the confidence interval of +/-15%. CONCLUSIONS: The neural models have demonstrated the possibility of their use in successfully predicting the relationship between glaucoma and diabetes in a real clinical environment. PMID- 29249343 TI - A universal deep learning approach for modeling the flow of patients under different severities. AB - BACKGROUND AND OBJECTIVE: The Accident and Emergency Department (A&ED) is the frontline for providing emergency care in hospitals. Unfortunately, relative A&ED resources have failed to keep up with continuously increasing demand in recent years, which leads to overcrowding in A&ED. Knowing the fluctuation of patient arrival volume in advance is a significant premise to relieve this pressure. Based on this motivation, the objective of this study is to explore an integrated framework with high accuracy for predicting A&ED patient flow under different triage levels, by combining a novel feature selection process with deep neural networks. METHODS: Administrative data is collected from an actual A&ED and categorized into five groups based on different triage levels. A genetic algorithm (GA)-based feature selection algorithm is improved and implemented as a pre-processing step for this time-series prediction problem, in order to explore key features affecting patient flow. In our improved GA, a fitness-based crossover is proposed to maintain the joint information of multiple features during iterative process, instead of traditional point-based crossover. Deep neural networks (DNN) is employed as the prediction model to utilize their universal adaptability and high flexibility. In the model-training process, the learning algorithm is well-configured based on a parallel stochastic gradient descent algorithm. Two effective regularization strategies are integrated in one DNN framework to avoid overfitting. All introduced hyper-parameters are optimized efficiently by grid-search in one pass. RESULTS: As for feature selection, our improved GA-based feature selection algorithm has outperformed a typical GA and four state-of-the-art feature selection algorithms (mRMR, SAFS, VIFR, and CFR). As for the prediction accuracy of proposed integrated framework, compared with other frequently used statistical models (GLM, seasonal-ARIMA, ARIMAX, and ANN) and modern machine models (SVM-RBF, SVM-linear, RF, and R-LASSO), the proposed integrated "DNN-I-GA" framework achieves higher prediction accuracy on both MAPE and RMSE metrics in pairwise comparisons. CONCLUSIONS: The contribution of our study is two-fold. Theoretically, the traditional GA-based feature selection process is improved to have less hyper-parameters and higher efficiency, and the joint information of multiple features is maintained by fitness-based crossover operator. The universal property of DNN is further enhanced by merging different regularization strategies. Practically, features selected by our improved GA can be used to acquire an underlying relationship between patient flows and input features. Predictive values are significant indicators of patients' demand and can be used by A&ED managers to make resource planning and allocation. High accuracy achieved by the present framework in different cases enhances the reliability of downstream decision makings. PMID- 29249344 TI - Computational methods for corpus callosum segmentation on MRI: A systematic literature review. AB - BACKGROUND AND OBJECTIVE: The corpus callosum (CC) is the largest white matter structure in the brain and has a significant role in central nervous system diseases. Its volume correlates with the severity and/or extent of neurodegenerative disease. Even though the CC's role has been extensively studied over the last decades, and different algorithms and methods have been published regarding CC segmentation and parcellation, no reviews or surveys covering such developments have been reported so far. To bridge this gap, this paper presents a systematic literature review of computational methods focusing on CC segmentation and parcellation acquired on magnetic resonance imaging. METHODS: IEEExplore, PubMed, EBSCO Host, and Scopus database were searched with the following search terms: ((Segmentation OR Parcellation) AND (Corpus Callosum) AND (DTI OR MRI OR Diffusion Tensor Imag* OR Diffusion Tractography OR Magnetic Resonance Imag*)), resulting in 802 publications. Two reviewers independently evaluated all articles and 36 studies were selected through the systematic literature review process. RESULTS: This work reviewed four main segmentation methods groups: model-based, region-based, thresholding, and machine learning; 32 different validity metrics were reported. Even though model-based techniques are the most recurrently used for the segmentation task (13 articles), machine learning approaches achieved better outcomes of 95% when analyzing mean values for segmentation and classification metrics results. Moreover, CC segmentation is better established in T1-weighted images, having more methods implemented and also being tested in larger datasets, compared with diffusion tensor images. CONCLUSIONS: The analyzed computational methods used to perform CC segmentation on magnetic resonance imaging have not yet overcome all presented challenges owing to metrics variability and lack of traceable materials. PMID- 29249345 TI - Analysis and multiclass classification of pathological knee joints using vibroarthrographic signals. AB - BACKGROUND AND OBJECTIVE: Vibroarthrography (VAG) is a method developed for sensitive and objective assessment of articular function. Although the VAG method is still in development, it shows high accuracy, sensitivity and specificity when comparing results obtained from controls and the non-specific, knee-related disorder group. However, the multiclass classification remains practically unknown. Therefore the aim of this study was to extend the VAG method classification to 5 classes, according to different disorders of the patellofemoral joint. METHODS: We assessed 121 knees of patients (95 knees with grade I-III chondromalacia patellae, 26 with osteoarthritis) and 66 knees from 33 healthy controls. The vibroarthrographic signals were collected during knee flexion/extension motion using an acceleration sensor. The genetic search algorithm was chosen to select the most relevant features of the VAG signal for classification. Four different algorithms were used for classification of selected features: logistic regression with automatic attribute selection (SimpleLogistic in Weka), multilayer perceptron with sigmoid activation function (MultilayerPerceptron), John Platt's sequential minimal optimization algorithm implementation of support vector classifier (SMO) and random forest tree (RandomForest). The generalization error of classification algorithms was evaluated by stratified 10-fold cross-validation. RESULTS: We obtained levels of accuracy and AUC metrics over 90%, more than 93% sensitivity and more than 84% specificity for the logistic regression-based method (SimpleLogistic) for a 2 class classification. For the 5-class method, we obtained 69% and 90% accuracy and AUC respectively, and sensitivity and specificity over 91% and 69%. CONCLUSIONS: The results of this study confirm the high usefulness of quantitative analysis of VAG signals based on classification techniques into normal and pathological knees and as a promising tool in classifying signals of various knee joint disorders and their stages. PMID- 29249346 TI - Surface electromyography based muscle fatigue detection using high-resolution time-frequency methods and machine learning algorithms. AB - BACKGROUND AND OBJECTIVE: Surface electromyography (sEMG) based muscle fatigue research is widely preferred in sports science and occupational/rehabilitation studies due to its noninvasiveness. However, these signals are complex, multicomponent and highly nonstationary with large inter-subject variations, particularly during dynamic contractions. Hence, time-frequency based machine learning methodologies can improve the design of automated system for these signals. METHODS: In this work, the analysis based on high-resolution time frequency methods, namely, Stockwell transform (S-transform), B-distribution (BD) and extended modified B-distribution (EMBD) are proposed to differentiate the dynamic muscle nonfatigue and fatigue conditions. The nonfatigue and fatigue segments of sEMG signals recorded from the biceps brachii of 52 healthy volunteers are preprocessed and subjected to S-transform, BD and EMBD. Twelve features are extracted from each method and prominent features are selected using genetic algorithm (GA) and binary particle swarm optimization (BPSO). Five machine learning algorithms, namely, naive Bayes, support vector machine (SVM) of polynomial and radial basis kernel, random forest and rotation forests are used for the classification. RESULTS: The results show that all the proposed time frequency distributions (TFDs) are able to show the nonstationary variations of sEMG signals. Most of the features exhibit statistically significant difference in the muscle fatigue and nonfatigue conditions. The maximum number of features (66%) is reduced by GA and BPSO for EMBD and BD-TFD respectively. The combination of EMBD- polynomial kernel based SVM is found to be most accurate (91% accuracy) in classifying the conditions with the features selected using GA. CONCLUSIONS: The proposed methods are found to be capable of handling the nonstationary and multicomponent variations of sEMG signals recorded in dynamic fatiguing contractions. Particularly, the combination of EMBD- polynomial kernel based SVM could be used to detect the dynamic muscle fatigue conditions. PMID- 29249347 TI - Enhancement of dynamic myocardial perfusion PET images based on low-rank plus sparse decomposition. AB - BACKGROUND AND OBJECTIVE: The absolute quantification of dynamic myocardial perfusion (MP) PET imaging is challenged by the limited spatial resolution of individual frame images due to division of the data into shorter frames. This study aims to develop a method for restoration and enhancement of dynamic PET images. METHODS: We propose that the image restoration model should be based on multiple constraints rather than a single constraint, given the fact that the image characteristic is hardly described by a single constraint alone. At the same time, it may be possible, but not optimal, to regularize the image with multiple constraints simultaneously. Fortunately, MP PET images can be decomposed into a superposition of background vs. dynamic components via low-rank plus sparse (L + S) decomposition. Thus, we propose an L + S decomposition based MP PET image restoration model and express it as a convex optimization problem. An iterative soft thresholding algorithm was developed to solve the problem. Using realistic dynamic 82Rb MP PET scan data, we optimized and compared its performance with other restoration methods. RESULTS: The proposed method resulted in substantial visual as well as quantitative accuracy improvements in terms of noise versus bias performance, as demonstrated in extensive 82Rb MP PET simulations. In particular, the myocardium defect in the MP PET images had improved visual as well as contrast versus noise tradeoff. The proposed algorithm was also applied on an 8-min clinical cardiac 82Rb MP PET study performed on the GE Discovery PET/CT, and demonstrated improved quantitative accuracy (CNR and SNR) compared to other algorithms. CONCLUSIONS: The proposed method is effective for restoration and enhancement of dynamic PET images. PMID- 29249348 TI - Automated pterygium detection method of anterior segment photographed images. AB - BACKGROUND AND BJECTIVE: Pterygium is an ocular disease caused by fibrovascular tissue encroachment onto the corneal region. The tissue may cause vision blurring if it grows into the pupil region. In this study, we propose an automatic detection method to differentiate pterygium from non-pterygium (normal) cases on the basis of frontal eye photographed images, also known as anterior segment photographed images. METHODS: The pterygium screening system was tested on two normal eye databases (UBIRIS and MILES) and two pterygium databases (Australia Pterygium and Brazil Pterygium). This system comprises four modules: (i) a preprocessing module to enhance the pterygium tissue using HSV-Sigmoid; (ii) a segmentation module to differentiate the corneal region and the pterygium tissue; (iii) a feature extraction module to extract corneal features using circularity ratio, Haralick's circularity, eccentricity, and solidity; and (iv) a classification module to identify the presence or absence of pterygium. System performance was evaluated using support vector machine (SVM) and artificial neural network. RESULTS: The three-step frame differencing technique was introduced in the corneal segmentation module. The output image successfully covered the region of interest with an average accuracy of 0.9127. The performance of the proposed system using SVM provided the most promising results of 88.7%, 88.3%, and 95.6% for sensitivity, specificity, and area under the curve, respectively. CONCLUSION: A basic platform for computer-aided pterygium screening was successfully developed using the proposed modules. The proposed system can classify pterygium and non-pterygium cases reasonably well. In our future work, a standard grading system will be developed to identify the severity of pterygium cases. This system is expected to increase the awareness of communities in rural areas on pterygium. PMID- 29249349 TI - Fully automated determination of arch angle on weight-bearing foot radiograph. AB - BACKGROUND AND OBJECTIVE: Flatfeet can be evaluated by measuring the calcaneal fifth metatarsal angle on a weight-bearing lateral foot radiograph. This study aimed to develop an automated method for determining the calcaneal-fifth metatarsal angle on weight-bearing lateral foot radiograph. METHOD: The proposed method comprises four processing steps: (1) identification of the regions including the calcaneus and fifth metatarsal bones in a foot image; (2) delineation of the contours of the calcaneus and the fifth metatarsal; (3) determination of the tangential lines of the two bones from the contours; and (4) determination of the calcaneal-fifth metatarsal angle between the two tangential lines as arch angle. RESULTS: The proposed method was evaluated using 300 weight bearing lateral foot radiographs. The arch angles determined by the proposed method were compared with those measured by a radiologist, and the errors between the automatically and manually determined angles were used to evaluate the precision of the method. The average error in the proposed method was found to be 1.12 degrees +/- 1.57 degrees In the study, in 73.33% of the cases, the arch angles could be determined automatically without redrawing any tangential lines; in 23.00% of the cases, the angles would be correctly determined by redrawing one of the tangential lines; further, in only 3.67% of the cases, both the calcaneal and fifth metatarsal tangential lines needed to be redrawn to determine the arch angles. CONCLUSION: The results revealed that the proposed method has potential for assisting doctors in measuring the arch angles on weight-bearing lateral foot radiographs more efficiently. PMID- 29249350 TI - A Diadochokinesis-based expert system considering articulatory features of plosive consonants for early detection of Parkinson's disease. AB - BACKGROUND AND OBJECTIVE: A new expert system is proposed to discriminate healthy people from people with Parkinson's Disease (PD) in early stages by using Diadochokinesis tests. METHODS: The system is based on temporal and spectral features extracted from the Voice Onset Time (VOT) segments of /ka/ syllables, whose boundaries are delimited by a novel algorithm. For comparison purposes, the approach is applied also to /pa/ and /ta/ syllables. In order to develop and validate the system, a voice recording database composed of 27 individuals diagnosed with PD and 27 healthy controls has been collected. This database reflects an average disease stage of 1.85 +/- 0.55 according to Hoehn and Yahr scale. System design is based on feature extraction, feature selection and Support Vector Machine learning. RESULTS: The novel VOT algorithm, based on a simple and computationally efficient approach, demonstrates accurate estimation of VOT boundaries on /ka/ syllables for both healthy and PD-affected speakers. The PD detection approach based on /k/ plosive consonant achieves the highest discrimination capability (92.2% using 10-fold cross-validation and 94.4% in the case of leave-one-out method) in comparison to the corresponding versions based on the other two plosives (/p/ and /t/). CONCLUSION: A high accuracy has been obtained on a database with a lower average disease stage than previous articulatory databases presented in the literature. PMID- 29249351 TI - Fast segmentation of the left ventricle in cardiac MRI using dynamic programming. AB - BACKGROUND AND OBJECTIVE: The segmentation of the left ventricle (LV) in cardiac magnetic resonance imaging is a necessary step for the analysis and diagnosis of cardiac function. In most clinical setups, this step is still manually performed by cardiologists, which is time-consuming and laborious. This paper proposes a fast system for the segmentation of the LV that significantly reduces human intervention. METHODS: A dynamic programming approach is used to obtain the border of the LV. Using very simple assumptions about the expected shape and location of the segmentation, this system is able to deal with many of the challenges associated with this problem. The system was evaluated on two public datasets: one with 33 patients, comprising a total of 660 magnetic resonance volumes and another with 45 patients, comprising a total of 90 volumes. Quantitative evaluation of the segmentation accuracy and computational complexity was performed. RESULTS: The proposed system is able to segment a whole volume in 1.5 seconds and achieves an average Dice similarity coefficient of 86.0% and an average perpendicular distance of 2.4 mm, which compares favorably with other state-of-the-art methods. CONCLUSIONS: A system for the segmentation of the left ventricle in cardiac magnetic resonance imaging is proposed. It is a fast framework that significantly reduces the amount of time and work required of cardiologists. PMID- 29249352 TI - Quantitative breast density analysis using tomosynthesis and comparison with MRI and digital mammography. AB - BACKGROUND AND OBJECTIVE: Breast density at mammography has been used as markers of breast cancer risk. However, newly introduced tomosynthesis and computer-aided quantitative method could provide more reliable breast density evaluation. METHODS: In the experiment, 98 tomosynthesis image volumes were obtained from 98 women. For each case, an automatic skin removal was used and followed by a fuzzy c-mean (FCM) classifier which separated the fibroglandular tissues from other tissues in breast area. Finally, percent of breast density and breast volume were calculated and the results were compared with MRI. In addition, the percent of breast density and breast area of digital mammography calculated using the software Cumulus (University of Toronto, Toronto, ON, Canada.) were also compared with 3-D modalities. RESULTS: Percent of breast density and breast volume, which were computed from tomosynthesis, MRI and digital mammography were 17.37% +/- 4.39% and 607.12 cm3 +/- 323.01 cm3, 20.3% +/- 8.6% and 537.59 cm3 +/- 287.74 cm3, and 12.03% +/- 4.08%, respectively. There were significant correlations on breast density as well as volume between tomosynthesis and MRI (R = 0.482 and R = 0.805), tomosynthesis and breast density with breast area of digital mammography (R = 0.789 and R = 0.877), and MRI and breast density with breast area of digital mammography (R = 0.482 and R = 0.857) (all P values < .001). CONCLUSIONS: Breast density and breast volume evaluated from tomosynthesis, MRI and breast density and breast area of digital mammographic images have significant correlations and indicate that tomosynthesis could provide useful 3-D information on breast density through proposed method. PMID- 29249353 TI - Improving healthcare management with data science. PMID- 29249354 TI - Frozen in a Moment in Time: The Experiences of Mothers Being Diagnosed With HIV Infection. PMID- 29249355 TI - Corrigendum to "Emissions of particulate-bound elements from biodiesel and ultra low sulfur diesel: Size distribution and risk assessment" [Chemosphere 90 2013 1005-1015]. PMID- 29249356 TI - Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to Chromatin Signaling. AB - Cell fate transitions involve rapid gene expression changes and global chromatin remodeling, yet the underlying regulatory pathways remain incompletely understood. Here, we identified the RNA-processing factor Nudt21 as a novel regulator of cell fate change using transcription-factor-induced reprogramming as a screening assay. Suppression of Nudt21 enhanced the generation of induced pluripotent stem cells, facilitated transdifferentiation into trophoblast stem cells, and impaired differentiation of myeloid precursors and embryonic stem cells, suggesting a broader role for Nudt21 in cell fate change. We show that Nudt21 directs differential polyadenylation of over 1,500 transcripts in cells acquiring pluripotency, although only a fraction changed protein levels. Remarkably, these proteins were strongly enriched for chromatin regulators, and their suppression neutralized the effect of Nudt21 during reprogramming. Collectively, our data uncover Nudt21 as a novel post-transcriptional regulator of cell fate and establish a direct, previously unappreciated link between alternative polyadenylation and chromatin signaling. PMID- 29249357 TI - IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure. AB - Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the limiters of energy expenditure are largely unknown. Here, we show that ablation of the anti-inflammatory cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Assay for transposase accessible chromatin sequencing (ATAC-seq), ChIP-seq, and RNA-seq reveal that IL 10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and C/EBPbeta recruitment to key enhancer regions. These findings expand our understanding of the relationship between inflammatory signaling pathways and adipose tissue function and provide insight into the physiological control of thermogenesis that could inform future therapy. PMID- 29249358 TI - Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells. AB - B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to antigen-experienced B cells. Indeed, NKT cells secrete an early wave of IL-4 and constitute up to 70% of the total IL-4 producing cells during the initial stages of infection. Importantly, the requirement of this innate immunity arm appears to be evolutionarily conserved because early NKT and IL-4 gene signatures also positively correlate with the levels of neutralizing antibodies in Zika-virus-infected macaques. In conclusion, our data support a model wherein a pre-TfH wave of IL-4 secreted by interfollicular NKT cells triggers the seeding of germinal center cells and serves as an innate link between viral infection and B cell immunity. PMID- 29249359 TI - R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling. AB - R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity associated protein (FTO) activity, thereby increasing global N6-methyladenosine (m6A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/MYC/CEBPA signaling. PMID- 29249361 TI - Pharmacogenomics of GPCR Drug Targets. AB - Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (~34%) Food and Drug Administration (FDA)-approved drugs and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug- and effector-binding sites in the human population. We experimentally show that certain variants of MU-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants could increase prescription precision, improving patients' quality of life, and relieve the economic and societal burden due to variable drug responsiveness. VIDEO ABSTRACT. PMID- 29249360 TI - Intrinsic Immunity Shapes Viral Resistance of Stem Cells. AB - Stem cells are highly resistant to viral infection compared to their differentiated progeny; however, the mechanism is mysterious. Here, we analyzed gene expression in mammalian stem cells and cells at various stages of differentiation. We find that, conserved across species, stem cells express a subset of genes previously classified as interferon (IFN) stimulated genes (ISGs) but that expression is intrinsic, as stem cells are refractory to interferon. This intrinsic ISG expression varies in a cell-type-specific manner, and many ISGs decrease upon differentiation, at which time cells become IFN responsive, allowing induction of a broad spectrum of ISGs by IFN signaling. Importantly, we show that intrinsically expressed ISGs protect stem cells against viral infection. We demonstrate the in vivo importance of intrinsic ISG expression for protecting stem cells and their differentiation potential during viral infection. These findings have intriguing implications for understanding stem cell biology and the evolution of pathogen resistance. PMID- 29249363 TI - Tackling Hypotheticals in Helminth Genomes. AB - Advancements in genome sequencing have led to the rapid accumulation of uncharacterized 'hypothetical proteins' in the public databases. Here we provide a community perspective and some best-practice approaches for the accurate functional annotation of uncharacterized genomic sequences. PMID- 29249362 TI - [Miliary tuberculosis]. AB - INTRODUCTION: Tuberculosis miliary is a severe and rare form of tuberculosis. It is often due to a haematogenous spread of the bacillus of Koch and represents less than 2 % of tuberculosis. PATIENTS AND METHODS: We conducted a retrospective study of 81 cases of tuberculous miliary collected at the Department of respiratory diseases of the Ibn Rochd university hospital in Casablanca between September 2003 and November 2016. RESULTS: A female predominance was noted with 58 % of the cases. The average age was 36 years. The history of tuberculosis was found in eight cases and tuberculous tuberculosis in eleven cases, postpartum in five cases, diabetes in three cases and trisomy 21 in one case. The clinical picture was dominated by altered general status in all cases, and fever in 69 cases (86 %). Chest x-ray showed a miliary aspect in all cases, cardiomegaly in two cases, pyopneumothorax in three cases, and opacities excavated in five other cases. The intradermal tuberculin reaction, performed in all cases, was positive in 26 cases, and sputum oscillations were positive in 21 cases. The dissemination report found cerebromeningeal involvement in nine cases, with cerebral tuberculomas in five cases, pericarditis in four cases, mediastinal and peripheral adenopathies in nine cases each. Bouchut tubercles were found in nine cases. Antibacillary therapy was started as a matter of urgency, according to the national TB control program with the old regimen (2SHRZ/7RH) and the new regimen (2RHZEb/7RH) in all cases. The outcome was good in 55 cases (68.9 %), 17 patients were lost to follow-up, and 11 deaths were reported. CONCLUSION: We insist on this work on the severity of the tuberculous miliary and the need for early and urgent therapeutic management. PMID- 29249364 TI - Resting state fMRI studies in SPG4-linked hereditary spastic paraplegia. AB - OBJECTIVE: The study aimed to investigate the functional alterations of spontaneous brain activity in patients with spastic paraplegia type 4 (SPG4), and the relationship with the severity of spasticity. METHODS: Twelve patients with SPG4 and ten healthy controls underwent resting-state functional magnetic resonance imaging (rs-fMRI). Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) were used to characterize regional neural function, and functional connectivity (FC) was used to evaluate the functional integration of the brain network. RESULTS: Compared to healthy controls, patients with SPG4 exhibited significantly decreased ReHo values in the medial superior frontal gyrus. ALFF values were lower in left insula and higher in right precentral and superior frontal gyrus of the patient group. Increased ALFF values in the right precentral gyrus negatively correlated with Spastic Paraplegia Rating Scale (SPRS) scores in the patients. The connectivity study showed that the SPG4 patients had one increased FC between the left middle frontal gyrus to the left middle orbitofrontal gyrus, and pairs of decreased FC. CONCLUSIONS: Our findings confirm that the baseline regional neural activity and interregional connectivity are altered in many brain regions in patients with SPG4, and certain changes are correlated with disease severity, providing potential diagnostic markers for SPG4. PMID- 29249365 TI - Comparative study of ipsilesional and contralesional repetitive transcranial magnetic stimulations for acute infarction. AB - BACKGROUND AND PURPOSE: Repetitive transcranial magnetic stimulation (rTMS) is reported to improve chronic post-stoke hemiparesis. However, application of rTMS during the acute phase of post-stroke has not fully been investigated. We investigated the safety and the efficacy of intermittent theta-burst stimulation (iTBS) of the affected motor cortex and 1-Hz stimulation of the unaffected hemisphere during the acute phase in patients with hemiparesis due to capsular infarction. METHODS: Twenty one patients who met the study criteria were randomly assigned to receive, starting within 7days after stroke onset and for a period of 10days, iTBS of the affected motor cortex hand area (n=8), 1-Hz stimulation of the unaffected motor cortex hand area (n=7), or sham stimulation (n=6). Upper limb motor function was evaluated before rTMS and 12weeks after onset of the stroke. Evaluation was based on the Fugl-Meyer Assessment (FMA), Stroke Impairment Assessment Set (SIAS), Modified Ashworth Scale (MAS), grip strength, and motor evoked potential (MEP) amplitude in the first dorsal interosseous (FDI) muscle. RESULTS: Both iTBS applied to the affected motor cortex hand area and 1 Hz stimulation applied to the unaffected motor cortex hand area enhanced motor recovery. In comparison to sham stimulation, iTBS increased the SIAS finger function test score, and 1-Hz stimulation decreased the MAS wrist and finger score. CONCLUSIONS: Ipsilesional iTBS and contralesional 1-Hz stimulation applied during the acute phase of stroke have different effects: ipsilesional iTBS improves movement of the affected limb, whereas contralesional 1-Hz stimulation reduces spasticity of the affected limb. PMID- 29249366 TI - Successful endovascular therapy for multiple intracranial arterial stenosis associated with medically intractable giant cell arteritis. PMID- 29249367 TI - Parallel fluctuation of anti-neurofascin 155 antibody levels with clinico electrophysiological findings in patients with chronic inflammatory demyelinating polyradiculoneuropathy. AB - BACKGROUND: The long-term clinical course and closely related biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with anti neurofascin 155 (NF155) antibodies remain to be elucidated. METHODS: We retrospectively studied the longitudinal clinical courses of three Japanese male anti-NF155 antibody-positive CIDP patients. Anti-NF155 antibody levels were measured by flow cytometry using HEK293 cell lines stably expressing human NF155. RESULTS: All three patients presented with chronic progressive sensorimotor disturbance, with ages at onset of 16, 26, and 34years old, and they were followed for 58, 31, and 38months, respectively, from the onset. All patients had postural tremor and generalized decreased deep tendon reflexes. Peak cerebrospinal fluid protein levels were >400mg/dl, and nerve conduction studies (NCS) showed severe demyelination patterns. Combined immunotherapies including intravenous immunoglobulin, plasma exchange, corticosteroids, and other immunosuppressants ameliorated clinical severity and NCS abnormalities, with improvements of >10kg in grip strength and at least 20% in F-wave latencies. However, their symptoms exacerbated after the immunotherapies were tapered. Anti NF155 antibody levels varied in parallel with the clinical and electrophysiological changes, or preceded them. CONCLUSION: The patients' clinical courses suggest that anti-NF155 antibody levels and NCS findings could be disease activity markers in anti-NF155 antibody-positive CIDP. PMID- 29249368 TI - Nationwide trends in medical expenditures among adults with epilepsy: 2003-2014. AB - OBJECTIVE: Healthcare expenditure among adults with epilepsy is high. There is a paucity of published data on trends in the nationwide economic impact of epilepsy. This study examines trends in healthcare expenditures and components in U.S. adults with epilepsy between 2003 and 2014. METHODS: We analyzed 12years of data representing a weighted sample of 1,942,413U.S. adults aged >=18years with epilepsy using Medical Expenditure Panel Survey Household Component (MEPS-HC), 2003-2014 data. We used a novel two-part model (adjusting for demographic, comorbidity, and time) to estimate the incremental healthcare expenditures by epilepsy status. Pre and post Affordable Care Act era costs were compared. RESULTS: Overall unadjusted annual mean medical expenditures for patients with epilepsy was $15,324. Individuals with epilepsy had nearly three times higher overall unadjusted mean expenditure than those without epilepsy ($15,324, 95%CI: 2778-17,871 vs. $5824, 95%CI: 5722-5926). The unadjusted annual mean medical expenditure decreased over time from $17,994 (95% CI $10,754-$25,234) in 2003/2006 to $13,848 (95% CI: $11,371-$16,324) in 2011/2014; a trend driven primarily by a decrease in inpatient expenditures from $5613 to $4113. Having a diagnosis of epilepsy increased health expenditure by $8598 which was 2.5 to 6 times greater than the equivalent incremental health expenditures for other selected comorbidities. Healthcare expenditure among adults with epilepsy was $4083 lower in the post- Affordable Care Act. CONCLUSION: Over the last decade, individuals with epilepsy incurred significantly higher medical expenditures than those without epilepsy, but overall healthcare expenditure decreased over time due to a decrease in inpatient expenditures. PMID- 29249369 TI - A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency. AB - Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD type I) is an autosomal recessive disorder of the electron transfer flavoprotein function characterized by a severe clinical and biochemical phenotype, including congenital abnormalities with unresponsiveness to riboflavin treatment as distinguishing features. From a retrospective study, relying mainly on metabolic data, we have identified a novel mutation, c.1067G>A (p.Gly356Glu) in exon 8 of ETFDH, in three South African Caucasian MADD patients with the index patient presenting the hallmark features of type I MADD and two patients with compound heterozygous (c.1067G>A+c.1448C>T) mutations presenting with MADD type III. SDS PAGE western blot confirmed the significant effect of this mutation on ETFDH structural instability. The identification of this novel mutation in three families originating from the South African Afrikaner population is significant to direct screening and strategies for this disease, which amongst the organic acidemias routinely screened for, is relatively frequently observed in this population group. PMID- 29249370 TI - A Japanese family with mutation in the proteinase inhibitor 12 L47P gene: A case report. PMID- 29249371 TI - Unilateral repetitive transcranial magnetic stimulation differentially affects younger and older adults completing a verbal working memory task. AB - Functional neuroimaging studies have found that lateralization of activity in the dorsolateral prefrontal cortex (dlPFC) is reduced with aging. In the present study, repetitive transcranial magnetic stimulation (rTMS) was used to disrupt dlPFC activity in order to test the relationship of dlPFC laterality and age in verbal working memory (WM). Young (n=36) and older (n=35) subjects received 1Hz rTMS (sham or active) to left or right dlPFC and WM performance was assessed pre- and post-stimulation via the n-back task. Significant increases in WM accuracy were observed following rTMS in the right dlPFC and sham conditions, but not with the left dlPFC stimulation. This was accompanied by a decrease in left P1 latency was also observed following left dlPFC stimulation. In contrast, older adults did not show a disruption in WM performance following rTMS in any of the stimulation conditions and exhibited increased left P3 amplitude following left stimulation. Our results show that changes in prefrontal laterality are evident with increasing age (left stimulation affects younger adults while older adults are not affected by stimulation) and this change is associated with specific neurophysiologic measures. PMID- 29249372 TI - Neural coupling between contralesional motor and frontoparietal networks correlates with motor ability in individuals with chronic stroke. AB - Movement is traditionally viewed as a process that involves motor brain regions. However, movement also implicates non-motor regions such as prefrontal and parietal cortex, regions whose integrity may thus be important for motor recovery after stroke. Importantly, focal brain damage can affect neural functioning within and between distinct brain networks implicated in the damage. The aim of this study is to investigate how resting state connectivity (rs-connectivity) within and between motor and frontoparietal networks are affected post-stroke in correlation with motor outcome. Twenty-seven participants with chronic stroke with unilateral upper limb deficits underwent motor assessments and magnetic resonance imaging. Participants completed the Chedoke-McMaster Stroke Assessment as a measure of arm (CMSA-Arm) and hand (CMSA-Hand) impairment and the Action Research Arm Test (ARAT) as a measure of motor function. We used a seed-based rs connectivity approach defining the motor (seed=contralesional primary motor cortex (M1)) and frontoparietal (seed=contralesional dorsolateral prefrontal cortex (DLPFC)) networks. We analyzed the rs-connectivity within each network (intra-network connectivity) and between both networks (inter-network connectivity), and performed correlations between: a) intra-network connectivity and motor assessment scores; b) inter-network connectivity and motor assessment scores. We found: a) Participants with high rs-connectivity within the motor network (between M1 and supplementary motor area) have higher CMSA-Hand stage (z=3.62, p=0.003) and higher ARAT score (z=3.41, p=0.02). Rs-connectivity within the motor network was not significantly correlated with CMSA-Arm stage (z=1.83, p>0.05); b) Participants with high rs-connectivity within the frontoparietal network (between DLPFC and mid-ventrolateral prefrontal cortex) have higher CMSA Hand stage (z=3.64, p=0.01). Rs-connectivity within the frontoparietal network was not significantly correlated with CMSA-Arm stage (z=0.93, p=0.03) or ARAT score (z=2.53, p=0.05); and c) Participants with high rs-connectivity between motor and frontoparietal networks have higher CMSA-Hand stage (rs=0.54, p=0.01) and higher ARAT score (rs=0.54, p=0.009). Rs-connectivity between the motor and frontoparietal networks was not significantly correlated with CMSA-Arm stage (rs=0.34, p=0.13). Taken together, the connectivity within and between the motor and frontoparietal networks correlate with motor outcome post-stroke. The integrity of these regions may be important for an individual's motor outcome. Motor-frontoparietal connectivity may be a potential biomarker of motor recovery post-stroke. PMID- 29249373 TI - Idiopathic cerebellar ataxia (IDCA): Diagnostic criteria and clinical analyses of 63 Japanese patients. AB - Cortical cerebellar atrophy (CCA) and multiple system atrophy with predominant cerebellar ataxia (MSA-C) are the two major forms of adult-onset sporadic ataxia. Contrary to MSA-C, there are neither diagnostic criteria nor neuroimaging features pathognomonic for CCA. Therefore, it is assumed that the category of CCA in the Japanese national registry include heterogeneous cerebellar ataxic disorders. To refine this category in more detail, we here used a clinical-based term, "idiopathic cerebellar ataxia (IDCA)", and proposed its diagnostic criteria. We collected 346 consecutive patients with the core features of the criteria (sporadic, insidious-onset and slowly progressive cerebellar ataxia in adults, and cerebellar atrophy on brain imaging). Of these, 212 (61.3%) were diagnosed with probable or possible MSA, and 30, who did not meet the diagnostic criteria for MSA at examination, were also excluded because of MRI findings suggestive of MSA. Twenty two were proven to have hereditary spinocerebellar ataxias by genetic testing, and 19 had secondary ataxias. Finally, the remaining 63 (18.2%) were diagnosed with IDCA. The mean (standard deviation) age at onset was 57.2 (10.8) years. Of these, 25 (39.7%) showed pure cerebellar ataxia, and the remaining 38 (60.3%) had some of extracerebellar features including abnormal tendon reflexes (46.0%), positive Babinski sign (9.5%), sensory disturbance (12.7%), cognitive impairment (9.5%), and involuntary movements (7.9%). Our results show that IDCA refined by the diagnostic criteria still includes clinically and genetically heterogeneous ataxic disorders. More extensive genetic analyses will be of significance for further clarification of this group. PMID- 29249374 TI - Anti-ZIC4 associated paraneoplastic cerebellar degeneration in a patient with both diffuse large B-cell lymphoma and incidental smoldering multiple myeloma. PMID- 29249375 TI - Towards remote monitoring of Parkinson's disease tremor using wearable motion capture systems. AB - The management of movement disorders is shifting from a centralized-clinical assessment towards remote monitoring and individualized therapy. While a variety of treatment options are available, ranging from pharmaceutical drugs to invasive neuromodulation, the clinical effects are inconsistent and often poorly measured. For instance, the lack of remote monitoring has been a major limitation to optimize therapeutic interventions for patients with Parkinson's Disease (PD). In this work, we focus on the assessment of full-body tremor as the most recognized PD symptom. Forty PD and twenty two healthy participants were recruited. The main assessment tool was an inertial measurement unit (IMU)-based motion capture system to quantify full-body tremor and to separate tremor-dominant from non tremor-dominant PD patients as well as from healthy controls. We developed a new measure and evaluated its clinical utility by correlating the results with the Unified Parkinson's Disease Rating Scale (UPDRS) scores as the gold standard. Significant correlation was observed between the UPDRS and the tremor severity scores for the selected tasks. The results suggest that it is feasible and clinically meaningful to utilize the suggested objective tremor score for the assessment of PD patients. Furthermore, this portable assessment tool could potentially be used in the home environment to monitor PD tremor and facilitate optimizing therapeutic interventions. PMID- 29249376 TI - Public stroke knowledge, awareness, and response to acute stroke: Multi-center study from 4 Egyptian governorates. AB - BACKGROUND AND PURPOSE: Acute stroke treatment has significantly improved over the years in Egypt. However, there is often notable delay in pre-hospital and in hospital management of acute stroke patients. The delay may be largely attributed to poor stroke knowledge and awareness of the general public and this study was aimed at the evaluation of the abovementioned factors. METHODS: Descriptive cross sectional study involving 1154 participants from 4 governorates using a questionnaire in Arabic, collecting sociodemographic data, participants' risk factors, and knowledge and stroke awareness (risk factors, symptoms, prevention, treatment and prognosis, action in response to acute stroke). Data were collected during the World stroke day October 29, 2015. RESULTS: Study participants were found to have a low level of awareness of stroke with median percent score of 35.7% and interquartile range (IQR) of 17.86. Higher income, level of education, having risk factors and knowing someone with stroke were significant predictors of a higher level of stroke awareness. CONCLUSION: In general, low public stroke awareness has been detected among Egyptians, and this is a call for healthcare authorities to invest in public education programmes among the Egyptian population. PMID- 29249377 TI - History and current difficulties in classifying inherited myopathies and muscular dystrophies. AB - The wide spectrum of hereditary muscular disorders leads to unavoidable difficulties in their classification, even for specialists. For this reason, new proposals are required that would ultimately replace our current rather complex classifications by a simpler structure. Our proposal will be limited to dystrophic and non-dystrophic myopathies (excluding metabolic disorders, mitochondriopathies, and channelopathies) for which similar proposals would also be relevant. Various genes (encoding structural proteins associated with the sarcolemma, nuclear membrane proteins, and proteins involved in myofiber metabolism have now been sequenced and mutations ascribed to specific forms of inherited muscular disorders. Based on our observations and our recent proposals in other neurogenetic conditions and informal discussions with specialists of neuromuscular disorders, the prerequisite for a simple and sound classification for inherited muscular disorders should encompass the clinical and pathological phenotypes (described in a simple and clear manner), the mode of inheritance, and the mutated gene. We think that the denomination of the different subtypes could be simplified considerably, although any new proposal of classification of muscular disorders will need to be discussed in the neurological and genetic communities. PMID- 29249378 TI - Cerebral amyloid angiopathy - The modified Boston criteria in clinical practice. AB - BACKGROUND: Early identification of patients with cerebral amyloid angiopathy (CAA) is relevant considering the increased risk for cerebral hemorrhage. A new set of diagnostic criteria for CAA was recently proposed, which include the presence of superficial siderosis. We aimed to assess the impact of applying these criteria regarding use of antithrombotic therapy. METHODS: Review of consecutive patients admitted to a Neurology Department from 2014 to 2016, with acute parenchymal or subarachnoid hemorrhage and/or atypical transient focal neurological episodes. Patients with a possible or probable CAA according to the original and modified Boston criteria were included. Information was collected regarding presentation, imaging findings and concomitant therapy. RESULTS: Among a total of 1436 admitted patients, 52 with acute hemorrhagic lesions or atypical TFNE were screened: 22 met criteria for CAA; 4 were deemed too young; 21 had other causes for hemorrhagic parenchymal lesions; and 5 had uncertain diagnosis. Using the modified Boston criteria, 8 patients fulfilled criteria for probable CAA and 14 for possible CAA. When we applied the original Boston criteria to the same patients, only 7 fulfilled criteria for probable CAA and 8 for possible CAA. Among the additional patients identified with the modified Boston criteria, 4 were using antithrombotic therapy. CONCLUSIONS: The use of the modified Boston criteria allowed for the identification of 7 additional patients, more than half of which were taking antithrombotic therapy. Systematic use of these criteria could have an important impact in clinical practice. Raising awareness on the different presentations of CAA among clinicians is of the utmost importance. PMID- 29249379 TI - Necrotic-hemorrhagic myelitis: A rare malignant variant of parainfectious acute disseminated encephalomyelitis in childhood. PMID- 29249380 TI - High resolution retinal scanning reveals regional structural differences between MS and NMOSD optic neuritis regardless of antibody status. AB - BACKGROUND: There is a need for biomarkers that can classify optic neuritis (ON) attacks as belonging to either neuromyelitis optica spectrum disorder with optic neuritis (NMOSD-ON) or relapsing remitting multiple sclerosis with optic neuritis (MS-ON). This study uses spectral domain optical coherence tomography (SD-OCT) data to perform a preliminary contrast between NMOSD-ON and MS-ON by analyzing peripapillary retinal nerve fiber layer and intra-macular layer patterns of injury. METHODS: In this cross-sectional study, we used SD-OCT to obtain peripapillary retinal nerve fiber layer and intra-macular layer data for 26 NMOSD ON, 25 MS-ON, and 26 healthy control (HC) age-matched eyes. Additionally, sub comparisons compared 11 NMOSD-ON eyes that were seronegative for IgG antibodies against aquaporin 4 (NMOSD-ON (-)) and 16 NMOSD-ON eyes that were seropositive (NMOSD-ON (+)) to age-matched MS-ON eyes. Layer thicknesses were assessed using an automated algorithm and were then statistically compared using generalized estimating equations to account for inter-eye correlations. RESULTS: Selective thinning was found in the pRNFL, mRNFL, and GCL in NMOSD-ON compared to MS-ON. Thinning in the pRNFL nasal sector was found to persist in both NMOSD-ON (-) (P=0.017) and NMOSD-ON (+) (P=0.021) compared to MS-ON. Thinning in the mRNFL temporal sector was found to persist in NMOSD-ON (+) compared to MS-ON. Diffuse thinning was found in the pRNFL, mRNFL, GCL and IPL in NMOSD-ON compared to HC, and while diffuse thinning was also found in the GCL and IPL in MS-ON compared to HC, selective thinning was found in the pRNFL and mRNFL. CONCLUSION: The nasal region of the pRNFL may be capable of distinguishing between NMOSD-ON and MS-ON regardless of antibody status. Additionally, NMOSD-ON may cause more profound nasal axonal and inferior arcuate neuronal degeneration compared to MS-ON. PMID- 29249381 TI - Co-localization of cystatin C and prosaposin in cultured neurons and in anterior horn neurons with amyotrophic lateral sclerosis. AB - Cystatin C (CST3) is a cysteine protease inhibitor that regulates lysosomal enzyme activity and is reported to be involved in the process of neurodegeneration. In the present study, we investigated whether CST3 interacts with other proteins and affects neurodegeneration in vitro and under disease conditions. We intended to identify any protein that interacts with CST3 by using a yeast two-hybrid system, and found prosaposin (PSAP) as a candidate protein. The binding of CST3 and PSAP was confirmed using an immunoprecipitation-based in vitro assay. An enzyme activity assay revealed that PSAP ameliorated CST3 mediated inhibition of cathepsin B activity. To investigate further, CST3 and PSAP were co-expressed in HeLa cells and in a human neuronal cell line (A1). Subsequent immunocytochemical studies demonstrated that they were co-localized mainly in the lysosomes. In spinal motor neurons of autopsy cases, both proteins showed a granular staining pattern. However, the staining intensities of CST3 and PSAP decreased in Bunina body-positive motor neurons of patients with amyotrophic lateral sclerosis (ALS). Further analysis with immunofluorescence staining revealed that CST3 was immunopositive in the inclusions of ALS motor neurons, where it was closely associated, and sometimes co-localized, with PSAP. CST3 immunoreactivity is recognized as a marker for Bunina bodies in ALS, suggesting that PSAP might also be included in Bunina bodies. The interaction of CST3 and PSAP may alter their functions, leading to motor neuron degeneration in ALS. PMID- 29249382 TI - A significant correlation between cauda equina conduction time and cerebrospinal fluid protein in chronic inflammatory demyelinating polyradiculoneuropathy. AB - We investigated the relationship between the involvement of the cauda equina in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and the increment of cerebrospinal fluid (CSF) protein. We measured cauda equina conduction time (CECT) in 14 CIDP patients using magnetic stimulation with a MATS coil. Statistical analysis revealed that CECT and CSF protein had a significant positive linear correlation. Conduction time of the peripheral nerve trunk, in contrast, had no significant linear correlation with CSF protein. We revealed that the involvement of the cauda equina and increment of CSF protein are closely related. In CIDP cases with elevated CSF protein, spinal nerves including the cauda equina are very likely involved. PMID- 29249383 TI - Neuropathic pain and SCI: Identification and treatment strategies in the 21st century. AB - Pain is a common complication in patients following spinal cord injury (SCI), with studies citing up to 80% of patients reporting some form of pain. Neuropathic pain (NP) makes up a substantial percentage of all pain symptoms in patients with SCI and is often complex. Given the high prevalence of NP in patients with SCI, proper identification and treatment is imperative. Indeed, identification of pain subtypes is a vital step toward determining appropriate treatment. A variety of pharmacological and non-pharmacological treatments can be undertaken including antiepileptics, tricyclic antidepressants, opioids, transcranial direct current stimulation, and invasive surgical procedures. Despite all the available treatment options and advances in the field of SCI medicine, providing adequate treatment of NP after SCI continues to be challenging. It is therefore extremely important for clinicians to have a strong foundation in the identification of SCI NP, as well as an understanding of appropriate treatment options. Here, we highlight the definitions and classification tools available for NP identification, and discuss current treatment options. We hope that this will not only provide a better understanding of NP for physicians in various subspecialties, but that it will also help guide future research on this subject. PMID- 29249384 TI - Intrathecal synthesis of oligoclonal IgG in patients with Viliuisk encephalomyelitis: The relationship between oligoclonal bands and clinical features. AB - Viliuisk encephalomyelitis (VE) is a neurodegenerative disease that afflicts aboriginal people of Yakutia in Siberia with unknown etiology. Oligoclonal IgG bands (OCBs) were discovered in the VE patients (Green et al., 2003). In this study we analysed the association of OCBs with clinical symptoms in 58 VE patients. Positive oligoclonal IgG are associated with a shorter duration of disease (p=0.002), older age of onset (p=0.023) and high frequency of main neurological VE symptoms such as dementia, frontal dysbasia, bulbar disorders, muscle atrophy and centrally caused pelvic disorders. Our results show that the OCBs in VE patients are associated with more severe central nervous system (CNS) damage and may cause secondary complications in the course of the disease. PMID- 29249385 TI - Rapid acquisition of acyclovir resistance in an immunodeficient patient with herpes simplex encephalitis. PMID- 29249386 TI - Eye movement abnormalities in AQP4-IgG positive neuromyelitis optica spectrum disorder. AB - BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) has been recognized as a disease characterized by severe visual afferent impairment. Abnormal eye movements, as the other important neuro-ophthalmic manifestation of NMOSD, were commonly overlooked. The aim of our study was to describe the ocular motor manifestations of AQP4-IgG positive NMOSD patients, and explore the value of eye movement abnormalities in the evaluation of the disabled disease. METHODS: Systemic clinical bedside ocular motor examinations and quantitative horizontal saccadic eye movement assessments were performed in 90 patients with AQP4-IgG positive NMOSD. General disability was evaluated by expanded disability status scale (EDSS). Vision-specific functional status was evaluated by the National Eye Institute-Visual Function Questionnaire (NEI-VFQ 25) and the 10-item neuro ophthalmic supplement. Brain magnetic resonance imaging (MRI) was acquired in all patients. RESULTS: In clinical examination, eye movement abnormalities were found in 38% of NMOSD patients. Abnormalities in the quantitative saccadic test were found in 67% of NMOSD patients, including 48% of patients with clinically normal eye movements. EDSS scores in patients with clinical eye movement abnormality were significantly higher (P<0.001) than those with a normal examination. The 10 item neuro-ophthalmic supplement score was significantly associated with quantitative saccadic eye movement abnormalities (P=0.031). CONCLUSIONS: Eye movement abnormalities were common in AQP4-IgG positive NMOSD patients, and were associated with general disability and specific visual handicap. The systemic clinical eye movement examination combined with the quantitative saccade test was easy to perform, and could provide additional useful information in evaluating NMOSD. PMID- 29249387 TI - Evaluation of comorbidities and health care resource use among patients with highly active neuromyelitis optica. AB - BACKGROUND: Neuromyelitis optica (NMO) is characterized by unpredictable attacks on the optic nerves and spinal cord, causing accumulations of neurological disability that may lead to blindness and paralysis. We examined comorbidities and health care use among patients with highly active NMO, defined as at least two relapses within 12months of the patient's first NMO encounter in the database. METHODS: This retrospective study of a US administrative claims database compared patients with highly active NMO to matched individuals without NMO. All outcomes, including Charlson Comorbidity Index (CCI) score, hospitalizations, and emergency department visits, were measured over the 12 month period following the patient's first NMO encounter in the database. RESULTS: A total of 1349 patients with NMO were identified. Of these, 134 had highly active NMO (80% female, mean age 45.6years) and were matched to 670 non NMO controls. Patients with highly active NMO had significantly greater comorbidity burden than non-NMO controls (mean CCI score: 4.1 versus 0.6; P<0.0001) and greater proportions of hospitalization (53.7% versus 4.0%; P<0.0001) and emergency department visits (60.5% versus 9.7%; P<0.0001). CONCLUSIONS: High occurrence of several acute and chronic conditions and extensive health care use highlight the significant medical burden among patients with highly active NMO. PMID- 29249389 TI - [Employment situation of general practitioners trained in a teaching unit of Alicante (Spain)]. PMID- 29249390 TI - Left Ventricular Assist Devices, Kidney Disease, and Dialysis. AB - Left ventricular assist devices (LVADs) improve survival in patients with advanced heart failure. As LVAD use increases, so do the number of patients with LVADs who also have kidney disease. However, there are only sparse data on how best to care for these patients. This review provides an overview of LVAD principles and indications, including blood pressure assessment and criteria for receipt of both destination and bridge to transplantation LVADs. Following LVAD implantation, kidney function may improve in the short term, particularly if cardiorenal physiology was present; in the longer term, data remain limited. Individuals with glomerular filtration rates chronically < 30mL/min/1.73m2, including those treated with maintenance dialysis, are generally ineligible for destination LVADs. However, select patients with advanced chronic kidney disease can be considered for LVADs as a bridge to heart or heart-kidney transplantation. Patients who develop acute kidney injury and require dialysis following LVAD implantation have high mortality rates. Although thrice-weekly hemodialysis is the most common modality for patients with LVADs, peritoneal dialysis and home hemodialysis are additional options. Peritoneal dialysis in particular may be associated with lower risk for bloodstream infection and fewer hemodynamic shifts. For those treated with hemodialysis, arteriovenous fistulas can successfully be used for vascular access. Many questions remain, including optimal anemia management and refinement of hemodialysis protocols for patients with an LVAD, and further research is needed in this field. PMID- 29249391 TI - Risk factors of secondary intervention for type II endoleaks in endovascular aneurysm repair: An 8-year single institution study. AB - BACKGROUND/OBJECTIVES: The natural history of type II endoleaks (T2ELs) is still not completely understood; however, it is widely accepted that those associated with aneurysmal sac growth are harmful. We aimed to review our experience with T2ELs in endovascular aneurysm repair (EVAR). METHODS: We retrospectively reviewed electronic medical records of all patients who underwent EVAR for infrarenal-type abdominal aortic aneurysms (AAAs) at a single institution from August 2007 to November 2015. Demographic and clinical data were collected. Preoperative contrast computed tomography scans were reviewed to determine aneurysm morphology (the maximum AAA diameter, number of lumbar arteries that enter the AAA sac, size of the inferior mesenteric artery (IMA), proximal neck diameter, proximal neck angle, existence of thrombosis, presence of atheroma, and existence of rupture). RESULTS: Sixty-two patients underwent EVAR; the follow-up duration was 35.82 +/- 31.89 months. There were statistically significant differences in female sex (P = .040), number of lumbar arteries on preoperative computed tomography scans (P = .010), and non-smoking status (P = .031) between patients with and without T2ELs. There were statistically significant differences in the maximum AAA diameter (P = .034) and size of the IMA (P = .043) between patients with and without secondary intervention in T2EL. There was one mortality after EVAR but no mortality associated with T2ELs. CONCLUSIONS: A more judicious approach that considers risk factors of T2ELs is needed before EVAR. The risk of secondary intervention in patients developing a T2EL after EVAR could increase with the maximum AAA diameter >=7 cm or IMA >=3 mm. PMID- 29249392 TI - Clinical impact of margin status on survival and recurrence pattern after curative-intent surgery for pancreatic cancer. AB - BACKGROUND/OBJECTIVE: The definition of R0 resection for invasive pancreatic ductal carcinoma (IPDC) is important. However, there are different definitions among several countries in the world. METHODS: From 2001 to 2015, 100 consecutive patients with IPDC who underwent pancreatic resection in our hospital were enrolled. We compared survival and recurrence patterns between the R0 group and R1 group based on the UICC (Union for International Cancer Control) classification (current-R0 vs. current-R1) and based on our revised classification, which defines R0 as a surgical margin of >1 mm (revised-R0 vs. revised-R1). RESULTS: The 100 patients comprised 58 males and 42 females, and their median age was 70 [32-87]. There were 84 patients in the current-R0 group and 43 in the revised-R0 group. There was no difference in overall survival (OS) or recurrence-free survival (RFS) between the current-R0 group and current-R1 group. However, there was a tendency toward a higher OS rate in the revised-R0 than revised-R1 group (log-rank p = 0.065), and RFS was significantly better in the revised-R0 than revised-R1 group (log-rank p = 0.002). There was no significant difference in the recurrence patterns between the current-R0 and current-R1 groups. In contrast, the local recurrence rate was significantly lower in the revised-R0 than revised-R1 group (21% vs. 42%, respectively; p = 0.026). CONCLUSION: The revised classification of surgical resection may be more useful than the current UICC classification for prediction of prognosis and local recurrence of IPDC. PMID- 29249393 TI - Therapeutic Benefit and Gene Network Regulation by Combined Gene Transfer of Apelin, FGF2, and SERCA2a into Ischemic Heart. AB - Despite considerable advances in cardiovascular disease treatment, heart failure remains a public health challenge. In this context, gene therapy appears as an attractive approach, but clinical trials using single therapeutic molecules result in moderate benefit. With the objective of improving ischemic heart failure therapy, we designed a combined treatment, aimed to simultaneously stimulate angiogenesis, prevent cardiac remodeling, and restore contractile function. We have previously validated IRES-based vectors as powerful tools to co express genes of interest. Mono- and multicistronic lentivectors expressing fibroblast growth factor 2 (angiogenesis), apelin (cardioprotection), and/or SERCA2a (contractile function) were produced and administrated by intramyocardial injection into a mouse model of myocardial infarction. Data reveal that combined treatment simultaneously improves vessel number, heart function parameters, and fibrosis prevention, due to FGF2, SERCA2a, and apelin, respectively. Furthermore, addition of SERCA2a in the combination decreases cardiomyocyte hypertrophy. Large scale transcriptome analysis reveals that the triple treatment is the most efficient in restoring angiogenic balance as well as expression of genes involved in cardiac function and remodeling. Our study validates the concept of combined treatment of ischemic heart disease with apelin, FGF2, and SERCA2a and shows that such therapeutic benefit is mediated by a more effective recovery of gene network regulation. PMID- 29249394 TI - Vanadium: A Panacea for Resistance to Oncolytic Immunotherapy? PMID- 29249395 TI - Synergy of Immune Checkpoint Blockade with a Novel Synthetic Consensus DNA Vaccine Targeting TERT. AB - Immune checkpoint blockade antibodies are setting a new standard of care for cancer patients. It is therefore important to assess any new immune-based therapies in the context of immune checkpoint blockade. Here, we evaluate the impact of combining a synthetic consensus TERT DNA vaccine that has improved capacity to break tolerance with immune checkpoint inhibitors. We observed that blockade of CTLA-4 or, to a lesser extent, PD-1 synergized with TERT vaccine, generating more robust anti-tumor activity compared to checkpoint alone or vaccine alone. Despite this anti-tumor synergy, none of these immune checkpoint therapies showed improvement in TERT antigen-specific immune responses in tumor bearing mice. alphaCTLA-4 therapy enhanced the frequency of T-bet+/CD44+ effector CD8+ T cells within the tumor and decreased the frequency of regulatory T cells within the tumor, but not in peripheral blood. CTLA-4 blockade synergized more than Treg depletion with TERT DNA vaccine, suggesting that the effect of CTLA-4 blockade is more likely due to the expansion of effector T cells in the tumor rather than a reduction in the frequency of Tregs. These results suggest that immune checkpoint inhibitors function to alter the immune regulatory environment to synergize with DNA vaccines, rather than boosting antigen-specific responses at the site of vaccination. PMID- 29249396 TI - Shed Skin Cancer, Not Collagen XVII: A New Approach to Targeting Skin Cancer Progression. PMID- 29249398 TI - Impact of structured programs on breastfeeding initiation rates in preterm neonates in a socioeconomically deprived area in France: A 10-year population based study. AB - : Structured programs have a positive impact on breastfeeding (BF) but have rarely been evaluated for preterm neonates, frequently combining prematurity and socioeconomic deprivation as risk factors of a low BF rate. We aimed to assess BF initiation rates in very preterm (<33 weeks' gestational age), moderately preterm (33-36 weeks), and term neonates from 2002 to 2011 in a French administrative district characterized by socioeconomic deprivation. Structured activities to promote and support BF have been implemented in this area since 2002; they all started in neonatal units. This retrospective population-based study analyzed 302,102 first health certificates. Overall, the BF initiation rate significantly increased, from 52.9% [95% CI: (52.3; 53.4)] in 2002 to 61.0% [95% CI: (60.4; 61.6)] in 2011. In 2002, BF initiation rates did not differ between groups, but in 2011, it was higher for very preterm than for term and moderately preterm neonates [74.7% (69.7; 79.6)] vs. 60.9% (60.3; 61.5) and 59.9% (57.6; 62.2), respectively, both P<0.001. In 2011, however, no difference was observed between moderately preterm children and term-born children (P=0.40). The 2.2% yearly increase observed in very preterm neonates significantly differed from the 0.9% yearly increase in the French general population (P<0.001). CONCLUSION: Structured BF programs initiated in neonatal care units may have a positive impact on BF initiation rates in very preterm neonates, but not in moderately preterm neonates, whose specific needs should be further evaluated. PMID- 29249397 TI - mRNA Vaccine with Antigen-Specific Checkpoint Blockade Induces an Enhanced Immune Response against Established Melanoma. AB - We reported a preclinical cancer vaccine that simultaneously introduced an mRNA antigen and an immune checkpoint blocking siRNA into the antigen-presenting cells. This was achieved by formulating both nucleic acid-based immunotherapeutics into a lipid-coated calcium phosphate (LCP) nanoparticle (NP) as a carrier to address the delivery challenge. The PEGylated lipid NPs were functionalized with mannose as the targeting ligand to facilitate the preferential uptake by the dendritic cells (DCs) in the lymph nodes after subcutaneous administration. The calcium phosphate core allowed acid-mediated dissolution in the endo-lysosomal compartment, which prompted rapid release of cargoes after cellular internalization of NP. LCP mRNA vaccine encoding TRP2 elicited a robust antigen-specific cytotoxic T cell response and a humoral immune response in a C57BL/6 mouse model of B16F10 melanoma. The immune responses efficaciously inhibited the melanoma growth. Moreover, co-delivery of PD-L1 siRNA and mRNA vaccine resulted in the downregulation of PD-L1 in the DCs that presented tumor antigens, significantly prompting T cell activation and proliferation. The enhanced T cell response had a profound inhibitory effect on tumor growth and metastasis. Generally, the work provided a paradigm for the development of an mRNA vaccine carrier to boost the anticancer immune response. PMID- 29249399 TI - [Contribution of teledermatology in a hospital pediatrics department]. AB - : The hospital of Versailles no longer has a dermatologist; consequently the pediatrics department suggested assess to the system put in place in 2015 based on the telemedicine software platform WebDCR developed throughout the hospital. The acceptability of this was based on its implementation as well as speed and ease of use. METHODS: In 2015, 47 reviews were submitted. RESULTS: No patient refusal was noted. The answer was obtained in 100 % of cases on the day the requests were made, during the week. A diagnosis was made in 36 % of cases and one or more hypotheses were formulated in the 64 % of the remaining cases. The review resulted in a further consultation in 28 % of cases, and in one case to transfer to the dermatology department. The quality of the data collected was considered good or excellent in 96 % of cases. DISCUSSION: This first teledermatology experiment seems to show its utility in terms of the services provided. Given the successful deployment of the system, it was extended to the pediatric emergency department. The response time was reduced to 1h. CONCLUSION: This first teledermatology experiment seems to show its real value in terms of services rendered. However, it is necessary to have more experience to confirm the contribution of this tool, and to reassess the sustainability and economic relevance of the device. PMID- 29249400 TI - Impact of obesity on biomarkers of iron and vitamin D status in children and adolescents: The risk of misinterpretation. PMID- 29249401 TI - [Infants living with their mothers in the Rennes, France, prison for women between 1998 and 2013. Facts and perspectives]. AB - Every year in France, nearly 50 infants live in a prison nursery with their mother. According to French law, infants can live with their mother in the prison nursery until they reach 18 months of age. The international community is concerned about the lack of validated social, medical and legal data on these infants living in prison. This was a retrospective and descriptive study. Medical and paramedical files of the General Council of Ile-et-Vilaine, France, were studied. Every infant born between 1998 and 2013 while their mother was in prison were included. Fifty-four files were collected. The average length of stay was 6.2 months (n=54). The type of the mother's prison sentence was property damage in 40 % of cases, personal injury in 51.1 % of cases and both in 8.9 % of cases (n=45). The length of the mother's imprisonment was on average 45 months, ranging from 3 to 216 months (n=34). After prison, 42.9 % of the infants were placed in foster care and 57.1 % resided with their family (n=42). This child-mother incarceration could be an opportunity for positive intergenerational paramedical, medical and social services. The lack of data and problems collecting data restrict our knowledge of these families. This should motivate a national follow up for these children. PMID- 29249402 TI - A phylogenetic classification of gastropod aquaporins. AB - Successful responses to the multifarious challenges of controlling water balance are critical for snails' survival in the great diversity of habitats they occupy. Advances are being made in understanding how such challenges are approached at the molecular level, including through the study of aquaporins, which are proteins functioning to facilitate the passage of water and other small molecules across cellular membranes. Deduced aquaporin amino acid sequences from partial genomic assemblies of three neritimorph species were added to available gastropod data and sequences from other taxa to make a phylogenetic classification of these proteins using maximum likelihood and Bayesian analyses. We identified ten groups, designated as G1 to G10, containing sequences from multiple major gastropod lineages. At least six of the groups appear to be encoded by multiple genes within at least some species. Five weakly-associated sequences from Neritimorpha were not allocated to a group. The designated groups G1, G2, G3, G4, G5 and G7 (previously defined as Malacoglyceroporins) formed clades containing only gastropod sequences and were strongly supported by Bayesian inference. G1, G2, G3 and G5 were also strongly supported by maximum likelihood analyses. Group G6 (previously defined as Malacoaquaporins)was included with sequences from the oyster, Crassostrea gigas in a strongly supported clade. Groups G8 and G9 included only gastropod sequences but were not strongly supported. Groups G8 and G10 were designated to include all the gastropod sequences belonging respectively to strongly-supported clades including human aquaglyceroporins and aquaammoniaporins. Most groups have been found in a wide range of gastropod lineages but all identified representatives of group G7 belong to Apogastropoda whereas G2 is known only from Patellogastropoda and Neritimorpha. PMID- 29249404 TI - Reply. PMID- 29249405 TI - Reply. PMID- 29249406 TI - Reply. PMID- 29249407 TI - New Models of Gastroenterology Practice. PMID- 29249408 TI - Small-Bowel Diverticulosis: Enteroscopic Diagnosis of an Unusual Cause of Overt Small Bowel Bleeding. PMID- 29249409 TI - Palpable Pancreatic Duct Due to Pancreatic Head Mass in a Patient With Chronic Calcific Pancreatitis. PMID- 29249410 TI - An Unexpected Finding During Colonoscopy: Pinworms. PMID- 29249413 TI - Editorial: Pathogenic templating proteins in Neurodegenerative Disease. PMID- 29249411 TI - Central corneal thickness measurement with Cirrus HD-OCT and Topcon SP-3000P. PMID- 29249412 TI - Comprehensive analysis of soft tissue changes in response to orthognathic surgery: mandibular versus bimaxillary advancement. AB - This study was performed to compare soft tissue changes in response to mandibular and bimaxillary advancement osteotomy. Preoperative and postoperative cone beam computed tomography scans of 24 cases were analysed: 12 underwent bimaxillary advancement and 12 underwent mandibular advancement. The skeletal surgical movements were measured and soft tissue changes were displayed on a three dimensional colour map. The intensity and shade of the colour indicated the magnitude and direction of the changes. In the bimaxillary advancement group, maxillary advancement was 5.5+/-2.7mm with anterior vertical impaction of 2.7+/ 2.5mm; mandibular advancement was 4.6+/-3.2mm. Most of the mediolateral soft tissue changes were limited to the anatomical boundaries of the paranasal region the columella together with the alar bases of the nose; these showed clear forward movement, which extended to involve most of the cheeks. In the mandibular surgery group, the mean advancement was 3.5+/-2.6mm. The chin region, lower lip, and inferior parts of the cheek showed forward shift with minimal changes at the vermilion border, which was only displaced in an upward direction. In conclusion, dense anatomical correspondence is a clinically meaningful method of producing a visual comprehensive analysis of the changes in response to orthognathic surgery. PMID- 29249414 TI - Correlation Between Severity of Temporomandibular Disorder, Pain Intensity, and Pressure Pain Threshold. AB - OBJECTIVE: The aim of the present study was to correlate the severity of temporomandibular disorder (TMD) with the pressure pain threshold over the temporomandibular joint and masticatory muscles. METHODS: A blind, cross sectional study was conducted involving 60 women ages 18 to 40 years with a diagnosis of myogenous TMD. Evaluations were performed using the Fonseca Anamnestic Index (FAI), the visual analogue scale, and algometry over the temporomandibular joint and masticatory muscles. Spearman's correlation coefficients (rs) were calculated to measure the association between TMD severity, pain intensity, and the pressure pain threshold. RESULTS: A moderate, significant, and negative correlation was found between TMD severity and the pressure pain threshold over the left masseter muscle (rs = -0.276; P = .034). No significant correlations were found for the other variables analyzed (P = .124 .985). CONCLUSIONS: Temporomandibular disorder measured using the FAI was associated to the pressure pain threshold over the masseter muscle. The significant and negative association found between the score of the FAI and the pressure pain threshold over the masseter muscle demonstrated that patients with more severe signs and symptoms of TMD had a lower pressure pain threshold. PMID- 29249415 TI - Association of Pain Catastrophizing With Static Balance, Mobility, or Functional Capacity in Patients With Knee Osteoarthritis: A Blind Cross-sectional Study. AB - OBJECTIVE: The aim of this study was to investigate whether catastrophizing is associated with static balance, mobility, and functional capacity in patients with knee osteoarthritis. METHODS: A blind, cross-sectional study was conducted involving 60 volunteers (males and females), ages 40 to 80 years, with a diagnosis of knee osteoarthritis. Patients were recruited from a physical therapy clinic in the city of Sao Paulo, Brazil. The following measures were used for the evaluations: Pain-Related Self-Statement Scale, Functional Reach Test, Timed Up and Go Test, Lower Extremity Functional Scale, and Western Ontario and McMaster University Osteoarthritis Index. In statistical analysis, histograms were created to determine distribution of data. Spearman's correlation coefficients (rs) were then calculated to determine the strength of the associations among the variables. RESULTS: No significant correlation was found between the Pain-Related Self-Statement Scale score and the other clinical measures employed in the present study: Functional Reach Test (rs = 0.151; P = .249), Timed Up and Go Test (rs = -0.147; P =.264), Lower Extremity Functional Scale (rs = 0.023; P = .860), and Western Ontario and McMaster University Osteoarthritis (rs = -0.222; P = .088). CONCLUSIONS: In this study, catastrophizing was not associated with static balance, mobility, or functional capacity in patients with knee osteoarthritis. PMID- 29249416 TI - LncRNA GAS5-AS1 inhibits myofibroblasts activities in oral submucous fibrosis. AB - BACKGROUND/PURPOSE: Emerging research findings suggest that long non-coding RNAs (lncRNAs) are key regulators to fibrosis formation. Nevertheless, the role of lncRNA GAS5-AS1 in the progression of precancerous oral submucous fibrosis (OSF) remains to be elucidated. METHODS: Quantitative real-time PCR were used to examine the expression of GAS5-AS1 in OSF tissues. The activities of myofibroblasts, including collagen contractility and cell migration, as well as the marker alpha-smooth muscle actin (SMA) were assessed following overexpression of GAS5-AS1. Also, we analyzed the expression of Smad activity in order to gain insight into the downstream regulator. RESULTS: The level of GAS5-AS1 was found significantly downregulated in the OSF tissues and fibrotic buccal mucosal fibroblasts (fBMFs). Ectopic expression of GAS5-AS1 significantly reduced the abilities of collagen gel contraction and migration in fBMFs or arecoline-treated BMFs. Moreover, we have shown that overexpression of GAS5-AS1 inhibited the expression of p-Smad and the marker of myofibroblasts. CONCLUSION: We showed the reduced expression of GAS5-AS1 in OSF tissues and demonstrated its effect on the myofibroblast activities and the level of p-Smad and alpha-SMA, indicating its potential contribution in OSF pathogenesis. PMID- 29249417 TI - Quantification of serum hepatitis B core antibody to predict off-entecavir relapse in patients with chronic hepatitis B. AB - BACKGROUND/PURPOSE: The predictors of off-therapy response in patients treated with neucleos(t)ide analogue (NA) have not been elucidated. It remained unexplored whether serum level of hepatitis B core antibody (anti-HBc) at the end of NA therapy was associated with relapse risks. METHODS: This prospective study monitored 82 chronic hepatitis B (CHB) patients after discontinuing entecavir. All patients had been treated for 3 years or longer and serologically negative for viral DNA and HBeAg at treatment cessation. Patients were monitored for virological relapse (viral DNA > 2000 IU/mL), and clinical relapse (serum alanine aminotransferase > 80 U/L plus virological relapse). The association between anti HBc levels and the risk of relapse was assessed by the Cox analysis. RESULTS: Clinical and virological relapses occurred in 29 and 60 participants, respectively, with the cumulative incidences of 23.7% (95% CI, 15.8-34.6%) and 62.0% (95% CI, 51.5-72.5%) at 1 year, and 36.2% (95% CI, 26.2-48.4%) and 78.8% (95% CI, 68.2-87.8%) at 2 years, respectively. There was a trend for an inverse association between anti-HBc and clinical relapse (crude hazard ratio [HR], 0.50; 95% CI, 0.24-1.05). All 3 patients with the level <100 IU/mL had a rapid clinical relapse (P = 0.002). This trend remained after adjustment for HBsAg and age (adjusted HR 0.50, 95% CI, 0.24-1.03). On the other hand, anti-HBc quantity was unrelated to virological relapse (crude HR, 0.97; 95% CI, 0.58-1.62; adjusted HR, 0.97; 95% CI, 0.58-1.60). CONCLUSION: This pilot study suggests a trend for an inverse association between anti-HBc levels and clinical relapse in CHB patients off entecavir. PMID- 29249419 TI - Antiplatelet therapy, vitamin K antagonist and low time in therapeutic range in patients with atrial fibrillation: Highway to bleed. PMID- 29249418 TI - Impact of different nitrate therapies on long-term clinical outcomes of patients with vasospastic angina: A propensity score-matched analysis. AB - BACKGROUND: Despite the short-term vasodilatory effects of nitrates, the prognostic effects of long-term nitrate therapy in patients with vasospastic angina (VSA) remains unclear. We investigated the prognostic impact of chronic nitrate therapy in VSA patients. METHODS: Between January 2003 and December 2014, a total of 1154 VSA patients proven by ergonovine provocation tests were classified into nitrate (n=676) and non-nitrate (n=478) groups according to prescriptions for oral nitrates, including isosorbide mononitrate (ISMN) and nicorandil. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of cardiac death, myocardial infarction, any revascularization, or rehospitalization due to recurrent angina. RESULTS: The nitrate group was found to have a higher risk of MACE (22.9% vs. 17.6%, hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.01-1.73, p=0.043) than the non nitrate group. After propensity score matching, the nitrate group had greater risks of MACE (HR 1.32, 95%CI 1.01-1.73, p=0.049). Patients who received the immediate-release formula of ISMN (HR 1.80, 95%CI 1.35-2.39, p<0.001) or were administered any forms of ISMN other than at bedtime (HR 1.90, 95%CI 1.41-2.57, p<0.001) had a significantly higher risk of MACE compared with the non-nitrate group. Nicorandil was shown to have a neutral effect on VSA patients (HR 1.11, 95%CI 0.73-1.69, p=0.62). CONCLUSIONS: The long-term use of nitrate therapy was associated with increased risk of adverse cardiac events in VSA patients. The use of immediate-release ISMN or the administration of ISMN other than at bedtime was related with poor outcomes of VSA patients. PMID- 29249420 TI - Hemodynamic factors associated with serum chloride in ambulatory patients with advanced heart failure. AB - BACKGROUND: Lower serum chloride (Cl) is associated with mortality in heart failure patients and may be more prognostically relevant than sodium. However, the association of hemodynamics and Cl levels is unknown. METHODS: 438 sequential patients with advanced chronic heart failure (ACHF) underwent invasive hemodynamic assessment with measured serum Cl levels during an evaluation for ACHF. Patients were followed for death, heart transplant (HT), or ventricular assist device placement (VAD). A backwards regression model determined hemodynamic predictors of Cl (removal, P<0.1) with candidate variables: Fick cardiac index (FCI), pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), mean arterial pressure (MAP), heart rate (HR), and pulmonary artery systolic pressure (PASP). All models were also adjusted for serum sodium and bicarbonate. RESULTS: In this cohort, the median Cl level was 102 [98 104]meq/L (range 86-113meq/L). Chloride was weakly correlated with FCI (rho 0.12, P=0.01) and MAP (rho 0.21, P<0.001); but not PCWP, RAP, HR or PASP (P>0.05 for all). In the multivariable model, FCI (beta 0.73meq/L/L/min/m2, P=0.002) but not RAP (P=0.3) or MAP (P=0.2), remained associated with Cl. Lower Cl was associated with increased risk of death, HT, or VAD placement (HR 0.94/meq/L, 95% CI 0.89 0.99, P=0.01). However, this association was attenuated after additional adjustment for BUN (P=0.27) and PCWP and FCI (0.48). CONCLUSIONS: Lower FCI, not lower MAP or higher cardiac filling pressures, was associated with lower chloride. Although lower chloride was associated with poor long-term outcomes, this risk attenuates with adjustment for more conventional clinical parameters. PMID- 29249421 TI - The interplay between atrial fibrillation and heart failure on long-term mortality and length of stay: Insights from the, United Kingdom ACALM registry. AB - BACKGROUND: There is concern that the development of heart failure and atrial fibrillation has a detrimental influence on clinical outcomes. The aim of this study was to assess all-cause mortality and length of hospital stay in patients with chronic and new-onset concomitant AF and HF. METHODS: Using the ACALM registry, we analysed adults hospitalised between 2000 and 2013 with AF and HF and assessed prevalence, mortality and length of hospital stay. Patients with HF and/or AF at baseline (study-entry) were compared with patients who developed new onset disease during follow-up. RESULTS: Of 929,552 patients, 31,695 (3.4%) were in AF without HF, 20,768 (2.2%) had HF in sinus rhythm, and 10,992 (1.2%) had HF in AF. Patients with HF in AF had the greatest all-cause mortality (70.8%), followed by HF in sinus rhythm (64.1%) and AF alone (45.1%, p<0.0001). Patients that developed new-onset AF, HF or both had significantly worse mortality (58.5%, 70.7% and 74.8% respectively) compared to those already with the condition at baseline (48.5%, 63.7% and 67.2% respectively, p<0.0001). Patients with HF in AF had the longest length of hospital stay (9.41days, 95% CI 8.90-9.92), followed by HF in sinus rhythm (7.67, 95% CI 7.34-8.00) and AF alone (6.05, 95% CI 5.78 6.31). CONCLUSIONS: Patients with HF in AF are at a greater risk of mortality and longer hospital stay compared to patients without the combination. New-onset AF or HF is associated with significantly worse prognosis than long-standing disease. PMID- 29249422 TI - Sacubitril/valsartan and short-term changes in the 6-minute walk test: A pilot study. AB - BACKGROUND: Impaired exercise capacity is the most disabling symptom in patients with heart failure with reduced ejection fraction (HFrEF). Despite sacubitril/valsartan showing reduced long-term morbidity and mortality over enalapril in HFrEF, its effects on short-term functional capacity remain uncertain. We sought to evaluate the effects of sacubitril/valsartan on a 30-day six-minute walk test in eligible patients with HFrEF. METHODS AND RESULTS: From November 1, 2016 to February 1, 2017, a total of 58 stable symptomatic patients with HFrEF were eligible for sacubitril/valsartan and underwent 6-MWT before and 30days after initiation of sacubitril/valsartan therapy. A mixed-effects model for repeated-measures was used to analyze the changes. Mean age was 70+/-11years. 72.4% males, 46.6% with ischemic heart disease, and 51.7% on NYHA functional class III were included. The mean (SD) values of baseline LVEF and 6MWT were 30+/ 7%, and 300+/-89m, respectively. The median (IQR) of NT-proBNP at baseline was 2701pg/ml (1087-4200). Compared with baseline, the 6-MWT distance increased significantly at 30days by 13.9% (+?=41.8m (33.4-50.2); p<0.001). CONCLUSIONS: In this pilot study, sacubitril/valsartan was associated with an improvement in exercise tolerance in symptomatic patients with HFrEF. PMID- 29249423 TI - Heart failure and atrial fibrillation: Can we break this nexus? PMID- 29249424 TI - Impact of aortic plaque on progression rate and prognosis of aortic stenosis. AB - BACKGROUNDS: Patients with aortic stenosis (AS) have a high prevalence of aortic plaque. However, no data exist regarding the clinical significance and prognostic value of aortic plaque in AS patients. This study examines the impact of aortic plaque on the rate of progression and clinical outcomes of AS. METHODS: We retrospectively investigated 1812 transesophageal echocardiographic examinations between 2008 and 2015. We selected 100 consecutive patients (mean age; 75.1+/ 7.4years) who showed maximal aortic jet velocity (AV-Vel) >=2.0m/s by transthoracic echocardiography (TTE) and received follow-up TTE (mean follow-up duration 25+/-17months), and the mean progression rate of AV-Vel was calculated. Clinical and echocardiographic characteristics, including severity of aortic plaque, and cardiac events were examined. RESULTS: At initial TTE, mean AV-Vel was 3.68+/-0.94m/s and mean aortic valve area 0.98+/-0.32cm2. Mean progression rate of AV-Vel was 0.41m/s/year in 38 patients with severe aortic plaque, and 0.03m/s/year in the remaining 62 patients without severe aortic plaque. Severe aortic plaque (odds ratio[OR], 8.32) and hemodialysis (OR, 6.03) were independent predictors of rapid progression. The event-free survival rate at 3years was significantly lower in patients with severe aortic plaque than in those without (52% vs 82%, p=0.002). Severe aortic plaque (hazard ratio[HR], 2.89) and AV-Vel at initial TTE (HR, 3.28) were identified as independent predictors of cardiac events. CONCLUSION: Severe aortic plaque was a predictor of rapid progression and poor prognosis in AS patients. Evaluation of aortic plaque provides additional information regarding surgical scheduling and follow-up. PMID- 29249425 TI - Evidence for functional PAR-4 thrombin receptor expression in cardiac fibroblasts and its regulation by high glucose: PAR-4 in cardiac fibroblasts. AB - BACKGROUND: Thrombin promotes cardiac fibroblast proliferation and fibrosis via protease-activated receptor (PAR-1). PAR-4 is reportedly absent in cardiac fibroblasts. In smooth muscle cells, PAR-4 expression is also low but increases upon hyperglycemia and contributes to vascular remodelling in diabetic mice. We examined if PAR-4 is a glucose-responsive gene with remodelling-related functions in cardiac fibroblasts. METHODS AND RESULTS: Cardiac PAR-4 increased in mice with streptozotocin- or diabetogenic diet (DD)-induced diabetes. PAR-4 mRNA and protein were detectable in cardiac fibroblasts from chow-fed mice and increased in high (HG, 25mM) vs. low glucose (LG; 5.5mM) cultures. Conversely PAR-4 mRNA was higher in fibroblasts from DD-fed mice but reduced in LG cultures. Cardiac fibroblasts in HG culture responded more strongly to thrombin or PAR-4 activating peptide in terms of migration (wound-scratch assay), remodelling-associated gene expression (interleukin 6, alpha smooth muscle actin) and oxidative stress (dihydroethidium fluorescence). CONCLUSION: PAR-4 is expressed in mouse cardiac fibroblasts and is dynamically regulated by extracellular glucose in vitro and diabetes in vivo, thereby impacting on fibroblast functions relevant for cardiac remodelling. These findings add further evidence for the usefulness of the recently developed PAR-4 antagonists in clinical settings. PMID- 29249426 TI - PAR-4 - The PARagon of protease-activated receptors? PMID- 29249427 TI - Prevalence and management of familial hypercholesterolemia in patients with coronary artery disease: The heredity survey. AB - BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low density lipoprotein cholesterol (LDL-C) predisposing to premature cardiovascular disease. Its prevalence varies and has been estimated around 1 in 200-500. The Heredity survey evaluated the prevalence of potential FH and the therapeutic approaches among patients with established coronary artery disease (CAD) or peripheral artery disease (PAD) in which it is less well documented. METHODS: Data were collected in patients admitted to programs of rehabilitation and secondary prevention in Italy. Potential FH was estimated using Dutch Lipid Clinic Network (DLCN) criteria. Potential FH was defined as having a total score>=6. RESULTS: Among the 1438 consecutive patients evaluated, the prevalence of potential FH was 3.7%. The prevalence was inversely related to age, with a putative prevalence of 1:10 in those with <55yrs of age (male) and <60yrs (female). Definite FH (DLCN score>8) had the highest percentages of patients after an ACS (75% vs 52.5% in the whole study population). At discharge, most patients were on high intensity statin therapy, but despite this, potential FH group still had a higher percentage of patients with LDL-C levels not at target and having a distance from the target higher than 50%. CONCLUSIONS: Among patients with established coronary heart disease, the prevalence of potential FH is higher than in the general population; the results suggest that a correct identification of potential FH, especially in younger patients, may help to better manage their high cardiovascular risk. PMID- 29249428 TI - Treatment gaps in severe hypercholesterolemia. PMID- 29249429 TI - Discrepancies in risk age and relative risk estimations of cardiovascular disease in patients with inflammatory joint diseases. AB - OBJECTIVE: The European guidelines on cardiovascular disease (CVD) prevention advise use of relative risk and risk age algorithms for estimating CVD risk in patients with low estimated absolute risk. Patients with inflammatory joint diseases (IJD) are associated with increased risk of CVD. We aimed to estimate relative risk and risk age across IJD entities and evaluate the agreement between 'cardiovascular risk age' and 'vascular age models'. METHODS: Using cross sectional data from a nationwide project on CVD risk assessment in IJD, risk age estimations were performed in patients with low/moderate absolute risk of fatal CVD. Risk age was calculated according to the cardiovascular risk age and vascular age model, and risk age estimations were compared using regression analysis and calculating percentage of risk age estimations differing >=5years. RESULTS: Relative risk was increased in 53% and 20% had three times or higher risk compared to individuals with optimal CVD risk factor levels. Furthermore, 20 42% had a risk age >=5years higher than their actual age, according to the specific risk age model. There were only minor differences between IJD entities regarding relative risk and risk age. Discrepancies >=5years in estimated risk age were observed in 14-43% of patients. The largest observed difference in calculated risk age was 24years. CONCLUSION: In patients with low estimated absolute risk, estimation of relative CVD risk and risk age may identify additional patients at need of intensive CVD preventive efforts. However, there is a substantial discrepancy between the risk age models. PMID- 29249430 TI - Prevalence of Takayasu arteritis in young women with acute ischemic heart disease. AB - OBJECTIVES: Takayasu arteritis (TA), a systemic vasculitis typically occurring in female patients aged <=40, can affect coronary arteries and cause ischemic heart disease (IHD). In this study, we investigated the prevalence of TA in young women presenting with IHD in the Emergency Department. METHODS: We evaluated hospital records of 158,860 consecutive female patients aged <40, who accessed the Emergency Department of our institution over 8 consecutive years (2007-2015). The prevalence of different etiologies of IHD was determined. Diagnosis of TA was established based on the 1990 ACR criteria. RESULTS: Overall, 1950 women aged <40 presented to the Emergency Department with chest pain, dyspnea, palpitations, angina, heart failure, or cardiac arrest; 40 had acute IHD. The etiology was 'classic' atherosclerosis in 24 cases (60%), TA in 4 cases (10%), vasospasm and sympathomimetic drug abuse in 3 cases each (7.5%), coronary artery dissection and microvascular angina in 2 cases each (5%), Takotsubo and radiation-induced cardiomyopathy in 1 case each (2.5%). DISCUSSION: Although a diagnosis of TA is likely to be overlooked, TA is not infrequent in younger females presenting with acute IHD, a finding relevant to the diagnosis and management of these patients. PMID- 29249431 TI - Prognosis of patients with echocardiographic abnormalities with special reference to fasting plasma glucose. PMID- 29249432 TI - Reply: Intersection of fasting plasma glucose, adverse cardiac remodeling, and clinical outcomes. PMID- 29249434 TI - Contractile reserve and the response to cardiac resynchronization therapy. PMID- 29249433 TI - Does presence of left ventricular contractile reserve improve response to cardiac resynchronization therapy? An updated meta-analysis. AB - BACKGROUND: Up to a third of patients undergoing cardiac resynchronization therapy (CRT) do not have a clinical or echocardiographic response. It is also unclear, whether contractile reserve (CR) could predict CRT response. This meta analysis examines whether the presence of CR improves response to CRT and whether this is modulated by other clinical factors. METHODS: Search of PubMed/EMBASE/Cochrane databases for articles examining response to CRT stratified by the presence or not of CR. End-point classified as clinical or echocardiographic response. The analysis compared response to CRT (echocardiographic or clinical) between patients with or without CR. RESULTS: 824 patients in 12 studies were included. The presence of left ventricular CR was associated with a significant reduction in echocardiographic non-responders to CRT compared to patients without CR (OR: 0.16, 95% CI 0.08-0.33, p<0.00001). The presence of left ventricular CR was associated with a significant reduction in clinical non-responders to CRT compared to patients without CR (OR: 0.23, 95% CI 0.14-0.37, p<0.00001). Sensitivity analysis showed no difference in response when pooling studies using left ventricular ejection fraction (LVEF) or non-LVEF markers of CR. Meta-regression showed that CR was associated with lower rates of non-responders and this was more pronounced in patients with a narrower mean QRS complex. CONCLUSIONS: Identification of CR is associated with improved response to CRT. Importantly, QRS width is a potential moderator variable which can explain part of the heterogeneity in echo response. The combination of CR and QRS width may modulate the response to CRT. PMID- 29249435 TI - The effects of remote ischaemic preconditioning on coronary artery function in patients with stable coronary artery disease. AB - BACKGROUND: Remote ischaemic preconditioning (RIPC) is a cardioprotective intervention invoking intermittent periods of ischaemia in a tissue or organ remote from the heart. The mechanisms of this effect are incompletely understood. We hypothesised that RIPC might enhance coronary vasodilatation by an endothelium dependent mechanism. METHODS: We performed a prospective, randomised, sham controlled, blinded clinical trial. Patients with stable coronary artery disease (CAD) undergoing elective invasive management were prospectively enrolled, and randomised to RIPC or sham (1:1) prior to angiography. Endothelial-dependent vasodilator function was assessed in a non-target coronary artery with intracoronary infusion of incremental acetylcholine doses (10-6, 10-5, 10 4mol/l). Venous blood was sampled pre- and post-RIPC or sham, and analysed for circulating markers of endothelial function. Coronary luminal diameter was assessed by quantitative coronary angiography. The primary outcome was the between-group difference in the mean percentage change in coronary luminal diameter following the maximal acetylcholine dose (Clinicaltrials.gov identifier: NCT02666235). RESULTS: 75 patients were enrolled. Following angiography, 60 patients (mean+/-SD age 57.5+/-8.5years; 80% male) were eligible and completed the protocol (n=30 RIPC, n=30 sham). The mean percentage change in coronary luminal diameter was -13.3+/-22.3% and -2.0+/-17.2% in the sham and RIPC groups respectively (difference 11.32%, 95%CI: 1.2- 21.4, p=0.032). This remained significant when age and sex were included as covariates (difference 11.01%, 95%CI: 1.01- 21.0, p=0.035). There were no between-group differences in endothelial-independent vasodilation, ECG parameters or circulating markers of endothelial function. CONCLUSIONS: RIPC attenuates the extent of vasoconstriction induced by intracoronary acetylcholine infusion. This endothelium-dependent mechanism may contribute to the cardioprotective effects of RIPC. PMID- 29249437 TI - Protection of the human coronary circulation by remote ischemic conditioning. PMID- 29249436 TI - Identification of patients with stable chest pain deriving minimal value from coronary computed tomography angiography: An external validation of the PROMISE minimal-risk tool. AB - BACKGROUND: The PROspective Multicenter Imaging Study for Evaluation of chest pain (PROMISE) minimal-risk tool was recently developed to identify patients with suspected stable angina at very low risk of coronary artery disease (CAD) and clinical events. We assessed the external validity of this tool within the context of the Scottish Computed Tomography of the HEART (SCOT-HEART) multicenter randomised controlled trial of patients with suspected stable angina due to coronary disease. METHODS: The minimal-risk tool was applied to 1764 patients with complete imaging and follow-up data. External validity was compared with the guideline-endorsed CAD Consortium (CADC) risk score and determined through tests of model discrimination and calibration. RESULTS: A total of 531 (30.1%, mean age 52.4years, female 62.0%) patients were classified as minimal-risk. Compared to the remainder of the validation cohort, this group had lower estimated pre-test probability of coronary disease according to the CADC model (30.0% vs 47.0%, p<0.001). The PROMISE minimal-risk tool improved discrimination compared with the CADC model (c-statistic 0.785 vs 0.730, p<0.001) and was improved further following re-estimation of covariate coefficients (c-statistic 0.805, p<0.001). Model calibration was initially poor (chi2 197.6, Hosmer-Lemeshow [HL] p<0.001), with significant overestimation of probability of minimal risk, but improved significantly following revision of the PROMISE minimal-risk intercept and covariate coefficients (chi2 5.6, HL p=0.692). CONCLUSION AND RELEVANCE: Despite overestimating the probability of minimal-risk, the PROMISE minimal-risk tool outperforms the CADC model with regards to prognostic discrimination in patients with suspected stable angina, and may assist clinicians in decisions regarding non-invasive testing. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01149590. PMID- 29249438 TI - Clinical outcome according to spasm type of single coronary artery provoked by intracoronary ergonovine tests in patients without significant organic stenosis. AB - BACKGROUND: This study aimed to evaluate clinical implications of single vessel coronary spasm provoked by intracoronary ergonovine provocation test in Korean population. METHOD: A total of 1248 patients who presented with single vessel coronary artery spasm induced by intracoronary ergonovine provocation test, excluding 1712 with negative spasms, multiple and mixed coronary artery spasms and missing data among 2960 patients in the VA-KOREA (Vasospastic Angina in Korea) registry, were classified into diffuse (n=705) and focal (n=543) groups. RESULTS: The 24-month incidences of a composite primary endpoints (cardiac death, new-onset arrhythmia, and acute coronary syndrome) were determined. Over a median follow-up of 30months, the composite primary end point occurred more frequently in the focal type patients than in the diffuse type patients (primary endpoint: adjusted hazard ratio [aHR], 1.658; 95% confidence interval [CI] 1.272 to 2.162, P<0.001). Especially, unstable angina in ACS components played a major role in this effect (hazard ratio [HR], 2.365; 95% confidence interval [CI] 1.100 to 5.087, P=0.028). CONCLUSION: Focal type of single vessel coronary artery spasm in vasospastic angina (VSA) patients is found to be associated with worse clinical outcomes. It is thought that the effect is stemmed from unstable angina among ACS rather than the other components of primary endpoint. Therefore, focal type of single vessel coronary artery spasm in patients with VSA should be more carefully assessed and managed with appropriate medication. PMID- 29249439 TI - FFR-guided multivessel stenting reduces urgent revascularization compared with infarct-related artery only stenting in ST-elevation myocardial infarction: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Randomized controlled trials (RCTs) have shown fractional flow reserve-guided (FFR) multivessel stenting to be superior to infarct-related artery (IRA) only stenting in patients with ST-elevation myocardial infarction (STEMI) and multivessel disease. This effect was mainly driven by a reduction in overall repeat revascularization. However, the ability to assess the effect of this strategy on urgent revascularization or reinfarction was underpowered in individual trials. METHODS: We searched Pubmed, EMBASE, Cochrane CENTRAL, and Web of Science for RCTs of FFR-guided multivessel stenting versus IRA-only stenting in STEMI with multivessel disease. The outcomes of interest were death, reinfarction, urgent, and non-urgent repeat revascularization. Risk ratios (RR) were pooled using the DerSimonian and Laird random-effects model. RESULTS: After review of 786 citations, 2 RCTs were included. The pooled results demonstrated a significant reduction in the composite of death, reinfarction, or revascularization in the FFR-guided multivessel stenting group versus IRA-only stenting group (RR [95%, Confidence Interval]: 0.49 [0.33-0.72], p<0.001). This risk reduction was driven mainly by a reduction in repeat revascularization, both urgent (0.41 [0.24-0.71], p=0.002) and non-urgent revascularization (0.31 [0.19 0.50], p<0.001). Pooled RR for reinfarction was lower in the FFR-guided strategy, but was not statistically significant (0.71[0.39-1.31], p=0.28). CONCLUSIONS: This systematic review and meta-analysis suggests that a strategy of FFR-guided multivessel stenting in STEMI patients reduces not only overall repeat revascularization but also urgent revascularization. The effect on reinfarction needs to be evaluated in larger trials. PMID- 29249440 TI - Clinical validation of an ultrasound quantification score for aortic valve calcifications. PMID- 29249441 TI - Ultrasound-based aortic valve calcium scoring method: Are we ready to use it? PMID- 29249443 TI - Postoperative arrhythmias after AVSD repair: The lack of regular periodic rhythm surveillance allows you to see only the tip of the iceberg. PMID- 29249442 TI - Incidence and risk factors of post-operative arrhythmias and sudden cardiac death after atrioventricular septal defect (AVSD) correction: Up to 47years of follow up. AB - BACKGROUND: Atrioventricular septal defect (AVSD) has an incidence of 4-5.3 per 10.000 live births and is associated with Down syndrome (DS). Data on arrhythmias and sudden cardiac death (SCD) after AVSD correction is scarce. AIM: To analyse the incidence of post-operative arrhythmias and SCD after AVSD correction and explore risk factors. METHODS: This is a retrospective multicenter study including patients after biventricular AVSD correction. Univariate and multivariate analyses were performed to explore risk factors. RESULTS: A total of 415 patients were included with a mean follow-up duration of 9years (range; <30days-47years). Early post-operative SVTs were documented in 33 patients (8%) and late post-operative SVTs in 15 patients (3.6%). Non-syndromic AVSD (p=0.022, HR=2.64; 95% CI=1.15-6.04) and cAVSD (p=0.005, HR=3.7; 95% CI=1.39-7.51) were independent risk factors for early post-operative SVTs and significant more late post-operative SVTs occurred in non-syndromic patients (p=0.016, HR=6.38; 95% CI=1.42-28.71) and in pAVSD (p=0.045, HR=3.703; 95% CI=1.03-13.32). Fifteen patients (3.6%) received a pacemaker. Non-syndromic AVSD (p=0.008, HR=15.82; 95% CI=2.04-122.47), pAVSD (p=0.017, HR=6.26; 95% CI=1.39-28.28) and re-operation (p=0.007, HR=4.911; 95% CI=1.54-15.64) were independent risk factors for postoperative pacemaker implantation. Late life-threatening ventricular arrhythmias and SCD occurred in 0.5% and 1.7% respectively. CONCLUSION: There is good long-term survival after AVSD correction and incidence of SCD is low. Non syndromic AVSD and cAVSD are independent risk factors for early post-operative SVTs. Non-syndromic AVSD patients have significant more early 3rd degree AVB and late post-operative SVTs. Non-syndromic patients with partial AVSD who have undergone reoperation have a significant higher risk of pacemaker implantation. PMID- 29249444 TI - Impact of quality of anticoagulation control on outcomes in patients with atrial fibrillation taking aspirin: An analysis from the SPORTIF trials. AB - BACKGROUND: Concomitant aspirin (ASA) is often prescribed in anticoagulated patients with atrial fibrillation (AF). We aimed to investigate the relationship between ASA use and quality of anticoagulation control determining major adverse outcomes. METHODS: An ancillary analysis of patients in the warfarin arm of the SPORTIF III and V trials was performed. Quality of anticoagulation control was defined using time in therapeutic range (TTR). RESULTS: 3624 AF patients on warfarin were available for analysis: 1712 (47.2%) were ASA non-users with good anticoagulation control (TTR>=65%) [Group I], 380 (10.5%) were ASA users with TTR>=65% [Group II], 1192 (32.9%) were ASA non-users with TTR<65% [Group III] and 340 (9.4%) were ASA users with TTR<65% [Group IV]. CHA2DS2-VASc was similar across the groups (p=0.350), conversely HAS-BLED was progressively higher (p<0.001). At follow-up, stroke/systemic embolism rates were similar across the groups (p=0.162). Conversely, a progressively higher rate for major bleeding was found (p=0.034), as well as higher rates for all-cause death in Group III and IV (p<0.001). Kaplan-Meier analyses found a progressively higher risk for major bleeding across the groups (p=0.005) and a higher all-cause death risk in Group III and IV (p<0.001). Cox regression analysis confirmed that Group III and IV were at higher risk for major bleeding (p=0.005) and all-cause death (p=0.010). CONCLUSIONS: Poor anticoagulation control is associated with higher bleeding risk, which is even greater with concomitant ASA use, with no difference in stroke/SE risk. Poor anticoagulation control is associated with a higher risk for all-cause death, independent of concomitant ASA use. PMID- 29249445 TI - Who Meets the Contraceptive Needs of Young Women in Sub-Saharan Africa? AB - PURPOSE: Despite efforts to expand contraceptive access for young people, few studies have considered where young women (age 15-24) in low- and middle-income countries obtain modern contraceptives and how the capacity and content of care of sources used compares with older users. METHODS: We examined the first source of respondents' current modern contraceptive method using the most recent Demographic and Health Survey since 2000 for 33 sub-Saharan African countries. We classified providers according to sector (public/private) and capacity to provide a range of short- and long-term methods (limited/comprehensive). We also compared the content of care obtained from different providers. RESULTS: Although the public and private sectors were both important sources of family planning (FP), young women (15-24) used more short-term methods obtained from limited-capacity, private providers, compared with older women. The use of long-term methods among young women was low, but among those users, more than 85% reported a public sector source. Older women (25+) were significantly more likely to utilize a comprehensive provider in either sector compared with younger women. Although FP users of all ages reported poor content of care across all providers, young women had even lower content of care. CONCLUSIONS: The results suggest that method and provider choice are strongly linked, and recent efforts to increase access to long-term methods among young women may be restricted by where they seek care. Interventions to increase adolescents' access to a range of FP methods and quality counseling should target providers frequently used by young people, including limited-capacity providers in the private sector. PMID- 29249446 TI - Seagrass-bivalve facilitative interactions: Trait-mediated effects along an environmental gradient. AB - Facilitative interactions are important forces in shaping community structure and function, and understanding how they respond to environmental changes has become an increasing concern in ecology. Lucinid bivalves play a significant role in seagrass meadows, through a mutualism in which the seagrass provides habitat and oxygen via the roots, while the bivalves and their associated bacteria eliminate sulfides from pore water, improving thus plant performance. In this study, we evaluated how this mutualism is modified along a gradient of organic matter content in the sediment, in a coastal bay dominated by Cymodocea nodosa meadows. We used a correlative approach, seeking statistical association between sediment organic matter content, lucinid abundance, and plant traits. Lucinid abundance was higher in vegetated that in bare areas. In vegetated areas, lucinid abundance decreased as organic matter content in the sediment increased, decrease seemingly associated to modification in plant traits, i.e. root abundance and morphology. In organic-rich sediments, roots are less abundant and less branched, reducing the potential habitat for lucinids and suggesting a weakening of the interaction. This finding contributes to our understanding of how facilitative interactions can be modified along human disturbance gradients, and how disturbances can reduce resilience of seagrasses through this modification. PMID- 29249447 TI - People with epilepsy are diagnosed most often with unspecified epilepsy, followed by focal epilepsy, generalized convulsive epilepsy, and generalized nonconvulsive epilepsy-US MarketScan data, 2010-2015. AB - The distribution of epilepsy types varies by age, etiology, provider diagnostic capabilities, and assessment criteria. No recent US study has examined the distribution of epilepsy types in a large, population-based sample of people with epilepsy. We used MarketScan data from January 1, 2010 through September 30, 2015, to estimate the proportion of epilepsy types among all (N=370,570) individuals diagnosed with epilepsy. We identified cases of epilepsy as individuals with at least one International Classification of Disease, 9th version (ICD-9) diagnostic code of 345.X and the use of at least one antiseizure drug described in the 2015 MarketScan Redbook. Unspecified epilepsy was more common (36.8%) than focal-localized epilepsy (24.6%), generalized convulsive epilepsy (23.8%), generalized nonconvulsive epilepsy (8.9%), other forms of epilepsy (5.2%), infantile spasm (0.3%), and epilepsia partialis continua (0.3%). The high proportion of epilepsy classified as unspecified might be lowered by improved training in epilepsy diagnosis and coding. PMID- 29249448 TI - Seizure activity and individual vulnerability on first-episode interictal psychosis in epilepsy. AB - OBJECTIVE: Despite a theoretical consensus that interictal psychosis (IIP) is related to various epilepsy-related factors, the impact of seizure activity on development of IIP remains inconclusive. This is the first controlled study using quantitative seizure-activity measures at the onset of IIP. METHODS: One hundred and eighty-one patients with epilepsy who exhibited first-episode IIP (IIP group) and 427 patients with epilepsy without psychotic episodes (control group) were enrolled. The control group was matched for age, epilepsy type, and duration of epilepsy. The two seizure-activity indices (seizure frequency at the time of onset of first-episode IIP and the number of seizures before the onset of IIP) were evaluated and compared between the IIP and control groups. Logistic regression analysis was used for extracting risk variables to develop first episode IIP. RESULTS: The sum of previous seizures was greater in the IIP than in control groups. This was particularly the case in the patients with partial epilepsies (PE). Higher seizure frequency in the patients with PE was associated with the development of first-episode IIP while no association was found in the whole cohort or in the patients with generalized epilepsies (GE). Subsequent multivariate analysis revealed the sum of previous seizures and family history of psychosis as risk variables to first-episode IIP. CONCLUSIONS: The accumulation of seizure-related damages and family history of psychosis is associated with the onset of IIP episodes, particularly in the patients with PE. Seizure activity and individual vulnerability to psychosis are likely to be interacted for as the development of IIP in patients with epilepsy. PMID- 29249449 TI - "By working together and caring for one another we can win this fight": A qualitative exploration of a traditional healer's perspectives of care of people with epilepsy in a South African urban township in Cape Town. AB - There is a gap in knowledge about the construction of care in the Global South where biomedical care remains largely inaccessible to many people, resulting in people seeking health care from the indigenous sector of health care. As part of a larger study, in this, article we present findings from a single individual interview with an indigenous healer using a semi-structured interview guide that was based on Kleinman's Explanatory Model Framework. Key themes that emerged from the thematic analysis of our indigenous healer's audio-recorded transcribed transcript were about "care". The four overarching subthemes were the following: (i) care in the family, (ii) care in the community, (iii) care in the health system, and (iv) respondents' construction of care. A key feature of care, for this healer, is its explicit location in lineages of community - care is seen not as an individual or organizational issue, but part of the shared social fabric. We argue that it is crucial to attend to the lay understandings and practices of care which reflect diverse ways of understanding care and relationality in context. Future research is needed to close this gap. PMID- 29249450 TI - Perfusion defects in pulmonary perfusion iodine maps: causes and semiology. AB - OBJECTIVE: to describe the usefulness of dual-energy CT for obtaining pulmonary perfusion maps to provide morphological and functional information in patients with pulmonary embolisms. To review the semiology of perfusion defects due to pulmonary embolism so they can be differentiated from perfusion defects due to other causes: alterations outside the range used in the iodine map caused by other diseases of the lung parenchyma or artifacts. CONCLUSION: CT angiography of the pulmonary arteries is the technique of choice for the diagnosis of pulmonary embolisms. New dual-energy CT scanners are useful for detecting perfusion defects secondary to complete or partial obstruction of pulmonary arteries and is most useful for detecting pulmonary embolisms in subsegmental branches. PMID- 29249451 TI - MiR-199-3p replacement affects E-cadherin expression through Notch1 targeting in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) represents the second cause of cancer-related mortality worldwide and is associated with poor prognosis, due to a high recurrence rate after curative treatments and a drug resistance phenotype. In this scenario, the identification of innovative and effective therapeutic strategies is an unmet clinical need. The safety and efficacy of microRNA (miRNA) mediated approaches in preclinical models and clinical trials have been widely described in cancer. MicroRNA-199a downregulation is a common feature of HCC where its reduced expression contributes to mTOR and c-Met pathways activation. Notch1 activation is also a common event in HCC, influencing epithelial-to mesenchymal transition, tumor invasion and recurrence at least in part through E cadherin regulation. Here we identified a negative correlation between miR-199a 3p and Notch1 or E-cadherin protein levels in HCC patients and demonstrated that miR-199a-3p regulates E-cadherin expression through Notch1 direct targeting in in vitro models. Moreover, we showed that a strong correlation exists between miR 199a-5p and miR-199a-3p in HCC specimens and that miR-199a-5p contributes to E cadherin regulation as well, underlying the complex network of interaction carried out by miR-199a and its influence on tumor aggressiveness. In conclusion, our findings suggest the restoration of miR-199a-3p physiologic levels as a possible therapeutic strategy for the treatment of HCC. PMID- 29249452 TI - Measuring self-efficacy, executive function, and temporal discounting in Kenya. AB - Developing countries have low adherence to medical regimens like water chlorination or antenatal and postnatal care, contributing to high infant and child mortality rates. We hypothesize that high levels of stress affect adherence through temporal discounting, self-efficacy, and executive control. Measurement of these constructs in developing countries requires adaptation of existing measures. In the current study, we adapt psychological scales and behavioral tasks, measuring each of these three constructs, for use among adults in Kenya. We translated and back-translated each measure to Kiswahili and conducted cognitive interviewing to establish cultural acceptability, refined existing behavioral tasks, and developed new ones. Then, in a laboratory session lasting 3 h, participants (N=511) completed the adapted psychological inventories and behavioral tasks. We report the psychometric properties of these measures. We find relatively low reliability and poor correlational evidence between psychological scales and behavioral tasks measuring the same construct, highlighting the challenges of adapting measures across cultures, and suggesting that assays within the same domain may tap distinct underlying processes. PMID- 29249453 TI - Stability analysis and dynamic regulation of multi-dimensional Taylor network controller for SISO nonlinear systems with time-varying delay. AB - Though many studies are focused on the stabilization of nonlinear systems with time-varying delay, they fail to involve the dynamic regulation without on-line optimization commonly. For this sake, feedback linearization, Lyapunov-Razumikhin theorem and polynomial approximation theorem are employed here to verify that the multi-dimensional Taylor network (MTN) controller can stabilize the single input single output (SISO) nonlinear time-varying delay systems through dynamic regulation of the system output with no need for on-line optimization. Here, the design of the controller is transformed into a convex optimization problem, which is tackled by means of the appropriate optimization method. Like its PD-like controller peers, the MTN controller functions well in eliminating the dependence on the system model. The effectiveness of the proposed approach is demonstrated and confirmed via two examples. PMID- 29249454 TI - Biomechanical consequences of running with deep core muscle weakness. AB - The deep core muscles are often neglected or improperly trained in athletes. Improper function of this musculature may lead to abnormal spinal loading, muscle strain, or injury to spinal structures, all of which have been associated with increased low back pain (LBP) risk. The purpose of this study was to identify potential strategies used to compensate for weakness of the deep core musculature during running and to identify accompanying changes in compressive and shear spinal loads. Kinematically-driven simulations of overground running were created for eight healthy young adults in OpenSim at increasing levels of deep core muscle weakness. The deep core muscles (multifidus, quadratus lumborum, psoas, and deep fascicles of the erector spinae) were weakened individually and together. The superficial longissimus thoracis was a significant compensator for 4 out of 5 weakness conditions (p < 0.05). The deep erector spinae required the largest compensations when weakened individually (up to a 45 +/- 10% increase in compensating muscle force production, p = 0.004), revealing it may contribute most to controlling running kinematics. With complete deep core muscle weakness, peak anterior shear loading increased on all lumbar vertebrae (up to 19%, p = 0.001). Additionally, compressive spinal loading increased on the upper lumbar vertebrae (up to 15%, p = 0.007) and decreased on the lower lumbar vertebrae (up to 8%, p = 0.008). Muscular compensations may increase risk of muscular fatigue or injury and increased spinal loading over numerous gait cycles may result in damage to spinal structures. Therefore, insufficient strength of the deep core musculature may increase a runner's risk of developing LBP. PMID- 29249455 TI - Biomechanical measurement and analysis of colchicine-induced effects on cells by nanoindentation using an atomic force microscope. AB - Colchicine is a drug commonly used for the treatment of gout, however, patients may sometimes encounter side-effects induced by taking colchicine, such as nausea, vomiting, diarrhea and kidney failure. In this regard, it is imperative to investigate the mechanism effects of colchicine on biological cells. In this paper, we present a method for the detection of mechanical properties of nephrocytes (VERO cells), hepatocytes (HL-7702 cells) and hepatoma cells (SMCC 7721 cells) in culture by atomic force microscope (AFM) to analyze the 0.1 MUg/mL colchicine-induced effects on the nanoscale for two, four and six hours. Compared to the corresponding control cells, the biomechanical properties of the VERO and SMCC-7721 cells changed significantly and the HL-7702 cells did not considerably change after the treatment when considering the same time period. Based on biomechanical property analyses, the colchicine solution made the VERO and SMCC 7721 cells harder. We conclude that it is possible to reduce the division rate of the VERO cells and inhibit the metastasis of the SMCC-7721 cells. The method described here can be applied to study biomechanics of many other types of cells with different drugs. Therefore, this work provides an accurate and rapid method for drug screening and mechanical analysis of cells in medical research. PMID- 29249456 TI - The rate of PD catheter complication does not increase with simultaneous abdominal surgery. AB - INTRODUCTION: Children with kidney failure requiring PD catheter placement often require additional intraabdominal surgery. However, the risk of complication related to simultaneous abdominal surgery at time of catheter placement is unknown. METHODS: Patients (0-18years) who underwent PD catheter placement (2012 2015) in the NSQIP-P database were reviewed. Complication rates between patients who underwent additional abdominal surgery at the time of PD catheter placement and those that did not were evaluated. One to one case control matching was performed for additional adjusted analysis. RESULTS: Of 563 patients who met inclusion criteria, 82 underwent simultaneous abdominal surgery at time of PD catheter placement. Patients in the simultaneous group had a higher rate of wound contamination but there was no difference in rates of SSI, 30-day PD catheter complication, or 30-day mortality compared with the nonsimultaneous group. There was no difference when overall simultaneous abdominal surgery or gastrointestinal surgery was evaluated. In our 1:1 adjusted analysis, there was a higher rate of PD catheter complication (11.3% vs. 2.8%, p=0.049) and SSI (31.0% vs. 4.2%, p<0.001) in the nonsimultaneous group. CONCLUSIONS: Thirty-day PD catheter complication and SSI in patients who underwent simultaneous abdominal surgery at time of catheter placement were noninferior to outcomes in the nonsimultaneous. LEVEL OF EVIDENCE: Level III, Treatment study, Retrospective comparative study. PMID- 29249457 TI - Assessing Liver Stiffness by 2-D Shear Wave Elastography in a Healthy Cohort. AB - The aim of this study was to assess the normal ranges of liver stiffness measurements (LSMs) in participants with healthy livers, using General Electric 2 D shear wave elastography (2-D-SWE-GE) compared with transient elastography (TE). We included 80 participants with healthy livers and without known liver disease, in whom liver stiffness was evaluated in the same session using two elastographic methods, TE and 2-D-SWE-GE. Reliable LSMs were defined for TE as the median of 10 measurements with a success rate of >=60% and an interquartile range (IQR) < 30%, and for 2-D-SWE-GE, as the median of 10 measurements acquired in a homogenous area and an IQR < 30%. Participants with LSMs > 6.5 kPa by TE were excluded. Reliable LSMs were obtained in 79 participants (98.7%) by means of 2-D-SWE-GE and in 80 participants (100%) by means of TE (p = 0.9). The mean LSM obtained by 2-D SWE-GE in our cohort of participants with healthy livers was 5.1 +/- 1.3 kPa, which was significantly higher than the LSM assessed by TE (4.3 +/- 0.9 kPa, p < 0.0001). In 2-D SWE-GE, mean LSMs were significantly higher for men than for women, 5.9 +/- 1.2 kPa versus 4.7 +/- 1.2 kPa (p = 0.0005). In conclusion, 2-D SWE-GE has very good feasibility (98.7%) in healthy persons. The mean LSM determined by 2-D-SWE-GE in healthy participants was 5.1 +/- 1.3 kPa. LSMs obtained by means of 2-D-SWE-GE were higher than those obtained by TE in participants with healthy livers. PMID- 29249458 TI - Evaluation of Large-Aperture Imaging Through the ex Vivo Human Abdominal Wall. AB - Current clinical abdominal imaging arrays are designed to maximize angular field of view rather than the extent of the coherent aperture. We illustrate, in ex vivo experiments, the use of a large effective aperture to perform high resolution imaging, even in the presence of abdominal wall-induced acoustic clutter and aberration. Point and lesion phantom targets were imaged through a water path and through three excised cadaver abdominal walls to create different clinically relevant clutter effects with matched imaging targets. A 7.36-cm effective aperture was used to image the targets at a depth of 6.4 cm, and image quality metrics were measured over a range of aperture sizes using synthetic aperture techniques. In all three cases, although degradation compared with the control was observed, lateral resolution improved with increasing aperture size without loss of contrast. Spatial compounding of the large-aperture data drastically improved lesion detectability and produced contrast-to-noise ratio improvements of 83%-106% compared with the large coherent aperture. These studies indicate the need for the development of large arrays for high-resolution abdominal diagnostic imaging. PMID- 29249460 TI - Editorial Comment. PMID- 29249459 TI - Translational Control Mechanisms in Persistent Pain. AB - Persistent pain, which is poorly treated and estimated to afflict one third of the world's population, is largely mediated by the sensitization of nociceptive neurons. This sensitization involves de novo gene expression to support biochemical and structural changes required to maintain amplified pain signaling that frequently persists even after injury to tissue resolves. While transcription-dependent changes in gene expression are important, recent work demonstrates that activity-dependent regulation of mRNA translation is key to controlling the cellular proteome and the development and maintenance of persistent pain. In this review, we highlight recent advances in translational regulation of gene expression in nociceptive circuits, with a focus on key signaling pathways and mRNA targets that may be tractable for the creation of next-generation pain therapeutics. PMID- 29249463 TI - Derivation of Human Trophoblast Stem Cells. AB - Trophoblast cells play an essential role in the interactions between the fetus and mother. Mouse trophoblast stem (TS) cells have been derived and used as the best in vitro model for molecular and functional analysis of mouse trophoblast lineages, but attempts to derive human TS cells have so far been unsuccessful. Here we show that activation of Wingless/Integrated (Wnt) and EGF and inhibition of TGF-beta, histone deacetylase (HDAC), and Rho-associated protein kinase (ROCK) enable long-term culture of human villous cytotrophoblast (CT) cells. The resulting cell lines have the capacity to give rise to the three major trophoblast lineages, which show transcriptomes similar to those of the corresponding primary trophoblast cells. Importantly, equivalent cell lines can be derived from human blastocysts. Our data strongly suggest that the CT- and blastocyst-derived cell lines are human TS cells, which will provide a powerful tool to study human trophoblast development and function. PMID- 29249462 TI - Muscle Stem Cells Exhibit Distinct Clonal Dynamics in Response to Tissue Repair and Homeostatic Aging. AB - The clonal complexity of adult stem cell pools is progressively lost during homeostatic turnover in several tissues, suggesting a decrease in the number of stem cells with distinct clonal origins. The functional impact of reduced complexity on stem cell pools, and how different tissue microenvironments may contribute to such a reduction, are poorly understood. Here, we performed clonal multicolor lineage tracing of skeletal muscle stem cells (MuSCs) to address these questions. We found that MuSC clonal complexity is maintained during aging despite heterogenous reductions in proliferative capacity, allowing aged muscle to mount a clonally diverse, albeit diminished, response to injury. In contrast, repeated bouts of tissue repair cause a progressive reduction in MuSC clonal complexity indicative of neutral drift. Consistently, biostatistical modeling suggests that MuSCs undergo symmetric expansions with stochastic fate acquisition during tissue repair. These findings establish distinct principles that underlie stem cell dynamics during homeostatic aging and muscle regeneration. PMID- 29249465 TI - Corrigendum to "Parenting very preterm infants and stress in Neonatal Intensive Care Units" (Early Hum. Dev. 101 (2016) 3-9). PMID- 29249461 TI - Improving Vaccine and Immunotherapy Design Using Biomaterials. AB - Polymers, lipids, scaffolds, microneedles, and other biomaterials are rapidly emerging as technologies to improve the efficacy of vaccines against infectious disease and immunotherapies for cancer, autoimmunity, and transplantation. New studies are also providing insight into the interactions between these materials and the immune system. This insight can be exploited for more efficient design of vaccines and immunotherapies. Here, we describe recent advances made possible through the unique features of biomaterials, as well as the important questions for further study. PMID- 29249464 TI - YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration. AB - Tissue regeneration requires dynamic cellular adaptation to the wound environment. It is currently unclear how this is orchestrated at the cellular level and how cell fate is affected by severe tissue damage. Here we dissect cell fate transitions during colonic regeneration in a mouse dextran sulfate sodium (DSS) colitis model, and we demonstrate that the epithelium is transiently reprogrammed into a primitive state. This is characterized by de novo expression of fetal markers as well as suppression of markers for adult stem and differentiated cells. The fate change is orchestrated by remodeling the extracellular matrix (ECM), increased FAK/Src signaling, and ultimately YAP/TAZ activation. In a defined cell culture system recapitulating the extracellular matrix remodeling observed in vivo, we show that a collagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous YAP/TAZ and induce conversion of cell fate. This provides a simple model for tissue regeneration, implicating cellular reprogramming as an essential element. PMID- 29249466 TI - Prevalence and risk factors of hepatitis B and C among hemodialysis patients in Tunisia. AB - OBJECTIVE: Hemodialysis patients are at increased risk of infection by hepatitis C and B viruses, which are significant causes of mortality and morbidity. Prevention of their transmission in hemodialysis units remains a challenge worldwide. We aimed to investigate the prevalence of these two infections and to explore major risk factors among patients on chronic hemodialysis. MATERIALS AND METHODS: We performed a cross-sectional study of 109 hemodialysis patients (mean duration of hemodialysis of seven years) between 2012 and 2014 in a Teaching Hospital of Monastir, Tunisia. Hepatitis B and C serological markers were searched for using a chemiluminescent assay. Genome detection was performed using a commercially available quantitative real-time PCR test. RESULTS: A total of 109 hemodialysis patients were enrolled (75 males and 34 females). Ages ranged from 21 to 81 years. Six (5.5%) of these 109 patients had HBV infection defined by a positive HBsAg in four (3.7%) patients and by a detectable DNA associated with an "isolated anti-HBc" profile in the remaining two patients. Hepatitis C was observed in eight patients (7.3%) and five of them had detectable RNA. Hemodialysis duration ?5years was the main risk factor for hepatitis C infection (P=0.01; OR: 3.11; 95% CI [1.57-13.71]). CONCLUSION: Our findings confirm the downward trend of the prevalence of both hepatitis B and C infections among Tunisian hemodialysis patients. Hemodialysis duration remains the main risk factor for hepatitis C infection. Occult hepatitis B infection should be suspected and investigated, especially among patients with an "isolated anti-HBc" profile. PMID- 29249467 TI - The Kampala declaration on sepsis - The recognition and treatment of severe illness starts at the bedside by recording vital signs. PMID- 29249468 TI - An interesting insight into breakfast and cardiovascular disease. PMID- 29249469 TI - Corrigendum to "Contribution of central and peripheral factors at peak exercise in heart failure patients with progressive severity of exercise limitation." [Int. J. Cardiol. 248 (2017) 252-256]. PMID- 29249470 TI - Heart rate as a prognostic marker and therapeutic target in acute and chronic heart failure. AB - Since increased heart rate (HR) is associated with higher mortality in several cardiac disorders, HR is considered not only a physiological indicator but also a prognostic and biological marker. In heart failure (HF), it represents a therapeutic target in chronic phase. The use or up-titration of beta-blockers, a milestone in HF with reduced left ventricular ejection fraction (LVEF) treatment, is at times limited by patients' hemodynamic profile or intolerance. Ivabradine, a HR-lowering drug inhibiting the f-current in pacemaker cells, has been shown to improve outcome in patients with chronic HF, in sinus rhythm with increased HR beyond beta-blocker therapy. The rationale for this review is to update the role of HR as a prognostic biomarker and a potential therapeutic target in other scenarios than chronic HF; namely, in patients with coexisting atrial fibrillation (AF), in HF with preserved LVEF (HFpEF), in acute HF, and in patients discharged after an episode of acute HF. Preliminary studies and case reports that evaluated the use of ivabradine in the setting of acute HF will be summarized. Recent results of HR reduction in the setting of HFpEF with ivabradine will be presented. Finally, data from large registries and trials that evaluated the prognostic impact of HR in patients with acute HF and sinus rhythm or AF will be reviewed, showing that only patients in sinus rhythm may benefit from HR reduction. PMID- 29249472 TI - Obesity: the sweet revenge of tax. PMID- 29249471 TI - Determinants and Prognostic Impact of Heart Failure and Left Ventricular Ejection Fraction in Acute Coronary Syndrome Settings. AB - INTRODUCTION AND OBJECTIVES: Contemporary data on the incidence and prognosis of heart failure (HF) and the influence of left ventricular ejection fraction (LVEF) in the setting of acute coronary syndrome (ACS) are scant. The aim of this study was to examine the relationship between LVEF and HF with long-term prognosis in a cohort of patients with ACS. METHODS: This is a retrospective observational study of 6208 patients consecutively admitted for ACS to 2 different Spanish hospitals. Baseline characteristics were examined and a follow-up period was established for registration of death and HF rehospitalization as the primary endpoint. RESULTS: Among the study participants, 5064 had ACS without HF during hospitalization: 290 (5.8%) had LVEF<40%, 540 (10.6%) LVEF 40% to 49%, and 4234 (83.6%) LVEF >= 50%. The remaining 1144 patients developed HF in the acute phase: 395 (34.6%) had LVEF<40%, 251 (21.9%) LVEF 40% to 49%, and 498 (43.5%) LVEF >= 50%. Patients with LVEF 40% to 49% had a demographic and clinical profile with intermediate features between the LVEF <40% and LVEF >= 50% groups. Kaplan-Meier curves showed that mortality and HF readmissions were statistically different depending on LVEF in the non-HF group but not in the HF group. Left ventricular ejection fraction >= 50% was an independent prognostic factor in the non-HF group only. CONCLUSIONS: In ACS, long-term prognosis is considerably worse in patients who develop HF during hospitalization than in patients without HF, irrespective of LVEF. This parameter is a strong prognostic predictor only in patients without HF. PMID- 29249473 TI - Reframing solidarity in Europe: Frontex, frontiers, and the fallacy of refugee quota. PMID- 29249475 TI - Correction to Lancet Public Health 2016; 1: e46-55. PMID- 29249474 TI - Eliminating the scourge of tobacco for a fairer and healthier world: New Zealand leads the way. PMID- 29249476 TI - The impact of sugared drink taxation and industry response. PMID- 29249477 TI - Levels of ambient air pollution according to mode of transport: a systematic review. AB - BACKGROUND: Controversy exists about the differences in air pollution exposure and inhalation dose between mode of transport. We aimed to review air pollution exposure and inhaled dose according to mode of transport and pollutant and their effect in terms of years of life expectancy (YLE). METHODS: In this systematic review, we searched ten online databases from inception to April 13, 2016, without language or temporal restrictions, for cohort, cross-sectional, and experimental studies that compared exposure to carbon monoxide, black carbon, nitrogen dioxide, and fine and coarse particles in active commuters (pedestrian or cyclist) and commuters using motorised transport (car, motorcycle, bus, or massive motorised transport [MMT-ie, train, subway, or metro]). We excluded studies that measured air pollution exposure exclusively with biomarkers or on the basis of simulated data, reviews, comments, consensuses, editorials, guidelines, in-vitro studies, meta-analyses, ecological studies, and protocols. We extracted average exposure and commuting time per mode of transport and pollutant to calculate inhaled doses. We calculated exposure and inhaled dose ratios using active commuters as the reference and summarised them with medians and IQRs. We also calculated differences in YLE due to fine particle inhaled dose and physical activity. FINDINGS: We identified 4037 studies, of which 39 were included in the systematic review. Overall, car commuters had higher exposure to all pollutants than did active commuters in 30 (71%) of 42 comparisons (median ratio 1.22 [IQR 0.90-1.76]), followed by those who commuted by bus in 57 (52%) of 109 (1.0 [0.79-1.41]), by motorcycle in 16 (50%) of 32 (0.99 [0.86-1.38]), by a car with controlled ventilation settings in 39 (45%) of 86 (0.95 [0.66-1.54]), and by MMT in 21 (38%) of 55 (0.67 [0.49-1.13]). Overall, active commuters had higher inhalation doses than did commuters using motorised transport (median ratio car with controlled ventilation settings 0.16 [0.10-0.28]; car 0.22 [0.15 0.30]; motorcycle 0.38 [0.26-0.78]; MMT 0.49 [0.34-0.81]; bus 0.72 [IQR 0.50 0.99]). Commuters using motorised transport lost up to 1 year in YLE more than did cyclists. INTERPRETATION: Proximity to traffic and high air interchange increased the exposure to air pollution of commuters using motorised transport. Larger inhalation rates and commuting time increased inhaled dose among active commuters. Benefits of active commuting from physical activity are larger than the risk from an increased inhaled dose of fine particles. FUNDING: Departamento Administrativo de Ciencia, Tecnologia e Innovacion (COLCIENCIAS), National Health and Medical Research Council, Nestle Nutrition (Nestec), Metagenics, and AXA. PMID- 29249478 TI - Mortality and causes of death in people diagnosed with HIV in the era of highly active antiretroviral therapy compared with the general population: an analysis of a national observational cohort. AB - BACKGROUND: Deaths in HIV-positive people have decreased since the introduction of highly active antiretroviral therapy (HAART) in 1996. Fewer AIDS-related deaths and an ageing cohort have resulted in an increase in the proportion of HIV patients dying from non-AIDS-related disorders. Here we describe mortality and causes of death in people diagnosed with HIV in the HAART era compared with the general population. METHODS: In this observational analysis, we linked cohort data collected by Public Health England (PHE) for individuals aged 15 years and older, diagnosed with HIV in England and Wales from 1997 to 2012, to the Office for National Statistics (ONS) national mortality register. Cohort inclusion began at diagnosis with follow-up clinical information collected every year from all 220 National Health Service (NHS) HIV outpatient clinics nationwide. To classify causes of death we used a modified Coding Causes of Death in HIV (CoDe) protocol, which uses death certificate data and clinical markers. We applied Kaplan-Meier analysis for survival curves and mortality rate estimation and Cox regression to establish independent predictors of all-cause mortality, adjusting for sex, infection route, age at diagnosis, region of birth, year of diagnosis, late diagnosis, and history of HAART. We used standardised mortality ratios (SMRs) to make comparisons with the general population. FINDINGS: Between 1997 and 2012, 88 994 people were diagnosed with HIV, contributing 448 839 person-years of follow up. By the end of 2012, 5302 (6%) patients had died (all-cause mortality 118 per 10 000 person-years, 95% CI 115-121). In multivariable analysis, late diagnosis was a strong predictor of death (hazard ratio [HR] 3.50, 95% CI 3.13-3.92). People diagnosed more recently had a lower risk of death (2003-07: HR 0.66, 95% CI 0.62-0.70; 2008-12: HR 0.65, 95% CI 0.60-0.71). Cause of death was determinable for 4808 (91%) of 5302 patients; most deaths (2791 [58%] of 4808) were attributable to AIDS-defining illnesses. Cohort mortality was significantly higher than the general population for all causes (SMR 5.7, 95% CI 5.5-5.8), particularly non-AIDS infections (10.8, 9.8-12.0) and liver disease (3.7, 3.3 4.2). All-cause mortality was highest in the year after diagnosis (SMR 24.3, 95% CI 23.4-25.2). INTERPRETATION: Despite the availability of free treatment and care in the UK, AIDS continues to account for the majority of deaths in HIV positive people, and mortality remains higher in HIV-positive people than in the general population. These findings highlight the importance of prompt diagnosis, care engagement, and optimum management of comorbidities in reducing mortality in people with HIV. FUNDING: Public Health England. PMID- 29249479 TI - Air pollution and health. PMID- 29249480 TI - Emergence of drug resistance in patients with tuberculosis cared for by the Indian health-care system: a dynamic modelling study. AB - BACKGROUND: India has the highest number of patients with tuberculosis and multidrug-resistant tuberculosis in the world. We used a transmission model to project the emergence of drug resistance in India due to incorrect tuberculosis management practices in multiple sectors, including public and private providers, chemists, and non-allopathic practitioners. METHODS: We constructed a dynamic Markov model to represent India's tuberculosis epidemic, including a probabilistic framework reflecting complex treatment-seeking pathways. Underlying drug resistance and the acquisition of drug resistance during treatment were included. India-specific epidemiological data, including tuberculosis management practices, were obtained from published literature. Outcomes, which included annual risk of infection, incidence of new disease, prevalence of untreated tuberculosis, and tuberculosis-related mortality, were stratified by underlying drug resistance, as well as by health sector to understand how each sector contributes to the emergence of drug resistance. FINDINGS: If tuberculosis management practices across sectors in India remain unchanged over the next 20 years, we estimated a 47% increase in the incidence of isoniazid resistance, a 152% increase in multidrug-resistant tuberculosis incidence, a 242% increase in prevalent untreated multidrug-resistant tuberculosis, and a 275% increase in the risk of multidrug-resistant tuberculosis infection. By 2032, an estimated 85% of multidrug-resistant tuberculosis will be primary multidrug-resistant tuberculosis compared with only 15% in 2012. The public sector contributed 87% of acquired multidrug-resistant tuberculosis, related to irregular adherence; the remainder came from the private sector, related to treatment non-completion. Chemists and non-allopathic practitioners do not treat with rifampicin, but because of the high rates of inappropriate isoniazid-containing regimens, and treatment non adherence, this would generate isoniazid resistance. INTERPRETATION: We predict a gradual transformation from the current epidemic of drug-susceptible tuberculosis to a drug-resistant epidemic. Evidence-based strategies to improve provider practices and patient adherence across health sectors are urgently needed to prevent this. FUNDING: United States Agency for International Development and the Canadian Institutes for Health Research. PMID- 29249481 TI - Better to know: the importance of early HIV diagnosis. PMID- 29249482 TI - Multidrug-resistant tuberculosis in India: looking back, thinking ahead. PMID- 29249484 TI - It's not how you finish, it's how you start? PMID- 29249483 TI - Component characterization and predictive modeling for green roof substrates optimized to adsorb P and improve runoff quality: A review. AB - This review is a synthesis of the current knowledge regarding the effects of green roof substrate components and their retentive capacity for nutrients, particularly phosphorus (P). Substrates may behave as either sources or sinks of P depending on the components they are formulated from, and to date, the total P adsorbing capacity of a substrate has not been quantified as the sum of the contributions of its components. Few direct links have been established among substrate components and their physicochemical characteristics that would affect P-retention. A survey of recent literature presented herein highlights the trends within individual component selection (clays and clay-like material, organics, conventional soil and sands, lightweight inorganics, and industrial wastes and synthetics) for those most common during substrate formulation internationally. Component selection will vary with respect to ease of sourcing component materials, cost of components, nutrient-retention capacity, and environmental sustainability. However, the number of distinct components considered for inclusion in green roof substrates continues to expand, as the desires of growers, material suppliers, researchers and industry stakeholders are incorporated into decision-making. Furthermore, current attempts to characterize the most often used substrate components are also presented whereby runoff quality is correlated to entire substrate performance. With the use of well described characterization (constant capacitance model) and modeling techniques (the soil assemblage model), it is proposed that substrates optimized for P adsorption may be developed through careful selection of components with prior knowledge of their chemical properties, that may increase retention of P in plant available forms, thereby reducing green roof fertilizer requirements and P losses in roof runoff. PMID- 29249486 TI - Type I thoracoabdominal aortic aneurysm: Intercostal reimplantation by the "snake" technique. PMID- 29249485 TI - Application of polymer-mesh device to remodel left ventricular-mitral valve apparatus in ischemic mitral regurgitation. AB - OBJECTIVES: Ischemic mitral regurgitation (IMR) results from ischemic left ventricular (LV) distortion and remodeling, which displaces the papillary muscles and tethers the mitral valve leaflets apically. The aim of this experimental study was to examine efficacy of an adjustable novel polymer filled mesh (poly mesh) device to reverse LV remodeling and reduce IMR. METHODS: Acute (N = 8) and chronic (8 weeks; N = 5) sheep models of IMR were studied. IMR was produced by ligation of circumflex branches to create myocardial infarction. An adjustable poly-mesh device was attached to infarcted myocardium in acute and chronic IMR models and compared with untreated sham sheep. Two- and 3-dimensional echocardiography and hemodynamic measurements were performed at baseline, post IMR, and post poly-mesh (humanely killed). RESULTS: In acute models, moderate IMR developed in all sheep and decreased to trace/mild (vena contracta: 0.50 +/- 0.09 cm to 0.26 +/- 0.12 cm; P < .01) after poly-mesh. In chronic models, IMR decreased in all sheep after poly-mesh, and this reduction persisted over 8 weeks (vena contracta: 0.42 +/- 0.09 cm to 0.08 +/- 0.12 cm; P < .01) with significant increase in the slope of end-systolic pressure-volume relationship (1.1 +/- 0.5 mm Hg/mL to 2.9 +/- 0.7 mm Hg/mL; P < .05). There was a significant reduction in LV volumes from chronic IMR to euthanasia stage with poly-mesh compared with sham group (%end-diastolic volume change -20 +/- 11 vs 15% +/- 16%, P < .01; %end systolic volume change -14% +/- 19% vs 22% +/- 22%, P < .05; poly-mesh vs sham group) consistent with reverse remodeling. CONCLUSIONS: An adjustable polymer filled mesh device reduces IMR and prevents continued LV remodeling during chronic follow-up. PMID- 29249488 TI - Don't toss the excess: Using the redundant truncal valve cusp may improve repair for truncus arteriosus. PMID- 29249487 TI - Association of body mass index with lung transplantation survival in the United States following implementation of the lung allocation score. AB - BACKGROUND: The association of body mass index (BMI) with survival after lung transplantation remains controversial, owing to conflicting evidence in the literature. Previous reports have used traditional BMI categories, included patients who underwent transplantation before implementation of the lung allocation score (LAS), or were limited by single-center experiences. Here we evaluated the association of individual BMI units with short-term and long-term mortality in a large national database following implementation of the LAS. METHODS: The Scientific Registry of Transplant Recipients database was used to collect data for 17,233 adult lung transplantations performed between May 2005 and June 2016. The primary outcome was all-cause mortality at 90 days and 1 year posttransplantation. Logistic regression modeling was used to independently predict mortality per BMI unit, adjusting for donor and recipient factors. RESULTS: BMI was an independent predictor of mortality at both 90 days and 1 year. At 90 days, a BMI of 25 was associated with the lowest predicted probability of death (0.053; 95% confidence interval [CI], 0.047-0.049), with increased odds of mortality at BMI <=20 and >=28. At 1 year, a BMI of 26 was associated with the lowest predicted probability of death (0.12; 95% CI, 0.11 0.13), with increased odds of mortality at BMI <=24 and >=28. CONCLUSIONS: Each individual BMI unit has a quantifiable effect on posttransplantation survival, and the patterns of effect do not fit into the predefined BMI categories. The mortality risk associated with BMI should be considered by transplant centers when making listing decisions and by regulatory bodies for estimating expected outcomes. PMID- 29249489 TI - Infectious aortitis: A bridge too far. PMID- 29249490 TI - Intercostal artery reimplantation with saphenous vein during thoracoabdominal aortic replacement. PMID- 29249491 TI - Laparoscopic transdiaphragmatic chest surgery: Early experience. AB - OBJECTIVE: We describe laparoscopic transdiaphragmatic (LTD) chest surgery without intercostal incisions and focus on technique and safety. The goal of LTD is to minimize postoperative pain. METHODS: We reviewed all patients undergoing LTD chest surgery (September 8, 2010-April 4, 2017). We place 4 abdominal ports with the patient in semilateral decubitus, make 2 diaphragmatic openings, and advance 2 ports into the chest. The intrathoracic operation is standard video assisted thoracoscopic surgery (VATS), and diaphragmatic openings are closed at the end. We compared narcotic use (morphine equivalents) between patients undergoing LTD lung resection with historical controls undergoing conventional VATS. RESULTS: We performed 28 LTD chest procedures (wedge, 19; lobectomy, 3; segmentectomy, 3; other, 3; right sided, 20). Indications were lung nodule (14), lung cancer (5), interstitial lung disease (6), and other (3). Median operative times were 138 minutes (96-240 minutes) for wedge resection and 296 minutes (255 356 minutes, including transcervical mediastinal lymphadenectomy) for anatomic resections. Respiratory complications occurred in 3 patients and other complications in 5 (total 8; 28.6%). Computed tomography in 22 patients (79%) at median 13 months (3-47 months) after surgery showed no diaphragmatic hernia. LTD chest surgery patients used less narcotics than conventional VATS without paravertebral block 24 to 48 hours postoperatively (P = .039). CONCLUSIONS: Early experience suggests that LTD chest surgery is feasible and safe on short- to midterm follow-up. The specific role of LTD chest surgery will require definition of patient selection criteria, further experience to reduce operative time, long term follow-up, and prospective comparison with conventional VATS. PMID- 29249492 TI - Tighten your belt or lose your pants? Not if it is tailored to the patient annuloplasty during remodeling. PMID- 29249493 TI - Exendin-4 improves cardiovascular function and survival in flow-induced pulmonary hypertension. AB - OBJECTIVES: Systemic left-to-right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon-like peptide, exendin-4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats. METHODS: Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin-4 (1 MUg/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology. RESULTS: Exendin-4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin 1beta levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin-4. Smooth muscle-myosin heavy chain-II and alpha smooth muscle actin protein levels increased in the pulmonary arteries of exendin 4-treated rats. Histology showed that exendin-4 decreased the main and intra acinar pulmonary artery medial thickness. CONCLUSIONS: Exendin-4 treatment improved pulmonary artery function in flow-induced PH via its direct vasoactive properties, anti-inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin-1beta and its downstream signaling molecules. Glucagon-like peptide analogs may possess pleiotropic therapeutic potential in flow-induced PH. PMID- 29249494 TI - Sternotomy extra-anatomic bypass for stent-graft extension. PMID- 29249495 TI - Off-pump versus on-pump: State of the ART? PMID- 29249496 TI - A step forward or running from risk? PMID- 29249497 TI - Chylothorax and pleural effusion in contemporary extracardiac fenestrated fontan completion. AB - BACKGROUND: We hypothesized that chylothorax could be a sign of intolerance to the Fontan physiology, and thus patients who develop chylothorax or pleural effusion have worse medium-term to long-term survival. METHODS: A total of 324 patients who underwent the Fontan operation between 2000 and 2013 were included. Chylothorax was defined as >=5 mL/kg/day of chylomicron-positive chest drainage fluid no earlier than postoperative day 5 or drainage with >80% lymphocytes. Outcomes were compared between the chylothorax and non-chylothorax groups by the Kaplan-Meier method and log-rank test. Independent predictors of chylothorax and number of days of any chest drainage were analyzed with multivariable logistic regression and multivariable generalized negative binomial regression for count data, respectively. RESULTS: Chylothorax occurred in 78 patients (24%). Compared with the non-chylothorax group, the chylothorax group had a longer duration of chest tube requirement (median, 18 days vs 9 days; P < .000) and a longer length of hospital stay (median, 19 days vs 10 days; P < .000). Eight patients (10.3%) required thoracic duct ligation. The chylothorax group had lower freedom from death (P = .013) and from composite adverse events (P = .021). No predictor was found for chylothorax. Pulmonary atresia (P = .031) and pre-Fontan pulmonary artery pressure (P = .01) were predictive of prolonged pleural effusion (>14 days). CONCLUSIONS: Occurrence of chylothorax following the Fontan operation can be a marker of poorer medium-term clinical outcomes. It is difficult to predict occurrence of chylothorax owing to its multifactorial nature and involvement of lymphatic compensatory capacity that is unmasked only after the Fontan operation. PMID- 29249498 TI - Skinning the cat: Another wrinkle for T-tube insertion. PMID- 29249499 TI - Spontaneous ventilation thoracoscopic thymectomy without muscle relaxant for myasthenia gravis: Comparison with "standard" thoracoscopic thymectomy. AB - OBJECTIVES: Myasthenia gravis (MG) benefits from thymectomy. However, its unpredictable response to muscle relaxants and volatile anesthetic agents may result in muscle weakness and subsequently in postoperative myasthenic crisis. The aim of this study was to determine the surgical outcomes after spontaneous ventilation compared with conventional intubated video-assisted thoracoscopic thymectomy (spontaneous-ventilation video-assisted thoracic thymectomy [SV-VATT] vs intubated video-assisted thoracic thymectomy) in patients with MG. METHODS: Data from all minimally invasive thymectomy procedures performed at our institute between January 2009 and June 2016 were collected. Patient characteristics, perioperative results, and treatment outcomes between SV-VATT (group 1) and the intubated video-assisted thoracic thymectomy (group 2) groups were compared. Furthermore, a propensity score-matching analysis was generated to control for selection bias due to nonrandom group assignment in a 1:1 manner. RESULTS: Thirty six patients were included in group 1 and 68 in group 2. Matching of patients according to propensity score resulted in a cohort that consisted of 27 patients in both groups. Patients had similar clinical characteristics in both groups. Operating time (P = .07) and lowest pulse oxygen saturation (P = .09) between the procedures were comparable after matching, but peak CO2 level at the end of expiration was significantly greater in group 1 both before and after matching (P < .01). Moreover, the incidence of postoperative myasthenic crisis and postoperative prolonged tracheal intubation was lower in group 1. The postoperative pain visual analog scale score (P < .01) and the length of hospital stay (P = .03) were shorter in group 1. CONCLUSIONS: SV-VATT is a feasible procedure in patients with MG. It might be beneficial by reducing postoperative myasthenic crisis and postoperative prolonged tracheal intubation. Further prospective research is needed. PMID- 29249500 TI - Initium novum? PMID- 29249501 TI - Predictors of survival in octogenarians after mitral valve surgery for degenerative disease: The Mitral Surgery in Octogenarians study. AB - OBJECTIVES: An increasing number of octogenarians are referred to undergo mitral valve surgery for degenerative disease, and percutaneous approaches are being increasingly used in this subgroup of patients. We sought to determine the survival and its predictors after Mitral Valve Surgery in Octogenarians (MiSO) in a multicenter UK study of high-volume specialized centers. METHODS: Pooled data from 3 centers were collected retrospectively. To identify the predictors of short-term composite outcome of 30 days mortality, acute kidney injury, and cerebrovascular accident, a multivariable logistic regression model was developed. Multiple Cox regression analysis was performed for late mortality. Kaplan-Meier curves were generated for long-term survival in various subsets of patients. Receiver operating characteristic analysis was done to determine the predictive power of the logistic European System for Cardiac Operative Risk Evaluation. RESULTS: A total of 247 patients were included in the study. The median follow-up was 2.9 years (minimum 0, maximum 14 years). A total of 150 patients (60.7%) underwent mitral valve repair, and 97 patients (39.3%) underwent mitral valve replacement. Apart from redo cardiac surgery (mitral valve repair 6 [4%] vs mitral valve replacement 11 [11.3%], P = .04) and preoperative atrial fibrillation (mitral valve repair 79 [52.6%] vs mitral valve replacement 34 [35.1%], P < .01), there was no significant difference in terms of any other preoperative characteristics between the 2 groups. Patient operative risk, as estimated by logistic European System for Cardiac Operative Risk Evaluation, was lower in the mitral valve repair group (10.2 +/- 11.8 vs 13.7 +/- 15.2 in mitral valve replacement; P = .07). No difference was found between groups for duration of cardiopulmonary bypass and aortic crossclamp times. The 30-day mortality for the whole cohort was 13.8% (mitral valve repair 4.7% vs mitral valve replacement 18.6%; P < .01). No differences were found in terms of postoperative cerebrovascular accident (2% vs 3.1%; P = .9), acute kidney injury requiring dialysis (6.7% vs 13.4%; P = .12), and superficial or deep sternal wound infection (10% vs 16.5%, P = .17; 2% vs 3.1%, P = .67, respectively). The final multiple regression model for short-term composite outcome included previous cardiac surgery (odds ratio [OR], 4.47; 95% confidence interval [CI], 1.37-17.46; P = .02), intra-aortic balloon pump use (OR, 4.77; 95% CI, 1.67-15.79; P < .01), and mitral valve replacement (OR, 7.7; 95% CI, 4.04-14.9; P < .01). Overall survival for the entire cohort at 1, 5, and 10 years was 82.4%, 63.7%, and 45.5% (mitral valve repair vs mitral valve replacement: 89.9% vs 70.7% at 1 year, 69.6% vs 54% at 5 years, and 51.8% vs 35.5% at 10 years; P = .0005). Cox proportional hazard model results showed mitral valve replacement (hazard ratio, 1.88; 95% CI, 1.22-2.89; P < .01) and intra-aortic balloon pump use (hazard ratio, 2.54; 95% CI, 1.26-5.13; P < .01) to be independent predictor factors affecting long-term survival. Logistic European System for Cardiac Operative Risk Evaluation did not perform well in predicting early mortality (area under the curve, 0.57%). CONCLUSIONS: In octogenarians, mitral valve repair for degenerative disease is associated with good survival and remains the gold standard, whereas mitral valve replacement is still associated with significant mortality. Logistic European System for Cardiac Operative Risk Evaluation was unable to predict early mortality in our cohort of patients. Larger international multicenter registries are required to optimize the decision-making process in such a high-risk subgroup. PMID- 29249502 TI - The profound impact of combined severe acidosis and malperfusion on operative mortality in the surgical treatment of type A aortic dissection. AB - OBJECTIVES: Surgery for type A aortic dissection is associated with a high operative mortality, and a variety of predictive risk factors have been reported. We hypothesized that a combination of risk factors associated with organ malperfusion and severe acidosis that are not currently documented in databases would be associated with a level of extreme operative risk that would warrant the consideration of treatment paradigms other than immediate ascending aortic surgery. METHODS: Charts of patients undergoing repair of acute type A aortic dissection between January 1, 1996, and May 1, 2016, were queried for preoperative malperfusion, preoperative base deficit, pH, bicarbonate, cardiopulmonary resuscitation, severe aortic insufficiency, redo status, and preoperative intubation. Multivariable logistic analyses were considered to evaluate interested variables and operative mortality. RESULTS: Between January 1, 1996, and May 1, 2016, 282 patients underwent surgical repair of type A aortic dissection. A total of 66 patients had a calculated base deficit -5 or greater. Eleven of 12 patients (92%) with severe acidosis (base deficit >=-10) with malperfusion had operative mortality. No patient with severe acidosis with abdominal malperfusion survived. Multivariable analyses identified base deficit, intubation, congestive heart failure, dyslipidemia/statin use, and renal failure as predictors of operative death. The most significant predictor was base deficit -10 or greater (odds ratio, 9.602; 95% confidence interval, 2.649-34.799). CONCLUSIONS: The combination of severe acidosis (base deficit >=-10) with abdominal malperfusion was uniformly fatal. Further research is needed to determine whether the identification of extreme risk warrants consideration of alternate treatment options to address the cause of severe acidosis before ascending aortic procedures. PMID- 29249503 TI - Introduction. PMID- 29249504 TI - Cognitive Disabilities and Long-term Outcomes in Children with Epilepsy: A Tangled Tail. AB - Cognitive problems ranging from mild specific learning problems to profound intellectual disability (ID) are very common in children with epilepsy. For most affected patients there is good evidence that the cognitive problems are present at the onset of seizures and do not deteriorate over time. There is no evidence that a few seizures lead to cognitive deterioration. An exception may occur in children with epileptic encephalopathies, although this contention is not always easy to prove. ID is a strong predictor of intractable epilepsy, and the greater the degree of the ID the greater the risk of medication resistant epilepsy. It is not known if specific learning disorders are associated with more severe epilepsy. Rolandic epilepsy is unusual because possibly one-third of patients have transient cognitive and behavioral difficulties during the active phase but later have normal adult social outcome. More longitudinal studies with baseline and repeated cognitive assessments are needed to fully understand the relationship of cognitive problems to childhood onset epilepsy. PMID- 29249505 TI - Early Life Epilepsies are a Comorbidity of Developmental Brain Disorders. AB - Early-life epilepsies are a series of disorders frequently accompanied by a broad range of morbidities that include cognitive, behavioral, neuromuscular, and sleep disturbances; enteric and other forms of autonomic dysfunction; sensory processing difficulties; and other issues. Usually these morbidities cluster together in a single patient. Rather than these being separate conditions, all, including the seizures, are manifestations or coexpressions of developmental brain disorders. Instead of viewing epilepsy as the disease and the other features as comorbidities, approaching early-life epilepsies as part of the spectrum of developmental brain disorders could have implications for multidisciplinary care models, anticipatory guidance, and counseling of parents, as well as the design of randomized trials and targeting important outcomes. Ultimately, such an approach could improve understanding and help optimize outcomes in these difficult to treat disorders of early childhood. PMID- 29249506 TI - Cognitive and Social Outcomes of Epileptic Encephalopathies. AB - The term "epileptic encephalopathy" denotes a disorder in which seizures or frequent interictal discharges exacerbate neurocognitive dysfunction beyond what would be expected on the basis of underlying etiology. However, many underlying causes of epileptic encephalopathy also result in neurocognitive deficits, and it can be challenging to discern to what extent these deficits can be improved with better seizure control. Additionally, as seizures in these conditions are typically refractory, children are often exposed to high doses of multiple antiepileptic drugs which further exacerbate these comorbidities. This review will summarize the neurocognitive and social outcomes in children with various epileptic encephalopathies. Prompt, accurate diagnosis of epilepsy syndrome and etiology allows selection of optimal therapy to maximize seizure control, limiting the impact of ongoing seizures and frequent epileptiform abnormalities on the developing brain. Furthermore, mandatory screening for comorbidities allows early recognition and focused therapy for these commonly associated conditions to maximize neurocognitive outcome. PMID- 29249507 TI - Neurocognitive Comorbidities in Pediatric Epilepsy: Lessons in the Laboratory and Clinical Profile. AB - Children with epilepsy are at risk for a variety of neurocognitive comorbidities. Animal models have increased our understanding about the neurobiological mechanisms underlying the association between seizures and these comorbidities. This article starts with an overview of the current data on animal model research, studying the influence of early-life seizures, followed by a summary of potential cellular and molecular mechanisms by which seizures can affect cognitive development. We then describe specific abnormal neuropsychological profiles that accompany specific pediatric epilepsy syndromes. Finally, we offer a potential guideline to the treatment and management of children with epilepsy and its neurocognitive comorbidities. PMID- 29249508 TI - Attention Deficit Hyperactivity Disorder and Associated Cognitive Dysfunction in Pediatric Epilepsy. AB - Attention deficit hyperactivity disorder (ADHD) is the most common neuropsychiatric comorbidity associated with childhood epilepsy, affecting about a third of children with epilepsy. In contrast, ADHD in the general population occurs in 4%-12% of school-aged children. The cause of this association remains unclear. It is likely that common mechanisms underlie the vulnerability for both executive deficits and epileptogenesis. There are characteristics unique to children with ADHD and epilepsy. The inattentive type of ADHD is more prevalent than the combined presentation in children with epilepsy, while the combined type is more common in the general population. Interestingly, there is an equal sex distribution of ADHD in patients with epilepsy, while in the general population, ADHD is 3-7 times more prevalent in boys. Specific features of ADHD seen in different epilepsy syndromes are frequently associated with executive deficits. Early screening of ADHD symptoms in children with epilepsy is essential, as timely interventions can improve academic and social function and outcomes. The mainstays of therapy include behavioral interventions and pharmacotherapy, with evidence demonstrating that stimulants are both safe and effective in children with ADHD and epilepsy. PMID- 29249509 TI - What is the Relationship Between Autism Spectrum Disorders and Epilepsy? AB - The association of epilepsy and autism spectrum disorders (ASD) is best understood by examining the relationship between social cognition, nonsocial cognition, and epilepsy. The relationship between ASD and epilepsy is bidirectional and is strongly linked to intellectual disability (ID). The risk of developing ASD in children with epilepsy is highest in children with early onset seizures, with a high prevalence in children with infantile spasms. The risk of developing epilepsy in children first diagnosed with ASD is highest in those with ID. The prevalence of seizures in ASD increases with age. When epilepsy and ASD coexist, they share common pathophysiological mechanisms. In epilepsy with and without ID, social-cognitive deficits are an important determinant of neurodevelopmental outcomes. Early recognition of social deficits is an important aspect of the comprehensive management of children with epilepsy. Treating the seizures in individuals with epilepsy and ASD is crucial but interventions that address social-cognitive deficits are necessary to maximize neurodevelopmental outcomes. PMID- 29249510 TI - Bone Health and Endocrine Comorbidities in Pediatric Epilepsy. AB - Antiseizure medications and dietary therapies have associated effects on the endocrine system. We provided an overview of the relationship between epilepsy treatment and bone health in children with epilepsy. Additionally, we discussed the effects of epilepsy treatment on other endocrine systems including thyroid function, growth, reproduction, and weight. The effect of epilepsy on bone health is multifactorial; there are direct and indirect effects of medication and dietary treatments as well as a decrease in physical activity, decreased sunlight exposure, decreased vitamin D levels, and additional comorbidities. Some medications have a greater effect on vitamin D and bone health than others, however all antiseizure medical treatments are associated with lower vitamin D levels in pediatric patients. We have provided practical suggestions for vitamin D surveillance in children with epilepsy as well as replacement strategies. Children with epilepsy have an increased likelihood of additional endocrine disorders including subclinical hypothyroidism, decreased growth, weight abnormalities, reproductive and sexual dysfunction. To a great extent, this is medication specific. Though more studies are needed to elucidate optimal treatment and monitoring of bone health and other endocrinopathies in children with epilepsy, it is critical that caregivers pay close attention to these issues to provide optimal comprehensive care to their patients. PMID- 29249511 TI - Pediatric Headache and Seizures. AB - Headache and seizures are two of the most common complaints seen in the field of pediatric neurology with headache being number one. Both these conditions may coexist. Where the difficulty begins is when the symptoms are not clear cut in making a diagnosis, and conditions are possible as either an atypical seizure or migraine variant. What further complicates matters is the fact that there are many underlying neurologic conditions that carry with them a higher likelihood of developing both headaches and seizures, making each a distinct possibility when obtaining a history from a parent about unusual spells. Although differentiating between seizure and headache may not be easy, with a focused yet thorough history and appropriate use of investigative tools, it can be done. Coming to the correct diagnosis is only the start; once seizures and or headaches have been appropriately diagnosed then the real challenge begins and that is finding a way to successfully treat the headaches and seizures. Within pediatric neurology, the acute options tend to be more diagnosis specific whereas the prophylactic ones may overlap and treat both headaches and seizures. In the following review, we will discuss the epidemiology of pediatric headaches and seizures, the overlap between these 2 conditions in diagnosis, as well as how to tell them apart, and the treatment options and prognosis of both common neurologic disorders in children. PMID- 29249512 TI - Cognitive and Behavioral Comorbidities: An Unwanted Effect of Antiepileptic Drugs in Children. AB - Epilepsy is one of the most common neurological disorders and, despite optimally chosen and dosed antiepileptic drugs (AEDs), approximately 20%-30% of patients will continue to have seizures. Behavior and cognition are negatively impacted by seizures, but AEDs are also a major contributor to behavioral and cognitive deficits. However, the cognitive and behavioral effect of AEDs in children is insufficiently emphasized in the literature. This review summarizes the cognitive and behavioral effects of AEDs in the pediatric population with the objective of helping pediatricians and pediatric neurologists to select the AEDs with the best profile for their individual patient's needs. PMID- 29249513 TI - Cognitive Outcome After Epilepsy Surgery in Children. AB - Cognitive dysfunction in children with epilepsy is primarily contributed by etiology, seizures, frequency of interictal epileptiform discharges, and adverse effects of antiepileptic drugs. The direct effect of epilepsy surgery on cognitive outcome depends on two key factors: the function that is present in the epileptogenic zone to be removed, and the dysfunction outside the epileptogenic zone caused by epilepsy. Studies on cognitive outcome in children after various types of epilepsy surgery estimate "no significant change" in about 70% of children, improvement in cognition in 10%-15%, and decline in 10%-15%. In young children with epileptic encephalopathy, the reversible dysfunction outside the epileptogenic zone is larger and hence carry better chances of improved outcome after successful surgery. If the epileptogenic zone harbors significant cognitive function (memory, language, or other function), then a decline in function may occur with its resection. Understanding the pathophysiological basis for the cognitive changes after epilepsy surgery assists in counseling patients and families before surgery. PMID- 29249514 TI - Effect of Epilepsy on Families, Communities, and Society. AB - The effect of epilepsy extends beyond those with the diagnosis and impacts families, communities and society. Caregiver and sibling quality of life is often negatively affected by frequent seizures, comorbid behavioral and sleep disorders and stigma surrounding the diagnosis. Furthermore, the negative effects can be magnified by individual coping styles and resources available to families of those with epilepsy. Beyond the family and immediate caregivers, epilepsy affects local communities by drawing additional resources from education systems. The direct costs of caring for an individual with epilepsy and the indirect costs associated with decreased productivity place financial strain on individuals and health care systems throughout the world. This review details factors affecting family and caregiver quality of life and provides several approaches through which health care providers may address these concerns. Furthermore, we examine the financial effect of epilepsy on society and review emerging strategies to lessen health care use for individuals with epilepsy. PMID- 29249515 TI - Ultrastructure of spermatozoa in cobia, Rachycentron canadum (Linnaeus, 1766). AB - Ultrastructure and development of spermatozoa in cobia, Rachycentron canadum are described. Sections through the testis show different developmental stages viz, Spermatocytes, spermatids and sperm. Spermatozoa of R. canadum exhibit the configuration of uniflagellated, anacrosomal Type I aquasperm, typical for externally fertilizing fish. Mature spermatozoon is seen with a prominent head and long cylindrical flagellum. Ultrastructure of sperm shows invaginated 'U' shaped nucleus and other organelles. The mitochondrial matrix is electron-dense with irregular arrangement of the cristae. The nucleus reveals a deep invagination (nuclear fossa) in which the centriolar complex is located. The centriolar complex lies inside the nuclear fossa and is composed of a proximal and a distal centriole. The two centrioles are placed perpendicular to each other. The flagellum has a typical eukaryotic organization (microtubule doublets 9 + 2 pattern) and measures around 36.21 +/- 0.42 MUm in length. This study for the first time provides a comprehensive detail on the ultrastructure and developmental process of sperm in cobia, R. canadum. PMID- 29249516 TI - Purification, structural and biophysical characterisation of the major seminal plasma protein from Texel rams. AB - Spermadhesins are a group of low molecular weight proteins present in seminal plasma. In Texel rams, they represent more than 70% of the seminal plasma proteins. Although their functions have not yet been fully clarified, there is much discussion about the role of these proteins in maintaining sperm viability during and after the semen freezing process. This work sought to isolate the major component of the seminal plasma from rams of the Texel breed (O. aries SPD2) and to evaluate its structural and biophysical characteristics in order to better understand its role in spermatic viability. The protein was isolated by centrifugation and ion exchange chromatography and its biophysical properties were evaluated by circular dichroism spectrometry. Molecular dynamics simulations of the modelled protein compared to the homologous bovine protein were also carried out. The results showed that O. aries SPD2 has a transition temperature (Tm) of 65 degrees C and a DeltaHm of 322.5 kJ mol-1, similar to the results for other spermadhesins described in the literature. The estimated composition of the secondary structure elements for the native protein is in agreement with that observed for the theoretical model. Its structural characteristics were preserved in simulations at temperatures of 27 degrees C and 40 degrees C, as was the case for bull spermadhesin. Taken together, these results suggest that the major component of the spermadhesins of Texel rams (O. aries SPD2) may play an important role in maintaining the viability of spermatozoa in fresh semen as well as after thawing. PMID- 29249517 TI - Khat and synthetic cathinones: Emerging drugs of abuse with dental implications. AB - The rising global availability of the stimulant and euphoric substances, khat and synthetic cathinones, has become a cause for concern in many countries, including the United States. Both substances are illegal in United States, although this has not deterred their use. Besides central nervous system effects, these drugs also cause sympathomimetic and orodental adverse effects, similar to those of amphetamine. Although synthetic cathinones are stronger than khat in most cases, the latter additionally contains tannins, which have astringent effects on tissues components, including those in the oral cavity. Recognizing the use prevalence and reported orodental adverse effects of khat and synthetic cathinones, dental practitioners should be more familiar with these substances to optimally treat and educate their patients abusing them. This paper reviews the pharmacology and adverse effects of khat and synthetic cathinones, along with the extent of their use in United States, with particular emphasis on dental implications. PMID- 29249518 TI - Inflammatory reaction of the anterior dorsal tongue presumably to sodium lauryl sulfate within toothpastes: a triple case report. AB - BACKGROUND: Sodium lauryl sulfate (SLS), a popular surface active agent ingredient within toothpastes, is known for its foaming action. Surface active agents increase the effectiveness of toothpastes with respect to dental plaque removal. SLS is a known irritant and also has allergenic potential. The authors report 3 patients with oral pain secondary to inflammation of the dorsal anterior tongue. These patients were all using toothpastes with SLS as an ingredient. RESULTS: The dorsal tongue lesions and oral pain resolved upon switching to toothpastes without SLS as an ingredient. CONCLUSIONS: Clinicians should be aware of the potential of SLS within toothpastes to cause oral mucosal inflammatory reactions of the anterior dorsal tongue. To our knowledge, these are the first case reports of oral mucosal inflammatory reactions of the anterior dorsal tongue associated with SLS containing toothpastes. PMID- 29249519 TI - A preliminary immunohistochemical study of signal transducer and activator of transcription (STAT) proteins in primary oral malignant melanoma. AB - OBJECTIVE: Primary oral malignant melanoma (POMM) is a rare type of malignancy with a very poor prognosis, the molecular pathogenesis of which remains elusive. The aim of this study was to assess the expression status of signal transducer and activator of transcription (STAT) proteins in POMM. STUDY DESIGN: Six POMMs were included in the study. Total protein levels of STAT1, STAT3, and STAT5a, as well as the tyrosine phosphorylated (activated) form of STAT3 (pSTAT3), were assessed immunohistochemically. RESULTS: Immunohistochemical evaluation of total STAT3 revealed diffuse and strong cytoplasmic and nuclear expression in the majority of tumor cells of all cases, whereas activated pSTAT3 had mostly mild nuclear expression in 5%-40% of malignant melanocytes in all cases. Evaluation of STAT1 and STAT5a identified mainly mild cytoplasmic expression in the absence of nuclear localization. CONCLUSION: The identification of aberrant STAT3 expression and activation in oral malignant melanocytes supports a possible role of this molecule in POMM. In contrast, STAT5a has only limited cytoplasmic expression, mitigating against its involvement in POMM. Also, STAT1's low levels may have implications for POMM sensitivity to interferon-based therapeutic strategies, considering the role of this molecule in cutaneous melanoma immunotherapy. PMID- 29249520 TI - Patients' osteometabolic control improves the management of medication-related osteonecrosis of the jaw. AB - OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a concern in patients taking anti resorptive drugs. The aim of this study was to test the hypothesis that preoperative individualized pharmacologic control of the patient's osteometabolic profile could lead to predictable healing of the surgically treated region and minimize the incidence of complications. STUDY DESIGN: This prospective study included 95 test patients (53 with osteoporosis and 42 with cancer), and 94 control patients (49 with osteoporosis and 45 with cancer) who were on anti resorptive therapy and were candidates for ONJ treatment. Test patients underwent osteometabolic profile assessment and personalized pharmacologic supplementation before intervention. In all cases, a drug holiday was scheduled for 3 months before and at least 3 months after the intervention. Healing was assessed clinically and radiographically. RESULTS: In the test group, after a mean follow up of 28.2 +/- 7.8 months, there was only 1 ONJ recurrence, and it was successfully resolved after the pharmacologic protocol was resumed. Five patients reported minor complications. Overall, 100% treatment success was observed. In the control group, after 28.1 +/- 4.9 months follow-up, 6 fistulae, 19 abscesses, and 34 dehiscences occurred. In total, 62.8% of patients in the control group had complications or adverse events. The difference between the 2 groups was highly significant. CONCLUSIONS: Strict osteometabolic control should be a routine measure in the management of patients taking anti-resorptive drugs. PMID- 29249521 TI - Reply to the letter to the editor about "Influence of lip retraction on the cone beam computed tomography assessment of bone and gingival tissues of the anterior maxilla". PMID- 29249522 TI - Anticoagulants are dental friendly. PMID- 29249523 TI - Divergent Patterns of Mitochondrial and Nuclear Ancestry Are Associated with the Risk for Preterm Birth. AB - OBJECTIVE: To examine linkages between mitochondrial genetics and preterm birth by assessing the risk for preterm birth associated with the inheritance of nuclear haplotypes that are ancestrally distinct from mitochondrial haplogroup. STUDY DESIGN: Genome-wide genotyping studies of cohorts of preterm and term individuals were evaluated. We determined the mitochondrial haplogroup and nuclear ancestry for individuals and developed a scoring for the degree to which mitochondrial ancestry is divergent from nuclear ancestry. RESULTS: Infants with higher degrees of divergent mitochondrial ancestry were at increased risk for preterm birth (0.124 for preterm vs 0.105 for term infants; P< .05). This finding was validated in 1 of 2 replication cohorts. We also observed that greater degrees of divergent ancestry correlated with earlier delivery within the primary study population, but this finding was not replicated in secondary cohorts born preterm. CONCLUSIONS: Individuals with divergent patterns of mitochondrial and nuclear ancestry are at increased risk for preterm birth. These findings may in part explain the higher rates of preterm birth in African Americans and in individuals with a matrilineal family history of preterm birth. PMID- 29249524 TI - Frequency and Cost of Vaccinations Administered Outside Minimum and Maximum Recommended Ages-2014 Data From 6 Sentinel Sites of Immunization Information Systems. AB - OBJECTIVE: To quantify vaccinations administered outside minimum and maximum recommended ages and to determine attendant costs of revaccination by analyzing immunization information system (IIS) records. STUDY DESIGN: We analyzed deidentified records of doses administered during 2014 to persons aged <18 years within 6 IIS sentinel sites (10% of the US population). We quantified doses administered outside of recommended ages according to the Advisory Committee on Immunization Practices childhood immunization schedule and prescribing information in package inserts, and calculated revaccination costs. To minimize misreporting bias, we analyzed publicly funded doses for which reported lot numbers and vaccine types were consistent. RESULTS: Among 3 394 047 doses with maximum age recommendations, 9755 (0.3%) were given after the maximum age. One type of maximum age violation required revaccination: 1344 (0.7%) of 194 934 doses of the 0.25-mL prefilled syringe formulation of quadrivalent inactivated influenza vaccine (Fluzone Quadrivalent, Sanofi Pasteur, Swiftwater, PA) were administered at age >=36 months (revaccination cost, $111 964). We identified a total of 7 529 165 childhood, adolescent, and lifespan doses with minimum age recommendations, 9542 of which (0.1%) were administered before the minimum age. The most common among these violations were quadrivalent injectable influenza vaccines (3835, or 0.7% of 526 110 doses administered before age 36 months) and Kinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium; DTaP-IPV) (2509, or 1.2% of 208 218 doses administered before age 48 months). The cost of revaccination for minimum age violations (where recommended) was $179 179. CONCLUSION: Administration of vaccines outside recommended minimum and maximum ages is rare, reflecting a general adherence to recommendations. Error rates were higher for several vaccines, some requiring revaccination. Vaccine schedule complexity and confusion among similar products might contribute to errors. Minimization of errors reduces wastage, excess cost, and inconvenience for parents and patients. PMID- 29249525 TI - Barth Syndrome: Different Approaches to Diagnosis. AB - The diagnosis of Barth syndrome is challenging owing to the wide phenotypic spectrum with allelic heterogeneity. Here we report 3 cases of Barth syndrome with phenotypic and allelic heterogeneity that were diagnosed by different approaches, including whole exome sequencing and final confirmation by reverse transcription polymease chain reaction. PMID- 29249526 TI - Curative Radiation Therapy at Time of Progression Under Active Surveillance Compared With Up-front Radical Radiation Therapy for Prostate Cancer. AB - PURPOSE: To describe and compare outcomes in men with initially presumed indolent prostate cancer receiving definitive radiation therapy after active surveillance (AS) versus those in a risk-matched cohort undergoing up-front radiation therapy. METHODS AND MATERIALS: Men prospectively enrolled in an AS program between 1992 and 2014 and subsequently undergoing curative radiation therapy (ie, image guided radiation therapy [IGRT] or low-dose-rate brachytherapy [LDR-BT]) were identified. Biochemical relapse-free rate (bRFR), metastasis-free rate (mFR), and overall survival (OS) were compared against a cohort of men treated up front, matched by age, clinical prognostic indices (risk group, prostate-specific antigen, cT category, Gleason score, percentage of involved biopsy cores), and radiation therapy modality. RESULTS: Of 1070 patients in the AS registry, 200 underwent definitive radiation therapy (143 IGRT and 57 LDR-BT) after a median of 32.9 (interquartile range [IQR] 20.6-59.8) months on surveillance. Main reasons for treatment were grade and volume upgrading (57.5% and 26%, respectively). Median follow-up after radiation therapy was 4.9 (IQR 3.1-7.5) years. At 5 years the bRFR, mFR, and OS were, respectively, 97%, 99%, and 98.5%. No patient died of prostate cancer. Adequate risk-matching was confirmed in an independent cohort comprising 359 patients receiving up-front IGRT (71%) or LDR-BT (29%) and followed for a median of 9 (IQR 3.1-7.5) years. There was no difference in the disease-specific outcomes (bRFR, mFR) between the 2 cohorts (Gray's P value of .257 and .934, respectively). In multivariate analyses, timing of radical radiation therapy (deferred vs up-front) was not correlated to biochemical relapse or metastases occurrence. CONCLUSIONS: Curative-intent radiation therapy (ie, dose-escalated IGRT or LDR-BT) after a period of AS renders excellent oncologic outcomes at 5 years. Deferring radical therapy after a period of AS does not seem to result in inferior oncologic outcomes compared with patients with similar risk characteristics undergoing up-front treatment. PMID- 29249527 TI - Positron Emission Tomography-Adjusted Intensity Modulated Radiation Therapy for Locally Advanced Non-Small Cell Lung Cancer. AB - PURPOSE: To perform a prospective trial examining positron emission tomography (PET)-based, dose-painted intensity modulated radiation therapy (IMRT) in the setting of locally advanced non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Patients with stage IIB-III NSCLC were treated with 25 fractions of dose-painted IMRT. Tumors or lymph nodes with metabolic tumor volume exceeding 25 cm3 were deemed "high risk" and received 65 Gy. Smaller lesions were treated with 57 Gy or 52.5 Gy (after November 2014). Patients received concurrent weekly carboplatin (area under the curve = 2) and paclitaxel (45 mg/m2). The primary study endpoint was the absence of high residual metabolic activity (maximum standardized uptake value > 6) in treated lesions on PET 12 to 16 weeks after completion of IMRT. RESULTS: Thirty-five subjects with 116 hypermetabolic lesions were eligible for analysis. The primary endpoint was met for 24 of 30 patients (80%) who underwent posttreatment PET, satisfying our efficacy objective. With a median follow-up duration of 23.8 months for living patients, progression in a lesion targeted with radiation therapy has been observed in 5 patients (14%). Treating progression in other sites and death without progression as competing risks, 2-year cumulative incidence rates of local disease progression in high risk lesions (n=24) and low-risk lesions (n=92) are 9% and 3%, respectively. The actuarial rate of overall survival at 2 years is 52%. CONCLUSIONS: Dose-painted IMRT based on pretreatment PET metrics with concurrent chemotherapy yields high rates of metabolic response and local disease control for locally advanced NSCLC. Future trials should test this approach to maximize the therapeutic ratio of thoracic radiation therapy. PMID- 29249528 TI - Critical Appraisal of the Risk of Secondary Cancer Induction From Breast Radiation Therapy With Volumetric Modulated Arc Therapy Relative to 3D Conformal Therapy. AB - PURPOSE: To evaluate the excess absolute risk (EAR) comparing volumetric modulated arc therapy (VMAT) and 3-dimensional (3D) conformal radiation therapy (CRT) in breast cancer radiation therapy treatment. METHODS AND MATERIALS: Two VMAT arrangements (VMAT_tang and VMAT_full, i.e. partial arcs with and without a sector of 0 Monitor Unit, respectively) and a 3D CRT (field-in-field [FinF]) plan were calculated with an accurate dose calculation algorithm, Acuros, in 20 patients presenting with early-stage breast cancer. The dose prescription was 40.05 Gy in 15 fractions. The planning aim was to maximize the dose reduction in the lungs, contralateral breast, heart, and coronary artery. EAR was estimated using different models: linear, linear-exponential, plateau, and full model, which better uses a carcinogenesis model and epidemiologic data for carcinoma induction and which accounts for cell repopulation or repair during the radiation therapy dose fractionation. EAR was computed for contralateral structures-breast and lung-as well as the ipsilateral lung. Normal tissue complication probability (NTCP) was computed to estimate the ipsilateral lung, heart, and skin toxicity, to balance with respect to second cancer induction. RESULTS: The planning objectives were fulfilled with all the planning techniques. EAR for contralateral breast carcinoma induction, estimated with the most accurate model, was 1.7, 2.4, and 8.5 (per 10,000 patients per year) with FinF, VMAT_tang, and VMAT_full, respectively. For the contralateral lung, these figures were 1.5, 1.6, and 7.3 (per 10,000 patients per year), respectively. NTCP for all the analyzed endpoints was significantly higher with FinF relative to both VMAT settings, with VMAT_full presenting the lowest toxicity risk. CONCLUSIONS: VMAT, in particular with the VMAT_tang setting, could have the same risk of second cancer induction as 3D CRT delivered with the FinF setting for the contralateral organs while reducing acute and late NTCP for the ipsilateral organs. VMAT might be considered a safe technique for breast cancer treatment for those aspects. PMID- 29249529 TI - Optimal High-Dose-Rate Brachytherapy Fractionation Scheme After Keloid Excision: A Retrospective Multicenter Comparison of Recurrence Rates and Complications. AB - PURPOSE: To determine the optimal brachytherapy dose and fractionation scheme for keloid treatment. METHODS AND MATERIALS: Patient cohorts from 3 centers treated with keloid excision followed by 2 * 9 Gy, 3 * 6 Gy, or 2 * 6 Gy high-dose-rate brachytherapy were retrospectively compared regarding recurrence (after at least 12 months' follow-up) and complications (after at least 1 month's follow-up), using logistic regression analyses. RESULTS: A total of 238 keloids were treated. An overall full recurrence rate of 8.3% was found. After correction for confounders (sex, skin color, keloid location, keloid duration) no statistically significant differences in recurrence rates could be discerned between fractionation schemes. There were 12.8% major and 45.6% minor complication rates. Lower radiation dose resulted in significantly fewer complications (odds ratio 0.35, P=.015). CONCLUSIONS: After excision of resistant keloids, high-dose-rate brachytherapy with a biological equivalent dose of approximately 20 Gy is recommended, on the basis of low recurrence and complication rates. PMID- 29249530 TI - Different dietary approaches and coronary plaque morphology. PMID- 29249531 TI - Body composition measures and cardiovascular risk in high-risk ethnic groups. AB - BACKGROUND & AIMS: Cardiovascular disease (CVD) is highly prevalent in Suriname, a middle-income country with predominantly people of African and Asian ancestry. We examined whether the more comprehensive body composition measures determined by bioelectrical impedance analysis (BIA) are superior to the more traditional BMI and waist measures in relation to cardiovascular risk. METHODS: Data from the cross-sectional Healthy Life in Suriname (HELISUR) study were used to calculate BMI, waist-hip ratio, waist-to-height ratio, and waist circumference. BIA was used to estimate fat percentage, fat-free mass index, and fat-to-fat-free mass ratio. High cardiovascular risk was defined as 1) a 10-year Framingham coronary heart disease risk score >=10% in African-Surinamese and >=12% in Asian Surinamese, and 2) an increased arterial stiffness (pulse wave velocity >10 m/s). Using logistic regression analysis, we pre-selected the strongest correlate (i.e. lowest p-value below 0.05) of all body composition items for both outcomes of cardiovascular risk separately, and subsequently, used forward logistic regression modelling to determine whether other measures added value to the initial model with the strongest correlate (-2 log-likelihood (-2LL) of initial model minus -2LL of new model, chi-square statistic >3.841, 1 df). Analyses were adjusted for sex, age and ethnicity. RESULTS: We examined 691 participants (65% women; 48% African-Surinamese) with a mean age of 42 (SD 14) years. Waist circumference was the strongest correlate for high 10-year CVD risk in the total group, in men and African-Surinamese. In Asian-Surinamese, fat-free mass index was the strongest correlate of high 10-year CVD risk. Increased arterial stiffness was most strongly related with waist-to-height ratio in the total group and in African-Surinamese, and with BMI in men. None of the measures were significantly associated in women (for both outcomes) and Asian-Surinamese (for increased arterial stiffness). Forward selection showed that only BMI added value next to waist-to-height ratio in the total group in relation to increased arterial stiffness. CONCLUSIONS: Waist measures, in particular waist circumference and waist-to-height ratio, and BMI should be used in African and Asian-Surinamese to identify who is at increased cardiovascular risk. Overall, we found little advantage in using BIA measures rather than simple anthropometric measures. PMID- 29249532 TI - Omega-3 PUFA modulate lipogenesis, ER stress, and mitochondrial dysfunction markers in NASH - Proteomic and lipidomic insight. AB - BACKGROUND & AIMS: Currently there is no FDA-approved therapy for nonalcoholic steatohepatitis (NASH). Increased n-6/n-3 polyunsaturated fatty acids (PUFA) ratio can induce endoplasmic reticulum (ER) stress and mitochondrial dysfunction that characterize NASH. Our recent study with n-3 PUFA showed improvement in individual histologic parameters like steatosis, ballooning and lobular inflammation. We hypothesized that n-3 PUFA therapy mediated improvement in histologic parameters is modulated by lipidomic and proteomic changes. METHODS: We therefore evaluated hepatic proteomic and plasma lipidomic profiles before and after n-3 PUFA therapy in subjects with NASH. In a double-blind, randomized, placebo-controlled trial, patients with NASH received 6-month treatment with n-3 PUFA (0.945 g/day [64% alpha-linolenic (ALA), 21% eicosapentaenoic (EPA), and 16% docosahexaenoic (DHA) acids]). Paired liver biopsy and plasma collected before and after-n-3 PUFA therapy were assessed using mass spectrometry and gas chromatography for hepatic proteomics and plasma lipidomics. Data were matched to UniProt and LIPID MAPS database, respectively. Cytoscape software was used to analyze functional pathways. Twenty-seven NASH patients with paired liver histology and plasma before and after n-3 PUFA treatment were studied. RESULTS: Treatment with n-3 PUFA significantly increased ALA, EPA, and glycerophospholipids, and decreased arachidonic acid (p < 0.05 for all). Further, proteomic markers of cell matrix, lipid metabolism, ER stress and cellular respiratory pathways were also modulated. Interestingly, these alterations reflected functional changes highly suggestive of decreased cellular lipotoxicity potential; reduced ER proteasome degradation of proteins and induction of chaperones; and a shift in cell energy homeostasis towards mitochondrial beta oxidation. CONCLUSION: Six-month treatment with omega-3 PUFAs significantly improved hepatic proteomic and plasma lipidomic markers of lipogenesis, endoplasmic reticulum stress and mitochondrial functions in patients with NASH. PMID- 29249533 TI - Is prescribed lower extremity weight-bearing status after geriatric lower extremity trauma associated with increased mortality? AB - OBJECTIVES: Evaluate whether mortality after discharge is elevated in geriatric fracture patients whose lower extremity weight-bearing is restricted. DESIGN: Retrospective cohort study SETTING: Urban Level 1 trauma center PATIENTS/PARTICIPANTS: 1746 patients >65 years of age INTERVENTION: Post operative lower extremity weight-bearing status MAIN OUTCOME MEASURE: Mortality, as determined by the Social Security Death Index RESULTS: Univariate analysis demonstrated that patients who were weight-bearing as tolerated on bilateral lower extremities (BLE) had significantly higher 5-year mortality compared to patients with restricted weight-bearing on one lower extremity and restricted weight-bearing on BLE (30%, 21% and 22% respectively, p < 0.001). Cox regression analysis controlling for variables including age, Charlson Comorbidity Index, Injury Severity Scale, combined UE/LE injury, injury mechanism (high vs low), sex, BMI and GCS demonstrated that, in comparison to patients who were weight bearing as tolerated on BLE, restricted weight-bearing on one lower extremity had a hazard ratio (HR) of 0.97 (95% confidence interval 0.78 to 1.20, p = 0.76) and restricted weight-bearing in BLE had a HR of 0.91 (95% confidence interval 0.60 to 1.36, p = 0.73). CONCLUSIONS: In geriatric patients, prescribed weight-bearing status did not have a statistically significant association with mortality after discharge, when controlling for age, sex, body mass index, medical comorbidities, Injury Severity Scale (ISS), mechanism of injury, nonoperative treatment and admission GCS. This remained true in when the analysis was restricted to operative injuries only. PMID- 29249534 TI - Preexisting psychiatric illness worsens acute care outcomes after orthopaedic trauma in obese patients. AB - PURPOSE: Pre-existing psychiatric illness, illicit drug use, and alcohol abuse adversely impact patients with orthopaedic trauma injuries. Obesity is an independent factor associated with poorer clinical outcomes and discharge disposition, and higher hospital resource use. It is not known whether interactions exist between pre-existing illness, illicit drug use and obesity on acute trauma care outcomes. PATIENTS AND METHODS: This cohort study is from orthopaedic trauma patients prospectively measured over 10 years (N = 6353). Psychiatric illness, illicit drug use and alcohol were classified by presence or absence. Body mass index (BMI) was analyzed as both a continuous and categorical measure (<30 kg/m2 [non-obese], 30-39.9 kg/m2 [obese] and >=40 kg/m2 [morbidly obese]). Main outcomes were the number of acute care services provided, length of stay (LOS), discharge home, hospital readmissions, and mortality in the hospital. RESULTS: Statistically significant BMI by pre-existing condition (psychiatric illness, illicit drug use) interactions existed for LOS and number of acute care services provided (beta values 0.012-0.098; all p < 0.05). The interaction between BMI and psychiatric illness was statistically significant for discharge to locations other than home (beta = 0.023; p = 0.001). DISCUSSION: Obese patients with orthopaedic trauma, particularly with preexisting mental health conditions, will require more hospital resources and longer care than patients without psychiatric illness. Early identification of these patients through screening for psychiatric illness and history of illicit drug use at admission is imperative to mobilize the resources and provide psychosocial support to facilitate the recovery trajectory of affected obese patients. PMID- 29249535 TI - A cote calibration - Making optimal use of time and space in quantitative high performance thin layer chromatography. AB - Quantitative High Performance Thin Layer Chromatography (HPTLC) requires the application of several standards to each plate, reducing the number of actual samples that can be analyzed in a single run. Using pure standard compounds and a selective detection method, the standards for quantitation can be applied besides - a cote - the chromatography area. This frees the sample application space to accommodate the maximal number of sample on each plate. Also, analysis time is spent exclusively on samples, drastically shortening the effective analysis time per sample and increasing sample throughput. Using this new calibration approach, the sample capacity of regular HPTLC methods can be increased or their scope be extended by an additional quantitative analysis. As a limitation, changes to the distribution of samples and standards within the plate as well as interferences from matrix compounds must be observed. We demonstrate the feasibility of this method by complementing an HPTLC method with a quantitative analysis of total anthocyanin content in colored wheat varieties. The quantitation was validated and compared to the conventional photometric analysis. As outcome, the additional photometric analysis could be replaced and rendered unnecessary, saving time, effort and equipment. This approach could also be employed to quantify highly retained substances, which are usually inaccessible for quantitative analysis. PMID- 29249536 TI - Adsorption behavior of optical brightening agent on microfibrillated cellulose studied through inverse liquid chromatography: The need to correct for axial dispersion effect. AB - Inverse liquid chromatography is a technique for studying solid/liquid interaction and most specifically for the determination of solute adsorption isotherm. For the first time, the adsorption behaviour of microfibrillated cellulose was assessed using inverse liquid chromatography. We showed that microfibrillated cellulose could adsorb 17 mg/g of tetrasulfonated optical brightening agent in typical papermaking conditions. The adsorbed amount of hexasulfonated optical brightening agent was lower (7 mg/g). The packing of the column with microfibrillated cellulose caused important axial dispersion (Da = 5e 7 m2/s). Simulation of transport phenomena in the column showed that neglecting axial dispersion in the analysis of the chromatogram caused significant error (8%) in the determination of maximum adsorbed amount. We showed that conventional chromatogram analysis technique such as elution by characteristic point could not be used to fit our data. Using a bi-Langmuir isotherm model improved the fitting, but did not take into account axial dispersion, thus provided adsorption parameters which may have no physical significance. Using an inverse method with a single Langmuir isotherm, and fitting the transport equation to the chromatogram was shown to provide a satisfactory fitting to the chromatogram data. In general, the inverse method could be recommended to analyse inverse liquid chromatography data for column packing with significant axial dispersion (Da > 1e-7 m2/s). PMID- 29249537 TI - Chromatographic performance of microfluidic liquid chromatography devices: Experimental evaluation of straight versus serpentine packed channels. AB - We prepared a series of planar titanium microfluidic (MULC) columns, each 100 mm long, with 0.15, 0.3 and 0.5 mm i.d.'s. The microfluidic columns were packed with 1.8 MUm C18 sorbent and tested under isocratic and gradient conditions. The efficiency and peak capacity of these devices were monitored using a micro LC instrument with minimal extra column dispersion. Columns with serpentine channels were shown to perform worse than those with straight channels. The loss of efficiency and peak capacity was more prominent for wider i.d. columns, presumably due to on-column band broadening imparted by the so-called "race track" effect. The loss of chromatographic performance was partially mitigated by tapering the turns (reduction in i.d. through the curved region). While good performance was obtained for 0.15 mm i.d. devices even without turn tapering, the performance of 0.3 mm i.d. columns could be brought on par with capillary LC devices by tapering down to 2/3 of the nominal channel width in the turn regions. The loss of performance was not fully compensated for in 0.5 mm devices even when tapering was employed; 30% loss in efficiency and 10% loss in peak capacity was observed. The experimental data for various devices were compared using the expected theoretical relationship between peak capacity Pc and efficiency N; (Pc 1) = N0.5 * const. While straight MULC columns showed the expected behavior, the devices with serpentine channels did not adhere to the plot. The results suggest that the loss of efficiency due to the turns is more pronounced than the corresponding loss of peak capacity. PMID- 29249538 TI - Co-elution phenomena in polymer mixtures studied by asymmetric flow field-flow fractionation. AB - Most polymers generally have complex characteristics. Analysis and understanding of these characteristics is crucial as they, for instance, influence functionality. Separation and analysis of samples of polymers, biopolymers in particular, is challenging since they often display broad distributions in size, structure and molar mass (M) and/or a tendency to form aggregates. Only few analytical techniques are suitable for the task. AF4-MALS-dRI is highly suited for the task, but the analysis can nevertheless be especially challenging for heterogeneous mixtures of polymers that exhibit wide size distributions or aggregation. For such systems, systematic and thorough method development is clearly a requirement. This is the purpose of the present work, where we approach the problem of heterogeneous polymer samples systematically by analyzing mixtures of two different polymers which are also characterized individually. An often observed phenomenon in AF4 of samples with a high polydispersity is a downturn in M vs. elution time, especially common at high retention. This result is often dismissed as an artifact attributed to various errors in detection and data processing. In this work, we utilize AF4-MALS-dRI to separate and analyze binary mixtures of the well-known polysaccharides pullulan and glycogen, or pullulan and poly(ethylene oxide), respectively, in solution. The results show that an observed downturn - or even an upturn - in M can be a correct result, caused by inherent properties of the analyzed polymers. PMID- 29249539 TI - Distillery effluent as a potential medium for bacterial cellulose production: A biopolymer of great commercial importance. AB - In the present study, an attempt was made to utilize the distillery effluent for the production of bacterial cellulose by a novel bacterial species, Gluconacetobacter oboediens. Maximum bacterial cellulose production of 0.85g/100ml was achieved in crude distillery effluent. The production was successfully scaled up to 1.0L size producing 8.1g of bacterial cellulose. Morphological, structural and thermal characterization of purified bacterial cellulose by SEM, FT-IR and TGA analysis showed that it is pure cellulose having good properties. Henceforth, the present study proved a concept that distillery effluent could be utilized for the production of bacterial cellulose, a biopolymer of immense importance, which in turn may be used for producing different value added products. PMID- 29249540 TI - A morphometric and analytical cadaver dissection study of a tumor-simulation balloon model. AB - We quantified the effects on anatomical cadaver dissection of a balloon-inflation tumor model positioned in the parasellar region and approached through an orbitozygomatic (OZ) craniotomy. A modified supraorbital OZ was performed bilaterally on 5 silicon-injected cadaver heads. Ten predetermined anatomical points assigned using a frameless stereotactic device were used to measure the working area of exposure, degree of surgical freedom, and horizontal and vertical angles of attack to specific target points before and after inflation of a balloon catheter mimicking a parasellar tumor. Balloon inflation displaced the central anatomical structures (pituitary stalk, lamina terminalis, anterior chiasm, and internal carotid artery [ICA]-posterior communicating artery and ICA A1 junctions) by 14-51% (p <= .05). With tumor simulation, the vertical angle of attack increased by 67% (p < .01), while the area of exposure increased by 83% (p < .01) and surgical freedom increased by 58% (p < .01). This tumor model also significantly displaced central anatomical sella-associated structures. Compared to a normal anatomical configuration, the tumor simulation (balloon) opened surgical corridors (especially vertical) and acted as a natural retractor, widening the angle of access to the infundibular apex-hypothalamic junction. Although this model cannot exactly mimic a tumor mass in a patient, the effects of tumor compression and sequential displacement of important structures can be combined into and then assessed in a cadaveric neurosurgical anatomical scenario for training and research. PMID- 29249541 TI - Cerebrospinal fluid biomarkers of Alzheimer's disease are associated with carotid plaque score and hemodynamics in intra- and extra-cranial arteries on ultrasonography. AB - Carotid plaque score (PS) and hemodynamic abnormalities in intra- and extra cranial arteries are related to Alzheimer's disease (AD) progression. As these parameters are measured conveniently and non-invasively by ultrasonography, we examined their association with cerebral spinal fluid (CSF) AD biomarkers amyloid beta (Abeta) and phosphorylated tau (p-tau). Carotid PS, mean flow velocity (MFV) in multiple intra- and extra-cranial arteries, CSF Abeta42 and p-tau, neurocognitive function (assessed by the Mini-Mental State Examination and Alzheimer's Disease Assessment Scale-cognitive subscale, Japanese version), and blood lipids (total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride) were measured in AD patients (n = 42), mild cognitive impairment patients (n = 20), and cognitively normal controls (n = 18). The results were also compared among groups defined by PS range. After adjusting for blood lipids as covariates, Abeta42 was higher in the PS = 1.1-2.0 mm group than in the higher PS groups (2.1-3.0, 3.1-5.0, 5.1-7.0, and >7.0 mm). However, subjects with very low PS (<1.1 mm) also had a low mean CSF Abeta42. Alternatively, CSF p-tau181 did not differ between PS groups. In multiple regression analysis, Abeta42 was not associated with MFVs; however, CSF p-tau181 showed a significant association with the MFV of the internal carotid and basilar arteries. Findings suggest that carotid plaque formation may accelerate Abeta42 deposition, although it is not necessary for deposition. Hemodynamics abnormalities may cause increased CSF p tau181. Ultrasonographic evaluation of PS and arterial hemodynamics may be a useful noninvasive method for estimating AD pathology. PMID- 29249542 TI - Conventional influenza vaccines influence the performance of a universal influenza vaccine in mice. AB - Universal influenza vaccines are designed to protect against diverse strains of influenza virus. Preclinical testing of new vaccine candidates is usually done in naive animals, despite intended use in the human population with its varied immune history including responses to previous vaccinations. As an approach more relevant to human use, we tested a candidate universal influenza vaccine in mice with a history of conventional vaccination. Female BALB/c mice were given two intramuscular doses of inactivated influenza vaccine (IIV) or diphtheria and tetanus toxoids vaccine (DT), one month apart. Another group was given two intranasal doses of live attenuated influenza virus (LAIV). One month after the second dose, mice were given the universal influenza vaccine: recombinant adenoviruses expressing influenza A nucleoprotein (A/NP) and matrix 2 (M2) (A/NP + M2-rAd). Immune responses to universal vaccine antigens A/NP and M2 were assessed by ELISA and interferon-gamma ELISPOT. Protection was tested by challenge with mouse-adapted A/FM/1/47 (H1N1) and monitoring for weight loss and survival. Universal vaccine performance was enhanced, inhibited or unaffected by particular prior vaccinations. Mice given Afluria IIV and LAIV had greater antibody and T-cell response to A/NP than mice without prior vaccination, providing examples of enhanced A/NP + M2-rAd performance. Though Fluvirin IIV partially inhibited, the universal vaccine still provided considerable protection unlike conventional vaccination. Fluzone IIV and DT had no effect on A/NP + M2 rAd performance. Thus our results demonstrate that universal vaccine candidate A/NP + M2-rAd was at least partially effective in mice with diverse prior histories. However, the degree of protection and nature of the immune responses may be affected by a history of conventional vaccination and suggests that performance in humans would be influenced by immune history. PMID- 29249543 TI - An updated influenza A(H3N2) vaccine generates limited antibody responses to previously encountered antigens in children. AB - BACKGROUND: Influenza vaccination may provide a "back-boost" to antibodies against previously encountered strains. If the back-boost effect is common, this could allow more aggressive vaccine updates, as emerging variants would be expected to both elicit de-novo responses and boost pre-existing responses against recently circulating strains. Here we used the emergence of an antigenically novel A(H3N2) strain to determine whether an antigenically updated vaccine boosted antibodies against historical strains. METHODS: We performed hemagglutination-inhibition (HI) assays on pre- and post-vaccination sera from 124 children 5-17 years old who received 2015-2016 inactivated influenza vaccine, containing an antigenically updated A(H3N2) strain. We evaluated the mean fold increase in HI titer against both the 2015-2016 vaccine strain and representative strains from two prior antigenic clusters. Factors associated with post vaccination titers against historical strains were evaluated using linear regression, adjusting for baseline titer. RESULTS: Geometric mean titers against each antigen examined increased significantly after vaccination (P < .0001). Mean fold increase was 3.29 against the vaccine strain and 1.22-1.46 against historical strains. Response to vaccine strain was associated with increased post vaccination titers against historical strains. CONCLUSIONS: A vaccine containing an antigenically novel A(H3N2) strain modestly boosted antibody responses against historical influenza strains in children. PMID- 29249544 TI - Single-dose varicella vaccine effectiveness in Brazil: A case-control study. AB - BACKGROUND: Varicella vaccine was introduced into the Brazilian Immunization Program in October 2013, as a single-dose schedule administered at 15 months of age. Its effectiveness had not yet been assessed in the country. METHODS: A matched case-control study was carried out in Sao Paulo and Goiania (Southeast and Midwest regions, respectively), Brazil. Suspected cases, were identified through a prospective surveillance established in the study sites. All cases had specimens from skin lesion collected for molecular laboratory testing. Cases were confirmed by either clinical or PCR of skin lesions and classified as mild, moderate, and severe disease. Two neighborhood controls were selected for each case. Cases and controls were aged 15-32 months and interviewed at home. Evidence of prior vaccination was obtained from vaccination cards. Univariate and multivariate logistic regression models were used, and odds ratio and its respective 95% confidence intervals were estimated. Vaccine effectiveness was estimated by comparing de odds of having received varicella vaccine among cases and controls. RESULTS: A total of 168 cases and 301 controls were enrolled. Moderate and severe illness, was found in 33.3% and 9.9% of the cases. Effectiveness of a single dose varicella vaccine was 86% (95%CI 72-92%) against disease of any severity and 93% (95%CI 82-97%) against moderate and severe disease. Out of 168 cases, 81.8% had positive PCR results for wild-type strains, and 22.0% were breakthrough varicella cases. Breakthrough cases were milder compared to non-breakthrough cases (p < .001). CONCLUSIONS: Effectiveness of single dose varicella vaccine in Brazil is comparable to that in other countries where breakthrough varicella cases have also been found to occur. The goal of the varicella vaccination program, along with disease burden and affordability should be taken into consideration when considering the adoption of a second dose of varicella vaccine into national immunization programs. PMID- 29249546 TI - Sustained frontal midline theta enhancements during effortful listening track working memory demands. AB - Recent studies demonstrate that frontal midline theta power (4-8 Hz) enhancements in the electroencephalogram (EEG) relate to effortful listening. It has been proposed that these enhancements reflect working memory demands. Here, the need to retain auditory information in working memory was manipulated in a 2-interval 2-alternative forced-choice delayed pitch discrimination task ("Which interval contained the higher pitch?"). On each trial, two square wave stimuli differing in pitch at an individual's ~70.7% correct threshold were separated by a 3-second ISI. In a 'Roving' condition, the lowest pitch stimulus was randomly selected on each trial (uniform distribution from 840 to 1160 Hz). In a 'Fixed' condition, the lowest pitch was always 979 Hz. Critically, the 'Fixed' condition allowed one to know the correct response immediately following the first stimulus (e.g., if the first stimulus is 979 Hz, the second must be higher). In contrast, the 'Roving' condition required retention of the first tone for comparison to the second. Frontal midline theta enhancements during the ISI were only observed for the 'Roving' condition. Alpha (8-13 Hz) enhancements were apparent during the ISI, but did not differ significantly between conditions. Since conditions were matched for accuracy at threshold, results suggest that frontal midline theta enhancements will not always accompany difficult listening. Mixed results in the literature regarding frontal midline theta enhancements may be related to differences between tasks in regards to working memory demands. Alpha enhancements may reflect task general effortful listening processes. PMID- 29249545 TI - Burden of medically attended influenza infection and cases averted by vaccination - United States, 2013/14 through 2015/16 influenza seasons. AB - BACKGROUND: In addition to preventing hospitalizations and deaths due to influenza, influenza vaccination programs can reduce the burden of outpatient visits for influenza. We estimated the incidence of medically-attended influenza at three geographically diverse sites in the United States, and the cases averted by vaccination, for the 2013/14 through 2015/16 influenza seasons. METHODS: We defined surveillance populations at three sites from the United States Influenza Vaccine Effectiveness Network. Among these populations, we identified outpatient visits laboratory-confirmed influenza via active surveillance, and identified all outpatient visits for acute respiratory illness from healthcare databases. We extrapolated the total number of outpatient visits for influenza from the proportion of surveillance visits with a positive influenza test. We combined estimates of incidence, vaccine coverage, and vaccine effectiveness to estimate outpatient visits averted by vaccination. RESULTS: Across the three sites and seasons, incidence of medically attended influenza ranged from 14 to 54 per 1000 population. Incidence was highest in children aged 6 months to 9 years (33 to 70 per 1000) and lowest in adults aged 18-49 years (21 to 27 per 1000). Cases averted ranged from 9 per 1000 vaccinees (Washington, 2014/15) to 28 per 1000 (Wisconsin, 2013/14). DISCUSSION: Seasonal influenza epidemics cause a considerable burden of outpatient medical visits. The United States influenza vaccination program has caused meaningful reductions in outpatient visits for influenza, even in years when the vaccine is not well-matched to the dominant circulating influenza strain. PMID- 29249548 TI - Patients with a long-standing cuff tear in one shoulder have high rates of contralateral cuff tears: a study of patients with arthroscopically verified cuff tears 22 years ago. AB - BACKGROUND: The prevalence of contralateral full-thickness cuff tears (FTTs) and cuff tear arthropathy (CTA) is presumed to be higher in patients with long standing cuff tears than in those with newly diagnosed tears, but data are currently lacking. METHODS: Sixty-one patients with 38 partial and 23 full thickness tears of 1 shoulder at arthroscopy were examined with bilateral radiographs, ultrasound, and the Constant-Murley score at a mean of 22 years (range, 21-25 years) after arthroscopy. RESULTS: The overall rate of full thickness tears in the contralateral shoulder was 50.8%. In patients with a full thickness tear and CTA (Hamada grade >=2) in the index shoulder at follow-up, 18 of 20 (90%) had a contralateral full-thickness tear and 4 of 20 (20%) had CTA. In patients with a partial tear in the index shoulder at follow-up, 3 of 22 (13.6%) had a contralateral full-thickness tear and none had CTA. CTA changes were more common in patients with FTT and a previous acromioplasty (P < .001). The correlation between shoulders was 0.72 for the number of tendons with FTT (P <.001), 0.31 for the Hamada grade (P = .016), and 0.65 for the absolute Constant Murley score (P <.001). The number of tendons with a full-thickness tear at follow-up was a risk factor (odds ratio, 3.28; 95% confidence interval, 1.67 6.44; P <.001) for a contralateral full-thickness tear. Patients with a partial or full-thickness tear in the contralateral shoulder had pain in 39.2% of cases. CONCLUSION: Patients with long-standing cuff tears have high rates of contralateral cuff tears. The severity of the condition is strongly correlated between the shoulders. Patients with full-thickness tears and a previous acromioplasty have a significantly higher frequency of CTA than patients with cuff tears who had not undergone a previous acromioplasty. PMID- 29249547 TI - Current pain prescribing habits for common shoulder operations: a survey of the American Shoulder and Elbow Surgeons membership. AB - BACKGROUND: Orthopedic surgeons are among the highest prescribers of narcotic pills, and no guidelines currently exist for appropriate management of postoperative pain within this field. The purpose of this study was to gain understanding of the current pain management strategies used perioperatively and postoperatively among orthopedic shoulder surgeons. METHODS: Members of the American Shoulder and Elbow Surgeons were e-mailed an online survey regarding methods for managing pain in the perioperative and postoperative setting for total shoulder arthroplasty, labral and capsular stabilization procedures, and rotator cuff repair. Postoperative narcotic prescribing amounts were converted into oral morphine equivalents. RESULTS: The survey response rate was 25.8% (170/658), with >90% of surgeons reporting use of a standard pain management regimen in the perioperative and postoperative periods. A regional nerve block was used on the operative day by >80% of surgeons for all 3 procedures. Short acting narcotics are prescribed for postoperative pain control by >85% of surgeons, with long-acting narcotics provided by <14%. More than 400 oral morphine equivalents of short-acting narcotic are prescribed by shoulder surgeons. Referral to a pain specialist or primary care physician is made after 12 weeks by 92.3% of surgeons if patients continue to require narcotic painkillers. CONCLUSION: The majority of shoulder surgeons use a standard pain management protocol in perioperative and postoperative settings. Regimens frequently include a regional nerve block, nonsteroidal anti-inflammatory drugs, and short-acting oral narcotics. Findings from this study provide guidelines on standard pain management strategies for common shoulder operations based on expert opinion. PMID- 29249549 TI - Diffuse ST-Segment Elevation After Hydrogen Sulfide Intoxication. PMID- 29249550 TI - Sternoclavicular Joint Infection Presenting as Nonspecific Chest Pain. AB - BACKGROUND: Sternoclavicular joint infection (SJI), to include septic arthritis (SA), is a rare cause of chest pain and is often found in patients with significant risk factors and sources for SA. Most acute care laboratory results lack significant sensitivity to rule out SA. Radiographic findings in common acute care imaging often does not reveal findings of SA and osteomyelitis in the acute phase of the infection. CASE REPORT: We present a patient without significant risk factors for SA, who initially presented with 3 days of pain to the left chest, left neck and shoulder. He had fever and was treated with a short course of antibiotics for possible pneumonia. His symptoms recurred along with fever 36 days after the initial onset of symptoms and was then diagnosed radiographically with left-sided SJI. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This case reinforces the need to maintain a broad differential diagnosis in the evaluation for chest pain and pursue advanced imaging, such as magnetic resonance imaging, when the pretest probability of SJI is high, especially in the acute phase of the infection. PMID- 29249551 TI - Validation of a Clinical Prediction Model for the Development of Neuromuscular Scoliosis: A Multinational Study. AB - BACKGROUND: The objective of this study was to evaluate the performance of a clinical prediction model of neuromuscular scoliosis via external validation. METHODS: We analyzed a series of 120 patients (mean age +/- standard deviation, 15.7 +/- 1.8 years; range: 12 to 18 years) with cerebral palsy, severe motor disorders, and cognitive impairment with and without neuromuscular scoliosis treated in two specialized units (70 patients from Nice, France, and 50 patients from Lublin, Poland) in a cross-sectional, double-blind study. Data on etiology, diagnosis, functional assessments, type of spasticity, epilepsy, scoliosis, and clinical history were collected prospectively between 2005 and 2015. Fisher's exact test and multiple logistic regressions were used to identify influential factors for developing spinal deformity. Thus, we applied a predictive model based on a logistic regression algorithm to predict the probability of scoliosis onset for new patients. RESULTS: Children with truncal tone disorders (P = Multivariate logistic regression highlighted previous hip surgery (P = 0.002 ~ 0.005), intractable epilepsy (P = 0.01 ~ 0.04) and female gender (0.07) as influent factors in the two cohorts. Average accuracy, sensitivity, and specificity of the predictive model were 74%. CONCLUSIONS: We validated a prediction model of neuromuscular scoliosis. In cerebral palsy subjects with the previouslymentioned predictors of scoliosis, the frequency of clinical examinations of spine and spinal x-ray should be increased to easily identify candidates for treatment. PMID- 29249552 TI - Pretreatment Cognition in Patients Diagnosed With Pediatric Brain Tumors. AB - BACKGROUND: There is a large body of literature identifying risk factors for the long-term cognitive alterations found in survivors of pediatric brain tumors. Less is known about baseline cognitive functioning in this population, but studies suggest that cognitive dysfunctions are often present at the time of diagnosis. This study aimed to identify potential risk factors for lower cognitive function at the time of pediatric brain tumor diagnosis. METHODS: Participants were children and adolescents (n = 101) diagnosed with a pediatric brain tumor between 2006 and 2015, who underwent a pretreatment neuropsychologic assessment. Multivariate regression models were used to estimate the association between gender, age at diagnosis, tumor size and location, increased intracranial pressure, epilepsy, and six different indicators of cognitive functioning. RESULTS: Overall, cognitive performance was relatively intact, with results close to norm means, but impairments were found in memory and cognitive processing speed. Male gender, older age, epilepsy, increased intracranial pressure, and larger tumors were all associated with lower cognitive function at the time of brain tumor diagnosis; whereas tumor location was not. CONCLUSIONS: Pretreatment neuropsychologic assessments, with some adjustments, can be carried out with children and adolescents with brain tumors. Our study adds to a small but growing body of literature documenting cognitive impairments at the time of diagnosis; these impairments may partly explain the longer-term deficits that commonly occur in pediatric brain tumor survivors. Consistent with previous research, pretreatment impairments were more common among boys, older children, and those with increased intracranial pressure, epilepsy, and larger tumors. The relationship between baseline and longer-term cognitive deficits requires further examination. PMID- 29249553 TI - Liver Angiomyolipomas in Tuberous Sclerosis Complex-Their Incidence and Course. AB - BACKGROUND: The purpose of this study was to evaluate the epidemiology and clinical significance of hepatic angiomyolipomas in patients with tuberous sclerosis complex. METHODS: We performed a retrospective analysis of clinical and imaging data from 187 patients with tuberous sclerosis complex. The prevalence, progression, and potential relationship between liver lesions and other clinical findings, including genetic associations, were assessed. RESULTS: Twenty-eight of 187 patients (14.9%) had hepatic lesions. There was a predominance of female over male patients in individuals with liver lesions (17 versus 11), with statistical significance in patients under five years of age (P < 0.05). All individuals having hepatic lesions who also had available genetic testing data (n = 20) were diagnosed with a TSC2 gene mutation. All patients with liver lesions had coexisting renal angiomyolipomas (AMLs) (P < 0.05). The age of onset of renal lesions was lower and their prevalence was significantly higher in patients with liver involvement (P < 0.05). In most instances, hepatic lesions measured several millimeters in diameter and were clinically asymptomatic. Progressive lesion growth was documented in six individuals but with no clinical consequences to date. CONCLUSIONS: This study confirms the association of hepatic lesions with TSC2 mutations, a common origin of liver and renal AMLs, as well as the predominance of female patients in this group. Hepatic AMLs are relatively common but mostly benign lesions. PMID- 29249554 TI - Life (and death) in Pink: The dangerous rise of synthetic opioids in the new psychoactive substances panorama. AB - Novel psychoactive substances represent a recent and unprecedented challenge in the global health panorama. Recently, among these, synthetic opioids are growing in number and prevalence of use, leaving behind them severe intoxications and victims, and fuelling the illicit drug market, particularly on the Dark Net. Further attention should be drawn to this alarming phenomenon, from both clinicians and policymakers. PMID- 29249556 TI - Both classic Gs-cAMP/PKA/CREB and alternative Gs-cAMP/PKA/p38beta/CREB signal pathways mediate exenatide-stimulated expression of M2 microglial markers. AB - GLP-1 receptor agonists, exenatide and GLP-1, promoted M2 type polarization in monocytes/macrophages and microglial cells. This study explored the signal basis underlying exenatide-stimulated expression of M2 microglia-specific genes, including the cytoplasmic marker Arg 1, surface marker CD206, and secretion protein marker IL-4. Treatment with exenatide in cultured primary microglial cells concentration dependently stimulated the expression of Arg 1, CD206 and IL 4, but did not significantly alter LPS-stimulated expression of TNF-alpha, IL 1beta and IL-6. The stimulatory effects of exenatide were completely prevented by the GLP-1 receptor antagonist exendin(9-39), but not altered by application of LPS. Furthermore, the adenylyl cyclase inhibitor DDA, PKA inhibitor H89 and CREB inhibitor KG501 completely blocked exenatide-induced overexpression of Arg 1, CD206 and IL-4. In addition, exenatide-stimulated expression of Arg 1 and CD206 was totally blocked by the p38 MAPK inhibitor SB203580 and gene silencer siRNA/p38beta (but not siRNA/p38alpha), whereas the expressed IL-4 was not significantly altered by the p38 inhibitor or other MAPK subtype inhibitors. These findings revealed that both classic Gs-cAMP/PKA/CREB and alternative Gs cAMP/PKA/p38beta/CREB mediated GLP-1 receptor agonism-induced overexpression of M2 microglial biomarkers. PMID- 29249555 TI - Simulating the Impact of Sugar-Sweetened Beverage Warning Labels in Three Cities. AB - INTRODUCTION: A number of locations have been considering sugar-sweetened beverage point-of-purchase warning label policies to help address rising adolescent overweight and obesity prevalence. METHODS: To explore the impact of such policies, in 2016 detailed agent-based models of Baltimore, Philadelphia, and San Francisco were developed, representing their populations, school locations, and food sources, using data from various sources collected between 2005 and 2014. The model simulated, over a 7-year period, the mean change in BMI and obesity prevalence in each of the cities from sugar-sweetened beverage warning label policies. RESULTS: Data analysis conducted between 2016 and 2017 found that implementing sugar-sweetened beverage warning labels at all sugar sweetened beverage retailers lowered obesity prevalence among adolescents in all three cities. Point-of-purchase labels with 8% efficacy (i.e., labels reducing probability of sugar-sweetened beverage consumption by 8%) resulted in the following percentage changes in obesity prevalence: Baltimore: -1.69% (95% CI= 2.75%, -0.97%, p<0.001); San Francisco: -4.08% (95% CI= -5.96%, -2.2%, p<0.001); Philadelphia: -2.17% (95% CI= -3.07%, -1.42%, p<0.001). CONCLUSIONS: Agent-based simulations showed how warning labels may decrease overweight and obesity prevalence in a variety of circumstances with label efficacy and literacy rate identified as potential drivers. Implementing a warning label policy may lead to a reduction in obesity prevalence. Focusing on warning label design and store compliance, especially at supermarkets, may further increase the health impact. PMID- 29249557 TI - The Electroencephalogram Speaks for the Patient: Identification and Treatment of Akinetic Mutism With Comorbid Delirium. PMID- 29249558 TI - Validating the Structure of the Depression and Somatic Symptoms Scale. AB - BACKGROUND: Depressed primary care patients may present with somatic symptoms first, complicating differential diagnosis. Clinicians have few instruments for assessing this comorbidity. OBJECTIVE: To evaluate the psychometrics of the translated Chinese Depression and Somatic Symptoms Scale (DSSS) in Americans. PROCEDURES: A total of 491 nonclinical but symptomatic ethnically-diverse individuals completed the DSSS and Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Factor analysis yielded 2 distinct factors: depression and somatic symptoms. DSSS and subscales showed internal consistency, reliability, and convergent validity with CES-D and subscales. CONCLUSIONS: These results support DSSS's trustworthiness for US populations. Using DSSS for patient assessment may assist diagnosis and inform interventions. PMID- 29249559 TI - Surgical burn secondary to the use of alcoholic chlorhexidine. AB - Surgical wound infection is one of the main sources of postoperative morbidity/mortality. Skin preparation with an antiseptic agent such as chlorhexidine alcohol solution is an effective method to reduce the incidence of surgical wound infections. Nevertheless, the use of alcohol solutions is associated with some risk as they are inflammable products. We report a case of a 51-year-old male who suffered an extensive burn associated with concurrent use of electrocautery and clorhexidine alcohol solution. PMID- 29249560 TI - Cultural and linguistic diversity increases the likelihood of compulsory community treatment. AB - BACKGROUND: People from culturally and linguistically diverse (CALD) backgrounds are over-represented in compulsory admissions to hospital but little is known about whether this also applies to community treatment orders (CTOs). AIMS: We investigated any differences between Australian- and foreign-born patients in the likelihood of CTO placement using state-wide databases from Western Australia. METHODS: Cases and controls from administrative health data were matched on age, sex, diagnosis and time of hospital discharge (the index date). Logistic regression was then used to identify potential predictors of a CTO. We also assessed if any differences in CTO placement between Australian- and foreign-born patients had effects on bed-days or community contacts in the subsequent year. RESULTS: We identified 2958 CTO cases and controls from November 1997 to December 2008 (total n=5916). Of these, 74% had schizophrenia or other non-affective psychoses. Patients who were born in New Zealand, the United Kingdom or Ireland had very similar rates of CTO placement compared to those who were Australian born. By contrast, there was a gradient of increasing risk of CTO placement for people born in Continental Europe (ORadj=1.36; 95% CI=1.07-1.71, p=0.01) and then the Rest of the World (ORadj=1.61; 95% CI=1.31-1.97, p<0.001). However, there was no evidence of additional benefit in terms of health service use in the following year. CONCLUSIONS: In common with other coercive treatments, people from culturally and linguistically diverse (CALD) backgrounds are more likely to be placed on CTOs. Further research is needed to establish if this is for similar reasons. PMID- 29249561 TI - Posterior Contained Rupture of an Abdominal Aortic Aneurysm Within the Psoas Muscle After Endovascular Repair. PMID- 29249562 TI - Synthesis, optical properties and cytotoxicity of meso-heteroatom substituted IR 786 analogs. AB - Eight near-infrared heptamethine cyanines have been successfully synthesized based on IR 786 with oxygen, sulfur and amine moieties at the central position. These dyes show diverse optical properties resulting from different substitutions. Particularly, the heptamethine dyes with amine moieties have larger Stokes shifts and higher quantum yields of fluorescence. We also investigated these dyes for tumor cell cytotoxicity using cell viability and in vitro proliferation assays. Two of the compounds showed high cytotoxicity against PC-3 cancer cells. PMID- 29249563 TI - Design and synthesis of pyrazolopyridine derivatives as sphingosine 1-phosphate receptor 2 ligands. AB - Eleven new sphingosine 1-phosphate receptor 2 (S1PR2) ligands were synthesized by modifying lead compound N-(2,6-dichloropyridin-4-yl)-2-(4-isopropyl-1,3-dimethyl 1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazine-1-carboxamide (JTE-013) and their binding affinities toward S1PRs were determined in vitro using [32P]S1P and cell membranes expressing recombinant human S1PRs. Among these ligands, 35a (IC50 = 29.1 +/- 2.6 nM) and 35b (IC50 = 56.5 +/- 4.0 nM) exhibit binding potency toward S1PR2 comparable to JTE-013 (IC50 = 58.4 +/- 7.4 nM) with good selectivity for S1PR2 over the other S1PRs (IC50 > 1000 nM). Further optimization of these analogues may identify additional and more potent and selective compounds targeting S1PR2. PMID- 29249564 TI - Synchronous tumours of the female reproductive tract. AB - Many ovarian endometrioid carcinomas present with concurrent endometrial carcinoma, and these organ-confined, low-grade synchronous endometrial and ovarian tumours consistently behave as independent primary tumours, rather than a single advanced-stage carcinoma; they are associated with a very favourable prognosis and there is no need for adjuvant treatment. This phenomenon of synchronous tumours involving two or more sites within the female reproductive tract is well recognised, occurring in 1-2% of cases. Although some tumours can be recognised as metastasis, in many the relationship between the synchronous tumours is uncertain. Recently, application of next generation sequencing to synchronous endometrial and ovarian carcinomas has shed light on the relationship between these tumours, but raised more questions about the biology of this curious phenomenon. Herein, we review synchronous tumours involving more than one site in the female genital tract, discuss the pathogenesis, and offer guidelines for how to handle in routine practice. PMID- 29249565 TI - Comparative study of RFLP-IS6110 and MIRU-VNTR from Mycobacterium tuberculosis isolated in the state of Minas Gerais, Brazil. AB - DNA genotyping of Mycobacterium tuberculosis has been widely applied in the understanding of disease transmission in many countries. The purpose of this study was to genotype the strains of M. tuberculosis isolated in patients with new tuberculosis (TB) cases in Minas Gerais, as well as to compare the similarity, discriminatory power, and agreement of the clusters between the IS6110 Restriction Fragment Length Polymorfism (RFLP) and 12 loci Variable Number Tandem Repeat - Mycobacterial Interspersed Repetitive Units (MIRU-VNTR) techniques. It was observed that 32% (66/204) of the isolated strains in the RFLP IS6110 and 50.9% (104/204) of the isolated strains in the MIRU-VNTR presented a similarity of equal to or above 85%. The RFLP-IS6110 and MIRU-VNTR proved to contain a high discriminatory power. The similarity index resulting from the RFLP showed no recent transmission. Good agreement was observed between the techniques when clusters were detected; however, the best epidemiological relationship was found when using the RFLP-IS6110. PMID- 29249566 TI - Evaluation of MLC leaf transmission on IMRT treatment plan quality of patients with advanced lung cancer. AB - The purpose of this paper was to evaluate the impact of leaf treatment of multileaf collimator (MLC) in plan quality of intensity-modulated radiotherapy (IMRT) of patients with advanced lung cancer. Five MLCs with different leaf transmissions (0.01%, 0.5%, 1.2%, 1.8%, and 3%) were configured for an accelerator in a treatment planning system. Correspondingly, 5 treatment plans with the same optimization setting were created and evaluated quantitatively for each patient (11 patients total) who was diagnosed with advanced lung cancer. All of the 5 plans for each patient met the dose requirement for the planning treatment volumes (PTVs) and had similar target dose homogeneity and conformity. On average, the doses to selected organs were as follows: (1) V5, V20, and the mean dose of total lung; (2) the maximum and mean dose to spinal cord planning organ-at-risk volume (PRV); and (3) V30 and V40 of heart, decreased slightly when MLC transmission was decreased, but with no statistical differences. There is a clear grouping of plans having total quality score (SD) value, which is used to evaluate plan quality: (1) more than 1 (patient nos. 1 to 3, 5, and 8), and more than 2.5 (patient no. 6); (2) less than 1 (patient nos. 7 and 10); (3) around 1 (patient nos. 4, 9, and 11). As MLC transmission increased, overall SD values increased as well and plan dose requirement was harder to meet. The clinical requirements were violated increasingly as MLC transmission became large. Total SD with and without normal tissue (NT) showed similar results, with no statistically significant differences. Therefore, decrease of MLC transmission did have minimum impact on plan, and it improved target coverage and reduced normal tissue radiation slightly, with no statistical significance. Plan quality could not be significantly improved by MLC transmission reduction. However, lower MLC transmission may have advantages on lung sparing to low- and intermediate dose exposure. Besides conventional fraction, hyperfraction, or stereotactic body radiotherapy (SBRT), the reduction on lung sparing is still essential because it is highly relevant to radiation pneumonitis (RP). It has potential to diminish incidence of RP and improve patient's quality of life after irradiation with lowered MLC transmission. PMID- 29249567 TI - [An update on the treatment of venous insufficiency in pregnancy]. AB - Chronic venous insufficiency is a long-term pathological condition resulting from anatomical or functional alterations of the venous system. This leads to the appearance of symptoms and physical signs that affect a large part of the population and particularly pregnant women, due to the physiology of pregnancy. The few published studies on the use of pharmacological treatments of venous insufficiency in this group of the population, often makes the management of this condition difficult in routine clinical practice. A review is presented in this article, with all the latest updates in the treatment of this condition during pregnancy. There are numerous general, and some pharmacological, recommendations, that we can safely offer the pregnant patient. PMID- 29249568 TI - [Reccomendations for the care of adults with Down's syndrome. Literature review]. AB - Over the years, the life expectancy for individuals with Down syndrome (DS) has increased significantly. This fact involves a higher risk for developing numerous medical conditions associated with the aging of adults with DS. A high level of awareness is required by the professional, due to the lack of clinical expressiveness and their higher pain threshold, often makes the diagnosis difficult. Health care professionals must be aware of the specific recommendations for the appropriate care of the adult population with DS. The aim of this article is to describe the most frequent comorbidities in adults with DS adults, to summarise the specific preventive recommendations after comparing the main guidelines published, and to evaluate them according to their specific needs. PMID- 29249569 TI - Hippo Signaling in the Immune System. AB - Hippo signaling has a pivotal role in organ size control, tissue regeneration, and cancer. Recent studies have demonstrated critical functions of Hippo signaling in cancer immunity, innate immune responses against pathogens, and autoimmune diseases, refreshing our understanding of the implications of this pathway in the context of disease and therapy design. PMID- 29249571 TI - Redox Functions of Heme Oxygenase-1 and Biliverdin Reductase in Diabetes. AB - In patients with diabetes, the hyperglycemia-driven excess generation of reactive oxygen species (ROS) induces oxidative stress (OS) in a variety of tissues. OS is closely associated with chronic inflammation and has a key role in the pathogenesis of vascular complications. The enzymes that generate ROS and gasotransmitters are redox regulated and are implicated in cellular signaling. As a result of cellular metabolism, cells produce significant amounts of carbon monoxide (CO), mainly from heme degradation catalyzed by heme oxygenases (HOs). These reactions also generate biliverdin, bilirubin (BR), and iron. The conversion of biliverdin to BR is catalyzed by biliverdin reductase-A (BVR-A). In this review, we focus on the importance of the HO-1/CO system and BVR in the pathophysiology and therapy of inflammation associated with diabetes. PMID- 29249572 TI - The changes in classical and nonlinear parameters after a maximal bout to elicit fatigue in competitive swimming. AB - The aim was to assess the effect of fatigue on linear and nonlinear parameters in swimming. Twenty-four fitness-oriented swimmers performed a maximal bout of 100 m at front-crawl to elicit fatigue. Before (pre-) and immediately after (post-test) the bout, participants swam an all-out 25 m to derive the speed fluctuation (dv), approximate entropy (ApEn) and fractal dimension (FD) from the speed-time series collected by a speedo-meter. Swim speed was 10.85% slower in the post-test than in the pre-test (p < .001, eta2 = 0.72). There was an effect of the fatigue on the dv with a moderate effect size. The dv increased shifting the 95CI band from 0.116-0.134 to 0.140-0.161. The ApEn showed non-significant variations between the pre- and post-test having the 95CI of pre- and post-test overlapped (pre: 0.659-0.700; post: 0.641-0.682). The FD showed as well a significant variation (the 95CI moved from 1.954-1.965 to 1.933-1.951). It can be concluded that in swimming there are changes in classical and nonlinear parameters under fatigue. PMID- 29249570 TI - Cullin 3-Based Ubiquitin Ligases as Master Regulators of Mammalian Cell Differentiation. AB - Specificity of the ubiquitin proteasome system is controlled by ubiquitin E3 ligases, including their major representatives, the multisubunit cullin-RING ubiquitin (Ub) ligases (CRLs). More than 200 different CRLs are divided into seven families according to their cullin scaffolding proteins (CUL1-7) around which they are assembled. Research over two decades has revealed that different CRL families are specialized to fulfill specific cellular functions. Whereas many CUL1-based CRLs (CRL1s) ubiquitylate cell cycle regulators, CRL4 complexes often associate with chromatin to control DNA metabolism. Based on studies about differentiation programs of mesenchymal stem cells (MSCs), including myogenesis, neurogenesis, chondrogenesis, osteogenesis and adipogenesis, we propose here that CRL3 complexes evolved to fulfill a pivotal role in mammalian cell differentiation. PMID- 29249573 TI - Cervical cancer screening among Lebanese women. AB - BACKGROUND: Cervical cancer is a very common malignancy amongst women worldwide. Pap smear is an effective and inexpensive screening test in asymptomatic women. The aim of this paper was to assess the prevalence of Pap smear screening for cervical cancer among Lebanese women and to determine associated sociodemographic and psychosocial characteristics. METHODS: This national survey included 2255 women, selected by multi-stage random cluster sampling across Lebanon. A questionnaire about practices and perceptions related to cervical cancer screening was developed based on the "Health Belief Model". RESULTS: The weighted national prevalence of "ever-use" of the Pap smear for screening purposes was 35%. Most important determinants of screening behavior were: residence within Greater Beirut, higher socio-economic status and educational attainment, marriage status, presence of a health coverage, awareness of Pap smear usefulness, knowing someone who had already done it, and a balance between perceived benefits and perceived barriers to Pap smear screening. CONCLUSION: Regular information campaigns regarding the availability and effectiveness of the test should be devised, targeting in priority the sexually vulnerable women in Lebanon. Moreover, healthcare providers should be encouraged to discuss with their patients the opportunity of obtaining a Pap smear. PMID- 29249574 TI - Ultimate force and stiffness of 2-piece zirconium dioxide implants with screw retained monolithic lithium-disilicate reconstructions. AB - PURPOSE: The aims were to analyze stiffness, ultimate force, and failure modes of a 2-piece zirconium dioxide (ZrO2) implant system. METHODS: Eleven 2-piece ZrO2 implants, each mounted with ZrO2 abutments plus bonded monolithic lithium disilicate (LS2) restorations, were grouped for 3.3mm (A) and 4.1mm (B) diameter samples. Quasi-static load was monotonically applied under a standardized test set-up (loading configuration according to DIN ISO 14801). The ultimate force was defined as the maximum force that implants are able to carry out until fracture; stiffness was measured as the maximum slope during loading. An unpaired t-test was performed between group A and B for ultimate force and stiffness (p<0.05). RESULTS: Force-displacement curves revealed statistically homogenous inner-group results for all samples. Failure modes showed characteristic fractures at the neck configuration of the implants independent of the diameter. Mean stiffness was 1099N/mm (+/-192) for group A, and significantly lower compared to group B with 1630N/mm (+/-274) (p<0.01); whereas mean ultimate force was 348N (+/-53) for group A, and significantly increased for group B with 684N (+/-29) (p<0.0001). CONCLUSIONS: The examined 2-piece ZrO2 implant system mounted to LS2-restorations seems to be a stable unit under in-vitro conditions with mechanical properties compared to loading capacity of physiological force. The metal-free implant reconstructions demonstrated high stiffness and ultimate force under quasi-static load for single tooth replacement under consideration of the dental indication of narrow and standard diameter implants. PMID- 29249575 TI - Combined cardiovascular and sweating autonomic testing to differentiate multiple system atrophy from Parkinson's disease. AB - OBJECTIVES: It can be difficult to differentiate multiple system atrophy (MSA) with predominant parkinsonism (MSA-P), a very disabling but rare disease, from Parkinson's disease (PD). Autonomic dysfunction, particularly cardiovascular autonomic neuropathy (CAN), is classically more pronounced in MSA. We investigated whether testing for CAN combined with sweat function assessment was helpful to differentiate patients with MSA from those with PD. METHODS: In this retrospective study, 62 patients with MSA-P and 96 with PD, comparable in age, BMI and sex ratio with disease duration of 4.3+/-2.5 years for MSA vs. 11.5+/-6 years for PD (P<0.0001) were tested for CAN using heart rate changes with deep breathing (HR-DB), stand test (HR-ST) and Valsalva maneuver (HR-VM) and blood pressure changes during stand test (BPs-ST and BPd-ST), Valsalva maneuver (BPs-VM II and IV), hand grip (BPd-HG) and the total "Ewing" score tests (EwS), and for sweating function using electrochemical skin conductance for hands and feet (HESC and FESC). RESULTS: In MSA-P abnormal EwS, HR-DB, BP-ST and ESC were more frequent compared to PD, despite longer disease duration for PD. Using a model adjusted for sex, BMI, age, disease duration and treatment, the Odds Ratio for having MSA-P vs. PD based on EwS was 2.71, on HR-DB 2.36, on BP-ST 2.87 and on ESC 4.94 while it was 11.68 (2.17-62.79) for the combination of the three last tests. CONCLUSION: Assessment of HR-DB, BP-ST and ESC, that is, rapid and non invasive could be helpful in combination as a first simple screening to differentiate MSA-P from PD. PMID- 29249576 TI - Low Tube Voltage and Iterative Model Reconstruction in Follow-up CT Angiography After Thoracic Endovascular Aortic Repair: Ultra-low Radiation Exposure and Contrast Medium Dose. AB - RATIONALE AND OBJECTIVES: This study aimed to investigate the feasibility of reducing radiation exposure and contrast medium (CM) dose in follow-up computed tomography angiography (CTA) after thoracic endovascular aortic repair (TEVAR) using low tube voltage and knowledge-based iterative model reconstruction (IMR). MATERIALS AND METHODS: Thirty-six patients that required follow-up CTA after TEVAR were included in this intra-individual study. The conventional protocol with standard tube voltage of 120 kVp and CM volume of 70 mL was applied in the first follow-up CTA of all the patients (control group A). The ultra-low CM dose protocol with low tube voltage of 80 kVp and weight-adapted CM volume of 0.4 mL/kg was utilized in the second follow-up CTA (study group B). Set A.FBP (group A filtered back-projection) contained images for group A that were reconstructed through FBP method. Three sets (B.FBP, B.HIR, and B.IMR) for group B were reconstructed using three methods, FBP, hybrid iterative reconstruction (HIR), and IMR, respectively. Objective measurements including aortic attenuations, image noise, contrast-to-noise ratios (CNRs), and figure of merit of CNR (FOMCNR), and subjective rating scores of the four image sets were compared. RESULTS: Compared to the images in set A.FBP, the images in set B.IMR had better quality in terms of equivalent attenuation values, equivalent subjective scores, lower noise, higher or equivalent CNRs, and higher FOMCNR. The quality of images in sets B.FBP and B.HIR was unacceptable. The radiation exposure and CM dose in group B were 1.94 mGy and 28 +/- 5 mL, respectively, representing reductions of 77.6% (P < .001) and 60% (P < .001) as compared to those in group A. CONCLUSIONS: In follow-up examinations after TEVAR, CTA with ultra-low radiation exposure and CM dose is feasible using low tube voltage and IMR for nonobese patients. PMID- 29249577 TI - Utilization of Transesophageal Echocardiography for Extraction of an Inferior Vena Cava Filter Fragment in the Right Ventricle. PMID- 29249578 TI - Echocardiographic Guidance and Troubleshooting for Venovenous Extracorporeal Membrane Oxygenation Using the Dual-Lumen Bicaval Cannula. PMID- 29249579 TI - Avoiding Acute Kidney Injury After Cardiac Surgery: Simple and Easy? PMID- 29249580 TI - Simultaneous Right-Sided and Left-Sided Infective Endocarditis: Management Challenges in a Multidisciplinary Setting. PMID- 29249581 TI - Vasodilator Agents in Pediatric Cardiac Surgery with Cardiopulmonary Bypass. PMID- 29249582 TI - Coronary Artery Bypass Grafting Using an Arteriovenous I-Conduit: Benefits and Drawbacks. PMID- 29249583 TI - Bronchial Blocker Versus Left Double-Lumen Endotracheal Tube for One-Lung Ventilation in Right Video-Assisted Thoracoscopic Surgery. AB - OBJECTIVE: The aim of this study was to compare the quality of lung deflation of a left-sided double-lumen endotracheal tube (DLT) with a bronchial blocker (BB) for one-lung ventilation in video-assisted thoracic surgery (VATS). DESIGN: A prospective, randomized, clinical study. SETTING: A university-affiliated teaching hospital. PARTICIPANTS: Forty-five adult patients undergoing esophageal tumor surgery using VATS with right lung deflation. INTERVENTIONS: Patients were assigned by a computer-generated randomization sequence to either the left-sided DLT or BB group. The correct positioning of the airway device was confirmed using fiberoptic bronchoscopy. MEASUREMENTS AND MAIN RESULTS: The variables assessed included: (1) time required to correctly place the devices and to achieve lung collapse; (2) the number of times the device malpositioned; (3) the quality of lung deflation as rated by the surgeon; (4) blood pressure and heart rate at baseline (T1), immediately before (T2) and after (T3) and 1 minute (T4) after intubation; (5) the number of patients with hypoxemia (SpO2 < 90%) during the one lung ventilation (OLV) period; and (6) postoperative hoarseness of voice, sore throat, or pulmonary infection. Of the 45 patients approached for the study, 21 patients in the DLT group and 19 patients in the BB group were analyzed. The time required to place the device in the correct position was similar between the 2 groups. The time to achieve right lung collapse in the BB group was significantly longer (mean difference: 3.232, 95% confidence interval [CI]: 1.993-4.471; p = 0.003). The quality of lung collapse, OLV duration, number of patients with device malposition, and hypoxemia in both groups were similar. There were more patients suffering hoarseness (odds ratio [OR]: 4.85, 95% CI: 1.08-21.76; p = 0.034) or sore throat (OR: 4.29, 95% CI: 1.14-16.18; p = 0.030) in the DLT group, while no patients developed postoperative lung infection in either group. Compared to T1, systolic blood pressure (sBP), diastolic BP (dBP), and heart rate (HR) at T2 in both groups were higher (p < 0.05) in the DLT group. Then, compared to T2, sBP and dBP at T3 and T4 and HR at T3 in the DLT group were higher (p < 0.05). CONCLUSIONS: The results of this study showed that BB is an effective alternative for left one-lung ventilation in right VATS, but requires a longer time to achieve complete lung collapse. Moreover, the use of BB caused less hemodynamic perturbation and can reduce postoperative hoarseness and sore throat. PMID- 29249584 TI - Planned Safety Analysis of the ACTS-CC 02 Trial: A Randomized Phase III Trial of S-1 With Oxaliplatin Versus Tegafur and Uracil With Leucovorin as Adjuvant Chemotherapy for High-Risk Stage III Colon Cancer. AB - BACKGROUND: This trial was designed to verify the superiority of 6 months of postoperative adjuvant chemotherapy with SOX (S-1 with oxaliplatin) with UFT (tegafur and uracil) with LV (leucovorin) in terms of disease-free survival in patients with high-risk stage III colon cancer. We report the results of a planned safety analysis. PATIENTS AND METHODS: Patients who underwent curative resection for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries) were randomly assigned to receive either UFT/LV (300-600 mg/d UFT with 75 mg/d LV on days 1-28, every 35 days, for 5 cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 with 80-120 mg/d S-1 on days 1-14, every 21 days, for 8 cycles). Treatment status and safety were evaluated. RESULTS: A total of 966 patients were enrolled, and 932 patients were included in safety analyses. The planned 6-month protocol treatment was received by 76.9% of the patients in the UFT/LV group and 65.8% of those in the SOX group. The overall incidence of any Grade adverse events (AEs) were 91.3% in the UFT/LV group and 98.7% in the SOX group, and those of Grade >= 3 AEs were 16.1% and 36.1%, respectively. As for Grade >= 3 AEs, leukopenia, neutropenia, thrombocytopenia, and sensory neuropathy were more common in the SOX group. The incidence of Grade >= 3 sensory peripheral neuropathy was 4.6% in the SOX group. CONCLUSION: The completion rate of adjuvant SOX and its incidence of AEs were acceptable in patients with colon cancer. PMID- 29249585 TI - Bariatric surgery barriers: a review using Andersen's Model of Health Services Use. AB - Severe obesity affects nearly 20 million adults in the United States and is associated with significant morbidity and mortality. Bariatric surgery is the most effective treatment for weight loss and resolution of obesity-related co morbidities. Of adults with severe obesity,<1% undergo bariatric surgery annually. Both contextual (health system, clinicians, and community) and individual factors contribute to the underutilization of bariatric surgery. In this review, we summarize potential barriers to undergoing bariatric surgery within the framework of Andersen's Behavioral Model of Health Services Use. PMID- 29249586 TI - Medium to long-term outcomes of bariatric surgery in older adults with super obesity. AB - BACKGROUND: Indications and outcomes of bariatric surgery in older adults suffering from morbid obesity remain controversial. We aimed to evaluate safety and medium to long-term outcomes of bariatric procedures in this patient population. SETTING: University Hospital, Canada. METHODS: This is a single center retrospective study of a prospectively collected database. We included patients aged >=60 years who underwent sleeve gastrectomy, Roux-en-Y gastric bypass, or biliopancreatic diversion with duodenal switch between January 2006 and December 2014 and had at least 2 years of follow-up. RESULTS: Of patients, 115 underwent bariatric surgeries (11 patients had 2 procedures). There were 66 were super-obese patients (body mass index>50 kg/m2). Of patients, 74% had sleeve gastrectomy, 16% Roux-en-Y gastric bypass, and 8% underwent biliopancreatic diversion with duodenal switch. Mean age and body mass index were 63.3 +/- 2.6 years and 51.7 +/- 8.1 kg/m2, respectively. Average follow-up time was 42 +/- 19 months. At baseline, 78% had hypertension, 60% had type 2 diabetes, and 30% had obstructive sleep apnea. There was no 30-day mortality. Complication rate was 14% (n = 16): 2 leaks post-Roux-en-Y gastric bypass, 1 leak post-biliopancreatic diversion with duodenal switch, 1 obstruction post-sleeve gastrectomy, 1 bleeding requiring transfusion, 1 liver injury with bile leak, 2 port-site hernias, 1 myocardial infarction, 2 gastrojejunal strictures, 1 wound infection, 1 urinary tract infection, and 3 gastric reflux exacerbations. Mean percent excess weight loss at 2 years was 52.2 +/- 23.8. Remission rates of hypertension, type-2 diabetes, and obstructive sleep apnea were 26%, 44%, and 38%, respectively. CONCLUSION: Bariatric surgery is safe and effective in improving obesity-related co-morbidities in older patients suffering from morbid obesity. Age alone should not preclude older patients from getting the best bariatric procedure for obesity and related co-morbidities. PMID- 29249587 TI - Correlations of Serum Cyclophilin A and Melatonin Concentrations with Hypertension-induced Left Ventricular Hypertrophy. AB - BACKGROUND AND AIMS: Cyclophilin A (CyPA) is an abundantly expressed pro inflammatory cytokine and a major secreted oxidative stress-induced factor (SOXF). Melatonin is an important chronobiological regulatory molecule that is mainly released from the pineal gland and exerts antioxidant effects by acting as a radical scavenger. Based on accumulating evidence, both CyPA and melatonin play important roles in cardiovascular diseases. However, further investigations are required to determine whether CyPA and melatonin are associated with hypertension induced left ventricular hypertrophy (LVH). METHODS: A total of 135 patients with essential hypertension were divided into an LVH (+) group and an LVH (-) group according to Doppler echocardiography results. Clinical data of the two groups were evaluated. RESULTS: High CyPA levels and low melatonin levels are independent risk factors for LVH (p = 0.000). In addition, body mass index (BMI) and systolic blood pressure (SBP) are correlated with the risk of LVH (p = 0.000). However, other factors did not display statistically significant associations (p >0.05). The Pearson correlation and linear regression analyses show that BMI, SBP, and CyPA levels were positively correlated with left ventricular mass (LVM) and the left ventricular mass index (LVMI) (p <0.05), whereas melatonin levels were negatively correlated with LVM and the LVMI (p = 0.000). Furthermore, according to the results of the Pearson correlation analysis, CyPA levels were negatively correlated with melatonin levels (p <0.01) in subjects with LVH. CONCLUSIONS: Based on these results, both CyPA and melatonin are closely related to the pathogenesis of LVH. As CyPA was negatively correlated with melatonin in patients with LVH, additional studies are required to determine whether melatonin may partially protect the myocardium by decreasing CyPA levels. PMID- 29249588 TI - An In-Depth Analysis of Publication Characteristics of Podium Presentations at the Arthroscopy Association of North America Annual Meetings, 2011-2014. AB - PURPOSE: To determine the publication rate of abstracts presented at the annual meetings of the Arthroscopy Association of North America (AANA) from 2011 through 2014 and to compare the level of evidence (LoE) between published and unpublished studies. METHODS: A comprehensive search was performed using PubMed and Google Scholar for all abstracts given as podium presentations at the 2011 through 2014 AANA Annual Meetings. A publication rate was calculated from all presented abstracts. Each abstract was reviewed to determine the study's LoE (I-V or nonclinical). Among published studies, the average time from presentation to publication was calculated. The journals in which these studies were published were also noted. RESULTS: A total of 290 abstracts were given as podium presentations at AANA Annual Meetings from 2011 through 2014. Of the 290 studies presented, 195 (195/290, 67%) were published in peer-reviewed journals. Of the 195 published studies, 184 (184/195, 94%) were published within 3 years of the meeting date. Studies were most frequently published in Arthroscopy (n = 59) and the American Journal of Sports Medicine (n = 48). The average time from presentation to publication was 12.2 months. Overall, there was no significant difference between published and unpublished studies in terms of LoE (P = .24). CONCLUSIONS: In recent years, studies presented at AANA Annual Meetings have achieved a high publication rate (67%). Based on other studies, this publication rate is comparable to recent American Orthopaedic Society for Sports Medicine (AOSSM) Annual Meetings and is higher than that of AANA Annual Meetings from previous years. The level of evidence of presented studies does not necessarily correlate with eventual publication. CLINICAL RELEVANCE: The publication rate and level of evidence of podium presentations at AANA demonstrate the scientific impact the annual meeting has for peers pursuing orthopaedic research. PMID- 29249589 TI - Acute Predictors of Social Integration Following Mild Stroke. AB - BACKGROUND: Despite an acknowledged need to accurately predict stroke outcome, there is little empirical evidence regarding acute predictors of participation restriction post stroke. The current study examines prediction of social integration following mild stroke, using combinations of acute poststroke factors. PATIENTS AND METHODS: In a prospective, longitudinal study, a cohort of 60 stroke survivors was followed up at 6 months post stroke. Hierarchical multiple regression analyses were employed to evaluate the value of acute poststroke variables in predicting social integration at 6 months post stroke. RESULTS: A combination of age, number of comorbidities, stroke severity, social support factors, and general self-efficacy in the acute poststroke period accounted for 42% of the variance in 6-month social integration. The largest amount of variance (20%) was explained by inclusion of social support factors, including number and types of support. Post hoc analysis was conducted to establish whether marital status was the mediating variable through which early poststroke social support factors exerted influence upon subsequent social integration. The new combination of acute variables accounted for 48% of the variance in 6-month social integration. Results suggested that subjects with partners perceived higher levels of functional social support and lower levels of participation restriction. DISCUSSION: Stroke survivors with partners may receive greater amounts of companionship and encouragement from their partners, which enhances self-esteem and confidence. Such individuals are possibly more able to participate in and maintain relationships, thus improving social integration. CONCLUSIONS: Social support factors, mediated via marital status, are the strongest predictors of subsequent social integration following mild stroke. PMID- 29249590 TI - Neuroprotective Effects of Oxytocin Hormone after an Experimental Stroke Model and the Possible Role of Calpain-1. AB - BACKGROUND: Different mechanisms will be activated during ischemic stroke. Calpain proteases play a pivotal role in neuronal death after ischemia damage through apoptosis. Anti-apoptotic activities of the oxytocin (OT) in different ischemic tissues were reported in previous studies. Recently, a limited number of studies have noted the protective effects of OT in the brain. In the present study, the neuroprotective potential of OT in an animal model of transient middle cerebral artery occlusion (tMCAO) and the possible role of calpain-1 in the penumbra region were assessed. METHODS: Adult male Wistar rats underwent 1 hour of tMCAO and were treated with nasal administration of OT. After 24 hours of reperfusion, infarct size was evaluated by triphenyltetrazolium chloride. Immunohistochemical staining and Western blotting were used to examine the expression of calpain-1. Nissl staining was performed for brain tissue morphology evaluation. RESULTS: OT reduced the infarct volume of the cerebral cortex and striatum compared with the ischemia control group significantly (P < .05). Calpain-1 overexpression, which was caused by ischemia, decreased after OT administration (P < .05). The number of pyknotic nuclei in neurons increased dramatically in the ischemic area and OT attenuated the apoptosis of neurons in the penumbra region (P < .01). CONCLUSION: We provided evidence for the neuroprotective role of OT after tMCAO through calpain-1 attenuation. PMID- 29249591 TI - Relationship between Cardiac Troponin and Thrombo-Inflammatory Molecules in Prediction of Outcome after Acute Ischemic Stroke. AB - BACKGROUND: In patients with acute ischemic stroke (AIS) without cardiovascular complications, we investigated the association of serum concentration of cardiac troponin (high-sensitivity cardiac troponin T [hs-cTnT]) with thrombo inflammatory markers. METHODS: Thirty-five patients with first-ever AIS were prospectively examined. Serum hs-cTnT was measured 6 and 24 hours after stroke, whereas S100B, high-sensitivity C-reactive protein (hsCRP), soluble CD40 ligand, tissue plasminogen activator (tPA), monocyte chemoattractant protein-1 (MCP-1), and P-selectin were measured 6 and 72 hours after stroke. Severity of stroke was assessed by the National Institutes of Health Stroke Scale (NIHSS) on admission, 24 hours later, and at discharge. RESULTS: Concentration of MCP-1 at 6 hours was higher in the serum of patients with worsened NIHSS by 24 hours (P = .009). Concentration of hs-cTnT at both 6 and 24 hours was higher, if NIHSS worsened by discharge (P = .026 and P = .001). A cutoff value for hs-cTnT measured at T24 greater than or equal to 9.4 predicted worsened NIHSS on discharge with a sensitivity of 81% and a specificity of 74% (area: .808, P = .002). Concentration of hs-cTnT at both 6 and 24 hours was also higher in nonsurvivors compared with survivors (P = .03, respectively), and correlated with (1) tPA levels at 6 hours (P = .001 and P = .002, respectively); (2) MCP-1 concentration at 6 hours (P = .01 and P = .015, respectively); and increased hsCRP levels at 72 hours (P = .01, respectively). Concentration of hs-cTnT at 24 hours was an independent predictor of worsened NIHSS at discharge (odds ratio: 1.58, 95% confidence interval: 1.063 2.370, P = .024). CONCLUSIONS: Elevated concentration of hs-cTnT measured 24 hours after AIS is an independent predictor of progressing neurologic deficit in patients without apparent myocardial damage, and also correlates with acute elevation of tPA and MCP-1. PMID- 29249592 TI - Robotic low anterior resection versus transanal total mesorectal excision in rectal cancer: A comparison of 115 cases. AB - BACKGROUND: Robotic low anterior resection (RLAR) and transanal total mesorectal excision (TaTME) are novel surgical techniques for resection of rectal cancer. To our knowledge, no data exist on direct comparison of these procedures in terms of oncological or functional parameters. METHODS: 60 RLAR and 55 TaTME for rectal cancer were compared in respect to patient characteristics, clinicopathological parameters, intraoperative and perioperative results and anatomopathological outcome. RESULTS: 62 surgeries addressed tumors of the lower third (53.9%). No intergroup differences in terms of patient characteristics and clinicopathological parameters were observed. Operating time did not differ between groups (p = 0.312), nor did the perioperative complication rate (p = 0.176). Circumferential resection margin was wider in the RLAR than in the TaTME group (p < 0.001), while no differences were found in the remaining oncological parameters. CONCLUSION: Our study shows comparable results for RLAR and TaTME in rectal cancer treatment. Both procedures should be considered equally feasible for low rectal cancer cases and as an alternative to conventional anterior resections (open or laparoscopic). Furthermore, both techniques allow excellent oncological outcome especially in patients with anatomical limitations. PMID- 29249593 TI - Evaluation of Delayed Endoleak Compared with Early Endoleak after Endovascular Aneurysm Repair. AB - PURPOSE: To identify prevalence and evaluate outcomes of delayed endoleak (DEL) compared with early endoleak (EEL) after endovascular aortic aneurysm repair (EVAR). MATERIALS AND METHODS: Data of 164 patients who underwent elective EVAR at a single center were retrospectively analyzed. DEL was defined as any type of endoleak that was first detected >= 12 months after EVAR. Patients who had < 1 year of follow-up were excluded. Endoleak was classified into a more aggressive category if a patient had > 1 type of endoleak. Analysis included 81 patients (82.7% male). Mean age was 73.1 years +/- 9.3. Median follow-up duration was 43 months (range, 12-135 months). RESULTS: Endoleak was present in 32 patients (39.5%), including 21 EEL (25.9%) and 11 DEL (13.6%). DEL consisted of 2 type I, 5 type II, 1 type III, and 3 type V (endotension). Median time to detection was 45 months (range, 15-60 months), and median follow-up duration was 62 months (range, 37-104 months). Compared with EEL, DEL had larger aneurysm diameters and higher rates of non-type II endoleak and reintervention. Type II DEL also required more reintervention procedures than type II EEL. CONCLUSIONS: DEL had a noteworthy incidence and occurred late after EVAR. It predominantly consisted of non-type II endoleak and appeared to have more reinterventions than EEL. Meticulous long-term imaging surveillance to identify and manage DEL is critical. PMID- 29249594 TI - Anatomic versus Metabolic Tumor Response Assessment after Radioembolization Treatment. AB - PURPOSE: To assess applicability of metabolic tumor response assessment on 18F fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) after radioembolization (RE) in patients with colorectal liver metastases (CRLM) by comparison with one-dimensional size-based response assessment on MR imaging. MATERIALS AND METHODS: This prospective cohort study comprised 38 patients with CRLM undergoing RE. MR imaging and 18F-FDG PET/CT imaging were performed at baseline, 1 month (n = 38), and 3 months (n = 21). Longest tumor diameter (LTD) reduction on MR imaging at these time points was compared with reduction in total lesion glycolysis (TLG) on 18F-FDG PET/CT. Hepatic response was compared between RECIST and total liver TLG and correlated with overall survival (OS). RESULTS: TLG and LTD were positively correlated in 106 analyzed metastases (38 patients) at 1 month and 58 metastases (22 patients) at 3 months. Agreement was poor, with LTD underestimating TLG response. A significant association with prolonged OS was found in total liver TLG at 1 month (HR 0.64, P < .01) and 3 months (HR 0.43, P < .01). For LTD, a significant association with OS was found at 3 months (HR 0.10, P < .01). Important differences in liver response classification were found, with total liver TLG identifying more patients and situations where there appeared to be treatment benefit compared with RECIST. CONCLUSIONS: TLG response assessment on 18F-FDG PET/CT appears to be more sensitive and accurate, especially at early follow-up, than size-based response assessment on MR imaging in patients with CRLM treated by RE. Semiautomated liver response assessment with total liver TLG is objective, reproducible, rapid, and prognostic. PMID- 29249595 TI - Is Emergency Transcatheter Hepatic Arterial Embolization Suitable for Spontaneously Ruptured Hepatocellular Carcinoma in Child-Pugh C Cirrhosis? AB - PURPOSE: To evaluate the utility of emergent transcatheter arterial embolization for spontaneously ruptured hepatocellular carcinoma (HCC) in patients with Child Pugh class C (CPC) liver cirrhosis presenting hemorrhagic shock. MATERIALS AND METHODS: A study of all 94 patients was retrospectively conducted from January 2006 to January 2016. Sixty patients underwent conservative treatment (control group) and 34 underwent embolization. RESULTS: Embolization provided better stabilization of hemodynamic status than conservative treatment (91.2% vs 61.7%), with greater overall survival (OS) rates at 30, 60, and 120 days (73.5%, 52.9%, and 29.4% vs 33.3%, 13.3%, and 0%, respectively). Mean follow-up duration was 51.07 days (range, 3-237 d). Median survival time was longer for the embolization group than the control group, specifically for patients with a shock index (SI) of >= 0.6 to < 1 (106.0 d +/- 39.4 vs 34.0 d +/- 4.7) or >= 1 (18.0 d +/- 7.5 vs 11.0 d +/- 3.2), those with CPC scores 10 or 11 (88.0 d +/- 29.4 vs 28.0 d +/- 4.5), and those with segmental (165.0 d +/- 20.6 vs 34.0 d +/- 9.7) or lobar (54.0 d +/- 7.9 vs 26.0 d +/- 3.4) portal vein tumor thrombus (PVTT). SI >= 1, Child-Pugh score of 12/13, tumor size >= 10 cm, and PVTT were independent factors in poor prognosis for OS. CONCLUSIONS: Emergent transcatheter arterial embolization is an effective intervention for ruptured HCC in patients with CPC liver function in hemorrhagic shock, particularly those with a SI >= 1, Child Pugh scores of 10/11, and first- or lower-order PVTT. PMID- 29249596 TI - Are you more concerned about or relieved by medicines? An explorative randomized study of the impact of telephone counseling by pharmacists on patients' beliefs regarding medicines and blood pressure control. AB - OBJECTIVES: The aim was to determine the impact of a telephone counseling service, provided bi-monthly by pharmacist, on patients' beliefs about antihypertensive medicines and blood pressure (BP) control. METHODS: Either hypertensive patients were randomly assigned to a control group (CG, usual care) or an intervention group (IG). All patients had BP values registered and filled in the Italian version of the Belief Medicine Questionnaire (BMQ). After 12 months, patients filled in the BMQ again and had their self-reported BP registered. The intervention consisted of an educational/counseling session based on patients' needs assessment provided bi-monthly by a pharmacist for one year via telephone. RESULTS: 80 CG and 84 IG patients were recruited. After 12 months, there were significant differences between IG and CG for both BMQ's Necessity and Concern score (p < 0.001; p < 0.001 respectively) and a significant reduction in BP values in IG (p < 0.001). CONCLUSIONS: The intervention improves BP control by modifying patients' perception about treatments and involving patients as participants in the management of their health. PRACTICE IMPLICATIONS: This paper could serve as a guideline for other studies to confirm the effectiveness of this intervention in modifying health behavior, and the role of hospital pharmacist. PMID- 29249597 TI - Physicians and patients' motivations to perform elective single or double-embryo transfers: A nationwide survey. AB - OBJECTIVES: To evaluate motivations to perform an elective single embryo transfer (e-SET). METHODS: Cross-sectional surveys to reproductive medicine specialists and to infertile patients undergoing assisted reproductive treatments. RESULTS: In the physician's survey (n = 278), we found that the main reasons for not offering e-SET were the physicians' belief that patients prefer optimizing the pregnancy rates regardless of the potential complications (57.1%). Regarding the decision making process, 76.7% of physicians thought that patients and doctors should make these decisions together and 93.3% would like to have a more formal decision-aid to help with counseling. In the patients' survey (n = 100), 21.3% chose e-SET, while 33% mentioned that complications associated to multiple pregnancies were insufficiently discussed. Among those patients, none chose to have e-SET, while 30% of those who had a full discussion selected e-SET (p = 0.05). CONCLUSIONS: Most physicians did not offer e-SET based on potential patients' negative feelings. Also, almost 30% take important decisions without the patient's participation. Patients that discussed more thoroughly this topic, more frequently selected e-SET. Almost all the physicians surveyed agreed that decision-aids could help in this important shared-decision process. PRACTICE IMPLICATIONS: Decision aids about e-SET vs DET are needed to help patients in the decision making process. PMID- 29249598 TI - Response to: reimplanting the superior mesenteric artery on the infra-renal aorta. PMID- 29249599 TI - Analysis of postoperative biochemical values and clinical outcomes after adrenalectomy for primary aldosteronism. AB - BACKGROUND: Primary aldosteronism causes hypertension and hypokalemia and is often surgically treatable. Diagnosis includes elevated plasma aldosterone, suppressed plasma renin activity, and elevated aldosterone renin ratio. Adrenalectomy improves hypertension and hypokalemia. Postoperative plasma aldosterone and plasma renin activity may be useful in documenting cure or failure. METHOD: A retrospective analysis of patients who underwent adrenalectomy for primary aldosteronism from 2010 to 2016 was performed, analyzing preoperative and postoperative plasma aldosterone, plasma renin activity, hypertension, and hypokalemia. The utility of postoperative testing was assessed. Clinical cure was defined as improved hypertension control and resolution of potassium loss. Biochemical cure was defined as aldosterone renin ratio reduction to <23.6. RESULTS: Forty-four patients were included; 20 had plasma aldosterone and plasma renin activity checked on postoperative day 1. In the study, 40/44 (91%) were clinically cured. All clinical failures had of biochemical failure at follow-up. Postoperative day 1aldosterone renin ratio <23.6 had PPV of 95% for clinical cure. Cured patients had mean plasma aldosterone drop of 33.1 ng/dL on postoperative day 1; noncured patient experienced 3.9 ng/dL increase. A cutoff of plasma aldosterone decrease of 10 ng/dL had high positive predictive value for clinical cure. CONCLUSION: Changes in plasma aldosterone and plasma renin activity after adrenalectomy correlate with improved hypertension and hypokalemia. The biochemical impact of adrenalectomy manifests as early as postoperative day 1. We propose a plasma aldosterone decrease of 10 ng/dL as a criterion to predict clinical cure. PMID- 29249600 TI - Exhaustion and Inflation at Antipodes of T Cell Responses to Chronic Virus Infection. AB - Viruses that have coevolved with their host establish chronic infections that are well tolerated by the host. Other viruses, that are partly adapted to their host, may induce chronic infections where persistent replication and viral antigen expression occur. The former induce highly functional and resilient CD8T cell responses called memory inflation. The latter induce dysfunctional and exhausted responses. The reasons compelling T cell responses towards inflationary or exhausted responses are only partly understood. In this review we compare the two conditions and describe mechanistic similarities and differences. We also provide a list of potential reasons why exhaustion or inflation occur in different virus infections. We propose that T cell-mediated transcriptional repression of viral gene expression provides a critical feature of inflation that allows peaceful virus and host coexistence. The virus is controlled, but its genome is not eradicated. If this mechanism is not available, as in the case of RNA viruses, the virus and the host are compelled to an arms race. If virus proliferation and spread proceed uncontrolled for too long, T cells are forced to strike a balance between viral control and tissue destruction, losing antiviral potency and facilitating virus persistence. PMID- 29249601 TI - Coccidiosis in Large and Small Ruminants. AB - Coccidiosis is an important parasitic disease of young ruminant livestock caused by the protozoan parasite of the genus Eimeria. Infection with Eimeria can lead to subclinical production losses and clinical disease. The most common clinical sign is diarrhea. Control of coccidiosis in cattle, sheep, and goats is based on sound management, the use of preventive medications, and treatment of clinical cases as necessary. PMID- 29249602 TI - Surgical Management of Abomasal and Small Intestinal Disease. AB - A bovine practitioner should master abdominal exploratory surgery (laparotomy). Several gastrointestinal (GI) problems require surgical correction to save the animal's life and to keep it in production. This article reviews the surgical preparation, procedures, and the postoperative care of several conditions affecting the GI tract of cattle. PMID- 29249603 TI - Negotiating the Traffic: Can Cognitive Science Help Make Autonomous Vehicles a Reality? AB - To drive safely among human drivers, cyclists and pedestrians, autonomous vehicles will need to mimic, or ideally improve upon, humanlike driving. Yet, driving presents us with difficult problems of joint action: 'negotiating' with other users over shared road space. We argue that autonomous driving provides a test case for computational theories of social interaction, with fundamental implications for the development of autonomous vehicles. PMID- 29249604 TI - Selectively Modulating Conformational States of USP7 Catalytic Domain for Activation. AB - Ubiquitin-specific protease 7 (USP7) deubiquitinase activity is controlled by a number of regulatory factors, including stimulation by intramolecular accessory domains. Alone, the USP7 catalytic domain (USP7cd) shows limited activity and apo USP7cd crystal structures reveal a disrupted catalytic triad. By contrast, ubiquitin-conjugated USP7cd structures demonstrate the canonical cysteine protease active-site geometry; however, the structural features of the USP7cd that stabilize the inactive conformation and the mechanism of transition between inactive and active states remain unclear. Here we use comparative structural analyses, molecular dynamics simulations, and in silico sequence re-engineering via directed sampling by RosettaDesign to identify key molecular determinants of USP7cd activation and successfully engineer USP7cd for improved activity. Full kinetic analysis and multiple X-ray crystal structures of our designs indicate that electrostatic interactions in the distal "switching loop" region and local packing in the hydrophobic core mediate subtle but significant conformational changes that modulate USP7cd activation. PMID- 29249605 TI - High-Resolution Cryoelectron Microscopy Structure of the Cyclic Nucleotide Modulated Potassium Channel MloK1 in a Lipid Bilayer. AB - Eukaryotic cyclic nucleotide-modulated channels perform their diverse physiological roles by opening and closing their pores to ions in response to cyclic nucleotide binding. We here present a structural model for the cyclic nucleotide-modulated potassium channel homolog from Mesorhizobium loti, MloK1, determined from 2D crystals in the presence of lipids. Even though crystals diffract electrons to only ~10 A, using cryoelectron microscopy (cryo-EM) and recently developed computational methods, we have determined a 3D map of full length MloK1 in the presence of cyclic AMP (cAMP) at ~4.5 A isotropic 3D resolution. The structure provides a clear picture of the arrangement of the cyclic nucleotide-binding domains with respect to both the pore and the putative voltage sensor domains when cAMP is bound, and reveals a potential gating mechanism in the context of the lipid-embedded channel. PMID- 29249606 TI - Structural and Functional Characterization of a Cross-Reactive Dengue Virus Neutralizing Antibody that Recognizes a Cryptic Epitope. AB - Understanding the molecular basis of the neutralizing antibody response to dengue virus (DENV) is an essential component in the design and development of effective vaccines and immunotherapeutics. Here we present the structure of a cross reactive, neutralizing antibody, 3E31, in complex with domain III (DIII) of the DENV envelope (E) protein and reveal a conserved, temperature-sensitive, cryptic epitope on DIII that is not available in any of the known conformations of E on the dengue virion. We observed that 3E31 inhibits E-mediated membrane fusion, suggesting that the antibody is able to neutralize virus through binding an as yet uncharacterized intermediate conformation of DENV E and sterically block trimer formation. Finally, we show that, unlike cross-reactive fusion peptide specific antibodies, 3E31 does not promote antibody-dependent enhancement of infection at sub-neutralizing concentrations. Our results highlight the 3E31 epitope on the E protein DIII as a promising target for immunotherapeutics or vaccine design. PMID- 29249607 TI - Intracellular Transfer of Na+ in an Active-State G-Protein-Coupled Receptor. AB - Playing a central role in cell signaling, G-protein-coupled receptors (GPCRs) are the largest superfamily of membrane proteins and form the majority of drug targets in humans. How extracellular agonist binding triggers the activation of GPCRs and associated intracellular effector proteins remains, however, poorly understood. Structural studies have revealed that inactive class A GPCRs harbor a conserved binding site for Na+ ions in the center of their transmembrane domain, accessible from the extracellular space. Here, we show that the opening of a conserved hydrated channel in the activated state receptors allows the Na+ ion to egress from its binding site into the cytosol. Coupled with protonation changes, this ion movement occurs without significant energy barriers, and can be driven by physiological transmembrane ion and voltage gradients. We propose that Na+ ion exchange with the cytosol is a key step in GPCR activation. Further, we hypothesize that this transition locks receptors in long-lived active-state conformations. PMID- 29249609 TI - Lessons from the domestic Ebola response: Improving health care system resilience to high consequence infectious diseases. AB - BACKGROUND: The domestic response to the West Africa Ebola virus disease (EVD) epidemic from 2014-2016 provides a unique opportunity to distill lessons learned about health sector planning and operations from those individuals directly involved. This research project aimed to identify and integrate these lessons into an actionable checklist that can improve health sector resilience to future high-consequence infectious disease (HCID) events. METHODS: Interviews (N = 73) were completed with individuals involved in the domestic EVD response in 4 cities (Atlanta, Dallas, New York, and Omaha), and included individuals who worked in academia, emergency management, government, health care, law, media, and public health during the response. Interviews were transcribed and analyzed qualitatively. Two focus groups were then conducted to expand on themes identified in the interviews. Using these themes, an evidence-informed checklist was developed and vetted for completeness and feasibility by an expert advisory group. RESULTS: Salient themes identified included health care facility issues specifically identifying assessment and treatment hospitals, isolation and treatment unit layout, waste management, community relations, patient identification, patient isolation, limitations on treatment, laboratories, and research considerations-and health care workforce issues-specifically psychosocial impact, unit staffing, staff training, and proper personal protective equipment. CONCLUSIONS: The experiences of those involved in the domestic Ebola response provide critical lessons that can help strengthen resilience of health care systems and improve future responses to HCID events. PMID- 29249608 TI - Combined 1H-Detected Solid-State NMR Spectroscopy and Electron Cryotomography to Study Membrane Proteins across Resolutions in Native Environments. AB - Membrane proteins remain challenging targets for structural biology, despite much effort, as their native environment is heterogeneous and complex. Most methods rely on detergents to extract membrane proteins from their native environment, but this removal can significantly alter the structure and function of these proteins. Here, we overcome these challenges with a hybrid method to study membrane proteins in their native membranes, combining high-resolution solid state nuclear magnetic resonance spectroscopy and electron cryotomography using the same sample. Our method allows the structure and function of membrane proteins to be studied in their native environments, across different spatial and temporal resolutions, and the combination is more powerful than each technique individually. We use the method to demonstrate that the bacterial membrane protein YidC adopts a different conformation in native membranes and that substrate binding to YidC in these native membranes differs from purified and reconstituted systems. PMID- 29249610 TI - Compression plate arthrodesis for osteoarthritis of the first carpometacarpal joint: A retrospective study of 77 cases. AB - Osteoarthritis of the first carpometacarpal joint (CMCJ1) is a common, painful condition with positive radiological findings in up to 32% of people over 50 years of age and up to 91% of people over 80 years of age. Currently, there is insufficient evidence to recommend one surgical treatment option over the others. We conducted a retrospective review of 77 patients treated for CMCJ1 osteoarthritis with plate arthrodesis between 1979 and 1996. The review included physical examination, including range of motion (ROM) of the thumb interphalangeal joint, metacarpophalangeal joint and CMCJ1, pinch grip, key grip and power grip strength, and a questionnaire on subjective outcomes (appearance, dexterity, load bearing, pain, strength, subjective overall result and if patients would choose the procedure again). The complication rate was 26%. However, the general patient satisfaction was high with 88% of patients saying they would choose to have the procedure done again. There was a significant decrease (side-to-side difference) in the ROM for palmar and radial abduction as well as opposition when compared to the opposite hand. Furthermore, there was a significant reduction (side-to-side difference) in pinch, key grip and power grip strength. ROM did not seem to have any influence on pain (and vice versa), load bearing, and the subjective overall result. No gender differences were noted. Despite the high complication rate, CMCJ1 arthrodesis remains a viable option for the treatment of CMCJ1 osteoarthritis in select patients requiring good thumb stability. PMID- 29249611 TI - Actinic keratosis and diabetes complications: A nationwide population-based study in South Korea (2009-2015). AB - AIM: As the associations between actinic keratosis (AK) and diabetes complications in patients with diabetes mellitus (DM) have never been investigated, this study aimed to evaluate any such associations in patients with DM. METHODS: This retrospective cohort study analyzed clinical data for DM patients aged>40 years who had undergone the health examination recommended by the South Korea National Health Insurance Program between 2009 and 2012 (n=2,056,580). All of these patients were classified according to the presence of diabetic retinopathy (DR), end-stage renal disease (ESRD) and history of DVD; myocardial infarction, stroke, transient ischaemic attacks. Newly diagnosed AK was identified using claims data from baseline to the date of diagnosis or 31 December 2015, whichever came first. RESULTS: Of the 2,056,580 patients with DM, 6404 (0.31%) developed AK. Those patients in the DR, ESRD and CVD groups were more likely to be diagnosed with AK (P<0.001, by log-rank test). After adjusting for age and gender, the risks for AK were significantly higher in the DR, ESRD and CVD groups: HR (95% CI): 1.29 (1.21-1.39), HR: 4.24 (3.28-5.47) and HR: 1.22 (1.13-1.31), respectively. CONCLUSION: This study has revealed that the incidence of AK is higher in diabetes patients with ocular, renal and cardiovascular complications. PMID- 29249612 TI - Does periodontitis affect diabetes incidence and haemoglobin A1c change? An 11 year follow-up study. AB - AIM: As periodontitis may contribute to the pathogenesis of diabetes, the effects of periodontitis on diabetes incidence and HbA1c change was quantified in a prospective cohort. METHODS: Data from an 11-year follow-up of the Study of Health in Pomerania were analyzed to evaluate the effects of periodontitis on incident diabetes and long-term HbA1c changes in 2047 subjects aged 20-81years. Diabetes was based on self-reported physician diagnoses, antidiabetic medication use, or HbA1c>=6.5% or non-fasting blood glucose levels >=11.1mmol/L. To assess periodontal status, periodontal pockets were probed, and their depth and clinical attachment levels measured. For both measures, means and percentages of sites>=3mm were calculated. In addition, all probing depths>=4mm were summed (cumulative probing depth). Modified Poisson and multivariable linear models were applied, adjusted for age, gender, highest level of general education, marital status, waist circumference, physical activity, smoking status and follow-up time. RESULTS: Over a mean follow-up period of 11.1years, 207 subjects developed diabetes. Baseline mean clinical attachment levels (CAL) and probing depths (PPD) were not significantly associated with either diabetes incidence [mean CALs, fourth quartile, incidence rate ratio=0.819, 95% confidence interval (CI): 0.489 1.370; P=0.446] or long-term changes in HbA1c (mean CAL, fourth quartile, beta= 0.086, 95% CI: -0.187, -0.016; P=0.098). Sensitivity analyses using alternative exposure definitions confirmed these results. CONCLUSION: Contrary to the currently available literature, no convincing evidence was found of any potential association between periodontitis and diabetes incidence or HbA1c change. PMID- 29249613 TI - Metabolically healthy and unhealthy weight statuses, health issues and related costs: Findings from the 2013-2015 European Health Examination Survey in Luxembourg. AB - AIM: To investigate the relationship between metabolically healthy and unhealthy weight statuses and a wide range of related health issues, and healthcare and loss-of-productivity costs. METHODS: A total of 693 men and 729 women, aged 25-64 years, took part in the European Health Examination Survey conducted in Luxembourg between 2013 and 2015. Metabolically unhealthy normal-weight profiles were defined as having two or more cardiometabolic abnormalities (high blood pressure, high fasting glucose or triglycerides, low HDL cholesterol and/or previously diagnosed hypertension or diabetes) in people with normal weight. Metabolically healthy overweight/obesity was defined as having fewer than two of the above-mentioned abnormalities in people with overweight or obesity. For the present report, the participants' anthropometric, clinical, biological, sociodemographic, lifestyle and health-related data were analyzed. RESULTS: Of the participants with normal weight, 20% had a metabolically unhealthy profile, whereas 60% with overweight and 30% with obesity had a metabolically healthy profile. Comparisons between metabolically healthy and unhealthy normal weight, overweight and/or obesity status revealed that participants presented with a metabolically unhealthy profile independently of weight status (P<0.0001). People with a metabolically healthy profile were more likely to perceive their health as good (66%; P<0.0001), and to report no physical pain (64%; P=0.03), no limitations in daily activities (66%; P=0.0008), no difficulties getting in or out of a bed or chair (63%; P=0.02) or dressing and undressing (63%; P=0.003), going shopping (63%; P=0.053) or doing occasional heavy housework (64%; P=0.007); they also displayed fewer gastrointestinal (63%; P=0.02), arthrosis (64%; P=0.001) and sleep apnoea issues (63%; P=0.002) compared with those with a metabolically unhealthy profile. Healthcare- and loss-of-productivity-related costs were higher with a metabolically unhealthy profile, with differences of up to ? 3000 (P=0.02). CONCLUSION: The present work has highlighted that, independently of weight status, people may develop a metabolically unhealthy profile associated with several health issues as well as higher healthcare and loss-of-productivity costs. PMID- 29249614 TI - Extracorporeal Cardiopulmonary Resuscitation for Refractory Out-of-Hospital Cardiac Arrest: The State of the Evidence and Framework for Application. AB - Out-of-hospital cardiac arrest (OHCA) affects 134 per 100,000 citizens annually. Extracorporeal cardiopulmonary resuscitation (ECPR), providing mechanical circulatory support, may improve the likelihood of survival among those with refractory OHCA. Compared with in-hospital ECPR candidates, those in the out-of hospital setting tend to be sudden unexpected arrests in younger and healthier patients. The aims of this review were to summarize, and identify the limitations of, the evidence evaluating ECPR for OHCA, and to provide an approach for ECPR program application. Although there are many descriptions of ECPR-treated cohorts, we identified a paucity of robust data showing ECPR effectiveness compared with conventional resuscitation. However, it is highly likely that ECPR, provided after a prolonged attempt with conventional resuscitation, does benefit select patient populations compared with conventional resuscitation alone. Although reliable data showing the optimal patient selection criteria for ECPR are lacking, most implementations sought young previously healthy patients with rapid high-quality cardiopulmonary resuscitation. Carefully planned development of ECPR programs, in high-performing emergency medical systems at experienced extracorporeal membrane oxygenation centres, may be reasonable as part of systematic efforts to determine ECPR effectiveness and globally improve care. Protocol evaluation requires regional-level assessment, examining the incremental benefit of survival compared with standard care, while accounting for resource utilization. PMID- 29249615 TI - Transcultural Pain Management: Theory, Practice, and Nurse-Client Partnerships. AB - Nursing is becoming increasingly aware of its impact as a global profession. Part of this evolution is the understanding that the Western evidence-based construct may not be reliably or universally applicable to transcultural settings and clients. In a global world, no 'one size fits all' and no singular approach to pain management is appropriate; there are, quite literally, infinite variations in cross-cultural dynamics. Nurses working in the field of pain management must be able to navigate their responsibilities within the global health context. The role of the pain management nurse in the global world is to provide individualized and culturally relevant pain management for clients, which is mindful of multifactorial contributors to the pain experience, such as the physiologic, affective, cognitive, behavioral, sociocultural, and environmental, and to view adequate pain management as an international human right. Through the skillful integration of theory, practice, and the ability to build respectful and responsible nurse-client partnerships, pain management nurses can deliver contextually relevant care that promotes safety, quality, and healing. PMID- 29249616 TI - Using Simulation to Enhance Education Regarding Epidural Analgesia for Registered Nurses. AB - BACKGROUND: Registered nurses (RNs) receive didactic training regarding caring for patients receiving epidural analgesia. Although RNs are tested on their knowledge after this training, their ability to critically think through adverse events has not been assessed at our institution. AIM: The aim of this study was to examine the feasibility and effectiveness of simulation education for RNs regarding the assessment and management of patients receiving epidural analgesia. METHOD: The study included an education intervention, which consisted of a 4-hour workshop. After obtaining informed consent, RNs completed a preworkshop evaluation of skill performance where they completed an Objective Structured Clinical Examination (OSCE) in which they demonstrated an epidural assessment of a standardized patient. RNs then completed a demographic and knowledge questionnaire followed by a lecture regarding care, management, and assessment of patients who are receiving epidural analgesia. After the lecture, RNs practiced epidural assessments within small groups. A postworkshop OSCE, questionnaire, and debriefing were completed before the end of the workshop. RESULTS: Thirty-seven RNs completed the workshop. The mean age of participants was 43 years. For the pre- and postworkshop knowledge questionnaire, there was significant improvement in answers related to epidural pharmacology and assessment of blockade questions. For the pre- and postworkshop OSCE, there was a significant increase in the number of correct procedures performed in all categories, with the exception of assessment of equipment. There was also a significant change in the proportion of RNs who stated that they felt confident in their assessment of a patient receiving epidural analgesia. PMID- 29249618 TI - Relaxation Therapy with Guided Imagery for Postoperative Pain Management: An Integrative Review. AB - : To identify the evidence in the literature about relaxation therapy with guided imagery for postoperative pain management. Integrative review. PubMed, Lilacs, Cochrane, Embase, Web of Science, Scopus and Cinahl, between August 2006 and December 2016. Descriptors: Postoperative Pain, Imagery (Psychotherapy) and Guided Imagery. STUDY SELECTION: original studies published in English, Spanish and Portuguese. 291 studies were identified and eight were selected. Descriptive data analysis, presented in detail, with a summary of the knowledge produced in each study. In the primary studies included, the use of guided imagery associated with other complementary therapies was highlighted: hand and foot "M" technique, education on postoperative pain management with analgesic drugs, relaxation exercises, respiration exercises, meditation, soothing biorhythmic music combined with positive and encouraging assertions and music with nature sounds. The knowledge synthesis resulting from this study indicates that evidence could be identified on the use of guided imagery associated with relaxation therapy as a complementary approach to drug analgesia in postoperative pain control strengthens its indication for nursing practice. This evidence, however, demonstrates that the quality of the use of this therapy is limited, and it is necessary to carry out new randomized clinical studies to fill the existing gaps in this topic. PMID- 29249617 TI - Living with Symptoms: A Qualitative Study of Black Adults with Advanced Cancer Living in Poverty. AB - Cancer is associated with disease-related and treatment-related symptoms. Little is known about the symptom experience of black individuals with advanced cancer especially those with limited financial resources. Therefore, the purpose of this study was to explore the symptom experience of black adults with advanced cancer living in poverty. This qualitative descriptive study focused on the perspectives of the participants experiencing at least two symptoms related to cancer. A purposive sample of 27 individuals receiving care at a public hospital in a southeastern city participated in the study. Semi-structured audiotaped interviews were conducted by two research interviewers. Content analysis was used to develop themes to describe the symptom experience. Two main themes emerged in terms of the participants' symptom experiences: (1) "living in pain," which included the overwhelming experience of pain, both physical and emotional, and (2) "symptoms associated with functioning in everyday life." Participants frequently used the context of activities in their daily lives to explain symptoms, including the effect of symptoms on the activities of eating, moving and doing, and communicating. People with advanced cancer work to negotiate a high frequency of multiple distressful symptoms of severe-to-moderate severity. Information gained from this study can help guide research in symptom science and provide direction for clinicians working with this minority group. PMID- 29249619 TI - Couples' Relationship Satisfaction and Its Association with Depression and Spouse Responses Within the Context of Chronic Pain Adjustment. AB - BACKGROUND: Chronic pain is one specific health condition where couple relationships have been directly linked to physical and psychological outcomes. Understanding how relationship satisfaction, couple dynamics, and pain adjustment interrelate is crucial for nurses who provide patient-centered care for patients with pain. AIMS: The current study was aimed at examining the associations of depressive symptoms and spouse response styles with relationship satisfaction in the context of West Haven-Yale Multidimensional Pain Inventory classifications. METHODS: Seventy-eight middle-aged outpatients with chronic pain (average pain duration of 8.98 years (SD = 9.51)) were recruited from a pain clinic in southeastern Michigan. Participants completed the Multidimensional Pain Inventory, from which pain adjustment classifications (adaptive, dysfunctional, interpersonally distressed) and spouse response styles were derived, the Dyadic Adjustment Scale to assess relationship satisfaction, and the Mood and Anxiety Symptom Questionnaire to assess depressive symptoms. RESULTS: Interpersonally distressed patients scored lower on relationship satisfaction than those classified as either adaptive or dysfunctional, F(2,66) = 6.38, p < .01. Significant inverse associations were found between punishing spouse response styles and relationship satisfaction for both interpersonally distressed and dysfunctional adjustment classifications: r = -.53, p < .05; r = -.57, p < .01, respectively. CONCLUSIONS: Overall, findings indicate that relationship satisfaction may be an area of concern among interpersonally distressed pain patients and that spouse response style may be a particularly important area of clinical attention. PMID- 29249620 TI - Moving Beyond Pain as the Fifth Vital Sign and Patient Satisfaction Scores to Improve Pain Care in the 21st Century. AB - In an attempt to address the issue of undertreated pain, the Pain as the Fifth Vital Sign (P5VS) Initiative was established to improve the quality of pain care across clinical settings. This initiative included policy efforts such as mandatory pain screening and the implementation of pain-related questions on patient satisfaction surveys. These policies have failed to enhance the treatment of pain and may have unintentionally contributed, in part, to the opioid epidemic. To assess pain more effectively, an inter-professional team approach using multi-dimensional pain assessment tools is needed. The inter-professional team can use these multi-dimensional tools to conduct comprehensive assessments to measure aspects of the pain experience (e.g., psychological, spiritual and socio-emotional pain; impact on daily functioning) beyond its sensory component and establish realistic goals that align with patients' needs. To implement multi dimensional pain assessments in busy clinical practices, nurses will need to play a central role. Nurses can work to ensure that patients complete the questionnaires prior to the visit. Nurses can also take the lead in the use of new technologies in the form of tablets, smart phones, and mobile apps to facilitate collecting patient-level data in the home or in a waiting room before their visits. PMID- 29249621 TI - Leveraging Interactive Patient Care Technology to Improve Pain Management Engagement. AB - BACKGROUND: Most children experience pain in hospitals; and their parents report dissatisfaction with how well pain was managed. Engaging patients and families in the development and evaluation of pain treatment plans may improve perceptions of pain management and hospital experiences. OBJECTIVES: The aim of this performance improvement project was to engage patients and families to address hospitalized pediatric patients' pain using interactive patient care technology. The goal was to stimulate conversations about pain management expectations and perceptions of treatment plan effectiveness among patients, parents, and health care teams. METHODS: Plan-Do-Study-Act was used to design, develop, test, and pilot new workflows to integrate the interactive patient care technology system with the automated medication dispensing system and document actions from both systems into the electronic health record. SETTING: The pediatric surgical unit and hematology/oncology unit of a free-standing, university-affiliated, urban children's hospital were selected to pilot this performance improvement project because of the high prevalence of pain from surgeries and hematologic and oncologic diseases, treatments, and invasive procedures. RESULTS: Documentation of pain assessments, nonpharmacologic interventions, and evaluation of treatment effectiveness increased. The proportion of positive family satisfaction responses for pain management significantly increased from fiscal year 2014 to fiscal year 2016 (p = .006). CONCLUSION: By leveraging interactive patient care technologies, patients and families were engaged to take an active role in pain treatment plans and evaluation of treatment outcomes. Improved active communication and partnership with patients and families can effectively change organizational culture to be more sensitive to patients' pain and patients' and families' hospital experiences. PMID- 29249623 TI - Growth hormone and insulin-like growth factor-I axis in type 1 diabetes. AB - The precise mechanisms relating type 1 diabetes (T1D) and poor glycemic control to the axis of growth hormone (GH), insulin like growth factor- I (IGF-I), and IGF binding protein-3 (IGFBP-3) remain to be definitively determined. GH resistance with low IGF-I as is frequently seen in patients with T1D is often related to portal hypoinsulization, and lack of upregulation of GH receptors. There are conflicting reports of the effect of a dysregulated GH/IGF-I axis on height in children and adolescents with T1D, as well as on chronic complications. This brief review discusses some of the interactions between the GH/IGF-I axis and T1D pathology, and vice-versa. PMID- 29249624 TI - Genetic short stature. AB - Adult height and growth patterns are largely genetically programmed. Studies in twins have indicated that the heritability of height is high (>80%), suggesting that genetic variation is the main determinant of stature. Height exhibits a normal (Gaussian) distribution according to sex, age, and ancestry. Short stature is usually defined as a height which is 2 standard deviations (S.D.) less than the mean height of a specific population. This definition includes 2.3% of the population and usually includes healthy individuals. In this group of short stature non-syndromic conditions, the genetic influence occurs polygenically or oligogenically. As a rule, each common genetic variant accounts for a small effect (1mm) on individual height variation. Recently, several studies demonstrated that some rare variants can cause greater effect on height, without causing a syndromic condition. In more extreme cases, height SDS below 2.5 or 3 (which would comprise approximately 0.6 and 0.1% of the population, respectively) is frequently associated with syndromic conditions and are usually caused by a monogenic defect. More than 1,000 inherited/genetic diseases have growth disorder as an important phenotype. These conditions are usually responsible for syndromic short stature. In the coming years, we expect to discover several genetic causes of short stature, thereby explaining the phenotype of what we currently classify as short stature of unknown cause. These discoveries will have a profound impact on the follow-up and treatment of these children. PMID- 29249622 TI - Differential Expression of NF2 in Neuroepithelial Compartments Is Necessary for Mammalian Eye Development. AB - The optic neuroepithelial continuum of vertebrate eye develops into three differentially growing compartments: the retina, the ciliary margin (CM), and the retinal pigment epithelium (RPE). Neurofibromin 2 (Nf2) is strongly expressed in slowly expanding RPE and CM compartments, and the loss of mouse Nf2 causes hyperplasia in these compartments, replicating the ocular abnormalities seen in human NF2 patients. The hyperplastic ocular phenotypes were largely suppressed by heterozygous deletion of Yap and Taz, key targets of the Nf2-Hippo signaling pathway. We also found that, in addition to feedback transcriptional regulation of Nf2 by Yap/Taz in the CM, activation of Nf2 expression by Mitf in the RPE and suppression by Sox2 in retinal progenitor cells are necessary for the differential growth of the corresponding cell populations. Together, our findings reveal that Nf2 is a key player that orchestrates the differential growth of optic neuroepithelial compartments during vertebrate eye development. PMID- 29249625 TI - Genetic disorders of GH action pathway. AB - While insensitivity to GH (GHI) is characterized by low IGF-I levels, normal or elevated GH levels, and lack of IGF-I response to GH treatment, IGF-I resistance is characterized by elevated IGF-I levels with normal/high GH levels. Several genetic defects are responsible for impairment of GH and IGF-I actions resulting in short stature that could affect intrauterine growth or be present in the postnatal period. The genetic defects affecting GH and/or IGF-I action can be divided into five different groups: GH insensitivity by defects affecting the GH receptor (GHR), the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1), the synthesis of insulin-like growth factors (IGF1, IGF2), the transport/bioavailability of IGFs (IGFALS, PAPPA2), and defects affecting IGF-I sensitivity (IGF1R). Complete GH insensitivity (GHI) was first reported by Zvi Laron and his colleagues in patients with classical appearance of GH deficiency, but presenting elevated levels of GH. The association of GH insensitivity with several clinical sings of immune-dysfunction and autoimmune dysregulation are characteristic of molecular defects in the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1). Gene mutations in the IGF1 and IGF2 genes have been described in patients presenting intrauterine growth retardation and postnatal short stature. Molecular defects have also been reported in the IGFALS gene, that encodes the acid-labile subunit (ALS), responsible to stabilize circulating IGF-I in ternary complexes, and more recently in the PAPPA2 gen that encodes the pregnancy-associated plasma protein-A2, a protease that specifically cleaves IGFBP-3 and IGFBP-5 regulating the accessibility of IGFs to their target tissues. Mutations in the IGF1R gene resulted in IGF-I insensitivity in patients with impaired intrauterine and postnatal growth. These studies have revealed novel molecular mechanisms of GH insensitivity/primary IGF-I deficiency beyond the GH receptor gene. In addition, they have also underlined the importance of several players of the GH-IGF axis in the complex system that promotes human growth. PMID- 29249626 TI - Discovery of novel scaffolds for gamma-secretase modulators without an arylimidazole moiety. AB - Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid beta 42 (Abeta42) and may therefore be useful in the management of Alzheimer's disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2 methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Abeta42 (IC50 = 7.1 uM) without changing total production of Abeta. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin 1-one (3m) as a potent inhibitor of Abeta42 (IC50 = 0.39 uM) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain. PMID- 29249627 TI - 123I intercomparison exercises: Assessment of measurement capabilities in UK hospitals. AB - Three comparison exercises have been performed in 1996, 1999 and 2015 with 123I to assess the UK hospitals measurement capabilities using radionuclide calibrators for this particular radionuclide. The exercise performed in 1996 showed that only 62% of the participants could measure the solution to within 10% of the standardised value and only 28% could measure within 5% of the certificated value. The intercomparison exercise performed in 1999 showed no improvement in the measurement capability, with only 66% of the participants measuring to within 10% of the standardised value. The exercise performed in 2015 showed great improvement in the hospitals measurement capability, 94% of participants reported results within 10% of the certificated activity and 85% of the participants reported results within the 5% of the reported activity. The intercomparison exercises are an important way to identify possible measurement problems within the medical community. Additionally, the intercomparison exercises provide hospitals with traceability to national primary standards and improve measurement capability within the Nuclear Medicine community. PMID- 29249628 TI - An analysis of blood donation barriers experienced by North American and Caribbean university students in Grenada, West Indies. AB - OBJECTIVES: To estimate the associations of nationality, university program, donation history and gender, with blood donation barriers experienced by non donating students on the day of a campus blood drive. This project focused particularly on nationality and the effect of the different blood donation cultures in the students' countries of origin. METHODS: A retrospective cohort study of 398 North American and Caribbean university students was conducted at St. George's University, Grenada, in 2010. Data were collected from non-donating students on campus while a blood drive was taking place. Log-binomial regression was used to estimate associations between the exposures of interest and donation barriers experienced by the students. RESULTS: North American (voluntary blood donation culture) students were more likely than Caribbean (replacement blood donation culture) students to experience "Lack of Time" (relative risk (RR) = 1.57; 95% confidence interval (CI): 1.19-2.07) and "Lack of Eligibility" (RR = 1.55; 95% CI: 1.08-2.22) as barriers to donation. Conversely, Caribbean students were a third as likely to state "Lack of Incentive" (RR = 0.32; 95% CI: 0.20 0.50), "Fear of Infection" (RR = 0.35; 95% CI: 0.21-0.58), and "Fear of Needles" (RR = 0.32; 95% CI: 0.21-0.48) were barriers than North American students. CONCLUSIONS: University students from voluntary blood donation cultures are likely to experience different barriers to donation than those from replacement cultures. Knowledge of barriers that students from contrasting blood donation systems face provides valuable information for blood drive promotion in university student populations that contain multiple nationalities. PMID- 29249629 TI - Students' experiences of embedded academic literacy support in a graduate entry nursing program: A qualitative study. AB - Graduate entry nursing (GEN) programs were designed to address the predicted nursing shortfall. In Australia, although these programs attract students from culturally and linguistically diverse (CALD) backgrounds, the workload is compounded by cultural differences and a new academic learning environment which presents additional challenges. This qualitative descriptive study explored the experiences of GEN students enrolled in the introductory unit of their nursing program with embedded academic literacy support in Sydney, Australia. Twenty-four commencing GEN students were interviewed in January 2016. Interviews were transcribed verbatim and thematically analysed. Three main themes emerged which illustrated that GEN students were 'diamonds in the rough'. They possessed a raw natural beauty that required some shaping and polishing to ensure academic needs were met. To ensure retention is high, institutions need to evaluate how best to support and harness the potential of these unique students. PMID- 29249630 TI - Cross-sectional evaluation of transmural healing in Crohn's disease: Mural and mesenteric parameters. PMID- 29249631 TI - Measurement of function in older adults transitioning from hospital to home: an integrative review. AB - Older adults often experience decline in functional status during the transition from hospital to home. In order to determine the effectiveness of interventions to prevent functional decline, researchers must have instruments that are reliable and valid for use with older adults. The purpose of this integrative review is to: (1) summarize the research uses and methods of administering functional status instruments when investigating older adults transitioning from hospital to home, (2) examine the development and existing psychometric testing of the instruments, and (3) discuss gaps and implications for future research. The authors conducted an integrative review of forty research studies that assessed functional status in older adults transitioning from hospital to home. This review reveals important gaps in the functional status instruments' psychometric testing, including limited testing to support their validity and reliability when administered by self-report and limited evidence supporting their ability to detect change over time. PMID- 29249632 TI - Perforator flaps from the lower leg for intraoral reconstruction: Experience of 131 flaps. AB - BACKGROUND: During the last decade, perforator flaps have become popular for defect cover in the head and neck because they increase the choice of reconstructive possibilities and can lead to minimal donor site morbidity. In particular, the lower leg is considered a suitable option, as it provides thin and pliable skin for intraoral lining. Having gained experience with 131 flaps raised from four different donor sites at the lower leg, the aim of this paper is to evaluate success rates and patient satisfaction, but also difficulties and pitfalls during flap transfer. METHODS: In a retrospective study, all perforator flaps from the lower leg that have been raised between January 2002 and December 2016 were evaluated according to flap type, indications, size, vascular anatomy, complications, success rates, and donor site morbidities. For this, the patient's charts including photographic documentation were analysed with particular respect to difficulties during raising and transferring the flaps and wound healing disturbances. The patient's ability to speak and swallow and the aesthetic and functional results at the donor sites were assessed by clinical examination during the first postoperative year. RESULTS: During the 14-year period, 53 soleus perforator flaps (I), 47 peroneal- (II), 18 medial sural- (III) and 13 lateral superficial sural artery perforator flaps (IV) have been used for intraoral reconstruction. Defects were located at all regions of the oral cavity, mostly the floor of the mouth (67), tongue (31), buccal mucosa (19) and others (14). The size of the flaps ranged from 2 * 4 cm to 6 * 9 cm with an average of 4 * 6 cm. Success rates were 93.6% (II), 90.5% (I), 88.8% (III) and 84.6% (IV) with an overall success rate of 90.8%. Intraoperative complications occurred in 22.1% and were related to small perforator arteries (11), spasm of perforator (8), perforator transection (2) or difficulties to carry out anastomoses directly to the perforating vessels (7). After successful transfer, the functional outcome was favourable with no need for secondary thinning, and most of the patients were satisfied with the donor site appearance. There was no functional limitation associated with the harvest of any of the four flap types. CONCLUSIONS: Perforator flaps from the lower leg show higher complication rates than conventional flaps but can be useful for small or medium sized defects if a hidden donor site without functional limitations is required. The vascular architecture and anatomic variations of perforators seem to make success rates of 95% or more difficult. PMID- 29249633 TI - Lymph node ratio as prognosticator in floor of mouth squamous cell carcinoma patients. AB - BACKGROUND: Recently, lymph node ratio (LNR) has been recognized as an important prognosticator for oral squamous cell carcinoma (OSCC). However, its relevance for the specific subsite floor of mouth (FOM) has not been investigated. This study was conducted to elucidate the prognostic significance of LNR for the subsite FOM among other prognostic factors. METHODS: A retrospective study of 155 patients with FOM SCC who received primary curative resection and neck dissection was conducted. We analyzed the impact of LNR among other clinicopathologic variables on overall survival (OS) in univariate and multivariate analysis. RESULTS: In univariate analysis, patients detected with LNR <= 0.07 (cutoff point: 0.07) showed an 85% 5-year OS rate, whereas for patients with LNR > 0.07 the OS rate reached 25% after 5-years (p < 0.001). The 5-year DFS rate was 72% for patients with LNR <= 0.07; on the contrary, patients with LNR > 0.07 the 5 year DFS rate was 17% (p < 0.001). LNR was detected as an independent predictor of OS in multivariate analysis (p = 0.032) for the subsite FOM. CONCLUSION: We concluded that LNR is an important predictor of prognosis in patients with FOM SCC, LNR should be considered in the choice of adjuvant treatment for these patients. PMID- 29249634 TI - The effects of dipeptidyl peptidase-4 on cardiac fibrosis in pressure overload induced heart failure. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors are hypoglycemic agents. DPP-4 inhibitor has cardioprotective effects after transverse aortic constriction (TAC), but role of DPP-4 on cardiac fibrosis after TAC is not well known. Our aim was to determine the effects of DPP-4 on cardiac fibrosis in murine TAC model. Wild-type mice and DPP-4 knockout mice were subjected to TAC. Wild-type mice were then treated with vehicle or DPP-4 inhibitor. DPP-4 activities in serum and heart tissue were significantly increased at 2 weeks after TAC, but they were significantly decreased by DPP-4 inhibitor treatment. The inhibition of DPP-4 did not affect left ventricular hypertrophy, but improved cardiac function and decreased myocardial and perivascular fibrosis after TAC. The inhibition of DPP-4 decreased the collagen type III/I ratio in myocardium. These results suggest that DPP-4 inhibition ameliorates the progression of heart failure after TAC by changing the quality and quantity of cardiac fibrosis. PMID- 29249635 TI - Study on physical properties of Ayurvedic nanocrystalline Tamra Bhasma by employing modern scientific tools. AB - BACKGROUND: Tamra Bhasma is derived from metallic copper that is recommended for different ailments of liver and spleen, dropsy, abdominal pain, heart disease, colitis, tumors, anemia, loss of appetite, tuberculosis, as well as eye problems. OBJECTIVES: The knowledge of crystallite size and active ingredients in Bhasma materials is limited restricting its use as nanomedicine in the modern era. Also, the 2015 Nobel prize in medicine has motivated many researchers towards traditional medicines. Therefore, the different chemical and physical properties of prepared Tamra Bhasma has been studied by modern experimental tools (XRD, VSM, SEM, FTIR and PL spectrometer) and the preliminary testing of Tamra Bhasma nanoparticles was examined on bacteria. MATERIALS AND METHODS: Bhasma is prepared by metals and minerals using three step procedures e.g. Shodhana, Bhavana and Marana. In the present work, for the preparation of Tamra Bhasma, pulverized copper wire was used and prepared by the principle of Puta (incineration) in an Electrical Muffle Furnace (EMF). RESULTS: X-ray diffraction analysis and scanning electron microscopy results revealed that the crystallite size of Bhasma powder was less than 100 nm and nanocrystallites of aglomerated size in micrometer. Magnetometer measurement supports its medicinal value. Photoluminescence (PL) properties of nanocrystalline Bhasma powder was investigated in UV-NIR region and shows luminescence in visible region. The antimicrobial study of Tamra Bhasma shows effectiveness on bacteria and, may be useful to control the bacterial infection disease. CONCLUSION: Scientific data obtained using modern scientific tools and evidence would support in utilizing the ancient Indian wisdom of Ayurveda for the development of newer drugs as a modern nanomedicine and in other possible technological applications. PMID- 29249637 TI - Corrigendum to "Moderate blast exposure results in increased IL-6 and TNFa in peripheral blood" [Brain Behav. Immun. 65 (2017) 90-94]. PMID- 29249636 TI - Anti-hyperglycemic and anti-hyperlipidaemic effect of Arjunarishta in high-fat fed animals. AB - BACKGROUND: Arjunarishta (AA), a formulation used as cardiotonic is a hydroalcoholic formulation of Terminalia arjuna (Roxb.) Wight and Arn. (TA) belonging to family Combretaceae. OBJECTIVE: To evaluate the anti-hyperglycemic and anti-hyperlipidemic effect of Arjunarishta on high-fat diet fed animals. MATERIALS AND METHODS: High-fat diet fed (HFD) Wistar rats were randomly divided into three groups and treated with phytochemically standardized Arjunarishta (1.8 ml/kg), and hydroalcoholic extract of T. arjuna (TAHA) (250 mg/kg) and rosuvastatin (10 mg/kg), for 3 months. Intraperitoneal glucose tolerance test, blood biochemistry, liver triglyceride and systolic blood pressure were performed in all the groups. Effect of these drugs on the expression of tumor necrosis factor-alpha (TNF-alpha) and insulin receptor substrate-1 (IRS-1) and peroxisome proliferators activated receptor gamma coactivator 1-alpha (PGC-1alpha) were studied in liver tissue using Quantitative Real-time PCR. RESULTS: HFD increased fasting blood glucose, liver triglyceride, systolic blood pressure and gene expression of TNF-alpha, IRS-1 and PGC-1alpha. Treatment of AA and TAHA significantly reduced fasting blood glucose, systolic blood pressure, total cholesterol and triglyceride levels. These treatments significantly decreased gene expression of TNF-alpha (2.4, 2.2 and 2.6 fold change); increased IRS-1 (2.8, 2.9 and 2.8 fold change) and PGC-1alpha (2.9, 3.7 and 3.3 fold change) as compared to untreated HFD. CONCLUSION: Anti-hyperglycemic, anti-hyperlipidemic effect of Arjunarishta may be mediated by decreased TNF-alpha and increased PGC 1alpha and IRS-1. PMID- 29249638 TI - Androgen receptor overexpression in prostate cancer in type 2 diabetes. AB - OBJECTIVE: While prostate cancer does not occur more often in men with diabetes, survival is markedly reduced in this patient group. Androgen signaling is a known and major driver for prostate cancer progression. Therefore, we analyzed major components of the androgen signaling chain and cell proliferation in relation to type 2 diabetes. METHODS: Tumor content of 70 prostate tissue samples of men with type 2 diabetes and 59 samples of patients without diabetes was quantified by an experienced pathologist, and a subset of 51 samples was immunohistochemically stained for androgen receptor (AR). mRNA expression of AR, insulin receptor isoform A (IR-A) and B (IR-B), IGF-1 receptor (IGF1R), Cyp27A1 and Cyp7B1, PSA gene KLK3, PSMA gene FOLH1, Ki-67 gene MKI67, and estrogen receptor beta (ESR2) were analyzed by RT-qPCR. RESULTS: AR mRNA and protein expression were associated with the tumor content only in men with diabetes. AR expression also correlated with downstream targets PSA (KLK3) and PSMA (FOLH1) and increased cell proliferation. Only in diabetes, AR expression was correlated to higher IR-A/IR-B ratio and lower IR-B/IGF1R ratio, thus, in favor of the mitogenic isoforms. Reduced Cyp27A1 and increased Cyp7B1 expressions in tumor suggest lower levels of protective estrogen receptor ligands in diabetes. CONCLUSIONS: We report elevated androgen receptor signaling and activity presumably due to altered insulin/IGF-1 receptors and decreased levels of protective estrogen receptor ligands in prostate cancer in men with diabetes. Our results reveal new insights why these patients have a worse prognosis. These findings provide the basis for future clinical trials to investigate treatment response in patients with prostate cancer and diabetes. PMID- 29249640 TI - Vessel Ligation Fundamentals: A Comparison of Technical Evaluations by Crowdsourced Nonclinical Personnel and Surgical Faculty. AB - BACKGROUND: Evaluation of fundamental surgical skills is invaluable to the training of medical students and junior residents. This study assessed the effectiveness of crowdsourcing nonmedical personnel to evaluate technical proficiency at simulated vessel ligation. STUDY DESIGN: Fifteen videos were captured of participants performing vessel ligation using a low-fidelity model (5 attending surgeons and 5 medical students before and after training). These videos were evaluated by nonmedical personnel recruited through Amazon Mechanical Turk, as well as by 3 experienced surgical faculty. Evaluation criteria were based on Objective Structured Assessment of Technical Skills (scale: 5-25). Results were compared using Wilcoxon signed rank-sum and Cronbach's alpha (alpha). RESULTS: Thirty-two crowd workers evaluated all 15 videos. Crowd workers scored attending surgeon videos significantly higher than pretraining medical student videos (20.5 vs 14.9, p < 0.001), demonstrating construct validity. Across all videos, crowd evaluations were more lenient than expert evaluations (19.1 vs 14.5, p < 0.001). However, average volunteer evaluations correlated more strongly with average expert evaluations (alpha = 0.95) than the strength of correlation between any 2 individual expert evaluators (alpha = 0.72-0.88). Combined reimbursement for all workers was $80.00. CONCLUSION: After adjustments for score inflation, crowdsourced can evaluate surgical fundamentals with excellent validity. This resource is considerably less costly and potentially more reliable than individual expert evaluations. PMID- 29249639 TI - T Cells Primed by Live Mycobacteria Versus a Tuberculosis Subunit Vaccine Exhibit Distinct Functional Properties. AB - Despite inducing strong T cell responses, Mycobacterium tuberculosis (Mtb) infection fails to elicit protective immune memory. As such latently infected or successfully treated Tuberculosis (TB) patients are not protected against recurrent disease. Here, using a mouse model of aerosol Mtb infection, we show that memory immunity to H56/CAF01 subunit vaccination conferred sustained protection in contrast to the transient natural immunity conferred by Mtb infection. Loss of protection to re-infection in natural Mtb memory was temporally linked to an accelerated differentiation of ESAT-6- and to a lesser extent, Ag85B-specific CD4 T cells in both the lung parenchyma and vasculature. This phenotype was characterized by high KLRG1 expression and low, dual production of IFN-gamma and TNF. In contrast, H56/CAF01 vaccination elicited cells that expressed low levels of KLRG1 with copious expression of IL-2 and IL 17A. Co-adoptive transfer studies revealed that H56/CAF01 induced memory CD4 T cells efficiently homed into the lung parenchyma of mice chronically infected with Mtb. In comparison, natural Mtb infection- and BCG vaccine-induced memory CD4 T cells exhibited a poor ability to home into the lung parenchyma. These studies suggest that impaired lung migratory capacity is an inherent trait of the terminally differentiated memory responses primed by mycobacteria/mycobacterial vectors. PMID- 29249641 TI - A case of liver abscess co-infected with Desulfovibrio desulfuricans and Escherichia coli and review of the literature. AB - A 73-year-old woman was admitted with consciousness disturbance following a fever. Abdominal computed tomography revealed a large liver abscess with which the presence of Desulfovibrio desulfuricans and Escherichia coli was confirmed by thorough blood and abscess content culture. Empiric meropenem treatment was switched to cefoperazone/sulbactam, followed by ampicillin/sulbactam based on susceptibility testing. Desulfovibrio desulfuricans is a common bacterium that rarely causes liver abscess and may be overlooked during co-infection due to overgrowth of the accompanying bacteria. Clinicians should bear Desulfovibrio desulfuricans in mind and select the appropriate antibiotics according to susceptibility testing when anaerobic bacteria are detected in a liver abscess. PMID- 29249642 TI - Corrigendum to "Serotype distribution of Streptococcus pneumoniae isolated from adult respiratory tract infections in nationwide Japanese surveillances from 2006 to 2014" [J Infect Chemother 23 (2017) 538-544]. PMID- 29249643 TI - Chronic nasal dysfunction. AB - Chronic nasal dysfunction is a clinical concept in the diagnostic and therapeutic management of sinonasal diseases, based on the evo-devo theory of formation of the nose according to which the nose is not a single organ but rather an association of three organs: olfactory nose, respiratory nose and paranasal sinuses. In chronic nasal dysfunction theory, etiological diagnosis takes account of the possible pathophysiological independence of nasal symptoms, in accordance with the different origins and physiology of the three organs constituting the nose. The diagnostic approach of the chronic nasal dysfunction concept breaks down the pathology so as to propose treatment(s) adapted to the diseased organ(s) and to the capacity for physiological resolution of dysfunction induced in one organ by pathology in a neighboring nasal organ. The ethmoid is not a sinus according to evo-devo, and therefore functional endoscopic endonasal surgery (FEES) cannot be restricted to functional endoscopic sinus surgery (FESS). Evo devo theory and the chronic nasal dysfunction concept offer an alternative to the concept of chronic rhinosinusitis with or without polyps for the management of sinonasal diseases. PMID- 29249644 TI - Current systemic therapies for metastatic renal cell carcinoma in older adults: A comprehensive review. AB - Physiological changes that occur during the aging process may impact drug metabolism and availability, consequently affecting treatment efficacy and tolerability. Despite being a disease of older adults, there is little data to guide treatment decisions for older patients with metastatic renal cell carcinoma (mRCC). The recent approval of many new agents for this disease poses a clinical challenge: how to best utilize these drugs in a population (older adults) who has been generally under-represented in clinical studies. Additionally, the presence of comorbid conditions, polypharmacy, frailty, and lack of social support place this group of patients in a very unique situation. In order to avoid under treatment, international societies' guidelines recommend routine use of geriatric tools to assess patients' suitability for systemic treatments. Here we provide a thorough review of age-related metabolic differences, safety and efficacy data for each drug approved for mRCC, and cover specific considerations for the management of older adults with this disease. PMID- 29249646 TI - Just between Us: An Integrative Review of Confidential Care for Adolescents. AB - INTRODUCTION: Confidential care is recommended for all adolescents to facilitate risk behavior screening and discussion of sensitive topics. Only 40% of adolescents receive confidential care. The purpose of this integrative review is to describe research related to the practice of confidential care for adolescents. Evidence was analyzed to identify strategies to increase confidential care and improve risk behavior screening. METHOD: Whittemore and Knafl's integrative literature review process was applied. RESULTS: The 26 research articles included in this review included patients', parents', and physicians' perspectives. Confidential care practice is inconsistent. Strategies to improve practice are known. CONCLUSIONS: Four key elements should be considered to establish a practice culture of confidential care for adolescents. Strategies for implementing the key elements of confidential care and supporting resources for efficient use of time alone are provided. PMID- 29249645 TI - Healthcare experience among older cancer survivors: Analysis of the SEER-CAHPS dataset. AB - OBJECTIVE: Little is known about factors affecting medical care experiences of cancer survivors. This study examined experience of care among cancer survivors and assessed associations of survivors' characteristics with their experience. MATERIALS AND METHODS: We used a newly-developed, unique data resource, SEER CAHPS (NCI's Surveillance Epidemiology and End Results [SEER] data linked to Medicare Consumer Assessment of Healthcare Providers and Systems [CAHPS] survey responses), to examine experiences of care among breast, colorectal, lung, and prostate cancer survivors age >66years who completed CAHPS >1year after cancer diagnosis and survived >=1year after survey completion. Experience of care was assessed by survivor-provided scores for overall care, health plan, physicians, customer service, doctor communication, and aspects of care. Multivariable logistic regression models assessed associations of survivors' sociodemographic and clinical characteristics with care experience. RESULTS: Among 19,455 cancer survivors with SEER-CAHPS data, higher self-reported general-health status was significantly associated with better care experiences for breast, colorectal, and prostate cancer survivors. In contrast, better mental-health status was associated with better care experience for lung cancer survivors. College educated and Asian survivors were less likely to indicate high scores for care experiences. Few differences in survivors' experiences were observed by sex or years since diagnosis. CONCLUSIONS: The SEER-CAHPS data resources allows assessment of factors influencing experience of cancer among U.S. cancer survivors. Higher self-reported health status was associated with better experiences of care; other survivors' characteristics also predicted care experience. Interventions to improve cancer survivors' health status, such as increased access to supportive care services, may improve experience of care. PMID- 29249647 TI - Associations between Introduction of Age-Inappropriate Foods and Early Eating Environments in Low-Socioeconomic Hispanic Infants. AB - PURPOSE: To examine the associations between feeding practices and eating environments of low-socioeconomic Hispanic infants. METHODS: Secondary analysis of cross-sectional data from a sample of 62 low-income immigrant Hispanic mothers and their infants (age range = 4-12 months). Measures of infant feeding practices (food groups and beverages consumption) and eating environment domains were included using the Infant Feeding Scale. RESULTS: TV exposure and allowing the infant to play with toys during meals significantly correlated with intake of energy-dense foods in 4- to 6-month-olds (p = .05). Among 7- to 9-month-olds, mealtime TV watching correlated with consumption of snacks (p = .05) and sweetened beverages (p = .01). Consumption of energy-dense foods was significantly different among groups with higher mean intake in older infants (p = < .01). CONCLUSION: Findings highlight the need for culturally and socioeconomically sensitive approaches to improve infant feeding practices and support low-income Hispanic families in providing healthy and nurturing eating environments required to prevent later obesity risk. PMID- 29249648 TI - Congenital central hypoventilation syndrome: An overview of etiopathogenesis, associated pathologies, clinical presentation, and management. AB - Congenital central hypoventilation syndrome (CCHS), known colloquially as Ondine's curse, is a rare disorder characterized by impaired autonomic control of breathing during sleep from the loss of vagal input and diminished sensitivity of CO2 receptors in the medulla. CCHS correlates to the malformation of the neural crest located in the brainstem; this consequently affects the loss of sensitivity of CO2 chemoreceptors, bringing about hypoventilation during sleep. The primary cause of CCHS is the mutation of the paired-like homeobox PHO2XB gene, found in 90% of the patients. This mutation not only affects breathing but also drives neurological abnormalities such as autonomic and neurocognitive dysfunction. Though typically congenital, there have been late-onset (i.e., acquired) cases reported. It is vital for physicians and clinicians to be able to diagnose CCHS due to its similar presentation to other syndromes and disorders, which may cause it to be misdiagnosed and may account for its deleterious effects. CCHS can lead to a constellation of symptoms, and consideration of diseases that present concomitantly with CCHS affords us a better understanding of the etiology of this illness. Although a rare syndrome, we aim to review the current literature to emphasize the pathogenesis, etiology, clinical presentation, symptoms, diagnosis, and current treatment methods of CCHS for clinicians to better identify and understand this condition. PMID- 29249649 TI - Systematic review on the impact of pancreatoduodenectomy on quality of life in patients with pancreatic cancer. AB - BACKGROUND: Patients undergoing pancreatoduodenectomy for pancreatic cancer have a high risk of major postoperative complications and a low survival rate. Insight in the impact of pancreatoduodenectomy on quality of life (QoL) is therefore of great importance. The aim of this systematic review was to assess QoL after pancreatoduodenectomy for pancreatic cancer. METHODS: A systematic review of the literature was performed according to the PRISMA guidelines. A systematic search of all the English literature available in PubMed and Medline was performed. All studies assessing QoL with validated questionnaires in pancreatic cancer patients undergoing pancreatoduodenectomy were included. RESULTS: After screening a total of 788 articles, the full texts of 36 articles were assessed, and 17 articles were included. QoL of physical and social functioning domains decreased in the first 3 months after surgery. Recovery of physical and social functioning towards baseline values took place after 3-6 months. Pain, fatigue and diarrhoea scores deteriorated postoperatively, but eventually resolved after 3-6 months. CONCLUSION: Pancreatoduodenectomy for malignant disease negatively influences QoL in the physical and social domains at short term. It will eventually recover to baseline values after 3-6 months. This information is valuable for counselling and expectation management of patients undergoing pancreatoduodenectomy. PMID- 29249650 TI - [Stained amniotic fluid and meconium amniotic fluid: Should they change our obstetric management ?] AB - OBJECTIVES: To assess if a stained or meconial amniotic fluid during labor is correlated with a greater risk of neonatal metabolic acidosis. METHODS: In a retrospective case-control study carried out in a level 3 maternity from 1st of January to 31st of December 2014, all patients who delivered a singleton eutrophic fetus in cephalic presentation after 37WG and with a stained or meconial amniotic fluid during labor were included. Obstetrical and neonatal outcomes were compared according to the amniotic fluid's color. RESULTS: At all, 302 patients in the group " Abnormal amniotic fluid" (198 patients with stained amniotic fluid, 104 with meconial amniotic fluid) vs. 302 in the group " clear amniotic fluid" were included. No significant difference on the rate of neonatal severe acidosis between the two groups were found. Fetal heart rhythm abnormalities were more frequent in case of meconial amniotic fluid (11,3% vs. 31,7%, P<0,0001). The composite endpoint, defined by the association of umbilical arterial pH <7,0+/-base excess >=12mmol/L+/-Apgar score at 5min <7, was more frequent in case of meconial amniotic fluid (4,0% vs. 12,5%, P=0,0018). CONCLUSION: The occurrence of severe neonatal metabolic acidosis was not more frequent in case of stained or meconial amniotic fluid, but with an increase in the use of fetal scalp pH and cesaerian deliveries when the fluid was meconial. PMID- 29249651 TI - [Minimally fluoroscopic ablation of an accessory pathway in a child with Ebstein's anomaly: A case report]. PMID- 29249652 TI - Know Your Numbers: Creation and implementation of a novel community health mobile application (app) by student pharmacists. AB - OBJECTIVES: A free mobile application (app), Know Your Numbers (KYN), was developed by student pharmacists to assist underserved community members to track their health numbers. The study objectives included creating a health app, implementing a pilot program, and analyzing the frequency of app use and perceptions of community members toward their health numbers, pharmacists, and health apps. SETTING: Student pharmacists recruited participants at the community clinics and health fairs organized in underserved communities of the Atlanta metropolitan area. PRACTICE DESCRIPTION: This study used a pre- and post-survey study design to compare perceptions before and after use of a health app. Eligible participants completed a 22-item pre-survey that assessed understanding of their health numbers, previous health app use, and perceptions of pharmacists. EVALUATION: Frequency of app use and change in perceptions of community members toward health numbers, pharmacists, and health apps before and after enrolling in KYN were analyzed with the use of descriptive statistics and Wilcoxon signed rank tests for matched pre- and post-surveys. RESULTS: Thirty-three participants were enrolled for 56 days. African American participants (93.9%) earned less than $25,000 annually (56.7%). On average, participants had 3.98 interactions per week. Before using the mobile health app, 84.8% of users felt comfortable using a health app, but only 9% used one regularly. The post-survey response rate was 27.2% (n = 9). More participants agreed that a health app helped them to meet their health goals after the program (24.4% to 100%; P = 0.0006). More than 90% of participants agreed in both surveys that it is important to check their health numbers regularly and that they trust pharmacists to provide accurate information. CONCLUSION: KYN is a novel mobile tool that promotes chronic disease self-management and the profession of pharmacy. These findings support the benefits of mobile health app's usability and its ability to assist in achieving personal health goals. PMID- 29249654 TI - The Std1 Activator of the Snf1/AMPK Kinase Controls Glucose Response in Yeast by a Regulated Protein Aggregation. AB - The ability to respond to available nutrients is critical for all living cells. The AMP-activated protein kinase (SNF1 in yeast) is a central regulator of metabolism that is activated when energy is depleted. We found that SNF1 activity in the nucleus is regulated by controlled relocalization of the SNF1 activator Std1 into puncta. This process is regulated by glucose through the activity of the previously uncharacterized protein kinase Vhs1 and its substrate Sip5, a protein of hitherto unknown function. Phosphorylation of Sip5 prevents its association with Std1 and triggers Std1 accretion. Reversible Std1 puncta formation occurs under non-stressful, ambient conditions, creating non-amyloid inclusion bodies at the nuclear-vacuolar junction, and it utilizes cellular chaperones similarly to the aggregation of toxic or misfolded proteins such as those associated with Parkinson's, Alzheimer's, and CJD diseases. Our results reveal a controlled, non-pathological, physiological role of protein aggregation in the regulation of a major metabolic cellular pathway. PMID- 29249653 TI - Replication Stress Shapes a Protective Chromatin Environment across Fragile Genomic Regions. AB - Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at regions of recurrent replication stress (RS). Upon aberrant fork stalling, DNA damage signaling and concomitant H2AX phosphorylation coordinate the FACT-dependent deposition of macroH2A1.2, a histone variant that promotes DNA repair by homologous recombination (HR). MacroH2A1.2, in turn, facilitates the accumulation of the tumor suppressor and HR effector BRCA1 at replication forks to protect from RS-induced DNA damage. Consequently, replicating primary cells steadily accrue macroH2A1.2 at fragile regions, whereas macroH2A1.2 loss in these cells triggers DNA damage signaling-dependent senescence, a hallmark of RS. Altogether, our findings demonstrate that recurrent DNA damage contributes to the chromatin landscape to ensure the epigenomic integrity of dividing cells. PMID- 29249656 TI - Brain-Computer Interface with Inhibitory Neurons Reveals Subtype-Specific Strategies. AB - Brain-computer interfaces have seen an increase in popularity due to their potential for direct neuroprosthetic applications for amputees and disabled individuals. Supporting this promise, animals-including humans-can learn even arbitrary mapping between the activity of cortical neurons and movement of prosthetic devices [1-4]. However, the performance of neuroprosthetic device control has been nowhere near that of limb control in healthy individuals, presenting a dire need to improve the performance. One potential limitation is the fact that previous work has not distinguished diverse cell types in the neocortex, even though different cell types possess distinct functions in cortical computations [5-7] and likely distinct capacities to control brain computer interfaces. Here, we made a first step in addressing this issue by tracking the plastic changes of three major types of cortical inhibitory neurons (INs) during a neuron-pair operant conditioning task using two-photon imaging of IN subtypes expressing GCaMP6f. Mice were rewarded when the activity of the positive target neuron (N+) exceeded that of the negative target neuron (N-) beyond a set threshold. Mice improved performance with all subtypes, but the strategies were subtype specific. When parvalbumin (PV)-expressing INs were targeted, the activity of N- decreased. However, targeting of somatostatin (SOM)- and vasoactive intestinal peptide (VIP)-expressing INs led to an increase of the N+ activity. These results demonstrate that INs can be individually modulated in a subtype-specific manner and highlight the versatility of neural circuits in adapting to new demands by using cell-type-specific strategies. PMID- 29249655 TI - The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer. AB - Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product alpha-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer. PMID- 29249657 TI - Cells Escape an Operational Mitotic Checkpoint through a Stochastic Process. AB - Improperly attached chromosomes activate the mitotic checkpoint that arrests cell division before anaphase. Cells can maintain an arrest for several hours but eventually will resume proliferation, a process we refer to as adaptation. Whether adapting cells bypass an active block or whether the block has to be removed to resume proliferation is not clear. Likewise, it is not known whether all cells of a genetically homogeneous population are equally capable to adapt. Here, we show that the mitotic checkpoint is operational when yeast cells adapt and that each cell has the same propensity to adapt. Our results are consistent with a model of the mitotic checkpoint where adaptation is driven by random fluctuations of APC/CCdc20, the molecular species inhibited by the checkpoint. Our data provide a quantitative framework for understanding how cells overcome a constant stimulus that halts cell cycle progression. PMID- 29249658 TI - Mechanisms Connecting the Conserved Protein Kinases Ssp1, Kin1, and Pom1 in Fission Yeast Cell Polarity and Division. AB - Connections between the protein kinases that function within complex cell polarity networks are poorly understood. Rod-shaped fission yeast cells grow in a highly polarized manner, and genetic screens have identified many protein kinases, including the CaMKK-like Ssp1 and the MARK/PAR-1 family kinase Kin1, that are required for polarized growth and cell shape, but their functional mechanisms and connections have been unknown [1-5]. We found that Ssp1 promotes cell polarity by phosphorylating the activation loop of Kin1. Kin1 regulates cell polarity and cytokinesis through unknown mechanisms [4-7]. We performed a large scale phosphoproteomic screen and found that Kin1 phosphorylates itself and Pal1 to promote growth at cell tips, and these proteins are interdependent for localization to growing cell tips. Additional Kin1 substrates for cell polarity and cytokinesis (Tea4, Mod5, Cdc15, and Cyk3) were also phosphorylated by a second kinase, the DYRK family member Pom1 [8]. Kin1 and Pom1 were enriched at opposite ends of growing cells, and they phosphorylated largely non-overlapping sites on shared substrates. Combined inhibition of both Kin1and Pom1 led to synthetic defects in their shared substrates Cdc15 and Cyk3, confirming a non redundant functional connection through shared substrates. These findings uncover a new Ssp1-Kin1 signaling pathway, and define its functional and mechanistic connection with Pom1 signaling for cell polarity and cytokinesis. These kinases are conserved in many eukaryotes including humans, suggesting that similar connections and mechanisms might operate in a broad range of cells. PMID- 29249659 TI - Genomic Analysis of Demographic History and Ecological Niche Modeling in the Endangered Sumatran Rhinoceros Dicerorhinus sumatrensis. AB - The vertebrate extinction rate over the past century is approximately 22-100 times greater than background extinction rates [1], and large mammals are particularly at risk [2, 3]. Quaternary megafaunal extinctions have been attributed to climate change [4], overexploitation [5], or a combination of the two [6]. Rhinoceroses (Family: Rhinocerotidae) have a rich fossil history replete with iconic examples of climate-induced extinctions [7], but current pressures threaten to eliminate this group entirely. The Sumatran rhinoceros (Dicerorhinus sumatrensis) is among the most imperiled mammals on earth. The 2011 population was estimated at <=216 wild individuals [8], and currently the species is extirpated, or nearly so, throughout the majority of its former range [8-12]. Understanding demographic history is important in placing current population status into a broader ecological and evolutionary context. Analysis of the Sumatran rhinoceros genome reveals extreme changes in effective population size throughout the Pleistocene. Population expansion during the early to middle Pleistocene was followed by decline. Ecological niche modeling indicated that changing climate most likely played a role in the decline of the Sumatran rhinoceros, as less suitable habitat on an emergent Sundaland corridor isolated Sumatran rhinoceros populations. By the end of the Pleistocene, the Sundaland corridor was submerged, and populations were fragmented and consequently reduced to low Holocene levels from which they would never recover. Past events denuded the Sumatran rhinoceros of genetic diversity through population decline, fragmentation, or some combination of the two and most likely made the species even more susceptible to later exploitation and habitat loss. VIDEO ABSTRACT. PMID- 29249660 TI - Complex Pattern Selectivity in Macaque Primary Visual Cortex Revealed by Large Scale Two-Photon Imaging. AB - Visual objects contain rich local high-order patterns such as curvature, corners, and junctions. In the standard hierarchical model of visual object recognition, V1 neurons were commonly assumed to code local orientation components of those high-order patterns. Here, by using two-photon imaging in awake macaques and systematically characterizing V1 neuronal responses to an extensive set of stimuli, we found a large percentage of neurons in the V1 superficial layer responded more strongly to complex patterns, such as corners, junctions, and curvature, than to their oriented line or edge components. Our results suggest that those individual V1 neurons could play the role in detecting local high order visual patterns in the early stage of object recognition hierarchy. PMID- 29249662 TI - Experience-Dependent Plasticity of Odor Representations in the Telencephalon of Zebrafish. AB - Sensory systems balance stability and plasticity to optimize stimulus representations in dynamic environments. We studied these processes in the olfactory system of adult zebrafish. Activity patterns evoked by repeated odor stimulation were measured by multiphoton calcium imaging in the olfactory bulb (OB) and in telencephalic area Dp, the homolog of olfactory cortex. Whereas odor responses in the OB were highly reproducible, responses of Dp neurons adapted over trials and exhibited substantial variability that could be attributed to ongoing activity and to systematic changes in neuronal representations following each stimulus. An NMDA receptor antagonist did not affect the magnitude of odor responses but strongly reduced the variability and experience-dependent modification of odor responses in Dp. As a consequence, odor representations became stable over trials. These results demonstrate that odor representations in higher brain areas are continuously modified by experience, supporting the view that olfactory processing is inseparable from memory, even in the absence of reinforcement. PMID- 29249661 TI - Patterns of Genomic Variation in the Opportunistic Pathogen Candida glabrata Suggest the Existence of Mating and a Secondary Association with Humans. AB - Candida glabrata is an opportunistic fungal pathogen that ranks as the second most common cause of systemic candidiasis. Despite its genus name, this yeast is more closely related to the model yeast Saccharomyces cerevisiae than to other Candida pathogens, and hence its ability to infect humans is thought to have emerged independently. Moreover, C. glabrata has all the necessary genes to undergo a sexual cycle but is considered an asexual organism due to the lack of direct evidence of sexual reproduction. To reconstruct the recent evolution of this pathogen and find footprints of sexual reproduction, we assessed genomic and phenotypic variation across 33 globally distributed C. glabrata isolates. We cataloged extensive copy-number variation, which particularly affects genes encoding cell-wall-associated proteins, including adhesins. The observed level of genetic variation in C. glabrata is significantly higher than that found in Candida albicans. This variation is structured into seven deeply divergent clades, which show recent geographical dispersion and large within-clade genomic and phenotypic differences. We show compelling evidence of recent admixture between differentiated lineages and of purifying selection on mating genes, which provides the first evidence for the existence of an active sexual cycle in this yeast. Altogether, our data point to a recent global spread of previously genetically isolated populations and suggest that humans are only a secondary niche for this yeast. PMID- 29249663 TI - HN1L Promotes Triple-Negative Breast Cancer Stem Cells through LEPR-STAT3 Pathway. AB - Here, we show that HEMATOLOGICAL AND NEUROLOGICAL EXPRESSED 1-LIKE (HN1L) is a targetable breast cancer stem cell (BCSC) gene that is altered in 25% of whole breast cancer and significantly correlated with shorter overall or relapse-free survival in triple-negative breast cancer (TNBC) patients. HN1L silencing reduced the population of BCSCs, inhibited tumor initiation, resensitized chemoresistant tumors to docetaxel, and hindered cancer progression in multiple TNBC cell line derived xenografts. Additionally, gene signatures associated with HN1L correlated with shorter disease-free survival of TNBC patients. We defined HN1L as a BCSC transcription regulator for genes involved in the LEPR-STAT3 signaling axis as HN1L binds to a putative consensus upstream sequence of STAT3, LEPTIN RECEPTOR, and MIR-150. Our data reveal that BCSCs in TNBC depend on the transcription regulator HN1L for the sustained activation of the LEPR-STAT3 pathway, which makes it a potentially important target for both prognosis and BCSC therapy. PMID- 29249664 TI - In Vitro Induction and In Vivo Engraftment of Lung Bud Tip Progenitor Cells Derived from Human Pluripotent Stem Cells. AB - The current study aimed to understand the developmental mechanisms regulating bud tip progenitor cells in the human fetal lung, which are present during branching morphogenesis, and to use this information to induce a bud tip progenitor-like population from human pluripotent stem cells (hPSCs) in vitro. We identified cues that maintained isolated human fetal lung epithelial bud tip progenitor cells in vitro and induced three-dimensional hPSC-derived organoids with bud tip-like domains. Bud tip-like domains could be isolated, expanded, and maintained as a nearly homogeneous population. Molecular and cellular comparisons revealed that hPSC-derived bud tip-like cells are highly similar to native lung bud tip progenitors. hPSC-derived epithelial bud tip-like structures survived in vitro for over 16 weeks, could be easily frozen and thawed, maintained multilineage potential, and successfully engrafted into the airways of immunocompromised mouse lungs, where they persisted for up to 6 weeks and gave rise to several lung epithelial lineages. PMID- 29249665 TI - FZD4 Marks Lateral Plate Mesoderm and Signals with NORRIN to Increase Cardiomyocyte Induction from Pluripotent Stem Cell-Derived Cardiac Progenitors. AB - The identification of cell surface proteins on stem cells or stem cell derivatives is a key strategy for the functional characterization, isolation, and understanding of stem cell population dynamics. Here, using an integrated mass spectrometry- and microarray-based approach, we analyzed the surface proteome and transcriptome of cardiac progenitor cells (CPCs) generated from the stage specific differentiation of mouse and human pluripotent stem cells. Through bioinformatics analysis, we have identified and characterized FZD4 as a marker for lateral plate mesoderm. Additionally, we utilized FZD4, in conjunction with FLK1 and PDGFRA, to further purify CPCs and increase cardiomyocyte (CM) enrichment in both mouse and human systems. Moreover, we have shown that NORRIN presented to FZD4 further increases CM output via proliferation through the canonical WNT pathway. Taken together, these findings demonstrate a role for FZD4 in mammalian cardiac development. PMID- 29249666 TI - Impaired IFNgamma-Signaling and Mycobacterial Clearance in IFNgammaR1-Deficient Human iPSC-Derived Macrophages. AB - Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of interferon gamma (IFNgamma) immunity and is characterized by severe infections by weakly virulent mycobacteria. Although IFNgamma is the macrophage activating factor, macrophages from these patients have never been studied. We demonstrate the generation of heterozygous and compound heterozygous (iMSMD cohet) induced pluripotent stem cells (iPSCs) from a single chimeric patient, who suffered from complete autosomal recessive IFNgammaR1 deficiency and received bone-marrow transplantation. Loss of IFNgammaR1 expression had no influence on the macrophage differentiation potential of patient-specific iPSCs. In contrast, lack of IFNgammaR1 in iMSMD-cohet macrophages abolished IFNgamma-dependent phosphorylation of STAT1 and induction of IFNgamma-downstream targets such as IRF 1, SOCS-3, and IDO. As a consequence, iMSMD-cohet macrophages show impaired upregulation of HLA-DR and reduced intracellular killing of Bacillus Calmette Guerin. We provide a disease-modeling platform that might be suited to investigate novel treatment options for MSMD and to gain insights into IFNgamma signaling in macrophages. PMID- 29249667 TI - O-GlcNAc on PKCzeta Inhibits the FGF4-PKCzeta-MEK-ERK1/2 Pathway via Inhibition of PKCzeta Phosphorylation in Mouse Embryonic Stem Cells. AB - Mouse embryonic stem cells (ESCs) differentiate into multiple cell types during organismal development. Fibroblast growth factor 4 (FGF4) signaling induces differentiation from ESCs via the phosphorylation of downstream molecules such as mitogen-activated protein kinase/extracellular signal-related kinase (MEK) and extracellular signal-related kinase 1/2 (ERK1/2). The FGF4-MEK-ERK1/2 pathway is inhibited to maintain ESCs in the undifferentiated state. However, the inhibitory mechanism of the FGF4-MEK-ERK1/2 pathway in ESCs is uncharacterized. O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) is a post-translational modification characterized by the attachment of a single N-acetylglucosamine (GlcNAc) to the serine and threonine residues of nuclear or cytoplasmic proteins. Here, we showed that the O-GlcNAc on the phosphorylation site of PKCzeta inhibits PKCzeta phosphorylation (activation) and, consequently, the FGF4-PKCzeta-MEK ERK1/2 pathway in ESCs. Our results demonstrate the mechanism for the maintenance of the undifferentiated state of ESCs via the inhibition of the FGF4-PKCzeta-MEK ERK1/2 pathway by O-GlcNAcylation on PKCzeta. PMID- 29249669 TI - Corrigendum to "Different dosing regimens for propofol induction in Obese patients" [Asian J Anesthesiol 51 (2) (2013) 53-57]. PMID- 29249670 TI - Effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in Phe508del homozygous cystic fibrosis patients. AB - OBJECTIVE: To investigate the effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in patients with cystic fibrosis (CF) (Phe508del/Phe508del). METHODS: A standard oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were performed to investigate glucose metabolism and insulin secretion before and after 6-8weeks of treatment with Lumacaftor/Ivacaftor in 5 Phe508del-homozygous CF patients. The area under the curve (AUC) for glucose and insulin levels was calculated using the trapezoidal approximation. RESULTS: 5 participants were investigated. Treatment with Lumacaftor/Ivacaftor was followed by an improvement of the 2h glucose levels in 3 patients and worsening in 2 patients. Analysis of the time course of blood glucose levels during OGTT revealed an increase of the AUC in 3 of 5 patients. In response to IVGTT, acute insulin secretion improved in 2 patients and worsened in 3. CONCLUSION: The investigation could not demonstrate that treatment with Lumacaftor/Ivacaftor had a consistent impact on glucose tolerance and insulin secretion. Further adequately-powered studies examining glucose metabolism are needed to properly evaluate drug response in the endocrine pancreas and to test whether this treatment could eventually prevent the development of cystic fibrosis-related diabetes (CFRD). PMID- 29249668 TI - GCN5 Regulates FGF Signaling and Activates Selective MYC Target Genes during Early Embryoid Body Differentiation. AB - Precise control of gene expression during development is orchestrated by transcription factors and co-regulators including chromatin modifiers. How particular chromatin-modifying enzymes affect specific developmental processes is not well defined. Here, we report that GCN5, a histone acetyltransferase essential for embryonic development, is required for proper expression of multiple genes encoding components of the fibroblast growth factor (FGF) signaling pathway in early embryoid bodies (EBs). Gcn5-/- EBs display deficient activation of ERK and p38, mislocalization of cytoskeletal components, and compromised capacity to differentiate toward mesodermal lineage. Genomic analyses identified seven genes as putative direct targets of GCN5 during early differentiation, four of which are cMYC targets. These findings established a link between GCN5 and the FGF signaling pathway and highlighted specific GCN5-MYC partnerships in gene regulation during early differentiation. PMID- 29249671 TI - Gastric submucosal haematoma caused by an amyloidoma in the setting of multiple myeloma. AB - This is a case of a 67-year-old woman with a history of multiple myeloma with amyloidosis who presented with massive hematemesis. Emergent upper endoscopy revealed a mass on the greater curvature of the stomach, which measured approximately 3 cm in width and 7 cm in length. The patient underwent a wedge resection of the gastric mass without complication. Microscopic examination of the gastric mass revealed amorphous deposits that were congophilic in nature and stained positive with Alcian blue. These findings are consistent with amyloidosis. The patient had a favourable postoperative recovery and was discharged from the hospital. This case highlights the need for clinicians to be aware of the possibility of spontaneous gastric haemorrhage secondary to light chain (AL) amyloidosis, especially in patients with a known bone marrow disorder. PMID- 29249672 TI - Prevalence of diabetes in three regions of Venezuela. The VEMSOLS study results. AB - OBJECTIVE: The prevalence of diabetes in multiple regions of Venezuela is unknown. To determine the prevalence of diabetes in five populations from three regions of Venezuela. METHODS: During 2006-2010, 1334 subjects >=20years were selected by multistage stratified random sampling from all households from 3 regions of Venezuela. Anthropometric measurements and biochemical analysis were obtained. Statistical methods were calculated using SPSS 20 software. FINDINGS: Mean (SE) age was 44.8 years (0.39) and 68.5% were females. The prevalence of diabetes was 8.3% (95% CI, 6.9%-10.0%), higher in men than women (11.2% and 7.0% respectively; p=0.01). The prevalence adjusted by age and gender was 8.0% (95% CI, 6.9%-9.9%). This figure increased with age, with the lowest prevalence in the 20-29year old group (1.8% [95% CI, 0.6%-4.8%]) and the highest in the oldest group (26.8% [95% CI, 16.2%-40.5%]). Subjects with overweight or obesity had no increased risk of diabetes compared with those with normal weight. However, in women, the presence of abdominal obesity was associated with an increase of the risk of diabetes by 77% (OR 1.77 [95% CI, 1.1%-2.9%]). The prevalence of prediabetes was 14.6% (95% CI, 12.8%-16.7%), and only 48.2% were aware of their diabetes condition. CONCLUSION: In this study, 8.3% of the subjects had diabetes and 14.6% prediabetes. Less than half of the subjects with diabetes were aware of their condition. These results point to a major public health problem, requiring the implementation of diabetes prevention programs. PMID- 29249673 TI - Aesthetic day surgery safety in a UK facility: A 4 year retrospective study and discussion of the literature. PMID- 29249674 TI - Psychosocial predictors of body image dissatisfaction in patients referred for NHS aesthetic surgery. AB - BACKGROUND: A limited number of studies have researched psychosocial predictors of body image dissatisfaction exclusively within the National Health Service (NHS) aesthetic surgery patient populations, despite aesthetic surgery being offered on an exceptional basis. The Adult Exceptional Aesthetic Referral Protocol (AEARP) defines criteria for aesthetic surgery under the NHS in Scotland. The protocol requires psychological assessment prior to surgery for the majority of aesthetic surgery procedures offered. It is therefore important to establish psychological predictors of body image dissatisfaction to aid with assessment and provision of psychological therapy for this patient group. METHOD: 334 consecutive potential aesthetic surgery patients referred for psychological assessment under the AEARP completed psychosocial self-report assessment measures as part of routine practice. Multiple regression analysis using the forced entry method was used to investigate psychosocial predictors of body image dissatisfaction. RESULTS: Multiple regression analysis indicated that younger age, greater symptoms of depression, lower levels of self-esteem and greater interpersonal sensitivity significantly predicted higher levels of self-reported body image dissatisfaction. Symptoms of anxiety did not significantly predict body image dissatisfaction. CONCLUSION: This study indicates that both self perception and perception of self in relation to others, especially fear of being judged by others, significantly relates to body image dissatisfaction in this patient group. Psychological assessment of patients' suitability for aesthetic surgery should consider factors such as the patients' interpersonal functioning. Psychological intervention targeted at symptoms of depression, difficulties with self-esteem and interpersonal functioning may be of significant benefit to patients either prior to undergoing surgery or as an alternative to aesthetic surgery. PMID- 29249675 TI - Robert Acland (1941-2016) innovator, microsurgeon, anatomist and teacher. PMID- 29249676 TI - Refining the cross-finger flap: Considerations of flap insetting, aesthetics and donor site morbidity. AB - We described a laterally based cross-finger flap for reconstruction of soft tissue defects in the fingers. This modification enables coverage of volar or dorsal soft tissue defects at the distal, middle or proximal phalanx. From March 2015 to January 2017, a total of 12 patients (13 fingers) underwent soft tissue reconstruction of the fingers with a laterally based cross-finger flap. The flap dimensions ranged from 13 *7 mm to 43 *13 mm. Eleven of the 13 flaps survived completely. The two flap failures were attributed to injuries in the donor fingers, rendering the blood supply of the flaps unreliable. All donor sites were closed primarily without the need for skin grafting, negating the problem of donor site morbidity that is associated with skin graft harvesting. The laterally based cross-finger flap is a versatile flap with less donor site morbidity and better aesthetics than a conventional cross-finger flap. We described the design of the flap, as well as the advantages and disadvantages, in doing a laterally based cross-finger flap. PMID- 29249677 TI - Factors associated to adherence to blood glucose self-monitoring in patients with diabetes treated with insulin. The dapa study. AB - OBJECTIVE: To assess adherence to self-monitoring of blood glucose and the main factors associated with it, particularly those related to self-perception of glycemia, in patients with diabetes on insulin therapy. PATIENTS AND METHODS: An epidemiological, observational, prospective, multicenter study conducted in standard clinical practice in primary care, outpatient centers, and hospitals from different Spanish regions. Sociodemographic, clinical and treatment data were collected. Patients were considered adherent to self-monitoring if they performed the minimum number of controls recommended by the Spanish Society of Diabetes (SED). RESULTS: Adherence was shown in 61.6% of patients. Factors associated to adherence included treatment with less than three insulin injections daily (OR 2.678; 95% CI 2.048- 3.5029; p <0.001), presence of peripheral vascular disease (OR 1.529; 95% CI 1.077 - 2.171; p=0.018), alcohol abstinence (OR 1.442; 95% CI 1.118 - 1.858; p=0.005), and collection of the glucose test strips from the pharmacy (OR 1.275; 95% CI 1.026 - 1.584; p=0.028). Adequate self-perception of glycemia was found in 21.4% of patients. CONCLUSIONS: Our results show a suboptimal adherence to the recommended protocol for blood glucose self-monitoring in patients with diabetes on insulin therapy. Independent variables associated to good adherence were treatment with less than three insulin injections dailyu, presence of peripheral vascular disease, alcohol abstinence, and collection of glucose test strips from the pharmacy. PMID- 29249678 TI - Identification of CHCHD10 variants in Chinese patients with Parkinson's disease. PMID- 29249679 TI - Cognitive profile and 18F-fluorodeoxyglucose PET study in LRRK2-related Parkinson's disease. AB - INTRODUCTION: LRRK2 gene mutations underlie the most common mendelian form of Parkinson's Disease (PD), designated PARK8, that shows clinical features similar to those in idiopathic PD (IPD). We assessed the cognitive functions and the cerebral metabolism measured with 18F-fluorodeoxyglucose (FDG)-PET in PARK8 patients compared with IPD. PATIENTS AND METHODS: We enrolled eight PARK8 patients and eight IPD patients, comparable for onset age, stage, severity and duration of disease. Mean age +/- SD was 61.8 +/- 10.9 years and disease duration 8.4 +/- 5.8 in PARK8, and 61.4 +/- 14.7 and 7.0 +/- 4.8 in IPD. All subjects underwent a wide neuropsychological assessment and a FDG-PET. Cerebral regional relative metabolic maps were evaluated using voxel-based analysis with statistical parametric mapping. RESULTS: Motor and non-motor phenotype and neuropsychological evaluation did not differ between PARK8 and IPD. We detected one case of dementia and four of Mild Cognitive Impairment in each group. At FDG PET, compared to controls, IPD patients revealed a significant relative posterior cortical hypometabolism in the left temporal and inferior parietal and in the right inferior and superior parietal regions, whereas patients with LRRK2 mutation, at a less conservative threshold, showed only a relative left inferior parietal hypometabolism. No differences were found between patients with PARK8 and IPD. CONCLUSIONS: The results confirm a comparable cognitive profile between LRRK2 and IPD patients. FDG-PET study showed a pattern of posterior cortical hypometabolism in both groups, although less severe in LRRK2-related PD. The milder decrease of cortical metabolism in PARK8 might be due to a less marked pathological involvement compared to IPD. PMID- 29249680 TI - Dopaminergic polymorphisms associated with medication responsiveness of gait in Parkinson's disease. AB - BACKGROUND: Gait dysfunction is a common symptom of Parkinson's disease that can cause significant disability and put patients at risk for falls. These symptoms show variable responsiveness to dopaminergic therapy. OBJECTIVE: To determine whether dopaminergic (rs1076560 DRD2 G > T and rs4680 catechole-o methyltranspherase (COMT) Val158Met) or brain derived neurotrophic factor (rs6265 BDNF Val66Met) genetic polymorphisms are associated with gait function and medication responsiveness in Parkinson's disease. METHOD: Gait function was evaluated on two days for patients (ON and OFF medication in a counterbalanced fashion) and a single session for controls. Investigators were blinded to genotype during data collection. Associations between genotype and medication responsiveness were analyzed using mixed model ANOVAs. A priori hypotheses were tested using GAITRite(r) electronic mat spatiotemporal gait parameters including step length, step width, velocity, portion of double and single support per gait cycle, and variability of these measures ON and OFF medication. RESULTS: We found that the DRD2 polymorphism, but neither COMT nor BDNF, was consistently associated with gait function and medication responsiveness in the patients. Specifically, Parkinson's disease patients with reduced striatal D2 expression (DRD2 T allele carriers) had worse gait dysfunction and showed greater dopamine responsiveness of gait function compared to patients who were homozygous for the G allele. There was no effect of any of the genetic polymorphisms on gait for controls. CONCLUSIONS AND RELEVANCE: The findings suggest that genetic subgrouping, in particular for DRD2, may be used to identify Parkinson's disease patient subgroups that are more dopamine responsive for gait function. PMID- 29249681 TI - More than ataxia - Movement disorders in ataxia-telangiectasia. AB - Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative disease caused by mutations in the ATM gene with progressive neurological dysfunction, multisystem abnormalities and cancer predisposition. Classically, AT is associated with cerebellar ataxia, oculocutaneous telangiectasia and oculomotor apraxia. The aim of this review is to describe the movement disorders observed in patients with AT. Movement disorders in AT patients described in the literature are reviewed. The selected articles were analyzed with a focus on clinical presentation, presence of movement disorders, and atypical cases or variants of the syndrome. In AT patients, particularly adults, chorea and dystonia are the most common movement disorders, besides cerebellar ataxia. Myoclonus, tremor and parkinsonism have been described less frequently in patients with AT. Archetypal findings, such as oculocutaneous abnormalities may not be uniformly present. AT can present with different movement disorders, in isolation or combined, with or without cerebellar ataxia or oculocutaneous telangiectasias. Neurologists with expertise in movement disorders should be aware of AT when investigating patients with movement disorders of unknown etiology. PMID- 29249682 TI - Deep brain stimulation for lesion-related tremors: A systematic review and meta analysis. AB - Deep brain stimulation (DBS) is an effective treatment for essential tremor or tremor in Parkinson's disease. The effectiveness of DBS in reducing tremors that develop after a structural lesion of the central nervous system (such as Holmes' tremor - HT) has only been addressed in case reports or series. We conducted a systematic review of all published original reports of DBS in central nervous system lesion-related tremor (excluding demyelinating disorders due to their non static nature). Where available, we extracted data regarding each patient's demographic, tremor and surgical details. Improvement was calculated as a percentage of change in any objective tremor rating scale. We identified 35 publications reporting on 82 patients. The ventral intermedius nucleus(VIM) of the thalamus was the preferred target (63.6%) and 18.2% targeted globus pallidus pars interna(GPi). Median improvement was 77.5% and 71.4% for patients with post stroke and post-traumatic tremor respectively. Seven subjects (13.5%) had less than 50% improvement. Therapeutic effectiveness was not associated with age, tremor duration, age of onset or follow-up time. A large range of stimulation parameters were used with median voltage, pulse width and frequency values higher for GPi (4.80 V, 105 us, 170 Hz) than for thalamic stimulation (3.0 V, 90 us, 140 Hz). DBS reports for Holmes' and lesional tremors treatment are scarce and highly heterogeneous limiting a proper summary analysis and comparisons. Even facing a probable report bias, a high number of subjects with good long-term tremor control were found. These results should promote the creation of tremor registries before clinical trials. PMID- 29249683 TI - Before and after the veterans affairs cooperative program 468 study: Deep brain stimulator target selection for treatment of Parkinson's disease. AB - INTRODUCTION: The Veterans Affairs Cooperative Study Program 468 study (CSP 468) produced significant findings regarding deep brain stimulation (DBS) target selection for Parkinson's Disease (PD) treatment, yet its impact on clinical practices has not been described. Here we assess how CSP 468 influenced target selection at a high-volume movement disorders treatment center. METHODS: We compared DBS target site selection between 4-year periods that immediately preceded and followed CSP 468 publication. Additionally, we examined how baseline clinical features influenced target selection following CSP 468. RESULTS: The STN was the predominant site of DBS implantation before and after CSP 468 publication (93.2% of cases, and 60.4%, respectively), but GPi targeting increased significantly following CSP 468 publication (from 5.3% to 37.4%; p < .001). Patients who underwent GPi stimulation following CSP 468 exhibited worse indices of depression (p < .001), less responsiveness to medications (p < .05), and a trend towards worse pre-operative cognitive performance (p = .06). In multi variate analysis, advanced patient age and depression were independent predictors of GPi targeting (p < .01). CONCLUSIONS: Key findings of CSP 468 were reflected in our target selection of DBS for Parkinson's Disease. Following CSP 468, GPi targeting increased, and it was selected for patients with poorer cognitive and mood indices. PMID- 29249684 TI - Thyroid hormones, lipid profile and anthropometric changes after programmed weight loss in Palestinian obese adult females. AB - OBJECTIVE: we aimed to investigate the changes in thyroid hormones, lipid profile and anthropometric measures after programmed weight loss in Palestinian obese adult females MATERIALS AND METHODS: This prospective study included 94 obese female (20-50 years old) as cases and 94 Non-obese of same age as controls for baseline comparisons. Obese female were assigned for low calorie diet (1200-1500 Kcal/day) in addition to a daily program of therapeutic exercise for six month. Parameters were measured, statistically analyzed and compared with control before and after study. RESULTS: baseline measurements showed significant differences between cases and control regarding BMI, TG, TC, LDL-C, TSH, T3 and T4. After six months of low calorie diet and exercise there was a significant decrease in BMI, TC, TG and LDL-C in cases as compared to their levels before the study (P <= 0.05). TSH was significantly increased, while, T3 and T4 were significantly decreased in the cases as compared to their levels before the study. Statistically significant correlations were reported between different parameters of the study. CONCLUSIONS: Low calorie diet and moderate intensity therapeutic exercise significantly improved the deteriorated health indicators in the cases which justifies the necessity for introducing such low calorie diet coupled with moderate exercise. PMID- 29249685 TI - Effects of beta-hydroxy-beta-methylbutyrate supplementation on strength and body composition in trained and competitive athletes: A meta-analysis of randomized controlled trials. AB - OBJECTIVES: The aim of this meta-analysis was to examine the evidence for the effectiveness of beta-hydroxy-beta-methylbutyrate supplementation interventions on modification in strength and body composition in trained and competitive athletes. DESIGN: Systematic review and meta-analysis. METHODS: A systematic search was performed using three databases: MEDLINE, EBSCO and Web of Science. The analysis was restricted to randomized controlled trials that examined the effect of HMB supplementation interventions on modification in bench and leg press strength, body mass, fat-free mass and fat mass. Effect sizes (ES) and 95% confidence intervals (CIs) were calculated using a fixed effect meta-analysis due to low value of the heterogeneity. The Egger test was used to determine the presence of publication bias, and the Q and I2 statistics were used to assess heterogeneity among studies. Significance was set at p<0.05. RESULTS: Six studies were selected for meta-analysis, as they fulfilled the inclusion criteria (n=193 participants). HMB supplementation interventions present a trivial non significant ES in all variables studied (bench press ES=0.00, leg press ES=0.09, body mass ES=-0.01, fat-free mass ES=0.16, and fat mass ES=-0.20; all cases p>0.05, and null heterogeneity I2=0.0% p>0.05). These results remained constant even analyzing by subgroups (HMB doses, duration of intervention, training level and diet co-intervention). CONCLUSIONS: This meta-analysis found no effect of HMB supplementation on strength and body composition in trained and competitive athletes. PMID- 29249686 TI - Reliability and validity of self-reported sitting and breaks from sitting in the workplace. AB - OBJECTIVES: Prolonged sitting is a health risk factor which is ubiquitous to the workplace, and breaking up prolonged sitting is widely recommended. This study evaluated the test-retest reliability and concurrent validity of a self-report measure of duration of sitting and breaks from sitting in the workplace. DESIGN: Cross-sectional study. METHODS: Fifty-nine workers who reported spending most of their work time sitting wore an activPAL inclinometer and the ActiGraph accelerometer for eight consecutive days, and completed single-item measures of duration of sitting (min/work hour) and breaks from sitting (frequency/per work hour), twice, seven days apart. RESULTS: Participants reported sitting at work for a median of 420min/day (Interquartile Range=360-450min/day) and taking one break (Interquartile Range=1.0-2.0) from sitting per work hour. For reported duration of workplace sitting, test-retest reliability was adequate (Intra-Class Correlations=0.78, 95% Confidence Intervals [CI]=0.65, 0.86), and concurrent validity fair against the activPAL (Spearman's Rho=0.24, CI-1.0,0.47) and the ActiGraph (Rho=0.39, CI=0.15, 0.68). For reported breaks from sitting (frequency/per work hour), test-retest reliability was adequate (Intra-Class Correlations=0.65, CI=0.48, 0.78) and concurrent validity fair against the activPAL (Spearman's Rho=0.39, CI=0.25, 0.74) and the ActiGraph (Spearman's Rho=0.30, CI=0.15, 0.69). Self-reported duration of sitting was biased toward over-reporting compared to the activPAL (median=45.4min) and under-reporting compared to the ActiGraph (median=21.7min). CONCLUSIONS: This study found adequate reliability and fair validity for self-reported duration of sitting (min/work day) and breaks from sitting (frequency/per work hour). Further validity research is needed using the inclinometer. PMID- 29249687 TI - Male Incontinence: The Etiology or Basis of Treatment. AB - CONTEXT: Elderly men are an increasing proportion of the aging population in the 21st century. Urinary incontinence reduces the quality of life and increases the burden of care for the aging population. OBJECTIVE: The primary objective of this review is to explore the etiopathology of common causes of incontinence in aging male patients. The focus is on the algorithm of the initial evaluation of these patients from both a primary care and a urologic standpoint. EVIDENCE ACQUISITION: A nonsystematic review of the literature was performed in September 2017. The data and evidence of this paper have been obtained by a PubMed search, and through official statements and recommendations from the International Consultation on Incontinence. Our search incorporated terms such as elderly, urinary incontinence, male, urodynamics, bladder outlet obstruction, BPH, neurologic, urethral stricture, spinal shock, and urethral sphincter injury. EVIDENCE SYNTHESIS: A total of 7204 papers were identified; 6838 were excluded for female populations and populations <65 yr. A broad differential diagnosis exists for urinary incontinence in aging male patients, and many patients will be found to have multifactorial incontinence, compounding the issue. Neurologic etiologies common in this population include cerebrovascular accidents, Parkinson's disease, and dementia. Spinal cord injuries and multiple sclerosis are less common. In this analysis, non-neurologic etiologies leading to incontinence are broadly grouped under bladder outlet obstruction, sphincter injury, overactive bladder, underactive bladder, polypharmacy, and urinary tract infections. CONCLUSIONS: We provide a review of the differential diagnosis of incontinence in an elderly male patient. There is a need for understanding etiopathology and recognizing that many patients may have a combination of the above. The assessment algorithm, modified from the International Continence Society, provides a pathway for the provider in evaluating and treating elderly patients. PATIENT SUMMARY: In this review, we have identified the sources of urinary incontinence in elderly male patients by neurologic and non-neurologic causes. We also discuss the basic evaluation and workup of an incontinent patient. PMID- 29249688 TI - A Head-to-head Comparison of Four Prognostic Models for Prediction of Lymph Node Invasion in African American and Caucasian Individuals. AB - BACKGROUND: Four nomograms are available for the prediction of lymph node invasion (LNI) prior to radical prostatectomy (RP): the Cagiannos, the 2012 Briganti, the Godoy, and the online-Memorial Sloan Kettering Cancer Center (MSKCC). None was tested in African Americans (AAs). OBJECTIVE: To perform a validation and head-to-head comparison of four nomograms for the prediction of LNI in AAs. DESIGN, SETTING, AND PARTICIPANTS: Within the Surveillance Epidemiology and End Results database (2010-2014), we identified 14 077 Caucasians and 2668 AAs with clinically localised prostate cancer. INTERVENTION: RP and pelvic lymph node dissection (PLND). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Predicted and observed LNI rates for the four nomograms were tested between AAs and Caucasians with Heagerty's concordance index (C-index), calibration plots, decision curve analyses (DCAs), and nomogram-derived cut-offs for avoided PLND and missed LNI cases. RESULTS AND LIMITATIONS: All C-index values were lower in AAs than in Caucasians: Cagiannos (76.1% vs 79.5%), Godoy (73.0% vs 79.4%), 2012-Briganti (73.3% vs 81.3%), and MSKCC (72.6% vs 81.6%). All four nomogram calibration plots showed invariably worse performances in AAs. In DCAs focusing on AAs, the Cagiannos nomogram provided the highest net benefit relative to the remaining three nomograms. In nomogram cut-off analyses testing the number of avoided PLND against the number of missed LNI cases, the Cagiannos nomogram yielded the best results when tested in AAs. However, in DCAs and cut off analyses that compared AAs with Caucasians, AAs yielded less favourable outcomes regardless of which nomogram was tested. We lack a central pathology review and standardisation of PLND templates. CONCLUSIONS: In AAs, the Cagiannos nomogram provides the optimal results relative to the remaining three nomograms. Nonetheless, all tested nomograms yielded worse metrics in AAs than in Caucasians. PATIENT SUMMARY: All four tested nomograms can be equally considered in Caucasians. Conversely, the Cagiannos nomogram should be preferred in African Americans. PMID- 29249689 TI - NAD+ Intermediates: The Biology and Therapeutic Potential of NMN and NR. AB - Research on the biology of NAD+ has been gaining momentum, providing many critical insights into the pathogenesis of age-associated functional decline and diseases. In particular, two key NAD+ intermediates, nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), have been extensively studied over the past several years. Supplementing these NAD+ intermediates has shown preventive and therapeutic effects, ameliorating age-associated pathophysiologies and disease conditions. Although the pharmacokinetics and metabolic fates of NMN and NR are still under intensive investigation, these NAD+ intermediates can exhibit distinct behavior, and their fates appear to depend on the tissue distribution and expression levels of NAD+ biosynthetic enzymes, nucleotidases, and presumptive transporters for each. A comprehensive concept that connects NAD+ metabolism to the control of aging and longevity in mammals has been proposed, and the stage is now set to test whether these exciting preclinical results can be translated to improve human health. PMID- 29249690 TI - JAK/STAT3-Regulated Fatty Acid beta-Oxidation Is Critical for Breast Cancer Stem Cell Self-Renewal and Chemoresistance. AB - Cancer stem cells (CSCs) are critical for cancer progression and chemoresistance. How lipid metabolism regulates CSCs and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and cancer chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self-renewal and expression of diverse lipid metabolic genes, including carnitine palmitoyltransferase 1B (CPT1B), which encodes the critical enzyme for fatty acid beta-oxidation (FAO). Moreover, mammary-adipocyte-derived leptin upregulates STAT3-induced CPT1B expression and FAO activity in BCSCs. Human breast-cancer derived data suggest that the STAT3-CPT1B-FAO pathway promotes cancer cell stemness and chemoresistance. Blocking FAO and/or leptin re-sensitizes them to chemotherapy and inhibits BCSCs in mouse breast tumors in vivo. We identify a critical pathway for BCSC maintenance and breast cancer chemoresistance. PMID- 29249693 TI - Site-Specific Installation of Succinyl Lysine Analog into Histones Reveals the Effect of H2BK34 Succinylation on Nucleosome Dynamics. AB - Posttranslational modifications of histones play key roles in the dynamic regulation of chromatin structure. Lysine succinylation is a new type of histone modification, but its biological significance in chromatin structure and dynamics remains unknown. Here we develop a chemical approach to site-specifically install a succinyl lysine analog into histones. This analog serves as an ideal structural and functional mimic to natural succinyl lysine. The incorporation of this succinylation mimic into histone H2B at lysine 34, a succinylation site at the nucleosomal DNA-histone interface, leads to significant decrease in nucleosome stability in vitro, which is consistent with the defects in chromatin structure of a budding yeast strain containing a lysine-to-glutamate mutation at the corresponding residue of yeast histone H2B. This study provides a simple method for the rapid generation of histones with site-specific succinylation mimics, and reveals novel regulatory mechanisms of histone succinylation in the dynamic organization of chromatin. PMID- 29249691 TI - Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms. AB - Genetic and functional studies underscore the central role of JAK/STAT signaling in myeloproliferative neoplasms (MPNs). However, the mechanisms that mediate transformation in MPNs are not fully delineated, and clinically utilized JAK inhibitors have limited ability to reduce disease burden or reverse myelofibrosis. Here we show that MPN progenitor cells are characterized by marked alterations in gene regulation through differential enhancer utilization, and identify nuclear factor kappaB (NF-kappaB) signaling as a key pathway activated in malignant and non-malignant cells in MPN. Inhibition of BET bromodomain proteins attenuated NF-kappaB signaling and reduced cytokine production in vivo. Most importantly, combined JAK/BET inhibition resulted in a marked reduction in the serum levels of inflammatory cytokines, reduced disease burden, and reversed bone marrow fibrosis in vivo. PMID- 29249694 TI - Objective, Quantitative, Data-Driven Assessment of Chemical Probes. AB - Chemical probes are essential tools for understanding biological systems and for target validation, yet selecting probes for biomedical research is rarely based on objective assessment of all potential compounds. Here, we describe the Probe Miner: Chemical Probes Objective Assessment resource, capitalizing on the plethora of public medicinal chemistry data to empower quantitative, objective, data-driven evaluation of chemical probes. We assess >1.8 million compounds for their suitability as chemical tools against 2,220 human targets and dissect the biases and limitations encountered. Probe Miner represents a valuable resource to aid the identification of potential chemical probes, particularly when used alongside expert curation. PMID- 29249697 TI - Editors' Note. PMID- 29249696 TI - Superhuman AI for heads-up no-limit poker: Libratus beats top professionals. AB - No-limit Texas hold'em is the most popular form of poker. Despite artificial intelligence (AI) successes in perfect-information games, the private information and massive game tree have made no-limit poker difficult to tackle. We present Libratus, an AI that, in a 120,000-hand competition, defeated four top human specialist professionals in heads-up no-limit Texas hold'em, the leading benchmark and long-standing challenge problem in imperfect-information game solving. Our game-theoretic approach features application-independent techniques: an algorithm for computing a blueprint for the overall strategy, an algorithm that fleshes out the details of the strategy for subgames that are reached during play, and a self-improver algorithm that fixes potential weaknesses that opponents have identified in the blueprint strategy. PMID- 29249692 TI - beta2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. AB - Catecholamines stimulate epithelial proliferation, but the role of sympathetic nerve signaling in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Catecholamines promoted ADRB2-dependent PDAC development, nerve growth factor (NGF) secretion, and pancreatic nerve density. Pancreatic Ngf overexpression accelerated tumor development in LSL-Kras+/G12D;Pdx1-Cre (KC) mice. ADRB2 blockade together with gemcitabine reduced NGF expression and nerve density, and increased survival of LSL-Kras+/G12D;LSL-Trp53+/R172H;Pdx1-Cre (KPC) mice. Therapy with a Trk inhibitor together with gemcitabine also increased survival of KPC mice. Analysis of PDAC patient cohorts revealed a correlation between brain derived neurotrophic factor (BDNF) expression, nerve density, and increased survival of patients on nonselective beta-blockers. These findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation. PMID- 29249698 TI - Rupture. PMID- 29249699 TI - The Two Longest Minutes. PMID- 29249695 TI - GDC-0879, a BRAFV600E Inhibitor, Protects Kidney Podocytes from Death. AB - Progressive kidney diseases affect approximately 500 million people worldwide. Podocytes are terminally differentiated cells of the kidney filter, the loss of which leads to disease progression and kidney failure. To date, there are no therapies to promote podocyte survival. Drug repurposing may therefore help accelerate the development of cures in an area of tremendous unmet need. In a newly developed high-throughput screening assay of podocyte viability, we identified the BRAFV600E inhibitor GDC-0879 and the adenylate cyclase agonist forskolin as podocyte-survival-promoting compounds. GDC-0879 protects podocytes from injury through paradoxical activation of the MEK/ERK pathway. Forskolin promotes podocyte survival by attenuating protein biosynthesis. Importantly, GDC 0879 and forskolin are shown to promote podocyte survival against an array of cellular stressors. This work reveals new therapeutic targets for much needed podocyte-protective therapies and provides insights into the use of GDC-0879-like molecules for the treatment of progressive kidney diseases. PMID- 29249700 TI - Introduction. AB - This symposium includes twelve personal, heartfelt narratives about joys, challenges, and, in some cases, trauma associated with labor and delivery experiences. This issue also includes three commentaries on these narratives by 1.) Raymond De Vries, PhD, 2.) Anne Lyerly, MD, MA, 3.) Jason Wasserman, PhD and Nicole Wasserman, MPH. This issue can provide information for clinicians and support staff on ways to facilitate patient and family engagement during this emotionally-laden time for parents. Supporting birth experiences, connecting with patients, involving them in decisions, and recognizing the disappointment and distress that can arise when complications abound may play a part in reducing postpartum mood disorders and improving maternal and infant health outcomes. PMID- 29249701 TI - From Natural to Medicalized: My Experience Moving From an Unmedicated Labor to a C-Section Delivery under General Anesthesia. PMID- 29249702 TI - Narrative Symposium: Challenges With Care During Labor and Delivery. PMID- 29249703 TI - A Tale of Two Labors. PMID- 29249704 TI - The Medicaid Prejudice. PMID- 29249705 TI - What If?: A Story of an Unwanted Medicalized Birth. PMID- 29249706 TI - Lessons Learned from 78 Long Days in the NICU. PMID- 29249707 TI - A Good Coach is Hard to Find: In Search of Supportive Maternity Care. PMID- 29249708 TI - Missing Plan B: An Unexpectedly Complicated Labor and Delivery. PMID- 29249710 TI - Eternally Grateful. PMID- 29249709 TI - Learning the Hard Way: Lessons on Gender and Power. PMID- 29249711 TI - Definitely Not a Home Water Birth: 83 Days Awaiting Twins on an Antenatal Unit. PMID- 29249712 TI - Premature Birth and Neglected Maternal Mental Health. PMID- 29249713 TI - The Million Dollar Cesarean. PMID- 29249714 TI - Obstetric Ethics and the Invisible Mother. AB - These mother-told stories of birth, describing disrespectful and harmful care, make the invisibility of birthing women visible. The concerns and needs of women in labor fade in the face of hospital policies and the perceived needs of their soon-to-be-born babies. Bioethics contributes to this lack of regard for mothers by framing the moral problems of birth in terms of maternal-fetal conflict, where the autonomy of the mother is weighed against the obligation of beneficence to the baby. Replacing the principlist commitment to autonomy with respect-an obligation that does not compete with beneficence-is a first step toward correcting the problems in care identified here. PMID- 29249715 TI - Of Pain and Childbirth. AB - Childbirth is often understood as a paradigmatically "happy" event where good outcomes are expected and the process anticipated as a reason for celebration. Yet the narratives in this volume reflect sadness and grief, even when a healthy child is born. In this essay, I interrogate the genesis of and our relationship to grief in birth. To the extent such grief is a product of the chasm between the imagined ideal and what women experience, we may redress such grief by orienting around a more robust and woman-centered notion of the "good birth". Yet there is a way in which grief is also intrinsic to birth, and turning away from the loss that birth by its nature entails may compound the suffering of childbearing women. Beginning with the observation that the one narrative in which grief is accepted and attended to-a full term stillbirth-also stands out for the exemplary care provided, I consider the possibility that making space for grief in births, including those with good outcomes, will lead us to better ways of thinking about birth and providing care for childbearing women. PMID- 29249716 TI - Making Sense of Everett's Arrival: A Commentary on the Power of Birth Narratives. AB - The birth of our daughter nearly 5 years ago went very well. But in a new city, with some experience on our side and access to a homelike natural birth center connected to a major area hospital, we thought it would be all the better when our son was born. We hadn't dreamed that the detection of a benign arrhythmia in the baby's heart would cascade into a situation that would not only undermine our entire birth plan, but force unwanted treatment and threats of abandonment. In this commentary, our intention is to illustrate the way in which narratives, and the commonalities between the stories shared by other authors in this issue and our own, can give profound depth and new insights into the things that happen to us. PMID- 29249717 TI - Education and Reproductive Autonomy: The Case of Married Nigerian Women. AB - In this article, we examine the influence of education on the exercise of married women's reproductive autonomy. We carried out 34 in-depth interviews (IDIs) with purposively sampled married Ikwerre women in Rivers State, Nigeria. The participants were between the ages of 22 and 60, had different educational backgrounds, and were in monogamous and polygynous marriages. Data were analyzed using MAXQDA 11 software. We found that although formal education enhanced women's ability to exercise reproductive autonomy, the culture of demanding absolute respect for men remains a major barrier. Formal education provides women with the knowledge that they need in order to access adequate health services for themselves and their children. Participants also believed that educating men was critical for the exercise of women's reproductive autonomy. The cultural aspects that promote female subordination and patriarchy should be addressed more openly in Nigeria. PMID- 29249718 TI - Screen Shots: When Patients and Families Publish Negative Health Care Narratives Online. AB - Social media sites and their relationship to health care is a subject of intense debate. Common discussions regarding social media address patient privacy, or e professionalism. This case study explores the tensions that arise for health care providers when negative patient statements surface in social media and blog forums. Recognizing that patients and families often find relief in sharing personal illness narratives, we contemplate if, and how, individual health care professionals and institutions should address complaints aired in public, unmoderated media. Our discussion begins by presenting a case of a family blogging on the Internet to share grievances (to deidentify the case, we have changed some details). Next, we offer an exploration of the impact on health care delivery when professionals become aware of specific criticisms published online. Strategies for managing electronic criticisms are then proposed. We conclude by proposing a novel E-THICS approach to address negative patient expressions via electronic word of mouth (eWOM). Our examination of this evolving issue focuses on maintaining satisfactory relationships between health care providers and patients/families when dealing with health care narratives published in open online media. PMID- 29249719 TI - The Social Construction of Imported Technologies: Reflections on the Social History of Technology in Modern Korea. AB - Can imported technologies be socially constructed? Starting from this puzzling question, this essay reflects on the various methodologies with which one can narrate the stories of technology in modern Korea. A focus on technological innovations and how they have been shaped by their societal milieu forces one to leave out a large part of the technological experience, especially when the bulk of the technologies-in-use have been imported from abroad. This poses a serious problem for the history of technology in Korea, a nation that relied heavily on foreign technologies as it went through rapid economic growth in the latter twentieth century. PMID- 29249720 TI - Superpower Underground: Switzerland's Rise to Global Bunker Expertise in the Atomic Age. AB - In the 1960s Switzerland started to build the world's largest system of civil defense shelters. Ever since, the tiny country has represented the gold standard for bunker design and technology, attracting worldwide interest amongst scientists, political elites, and private consumers. This essay examines the development, forms, and global reach of Swiss bunker expertise. It emphasizes the knowledge transfer and the networks of cooperation with West Germany and the United States upon which the career of Swiss bunker research was founded. At the same time, attention is drawn to the translation processes by which knowledge was locally adapted and technoscientific expertise was gained, strategically diffused, and marketed, thereby securing Swiss predominance in the field. In sum, the present study of Swiss bunker expertise showcases the often-ridiculed civil defense programs of the atomic age as a fertile ground for historians of cold war science and technology, allowing us to reveal a whole range of relevant and detailed engagements with nuclear practices and technology apart from completed atomic bombs. The essay also makes a case for exploring cold war scientific and technological achievements in a transnational frame while not losing sight of local conditions, national and economic interests, and narratives. PMID- 29249721 TI - Learning to File: Reconfiguring Information and Information Work in the Early Twentieth Century. AB - This article uses textbooks and advertisements to explore the formal and informal ways in which people were introduced to vertical filing in the early twentieth century. Through the privileging of "system" an ideal mode of paperwork emerged in which a clerk could "grasp" information simply by hand without having to understand or comprehend its content. A file clerk's hands and fingers became central to the representation and teaching of filing. In this way, filing offered an example of a distinctly modern form of information work. Filing textbooks sought to enhance dexterity as the rapid handling of paper came to represent information as something that existed in discrete units, in bits that could be easily extracted. Advertisements represented this mode of information work in its ideal form when they frequently erased the worker or reduced him or her to hands, as "instant" filing became "automatic" filing, with the filing cabinet presented as a machine. PMID- 29249722 TI - Seismic Politics: Risk and Reconstruction after the 1960 Earthquake in Agadir, Morocco. AB - On 29 February 1960, an earthquake struck the city of Agadir, Morocco, killing between ten and fifteen thousand Moroccans and Europeans and damaging the majority of the city's structures. Drawing on data from seismographs, witness accounts, and direct observations of destruction, international teams of experts working in the aftermath of the disaster rewrote Agadir as a seismically vulnerable space. In the process, they depoliticized destruction and assigned responsibility for the devastation of the city's poorest neighborhoods to "natural" forces and ineffective "traditional" building practices. Once established in the work of geologists, seismologists, and engineers, the notion of seismic risk shaped the material and moral trajectories of reconstruction during the first decade of Morocco's independence from France. As it cut across scientific, engineering, and bureaucratic domains, seismic risk gave rise to projects aimed less at controlling nature than at redistributing vulnerability and authority among experts, administrators, and inhabitants in Agadir. PMID- 29249723 TI - Medical Machines as Symbols of Science?: Promoting Electrotherapy in Victorian Canada. AB - This article tackles a common assumption in the historiography of medical technology, that new medical instruments in the nineteenth century were universally seen as symbols of the scientific nature of medical practice. The article examines the strategies used by Jenny Trout, the first woman in Canada licensed to practice medicine, and J. Adams, a homeopathic physician, to advertise electrotherapy to the residents of Toronto in the 1870s and 1880s. While electrotherapy involved complex electrical technology, the doctors in this study did not draw attention to their instruments as proof of the legitimacy of their practice. In fact the technology is almost entirely absent from their promotional texts. While both doctors wanted their practice to be associated with scientific medicine, neither saw their instruments as immediately or obviously symbolic of science. PMID- 29249724 TI - Glassmaking Goes Public: The Cultural Background to Antonio Neri's L'Arte Vetraria (1612). AB - Glassmaking has prospered as an art since the late Middle Ages. It is therefore surprising that the first systematic treatise exclusively devoted to it appeared as late as 1612. In this article I explore the experimental background of Antonio Neri's L'Arte Vetraria, and its intimate connection with an ancient alchemical tradition and with more contemporary efforts to introduce technical innovations. Furthermore, the active role played by Antonio Neri, a clergyman and alchemist in the service of Antonio de' Medici, sheds new light on the patronage of the Medici court. This article aims at contextualizing Neri's book within the Florentine tradition of glassmaking and, above all, within Francesco I de Medici's alchemical interests in this art. Finally, the almost contemporary publication of Galileo's Sidereus Nuncius and Neri's L'Arte Vetraria raises the question of the role played by alchemists like Neri and by Florentine glassmakers in the making of optical instruments. PMID- 29249725 TI - To the Editor. PMID- 29249726 TI - Volume 58 (2017). PMID- 29249727 TI - Expression, purification, and biological characterization of Anaplasma phagocytophilum enolase. AB - The obligate intracellular bacteria Anaplasma phagocytophilum is the etiological agent of human granulocytic anaplasmosis (HGA), an acute febrile tick-borne disease. A. phagocytophilum has a complex lifecycle within both vertebrate reservoirs and tick vectors, and employs a range of different molecules to infect and multiply within the host cells. Enolase is an essential glycolytic enzyme in intracellular glucose metabolism, but is also a multifunctional protein expressed on the pathogen surface, that binds to and promotes plasminogen conversion to plasmin. In this study, we generated recombinant ApEno protein (rApEno), and confirmed that rApEno retains its enzymatic activity. Furthermore, we demonstrated that rApEno binds to human plasminogen, and that this binding could be significantly reduced in the presence of lysine analogs (epsilon-aminocaproic acid). Additionally, rApEno promotes plasminogen to plasmin conversion in the presence of plasminogen activator. In conclusion, A. phagocytophilum enolase is a multifunctional protein which can catalyze the dehydration of 2-phospho-D glycerate to phosphoenolpyruvate, and facilitate binding to host plasminogen. PMID- 29249729 TI - Bilateral anterior segment dysgenesis with the presumed Peters' anomaly in a cat. AB - A seven-month-old female domestic shorthaired cat was presented for buphthalmos in the right eye and corneal cloudiness in the left eye. Full ophthalmic examinations were performed for both eyes and enucleation was done for the right nonvisual eye. Congenital glaucoma caused by anterior segment dysgenesis was confirmed for the right eye. In the left eye, slit-lamp examination revealed focal corneal edema with several iris strands from iris collarette to the affected posterior corneal surfaces. Circular posterior corneal defect was suggested to be the cause of edema. Goniodysgenesis, additionally, was identified. Taken together, the diagnosis of Peters' anomaly which is a subtype of anterior segment dysgenesis was suggested in the left eye. PMID- 29249730 TI - Serological and molecular surveys of Babesia bovis and Babesia bigemina among native cattle and cattle imported from Thailand in Hue, Vietnam. AB - Serum and DNA from blood samples collected from Vietnamese yellow cattle (n=101) and cattle imported from Thailand (n=54) at a Vietnamese slaughter house were screened for Babesia bovis and Babesia bigemina infections by enzyme-linked immunosorbent assay (ELISA) and PCR. The positive rates determined by ELISA (B. bovis and B. bigemina) or PCR (B. bigemina) in the Vietnamese cattle were significantly higher than those found in Thai cattle. Some PCR-positive Vietnamese animals were ELISA-negative, whereas all PCR-positive Thai cattle were ELISA-positive, suggesting that the animals were infected in Thailand. Importing Babesia-infected cattle may lead to the introduction of new parasite strains, possibly compromising the development of anti-Babesia immune control strategies in Vietnam. PMID- 29249728 TI - Characterization of four Escherichia albertii isolates collected from animals living in Antarctica and Patagonia. AB - Escherichia albertii is a recently discovered species with a limited number of well characterized strains. The aim of this study was to characterize four of the E. albertii strains, which were among 41 identified Escherichia strains isolated from the feces of living animals on James Ross Island, Antarctica, and Isla Magdalena, Patagonia. Sequencing of 16S rDNA, automated ribotyping, and rep-PCR were used to identify the four E. albertii isolates. Phylogenetic analyses based on multi-locus sequence typing showed these isolates to be genetically most similar to the members of E. albertii phylogroup G3. These isolates encoded several virulence factors including those, which are characteristic of E. albertii (cytolethal distending toxin and intimin) as well as bacteriocin determinants that typically have a very low prevalence in E. coli strains (D, E7). Moreover, E. albertii protein extracts caused cell cycle arrest in human cell line A375, probably because of cytolethal distending toxin activity. PMID- 29249732 TI - Histological Chorioamnionitis as a Risk Factor for Preterm Birth without Disturbing Fetal Heart Rate: A Case-Control Study. AB - Histological chorioamnionitis (CAM) is one form of intrauterine inflammation that is often seen in cases of preterm birth and are usually confirmed based on pathological examination after delivery. Histological CAM is related to significant neonatal morbidity and mortality; however, its etiology is unknown. The objective of this study was to determine the risk factors for histological CAM, using medical background, including fetal heart rate (FHR) patterns in preterm birth cases. The preterm birth cases delivered between 28 and 36 weeks were categorized into two groups according to the presence of histological CAM. Ninety-five preterm infants were included: 48 infants without histological CAM and 47 cases with histological CAM. The odds ratio for histological CAM was adjusted for FHR patterns, gestational age, and delivery mode (vaginal delivery or Caesarean section). Logistic regression analysis showed that vaginal delivery and gestational age were associated with histological CAM (odds Ratio [OR]: 3.1, 95% confidence interval [CI]: 1.0-9.4, p < 0.05, and OR: 0.8, 95% CI: 0.6-0.9, p < 0.05, respectively). However, there were no specific FHR patterns associated with histological CAM. Our study indicates that in preterm birth cases, histological CAM is not related to any specific FHR pattern. However, labor uterine contraction and immature gestational age at the delivery are related to histological CAM. These results may provide better delivery management methods for preterm birth cases. PMID- 29249731 TI - Histochemical properties of bovine and ovine mammary glands during fetal development. AB - In order to obtain more information on the development of bovine and ovine fetal mammary glands, a series of mammary glands from fetuses of different ages were analyzed. A total of 16 bovine fetuses with curved crown rump lengths ranging from 12 cm (80 days) to 75 cm (240 days) and 15 ovine fetuses ranging from 55 days to 131 days were examined. We used hematoxylin and eosin stain and Oil-Red-O stain to analyze the developmental and morphogenetic processes of mammary glands. In addition, we used immunohistochemical staining to determine the pattern of expression of cytokeratin 18 (CK18) during luminal epithelial differentiation, alpha-smooth-muscle actin (alpha-SMA) for myoepithelial differentiation, Ki-67 for cell proliferation, and estrogen receptor alpha (ERalpha). Our analyzes showed: (a) The primary mammary duct begin to proliferate in a lengthwise within the teat at 90 days in bovine fetuses and 63 days in ovine fetus; (b) luminal epithelial cells and myoepithelial cells appeared from 90 days in bovine fetuses and 63 days in ovine fetus; (c) proliferation of epithelial cells appeared to coincide with the development of the primary and secondary ducts; and (d) ERalpha was not found in the fetal mammary gland, but adipocytes showed the presence of ERalpha. Overall, these results indicate that the sequence of events in the prenatal development of the mammary gland of sheep is similar to that of cattle. PMID- 29249733 TI - Variations in the course of the superior gluteal artery in relation to the lumbosacral plexus. AB - The course of the superior gluteal artery (SGA) as it passes through the lumbosacral plexus is variable. The variations of the arterial course in relation to the lumbosacral plexus have focused on statistical analysis, and it is limited arterial diversity. In this study, we investigated the positional relation between the SGA and the furcal nerve (FN): guide to segmentation of the lumbosacral plexus, arising from the L4, ie, the contribution to the femoral nerve, obturator nerve, and lumbosacral trunk. We could classify the pathway of the SGA into three types based on its positional relation to the FN. The SGA courses under the ramus from which the FN originates (Type A), under the ramus one segment below the origin of the FN (Type B), or between the obturator nerve and the lumbosacral trunk (Type C). The SGA pathway in Types A and B showed a cranial or caudal shift along with cranial or caudal deviation of the FN. In summary, the variation in the SGA pathway was correlated with cranial or caudal shift of the FN. Our findings indicate that variations of the SGA pathway are associated not only with arterial transformation, but also with diversity of the lumbosacral plexus. PMID- 29249734 TI - Morphology of the lingual papillae of the polar bear (Ursus maritimus). AB - We examined the dorsal lingual surfaces of a newborn and an old polar bears by using scanning electron microscopy. In the newborn polar bear, the filiform papilla on the lingual apex was cylindrical in shape. The connective tissue core of the filiform papillae was needle-shaped and that of the fungiform papillae was funnel-shaped. The filiform papillae on the lingual body was dome-shaped. The connective tissue core of the filiform papillae was U-shaped and that of the fungiform papillae was column-shaped. On the lingual apex and body, there could not distinguish the filiform from fungiform papillae. The connective tissue core of the filiform papilla was different from the fungiform papilla. The vallate papillae were surrounded by a groove and pad and the surface was smooth. In the old bear, the filiform papilla on the lingual apex had several pointed processes. The processes of the filiform papilla on the lingual body were larger than those of the lingual apex. The vallate papillae were surrounded by a groove and pad and the surface was rough. There are no foliate papillae. PMID- 29249735 TI - Longitudinal observation of maxillary sinus bony bridges and septa in childhood. AB - The rate of septum presence in the maxillary sinus has been reported to be over 30%. It was considered that a bony bridge might change to a maxillary sinus septum with growth in a previous study using dry child skulls. In the present investigation, maxillary sinus bony bridges and septa were longitudinally observed using computed tomography (CT). Multislice CT was performed in three patients. A bony bridge was defined as a bony structure between the maxillary sinus wall and dental germ. Also, a septum was defined as a pointed bony structure in the inferior wall of the maxillary sinus. The height and angle of the bony bridge/septum and the distance between the base of the bony bridge/septum and bony palate were measured. In three patients, the bony bridge in the maxillary sinus floor was observed in the second molar on the first CT, and the maxillary sinus septum was observed on the second CT at the same site. In conclusion, it was longitudinally observed that a bony bridge changed to a maxillary sinus septum with growth, such as root formation and tooth eruption. PMID- 29249736 TI - The palatomaxillary suture revisited: A histological and immunohistochemical study using human fetuses. AB - In human fetuses, the palatine process of the maxilla is attached to the inferior aspect of the horizontal plate of the palatine bone (HPPB). The fetal palatomaxillary suture is so long that it extends along the anteroposterior axis rather than along the transverse axis. The double layered bony palate disappears in childhood and the transverse suture is formed. To better understand the development of the double layered bone palate, we examined histological sections obtained from 25 fetuses of gestational age 9-11, 16-18 and 30 weeks. The double layered palate was seen in all of the specimens examined. Inferior angulation of the posterior end of the HPPB was evident at 9-11 weeks, but the initial palatine aponeurosis did not attach to the angulation but to a slightly anterior site. Both the maxilla and the HPPB were tightly attached to the vomer at 16-18 weeks. In both bones, bilateral plates met at the midline. The palatomaxillary suture was filled with short, randomly arranged collagen fibers. The nasal end of the suture was covered by a tight periosteum. Immunohistochemical examination of 3 fetuses at 16-18 weeks showed: 1) no expression of versican, tenascin-c or type II collagen in the suture; 2) few mitotic cells positive for proliferating cell nuclear antigen; 3) no or few CD34-positive developing vessels; and 4) no CD68 positive macrophages. These findings suggested that the fetal palatomaxillary suture was inactive for reconstruction and growth and that soft palate muscles likely did not contribute to the development of the double layered configuration. PMID- 29249737 TI - Evidence of Pulmonary Vascular Reverse Remodeling After Pulmonary Artery Banding Performed in Early Infancy in Patients With Congenital Heart Defects. AB - BACKGROUND: Histomorphometric evidence of the effect of pulmonary artery banding (PAB) in infancy on pulmonary vascular reverse remodeling has not been fully described.Methods and Results:We retrospectively reviewed 34 patients who underwent serial lung biopsies before and after PAB.Index of pulmonary vascular disease (IPVD) as a measure of the degree of progression of pulmonary arteriopathy significantly decreased after PAB (1.22+/-0.25 at 1st and 1.13+/ 0.21 at 2nd biopsy, P=0.04). Additionally,DR=100 umas an indicator of medial thickness of pulmonary arteries significantly decreased after PAB (15.6+/-3.7 at 1st and 11.4+/-2.6 at 2nd biopsy, P<0.0001). Patients were divided into 3 groups by age at PAB: <3 months (Group 1), between 3 and 6 months (Group 2), and >6 months (Group 3). The average secondDR=100 umof groups 1 and 2 was significantly lower than that of group 3 (11.1+/-2.2 and 9.8+/-2.0 vs. 14.9+/-2.8, respectively; P<0.0001). Additionally, the second IPVD was also significantly lower in groups 1 and 2 than in group 3 (1.1+/-0.2 and 1.1+/-0.2 vs. 1.3+/-0.4, respectively; P=0.02). CONCLUSIONS: Histomorphometric evidence of post-PAB pulmonary vascular reverse remodeling is robust. The magnitude of vascular reversibility is pronounced when PAB is performed before 6 months of age. PMID- 29249738 TI - Factors Contributing to the Self-Reported Prevalence of Multiple Chemical Sensitivity in Public Facility Workers and the General Population of Korea. AB - Multiple chemical sensitivity (MCS), an acquired disorder with multiple recurrent symptoms, has been studied for its association with diverse environmental factors. The present study investigated the factors associated with the self reported prevalence of MCS in public facility workers and the general population in Korea. The Quick Environmental Exposure Sensitivity Inventory (QEESI) questionnaire was obtained from public facility workers (N=530) and the general population (N=500) to determine the prevalence of MCS and the degree of its risk. Information about demographic characteristics, subjective perceptions of sick building syndrome or sick house syndrome or allergy (SBS/SHS/Allergy), and certain home- or workplace-related events were also obtained. There was not a statistical difference between the public facility workers and the general population in the QEESI scores. The overall prevalence of MCS was 14.4% and there was no statistical difference between the two groups. Regarding the overall degree of risk of MCS, 21.8% of the study subjects were categorized as "very suggestive", and there was no significant difference between the two groups. Gender and the subjective perception of SBS/SHS/Allergy significantly affected the prevalence of MCS and the MCS risk criteria. Considering the absence of diagnostic criteria and/or treatment methods for MCS in Korea, these results can be utilized in establishing future strategies to manage MCS. PMID- 29249739 TI - Feelings about Nursing Assistants that Enhance the Work Motivation of Japanese Registered Nurses and Licensed Practical Nurses. AB - Registered nurses and licensed practical nurses have received professional education, but to enhance their work motivation it is necessary to create work environments in which they can concentrate on their jobs as specialists. One of the methods to develop such work environments is to use nursing assistants effectively. We investigated professional nurses' feelings toward nursing assistants and then examined the associations between those feelings and their work motivation. The analyzed subjects were 2,170 female nurses working in 25 hospitals with from 55 to 458 beds. The average age of the respondents was 38.0 (standard deviation, 10.6 years). Factor analyses extracted four factors of professional nurses' feelings toward nursing assistants: 1. knowledge related to healthcare, 2. nursing assistants' attitudes toward work, 3. human relations, and 4. distinguishing between professional nurses' work and nursing assistants' work. Using multiple linear regression analysis, our results revealed that scores of maintaining a high motivation to work thanks to nursing assistants became lower as the ages of the respondents increased. Scores of maintaining a high motivation to work thanks to nursing assistants became higher as professional nurses gained satisfaction from: knowledge related to healthcare, nursing assistants' attitudes toward work, and human relations. Hospital managers should consider these findings to improve working environments in which professional nurses can feel motivated to work. PMID- 29249740 TI - A Case of Infectious Enterocolitis with Hyperammonemia. AB - Case reports of hyperammonemia due to urease-producing bacteria are found occasionally, but most of them are associated with urinary tract infections. We experienced a case of infectious enterocolitis with hyperammonemia in which the causative bacteria was speculated to be urease-producing bacteria. A Japanese woman in her 70s had been diagnosed with microscopic polyangiitis in a nearby hospital and was transferred to our hospital. Although the microscopic polyangiitis was relatively under control after treatment with steroids and rituximab, frequent diarrhea with hyperammonemia (324 ug/dl) appeared and she became comatose. Her blood ammonia decreased to 47 ug/dl and her consciousness recovered to a normal state after antibiotic treatment for infectious enterocolitis and ammonia detoxification therapy. Liver dysfunction, portosystemic shunt, excessive protein intake and constipation were not observed, and she took no medications that would cause hyperammonemia. Although culture results could not identify urease-producing bacteria, considering the clinical course, acute hyperammonemia was suspected to be due to urease-producing bacteria infection. It is necessary to consider the influence of urease-producing bacteria as a cause of acute hyperammonemia not only in urinary tract infections but also in infective enterocolitis. PMID- 29249741 TI - [A Survey about the Radiation Effects and A Health Survey of Fukushima Inhabitants after the Fukushima Daiichi Nuclear Power Plant Accident]. AB - According to questionnaire surveys in 2011 and 2013 about the health effects of radiation after the Fukushima Daiichi Nuclear Power Plant Accident, the guardians of child patients were more anxious than doctors and medical students. Also, according to the thyroid examinations in a Fukushima health survey, 190 cases of thyroid cancer were reported, and anxiety about radiation effects remained. This study is based on a survey about the guardians of child patients anxiety about radiation effects six years after the nuclear power plant accident, and includes a questionnaire survey about radiation effects and thyroid examinations in a Fukushima health survey. Anonymous question sheets with 20 questions were sent to pediatric medical facilities in Fukushima, and the parents of children who consulted the pediatric and medical staff answered the questionnaire. Thirty percent of the guardians of child patients had never been educated about radiation and 67% had never been educated about the effects of radiation on humans. The guardians of child patients were more anxious than the medical staff about thyroid cancer, health effects on children and genetic effects. Our results indicate that the guardians of child patients think that the increase in the incidence of thyroid cancer is due to radiation effects after the nuclear power plant accident and they desire continued thyroid examinations. PMID- 29249742 TI - [Analysis of Advanced or Postoperative Recurrent Non-small Lung Cancer Cases Treated with Nivolumab]. AB - Recent developments in cancer immunotherapy are remarkable. Many reports have described the clinical effects of immune checkpoint inhibitors (ICIs), supporting their utility as a promising therapy that will achieve prominent effects even in patients resistant to cytotoxic anticancer drugs or gene-targeting therapy. ICIs may also prolong overall survival. We analyzed 10 cases of advanced lung cancer targeted with nivolumab, which is one of ICIs in our hospital and reviewed the literature regarding ICIs. We retrospectively analyzed 10 cases that consisted of 6 males and 4 females, which comprised 7 adenocarcinomas, 2 squamous cell carcinomas and one pleomorphic carcinoma. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase mutations were negative in all the adenocarcinoma cases. The 10 analyzed cases included 9 inoperable cases and 1 postoperative recurrent case, 8 second-line cases, a third-line case, and a fourth-line case. The average frequency of administrations of nivolumab was 7.4 times. The survival rate was calculated by using the Kaplan-Meier method. The clinical responses to nivolumab were partial response in 2 cases, stable disease in 4 cases, and progressive disease in 4 cases. In the 10 cases, the response rate and disease control rate were 20% and 60%, respectively. The median progression-free survival time and median survival time were 115 days and 126 days, respectively. We observed 2 cases of dermatitis and one each of pyrexia, general fatigue and drug induced pneumonia as adverse events (AEs). One of these AEs was severe (Stevens Johnson syndrome grade 4) but could be treated by steroid pulse therapy, steroid ointment and instillation. Among the 10 examined cases of advanced lung cancer treated with ICIs at our hospital, ICIs proved effective in 2 cases. However, we also experienced a case with Stevens-Johnson syndrome grade 4 as a severe AE. These findings suggest that while ICIs may be effective in treating patients, candidates for ICIs must be carefully selected and cautiously observed. PMID- 29249743 TI - [The Role of Mid-Career Nurses in Educating New Nurses: from the Perspective of Self-Efficacy]. AB - This study sought to clarify the relationship between the educational role behavior of mid-career nurses toward new nurses, and their sense of self efficacy. Educational role behaviors of mid-career nurses toward new nurses were set to 13 items related to career ladder and previous researches. To identify the relationship between the sense of self-efficacy in mid-career nurses and performing these 13 behaviors in their educational role toward new nurses, we had 310 mid-career nurses complete a questionnaire survey and analyzed the resulting data using Spearman's rank correlation coefficient, Mann-Whitney U test, and Kruskal-Wallis test. We found that mid-career nurses who had served as preceptors (senior nurses who teach practical nursing skills to new nurses on a one-on-one basis) four or more times had a significantly higher sense of self-efficacy than those who had served as preceptors three times or less for four behaviors only (1. demonstrating specific methods when instructing new nurses on various support methods, 7. being receptive to new nurses, 11. striving for professional self improvement in practical nursing as a mid-career nurse, and 12. co-ordinating interpersonal relationships in the organization). No relationships were observed between the total number of years of nursing experience and the number of years of working at the station concerned. For all 13 educational role behaviors, Spearman's rank correlation coefficients of 0.5-0.7 indicated a significant relationship between implementation of the educational role behavior and a sense of self-efficacy. We believe that the high sense of self-efficacy that results from the performance of the 13 behaviors by mid-career nurses in their role of teaching new nurses leads them to demonstrate these behaviors in their everyday practice. It was also found that experience alone did not mean that mid-career nurses could adopt educational role behaviors with little burden, suggesting that support is universally necessary, regardless of experience. PMID- 29249744 TI - [A Successful Case of Tracheal Segmental Resection and Reconstruction for Cicatricial Tracheal Stenosis]. AB - A 45-year-old man had consciousness disorder due to fall trauma had received ventilation support and tracheostomy. Two months later, the tracheostomy tube was removed. One year later, he suffered from severe cicatricial tracheal stenosis. Under a diagnosis of post-intubation tracheal stenosis, he underwent circumferential resection and end-to-end anastomosis of the trachea. The central part of the resected trachea of 3 cartilage rings showed a stenosis like a pin hole. The post operative course was uneventful, and there was no stenosis or sutural insufficiency on examination by bronchoscopy. Tracheal resection and reconstruction is rare but effective for refractory tracheal stenosis. PMID- 29249747 TI - Oral immunization with recombinant protein antigen expressed in tobacco against fish nervous necrosis virus. AB - Nervous necrosis virus (NNV), also known as betanodavirus, has been recently implicated in mass mortalities of cultured marine fish. An effective vaccine is urgently needed to protect fish against this virus. However, parenteral immunization methods are very stressful. Individual immunization for thousands of fish is very labor intensive and expensive. Therefore, we expressed NNV coat protein in tobacco chloroplasts and used it as an oral vaccine to induce immunities in fish followed by challenges with NNV. Our results revealed that mice (IgG and IgA) and fish (IgM) immunized with the oral vaccine developed significantly higher antibody titers against the NNV coat protein. Fish were partially protected against viral challenge. Taken together, our results demonstrated that a plant-based vaccine could effectively induce immune response and protect groupers against NNV. The present method could be used to develop oral fish vaccine in the future. PMID- 29249748 TI - Blood biochemistry and hematological changes in rats after administration of a mixture of three anesthetic agents. AB - Currently, given the concerns regarding animal welfare, it is required that anesthesia or analgesia be used during surgery in experimental animals. Therefore, it is important to understand how anesthesia affects the health conditions of experimental animals. In this study, rat blood biochemistry and hematological changes were examined following administration of a mixture of three anesthetic agents-medetomidine, midazolam and butorphanol (MMB). One of three MMB dose combinations was subcutaneously administered to rats. After 1 hr, rats were treated with atipamezole, to reverse the anesthetic effects. Blood biochemistry and hematological parameters were assessed at 1, 4 and 24 hr post MMB treatment. We also recorded body weight and food intake at 0, 2, 4, 6 and 24 hr post-MMB administration. Following MMB administration, transient increases were observed in glucose (GLUC) levels, hematocrit (HCT) values and hemoglobin (HGB) levels, whereas transient decreases were observed in total protein (TP) content and white blood cell (WBC) counts. Most of these parameters returned to control values 24 hr following MMB administration. Additionally, body weight and food intake decreased in MMB-treated rats. In conclusion, intermediate and high doses of MMB changed some blood biochemistry and hematological parameters, body weight and food intake. In contrast, low-dose MMB did not cause these effects. Therefore, depending on the experimental design, MMB may influence the results of studies that use laboratory animals. Consequently, anesthetic agents used in laboratory animals should be chosen based on detailed knowledge of their pharmacological effects. PMID- 29249749 TI - Imidazole-induced contractions in bovine tracheal smooth muscle are not dependent on the cAMP pathway. AB - The mechanism of imidazole-induced contraction on the bovine tracheal smooth muscle was investigated. Imidazole induced muscle contraction in a concentration dependent manner on bovine, porcine and guinea-pig tracheas, but not in rat or mouse. In bovine tracheas, imidazole was cumulatively applied and induced muscle tension and increasesd intracellular Ca2+ level in a concentration -dependent manner. Imidazole, even at 300 uM, the concentration at which maximum contractile response occurs, did not significantly increase in cAMP content relative to control. Atropine inhibited imidazole-induced contraction at a concentration- dependent manner and pretreatment of hemicholinium-3 almost abolished imidazole induced contraction. Conversely, pretreatment of tripelennamine, indomethacin or tetrodotoxin did not affect imidazole-induced contraction. Acetylcholine or eserine induced contraction in bovine, porcine, guinea pig, rat and mice trachea in a concentration-dependent manner. However, there was little difference in the rank order of maximum contraction of these agents. Imidazole-induced contraction was greater in bovine trachea compared to the other species tested. Further, cAMP did not appear to play a role in imidazole-induced contraction, suggesting other mechanisms, such as the release of endogenous acetylcholine. PMID- 29249751 TI - [ROLE AND TRAINING PLAN OF A NEW ALLERGY SPECIALIST; FROM A POINT OF VIEW OF PEDIATRICS]. PMID- 29249750 TI - Progranulin deficiency leads to prolonged persistence of macrophages, accompanied with myofiber hypertrophy in regenerating muscle. AB - Skeletal muscle has an ability to regenerate in response to injury due to the presence of satellite cells. Injury in skeletal muscle causes infiltration of pro inflammatory macrophages (M1 macrophages) to remove necrotic myofibers, followed by their differentiation into anti-inflammatory macrophages (M2 macrophages) to terminate the inflammation. Since both M1 and M2 macrophages play important roles, coordinated regulation of their kinetics is important to complete muscle regeneration successfully. Progranulin (PGRN) is a pluripotent growth factor, having a protective role against the inflamed tissue. In the central nervous system, PGRN regulates inflammation by inhibiting the activation of microglia. Here we used muscle injury model of PGRN-knockout (PGRN-KO) mice to elucidate whether it has a role in the kinetics of macrophages during muscle regeneration. We found the prolonged persistence of macrophages at the late phase of regeneration in PGRN-KO mice, and these macrophages were suggested to be M2 macrophages since this was accompanied with an increased CD206 expression. We also observed muscle hypertrophy in PGRN-KO mice at the late stage of muscle regeneration. Since M2 macrophages are known to have a role in maturation of myofibers, this muscle hypertrophy may be due to the presence of increased number of M2 macrophages. Our results suggest that PGRN plays a role in the regulation of kinetics of macrophages for the systemic progress of muscle regeneration. PMID- 29249752 TI - [THE ROLE ASSIGNMENT OF ENT CLINICIANS AS AN ALLERGOLOGIST]. PMID- 29249753 TI - [JAPANESE PEDIATRIC GUIDELINE FOR THE TREATMENT AND MANAGEMENT OF ASTHMA 2017 WHAT'S NEW IN JPGL 2017]. PMID- 29249754 TI - [AIRWAY MUCUS HYPERSECRETION AS A THERAPEUTIC TARGET OF ASTHMA]. PMID- 29249755 TI - [MOLECULAR MECHANISMS FOR CUTANEOUSLY SENSITIZED FOOD ALLERGY : EXPERIMENTAL EVIDENCES FOR DUAL ALLERGEN EXPOSURE HYPOTHESIS]. PMID- 29249756 TI - [A CASE OF PERTUSSIS IN ADULT THAT COULD BE DIAGNOSED BY DETECTION OF BORDETELLA PERTUSSIS FROM SPUTUM]. AB - Bordetella pertussis isolation by culture has low detection sensitivity for diagnosing pertussis; the diagnosis is confirmed by measuring serum anti pertussis toxin (anti-PT) or anti-filamentous hemagglutinin antibody titers, and by genetic testing (polymerase chain reaction/loop-mediated isothermal amplification). Isolation of B. pertussis in adults is difficult, resulting in a delayed diagnosis, as a delayed cough may present >=3 months after onset. Differentiation from bronchial asthma is also important. We encountered an adult patient in whom B. pertussis was isolated by culture who previously received rituximab for mucosa-associated lymphoid tissue (MALT) lymphoma and steroids for prolonged cough. No elevation of anti-PT antibody titers was observed in the patient. PMID- 29249757 TI - [FAMILIAL SUMMER-TYPE HYPERSENSITIVITY PNEUMONITIS INDUCED IN SUMMER AND WINTER AT THE WORK PLACE]. AB - We report two family members, a 64-year-old woman (patient 1) and her 37-year-old son (patient 2) diagnosed with summer-type hypersensitivity pneumonitis (SHP). Both patients had high serum titers of anti-Trichosporon asahii antibody. The patients lived in the same house and worked in the same barbershop. Patient 1 was diagnosed with SHP in the summer, and she reacted positively to the provocation test at the work place, but not in the house. Patient 2 was diagnosed with SHP in the winter. Generally, SHP develops and is diagnosed in the summer. The home environment is responsible for most cases of familial SHP. Therefore, our cases of familial SHP are unusual and may suggest that the clinical characteristics of SHP have changed, due to alterations in social and environmental conditions. PMID- 29249758 TI - [A CASE OF HYPERSENSITIVITY REACTION TO ENOKITAKE (FLAMMULINA VELUTIPES) INGESTION]. AB - We experienced a case of 10-year-old girl who developed hypersensitivity reactions after eating enokitake. The patient had food allergy to egg until 5 years old. When she was 4 years old, she ate enokitake with a hot-pot dish. Later, she felt itching in her mouth. Therefore, she never ate enokitake since that time. At the age of 10, she drank only the soup of enokitake with school lunch. After that she felt discomfort and itching in her oral cavity. The result of enokitake and other mushrooms (siitake, simeji, and eringi) skin prick to prick test were all positive. We performed Western blotting with enokitake extracts and the patient's serum. Enokitake protein's band (75kDa) reacted specifically with the patient's IgE. At the same time Western blotting was performed with the patient's serum of previously reported enokitake anaphylaxis, but a 75kDa band showing specific reaction in this case was not observed. This band we identified was a novel enokitake allergen. PMID- 29249759 TI - [A CASE OF A 7-YEAR-OLD GIRL WITH ANAPHYLAXIS CAUSED BY PECTIN IN ALBEDO OF CITRUS UNSHIU BUT NOT BY THE FRUIT ITSELF]. AB - Pectin is used in several foods as an additive and a thickner. But some cases of anaphylaxis have been reported. Most of these are induced by occasional exposures; however, no cases of anaphylaxis after eating a Citrus unshiu, the albedo of which is rich in pectin, have been reported.A 7-year-old girl developed barking cough and pruritus approximately two hours after eating a frozen Citrus unshiu. She had a history of anaphylaxis induced by consuming cashew nuts. Skin testing and basophil activation tests were performed using a commercially available pectin product. Both tests were positive. In an oral food challenge test, she felt abdominal pain and nausea only after eating fruit, along with the albedo, of Citrus unshiu. We concluded that this case was induced by pectin present in the albedo of Citrus unshiu, but not by the fruit itself. We should consider that patients with cashew nut allergies have a possibility of pectin allergies as well, and that pectin in the albedo of Citrus unshiu may induce anaphylaxis. PMID- 29249760 TI - ? PMID- 29249761 TI - ? PMID- 29249762 TI - ? PMID- 29249763 TI - Intravascular Lymphoma with an Acute Course of Cerebellar Hemorrhage: A Case Report. AB - Intravascular lymphoma (IVL) has been characterized in many case reports by multiple white matter lesions reflecting ischemic changes. In contrast, there are very few case reports of cerebral or cerebellar hemorrhage resulting from IVL. A 56-year-old woman was referred to our department with two-week history of headache, nausea, and poor appetite. Gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) showed dilated veins on the cerebellar surface. No ischemic lesions were detected on diffusion-weighted images. Three days after admission, the patient had a large cerebellar hemorrhage, prompting emergency surgery. Unfortunately, the patient died on the 11th postoperative day. Massive CD20 positive lymphoma cells were recognized in the cerebellar veins, but not in the arteries or the parenchyma of the brain. This is the rare case report of a cerebellar hemorrhage complication from IVL that might have been caused by venous congestion. The dilated veins on the cerebellar surface recognized from the Gd enhanced T1-weighted images were specific clues in this case. PMID- 29249765 TI - Acute Cerebellar Ataxia Induced by Nivolumab. AB - A 54-year-old woman with adenocarcinoma of the lung and lymph node metastasis experienced nystagmus and cerebellar ataxia 2 weeks after initiating nivolumab therapy. An evaluation for several autoimmune-related antibodies and paraneoplastic syndrome yielded negative results. We eventually diagnosed the patient with nivolumab-induced acute cerebellar ataxia, after excluding other potential conditions. Her ataxic gait and nystagmus resolved shortly after intravenous steroid pulse therapy followed by the administration of decreasing doses of oral steroids. Nivolumab, an immune checkpoint inhibitor, is known to induce various neurological adverse events. However, this is the first report of acute cerebellar ataxia associated with nivolumab treatment. PMID- 29249764 TI - Lupus Nephritis with Thymoma Managed by Thoracoscopic Surgery and Prednisolone. AB - A 48-year-old woman was admitted to our hospital to undergo evaluation for fatigue, severe weight loss, and nephrotic range proteinuria. Light microscopy of a renal biopsy specimen revealed class III (A) lupus nephritis, while immunofluorescence and electron microscopy only showed sparse immune deposits with findings that were not typical of lupus nephritis. Computed tomography revealed a mass in the anterior mediastinum, which was resected. The examination of the surgical specimen revealed type A noninvasive thymoma. In combination with thymomectomy, postoperative steroid therapy achieved the prompt remission of lupus nephritis. In this patient, thymoma-related autoimmunity may have contributed to the exacerbation of lupus nephritis. PMID- 29249766 TI - Occurrence of Dermatomyositis Immediately after Mastectomy Subsequent to Severe Chemotherapeutic Drug Eruption. AB - We herein report a patient with breast cancer who developed dermatomyositis (DM) immediately after mastectomy. She had a history of severe drug eruption during neoadjuvant chemotherapy six months previously. Within a month after the operation, myalgia and rash, including Gottron's papules, developed, and skeletal muscle enzymes elevated, so she was diagnosed with probable DM according to the Bohan and Peter criteria. In many neoplastic DM cases, the course of the disease parallels the course of the malignancy. Possible mechanisms were suggested to explain the development of DM in the present case and offer new insight into autoimmune diseases. PMID- 29249767 TI - High-risk Pulmonary Embolism: Should We Be Less Patient with Thrombolytic Therapy? PMID- 29249768 TI - A Case of Massive Pulmonary Embolism Following Varicose Vein Surgery That Was Successfully Treated with Thrombolytic Therapy. PMID- 29249769 TI - Open Conversion for Type A Ascending Aortic Dissection after Thoracic Endovascular Aortic Repair by the Chimney Graft Technique. AB - An 83-year-old man with aortic arch aneurysm underwent zone 0 thoracic endovascular aortic repair (TEVAR) by the chimney graft technique with two supra aortic arch debranching grafts and developed subacute type A ascending aortic dissection. We performed emergency open conversion with circulatory arrest under deep hypothermia. The tip of the chimney graft (around the sino-tubular junction in the ascending aorta) was stiff, making it difficult to inspect the lumen and perform anastomosis. Deep hypothermic circulatory arrest and cutting the endograft stents to mobilize the graft were necessary for secure anastomosis. PMID- 29249770 TI - Elevation of Serum Carcinoembryonic Antigen Concentration Caused by Everolimus Induced Lung Injury: A Case Report. AB - A 66-year-old woman underwent right nephrectomy for treatment of renal cell carcinoma (RCC). Two years later, she underwent wedge resection of the right lung for treatment of metastatic RCC and primary adenocarcinoma of the lung. She began oral sorafenib for the remaining nodules of the left lung, which were suspected to be metastatic RCC. Two years later, the sorafenib was changed to everolimus because of slight enlargement of the left pulmonary nodules. The carcinoembryonic antigen (CEA) concentration then increased to 25.7 ng/mL, and chest computed tomography (CT) revealed ground-glass opacities (GGO) in the bilateral lungs. Everolimus-induced lung injury was suspected, and she discontinued the everolimus. Two months later, the serum CEA concentration decreased to almost within the reference range at 5.9 ng/mL, and the GGO disappeared on chest CT. In conclusion, we encountered a patient who developed an elevated serum CEA concentration caused by everolimus-induced lung injury. PMID- 29249771 TI - Synthesis of Novel Class of N-Alkyl-isatin-3-iminobenzoic Acid Derivatives and Their Biological Activity in Zebrafish Embryos and Human Cancer Cell Lines. AB - Isatin (1H-indole-2,3-dione) and many of its derivatives are reported to have pharmacological properties. In this study, we report the synthesis and biological activity of a new class of N-alkyl-isatin-3-iminobenzoic acid derivatives prepared via the condensation of N-alkyl isatin with 4-aminobenzoic acid by conventional, microwave, and ultrasonic methods. Microwave irradiation yielded the products in a shorter reaction time with higher yields and purities. The compounds were screened in zebrafish embryos, and also in three human cancer cell lines (MCF7, HepG2, and Jurkat) and one normal human cell line i.e., human foreskin cell line (HFF-1). Two compounds (3c, 3f) were found to be highly effective against hematopoiesis in live zebrafish embryo at 10 uM concentration. The developmental stage-dependent treatment indicated that these compounds interfered with the differentiation of hemangioblasts to hematopoietic cells in zebrafish embryos. The comparative screening of semaxanib (SU5416) (a known isatin derivatives), to compounds synthesized in this study, revealed the contrasting effects of these two classes of isatin derivatives on zebrafish hematopoiesis. Most of the N-alkyl-isatin-3-iminobenzoic acid derivatives were toxic on cancer and non-cancer tested human cells lines, however, the compounds 3c and 3f specifically affected the cell viability of Jurkat cells (human hematological cell line) with least IC50 values of 16.5 and 7.8 uM. The structure activity relationship (SAR) analysis indicated that the substitution pattern of the isatin at the 5-position was vital for activity. The in vivo and in vitro biological activities of these compounds suggested their potential use as pharmaceutical compounds for human leukemia treatment. PMID- 29249772 TI - Inhibition of adenosine monophosphate-activated protein kinase suppresses bone morphogenetic protein-2-induced mineralization of osteoblasts via Smad independent mechanisms. AB - Previous studies showed that adenosine monophosphate-activated protein kinase (AMPK), which plays as an intracellular energy sensor, promotes the differentiation and mineralization of osteoblasts via enhancing expression of bone morphogenetic protein (BMP)-2, which is a potent inducer of osteoblastogenesis. Thus, the aim of this study was to examine the roles of AMPK in BMP-2-induced osteoblastogenesis. We used a murine osteoblastic cell line MC3T3-E1 and a murine marrow stromal cell line ST2. BMP-2 (50 and 100 ng/mL) stimulated alkaline phosphatase (ALP) activity and enhanced mineralization of MC3T3-E1 cells, while the effects of BMP-2 were partly abolished by an inhibitor of AMPK, ara-A (0.1 mM). Real-time PCR showed that BMP-2 significantly increased the mRNA expressions of Alp, osteocalcin (Ocn), Runx2, Osterix and Dlx-5 in MC3T3 E1 cells, while co-incubation of ara-A significantly decreased the BMP-2 stimulated expression of Alp, Ocn, and Runx2. Moreover, co-incubation of ara-A suppressed the BMP-2-induced upregulation of Alp and Ocn in ST2 cells. Western blot analysis showed that BMP-2 phosphorylated Smad1/5 although it did not affect AMPK phosphorylation in MC3T3-E1 cells. Furthermore, a BMP receptor inhibitor LDN 193189 inhibited the phosphorylation of Smad1/5, but did not affect AMPK. In addition, co-incubation of ara-A did not affect BMP-2-induced phosphorylation of Smad1/5. These findings suggest that the inhibition of AMPK activation reduces the osteo-inductive effects of BMP-2 by decreasing the expression of Alp, Ocn, and Runx2 through Smad-independent mechanisms in osteoblastic cells. PMID- 29249773 TI - Does pneumoperitoneum affect perfusion index and pleth variability index in patients receiving combined epidural and general anesthesia? AB - Plethysmographic variability index (PVI) is a dynamic index used for the purpose of fluid responsiveness in patients, and the effect of pneumoperitoneum on PVI is still unclear. We therefore attempted to determine whether PVI and perfusion index (PI) change before/after pneumoperitoneum in patients receiving combined epidural and general anesthesia, which is a common anesthesia method with intravenous remifentanil. Twenty patients underwent laparoscopic cholecystectomy or colectomy. Immediately before pneumoperitoneum, variables were measured at baseline I and were then measured every min for 5 min after pneumoperitoneum start. Immediately before pneumoperitoneum release, variables were measured at baseline II and were measured every min for 5 min after pneumoperitoneum release. Compared with baseline I values, after pneumoperitoneum start, significant increases occurred in stroke volume variation (SVV) at 1-5 min, and significant decreases occurred in PI at 1-5 min. PVI did not change. Compared with baseline II values, after pneumoperitoneum release, significant increases occurred in PI at 1-5 min, and significant decreases occurred in PVI at 4-5 min and SVV at 1-5 min. In patients receiving combined epidural and general anesthesia, we newly found that PI decreased but PVI remained unchanged with a sufficient dose of remifentanil and epidural anesthesia that can block noxious stimuli and also most sympathetic activity. Furthermore, we reconfirmed that PI increased and PVI decreased upon release of pneumoperitoneum. PI and PVI values must be estimated cautiously during and after pneumoperitoneum. PMID- 29249774 TI - Effects of lifestyle advice provided by pharmacists on blood pressure: The COMmunity Pharmacists ASSist for Blood Pressure (COMPASS-BP) randomized trial. AB - The COMmunity Pharamcists ASSist for Blood Pressure (COMPASS-BP) study aimed to assess the effectiveness of lifestyle support programs administered in community pharmacies on hypertension control. This open-label, two-armed parallel group, cluster-randomized controlled trial included 73 pharmacies (clusters) in Japan randomized to a control or intervention group. Eligible hypertensive patients (n = 125), aged 20-75 years, received the intervention (n = 64) or the control treatment (n = 61), as dictated by their pharmacy randomization. Patients in the intervention group received brochures and healthy lifestyle advice from pharmacists using motivational interviewing methods during pharmacy visits over a 12-week period, with their usual pharmacy care. Conversely, the control group just received usual care. The main outcome measure was a change in morning systolic blood pressure (SBP) from baseline to week 12. The intervention group exhibited a decrease in morning SBP that was 6.0 mmHg greater than that of the control group (95% confidence interval [CI]: -11.0 to -0.9, p = 0.021). In a mixed-effect model for repeated measures analysis, the intergroup difference in morning SBP decrease was -4.5 mmHg (95% CI: -8.5 to -0.6, p = 0.024). Our findings indicate that implementation of a lifestyle advice program in pharmacies is feasible and may lead to reduced blood pressure. PMID- 29249776 TI - [Diseases requiring severe-level care certification for long-term care insurance]. AB - Objectives Extending health expectancy is important; however, health and welfare programs in local areas and communities present their own issues. This study aimed to identify main diseases requiring severe-level care certification for long-term care insurance based on information gathered from opinion papers prepared by primary doctors.Methods Data were obtained for 4,089 patients aged ?65 years who were certified for long-term care insurance for the first time between April 1, 2013, and March 31, 2015. Their disorders were categorized into the groups used in the Comprehensive Survey of Living Conditions long-term care questionnaire. The subjects were categorized into "mild" and "severe" groups according to their long-term care insurance levels. Subjects in the severe group were long-term care insurance levels 2-5. The associations with diseases in the two groups were examined using chi-square tests according to gender. Multiple logistic regression analyses were conducted for those diseases which showed significant associations by chi-square test for the dependent variables after adjusting for age.Results Malignancy was the most frequent disorder in men, whereas joint disease was most frequent in mild group women. In men, there was a significant difference in the frequency of diseases between the mild and severe groups for stroke (P<0.001), malignancy (P<0.001), joint disease (P<0.001), diabetes (P=0.015), fracture and falls (P=0.028), and others (P<0.001) by chi square tests. In women, there was a significant difference in the frequency of diseases between the mild and severe groups for stroke (P<0.001), malignancy (P<0.001), joint disease (P<0.001), dementia (P<0.001), Parkinson's disease (P=0.003), and others (P<0.001). In men, multivariate logistic regression analysis revealed that stroke, malignancy, and fracture and falls were significantly and positively associated with severe-level, long-term care insurance, while joint disease and hypertension were negatively associated. In women, stroke, malignancy, dementia, and Parkinson's disease were significantly associated with severe long-term care insurance level, while joint disease and hypertension were negatively associated.Conclusion The main diseases requiring severe-level care in both men and women were stroke and malignancy. These diseases occurred in large numbers among those less than 74 years of age. This finding suggests the importance of preventing lifestyle-related diseases before the age of 65 years in order to avoid requiring nursing care. PMID- 29249775 TI - Effects of gonadotropin-releasing hormone agonist on human chorionic gonadotropin activity in granulosa cells of immature female rats. AB - Although the expression of gonadotropin-releasing hormone (GnRH) in the ovaries is well established, its physiological role remains unknown. The aim of this study was to determine whether ovarian GnRH mediates the actions of human chorionic gonadotropin (hCG) in the granulosa cells of immature female rats. Follicular growth was induced by administration of pregnant mare serum gonadotropin (PMSG, 15 IU/0.15 ml) on day 25 after birth, and hCG (20 IU/0.2 ml) was administered on day 27 revealing the increase of plasma progesterone level. Primary cultures of granulosa cells were established from large follicles 2 days after PMSG treatment. Progesterone synthesis was augmented by hCG in a dose dependent manner. Annexin A5 (ANXA5), a biomarker of GnRH, was expressed in the granulosa-luteal cells after hCG treatment, as shown by immunohistochemistry, suggesting that hCG treatment induced GnRH action. The GnRH mRNA level was increased by hCG, and treatment with GnRH agonist (GnRHa) increased ANXA5 mRNA levels in the primary cultures of granulosa cells. Concomitant incubation of GnRH (10-7 M) or GnRHa (fertirelin acetate, 10-8 M) with hCG suppressed progesterone synthesis during a 3 h incubation period. The mRNA expression of luteinizing hormone receptor (LHR) and follicle-stimulating hormone receptor (FSHR) was synergistically stimulated and suppressed by hCG and GnRHa, respectively. GnRHa stimulated p21 expression, and GnRHa and hCG synergistically reduced the mRNA expression levels of p27 and FOXO1. These data suggest that GnRH induced by LH may have a role for the LH-mediated luteinization of granulosa cells. In addition, ANXA5 may be involved in GnRH action. GnRH-ANXA5 would be an important mechanism in cell differentiation. PMID- 29249777 TI - [Relationship between exercise adherence and personality characteristics in persons experienced in the Medical Fitness program]. AB - Objective We examined effective exercise adherence support methods for persons experienced in the Medical Fitness (MF) program to clarify the relation of personality traits with exercise adherence and the factors that improve exercise adherence.Methods Subjects were 283 adults who had registered as members in the MF program at an affiliate of Hospital A. We implemented an anonymous self administered questionnaire by postal mail. Using the Japanese version of the Ten Item Personality Inventory (which contains 10 items that measure the Big Five personality traits), we evaluated the following characteristics: "Extraversion", "Agreeableness", "Conscientiousness", "Neuroticism", and "Openness". The subjects who reported exercising regularly at the time of survey were considered persons with subjective exercise adherence.Results In persons with subjective exercise adherence, "Conscientiousness" was significantly lower (P=0.003) among men and "Neuroticism" was significantly higher (P=0.018) among women when compared to persons with subjective exercise adherence. There was no correlation between the things that emphasize exercise adherence and "Conscientiousness" among men. There was a negative correlation between "can achieve goal" and "Neuroticism" among women.Conclusions It is essential to consider personality and gender differences when devising exercise adherence support measures for the MF program. Our results suggest that women with high neuroticism do not need "can achieve goal" to maintain their exercise habits; therefore, it is necessary to examine teaching methods that do not focus on only goal achievement as part of exercise adherence support for MF. PMID- 29249778 TI - [The need for medical interpreters: a questionnaire survey of municipal hospitals in Japan]. AB - Objectives This study aimed to investigate the need for medical interpreters, in relation to hospital size, the number of foreign patients accepting, and risk management in municipal hospitals in Japan.Methods In 2016, we conducted a questionnaire survey at 894 municipal hospitals in Japan. The questionnaire included hospital characteristics, the number of foreign patients, the need for medical interpreters, and the respondents' background. We used the incident classification of the Safety Management Council of National University Hospitals (0-5 levels and others). We applied pairwise analysis to hospital size: small hospitals (20-99 beds), medium hospitals (100-399 beds), and large hospitals (400 or more beds).Results The response rates of the small, medium, and large hospital were 30.1%, 32.5%, and 32.8%, respectively. The percentage of hospitals that had accepted foreign patients over the previous year ranged from 84.9% to 97.6%, a higher with larger hospitals. Larger hospitals attended to emergencies, hospitalization, and surgical patients more frequently than the smaller hospitals. Hospital staff who communicated with non-Japanese-speaking foreign patients via ad-hoc interpreters accompanying the patients ranged from 84.3% to 86.7% in larger hospitals. Of the staff at small, medium, and large hospitals, 66.7%, 58.5%, and 44.7%, respectively, considered the interpretations of the ad hoc interpreters accompanying the patient to be accurate. Of the small, medium, and large hospitals, 31.6%, 76.5% and 92.3% claimed that they would use interpreting services if the interpretation costs were covered by the National Health Insurance System (P<0.001). When foreign patients are accepted, 75.7%, 84.7% and 94.6% of small, medium and large hospitals require trained medical interpreters, respectively (P=0.014). Hospital staff reporting that the most common reason for using an interpreter was to reduce medical risks ranged from 81.1% to 94.3%. Of the 274 hospital staff surveyed, 4.7% had experiences of incidents due to the language barriers when dealing with foreign patients. The incident classification was as follows: 3 cases with Impact Level 0, including MRI withdrawal; 9 cases with Level 1, including unauthorized discharge and self extraction of an in-travenous drip; 1 case of precipitate labor; 1 case of Level 5 death; and 3 other cases. Small hospitals have not been reporting incidents, but larger hospitals, despite the small number of foreign patients, have been reporting incidents.Conclusion Large or medium-sized hospitals need medical interpreters more than smaller hospitals because of the greater number of foreign patients being attended to, and diversity and complexity of reasons for seeking hospital services. Our results suggest that language barriers when dealing with foreign patients are a threat to patient safety. The majority of the responding Japanese municipal hospitals believe that they require trained language interpreters to improve risk management. PMID- 29249779 TI - [Relationship between fruit and vegetable gardening and health-related factors: male community gardeners aged 50-74 years living in a suburban area of Japan]. AB - Objectives The aims of the study were as follows: 1) to investigate the relationship between community fruit and vegetable (FV) gardening and perceived changes in health-related factors by utilizing community gardens and 2) to determine the relationship of community FV gardening and other types of gardening on health-related factors among men aged 50-74 years living in a suburban area of Japan.Methods In this cross-sectional study, we targeted men aged 50-74 years living in a city in Gunma Prefecture. A survey solicited demographic characteristics, FV gardening information, and health-related factors [BMI, self rated health status, FV intake, physical activity (PA), and perceived neighborhood social cohesion (PNSC)]. The participants were divided into three groups: community gardeners, other types of gardeners, and non-gardeners. Items related to community gardening and perceived changes in health-related factors were presented only to community gardeners. The relationship between community gardening and perceived changes in health-related factors were analyzed by computing correlation coefficients. The relationships between FV gardening and specific health-related factors were analyzed by logistic regression modeling.Results Significant positive correlations were observed between community FV gardening (the frequency of community gardening, the product of community gardening time and frequency of community gardening) and perceived changes in health-related factors (frequency of FV intake, amount of FV intake, and PA). The logistic regression models showed that 1) the number of participants with >=23 METs h/week of PA was significantly greater among community gardeners than among non-gardeners; 2) the number of participants whose frequency of total vegetable intake, total vegetable intake (excluding juice), and total FV intake (excluding juice) was >=5 times/day was significantly greater among other types of gardeners than non-gardeners; 3) participants with scores >= the median of PNSC were significantly greater among other types of gardeners than non gardeners; and 4) participants who spent >=4 hours/day sitting were significantly fewer among other types of gardeners than non-gardeners.Conclusion Higher frequency of community gardening appears to induce greater perceived positive changes on FV intake and PA. It was indicated that FV gardening in community gardens contributes to increased PA, whereas other types of FV gardening contribute to increased FV intake frequency and decreased sitting time. In the future, higher-quality studies-for example, intervention studies using more rigorous measurements-will be necessary. PMID- 29249780 TI - Palliative Reirradiation for Painful Bone Metastases: Clinical Cases and Literature Review. AB - Reirradiation to previously irradiated peripheral bone metastases for pain has been shown to be safe and effective, but no specific trial has been completed to define the indications for reirradiation of patients with recurrent symptoms of metastatic bone disease. Thus, we aimed to assess the effectiveness and prognostic factors of reirradiation for painful bone metastases. To do so, we reviewed the cases of 14 patients with painful bone metastases who had undergone reirradiation at our hospital. A favorable pain response after reirradiation was achieved in 50% (7/14) of the patients. An interval from initial radiotherapy >6 months was a significant prog nostic factor for pain response (p = 0.03). Performance status was correlated with pain response, with borderline significance (p = 0.06). No severe adverse events were reported. We conclude that reirradiation of painful bone metastases is effective in providing pain relief, especially for patients with a long interval from initial radiation and good performance status. PMID- 29249781 TI - Nrf2 inhibition affects cell cycle progression during early mouse embryo development. AB - Brusatol, a quassinoid isolated from the fruit of Bruceajavanica, has recently been shown to inhibit nuclear factor erythroid 2-related factor 2 (Nrf2) via Keap1-dependent ubiquitination and proteasomal degradation or protein synthesis. Nrf2 is a transcription factor that regulates the cellular defense response. Most studies have focused on the effects of Nrf2 in tumor development. Here, the critical roles of Nrf2 in mouse early embryonic development were investigated. We found that brusatol treatment at the zygotic stage prevented the early embryo development. Most embryos stayed at the two-cell stage after 5 days of culture (P < 0.05). This effect was associated with the cell cycle arrest, as the mRNA level of CDK1 and cyclin B decreased at the two-cell stage after brusatol treatment. The embryo development potency was partially rescued by the injection of Nrf2 CRISPR activation plasmid. Thus, brusatol inhibited early embryo development by affecting Nrf2-related cell cycle transition from G2 to M phase that is dependent on cyclin B-CDK1 complex. PMID- 29249782 TI - [Risk Factors for Post-operative Respiratory Failure and Respiratory Tract Infections Following Cardiovascular Surgery]. AB - INTRODUCTION: Respiratory failure and respiratory tract infections are frequently observed as post-operative pulmonary complications, and significantly contribute to morbidity and mortality. However, the risk factors of post-operative respiratory failure and respiratory tract infections are controversial, and how these factors affect on incidence of complications is still unclear. OBJECTIVE: To identify risk factors of post-operative respiratory failure and respiratory tract infections, and evaluate its impact on incidences after cardiovascular surgery. METHODS: From June 2013 to May 2015, adult patients undergoing cardiovascular surgery in the department of cardiovascular surgery and post operative rehabilitation of Nagasaki University Hospital (Nagasaki, Japan) were retrospectively investigated. RESULTS: Fifty-two of 416 patients(12.5%)suffered from post-operative respiratory failure and respiratory tract infections. Identified risk stratification indicates the relevant operative factors were more important than pre-operative factors. The operative time (OR 1.696, 95% CI 1.302~2.211), post-operative water balance( OR 1.025, 95% CI 1.004~1.046)and emergency operation( OR 3.607, 95% CI 1.492~8.716)were significant independent risk factors in the development of post-operative respiratory failure and respiratory tract infections. CONCLUSIONS: These results indicated that the operative factors are more important as onset of post-operative respiratory failure and respiratory tract infections after cardiovascular surgery. PMID- 29249783 TI - [Utility of Partial Splenic Embolization Prior to Lung Resection in Patients Demonstrating Platelet Transfusion Refractoriness Due to Hypersplenism]. AB - It is often difficult to control perioperative bleeding in patients with liver cirrhosis and concurrent thrombocytopenia and coagulation factor deficiency. Partial splenic embolization (PSE), an auxiliary treatment strategy in management of liver cirrhosis and hepatocellular carcinoma, can not only increase platelets but also improve liver function. With advances in interventional radiology, PSE is a safer and more reliable procedure compared to a splenectomy. We present the case of a 69-year-old man diagnosed with left lung cancer, with thrombocytopenia, and hepatitis C virus-related cirrhosis. Although he was administered prophylactic platelet transfusion prior to operation, he was noted to be refractory to platelet transfusion. PSE was performed to improve his thrombocytopenia, following which we could safely perform left upper lobectomy of the lung and ND2a-1 lymph node dissection without any major bleeding. PSE is useful induction therapy to provide a wider choice of treatment options for patients with thrombocytopenia. PMID- 29249784 TI - [Surgical Embolectomy for Acute Massive Pulmonary Thromboembolism Requiring Percutaneous Cardiopulmonary Support after Thoracoabdominal Aorta Replacement]. AB - A 48-year-old man was admitted to our hospital and underwent thoracoabdominal aorta replacement. Eight days postoperatively, he developed severe dyspnea and transient drop in blood pressure suddenly following walk rehabilitation. Contrast enhanced computed tomography showed thrombi in the bilateral main pulmonary artery. Respiratory failure and unstable hemodynamics developed, which required percutaneous cardiopulmonary support (PCPS). Because catheter embolectomy and thrombolytic therapy via pulmonary artery catheter were not effective, surgical thrombectomy was performed. PCPS was successfully removed on the following day. The patient was extubated on postoperative day 10 and discharged without complications on day 46 following rehabilitation. It is important to save a critically ill patient with acute pulmonary embolism requiring PCPS, and surgical treatment should be performed without delay in such patients. PMID- 29249785 TI - [Successful Early Surgical Treatment for Infected Traumatic Pulmonary Pseudocyst]. AB - Almost all traumatic pulmonary pseudocysts (TPP), such as cavitary pulmonary lesions after blunt chest trauma, resolve spontaneously. On the contrary, secondary infection of a TPP should be considered in the presence of purulent sputum or hemosputum and a persistent cavity. We report a case of an infected TPP that was successfully treated by early surgical treatment. A 25-year-old man was transferred to our hospital with a TPP, shown by computed tomography (CT) as having a thick-walled large cavity, after the acute phase of blunt chest trauma. Purulent hemosputum suggested infection of the cavity. Serial CT scans of the chest revealed a persistent cavity. The thick-walled large cavity was diagnosed as a secondary infection of the TPP, that is, a potential lung abscess. We resected the cavity before a systemic inflammatory reaction occurred. PMID- 29249786 TI - [Intrapulmonary Thymoma Suspected of Malignancy]. AB - A 68-year-old woman was found a nodule of the right lower lobe. Malignancy was suspected by positive positron emission tomography-computed tomography finding. Wedge resection was performed to establish the diagnosis, and the pathological diagnosis was a type AB thymoma. At 13 months after operation, no recurrence was observed. PMID- 29249787 TI - [Anterior Mediastinal Myxoid Liposarcoma Detected by Chest Computed Tomogram in the Patient with Pneumothorax]. AB - A 57-year-old woman visited our hospital with left chest pain. Chest computed tomography (CT) scanning showed left pneumothorax with apical bullae and a nodular shadow in the left anterior mediastinum accidentally. However, a week later, we could not detect a mediastinal shadow on chest CT image after healing of left pneumothorax. Video assisted thoracoscopic surgery was scheduled in order to remove bullae and evaluate an anterior mediastinal lesion. The mediastinal lesion was tumorous and resected with around pericardial fat tissue. Pathological diagnosis was a myxoid liposarcoma of 15*10mm in size without infiltration into the surrounding tissue. The postoperative course was uneventful without recurrence 6 months later. PMID- 29249788 TI - [Usefulness of Thoracic Endovascular Aortic Repair for the Treatment of Massive Hemoptysis Due to Bronchiectasis;Report of Two Cases]. AB - Massive hemoptysis caused by bronchiectasis threatens life, so early bronchial arterial embolization (BAE) is needed. In case 1, a 80-year-old female complained of hemoptysis and back pain caused by bronchiectasis and Stanford type B aortic dissection. In case 2, a 78-year-old male had history of the surgery of descending thoracic aortic aneurysm and bronchiectasis combined with aortopulmonary fistula. Both cases in bronchiectasis with massive hemoptysis were difficult to perform BAE due to complicated with acute aortic dissection and aortopulmonary fistula. We applied Thoracic endovascular aortic repair (TEVAR) to these cases by its occlusive effects of the orifice of bronchial artery and collateral flow from intercostal arteries. Their postoperative courses were satisfactory without hemoptysis. We suggest that TEVAR can become the one of the option for the treatment of massive hemoptysis that is not indicated to BAE. PMID- 29249789 TI - [Native Aortic Valve Endocarditis Caused by Nocardia asteroides;Report of a Case]. AB - Infection by Nocardia sp. is rare and usually affects immuno-depressed patients, such as those receiving chemotherapy and long-term steroid therapy. Cardiac involvement is uncommon and usually occurs as endocarditis. We present a case of native aortic valve endocarditis caused by Nocardia asteroides. Aortic valve translocation method was chosen because of extensive root infection with major disruption of the aortic annulus. Over 2 years after the surgery, there is no recurrence and no enlargement of the aortic annulus. PMID- 29249790 TI - [Ascending Aorta Replacement and Extended Myectomy for Acute Aortic Dissection and Coexistent Hypertrophic Obstructive Cardiomyopathy;Report of a Case]. AB - Emergent ascending aortic replacement and extended myectomy were performed in a woman with acute aortic dissection who was aged 63 years. Preoperative transthoracic echocardiography performed in the intensive care unit showed only slight left ventricular outflow tract (LVOT) obstruction, but intraoperative transesophageal echocardiography after induction of anesthesia revealed pericardial effusion, systolic anterior motion(SAM), and associated mitral regurgitation(MR). Perioperative SAM and MR are sometimes facilitated under various hemodynamic conditions, but in this case, the left ventricular wall was thick and LVOT appeared to be obstructive by a hypertrophied septum. Structural hypertrophic obstructive cardiomyopathy (HOCM) was diagnosed, and septal myectomy and aortic replacement were performed. After ascending aortic replacement and simultaneous extended myectomy with resection of abnormal band, weaning from cardiopulmonary bypass was smooth without SAM and MR. The patient was discharged from hospital 24 days postoperatively with no major complications. Extended myectomy should be considered if structural HOCM is diagnosed, even when aortic replacement for the dissected aorta is the primary procedure. PMID- 29249791 TI - [Redo Coronary Artery Bypass Grafting Through Left Thoracotomy in Patient with Patent Left Internal Thoracic Artery Graft;Report of a Case]. AB - A 61-year-old man was admitted because of unstable angina. The patient had a history of CABG [LITA-left anterior descending artery(LAD), aorta-saphenous vein graft(SVG)-posterolateral branch (PL)-diagonal branch (D1)]4 years ago. Coronary angiography revealed an occlusion of old SVG at proximal anastomosis site and a stenosis of native high lateral artery (HL). To reduce the risk of cardiac injury and damage to the patent grafts due at sternal reentry, we performed redo CABG through left thoracotomy. The proximal site of SVG was anastomosed to descending aorta using automated proximal anastomosis system. The SVG was anastomosed to the HL and old SVG in a sequential mode. Postoperative course was uneventful and the patient was discharged on postoperative day 14. Redo CABG through left thoracotomy provides safe and effective surgical approach in patient who requires revascularization of left circumflex territory. PMID- 29249792 TI - [Valve Replacement for Infective Endocarditis of Pulmonary Valve;Report of a Case]. AB - Generally, infective endocarditis is found at the left side of the heart. The right side infective endocaritis accounts for only 5~10% of all cases of infective endocarditis. The right side infective endocarditis occurs especially among drug users employing intravenous injection. A typical site of infection is the tricupid valve, and isolated pulmonary valve involvement is rare. It is assumed that its rarity is due to the low pressure gradients within the right heart, the low prevalence of valve disease, and the lower oxygen content of the venous blood. We describe a case of isolated pulmonary valve endocarditis requiring valve replacement. Antibiotic therapy was conducted for 4 weeks before surgery and 2 weeks after surgery. Clinical course was favorable and the patent was discharged home 18 days after surgery. PMID- 29249793 TI - [Coronary Artery Perforation Secondary to Primary Percutaneous Coronary Intervention;Report of a Case]. AB - Stent perforation of a coronary artery during percutaneous coronary intervention (PCI) is a rare but life-threatening complication. A 70-year-old man was admitted to our hospital for management of acute coronary syndrome. PCI was attempted for the left circumflex artery(LCX);however, catheterization was complicated by perforation of the LCX by the stent. He developed cardiac tamponade and was resuscitated using percutaneous cardiopulmonary support. Emergency surgery( ligation of the LCX and aorto-coronary bypass grafting for the distal LCX) was performed. His postoperative course was uneventful, and the patient was discharged on the 20th postoperative day. Collaboration between cardiologists and surgeons is essential to salvage such a critical patient. PMID- 29249794 TI - [Surgical Case of Pulmonary Blastoma;Report of a Case]. AB - A 81-year-old man consulted our hospital because of an abnormal shadow on a chest radiography in the right lower field. Computed tomography of the chest showed a mass shadow measuring 41 mm in diameter in the lower lobe of the right lung. There was no lymph node swelling in the hilum or mediastinum. A diagnosis of the lung cancer was suspected and the patient underwent right lower lobectomy with standard nodal dissection. Microscopically, the tumor revealed the epithelial component mimicking fetal lung tissue and proliferative mesenchymal component consisting of immature and heteromorphic nuclear cells as well. The final diagnosis was pulmonary blastoma classified as pathological stage IIB. He was not scheduled for adjuvant chemotherapy due to his older age. PMID- 29249795 TI - Cardiac Hypertrophy and Brain Natriuretic Peptide Levels in an Ovariectomized Rat Model Fed a High-Fat Diet. AB - BACKGROUND Heart failure in women increases around the time of menopause when high-fat diets may result in obesity. The heart produces brain natriuretic peptide (BNP), also known as B-type natriuretic peptide. This aims of this study were to assess cardiac hypertrophy and BNP levels in ovariectomized rats fed a high-fat diet. MATERIAL AND METHODS Forty-eight female Wistar rats were divided into four groups: sham-operated rats fed a control diet (SC) (n=12); ovariectomized rats fed a control diet (OC) (n=12); sham-operated rats fed a high fat diet (SF) (n=12); and ovariectomized rats fed a high-fat diet (OF) (n=12). Body weight and blood pressure were measured weekly for 24 weeks. Rats were then euthanized, and plasma samples and heart tissue were studied for gene expression, hydroxyproline levels, and histological examination. RESULTS A high-fat diet and ovariectomy (group OF) increased the weight body and the systolic blood pressure after three months and five months, respectively. Cardiomyocyte hypertrophy was associated with increased expression of ventricular BNP, decreased natriuretic peptide receptor (NPR)-A and increased levels of hydroxyproline and transforming growth factor (TGF)-beta. The plasma levels of BNP and estradiol were inversely correlated; expression of estrogen receptor (ER)beta and ERalpha were reduced. CONCLUSIONS The findings of this study showed that, in the ovariectomized rats fed a high-fat diet, the BNP-NPR-A receptor complex was involved in cardiac remodeling. BNP may be a marker of cardiac hypertrophy in this animal model. PMID- 29249798 TI - Effects of anesthesia methods on insulin, blood glucose, immune and postoperative infection of gastric cancer patients complicated with diabetes mellitus. PMID- 29249796 TI - Atypical Presentation of Radiation-Associated Breast Angiosarcoma: A Case Report and Review of Literature. AB - BACKGROUND Radiation-associated breast angiosarcoma is a rare clinical entity that is thought to be increasing in incidence. CASE REPORT Here we present the case of a 67-year-old female with a history of left breast invasive ductal carcinoma who received breast conserving surgery and radiation therapy eight years ago. She then presented with a painless mild skin discoloration of the left breast that had been present for over one year. Mammograms and ultrasounds were normal. A punch biopsy and a subsequent excisional biopsy revealed the diagnosis of angiosarcoma. The patient was treated with mastectomy and had no subsequent recurrences. CONCLUSIONS The long-term clinical surveillance for all patients who receive breast conservation surgery is recommended and a high degree of suspicion should be exercised in view of potential atypical presentations of this disease. PMID- 29249797 TI - Factors Affecting Liver Regeneration in Living Donors After Hepatectomy. AB - BACKGROUND The safety of living liver donors is the paramount priority of liver transplantation surgeons. The liver has an effective regeneration capacity. The regeneration rate of the liver remnant in living liver donors provides much information useful in liver surgery. The outcome of the remnant liver after hepatectomy can be affected by many different perioperative factors. MATERIAL AND METHODS A total of 46 patients were enrolled in the study. Retrospective clinical data, including preoperative and postoperative early and late computed tomography liver volumetry measurements, estimated resection volumes, resected liver weights, and postoperative laboratory values, were statistically evaluated according to the liver resection type. RESULTS No significant difference was detected in age, sex, calculated and computed tomography estimated total liver volume, intraoperative Hb decrease, postoperative complications, or postoperative portal vein flow rate. Postoperative liver enlargement rates were significant higher in the right hemihepatectomy (RHH) group than in the left lateral sectionectomy (LLS) group. The size of the liver remnant or graft has a major effect on regeneration rate. Postoperative biliary leakage did not have any significant effect on liver regeneration. No post-hepatectomy liver failure was detected among the liver donors. CONCLUSIONS Liver hypertrophy depends on the extent of liver resection. The cause of volume decrease in the LLS group after hepatectomy in our series appears to be the gradual atrophy of liver segment 4. RHH and LLS surgeries differ from each other in terms of resected liver volume, as well as inflammatory activity, and the latter appears to affect liver regeneration. PMID- 29249799 TI - Mutations and karyotype in myelodysplastic syndromes: TP53 clusters with monosomal karyotype, RUNX1 with trisomy 21, and SF3B1 with inv(3)(q21q26.2) and del(11q). PMID- 29249800 TI - DBC1 promotes castration-resistant prostate cancer by positively regulating DNA binding and stability of AR-V7. AB - Constitutively active AR-V7, one of the major androgen receptor (AR) splice variants lacking the ligand-binding domain, plays a key role in the development of castration-resistant prostate cancer (CRPC) and anti-androgen resistance. However, our understanding of the regulatory mechanisms of AR-V7-driven transcription is limited. Here we report DBC1 as a key regulator of AR-V7 transcriptional activity and stability in CRPC cells. DBC1 functions as a coactivator for AR-V7 and is required for the expression of AR-V7 target genes including CDH2, a mesenchymal marker linked to CRPC progression. DBC1 is required for recruitment of AR-V7 to its target enhancers and for long-range chromatin looping between the CDH2 enhancer and promoter. Mechanistically, DBC1 enhances DNA-binding activity of AR-V7 by direct interaction and inhibits CHIP E3 ligase mediated ubiquitination and degradation of AR-V7 by competing with CHIP for AR-V7 binding, thereby stabilizing and activating AR-V7. Importantly, DBC1 depletion suppresses the tumorigenic and metastatic properties of CRPC cells. Our results firmly establish DBC1 as a critical AR-V7 coactivator that plays a key role in the regulation of DNA binding and stability of AR-V7 and has an important physiological role in CRPC progression. PMID- 29249801 TI - FOXC1-induced non-canonical WNT5A-MMP7 signaling regulates invasiveness in triple negative breast cancer. AB - Triple-negative breast cancer (TNBC) has high rates of local recurrence and distant metastasis, partially due to its high invasiveness. The Forkhead box C1 (FOXC1) transcription factor has been shown to be specifically overexpressed in TNBC and associated with poor clinical outcome. How TNBC's high invasiveness is driven by FOXC1 and its downstream targets remains poorly understood. In the present study, pathway-specific PCR array assays revealed that WNT5A and matrix metalloproteinase-7 (MMP7) were upregulated by FOXC1 in TNBC cells. Interestingly, WNT5A mediates the upregulation of MMP7 by FOXC1 and the WNT5A MMP7 axis is essential for FOXC1-induced invasiveness of TNBC cells in vitro. Xenograft models showed that the lung extravasation and metastasis of FOXC1 overexpressing TNBC cells were attenuated by knocking out WNT5A, but could be restored by MMP7 overexpression. Mechanistically, FOXC1 can bind directly to the WNT5A promoter region to activate its expression. Engineered DNA-binding molecule mediated chromatin immunoprecipitation (enChIP), coupled with mass spectrometry, identified FOXC1-interacting proteins including a group of heterogeneous nuclear ribonucleoproteins involved in WNT5A transcription induction. Finally, we found that WNT5A activates NF-kappaB signaling to induce MMP7 expression. Collectively, these data demonstrate a FOXC1-elicited non-canonical WNT5A signaling mechanism comprising NF-kappaB and MMP7 that is essential for TNBC cell invasiveness, thereby providing implications toward developing an effective therapy for TNBC. PMID- 29249802 TI - A CREB3-regulated ER-Golgi trafficking signature promotes metastatic progression in breast cancer. AB - In order to better understand the process of breast cancer metastasis, we have generated a mammary epithelial progression series of increasingly aggressive cell lines that metastasize to lung. Here we demonstrate that upregulation of an endoplasmic reticulum (ER) to Golgi trafficking gene signature in metastatic cells enhances transport kinetics, which promotes malignant progression. We observe increased ER-Golgi trafficking, an altered secretome and sensitivity to the retrograde transport inhibitor brefeldin A (BFA) in cells that metastasize to lung. CREB3 was identified as a transcriptional regulator of upregulated ER-Golgi trafficking genes ARF4, COPB1, and USO1, and silencing of these genes attenuated the metastatic phenotype in vitro and lung colonization in vivo. Furthermore, high trafficking gene expression significantly correlated with increased risk of distant metastasis and reduced relapse-free and overall survival in breast cancer patients, suggesting that modulation of ER-Golgi trafficking plays an important role in metastatic progression. PMID- 29249804 TI - Marked elevation of serum lactate dehydrogenase in primary myelofibrosis: clinical and prognostic correlates. PMID- 29249803 TI - Possible role of the gut microbiota-brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model. AB - Accumulating evidence suggests that the gut microbiota-brain axis plays a role in the pathogenesis of depression, thereby contributing to the antidepressant actions of certain compounds. (R)-ketamine has a greater potency and longer lasting antidepressant effects than (S)-ketamine. Here, we investigated whether the gut microbiota plays a role in the antidepressant effects of these two ketamine enantiomers. The role of the gut microbiota in the antidepressant effects of ketamine enantiomers in a chronic social defeat stress (CSDS) model of depression was examined using 16S ribosomal RNA gene sequencing of fecal samples. At the phylum level, CSDS-susceptible mice showed alterations in the levels of Tenericutes and Actinobacteria; however, neither ketamine enantiomers influenced these alterations. At the class level, both ketamine enantiomers significantly attenuated the increase in the levels of Deltaproteobacteria in the susceptible mice after CSDS. Furthermore, (R)-ketamine, but not (S)-ketamine, significantly attenuated the reduction in the levels of Mollicutes in the susceptible mice. At the genus level, both ketamine enantiomers significantly attenuated the decrease in the levels of Butyricimonas in the susceptible mice. Notably, (R)-ketamine was more potent than (S)-ketamine at reducing the levels of Butyricimonas in the susceptible mice. In conclusion, this study suggests that the antidepressant effects of two enantiomers of ketamine in CSDS model may be partly mediated by the restoration of the gut microbiota. Furthermore, the specific effect of (R) ketamine on the levels of Mollicutes and Butyricimonas may explain its robust antidepressant action. PMID- 29249805 TI - Clustered repetitive transcranial magnetic stimulation for the prevention of depressive relapse/recurrence: a randomized controlled trial. AB - Repetitive transcranial magnetic stimulation (rTMS) may have the potential to prevent depressive relapse. This assessor-blinded, randomized controlled study was designed to evaluate the efficacy and safety of rTMS as a mono- and combination therapy in the prevention of depressive relapse/recurrence. A total of 281 depressed patients who had achieved stable full or partial remission on a 6-month antidepressant (ADP) run-in treatment were randomly assigned to an rTMS (n = 91), ADP (n = 108), or combined (rTMS + ADP, n = 82) treatment group for 12 months. Monthly clustered rTMS was conducted in 5-10 sessions over a 3-5-day period. Maintenance outcomes were assessed using time to relapse/recurrence and relapse/recurrence rate. Overall, 71.2% (200/281) of the participants completed the treatment per the protocol. rTMS + ADP and rTMS significantly reduced the risk of relapse/recurrence compared with ADP (P = 0.000), with hazard ratios of 0.297 and 0.466, respectively. Both rTMS-containing regimens produced significantly lower relapse/recurrence rates than ADP (15.9% and 24.2% vs. 44.4%, P < 0.001). In the relapsed/recurrent subgroup, first-episode depressed, rTMS treated patients had a markedly lower relapse/recurrence rate than ADP-treated patients. Five patients on the ADP-containing regimens, but none on rTMS alone, developed acute mania. The rTMS-containing regimens had considerably more certain side effects than did the ADP group. We concluded that TMS, whether as a mono- or additional therapy, is superior to antidepressants in preventing depressive relapse/recurrence, particularly in first-episode depressed patients. The treatment does not increase the risk of manic switch, but may increase the risk of certain side effects. PMID- 29249806 TI - Cortical high gamma network oscillations and connectivity: a translational index for antipsychotics to normalize aberrant neurophysiological activity. AB - Oscillatory activity in the gamma frequency range is a critical mechanism, which integrates neural networks within and across brain structures during cognitive processes. In schizophrenia, abnormalities in high gamma oscillations are ubiquitous and most likely reflect dysfunction in neuronal networks. In conscious rats, disturbed network oscillations associated with positive symptoms and cognitive deficits were modeled in different cortical areas by the dopaminergic agonist (amphetamine) and the N-methyl-D-aspartate (NMDA) receptor antagonists (PCP and MK801). Subsequently, the efficacies of marketed atypical antipsychotics (olanzapine, risperidone, and clozapine) to normalize dysfunctional oscillations and network connectivity were examined. Acute NMDA antagonists elicited aberrant synchrony in the gamma frequency oscillations. In addition, coherent slow alpha network activity was observed with MK801 and amphetamine, both of whose oscillatory rhythms were correlated with pronounced locomotor activity. All antipsychotics commonly decreased slow alpha and high gamma network oscillations in different cortical regions as well as motion behavior. In the combined treatments, antipsychotics attenuated NMDA antagonist-induced abnormalities in functional network oscillations and connectivity, whose effects on motor behavior is mechanistically related. These results suggest that pharmacologically induced disruption of cortical gamma oscillations and network connectivity in rats is a candidate model to study dysfunctional oscillatory patterns described in positive and negative symptoms of schizophrenia. The efficacy of antipsychotics to rescue cortical network oscillatory patterns is in line with the idea that glutamatergic and dopaminergic systems play a role in maintaining the integrity of cortical circuits. Thus, gamma oscillations could provide a powerful translational index to assess the integrity of neural networks and to evaluate the efficacy of drugs with potential antipsychotic properties. PMID- 29249807 TI - Viral subversion of B cell responses within secondary lymphoid organs. AB - Antibodies play a crucial role in virus control. The production of antibodies requires virus-specific B cells to encounter viral antigens in lymph nodes, become activated, interact with different immune cells, proliferate and enter specific differentiation programmes. Each step occurs in distinct lymph node niches, requiring a coordinated migration of B cells between different subcompartments. The development of multiphoton intravital microscopy has enabled researchers to begin to elucidate the precise cellular and molecular events by which lymph nodes coordinate humoral responses. This Review discusses recent studies that clarify how viruses interfere with antibody responses, highlighting how these mechanisms relate to our topological and temporal understanding of B cell activation within secondary lymphoid organs. PMID- 29249808 TI - Brain structure in women at risk of postpartum psychosis: an MRI study. AB - Postpartum psychosis (PP) is the most severe psychiatric disorder associated with childbirth. The risk of PP is very high in women with a history of bipolar affective disorder or schizoaffective disorder. However, the neurobiological basis of PP remains poorly understood and no study has evaluated brain structure in women at risk of, or with, PP. We performed a cross-sectional study of 256 women at risk of PP and 21 healthy controls (HC) in the same postpartum period. Among women at risk, 11 who developed a recent episode of PP (PPE) (n = 2 with lifetime bipolar disorder; n = 9 psychotic disorder not otherwise specified) and 15 at risk women who did not develop an episode of PP (NPPE) (n = 10 with lifetime bipolar disorder; n = 1 with schizoaffective disorder; n = 1 with a history of PP in first-degree family member; n = 3 with previous PP). We obtained T1-weighted MRI scans at 3T and examined regional gray matter volumes with voxel based morphometry and cortical thickness and surface area with Freesurfer. Women with PPE showed smaller anterior cingulate gyrus, superior temporal gyrus and parahippocampal gyrus compared to NPPE women. These regions also showed decreased surface area. Moreover, the NPPE group showed a larger superior and inferior frontal gyrus volume than the HC. These results should be interpreted with caution, as there were between-group differences in terms of duration of illness and interval between delivery and MRI acquisition. Nevertheless, these are the first findings to suggest that MRI can provide information on brain morphology that characterize those women at risk of PP more likely to develop an episode after childbirth. PMID- 29249809 TI - The direct role of 5-lipoxygenase on tau pathology, synaptic integrity and cognition in a mouse model of tauopathy. AB - Neurodegenerative tauopathies are characterized by pathological accumulation of highly phosphorylated isoforms of tau protein, which leads to progressive neuronal loss. Neuroinflammation often accompanies tau-driven diseases; however, the direct role of neuroinflammation in tauopathies remains unknown. The 5 lipoxygenase (5LO) is a pro-inflammatory enzyme, which produces several bioactive metabolites and is widely expressed in the central nervous system. Previously, our group showed that 5LO influences the Alzheimer's disease (AD) phenotype of APP transgenic mice as well as a mouse model with plaques and tangles. However, whether this protein directly modulates tau phosphorylation and subsequent neuropathology remains to be fully investigated. In the current study, we provide evidence for an age-dependent and region-specific upregulation of the 5LO pathway (protein, message and activity) in a transgenic mouse model of tauopathy, the P301S line. In addition, we demonstrate that genetic deletion of 5LO in this mouse model results in significant memory improvement, reduces tau phosphorylation at specific epitopes as well as neuroinflammation and rescues synaptic pathology. In vitro studies confirmed that 5LO directly modulates tau phosphorylation at the same epitopes as for the brain tissues. Taken together, our data reveal an active involvement of the 5LO pathway in the development of the tauopathy phenotype and provide strong support to the hypothesis that this enzymatic protein should be considered a novel and viable therapeutic target for the treatment of human tauopathy. PMID- 29249810 TI - Schizophrenia and depression, two poles of endocannabinoid system deregulation. AB - The activity of certain G protein-coupled receptors (GPCRs) and of glutamate N Methyl-D-aspartate receptors (NMDARs) is altered in both schizophrenia and depression. Using postmortem prefrontal cortex samples from subjects with schizophrenia or depression, we observed a series of opposite changes in the expression of signaling proteins that have been implicated in the cross-talk between GPCRs and NMDARs. Thus, the levels of HINT1 proteins and NMDAR NR1 subunits carrying the C1 cytosolic segment were increased in depressives and decreased in schizophrenics, respect to matched controls. The differences in NR1 C1 subunits were compensated for via altered expression of NR1 subunits lacking the C1 segment; thus, the total number of NR1 subunits was comparable among the three groups. GPCRs influence the function of NR1 C1-containing NMDARs via PKC/Src, and thus, the association of mu-opioid and dopamine 2 receptors with NR1 C1 subunits was augmented in depressives and decreased in schizophrenics. However, the association of cannabinoid 1 receptors (CB1Rs) with NR1 C1 remained nearly constant. Endocannabinoids, via CB1Rs, control the presence of NR1 C1 subunits in the neural membrane. Thus, an altered endocannabinoid system may contribute to the pathophysiology of schizophrenia and depression by modifying the HINT1-NR1 C1/GPCR ratio, thereby altering GPCR-NMDAR cross-regulation. PMID- 29249811 TI - Increased decision thresholds trigger extended information gathering across the compulsivity spectrum. AB - Indecisiveness and doubt are cognitive phenotypes of compulsive disorders, including obsessive-compulsive disorder. Little is known regarding the cognitive mechanisms that drive these behaviours across a compulsivity spectrum. Here, we used a sequential information gathering task to study indecisiveness in subjects with high and low obsessive-compulsive scores. These subjects were selected from a large population-representative database, and matched for intellectual and psychiatric factors. We show that high compulsive subjects sampled more information and performed better when sampling was cost-free. When sampling was costly, both groups adapted flexibly to reduce their information gathering. Computational modelling revealed that increased information gathering behaviour could be explained by higher decision thresholds that, in turn, were driven by a delayed emergence of impatience or urgency. Our findings show that indecisiveness generalises to a compulsivity spectrum beyond frank clinical disorder, and this behaviour can be explained within a decision-theoretic framework as arising from an augmented decision threshold associated with an attenuated urgency signal. PMID- 29249813 TI - Inserting proteins into the bacterial cytoplasmic membrane using the Sec and YidC translocases. AB - This corrects the article DOI: 10.1038/nrmicro3595. PMID- 29249814 TI - Splicing: Going in circles. PMID- 29249812 TI - Uncovering the mechanisms of Acinetobacter baumannii virulence. AB - Acinetobacter baumannii is a nosocomial pathogen that causes ventilator associated as well as bloodstream infections in critically ill patients, and the spread of multidrug-resistant Acinetobacter strains is cause for concern. Much of the success of A. baumannii can be directly attributed to its plastic genome, which rapidly mutates when faced with adversity and stress. However, fundamental virulence mechanisms beyond canonical drug resistance were recently uncovered that enable A. baumannii and, to a limited extent, other medically relevant Acinetobacter species to successfully thrive in the health-care environment. In this Review, we explore the molecular features that promote environmental persistence, including desiccation resistance, biofilm formation and motility, and we discuss the most recently identified virulence factors, such as secretion systems, surface glycoconjugates and micronutrient acquisition systems that collectively enable these pathogens to successfully infect their hosts. PMID- 29249815 TI - Translational genetics: CRISPR therapies - making the grade not the cut. PMID- 29249816 TI - Novel schizophrenia risk factor pathways regulate FEZ1 to advance oligodendroglia development. AB - Neuropsychiatric disorders, represented by schizophrenia, affect not only neurons but also myelinating oligodendroglia (OL), both contribute to the complex etiology. Although numerous susceptibility genes for schizophrenia have been identified, their function has been primarily studied in neurons. Whether malfunction of risk genes underlies OL defects in schizophrenia pathogenesis remains poorly understood. In this study, we investigated the function and regulation of the well-recognized schizophrenia risk factor, Fasciculation and Elongation Protein Zeta-1 (FEZ1), in OL. We found that FEZ1 is expressed in oligodendroglia progenitor cells (OPCs) derived from rodent brains and human induced pluripotent stem cells (iPSCs) in culture and in myelinating oligodendrocytes in the brain. In addition, a vigorous upregulation of FEZ1 occurs during OPC differentiation and myelinogenesis, whereas knockdown of FEZ1 significantly attenuates the development of OL process arbors. We further showed that transcription of the Fez1 gene in OL cells is governed by a sophisticated functional interplay between histone acetylation-mediated chromatin modification and transcription factors that are dysregulated in schizophrenia. At the post transcriptional level, the selective RNA-binding protein QKI, a glia-specific risk factor of schizophrenia, binds FEZ1 mRNA. Moreover, QKI deficiency results in a marked reduction of FEZ1 specifically in OL cells of the quakingviable (qkv) hypomyelination mutant mice. These observations have uncovered novel pathways that involve multifaceted genetic lesions and/or epigenetic dysregulations in schizophrenia, which converge on FEZ1 regulation and cause OL impairment in neuropsychiatric disorders. PMID- 29249817 TI - Drug-induced inhibition of phosphorylation of STAT5 overrides drug resistance in neoplastic mast cells. AB - Systemic mastocytosis (SM) is a mast cell (MC) neoplasm with complex pathology and a variable clinical course. In aggressive SM (ASM) and MC leukemia (MCL), responses to conventional drugs are poor and the prognosis is dismal. R763 is a multi-kinase inhibitor that blocks the activity of Aurora-kinase-A/B, ABL1, AKT and FLT3. We examined the effects of R763 on proliferation and survival of neoplastic MC. R763 produced dose-dependent inhibition of proliferation in the human MC lines HMC-1.1 (IC50 5-50 nM), HMC-1.2 (IC50 1-10 nM), ROSAKIT WT (IC50 1 10 nM), ROSAKIT D816V (IC50 50-500 nM) and MCPV-1.1 (IC50 100-1000 nM). Moreover, R763 induced growth inhibition in primary neoplastic MC in patients with ASM and MCL. Growth-inhibitory effects of R763 were accompanied by signs of apoptosis and a G2/M cell cycle arrest. R763 also inhibited phosphorylation of KIT, BTK, AKT and STAT5 in neoplastic MC. The most sensitive target appeared to be STAT5. In fact, tyrosine phosphorylation of STAT5 was inhibited by R763 at 10 nM. At this low concentration, R763 produced synergistic growth-inhibitory effects on neoplastic MC when combined with midostaurin or dasatinib. Together, R763 is a novel promising multi-kinase inhibitor that blocks STAT5 activation and thereby overrides drug-resistance in neoplastic MC. PMID- 29249818 TI - Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia. AB - Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ?1 mutation during remission at a variant allele frequency of ?2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (P<0.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio, 2.34; P=0039) and overall survival (hazard ratio, 2.14; P=036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide postremission treatment.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.350. PMID- 29249819 TI - Chromothripsis in acute myeloid leukemia: Biological features and impact on survival. AB - Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study define incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix(r)) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (P=0.002), ELN high risk (HR) (P<0.001), lower white blood cell (WBC) count (P=0.040), TP53 loss and/or mutations (P<0.001) while FLT3 (P=0.025) and NPM1 (P=0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis positive patients showed a worse overall survival (OS) (P<0.001) compared with HR patients (P=0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e. TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, 17. CBA. FISH showed that chromothripsis is associated with marker, derivative and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.351. PMID- 29249820 TI - SETD2-mediated crosstalk between H3K36me3 and H3K79me2 in MLL-rearranged leukemia. AB - Previously, we identified SETD2 loss-of-function mutations in 22% of MLL rearranged (MLLr) acute leukemia patients, implicating a mechanism for cooperativity between SETD2 mutations and MLL fusions. However, the detailed mechanism of how SETD2-H3K36me3 downregulation accelerates MLLr leukemia remains unclear. Here, we show that in MLLr leukemia, both H3K79me2 and H3K36me3 are aberrantly elevated and co-enriched in a group of genes. SETD2 inactivation leads to a global reduction of H3K36me3 and a further elevation of H3K79me2, but does not change the expression of known MLL fusion target genes. Instead, this pattern of histone changes is associated with transcriptional deregulation of a novel set of genes; downregulating tumor suppressors (for example, ASXL1) and upregulating oncogenes (for example, ERG). Taken together, our findings reveal a global crosstalk between the oncogenic DOT1L-H3K79me2 axis and the tumor suppressive SETD2-H3K36me3 axis in gene regulation, provide molecular insights into how SETD2 mutations accelerate MLLr leukemogenesis through differential regulation of additional tumor suppressors and oncogenes. PMID- 29249821 TI - AZA-MS: a novel multiparameter mass spectrometry method to determine the intracellular dynamics of azacitidine therapy in vivo. AB - The cytidine analogue, 5-azacytidine (AZA; 5-AZA-cR), is the primary treatment for myelodysplastic syndrome and chronic myelomonocytic leukaemia. However, only ~50% of treated patients will respond to AZA and the drivers of AZA resistance in vivo are poorly understood. To better understand the intracellular dynamics of AZA upon therapy and decipher the molecular basis for AZA resistance, we have developed a novel, multiparameter, quantitative mass spectrometry method (AZA MS). Using AZA-MS, we have accurately quantified the abundance of the ribonucleoside (5-AZA-cR) and deoxyribonucleoside (5-AZA-CdR) forms of AZA in RNA, DNA and the cytoplasm within the same sample using nanogram quantities of input material. We report that although AZA induces DNA demethylation in a dose dependent manner, it has no corresponding effect on RNA methylation. By applying AZA-MS to primary bone marrow samples from patients undergoing AZA therapy, we have identified that responders accumulate more 5-AZA-CdR in their DNA compared with nonresponders. AZA resistance was not a result of impaired AZA metabolism or intracellular accumulation. Furthermore, AZA-MS has helped to uncover different modes of AZA resistance. Whereas some nonresponders fail to incorporate sufficient 5-AZA-CdR into DNA, others incorporate 5-AZA-CdR and effect DNA demethylation like AZA responders, but show no clinical benefit. PMID- 29249822 TI - Phase I/II trial of the oral regimen ixazomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma. AB - In this phase I/II trial, a triplet regimen of ixazomib (Ixa: 3 or 4 mg), pomalidomide (Pom: 4 mg), and dexamethasone (Dex: 40 mg) was administered to 32 lenalidomide-refractory multiple myeloma (MM) patients; 31 were evaluable for response and toxicity. At dose level 1 (DL1, 3 mg Ixa), 1/3 patients experienced grade 3 fatigue, grade 3 lung infection, grade 4 neutropenia, and grade 4 thrombocytopenia; all were considered dose limiting. Per 3+3 phase I design, an additional 3 patients were enrolled to DL1, with no further dose limiting toxicity (DLT). At dose level 2 (DL2, 4 mg Ixa), 1/3 patients had dose-limiting febrile neutropenia, neutropenia, and thrombocytopenia (grade 4 each). DL2 was expanded to enroll 3 additional patients with no further DLT, establishing the recommended phase II dose (RP2D). In phase II, 19 additional patients were treated at RP2D. With a median follow-up of 11.9 months, 48% achieved ?partial response (PR), with 5 patients (20%) achieving very good partial response (VGPR) and 76% experiencing ?stable disease. The most common adverse events (?grade 2) were anemia, neutropenia, thrombocytopenia, and infections. Peripheral neuropathy was infrequent. In summary, Ixa/Pom/Dex is a well-tolerated and effective oral combination therapy for patients with relapsed/refractory MM.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.352. PMID- 29249824 TI - Associations of genetic determinants of serum vitamin B12 and folate concentrations with hay fever and asthma: a Mendelian randomization meta analysis. AB - BACKGROUND/OBJECTIVES: Studies of the effect of vitamin B12 and folate on the risk of asthma and hay fever have shown inconsistent results that may be biased by reverse causation and confounding. We used a Mendelian randomization approach to examine a potential causal effect of vitamin B12 and folate on hay fever, asthma, and selected biomarkers of allergy by using 11 vitamin B12-associated single-nucleotide polymorphisms (SNPs) and 2 folate-associated SNPs as unconfounded markers. SUBJECTS/METHODS: We included 162,736 participants from 9 population-based studies including the UK Biobank. Results were combined in instrumental variable and meta-analyses and effects expressed as odds ratios (ORs) or estimates with 95% confidence interval (CI). RESULTS: Using genetic proxies for B12 and folate, instrumental variable analyses did not show evidence for associations between serum B12 and hay fever: OR = 1.02 (95% CI: 0.98, 1.05), asthma: OR = 0.99 (95% CI: 0.95, 1.04), allergic sensitization: OR = 1.02 (95% CI: 0.74, 1.40), or change in serum IgE: 10.0% (95% CI: -9.6%, 29.6%) per 100 pg/ml B12. Similarly, there was no evidence for association between serum folate and hay fever: OR = 0.74 (95% CI: 0.45, 1.21), asthma: OR = 0.80 (95% CI: 0.43, 1.49), or allergic sensitization: OR = 1.92 (95% CI: 0.11, 33.45), but there was a statistically significant association with change in serum IgE: 2.0% (95% CI: 0.43%, 3.58%) per 0.1 ng/ml serum folate. CONCLUSIONS: Our results did not support the hypothesis that levels of vitamin B12 and folate are causally related to hay fever, asthma, or biomarkers of allergy, but we found evidence of a positive association between serum folate and serum total IgE. PMID- 29249825 TI - Reliability and comparative validity of a Diet Quality Index for assessing dietary patterns of preschool-aged children in Sydney, Australia. AB - BACKGROUND/OBJECTIVES: To report on the reliability and validity of a Diet Quality Index (DQI) to assess preschoolers dietary patterns using a short food frequency questionnaire (sFFQ) and 3-day food records (3d-FR). SUBJECTS/METHODS: Seventy-seven preschool carers/parents completed a telephone interview on preschoolers (2-5-year olds) dietary habits in metropolitan Sydney. Agreement in scores was assessed using intraclass correlation (ICC) and paired t-tests for repeated sFFQ-DQI scores and Bland-Altman methods and paired t-tests for sFFQ-DQI and 3d-FR-DQI scores. RESULTS: Mean-total sFFQ-DQI ICC scores was high = 0.89, 95% CI (0.81, 0.93). There was weak agreement between sFFQ-DQI and 3d-FR-DQI scores (r = 0.36, p < 0.01). The 3d-FR-DQI scores were positively associated with carbohydrate, folate, beta-carotene, magnesium, calcium, protein, total fat and negatively associated with sugar, starch, niacin, vitamin C, phosphorus, polyunsaturated fat, and monounsaturated fat. CONCLUSIONS: The sFFQ-DQI demonstrated good reliability but weak validity. Associations between nutrients and 3d-FR-DQI scores indicate promising usability and warrants further investigation. Further research is needed to establish its validity in accurately scoring children's diet quality using sFFQ compared to 3d-FR before the tool can be implemented for use in population settings. PMID- 29249826 TI - Gene expression associated with PTSD in World Trade Center responders: An RNA sequencing study. AB - The gene expression approach has provided promising insights into the pathophysiology of posttraumatic stress disorder (PTSD). However, few studies used hypothesis-free transcriptome-wide approach to comprehensively understand gene expression underpinning PTSD. A transcriptome-wide expression study using RNA sequencing of whole blood was conducted in 324 World Trade Center responders (201 with never, 81 current, 42 past PTSD). Samples from current and never PTSD reponders were randomly split to form discovery (N = 195) and replication (N = 87) cohorts. Differentially expressed genes were used in pathway analysis and to create a polygenic expression score. There were 448 differentially expressed genes in the discovery cohort, of which 99 remained significant in the replication cohort, including FKBP5, which was found to be up-regulated in current PTSD regardless of the genotypes. Several enriched biological pathways were found, including glucocorticoid receptor signaling and immunity-related pathways, but these pathways did not survive FDR correction. The polygenic expression score computed by aggregating 30 differentially expressed genes using the elastic net algorithm achieved sensitivity/specificity of 0.917/0.508, respectively for identifying current PTSD in the replication cohort. Polygenic scores were similar in current and past PTSD, with both groups scoring higher than trauma-exposed controls without any history of PTSD. Together with the pathway analysis results, these findings point to HPA-axis and immune dysregulation as key biological processes underpinning PTSD. A novel polygenic expression aggregate that differentiates PTSD patients from trauma-exposed controls might be a useful screening tool for research and clinical practice, if replicated in other populations. PMID- 29249827 TI - Schizophrenia-risk and urban birth are associated with proteomic changes in neonatal dried blood spots. AB - In the present study, we tested whether there were proteomic differences in blood between schizophrenia patients after the initial onset of the disorder and controls; and whether those differences were also present at birth among neonates who later developed schizophrenia compared to those without a psychiatric admission. We used multiple reaction monitoring mass spectrometry to quantify 77 proteins (147 peptides) in serum samples from 60 first-onset drug-naive schizophrenia patients and 77 controls, and 96 proteins (152 peptides) in 892 newborn blood-spot (NBS) samples collected between 1975 and 1985. Both serum and NBS studies showed significant alterations in protein levels. Serum results revealed that Haptoglobin and Plasma protease C1 inhibitor were significantly upregulated in first-onset schizophrenia patients (corrected P < 0.05). Alpha-2 antiplasmin, Complement C4-A and Antithrombin-III were increased in first-onset schizophrenia patients (uncorrected P-values 0.041, 0.036 and 0.013, respectively) and also increased in newborn babies who later develop schizophrenia (P-values 0.0058, 0.013 and 0.044, respectively). We also tested whether protein abundance at birth was associated with exposure to an urban environment during pregnancy and found highly significant proteomic differences at birth between urban and rural environments. The prediction model for urbanicity had excellent predictive performance in both discovery (area under the receiver operating characteristic curve (AUC) = 0.90) and validation (AUC = 0.89) sample sets. We hope that future biomarker studies based on stored NBS samples will identify prognostic disease indicators and targets for preventive measures for neurodevelopmental conditions, particularly those with onset during early childhood, such as autism spectrum disorder. PMID- 29249828 TI - Analysis of the joint effect of SNPs to identify independent loci and allelic heterogeneity in schizophrenia GWAS data. AB - We have tested published methods for capturing allelic heterogeneity and identifying loci of joint effects to uncover more of the "hidden heritability" of schizophrenia (SCZ). We used two tools, cojo-GCTA and multi-SNP, to analyze meta statistics from the latest genome-wide association study (GWAS) on SCZ by the Psychiatric Genomics Consortium (PGC). Stepwise regression on markers with p values <10-7 in cojo-GCTA identified 96 independent signals. Eighty-five passed the genome-wide significance threshold. Cross-validation of cojo-GCTA by CLUMP was 76%, i.e., 26 of the loci identified by the PGC using CLUMP were found to be dependent on another locus by cojo-GCTA. The overlap between cojo-GCTA and multi SNP was better (up to 92%). Three markers reached genome-wide significance (5 * 10-8) in a joint effect model. In addition, two loci showed possible allelic heterogeneity within 1-Mb genomic regions, while CLUMP analysis had identified 16 such regions. Cojo-GCTA identified fewer independent loci than CLUMP and seems to be more conservative, probably because it accounts for long-range LD and interaction effects between markers. These findings also explain why fewer loci with possible allelic heterogeneity remained significant after cojo-GCTA analysis. With multi-SNP, 86 markers were selected at the threshold 10-7. Multi SNP identifies fewer independent signals, due to splitting of the data and use of smaller samples. We recommend that cojo-GCTA and multi-SNP are used for post-GWAS analysis of all traits to call independent loci. We conclude that only a few loci in SCZ show joint effects or allelic heterogeneity, but this could be due to lack of power for that data set. PMID- 29249829 TI - A polygenic score for schizophrenia predicts glycemic control. AB - Schizophrenia is substantially comorbid with type 2 diabetes (T2D), but the molecular basis of this effect is incompletely understood. Here, we show that a cortical schizophrenia expression score predicts glycemic control from pancreatic islet cell expression. We used machine learning to identify a cortical expression signature in 212 schizophrenia patients and controls, which explained ~25% of the illness-associated variance. The algorithm was predicted in expression data from 51 subjects (9 with T2D), explained up to 26.3% of the variance in the glycemic control indicator HbA1c and could significantly differentiate T2D patients from controls. The cross-tissue prediction was driven by processes previously linked to diabetes. Genes contributing to this prediction were involved in the electron transport chain as well as kidney development and support oxidative stress as a molecular process underlying the comorbidity between both conditions. Together, the present results suggest a molecular commonality between schizophrenia and glycemic markers of type 2 diabetes. PMID- 29249831 TI - Cultural Meanings and the Aggregation of Actions: The Case of Sex and Schooling in Malawi. PMID- 29249833 TI - Photonic-band-gap gyrotron amplifier with picosecond pulses. AB - We report the amplification of 250 GHz pulses as short as 260 ps without observation of pulse broadening using a photonic-band-gap circuit gyrotron traveling-wave-amplifier. The gyrotron amplifier operates with a device gain of 38 dB and an instantaneous bandwidth of 8 GHz. The operational bandwidth of the amplifier can be tuned over 16 GHz by adjusting the operating voltage of the electron beam and the magnetic field. The amplifier uses a 30 cm long photonic band-gap interaction circuit to confine the desired TE03-like operating mode while suppressing lower order modes which can result in undesired oscillations. The circuit gain is >55 dB for a beam voltage of 23 kV and a current of 700 mA. These results demonstrate the wide bandwidths and a high gain achievable with gyrotron amplifiers. The amplification of picosecond pulses of variable lengths, 260-800 ps, shows good agreement with the theory using the coupled dispersion relation and the gain-spectrum of the amplifier as measured with quasi-CW input pulses. PMID- 29249830 TI - "DNA Methylation signatures in panic disorder". AB - Panic disorder (PD) affects about four million Europeans, with women affected twice as likely as men, causing substantial suffering and high economic costs. The etiopathogenesis of PD remains largely unknown, but both genetic and environmental factors contribute to risk. An epigenome-wide association study (EWAS) was conducted to compare medication-free PD patients (n = 89) with healthy controls (n = 76) stratified by gender. Replication was sought in an independent sample (131 cases, 169 controls) and functional analyses were conducted in a third sample (N = 71). DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip. One genome-wide association surviving FDR of 5% (cg07308824, P = 1.094 * 10-7, P-adj = 0.046) was identified in female PD patients (N = 49) compared to controls (N = 48). The same locus, located in an enhancer region of the HECA gene, was also hypermethylated in female PD patients in the replication sample (P = 0.035) and the significance of the association improved in the meta-analysis (P-adj = 0.004). Methylation at this CpG site was associated with HECA mRNA expression in another independent female sample (N = 71) both at baseline (P = 0.046) and after induction by dexamethasone (P = 0.029). Of 15 candidates, 5 previously reported as associated with PD or anxiety traits also showed differences in DNA methylation after gene-wise correction and included SGK1, FHIT, ADCYAP1, HTR1A, HTR2A. Our study examines epigenome-wide differences in peripheral blood for PD patients. Our results point to possible sex-specific methylation changes in the HECA gene for PD but overall highlight that this disorder is not associated with extensive changes in DNA methylation in peripheral blood. PMID- 29249832 TI - High-speed single-shot optical focusing through dynamic scattering media with full-phase wavefront shaping. AB - In biological applications, optical focusing is limited by the diffusion of light, which prevents focusing at depths greater than ~1 mm in soft tissue. Wavefront shaping extends the depth by compensating for phase distortions induced by scattering and thus allows for focusing light through biological tissue beyond the optical diffusion limit by using constructive interference. However, due to physiological motion, light scattering in tissue is deterministic only within a brief speckle correlation time. In in vivo tissue, this speckle correlation time is on the order of milliseconds, and so the wavefront must be optimized within this brief period. The speed of digital wavefront shaping has typically been limited by the relatively long time required to measure and display the optimal phase pattern. This limitation stems from the low speeds of cameras, data transfer and processing, and spatial light modulators. While binary-phase modulation requiring only two images for the phase measurement has recently been reported, most techniques require at least three frames for the full-phase measurement. Here, we present a full-phase digital optical phase conjugation method based on off-axis holography for single-shot optical focusing through scattering media. By using off-axis holography in conjunction with graphics processing unit based processing, we take advantage of the single-shot full-phase measurement while using parallel computation to quickly reconstruct the phase map. With this system, we can focus light through scattering media with a system latency of approximately 9 ms, on the order of the in vivo speckle correlation time. PMID- 29249834 TI - Photoinduced Cycloadditions in the Diversity-Oriented Synthesis Toolbox: Increasing Complexity with Straightforward Postphotochemical Modifications. AB - Rapid growth of complexity and unprecedented molecular architectures are realized via the excited-state intramolecular proton transfer (ESIPT) in o acylamidobenzaldehydes and ketones followed by [4+2] or [4+4] cycloadditions with subsequent postphotochemical modifications. The approach is congruent with Diversity-Oriented Synthesis: photoprecursors are synthesized in a modular fashion allowing for up to four diversity inputs. The complexity of the primary photoproducts is further enhanced using straightforward and high-yielding postphotochemical modification steps such as reactions with nitrile oxides, nitrones, Povarov reaction, and oxa-Diels-Alder reaction. PMID- 29249835 TI - Evaluation of Smoke-free Foster Care Education for Foster and Adoptive Caregivers. AB - Only half of the states in the U.S. mandate that foster homes have a smoking ban. It is beneficial to promote training about the impacts of exposure to secondhand smoke to foster caregivers. This article presents the evaluation of a training delivered to foster and adoptive parents in Georgia. The topics with highest values learned were: 5 steps to creating a smoke-free home, benefits of a smoke free home, dangers of secondhand smoke, and thirdhand smoke. PMID- 29249836 TI - Towards Clarity in Research on "Non-Cognitive" Skills: Linking Executive Functions, Self-Regulation, and Economic Development to Advance Life Outcomes for Children, Adolescents and Youth Globally. PMID- 29249837 TI - A Gender Bias Habit-Breaking Intervention Led to Increased Hiring of Female Faculty in STEMM Departments. AB - Addressing the underrepresentation of women in science is a top priority for many institutions, but the majority of efforts to increase representation of women are neither evidence-based nor rigorously assessed. One exception is the gender bias habit-breaking intervention (Carnes et al., 2015), which, in a cluster-randomized trial involving all but two departmental clusters (N = 92) in the 6 STEMM focused schools/colleges at the University of Wisconsin - Madison, led to increases in gender bias awareness and self-efficacy to promote gender equity in academic science departments. Following this initial success, the present study compares, in a preregistered analysis, hiring rates of new female faculty pre- and post manipulation. Whereas the proportion of women hired by control departments remained stable over time, the proportion of women hired by intervention departments increased by an estimated 18 percentage points (OR = 2.23, dOR = 0.34). Though the preregistered analysis did not achieve conventional levels of statistical significance (p < 0.07), our study has a hard upper limit on statistical power, as the cluster-randomized trial has a maximum sample size of 92 departmental clusters. These patterns have undeniable practical significance for the advancement of women in science, and provide promising evidence that psychological interventions can facilitate gender equity and diversity. PMID- 29249838 TI - Music-of-light stethoscope: a demonstration of the photoacoustic effect. AB - In this paper we present a system aimed at demonstrating the photoacoustic (PA) effect for educational purposes. PA imaging is a hybrid imaging modality that requires no contrast agent and has a great potential for spine and brain lesion characterisation, breast cancer and blood flow monitoring notably in the context of fetal surgery. It relies on combining light excitation with ultrasound reception. Our brief was to present and explain PA imaging in a public-friendly way suitable for a variety of ages and backgrounds. We developed a simple, accessible demonstration unit using readily available materials. We used a modulated light emitting diode (LED) torch and an electronic stethoscope. The output of a music player was used for light modulation and the chest piece of the stethoscope covered by a black tape was used as an absorbing target and an enclosed chamber. This demonstration unit was presented to the public at the Bloomsbury Festival On Light in October 2015. Our stall was visited by over 100 people of varying ages. Twenty families returned in-depth evaluation questionnaires, which show that our explanations of the photoacoustic effect were well understood. Their interest in biomedical engineering was increased. PMID- 29249839 TI - A Calibrated Power Prior Approach to Borrow Information from Historical Data with Application to Biosimilar Clinical Trials. AB - A biosimilar refers to a follow-on biologic intended to be approved for marketing based on biosimilarity to an existing patented biological product (i.e., the reference product). To develop a biosimilar product, it is essential to demonstrate biosimilarity between the follow-on biologic and the reference product, typically through two-arm randomization trials. We propose a Bayesian adaptive design for trials to evaluate biosimilar products. To take advantage of the abundant historical data on the efficacy of the reference product that is typically available at the time a biosimilar product is developed, we propose the calibrated power prior, which allows our design to adaptively borrow information from the historical data according to the congruence between the historical data and the new data collected from the current trial. We propose a new measure, the Bayesian biosimilarity index, to measure the similarity between the biosimilar and the reference product. During the trial, we evaluate the Bayesian biosimilarity index in a group sequential fashion based on the accumulating interim data, and stop the trial early once there is enough information to conclude or reject the similarity. Extensive simulation studies show that the proposed design has higher power than traditional designs. We applied the proposed design to a biosimilar trial for treating rheumatoid arthritis. PMID- 29249840 TI - Nickel-Mediated Synthesis of Isoindolinones at Room Temperature. AB - This communication describes a method for the Ni(cod) 2-mediated intramolecular arylation of alkyl C-H bonds adjacent to the nitrogen atom in benzamide substrates. The transformation proceeds at room temperature and exhibits selectivity for functionalization of more substituted C-H bonds. The yields of the desired isoindolinone products are higher with benzamide substrates containing tertiary alkyl groups on the nitrogen atom than with those bearing primary or secondary alkyls. The results described herein suggest a mechanism involving radical intermediates for these reactions. PMID- 29249841 TI - Iodine-mediated rearrangements of diallylsilanes. AB - Diallylsilanes can be made to rearrange upon treatment with I2. Of the silanes tested, diallyldiphenylsilane showed the greatest propensity to undergo this intramolecular carbocation allylation process. After etherification of the initially formed iodosilane, the products from this transformation represent useful synthetic intermediates, suitable for alkylation and cross metathesis/annulation reactions. PMID- 29249842 TI - Mapping the Growing Discipline of Dissemination and Implementation Science in Health. AB - Background: The field of dissemination and implementation (D&I) research in health has grown considerably in the past decade. Despite the potential for advancing the science, limited research has focused on mapping the field. Methods: We administered an online survey to individuals in the D&I field to assess participants' demographics and expertise, as well as engagement with journals and conferences, publications, and grants. A combined roster-nomination method was used to collect data on participants' advice networks and collaboration networks; participants' motivations for choosing collaborators was also assessed. Frequency and descriptive statistics were used to characterize the overall sample; network metrics were used to characterize both networks. Among a sub-sample of respondents who were researchers, regression analyses identified predictors of two metrics of academic performance (i.e., publications and funded grants). Results: A total of 421 individuals completed the survey, representing a 30.75% response rate of eligible individuals. Most participants were White (n = 343), female (n = 284, 67.4%), and identified as a researcher (n = 340, 81%). Both the advice and the collaboration networks displayed characteristics of a small world network. The most important motivations for selecting collaborators were aligned with advancing the science (i.e., prior collaborators, strong reputation, and good collaborators) rather than relying on human proclivities for homophily, proximity, and friendship. Among a sub-sample of 295 researchers, expertise (individual predictor), status (advice network), and connectedness (collaboration network) were significant predictors of both metrics of academic performance. Conclusions: Network-based interventions can enhance collaboration and productivity; future research is needed to leverage these data to advance the field. PMID- 29249843 TI - Female Spider Monkeys (Ateles geoffroyi) Cope with Anthropogenic Disturbance Through Fission-Fusion Dynamics. AB - Most primates live in habitats with some level of anthropogenic disturbance, and such disturbances have a larger impact on frugivorous primates that are more sensitive to ecological disruptions than folivores. Fecal glucocorticoid metabolites provide insight into how the external environment affects internal physiological state, and thus provide information on how anthropogenic pressures become embodied. Here, I examine how subgroup size and glucocorticoids vary with high and low fruit abundance, and how fruit abundance, subgroup size, and activity budget affect fecal glucocorticoid metabolites in female spider monkeys (Ateles geoffroyi) living in an anthropogenically disturbed habitat. I measured these variables via behavioral, ecological, and fecal sampling for 15 months in 17 female spider monkeys at El Zota Biological Field Station. Subgroup size was significantly larger during periods of high fruit abundance, but glucocorticoids did not differ between periods of low and high fruit abundance. Monthly fruit abundance predicted subgroup sizes significantly, but did not predict fecal glucocorticoid concentrations. Increased resting time and reproductive state predicted fecal glucocorticoid concentrations significantly, but travel and foraging time had no significant effect on glucocorticoid concentrations. Individual resting time over the study period correlated negatively with glucocorticoid concentrations. These results suggest that spider monkeys cope with variation in fruit abundance by adjusting subgroup size, and that these adjustments may mitigate environmental stress in this mildly seasonal environment. The large, relatively productive forest size at this site, and the availability of anthropogenic food sources, enable this population of spider monkeys to cope with human-induced habitat disturbance. PMID- 29249844 TI - The relationship between urban forests and income: A meta-analysis. AB - Urban trees provide substantial public health and public environmental benefits. However, scholarly works suggest that urban trees may be unequally distributed among poor and minority urban communities, meaning that these communities are potentially being deprived of public environmental benefits, a form of environmental injustice. The evidence of this problem is not uniform however, and evidence of inequity varies in size and significance across studies. This variation in results suggests the need for a research synthesis and meta analysis. We employed a systematic literature search to identify original studies which examined the relationship between urban forest cover and income (n=61) and coded each effect size (n=332). We used meta-analytic techniques to estimate the average (unconditional) relationship between urban forest cover and income and to estimate the impact that methodological choices, measurement, publication characteristics, and study site characteristics had on the magnitude of that relationship. We leveraged variation in study methodology to evaluate the extent to which results were sensitive to methodological choices often debated in the geographic and environmental justice literature but not yet evaluated in environmental amenities research. We found evidence of income-based inequity in urban forest cover (unconditional mean effect size = 0.098; s.e. = .017) that was robust across most measurement and methodological strategies in original studies and results did not differ systematically with study site characteristics. Studies that controlled for spatial autocorrelation, a violation of independent errors, found evidence of substantially less urban forest inequity; future research in this area should test and correct for spatial autocorrelation. PMID- 29249845 TI - Contextual Factors Associated with the Use of Corporal Punishment in U.S. Public Schools. PMID- 29249847 TI - Thermodynamic Properties at Saturation Derived from Experimental Two-Phase Isochoric Heat Capacity of 1-Hexyl-3-methylimidazolium Bis[(trifluoromethyl)sulfonyl]imide. AB - New measurements are reported for the isochoric heat capacity of the ionic liquid substance 1-hexyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([C6mim][NTf2]). These measurements extend the ranges of our earlier study [N.G. Polikhronidi et al., Phys. Chem. Liq. 52, 657 (2014)] by 5 % of the compressed liquid density and by 75 kelvins. An adiabatic calorimeter was used to measure one-phase (CV1) liquid and two-phase (CV2) liquid + vapor isochoric heat capacities, densities (rhoS ), and phase-transition temperatures (TS ) of the ionic liquid (IL) substance. The combined expanded uncertainty of the density rho and isochoric heat capacity CV measurements at the 95 % confidence level with a coverage factor of k = 2 is estimated to be 0.15 % and 3 %, respectively. Measurements are concentrated in the immediate vicinity of the liquid + vapor phase transition curve, in order to closely observe phase transitions. The present measurements and those of our earlier study are analyzed together, and are presented in terms of thermodynamic properties (TS, rhoS, CV1 and CV2) evaluated at saturation and in terms of key derived thermodynamic properties Cp, CS, [Formula: see text], and [Formula: see text] on the liquid + vapor phase transition curve. A thermodynamic relation by Yang and Yang is used to confirm the internal consistency of measured two-phase heat capacities CV2, which are observed to fall perfectly on a line as a function of specific volume at a constant temperature. The observed linear behavior is exploited to evaluate contributions to the quantity CV2 = f(V,T) from chemical potential [Formula: see text] and from vapor pressure [Formula: see text]. The physical nature and specific details of the temperature and specific volume dependence of the two phase isochoric heat capacity and some features of the other derived thermodynamic properties of IL at liquid saturation curve are considered in detail. PMID- 29249846 TI - Development and implementation of a screen-and-refer approach to addressing maternal depression, substance use, and intimate partner violence in home visiting clients. AB - Perinatal maternal depression (MD), substance use (SU), and intimate partner violence (IPV) are critical public health concerns with significant negative impacts on child development. Bolstering the capacity of home visiting (HV) programs to address these significant risk factors has potential to improve child and family outcomes. This study presents a description and mixed-methods feasibility evaluation of the "Home Visitation Enhancing Linkages Project (HELP)," a screen-and-refer approach to addressing MD, SU, and IPV within HV aimed at improving risk identification and linkage to treatment among HV clients. HELP was a three-phase intervention that included three evidence-based interventions: screening, motivational interviewing (MI), and case management (CM). This study presents quantitative fidelity data from 21 home visitors reporting on 116 clients in 4 HV programs, as well as qualitative data from structured interviews with 14 home visitors. Nearly all clients were screened and 22% screened positive on at least one risk domain. Rates of MI and CM implementation were lower than expected, however home visitors implemented general supportive interventions at high rates. Home visitor interviews revealed the following factors that may have impacted HELP implementation: client disclosure of risk, barriers to treatment access, systems integration, home visitor role perception, and integration of HELP into the broader HV curriculum. Implications of study findings for the design of future attempts to address maternal risk within HV are discussed. PMID- 29249848 TI - Halide Control of N,N-Coordination versus N,C-Cyclometalation and Stereospecific Phenyl Ring Deuteration of Osmium(II) p-Cymene Phenylazobenzothiazole Complexes. AB - We report the synthesis of halido Os(II) p-cymene complexes bearing bidentate chelating phenylazobenzothiazole (AZBTZ) ligands. Unlike the analogous phenylazopyridine (AZPY) complexes, AZBTZ-NMe2 is capable of both N,N coordination to Os(II) and cyclometalation to form N,C-coordinated species. N,C Coordination occurs via an azo nitrogen and an ortho carbon on the aniline ring, as identified by 1H NMR and X-ray crystallography of [Os(p-cym)(N,N-AZBTZ NMe2)Cl]PF6 (1a), [Os(p-cym)(N,N-AZBTZ-NMe2)Br]PF6 (2a), [Os(p-cym)(N,C-AZBTZ NMe2)Br] (2b), and [Os(p-cym)(N,C-AZBTZ-NMe2)I] (3b). The N,C-coordinated species is more stable and is not readily converted to the N,N-coordinated complex. Analysis of the crystal structures suggests that their formation is influenced by steric interactions between the p-cym and AZBTZ-NMe2 ligands: in particular, larger monodentate halide ligands favor N,C-coordination. The complexes [Os(p cym)(N,N-Me2-AZBTZ-NH2)Cl]PF6 (4) and [Os(p-cym)(N,N-Me2-AZBTZ-NH2)I]PF6 (5) were synthesized with methyl groups blocking the ortho positions on the aniline ring, forcing an N,N-coordination geometry. 1H NMR NOE experiments confirmed hindered rotation of the arene ligand and steric crowding around the metal center. Complex 2b exhibited unexpected behavior under acidic conditions, involving regiospecific deuteration of the aniline ring at the meta position, as observed by 1H NMR and high-resolution ESI-MS. Deuterium exchange occurs only under acidic conditions, suggesting an associative mechanism. The calculated partial charges on 2b show that the meta carbon is significantly more negatively charged, which may account for the regiospecificity of deuterium exchange. PMID- 29249849 TI - Optimal Design of a Resonance-Based Voltage Boosting Rectifier for Wireless Power Transmission. AB - This paper presents the design procedure for a new multi-cycle resonance-based voltage boosting rectifier (MCRR) capable of delivering a desired amount of power to the load (PDL) at a designated high voltage (HV) through a loosely-coupled inductive link. This is achieved by shorting the receiver (Rx) LC-tank for several cycles to harvest and accumulate the wireless energy in the RX inductor before boosting the voltage by breaking the loop and transferring the energy to the load in a quarter cycle. By optimizing the geometries of the transmitter (Tx) and Rx coils and the number of cycles, N, for energy harvesting, through an iterative design procedure, the MCRR can achieve the highest PDL under a given set of design constraints. Governing equations in the MCRR operation are derived to identify key specifications and the design guidelines. Using an exemplary set of specs, the optimized MCRR was able to generate 20.9 VDC across a 100 kOmega load from a 1.8 Vp, 6.78 MHz sinusoid input in the ISM-band at a Tx/Rx coil separation of 1.3 cm, power transfer efficiency (PTE) of 2.2%, and N = 9 cycles. At the same coil distance and loading, coils optimized for a conventional half wave rectifier (CHWR) were able to reach only 13.6 VDC from the same source. PMID- 29249851 TI - Effective attenuation lengths for quantitative determination of surface composition by Auger-electron spectroscopy and X-ray photoelectron spectroscopy. AB - The effective attenuation length (EAL) is normally used in place of the inelastic mean free path (IMFP) to account for elastic-scattering effects when describing the attenuation of Auger electrons and photoelectrons from a planar substrate by an overlayer film. An EAL for quantitative determination of surface composition by Auger-electron spectroscopy (AES) or X-ray photoelectron spectroscopy (XPS) is similarly useful to account for elastic-scattering effects on the signal intensities. We calculated these EALs for four elemental solids (Si, Cu, Ag, and Au) and for energies between 160 eV and 1.4 keV. The XPS calculations were made for two instrumental configurations while the AES calculations were made from the XPS formalism after "switching off" the XPS anisotropy. The EALs for quantitative determination of surface composition by AES and XPS were weak functions of emission angle for emission angles between 0 and 50 degrees . The ratios of the average values of these EALs to the corresponding IMFPs could be fitted to a second-order function of the single-scattering albedo, a convenient measure of the strength of elastic-scattering effects. EALs for quantitative determination of surface composition by AES and XPS for other materials can be simply found from this relationship. PMID- 29249850 TI - Riders in the sky (islands): using a mega-phylogenetic approach to understand plant species distribution and coexistence at the altitudinal limits of angiosperm plant life. AB - Aim: Plants occurring on high-alpine summits are generally expected to persist due to adaptations to extreme selective forces caused by the harshest climates where angiosperm life is known to thrive. We assessed the relative effects of this strong environmental filter and of other historical and stochastic factors driving plant community structure in very high-alpine conditions (up to 4,000m). Location: European Alps, Ecrins National Park, France. Methods: Using species occurrence data collected from floristic surveys on 15 summits (2,791 m - 4,102 m a.s.l.) throughout the Ecrins range, along with existing molecular sequence data obtained from GenBank, we used a mega-phylogenetic approach to evaluate the phylogenetic structure of high-alpine plant species assemblages. We used three nested species pools and two null models to address the importance of species specific and species-neutral processes for driving coexistence. Results: Compared to the entire species pool of the study region, alpine summits exhibited a strong signal of phylogenetic clustering. Restricting statistical sampling to environmentally and historically defined species pools reduced the significance of this pattern. However, we could not reject a model that explicitly incorporates neutral colonization and local extinction in shaping community structure for dominant plant orders. Between summits, phylogenetic turnover was generally lower than expected. Environmental drivers did not explain overall phylogenetic patterns, but we found significant geographic and climatic structure in phylogenetic diversity at finer taxonomic scales. Main conclusions: Although we found evidence for strong phylogenetic clustering within alpine summits, we were not able to reject models of species-neutral processes to explain patterns of floristic diversity. Our results suggest that plant community structure in high-alpine regions can also be shaped by neutral processes, and not through the sole action of environmental selection as traditionally assumed for harsh and stressful environments. PMID- 29249852 TI - Respect. PMID- 29249853 TI - The Role of Palliative Care in Oncology. AB - Palliative care is a powerful adjunct to oncology that adds distinct value to the physical, mental, and psychosocial well-being of patients living with cancer. Its expanding role and integration with standard oncologic care has proven clinical benefit, as the practice of palliative care can help alleviate symptom burden, enhance illness and prognostic understanding, and improve both the quality of life and overall survival for patients. The primary aim of this review article is to highlight the significant interplay between palliative care and oncology and, in doing so, shed light on the areas for improvement and modern challenges that exist to meet the complex palliative care needs of patients with cancer. PMID- 29249854 TI - Incorporating Quality of Life Metrics in Interventional Oncology Practice. AB - Interventional radiologists care for a large number of cancer patients with the breadth of palliative intent minimally invasive procedures that we provide. Understanding our meaningful impact on patients' quality of life is essential toward validating our role in the palliation of cancer patients. As such, it is critically important for interventional radiologists to understand common instruments used for the reporting of patient's quality of life measures. Common instruments used to measure pain and quality of life for cancer patients include the numerical rating scale, visual analog scale, brief pain inventory, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, and the Functional Assessment of Cancer Therapy. An ideal quality of life instrument should be a patient reported outcome measure across multiple domains (e.g., physical health, psychological, social), and be both validated and reliable. PMID- 29249855 TI - Metastatic Osseous Pain Control: Radiation Therapy. AB - Metastatic disease to the bone is a common manifestation of advanced cancer, and can result in pain, pathologic fractures, hypercalcemia, and overall functional compromise. External beam radiation is a proven, highly efficacious, and noninvasive therapy that can provide symptomatic relief from painful osseous lesions. When deciding upon the best treatment regimen, it is important to consider patient factors such as overall life expectancy, performance status, disease burden, and site of osseous metastatic pain. Determination of best treatment ideally requires multidisciplinary input from radiologists, medical oncologists, surgeons, pain management, and palliative care specialists together with radiation oncologists. PMID- 29249856 TI - Metastatic Osseous Pain Control: Bone Ablation and Cementoplasty. AB - Nociceptive and/or neuropathic pain can be present in all phases of cancer (early and metastatic) and are not adequately treated in 56 to 82.3% of patients. In these patients, radiotherapy achieves overall pain responses (complete and partial responses combined) up to 60 and 61%. On the other hand, nowadays, ablation is included in clinical guidelines for bone metastases and the technique is governed by level I evidence. Depending on the location of the lesion in the peripheral skeleton, either the Mirels scoring or the Harrington (alternatively the Levy) grading system can be used for prophylactic fixation recommendation. As minimally invasive treatment options may be considered in patients with poor clinical status or limited life expectancy, the aim of this review is to detail the techniques proposed so far in the literature and to report the results in terms of safety and efficacy of ablation and cementoplasty (with or without fixation) for bone metastases. Percutaneous image-guided treatments appear as an interesting alternative for localized metastatic lesions of the peripheral skeleton. PMID- 29249857 TI - Symptomatic Fluid Drainage: Tunneled Peritoneal and Pleural Catheters. AB - Malignant ascites and pleural effusion are significant contributors to patient symptoms such as shortness of breath, abdominal distension, and nausea in the setting of cancer. There are numerous methods employed to control such symptoms such as serial drainages, pleurodesis, and tunneled drainage catheters. Tunneled drainage catheters are a safe, effective, and a minimally invasive procedure to palliate the symptoms of malignant ascites and pleural effusion. PMID- 29249858 TI - Symptomatic Fluid Drainage: Peritoneovenous Shunt Placement. AB - Ascites causes significant discomfort and has negative impact on patient's quality of life. Medical therapies including dietary restriction and diuretics are successful in only 40 to 44% of patients with malignant ascites and repeated paracentesis only provides temporary symptomatic relief. Therefore, a more permanent solution is necessary. Indwelling catheters or peritoneovenous shunt placement can provide more permanent symptomatic relief and improve patients' quality of life. Unlike indwelling catheters, peritoneovenous shunts do not limit patients' life style and therefore should be offered as first option in patients who are good candidates. Denver shunt (CareFusion-BD Worldwide) is the current available peritoneovenous shunt. In this article, the indications, contraindications, technical aspects of shunt placement, and techniques to prevent postprocedure complications will be discussed. PMID- 29249859 TI - Bowel Obstruction: Decompressive Gastrostomies and Cecostomies. AB - Over the past 30 years, image-guided placement of gastrostomies and cecostomies for gastrointestinal decompression has developed into a safe and effective treatment for symptomatic bowel obstruction. Gastrostomies and cecostomies relieve patient symptoms, can prevent serious complications such as colonic perforation, and may bridge patients to more definitive treatment for the underlying cause of obstruction. This article will review the history of decompressive gastrostomies and cecostomies as well as the indications, contraindications, technique, complications, and outcomes of these procedures. PMID- 29249860 TI - Palliative Percutaneous Biliary Interventions in Malignant High Bile Duct Obstruction. AB - The optimal palliative intervention for malignant biliary obstruction is internal drainage by placement of a metallic stent. For patients with hilar biliary obstruction or low bile duct obstruction in whom endoscopy is not feasible, a percutaneous transhepatic approach in interventional radiology is preferred. This article reviews the rationale for this approach, periprocedural management, and techniques to optimize stent patency. PMID- 29249861 TI - Biliary Obstruction: Endoscopic Approaches. AB - Painless jaundice is a harbinger of malignant biliary obstruction, with the majority of cases due to pancreatic adenocarcinoma. Despite advances in treatment, including improved surgical techniques and neoadjuvant (preoperative) chemotherapy, long-term survival from pancreatic cancer is rare. This lack of significant improvement in outcomes is believed to be due to multiple reasons, including the advanced stage at diagnosis and lack of an adequate biomarker for screening and early detection, prior to the onset of jaundice or epigastric pain. Close attention is required to select appropriate patients for preoperative biliary decompression, and to prevent morbid complications from biliary drainage procedures, such as pancreatitis and cholangitis. Use of small caliber plastic biliary stents during endoscopic retrograde cholangiopancreatography should be minimized, as metal stents have increased area for improved bile flow and a reduced risk of adverse events during neoadjuvant therapy. Efforts are underway by translational scientists, radiologists, oncologists, surgeons, and gastroenterologists to augment lifespan for our patients and to more readily treat this deadly disease. In this review, the authors discuss the rationale and techniques of endoscopic biliary intervention, mainly focusing on malignant biliary obstruction by pancreatic cancer. PMID- 29249863 TI - Palliative Embolization for Refractory Bleeding. AB - Bleeding is a common and often challenging complication of malignancy. Etiologies of hemorrhage in this patient population vary, and bleeding may present as an acute, life-threatening emergency or a chronic, low-volume blood loss. For patients with advanced malignancies, interventions to manage bleeding must be balanced by the patient's life expectancy and quality of life. As such, minimally invasive procedures such as transarterial embolization are useful therapeutic options in appropriately selected patients. There is a rich history of palliative transarterial embolization for refractory bleeding in cancer patients. This technique was first applied in the 1970s and has since become an established treatment tool for malignancy-related bleeding throughout the body. While the preponderance of published data comprised case reports and small retrospective studies, the use of embolization continues to expand as experience grows and techniques are refined. In this review, we summarize the literature and provide our perspective on embolization for refractory bleeding in cancer patients. PMID- 29249864 TI - Malignant Venous Obstruction: Superior Vena Cava Syndrome and Beyond. AB - Venous obstruction in the cancer population can result in substantial morbidity and, in extreme cases, mortality. While venous obstruction can be caused by both benign and malignant etiologies in this population, the management of malignant venous obstruction as a palliative measure can be somewhat nuanced with respect to nonprocedural and procedural management, both with respect to treatment of the underlying malignancy as well as treatment of venous hypertension, which may be associated with venous thrombosis. Symptom severity, primary malignancy, functional status, and prognosis are all fundamental to the patient workup and dictate both the timing and extent of endovascular intervention. The morbidity and mortality associated with malignant obstructions of central venous structures, specifically the superior vena cava and inferior vena cava, can be significantly improved with endovascular management in appropriately selected patients. Thus, the pertinent literature regarding the clinical presentation, workup, and endovascular management of malignant central venous obstruction syndromes, with directed attention to superior vena cava syndrome and inferior vena cava syndrome, will be reviewed in this article. PMID- 29249865 TI - Heparin-Induced Thrombocytopenia and Thrombosis: Preventing your Thrombolysis Practice from Taking a HITT. AB - Heparin-induced thrombocytopenia and thrombosis (HITT) is an under-recognized cause of deep venous thrombosis treatment failure and of complications during catheter-directed thrombolysis. After a review of HITT pathophysiology, diagnosis, and management, three different cases are presented in this article. Each case highlights subtleties and challenges of HITT diagnosis and management. An example of a practical approach to the diagnosis of HITT is presented. PMID- 29249862 TI - Celiac Plexus Block and Neurolysis in the Management of Chronic Upper Abdominal Pain. AB - Chronic upper abdominal pain occurs as a complication of various malignant and benign diseases including pancreatic cancer and chronic pancreatitis, and when present may contribute to lower quality of life and higher mortality. Though various pain management strategies are available as part of a multimodal approach, they are often incompletely effective and accompanied by side effects. Pain originating in upper abdominal viscera is transmitted through the celiac plexus, which is an autonomic plexus located in the retroperitoneum at the root of the celiac trunk. Direct intervention at the level of the plexus, referred to as celiac plexus block or neurolysis depending on the injectate, is a minimally invasive therapeutic strategy which has been demonstrated to decrease pain, improve function, and reduce opiate dependence. Various percutaneous techniques have been reported, but, with appropriate preprocedural planning, use of image guidance (usually computed tomography), and postprocedural care, the frequency and severity of complications is low and the success rate high regardless of approach. The main benefit of the intervention may be in reduced opiate dependence and opiate-associated side effects, which in turn improves quality of life. Celiac plexus block and neurolysis are safe and effective treatments for chronic upper abdominal pain and should be considered early in patients experiencing such symptoms. PMID- 29249866 TI - Boosted Multivariate Trees for Longitudinal Data. AB - Machine learning methods provide a powerful approach for analyzing longitudinal data in which repeated measurements are observed for a subject over time. We boost multivariate trees to fit a novel flexible semi-nonparametric marginal model for longitudinal data. In this model, features are assumed to be nonparametric, while feature-time interactions are modeled semi-nonparametrically utilizing P-splines with estimated smoothing parameter. In order to avoid overfitting, we describe a relatively simple in sample cross-validation method which can be used to estimate the optimal boosting iteration and which has the surprising added benefit of stabilizing certain parameter estimates. Our new multivariate tree boosting method is shown to be highly flexible, robust to covariance misspecification and unbalanced designs, and resistant to overfitting in high dimensions. Feature selection can be used to identify important features and feature-time interactions. An application to longitudinal data of forced 1 second lung expiratory volume (FEV1) for lung transplant patients identifies an important feature-time interaction and illustrates the ease with which our method can find complex relationships in longitudinal data. PMID- 29249867 TI - Reflection: A Socratic approach. AB - Reflection is a fuzzy concept. In this article we reveal the paradoxes involved in studying the nature of reflection. Whereas some scholars emphasize its discursive nature, we go further and underline its resemblance to the self-biased dialogue Socrates had with the slave in Plato's Meno. The individual and internal nature of the reflection process creates difficulty for studying it validly and reliably. We focus on methodological issues and use Hans Linschoten's view of coupled systems to identify, analyze, and interpret empirical research on reflection. We argue that researchers and research participants can take on roles in several possible system couplings. Depending on who controls the manipulation of the stimulus, who controls the measuring instrument, who interprets the measurement and the response, different types of research questions can be answered. We conclude that reflection may be validly studied by combining different couplings of experimenter, manipulation, stimulus, participant, measurement, and response. PMID- 29249868 TI - Making dialogue with an existential voice in transition from military to civilian life. AB - Dialogical Self Theory has contributed to the endeavors to map and grid self identity work in transition from military to civilian life throughout an empirical and longitudinal research project which focuses on existential dimensions. This article is based on a case study from this project and centers upon Sergeant Jonas, who, upon his return from deployment in Afghanistan, struggled with his transition as a new existential position was vocalized throughout the following annual interviews. This voice narrated feelings of meaninglessness, emptiness, and of having been deceived. In turn, this existential voice required an answer to a question which apparently had no answer. The meaning-making eventually evolved into an acceptance which enabled Jonas to proceed with his life. Dialogical processes between positions are important in order to go on with life amid existential concerns in the aftermath of military service since dialogicality of the self opens up a complex of dynamics of meaning-making processes, negotiations, and transformations. Based on the findings, it is suggested that the Personal Position Repertoire could potentially be strengthened by the addition of an internal existential position to its standard repertoire, at least when working with military personnel and/or veterans. PMID- 29249869 TI - Short-Term Postoperative Cognitive Dysfunction and Inflammatory Response in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Pilot Study. AB - Objectives: To assess the association between short-term postoperative cognitive dysfuction (POCD) and inflammtory response in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Design: A prospective cohort study. Setting: University medical centre. Participants: Fifty one adult patients who had undergone CRS-HIPEC and twenty control participants. Measurements: The inflammatory marker levels in plasma and cognitive function were measured. Results: Twenty (39.2%, 20/51) patients developed POCD at 1 w after CRS-HIPEC. The patients with POCD had higher serum interleukin 1beta (IL 1beta), serum amyloid A (SAA), S100 calcium-binding protein beta (S-100beta), and high mobility group box-1 protein (HMGB-1) levels at 1 and 24 h postoperatively than patients without POCD. There was an association between POCD and the maximum IL-1beta and S-100beta concentrations in serum, which remained following adjustment for age and FBS. Conclusion: In this pilot study, perioperative inflammatory marker levels increase significantly after CRS-HIPEC in adult patients, and such elevations are associated with the development of short-term cognitive dysfunction after this complex surgery. These results suggested the need for a larger RCT to replicate and confirm these findings. PMID- 29249870 TI - Effects of FTY720 on Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats. AB - Background: Sphingosine-1-phosphate (S1P) is a biologically active lysophospholipid mediator involved in modulating inflammatory process. We investigated the effects of FTY720, a structural analogue of S1P after phosphorylation, on lung injury induced by hindlimb ischemia reperfusion (IR) in rats. Methods: Fifty Sprague-Dawley rats were divided into groups SM, IR, F3, F5, and F10. Group SM received sham operation, and bilateral hindlimb IR was established in group IR. The rats in groups F3, F5, and F10 were pretreated with 3, 5, and 10 mg/kg/d FTY720 for 7 days before IR. S1P lyase (S1PL), sphingosine kinase (SphK) 1, and SphK2 mRNA expressions, wet/dry weight (W/D), and polymorphonuclear/alveolus (P/A) in lung tissues were detected, and the lung injury score was evaluated. Results: W/D, P/A, and mRNA expressions of S1PL, SphK1, and SphK2 were higher in group IR than in group SM, while these were decreased in both groups F5 and F10 as compared to IR (p < 0.05). The lung tissue presented severe lesions in group IR, which were attenuated in groups F5 and F10 with lower lung injury scores than in group IR (p < 0.05). Conclusions: FTY720 pretreatment could attenuate lung injury induced by hindlimb IR by modulating S1P metabolism and decreasing pulmonary neutrophil infiltration. PMID- 29249873 TI - Plagiarism sensitized. PMID- 29249872 TI - Taenia crassiceps Antigens Control Experimental Type 1 Diabetes by Inducing Alternatively Activated Macrophages. AB - Type 1 diabetes (T1D) is an autoimmune disease caused by the selective destruction of the pancreatic beta-cells, causing inability to produce insulin. Proinflammatory cytokines such as IL-1beta, IL-6, TNF-alpha, IFN-gamma, IL-12, IL 17, and NO can be released by CD4 and CD8+ lymphocytes as well as by classically activated macrophages (CAMphis), which are important in the development of T1D. Helminth infections have been shown to prevent T1D, mainly through Th2-biased responses and increased recruitment of regulatory cell populations. Previously, we have shown that Taenia crassiceps infection in mice significantly reduces hyperglycemia, insulitis, and the incidence of T1D. In this study, we determined whether T. crassiceps-derived products such as soluble (TcS) or excreted/secreted (TcES) antigens might have a beneficial influence on the development of experimental T1D. Treatment with different doses before or after induction of T1D was analyzed. Mice that were pretreated with TcS were unable to develop T1D, whereas those receiving TcES early after T1D induction displayed significantly reduced insulitis and hyperglycemia along with increased recruitment of alternatively activated macrophages (AAMphis) and myeloid-derived suppressor cells (MDSCs). Finally, we examined the modulatory role of AAMphis on T1D by depleting macrophages with clodronate-loaded liposomes, demonstrating that AAMphis are key cells in T1D regulation. PMID- 29249871 TI - Contribution of In Vivo and Organotypic 3D Models to Understanding the Role of Macrophages and Neutrophils in the Pathogenesis of Psoriasis. AB - Psoriasis, a common chronic immune-mediated skin disease, is histologically characterized by a rapid keratinocyte turnover and differentiation defects. Key insights favor the idea that T cells are not the only key actors involved in the inflammatory process. Innate immune cells, more precisely neutrophils and macrophages, provide specific signals involved in the initiation and the maintenance of the pathogenesis. Current data from animal models and, to a lesser extent, three-dimensional in vitro models have confirmed the interest in leaning towards other immune cell types as a potential new cellular target for the treatment of the disease. Although these models do not mimic the complex phenotype nor all human features of psoriasis, their development is necessary and essential to better understand reciprocal interactions between skin cells and innate immune cells and to emphasize the crucial importance of the local lesional microenvironment. In this review, through the use of in vivo and 3D organotypic models, we aim to shed light on the crosstalk between epithelial and immune components and to discuss the role of secreted inflammatory molecules in the development of this chronic skin disease. PMID- 29249874 TI - A systematic review on the effectiveness of titratable over nontitratable mandibular advancement appliances for sleep apnea. AB - Background: Mandibular advancement appliances are being tested for use in patients with obstructive sleep apnea (OSA). However, the effectiveness of titration of these appliances does not have conclusive evidence. Systematic reviews help us to compile all available clinical evidence using statistical principles. Hence, the aim of this systematic review is to identify the effectiveness of titratable over nontitratable mandibular advancement appliances in patients with mild to moderate OSA. This review objective is to identify if titration of these appliances produce significant benefits over fixed appliances. Materials and Methodology: Electronic databases were searched to identify eligible studies based on set inclusion criteria. Data extraction form was created and the data were extracted. The participants were mild to moderate OSA patients who received mandibular advancement appliances. Studies included a comparison between titratable and nontitratable mandibular advancement appliance. Results: Of the five included studies, three were observational and two were a randomized trial. All these studies were conducted in adults. The outcome attributes were polysomnographic readings and apnea-hypopnea index (AHI). A significant heterogeneity was seen between the eligible studies and hence a meta analysis could not be performed. Conclusion: The results from this systematic review did not show significant advantages of titratable appliances, although titratable appliances performed better from individual studies as regards to reduction in AHI and polysomnography. The reason is the lack of sufficient clinical trials on the same. More high quality randomized controlled trials comparing titratable and fixed appliances have to be initiated to get to conclusive evidence. PMID- 29249875 TI - Evaluation of fracture resistance of ceramic veneers with different preparation designs and loading conditions: An in vitro study. AB - Purpose: The purpose of this study was to evaluate the effect of incisal butt joint and incisal overlap design on the fracture resistance of ceramic veneers under two different loading conditions, i.e., 125 degrees and 60 degrees representing protrusive and intercuspal movements, respectively. Materials and Methods: Thirty-two maxillary central incisors were divided into two groups of sixteen specimens each and were prepared with incisal butt joint and incisal overlap design. Ceramic veneers were fabricated and cemented. Both the groups were further divided and mechanical testing to evaluate the fracture resistance were done using the universal testing machine. The values were recorded in Newton along with the assessment of the failure mode of both veneer and the tooth. Results: Unpaired t-test showed a significant difference (P < 0.05) with butt joint design having higher fracture resistance than palatal overlap design with the mean value of 409.50N at 60 degrees angle and 473.37N at 125 degrees angle. Paired t-test depicted a significant difference for both the designs at 125 degrees than at 60 degrees angle (P < 0.05). Chi-square analysis showed more number of intact veneers with butt joint design; however, there was no significant difference (P > 0.05). Failure mode of teeth showed more number of coronal fracture followed by cervical fracture and root fracture, but there was no significant difference between the two groups (P > 0.05). Conclusion: Butt joint design had higher fracture resistance than palatal overlap design. Under functional loads for both designs, fracture resistance was higher at 125 degrees than at 60 degrees angle. PMID- 29249876 TI - Comparison of the flexural strength of polymethyl methacrylate resin reinforced with multiwalled carbon nanotubes and processed by conventional water bath technique and microwave polymerization. AB - Purpose: This in vitro study was done to compare the flexural strength of polymethyl methacrylate resin reinforced with multiwalled carbon nanotubes (MWCNTs) and processed by conventional water bath technique and using microwave energy. Materials and Methods: A total of 180 acrylic resin specimens measuring 65 mm * 10 mm * 2.5 mm were fabricated, with conventional water bath groups and microwave group having ninety specimens each. Ninety specimens were divided into thirty specimens as control and subgroups containing 0.025% MWCNTs and 0.050% MWCNTs with thirty specimens each. The specimens were tested for flexural strength by three-point bending test on universal testing machine. The statistical analysis was done using Student's t-test and one-way analysis of variance, and the intercomparison between each group was done using Tukey's post hoc analysis. Results: The mean flexural strength of specimens cured by water bath technique was 95.563 MPa and microwave technique was 118.416 MPa. Control Group B possesses highly significant increase in flexural strength than Control Group A with P < 0.01. Unpaired Student's t-test showed that Subgroup B1 and Subgroup B2 possess highly significant increase in flexural strength than Subgroup A1and Subgroup A2. Conclusion: Heat polymerized denture base resin with and without reinforcement of MWCNTs and polymerized by microwave technique possess higher flexural strength than heat polymerized fiber reinforced denture resin polymerized by water bath technique. MWCNTs could be used as an effective reinforcement material for denture base resin polymerized by either water bath technique or microwave energy. PMID- 29249877 TI - Effect of bar cross-section and female housing material on retention of mandibular implant bar overdentures: A comparative in vitro study. AB - Aim: The aim of this study is to evaluate the effect of different cross-sections of bar connecting two implants on the retention of mandibular overdentures with Hader clip or lined with heat-cured resilient liner as a housing material. The retentive values after simulated 1.5 years of service were also recorded. Materials and Methods: Edentulous mandibular acrylic model was constructed with two dummy implants located in the canine region and connected with cast bar assembly. According to bar cross-section and anchoring method, four groups (n = 10) of identical overdentures were used as Hader bar/clip group (HCG), Hader bar/silicone liner female housing group (HSG), oval bar/silicone liner female housing group (OSG), and round bar/silicone liner female housing group (RSG). Each overdenture sample was subjected to simulated wear up to 2740 manual insertions/separations. The mean retentive forces were measured at the baseline and after every 500 insertions. The data were statistically analyzed using one way analysis of variance. Results: The present study demonstrated that all bar cross-sections showed a significant difference at the baseline (P < 0.05), but HSG showed greater initial retention compared to HCG, OSG, and RSG. OSG showed a significant higher retention after 2740 insertions (simulated five insertions/day). Conclusions: Within the limitation of this in vitro study and for a similar period of service, heat-cured silicone female housing for Hader bar could maintain greater retention for two-implant-retained overdentures than provided by conventional plastic clip after 1.5 year. The oval bar recorded reasonable initial retention values and maintained these values for 1.5 years of service. PMID- 29249878 TI - Infection control knowledge and practice: A cross-sectional survey on dental laboratories in dental institutes of North India. AB - Aim and Objectives: The aim of the study was to assess the knowledge of dental laboratory technicians regarding infection control and modes of infection control employed by them. Settings and Design: A self-assessment questionnaire-based survey was carried out among dental technicians to assess the knowledge and practice of infection control in dental laboratories. Materials and Methods: Survey instrument containing 16 questions were randomly distributed to 70 dental colleges of North India regarding knowledge of infection control methods and infection control practised in laboratories. Data were collected and analyzed. Results: The response showed that 30.76% of dental technicians receive 30-50 or more than 50 impressions in a week. About 96.15% of the technicians used a plastic bag to carry impressions. Twenty-five percent of the dental technicians were aware of infection control protocol. Fifty-five percent of the technicians received impressions while wearing gloves and 61.53% of the institutes had a separate receiving area. Nearly 71.15% of the technicians communicate with the doctor regarding the disinfection of impression received in the laboratory. Almost 30.76% of the dental technicians disinfect all the impressions and 67.30% technicians use immersion for disinfection of impressions. Only 38.46% responded that they immerse impressions for 10 min for disinfection. About 73.07% use gloves, 90.38% use mouth masks, 57.69% wear eye shields, and 88.46% wear aprons while working. Nearly 78.84% of the technicians received vaccination against hepatitis B virus. Almost 69.23% of the technicians change pumice slurry after regular intervals, and 75% do not add any disinfectant. Nearly 59.61% of technicians disinfect the prostheses before sending it to the clinic, and 42.30% disinfect them by immersion technique. About disposal of waste, 80.76% said that they dispose the waste properly. Conclusion: To summarize, most of the technicians were not aware of basic infection control protocols. PMID- 29249879 TI - A spectrophotometric analysis of extraoral aging conditions on the color stability of maxillofacial silicone. AB - Context: Surveys have reported color fading as the most frequent reasons patients given for disliking their prostheses. Aim: The aim of the study is to compare the color variation between two maxillofacial silicone elastomers after subjecting them to extraoral aging conditions. Subjects and Methods: A total of 80 samples were made from M511 Maxillofacial Rubber (Part A: Part B = 10:1) and Z004 Platinum Silicone Rubber (Part A: Part B = 1:1) and divided into two main Groups A and B (40 each). These main groups were then subdivided into five subgroups (A1B1, A2B2, A3B3, A4B4, and A5B5) (n = 8); outdoor weathering, acidic perspiration, sebum (for 6 months), and neutral soap and disinfectant (for 30 h), respectively. Baseline L*a*b* values were recorded. The samples were subjected to the extraoral aging conditions, and the L* a*b* values were recorded after the aging period using a spectrophotometer. Statistical Analysis: The intergroup comparison was done by Kruskal-Wallis test, whereas the intragroup comparison was done by Mann-Whitney test. Results: All groups exhibited visually detectable, mean color differences that ranged from 3.06-5.21, except for A4B4. There was no statistical significance between the two materials when subjected to extraoral aging conditions. Conclusions: Visually perceptible and clinically unacceptable color changes occur when exposed to various extraoral aging conditions except for neutral soap solution immersion, for which values of Delta E* were clinically acceptable (DeltaE < 3). It can be said for all practical purposes, clinically, the choice between M511 Maxillofacial Rubber (Part A: Part B = 10:1) and Z004 Platinum Silicone Rubber (Part A: Part B = 1:1) would yield more or less the same results, with unacceptable norms in terms of color stability under extraoral aging conditions. PMID- 29249880 TI - A comparative evaluation of chewing efficiency, masticatory bite force, and patient satisfaction between conventional denture and implant-supported mandibular overdenture: An in vivo study. AB - Purpose: The purpose of this within-subject crossover clinical trial was to compare and evaluate the chewing efficiency, masticatory bite force, and patient satisfaction with conventional dentures and two implant-retained mandible overdentures after 4 weeks of usage. Method: This within-subject crossover clinical trial was carried out in the Department of Prosthodontics in K.D Dental College and Hospital. A total 15 patients were selected for the study. To report the changes in chewing efficiency by chewing 6gms of peanuts with 40 chewing strokes and comparing the particle size of the chewed material between two implant retained mandibular overdenture with that of conventional denture using micro vu excel gantry type visual measurement machine. To report changes in masticatory bite force after transition of conventional complete denture patient to implant retained overdenture after using the prosthesis for four weeks each and recorded by digital transducer. To assess the patient satisfaction after transition of conventional complete denture patient to implant retained mandibular overdenture with help of OHIP edent patient satisfaction questionnaire. Results: The chewing efficiency for implant retained overdenture increased significantly than that of conventional denture. The particle size decreased to 76.34% for implant supported overdenture than that of conventional denture. The chewing strokes required by conventional denture was 69 strokes and that by implant supported overdenture which was 40 strokes to get the same mean particle size. The patients satisfaction after receiving the implant retained overdenture was significantly higher than that of complete denture. Conclusion: The provision of two mandibular implants significantly improves measures of oral function and better quality of life for edentulous patients. PMID- 29249881 TI - Marginal and internal fit of cobalt-chromium copings fabricated using the conventional and the direct metal laser sintering techniques: A comparative in vitro study. AB - Background and Objectives: This in vitro study seeks to evaluate and compare the marginal and internal fit of cobalt-chromium copings fabricated using the conventional and direct metal laser sintering (DMLS) techniques. Methods: A master model of a prepared molar tooth was made using cobalt-chromium alloy. Silicone impression of the master model was made and thirty standardized working models were then produced; twenty working models for conventional lost-wax technique and ten working models for DMLS technique. A total of twenty metal copings were fabricated using two different production techniques: conventional lost-wax method and DMLS; ten samples in each group. The conventional and DMLS copings were cemented to the working models using glass ionomer cement. Marginal gap of the copings were measured at predetermined four points. The die with the cemented copings are standardized-sectioned with a heavy duty lathe. Then, each sectioned samples were analyzed for the internal gap between the die and the metal coping using a metallurgical microscope. Digital photographs were taken at *50 magnification and analyzed using measurement software. Statistical analysis was done by unpaired t-test and analysis of variance (ANOVA). Results: The results of this study reveal that no significant difference was present in the marginal gap of conventional and DMLS copings (P > 0.05) by means of ANOVA. The mean values of internal gap of DMLS copings were significantly greater than that of conventional copings (P < 0.05). Conclusions: Within the limitations of this in vitro study, it was concluded that the internal fit of conventional copings was superior to that of the DMLS copings. Marginal fit of the copings fabricated by two different techniques had no significant difference. PMID- 29249882 TI - Effect of time interval between core preparation and post cementation on pushout bond strength of glass fiber-reinforced posts. AB - Introduction: The aim of this study was to investigate the effect of timing of coronal preparation on the pushout bond strength of fiber postluted with resin cement in the root canal. Materials and Methods: In this experimental study, 48 mandibular human premolars were selected in a 3-week range. After root canal treatment and postspace preparation, a post #2(Angelus, Brazil) was cemented into the canal by a resin-based cement (Bifix SE, VOCO, Germany). Cylindrical resin composite cores were built on the posts. Then, the specimens were divided into 4 groups of 12 specimens each: one control group without core preparation and 3 experimental groups with core preparation that was done 15 min, 1 h, and 24 h after postcementation. One day after postcementation, each root was sectioned into 3 segments. Each slice was connected to universal testing machine. The load was applied at the speed of 0.5 mm/min till failure happened. The collected data were analyzed (SPSS/PC 20.0; SPSS Inc., Chicago, IL, USA) using two-way ANOVA and post hoc Tukey test at P < 0.05 level of significance. Results: Mean shear bond strength differences among interventional groups were not statistically significant (P > 0.05). Nevertheless, there were significant differences among root regions (P < 0.001). Conclusion: It was concluded that core preparation and its timing does not affect adversely retention of fiber post and bond strength is higher in the cervical segment. PMID- 29249883 TI - Effect of joining the sectioned implant-supported prosthesis on the peri-implant strain generated in simulated mandibular model. AB - Aim: The aim of this study is to evaluate the strain developed in simulated mandibular model before and after the joining of an implant-supported screw retained prosthesis by different joining techniques, namely, arc welding, laser welding, and soldering. Materials and Methods: A specimen simulating a mandibular edentulous ridge was fabricated in heat-cured acrylic resin. 4-mm holes were drilled in the following tooth positions; 36, 33, 43, 46. Implant analogs were placed in the holes. University of California, Los Angeles, abutment was attached to the implant fixture. Eight strain gauges were attached to the acrylic resin model. Six similar models were made. Implant-supported screw-retained fixed prosthesis was fabricated in nickel-chromium alloy. A load of 400 N was applied on the prosthesis using universal testing machine. Resultant strain was measured in each strain gauge. All the prostheses were sectioned at the area between 36 and 33, 33 and 43, and 43 and 46 using 35 micrometer carborundum disc, and strain was measured in each strain gauge after applying a load of 400 N on the prosthesis. Specimens were joined by arc welding, soldering, and laser welding. After joining, a load of 400 N was applied on each prosthesis and the resultant strain was measured in each strain gauge. Results: Highest mean strain values were recorded before sectioning of the prostheses (889.9 microstrains). Lowest mean strain values were recorded after sectioning the prosthesis and before reuniting it (225.0 microstrains). Conclusions: Sectioning and reuniting the long span implant prosthesis was found to be a significant factor in influencing the peri-implant strain. PMID- 29249884 TI - Effect of newly developed pigments and ultraviolet absorbers on the color change of pigmented silicone elastomer. AB - Aim and Objective: The aim and objective of the study is to evaluate effect of ultraviolet (UV) stabilizer (UV absorber Chimassorb 81) on color change of pigmented silicone elastomer when commercially available (red and yellow), and newly developed pigments (sicotrans red and sicopal brown) were used. Materials and Methods: Two commercially available pigments - red (P112 Brilliant Red) and yellow (P106 Yellow) and two newly developed pigments - sicotrans red and sicopal brown were studied. In total eight groups made up of nine samples each were fabricated using elastomer with the combinations of the above pigments and UV stabilizer (Chimassorb 81). Groups 1, 3, 5, and 7 contain elastomer in combination with sicotrans red, sicopal brown, yellow and red pigments, respectively. Similarly, groups 2, 4, 6, and 8 along with elastomer and pigments (sicotrans sed, sicopal brown, yellow and red, respectively) contain the UV stabilizer (Chimassorb 81). Samples were subjected to aging in an accelerated weathering chamber (Weather-Ometer). Color values CIE (Commission Internationale d'Eclairage) L*, a*, and b * were measured at baseline and after 1000 h of weathering. Change in color (Delta E) was calculated. Results: All groups showed a significant color change at 1000 h. Groups 1, 2, 3, and 4 showed a statistically significant less change in both colors (sico trans red and sicopal brown) compared to groups 5,6,7, and 8 (commercial pigments-Red and Yellow). Overall, the change in the color in groups with the UV stabilizer (Chimassorb) was less when compared to the groups where the stabilizer was not used. Conclusion: The newly developed pigment led to increased color stability as compared to commercially available pigments. Addition of UV stabilizer, Chimassorb led to a further reduction in color change of the pigmented elastomer. PMID- 29249885 TI - Effect of plant extract denture cleansing on heat-cured acrylic denture base resin: An in vitro study. AB - Aim: Various chemical solutions have been recommended for denture disinfection; however, the immersion effect on the properties of denture base resin may also have effect on strength of the resin material. The purpose of this in vitro study was to compare and evaluate the flexural strength of heat-cure acrylic denture base resin by combination method of denture cleansing and plant extract immersion. Materials and Methods: In this study, ninety specimens of heat-cure acrylic denture base resin material were fabricated with dimensions of 65 mm * 10 mm * 3.3 mm. The specimens were divided into three groups, namely, Group I-III of thirty specimens each and were immersed in distilled water, denture cleanser, and thyme essential oil, respectively. The flexural strength of specimen was evaluated. Results: Natural plant extract showed better flexural strength than immersed in denture cleanser and control group but statistically was not significant. Conclusion: The study concluded that plant extract, namely, thyme essential oil, showed better flexural strength than combination method and can be used as denture cleanser. PMID- 29249886 TI - The use of cone beam computed tomography and three dimensional printing technology in the restoration of a maxillectomy patient using a dental implant retained obturator. AB - This case report presents an alternative method for fabricating an obturator for patients that develop xerostomia and mild trismus following radiation to the Head and Neck region. Multiple initial impression stages are avoided leading to less irritation to soft tissues and less discomfort to the patient. A 69-year-old male patient was referred to our dental practice by the Maxillofacial Surgery Department of the local General Hospital. The patient had undergone a right maxillectomy for removal of a Squamous Cell Carcinoma 2 weeks prior. Four endosseous dental implants were placed in the remaining upper jaw and 2 implants were inserted into the canine region of his edentulous mandible 3 weeks after ablative surgery. Five months following completion of radiotherapy and chemotherapy, a cone beam computed tomography of the maxilla was obtained, and a three dimensional model was constructed using an appropriate resin. Using the model as the detailed primary cast, a custom acrylic special tray was fabricated for the final impression of the remaining maxilla and the maxillary defect. An implant retained maxillary obturator and an implant retained mandibular overdenture were constructed to restore patient's speech, mastication and deglutition. The method presented here can limit the impression stages needed for construction of a maxillary obturator prosthesis to a single impression procedure advocating a partial digital workflow process. This can be very beneficial to the patient suffering from postradiation side-effects such as trismus, mucositis, and xerostomia. PMID- 29249887 TI - Prosthetic rehabilitation of a mandibular root amputated molar using single crown. AB - In teeth with furcation involvement, root amputation is one of the treatment choices. A challenge which a dentist may encounter with is the prosthetic treatment of such teeth when their adjacent teeth are intact. According to the current goal of operative dentistry based on conservative treatment, it would be desirable to do in a manner resulting in minimal damage to the adjacent sound teeth. In the following case report, a step-by-step conservative treatment sequences of a mandibular molar with distal root amputation which not involving surrounding teeth is described. During 18 months follow-up, the results were satisfactory. PMID- 29249888 TI - Photoassisted access to complex polyheterocycles containing a beta-lactam moiety. AB - Intramolecular cycloadditions of aza-o-xylylenes generated via excited state intramolecular proton transfer (ESIPT) to furanacetic acid-based unsaturated pendants was shown to overcome the unfavorable energetics of the azetidinone ring formation, offering rapid access to beta-lactams as primary photoproducts. These 2,3- and 3,4-dihydrofuran-containing reactive intermediates are suitable for a broad spectrum of postphotochemical transformations yielding complex polyheterocyclic molecular architectures possessing the beta-lactam moiety. PMID- 29249889 TI - The effect of early childhood stunting on children's cognitive achievements: Evidence from young lives Ethiopia. AB - Background: There is little empirical evidence on the effect of childhood malnutrition on children's cognitive achievements in low income countries like Ethiopia. A longitudinal data is thus vital to understand the factors that influence cognitive development of children over time, particularly how early childhood stunting affects cognitive achievement of children up to the age of 8 years. Objective: To examine the effect of early childhood stunting on cognitive achievements of children using longitudinal data that incorporate anthropometric measurements and results of cognitive achievement tests such as Peabody Picture Vocabulary Test and Cognitive Development Assessment quantitative tests. Method: Defining stunted children as those having a standardized height for age z-score less than -2; we used a Propensity Score Matching (PSM) to examine the effect of early childhood stunting on measures of cognitive performance of children. The balance of the propensity score matching techniques was checked and found to be satisfied (P<0.01). Results: Early childhood stunting is significantly negatively associated with cognitive performance of children. Controlled for confounding variables such as length of breastfeeding, relative size of the child at birth, health problems of early childhood such as acute respiratory illness and malaria, baseline household wealth, child gender, household size and parental education, estimates from PSM show that stunted children scored 16.1% less in the Peabody Picture Vocabulary Test and 48.8% less in the Quantitative Assessment test at the age of eight, both statistically significant at P<0.01. Conclusions: It is important to realize the importance of early investment in terms of child health and nutrition until five years for the cognitive performance of children. As household wealth and parental education are particularly found to play an important role in children's nutritional achievements, policy measures that are directed in improving household's livelihood may have a spill-over impact in improving child nutritional status, and consequently cognitive development and schooling. PMID- 29249891 TI - New Frontiers in Analyzing Dynamic Group Interactions: Bridging Social and Computer Science. AB - This special issue on advancing interdisciplinary collaboration between computer scientists and social scientists documents the joint results of the international Lorentz workshop, "Interdisciplinary Insights into Group and Team Dynamics," which took place in Leiden, The Netherlands, July 2016. An equal number of scholars from social and computer science participated in the workshop and contributed to the papers included in this special issue. In this introduction, we first identify interaction dynamics as the core of group and team models and review how scholars in social and computer science have typically approached behavioral interactions in groups and teams. Next, we identify key challenges for interdisciplinary collaboration between social and computer scientists, and we provide an overview of the different articles in this special issue aimed at addressing these challenges. PMID- 29249890 TI - Autophagy in drug-induced liver toxicity. AB - Liver injury resulting from exposure to drugs and chemicals is a major health problem. Autophagy is an important factor in a wide range of diseases, such as cancer, liver disease, muscular disorder, neurodegeneration, pathogen infection, and aging, and emerging evidence indicates that autophagy makes a substantial contribution to the pathogenesis of drug- and chemical-induced liver toxicity. In this review, we summarize current knowledge on autophagy triggered by toxicants/toxins, the protective role of autophagy in liver toxicity, and the underlying molecular mechanisms. We also highlight experimental approaches for studying autophagy. PMID- 29249892 TI - Toward Developing Laboratory-Based Parent-Adolescent Conflict Discussion Tasks that Consistently Elicit Adolescent Conflict-Related Stress Responses: Support from Physiology and Observed Behavior. AB - Parent-adolescent conflict poses risk for youth maladjustment. One potential mechanism of this risk is that stress in the form of increased arousal during conflict interactions results in adolescents' impaired decision-making. However, eliciting consistent adolescent stress responses within laboratory-based tasks of parent-adolescent conflict (i.e., conflict discussion tasks) is hindered by task design. This limitation may stem from how conflict topics are assessed and selected for discussion. Within a sample of 47 adolescents (ages 14-17) and parents, we investigated whether a modified version of a conflict discussion task could elicit physiological (i.e., arousal) and behavioral (i.e., hostility) displays of adolescents' conflict-related stress responses. We assessed parent adolescent conflict via structured interview to identify topics for dyads to discuss during the task. We randomly assigned dyads to complete a 5-minute task to discuss either a putatively benign topic (i.e., control condition) or a conflict topic while undergoing direct assessments of continuous arousal. Trained raters coded dyad members' hostile behavior during the task. Adolescents in the conflict condition exhibited significantly greater levels of arousal than adolescents in the control condition. We observed an interaction between discussion condition and baseline conflict. Specifically, higher baseline conflict predicted greater hostile behavior for adolescents in the conflict condition, yet we observed the inverse relation for adolescents in the control condition. Our modified laboratory discussion task successfully elicited both physiological and behavioral displays of adolescent conflict-related stress. These findings have important implications for leveraging experimental paradigms to understand causal links between parent-adolescent conflict and adolescent psychopathology, and their underlying mechanisms. PMID- 29249893 TI - Efforts to Promote Reintegration and Rehabilitation of Traumatized Former Child Soldiers: Reintegration of Former Child Soldiers in Sierra Leone: The Role of Caregivers and Their Awareness of the Violence Adolescents Experienced During the War. AB - This article explores the role of caregivers in the reintegration of former child soldiers from Sierra Leone. Using data on 282 youth and their respective caregivers, our aim is to focus on the caregiver-child relationship after reintegration. We investigate the extent to which caregivers know about child soldiers' experiences of direct and indirect violence, as well as involvement in war activities. We further examine variables that might shape the degree of caregiver knowledge of child's war experiences. Finally, we examine if caregiver knowledge of war experiences is associated with child's psychosocial outcomes. Findings highlight the importance of developing thoughtful programs that consider the needs of the child in the context of the family and caregivers with whom he or she is reunified. PMID- 29249894 TI - Spleen Tyrosine Kinase Inhibition Modulates p53 Activity. AB - Spleen tyrosine kinase (SYK) is a cytoplasmic enzyme that promotes survival and proliferation of B cells. SYK inhibition has shown promising results in the treatment of arthritis and chronic lymphocytic leukemia (CLL). However, in other context, it has been shown that SYK overexpression in epithelial cancer cells induced senescence in p53-dependent mechanism, which underscored its antineoplastic activity in vitro. Here, we show that SYK was induced in response of DNA damage in parallel with p53 levels. In addition, using chemical inhibitors of SYK reduced p53 levels in HCT116 and HT1080 cell lines, which underlines the role of SYK inhibition on p53 activity. Furthermore, SYK inhibition modulated the cell growth, which resulted in a decreasing in cell death. Interestingly, SYK expression showed a positive prognosis in patients with solid tumors in correlations with their survival rates, as expected negative correlation was seen between SYK expression and survival rate of patients with CLL. In conclusion, these findings demonstrate that SYK inhibition modulates p53 expression and activity in HCT116 and HT1080 cells. Reconsidering using of SYK inhibitors in clinical setting in the future should be evaluated carefully in accordance with these findings to prevent the formation of secondary malignancies. PMID- 29249895 TI - Personality and Body Weight: Mechanisms, Longitudinal Associations and Context. AB - Models of personality and health have grown in complexity as more is discovered about how traits are related to health-related behaviors, morbidity, and mortality. The present article applies a model of personality and health that incorporates longitudinal relations, behavioral and physiological mechanisms, and context to the relation between Five-Factor Model personality traits and body mass index (BMI) and obesity (BMI>=30). Conscientiousness is associated consistently with lower body weight; the relation between the other traits and BMI is more complex. Conscientiousness is also associated with risk of obesity over time, and specific aspects of Conscientiousness and Neuroticism are associated with greater weight gain and are also sensitive to changes in weight over time. Behavioral (e.g., physical activity) and physiological (e.g., inflammation) factors explain part of the association between personality and BMI. Finally, the broader social environment shapes the expression of personality in relation to body weight. This review highlights replicable associations between personality and BMI and potential mechanisms of this association. Future research needs to better address how specific aspects of the social and family environment moderate the relation between personality and BMI and take a lifespan perspective to better incorporate how traits contribute to weight starting in childhood. PMID- 29249896 TI - The contemptuous separation: Facial expressions of emotion and breakups in young adulthood. AB - The importance of studying specific and expressed emotions after a stressful life event is well known, yet few studies have moved beyond assessing self-reported emotional responses to a romantic breakup. This study examined associations between computer-recognized facial expressions and self-reported breakup-related distress among recently separated college-aged young adults (N = 135; 37 men) on four visits across 9 weeks. Participants' facial expressions were coded using the Computer Expression Recognition Toolbox while participants spoke about their breakups. Of the seven expressed emotions studied, only Contempt showed a unique association with breakup-related distress over time. At baseline, greater Contempt was associated with less breakup-related distress; however, over time, greater Contempt was associated with greater breakup-related distress. PMID- 29249898 TI - Optimal group testing designs for estimating prevalence with uncertain testing errors. AB - We construct optimal designs for group testing experiments where the goal is to estimate the prevalence of a trait using a test with uncertain sensitivity and specificity. Using optimal design theory for approximate designs, we show that the most efficient design for simultaneously estimating the prevalence, sensitivity, and specificity requires three different group sizes with equal frequencies. However, if estimating prevalence as accurately as possible is the only focus, the optimal strategy is to have three group sizes with unequal frequencies. Based on a Chlamydia study in the United States, we compare performances of competing designs and provide insights into how the unknown sensitivity and specificity of the test affect the performance of the prevalence estimator. We demonstrate that the proposed locally D- and Ds -optimal designs have high efficiencies even when the prespecified values of the parameters are moderately misspecified. PMID- 29249897 TI - Is it Time for a Sudden Infant Death Syndrome (SIDS) Awareness Campaign? Community Stakeholders' Perceptions of SIDS. AB - Background: Sudden infant death syndrome (SIDS) remains a leading cause of infant death in the United States and in Virginia, the SIDS rate is higher than the national average. We sought to gauge the perceptions among community-identified stakeholders as to community resource needs to reduce SIDS. Methods: We used snowball sampling to identify important community stakeholders to be interviewed as key informants. A semi-structured interview lasting 45 min-2 hours was delivered to determine resource needs to reduce SIDS, and whether high-risk community members were aware of SIDS risk factors among stakeholders representing a variety of disciplines. Interviews were conducted in two geographic areas with higher than average rates of infant mortality, an urban district, Winchester City, VA and a rural district, Page County, VA. Results: A total of 74 interviews were completed with stakeholders in healthcare, health departments, social services, law enforcement, education/childcare, faith-based institutions, non profit agencies and non-affiliated community members. The majority of respondents perceive that high-risk community members are not aware of factors that can lead to SIDS (50%). Participants suggested that more "education" is needed to further reduce the rates of SIDS in their communities (73%). Respondents detailed that more pervasive, strategic, and multi-channeled education is necessary to reduce cases of SIDS. Conclusion: Community leaders perceive that high-risk community members are not fully aware of risk factors that can lead to SIDS. Maternal/child health stakeholders in these Virginia locales suggested more community-based education as a potential solution to SIDS. PMID- 29249899 TI - From fantasy to reality: managing biomedical risk emotions in and through fictional media. AB - In this article, we explore the role that fictional media (film and television) play in evoking and managing collective and individual anxieties towards biomedical research. We draw on two data sets: fictional media depictions of human research subjects and interviews with Phase I clinical trial participants conducted in the USA in 2013. We show how fictional media provide an outlet for collective uncertainties surrounding biomedical research through depictions that mock and dehumanise research participants, using such emotions of shock, disgust, pity, amusement and humour. We analyse how themes from fictional media are also used to manage actual clinical trial participants' own anxiety concerning the unknown risks of research participation. By contrasting the reality of their research experience with fantasy derived from entertainment media, clinical trial participants minimise the seriousness of the side effects they have or may experience in actual Phase I clinical trials. We conclude that fictional media serve an important role in the collective and individual management of risk emotion. PMID- 29249900 TI - Effect of interaction of external surfaces on the symmetry and lattice distortion of CdSe nanocrystals by molecular dynamics simulations. AB - The effect of interaction of low-index atomic planes, (100), (110), and (111) terminating CdSe platelet nanocrystals is examined using molecular dynamics (MD) simulations. Asymmetry of the environment of atoms at the end surface layers leads to anisotropic deformation of the cubic lattice and to a relative shift of Cd and Se sub-lattices. Interference of distortions of the crystal lattice originating at the terminal surfaces leads to changes of symmetry of the CdSe lattice in the whole sample volume. In the models, 2-3 nm thick, for all types of surfaces under examination, the initial cubic lattice symmetry gets lost in the whole sample volume. Graphical abstract?. PMID- 29249901 TI - The paradox of long-term ungulate impact: increase of plant species richness in a temperate forest. AB - Questions: Did high densities of wild ungulates cause a decline in plant species richness in a temperate oakwood? How did species composition change after nearly five decades? Did ungulates facilitate the spread of ruderal species and supress endangered species? Did dispersal strategies play a role in these processes? Location: Krumlov Wood, SE Czech Republic. Methods: In 2012, we resampled 58 quasi-permanent vegetation plots first surveyed in 1960s. Between the surveys, 36 plots were enclosed in a game preserve with artificially high density of ungulates (mostly deer, mouflon and wild boar; ca. 55 animals per square km). We analysed the differences in temporal changes between plots inside and outside the game preserve, focusing on species diversity and composition. We assessed species characteristics relevant to grazing to understand compositional changes. Results: Ungulates significantly increased alpha and gamma diversity and caused significant vegetation homogenization inside the game preserve. Vegetation homogenization and the increase in species richness resulted from massive enrichment by ruderal species. However, richness of endangered species decreased. Species dispersed by animals internally (endozoochory) increased, while species dispersed externally (epizoochory) or by wind (anemochory) decreased. Conclusions: Contrary to our expectations, our long-term data showed that artificially high ungulate densities substantially increased plant species richness. Apparently, the establishment of ruderal herbs was supported by frequent disturbances and ungulate-mediated dispersal. At the same time, species richness of non-ruderal plants did not change, probably because ungulates hindered the regeneration of woody species and maintained an open forest canopy. In conclusion, high ungulate density led to the spread of ruderal species, which in turn strongly contributed to the observed shift towards nutrient-richer conditions and taxonomically more homogenous communities. PMID- 29249902 TI - Test-Retest Reliability of Two Consecutive Mean Sleep Latency Tests in Patients with Hypersomnia. AB - Reliability of mean sleep latency testing (MSLT) over consecutive days in patients with hypersomnia is unknown. We reviewed MSLTs of patients with hypersomnia without cataplexy who underwent our two consecutive MSLT protocol (N=29). Average MSLs were 10.9 and 10.9 minutes for days 1 and 2, respectively. Agreement for pathological hypersomnia (defined as MSL<=8 minutes) between MSLT days showed k=0.85 for all (N=29) and k=0.76 for those without sleep apnea (N=20). In patients with subjective complaints of hypersomnia, a single MSLT is sufficient (vs. addition of 2nd day MSLT) in the setting of carefully implemented protocol controlling for potential confounding variables. PMID- 29249903 TI - Visual analysis of online social media to open up the investigation of stance phenomena. AB - Online social media are a perfect text source for stance analysis. Stance in human communication is concerned with speaker attitudes, beliefs, feelings and opinions. Expressions of stance are associated with the speakers' view of what they are talking about and what is up for discussion and negotiation in the intersubjective exchange. Taking stance is thus crucial for the social construction of meaning. Increased knowledge of stance can be useful for many application fields such as business intelligence, security analytics, or social media monitoring. In order to process large amounts of text data for stance analyses, linguists need interactive tools to explore the textual sources as well as the processed data based on computational linguistics techniques. Both original texts and derived data are important for refining the analyses iteratively. In this work, we present a visual analytics tool for online social media text data that can be used to open up the investigation of stance phenomena. Our approach complements traditional linguistic analysis techniques and is based on the analysis of utterances associated with two stance categories: sentiment and certainty. Our contributions include (1) the description of a novel web-based solution for analyzing the use and patterns of stance meanings and expressions in human communication over time; and (2) specialized techniques used for visualizing analysis provenance and corpus overview/navigation. We demonstrate our approach by means of text media on a highly controversial scandal with regard to expressions of anger and provide an expert review from linguists who have been using our tool. PMID- 29249904 TI - The inodilator levosimendan as a treatment for acute heart failure in various settings. AB - Levosimendan is an inodilator developed for treatment of acute heart failure. It was shown to enhance cardiac contractility, and to exert a vasodilatory effect in all vascular beds. In some trials, the use of levosimendan was associated with cardioprotective effects. These distinctive qualities may be relevant to its use in a range of acute heart failure settings and/or complications, including acute coronary syndromes and cardiogenic shock. It is conjectured that part of the benefit of levosimendan may arise from restoration of ventriculo-arterial coupling via optimization of the ratio of arterial to ventricular elastance and the transfer of mechanical energy. Full confirmation of the effectiveness of levosimendan is still awaited in many of these scenarios; however, the range of potential applications highlights both the versatility of levosimendan and the relative lack of proven interventions in many of these situations. PMID- 29249905 TI - The inodilator levosimendan in repetitive doses in the treatment of advanced heart failure. AB - Inotropes may be an appropriate response for some patients with advanced heart failure who remain highly symptomatic despite optimization of evidence-based therapy. These patients need to be supported waiting for a heart transplant or ventricular assist device, or may be candidates for inotropy as an intervention in its own right to maintain a patient in the best achievable circumstances. Objectives in such a situation include relieving symptoms, improving quality of life and reducing unplanned hospitalizations and the costs associated with such admissions. Levosimendan, a calcium sensitizer and potassium channel opener with inotrope and vasodilator actions, has emerged as a potentially valuable addition to the armamentarium in this context, used in repeated or intermittent cycles of therapy. Detailed proposals and guidance are offered for the identification of candidate patients with good prospects of a beneficial response to levosimendan, and for the safe and effective implementation of a course of therapy. PMID- 29249906 TI - The potential of the inodilator levosimendan in maintaining quality of life in advanced heart failure. AB - Maintaining adequate quality of life (QoL) is an important therapeutic objective for patients with advanced heart failure and, for some patients, may take precedence over prolonging life. Achieving good QoL in this context may involve aspects of patient care that lie outside the familiar limits of heart failure treatment. The inodilator levosimendan may be advantageous in this setting, not least because of its sustained duration of action, ascribed to a long-acting metabolite designated OR-1896. The possibility of using this drug in an outpatient setting is a notable practical advantage that avoids the need for patients to attend a clinic appointment. Intermittent therapy can be integrated into a wider system of outreach and patient monitoring. Practical considerations in the use of levosimendan as part of a palliative or end-of-life regimen focused on preserving QoL include the importance of starting therapy at low doses and avoiding bolus administration unless immediate effects are required and patients have adequate baseline arterial blood pressure. PMID- 29249907 TI - Pharmacological approaches to cardio-renal syndrome: a role for the inodilator levosimendan. AB - Pathological interplay between the heart and kidneys-also known as cardio-renal syndrome (CRS)-is frequently encountered in heart failure and is linked to worse prognosis and quality of life. Drug therapies for this complex situation may include nitroprusside or the recombinant B-type natriuretic peptide nesiritide for patients with acute CRS with normal or high blood pressure, and inotropes or inodilators for patients with acute CRS with low blood pressure. Clinical data for a renal-protective action of levosimendan are suggestive, and meta-analysis data obtained in a range of low-output states are consistent with a levosimendan induced benefit. Evidence of favourable organ-specific effects of levosimendan, including pre-glomerular vasodilation and increased renal artery diameter and renal blood flow, were collected both in preclinical and clinical studies. Larger randomized controlled trials are however needed to confirm the renal effects of levosimendan in various clinical settings. PMID- 29249908 TI - Parent Physical and Mental Health Comorbidity and Adolescent Behavior. AB - The objectives of this study were to ascertain behavioral outcomes 10-11 years after 9/11 in adolescents ages 11-18 years (0-8 years old at the time of 9/11) enrolled in the World Trade Center Health Registry (Registry), and relate these outcomes to their 9/11-exposures and to parent health. Behavioral difficulties among adolescents were assessed using the adolescent-reported Strengths and Difficulties Questionnaire (SDQ). Parental post-traumatic stress disorder (PTSD) was assessed using a 9/11-specific PTSD Checklist-Civilian Version, a cut-off score of 44 or greater was considered probable PTSD. Multivariable logistic regression was used to estimate associations of 9/11-exposure and parental health with abnormal/borderline SDQ scores, adjusting for demographic variables that were significantly associated with the SDQ score in bivariate analyses. Of the 449 adolescents, 12.5% (n=56) had abnormal/borderline SDQ scores. In the multivariable model, adolescents with severe/ moderate 9/11-exposures were 2.4 times more likely to have abnormal/borderline SDQ scores compared to adolescents with mild 9/11-exposures (95% Confidence Interval (CI): 1.1-6.4). Adolescents who had a parent with 9/11-related PTSD and at least one comorbid chronic condition were 4.2 times more likely to have abnormal/borderline SDQ scores compared to adolescents with a parent who had no reported chronic health conditions. Adolescents whose parent reported 14 or more poor mental health days in the preceding 30 days were 3.4 times more likely to have abnormal/borderline SDQ scores (95% CI: 1.2-9.5) The finding that parents' health appears to influence adolescent behavior problems 10-11 years following a disaster may have implications for healthcare practitioners and disaster response planners. PMID- 29249909 TI - We're Here and We're Queer: Sexual Orientation and Sexual Fluidity Differences Between Bisexual and Queer Women. AB - Theorists and researchers have noted an overlap between bisexually-identified and queer-identified individuals. Whereas early definitions of bisexuality may have been predominantly binary (i.e., attracted to women and men), in recent years there has been a move toward a more "queer" understanding of bisexuality (e.g., attraction to more than one gender beyond female and male). The purpose of this study was to examine similarities and differences between bisexually-identified and queer-identified adult women, ages 18-66 years, on sociodemographic characteristic, two dimensions of sexual orientation (sexual behaviors and attractions), fluidity in attractions and sexual orientation identity, and identity centrality and affirmation in an online sample (N = 489), which was mostly from the United States (73.5%). Our results indicated that bisexual and queer women were similar in terms of sociodemographic characteristics, with the exception of education; queer women were more educated than bisexual women. Queer women were also more likely than bisexual women to report variability in their sexual behaviors and attractions and more fluidity in their sexual orientation identity. Additionally, queer women reported higher levels of identity centrality and affirmation than bisexual women. Considerations for sexual minority women's health research are discussed. PMID- 29249910 TI - COMPUTATION OF R IN AGE-STRUCTURED EPIDEMIOLOGICAL MODELS WITH MATERNAL AND TEMPORARY IMMUNITY. AB - For infectious diseases such as pertussis, susceptibility is determined by immunity, which is chronological age-dependent. We consider an age-structured epidemiological model that accounts for both passively acquired maternal antibodies that decay and active immunity that wanes, permitting reinfection. The model is a 6-dimensional system of partial differential equations (PDE). By assuming constant rates within each age-group, the PDE system can be reduced to an ordinary differential equation (ODE) system with aging from one age-group to the next. We derive formulae for the effective reproduction number R and provide their biological interpretation in some special cases. We show that the disease free equilibrium is stable when R < 1 and unstable if R > 1. PMID- 29249911 TI - Lexical Reading in Dysfluent Readers of German. AB - Dyslexia in consistent orthographies like German is characterized by dysfluent reading, which is often assumed to result from failure to build up an orthographic lexicon and overreliance on decoding. However, earlier evidence indicates effects of lexical processing at least in some German dyslexic readers. We investigated variations in reading style in an eye-tracking paradigm with German dysfluent 3rd and 4th graders. Twenty-six TypFix-readers (fixation counts within the range of 47 age-matched typical readers) were compared with 42 HighFix readers (increased fixation counts). Both groups showed lexical access: Words were read more efficiently than nonwords and pseudohomophones. TypFix-readers showed stronger reliance on lexical reading than HighFix-readers (smaller length effects for number of fixations and total reading time, stronger lexicality effects for gaze duration, stronger word-pseudohomophone effects for mean saccade amplitude). We conclude that in both groups, sublexical and lexical reading processes were impaired due to inefficient visual-verbal integration. PMID- 29249912 TI - Paying Research Participants: Regulatory Uncertainty, Conceptual Confusion, and a Path Forward. AB - The practice of offering payment to individuals in exchange for their participation in clinical research is widespread and longstanding. Nevertheless, such payment remains the source of substantial debate, in particular about whether or the extent to which offers of payment coerce and/or unduly induce individuals to participate. Yet, the various laws, regulations, and ethical guidelines that govern the conduct of human subjects research offer relatively little in the way of specific guidance regarding what makes a payment offer ethically acceptable-or not. Moreover, there is a lack of definitional agreement regarding what the terms coercion and undue inducement mean in the human subjects research context. It is, therefore, unsurprising that investigators and Institutional Review Boards (IRBs) experience confusion about how to evaluate offers of payment, and lean toward conservative approaches. These trends are exemplified by our pilot data regarding the ways in which some IRB members and investigators (mis)understand the concepts of coercion and undue inducement, as well as the ways in which certain research institutions oversee offers of payment at a local level. This article systematically examines the legal and ethical dimensions of offering payment to research participants. It argues that many concerns about offers of payment to research participants can be attributed to the misguided view that such offers ought to be treated differently than offers of payment in other contexts, a form of "research exceptionalism." We show that rejection of research exceptionalism with respect to payment helps settle open debates about both how best to define coercion and undue influence, and how to understand the relation between these concepts and offers of payment. We argue for adoption of our preferred definitions, ideally by regulatory authorities, and against the conventional conservatism toward payment of research participants. Instead, we draw attention to the rarely asked, even radical, question: are research participants paid enough? We conclude by arguing that we ought to change the default to favor, rather than encourage suspicion of, offers of payment to research participants. PMID- 29249913 TI - New Strategies to Improve Polypectomy During Colonoscopy. AB - In the United States, colorectal cancer (CRC) is the second-leading cause of cancer-related deaths. The most effective strategy for prevention of CRC is to screen for and remove precancerous polyps. There are various ways to screen for CRC. In the United States, the most common method is colonoscopy. Polyps are classified primarily through pathology. Size is the primary risk factor for malignancy. In general, the bigger the polyp, the greater the risk for malignancy. There are 3 basic options for removal: standard polypectomy; advanced resection techniques, known as endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD); and surgical removal. In the past 10 years, the use of surgical removal has significantly decreased. Noninvasive, nonmalignant polyps can be removed endoscopically. EMR and ESD are very effective and achieve similar clinical outcomes. Both procedures begin with a submucosal injection. The submucosal lift is one of the most significant advances that have been made in polypectomy. Traditionally, the approach to achieving a submucosal lift has relied on the use of a saline solution. Saline is inexpensive and widely available, but it dissipates quickly. Various viscous agents have been added to saline to maintain mucosal lifting throughout the procedure. Although most are effective, they are used off-label. The only solution approved by the US Food and Drug Administration for the submucosal lift procedure is Eleview. In a clinical trial, Eleview decreased the mean total injected volume and the mean total injected volume per lesion as compared with saline. Other advances in polypectomy techniques include the use of cold snare polypectomy and high-definition colonoscopes. The quality of the colonoscopy can also be improved if a physician knows and monitors his or her adenoma detection rate. PMID- 29249915 TI - The Gambling Establishment and the Exercise of Power: a Commentary on Hancock and Smith. PMID- 29249914 TI - Lifestyle, Diet, and Colorectal Cancer Risk According to (Epi)genetic Instability: Current Evidence and Future Directions of Molecular Pathological Epidemiology. AB - Purpose of Review: In this review, we describe molecular pathological epidemiology (MPE) studies from around the world that have studied diet and/or lifestyle factors in relation to molecular markers of (epi)genetic pathways in colorectal cancer (CRC), and explore future perspectives in this realm of research. The main focus of this review is diet and lifestyle factors for which there is evidence for an association with CRC as identified by the World Cancer Research Fund reports. In addition, we review promising hypotheses, that warrant consideration in future studies. Recent Findings: Associations between molecular characteristics of CRC have been published in relation to smoking, alcohol consumption; body mass index (BMI); waist:hip ratio; adult attained height; physical activity; early life energy restriction; dietary acrylamide, fiber, fat, methyl donors, omega 3 fatty acids; meat, including total protein, processed meat, and heme iron; and fruit and vegetable intake. Summary: MPE studies help identify where associations between diet, lifestyle, and CRC risk may otherwise be masked and also shed light on how timing of exposure can influence etiology. Sample size is often an issue, but this may be addressed in the future by pooling data. PMID- 29249916 TI - Bile acid quantification of 20 plasma metabolites identifies lithocholic acid as a putative biomarker in Alzheimer's disease. AB - Introduction: There is still a clear need for a widely available, inexpensive and reliable method to diagnose Alzheimer's disease (AD) and monitor disease progression. Liquid chromatography-mass spectrometry (LC-MS) is a powerful analytic technique with a very high sensitivity and specificity. Objectives: The aim of the present study is to measure concentrations of 20 bile acids using the novel Kit from Biocrates Life Sciences based on LC-MS technique. Methods: Twenty bile acid metabolites were quantitatively measured in plasma of 30 cognitively healthy subjects, 20 patients with mild cognitive impairment (MCI) and 30 patients suffering from AD. Results: Levels of lithocholic acid were significantly enhanced in plasma of AD patients (50 +/- 6 nM, p = 0.004) compared to healthy controls (32 +/- 3 nM). Lithocholic acid plasma levels of MCI patients (41 +/- 4 nM) were not significantly different from healthy subjects or AD patients. Levels of glycochenodeoxycholic acid, glycodeoxycholic acid and glycolithocholic acid were significantly higher in AD patients compared to MCI patients (p < 0.05). All other cholic acid metabolites were not significantly different between healthy subjects, MCI patients and AD patients. ROC analysis shows an overall accuracy of about 66%. Discriminant analysis was used to classify patients and we found that 15/23 were correctly diagnosed. We further showed that LCA levels increased by about 3.2 fold when healthy subjects converted to AD patients within a 8-9 year follow up period. Pathway analysis linked these changes to a putative toxic cholesterol pathway. Conclusion: In conclusion, 4 bile acids may be useful to diagnose AD in plasma samples despite limitations in diagnostic accuracy. PMID- 29249917 TI - Postprandial metabolite profiles associated with type 2 diabetes clearly stratify individuals with impaired fasting glucose. AB - Introduction: Fasting metabolite profiles have been shown to distinguish type 2 diabetes (T2D) patients from normal glucose tolerance (NGT) individuals. Objectives: We investigated whether, besides fasting metabolite profiles, postprandial metabolite profiles associated with T2D can stratify individuals with impaired fasting glucose (IFG) by their similarities to T2D. Methods: Three groups of individuals (age 45-65 years) without any history of IFG or T2D were selected from the Netherlands Epidemiology of Obesity study and stratified by baseline fasting glucose concentrations (NGT (n = 176), IFG (n = 186), T2D (n = 171)). 163 metabolites were measured under fasting and postprandial states (150 min after a meal challenge). Metabolite profiles specific for a high risk of T2D were identified by LASSO regression for fasting and postprandial states. The selected profiles were utilised to stratify IFG group into high (T2D probability >= 0.7) and low (T2D probability <= 0.5) risk subgroups. The stratification performances were compared with clinically relevant metabolic traits. Results: Two metabolite profiles specific for T2D (nfasting = 12 metabolites, npostprandial = 4 metabolites) were identified, with all four postprandial metabolites also being identified in the fasting state. Stratified by the postprandial profile, the high-risk subgroup of IFG individuals (n = 72) showed similar glucose concentrations to the low-risk subgroup (n = 57), yet a higher BMI (difference: 3.3 kg/m2 (95% CI 1.7-5.0)) and postprandial insulin concentrations (21.5 mU/L (95% CI 1.8-41.2)). Conclusion: Postprandial metabolites identified T2D patients as good as fasting metabolites and exhibited enhanced signals for IFG stratification, which offers a proof of concept that metabolomics research should not focus on the fasting state alone. PMID- 29249918 TI - Sphenoethmoid Cell: The Battle for Places Inside of the Nose Between a Posterior Ethmoid Cell and Sphenoid Sinus: 3D-Volumetric Quantification. AB - Background: Sphenoethmoid cells may be above the sphenoid sinus with/ or without con-tact to optical nerve. Although sphenoethmoid cells are theoretically considered to possibly influence the sphenoid sinus volume, we could not find any study in the literature on this issue. Aims: The aim of our study was to detect sphenoethmoid cells and measure the sphenoid sinus vol-ume using multiplanar computerized tomography and also investigate the correlation between the presence of sphenoethmoid cells and the sphenoid sinus volume. Methods: Retrospectively 141 patients who had available paranasal computerized tomography images were included in this study. The sphenoid sinus volumes of each patient were calculated individually for each side, and the relationship between the presence of sphenoethmoid cell and sphenoid sinus volume was investigated. Results: Sphenoethmoid cells were detected at 106 (37.5%) of the total 282 sides in 141 patients. No gender difference was observed. The total sphenoid sinus volume was significantly lower in the group of patients who had bilateral sphenoethmoid cells than in the sphenoethmoid cell negative group. In patients with a unilateral sphenoethmoid cell, a significant decrease in the sphenoid sinus volume was observed only for the side where the sphenoethmoid cell was located. Conclusion: It was observed that the sphenoethmoid cells caused a significant reduction in the sphe-noid sinus volume on the side where they were located. In the case of low sphenoid sinus aeration, the sphenoethmoid cell should be kept in mind. Further studies with an extended patient series are required to explore this issue. PMID- 29249919 TI - Abortion and conscientious objection: rethinking conflicting rights in the Mexican context. AB - Since 2007, when Mexico City decriminalized abortion during the first trimester, a debate has been taking place regarding abortion and the right to conscientious objection (CO). Many people argue that, since the provision of abortions (or "legal terminations of pregnancy" as they are called under Mexico City's law) is now a statutory duty of healthcare personnel there can be no place for "conscientious objection." Others claim that, even if such an objection were to be allowed, it should not be seen as a right, since talk about a right to CO may lead to a slippery slope where we may end up recognizing a right to disobey the law. In this paper, I argue that there is a right to CO and that this may be justified through the notions of autonomy and integrity, which a liberal democracy should respect. However, it cannot be an absolute right, and in the case of abortion, it conflicts with women's reproductive rights. Therefore, CO should be carefully regulated so that it does not obstruct the exercise of women's reproductive rights. Regulation should address questions about who is entitled to object, how such objection should take place, and what can legitimately be objected to. PMID- 29249920 TI - Art and theatre for health in rural Cambodia. AB - This article describes our experience using art and theatre to engage rural communities in western Cambodia to understand malaria and support malaria control and elimination. The project was a pilot science-arts initiative to supplement existing engagement activities conducted by local authorities. In 2016, the project was conducted in 20 villages, involved 300 community members and was attended by more than 8000 people. Key health messages were to use insecticide treated bed-nets and repellents, febrile people should attend village malaria workers, and to raise awareness about the risk of forest-acquired malaria. Building on the experience and lessons learnt in the year prior, the 2017 project which was conducted in 15 villages involved 600 community members and attracted more than 12,000 people. In addition to the malaria theme, upon discussion with local health authorities, secondary theme (infant vaccination) was added to the 2017 project. We learnt the following lessons from our experience in Cambodia: involving local people including children from the beginning of the project and throughout the process is important; messages should be kept simple; it is necessary to take into consideration practical issues such as location and timing of the activities; and that the project should offer something unique to communities. PMID- 29249921 TI - Lentinula edodes beta-glucan enriched diet induces pro- and anti-inflammatory macrophages in rabbit. AB - beta-glucans exhibited in cell walls of several pathogens as bacteria or fungi are sensed by pathogen recognition receptors such as scavenger receptors present in antigen presenting cells, i.e., macrophages. beta-glucans obtained from Shiitake mushrooms were chemically characterized. A beta-glucan supplemented diet was assayed for 30 days in rabbits aiming to characterize the immune response elicited in blood-derived macrophages. M1 and M2 profiles of macrophage differentiation were confirmed in rabbits by in vitro stimulation with IFN-gamma and IL-4 and marker quantification of each differentiation pathway. Blood derived macrophages from rabbits administered in vivo with the beta-glucan supplemented diet showed higher IL-4, IFN-gamma and RAGE together with lower IL-10 relative expression, indicative of an ongoing immune response. Differences in IL-1beta, IL 13 and IL-4 expression were also found in rabbit sera by ELISA suggesting further stimulation of the adaptive response. Recent challenges in the rabbit industry include the search of diet supplements able to elicit an immune stimulation with particular interest in facing pathogens such as viruses or bacteria. beta-glucans from fungi may contribute to maintain an immune steady state favouring protection and thus reducing antibiotic treatment. PMID- 29249922 TI - Rice bran mineral extract increases the expression of anagen-related molecules in human dermal papilla through wnt/catenin pathway. AB - The objective of this study is to evaluate of rice bran mineral extract (RBM) increases the expression of anagen-related molecules in human dermal papilla (DOCs). Four treatment groups were established to evaluate the efficacy of RBM, including a negative control, positive control (ascorbic acid), RBM and ortho silicic acid (Si(OH)4) (OSA) group. Three days after the DPCs were administered the various treatments, western blot analysis showed that type I collagen expression was increased 2.5-fold in the OSA group and 4-fold in the RBM group, and ALP expression was increased 1.5-fold in the OSA and RBM group while the expression of fibronectin was increased ~3-fold in the OSA group and 2.5-fold in the RBM group. Also, the expression of Wnt-3alpha and beta-catenin protein was increased in OSA and RBM group compared to control group. Furthermore, the expression of IL-1a was decreased by more than 50% in the OSA and RBM groups compared to the negative control. Analysis of mRNA expression by RT-qPCR showed that type I collagen increased 1.2-fold in the OSA- and RBM-treated DPCs, whereas type IV collagen increased 2.7-fold in the OSA group and 3.5-fold in the RBM group. However, TGF-beta2 mRNA decreased about 80% in the OSA and RBM groups, respectively. Immunohistochemical staining of the DPCs for versican protein showed a significant increase in the OSA- and RBM-treated groups compared to the negative control. Thus, RBM have a potential to recover of DPCs activity and decreased inflammatory-related markers. It can be expected that hair loss prevention and hair growth enhancement can be expected when RBM is applied as a cosmetic product. PMID- 29249923 TI - An exploration of socio-economic and food characteristics of high trans fatty acid consumers in the Dutch and UK national surveys after voluntary product reformulation. AB - Trans fatty acids (TFA) increase the risk of mortality and chronic diseases. TFA intakes have fallen since reformulation, but may still be high in certain, vulnerable, groups. This paper investigates socio-economic and food consumption characteristics of high TFA consumers after voluntary reformulation in the Netherlands and UK. Post-reformulation data of adults aged 19-64 was analysed in two national surveys: the Dutch National Food Consumption Survey (DNFCS) collected 2007-2010 using 2*24hr recalls (N = 1933) and the UK National Diet and Nutrition Survey (NDNS) years 3&4 collected 2010/11 and 2011/12 using 4-day food diaries (N = 848). The socio-economic and food consumption characteristics of the top 10% and remaining 90% TFA consumers were compared. Means of continuous data were compared using t-tests and categorical data means using chi-squared tests. Multivariate logistic regression models indicated which socio-demographic variables were associated with high TFA consumption. In the Dutch analyses, women and those born outside the Netherlands were more likely to be top 10% TFA consumers than men and Dutch-born. In the UK unadjusted analyses there was no significant trend in socio-economic characteristics between high and lower TFA consumers, but there were regional differences in the multivariate logistic regression analyses. In the Netherlands, high TFA consumers were more likely to be consumers of cakes, buns & pastries; cream; and fried potato than the remaining 90%. Whereas in the UK, high TFA consumers were more likely to be consumers of lamb; cheese; and dairy desserts and lower crisps and savoury snack consumers. Some socio-demographic differences between high and lower TFA consumers were evident post-reformulation. High TFA consumers in the Dutch 2007 10 survey appeared more likely to obtain TFA from artificial sources than those in the UK survey. Further analyses using more up-to-date food composition databases may be needed. PMID- 29249924 TI - The comparative study among different fractions of muscadine grape 'Noble' pomace extracts regarding anti-oxidative activities, cell cycle arrest and apoptosis in breast cancer. AB - As a by-product of wine making, pomace contains rich amounts of phenolic compounds that can be potentially utilized as raw materials to make beneficial products especially for the anti-cancer agents including the breast cancer. Muscadinia rotundifolia 'Noble' is a wine-making grape cultivar, and to better use 'Noble' pomace, the most effective phenolic fractions in cancer inhibition must be identified. In this study, anti-oxidative activities of three separated fractions of 'Noble' pomace (F1, F2 and F3) were compared in 2,2-diphenyl-1 picrylhydrazyl and 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) radical scavenging (DPPH and ABTS) assays as well as the ferric-reducing antioxidant power (FRAP) assay. The ability of different fractions to induce cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells was also evaluated by flow cytometry and Western blot analysis. Fraction F3, which contained a mixture of anthocyanidins and ellagic acids, exhibited the strongest anti oxidative activity, as determined at both low and high concentrations in the DPPH and FRAP assays. F3 also demonstrated the greatest ability to induce apoptosis via caspase activation and cell cycle arrest by downregulating cyclin A and upregulating p21. F3 was thus the most effective bioactive fraction among those prepared from muscadine grape 'Noble' pomace. PMID- 29249925 TI - Determining Excitatory and Inhibitory Neuronal Activity from Multimodal fMRI Data Using a Generative Hemodynamic Model. AB - Hemodynamic responses, in general, and the blood oxygenation level-dependent (BOLD) fMRI signal, in particular, provide an indirect measure of neuronal activity. There is strong evidence that the BOLD response correlates well with post-synaptic changes, induced by changes in the excitatory and inhibitory (E-I) balance between active neuronal populations. Typical BOLD responses exhibit transients, such as the early-overshoot and post-stimulus undershoot, that can be linked to transients in neuronal activity, but they can also result from vascular uncoupling between cerebral blood flow (CBF) and venous cerebral blood volume (venous CBV). Recently, we have proposed a novel generative hemodynamic model of the BOLD signal within the dynamic causal modeling framework, inspired by physiological observations, called P-DCM (Havlicek et al., 2015). We demonstrated the generative model's ability to more accurately model commonly observed neuronal and vascular transients in single regions but also effective connectivity between multiple brain areas (Havlicek et al., 2017b). In this paper, we additionally demonstrate the versatility of the generative model to jointly explain dynamic relationships between neuronal and hemodynamic physiological variables underlying the BOLD signal using multi-modal data. For this purpose, we utilized three distinct data-sets of experimentally induced responses in the primary visual areas measured in human, cat, and monkey brain, respectively: (1) CBF and BOLD responses; (2) CBF, total CBV, and BOLD responses (Jin and Kim, 2008); and (3) positive and negative neuronal and BOLD responses (Shmuel et al., 2006). By fitting the generative model to the three multi-modal experimental data-sets, we showed that the presence or absence of dynamic features in the BOLD signal is not an unambiguous indication of presence or absence of those features on the neuronal level. Nevertheless, the generative model that takes into account the dynamics of the physiological mechanisms underlying the BOLD response allowed dissociating neuronal from vascular transients and deducing excitatory and inhibitory neuronal activity time-courses from BOLD data alone and from multi-modal data. PMID- 29249926 TI - Alzheimer Classification Using a Minimum Spanning Tree of High-Order Functional Network on fMRI Dataset. AB - Functional magnetic resonance imaging (fMRI) is one of the most useful methods to generate functional connectivity networks of the brain. However, conventional network generation methods ignore dynamic changes of functional connectivity between brain regions. Previous studies proposed constructing high-order functional connectivity networks that consider the time-varying characteristics of functional connectivity, and a clustering method was performed to decrease computational cost. However, random selection of the initial clustering centers and the number of clusters negatively affected classification accuracy, and the network lost neurological interpretability. Here we propose a novel method that introduces the minimum spanning tree method to high-order functional connectivity networks. As an unbiased method, the minimum spanning tree simplifies high-order network structure while preserving its core framework. The dynamic characteristics of time series are not lost with this approach, and the neurological interpretation of the network is guaranteed. Simultaneously, we propose a multi-parameter optimization framework that involves extracting discriminative features from the minimum spanning tree high-order functional connectivity networks. Compared with the conventional methods, our resting-state fMRI classification method based on minimum spanning tree high-order functional connectivity networks greatly improved the diagnostic accuracy for Alzheimer's disease. PMID- 29249927 TI - Principled Approaches to Direct Brain Stimulation for Cognitive Enhancement. AB - In this brief review, we identify key areas of research that inform a systematic and targeted approach for invasive brain stimulation with the goal of modulating higher cognitive functions such as memory. We outline several specific challenges that must be successfully navigated in order to achieve this goal. Specifically, using direct brain stimulation to support memory requires demonstrating that (1) there are reliable neural patterns corresponding to different events and memory states, (2) stimulation can be used to induce these target activity patterns, and (3) inducing such patterns modulates memory in the expected directions. Invasive stimulation studies typically have not taken into account intrinsic brain states and dynamics, nor have they a priori targeted specific neural patterns that have previously been identified as playing an important role in memory. Moreover, the effects of stimulation on neural activity are poorly understood and are sensitive to multiple factors including the specific stimulation parameters, the processing state of the brain at the time of stimulation, and neuroanatomy of the stimulated region. As a result, several studies have reported conflicting results regarding the use of direct stimulation for memory modulation. Here, we review the latest findings relevant to these issues and discuss how we can gain better control over the effects of direct brain stimulation for modulating human memory and cognition. PMID- 29249928 TI - The Antioxidant Cofactor Alpha-Lipoic Acid May Control Endogenous Formaldehyde Metabolism in Mammals. AB - The healthy human body contains small amounts of metabolic formaldehyde (FA) that mainly results from methanol oxidation by pectin methylesterase, which is active in a vegetable diet and in the gastrointestinal microbiome. With age, the ability to maintain a low level of FA decreases, which increases the risk of Alzheimer's disease and dementia. It has been shown that 1,2-dithiolane-3-pentanoic acid or alpha lipoic acid (ALA), a naturally occurring dithiol and antioxidant cofactor of mitochondrial alpha-ketoacid dehydrogenases, increases glutathione (GSH) content and FA metabolism by mitochondrial aldehyde dehydrogenase 2 (ALDH2) thus manifests a therapeutic potential beyond its antioxidant property. We suggested that ALA can contribute to a decrease in the FA content of mammals by acting on ALDH2 expression. To test this assumption, we administered ALA in mice in order to examine the effect on FA metabolism and collected blood samples for the measurement of FA. Our data revealed that ALA efficiently eliminated FA in mice. Without affecting the specific activity of FA-metabolizing enzymes (ADH1, ALDH2, and ADH5), ALA increased the GSH content in the brain and up-regulated the expression of the FA-metabolizing ALDH2 gene in the brain, particularly in the hippocampus, but did not impact its expression in the liver in vivo or in rat liver isolated from the rest of the body. After ALA administration in mice and in accordance with the increased content of brain ALDH2 mRNA, we detected increased ALDH2 activity in brain homogenates. We hypothesized that the beneficial effects of ALA on patients with Alzheimer's disease may be associated with accelerated ALDH2-mediated FA detoxification and clearance. PMID- 29249929 TI - Pigeons (C. livia) Follow Their Head during Turning Flight: Head Stabilization Underlies the Visual Control of Flight. AB - Similar flight control principles operate across insect and vertebrate fliers. These principles indicate that robust solutions have evolved to meet complex behavioral challenges. Following from studies of visual and cervical feedback control of flight in insects, we investigate the role of head stabilization in providing feedback cues for controlling turning flight in pigeons. Based on previous observations that the eyes of pigeons remain at relatively fixed orientations within the head during flight, we test potential sensory control inputs derived from head and body movements during 90 degrees aerial turns. We observe that periods of angular head stabilization alternate with rapid head repositioning movements (head saccades), and confirm that control of head motion is decoupled from aerodynamic and inertial forces acting on the bird's continuously rotating body during turning flapping flight. Visual cues inferred from head saccades correlate with changes in flight trajectory; whereas the magnitude of neck bending predicts angular changes in body position. The control of head motion to stabilize a pigeon's gaze may therefore facilitate extraction of important motion cues, in addition to offering mechanisms for controlling body and wing movements. Strong similarities between the sensory flight control of birds and insects may also inspire novel designs of robust controllers for human engineered autonomous aerial vehicles. PMID- 29249930 TI - Effects of Field-Map Distortion Correction on Resting State Functional Connectivity MRI. AB - Magnetic field inhomogeneities cause geometric distortions of echo planar images used for functional magnetic resonance imaging (fMRI). To reduce this problem, distortion correction (DC) with field map is widely used for both task and resting-state fMRI (rs-fMRI). Although DC with field map has been reported to improve the quality of task fMRI, little is known about its effects on rs-fMRI. Here, we tested the influence of field-map DC on rs-fMRI results using two rs fMRI datasets derived from 40 healthy subjects: one with DC (DC+) and the other without correction (DC-). Independent component analysis followed by the dual regression approach was used for evaluation of resting-state functional connectivity networks (RSN). We also obtained the ratio of low-frequency to high frequency signal power (0.01-0.1 Hz and above 0.1 Hz, respectively; LFHF ratio) to assess the quality of rs-fMRI signals. For comparison of RSN between DC+ and DC- datasets, the default mode network showed more robust functional connectivity in the DC+ dataset than the DC- dataset. Basal ganglia RSN showed some decreases in functional connectivity primarily in white matter, indicating imperfect registration/normalization without DC. Supplementary seed-based and simulation analyses supported the utility of DC. Furthermore, we found a higher LFHF ratio after field map correction in the anterior cingulate cortex, posterior cingulate cortex, ventral striatum, and cerebellum. In conclusion, field map DC improved detection of functional connectivity derived from low-frequency rs-fMRI signals. We encourage researchers to include a DC step in the preprocessing pipeline of rs fMRI analysis. PMID- 29249931 TI - Preliminary Evidence of "Other-Race Effect"-Like Behavior Induced by Cathodal tDCS over the Right Occipital Cortex, in the Absence of Overall Effects on Face/Object Processing. AB - Neuromodulation techniques such as tDCS have provided important insight into the neurophysiological mechanisms that mediate cognition. Albeit anodal tDCS (a-tDCS) often enhances cognitive skills, the role of cathodal tDCS (c-tDCS) in visual cognition is largely unexplored and inconclusive. Here, in a single-blind, sham controlled study, we investigated the offline effects of 1.5 mA c-tDCS over the right occipital cortex of 86 participants on four tasks assessing perception and memory of both faces and objects. Results demonstrated that c-tDCS does not overall affect performance on the four tasks. However, post-hoc exploratory analysis on participants' race (Caucasian vs. non-Caucasians), showed a "face specific" performance decrease (~10%) in non-Caucasian participants only. This preliminary evidence suggests that c-tDCS can induce "other-race effect (ORE) like" behavior in non-Caucasian participants that did not show any ORE before stimulation (and in case of sham stimulation). Our results add relevant information about the breadth of cognitive processes and visual stimuli that can be modulated by c-tDCS, about the design of effective neuromodulation protocols, and have important implications for the potential neurophysiological bases of ORE. PMID- 29249932 TI - No Interaction between tDCS Current Strength and Baseline Performance: A Conceptual Replication. AB - Several recent studies have reported non-linear effects of transcranial direct current stimulation (tDCS), which has been attributed to an interaction between the stimulation parameters (e.g., current strength, duration) and the neural state of the cortex being stimulated (e.g., indexed by baseline performance ability, age) (see Fertonani and Miniussi, 2016). We have recently described one such non-linear interaction between current strength and baseline performance on a visuospatial attention (landmark) task (Benwell et al., 2015). In this previous study, we induced a small overall rightward shift of spatial attention across 38 participants using bi-hemispheric tDCS applied for 20 min (concurrent left posterior parietal (P5) anode and right posterior parietal (P6) cathode) relative to a sham protocol. Importantly, this shift in bias was driven by a state dependent interaction between current intensity and the discrimination sensitivity of the participant at baseline (pre-stimulation) for the landmark task. Individuals with high discrimination sensitivity (HDS) shifted rightward in response to low- (1 mA) but not high-intensity (2 mA) tDCS, whereas individuals with low discrimination sensitivity (LDS) shifted rightward with high- but not low-intensity stimulation. However, in Benwell et al. (2015) current strength was applied as a between-groups factor, where half of the participants received 1 mA and half received 2 mA tDCS, thus we were unable to compare high and low intensity tDCS directly within each individual. Here we aimed to replicate these findings using a within-group design. Thirty young adults received 15 min of 1 and 2 mA tDCS, and a sham protocol, each on different days, to test the concept of an interaction between baseline performance and current strength. We found no overall rightward shift of spatial attention with either current strength, and no interaction between performance and current strength. These results provide further evidence of low replicability of non-invasive brain stimulation protocols, and the need for further attempts to replicate the key experimental findings within this field. PMID- 29249933 TI - Chronic Organic Solvent Exposure Changes Visual Tracking in Men and Women. AB - Organic solvents can change CNS sensory and motor function. Eye-movement analyses can be important tools when investigating the neurotoxic changes that result from chronic organic solvent exposure. The current research measured the eye-movement patterns of men and women with and without histories of chronic organic solvent exposure. A total of 44 volunteers between 18 and 41 years old participated in this study; 22 were men (11 exposed and 11 controls), and 22 were women (11 exposed and 11 controls). Eye movement was evaluated using a 250-Hz High-Speed Video Eye Tracker Toolbox (Cambridge Research Systems) via an image of a maze. Specific body indices of exposed and non-exposed men and women were measured with an Inbody 720 to determine whether the differences in eye-movement patterns were associated with body composition. The data were analyzed using IBM SPSS Statistics version 20.0.0. The results indicated that exposed adults showed significantly more fixations (t = 3.82; p = 0.001; r = 0.51) and longer fixations (t = 4.27; p = 0.001, r = 0.54) than their non-exposed counterparts. Comparisons within men (e.g., exposed and non-exposed) showed significant differences in the number of fixations (t = 2.21; p = 0.04; r = 0.20) and duration of fixations (t = 3.29; p = 0.001; r = 0.35). The same was true for exposed vs. non-exposed women, who showed significant differences in the number of fixations (t = 3.10; p = 0.001; r = 0.32) and fixation durations (t = 2.76; p = 0.01; r = 0.28). However, the results did not show significant differences between exposed women and men in the number and duration of fixations. No correlations were found between eye movement pattern and body composition measures (p > 0.05). These results suggest that chronic organic solvent exposure affects eye movements, regardless of sex and body composition, and that eye tracking contributes to the investigation of the visual information processing disorders acquired by workers exposed to organic solvents. PMID- 29249934 TI - The Psychoactive Agent Crocin Can Regulate Hypothalamic-Pituitary-Adrenal Axis Activity. AB - Post-traumatic stress disorder (PTSD) occurs following life-threatening events. The activity of the hypothalamic-pituitary-adrenal (HPA) axis, which serves as the first line of defense against stress, is dysfunctional in this disorder. The current study aimed to investigate the role of Crocin in normalizing HPA function in an animal model of PTSD induced by electric foot shock. Rats were treated with Crocin 5 min prior to stress induction. The stimulus was re-introduced after 21 days, and we measured individual behaviors such as sniffing, rearing, grooming, and freezing. Enzyme-linked immunosorbent assays were performed to measure plasma levels of Corticosterone. On day 28, after rats were weighed and sacrificed, the adrenal and thymus glands were removed and subjected to real-time polymerase chain reaction to quantify the gene expression of corticotrophin-releasing hormone (CRH), glucocorticoid receptor (GluR), and arginine vasopressin (AVP). Our results demonstrate that rats re-exposed to a stressor developed characteristic symptoms of PTSD, but these were attenuated by Crocin. Treated rats showed significant changes in CRH expression in the hypothalamus, GluR expression in the pituitary, plasma Corticosterone levels, and freezing behavior. Together, these findings suggest that Crocin can regulate HPA axis activity in PTSD. It may serve an appropriate treatment for subjects who experience a traumatic event. PMID- 29249936 TI - Editorial: The Trigeminocardiac Reflex: Beyond the Diving Reflex. PMID- 29249935 TI - Loss of Neuroprotective Factors in Neurodegenerative Dementias: The End or the Starting Point? AB - Recent clinical, genetic and biochemical experimental evidences highlight the existence of common molecular pathways underlying neurodegenerative diseases. In this review, we will explore a key common pathological mechanism, i.e., the loss of neuroprotective factors, across the three major neurodegenerative diseases leading to dementia: Alzheimer's disease (AD), Frontotemporal dementia (FTD) and Lewy body dementia (LBD). We will report evidences that the Brain Derived Neurotrophic Factor (BDNF), the most investigated and characterized brain neurotrophin, progranulin, a multi-functional adipokine with trophic and growth factor properties, and cystatin C, a neuroprotective growth factor, are reduced in AD, FTD, and LBD. Moreover, we will review the molecular mechanism underlying the loss of neuroprotective factors in neurodegenerative diseases leading to dementia, with a special focus on endo-lysosomal pathway and intercellular communication mediated by extracellular vesicles. Exploring the shared commonality of disease mechanisms is of pivotal importance to identify novel potential therapeutic targets and to develop treatments to delay, slow or block disease progression. PMID- 29249939 TI - Co-expression Patterns between ATN1 and ATXN2 Coincide with Brain Regions Affected in Huntington's Disease. AB - Cytosine-adenine-guanine (CAG) repeat expansions in the coding regions of nine polyglutamine (polyQ) genes (HTT, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, ATN1, AR, and TBP) are the cause of several neurodegenerative diseases including Huntington's disease (HD), six different spinocerebellar ataxias (SCAs), dentatorubral-pallidoluysian atrophy, and spinobulbar muscular atrophy. The expanded CAG repeat length in the causative gene is negatively related to the age at-onset (AAO) of clinical symptoms. In addition to the expanded CAG repeat length in the causative gene, the normal CAG repeats in the other polyQ genes can affect the AAO, suggesting functional interactions between the polyQ genes. However, there is no detailed assessment of the relationships among polyQ genes in pathologically relevant brain regions. We used gene co-expression analysis to study the functional relationships among polyQ genes in different brain regions using the Allen Human Brain Atlas (AHBA), a spatial map of gene expression in the healthy brain. We constructed co-expression networks for seven anatomical brain structures, as well as a region showing a specific pattern of atrophy in HD patients detected by magnetic resonance imaging (MRI) of the brain. In this HD associated region, we found that ATN1 and ATXN2 were co-expressed and shared co expression partners which were enriched for DNA repair genes. We observed a similar co-expression pattern in the frontal lobe, parietal lobe, and striatum in which this relation was most pronounced. Given that the co-expression patterns for these anatomical structures were similar to those for the HD-associated region, our results suggest that their disruption is likely involved in HD pathology. Moreover, ATN1 and ATXN2 also shared many co-expressed genes with HTT, the causative gene of HD, across the brain. Although this triangular relationship among these three polyQ genes may also be dysregulated in other polyQ diseases, stronger co-expression patterns between ATN1 and ATXN2 observed in the HD associated region, especially in the striatum, may be more specific to HD. PMID- 29249938 TI - Peli1 Contributions in Microglial Activation, Neuroinflammatory Responses and Neurological Deficits Following Experimental Subarachnoid Hemorrhage. AB - Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is closely associated with neuroinflammation. Microglial activation is an early event that leads to neuroinflammation after SAH. Peli1 is an E3 ubiquitin ligase that mediates the induction of pro-inflammatory cytokines in microglia. Here we report Peli1 contributions in SAH mediated brain pathology. An SAH model was induced by endovascular perforation in adult male C57BL/6J mice. Peli1 was markedly induced in mice brains in a time-dependent manner and was predominantly expressed in CD16/32-positive microglia after SAH. Using genetic approaches, we demonstrated that decreased Peli1 significantly improved neurological deficits, attenuated brain edema, reduced over-expression of pro-inflammatory cytokine IL-6 and modified apoptotic/antiapoptotic biomarkers. In addition, Peli1 downregulation suppressed ERK and JNK phosphorylation levels via the downregulation of cIAP1/2 expression, subsequently reducing inducible nitric oxide synthase (iNOS) expression after SAH. Therefore, these findings demonstrate that Peli1 contributes to microglia-mediated neuroinflammation in EBI by mediating cIAP1/2 activation, thus promoting the activation of MyD88-dependent MAPK pathway after experimental SAH. Our findings also showed that Peli1 could promote the expression of M1 microglia polarization biomarker CD16/32 and iNOS after SAH. Targeting Peli1 exerts neuroprotective effects during EBI after SAH, thus could provide potential option for prevention-therapy in high-risk individuals. PMID- 29249937 TI - Glycosylphosphatidylinositol-Anchored Immunoglobulin Superfamily Cell Adhesion Molecules and Their Role in Neuronal Development and Synapse Regulation. AB - Immunoglobulin superfamily (IgSF) cell adhesion molecules (CAMs) are cell surface glycoproteins that not only mediate interactions between neurons but also between neurons and other cells in the nervous system. While typical IgSF CAMs are transmembrane molecules, this superfamily also includes CAMs, which do not possess transmembrane and intracellular domains and are instead attached to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. In this review, we focus on the role GPI-anchored IgSF CAMs have as signal transducers and ligands in neurons, and discuss their functions in regulation of neuronal development, synapse formation, synaptic plasticity, learning, and behavior. We also review the links between GPI-anchored IgSF CAMs and brain disorders. PMID- 29249940 TI - Propofol Exposure in Early Life Induced Developmental Impairments in the Mouse Cerebellum. AB - Propofol is a widely used anesthetic in the clinic while several studies have demonstrated that propofol exposure may cause neurotoxicity in the developing brain. However, the effects of early propofol exposure on cerebellar development are not well understood. Propofol (30 or 60 mg/kg) was administered to mice on postnatal day (P)7; Purkinje cell dendritogenesis and Bergmann glial cell development were evaluated on P8, and granule neuron migration was analyzed on P10. The results indicated that exposure to propofol on P7 resulted in a significant reduction in calbindin-labeled Purkinje cells and their dendrite length. Furthermore, propofol induced impairments in Bergmann glia development, which might be involved in the delay of granule neuron migration from the external granular layer (EGL) to the internal granular layer (IGL) during P8 to P10 at the 60 mg/kg dosage, but not at the 30 mg/kg dosage. Several reports have suggested that the Notch signaling pathway plays instructive roles in the morphogenesis of Bergmann glia. Here, it was revealed that propofol treatment decreased Jagged1 and Notch1 protein levels in the cerebellum on P8. Taken together, exposure to propofol during the neonatal period impairs Bergmann glia development and may therefore lead to cerebellum development defects. Our results may aid in the understanding of the neurotoxic effects of propofol when administrated to infants. PMID- 29249941 TI - Correlating Anatomy and Function with Gene Expression in Individual Neurons by Combining in Vivo Labeling, Patch Clamp, and Single Cell RNA-seq. AB - The classification of neurons into distinct types is an ongoing effort aimed at revealing and understanding the diversity of the components of the nervous system. Recently available methods allow us to determine the gene expression pattern of individual neurons in the mammalian cerebral cortex to generate powerful categorization schemes. For a thorough understanding of neuronal diversity such genetic categorization schemes need to be combined with traditional classification parameters like position, axonal projection or response properties to sensory stimulation. Here we describe a method to link the gene expression of individual neurons with their position, axonal projection, or sensory response properties. Neurons are labeled in vivo based on their anatomical or functional properties and, using patch clamp pipettes, their RNA individually harvested in vitro for RNAseq. We validate the methodology using multiple established molecularly and anatomically distinct cell populations and explore molecular differences between uncharacterized neurons in mouse visual cortex. Gene expression patterns between L5 neurons projecting to frontal or contralateral cortex are distinct while L2 neurons differing in position, projection, or function are molecularly similar. With this method we can determine the genetic expression pattern of functionally and anatomically identified individual neurons. PMID- 29249942 TI - Secretin Modulates the Postnatal Development of Mouse Cerebellar Cortex Via PKA- and ERK-dependent Pathways. AB - Postnatal development of the cerebellum is critical for its intact function such as motor coordination and has been implicated in the pathogenesis of psychiatric disorders. We previously reported that deprivation of secretin (SCT) from cerebellar Purkinje neurons impaired motor coordination and motor learning function, while leaving the potential role of SCT in cerebellar development to be determined. SCT and its receptor (SCTR) were constitutively expressed in the postnatal cerebellum in a temporal and cell-specific manner. Using a SCT knockout mouse model, we provided direct evidence showing altered developmental patterns of Purkinje cells (PCs) and granular cells (GCs). SCT deprivation reduced the PC density, impaired the PC dendritic formation, induced accelerated GC migration and potentiated cerebellar apoptosis. Furthermore, our results indicated the involvement of protein kinase A (PKA) and extracellular signal regulated kinase (ERK) signaling pathways in SCT-mediated protective effects against neuronal apoptosis. Results of this study illustrated a novel function of SCT in the postnatal development of cerebellum, emphasizing the necessary role of SCT in cerebellar-related functions. PMID- 29249944 TI - A Sweet Talk: The Molecular Systems of Perineuronal Nets in Controlling Neuronal Communication. AB - Perineuronal nets (PNNs) are mesh-like structures, composed of a hierarchical assembly of extracellular matrix molecules in the central nervous system (CNS), ensheathing neurons and regulating plasticity. The mechanism of interactions between PNNs and neurons remain uncharacterized. In this review, we pose the question: how do PNNs regulate communication to and from neurons? We provide an overview of the current knowledge on PNNs with a focus on the cellular interactions. PNNs ensheath a subset of the neuronal population with distinct molecular aspects in different areas of the CNS. PNNs control neuronal communication through molecular interactions involving specific components of the PNNs. This review proposes that the PNNs are an integral part of neurons, crucial for the regulation of plasticity in the CNS. PMID- 29249943 TI - The Suprachiasmatic Nucleus of the Dromedary Camel (Camelus dromedarius): Cytoarchitecture and Neurochemical Anatomy. AB - In mammals, biological rhythms are driven by a master circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Recently, we have demonstrated that in the camel, the daily cycle of environmental temperature is able to entrain the master clock. This raises several questions about the structure and function of the SCN in this species. The current work is the first neuroanatomical investigation of the camel SCN. We carried out a cartography and cytoarchitectural study of the nucleus and then studied its cell types and chemical neuroanatomy. Relevant neuropeptides involved in the circadian system were investigated, including arginine-vasopressin (AVP), vasoactive intestinal polypeptide (VIP), met-enkephalin (Met-Enk), neuropeptide Y (NPY), as well as oxytocin (OT). The neurotransmitter serotonin (5-HT) and the enzymes tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) were also studied. The camel SCN is a large and elongated nucleus, extending rostrocaudally for 9.55 +/- 0.10 mm. Based on histological and immunofluorescence findings, we subdivided the camel SCN into rostral/preoptic (rSCN), middle/main body (mSCN) and caudal/retrochiasmatic (cSCN) divisions. Among mammals, the rSCN is unusual and appears as an assembly of neurons that protrudes from the main mass of the hypothalamus. The mSCN exhibits the triangular shape described in rodents, while the cSCN is located in the retrochiasmatic area. As expected, VIP-immunoreactive (ir) neurons were observed in the ventral part of mSCN. AVP-ir neurons were located in the rSCN and mSCN. Results also showed the presence of OT-ir and TH-ir neurons which seem to be a peculiarity of the camel SCN. OT-ir neurons were either scattered or gathered in one isolated cluster, while TH-ir neurons constituted two defined populations, dorsal parvicellular and ventral magnocellular neurons, respectively. TH colocalized with VIP in some rSCN neurons. Moreover, a high density of Met-Enk-ir, 5-HT-ir and NPY-ir fibers were observed within the SCN. Both the cytoarchitecture and the distribution of neuropeptides are unusual in the camel SCN as compared to other mammals. The presence of OT and TH in the camel SCN suggests their role in the modulation of circadian rhythms and the adaptation to photic and non-photic cues under desert conditions. PMID- 29249945 TI - Perceived Conventionality in Co-speech Gestures Involves the Fronto-Temporal Language Network. AB - Face-to-face communication is multimodal; it encompasses spoken words, facial expressions, gaze, and co-speech gestures. In contrast to linguistic symbols (e.g., spoken words or signs in sign language) relying on mostly explicit conventions, gestures vary in their degree of conventionality. Bodily signs may have a general accepted or conventionalized meaning (e.g., a head shake) or less so (e.g., self-grooming). We hypothesized that subjective perception of conventionality in co-speech gestures relies on the classical language network, i.e., the left hemispheric inferior frontal gyrus (IFG, Broca's area) and the posterior superior temporal gyrus (pSTG, Wernicke's area) and studied 36 subjects watching video-recorded story retellings during a behavioral and an functional magnetic resonance imaging (fMRI) experiment. It is well documented that neural correlates of such naturalistic videos emerge as intersubject covariance (ISC) in fMRI even without involving a stimulus (model-free analysis). The subjects attended either to perceived conventionality or to a control condition (any hand movements or gesture-speech relations). Such tasks modulate ISC in contributing neural structures and thus we studied ISC changes to task demands in language networks. Indeed, the conventionality task significantly increased covariance of the button press time series and neuronal synchronization in the left IFG over the comparison with other tasks. In the left IFG, synchronous activity was observed during the conventionality task only. In contrast, the left pSTG exhibited correlated activation patterns during all conditions with an increase in the conventionality task at the trend level only. Conceivably, the left IFG can be considered a core region for the processing of perceived conventionality in co-speech gestures similar to spoken language. In general, the interpretation of conventionalized signs may rely on neural mechanisms that engage during language comprehension. PMID- 29249946 TI - Moderate Partially Reduplicated Conditioned Stimuli as Retrieval Cue Can Increase Effect on Preventing Relapse of Fear to Compound Stimuli. AB - The theory of memory reconsolidation argues that consolidated memory is not unchangeable. Once a memory is reactivated it may go back into an unstable state and need new protein synthesis to be consolidated again, which is called "memory reconsolidation". Boundary studies have shown that interfering with reconsolidation through pharmacologic or behavioral intervention can lead to the updating of the initial memory, for example, erasing undesired memories. Behavioral procedures based on memory reconsolidation interference have been shown to be an effective way to inhibit fear memory relapse after extinction. However, the effectiveness of retrieval-extinction differs by subtle differences in the protocol of the reactivation session. This represents a challenge with regard to finding an optimal operational model to facilitate its clinical use for patients suffering from pathogenic memories such as those associated with post traumatic stress disorder. Most of the laboratory models for fear learning have used a single conditioned stimulus (CS) paired with an unconditioned stimulus (US). This has simplified the real situation of traumatic events to an excessive degree, and thus, limits the clinical application of the findings based on these models. Here, we used a basic visual compound CS model as the CS to ascertain whether partial repetition of the compound CSs in conditioning can reactivate memory into reconsolidation. The results showed that the no retrieval group or the 1/3 ratio retrieval group failed to open the memory reconsolidation time window. The 2/3 repetition retrieval group and the whole repetition retrieval group were able to prevent fear reinstatement, whereas only a 2/3 ratio repetition of the initial compound CS as a reminder could inhibit spontaneous recovery. We inferred that a retrieval-extinction paradigm was also effective in a more complex model of fear if a sufficient prediction error (PE) could be generated in the reactivation period. In addition, in order to achieve an optimal effect, a CS of moderate discrepancy should be used as a reminder. PMID- 29249947 TI - Global Electroencephalography Synchronization as a New Indicator for Tracking Emotional Changes of a Group of Individuals during Video Watching. AB - In the present study, we investigated whether global electroencephalography (EEG) synchronization can be a new promising index for tracking emotional arousal changes of a group of individuals during video watching. Global field synchronization (GFS), an index known to correlate with human cognitive processes, was evaluated; this index quantified the global temporal synchronization among multichannel EEG data recorded from a group of participants (n = 25) during the plays of two short video clips. The two video clips were each about 5 min long and were designed to evoke negative (fearful) or positive (happy) emotion, respectively. Another group of participants (n = 37) was asked to select the two most emotionally arousing (most touching or most fearful) scenes in each clip. The results of these questionnaire surveys were used as the ground-truth to evaluate whether the GFS could detect emotional highlights of both video clips. The emotional highlights estimated using the grand-averaged GFS waveforms of the first group were also compared with those evaluated from galvanic skin response, photoplethysmography, and multimedia content analysis, which are conventional methods used to estimate temporal changes in emotional arousal during video plays. From our results, we found that beta-band GFS values decreased during high emotional arousal, regardless of the type of emotional stimulus. Moreover, the emotional highlights estimated using the GFS waveforms coincided best with those found by the questionnaire surveys. These findings suggest that GFS might be applicable as a new index for tracking emotional arousal changes of a group of individuals during video watching, and is likely to be used to evaluate or edit movies, TV commercials, and other broadcast products. PMID- 29249948 TI - Psychopathy Moderates the Relationship between Orbitofrontal and Striatal Alterations and Violence: The Investigation of Individuals Accused of Homicide. AB - Brain structural abnormalities in the orbitofrontal cortex (OFC) and striatum (caudate and putamen) have been observed in violent individuals. However, a uni modal neuroimaging perspective has been used and prior findings have been mixed. The present study takes the multimodal structural brain imaging approaches to investigate the differential gray matter volumes (GMV) and cortical thickness (CTh) in the OFC and striatum between violent (accused of homicide) and non violent (not accused of any violent crimes) individuals with different levels of psychopathic traits (interpersonal and unemotional qualities, factor 1 psychopathy and the expressions of antisocial disposition and impulsivity, factor 2 psychopathy). Structural Magnetic Resonance Imaging data, psychopathy and demographic information were assessed in sixty seven non-violent or violent adults. The results showed that the relationship between violence and the GMV in the right lateral OFC varied across different levels of the factor 1 psychopathy. At the subcortical level, the psychopathy level (the factor 1 psychopathy) moderated the positive relationship of violence with both left and right putamen GMV as well as left caudate GMV. Although the CTh findings were not significant, overall findings suggested that psychopathic traits moderated the relationship between violence and the brain structural morphology in the OFC and striatum. In conclusion, psychopathy takes upon a significant role in moderating violent behavior which gives insight to design and implement prevention measures targeting violent acts, thereby possibly mitigating their occurrence within the society. PMID- 29249949 TI - Modulation of Neural Activity during Guided Viewing of Visual Art. AB - Mobile Brain-Body Imaging (MoBI) technology was deployed to record multi-modal data from 209 participants to examine the brain's response to artistic stimuli at the Museo de Arte Contemporaneo (MARCO) in Monterrey, Mexico. EEG signals were recorded as the subjects walked through the exhibit in guided groups of 6-8 people. Moreover, guided groups were either provided with an explanation of each art piece (Guided-E), or given no explanation (Guided-NE). The study was performed using portable Muse (InteraXon, Inc, Toronto, ON, Canada) headbands with four dry electrodes located at AF7, AF8, TP9, and TP10. Each participant performed a baseline (BL) control condition devoid of artistic stimuli and selected his/her favorite piece of art (FP) during the guided tour. In this study, we report data related to participants' demographic information and aesthetic preference as well as effects of art viewing on neural activity (EEG) in a select subgroup of 18-30 year-old subjects (Nc = 25) that generated high quality EEG signals, on both BL and FP conditions. Dependencies on gender, sensor placement, and presence or absence of art explanation were also analyzed. After denoising, clustering of spectral EEG models was used to identify neural patterns associated with BL and FP conditions. Results indicate statistically significant suppression of beta band frequencies (15-25 Hz) in the prefrontal electrodes (AF7 and AF8) during appreciation of subjects' favorite painting, compared to the BL condition, which was significantly different from EEG responses to non-favorite paintings (NFP). No significant differences in brain activity in relation to the presence or absence of explanation during exhibit tours were found. Moreover, a frontal to posterior asymmetry in neural activity was observed, for both BL and FP conditions. These findings provide new information about frequency-related effects of preferred art viewing in brain activity, and support the view that art appreciation is independent of the artists' intent or original interpretation and related to the individual message that viewers themselves provide to each piece. PMID- 29249950 TI - Non-linear Relationship between BOLD Activation and Amplitude of Beta Oscillations in the Supplementary Motor Area during Rhythmic Finger Tapping and Internal Timing. AB - Functional imaging studies using BOLD contrasts have consistently reported activation of the supplementary motor area (SMA) both during motor and internal timing tasks. Opposing findings, however, have been shown for the modulation of beta oscillations in the SMA. While movement suppresses beta oscillations in the SMA, motor and non-motor tasks that rely on internal timing increase the amplitude of beta oscillations in the SMA. These independent observations suggest that the relationship between beta oscillations and BOLD activation is more complex than previously thought. Here we set out to investigate this rapport by examining beta oscillations in the SMA during movement with varying degrees of internal timing demands. In a simultaneous EEG-fMRI experiment, 20 healthy right handed subjects performed an auditory-paced finger-tapping task. Internal timing was operationalized by including conditions with taps on every fourth auditory beat, which necessitates generation of a slow internal rhythm, while tapping to every auditory beat reflected simple auditory-motor synchronization. In the SMA, BOLD activity increased and power in both the low and the high beta band decreased expectedly during each condition compared to baseline. Internal timing was associated with a reduced desynchronization of low beta oscillations compared to conditions without internal timing demands. In parallel with this relative beta power increase, internal timing activated the SMA more strongly in terms of BOLD. This documents a task-dependent non-linear relationship between BOLD and beta-oscillations in the SMA. We discuss different roles of beta synchronization and desynchronization in active processing within the same cortical region. PMID- 29249951 TI - Diffusion Tensor Imaging Tractography Reveals Disrupted White Matter Structural Connectivity Network in Healthy Adults with Insomnia Symptoms. AB - Neuroimaging studies have revealed that insomnia is characterized by aberrant neuronal connectivity in specific brain regions, but the topological disruptions in the white matter (WM) structural connectivity networks remain largely unknown in insomnia. The current study uses diffusion tensor imaging (DTI) tractography to construct the WM structural networks and graph theory analysis to detect alterations of the brain structural networks. The study participants comprised 30 healthy subjects with insomnia symptoms (IS) and 62 healthy subjects without IS. Both the two groups showed small-world properties regarding their WM structural connectivity networks. By contrast, increased local efficiency and decreased global efficiency were identified in the IS group, indicating an insomnia-related shift in topology away from regular networks. In addition, the IS group exhibited disrupted nodal topological characteristics in regions involving the fronto limbic and the default-mode systems. To our knowledge, this is the first study to explore the topological organization of WM structural network connectivity in insomnia. More importantly, the dysfunctions of large-scale brain systems including the fronto-limbic pathways, salience network and default-mode network in insomnia were identified, which provides new insights into the insomnia connectome. Topology-based brain network analysis thus could be a potential biomarker for IS. PMID- 29249952 TI - Enhanced Motor Imagery-Based BCI Performance via Tactile Stimulation on Unilateral Hand. AB - Brain-computer interface (BCI) has attracted great interests for its effectiveness in assisting disabled people. However, due to the poor BCI performance, this technique is still far from daily-life applications. One of critical issues confronting BCI research is how to enhance BCI performance. This study aimed at improving the motor imagery (MI) based BCI accuracy by integrating MI tasks with unilateral tactile stimulation (Uni-TS). The effects were tested on both healthy subjects and stroke patients in a controlled study. Twenty-two healthy subjects and four stroke patients were recruited and randomly divided into a control-group and an enhanced-group. In the control-group, subjects performed two blocks of conventional MI tasks (left hand vs. right hand), with 80 trials in each block. In the enhanced-group, subjects also performed two blocks of MI tasks, but constant tactile stimulation was applied on the non dominant/paretic hand during MI tasks in the second block. We found the Uni-TS significantly enhanced the contralateral cortical activations during MI of the stimulated hand, whereas it had no influence on activation patterns during MI of the non-stimulated hand. The two-class BCI decoding accuracy was significantly increased from 72.5% (MI without Uni-TS) to 84.7% (MI with Uni-TS) in the enhanced-group (p < 0.001, paired t-test). Moreover, stroke patients in the enhanced-group achieved an accuracy >80% during MI with Uni-TS. This novel approach complements the conventional methods for BCI enhancement without increasing source information or complexity of signal processing. This enhancement via Uni-TS may facilitate clinical applications of MI-BCI. PMID- 29249953 TI - Learning Peri-saccadic Remapping of Receptive Field from Experience in Lateral Intraparietal Area. AB - Our eyes move constantly at a frequency of 3-5 times per second. These movements, called saccades, induce the sweeping of visual images on the retina, yet we perceive the world as stable. It has been suggested that the brain achieves this visual stability via predictive remapping of neuronal receptive field (RF). A recent experimental study disclosed details of this remapping process in the lateral intraparietal area (LIP), that is, about the time of the saccade, the neuronal RF expands along the saccadic trajectory temporally, covering the current RF (CRF), the future RF (FRF), and the region the eye will sweep through during the saccade. A cortical wave (CW) model was also proposed, which attributes the RF remapping as a consequence of neural activity propagating in the cortex, triggered jointly by a visual stimulus and the corollary discharge (CD) signal responsible for the saccade. In this study, we investigate how this CW model is learned naturally from visual experiences at the development of the brain. We build a two-layer network, with one layer consisting of LIP neurons and the other superior colliculus (SC) neurons. Initially, neuronal connections are random and non-selective. A saccade will cause a static visual image to sweep through the retina passively, creating the effect of the visual stimulus moving in the opposite direction of the saccade. According to the spiking-time-dependent plasticity rule, the connection path in the opposite direction of the saccade between LIP neurons and the connection path from SC to LIP are enhanced. Over many such visual experiences, the CW model is developed, which generates the peri saccadic RF remapping in LIP as observed in the experiment. PMID- 29249954 TI - An Extended Passive Motion Paradigm for Human-Like Posture and Movement Planning in Redundant Manipulators. AB - A major challenge in robotics and computational neuroscience is relative to the posture/movement problem in presence of kinematic redundancy. We recently addressed this issue using a principled approach which, in conjunction with nonlinear inverse optimization, allowed capturing postural strategies such as Donders' law. In this work, after presenting this general model specifying it as an extension of the Passive Motion Paradigm, we show how, once fitted to capture experimental postural strategies, the model is actually able to also predict movements. More specifically, the passive motion paradigm embeds two main intrinsic components: joint damping and joint stiffness. In previous work we showed that joint stiffness is responsible for static postures and, in this sense, its parameters are regressed to fit to experimental postural strategies. Here, we show how joint damping, in particular its anisotropy, directly affects task-space movements. Rather than using damping parameters to fit a posteriori task-space motions, we make the a priori hypothesis that damping is proportional to stiffness. This remarkably allows a postural-fitted model to also capture dynamic performance such as curvature and hysteresis of task-space trajectories during wrist pointing tasks, confirming and extending previous findings in literature. PMID- 29249955 TI - Expression of Sirtuins in the Retinal Neurons of Mice, Rats, and Humans. AB - Sirtuins are a class of histone deacetylases (HDACs) that have been shown to regulate a range of pathophysiological processes such as cellular aging, inflammation, metabolism, and cell proliferation. There are seven mammalian Sirtuins (SIRT1-7) that play important roles in stress response, aging, and neurodegenerative diseases. However, the location and function of Sirtuins in neurons are not well defined. This study assessed the retinal expression of Sirtuins in mice, rats, and humans and measured the expression of Sirtuins in aged and injured retinas. Expression of all 7 Sirtuins was confirmed by Western blot and Real-Time PCR analysis in all three species. SIRT1 is highly expressed in mouse, rat, and human retinas, whereas SIRT2-7 expression was relatively lower in human retinas. Immunofluorescence was also used to examine the expression and localization of Sirtuins in rat retinal neurons. Importantly, we demonstrate a marked reduction of SIRT1 expression in aged retinal neurons as well as retinas injured by acute ischemia-reperfusion. On the other hand, none of the other Sirtuins exhibit any significant age-related changes in expression except for SIRT5, which was significantly higher in the retinas of adults compared to both young and aged rats. Our work presents the first composite analysis of Sirtuins in the retinal neurons of mice, rats, and humans, and suggests that increasing the expression and activity of SIRT1 may be beneficial for the treatment of glaucoma and other age-related eye dysfunction. PMID- 29249956 TI - The Mirror Neurons Network in Aging, Mild Cognitive Impairment, and Alzheimer Disease: A functional MRI Study. AB - The aim of the current study is to investigate the integrity of the Mirror Neurons (MN) network in normal aging, Mild Cognitive Impairment (MCI), and Alzheimer disease (AD). Although AD and MCI are considered "cognitive" diseases, there has been increasing recognition of a link between motor function and AD. More recently the embodied cognition hypothesis has also been developed: it postulates that a part of cognition results from the coupling between action and perception representations. MN represent a neuronal population which links perception, action, and cognition, therefore we decided to characterize MN functioning in neurodegenerative cognitive decline. Three matched groups of 16 subjects (normal elderly-NE, amnesic MCI with hippocampal atrophy and AD) were evaluated with a focused neuropsychological battery and an fMRI task specifically created to test MN: that comprised of an observation run, where subjects were shown movies of a right hand grasping different objects, and of a motor run, where subjects observed visual pictures of objects oriented to be grasped with the right hand. In NE subjects, the conjunction analysis (comparing fMRI activation during observation and execution), showed the activation of a bilateral fronto-parietal network in "classical" MN areas, and of the superior temporal gyrus (STG). The MCI group showed the activation of areas belonging to the same network, however, parietal areas were activated to a lesser extent and the STG was not activated, while the opposite was true for the right Broca's area. We did not observe any activation of the fronto-parietal network in AD participants. They did not perform as well as the NE subjects in all the neuropsychological tests (including tests of functions attributed to MN) whereas the MCI subjects were significantly different from the NE subjects only in episodic memory and semantic fluency. Here we show that the MN network is largely preserved in aging, while it appears involved following an anterior-posterior gradient in neurodegenerative decline. In AD, task performance decays and the MN network appears clearly deficient. The preservation of the anterior part of the MN network in MCI could possibly supplement the initial decay of the posterior part, preserving cognitive performance. PMID- 29249957 TI - Executive Functions in Healthy Older Adults Are Differentially Related to Macro- and Microstructural White Matter Characteristics of the Cerebral Lobes. AB - Aging is associated with microstructural white matter (WM) changes. WM microstructural characteristics, measured with diffusion tensor imaging (DTI), are different in normal appearing white matter (NAWM) and WM hyperintensities (WMH). It is largely unknown how the microstructural properties of WMH are associated with cognition and if there are regional effects for specific cognitive domains. We therefore examined within 200 healthy older participants (a) differences in microstructural characteristics of NAWM and WMH per cerebral lobe; and (b) the association of macrostructural (WMH volume) and microstructural characteristics (within NAWM and WMH separately) of each lobe with measures of executive function and processing speed. Multi-modal imaging (i.e., T1, DTI, and FLAIR) was used to assess WM properties. The Stroop and the Trail Making Test were used to measure inhibition, task-switching (both components of executive function), and processing speed. We observed that age was associated with deterioration of white matter microstructure of the NAWM, most notably in the frontal lobe. Older participants had larger WMH volumes and lowest fractional anisotropy values within WMH were found in the frontal lobe. Task-switching was associated with cerebral NAWM volume and NAWM volume of all lobes. Processing speed was associated with total NAWM volume, and microstructural properties of parietal NAWM, the parietal WMH, and the temporal NAWM. Task-switching was related to microstructural properties of WMH of the frontal lobe and WMH volume of the parietal lobe. Our results confirm that executive functioning and processing speed are uniquely associated with macro- and microstructural properties of NAWM and WMH. We further demonstrate for the first time that these relationships differ by lobar region. This warrants the consideration of these distinct WM indices when investigating cognitive function. PMID- 29249958 TI - Unlocking Neurocognitive Substrates of Late-Life Affective Symptoms Using the Research Domain Criteria: Worry Is an Essential Dimension. AB - While investigations have sought to identify the distinct and shared contributions of anxiety and depression to neurocognitive processes in late life, less is known regarding the further contribution of worry, a unique and critical dimension of affective dysregulation. Capturing the full range of symptoms, as inspired by the NIH Research Domain Criteria (RDoC), may provide finer-grained information on inter-relationships among worry, anxiety and depression on neurocognitive processing in later life. The objective of this study was to determine if the dimensional trait of worry intensifies known negative associations of dimensional measures of anxiety and depressive symptoms with neurocognitive processes, specifically cognitive control and memory processes. Using a cross-sectional and observational design, this study was conducted within a translational research center located with a Veterans medical center in Northern California. One hundred and nineteen community-residing older adults ages 65-91 years participated, and were characterized with psychiatric and neurocognitive dimensional measures. Affective symptom severity was assessed with the Penn State Worry Questionnaire, the Beck Anxiety Inventory (BAI), and the Beck Depression Inventory-II. Primary neurocognitive outcomes were inhibitory control assessed using a Stroop paradigm and delayed verbal memory assessed with the Rey Auditory Verbal Learning Test. Secondary outcomes included other less frequently examined cognitive control mechanisms (working memory, information processing, and verbal fluency) and memory processes (visual delayed memory). Contrary to prediction, the dimensional trait of worry attenuated negative associations between anxiety and depressive symptoms and inhibitory control on the one hand, and between depressive symptoms and delayed verbal memory processes on the other. In the secondary models, symptom dimensions were not associated with other cognitive control or visual delayed memory processes. Our fine-grained approach, in line with the NIMH RDoC model, suggests the neurocognitive processes associated with dimensional measures of late-life affective symptoms are dissociable. Specifically, dimensional measures of worry operate independently from other anxiety and depression symptoms to reveal differential patterns of neurocognitive processes associated with affective dysregulation. PMID- 29249959 TI - Neurofeedback for Tinnitus Treatment - Review and Current Concepts. AB - An effective treatment to completely alleviate chronic tinnitus symptoms has not yet been discovered. However, recent developments suggest that neurofeedback (NFB), a method already popular in the treatment of other psychological and neurological disorders, may provide a suitable alternative. NFB is a non-invasive method generally based on electrophysiological recordings and visualizing of certain aspects of brain activity as positive or negative feedback that enables patients to voluntarily control their brain activity and thus triggers them to unlearn typical neural activity patterns related to tinnitus. The purpose of this review is to summarize and discuss previous findings of neurofeedback treatment studies in the field of chronic tinnitus. In doing so, also an overview about the underlying theories of tinnitus emergence is presented and results of resting state EEG and MEG studies summarized and critically discussed. To date, neurofeedback as well as electrophysiological tinnitus studies lack general guidelines that are crucial to produce more comparable and consistent results. Even though neurofeedback has already shown promising results for chronic tinnitus treatment, further research is needed in order to develop more sophisticated protocols that are able to tackle the individual needs of tinnitus patients more specifically. PMID- 29249960 TI - Behavioral and Neuroimaging Evidence for Facial Emotion Recognition in Elderly Korean Adults with Mild Cognitive Impairment, Alzheimer's Disease, and Frontotemporal Dementia. AB - Background: Facial emotion recognition (FER) is impaired in individuals with frontotemporal dementia (FTD) and Alzheimer's disease (AD) when compared to healthy older adults. Since deficits in emotion recognition are closely related to caregiver burden or social interactions, researchers have fundamental interest in FER performance in patients with dementia. Purpose: The purpose of this study was to identify the performance profiles of six facial emotions (i.e., fear, anger, disgust, sadness, surprise, and happiness) and neutral faces measured among Korean healthy control (HCs), and those with mild cognitive impairment (MCI), AD, and FTD. Additionally, the neuroanatomical correlates of facial emotions were investigated. Methods: A total of 110 (33 HC, 32 MCI, 32 AD, 13 FTD) older adult participants were recruited from two different medical centers in metropolitan areas of South Korea. These individuals underwent an FER test that was used to assess the recognition of emotions or absence of emotion (neutral) in 35 facial stimuli. Repeated measures two-way analyses of variance were used to examine the distinct profiles of emotional recognition among the four groups. We also performed brain imaging and voxel-based morphometry (VBM) on the participants to examine the associations between FER scores and gray matter volume. Results: The mean score of negative emotion recognition (i.e., fear, anger, disgust, and sadness) clearly discriminated FTD participants from individuals with MCI and AD and HC [F(3,106) = 10.829, p < 0.001, eta2 = 0.235], whereas the mean score of positive emotion recognition (i.e., surprise and happiness) did not. A VBM analysis showed negative emotions were correlated with gray matter volume of anterior temporal regions, whereas positive emotions were related to gray matter volume of fronto-parietal regions. Conclusion: Impairment of negative FER in patients with FTD is cross-cultural. The discrete neural correlates of FER indicate that emotional recognition processing is a multi-modal system in the brain. Focusing on the negative emotion recognition is a more effective way to discriminate healthy aging, MCI, and AD from FTD in older Korean adults. PMID- 29249961 TI - Gait Speed and Gait Variability Are Associated with Different Functional Brain Networks. AB - Gait speed and gait variability are clinically meaningful markers of locomotor control that are suspected to be regulated by multiple supraspinal control mechanisms. The purpose of this study was to evaluate the relationships between these gait parameters and the functional connectivity of brain networks in functionally limited older adults. Twelve older adults with mild-to-moderate cognition "executive" dysfunction and relatively slow gait, yet free from neurological diseases, completed a gait assessment and a resting-state fMRI. Gait speed and variability were associated with the strength of functional connectivity of different brain networks. Those with faster gait speed had stronger functional connectivity within the frontoparietal control network (R = 0.61, p = 0.04). Those with less gait variability (i.e., steadier walking patterns) exhibited stronger negative functional connectivity between the dorsal attention network and the default network (R = 0.78, p < 0.01). No other significant relationships between gait metrics and the strength of within- or between- network functional connectivity was observed. Results of this pilot study warrant further investigation to confirm that gait speed and variability are linked to different brain networks in vulnerable older adults. PMID- 29249962 TI - The Impact of Age and Cognitive Reserve on Resting-State Brain Connectivity. AB - Cognitive reserve (CR) is a protective mechanism that supports sustained cognitive function following damage to the physical brain associated with age, injury, or disease. The goal of the research was to identify relationships between age, CR, and brain connectivity. A sample of 90 cognitively normal adults, ages 45-64 years, had their resting-state brain activity recorded with electroencephalography (EEG) and completed a series of memory and executive function assessments. CR was estimated using years of education and verbal IQ scores. Participants were divided into younger and older age groups and low- and high-CR groups. We observed greater left- than right-hemisphere coherence in younger participants, and greater right- than left-hemisphere coherence in older participants. In addition, greater coherence was observed under eyes-closed than eyes-open recording conditions for both low-CR and high-CR participants, with a more substantial difference between recording conditions in individuals high in CR regardless of age. Finally, younger participants low in CR exhibited greater mean coherence than younger participants high in CR, whereas the opposite pattern was observed in older participants, with greater coherence in older participants high in CR. Together, these findings suggest the possibility of a shift in the relationship between CR and brain connectivity during aging. PMID- 29249964 TI - Blood-Brain Barrier Dysfunction Precedes Cognitive Decline and Neurodegeneration in Diabetic Insulin Resistant Mouse Model: An Implication for Causal Link. AB - Diabetic insulin resistance and pro-diabetic diet are reported to increase dementia risk through unknown mechanisms. Emerging evidence suggests that the integrity of blood-brain barrier (BBB) is central to the onset and progression of neurodegeneration and cognitive impairment. Therefore, the current study investigated the effect of pro-diabetic diets on cognitive dysfunction in association to BBB integrity and its putative mechanisms. In C57BL/6J mice chronically ingested with a diet enriched in fat and fructose (HFF), Morris Water Maze (MWM) test indicated no significant cognitive decline after 4 weeks of HFF feeding compared to low-fat (LF) fed control. However, at this stage, BBB dysfunction accompanied by heightened neuroinflammation in cortex and hippocampal regions was already evident. After 24 weeks, HFF fed mice showed significantly deteriorated cognitive function concomitant with substantial neurodegeneration, which both showed significant associations with increased BBB permeability. In addition, the data indicated that the loss of BBB tight junctions was significantly associated with heightened inflammation and leukocyte infiltration. The data collectively suggest that in mice maintained on pro-diabetic diet, the dysfunctional BBB associated to inflammation and leukocyte recruitment precedes the neurodegeneration and cognitive decline, possibly indicating causal association. PMID- 29249963 TI - Exploring the Association between Alzheimer's Disease, Oral Health, Microbial Endocrinology and Nutrition. AB - Longitudinal monitoring of patients suggests a causal link between chronic periodontitis and the development of Alzheimer's disease (AD). However, the explanation of how periodontitis can lead to dementia remains unclear. A working hypothesis links extrinsic inflammation as a secondary cause of AD. This hypothesis suggests a compromised oral hygiene leads to a dysbiotic oral microbiome whereby Porphyromonas gingivalis, a keystone periodontal pathogen, with its companion species, orchestrates immune subversion in the host. Brushing and chewing on teeth supported by already injured soft tissues leads to bacteremias. As a result, a persistent systemic inflammatory response develops to periodontal pathogens. The pathogens, and the host's inflammatory response, subsequently lead to the initiation and progression of multiple metabolic and inflammatory co-morbidities, including AD. Insufficient levels of essential micronutrients can lead to microbial dysbiosis through the growth of periodontal pathogens such as demonstrated for P. gingivalis under low hemin bioavailability. An individual's diet also defines the consortium of microbial communities that take up residency in the oral and gastrointestinal (GI) tract microbiomes. Their imbalance can lead to behavioral changes. For example, probiotics enriched in Lactobacillus genus of bacteria, when ingested, exert some anti-inflammatory influence through common host/bacterial neurochemicals, both locally, and through sensory signaling back to the brain. Early life dietary behaviors may cause an imbalance in the host/microbial endocrinology through a dietary intake incompatible with a healthy GI tract microbiome later in life. This imbalance in host/microbial endocrinology may have a lasting impact on mental health. This observation opens up an opportunity to explore the mechanisms, which may underlie the previously detected relationship between diet, oral/GI microbial communities, to anxiety, cognition and sleep patterns. This review suggests healthy diet based interventions that together with improved life style/behavioral changes may reduce and/or delay the incidence of AD. PMID- 29249966 TI - Lithium Suppresses Hedgehog Signaling via Promoting ITCH E3 Ligase Activity and Gli1-SUFU Interaction in PDA Cells. AB - Dysregulation of Hedgehog (Hh) signaling pathway is one of the hallmarks of pancreatic ductal adenocarcinoma (PDA). Lithium, a clinical mood stabilizer for the treatment of mental disorders, is known to suppress tumorigenic potential of PDA cells by targeting the Hh/Gli signaling pathway. In this study, we investigated the molecular mechanism of lithium induced down-regulation of Hh/Gli1. Our data show that lithium promotes the poly-ubiquitination and proteasome-mediated degradation of Gli1 through activating E3 ligase ITCH. Additionally, lithium enhances interaction between Gli1 and SUFU via suppressing GSK3beta, which phosphorylates SUFU and destabilizes the SUFU-Gli1 inhibitory complex. Our studies illustrate a novel mechanism by which lithium suppresses Hh signaling via simultaneously promoting ITCH-dependent Gli1 ubiquitination/degradation and SUFU-mediated Gli1 inhibition. PMID- 29249965 TI - The "Aging Factor" Eotaxin-1 (CCL11) Is Detectable in Transfusion Blood Products and Increases with the Donor's Age. AB - Background: High blood levels of the chemokine eotaxin-1 (CCL11) have recently been associated with aging and dementia, as well as impaired memory and learning in humans. Importantly, eotaxin-1 was shown to pass the blood-brain-barrier (BBB) and has been identified as crucial mediator of decreased neurogenesis and cognitive impairment in young mice after being surgically connected to the vessel system of old animals in a parabiosis model. It thus has to be assumed that differences in eotaxin-1 levels between blood donors and recipients might influence cognitive functions also in humans. However, it is unknown if eotaxin-1 is stable during processing and storage of transfusion blood components. This study assesses eotaxin-1 concentrations in fresh-frozen plasma (FFP), erythrocyte concentrate (EC), and platelet concentrate (PC) in dependence of storage time as well as the donor's age and gender. Methods: Eotaxin-1 was measured in FFP (n = 168), EC (n = 160) and PC (n = 8) ready-to-use for transfusion employing a Q-Plex immunoassay for eotaxin-1. Absolute quantification of eotaxin-1 was performed with Q-view software. Results: Eotaxin-1 was consistently detected at a physiological level in FFP and EC but not PC. Eotaxin-1 levels were comparable in male and female donors but increased significantly with rising age of donors in both, FFP and EC. Furthermore, eotaxin-1 was not influenced by storage time of either blood component. Finally, eotaxin-1 is subject to only minor fluctuations within one donor over a longer period of time. Conclusion: Eotaxin-1 is detectable and stable in FFP and EC and increases with donor's age. Considering the presumed involvement in aging and cognitive malfunction, differences in donor and recipient eotaxin-1 levels might affect mental factors after blood transfusion. PMID- 29249967 TI - Psoralea corylifolia L. Attenuates Nonalcoholic Steatohepatitis in Juvenile Mouse. AB - Psoralea corylifolia L. (PC) is a traditional Chinese herb used to treat yang deficiency of the spleen and kidney in pediatric disease. Recent studies have shown its liver protection and anti-oxidative effects. The aim of this study was to explore the effect and mechanism of PC on nonalcoholic steatohepatitis in juvenile mice. The juvenile mouse model of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) was established by being fed a high-fat diet in maternal-offspring manner. PC granules were prepared and the quality was assessed. The main components were identified by high performance liquid chromatography. Then, different dosages of PC were administered for 6 weeks. Homeostatic model assessment of insulin resistance, plasma liver enzymes, hepatic morphology, hepatic superoxide anion, and triglyceride/total cholesterol levels were examined. The changes of nuclear factor-kappaB (NF-kappaB) activity phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) and protein kinase C alpha (PKC-alpha)/nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase signaling pathways in hepatic tissues were also determined. Our data demonstrated that PC significantly improved liver dysfunction, liver triglyceride/total cholesterol accumulation and insulin resistance in juvenile NAFLD/NASH mice. PC also alleviated hepatic steatosis, inflammatory cell infiltration, and fibroplasia in the portal area. Additionally, PC inhibited the activation of NF kappaB and the mRNA expression of inflammatory factors while enhancing PI3K/Akt signaling in hepatic tissues. PC could also reduce hepatic superoxide anion levels, and NADPH oxidase activity as well as p47phox protein expression and PKCalpha activation in hepatic tissues. The results suggest that PC is effective in the treatment of NASH in juvenile mice. The mechanism may be related to the attenuation of hepatic oxidative stress through the PKC-alpha/NADPH oxidase signaling pathway. PMID- 29249968 TI - Purinergic Receptors in Adipose Tissue As Potential Targets in Metabolic Disorders. AB - Extracellular nucleosides and nucleotides, such as adenosine and adenosine triphosphate (ATP), are involved in many physiological and pathological processes in adipose tissue (AT). It is becoming accepted that, in addition to the well established sympathetic and hormonal system, purinergic receptors contribute significantly to regulation of adipocyte functions. Several receptor subtypes for both adenosine (P1) and ATP (P2X and P2Y) have been characterized in white adipocytes (WA) and brown adipocytes (BA). The effects mediated by adenosine and ATP on adipocytes are multiple and often differing, depending on specific receptors activated. Using a variety of agonists, antagonists and transgenic animals it has been demonstrated that adenosine and P2 receptors are involved in lipolysis, lipogenesis, adipokines secretion, glucose uptake, adipogenesis, cell proliferation, inflammation, and other processes. Given their central role in regulating many AT functions, purinergic receptors are considered potential therapeutic targets in different pathological conditions, such as obesity and type-2 diabetes. To achieve this goal, specific and potent P1 and P2 receptors activators and inhibitors are being developed and show promising results. However, more insight is needed into the function of P2 receptors in brown and beige adipocytes and their potential role in thermogenesis. This review aims at summarizing current knowledge on the patho-/physiological role of P1, P2X, and P2Y receptors in WA and BA and their potential exploitation for pharmacological intervention. Furthermore, we analyze impact of purinergic signaling in AT - in health and metabolic diseases. PMID- 29249969 TI - ToxiM: A Toxicity Prediction Tool for Small Molecules Developed Using Machine Learning and Chemoinformatics Approaches. AB - The experimental methods for the prediction of molecular toxicity are tedious and time-consuming tasks. Thus, the computational approaches could be used to develop alternative methods for toxicity prediction. We have developed a tool for the prediction of molecular toxicity along with the aqueous solubility and permeability of any molecule/metabolite. Using a comprehensive and curated set of toxin molecules as a training set, the different chemical and structural based features such as descriptors and fingerprints were exploited for feature selection, optimization and development of machine learning based classification and regression models. The compositional differences in the distribution of atoms were apparent between toxins and non-toxins, and hence, the molecular features were used for the classification and regression. On 10-fold cross-validation, the descriptor-based, fingerprint-based and hybrid-based classification models showed similar accuracy (93%) and Matthews's correlation coefficient (0.84). The performances of all the three models were comparable (Matthews's correlation coefficient = 0.84-0.87) on the blind dataset. In addition, the regression-based models using descriptors as input features were also compared and evaluated on the blind dataset. Random forest based regression model for the prediction of solubility performed better (R2 = 0.84) than the multi-linear regression (MLR) and partial least square regression (PLSR) models, whereas, the partial least squares based regression model for the prediction of permeability (caco-2) performed better (R2 = 0.68) in comparison to the random forest and MLR based regression models. The performance of final classification and regression models was evaluated using the two validation datasets including the known toxins and commonly used constituents of health products, which attests to its accuracy. The ToxiM web server would be a highly useful and reliable tool for the prediction of toxicity, solubility, and permeability of small molecules. PMID- 29249970 TI - Validation of a Case-Finding Algorithm for Identifying Patients with Non-small Cell Lung Cancer (NSCLC) in Administrative Claims Databases. AB - Objective: To assess the validity of a treatments- and tests-based Case-Finding Algorithm for identifying patients with non-small cell lung cancer (NSCLC) from claims databases. Data sources: Primary data from the HealthCore Integrated Research Environment (HIRE)-Oncology database and the HealthCore Integrated Research Database (HIRD) were collected between June 1, 2014, and October 31, 2015. Study design: A comparative statistical evaluation using receiver operating characteristic (ROC) curve analysis and other validity measures was used to validate the NSCLC Case-Finding Algorithm vs. a control algorithm. Data collection: Patients with lung cancer were identified based on diagnosis and pathology classifications as NSCLC or small-cell lung cancer. Records from identified patients were linked to claims data from Anthem health plans. Three month pre-index and post-index data were included. Principal findings: The NSCLC Case-Finding Algorithm had an area under the curve (AUC) of 0.88 compared with 0.53 in the control (p < 0.0001). Promising diagnostic accuracy was observed for the NSCLC Case-Finding Algorithm based on sensitivity (94.8%), specificity (81.1%), positive predictive value (PPV) (95.3%), negative predictive value (NPV) (79.6%), accuracy (92.1%), and diagnostic odds ratio (DOR) (78.8). Conclusions: The NSCLC Case-Finding Algorithm demonstrated strong validity for distinguishing patients with NSCLC from those with SCLC in claims data records and can be used for research into NSCLC populations. PMID- 29249971 TI - Inhibition of A2A Adenosine Receptor Signaling in Cancer Cells Proliferation by the Novel Antagonist TP455. AB - Several evidences indicate that the ubiquitous nucleoside adenosine, acting through A1, A2A, A2B, and A3 receptor (AR) subtypes, plays crucial roles in tumor development. Adenosine has contrasting effects on cell proliferation depending on the engagement of different receptor subtypes in various tumors. The involvement of A2AARs in human A375 melanoma, as well as in human A549 lung and rat MRMT1 breast carcinoma proliferation has been evaluated in view of the availability of a novel A2AAR antagonist, with high affinity and selectivity, named as 2-(2 furanyl)-N5-(2-methoxybenzyl)[1,3]thiazolo[5,4-d]pyrimidine-5,7-diammine (TP455). Specifically, the signaling pathways triggered in the cancer cells of different origin and the antagonist effect of TP455 were investigated. The A2AAR protein expression was evaluated through receptor binding assays. Furthermore, the effect of A2AAR activation on cell proliferation at 24, 48 and 72 hours was studied. The selective A2AAR agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N ethylcarboxamidoadenosine hydrochloride (CGS21680), concentration-dependently induced cell proliferation in A375, A549, and MRMT1 cancer cells and the effect was potently antagonized by the A2AAR antagonist TP455, as well as by the reference A2AAR blocker 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3 a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). As for the signaling pathway recruited in this response we demonstrated that, by using the specific inhibitors of signal transduction pathways, the effect of A2AAR stimulation was induced through phospholipase C (PLC) and protein kinase C-delta (PKC-delta). In addition, we evaluated, through the AlphaScreen SureFire phospho(p) protein assay, the kinases enrolled by A2AAR to stimulate cell proliferation and we found the involvement of protein kinase B (AKT), extracellular regulated kinases (ERK1/2), and c-Jun N-terminal kinases (JNKs). Indeed, we demonstrated that the CGS21680 stimulatory effect on kinases was strongly reduced in the presence of the new potent compound TP455, as well as by ZM241385, confirming the role of the A2AAR. In conclusion, the A2AAR activation stimulates proliferation of A375, A549, and MRMT1 cancer cells and importantly TP455 reveals its capability to counteract this effect, suggesting selective A2AAR antagonists as potential new therapeutics. PMID- 29249972 TI - Pathophysiological Role of Transient Receptor Potential Ankyrin 1 in a Mouse Long Lasting Cystitis Model Induced by an Intravesical Injection of Hydrogen Peroxide. AB - Chronic inflammatory bladder disorders, such as interstitial cystitis/bladder pain syndrome, are associated with poor quality of life. The exact pathological processes remain unclear, but accumulating evidence suggests that reactive oxidative species (ROS) are involved in urinary bladder disorders. Transient receptor potential ankyrin 1 (TRPA1), the most sensitive TRP channel to ROS, was shown to be responsible for urinary bladder abnormalities and hyperalgesia in an acute cystitis model. However, the roles of TRPA1 in chronic inflammatory bladder are not fully understood. We previously established a novel mouse cystitis model induced by intravesical injection of hydrogen peroxide (H2O2), resulting in long lasting frequent urination, bladder inflammation, pain-related behavior, and histopathological changes. In the present study, we investigated the pathophysiological role of TRPA1 in the H2O2-induced long-lasting cystitis mouse model. Under anesthesia, 1.5% H2O2 solution was introduced transurethrally into the bladder of female wild-type (WT) and TRPA1-knockout mice and maintained for 30 min. This increased the number of voids in WT mice at 1 and 7 days after injection, but reduced the number in TRPA1-knockout mice at 1 day but not 7 days after injection. Spontaneous locomotor activities (increase in freezing time and decrease in distance moved) were reduced at 3 h after injection in WT mice, whereas the spontaneous visceral pain-related behaviors were attenuated in TRPA1 knockout mice. Furthermore, upregulation of c-fos mRNA in the spinal cord at 1 day after injection was observed in WT but not TRPA1-knockout mice. However, there was no difference in histopathological changes in the urinary bladder, such as edematous thickening in the submucosa, between WT and TRPA1-knockout mice at 1 or 7 days after injection. Finally, Trpa1 mRNA levels in the L5-S1 dorsal root ganglion were not altered, but levels in the urinary bladder were drastically increased at 1 and 7 days after injection. Taken together, these results suggest that TRPA1 contributes to acute bladder hyperactivity such as frequent urination and bladder pain, but does not appear to play a major role in the pathological processes of long-lasting cystitis. PMID- 29249973 TI - Odorant Receptor 51E2 Agonist beta-ionone Regulates RPE Cell Migration and Proliferation. AB - The odorant receptor 51E2 (OR51E2), which is well-characterized in prostate cancer cells and epidermal pigment cells, was identified for the first time as the most highly expressed OR in human fetal and adult retinal pigment epithelial (RPE) cells. Immunofluorescence staining and Western blot analysis revealed OR51E2 localization throughout the cytosol and in the plasma membrane. Additionally, immunohistochemical staining of diverse layers of the eye showed that the expression of OR51E2 is restricted to the pigment cells of the RPE and choroid. The results of Ca2+-imaging experiments demonstrate that activation of OR51E2 triggers a Ca2+ dependent signal pathway in RPE cells. Downstream signaling of OR51E2 involves the activation of adenylyl cyclase, ERK1/2 and AKT. The activity of these protein kinases likely accounts for the demonstrated increase in the migration and proliferation of RPE cells upon stimulation with the OR51E2 ligand beta-ionone. These findings suggest that OR51E2 is involved in the regulation of RPE cell growth. Thus, OR51E2 represents a potential target for the treatment of proliferative disorders. PMID- 29249975 TI - Fluoride Alters Klk4 Expression in Maturation Ameloblasts through Androgen and Progesterone Receptor Signaling. AB - Fluorosed maturation stage enamel is hypomineralized in part due to a delay in the removal of matrix proteins to inhibit final crystal growth. The delay in protein removal is likely related to reduced expression of kallikrein-related peptidase 4 (KLK4), resulting in a reduced matrix proteinase activity that found in fluorosed enamel. Klk4 transcription is known to be regulated in other cell types by androgen receptor (AR) and progesterone receptors (PR). In this study, we determined the possible role of fluoride in down-regulation of KLK4 expression through changes in AR and PR. Immunohistochemical localization showed that both AR and PR nuclear translocation was suppressed in fluoride exposed mice. However, when AR signaling was silenced in mouse ameloblast-lineage cells (ALCs), expression of both Pgr and Klk4 were increased. Similar to the effect from AR silencing, fluoride also upregulated Pgr in ALCs, but downregulated Klk4. This finding suggests that though suppression of AR transactivation by fluoride increases Prg expression, inhibition of PR transactivation by fluoride has a much greater effect, ultimately resulting in downregulation of Klk4 expression. These findings indicate that in ameloblasts, PR has a dominant role in regulating Klk4 expression. We found that when AR was retained in the cytoplasm in the presence of fluoride, that co-localized with heat shock protein 90 (HSP90), a well-known chaperone for steroid hormone receptors. HSP90 also known to regulate TGF-beta signaling. Consistent with the effect of fluoride on AR and HSP90, we found evidence of reduced TGF-beta signaling activity in fluorosed ameloblasts as reduced immunolocalization of TGFB1 and TGFBR-2 and a significant increase in Cyclin D1 mRNA expression, which also possibly contributes to the reduced AR signaling activity. In vitro, when serum was removed from the media, aluminum was required for fluoride to inhibit the dissociation of HSP90 from AR. In conclusion, fluoride related downregulation of Klk4 is associated with reduced nuclear translocation of AR and PR, and also reduced TGF-beta signaling activity, all of which are regulated by HSP90. We suggest that a common mechanism by which fluoride affects AR, PR, and TGF-beta signaling is through inhibiting ATP dependent conformational cycling of HSP90. PMID- 29249974 TI - Computational Modeling in Liver Surgery. AB - The need for extended liver resection is increasing due to the growing incidence of liver tumors in aging societies. Individualized surgical planning is the key for identifying the optimal resection strategy and to minimize the risk of postoperative liver failure and tumor recurrence. Current computational tools provide virtual planning of liver resection by taking into account the spatial relationship between the tumor and the hepatic vascular trees, as well as the size of the future liver remnant. However, size and function of the liver are not necessarily equivalent. Hence, determining the future liver volume might misestimate the future liver function, especially in cases of hepatic comorbidities such as hepatic steatosis. A systems medicine approach could be applied, including biological, medical, and surgical aspects, by integrating all available anatomical and functional information of the individual patient. Such an approach holds promise for better prediction of postoperative liver function and hence improved risk assessment. This review provides an overview of mathematical models related to the liver and its function and explores their potential relevance for computational liver surgery. We first summarize key facts of hepatic anatomy, physiology, and pathology relevant for hepatic surgery, followed by a description of the computational tools currently used in liver surgical planning. Then we present selected state-of-the-art computational liver models potentially useful to support liver surgery. Finally, we discuss the main challenges that will need to be addressed when developing advanced computational planning tools in the context of liver surgery. PMID- 29249976 TI - Thoracic Aortic Aneurysm Development in Patients with Bicuspid Aortic Valve: What Is the Role of Endothelial Cells? AB - Bicuspid aortic valve (BAV) is the most common type of congenital cardiac malformation. Patients with a BAV have a predisposition for the development of thoracic aortic aneurysm (TAA). This pathological aortic dilation may result in aortic rupture, which is fatal in most cases. The abnormal aortic morphology of TAAs results from a complex series of events that alter the cellular structure and extracellular matrix (ECM) composition of the aortic wall. Because the major degeneration is located in the media of the aorta, most studies aim to unravel impaired smooth muscle cell (SMC) function in BAV TAA. However, recent studies suggest that endothelial cells play a key role in both the initiation and progression of TAAs by influencing the medial layer. Aortic endothelial cells are activated in BAV mediated TAAs and have a substantial influence on ECM composition and SMC phenotype, by secreting several key growth factors and matrix modulating enzymes. In recent years there have been significant advances in the genetic and molecular understanding of endothelial cells in BAV associated TAAs. In this review, the involvement of the endothelial cells in BAV TAA pathogenesis is discussed. Endothelial cell functioning in vessel homeostasis, flow response and signaling will be highlighted to give an overview of the importance and the under investigated potential of endothelial cells in BAV-associated TAA. PMID- 29249977 TI - Response of Turkey Muscle Satellite Cells to Thermal Challenge. II. Transcriptome Effects in Differentiating Cells. AB - Background: Exposure of poultry to extreme temperatures during the critical period of post-hatch growth can seriously affect muscle development and thus compromise subsequent meat quality. This study was designed to characterize transcriptional changes induced in turkey muscle satellite cells by thermal challenge during differentiation. Our goal is to better define how thermal stress alters breast muscle ultrastructure and subsequent development. Results: Skeletal muscle satellite cells previously isolated from the Pectoralis major muscle of 7 wk-old male turkeys (Meleagris gallopavo) from two breeding lines: the F-line (16 wk body weight-selected) and RBC2 (randombred control line) were used in this study. Cultured cells were induced to differentiate at 38 degrees C (control) or thermal challenge temperatures of 33 or 43 degrees C. After 48 h of differentiation, cells were harvested and total RNA was isolated for RNAseq analysis. Analysis of 39.9 Gb of sequence found 89% mapped to the turkey genome (UMD5.0, annotation 101) with average expression of 18,917 genes per library. In the cultured satellite cells, slow/cardiac muscle isoforms are generally present in greater abundance than fast skeletal isoforms. Statistically significant differences in gene expression were observed among treatments and between turkey lines, with a greater number of genes affected in the F-line cells following cold treatment whereas more differentially expressed (DE) genes were observed in the RBC2 cells following heat treatment. Many of the most significant pathways involved signaling, consistent with ongoing cellular differentiation. Regulation of Ca2+ homeostasis appears to be significantly affected by temperature treatment, particularly cold treatment. Conclusions: Satellite cell differentiation is directly influenced by temperature at the level of gene transcription with greater effects attributed to selection for fast growth. At lower temperature, muscle-associated genes in the satellite cells were among the genes with the greatest down regulation consistent with slower differentiation and smaller myotubes. Fewer expression differences were observed in the differentiating cells than previously observed for proliferating cells. This suggests the impact of temperature on satellite cells occurs primarily at early points in satellite cell activation. PMID- 29249978 TI - Prediction of Scar Size in Rats Six Months after Burns Based on Early Post-injury Polarization-Sensitive Optical Frequency Domain Imaging. AB - Hypertrophic scars remain a major clinical problem in the rehabilitation of burn survivors and lead to physical, aesthetic, functional, psychological, and social stresses. Prediction of healing outcome and scar formation is critical for deciding on the best treatment plan. Both subjective and objective scales have been devised to assess scar severity. Whereas scales of the first type preclude cross-comparison between observers, those of the second type are based on imaging modalities that either lack the ability to image individual layers of the scar or only provide very limited fields of view. To overcome these deficiencies, this work aimed at developing a predictive model of scar formation based on polarization sensitive optical frequency domain imaging (PS-OFDI), which offers comprehensive subsurface imaging. We report on a linear regression model that predicts the size of a scar 6 months after third-degree burn injuries in rats based on early post-injury PS-OFDI and measurements of scar area. When predicting the scar area at month 6 based on the homogeneity and the degree of polarization (DOP), which are signatures derived from the PS-OFDI signal, together with the scar area measured at months 2 and 3, we achieved predictions with a Pearson coefficient of 0.57 (p < 10-4) and a Spearman coefficient of 0.66 (p < 10-5), which were significant in comparison to prediction models trained on randomly shuffled data. As the model in this study was developed on the rat burn model, the methodology can be used in larger studies that are more relevant to humans; however, the actual model inferred herein is not translatable. Nevertheless, our analysis and modeling methodology can be extended to perform larger wound healing studies in different contexts. This study opens new possibilities for quantitative and objective assessment of scar severity that could help to determine the optimal course of therapy. PMID- 29249979 TI - Potential Contributions of miR-200a/-200b and Their Target Gene-Leptin to the Sexual Size Dimorphism in Yellow Catfish. AB - Sexual size dimorphism is the consequence of differential expression of sex biased genes related to feeding and growth. Leptin is known to regulate energy balance by regulating food intake. In order to investigate the molecular mechanism of sexual size dimorphism in yellow catfish (Pelteobagrus fulvidraco), the expression of leptin (lep) and its functional receptor (lepr) were detected during larval development. Both lep and lepr have lower expression in males than in females during 1-4 weeks post hatching. 17a-Methyltestosterone (MT) treatment resulted in decreased expression of lep and lepr in both male and female larval fish. Interestingly, the mRNA levels of lep and lepr in juvenile male were significantly decreased compared with juvenile female during short-term fasting periods. Lep was predicted to be a potential target of miR-200a and miR-200b that had an opposite expression pattern to lep in male and female larvas. The results of luciferase reporter assay suggested that lep is a target of miR-200a/-200b. Subsequently, male hormone and fasting treatment have opposite effects on the expression of miR-200a/-200b and lep between males and females. In summary, our results suggest that sexual size dimorphism in fish species is probably caused by the sexually dimorphic expression of leptin, which could be negatively regulated by miR-200a/-200b. PMID- 29249980 TI - Functional Study of Cytochrome P450 Enzymes from the Brown Planthopper (Nilaparvata lugens Stal) to Analyze Its Adaptation to BPH-Resistant Rice. AB - Plant-insect interactions constitute a complex of system, whereby plants synthesize toxic compounds as the main defense strategy to combat herbivore assault, and insects deploy detoxification systems to cope with toxic plant compounds. Cytochrom P450s are among the main detoxification enzymes employed by insects to combat the chemical defenses of host plants. In this study, we used Nilaparvata lugens (BPH) to constitute an ideal system for studying plant-insect interactions. By feeding BPHs with artificial diets containing ethanol extracts, we show that biotype Y BPHs have a greater ability to metabolize exogenous substrates than biotype 1 BPHs. NlCPR knockdown inhibited the ability of BPHs to feed on YHY15. qRT-PCR was used to screen genes in the P450 family, and upregulation of CYP4C61, CYP6AX1, and CYP6AY1 induced by YHY15 was investigated. When the three P450 genes were knocked down, only CYP4C61 dsRNA treatment was inhibited the ability of BPHs to feed on YHY15. These results indicate that BPH P450 enzymes are a key factor in the physiological functions of BPH when feeding on BPH-resistant rice. PMID- 29249981 TI - Differences in Exercise Capacity and Responses to Training in 24 Inbred Mouse Strains. AB - Changes in cardiorespiratory fitness in response to a standardized exercise training protocol differ substantially between individuals. Results from cross sectional, twin, and family studies indicate genetics contribute to individual differences in both baseline exercise capacity and the response to training. Exercise capacity and responses to training also vary between inbred strains of mice. However, such studies have utilized a limited number of inbred strains. Therefore, the aim of this study was to characterize exercise-training responses in a larger number of genetically diverse strains of inbred mice and estimate the contribution of genetic background to exercise training responses. Eight-week old male mice from 24 inbred strains (n = 4-10/strain) performed a graded exercise test before and after 4 weeks of exercise training. Before training, exercise capacity was significantly different between strains when expressed as time (range = 21-42 min) and work performed (range = 0.42-3.89 kg.m). The responses to training also were significantly different between strains, ranging from a decrease of 2.2 min in NON/ShiLtJ mice to an increase of 8.7 min in SWR/J mice. Changes in work also varied considerably between the lowest (-0.24 kg.m in NON/ShiLtJ) and highest (+2.30 kg.m in FVB/NJ) performing strains. Heart and skeletal muscle masses also varied significantly between strains. Two broad sense heritability estimates were calculated for each measure of exercise capacity and for responses to training. For change in run time, the intraclass correlation between mice within the same inbred strain (rI) was 0.58 and the coefficient of genetic determination (g2) was 0.41. Heritability estimates were similar for the change in work: rI = 0.54 and g2 = 0.37. In conclusion, these results indicate genetic background significantly influences responses to exercise training. PMID- 29249982 TI - Genetic Association between Matrix Metalloproteinases Gene Polymorphisms and Risk of Prostate Cancer: A Meta-Analysis. AB - Background and Objective: Studies suggests that matrix metalloproteinase (MMP)-2 1306 C/T and MMP-1-1607 1G/2G polymorphisms affect the risk of prostate cancer. However, the conclusions remain controversial and no pooled evidence of this topic has been published. Therefore, we aimed to perform a meta-analysis to shed some light on the controversial conclusion pertaining to the associations of MMP 2-1306 C/T and MMP-1-1607 1G/2G polymorphisms with prostate cancer susceptibility. Methods: A thorough literature search was performed up to August, 2016 with the PubMed, EMBASE, CBM, CNKI, and Wanfang databases. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were calculated to address the correlations between these polymorphisms and risk of prostate cancer. Results: The meta-analysis included six studies (1,921 patients and 1,988 controls) on MMP-2-1306 C/T polymorphism and three studies on MMP-1-1607 1G/2G polymorphism (438 patients and 394 controls), respectively. The overall results of meta-analysis showed that an elevated risk of the disease was implicated in MMP-2-1306 C/T polymorphism under two genetic models (CT vs. CC: OR = 1.78, 95% CI = 1.33-2.38; TT+CT vs. CC: OR = 1.62, 95% CI = 1.24-2.12) and no significant association was observed between MMP-1-1607 1G/2G polymorphism and the risk of prostate cancer. The subgroup analysis results of MMP-2-1306 C/T polymorphism were similar to the overall results. However, decreased risk of prostate cancer was observed in the Caucasians for MMP-1-1607 1G/2G polymorphism. Conclusions: Current meta-analysis indicates that MMP-2-1306 C/T polymorphism is associated with elevated risk of prostate cancer, but MMP-1-1607 1G/2G polymorphism may inhibit the occurrence of prostate cancer in Caucasians. Further studies are warranted to verify the conclusions. PMID- 29249983 TI - Co-expression Network Approach Reveals Functional Similarities among Diseases Affecting Human Skeletal Muscle. AB - Diseases affecting skeletal muscle exhibit considerable heterogeneity in intensity, etiology, phenotypic manifestation and gene expression. Systems biology approaches using network theory, allows for a holistic understanding of functional similarities amongst diseases. Here we propose a co-expression based, network theoretic approach to extract functional similarities from 20 heterogeneous diseases comprising of dystrophinopathies, inflammatory myopathies, neuromuscular, and muscle metabolic diseases. Utilizing this framework we identified seven closely associated disease clusters with 20 disease pairs exhibiting significant correlation (p < 0.05). Mapping the diseases onto a human protein-protein interaction network enabled the inference of a common program of regulation underlying more than half the muscle diseases considered here and referred to as the "protein signature." Enrichment analysis of 17 protein modules identified as part of this signature revealed a statistically non-random dysregulation of muscle bioenergetic pathways and calcium homeostasis. Further, analysis of mechanistic similarities of less explored significant disease associations [such as between amyotrophic lateral sclerosis (ALS) and cerebral palsy (CP)] using a proposed "functional module" framework revealed adaptation of the calcium signaling machinery. Integrating drug-gene information into the quantitative framework highlighted the presence of therapeutic opportunities through drug repurposing for diseases affecting the skeletal muscle. PMID- 29249984 TI - Maternal and Embryonic Stress Influence Offspring Behavior in the Cuttlefish Sepia officinalis. AB - Stress experienced during prenatal development-either applied to reproducing females (maternal stress), directly to developing offspring (embryonic stress) or in combination-is associated with a range of post-natal behavioral effects in numerous organisms. We conducted an experiment to discern if maternal and embryonic stressors affect the behavior of hatchlings of the cuttlefish Sepia officinalis, a species with features that allow for the examination of these stress types in isolation. Separating the impact of stress transmitted through the mother vs. stress experienced by the embryo itself will help clarify the behavioral findings in viviparous species for which it is impossible to disentangle these effects. We also compared the effect of a naturally-occurring (predator cue) and an "artificial" (bright, randomly-occurring LED light) embryonic stressor. This allowed us to test the hypothesis that a threat commonly faced by a species (natural threat) would be met with a genetically-programmed and adaptive response while a novel one would confound innate defense mechanisms and lead to maladaptive effects. We found that the maternal stressor was associated with significant differences in body patterning and activity patterns. By contrast, embryonic exposure to stressors increased the proportion of individuals that pursued prey. From these results, it appears that in cuttlefish, maternal and embryonic stressors affect different post-natal behavior in offspring. In addition, the effect of the artificial stressor suggests that organisms can sometimes react adaptively to a stressor even if it is not one that has been encountered during the evolutionary history of the species. PMID- 29249986 TI - Monitoring Energy Expenditure Using a Multi-Sensor Device-Applications and Limitations of the SenseWear Armband in Athletic Populations. AB - In order to monitor their energy requirements, athletes may desire to assess energy expenditure (EE) during training and competition. Recent technological advances and increased customer interest have created a market for wearable devices that measure physiological variables and bodily movement over prolonged time periods and convert this information into EE data. This mini-review provides an overview of the applicability of the SenseWear armband (SWA), which combines accelerometry with measurements of heat production and skin conductivity, to measure total daily energy expenditure (TDEE) and its components such as exercise energy expenditure (ExEE) in athletic populations. While the SWA has been shown to provide valid estimates of EE in the general population, validation studies in athletic populations indicate a tendency toward underestimation of ExEE particularly during high-intensity exercise (>10 METs) with an increasing underestimation as exercise intensity increases. Although limited information is available on the accuracy of the SWA during resistance exercise, high-intensity interval exercise, or mixed exercise forms, there seems to be a similar trend of underestimating high levels of ExEE. The SWA, however, is capable of detecting movement patterns and metabolic measurements even at high exercise intensities, suggesting that underestimation may result from limitations in the proprietary algorithms. In addition, the SWA has been used in the assessment of sleep quantity and quality as well as non-exercise activity thermogenesis. Overall, the SWA provides viable information and remains to be used in various clinical and athletic settings, despite the termination of its commercial sale. PMID- 29249985 TI - Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease. AB - Lysosomal storage disorders (LSD) are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B) and type C diseases Niemann-Pick type C (NPC) are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Besides these alterations in lysosomal homeostasis and function due to accumulation of specific lipid species, the lysosomal functional defects can have far-reaching consequences, disrupting intracellular trafficking of sterols, lipids and calcium through membrane contact sites (MCS) of apposed compartments. Although MCS between endoplasmic reticulum and mitochondria have been well studied and characterized in different contexts, emerging evidence indicates that lysosomes also exhibit close proximity with mitochondria, which translates in their mutual functional regulation. Indeed, as best illustrated in NPC disease, alterations in the lysosomal-mitochondrial liaisons underlie the secondary accumulation of specific lipids, such as cholesterol in mitochondria, resulting in mitochondrial dysfunction and defective antioxidant defense, which contribute to disease progression. Thus, a better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease. PMID- 29249988 TI - Stemodia maritima L. Extract Decreases Inflammation, Oxidative Stress, and Alveolar Bone Loss in an Experimental Periodontitis Rat Model. AB - Periodontitis is very prevalent worldwide and is one of the major causes of tooth loss in adults. About 80% of the worldwide population use medicinal plants for their health care. Stemodia maritima L. (S. maritima) antioxidant and antimicrobial effects in vitro as well as anti-inflammatory properties. Herein, the potential therapeutic effect of S. maritima was assessed in rats subjected to experimental periodontitis (EP). EP was induced in female Wistar rats by nylon thread ligature around 2nd upper left molars for 11 days. Animals received (per os) S. maritima (0.2; 1 or 5 mg/kg) or vehicle (saline + DMSO) 1 h before ligature and then once daily for 11 days. The naive group had no manipulation. After this time-point, the animals were terminally anesthetized, and the maxillae were removed for morphometric and histological analyzes (HE). Gingival tissues were dissected to cytokine levels detection (TNF-alpha, IL1-beta, CINC-1, and IL 10), enzymes superoxide dismutase (SOD), and catalase (CAT) analysis, as well as gene expression (TNF-alpha, IL-1beta, RANK, and iNOS) by qRT-PCR. Systemic parameters (weight variation, plasma levels of hepatic enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT), creatinine, total alkaline phosphatase (TALP), and bone alkaline phosphatase (BALP) were performed. Histological analysis of the stomach, liver, kidney, and heart was also performed. S. maritima (5 mg/kg) decreased alveolar bone loss, TNF-alpha and CINC 1 gingival levels, oxidative stress, and transcription of TNF-alpha, IL1-beta, RANK, and iNOS genes. It elevated both BALP activity and IL-10 gingival levels. The animals showed no any signs of toxicity. In conclusion, S. maritima reduced pro-inflammatory cytokine production, oxidative stress, and alveolar bone loss in a pre-clinical trial of periodontitis. S. maritima is a potential tool for controlling the development of periodontitis. PMID- 29249989 TI - The 2D:4D Marker and Different Forms of Internet Use Disorder. AB - Internet use disorder (IUD) presents a growing problem worldwide. Among others, it manifests in loss of control over Internet usage and social problems due to problematic Internet use. Although IUD currently is not an official diagnosis in DSM-5 or ICD-10, mounting evidence suggests that IUD indeed could be categorized as a behavioral addiction. On a systemic neuroscientific level, IUD is well characterized and dysfunctions in the fronto-striatal-limbic loop have been observed in persons being afflicted with IUD. On a molecular level underlying these neural dysfunctions less is known. Therefore, the present research investigates the influence of prenatal testosterone as measured via the 2D:4D marker of the hand on IUD. Testosterone represents an interesting hormonal marker, because sex differences in IUD have been observed, e.g., males show higher tendencies toward Internet gaming disorder (IGD) or females toward overusage of online social networks (both compared to the contrary sex). In N = 217 participants associations between the 2D:4D marker of the hand and both unspecified IUD and specific forms of IUD were investigated. It appeared that more female hands (right side; characterized by higher digit ratio of the index to the ring finger, i.e., >1, meaning lower prenatal testosterone) were associated with lower IGD (rho = -0.17, p = 0.01, N = 211). This effect was driven by the facet of loss of control of Internet Gaming in the whole sample (rho = -0.20, p < 0.01, N = 211) and the female subsample (rho = -0.20, p = 0.02, N(f) = 137). Aside from this, a negative association appeared between the facet of loss of control of generalized IUD and the right digit ratio in males underlining earlier work. In sum, the present work demonstrates that the 2D:4D marker is an interesting marker for Internet addiction and can be easily included as a biomarker to understand the biological underpinnings of Internet (over )usage. PMID- 29249987 TI - Imbalances in the Development of Muscle and Tendon as Risk Factor for Tendinopathies in Youth Athletes: A Review of Current Evidence and Concepts of Prevention. AB - Tendons feature the crucial role to transmit the forces exerted by the muscles to the skeleton. Thus, an increase of the force generating capacity of a muscle needs to go in line with a corresponding modulation of the mechanical properties of the associated tendon to avoid potential harm to the integrity of the tendinous tissue. However, as summarized in the present narrative review, muscle and tendon differ with regard to both the time course of adaptation to mechanical loading as well as the responsiveness to certain types of mechanical stimulation. Plyometric loading, for example, seems to be a more potent stimulus for muscle compared to tendon adaptation. In growing athletes, the increased levels of circulating sex hormones might additionally augment an imbalanced development of muscle strength and tendon mechanical properties, which could potentially relate to the increasing incidence of tendon overload injuries that has been indicated for adolescence. In fact, increased tendon stress and strain due to a non-uniform musculotendinous development has been observed recently in adolescent volleyball athletes, a high-risk group for tendinopathy. These findings highlight the importance to deepen the current understanding of the interaction of loading and maturation and demonstrate the need for the development of preventive strategies. Therefore, this review concludes with an evidence-based concept for a specific loading program for increasing tendon stiffness, which could be implemented in the training regimen of young athletes at risk for tendinopathy. This program incorporates five sets of four contractions with an intensity of 85-90% of the isometric voluntary maximum and a movement/contraction duration that provides 3 s of high magnitude tendon strain. PMID- 29249991 TI - Prevalence of Cigarette Smoking and Nicotine Dependence in Men and Women Residing in Two Provinces in China. AB - Aims: Although it is known that there is a high smoking prevalence among Chinese, key issues such as social and environmental factors impacting smoking initiation and persistence, the percentage of smokers considered nicotine dependence (ND), and the availability and use of ND treatments have rarely been investigated. Methods: To address these issues, from 2012 to 2014, we conducted a large-scale study in the Zhejiang and Shanxi provinces of China using the Fagerstrom Test for Nicotine Dependence and other validated questionnaires. Results: Of the 17,057 subjects, consisting of 13,476 males and 3,581 females aged 15 years or older, the prevalence of male smoking was 66.1% [95% confidence interval (CI) 65.5%, 66.9%] and that of female smoking was 3.2% (95% CI 3.0%, 3.8%). Among males, 25.8% (95% CI 25.0%, 26.5%) were low-to-moderate ND, and 11.8% (95% CI 11.2%, 12.3%) were high ND (H-ND), persons who have significant difficulty quitting without treatment. The degrees of ND were related to age, extent of education, and annual family income. The social-environmental factors examined conveyed a higher risk for smoking initiation, which is particularly true for the influence of smoking by friends. Furthermore, current smokers had a significantly higher risk of suffering respiratory and digestive symptoms. Conclusion: These data not only show a high smoking prevalence in Chinese men but also reveal that a relatively large number of smokers are H-ND. Considering that few Chinese smokers seek ND treatment, a comprehensive smoking prevention and treatment program designed specifically for Chinese is greatly needed. PMID- 29249990 TI - Mediators Linking Childhood Adversities and Trauma to Suicidality in Individuals at Risk for Psychosis. AB - Suicidality is highly prevalent in patients at clinical high risk (CHR) for psychosis. Childhood adversities and trauma are generally predictive of suicidality. However, the differential effects of adversity/trauma-domains and CHR-criteria, i.e., ultra-high risk and basic symptom criteria, on suicidality remain unclear. Furthermore, the underlying mechanisms and, thus, worthwhile targets for suicide-prevention are still poorly understood. Therefore, structural equation modeling was used to test theory-driven models in 73 CHR-patients. Mediators were psychological variables, i.e., beliefs about one's own competencies as well as the controllability of events and coping styles. In addition, symptomatic variables (depressiveness, basic symptoms, attenuated psychotic symptoms) were hypothesized to mediate the effect of psychological mediators on suicidality as the final outcome variable. Results showed two independent pathways. In the first pathway, emotional and sexual but not physical adversity/trauma was associated with suicidality, which was mediated by dysfunctional competence/control beliefs, a lack of positive coping-strategies and depressiveness. In the second pathway, cognitive basic symptoms but not attenuated psychotic symptoms mediated the relationship between trauma/adversity and suicidality. CHR-patients are, thus, particularly prone to suicidality if adversity/trauma is followed by the development of depressiveness. Regarding the second pathway, this is the first study showing that adversity/trauma led to suicidality through an increased risk for psychosis as indicated by cognitive basic symptoms. As insight is generally associated with suicidality, this may explain why self-experienced basic symptoms increase the risk for it. Consequently, these mediators should be monitored regularly and targeted by integrated interventions as early as possible to enhance resilience against suicidality. PMID- 29249993 TI - Unexpected Improvement of Hand Motor Function with a Left Temporoparietal Low Frequency Repetitive Transcranial Magnetic Stimulation Regime Suppressing Auditory Hallucinations in a Brainstem Chronic Stroke Patient. AB - We here report paradoxical hand function recovery in a 61-year-old male tetra paretic chronic patient following a stroke of the brainstem (with highly degraded right and abolished left-hand finger flexion/extension disabling him to manipulate objects) who experienced insidious auditory hallucinations (AHs) 4 years after such event. Symptomatic treatment for AHs was provided with periodical double sessions of low-frequency repetitive transcranial magnetic stimulation (rTMS) (daily 1 Hz, 2 * 1,200 pulses interleaved by 1 h interval) delivered to the left temporoparietal junction across two periods of 5 and 3 weeks, respectively. At the end of each stimulation period, AHs disappeared completely. Most surprisingly and totally unexpectedly, the patient experienced beneficial improvements of long-lasting impairments in his right-hand function. Detailed examination of onset and offset of rTMS stimulation regimes strongly suggests a temporal relation with the remission and re-appearance of AHs and also with a fragile but clinically meaningful improvements of right (but not left) hand function contingent to the accrual of stimulation sessions. On the basis of post-recovery magnetic resonance imaging structural and functional evidence, mechanistic hypotheses that could subtend such unexpected motor recovery are critically discussed. PMID- 29249992 TI - Gender Differences and Psychopathological Features Associated With Addictive Behaviors in Adolescents. AB - Background: The aims of the study were to assess prevalence and gender differences of addictive behaviors (substance- and non-substance-related) in an adolescent population, and their association with psychopathological features and academic performance. Material and methods: A sample of high school Italian students (n = 996; M = 240, F = 756) was examined using a self-report survey concerning sociodemographic characteristics, cigarette smoking, alcohol and substance use, perceived academic performance, activities, and behaviors (Internet use, gambling, and physical exercising). The Internet Addiction Test, the South Oaks Gambling Screen-revised Adolescent, and the Exercise Addiction Inventory-Short Form were administered to identify problematic behaviors. The Barratt Impulsiveness Scale for Adolescent, the Snaith-Hamilton Pleasure Scale, the Dissociative Experience Scale for Adolescent, and the Toronto Alexithymia Scale were used to investigate psychopathological dimensions. Results: Frequent alcohol intake and lifetime substances consumption were more common among males. The occurrence of other addictive behaviors was 22.1% for problematic Internet use (M = F), 9.7% for at-risk/problematic gambling (M > F), and 6.2% for maladaptive physical exercise (M = F). We also found an association between substance-/non-substance-related addictive behaviors and psychopathological dimensions. Addictive behaviors were more frequent among students reporting poor school performance. Conclusion: Our study showed a relevant prevalence of addictive behaviors in a sample of Italian high school students, with specific gender differences. We underlined the cooccurrence of substance and non-substance related addictive behaviors, and their association with worse school performance. Dissociative proneness, anhedonia, alexithymia, and impulsivity were associated with addictive behaviors in adolescents and might represent vulnerability factors for the development of psychiatric disorders in adulthood. A better understanding of psychopathological features associated with addictive behaviors might be useful for the prevention/early intervention. PMID- 29249994 TI - Six Tips on How to Bring Epic Wins to Health Care. PMID- 29249996 TI - Metasynthesis: An Original Method to Synthesize Qualitative Literature in Psychiatry. AB - Background: Metasynthesis-the systematic review and integration of findings from qualitative studies-is an emerging technique in medical research that can use many different methods. Nevertheless, the method must be appropriate to the specific scientific field in which it is used. The objective is to describe the steps of a metasynthesis method adapted from Thematic Synthesis and phenomenology to fit the particularities of psychiatric research. Method: We detail each step of the method used in a metasynthesis published in 2015 on adolescent and young adults suicidal behaviors. We provide clarifications in several methodological points using the latest literature on metasyntheses. The method is described in six steps: define the research question and the inclusion criteria, select the studies, assess their quality, extract and present the formal data, analyze the data, and express the synthesis. Conclusion: Metasyntheses offer an appropriate balance between an objective framework, a rigorously scientific approach to data analysis and the necessary contribution of the researcher's subjectivity in the construction of the final work. They propose a third level of comprehension and interpretation that brings original insights, improve the global understanding in psychiatry, and propose immediate therapeutic implications. They should be included in the psychiatric common research toolkit to become better recognized by clinicians and mental health professionals. PMID- 29249995 TI - Homer2 and Alcohol: A Mutual Interaction. AB - The past two decades of data derived from addicted individuals and preclinical animal models of addiction implicate a role for the excitatory glutamatergic transmission within the mesolimbic structures in alcoholism. The cellular localization of the glutamatergic receptor subtypes, as well as their signaling efficiency and function, are highly dependent upon discrete functional constituents of the postsynaptic density, including the Homer family of scaffolding proteins. The consequences of repeated alcohol administration on the expression of the Homer family proteins demonstrate a crucial and active role, particularly for the expression of Homer2 isoform, in regulating alcohol-induced behavioral and cellular neuroplasticity. The interaction between Homer2 and alcohol can be defined as a mutual relation: alcohol consumption enhances the expression of Homer2 protein isoform within the nucleus accumbens and the extended amygdala, cerebral areas where, in turn, Homer2 is able to mediate the development of the "pro-alcoholic" behavioral phenotype, as a consequence of the morpho-functional synaptic adaptations. Such findings are relevant for the detection of the strategic molecular components that prompt alcohol-induced functional and behavioral disarrangement as targets for future innovative treatment options. PMID- 29249997 TI - Acoustic Constraints and Musical Consequences: Exploring Composers' Use of Cues for Musical Emotion. AB - Emotional communication in music is based in part on the use of pitch and timing, two cues effective in emotional speech. Corpus analyses of natural speech illustrate that happy utterances tend to be higher and faster than sad. Although manipulations altering melodies show that passages changed to be higher and faster sound happier, corpus analyses of unaltered music paralleling those of natural speech have proven challenging. This partly reflects the importance of modality (i.e., major/minor), a powerful musical cue whose use is decidedly imbalanced in Western music. This imbalance poses challenges for creating musical corpora analogous to existing speech corpora for purposes of analyzing emotion. However, a novel examination of music by Bach and Chopin balanced in modality illustrates that, consistent with predictions from speech, their major key (nominally "happy") pieces are approximately a major second higher and 29% faster than their minor key pieces (Poon and Schutz, 2015). Although this provides useful evidence for parallels in use of emotional cues between these domains, it raises questions about how composers "trade off" cue differentiation in music, suggesting interesting new potential research directions. This Focused Review places those results in a broader context, highlighting their connections with previous work on the natural use of cues for musical emotion. Together, these observational findings based on unaltered music-widely recognized for its artistic significance-complement previous experimental work systematically manipulating specific parameters. In doing so, they also provide a useful musical counterpart to fruitful studies of the acoustic cues for emotion found in natural speech. PMID- 29249999 TI - Audio Spatial Representation Around the Body. AB - Studies have found that portions of space around our body are differently coded by our brain. Numerous works have investigated visual and auditory spatial representation, focusing mostly on the spatial representation of stimuli presented at head level, especially in the frontal space. Only few studies have investigated spatial representation around the entire body and its relationship with motor activity. Moreover, it is still not clear whether the space surrounding us is represented as a unitary dimension or whether it is split up into different portions, differently shaped by our senses and motor activity. To clarify these points, we investigated audio localization of dynamic and static sounds at different body levels. In order to understand the role of a motor action in auditory space representation, we asked subjects to localize sounds by pointing with the hand or the foot, or by giving a verbal answer. We found that the audio sound localization was different depending on the body part considered. Moreover, a different pattern of response was observed when subjects were asked to make actions with respect to the verbal responses. These results suggest that the audio space around our body is split in various spatial portions, which are perceived differently: front, back, around chest, and around foot, suggesting that these four areas could be differently modulated by our senses and our actions. PMID- 29249998 TI - Regulating Rumination by Anger: Evidence for the Mutual Promotion and Counteraction (MPMC) Theory of Emotionality. AB - Unlike the strategy of cognitive regulation that relies heavily on the top-down control function of the prefrontal cortex (PFC), which was recently found may be critically impaired in stressful situations, traditional Chinese philosophy and medicine views different types of emotionality as having mutual promotion and counteraction (MPMC) relationships, implying a novel approach that requires less cognition to emotional regulation. Actually, our previous studies have indicated that anger responses could be successfully regulated via the induction of sadness, and this efficiency could not be influenced by stress, thus providing evidences for the hypothesis of "sadness counteracts anger" (SCA) proposed by the MPMC theory of emotionality (Zhan et al., 2015, 2017). In this study, we experimentally examined the MPMC hypothesis that "anger counteracts rumination" (ACR) which postulates that rumination may be alleviated by the anger emotion. In Study 1, all participants were initially caused state rumination and then induced anger, joy or neutral mood, the results showed that the rumination-related affect was alleviated after anger induction relative to that after joy or neutral mood induction. In Study 2, female participants with high trait rumination were recruited and divided into two groups for exposure to an anger or neutral emotion intervention, the result indicated that the anger intervention group exhibited a greater decline in trait rumination than the neutral emotion intervention group. These findings provided preliminary evidence supporting the hypothesis of ACR, which suggested a new strategy that employs less cognitive resources to regulating state and trait rumination by inducing anger. PMID- 29250000 TI - Social Fear Conditioning Paradigm in Virtual Reality: Social vs. Electrical Aversive Conditioning. AB - In a previous study we could show that social fear can be induced and extinguished using virtual reality (VR). In the present study, we aimed to investigate the belongingness effect in an operant social fear conditioning (SFC) paradigm which consisted of an acquisition and an extinction phase. Forty-three participants used a joystick to approach different virtual male agents that served as conditioned stimuli. Participants were randomly allocated to one of two experimental conditions. In the electroshock condition, the unconditioned stimulus (US) used during acquisition was an electric stimulation. In the social threat condition, the US consisted of an offense: a spit in the face, mimicked by a sound and a weak air blast to the participant's neck combined with an insult. In both groups the US was presented when participants were close to the agent (75% contingency for CS+). Outcome variables included subjective, psychophysiological and behavioral data. As expected, fear and contingency ratings increased significantly during acquisition and the differentiation between CS+ and CS- vanished during extinction. Furthermore, a clear difference in skin conductance between CS+ and CS- at the beginning of the acquisition indicated that SFC had been successful. However, a fast habituation to the US was found toward the end of the acquisition phase for the physiological response. Furthermore, participants showed avoidance behavior toward CS+ in both conditions. The results show that social fear can successfully be induced and extinguished in VR in a human sample. Thus, our paradigm can help to gain insight into learning and unlearning of social fear. Regarding the belongingness effect, the social threat condition benefits from a better differentiation between the aversive and the non-aversive stimuli. As next step we suggest comparing social phobic patients to healthy controls in order to investigate possible differences in discrimination learning and to foster the development of more efficient treatments for social phobia. PMID- 29250001 TI - Using the Hands to Represent Objects in Space: Gesture as a Substrate for Signed Language Acquisition. AB - An ongoing issue of interest in second language research concerns what transfers from a speaker's first language to their second. For learners of a sign language, gesture is a potential substrate for transfer. Our study provides a novel test of gestural production by eliciting silent gesture from novices in a controlled environment. We focus on spatial relationships, which in sign languages are represented in a very iconic way using the hands, and which one might therefore predict to be easy for adult learners to acquire. However, a previous study by Marshall and Morgan (2015) revealed that this was only partly the case: in a task that required them to express the relative locations of objects, hearing adult learners of British Sign Language (BSL) could represent objects' locations and orientations correctly, but had difficulty selecting the correct handshapes to represent the objects themselves. If hearing adults are indeed drawing upon their gestural resources when learning sign languages, then their difficulties may have stemmed from their having in manual gesture only a limited repertoire of handshapes to draw upon, or, alternatively, from having too broad a repertoire. If the first hypothesis is correct, the challenge for learners is to extend their handshape repertoire, but if the second is correct, the challenge is instead to narrow down to the handshapes appropriate for that particular sign language. 30 sign-naive hearing adults were tested on Marshall and Morgan's task. All used some handshapes that were different from those used by native BSL signers and learners, and the set of handshapes used by the group as a whole was larger than that employed by native signers and learners. Our findings suggest that a key challenge when learning to express locative relations might be reducing from a very large set of gestural resources, rather than supplementing a restricted one, in order to converge on the conventionalized classifier system that forms part of the grammar of the language being learned. PMID- 29250002 TI - Symbolic Numerical Distance Effect Does Not Reflect the Difference between Numbers. AB - In a comparison task, the larger the distance between the two numbers to be compared, the better the performance-a phenomenon termed as the numerical distance effect. According to the dominant explanation, the distance effect is rooted in a noisy representation, and performance is proportional to the size of the overlap between the noisy representations of the two values. According to alternative explanations, the distance effect may be rooted in the association between the numbers and the small-large categories, and performance is better when the numbers show relatively high differences in their strength of association with the small-large properties. In everyday number use, the value of the numbers and the association between the numbers and the small-large categories strongly correlate; thus, the two explanations have the same predictions for the distance effect. To dissociate the two potential sources of the distance effect, in the present study, participants learned new artificial number digits only for the values between 1 and 3, and between 7 and 9, thus, leaving out the numbers between 4 and 6. It was found that the omitted number range (the distance between 3 and 7) was considered in the distance effect as 1, and not as 4, suggesting that the distance effect does not follow the values of the numbers predicted by the dominant explanation, but it follows the small-large property association predicted by the alternative explanations. PMID- 29250004 TI - A Lifespan Perspective on Entrepreneurship: Perceived Opportunities and Skills Explain the Negative Association between Age and Entrepreneurial Activity. AB - Researchers and practitioners are increasingly interested in entrepreneurship as a means to fight youth unemployment and to improve financial stability at higher ages. However, only few studies so far have examined the association between age and entrepreneurial activity. Based on theories from the lifespan psychology literature and entrepreneurship, we develop and test a model in which perceived opportunities and skills explain the relationship between age and entrepreneurial activity. We analyzed data from the 2013 Global Entrepreneurship Monitor (GEM), while controlling for gender and potential variation between countries. Results showed that age related negatively to entrepreneurial activity, and that perceived opportunities and skills for entrepreneurship mediated this relationship. Overall, these findings suggest that entrepreneurship research should treat age as a substantial variable. PMID- 29250003 TI - Pacifier Overuse and Conceptual Relations of Abstract and Emotional Concepts. AB - This study explores the impact of the extensive use of an oral device since infancy (pacifier) on the acquisition of concrete, abstract, and emotional concepts. While recent evidence showed a negative relation between pacifier use and children's emotional competence (Niedenthal et al., 2012), the possible interaction between use of pacifier and processing of emotional and abstract language has not been investigated. According to recent theories, while all concepts are grounded in sensorimotor experience, abstract concepts activate linguistic and social information more than concrete ones. Specifically, the Words As Social Tools (WAT) proposal predicts that the simulation of their meaning leads to an activation of the mouth (Borghi and Binkofski, 2014; Borghi and Zarcone, 2016). Since the pacifier affects facial mimicry forcing mouth muscles into a static position, we hypothesize its possible interference on acquisition/consolidation of abstract emotional and abstract not-emotional concepts, which are mainly conveyed during social and linguistic interactions, than of concrete concepts. Fifty-nine first grade children, with a history of different frequency of pacifier use, provided oral definitions of the meaning of abstract not-emotional, abstract emotional, and concrete words. Main effect of concept type emerged, with higher accuracy in defining concrete and abstract emotional concepts with respect to abstract not-emotional concepts, independently from pacifier use. Accuracy in definitions was not influenced by the use of pacifier, but correspondence and hierarchical clustering analyses suggest that the use of pacifier differently modulates the conceptual relations elicited by abstract emotional and abstract not-emotional. While the majority of the children produced a similar pattern of conceptual relations, analyses on the few (6) children who overused the pacifier (for more than 3 years) showed that they tend to distinguish less clearly between concrete and abstract emotional concepts and between concrete and abstract not-emotional concepts than children who did not use it (5) or used it for short (17). As to the conceptual relations they produced, children who overused the pacifier tended to refer less to their experience and to social and emotional situations, use more exemplifications and functional relations, and less free associations. PMID- 29250005 TI - The Effect of Trait Self-Awareness, Self-Reflection, and Perceptions of Choice Meaningfulness on Indicators of Social Identity within a Decision-Making Context. AB - Theorists operating from within a narrative identity framework have suggested that self-reflective reasoning plays a central role in the development of the self. Typically, however, narrative identity researchers have investigated this relationship using correlational rather than experimental methods. In the present study, leveraging on a classic research paradigm from within the social identity literature we developed an experiment to test the extent to which self-reflection might have a causal impact on the self-concept within a decision-making context. In a minimal group paradigm participants were prompted to reflect on their painting choices either before or after allocating points to in-group? out-group members. As anticipated, self-reflection augmented social identification, but only when participants felt their choices were personally meaningful. Participants who reasoned about their choices and felt they were subjectively meaningful showed stronger similarity and liking for in-group members compared to those who did not reflect on their choices or found them to be subjectively meaningless. Hence, reflecting on and finding meaning in one's choices may be an important step in linking behavior with in-group identification and thus the self concept in turn. The absence of any effects on in-group favoritism (a third indicator of social identification measured) as well as implications of the study's findings for self-perception, cognitive dissonance and social identity processes are also discussed. PMID- 29250008 TI - Music and Technology: The Curative Algorithm. PMID- 29250006 TI - Developmental Changes in Learning: Computational Mechanisms and Social Influences. AB - Our ability to learn from the outcomes of our actions and to adapt our decisions accordingly changes over the course of the human lifespan. In recent years, there has been an increasing interest in using computational models to understand developmental changes in learning and decision-making. Moreover, extensions of these models are currently applied to study socio-emotional influences on learning in different age groups, a topic that is of great relevance for applications in education and health psychology. In this article, we aim to provide an introduction to basic ideas underlying computational models of reinforcement learning and focus on parameters and model variants that might be of interest to developmental scientists. We then highlight recent attempts to use reinforcement learning models to study the influence of social information on learning across development. The aim of this review is to illustrate how computational models can be applied in developmental science, what they can add to our understanding of developmental mechanisms and how they can be used to bridge the gap between psychological and neurobiological theories of development. PMID- 29250010 TI - Internal Grammar and Children's Grammatical Creativity against Poor Inputs. AB - This article is about the unexpected linguistic behavior that young children sometimes display by producing structures that are only marginally present in the adult language in a constrained way, and that adults do not adopt in the same experimental conditions. It is argued here that children's capacity to overextend the use of given syntactic structures thereby resulting in a grammatical creative behavior is the sign of an internal grammatical pressure which manifests itself given appropriate discourse conditions and factors of grammatical complexity and which does not necessarily require a rich input to be put into work. This poverty of the stimulus type situation is illustrated here through the overextended use of a-Topics and reflexive-causative passives by young Italian speaking children when answering eliciting questions concerning the direct object of the clause. PMID- 29250009 TI - Links between an Owner's Adult Attachment Style and the Support-Seeking Behavior of Their Dog. AB - The aim of this study was to investigate if an owner's adult attachment style (AAS) influences how their dog interacts and obtains support from them during challenging events. A person's AAS describes how they perceive their relationship to other people, but it may also reflect their caregiving behavior, and so their behavior toward the dog. We measured the AAS of 51 female Golden retriever owners, using the Adult Attachment Style Questionnaire (ASQ), and observed the reactions of the dog-owner dyads in response to different challenging situations [visual surprise, auditory stressor and social stressors like a person approaching dressed as ghost or in coat, hat and sunglasses]. In addition, the dog was left alone in a novel environment for 3 min. Interactions between the dog and owner were observed both before and after separation. Spearman rank correlation tests were made (between owner AAS and dog behavior) and where correlations were found, Mann-Whitney U-tests were made on the dogs' behavioral response between high and low scoring groups of owners of the different subscales of the ASQ. The more secure the owner (ASQ subscale 'Confidence'), the longer the dog was oriented to the two sudden stressors (the visual and auditory stressor). The more anxious the owner (ASQ subscale 'Attachment anxiety'), the longer the dog oriented toward the owner during the approach of the strange-looking person and the dog showed less lip licking during separation from the owner. The more avoidant the owner (ASQ subscale 'Avoidant attachment'), the longer the dog oriented toward the owner during the visual stressor, the less it was located behind the owner during the auditory stressor and the less it was oriented toward the auditory stressor. These links between owner attachment style and dog behavior imply that dogs may develop different strategies to handle challenging situations, based on the type of support they get from their owner. PMID- 29250007 TI - How Do Stress Exposure and Stress Regulation Relate to Borderline Personality Disorder? AB - Borderline personality disorder (BPD) is a severe and frequent disorder characterized by a pervasive pattern of instability affecting impulse control, emotional regulation, cognitive processing, self-image and interpersonal relationships. Patients' personal histories are often marked by stressful or traumatic experiences, either unique or repeated. Moreover, while clinical signs of the disorder include both chronic and acute features, acute features are mostly triggered by acute stressful situations. Such features include transient cognitive distortion, intense anger, uncontrollable impulsivity, and self-harm behavior - including suicide - and contribute to the burden of the disease. In this paper, we review the various aspects (epidemiological, clinical, and physiological) contributing to the relationship between BDP and stress. In particular, we explore the statistical association between stress exposure and the emergence of BPD while taking into account other psychopathologies, such as post-traumatic stress disorder. Then, the different aspects of stress responses (namely, the phenomenological, behavioral, hormonal, neuro-vegetative and neural responses) are reviewed in BPD patients. Pathophysiological hypotheses are formulated to explain the differences in responses between BPD patients and healthy subjects and their relation to BPD symptoms. Although the pathogenesis remains uncertain, our conclusions seem to reflect a specific biological and neural pattern of altered stress perception and regulation in BPD. PMID- 29250011 TI - Importance of the Motivational Climate in Goal, Enjoyment, and the Causes of Success in Handball Players. AB - The purpose of the study is to examine the effects of the motivational climate created by the coach and perceived by a group of young handball players on their goal orientations, their beliefs regarding reasons for success and their self satisfaction. The study participants were 159 young handball players. Players were administered a battery composed of tests to measure the above-mentioned motivational constructs. Results showed that a perceived mastery-oriented motivational climate was positively related to a task-centered goal orientation, enjoyment, and a belief that success may be achieved through effort. In contrast, a perceived performance-orientated training climate was linked to an ego-centered goal orientation, boredom, or lack of enthusiasm, and a belief that the routes of success in this sport are the abilities and the use of deception techniques. On the whole, this study underlines the educational role of the coach in young handball players. Specifically, the coach's socializing role influences both handball player's commitment and positive motivational profile as well as sport performance. PMID- 29250013 TI - Occupations at Risk and Organizational Well-Being: An Empirical Test of a Job Insecurity Integrated Model. AB - One of the more visible effects of the societal changes is the increased feelings of uncertainty in the workforce. In fact, job insecurity represents a crucial occupational risk factor and a major job stressor that has negative consequences on both organizational well-being and individual health. Many studies have focused on the consequences about the fear and the perception of losing the job as a whole (called quantitative job insecurity), while more recently research has begun to examine more extensively the worries and the perceptions of losing valued job features (called qualitative job insecurity). The vast majority of the studies, however, have investigated the effects of quantitative and qualitative job insecurity separately. In this paper, we proposed the Job Insecurity Integrated Model aimed to examine the effects of quantitative job insecurity and qualitative job insecurity on their short-term and long-term outcomes. This model was empirically tested in two independent studies, hypothesizing that qualitative job insecurity mediated the effects of quantitative job insecurity on different outcomes, such as work engagement and organizational identification (Study 1), and job satisfaction, commitment, psychological stress and turnover intention (Study 2). Study 1 was conducted on 329 employees in private firms, while Study 2 on 278 employees in both public sector and private firms. Results robustly showed that qualitative job insecurity totally mediated the effects of quantitative on all the considered outcomes. By showing that the effects of quantitative job insecurity on its outcomes passed through qualitative job insecurity, the Job Insecurity Integrated Model contributes to clarifying previous findings in job insecurity research and puts forward a framework that could profitably produce new investigations with important theoretical and practical implications. PMID- 29250012 TI - The Effectiveness of a Body-Affective Mindfulness Intervention for Multiple Sclerosis Patients with Depressive Symptoms: A Randomized Controlled Clinical Trial. AB - Purpose: Mindfulness interventions have been shown to treat depressive symptoms and improve quality of life in patients with several chronic diseases, including multiple sclerosis, but to date most evaluation of the effectiveness of mindfulness interventions in multiple sclerosis have used patients receiving standard care as the control group. Hence we decided to evaluate the effectiveness of a group-based body-affective mindfulness intervention by comparing it with a psycho-educational intervention, by means of a randomized controlled clinical trial. The outcome variables (i.e., depression, anxiety, perceived stress, illness perception, fatigue and quality of life) were evaluated at the end of the interventions (T1) and after a further 6 months (T2). Methods: Of 90 multiple sclerosis patients with depressive symptoms (Beck Depression Inventory-II score greater than 13) who were randomized, 71 completed the intervention (mindfulness group n = 36; psycho-educational group n = 35). The data were analyzed with GLM repeated-measures ANOVA followed by pairwise comparisons. Results: Per-protocol analysis revealed a time by group interaction on Beck Depression Inventory-II score, with the mindfulness intervention producing a greater reduction in score than the psycho-educational intervention, both at T1 and at T2. Furthermore, the mindfulness intervention improved patients' quality of life and illness perception at T1 relative to the baseline and these improvements were maintained at the follow-up assessment (T2). Lastly, both interventions were similarly effective in reducing anxiety and perceived stress; these reductions were maintained at T2. A whole-sample intention-to-treat (ITT) analysis broadly confirmed the effectiveness of the mindfulness intervention. Conclusion: In conclusion, these results provide methodologically robust evidence that in multiple sclerosis patients with depressive symptoms mindfulness interventions improve symptoms of depression and anxiety and perceived stress, modulate illness representation and enhance quality of life and that the benefits are maintained for at least 6 months. Trial registration: the study was registered in the ClinicalTrials.gov registry (NCT02611401). PMID- 29250014 TI - Gender Differences in Posttraumatic Stress Symptoms after a Terrorist Attack: A Network Approach. AB - Background: Posttraumatic stress symptoms are more prevalent in women than in men. To improve our understanding of gender differences in PTSD, detailed knowledge about the underlying symptom networks and gender specific symptom profiles is needed. Objective: We aimed to describe the gender differences in levels of individual posttraumatic stress symptoms after a terrorist attack, as well as identify possible gender differences in associations between posttraumatic stress symptoms. Method: This study used survey data from ministerial employees directly (n = 190) and indirectly (n = 1,615) exposed to the 2011 Oslo bombing. Data was collected approximately 10 months after the event. In order to investigate gender differences in levels of symptoms, we used bootstrapped means and standard deviations. Network analyses were conducted to identify gender differences in the associations between posttraumatic stress symptoms. Results: Women reported higher levels of all symptoms, and the strongest effect sizes were found for symptoms of re-experiencing, and anxious and dysphoric arousal. Among individuals with considerable levels of posttraumatic stress symptoms, women reported higher levels of physiological cue activity and exaggerated startle response. No significant gender differences in the networks of posttraumatic stress were found. Conclusions: The present results find no indication that the gender difference in prevalence of PTSD can be explained by differences in associations between symptoms. In order to determine if this finding can be applied to other participants and circumstances, future studies should seek to replicate this study in both community and clinical samples. PMID- 29250015 TI - The Stability of Individual Well-Being in Short Windows of Time: Women's Perceptions across the Ovulatory Cycle. AB - Empirical research on well-being has rapidly increased in recent years. One of the most dominant issue concerns the degree of cross-situational consistency and stability of well-being across time, and this is of particular relevance to women life. The aim of this study was to verify the stability of women well-being in short windows of time, specifically across menstrual cycle phases. A within subject design with 25 normally cycling women (range: 19-26 years) was carried out. The multidimensional assessment of well-being included the administration of psychological well-being, self-esteem, and emotional self-efficacy beliefs questionnaires during both high and low-fertility phases. The results showed the stability of the level of individual well-being across menstrual cycle phases. Albeit preliminary, results indicated that women representations of their well being do not change according to menstrual cycle. Rather, an effective organization and integration of the entire self-system appears sustained by the stability of well-being measured through a multi-componential assessment over short periods of time. PMID- 29250016 TI - For the Love of Nature: Exploring the Importance of Species Diversity and Micro Variables Associated with Favorite Outdoor Places. AB - Although the restorative benefits of nature are widely acknowledged, there is a limited understanding of the attributes of natural environments that are fundamental to restorative experiences. Faced with growing human populations and a greater awareness of the wellbeing benefits natural environments provide, park agencies and planners are increasingly challenged with balancing human and ecological outcomes in natural areas. This study examines the physical and experiential qualities of natural environments people referred to when describing their connection to their most valued natural environments in an online questionnaire. Recruited primarily via a public radio program, respondents were asked to identify their favorite places and explain what they loved about those places. Favorite places are considered exemplars of restorative environments and were classified based on an existing park typology. Reasons people liked particular sites were classified into three domains: setting, activity, or benefit. Content analysis was used to identify the attributes most commonly associated with favorite places. These attributes were then related to the four components of restorative environments according to Attention Restoration Theory. In contrast to previous research, we found that "fascination" was the most important component of favorite places. Possible reasons for this contrast, namely, respondents' median age, and the likelihood of a high degree of ecological literacy amongst the study population are discussed. South Australians' favorite environments comprise primarily hilly, wooded nature parks, and botanical gardens, in stark contrast to the vast arid areas that dominate the state. Micro-variables such as birds, plants, wildlife, native species, and biodiversity appear particularly important elements used to explain people's love of these sites. We discuss the implications of these findings and their potential value as an anchor for marketing campaigns seeking to encourage contact with nature, as well as education programs designed to improve people's understanding of important but intangible concepts such as biodiversity. The findings have clear, practical implications for park managers given the modifiable nature of many of the attributes identified as being most important to our respondents, and we believe attention to such elements has the potential to simultaneously enhance people's nature experiences, optimize restorative outcomes, and improve environmental stewardship. PMID- 29250017 TI - "When Music Speaks": Auditory Cortex Morphology as a Neuroanatomical Marker of Language Aptitude and Musicality. AB - Recent research has shown that the morphology of certain brain regions may indeed correlate with a number of cognitive skills such as musicality or language ability. The main aim of the present study was to explore the extent to which foreign language aptitude, in particular phonetic coding ability, is influenced by the morphology of Heschl's gyrus (HG; auditory cortex), working memory capacity, and musical ability. In this study, the auditory cortices of German speaking individuals (N = 30; 13 males/17 females; aged 20-40 years) with high and low scores in a number of language aptitude tests were compared. The subjects' language aptitude was measured by three different tests, namely a Hindi speech imitation task (phonetic coding ability), an English pronunciation assessment, and the Modern Language Aptitude Test (MLAT). Furthermore, working memory capacity and musical ability were assessed to reveal their relationship with foreign language aptitude. On the behavioral level, significant correlations were found between phonetic coding ability, English pronunciation skills, musical experience, and language aptitude as measured by the MLAT. Parts of all three tests measuring language aptitude correlated positively and significantly with each other, supporting their validity for measuring components of language aptitude. Remarkably, the number of instruments played by subjects showed significant correlations with all language aptitude measures and musicality, whereas, the number of foreign languages did not show any correlations. With regard to the neuroanatomy of auditory cortex, adults with very high scores in the Hindi testing and the musicality test (AMMA) demonstrated a clear predominance of complete posterior HG duplications in the right hemisphere. This may reignite the discussion of the importance of the right hemisphere for language processing, especially when linked or common resources are involved, such as the inter-dependency between phonetic and musical aptitude. PMID- 29250018 TI - Forming Facial Expressions Influences Assessment of Others' Dominance but Not Trustworthiness. AB - Forming specific facial expressions influences emotions and perception. Bearing this in mind, studies should be reconsidered in which observers expressing neutral emotions inferred personal traits from the facial expressions of others. In the present study, participants were asked to make happy, neutral, and disgusted facial expressions: for "happy," they held a wooden chopstick in their molars to form a smile; for "neutral," they clasped the chopstick between their lips, making no expression; for "disgusted," they put the chopstick between their upper lip and nose and knit their brows in a scowl. However, they were not asked to intentionally change their emotional state. Observers judged happy expression images as more trustworthy, competent, warm, friendly, and distinctive than disgusted expression images, regardless of the observers' own facial expression. Observers judged disgusted expression images as more dominant than happy expression images. However, observers expressing disgust overestimated dominance in observed disgusted expression images and underestimated dominance in happy expression images. In contrast, observers with happy facial forms attenuated dominance for disgusted expression images. These results suggest that dominance inferred from facial expressions is unstable and influenced by not only the observed facial expression, but also the observers' own physiological states. PMID- 29250019 TI - Commentary: The Affective Core of the Self: A Neuro-Archetypical Perspective on the Foundations of Human (and Animal) Subjectivity. PMID- 29250020 TI - Back to the Future of Quantitative Psychology and Measurement: Psychometrics in the Twenty-First Century. PMID- 29250021 TI - Modulating Mimetic Preference with Theta Burst Stimulation of the Inferior Parietal Cortex. AB - We like an object more when we see someone else reaching for it. To what extent is action observation causally linked to object valuation? In this study, we set out to answer to this question by applying continuous theta burst stimulation (cTBS) over the left inferior parietal lobule (IPL). Previous studies pointed to this region as critical in the representation of others' actions and in tool manipulation. However, it is unclear to what extent IPL's involvement simply reflects action observation, rather than a casual role in objects' valuation. To clarify this issue, we measured cTBS-dependent modulations of participants' "mimetic preference ratings", i.e., the difference between the ratings of pairs of familiar objects that were (vs. were not) reached out for by other individuals. Our result shows that cTBS increased mimetic preference ratings for tools, when compared to a control condition without stimulation. This effect was selective for items that were reached for or manipulated by another individual, whilst it was not detected in non-tool objects. Although preliminary, this finding suggests that the automatic and covert simulation of an observed action, even when there is no intention to act on an object, influences explicit affective judgments for objects. This work supports embodied cognition theories by substantiating that our subjective preference is grounded in action. PMID- 29250022 TI - Automatic Evaluations and Exercising: Systematic Review and Implications for Future Research. AB - The general purpose of this systematic review was to summarize, structure and evaluate the findings on automatic evaluations of exercising. Studies were eligible for inclusion if they reported measuring automatic evaluations of exercising with an implicit measure and assessed some kind of exercise variable. Fourteen nonexperimental and six experimental studies (out of a total N = 1,928) were identified and rated by two independent reviewers. The main study characteristics were extracted and the grade of evidence for each study evaluated. First, results revealed a large heterogeneity in the applied measures to assess automatic evaluations of exercising and the exercise variables. Generally, small to large-sized significant relations between automatic evaluations of exercising and exercise variables were identified in the vast majority of studies. The review offers a systematization of the various examined exercise variables and prompts to differentiate more carefully between actually observed exercise behavior (proximal exercise indicator) and associated physiological or psychological variables (distal exercise indicator). Second, a lack of transparent reported reflections on the differing theoretical basis leading to the use of specific implicit measures was observed. Implicit measures should be applied purposefully, taking into consideration the individual advantages or disadvantages of the measures. Third, 12 studies were rated as providing first-grade evidence (lowest grade of evidence), five represent second grade and three were rated as third-grade evidence. There is a dramatic lack of experimental studies, which are essential for illustrating the cause-effect relation between automatic evaluations of exercising and exercise and investigating under which conditions automatic evaluations of exercising influence behavior. Conclusions about the necessity of exercise interventions targeted at the alteration of automatic evaluations of exercising should therefore not be drawn too hastily. PMID- 29250023 TI - Development of a Measure of Sleep, Circadian Rhythms, and Mood: The SCRAM Questionnaire. AB - Sleep quality, circadian phase, and mood are highly interdependent processes. Remarkably, there is currently no self-report questionnaire that measures all three of these clinically significant functions: The aim of this project was to address this deficit. In Study 1, 720 participants completed a set of potential items was generated from existing questionnaires in each of the three domains and refined to follow a single presentation format. Study 2 used an independent sample (N = 498) to interrogate the latent structure. Exploratory factor analysis was used to identify a parsimonious, three-factor latent structure. Following item reduction, the optimal representation of sleep quality, circadian phase, and mood was captured by a questionnaire with three 5-item scales: Depressed Mood, Morningness, and Good Sleep. Confirmatory factor analysis found the three-scale structure provided adequate fit. In both samples, Morningness and Good Sleep were positively associated, and each was negatively associated with the Depressed Mood scale. Further research is now required to quantify the convergent and discriminant validity of its three face-valid and structurally replicated scales. The new sleep, circadian rhythms, and mood (SCRAM) questionnaire is the first instrument to conjointly measure sleep quality, circadian phase, and mood processes, and has significant potential as a clinical tool. PMID- 29250024 TI - Clinical Predictors of Progressive Hemorrhagic Injury in Children with Mild Traumatic Brain Injury. AB - Objective: Traumatic brain injury (TBI) occurs commonly in children. Repeat computed tomography (CT) follow up of TBI patients is often scheduled to identify progressive hemorrhagic injury (PHI). However, the utility of repeated CT scans, especially in children with mild TBI [Glasgow Coma Scale (GCS) scores of 13-15], has been debated. The purposes of the present study were to identify clinical predictors of PHI in children with mild TBI and to clarify relevant clinical factors via radiological examination. Methods: From 2014 to 2016, we retrospectively enrolled children <15 years of age with mild TBI. We recorded age, sex, GCS scores on admission, causes of head injury, timing of initial CT, any loss of consciousness, vomiting and seizure data, and type of TBI. Based on repeat CT findings, patients were dichotomized into either a PHI group or a non PHI group. Also, clinical data were comparatively reviewed. Multivariate logistic regression analysis was used to identify clinical predictors of PHI. Results: Of the 175 enrolled children, 15 (8.6%) experienced PHI. Univariate analysis revealed that GCS score on admission, cause of head injury, vomiting, seizure, and TBI type were associated with PHI. Multivariate logistic regression analysis showed that a GCS score of 13 and epidural hemorrhage (EDH) were independently associated with PHI (hazard ratio = 0.131, P = 0.018; hazard ratio = 6.612, P = 0.027, respectively). Conclusion: A GCS score of 13 and EDH were associated with PHI. These factors should be considered when deciding whether to repeat CT on children with mild TBI. PMID- 29250025 TI - Procedure-Related Complication of Willis Covered Stent in the Treatment of Blood Blister-Like Aneurysm: Stent Detachment from Dilating Balloon. AB - The use of Willis covered stent (WCS) for intracranial aneurysms has increased based on the promising results of previous studies about its safety and effectiveness. With the accumulation of cases, reports about peri-procedural complications are emerging. In our department, 25 patients were treated with WCS during December 2015 to March 2017. We here reported an unexpected technical complication occurred in the treatment with the WCS for a blood blister-like aneurysm (BBA). During the procedure, the distal end of the stents detached from the dilating balloon partially or as a whole. This was attributed to the tortuosity of the access route and the extracorporeal gas exhaust maneuver. Then we applied a half-dilating technique to retrieve the detached stent. The procedures were detailed in this report and the possible reasons and approaches to avoid it were explored. PMID- 29250026 TI - Visual Tracking in Development and Aging. AB - A moving target is visually tracked with a combination of smooth pursuit and saccades. Human visual tracking eye movement develops through early childhood and adolescence, and declines in senescence. However, the knowledge regarding performance changes over the life course is based on data from distinct age groups in isolation using different procedures, and thus is fragmented. We sought to describe the age-dependence of visual tracking performance across a wide age range and compare it to that of simple visuo-manual reaction time. We studied a cross-sectional sample of 143 subjects aged 7-82 years old (37% male). Eye movements were recorded using video-oculography, while subjects viewed a computer screen and tracked a small target moving along a circular trajectory at a constant speed. For simple reaction time (SRT) measures, series of key presses that subjects made in reaction to cue presentation on a computer monitor were recorded using a standard software. The positional precision and smooth pursuit velocity gain of visual tracking followed a U-shaped trend over age, with best performances achieved between the ages of 20 and 50 years old. A U-shaped trend was also found for mean reaction time in agreement with the existing literature. Inter-individual variability was evident at any age in both visual tracking and reaction time metrics. Despite the similarity in the overall developmental and aging trend, correlations were not found between visual tracking and reaction time performances after subtracting the effects of age. Furthermore, while a statistically significant difference between the sexes was found for mean SRT in the sample, a similar difference was not found for any of the visual tracking metrics. Therefore, the cognitive constructs and their neural substrates supporting visual tracking and reaction time performances appear largely independent. In summary, age is an important covariate for visual tracking performance, especially for a pediatric population. Since visual tracking performance metrics may provide signatures of abnormal neurological or cognitive states independent of reaction time-based metrics, further understanding of age dependent variations in normal visual tracking behavior is necessary. PMID- 29250027 TI - Derivation of a Three Biomarker Panel to Improve Diagnosis in Patients with Mild Traumatic Brain Injury. AB - Background: Nearly 5 million emergency department (ED) visits for head injury occur each year in the United States, of which <10% of patients show abnormal computed tomography (CT) findings. CT negative patients frequently suffer protracted somatic, behavioral, and neurocognitive dysfunction. Our goal was to evaluate biomarkers to identify mild TBI (mTBI) in patients with suspected head injury. Methods: An observational ED study of head-injured and control patients was conducted at Johns Hopkins University (HeadSMART). Head CT was obtained (ACEP criteria) in patients with Glasgow Coma Scale scores of 13-15 and aged 18-80. Three candidate biomarker proteins, neurogranin (NRGN), neuron-specific enolase (NSE), and metallothionein 3 (MT3), were evaluated by immunoassay (samples <24 h from injury). American Congress of Rehabilitation Medicine (ACRM) criteria were used for diagnosis of mTBI patients for model building. Univariate analysis, logistic regression, and random forest (RF) algorithms were used for data analysis in R. Overall, 662 patients were studied. Statistical models were built using 328 healthy controls and 179 mTBI patients. Results: Median time from injury was 5.9 h (IQR, 4.0; range 0.8-24 h). mTBI patients had elevated NSE, but decreased MT3 versus controls (p < 0.01 for each). NRGN was also elevated but within 2-6 h after injury. In the derivation set, the best model to distinguish mTBI from healthy controls used three markers, age, and sex as covariates (C statistic = 0.91, sensitivity 98%, specificity 72%). Panel test accuracy was validated with the 155 remaining ACRM+ mTBI patients. Applying the RF model to the ACRM+ mTBI validation set resulted in 78% correctly classified as mTBI (119/153). CT positive and CT negative validation subsets were 91% and 75% correctly classified. In samples taken <2 h from injury, 100% (10/10) samples classified correctly, indicating that hyperacute testing is possible with these biomarker assays. The model accuracy varied from 72-100% overall, and had greater accuracy with increasing severity, as shown by comparing CT+ with CT- (91% versus 75%), and Injury Severity Score >=16 versus <16 (88% versus 72%, respectively). Objective blood tests, detecting NRGN, NSE, and MT3, can be used to identify mTBI, irrespective of neuroimaging findings. PMID- 29250028 TI - The Structural Imaging Characteristics and Its Clinical Relevance in Patients with Cerebral Venous Thrombosis-A Retrospective Analysis from One Single Center in China. AB - Background: Few studies have investigated structural imaging findings of cerebral venous thrombosis (CVT) in China. The structural imaging [head computed tomography (CT) and routine brain magnetic resonance imaging (MRI)] can assess any parenchymal lesion secondary to the venous thrombosis and reveal direct signs of intraluminal thrombus. In recent years, many patients can be diagnosed with CVT more rapidly and directly by structural imaging. The aim of the present study is to determine the performance of structural imaging in the diagnosis and outcome of CVT in a large cohort single center of Chinese patients. Methods: We evaluated consecutive patients admitted to our hospital with CVT receiving structural imaging from 1991 to 2015. A neuroradiologist, blinded to clinical data, independently reviewed the structural imaging, including head CT and routine MRI for parenchymal lesions and signs of dural venous sinus thrombosis, as well as the MRV/DSA findings. The Clinical and laboratory data were reviewed and recorded for further analysis. Results: 117 patients were included in this study, 68 (58.1%) were females. Parenchymal lesions were identified in 56.4% (66/117) of the patients on structural imaging, including focal edema in 30.8%, hemorrhage in 19.7%, and brain swelling in 4.3% of the patients. Patients with parenchymal lesions presented with more often seizures (P < 0.001) and less often headache (P = 0.049). Intraluminal thrombus within the sinuses or veins on structural imaging was found in 28.2% (33/117) of the patients. Patients with both intraluminal thrombus and parenchymal lesions on structural imaging had more acute onset (P = 0.01) and present more consciousness disturbance (P = 0.007). Conclusion: Intracranial lesions on structural imaging are frequently found in patients with CVT. Patients with parenchymal lesions on structural imaging, especially with intraluminal thrombus simultaneously, tend to have a severe clinical picture and might lead to a devastating or fatal outcome. Structural imaging may help on early diagnosis and predict the poor outcome of CVT. PMID- 29250029 TI - Ischemic Strokes Due to Large-Vessel Occlusions Contribute Disproportionately to Stroke-Related Dependence and Death: A Review. AB - Background: Since large-vessel occlusion (LVO)-related acute ischemic strokes (AIS) are associated with more severe deficits, we hypothesize that the endovascular thrombectomy (ET) may disproportionately benefit stroke-related dependence and death. Methods: To delineate LVO-AIS impact, systematic search identified studies measuring dependence or death [modified Rankin Scale (mRS) 3 6] or mortality following ischemic stroke among consecutive patients presenting with both LVO and non-LVO events within 24 h of symptom onset. Results: Among 197 articles reviewed, 2 met inclusion criteria, collectively enrolling 1,467 patients. Rates of dependence or death (mRS 3-6) within 3-6 months were higher after LVO than non-LVO ischemic stroke, 64 vs. 24%, odds ratio (OR) 4.46 (CI: 3.53-5.63, p < 0.0001). Mortality within 3-6 months was higher after LVO than non LVO ischemic stroke, 26.2 vs. 1.3%, OR 4.09 (CI: 2.5-6.68), p < 0.0001. Consequently, while LVO ischemic events accounted for 38.7% (CI: 21.8-55.7%) of all acutely presenting ischemic strokes, they accounted for 61.6% (CI: 41.8 81.3%) of poststroke dependence or death and 95.6% (CI: 89.0-98.8%) of poststroke mortality. Using literature-based projections of LVO cerebral ischemia patients treatable within 8 h of onset, ET can be used in 21.4% of acutely presenting patients with ischemic stroke, and these events account for 34% of poststroke dependence and death and 52.8% of poststroke mortality. Conclusion: LVOs cause a little more than one-third of acutely presenting AIS, but are responsible for three-fifths of dependency and more than nine-tenths of mortality after AIS. At the population level, ET has a disproportionate benefit in reducing severe stroke outcomes. PMID- 29250032 TI - Involvement of Amylin and Leptin in the Development of Projections from the Area Postrema to the Nucleus of the Solitary Tract. AB - The area postrema (AP) and the nucleus of the solitary tract (NTS) are important hindbrain centers involved in the control of energy homeostasis. The AP mediates the anorectic action and the inhibitory effect on gastric emptying induced by the pancreatic hormone amylin. Amylin's target cells in the AP project to the NTS, an integrative relay center for enteroceptive signals. Perinatal hormonal and metabolic factors influence brain development. A postnatal surge of the adipocyte derived hormone leptin represents a developmental signal for the maturation of projections between hypothalamic nuclei controlling energy balance. Amylin appears to promote neurogenesis in the AP in adult rats. Here, we examined whether amylin and leptin are required for the development of projections from the AP to the NTS in postnatal and adult mice by conducting neuronal tracing studies with DiI in amylin- (IAPP-/-) and leptin-deficient (ob/ob) mice. Compared to wild-type littermates, postnatal (P10) and adult (P60) IAPP-/- mice showed a significantly reduced density of AP-NTS projections. While AP projections were also reduced in postnatal (P14) ob/ob mice, AP-NTS fiber density did not differ between adult ob/ob and wild-type animals. Our findings suggest a crucial function of amylin for the maturation of neuronal brainstem pathways controlling energy balance and gastrointestinal function. The impaired postnatal development of neuronal AP-NTS projections in ob/ob mice appears to be compensated in this experimental model during later brain maturation. It remains to be elucidated whether an amylin- and leptin-dependent modulation in neuronal development translates into altered AP/NTS-mediated functions. PMID- 29250033 TI - One-third of an Archivial Series of Papillary Thyroid Cancer (Years 2007-2015) Has Coexistent Chronic Lymphocytic Thyroiditis, Which Is Associated with a More Favorable Tumor-Node-Metastasis Staging. AB - The significance and impact of the coexistence of chronic lymphocytic thyroiditis (CLT) with thyroid cancer is still debated. To verify the influence of CLT on papillary thyroid cancer (PTC), we retrospectively collected 505 PTC cases and analyzed age at diagnosis, sex, size, lymph node status, and staging. We found that CLT was present in 168 PTC (33.3%). Compared with the 337 patients without CLT (non-CLT), CLT patients were younger (44.42 +/- 13.72 vs. 47.21 +/- 13.76 years, P = 0.03), had smaller tumors (9.39 +/- 6.10 vs. 12 +/- 9.71 mm, P = 0.002), and lower rate of lymph node metastases (12.5 vs. 21.96%, P = 0.01, OR = 0.508). Tumor-node-metastasis (TNM) staging (T1a through T4) was more favorable for the CLT group compared to the non-CLT group (for instance, T1a = 65.5 vs. 49.8%, T3 = 4.8 vs. 23.4%). This study shows that one in three patients with PTC harbors CLT, which is associated with a more favorable TNM staging, consistently with a favorable outlook of PTC. PMID- 29250030 TI - Cytokines in Male Fertility and Reproductive Pathologies: Immunoregulation and Beyond. AB - Germline development in vivo is dependent on the environment formed by somatic cells and the differentiation cues they provide; hence, the impact of local factors is highly relevant to the production of sperm. Knowledge of how somatic and germline cells interact is central to achieving biomedical goals relating to restoring, preserving or restricting fertility in humans. This review discusses the growing understanding of how cytokines contribute to testicular function and maintenance of male reproductive health, and to the pathologies associated with their abnormal activity in this organ. Here we consider both cytokines that signal through JAKs and are regulated by SOCS, and those utilizing other pathways, such as the MAP kinases and SMADs. The importance of cytokines in the establishment and maintenance of the testis as an immune-privilege site are described. Current research relating to the involvement of immune cells in testis development and disease is highlighted. This includes new data relating to testicular cancer which reinforce the understanding that tumorigenic cells shape their microenvironment through cytokine actions. Clinical implications in pathologies relating to local inflammation and to immunotherapies are discussed. PMID- 29250034 TI - Editorial: Trends in Comparative Endocrinology and Neurobiology. PMID- 29250035 TI - Light-Enhanced Microbial Organic Carbon Yield. AB - Molecular evidence for proteorhodopsin- and bacteriochlorophyll-based photoheterotrophy is widespread in oligotrophic marine microbial community metagenomes, and has been implicated in light-enhanced growth rates, substrate uptake rates, and anapleurotic carbon fixation, thus complicating the web of interactions within the 'microbial loop.' We quantified photoheterotrophic metabolism of the oxidized organic acid glycolate, a fast-turnover and exclusively phytoplankton-derived substrate at an oligotrophic site in the subtropical North Pacific Ocean. As expected, concentration-dependent changes in uptake rates were observed over the diel cycle, with maxima occurring at midday. Although no light-enhanced substrate uptake rates were observed, samples exposed to light altered the balance between assimilation and respiration, resulting in an approximately four-fold increase in glycolate-specific assimilation efficiency. Energy demand for such a metabolic adjustment was linearly related to light, consistent with photoheterotrophy. PMID- 29250031 TI - New Insights into the Mechanism of Action of Soluble Klotho. AB - The klotho gene encodes a type I single-pass transmembrane protein that contains a large extracellular domain, a membrane spanning segment, and a short intracellular domain. Klotho protein exists in several forms including the full length membrane form (mKl) and a soluble circulating form [soluble klotho (sKl)]. mKl complexes with fibroblast growth factor receptors to form coreceptors for FGF23, which allows it to participate in FGF23-mediated signal transduction and regulation of phosphate and calcium homeostasis. sKl is present in the blood, urine, and cerebrospinal fluid where it performs a multitude of functions including regulation of ion channels/transporters and growth factor signaling. How sKl exerts these pleiotropic functions is poorly understood. One hurdle in understanding sKl's mechanism of action as a "hormone" has been the inability to identify a receptor that mediates its effects. In the body, the kidneys are a major source of sKl and sKl levels decline during renal disease. sKl deficiency in chronic kidney disease makes the heart susceptible to stress-induced injury. Here, we summarize the current knowledge of mKl's mechanism of action, the mechanistic basis of sKl's protective, FGF23-independent effects on the heart, and provide new insights into the mechanism of action of sKl focusing on recent findings that sKl binds sialogangliosides in membrane lipid rafts to regulate growth factor signaling. PMID- 29250036 TI - Distribution of Abundant and Active Planktonic Ciliates in Coastal and Slope Waters Off New England. AB - Despite their important role of linking microbial and classic marine food webs, data on biogeographical patterns of microbial eukaryotic grazers are limited, and even fewer studies have used molecular tools to assess active (i.e., those expressing genes) community members. Marine ciliate diversity is believed to be greatest at the chlorophyll maximum, where there is an abundance of autotrophic prey, and is often assumed to decline with depth. Here, we assess the abundant (DNA) and active (RNA) marine ciliate communities throughout the water column at two stations off the New England coast (Northwest Atlantic)-a coastal station 43 km from shore (40 m depth) and a slope station 135 km off shore (1,000 m). We analyze ciliate communities using a DNA fingerprinting technique, Denaturing Gradient Gel Electrophoresis (DGGE), which captures patterns of abundant community members. We compare estimates of ciliate communities from SSU-rDNA (abundant) and SSU-rRNA (active) and find complex patterns throughout the water column, including many active lineages below the photic zone. Our analyses reveal (1) a number of widely-distributed taxa that are both abundant and active; (2) considerable heterogeneity in patterns of presence/absence of taxa in offshore samples taken 50 m apart throughout the water column; and (3) three distinct ciliate assemblages based on position from shore and depth. Analysis of active (RNA) taxa uncovers biodiversity hidden to traditional DNA-based approaches (e.g., clone library, rDNA amplicon studies). PMID- 29250037 TI - Comparative Analysis of Proteome-Wide Lysine Acetylation in Juvenile and Adult Schistosoma japonicum. AB - Schistosomiasis is a devastating parasitic disease caused by tremotodes of the genus Schistosoma. Eggs produced by sexually mature schistosomes are the causative agents of for pathogenesis and transmission. Elucidating the molecular mechanism of schistosome development and sexual maturation would facilitate the prevention and control of schistosomiasis. Acetylation of lysine is a dynamic and reversible post-translational modification playing keys role in many biological processes including development in both eukaryotes and prokaryotes. To investigate the impacts of lysine acetylation on Schistosoma japonicum (S. japonicum) development and sexual maturation, we used immunoaffinity-based acetyllysine peptide enrichment combined with mass spectrometry (MS), to perform the first comparative analysis of proteome-wide lysine acetylation in both female and male, juvenile (18 days post infection, 18 dpi) and adult (28 dpi) schistosome samples. In total, we identified 874 unique acetylated sites in 494 acetylated proteins. The four samples shared 47 acetylated sites and 46 proteins. More acetylated sites and proteins shared by both females and males were identified in 28 dpi adults (189 and 143, respectively) than in 18 dpi schistosomula (76 and 59, respectively). More stage-unique acetylated sites and proteins were also identified in 28 dpi adults (494 and 210, respectively) than in 18 dpi schistosomula (73 and 44, respectively). Functional annotation showed that in different developmental stages and genders, a number of proteins involving in muscle movement, glycometabolism, lipid metabolism, energy metabolism, environmental stress resistance, antioxidation, etc., displayed distinct acetylation profiles, which was in accordance with the changes of their biological functions during schistosome development, suggesting that lysine acetylation modification exerted important regulatory roles in schistosome development. Taken together, our data provided the first comparative global survey of lysine acetylation in juvenile and adult S. japonicum, which would deepen our understanding of the molecular mechanism of schistosome development and sexual maturation, and provide clues for the development of new anti schistosome strategies. PMID- 29250039 TI - Molecular Epidemiology and Colistin Resistant Mechanism of mcr-Positive and mcr Negative Clinical Isolated Escherichia coli. AB - Transmissible colistin resistance mediated by the mcr gene has been reported worldwide, but clinical isolates of mcr-negative colistin-resistant Escherichia coli are rarely reported. The aim of this study was to evaluate the mechanism of colistin resistance among mcr-positive and mcr-negative E. coli clinical isolates by performing a molecular epidemiological surveillance. For the first time ever, we show nearly the same isolation ratio for mcr-negative and mcr-positive colistin-resistant clinical isolates (47.5 and 52.5%, respectively), with no demonstrable nosocomial transmission. We provide evidence for the prevalence of the mcr-positive IncX4 plasmid and its high potential for horizontal transfer, with no obvious sequence type (ST) preference. In addition, the minimal inhibitory concentrations (MICs) of colistin of the mcr-negative E. coli isolates were obviously higher than those of mcr-positive isolates. Apart from the usually detected genes, i.e., pmrAB, phoPQ, and mgrB, other genes may be associated with the colistin resistance in mcr-negative E. coli. To the best of our knowledge, this is the first paper to report the molecular epidemiological surveillance and the proper mechanism of colistin resistance in mcr-negative E. coli clinical isolates. Together, the results show that colistin resistance was prevalent not only in the mcr-positive clinical E. coli isolates but also in the mcr-negative isolates. PMID- 29250038 TI - Double-Serine Fluoroquinolone Resistance Mutations Advance Major International Clones and Lineages of Various Multi-Drug Resistant Bacteria. AB - The major international sequence types/lineages of methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae and ESBL-producing E. coli were demonstrated to have been advanced by favorable fitness balance associated with high-level resistance to fluoroquinolones. The paper shows that favorable fitness in the major STs/lineages of these pathogens was principally attained by the capacity of evolving mutations in the fluoroquinolone-binding serine residues of both the DNA gyrase and topoisomerase IV enzymes. The available information on fitness balance incurred by individual and various combinations of mutations in the enzymes is reviewed in multiple species. Moreover, strong circumstantial evidence is presented that major STs/lineages of other multi-drug resistant bacteria, primarily vancomycin-resistant Enterococcus faecium (VRE), emerged by a similar mechanism. The reason(s) why the major ST/lineage strains of various pathogens proved more adept at evolving favorable mutations than most isolates of the same species remains to be elucidated. PMID- 29250040 TI - In Vitro Activity of Neomycin, Streptomycin, Paromomycin and Apramycin against Carbapenem-Resistant Enterobacteriaceae Clinical Strains. AB - We determined the in vitro susceptibility of four aminoglycosides, which are not of the 4,6-disubstituted deoxystreptamine (DOS) subclass against a collection of carbapenem-resistant Enterobacteriaceae (CRE). CRE clinical strains (n = 134) were collected from multiple hospitals in China and carried blaNDM (blaNDM-1, blaNDM-5 or blaNDM-7; n = 66), blaKPC-2 (n = 62) or blaIMP-4 (n = 7; including one carrying blaNDM-1 and blaIMP-4). MICs of neomycin, paromomycin, streptomycin and apramycin as well as three 4,6-disubstituted DOS aminoglycosides (amikacin, gentamicin and tobramycin) were determined using the broth microdilution with breakpoints defined by the Clinical Laboratory Standards Institute (for amikacin, gentamicin and tobramycin), US Food and Drug Administration (streptomycin), the National Antimicrobial Resistance Monitoring System (apramycin) or la Societe Francaise de Microbiologie (neomycin and paromomycin). Apramycin-resistant strains were subjected to whole genome sequencing using Illumina X10 platform. Among CRE strains, 65.7, 64.9, 79.1, and 95.5% were susceptible to neomycin (MIC50/MIC90, 8/256 MUg/ml), paromomycin (4/>256 MUg/ml), streptomycin (16/256 MUg/ml) and apramycin (4/8 MUg/ml), respectively, while only 55.2, 28.4, and 35.1% were susceptible to amikacin (32/>256 MUg/ml), gentamicin (128/>256 MUg/ml) and tobramycin (64/>256 MUg/ml), respectively. Six CRE strains including five Escherichia coli of different sequence types and one Klebsiella pneumoniae were resistant to apramycin and the apramycin-resistant gene aac(3)-IVa was detected in all of these strains. In conclusion, neomycin, paromomycin, streptomycin and apramycin retain activity against most CRE strains. Although none of these non 4,6-disubstituted DOS aminoglycosides are suitable for intravenous use in human at present, these agents warrant further investigations to be used against CRE infections. PMID- 29250042 TI - Characterization of the CrbS/R Two-Component System in Pseudomonas fluorescens Reveals a New Set of Genes under Its Control and a DNA Motif Required for CrbR Mediated Transcriptional Activation. AB - The CrbS/R system is a two-component signal transduction system that regulates acetate utilization in Vibrio cholerae, P. aeruginosa, and P. entomophila. CrbS is a hybrid histidine kinase that belongs to a recently identified family, in which the signaling domain is fused to an SLC5 solute symporter domain through aSTAC domain. Upon activation by CrbS, CrbR activates transcription of the acs gene, which encodes an acetyl-CoA synthase (ACS), and the actP gene, which encodes an acetate/solute symporter. In this work, we characterized the CrbS/R system in Pseudomonas fluorescens SBW25. Through the quantitative proteome analysis of different mutants, we were able to identify a new set of genes under its control, which play an important role during growth on acetate. These results led us to the identification of a conserved DNA motif in the putative promoter region of acetate-utilization genes in the Gammaproteobacteria that is essential for the CrbR-mediated transcriptional activation of genes under acetate-utilizing conditions. Finally, we took advantage of the existence of a second SLC5 containing two-component signal transduction system in P. fluorescens, CbrA/B, to demonstrate that the activation of the response regulator by the histidine kinase is not dependent on substrate transport through the SLC5 domain. PMID- 29250044 TI - Clonal Diversity, Virulence Potential and Antimicrobial Resistance of Escherichia coli Causing Community Acquired Urinary Tract Infection in Switzerland. AB - Objectives: The aim of this study was to assess the clonal structure, virulence potential and antibiotic susceptibility of uropathogenic Escherichia coli (UPEC) isolates causing community acquired urinary tract infection (CAUTI) in unselected primary care patients in Switzerland. Methods: We performed multilocus sequence typing, virulence factor determination, and phenotypic and genotypic antimicrobial resistance testing on 44 non-duplicate UPEC isolates. Results: Twenty-seven different sequence types (STs) were identified. Major UPEC clones were represented by 19 (43.2%) of the isolates, including E. coli ST131, ST69 (both 13.6%), ST73 (6.8%), ST10 (4.5%), ST127, ST140, (both 2.3%). Five (11.4%) isolates belonged to ST141. Aggregate virulence factor (VF) scores were highest among isolates belonging to ST127 and ST141. Overall, 50% of the isolates were susceptible to all 12 antimicrobials tested, and all isolates remained susceptible to fosfomycin and nitrofurantoin. Resistance to sulfamethoxazole and ciprofloxacin were found in 31.8, and 15.9% of the isolates, respectively. Plasmid-mediated resistance genes were detected in ST69 and ST131 and included aac(6')-Ib-cr (2.3% of all isolates) blaCTX-M-14 and blaCTX-M-15 (9%), and mph(A) (13.6%). None of the isolates tested positive for mcr-1 or mcr-2. Conclusions: Our results show that CAUTI in Switzerland is caused by a wide variety of UPEC STs for which fosfomycin remains a good treatment option. We suggest that ST141 is an emerging clone associated with UTI in the community, and warrants closer attention. Moreover, the high rate of E. coli harboring mph(A) from patients without a history of antimicrobial therapy or hospitalization indicates that UPEC is an important reservoir for mph(A). PMID- 29250043 TI - Application of Proteomics for the Investigation of the Effect of Initial pH on Pathogenic Mechanisms of Fusarium proliferatum on Banana Fruit. AB - Fusarium proliferatum is an important pathogen and causes a great economic loss to fruit industry. Environmental pH-value plays a regulatory role in fungi pathogenicity, however, the mechanism needs further exploration. In this study, F. proliferatum was cultured under two initial pH conditions of 5 and 10. No obvious difference was observed in the growth rate of F. proliferatum between two pH-values. F. proliferatum cultured under both pH conditions infected banana fruit successfully, and smaller lesion diameter was presented on banana fruit inoculated with pH 10-cultured fungi. Proteomic approach based on two-dimensional electrophoresis (2-DE) was used to investigate the changes in secretome of this fungus between pH 5 and 10. A total of 39 differential spots were identified using matrix-assisted laser desorption/ionization tandem time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) and liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Compared to pH 5 condition, proteins related to cell wall degrading enzymes (CWDEs) and proteolysis were significantly down-regulated at pH 10, while proteins related to oxidation-reduction process and transport were significantly up-regulated under pH 10 condition. Our results suggested that the downregulation of CWDEs and other virulence proteins in the pH 10-cultured F. proliferatum severely decreased its pathogenicity, compared to pH 5-cultured fungi. However, the alkaline environment did not cause a complete loss of the pathogenic ability of F. proliferatum, probably due to the upregulation of the oxidation-reduction related proteins at pH 10, which may partially compensate its pathogenic ability. PMID- 29250045 TI - Temperature Increase Enhances Aedes albopictus Competence to Transmit Dengue Virus. AB - Dengue is a mosquito-borne disease that has been an epidemic in China for many years. Aedes albopictus is the dominant Aedes mosquito species and the main vector of dengue in China. Epidemiologically, dengue mainly occurs in Guangdong Province; it does not occur or rarely occurs in other areas of mainland China. This distribution may be associated with climate, mosquito density, and other factors in different regions; however, the effect of temperature on the vector competence of Ae. albopictus for dengue viruses (DENV) remains unclear. In this study, Ae. albopictus was orally infected with dengue virus 2 (DENV-2) and reared at constant temperatures (18, 23, 28, and 32 degrees C) and a fluctuating temperature (28-23-18 degrees C). The infection status of the midguts, ovaries, and salivary glands of each mosquito was detected by polymerase chain reaction (PCR) at 0, 5, 10, and 15 days post-infection (dpi). DENV-2 RNA copies from positive tissues were quantified by quantitative real time PCR (qRT-PCR). At 18 degrees C, DENV-2 proliferated slowly in the midgut of Ae. albopictus, and the virus could not spread to the salivary glands. At 23 and 28 degrees C, DENV-2 was detected in the ovaries and salivary glands at 10 dpi. The rates of infection, dissemination, population transmission, and DENV-2 copies at 28 degrees C were higher than those at 23 degrees C at any time point. At 32 degrees C, the extrinsic incubation period (EIP) for DENV-2 in Ae. albopictus was only 5 dpi, and the vector competence was the highest among all the temperatures. Compared with 28 degrees C, at 28-23-18 degrees C, the positive rate and the amount of DENV-2 in the salivary glands were significantly lower. Therefore, temperature is an important factor affecting the vector competence of Ae. albopictus for DENV-2. Within the suitable temperature range, the replication of DENV-2 in Ae. albopictus accelerated, and the EIP was shorter with a higher temperature. Our results provide a guide for vector control and an experimental basis for differences in the spatial distribution of dengue cases. PMID- 29250041 TI - Stenotrophomonas maltophilia as an Emerging Ubiquitous Pathogen: Looking Beyond Contemporary Antibiotic Therapy. AB - Stenotrophomonas maltophilia is a commensal and an emerging pathogen earlier noted in broad-spectrum life threatening infections among the vulnerable, but more recently as a pathogen in immunocompetent individuals. The bacteria are consistently being implicated in necrotizing otitis, cutaneous infections including soft tissue infection and keratitis, endocarditis, meningitis, acute respiratory tract infection (RTI), bacteraemia (with/without hematological malignancies), tropical pyomyositis, cystic fibrosis, septic arthritis, among others. S. maltophilia is also an environmental bacteria occurring in water, rhizospheres, as part of the animals' microflora, in foods, and several other microbiota. This review highlights clinical reports on S. maltophilia both as an opportunistic and as true pathogen. Also, biofilm formation as well as quorum sensing, extracellular enzymes, flagella, pili/fimbriae, small colony variant, other virulence or virulence-associated factors, the antibiotic resistance factors, and their implications are considered. Low outer membrane permeability, natural MDR efflux systems, and/or resistance genes, resistance mechanisms like the production of two inducible chromosomally encoded beta-lactamases, and lack of carefully compiled patient history are factors that pose great challenges to the S. maltophilia control arsenals. The fluoroquinolone, some tetracycline derivatives and trimethoprim-sulphamethaxole (TMP-SMX) were reported as effective antibiotics with good therapeutic outcome. However, TMP-SMX resistance and allergies to sulfa together with high toxicity of fluoroquinolone are notable setbacks. S. maltophilia's production and sustenance of biofilm by quorum sensing enhance their virulence, resistance to antibiotics and gene transfer, making quorum quenching an imperative step in Stenotrophomonas control. Incorporating several other proven approaches like bioengineered bacteriophage therapy, Epigallocatechin-3-gallate (EGCG), essential oil, nanoemulsions, and use of cationic compounds are promising alternatives which can be incorporated in Stenotrophomonas control arsenal. PMID- 29250046 TI - The Emerging Fish Pathogen Flavobacterium spartansii Isolated from Chinook Salmon: Comparative Genome Analysis and Molecular Manipulation. AB - Flavobacterium spartansii strain T16T was isolated from a disease outbreak in hatchery-reared Chinook salmon (Oncorhynchus tshawytscha) fingerlings. To gain insight into its genomic content, structure and virulence pathogenesis factors, comparative genome analyses were performed using genomes from environmental and virulent Flavobacterium strains. F. spartansii shared low average nucleotide identity (ANI) to well-known fish-pathogenic flavobacteria (e.g., F. columnare, F. psychrophilum, and F. branchiophilum), indicating that it is a new and emerging fish pathogen. The genome in T16T had a length of 5,359,952 bp, a GC content 35.7%, and 4,422 predicted protein-coding sequences. Flavobacterium core genome analysis showed that the number of shared genes decreased with the addition of input genomes and converged at 1182 genes. At least 8 genomic islands and 5 prophages were predicted in T16T. At least 133 virulence factors associated with virulence in pathogenic bacteria were highly conserved in F. spartansii T16T. Furthermore, genes linked to virulence in other bacterial species (e.g., those encoding for a type IX secretion system, collagenase and hemolysin) were found in the genome of F. spartansii T16T and were conserved in most of the analyzed pathogenic Flavobacterium. F. spartansii was resistant to ampicillin and penicillin, consistent with the presence of multiple genes encoding diverse lactamases and the penicillin-binding protein in the genome. To allow for future investigations into F. spartansii virulence in vivo, a transposon-based random mutagenesis strategy was attempted in F. spartansii T16T using pHimarEm1. Four putative gliding motility deficient mutants were obtained and the insertion sites of pHimarEm1 in the genome of these mutants were characterized. In total, study results clarify some of the mechanisms by which emerging flavobacterial fish pathogens may cause disease and also provide direly needed tools to investigate their pathogenesis. PMID- 29250048 TI - Molecular Characterization of Prothionamide-Resistant Mycobacterium tuberculosis Isolates in Southern China. AB - Prothionamide (PTH) has been widely used in the treatment of tuberculosis (TB), especially multidrug resistant tuberculosis (MDR-TB), while data regarding prevalence of resistance-causing mutation is limited. In this study, we aimed to investigate the molecular characteristics of PTH-resistant MTB isolates, and also analyzed the risk factors for PTH resistance among Mycobacterium tuberculosis (MTB) isolates in southern China. A total of 282 MTB isolates were enrolled in from Guangzhou Chest Hospital. Among these isolates, 46 (16.3%) were resistant to PTH. Statistical analysis revealed that PTH resistance was more likely to be associated with resistance to levofloxacin (LFX; OR: 2.18, 95% CI: 1.02-4.63; P = 0.04). Of the 46 PTH-resistant MTB isolates, 37 (80.4%) isolates harbored 19 different mutation types, including 10 (21.7%) isolates with double nucleotide substitutions and 27 (58.7%) with single nucleotide substitution. The mutations in ethA (51.4%, 19/37) were most frequently observed among PTH-resistant isolates, followed by 16 (43.2%) in the promoter of inhA and 6 (16.2%) in inhA. In addition, no significant difference was found in the distribution of isolates with different mutation types between Beijing and non-Beijing genotypes (P > 0.05). In conclusion, our data demonstrate that high diversity of genetic mutations conferring PTH resistance is identified among MTB isolates from southern China. Mutations in inhA, ethA, mshA, and ndh genes confer increased resistance of MTB to PTH. Ancient Beijing genotype strains have higher proportion of drug resistance compared with modern Beijing strains. In addition, PTH resistance is more likely to be observed in the LFX-resistant MTB isolates. PMID- 29250047 TI - The Different Faces of Rolling-Circle Replication and Its Multifunctional Initiator Proteins. AB - Horizontal gene transfer (HGT) contributes greatly to the plasticity and evolution of prokaryotic and eukaryotic genomes. The main carriers of foreign DNA in HGT are mobile genetic elements (MGEs) that have extremely diverse genetic structures and properties. Various strategies are used for the maintenance and spread of MGEs, including (i) vegetative replication, (ii) transposition (and other types of recombination), and (iii) conjugal transfer. In many MGEs, all of these processes are dependent on rolling-circle replication (RCR). RCR is one of the most well characterized models of DNA replication. Although many studies have focused on describing its mechanism, the role of replication initiator proteins has only recently been subject to in-depth analysis, which indicates their involvement in multiple biological process associated with RCR. In this review, we present a general overview of RCR and its impact in HGT. We focus on the molecular characteristics of RCR initiator proteins belonging to the HUH and Rep_trans protein families. Despite analogous mechanisms of action these are distinct groups of proteins with different catalytic domain structures. This is the first review describing the multifunctional character of various types of RCR initiator proteins, including the latest discoveries in the field. Recent reports provide evidence that (i) proteins initiating vegetative replication (Rep) or mobilization for conjugal transfer (Mob) may also have integrase (Int) activity, (ii) some Mob proteins are capable of initiating vegetative replication (Rep activity), and (iii) some Rep proteins can act like Mob proteins to mobilize plasmid DNA for conjugal transfer. These findings have significant consequences for our understanding of the role of RCR, not only in DNA metabolism but also in the biology of many MGEs. PMID- 29250049 TI - Using Click-Chemistry for Visualizing in Situ Changes of Translational Activity in Planktonic Marine Bacteria. AB - A major challenge in microbial ecology is linking diversity and function to determine which microbes are actively contributing to processes occurring in situ. Bioorthogonal non-canonical amino acid tagging (BONCAT) is a promising technique for detecting and quantifying translationally active bacteria in the environment. This technique consists of incubating a bacterial sample with an analog of methionine and using click-chemistry to identify the cells that have incorporated the substrate. Here, we established an optimized protocol for the visualization of protein-synthesizing cells in oligotrophic waters that can be coupled with taxonomic identification using Catalyzed Reporter Deposition Fluorescent in Situ Hybridization. We also evaluated the use of this technique to track shifts in translational activity by comparing it with leucine incorporation, and used it to monitor temporal changes in both cultures and natural samples. Finally, we determined the optimal concentration and incubation time for substrate incorporation during BONCAT incubations at an oligotrophic site. Our results demonstrate that BONCAT is a fast and powerful semi quantitative approach to explore the physiological status of marine bacteria. PMID- 29250050 TI - Anilinopyrimidine Resistance in Botrytis cinerea Is Linked to Mitochondrial Function. AB - Crop protection anilinopyrimidine (AP) fungicides were introduced more than 20 years ago for the control of a range of diseases caused by ascomycete plant pathogens, and in particular for the control of gray mold caused by Botrytis cinerea. Although early mode of action studies suggested an inhibition of methionine biosynthesis, the molecular target of this class of fungicides was never fully clarified. Despite AP-specific resistance having been described in B. cinerea field isolates and in multiple other targeted species, the underlying resistance mechanisms were unknown. It was therefore expected that the genetic characterization of resistance mechanisms would permit the identification of the molecular target of these fungicides. In order to explore the widest range of possible resistance mechanisms, AP-resistant B. cinerea UV laboratory mutants were generated and the mutations conferring resistance were determined by combining whole-genome sequencing and reverse genetics. Genetic mapping from a cross between a resistant field isolate and a sensitive reference isolate was used in parallel and led to the identification of an additional molecular determinant not found from the characterized UV mutant collection. Together, these two approaches enabled the characterization of an unrivaled diversity of resistance mechanisms. In total, we report the elucidation of resistance conferring mutations within nine individual genes, two of which are responsible for almost all instances of AP resistance in the field. All identified resistance conferring genes encode proteins that are involved in mitochondrial processes, suggesting that APs primarily target the mitochondria. The functions of these genes and their possible interactions are discussed in the context of the potential mode of action for this important class of fungicides. PMID- 29250051 TI - Successful Establishment of Plasmids R1 and pMV158 in a New Host Requires the Relief of the Transcriptional Repression of Their Essential rep Genes. AB - Although differing in size, encoded traits, host range, and replication mechanism, both narrow-host-range theta-type conjugative enterobacterial plasmid R1 and promiscuous rolling-circle-type mobilizable streptococcal plasmid pMV158 encode a transcriptional repressor protein, namely CopB in R1 and CopG in pMV158, involved in replication control. The gene encoding CopB or CopG is cotranscribed with a downstream gene that encodes the replication initiator Rep protein of the corresponding plasmid. However, whereas CopG is an auto-repressor that inhibits transcription of the entire copG-repB operon, CopB is expressed constitutively and represses a second, downstream promoter that directs transcription of repA. As a consequence of the distinct regulatory pathways implied by CopB and CopG, these repressor proteins play a different role in control of plasmid replication during the steady state: while CopB has an auxiliary role by keeping repressed the regulated promoter whenever the plasmid copy number is above a low threshold, CopG plays a primary role by acting coordinately with RNAII. Here, we have studied the role of the regulatory circuit mediated by these transcriptional repressors during the establishment of these two plasmids in a new host cell, and found that excess Cop repressor molecules in the recipient cell result in a severe decrease in the frequency and/or the velocity of appearance of transformant colonies for the cognate plasmid but not for unrelated plasmids. Using the pMV158 replicon as a model system, together with highly sensitive real time qPCR and inverse PCR methods, we have also analyzed the effect of CopG on the kinetics of repopulation of the plasmid in Streptococcus pneumoniae. We show that, whereas in the absence of CopG pMV158 repopulation occurs mainly during the first 45 min following plasmid transfer, the presence of the transcriptional repressor in the recipient cell severely impairs the replicon repopulation and makes the plasmid replicate at approximately the same rate as the chromosome at any time after transformation, which results in maximal plasmid loss rate in the absence of selection. Overall, these findings indicate that unrepressed activity of the Cop-regulated promoter is crucial for the successful colonization of the recipient bacterial cells by the plasmid. PMID- 29250052 TI - Balanced Fertilization Decreases Environmental Filtering on Soil Bacterial Community Assemblage in North China. AB - Although increasing evidences have emerged for responses of soil microorganisms to fertilizations, the knowledge regarding community assemblages that cause variations in composition is still lacking, as well as the possible feedback to soil fertility. Phylogenetic conservatism of species indicates their similar environmental preferences and/or function traits and phylogenetic signals further can infer community assemblages and influenced ecological processes. Here, we calculated the mean pairwise phylogenetic distance and nearest relative index, characterizing phylogenetic signal and the undergone ecological process to evaluate the community assembly of soil bacterial phylotypes in 20-year fertilized soils. The bacterial community assembly is structured by environmental filtering, regardless of fertilization regime. Soil phosphorous (P) availability imposes selection on community assemblage and influences their community turnover among fertilizations. When P nutrient lacks, the effect of environmental filtering becomes stronger, hence bacterial functional traits become more coherent; this process results into increased intraspecific interactions characterized by co-occurrence network analysis. In contrast, when P nutrient becomes abundant, the environmental selection is mitigated; function traits are evened. This process reduces intraspecific interactions and increases carbon sequestration efficiency, which is finally of great favor to the increases in soil fertility. This study has made the first attempt, at the bacterial level, to understand how fertilization affects agroecosystems. When more phylogenetic information on how nutrient cycling-related microbes respond to fertilization becomes available, the systematic knowledge will eventually provide guidance to optimal fertilization strategies. PMID- 29250053 TI - Soil Bacterial Community Structure and Co-occurrence Pattern during Vegetation Restoration in Karst Rocky Desertification Area. AB - Vegetation restoration has been widely used in karst rocky desertification (KRD) areas of southwestern China, but the response of microbial community to revegetation has not been well characterized. We investigated the diversity, structure, and co-occurrence patterns of bacterial communities in soils of five vegetation types (grassland, shrubbery, secondary forest, pure plantation and mixed plantation) in KRD area using high-throughput sequencing of the 16S rRNA gene. Bray-Curtis dissimilarity analysis revealed that 15 bacterial community samples were clustered into five groups that corresponded very well to the five vegetation types. Shannon diversity was positively correlated with pH and Ca2+ content but negatively correlated with organic carbon, total nitrogen, and soil moisture. Redundancy analysis indicated that soil pH, Ca2+ content, organic carbon, total nitrogen, and soil moisture jointly influenced bacterial community structure. Co-occurrence network analysis revealed non-random assembly patterns of bacterial composition in the soils. Bryobacter, GR-WP33-30, and Rhizomicrobium were identified as keystone genera in co-occurrence network. These results indicate that diverse soil physicochemical properties and potential interactions among taxa during vegetation restoration may jointly affect the bacterial community structure in KRD regions. PMID- 29250054 TI - Candida albicans Hap43 Domains Are Required under Iron Starvation but Not Excess. AB - Iron availability is a central factor in infections, since iron is a critical micronutrient for all living organisms. The host employs both iron limitation and toxicity strategies to control microbial growth, and successful pathogens are able to tightly coordinate iron homeostasis in response to changing iron levels. As a commensal and opportunistic pathogen, Candida albicans copes with both iron deficiency and excess via the precise regulation of iron acquisition, consumption and storage. The C. albicans transcription factor Hap43 is known to be required for the iron starvation response, while specific domains of its ortholog, HapX, in Aspergillus fumigatus, were recently shown to regulate iron uptake and consumptions genes under both low and high iron levels. Therefore, we investigated the contribution of C. albicans Hap43 domains in response to changing iron levels. We found the C-terminus of Hap43 to be essential for the activation of iron uptake genes during iron starvation, whereas, in contrast to A. fumigatus, Hap43 was not required in mediating adaptation to iron resistance. These data indicate that the generally conserved metal acquisition systems in fungal pathogens can show individual adaptations to the host environment. PMID- 29250055 TI - The Microbiome of Potentially Malignant Oral Leukoplakia Exhibits Enrichment for Fusobacterium, Leptotrichia, Campylobacter, and Rothia Species. AB - Oral leukoplakia presents as a white patch on the oral mucosa and is recognized as having significant malignant potential. Although colonization of these patches with Candida albicans is common, little is known about the bacterial microbiota of these patches. In the current study we analyzed the microbiome of oral leukoplakia in 36 patients compared to healthy mucosal tissue from the same patients and healthy control subjects to determine if specific microbial enrichments could be identified early in the malignant process that could play a role in the progression of the disease. This was carried out by sequence analysis of the V1-V2 region of the bacterial 16S rRNA gene using the Illumina MiSeq. Oral leukoplakia exhibited increased abundance of Fusobacteria and reduced levels of Firmicutes (Metastats P < 0.01). Candida colonization was also more prevalent in leukoplakia patients relative to healthy controls (P = 0.025). Bacterial colonization patterns on oral leukoplakia were highly variable and five distinct bacterial clusters were discerned. These clusters exhibited co-occurrence of Fusobacterium, Leptotrichia, and Campylobacter species (Pearson P < 0.01), which is strikingly similar to the microbial co-occurrence patterns observed on colorectal cancers (Warren et al., 2013). Increased abundance of the acetaldehydogenic microorganism Rothia mucilaginosa was also apparent on oral leukoplakias from lingual sites (P 0.0012). Severe dysplasia was associated with elevated levels of Leptotrichia spp. and Campylobacter concisus (P < 0.05). Oral leukoplakia exhibits an altered microbiota that has similarities to the microbiome of colorectal cancer. PMID- 29250056 TI - Reduced Endoplasmic Reticulum Stress-Mediated Autophagy Is Required for Leptin Alleviating Inflammation in Adipose Tissue. AB - Leptin is an adipocyte-derived hormone and maintains adipose function under challenged conditions. Autophagy is also essential to maintain cellular homeostasis and regulate characteristics of adipose tissue. However, the effects of leptin on autophagy of adipocyte remain elusive. Here, we demonstrated endoplasmic reticulum (ER) stress and leptin were correlated with autophagy and inflammation by transcriptome sequencing of adipose tissue. Leptin-mediated inhibition of autophagy was involved in upstream reduction of ER stress proteins such as Chop, GRP78, and Atf4, since blockage of autophagy using pharmacological approach had no effect on tunicamycin-induced ER stress. Moreover, we determined KLF4, the potential transcriptional factor of Atf4, was required for the leptin mediated autophagy in the regulation of adipocyte inflammation. Importantly, ATF4 physically interacted with ATG5 and subsequently formed a complex to promote adipocyte autophagy. Further analysis revealed that Atg5, a core component of autophagosome, was the target for leptin-mediate autophagy. In addition, leptin alleviated ER stress-induced inflammation by reducing autophagy-mediated degradation of IkappaB in adipocytes. Exogenous leptin treatment also ameliorated autophagy and inflammation of white adipose tissue in ob/ob mice. Taken together, our results indicated that leptin inhibited ER stress-mediated autophagy and inflammation through the negatively regulation of Atf4/Atg5 complex in adipocytes. These findings identify a new potential means for intervention of autophagy to prevent or treat obese caused metabolic syndrome of mammals. PMID- 29250058 TI - Caveolin-1 and Caveolin-2 Can Be Antagonistic Partners in Inflammation and Beyond. AB - Caveolins, encoded by the CAV gene family, are the main protein components of caveolae. In most tissues, caveolin-1 (Cav-1) and caveolin-2 (Cav-2) are co expressed, and Cav-2 targeting to caveolae depends on the formation of heterooligomers with Cav-1. Notwithstanding, Cav-2 has unpredictable activities, opposing Cav-1 in the regulation of some cellular processes. While the major roles of Cav-1 as a modulator of cell signaling in inflammatory processes and in immune responses have been extensively discussed elsewhere, the aim of this review is to focus on data revealing the distinct activity of Cav-1 and Cav-2, which suggest that these proteins act antagonistically to fine-tune a variety of cellular processes relevant to inflammation. PMID- 29250061 TI - Editorial: Immunobiotics-Interactions of Beneficial Microbes with the Immune System. PMID- 29250057 TI - Update on Dendritic Cell-Induced Immunological and Clinical Tolerance. AB - Dendritic cells (DCs) as highly efficient antigen-presenting cells are at the interface of innate and adaptive immunity. As such, they are key mediators of immunity and antigen-specific immune tolerance. Due to their functional specialization, research efforts have focused on the characterization of DCs subsets involved in the initiation of immunogenic responses and in the maintenance of tissue homeostasis. Tolerogenic DCs (tolDCs)-based therapies have been designed as promising strategies to prevent and control autoimmune diseases as well as allograft rejection after solid organ transplantation (SOT). Despite successful experimental studies and ongoing phase I/II clinical trials using autologous tolDCs in patients with type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and in SOT recipients, additional basic research will be required to determine the optimal DC subset(s) and conditioning regimens for tolDCs-based treatments in vivo. In this review, we discuss the characteristics of human DCs and recent advances in their classification, as well as the role of DCs in immune regulation and their susceptibility to in vitro or in vivo manipulation for the development of tolerogenic therapies, with a focus on the potential of tolDCs for the treatment of autoimmune diseases and the prevention of allograft rejection after SOT. PMID- 29250059 TI - Survival Mechanisms Used by Some Leishmania Species to Escape Neutrophil Killing. AB - Neutrophils are the most abundant leukocytes in human blood. Upon microbial infection, they are massively and rapidly recruited from the circulation to sites of infection where they efficiently kill pathogens. To this end, neutrophils possess a variety of weapons that can be mobilized and become effective within hours following infection. However, several microbes including some Leishmania spp. have evolved a variety of mechanisms to escape neutrophil killing using these cells as a basis to better invade the host. In addition, neutrophils are also present in unhealing cutaneous lesions where their role remains to be defined. Here, we will review recent progress in the field and discuss the different strategies applied by some Leishmania parasites to escape from being killed by neutrophils and as recently described for Leishmania mexicana, even replicate within these cells. Subversion of neutrophil killing functions by Leishmania is a strategy that allows parasite spreading in the host with a consequent deleterious impact, transforming the primary protective role of neutrophils into a deleterious one. PMID- 29250060 TI - Epigenomic Views of Innate Lymphoid Cells. AB - The discovery of innate lymphoid cells (ILCs) with selective production of cytokines typically attributed to subsets of T helper cells forces immunologists to reassess the mechanisms by which selective effector functions arise. The parallelism between ILCs and T cells extends beyond these two cell types and comprises other innate-like T lymphocytes. Beyond the recognition of specialized effector functionalities in diverse lymphocytes, features typical of T cells, such as plasticity and memory, are also relevant for innate lymphocytes. Herein, we review what we have learned in terms of the molecular mechanisms underlying these shared functions, focusing on insights provided by next generation sequencing technologies. We review data on the role of lineage-defining- and signal-dependent transcription factors (TFs). ILC regulomes emerge developmentally whereas the much of the open chromatin regions of T cells are generated acutely, in an activation-dependent manner. And yet, these regions of open chromatin in T cells and ILCs have remarkable overlaps, suggesting that though accessibility is acquired by distinct modes, the end result is that convergent signaling pathways may be involved. Although much is left to be learned, substantial progress has been made in understanding how TFs and epigenomic status contribute to ILC biology in terms of differentiation, specification, and plasticity. PMID- 29250062 TI - Translating Mechanism of Regulatory Action of Tolerogenic Dendritic Cells to Monitoring Endpoints in Clinical Trials. AB - Tolerogenic dendritic cells (tolDCs) have reached patients with autoimmune and inflammatory disease, at least in clinical trials. The safety of tolDCs as intervention therapy has been established, but the capacity to modulate autoimmune response in vivo remains to be demonstrated. Studies have revealed a diversity of regulatory mechanisms that tolDCs may employ in vivo. These mechanisms differ between various types of modulated tolDC. The most often foreseen action of tolDCs is through regulatory polarization of naive T cells or activation of existing regulatory T cells, which should ultimately diminish autoimmune inflammation. Yet, selection of a target autoantigen remains critical to expedite tissue specific tolerance induction, while measuring immune modulation incited by tolDCs in vivo provides a great challenge. We will discuss the regulatory action of different types of tolDCs and the possible methods to monitor immunological efficacy endpoints for the next generation clinical trials. PMID- 29250063 TI - M(IL-4) Tissue Macrophages Support Efficient Interferon-Gamma Production in Antigen-Specific CD8+ T Cells with Reduced Proliferative Capacity. AB - CD8+ cytotoxic T cell (CTL) responses are necessary for the lysis of virally infected cells and control of infection. CTLs are activated when their TCRs bind a major histocompatibility complex (MHC)-I/peptide complex on the surface of antigen presenting cells such as macrophages (MPhi). It is now apparent that MPhi display remarkable plasticity in response to environmental signals to polarize into classically activated M(LPS + IFN-gamma) or alternatively activated M(IL-4). However, little is known about how MPhi activation status influences their antigen presentation function to CD8+ T cell in models of virus infection. Consequently, we tested how polarization of spleen-derived (Sp)-MPhi impacts direct presentation of viral antigens to influence effector and proliferative CD8+ T-cell responses. We show that M(IL-4) Sp-MPhi retain MHC-I surface expression and the ability to stimulate IFN-gamma production by CTL following peptide stimulation and lymphocytic choriomeningitis virus infection to levels similar to M0 and M(LPS + IFN-gamma) MPhi. However, memory CD8+ T cells cultured in the presence of M(IL-4) MPhi underwent significantly reduced proliferation and produced similar IFN-gamma levels as coculturing with M0 or M(LPS + IFN-gamma) cells. Thus, these results show a novel ability of polarized MPhi to regulate CD8+ T-cell proliferation and effector functions during virus infection. PMID- 29250064 TI - P17, an Original Host Defense Peptide from Ant Venom, Promotes Antifungal Activities of Macrophages through the Induction of C-Type Lectin Receptors Dependent on LTB4-Mediated PPARgamma Activation. AB - Despite the growing knowledge with regard to the immunomodulatory properties of host defense peptides, their impact on macrophage differentiation and on its associated microbicidal functions is still poorly understood. Here, we demonstrated that the P17, a new cationic antimicrobial peptide from ant venom, induces an alternative phenotype of human monocyte-derived macrophages (h-MDMs). This phenotype is characterized by a C-type lectin receptors (CLRs) signature composed of mannose receptor (MR) and Dectin-1 expression. Concomitantly, this activation is associated to an inflammatory profile characterized by reactive oxygen species (ROS), interleukin (IL)-1beta, and TNF-alpha release. P17 activated h-MDMs exhibit an improved capacity to recognize and to engulf Candida albicans through the overexpression both of MR and Dectin-1. This upregulation requires arachidonic acid (AA) mobilization and the activation of peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear receptor through the leukotriene B4 (LTB4) production. AA/LTB4/PPARgamma/Dectin-1-MR signaling pathway is crucial for P17-mediated anti-fungal activity of h-MDMs, as indicated by the fact that the activation of this axis by P17 triggered ROS production and inflammasome-dependent IL-1beta release. Moreover, we showed that the increased anti-fungal immune response of h-MDMs by P17 was dependent on intracellular calcium mobilization triggered by the interaction of P17 with pertussis toxin sensitive G-protein-coupled receptors on h-MDMs. Finally, we also demonstrated that P17-treated mice infected with C. albicans develop less severe gastrointestinal infection related to a higher efficiency of their macrophages to engulf Candida, to produce ROS and IL-1beta and to kill the yeasts. Altogether, these results identify P17 as an original activator of the fungicidal response of macrophages that acts upstream PPARgamma/CLRs axis and offer new immunomodulatory therapeutic perspectives in the field of infectious diseases. PMID- 29250065 TI - Differentiation and Functionality of Bone Marrow-Derived Mast Cells Depend on Varying Physiologic Oxygen Conditions. AB - Mast cells (MCs) are long-living multifunctional innate immune cells that originate from hematopoietic precursors and specifically differentiate in the destination tissue, e.g., skin, respiratory mucosa, intestine, where they mediate immune cell recruitment and antimicrobial defense. In vivo these tissues have characteristic physiological oxygen levels that are considerably lower than the atmospheric oxygen conditions (159 mmHg, 21% O2; 5% CO2) traditionally used to differentiate MCs and to study their functionality in vitro. Only little is known about the impact of physiological oxygen conditions on the differentiation process of MCs. This study aimed to characterize the differentiation of immature murine bone marrow-derived MCs under physioxia in vitro (7% O2; 53 mmHg; 5% CO2). Bone marrow-derived suspension cells were differentiated in the presence of interleukin-3 with continuous, non-invasive determination of the oxygen level using a Fibox4-PSt3 measurement system without technique-caused oxygen consumption. Trypan blue staining confirmed cellular viability during the specified period. Interestingly, MCs cultivated at 7% O2 showed a significantly delayed differentiation rate defined by CD117-positive cells, analyzed by flow cytometry, and reached >95% CD117 positive population at day 32 after isolation. Importantly, MCs differentiated under physioxia displayed a decreased transcript expression level of hif-1alpha and selected target genes vegf, il-6, and tnf alpha, but an increase of foxo3 and vhl expression compared to MCs cultivated under normoxia. Moreover, the production of reactive oxygen species as well as the amount of intracellular stored histamine was significantly lower in MCs differentiated under low oxygen levels, which might have consequences for their function such as immunomodulation of other immune cells. These results show for the first time that physioxia substantially affect maturation and the properties of MCs and highlight the need to study their function under physiologically relevant oxygen conditions. PMID- 29250066 TI - Dendritic Cells Transduced with Single Immunoglobulin IL-1-Related Receptor Exhibit Immature Properties and Prolong Islet Allograft Survival. AB - Members of toll-like receptor-interleukin 1 receptor signaling [TLR/IL-1R (TIR)] superfamily mediate maturation of dendritic cells (DCs) and launch immune response in transplanted organs. In this study, we hypothesized that TIR8, also known as single immunoglobulin IL-1-related receptor (SIGIRR) molecule, refrain DCs from maturation and induce immune tolerance of transplanted organ. DCs were transduced with the recombinant adenovirus Ad5F35 to highly express SIGIRR (DC SIGIRR), then injected to murine recipient before islet transplantation. It revealed that DCs transduced with SIGIRR had low expression of major histocompatibility and costimulatory molecules along with strong phagocytic ability in vitro assay. The data demonstrated that recipients treated with DC SIGIRR had satisfying islet allograft function and long survival times, with an increase of Treg and reduction of Th17 in both spleen and draining lymph nodes in vivo. Therefore, genetic modification of SIGIRR inhibits DC activation and maturation, affects differentiation of T cell subsets, protects allograft biological function, and prolongs graft survival. PMID- 29250068 TI - Cellular and Molecular Mechanisms of Anterior Chamber-Associated Immune Deviation (ACAID): What We Have Learned from Knockout Mice. AB - Anterior chamber-associated immune deviation (ACAID) is a well-known phenomenon that can occur after an antigen is introduced without any danger signal into the anterior chamber of a murine eye. It is reported to lead to an antigen-specific immune deviation throughout the body. Despite the relatively little evidence of this phenomenon in humans, it has been suggested as a potential prophylactic strategy in allograft rejections and in several autoimmune diseases. Cellular and molecular mechanisms of ACAID have been explored in different murine models mainly as proofs of concept, first by direct analyses of immune components in normal immunocompetent settings and by cell transfer experiments. Later, use of knockout (KO) mice has helped considerably to decipher ACAID mechanisms. However, several factors raise questions about the reliability and validity of studies using KO murine models. This mini-review summarizes results obtained with KO mice and discusses their advantages, their potential weaknesses, and their potential methods for further progress. PMID- 29250069 TI - Histamine Regulates the Inflammatory Profile of SOD1-G93A Microglia and the Histaminergic System Is Dysregulated in Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease where activated glia release pro-inflammatory cytokines that trigger a vicious cycle of neurodegeneration in the absence of resolution of inflammation. Given the well established role of histamine as a neuron-to-glia alarm signal implicated in brain disorders, the aim of this study was to investigate the expression and regulation of the histaminergic pathway in microglial activation in ALS mouse model and in humans. By examining the contribution of the histaminergic system to ALS, we found that particularly via H1 and H4 receptors, histamine promoted an anti-inflammatory profile in microglia from SOD1-G93A mice by modulating their activation state. A decrease in NF-kappaB and NADPH oxidase 2 with an increase in arginase 1 and P2Y12 receptor was induced by histamine only in the ALS inflammatory environment, but not in the healthy microglia, together with an increase in IL-6, IL-10, CD163, and CD206 phenotypic markers in SOD1-G93A cells. Moreover, histaminergic H1, H2, H3, and H4 receptors, and histamine metabolizing enzymes histidine decarboxylase, histamine N-methyltransferase, and diamine oxidase were found deregulated in spinal cord, cortex, and hypothalamus of SOD1 G93A mice during disease progression. Finally, by performing a meta-analysis study, we found a modulated expression of histamine-related genes in cortex and spinal cord from sporadic ALS patients. Our findings disclose that histamine acts as anti-inflammatory agent in ALS microglia and suggest a dysregulation of the histaminergic signaling in ALS. PMID- 29250067 TI - Group 2 Innate Lymphoid Cells Exhibit a Dynamic Phenotype in Allergic Airway Inflammation. AB - Group 2 innate lymphoid cells (ILC2) are implicated in allergic asthma as an early innate source of the type 2 cytokines IL-5 and IL-13. However, their induction in house dust mite (HDM)-mediated airway inflammation additionally requires T cell activation. It is currently unknown whether phenotypic differences exist between ILC2s that are activated in a T cell-dependent or T cell-independent fashion. Here, we compared ILC2s in IL-33- and HDM-driven airway inflammation. Using flow cytometry, we found that surface expression levels of various markers frequently used to identify ILC2s were dependent on their mode of activation, highly variable over time, and differed between tissue compartments, including bronchoalveolar lavage (BAL) fluid, lung, draining lymph nodes, and spleen. Whereas in vivo IL-33-activated BAL fluid ILC2s exhibited an almost uniform CD25+CD127+T1/ST2+ICOS+KLRG1+ phenotype, at a comparable time point after HDM exposure BAL fluid ILC2s had a very heterogeneous surface marker phenotype. A major fraction of HDM-activated ILC2s were CD25lowCD127+T1/ST2low ICOSlowKLRG1low, but nevertheless had the capacity to produce large amounts of type 2 cytokines. HDM-activated CD25low ILC2s in BAL fluid and lung rapidly reverted to CD25high ILC2s upon in vivo stimulation with IL-33. Genome-wide transcriptional profiling of BAL ILC2s revealed ~1,600 differentially expressed genes: HDM-stimulated ILC2s specifically expressed genes involved in the regulation of adaptive immunity through B and T cell interactions, whereas IL-33 stimulated ILC2s expressed high levels of proliferation-related and cytokine genes. In both airway inflammation models ILC2s were present in the lung submucosa close to epithelial cells, as identified by confocal microscopy. In chronic HDM-driven airway inflammation ILC2s were also found inside organized cellular infiltrates near T cells. Collectively, our findings show that ILC2s are phenotypically more heterogeneous than previously thought, whereby their surface marker and gene expression profile are highly dynamic. PMID- 29250070 TI - The Immunomodulatory Potential of tolDCs Loaded with Heat Shock Proteins. AB - Disease suppressive T cell regulation may depend on cognate interactions of regulatory T cells with self-antigens that are abundantly expressed in the inflamed tissues. Heat shock proteins (HSPs) are by their nature upregulated in stressed cells and therefore abundantly present as potential targets for such regulation. HSP immunizations have led to inhibition of experimentally induced inflammatory conditions in various models. However, re-establishment of tolerance in the presence of an ongoing inflammatory process has remained challenging. Since tolerogenic DCs (tolDCs) have the combined capacity of mitigating antigen specific inflammatory responses and of endowing T cells with regulatory potential, it seems attractive to combine the anti-inflammatory qualities of tolDCs with those of HSPs. PMID- 29250071 TI - Dimensionality of Motion and Binding Valency Govern Receptor-Ligand Kinetics As Revealed by Agent-Based Modeling. AB - Mathematical modeling and computer simulations have become an integral part of modern biological research. The strength of theoretical approaches is in the simplification of complex biological systems. We here consider the general problem of receptor-ligand binding in the context of antibody-antigen binding. On the one hand, we establish a quantitative mapping between macroscopic binding rates of a deterministic differential equation model and their microscopic equivalents as obtained from simulating the spatiotemporal binding kinetics by stochastic agent-based models. On the other hand, we investigate the impact of various properties of B cell-derived receptors-such as their dimensionality of motion, morphology, and binding valency-on the receptor-ligand binding kinetics. To this end, we implemented an algorithm that simulates antigen binding by B cell derived receptors with a Y-shaped morphology that can move in different dimensionalities, i.e., either as membrane-anchored receptors or as soluble receptors. The mapping of the macroscopic and microscopic binding rates allowed us to quantitatively compare different agent-based model variants for the different types of B cell-derived receptors. Our results indicate that the dimensionality of motion governs the binding kinetics and that this predominant impact is quantitatively compensated by the bivalency of these receptors. PMID- 29250072 TI - Alterations in B Cell Compartment Correlate with Poor Neutralization Response and Disease Progression in HIV-1 Infected Children. AB - Several B cell defects are reported in HIV-1 infected individuals including variation in B cell subsets, polyclonal B cell activation and exhaustion, with broadly neutralizing antibodies elicited in less than 10-20% of the infected population. HIV-1 disease progression is faster in children than adults. B Lymphocyte Stimulator (BLyS), expressed on dendritic cells (DCs), is a key regulator of B cell homeostasis. Understanding how DCs influence B cell phenotype and functionality (viral neutralization), thereby HIV-1 disease outcome in infected children, is important to develop interventional strategies for restoration of B cell function. In this study, a total of 38 vertically transmitted HIV-1 infected antiretroviral therapy (ART) naive children and 25 seronegative controls were recruited. Based on the CD4 counts and years post infection, infected children were categorized as long-term non-progressors (LTNPs) (n = 20) and progressors (n = 18). Eight of these progressors were followed up at 6-12 months post-ART. Percentages (%) of DCs, B cell subsets, and expression of BLyS on DCs were analyzed by flow-cytometry. Plasma levels of B cell growth factors were measured by ELISA and viral neutralization activity was determined using TZM-bl assay. Lower (%) of myeloid DCs (mDCs), plasmacytoid DCs, and high expression of BLyS on mDCs were observed in HIV-1 infected progressors than seronegative controls. Progressors showed lower % of naive B cells, resting memory B cells and higher % of mature activated, tissue-like memory B cells as compared to seronegative controls. Higher plasma levels of IL-4, IL-6, IL-10, and IgA were observed in progressors vs. seronegative controls. Plasma levels of IgG were high in progressors and in LTNPs than seronegative controls, suggesting persistence of hypergammaglobulinemia at all stages of disease. High plasma levels of BLyS in progressors positively correlated with poor viral neutralizing activity. Interestingly on follow up, treatment naive progressors, post-ART showed increase in resting memory B cells along with reduction in plasma BLyS levels that correlated with improvement in viral neutralization. This is the first study to demonstrate that reduction in plasma BLyS levels correlates with restoration of B cell function, in terms of viral neutralization in HIV-1 infected children. PMID- 29250074 TI - Early-Life Human Microbiota Associated With Childhood Allergy Promotes the T Helper 17 Axis in Mice. AB - The intestinal microbiota influences immune maturation during childhood, and is implicated in early-life allergy development. However, to directly study intestinal microbes and gut immune responses in infants is difficult. To investigate how different types of early-life gut microbiota affect immune development, we collected fecal samples from children with different allergic heredity (AH) and inoculated germ-free mice. Immune responses and microbiota composition were evaluated in the offspring of these mice. Microbial composition in the small intestine, the cecum and the colon were determined by 16S rRNA sequencing. The intestinal microbiota differed markedly between the groups of mice, but only exposure to microbiota associated with AH and known future allergy in children resulted in a T helper 17 (Th17)-signature, both systemically and in the gut mucosa in the mouse offspring. These Th17 responses could be signs of a particular microbiota and a shift in immune development, ultimately resulting in an increased risk of allergy. PMID- 29250073 TI - Myeloid Cell Interaction with HIV: A Complex Relationship. AB - Cells of the myeloid lineage, particularly macrophages, serve as primary hosts for HIV in vivo, along with CD4 T lymphocytes. Macrophages are present in virtually every tissue of the organism, including locations with negligible T cell colonization, such as the brain, where HIV-mediated inflammation may lead to pathological sequelae. Moreover, infected macrophages are present in multiple other tissues. Recent evidence obtained in humanized mice and macaque models highlighted the capacity of macrophages to sustain HIV replication in vivo in the absence of T cells. Combined with the known resistance of the macrophage to the cytopathic effects of HIV infection, such data bring a renewed interest in this cell type both as a vehicle for viral spread as well as a viral reservoir. While our understanding of key processes of HIV infection of macrophages is far from complete, recent years have nevertheless brought important insight into the uniqueness of the macrophage infection. Productive infection of macrophages by HIV can occur by different routes including from phagocytosis of infected T cells. In macrophages, HIV assembles and buds into a peculiar plasma membrane connected compartment that preexists to the infection. While the function of such compartment remains elusive, it supposedly allows for the persistence of infectious viral particles over extended periods of time and may play a role on viral transmission. As cells of the innate immune system, macrophages have the capacity to detect and respond to viral components. Recent data suggest that such sensing may occur at multiple steps of the viral cycle and impact subsequent viral spread. We aim to provide an overview of the HIV-macrophage interaction along the multiple stages of the viral life cycle, extending when pertinent such observations to additional myeloid cell types such as dendritic cells or blood monocytes. PMID- 29250075 TI - Identification and Characterization of Neoantigens As Well As Respective Immune Responses in Cancer Patients. AB - Cancer immunotherapy has recently emerged as a powerful tool for the treatment of diverse advanced malignancies. In particular, therapeutic application of immune checkpoint modulators, such as anti-CTLA4 or anti-PD-1/PD-L1 antibodies, have shown efficacy in a broad range of malignant diseases. Although pharmacodynamics of these immune modulators are complex, recent studies strongly support the notion that altered peptide ligands presented on tumor cells representing neoantigens may play an essential role in tumor rejection by T cells activated by anti-CTLA4 and anti-PD-1 antibodies. Neoantigens may have diverse sources as viral and mutated proteins. Moreover, posttranslational modifications and altered antigen processing may also contribute to the neoantigenic peptide ligand landscape. Different approaches of target identification are currently applied in combination with subsequent characterization of autologous and non-self T-cell responses against such neoantigens. Additional efforts are required to elucidate key characteristics and interdependences of neoantigens, immunodominance, respective T-cell responses, and the tumor microenvironment in order to define decisive determinants involved in effective T-cell-mediated tumor rejection. This review focuses on our current knowledge of identification and characterization of such neoantigens as well as respective T-cell responses. It closes with challenges to be addressed in future relevant for further improvement of immunotherapeutic strategies in malignant diseases. PMID- 29250076 TI - Macrophage-Microbe Interactions: Lessons from the Zebrafish Model. AB - Macrophages provide front line defense against infections. The study of macrophage-microbe interplay is thus crucial for understanding pathogenesis and infection control. Zebrafish (Danio rerio) larvae provide a unique platform to study macrophage-microbe interactions in vivo, from the level of the single cell to the whole organism. Studies using zebrafish allow non-invasive, real-time visualization of macrophage recruitment and phagocytosis. Furthermore, the chemical and genetic tractability of zebrafish has been central to decipher the complex role of macrophages during infection. Here, we discuss the latest developments using zebrafish models of bacterial and fungal infection. We also review novel aspects of macrophage biology revealed by zebrafish, which can potentiate development of new therapeutic strategies for humans. PMID- 29250077 TI - Mucosal-Associated Invariant T Cells in Regenerative Medicine. AB - Although antibiotics to inhibit bacterial growth and small compounds to interfere with the productive life cycle of human immunodeficiency virus (HIV) have successfully been used to control HIV infection, the recent emergence of the drug resistant bacteria and viruses poses a serious concern for worldwide public health. Despite intensive scrutiny in developing novel antibiotics and drugs to overcome these problems, there is a dilemma such that once novel antibiotics are launched in markets, sooner or later antibiotic-resistant strains emerge. Thus, it is imperative to develop novel methods to avoid this vicious circle. Here, we discuss the possibility of using induced pluripotent stem cell (iPSC)-derived, innate-like T cells to control infection and potential application of these cells for cancer treatment. Mucosal-associated invariant T (MAIT) cells belong to an emerging family of innate-like T cells that link innate immunity to adaptive immunity. MAIT cells exert effector functions without priming and clonal expansion like innate immune cells and relay the immune response to adaptive immune cells through production of relevant cytokines. With these characteristics, MAIT cells are implicated in a wide range of human diseases such as autoimmune, infectious, and metabolic diseases, and cancer. Circulating MAIT cells are often depleted by these diseases and often remain depleted even after appropriate remedy because MAIT cells are susceptible to activation-induced cell death and poor at proliferation in vivo, which threatens the integrity of the immune system. Because MAIT cells have a pivotal role in human immunity, supplementation of MAIT cells into immunocompromised patients suffering from severe depletion of these cells may help recapitulate or recover immunocompetence. The generation of MAIT cells from human iPSCs has made it possible to procure MAIT cells lost from disease. Such technology creates new avenues for cell therapy and regenerative medicine for difficult-to-cure infectious diseases and cancer and contributes to improvement of our welfare. PMID- 29250079 TI - HIV As Trojan Exosome: Immunological Paradox Explained? AB - The HIV pandemic is still a major global challenge, despite the widespread availability of antiretroviral drugs. An effective vaccine would be the ideal approach to bringing the pandemic to an end. However, developing an effective HIV vaccine has proven to be an elusive goal. Three major human HIV vaccine trials revealed a strong trend toward greater risk of infection among vaccine recipients versus controls. A similar observation was made in a macaque SIV vaccine study. The mechanism explaining this phenomenon is not known. Here, a model is presented that may explain the troubling results of vaccine studies and an immunological paradox of HIV pathogenesis: preferential infection of HIV-specific T cells. The central hypothesis of this perspective is that as "Trojan exosomes" HIV particles can directly activate HIV-specific T cells enhancing their susceptibility to infection. Understanding the biology of HIV as an exosome may provide insights that enable novel approaches to vaccine development. PMID- 29250078 TI - Mevalonate Metabolism in Immuno-Oncology. AB - Immuno-oncology not only refers to the multifaceted relationship between our immune system and a developing cancer but also includes therapeutic approaches that harness the body's immune system to fight cancer. The recognition that metabolic reprogramming governs immunity was a key finding with important implications for immuno-oncology. In this review, we want to explore how activation and differentiation-induced metabolic reprogramming affects the mevalonate pathway for cholesterol biosynthesis in immune and cancer cells. Glycolysis-fueled mevalonate metabolism is a critical pathway in immune effector cells, which may, however, be shared by cancer stem cells, complicating the development of therapeutic strategies. Additional engagement of fatty acidy oxidation, as it occurs in regulatory immune cells as well as in certain tumor types, may influence mevalonate pathway activity. Transcellular mevalonate metabolism may play an as yet unanticipated role in the crosstalk between the various cell types and may add another level of complexity. In humans, a subset of gammadelta T cells is specifically adapted to perform surveillance of mevalonate pathway dysregulation. While the mevalonate pathway remains an important target in immuno-oncology, in terms of personalized medicine, it may be the type or stage of a malignant disease that determines whether mevalonate metabolism requires training or attenuation. PMID- 29250080 TI - Molecular Diversity Analysis and Genetic Mapping of Pod Shatter Resistance Loci in Brassica carinata L. AB - Seed lost due to easy pod dehiscence at maturity (pod shatter) is a major problem in several members of Brassicaceae family. We investigated the level of pod shatter resistance in Ethiopian mustard (Brassica carinata) and identified quantitative trait loci (QTL) for targeted introgression of this trait in Ethiopian mustard and its close relatives of the genus Brassica. A set of 83 accessions of B. carinata, collected from the Australian Grains Genebank, was evaluated for pod shatter resistance based on pod rupture energy (RE). In comparison to B. napus (RE = 2.16 mJ), B. carinata accessions had higher RE values (2.53 to 20.82 mJ). A genetic linkage map of an F2 population from two contrasting B. carinata selections, BC73526 (shatter resistant with high RE) and BC73524 (shatter prone with low RE) comprising 300 individuals, was constructed using a set of 6,464 high quality DArTseq markers and subsequently used for QTL analysis. Genetic analysis of the F2 and F2:3 derived lines revealed five statistically significant QTL (LOD >= 3) that are linked with pod shatter resistance on chromosomes B1, B3, B8, and C5. Herein, we report for the first time, identification of genetic loci associated with pod shatter resistance in B. carinata. These characterized accessions would be useful in Brassica breeding programs for introgression of pod shatter resistance alleles in to elite breeding lines. Molecular markers would assist marker-assisted selection for tracing the introgression of resistant alleles. Our results suggest that the value of the germplasm collections can be harnessed through genetic and genomics tools. PMID- 29250081 TI - Cosmopolitan Species As Models for Ecophysiological Responses to Global Change: The Common Reed Phragmites australis. AB - Phragmites australis is a cosmopolitan grass and often the dominant species in the ecosystems it inhabits. Due to high intraspecific diversity and phenotypic plasticity, P. australis has an extensive ecological amplitude and a great capacity to acclimate to adverse environmental conditions; it can therefore offer valuable insights into plant responses to global change. Here we review the ecology and ecophysiology of prominent P. australis lineages and their responses to multiple forms of global change. Key findings of our review are that: (1) P. australis lineages are well-adapted to regions of their phylogeographic origin and therefore respond differently to changes in climatic conditions such as temperature or atmospheric CO2; (2) each lineage consists of populations that may occur in geographically different habitats and contain multiple genotypes; (3) the phenotypic plasticity of functional and fitness-related traits of a genotype determine the responses to global change factors; (4) genotypes with high plasticity to environmental drivers may acclimate or even vastly expand their ranges, genotypes of medium plasticity must acclimate or experience range-shifts, and those with low plasticity may face local extinction; (5) responses to ancillary types of global change, like shifting levels of soil salinity, flooding, and drought, are not consistent within lineages and depend on adaptation of individual genotypes. These patterns suggest that the diverse lineages of P. australis will undergo intense selective pressure in the face of global change such that the distributions and interactions of co-occurring lineages, as well as those of genotypes within-lineages, are very likely to be altered. We propose that the strong latitudinal clines within and between P. australis lineages can be a useful tool for predicting plant responses to climate change in general and present a conceptual framework for using P. australis lineages to predict plant responses to global change and its consequences. PMID- 29250082 TI - Physiological and Proteomic Analysis of the Rice Mutant cpm2 Suggests a Negative Regulatory Role of Jasmonic Acid in Drought Tolerance. AB - It is widely known that numerous adaptive responses of drought-stressed plants are stimulated by chemical messengers known as phytohormones. Jasmonic acid (JA) is one such phytohormone. But there are very few reports revealing its direct implication in drought related responses or its cross-talk with other phytohormones. In this study, we compared the morpho-physiological traits and the root proteome of a wild type (WT) rice plant with its JA biosynthesis mutant coleoptile photomorphogenesis 2 (cpm2), disrupted in the allene oxide cyclase (AOC) gene, for insights into the role of JA under drought. The mutant had higher stomatal conductance, higher water use efficiency and higher shoot ABA levels under severe drought as compared to the WT. Notably, roots of cpm2 were better developed compared to the WT under both, control and drought stress conditions. Root proteome was analyzed using the Tandem Mass Tag strategy to better understand this difference at the molecular level. Expectedly, AOC was unique but notably highly abundant under drought in the WT. Identification of other differentially abundant proteins (DAPs) suggested increased energy metabolism (i.e., increased mobilization of resources) and reactive oxygen species scavenging in cpm2 under drought. Additionally, various proteins involved in secondary metabolism, cell growth and cell wall synthesis were also more abundant in cpm2 roots. Proteome-guided transcript, metabolite, and histological analyses provided further insights into the favorable adaptations and responses, most likely orchestrated by the lack of JA, in the cpm2 roots. Our results in cpm2 are discussed in the light of JA crosstalk to other phytohormones. These results together pave the path for understanding the precise role of JA during drought stress in rice. PMID- 29250083 TI - Comparative Analysis of Chrysanthemum Stunt Viroid Accumulation and Movement in Two Chrysanthemum (Chrysanthemum morifolium) Cultivars with Differential Susceptibility to the Viroid Infection. AB - Chrysanthemum stunt viroid (CSVd) was inoculated into two chrysanthemum (Chrysanthemum morifolium) cultivars, the CSVd-susceptible cultivar Piato and the CSVd-resistant cultivar Mari Kazaguruma. For CSVd inoculation, grafting and Agrobacterium-mediated inoculation were used. In grafting experiments, CSVd was detectable in Mari Kazaguruma after grafting onto infected Piato, but after removal of infected rootstocks, CSVd could not be detected in the uppermost leaves. In agroinfection experiments, CSVd systemic infection was observed in Piato but not in Mari Kazaguruma. However, agro-inoculated leaves of Mari Kazaguruma accumulated circular CSVd RNA to levels equivalent to those in Piato at 7 days post-inoculation. In situ detection of CSVd in inoculated leaves revealed that CSVd was absent in phloem of Mari Kazaguruma, while CSVd strongly localized to this site in Piato. We hypothesize that CSVd resistance in Mari Kazaguruma relates not to CSVd replication but to CSVd movement in leaves. PMID- 29250084 TI - Diversity and Functional Analysis of the FeMo-Cofactor Maturase NifB. AB - One of the main hurdles to engineer nitrogenase in a non-diazotrophic host is achieving NifB activity. NifB is an extremely unstable and oxygen sensitive protein that catalyzes a low-potential SAM-radical dependent reaction. The product of NifB activity is called NifB-co, a complex [8Fe-9S-C] cluster that serves as obligate intermediate in the biosyntheses of the active-site cofactors of all known nitrogenases. Here we study the diversity and phylogeny of naturally occurring NifB proteins, their protein architecture and the functions of the distinct NifB domains in order to understand what defines a catalytically active NifB. Focus is on NifB from the thermophile Chlorobium tepidum (two-domain architecture), the hyperthermophile Methanocaldococcus infernus (single-domain architecture) and the mesophile Klebsiella oxytoca (two-domain architecture), showing in silico characterization of their nitrogen fixation (nif) gene clusters, conserved NifB motifs, and functionality. C. tepidum and M. infernus NifB were able to complement an Azotobacter vinelandii (DeltanifB) mutant restoring the Nif+ phenotype and thus demonstrating their functionality in vivo. In addition, purified C. tepidum NifB exhibited activity in the in vitro NifB dependent nitrogenase reconstitution assay. Intriguingly, changing the two-domain K. oxytoca NifB to single-domain by removal of the C-terminal NifX-like extension resulted in higher in vivo nitrogenase activity, demonstrating that this domain is not required for nitrogen fixation in mesophiles. PMID- 29250086 TI - Dianthus chinensis L.: The Structural Difference between Vascular Bundles in the Placenta and Ovary Wall Suggests Their Different Origin. AB - Dianthus chinensis is a perennial herbaceous plant with great ornamental, botanical, ecological, and medicinal value. The pistil of D. chinensis is composed of two fused carpels with free central placenta and two separate styles. The placenta is a columnar structure extending about two-thirds the length of the maturing fruit, which is typical of the Caryophyllaceous. Traditionally, free central placenta is thought to have evolved from axial placenta by septal disappearance, and axial placenta to have occurred through fusion of conduplicate carpels with marginal placenta. However, the traditional opinion is becoming more and more inconsistent with the new data gained in recent research of angiosperm systematics. To clarify the origin of D. chinensis pistil, the present anatomical study was carried out. The results show that the vascular system of placenta is independent to that of the ovary wall in D. chinensis. Moreover, in the central part of placenta there are one or two amphicribral bundles, and correspondingly numerous ones in the pistil which supply the ovules/seeds. It is obvious that the central amphicribral bundles in placenta are comparable to the counterparts in branches but not to those in leaves or their derivatives. Therefore, it is reasonable to deduce that the placenta of D. chinensis was not derived from conduplicate carpels through fusion of collateral vascular bundles, and actually a floral axis with ovules/seeds laterally adhering. On the contrary, the ovary wall was the lateral appendages of the floral axis. The result of the present study is completely in agreement with Unifying Theory, in which the placenta is taken as an ovule-bearing branch. Except for D. chinensis, the similar vascular organization has been observed in placenta of numerous isolated taxa. But till now, it is uncertain that whether this vascular organization pattern is popular in the whole angiosperms or not. More intensive and extensive investigations are needed. PMID- 29250085 TI - Metalaxyl Effects on Antioxidant Defenses in Leaves and Roots of Solanum nigrum L. AB - Overuse of pesticides has resulted in environmental problems, threating public health through accumulation in food chains. Phytoremediation is a powerful technique to clean up contaminated environments. However, it is necessary to unravel the metabolic mechanisms underlying phytoremediation in order to increase the efficiency of this process. Therefore, growth, physiological and biochemical responses in leaves and roots of Solanum nigrum L. exposed to the commonly used fungicide metalaxyl were investigated. This species shows characteristics that make it valuable as a potential tool for the remediation of organic pollutants. We found that once inside the plant, metalaxyl altered carbon metabolism, which resulted in a reduction of growth and lower biomass accumulation due to impairment of carbohydrate production (total soluble sugar, starch, rubisco) and increased photorespiration (glycolate oxidase, Gly/Ser ratio). A significant increase of antioxidant defenses (polyphenols, flavonoids, tocopherols, ascorbate, glutathione, superoxide dismutase, catalase, peroxidases, monodehydroascorbate- and dehydroascorbate reductase, gluthatione reductase) kept reactive oxygen species (ROS) levels under control (superoxide anion) leaving cell membranes undamaged. The results suggest that enhancing carbon assimilation and antioxidant capacity may be target parameters to improve this species' phytoremediation capacities. Highlights * Metalaxyl inhibits growth by reducing photosynthesis and inducing photorespiration * Elevated antioxidant defenses protect metalaxyl-treated plants from oxidative damage * Ascorbate and glutathione are key antioxidants in metalaxyl tolerance. PMID- 29250087 TI - Down-Regulation of OsEMF2b Caused Semi-sterility Due to Anther and Pollen Development Defects in Rice. AB - Anther and pollen development are crucial processes of plant male reproduction. Although a number of genes involved in these processes have been identified, the regulatory networks of pollen and anther development are still unclear. EMBRYONIC FLOWER 2b (OsEMF2b) is important for rice development. Its biological function in floral organ, flowering time and meristem determinacy have been well-studied, but its role, if only, on male reproduction is still unknown, because null mutants of OsEMF2b barely have anthers. In this study, we identified a weak allele of OsEMF2b, osemf2b-4. The T-DNA insertion was located in the promoter region of OsEMF2b, and OsEMF2b expression was significantly decreased in osemf2b-4. The osemf2b-4 mutant exhibited much more normal anthers than null mutants of OsEMF2b, and also showed defective floret development similar to null mutants. Cytological analysis showed various defects of anther wall and pollen development in osemf2b 4, such as slightly or extremely enlarged tapetum, irregular or normal morphology microspores, and partial or complete sterility. OsEMF2b was highly expressed in tapetum and microspores, and the protein was localized in the nucleus. The expression of 15 genes essential for anther and pollen development was investigated in both WT and osemf2b-4. Fourteen genes including GAMYB was up regulated, and only PTC1 was down-regulated in osemf2b-4. This suggests that up regulated GAMYB and down-regulated PTC1 might contribute to the defective anther and pollen development in osemf2b-4. Overall, our work suggests that OsEMF2b plays an essential role during post-meiotic anther and pollen development. PMID- 29250088 TI - Comparison of Genetic Diversity between Chinese and American Soybean (Glycine max (L.)) Accessions Revealed by High-Density SNPs. AB - Soybean is one of the most important economic crops for both China and the United States (US). The exchange of germplasm between these two countries has long been active. In order to investigate genetic relationships between Chinese and US soybean germplasm, 277 Chinese soybean accessions and 300 US soybean accessions from geographically diverse regions were analyzed using 5,361 SNP markers. The genetic diversity and the polymorphism information content (PIC) of the Chinese accessions was higher than that of the US accessions. Population structure analysis, principal component analysis, and cluster analysis all showed that the genetic basis of Chinese soybeans is distinct from that of the USA. The groupings observed in clustering analysis reflected the geographical origins of the accessions; this conclusion was validated with both genetic distance analysis and relative kinship analysis. FST-based and EigenGWAS statistical analysis revealed high genetic variation between the two subpopulations. Analysis of the 10 loci with the strongest selection signals showed that many loci were located in chromosome regions that have previously been identified as quantitative trait loci (QTL) associated with environmental-adaptation-related and yield-related traits. The pattern of diversity among the American and Chinese accessions should help breeders to select appropriate parental accessions to enhance the performance of future soybean cultivars. PMID- 29250089 TI - Abiotic Stress Phenotypes Are Associated with Conserved Genes Derived from Transposable Elements. AB - Plant phenomics offers unique opportunities to accelerate our understanding of gene function and plant response to different environments, and may be particularly useful for studying previously uncharacterized genes. One important type of poorly characterized genes is those derived from transposable elements (TEs), which have departed from a mobility-driven lifestyle to attain new adaptive roles for the host (exapted TEs). We used phenomics approaches, coupled with reverse genetics, to analyze T-DNA insertion mutants of both previously reported and novel protein-coding exapted TEs in the model plant Arabidopsis thaliana. We show that mutations in most of these exapted TEs result in phenotypes, particularly when challenged by abiotic stress. We built statistical multi-dimensional phenotypic profiles and compared them to wild-type and known stress responsive mutant lines for each particular stress condition. We found that these exapted TEs may play roles in responses to phosphate limitation, tolerance to high salt concentration, freezing temperatures, and arsenic toxicity. These results not only experimentally validate a large set of putative functional exapted TEs recently discovered through computational analysis, but also uncover additional novel phenotypes for previously well-characterized exapted TEs in A. thaliana. PMID- 29250090 TI - Inference of Transcription Regulatory Network in Low Phytic Acid Soybean Seeds. AB - A dominant loss of function mutation in myo-inositol phosphate synthase (MIPS) gene and recessive loss of function mutations in two multidrug resistant protein type-ABC transporter genes not only reduce the seed phytic acid levels in soybean, but also affect the pathways associated with seed development, ultimately resulting in low emergence. To understand the regulatory mechanisms and identify key genes that intervene in the seed development process in low phytic acid crops, we performed computational inference of gene regulatory networks in low and normal phytic acid soybeans using a time course transcriptomic data and multiple network inference algorithms. We identified a set of putative candidate transcription factors and their regulatory interactions with genes that have functions in myo-inositol biosynthesis, auxin-ABA signaling, and seed dormancy. We evaluated the performance of our unsupervised network inference method by comparing the predicted regulatory network with published regulatory interactions in Arabidopsis. Some contrasting regulatory interactions were observed in low phytic acid mutants compared to non-mutant lines. These findings provide important hypotheses on expression regulation of myo-inositol metabolism and phytohormone signaling in developing low phytic acid soybeans. The computational pipeline used for unsupervised network learning in this study is provided as open source software and is freely available at https://lilabatvt.github.io/LPANetwork/. PMID- 29250091 TI - Exogenous Calcium Enhances the Photosystem II Photochemistry Response in Salt Stressed Tall Fescue. AB - Calcium enhances turfgrass response to salt stress. However, little is known about PSII photochemical changes when exogenous calcium was applied in salinity stressed turfgrass. Here, we probe into the rearrangements of PSII electron transport and endogenous ion accumulation in tall fescue (Festuca arundinacea Schreber) treated with exogenous calcium under salt stress. Three-month-old seedlings of genotype "TF133" were subjected to the control (CK), salinity (S), salinity + calcium nitrate (SC), and salinity + ethylene glycol tetraacetic acid (SE). Calcium nitrate and ethylene glycol tetraacetic acid was used as exogenous calcium donor and calcium chelating agent respectively. At the end of a 5-day duration treatment, samples in SC regime had better photochemistry performance on several parameters than salinity only. Such as the Area (equal to the plastoquinone pool size), N (number of [Formula: see text] redox turnovers until Fm is reached), psiE0, or deltaRo (Efficiencdy/probability with which a PSII trapped electron is transferred from QA to QB or PSI acceptors), ABS/RC (Absorbed photon flux per RC). All the above suggested that calcium enhanced the electron transfer of PSII (especially beyond [Formula: see text]) and prevented reaction centers from inactivation in salt-stressed tall fescue. Furthermore, both grass shoot and root tissues generally accumulated more C, N, Ca2+, and K+ in the SC regime than S regime. Interrelated analysis indicated that psiE0, deltaRo, ABS/RC, C, and N content in shoots was highly correlated to each other and significantly positively related to Ca2+ and K+ content in roots. Besides, high salt increased ATP6E and CAMK2 transcription level in shoot at 1 and 5 day, respectively while exogenous calcium relieved it. In root, CAMK2 level was reduced by Salinity at 5 day and exogenous calcium recovered it. These observations involved in electron transport capacity and ion accumulation assist in understanding better the protective role of exogenous calcium in tall fescue under salt stress. PMID- 29250093 TI - XAP5 CIRCADIAN TIMEKEEPER Positively Regulates RESISTANCE TO POWDERY MILDEW8.1 Mediated Immunity in Arabidopsis. AB - Ectopic expression of the Arabidopsis RESISTANCE TO POWDERY MILDEW8.1 (RPW8.1) boosts pattern-triggered immunity leading to enhanced resistance to different pathogens in Arabidopsis and rice. However, the underlying regulatory mechanism remains largely elusive. Here, we report that XAP5 CIRCADIAN TIMEKEEPER (XCT, At2g21150) positively regulates RPW8.1-mediated cell death and disease resistance. Forward genetic screen identified the b3-17 mutant that exhibited less cell death and susceptibility to powdery mildew and bacterial pathogens. Map based cloning identified a G-to-A point mutation at the 3' splice site of the 8th intron, which resulted in splice shift to 8-bp down-stream of the original splice site of XCT in b3-17, and introduced into a stop codon after two codons leading to a truncated XCT. XCT has previously been identified as a circadian clock gene required for small RNA biogenesis and acting down-stream of ETHYLENE-INSENSITIVE3 (EIN3) in the ethylene-signaling pathway. Here we further showed that mutation or down-regulation of XCT by artificial microRNA reduced RPW8.1-mediated immunity in R1Y4, a transgenic line expressing RPW8.1-YFP from the RPW8.1 native promoter. On the contrary, overexpression of XCT in R1Y4 background enhanced RPW8.1-mediated cell death, H2O2 production and resistance against powdery mildew. Consistently, the expression of RPW8.1 was down- and up-regulated in xct mutant and XCT overexpression lines, respectively. Taken together, these results indicate that XCT positively regulates RPW8.1-mediated cell death and disease resistance, and provide new insight into the regulatory mechanism of RPW8.1-mediated immunity. PMID- 29250094 TI - Variability of Pyrrolizidine Alkaloid Occurrence in Species of the Grass Subfamily Pooideae (Poaceae). AB - Pyrrolizidine alkaloids (PAs) are a class of secondary metabolites found in various unrelated angiosperm lineages including cool-season grasses (Poaceae, subfamily Pooideae). Thesinine conjugates, saturated forms of PA that are regarded as non-toxic, have been described to occur in the two grass species Lolium perenne and Festuca arundinacea (Poaceae, subfamily Pooideae). In a wider screen, we tested various species of the Pooideae lineage, grown under controlled conditions, for their ability to produce thesinine conjugates or related structures. Using an LC-MS based targeted metabolomics approach we were able to show that PA biosynthesis in grasses is limited to a group of very closely related Pooideae species that produce a limited diversity of PA structures. High variability in PA levels was observed even between individuals of the same species. These individual accumulation patterns are discussed with respect to a possible function and evolution of this type of alkaloid. PMID- 29250092 TI - Arabidopsis TCP Transcription Factors Interact with the SUMO Conjugating Machinery in Nuclear Foci. AB - In Arabidopsis more than 400 proteins have been identified as SUMO targets, both in vivo and in vitro. Among others, transcription factors (TFs) are common targets for SUMO conjugation. Here we aimed to exhaustively screen for TFs that interact with the SUMO machinery using an arrayed yeast two-hybrid library containing more than 1,100 TFs. We identified 76 interactors that foremost interact with the SUMO conjugation enzyme SCE1 and/or the SUMO E3 ligase SIZ1. These interactors belong to various TF families, which control a wide range of processes in plant development and stress signaling. Amongst these interactors, the TCP family was overrepresented with several TCPs interacting with different proteins of the SUMO conjugation cycle. For a subset of these TCPs we confirmed that the catalytic site of SCE1 is essential for this interaction. In agreement, TCP1, TCP3, TCP8, TCP14, and TCP15 were readily SUMO modified in an E. coli sumoylation assay. Strikingly, these TCP-SCE1 interactions were found to redistribute these TCPs into nuclear foci/speckles, suggesting that these TCP foci represent sites for SUMO (conjugation) activity. PMID- 29250095 TI - Biochemical and Transcriptional Regulation of Membrane Lipid Metabolism in Maize Leaves under Low Temperature. AB - Membrane lipid modulation is one of the major strategies plants have developed for cold acclimation. In this study, a combined lipidomic and transcriptomic analysis was conducted, and the changes in glycerolipids contents and species, and transcriptional regulation of lipid metabolism in maize leaves under low temperature treatment (5 degrees C) were investigated. The lipidomic analysis showed an increase in the phospholipid phosphatidic acid (PA) and a decrease in phosphatidylcholine (PC). And an increase in digalactosyldiacylglycerol and a decrease in monogalactosyldiacylglycerol of the galactolipid class. The results implied an enhanced turnover of PC to PA to serve as precursors for galactolipid synthesis under following low temperature treatment. The analysis of changes in abundance of various lipid molecular species suggested major alterations of different pathways of plastidic lipids synthesis in maize under cold treatment. The synchronous transcriptomic analysis revealed that genes involved in phospholipid and galactolipid synthesis pathways were significantly up-regulated, and a comprehensive gene-metabolite network was generated illustrating activated membrane lipids adjustment in maize leaves following cold treatment. This study will help to understand the regulation of glycerolipids metabolism at both biochemical and molecular biological levels in 18:3 plants and to decipher the roles played by lipid remodeling in cold response in major field crop maize. PMID- 29250096 TI - Methylation Sensitive Amplification Polymorphism Sequencing (MSAP-Seq)-A Method for High-Throughput Analysis of Differentially Methylated CCGG Sites in Plants with Large Genomes. AB - Epigenetic mechanisms, including histone modifications and DNA methylation, mutually regulate chromatin structure, maintain genome integrity, and affect gene expression and transposon mobility. Variations in DNA methylation within plant populations, as well as methylation in response to internal and external factors, are of increasing interest, especially in the crop research field. Methylation Sensitive Amplification Polymorphism (MSAP) is one of the most commonly used methods for assessing DNA methylation changes in plants. This method involves gel based visualization of PCR fragments from selectively amplified DNA that are cleaved using methylation-sensitive restriction enzymes. In this study, we developed and validated a new method based on the conventional MSAP approach called Methylation Sensitive Amplification Polymorphism Sequencing (MSAP-Seq). We improved the MSAP-based approach by replacing the conventional separation of amplicons on polyacrylamide gels with direct, high-throughput sequencing using Next Generation Sequencing (NGS) and automated data analysis. MSAP-Seq allows for global sequence-based identification of changes in DNA methylation. This technique was validated in Hordeum vulgare. However, MSAP-Seq can be straightforwardly implemented in different plant species, including crops with large, complex and highly repetitive genomes. The incorporation of high throughput sequencing into MSAP-Seq enables parallel and direct analysis of DNA methylation in hundreds of thousands of sites across the genome. MSAP-Seq provides direct genomic localization of changes and enables quantitative evaluation. We have shown that the MSAP-Seq method specifically targets gene containing regions and that a single analysis can cover three-quarters of all genes in large genomes. Moreover, MSAP-Seq's simplicity, cost effectiveness, and high-multiplexing capability make this method highly affordable. Therefore, MSAP Seq can be used for DNA methylation analysis in crop plants with large and complex genomes. PMID- 29250097 TI - Genetic Parameters and the Impact of Off-Types for Theobroma cacao L. in a Breeding Program in Brazil. AB - Breeding programs of cacao (Theobroma cacao L.) trees share the many challenges of breeding long-living perennial crops, and genetic progress is further constrained by both the limited understanding of the inheritance of complex traits and the prevalence of technical issues, such as mislabeled individuals (off-types). To better understand the genetic architecture of cacao, in this study, 13 years of phenotypic data collected from four progeny trials in Bahia, Brazil were analyzed jointly in a multisite analysis. Three separate analyses (multisite, single site with and without off-types) were performed to estimate genetic parameters from statistical models fitted on nine important agronomic traits (yield, seed index, pod index, % healthy pods, % pods infected with witches broom, % of pods other loss, vegetative brooms, diameter, and tree height). Genetic parameters were estimated along with variance components and heritabilities from the multisite analysis, and a trial was fingerprinted with low-density SNP markers to determine the impact of off-types on estimations. Heritabilities ranged from 0.37 to 0.64 for yield and its components and from 0.03 to 0.16 for disease resistance traits. A weighted index was used to make selections for clonal evaluation, and breeding values estimated for the parental selection and estimation of genetic gain. The impact of off-types to breeding progress in cacao was assessed for the first time. Even when present at <5% of the total population, off-types altered selections by 48%, and impacted heritability estimations for all nine of the traits analyzed, including a 41% difference in estimated heritability for yield. These results show that in a mixed model analysis, even a low level of pedigree error can significantly alter estimations of genetic parameters and selections in a breeding program. PMID- 29250098 TI - Reconstruction of Oryza sativa indica Genome Scale Metabolic Model and Its Responses to Varying RuBisCO Activity, Light Intensity, and Enzymatic Cost Conditions. AB - To combat decrease in rice productivity under different stresses, an understanding of rice metabolism is needed. Though there are different genome scale metabolic models (GSMs) of Oryza sativa japonica, no GSM with gene-protein reaction association exist for Oryza sativa indica. Here, we report a GSM, OSI1136 of O.s. indica, which includes 3602 genes and 1136 metabolic reactions and transporters distributed across the cytosol, mitochondrion, peroxisome, and chloroplast compartments. Flux balance analysis of the model showed that for varying RuBisCO activity (Vc/Vo) (i) the activity of the chloroplastic malate valve increases to transport reducing equivalents out of the chloroplast under increased photorespiratory conditions and (ii) glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate kinase can act as source of cytosolic ATP under decreased photorespiration. Under increasing light conditions we observed metabolic flexibility, involving photorespiration, chloroplastic triose phosphate and the dicarboxylate transporters of the chloroplast and mitochondrion for redox and ATP exchanges across the intracellular compartments. Simulations under different enzymatic cost conditions revealed (i) participation of peroxisomal glutathione-ascorbate cycle in photorespiratory H2O2 metabolism (ii) different modes of the chloroplastic triose phosphate transporters and malate valve, and (iii) two possible modes of chloroplastic Glu-Gln transporter which were related with the activity of chloroplastic and cytosolic isoforms of glutamine synthetase. Altogether, our results provide new insights into plant metabolism. PMID- 29250099 TI - Dissection of Recombination Attributes for Multiple Maize Populations Using a Common SNP Assay. AB - Recombination is a vital characteristic for quantitative trait loci mapping and breeding to enhance the yield potential of maize. However, recombination characteristics in globally used segregating populations have never been evaluated at similar genetic marker densities. This study aimed to divulge the characteristics of recombination events, recombinant chromosomal segments, and recombination frequency for four dissimilar populations. These populations were doubled haploid (DH), recombination inbred line (RIL), intermated B73xMo17 (IBM), and multi-parent advanced generation inter-cross (MAGIC), using the Illumina MaizeSNP50 BeadChip to provide markers. Our results revealed that the average number of recombination events was 16, 41, 72, and 86 per line in DH, RIL, IBM, and MAGIC populations, respectively. Accordingly, the average length of recombinant chromosomal segments was 84.8, 47.3, 29.2, and 20.4 Mb in DH, RIL, IBM, and MAGIC populations, respectively. Furtherly, the recombination frequency varied in different genomic regions and population types [DH (0-12.7 cM/Mb), RIL (0-15.5 cM/Mb), IBM (0-24.1 cM/Mb), MAGIC (0-42.3 cM/Mb)]. Utilizing different sub-sets of lines, the recombination bin number and size were analyzed in each population. Additionally, different sub-sets of markers and lines were employed to estimate the recombination bin number and size via formulas for relationship in these populations. The relationship between recombination events and recombination bin length was also examined. Our results contribute to determining the most suitable number of genetic markers, lines in each population, and population type for successful mapping and breeding. PMID- 29250100 TI - Corrigendum: The Comparison of Expressed Candidate Secreted Proteins from Two Arbuscular Mycorrhizal Fungi Unravels Common and Specific Molecular Tools to Invade Different Host Plants. AB - [This corrects the article on p. 124 in vol. 8, PMID: 28223991.]. PMID- 29250101 TI - Perspective: Is Random Monoallelic Expression a Contributor to Phenotypic Variability of Autosomal Dominant Disorders? AB - Several factors have been proposed as contributors to interfamilial and intrafamilial phenotypic variability in autosomal dominant disorders, including allelic variation, modifier genes, environmental factors and complex genetic and environmental interactions. However, regardless of the similarity of genetic background and environmental factors, asymmetric limb or trunk anomalies in a single individual and variable manifestation between monozygotic twins have been observed, indicating other mechanisms possibly involved in expressivity of autosomal dominant diseases. One such example is Holt-Oram syndrome (HOS), which is characterized by congenital cardiac defects and forelimb anomalies, mainly attributed to mutations in the TBX5 gene. We hypothesize that monoallelic expression of the TBX5 gene occurs during embryo development, and, in the context of a mutation, random monoallelic expression (RME) can create discrepant functions in a proportion of cells and thus contribute to variable phenotypes. A hybrid mouse model was used to investigate the occurrence of RME with the Tbx5 gene, and single-cell reverse transcription PCR and restriction digestion were performed for limb bud cells from developing embryos (E11.5) of the hybrid mice. RME of Tbx5 was observed in approximately two-thirds of limb bud cells. These results indicate that RME of the Tbx5 gene occurs frequently during embryo development, resulting in a mosaic expression signature (monoallelic, biallelic, or null) that may provide a potential explanation for the widespread phenotypic variability in HOS. This model will further provide novel insights into the variability of autosomal dominant traits and a better understanding of the complex expressivity of disease conditions. PMID- 29250103 TI - Single-Molecule Long-Read Transcriptome Dataset of Halophyte Halogeton glomeratus. PMID- 29250102 TI - Analysis of the Expression of Repetitive DNA Elements in Osteosarcoma. AB - Osteosarcoma (OS) is a rare malignant bone tumor. It affects mostly young persons and has poor outcome with the present treatment. No improvement was observed since the introduction of chemotherapy. The better understanding of osteosarcoma development could indicate better management strategy. Repetitive DNA elements were found to play a role in cancer mechanism especially in epithelial tumors but not yet analyzed in osteosarcoma. We conducted the study to analyse the expression profile of repetitive elements (RE) in osteosarcoma. Methods: Fresh bone paired (tumor and normal bone) samples were obtained from excised parts of tumors of 18 patients with osteosarcoma. We performed sequencing of RNA extracted from 36 samples (18 tumor tissues and 18 normal bone for controls), mapped raw reads to the human genome and identified the REs. EdgeR package was used to analyse the difference in expression of REs between osteosarcoma and normal bone. Results: 82 REs were found differentially expressed (FDR < 0.05) between osteosarcoma and normal bone. Out of all significantly changed REs, 35 were upregulated and 47 were downregulated. HERVs (THE1C-int, LTR5, MER57F and MER87B) and satellite elements (HSATII, ALR-alpha) were the most significantly differential expressed elements between osteosarcoma and normal tissues. These results suggest significant impact of REs in the osteosarcoma. The role of REs should be further studied to understand the mechanism they have in the genesis of osteosarcoma. PMID- 29250105 TI - Dietary sugar and Barrett's esophagus. AB - Introduction: Barrett's esophagus (BE) represents the premalignant morphology of gastroesophageal reflux disease (GERD). Evidence indicates a positive correlation between GERD vs. obesity and increased sugar consumption. Methods: Here we analyzed recently published data (2006-2017) on the role of dietary sugar intake for BE development (main focus year 2017). Results: Recent investigations found a positive association between obesity, hip waist ratio and dietary sugar intake and Barrett's esophagus. Conclusion: Sugar intake positively associates with BE. A low carbohydrate diet should be recommended for persons with BE and GERD. PMID- 29250104 TI - The effect of future ambient air pollution on human premature mortality to 2100 using output from the ACCMIP model ensemble. AB - Ambient air pollution from ground-level ozone and fine particulate matter (PM2.5) is associated with premature mortality. Future concentrations of these air pollutants will be driven by natural and anthropogenic emissions and by climate change. Using anthropogenic and biomass burning emissions projected in the four Representative Concentration Pathway scenarios (RCPs), the ACCMIP ensemble of chemistry-climate models simulated future concentrations of ozone and PM2.5 at selected decades between 2000 and 2100. We use output from the ACCMIP ensemble, together with projections of future population and baseline mortality rates, to quantify the human premature mortality impacts of future ambient air pollution. Future air pollution-related premature mortality in 2030, 2050 and 2100 is estimated for each scenario and for each model using a health impact function based on changes in concentrations of ozone and PM2.5 relative to 2000 and projected future population and baseline mortality rates. Additionally, the global mortality burden of ozone and PM2.5 in 2000 and each future period is estimated relative to 1850 concentrations, using present-day and future population and baseline mortality rates. The change in future ozone concentrations relative to 2000 is associated with excess global premature mortality in some scenarios/periods, particularly in RCP8.5 in 2100 (316 thousand deaths/year), likely driven by the large increase in methane emissions and by the net effect of climate change projected in this scenario, but it leads to considerable avoided premature mortality for the three other RCPs. However, the global mortality burden of ozone markedly increases from 382,000 (121,000 to 728,000) deaths/year in 2000 to between 1.09 and 2.36 million deaths/year in 2100, across RCPs, mostly due to the effect of increases in population and baseline mortality rates. PM2.5 concentrations decrease relative to 2000 in all scenarios, due to projected reductions in emissions, and are associated with avoided premature mortality, particularly in 2100: between -2.39 and -1.31 million deaths/year for the four RCPs. The global mortality burden of PM2.5 is estimated to decrease from 1.70 (1.30 to 2.10) million deaths/year in 2000 to between 0.95 and 1.55 million deaths/year in 2100 for the four RCPs, due to the combined effect of decreases in PM2.5 concentrations and changes in population and baseline mortality rates. Trends in future air pollution-related mortality vary regionally across scenarios, reflecting assumptions for economic growth and air pollution control specific to each RCP and region. Mortality estimates differ among chemistry-climate models due to differences in simulated pollutant concentrations, which is the greatest contributor to overall mortality uncertainty for most cases assessed here, supporting the use of model ensembles to characterize uncertainty. Increases in exposed population and baseline mortality rates of respiratory diseases magnify the impact on premature mortality of changes in future air pollutant concentrations and explain why the future global mortality burden of air pollution can exceed the current burden, even where air pollutant concentrations decrease. PMID- 29250106 TI - Update on the management of Barrett's esophagus in Austria. AB - Background: Barrett's esophagus (BE) is the premalignant manifestation of gastroesophageal reflux disease (GERD). Radiofrequency ablation (RFA) with and without endoscopic resection (ER) is a novel treatment for BE. Methods: Here we present a single-center update of the recommendations of a recent (June 2015) interdisciplinary expert panel meeting on the management of BE with dysplasia as well as cancer-positive and cancer-negative BE. We conducted a PubMed search of studies published in 2016 and 2017 on the topic of BE and RFA. Results: Our update reconfirms that BE positive for T1a cancer as well as low- and high-grade dysplasia justifies the use of RFA +/- ER, offering an 80-100% rate of BE clearance. RFA +/- ER of dysplastic BE is tenfold more effective for cancer prevention when compared with surveillance. Risk factors for recurrence and follow-up treatments include baseline histopathology (dysplasia/T1a cancer), esophagitis, hiatal hernia >3 cm, smoking habits, BE segments >3 cm, and >10 years of GERD symptoms. A baseline diagnosis for dysplasia and T1a cancer should include a second expert pathologist opinion. Recent data justify the use of RFA for nondysplastic BE only in controlled clinical trials. Antireflux surgery can be offered to those with function-test-proven, GERD-symptom-positive BE before, during, or after RFA +/- ER. Additionally, there is growing evidence that the intake of a sugar-rich diet is positively correlated with the development of GERD, BE, and cancer. Conclusion: RFA +/- ER should be offered for dysplastic BE and T1a cancer after ER as well as for nondysplastic BE with additional risk factors in controlled trials. Antireflux surgery can be offered to patients with function-test-proven GERD-symptom-positive BE. Diet considerations should be included in the management of GERD and BE. PMID- 29250107 TI - Narrow-Energy-Width CT Based on Multivoltage X-Ray Image Decomposition. AB - A polychromatic X-ray beam causes the grey of the reconstructed image to depend on its position within a solid and the material being imaged. This factor makes quantitative measurements via computed tomography (CT) imaging very difficult. To obtain a narrow-energy-width reconstructed image, we propose a model to decompose multivoltage X-ray images into many narrow-energy-width X-ray images by utilizing the low frequency characteristics of X-ray scattering. It needs no change of hardware in the typical CT system. Solving the decomposition model, narrow-energy width projections are obtained and it is used to reconstruct the image. A cylinder composed of aluminum and silicon is used in a verification experiment. Some of the reconstructed images could be regarded as real narrow-energy-width reconstructed images, which demonstrates the effectiveness of the proposed method. PMID- 29250108 TI - Convolutional Neural Networks with 3D Input for P300 Identification in Auditory Brain-Computer Interfaces. AB - From allowing basic communication to move through an environment, several attempts are being made in the field of brain-computer interfaces (BCI) to assist people that somehow find it difficult or impossible to perform certain activities. Focusing on these people as potential users of BCI, we obtained electroencephalogram (EEG) readings from nine healthy subjects who were presented with auditory stimuli via earphones from six different virtual directions. We presented the stimuli following the oddball paradigm to elicit P300 waves within the subject's brain activity for later identification and classification using convolutional neural networks (CNN). The CNN models are given a novel single trial three-dimensional (3D) representation of the EEG data as an input, maintaining temporal and spatial information as close to the experimental setup as possible, a relevant characteristic as eliciting P300 has been shown to cause stronger activity in certain brain regions. Here, we present the results of CNN models using the proposed 3D input for three different stimuli presentation time intervals (500, 400, and 300 ms) and compare them to previous studies and other common classifiers. Our results show >80% accuracy for all the CNN models using the proposed 3D input in single trial P300 classification. PMID- 29250109 TI - High Performance Implementation of 3D Convolutional Neural Networks on a GPU. AB - Convolutional neural networks have proven to be highly successful in applications such as image classification, object tracking, and many other tasks based on 2D inputs. Recently, researchers have started to apply convolutional neural networks to video classification, which constitutes a 3D input and requires far larger amounts of memory and much more computation. FFT based methods can reduce the amount of computation, but this generally comes at the cost of an increased memory requirement. On the other hand, the Winograd Minimal Filtering Algorithm (WMFA) can reduce the number of operations required and thus can speed up the computation, without increasing the required memory. This strategy was shown to be successful for 2D neural networks. We implement the algorithm for 3D convolutional neural networks and apply it to a popular 3D convolutional neural network which is used to classify videos and compare it to cuDNN. For our highly optimized implementation of the algorithm, we observe a twofold speedup for most of the 3D convolution layers of our test network compared to the cuDNN version. PMID- 29250110 TI - A Time-Series Water Level Forecasting Model Based on Imputation and Variable Selection Method. AB - Reservoirs are important for households and impact the national economy. This paper proposed a time-series forecasting model based on estimating a missing value followed by variable selection to forecast the reservoir's water level. This study collected data from the Taiwan Shimen Reservoir as well as daily atmospheric data from 2008 to 2015. The two datasets are concatenated into an integrated dataset based on ordering of the data as a research dataset. The proposed time-series forecasting model summarily has three foci. First, this study uses five imputation methods to directly delete the missing value. Second, we identified the key variable via factor analysis and then deleted the unimportant variables sequentially via the variable selection method. Finally, the proposed model uses a Random Forest to build the forecasting model of the reservoir's water level. This was done to compare with the listing method under the forecasting error. These experimental results indicate that the Random Forest forecasting model when applied to variable selection with full variables has better forecasting performance than the listing model. In addition, this experiment shows that the proposed variable selection can help determine five forecast methods used here to improve the forecasting capability. PMID- 29250111 TI - Ruling Out Brain CT Contraindications prior to Intravenous Thrombolysis: Diagnostic Equivalence between a Primary Interpretation Workstation and a Mobile Tablet Computer. AB - Objective: The aim of this study was to evaluate the equivalence of brain CT interpretations performed using a diagnostic workstation and a mobile tablet computer, in a telestroke service. Materials and Methods: The ethics committee of our institution approved this retrospective study. A factorial design with 1452 interpretations was used. The assessed variables were the type of stroke classification, the presence of contraindications to the tPA administration, the presence of a hyperdense intracranial artery sign (HMCA), and the Alberta Stroke Program Early CT Score (ASPECTS) score. These variables were evaluated to determine the effect that the reading system had on their magnitudes. Results: The achieved distribution of observed lesions using both the reading systems was not statistically different. The differences between the two reading systems to claim equivalence were 1.6% for hemorrhagic lesions, 4.5% for cases without lesion, and 5.2 for overall ischemic lesion. Equivalence was achieved at 2.1% for ASPECTS <= 6, 6.5% for the presence of imaging contraindication to the tPA administration, and 7.2% for the presence of HMCA. Conclusion: The diagnostic performance for detecting acute stroke is likely equivalent whether a tablet computer or a diagnostic workstation is used or not. PMID- 29250112 TI - Early Human Migrations (ca. 13,000 Years Ago) or Postcontact Europeans for the Earliest Spread of Mycobacterium leprae and Mycobacterium lepromatosis to the Americas. AB - For over a century, it has been widely accepted that leprosy did not exist in the Americas before the arrival of Europeans. This proposition was based on a combination of historical, paleopathological, and representational studies. Further support came from molecular studies in 2005 and 2009 that four Mycobacterium leprae single-nucleotide polymorphisms (SNPs) and then 16 SNP subtypes correlated with general geographic regions, suggesting the M. leprae subtypes in the Americas were consistent with European strains. Shortly thereafter, a number of studies proposed that leprosy first came to the Americas with human migrations around 12,000 or 13,000 years ago. These studies are based primarily on subsequent molecular data, especially the discovery of a new leprosy species Mycobacterium lepromatosis and its close association with diffuse lepromatous leprosy, a severe, aggressive form of lepromatous leprosy, which is most common in Mexico and the Caribbean Islands. A review of these and subsequent molecular data finds no evidence for either leprosy species in the Americas before the arrival of Europeans, and strains of both species of leprosy found in eastern Mexico, Caribbean Islands, and Brazil came from Europe while strains found in western Mexico are consistent with their arrival via direct voyages from the Philippines. PMID- 29250113 TI - Encapsulation of Nicardipine Hydrochloride and Release from Biodegradable Poly(D,L-lactic-co-glycolic acid) Microparticles by Double Emulsion Process: Effect of Emulsion Stability and Different Parameters on Drug Entrapment. AB - Poly(D,L-lactic-co-glycolic acid) (PLGA) is an important material used in drug delivery when controlled release is required. The purpose of this research is to design and characterize PLGA microparticles (PLGA MPs) implants for the controlled release of nicardipine hydrochloride (NCH) in vitro. This study used the water-in-oil-in-water (w1/o/w2) double emulsion and solvent diffusion/evaporation approach to prepare PLGA MPs. Optimal processing conditions were found, such as polymer content, surfactant type, stabilizer concentration, inner and outer aqueous phase volumes, and stirring speed. The PLGA MPs for use as nicardipine hydrochloride (NCH) loading and release had spherical morphology, and the average diameter was smaller than 5.20 +/- 0.25 MUm. The release kinetics were modeled to elucidate the possible mechanism of drug release. In vitro release studies indicated that the NCH release rate is slow and continuous. PLGA MPs are an interesting alternative drug delivery system, especially for use with NCH for biomedical applications. PMID- 29250114 TI - Tissue-Engineered Vascular Graft of Small Diameter Based on Electrospun Polylactide Microfibers. AB - Tubular vascular grafts 1.1 mm in diameter based on poly(L-lactide) microfibers were obtained by electrospinning. X-ray diffraction and scanning electron microscopy data demonstrated that the samples treated at T = 70 degrees C for 1 h in the fixed state on a cylindrical mandrel possessed dense fibrous structure; their degree of crystallinity was approximately 44%. Strength and deformation stability of these samples were higher than those of the native blood vessels; thus, it was possible to use them in tissue engineering as bioresorbable vascular grafts. The experiments on including implantation into rat abdominal aorta demonstrated that the obtained vascular grafts did not cause pathological reactions in the rats; in four weeks, inner side of the grafts became completely covered with endothelial cells, and fibroblasts grew throughout the wall. After exposure for 12 weeks, resorption of PLLA fibers started, and this process was completed in 64 weeks. Resorbed synthetic fibers were replaced by collagen and fibroblasts. At that time, the blood vessel was formed; its neointima and neoadventitia were close to those of the native vessel in structure and composition. PMID- 29250115 TI - Thrombin-Induced Calpain Activation Promotes Protease-Activated Receptor 1 Internalization. AB - The serine protease thrombin activates Protease-Activated Receptors (PARs), a family of G-protein-coupled receptors (GPCRs) activated by the proteolytic cleavage of their extracellular N-terminal domain. Four members of this family have been identified: PAR1-4. The activation of Protease-Activated Receptor 1(PAR1), the prototype of this receptor family, leads to an increase in intracellular Ca+2 concentration ([Ca+2]i) mediated by Gq11alpha coupling and phospholipase C (PLC) activation. We have previously shown that the stimulation of PAR1 by thrombin promotes intracellular signaling leading to RPE cell transformation, proliferation, and migration which characterize fibroproliferative eye diseases leading to blindness. Within this context, the elucidation of the mechanisms involved in PAR1 inactivation is of utmost importance. Due to the irreversible nature of PAR1 activation, its inactivation must be efficiently regulated in order to terminate signaling. Using ARPE-19 human RPE cell line, we characterized thrombin-induced [Ca+2]i increase and demonstrated the calcium-dependent activation of MU-calpain mediated by PAR1. Calpains are a family of calcium-activated cysteine proteases involved in multiple cellular processes including the internalization of membrane proteins through clathrin-coated vesicles. We demonstrated that PAR1-induced calpain activation results in the degradation of alpha-spectrin by calpain, essential for receptor endocytosis, and the consequent decrease in PAR1 membrane expression. Collectively, the present results identify a novel MU-calpain-dependent mechanism for PAR1 inactivation following exposure to thrombin. PMID- 29250117 TI - Ustekinumab and Vedolizumab Dual Biologic Therapy in the Treatment of Crohn's Disease. AB - We present a case of refractory ileocolonic Crohn's disease in a 27-year-old female treated with dual ustekinumab and vedolizumab biologic therapy. She had mucosal healing for the first time in 13 years after a 10-month treatment of ustekinumab overlapped with 6 months of vedolizumab. No side effects were observed during the 6 months of dual biologic therapy. Short-term dual biologic therapy may be considered as a treatment option for induction of remission in refractory cases of Crohn's disease. PMID- 29250116 TI - Chimerism in Myeloid Malignancies following Stem Cell Transplantation Using FluBu4 with and without Busulfan Pharmacokinetics versus BuCy. AB - In the era of precision medicine, the impact of personalized dosing of busulfan is not clear. We undertook a retrospective analysis of 78 patients with myeloid malignancies who received fludarabine and busulfan (FluBu4) with or without measuring Bu pharmacokinetics (Bu PK) and those who received busulfan with cyclophosphamide (BuCy). Fifty-five patients received FluBu4, of whom 21 had Bu PK measured, and 23 patients received BuCy. Total donor cell chimerism showed that the percentage of patients maintaining 100% donor chimerism on day 100 was 66.7%, 38.2%, and 73.9% in the FluBu4 with PK, FluBu4 with no PK, and BuCy, respectively (P = .001). Patients who had decreasing donor chimerism by day 100 were 23.8%, 52.9%, and 26.1% in the FluBu4 with PK, FluBu4 with no PK, and BuCy, respectively (P = .04). Bu PK group had fewer patients with less than 95% donor chimerism on day 30, which was not statistically significant, 5% (FluBu4 PK), 31% (FluBu4 with no PK), and 21% (BuCy) (P = .18). Survival distributions were not statistically significant (P = .11). Thus, personalized drug dosing can impact donor chimerism in myeloid malignancies. This will need to be examined in larger retrospective multicenter studies and prospective clinical trials. PMID- 29250118 TI - IL-1/TNF-alpha Inflammatory and Anti-Inflammatory Synchronization Affects Gingival Stem/Progenitor Cells' Regenerative Attributes. AB - Cytokines play major roles in tissue destruction/repair. The present study investigates proliferative and osteogenic differentiation potentials of gingival mesenchymal stem/progenitor cells (G-MSCs), influenced by IL-1/TNF-alpha inflammatory/anti-inflammatory conditions. Human G-MSCs were isolated, characterized, and cultured in basic medium (control group, M1), in basic medium with IL-1beta, TNF-alpha, and IFN-gamma (inflammatory group, M2) and with IL 1ra/TNF-alphai added to M2 (anti-inflammatory group, M3). MTT tests at days 1, 3, and 7 and CFU assay at day 12 were conducted. Osteogenic differentiation was analyzed by bone-specific transcription factors (RUNX2), alkaline phosphatase (ALP), type I collagen (Col-I), osteopontin (OPN), and osteonectin (ON) expression at days 1, 3, 7, and 14 and Alizarin red staining at day 14. At day 3, the control group showed the highest cell numbers. At day 7, cell numbers in inflammatory and anti-inflammatory group outnumbered the control group. At day 12, CFUs decreased in the inflammatory and anti-inflammatory groups, with altered cellular morphology. The anti-inflammatory group demonstrated elevated bone specific transcription factors at 14 days. After 14 days of osteogenic induction, calcified nodules in the anti-inflammatory group were higher compared to control and inflammatory groups. For regeneration, initial inflammatory stimuli appear essential for G-MSCs' proliferation. With inflammatory persistence, this positive effect perishes and is followed by a short-term stimulatory one on osteogenesis. At this stage, selective anti-inflammatory intervention could boost G-MSCs' differentiation. PMID- 29250120 TI - Human Chorionic Plate-Derived Mesenchymal Stem Cells Restore Hepatic Lipid Metabolism in a Rat Model of Bile Duct Ligation. AB - In cholestatic liver diseases, impaired bile excretion disrupts lipid homeostasis. We investigated changes of lipid metabolism, including mitochondrial beta-oxidation, in a rat model of bile duct ligation (BDL) in which chorionic plate-derived mesenchymal stem cells (CP-MSCs) were transplanted. Serum cholesterol level, which was elevated after BDL, was significantly decreased following CP-MSC transplantation. The expression levels of genes involved in intracellular lipid uptake, including long-chain fatty acyl-CoA synthetases and fatty acid transport proteins, were decreased in rats after BDL; however, they were not significantly changed by subsequent CP-MSC transplantation. Carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme in mitochondrial beta oxidation, was upregulated after BDL and then was downregulated after CP-MSC transplantation. CPT1A expression was changed via microRNA-33-a posttranscriptional regulator of CPT1A-in a peroxisome proliferator-activated receptor alpha-independent manner. Cellular adenosine triphosphate production-an indicator of mitochondrial function-was reduced after BDL and was restored by CP MSC transplantation. Expression levels of heme oxygenases also were significantly affected following BDL and CP-MSC transplantation. Lipid metabolism is altered in response to chronic cholestatic liver injury and can be restored by CP-MSC transplantation. Our study findings support the therapeutic potential of CP-MSCs in cholestatic liver diseases and help in understanding the fundamental mechanisms by which CP-MSCs affect energy metabolism. PMID- 29250119 TI - Urine-Derived Stem Cells: The Present and the Future. AB - Stem cell research provides promising strategies in improving healthcare for human beings. As a noninvasively obtained and easy-to-culture cell resource with relatively low expense, urine-derived stem cells have special advantages. They have been extensively studied on its proliferation ability and differentiation potential and were being reprogrammed to model diseases during the last decade. In this review, we intend to summarize the latest progress on the research of urine-derived stem cells for its broad application mainly in regenerative medicine and disease modeling, as well as in what is challenging currently. This minireview will highlight the potential application of urine-derived stem cells and provides possible direction of further research in the future. PMID- 29250121 TI - The Rapidly Evolving Concept of Whole Heart Engineering. AB - Whole heart engineering represents an incredible journey with as final destination the challenging aim to solve end-stage cardiac failure with a biocompatible and living organ equivalent. Its evolution started in 2008 with rodent organs and is nowadays moving closer to clinical application thanks to scaling-up strategies to human hearts. This review will offer a comprehensive examination on the important stages to be reached for the bioengineering of the whole heart, by describing the approaches of organ decellularization, repopulation, and maturation so far applied and the novel technologies of potential interest. In addition, it will carefully address important demands that still need to be satisfied in order to move to a real clinical translation of the whole bioengineering heart concept. PMID- 29250122 TI - Estimating the Health Risk Associated with the Use of Ecological Sanitation Toilets in Malawi. AB - Use of Ecological Sanitation (EcoSan) sludge is becoming popular due to increasing price of organic fertilizers in Malawi; however, there is little evidence on the associated risks. Quantitative microbiological risk assessment (QMRA) was done to determine health risks associated with use of EcoSan. Pathogens considered included Escherichia coli (E. coli), Salmonella, and soil transmitted helminths (STHs). Exponential and Beta Poisson models were used to estimate the risk from helminthic and bacterial pathogens, respectively. Main exposure pathways were through poor storage of sludge, contamination of foods during drying, walking barefoot on the ground contaminated with sludge, pit emptying without protection, and application of sludge in the fields. Estimated annual risk for Ascaris lumbricoides, Taenia, and hookworms was approximately over 5.6 * 10-1 for both Fossa Alternas (FAs) and Urine Diverting Dry Toilet (UDDTs). Risk from E. coli and Salmonella was 8.9 * 10-2 and above. The risks were higher than WHO acceptable risk for use of faecal sludge in crops of 10-4 infections per year. Promoters and users of EcoSan latrines need to consider advocating for strict guidelines to reduce the risk. PMID- 29250123 TI - The pleasure of pursuit: recreational hunters in rural Southwest China exhibit low exit rates in response to declining catch. AB - Hunting is one of the greatest threats to tropical vertebrates. Examining why people hunt is crucial to identifying policy levers to prevent excessive hunting. Overhunting is particularly relevant in Southeast Asia, where a high proportion of mammals and birds are globally threatened. We interviewed hunters in Southwest China to examine their social behavior, motivations, and responses to changes in wildlife abundance. Respondents viewed hunting as a form of recreation, not as an economic livelihood, and reported that they would not stop hunting in response to marked declines in expected catch. Even in scenarios where the expected catch was limited to minimal quantities of small, low-price songbirds, up to 36.7% of respondents said they would still continue to hunt. Recreational hunting may be a prominent driver for continued hunting in increasingly defaunated landscapes; this motivation for hunting and its implications for the ecological consequences of hunting have been understudied relative to subsistence and profit hunting. The combination of a preference for larger over smaller game, reluctance to quit hunting, and weak enforcement of laws may lead to hunting-down-the-web outcomes in Southwest China. PMID- 29250124 TI - Cytotoxicity and Proapoptotic Effects of Allium atroviolaceum Flower Extract by Modulating Cell Cycle Arrest and Caspase-Dependent and p53-Independent Pathway in Breast Cancer Cell Lines. AB - Breast cancer is the second leading cause of cancer death among women and despite significant advances in therapy, it remains a critical health problem worldwide. Allium atroviolaceum is an herbaceous plant, with limited information about the therapeutic capability. We aimed to study the anticancer effect of flower extract and the mechanisms of action in MCF-7 and MDA-MB-231. The extract inhibits the proliferation of the cells in a time- and dose-dependent manner. The underlying mechanism involved the stimulation of S and G2/M phase arrest in MCF-7 and S phase arrest in MDA-MB-231 associated with decreased level of Cdk1, in a p53 independent pathway. Furthermore, the extract induces apoptosis in both cell lines, as indicated by the percentage of sub-G0 population, the morphological changes observed by phase contrast and fluorescent microscopy, and increase in Annexin-V-positive cells. The apoptosis induction was related to downregulation of Bcl-2 and also likely to be caspase-dependent. Moreover, the combination of the extract and tamoxifen exhibits synergistic effect, suggesting that it can complement current chemotherapy. LC-MS analysis displayed 17 major compounds in the extract which might be responsible for the observed effects. Overall, this study demonstrates the potential applications of Allium atroviolaceum extract as an anticancer drug for breast cancer treatment. PMID- 29250125 TI - Yi-Qi-Ping-Chuan-Fang Reduces TSLP Elevation Caused by LPS + Poly(I:C) via Inhibiting TLR4/MYD88/NF-kappaB Signaling Pathway. AB - Objective: To explore the correlation between Thymic Stromal Lymphopoietin (TSLP) and the Nuclear Factor- (NF-) kappaB signaling pathways in bronchial epithelial cells and to clarify whether the traditional Chinese medicine formula Yi-Qi-Ping Chuan-Fang (YQPC) reduces inflammation by inhibiting TSLP/NF-kappaB signaling pathways. Methods: Cells were stimulated with LPS + Poly(I:C) and treated with YQPC. The expressions of TSLP and NF-kappaB signaling pathways related proteins P65, IkappaK, IkappaBa, P-P65, P-IkappaK, P-IkappaBa were detected. The effects of NF-kappaB upstream molecules, Toll-like receptors 3 and 4, myeloid differentiation primary response gene 88 (Myd88), TIR-domain-containing adapter inducing interferon-beta (TRIF), and downstream inflammatory cytokines, TNF alpha, IL-1beta, IL-6, and IL-8, were assessed. Results: The mRNA and protein expressions of TSLP were significantly increased after LPS + Poly(I:C) stimulation, the total protein IkappaBa and IkappaK decreased (P < 0.05), and the phosphorylated protein P-P65, P-IkappaK, and P-IkappaBalpha increased. After YQPC treatment, the expression of TSLP, P-P65, P-IkappaBa, and P-IkappaK was significantly inhibited (P < 0.05). The activation of TLR4 and MyD88 decreased, and release of IL-1beta, IL-6, IL-8, and TNF-alpha reduced (P < 0.05). Conclusion: In summary, the expression of TSLP is activated by the NF-kappaB signaling pathway. YQPC alleviated inflammation by inhibiting TSLP through regulating the NF-kappaB activation and translocation. PMID- 29250126 TI - Polydatin Protects Rat Liver against Ethanol-Induced Injury: Involvement of CYP2E1/ROS/Nrf2 and TLR4/NF-kappaB p65 Pathway. AB - Excessive alcohol consumption leads to serious liver injury, associating with oxidative stress and inflammatory response. Previous study has demonstrated that polydatin (PD) exerted antioxidant and anti-inflammatory effects and attenuated ethanol-induced liver damage, but the research remained insufficient. Hence, this experiment aimed to evaluate the hepatoprotective effect and potential mechanisms of PD on ethanol-induced hepatotoxicity. Our results showed that PD pretreatment dramatically decreased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in the serum, suppressed the malonaldehyde (MDA) and triglyceride (TG) content and the production of reactive oxygen species (ROS), and enhanced the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), andalcohol dehydrogenase (ADH), and aldehyde dehydrogenase (ALDH), paralleled by an improvement of histopathology alterations. The protective effect of PD against oxidative stress was probably associated with downregulation of cytochrome P450 2E1 (CYP2E1) and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target gene haem oxygenase-1 (HO-1). Moreover, PD inhibited the release of proinflammatory cytokines (TNF-alpha, IL 1beta, and IL-6) via downregulating toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-kappaB) p65. To conclude, PD pretreatment protects against ethanol-induced liver injury via suppressing oxidative stress and inflammation. PMID- 29250127 TI - Cardioprotective Effect of Danshensu against Ischemic/Reperfusion Injury via c Subunit of ATP Synthase Inhibition. AB - Mitochondrial permeability transition pore (MPTP) opening is the main culprit of ischemic/reperfusion (IR) injury. It is reported that c-subunit of ATP synthase is the core component of MPTP. Danshensu (DSS), a monomer isolated from the traditional Chinese herb Danshen, has showed cardioprotective effect against IR injury through unknown mechanism. In this study, rat hearts were suspended in Langendorff instrument and perfused with Krebs-Henseleit (KH) buffer containing DSS for 60 minutes, followed by 30 minutes of global ischemia. Parameters including heart rate, left ventricular developed pressure, and the rate of left ventricle diastolic pressure change were recorded to assess their cardiac function. All these indexes were improved in DSS group. The rate of cardiomyocytes apoptosis and MPTP opening were both inhibited in DSS group. In addition, DSS administration leads to downregulation of c-subunit of ATP synthase in both mRNA and protein levels. Consistently, when c-subunit of ATP synthase was overexpressed in H9C2 cells through pcDNA3/5G1 plasmid transfection, MPTP opening was enhanced when the cardioprotective effect of DSS also tapers. In conclusion, DSS could alleviate cardiac IR injury via inhibiting c-subunit of ATP synthase expression. PMID- 29250129 TI - Gays vs. Russia: media representations, vulnerable bodies and the construction of a (post)modern West. AB - This essay analyses the recent focus on Russian human rights violations in Anglophone media, scrutinising the ideological agenda of the visual politics which strategically foreground victimised bodies of Russian dissidents. Notwithstanding the importance of a critique on human rights violations, the article points to the unwanted but very real side effects the current mediatisations of violence have, from structural victimisation and the creation of 'gay martyrs' to the resignification of the West as progressive and 'gay' and Russia as backward and heterosexual. A close reading of popular press photographs of wounded Russian gay youth and the textual context - arguably representative for the Western media focus on the 'Eastern' violation of human rights between 2012 and 2014 - serves to illustrate how an image of Russian nation and Russian state politics is forged within Anglophone media discourses meant to reinforce the positive identity of the self-same by evoking pity, empathy and a responsible helpful attitude toward the endangered othered. The essay argues that Anglophone media's focus on the vulnerability of Russian LGBTIQ+ bodies, consciously or unconsciously, reduces the subjects to this vulnerability, confirming feelings of moral superiority within the enlightened audience. The study highlights the important role that Russia's vulnerable citizens play not only in the construction of values such as 'tolerance' and 'acceptance' and evaluations like 'progressive' and 'modern', but also in perceptions of the nation and its people and the reaffirmation of the dualistic divide between 'The East' and 'The West'. PMID- 29250128 TI - Recovering vector displacement estimates in quasistatic elastography using sparse relaxation of the momentum equation. AB - We consider the problem of estimating the 2D vector displacement field in a heterogeneous elastic solid deforming under plane stress conditions. The problem is motivated by applications in quasistatic elastography. From precise and accurate measurements of one component of the 2D vector displacement field and very limited information of the second component, the method reconstructs the second component quite accurately. No a priori knowledge of the heterogeneous distribution of material properties is required. This method relies on using a special form of the momentum equations to filter ultrasound displacement measurements to produce more precise estimates. We verify the method with applications to simulated displacement data. We validate the method with applications to displacement data measured from a tissue mimicking phantom, and in-vivo data; significant improvements are noticed in the filtered displacements recovered from all the tests. In verification studies, error in lateral displacement estimates decreased from about 50% to about 2%, and strain error decreased from more than 250% to below 2%. PMID- 29250130 TI - Pilot and feasibility study of a parenting intervention delivered by parent peers. AB - Preventive parenting interventions delivered by parent peer specialists may be a viable alternative to professional-led interventions and offer an advantage of increasing access in medically underserved areas. The objective of this pilot study was to assess the feasibility and preliminary outcomes of a 10-session, peer specialist-delivered preventive parenting intervention (Smart and Secure Children) for child disruptive behavior. The intervention was evaluated among a small sample of parents (N = 15) of preschoolers (2-5 years) residing in medically underserved communities. Pediatricians referred families to the intervention, which was delivered in primary care practices within medically underserved communities. To determine feasibility, we calculated percentages of pediatricians who referred parents to the intervention, parent peer specialists who completed 40-h interventionist and leadership training, and the average number of sessions attended by parents. Enrolled parents completed questionnaires assessing child disruptive behavior, parenting stress and parenting competence at pre-and post-intervention. Descriptive statistics demonstrated the majority of pediatricians within the clinics referred families, and all parent peer specialists completed training to deliver the intervention. On average, 60% of sessions were attended by parents. Pairwise t-tests showed pre-to-post intervention improvements in number of child disruptive behaviors perceived as a problem by parents, parenting stress and parenting competence. No significant change was found in parent-reported frequency of child disruptive behaviors. Results suggests adequate feasibility of the Smart and Secure Children Intervention, and that it holds promise for improving parenting stress and competence, and decreasing the number of child behaviors that are perceived as a problem by parents. Future directions for research are discussed. PMID- 29250131 TI - Measles in our time: the US experience. PMID- 29250132 TI - Posterior Estimates of Dynamic Constants in HIV Transmission Modeling. AB - In this paper, we construct a linear differential system in both continuous time and discrete time to model HIV transmission on the population level. The main question is the determination of parameters based on the posterior information obtained from statistical analysis of the HIV population. We call these parameters dynamic constants in the sense that these constants determine the behavior of the system in various models. There is a long history of using linear or nonlinear dynamic systems to study the HIV population dynamics or other infectious diseases. Nevertheless, the question of determining the dynamic constants in the system has not received much attention. In this paper, we take some initial steps to bridge such a gap. We study the dynamic constants that appear in the linear differential system model in both continuous and discrete time. Our computations are mostly carried out in Matlab. PMID- 29250133 TI - Periodically Pulsed Immunotherapy in a Mathematical Model of Tumor, CD4+ T Cells, and Antitumor Cytokine Interactions. AB - Immunotherapy is one of the most recent approaches for controlling and curing malignant tumors. In this paper, we consider a mathematical model of periodically pulsed immunotherapy using CD4+ T cells and an antitumor cytokine. Mathematical analyses are performed to determine the threshold of a successful treatment. The interindividual variability is explored by one-, two-, and three-parameter bifurcation diagrams for a nontreatment case. Numerical simulation conducted in this paper shows that (i) the tumor can be regulated by administering CD4+ T cells alone in a patient with a strong immune system or who has been diagnosed at an early stage, (ii) immunotherapy with a large amount of an antitumor cytokine can boost the immune system to remit or even to suppress tumor cells completely, and (iii) through polytherapy the tumor can be kept at a smaller size with reduced dosages. PMID- 29250134 TI - Image Fusion of CT and MR with Sparse Representation in NSST Domain. AB - Multimodal image fusion techniques can integrate the information from different medical images to get an informative image that is more suitable for joint diagnosis, preoperative planning, intraoperative guidance, and interventional treatment. Fusing images of CT and different MR modalities are studied in this paper. Firstly, the CT and MR images are both transformed to nonsubsampled shearlet transform (NSST) domain. So the low-frequency components and high frequency components are obtained. Then the high-frequency components are merged using the absolute-maximum rule, while the low-frequency components are merged by a sparse representation- (SR-) based approach. And the dynamic group sparsity recovery (DGSR) algorithm is proposed to improve the performance of the SR-based approach. Finally, the fused image is obtained by performing the inverse NSST on the merged components. The proposed fusion method is tested on a number of clinical CT and MR images and compared with several popular image fusion methods. The experimental results demonstrate that the proposed fusion method can provide better fusion results in terms of subjective quality and objective evaluation. PMID- 29250135 TI - A Hybrid Wavelet-Based Method for the Peak Detection of Photoplethysmography Signals. AB - The noninvasive peripheral oxygen saturation (SpO2) and the pulse rate can be extracted from photoplethysmography (PPG) signals. However, the accuracy of the extraction is directly affected by the quality of the signal obtained and the peak of the signal identified; therefore, a hybrid wavelet-based method is proposed in this study. Firstly, we suppressed the partial motion artifacts and corrected the baseline drift by using a wavelet method based on the principle of wavelet multiresolution. And then, we designed a quadratic spline wavelet modulus maximum algorithm to identify the PPG peaks automatically. To evaluate this hybrid method, a reflective pulse oximeter was used to acquire ten subjects' PPG signals under sitting, raising hand, and gently walking postures, and the peak recognition results on the raw signal and on the corrected signal were compared, respectively. The results showed that the hybrid method not only corrected the morphologies of the signal well but also optimized the peaks identification quality, subsequently elevating the measurement accuracy of SpO2 and the pulse rate. As a result, our hybrid wavelet-based method profoundly optimized the evaluation of respiratory function and heart rate variability analysis. PMID- 29250136 TI - alpha-klotho and anemia in patients with chronic kidney disease patients: A new perspective. AB - Normocytic normochromic anemia is a common complication of chronic kidney disease (CKD) and is associated with numerous adverse consequences. Certain symptoms previously attributed to CKD are now known to be a consequence of anemia. Anemia contributes to an increased cardiac output, and the development of left ventricular hypertrophy, angina and congestive heart failure, leading to high morbidity and mortality in patients with CKD. The multifunctional alpha-klotho (KL) protein, which is predominantly expressed in the kidneys, is associated with the occurrence of anemia in patients with CKD. The present review presents current evidence on the potential role of alpha-KL in renal anemia. Low expression of alpha-KL appears to improve anemia in patients with CKD, and has been hypothesized to be a compensatory mechanism to attenuate the effects of anemia in patients with CKD. Further understanding of the role of alpha-KL in renal anemia may offer novel insights into the treatment of patients with CKD complicated with anemia. PMID- 29250137 TI - Enhanced osseointegration of titanium implants in a rat model of osteoporosis using multilayer bone mesenchymal stem cell sheets. AB - The present study aimed to investigate whether bone marrow-derived mesenchymal stem cell (BMSC) sheets combined with titanium implants enhanced implant osseointegration in an ovariectomized (OVX) rat model of osteoporosis. Sprague Dawley rats were randomly assigned into a test group and control group. Allogenic BMSCs were collected from the rats, cultured and stored via cryopreservation. At 6 months post-ovariectomy, establishment of the OVX model was confirmed by micro computed tomography (CT) measurements. BMSC sheets were subsequently layered and wrapped over titanium implants for implantation. Unmodified implants served as the control. At 8 weeks post-implantation, samples were observed by micro-CT reconstruction and histomorphometric evaluation. Micro-CT reconstruction identified a marked improvement in the surrounding bone volume following treatment, with data analyses indicating a significant increase in bone volume in the BMSC-implant group compared with the control implant group (P<0.05). In addition, histological staining identified new bone formation and an increased rate of bone-implant contact surrounding the BMSC-implant constructs. These results indicate that the use of BMSC sheets as a novel tissue engineering approach improves the osseointegration of titanium implants in an osteoporosis model. This method may expand the operative indications in patients with osteoporosis and improve the success rate of clinical dental implant treatments. PMID- 29250138 TI - Apelin as a novel drug for treating preeclampsia. AB - Preeclampsia is a pregnancy-specific disorder of new-onset hypertension and proteinuria after 20 weeks' gestation, often resulting in poor outcome. Previous studies demonstrated that apelin is an endogenous active peptide with visodilation and anti-oxidative stress capabilities. The present study investigated the effects of apelin in a rat model of preeclampsia induced by reduced uterine perfusion pressure (RUPP). Rats with RUPP displayed hypertension and poor pregnancy outcomes, such as decreased fetal and placental weight. Of note, apelin treatment significantly ameliorated the symptoms of preeclampsia, improved the impaired endothelial nitric oxide synthase/nitric oxide signaling and attenuated activation of oxidative stress in RUPP rats. Apelin may be a potential agent for preventing and treating preeclampsia. PMID- 29250139 TI - Comprehensive analysis of long non-coding RNA and mRNA expression profiles in rheumatoid arthritis. AB - Abnormal expression of long non-coding RNA (lncRNA) has been demonstrated to be involved in a variety of human diseases. However, the role of lncRNA remains largely unknown in rheumatoid arthritis (RA). The present study aimed to investigate whether lncRNA are differentially expressed in RA. Differentially expressed lncRNA and mRNA in peripheral blood mononuclear cells from individuals with RA and healthy controls were detected using a human lncRNA microarray containing 30,586 lncRNA and 26,109 coding transcripts. Several candidate lncRNA and mRNA in 24 paired samples were verified by reverse transcription-quantitative polymerase chain reaction analysis. Bioinformatics analyses (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) were used to evaluate signaling pathways and biological functions influenced by the differentially expressed mRNA. A total of 5,045 lncRNA (upregulated, 2,410; downregulated, 2,635) and 3,289 mRNA (upregulated, 1,403; downregulated, 1,886) were differentially expressed in patients with RA (fold change >2; P<0.05). The majority of abnormal lncRNA were from intergenic spacer regions (42%), natural antisense (19%) and intronic antisense (15%) to protein-coding loci. lncRNA target prediction indicated the presence of 135 potential lncRNA-mRNA target pairs for the 85 aberrant lncRNA and 109 aberrant mRNA. Significantly enriched (P<0.05) signaling pathways based on deregulated mRNA were mostly implicated in bile secretion, T cell receptor signaling pathway and systemic lupus erythematosus. In summary, to the best of our knowledge, the present study executed global expression profiling of lncRNA and mRNA involved in RA for the first time. These results may provide important insights regarding lncRNA in RA pathogenesis and provide potential therapeutic targets. PMID- 29250140 TI - Effects of dimethyl carbonate-induced autophagic activation on follicular development in the mouse ovary. AB - Dimethyl carbonate (DMC) is a widely used industrial chemical, which may be increasingly used in the future. However, its toxicity profile remains largely unknown. The present study was designed to investigate the effects of DMC exposure on the ovaries and the effect of autophagy activation on follicular development. Rats were randomly divided into a control group and low, medium and high dose DMC groups (all n=10). Histological analyses identified no marked differences in the rate of apoptosis between the control and low dose groups; however, marked apoptosis occurred in the medium and high dose groups. The expression of cleaved caspase-3 was significantly increased in the medium and high dose groups, which was consistent with changes observed in the expression of Bcl-2 and Bax. These results indicated that DMC exposure induces toxicity on ovarian function via the induction of apoptosis. The increased expression of the autophagy-related proteins light chain 3II, beclin-1 and p62 following exposure to DMC further indicated that autophagy was activated primarily in the granulosa cells of ovarian follicles in a dose-dependent manner. In addition, the changes in the expression of hypoxia inducible factor 1 alpha subunit (HIF-1alpha) and its target protein BCL2 interacting protein 3 (BNIP3) indicated that they may serve a role in the follicular development process induced by DMC. The results of the current study demonstrated that DMC exposure activated autophagy in the ovarian tissue. Furthermore, exposure to low doses of DMC may protect follicular development by activating the HIF-1alpha/BNIP3 signaling pathway. Taken together, these results indicate that exposure to medium and high doses of DMC induced follicular atresia by activating the apoptotic signaling pathway. This may be an important mechanism of regulating follicular development and ovarian function in mammals. PMID- 29250141 TI - Gynostemma pentaphyllum is neuroprotective in a rat model of cardiopulmonary resuscitation. AB - Asphyxial cardiac arrest (ACA)-induced ischemia results in acute and delayed neuronal cell death. The early reperfusion phase is critical for the outcome. Intervention strategies directed to this period are promising to reduce ACA/resuscitation-dependent impairments. This study focused on the evaluation of the protective potential of an extract from Gynostemma pentaphyllum (GP), a plant used in traditional medicine with antioxidative, glucose lowering and neuroprotective activities, in an ACA rat model. We tested the following parameters: i) Basic systemic parameters such as pCO2 and blood glucose value within the first 30 min post-ACA; ii) mitochondrial response by determining activities of citrate synthase, respiratory chain complexes I + III and II + III, and the composition of cardiolipin 6 and 24 h post-ACA; iii) neuronal vitality of the CA1 hippocampal region by immunohistochemistry 24 h and 7 days post-ACA; and iv) cognitive function by a novel object recognition test 7 days post-ACA. GP, administered after reaching spontaneous circulation, counteracted the following: i) ACA-mediated increases in arterial CO2 tension and blood glucose values; ii) transient increase in the activity of the respiratory chain complexes II + III; iii) elevation in cardiolipin content; iv) hippocampal CA1 neurodegeneration, and v) loss of normal novelty-object seeking. The protective effects of GP were accompanied by side effects of the vehicle DMSO, such as the stimulation of citrate synthase activity in control animals, inhibition of cardiolipin synthesis in ACA animals and complex II + III activity in both control and ACA animals. The results emphasize the importance of the early post-resuscitation phase for the neurological outcome after ACA/resuscitation, and demonstrated the power of GP substitution as neuroprotective intervention. Moreover, the results underline the need of a careful handling of the popular vehicle DMSO. PMID- 29250142 TI - Cerebral embolism secondary to cardiac amyloidosis: A case report and literature review. AB - Cardiac amyloidosis (CA) describes a group of heterogeneous diseases that are characterized by the extracellular fibril deposition of amyloid protein in the myocardium. The abnormal protein is usually derived from light-chain amyloidosis, mutant transthyretin amyloidosis and wild-type transthyretin. Patients with ischemic strokes and amyloidosis have been sporadically reported, however, they are not well summarized. In the present study, a case of cerebral ischemic stroke, secondary to CA was described. This patient presented with dyspnea on exertion, without any evidence of atrial fibrillation. A biopsy revealed deposition of amyloid in the myocardium and Congo Red staining was positive. He suffered from acute infarction of left basal ganglia, resulting from occlusion of the left middle cerebral arterial 6 months prior to admission. However, re examination of cerebral magnetic resonance imaging in the present hospital revealed an old infarction in the region of the left basal ganglia with a normal appearance of the left middle cerebral artery. Transesophageal echocardiography (TEE) and cardiac magnetic resonance (CMR) both discovered intra-cardiac thrombi, confirming the diagnosis of cardiogenic cerebral embolism. The present study indicates that patients with CA may additionally present with cardiogenic cerebral embolism, and TEE and CMR imaging may help to avoid missing the presence of intra-cardiac thrombi. PMID- 29250143 TI - Molecular mechanisms underlying the alpha-tomatine-directed apoptosis in human malignant glioblastoma cell lines A172 and U-118 MG. AB - In the present study, the molecular mechanisms involved in the alpha-tomatine induced apoptosis in human glioblastoma cell lines A172 and U-118 MG were investigated. Wright staining and ApopTag assays were conducted to confirm the apoptosis induced by alpha-tomatine treatment. Fura-2 assay determined an enhancement in free Ca2+ intracellularly, indicating the occurrence of Ca2+ dependent apoptosis induction. Western blot experiments were also performed to predict the apoptosis by measuring the changes in the Bax:Bcl-2 ratio. Increase of calpain activity triggered caspase-12 expression, which in turn further activated caspase-9. In addition, an increase in the ratio of Bax:Bcl-2 accounted for the mitochondrial release of cytochrome c into the cytosol for caspase-3 and caspase-9 activation. Elevated activity of calpain and caspase-3 yielded spectrin breakdown products with 145 and 120 kDa, respectively. Caspase-3 activation further cleaved the inhibitor of caspase activated DNase, while the apoptosis inducing factor detected in the cytosol suggested that apoptosis was independent of caspase. The apoptosis induction was further supported by decreased expression levels of nuclear factor-kappaB and increased expression of the inhibitor of nuclear factor, IkappaBalpha. In conclusion, the presented experimental results revealed the stimulation of different molecular mechanisms for alpha-tomatine mediated apoptosis in A172 and U-118 MG human glioblastoma cell lines. PMID- 29250144 TI - Formononetin ameliorates mast cell-mediated allergic inflammation via inhibition of histamine release and production of pro-inflammatory cytokines. AB - Various allergic diseases cause allergic inflammation, which is mediated by mast cells. The current study investigated the anti-allergic inflammatory effects of formononetin and its mechanism of action in vitro using mast cells. Levels of histamine and pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6, were measured to assess the effects of formononetin on allergic inflammation. The activation of intracellular calcium and nuclear factor (NF)-kappaB, as well as the activity of caspase-1, were assessed to determine the mechanism of action. It was determined that difference concentrations of formononetin (0.1, 1 and 10 uM) suppressed histamine release and secretion of TNF-alpha, IL-1beta and IL-6. Further investigations indicated that the effects of formononetin were associated with a reduction of intracellular calcium, suppression of NF-kappaB activation and upstream IkappaKalpha phosphorylation and inhibition of caspase-1 activity. Therefore, the results of the current study demonstrated that formononetin ameliorated mast cell mediated allergic inflammation. PMID- 29250145 TI - Evaluation of the acute and chronic toxicity of the jiangu capsules. AB - Saussureae involucratae Flos is the primary component of the jiangu capsule, which also consists of 12 types of natural medicine. It is a traditional Chinese medicine used to treat a number of conditions including arthralgia, cold and sore muscles, stiff limbs, inconvenient flexion and activity limitation caused by different types of osteoarthritis. The present study was performed to assess the safety of the jiangu capsule following acute and chronic administration in mice and rats. In the acute study, mice were treated with the jiangu capsule orally at 16 g/kg/day, the highest dose, for 14 days. In the chronic oral toxicity study, rats were treated with 2, 4 and 8 g/kg/day of the jiangu capsule for 6 months. The general condition, body weight changes, food and water consumption, hematological and biochemical parameters, urinalysis, systematic anatomy and organ weights of the rats were monitored and histopathological examination was performed at the end of 3 and 6 months' daily administration, and following 14 days of withdrawal. There were no signs of toxicity in the general condition and body weight of the mice was not significantly affected by the treatment. Furthermore, necropsy findings for the animals in the acute and chronic toxicity studies demonstrated that no mortalities had occurred. The results of the current study indicate that treatment with the jiangu capsule did not induce mortality or any detectable abnormalities in mice and rats. PMID- 29250147 TI - MicroRNA-92b promotes cell proliferation and invasion in osteosarcoma by directly targeting Dickkopf-related protein 3. AB - Deregulation of microRNA-92b (miR-92b) has been implicated in osteosarcoma. However, the underlying regulatory mechanism of miR-92b in osteosarcoma growth and metastasis remains largely unclear. In the present study, reverse transcription-quantitative polymerase chain reaction and western blotting were used to measure mRNA and protein expression. MTT and Transwell assays were conducted to determine cell proliferation and invasion, and a luciferase reporter assay was performed to confirm the association between miR-92b and Dickkopf3 related protein (DKK3). The results demonstrated that miR-92b was significantly upregulated in osteosarcoma tissues compared with matched adjacent non-tumor tissues. Additionally, high miR-92b levels were significantly associated with lung metastasis and advanced tumor, node, metastasis stage (P<0.05) but not with age, sex, tumor size, location, serum lactate dehydrogenase or serum alkaline phosphatase. miR-92b expression was also significantly upregulated in osteosarcoma cell lines compared with normal osteoblast cells. Knockdown of miR 92b significantly inhibited the proliferation and invasion of osteosarcoma U2OS cells (P<0.01). By contrast, overexpression of miR-92b significantly increased U2OS cell proliferation and invasion (P<0.01). DKK3 was identified as a target gene of miR-92b and it was demonstrated that DKK3 expression was negatively regulated by miR-92b in U2OS cells. Restoration of DKK3 expression abrogated the increased proliferation and invasion of U2OS cells induced by miR-92b overexpression. Notably, DKK3 was significantly downregulated in osteosarcoma tissues compared with adjacent non-tumor tissues and its expression was inversely correlated to miR-92b levels in osteosarcoma tissues. Taken together, these data indicate that miR-92b promotes cell proliferation and invasion in osteosarcoma by targeting DKK3. Therefore, miR-92b may become a potential therapeutic target for osteosarcoma. PMID- 29250146 TI - Advanced research on deep brain stimulation in treating mental disorders. AB - Deep brain stimulation is a method that involves using an electric stimulus on a specific target in the brain with stereotaxis. It is a minimally invasive, safe, adjustable and reversible nerve involvement technology. At present, this technique is widely applied to treat movement disorders and has produced promising effects on mental symptoms, including combined anxiety and depression. Deep brain stimulation has therefore been employed as a novel treatment for depression, obsessive-compulsive disorder, habituation, Tourette's syndrome, presenile dementia, anorexia nervosa and other refractory mental illnesses. Many encouraging results have been reported. The aim of the present review was to briefly describe the mechanisms, target selection, side effects, ethical arguments and risks associated with deep brain stimulation. Although deep brain stimulation is a developing and promising treatment, a large amount of research is still required to determine its curative effect, and the selection of patients and targets must be subjected to strict ethical standards. PMID- 29250148 TI - Changes in plasma von Willebrand factor and von Willebrand factor cleaving protease in thrombotic thrombocytopenic purpura: A case report. AB - The present case report described a patient with thrombotic thrombocytopenic purpura (TTP), who presented to the China-Japan Union Hospital of Jilin University (Changchun, China), and the changes in plasma von Willebrand factor (vWF) and vWF cleaving protease (vWF-cp) observed during treatment. Computed tomography and diffusion-weighted magnetic resonance (MR) imaging of the brain, cerebral MR angiography and other experimental tests were performed and the patient was subsequently diagnosed with TTP. The patient underwent treatment with plasma exchange, glucocorticoids and supportive care. Hematologic and biochemical parameters began to gradually improve over the 12 days after admission; platelet count, serum creatinine and serum lactate dehydrogenase concentrations returned to their normal ranges, plasma vWF concentration decreased to normal levels over the 30 days after admission, and vWF-cp activity increased compared with the levels detected in healthy volunteers. Monthly rituximab treatment was administered 4 times following patient discharge to prevent relapse, and no recurrence was detected at the 20-month follow-up. Plasma exchange therapy is effective in patients with TTP. After low-dose rituximab treatment, recurrent TTP has not been detected found till now. In the present case, vWF concentration and vWF-cp activity were measured at 8, 10, 23 and 32 days after admission; compared with the control group, patient's vWF concentration gradually decreased and vWF cp activity slowly increased, suggesting that the patient had a favorable prognosis and a low risk of recurrence. PMID- 29250149 TI - Effects of atorvastatin on porcine aqueous humour outflow and trabecular meshwork cells. AB - Primary open-angle glaucoma (POAG) with complex pathogenesis is one of the many major causes of blindness. It is widely accepted that the major cause of POAG is the dysregulation of the trabecular meshwork (TM), which regulates the resistance to aqueous humour outflow. Intraocular pressure is elevated with increasing outflow resistance in the conventional pathway, which consists of the TM and Schlemm's canal. The TM is a filter made up of extracellular matrix (e.g., collagens), most of which is organized into a network of beams covered by endothelial-like trabecular cells. Currently, lack of effective anti-glaucoma drugs acting on TM to normalize trabecular outflow represents a bottleneck for POAG therapy. Atorvastatin, a lipid-lowering drug, has been proven to be of benefit for POAG. The present study aimed to investigate the possible mechanisms of action of atorvastatin on the TM by using a porcine aqueous humour outflow model in vivo and TM cells in vitro. Perfusion of enucleated porcine eyes with atorvastatin (50-200 uM) for 2 h increased aqueous humour outflow (P<0.05, n=6), possibly via regulating the morphology of TM cells and the distribution of the cytoskeleton. Atorvastatin decreased adhesion molecules at the mRNA and protein level. No cytotoxicity of atorvastatin on TM cells was observed at concentrations of <100 uM. The atorvastatin-induced effects mentioned above were reversible after removal of the compound only if the atorvastatin concentration was <100 uM. The present study demonstrated that atorvastatin efficaciously elevated aqueous humour outflow, possibly due to affecting TM-cell morphology, cytoskeleton and cell junctions. Statins may be potential therapeutic agents for lowering intraocular pressure in POAG. PMID- 29250150 TI - Experimental research on preventing mechanical phlebitis arising from indwelling needles in intravenous therapy by external application of mirabilite. AB - Various types of complications arising from intravenous indwelling needles have become a challenge in clinical care. It is urgent to seek a simple and cost effective method for prevention and treatment of phlebitis. We investigated the roles of mirabilite in preventing and treating phlebitis caused by intravenous indwelling needles and provide guidance for prevention and treatment of mechanical phlebitis caused by intravenous indwelling needles. A total of 57 healthy congeneric big-eared New Zealand rabbits were randomly divided into 3 groups: blank control, indwelling needle, and group with external application of mirabilite. The ear vein of each rabbit was punctured with an intravenous indwelling needle. The ear vein specimens were taken at 3, 5, and 7 days after indwelling. The hematoxylin and eosin stained pathological tissue sections of the ear veins of the rabbits in each group were observed. The expression levels of IL 1 and IL-6, and tumour necrosis factor-alpha (TNF-alpha) in the vascular tissue of the ear veins of the rabbits in each group were detected with the immunofluorescence method. In the blank control group, there was no inflammatory cellular infiltration and no proliferation of fibrous tissue around the vascular wall. With the increase of the indwelling time, proliferation of fibrous tissue in vascular wall, increased inflammatory cellular infiltration and organized thrombus in the vascular tissue occurred in the ear veins of the rabbits in the indwelling needle group and group with external application of mirabilite. Compared with the indwelling needle group, the group with external application of mirabilite had significantly decreased fibrous tissue in the vascular wall and significantly decreased inflammatory cellular infiltration. At the same point in indwelling time, the expression levels of IL-1, IL-6, and TNF-alpha in the indwelling needle and group with external application of mirabilite were significantly higher than that in the blank control group (P<0.05). The expression levels of IL-1, IL-6, and TNF-alpha in the group with external application of mirabilite were lower than that in the indwelling needle group (P<0.05). The expression levels of IL-1, IL-6, and TNF-alpha are positively correlated with the indwelling time within the same group at different points in time. In conclusion, external application of mirabilite can significantly decrease infiltration of venous inflammatory cells of the rabbit ear margin, proliferation of fibrous tissue and thrombosis in the vascular wall, significant decrease the expression levels of IL-1, IL-6, and TNF-alpha in the mechanical phlebitis caused by intravenous indwelling needles, and decrease the inflammatory responses of the ear veins of rabbits. PMID- 29250151 TI - Efficacy of combined treatment with vacuum sealing drainage and recombinant human epidermal growth factor for refractory wounds in the extremities and its effect on serum levels of IL-6, TNF-alpha and IL-2. AB - The objective of this study was to investigate the efficacy of combined treatment with vacuum sealing drainage (VSD) and recombinant human epidermal growth factor (rhEGF) for refractory wounds in the extremities, and its effect on serum levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and IL-2. Ninety-eight patients with refractory wounds in the extremities were recruited and randomly divided into the combined treatment group (underwent VSD and rhEGF treatment) and control group (underwent VSD only) with 49 cases each. Formation of granulation tissue on the wound surface was assessed and scored. The wound healing rate was calculated after 1 week of treatment, and the time of complete healing was recorded. Serum levels of IL-6, IL-2, and TNF-alpha were measured using enzyme-linked immunosorbent assay. After 1 week of treatment, granulation tissue formation on wound surfaces was significantly improved (p<0.05) compared with that before treatment in both groups. Moreover, granulation tissue formation on wound surfaces was superior in the combined treatment group than in the control group (p<0.05). The wound healing rate was 63.50+/-4.75% in the combined treatment group and 31.79+/-3.52% in the control group, and the difference was statistically significant (p<0.05). The time of complete healing was 15.11+/-2.24 days in the combined treatment group and 19.63+/-2.76 days in the control group, and the difference was statistically significant (p<0.05). The serum levels of IL 6, IL-2, and TNF-alpha, in the two groups were significantly lower than those before treatment (p<0.05). Moreover, the levels in the combined treatment group were significantly lower than those in the control group (p<0.05). In conclusion, combined treatment with VSD and rhEGF reduced inflammation and shortened the time of complete healing of refractory wounds in the extremities. Measurement of the levels of related inflammatory factors provided a reference for the prognosis of refractory wounds. PMID- 29250152 TI - Therapeutic effect of percutaneous endoscopic lumbar discectomy on lumbar disc herniation and its effect on oxidative stress in patients with lumbar disc herniation. AB - This study investigated the therapeutic effect of percutaneous endoscopic lumbar discectomy on lumbar disc herniation, and explored its effect on oxidative stress in patients with lumbar disc herniation. One hundred and ten patients with lumbar disc herniation were selected in The Affiliated People's Hospital of Shanxi Medical University from May 2015 to May 2016. Patients were divided into control group (n=50) and observation group (n=60) according to different surgical methods. Patients in control group were subjected to traditional open discectomy, while patients in observation group were treated with percutaneous endoscopic lumbar discectomy. Surgical-related indicators, ODI and VAS scores before and 3 months after surgery, serum inflammatory factors and oxidative stress indicators were compared between 2 groups. There was no significant difference in operation time between the groups. Blood loss, incision size and time of bed rest in observation group were better than those in control group (P<0.05). Compared with preoperative levels, ODI and VAS scores of the two groups were significantly reduced at 3 months after surgery, but the scores of observation group were significantly higher than those of control group (P<0.05). There were no significant differences in the levels of serum inflammatory factors TNF-alpha and CRP and oxidative stress indicators MDA, MPO, SOD and TAC between the two groups before surgery (P>0.05). Levels of serum inflammatory factors TNF-alpha and CRP and oxidative stress indicators MDA and MPO were significantly lower and levels of oxidative stress indicators SOD and TAC were significantly higher in observation group than in control group (P<0.05). Therefore, treatment of lumbar disc herniation with percutaneous endoscopic lumbar discectomy has the advantages of small trauma, less blood loss and fast recovery, and can effectively improve the dysfunction, reduce pain and serum levels of inflammatory factors, and improve the levels of oxidative stress indicators, thereby improving the surgical results. Thus, this method should be considered for wide-use. PMID- 29250153 TI - The inhibitory effects of soybean isoflavones on testicular cell apoptosis in mice with type 2 diabetes. AB - The aim of the study was to investigate the inhibitory effects of soybean isoflavones (SI) on testicular cell apoptosis in mice with type-2 diabetes, as well as any possible mechanisms of action. Thirty male C57BL/6J mice were randomly divided into the control, diabetic (model), and treatment (SI) groups (n=10 each). After treatment for 20 weeks, testicular cell apoptosis was detected and evaluated using DAPI staining. The expression and distribution of caspase-3 protein in testicular tissues was detected via immunohistochemistry, while caspase-3 mRNA expression was detected using RT-PCR. Bax and Bcl-2 protein expression was detected by western blot analysis. At week 20, DAPI staining showed that SI treatment significantly decreased testicular tissue cell apoptosis in diabetic mice. Immunohistochemical staining revealed that caspase-3 expression in the SI group was significantly reduced relative to the model group. RT-PCR showed that SI treatment significantly decreased caspase-3 mRNA expression relative to the model group. Western blot analysis revealed that SI treatment significantly decreased Bax protein expression and increased Bcl-2 protein expression (P<0.01). SI exhibited an inhibitory effect on testicular tissue cell apoptosis in mice with type 2 diabetes, with this effect possibly mediated by a decreased expression of caspase-3 and Bax and increased Bcl-2 protein expression. PMID- 29250154 TI - MicroRNA-24 inhibits the proliferation and migration of endothelial cells in patients with atherosclerosis by targeting importin-alpha3 and regulating inflammatory responses. AB - The aim of the present study was to measure the level of microRNA (miRNA or miR) 24 in the serum of patients with atherosclerosis and to investigate the effect of miR-24 on the expression of importin-alpha3 and tumor necrosis factor (TNF) alpha, as well as the proliferation and migration of vascular endothelial cells. A total of 30 patients with atherosclerosis admitted to hospital between January and June 2016 were enrolled in the present study; 30 healthy subjects with a similar age range were enrolled as controls. Peripheral blood (10 ml) was collected from all participants. Human umbilical vein endothelial cells (HUVECs) were transfected with miR-24 mimic using Lipofectamine 2000. TargetScan was used to elucidate whether importin-alpha3 (KPNA4) was a target gene of miR-24. Expression levels of miR-24 and mRNAs were measured using reverse transcription quantitative polymerase chain reaction, and protein expression was determined using western blotting. Cell Counting Kit 8 assay was used to assess the proliferation of HUVECs, and a Transwell assay was performed to detect the migration of HUVECs. Expression of miR-24 in peripheral blood from patients with atherosclerosis was significantly lower when compared with healthy subjects (P<0.05). Overexpression of miR-24 was demonstrated to significantly inhibit the transcription and translation of the importin-alpha3 gene (P<0.05) and negatively regulate the expression of endothelial inflammatory factor TNF-alpha (P<0.05). Furthermore, overexpression of miR-24 significantly inhibited the proliferation and migration of HUVECs (P<0.05), and miR-24 knockdown significantly promoted these processes (P<0.05). The results of the present study suggest that miR-24 exerts its effect in atherosclerosis by blocking the nuclear factor-kappaB signaling pathway, regulating inflammation in endothelial cells, and inhibiting the proliferation and migration of vascular endothelial cells. PMID- 29250155 TI - Correlation of diffusion tensor imaging parameters and Gleason scores of prostate cancer. AB - The aim of the present study was to explore the association between the parameters of diffusion tensor imaging (DTI), including fractional anisotropy (FA) values, apparent diffusion coefficient (ADC) values and the diffusion tensor tractography (DTT) map, with the Gleason score of prostate cancer (PCa). A retrospective study of 50 cases of PCa confirmed by biopsy or surgical pathology was performed. Conventional magnetic resonance imaging and DTI scans were conducted in these cases. The 50 cases of PCa were divided into three groups, including low, intermediate and high grade, according to the Gleason score. Post DTI processing was performed using Neuro 3D software, in order to measure the FA and ADC values, and map the prostate fibers. Differences in FA and ADC values among the various PCa groups were examined using analysis of variance, while the correlation of FA and ADC values with the Gleason score was studied using Pearson correlation analysis. The obtained DTT map clearly demonstrated the spatial structure of the prostate fibers. The fibers of the cancer area were dense without interruption in the low-grade group, sparse and disordered in the intermediate-grade group, and were disordered, sparse or even absent in the high grade group. The FA values were 0.284+/-0.313, 0.293+/-0.347 and 0.369+/-0.347, respectively, with statistically significant differences observed among the three groups (F=234.533; P<0.05) and between each group (P<0.05). In addition, the FA value of PCa was positively correlated with the Gleason score (r=0.884; P<0.05). The ADC values of the low-, intermediate- and high-grade groups were 1.070+/ 0.072*10-3, 0.961+/-0.081*10-3 and 0.821+/-0.048*10-3, respectively, which demonstrated statistically significant differences among the three groups (F=49.987; P<0.05) and between each group (P<0.05). Furthermore, the ADC values of PCa were negatively correlated with Gleason score (r=-0.810; P<0.05). In conclusion, there was an association between DTI parameters and Gleason score, which may be used to evaluate the grading and prognosis of PCa. PMID- 29250156 TI - Restoration of osteogenic differentiation by overexpression of cannabinoid receptor 2 in bone marrow mesenchymal stem cells isolated from osteoporotic patients. AB - Cannabinoid receptor 2 (CNR2) has a critical role in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). CNR2 expression was found to be downregulated in osteoporotic patients. The present study aimed to investigate the functionality of CNR2 in restoring osteogenic differentiation and mineralization of BMSCs isolated from osteoporotic patients. CNR2 was overexpressed in osteoporotic BMSCs by a lentivirus. Alkaline phosphatase (ALP) activity staining and alizarin red S staining were performed to examine the osteogenic differentiation of osteoporotic BMSCs. Reverse-transcription quantitative polymerase chain reaction analysis was performed to examine the expression of osteogenic genes in BMSCs. Western blot analysis was used to study the activation of p38 mitogen-activated protein kinase (MAPK) during osteogenic differentiation of osteoporotic BMSCs after lentivirus-mediated overexpression of CNR2. The results demonstrated that overexpression of CNR2 in osteoporotic BMSCs increased ALP activity, promoted expression of osteogenic genes and enhanced deposition of mineralized extracellular matrix. In addition, phosphorylation of p38 MAPK was found to be increased by overexpression of CNR2. In conclusion, the present study indicated that restoration of CNR2 recovered the osteogenic differentiation of BMSCs isolated from osteoporotic patients. This finding may provide a novel strategy for a treatment approach for osteoporosis. PMID- 29250157 TI - Myrtol improves post-traumatic knee osteoarthritis by regulation of reactive oxygen species, transforming growth factor beta1 and apoptosis in a mouse model. AB - The present study tested whether myrtol improves post-traumatic knee osteoarthritis (PTKO) by regulating the reactive oxygen species (ROS), transforming growth factor beta1 (TGF-beta1) and apoptosis in a mouse model. PTKO model mice were administered with 150, 300 or 450 mg/kg myrtol for 8 weeks. ELISA analysis was used to measure tumor necrosis factor-alpha, interleukin-6, malondialdehyde, superoxide dismutase, reactive oxygen species and TGF-beta1 levels. Caspase-3 and Bax protein expressions were analyzed using western blot analysis. In the current study, treatment with myrtol improved the tissue damage and osteoarthritis score, while it also reversed the subchondral bone thickness, subchondral bone density, trabecular bone volume/relative trabecular bone volume ratio and trabecular bone spacing in PTKO mice. The activity of tumor necrosis factor alpha, interleukin-6, TGF-beta1, malondialdehyde, superoxide dismutase and ROS were effectively inhibited, and the protein expression of caspase-3 and Bax were clearly suppressed by treatment with myrtol in a mouse model of PTKO. In conclusion, the results demonstrated that myrtol treatment improved PTKO through the suppression of inflammation, oxidative stress, ROS, TGF-beta1 and Bax/caspase 3 in mice, and myrtol may be a potential agent for clinical therapy. PMID- 29250158 TI - Function of miR-25 in the invasion and metastasis of esophageal squamous carcinoma cells and bioinformatical analysis of the miR-106b-25 cluster. AB - MicroRNAs (miRNAs/miRs) are a class of small, non-coding RNA molecules that serve a key function in carcinogenesis and tumor progression. Recent evidence indicates that miRNAs may act as powerful regulators of migration and invasion. The present study aimed to investigate the effect of miR-25 on the invasion and metastasis of KYSE-150 and EC109 esophageal squamous cell carcinoma (ESCC) cells, and predict the mechanism of this effect by bioinformatically analyzing the miR-106b-25 cluster. In order to alter the expression of miR-25 in the two cell lines, a miR 25 inhibitor or mimic were transfected into the cells, which were then studied via Transwell migration and invasion assays. Subsequently, the target genes of the miR-106b-25 cluster were predicted using miRanda, PicTar, TargetScan and miRTarbase, and the functions of the target genes were predicted via Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Then, a protein-protein interaction (PPI) network was produced using the Search Tool for the Retrieval of Interacting Genes. The results revealed that overexpressing miR-25 led to significantly increased cell migration and invasion in KYSE150 and EC109 cells. Suppressing miR-25 resulted in significantly decreased cell migration and invasion in KYSE150 cells, while the result was not significant in EC109 cells. Target genes of the miR-106b-25 cluster were significantly enriched in the biological process regulation of cellular metabolic process and several cancer-associated pathways, such as those for glioma and melanoma. The PPI network revealed that PTEN, TP53, MDM2, E2F1, PRMT5, MCM2, RB1, CDKN1A, SHAD7 and EZH2 may serve core roles within the network and associate with one another during the pathogenesis of ESCC. These results indicate that a high expression of miR-25 promotes the invasion and metastasis of ESCC cells, while the influence of low expression of miR-25 differs with cells with different degrees of differentiation. Invasion and metastasis are not effected in cells with poor differentiation, while they were decreased in well differentiated cells. Furthermore, PTEN, TP53, MDM2, E2F1, PRMT5, MCM2, RB1, CDKN1A, SHAD7 and EZH2 may be targeted by the miR-106b-25 cluster, and act together to regulate the development of ESCC. PMID- 29250159 TI - TBX1 loss-of-function mutation contributes to congenital conotruncal defects. AB - Conotruncal defects (CTDs) account for ~30% of all types of congenital heart disease and contribute to increased morbidity and mortality rates. Increasing evidence suggests that genetic risk factors are involved in the pathogenesis of CTDs. Mutations in a number of genes, including the TBX1 gene that codes for a T box transcription factor essential for normal cardiovascular development, may contribute to the development of CTD. CTDs are genetically heterogeneous and the genetic defects responsible for CTDs in the majority of patients remain unknown. The present study sequenced the coding regions and splicing junction boundaries of TBX1 in 136 patients with CTDs and 300 matched healthy individuals. The disease-causing potential of the identified TBX1 sequence variation was evaluated using MutationTaster, PolyPhen-2, SIFT and PROVEN software. The functional characteristics of the mutant TBX1 gene were defined using a dual-luciferase reporter assay system. A novel heterozygous TBX1 mutation, p.S233Y, was identified in a patient with transposition of the great arteries (TGA) and a ventricular septal defect. This mutation was absent in the 300 controls and altered the amino acid produced, serine, which is evolutionarily conserved across several species, and was predicted to be pathogenic in silico. Luciferase assays conducted in COS-7 cells demonstrated that the newly identified TBX1 mutation was associated with significantly diminished transcriptional activation of the ANF promoter compared with the wild-type TBX1. To the best of our knowledge, the present study is the first to associate a TBX1 loss-of-function mutation with enhanced susceptibility to TGA, which adds significant insight to the molecular mechanism of TGA. PMID- 29250160 TI - Rutin inhibits coronary heart disease through ERK1/2 and Akt signaling in a porcine model. AB - Rutin has a variety of pharmacological actions, including radical reactivity, and protective activity against lipid peroxidation, viruses and acute pancreatitis; thus, it may be used as a treatment for many diseases. The present study aimed to investigate whether rutin inhibits coronary heart disease through extracellular signal-regulated kinase (ERK) 1/2 and Akt signaling in a porcine model. Male Chinese miniature pigs were randomly divided into four groups: A sham group, a coronary heart disease (CHD) model group, a group receiving 15 mg/kg rutin for 8 weeks following CHD modeling and a group receiving 45 mg/kg rutin for 8 weeks following CHD modeling. The results suggested that treatment with rutin suppressed the reduction in left ventricular ejection fraction and increase in systolic internal diameter that occurred in CHD model pigs. Rutin administration reduced the infarct size of the myocardium, attenuated LVEF, increased LVID and inhibited urine protein concentration, BUN and Scr expression levels in CHD model pigs. Results from western blot analysis demonstrated that in CHD pigs treated with 45 mg/kg rutin, the CHD-associated increases in transforming growth factor beta1 and SMAD2 expression and reductions in phosphorylated (p)-ERK1/2 and p-Akt expression were attenuated. The present study suggests that rutin inhibits coronary heart disease through ERK1/2 and Akt signaling pathways in a porcine model. PMID- 29250161 TI - Detection of K-ras gene mutations in feces by magnetic nanoprobe in patients with pancreatic cancer: A preliminary study. AB - The present study aimed to investigate the feasibility and effectiveness of detecting K-ras mutation by using magnetic nanoparticles in fecal samples of patients with pancreatic cancer at different stages. The novel methodology of K ras mutation detection was compared to the existing methodology of cancer antigen (CA)19-9 examination. Patients with pancreatic cancer (n=88), pancreatic benign diseases who displayed chronic pancreatitis (n=35), pancreatic mucinous cyst neoplasms (n=10) and pancreatic serous cyst (n=9) admitted to the Department of Surgery, Jiaxing Second Hospital were enrolled in the present study. Fecal samples were collected from all patients, DNA was extracted and magnetic nanoprobe was then used to detect K-ras mutation. The results obtained using the novel magnetic nanoprobe detection technique showed a K-ras mutation rate of 81.8% (72/88) in the patients with pancreatic cancer and 18.5% (10/54) in patients with pancreatic benign diseases. In patients with pancreatic cancer, the K-ras mutation rate was comparable in stages I + IIA and IIB + III + IV (78.9 vs. 84.0%; P>0.05). The sensitivity and specificity of K-ras mutation for detection of pancreatic cancer was 81.8 and 81.5%, respectively. Sixty-eight pancreatic cancer patients had >37 U/ml CA99 with a sensitivity and specificity for pancreatic cancer detection of 77.3 and 77.8%, which was not significantly lower than detection by the fecal K-ras mutations (P>0.05). Combinational detection of fecal K-ras mutations and serum CA19-9 significantly increased the sensitivity regarding pancreatic cancer detection to 97.7% (P<0.05), while the specificity was not enhanced (80.9%; P>0.05) compared with fecal K-ras mutations or CA19-9 alone. The findings showed that the magnetic nanoprobe is able to detect fecal K ras mutations in different stages of pancreatic cancer, with comparable sensitivity and specificity to CA19-9 examination for differentiating pancreatic cancer. Furthermore, combined detection of CA19-9 and K-ras mutations has enhanced sensitivity compared with CA19-9 alone. PMID- 29250162 TI - Changes in body composition and mRNA expression of ghrelin and lipoprotein lipase in rats treated with leuprolide acetate, a GnRH agonist. AB - Leuprolide acetate (LA), a gonadotropin-releasing hormone (GnRH) agonist, was identified to cause changes in body weight in experimental and clinical trials; however, to date, the effect of LA on the body composition has not been properly assessed. The aim of the present study was to evaluate the long-term effect of LA administration on body composition and the mRNA expression of ghrelin and lipoprotein lipase (LPL) in rats. Ovariectomized (OVX), ovariectomized and LA treated (OVX+LA), non-ovariectomized (CTRL) and non-ovariectomized but LA-treated (LA) rats were used. LA treatment was performed by intramuscular injection at 5 ug/kg every 72 h over 120 days. Analysis of body composition and mRNA expression of ghrelin and lipoprotein lipase were performed. The results indicated significant changes in body composition after treatment; in the OVX, LA, OVX+LA and CTRL group, the body weight was increased by 216.1, 183.7, 175.4 and 150.1%, respectively, compared with baseline. The fat mass in the LA group was 14% higher than that in the CTRL group, while that in the OVX group was 19% higher than that in the OVX+LA, and the fat-free mass was similar between the LA and CTRL as well as the OVX and OVX+LA groups. Following 120 days of treatment, the mRNA expression of ghrelin and LPL in the LA group was ~20% higher than that in the CTRL group, while that in the OVX+LA was downregulated in comparison with that in the OVX group. The results of the present study confirmed changes in body composition and mRNA expression of ghrelin and LPL caused by long-term administration of LA. LA may contribute to regulate food consumption and exert control over adipogenesis. PMID- 29250163 TI - miR-502-mediated histone methyltransferase SET8 expression is associated with clear cell renal cell carcinoma risk. AB - Genetic variants may affect the interactions between microRNAs (miRNAs/miRs) and their target genes by modulating their binding affinity or by creating, or destroying a miRNA-binding site. SET domain containing (lysine methyltransferase) 8 (SET8) is the sole lysine methyltransferase that catalyzes the monomethylation of histone H4 lysine 20, and is associated with tumor growth, invasion and metastasis. In the present study, the rs16917496 polymorphism within the miR-502 binding site of the SET8 mRNA 3' untranslated region (3'UTR) in patients with clear cell renal cell carcinoma (ccRCC) and healthy controls was genotyped. The SET8 CC genotype was associated with a decreased ccRCC risk compared with the CT [P=0.003; odds ratio (OR)=0.318; 95% confidence interval (CI), 0.146-0.691], TT (P=0.011; OR=0.402; 95% CI, 0.197-0.819) and CT+TT (P=0.004; OR=0.370; 95% CI, 0.186-0.736) genotypes. The SET8 CC genotype was associated with reduced SET8 expression based on immunostaining of ccRCC tissue. Low SET8 protein levels were negatively associated with tumor-node-metastasis staging in patients with ccRCC according to the size of tumor and lymph node metastases. SET8-knockdown inhibited renal carcinoma 786-O cell proliferation, migration and invasion. c-Myc and matrix metalloproteinase-7 mRNA expression were downregulated upon SET8 knockdown in renal carcinoma 786-O cells. These data indicated that SET8 may be a functional tumor promoter and that its activation, which is partially regulated by changing the miR-502 and SET8 3'UTR binding affinity, may serve an important role in ccRCC development. PMID- 29250164 TI - Radiofrequency heat-enhanced direct intratumoral chemotherapy for prostate cancer. AB - A novel, minimally invasive interventional technique, radiofrequency heat (RFH), has been suggested to improve the efficacy of chemotherapy for solid organ tumors. However, the treatment for prostate cancer has not been completely characterized. The aim of the present study was to investigate the in vitro and in vivo efficiency of chemotherapy in combination with RFH for the treatment of prostate cancer. The following four treatment groups were included: i) No treatment (control); ii) RFH-only; iii) chemotherapy (docetaxel)-only; and iv) combination therapy of docetaxel and RFH in human prostate cancer (HPC) cell lines and mice with HPC xenografts. In the in vitro experiments, a heating guidewire was attached under the bottom of the last chamber of the four-chamber cell culture slide, and was then connected to a radiofrequency (RF) generator. In the in vivo experiments, a tumor model was generated by subcutaneously injecting human prostate cancer cells into 24 male nu/nu mice. RFH was conducted by inserting the 0.022-inch heating-guidewire into the tumor. The follow-up magnetic resonance imaging demonstrated a significant reduction in the average tumor size in animals treated with combination therapy compared with those receiving RFH only and chemotherapy-only. The number of apoptotic cells and the average apoptotic index of the combination therapy group were significantly higher compared with those of the other three treatment groups. In conclusion, the results of the present study suggested that RFH is able to increase the therapeutic efficiency of docetaxel in prostate cancer, and this study serves as a foundation for the future development of an interventional molecular image guided local treatment strategy for prostate cancer that integrates RF technology, interventional oncology and direct intratumoral chemotherapy, as a replacement for systemic chemotherapy. PMID- 29250165 TI - Evaluating the associations between human circadian rhythms and dysregulated genes in liver cancer cells. AB - Network analysis is a useful approach in cancer biology as it provides information regarding the genes and proteins. In our previous study, a network analysis was performed on dysregulated genes in HepG2 cells, a hepatoblastoma cell line that lacks the viral infection, compared with normal hepatocytes, identifying the presence of 26 HUB genes. The present study aimed to identify whether these previously identified HUB genes participate in the network that controls the human circadian rhythms. The results of the present study demonstrated that 20/26 HUB genes were associated with the metabolic processes that control human circadian rhythms, which supports the hypothesis that a number of cancer types are dependent from circadian cycles. In addition, it was revealed that the CLOCK circadian regulator gene was associated, via cytoskeleton associated protein 5 (CKAP5), with the HUB genes of the HepG2 network, and that CKAP5 was associated with three other circadian genes (casein kinase 1epsilon, casein kinase 1delta and histone deacetylase 4) and 10 HepG2 genes (SH2 domain containing, ZW10 interacting kinetochore protein, aurora kinase B, cell division cycle 20, centromere protein A, inner centromere protein, mitotic arrest deficient 2 like 1, baculoviral IAP repeat containing 5, SPC24 NDC80 kinetochore complex component and kinesin family member 2C). Furthermore, the genes that associate the circadian system with liver cancer were demonstrated to encode intrinsically disordered proteins. Finally, the results of the present study identified the microRNAs involved in the network formed by the overlapping of HepG2 and circadian genes. PMID- 29250166 TI - Reactivity of thyroid papillary carcinoma cells to thyroid stimulating hormone dominated endocrine therapy. AB - This study investigated the effect of thyroid stimulating hormone (TSH) on the proliferation of papillary thyroid carcinoma (PTC) cells and the therapeutic effect of levothyroxine sodium (TH). PTC cells (TPC-1) were cultured using 0.1, 1.0 and 10 U/l TSH and 10-2, 10-4 and 10-6 mol/l TH. After the appropriate concentration was screened, TPC-1 cells were further divided into control group, TSH group, TH group and TSH+TH group. The cell proliferation was detected via methyl thiazolyl tetrazolium (MTT) method, TPC-1 cell cycle was detected via flow cytometer, and the mRNA and protein expression of cyclin D1 were detected via real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Compared with control group, TSH significantly promoted the proliferation of TPC-1 cells (P<0.05 or P<0.01), obviously promoted the transition of TPC-1 cells from G1 phase to S phase (P<0.01) and remarkably increased the mRNA and protein expression of cyclin D1 (P<0.01); but TH had a significant inhibitory effect on these results of TSH (P<0.05 or P<0.01). TSH can promote the proliferation of PTC cells, and the appropriate complement of TH can inhibit its proliferation. PMID- 29250167 TI - Associations between abnormal vitamin D metabolism pathway function and non-small cell lung cancer. AB - Lung cancer is a type of malignant tumor derived from the respiratory system, which is the leading cause of cancer-associated mortality worldwide, of which ~80% of cases are attributable to non-small cell lung cancer (NSCLC). A previous study demonstrated that 1alpha,25-Dihydroxyvitamin D3 (1alpha,25(OH)2D3), derived from the vitamin D metabolic pathway contributes an antitumor effect. Aberrant expression of the essential enzyme encoding genes, Cytochrome P450 Family 27 Subfamily A Member 1 (CYP27A1), Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1), and Cytochrome P450 Family 24 Subfamily A Member 1 (CYP24A1) may be associated with lung cancer. However, a lack of evidence exists concerning the association between CYP27A1, CYP27B1, CYP24A1 expression and NSCLC. The aim of the present study was to investigate the functions of CYP27A1, CYP27B1 and CYP24A1 expression in NSCLC. Lung cancer tissue and para-carcinoma control tissue were collected from patients with NSCLC. Reverse transcription-quantitative polymerase chain reaction was applied to analyze CYP27A1, CYP27B1 and CYP24A1 mRNA expression in lung cancer tissues. An association analysis was performed between the aforementioned metabolic enzymes and patients with NSCLC age, gender, tumor node metastasis (TNM) stage, pathological type, differentiation and prognosis. CYP27B1 and CYP24A1 mRNA were upregulated in NSCLC compared with controls (P<0.05). However, no significant differences in CYP27A1 expression were observed between NSCLC and control. In addition, CYP24A1 expression was not associated with age, sex, smoking or TNM stage, but was associated with pathological type, differentiation and prognosis (P<0.05). CYP27B1 expression was significantly associated with TNM stage, differentiation, and prognosis, but not age, sex, smoking or pathological type. In conclusion, CYP27B1 and CYP24A1 may be considered as independent prognostic factors of NSCLC and may be novel therapeutic targets to assist clinical diagnosis, treatment and prognosis of the disease. PMID- 29250168 TI - Anti-angiogenic effect of Livistona chinensis seed extract in vitro and in vivo. AB - The present study aimed to detect the impact of the ethanol extract of the Livistona chinensis seed (EELC) on angiogenesis in human umbilical vein endothelial cells (HUVECs). A chorioallantoic membrane (CAM) assay was used to detect the anti-angiogenic activity of EELC in vivo. In vitro, the effect of EELC on the proliferation, migration and angiogenesis of HUVECs was determined by an MTT assay, a wound healing assay and a tube formation assay, respectively. The vascular endothelial growth factor (VEGF)-A and VEGF receptor (VEGFR)-2 protein and mRNA level were measured with ELISA and reverse transcription-semi quantitative polymerase chain reaction. It was observed that EELC significantly decreased the formation of new vessels in the CAM assay. EELC inhibited the proliferation and migration of HUVECs. The extent of tube formation by HUVECs was also reduced by EELC. In addition, EELC treatment reduced the level of VEGF-A and VEGFR-2 mRNA and protein. The results suggest that EELC inhibits tumor angiogenesis through inhibiting the proliferation and migration of HUVECs, and by downregulating VEGF and VEGFR. PMID- 29250170 TI - Liver X receptors as potential targets for cancer therapeutics. AB - Liver X receptors (LXRs) are important members of the nuclear receptor family that were originally determined to function in cholesterol transport and the regulation of immune responses. Synthetic LXR ligands have been developed to treat various diseases including diabetes, Alzheimer's disease and atherosclerosis. Previous studies have suggested that LXRs are also involved in numerous types of cancer and are therefore potential targets for cancer therapeutics. The present review summarizes LXR ligands and their mechanisms of action, the effects of LXRs in different types of cancer and their potential applications in clinical treatment. Together, the studies discussed in the present review indicate that LXRs may be potential targets for cancer therapeutics. PMID- 29250169 TI - Therapeutic strategies against cancer stem cells in human colorectal cancer. AB - Colorectal cancer (CRC) is the third most frequent malignancy and represents the fourth most common cause of cancer-associated mortalities in the world. Despite many advances in the treatment of CRC, the 5-year survival rate of patients with CRC remains unsatisfactory due to tumor recurrence and metastases. Recently, cancer stem cells (CSCs), have been suggested to be responsible for the initiation and relapse of the disease, and have been identified in CRC. Due to their basic biological features, which include self-renewal and pluripotency, CSCs may be novel therapeutic targets for CRC and other cancer types. Conventional therapeutics only act on proliferating and mature cancer cells, while quiescent CSCs survive and often become resistant to chemotherapy. In this review, markers of CRC-CSCs are evaluated and the recently introduced experimental therapies that specifically target these cells by inducing CSC proliferation, differentiation and sensitization to apoptotic signals via molecules including Dickkopf-1, bone morphogenetic protein 4, Kindlin-1, tankyrases, and p21-activated kinase 1, are discussed. In addition, novel strategies aimed at inhibiting some crucial processes engaged in cancer progression regulated by the Wnt, transforming growth factor beta and Notch signaling pathways (pyrvinium pamoate, silibinin, PRI-724, P17, and P144 peptides) are also evaluated. Although the metabolic alterations in cancer were first described decades ago, it is only recently that the concept of targeting key regulatory molecules of cell metabolism, such as sirtuin 1 (miR-34a) and AMPK (metformin), has emerged. In conclusion, the discovery of CSCs has resulted in the definition of novel therapeutic targets and the development of novel experimental therapies for CRC. However, further investigations are required in order to apply these novel drugs in human CRC. PMID- 29250171 TI - Computational identification of microRNAs and their targets in liver cirrhosis. AB - Previous studies have revealed that the deregulation of circulating miRNAs is associated with liver cirrhosis. The present study aimed to identify reliable candidate biomarkers to improve the early detection of liver cirrhosis. An integrated analysis of expression profiles of microRNAs (miRNAs/miRs) and mRNAs in liver cirrhosis tissues from the GEO database was performed. Next, the regulatory targets of the differentially expressed miRNAs in liver cirrhosis tissues were predicted. In addition, a regulatory network of miRNA-target genes was constructed. A total of 4 eligible mRNA expression profiling studies and 2 miRNA expression profiling studies met the inclusion criteria, and were thus included. A total of 48 differentially expressed miRNAs and 1,773 differentially expressed genes were identified in liver cirrhosis tissues compared with normal tissues. There were 240 miRNA-target pairs whose expression was negatively correlated. In the miRNA-target regulatory network, overexpression of miR-21 and miR-199a-3p was suggested to be closely associated with the progression of liver cirrhosis. In addition, functional enrichment analysis of the target genes indicated that cell cycle was the most significantly enriched pathway, and the dysregulation of leukemia inhibitory factor, cancerous inhibitor of protein phosphatase 2A and retinoblastoma-associated protein 1 clearly suggested their importance in the development of liver cirrhosis. We hypothesized that miR-21 and miR-199a-3p may be promising non-invasive diagnostic biomarkers for the early diagnosis of liver cirrhosis. The miRNA-target regulatory network may provide additional insight into the current data regarding the role of miRNAs in liver cirrhosis. PMID- 29250172 TI - Association between integrin-linked kinase and hyperthermia in oral squamous cell carcinoma. AB - The present study aimed to observe the effect of the biological functions of integrin-linked kinase (ILK) silencing combined with hyperthermia on Tca8113 cells. Lentivirus-mediated short hairpin RNA (shRNA)-targeting ILK was transfected into oral squamous cell carcinoma (OSCC) Tca8113 cells and, combined with hyperthermia, several experimental methods were used to detect their biological behavior in vitro. On the basis of in vitro experiments, Tca8113 cells were transplanted into nude mice models, and ILK-shRNA-lentivirus was injected into the nude mice transplanted tumor and combined with hyperthermia. Tumor morphology and the associated protein expression changes were determined. Subsequent to ILK silencing combined with hyperthermia, the growth, migration and proliferation of Tca8113 cells were significantly inhibited. Flow cytometry revealed that the cells were blocked in the S phase, and western blot analysis demonstrated that ILK, phosphorylated (p)-RAC-alpha serine/threonine-protein kinase (Akt), p-glycogen synthase kinase-3beta and p-heat shock factor 1 protein expression levels were significantly decreased, while apoptosis-associated protein B-cell lymphoma-2-associated X protein expression and the efficacy of hypothermia were significantly increased. By ILK silencing combined with hyperthermia, a significant therapeutic effect on transplanted tumors was observed in nude mice. Immunohistochemistry revealed the same results as the in vitro experiments. ILK silencing combined with hyperthermia can inhibit the growth, proliferation and migration of Tca8113 cells, promote Tca8113 cell apoptosis, inhibit the phosphatidylinositol-3-kinase/Akt signaling pathway and increase hyperthermia sensitivity; the combination therapy exhibits a synergistic sensitizing effect. Therefore, ILK silencing combined with hypothermia may serve as a novel combination therapy strategy against OSCC. PMID- 29250174 TI - Increased expression of tumor protein D54 is associated with clinical progression and poor prognosis in patients with prostate cancer. AB - Tumor protein D54 (TPD54) has been reported to be involved in the prognosis of several cancers. However, the involvement of TPD54 in prostate cancer (PCa) is yet to be elucidated. In the present study, 117 patients with PCa were enrolled. The mRNA and protein levels of TPD54 in PCa tissues and adjacent normal prostate tissues were analyzed by quantitative polymerase chain reaction and western blotting. TPD54 expression was also determined by immunohistochemistry (IHC) in paraffin-embedded PCa tissues. The association between TPD54 expression and clinicopathological features and prognosis was evaluated. The results revealed that the expression levels of TPD54 mRNA and protein were upregulated in PCa tissues compared with adjacent normal prostate tissues. In addition, moderate/strong staining of TPD54 was observed in 91.4% (107/117) of PCa tissues, but only in 32.5% (38/117) of adjacent normal prostate tissues, as assessed by IHC. TPD54 expression was significantly associated with Gleason score (P=0.0001). In addition, patients with PCa with moderate/strong TPD54 expression had shorter biochemical recurrence-free survival times compared with those with negative/weak TPD54 expression (P=0.002). Multivariate analysis indicated that TPD54 overexpression was an independent prognostic factor for patients with PCa (hazard ratio, 2.259; 95% confidence interval, 1.09-4.679; P=0.028). Taken together, these results indicated that TPD54 is a predictor of poor outcome for patients with PCa, and may be a potential prognostic marker for patients with PCa. PMID- 29250173 TI - Hypoxia-inducible factor 1 mediates intermittent hypoxia-induced migration of human breast cancer MDA-MB-231 cells. AB - Metastasis is the major cause of triple-negative breast cancer (TNBC)-associated mortality. Hypoxia promotes cancer cell migration and remote metastasis, which occur with hypoxia inducible factor 1alpha (HIF-1alpha) stabilization and vimentin upregulation. However, the evolutionary dynamics that link the changes in HIF-1alpha and vimentin levels under hypoxic conditions are not well understood. In the present study, the effects of intermittent hypoxia (IH), continuous hypoxia (CH) and normoxia on the migration and proliferation of human TNBC MDA-MB-231 cells were investigated. The results demonstrated that IH significantly increased the migration of MDA-MB-231 cells, and this effect was dependent on the number of cycles of hypoxia-reoxygenation. Unexpectedly, IH significantly inhibited cell proliferation, while CH only caused such an effect if hypoxia extended for >=3 days. IH and CH induced HIF-1alpha protein accumulation and vimentin upregulation, with a greater effect observed in IH. Knockdown of HIF-1alpha with siRNA abolished IH-induced cell migration and vimentin upregulation. In summary, multiple cycles of hypoxia and reoxygenation have a more pronounced effect on the promotion of TNBC invasiveness than CH; HIF 1alpha activation and downstream vimentin upregulation may account for this phenotypic change. PMID- 29250175 TI - ATP7B expression in human glioblastoma is related to temozolomide resistance. AB - Glioblastoma multiforme (GBM) is one of the most aggressive types of brain malignancy, with resistance to chemotherapy being a primary treatment obstacle. ATPase copper transporting beta (ATP7B) is involved in multidrug resistance; however, its expression in GBM remains to be evaluated. In the present study, GBM specimens from 79 patients who underwent gross total tumor removal followed by concomitant temozolomide (TMZ) chemotherapy and radiotherapy were assessed immunohistochemically. The association between the overall survival times of patients and the expression of ATP7B in neoplastic cells was evaluated. In 12/79 tumors (15.2%) >10% of neoplastic cells were immunohistochemically-positive for ATP7B, and categorized as high-ATP7B GBM. In the remaining 67 tumors (84.8%) the rate of ATP7B-positive cells was <10% and recorded as low-ATP7B GBM. The median overall survival times of patients with high- and low-ATP7B GBM were 14.6, and 24.7 months, respectively. High expression of ATP7B was identified to be associated with shorter overall survival times (hazard ratio, 0.452; 95% confidence interval, 0.206-0.994; P=0.048). Of the 79 patients, 12 underwent a second operation due to recurrence. These tissue samples were also subjected to immunohistochemical study. The ATP7B positivity rate of tumor cells obtained during the second surgery was significantly higher compared with that in the first surgery (9.17+/-2.56 vs. 2.75+/-0.55%; P=0.008). In addition, two ATP7B transfected GBM cell lines were identified to be significantly resistant (3.8- and 1.7-fold, respectively) to TMZ compared with the control cell line. The findings of the present study suggest that ATP7B influences GBM resistance to TMZ. PMID- 29250176 TI - Leucine-rich repeat-containing G protein-coupled receptor 5 and CD133 expression is associated with tumor progression and resistance to preoperative chemoradiotherapy in low rectal cancer. AB - Preoperative chemoradiotherapy has been performed as a standard therapy for advanced low rectal cancer. Cancer stem cells (CSCs) have been reported to contribute to resistance to treatment and patient prognosis. Leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) and cluster of differentiation (CD133) are putative markers for CSCs. However, their prognostic ability remains unknown, and evaluation of a single marker can be insufficient due to the heterogeneity of cancer. LGR5 and CD133 expression was immunohistochemically evaluated in surgical specimens of 56 patients who received curative resection following chemoradiotherapy for advanced low rectal cancer. In addition, the correlations between their expression levels, and clinicopathological features and patient prognosis were asessed. LGR5 expression was significantly correlated with lymphatic invasion, lymph node metastasis, and tumor node metastasic (TNM) stage. CD133 expression was significantly correlated with vascular invasion and the tumor regression grade. Combined expression was significantly correlated with lymphatic invasion, tumor regression grade and TNM stage, but not with overall, and disease-free survival. LGR5 and CD133 expressions may represent useful markers associated with tumor progression and resistance to chemoradiotherapy in patients with low rectal cancer. Furthermore, combined expression of these markers may be a more useful marker compared with the expression of each single marker. PMID- 29250177 TI - MicroRNA-139 targets fibronectin 1 to inhibit papillary thyroid carcinoma progression. AB - Thyroid cancer is the most common tumour of the endocrine system, and its incidence rate has markedly increased over the past several decades. Aberrantly expressed microRNAs (miRNAs) are reportedly involved in the formation and progression of papillary thyroid carcinoma (PTC) by regulating their target genes. Thus, miRNAs may be potential molecular biomarkers for the prediction and prognosis of PTC, and also as novel therapeutic targets for patients with PTC. miR-139 has recently been reported to be aberrantly expressed in several types of cancer. However, the expression levels, biological functions and the associated molecular mechanism of miR-139 in PTC have not been clearly elucidated. The results of the present study revealed that miR-139 expression was downregulated in PTC tissues and cell lines when compared with adjacent normal tissues and normal human thyroid cells, respectively. The restoration of miR-139 expression suppressed cellular proliferation and invasion in PTC in vitro. In addition, fibronectin 1 (FN1) was identified as a direct target of miR-139 in PTC. Furthermore, FN1 was highly expressed in PTC tissues and negatively associated with miR-139 expression. Moreover, the tumour-suppressive effects of miR-139 overexpression on PTC cells were ameliorated by ectopic FN1 expression. To the best of our knowledge, the present study is the first to demonstrate that miR-139 may serve as a tumour suppressor and serve important roles in inhibiting tumourigenesis by targeting FN1 in PTC cells. PMID- 29250178 TI - Toll-like receptor-9 in hypoxic nasopharyngeal carcinoma cells and its correlation with cell proliferation and apoptosis. AB - The purpose of this study was to investigate the correlation between the expression of Toll-like receptor-9 (TLR-9) and cell proliferation and apoptosis in hypoxic nasopharyngeal carcinoma cells. Human nasopharyngeal carcinoma cell line HNE-1 (EBV positive) and CNE-1 (EBV negative) were used. Cells were divided into normal control group, hypoxia group and hyperoxia group. Hypoxic conditions were 5% CO2 and 0.01% partial pressure of oxygen, hyperoxia conditions were 5% CO2 and 10% partial pressure of oxygen. Reverse transcription-PCR (RT-PCR) and western blot analysis were used to detect the expression of TLR-9 mRNA and protein at 6, 12 and 24 h after the beginning of cell culture. MTT assay was used to detect the cell proliferation rate and flow cytometry was used to detect cell apoptosis rate. Expression levels of TLR-9 mRNA and protein in hypoxia group reached the peak at 12 h after the beginning of cell culture, and were significantly higher than those of hyperoxia group at all time-points, expression levels of TLR-9 mRNA and protein of control group were the lowest, difference between groups were all statistically significant (P<0.05). No significant changes in expression levels of TLR-9 mRNA and protein were found in control group and hyperoxia group between different time-points (P>0.05). Compared with the other two groups, cell proliferation rate was gradually decreased and apoptotic rate was gradually decreased in hypoxia group, significant differences were found between hypoxia group, and control group and hyperoxia group (P<0.05), no significant differences were found between control group and hyperoxia group (P>0.05). In conclusion, TLR-9 was highly expressed in hypoxic nasopharyngeal carcinoma cells regulating cell proliferation and apoptosis, which may be an important mechanism of tumorigenesis and a potential target for intervention therapy. PMID- 29250179 TI - No association between triple-negative breast cancer and prognosis of patients receiving breast-conserving treatment. AB - The role of triple-negative breast cancer (TNBC) in breast-conserving treatment is controversial. The present study aimed at evaluating the prognosis of patients with TNBC following breast-conserving treatment (BCT) within 5 years. The present study investigated a cohort of 757 patients with early stage breast cancer, diagnosed and treated with BCT between January 2002 and March 2010 at Tianjin Medical University Cancer Institute and Hospital. The patients were divided into three groups according to receptor expression: Estrogen receptor (ER) or progesterone receptor (PR)-positive; epidermal growth factor receptor 2 (HER2) enriched: ER and PR negative but HER2-positive; TNBC: ER, PR and HER2 receptor negative. The primary endpoint was recurrence or mortality within 5 years after breast cancer diagnosis. Multivariable Cox analysis was used to determine the risk of locoregional relapse, distant metastases, total relapse and mortality associated with the intrinsic subtypes. Of the 757 patients with status of all receptors available, 541 (71.5%) were luminal, 66 (8.7%) were HER2-enriched and 150 (19.8%) were TNBC. Patients with TNBC were more likely to have histological grade III tumors (27.3%) compared with luminal (8.3%) and HER2-enriched (16.7%) subtypes (P<0.001). Within 5 years, locoregional recurrence rate was 2.4, 7.6 and 7.3% for luminal, HER2-enriched and TNBC, respectively (P=0.005). Mortality rate was 2.2, 9.1 and 4.7% for luminal, HER2-enriched and TNBC, respectively (P=0.007). There was no significant difference in rates of distant metastases (P=0.164) and total relapse (P=0.138). TNBC was not an independent prognostic predictor for women treated with BCT within 5 years after breast cancer diagnosis on multivariate analysis. Patients with TNBC were not at significantly increased 5-year risks of locoregional recurrence, distant metastasis, total relapse or mortality at so remain appropriate candidates for BCT. PMID- 29250180 TI - Bioinformatics analysis of gene expression profiles to identify causal genes in luminal B2 breast cancer. AB - Patients with the luminal B subtype of breast cancer exhibit a poor prognosis, high metastatic risk and high incidence of chemotherapy resistance. Luminal B breast cancer is sub-classified into B1 and B2. The pathophysiological mechanism of luminal B2 breast cancer (LB2BC) progression has yet to be characterized. Therefore, the present study aimed to identify the genes involved in the pathogenesis of LB2BC. The data of 117 LB2BC expression profiles were downloaded from The Cancer Genome Atlas (TCGA) and differentially expressed genes (DEGs) were identified by comparison with non-tumor tissue expression profiles. Gene Ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and protein-protein interaction (PPI) networks were used to obtain insight into the functions of DEGs. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was performed to validate the expression level of DEGs in tissue samples. A total of 2,251 DEGs, including 759 upregulated and 1,492 downregulated genes, were identified between LB2BC and non tumor tissues. The top 15 upregulated and downregulated genes were used to construct a PPI network: Epidermal growth factor receptor (EGFR), fibronectin-1 (FN1) and Polo-like kinase-1 had the highest connectivity degrees. KEGG analysis identified that DEGs were most significantly enriched in 'focal adhesion', 'pathways in cancer' and 'ECM-receptor interaction' pathways. The results of RT qPCR demonstrated that EGFR was significantly downregulated in LB2BC, whereas FN1 was significantly upregulated, whereas neurotrophic receptor tyrosine kinase 2 (NTRK2) trended towards downregulation. In conclusion, the DEGs identified in the present study, including NTRK2, FN1 and EGFR, may serve pivotal roles in the tumorigenesis of LB2BC by affecting the 'focal adhesion', 'pathways in cancer' and 'ECM-receptor interaction' KEGG pathways. PMID- 29250181 TI - Human thymic stromal lymphopoietin promotes the proliferation and invasion of cervical cancer cells by downregulating microRNA-132 expression. AB - Thymic stromal lymphopoietin (TSLP), produced by cervical cancer (CC) cells, promotes angiogenesis, and the recruitment and functional regulation of eosinophils. It has been reported that microRNA (miR)-132 is aberrantly decreased in CC tissues. However, the function and mechanism of TSLP on the biological behaviors of CC cells is largely unknown. The aim of the present study was to investigate the effect of TSLP on the expression of miR-132 and the proliferation and invasion in vitro of CC cell lines, namely, HeLa and SiHa cells. The transcrpitional level of miR-132 was analyzed using reverse transcription quantitative polymerase chaon reaction. The proliferation, invasion, and the expression of proliferation and invasion-related molecules in HeLa and SiHa cells in vitro were evaluated using bromodeoxyuridine cell proliferation, Matrigel invasion assays, flow cytometry and ELISA, respectively. Here, it was revealed that recombinant human TSLP (rhTSLP) downregulated the expression levels of miR 132 in HeLa and SiHa cells, and by contrast, the neutralizing antibodies for TSLP or TSLP receptor (TSLPR) upregulated miR-132 expression levels in HeLa and SiHa cells. The overexpression of miR-132 resulted in a lowered proliferation and invasiveness, decreased levels of proliferation-associated molecules marker of proliferation Ki-67 and proliferating cell nuclear antigen, and the decreased production of matrix metalloproteinase (MMP)2 and MMP9 in HeLa and SiHa cells. Compared with the control group, there was a higher level of proliferation and invasion in HeLa and SiHa cells following stimulation with rhTSLP. However, these effects induced by rhTSLP were significantly impaired in HeLa and SiHa cells with miR-132 overexpression. The results of the present study indicated that TSLP produced by CC cells downregulated miR-132 expression, and stimulated the proliferation and invasion of CC cells, thereby further promoting the development of CC. PMID- 29250182 TI - Peripheral lung adenocarcinomas harboring epithelial growth factor receptor mutations with microRNA-135b overexpression are more likely to invade visceral pleura. AB - Lung adenocarcinoma, characterized by its early and aggressive local invasion and high metastatic potential, is the most frequently observed histological type of non-small-cell lung cancer (NSCLC). Visceral pleural invasion (VPI) caused by peripheral lung adenocarcinomas is closely associated with the poor prognosis of patients with NSCLC. The association between VPI and some clinicopathological characteristics has been observed in the past few decades. However, the molecular mechanism of VPI in lung adenocarcinomas is unknown. In the present, the expression level of microRNA (miR-)135b and epidermal growth factor receptor (EGFR) mutations using the reverse transcription-quantitative polymerase chain reaction and DNA sequencing, respectively. In addition, the present study aimed at exploring the association between the miR-135b level, EGFR mutations and VPI in peripheral lung adenocarcinoma. The results of the present study demonstrated that miR-135b was significantly upregulated in lung adenocarcinoma compared with adjacent normal tissue and positively associated EGFR mutations in peripheral lung adenocarcinoma. Furthermore, it was identified that lung adenocarcinomas with EGFR mutations and miR-135b overexpression were more likely to invade visceral pleura. Taken together, these findings indicate that miR-135b overexpression is positively associated with mutations to EGFR, which may promote the development of peripheral lung adenocarcinomas by the formation of VPI. This indicates that the two factors may serve as prognostic markers and molecular targets for the treatment of peripheral lung adenocarcinomas. PMID- 29250183 TI - Ampelopsin-induced reactive oxygen species enhance the apoptosis of colon cancer cells by activating endoplasmic reticulum stress-mediated AMPK/MAPK/XAF1 signaling. AB - Ampelopsin (Amp) is bioactive natural product and exerts anti-cancer effects against several cancer types. The present study investigated the anti-colon cancer activity of Amp and explored its mechanism of action. The treatment of colon cancer cells with Amp resulted in the dose- and time-dependent induction of apoptosis via the activation of endoplasmic reticulum (ER) stress, 5' adenosine monophosphate-activated protein kinase (AMPK), and c-Jun N-terminal protein kinase (JNK)/p38 mitogen-activated protein kinases (MAPKs). Salubrinal, an ER stress inhibitor, prevented the upregulation of ER stress-associated proteins, including phosphorylated protein kinase RNA-like ER kinase, phosphorylated eukaryotic translation initiation factor 2alpha, glucose-regulated protein 78, and CCAAT/enhancer-binding protein homologous protein, as well as suppressing AMPK activation and the MAPK signaling pathway. Knockdown of AMPK by RNA interference failed to block ER stress. Additionally, SP600125 (a JNK inhibitor) and SB203580 (a p38-MAPK inhibitor) effectively inhibited apoptosis and attenuated the expression of X-linked IAP-associated factor 1 (XAF1) and apoptotic Bcl-2 family proteins (BCL2 antagonist/killer 1 and BCL2-associated X protein) in Amp-treated colon cancer cells. Furthermore, reactive oxygen species (ROS)-mediated ER stress/AMPK apoptotic signaling pathway in Amp-treated colon cancer cells were markedly inhibited by treatment with N-acetyl-L-cysteine, a ROS scavenger. These results demonstrate that treatment with Amp induces the apoptotic death of colon cancer cells through ER stress-initiated AMPK/MAPK/XAF1 signaling. These results also provide experimental information for developing Amp as therapeutic drug against colon cancer. PMID- 29250184 TI - Imbalance in circulatory iNKT, Th17 and T regulatory cell frequencies in patients with B-cell non-Hodgkin's lymphoma. AB - T cells are important in B-cell non-Hodgkin's lymphoma immunity, however the function of T cell subsets, including natural killer (iNKT), T helper (Th)17, and T regulatory cells remains to be elucidated. The present study analyzed the frequencies of iNKT, Th17 and T regulatory cells in the peripheral blood of 41 patients with B-cell non-Hodgkin lymphoma at diagnosis, then during and following immunochemotherapy R-CHOP/R-CVP. At lymphoma diagnosis, iNKT and Th17 frequencies were decreased and T regulatory cell frequencies were increased compared with healthy control group. The Th17 cell percentage was lower in patients with a worse prognosis and at a more advanced clinical stage and in contrast, the percentage of T regulatory cells was increased in patients at advanced stages of lymphoma, compared to earlier stages. There was an increase of iNKT and Th17 cells following R-CHOP/R-CVP therapy. In patients that responded, both prior to and following-treatment, percentages of iNKT and Th17 were higher and T regulatory cells were lower compared with patients with subsequent disease progression. Taken together, the results obtained demonstrated the opposing effects of T cell subsets in B-cell lymphoma immunity, with iNKT and Th17 inhibiting and T regulatory cells enhancing tumor growth. These alterations may be caused by malignant B-cells, however there may also be an axis of inverse feedback between T regulatory cells and their interaction with Th17 and iNKT cells. PMID- 29250185 TI - Inhibition of Gli1-mediated prostate cancer cell proliferation by inhibiting the mTOR/S6K1 signaling pathway. AB - Ectopic activation of the canonical Hedgehog signaling pathway is involved in the development and progression of prostate cancer, which is one of the leading causes of cancer-associated mortality in males worldwide. However, the role of the non-canonical Hedgehog signaling pathway in prostate cancer remains generally unexplored. In the present study, it was identified that Gli (glioma-associated oncogene)1 and Gli2 were highly expressed at the protein level in the androgen independent prostate cancer cell lines PC3 and DU145, but not in the androgen dependent cancer cell line LNCaP. Silencing of Gli1 using small interfering RNA markedly decreased PC3 cell viability and liquid colony formation in vitro. The Gli1/2-specific inhibitor GANT61 markedly decreased cell viability by inducing cell apoptosis in PC3 and DU145 cells. GANT61 also alleviated liquid colony formation efficiency in PC3 and DU145 cells, suggesting that the activity of Gli1 is required for prostate cancer cell survival. To explore further the upstream signaling pathway involved in the regulation of Gli1 expression, it was identified that tumor necrosis factor alpha-triggered mammalian target of rapamycin (mTOR)/p70 ribosomal protein S6 kinase 1 (S6K1) activation was required for Gli1 expression. Pharmacological and genetic inhibition of S6K1 activation markedly decreased Gli1 and its downstream target gene mRNA expression. In addition, the phosphoinositide 3-kinase/mTOR inhibitor BEZ235 markedly decreased in vitro PC3 cell proliferation. The results of the present study indicate that the non-canonical Hedgehog pathway (mTOR/S6K1/Gli1) contributes to the development and progression of prostate cancer and that Gli1 is a potential therapeutic target in the treatment of prostate cancer. PMID- 29250186 TI - Knockdown of long non-coding RNA HOTAIR sensitizes hepatocellular carcinoma cell to cisplatin by suppressing the STAT3/ABCB1 signaling pathway. AB - Long non-coding RNA HOX transcript antisense RNA (HOTAIR) has been demonstrated to exhibit oncogenic activity in several types of cancer, including hepatocellular carcinoma (HCC). However, the association between HOTAIR and HCC multidrug resistance remains uncertain. The present study aimed to investigate the role of HOTAIR in HCC chemoresistance; it was found that knockdown of HOTAIR expression in HCC Huh7 cells resulted in decreased cell proliferation and increased chemosensitivity to cisplatin. Furthermore, expression levels of ATP binding cassette subfamily B member 1 (ABCB1) mRNA and protein were decreased in Huh7 cells upon HOTAIR-knockdown. In addition, HOTAIR-knockdown reduced the levels of phosphorylated signal transducer and activator of transcription 3 (STAT3), and inhibition of STAT3 phosphorylation reduced HOTAIR-mediated ABCB1 expression. Together, these findings indicated that knockdown of HOTAIR in Huh7 cells decreased STAT3 activity and ABCB1 expression, and increased chemosensitivity to cisplatin. Thus HOTAIR could serve as a novel potential therapeutic target to reverse multidrug resistance in HCC. PMID- 29250187 TI - Knockdown of Rhotekin 2 expression suppresses proliferation and induces apoptosis in colon cancer cells. AB - Colon cancer is one of the most common malignant tumors in the human body, ranking second as a gastrointestinal tumor. It has a high incidence in Europe, America and China and more than 1 million new cases of colon cancer are reported worldwide each year. The incidence of colon cancer in China has increased from 12/0.1 million in the early 1970s to 56/0.1 million at present with an annual growth rate of 4.2%, which far exceeds the international level (2%). Rhotekin (RTKN) 2, a Rho-guanosine triphosphatase (GTPase) effector, has been reported to be anti-apoptotic. However, the molecular mechanism underlying the biological function of RTKN2 in colon cancer remains unknown. The present study investigated whether the mRNA expression level of RTKN2 was markedly higher in 30 human colon cancer specimens compared with adjacent non-cancerous tissues. The results showed that the protein expression level of RTKN2 was significantly higher in SW480 and HCT116 cells, compared with HIEC cells. Knockdown of RTKN2 in the SW480 and HCT116 colon cancer cells, by lentivirus-mediated RNA interference led to the notable inhibition of cell proliferation and cell cycle progression, by reducing the expression levels of the PCDA, Cyclin D1 and c-myc cell cycle-associated proteins. The inhibitory effect of RTKN2 silencing on the proliferation of colon cancer cells may be partially realized by inhibiting the Wnt/beta-catenin signaling pathway. Furthermore, the silencing of RTKN2 in the cells induced apoptosis by reducing the expression level of Bax and increasing the expression level of Bcl2. These results show that RTKN2 is involved in the carcinogenesis and progression of human colon cancer, indicating that RTKN2 may be a molecular target in colon cancer therapy. PMID- 29250188 TI - Low miR-210 and CASP8AP2 expression is associated with a poor outcome in pediatric acute lymphoblastic leukemia. AB - The prognostic significance of microRNA (miR)-210 and the caspase 8-associated protein 2 (CASP8AP2) gene in children with acute lymphoblastic leukemia (ALL) has been validated and CASP8AP2 has been demonstrated as a target of miR-210. In the present study, the reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to determine miR-210 and CASP8AP2 expression in 91 children with ALL. Associations between gene expression levels and the prognostic value of combined detection of the two indicators were analyzed. Results from a receiver operating characteristic curve demonstrated that threshold values of miR-210 and CASP8AP2 were 3.8243 and 0.4760, respectively. Although the expression of miR-210 and CASP8AP2 were not associated at the mRNA level in pediatric ALL, combined detection of the two predicted ALL prognosis with an increased accuracy. Furthermore, an equation was devised including minimal residual disease at day 33 and expression of miR-210 and CASP8AP2, which may enable bone marrow relapse to be predicted more precisely compared with the current risk stratification. PMID- 29250189 TI - DDR2 facilitates papillary thyroid carcinoma epithelial mesenchymal transition by activating ERK2/Snail1 pathway. AB - The upregulation of discoidin domain receptor tyrosine kinase 2 (DDR2) has been reported to be associated with poor prognosis and metastasis in numerous tumor types by inducing epithelial-mesenchymal transition (EMT); however, the expression profile of DDR2 in papillary thyroid carcinoma (PTC) with local metastasis and the effect of DDR2 on PTC cells remain unknown. The aim of the present study was to investigate the expression levels of DDR2 in tumor tissues of patients with PTC with local metastasis and cell lines and to determine the effect of DDR2 on EMT in PTC cells. In the present study, it was demonstrated that DDR2 was significantly increased in tumor tissues of patients with PTC with local metastasis and human PTC cell lines. The overexpression of DDR2 by lentiviral transfection decreased E-cadherin protein, increased Vimentin protein, and promoted cell migration and invasion. The inhibition of DDR2 reversed transforming growth factor-beta- and collagen I-induced EMT. EMT induced by DDR2 overexpression was suggested to be dependent on increased Snail1 protein level following extracellular signal-regulated kinase (ERK)2 activation. The inhibition of Snail1 or ERK2 was sufficient to abrogate DDR2-induced PTC cell EMT. In conclusion, these results indicate that DDR2 is upregulated in PTC tissues with local metastasis. Overexpression of DDR2 induced EMT in PTC cells by activating ERK2 and stabilizing Snail1, making it a promising therapeutic target for reducing PTC local or distant metastasis. PMID- 29250190 TI - Role of exosomes in hepatocellular carcinoma cell mobility alteration. AB - Exosomes have gained increased research focus due to their key roles as messengers. The components of exosomes include proteins and RNAs that may be horizontally transferred between adjacent or distant cells. Hepatocellular carcinoma (HCC) is among the most malignant types of cancer worldwide, with exosomes implicated to play a crucial role in its regulation; however, the possible function of exosomes in modulating the motile ability of tumor cells and key molecules in HCC remain largely unknown. To investigate the regulatory effect of exosomes on the motile ability of HCC cells, exosomes from the culture medium of different HCC origins (high metastatic MHCC97-H and low metastatic MHCC97-L cells) were isolated for in vitro migration and invasion assays. The results indicated that the motile ability of MHCC97-L cells was significantly increased by pretreatment with MHCC97-H-derived exosomes when compared with MHCC97-L exosome pretreatment (P<0.05). To further characterize the function of exosomes at the molecular level, protein profiling of exosomes from different cell origins was performed, which identified 129 proteins. Among these, adenylyl cyclase associated protein 1, a protein implicated in HCC metastasis, was significantly enriched in exosomes from cells with high motile ability (P<0.05). The results of the present study validated the regulatory effect of exosomes on the motile ability of HCC cells. Furthermore, systematic analysis of the protein profiles of exosomes from different origins identified potential factors correlated with HCC metastasis, which may provide a basis for future functional analysis of exosomes regarding their involvement in cancer metastasis and recurrence. PMID- 29250191 TI - Galectin-3 rs4652 A>C polymorphism is associated with the risk of gastric carcinoma and P-glycoprotein expression level. AB - Galectin-3 serves an important function in cancer development and progression. The present study aimed to explore the association between single nucleotide polymorphisms in galectin-3, and the susceptibility to chemotherapy drug resistance of gastric carcinoma. The present study was a case-control study including 479 patients with gastric carcinoma and 458 cancer-free controls in a population from the Fujian province in Southeast China. Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry was used to determine the genotype of rs4644 and rs4652, and immunohistochemistry was used to identify the expression level of various proteins associated with chemotherapeutic drug resistance. The results revealed that individuals exhibiting the rs4652 CA/AA genotype had a significantly increased risk of developing gastric carcinoma compared with the rs4652 CC genotype (adjusted odds ratio, 1.51; 95% confidence interval, 1.05-2.18; adjusted P=0.03). In addition, it was demonstrated that there were significant differences in the P-glycoprotein expression level depending on rs4652 genotypic distributions (chi2=9.063; P=0.028). Therefore, the present study demonstrated that rs4652 single nucleotide polymorphisms of the galectin-3 gene contribute to the susceptibility to and chemotherapeutic drug resistance of gastric carcinoma. PMID- 29250192 TI - CREB5 promotes tumor cell invasion and correlates with poor prognosis in epithelial ovarian cancer. AB - CAMP responsive element binding protein 5 (CREB5) has crucial roles in regulating cell growth, proliferation, differentiation and cell cycle regulation. CREB5 has been identified to be overexpressed in several types of human cancer. However, the expression characteristics of CREB5 in epithelial ovarian cancer remains unknown, and its potential clinical prognostic significance has not yet been elucidated. In the present study, quantitative polymerase chain reaction (qPCR) and western blot analysis were performed to detect CREB5 mRNA and protein expression levels in 10 fresh tissue and cell lines epithelial ovarian cancer. Furthermore, CREB5 expression was analyzed using immunohistochemical analysis in 125 clinicopathologically characterized ovarian cancers: Stage I+II (n=31), stage III (n=70), stage IV (n=24). The patient survival rate was evaluated using Kaplan Meier analysis. CREB5 was significantly overexpressed at both the mRNA and protein levels in epithelial ovarian cancer cells. There was a significant positive correlation between high CREB5 expression and increasing the International Federation of Gynecology and Obstetrics (FIGO) stage and pelvic lymph node metastasis (P<0.05). Patients with high CREB5 expression had a shorter overall survival, whereas patients with low CREB5 expression had longer survival. In addition, patients with high CREB5 expression had shorter relapse-free survival whereas patients with low CREB5 expression had longer relapse-free survival. Univariate logistic regression analysis and stepwise multivariate analysis all revealed that the FIGO stage and high CREB5 expression were significant risk factors for epithelial ovarian cancer (P<0.001), which suggested that CREB5 upregulation may be associated with a poor prognosis; therefore, it may be an independent prognostic indicator of epithelial ovarian cancer and may serve as a tumor-aggressive gene. PMID- 29250193 TI - Role of CCL20/CCR6 and the ERK signaling pathway in lung adenocarcinoma. AB - Previous studies have revealed that carcinoma-associated fibroblasts communicate microenvironment-derived signals through chemokine/chemokine receptor interaction, resulting in carcinogenesis. C-C motif chemokine ligand 20 (CCL20)/C C motif chemokine receptor 6 (CCR6) interactions are involved in the pathogenesis of colonic malignancies. The present study aimed to characterize the roles of CCL20/CCR6 and the extracellular signal-regulated kinase (ERK) signaling pathway in lung adenocarcinoma growth. Lung adenocarcinoma samples obtained at surgery were assessed for the expression, tissue localization and production of CCL20/CCR6. In addition, colony formation, ERK signaling and chemokine production were measured to assess the responsiveness of the A549 cell line to CCL20 stimulation. CCL20 and CCR6 were found to be highly expressed in the majority of samples in the recurrence group (76 and 66%, respectively). The staining indexes of CCL20 and CCR6 in the recurrence group were 149.3 and 134.4, respectively, which were significantly higher than those in the non-recurrence group (57.2 and 58.0, respectively); the protein and mRNA expression levels determined by western blot and reverse transcription-quantitative polymerase chain reaction were also found to be high in the recurrence group For A549 cells, the colony-forming capacity was increased by CCL20 stimulation, and this effect was dependent in part on ERK phosphorylation. Collectively, the findings suggest that CCR6 and CCL20 may serve a role in lung adenocarcinoma, leading to proliferation and migration via autocrine or paracrine mechanisms. The disruption of CCL20/CCR6 interactions may be a promising strategy for the treatment of cancer. PMID- 29250194 TI - Rho GDP dissociation inhibitor-beta in renal cell carcinoma. AB - Rho GDP dissociation inhibitor-beta (ARHGDIB) is an important mediator of cell signaling. The expression of ARHGDIB is associated with tumor growth and metastasis in a variety of non-genitourinary cancers; however, the role of ARHGDIB in renal cell carcinoma (RCC) has not yet been evaluated. In the present study, tissue samples from 105 patients undergoing surgery for RCC were obtained. The expression levels of ARHGDIB mRNA in normal kidney tissues and in corresponding cancer tissues were analyzed by reverse transcription-quantitative polymerase chain reaction. Differences in relative mRNA expression levels were assessed using paired two-sample t-tests. Expression levels were analyzed with respect to various clinical parameters, and associations were tested using a bivariate logistic regression model. Relative mRNA expression levels in healthy renal tissues compared with cancerous tissues from the same kidney were assessed using paired t-tests. Expression data were compared with respect to survival data by the Kaplan-Meier method/Cox regression analysis. The results revealed that the relative mRNA expression level of ARHGDIB was significantly higher in the lysates of RCC tumor tissues (P<0.001) when compared with healthy renal tissues in a paired analysis of 74 samples; this finding was consistent with the analysis of ARHGDIB mRNA expression levels in all RCC samples, as well as in the subset of clear cell RCC (ccRCC) samples. The relative mRNA expression level of ARHGDIB was also increased in ccRCC tissues compared with papillary RCC tissues (P<0.001). On univariate Cox regression analysis, recurrence-free survival (RFS) was significantly associated with metastasis, locally advanced disease and tumor grade (P=0.018, P=0.002 and P<0.001, respectively). Furthermore, in the subgroup of patients with ccRCC, increased ARHGDIB mRNA expression was significantly associated with a longer RFS time (P=0.001). In summary, the results indicate that ARHGDIB mRNA is highly expressed in RCC tissues in general and is positively associated with RFS in ccRCC. As ARHGDIB has a known effect on angiogenesis and immune modulation, the present study suggests that the functional analysis of ARHGDIB should be performed in the future. PMID- 29250195 TI - Anti-angiogenic therapies for the treatment of angiosarcoma: a clinical update. AB - Angiosarcomas are rare aggressive endothelial tumours, and are associated with a poor prognosis. Due to their vascular nature, there is great interest in their response to anti-angiogenic agents. A number of small prospective studies have reported angiosarcoma response to vascular-targeted agents, including agents that target vascular endothelial growth factor. To date, the response to these agents has been disappointing, and similar to the response observed in other soft tissue sarcoma subtypes. This short review will summarise the recent data in this field. PMID- 29250197 TI - Antiangiogenic therapies in urogenital malignancies: Fiction or fact? AB - The use of antiangiogenic agents in cancer therapy has become an attractive target in oncological research. However, concerning the uro-oncological field, current guidelines only recommend the use of antiangiogenic agents in metastatic renal cell cancer. Yet in recent years, several approaches for sequential treatment with angiogenesis inhibitors in other urogenital malignancies apart from renal cell cancer are ongoing. Thus, the present review article aims to provide an overview about clinical studies with antiangiogenic agents in prostate , bladder-, testicular-, as well as penile cancer patients. For this, a literature search was conducted using Medline; moreover we performed a systematic review of data presented at this year's important urooncological meetings. Preliminary data revealed that there are several promising studies ongoing in prostate-, bladder-, testicular-, as well as penile cancer; however, larger studies should be conducted to optimize the use of antiangiogenic agents in clinical practice. PMID- 29250196 TI - Antiangiogenic therapy in breast cancer. AB - Based on a strong rationale for anti-VEGF (vascular endothelial growth factor) treatment in breast cancer and promising preclinical data, great hopes have been placed on the anti-VEGF antibody bevacizumab. Clinical trials, however, reported conflicting results. In metastatic human epidermal growth factor receptor 2(HER2) negative breast cancer, the addition of bevacizumab to standard chemotherapy improved consistently progression-free survival (PFS), however, without effect on overall survival (OS). In early breast cancer bevacizumab increased the pathologic complete response rate (pCR) after neoadjuvant therapy, but adjuvant trials did not demonstrate an effect on long-term survival. Unfortunately, despite extensive research, there is still no biomarker for bevacizumab efficacy available, making patient selection difficult. This review summarizes all phase III trials investigating efficacy and toxicity of bevacizumab in early, locally advanced and metastatic breast cancer. It recapitulates the main toxicities, gives an overview on biomarker studies and discusses the role and future aspects of antiangiogenic therapy in breast cancer. PMID- 29250198 TI - Novel concepts of antiangiogenic therapies in metastatic renal cell cancer. AB - The era of antiangiogenic drugs targeting the vascular endothelial growth factor (VEGF) signaling pathway has become a mainstay in the treatment of metastatic renal cell carcinoma (mRCC), showing primary responses in 65-70% of patients. Nevertheless, most of those patients progress to angiogenesis inhibitors over time due to different modes of resistance (adaptive and intrinsic). Both in vitro and in vivo analyses provided evidence that PD-L1 upregulation in hypoxia conditions is dependent on hypoxia-inducible factor (HIF)-2alpha and is associated with an overexpression of VEGF. Thus, additional blockade of PD-L1 along with inhibition of angiogenesis pathways seems to represent a novel and innovative treatment concept in mRCC. In this short review, we provide an overview on ongoing phase III trials combining antiangiogenic therapies with checkpoint inhibitors in the first-line setting. Moreover, we critically analyze the impact of recently approved therapeutic antiangiogenic agents and checkpoint inhibitors after progression to first-generation tyrosine kinase inhibitors and their mode of action. In addition, response and resistance hypotheses and biomarkers to antiangiogenic therapy in clinical practice are critically discussed. PMID- 29250199 TI - ASCO update on lymphoma. AB - s concerning indolent and aggressive lymphoma and multiple myeloma with clinical relevance from the ASCO 2017 meeting are discussed. PMID- 29250200 TI - Update on squamous cell carcinoma of the head and neck: ASCO annual meeting 2017. AB - At the annual ASCO meeting clinically relevant data concerning the management of advanced head and neck cancer that will influence clinical practice in the future were presented. Chemoradiation with high-dose cisplatin remains the mainstay of treatment for patients with locally advanced squamous cell head and neck cancer. Adjuvant therapy with afatinib following chemoradiation failed to show clinical benefit. The combination of bevacizumab with platinum-based chemotherapy improved progression-free survival but did not lead to a significant difference in overall survival compared to chemotherapy alone. However, the addition of immunotherapy may improve multimodal treatment concepts in locally advanced disease and new treatment combinations might overcome resistance to checkpoint inhibition. PMID- 29250201 TI - ASCO update: lung cancer. AB - In the past few years there have been major changes in the treatment landscape in oncology; lung cancer is affected by those changes like almost no other solid tumor. The rise of further second- and third-line tyrosine kinase inhibitors offers sequential therapy for patients with mutated non-small-cell lung cancer. Immunotherapy has found its way into clinical routine and presents us with new challenges in managing side effects, evaluating treatment response and deciding on how long we treat our patients. The treatment algorithm of lung cancer has changed in the last month and further practice-changing trials are coming up, so treating lung cancer patients shows nowadays a more challenging perspective with the possibility of subsequently applied individual therapies. This article provides a brief overview of the highlights presented at the ASCO (American Society of Clinical Oncology) annual meeting this year in Chicago. PMID- 29250202 TI - ASCO 2017: highlights in breast cancer. AB - At the 2017 ASCO Annual Meeting, several pertinent studies in the field of breast cancer were presented and some are deemed as being potentially practice changing. BrighTNess was the first phase III study to investigate the addition of carboplatin to standard neoadjuvant chemotherapy in triple-negative breast cancer; while toxicity was increased in the experimental group, a significantly higher pathologic complete remission (pCR) rate was observed as well suggesting that adding carboplatin to neoadjuvant anthracycline, cyclophosphamide and taxane containing regimens is efficacious in otherwise healthy patients. In metastatic breast cancer patients harbouring BRCA germ-line mutations, the PARP(poly [ADP ribose] polymerase)-inhibitor olaparib was superior to conventional chemotherapy defining a potential novel treatment standard in this high-risk population. In the adjuvant setting, the APHINITY trial compared dual HER2-directed antibody therapy with trastuzumab plus pertuzumab to trastuzumab alone. A small benefit in favour of the combination was observed which was more pronounced in node-positive subjects. In hormone-receptor positive metastatic disease, several studies evaluating the role of CDK4/6 (cyclin-dependendent kinases 4 and 6) inhibitors were presented with data again indicating that adding CDK4/6 inhibitors to endocrine therapy results in a clinically relevant prolongation of progression free survival. PMID- 29250203 TI - ASCO 2017-highlights of gynecological cancer. AB - At this year's ASCO annual meeting several important studies in the field of gynecological cancer were presented. Here we report a personal selection of the most interesting and clinically relevant data. PMID- 29250204 TI - ASCO-update: gastrointestinal tumors. AB - A multitude of new molecular and immunologic insights into gastrointestinal tumors have been presented at the ASCO meeting 2017; however, we have focused our update on practice-changing phase 3 trials and tried to set them into clinical perspective. Furthermore, we will elaborate on updated data on immunotherapeutics in gastroesophageal cancers, since drug approvals may be anticipated before convening for the next meeting in 2018. PMID- 29250205 TI - Next generation sequencing: clinical applications in solid tumours. AB - Next generation sequencing (NGS) has unravelled the genetic alterations that underlie the pathogenesis of cancer. It is now becoming integrated into routine clinical diagnostics of malignant tumours. NGS supports diagnosis, identifies therapeutic targets, reveals resistance mechanisms and facilitates disease monitoring. It takes a central function in the implementation of cancer therapies adapted to the molecular alterations of tumours. PMID- 29250206 TI - Aggressive lymphoma 2016: revision of the WHO classification. AB - Aggressive lymphomas are a heterogeneous group of malignancies reflecting clinical, biological and pathological diversity. Diffuse large B-cell lymphoma is the most common histological subtype and therefore will constitute the key aspect in this article. This lymphoma affects patients of all age groups with wide range presentations concerning localization, morphology and molecular mechanisms. The median age at presentation is about 60 years with a slight male preponderance. Up to 50% of patients present with advanced disease. About 70% of these lymphomas occur nodal, about 30% extranodal, the most common sites of the latter being the gastrointestinal tract, Waldeyer's ring, skin, cerebrum, mediastinum, testis, salivary gland, thyroid and bone. However, diffuse large B-cell lymphoma can involve virtually any organ.Since the last WHO classification 2008 the adoption of new genomic technologies has provided new insights into the biology of these lymphomas and led to the identification of distinct separate molecular entities and novel pathogenic pathways. These findings induced an expanding number of entities in the new WHO classification of 2016, the knowledge of which is essential concerning treatment options and survival of the patients. Therefore, the clinicians request an accurate diagnosis from the investigating pathologist, which can be quite challenging. The diagnosis of lymphomas requires multiple immunohistochemical studies, and often additional tests, such as fluorescent in situ hybridization and/or polymerase chain reaction techniques and occasionally, in particular cases, next generation sequencing for identification of recurrent somatic mutations. This review summarizes relevant aspects of the new WHO classification in aggressive B-cell lymphomas, especially from a haematopathologist's point of view. PMID- 29250207 TI - Dynamic Prediction of Renal Failure Using Longitudinal Biomarkers in a Cohort Study of Chronic Kidney Disease. AB - In longitudinal studies, prognostic biomarkers are often measured longitudinally. It is of both scientific and clinical interest to predict the risk of clinical events, such as disease progression or death, using these longitudinal biomarkers as well as other time-dependent and time-independent information about the patient. The prediction is dynamic in the sense that it can be made at any time during the follow-up, adapting to the changing at-risk population and incorporating the most recent longitudinal data. One approach is to build a joint model of longitudinal predictor variables and time to the clinical event, and draw predictions from the posterior distribution of the time to event conditional on longitudinal history. Another approach is to use the landmark model, which is a system of prediction models that evolve with the follow-up time. We review the pros and cons of the two approaches, and present a general analytical framework using the landmark approach. The proposed framework allows the measurement times of longitudinal data to be irregularly spaced and differ between subjects. We propose a unified kernel weighting approach for estimating the model parameters, calculating predicted probabilities, and evaluating prediction accuracy through double time-dependent Receiver Operating Characteristics (ROC) curves. We illustrate the proposed analytical framework using the African American Study of Kidney Disease and Hypertension (AASK) to develop a landmark model for dynamic prediction of end stage renal diseases or death among patients with chronic kidney disease. PMID- 29250208 TI - Electrochemical and optical biosensors for early-stage cancer diagnosis by using graphene and graphene oxide. AB - Conventional instruments for cancer diagnosis including magnetic resonance imaging, computed tomography scan, are expensive and require long-waiting time, whilst the outcomes have not approached to the successful early-stage diagnosis yet. Due to the special properties of graphene-based nanocomposites, e.g., good electrical and thermal conductivity, luminescence, and mechanic flexibility, these ultra-thin two-dimensional nanostructures have been extensively used as platforms for detecting biomolecules and cells. Herein, we discuss the development of two types of graphene and graphene oxide-based biosensors: electrochemical and optical, aimed for tumor detection and early diagnosis of cancer. Moreover, we highlight the challenges of their use as biosensors for cancer detection. Efficient surface modification and suitable bio-conjugation of graphene and graphene oxide is discussed, including key role in improvement of the biocompatibility, and improved performance in terms of selectivity and sensitivity towards the early diagnosis of cancer. PMID- 29250209 TI - Spine-on-a-chip: Human annulus fibrosus degeneration model for simulating the severity of intervertebral disc degeneration. AB - The aetiology of intervertebral disc (IVD) degeneration accompanied by low back pain (LBP) is largely unknown, and there are no effective fundamental therapies. Symptomatic IVD is known to be associated with nerve root compression. However, even in the absence of nerve compression, LBP occurs in patients with IVD degeneration. We hypothesize that this phenomenon is associated with a concentration of pro-inflammatory cytokines such as interleukin (IL)-1beta and tumour necrosis factor-alpha (TNF-alpha), which can lead to altered histologic features and cellular phenotypes observed during IVD degeneration. This study investigated the effects of the concentration of IL-1beta and macrophage derived soluble factor including IL-1beta and TNF-alpha on the painful response of human annulus fibrosus (AF) cells using a newly developed spine-on-a-chip. Human AF cells were treated with a range of concentrations of IL-1beta and macrophage soluble factors. Our results show that increasing the concentration of inflammatory initiator caused modulated expression of pain-related factors, angiogenesis molecules, and catabolic enzymes. Furthermore, accumulated macrophage derived soluble factors resulted in morphological changes in human AF cells and kinetic alterations such as velocity, dendritic length, cell area, and growth rate, similar to that reported within degenerative IVD. Thus, a better understanding of the relationships between molecular and kinetic alterations can provide fundamental information regarding the pathology of IVD degenerative progression. PMID- 29250210 TI - Quantification of Multiple Tumor Clones Using Gene Array and Sequencing Data. AB - Cancer development is driven by genomic alterations, including copy number aberrations. The detection of copy number aberrations in tumor cells is often complicated by possible contamination of normal stromal cells in tumor samples and intratumor heterogeneity, namely the presence of multiple clones of tumor cells. In order to correctly quantify copy number aberrations, it is critical to successfully de-convolute the complex structure of the genetic information from tumor samples. In this article, we propose a general Bayesian method for estimating copy number aberrations when there are normal cells and potentially more than one tumor clones. Our method provides posterior probabilities for the proportions of tumor clones and normal cells. We incorporate prior information on the distribution of the copy numbers to prioritize biologically more plausible solutions and alleviate possible identifiability issues that have been observed by many researchers. Our model is flexible and can work for both SNP array and next-generation sequencing data. We compare our method to existing ones and illustrate the advantage of our approach in multiple datasets. PMID- 29250211 TI - Error Aggregation in the Reengineering Process from 3D Scanning to Printing. AB - This work aims to study the aggregation of dimensional errors in the reengineering processes using 3D scanning and printing without initial design drawings. A 57-tooth spur gear is used as an example to facilitate the discussion. Two approaches are investigated. The first one builds the gear model based upon measurement taken from a caliper, and the second approach uses a 3D scanner to collect geometry data. Dimensional errors in each stage of these two approaches are investigated. Particular attention is paid to the geometry data flow in the reengineering process from data acquisition and editing to model construction. Recommendations are made in regard to error estimation and alleviation. PMID- 29250212 TI - Effects of Concentration and Surface Pressure on MBP Interaction with Cholesterol in Langmuir Films. AB - Predicting the mechanism of MBP binding to cholesterol is meaningful in understanding how MBP participate in lateral membrane organization. The interaction of MBP with cholesterol monolayer was investigated at three surface pressures on 10 mM Tris-HCl buffer with the different concentrations of MBP. The results show that pi-A isotherms shift to larger molecular area at all pressures. By means of analyzing pi-T curves, a surface pressure increase was obtained. Results indicated that the greater the protein concentration in the subphase, the larger the increase of surface pressure. In addition, changes in monolayer surface morphology and domain formation were performed by AFM. These results provide more direct and convincing evidence for the MBP interaction with cholesterol. The MBP-cholesterol interaction suggests a significant concentrations and surface pressure dependence and is probably governed by hydrogen bonds. The date presented could help to understand at least one of the molecular mechanisms through which MBP affects lateral organization of the cholesterol membrane. PMID- 29250213 TI - Investigation of Surface Behavior of DPPC and Curcumin in Langmuir Monolayers at the Air-Water Interface. AB - Langmuir monolayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and a mixture of DPPC with curcumin (CUR) have been investigated at the air-water interface through a combination of surface pressure measurements and atomic force microscopy (AFM) observation. By analyzing the correlation data of mean molecular areas, the compressibility coefficient, and other thermodynamic parameters, we obtained that the interaction between the two components perhaps was mainly governed by the hydrogen bonding between the amino group of DPPC and the hydroxyl groups of CUR. CUR markedly affected the surface compressibility, the thermodynamic stability, and the thermodynamic phase behaviors of mixed monolayers. The interaction between CUR and DPPC was sensitive to the components and the physical states of mixed monolayers under compression. Two-dimensional phase diagrams and interaction energies indicated that DPPC and CUR molecules were miscible in mixed monolayers. AFM images results were in agreement with these analyses results of experimental data. This study will encourage us to further research the application of CUR in the biomedical field. PMID- 29250214 TI - Secondary Prevention of Alcohol Problems in Rural Areas Using a Bibliotherapy Based Approach. AB - This study investigated the relative effects of three 12-week secondary prevention interventions for problem drinking men and women in rural counties in New York State. The participants were 111 self-referred men and women without severe dependence on alcohol who nevertheless reported heavy drinking and a desire to reduce their alcohol consumption. They were assigned randomly to one of three 12-week interventions focused on reducing alcohol intake: bibliotherapy (a self-directed manual) alone, bibliotherapy with one telephone-administered motivational interview, or bibliotherapy with one telephone-administered motivational interview and six biweekly telephone therapy sessions. Results showed that, across conditions, participants significantly increased their abstinent and light drinking days and significantly decreased their heavy drinking days over the course of treatment and a 12-month follow-up period. In addition, participants reported moderate reductions in alcohol consequences and increases in confidence not to drink heavily across a variety of situations from pre- to posttreatment, with these changes remaining stable across the course of the follow-up. Use of the drinking reduction strategies presented in the self directed manual also remained stable from posttreatment to the 12-month follow up. These results provide support for consideration of bibliotherapy for rural problem drinkers who are not severely dependent on alcohol, with or without the addition of telephone contacts. PMID- 29250215 TI - The Measurement of Cognitive Schemas: Validation of the Psychological Distance Scaling Task in a Community Mental Health Sample. AB - Objective: The purpose of this study was to examine the validity of the Psychological Distance Scaling Task (PDST), a measure of cognitive schema organization, in a community mental health setting. We also compared validity among African Americans and Caucasians. Method: In order to accommodate participants with low education levels, 26 out of 80 PDST word stimuli were replaced with similar words at a lower reading level. A sample of 466 (42% African American; 50% Caucasian; 8% other) community patients with major depressive disorder completed the PDST and a variety of depressive symptom measures. Results: The modified PDST demonstrated acceptable validity within all subscales. Validity coefficients resembled those reported in prior studies and were similar within minority and non-minority subsamples. Conclusions: The modified PDST appears to be a valid measure of schema organization in a low income, racially diverse population seeking treatment for depression at community clinics. PMID- 29250216 TI - Longitudinal Differences in Spirituality and Religiousness between Men and Women in Treatment for Alcohol Use Disorders. AB - This study compares men and women with alcohol use disorders on levels and trajectories of spirituality and religiousness over 30 months while controlling for critical covariates. Men (n=92) and women (n=65) entering abstinence-based treatment were assessed for drinking behavior, spirituality, and psychosocial variables in a longitudinal panel study. Multiple regression tested for baseline differences and multi-level models tested for differences from baseline to 6 months (early recovery) and from 6 to 30 months (later recovery) in seven dimensions of spirituality/religiousness. Between baseline and 6 months, women had higher scores than men for forgiveness of others and lower scores than men for negative religious coping. Between 6 and 30 months, the acceleration of positive change in self forgiveness was significantly greater for women than men. Differences in negative religious coping and forgiveness might relate to differences in shame and guilt and their resolution by gender. Future research should examine whether gender differences in spirituality serve as an asset to women as they pursue addiction recovery. PMID- 29250217 TI - Atrial Fibrillation is Associated with Increased Pacemaker Implantation Rates in the Placement of AoRTic Transcatheter Valve (PARTNER) Trial. AB - Atrial fibrillation (AF) is associated with worse outcomes in many cardiovascular diseases. There are few data examining pacemaker implantation rates and indications in patients with AF who undergo transcatheter aortic valve replacement (TAVR). To examine the impact of AF on the incidence of and indications for pacemakers in patients undergoing TAVR, we evaluated data of 1723 patients without pre-existing pacemakers who underwent TAVR in the Placement of AoRTic TraNscathetER Valve (PARTNER) trial. Permanent pacemaker implantation rates and indications were compared in groups based on baseline and discharge heart rhythm: sinus rhythm (SR) vs. AF. 1211 patients manifested SR at baseline/SR at discharge (SR/SR), 105 SR baseline/AF discharge (SR/AF), and 407 AF baseline/AF discharge (AF/AF). Patients who developed and were discharged with AF (SR/AF) had the highest rates of pacemaker implantation at 30 days (13.7% SR/AF vs. 5.4% SR/SR, p=0.0008 and 5.9% AF/AF, p=0.008) and 1 year (17.7% SR/AF vs. 7.1% SR/SR, p=0.0002 and 8.1% AF/AF, p=0.0034). Conversion from SR to AF by discharge was an independent predictor of increased pacemaker implantation at 30 days (HR 2.19 vs. SR/SR, 95% CI 1.23-3.93, p=0.008) and 1 year (HR 1.91 vs. SR/SR, 95% CI 1.33-3.80). Pacemaker indications differed between groups, with relatively more implanted in the AF groups for sick sinus syndrome (SSS) versus AV block. In conclusion, conversion to AF is an independent predictor of permanent pacemaker implantation in TAVR patients. Indications differ depending on heart rhythm, with patients in AF manifesting clinically significant tachy brady syndrome versus AV block. PMID- 29250218 TI - Excellent symptom rhythm correlation in patients with palpitations using a novel Smartphone based event recorder. AB - Background: Definitive diagnosis of arrhythmia relies on "symptom-rhythm correlation" when electrocardiographic (ECG) evidence of the patient's cardiac rhythm is obtained at the time of symptoms. The AliveCor smartphone App and device (AliveCor Inc, California, USA) has recently been introduced as an easy to use cardiac event recorder. The aim of this study was to investigate whether the smartphone based event recorder could be effectively used to achieve symptom rhythm correlation in unselected patients with palpitations. Methods: 20 patients (13 female, mean age 35+/-16 years) underwent evaluation of their palpitations for 12 weeks using 2nd generation AliveCor monitors. Results: Symptom rhythm correlation was achieved in 85% of patients with 45% detecting an arrhythmia. Of a total of 966 ECGs available for review 96% were interpretable. Conclusion: The novel smartphone based event recorder is an efficient tool for achieving symptom rhythm correlation in patients with palpitations. By utilising their Smartphone, ECG recording is easily and readily accessible to patients when palpitations occur. PMID- 29250219 TI - Use of acoustic cardiography immediately following electrical cardioversion to predict relapse of atrial fibrillation. AB - Predicting atrial fibrillation (AF) recurrence after successful electrical cardioversion (ECV) is difficult. The main aim of this study was to investigate whether acoustic cardiography (AUDICOR(r) 200) immediately post-ECV might provide indices for AF relapse following cardioversion. Acoustic cardiography parameters included Electromechanical Activation Time (EMAT), Left Ventricular Systolic Time (LVST), QRS duration, heart rate and third heart sound intensity (S3 Strength). We analysed data from 140 patients who underwent successful cardioversion and in whom AUDICOR results and echocardiographic measurements immediately after (baseline) ECV were available. Patients were prospectively followed-up at 4-6 weeks, 3 and 12 months post-ECV, and sinus rhythm maintenance was evaluated using acoustic cardiography and Holter electrocardiography. The effect of each baseline AUDICOR parameter on the hazard of AF relapse was investigated using Cox proportional hazards (PH) models. Fifty patients (35.7%) had AF relapse. Of all the AUDICOR parameters, only S3 Strength exhibited consistent predictive value. Increasing S3 Strength increased the hazard of relapse in a univariable Cox PH model (HR=2.52, p=0.003), and in two multivariable Cox PH model constructions (Model 1 excluded heart rate and Model II excluded EMAT/RR, LVST and LVST/RR) both of which included the parameters as continuous variables (Model I: HR=1.15, p=0.042; Model II: HR=1.14, p=0.045) or the parameters dichotomized according to suggested cut-points (Model I: HR=2.5, p=0.007; Model II: HR=2.09, p=0.031). In conclusion, this study suggests that acoustic cardiography may be a simple inexpensive and quantitative bedside method to assist in prediction of AF recurrence after ECV. PMID- 29250220 TI - Impact of Radiofrequency Ablation of Atrial Fibrillation on Pulmonary Vein Cross Sectional Area: Implications for the Diagnosis of Pulmonary Vein Stenosis. AB - Introduction: Restoration of normal sinus rhythm by radiofrequency ablation (RFA) in atrial fibrillation (AF) patients can result in a reduction of left atrial (LA) volume and pulmonary vein (PV) dimensions. It is not clear if this PV size reduction represents a secondary effect of overall LA volume reduction or true PV stenosis. We assessed the relationship between LA volume reduction and PV orifice area pre- and post-RFA. Methods: A retrospective cohort study was conducted at a tertiary care academic hospital. Pre- and post-RFA cardiac computed tomography (CT) studies of 100 consecutive AF patients were reviewed. Studies identifying obvious segmental PV narrowing were excluded. Left atrial volumes and PV orifice cross-sectional areas (PVOCA) were measured using proprietary software from the CT scanner vendor (GE Healthcare, Waukesha, WI). Results: The cohort had a mean age of 60 +/- 8 years, 73% were male, and 90% were Caucasian. Non-paroxysmal AF was present in 76% of patients with a mean duration from diagnosis to RFA of 55 +/- 54 months. Mean procedural time was 244 +/- 70 min. AF recurred in 27% at 3 month follow-up. Pre-RFA LA volumes were 132 +/- 60 ml and mean PVOCA was 2.89 +/ 2.32 cm2. In patients with successful ablation, mean LA volume decreased by 10% and PVOCA decreased by 21%. PVOCA was significantly reduced in patients with successful RFA compared to those who had recurrence (2.18 +/- 1.12 vs. 2.8 +/- 1.9 cm2, p = 0.04) but reduction in LA volume between groups was not significant (118 +/- 42 vs. 133 +/- 54 ml, p=0.15). Conclusions: The study demonstrates that both PV orifice dimensions and LA volume are reduced after successful AF ablation. These data warrant a reassessment of criteria for diagnosing PV stenosis based on changes in PV caliber alone, ideally incorporating LA volume changes. PMID- 29250221 TI - Sinus Rhythm Restoration after Radiofrequency Ablation Improves Survival in Patients Undergoing Mitral Valve Surgery : A Eight Year Single Center Study. AB - Background: The usefulness of radiofrequency (RF) ablation in restoring sinus rhythm in patients with permanent atrial fibrillation (AF) undergoing surgery for mitral valve has been demonstrated. But whether sinus rhythm recovery affects long-term survival is less clear. Methods: This study included 301 consecutive patients (126 men and 175 women, age 69+/-6 years) undergoing radiofrequency ablation of persistent atrial fibrillation along with mitral valve surgery. Radiofrequency ablation was performed using unipolar probe in 55.3%, bipolar probe in the remaining 44.7% of cases. Results: Four patients died during hospitalization. At follow-up, sinus rhythm was present in 76% of the surviving patients. 71 patients never recovered sinus rhythm after hospital discharge. Mortality and recurrent hospitalization were significantly lower in patients with sinus rhythm at the end of follow-up in comparison to permanent AF. The incidence of stroke was also lower in patients with stable sinus rhythm. Larger atria, pulmonary hypertension and history of rheumatic disease were associated with the persistence of AF despite radiofrequency ablation. Although survival and functional capacity were significantly lower in patients with permanent AF at multivariate analysis only age and pulmonary artery pressure before surgery were independently associated with mortality. Conclusion: Sinus rhythm restoration by RF ablation in patients undergoing mitral valve surgery is associated with an improved long-term survival. However our results suggest that a more severe hemodynamic impairment, expressed by higher pulmonary artery pressure, and increasing age are the only independent factors related to long-term survival. PMID- 29250222 TI - Effects of Computerized Decision Support Systems on Management of Atrial Fibrillation: A Scoping Review. AB - Background: Potential role of computerized decision support system on management of atrial fibrillation is not well understood. Objectives: To systematically review studies that evaluate the effects of computerized decision support systems and decision aids on aspects pertaining to atrial fibrillation. Data Sources: We searched Medline, Scopus and Cochrane database. Last date of search was 2016, January 10. Selection criteria: Computerized decision support systems that help manage atrial fibrillation and decision aids that provide useful knowledge for patients with atrial fibrillation and help them to self-care. Data collection and analysis: Two reviewers extracted data and summarized findings. Due to heterogeneity, meta-analysis was not feasible; mean differences of outcomes and confidence intervals for a difference between two Means were reported. Results: Seven eligible studies were included in the final review. There was one observational study without controls, three observational studies with controls, one Non-Randomized Controlled Trial and two Randomized Controlled Trials. The interventions were three decision aids that were used by patients and four computerized decision support systems. Main outcomes of studies were: stroke events and major bleeding (one article), Changing doctor-nurse behavior (three articles), Time in therapeutic International Normalized Ratio range (one article), decision conflict scale (two articles), patient knowledge and anxiety about stroke and bleeding (two articles). Conclusions: A computerized decision support system may decrease decision conflict and increase knowledge of patients with atrial fibrillation (AF) about risks of AF and AF treatments. Effect of computerized decision support system on outcomes such as changing doctor-nurse behavior, anxiety about stroke and bleeding and stroke events could not be shown.We need more studies to evaluate the role of computerized decision support system in patients with atrial fibrillation. PMID- 29250223 TI - California study of Ablation (CAABL):early utilization after index hospitalization for non-valvular atrial fibrillation. AB - Background: Catheter ablation (ABL) for non-valvular AF (NVAF) is recommended for symptomatic patients refractory to medical therapy and its success is related to the duration of the arrhythmia prior to intervention.Our aim was to assess the early utilization and the factors that prompted ABL in patients hospitalized for new onset NVAF. Methods: Using de-identified administrative discharge records for hospitalizations and emergency department (ED) visits, we determined the patients who had a first-time (since 1991) health record diagnosis of AF between2005 - 2011. We linked ambulatory surgery encounters for ABL based on ICD 9 code occurring within two years of initial hospitalization. After excluding other cardiac arrhythmias, atrio-ventricular nodal ablation or pacemaker/defibrillator placement and cardiac valve disease, bivariate comparisons were made with those who did not undergo ABL. Results: During the study period,3,440 of 424,592 patients (0.81%) hospitalized for new onset NVAF underwent ABL. Parameters significantly (p<0.001) associated with ABL compared tonon-ABL patientsincluded: principal diagnosis of AF (55% vs 25%), age 35-64 yrs (46.1% vs. 22.4%), male (58.9% vs. 48.2%), private insurance (46.6% vs. 21.1%), Caucasian (81.0% vs.71.6%), lower frequency of ED visit < 6 months before index AF hospitalization (10.7% vs. 15.9%), lower severityofillness at time of AF diagnosis (16.5% vs. 35.6%) anda lower prevalence ofmajor comorbidities (p< 0.001). Conclusions: Ablation has low utilization for treatment of new onset NVAF within two years of diagnosis. Earlier utilization of ABL may reduce health care burden related to NVAF and requires further evaluation. PMID- 29250224 TI - Pulmonary Vein Isolation for Treatment of Paroxysmal Atrial Fibrillation on Patient with Situs Inversus Totalis. AB - A 56-year-old male with paroxysmal atrial fibrillation refractory to class IC and class III antiarrhythmic drugs was admitted to our hospital for radiofrequency catheter ablation of atrial fibrillation. During preoperative examination situs inversus totalis was revealed. Pulmonary vein (PV) isolation was successfully performed with atrial fibrillation termination and elimination of all PV potentials. The procedure was performed without any complications. Our report shows that PV isolation for treatment of drug-refractory atrial fibrillation can be safely performed in patients with dextrocardia and situs inversus totalis. PMID- 29250225 TI - Atrial Fibrillation in Patients with Congenital Heart Disease. AB - Advances in surgical techniques have led to the survival of most patients with congenital heart disease (CHD) up to their adulthood. During their lifetime, many of them develop atrial tachyarrhythmias due to atrial dilatation and scarring from surgical procedures. More complex defects and palliative repairs are linked to a higher incidence and earlier occurrence of arrhythmias. Atrial fibrillation (AF) is common in patients who have atrial septal defects repaired after age 55 and in patients with tetralogy of Fallot repaired after age 45. Patients with dextrotransposition of the great arteries who undergo Mustard or Senning atrial switch procedures have an increased risk of atrial flutter due to atrial baffle suture lines. Patients with Ebstein's anomaly are also prone to supraventricular tachycardias caused by accessory bypass tracts. Patients with a single ventricle who undergo Fontan palliation are at risk of developing persistent or permanent AF due to extreme atrial enlargement and hypertrophy. In addition, obtaining vascular access to the pulmonary venous atrium can present unique challenges during radiofrequency ablation for patients with a Fontan palliation. Patients with cyanotic CHD who develop AF have substantial morbidity because of limited hemodynamic reserve and a high viscosity state. Amiodarone is an effective therapy for patients with arrhythmias from CHD, but its use carries long-term risks for toxicity. Dofetilide and sotalol have good short-term effectiveness and are reasonable alternatives to amiodarone. Pulmonary vein isolation is associated with better outcomes in patients taking antiarrhythmic medications. Anticoagulants are challenging to prescribe for patients with CHD because of a lack of data that can be extrapolated to this patient population. Surgical ablation is the gold standard for invasive rhythm control in patients with CHD and should be considered at the time of surgical repair or revision of congenital heart defects. When possible, patients with complex CHD should be referred for care to an adult congenital heart disease center of excellence. PMID- 29250226 TI - Scar homogenization in AF ablation: Evolution and practice. AB - Laboratory studies, histology studies, image studies and the clinical studies all prove the positive correlation between atrial fibrillation and atrial fibrosis from different perspectives. Atrial fibrosis, by separating myocardial cell coupling, diminishing conduction velocity and promoting anisotropic conduction, produce the substrate to sustain atrial fibrillation (AF). These fibrotic areas can be translated into signal abnormalities (low voltage and complex electrgram), and be depicted by electroanatomic high density map. Ablation targeting these areas after circumferential pulmonary vein produces isolation as the additional substrate modification strategy has proved its beneficial results. However, the unified methodology regarding the scar definition, the mapping rhythm (AF or sinus rhythm) and the modification endpoint is yet to be negotiated. Large-scale clinical trials, long-term follow-up results are needed to prove its contribution to the overall success rate of AF ablation. PMID- 29250227 TI - Routine use of intracardiac echocardiography for atrial flutter ablation is associated with reduced fluoroscopy time, but not with a reduction of radiofrequency energy delivery time. AB - Background: The ablation of cavotricuspid-isthmus (CTI) atrial flutter (AFL) dependent atrial flutter could be difficult in patients with complex anatomy of the CTI.The aim of the study was to assess whether the use of intracardiac echocardiography (ICE) was associated with less fluoroscopy time and faster ablations of cavotricuspid isthmus dependent atrial flutter (CTI-AFL). Methods: Patients with an indication for an ablation of a CTI-AFL were enrolled. Patients in which ablation of a CTI-AFLas part of an atrial fibrillation ablation were not included. Randomization was done using the envelope method. Standard techniques (i.e., coronary sinus, 20-polar halo catheter, and an ablation catheter), and criteria of success (bidirectional block through the CTI) were used. In patients randomized to the ablation with ICE, a 10F AcuNav ICE probe (Siemens, Germany)was used. Results: Seventy-nine patients were enrolled; 40 were randomized to ablation with ICE and 39 without ICE. The X-ray exposure was shorter (3.29+/-2.6 vs. 5.94+/-3.43 min, p<0.001) and total X-ray dose was reduced (3.30+/-1.98 vs. 6.68+/-5.25 Gy.cm2, p<0.001) in the ICE group. However, the total RF energy ablation time was not different between groups (ICE group: 604.56+/-380.46sec vs. 585.82+/-373.39 sec, p=0.8). The procedure duration was slightly longer in the ICE group (82.0+/-20.8 vs. 72.1+/-19.0 min, p=0.03). Procedural success was 100% (40/40) in the ICE group and 95% (37/39) in the control group. Two control patients required crossover to ICE at a prespecified point to achieve bidirectional block. There were two femoral hematomas in the ICE group and one in the control group. Conclusion: The use of ICE for atrial flutter ablation is associated with less fluoroscopy time and improved ability to achieve bidirectional block compared to traditional conventional flutter ablation methods. However, it is not asoociated with reduced ablation time or overall procedure duration. PMID- 29250228 TI - Is CHA2DS2-VASc Score Different in Patients with Non-valvular Atrial Fibrillation Suffering from Cerebral and Non-cerebral Thromboembolism?CHA2DS2-VASc Score in Thromboembolism. AB - Background: Thromboembolic complication is directly related to CHA2DS2-VASc score in patients with non-valvular atrial fibrillation (NVAF). In this study we compared the CHA2DS2-VASc score and in-hospital mortality between NVAF patients with non-cerebral thromboembolism and those with stroke. Methods: We retrospectively reviewed medical records of 213 patients with NVAF who experienced stroke and 115 patients with NVAF who experienced non-cerebral thromboembolism between 2010 and 2015. In all patients, CHA2DS2-VASc score before the event was calculated. Results: The mean CHA2DS2-VASc score was similar in patients with stroke (4.52+/-1.66) and those with non-cerebral thromboembolism (4.29+/-2.02) (p=0.196). In-hospital mortality rate was similar between the groups (19% vs. 17%, p=0.756). The rates of coronary artery disease (52% vs. 38%, p=0.014), prior transient ischemic attack (16% vs. 5%, p=0.001), and prior non cerebral thromboembolism (18% vs. 3%, p<0.001) were higher in patients with non cerebral thromboembolism. Warfarin (55% vs. 14% p<0.001) and antiplatelet use (56% vs. 40%, p=0.004) was more common in the non-cerebral embolism group, while non-vitamin K antagonist oral anticoagulant (NOAC) use was more common in the stroke group (15% vs. 7% p=0.026). Conclusion: The patients with stroke had similar CHA2DS2-VASc score and in-hospital mortality compared to patients with non-cerebral thromboembolism. PMID- 29250229 TI - Leadless Pacemakers - Implant, Explant and Long-Term Safety and Efficacy Data. AB - Implantable cardiac pacemakers have seen remarkable progress in the last sixty years and remained as cornerstone therapy for symptomatic bradycardia. Despite this progress the current day traditional transvenous implanted pacemaker systems are limited by the need for a surgically created pocket for the generator, indwelling leads in the vascular system and lastly passage through the tricuspid valve. A majority of the implant and explant related complications are due to the surgical pocket and indwelling leads. Leadless pacemakers represent a major leap in technology and emerged as an alternative to traditional systems promises to eliminate lead and pocket associated complications. As with any disruptive technology, some questions remain unanswered with the leadless pacing systems, specifically longevity and end of life management for the device. Despite the unknowns, as the technology progresses, it is possible that pacing leads will become extinct and pacemakers will miniaturize even further. This review summarizes the available technology, implant and explant details, and long-term safety and efficacy data for leadless pacemakers. PMID- 29250230 TI - Ablation of "Background Tachycardia" in Long Standing Atrial Fibrillation: Improving the Outcomes by Unmasking a Residual Atrial Fibrillation Perpetuator. AB - Background: Catheter ablation of long-standing persistent AF (LSAF) remains challenging. Since AF-Nest (AFN) description, we have observed that a stable, protected, fast source firing, namely "Background Tachycardia"(BT), could be hidden beneath the chaotic AF. Following pulmonary vein isolation (PVI)+AFN ablation one or more BT may arise or be induced in 30-40% of patients, which could be the culprit forAF maintenance and ablation recurrences. Methods and Results: We studied 114 patients, from 322 sequential LSAF regular ablations, having spontaneous or induced residual BT after EGM-guided PVI+AFN ablation of LSAF; 55.6+/-11y/o, 97males (85.1%), EF=65.5+/-8%, LA=42.8+/-6.7mm. Macroreentrant tachycardias were excluded. Pre-ablationAF 12-leads ECG Digital processing(DP) and spectral analysis(SA) was performed searching for BT before AF ablation and its correlation with BT during ablation.After PVI, 38.1+/-9 AFN sites/patient and 135 sustained BTs (1-3, 1.2+/-0.5/patient) were ablated. BT cycle length(CL) was 246.3+/-37.3ms. In 79 patients presenting suitable DP for SA, the BT-CL was 241.6+/-34.3ms with intra procedure BT-CL correlation r=0.83/p<0.01. Following BT ablation, AF could not be induced. During FU of 13 >60 months(22.8+/-12m), AF freedom for BT RF(+) vs. BT RF(-) groups were 77.9% vs. 56.4% (p=0.009), respectively. There was no significant complication. Conclusion: BT ablation following PVI and AFN ablation improved long-term outcomes ofLSAF ablation. BT is likely due to sustained microreentry, protected during AF by entry block. BT can be suspected by spectral analysis of the pre ablation ECG and is likely one important AF perpetuator by causing electrical resonance of the AFN. This ablation strategy warrants randomized, multicenter investigation. PMID- 29250232 TI - The Role of Implantable Cardiac Monitors in Atrial Fibrillation Management. AB - Continuous heart rhythm monitoring using implantable cardiac monitors (ICMs) for atrial fibrillation (AF) management is steadily increasing in current clinical practice, even in the absence of an established indication provided by international guidelines. The increasing use of such devices is mainly associated with recent technological improvements including miniaturization, easier implant procedures, and remote monitoring, all of which make this strategy continuously more appealing and promising. For these and other reasons, ICMs have been proven to be a safe and highly effective tool for detecting AF episodes. However, ICMs are not the best option for every patient, as limitations exist. Therefore, it is imperative to weigh the possible benefits against the potential limitations of using these devices when deciding individualized patient care. PMID- 29250231 TI - Laser catheter ablation of long- lasting persistent atrial fibrillation: Longterm results. AB - Catheter ablation of atrial fibrillation (AF) is a current therapeutic option but its efficacy for the treatment of long-lasting persistent AF (l-lpAF) remains suboptimal. We tested the laser method as an alternative for catheter ablation of l-lpAF by using an open-irrigated electrode laser mapping and ablation (ELMA) catheter. Laser ablation was attempted in 48 patients aged 50-81 years (69 +/- 7.6 y, female = 28) with drug resistant (3.5 trials) l-lpAF (>=12 months). All of the patients had comorbidities: congestive heart failure NYHA II-III (100%), hypertension 29 (60%), coronary artery disease 19 (40%), and heart valve defect 17 (35%). None of the patients had diabetes or obstructive sleep apnea. All were in AF at the beginning of the procedure. Continuous wave (cw) 1064nm Nd:YAG laser applications at 15W/10-20s (14-26/patient) were applied via the ELMA catheter until local electrical activity displayed on the monitor in the bipolar focused local electrograms (LEG) recorded via the pin electrodes from the tip of the catheter was abolished permanently and sinus rhythm was achieved. Online monitoring of electrical potential amplitudes in the focused LEG recorded via the pin-electrodes of the ELMA catheter allowed for validation of ablation success. Procedure duration ranged from 82-175 min (118 +/- 72 min), number of lesions were14-26 (19 +/- 4) per patient and X-ray exposure times ranged from 15-82 min (23.2 +/- 12 min). Interventions were without complications. After the ablation procedure all the patients were in sinus rhythm, off medication, however, 12 (25%) needed a repeat study for various arrhythmias. During followup of 9 months to 29.3 years (8.2 +/- 6.5 years) patients' quality of life improved significantly and during final follow-up control all except two were off medication still in sinus rhythm (lifelong success rate = 96%). As compared to other catheter ablation methods the laser method is an intriguing alternative for catheter ablation of l-lpAF. PMID- 29250233 TI - Monitoring esophageal temperature during catheter ablation. AB - I comment on a paper just appeared on JAFIB, aimed at providing an index quantifying the convenience of monitoring esophageal temperature during catheter ablation. The authors base their calculation on the data from four papers. I point out that the data from the two papers strongly against monitoring should be interpreted differently and I suggest how to retrieve more data for a more reliable determination of the said index. In addition, I briefly discuss the so called antenna effect, sometimes put forward to discourage temperature monitoring. PMID- 29250234 TI - Postpacing Interval During Right Ventricular Overdrive Pacing to Discriminate Supraventricular from Ventricular tachycardia. AB - Introduction: Failure to differentiate supraventricular from ventricular arrhythmias is the most frequent cause of inappropriate implantable cardioverter defibrillator (ICD) therapies. We hypothesized that the postpacing interval (PPI) after overdrive right ventricular pacing may differentiate ventricular (VT) from supraventricular tachycardia (SVT) such as sinus tachycardia, atrial flutter and atrial tachycardia. This hypothesis is based on the entrainment maneuver. Reentrant tachycardia circuit for VTs would haveshorter distance to RV apex than SVTs have, and the conduction time between a ventricular pacing site and the tachycardia origin is expected to be shorter in VTs than in SVTs. Methods: 220episodes from 38 patients with single chamber ICDs that RV overdrive pacing could not terminate or change the tachycardia cycle length (TCL) were retrospectively reviewed. Episodes were classified as VTs (n=115) and SVTs (n=105). TCLs, PPIs and PPI-TCL were compared between groups. Results: The cycle length of VTs was shorter than SVTs (320.6+/-30.3 vs 366.5+/-40 ms, p=0.001). PPI and PPI-TCL of VTs were shorter than SVTs (504.7+/-128.3 vs 689.2+/-121.8 ms, p=0.001, 184+/-103 vs 322.6+/-106.6 ms, p=0.001; respectively). ROC curve analysis demonstrated a 525 ms cut-off value for PPI has 89% sensitivity and 57.4% specificity to predict inappropriate ICD therapies due to SVTs (AUC:0.852). Similarly, A PPI-TCL <195 ms favored VT as a diagnosis rather than SVT with a 90% sensitivity, and 51% specificity (AUC:0.838). Conclusion: Analyzing of PPI during overdrive pacing from RV apex may discriminate supraventricular from ventricular tachycardia. This criterion may have a potential role in implantable devices that use a single ventricular lead. PMID- 29250235 TI - A Simplified Trans-Septal Puncture Technique using a Needle Free Approach for Cryoablation of Atrial Fibrillation. AB - Background: Trans-septal puncture (TSP) is routinely performed during treatment of atrial fibrillation (AF) and other electrophysiology procedures. The purpose of this retrospective observational study was the analysis of a novel needle free technique employed to gain access to the left atrium (LA). Methods: The SafeSept Needle Free guidewire was delivered, using no needle, to the interatrial septum via a standard cryoablation sheath and dilator under transoesophageal guidance. The wire was then advanced into the LA with position confirmed by fluoroscopy. All cases were performed under general anaeasthetic (GA). Results: The novel procedure was performed in 43 patients (38 paroxysmal AF (88.4%) and 5 persistent AF (11.4%)) with 100% success rate in accessing the LA. The procedure times (51.70 +/-18.18) and fluoroscopy times (2.75 +/- 3.35) were recorded. There were no complications seen in the cohort. Conclusion: Using SafeSept Needle Free wire for TSP had a high success rate and resulted in no complications, with the potential to reduce procedure and fluoroscopy times. PMID- 29250236 TI - Post-Ictal Transient Atrial Fibrillation As A Rare Manifestation Of Grand Mal Seizure. AB - Atrial fibrillation (AF) most frequently occurs as a consequence of multiple etiologies including valvular disease, coronary artery disease, hyperthyroidism, alcohol ingestion, and pulmonary embolism. However, on rare occasion transient AF may be a result of generalized tonic-clonic seizures (GTCS). A 33-year-old-man presented to the emergency department following GTCS in AF with rapid ventricular response. He had no previous documented history. Diagnostic evaluation including electrolytes, thyroid function, cardiac enzymes, serum and urine drug screen, and two-dimensional echocardiogram were unremarkable. Diltiazem was initiated for rate control with spontaneous conversion to sinus rhythm with no recurrence. AF post-seizure is a rare phenomenon but should be considered in epileptic patients. Anticoagulation must be considered in AF due to the risk of cardioembolic stroke but should be weighed against the potential risk of head injury and subsequent intracranial bleed in patients with grand mal seizures. PMID- 29250237 TI - Resolution of AV block after ablation for atrial fibrillation. AB - We report a case with complete atrioventricular block (AVB) present both during sinus rhythm and with atrial fibrillation (AF). He had declined pacemaker placement and opted for ablation for the symptomatic AF. He underwent staged hybrid approach with video-assisted thoracoscopic surgical maze (VATS) followed by endocardial ablation. VATS included ganglionic plexi cauterization. One month after the endocardial procedure, he had complete resolution of AF and AVB and remains so at 18 months follow up. We discuss possible abolition of vagal input for this improvement in AV conduction. PMID- 29250238 TI - Feasibility and Usability of a Mobile Application to Assess Symptoms and Affect in Patients with Atrial Fibrillation: A Pilot Study. AB - Background: Atrial fibrillation (AF) is the most prevalent arrhythmia leading to hospital admissions. The majority of patients with AF report symptoms that are believed to be associated with the arrhythmia. The symptoms related to AF traditionally are collected during a clinic visit that is influenced by biases associated with recalling the experience over a limited period of time. Purpose: We designed this pilot study to assess the usability and feasibility of a mobile application to assess symptoms in patients with AF. Methods: We designed a mobile application (miAfib) to assess symptoms (chest pain, palpitation, shortness of breath, fatigue, dizziness/lightheadedness), positive affect (happy, excited, content) and negative affect (worried, angry, sad) on multiple occasions throughout the day based on iOS platform. We performed a four-week feasibility trial to examine user adherence, acceptance and experiences with the mobile application. We administered questionnaires to assess factors affecting usage and self-reported acceptance of the application based on a five-point Likert scale with zero representing strongly disagree and 5 representing strongly disagree with. Results: We included ten patients with paroxysmal and persistent AF. The mean number of completed assessments each day was 2.81 +/- 1.59 with 94.7% of days with at least one assessment. The users found the application easy to use (4.75+/-0.46), intended to use it in the future (4.37+/-1.06) and found it easy to integrate into daily routine (4.5+/-1.07). Conclusion: In this pilot study, we found participants in this four-week trial reliably used the application and were able to use the app to report their daily symptoms and affect regularly. Participants reported that they found the application easy to use and would consider using the application in the future. PMID- 29250239 TI - Frequent Premature Ventricular Contractions and Cardiomyopathy, Chicken and Egg situation. AB - Premature ventricular contractions (PVCs) are usually regarded as benign in the absence of structural heart disease. However, frequent PVCs can lead to depressed LV function, called PVC-induced cardiomyopathy and can be reversible after suppression of PVCs. On the other hand, PVCs can be a part of underlying structural heart disease and may be linked to increased risk of sudden death. In this work, we reviewed the current literature on PVC-induced cardiomyopathy based on a case presentation. PMID- 29250240 TI - Towards a Mechanistic Understanding and Treatment of a Progressive Disease: Atrial Fibrillation. AB - Atrial fibrosis appears to be a key factor in the genesis and/or perpetuation of atrial fibrillation (AF). The pathological distribution of atrial fibrosis is geographically consistent with the attachments between the posterior left atrium and the pericardium along the reflections where wall stiffness is increased and structural changes are found. While there is a wide range of complex etiological factors and electrophysiological mechanisms in AF, there is evidence for a common pathophysiological pathway that could account for deliberate substrate formation and progression of AF. Anatomical stresses along the atrium, mediated by the elastic modulus mismatch between atrial tissue and the pericardium, result in inflammatory and fibrotic changes which create the substrate for atrial fibrillation. This may explain the anatomical predominance of pulmonary vein triggers earlier in the development of atrial fibrillation and the increasing involvement of the atrium as the disease progresses. Ablative treatments that address the progressive nature of atrial fibrillation and fibrosis may yield improved success rates. PMID- 29250241 TI - Scar Homogenization in Atrial Fibrillation Ablation: Evolution and Practice. AB - Atrial fibrillation (AF) ablation has emerged as the preferred rhythm control strategy for symptomatic paroxysmal AF refractory or intolerant to at least one class I or III antiarrhythmic medication. Since the initial observation by Haissaguerre and colleagues, of pulmonary vein triggers initiating atrial fibrillation (AF), pulmonary vein isolation (PVI) has become the cornerstone for paroxysmal AF ablation therapy. PMID- 29250242 TI - New migraine with visual disturbance after cryoballoon ablation of atrial fibrillation. AB - We report the case of a 58-year-old woman who developed a headache and visual disturbances after a cryoballoon ablation procedure for atrial fibrillation at our institution. She presented to the emergency department four days post ablation and was admitted the hospital for overnight observation. Serial neurological examinations and neuroimaging were unremarkable for stroke or transient ischemic attack. The patient had some brief transient visual changes which resolved completely after several days, with no further clinical sequelae. She followed up in the outpatient neuro-ophthalmology clinic and had a normal visual field examination. She was given a diagnosis of new onset migraine with visual aura. PMID- 29250243 TI - Efficacy of Catheter Ablation and Concomitant Antiarrhythmic Drugs on the Reduction of the Arrhythmia Burden in Patients with Long-Standing Persistent Atrial Fibrillation. AB - Background: Little is known about the long-term outcome and recurrent form recurrence after catheter ablation of atrial fibrillation (AF) in patients with long-standing persistent AF. Methods: Two hundred thirty-six patients with persistent AF (193 men; age, 61.5+/-10.7 years) were enrolled, and were classified according to the duration of AF: AF duration of <1 year (group A, n=99), between 1 to 5 years (group B, n=101), and >=5 years (group C, n=36). The long-term recurrence rate and recurrent form were compared among the groups. Results: During a median follow-up of 3.7 years, the recurrence rate was significantly worse in group C after the index and multiple procedures (Log-Rank, both for a P<0.001 in comparison to group A). In the multivariate analysis, the duration was an independent predictor of an arrhythmia recurrence (HR, 1.206; 95%CI, 1.053 to 1.381; P=0.007). Recurrent AF became permanent in 8 patients (3.4%), which was not associated with a difference in the groups (Log-rank, P=0.055), while antiarrhythmic drugs (AADs) were continued in 70% of the recurrent patients. Conclusion: Despite a high AF recurrence rate in the patients with an AF duration of >=5 years, the majority of the patients with recurrence who continued on AADs had a paroxysmal form of AF. Catheter ablation and concomitant AADs may be effective in reducing the AF burden in such patients with an advanced AF disease stage. PMID- 29250245 TI - Ashman phenomenon dynamicity during atrial fibrillation: the critical role of the long cycles. AB - A case of a patient with Atrial Fibrillation and intermittent wide complex beats. What's the mechanism? PMID- 29250244 TI - Atrioesophageal Fistula After Atrial Fibrillation Ablation: A single center series. AB - Background: The incidence of atrioesophageal fistula (AEF) after atrial fibrillation catheter ablation is reported to be 0.015%-0.04%, though it is likely underreported due to a number of factors including misdiagnosis. We report our institutional experience with AEF. Methods: Patients with confirmed diagnosis of AEF between 2004 and 2016 at our institution were identified (n=5) and their clinical characteristics and outcome were analyzed. Results: AEF occurred in 5 patients who underwent AF catheter ablation (3 ablated at our institution; 2 transferred from outside hospitals after diagnosis of AEF). Symptoms were chest pain (n=3), fever (n=3), TIA/stroke (n=3), dysphagia (n=1), and headache (n=1). Chest pain was the earliest symptom and occurred 21-24 days post-RFA. One patient had sudden death without preceding symptoms. Findings included leukocytosis (WBC count range of 17200-19,000) and sepsis. Chest CT was obtained in 3 patients and showed air in the left atrium or mediastinum. Three patients had evidence of multifocal stroke on MRI. Three patients died before surgery could be performed. Two patients (40%) underwent emergent surgery which included partial excision of atrial wall, closure with bovine pericardial patch and closure of esophageal lesion. Surgical outcomes were favorable (100% survival). Conclusion: Chest pain and fever were the early symptoms of AEF and occurred before the neurologic complications. Chest CT was an excellent tool for detection of AEF. All patients who were diagnosed correctly and underwent surgery survived. Early detection is imperative as prompt surgery may improve survival. Health-care community education is the key to ensure early detection and transfer to a qualified surgical center. PMID- 29250247 TI - Coronary Air Embolism during Cryoablation of Atrial Fibrillation: A Catastrophic Complication and Its Management. AB - Various acute complications and their management during ablation of atrial fibrillation have been described. In the current report, coronary air embolism, its acute adverse effects and management of the problem were presented in a patient underwent cryoballoon ablation of atrial fibrillation. PMID- 29250248 TI - Congenital Absence of Left Atrial Appendage. AB - Isolated absence of left atrial appendage is a very rare entity and is usually encountered as an incidental finding during routine imaging for other purposes. Lately, with increasing fund of knowledge about its potential role in cardio embolic phenomena, we have seen an increased trend in the use different techniques to exclude left atrial appendage from main left atrial chamber, in an effort to alleviate the stroke risk and therefore the need for long term anticoagulation. Clinical implications of absent left atrial appendage in such patients remains a mystery. PMID- 29250246 TI - Leaks after left atrial appendage ligation with Lariat device: Incidence, pathophysiology, clinical implications and methods of closure- A case based discussion. AB - Catheter based left atrial appendage (LAA) closure techniques are emerging as a promising alternative for stroke prevention in patients who cannot tolerate oral anticoagulation. Lariat procedure involves percutaneous catheter based epicardial ligation of the LAA with a suture via an endo-epicardial hybrid approach. It offers the advantage of not leaving behind a focus for thrombus formation or embolization. Similar to surgical ligation of the left atrial appendage, Lariat ligation is limited by leaks in a small percentage of patients. The incidence of leaks is variable and can be seen in the immediate post procedure period or during follow up. The electrical and mechanical implications of leaks are still under debate. In this review, we discuss the incidence, pathophysiology, clinical implications and methods of closure of leaks after Lariat. In the end, we present a case of a Lariat leak closed with an Amplatzer septal occluder. PMID- 29250249 TI - Arrhythmia-Induced Cardiomyopathy: Prevalent, Under-recognized, Reversible. AB - Arrhythmia-induced cardiomyopathy (AIC) is a clinical condition in which a persistent tachyarrhythmia or frequent ectopy contribute to ventricular dysfunction leading to systolic heart failure. AIC can be partially or completely corrected with adequate treatment of the culprit arrhythmia. Several molecular and cellular alterations by which tachyarrhythmias lead to cardiomyopathy have been identified. AIC can affect children and adults, can be clinically silent in the form of asymptomatic tachycardia with cardiomyopathy, or can present with manifest heart failure. A high index of suspicion for AIC and aggressive treatment of the culprit arrhythmia can result in resolution of heart failure symptoms and improvement in cardiac function. Recurrent arrhythmia, following recovery from the index episode, can hasten the left ventricular dysfunction and result in HF, suggesting persistent adverse remodeling despite recovery of left ventricular function. Several aspects of AIC, such as predisposing factors, early diagnosis, preventive measures to avoid adverse remodeling, and long-term prognosis, remain unclear, and need further research. PMID- 29250250 TI - Basic Properties And Clinical Applications Of The Intracardiac. AB - The electric signals detected by intracardiac electrodes provide information on the occurrence and timing of myocardial depolarization, but are not generally helpful to characterize the nature and origin of the sensed event. A novel recording technique referred to as intracardiac ECG (iECG) has overcome this limitation. The iECG is a multipolar signal, which combines the input from both atrial and ventricular electrodes of a dual-chamber pacing system in order to assess the global electric activity of the heart. The tracing resembles a surface ECG lead, featuring P, QRS and T waves. The time-course of the waveform representing ventricular depolarization (iQRS) does correspond to the time-course of the surface QRS with any ventricular activation modality. Morphological variants of the iQRS waveform are specifically associated with each activity pattern, which can therefore be diagnosed by evaluation of the iECG tracing. In the event of tachycardia, SVTs with narrow QRS can be distinguished from other arrhythmia forms based upon the preservation of the same iQRS waveform recorded in sinus rhythm. In ventricular capture surveillance, real pacing failure can be reliably discriminated from fusion beats by the analysis of the area delimited by the iQRS signal. Assessing the iQRS waveform correspondence with a reference template could be a way to check the effectiveness of biventricular pacing, and to discriminate myocardial capture alone from additional His bundle recruitment in para-Hisian stimulation. The iECG is not intended as an alternative to conventional intracavitary sensing, which remains the only tool suitable to drive the sensing function of a pacing device. Nevertheless, this new electric signal can add the benefits of morphological data processing, which might have important implications on the quality of the pacing therapy. PMID- 29250251 TI - Management of Atrial Fibrillation Post Bypass Surgery with Intravenous Sotalol: A Case Study. AB - Intravenous sotalol has been available for many years outside of the United States, but has only recently become available in the US. The safety and feasibility of intravenous sotalol for the prevention of recurrent atrial fibrillation following bypass surgery has not been described. The present case study is of a patient with several other co-morbidities undergoing coronary artery bypass graft surgery, who post-operatively developed atrial fibrillation. The patient received intravenous sotalol and was then transitioned to oral sotalol. The patient remained hemodynamically stable, with normal QTc and without further atrial fibrillation or tachyarrhythmias in the post-operative period until discharge. Intravenous sotalol is a reasonable alternative to intravenous amiodarone in the post bypass surgery patient with better tolerability and safety profile. PMID- 29250252 TI - Esophageal Temperature Monitoring During Radiofrequency Ablation of Atrial Fibrillation: A Meta-Analysis. AB - Objective: Atrio-esophageal fistula is an infrequent but devastating complication of catheter-based ablation of atrial fibrillation (AF). Thermal esophageal injury may be the precursor of atrio-esophageal fistula. Here, we evaluated the role of esophageal temperature monitoring in preventing thermal esophageal injury during pulmonary vein isolation for AF with radiofrequency energy. Methods: In this meta analysis, we searched the PubMed, Cochrane, Scopus, Embase, and Refworks databases for all published studies from January 2004 to June 2016 to evaluate the role of esophageal temperature monitoring. We searched for terms esophageal temperature monitoring, AF, radiofrequency ablation, atrio-esophageal fistula, and thermal esophageal injury. We included studies comparing luminal esophageal temperature (LET) monitoring with no LET monitoring during radiofrequency ablation of AF. We excluded studies in which post-ablation esophagogastroduodenoscopy (EGD) was not performed to identify esophageal thermal injuries. To perform the meta-analysis, we used Review Manager statistical software and a fixed-effects modeling to derive the outcomes. Given significant heterogeneity between the studies, we used meta-regression analysis to adjust for age and sex. Results: We identified 4 non-randomized controlled trials that met our search criteria and included a total of 411 patients (n=235 in the LET monitoring group; n=176 in the no LET monitoring group) in the analysis. There were 21 (8.9%) patients with thermal esophageal injury in the LET monitoring group and 12 (6.8%) in the no LET monitoring group. The pooled odds ratio was 0.66 (0.23-1.89), indicating no statistically significant differences between the 2 groups with regard to esophageal injury. Because of the small sample size and the non-randomized nature of the trials, we observed significant heterogeneity in outcomes among the trials. Conclusion: The role of esophageal temperature monitoring in reducing the risk of esophageal thermal lesions during pulmonary vein isolation for AF has not been established, and more studies including randomized controlled trials are needed to assess its true impact. PMID- 29250253 TI - Dilated cardiomyopathy with severe arrhythmias in Emery-Dreifuss muscular dystrophy: from ablation to heart transplantation. AB - : We present 38-years male patient. He has suffered from muscle weakness since 5 years. Arrhythmias appeared at the age of 32. In 37 years he had sick sinus syndrome, transient AV block II degree, paroxysmal atrial fibrillation, atrial flutter, ventricular arrhythmias. At this time, dilated cardiomyopathy was also detected. The evaluation revealed knees and elbows contractures, increased level of creatine kinase. The genetic testing revealed a frame shift deletion c.del619C in the emerin (EMD) gene and c.IVS4-13T> A in the lamin (LMNA) gene, and c.del619C deletion in the heterozygous state in a patient's mother. Radiofrequency ablation of cavotricuspid isthmus, implantable cardioverter defibrillator (ICD) implantation were performed. Heart transplantation was performed nine months later, due to severe heart failure and electrical storm. A morphological evaluation revealed sclerosis, atrophy and hypertrophy of cardiomyocytes. He underwent an induction therapy with (basiliximab) methylprednisolone, tacrolimus, mycophenolate after heart transplantation. During 40 months after transplantation, patient's condition is satisfactory. CONCLUSION: heart failure in Emery-Dreifuss muscular dystrophy can progress quickly unless the previously stable condition. The use of correct regimens of immunosuppression therapy provides good long-term results of the heart transplantation. PMID- 29250254 TI - Inappropriate dosing of direct oral anticoagulants in patients with atrial fibrillation. AB - Atrial fibrillation (AF) is a common cardiovascular disease for which newer oral anticoagulants are available. The main objective of this study was to evaluate the appropriateness in prescriptions of direct oral anticoagulant (DOACs), more specifically apixaban, dabigatran and rivaroxaban. This was a singlecentre, retrospective study conducted in the province of Quebec, Canada. Adult subjects hospitalized between October 2011 and October 2014, with a diagnosis of AF, and a DOAC prescription were included. Data were retrieved from the electronic medical records and prescriptions were evaluated according to appropriateness criteria. A total of 500 subjects were included (235 subjects on dabigatran,222 on rivaroxaban and 43 on apixaban). Overall, 70.4% (95% confidence interval [Cl] 66.4-74.1) of DOAC prescriptions were considered appropriate. About 24% of subjects received an inappropriate dose of apixaban, dabigatran or rivaroxaban. A reduced dose was prescribed in 56.8% of subjects with no clearindication, and 43.2% received a dose that was not reduced while indicated. DOACs were frequentlyprescribed at a dose that was considered inappropriate. There is a need to strengthen dosing recommendations of DOACs in clinical practice. PMID- 29250255 TI - Adjunctive Therapies for Catheter Ablation of Non-Paroxysmal Atrial Fibrillation. AB - The success rate of pulmonary vein antral isolation (PVAI) for paroxysmal atrial fibrillation (AF) has not been realized for persistent or long-standing AF, collectively termed nonparoxysmal AF. Many investigators have described adjunctive ablation strategies to improve outcomes for catheter ablation in patients with non-paroxysmal AF. In this focused review we aim to describe these therapies and current evidence pertaining to their utilization. At present, left atrial posterior wall (LAPW) ablation, non-pulmonary vein (non-PV) trigger ablation and rotor ablation appear to improve outcomes for patients with non paroxysmal AF when performed in conjunction with PVAI. Randomized controlled trials are necessary to further elucidate such claims. PMID- 29250256 TI - Natural History of Implantable Cardioverter-Defibrillator Implanted at or after the Age of 70 years in a Veteran Population: A Single Center Study. AB - Background: The median age of patients in major Implantable Cardioverter defibrillator (ICD)trials (MUSTT, MADIT-I, MADIT-II, and SCD-HeFT) was 63-67 years; with only 11% >=70 years. There is little follow-up data on patients over 70 years of age who received an ICD for primary/secondary prevention of sudden cardiac death, particularly for veterans. Objective: The aim of this study was to study the natural history of ICD implantation for veterans over 70 years of age. Methods: We retrospectively reviewed single center ICD data in 216 patients with a mean age at implantation 76 +/- 4 years. The ICD indication was primary prevention in 161 patients and secondary prevention in 55 patients. The ICD indication was unavailable in 4 patients. Results: Mean duration of follow up was 1686 +/- 1244 days during which 114 (52%) patients died. Of these, 31% died without receiving any appropriate ICD therapy. Overall, 60/216 (28%) received appropriate therapy and 28/216 (13%) received inappropriate therapy. Patients who had ICD implantation for secondary prophylaxis had statistically more (p= 0.02) appropriate therapies compared to patients who had ICD implantation for primary prevention. Indication for implantation and hypertension predicted appropriate therapy, while age at the time of implantation and presence of atrial fibrillation predicted inappropriate therapies. Overall, 7.7% had device related complications. Conclusions: Although 28% septuagenarians in this study received appropriate ICD therapy, they had high rates of mortality, inappropriate therapy, and device complications. ICD implantation in the elderly merits individualized consideration, with higher benefit for secondary prevention. PMID- 29250257 TI - Structured care of patients with atrial fibrillation improves guideline adherence. AB - Aims: There are many reports of lack of guideline adherence in the treatment of patients with atrial fibrillation (AF), and AF affects health-related quality of life (HRQoL) negatively. The aim of this study was to investigate whether structured care compared to standard care of a general AF population could improve guideline adherence and HRQoL, and reduce symptoms,anxiety and depression. Methods: In total, 176 patients were recruited to the intervention and 146 patients to the control group.The intervention consisted of a structured follow-up program, while patients serving as controls received standard care. The primary outcome was guideline adherence evaluated through: appropriate use of oral anticoagulants (OAC) and antiarrhythmics, whether echocardiogram and thyroid lab tests were performed, and patient-reported outcome measures (PROMs), assessed with the questionnaires SF-36, EQ-5D, HADS and ASTA at baseline and after one year. Results: Guideline adherence was significantly better in the intervention group, 91% vs. 63% (p < 0.01), mainly due to appropriate OAC treatment 94% vs. 74% (p < 0.01). Symptoms assessed with ASTA were less frequent and the negative impact of AF was reduced in the intervention group after one year/ at follow-up. Five scales in SF-36, and the visual analogue scale for current health status in EQ-5D (EQ-VAS), improved significantly in both groups. Conclusion: Structured care of patients with AF significantly improved guideline adherence and patients reported fewer symptoms and a reduced negative impact on disease-specific HRQoL compared to standard care at one year follow-up. PMID- 29250258 TI - How To Manage Oral Anticoagulation Periprocedurally During Ablations And Device Implantations. AB - More than 150, 000 patients undergo ablation for atrial fibrillation (AF) each year.Current guidelines recommend oral anticoagulation in all patients undergoing AF ablation. A large number of patients undergoing cardiac implantable electronic devices (CIEDs) are on long-term oral anticoagulation. These patients are at increased risk for thromboembolism with interruption of oral anticoagulation. Due to the increased risk for bleeding complications during the procedure combined with the need to prevent thromboembolism, periprocedural management of anticoagulation in these patients can be challenging. In this article we review the current evidence for periprocedural management of oral anticoagulation in patients undergoing ablation and CIED implantation. PMID- 29250259 TI - His Bundle Pacing Or Biventricular Pacing For Cardiac Resynchronization Therapy In Heart Failure: Discovering New Methods For An Old Problem. AB - Heart failure (HF) is one of the biggest epidemics of modern cardiovascular medicine. Cardiac resynchronization therapy (CRT) with biventricular (BiV) pacing has proven to have an integral role in the management of patients with reduced left ventricular (LV) function and left bundle branch blocks (LBBB). However, CRT with BiV pacing is not always feasible and even when it is, the percentage of non responders remains high. Limitations in LV lead implantation due to anatomical or other constraints; non response to BiV pacing due to lead position or patient related factors and lack of benefit in patients with RBBB and patients with AV block and low normal LV function limit the use of BiV pacing. Permanent His Bundle pacing (HBP) is now a feasible alternative to BiV pacing for CRT therapy. This allows for recruitment of BBB disease and ventricular activation in a more physiological fashion. In this paper we review the physiology of HBP, available data on HBP for CRT and highlight how HBP can be a potential alternative in patients in whom BiV pacing did not provide clinical response or was unsuccessful. PMID- 29250260 TI - Neuro-atriomyodegenerative origin of atrial fibrillation and superimposed conventional risk factors: continued search to configure the genuine etiology of "eternal arrhythmia". AB - Atrial fibrillation (AF) is the most challenging rhythm disturbance worldwide. Arrhythmia and its behavior represent complex pathogenesis highly opposing to contemporary curative modalities. Increasing age of patients carries a certain level of risk for AF. Some underlying diseases in concordance with aging actually accelerate the occurrence of AF. Underestimated superimposed risk factors - aging plus any known risk factor or condition (hypertension, diabetes etc.) - elicit great interest and concern. In light of these concerns we offer an elaborated universal hypothesis in attempt to elucidate the genuine origin of AF substrate. Putative chronic toxicity - toxins and/or involution related pseudo-toxins potentially generate micro- and macro-structural changes in atrial myocardium thus inciting both intracellular damage (degeneration of myocites, apoptosis) and extracellular fibrotic proliferation (interstitial fibrosis, formation of matrices, degeneration of cells with fibrotic replacement). The co-products of related underlying diseases in cooperation with cellular senescence, endogenous overproduction of specific lipids/lipoproteins and other pro-atherosclerotic and/or inflammatory components generate a total atrial response - vascular/microvascular damage, intracellular and extracellular injuries. These organizational arrangements covering the entire atrial myocardium and perhaps ganglionated plexi/autonomic branches of the nervous system eventually cause clinical havoc - atrial overstretch, atrial adaptation/maladaptation, electromechanical dysfunction, arrhythmias, heart failure, etc. In essence, valvular heart disease potentially evokes similar changes "violating" thin atrial walls to obey the same scenario. Depicted atriomyodegenerative processes most likely represent the true nature of AF substrate development. Available clinical and morphological evidence potentially designates the atriomyodegenerative or plausible neuro-atriomyodegenerative origin of AF. Deductively fusion of reasons rather than purely heterogeneity is responsible for AF induction. Thus, the uniform approach and synoptic vision of clinical and pathohistological entity may offer an alternative or refreshed viewpoint in AF substrate formation. PMID- 29250262 TI - SVT Therapy - Yesterday, Today and Tomorrow? AB - This essay is a brief review of advances in treatment of patients with supraventricular tachycardia (SVT) over the past 55 years. We review the knowledge base available in terms of arrhythmia diagnosis and the limited availability of drug therapy. Significant advances resulted in the introduction of direct-current defibrillators as well as introduction of ambulatory ECG recordings. We also witnessed a tremendous increase in an understanding of the mechanisms of SVT which in turn led to the development of first surgical and subsequently catheter based techniques for localization and ablation of foci or pathways responsible for arrhythmias. More recently, surgical and catheter techniques have been introduced in an attempt to cure atrial fibrillation. These techniques have proven especially effective for those with paroxysmal atrial fibrillation and less effective for those with long standing persistent fibrillation. The future brings hope for more extensive use of non-invasive techniques both to diagnose arrhythmia mechanisms together with techniques to ablate cardiac foci without patient instrumentation and finally in the use of gene therapy for patients with cardiac arrhythmia. PMID- 29250263 TI - Apixaban-Induced Resolution of A Massive Left Atrial and Appendage Thrombosis in a Very Elderly Patient. AB - A 86-year-old woman with first diagnosed atrial fibrillation (AF) underwent mitral valve annuloplasty 10 years before was admitted to our Unit due to congestive heart failure. Trans-thoracic echocardiogram (TTE) revealed a large fluctuant echogenic mass in the posterior wall of the left atrium. Trans esophageal echo (TEE) showed the origin of the mass within the left atrial appendage. An adjusted dose of the novel oral anticoagulant (NOAC) apixaban, was prescribed. A complete disappearance was appreciated by examination at 12 weeks after the first drug administration. Although apixaban, resulted superior to warfarin in preventing stroke and thrombo-embolic events in patients with non valvular AF, while causing less bleeding, few data are actually available regarding the efficacy and safety of this drug in left atrium and appendage thrombosis management. Our report shows that this NOAC could be a simple and useful option to manage huge atrial thrombosis in very elderly patients. PMID- 29250261 TI - Impact of Alcohol Consumption on Atrial Fibrillation Outcomes Following Pulmonary Vein Isolation. AB - Background: Moderate to heavy alcohol use has been shown to be associated with increased atrial fibrillation (AF) incidence. However, the relationship between alcohol use and AF recurrence after pulmonary vein isolation (PVI) is not well known. Objective: We sought to study the impact of different alcohol consumption levels on outcomes after AF ablation. Methods: A retrospective analysis was performed of 226 consecutive patients undergoing first time PVI for AF. Clinical data were collected including alcohol intake classified into 3 groups: none-rare (< 1 drink/ week), moderate (1-7 drinks/ week), and heavy (> 7 drinks/ week). Patients were followed for recurrences within the first 3 months (blanking period; early recurrence) and after 3 months up to 1 year (late recurrence) after the ablation. Results: Paroxysmal and persistent AF had early recurrence rates of 29.1% and 32.2%, and late recurrence rates of 30.2% and 44.1%, respectively. The none-rare alcohol group had a higher frequency of diabetes mellitus (p=0.007). Neither moderate or heavy alcohol consumption, in reference to the none-rare group, was significantly predictive of early or late AF recurrence on adjusted multivariate logistic regression analysis (p>0.05). Conclusion: Despite known associations between alcohol and incidence of AF, alcohol consumption is not associated with early or late AF recurrence after PVI in this cohort. PMID- 29250264 TI - Comparison of initial LA patterns as the road to successful endocardial box lesion ablation. AB - Atrial fibrillation (AF) is the most common arrhythmia in the population. Still there is no unity in understanding of mechanisms and their influence on catheter ablation results. In our study we tried to evaluate accurate initial quantitative indicators of electromechanical remodeling that can border patients from expected good to expected poor results of catheter ablation. We performed electroanatomical mapping and ablation procedures in 94 patient (45 female) in 2012 with 3-year follow-up period. The target points were left atria surface area, complex fragmentation atrial electrograms (CFAE) duration and surface area. We investigated primary procedure efficacy and initial preoperative patterns of patients in sinus rhythm after 3-year follow-up. Patients with paroxysmal AF had about 3-4 such areas with the median duration of fragmentation 84,5msec and area 10.4cm2. In persistent AF were 5-6 zones, duration of 149 msec and area 22.95cm2. In long standing (LS) persistent AF 6-9 zones with duration up to 200 msec and area close to 30cm2. General efficacy of radiofrequency ablation (RFA) in paroxysmal group was 58,8%, in persistent 33.3% and in LS persistent 12.9% according to Kaplan-Meyer curve with p=0.001. Retrospectively we found that every index in AF recurrence group was 1,5-2 times higher than its equivalent in sinus group. LA surface area was 131.8cm2 vs 103.7cm2 respectively. Median CFAE duration in AF patients was 157msec and 87.5msec in sinus patients. The principal index of CFAE square area was 2,5 times bigger (24.6cm2 vs 10.3cm2 relatively). We concluded that parameters of mechanical (LA volume and surface area) and electrical (CFAE duration and surface area) remodeling have to be defining in tactics and prognosis of catheter ablation in different types of AF. In order to achieve higher efficacy we advise to use stepwise tactic. PMID- 29250265 TI - Pacemaker Implantation in Elderly Patients: Safety of Various Regimens of Anticoagulant Therapy. AB - Objective: To study incidence of hemorrhagic complications after pacemaker implantation in elderly patients receiving antithrombotic therapy with warfarin or uninterrupted dabigatran. Methods: 126 patients aged 83 [82; 85] years who receive continuous antithrombotic therapy after pacemaker implantation, were enrolled in the study. Adverse event data were collected during hospitalization and further 12 weeks. Results: 95 subjects (75.4%) from general number of enrolled patients received elective anticoagulant warfarin therapy and 31 subjects (24.6%) were treated with dabigatran. All patients of dabigatran group received 220 mg/day skipping the last dose before a surgery and resumed the drug intake in 36-48 hours after it. Patients of warfarin group underwent surgery if INR was NMT 3; they didn't stop taking the drug for the duration of operation.No statistically significant differences of hematoma incidence were detected in dabigatran (incidence is 0.065, 95%CI (-0.02-0.15)) and warfarin (incidence is 0.05, 95%CI (0.006-0.01)) groups, p(Fisher)= 0.55. Three cases of nonfatal gastrointestinal bleeding (warfarin group) and 1 similar event in dabigatran group were detected during a follow-up (12 [6; 20] weeks): RR= 0.98 (warfarin group), p(Fisher)=0.68. No statistically significant difference of age, sex composition, history of IHD and diabetes was detected between groups by comparison of individual characteristics of patients whose surgeries were complicated/non-complicated by hematoma formation. Upon that, hematoma formation rate was significantly higher in patients with adjunctive pacemaker muscular fixation: 71.4% vs 31.9% (patients without hematomas), p(Fisher)= 0.045. Conclusion: Incidence of hematoma formation after pacemaker implantation in patients > 75 years receiving warfarin or dabigatran, is the same as in general population of patients treated with anticoagulants. Adjunctive pacemaker muscular fixation is a significant risk factor of hematoma formation. PMID- 29250266 TI - Intravenous Sotalol - Reintroducing a Forgotten Agent to the Electrophysiology Therapeutic Arsenal. AB - Sotalol is a racemic mixture possessing beta-blocker and class III anti arrhythmic properties. Approved by US food and drug administration (FDA) since 2009 based on its bioequivalence with oral sotalol, clinicians are less familiar with the potential uses of the intravenous form despite its re-launch in United States in 2015. Available literature suggests that intravenous sotalol in recommended doses can be safely administered in adult and pediatric population achieving rapid reliable therapeutic plasma concentration and without additional proarrhythmic effects when compared to its oral form as well as other antiarrhythmic medications. Intravenous sotalol may have potential uses as an alternative agent for highly symptomatic atrial fibrillation post cardiac surgery as well as in life threatening ventricular arrhythmias. As with its oral form, judicious use with close attention to QTc and renal function is warranted. Further studies are needed to better understand the safety, efficacy and different dosing regimens of parenteral sotalol in adults and children. PMID- 29250268 TI - Reconnection Rate and Long-Term Outcome with Adenosine Provocation During Cryoballoon Ablation for Pulmonary Vein Isolation. AB - Background: Adenosine can unmask dormant conduction during pulmonary vein isolation (PVI) for atrial fibrillation (AF). Studies of adenosine use in radiofrequency PVI show high reconnection rates and conflicting results for long term success, however there is limited data with cryoballoon ablation (CBA). Methods: A prospectively maintained database of patients undergoing first CBA at a single institution was analyzed. Adenosine use was at the discretion of the primary operator. Additional freezes were delivered for reconnected veins until dormant conduction was eliminated. The primary endpoint, time to AF recurrence defined as any episode < 30 seconds after a 3-month blanking period, was assessed by Kaplan-Meier analysis. Results: From 2011 to 2015, 406 patients underwent CBA, 361 of whom had > 3 months follow-up. The mean age was 61.7 years, 69% were male, and the prevalence of paroxysmal AF was 79% with no significant difference between those that did and did not receive adenosine (77% vs 86%, respectively, p = 0.23). Adenosine testing was performed in 78 patients (21.6%) with a mean dose of 10.6 mg/vein. Of the 306 veins evaluated, 17 (6%) demonstrated dormant conduction. Over a median 14.4 months follow-up, there was no significant difference in freedom from AF with adenosine use (p= 0.86). Conclusions: Dormant conduction with adenosine is uncommon following CBA and its use does not improve long-term success rates. PMID- 29250267 TI - Defibrillation Testing During ICD Implantation - Should we or Should we Not? AB - The implantable cardioverter defibrillator (ICD) is an established therapy for improving mortality for primary and secondary prevention of sudden cardiac death. Whether to perform defibrillation threshold testing (DFT) either intraoperatively or post-operatively remains a controversial issue. The DFT is defined as the minimum energy required at which two shocks can successfully terminate ventricular fibrillation and dates from the era of surgically implanted devices with epicardial patches. Typically, a safety margin of at least 10J is employed for device programming, though some trial data suggest that a margin of 5J could be just as effective. Various methods have been utilized to perform DFT testing, and no particular method has been shown to be superior to another [Figure 1]. Previously, guideline recommendations addressed the indications for ICD implantation but did not comment on DFT testing. Recent consensus statements now provide some guidance as to when it is appropriate to perform or not perform DFT testing in light of new trial data. This review will address some of the risk factors for having a higher DFT, impact of DFT testing on patient outcomes, and some of the risks and contraindications of DFT testing. PMID- 29250269 TI - Bonus vs No Bonus Cryoballoon Isolation for Paroxysmal Atrial Fibrillation Ablation. AB - Aims: To evaluate the benefit of Bonus freeze using second generation cryoballoon after pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation (PAF). Methods: A bonus freeze is performed after proven pulmonary vein isolation (PVI) for cryoballoon ablation of paroxysmal atrial fibrillation (PAF) as standard. In the current study, no additional freeze (No Bonus) after PVI was compared with additional freeze (Bonus) after PVI using second generation cryoballoon. Results: A total of 136 patients (mean age 58 +/- 13 years, 76 male) were included. No Bonus and Bonus groups had 56 and 80 patients, respectively. Follow-up electrocardiography and Holter monitoring were performed at 1, 3, 6, 12 months, and biannually thereafter. The PVI rate was similar after the initial ablation (82% in No Bonus group, 80% in Bonus group, p>0.05) and, at the end of the procedure (99% in No Bonus group and 99% in Bonus group, p>0.05). The median procedure and fluoroscopy times in No Bonus group were 67 (60-74) minutes and 13 (10-15) minutes, which were significantly shorter than the median durations, 85 (76-90) minutes and 17 (15-21) minutes in Bonus group, respectively (all p<0.001). Phrenic nerve palsy was observed less frequently in No Bonus group compared to Bonus group (1 patient (2%) vs. 5 patients (6%), respectively) without statistically significant difference. During a median follow-up of 13 (11 15) months, the rates of patients free from AF were 82% in No Bonus group and 84% in Bonus group, respectively (p>0.05). Conclusions: The rate of sinus rhythm at 18 months was similar in patients with PAF who received bonus cryoablation vs patients who did not receive bonus cryoablation. PMID- 29250271 TI - Valproic Acid as a Cause of Transient Atrio-Ventricular Conduction Block Episodes. AB - Herein we share, to our knowledge for the first time, a a case of valproic acid use complicated by symptomatic atrio-ventricular conduction block episodes on Holter monitoring. Symptomatic atrio-ventricular block episodes should be considered as an unusual side effect of valproic acid despite normal blood therapeutic level. Before consideration of pacemaker implantation in such cases, valproic acid usage should be investigated, and dose reduction should be attempted. PMID- 29250270 TI - High Voltage Guided Pulmonary Vein Isolation in Paroxysmal Atrial Fibrillation. AB - Background: Ablation of the pulmonary vein (PV) antrum using an electroanatomic mapping system is standard of care for point-by-point pulmonary vein isolation (PVI). Focused ablation at critical areas is more likely to achieve intra procedural PV isolation and decrease the likelihood for reconnection and recurrence of atrial fibrillation (AF). Therefore this prospective pilot study is to investigate the short-term outcome of a voltage-guided circumferential PV ablation (CPVA) strategy. Methods: We recruited patients with a history of paroxysmal atrial fibrillation (AF). The EnSite NavX system (St. Jude Medical, St Paul, Minnesota, USA) was employed to construct a three-dimensional geometry of the left atrium (LA) and voltage map. CPVA was performed; with radiofrequency (RF) targeting sites of highest voltage first in a sequential clockwise fashion then followed by complete the gaps in circumferential ablation. Acute and short term outcomes were compared to a control group undergoing conventional standard CPVA using the same 3D system. Follow-up was scheduled at 3, 6 and 12 months. Results: Thirty-four paroxysmal AF patients with a mean age of 40 years were included. Fourteen patients (8 male) underwent voltage mapping and 20 patients underwent empirical, non-voltage guided standard CPVA. A mean of 54 +/- 12 points per PV antrum were recorded. Mean voltage for right and left PVs antra were 1.7+/ 0.1 mV and 1.9+/-0.2 mV, respectively. There was a trend towards reduced radiofrequency time (40.9+/-17.4 vs. 48.1+/-15.5 mins; p=0.22). Conclusion: Voltage-guided CPVA is a promising strategy in targeting critical points for PV isolation with a lower trend of AF recurrence compared with a standard CPVA in short-term period. Extended studies to confirm these findings are warranted. PMID- 29250272 TI - Percutaneous Left Atrial Appendage Closure: is there a Role in Valvular Atrial Fibrillation. AB - Atrial fibrillation, a chronic and highly morbid cardiovascular condition which affects over 33 million people worldwide, can be broadly categorized as valvular vs non-valvular in etiology. However, definitions of valvular atrial fibrillation have varied widely in the literature, and there is no clear consensus definition to date. Historically, patients with atrial fibrillation in the setting of rheumatic mitral valve disease have constituted a particularly high risk group for cardioembolic stroke, and for this reason many contemporary trials of pharmaceutical and device therapies for atrial fibrillation have systematically excluded patients with valvular heart disease. Therefore, vitamin K antagonism remains the favored approach to mitigate stroke risk in valvular atrial fibrillation, and the optimal strategy to treat atrial fibrillation patients with valvular heart disease who cannot tolerate oral anticoagulation therapy is unknown. Recent trials have demonstrated an important role for percutaneous left atrial appendage occlusion devices in patients with non-valvular atrial fibrillation, but the role of these devices in patients with valvular atrial fibrillation is uncertain. Given the worldwide burden of valvular atrial fibrillation, future trials intended to clarify the role of percutaneous left atrial appendage closure devices in valvular atrial fibrillation should provide important insight for the care of millions of patients. PMID- 29250273 TI - Left Atrial Appendage characteristics in patients with Persistent Atrial Fibrillation undergoing catheter ablation (LAAPAF Study). AB - Background: Despite technological and scientific efforts, the recurrence rate of persistent atrial fibrillation (AF) remains high. Several studies have shown that in addition to pulmonary vein (PV) isolation other non-PV triggers, particularly left atrial appendage may be the source of initiation and maintenance of AF. There are few studies showing the role of left atrial appendage (LAA) isolation in order to obtain higher success rate in persistent AF patients. Objective: We analyzed the LAA volume, volume index and shape relative to the LA in patients with persistent AF undergoing AF ablation. Methods: Fifty-nine consecutive patients with persistent AF who underwent catheter ablation were enrolled. Computerized tomography (CT) was performed in order to assess left atrial and PV anatomy including the LAA. Digital subtraction software (GE Advantage Workstation 4.3) was used to separate the LAA from the LA and calculate: LA volume (LAV), LA volume index (LAV/body surface area), LAA volume (LAAV), LAA volume index (LAA volume/LA volume), and LAA morphology [chicken wing (CW) or non-chicken wing (NCW)]. Results: The mean age was 64.6 +/- 9.8 years, 44 % male, and LA diameter 47.6 +/- 7.8 mm. Median follow-up (FU) was 13 months. All patients had antral isolation of PVs and ablation of complex fractionation +/- linear ablation (roof line/superior coronary sinus/mitral line). Among 59 patients with persistent AF, 26 (44 %) patients were diagnosed with AF recurrences. Mean LAV was 145.0 +/- 45.9 ml, LAVI 68.9 +/- 20.0 ml/m2, LAAV 10.3 +/- 4.0 ml, and LAAVI 7.3 +/- 2.7 ml/m2. LAA shape was non-chicken wing (NCW) in the majority of patients (51 %). LAA parameters were not significantly different between patients with and without AF recurrence (LAAV 11.0 +/- 4.3 ml vs. 9.7 +/- 3.8 ml, p=0.26; LAAVI 7.5 +/- 3.0 ml/m2 vs. 7.2 +/- 2.5 ml/m2, p=0.71; LAA shape of NCW 50 % vs 52 %, p=0.75, respectively). LAV was significantly correlated with the LAAV (r: o.47, p=0.009). The incidence of NCW LAA was significantly higher in patients with previous stroke/TIA (80 % vs. 20 %, p=0.04). Conclusion: The LAA anatomical characteristics (volume/volume index and the shape) were comparable in patients with/out AF recurrence post PVI. It remains to be determined if additional LAA isolation will impact outcomes in patients with persistent AF. PMID- 29250274 TI - Prevention of Cardiac Implantable Electronic Device Infections: Update and Evaluation of the Potential Role for Capsulectomy or the Antibiotic Pouch. AB - Cardiac implantable electronic device (CIED) infections can have devastating implications for patient morbidity and mortality. Over the past decade, the infection rate has risen out of proportion to implant rates, and has prompted the development of innovative solutions designed to reduce infections. The first section of this review provides a summary of the contemporary knowledge regarding the incidence, prevalence, microbiology, and risk factors for cardiac implantable electronic device infections. The second section addresses prevention with an emphasis on the potential role of novel procedural approaches, such as capsulectomy and the antibacterial envelope, in reducing CIED infection. PMID- 29250275 TI - Rescue Leadless Pacemaker Implantation in a Pacemaker-Dependent Patient with Congenital Heart Disease and no Alternative Routes for Pacing. AB - Congenital heart disease patients are considered a unique group of patients regarding their high risk of conduction abnormalities , whether de novo or surgically induced , and the challenges in both implantation and management of device related complications. We present a case of a pacemaker-dependent patient with congenital heart disease who experienced complications of both previous epicardial and transvenous pacing which rendered her a non-suitable candidate of both routes. PMID- 29250276 TI - Comparison of the Efficancy and Complication Rates of the Hybrid Maze, Complete Cox-Maze and Catheter Ablation in the Treatment of Atrial Fibrillation. AB - Introduction: Atrial fibrillation is the most common cardiac arrhythmia in the United States. It has been associated with a reduction in patient quality of life and more serious complications such as stroke and heart failure. The aim of this study was to compare the efficacy of commonly performed invasive procedures in keeping patients in normal sinus rhythm. Methods and Results: A retrospective chart review was performed on all patients who underwent primary radiofrequency catheter ablation, the complete Cox-maze, or the hybrid maze at OSF Saint Anthony Medical Center between January 2010 and December 2013 (n=140). Immediately post procedure, arrhythmia recurrence rates did not differ between the groups (p = 0.28). At all follow-up points thereafter, however, differences in procedural efficacy between surgical and catheter therapy remained highly significant (p < 0.001). At 2 years, 20.3% of the catheter ablation patients were in normal sinus rhythm, when compared to 57.9% of hybrid maze and 72.7% the complete Cox-maze groups. A difference in major complication rates was noted (p = 0.04), with the complete Cox-maze having a 17.4%, the hybrid having 22.7%, and the catheter ablation group having 5.6%. Conclusions: This study was unable to detect differences in the efficacy rates of the surgical procedures, however they were both superior to catheter ablation. Although the hybrid approach is considered minimally invasive, complication rates were similar to those of the complete Cox maze. Catheter ablation was the safest procedure, and since evidence of reduced mortality after the use of aggressive rhythm therapy is currently lacking, the results suggest that hybrid surgery for atrial fibrillation should be used after the failure of more conservative measures. PMID- 29250277 TI - Evaluating the Utility of mHealth ECG Heart Monitoring for the Detection and Management of Atrial Fibrillation in Clinical Practice. AB - Background: Little attention has focused on the integration of mobile health (mHealth) technology with self-management approaches to improve the detection and management of atrial fibrillation (AF) in clinical practice. Objective: The objective of this study was to investigate the differences between mHealth and usual care over a 6-month follow-up period among patients with a known history of atrial fibrillation. Methods: A pilot cohort from within the larger ongoing randomized trial, iPhone(r) Helping Evaluate Atrial fibrillation Rhythm through Technology (iHEART), was evaluated to determine differences in detection of AF and atrial flutter (AFL) recurrence rates (following treatment to restore normal rhythm) between patients undergoing daily smartphone ECG monitoring and age and gender matched control patients. SF-36v2TM QoL assessments were administered at baseline and 6 months to a subset of the patients undergoing daily ECG monitoring. Differences between groups were assessed by t-test, Fisher's exact test, and Cox proportional hazard models. Results: Among the 23 patients with smartphone ECG monitors (16 males and 7 females, mean age 55 +/- 10), 14 (61%) had detection of recurrent AF/AFL versus 30% of controls. During the follow-up period, patients given smartphone ECG monitors were more than twice as likely to have an episode of recurrent AF/AFL detected (hazard ratio: 2.55; 95% CI: 1.06 - 6.11; p = 0.04). Among the 13 patients with baseline and 6 month QoL assessments, significant improvements were observed in the physical functioning (p = 0.009), role physical (p = 0.007), vitality (p = 0.03), and mental health domains (p = 0.02). Conclusions: Cardiac mHealth self-monitoring is a feasible and effective mechanism for enhancing AF/AFL detection that improves quality of life. PMID- 29250278 TI - The Nonvitamin K Antagonist Oral Anticoagulants and Atrial Fibrillation: Challenges and Considerations. AB - : The nonvitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban are used for the reduction of the risk of stroke or systemic embolism (SEE) in patients with nonvalvular atrial fibrillation (NVAF). The purpose of this review is to highlight the safety and efficacy results of the pivotal NOAC clinical trials for use in NVAF, discuss some of the unique management challenges in the use of NOACs in special populations, summarize data on emerging and novel indications, and address potential future directions. Methods: A literature search was conducted and to identify relevant clinical trials and studies regarding the use of NOACs for the prevention of stroke or SEE in patients with atrial fibrillation. Results: Relative to warfarin, NOACs are as effective or superior in the prevention of stroke or SEE, and are associated with similar or lower rates of major bleeding and significantly decreased rates of intracranial bleeding, but may be associated with a slightly increased risk of gastrointestinal bleeding in patients with AF. The NOACs are not indicated for use and have not been widely tested in AF patients with other cardiovascular conditions. Additional ongoing and planned clinical trials will provide additional information regarding the use of NOACs in these patients. In situations requiring rapid reversal of anticoagulation, the availability of specific antidotes will improve safety and facilitate NOAC use. Conclusions: Use of NOACs in clinical practice requires consideration of patient characteristics as well as potentially required procedures. PMID- 29250279 TI - Baseline Demographics, Safety, and Patient Acceptance of an Insertable Cardiac Monitor for Atrial Fibrillation Screening: The REVEAL-AF Study. AB - Given the high prevalence and risk of stroke associated with atrial fibrillation (AF), detection strategies have important public health implications. The ongoing prospective, single-arm, open-label, multicenter REVEAL AF trial is evaluating the incidence of previously undetected AF using an insertable cardiac monitor (ICM) in patients without prior AF or device implantation, but who could be at risk for AF due to their demographic characteristics, +/- non-specific but compatible symptoms. Enrollment required an elevated AF risk profile defined as CHADS2>=3 or CHADS2=2 plus one or more of the following: coronary artery disease, renal impairment, sleep apnea or chronic obstructive pulmonary disease. Exclusions included stroke or transient ischemic attack occurring in the previous year. Of 450 subjects screened, 399 underwent a device insertion attempt, and 395 were included in the final analysis (Reveal XT: n=122; Reveal LINQ: n=273; excluded: n=4). Participants were primarily identified by demographic characteristics and the presence of nonspecific symptoms, but without prior documentation of "overt" AF. The most common symptoms were palpitations (51%), dizziness/lightheadedness/pre-syncope (36%), and shortness of breath (36%). Over 100 subjects were enrolled in each pre-defined CHADS2 subgroup (2, 3 and >=4). AF risk factors not included in the CHADS2 score were well represented (prevalence>=15%). Procedure and/or device related serious adverse events were low, with the miniaturized Reveal LINQ ICM having a more favorable safety profile than the predicate Reveal XT (all: n=13 [3.3%]; LINQ: n=6 [2.2%]; XT: n=7 [5.7%]). These data demonstrate that REVEAL AF was successful in enrolling its target population, high risk patients were willing to undergo ICM monitoring for AF screening, and ICM use in this group is becoming increasingly safe with advancements in technology. A clinically meaningful incidence of device detected AF in this study will inform clinical decisions regarding ICM use for AF screening in patients at risk. PMID- 29250280 TI - Time to Revisit the Time in the Therapeutic Range. AB - In recent clinical trials, the ?"quality?" of warfarin management has been characterized by the time in therapeutic range (TTR) -- with the therapeutic range being an INR between 2.0 and 3.0. In many reviews of recent clinical trials, differences in the TTR have been used comparatively to critique and contrast the trials. However, TTR is a more complex measurement than is commonly appreciated, and many factors that underlie the TTR calculation, which can differ from trial to trial, have not been adequately addressed. This manuscript attempts to explain these issues so as to help the reader understand the factors that contribute to TTR and to understand the limitations of TTR so as to better understand anticoagulation trial results. It also addresses the issue of INRs below or above the therapeutic range, that can differ among trials, that are not provided simply by presenting a TTR value, but that can in a substantial way affect the bleeding risk and embolism-prevention likelihood of anticoagulation in a trial. PMID- 29250281 TI - Peri-procedural Corticosteroid Use in Improving Outcomes Following Atrial Fibrillation Ablation: Back to Square One? PMID- 29250282 TI - Use of Oral Steroid and its Effects on Atrial Fibrillation Recurrence and Inflammatory Cytokines Post Ablation - The Steroid AF Study. AB - Background: Use of corticosteroids before and after atrial fibrillation (AF) ablation can decrease acute inflammation and reduce AF recurrence. Purpose: To assess the efficacy of oral prednisone in improving the outcomes of pulmonary vein isolation with radiofrequency ablation and its effect on inflammatory cytokine. Methods: A total of 60 patients with paroxysmal AF undergoing radiofrequency ablation were randomized (1:1) to receive either 3 doses of 60 mg daily of oral prednisone or a placebo. Inflammatory cytokine levels (TNF-alpha, IL-1, IL6, IL-8) were measured at baseline, prior to ablation, immediately after ablation, and 24 hours post ablation. Patients underwent 30 day event monitoring at 3 months, 6 months and 12 months post procedure. Results: Immediate post ablation levels of inflammatory cytokines were lower in the steroid group when compared to the placebo group; IL-6: 9.0 +/-7 vs 15.8 +/-13 p=0.031; IL-8: 10.5 +/-9 vs 15.3 +/-8; p=0.047 respectively. Acute PV reconnection rates during the procedure (7/23% vs 10/36%; p = 0.39), and RF ablation time (51+/-13 vs 56+/-11 min, p = 0.11) trended to be lower in the placebo group than the steroid group. There was no difference in the incidence of early recurrence of AF during the blanking period and freedom from AF off AAD at 12 months between both groups (5/17% vs 8/27%; p = 0.347 and 21/70% vs 18/60%; p=0.417 in placebo and steroid groups respectively). Conclusion: Although oral corticosteroids have significant effect in lowering certain cytokines, it did not impact the clinical outcomes of AF ablation. PMID- 29250284 TI - Incorporating Stroke and Bleeding Risk Stratification Tools into Atrial Fibrillation Management Making Sense of the Alphabet Soup. AB - Atrial fibrillation (AF) is a common arrhythmia managed by many physicians in a variety of clinical settings. One of the most important clinical decisions related to effective AF management centers upon the need to perform accurate thromboembolic risk stratification followed by effective management decisions that align with established guidelines. This manuscript will review the present state of the art and provide guidance to physicians to enhance patient outcomes. PMID- 29250286 TI - Rhythm control for post-operative atrial fibrillation. Still a promising future? PMID- 29250283 TI - Stroke Prevention for Patients with Atrial Fibrillation: Beyond the Guidelines. AB - Atrial fibrillation (AF) is the most common serious heart rhythm disorder, with a lifetime incidence of 1 in 4 for patients >40 years of age[1]. AF is a major cause of death and disability, as it is associated with a 4-5 fold increase in the risk of ischemic stroke[2]. In patients with AF, oral anticoagulation (OAC) therapy can reduce the risk of stroke by about two-thirds and the risk of all cause mortality by approximately one-quarter, but is associated with an increased risk of bleeding[3], [4]. Atrial fibrillation (AF) is the most common serious heart rhythm disorder and is associated with an increased risk of ischemic stroke. This risk can be moderated with oral anticoagulation therapy, but the decision to do so must be balanced against the risks of bleeding. Herein, we discuss three emerging areas where more high-quality evidence is required to guide risk stratification: 1) the relationships between the pattern and burden of AF and stroke 2) the risk conferred by short episodes of device-detected "sub clinical" atrial fibrillation (SCAF) and 3) the significance of AF that occurs transiently with stress (AFOTS), as is often detected during medical illness or after surgery. Risk stratification is important to identify patients with AF who can benefit from OAC therapy. There are, however, several common clinical scenarios where guidelines do not yet provide direction for stroke prevention; or do so based on limited high-quality evidence. PMID- 29250285 TI - A novel de novo mutation in Lamin A/C gene in Emery Dreifuss Muscular Dystrophy patient with atrial paralysis. AB - We present a 26 year old female Indonesian patient with full spectrum Emery Dreifuss Muscular Dystrophy (EDMD) characterized with contracture of elbows, heel cord and pelvic muscle wasting and weakness and atrial paralysis, as rare cardiac findings in EDMD . A novel de novo pathogenic heterozygous missense mutation (NM_170707.3: c.122G>T, p.Arg41Leu) in exon 1 was detected. Preventing atrial paralytic patients from systemic embolism is important. Early diagnosis, intervention, targeted management and counseling are necessary for a better health and life quality of individuals with EDMD. PMID- 29250287 TI - The Significance Of Troponin Elevation In Atrial Fibrillation. AB - Cardiac troponin assays have provided a significant contribution for the early diagnosis of cardiovascular events. There is significant evidence about the association between the absolute value of elevated cardiac troponin levels with the prognosis of patients with chest pain. However, it is well-known that elevated cardiac troponin levels may occur in situations other than acute coronary syndromes, as it happens with atrial fibrillation. The significance and prognosis of this elevation are not entirely clear. We review the evidence about the meaning of such elevation in the setting of atrial fibrillation. PMID- 29250288 TI - Thermal Field in Cryoablation Procedures for Pulmonary Veins Isolation: Importance of Esophageal Temperature Monitoring. AB - Background: Cryoablation procedures for pulmonary veins isolation have proved to be a successful treatment of atrial fibrillation, but exposure of surrounding organs to excessively low temperatures is potentially dangerous. Hence the importance of monitoring esophageal temperature and at the same time predicting the thermal field induced by the procedure, so to provide clinicians with a valuable tool to take critical decisions. Methods and Results: We formulate a mathematical model for computing the temperature in the relevant region and we use numerical simulations to interpret recorded clinical data. The temperature at the outer esophageal surface can be much lower than the luminal one. Observing the esophageal lumen cooling rate at the early stage of the procedure it is possible to forecast whether temperature is bound to reach dangerous values; the same quantity has a correlation with the steepness of the transesophageal thermal gradient. Conclusion: Monitoring the time evolution of luminal esophageal temperature is of fundamental importance not only to realize but also to predict well in advance critical developments of the procedure. PMID- 29250290 TI - Giant Left Atrial Appendage Aneurysm Mimicking Mediastinal Mass and Associated with Incessant Atrial Arrhythmias. AB - Left atrial appendage aneurysm (LAAA) is a rare entity. Clinical manifestations include arrhythmias and systemic embolization. We show here an example of a large and ectopic LAAA mimicking a mediastinal mass on chest X-ray and presenting with incessant atrial arrhythmias. Subsequent investigations leading to the correct diagnosis are described. PMID- 29250289 TI - Mechanistic Insights Into Durable Pulmonary Vein Isolation Achieved by Second Generation Cryoballoon Ablation. AB - Background: The mechanism explaining the efficacy of cryoballoon ablation (CBA) for atrial fibrillation has not been clarified. Methods and Results: We compared lesion characteristics between patients in whom pulmonary vein isolation (PVI) was performed by CBA (n=56) and those by contact force (CF)-based RF ablation (n=56). We evaluated the 3-dimensional PV morphology before and after cryoballoon inflation. After PVI, a 3D left atrial voltage map was created. Pacing (10 mA and 2 ms) was performed within the low voltage area from the ablation line, and electrically unexcitable ablated tissue was identified. ATP-provoked dormant conduction after PVI occurred in 9 of the 224 (4%) PVs in the CBA group and in 13 of the 224 (6%) PVs in the CF group (P=0.3935). The inflated balloon stretched the PV from the original PV ostial surface by 7.1+/-3.5 mm, but at sites with (vs, sites without) residual PV potential/dormant conduction, the extent of the PV distension was reduced (4.0+/-4.0 mm vs. 7.2+/-3.4 mm, P<0.0001). The unexcitable ablated tissue around the PVs was significantly wider in CB patients than in CF patients (16.7+/-5.1 mm vs. 5.3+/-2.3 mm, P<0.0001). Conclusions: Use of the cryoballoon significantly distends the PV. Without this extensive distention, PVI may not be successful. CBA seems to yield wide unexcitable ablation zones. These factors seem to explain the durability of CBA lesions. PMID- 29250291 TI - Clinical Role of Dominant Frequency Measurements in Atrial Fibrillation Ablation A Systematic Review. AB - Introduction: Experimental data strongly supports a role for high-frequency sources in the perpetuation of atrial fibrillation, it follows that identification of areas exhibiting spectra containing high dominant frequencies (DF) may represent perpetuating sources and targeted elimination might terminate AF. The aim of this review is to present and critically appraise the literature on DF studied in association with AF ablation. Methods And Results: A systematic review was done including the PubMed (MEDLINE), Cochrane Central Register of Controlled Trials (Central), Scientific Electronic Library Online (SciELO), and HighWire Press databases. The searches were made by combining the terms "Dominant Frequency", "Atrial Fibrillation", and "Catheter Ablation" and their translations for the English and non-English based databases. Ten articles were selected from a total of 327 articles found after the initial search. The ablation strategy varied, most studies performed pulmonary vein isolation alone or associated with complex fractionated atrial electrogram ablation with or without an additional intervention. The use or not of DF sites as ablation target was distinguishable between the articles. Four articles ablated DF sites as a major intervention or in addition to a traditional approach. The remaining 6 articles assessed DF sites pre and post ablation and associated these data with clinical outcome. Conclusion: No prior study has systematically comprised information for clinical use of DF. The current literature supports global DF as a useful marker of ablation outcome; however direct intervention targeting DF appears premature with mixed results and too few studies. PMID- 29250292 TI - Comparison of the Efficacy of PVAC(r) and nMARQTM for paroxysmal atrial fibrillation. AB - Pulmonary vein isolation (PVI) has become the mainstay of therapy for atrial fibrillation (AF) and one of the most frequently performed procedures in the cardiac electrophysiology laboratory. PVI by a single-tip radiofrequency (RF) ablation catheter remains a complex and time-consuming procedure, especially in centers with limited experience. In order to simplify the PVI procedure, to shorten it and reduce the complication rate, circular multi-electrode catheters were introduced for simultaneous mapping and ablation. The common concept of these "single-shot" AF ablation technologies is the creation of circular lesions for PVI by placing the ablation device at the antrum of the pulmonary veins without the need for continuous repositioning. In this review we describe the main features of two circular non-balloon ablation catheters- PVAC(r), which is based on the phased RF, duty-cycled ablation technology, and nMARQTM, the irrigated multi-electrode electro-anatomically guided catheter - and compare the clinical outcomes of these technologies, mainly for paroxysmal AF patients, based on current available data. PMID- 29250293 TI - Hypothetical "anatomy" of Brugada phenomenon: "Long QT sine Long QT" syndrome implicating morphologically undefined specific "Brugada's myocells". AB - The Brugada syndrome (BrS) is associated with increased risk of ventricular arrhythmias and sudden cardiac death. It generates genetically mediated arrhythmias posing a true pathophysiological challenge. In search of the similarities between BrS and long QT syndrome some novel insights are suggested. In patients with BrS the duration of QT interval is usually normal. Some investigators have found prolonged QT interval in the syndrome's natural course or the duration of QT segment have been extended by provocative tests unmasking BrS. Thus, BrS might be characterized as "long QT sine long QT" syndrome. The existence of two functional types of myocites is suspected. Regarding structure and function the majority of ventricular myocardium is probably mostly healthy. The rest of myocardium (preferably the subepicardium of right ventricular outflow tract) due to its genotypic peculiarities demonstrates no negative influence on ventricular performance until early adulthood is reached and/or other unstable preconditions are fulfilled (nocturnal time, fever, specific drugs, etc.). Based on published findings of positive outcomes, following the epicardial ablation of the right ventricular outflow tract region, a new hypothetical concept suggesting the presence of specific, genetically affected "Brugada's myocells" is proposed. These cells as a suitable arrhythmogenic substrate reside intramurally within the subepicardial region of the outflow tract of right ventricle. In the daytime these cells likely are dormant but at rest their nocturnal proarrhythmic behavior is activated occasionally. Presumptions regarding the pathophysiology of BrS might be the focus of further discussion. PMID- 29250294 TI - Use of Barbed Suture for Wound Closure in Electrophysiology Device Procedures. AB - BACKGROUND: Barbed suture use in surgical fields such as gynecology and orthopedic surgery has been associated with faster wound closure, improved cosmesis, increased cost-effectiveness and potentially decreased rates of infection. However, the use of barbed suture in electrophysiology device procedures has not been reported. OBJECTIVE: This study aims to (1) investigate the safety and effectiveness of barbed suture in wound closure in patients after EP implantable cardioverter defibrillators and loop recorders (CIED) procedures, (2) to determine whether these sutures have an advantage in device implant procedures by improving incision integrity, (3) and to find out whether these sutures would potentially lead to lower rates of infections compared to non barbed sutures. METHODS: We retrospectively compared the closure success and complications in 413 patients undergoing CIED procedures without Quill sutures and with Quill sutures. The primary outcome was closure success and pocket infection/dehiscence within 3 months of CIED. RESULTS: Of the 413 patients who were followed up in 3 months, there was a non-significant trend toward a lower infection rate with barbed versus non-barbed suture 1.31%, vs 1.63% p= 0.78. CONCLUSION: This study confirms the safety and usefulness of barbed suture material for wound closure during CIED procedures. PMID- 29250295 TI - Early Pulmonary Vein Conduction Recovery after Catheter Ablation of Atrial Fibrillation. AB - Background: Pulmonary vein electrical isolation (PVI) is an effective treatment for atrial fibrillation (AF). However, recurrence of pulmonary vein (PV) conduction after ablation may limit long-term success. Early identification and treatment of acute PV conduction recovery during initial ablation may have an impact on subsequent clinical results. Objective: To assess the prevalence of acute PV conduction recovery during the observation time after PV isolation for paroxysmal AF, and to evaluate the impact of re-isolation treatment on long-term clinical results. Methods: 76 patients with paroxysmal AF were randomized to 2 groups to undergo PVI. Group A (Study Group: 38 patients): 30 minutes of observation were given following PV isolation for detection of acute PV reconnection, with re-ablation of reconnected PVs. Group B (Control Group: 38 patients). Ablation procedure was done either by conventional method or using 3D electro-anatomical mapping. Symptoms, ECG and Holter monitoring were used to evaluate the clinical effectiveness of ablation. Any episode of symptomatic or asymptomatic atrial tachyarrhythmia that lasted more than 30 seconds documented with ECG or Holter monitoring was considered a recurrence. Results: There was no statistically significant difference in age, sex, AF history, previous AF ablation, structural heart diseases & antiarrhythmic drug history among both groups. In the study group, 14 patients (36.8%) showed no PV reconnection, while 24 patients (63.2%) showed acute PV reconnection within 30 minutes. The LSPV showed the highest rate of acute PV reconnection during the observation period (66.6% of patients showing PV reconnection). AF recurred in only 6 patients (15.8%) in the study group in comparison to 20 patients (52.6%) having AF recurrence post-ablation in the control group. Among 24 patients of the study group, who showed PV reconnection which was re-isolated, only 4 patients (16.7%) had AF recurrence on follow up. In patients who did not show PV reconnection (14 patients), only 2 patients (14.3%) had AF recurrence on follow up. Conclusion: Re isolation of recovered PV conduction contributed to the improvement in the success rate of ablation for paroxysmal AF. PMID- 29250296 TI - Focal Atrial Fibrillation from the Superior Vena Cava. AB - We report the case of a 66 year-old male who underwent catheter ablation for drug refractory paroxysmal atrial fibrillation (AF) at our institution. Radiofrequency catheter ablation was performed using a three-dimensional electroanatomical mapping system. During ablation of the pulmonary veins (PV), right atrial ectopics were noted to repeatedly trigger AF and atrial tachycardia (AT). After PV isolation, mapping of the right atrium revealed that the superior vena cava (SVC) was in AF, while both atria were in an organized AT. Segmental ablation was performed around the SVC ostium, resulting in vein isolation and immediate restoration of sinus rhythm, while the SVC remained in AF. This case highlights the importance of the SVC in some AF patients as a potential source for non-PV triggers. SVC isolation can be safely achieved in most cases to improve outcomes. PMID- 29250298 TI - Smartphone-based Arrhythmia Detection: Should we encourage patients to use the ECG in their pocket? AB - The detection of atrial fibrillation (AF) is important for stroke prevention in patients with AF. This paper aimed to investigate the current landscape of smartphone-based arrhythmia detection and monitoring. The current technology can be divided into smartphone-based photoplethysmography (PPG) and smartphone-based single-lead electrocardiograms (ECGs). Our literature review concluded there are currently no validated PPG applications for the detection of arrhythmias available to the general population. However, an initial validation study indicates that the current development in Cardiio Rhythm PPG application, when made available, could provide an accurate and reliable means to detect AF in patients at risk of developing AF. The smartphone-based single-lead ECG devices are more promising. Multiple studies have shown the AliveCor smartphone ECG to be a reliable and accurate means of detecting atrial fibrillation. A drawback is that this device strictly provides data and is not capable of making a diagnosis of atrial fibrillation. The recorded ECG needs to be sent to a physician or medical professional for further review. In conclusion, these devices show promise in arrhythmia assessment, managing patients with AF, and diagnosing AF early in high risk patients. Caution should be used when assessing data provided by these devices, as validation in a real-world setting is still underway. PMID- 29250299 TI - Oxidative Stress-Related Parthanatos of Circulating Mononuclear Leukocytes in Heart Failure. AB - Background: The present study aims to examine the oxidative stress-related activation of poly(ADP-ribose) polymerase (PARP), a cause of parthanatos in circulating mononuclear leukocytes of patients with chronic heart failure (CHF), that was rarely investigated in the human setting yet. Methods: Patients with CHF (n = 20) and age- and body mass index-matched volunteers (n = 15) with a normal heart function were enrolled. C-reactive protein, N-terminal probrain-type natriuretic peptide (pro-BNP), plasma total peroxide level (PRX), plasma total antioxidant capacity (TAC), oxidative stress index (OSI), leukocyte lipid peroxidation (4-hydroxynonenal; HNE), protein tyrosine nitration (NT), poly(ADP ribosyl)ation (PARylation), and apoptosis-inducing factor (AIF) translocation were measured in blood samples of fasting subjects. Results: Plasma PRX, leukocyte HNE, NT, PARylation, and AIF translocation were significantly higher in the heart failure group. Pro-BNP levels in all study subjects showed a significant positive correlation to PRX, OSI, leukocyte HNE, NT, PARylation, and AIF translocation. Ejection fraction negatively correlated with the same parameters. Among HF patients, a positive correlation of pro-BNP with PRX, OSI, and PARylation was still present. Conclusions: Markers of oxidative-nitrative stress, PARP activation, and AIF translocation in blood components showed correlation to reduced cardiac function and the clinical appearance of CHF. These results may reinforce the consideration of PARP inhibition as a potential therapeutic target in CHF. PMID- 29250301 TI - Antioxidant Phytochemicals at the Pharma-Nutrition Interface. PMID- 29250300 TI - Cultivation and Immortalization of Human B-Cells Producing a Human Monoclonal IgM Antibody Binding to MDA-LDL: Further Evidence for Formation of Atherogenic MDA LDL Adducts in Humans In Vivo. AB - Oxidatively modified low-density lipoprotein (oLDL) is firmly believed to play an important role in the initiation and development of atherosclerosis, and malonic dialdehyde (MDA) is one of the major lipid peroxidation breakdown products involved in this process. In recent decades, antibodies against MDA-LDL have been detected in human and animal sera. In our study, human B-cells from the peripheral blood of a healthy female donor were fused with the SP2/0 mouse myeloma cell line. Antibody-producing hybridomas were detected by MDA-LDL-IgG/IgM enzyme-linked immunosorbent assays (ELISA) and Cu++-oxidized LDL IgG/IgM (oLAb) ELISA. Cells with supernatants emitting positive signals for antibodies were then cloned and after sufficient multiplication frozen and stored under liquid nitrogen. Due to the loss of antibody-producing ability, we established an MDA LDL-IgM-producing cell line by recloning. This allowed isolation and immortalization of several human B-cells. The human donor had not been immunized with MDA-modified proteins, thus obviously producing MDA-LDL antibodies in vivo. Furthermore, using these antibodies for in vitro experiments, we were able to demonstrate that MDA epitopes are among the epitopes generated during Cu++-LDL oxidation as well. Finally, these antibodies compete in ELISA and cell culture experiments with MDA as a challenging toxin or ligand. PMID- 29250297 TI - Pulmonary Vein Isolation with the Multipolar nMARQTM Ablation Catheter: Efficacy And Safety In Acute And Long-Term Follow Up. AB - Pulmonary vein isolation (PVI) is an established therapy for atrial fibrillation (AF). One challenge in the catheter-based treatment of this arrhythmia is to develop an effective and safe ablation approach to achieve durable and consistent lesions around the PVs. The multipolar irrigated radiofrequency (RF) ablation catheter nMARQTM was designed as a single-shot device with the aim to achieve these goals. This article reviews the current literature with respect to acute- and long- term success rates after PVI with this circular mapping and ablation device. Furthermore, since this device recently became discredited to potential lethal complications, we will also focus on the data available on safety issues with this ablation system. PMID- 29250302 TI - A Portable, Arbitrary Waveform, Multichannel Constant Current Electrotactile Stimulator. AB - In this paper, we present the design and performance of a portable, arbitrary waveform, multichannel constant current electrotactile stimulator that costs less than $30 in components. The stimulator consists of a stimulation controller and power supply that are less than half the size of a credit card and can produce +/ 15 mA at +/-150 V. The design is easily extensible to multiple independent channels that can receive an arbitrary waveform input from a digital-to-analog converter, drawing only 0.9 W/channel (lasting 4-5 hours upon continuous stimulation using a 9 V battery). Finally, we compare the performance of our stimulator to similar stimulators both commercially available and developed in research. PMID- 29250303 TI - Income reliably predicts daily sadness, but not happiness: A replication and extension of Kushlev, Dunn, & Lucas (2015). AB - Kushlev, Dunn, and Lucas (2015) found that income predicts less daily sadness-but not greater happiness-among Americans. The present study used longitudinal data from an approximately representative German sample to replicate and extend these findings. Our results largely replicated Kushlev and colleagues': income predicted less daily sadness (albeit with a smaller effect size), but was unrelated to happiness. Moreover, the association between income and sadness could not be explained by demographics, stress, or daily time-use. Extending Kushlev and colleagues' findings, new analyses indicated that only between persons variance in income (but not within-persons variance) predicted daily sadness-perhaps because there was relatively little within-persons variance in income. Finally, income predicted less daily sadness and worry, but not less anger or frustration-potentially suggesting that income predicts less "internalizing" but not less "externalizing" negative emotions. Together, our study and Kushlev and colleagues' provide evidence that income robustly predicts select daily negative emotions-but not positive ones. PMID- 29250304 TI - Trauma-related memories in PTSD after interpersonal violence: an ambulatory assessment study. AB - Background: Ambulatory assessment (AA) is increasingly recommended for assessing symptoms of posttraumatic stress disorder (PTSD). Previous AA studies provided new insights into the phenomenology of trauma-related memories, but also divergent findings. Notably, the range of trauma-related memories (a major target of psychotherapeutic interventions) reported in AA studies was as wide as 7.3 to 74.5 per week which might result from different methods used in these studies. Objective: We aimed at assessing the frequency of trauma-related memories in PTSD related to interpersonal violence and investigated whether this frequency is dependent upon the method. Method: For each patient trauma-related memories were assessed using two variants of smartphone-based AA: (1) Event-based sampling (EBS), i.e. participants entered data on each intrusive memory as it occurred; (2) Time-based sampling (TBS), i.e. participants reported the number of trauma related memories they had experienced during the last two hours after they had been alerted by the smartphone. The numbers reported during the TBS-block were either analysed as reported by the participants or restricted to one per hour (rTBS). The impact of smartphone-assessments on trauma-related memories was assessed during a post-monitoring questionnaire. Results: While trauma-related memories were frequent across assessments, the methodology had a huge impact on the numbers: EBS (median = 7) and rTBS (median = 6) yielded significantly lower weekly numbers of intrusive trauma-related memories than TBS (median = 49). Accordingly, the possibility to report unrestricted numbers of trauma-related memories clearly impacted the results. The post-monitoring questionnaire identified another source for the divergent findings: while feeling disrupted by the smartphone-assessments was unrelated to the numbers reported during EBS, feeling disrupted was related to an increase of trauma-related memories during TBS and rTBS. Conclusions: The method clearly impacts the recorded number of trauma-related memories. Future research should clarify whether other variables (e.g. the subjective stress related to intrusive memories) are less dependent on the methodology. PMID- 29250305 TI - PTSD symptomics: network analyses in the field of psychotraumatology. AB - Recent years have seen increasing attention on posttraumatic stress disorder (PTSD) research. While research has largely focused on the dichotomy between patients diagnosed with mental disorders and healthy controls - in other words, investigations at the level of diagnoses - recent work has focused on psychopathology symptoms. Symptomics research in the area of PTSD has been scarce so far, although several studies have focused on investigating the network structures of PTSD symptoms. The present special issue of EJPT adds to the literature by curating additional PTSD network studies, each looking at a different aspect of PTSD. We hope that this special issue encourages researchers to conceptualize and model PTSD data from a network perspective, which arguably has the potential to inform and improve the efficacy of therapeutic interventions. PMID- 29250306 TI - A 3D Scan Model and Thermal Image Data Fusion Algorithms for 3D Thermography in Medicine. AB - Objectives: At present, medical thermal imaging is still considered a mere qualitative tool enabling us to distinguish between but lacking the ability to quantify the physiological and nonphysiological states of the body. Such a capability would, however, facilitate solving the problem of medical quantification, whose presence currently manifests itself within the entire healthcare system. Methods: A generally applicable method to enhance captured 3D spatial data carrying temperature-related information is presented; in this context, all equations required for other data fusions are derived. The method can be utilized for high-density point clouds or detailed meshes at a high resolution but is conveniently usable in large objects with sparse points. Results: The benefits of the approach are experimentally demonstrated on 3D thermal scans of injured subjects. We obtained diagnostic information inaccessible via traditional methods. Conclusion: Using a 3D model and thermal image data fusion allows the quantification of inflammation, facilitating more precise injury and illness diagnostics or monitoring. The technique offers a wide application potential in medicine and multiple technological domains, including electrical and mechanical engineering. PMID- 29250307 TI - Bitopic fluorescent antagonists of the A2A adenosine receptor based on pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine functionalized congeners. AB - A pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine antagonist of the A2A adenosine receptor (AR) was functionalized as amine congeners, fluorescent conjugates and a sulfonate, and the A2AAR binding modes were predicted computationally. The optimal n-butyl spacer was incorporated into the following A2AAR-selective (Ki, nM) conjugates: BODIPY630/650 derivative 11 (MRS7396, 24.6) and AlexaFluor488 derivative 12 (MRS7416, 30.3). Flow cytometry of 12 in hA2AAR expressing HEK-293 cells displayed saturable binding (low nonspecific) and inhibition by known A2AAR antagonists. Water-soluble sulfonate 13 was a highly potent (Ki = 6.2 nM) and selective A2AAR antagonist based on binding and functional assays. Docking and molecular dynamics simulations predicted the regions of interaction of the distal portions of these chain-extended ligands with the A2AAR. The BODIPY630/650 fluorophore of 11 was buried in a hydrophobic interhelical (TM1/TM7) region, while AlexaFluor488 of 12 associated with the hydrophilic extracellular loops. In conclusion, we have identified novel high affinity antagonist probes for A2AAR drug discovery and characterization. PMID- 29250308 TI - Increasing the Complexity of the Illumination May Reduce Gloss Constancy. AB - We examined in which way gradual changes in the geometric structure of the illumination affect the perceived glossiness of a surface. The test stimuli were computer-generated three-dimensional scenes with a single test object that was illuminated by three point light sources, whose relative positions in space were systematically varied. In the first experiment, the subjects were asked to adjust the microscale smoothness of a match object illuminated by a single light source such that it has the same perceived glossiness as the test stimulus. We found that small changes in the structure of the light field can induce dramatic changes in perceived glossiness and that this effect is modulated by the microscale smoothness of the test object. The results of a second experiment indicate that the degree of overlap of nearby highlights plays a major role in this effect: Whenever the degree of overlap in a group of highlights is so large that they perceptually merge into a single highlight, the glossiness of the surface is systematically underestimated. In addition, we examined the predictability of the smoothness settings by a linear model that is based on a set of four different global image statistics. PMID- 29250309 TI - Phyllodes tumor masquerading as a fungating breast mass. AB - Phyllodes tumor of the breast is an uncommonly encountered disease. The tumor presenting as fungating breast mass or 'ruptured' breast is an even more rare presentation of an unusual disease. This report documents the case of a 60-year old female with delayed presentation of a large exophytic mass of the left breast. Biopsy of this lesion was non-diagnostic, so excision via left total mastectomy was performed. The final pathology was consistent with malignant phyllodes tumor. This report highlights the features of a rare breast cancer, the challenges in obtaining a definitive diagnosis, and the treatment of this disease, in an effort to provide clinicians with an example of the management of such a peculiar entity. PMID- 29250310 TI - Histoplasmosis hepatitis after orthotopic liver transplantation. AB - Histoplasmosis is an endemic mycosis in the Ohio and Mississippi River valleys and can cause disseminated infection in immunocompromised hosts. Disseminated histoplasmosis is often respiratory in nature and most cases in transplant patients occur within 2 years post-transplantation. A 32-year-old male on mycophenolate and tacrolimus who underwent an orthotopic liver transplantation 10 years prior presented with generalized body aches, fevers, mild congestion, dysuria and elevated transaminases. Liver biopsy revealed epithelioid granulomas with narrow-based budding yeast, suggesting histoplasma. Liver involvement in disseminated histoplasmosis is well characterized however the disease is usually pulmonary in origin. Only three other case reports describe isolated granulomatous hepatitis, and this is the first to our knowledge to occur in a liver transplant allograft. A high index of suspicion is essential for diagnosis and prompt treatment of histoplasmosis in transplant patients considering their immunocompromised state. PMID- 29250311 TI - An unusual presentation of eosinophilic angiocentric fibrosis. AB - Eosinophilic angiocentric fibrosis (EAF) is a rare, benign condition affecting the respiratory mucosa and is generally characterized by a locally destructive growth. We present a case of a lady with a saddle nose deformity that had for many years been treated as granulomatosis with polyangiitis (GPA), of which saddle nose deformity is a classic feature. At the time of surgery, she was found to have subglottic stenosis another classic feature of GPA, however, histology demonstrated EAF. We discuss the difference between the two conditions and highlight the importance of making the correct diagnosis. PMID- 29250312 TI - Severe Fournier's gangrene-a conjoint challenge of gynaecology and plastic surgery. AB - Necrotizing fasciitis (NF) is a rare soft tissue infection characterized by rapidly progressing necroses and a high mortality. Prompt diagnosis and immediate medical treatment including radical debridement and broad spectrum antibiotics are the key to successful management. We report on a 46-year-old diabetic female who developed extensive, deep necroses in the perineal area and proximal thighs within a few days. After initial gynaecological consultation, she was transferred directly to our department. Due to the suspicion of NF, an immediate radical debridement was performed. Two more debridements were necessary to control the infection. After stabilization, the extensive soft tissue defect was reconstructed using a combination of plastic reconstructive procedures. Due to early diagnosis, direct referral and immediate surgical treatment, the patient survived. PMID- 29250313 TI - Functional outcome after hand replantation in Guatemala. AB - Amputations of a traumatic origin are very frequent in developing countries, in the case of Guatemala these are a result of work accidents very closely related to poor work conditions existing for manual workers, as well as social violence and the lack of security that governs society. The present case shows a patient that suffered a left hand amputation at wrist level. Amputated hand was transported swiftly and in adequate conditions, maintaining cold chain at all times until arrival at Hospital for replantation. After 14 months, patient has evolved satisfactorily and obtained functional result of the hand. PMID- 29250314 TI - A case of long-survival insulinoma with multiple neuroendocline tumour type 1 controlled by multimodal therapy. AB - Insulinomas with multiple neuroendocrine tumour type 1 (MEN1) sometimes have metachronous or recurrent tumours. However, the treatment for these tumours is controversial, and published reports regarding multimodal therapy for insulinomas are limited. We report a 73-year-old woman with recurrent insulinoma with MEN1 successfully controlled by multimodal therapy. She had several complications, and poor performance status. Her hypoglycaemia did not improve after 6-month octreotide LAR; as such, she underwent enucleation of the pancreatic tumour. Within 7 years after the first operation, she underwent four succeeding surgeries for recurrent tumours. Her medications during follow-up were octreotide-LAR and Everolimus. Insulinoma can be managed through various treatment options. Medical treatment includes octreotide-LAR and Everolimus, while surgical approach includes enucleation and pancreaticoduodenectomy. Some tumours, particularly those that are MEN1, can recur repeatedly. Thus, several treatments are needed to control them. We highlight the importance of multimodal therapy, including repeated surgery, for the control of the disease. PMID- 29250315 TI - Hepatic portal venous gas: acute deterioration in an elderly patient. AB - A 91-year-old female presented to the Emergency Department with a 10-day history of constipation and abdominal pain. Abdominal examination was normal and rectal examination showed faecal loading. A phosphate enema was given and the patient was admitted. Overnight, the patient's GCS dropped from 15/15 to 3/15 and an arterial blood gas showed a lactate of 8 mmol/L (1.5 on admission). Abdomen remained soft throughout. A CT scan showed a large amount of free air and free fluid within the abdomen and pelvis, highly suspicious for perforation. Hepatic portal venous gas (HPVG) was visible, with portal venous air fluid levels noted. The patient was treated palliatively and died shortly thereafter. HPVG is a recognized but rarely identified radiological sign, which is a poor prognostic indicator, with most cases subsequently proving terminal, often due to subsequent bowel necrosis. PMID- 29250316 TI - Unintended consequences of machine learning in medicine? AB - Machine learning (ML) has the potential to significantly aid medical practice. However, a recent article highlighted some negative consequences that may arise from using ML decision support in medicine. We argue here that whilst the concerns raised by the authors may be appropriate, they are not specific to ML, and thus the article may lead to an adverse perception about this technique in particular. Whilst ML is not without its limitations like any methodology, a balanced view is needed in order to not hamper its use in potentially enabling better patient care. PMID- 29250317 TI - Prospective observational research on the clinical profile and outcome analysis among a cohort of patients sustaining traumatic cervical spine and cord injury in a peripheral tertiary spine care centre in Nepal. AB - Background: In developing nations like Nepal, spinal cord injury has multispectral consequences for both the patient and their family members. It has the tendency to cripple and handicap the patients, and burn out their caretakers, both physically and mentally. Furthermore, the centralization of health care with only a handful of dedicated rehabilitation centers throughout Nepal further places patients into disarray. This study was carried out as a pilot study to determine the modes of injury, age groups affected, clinical profiles and patterns of injury sustained, as well as the efficacy of managing a subset of patients, who have sustained cervical spine and cord injuries. Methods: This was a prospective cohort study comprising of 163 patients enrolled over a period of three years that were managed in the spine unit of College of Medical Sciences, Bharatpur, Nepal. Results: Road traffic accidents were implicated in 51% of these patients. 65% of them were in the age group of 30-39 years. Traumatic subluxation occurred in 73 patients with maximum involvement of the C4/5 region (28.76%). Good outcome was seen in patients with ASIA 'C' and 'D' with 55% of patients showed improvement from 'C' to 'D' and 95% of patients showed improvement from 'D' to 'E' at 1 year follow up. The overall mortality in the patients undergoing operative interventions was only 1.98%. Conclusions: The prevalence of cervical spine injuries in the outreach area is still significant. The outcome of managing these patients, even in the context of a resource limited setup in a spine unit outside the capital city of a developing nation, can be as equally as effective and efficient compared to the outcome from a well-equipped and dedicated spine unit elsewhere. PMID- 29250318 TI - Do we know enough to find an adjunctive therapy for cerebral malaria in African children? AB - Cerebral malaria is the deadliest complication of malaria, a febrile infectious disease caused by Plasmodium parasite. Any of the five human Plasmodium species can cause disease, but, for unknown reasons, in approximately 2 million cases each year P. falciparum progresses to severe disease, ultimately resulting in half a million deaths. The majority of these deaths are in children under the age of five. Currently, there is no way to predict which child will progress to severe disease and there are no adjunctive therapies to halt the symptoms after onset. Herein, we discuss what is known about the disease mechanism of one form of severe malaria, cerebral malaria, and how we might exploit this understanding to rescue children in the throes of cerebral disease. PMID- 29250319 TI - Patients with uninjured lungs may also benefit from lung-protective ventilator settings. AB - Although mechanical ventilation is a life-saving strategy in critically ill patients and an indispensable tool in patients under general anesthesia for surgery, it also acts as a double-edged sword. Indeed, ventilation is increasingly recognized as a potentially dangerous intrusion that has the potential to harm lungs, in a condition known as 'ventilator-induced lung injury' (VILI). So-called 'lung-protective' ventilator settings aiming at prevention of VILI have been shown to improve outcomes in patients with acute respiratory distress syndrome (ARDS), and, over the last few years, there has been increasing interest in possible benefit of lung-protective ventilation in patients under ventilation for reasons other than ARDS. Patients without ARDS could benefit from tidal volume reduction during mechanical ventilation. However, it is uncertain whether higher levels of positive end-expiratory pressure could benefit these patients as well. Finally, recent evidence suggests that patients without ARDS should receive low driving pressures during ventilation. PMID- 29250320 TI - P53 at the start of the 21st century: lessons from elephants. AB - Crucial, natural protection against tumour onset in humans is orchestrated by the dynamic protein p53. The best-characterised functions of p53 relate to its cellular stress responses. In this review, we explore emerging insights into p53 activities and their functional consequences. We compare p53 in humans and elephants, in search of salient features of cancer protection. PMID- 29250321 TI - Recent advances in managing septal defects: atrial septal defects. AB - The purpose of this review is to discuss the management of atrial septal defects (ASD), paying particular attention to the most recent developments. There are four types of ASDs: ostium secundum, ostium primum, sinus venosus, and coronary sinus defects. The fifth type, patent foramen ovale-which is present in 25 to 30% of normal individuals and considered a normal variant, although it may be the seat of paradoxical embolism, particularly in adults-is not addressed in this review. The indication for closure of the ASDs, by and large, is the presence of right ventricular volume overload. In asymptomatic patients, the closure is usually performed at four to five years of age. While there was some earlier controversy regarding ASD closure in adult patients, currently it is recommended that the ASD be closed at the time of presentation. Each of the four defects is briefly described followed by presentation of management, whether by surgical or percutaneous approach, as the case may be. Of the four types of ASDs, only the ostium secundum defect is amenable to percutaneous occlusion. For ostium secundum defects, transcatheter closure has been shown to be as effective as surgical closure but with the added benefits of decreased hospital stay, avoidance of a sternotomy, lower cost, and more rapid recovery. There are several FDA-approved devices in use today for percutaneous closure, including the Amplatzer(r) Septal Occluder (ASO), Amplatzer(r) Cribriform device, and Gore HELEX(r) device. The ASO is most commonly used for ostium secundum ASDs, the Gore HELEX(r) is useful for small to medium-sized defects, and the cribriform device is utilized for fenestrated ASDs. The remaining types of ASDs usually require surgical correction. All of the available treatment modes are safe and effective and prevent the development of further cardiac complications. PMID- 29250322 TI - Rehabilitation following hemorrhagic stroke: building the case for stroke-subtype specific recovery therapies. AB - Intracerebral hemorrhage (ICH), a form of brain bleeding and minor subtype of stroke, leads to significant mortality and long-term disability. There are currently no validated approaches to promote functional recovery after ICH. Research in stroke recovery and rehabilitation has largely focused on ischemic stroke, but given the stark differences in the pathophysiology between ischemic and hemorrhagic stroke, it is possible that strategies to rehabilitate the brain in distinct stroke subtypes will be different. Here, we review our current understanding of recovery after primary intracerebral hemorrhage with the intent to provide a framework to promote novel, stroke-subtype specific approaches. PMID- 29250323 TI - Strategies for prevention of gastrointestinal cancers in developing countries: a systematic review. AB - Background: Gastrointestinal cancers account for one third of total cancer incidence and mortality in developing countries. To date, there is no systematic synthesis of evidence regarding strategies to prevent gastrointestinal cancers in developing countries. We aimed to provide a systematic overview of studies evaluating strategies for prevention or early detection of the three most common gastrointestinal cancers (gastric, liver and colorectal cancer) in developing countries. Methods: We searched MEDLINE, Web of Science and WHO Global Index Medicus databases for relevant articles published until October 2016 using combinations of the search terms "gastrointestinal", "digestive system", "gastric", "liver", "colorectal", "cancer", "prevention", "early detection" and "developing country" (including names). Results: Overall, 73 articles met the inclusion criteria, providing information on short- and long-term outcomes (up to 30 years) from various intervention studies (~45% randomized). Trials on hepatitis B vaccination consistently showed vaccine efficacy over time and indicated long-term preventive effects on liver cancer incidence that start to become measurable at the population level. Studies on anti-H. pylori treatment suggested a reduction in gastric cancer incidence reaching statistical significance after long-term follow-up, while evidence regarding a preventive effect in persons with precancerous lesions is still inconclusive. The studies regarding colorectal cancer focused on early detection, ~90% of which were restricted to intermediate endpoints. Conclusion: In conclusion, there were a number of studies on gastric and liver cancer prevention in developing countries showing promising results after long-term follow-up. Important next steps include pooled meta-analyses as far as possible given the heterogeneity between studies as well as implementation research. PMID- 29250324 TI - Incorporating patient-reported symptom assessments into routine care for people with chronic kidney disease. AB - In this issue of Clinical Kidney Journal, Brown and colleagues show that symptom burden is high across all stages of chronic kidney disease (CKD). Still, management of symptoms in kidney patients leaves room for improvement, which may partly stem from symptoms being underreported. The use of patient-reported questionnaires may facilitate a more systematic approach to symptom assessment, but to date, the majority of these instruments have been used only in the context of research studies. In this editorial, we review how systematic patient-reported symptom assessments can be incorporated in CKD care. We show examples from an initiative in the UK where 14 renal units explored how to collect and use symptom burden assessments as part of their routine ways of working. We also discuss how to move from paper-based questionnaires towards digital collection of patient reported symptom data. Lastly, we introduce wearable and smartphone sensors as novel methods for collecting information to support and enrich symptom assessments while minimizing data collection burden. PMID- 29250325 TI - Modern biotechnology-based therapeutic approaches against HIV infection. AB - The causative agent of acquired immune deficiency syndrome (AIDS) is human immunodeficiency virus (HIV). Since its discovery before 30 years, a number of drugs known as highly active antiretroviral therapy have been developed to suppress the life cycle of the virus at different stages. With the current therapeutic approaches, ending AIDS means providing treatment to 35 million individuals living with HIV for the rest of their lives or until a cure is developed. Additionally, therapy is associated with various other challenges such as potential of drug resistance, toxicity and presence of latent viral reservoir. Therefore, it is imperative to search for treatments and to identify new therapeutic approaches against HIV infection to avoid daily intake of drugs. The aim of the current review was to summarize different therapeutic strategies against HIV infection, including stem cell therapy, RNA interference, CRISPR/Cas9 pathways, antibodies, intrabodies and nanotechnology. Silencing RNA against chemokine receptor 5 and other HIV RNAs have been tested and found to elicit homology-based, post-transcriptional silencing. The CRISPR/Cas9 is a gene editing technology that produces a double-stranded nick in the virus DNA, which is repaired by the host machinery either by non-homology end joining mechanism or via homology recombination leading to insertion, deletion mutation which further leads to frame shift mutation and non-functional products. Intrabodies are intracellular-expressed antibodies that are directed towards the targets inside the cell unlike the naturally expressed antibodies which target outside the cell. Different nanotechnology-based therapeutic approaches are also in progress against HIV. HIV eradication is not feasible without deploying a cure or vaccine alongside the treatment. PMID- 29250326 TI - Palliative treatment efficacy of glucose inhibition combined with chemotherapy for non-small cell lung cancer with widespread bone and brain metastases: A case report. AB - Otto Warburg observed in 1924 that cancer cells were dependent exclusively on glycolysis for the production of energy even in the presence of oxygen (the 'Warburg effect'). Consequently, cancer cells require ~19 times more glucose uptake to obtain equivalent amounts of energy as normal cells. The Warburg effect is the scientific basis for positron emission tomography (PET), which has markedly improved cancer detection. During chemotherapy, cancer cells may upregulate their expression of multi-drug resistance proteins and ultimately cause treatment failure. As multi-drug resistance proteins require energy to operate, the present report evaluated the potential clinical efficacy of lowering blood glucose with insulin during chemotherapy for a patient with advanced pulmonary adenocarcinoma with multiple metastases. A 64-year-old male was admitted to the Department of Medical Oncology at Changzhou Tumor Hospital (Changzhou, China) due to an irritating cough and multiple bone pain. PET/computed tomography (CT) with F-18 fluorodeoxy glucose (18F-FDG) identified multiple hypermetabolic foci in the right hilum, right upper lung, shoulder blades, thoracic vertebrae, lumbar, sacrum, bilateral iliac crest and pelvis. Additionally, magnetic resonance imaging detected multiple metastases in the brain. The patient received 56 repeat treatments with insulin to induce hypoglycemia combined with reduced doses of chemotherapy over an 8-month period. For each treatment, insulin at 0.2 U/kg body weight was injected intravenously (i.v.), and when blood glucose level reached 2.5-3.0 mmol/l, navelbine (10 mg), cisplatin (10 mg) and fluorouracil (250 mg) were injected (i.v.) over a period of ~10 min. The patient's blood glucose level was returned to normal immediately after chemotherapy with an i.v. injection of 20 ml 50% glucose solution. During the 8-month chemotherapy regimen, the patient received two PET/CT follow-ups. The results demonstrated that the levels of 18F-FDG uptake in all lesions had been reduced. In addition, the patient exhibited improved appetite and weight gain, a reduced cough, and had less pain. The levels of tumor markers, namely carcinoembryonic antigen, carcinoma antigen 15-3, CYRA21-1, neuron-specific enolase, also declined gradually. These results suggest that controlled, mild hypoglycemia may be safely combined with low dose chemotherapy to provide clinical benefit for advanced non-small cell lung cancer. PMID- 29250327 TI - Tolvaptan is effective in treating patients with refractory ascites due to cirrhosis. AB - The treatment of refractory ascites due to cirrhosis is a clinical challenge for hepatologists. Tolvaptan, a novel aquaporin modulator, was made available in Japan in 2013 for the treatment of patients with refractory ascites due to cirrhosis. Despite the potential of this drug, few reports are available regarding its clinical use. The aim of the present study was to clarify the efficacy of tolvaptan in patients with refractory ascites due to cirrhosis and to review the clinical outcomes of treatment. Medical records were retrospectively reviewed for 65 patients with refractory ascites due to cirrhosis who were treated daily with 7.5 mg tolvaptan. The median follow-up time, defined as the period between starting tolvaptan and the last clinic visit or date of mortality, was 175 days (interquartile range 56-406). After one week of tolvaptan treatment, the mean weight reduction was 3.4 kg, with a response rate of 69% (45/65). Subsequently, factors associated with the response to tolvaptan were analyzed. On univariate analysis, maintaining serum sodium (Na) >=140 mEq/l and an estimated glomerular filtration rate (eGFR) >=55 ml/min were significant predictors of response (P<0.05). On multivariate analysis, hepatitis C virus etiology, maintaining serum Na >=140 mEq/l and an eGFR >=55 ml/min were significant predictors of response (P<0.05). Factors associated with survival were also analyzed using the Cox proportional hazard model. On multivariate analysis, responsiveness to tolvaptan was a predictor of long-term survival (P=0.002), and hyperbilirubinemia was associated with short-term survival (P=0.028). Additionally, Kaplan-Meier analysis with a log-rank test indicated longer survival times in tolvaptan responders than non-responders (P=0.011). In conclusion, tolvaptan was effective in treating patients with refractory ascites due to cirrhosis. In particular, tolvaptan treatment was highly effective for patients with hepatitis C virus etiology and normal serum Na and renal function. Furthermore, response to tolvaptan was associated with longer survival time while hyperbilirubinemia was associated with shorter survival time. PMID- 29250328 TI - Sequence analysis of hepatitis C virus nonstructural protein 3-4A serine protease and prediction of conserved B and T cell epitopes. AB - The hepatitis C virus (HCV) is a global health issue. The nonstructural protein 3 (NS3)-4Agene of HCV is responsible for serine protease activity. The aim of the present study was to develop a global consensus sequence of HCV serine protease, analyze conserved residues, and predict highly conserved B- and T-cell binding epitopes in the NS3-4A protein. A total of 160 NS3-4A sequences from the six genotypes of HCV were refracted in the current study. The amino acid sequences were aligned to obtain a global consensus sequence. The location of possible B- and T-cell epitopes were predicted in the HCV NS3-4A consensus sequence by employing bioinformatics tools. Despite the high mutation rate of HCV, the functionally important residues are highly conserved. These include residues that form the catalytic triad (His57, Asp81 and Ser139), the S1 and S6 pocket, zinc binding site (Cys97, Cys99, Cys145 and His149) and the substrate binding groove. The epitopes B1, B8 and B9 are predicted to be ideal candidates for B-cell-based vaccine and are >95% conserved across six major HCV genotypes. The major histocompatibility complex (MHC) class I epitopes, M4, M5, M7 and M10, and MHC class II epitopes, T5, T7 and T10 are ideal epitopes for vaccine development with high antigenicity scores and high conservancy across major HCV genotypes. The predicted B- and T-cell epitopes are ideal targets for vaccine development, and are capable of producing a strong immune response for all major genotypes of HCV. PMID- 29250329 TI - Effect of AGTR1 and BDKRB2 gene polymorphisms on atorvastatin metabolism in a Mexican population. AB - Discrepancies in the response to drugs are partially due to polymorphisms in genes involved in drug metabolism and transport. The frequency, pattern and impact of these polymorphisms vary among populations. In the present study, the pharmacokinetics and pharmacogenetics of atorvastatin (ATV) in a Mexican population were investigated. The study cohort exhibited differing ATV metabolizing phenotypes, and in subsequent allelic discrimination assays, single nucleotide polymorphisms in the angiotensinogen, angiotensin II type 1 receptor (AGTR1) and bradykinin B2 receptor (BDKRB2) genes were genotyped and their effects on the pharmacokinetic parameters of ATV were assessed. Additionally, association studies were performed to test for a correlation between metabolizing phenotypes and genetic variants. It was observed that carriers of the genotypes A/C and C/T in AGTR1 and BDKRB2 had higher area under the plasma concentration time curve values from time 0 to the time of the last measurement and from time 0 extrapolated to infinity, and lower values of clearance of the fraction dose absorbed compared with homozygous carriers (P<0.05). Only the C/C genotype of BDKRB2 was associated with the fast metabolizer phenotype. These data suggest that AGTR1 and BDKRB2 are involved in ATV pharmacokinetics; a novel finding that requires confirmation in further studies. PMID- 29250330 TI - BBP-Functionalized Biomimetic Nanofibrous Scaffold Can Capture BMP2 and Promote Osteogenic Differentiation. AB - Bone morphogenetic proteins (BMPs, e.g., BMP2 and 7) are potent mediators for bone repair, however, their clinical use has been limited by their safety and cost-effectiveness. Therefore, innovative strategies that can improve the efficacy of BMPs, and thereby, use a lower dose of exogenous BMPs are highly desired. Inspired by the natural interaction between extracellular matrix (ECM) and growth factors, we hypothesize that bone matrix-mimicking nanofibrous scaffold functionalized with BMP binding moieties can selectively capture and stabilize BMPs, and thereby, promote BMP-induced osteogenic differentiation. To test our hypothesis, a gelatin nanofibrous scaffold was fabricated using thermally induced phase separation together with a porogen leaching technique (TIPS&P) and functionalized by a BMP-binding peptide (BBP) through cross-linking. Our data indicated that BBP decoration largely improved the BMP2 binding and retention capacity of the nanofibrous scaffolds without compromising their macro/microstructure and mechanical properties. Importantly, the BBP functionalized gelatin scaffolds were able to significantly promote BMP2-induced osteogenic differentiation. Moreover, BBP alone was able to significantly stimulate endogenous BMP2 expression and improve osteogenic differentiation. Compared to other affinity-based drug delivery strategies, e.g., heparin and antibody-mediated growth factor delivering techniques, we expect BBP functionalized scaffolds will be a safer, more feasible and selective strategy for endogenous BMP stimulating and binding. Therefore, our data suggests a promising application of using the BBP-decorated gelatin nanofibrous scaffold to stimulate/capture BMPs and promote endogenous bone formation in situ in contrast to relying on the administration of high doses of exogenous BMPs and transplantation of cells. PMID- 29250331 TI - Dually responsive mesoporous silica nanoparticles regulated by upper critical solution temperature polymers for intracellular drug delivery. AB - We synthesized a new type of upper critical solution temperature (UCST) thermally responsive polymers (TRPs) with varying responsive temperatures (cloud points). We then grafted one of the TRPs with a cloud point of 42 degrees C on the surface of mesoporous silica nanoparticles (MSN) using disulfide bonds to achieve a novel, dual responsive release system. With this system, the cargo release profiles are responsive to both temperature and reducing agents. When loaded with doxorubicin hydrochloride (DOX), the system could deliver DOX into breast cancer cells (SK-BR-3) in a controlled fashion and present high toxicity. PMID- 29250333 TI - Prudent parenting: murre now or murre later? PMID- 29250334 TI - Heart-warming hip preservation. PMID- 29250332 TI - Within-sample variation in snowshoe hare faecal glucocorticoid metabolite measurements. AB - Faecal glucocorticoid metabolite (FGM) concentrations are used increasingly as a non-invasive measure to index physiological stress experienced by diverse taxa. However, FGM may not be evenly distributed throughout a faecal mass or faecal pellet group. Moreover, within-sample variation in FGM measurements associated with different sampling and/or processing techniques is rarely reported despite potentially having important implications for inferring stress levels in free ranging wildlife. Using a captive collection of snowshoe hares (Lepus americanus), we (i) assessed repeatability of FGM measurements (i.e. precision) from two processing techniques (measurements derived from dividing whole pellet groups into equal proportions prior to processing [G1], measurements from subsamples derived from thoroughly homogenized whole pellet groups [G2]) and (ii) conducted a power analysis to estimate sample-size requirements for detecting statistically significant differences in FGM concentrations at a population level. Our results indicate that the mean percent coefficient of variation (%CV) for within-sample FGM variation was slightly higher for G1 (%CV = 35, range 13.45 65.37) than for G2 (%CV = 23, range 7.26-47.94), though not statistically significant (two sample t-test, n = 8, t = 1.57, P = 0.16). Thus, FGM is relatively evenly distributed within snowshoe hare faecal pellet groups. However, subsampling from homogenized whole pellet groups may be more appropriate when the sampling time frame is less controlled (e.g. multiple defecation events) because a subsample derived from a homogenized whole pellet group might be more representative of the animal's 'average' physiological state compared to FGM concentrations derived from a few haphazardly selected faecal pellets. Power analysis results demonstrated the importance of a priori consideration of sample sizes. Relatively small effect sizes (e.g. <20%) may require sampling that is logistically and/or cost prohibitive. Yet for many situations of ecological or conservation interest, treatment effects may be substantial (>25%) and thus moderate sample sizes may be sufficient for testing research hypotheses regarding changes FGM concentrations. PMID- 29250335 TI - Technical particularities of joint preserving hip surgery in osteopetrosis. AB - Proximal femoral fracture and coxarthrosis are the most common orthopaedic problems of osteopetrosis. Fracture fixation is difficult and one-third fail, with total hip replacement as the final solution. There is little reported experience about how to deal with this particular type of bone and what has been published to date is surprisingly non-specific. Corrective osteotomies are mainly undertaken in children for non-union of a fractured femoral neck and/or for coxa vara. However, any information about technical problems and solutions is scarce and barely instructive. Osteotomy experience for osteopetrosis in youngsters and young adults has not been reported. Osteopetrosis bone is characterized by a small tolerance for displacement and by the high friction experienced when penetrating instruments and implants are used. This article describes the risks of hip surgery in the presence of osteopetrosis and also discusses osteotomies around the hip and how to limit any related complications. Four patients, who underwent different types of hip preservation procedure, have been used to illustrate the difficulties that can be encountered. The article also suggests ways to make osteotomies feasible in osteopetrosis bone, even in adults. PMID- 29250337 TI - How to address ischiofemoral impingement? Treatment algorithm and review of the literature. AB - Ischiofemoral impingement (IFI) is a rare cause of hip pain defined by a narrowing of the space between the lateral aspect of the os ischium and the lesser trochanter of the femur. Several underlying anatomic, functional and iatrogenic pathologies have been identified for symptomatic IFI in native hip joints and after total hip arthroplasty. Clinical symptoms vary but most commonly consist of pain of the lower buttock and groin including the inner thigh, and a snapping or clunking phenomenon is often reported. Symptoms may be provoked by a combined extension, adduction and external rotation during physical examination and during long-stride walking. Radiographs of the pelvis and an axial or false profile-view of the hip as well as magnetic resonance imaging (MRI)-scans should be obtained to strengthen the diagnosis. On MRI, the quadratus femoris muscle signal and the space confined by the anatomic structures surrounding the muscle, the quadratus femoris space, are to be assessed. Targeted infiltration of the muscle can be helpful both diagnostically and therapeutically. The literature on differential diagnoses and treatment options for IFI is limited; therapeutic suggestions are offered only in case reports and series. With this work, we aim to give a systematic approach to the non-surgical and surgical treatment options for IFI based upon the current literature and the authors' personal experience. PMID- 29250336 TI - Preoperative planning for redirective, periacetabular osteotomies. AB - Redirective, periacetabular osteotomies (PAO) represent a group of surgical procedures for treatment of developmental dysplasia of the hip (DDH) in skeletally mature and immature patients. The ultimate goal of all procedures is to reduce symptoms, improve function and delay or prevent progression of osteoarthritis. During the last two decades, the understanding of the underlying pathomechanisms has continuously evolved. This is mainly attributable to the development of the femoroacetabular impingement concept that has increased the awareness of the underlying three-dimensional complexity associated with DDH. With increasing knowledge about the pathobiomechanics of dysplastic hips, diagnostic tools have improved allowing for sophisticated preoperative analyses of the morphological and pathobiomechanical features, and early recognition of degenerative changes, which may alter the long-term outcome. As redirective, PAO are technically demanding procedures, preoperative planning is crucial to avoid intraoperative obstacles and to sufficiently address the patient-specific deformity. Although conventional radiography has been used for decades, it has not lost its primary role in the diagnostic work-up of patients with DDH. Furthermore, an increasing number of modern imaging techniques exists allowing for assessment of early cartilage degeneration (biochemical magnetic resonance imaging) as well as 3D planning and computer-based virtual treatment simulation of PAO. This article reviews the literature with regard to the current concepts of imaging of DDH, preoperative planning and treatment recommendations for redirective, PAO. PMID- 29250338 TI - Early recovery after hip arthroscopy for femoroacetabular impingement syndrome: a prospective, observational study. AB - The early post-operative course after hip arthroscopy for femoroacetabular impingement syndrome has not been thoroughly characterized or correlated to factors that may influence recovery. The aim of this study was to report on early pain, function and attitudes towards rehabilitation and to determine predictors of early recovery after hip arthroscopy. Sixty-two patients reported pre operative pain, iHOT-12 (hip functional score), psychological status and other baseline characteristics. Pain, iHOT-12, hip flexion and several other outcomes were measured through 6 weeks post-operative. Baseline characteristics were correlated with outcomes using univariate and multivariable models. Pain relief started on post-operative day 1 and consistently improved throughout the 6 weeks of follow-up. The average patient's pain was reduced from a pre-operative level of 5/10 to 2/10 by 6 weeks post-operative. Similarly, iHOT-12 improved from 33/100 to 57/100 whereas hip flexion increased by 9 degrees by 6 weeks post operative. At 2 weeks post-operative, pre-operative anti-inflammatory usage was associated with greater improvement in pain and swelling; pre-operative opioid usage with poorer patient-reported helpfulness of and adherence to rehabilitation; and higher ASA (American Society of Anesthesiologists) score and lower procedure time with improvement of the pre-operative pain complaint. At 6 weeks, greater depression was associated with lower post-operative pain reduction but greater pre-operative pain complaint improvement. Continuous passive motion usage was associated with increased hip flexion. Pain improved from pre-operative by Day 1 after hip arthroscopy, and early functional improvements were seen by 6 weeks post-operative. Pre-operative anti-inflammatory and opioid usage, depression, race, ASA score, procedure time and continuous passive motion usage were significantly associated with study outcomes. PMID- 29250339 TI - Does duration of symptoms affect clinical outcome after hip arthroscopy for labral tears? Analysis of prospectively collected outcomes with minimum 2-year follow-up. AB - Limited research exists on the possible association between duration of symptoms and clinical outcomes following hip arthroscopy for labral tears. The purpose of this study was to evaluate whether duration of symptoms affected clinical and patient-reported outcome (PRO) scores following hip arthroscopy for labral tears. From 2008 to 2011, data were collected prospectively on all patients undergoing primary hip arthroscopy for labral tears. Workers' compensation cases, dysplasia cases and patients with previous ipsilateral hip surgeries were excluded. A total of 738 patients were identified with a minimum of 2-year follow-up, and clinical and PRO data were available for 680 patients. Uni- and multivariate analyses were performed to determine the relationship between duration of symptoms along with other variables and PROs. Overall, patients experienced significant improvements in all clinical and PRO scores. Results of univariate analysis revealed that all PROs were negatively associated with increasing Log10 months of symptoms as were pain and satisfaction scores. During multivariate analyses, increasing Log10 months of symptoms, age, body mass index and trauma were all negatively associated with PROs (P < 0.05). Our study demonstrates that clinical and PRO scores were negatively associated with increasing duration of symptoms prior to hip arthroscopy for treatment of labral tears. Although this implies that delay in treatment may adversely affect outcome, conservative treatment remains the gold standard first line of treatment. Surgeons should incorporate this information into their treatment algorithm to maximize patient outcomes following treatment for labral tears. Level of evidence: Level IV, prospective case series. PMID- 29250340 TI - Revision hip arthroscopy: findings and outcomes. AB - The purpose of this study is to report on the operative findings and the outcomes of revision hip arthroscopy. All hip arthroscopy cases are prospectively assessed with a modified Harris Hip Score (mHHS) preoperatively and postoperatively. This study consists of 190 consecutive hips (186 patients) who underwent revision arthroscopy with minimum 2-year follow-up. There were 69 males and 117 females with a mean age of 32.7 (14-64). The mean time from index to revision procedure was 24.5 months (3-146). Common diagnoses included labral tears (102) and unaddressed or residual femoroacetabular impingement (FAI) (49 cam, 11 pincer, and 20 combined). In addition to FAI correction, there were 82 labral debridements, 28 repairs/refixations, and 6 excisions of labral calcifications. Ninety-three underwent various amounts of synovectomy and 21 underwent iliopsoas release/debridement. At a mean follow-up of 46.9 months, 84.5% of patients reported symptomatic improvement. Twenty patients underwent subsequent surgery at mean of 51 months (11 repeat arthroscopy and 9 THA). Among 166 patients who had no further surgery, the mHHS had improved 27.1.8 points from a preoperative mean of 54.5 to 81.6. Patients who underwent treatment of FAI demonstrated a mean mHHS improvement of 25.7 points. Complications included two cases of transient pudendal neurapraxia, one case of transient quadriceps weakness, one case of retroperitoneal extravasation, and one case of perioperative myocardial infarction. In conclusion, for properly selected patients with persistent or recurrent symptoms following previous hip arthroscopy, revision surgery can result in favorable outcomes with an acceptably low complication rate. PMID- 29250341 TI - Results of hip arthroscopy in patients with MRI diagnosis of subchondral cysts-a case series. AB - The aim of this article is to examine the results of arthroscopic management of patients with labral pathology who have preoperative magnetic resonance images (MRIs) demonstrating subchondral cysts. This institution's database was searched for patients who underwent hip arthroscopy and had subchondral cysts on MRI and >2-year follow-up. Exclusion criteria included previous hip surgery, Tonnis grade >1, inflammatory arthritis, Perthes, slipped capital femoral epiphysis or abductor repair. Patient-reported outcome (PRO) scores including visual analog scale, modified Harris hip score (mHHS), non-arthritic hip score and hip outcome score sports-specific subscale (HOS-SSS) were gathered preoperatively, at 3 months, and annually thereafter. The change in PRO scores was compared with the minimally clinical important difference (MCID) to quantify improvement. Sixty nine patients were eligible for this study, of which 65 (94%) had >2-year follow up. All PROs were significantly improved at latest follow-up (P < 0.001). Mean patient satisfaction was 7.2. There was no correlation between Outerbridge grade III or IV cartilage damage noted during arthroscopy and subchondral femoral and acetabular cysts noted on MRI. Seventeen patients required reoperation [13 total hip arthroplasty (THAs) and 4 revision arthroscopies]. Patients with femoral subchondral cysts converted to THA 36% of the time. MCIDs for mHHS and HOS-SSS were surpassed by 63% and 68% of patients, respectively. Hip arthroscopies performed on patients with subchondral cysts present on preoperative MRI should be approached with caution. The rate of conversion to hip arthroplasty appears to be higher than that reported in the literature for patients who undergo arthroscopy without preoperative subchondral cysts. For patients who did not require hip arthroplasty or revision arthroscopy, patients demonstrated significant improvement in symptoms compared with the preoperative state. PMID- 29250342 TI - Hip dysplasia in wrestlers: three lessons learned. AB - Hip problems due to dysplasia are commonly associated with female athletes in sports demanding supraphysiologic motion, such as ballet, gymnastics and figure skating. However, hip problems are rarely mentioned among wrestlers, a male sport in which flexibility is advantageous. Dysplasia may have a mostly unrecognized prevalence among wrestlers that can lead to problems and benefit from reorientation periacetabular osteotomy (PAO). Study design in this research is Level 4 evidence case reports. Three consecutive intercollegiate wrestlers ages 20, 21 and 22 years underwent PAO for dysplasia and are reported. Two underwent concomitant arthroscopy. Each returned successfully to intercollegiate wrestling at 6, 8 and 11 months. There were no complications. This work concludes that dysplasia has an unknown but mostly unrecognized prevalence among wrestlers. With proper recognition and treatment with PAO, there is a reasonable expectation that they could return to wrestling. PMID- 29250343 TI - Ligamentum teres reattachment post-surgical dislocation of the hip: a case report. Regenerative capacity reaffirming its greater role in hip stability and function? PMID- 29250344 TI - Development, construct validity, and reproducibility of a mimetic sealed jar measuring the dynamics of opening. AB - Measurement of the dynamic kinetics involved in opening a jar may enable health care professionals to understand and train individuals in optimal hand/grip mechanics. This technical note details the design, validity, and reproducibility testing of a mimetic jar capable of measuring the forces and moments and isolated digital forces applied to the lid of the jar. An ecological jar instrument was designed with a torque limiter to provide a natural opening mechanism while a six axis load cell and force sensing resistors recorded the way individuals applied force to the jar and lid during opening of a sealed container. A total of 115 volunteers participated in a validation of the device and an additional 36 participated in repeatability testing. Compared with prior instruments, this mimetic jar provides more force data and a simulated opening experience - making this jar instrument unique. Future studies utilizing the jar designed herein may allow health care professionals to evaluate patients suffering from debilitating osteoarthritis, fibromyalgia or other neuromuscular conditions and offer improvement strategies. PMID- 29250345 TI - A two-dimensional Zn coordination polymer with a three-dimensional supra molecular architecture. AB - The title compound, poly[bis-{MU2-4,4'-bis-[(1,2,4-triazol-1-yl)meth-yl]biphenyl kappa2N4:N4'}bis-(nitrato-kappaO)zinc(II)], [Zn(NO3)2(C18H16N6)2] n , is a two dimensional zinc coordination polymer constructed from 4,4'-bis-[(1H-1,2,4 triazol-1-yl)meth-yl]-1,1'-biphenyl units. It was synthesized and characterized by elemental analysis and single-crystal X-ray diffraction. The ZnII cation is located on an inversion centre and is coordinated by two O atoms from two symmetry-related nitrate groups and four N atoms from four symmetry-related 4,4' bis-[(1H-1,2,4-triazol-1-yl)meth-yl]-1,1'-biphenyl ligands, forming a distorted octa-hedral {ZnN4O2} coordination geometry. The linear 4,4'-bis-[(1H-1,2,4 triazol-1-yl)meth-yl]-1,1'-biphenyl ligand links two ZnII cations, generating two dimensional layers parallel to the crystallographic (132) plane. The parallel layers are connected by C-H?O, C-H?N, C-H?pi and pi-pi stacking inter-actions, resulting in a three-dimensional supra-molecular architecture. PMID- 29250346 TI - Structural parameters of dimethyl sulfoxide, DMSO, at 100 K, based on a redetermination by use of high-quality single-crystal X-ray data. AB - The title compound, C2H6OS, is a high melting, polar and aprotic solvent widely used in organic and inorganic chemistry. It serves as a H-atom acceptor in hydrogen bonding and is used as an ambidentate ligand in coordination chemistry. The evaluation of the influence of inter-molecular inter-actions on the inter-nal structural parameters of the chemically bonded DMSO mol-ecules affords precise structural data of the free mol-ecule as a point of reference. So far, valid data have been obtained only by use of neutron powder diffraction [Ibberson (2005 ?). Acta Cryst. C61, o571-o573]. In the present redetermination, structural data have been obtained from a single-crystal X-ray diffraction experiment at 100 K, revealing a better comparison with DMSO mol-ecules in other crystal structures. In the solid state, the pyramidal mol-ecule exhibits a nearly perfect Cs symmetry [including H atoms, which are eclipsed with respect to the C?C axis], with a C-S C bond angle of 97.73 (7) degrees and an S-O bond length of 1.5040 (10) A, corresponding very well with an S=O double bond, and with almost equal S-C bond lengths [mean value = 1.783 (4) A] and O-S-C bond angles [mean value = 106.57 (4) degrees ]. The crystal packing is influenced by C-H?O inter-actions (2.42-2.47 A) between all three H atoms of only one methyl group with the O atoms of three neighbouring DMSO mol-ecules. The inter-actions of the O atom with H atoms (or Lewis acids, or hydrogen-donor groups) of adjacent mol-ecules in relation to the orientation of the complete DMSO mol-ecule are described in terms of the angle omega and the distance dnorm; omega is the angle between the pseudo-mirror plane of the mol-ecule and the plane defined through the S=O bond and the inter-acting atom, and dnorm is the distance of the inter-acting atom from the plane perpendicular to the S=O bond. PMID- 29250347 TI - Crystal structures of the dioxane hemisolvates of N-(7-bromo-methyl-1,8 naphthyridin-2-yl)acetamide and bis-[N-(7-di-bromo-methyl-1,8-naphthyridin-2 yl)acetamide]. AB - The syntheses and crystal structures of N-(7-bromo-methyl-1,8-naphthyridin-2 yl)acetamide dioxane hemisolvate, C11H10BrN3O.0.5C4H8O2, (I), and bis-[N-(7-di bromo-methyl-1,8-naphthyridin-2-yl)acetamide] dioxane hemisolvate, 2C11H9Br2N3O.0.5C4H8O2, (II), are described. The mol-ecules adopt a conformation with the N-H hydrogen pointing towards the lone electron pair of the adjacent naphthyridine N atom. The crystals of (I) are stabilized by a three-dimensional supra-molecular network comprising N-H?N, C-H?N and C-H?O hydrogen bonds, as well as C-Br?pi halogen bonds. The crystals of compound (II) are stabilized by a three dimensional supra-molecular network comprising N-H?N, C-H?N and C-H?O hydrogen bonds, as well as C-H?pi contacts and C-Br?pi halogen bonds. The structure of the substituent attached in the 7-position of the naphthyridine skeleton has a fundamental influence on the pattern of inter-molecular noncovalent bonding. While the Br atom of (I) participates in weak C-Br?Oguest and C-Br?pi contacts, the Br atoms of compound (II) are involved in host-host inter-actions via C Br?O=C, C-Br?N and C-Br?pi bonding. PMID- 29250348 TI - Crystal structure of 7beta-hy-droxy-royleanone isolated from Taxodium ascendens (B.). AB - The title compound, C20H28O4 [systematic name: (4bS,8aS,10S)-3,10-dihy-droxy-2 isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octa-hydro-phenanthrene-1,4-dione], is an abietane-type diterpene, which was isolated from Taxodium ascendens (B.). The compound crystallizes in the chiral space group P21, but it was not possible to determine the absolute structure of the mol-ecule in the crystal by resonant scattering. The mol-ecular structure is stabilized by two intra-molecular O-H?O hydrogen bonds, enclosing S(5) and S(6) ring motifs. In the crystal, mol-ecules are linked by O-H?O and C-H?O hydrogen bonds, forming chains along the [010] direction. The crystal structure of the 10R stereoisomer of the title compound, isolated from the roots of Premna obtusifolia (Verbenaceae), has been reported. It crystallized in the chiral space group P212121, and the absolute structure was determined as (4bS,8aS,10R), by resonant scattering using Cu Kalpha radiation [Razak et al. (2010 ?). Acta Cryst. E66, o1566-o1567]. PMID- 29250349 TI - Crystal structure of (1S,2S,5R)-5-acetyl-amino-4-oxo-2,3-diphenyl-1,3-thia-zinan 1-ium-1-olate. AB - The asymmetric unit of the enanti-omerically pure title compound, C18H18N2O3S, comprises two independent mol-ecules (A and B) having almost identical conformations. When overlayed, the alignment-r.m.s. deviation value is 0.30 A. The six-membered heterocycle has a twisted half-chair conformation in both mol ecules. The O atom on the S atom of the ring is pseudo-axial on the thia-zine ring and trans to both a phenyl group substituent and the acetamide group in each case. The two benzene rings in each mol-ecule are almost orthogonal to each other, with inter-planar dihedral angles of 83.79 (17) and 86.95 (16) degrees . The acetamide group is pseudo-equatorial and a phenyl ring is pseudo-axial on the thia-zine ring. Both mol-ecules show a weak intra-molecular C-H?O inter-action between H-atom donors of one of the phenyl rings and the acetamide group. In the crystal, an inter-molecular N-H?O(thia-zine) hydrogen bond links B mol-ecules along the 21 (b) screw axis and, in addition, an N-H?O(acetamide) hydrogen bond links A and B mol-ecules across a. A two-dimensional layered structure lying parallel to (001) is generated, also involving weak inter-molecular C-H?O inter actions. PMID- 29250350 TI - A copper(II) paddle-wheel structure of tranexamic acid: di-chloro-tetra-kis-[MU-4 (ammonio-meth-yl)cyclo-hexane-1-carboxyl-ato-O,O']dicopper(II) dichloride hexa hydrate. AB - Tranexamic acid [systematic name: trans-4-(amino-meth-yl)cyclo-hexane-1-carb-oxy lic acid], is an anti-fibrinolytic amino acid that exists as a zwitterion [trans 4-(ammonio-meth-yl)cyclo-hexane-1-carboxyl-ate] in the solid state. Its reaction with copper chloride leads to the formation of a compound with a copper(II) paddle-wheel structure that crystallizes as a hexa-hydrate, [Cu2Cl2(C8H15NO2)4]2+.2Cl-.6H2O. The asymmetric unit is composed of a copper(II) cation, two zwitterionic tranexamic acid units, a coordinating Cl- anion and a free Cl- anion, together with three water mol-ecules of crystallization. The whole structure is generated by inversion symmetry, with the Cu?Cu axle of the paddle-wheel dication being located about a center of symmetry. The cyclo-hexane rings of the zwitterionic tranexamic acid units have chair conformations. The carboxyl-ate groups that bridge the two copper(II) cations are inclined to one another by 88.4 (8) degrees . The copper(II) cation is ligated by four carboxyl ate O atoms in the equatorial plane and by a Cl- ion in the axial position. Hence, it has a fivefold O4Cl coordination sphere with a perfect square-pyramidal geometry and a tau5 index of zero. In the crystal, the paddle-wheel dications are linked by a series of N-H?Cl hydrogen bonds, involving the coordinating and free Cl- ions, forming a three-dimensional network. This network is strengthened by a series of N-H?Owater, Owater-H?Cl and Owater-H?O hydrogen bonds. PMID- 29250351 TI - Lithium tetra-chlorido-aluminate, LiAlCl4: a new polymorph (oP12, Pmn21) with Li+ in tetra-hedral inter-stices. AB - Dissolving lithium chloride and aluminium chloride in boiling para- or meta xylene and keeping the colourless solution at room temperature led to crystal growth of a new modification of lithium tetra-chlorido-aluminate, LiAlCl4, which represents a second modification (oP12, Pmn21) of the ternary salt besides the long known monoclinic form [LiAlCl4(mP24, P21/c); Mairesse et al. (1977 ?). Cryst. Struct. Commun.6, 15-18]. The crystal structures of both modifications can be described as slightly distorted hexa-gonal closest packings of chloride anions. While the lithium cations in LiAlCl4(mP24) are in octa-hedral coordination and the aluminium and lithium ions in the solid of ortho-rhom-bic LiAlCl4 occupy tetra-hedral inter-stices with site symmetries m and 1, respectively, the lithium cation site being half-occupied (defect wurtz-stannite type structure). From differential scanning calorimetry (DSC) measurements, no evidence for a phase transition of the ortho-rhom-bic modification is found until the material melts at 148 degrees C (Tpeak = 152 degrees C). The melting point is nearly identical to the literature data for LiAlCl4(mP24) [146 degrees C; Weppner & Huggins (1976 ?). J. Electrochem. Soc.124, 35-38]. From the melts of both polymorphs, the monoclinic modification recrystallizes. PMID- 29250352 TI - Crystal structures of 2-(benzene-carbo-thio-yloxy)ethyl benzene-carbo-thio-ate and 2-(benzene-carbo-thio-yloxy)ethyl benzoate. AB - The title compounds, C16H14O2S2 and C16H14O3S, which are monomeric models (models D and E) for a polythio-noester and a poly(ester-co-thio-noester), respectively, crystallize in the space group P21/c and are isostructural with each other. The mol-ecule in each crystal is located on an inversion centre and has an all-trans structure. The asymmetric unit comprises one half-mol-ecule. In the crystal, there are inter-molecular C?S contacts [3.391 (3) and 3.308 (3) A for models D and E, respectively] and C-H?pi inter-actions, which form a layer structure parallel to the bc plane. The carbonyl and thio-carbonyl groups of the model E compound are each disordered over two equivalent sites about the inversion centre with equal occupancies. PMID- 29250353 TI - Manganese(II) chloride complexes with pyridine N-oxide (PNO) derivatives and their solid-state structures. AB - Three manganese(II) N-oxide complexes have been synthesized from the reaction of manganese(II) chloride with either pyridine N-oxide (PNO), 2-methyl-pyridine N oxide (2MePNO) or 3-methyl-pyridine N-oxide (3MePNO). The compounds were synthesized from methano-lic solutions of MnCl2.4H2O and the respective N-oxide, and subsequently characterized structurally by single-crystal X-ray diffraction. The compounds are catena-poly[[aqua-chlorido-manganese(II)]-di-MU-chlorido-[aqua chlorido-manganese(II)]-bis-(MU-pyridine N-oxide)], [MnCl2(C5H5NO)(H2O)] n or [MnCl2(PNO)(H2O)] n (I), catena-poly[[aqua-chlorido-man-gan-ese(II)]-di-MU chlorido-[aqua-chlorido-manganese(II)]-bis-(MU-2-methyl-pyridine N-oxide)], [MnCl2(C6H7NO)(H2O)] n or [MnCl2(2MePNO)(H2O)] n (II), and bis-(MU-3-methyl pyridine N-oxide)bis-[di-aqua-dichlorido-manganese(II)], [Mn2Cl4(C6H7NO)2(H2O)4] or [MnCl2(3MePNO)(H2O)2]2 (III). The MnII atoms are found in pseudo-octa-hedral environments for each of the three complexes. Compound I forms a coordination polymer with alternating pairs of bridging N-oxide and chloride ligands. The coordination environment is defined by two PNO bridging O atoms, two chloride bridging atoms, a terminal chloride, and a terminal water. Compound II also forms a coordination polymer with a similar metal cation; however, the coordination polymer is bridged between MnII atoms by both a single chloride and 2MePNO. The distorted octahedrally coordinated metal cation is defined by two bridging 2MePNO trans to each other, two chlorides, also trans to one another in the equatorial (polymeric) plane, and a terminal chloride and terminal water. Finally, complex III forms a dimer with two bridging 3MePNOs, two terminal chlorides and two terminal waters forming the six-coordinate metal environment. All three compounds exhibit hydrogen bonding between the coordinating water(s) and terminal chlorides. PMID- 29250354 TI - Crystal structure of flucetosulfuron. AB - The title compound, {systematic name: 1-[3-({[(4,6-di-meth-oxy-pyrimidin-2 yl)carbamo-yl]amino}-sulfon-yl)pyridin-2-yl]-2-fluoro-propyl 2-meth-oxy-acetate}, C18H22FN5O8S, is used as a herbicide (pyrimidinyl-sulfonyl-urea herbicide). The dihedral angle between the mean planes of the pyridine and pyrimidine rings is 86.90 (7) degrees . In the crystal, N/C-H?O hydrogen bonds, C-H?F and C-H?pi inter-actions link adjacent mol-ecules, forming a chain along [020]. A further two C-H?O hydrogen bonds together with weak pi-pi inter-actions [ring centroid separation = 3.7584 (12) A] further aggregate the structure into a three dimensional architecture. PMID- 29250355 TI - Synthesis and crystal structures of two new tin bis-(carboranylamidinate) complexes. AB - Reaction of 2 equiv. of the lithium carboranylamidinate Li[o (C2H10B10)C(NCy)(NHCy)] with SnCl2 in THF afforded the stannylene compound bis(N,N'-dicyclohexylamidinatocarboranate)tin(II), SnII[o (C2H10B10)C(NCy)(NHCy)]2 (1). A similar reaction of SnCl4 with 2 equiv. of Li[o (C2H10B10)C(N i Pr)(NH i Pr)] unexpectedly afforded the known solvated penta chlorido-stannate(IV) salt [Li(THF)4][SnCl5(THF)] as the main reaction product. Small amounts of the new chlorido-tin(IV) bis-(carboranylamidinate) bis(N,N' diiso-propylamidinatocarboranate)chloridotin(IV), SnIVCl[o-(C2H10B10)C(N i Pr)(NH i Pr)][o-(C2H10B10)C(N i Pr)2] (2), were isolated as a by-product. Single-crystal X-ray structure analysis revealed a kappaC,kappaN-chelating coordination of the carboranylamidinate ligands in both 1 and 2. The Sn atom in 1 adopts a pseudo trigonal-bipyramidal coordination under participation of a stereoactive lone pair. In 2, a trigonal-bipyramidal coordination of Sn is completed by a chlorido ligand. PMID- 29250356 TI - Crystal structure and DFT study of (E)-2,6-di-tert-butyl-4-{[2-(pyridin-2 yl)hydrazin-1-yl-idene)meth-yl}phenol. AB - The title compound, C20H27N3O, was synthesized by condensation reaction of 3,5-di tert-butyl-4-hy-droxy-benzaldehyde and 2-hydrazinyl-pyridine, and crystallizes in the centrosymmetric monoclinic space group C2/c. The conformation about the C=N bond is E. The dihedral angle between the rings is 18.1 (3) degrees . An inter molecular N-H?N hydrogen bond generates an R22(8) ring motif. In the crystal, N H?N hydrogen bonds connect pairs of mol-ecules, forming dimers. Density functional theory (DFT) optimized structures at the B3LYP/6-311 G(d,p) level are compared with the experimentally determined mol-ecular structure in the solid state. PMID- 29250357 TI - Structure cristalline et analyses thermique et de surface Hirshfeld du diperchlorate de 4-aza-niumyl-2,2,6,6-tetramethylpiperidin-1-ium. AB - The synthesis of 4-aza-niumyl-2,2,6,6-tetra-methyl-piperidin-1-ium diperchlorate, C9H22N22+.2ClO4-, was carried out from an aqueous reaction of perchloric acid with 4-amino-2,2,6,6-tetra-methyl-piperidine. This compound was characterized by TGA-DSC analysis and single-crystal X-ray diffraction. The piperidine ring of the dication adopts a chair conformation and the orientation of the C-NH3 bond is equatorial. One of the two crystallographically independent perchlorate anions exhibits disorder [occupancies 0.625 (7) and 0.375 (7)]. The crystal packing is constituted by a succession of mixed layers parallel to the (-102) plane, made up of C9H22N22+ dications and ClO4- anions. These ions are linked by normal and bifurcated N-H?O hydrogen bonds with R44(12) graph-set motifs, generating a two dimensional network. The inter-molecular inter-actions in the crystal structure were qu-anti-fied and analysed using Hirshfeld surface analysis. PMID- 29250358 TI - Bis[N-2-hy-droxy-ethyl,N-methyl-dithio-carbamato-kappa2S,S)'-4-{[(pyridin-4-yl methyl-idene)hydrazinyl-idene}meth-yl]pyridine-kappaN1)zinc(II): crystal structure and Hirshfeld surface analysis. AB - In the title compound, [Zn(C4H8NOS2)2(C12H10N4)], the ZnII atom exists within a NS4 donor set defined by two chelating di-thio-carbamate ligands and a pyridyl-N atom derived from a terminally bound 4-pyridine-aldazine ligand. The distorted coordination geometry tends towards square-pyramidal with the pyridyl-N atom occupying the apical position. In the crystal, hydroxyl-O-H?O(hydrox-yl) and hydroxyl-O-H?N(pyrid-yl) hydrogen-bonding give rise to a supra-molecular double chain along [1-10]; methyl-C-H?pi(chelate ring) inter-actions help to consolidate the chain. The chains are connected into a three-dimensional architecture via pyridyl-C-H?O(hydrox-yl) inter-actions. In addition to the contacts mentioned above, the Hirshfeld surface analysis points to the significance of relatively weak pi-pi inter-actions between pyridyl rings [inter-centroid distance = 3.901 (3) A]. PMID- 29250359 TI - New monoclinic form of {O-Ethyl N-(4-nitro-phen-yl)thio-carbamato-kappaS}(tri-4 tolyl-phosphane-kappaP)gold(I): crystal structure and Hirshfeld surface analysis. AB - The title phosphanegold(I) thiol-ate compound, [Au(C9H9N2O3S)(C21H21P)], is a second monoclinic polymorph (space group P21/c) that complements a previously reported Cc polymorph [Broker & Tiekink (2008 ?). Acta Cryst. E64, m1582]. An SP donor set defines an approximately linear geometry about the gold atom in both forms. The key distinguishing feature between the present structure and the previously reported polymorph rests with the relative disposition of the thiol ate ligand. In the title compound, the orientation is such to place the oxygen atom in close contact with the gold atom [Au?O = 2.915 (2) A], in contrast to the aryl ring in the original polymorph. In the crystal, linear supra-molecular chains along the a-axis direction mediated by C-H?pi and nitro-O?pi inter-actions are found. These pack with no directional inter-actions between them. The analysis of the Hirshfeld surfaces for both forms of [Au(C9H9N3O3S)(C21H21P)] indicates quite distinctive inter-action profiles relating to the differences in inter-molecular contacts found in their respective crystals. PMID- 29250360 TI - Crystal structure of fipronil. AB - The title compound, C12H4Cl2F6N4OS {systematic name: 5-amino-1-[2,6-di-chloro-4 (tri-fluoro-meth-yl)phen-yl]-4-[(tri-fluoro-methane)sulfinyl]-1H-pyrazole-3-carbo nitrile}, is a member of the phenyl-pyrazole group of acaricides, and one of the phenyl-pyrazole group of insecticides. The dihedral angle between the planes of the pyrazole and benzene rings is 89.03 (9) degrees . The fluorine atoms of the tri-fluoro-methyl substituent on the benzene ring are disordered over two sets of sites, with occupancy ratios 0.620 (15):0.380 (15). In the crystal, C-N?pi inter actions [N?ring centroid = 3.607 (4) A] together with N-H?N and C-H?F hydrogen bonds form a looped chain structure along [10[Formula: see text]]. Finally, N-H?O hydrogen bonds and C-Cl?pi inter-actions [Cl?ring centroid = 3.5159 (16) A] generate a three-dimensional structure. Additionally, there are a short inter molecular F? F contacts present. PMID- 29250361 TI - Crystal structure of ochraceolide A isolated from Elaeodendron trichotomum (Turcz.) Lundell. AB - The title compound, C30H44O3 [systematic name: 6aR,6 bR,8aS,9aR,12aR,14bR) 4,4,6a,6;b,8a,14b-hexa-methyl-12-methyl-eneicosa-hydro-3H phenanthro[1',2':6,7]indeno-[2,1-b]furan-3,11(2H)-dione], is a triterpene lactone, which was isolated from di-chloro-methane extract of Elaeodendron trichotomum (Turcz.) Lundell (celastraceae) stem bark. The compound has a lupane skeleton and consists of four fused six-membered rings and two five-membered rings. In the crystal, mol-ecules are linked by weak C-H?O hydrogen bonds into a three-dimensional network. The configuration of ochraceolide A was proposed based on analogue compounds which belong to the lupane type. PMID- 29250362 TI - Bis(3,5-dimeth-oxy-2-{[2-(pyridin-2-yl)ethyl-imino-kappaN]-meth-yl}phenolato kappaO)bis-(dimethyl sulfoxide)-manganese(III) perchlorate methanol 0.774 solvate. AB - The title compound, [Mn(C16H17N2O3)2(C2H6OS)2]ClO4.0.774CH3OH, comprises a central octa-hedrally coordinated MnIII cation, with two bidentate Schiff base ligands occupying the equatorial positions and two dimethyl sulfoxide (DMSO) ligands occupying the axial positions. There are two independant cations in the asymmetric unit, with the MnIII atoms of both cations being positioned on crystallographic centers of inversion. The perchlorate anion is disordered over two equivalent conformations, with occupancies of 0.744 (3) and 0.226 (3). In addition, there is a methanol solvent mol-ecule in the crystal lattice that is too close to the minor component of the perchlorate anion to be present simultaneously and thus it was refined to have the same occupancy as the major component of this anion. There is a Jahn-Teller distortion which results in Mn ODMSO axial bond lengths of 2.2365 (12) and 2.2368 (12) A in the two cations. In the crystal, inter-molecular pi-pi stacking between the non-coordinating pyridine rings of each cation is observed. This pi-pi stacking, along with extensive O-H?O hydrogen bonding and C-H?O inter-actions, link the components into a complex three-dimensional array. PMID- 29250363 TI - Crystal structures of 2-methyl-pyridinium hydrogen 2,3-bis-(4-methyl-benzo yloxy)succinate and bis-[4-methyl-pyridinium hydrogen 2,3-bis-(4-methyl-benzo yloxy)succinate] penta-hydrate. AB - The title salt (I), C6H8N+.C20H17O8-, comprises a 2-methyl-pyridinium cation and a 2,3-bis-(4-methyl-benzo-yloxy)succinate mono-anion while the salt (II), 2C6H8N+.2C20H17O8-.5H2O, consists of a pair of 4-methyl-pyridinium cations and 2,3-bis-(4-methyl-benzo-yloxy)succinate mono-anions and five water mol-ecules of solvation in the asymmetric unit. In (I), the dihedral angle between the aromatic rings of the anion is 40.41 (15) degrees , comparing with 43.0 (3) and 85.7 (2) degrees in the conformationally dissimilar anion mol-ecules in (II). The pyridine ring of the cation in (I) is inclined at 23.64 (16) and 42.69 (17) degrees to the two benzene moieties of the anion. In (II), these comparative values are 4.7 (3), 43.5 (3) degrees and 43.5 (3), 73.1 (3) degrees for the two associated cation and anion pairs. The crystal packing of (I) is stabilized by inter-ionic N-H?O, O-H?O and C-H?O hydrogen bonds as well as weak C-H?pi inter actions, linking the ions into infinite chains along [100]. In the crystal packing of (II), the anions and cations are also linked by N-H?O and O-H?O hydrogen bonds involving also the water mol-ecules, giving a two-dimensional network across (001). The crystal structure is also stabilized by weak C-H?O and C-H?pi inter-actions. PMID- 29250364 TI - Crystal structures of N,N-dimethyl-(2-(2,2-diphen-yl)-2-prop-2-yn-yloxy)acet oxy)ethyl-amine and N,N-dimethyl-(2-(2,2-diphen-yl)-2-prop-2-yn-yl--oxy)acet oxy)ethyl-ammonium 2,4,6-tri-nitro-phenolate. AB - The N,N-di-methyl-ethylamminium unit in N,N-dimethyl-[2-(2,2-diphen-yl)-2-prop-2 ynyloxyacet-oxy]ethyl-amine, C21H23NO3 (I), is disordered over two sets of atomic sites having occupancies of 0.880 (3) and 0. 120 (3), but there are no direction specific inter-actions between the mol-ecules of (I). The cation in N,N-dimethyl [2-(2,2-diphen-yl)-2-prop-2-ynyloxyacet-oxy]ethyl-ammonium 2,4,6-tri-nitro phenolate (picrate), C21H24NO3+.C6H2N3O7- (II), shows a similar type of disorder, with occupancies of 0.654 (11) and 0.346 (11), although the overall conformation of the cation in (II) is different from that in the neutral (I). The component ions are are linked by an almost planar three-centre N-H?(O)2 hydrogen bond, and the ion pairs are further linked by a combination of three C-H?O hydrogen bonds to form sheets. Comparisons are made with some related structures. PMID- 29250365 TI - Crystal structure of 5-(dibenzo-furan-4-yl)-2'-deoxy-uridine. AB - The mol-ecule of the title compound, C21H18N2O6, has a bent rather than a linear conformation supported by three intra-molecular C-H?O hydrogen bonds. The packing in the crystal lattice is largely determined by inter-actions between hydrogen atoms with oxygen atom lone pairs with one mol-ecule inter-acting with neigbouring mol-ecules via O-H?O, N-H?O and C-H?O hydrogen bonds. The title compound crystallizes in the chiral ortho-rhom-bic space group P212121. Its absolute structure could not be determined crystallographically and was assumed with reference to that of the reactant 5-iodo-2'-de-oxy-uridine. PMID- 29250366 TI - Unusual formation of (E)-11-(amino-methyl-ene)-8,9,10,11-tetra-hydro pyrido[2',3':4,5]pyrimido[1,2-a]azepin-5(7H)-one and its crystal structure. AB - Selective C-formyl-ation of 8,9,10,11-tetra-hydro-pyrido[2',3':4,5]pyrimido[1,2 a]-azepin-5(7H)-one has been studied for the first time. It was revealed that formyl-ation proceeds by the formation of an inter-mediate salt, which due to the re-amination process on treatment with aqueous ammonia transformed into the corresponding (E)-11-(amino-methyl-ene)-8,9,10,11-tetra-hydro-pyrido[2',3':4,5] pyrimido[1,2-a]azepin-5(7H)-one, C13H14N4O, as an E-isomer. Formyl-ation was carried out by Vilsmeier-Haack reagent and the structure of the synthesized compound was confirmed by X-ray structural analysis, spectroscopic and LC-MS methods. In the mol-ecule, the seven-membered penta-methyl-ene ring adopts a twist-boat conformation. PMID- 29250367 TI - Crystal structures of {MU2-N,N'-bis-[(pyridin-3-yl)meth-yl]ethanedi-amide}tetra kis-(di-methyl-carbamodi-thio-ato)dizinc(II) di-methyl-formamide disolvate and {MU2-N,N'-bis-[(pyridin-3-yl)meth-yl]ethanedi-amide}tetra-kis-(di-n-propyl carbamodi-thio-ato)dizinc(II). AB - The title structures, [Zn2(C3H6NS2)4(C14H14N4O2)].2C3H7NO (I) and [Zn2(C7H14NS2)4(C14H14N4O2)] (II), each feature a bidentate, bridging bipyridyl type ligand encompassing a di-amide group. In (I), the binuclear compound is disposed about a centre of inversion, leading to an open conformation, while in (II), the complete mol-ecule is completed by the application of a twofold axis of symmetry so that the bridging ligand has a U-shape. In each of (I) and (II), the di-thio-carbamate ligands are chelating with varying degrees of symmetry, so the zinc atom is within an NS4 set approximating a square-pyramid for (I) and a trigonal-bipyramid for (II). The solvent di-methyl-formaide (DMF) mol-ecules in (I) connect to the bridging ligand via amide-N-H?O(DMF) and various amide-, DMF-C H?O(amide, DMF) inter-actions. The resultant three-mol-ecule aggregates assemble into a three-dimensional architecture via C-H?pi(pyridyl, chelate ring) inter actions. In (II), undulating tapes sustained by amide-N-H?O(amide) hydrogen bonding lead to linear supra-molecular chains with alternating mol-ecules lying to either side of the tape; no further directional inter-actions are noted in the crystal. PMID- 29250368 TI - 4-Amino-benzoic acid 4-methyl-pyridine/4-methyl-pyridinium 4-amino-benzoate 0.58/0.42: a redetermination from the original data. AB - The title structure, 4-amino-benzoic acid 4-methyl-pyridine/4-methyl-pyridinium 4 amino-benzoate 0.58/0.42, 0.58(C6H7N.C7H7NO2).0.42(C6H8N+.C7H6NO2-), has been redetermined from the data published by Kumar et al. (2015 ?). Acta Cryst. E71, o125-o126. The improvement of the present redetermination consists in the introduction of disorder of the methyl group over two positions as well as in the correction of the positional parameters of the hydrogen atoms that are involved in the O-H?N or N-H?O hydrogen bonds. After the correction, the hydroxyl hydrogen atom turned out to be disordered over two positions about the centre of the O?N bond, which is relatively long [2.642 (2) A], while the H atoms of the primary amine group account more realistically for the hydrogen-bond pattern after the removal of the positional constraints. All the O-H?N or N-H?O hydrogen bonds which are present in the title structure are of moderate strength. PMID- 29250369 TI - Crystal structure of ebastinium 3,5-di-nitro-benzoate. AB - Ebastine, 4-(benzhydr-yloxy)-1-[4-(4-tert-butyl-phen-yl)-4-oxobut-yl]piperidine, reacts with 3,5-di-nitro-benzoic acid in methanol solution to give the title 1:1 salt, ebastinium 3,5-di-nitro-benzoate, C32H40NO2+.C7H3N2O6-. In the cation, the disubstituted aryl ring exhibits orientational disorder over two sets of atomic sites having occupancies 0.706 (4) and 0.294 (6), with a dihedral angle of 41.2 (5) degrees between the two orientations: the bulky Ph2CH-O- substituent occupies an axial site on the piperidine ring. The two ions in the selected asymmetric unit are linked by a nearly linear N-H?O hydrogen bond and this, in combination with two C-H?O hydrogen bonds, links the ions into complex sheets. PMID- 29250370 TI - Crystal structure of 2,2'-bi-pyrrole. AB - The complete mol-ecule of the title compound, C8H8N2, is generated by a crystallographic center of symmetry. In the crystal, short N-H?pi [H?pi = 2.499 (19) A] inter-actions link the mol-ecules into a herringbone structure. PMID- 29250371 TI - Crystal structure of sodium di-hydrogen arsenate. AB - Single crystals of the title compound, Na(H2AsO4), were obtained by partial neutralization of arsenic acid with sodium hydroxide in aqueous solution. The crystal structure of Na(H2AsO4) is isotypic with the phosphate analogue and the asymmetric unit consists of two sodium cations and two tetra-hedral H2AsO4- anions. Each of the sodium cations is surrounded by six O atoms of five H2AsO4- groups, defining distorted octa-hedral coordination spheres. In the extended structure, the sodium cations and di-hydrogen arsenate anions are arranged in the form of layers lying parallel to (010). Strong hydrogen bonds [range of O?O distances 2.500 (3)-2.643 (3) A] between adjacent H2AsO4- anions are observed within and perpendicular to the layers. The isotypic structure of Na(H2PO4) is comparatively discussed. PMID- 29250372 TI - A monoclinic polymorph of 1,2-bis-[(1-methyl-1H-tetra-zol-5-yl)sulfan-yl]ethane (BMTTE). AB - The synthesis and crystal structure of a monoclinic (P21/c) polymorph of the title compound, C6H10S2N8, are reported. The mol-ecule has pseudo-twofold rotational symmetry, with the tetra-zole rings being inclined to one another by 5.50 (6) degrees . In the crystal, mol-ecules are linked by C-H?N hydrogen bonds, forming chains propagating along [101] and enclosing R22(20) ring motifs. The chains are linked by offset pi-pi inter-actions involving the tetra-zole rings [inter-centroid distances vary from 3.3567 (7) to 3.4227 (7) A], forming layers parallel to the ac plane. The crystal structure of the triclinic polymorph (P [Formula: see text]) has been described previously [Li et al. (2011 ?). Acta Cryst. E67, o1669]. PMID- 29250373 TI - (E)-2,6-Di-bromo-4-{2-[1-(1H,1H,2H,2H-perfluoro-oct-yl)pyridinium-4-yl]ethen yl}phenolate methanol disolvate, a fluoro-ponytailed solvatochromic dye. AB - The title compound, C21H12Br2F13NO.2CH3OH, was obtained by condensation of 4 methyl-1-(1H,1H,2H,2H-perfluoro-oct-yl)pyridinium iodide and 3,5-di-bromo-4-hy droxy-benzaldehyde, followed by deprotonation. It crystallizes as a methanol disolvate and exhibits short O-H?O hydrogen bonds and a disordered perfluoro alkyl chain [occupancy ratio 0.538 (7):0.462 (7)]. Significant pi-pi stacking inter-actions are observed between the benzene and pyridine rings of neighbouring mol-ecules along the b-axis direction. PMID- 29250374 TI - Crystal structure of 4-meth-oxy-N-(piperidine-1-carbono-thio-yl)benzamide. AB - In the title compound, C14H18N2O2S, the piperidine ring has a chair conformation. Its mean plane is twisted with respect to the 4-meth-oxy-benzoyl ring, with a dihedral angle of 63.0 (3) degrees . The central N-C(=S)-N(H)-C(=O) bridge is twisted with an N-C-N-C torsion angle of 74.8 (6) degrees . In the crystal, mol ecules are linked by N-H?O and C-H?O hydrogen bonds, forming chains along the c axis direction. Adjacent chains are linked by C-H?pi inter-actions, forming layers parallel to the ac plane. The layers are linked by offset pi-pi inter actions [inter-centroid distance = 3.927 (3) A], forming a supra-molecular three dimensional structure. PMID- 29250375 TI - Aqua-chlorido-(2-{[6-(di-methyl-amino)-pyrimidin-4-yl]sulfan-yl}pyrimidine-4,6-di amine)-copper(II) chloride hydrate. AB - A copper(II) complex of the non-symmetric bidentate ligand 2-{[6-(di-methyl amino)-pyrimidin-4-yl]sulfan-yl}pyrimidine-4,6-di-amine (L1) is reported. The single-crystal X-ray structure of aqua-[aqua/chlorido-(0.49/0.51)](2-{[6-(di methyl-amino)-pyrimidin-4-yl]sulfan-yl}pyrimidine-4,6-di-amine)-copper(II) 0.49 chloride 1.51-hydrate, [CuCl1.51(C10H13N7S)(H2O)1.49]Cl0.49.1.51H2O or [(L1)Cl1.51(H2O)1.49Cu]0.49Cl.1.51H2O, exhibits distorted square-pyramidal geometry around the metal centre, with disorder in the axial position, occupied by chloride or water. The six-membered metal-chelate ring is in a boat conformation, and short inter-molecular S?S inter-actions are observed. In addition to its capacity for bidentate metal coordination, the ligand has the ability to engage in further supra-molecular inter-actions as both a hydrogen bond donor and acceptor, and multiple inter-actions with lattice solvent water mol-ecules are present in the reported structure. PMID- 29250376 TI - Crystal structure of {[1'-(di-phenyl-phosphino)ferrocen-yl]meth-yl}di-methyl ammonium chloride monohydrate. AB - Individual ions and the solvating water mol-ecule constituting the structure of the title compound, [Fe(C8H13N)(C17H14P)]Cl.H2O, assemble into dimeric units located around crystallographic inversion centers via N-H?Cl and O-H?Cl hydrogen bonds. These discrete fragments are further inter-connected into chains by C-H?O inter-actions. The disubstituted ferrocene core in the {[1'-(di-phenyl phosphino)ferrocen-yl]meth-yl}di-methyl-ammonium cation has an approximate synclinal eclipsed conformation and is tilted by 3.40 (11) degrees . PMID- 29250377 TI - Crystal structure of an AgI inter-calation compound: catena-poly[[silver(I)-MU-N (pyridin-3-ylmeth-yl)pyridin-3-amine-kappa2N:N'] hexa-fluorido-phosphate aceto nitrile disolvate]. AB - The asymmetric unit in the title compound, [Ag(C11H11N3)]PF6.2CH3CN or {[AgL].PF6.2CH3CN} n , L = N-(pyridin-3-ylmeth-yl)pyridin-3-amine, comprises one AgI atom, one L ligand, two aceto-nitrile solvent mol-ecules and one PF6- anion disordered over two orientations in a 0.567 (11):0.433 (11) ratio. Each AgI atom is coordinated by two pyridine N atoms from two L ligands in a slightly distorted linear coordination geometry [N-Ag-N = 170.55 (8) degrees ]. Each L ligand bridges two AgI ions, resulting in the formation of a zigzag chain propagating along the [101] direction. In the crystal, Ag?Ag contacts [3.3023 (5) A] and inter-molecular pi-pi stacking inter-actions [centroid-to-centroid distance = 3.5922 (15) A] between the pyridine rings link these chains into a corrugated layer parallel to the ([Formula: see text]01) plane. The layers are stacked with a separation of 10.4532 (5) A, and aceto-nitrile solvent mol-ecules and PF6- anions as guests are inter-calated between the layers. The layers are connected through several N/C-H?F hydrogen bonds and P-F?pi inter-actions [F?ring centroid = 3.241 (8) A] between the layer and the inter-calated guests and between the inter-calated guests, forming a three-dimensional supra-molecular network. PMID- 29250378 TI - Crystal structures of three hydrogen-bonded 1:2 compounds of chloranilic acid with 2-pyridone, 3-hy-droxy-pyridine and 4-hyroxypyridine. AB - The crystal structures of the 1:2 compounds of chloranilic acid (systematic name: 2,5-di-chloro-3,6-dihy-droxy-1,4-benzo-quinone) with 2-pyridone, 3-hy-droxy pyridine and 4-hyroxypyridine, namely, bis-(2-pyridone) chloranilic acid, 2C5H5NO.C6H2Cl2O4, (I), bis-(3-hy-droxy-pyridinium) chloranilate, 2C5H6NO+.C6Cl2O42-, (II), and bis-(4-hy-droxy-pyridinium) chloranilate, 2C5H6NO+.C6Cl2O42-, (III), have been determined at 120 K. In the crystal of (I), the base mol-ecule is in the lactam form and no acid-base inter-action involving H-atom transfer is observed. The acid mol-ecule lies on an inversion centre and the asymmetric unit consists of one half-mol-ecule of chloranilic acid and one 2 pyridone mol-ecule, which are linked via a short O-H?O hydrogen bond. 2-Pyridone mol-ecules form a head-to-head dimer via a pair of N-H?O hydrogen bonds, resulting in a tape structure along [201]. In the crystals of (II) and (III), acid-base inter-actions involving H-atom transfer are observed and the divalent cations lie on an inversion centre. The asymmetric unit of (II) consists of one half of a chloranilate anion and one 3-hy-droxy-pyridinium cation, while that of (III) comprises two independent halves of anions and two 4-hy-droxy-pyridinium cations. The primary inter-molecular inter-action in (II) is a bifurcated O H?(O,O) hydrogen bond between the cation and the anion. The hydrogen-bonded units are further linked via N-H?O hydrogen bonds, forming a layer parallel to the bc plane. In (III), one anion is surrounded by four cations via O-H?O and C-H?O hydrogen bonds, while the other is surrounded by four cations via N-H?O and C H?Cl hydrogen bonds. These inter-actions link the cations and the anions into a layer parallel to (301). PMID- 29250379 TI - Crystal structure of fac-tri-carbonyl-chlorido-bis-(4-hy-droxy-pyridine) rhenium(I)-pyridin-4(1H)-one (1/1). AB - The asymmetric unit of the title compound, [ReCl(C5H5NO)2(CO)3].C5H5NO, contains one mol-ecule of the complex fac-[ReCl(4-pyOH)2(CO)3] (where 4-pyOH represents 4 hy-droxy-pyridine) and one mol-ecule of pyridin-4(1H)-one (4-HpyO). In the mol ecule of the complex, the Re atom is coordinated to two N atoms of the two 4-pyOH ligands, three carbonyl C atoms, in a facial configuration, and the Cl atom. The resulting geometry is slightly distorted octa-hedral. In the crystal structure, both fragments are associated by hydrogen bonds; two 4-HpyO mol-ecules bridge between two mol-ecules of the complex using the O=C group as acceptor for two different HO- groups of coordinated 4-pyOH from two neighbouring metal complexes. The resulting square arrangements are extented into infinite chains by hydrogen bonds involving the N-H groups of the 4-HpyO mol-ecule and the chloride ligands. The chains are further stabilized by pi-stacking inter-actions. PMID- 29250380 TI - Crystal structures of 1-benzene-sulfon-yl-2-methyl-3-(4-nitro-benzoyl)-2,3-di hydro-1H-indole and 1-benzene-sulfon-yl-2-methyl-3-[(thio-phen-2-yl)carbon-yl] 2,3-di-hydro-1H-indole. AB - In the title indole derivatives, C22H16N2O5S, (I) and C20H15NO3S2, (II), the sulfonyl-bound phenyl rings are almost orthogonal to the indole ring system, subtending dihedral angles of 88.33 (10) and 87.58 (16) degrees , respectively. In both compounds, the sulfonyl S atom has a distorted tetra-hedral geometry [O-S O = 119.98 (9) and N-S-C = 104.01 (8) degrees for compound (I) and O-S-O = 120.08 (18) and N-S-C = 104.91 (14) degrees for compound (II)] and the sum of the bond angles at N indicates sp2 hybridization. The mol-ecules of both (I) and (II) feature intra-molecular C-H?O hydrogen bonds that generate S(6) ring motifs with the sulfone O atom. In the crystals, mol-ecules of (I) are linked by C-H-O hydrogen bonds, forming R44(18) ring motifs while mol-ecules of (II) are linked by C-H-O and C-H-S hydrogen bonds, forming R22(12) ring motifs. Compound (II) was refined as an inversion twin. PMID- 29250381 TI - Crystal structure of a new polymorph of di(thio-phen-3-yl) ketone. AB - The crystal structure of the title compound, C9H6OS2, represents a new polymorph. The crystal structure was solved in the ortho-rhom-bic space group Pbcn with one half of the mol-ecule in the asymmetric unit. The thio-phene rings are perfectly planar and twisted with respect to each other, showing the mol-ecule to be in an S,O-trans/S,O-trans conformation. In the crystal, C-H?O hydrogen bonds connect the mol-ecules into layers extending parallel to the ab plane. The crystal structure also features pi-pi inter-actions. PMID- 29250382 TI - N,N',N'' versus N,N',O imine-containing coordination motifs: ligand-directed synthesis of mononuclear and binuclear CuII compounds. AB - It is demonstrated here that tridentate imine ligands can control the nuclearity of copper(II) complexes based on the donor atoms present in the ligand. The N,N',N''-donating imine ligand led to a mononuclear compound, namely di-chlorido [N,N-dimethyl-N'-(pyridin-2-yl-methyl-idene)ethane-1,2-di-amine]copper(II) monohydrate, [CuCl2(C10H15N3)].H2O, 1, while the N,N',O-donating imine ligand produced a binuclear metal complex, namely MU2-chlorido-di-chlorido-(MU2-2-{[2 (di-methyl-amino)-ethyl]imino-methyl}phenolato)(N,N-dimethyl-ethylene-di-amine) dicopper(II) 0.11-hydrate, [Cu2(C11H15N2O)Cl3(C4H12N2)].0.11H2O, 2. The structure of 2 is a remarkable example of a binuclear copper(II) complex containing a single substituted 2-imino-methyl-phenolate ligand that has two copper(II) sites in square-pyramidal coordination. PMID- 29250383 TI - (Aceto-nitrile-kappaN)aqua-[N,N'-bis-(pyridin-2-yl-methyl)ethane-1,2-di-amine kappa4N,N',N'',N''']zinc(II) perchlorate. AB - The structure of the title compound, [Zn(C14H18N4)(C2H3N)(H2O)](ClO4)2, contains a six-coordinate cation consisting of the tetra-dentate bis-picen ligand, coordinated water, and coordinated aceto-nitrile, with the latter two ligands adopting a cis configuration. There are two formula units in the asymmetric unit. Both cations show almost identical structural features with the bis-picen ligand adopting the more common cis-beta conformation. One of the four perchlorate anions is disordered over two positions, with occupancies of 0.9090 (15) and 0.0910 (15). There is extensive inter-ionic hydrogen bonding between the perchlorate anions and O-H and N-H groups in the cations, including a bifurcated hydrogen bond between an N-H group and two O atoms of one perchlorate anion. As a result of this extended hydrogen-bond network, the ions are linked into a complex three-dimensional array. PMID- 29250384 TI - Crystal structure and Hirshfeld surface analysis of pulcherrin J. AB - The title compound, C29H36O4 [systematic name (4aR,5R,6aS,7R,11aS,11bR)-4a hydroxy-4,4,7,11b-tetramethyl-1,2,3,4,4a,5,6,6a,7,11,11a,11b-dodecahydrophen anthro[3,2-b]furan-5-yl cinnamate], a natural diterpene known as pulcherrin J, was isolated from stem barks of medicinally important Caesalpinia pulcherrima (L.). The crystal structure of pulcherrin J shows it to be composed of a central core of three trans-fused cyclo-hexane rings and a near planar five-membered furan ring, along with an axially oriented cinnamate moiety and an -hydroxy substituent attached at positions 4a and 5 of the steroid ring system, respectively. The absolute structure was established with the use of Cu Kalpha radiation. In the crystal, mol-ecules are linked by O-H?O hydrogen bonds to generate [100] C(8) chains. Hirshfeld surface analysis indicates that the most significant contacts in packing are H?H (67.5%), followed by C?H (19.6%) and H?O (12.9%). PMID- 29250385 TI - Crystal structure and identification of resonance forms of diethyl 2-(3-oxoiso 1,3-di-hydro-benzo-furan-1-yl-idene)malonate. AB - The reaction of diethyl malonate with phthaloyl chloride in aceto-nitrile in the presence of tri-ethyl-amine and magnesium chloride results in the formation of the title compound, diethyl 2-(3-oxo-1,3-di-hydro-2-benzo-furan-1-yl idene)propane-dioate, C15H14O6. One of the ester groups of the diethyl malonate fragment is almost coplanar with the isobenzo-furan unit, while the plane of the other group is perpendicular to it [dihedral angles = 5.45 (3) and 83.30 (3) degrees , respectively]. The C-C and C-O distances both in the heterocyclic furan ring and the diethyl malonate fragment are indicative of the dipolar delocalization occurring within the isobenzo-furan unit. This delocalization is likely to be responsible for the unusual inter-molecular O?O contact [2.756 (2) A], established between the O atom of the furan ring and the carbonyl O atom of the diethyl malonate fragment. In the crystal, weak C-H?O inter-actions are observed, which link the mol-ecules into [100] chains. PMID- 29250386 TI - MIn(HAsO4)2 (M = K, Rb, Cs): three new hydrogen-arsenates adopting two different structure types. AB - Potassium indium bis-[hydrogen arsenate(V)], KIn(HAsO4)2, rubidium indium bis [hydrogen arsenate(V)], RbIn(HAsO4)2, and caesium indium bis-[hydrogen arsenate(V)], CsIn(HAsO4)2, were grown under mild hydro-thermal conditions (T = 493 K, 7-8 d). KIn(HAsO4)2 adopts the KSc(HAsO4)2 structure type (space group C2/c), while RbIn(HAsO4)2 and CsIn(HAsO4)2 crystallize in the space group R-3c and are the first arsenate representatives of the RbFe(HPO4)2 structure type. All three compounds have tetra-hedral-octa-hedral framework topologies. The M+ cations, located in voids of the respective framework, are slightly disordered in RbIn(HAsO4)2. In KIn(HAsO4)2, there is a second K-atom position with a very low occupancy, which may suggest that the K atom can easily move in the channels extending along [101]. PMID- 29250387 TI - Crystal structure of a twisted-ribbon type double-stranded AgI coordination polymer: catena-poly[[silver(I)-MU3-bis-(pyridin-3-ylmeth-yl)sulfane kappa3N:N':S] nitrate]. AB - The asymmetric unit in the title compound, {[Ag(C12H12N2S)].NO3} n or {[AgL].NO3} n , L = bis-(pyridin-3-ylmeth-yl)sulfane, consists of an AgI cation bound to a pyridine N atom of an L ligand and an NO3- anion that is disordered over two orientations in an 0.570 (17):0.430 (17) occupancy ratio. Each AgI cation is coordinated by two pyridine N atoms from adjacent L ligands to form an infinite zigzag chain along [110]. In addition, each AgI ion binds to an S donor from a third L ligand in an adjacent parallel chain, resulting in the formation of a twisted-ribbon type of double-stranded chain propagating along the [110] or [1 10] directions. The AgI atom is displaced out of the trigonal N2S coordination plane by 0.371 (3) A because of inter-actions between the AgI cation and O atoms of the disordered nitrate anions. Inter-molecular pi-pi stacking inter-actions [centroid-to-centroid distance = 3.824 (3) A] occur between one pair of corresponding pyridine rings in the double-stranded chain. In the crystal, the double-stranded chains are alternately stacked along the c axis with alternate stacks linked by inter-molecular pi-pi stacking inter-actions [centroid-to centroid distance = 3.849 (3) A], generating a three-dimensional supra-molecular architecture. Weak inter-molecular C-H?O hydrogen bonds between the polymer chains and the O atoms of the nitrate anions also occur. PMID- 29250388 TI - (E)-7-[(4-Nitro-phen-yl)diazen-yl]-3a-(p-tol-yl)-2,3,3a,4-tetra-hydro-1H benzo[d]pyrrolo-[1,2-a]imidazol-1-one 0.58-dimethyl sulfoxide 0.42-aceto-nitrile solvate: crystal structure, Hirshfeld analysis and DFT estimation of the energy of inter-molecular inter-actions. AB - In the crystal structure of the title compound, C23H19N5O3.0.58C2H6OS.0.42C2H3N, prepared by the azo coupling of the 4-nitro-phenyl-diazo-nium salt with 3a-(p-tol yl)-2,3,3a,4-tetra-hydro-1H-benzo[d]pyrrolo-[1,2-a]imidazol-1-one, the azo mol ecules are linked by N-H?O hydrogen bonds into chains along the a-axis direction, and by the pi-pi inter-action into [101] chains. The dimethyl sulfoxide and aceto nitrile solvent mol-ecules occupy the same positions, with populations of 0.585 (3) and 0.415 (3), respectively. These mol-ecules take part in C-H?O(N) and C H?pi contacts. The energy of the pi-pi inter-actions was estimated using DFT calculations. The Hirshfeld mol-ecular surface analysis revealed the positions of the most important inter-molecular contacts, such as hydrogen bonds and pi-pi inter-actions. PMID- 29250389 TI - Supra-molecular patterns and Hirshfeld surface analysis in the crystal structure of bis-(2-amino-4-meth-oxy-6-methyl-pyrimidinium) isophthalate. AB - In the title mol-ecular salt, 2C6H10N3O+.C8H4O42-, the N atom of each of the two 2-amino-4-meth-oxy-6-methyl-pyrimidine mol-ecules lying between the amine and methyl groups has been protonated. The dihedral angles between the pyrimidine rings of the cations and the benzene ring of the succinate dianion are 5.04 (8) and 7.95 (8) degrees . Each of the cations is linked to the anion through a pair of N-H?O(carboxyl-ate) hydrogen bonds, forming cyclic R22(8) ring motifs which are then linked through inversion-related N-H?O hydrogen bonds, giving a central R24(8) motif. Peripheral amine N-H?O hydrogen-bonding inter-actions on either side of the succinate anion, also through centrosymmetric R22(8) extensions, form one-dimensional ribbons extending along [211]. The crystal structure also features pi-pi stacking inter-actions between the aromatic rings of the pyrimidine cations [minimum ring centroid separation = 3.6337 (9) A]. The inter molecular inter-actions were also investigated using Hirshfeld surface studies and two-dimensional fingerprint images. PMID- 29250390 TI - Nitro-sonium complexation by the tetra-phospho-nate cavitand 5,11,17,23-tetra methyl-6,10:12,16:18,22:24,4-tetra-kis-(phenyl-phospho-nato kappa2O,O)resorcin(4)arene. AB - The crystal structure of a new supra-molecular complex between the tetra-phos-pho nate cavitand 5,11,17,23-tetra-methyl-6,10:12,16:18,22:24,4-tetra-kis(phenyl phospho-nato-kappa2O,O')resorcin(4)arene and the nitrosyl cation NO+, as the BF4- salt, is reported. The complex, of general formula [(C56H44P4O12)(NO)]BF4.CH2Cl2 or NO@Tiiii[H, CH3, C6H5] BF4.CH2Cl2, crystallizes in the space group P-1. The nitrosyl cation is disordered over two equivalent positions, with occupancies of 0.503 (2) and 0.497 (2), and inter-acts with two adjacent P=O groups at the upper rim of the cavitand through dipole-charge inter-actions. In the lattice, the cavitands are connected through a series of C-H?pi inter-actions involving the methyl and methyl-enic H atoms and the aromatic rings of the macrocycle. The structure is further stabilized by the presence of C-H?F inter-actions between the hydrogen atoms of the cavitands and the F atoms of the tetra-fluorido-borate anion. As a result of the disorder, the lattice di-chloro-methane mol-ecules could not be modelled in terms of atomic sites, and were treated using the PLATON SQUEEZE procedure [Spek (2015 ?). Acta Cryst. C71, 9-18]. The complexation process has also been studied in solution through NMR titrations. PMID- 29250391 TI - Crystal structure of the BaII-based CoII-containing one-dimensional coordination polymer poly[[aqua{MU4-2,2'-[(4,10-dimethyl-1,4,7,10-tetra-aza-cyclo-dodecane-1,7 di-yl)bis(methylidene)]bis-(4-oxo-4H-pyran-3-olato)}-perchloratocobaltbarium] perchlorate]. AB - The title compound, {[Ba{Co(H-2L1)}(ClO4)(H2O)]ClO4} n , L1 = 4,10-bis-[(3-hy droxy-4-pyron-2-yl)meth-yl]-1,7-dimethyl-1,4,7,10-tetra-aza-cyclo-dodeca-ne, is a one-dimensional coordination polymer. The asymmetric unit consists of a {Ba[Co(H 2L1)](ClO4)(H2O)}+ cationic fragment and a non-coordinating ClO4- anion. In the neutral [Co(H-2L1)] moiety, the cobalt ion is hexa-coordinated in a trigonal prismatic fashion by the surrounding N4O2 donor set. The Ba2+ ion is nine coordinated and exhibits a distorted [BaO9] monocapped square-anti-prismatic geometry, the six oxygen atoms coming from three distinct [Co(H-2L1)] moieties, while the remaining three vertices are occupied by the oxygen atoms of a bidentate perchlorate anion and a water mol-ecule. A barium-MU2-oxygen motif develops along the a axis, connecting symmetry-related dinuclear BaII-CoII cationic fragments in a wave-like chain, forming a one-dimensional metal coordination polymer. Non-coordinating ClO4- anions are located in the space between the chains. Weak C-H?O hydrogen bonds involving both coordinating and non coordinating perchlorate anions build the whole crystal architecture. To our knowledge, this is the first example of a macrocyclic ligand forming a BaII-based one-dimensional coordination polymer, containing CoII ions surrounded by a N4O2 donor set. PMID- 29250392 TI - Crystal structure and Hirshfeld surface analysis of (2E,2'E)-3,3'-(1,4-phenyl ene)bis-[1-(2,4-di-fluoro-phen-yl)prop-2-en-1-one]. AB - The asymmetric unit of the title compound, C24H14F4O2, comprises of one and a half mol-ecules; the half-mol-ecule is completed by crystallographic inversion symmetry. In the crystal, mol-ecules are linked into a three-dimensional network by C-H?F and C-H?O hydrogen bonds. Some of the C-H?F links are unusually short (< 2.20 A). Hirshfeld surface analyses (dnorm surfaces and two-dimensional fingerprint plots) for the title compound are presented and discussed. PMID- 29250393 TI - Crystal structure of diethyl 3,3'-[(2,4-di-chloro-phen-yl)methyl-idene]bis-(1H indole-2-carboxyl-ate). AB - In the title compound, C29H24Cl2N2O4, the mean planes of the two indole ring systems (r.m.s. deviations = 0.1249 and 0.0075 A) are approximately perpendic ular to one another, with a dihedral angle of 80.9 (5) degrees between them. The benzene ring is inclined to the mean planes of the two indole ring systems by 76.1 (3) and 78.3 (4) degrees . Weak intra-molecular C-H?pi inter-actions affect the mol-ecular conformation. In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into inversion dimers which are further linked into supra molecular chains by N-H?O hydrogen bonds and short Cl-Cl contacts. PMID- 29250394 TI - Crystal structure of N-[6-amino-5-(benzo[d]thia-zol-2-yl)-3-cyano-4-methyl sulfanyl-2-oxo-1,2-di-hydro-pyridin-1-yl]-4-methyl-benzene-sulfonamide di-methyl formamide monosolvate. AB - In the title compound, C21H17N5O3S3.C3H7NO, the toluene-sulfonamide ring and the combined ring system involving the pyridone and benzo-thia-zole rings subtend an inter-planar angle of 39.86 (4) degrees . The pyridone and benzo-thiazyl rings are linked by the intra-molecular hydrogen bond N-Hamine?Nthia-zole. The DMF O atom accepts two classical hydrogen bonds. The mol-ecules are linked by hydrogen bonds and an S?O contact to form layers parallel to the bc plane. PMID- 29250395 TI - Crystal structure of the formal 20 electron zirconocene penta-fulvene complex Cp2Zr(eta5,eta1-adamantyl-idene-penta-fulvene):toluene:n-hexane = 1:0.125:0.125. AB - The crystal structure of a solvated zirconocene penta-fulvene complex with a bulky adamantyl-idene substitution pattern, namely (eta5,eta1-adamantyl-idene penta-fulvene)bis-(eta5-cyclo-penta-dien-yl)zirconium(IV)-toluene-n-hexane (8/1/1), [Zr(C15H18)(C5H5)2].0.125C7H8.0.125C6H14, is reported. Reducing zirconocene dichloride with magnesium results in the formation of a low-valent zirconocene reagent that reacts readily with adamantyl-idene-penta-fulvene to give the aforementioned complex. Single crystal X-ray diffraction proves the dianion-like eta5:eta1 binding mode of the fulvene ligand to the central ZrIV atom. The asymmetric unit contains four independent mol-ecules of [eta5:eta1 adamantyl-idene-penta-fulvene]bis-[(eta5)-cyclo-penta-dien-yl]zirconium(IV), together with half a mol-ecule of toluene disordered with half a mol-ecule of n hexane (the solvent mol-ecules have no direct influence on the complex). In each of the four complex mol-ecules, the central ZrIV atom has a distorted tetra hedral coordination environment. The measured crystal consisted of two domains with a refined ratio of 0.77:0.23. PMID- 29250396 TI - Crystal structure of (1S,2R)-2-hy-droxy-1,2-di-phenyl-ethan-1-aminium (S)-2-aza niumyl-butane-dioate monohydrate. AB - The title diastereomeric salt, formed between 2-amino-1,2-di-phenyl-ethanol (ADE) and aspartic acid (ASP), C14H16NO+.C4H6NO4-.H2O, crystallizes as a monohydrate. The 1,2-di-phenyl-ethyl group in the cation has a cis conformation, and the aspartic acid anion is in the zwitterionic form. In the crystal, the ASP anions are linked via N-H?O hydrogen bonds to form a 21 helix along the b-axis direction. The helices are linked by the ADE cations via O-H?O and N-H?O hydrogen bonds, forming layers parallel to the bc plane. There are channels in the layers that are occupied by water mol-ecules, which link to both the anions and cations via Owater-H?O and N-H?Owater hydrogen bonds. There are also C-H?O and C-H?pi inter-actions present within the layers. PMID- 29250397 TI - Synthesis and crystal structure of a new pyridinium bromide salt: 4-methyl-1-(3 phen-oxy-prop-yl)pyridinium bromide. AB - In the cation of the title mol-ecular salt, C15H18NO+.Br-, the pyridinium and phenyl rings are inclined to one another by 11.80 (8) degrees . In the crystal, the Br- anion is linked to the cation by a C-H?Br hydrogen bond. The cations stack along the b-axis direction and are linked by further C-H?Br inter-actions, and offset pi-pi inter-actions [inter-centroid distances = 3.5733 (19) and 3.8457 (19) A], forming slabs parallel to the ab plane. The effects of the C-H?X- inter action on the NMR signals of the ortho- and meta-pyridinium protons in a series of related ionic liquids, viz. 4-methyl-1-(4-phen-oxy-but-yl)pyridin-1-ium salts, are reported and discussed. PMID- 29250398 TI - Crystal structures of (E)-1-{3-[(5-fluoro-2-hy-droxy-benzyl-idene)amino]-phen yl}ethanone and of a fourth polymorph of (E)-1-{3-[(2-hy-droxy-3-meth-oxy-benzyl idene)amino]-phen-yl}ethanone. AB - In the mol-ecules of both (E)-1-{3-[(5-fluoro-2-hy-droxy-benzyl-idene)amino]-phen yl}ethanone, C15H12FNO2, (I), and (E)-1-{3-[(2-hy-droxy-3-meth-oxy-benzyl idene)amino]-phen-yl}ethanone, C16H15NO3, (II), which crystallizes with Z' = 2 in space group Pca21, there are intra-molecular O-H?N hydrogen bonds, and the non-H atoms in each mol-ecule are essentially coplanar. In the crystal of (I), mol ecules are linked by a single C-H?O hydrogen bond to form a C(8) chain, whereas in the crystal of (II), mol-ecules are linked by three C-H?O hydrogen bonds to form sheets within which orthogonal C22(16) and C22(17) chains can be identified. Comparisons are made with some related structures. PMID- 29250399 TI - Crystal structures of two 1:2 dihydrate compounds of chloranilic acid with 2-carb oxy-pyridine and 2-carb-oxy-quinoline. AB - The crystal structure of the 1:2 dihydrate compound of chloranilic acid (systematic name: 2,5-di-chloro-3,6-dihy-droxy-1,4-benzo-quinone) with 2-carb-oxy pyridine (another common name: picolinic acid; systematic name: pyridine-2-carb oxy-lic acid), namely, 2C6H5.5NO20.5+.C6HCl2O4-.2H2O, (I), has been determined at 180 K, and the structure of the 1:2 dihydrate compound of chloranilic acid with 2 carb-oxy-quinoline (another common name: quinaldic acid; systematic name: quinoline-2-carb-oxy-lic acid), namely, 2C10H7NO2.C6H2Cl2O4.2H2O, (II), has been redetermined at 200 K. This determination presents a higher precision crystal structure than the previously published structure [Marfo-Owusu & Thompson (2014 ?). X-ray Struct. Anal. Online, 30, 55-56]. Compound (I) was analysed as a disordered structure over two states, viz. salt and co-crystal. The salt is bis (2-carb-oxy-pyridinium) chloranilate dihydrate, 2C6H6NO2+.C6Cl2O42-.2H2O, and the co-crystal is bis-(pyridinium-2-carboxyl-ate) chloranilic acid dihydrate, 2C6H5NO2.C6H2Cl2O4.2H2O, including zwitterionic 2-carb-oxy-pyridine. In both salt and co-crystal, the water mol-ecule links the chloranilic acid and 2-carb-oxy pyridine mol-ecules through O-H?O and N-H?O hydrogen bonds. The 2-carb-oxy pyridine mol-ecules are connected into a head-to-head inversion dimer by a short O-H?O hydrogen bond, in which the H atom is disordered over two positions. Compound (II) is a 1:2 dihydrate co-crystal of chloranilic acid and zwitterionic 2-carb-oxy-quinoline. The water mol-ecule links the chloranilic acid and 2-carb oxy-quinoline mol-ecules through O-H?O hydrogen bonds. The 2-carb-oxy-quinoline mol-ecules are connected into a head-to-tail inversion dimer by a pair of N-H?O hydrogen bonds. PMID- 29250400 TI - Crystal structures of 1-hy-droxy-4-prop-yloxy-9,10-anthra-quinone and its acetyl derivative. AB - 1-Hy-droxy-4-prop-yloxy-9,10-anthra-quinone, C17H14O4, (I), and its acetyl derivative, 4-acet-yloxy-4-prop-yloxy-9,10-anthra-quinone, C19H16O5, (II), were synthesized from the commercially available dye quinizarin. In both compounds, the anthra-quinone frameworks are close to planarity. There is a large difference in the conformation of the prop-yloxy group; the mol-ecule of (I) adopts a gauche conformation [O-C-C-C = -64.4 (2) degrees ], although the mol-ecule of (II) takes a trans-planar conformation (zigzag) [O-C-C-C = 176.1 (3) degrees ]. In the mol ecule of (I), there is an intra-molecular O-H?O hydrogen bond. In both crystals, the mol-ecules are linked by C-H ?O hydrogen bonds. A difference in the mol ecular arrangements of (I) and (II) is found along the stacking directions. PMID- 29250401 TI - Crystal structures of two (Z)-2-(4-oxo-1,3-thia-zolidin-2-yl-idene)acetamides. AB - The crystal structures of two (oxo-thia-zolidin-2-yl-idene)acetamides, namely (Z) 2-[2-(morpholin-4-yl)-2-oxo-ethyl-idene]thia-zolidin-4-one, C9H12N2O3S, (I), and (Z)-N-(4-meth-oxy-phen-yl)-2-(4-oxo-thia-zolidin-2-yl-idene)acetamide, C12H12N2O3S, (II), are described and compared with a related structure. The Z conformation was observed for both the compounds. In (I), the morpholin-4-yl ring has a chair conformation and its mean plane is inclined to the thia-zolidine ring mean plane by 37.12 (12) degrees . In (II), the benzene ring is inclined to the mean plane of the thia-zolidine ring by 20.34 (14) degrees . In the crystal of (I), mol-ecules are linked by N-H?O hydrogen bonds, forming C(6) chains along the b-axis direction. The edge-to-edge arrangement of the mol-ecules results in short C-H?O and C-H?S inter-actions, which consolidate the chain into a ribbon-like structure. In the crystal of (II), two N-H?O hydrogen bonds result in the formation of C(8) chains along the b-axis direction and C(6) chains along the c axis direction. The combination of these inter-actions leads to the formation of layers parallel to the bc plane, enclosing R44(28) rings involving four mol ecules. PMID- 29250402 TI - Crystal structure of BaMn2(AsO4)2 containing discrete [Mn4O18]28- units. AB - In our attempt to search for mixed alkaline-earth and transition metal arsenates, the title compound, barium dimanganese(II) bis-(arsenate), has been synthesized by employing a high-temperature RbCl flux. The crystal structure of BaMn2(AsO4)2 is made up of MnO6 octa-hedra and AsO4 tetra-hedra assembled by sharing corners and edges into infinite slabs with composition [Mn2(AsO4)2]2- that extend parallel to the ab plane. The barium cations reside between parallel slabs maintaining the inter-slab connectivity through coordination to eight oxygen anions. The layered anionic framework comprises weakly inter-acting [Mn4O18]28- tetra-meric units. In each tetra-mer, the manganese(II) cations are in a planar arrangement related by a center of inversion. Within the slabs, the tetra-meric units are separated from each other by 6.614 (2) A (Mn?Mn distances). The title compound has isostructural analogues amongst synthetic SrM2(XO4)2 compounds with M = Ni, Co, and X = As, P. PMID- 29250403 TI - Crystal structure of (1S,4S)-2,5-diazo-niabi-cyclo[2.2.1]heptane dibromide. AB - The cage of 2,5-di-aza-bicyclo-[2.2.1]heptane is frequently employed in synthetic chemistry as a rigid bicyclic counterpart of the piperazine ring. The 2,5-di azabicyclo-[2.2.1]heptane scaffold is incorporated into a variety of compounds having pharmacological and catalytic applications. The unsubstituted parent ring of the system, 2,5-di-aza-bicyclo-[2.2.1]heptane itself, has not been structurally characterized. We herein report on the mol-ecular structure of the parent ring in (1S,4S)-2,5-diazo-niabi-cyclo-[2.2.1]heptane dibromide, C5H12N22+.2Br-. The asymmetric unit contains two crystallographically independent cages of 2,5-di-aza-bicyclo-[2.2.1]heptane. Each cage is protonated at the two nitro-gen sites. The overall charge balance is maintained by four crystallographically independent bromide ions. In the crystal, the components of the structure are linked via a complex three-dimensional network of N-H?Br hydrogen bonds. PMID- 29250404 TI - Crystal structure of r-1,c-2-dibenzoyl-t-3,t-4-bis-(2-nitro-phen-yl)cyclo-butane. AB - The condensation reaction of aceto-phenone (1-phenyl-ethan-1-one) with 2-nitro benzaldehyde in the molten state yielded the expected chalcone, (E)-3-(2-nitro phen-yl)-1-phenyl-prop-2-en-1-one, and, unexpectedly, the title compound, C30H22N2O6, which results from the syn head-to-head [2 + 2] cyclo-addition of the chalcone. The mol-ecular structure of the dimer shows that the four benzene rings of the substituents are oriented in such a way that potential steric hindrance is minimized, whilst allowing some degree of inter-molecular pi-pi inter-actions for crystal stabilization. In the mol-ecule, one nitro group is disordered over two positions, with occupancies for each part of 0.876 (7) and 0.127 (7). PMID- 29250405 TI - A one-dimensional HgII coordination polymer based on bis-(pyridin-3-ylmeth yl)sulfane. AB - The reaction of mercury(II) chloride with bis-(pyridin-3-ylmeth-yl)sulfane (L, C12H12N2S) in methanol afforded the title crystalline coordination polymer catena poly[[di-chlorido-mercury(II)]-MU-bis-(pyridin-3-ylmeth-yl)sulfane-kappa2N:N'], [HgCl2L] n . The asymmetric unit consists of one HgII cation, one L ligand and two chloride anions. Each HgII ion is coordinated by two pyridine N atoms from separate L ligands and two chloride anions. The metal adopts a highly distorted tetra-hedral geometry, with bond angles about the central atom in the range 97.69 (12)-153.86 (7) degrees . Each L ligand bridges two HgII ions, forming an infinite -(Hg-L) n - zigzag chain along the b axis, with an Hg?Hg separation of 10.3997 (8) A. In the crystal, adjacent chains are connected by inter-molecular C H?Cl hydrogen bonds, together with Hg-Cl?pi inter-actions [chloride-to-centroid distance = 3.902 (3) A], that form between a chloride anion and the one of the pyridine rings of L, generating a two-dimensional layer extending parallel to (101). These layers are further linked by inter-molecular C-H?pi hydrogen bonds, forming a three-dimensional supra-molecular network. PMID- 29250406 TI - Crystal structure of aqua-(1H-pyrazole-kappaN2)(pyridine-2,6-di-carboxyl-ato kappa3O2,N,O6)copper(II) dihydrate. AB - In the title compound, [Cu(C7H3NO4)(C3H4N2)(H2O)].2H2O, the CuII atom is coordinated by three O atoms and two N atoms, provided by a tridentate pyridine 2,6-di-carboxyl-ate (pdc), one pyrazole and one water ligand, forming a slightly distorted square-pyramidal geometry [range of O-Cu-O and O-Cu-N bond angles = 79.55 (8)-166.22 (10) degrees ]. The water mol-ecule is positioned at the apical position. In the crystal, the complex mol-ecule and the two crystallographically independent non-coordinating water mol-ecules are linked into a supra-molecular layer structure parallel to the ab plane via O-H?O and N-H?O hydrogen bonds. PMID- 29250407 TI - Crystal structures of salen-type ligands 2-[(1E)-({1-(3-chloro-phen-yl)-2-[(E)-(2 hy-droxy-benzyl-idene)amino]-prop-yl}imino)-meth-yl]phenol and 2-[(1E)-({1-(4 chloro-phen-yl)-2-[(E)-(2-hy-droxy-benzyl-idene)amino]-prop-yl}imino)-meth yl]phenol. AB - The title compounds, C23H21ClN2O2, differ from each other only by the position of the Cl atom on the corresponding benzene ring: meta relative to the central sp3 C atom for (I) and para for (II). In (I), the hy-droxy-phenyl rings are almost parallel, the dihedral angle between the mean planes being 9.2 (2) degrees , but in (II), the relative position of the ring is different, characterized by a dihedral angle of 48.5 (1) degrees . Compound (I) features intra-molecular O-H?N and inter-molecular C-H?O hydrogen bonds, while in (II), intra-molecular O-H?N, C H?N hydrogen bonds and weak inter-molecular C-H?pi inter-actions are observed. Compound (I) was refined as an inversion twin. PMID- 29250408 TI - Crystal structure of a zigzag CoII coordination polymer: catena-poly[[di-chlorido bis-(methanol-kappaO)cobalt(II)]-MU-bis-(pyridin-3-ylmeth-yl)sulfane-kappa2N:N']. AB - Reaction of bis-(pyridin-3-ylmeth-yl)sulfane (L) with cobalt(II) chloride in methanol led to the formation of the title coordination polymer, [CoCl2(C12H12N2S)(CH3OH)2] n , in which the CoII cation lies on a crystallographic inversion centre and the S atom of the L ligand lies on a twofold rotation axis. Each CoII ion is coordinated by two pyridine N atoms from two bridging L ligands, two O atoms from methanol mol-ecules and two chloride anions, all inversion-related. The complex unit has an elongated octa-hedral geometry, in which N2O2 donor atoms occupy the equatorial positions and two chloride anions occupy the axial positions. Each L ligand links two CoII ions, forming an infinite zigzag chain propagating along the c-axis direction and further stabilized by O-H?Cl hydrogen bonds between the methanol mol-ecules and the chloride anions. Adjacent chains in the structure are connected by inter molecular C-H?Cl hydrogen bonds, resulting in the formation of a three dimensional supra-molecular architecture. PMID- 29250409 TI - Stoichiometric and polymorphic salt of imidazolium picrate monohydrate. AB - The asymmetric unit of the title co-crystal salt, 1H-imidazol-3-ium 2,4,6-tri nitro-phenolate monohydrate, C4H7N2+.C6H2N3O7-.H2O, contains one imidazolium cation, one picrate anion and one solvent water mol-ecule of crystallization. The phenolic proton has been transferred to an imidazole N atom. In the crystal, the components are linked by N-H?O and O-H?O hydrogen bonds into a three-dimensional network which is further consolidated by weak C-H?O hydrogen bonds. In addition, pi-pi stacking inter-actions occur between pairs of imidazolium cations and picrate anions. If only the classical N-H?O and O-H?O hydrogen bonds are considered, the component ions are linked into a three-dimensional threefold inter-penetrating network of the topological type utp [or (10,3)-d]. Hirshfeld surface analysis indicates the crystal structure is mainly stabilized by H?.O contacts of the hydrogen bonds. PMID- 29250410 TI - A new monoclinic polymorph of N-(3-methyl-phen-yl)eth-oxy-carbo-thio-amide: crystal structure and Hirshfeld surface analysis. AB - The title compound, C10H13NOS, is a second monoclinic polymorph (space group P21/c, Z' = 2) of the previously reported C2/c (Z = 1) polymorph [Tadbuppa & Tiekink (2005 ?). Z. Kristallogr. New Cryst. Struct. 220, 395-396]. Two independent mol-ecules comprise the asymmetric unit of the new polymorph and each of these exists as a thioamide-thione tautomer. In each molecule, the central CNOS chromophore is strictly planar [r.m.s. deviations = 0.0003 and 0.0015 A] and forms dihedral angles of 6.17 (5) and 20.78 (5) degrees with the N-bound 3-tolyl rings, thereby representing the major difference between the mol-ecules. The thione-S and thio-amide-N-H atoms are syn in each mol-ecule and this facilitates the formation of an eight-membered thio-amide {?SCNH}2 synthon between them; the dimeric aggregates are consolidated by pairwise 3-tolyl-C-H?S inter-actions. In the extended structure, supra-molecular layers parallel to (102) are formed via a combination of 3-tolyl-C-H?pi(3-tol-yl) and weak pi-pi inter-actions [inter centroid distance between 3-tolyl rings = 3.8535 (12) A]. An analysis of the Hirshfeld surfaces calculated for both polymorphs reveals the near equivalence of one of the independent mol-ecules of the P21/c form to that in the C2/c form. PMID- 29250411 TI - Crystal structure of poly[[MU3-(S)-2-amino-3-hydroxy-propano-ato]-cis-di-MU chlorido-caesium-palladium(II)]. AB - The structure of the title compound, [CsPd(C3H6NO3)Cl2] n , previously shown to have anti-cancer activity in rodent test systems and recently found to have anti fungal activity, has been determined. The Pd centre is in a square-planar coordination environment with two chlorine atoms in cis positions and the remaining two coordination sites being coordinated by N and O atoms from deprotonated l-serine. Each of the Cs cations shows ninefold coordination with six chlorine and three O atoms resulting in a coordination environment that is similar to the well known Cs2SO4 structure. X-ray crystal structures of only three di-chlorido-palladium(II)-amino acid complexes have been determined so far and the present paper describes one of those. PMID- 29250412 TI - Deca-chloro-cyclo-penta-silanes coordinated by pairs of chloride anions, with different cations, but the same solvent mol-ecules. AB - We have determined the crystal structures of two deca-chloro-cyclo-penta-silanes, namely bis-(tetra-n-butyl-ammonium) dichloride deca-chloro-cyclo-penta-silane di chloro-methane disolvate, 2C16H36N+.2Cl-.Si5Cl10.2CH2Cl2, (I), and bis-(tetra ethyl-ammonium) dichloride deca-chloro-cyclo-penta-silane di-chloro-methane disolvate, 2C8H20N+.2Cl-.Si5Cl10.2CH2Cl2, (II), both of which crystallize with discrete cations, anions, and solvent mol-ecules. In (I), the complete deca chloro-cyclo-penta-silane ring is generated by a crystallographic twofold rotation axis. In (II), one cation is located on a general position and the other two are disordered about centres of inversion. These are the first structures featuring the structural motif of a five-membered cyclo-penta-silane ring coordinated from both sides by a chloride ion. The extended structures of (I) and (II) feature numerous C-H?Cl inter-actions. In (II), the N atoms are located on centres of inversion and as a result, the ethyl-ene chains are disordered over equally occupied orientations. PMID- 29250413 TI - Buthalital and methitural - 5,5-substituted derivatives of 2-thio-barbituric acid forming the same type of hydrogen-bonded chain. AB - The mol-ecule of buthalital, (I) [systematic name: 5-(2-methyl-prop-yl)-5-(prop-2 en-1-yl)-2-sulfanyl-idene-1,3-diazinane-4,6-dione], C11H16N2O2S, exhibits a planar pyrimidine ring, whereas the pyrimidine ring of methitural, (II) [systematic name: 5-(1-methyl-but-yl)-5-[2-(methyl-sulfan-yl)eth-yl]-2-sulfanyl idene-1,3-diazinane-4,6-dione], C12H20N2O2S2, is slightly puckered. (I) and (II) contain the same hydrogen-bonded chain structure in which each mol-ecule is connected, via four N-H?O=C hydrogen bonds, to two other mol-ecules, resulting in a hydrogen-bonded chain displaying a sequence of R22(8) rings. The same type of N H?O=C hydrogen-bonded chain has previously been found in several 5,5 disubstituted derivatives of barbituric acid which are chemically closely related to (I) and (II). PMID- 29250414 TI - Crystal structures of 2,6-di-bromo-4-methyl-benzo-nitrile and 2,6-di-bromo-4 methyl-phenyl isocyanide. AB - In the title crystals, C8H5Br2N, which are isomorphous, the steric bulk of the methyl group causes neighboring mol-ecules to become mutually inclined. This prevents the formation of planar or nearly planar sheets, which were observed in the tri-chloro and tri-bromo analogs. Instead of CN/NC?Br contacts, tetra-meric Br?Br contacts are observed. These contacts form tetra-gonally puckered sheets parallel to (001). The CN/NC and methyl groups are grouped at the peaks and troughs. Both mol-ecules lie across crystallographic mirror planes; thus, the methyl H atoms are disordered over two sets of sites with equal occupancy. The title nitrile is a redetermination. The refinement converged at R[F2 > 2sigma(F2)] = 0.020, whereas the original determination [Gleason & Britton, (1976 ?). Cryst. Struct. Commun.5, 229-232] had R = 0.112. PMID- 29250415 TI - Crystal structure of cis-1-phenyl-8-(pyridin-2-ylmeth-yl)dibenzo[1,2-c:2,1-h] 2,14-dioxa-8-aza-1-borabi-cyclo-[4.4.0]deca-3,8-diene. AB - The title compound, C26H23BN2O2, was obtained as by product during synthetic attempts of a complexation reaction between the tripodal ligand H2L [N,N-bis-(2 hy-droxy-benz-yl)(pyridin-2-yl)methyl-amine] and manganese(III) acetate in the presence of NaBPh4. The isolated B-phenyl dioxaza-borocine contains an N->B dative bond with a cis conformation. In the crystal, C-H?O hydrogen bonds define chains parallel to the b-axis direction. A comparative analysis with other structurally related derivatives is also included, together with a rationalization of the unexpected production of this zwitterionic heterocycle. PMID- 29250416 TI - Formation and structural characterization of a europium(II) mono(scorpionate) complex and a sterically crowded pyraza-bole. AB - The reaction of EuI2(THF)2 with potassium hydro-tris-(3,5-diiso-propyl-pyrazol yl)borate (K[HB(3,5- iPr2pz)3] (= KTp iPr2, pz = pyrazol-yl) in a molar ratio of 1:1.5 resulted in extensive ligand fragmentation and formation of the europium(II) mono(scorpionate) complex bis-(3,5-diisopropyl-1H-pyrazole)[hydro tris-(3,5-diiso-propyl-pyrazol-yl)borato]iodido-europium(II), [Eu(C27H46BN6)I(C9H16N2)2] or (Tp iPr2)(3,5- iPr2pzH)2EuIII, 1, in high yield (78%). As a typical by-product, small amounts of the sterically crowded pyraza bole derivative trans-4,8-bis-(3,5-diiso-propyl-pyrazol-1-yl)-1,3,5,7-tetra-iso propyl-pyraza-bole, C36H62B2H8 or trans-{(3,5- iPr2pz)HB(MU-3,5- iPr2pz)}2, 2, were formed. Both title compounds have been structurally characterized through single-crystal X-ray diffraction. In 1, two isopropyl groups are each disordered over two orientations with occupancy ratios of 0.574 (10):0.426 (10) and 0.719 (16):0.281 (16). In 2, one isopropyl group is similarly disordered, occupancy ratio 0.649 (9):0.351 (9). PMID- 29250417 TI - Crystal structure of poly[[di-MU3-acetato-tetra-aqua-bis-(MU2-cyclo-hexane-1,4-di carboxyl-ato)dilanth-an-um(III)] dihydrate]. AB - The title compound, {[La2(CH3COO)2(C8H10O4)2(H2O)4].2H2O} n or [La2(ac)2(e,a-cis 1,4-chdc)2(H2O)4].2H2O, where ac is acetate and 1,4-chdc is cyclo-hexane-1,4-di carboxyl-ate anion, is a binuclear lanthanum(III) complex. Each metal atom is deca-coordinated by four O atoms from two distinct 1,4-chdc2- ligands, four O atoms from three acetate groups and two O atoms from coordinated water mol-ecules to form a distorted bicapped square-anti-prismatic geometry. Two non-coordinated water mol-ecules are also present in the formula unit. The most remarkable feature of this compound is that it possesses a only cis conformation for cyclo hexane-1,4-di-carb-oxy-lic acid, although the raw material consists of a mixture of cis and trans isomers. The MU3-eta2:eta2 coordination mode of the bridging acetate group and the flexible di-carboxyl-ate fragments of 1,4-chdc2- results in the formation of infinite two-dimensional lanthanide-carboxyl-ate layers within the crystal structure. The directionality of strong inter-molecular O-H?O and weak C-H?O inter-actions provides robustness to the layers, which leads to the construction of a three-dimensional supra-molecular network. The crystal studied was refined as a two-component twin. PMID- 29250418 TI - Crystal structure of 3,6,6-trimethyl-4-oxo-1-(pyridin-2-yl)-4,5,6,7-tetra-hydro 1H-indazol-7-aminium chloride and its monohydrate. AB - The title compounds, C15H19N4O+.Cl- and C15H19N4O+.Cl-.H2O, obtained in attempts to synthesize metal complexes using tetra-hydro-indazole as a ligand, were characterized by NMR, IR and X-ray diffraction techniques. The partially saturated ring in the tetra-hydro-indazole core adopts a sofa conformation. An intra-molecular N-H?N hydrogen bond formed by the protonated amino group and the N atom of the pyridyl substituent is found in the first structure. In the hydro chloride, the organic moieties are linked by two N-H?Cl- hydrogen bonds, forming a C(4) graph-set. In the hydrate crystal, a Cl- anion and a water mol-ecule assemble the moieties into infinite bands showing hydrogen-bond patterns with graph sets C(6), R64(12) and R42(8). Organic moieties form pi-pi stacked supra molecular structures running along the b axis in both structures. PMID- 29250419 TI - Crystal structure, thermal and fluorescence properties of 2,2':6',2''-terpyridine 1,1',1''-triium tetra-chlorido-nickelate(II) chloride. AB - The title compound, (C15H14N3)[NiCl4]Cl, comprises an NiII cation tetra-hedrally coordinated by four chloride anions, a non-coordinating chloride anion and an essentially planar terpyridinium trication (tpyH33+), in which the central pyridinium ring forms dihedral angles of 5.7 (2) and 6.0 (2) degrees with the peripheral pyridinium rings. Three inter-species N-H?Cl hydrogen bonds are formed with the Cl- anion, which also forms a link between the (tpyH33+) cations through an aromatic C-H?Cl inter-action, forming a zigzag chain extending along the 21 (b) screw axis. Two of the anionic Cl atoms of the [NiCl4]2- anions form Ni-Cl?pi inter-actions with separate pyridinium rings [Ni?Cg = 3.669 (3) and 3.916 (4) A]. In the crystal, successive undulating inorganic and organic layers are formed, extending across the (100) plane. Thermogravimetric and differential thermal analysis (TGA/DTA) indicate that the compound starts to decompose at 313 K and may be a candidate for use as a blue-light luminescent material. PMID- 29250420 TI - Crystal structure of a di-aryl carbonate: 1,3-phenyl-ene bis-(phenyl carbonate). AB - The whole mol-ecule of the title compound, C20H14O6, is generated by mirror symmetry, the mirror bis-ecting the central benzene ring. The carbonate groups adopt an s-cis-s-cis conformation, with torsion angles of 58.7 (2) and 116.32 (15) degrees . The crystal structure of 1,3-phenyl-ene bis-(phenyl carbonate) contains no strong hydrogen bonds, though weak C-H?O and offset pi-pi inter actions are observed, forming layers parallel to the ac plane. PMID- 29250421 TI - Crystal structures of three ortho-substituted N-acyl-hydrazone derivatives. AB - To explore the effect of the nature of substitutions on the structural parameters and hydrogen-bond inter-actions in N-acyl-hydrazone derivatives, the crystal structures of three ortho-substituted N-acyl-hydrazone derivatives, namely (E)-N {2-[2-(2-chloro-benzyl-idene)hydrazin-yl]-2-oxoeth-yl}-4-methyl-benzene-sulfon amide, C16H16ClN3O3S (I), (E)-N-{2-[2-(2-methyl-benzyl-idene)hydrazin-yl]-2 oxoeth-yl}-4-methyl-benzene-sulfonamide, C17H19N3O3S (II), and (E)-N-{2-[2-(2 nitro-benzyl-idene)hydrazin-yl]-2-oxoeth-yl}-4-methyl-benzene-sulfonamide, C16H16N4O5S (III), have been determined. The structures of the three compounds display similar mol-ecular conformations and hydrogen-bond patterns. The hydrazone part of the mol-ecule, C-C-N-N=C, is almost planar in all the compounds, with the C-C-N-N and C-N-N=C torsion angles being 179.5 (3) and 177.1 (3) degrees , respectively, in (I), -179.4 (2) and -177.1 (3) degrees in (II) and -179.7 (2) and 173.4 (2) degrees in (III). The two phenyl rings on either side of the chain are approximately parallel to each other. In the crystal, the mol-ecules are linked to each other via N-H?O hydrogen bonds, forming ribbons with R22(8) and R22(10) ring motifs. The introduction of electron-withdrawing groups (by a chloro or nitro group) to produce compounds (I) or (III) results in C-H?O hydrogen-bonding inter-actions involving the sulfonyl O atoms of adjacent ribbons, forming layers parallel to the ab plane in (I) or a three-dimensional network in (III). In (III), one O atom of the nitro group is disordered over two orientations with refined occupancy ratio of 0.836 (12):0.164 (12). PMID- 29250422 TI - Crystal structure of mer-tris-{2,6-di-fluoro-3-[5-(2-fluoro-phen-yl)pyridin-2-yl kappaN]pyridin-4-yl-kappaC4}iridium(III) di-chloro-methane hemisolvate n-hexane hemisolvate. AB - The asymmetric unit of the title compound, [Ir(C17H11F2N2)3].0.5CH3(CH2)4CH3.0.5CH2Cl2, comprises one IrIII atom, three 2,6 di-fluoro-3-[5-(2-fluoro-phen-yl)pyridin-2-yl]pyridin-4-yl ligands and half each of an n-hexane and a di-chloro-methane solvent mol-ecule located about crystallographic inversion centres. The IrIII atom displays a distorted octa hedral coordination geometry, having three C,N-chelating 2,6-di-fluoro-3-[5-(2 fluoro-phen-yl)pyridin-2-yl]pyridin-4-yl ligands arranged in a meridional manner. The IrIII ion lies almost in the equatorial plane [deviation = 0.0069 (15) A]. The average distance [2.041 (3) A] of Ir-C bonds is slightly shorter than that [2.076 (3) A] of Ir-N bonds. A variety of intra- and inter-molecular C-H?F and C H?pi hydrogen bonds, as well as inter-molecular C-F?pi inter-actions, contribute to the stabilization of the mol-ecular and crystal structures, and result in the formation of a two-dimensional network parallel to the ab plane. No inter-actions between n-hexane solvent mol-ecules and the other components in the title compound are observed. PMID- 29250423 TI - Crystal structure of diethyl 3,3'-[(4-nitro-phen-yl)methyl-ene]bis-(1H-indole-2 carboxyl-ate). AB - In the title compound, C29H25N3O6, the mean planes of the two indole ring systems (r.m.s. deviations = 0.0115 and 0.0082 A) are approximately perpendic-ular to one another, making a dihedral angle of 89.7 (5) degrees ; the benzene ring is twisted with respect to the two indole ring systems by 52.6 (4) and 88.2 (3) degrees . In the crystal, pairs of N-H?O hydrogen bonds link the mol-ecules into the inversion dimers, which are further linked into supra-molecular chains along the b-axis direction. Weak C-H?O hydrogen bonds and C-H?pi inter-actions are also observed in the crystal. PMID- 29250424 TI - Crystal structure of bis-{MU2-2,2'-[(4,10-dimethyl-1,4,7,10-tetra-aza-cyclo dodecane-1,7-di-yl)bis(meth-yl-ene)]bis-(4-oxo-4H-pyran-3-olato)}dicobalt-calcium bis-(perchlorate) 1.36-hydrate. AB - The title compound, [CaCo2(C22H30N4O6)2](ClO4)2.1.36H2O or {Ca[Co(H 2L1)]2}.2ClO4.1.36H2O {where L1 is 4,10-bis-[(3-hy-droxy-4-pyron-2-yl)meth-yl] 1,7-dimethyl-1,4,7,10-tetra-aza-cyclo-dodecane}, is a trinuclear complex whose asymmetric unit comprises a quarter of the {Ca[Co(H-2L1)]2}2+ trinuclear complex, half of a perchlorate ion and 0.34-water mol-ecules. In the neutral [Co(H-2L1)] moiety, the cobalt ion is hexa-coordinated in a trigonal-prismatic fashion by the surrounding N4O2 donor set. A Ca2+ cation holds together two neutral [Co(H-2L1)] moieties and is octa-coordinated in a distorted trigonal-dodeca-hedral fashion by the surrounding O atoms belonging to the deprotonated oxide and carbonyl groups of two [Co(H-2L1)] units. The coordination of the CoII cation preorganizes L1 and an electron-rich area forms, which is able to host hard metal ions. The comparison between the present structure and the previously published ones suggests a high versatility of this ligand; indeed, hard metal ions with different nature and dimensions lead to complexes having different stoichiometry (mono- and dinuclear monomers and trinuclear dimers) or even a polymeric structure. The heterotrinuclear CoII-CaII-CoII complexes are connected in three dimensions via weak C-H?O hydrogen bonds, which are also responsible for the inter-actions with the perchlorate anions and the lattice water mol-ecules. The perchlorate anion is disordered about a twofold rotation axis and was refined giving the two positions a fixed occupancy factor of 0.5. The crystal studied was refined as a two-component inversion twin [BASF parameter = 0.14 (4)]. PMID- 29250425 TI - Crystal structure and Hirshfeld surface analysis of hexa-kis-(MU-benzoato kappa2O:O')bis-(pyridine-3-carbo-nitrile-kappaN1)trizinc(II). AB - The asymmetric unit of the title complex, [Zn3(C7H5O2)6(C6H4N2)2], contains one half of the complex mol-ecule, i.e. one and a half ZnII cations, three benzoate (Bnz) and one pyridine-3-carbo-nitrile (Cpy) mol-ecule; the Bnz anions act as bidentate ligands through the carboxyl-ate O atoms, while the Cpy ligand acts as a monodentate N(pyridine)-bonding ligand. The complete centrosymmetric trinuclear complex thus comprises a linear array of three ZnII cations. The central ZnII cation shows an octa-hedral coordination and is bridged to each of the terminal ZnII cations by three Bnz anions. By additional coordination of the CPy ligand, the terminal ZnII cations adopt a trigonal-pyramidal coordination environment. In the crystal, the Bnz anions link to the Cpy N atoms via weak C-H?N hydrogen bonds, forming a two-dimensional network. C-H?pi and pi-pi inter-actions [between the benzene and pyridine rings of adjacent mol-ecules with an inter-centroid distance of 3.850 (4) A] help to consolidate a three-dimensional architecture. The Hirshfeld surface analysis confirms the role of H-atom contacts in establishing the packing. PMID- 29250426 TI - Crystal structure of methyl 2-[5-(2-hy-droxy-phen-yl)-2H-tetra-zol-2-yl]acetate. AB - The title compound, C10H10N4O3, was synthesized by the esterification of hy-droxy phenyl tetra-zole. There is an intra-molecular O-H?N hydrogen bond present involving the hy-droxy group and the tetra-zole ring. The tetra-zole ring is inclined to the phenol ring by 2.85 (13) degrees , while the methyl acetate group is almost normal to the tetra-zole ring, making a dihedral angle of 82.61 (14) degrees . In the crystal, mol-ecules are linked by pairs of C-H?O hydrogen bonds, forming inversion dimers. Within the dimers, the phenol rings are linked by offset pi-pi inter-actions [inter-centroid distance = 3.759 (2) A]. There are no further significant inter-molecular inter-actions present in the crystal. The hy droxy group is disordered about positions 2 and 6 on the benzene ring, with a refined occupancy ratio of 0.531 (5):0.469 (5). PMID- 29250427 TI - Crystal structure of 3-(4,4-di-fluoro-5,7-dimethyl-4-bora-3a,4a-di-aza-s-indacen 3-yl)propanoic acid. AB - The crystal structure of the title compound, C14H15BF2N2O2, which comprises a boron-dipyrromethene (BODIPY) backbone and a propionic acid group, has been determined at 100 K. The BODIPY fused-ring system is nearly planar, with a maximum deviation from the mean plane of 0.032 (2) A. In the crystal, pairs of O H?O hydrogen bonds connect the mol-ecules, forming inversion dimers. The dimers are linked via C-H?O hydrogen bonds, forming a tape along the a axis. The tapes are stacked along the c axis through C-H?F hydrogen bonds and pi-pi inter actions. PMID- 29250428 TI - Crystal structure of catena-poly[[[tetra-aqua-iron(II)]-trans-MU-1,2-bis-(pyridin 4-yl)ethene-kappa2N:N'] bis-(p-toluene-sulfonate) methanol disolvate]. AB - In the title polymeric complex, {[Fe(C12H10N2)2(H2O)4](CH3C6H4SO3)2.2CH3OH} n , the FeII cation, located on an inversion centre, is coordinated by four water mol ecules in the equatorial positions and two 1,2-bis-(pyridin-4-yl)ethene mol ecules in the axial positions. This results in a distorted octa-hedral geometry for the [N2O4] coordination polyhedron. The 1,2-bis-(pyridin-4-yl)ethene mol ecules bridge the FeII cations, forming polymeric chains running along the a-axis direction. Stabilization of the crystal structure is provided by O-H?O hydrogen bonds; these are formed by coordinated water mol-ecules as donors towards the O atoms of the methanol mol-ecules and tosyl-ate anions as acceptors of protons, leading to the formation of a three-dimensional supra-molecular network. Weak C H?O hydrogen bonds are also observed in the crystal. PMID- 29250429 TI - On the effective depth of viral sequence data. AB - Genome sequence data are of great value in describing evolutionary processes in viral populations. However, in such studies, the extent to which data accurately describes the viral population is a matter of importance. Multiple factors may influence the accuracy of a dataset, including the quantity and nature of the sample collected, and the subsequent steps in viral processing. To investigate this phenomenon, we sequenced replica datasets spanning a range of viruses, and in which the point at which samples were split was different in each case, from a dataset in which independent samples were collected from a single patient to another in which all processing steps up to sequencing were applied to a single sample before splitting the sample and sequencing each replicate. We conclude that neither a high read depth nor a high template number in a sample guarantee the precision of a dataset. Measures of consistency calculated from within a single biological sample may also be insufficient; distortion of the composition of a population by the experimental procedure or genuine within-host diversity between samples may each affect the results. Where it is possible, data from replicate samples should be collected to validate the consistency of short-read sequence data. PMID- 29250431 TI - Virulence evolution of a sterilizing plant virus: Tuning multiplication and resource exploitation. AB - Virulence evolution may have far-reaching consequences for virus epidemiology and emergence, and virologists have devoted increasing effort to understand the modulators of this process. However, still little is known on the mechanisms and determinants of virulence evolution in sterilizing viruses that, as they prevent host reproduction, may have devastating effects on host populations. Theory predicts that sterilizing parasites, including viruses, would evolve towards lower virulence and absolute host sterilization to optimize the exploitation of host resources and maximize fitness. However, this hypothesis has seldom been analyzed experimentally. We investigated the evolution of virulence of the sterilizing plant virus Turnip mosaic virus (TuMV) in its natural host Arabidopsis thaliana by serial passage experiments. After passaging, we quantified virus accumulation and infectivity, the effect of infection on plant growth and development, and virulence of the ancestral and passaged viral genotypes in A. thaliana. Results indicated that serial passaging increased the proportion of infected plants showing absolute sterility, reduced TuMV virulence, and increased virus multiplication and infectivity. Genomic comparison of the ancestral and passaged TuMV genotypes identified significant mutation clustering in the P1, P3, and 6K2 proteins, suggesting a role of these viral proteins in the observed phenotypic changes. Our results support theoretical predictions on the evolution of virulence of sterilizing parasites and contribute to better understand the phenotypic and genetic changes associated with this process. PMID- 29250430 TI - Divergent HIV-1 strains (CRF92_C2U and CRF93_cpx) co-circulating in the Democratic Republic of the Congo: Phylogenetic insights on the early evolutionary history of subtype C. AB - Molecular epidemiological studies revealed that the epicenter of the HIV pandemic was Kinshasa, the capital city of the Democratic Republic of the Congo (DRC) in Central Africa. All known subtypes and numerous complex recombinant strains co circulate in the DRC. Moreover, high intra-subtype diversity has been also documented. During two previous surveys on HIV-1 antiretroviral drug resistance in the DRC, we identified two divergent subtype C lineages in the protease and partial reverse transcriptase gene regions. We sequenced eight near full-length genomes and classified them using bootscanning and likelihood-based phylogenetic analyses. Four strains are more closely related to subtype C although within the range of inter sub-subtype distances. However, these strains also have small unclassified fragments and thus were named CRF92_C2U. Another strain is a unique recombinant of CRF92_C2U with an additional small unclassified fragment and a small divergent subtype A fragment. The three remaining strains represent a complex mosaic named CRF93_cpx. CRF93_cpx have two fragments of divergent subtype C sequences, which are not conventional subtype C nor the above described C2, and multiple divergent subtype A-like fragments. We then inferred the time-scaled evolutionary history of subtype C following a Bayesian approach and a partitioned analysis using major genomic regions. CRF92_C2U and CRF93_cpx had the most recent common ancestor with conventional subtype C around 1932 and 1928, respectively. A Bayesian demographic reconstruction corroborated that the subtype C transition to a faster phase of exponential growth occurred during the 1950s. Our analysis showed considerable differences between the newly discovered early-divergent strains and the conventional subtype C and therefore suggested that this virus has been diverging in humans for several decades before the HIV/M diversity boom in the 1950s. PMID- 29250432 TI - Selection on non-antigenic gene segments of seasonal influenza A virus and its impact on adaptive evolution. AB - Most studies on seasonal influenza A/H3N2 virus adaptation have focused on the main antigenic gene, hemagglutinin. However, there is increasing evidence that the genome-wide genetic background of novel antigenic variants can influence these variants' emergence probabilities and impact their patterns of dominance in the population. This suggests that non-antigenic genes may be important in shaping the viral evolutionary dynamics. To better understand the role of selection on non-antigenic genes in the adaptive evolution of seasonal influenza viruses, we have developed a simple population genetic model that considers a virus with one antigenic and one non-antigenic gene segment. By simulating this model under different regimes of selection and reassortment, we find that the empirical patterns of lineage turnover for the antigenic and non-antigenic gene segments are best captured when there is both limited viral coinfection and selection operating on both gene segments. In contrast, under a scenario of only neutral evolution in the non-antigenic gene segment, we see persistence of multiple lineages for long periods of time in that segment, which is not compatible with observed molecular evolutionary patterns. Further, we find that reassortment, occurring in coinfected individuals, can increase the speed of viral adaptive evolution by primarily reducing selective interference and genetic linkage effects. Together, these findings suggest that, for influenza, with six internal or non-antigenic gene segments, the evolutionary dynamics of novel antigenic variants are likely to be influenced by the genome-wide genetic background as a result of linked selection among both beneficial and deleterious mutations. PMID- 29250434 TI - The Relaxation Wall: Experimental Limits to Improving MPI Spatial Resolution by Increasing Nanoparticle Core size. AB - Magnetic Particle Imaging (MPI) is a promising new tracer modality with zero attenuation in tissue, high contrast and sensitivity, and an excellent safety profile. However, the spatial resolution of MPI is currently around 1 mm in small animal scanners. Especially considering tradeoffs when scaling up MPI scanning systems to human size, this resolution needs to be improved for clinical applications such as angiography and brain perfusion. One method to improve spatial resolution is to increase the magnetic core size of the superparamagnetic nanoparticle tracers. The Langevin model of superparamagnetism predicts a cubic improvement of spatial resolution with magnetic core diameter. However, prior work has shown that the finite temporal response, or magnetic relaxation, of the tracer increases with magnetic core diameter and eventually leads to blurring in the MPI image. Here we perform the first wide ranging study of 5 core sizes between 18-32 nm with experimental quantification of the spatial resolution of each. Our results show that increasing magnetic relaxation with core size eventually opposes the expected Langevin behavior, causing spatial resolution to stop improving after 25 nm. Different MPI excitation strategies were experimentally investigated to mitigate the effect of magnetic relaxation. The results show that magnetic relaxation could not be fully mitigated for the larger core sizes and the cubic resolution improvement predicted by the Langevin was not achieved. This suggests that magnetic relaxation is a significant and unsolved barrier to achieving the high spatial resolutions predicted by the Langevin model for large core size SPIOs. PMID- 29250433 TI - Insights into origin and evolution of alpha-proteobacterial gene transfer agents. AB - Several bacterial and archaeal lineages produce nanostructures that morphologically resemble small tailed viruses, but, unlike most viruses, contain apparently random pieces of the host genome. Since these elements can deliver the packaged DNA to other cells, they were dubbed gene transfer agents (GTAs). Because many genes involved in GTA production have viral homologs, it has been hypothesized that the GTA ancestor was a virus. Whether GTAs represent an atypical virus, a defective virus, or a virus co-opted by the prokaryotes for some function, remains to be elucidated. To evaluate these possibilities, we examined the distribution and evolutionary histories of genes that encode a GTA in the alpha-proteobacterium Rhodobacter capsulatus (RcGTA). We report that although homologs of many individual RcGTA genes are abundant across bacteria and their viruses, RcGTA-like genomes are mainly found in one subclade of alpha proteobacteria. When compared with the viral homologs, genes of the RcGTA-like genomes evolve significantly slower, and do not have higher %A+T nucleotides than their host chromosomes. Moreover, they appear to reside in stable regions of the bacterial chromosomes that are generally conserved across taxonomic orders. These findings argue against RcGTA being an atypical or a defective virus. Our phylogenetic analyses suggest that RcGTA ancestor likely originated in the lineage that gave rise to contemporary alpha-proteobacterial orders Rhizobiales, Rhodobacterales, Caulobacterales, Parvularculales, and Sphingomonadales, and since that time the RcGTA-like element has co-evolved with its host chromosomes. Such evolutionary history is compatible with maintenance of these elements by bacteria due to some selective advantage. As for many other prokaryotic traits, horizontal gene transfer played a substantial role in the evolution of RcGTA-like elements, not only in shaping its genome components within the orders, but also in occasional dissemination of RcGTA-like regions across the orders and even to different bacterial phyla. PMID- 29250435 TI - Dissecting the hemagglutinin head and stalk-specific IgG antibody response in healthcare workers following pandemic H1N1 vaccination. AB - Traditionally, neutralising antibodies that are directed to the major surface glycoprotein hemagglutinin (HA) head domain are measured as surrogate correlates of protection against influenza. In addition to neutralization, hemagglutinin specific antibodies may provide protection by mediating antibody-dependent cellular cytotoxicity (ADCC). During the 2009 pandemic, vaccination induced HA specific antibodies that were mostly directed to the conserved HA stalk domain. However, the protective role of these antibodies has not been investigated in detail. We quantified the HA head and stalk-specific antibodies, their avidity, ability to neutralise virus and activate natural killer cells in an ADCC assay. We analyzed sera obtained from 14 healthcare workers who had low hemagglutination inhibition (HI) antibody titres at 3 months after pandemic H1N1 vaccination as well as from 22 controls. Vaccination resulted in a HA stalk dominant antibody response in both low responders and controls. Revaccination of low responders, 5 months later, resulted in a boost in antibodies, with HA head-specific antibodies dominating the response. Comparative analysis of head and stalk antibody avidities revealed that stalk-specific antibodies were qualitatively superior. Furthermore, stalk-specific antibodies mediated virus neutralization and had significantly higher ADCC activity than head-specific antibodies. Despite the head and stalk-specific antibodies being lower in low responders, they had comparable antibody avidity, ADCC functionality and neutralising capacity to those of controls who had high HI titres post-vaccination. Thus, our study has demonstrated that HA stalk-specific antibodies may have an important role in protection through neutralization and ADCC in low responders who do not maintain seroprotective HI antibodies. PMID- 29250436 TI - A chimeric haemagglutinin-based influenza split virion vaccine adjuvanted with AS03 induces protective stalk-reactive antibodies in mice. AB - Seasonal influenza virus vaccines are generally effective at preventing disease, but need to be well matched to circulating virus strains for maximum benefit. Influenza viruses constantly undergo antigenic changes because of their high mutation rate in the immunodominant haemagglutinin (HA) head domain, which necessitates annual re-formulation and re-vaccination for continuing protection. In case of pandemic influenza virus outbreaks, new vaccines need to be produced and quickly distributed. Novel influenza virus vaccines that redirect the immune response towards more conserved epitopes located in the HA stalk domain may remove the need for annual vaccine re-formulation and could also protect against emergent pandemic strains to which the human population is immunologically naive. One approach to create such universal influenza virus vaccines is the use of constructs expressing chimeric HAs. By sequential immunization with vaccine strains expressing the same conserved HA stalk domain and exotic HA heads to which the host is naive, antibodies against the stalk can be boosted to high titres. Here we tested a monovalent chimeric HA-based prototype universal influenza virus split virion vaccine candidate with and without AS03 adjuvant in primed mice. We found that the chimeric HA-based vaccination regimen induced higher stalk antibody titres than the seasonal vaccine. The stalk antibody responses were long lasting, cross-reactive to distantly related HAs and provided protection in vivo in a serum transfer challenge model. The results of this study are promising and support further development of a universal influenza vaccine candidate built on the chimeric HA technology platform. PMID- 29250437 TI - Heterologous prime-boost vaccination with H3N2 influenza viruses of swine favors cross-clade antibody responses and protection. AB - The emergence of multiple novel lineages of H1 and H3 influenza A viruses in swine has confounded control by inactivated vaccines. Because of substantial genetic and geographic heterogeneity among circulating swine influenza viruses, one vaccine strain per subtype cannot be efficacious against all of the current lineages. We have performed vaccination-challenge studies in pigs to examine whether priming and booster vaccinations with antigenically distinct H3N2 swine influenza viruses could broaden antibody responses and protection. We prepared monovalent whole inactivated, adjuvanted vaccines based on a European and a North American H3N2 swine influenza virus, which showed 81.5% aa homology in the HA1 region of the hemagglutinin and 83.4% in the neuraminidase. Our data show that (i) Priming with European and boosting with North American H3N2 swine influenza virus induces antibodies and protection against both vaccine strains, unlike prime-boost vaccination with a single virus or a single administration of bivalent vaccine. (ii) The heterologous prime-boost vaccination enhances hemagglutination inhibiting, virus neutralizing and neuraminidase inhibiting antibody responses against H3N2 viruses that are antigenically distinct from both vaccine strains. Antibody titers to the most divergent viruses were higher than after two administrations of bivalent vaccine. (iii) However, it does not induce antibodies to the conserved hemagglutinin stalk or to other hemagglutinin subtypes. We conclude that heterologous prime-boost vaccination might broaden protection to H3N2 swine influenza viruses and reduce the total amount of vaccine needed. This strategy holds potential for vaccination against influenza viruses from both humans and swine and for a better control of (reverse) zoonotic transmission of influenza viruses. PMID- 29250438 TI - Faraday Waves-Based Integrated Ultrasonic Micro-Droplet Generator and Applications. AB - An in-depth review on a new ultrasonic micro-droplet generator which utilizes megahertz (MHz) Faraday waves excited by silicon-based multiple Fourier horn ultrasonic nozzles (MFHUNs) and its potential applications is presented. The new droplet generator has demonstrated capability for producing micro droplets of controllable size and size distribution and desirable throughput at very low electrical drive power. For comparison, the serious deficiencies of current commercial droplet generators (nebulizers) and the other ultrasonic droplet generators explored in recent years are first discussed. The architecture, working principle, simulation, and design of the multiple Fourier horns (MFH) in resonance aimed at the amplified longitudinal vibration amplitude on the end face of nozzle tip, and the fabrication and characterization of the nozzles are then described in detail. Subsequently, a linear theory on the temporal instability of Faraday waves on a liquid layer resting on the planar end face of the MFHUN and the detailed experimental verifications are presented. The linear theory serves to elucidate the dynamics of droplet ejection from the free liquid surface and predict the vibration amplitude onset threshold for droplet ejection and the droplet diameters. A battery-run pocket-size clogging-free integrated micro droplet generator realized using the MFHUN is then described. The subsequent report on the successful nebulization of a variety of commercial pulmonary medicines against common diseases and on the experimental antidote solutions to cyanide poisoning using the new droplet generator serves to support its imminent application to inhalation drug delivery. PMID- 29250439 TI - The Effect of Deworming Using Triple-Dose Albendazole on Nutritional Status of Children in Perobatang Village, Southwest Sumba, Indonesia. AB - High prevalence of STH leads to malnutrition, anemia, cognitive impairment, and growth disorders. Triple-dose albendazole 400 mg is a broad-spectrum anthelminthic; however, its effectiveness varies in every region. This study aims to determine the benefits of deworming using triple-dose albendazole on children's nutritional status in Perobatang Village, Southwest Sumba, Indonesia. This pre-post study was conducted in July 2016 and January 2017. Children aged 1 15 years were asked to collect stool for diagnosis of STH infection (Kato-Katz method), were measured for anthropometry status to obtain the nutritional status, and took albendazole 400 mg for three consecutive days. Data was analyzed with SPSS version 20. Prevalence of STH prior to the treatment was 95.4%: T. trichiura 85.2%, A. lumbricoides 71.6%, and hookworm 18.2%. After treatment, prevalence of STH decreased significantly (McNemar test, p < 0.001) to 53.4%, (T. trichiura 39.8%, A. lumbricoides 22.7%, and hookworm 1.1%). Before treatment, 33% participants were in normal nutritional status, 47.7% underweight, and 19.3% severely underweight. After treatment, children in normal nutritional status increased to 75%, underweight children decreased to 25%, and there were no severely underweight children. In conclusion, deworming with triple-dose albendazole 400 mg is effective in improving the nutritional status of children in Perobatang Village. PMID- 29250440 TI - Estimation of the Corneal Young's Modulus In Vivo Based on a Fluid-Filled Spherical-Shell Model with Scheimpflug Imaging. AB - Current intraocular pressure (IOP) measurement using air puff could be erroneous without applying proper corrections. Although noncontact tonometry is not considered to be accurate, it is still popularly used by eye clinics. It is thus necessary to extract the correct information from their results. This study proposes a practical approach to correctly measure IOP in vivo. By embedding a new model-based correction to the Corvis(r) ST, we can extract the corneal Young's modulus from the patient data. This Young's modulus can be used to correct the IOP readings. The tests were applied to 536 right eyes of 536 healthy subjects (228 male and 308 female) between March of 2012 and April of 2016. The tests were applied to patients at the Department of Ophthalmology, National Taiwan University Hospital and the Hung-Chuo Eye Clinics. The statistical analysis showed that the value for the Young's modulus was independent of all the other parameters collected from the Corvis ST, including the corneal thickness and the intraocular pressure. Therefore, it is important to independently measure the Young's modulus instead of depending on the correlation with the other parameters. This study adds the methodology of measuring corneal stiffness in vivo for ophthalmologists' reference in diagnosis. PMID- 29250441 TI - On Characterizing the Interactions between Proteins and Guanine Quadruplex Structures of Nucleic Acids. AB - Guanine quadruplexes (G4s) are four-stranded secondary structures of nucleic acids which are stabilized by noncanonical hydrogen bonding systems between the nitrogenous bases as well as extensive base stacking, or pi-pi, interactions. Formation of these structures in either genomic DNA or cellular RNA has the potential to affect cell biology in many facets including telomere maintenance, transcription, alternate splicing, and translation. Consequently, G4s have become therapeutic targets and several small molecule compounds have been developed which can bind such structures, yet little is known about how G4s interact with their native protein binding partners. This review focuses on the recognition of G4s by proteins and small peptides, comparing the modes of recognition that have thus far been observed. Emphasis will be placed on the information that has been gained through high-resolution crystallographic and NMR structures of G4/peptide complexes as well as biochemical investigations of binding specificity. By understanding the molecular features that lead to specificity of G4 binding by native proteins, we will be better equipped to target protein/G4 interactions for therapeutic purposes. PMID- 29250442 TI - Conceptualising the Factors Affecting Retention in Care of Patients on Antiretroviral Treatment in Kabwe District, Zambia, Using the Ecological Framework. AB - Background: HIV remains a major public health challenge in Zambia. The roll-out of antiretroviral treatment (ART) has engendered new challenges in retention in care. Objective: To conceptualise the factors affecting retention in care of ART patients at three primary healthcare facilities using the ecological framework. Method: Qualitative data were collected through in-depth interviews with 45 ART patients and three focus group discussions with 20 healthcare providers from three primary healthcare facilities in Kabwe district, Zambia, and subjected to thematic content analysis. Results: Individual level barriers to retention in care included side effects, gaining weight, belief in faith healing, and use of herbal remedies and alcohol. Interpersonal barriers such as stigma and nondisclosure of HIV status were reported. At the institutional level, inadequate space in the clinic, long waiting times, long travel distances, and shortage of third-line drugs presented barriers to retention in care. Food shortages and patient mobility were reported as community barriers to retention in care. Conclusion: The ecological framework conceptualises the complex and dynamic factors affecting retention in ART care and highlights the need for multifaceted interventions that combine health education, disease management, and opportunities for income generation in a socially responsive and accountable environment. PMID- 29250443 TI - Using Reduced Inoculum Densities of Mycobacterium tuberculosis in MGIT Pyrazinamide Susceptibility Testing to Prevent False-Resistant Results and Improve Accuracy: A Multicenter Evaluation. AB - The primary platform used for pyrazinamide (PZA) susceptibility testing of Mycobacterium tuberculosis is the MGIT culture system (Becton Dickinson). Since false-resistant results have been associated with the use of this system, we conducted a multicenter evaluation to determine the effect of using a reduced cell density inoculum on the rate of false resistance. Two reduced inoculum densities were compared with that prescribed by the manufacturer (designated as "BD" method). The reduced inoculum methods (designated as "A" and "C") were identical to the manufacturer's protocol in all aspects with the exception of the cell density of the inoculum. Twenty genetically and phenotypically characterized M. tuberculosis isolates were tested in duplicate by ten independent laboratories using the three inoculum methods. False-resistant results declined from 21.1% using the standard "BD" method to 5.7% using the intermediate ("A") inoculum and further declined to 2.8% using the most dilute ("C") inoculum method. The percentages of the resistant results that were false-resistant declined from 55.2% for the "BD" test to 28.8% and 16.0% for the "A" and "C" tests, respectively. These results represent compelling evidence that the occurrence of false-resistant MGIT PZA susceptibility test results can be mitigated through the use of reduced inoculum densities. PMID- 29250444 TI - Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism. AB - The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD) with distinct de novo genetic events. We hypothesized that gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP, n = 62), de novo deletion copy number variations (DEL, n = 74), de novo likely gene-disrupting mutations (LGDM, n = 267), and children without a known genetic etiology (NON, n = 2111). Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships. PMID- 29250446 TI - A Laboratory Assessment of Two Local Strains of the Beauveria bassiana (Bals.) Vuill. against the Tetranychus urticae (Acari: Tetranychidae) and Their Potential as a Mycopesticide. AB - This study was conducted to assess highly pathogenic Beauveria bassiana isolates to be used in biocontrol and to determine their potentials as mycopesticide. For this purpose, two B. bassiana isolates, which were locally isolated from T. urticae, were chosen. Firstly, three suspensions were investigated at the degree of humidity of 65 +/- 5% and 100% RH. Secondly, these strains were selected according to their tendency to mass production, tolerance to UV radiation, and capability of producing spore at the different temperatures. Finally, identification of the selected isolate was performed by using ITS rDNA analysis. Both tested fungal isolates were pathogenic to the T. urticae. Mycelial growths of isolate AT076 at 20 degrees C and 30 degrees C were found to be greater than isolate AT007. It was observed that isolate AT076 had more spore production with 1.61 * 107 spore/disc at 30 degrees C and 44.33% germination after UV radiation for 15 min. The numbers of spores per 5 mm disk area for isolates AT076 and AT007 were found to be 1.2 * 106 and 1.0 * 106. These results show that isolate AT076 was more virulent and more UV-tolerant and had higher tendency to mass production compared to isolate AT007 against T. urticae. As a result of this study, isolate AT076 can be used in the biocontrol as mycopesticide. PMID- 29250445 TI - Identification of Factors Influencing Cumulative Long-Term Radiation Exposure in Patients Undergoing EVAR. AB - Patients who undergo endovascular repair of aortic aneurysms (EVAR) require life long surveillance because complications including, in particular, endoleaks, aneurysm rupture, and graft dislocation are diagnosed in a certain share of the patient population and may occur at any time after the original procedure. Radiation exposure in patients undergoing EVAR and post-EVAR surveillance has been investigated by previous authors. Arriving at realistic exposure data is essential because radiation doses resulting from CT were shown to be not irrelevant. Efforts directed at identification of factors impacting the level of radiation exposure in both the course of the EVAR procedure and post-EVAR endovascular interventions and CTAs are warranted as potentially modifiable factors may offer opportunities to reduce the radiation. In the light of the risks found to be associated with radiation exposure and considering the findings above, those involved in EVAR and post-EVAR surveillance should aim at optimal dose management. PMID- 29250447 TI - Electronic Northern Analysis of Genes and Modeling of Gene Networks Underlying Bovine Milk Fat Production. AB - Milk fat is one of the most important economic traits in dairy animals. Yet, the biological machinery involved in milk fat synthesis remains poorly understood. In the present study, expression profiling of 45 genes involved in lipid biosynthesis and secretion was performed using a computational approach to identify those genes that are differentially expressed in mammary tissue. Transcript abundance was observed for genes associated with nine bioprocesses, namely, fatty acid import into cells, xenobiotic and cholesterol transport, acetate and fatty acid activation and intracellular transport, fatty acid synthesis and desaturation, triacylglycerol synthesis, sphingolipid synthesis, lipid droplet formation, ketone body utilization, and regulation of transcription in mammary, skin, and muscle tissue. Relative expression coefficient of the genes was derived based on the transcript abundance across the three tissue types to determine the genes that were preferentially expressed during lactation. 13 genes (ACSS1, ACSS2, ADFP, CD36, FABP3, FASN, GPAM, INSIG1, LPL, SCD5, SPTLC1, SREBF1, and XDH) showed higher expression in the mammary tissue of which 6 (ADFP, FASN, GPAM, LPL, SREBF1, and XDH) showed higher expression during adulthood. Further, interaction networks were mapped for these genes to determine the nature of interactions and to identify the major genes in the milk fat biosynthesis and secretion pathways. PMID- 29250448 TI - Glucose Intake Alters Expression of Neuropeptides Derived from Proopiomelanocortin in the Lateral Hypothalamus and the Nucleus Accumbens in Fructose Preference Rats. AB - To study the neuroendocrine mechanism of sugar preference, we investigated the role of glucose feeding in the regulation of expression levels of neuropeptides derived from proopiomelanocortin (POMC) in the lateral hypothalamus (LH) and nucleus accumbens (NAc) in fructose preference rats. Fructose preference rats were induced by using the lithium chloride backward conditioning procedure. The fructose preference was confirmed by the two-bottle test. The drinking behavior of rats was assessed by the fructose concentration gradient test. The preference of 10% glucose or 0.1% saccharine was assessed, and the expression levels of neuropeptides derived from POMC in the LH and the NAc in fructose preference rats were measured by Western blot analysis. Fructose preference rats displayed a greater fructose preference than control rats. Furthermore, fructose preference rats preferred glucose solution rather than saccharine solution, while control rats preferred saccharine solution rather than glucose solution. The expression levels of neuropeptides derived from POMC in the LH and the NAc were changed by glucose but not saccharine intake. In summary, the data suggests that glucose intake increases the expression of neuropeptides derived from POMC in the LH and the NAc in fructose preference rats. PMID- 29250449 TI - Short-Lasting Unilateral Neuralgiform Headache Attacks with Conjunctival Injection and Tearing in a Patient with Varicella-Zoster Virus Encephalomyelitis. AB - Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing syndrome (SUNCT) is a type of trigeminal autonomic cephalalgia. Its etiology is generally idiopathic, though rarely it has been associated with viral infections. We describe the fourth case reported in the literature of SUNCT in association with viral meningoencephalitis. PMID- 29250450 TI - Vaginal Endosalpingiosis Case Report: A Rare Entity Presenting as Intermenstrual Bleeding. AB - Endosalpingiosis is a benign and rare entity whose pathophysiology remains unknown. It has been described in pelvic organs, the abdomen, or axillar lymph nodes. Its underrecognition has occasionally led to its misinterpretation for an adenocarcinoma. This case reports the treatment and follow-up of vaginal endosalpingiosis, presenting as a vaginal polyp in a premenopausal women with intermenstrual bleeding. To our knowledge this is the first reported case of vaginal endosalpingiosis and the second mucosal localization after bladder endosalpingiosis. PMID- 29250451 TI - Hypokalemic Paralysis Secondary to Immune Checkpoint Inhibitor Therapy. AB - Introduction of immune checkpoint inhibitors (ICIs) has led to significant improvements in the treatment of multiple malignancies. Anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) are two essential ICIs that have been FDA approved since 2011. As the use of immunotherapy in melanoma and other malignancies increases, the potential of adverse events also increases. Overall, anti-PD-1 agents are well tolerated. In rare instances, colitis, endocrinopathies, skin, and renal toxicities have been observed. A 58-year-old male with a history of stage 4 cutaneous melanoma presented with quadriplegia while on nivolumab. Routine blood test revealed low potassium, low bicarbonate, and high serum creatinine. Admission diagnosis included hypokalemia, acute kidney injury, and renal tubal acidosis. The offending drug was discontinued, and the patient was started on high-dose corticosteroids. On discharge, paralysis was resolved. Renal function and potassium were normalized. Nivolumab was discontinued, and he was started on pembrolizumab. Literature suggests that, although rare, patients receiving ICE may develop immune-mediated nephritis and renal dysfunction. The mainstay of immune-related adverse event (irAE) management is immune suppression. Hence, given the increasing frequency of immunotherapy use, awareness should be raised in regard to irAEs and their appropriate management. PMID- 29250452 TI - Optical Coherence Tomography Angiography of Macular Telangiectasia Type 2 with Associated Subretinal Neovascular Membrane. AB - Optical coherence tomography angiography (OCTA) is a recently established noninvasive technology for evaluation of the retinal and choroidal vasculature. The literature regarding the findings in macular telangiectasia type 2 (MacTel2) is scarce. We report the OCTA findings associated with a subject with MacTel2 and secondary subretinal neovascularization (SNV). The commercially available Cirrus 5000 with AngioPlex (Zeiss, Jena, Germany) was used, without any subsequent image modification or processing. Subretinal neovascularization was detectable with OCTA at the level of the outer retina and choriocapillaris. Microvascular abnormalities associated with MacTel2 were present mostly in the deep capillary plexus of the retina temporally. PMID- 29250453 TI - Pulmonary Neuroendocrine Cell Hyperplasia Associated with Surfactant Protein C Gene Mutation. AB - Familial interstitial lung disease (ILD) is defined as presence of ILD in 2 or more family members. Surfactant protein C (SFTPC) gene mutations are rare, but well-known cause of familial ILD. We reported a 20-year-old male, who was referred for lung transplantation. He was symptomatic at age 3 and underwent surgical lung biopsy at age 6, which revealed a nonspecific interstitial pneumonia (NSIP) pattern. Genetic workup revealed a novel SFTPC mutation in the first intron with a C to A transversion. At age 21, he underwent bilateral lung transplantation. Explanted lung histology suggested NSIP. In addition there was pulmonary neuroendocrine cell (PNEC) hyperplasia and carcinoid tumorlets. His mother had undergone lung transplantation several years earlier, and her explanted lung showed similar pathology. SFTPC mutations are inherited in an autosomal dominant pattern. Various types of ILD have been associated with SFTPC mutation including NSIP, usual interstitial pneumonia (UIP), and desquamative interstitial pneumonia (DIP). PNEC hyperplasia has been described to occur in association with lung inflammation but has not been previously described with familial ILD associated with SFTPC mutation. PMID- 29250454 TI - Electrochemical Behaviour of Tinidazole at 1,4-Benzoquinone Modified Carbon Paste Electrode and Its Direct Determination in Pharmaceutical Tablets and Urine by Differential Pulse Voltammetry. AB - A simple and highly sensitive electrochemical method based on a 1,4-benzoquinone modified carbon paste electrode (1,4-BQMCPE) was described for the determination of tinidazole (TDZ). In Britton Robinson buffer solution, TDZ yields well-defined irreversible reduction peak at -0.344 V on a 1,4-BQMCPE. Compared with that on a bare CPE, the reduction peak of TDZ increased significantly on the modified CPE and the effects of different parameters on the voltammetric responses were also investigated. Differential pulse voltammetric method was proposed and optimized for TDZ determination and its reductive peak current response at 1,4-BQMCPE was found to show linear dependence on the concentration of TDZ in the range of 1.0 * 10-6 to 5.0 * 10-4 M with a linear regression equation, correlation coefficient, limit of detection (LOD), and limit of quantification (LOQ) of IPC (MUA) = 0.19958 + 0.02657C (MUM), 0.99486, 1.10 * 10-7 M, and 3.77 * 10-7, respectively. Excellent recovery results for spiked TDZ in pharmaceutical tablet samples ranging within 97.44-97.51% and in urine ranging within 95.37-96.91% were observed. The selectivity of the method for TDZ was further studied in the presence of selected potential interferents and confirmed the potential applicability of the developed method for the determination of TDZ. PMID- 29250455 TI - Changes in urinary metabolic profiles of colorectal cancer patients enrolled in a prospective cohort study (ColoCare). AB - Introduction: Metabolomics is a valuable tool for biomarker screening of colorectal cancer (CRC). In this study, we profiled the urinary metabolomes of patients enrolled in a prospective patient cohort (ColoCare). We aimed to describe changes in the metabolome in the longer clinical follow-up and describe initial predictors as candidate markers with possibly prognostic significance. Methods: In total, 199 urine samples from CRC patients pre-surgery (n=97), 1-8 days post-surgery (n=12) and then after 6 and 12 months (n=52 and 38, respectively) were analyzed using both GC-MS and 1H-NMR. Both datasets were analyzed separately with built in uni- and multivariate analyses of Metaboanalyst 2.0. Furthermore, adjusted linear mixed effects regression models were constructed. Results: Many concentrations of the metabolites derived from the gut microbiome were affected by CRC surgery, presumably indicating a tumor-induced shift in bacterial species. Associations of the microbial metabolites with disease stage indicate an important role of the gut microbiome in CRC.We were able to differentiate the metabolite profiles of CRC patients prior to surgery from those at any post-surgery timepoint using a multivariate model containing 20 marker metabolites (AUCROC=0.89; 95% CI:0.84-0.95). Conclusion: To the best of our knowledge, this is one of the first metabolomic studies to follow CRC patients in a prospective setting with repeated urine sampling over time. We were able to confirm markers initially identified in case-control studies and pin point metabolites which may serve as candidates for prognostic biomarkers of CRC. PMID- 29250456 TI - Enhanced Rigidification within a Double Mutant of Soybean Lipoxygenase Provides Experimental Support for Vibronically Nonadiabatic Proton-Coupled Electron Transfer Models. AB - Soybean lipoxygenase (SLO) is a prototype for nonadiabatic hydrogen tunneling reactions and, as such, has served as the subject of numerous theoretical studies. In this work, we report a nearly temperature-independent kinetic isotope effect (KIE) with an average KIE value of 661 +/- 27 for a double mutant (DM) of SLO at six temperatures. The data are well-reproduced within a vibronically nonadiabatic proton-coupled electron transfer model in which the active site has become rigidified compared to wild-type enzyme and single-site mutants. A combined temperature-pressure perturbation further shows that temperature dependent global motions within DM-SLO are more resistant to perturbation by elevated pressure. These findings provide strong experimental support for the model of hydrogen tunneling in SLO, where optimization of both local protein and ligand motions and distal conformational rearrangements is a prerequisite for effective proton vibrational wave function overlap between the substrate and the active-site iron cofactor. PMID- 29250457 TI - Current OCT Approaches Do Not Reliably Identify TCFAs. AB - It is now clearly established that Thin-Capped Fibroatheromas (TCFAs) lead to most Acute Coronary Syndromes (ACSs). The ability to selectively intervene on TCFAs predisposed to rupture and ACSs would dramatically alter the practice of cardiology. While the ability of OCT to identify thin walled plaques at micron scale resolutions has represented a major advance, it is a misconception that it can reliably identify TCFAs. One major reason is that the 'diffuse border' criteria currently used to determine 'lipid plaque' is almost undoubtedly from high scattering in the intima and not because of core composition (necrotic core). A second reason is that, rather than looking at lipid collections, studies need to be focused on identifying necrotic cores with OCT. Necrotic cores are characteristic of TCFAs and not lipid collections. Numerous other OCT approaches are available which can potentially accurately assess TCFAs, but these have not been aggressively pursed which we believe likely stems in part from the misconceptions over the efficacy of 'diffuse borders'. PMID- 29250458 TI - Comparison of Psychological Response between Concussion and Musculoskeletal Injury in Collegiate Athletes. AB - The psychological response to musculoskeletal injuries has been well documented, however, research on the psychological response to concussion is limited. The Profile of Mood States (POMS) and the State-Trait Anxiety Inventory (STAI) have recently been used to assess the psychological recovery of concussions. Although some studies indicate that psychological response is different for musculoskeletal injuries and concussion, there is currently not enough information to indicate this difference occurs at specific clinical milestones. The purpose of this study was to compare the psychological responses of student athletes who have been diagnosed with a concussion to those of athletes diagnosed with musculoskeletal injuries with similar recovery duration. Fifteen collegiate athletes who sustained a musculoskeletal injury were recruited and matched with 15 previously collected concussion participants. The main outcome measures were the scores of POMS constructs: tension-anxiety, anger-hostility, fatigue-inertia, depression-dejection, vigor-activity, confusion-bewilderment, and total mood disturbance and STAI (state anxiety only). Two-way MANOVAs was run to determine the effects of group and time on POMS and STAI constructs. There were no significant interactions identified, but follow-up ANOVAs identified a main effect for time for most POMS subscales, with POMS scores improving over time in both groups. Analyses also revealed that tension-anxiety, vigor-activity and the STAI were not affected by time or group. The findings of this study, that both groups' psychological response to injury improves over time and at similar clinical milestones suggests reduction in sports and team related activities may play a substantial role in the psychological response to either concussion or musculoskeletal injury. PMID- 29250459 TI - Intrahepatic Cholestasis of Pregnancy Refractory to Multiple Medical Therapies and Plasmapheresis. AB - Objectives We report on a patient suffering from intractable itching secondary to intrahepatic cholestasis of pregnancy (ICP) unresponsive to conventional medical therapies. She was started on a regimen of therapeutic plasma exchange (TPE), which is often efficacious in relieving patient's itching from all causes of cholestasis, including ICP. Methods We performed a retrospective review of a patient's medical record. Results Following initial TPE, the patient reported dramatic relief of her itching and consequent insomnia. However, this effect was short lived, as subsequent TPE provided minimal relief, and may have actually worsened her itching. Out of concern for poor fetal outcomes, delivery was induced at 34 weeks gestational age. The child had an uncomplicated neonatal intensive care unit stay following delivery, and the mother reported > 90% relief of her symptoms 2 weeks after delivery. Conclusion TPE often provides longer term relief of itching because of ICP; however, it is not a panacea for these symptoms, and sometimes only delivery of the fetus can relieve maternal symptoms. In addition to the refractoriness to TPE, the case is also unusual for the early onset of ICP symptoms and the comorbidity of hepatitis C. PMID- 29250460 TI - Biologically Triggered Delivery of EGF from Polymer Fiber Patches. AB - Wound healing is modulated by complex spatial and temporal regulation of growth factors within a wound site. Regenerative medicine seeks to generate materials that can mimic this environment for the healing of chronic or traumatic wounds. Herein, we report a programmed release of epidermal growth factor (EGF) from coextruded polymer fiber patches, which is triggered by the natural biological cascade of wound healing. Genetically engineered EGF containing a matrix metalloproteinase (MMP) cleavage site was covalently conjugated to a nonwoven poly(epsilon-caprolactone) (PCL) fiber mat fabricated by multilayered melt coextrusion. The genetically modified EGF showed rapid release in the presence of a biological trigger, MMP-9, while a control protein showed negligible release. The biologically responsive fiber mat dramatically enhanced proliferation and migration of human keratinocytes in the presence of MMP-9. This study describes the release of a critical wound-healing growth factor as triggered by the biology inherent in the healing process. PMID- 29250461 TI - Differing case definitions point to the need for an accurate diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome. PMID- 29250462 TI - Cranial osteology of the pampathere Holmesina floridanus (Xenarthra: Cingulata; Blancan NALMA), including a description of an isolated petrosal bone. AB - The present study entails descriptions of several well-preserved skulls from the pampathere species Holmesina floridanus, recovered from Pliocene localities in central Florida and housed in the collections of the Florida Museum of Natural History. Bone by bone descriptions have allowed detailed reconstructions of cranial morphology. Cranial foramina are described and illustrated in detail, and their contents inferred. The first ever description of an isolated pampathere petrosal is also included. Cranial osteology of Holmesina floridanus is compared to that of Pleistocene species of Holmesina from both North and South America (Holmesina septentrionalis, Holmesina occidentalis), as well as to the other well known pampathere genera, to closely related taxa among glyptodonts (Propalaehoplophorus), and to extinct and extant armadillos (Proeutatus, Euphractus). This study identifies a suite of apomorphic cranial features that serve to diagnose a putative, progressive series of more inclusive monophyletic groups, including the species Holmesina floridanus, the genus Holmesina, pampatheres, pampatheres plus glyptodonts, and a clade formed by pampatheres, glyptodonts, and Proeutatus. The study highlights the need for further anatomical investigations of pampathere cranial anatomy, especially those using modern scanning technology, and for analyses of pampathere phylogenetic relationships. PMID- 29250464 TI - Artificial night light alters nocturnal prey interception outcomes for morphologically variable spiders. AB - Artificial night light has the potential to significantly alter visually dependent species interactions. However, examples of disruptions of species interactions through changes in light remain rare and how artificial night light may alter predator-prey relationships are particularly understudied. In this study, we examined whether artificial night light could impact prey attraction and interception in Nephila pilipes orb weaver spiders, conspicuous predators who make use of yellow color patterns to mimic floral resources and attract prey to their webs. We measured moth prey attraction and interception responses to treatments where we experimentally manipulated the color/contrast of spider individuals in the field (removed yellow markings) and also set up light manipulations. We found that lit webs had lower rates of moth interception than unlit webs. Spider color, however, had no clear impact on moth interception or attraction rates in lit nor unlit webs. The results show that night light can reduce prey interception for spiders. Additionally, this study highlights how environmental and morphological variation can complicate simple predictions of ecological light pollution's disruption of species interactions. PMID- 29250463 TI - Introgression between ecologically distinct species following increased salinity in the Colorado Delta- Worldwide implications for impacted estuary diversity. AB - We investigate hybridization and introgression between ecologically distinct sister species of silverside fish in the Gulf of California through combined analysis of morphological, sequence, and genotypic data. Water diversions in the past century turned the Colorado River Delta from a normal estuary to a hypersaline inverse estuary, raising concerns for the local fauna, much of which is endangered. Salinity differences are known to generate ecological species pairs and we anticipated that loss of the fresher-water historic salinity regime could alter the adaptive factors maintaining distinction between the broadly distributed Gulf-endemic Colpichthys regis and the narrowly restricted Delta endemic Colpichthys hubbsi, the species that experienced dramatic environmental change. In this altered environmental context, these long-isolated species (as revealed by Cytochrome b sequences) show genotypic (RAG1, microsatellites) evidence of active hybridization where the species ranges abut, as well as directional introgression from C. regis into the range center of C. hubbsi. Bayesian group assignment (STRUCTURE) on six microsatellite loci and multivariate analyses (DAPC) on both microsatellites and phenotypic data further support substantial recent admixture between the sister species. Although we find no evidence for recent population decline in C. hubbsi based on mitochondrial sequence, introgression may be placing an ancient ecological species at risk of extinction. Such introgressive extinction risk should also pertain to other ecological species historically sustained by the now changing Delta environment. More broadly, salinity gradient associated ecological speciation is evident in silverside species pairs in many estuarine systems around the world. Ecological species pairs among other taxa in such systems are likely poorly understood or cryptic. As water extraction accelerates in river systems worldwide, salinity gradients will necessarily be altered, impacting many more estuary and delta systems. Such alteration of habitats will place biodiversity at risk not only from direct effects of habitat destruction, but also from the potential for the breakdown of ecological species. Thus, evolutionary response to the anthropogenic alteration of salinity gradients in estuaries merits investigation as the number of impacted systems increases around the globe, permitting parallel study of multiple systems, while also permitting a conservation management response to help preserve this little championed component of biodiversity. PMID- 29250465 TI - The distribution and numbers of cheetah (Acinonyx jubatus) in southern Africa. AB - Assessing the numbers and distribution of threatened species is a central challenge in conservation, often made difficult because the species of concern are rare and elusive. For some predators, this may be compounded by their being sparsely distributed over large areas. Such is the case with the cheetah Acinonyx jubatus. The IUCN Red List process solicits comments, is democratic, transparent, widely-used, and has recently assessed the species. Here, we present additional methods to that process and provide quantitative approaches that may afford greater detail and a benchmark against which to compare future assessments. The cheetah poses challenges, but also affords unique opportunities. It is photogenic, allowing the compilation of thousands of crowd-sourced data. It is also persecuted for killing livestock, enabling estimation of local population densities from the numbers persecuted. Documented instances of persecution in areas with known human and livestock density mean that these data can provide an estimate of where the species may or may not occur in areas without observational data. Compilations of extensive telemetry data coupled with nearly 20,000 additional observations from 39 sources show that free-ranging cheetahs were present across approximately 789,700 km2 of Namibia, Botswana, South Africa, and Zimbabwe (56%, 22%, 12% and 10% respectively) from 2010 to 2016, with an estimated adult population of 3,577 animals. We identified a further 742,800 km2 of potential cheetah habitat within the study region with low human and livestock densities, where another ~3,250 cheetahs may occur. Unlike many previous estimates, we make the data available and provide explicit information on exactly where cheetahs occur, or are unlikely to occur. We stress the value of gathering data from public sources though these data were mostly from well-visited protected areas. There is a contiguous, transboundary population of cheetah in southern Africa, known to be the largest in the world. We suggest that this population is more threatened than believed due to the concentration of about 55% of free-ranging individuals in two ecoregions. This area overlaps with commercial farmland with high persecution risk; adult cheetahs were removed at the rate of 0.3 individuals per 100 km2 per year. Our population estimate for confirmed cheetah presence areas is 11% lower than the IUCN's current assessment for the same region, lending additional support to the recent call for the up-listing of this species from vulnerable to endangered status. PMID- 29250467 TI - Incremental growth of therizinosaurian dental tissues: implications for dietary transitions in Theropoda. AB - Previous investigations document functional and phylogenetic signals in the histology of dinosaur teeth. In particular, incremental lines in dentin have been used to determine tooth growth and replacement rates in several dinosaurian clades. However, to date, few studies have investigated the dental microstructure of theropods in the omnivory/herbivory spectrum. Here we examine dental histology of Therizinosauria, a clade of large-bodied theropods bearing significant morphological evidence for herbivory, by examining the teeth of the early diverging therizinosaurian Falcarius utahensis, and an isolated tooth referred to Suzhousaurus megatherioides, a highly specialized large-bodied representative. Despite attaining some of the largest body masses among maniraptoran theropod dinosaurs, therizinosaurian teeth are diminutive, measuring no more than 0.90 cm in crown height (CH) and 0.38 cm in crown base length (CBL). Comparisons with other theropods and non-theropodan herbivorous dinosaurs reveals that when controlling for estimated body mass, crown volume in therizinosaurians plots most closely with dinosaurs of similar dietary strategy as opposed to phylogenetic heritage. Analysis of incremental growth lines in dentin, observed in thin sections of therizinosaurian teeth, demonstrates that tooth growth rates fall within the range of other archosaurs, conforming to hypothesized physiological limitations on the production of dental tissues. Despite dietary differences between therizinosaurians and hypercarnivorous theropods, the types of enamel crystallites present and their spatial distribution-i.e., the schmelzmuster of both taxa-is limited to parallel enamel crystallites, the simplest form of enamel and the plesiomorphic condition for Theropoda. This finding supports previous hypotheses that dental microstructure is strongly influenced by phylogeny, yet equally supports suggestions of reduced reliance on oral processing in omnivorous/herbivorous theropods rather than the microstructural specializations to diet exhibited by non-theropodan herbivorous dinosaurs. Finally, although our sample is limited, we document a significant reduction in the rate of enamel apposition contrasted with increased relative enamel thickness between early and later diverging therizinosaurians that coincides with anatomical evidence for increased specializations to herbivory in the clade. PMID- 29250468 TI - Measurement of sedentary behaviour in population health surveys: a review and recommendations. AB - Background: The purpose of this review was to determine the most valid and reliable questions for targeting key modes of sedentary behaviour (SB) in a broad range of national and international health surveillance surveys. This was done by reviewing the SB modules currently used in population health surveys, as well as examining SB questionnaires that have performed well in psychometric testing. Methods: Health surveillance surveys were identified via scoping review and contact with experts in the field. Previous systematic reviews provided psychometric information on pediatric questionnaires. A comprehensive search of four bibliographic databases was used to identify studies reporting psychometric information for adult questionnaires. Only surveys/studies published/used in English or French were included. Results: The review identified a total of 16 pediatric and 18 adult national/international surveys assessing SB, few of which have undergone psychometric testing. Fourteen pediatric and 35 adult questionnaires with psychometric information were included. While reliability was generally good to excellent for questions targeting key modes of SB, validity was poor to moderate, and reported much less frequently. The most valid and reliable questions targeting specific modes of SB were combined to create a single questionnaire targeting key modes of SB. Discussion: Our results highlight the importance of including SB questions in survey modules that are adaptable, able to assess various modes of SB, and that exhibit adequate reliability and validity. Future research could investigate the psychometric properties of the module we have proposed in this paper, as well as other questionnaires currently used in national and international population health surveys. PMID- 29250466 TI - Arsenophonus and Sodalis replacements shape evolution of symbiosis in louse flies. AB - Symbiotic interactions between insects and bacteria are ubiquitous and form a continuum from loose facultative symbiosis to greatly intimate and stable obligate symbiosis. In blood-sucking insects living exclusively on vertebrate blood, obligate endosymbionts are essential for hosts and hypothesized to supplement B-vitamins and cofactors missing from their blood diet. The role and distribution of facultative endosymbionts and their evolutionary significance as seeds of obligate symbioses are much less understood. Here, using phylogenetic approaches, we focus on the Hippoboscidae phylogeny as well as the stability and dynamics of obligate symbioses within this bloodsucking group. In particular, we demonstrate a new potentially obligate lineage of Sodalis co-evolving with the Olfersini subclade of Hippoboscidae. We also show several likely facultative Sodalis lineages closely related to Sodalis praecaptivus (HS strain) and suggest repeated acquisition of novel symbionts from the environment. Similar to Sodalis, Arsenophonus endosymbionts also form both obligate endosymbiotic lineages co evolving with their hosts (Ornithomyini and Ornithoica groups) as well as possibly facultative infections incongruent with the Hippoboscidae phylogeny. Finally, we reveal substantial diversity of Wolbachia strains detected in Hippoboscidae samples falling into three supergroups: A, B, and the most common F. Altogether, our results prove the associations between Hippoboscoidea and their symbiotic bacteria to undergo surprisingly dynamic, yet selective, evolutionary processes strongly shaped by repeated endosymbiont replacements. Interestingly, obligate symbionts only originate from two endosymbiont genera, Arsenophonus and Sodalis, suggesting that the host is either highly selective about its future obligate symbionts or that these two lineages are the most competitive when establishing symbioses in louse flies. PMID- 29250469 TI - Substitutions into amino acids that are pathogenic in human mitochondrial proteins are more frequent in lineages closely related to human than in distant lineages. AB - Propensities for different amino acids within a protein site change in the course of evolution, so that an amino acid deleterious in a particular species may be acceptable at the same site in a different species. Here, we study the amino acid changing variants in human mitochondrial genes, and analyze their occurrence in non-human species. We show that substitutions giving rise to such variants tend to occur in lineages closely related to human more frequently than in more distantly related lineages, indicating that a human variant is more likely to be deleterious in more distant species. Unexpectedly, substitutions giving rise to amino acids that correspond to alleles pathogenic in humans also more frequently occur in more closely related lineages. Therefore, a pathogenic variant still tends to be more acceptable in human mitochondria than a variant that may only be fit after a substantial perturbation of the protein structure. PMID- 29250470 TI - Protective effect of Rhus coriaria fruit extracts against hydrogen peroxide induced oxidative stress in muscle progenitors and zebrafish embryos. AB - Background and Purpose: Oxidative stress is involved in normal and pathological functioning of skeletal muscle. Protection of myoblasts from oxidative stress may improve muscle contraction and delay aging. Here we studied the effect of R. coriaria sumac fruit extract on human myoblasts and zebrafish embryos in conditions of hydrogen peroxide-induced oxidative stress. Study Design and Methods: Crude ethanolic 70% extract (CE) and its fractions was obtained from sumac fruits. The composition of sumac ethyl acetate EtOAc fraction was studied by 1H NMR. The viability of human myoblasts treated with CE and the EtOAc fraction was determined by trypan blue exclusion test. Oxidative stress, cell cycle and adhesion were analyzed by flow cytometry and microscopy. Gene expression was analyzed by qPCR. Results: The EtOAc fraction (IC50 2.57 ug/mL) had the highest antioxidant activity and exhibited the best protective effect against hydrogen peroxide-induced oxidative stress. It also restored cell adhesion. This effect was mediated by superoxide dismutase 2 and catalase. Pre treatment of zebrafish embryos with low concentrations of the EtOAc fraction protected them from hydrogen peroxide-induced death in vivo. 1H NMR analysis revealed the presence of gallic acid in this fraction. Conclusion: Rhus coriaria extracts inhibited or slowed down the progress of skeletal muscle atrophy by decreasing oxidative stress via superoxide dismutase 2 and catalase-dependent mechanisms. PMID- 29250471 TI - A molecular phylogenetic appraisal of the acanthostomines Acanthostomum and Timoniella and their position within Cryptogonimidae (Trematoda: Opisthorchioidea). AB - The phylogenetic position of three taxa from two trematode genera, belonging to the subfamily Acanthostominae (Opisthorchioidea: Cryptogonimidae), were analysed using partial 28S ribosomal DNA (Domains 1-2) and internal transcribed spacers (ITS1-5.8S-ITS2). Bayesian inference and Maximum likelihood analyses of combined 28S rDNA and ITS1 + 5.8S + ITS2 sequences indicated the monophyly of the genus Acanthostomum (A. cf. americanum and A. burminis) and paraphyly of the Acanthostominae. These phylogenetic relationships were consistent in analyses of 28S alone and concatenated 28S + ITS1 + 5.8S + ITS2 sequences analyses. Based on molecular phylogenetic analyses, the subfamily Acanthostominae is therefore a paraphyletic taxon, in contrast with previous classifications based on morphological data. Phylogenetic patterns of host specificity inferred from adult stages of other cryptogonimid taxa are also well supported. However, analyses using additional genera and species are necessary to support the phylogenetic inferences from this study. Our molecular phylogenetic reconstruction linked two larval stages of A. cf. americanum cercariae and metacercariae. Here, we present the evolutionary and ecological implications of parasitic infections in freshwater and brackish environments. PMID- 29250472 TI - Disentangling diatom species complexes: does morphometry suffice? AB - Accurate taxonomic resolution in light microscopy analyses of microalgae is essential to achieve high quality, comparable results in both floristic analyses and biomonitoring studies. A number of closely related diatom taxa have been detected to date co-occurring within benthic diatom assemblages, sharing many morphological, morphometrical and ecological characteristics. In this contribution, we analysed the hypothesis that, where a large sample size (number of individuals) is available, common morphometrical parameters (valve length, width and stria density) are sufficient to achieve a correct identification to the species level. We focused on some common diatom taxa belonging to the genus Gomphonema. More than 400 valves and frustules were photographed in valve view and measured using Fiji software. Several statistical tools (mixture and discriminant analysis, k-means clustering, classification trees, etc.) were explored to test whether mere morphometry, independently of other valve features, leads to correct identifications, when compared to identifications made by experts. In view of the results obtained, morphometry-based determination in diatom taxonomy is discouraged. PMID- 29250473 TI - Trauma Resuscitation in a Left Ventricular Assist Device Patient: An Emergency Medicine Simulation Scenario. AB - Heart failure is a leading cause of death worldwide. While heart transplantation is the most successful treatment for end-stage heart failure, the scarcity in donor hearts has ushered in the use of alternative therapies, such as the left ventricular assist device (LVAD). This patient population may present with low frequency, but they require disease-specific management. Learners may fine-tune these principles in a safe learning environment, such as a medical simulation lab. Here, we present a case in which a patient with a LVAD sustained serious traumatic injuries. PMID- 29250474 TI - The Most Recent Oncologic Emergency: What Emergency Physicians Need to Know About the Potential Complications of Immune Checkpoint Inhibitors. AB - Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmable cell death protein 1 (PD-1)/PD-L1 have shown antitumor activity in cancers such as melanoma, non-small cell lung cancer, renal cell carcinoma, and urothelial cancer. Certain checkpoint inhibitors have been approved for use in Canada, and are becoming a mainstay in the treatment of melanoma and other malignancies. These drugs have a unique side effect profile and are known to cause immune-related adverse events (irAEs). These adverse events often appear to originate from an infectious etiology, when in fact they result from the enhanced immune response caused by immune checkpoint therapy. IrAEs are primarily treated with corticosteroids, which suppress the overactive immune response that is secondary to the treatment. IrAEs can occur in any organ system, but adverse events in the skin, gastrointestinal, endocrine, and pulmonary systems are among the most common. As an emergency physician, one must be familiar with these drugs and their adverse events in order to identify patients presenting with irAE and treat them accordingly. This paper provides a brief introduction to immune checkpoint inhibitors, discusses the most common irAEs relevant to emergency physicians, and gives suggestions on how to manage patients presenting to the emergency department (ED) suffering from irAEs. PMID- 29250475 TI - Retraction: Radiological and Functional Outcome of Medial Epicondyle Fracture Treated Surgically in Children and Adolescents: A Retrospective Study. AB - [This retracts the article DOI: 10.7759/cureus.953.]. PMID- 29250476 TI - Dynamic Network Model for Smart City Data-Loss Resilience Case Study: City-to City Network for Crime Analytics. AB - Today's cities generate tremendous amounts of data, thanks to a boom in affordable smart devices and sensors. The resulting big data creates opportunities to develop diverse sets of context-aware services and systems, ensuring smart city services are optimized to the dynamic city environment. Critical resources in these smart cities will be more rapidly deployed to regions in need, and those regions predicted to have an imminent or prospective need. For example, crime data analytics may be used to optimize the distribution of police, medical, and emergency services. However, as smart city services become dependent on data, they also become susceptible to disruptions in data streams, such as data loss due to signal quality reduction or due to power loss during data collection. This paper presents a dynamic network model for improving service resilience to data loss. The network model identifies statistically significant shared temporal trends across multivariate spatiotemporal data streams and utilizes these trends to improve data prediction performance in the case of data loss. Dynamics also allow the system to respond to changes in the data streams such as the loss or addition of new information flows. The network model is demonstrated by city-based crime rates reported in Montgomery County, MD, USA. A resilient network is developed utilizing shared temporal trends between cities to provide improved crime rate prediction and robustness to data loss, compared with the use of single city-based auto-regression. A maximum improvement in performance of 7.8% for Silver Spring is found and an average improvement of 5.6% among cities with high crime rates. The model also correctly identifies all the optimal network connections, according to prediction error minimization. City-to city distance is designated as a predictor of shared temporal trends in crime and weather is shown to be a strong predictor of crime in Montgomery County. PMID- 29250477 TI - Parent-Child Behavioral Interactions during Pediatric Immunizations in a Latino Sample. AB - A number of studies have found that specific parent behaviors are strong predictors of child medical procedural distress or coping. These findings have informed treatment protocols to lower children's distress during invasive medical events. However, the vast majority of this research has been conducted on predominately North American, English-speaking, Caucasian samples. One growing population that faces healthcare disparities is Latinos living in the U.S. The purpose of this study was to explore the types and frequencies of parent and child behavior, as well as the association between parent behavior and child distress and coping in a sample of Spanish-speaking Latino-American parent-child dyads. Nineteen 4- to 6-year-old Latino children receiving routine immunizations and their parents were video recorded, and behaviors were coded with commonly used schemes. The findings suggest that there may be differences in Latino parent and child behavior when compared to the extant - predominately English-speaking, Caucasian North American - literature. This study provides an initial examination of how cultural constructs may relate to parent-child behavior in Spanish speaking Latino families in the U.S. Future research is warranted as findings can inform culturally sensitive clinical practice. PMID- 29250479 TI - A Short Report on Single Stage Transcatheter Aortic Valve Replacement and Carotid Stenting. AB - No consensus exists on the timing, safety, and efficacy of treating severe symptomatic aortic and carotid stenosis. In the older population and in the presence of multiple comorbidities that arise during the surgery, a less invasive transcatheter treatment may be the only reasonable option. We discuss this topic by analyzing a case of an 84-year-old man who underwent a combined single-stage transcatheter procedure. PMID- 29250478 TI - An Unusual Complication of Congenital Diaphragmatic Hernia. AB - A term newborn was referred to our unit with a postnatal diagnosis of a right sided congenital diaphragmatic hernia (CDH). She was managed with high-frequency oscillatory ventilation, inotropic support, and nitric oxide, with planned surgical repair when she was medically optimized. On day 6 of life, there was an acute deterioration causing difficulty maintaining adequate ventilation and the infant requiring increasing analgesia and paralysis, especially during abdominal examination. A repeat X-ray showed distended bowel loops in the right hemithorax when compared with previous films raising suspicion of bowel obstruction. The infant proceeded to emergency laparotomy in the neonatal intensive care unit. She was found to have a right-sided Bochdalek (posterolateral) defect. The entire small bowel was within the thoracic cavity and appeared dusky secondary to obstruction caused by compression of a herniated right liver lobe against the hernia defect. Bowel perfusion improved after reduction and a BioDesign patch was used to repair the defect. The infant went on to have a straightforward recovery and was transferred to her local hospital for ongoing care on day 17. Bowel obstruction is an uncommon complication in the perinatal period in infants with CDH. A high index of suspicion for bowel compromise is needed in neonates who deteriorate acutely after a period of stabilization. Imaging should be obtained as soon as possible and early surgical intervention may be life-saving. PMID- 29250480 TI - Cultural competence in working with the Arab Australian community: a conceptual review and the experience of the Arab Council Australia (ACA) gambling help counselling service. AB - Although Culturally And Linguistically Diverse (CALD) communities participate less in gambling than the general population, those who gamble are more likely to show signs of disordered gambling (Moore and Ohtsuka International Gambling Studies, 1, 87-101, 2001; Raylu and Oei Clinical Psychology Review, 23, 1087 1114, 2004; Yamine and Thomas The impact of gaming on specific cultural groups, Victorian Casino and Gaming Authority, Melbourne, 2000). Research data on gambling problems and interventions in the Arab Australian community are extremely scarce. Therefore, this article will present an overview of the Arab Australian community and cultural issues regarding gambling within the Arab Australian community. Identifying these issues is important to work effectively with Arab Australians clients and those from other CALD backgrounds. The article also presents a conceptual review of peer-reviewed research articles on cultural competence in working with the Arab clients, the overview of Arab migration history to Australia and a summary of recent events that suggest a tension between Arab and non-Arab Australian communities. Observations and experiences that were encountered during the gambling counselling service operating in the Australian Arab community in New South Wales are also discussed. The research data to validate the effectiveness and positive impact of cultural competence are still in its early stages. However, a small number of community education resources have been available for working with the Arab community. From the data in annual reviews on the Arab Council Australia gambling counselling service, it was identified that cultural beliefs and expectations influence risk-taking decisions, identification of gambling issues, and preference of help seeking within the client's social network. Further, culturally-specific sensitive issues related to political and global security events, which in turn influenced openness and willingness for the help-seeking of the Arab Australians, were identified. In conclusion, we propose that recognising diversity within the Arab Australian community is a prerequisite for increasing cultural competence and cultural sensitivity for helping professionals working with Arab Australians. PMID- 29250482 TI - Dynamic modelling and natural characteristic analysis of cycloid ball transmission using lumped stiffness method. AB - The vibration of robot joint reducer is the main factor that causes vibration or motion error of robot system. To improve the dynamic precision of robot system, the cycloid ball transmission used in robot joint is selected as study object in this paper. An efficient dynamic modelling method is presented-lumped stiffness method. Based on lumped stiffness method, a translational-torsional coupling dynamics model of cycloid ball transmission system is established. Mesh stiffness variation excitation, damping of system are all intrinsically considered in the model. The dynamic equation of system is derived by means of relative displacement relationship among different components. Then, the natural frequencies and vibration modes of the derivative system are presented by solving the associated eigenvalue problem. Finally, the influence of the main structural parameters on the natural frequency of the system is analysed. The present research can provide a new idea for dynamic analysis of robot joint reducer and provide a more simplify dynamic modelling method for robot system with joint reducer. PMID- 29250481 TI - The loss of binary: Pushing the herpesvirus latency paradigm. AB - Purpose of Review: Herpesvirus latency has been viewed as a binary state where replication is either on or off. During latency, gene expression is thought to be restricted to non-coding RNAs or very few proteins so that the virus avoids detection by the immune system. However, a number of recent studies across herpesvirus families call into question the existence of a binary switch for latency, and suggest that latency is far more dynamic than originally presumed. These studies are the focus of this review. Recent Findings: Highly sensitive and global approaches to investigate viral gene expression in the context of latency have revealed low level viral transcripts, and in some cases protein, from each of the three kinetic gene classes during the latent alpha and beta herpesvirus infection either in vitro or in vivo. Further, low level, asymptomatic virus shedding persists following acute infection. Together, these findings have raised questions about how silent the latent infection truly is. Summary: Emerging evidence suggests that viral gene expression associated with latent states may be broader and more dynamic than originally presumed during herpesvirus latency. This is an important possibility to consider in understanding the molecular programs associated with the establishment, maintenance and reactivation of herpesvirus latency. Here, we review these findings and detail how they contribute to the emergence of a biphasic model of reactivation. PMID- 29250484 TI - Predictive and Prognostic Brain Metastases Assessment in Luminal Breast Cancer Patients: FN14 and GRP94 from Diagnosis to Prophylaxis. AB - FN14 has been implicated in many intracellular signaling pathways, and GRP94 is a well-known endoplasmic reticulum protein regulated by glucose. Recently, both have been associated with metastasis progression in breast cancer patients. We studied the usefulness of FN14 and GRP94 expression to stratify breast cancer patients according their risk of brain metastasis (BrM) progression. We analyzed FN14 and GRP94 by immunohistochemistry in a retrospective multicenter study using tissue microarrays from 208 patients with breast carcinomas, of whom 52 had developed BrM. Clinical and pathological characteristics and biomarkers expression in Luminal and non-Luminal patients were analyzed using a multivariate logistic regression model adjusted for covariates, and brain metastasis-free survival (BrMFS) was estimated using the Kaplan-Meier method and the Cox proportional hazards model. FN14 expression was associated with BrM progression mainly in Luminal breast cancer patients with a sensitivity (53.85%) and specificity (89.60%) similar to Her2 expression (46.15 and 89.84%, respectively). Moreover, the likelihood to develop BrM in FN14-positive Luminal carcinomas increased 36.70-fold (3.65-368.25, p = 0.002). Furthermore, the worst prognostic factor for BrMFS in patients with Luminal carcinomas was FN14 overexpression (HR = 8.25; 95% CI: 2.77-24.61; p = 0.00015). In these patients, GRP94 overexpression also increased the risk of BrM (HR = 3.58; 95% CI: 0.98-13.11; p = 0.054-Wald test). Therefore, FN14 expression in Luminal breast carcinomas is a predictive/prognostic biomarker of BrM, which combined with GRP94 predicts BrM progression in non-Luminal tumors 4.04-fold (1.19-8.22, p = 0.025), suggesting that both biomarkers are useful to stratify BrM risk at early diagnosis. We propose a new follow-up protocol for the early prevention of clinical BrM of breast cancer patients with BrM risk. PMID- 29250485 TI - Non-Invasive Prostate Cancer Characterization with Diffusion-Weighted MRI: Insight from In silico Studies of a Transgenic Mouse Model. AB - Diffusion-weighted magnetic resonance imaging (DWI) enables non-invasive, quantitative staging of prostate cancer via measurement of the apparent diffusion coefficient (ADC) of water within tissues. In cancer, more advanced disease is often characterized by higher cellular density (cellularity), which is generally accepted to correspond to a lower measured ADC. A quantitative relationship between tissue structure and in vivo measurements of ADC has yet to be determined for prostate cancer. In this study, we establish a theoretical framework for relating ADC measurements with tissue cellularity and the proportion of space occupied by prostate lumina, both of which are estimated through automatic image processing of whole-slide digital histology samples taken from a cohort of six healthy mice and nine transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. We demonstrate that a significant inverse relationship exists between ADC and tissue cellularity that is well characterized by our model, and that a decrease of the luminal space within the prostate is associated with a decrease in ADC and more aggressive tumor subtype. The parameters estimated from our model in this mouse cohort predict the diffusion coefficient of water within the prostate-tissue to be 2.18 * 10-3 mm2/s (95% CI: 1.90, 2.55). This value is significantly lower than the diffusion coefficient of free water at body temperature suggesting that the presence of organelles and macromolecules within tissues can drastically hinder the random motion of water molecules within prostate tissue. We validate the assumptions made by our model using novel in silico analysis of whole-slide histology to provide the simulated ADC (sADC); this is demonstrated to have a significant positive correlation with in vivo measured ADC (r2 = 0.55) in our mouse population. The estimation of the structural properties of prostate tissue is vital for predicting and staging cancer aggressiveness, but prostate tissue biopsies are painful, invasive, and are prone to complications such as sepsis. The developments made in this study provide the possibility of estimating the structural properties of prostate tissue via non-invasive virtual biopsies from MRI, minimizing the need for multiple tissue biopsies and allowing sequential measurements to be made for prostate cancer monitoring. PMID- 29250483 TI - Illuminating Brain Activities with Fluorescent Protein-Based Biosensors. AB - Fluorescent protein-based biosensors are indispensable molecular tools for life science research. The invention and development of high-fidelity biosensors for a particular molecule or molecular event often catalyze important scientific breakthroughs. Understanding the structural and functional organization of brain activities remain a subject for which optical sensors are in desperate need and of growing interest. Here, we review genetically encoded fluorescent sensors for imaging neuronal activities with a focus on the design principles and optimizations of various sensors. New bioluminescent sensors useful for deep tissue imaging are also discussed. By highlighting the protein engineering efforts and experimental applications of these sensors, we can consequently analyze factors influencing their performance. Finally, we remark on how future developments can fill technological gaps and lead to new discoveries. PMID- 29250486 TI - Systemic Therapy in Metastatic or Unresectable Well Differentiated/Dedifferentiated Liposarcoma. AB - Liposarcoma is one of the most common subtypes of soft-tissue sarcoma and consists of three main subtypes, of which well-differentiated liposarcoma and dedifferentiated liposarcoma account for 40-45%. The current mainstay of systemic treatment for patients with metastatic or unresectable disease remains doxorubicin with or without ifosfamide in the first-line setting. Recently, eribulin and trabectedin have been approved by the US Food and Drug Administration for recurrent liposarcomas and progress in molecular characterization of these tumors has opened up new and potential novel treatment targets. This review will focus on the evidence base for current treatment strategies and will also discuss potential future options. PMID- 29250487 TI - Mitochondrial Dysfunction: A Novel Potential Driver of Epithelial-to-Mesenchymal Transition in Cancer. AB - Epithelial-to-mesenchymal transition (EMT) allows epithelial cancer cells to assume mesenchymal features, endowing them with enhanced motility and invasiveness, thus enabling cancer dissemination and metastatic spread. The induction of EMT is orchestrated by EMT-inducing transcription factors that switch on the expression of "mesenchymal" genes and switch off the expression of "epithelial" genes. Mitochondrial dysfunction is a hallmark of cancer and has been associated with progression to a metastatic and drug-resistant phenotype. The mechanistic link between metastasis and mitochondrial dysfunction is gradually emerging. The discovery that mitochondrial dysfunction owing to deregulated mitophagy, depletion of the mitochondrial genome (mitochondrial DNA) or mutations in Krebs' cycle enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, activate the EMT gene signature has provided evidence that mitochondrial dysfunction and EMT are interconnected. In this review, we provide an overview of the current knowledge on the role of different types of mitochondrial dysfunction in inducing EMT in cancer cells. We place emphasis on recent advances in the identification of signaling components in the mito-nuclear communication network initiated by dysfunctional mitochondria that promote cellular remodeling and EMT activation in cancer cells. PMID- 29250489 TI - Identification of Conserved ABC Importers Necessary for Intracellular Survival of Legionella pneumophila in Multiple Hosts. AB - It is established that the human pathogen Legionella pneumophila becomes significantly augmented for infection of macrophages after intracellular growth in amoebae when compared to like-strains cultivated in laboratory media. Based on this observation, we reasoned that the most critical virulence determinants of L.p. are expressed by responding to stimuli generated by the protozoan host specifically; a process we term "protozoan-priming." We sought to identify L.p. virulence factors that were required for replication in amoebae in order to highlight the genes necessary for production of the most infectious form of the bacterium. Using a transposon mutagenesis screen, we successfully identified 12 insertions that produced bacteria severely attenuated for growth in amoebae, while retaining a functional Dot/Icm type IVb secretion system. Seven of these insertion mutants were found dispensable for growth in macrophages, revealing attractive therapeutic targets that reside upstream of the pathogen-human interface. Two candidates identified, lpg0730 and lpg0122 were required for survival and replication in amoebae and macrophage host cells. Both genes are conserved among numerous important human pathogenic bacteria that can persist or replicate in amoebae. Each gene encodes a component of an ATP binding cassette (ABC) transport complex of unknown function. We demonstrate the lpg0730 ortholog in Francisella tularensis subsp. novicida to be essential for colonization of both protozoan and mammalian host cells, highlighting conserved survival mechanisms employed by bacteria that utilize protozoa as an environmental reservoir for replication. PMID- 29250488 TI - From Many Hosts, One Accidental Pathogen: The Diverse Protozoan Hosts of Legionella. AB - The 1976 outbreak of Legionnaires' disease led to the discovery of the intracellular bacterial pathogen Legionella pneumophila. Given their impact on human health, Legionella species and the mechanisms responsible for their replication within host cells are often studied in alveolar macrophages, the primary human cell type associated with disease. Despite the potential severity of individual cases of disease, Legionella are not spread from person-to-person. Thus, from the pathogen's perspective, interactions with human cells are accidents of time and space-evolutionary dead ends with no impact on Legionella's long-term survival or pathogenic trajectory. To understand Legionella as a pathogen is to understand its interaction with its natural hosts: the polyphyletic protozoa, a group of unicellular eukaryotes with a staggering amount of evolutionary diversity. While much remains to be understood about these enigmatic hosts, we summarize the current state of knowledge concerning Legionella's natural host range, the diversity of Legionella-protozoa interactions, the factors influencing these interactions, the importance of avoiding the generalization of protozoan-bacterial interactions based on a limited number of model hosts and the central role of protozoa to the biology, evolution, and persistence of Legionella in the environment. PMID- 29250490 TI - Microbiota Modulate Anxiety-Like Behavior and Endocrine Abnormalities in Hypothalamic-Pituitary-Adrenal Axis. AB - Intestinal microbes are an important system in the human body, with significant effects on behavior. An increasing body of research indicates that intestinal microbes affect brain function and neurogenesis, including sensitivity to stress. To investigate the effects of microbial colonization on behavior, we examined behavioral changes associated with hormones and hormone receptors in the hypothalamic-pituitary-adrenal (HPA) axis under stress. We tested germ-free (GF) mice and specific pathogen-free (SPF) mice, divided into four groups. A chronic restraint stress (CRS) protocol was utilized to induce external pressure in two stress groups by restraining mice in a conical centrifuge tube for 4 h per day for 21 days. After CRS, Initially, GF restraint-stressed mice explored more time than SPF restraint-stressed mice in the center and total distance of the OFT. Moreover, the CRH, ACTH, CORT, and ALD levels in HPA axis of GF restraint stressed mice exhibited a significantly greater increase than those of SPF restraint-stressed mice. Finally, the Crhr1 mRNA levels of GF CRS mice were increased compared with SPF CRS mice. However, the Nr3c2 mRNA levels of GF CRS mice were decreased compared with SPF CRS mice. All results revealed that SPF mice exhibited more anxiety-like behavior than GF mice under the same external stress. Moreover, we also found that GF mice exhibited significant differences in, hormones, and hormone receptors compared with SPF mice. In conclusion, Imbalances of the HPA axis caused by intestinal microbes could affect the neuroendocrine system in the brain, resulting in an anxiety-like behavioral phenotype. This study suggested that intervention into intestinal microflora may provide a new approach for treating stress-related diseases. PMID- 29250492 TI - Transcriptional Immunoprofiling at the Tick-Virus-Host Interface during Early Stages of Tick-Borne Encephalitis Virus Transmission. AB - Emerging and re-emerging diseases transmitted by blood feeding arthropods are significant global public health problems. Ticks transmit the greatest variety of pathogenic microorganisms of any blood feeding arthropod. Infectious agents transmitted by ticks are delivered to the vertebrate host together with saliva at the bite site. Tick salivary glands produce complex cocktails of bioactive molecules that facilitate blood feeding and pathogen transmission by modulating host hemostasis, pain/itch responses, wound healing, and both innate and adaptive immunity. In this study, we utilized Illumina Next Generation Sequencing to characterize the transcriptional immunoprofile of cutaneous immune responses to Ixodes ricinus transmitted tick-borne encephalitis virus (TBEV). A comparative immune gene expression analysis of TBEV-infected and uninfected tick feeding sites was performed. Our analysis reveals that ticks create an inflammatory environment at the bite site during the first 3 h of feeding, and significant differences in host responses were observed between TBEV-infected and uninfected tick feeding. Gene-expression analysis reveals modulation of inflammatory genes after 1 and 3 h of TBEV-infected tick feeding. Transcriptional levels of genes specific to chemokines and cytokines indicated a neutrophil-dominated immune response. Immunohistochemistry of the tick feeding site revealed that mononuclear phagocytes and fibroblasts are the primary target cells for TBEV infection and did not detect TBEV antigens in neutrophils. Together, the transcriptional and immunohistochemistry results suggest that early cutaneous host responses to TBEV infected tick feeding are more inflammatory than expected and highlight the importance of inflammatory chemokine and cytokine pathways in tick-borne flavivirus transmission. PMID- 29250493 TI - Determination of Lipoprotein Z-Specific IgA in Tuberculosis and Latent Tuberculosis Infection. AB - Tuberculosis (TB) remains one of the most severe infectious diseases. It is still of paramount importance to establish more accurate, rapid, and efficient diagnostic methods. Since infection with Mycobacterium tuberculosis (M. tb) is largely mediated through the respiratory tract, IgA responses against mycobacterial proteins are worthy of investigation for their potential clinical utility. In this study, the IgA response targeting lipoprotein Z (LppZ) was determined by using a homemade ELISA with plasma of TB patients (N = 125), LTBI individuals (N = 92), healthy controls (HCs) (N = 165), as well as TB patients undergoing anti-TB treatment (N = 9). In parallel the antigen-specific IFN-gamma release from PBMCs triggered by LppZ and M. tb-specific ESAT-6 or CFP-10 was detected by using an ELISPOT assay. It was found that the LppZ-specific IgA level was dramatically higher in TB patients than in HCs (p < 0.0001). Compared to that before anti-TB treatment, the LppZ-specific IgA level decreased substantially after 2 months of anti-TB treatment (p = 0.0297) and remained at low levels until the end of the treatment. What is more, pulmonary TB patients exhibited significantly higher LppZ-specific IgA-values than extra-pulmonary TB patients (p = 0.0296). Interestingly, the LppZ-specific IgA-values were negatively correlated to the amounts of IFN-gamma released in response to LppZ with statistical significance (r = -0.5806, p = 0.0002). LppZ-specific IgA level was also higher in LTBI individuals than in HCs (p < 0.0001). Additionally there were some PPD+ HC individuals with high LppZ-specific IgA levels but the potential of this assay for identifying leaky LTBI in PPD+ HCs needs to be further investigated through follow-up studies. The sensitivity of detecting TB solely with ESAT-6 or CFP-10 specific IFN-gamma release was increased by including the LppZ-specific IgA results, respectively, from 86.11 to 100% and 88.89 to 100%; the sensitivity of screening for LTBI was increased from 80.36 to 83.93% and 57.14 to 69.64%, respectively. The higher LppZ-specific IgA responses in TB and LTBI populations than in controls indicated high immunoreactivity to LppZ upon M. tb infection. Although the assay was not efficient enough for independent application in sero diagnosis, LppZ-specific IgA might become a complementary biomarker for the improvement of TB and LTBI screening. PMID- 29250494 TI - Diagnosis and Treatment of Inflammatory Joint Disease. AB - Arthritis damages the cartilage within joints, resulting in degenerative changes, including loss of function and joint instability. Ankylosing spondylitis (AS) is a chronic inflammatory condition affecting the spine and bone-to-tendon attachment area within the sacroiliac joint leading to back pain and progressive spinal stiffness. In the final stages, AS causes hyperkyphosis-a condition closely tied to the human leukocyte antigen-B27 gene. Rheumatoid arthritis is a chronic, systemic autoimmune disease characterized by the simultaneous inflammation of the synovium of multiple joints, leading to joint damage (e.g., destruction, deformation and disability). In the past, nonsteroidal anti inflammatory drugs or conventional disease-modifying antirheumatic drug (DMARDs) have been used for the treatment of these autoimmune diseases, but biologic DMARDs have recently been introduced with excellent results. Gout is a chronic inflammatory disease that causes an alteration of joints resulting in severe pain. Specifically, gout is associated with an accumulation of uric acid within the body resulting from dysregulated purine metabolism, causing recurrent paroxysmal inflammation in the joints. Allopurinol and febuxostat are the primary treatment options for individuals with gout. It is necessary to have an accurate understanding of the pathogenesis, pathological ecology and treatment of AS, rheumatoid arthritis, and gouty arthritis, which are the representative diseases that may cause inflammatory arthritis. PMID- 29250495 TI - Results of Total Hip Arthroplasty with 36-mm Metallic Femoral Heads on 1st Generation Highly Cross Linked Polyethylene as a Bearing Surface in Less than Forty Year-old Patients: Minimum Ten-year Results. AB - Purpose: We evaluated long-term clinical and radiographic results in patients underwent primary total hip arthroplasty (THA) using 36-mm metallic femoral head and 1st generation highly cross-linked polyethylene among patients aged 40 years and less, with minimum 10 years follow-up. Materials and Methods: We retrospectively reviewed 20 hips underwent primary THA by one hip surgeon using 36-mm femoral head and 1st generation highly cross-linked polyethylene from 2004 to 2006. Mean follow up was 131.55 months. Clinical follow-ups included functional measurements. And we evaluated post operative complications, prosthesis loosening, failure, and osteolysis. For radiologic evaluations, together with position of acetabular cup at 6 weeks later of postoperation, we separately calculated the penentrations of femoral heads into polyethylene liners during postoperation and one year later check-ups, and during one year later check-ups and final check-ups. Polywear pro3D 5.10 software was used to measure penetrations of femoral head. Results: Mean acetabular cup inclination and anteversion were 49.02 degrees and 10.19 degrees , respectively. Mean thickness of the polyethylene liner at 45 degrees was 6.44 mm. There were no major complications such as implant loosening or osteolysis, and one case of dislocation occurred. Average modified Harris hip score at final follow-up was 91, and Merle d'Aubigne and Postel scores 15 were or over. Average femoral head penetration of bedding wear was 0.170+/-0.039 mm/year. Steady-state wear rates was 0.059+/-0.006 mm/year. Conclusion: Results of THA with 36-mm metallic femoral heads on 1st generation highly cross linked as a bearing surface in less than 40 year-old patients were satisfactory. PMID- 29250496 TI - Primary Total Hip Arthroplasty Using Summit(r) Stems in Korean: Minimum Four-year Follow-up. AB - Purpose: The aim of this study was to assess the mid-term results of primary cementless total hip arthroplasty (THA) using Summit(r) stems. Materials and Methods: One hundred twenty-eight arthroplasties in 121 patients who were performed THA from December 2004 to March 2013, were reviewed retrospectively a minimum of 4 years follow-up (mean age, 60.3 years; mean postoperative follow up period, 86.3 months). For a clinical evaluation, the Harris hip score (HHS) was used to assess outcome. Radiographic evaluation was done through spot welds, subsidence, stress shielding, canal filling. Results: The mean HHS was 69.8 points preoperatively, and it improved significantly to 96.3 points at the final follow-up. Postoperatively, 10 patients experienced thigh pain and 7 patients showed a moderate limping gait. There was not only early stem subsidence but there was no more subsidence at last follow up. One hundred eighteen hips showed radiographic signs of stem bone ingrowth, and 10 hips showed fibrous ingrowth at the last follow-up. Stress shielding occurred in 85 hips and third degree stress shielding was observed in 6 hips. Complication arose in 10 hips due to dislocation. Although revisions due to recurrent dislocations led to acetabular component revision in one hip, no revisions arose due to isolated aseptic loosening of the femoral component. Conclusion: The clinical and radiological mid term results of primary THA using Summit(r) stems revealed solid initial fixation and bone ingrowth stable fixation. Considering the satisfactory clinical results, Summit(r) stems may be a good treatment option in Korean patients who were required hip arthroplasty. PMID- 29250491 TI - Human Primary Epithelial Cells Acquire an Epithelial-Mesenchymal-Transition Phenotype during Long-Term Infection by the Oral Opportunistic Pathogen, Porphyromonas gingivalis. AB - Porphyromonas gingivalis is a host-adapted oral pathogen associated with chronic periodontitis that successfully survives and persists in the oral epithelium. Recent studies have positively correlated periodontitis with increased risk and severity of oral squamous cell carcinoma (OSCC). Intriguingly, the presence of P. gingivalis enhances tumorigenic properties independently of periodontitis and has therefore been proposed as a potential etiological agent for OSCC. However, the initial host molecular changes induced by P. gingivalis infection which promote predisposition to cancerous transformation through EMT (epithelial-mesenchymal transition), has never been studied in human primary cells which more closely mimic the physiological state of cells in vivo. In this study, we examine for the first time in primary oral epithelial cells (OECs) the expression and activation of key EMT mediators during long-term P. gingivalis infection in vitro. We examined the inactive phosphorylated state of glycogen synthase kinase-3 beta (p GSK3beta) over 120 h P. gingivalis infection and found p-GSK3beta, an important EMT regulator, significantly increases over the course of infection (p < 0.01). Furthermore, we examined the expression of EMT-associated transcription factors, Slug, Snail, and Zeb1 and found significant increases (p < 0.01) over long-term P. gingivalis infection in protein and mRNA expression. Additionally, the protein expression of mesenchymal intermediate filament, Vimentin, was substantially increased over 120 h of P. gingivalis infection. Analysis of adhesion molecule E cadherin showed a significant decrease (p < 0.05) in expression and a loss of membrane localization along with beta-catenin in OECs. Matrix metalloproteinases (MMPs) 2, 7, and 9 are all markedly increased with long-term P. gingivalis infection. Finally, migration of P. gingivalis infected cells was evaluated using scratch assay in which primary OEC monolayers were wounded and treated with proliferation inhibitor, Mitomycin C. The cellular movement was determined by microscopy. Results displayed P. gingivalis infection promoted cell migration which was slightly enhanced by co-infection with Fusobacterium nucleatum, another oral opportunistic pathogen. Therefore, this study demonstrates human primary OECs acquire initial molecular/cellular changes that are consistent with EMT induction during long-term infection by P. gingivalis and provides a critically novel framework for future mechanistic studies. PMID- 29250497 TI - Extensive Surgical Wound Lavage Reduces the Incidence and Severity of Heterotopic Ossification in Primary Total Hip Replacement: A Study of 175 Hip Replacements. AB - Purpose: One of the local factors contributing to the formation of heterotopic ossification includes bone debris generated during the surgery. This risk can be partially nullified by use of saline wash. Our research aim was to ascertain if extensive intraoperative lavage can reduce the incidence and severity of heterotopic ossification in primary total hip arthroplasty. Materials and Methods: A retrospective case control radiological study of 145 patients (175 hip replacements). The control group received minimal intra-operative lavage (<1,000 mL); consisted of 90 primary hip replacements. The index group received extensive saline lavage (>3,000 mL), and included 85 primary hip replacements. Brooker classification was used to grade radiographs at one year for development of heterotopic ossification. Results: Sixty-six patients in control group had heterotopic ossification, with six showing a significant grade (grade 3 or 4). Thirty-five patients in the index group had heterotopic ossification with no incidence of severe grade. Majority patients in the index group showed a predominantly grade 1 heterotopic ossification; 28 out of 35, as compared to 37 out of 66 in control group. There was a statistically significant difference in the incidence (P<0.05) as well as severity of heterotopic ossification between the groups (P<0.05). Conclusion: We conclude that use of extensive lavage during total hip replacement reduces the incidence as well as severity of heterotopic ossification. PMID- 29250498 TI - Perioperative Comparison of Hip Arthroplasty Using the Direct Anterior Approach with the Posterolateral Approach. AB - Purpose: The aim of the current study is to report the advantage and disadvantage of total hip arthroplasty performed in direct anterior approach (DAA) by comparing it to the posterolateral approach (PLA). Materials and Methods: Twenty five hip arthroplasty done in DAA (12 total hip arthroplasty [THA] and 13 bipolar hemiarthroplasty [BHA]) were compared with the same number done in PLA (13 THA and 12 BHA). Intraoperative assessments including operation time, anesthetic time, bleeding amount were recorded with intraoperative complications. Immediate postoperatively, position of the prosthesis and leg length discrepancy were measured and were compared between the two approaches. Results: The operation time was 22 minutes and 19 minutes longer in DAA for THA and BHA respectively while the anesthetic time difference was 26 and 10 respectively. However, these parameters showed no statistical difference. No significance was found when bleeding amount was compared. For DAA, cup alignment was within safe zone in 100% both for inclination and for anteversion while this was 83.3% and 75.0% respectively in PLA. Leg length difference was 3 mm in DAA and 5 mm in PLA but had no significant difference. Tensor fascia lata tear was the most common complication occurring in 9 patients. Conclusion: Although significant was not reached there was trend toward more operation time and anesthetic time when DAA was used. However, the trend also showed that cup and stem were likely to be in more accurate position and in adequate size which is likely due to the accurate use of fluoroscopy. PMID- 29250499 TI - Utility of Radiographs, Computed Tomography, and Three Dimensional Computed Tomography Pelvis Reconstruction for Identification of Acetabular Defects in Residency Training. AB - Purpose: The Paprosky classification system of acetabular defects is complex and its reliability has been questioned. The purpose of this study was to evaluate the effectiveness of different radiologic imaging modalities in classifying acetabular defects in revision total hip arthroplasty (THA) and their value of at different levels of training. Materials and Methods: Bone defects in 8 revision THAs were classified by 2 fellowship-trained adult reconstruction surgeons. A timed presentation with representative images for each case (X-ray, two dimensional computed tomography [CT] and three-dimensional [3D] reconstructions) was shown to 35 residents from the first postgraduate year of training year of training (PGY-1 to PGY-5), 2 adult reconstruction fellows and 2 attending orthopaedic surgeons. The Paprosky classification of bone defects was recorded. The influence of image modality and level of training on classification were analyzed using chi-square analysis (alpha=0.05). Results: Overall correct classification was 30%. The level of training had no influence on correct classification (P=0.531). Using X-ray led to 37% correctly identified defects, CT scans to 33% and 3D reconstructions to 20% of correct answers (P<0.001). There was no difference in correct classification based defect type (P<0.001). Regardless of level of training or imaging, 64% of observers recognized type 1 defects, compared to only 16% correct recognition of type 3B defects. Conclusion: Using plain X-rays led to an increased number of correct classification, while regular CT scan and 3D CT reconstructions did not improve accuracy. The classification system of acetabular defects can be used for treatment decisions; however, advanced imaging may not improve its utilization. PMID- 29250500 TI - Epidemiology of Pelvic Ring Fractures in a Level 1 Trauma Center in the Netherlands. AB - Purpose: This study was conducted to study the epidemiology, classification, treatment and outcome of a large patient group with pelvic ring injury in a level 1 trauma center in the Netherlands. Materials and Methods: In the period of 2004 to 2014, we encountered 537 patients with a pelvic fracture. Many of them are due to a high energy trauma and therefore many concomitant injuries are observed. Tile A fractures were seen in 137 patients (25.5%), Tile B fractures in 211 (39.3%) and Tile C fractures in 189 patients (35.2%). Results: Patients with unstable fracture types (Tile B1 and B3, Tile C) had significantly higher injury severity score, transfusion rates, need for laparotomy and definitive operative stabilization and complication rate. However, mortality did not differ significantly among Tile A, B or C fractures. Conclusion: Overall outcome was good with a mortality rate of 13.6%, which is comparable with other rAelpmorotsst. half of the patients treated could directly be dismissed to their own homes. PMID- 29250501 TI - Fixation of Trochanteric Fragments in Cementless Bipolar Hemiarthroplasty of Unstable Intertrochanteric Fracture: Cerclage Wiring. AB - Purpose: Bipolar hemiarthroplasty (HA) is an option for the treatment of unstable intertrochanteric fracture in elderly patients. There is a raising concern regarding cable-grip related complications for the fixation of trochanteric fragments. Therefore, the aim of this study was to evaluate outcome of cementless HA with fixation for the trochanteric fragments using monofilament wires in unstable intertrochanteric fracture. Materials and Methods: We reviewed 92 cementless bipolar HAs using a grit-blasted long stem design for unstable intertrochanteric fractures in 91 elderly patients with a mean age of 81.7 years. During the arthroplasty, trochanteric fracture fragments were fixed using 1 or 2 vertical wires and transverse wires. We evaluated the clinical outcomes such as abductor power, ambulatory ability and wire-related complications, and radiologic outcomes including the union of the trochanteric fragment and subsidence of stem. Results: Sixty-two patients were followed for a minimum of 2 years (mean, 59 months) postoperatively. The mean abductor power and Koval category was 4.1 (range, 3 to 5) and 4.6 (range, 1 to 6). The wire was broken in 3 hips (4.8%) and the nonunion of the greater trochanter occurred in 1 hips (1.6%). Two stems subsided by 3 mm and 8 mm, respectively, during postoperative 6 weeks, after which the subsidence was not progressive. Conclusion: Cerclage wiring of the trochanter using monofilament wire leads to acceptable outcome in cementless HA for senile patients with unstable intertrochanteric fracture. Cerclage wiring using a monofilament wire is recommended for the fixation of trochanteric fragments. PMID- 29250502 TI - Outcomes of Cephalomedullary Nailing in Basicervical Fracture. AB - Purpose: A basicervical femoral fracture is defined as a fracture of base of neck of femur that occurs medially from intertrochanteric line above lesser trochanter. In this study, we intended to evaluate radiological and clinical results of basicervical femoral fractures treated by intramedullary nailing. Materials and Methods: Fifteen patients, who underwent intramedullary nailing among 50 patients, out of 50 who were diagnosed with basicervical femoral fractures from July 2012 to May 2015 were studied. All of 15 patients' fracture were two-part basicervical fractures. Using radiography, we characterized the: i) state of reduction, ii) location of the lag screw, iii) tip apex distance (TAD), and iv) sliding distance of lag screw and bone union. Additionally, we performed clinical assessment before injury and at final follow-up. Results: In radiological assessment, we achieved acceptable reduction state in all patients. All lag screws were fixated on appropriate locations. Mean TAD was 17.3 mm (11.0 21.1 mm), which showed insertion point of <25 mm in all cases. The mean sliding distance of the lag screw was 5.1 mm (0.1-16.0 mm) at the final follow-up. The mean bone union period was 4.8 months (3-10 months) with achieving in all cases. In clinical assessment, Harris hip score, visual analogue scale score and Western Ontario and McMaster Universities Arthritis Index score, all of them significantly improved postoperatively compared with preoperative scores (P<0.05). Conclusion: In elderly patients with basicervical femoral fractures, treatment with intramedullary nailing showed satisfactory results, considered to be a useful method if performed with skilled technique. PMID- 29250504 TI - Acetabular Insufficiency Fracture Following Prolonged Alendronate Use and the Failure of Total Hip Arthroplasty in "Frozen" Bone: Two Cases Report. AB - Atypical insufficiency fracture of the femur following prolonged bisphosphonate use is well described. Regardless of the cause, insufficiency fracture of the acetabulum is extremely rare, and no reports have described insufficiency fractures of the acetabulum that are associated with prolonged bisphosphonate use. This report demonstrates the possibility of insufficiency fracture at the acetabulum following long-term alendronate use and the necessity of particular care in managing insufficiency fractures in "frozen" bone. We describe two cases of insufficiency fracture of the acetabulum following 6 years of alendronate use. Given the patients' medical histories and bone biopsy findings, these insufficiency fractures were thought to be attributable to alendronate use. One case involved the left hip and the presence of pelvic fractures on the opposite side. The patient was treated using cementless total hip arthroplasty (THA), which failed 1 year after surgery. The hip was revised with a massive bone graft and a supportive wire mesh. The other case was managed via THA with a Ganz reinforcement ring due to concerns regarding the use of a cementless implant. PMID- 29250503 TI - Risk Factors for Neck Shortening in Patients with Valgus Impacted Femoral Neck Fractures Treated with Three Parallel Screws: Is Bone Density an Affecting Factor? AB - Purpose: The purpose of this study is to analyze the relationship between significant femoral neck shortening (SFNS) and bone density after three parallel screw fixation in valgus impacted femoral neck fracture, and to analyze the risk factors for SFNS. Materials and Methods: This is retrospective study of 83 patients. We performed univariate analysis for patient information, bone density, fracture configuration and screw position divided into SFNS group (n=13) and non SFNS group (n=70) and performed multivariate analysis using logistic regression model. We also analyzed the relationship between SFNS and complications such as osteonecrosis of femoral head and nonunion. Results: There was a significant difference in age, screw non-parallelism and bone mineral density of intertrochanteric and total hip area in the univariate analysis between the two groups (P<0.05). In multivariate analysis, old age (odds ratio [OR], 1.10; 95% confidence interval [CI], 1.03-1.21) and screw non-parallelism (OR, 2.95; 95% CI, 1.44-6.59) were significant risk factors for SFNS. The incidence of SFNS was significantly higher in the complication group (P=0.027). Conclusion: Bone density did not significantly affect SFNS in valgus impacted femoral neck fractures treated with three parallel screws. The risk factors of SFNS were old age and screw non-parallelism. Therefore, we recommend using other fixation method to prevent SFNS in older ages and making the screw position as parallel as possible when performing screw fixation in valgus impacted femoral neck fracture. PMID- 29250505 TI - Acute Isolated Tear of Gluteus Medius in Young Male. AB - The hip rotator cuff tear usually develops in the middle-aged through gradual degenerative changes, similar to rotator cuff tears in the shoulder. An acute tear in the hip abductor by a traumatic event in young ages is very uncommon. The authors experienced an unusual case of an acute traumatic tear isolated to the gluteus medius in a young male; thus, we report the treatment results in this rare case with a review of the literature. PMID- 29250506 TI - Development of second primary cancer in Korean breast cancer survivors. AB - Purpose: Breast cancer survivors have slightly increased the risk of second primary cancers. Breast, colon, uterine, and ovarian cancers are common secondary cancers in breast cancer survivors. In this study, we assessed the development of second primary cancers of breast cancer survivors in Korea. Methods: Medical records of patients with breast cancer in 3 tertiary medical institutions were reviewed retrospectively. We evaluated secondary malignancy diagnosed at least 2 months after the breast cancer diagnosis. Based on the International Classification of Disease-9 codes of malignancies, secondary primary breast cancer records were evaluated with person-year adjustment. The standardized incidence ratio (SIR) was assessed using national cancer incidence. Results: A total of 3,444 treatment records were included from 3 medical centers. The cumulative incidence of overall second primary cancers was 2.8% (n = 93). The SIR was significantly higher in all sites (1.56; 95% confidence interval [CI], 1.26 1.91), endometrial cancer (5.65; 95% CI, 2.06-12.31), biliary tract cancer (3.96; 95% CI, 1.19-8.60), and thyroid cancer (2.29; 95% CI, 1.67-3.08). Conclusion: The incidence of cancer was higher in breast cancer survivors compared to general population. Surveillance of secondary cancer in this group should be recommended individually considering the benefit related to the prognosis of primary breast cancer. PMID- 29250507 TI - Increased survival in hepatitis c patients who underwent living donor liver transplant: a case-control study with propensity score matching. AB - Purpose: There is no consensus regarding the difference in outcomes of HCV in patients who receive living donor liver transplantation (LDLT) or compared to deceased donor liver transplantation (DDLT). The aims of this study were to compare characteristics between LDLT and DDLT groups and to identify risk factors affecting patient survival. Methods: We retrospectively reviewed the multicenter records of 192 HCV RNA-positive patients who underwent liver transplantation. Results: Thirty-five patients underwent DDLT, and 146 underwent LDLT. The 1-, 3-, and 5-year patient survival rates were 66.7%, 63.0%, and 63.0% in the DDLT group and 86.1%, 82.3%, and 79.5% in the LDLT group (P = 0.024), respectively. After propensity matching, the patient survival curve of the LDLT group was higher than that of the DDLT group. However, there was no statistically significant difference in patient survival between the 2 groups (P = 0.061). Recipient age >= 60 years, LDLT, and use of tacrolimus were positively associated with patient survival in multivariate analyses. Conclusion: LDLT appears to be suitable for HCV-infected patients if appropriate living donor is available. PMID- 29250508 TI - Quantitative assessment of liver fibrosis using shore durometer. AB - Purpose: The purpose of the present study was to investigate whether hardness of liver surface correlated with degree of liver fibrosis, and its association with posthepatectomy liver failure (PHLF). Methods: A shore durometer was used to measure hepatic hardness in 41 patients with hepatocellular carcinoma (HCC) and in 10 patients with normal liver. We investigated how hepatic hardness correlates with various values indicating the degree of liver fibrosis, and how it correlates with PHLF. Results: In the normal liver group, the surface shore units (SU) was 15.06 +/- 2.64. In the HCC group, there was a correlation between surface SU and preoperative results indicating liver fibrosis. Among patients with PHLF after resecting over 3 segments, the surface SU of patients with grade A PHLF was 21.85 +/- 5.63, and the surface SU of patients with grade C PHLF was 35.75 +/- 9.26. In patients with PHLF after resecting 2 or less segments, the surface SU of patients with PHLF grade A was 20.95 +/- 5.18, and the surface SU of patients with PHLF grade B was 31.60 +/- 5.57. In predicting PHLF, surface SU was more effective than preoperative platelet count, spleen volume, or liver fibrosis index. Conclusion: Hepatic hardness measured by the shore durometer was correlated with the degree of liver fibrosis. Liver surface SU was a more effective parameter for predicting PHLF, as compared to other indicators evaluated before hepatectomy. The decision to perform major hepatectomy should be reconsidered in cases with a liver surface SU of >30. PMID- 29250509 TI - Laparoscopic reinforcement suture on staple-line of duodenal stump using barbed suture during laparoscopic gastrectomy for gastric cancer. AB - Purpose: Duodenal stump fistula (DSF) is a serious complication after gastrectomy for gastric cancer. Although risk evaluation and management of DSF were presented by some investigators, there was no technical attempt has been made to prevent DSF during laparoscopic gastrectomy until now. Methods: Consecutive 99 patients were enrolled from April 2014 to February 2016 in 2 institutes. All patients were performed laparoscopic gastrectomy for gastric cancer. After cutting of duodenal stump, laparoscopic reinforcement suture (LARS) commenced with continuous invagination method or interrupted method by barbed suture. Clinicopathologic features and postoperative outcomes were analyzed. Results: Fifty-six patients had comorbidity including 5 patients with duodenal ulcer. Most patients were performed distal gastrectomy with B-II, and 10 patients total gastrectomy with Roux en Y esophagojejunostomy. Although there were 2 esophagojejunostomy leakage and 1 artificial lesser curvature leakage, DSF did not occurred at all in this study. Mean operation time was 3 hours and mean LARS procedure time was 8 minutes. Conclusion: LARS of duodenal stump can be considered as one of prevention methods of DSF during laparoscopic gastrectomy for gastric cancer. So this new technique will be necessary to appropriately evaluate by prospective randomized controlled trial in the future. PMID- 29250510 TI - Clinical features of gastric emptying after distal gastrectomy. AB - Purpose: Gastric emptying may influence the quality of life of patients who undergo distal gastrectomy. Little is known, however, about gastric emptying after distal gastrectomy. The aim of our study was to investigate gastric emptying patterns after distal gastrectomy. Methods: This gastric-emptying study investigated patients who underwent distal gastrectomy in the 6 months or more before May 2008 to July 2013 at Chungbuk National University Hospital with a study sample of 205 patients. We analyzed patterns of gastric emptying. Results: Delayed gastric emptying was found in 109 of the 205 patients (53.2%). Food stasis was more frequent in a group with delayed gastric emptying. In multivariate analysis, risk factors for gastroparesis were laparoscopic operation (hazard ratio [HR], 2.731; P = 0.008) and duration of less than 24 months after distal gastrectomy (HR, 2.795; P = 0.001). Delayed gastric emptying tended to decrease with duration of the postoperative period. Conclusion: Delayed gastric emptying is common in distal gastrectomy, and is related to laparoscopic operation and duration of the postoperative period. Food stasis was more frequent in a group with delayed gastric emptying. PMID- 29250512 TI - Comparison of partially-absorbable lightweight mesh with heavyweight mesh for inguinal hernia repair: multicenter randomized study. AB - Purpose: Prosthetic mesh is widely used for inguinal hernia repair; however, pain and stiffness can develop. This study was a prospective, multicenter, single blind, randomized trial to assess postoperative pain and quality of life according to mesh type after inguinal hernia repair. Methods: Forty-seven patients who underwent Lichtenstein repair for unilateral inguinal hernia with prosthetic mesh were enrolled and randomly allocated to the partially-absorbable lightweight mesh (LW group, n = 24) or heavyweight mesh group (HW group, n = 23). Data were collected using a visual analogue scale (VAS), Carolinas Comfort Scale (CCS), and Activities Assessment Scale (AAS) at screening and postoperative day 1, 7, 90, and 120; foreign body sensation, sense of stiffness, and sense of pull during activity were also evaluated. Results: There were no significant differences in patients' demographics and clinical characteristics between groups. The VAS at day 90 was significantly lower in the LW group (0.46 +/- 0.78 vs. 0.96 +/- 0.82, P = 0.027). The CCS and AAS were significantly lower in the LW group at day 1 (51.33 +/- 20.29 vs. 64.65 +/- 22.64, P = 0.047 and 39.83 +/- 9.88 vs. 46.43 +/- 7.82, P = 0.015, respectively). Foreign body sensation was significantly lower in the LW group at day 120 (4.2% vs. 30.4 %, P = 0.023), as was sense of stiffness (P = 0.023). The sense of pull during activity was lower in the LW group at day 90 and 120 (P = 0.012 and P = 0.022, respectively). There was no recurrence or serious complication during follow-up. Conclusion: Partially absorbable lightweight prosthetic mesh can be used for inguinal hernia repair safely and improve functional outcomes and quality of life after surgery. PMID- 29250511 TI - Efficacy and safety of a novel partially absorbable mesh in totally extraperitoneal hernia repair. AB - Purpose: Partially absorbable mesh has been introduced and used for inguinal hernia repair for the purpose of minimizing pain and improving abdominal wall compliance. In this study, we evaluate the efficacy and safety of ProFlex mesh, a partially absorbed mesh with new structural architecture. Methods: We retrospectively reviewed 64 cases of totally extraperitoneal herniorrhapy (TEP) from January 2013 to December 2014 for their clinical features, including operation time, pain, postoperative complications, and recurrence. Results: There were no significant differences in operation time, hospital stay, postoperative pain, or complications between the 28 patients who received the ProFlex mesh and the 36 who received nonabsorbable lightweight mesh, although one patient who received the nonabsorbable had a recurrence during follow-up. There were differences in operation time, complications, and hospital stay according to the surgeon's previous operation volume. Conclusion: This study showed that there were significant differences in the fixation strength of different polypropylene meshes in combination with various fibrin glues. ProFlex, a partially absorbable mesh with new architecture, was feasible and safe in TEP. PMID- 29250513 TI - Extensive silicone lymphadenopathy after breast implant insertion mimicking malignant lymphadenopathy. AB - Silicone implants are widely used in aesthetic and reconstructive breast surgery. Silicone lymphadenopathy is a well-known rare complication of implant insertion. Silicone leakage from a rupture or silicone bleeding can accumulate in lymph nodes. Foreign body reactions in the affected lymph nodes may be misdiagnosed as metastasis or malignant lymphadeno pathy upon initial presentation if silicone lymphadenopathy is not considered in the initial diagnosis. We report a case of siliconoma with extensive involvement of multiple lymph nodes mimicking malignant features to emphasize that clinicians should carefully evaluate each patient's medical history and disease status during differential diagnosis. PMID- 29250514 TI - Perianal Paget disease: a report of 2 cases. AB - Extramammary Paget disease (EMPD) is a rare cutaneous neoplasm. Perianal Paget disease (PPD) is a subset of EMPD manifesting perianal lesions. Two cases of PPD in Severance Hospital are described in this article. A 65-year-old female and 78 year-old male patients visited our institution because of an unhealed perianal skin lesion despite treatment for a long period with topical agents. PPD was diagnosed by skin biopsies in both cases, and the patients underwent surgical treatment. Clinical manifestations, preoperative work-ups, and surgical treatments including different reconstruction methods are described in detail. As only sporadic PPD cases have been reported and no standard treatment has been established, we hope that our experience could contribute to improving the diagnosis and treatment of PPD patients. PMID- 29250515 TI - Basics of Functional Echocardiography in Children and Neonates. AB - Functional echocardiography has become an invaluable tool in the pediatric and neonatal intensive care unit. "Point-of-care," "target," or "focus" echocardiography allows bedside cardiac ultrasound evaluation of the hemodynamic status of the patient, helps in directing treatment, thus improves patients care. In order to be able to perform functional echocardiography, it is essential to understand the principles of ultrasound, to know the echocardiographic equipment and settings necessary to acquire the images. This article focuses therefore on the basics of cardiac ultrasound. It is meant to give an overview of two dimensional echocardiographic views, M-mode imaging and Doppler echocardiography for neonatologists and pediatric intensivists. It is richly illustrated for better understanding with some examples of clinical applications of functional echocardiography in the intensive care setting. PMID- 29250516 TI - Use of Therapeutic Plasma Exchange during Extracorporeal Life Support in Critically Ill Cardiac Children with Thrombocytopenia-Associated Multi-Organ Failure. AB - Background: Thrombocytopenia-associated multi-organ failure (TAMOF) in children is a well-described factor for increased hospital mortality. Low cardiac output syndrome (LCOS) and the effects of cardiopulmonary bypass may manifest with several adverse physiologic and immunologic effects, with varying degrees of thrombocytopenia and multi-organ dysfunction, sometimes very similar to TAMOF. LCOS is a common occurrence in children with critical heart disease, presenting in as much as 23.8% of infants postoperative of congenital heart surgery. Therapeutic plasma exchange (TPE) has been offered as a promising therapy for TAMOF; however, the therapeutic implications of this modality in children with critical heart disease and a clinical diagnosis of TAMOF are unknown. Objectives: We describe our institutional experience with TPE as an adjuvant rescue therapy for children with critical heart disease and a clinical diagnosis of TAMOF, while supported by extracorporeal membrane oxygenation (ECMO). Methods: Single-center retrospective analysis of children with critical heart disease admitted to the CICU and supported by ECMO, undergoing TPE for a clinical diagnosis of TAMOF between January 2006 and June 2015. Results: Forty-one patients were included for analysis. Median age and weight of patients was 0.6 years (range 0.0-17.2) and 8.5 kg (range 1.5-80.0). TPE was initiated at a median of 1 day (0-13) after initiation of ECMO. Modified organ failure index (MOFI) and platelet count improved after TPE start (p < 0.001). Patients with early TPE initiation after ECMO cannulation (<1 day) showed more improvement in MOFI and platelet counts than patients with late TPE initiation (p < 0.001 for each). Overall survival to hospital discharge was 53.7%. The within-groups hospital survival was 73.3% for patients with heart failure, 34.8% for patients with congenital heart disease, and 100% for those with other cardiac disease (p = 0.016). Conclusion: In children with critical cardiac disease and clinical diagnosis of TAMOF necessitating ECMO for hemodynamic support, concurrent TPE may be associated with an improvement in organ failure and platelet count, particularly when started early. Further studies are warranted to establish the most effective use of TPE and its effect on survival in this population. PMID- 29250517 TI - Serum Interleukin-6 and CCL11/Eotaxin May Be Suitable Biomarkers for the Diagnosis of Chronic Nonbacterial Osteomyelitis. AB - Objectives: Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis (CNO), is an autoinflammatory bone disorder. In the absence of diagnostic criteria or biomarkers, CNO/CRMO remains a diagnosis of exclusion. The aim of this study was to identify biomarkers for diagnosing multifocal disease (CRMO). Study design: Sera from 71 pediatric CRMO patients, 11 patients with osteoarticular infections, 62 patients with juvenile idiopathic arthritis (JIA), 7 patients with para-infectious or reactive arthritis, and 43 patients with acute leukemia or lymphoma, as well as 59 healthy individuals were collected. Multiplex analysis of 18 inflammation- and/or bone remodeling-associated serum proteins was performed. Statistical analysis included univariate ANOVA, discriminant analysis, univariate receiver operating characteristic (ROC) analysis, and logistic regression analyses. Results: For 14 of 18 blood serum proteins, significant differences were determined between CRMO patients, at least one alternative diagnosis, or healthy controls. Multi component discriminant analysis delivered five biomarkers (IL-6, CCL11/eotaxin, CCL5/RANTES, collagen Ialpha, sIL-2R) for the diagnosis of CRMO. ROC analysis allowed further reduction to a core set of 2 biomarkers (CCL11/eotaxin, IL-6) that are sufficient to discern between CRMO, healthy controls, and alternative diagnoses. Conclusion: Serum biomarkers CCL11/eotaxin and IL-6 differentiate between patients with CRMO, healthy controls, and alternative diagnoses (leukemia and lymphoma, osteoarticular infections, para-infectious arthritis, and JIA). Easily accessible biomarkers may aid in diagnosing CRMO. Further studies testing biomarkers in larger unrelated cohorts are warranted. PMID- 29250518 TI - Whole-Genome Sequencing in Newborn Screening-Attitudes and Opinions of Bulgarian Pediatricians and Geneticists. AB - Objective: The aim of this study was to assess the attitudes and opinions on the potential use of whole-genome sequencing (WGS) in conjunction with the traditional newborn screening (NBS). We conducted an online survey among pediatricians and geneticists from Bulgaria. The study was based on the concept of non-selective WGS for all newborns and analysis of all genes. Results/conclusion: In total, 120 out of 299 invited participants completed the survey, with an overall response rate of 40.1%. While half of the pediatricians surveyed supported population-based non-selective WGS in NBS, 65.2% of the geneticists expressed concerns. Most participants underlined that ethical issues were as important as medical ones and called for a stricter protection of affected individuals against any abuse of their personal data. Extensive genetic counseling and psychological support to families were mentioned as key elements in this potential activity. Nevertheless, both pediatricians and geneticists considered that NBS in Bulgaria could be further developed, with selective WGS being suggested as a potential option. While non-selective WGS for all newborns is not currently perceived as feasible, pediatricians and geneticists do believe that selective WGS could strengthen current NBS programs. Cross-border project collaborations may set the stage for generating experience and evidence on these complex issues. PMID- 29250519 TI - Evaluating the Surveillance System for Spotted Fever in Brazil Using Machine Learning Techniques. AB - This work analyses the performance of the Brazilian spotted fever (SF) surveillance system in diagnosing and confirming suspected cases in the state of Rio de Janeiro (RJ), from 2007 to 2016 (July) using machine-learning techniques. Of the 890 cases reported to the Disease Notification Information System (SINAN), 11.7% were confirmed as SF, 2.9% as dengue, 1.6% as leptospirosis, and 0.7% as tick bite allergy, with the remainder being diagnosed as other categories (10.5%) or unspecified (72.7%). This study confirms the existence of obstacles in the diagnostic classification of suspected cases of SF by clinical signs and symptoms. Unlike man-capybara contact (1.7% of cases), man-tick contact (71.2%) represents an important risk indicator for SF. The analysis of decision trees highlights some clinical symptoms related to SF patient death or cure, such as: respiratory distress, convulsion, shock, petechiae, coma, icterus, and diarrhea. Moreover, cartographic techniques document patient transit between RJ and bordering states and within RJ itself. This work recommends some changes to SINAN that would provide a greater understanding of the dynamics of SF and serve as a model for other endemic areas in Brazil. PMID- 29250520 TI - Design, Synthesis, and Evaluation of Ribose-Modified Anilinopyrimidine Derivatives as EGFR Tyrosine Kinase Inhibitors. AB - The synthesis of a series of ribose-modified anilinopyrimidine derivatives was efficiently achieved by utilizing DBU or tBuOLi-promoted coupling of ribosyl alcohols with 2,4,5-trichloropyrimidine as key step. Preliminary biological evaluation of this type of compounds as new EGFR tyrosine kinase inhibitors for combating EGFR L858R/T790M mutant associated with drug resistance in the treatment of non-small cell lung cancer revealed that 3-N-acryloyl-5-O anilinopyrimidine ribose derivative 1a possessed potent and specific inhibitory activity against EGFR L858R/T790M over WT EGFR. Based upon molecular docking studies of the binding mode between compound 1a and EGFR, the distance between the Michael receptor and the pyrimidine scaffold is considered as an important factor for the inhibitory potency and future design of selective EGFR tyrosine kinase inhibitors against EGFR L858R/T790M mutants. PMID- 29250521 TI - Mitotic Regulation by NEK Kinase Networks. AB - Genetic studies in yeast and Drosophila led to identification of cyclin-dependent kinases (CDKs), Polo-like kinases (PLKs) and Aurora kinases as essential regulators of mitosis. These enzymes have since been found in the majority of eukaryotes and their cell cycle-related functions characterized in great detail. However, genetic studies in another fungal species, Aspergillus nidulans, identified a distinct family of protein kinases, the NEKs, that are also widely conserved and have key roles in the cell cycle, but which remain less well studied. Nevertheless, it is now clear that multiple NEK family members act in networks to regulate specific events of mitosis, including centrosome separation, spindle assembly and cytokinesis. Here, we describe our current understanding of how the NEK kinases contribute to these processes, particularly through targeted phosphorylation of proteins associated with the microtubule cytoskeleton. We also present the latest findings on molecular events that control the activation state of the NEKs and how these are revealing novel modes of enzymatic regulation relevant not only to other kinases but also to pathological mechanisms of disease. PMID- 29250524 TI - Editorial: Are Rodent Models Fit for Investigation of Human Obesity and Related Diseases? PMID- 29250522 TI - Fibromyalgia Syndrome: A Metabolic Approach Grounded in Biochemistry for the Remission of Symptoms. AB - Fibromyalgia syndrome (FMS) is a chronic, complex, and heterogeneous disorder of still poorly understood etiopathophysiology associated with important musculoskeletal widespread pain, fatigue, non-restorative sleep, and mood disturbances. It is estimated to afflict 2-3% of the worldwide population, with clean prevalence among women. The objective of this paper is to propose a novel treatment for symptomatic remission of FMS, grounded in biochemistry and consisting in the withdrawal from the diet of molecules that can indirectly trigger the symptoms. The hypothesis develops from the evidence that low serotonin levels are involved in FMS. Serotonin is synthesized starting from the essential amino acid tryptophan. The presence of non-absorbed molecules in the gut, primarily fructose, reduces tryptophan absorption. Low tryptophan absorption leads to low serotonin synthesis that triggers FMS symptoms. Moreover not absorbed sugars could also produce a microbiota deterioration activating a positive feedback loop: the increasing microbiota deterioration reduces the functionality of absorption both of fructose and tryptophan in the gut, entering a vicious circle. The therapeutic idea is to sustain serotonin synthesis allowing the proper tryptophan absorption. The core of the cure treatment is the exclusion from the diet of some carbohydrates and the marked reduction of some others. The main target is the limitation of total dietary fructose as marked as possible. It could be an effective strategy to get the remission of symptoms acting on the impaired biochemical pathways. The straying from the treatment is expected to cause the reappear of the symptoms. PMID- 29250523 TI - User Experience, Actual Use, and Effectiveness of an Information Communication Technology-Supported Home Exercise Program for Pre-Frail Older Adults. AB - Objective: The main objective of this study was to investigate the use and user experience of an Information Communication Technology-supported home exercise program when offered for independent use to pre-frail older adults. Our secondary aim was to explore whether the program improved quality of life and health status compared to a control group. Methods: A cohort multiple randomized controlled trail is being performed. Physically pre-frail older adults (65-75 years) living independently at home were included and randomly assigned to a control group or an intervention group. The intervention group received a home exercise program (strength, balance, and flexibility exercises) for a minimal duration of 12 weeks. The control group received usual care. Primary outcomes were: use of the intervention (frequency and duration), adherence to a 3-day exercise protocol and user experience [System Usability Scale (SUS); rating 1-10]. Secondary outcomes were quality of life measured with the SF12 (Physical Component Scale and Mental Component Scale) and health status (EQ-5D), assessed before the study starts and after 12 weeks of exercising. Results: Thirty-seven independently living older adults participated in the study. Sixteen participants were allocated to the intervention group and 21 to the control group. The average score on the SUS was 84.2 (+/-13.3), almost reaching an excellent score. Participants rated the intervention with an 8.5. Eighty percent of the participants finished the 12 week exercise protocol. The adherence to the 3-day exercise protocol was 68%. Participants in the intervention group trained on average 2.2 times (+/-1.3) each week. The mean duration of login for each exercise session was 24 min. The Mental Component Scale of the SF12 was significantly higher in the intervention group compared to the control group. A trend was seen in the change over time in the health status between groups. Conclusions: This study provides evidence that a home-based exercise program is easy to use and has potential in improving quality of life and health status of pre-frail older adults who live at home. However, further refinement of the program is required to improve adherence and maximize the benefits and potential of exercising in the home environment. Trial Registration: Unique Identifier: NTR5304. URL: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5304. PMID- 29250525 TI - Early Surgical Intervention following Inguinal Hernia Repair with Severe Postoperative Pain. AB - Introduction: Severe postoperative pain is an important risk factor for onset of chronic inguinal pain following inguinal hernia repair. All measures must be taken to eliminate postoperative pain. Materials and methods: This case report highlights the problems of severe postoperative pain following transabdominal preperitoneal patch plasty (TAPP) inguinal hernia repair and describes a systematic treatment path that may include surgical intervention. Results: Following TAPP operation for lateral inguinal hernia, this patient who had been operated on in an external hospital still experienced intense, stabbing inguinal pain on postoperative day 7 during movement, despite optimal pain treatment. Diagnostic examination did not reveal any findings of note. The surgical report documented that the surgeon had used metallic tacks for mesh fixation, i.e., at the pectineal line of the pubic bone, pubic symphysis, upper margin of the mesh, and for closure of the peritoneum. During surgical revision on postoperative day 7, eight tacks and the mesh were removed and, following further dissection, a new mesh was placed and fixed with glue. The patient's intense stabbing pain resolved immediately after surgery. Conclusion: Since the results of late intervention for chronic inguinal pain are anything but satisfactory, early surgical intervention should be considered for patients with severe postoperative pain >3 days of suspected surgical origin. PMID- 29250526 TI - MK-STYX Alters the Morphology of Primary Neurons, and Outgrowths in MK-STYX Overexpressing PC-12 Cells Develop a Neuronal Phenotype. AB - We previously reported that the pseudophosphatase MK-STYX (mitogen activated kinase phosphoserine/threonine/tyrosine binding protein) dramatically increases the number of what appeared to be primary neurites in rat pheochromocytoma (PC 12) cells; however, the question remained whether these MK-STYX-induced outgrowths were bona fide neurites, and formed synapses. Here, we report that microtubules and microfilaments, components of the cytoskeleton that are involved in the formation of neurites, are present in MK-STYX-induced outgrowths. In addition, in response to nerve growth factor (NGF), MK-STYX-expressing cells produced more growth cones than non-MK-STYX-expressing cells, further supporting a model in which MK-STYX has a role in actin signaling. Furthermore, immunoblot analysis demonstrates that MK-STYX modulates actin expression. Transmission electron microscopy confirmed that MK-STYX-induced neurites form synapses. To determine whether these MK-STYX-induced neurites have pre-synaptic or post synaptic properties, we used classical markers for axons and dendrites, Tau-1 and MAP2 (microtubule associated protein 2), respectively. MK-STYX induced neurites were dopaminergic and expression of both Tau-1 and MAP2 suggests that they have both axonal and dendritic properties. Further studies in rat hippocampal primary neurons demonstrated that MK-STYX altered their morphology. A significant number of primary neurons in the presence of MK-STYX had more than the normal number of primary neurites. Our data illustrate the novel findings that MK-STYX induces outgrowths in PC-12 cells that fit the criteria for neurites, have a greater number of growth cones, form synapses, and have pre-synaptic and post-synaptic properties. It also highlights that the pseudophosphatase MK-STYX significantly alters the morphology of primary neurons. PMID- 29250527 TI - Competitive Inhibitors Unveil Structure/Function Relationships in Human D-Amino Acid Oxidase. AB - D-amino acid oxidase (DAAO) catalyzes the oxidative deamination of several neutral D-amino acids and is the enzyme mainly responsible (together with serine racemase) for degrading D-serine (D-Ser) in the central nervous system of mammals. This D-amino acid, which binds the coagonist site of the N-methyl-D aspartate receptor, is thus a key neuromodulator of glutamatergic neurotransmission. Altered D-Ser metabolism results in several pathological conditions (e.g., amylotrophic lateral sclerosis or schizophrenia, SZ) for which effective "broad spectrum" pharmaceutical drugs are not yet available. In particular, the correlation between reduced D-Ser concentration and SZ led to a renaissance of biochemical interest in human DAAO (hDAAO). In the last 10 years, public and corporate research laboratories undertook huge efforts to study the structural, enzymatic, and physiological properties of the human flavoenzyme and to identify novel effective inhibitors which, acting as pharmaceutical drugs, could decrease hDAAO activity, thus restoring the physiological concentration of D-Ser. Although, none of the identified hDAAO inhibitors has reached the market yet, from a biochemical point of view, these compounds turned out to be invaluable for gaining a detailed understanding of the structure/function relationships at the molecular level in the mammalian DAAO, in particular of the interaction between ligand and the enzyme. This detailed knowledge, together with several recent studies concerning the interaction of the human enzyme with other protein regulative partners, its subcellular localization, and in vivo degradation, contributed to gaining comprehensive knowledge of the structure, function, and physiopathological role of this important human enzyme. PMID- 29250528 TI - Questionnaire-Based Assessment of Wild Boar/Domestic Pig Interactions and Implications for Disease Risk Management in Corsica. AB - Wild boars and domestic pigs belong to the same species (Sus scrofa). When sympatric populations of wild boars, feral pigs, and domestic pigs share the same environment, interactions between domestic and wild suids (IDWS) are suspected to facilitate the spread and maintenance of several pig pathogens which can impact on public health and pig production. However, information on the nature and factors facilitating those IDWS are rarely described in the literature. In order to understand the occurrence, nature, and the factors facilitating IDWS, a total of 85 semi-structured interviews were implemented face to face among 25 strict farmers, 20 strict hunters, and 40 hunting farmers in the main traditional pig farming regions of Corsica, where IDWS are suspected to be common and widespread. Different forms of IDWS were described: those linked with sexual attraction of wild boars by domestic sows (including sexual interactions and fights between wild and domestic boars) were most frequently reported (by 61 and 44% of the respondents, respectively) in the autumn months and early winter. Foraging around common food or water was equally frequent (reported by 60% of the respondents) but spread all along the year except in winter. Spatially, IDWS were more frequent in higher altitude pastures were pig herds remain unattended during summer and autumn months with limited human presence. Abandonment of carcasses and carcass offal in the forest were equally frequent and efficient form of IDWS reported by 70% of the respondents. Certain traditional practices already implemented by hunters and farmers had the potential to mitigate IDWS in the local context. This study provided quantitative evidence of the nature of different IDWS in the context of extensive commercial outdoor pig farming in Corsica and identified their spatial and temporal trends. The identification of those trends is useful to target suitable times and locations to develop further ecological investigations of IDWS at a finer scale in order to better understand diseases transmission patterns between populations and promote adapted management strategies. PMID- 29250529 TI - The effectiveness of a nurse-led illness perception intervention in COPD patients: a cluster randomised trial in primary care. AB - The new COPD-GRIP (Chronic Obstructive Pulmonary Disease - Guidance, Research on Illness Perception) intervention translates evidence regarding illness perceptions and health-related quality of life (HRQoL) into a nurse intervention to guide COPD patients and to improve health outcomes. It describes how to assess and discuss illness perceptions in a structured way. This study aimed to assess the effectiveness of the intervention in primary care. A cluster randomised controlled trial was conducted within 30 general practices and five home-care centres, including 204 COPD patients. 103 patients were randomly assigned to the intervention group and 101 patients to the usual-care group. To assess differences, repeated multilevel linear mixed modelling analyses were used. Primary outcome was change in health status on the Clinical COPD Questionnaire (CCQ) at 9 months. Secondary outcomes were HRQoL, daily activities, health education impact and changes in illness perceptions. There was no significant difference between the groups in the CCQ at 9 months. We found a significant increase in health-directed behaviour at 6 weeks (p=0.024) and in personal control (p=0.005) at 9 months in favour of the intervention group. The COPD-GRIP intervention, practised by nurses, did not improve health status in COPD patients in primary care. However, the intervention has benefits in improving the ability to control the disease and health-related behaviours in the short term. Therefore, taking illness perceptions into account when stimulating healthy behaviours in COPD patients should be considered. Further study on influencing the health status and HRQoL is needed. PMID- 29250530 TI - The impact of different spirometric definitions on the prevalence of airway obstruction and their association with respiratory symptoms. AB - The fixed ratio criterion of forced expiratory volume in 1 s/forced vital capacity <0.70 for diagnosing airway obstruction may overdiagnose the condition, particularly in the elderly, so the lower limit of normal (LLN) is recommended as the most appropriate criterion. Our aim was to compare LLN versus fixed ratio on the prevalence of chronic obstructive pulmonary disease (COPD) and examine the association between respiratory symptoms and airway obstruction defined by LLN and fixed ratio. 12 449 twins aged 40-80 years participated in a nationwide survey using the Danish Twin Registry. They completed a questionnaire, underwent clinical examination and recorded prebronchodilator spirometry. Individuals with self-reported asthma were excluded. Clinical COPD was defined by respiratory symptoms together with airway obstruction. 10 329 individuals were included, with a mean+/-sd age of 58.4+/-9.6 years and mean body mass index of 26.6+/-4.4 kg.m 2; 20% were current smokers, 37% former smokers and 43% never-smokers; and 48% were male. The prevalence of LLN airway obstruction (LLN-AO) and fixed ratio airway obstruction (FR-AO) was 5.6% and 18.0%, respectively (p<0.001). Overall, 26% reported current respiratory symptoms, but 50% of those with LLN-AO had respiratory symptoms compared to 39% with FR-AO, p<0.001. The prevalence of clinical LLN-COPD and fixed ratio COPD was 2.6% and 6.3%, respectively (p<0.001). Individuals with LLN-AO had a significantly higher probability of reporting respiratory symptoms compared with both healthy individuals and FR-AO when adjusted for sex, age and ever-smoking. The use of fixed ratio more than doubled the prevalence of clinical COPD compared with LLN, this being more pronounced with increased age, and identified subjects with a lower prevalence of respiratory symptoms than LLN-AO. PMID- 29250531 TI - Impact of Blood Vessel Quantity and Vascular Expression of CD133 and ICAM-1 on Survival of Glioblastoma Patients. AB - Glioblastoma (GB) is the most angiogenic tumor. Nevertheless, antiangiogenic therapy has not shown significant clinical efficacy. The aim of this study was to assess blood vessel characteristics on survival of GB patients. Surgically excised GB tissues were histologically examined for overall proportion of glomeruloid microvascular proliferation (MP) and the total number of blood vessels. Also, immunohistochemical vascular staining intensities of CD133 and ICAM-1 were determined. Vessel parameters were correlated with patients' overall survival. The survival time depended on the number of blood vessels (p = 0.03) but not on the proportion of MP. Median survival times for patients with low (=median) number of blood vessels were 9.0 months (95% CI: 7.5-10.5) and 12.0 months (95% CI: 9.3-14.7). Also, median survival times for patients with low (=median) vascular expression level of CD133 were 9.0 months (95% CI: 8.0-10.1) and 12.0 months (95% CI: 10.3-13.7). In contrast, the staining intensity of vascular ICAM-1 did not affect survival. In multivariate analysis, the number of blood vessels emerged as an independent predictor for longer overall survival (HR: 2.4, 95% CI: 1.2-5.0, p = 0.02). For success in antiangiogenic therapy, better understanding about tumor vasculature biology is needed. PMID- 29250532 TI - Insights on Genomic and Molecular Alterations in Multiple Myeloma and Their Incorporation towards Risk-Adapted Treatment Strategy: Concise Clinical Review. AB - Although recent advances in novel treatment approaches and therapeutics have shifted the treatment landscape of multiple myeloma, it remains an incurable plasma cell malignancy. Growing knowledge of the genome and expressed genomic information characterizing the biologic behavior of multiple myeloma continues to accumulate. However, translation and incorporation of vast molecular understanding of complex tumor biology to deliver personalized and precision treatment to cure multiple myeloma have not been successful to date. Our review focuses on current evidence and understanding of myeloma biology with characterization in the context of genomic and molecular alterations. We also discuss future clinical application of the genomic and molecular knowledge, and more translational research is needed to benefit our myeloma patients. PMID- 29250533 TI - PD-L1 Promotes Self-Renewal and Tumorigenicity of Malignant Melanoma Initiating Cells. AB - Recent studies have indicated that therapeutic antibodies targeting PD-L1 show remarkable efficacy in clinical trials in multiple tumors and that a melanoma cell-intrinsic PD-1: PD-L1 axis promotes tumor growth. However, few studies have shown tumor-intrinsic PD-L1 effects in malignant melanoma initiating cells (MMICs). Here, we aim to determine the possible regulatory effects of PD-L1 on MMICs. The ALDEFLUOR kit was used to identify ALDH+ MMICs. Flow cytometry was used to examine the expression of PD-L1 on ALDH+ MMICs. To determine the role of PD-L1 in MMICs self-renewal, we cultured melanoma cells with anti-PD-L1 and measured tumorsphere formation and apoptosis. In addition, the effects of anti-PD L1 on tumorigenicity and residual ALDH+ MMICs in tumors were evaluated in vivo. We demonstrated that melanoma cell-intrinsic PD-L1 was expressed in ALDH+ MMICs. Blocking PD-L1 in melanoma cell lines impaired tumorsphere formation and induced the apoptosis of sphere cells. In addition, blocking PD-L1 inhibited tumor growth in vivo. We observed residual ALDH+ MMICs within the tumor. The results showed that blocking PD-L1 also significantly decreased the residual ALDH+ MMICs in the tumors. In conclusion, these results suggest a new mechanism underlying melanoma progression and PD-L1-targeted therapy, which is distinct from the immunomodulatory actions of PD-L1. PMID- 29250534 TI - Relation of ABO Blood Groups to the Plaque Characteristic of Coronary Atherosclerosis. AB - The ABO blood types related to morphological characteristics of atherosclerosis plaque are not clear. We aimed to evaluate the relationship between ABO blood groups and the coronary plaque characteristic. We retrospectively identified the target lesions in 392 acute coronary syndrome patients who underwent optical coherence tomography examination before stenting. Subjects were divided into different groups according to different blood types. The fibrous cap thickness was significantly thicker in O type compared with non-O type (0.075 +/- 0.033 mm versus 0.061 +/- 0.024, p < 0.001). Meanwhile, the incidence of thin-cap fibroatheroma was also significantly higher in O type compared with non-O type (51.0% versus 71.5%, p < 0.001). The O type showed a significantly larger minimum lumen area [1.26 (0.82, 2.13) versus 1.05 (0.67, 1.82), p = 0.020] and minimum lumen diameter [1.03 (0.74, 1.31) versus 0.95 (0.66, 1.25), p = 0.039] compared with non-O type. There were no differences found in incidence of lipid plaque, plaque rupture, and thrombus between different blood type groups even between O type and non-O type group (p > 0.05). The plaques of O type blood group were exhibited more stably compared with non-O type blood group. Moreover, the non-O type blood group have more serious coronary artery stenosis than O type blood group. PMID- 29250535 TI - HPV16 E6 Promotes Breast Cancer Proliferation via Upregulation of COX-2 Expression. AB - Background. Breast cancer remains the leading cause of cancer-related mortality worldwide. It has been indicated that human papillomaviruses 16 (HPV16) might participate in the pathogenesis and development of breast cancer. However, the detected rate of HPV16 varies with region. We will investigate HPV16 E6 expression in North China and explore the effects and mechanism of HPV16 E6 on breast cancer proliferation in this study. Methods. The expressions of HPV16 E6 and COX-2 in paraffin-embedded tissues of the invasive ductal breast cancer were detected by qPCR and IHC. The effects of HPV16 E6 on breast cancer proliferation were determined by function studies. The mechanism of HPV16 E6 in promoting breast cancer proliferation was explored by Western blot and Dual-Luciferase Reporter Assay. Results. HPV16 E6 was positive in 28% invasive ductal breast carcinoma in North China; HPV16 E6 promoted breast cancer proliferation. Inhibition of COX-2 by siCOX-2 or Celecoxib attenuated the proliferation of breast cancer cells with HPV16 E6 expression; and the upregulation of COX-2 could be suppressed by the inhibition of NF-kappaB activity. Conclusion. HPV16 E6 promotes breast cancer proliferation by activation of NF-kappaB signaling pathway and increase of COX-2 expression. COX-2 will be a potential target for HPV16 E6 associated breast cancer. PMID- 29250536 TI - Transient Receptor Potential Melastatin 2 Negatively Regulates LPS-ATP-Induced Caspase-1-Dependent Pyroptosis of Bone Marrow-Derived Macrophage by Modulating ROS Production. AB - Background: Pyroptosis, a new form of cell death, which has special morphological characteristics, depends on caspase-1 activation and occupies an important role in inflammatory immune diseases and ischemia-reperfusion injury. ROS is a common activator of NLR/caspase-1. Transient receptor potential melastatin 2 (TRPM2), a selective cation channel, is involved in inflammatory regulation. This study was designed to explore the role of TRPM2 in activating caspase-1 and caspase-1 dependent pyroptosis of mouse BMDMs. Methods: BMDMs isolated from WT and TRPM2-/- mice were treated with LPS and ATP, along with ROS inhibitor (NAC and DPI), caspase-1 inhibitor (Z-YVAD), or not. The activation of caspase-1 was measured by western blot. EtBr and EthD-2 staining were used to assess the incidence of pyroptosis. Results: Compared with WT, the activated caspase-1-P10 was higher and the percentage of EtBr positive cells was also increased in TRPM2-/- group, which were both inhibited by Z-YVAD, NAC, or DPI. ASC oligomerization was increased in TRPM2-/- group. Conclusion: Deletion of TRPM2 can enhance the activation of caspase-1 and pyroptosis, which may be via modulating ROS production, suggesting that TRPM2 plays a critical role in immune adjustment. PMID- 29250537 TI - Efficacy and Safety of Halometasone Cream to Treat Chronic Generalized Eczema and the Effects of Halometasone Cream on Serum Cortisol Levels. AB - The aim of the study was to investigate the efficacy and safety of halometasone cream to treat chronic generalized eczema and the effects of halometasone cream on serum cortisol (COR) levels. Sixty consecutive outpatients diagnosed with chronic generalized eczema between January and April 2017 were included and divided into groups A, B, and C with a lesion area of 30%-40%, 41%-50%, and 51% 60%, respectively. Groups A, B, and C were treated with halometasone cream with a daily dose of 15 g, 20 g, and 30 g for 7-14 days, respectively. Ten patients were randomly selected from each group for serum COR measurement at days 0, 7, and 14. On day 14, group B had significantly higher cure rate (47.1%) than groups A (17.9%) and C (13.3%) and significantly higher effectiveness rate (82.4%) than group C (40.0%) (all P < 0.05). Serum COR levels were not affected in group A but were reduced significantly in groups B and C on days 7 and 14 (all P < 0.05). No adverse reaction was observed. Halometasone cream appeared to relieve chronic generalized eczema effectively and safely. High dosage (>=20 g daily for 14 days) may temporarily reduce endogenous COR production substantially, although it may be more effective. PMID- 29250538 TI - Shape and Boundary Similarity Features for Accurate HCC Image Recognition. AB - Nucleus morphology is of great importance in conventional cancer pathological diagnosis, which could provide information difference between normal and abnormal nuclei visually. Therefore, this paper proposes two novel kinds of features for normal and hepatocellular carcinoma (HCC) nucleus recognition, including shape and boundary similarity. First, each individual nucleus patch with the fixed size is obtained using center-proliferation segmentation (CPS) method. Then, nucleus shape library is constructed based on manual selection by pathologists, which is utilized to measure nucleus shape similarity via Dice, Jaccard, precision, and recall coefficients. Meanwhile, boundary similarity is evaluated through triangles composed of some boundary feature points for each nucleus. Finally, the conventional random forest (RF) is used to train and test the classification model for HCC nucleus recognition. Extensive cross-validation tests could facilitate the selection of the optimal feature set and the experiment comparison results demonstrate that our proposed morphological features are more beneficial for classification compared with other traditional characteristics. PMID- 29250539 TI - Xanthine-Catechin Mixture Enhances Lithium-Induced Anti-Inflammatory Response in Activated Macrophages In Vitro. AB - Lithium (Li) is a chemical element used for treating and preventing bipolar disorder (BD) and exerts positive effects such as anti-inflammatory effects as well as undesirable side effects. These effects of Li can be influenced by interaction with some nutritional elements. Therefore, we investigated the potential effects of xanthine (caffeine and theobromine) and catechin molecules present in some food beverages broadly consumed worldwide, such as coffee and tea, on Li-induced anti-inflammatory effects. In the present study, we concomitantly exposed RAW 264.7 macrophages to Li, isolated xanthine and catechin molecules, and a xanthine-catechin mixture (XC mixture). We evaluated the effects of these treatments on cell proliferation, cell cycle progression, oxidative and antioxidant marker expression, cytokine levels, gene expression, and GSK-3beta enzyme expression. Treatment with the XC mixture potentialized Li-induced anti inflammatory effects by intensification of the following: GSK-3beta inhibitory action, lowering effect on proinflammatory cytokines (IL-1beta, IL-6, and TNFalpha), and increase in the levels of IL-10 that is an anti-inflammatory cytokine. Despite the controversial nature of caffeine consumption by BD patients, these results suggested that consumption of caffeine, in low concentrations, mixed with other bioactive molecules along with Li may be safe. PMID- 29250540 TI - The Influence of Recognition and Social Support on European Health Professionals' Occupational Stress: A Demands-Control-Social Support-Recognition Bayesian Network Model. AB - Healthcare professionals undergo high levels of occupational stress as a result of their working conditions. Thus, the aim of this study is to develop a model that focuses on healthcare professionals so as to analyze the influence that job demands, control, social support, and recognition have on the likelihood that a worker will experience stress. The data collected correspond to 2,211 healthcare workers from 35 countries, as reported in the sixth European Working Condition Survey (EWCS). The results obtained from this study allow us to infer stress under several working condition scenarios and to identify the more relevant variables in order to reduce this stress in healthcare professionals, which is of paramount importance to managing the stress of workers in this sector. The Bayesian network proposed indicates that emotional demands have a greater influence on raising the likelihood of stress due to workload than do family demands. The results show that the support of colleagues, in general, has less effect on reducing stress than social support from superiors. Furthermore, the sensitivity analysis shows that, in high-demand and low-control situations, recognition clearly impacts stress, drastically reducing it. PMID- 29250541 TI - Gene Prediction in Metagenomic Fragments with Deep Learning. AB - Next generation sequencing technologies used in metagenomics yield numerous sequencing fragments which come from thousands of different species. Accurately identifying genes from metagenomics fragments is one of the most fundamental issues in metagenomics. In this article, by fusing multifeatures (i.e., monocodon usage, monoamino acid usage, ORF length coverage, and Z-curve features) and using deep stacking networks learning model, we present a novel method (called Meta MFDL) to predict the metagenomic genes. The results with 10 CV and independent tests show that Meta-MFDL is a powerful tool for identifying genes from metagenomic fragments. PMID- 29250542 TI - Comparative Transcriptome Analysis Reveals Related Regulatory Mechanisms of Androgenic Gland in Eriocheir sinensis. AB - Chinese mitten crab (Eriocheir sinensis) is one of the most commercially important aquaculture species in China. The androgenic gland (AG) of crustaceans plays pivotal roles in the regulation of male differentiation and in maintaining the male sexual characteristics. In order to reveal related mechanisms in AG, we compared transcriptomes of AG between proliferation and secretion phase. A total of 72,000 unigenes and 4,027 differentially expressed genes were obtained. Gene ontology enrichment analysis indicated that biological processes and metabolic pathways related to protein synthesis and secretion such as transcription, translation, and signal transduction were significantly enriched. Critical genes such as IAG, SXL, TRA-2, SRY, FTZ-F1, FOXL2, and FEM-1 were identified and potentially involved in maintaining the testis development and spermatogenesis. Ribosomes pathway revealed the cause of insulin-like androgenic gland hormone secretion increase. Three insulin-like receptors were thought to be associated with growth and spermatogenesis. In the neuroactive ligand-receptor interaction pathway, the expression of octopamine receptor, 5-HT receptor 1, and melatonin receptor was significantly changed, which revealed the key regulation mechanism of aggressive and mating behavior of males. Comparative transcriptome analysis provided new insights into the genome-wide molecular mechanisms of AG development and the regulatory mechanisms of male development. PMID- 29250543 TI - Efficient Expression of Maltohexaose-Forming alpha-Amylase from Bacillus stearothermophilus in Brevibacillus choshinensis SP3 and Its Use in Maltose Production. AB - The maltohexaose-forming, Ca2+-independent alpha-amylase gene from Bacillus stearothermophilus (AmyMH) was efficiently expressed in Brevibacillus choshinensis SP3. To improve the production of AmyMH in B. choshinensis SP3, the temperature and initial pH of culture medium were optimized. In addition, single factor and response surface methodologies were pursued to optimize culture medium. Addition of proline to the culture medium significantly improved the production of recombinant alpha-amylase in B. choshinensis SP3. This improvement may result from improved cellular integrity of recombinant B. choshinensis SP3 in existence of proline. Culture medium optimization resulted in an 8-fold improvement in alpha-amylase yield, which reached 1.72 * 104 U.mL-1. The recombinant alpha-amylase was applied to the production of maltose on a laboratory scale. A maltose content of 90.72%, which could be classified as an extremely high maltose syrup, could be achieved using 15% (m/v) corn starch as the substrate. This study demonstrated that the B. choshinensis SP3 expression system was able to produce substantial quantities of recombinant alpha-amylase that has potential application in the starch industry. PMID- 29250544 TI - Choroidal Thickness in Women with Uncomplicated Pregnancy: Literature Review. AB - Pregnancy is a time when many changes occur in a woman's body. The goal of these changes is the provision of optimum conditions for the development of the foetus. Pregnancy also affects eye physiology. Well recognized physiological changes include a reduced corneal sensitivity, an increase in its central thickness and curvature, and a decrease in intraocular pressure. The association between choroidal thickness and pregnancy is not clear. Haemodynamic and hormonal changes taking place during pregnancy and the question of whether these changes are reflected by choroidal thickness are especially important. It is assumed that the choroid, which is one of the most highly vascularized tissues characterized by the highest blood flow to tissue volume ratio in the whole body, should respond by an increase in its thickness to an increase in blood flow and drop in the value of peripheral resistance. Measurement of choroidal thickness using enhanced depth imaging optical coherence tomography (EDI-OCT) in women with uncomplicated pregnancy provides important information concerning the effects of physiological changes in the eye. PMID- 29250545 TI - Efficacy and Mechanism of Preoperative Simvastatin Therapy on Myocardial Protection after Extracorporeal Circulation. AB - Background: Cardiopulmonary bypass (CPB) causes systemic inflammatory response and ischemia-reperfusion (IR) injury. Objective: To investigate the effect and mechanism of simvastatin on myocardial injury in cardiac valve surgery with CPB. Methods: One hundred thirty patients were randomly assigned to the statin group (n = 65) or control group (n = 65). Simvastatin was administered preoperatively and postoperatively. Duration of intensive care unit stay, duration of assisted ventilation, and left ventricular ejection fraction were recorded. Plasma was analysed for troponin T (cTnT), isoenzyme of creatine kinase (CK-MB), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-8 (IL 8). Ultrastructure of the myocardium and autophagosomes were observed. Beclin-1, LC3-II/I, P62, AMPK, and the phosphorylation of AMPK in cardiomyocytes were detected. Results: Simvastatin significantly reduced the duration of assisted ventilation (P = 0.030) and ejection fraction was significantly higher in the statin group (P = 0.024). Simvastatin significantly reduced the levels of cTnT, CK-MB, TNF-alpha, IL-6, and IL-8 (P < 0.05), reduced the expression of LC3-II/LC3 I and Beclin 1, and increased the expression of phosphorylation of AMPK. Simvastatin reduced the generation of autophagosomes and the ultrastructural injuries to myocardium. Conclusion: Perioperative statin therapy reduced myocardial injury by regulating myocardial autophagy and activating the phosphorylation of AMPK. The registration number of this study is ChiCTR-TRC 14005164. PMID- 29250546 TI - Effect of Excess Iodide Intake on Salivary Glands in a Swiss Albino Mice Model. AB - Iodine is an important micronutrient required for nutrition. Excess iodine has adverse effects on thyroid, but there is not enough information regarding its effect on salivary glands. In addition to food and iodized salt, skin disinfectants and maternal nutritional supplements contain iodide, so its intake could be excessive during pregnancy, lactation, and infancy. The aim of this work was to evaluate the effect of excess iodide ingestion on salivary glands during mating, gestation, lactation, and postweaning period in mouse. During assay, mice were allocated into groups: control and treatment groups (received distilled water with NaI 1 mg/mL). Water intake, glandular weight, and histology were analyzed. Treatment groups showed an increase in glandular weight and a significantly (p < 0.05) higher water intake than control groups. Lymphocyte infiltration was observed in animals of treatment groups, while there was no infiltration in glandular sections of control groups. Results demonstrated that a negative relationship could exist between iodide excess and salivary glands. This work is novel evidence that high levels of iodide intake could induce mononuclear infiltration in salivary glands. These results should be considered, especially in pregnant/lactating women, to whom a higher iodine intake is usually recommended. PMID- 29250547 TI - Multilevel Thresholding Method Based on Electromagnetism for Accurate Brain MRI Segmentation to Detect White Matter, Gray Matter, and CSF. AB - This work explains an advanced and accurate brain MRI segmentation method. MR brain image segmentation is to know the anatomical structure, to identify the abnormalities, and to detect various tissues which help in treatment planning prior to radiation therapy. This proposed technique is a Multilevel Thresholding (MT) method based on the phenomenon of Electromagnetism and it segments the image into three tissues such as White Matter (WM), Gray Matter (GM), and CSF. The approach incorporates skull stripping and filtering using anisotropic diffusion filter in the preprocessing stage. This thresholding method uses the force of attraction-repulsion between the charged particles to increase the population. It is the combination of Electromagnetism-Like optimization algorithm with the Otsu and Kapur objective functions. The results obtained by using the proposed method are compared with the ground-truth images and have given best values for the measures sensitivity, specificity, and segmentation accuracy. The results using 10 MR brain images proved that the proposed method has accurately segmented the three brain tissues compared to the existing segmentation methods such as K means, fuzzy C-means, OTSU MT, Particle Swarm Optimization (PSO), Bacterial Foraging Algorithm (BFA), Genetic Algorithm (GA), and Fuzzy Local Gaussian Mixture Model (FLGMM). PMID- 29250548 TI - Computational Molecular Networks and Network Pharmacology. PMID- 29250549 TI - Identifying Human Phenotype Terms by Combining Machine Learning and Validation Rules. AB - Named-Entity Recognition is commonly used to identify biological entities such as proteins, genes, and chemical compounds found in scientific articles. The Human Phenotype Ontology (HPO) is an ontology that provides a standardized vocabulary for phenotypic abnormalities found in human diseases. This article presents the Identifying Human Phenotypes (IHP) system, tuned to recognize HPO entities in unstructured text. IHP uses Stanford CoreNLP for text processing and applies Conditional Random Fields trained with a rich feature set, which includes linguistic, orthographic, morphologic, lexical, and context features created for the machine learning-based classifier. However, the main novelty of IHP is its validation step based on a set of carefully crafted manual rules, such as the negative connotation analysis, that combined with a dictionary can filter incorrectly identified entities, find missed entities, and combine adjacent entities. The performance of IHP was evaluated using the recently published HPO Gold Standardized Corpora (GSC), where the system Bio-LarK CR obtained the best F measure of 0.56. IHP achieved an F-measure of 0.65 on the GSC. Due to inconsistencies found in the GSC, an extended version of the GSC was created, adding 881 entities and modifying 4 entities. IHP achieved an F-measure of 0.863 on the new GSC. PMID- 29250550 TI - Prostate Cancer: From Genomics to the Whole Body and Beyond. PMID- 29250551 TI - Bioconversion of Sugarcane Vinasse into High-Added Value Products and Energy. AB - Vinasse, a residue from bioethanol production containing high organic matter concentration, was used as substrate in submerged fermentation of Pseudomonas aeruginosa PA1 for biosurfactant production. About 2.7 g/L of rhamnolipids was obtained, with surface tension of 29.2 mN/m and critical micelle concentration of 80.3 mg/L. After separation of rhamnolipid and biomass, residual fermentation media were submitted to anaerobic biodegradation in mesophilic conditions. The residual medium derived from fermentation with vinasse diluted to 1 : 1, without addition of nitrogen, C : N 21, and for 168 h, led to 63.2% chemical oxygen demand (COD) removal and 97.6 mL CH4/g CODremoved. Compared to results obtained with fresh vinasse (73.7% COD removal and 112.4 mL CH4/g CODremoved), it could be concluded that both processes can be integrated in order to add value to the residue and obtain energy, reducing production costs and at the same time environmental impacts related to vinasse disposal. PMID- 29250552 TI - Risk Factors of Recurrence and Malignant Transformation of Sinonasal Inverted Papilloma. AB - Sinonasal inverted papilloma is a relatively rare disease; however, it is prevalent enough for every ENT practitioner to encounter it several times throughout medical routines. Despite the developments in experimental and clinical medicine as well as surgical techniques, our knowledge of this disease is still inadequate. With improved imaging and better diagnostic techniques, proper diagnosis and qualification for surgical approaches leave no doubt. Although the endoscopic approach seems to be the gold standard for such condition, some cases may additionally require an external approach. Regardless of the type of surgery, postoperative management is crucial for both healing and long-term follow-up. Unfortunately, the procedures are still lacking in explicit and standardized postoperative management guidelines. Moreover, an important issue is still the need for a biomarker indicative of inverted papilloma and its malignant transformation. Several particles, within the spotlight of the researchers, have been SCCA, Ki-67, Bcl-2, Wnt proteins, and many more. Nevertheless, the topic requires further investigations. PMID- 29250553 TI - Endophytic Fungi as Pretreatment to Enhance Enzymatic Hydrolysis of Olive Tree Pruning. AB - Olive tree pruning, as one of the most abundant lignocellulosic residues in Mediterranean countries, has been evaluated as a source of sugars for fuel and chemicals production. A mild acid pretreatment has been combined with a fungal pretreatment using either two endophytes (Ulocladium sp. and Hormonema sp.) or a saprophyte (Trametes sp. I-62). The use of endophytes is based on the important role that some of them play during the initial stages of wood decomposition. Without acid treatment, fungal pretreatment with Ulocladium sp. provided a nonsignificant enhancement of 4.6% in glucose digestibility, compared to control. When a mild acid hydrolysis was carried out after fungal pretreatments, significant increases in glucose digestibility from 4.9% to 12.0% (compared to control without fungi) were observed for all fungal pretreatments, with maximum values yielded by Hormonema sp. However, despite the observed digestibility boost, the total sugar yields (taking into account solid yield) were not significantly increased by the pretreatments. Nevertheless, based on these preliminary improvements in digestibility, this work proves the potential of endophytic fungi to boost the production of sugar from olive tree pruning, which would add an extra value to the bioeconomy of olive crops. PMID- 29250554 TI - Assessment of Drug-Drug Interaction in Ayder Comprehensive Specialized Hospital, Mekelle, Northern Ethiopia: A Retrospective Study. AB - Introduction: Adverse drug interaction is a major cause of morbidity and mortality. Its occurrence is influenced by a multitude of factors. The influences of drug-drug interactions (DDIs) can be minimized through creation of awareness to health care professionals. Objective: The objective of this study was to assess DDIs in Ayder Comprehensive Specialized Hospital (ACSH). Methodology: A retrospective study design was employed on patient prescriptions available in the outpatient department of pharmacy and filled from September 2016 to February 2017 in ACSH. Result: From the 600 prescription records assessed, the average number of drugs on single prescription was 2.73. Regarding the interaction observed 34 (9.63%) prescriptions with major drug-drug interaction, 210 (59.5%) moderate, 87 (24.65%) minor, and 22 (6.22%) unknown were identified. Age category showed significant association to affect the occurrence of DDIs and polypharmacy had statistically significant association with DDIs in bivariate analysis which was lost in adjusted OR. Conclusion: From the current study it can be concluded that nearly half of the prescription ordered in ACSH contained DDIs and from the prescription with interacting medications majority of them had moderate DDIs. PMID- 29250556 TI - New Insights into Diabetic Kidney Disease: The Potential Pathogenesis and Therapeutic Targets. PMID- 29250555 TI - A Comparison of Screening Tools for the Early Detection of Peripheral Neuropathy in Adults with and without Type 2 Diabetes. AB - Objective: Examine the effectiveness of the 128 Hz tuning fork, two monofilaments, and Norfolk Quality of Life Diabetic Neuropathy (QOL-DN) questionnaire as tools for the early detection of diabetic peripheral neuropathy (DPN) in overweight, obese, and inactive (OOI) adults or those who have prediabetes (PD) or type 2 diabetes (T2D). Research Design and Methods: Thirty four adults (mean age 58.4 years +/- 12.1) were divided by glycemia (10 OOI normoglycemic, 13 PD, and 11 T2D). Sural nerves were tested bilaterally with the NC-stat DPNCheck to determine sural nerve amplitude potential (SNAP) and sural nerve conduction velocity (SNCV). All other testing results were compared to SNAP and SNCV. Results: Total 1 g monofilament scores significantly correlated with SNAP values and yielded the highest sensitivity and specificity combinations of tested measures. Total QOL-DN scores negatively correlated with SNAP values, as did QOL-DN symptoms. QOL-DN activities of daily living correlated with the right SNAP, and the QOL-DN small fiber subscore correlated with SNCV. Conclusions: The 1 g monofilament and total QOL-DN are effective, low-cost tools for the early detection of DPN in OOI, PD, and T2D adults. The 128 Hz tuning fork and 10 g monofilament may assist DPN screening as a tandem, but not primary, early DPN detection screening tools. PMID- 29250557 TI - Stabilized beta-Catenin Ameliorates ALPS-Like Symptoms of B6/lpr Mice. AB - Autoimmune lymphoproliferative syndrome (ALPS) is an incurable disease mainly caused by the defect of Fas-mediated apoptosis and characterized by nonmalignant autoimmune lymphoproliferation. Stabilized beta-catenin could not only potentiate Fas-mediated T cell apoptosis via upregulating the expression of Fas on activated T cells, but also potentiate T cell apoptosis via intrinsic apoptotic pathway. In the present study, we introduced beta-catTg into lpr/lpr mice and aimed to explore the potential role of stabilized beta-catenin (beta-catTg) in the development of ALPS-like phenotypes of lpr/lpr mice. We found that the total splenocyte cells and some compositions were slightly downregulated in beta catTglpr/lpr mice, especially the CD4 and CD8 TEM cells were significantly reduced. Meanwhile, stabilized beta-catenin obviously decreased the numbers of spleen TCRbeta+CD4-CD8- T (DNT) cells, and the levels of some serum proinflammatory factors also were lowered in beta-catTglpr/lpr mice. Beyond that, stabilized beta-catenin slightly lowered the levels of the serum autoantibodies and the scores of kidney histopathology of beta-catTglpr/lpr mice compared with lpr/lpr mice. Our study suggested that stabilized beta-catenin ameliorated some ALPS-like symptoms of lpr/lpr mice by potentiating Fas-independent signal mediated T cell apoptosis, which might uncover a potential novel therapeutic direction for ALPS. PMID- 29250558 TI - Are the Therapeutic Effects of Huangqi (Astragalus membranaceus) on Diabetic Nephropathy Correlated with Its Regulation of Macrophage iNOS Activity? AB - Objective: To investigate the correlation between the clinical effects of Huangqi (Astragalus membranaceus) on different stages of diabetic nephropathy (DN) and the pharmacological effect of Huangqi on the activity of inducible nitric oxide synthase (iNOS) in macrophages in different states. Methods: The PubMed, China National Knowledge Infrastructure, and Wanfang databases were searched. Clinical data was sourced from papers on treatment of different stages of DN with Huangqi, and pharmacological data was from papers on the effects of Huangqi on the iNOS activity of macrophages in a resting or an activated state. Results: Meta analysis of Huangqi injections on stages III and III-IV DN and randomized controlled trials on other stages showed that Huangqi had therapeutic effects on different stages of DN and on macrophages in different states: inducing normal macrophages in a resting state to generate nitric oxide (NO), tumor necrosis factor-alpha, and so forth upon iNOS activation; inhibiting NO generation by normal lipopolysaccharide- (LPS-) activated macrophages; and enhancing NO generation by LPS-induced macrophages from patients with renal failure. Conclusions: Huangqi can regulate iNOS activity of macrophages in different states in vitro. These biphasic or antagonistic effects may explain why Huangqi can be used to treat different stages of DN. PMID- 29250559 TI - Beta-Defensin-2 and Beta-Defensin-3 Reduce Intestinal Damage Caused by Salmonella typhimurium Modulating the Expression of Cytokines and Enhancing the Probiotic Activity of Enterococcus faecium. AB - The intestinal microbiota is a major factor in human health and disease. This microbial community includes autochthonous (permanent inhabitants) and allochthonous (transient inhabitants) microorganisms that contribute to maintaining the integrity of the intestinal wall, modulating responses to pathogenic noxae and representing a key factor in the maturation of the immune system. If this healthy microbiota is disrupted by antibiotics, chemotherapy, or a change in diet, intestinal colonization by pathogenic bacteria or viruses may occur, leading to disease. To manage substantial microbial exposure, epithelial surfaces of the intestinal tract produce a diverse arsenal of antimicrobial peptides (AMPs), including, of considerable importance, the beta-defensins, which directly kill or inhibit the growth of microorganisms. Based on the literature data, the purpose of this work was to create a line of intestinal epithelial cells able to stably express gene encoding human beta-defensin-2 (hBD-2) and human beta-defensin-3 (hBD-3), in order to test their role in S. typhimurium infections and their interaction with the bacteria of the gut microbiota. PMID- 29250562 TI - Probabilistic Simulation Framework for EEG-Based BCI Design. AB - A simulation framework could decrease the burden of attending long and tiring experimental sessions on the potential users of brain computer interface (BCI) systems. Specifically during the initial design of a BCI, a simulation framework that could replicate the operational performance of the system would be a useful tool for designers to make design choices. In this manuscript, we develop a Monte Carlo based probabilistic simulation framework for electroencephalography (EEG) based BCI design. We employ one event related potential (ERP) based typing and one steady state evoked potential (SSVEP) based control interface as testbeds. We compare the results of simulations with real time experiments. Even though over and under estimation of the performance is possible, the statistical results over the Monte Carlo simulations show that the developed framework generally provides a good approximation of the real time system performance. PMID- 29250561 TI - TNF Tolerance in Monocytes and Macrophages: Characteristics and Molecular Mechanisms. AB - Tumor necrosis factor (TNF) tolerance in monocytes and macrophages means that preexposure to TNF reduces the sensitivity in these cells to a subsequent restimulation with this cytokine. Differential effects arise following preincubation with both low and high doses of TNF resulting in absolute as well as induction tolerance affecting specific immunologically relevant gene sets. In this review article, we summarize the relevance of TNF tolerance in vivo and the molecular mechanisms underlying these forms of tolerance including the role of transcription factors and signaling systems. In addition, the characteristics of cross-tolerance between TNF and lipopolysaccharide (LPS) as well as pathophysiological aspects of TNF tolerance are discussed. We conclude that TNF tolerance may represent a protective mechanism involved in the termination of inflammation and preventing excessive or prolonged inflammation. Otherwise, tolerance may also be a trigger of immune paralysis thus contributing to severe inflammatory diseases such as sepsis. An improved understanding of TNF tolerance will presumably facilitate the implementation of diagnostic or therapeutic approaches to more precisely assess and treat inflammation-related diseases. PMID- 29250563 TI - lambda = 2.4 - 5 MUm spectroscopy with the JWST NIRCam instrument. AB - The James Webb Space Telescope near-infrared camera (JWST NIRCam) has two 2'. 2 * 2'.2 fields of view that can be observed with either imaging or spectroscopic modes. Either of two R ~ 1500 grisms with orthogonal dispersion directions can be used for slitless spectroscopy over lambda = 2.4 - 5.0 MUm in each module, and shorter wavelength observations of the same fields can be obtained simultaneously. We describe the design drivers and parameters of the grisms and present the latest predicted spectroscopic sensitivities, saturation limits, resolving powers, and wavelength coverage values. Simultaneous short wavelength (0.6 - 2.3 MUm) imaging observations of the 2.4 - 5.0 MUm spectroscopic field can be performed in one of several different filter bands, either in-focus or defocused via weak lenses internal to NIRCam. The grisms are available for single object time series spectroscopy and wide-field multi-object slitless spectroscopy modes in the first cycle of JWST observations. We present and discuss operational considerations including subarray sizes and data volume limits. Potential scientific uses of the grisms are illustrated with simulated observations of deep extragalactic fields, dark clouds, and transiting exoplanets. Information needed to plan observations using these spectroscopic modes are also provided. PMID- 29250564 TI - Measuring arterial wall perfusion using photon-counting computed tomography (CT): improving CT number accuracy of artery wall using image deconvolution. AB - Changes in arterial wall perfusion mark the onset of atherosclerosis. A characteristic change is the increased spatial density of vasa vasorum (VV), the microvessels in the arterial walls. Measuring this increased VV (IVV) density using contrast-enhanced computed tomography (CT) has had limited success due to blooming effects from contrast media. If the system point-spread function (PSF) is known, then the blooming effect can be modeled as a convolution between the true signal and the PSF. We report the application of image deconvolution to improve the CT number accuracy in the arterial wall of a phantom and in a porcine model of IVV density, both scanned using a whole-body research photon-counting CT scanner. A 3D-printed carotid phantom filled with three concentrations of iodinated contrast material was scanned to assess blooming and its effect on wall CT number accuracy. The results showed a reduction in blooming effects following image deconvolution, and, consequently, a better delineation between lumen and wall was achieved. Results from the animal experiment showed improved CT number difference between the carotid with IVV density and the normal carotid artery after deconvolution, enabling the detection of VV proliferation, which may serve as an early indicator of atherosclerosis. PMID- 29250560 TI - Pulmonary Susceptibility of Neonates to Respiratory Syncytial Virus Infection: A Problem of Innate Immunity? AB - Human respiratory syncytial virus (RSV) is a common and highly contagious viral agent responsible for acute lower respiratory infection in infants. This pathology characterized by mucus hypersecretion and a disturbed T cell immune response is one of the major causes of infant hospitalization for severe bronchiolitis. Although different risk factors are associated with acute RSV bronchiolitis, the immunological factors contributing to the susceptibility of RSV infection in infants are not clearly elucidated. Epidemiological studies have established that the age at initial infection plays a central role in the severity of the disease. Thus, neonatal susceptibility is intrinsically linked to the immunological characteristics of the young pulmonary mucosa. Early life is a critical period for the lung development with the first expositions to external environmental stimuli and microbiota colonization. Furthermore, neonates display a lung immune system that profoundly differs to those from adults, with the predominance of type 2 immune cells. In this review, we discuss the latest information about the lung immune environment in the early period of life at a steady state and upon RSV infection and how we can modulate neonatal susceptibility to RSV infection. PMID- 29250566 TI - Down syndrome detection based on facial features using a geometric descriptor. AB - Down syndrome is one of the most common genetic disorders caused by chromosome abnormalities in humans. Among other physical characteristics, certain facial features are typically associated in people with Down syndrome. We investigate the problem of Down syndrome detection from a collection of face images. As the main contribution, a compact geometric descriptor is used to extract facial features from the images. Experiments are conducted on an available dataset to demonstrate the performance of the proposed methodology. PMID- 29250565 TI - Localizing landmark sets in head CTs using random forests and a heuristic search algorithm for registration initialization. AB - Cochlear implants (CIs) use electrode arrays that are surgically inserted into the cochlea to stimulate frequency-mapped nerve endings to treat patients with hearing loss. CIs are programmed postoperatively by audiologists using behavioral tests without information on electrode-cochlea spatial relationship. We have recently developed techniques to segment the intracochlear anatomy and to localize individual contacts in clinically acquired computed tomography (CT) images. Using this information, we have proposed a programming strategy that we call image-guided CI programming (IGCIP), and we have shown that it significantly improves outcomes for both adult and pediatric recipients. One obstacle to large scale deployment of this technique is the need for manual intervention in some processing steps. One of these is the rough registration of images prior to the use of automated intensity-based algorithms. Although seemingly simple, the heterogeneity of our image set makes this task challenging. We propose a solution that relies on the automated random forest-based localization of multiple landmarks used to estimate an initial transformation with a point-based registration method. Results show that it produces results that are equivalent to a manual initialization. This work is an important step toward the full automation of IGCIP. PMID- 29250567 TI - Multicenter survey of PET/CT protocol parameters that affect standardized uptake values. AB - Clinical trials that evaluate cancer treatments may benefit from positron emission tomography (PET) imaging, which for many cancers can discriminate between effective and ineffective treatments. However, the image metrics used to quantify disease and evaluate treatment may be biased by many factors related to clinical protocols and PET system settings, many of which are site- and/or manufacturer-specific. An observational study was conducted using two surveys that were designed to record key sources of bias and variability in PET imaging. These were distributed to hospitals across the United States. The first round of surveys was designed and distributed by the American College of Radiology's Centers of Quantitative Imaging Excellence program in 2011. The second survey expanded on the first and was completed by the National Cancer Institute's Quantitative Imaging Network. Sixty-three sites responded to the first survey and 36 to the second. Key imaging parameters varied across participating sites. The range of reported methods for image acquisition and reconstruction suggests that signal biases are not matched between sites. Patient preparation was also inconsistent, potentially contributing additional variability. For multicenter clinical trials, efforts to control biases through standardization of imaging procedures should precede patient measurements. PMID- 29250568 TI - Selecting electrode configurations for image-guided cochlear implant programming using template matching. AB - Cochlear implants (CIs) are neural prostheses that restore hearing using an electrode array implanted in the cochlea. After implantation, the CI processor is programmed by an audiologist. One factor that negatively impacts outcomes and can be addressed by programming is cross-electrode neural stimulation overlap (NSO). We have proposed a system to assist the audiologist in programming the CI that we call image-guided CI programming (IGCIP). IGCIP permits using CT images to detect NSO and recommend deactivation of a subset of electrodes to avoid NSO. We have shown that IGCIP significantly improves hearing outcomes. Most of the IGCIP steps are robustly automated but electrode configuration selection still sometimes requires manual intervention. With expertise, distance-versus-frequency curves, which are a way to visualize the spatial relationship learned from CT between the electrodes and the nerves they stimulate, can be used to select the electrode configuration. We propose an automated technique for electrode configuration selection. A comparison between this approach and one we have previously proposed shows that our method produces results that are as good as those obtained with our previous method while being generic and requiring fewer parameters. PMID- 29250569 TI - Influence of radiology expertise on the perception of nonmedical images. AB - Identifying if participants with differing diagnostic accuracy and visual search behavior during radiologic tasks also differ in nonradiologic tasks is investigated. Four clinician groups with different radiologic experience were used: a reference expert group of five consultant radiologists, four radiology registrars, five senior house officers, and six interns. Each of the four clinician groups is known to have significantly different performance in the identification of pneumothoraces in chest x-ray. Each of the 20 participants was shown 6 nonradiologic images (3 maps and 3 sets of geometric shapes) and was asked to perform search tasks. Eye movements were recorded with a Tobii TX300 (Tobii Technology, Stockholm, Sweden) eye tracker. Four eye-tracking metrics were analyzed. Variables were compared to identify any differences among the groups. All data were compared by using nonparametric methods of analysis. The average number of targets identified in the maps did not change among groups [[Formula: see text] of 6 targets (range 5.6 to 6 [Formula: see text])]. None of the four eye-tracking metrics investigated varied with experience in either search task ([Formula: see text]). Despite clear differences in radiologic experience, these clinician groups showed no difference in nonradiologic search pattern behavior or skill across complex images. This is another viewpoint adding to the evidence that radiologic image interpretation is a learned skill and is task specific. PMID- 29250570 TI - Estimating detectability index in vivo: development and validation of an automated methodology. AB - This study's purpose was to develop and validate a method to estimate patient specific detectability indices directly from patients' CT images (i.e., in vivo). The method extracts noise power spectrum (NPS) and modulation transfer function (MTF) resolution properties from each patient's CT series based on previously validated techniques. These are combined with a reference task function (10-mm disk lesion with [Formula: see text] HU contrast) to estimate detectability indices for a nonprewhitening matched filter observer model. This method was applied to CT data from a previous study in which diagnostic performance of 16 readers was measured for the task of detecting subtle, hypoattenuating liver lesions ([Formula: see text]), using a two-alternative-forced-choice (2AFC) method, over six dose levels and two reconstruction algorithms. In vivo detectability indices were estimated and compared to the human readers' binary 2AFC outcomes using a generalized linear mixed-effects statistical model. The results of this modeling showed that the in vivo detectability indices were strongly related to 2AFC outcomes ([Formula: see text]). Linear comparison between human-detection accuracy and model-predicted detection accuracy (for like conditions) resulted in Pearson and Spearman correlation coefficients exceeding 0.84. These results suggest the potential utility of using in vivo estimates of a detectability index for an automated image quality tracking system that could be implemented clinically. PMID- 29250571 TI - Estimability index for volume quantification of homogeneous spherical lesions in computed tomography. AB - Volume of lung nodules is an important biomarker, quantifiable from computed tomography (CT) images. The usefulness of volume quantification, however, depends on the precision of quantification. Experimental assessment of precision is time consuming. A mathematical estimability model was used to assess the quantification precision of CT nodule volumetry in terms of an index ([Formula: see text]), incorporating image noise and resolution, nodule properties, and segmentation software. The noise and resolution were characterized in terms of noise power spectrum and task transfer function. The nodule properties and segmentation algorithm were modeled in terms of a task function and a template function, respectively. The [Formula: see text] values were benchmarked against experimentally acquired precision values from an anthropomorphic chest phantom across 54 acquisition protocols, 2 nodule sizes, and 2 volume segmentation softwares. [Formula: see text] exhibited correlation with experimental precision across nodule sizes and acquisition protocols but dependence on segmentation software. Compared to the assessment of empirical precision, which required [Formula: see text] to perform the segmentation, the [Formula: see text] method required [Formula: see text] from data collection to mathematical computation. A mathematical modeling of volume quantification provides efficient prediction of quantitative performance. It establishes a method to verify quantitative compliance and to optimize clinical protocols for chest CT volumetry. PMID- 29250573 TI - Single-Photon Quantum Contextuality on a Chip. AB - In classical physics, properties of objects exist independently of the context, i.e., whether and how measurements are performed. Quantum physics showed this assumption to be wrong, and that Nature is indeed "contextual". Contextuality has been observed in the simplest physical systems, such as single particles, and plays fundamental roles in quantum computation advantage. Here, we demonstrate for the first time quantum contextuality in an integrated photonic chip. The chip implements different combinations of measurements on a single photon delocalized on four distinct spatial modes, showing violations of a Clauser-Horne-Shimony Holt (CHSH)-like noncontextuality inequality. This paves the way to compact and portable devices for contextuality-based quantum-powered protocols. PMID- 29250574 TI - RNA Interference Screening to Identify Proliferation Determinants in Breast Cancer Cells. AB - RNAi screening technology has revealed unknown determinants of various biological signaling pathways in biomedical studies. This protocol provided detailed information about how to use RNAi screening to identify proliferation determinants in breast tumor cells. siRNA-based libraries targeting against Estrogen receptor (ER)-network, including 631 genes relevant to estrogen signaling, was constructed for screening in breast cancer cells. Briefly, reverse transfection of siRNA induced transient gene knockdown in MCF7 cells. First, the transfection reagent for MCF7 cells was selected. Next, the Z'-score assay was used to monitor if screening conditions yielded efficiently. Then, the ER-network siRNA library screening was preceded by automatic machines under optimized experimental conditions. PMID- 29250572 TI - The Link between Musculoskeletal Pain, Lifestyle Behaviors, Exercise Self Efficacy, and Quality of Life in Overweight and Obese Individuals. AB - Objective: To determine the extent musculoskeletal (MS) pain in the low back and knee (weight-bearing (WB) joints), shoulder and wrist (non-weight bearing joints), and exercise self-efficacy mediates associations between overweight and obesity levels based on BMI (4 levels: overweight, obese class I, II, or III), physical function, emotional role, social interference, and physical activity (PA) levels. Design: Cross-sectional study. Setting: Four long-term nursing home facilities in the Northeast U.S. Participants: 99 overweight or obese (BMI > 25) nursing home employees. Interventions: Self-reported survey administered to employees who met inclusion and exclusion criteria. Main Outcome Measures: General health status, physical function, emotional role, Exercise Self-Efficacy Scale (ESE), physical activity (PA), and frequency of pain at each joint. Results: Reported pain frequency were 66.3%, 54.4%, 42.2%, and 24.1% for lower back, knee, shoulder, and wrist, respectively. Higher obesity levels were associated with lower physical function (r=-0.109, p=0.284). PA decreased with higher obesity levels (r=-0.248, p<0.05), particularly in moderate PA (r=-0.293, p<0.05). Obesity was associated with a lower ESE (r=-0.239, p<0.05). Wrist pain significantly mediated the effect of obesity on moderate physical function, emotional role, and ESE. ESE was a significant mediator between obesity and moderate and vigorous PA. Conclusions: Overweight and obese nursing home employees are at higher risk for developing musculoskeletal disorders due to high demand, low control jobs, and the associated biomedical compromises while working. To increase the effectiveness of weight loss interventions for this population, the mediating effects of MS pain with higher levels of obesity should be considered. PMID- 29250575 TI - Nanotechnology, nanosurfaces and silicone gel breast implants: current aspects. AB - Nanotechnology is defined as the design of products that interact with biological systems on the nanoscopic scale. Creating a controlled nanotexture and understanding the ways in which surface properties impact inflammatory response is of the utmost significance in designing implants that can provide satisfactory outcomes. PMID- 29250577 TI - Cigarette Design Features: Effects on Emission Levels, User Perception, and Behavior. AB - Objectives: This paper describes the effects of non-tobacco, physical cigarette design features on smoke emissions, product appeal, and smoking behaviors - 3 factors that determine smoker's exposure and related health risks. Methods: We reviewed available evidence for the impact of filter ventilation, new filter types, and cigarettes dimensions on toxic emissions, smoker's perceptions, and behavior. For evidence sources we used scientific literature and websites providing product characteristics and marketing information. Results: Whereas filter ventilation results in lower machine-generated emissions, it also leads to perceptions of lighter taste and relative safety in smokers who can unwittingly employ more intense smoking behavior to obtain the desired amount of nicotine and sensory appeal. Filter additives that modify smoke emissions can also modify sensory cues, resulting in changes in smoking behavior. Flavor capsules increase the cigarette's appeal and novelty, and lead to misperceptions of reduced harm. Slim cigarettes have lower yields of some smoke emissions, but smoking behavior can be more intense than with standard cigarettes. Conclusions: Physical design features significantly impact machine-measured emission yields in cigarette smoke, product appeal, smoking behaviors, and exposures in smokers. The influence of current and emerging design features is important in understanding the effectiveness of regulatory actions to reduce smoking-related harm. PMID- 29250576 TI - Repair bond strength of nanohybrid composite resins with a universal adhesive. AB - Objective: To investigate the repair bond strength of fresh and aged nanohybrid and hybrid composite resins using a universal adhesive (UA). Materials and methods: Fresh and aged substrates were prepared using two nanohybrid (Venus Pearl, Heraus Kulzer; Filtek Supreme XTE, 3 M ESPE) and one hybrid (Z100, 3 M ESPE) composite resin, and randomly assigned to different surface treatments: (1) no treatment (control), (2) surface roughening with 320-grit (SR), (3) SR + UA (iBOND, Heraus Kulzer), (4) SR + Silane (Signum, Ceramic Bond I, Heraeus Kulzer) + UA, (5) SR + Sandblasting (CoJet, 3 M ESPE) + Silane + UA. After surface treatment, fresh composite resin was added to the substrates at 2 mm layer increments to a height of 5 mm, and light cured. Restored specimens were water stored for 24 h and sectioned to obtain 1.0 * 1.0 mm beams (n = 12), and were either water-stored for 24 h at 37 degrees C, or water-stored for 24 h, and then thermocycled for 6000 cycles before microtensile bond strength (uTBS) testing. Data were analyzed with ANOVA and Tukey's HSD tests (p = .05). Results: Combined treatment of SR, sandblasting, silane and UA provided repair bond strength values comparable to the cohesive strength of each tested resin material (p < .05). Thermocycling significantly reduced the cohesive strength of the composite resins upto 65% (p < .05). Repair bond strengths of UA-treated groups were more stable under thermocycling. Conclusions: Universal adhesive application is a reliable method for composite repair. Sandblasting and silane application slightly increases the repair strength for all substrate types. PMID- 29250578 TI - Symptomatic Urinary Tract Infections in Renal Transplant Recipients after Cystoscopy for Ureteral Stent Removal. AB - Introduction: Symptomatic urinary tract infection (UTI) is a known complication of cystoscopy with ureteral stent removal. However, little is known about the incidence and risk factors for post-cystoscopy UTI in renal transplant recipients, who likely represent a high-risk cohort. Our aim was to determine the infection rate following cystoscopy with stent removal in this population and identify opportunities for care improvement. Methods: We performed a retrospective cohort study of office cystoscopies with stent removal in renal transplant recipients performed at a single institution from April 2012 through May 2014. Strict criteria were used to determine presence of symptomatic UTI within one month of the procedure. Fisher's exact tests were completed to examine associations between patient characteristics and post-transplant outcomes with UTI. Results: A total of 324 patients were included. Mean age was 50.0 (SD 13.1) years, and 187 (57.7%) patients were male. Within this group,165 (52.5%) patients received a pre-procedural oral fluoroquinolone antibiotic dose prior to the procedure. Nine patients had symptomatic UTIs (2.8%), of which three infections (33.3%) were due to quinolone-resistant organisms. Female sex (P =0.04), but no other patient or post-operative characteristic was associated with symptomatic UTI, including the use of peri-procedural antibiotics. Conclusions: The incidence of symptomatic UTI after cystoscopy with ureteral stent removal in renal transplant recipients is less than three percent and comparable to post cystoscopy UTI risk in the general population. Female sex is associated with symptomatic UTI. Further investigation is needed to identify groups most at risk for UTI and other complications. PMID- 29250579 TI - Civil rights as determinants of public health and racial and ethnic health equity: Health care, education, employment, and housing in the United States. AB - This essay examines how civil rights and their implementation have affected and continue to affect the health of racial and ethnic minority populations in the United States. Civil rights are characterized as social determinants of health. A brief review of US history indicates that, particularly for Blacks, Hispanics, and American Indians, the longstanding lack of civil rights is linked with persistent health inequities. Civil rights history since 1950 is explored in four domains-health care, education, employment, and housing. The first three domains show substantial benefits when civil rights are enforced. Discrimination and segregation in housing persist because anti-discrimination civil rights laws have not been well enforced. Enforcement is an essential component for the success of civil rights law. Civil rights and their enforcement may be considered a powerful arena for public health theorizing, research, policy, and action. PMID- 29250580 TI - A prospective comparison of cold snare polypectomy using traditional or dedicated cold snares for the resection of small sessile colorectal polyps. AB - Background and study aims: The evidence for efficacy and safety of cold snare polypectomy is limited. The aim of this study was to assess the completeness of resection and safety of cold snare polypectomy, using either traditional or dedicated cold snares. Patients and methods: This was a prospective, non randomized study performed at a single tertiary hospital. Adult patients with at least one colorectal polyp (size <= 10 mm) removed by cold snare were included. In the first phase, all patients had polyps removed by traditional snare without diathermy. In the second phase, all patients had polyps removed by dedicated cold snare. Complete endoscopic resection was determined from histological examination of quadrantic polypectomy margin biopsies. Immediate or delayed bleeding within 2 weeks was recorded. Results: In total, 181 patients with 299 eligible polyps (n = 93 (173 polyps) traditional snare group, n = 88 (126 polyps) dedicated cold snare group) were included. Patient demographics and procedure indications were similar between groups. Mean polyp size was 6 mm in both groups ( P = 0.25). Complete polyp resection was 165 /173 (95.4 %; 95 %CI 90.5 - 97.6 %) in the traditional snare group and 124/126 (98.4 %; 95 %CI 93.7 - 99.6 %) in the dedicated cold snare group ( P = 0.16). Serrated polyps, compared with adenomatous polyps, had a higher rate of incomplete resection (7 % vs. 2 %, P = 0.03). There was no statistically significant difference in the rate of immediate bleeding (3 % vs. 1 %, P = 0.41) and there were no delayed hemorrhages or perforations. Conclusions: Cold snare polypectomy is effective and safe for the complete endoscopic resection of small (<= 10 mm) colorectal polyps with either traditional or dedicated cold snares. PMID- 29250581 TI - Magnifying image-enhanced endoscopy for collagenous colitis. AB - Background and study aims We report a case series of 5 patients with collagenous colitis (CC) presenting with chronic watery diarrhea, who were subjected to magnifying, chromoendoscopy and narrow band imaging (NBI). Magnifying chromoendoscopy revealed whitish-clouded, honeycomb-like appearance at orifices of the crypts. NBI with high magnification revealed irregular caliber variation of the subepithelial capillary network. Presence of these features corresponded with histological characteristics of CC indicated by thickening of the subepithelial collagen layer. We concluded that magnifying image-enhanced endoscopy is a reliable tool to diagnose CC. PMID- 29250582 TI - Magnifying advanced endoscopy in collagenous colitis: now you see? PMID- 29250583 TI - Slow-growing amelanotic malignant melanoma of the esophagus with long survival: a case report and review of the literature. AB - Background and study aims We report a case of amelanotic malignant melanoma of the esophagus (AMME), an exceedingly rare disease. A 77-year-old Japanese woman presented to our hospital with features suggestive of a middle esophageal submucosal tumor, which was diagnosed pathologically as AMME. The patient underwent thoracoscopic resection of the esophagus and laparoscopic gastric tube reconstruction. Three years after surgery, computed tomography showed no recurrence. Generally, the prognosis of malignant melanoma of the esophagus is very poor. However, our patient had no recurrence, and is alive 3 years after surgery and 5 years after the tumor was first detected. PMID- 29250585 TI - Evaluation of a novel, hybrid model (Mumbai EUS II) for stepwise teaching and training in EUS-guided biliary drainage and rendezvous procedures. AB - Background and aims: EUS-guided biliary drainage (EUS-BD) and rendezvous (EUS RV) are acceptable rescue options for patients with failed endoscopic retrograde cholangiopancreatography (ERCP). However, there are limited training opportunities at most centers owing to low case volumes. The existing models do not replicate the difficulties encountered during EUS-BD. We aimed to develop and validate a model for stepwise learning of EUS-BD and EUS-RV, which replicates the actual EUS-BD procedures. Methods: A hybrid model was created utilizing pig esophagus and stomach, with a synthetic duodenum and biliary system. The model was objectively assessed on a grade of 1 - 4 by two experts. Twenty-eight trainees were given initial training with didactic lectures and live procedures. This was followed by hands-on training in EUS-BD and EUS-RV on the hybrid model. Trainees were assessed for objective criteria of technical difficulties. Results: Both the experts graded the model as very good or above for all parameters. All trainees could complete the requisite steps of EUS-BD and EUS-RV in a mean time of 11 minutes (8 - 18 minutes). Thirty-six technical difficulties were noted during the training (wrong scope position, 13; incorrect duct puncture, 12; guidewire related problems, 11). Technical difficulties peaked for EUS-RV, followed by hepaticogastrostomy (HGS) and choledochoduodenostomy (CDS) (20, 9, and 7, P = 0.001). At 10 days follow-up, nine of 28 trainees had successfully performed three EUS-RV and seven EUS-BD procedures independently. Conclusions: The Mumbai EUS II hybrid model replicates situations encountered during EUS-RV and EUS-BD. Stepwise mentoring improves the chances of success in EUS-RV and EUS BD procedures. PMID- 29250586 TI - Endoscopic ultrasound-guided placement of plastic pigtail stents for the drainage of refractory malignant ascites. AB - Endoscopic ultrasound (EUS)-guided drainage is now the treatment of choice in cases of pancreatic pseudocysts and walled-off necrosis, especially in the absence of luminal bulging and in patients with portal hypertension. Malignant refractory ascites usually heralds a poor prognosis and substantially impairs the quality of life of patients because of the symptoms experienced and the need for repeated paracentesis. EUS-guided placement of lumen-apposing, fully covered, self-expandable metal stents (FCSEMS) has been reported for the drainage of malignant ascites. Herein, we present the results of EUS-guided placement of plastic pigtails stents for the drainage of refractory malignant ascites in three patients. The aim was to improve symptoms and minimize the possible drawbacks of large-caliber FCSEMS. In this preliminary experience, EUS-guided placement of plastic stents was feasible and avoided further paracentesis. PMID- 29250584 TI - Endoscopic full-thickness resection for T1 early rectal cancer: a case series and video report. AB - Background and study aims: Endoscopic treatment of malignant colorectal polyps is often challenging, especially for early rectal cancer (ERC) localized close to the dentate line. Conversely, the surgical approach may result in temporary or definitive stoma and in frequent post-surgical complications. The Full-Thickness Resection Device (FTRD (r) ) System (Ovesco Endoscopy, Tubingen, Germany) is a novel system that, besides having other indications, appears to be promising for wall-thickness excision of intestinal T1 carcinoma following incomplete endoscopic resection. However, follow-up data on patients treated with this device are scarce, particularly for ERC. Patients and methods: Six consecutive patients with incomplete endoscopic resection of T1-ERC were treated with the FTRD and their long-term outcomes were evaluated based on a detailed clinical and instrumental assessment. Results: The endoscopic en bloc full-thickness resection was technically feasible in all patients. The histopathologic analysis showed a complete endoscopic resection in all cases, and a full-thickness excision in four. Neither complications, nor disease recurrence were observed during the 1-year follow-up period. Conclusions: The FTRD System is a promising tool for treating ERC featuring a residual risk of disease recurrence after incomplete endoscopic mucosal resection in patients unfit for surgery or refusing a surgical approach. PMID- 29250587 TI - EUS-guided gallbladder drainage using a lumen-apposing self-expandable metal stent in patients with coagulopathy or anticoagulation therapy: a case series. AB - Background and study aims We report our experience in endoscopic ultrasound guided gallbladder drainage performed emergently in 4 prohibitive surgical risk patients with concurrent coagulopathy or on anticoagulant therapy using an electrocautery enhanced lumen apposing self expanding metal stent (LA-SEMS). PMID- 29250589 TI - Global localization of 3D point clouds in building outline maps of urban outdoor environments. AB - This paper presents a method to localize a robot in a global coordinate frame based on a sparse 2D map containing outlines of building and road network information and no location prior information. Its input is a single 3D laser scan of the surroundings of the robot. The approach extends the generic chamfer matching template matching technique from image processing by including visibility analysis in the cost function. Thus, the observed building planes are matched to the expected view of the corresponding map section instead of to the entire map, which makes a more accurate matching possible. Since this formulation operates on generic edge maps from visual sensors, the matching formulation can be expected to generalize to other input data, e.g., from monocular or stereo cameras. The method is evaluated on two large datasets collected in different real-world urban settings and compared to a baseline method from literature and to the standard chamfer matching approach, where it shows considerable performance benefits, as well as the feasibility of global localization based on sparse building outline data. PMID- 29250588 TI - A non-rigid map fusion-based direct SLAM method for endoscopic capsule robots. AB - Since the development of capsule endoscopy technology, medical device companies and research groups have made significant progress to turn passive capsule endoscopes into robotic active capsule endoscopes. However, the use of robotic capsules in endoscopy still has some challenges. One such challenge is the precise localization of the actively controlled robot in real-time. In this paper, we propose a non-rigid map fusion based direct simultaneous localization and mapping method for endoscopic capsule robots. The proposed method achieves high accuracy for extensive evaluations of pose estimation and map reconstruction performed on a non-rigid, realistic surgical EsophagoGastroDuodenoscopy Simulator and outperforms state-of-the art methods. PMID- 29250590 TI - A deep learning based fusion of RGB camera information and magnetic localization information for endoscopic capsule robots. AB - A reliable, real time localization functionality is crutial for actively controlled capsule endoscopy robots, which are an emerging, minimally invasive diagnostic and therapeutic technology for the gastrointestinal (GI) tract. In this study, we extend the success of deep learning approaches from various research fields to the problem of sensor fusion for endoscopic capsule robots. We propose a multi-sensor fusion based localization approach which combines endoscopic camera information and magnetic sensor based localization information. The results performed on real pig stomach dataset show that our method achieves sub-millimeter precision for both translational and rotational movements. PMID- 29250592 TI - Actin Cytoskeleton-Mediated Constriction of Membrane Organelles via Endoplasmic Reticulum Scaffolding. AB - Intracellular organelles constantly undergo fission to facilitate turnover, transport, and functional changes. The cytoskeleton has long been understood to play a role in these events, and recent work strongly suggests that several conserved molecular players cooperate with the cytoskeleton to mediate the fission process. Membrane curvature-inducing, membrane scission proteins, and force-inducing cytoskeletal proteins all cooperate to drive the fission process. Recent work suggests that the endoplasmic reticulum serves as the linchpin that orchestrates and spatially organizes fission via these curvature-inducing, scission, and force-producing molecules. This all leads us to postulate a "universal theory" of organelle fission with distinct biophysical and biochemical features mediated by a finite number of physical and molecular constraints. This new physical paradigm deserves special attention from those who wish to model these processes, since previous theoretical and experimental attempts to elucidate these fission mechanisms have not included the organizing factor of the endoplasmic reticulum. Here we review the basic concepts of this new model for organelle fission, and explore the implications thereof. Previous studies that didn't include this component can now be interpreted in light of these new data and serve as a useful guide for understanding how this process happens in vivo. Thus, this review provides direction for future modeling and experimental efforts to better understand how these complex systems and processes are regulated in both healthy and diseased biological systems. PMID- 29250591 TI - Shank Proteins Differentially Regulate Synaptic Transmission. AB - Shank proteins, one of the principal scaffolds in the postsynaptic density (PSD) of the glutamatergic synapses, have been associated with autism spectrum disorders and neuropsychiatric diseases. However, it is not known whether different Shank family proteins have distinct functions in regulating synaptic transmission, and how they differ from other scaffold proteins in this aspect. Here, we investigate the role of Shanks in regulating glutamatergic synaptic transmission at rat hippocampal SC-CA1 synapses, using lentivirus-mediated knockdown and molecular replacement combined with dual whole-cell patch clamp in hippocampal slice culture. In line with previous findings regarding PSD-MAGUK scaffold manipulation, we found that loss of scaffold proteins via knockdown of Shank1 or Shank2, but not Shank3, led to a reduction of the number but not the unitary response of AMPAR-containing synapses. Only when both Shank1 and Shank2 were knocked down, were both the number and the unitary response of active synapses reduced. This reduction was accompanied by a decrease in NMDAR-mediated synaptic response, indicating more profound deficits in synaptic transmission. Molecular replacement with Shank2 and Shank3c rescued the synaptic transmission to the basal level, and the intact sterile alpha-motif (SAM) of Shank proteins is required for maintaining glutamatergic synaptic transmission. We also found that altered neural activity did not influence the effect of Shank1 or Shank2 knockdown on AMPAR synaptic transmission, in direct contrast to the activity dependence of the effect of PSD-95 knockdown, revealing differential interaction between activity-dependent signaling and scaffold protein families in regulating synaptic AMPAR function. PMID- 29250593 TI - Methods To Assess Shear-Thinning Hydrogels for Application As Injectable Biomaterials. AB - Injectable hydrogels have gained popularity as a vehicle for the delivery of cells, growth factors, and other molecules to localize and improve their retention at the injection site, as well as for the mechanical bulking of tissues. However, there are many factors, such as viscosity, storage and loss moduli, and injection force, to consider when evaluating hydrogels for such applications. There are now numerous tools that can be used to quantitatively assess these factors, including for shear-thinning hydrogels because their properties change under mechanical load. Here, we describe relevant rheological tests and ways to measure injection force using a force sensor or a mechanical testing machine toward the evaluation of injectable hydrogels. Injectable, shear thinning hydrogels can be used in a variety of clinical applications, and as an example we focus on methods for injection into the heart, where an understanding of injection properties and mechanical forces is imperative for consistent hydrogel delivery and retention. We discuss methods for delivery of hydrogels to mouse, rat, and pig hearts in models of myocardial infarction, and compare methods of tissue postprocessing for hydrogel preservation. Our intent is that the methods described herein can be helpful in the design and assessment of shear thinning hydrogels for widespread biomedical applications. PMID- 29250594 TI - Biomaterial Property Effects on Platelets and Macrophages: An in Vitro Study. AB - The purpose of this study was to evaluate the effects of surface properties of bone implants coated with hydroxyapatite (HA) and beta-tricalcium phosphate (beta TCP) on platelets and macrophages upon implant installation and compare them to grit-blasted Ti and Thermanox used as a control. Surface properties were characterized using scanning electron microscopy, profilometry, crystallography, Fourier transform infrared spectroscopy, and coating stability. For platelets, platelet adherence and morphology were assessed. For macrophages, morphology, proliferation, and polarization were evaluated. Surface characterization showed similar roughness of ~2.5 MUm for grit-blasted Ti discs, both with and without coating. Coating stability assessment showed substantial dissolution of HA and beta-TCP coatings. Platelet adherence was significantly higher for grit-blasted Ti, Ti-HA, and Ti-beta-TCP coatings compared to that of cell culture control Thermanox. Macrophage cultures revealed a decreased proliferation on both HA and beta-TCP coated discs compared to both Thermanox and grit-blasted Ti. In contrast, secretion of pro-inflammatory cytokine TNF-alpha and anti-inflammatory cytokine TGF-beta were marginal for grit-blasted Ti and Thermanox, while a coating-dependent increased secretion of pro- and anti-inflammatory cytokines was observed for HA and beta-TCP coatings. The results demonstrated a significantly upregulated pro-inflammatory and anti-inflammatory cytokine secretion and marker gene expression of macrophages on HA and beta-TCP coatings. Furthermore, HA induced an earlier M1 macrophage polarization but more M2 phenotype potency than beta-TCP. In conclusion, our data showed that material surface affects the behaviors of first cell types attached to implants. Due to the demonstrated crucial roles of platelets and macrophages in bone healing and implant integration, this information will greatly aid the design of metallic implants for a higher rate of success in patients. PMID- 29250595 TI - Comparison of NMDA and AMPA Channel Expression and Function between Embryonic and Adult Neurons Utilizing Microelectrode Array Systems. AB - Microelectrode arrays (MEAs) are innovative tools used to perform electrophysiological experiments for the study of electrical activity and connectivity in populations of neurons from dissociated cultures. Reliance upon neurons derived from embryonic tissue is a common limitation of neuronal/MEA hybrid systems and perhaps of neuroscience research in general, and the use of adult neurons could model fully functional in vivo parameters more closely. Spontaneous network activity was concurrently recorded from both embryonic and adult rat neurons cultured on MEAs for up to 10 weeks in vitro to characterize the synaptic connections between cell types. The cultures were exposed to synaptic transmission antagonists against NMDA and AMPA channels, which revealed significantly different receptor profiles of adult and embryonic networks in vitro. In addition, both embryonic and adult neurons were evaluated for NMDA and AMPA channel subunit expression over five weeks in vitro. The results established that neurons derived from embryonic tissue did not express mature synaptic channels for several weeks in vitro under defined conditions. Consequently, the embryonic response to synaptic antagonists was significantly different than that of neurons derived from adult tissue sources. These results are especially significant because most studies reported with embryonic hippocampal neurons do not begin at two to four weeks in culture. In addition, the utilization of MEAs in lieu of patch-clamp electrophysiology avoided a large-scale, labor-intensive study. These results establish the utility of this unique hybrid system derived from adult hippocampal tissue in combination with MEAs and offer a more appropriate representation of in vivo function for drug discovery. It has application for neuronal development and regeneration as well as for investigations into neurodegenerative disease, traumatic brain injury, and stroke. PMID- 29250596 TI - Glucose-Stimulated Insulin Response of Silicon Nanopore-Immunoprotected Islets under Convective Transport. AB - Major clinical challenges associated with islet transplantation for type 1 diabetes include shortage of donor organs, poor engraftment due to ischemia, and need for immunosuppressive medications. Semipermeable membrane capsules can immunoprotect transplanted islets by blocking passage of the host's immune components while providing exchange of glucose, insulin, and other small molecules. However, capsules-based diffusive transport often exacerbates ischemic injury to islets by reducing the rate of oxygen and nutrient transport. We previously reported the efficacy of a newly developed semipermeable ultrafiltration membrane, the silicon nanopore membrane (SNM) under convective driven transport, in limiting the passage of pro-inflammatory cytokines while overcoming the mass transfer limitations associated with diffusion through nanometer-scale pores. In this study, we report that SNM-encapsulated mouse islets perfused in culture solution under convection outperformed those under diffusive conditions in terms of magnitude (1.49-fold increase in stimulation index and 3.86-fold decrease in shutdown index) and rate of insulin secretion (1.19-fold increase and 6.45-fold decrease during high and low glucose challenges), respectively. Moreover, SNM-encapsulated mouse islets under convection demonstrated rapid glucose-insulin sensing within a physiologically relevant time-scale while retaining healthy islet viability even under cytokine exposure. We conclude that encapsulation of islets with SNM under convection improves islet in vitro functionality. This approach may provide a novel strategy for islet transplantation in the clinical setting. PMID- 29250597 TI - Cryo-mediated exfoliation and fracturing of layered materials into 2D quantum dots. AB - Atomically thin quantum dots from layered materials promise new science and applications, but their scalable synthesis and separation have been challenging. We demonstrate a universal approach for the preparation of quantum dots from a series of materials, such as graphite, MoS2, WS2, h-BN, TiS2, NbS2, Bi2Se3, MoTe2, Sb2Te3, etc., using a cryo-mediated liquid-phase exfoliation and fracturing process. The method relies on liquid nitrogen pretreatment of bulk layered materials before exfoliation and breakdown into atomically thin two dimensional quantum dots of few-nanometer lateral dimensions, exhibiting size confined optical properties. This process is efficient for a variety of common solvents with a wide range of surface tension parameters and eliminates the use of surfactants, resulting in pristine quantum dots without surfactant covering or chemical modification. PMID- 29250598 TI - Real-space analysis of diffusion behavior and activation energy of individual monatomic ions in a liquid. AB - Investigation of the local dynamic behavior of atoms and molecules in liquids is crucial for revealing the origin of macroscopic liquid properties. Therefore, direct imaging of single atoms to understand their motions in liquids is desirable. Ionic liquids have been studied for various applications, in which they are used as electrolytes or solvents. However, atomic-scale diffusion and relaxation processes in ionic liquids have never been observed experimentally. We directly observe the motion of individual monatomic ions in an ionic liquid using scanning transmission electron microscopy (STEM) and reveal that the ions diffuse by a cage-jump mechanism. Moreover, we estimate the diffusion coefficient and activation energy for the diffusive jumps from the STEM images, which connect the atomic-scale dynamics to macroscopic liquid properties. Our method is the only available means to observe the motion, reactions, and energy barriers of atoms/molecules in liquids. PMID- 29250599 TI - Reactivity of prehydrated electrons toward nucleobases and nucleotides in aqueous solution. AB - DNA damage induced via dissociative attachment by low-energy electrons (0 to 20 eV) is well studied in both gas and condensed phases. However, the reactivity of ultrashort-lived prehydrated electrons ([Formula: see text]) with DNA components in a biologically relevant environment has not been fully explored to date. The electron transfer processes of [Formula: see text] to the DNA nucleobases G, A, C, and T and to nucleosides/nucleotides were investigated by using 7-ps electron pulse radiolysis coupled with pump-probe transient absorption spectroscopy in aqueous solutions. In contrast to previous results, obtained by using femtosecond laser pump-probe spectroscopy, we show that G and A cannot scavenge [Formula: see text] at concentrations of <=50 mM. Observation of a substantial decrease of the initial yield of hydrated electrons ([Formula: see text]) and formation of nucleobase/nucleotide anion radicals at increasing nucleobase/nucleotide concentrations present direct evidence for the earliest step in reductive DNA damage by ionizing radiation. Our results show that [Formula: see text] is more reactive with pyrimidine than purine nucleobases/nucleotides with a reactivity order of T > C > A > G. In addition, analyses of transient signals show that the signal due to formation of the resulting anion radical directly correlates with the loss of the initial [Formula: see text] signal. Therefore, our results do not agree with the previously proposed dissociation of transient negative ions in nucleobase/nucleotide solutions within the timescale of these experiments. Moreover, in a molecularly crowded medium (for example, in the presence of 6 M phosphate), the scavenging efficiency of [Formula: see text] by G is significantly enhanced. This finding implies that reductive DNA damage by ionizing radiation depends on the microenvironment around [Formula: see text]. PMID- 29250600 TI - Molecular behavior of zero-dimensional perovskites. AB - Low-dimensional perovskites offer a rare opportunity to investigate lattice dynamics and charge carrier behavior in bulk quantum-confined solids, in addition to them being the leading materials in optoelectronic applications. In particular, zero-dimensional (0D) inorganic perovskites of the Cs4PbX6 (X = Cl, Br, or I) kind have crystal structures with isolated lead halide octahedra [PbX6]4- surrounded by Cs+ cations, allowing the 0D crystals to exhibit the intrinsic properties of an individual octahedron. Using both experimental and theoretical approaches, we studied the electronic and optical properties of the prototypical 0D perovskite Cs4PbBr6. Our results underline that this 0D perovskite behaves akin to a molecule, demonstrating low electrical conductivity and mobility as well as large polaron binding energy. Density functional theory calculations and transient absorption measurements of Cs4PbBr6 perovskite films reveal the polaron band absorption and strong polaron localization features of the material. A short polaron lifetime of ~2 ps is observed in femtosecond transient absorption experiments, which can be attributed to the fast lattice relaxation of the octahedra and the weak interactions among them. PMID- 29250601 TI - Nanoscale magnetic imaging using circularly polarized high-harmonic radiation. AB - This work demonstrates nanoscale magnetic imaging using bright circularly polarized high-harmonic radiation. We utilize the magneto-optical contrast of worm-like magnetic domains in a Co/Pd multilayer structure, obtaining quantitative amplitude and phase maps by lensless imaging. A diffraction-limited spatial resolution of 49 nm is achieved with iterative phase reconstruction enhanced by a holographic mask. Harnessing the exceptional coherence of high harmonics, this approach will facilitate quantitative, element-specific, and spatially resolved studies of ultrafast magnetization dynamics, advancing both fundamental and applied aspects of nanoscale magnetism. PMID- 29250602 TI - RAF Inhibitor Therapy Promotes Melanocytic Antigen Expression and Enhanced Anti Tumor Immunity in Melanoma. AB - Melanoma remains a major cause of morbidity and mortality worldwide, however tremendous advances have been made in its treatment over the past several years. The discovery of genomic alterations that contribute to oncogenicity has ushered in a new era of molecularly-targeted therapy. Importantly, over half of melanomas harbor a mutation in the BRAF gene that leads to constitutive signaling down the MAPK pathway and multiple subsequent deleterious effects. Pharmacologic agents targeting this mutation have been developed and several are now FDA-approved, having yielded high response rates to therapy although these are tempered by a short duration of response. Multiple molecular mechanisms of resistance have been identified; however until recently few studies had delved into the immune effects of BRAF inhibitors. The effect of BRAF inhibition on anti-tumor immunity will be discussed herein, as will potential implications of these findings in the treatment of melanoma. PMID- 29250603 TI - Slow Cooling of Hot Polarons in Halide Perovskite Solar Cells. AB - Halide perovskites show unusual thermalization kinetics for above-bandgap photoexcitation. We explain this as a consequence of excess energy being deposited into discrete large polaron states. The crossover between low-fluence and high-fluence "phonon bottleneck" cooling is due to a Mott transition where the polarons overlap (n >= 1018 cm-3) and the phonon subpopulations are shared. We calculate the initial rate of cooling (thermalization) from the scattering time in the Frohlich polaron model to be 78 meV ps-1 for CH3NH3PbI3. This rapid initial thermalization involves heat transfer into optical phonon modes coupled by a polar dielectric interaction. Further cooling to equilibrium over hundreds of picoseconds is limited by the ultralow thermal conductivity of the perovskite lattice. PMID- 29250604 TI - Behavioral Genetics in Criminal Court. AB - Introduction of behavioral genetic evidence of a predisposition to violent or impulsive behavior is on the rise in criminal trials. However, a panoply of data suggests that such evidence is ineffective at reducing judgments of culpability and punishment, and therefore its use in the legal process is likely to diminish. PMID- 29250605 TI - Successful collection of stool samples for microbiome analyses from a large community-based population of elderly men. AB - The relationship of the gastrointestinal microbiome to health and disease is of major research interest, including the effects of the gut microbiota on age related conditions. Here we report on the outcome of a project to collect stool samples on a large number of community dwelling elderly men using the OMNIgene GUT stool/feces collection kit (OMR-200, DNA Genotek, Ottawa, Canada). Among 1,328 men who were eligible for stool collection, 982 (74%) agreed to participate and 951 submitted samples. The collection process was reported to be acceptable, almost all samples obtained were adequate, the process of sample handling by mail was uniformly successful. The DNA obtained provided excellent results in microbiome analyses, yielding an abundance of species and a diversity of taxa as would be predicted. Our results suggest that population studies of older participants involving remote stool sample collection are feasible. These approaches would allow large scale research projects of the association of the gut microbiota with important clinical outcomes. PMID- 29250607 TI - Fitting dynamic models to epidemic outbreaks with quantified uncertainty: A Primer for parameter uncertainty, identifiability, and forecasts. AB - Mathematical models provide a quantitative framework with which scientists can assess hypotheses on the potential underlying mechanisms that explain patterns in the observed data at different spatial and temporal scales, generate estimates of key kinetic parameters, assess the impact of interventions, optimize the impact of control strategies, and generate forecasts. We review and illustrate a simple data assimilation framework for calibrating mathematical models based on ordinary differential equation models to time series data describing the temporal progression of case counts relating to population growth or infectious disease transmission dynamics. In contrast to Bayesian estimation approaches that always raise the question of how to set priors for the parameters, this frequentist approach relies on modeling the error structure in the data. We discuss issues related to parameter identifiability, uncertainty quantification and propagation as well as model performance and forecasts along examples based on phenomenological and mechanistic models parameterized using simulated and real datasets. PMID- 29250606 TI - Modern Approaches to Chemical Toxicity Screening. AB - Chemical toxicity has a serious impact on public health, and toxicity failures of drug candidates drive up drug development costs. Many in vitro bioassays exist for toxicity screening, and newer versions of these tend to be high throughput or high content assays, some of which rely on electrochemical detection. Toxicity very often results from metabolites of the chemicals we are exposed to, so it is important that assays feature metabolic conversion. Combining bioassays, computational predictions, and accurate chemical pathway elucidation presents our best chance for reliable toxicity prediction. Employing electrochemical and electrochemiluminescent approaches, cell-free microfluidic arrays can measure relative rates of formation of DNA-metabolite adduct formation (a measure of genotoxicity) as well as DNA oxidation levels resulting from enzyme-generated metabolites. Enzymes for several organ types can be studied simultaneously. These arrays can be used to identify the most reactive metabolites, and subsequent mechanistic details can then be investigated with high throughput LC-HPLC using enzyme/DNA-coated magnetic beads. PMID- 29250608 TI - The effect of the Environmental Protection Agency maximum contaminant level on arsenic exposure in the USA from 2003 to 2014: an analysis of the National Health and Nutrition Examination Survey (NHANES). AB - Background: The current US Environmental Protection Agency (EPA) maximum contaminant level (MCL) for arsenic in public water systems (10 ug/L) took effect in 2006. Arsenic is not federally regulated in private wells. The impact of the 2006 MCL on arsenic exposure in the US, as confirmed through biomarkers, is presently unknown. We evaluated national trends in water arsenic exposure in the US, hypothesizing that urinary arsenic levels would decrease over time among participants using public water systems but not among those using well water. We further estimated the expected number of avoided lung, bladder, and skin cancer cases. Methods: We evaluated 14,127 participants in the National Health and Nutrition Examination Survey (NHANES) 2003-2014 with urinary dimethylarsinate (DMA) and total arsenic available. To isolate water exposure, we expanded a residual-based method to remove tobacco and dietary contributions of arsenic. We applied EPA risk assessment approaches to estimate the expected annual number of avoided cancer cases comparing arsenic exposure in 2013-2014 vs. 2003-2004. Findings: Among public water users, fully adjusted geometric means (GMs) of DMA decreased from 3.01 ug/L in 2003-2004 to 2.49 ug/L in 2013-2014 (17% reduction; 95% confidence interval 10%, 24%; p-trend<0.01); no change was observed among well water users (p-trend= 0.35). Assuming these estimated exposure reductions will remain similar across a lifetime, we estimate a reduction of 200 to 900 lung and bladder cancer cases per year depending on the approach used. Interpretation: The decline in urinary arsenic among public water but not private well users in NHANES 2003-2014 indicates that the implementation of the current MCL has reduced arsenic exposure in the US population. Our study supports prior work showing that well water users are inadequately protected against drinking water arsenic, and confirms the critical role of federal drinking water regulations in reducing toxic exposures and protecting human health. Funding: This work was supported by the National Institute of Environmental Health Sciences (1R01ES025216, R01ES021367, 5P30ES009089 and P42ES010349). A. E. Nigra was supported by 5T32ES007322. PMID- 29250609 TI - Spellbinding Effects of the Acidic COOH-Terminus of Factor Va Heavy Chain on Prothrombinase Activity and Function. AB - Human factor Va (hfVa) is the important regulatory subunit of prothrombinase. Recent modeling data have suggested a critical role for amino acid Arg701 of hfVa for human prothrombin (hPro) activation by prothrombinase. Furthermore, it has also been demonstrated that hfVa has a different effect than that of bovine fVa on prethrombin-1 activation by prothrombinase. The difference between the two cofactor molecules was also found within the Asn700-Arg701 dipeptide in the human factor V (hfV) molecule, which is replaced by the Asp-Glu sequence in bfV. As a consequence, we produced a recombinant hfV (rhfV) molecule with the substitution 700NR701->DE. rhfVNR->DE together with the wild-type molecule (rhfVWT) were expressed in COS7 cells, purified, and tested for their capability to function within prothrombinase. Kinetic studies showed that the Kd of rhfVaNR->DE for human fXa as well as the kcat and Km of prothrombinase made with rhfVaNR->DE for hPro activation were similar to the values obtained following hPro activation by prothrombinase made with rhfVaWT. Remarkably, sodium dodecyl sulfate polyacrylamide gel electrophoresis analyses of hPro activation time courses demonstrated that the rate of cleavage of hPro by prothrombinase reconstituted with rhfVaNR->DE was significantly delayed with substantial accumulation of meizothrombin, and delayed thrombin generation, when compared to activation of hPro by prothrombinase made with rhfVaWT. These unanticipated results provide significant insights on the role of the carboxyl-terminal end of the heavy chain of hfVa for hPro cleavage and activation by prothrombinase and show that residues 700NR701 regulate at least in part the enzyme-substrate/product interaction during fibrin clot formation. PMID- 29250611 TI - Validity and power of minimization algorithm in longitudinal analysis of clinical trials. AB - We studied the validity of longitudinal statistical inferences of clinical trials using minimization, a dynamic randomization algorithm designed to minimize treatment imbalance for prognostic factors. Repeated measures analysis of covariance and the random intercept and slope models, were used to simulate longitudinal clinical trials randomized by minimization or simple randomization. The simulations represented a wide range of analyses in real-world trials, including missing data caused by dropouts, unequal allocation of treatment arms, and efficacy analyses on either the original outcome or its change from baseline. We also analyzed the database from the Dominantly Inherited Alzheimer Network (DIAN), and used the estimated parameters to simulate the ongoing DIAN trial. Our analyses demonstrated minimization had conservative type I errors when the prognostic factor used in the minimization algorithm had a relatively strong correlation with the outcome and was not adjusted for in analyses. In contrast, adjusted tests for the prognostic factor as a covariate resulted in type I errors close to the nominal significance level. In many simulation scenarios, the adjusted tests using minimization had slightly greater statistical power than those using simple randomization, whereas in the other scenarios, the power of adjusted tests using these two randomization methods are almost indistinguishable. PMID- 29250612 TI - Knowledge, Attitudes, and Perceived Risks Related to Diabetes Mellitus Among University Students in Uganda: A Cross-Sectional Study. AB - Background: Diabetes mellitus is on the rise in low-income countries, including Uganda, owing to the 'westernization' of individual lifestyles. It remains unanswered whether the majority of university students who are rapidly embracing 'western' lifestyles have any knowledge of diabetes or perceive themselves to be at risk of acquiring the disease. The aim of the study was to assess the knowledge, attitudes, and perceived risks related to diabetes mellitus among university students in Uganda. Methods: This descriptive cross-sectional study was conducted in 4 universities in Uganda from August to November 2013. The data collection tool included questions on risk factors, symptoms, personal risks, and practices to prevent diabetes mellitus. We interviewed 378 university students using pretested self-administered semi-structured questionnaires. Only students who consented to participate in the study were included. Data were entered into EpiData version 3.1 and analysed using SPSS version 18. Results: Almost all (99%) of the students had knowledge about diabetes mellitus. The majority (83.1%) reported that diabetes mellitus is not completely a genetic/hereditary disease. Only a minority of respondents reported that they should worry about diabetes before 45 years of age. Common symptoms of diabetes reported by the respondents included constant hunger, blurred vision, fatigue, and frequent urination. Conclusions: Our study revealed that the majority of university students in Uganda had good knowledge about the risk factors and symptoms of diabetes mellitus. The majority also perceived themselves to be at risk of diabetes. PMID- 29250610 TI - Increased Neuronal DNA/RNA Oxidation in the Frontal Cortex of Mice Subjected to Unpredictable Chronic Mild Stress. AB - Background: Chronic stress is implicated in the development of various psychiatric illnesses including major depressive disorder. Previous reports suggest that patients with major depressive disorder have increased levels of oxidative stress, including higher levels of DNA/RNA oxidation found in postmortem studies, especially within brain regions responsible for the cognitive and emotional processes disrupted in the disorder. Here, we aimed to investigate whether unpredictable chronic mild stress in mice induces neuronal DNA/RNA oxidation in the prelimbic, infralimbic, and cingulate cortices of the frontal cortex and the basolateral amygdala and to explore potential associations with depressive-like behaviors. We expected that animals subjected to unpredictable chronic mild stress will present higher levels of DNA/RNA oxidation, which will be associated with anxiety-/depressive-like behaviors. Methods: C57BL/6J mice were assigned to unpredictable chronic mild stress or nonstress conditions (n = 10/group, 50% females). Following five weeks of unpredictable chronic mild stress exposure, mice were tested in a series of behavioral tests measuring anxiety- and depressive-like behaviors. Frontal cortex and amygdala sections were then immunolabeled for neuronal nuclei, a marker of post-mitotic neurons and anti-8 hydroxy-2-deoxyguanosine/8-oxo-7,8-dihydroguanosine, which reflects both DNA and RNA oxidation. Results: Levels of neuronal DNA/RNA oxidation were increased in the frontal cortex of mice subjected to unpredictable chronic mild stress (p = 0.0207). Levels of neuronal DNA/RNA oxidation in the frontal cortex were positively correlated with z-emotionality scores for latency to feed in the novelty-suppressed feeding test (p = 0.0031). Statistically significant differences were not detected in basolateral amygdala levels of neuronal DNA/RNA oxidation between nonstress- and unpredictable chronic mild stress-exposed mice, nor were correlations found with behavioral performances for this region. Conclusion: Our results demonstrate that unpredictable chronic mild stress induces a significant increase in neuronal DNA/RNA oxidation in the frontal cortex that correlate with behavioral readouts of the stress response. A lack of DNA/RNA oxidation alterations in the basolateral amygdala suggests greater vulnerability of frontal cortex neurons to DNA/RNA oxidation in response to unpredictable chronic mild stress. These findings add support to the hypothesis that chronic stress-induced damage to DNA/RNA may be an additional molecular mechanism underlying cellular dysfunctions associated with chronic stress and present in stress-related disorders. PMID- 29250613 TI - Deformable Image Registration based on Similarity-Steered CNN Regression. AB - Existing deformable registration methods require exhaustively iterative optimization, along with careful parameter tuning, to estimate the deformation field between images. Although some learning-based methods have been proposed for initiating deformation estimation, they are often template-specific and not flexible in practical use. In this paper, we propose a convolutional neural network (CNN) based regression model to directly learn the complex mapping from the input image pair (i.e., a pair of template and subject) to their corresponding deformation field. Specifically, our CNN architecture is designed in a patch-based manner to learn the complex mapping from the input patch pairs to their respective deformation field. First, the equalized active-points guided sampling strategy is introduced to facilitate accurate CNN model learning upon a limited image dataset. Then, the similarity-steered CNN architecture is designed, where we propose to add the auxiliary contextual cue, i.e., the similarity between input patches, to more directly guide the learning process. Experiments on different brain image datasets demonstrate promising registration performance based on our CNN model. Furthermore, it is found that the trained CNN model from one dataset can be successfully transferred to another dataset, although brain appearances across datasets are quite variable. PMID- 29250614 TI - Effect of alkyl chain length on the properties of triphenylamine-based hole transport materials and their performance in perovskite solar cells. AB - A new series of diacetylide-triphenylamine (DATPA) derivatives with five different alkyl chains in the para position, MeO, EtO, nPrO, iPrO and BuO, were synthesised, fully characterised and their function as hole-transport materials in perovskite solar cells (PSC) studied. Their thermal, optical and electrochemical properties were investigated along with their molecular packing and charge transport properties to analyse the influence of different alkyl chains in the solar cell parameters. The shorter alkyl chain facilitates more compact packing structures which enhanced the hole mobilities and reduced recombination. This work suggests that the molecule with the methoxy substituent (MeO) exhibits the best semiconductive properties with a power conversion efficiency of up to 5.63%, an open circuit voltage (Voc) of 0.83 V, a photocurrent density (Jsc) of 10.84 mA cm-2 and a fill factor of 62.3% in perovskite solar cells. Upon replacing the methoxy group with longer alkyl chain substituents without changing the energy levels, there is a decrease in the charge mobility as well as PCE (e.g. 3.29% for BuO-DATPA). The alkyl chain length of semiconductive molecules plays an important role in achieving high performance perovskite solar cells. PMID- 29250615 TI - The Bethe-Salpeter equation in chemistry: relations with TD-DFT, applications and challenges. AB - We review the many-body Green's function Bethe-Salpeter equation (BSE) formalism that is rapidly gaining importance for the study of the optical properties of molecular organic systems. We emphasize in particular its similarities and differences with time-dependent density functional theory (TD-DFT), both methods sharing the same formal O(N4) computing time scaling with system size. By comparison with higher level wavefunction based methods and experimental results, the advantages of BSE over TD-DFT are presented, including an accurate description of charge-transfer states and an improved accuracy for the challenging cyanine dyes. We further discuss the models that have been developed for including environmental effects. Finally, we summarize the challenges to be faced so that BSE reaches the same popularity as TD-DFT. PMID- 29250616 TI - A highly stable indium based metal organic framework for efficient arsenic removal from water. AB - A new porous indium metal organic framework namely (AUBM-1) was successfully synthesized via a solvothermal reaction of pyromellitic acid and indium chloride. Single crystal X-ray analysis revealed the formation of a 3D framework with a pts topology. The resulting MOF structure showed high chemical stability at different pH values. Thus, the activated indium MOF was applied for As removal from water for the first time and showed a high arsenate uptake capacity of 103.1 mg g-1 at neutral pH, which is higher than the commercial adsorbents (usually less than 100 mg g-1 at neutral pH). Finally, the kinetics and thermodynamic studies revealed that the As adsorption was an endothermic process and followed a pseudo-second order kinetic model. PMID- 29250617 TI - H-Bonded anion-anion complex trapped in a squaramido-based receptor. AB - Herein we report the experimental observation (X-ray characterization) of an anion-anion complex (anion = hydrogen fumarate) stabilized by H-bonds that is trapped in a secondary squaramide receptor. High level ab initio calculations indicate that the anion-anion complex is thermodynamically unstable but kinetically stable with respect to the isolated anions. PMID- 29250623 TI - Reversible crystal-to-amorphous structural transformations and magnetic variations in single end-on azide-bridged MII (M = Mn, Ni) coordination polymers. AB - MII (M = Mn, Ni) coordination frameworks, singly linked by end-on azide ligands, were prepared by employing the long, flexible spacer ligand, p-XBP4. These two dimensional layer structures underwent reversible crystal-to-amorphous phase transformations during the hydration-dehydration process. Moreover, the magnetic nature changes from antiferromagnetic to ferromagnetic coupling when moving from Mn to Ni. PMID- 29250624 TI - Microscopic evidence for the dissociation of water molecules on cleaved GaN(11[combining macron]00). AB - The dissociation of water molecules absorbed on a cleaved non-polar GaN(11[combining macron]00) surface was studied primarily with synchrotron-based photoemission spectra and density-functional-theory calculations. The adsorbed water molecules are spontaneously dissociated into hydrogen atoms and hydroxyl groups at either 300 or 130 K, which implies a negligible activation energy (<11 meV) for the dissociation. The produced H and OH were bound to the surface nitrogen and gallium on GaN(11[combining macron]00) respectively. These results highlight the promising applications of the non-polar GaN(11[combining macron]00) surface in water dissociation and hydrogen generation. PMID- 29250622 TI - Targeted photodynamic therapy in visible light using BODIPY-appended copper(ii) complexes of a vitamin B6 Schiff base. AB - Copper(ii) complexes [Cu(L1/L2/L3)(A)] (1-3), where H2A.HCl is a vitamin B6 Schiff base, viz. 3-hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl) 2-methylpyridin-1-ium chloride, L1 and L2 are 2-(2-pyridyl)benzimidazole based borondipyrromethene (BODIPY) ligands and L3 is 2-(2-pyridyl)benzimidazole, were prepared, characterized and their visible light-induced anti-cancer activity was studied. Complex 3, characterized by X-ray crystallography, exhibits a distorted square-pyramidal geometry for copper (tau = 0.33). Complexes 1 and 2 showed absorption bands at 500 and 535 nm, respectively, in 20% DMSO/Dulbecco's phosphate buffered saline (DPBS) medium. Complex 1 exhibited emission at ~510 nm (lambdaexc = 480 nm) (PhiF = 0.1) in 20% DMSO/DPBS, while the non-emissive diiodo BODIPY complex 2 is an efficient photosensitizer. The green fluorescent complex 1 enabled us to study its cellular uptake and localization. It showed selective uptake in proliferating cancer cells and significant mitochondrial localization (Pearson's coefficient = 0.7). Complex 2 showed excellent photocytotoxicity (400 700 nm, 10 J cm-2) in HeLa, MCF-7 and HepG2 cancer cells with IC50 values within 0.4-0.6 MUM, while remaining less toxic in the dark and in non-cancerous HPL1D cells (photocytotoxic index ~50). Complex 2, remarkable in targeting cancer cells over non-cancerous cells, showed photoinduced generation of singlet oxygen, causing apoptotic cell death, thus satisfying the major requirements of targeted photodynamic therapy. PMID- 29250625 TI - VGCF 3D conducting host coating on glass fiber filters for lithium metal anodes. AB - We report a rational design of vapor grown carbon fiber (VGCF) 3D conducting host coating on a glass fiber filter for its use as a lithium metal anode to inhibit dendrite growth and enhance cycling stability. The high coulombic efficiency of 91.1% and stable cycling can be maintained after 100 cycles (965 h) at the current density of 0.5 mA cm-2 for the capacity of 2.5 mAh cm-2 in the carbonate electrolyte. PMID- 29250627 TI - NHC-catalyzed [4+2] cycloaddition reactions for the synthesis of 3'-spirocyclic oxindoles via a C-F bond cleavage protocol. AB - A chiral NHC-catalyzed cycloaddition of gamma-fluoroenals is developed. The nucleophilic gamma-carbon generated via C-F bond cleavage undergoes highly enantioselective cycloaddition (up to >99% ee) to isatins and provides 3' spirocyclic oxindoles in good yields (up to 91%). PMID- 29250629 TI - Folding induced supramolecular assembly into pH-responsive nanorods with a protein repellent shell. AB - We report the synthesis of ABA' triblock peptide-polysarcosine-peptide conjugates featuring two complementary phenylalanine-histidine pentapeptide strands A/A'. These sequences encode for antiparallel beta-sheet formation into folded conjugates, which promote the self-assembly into polysarcosine-shielded core shell nanorods. These do not cause aggregation of serum proteins in human blood plasma underlining an enhanced stability. PMID- 29250630 TI - Nickel-catalyzed amination of aryl fluorides with primary amines. AB - The Ni-catalyzed cross-coupling reaction between aryl fluorides and primary amines was enabled by the 1,2-bis(dicyclohexylphosphino)benzene (DCYPBz) or 1,2 bis(dicyclohexylphosphino)ethane (DCYPE) ligands. Both N-alkyl- and N-aryl substituted primary amines participated in the selective reaction to form secondary amines. This protocol would potentially be useful for late-stage diversification of fluorinated compounds with complex structures for the synthesis of functionally interesting aniline derivatives. PMID- 29250631 TI - Unique cohesive nature of the beta1-isomer of [70]PCBM fullerene on structures and photovoltaic performances of bulk heterojunction films with PffBT4T-2OD polymers. AB - The effects of regioisomer and diastereomer separations of [70]PCBM on structures and photovoltaic properties of PffBT4T-2OD:[70]PCBM blend films have systematically been investigated for the first time. Decreasing the amount of a diastereomer of beta-[70]PCBM with high aggregation tendency (beta1-[70]PCBM) improved the photovoltaic performances. PMID- 29250632 TI - 1,2-Dihalodigermenes bearing bulky Eind groups: synthesis, characterization, and conversion to halogermylenoids. AB - 1,2-Dihalodigermenes, (E)-(Eind)XGe[double bond, length as m-dash]GeX(Eind) (X = Br and Cl), bearing the fused-ring bulky Eind group (Eind = 1,1,3,3,5,5,7,7 octaethyl-s-hydrindacen-4-yl) have been isolated as orange-yellow crystals by the ligand redistribution reaction between the diarylgermylene, (Eind)2Ge:, and GeX2.dioxane in toluene via the cleavage and recombination of the Ge-C and Ge-X bonds. The dihalodigermenes have a Ge[double bond, length as m-dash]Ge double bond character in the crystalline state, but dissociate into halogermylenes, (Eind)XGe:, in solution. The addition of excess LiBr to the THF solution of the bromogermylene, (Eind)BrGe:, led to the formation of an equilibrium mixture containing the lithium bromogermylenoid, [Li+][(Eind)GeBr2]-. The bromogermylenoid can be isolated as a cryptand-separated potassium ion pair, [K+(crypt-222)][(Eind)GeBr2]-, which has been structurally characterized. PMID- 29250633 TI - In situ probing electronic dynamics at organic bulk heterojunction/aqueous electrolyte interfaces by charge modulation spectroscopy. AB - Interfacing an organic bulk heterojunction (OBHJ) with an aqueous electrolyte (aqE) solution has the potential for applications in biological sensing and neuronal stimulus, by taking advantage of the benefits of the high excitation efficiency and biocompatibility of the OBHJ. At the OBHJ/aqE interface, local charge transfer and transport processes, which are influenced by the polymer/fullerene interface and ion migration, are critically important for device performance but poorly understood. Here, we have introduced charge modulation spectroscopy (CMS) in aqE-gated heterojunction transistors to in situ investigate electronic dynamics at the OBHJ/aqE interface. By correlating impedance spectroscopy measurements and the gating-voltage dependence of the mobility, we show that the existence of local disordered structures, caused by an intermixed fullerene phase, can induce electrochemical doping effects with ion injections. These ions will be trapped in fullerene domains, thus limiting carrier transports via strong carrier-ion interactions with ion-induced trapping. However, carrier-ion interactions have little influence over the charge transfer process due to the existing large energy-offset between the polymer and the fullerene. Furthermore, time-resolved CMS responses reveal that carrier-ion interactions can induce obvious perturbations in polaron relaxations. Our findings provide possibilities for the design and manipulation of novel and low cost sensing systems for future bio-recognition devices. PMID- 29250634 TI - Performance assessment of a portable nephelometer for outdoor particle mass measurement. AB - The availability of portable nephelometers has improved assessment of exposure to atmospheric particles at a high resolution regarding space and time. However, nephelometer performance has seldom been evaluated for outdoor measurements, especially in Chinese cities. During 37 days of measurements at four outdoor sites in Shanghai, we assessed a popular nephelometer called SidePak (TSI Inc., USA) for PM1.0, PM2.5 and PM10 mass measurements and compared them to US federal reference methods (FRMs) based on different measurement principles. The nephelometer showed high measurement precision and stability and was strongly correlated with FRMs, making it superior to the portable light scattering monitors reported in the past and thus indicating the maturity of this principle. The nephelometer measurements overestimated all those of FRMs by a factor of two, which is higher than in evaluations in other international cities. This overestimation showed a descending order for PM1.0 (2.9-fold), PM2.5 (2.2-fold) and PM10 (1.9-fold) relative to the FRMs of tapered element oscillating microbalance or beta attenuation combined with nephelometry, based on whole samples. Sites that are far from direct pollution sources showed very good agreement between the nephelometer and FRMs for PM2.5 mass measurements, while, by comparison, the roadside site showed a lower SidePak/FRM PM2.5 ratio, which is likely due to higher abundance of elemental carbon in roadside particles. Relative humidity (RH) was shown to be a key factor that distorted the measurement of the nephelometer. An empirical formula incorporating an RH adjustment developed to correct the nephelometer could produce a reasonable result, even across the various sites. This study demonstrates the great potential of the nephelometer for outdoor particle mass measurements, but for accurate and comparable data, a site-specific calibration is strongly recommended before using. PMID- 29250635 TI - Control of the optical properties of cadmium selenide nanoparticles using magadiite. AB - The preparation of cadmium selenide nanoparticles in the interlayer space of magadiite, a layered sodium silicate, modified with the cetyltrimethylammonium cation was studied. The preparation was based on the formation of cadmium selenide by the reaction between the cetyltrimethylammonium modified magadiite and an aqueous mixture of cadmium sulfate and sodium selenosulfite at room temperature. The resulting hybrids were characterized by XRD, FT-IR, HRTEM, TG DTA, as well as UV-visible and photoluminescence spectroscopy. The expansion of the interlayer spaces as well as TG-DTA results indicated the presence of the cetyltrimethylammonium cation and cadmium selenide in the hybrids. The HRTEM images showed the presence of cadmium selenide in the diameter range of 2-3 nm in the interlayer space of magadiite. The luminescence intensity of the cadmium selenide varied depending on the particle size, which was controlled by the loading amount of cadmium selenide precursor. PMID- 29250637 TI - An all-liquid crystal based high-performance laser protection system via linear/nonlinear dual-mechanisms. AB - Novel mesogenic [60]fullerenes have been synthesized and doped into cholesteric liquid crystals (CLCs) to achieve a dual-mechanism laser protection system that is effective for both pulsed and broadband cw lasers, simultaneously. It was found that this system integrated a good OPL response, broadband protection range, and high practicability with great potentials in flexible and even wearable protection devices. PMID- 29250636 TI - A nickel(ii)-manganese(ii)-azido layered coordination polymer showing a three dimensional ferrimagnetic order at 35 K. AB - The work in this report describes the synthesis, characterization, crystal structure and magnetic properties of a two-dimensional azido-bridged NiIIMnII heterometallic coordination polymer, [{(NiIILMnII)2(MU1,1,3-N3)2}(MU1,3-N3)2]n (1), in which the H2L Schiff base is the [2 + 1] condensation product of 3 methoxysalicylaldehyde and 1,3-diaminopropane. In 1, two bis(MU-phenoxo)-MU1,1,3 azido-NiIIMnII dinuclear units are interlinked to form a dimer-of-dinuclear moiety {NiIIMnII}2; the {NiIIMnII}2 structural units are further interlinked with each other by MU1,3-azido ligands to form a layered coordination polymer. Upon cooling, the chiMT product slowly decreases from 300 K to about 100 K, then increases abruptly from 3.74 cm3 K mol-1 at 100 K to 113.2 cm3 K mol-1 at 30 K, indicating a ferrimagnetic behaviour; a three-dimensional magnetic order below 37 K was determined by the divergence in the ZFC-FC measurements and ac measurements, in which the peak temperature 35 K in the in-phase at different frequencies suggests that the Curie temperature is 35 K, whereas the out-of-phase is somewhat frequency dependent, due to the glassy magnet behaviour. The title compound is among the rare examples of metallo-organic systems having a magnetic ordering Curie temperature above 30 K. Other interesting aspects in 1 regarding magnetic properties and structural features are discussed. PMID- 29250638 TI - Organic dye-sensitized solar cells containing alkaline iodide-based gel polymer electrolytes: influence of cation size. AB - The electrolyte used in dye-sensitized solar cells (DSSCs) plays a key role in the process of current generation, and hence the analysis of charge-transfer mechanisms both in its bulk and at its interfaces with other materials is of fundamental importance. Because of solvent confinement, gel polymer electrolytes are more practical and convenient to use with respect to liquid electrolytes, but in-depth studies are still necessary to optimize their performances. In this work, gel polymer electrolytes of general formulation polyacrylonitrile (PAN)/ethylene carbonate (EC)/propylene carbonate (PC)/MI, where M+ is a cation in the alkaline series Li-Cs, were prepared and used in DSSCs. Their ionic conductivities were determined by impedance analysis, and their temperature dependence showed Arrhenius behavior within the experimental window. FT-IR studies of the electrolytes confirmed the prevalence of EC coordination around the cations. Photo-anodes were prepared by adsorbing organic sensitizer D35 on nanocrystalline TiO2 thin films, and employed to build DSSCs with the gel electrolytes. Nanosecond transient spectroscopy results indicated a slightly faster dye regeneration process in the presence of large cations (Cs+, Rb+). Moreover, a negative shift of TiO2 flat-band potential with the decreasing charge density of the cations (increasing size) was observed through Mott-Schottky analysis. In general, results indicate that cell efficiencies are mostly governed by photocurrent values, in turn depending on the conductivity increase with cation size. Accordingly, the best result was obtained with the Cs+-containing cell, although in this case a slight reduction of photovoltage compared to Rb+ was observed. PMID- 29250639 TI - Diverse ring opening of thietanes and other cyclic sulfides: an electrophilic aryne activation approach. AB - Organosulfides are a common class of structure units in bioactive molecules and functional materials motivating continuous developments of efficient synthetic methods. Herein, we report an electrophilic aryne-activated ring opening protocol of one or two heteroatom containing saturated sulfur heterocycles. This three component transformation proceeds under mild reaction conditions and displays exceptional generality of nucleophiles (C, O, S, N, and F centered nucleophiles), giving structurally diverse thioethers in good yields. PMID- 29250640 TI - Nonradiative dynamics determined by charge transfer induced hydrogen bonding: a combined femtosecond time-resolved fluorescence and density functional theoretical study of methyl dimethylaminobenzoate in water. AB - As a case study of the interplay and the consequence of the interplay between intramolecular charge transfer (ICT) and intermolecular hydrogen (H)-bonding, a combined femtosecond time-resolved fluorescence (fs-TRF) and density functional theoretical (DFT) and time-dependent DFT (TDDFT) study has been conducted on methyl dimethylaminobenzoate (MDMABA) largely in a water solvent. Direct observation of the broadband spectra, anisotropy, and kinetic decays of fs-TRF from photo-excited MDMABA revealed a rapid ICT reaction occurring with a time constant of ~0.7 ps from an initial locally excited (LE) state identified to have the Lapipi* character; this produced a weakly emissive ICT state featuring radiative rate constant decreased by more than two orders of magnitude. The fluorescence of the ICT state is strongly quenched exhibiting a decay time of ~49.7 ps, unusually faster than the nanosecond range lifetime in a polar aprotic solvent when intersystem crossing (ISC) is the major deactivation channel. This, according to the study of the solvent kinetic isotope effect, is identified to originate from an instantly enhanced strong solute-solvent H-bonding induced by the ICT reaction which allows elimination of the ISC, and enables the nonradiative decay to proceed almost entirely through the otherwise inaccessible internal conversion from the ICT state. The enhancement of H-bonding is verified by the calculation which presents theoretical evidence for not only the binding site and binding energy of the H-bonding configuration but also the electronic and structural characterization, lending support to the twisted ICT (TICT) description of the photo-excited MDMABA. This study contributes a prominent example for the extraordinary ability of water and a decisive role of ICT promoted H-bonding in offering a highly effective molecular mechanism for rapid elimination of the electronic excitation energy. The results contain an important insight for the in-depth understanding of the excited state H-bonding dynamics, and also have significant implication for clarifying the "sunscreen controversy" of the DMABA type of UVB sunscreen molecule. PMID- 29250642 TI - Seebeck coefficients of regioregular poly(3-hexylthiophene) correlated with doping levels. AB - Thermoelectric properties of regioregular poly(3-hexylthiophene) (P3HT) were investigated in correlation with doping level measured by a potential-step chronocoulometry (PSC) method. It was found that the log-log plot of Seebeck coefficients against doping levels showed a good linearity, whose slope value was around -1. PMID- 29250643 TI - Photo-induced H2 evolution from water via the dissociation of excitons in water dispersible single-walled carbon nanotube sensitizers. AB - To observe a clear-cut example of the formation of mobile carriers from excitons on semiconducting single-walled carbon nanotubes (s-SWCNTs) surrounded by a medium with a high dielectric constant, water-dispersible s-SWCNT nanocomposites were fabricated by physical modifications using poly(amidoamine) dendrimers that contain an aliphatic core. The evolution of H2 from water using these s SWCNT/dendrimer nanocomposites as photosensitizers under irradiation with visible light demonstrated a photo-induced electron transfer from the s-SWCNTs to the co catalysts. PMID- 29250645 TI - Photocatalytic hydrogenation of azobenzene to hydrazobenzene on cadmium sulfide under visible light irradiation. AB - Visible-light irradiation (lambda < 600 nm) of commercially-available CdS in alcohol successfully promotes hydrogenation of azobenzene to hydrazobenzene with more than 95% selectivity. This is promoted by strong adsorption of azobenzene to the photoformed zerovalent Cd species adjacent to the surface S vacancies on CdS; this leads to efficient reduction to hydrazobenzene. PMID- 29250646 TI - TIMPs expression in lentigo maligna/lentigo maligna melanoma versus aged skin - a review of the literature and personal experience. AB - Mechanisms involved in melanoma invasiveness and metastasis are essential to understanding the behavior of this aggressive melanocytic skin cancer. The epithelial-mesenchymal transition (EMT) is considered fundamental for overcoming the in situ stage of melanoma and its proliferation beyond the basal membrane. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are key molecules involved in EMT about whose expression in lentigo maligna (LM) and lentigo maligna melanoma (LMM) little has been studied so far. In this article, our main aim was to review the role of TIMPs in invasiveness and aggressiveness of LM/LMM in order to detect EMT modifications in this type of melanoma. We also presented some partial personal unpublished results. It is well established by now that progression of melanoma depends on ECM remodeling, TIMPs family being one of the most important regulators of this process. Considering the multitude of molecules involved in cancer invasiveness and their complex interaction, it is too early to analyze and to conclude upon the significance of different expression of TIMPs in LM/LMM. We consider some correlations are needed to be done also with other consecrated histological (as Clark level, Breslow indexes, presence of ulceration, mitotic index, intratumor inflammatory infiltrate, etc.) and immunohistochemical markers [cadherins, vascular endothelial growth factor (VEGF), bcl-2, etc.] of prognosis and metastasis. In this light, we consider that our study could further clarify the significance of TIMPs expression in this specific type of melanoma. PMID- 29250647 TI - Protective and therapeutic possibility of medical herbs for liver cirrhosis. AB - Liver damage is a serious medical problem worldwide and is caused by primary or secondary metabolic, microbiological, toxicological, immunological and circulatory etiological factors. The objective of this paper is to analyze the hepatoprotective effect of various plants, their biologically active compounds and extracts and the possibility of these compounds to attenuate complex pathophysiology processes during chronic inflammation and the development of liver cirrhosis. This review summarizes several plants whose hepatoprotective effects have been demonstrated and partially describes the mechanisms of inflammation inhibition. It is known that fibrosis includes an oxidative damage, inflammatory and immune response and star-shaped cells and their activation in hepatocytes. Effects of particular phytocompounds and their anti-inflammatory mechanisms have been studied in several cell lines in vitro, in vivo in different animal models, as well as in some clinical studies. Results suggest that mechanisms include reduction of oxidative stress, suppression of the inflammatory and immune response, as well as the inhibition of the activation of hepatic stellate cells (HSCs), decreasing extracellular matrix (ECM) deposition and induction of apoptosis, protection of hepatocytes from apoptosis and creating apoptotic bodies, which are phagocytic and activate HSCs. Medical herbs are abundant, economical and versatile and thus are potential alternative agents with anti-inflammatory mechanism. They can be a source of bioactive compounds, and with the aim of preventing the formation and progression of fibrosis, they can find wide applications in medical practice. The obtained results should promote further research in order to identify safe and effective protective and therapeutic resources. PMID- 29250648 TI - Cytological, histopathological and immunological aspects of autoimmune thyroiditis: a review. AB - Autoimmune thyroiditis (AT) is a disease that may be associated with many other autoimmune endocrine and non-endocrine disorders. This disease is mediated by both humoral and cellular mechanisms and it is the result of combined effects of human leukocyte antigen (HLA) class II genes and non-HLA genes polymorphisms. The clinical course of AT is variable and may be characterized by spontaneous remission and by irreversible thyroid insufficiency as the consequence of atrophic and fibrous transformation of the thyroid gland in other cases. In this paper, the AT's etiology and immunological mechanism along with its cytological and histopathological features are reviewed in order to increase our understanding about the mechanism involved in pathogenesis of this disease and to open new directions of investigations that will be useful in a better clinical practice. PMID- 29250649 TI - Inflammatory juvenile compound conjunctival nevi. A clinicopathological study and literature review. AB - AIM: The conjunctival nevus affecting children and adolescents is a rare condition and the literature showed only few reports on this issue. The aim of this article is to determine the histopathological features for the correct diagnosis of an inflammatory juvenile compound nevus of the conjunctiva (IJCNC) in order to make the difference between this tumor and other lesions, like conjunctival melanoma or lymphoma, very similar from a gross point of view. This article is a clinical pathological study of two cases of IJCNC with particular histopathological characteristics, who were admitted at the 2nd Ophthalmology Clinic, "Prof. Dr. Nicolae Oblu" Emergency Clinical Hospital, Iasi, Romania, over a period of five years (from July 1, 2012 to June 30, 2017). Both patients were adolescents, a boy (13-year-old) and a girl (12-year-old). Both lesions were bulbar juxtalimbal located and grew in size over one year. Seen at slit-lamp biomicroscopy, the first one presented as a non-pigmented lesion, while the second was a pigmented nevus, but their dimensions did not exceed 10 mm in diameter. From a histopathological point of view, both of them showed a nested junctional growth pattern, along with intra- and subepithelial location, of the nevomelanocytes. Tumoral cells demonstrated different degrees of atypical cytology, but in the second case, it was more obvious. Microscopic examination also revealed epithelial cystic inclusions, and prominent inflammation in the stroma of these two nevi. One of the cases presented heavy inflammation that took the form of lymphoid follicles and sheets of eosinophils, but the other showed only diffuse inflammation with lymphocytes plasma cells, and eosinophils within its stroma. The immunohistochemical characterization (anti-melan A, anti-S100 protein and anti-cytokeratin AE1/AE3 antibodies) of the tumoral cells helped to the diagnosis. CONCLUSIONS: IJCNC represent a small group of nevi that develop in adolescents and have some particular histopathological features. The pathological diagnosis is difficult as the microscopic features are very similar to a conjunctival melanoma, but a detailed microscopic examination, immunohistochemical stainings and the young age of the patient could help in establishing the benign nature of these lesions. PMID- 29250650 TI - PV-1 expression could distinguish the subset of caveolae-presenting telocytes that are endothelial progenitors. AB - Telocytes (TCs) are stromal cells with characteristic long, thin and moniliform prolongations termed telopodes. They were formerly termed interstitial Cajal-like cells. A characteristic set of markers to identify TCs in light microscopy has not been established until now. Transmission electron microscopy (TEM) is a better tool for identifying TCs. Telocytes display caveolae and can express caveolin-1. On the other hand, endothelial cells (ECs) as well as endothelial progenitor cells (EPCs) have caveolae. Recent evidence suggests that a subset of TCs are in fact EPCs. The distinction of this progenitor subset of TCs can be easily made by a specific set of ultrastructure markers, as follows. Caveolae of endothelial cells present stomatal diaphragms (SDs). The plasmalemma vesicle associated protein-1 (PV-1), which is identical with the Pathologische Anatomie Leiden endothelium (PAL-E), is specifically identifying the ECs SDs of caveolae. We therefore raise the reasonable hypothesis that the EPCs subset of caveolae presenting TCs could be accurately identified, without exploration in TEM, by the positive expression of PV-1 or PAL-E in the SDs. PMID- 29250651 TI - Immunohistochemical significance of ER alpha, inhibin A, calretinin, and Ki67 expression in granulosa cell ovarian tumors. AB - Adult granulosa cell tumors (AGCTs) have a heterogeneous morphology and an unpredictable behavior, which can lead to a misinterpreted diagnosis. The aim of our study was to assess the immunoexpression of estrogen receptor (ER) alpha, Ki67, calretinin, and inhibin A in AGCTs, in order to evaluate their value in diagnosis and prognosis of this type of tumor. Immunohistochemical stainings for these markers were performed in 21 cases of AGCTs. The immunopositivity evaluation of calretinin and inhibin A was scored according to the percentage of staining intensity and the extent of positive cells, of ER alpha was scored based on the percentage of positive cells, and Ki67 score was recorded as the percentage of positively stained nuclei across the tumor, without taking in consideration the staining intensity. ER was positive in nine cases, Ki67 was expressed in 12 cases, calretinin showed positive immunoreactivity in 16 cases, and inhibin A was positive in 14 cases. Stromal cells presented also immunopositivity for inhibin A and calretinin in the negative cases. ER alpha and calretinin immunoexpression can help in identification of cell components of AGCT. Our results regarding Ki67 expression emphasize the potential utility of this marker in tumor behavior prediction. Inhibin A immunopositivity has an important value in AGCT diagnosis, in association to the other evaluated markers. Additional studies are needed to identify new specific and sensitive markers for AGCT or, at least, of a panel of markers which might contribute to a more accurate characterization of these tumors. PMID- 29250652 TI - E-cadherin, beta-catenin and Snail immunoexpression in laryngeal squamous cell carcinoma. AB - E-cadherin, beta-catenin and Snail are important molecules involved in cellular adhesion and epithelial-mesenchymal transition. Loss of E-cadherin expression, nuclear relocation of beta-catenin and high expression of Snail are connected to tumor progression, rapid cell growth and metastasis. The aim of our study was to analyze the immunohistochemical expression of beta-catenin, E-cadherin and Snail, depending on clinico-morphological aspects of the laryngeal squamous cell carcinomas. Our results revealed variable E-cadherin, beta-catenin and Snail expression, depending on differentiation degree and tumor stage. These markers can be helpful in identifying the aggressive laryngeal squamous carcinomas. PMID- 29250653 TI - Integrative clinico-biological, pharmacogenetic, neuroimagistic, neuroendocrinological and psychological correlations in depressive and anxiety disorders. AB - We approach the theme of modern treatment strategies, based on clinico biological, pharmacogenetic, neuroimagistic, neuroendocrinological and psychological integrative correlations in the management of depressive and comorbid anxiety disorders. We target to evaluate the efficacy of the pharmacogenetic testing and the evolution, functioning of patients in correlation with specific neurobiological, neuroimagistic and neuroendocrinological markers. Our research was conducted between 2010-2016 on 80 children and adolescents with depressive and comorbid anxiety disorders - 40 children (G1 group), who benefited in choosing the pharmacotherapy from pharmacogenetic testing and 40 children without testing (G2 group). Also, the patients were evaluated through magnetic resonance (MR) spectroscopy at baseline and after pharmacotherapy. The efficacy of the chosen therapy in correlation with the pharmacogenetic testing was evaluated through the mean change in the CDRS (Children's Depression Rating Scale) total scores, in the CGI-S/I (Clinical Global Impression - Severity/Improvement), CGAS (Children's Global Assessment Scale) and through the change of the relevant neurobiological markers and MR spectroscopy metabolites. We evaluated the side effects through the PAERS (Pediatric Adverse Events Rating Scale)-Clinician. Our results show statistically significant differences of the clinical scores between the studied groups: for those subjects who benefited of pharmacogenetic testing, the CDRS, the global functioning scores prove a higher clinical improvement, a better compliance and lower PAERS side effects scores and also improvement concerning the MR spectroscopy dosed metabolites values. Our research was a proof sustaining the use of the pharmacogenetic testing in clinical practice and the value of investigating relevant neurobiological, neuroimagistic and neuroendocrinological markers for a personalized therapy in depressive disorders. PMID- 29250654 TI - Collagen I and III, MMP-1 and TIMP-1 immunoexpression in dilated cardiomyopathy. AB - The extracellular matrix (ECM) remodeling represents the pathological substrate of dilated cardiomyopathy (DCM). In this study, we statistically analyzed the immunoexpression of collagen I and III, matrix metalloproteinase-1 (MMP-1) and its tissue inhibitor-1 (TIMP-1) in the myocardial tissue in 18 cases of DCM compared to a control group. We observed a significant increase in the immunoexpression of collagen I and III in patients with DCM and a significant reduction in the immunoexpression of MMP-1 compared with the control group. Also, the collagen I and TIMP-1 expression indicated a positive linear correlation and respectively a negative linear relationship with collagen III and MMP-1. The analyzed markers in this study can be used to quantify the degree of collagen sclerosis from the ECM of DCM. PMID- 29250655 TI - Eosinophilic colitis: experience in a large tertiary hospital. AB - BACKGROUND: Eosinophilic colitis (EC) is a rare and ill-defined entity with an unknown pathogenesis and an unsatisfactory treatment response. The standard histopathological criteria for EC diagnosis lack specificity and not all the cases fulfilling those criteria are considered clinically as EC and treated. The objective of this study is to refine diagnostic criteria for EC. METHODS: Retrospective study of all the cases with a histopathological diagnosis of EC in Hospital Clinico San Carlos (Madrid, Spain) from 2006 to 2016. We have reviewed their clinical and pathological features and tried to define the features differentiating cases considered EC on clinical grounds. RESULTS: We identified 106 EC cases. In 22 cases, a clinical EC diagnosis was established. Confirmed EC was associated with younger age, female gender, diarrhea, higher maximum number of eosinophils/HPF (high-power field), intraepithelial eosinophils, architectural distortion and absence of acute inflammation. We chose a cut-off point of 40 for both mean and maximum number of eosinophils/HPF. A mean number of eosinophils/HPF higher than 40 was related to architectural distortion, mucosal atrophy, signs of eosinophil activation and submucosal infiltration. Cases with a maximum number of eosinophils/HPF higher than 40 showed more architectural distortion, intraepithelial eosinophils, submucosal infiltration and lack of lymphoplasmacytic infiltration. CONCLUSIONS: Histopathological diagnosis of EC is not well correlated with clinical EC. An increase in specificity can be achieved by raising the cut-off point to 40 eosinophils/HPF and by combining mean and maximum number of eosinophils with other microscopic and clinical features suggestive of EC. PMID- 29250656 TI - Immunohistochemical reaction of the glandular epithelium in endometrial hyperplasia compared to endometrial carcinoma. AB - The histopathological and immunohistochemical diagnosis of endometrial biopsies is used for estimating the risk of progression in endometrial hyperplastic lesions in carcinoma and for guiding the clinical management. The objective of this study was to evaluate the immunohistochemical expression of the estrogen receptor (ER) and progesterone receptor (PR), p14, p53, phosphatase and tensin homolog (PTEN), Ki67, in patients with endometrial hyperplasia (EH) with/without atypia versus endometrioid endometrial carcinoma type 1. After the histopathological determining of the lesion type at endometrial level, the cases were studied using immunohistochemical methods, namely by the use of an antibody panel. The immunohistochemical staining of PR was nuclearly and cytoplasmatically positive in EH with/without atypia and cytoplasmatically negative in endometrioid carcinoma, and in ER, the immunohistochemical staining was cytoplasmatically negative in the forms of EH without atypia and positive in various stages of intensity in the rest of the cases. The immunohistochemical staining of p14 was moderately expressed in the endometrioid carcinoma and negative in EH without atypia at nuclear level, and at cytoplasm level, it generally had a positive expression. In our study, the nuclear and cytoplasmic study of immunoxpression p53, both in hyperplastic lesions and in the endometroid endometrial carcinoma, was negative, similar to the immunohistochemical expression of PTEN. At nuclear level, the immunohistochemical staining of Ki67 was positive in EH with atypia and in endometrioid endometrial carcinoma, while at cytoplasm level, it was positive only in endometrioid endometrial carcinoma. The nuclear and cytoplasmic study of this immunohistochemical marker panel shows a different reactivity in EH with/without atypia and endometrioid endometrial carcinoma. PMID- 29250657 TI - Streptococcal tonsillitis related reactive arthritis - clinical, ultrasound imaging and immunohistochemical study. AB - In clinical practice and literature studies, the most common condition associated to streptococcal tonsillitis used to be acute rheumatic fever (ARF). Several publications in the late years report a more frequent and distinctive entity from ARF following beta-hemolytic group A streptococcus infection in patients with post-infectious arthritis, that do not fulfill the modified Jones criteria, the so-called post-streptococcal reactive arthritis (PSRA). A distinctive pattern of clinical framing and biological profile in patients with PSRA following streptococcal tonsillitis is described, with a non-migratory, additive, recent onset (7-10 days) arthritis that affects small and large joints as well, with a bimodal peak of incidence at 8-14 and 21-37 years of age, with variate response to non-steroidal anti-inflammatory drugs and has a tendency for recurrence and persistence. Sacroiliitis, although rare, is described in human leukocyte antigen (HLA)-B27 positive PSRA patients. The main objective of the current study was to evaluate various immunohistochemical patterns of streptococcal tonsillitis in patients with PSRA and find possible correlations with the clinical, biological and ultrasound profile. PMID- 29250658 TI - Evaluation of Helicobacter pylori infection in patients with eso-gastro-duodenal pathology. AB - Helicobacter pylori (HP) infection is one of the most frequent bacterial infections in humans. The studies performed in the last 30 years showed that this bacterium is the main cause of chronic gastritis and the main etiological agent of peptic ulcer and gastric cancer. We investigated the prevalence of HP infection in a group of 1525 patients who addressed a gastroenterology medical center between 2010-2014, in Craiova, Romania, for dyspeptic symptoms. The patients underwent a clinical, endoscopic and serologic investigation for highlighting a possible HP infection. The age of the patients with gastric duodenal pathology varied between 16 and 87 years old. Of the 1525 patients, a number of 971 (63.67%) were diagnosed with HP infection, while the rest of 554 (36.33%) were not infected. The study on the distribution of gastric duodenal pathology and HP infection showed that the lesions of the upper digestive tract and HP infection emerged quite early, a number of 29 patients being aged less than 20 years old; among these, 21 (72.41%) patients were HP positive and only eight (27.59%) were HP negative. In the age group of 20-29 years old there were recorded 184 patients, of which 120 (65.22%) were HP positive and only 64 (34.78%) were HP negative. There may be observed that in the age group of 20-29 years old, both the patients with gastric duodenal pathology and the ones with HP infection increased six times in comparison to the first decade. Most cases were recorded in the patients aged between 50 and 69 years old. The two decades comprised a total number of 607 (39.8%) patients, of which 375 (61.78%) were HP positive and 232 (38.22%) were HP negative. By evaluating the distribution of HP infection according to the social environment, there was observed that there were no significant differences between the patients coming from the urban area and the ones from the rural area, as far as the HP infection was concerned. PMID- 29250659 TI - Could oral cytomorphometry be of value in distinguishing diabetes mellitus? AB - The present study refers to a quantitative, morphometric analysis of exfoliative cytology smears collected from diabetes mellitus (DM) patients, in order to distinguish subtle changes in cellular and nuclear parameters. The study was carried out on 30 adult subjects: a control group of 10 healthy subjects and a study group of 20 diabetic subjects (type 1 and type 2 DM). Another factor that was taken into consideration was the abundance of the microbial flora. The oral smears were stained using Hematoxylin and Eosin and several parameters were measured (nuclear diameter, perimeter and area, cell large diameter and area), and calculated: nuclear/cytoplasmic ratio and nuclear roundness factor. We found out that the cells collected from DM patients had higher values of the nuclear parameters (the nuclei were larger) and lower cell dimensions. The nuclear to cytoplasmic ratio was increased in these patients, but the nuclear roundness factor was closer to one in the study group. Also, an increased number of bacteria, often seen in DM patients, decreased the nuclear parameters. Our findings complete recently descriptive cytology studies with the morphological measurements in case of bacterial abundance and sustain the possible value as screening method for morphometry. PMID- 29250661 TI - Effects of malalignment angle on the contact stress of knee prosthesis components, using finite element method. AB - In this paper, the complex 3D virtual model of the prosthetic knee is obtained using embedded applications: DesignModeler and SpaceClaim under ANSYS Workbench 14.5 software package. A number of six cases of prosthetic knee joint assembly, depending on the malalignment angle, are developed. Stress maps and the values of the maximum von Mises stress on the three prosthesis components: polyethylene insert, tibial component and femoral component, for all studied prosthetic knee assemblies were obtained. The results show that as the malalignment angle increases, the values of von Mises stresses increase in all prosthesis components. The parameterized virtual models of the knee prosthesis components allow different changes in shape or dimensions, which can lead to the optimization of the implant and to the improvement of the prosthetic knee biomechanics. PMID- 29250660 TI - The relationship between glomerular function and podocyte structure of pre proteinuria and acute nephrosis in puromycin aminonucleoside-induced rat models: a comparative electron microscopic study. AB - Puromycin aminonucleoside (PA) has been generally utilized as model of podocyte injury followed by massive proteinuria, severe damage on endocytotic activity of epithelial cells and postmodification of endocytosed compounds. However, total PA nephrosis (PAN) mechanism cannot be understood. We aimed to study glomerular function, foot process degeneration and transport pathways of podocytes in pre proteinuria and acute PAN rats. Eighteen male Wistar albino rats were divided into three groups: control, pre-proteinuria and acute nephrosis groups (n=6). PA was injected into pre-proteinuria group for three times and acute group for nine times. Proteinuria levels in urine, creatinine and albumin levels in blood were detected 24 hours after PA injections. Renal cortex samples were prepared for transmission electron microscopy. Proteinuria levels in acute group significantly elevated, whereas creatinine clearance, serum albumin levels and urine volumes diminished compared to control and pre-proteinuria groups. In pre-proteinuria group, hypertrophy and structurally rich cytoplasm were detected only within podocytes. Acute group had various protein absorption granules secreted from podocyte cytoplasm to the urinary space through exocytosis after lysosomal digestion; but not observed in pre-proteinuria group. The number of slit pores in pre-proteinuria group decreased, particularly related to fusion of foot processes, subsequently leading to proteinuria. We concluded that foot process fusion begins prior to development of proteinuria although their serum albumin and creatinine clearance levels do not differ significantly. Additionally, we suggested that in acute PAN, first affected glomerular cells could be podocytes and there could be a correlation between glomerular function and number of slit pores. PMID- 29250662 TI - The prognostic role of Bcl-2, Ki67, c-MYC and p53 in diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphoid malignancies, which counts for more than a third of non-Hodgkin's lymphoma cases. The aim of the current study is to evaluate the prognostic role of several immunohistochemical (IHC) markers involved in the pathological process of DLBCL. This is a retrospective analysis of the 97 de novo DLBCL patients admitted between January 2007 and December 2016 in the Department of Hematology, "Filantropia" Municipal Hospital, Craiova, Romania. The expression of Bcl-2, Ki67, c-MYC and p53 was assessed by immunohistochemistry. A significant level of association was observed between high prognostic index values and Bcl-2, Ki67, c MYC and p53 positive cases. Moreover, overall survival and disease-free survival were higher in patients with negative expression for these markers. Bcl-2, Ki67, c-MYC and p53 could make important diagnostic and therapeutic targets; therefore, their routine assessment should be mandatory. PMID- 29250663 TI - Immunohistochemical diagnosis of Krukenberg tumors. AB - The diagnosis of Krukenberg tumors, as in other types of metastatic tumors of unknown primary origin, can often be a challenge for clinicians. In many cases, traditional diagnostic methods are insufficient, requiring immunohistochemistry analysis for identifying the origin of metastatic tumors. In our study, we examined a total of 34 female patients with Krukenberg tumors with different sites of the primary tumor: gastric (n=18), colorectal (n=6) or breast (n=7) and tumors with unknown origin (n=3). Cytokeratin (CK) 7 and CK20, carcinoembryonic antigen (CEA) and cancer antigen (CA) 125 were applied. The analysis of immunohistochemical profiles for CEA and CA125 showed that, regardless of the histological origin, the predominant immunohistochemical profile was CEA(+)/CA125(-). CK7/CK20 profile was different depending on the histological origin of the Krukenberg tumors. Thus, for the cases of gastric origin, CK7( )/CK20(-) was present in 66.7% (12/18) of the cases. For the cases with colorectal origin, the predominant immunohistochemical profile was CK7( )/CK20(+), in a percentage of 66.7% (4/6). The combination CK7(+)/CK20(-) was found in 85.7% (6/7) among cases of breast origin. Consequently, the immunohistochemical profile CK7/CK20 can have a key role in identifying the primary tumor in patients with Krukenberg tumors of unknown origin. PMID- 29250664 TI - Morphological changes in support mechanism of superficial face layers in Moebius syndrome. AB - Moebius syndrome, also called congenital facial paralysis is a rare neurological disease, whose etiology is not fully elucidated. It affects especially facial and oculomotor cranial nerves and its clinical feature is peripheral facial paralysis. The objective of the study is to highlight the anatomical and functional changes in the Moebius syndrome and establish certain criteria that should be the basis for reparative surgery in this disease. For this purpose, we used a group of six patients diagnosed with this pathology, in whom we pursued functional anatomical and histological changes of the superficial layers of the face that we have grouped in terms of their clinical impact. All the data obtained were centralized in order to assess anatomical functional changes occurring after evolution in time of lesions caused by Moebius syndrome. The results of the study led us to conclude that the face is made up of three main regions - median, medial and lateral -, which behave differently both in atresia of the facial nerve and in healthy individuals. This has an important echo on the way we emphasized the functional anatomy of superficial layers of the face and in surgery. PMID- 29250665 TI - The correlation between insulin-like growth factor with glycemic control, glomerular filtration rate, blood pressure, hematological changes or body mass index in patients with type 2 diabetes mellitus. AB - Insulin-like growth factor (IGF) family is made up of two polypeptides, IGF-I and IGF-II, six specific binding proteins (IGFBPs 1-6) and specific receptors. IGF-I is involved in the regulation of growth and cellular proliferation and has a similar structure to insulin. The major IGF transport function is attributed to IGFBP-3. Some studies have highlighted the association between IGF and diabetes. The aims of this study were to analyze the correlation between IGF with glycemic control, glomerular filtration rate (GFR), blood pressure, hematological changes or body mass index (BMI) in patients with type 2 diabetes mellitus (T2DM). Thirty patients with T2DM and thirty non-diabetic control patients were included in this study. Clinical, anthropometric, biochemical parameters and morphology of blood smear were recorded. Blood pressure was determined by mercury sphygmomanometer. The anthropometric measurement included BMI. The biochemical parameters included fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), GFR, serum IGF-I, IGFBP-3 levels. The IGF-I/IGFBP-3 ratio was evaluated. The plasma glucose was determined enzymatically, HbA1c was determined by high-performance liquid chromatography (HPLC) and GFR was calculated automatically. IGF-I was measured by immunoradiometric assay (ELISA - enzyme-linked immunosorbent assay) and IGFBP-3 by sensitivity immunoassay. For the analysis of the morphology of blood smear, May-Grunwald-Giemsa (MGG) was used as staining technique. The microscopic examination was performed initially with the objectives of 10*/20* and subsequently with an immersion objective of 100*. Image acquisition was done after the examination of the preparations obtained with a 40* objective, using Image Pro Plus 6.0 software. In the present study, we observed that T2DM leads to an increase in the IGF-I and IGFBP-3 levels. No relationship was obtain between IGF-I, IGFBP-3 levels and IGF-I/IGFBP-3 ratio with neither parameters studied. The difference of serum IGF-I and IGFBP-3 levels between patients with T2DM and subjects without diabetes showed that IGF-I may be a useful marker for diabetes mellitus and IGFBP-3 for possible complications of this affection. PMID- 29250666 TI - Immunoexpression of transcription factors in urothelial bladder carcinomas. AB - Transcription factors play a central role in the epithelial-mesenchymal transition (EMT), which is one of the biomolecular mechanisms involved in the progression of urothelial carcinomas of the bladder (UCB). In this study, we analyzed the immunoexpression of Twist 1, Snail, Slug and beta-catenin in relation to histopathological prognostic parameters of UCB. The obtained results indicated the association of Snail and beta-catenin expression with low grade and early stage of UCB, as well as the association of Twist 1 and Slug expression with high grade and advanced stage lesions. The specific or sequential action of transcription factors in the bladder tumoral EMT may be useful for identifying the aggressive lesions. PMID- 29250667 TI - Effect of the veins histopathological characteristics and preexisting medical conditions on arteriovenous fistula maturation and primary patency in patients with end-stage renal disease: an observational, prospective study. AB - We assessed the veins histopathological characteristics and preexisting medical conditions before arteriovenous fistula (AVF) creation, and their correlation with AVF outcome and primary patency in patients with end-stage renal disease (ESRD). In this observational, prospective, mono-center study in Romania, patients with artery and venous diameters =2 mm and =2.5 mm, respectively, were enrolled. Vein specimens were harvested at AVF creation and evaluated by Hematoxylin and Eosin, Masson's trichrome and Orcein stainings, in terms of intimal hyperplasia, elastic fibers disposition, medial hypertrophy and smooth muscle cell disorganization and fibrosis (graded from mild to severe). Venous diameters and blood flow one/two-months post-AVF creation, AVF maturation at dialysis start, two-year primary patency were assessed. Of 115 examined patients, 50 were enrolled and underwent AVF creation. Of six (12%) patients with no vein morphological changes, 11 (22%) with mild histopathological changes, 19 (38%) with moderate and 14 (28%) with severe histopathological changes, four (67%), eight (73%), 17 (89%) and 12 (86%), respectively, had mature AVF. Regardless of histopathological characteristics, non-mature AVF were recorded in older patients and with smaller venous diameter. One/two-months post-AVF creation, in all patients with mature AVF, venous diameter and ultrasonographic blood flow were similar. Two years post-AVF creation, 26 patients had functional AVF; non functional AVFs were recorded more likely in women and functional AVFs were most likely located on forearm. The veins histopathological modifications may not negatively influence AVF maturation in ESRD patients. AVF maturation failure may most likely be related to age and venous diameter at AVF creation. PMID- 29250668 TI - Osseointegration of chemically modified sandblasted and acid-etched titanium implant surface in diabetic rats: a histological and scanning electron microscopy study. AB - INTRODUCTION: The aim of this study is to assess the osseointegration of different dental implants surfaces in diabetic rats. MATERIALS AND METHODS: In this study, were used 56 male Wistar rats, average weight of 300-350 g. Diabetes was induced by a single intraperitoneal injection of Streptozotocin. The glucose levels and weight of rats were periodically evaluated. After the diabetes mellitus is confirmed, the sandblasted, large-grit, acid-etched (SLA) and SLActive endosseous dental implants (TAG dental implants, TAG Medical, Israel), made of titanium alloy, Ti-6Al-4V, 1 mm diameter and 3 mm in length were inserted in the distal metaphysis of the left femur. RESULTS: Diabetic rats have naturally lower number of bone cells and bone-implant contact (BIC%) than healthy rats when using the SLA implant, but when using SLActive implant, diabetic and healthy rats have the same numbers. CONCLUSIONS: The use of the SLActive surface resulted in positive effects in healthy and especially in diabetic animals, which demonstrate that could improve the osseointegration progress in humans with diabetes. PMID- 29250669 TI - The clinical-morphological profile of bone and joints tuberculosis - our experience in relation to literature data. AB - AIM: The authors made a morphological assessment of musculoskeletal tissue samples from patients admitted in Surgical Departments of the Emergency County Hospital of Craiova, Romania, between 1990 and 2015, proved as presenting tuberculous lesions in the Department of Pathology of the same Hospital. MATERIALS AND METHODS: The studied material consisted of bone, joint and sometimes muscle tissue fragments resulted from biopsies or surgical excisions from 54 cases coming out of 841 patients investigated in the above-mentioned period of time, where the established histological diagnosis was tuberculosis (TB). For diagnostic confirmation, Ziehl-Neelsen staining has been used as a rule but, in some cases, immunohistochemistry was also used. RESULTS: TB lesions have prevailed in men and around the age of 50 despite the tissue involved (either bones or joints or both structures). Bone tissue, lower limb and right side of the body have been more frequently touched by the TB lesions. Axial bones (spine, ribs and hip bone) and knee joint have been the favorite sites. From morphological point of view, the inflammatory cellular population has been dominated by the epithelioid and giant Langhans cells that surrounded areas less or more extended of classical acidophilic fine granular necrosis. The fibrosis was observed more frequently around bone lesions, usually in an incipient phase. Overall, the granulomatous reaction was of reactive type but one should notice hyporeactive or areactive, disorganized reaction encountered quite often in bone or associated bone and joints lesions. CONCLUSIONS: Osteoarticular tuberculosis (OATB) has a complex and dynamic clinical morphological picture, which is still partly known, described and understood especially in the field of morphological changes. Further detailed and integrative analysis of both clinical and morphological aspects is required so the suspicion of diagnosis at the admission becomes as soon as possible certitude. PMID- 29250670 TI - An overview of resistance profiles ESKAPE pathogens from 2010-2015 in a tertiary respiratory center in Romania. AB - : Lower respiratory tract infections (LRTIs) is an umbrella term that covers a wide spectrum of diseases, comprising mild and severe, acute and chronic conditions. A wide spectrum of pathogens can be implicated, from viruses to pyogenic and atypical bacteria. A special place should be reserved for slow growing bacteria (Mycobacteria spp., Nocardia spp.) and parasites (i.e., hydatic cysts caused by Echinococcus granulosus). OBJECTIVE: The objective of this study is to observe, analyze and establish the drug susceptibility patterns for Enterococcus spp., Staphylococcus aureus, Klebsiella spp., Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. (the ESKAPE pathogens) in the "Marius Nasta" Institute for Pulmonary Medicine (MNIPM), Bucharest, Romania. MATERIALS AND METHODS: A retrospective healthcare record based study was undertaken to establish the drug susceptibility patterns. We assessed all antibiograms of the ESKAPE pathogens isolated from respiratory samples from adult inpatients hospitalized between 2010-2015 at the MNIPM. RESULTS: We analyzed 2859 isolates (61% of the 4683 ESKAPE isolates). P. aeruginosa was the most frequent pathogen, while Enterococcus spp. and Enterobacter spp. were practically non present. The antibiotic profile of P. aeruginosa isolates presented more resistance in the Intensive Care Unit (ICU)/Surgery wards, probably resulting from antibiotic pressure. The other non-fermenter, A. baumannii, while less frequent (and the only pathogen more frequent in the surgery department) had an even more resistant profile, to almost all antibiotics, with the exception of Colistin. Methicillin-resistant S. aureus (MRSA) accounted for about 60% of all isolates, more in the ICU/Surgery ward. K. pneumoniae presents a less resistance and shows more stability when analyzing the antibiogram pattern in the Medical wards. DISCUSSION: For methodological or procedural reasons, Enterococcus spp. and Enterobacter spp. were underrepresented in the study. Interventional programs comprising antibiotic stewardship and active surveillance need to be implemented to alleviate the antibiotic profile. Further research needs to focus on more detailed characterization of the molecular mechanisms leading to the high resistance detailed herein. CONCLUSIONS: This study adds to the body of literature reporting the antibiotic resistance landscape in Romania, for these highly resistant pathogens. PMID- 29250671 TI - Correlation between leptin and ghrelin expression in adipose visceral tissue and clinical-biological features in malignant obesity. AB - Morbid obesity is a metabolic disease characterized by an excessive accumulation of adipose tissue (=40%). This disorder is commonly associated with cardiovascular disease, arteriosclerosis, type 2 diabetes, hypothyroidism and some types of cancer. The most common metabolic signals associated with the disease are leptin, ghrelin, with antagonic effects. Our study aimed at highlighting leptin and ghrelin expression levels, as well as establishing correlations between them and clinical-biological parameters in obese patients. The biological material was taken intraoperatively from the visceral adipose tissue. Expression of genes of interest was performed after total RNA extraction and reverse transcription-polymerase chain reaction (RT-PCR) and amplification with TaqMan specific primers. The results of the study showed significant differences in the expression of leptin mRNA between obese patients and the control group as well as the gender of the subjects. Ghrelin levels correlated positively with obesity, but not with gender. There were no significant correlations between the expression of the genes of interest and the parameters studied (age, body mass index - BMI, cholesterol, triglycerides, glycemia, diabetes, hypothyroidism and hypertension). The results of the study suggest that the evaluation of leptin levels can be used clinically in assessing the metabolic status of the patient with malignant obesity. PMID- 29250672 TI - Association of the blood serum cytokines' rate and lymphocytes' apoptosis with polymorphic variants of the BCL-2 (rs17759659), CTLA-4 (rs231775) and APO-1/FAS (rs2234767) genes in patients with nodular goiters in autoimmune thyroiditis and thyroid adenoma. AB - The paper analyses results of serum cytokines and lymphocyte apoptosis study in patients with nodular goiter against the background of autoimmune thyroiditis (NGAIT) and thyroid adenoma (TA) based on the cell preparedness to apoptosis (content of lymphocytes carrying apoptosis marker - CD95+-receptor), the number of apoptotic lymphocytes (annexin V+-lymphocytes) and the content of proapoptotic tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6, as well as anti-inflammatory IL-4 cytokine in serum, considering the polymorphism of BCL 2 (rs17759659), CTLA-4 (rs231775) and APO-1/FAS (rs2234767) genes. The results show that under the damaging action of peroxidation products in the thyroid structures, activation of Fas- and caspase-dependent mechanisms of influence on pro- and anti-apoptotic targets, the induced hyperproduction and release of TNF alpha from thyroid-stimulated lymphocytes stimulate an additional synthesis of other pro-inflammatory cytokines IL-1beta and IL-6, as well as compensatory anti inflammatory proteins including IL-4. There is a synchronized increase in secretion of the soluble form of TNF-alpha receptor (sTNFR), which prevents binding the corresponding cytokine to a specific membranous shedding of a number of receptors and separates the apoptotic signals. The above-mentioned changes associate with the polymorphic variants of BCL-2 (rs17759659), CTLA-4 (rs231775) genes and only for some figures, they are almost three times weaker with FAS (rs2234767). PMID- 29250673 TI - Eu3+-doped ZnO nanostructures: advanced characterizations, photoluminescence and cytotoxic effect. AB - In this work, several nanostructures (nanopowders and nanostars) of undoped and 1%, 3% and 5% europium (Eu3+)-doped ZnO have been synthesized via coprecipitation method using oxalic acid and sodium hydroxide as precipitation agents. Starting from zinc acetate and europium acetate, nanopowders were obtained by coprecipitation with oxalic acid. ZnO based nanostars were synthesized by coprecipitation of Zn2+ and Eu3+ with hydroxide ions (HO-), when zinc chloride and europium acetate were used as reagents. The structure and morphology of the as-prepared ZnO nanopowders and nanostars were investigated by X-ray diffraction and electron microscopy. Only wurtzite structure of ZnO was identified in all the samples based on ZnO. Transmission electron microscopy (TEM) investigations have shown an average particle/crystallite size range from 23 to 29 nm and polyhedral and spherical morphology with tendency to form aggregates for nanopowders. Cytotoxicity tests on MG-63 cell lines was also performed. Photocatalytic activity of ZnO nanopowders have reached higher values compared to ZnO nanostars. The photocatalytic test indicates that the ZnO nanopowders have better activity than the nanostars, most probably because of the higher specific surface. Doping the ZnO with Eu2O3 does not seem to alter it in a decisive manner. The toxicity results indicated that ZnO nanoparticles (NPs) high toxicity on tumoral cells is also induced by particle size and, consequently, the dissolution of Zn2+ ions is dependent on the size of the particles, increasing with the particles size. PMID- 29250674 TI - In vivo confocal microscopy quantification of reactive oxygen species: a working model in rat kidney. AB - Oxidative stress is a culprit responsible for the development of acute and chronic kidney diseases. We aimed to establish a working model for the dynamic in vivo assessment of reactive oxygen species (ROS) production in rat kidney. A randomized controlled study was performed in 36 adult male Wistar rats subjected to unilateral urinary obstruction (UUO) via ureteral ligation and compared to SHAM controls. Dihydroethidium (DHE) was injected in the femoral vein and in vivo confocal microscopy was performed in the 2nd, 6th and 10th day, respectively after surgery. Maximal ROS levels elicited by UUO were recorded on the 6th day. However, the absolute difference of the means of DHE fluorescence intensity between UUO and SHAM was the highest on the 10th day. Our working model can monitor ROS production at different time frames and our initial findings suggest that the surgery-related ROS levels decline after an initial increase in the first days, whereas the ones elicited by chronic ligation continue to raise. PMID- 29250675 TI - Acupuncture causes serotonin release by mast cells. AB - Mast cells (MCs) are important object in experimental acupuncture due to their putative involvement in local reactions to needling. In the rat, they are shown to contain in their granules, among other tissue mediators, serotonin, also called 5-hydroxytryptamine (5-HT). The aim of this study is to examine the normal distribution of 5-HT-containing MCs in soft tissues of Zusanli (ST36) acupuncture point (acupoint) and their morphological changes caused by experimental acupuncture. We observed 5-HT-immunopositive MCs in the tissues and in the vicinity of the needle tract formed after acupuncture. As a result of acupuncture needling, the tissue integrity is disrupted and certain folds are formed in the direction of the needle tract. Connective tissue in the vicinity of the needle tract gets compressed and displaced, together with the 5-HT-immunoreactive MCs seen there. Some of those 5-HT-immunopositive MCs showed signs of degranulation with numerous discharged granules, some of them found at a considerable distance form the cell. Furthermore, 5-HT-immunopositive MCs are unevenly distributed in soft tissues of ST36 acupoint. Larger numbers of 5-HT-containing MCs were visualized in subcutis and dermis, compared to the observed in striated muscles. Placing the acupuncture needle into the rat skin caused a formation of an apparent needle tract, tissue displacement and degranulation of 5-HT immunopositive MCs. The demonstrated serotonin release by means of MC degranulation might be involved in the local tissue response to acupuncture. PMID- 29250676 TI - Rare variant of celiac trunk branching pattern associated with modifications of hepatic arterial vascularization. AB - The routine dissection of a male body revealed multiple anatomical variations of the celiac trunk and hepatic artery vascularization. The origin of the celiac trunk was on the left side of the abdominal aorta, next to the T12-L1 intervertebral disk. The celiac trunk gave off five branches: the left inferior phrenic artery, the left gastric artery, the accessory right hepatic artery, the common hepatic artery and the splenic artery (the last two arteries had a common origin in a hepatosplenic trunk). A right branch detached off the left gastric artery and anastomosed with the hepatic artery proper. The proper hepatic artery also anastomosed with the accessory right hepatic artery at the same level. Consequently, the entire hepatic arterial supply was from the celiac trunk - through two arteries directly and a third via the left gastric artery. The anatomical variant described in this case can be considered very rare. Thorough knowledge of such variants is important both for upper abdominal surgery and for imagistic and interventional radiology. PMID- 29250677 TI - Malignant cutaneous mixed tumor with sebaceous differentiation. AB - Malignant cutaneous mixed tumor (CMT) is a very rare adnexal tumor with biphasic differentiation. In rare cases, a benign CMT (chondroid syringoma) undergoes malignant transformation. Sebaceous differentiation in a cutaneous malignant mixed tumor has not been previously reported. We present a malignant CMT with sebaceous differentiation, which occurred on the scalp of an 81-year-old man. The tumor showed epithelial elements composed of relatively small and bland-appearing ductal and cord-like structures lined by small, cuboidal-shaped adnexal cells, with a few large, dilated gland-like spaces lined by larger, apocrine-appearing cells with abundant eosinophilic-staining cytoplasm. However, the majority of the epithelial component was composed of nests and islands of markedly enlarged and atypical cells with pale/clear to ground-glass cytoplasm. Focally, there was sebaceous differentiation identified, in the form of prominent multivacuolated cytoplasm, with nuclear indentations. The stroma showed a mixture of myxoid and hyalinized/chondroid-appearing areas with focal calcifications. There was strong and diffuse staining of the sebaceous cells by cytokeratin (CK) 7, epithelial membrane antigen (EMA), and androgen receptor (AR). Mismatch repair proteins were investigated by immunohistochemistry, without evidence of loss of expression of MutS protein homolog 6 (MSH6), MutS protein homolog 2 (MSH2), MutL protein homolog 1 (MLH1), or postmeiotic segregation increased 2 (PMS2) in the sebaceous cells. PMID- 29250678 TI - Mass effect: a plethora of symptoms caused by an otherwise benign transitional pituitary meningioma. Case report. AB - Meningiomas are among the most commonly encountered tumors of the central nervous system, being more frequent in females. We present the case of a dyslipidemic male patient, previously diagnosed with coronary artery disease for which he previously underwent percutaneous coronary intervention with the placement of two bare metal stents on the left anterior descending artery. He was presented to the emergency department for atypical angina and a seven-day history of dizziness when switching from clino- to orthostatism, reduced visual acuity, diplopia and vomiting. Electrocardiogram (ECG), both at rest and exercise test were suggestive for myocardial ischemia. Echocardiography revealed myocardial hypokinesia in the territory of the right coronary artery and of the left descending artery, while coronarography showed insignificant intra-stent stenosis. Imaging techniques revealed a frontobasal extraneuraxial mass, creating a compressive effect on both middle cerebral arteries and on the optic chiasm as well as thickening of the dura mater adjacent to the mass. Endocrinology blood tests showed hypocortisolemia, hyperprolactinemia and low levels of free thyroxine (fT4), suggesting secondary combined pituitary hormone deficiency. The patient underwent surgery and total resection of the tumor was performed. Definite diagnosis - transitional meningioma - was obtained through histological examination and immunohistochemistry. The key feature of this case was the extra-cardiac cause of angina accompanied by ECG abnormalities in a patient with stable coronary heart disease, in whom the clinical presentation was secondary to blood pressure variations in the context of pituitary and adrenal deficiency. PMID- 29250680 TI - Granular ameloblastoma: report of two cases with atypical cytological aspects. AB - Ameloblastoma is an aggressive odontogenic tumor, which arises from odontogenic epithelium. Ameloblastomas can present in several clinical and histomorphological patterns. The granular cell variant accounts for only 3.5% to 5% of ameloblastomas. We have presented two cases of granular cell ameloblastoma (GCA) occurring in a 44-year-old and 50-year-old man, respectively. Case No. 1 on incisional biopsy was diagnosed as unicystic ameloblastoma (UA), which later after excisional biopsy was finally diagnosed as GCA owing to the features observed in excisional biopsied tissue. Case No. 2 on incisional biopsy showed darker and lighter stained cells arranged in small follicular pattern, and anastomosing cords. Meticulous immunohistochemistry, histochemical examination and careful literature search helped us to diagnose it as GCA. We have made an attempt to elucidate the diagnosis of GCA especially in cases of GCA with unusual granular component. PMID- 29250679 TI - Bilateral serous surface papillary borderline ovarian tumor in 19-year-old patient. Ultrasound, immunohistochemical and therapeutic particularities of reproductive age. AB - Borderline tumors have a histological aspect of atypical epithelial proliferation without stromal invasion and typically occur in fertile ages, approximately one third of women diagnosed are younger than 40. Serous borderline tumors are the most encountered and they can present micropapillary features that are associated with a higher rate of recurrence and the possibility of peritoneal implants. We present the case of a serous borderline ovarian tumor in a young patient and the diagnosis and treatment particularities. The patient presented with no symptoms, for a specialist advice, in the context of failure obtaining spontaneous pregnancy over a period of seven months. Paraclinical, the only modified parameter was CA 125, respectively a slight increase of its value. The atypical appearance on abdominal and transvaginal ultrasound indicated a presumptive diagnosis; both ovaries with multiple irregular vegetation, moderately vascular on Doppler examination, with the starting point in epithelial capsule shell, that appeared thick and hyperechogenic. About 7 cm of pelvic fluid was also present. During exploratory laparoscopic intervention, the surrounding tissue of both ovaries was biopsied and the fragments were sent for histopathological and immunohistochemical exam. Immunohistochemical assays correlated with the histopathological analysis and anatomical clinical data confirmed the diagnosis. After informed consent, the patient underwent radical surgery with a quick and uneventful recovery. The series of investigations had the objective to establish the best management of the case and reviewing the possibility of a conservative surgery. Patient clinical aspect matched with the patterns of ovarian borderline tumors by the asymptomatic presence of the bilateral adnexal masses. PMID- 29250681 TI - Acinic cell carcinoma of minor salivary glands - case report. AB - Salivary gland tumors have a high incidence (90%) within the parotid gland. The acinic cell carcinoma (ACC) represents only 1-3% of the salivary gland tumors, most frequently affecting the parotid. The minor salivary glands rarely develop ACC and when the ACC is localized in these glands, generally, it has a less aggressive evolution. The main criterion in the diagnostic of ACC is the histological examination with the regular Hematoxylin-Eosin (HE) staining and additionally Periodic Acid-Schiff (PAS) special staining. Immunohistochemical (IHC) examination confirms the origin of the tumor cells and the cellular proliferation index. Therapeutic management consists of surgical excision and radiotherapy. Left jugular tumor was the clinical diagnosis in the case we presented. The computed tomography (CT) examination revealed a voluminous expansive process of the left cheek. Surgery was performed with tumor resection and the skin defect was threatened. The histopathological (HP) and IHC exams have established the diagnosis of minor salivary glands adenocarcinoma with increased tumor proliferation index. The evolution was unfavorable to tumor recurrence in a short time of one year. PMID- 29250682 TI - Extramammary Paget's disease in an HIV-positive patient. AB - Extramammary Paget's disease (EMPD) is an uncommon intraepithelial carcinoma usually found as an irregular, pruritic plaque on the apocrine-rich anogenital skin. Diagnosis of EMPD is challenging due to the rarity of the disease and the uncharacteristic clinical aspect and requires histopathological confirmation. We report the case of a 62-year-old human immunodeficiency virus (HIV)-positive male, which presents with a lesion of the left part of pubic area with clinical and dermatoscopic appearance suggestive for Bowen's disease but with histopathological diagnosis of EMPD. We present pathological and immunohistochemical data to confirm the diagnosis. PMID- 29250683 TI - Hemorrhagic polypoid gastric and colonic metastases nine years after uterine leiomyosarcoma - case report. AB - INTRODUCTION: Uterine leiomyosarcoma (ULMS) is a rare tumor, representing 1-2% of all uterine malignancies. It is highly aggressive, with high metastatic rate, especially in lungs, peritoneal cavity, retroperitoneum, bones and liver, usually during the first years after diagnosis. CASE PRESENTATION: A 58-year-old woman, with subtotal hysterectomy and bilateral adnexectomy, followed by radiochemotherapy for spindle-type ULMS nine years ago, presented with gastrointestinal bleeding and severe anemia. Three polyps ranging from 2 cm to 5 cm in diameter were found at gastroscopy, the largest being ulcerated, which required a total gastrectomy three months later. Colonoscopy identified two pedunculated polyps on the descending colon, 2 cm and 3.5 cm in diameter. Histologically, both sites revealed proliferations of spindle cells with whorled pattern, moderate to severe nuclear atypia, 5 to 8 mitotic figures (MFs)/10 high power fields (HPFs) and additional necrosis in the gastric tumors. Immunohistochemistry was negative for CD117, DOG1, S100 and CD34 and positive for smooth muscle actin (SMA), estrogen receptor (ER) and progesterone receptor (PR). Twenty percent of nuclei stained positive for Ki67. The diagnosis was synchronous hemorrhagic gastric and colonic polypoid metastases of ULMS. Thoracic computed tomography (CT) and abdominal ultrasonography were negative for other metastatic lesions, while abdominal CT revealed abdominal and pelvic lymphadenopathy. CONCLUSIONS: This case illustrates a distinct pattern of metastasis that is an extremely rare gastric and colonic location and an expanded disease-free period of nine years since the initial treatment. A long-term clinical and imaging follow-up of this patient is essential. PMID- 29250684 TI - A rare case of Meckel-Gruber syndrome. AB - Meckel-Gruber syndrome (MKS) is a lethal, autosomal recessive transmitted anomaly, characterized by the ultrasound triad: occipital meningoencephalocele, bilateral polycystic kidney, postaxial polydactyly. The incidence is between 1/13 250 and 1/140 000 live births, being a rare anomaly. We report a MKS case of feminine gender diagnosed on two ultrasound findings (bilateral polycystic kidney, occipital meningoencephalocele). This case highlights the presence of MKS in a young female without family history. PMID- 29250685 TI - Atretic aortic coarctation - transradial approach. Case series and review of the literature. AB - Stenting of aortic coarctation became the method of choice. In severe aortic coarctation, when retrograde crossing of the coarctation is impossible, a secondary approach with antegrade arterial crossing proved to be the solution in many cases. Here we report two cases of severe aortic coarctation in males aged 12 and 14, respectively, in which we used a secondary transradial approach (right and left) followed by guidewire snaring. For the first case, a right radial-right femoral arterio-arterial circuit was created, which offered a stable position during stent implantation. In both cases, we predilated the lesion and then implanted a 45 mm Cheatham-platinum (CP) covered stent. The final result was very good in both patients; only the first one required post-dilatation of both ends of the stent. Asymptomatic post-procedural absence of left radial pulse was noticed in the second case. In conclusion, even in the case of children, secondary transradial approach is suitable for antegrade crossing of the coarctation in extremely severe cases and possibly in stabilization of the circuit for stent implantation. PMID- 29250686 TI - Ovarian strumal carcinoid - case report. AB - Strumal carcinoid represents a rare form of ovarian teratoma, consisting of both thyroid tissue and carcinoid structures. The carcinoid component is a well differentiated neuroendocrine tumor with excellent prognosis. Strumal carcinoid tumors are commonly found in peri-menopausal women who are not usually interested in preserving their fertility and who are thus open to radical surgical treatment. In this report, we present a 24-year-old, nulliparous patient with strumal carcinoid, confirmed by histopathology and a large panel of immunohistochemistry (IHC) markers, who wished to preserve her fertility. In this case, a conservative surgical treatment (salpingo-oophorectomy) served to preserve vital and reproductive prognosis, and correct tumor classification was of extreme importance. The morphological examination of strumal carcinoid showed struma ovarii with a thyroid follicle-like structure [positive for thyroid transcription factor 1 (TTF1), thyroglobulin, CD56, cytokeratin (CK) 19, and negative for Hector Battifora and mesothelioma 1 (HBME1)], and a neuroendocrine cell component with a trabecular arrangement and island growth (positive for synaptophysin, chromogranin, CD56, and CK7 negative), which were interlocked and intimately associated. Papillary thyroid carcinoma of follicular type was ruled out by CD56 positivity and HBME1 negativity. Medullary thyroid carcinoma with strumal component was excluded by calcitonin negative staining. Solid rosette like structures with negative glial fibrillary acidic protein (GFAP) staining ruled out a neuroectodermal component. A multilocular mucinous cystadenoma was identified without other teratoma components. Strumal carcinoid requires a meticulous examination to rule out other entities with malignant behavior and poor prognosis. In this case, a conservative treatment is sufficient to remove the tumor, preserving vital and reproductive prognosis. PMID- 29250687 TI - Lymphoproliferative disorder in a twin female teenager post kidney transplantation. AB - Post-transplant lymphoproliferative disorder (PTLD) is defined as a heterogeneous group of lymphoid and plasmocytic proliferations with variable malignant potential. They often arise in immunocompromised post solid organ transplant (SOT) patients linked with Epstein-Barr virus (EBV) infection. Clinical manifestations include fever, lymphadenopathy and organ involvement. Diagnosis of PTLD requires morphopathological tissue examination. Treatment of EBV-related PTLD in SOT patients includes immunosuppressive (IS) agents' reduction, use of antiviral medication, anti-B-lymphocyte antibodies and chemotherapy for high-risk patients. We report a case of late EBV-related PTLD occurring in a young female, coming from twins, nine years after renal transplant from deceased donor. Both sisters were diagnosed at the age of 10 with chronic kidney disease (CKD) based on nephronophthisis and underwent the first simultaneous renal transplant from deceased donor in Romania. PTLD Hodgkin's-like lymphoma and EBV-positive lesions were to be found in autopsy. Routine EBV viral load testing and immune condition in SOT patients could identify PTLD risk factors therefore early treatment can be applied. Monitoring EBV serology and immunological parameters are preferred as strategy for PTLD prevention. PMID- 29250688 TI - Pulmonary Langerhans cell histiocytosis in a 26-year-old female: still a diagnostic challenge. AB - Langerhans cell histiocytosis (LCH) is a rare disorder caused by monoclonal Langerhans cells proliferation in bone, skin, lung, lymph nodes, liver, spleen, nervous or hematopoietic system. Pulmonary LCH is a diagnostic trap that is displayed on computed tomography (CT) as an interstitial disorder with honeycomb aspect. In this paper, we present an unusual case of a 26-year-old female that was hospitalized with progressive worsening dyspnea and history of recurrent pneumonia. Lung biopsy showed fibrosis of the interalveolar septa, architectural distortion and large cells with foamy cytoplasm and convoluted nuclei that were marked by CD68, S-100 and the specific antibody CD1a that allowed establishing the diagnosis of pulmonary LCH. The only extrapulmonary manifestations were femoral bone cysts that were radiologically seen 10 years before and were not modified along the years. The therapy consisted on smoking cessation and oral corticosteroids without significant improvement of the clinical symptoms and enlargement of the cystic spaces during six months of follow-up. This case highlights for a rare disorder of the lung that should be taken into account in young patients with progressive pulmonary fibrosis. PMID- 29250689 TI - Anatomic variants in Dandy-Walker complex. AB - Dandy-Walker complex (DWC) is a malformative association of the central nervous system. DWC includes four different types: Dandy-Walker malformation (vermis agenesis or hypoplasia, cystic dilatation of the fourth ventricle and a large posterior fossa); Dandy-Walker variant (vermis hypoplasia, cystic dilatation of the fourth ventricle, normal posterior fossa); mega cysterna magna (large posterior fossa, normal vermis and fourth ventricle) and posterior fossa arachnoid cyst. We present and discuss four cases with different morphological and clinical forms of the Dandy-Walker complex. In all four cases, diagnosis was reached by incorporation of clinical (macrocephaly, seizures) and imaging [X-ray, computed tomography (CT), magnetic resonance imaging (MRI)] data. Two patients were diagnosed with Dandy-Walker complex, one patient was diagnosed with Dandy Walker variant in a rare association with neurofibromatosis and one patient was diagnosed with a posterior fossa arachnoid cyst associated with left-sided Claude Bernard-Horner syndrome, congenital heart disease (coarctation of the aorta, mitral stenosis) and gastroesophageal reflux. In all forms of DWC, the clinical, radiological and functional manifestations are variable and require adequate diagnostic and therapeutic measures. PMID- 29250690 TI - Difficulty in positive diagnosis of ascites and in differential diagnosis of a pulmonary tumor. AB - Ascites is the most frequent complication of cirrhosis and occurs only when the portal hypertension has already installed but ascites is caused by neoplasms, heart failure, tuberculosis, pancreatic illnesses, as well as other kind of affections. We describe the case of a 67-year-old patient, a retired person, without significant personal or familial history, nonsmoker, infrequent alcohol and coffee consumer with following chief complaints at onset: loss of appetite, weight loss, serious physical asthenia, delayed intestinal transit, diffuse abdominal pain and increase of abdominal circumference. Initially was misdiagnosed with liver cirrhosis. After discharged from our Clinic, suspicion of diagnosis was mesothelioma as well as after first thoracoscopy and pleural biopsy performed in a Clinic of Thoracic Surgery. Several pleural fragments collected by biopsy were sampled for the histopathological exam. The stainings used were Hematoxylin-Eosin (HE) and Periodic Acid-Schiff (PAS) for the mucopolysaccharides. For the immunohistochemistry was used the labeled Streptavidin-Biotin (LSAB)-Horseradish peroxidase (HRP) method, as well as the antibodies: cytokeratin (CK) cocktail (AE1/AE3), vimentin, calretinin, CK7, CK5/6, CK20, epithelial specific antigen/epithelial cell adhesion molecule (Ep CAM) (BerEP4), thyroid transcription factor-1 (TTF-1), E-cadherin, CDX2, carcinoembryonic antigen (CEA) and the Hector Battifora mesothelial antigen-1 (HBME-1). The aspect at immunohistochemistry establishes a positive diagnostic of poorly differentiated mucinous pulmonary adenocarcinoma, with "signet ring" cells. The rapid and accurate determination of the diagnostics will allow not only for a decrease in the expenses for inefficient treatments, but also for the guidance of the patients towards clinics or centers able to provide and supervise these treatments. PMID- 29250691 TI - Nephrotic syndrome secondary to amyloidosis in a patient with monoclonal gammopathy with renal significance (MGRS). AB - Monoclonal gammopathy with renal significance (MGRS) is a relative new-described entity, diagnosed especially in older patients and deriving from the group with monoclonal gammopathy of undetermined significance (MGUS). Various renal lesions may arise in MGRS, according to the ultrastructural characteristics of the monoclonal immunoglobulin deposition in the kidney, from proliferative glomerulopathies and amyloidosis to light chain proximal tubulopathy and crystal storing histiocytosis. Although both are considered premalign or non-malignant hematological conditions, kidney involvement in MGRS aggravates the prognosis of the patients and need to be treated aggressively. We discuss the case of a 44 year-old female patient admitted in our Department of Nephrology for clinical picture of impure nephrotic syndrome and decreased renal function associated with Bence-Jones proteinuria. Renal biopsy was performed, and fibrillar amyloid deposits were demonstrated both in glomerular and tubular basement membranes; the immunofluorescence identified the presence of kappa chains. Bone marrow aspiration and biopsy showed <10% plasmocytic proliferation confirming the diagnosis of MGRS. PMID- 29250692 TI - Esophageal atresia with distal fistula - unusual case series. Considerations related to epidemiological aspects, malformative associations, and prenatal diagnosis. AB - BACKGROUND: Esophageal atresia (EA) is the most frequent and severe congenital anomaly of the esophagus, occurring in 1:2500-1:4500 live births. Five types of EA have been described, EA with tracheoesophageal fistula (TEF) being the most frequent. AIM: The aim of this paper is to evaluate epidemiological aspects, malformative associations, and prenatal diagnosis in an unusual case series of EA with distal TEF. CASE PRESENTATIONS: The authors are analyzing a series of seven cases of EA with distal TEF. The seven cases of EA with TEF presented occurred during a period of two years, resulting in an unusually increased rate - 1.1:1000 live births. Except a late suspicion of EA (one day before delivery), EA was not diagnosed during prenatal scans despite association with polyhydramnios in two cases and single umbilical artery in four cases. None of the two cases of unilateral renal agenesis or anorectal malformations were diagnosed on prenatal ultrasound scans. In two of the cases, EA was part of VACTERL (vertebral defects, anorectal malformations, heart defects, EA with or without TEF, renal anomalies/dysplasia, and limb defects) association. Despite lack of prenatal diagnosis, postnatal diagnosis of EA was suspected at birth in four cases, at two hours in one case. CONCLUSIONS: An increased index of suspicion for congenital structural defects, particularly for EA, should be maintained in the presence of a single umbilical artery and/or polyhydramnios on prenatal ultrasound scan. Prenatal diagnosis of EA offers the chance for parental counseling, planned birth and transfer for corrective surgery and decreases the risk for postnatal aspiration pneumonia associated with early feedings. PMID- 29250694 TI - Middle mesial canal of the permanent mandibular first molars: an anatomical challenge directly related to the outcome of endodontic treatment. AB - To effectively clean and shape the mandibular permanent first molars it is mandatory to understand in detail their complex internal anatomy. The middle mesial canal is an additional canal located between the usual mesiobuccal and mesiolingual canals in the mesial root of mandibular first molars. The incidence of the middle mesial canal, its relationship with main canals of the mesial root and the possibility for it to be negotiated is an important practical issue in endodontics. To identify the presence of this canal is mandatory. Accordingly, a modified endodontic access, the use of the operating microscope and periapical radiographs in two different horizontal projections are indicated to enhance the long-term favorable outcome of the endodontic treatment. PMID- 29250693 TI - Non-Hodgkin's lymphoma, rare localization at the base of the tongue - case presentation. AB - The extranodal malignant lymphomas occur mainly in the region of the head and neck, after the gastrointestinal tract. The most common site of the head and neck lymphoma is at the lymphatics ring of Waldeyer, followed by the nasosinusal region. Localization at the base of the tongue is extremely rare. The authors reported a case of a 50-year-old male with a non-Hodgkin's lymphoma, which developed at the base of tongue. An unusual sensation described as a foreign body at the hypopharyngeal region associated with progressive dysphagia were the main symptoms for which the patient was referred to our Hospital. The fibroscopic exam has revealed an oval tumor of the base of tongue, with large dimensions, sessile emergent base and smooth superficial mucosa. The tumor was removed using an endoscopic transoral approach, followed by the histopathological and immunohistochemical examination, which have been suggestive for non-Hodgkin's lymphoma with small B-cells. The treatment continued with chemotherapy, while radiotherapy was not necessary due to the fact that the tumor was completely removed. PMID- 29250695 TI - Adenocarcinoma versus pancreatic neuroendocrine tumor - case report. AB - Pancreatic cancer represents one of the most aggressive types of cancer, resulting in a late diagnosis and rapid death (poor overall survival). After adenocarcinoma (counting almost 80% of cases of pancreatic cancer), the second category, as frequency, is represented by the family of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Pancreatic cancer is characterized by genetic heterogeneity and may results in different evolution among metastases, which may acquire driver mutations with the ability to transform under the action of several cancer treatments. Here we report a case of a 64-year-old patient diagnosed with pancreatic tumor localized on the body and tail, invasive in the splenic and portal vein, pT3pN0M0 (adenocarcinoma pancreatic cancer), treated with a multimodal approach: surgery (splenectomy and distal pancreatectomy, with suture of the portal vein), chemotherapy, in 2010, that relapsed in 2015, with local recurrence that was resected and distant liver metastases. Immunohistochemistry of the recurrence tumor showed a neuroendocrine transformation of the tumor, with major implications in treatment and prognosis. Computed tomography examination, as well as histopathological and immunohistochemically testing, sustained positive and differential diagnosis. PMID- 29250696 TI - Nephrotic syndrome after autologous hematopoietic stem cell transplantation: a case report. AB - Nephrotic syndrome (NS) is a rare complication of hematopoietic cell transplantation (HCT) and is thought to represent a renal manifestation of chronic graft-versus-host disease (cGVHD). Glomerulopathies occur less often in recipients of autologous as compared to allogeneic HCT and, in this setting, renal pathology is less well characterized. This case report describes a 54-year old man admitted for the evaluation of a nephrotic-range proteinuria. His past medical history included a ? light-chain secreting multiple myeloma (MM) for which he underwent autologous HCT. Prior to admission, the level of proteinuria on successive check-ups was over 3.5 g/day, while on treatment with Losartan for the past six months for mild arterial hypertension. At the time of admission, the clinical examination was unremarkable and there were not any signs of cGVHD. Initial testing showed a nephrotic-range proteinuria (5.6 g/day) with normal renal function, while excluding secondary causes of NS. The patient underwent a kidney biopsy that revealed the classic variant of focal and segmental glomerulosclerosis (FSGS). The patient was started on Cyclosporine 5 mg/kg/day and, after nine months, he experienced a partial remission (proteinuria 1.2 g/day). This is the first report of FSGS as the etiology of autologous HCT associated NS. PMID- 29250697 TI - Two girl patients with medulloblastoma. Case reports. AB - : In childhood, the most common type of brain tumors is medulloblastoma, a highly malignant primary brain tumor that is found in the cerebellum or posterior fossa. The tumor mass increases and generates obstructive hydrocephalus. Risk factors (that might be involved in some cases) include the genetic syndrome such as type 1 neurofibromatosis, exposure to ionizing radiation and Epstein-Barr virus. Medulloblastoma is associated with recessively inherited Turcot disease and with conditions as ataxia-telangiectasia syndrome in several cases. The authors presented two cases of female patients (aged one year and eight months old, respectively 4-year-old), both of them with weight deficiency, with personal history of head trauma. First case, M.D.M., was admitted in Emergency Room of the Emergency County Hospital, Craiova, Romania, for symptoms that included headaches, impaired vision, vomiting, mental disorders, ataxia and body imbalance. The reason for refer to the Surgical Unit care was posterior fossa tumor diagnosed by computed tomography (CT) scan. The second case, V.F., a 4-year old girl, was admitted to First Pediatrics Clinic of the same Hospital, on October 2014, for seizures, early morning vomiting, loss of appetite, inability to walk and stand and also, mental delay. She had "cafe au lait" spots on her trunk, suggesting type 1 neurofibromatosis. A brain CT scan revealed a tumor being developed in the fourth ventricle (in the vermis of the cerebellum). Both the girls underwent curative surgery in different Clinics from Bucharest. The two girls with the same diagnosis showed contrasting post-surgical evolution: M.D.M. still survives, while V.F. survived only for six months following first surgical intervention. The first patient, M.D.M., received chemotherapy before and after the surgery, which a slow but favorable recovery noted. For the second patient, the brain CT scan performed four months after surgery showed multiple masses in the cerebral posterior fossa, suggestive of leptomeningeal metastases, but without local recurrence of the medulloblastoma. The patient started chemotherapy and, after two sessions, she went for second surgical treatment. Six months after the second surgery, the second female patient, V.F., died. The objective of this study is to find the reasons of their different clinical evolution. The authors emphasized the clinical similarities of the patients, both being female, having similar symptoms and incidental medical events (upper and lower respiratory tract infections and head trauma) but most important, they stressed out the factors which contributed to the different clinical outcome, the second patient having a more aggressive form of medulloblastoma and receiving chemotherapy only after leptomeningeal metastases were evidenced. In addition, as for the second patient, she might had clinical criteria for type 1 neurofibromatosis (the author specified the number of the "cafe au lait" spots being over 6, like her brother, mental delay, without other clinical signs), which might have contributed to the poor outcome. The etiology of medulloblastoma can also be involved with chromosome 17 and the diagnosis of such a brain tumor can be an evolutive criterion for neurofibromatosis. The diagnosis can provided only by genetic tests. There is a vital risk and a reason for the lethal evolution of V.F. PATIENT: As medulloblastoma is a very aggressive malignant tumor, the approximate cumulative survival rate for preschool age group having a histological follow-up was found to be 47% over a span of five years of rigorous treatment. PMID- 29250698 TI - Genetic disorder in carbohydrates metabolism: hereditary fructose intolerance associated with celiac disease. AB - Celiac disease (CD) has been associated with several genetic and immune disorders, but association between CD and hereditary fructose intolerance (HFI) is extremely rare. HFI is an autosomal recessive disease caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase). We report the case of a 5-year-old boy suffering from CD, admitted with an initial diagnosis of Reye's-like syndrome. He presented with episodic unconsciousness, seizures, hypoglycemia, hepatomegaly and abnormal liver function. The patient has been on an exclusion diet for three years, but he still had symptoms: stunting, hepatomegaly, high transaminases, but tissue transglutaminase antibodies were negative. Liver biopsy showed hepatic steatosis and mitochondrial damage. The dietary history showed an aversion to fruits, vegetables and sweet-tasting foods. The fructose tolerance test was positive, revealing the diagnostic of hereditary fructose intolerance. Appropriate dietary management and precautions were recommended. The patient has been symptom-free and exhibited normal growth and development until 10 years of age. PMID- 29250699 TI - Surgical treatment in a case of giant macrodystrophia lipomatosa of the forefoot. AB - Macrodystrophia lipomatosa is a rare, congenital, non-hereditary disease, characterized by local gigantism of the fingers or toes. We report the case of a 37-month-old boy, with no prior past medical history, who presented with a gigantic dystrophy of the left forefoot. The location of the deformity was involving the plantar and dorsal aspect of the foot, and digits 1 to 4. After clinical examination, imaging study assessment, and differential diagnosis considerations, it was established that macrodystrophia lipomatosa was the cause of the deformity. A reconstructive surgical intervention was planned. The hypertrophied tissues were excised, resulting in a reduction in the forefoot's volume. The patient had a favorable postoperative course and ambulation was allowed with a custom-made shoe. The case represents a rare pathological entity with complex diagnostic and therapeutic considerations. As far as treatment options, the surgeon must decide between a reconstructive surgical intervention and amputation. PMID- 29250700 TI - Ethical dilemmas in communicating bad news following histopathology examination. AB - PURPOSE: The study proposes an analysis of the ethical aspects that occur in communicating bad news following histopathology laboratory tests in medical practice, in particular in the case of the anatomical pathology diagnosis confirming a medical condition of poor prognosis. BACKGROUND: Over the last decades, the progress of science and technology in the medical field, as well as the explosive increase of specialist information available on the Internet have led to unprecedented ethical issues related to the communication modality of histopathology test results to patients. CONTENT: The paper analyses from an ethical and legislative perspective the main ethical dilemmas that occur when choosing a modality for communicating test results. DISCUSSION AND CONCLUSIONS: While communicating bad news is an essential ability for medical professionals, it should be used within the context of observing the patients' right to decide whether they wish to receive such information or not and their right to their own autonomy, by means of a personalized protocol for communicating bad news in current medical practice. PMID- 29250701 TI - The performance of mobile screening units in a breast cancer screening program in Brazil. AB - PURPOSE: In Brazil, access to breast cancer screening outside of urban centers is limited. This study aims to describe the coverage and performance of a breast cancer screening program implemented with Mobile Screening Units (MSU) in northern Sao Paulo state. METHODS: This is a retrospective cohort study of a population-based mammography program targeting women ages 40-69 in 108 municipalities from 12/2010 to 07/2015. Screening coverage rates were estimated using the Brazil 2010 census data. We calculated performance measures for the number of exams, recalls, and detected cases of cancer. Screen-detected cases were compared to clinically detected cases using hospital cancer registry data and a propensity-score matching method. The down-staging of screen-detected cases relative to clinically detected cases was assessed using logistic regression to calculate risk ratios (RRs) with 95% confidence intervals. RESULTS: 122,634 women were screened through the MSU program, representing a cumulative coverage rate of 54.8% in the target population. For initial and subsequent rounds, recall rates were 12.25 and 6.10% and cancer detection rates were 3.63 (95% CI 3.23-4.10) and 1.94 (95% CI 1.59-2.41), respectively. 92.51% of referrals were successful. Screen-detected cases had more favorable prognoses than clinically detected cases, including smaller tumor size and a decreased risk of late-stage detection (RR 0.14 95% CI 0.074-0.25). CONCLUSIONS: MSUs are a feasible method for the delivery of mammography services in this setting. Patients who had breast cancer detected on an MSU had favorable prognostic factors when compared with clinically detected cases arising from the same target population. PMID- 29250702 TI - Delivery of adjuvant chemotherapy among stage III colon cancer patients at a public versus private hospital in New York City. AB - PURPOSE: Prior studies of timeliness of adjuvant chemotherapy (AC) initiation in stage III colon cancer have suggested longer time to AC at public compared with private hospitals. Few studies have explored differences in AC completion. We investigated whether timely initiation and completion of AC differed between a public and private hospital, affiliated with the same academic institution in a large, urban setting. METHODS: We conducted a retrospective cohort study of stage III colon cancer patients who had surgery and AC at the same medical center between 2008 and 2015, either at its affiliated public hospital (n = 43) or private hospital (n = 79). We defined timely initiation as receiving AC within 60 days postoperatively, and completion as receiving >= 75% of planned AC. Univariate and stepwise multivariable logistic regressions were used to identify factors associated with AC delivery. RESULTS: Median number of days to AC was significantly greater among patients at the public (53, range 31-231) compared with the private hospital (43, range 25-105; p = 0.002). However, the percentage of patients with timely AC initiation did not differ substantially by hospital (74 vs 81%, p = 0.40). In multivariable analysis, age (OR 0.95/year, 95% CI 0.91 0.99) and laparoscopic versus open surgery (OR 5.65, 95% CI 1.92-16.62) were significant factors associated with timely AC initiation. Moreover, AC completion did not differ significantly between public (83.7%) and private (89.9%) hospital patients (p = 0.32). CONCLUSIONS: The proportions of patients with timely initiation and completion of AC were similar at a public and private hospital affiliated with a large, urban medical center. Future research should investigate how specific system-level factors help alleviate this expected difference in timely care delivery. PMID- 29250703 TI - Plasticity in deep and superficial white matter: a DTI study in world class gymnasts. AB - Brain white matter (WM) could be generally categorized into two types, deep and superficial WM. Studies combining these two types WM are important for a better understanding of brain plasticity induced by motor training. In this study, we applied both univariate and multivariate approaches to study gymnastic training induced plasticity in brain WM. Specifically, we acquired diffusion tensor imaging data from 13 world class gymnasts and 14 non-athlete normal controls, reconstructed brain deep and superficial WM tracts, estimated and compared their fractional anisotropy (FA) difference between the two groups. Taking FA values as the features, we applied logistic regression and support vector machine to distinguish the gymnasts from the controls. Compared to the controls, the gymnasts showed lower FA in four regional deep WM tracts, including the occipital lobe portion of left inferior fronto-occipital fasciculus (IFOF.L), occipital and temporal lobe portion of right inferior longitudinal fasciculus (ILF.R), insular cortex portion of right uncinate fasciculus (UF.R), and parietal lobe portion of right arcuate fasciculus (AF.R). Meanwhile, we found lower FA in the superficial U-shaped tracts within the frontal lobe in the gymnasts compared to the controls. In addition, we detected that mean FA in either the AF.R or the U-shaped tracts connecting the left pars triangularis and superior frontal gyrus was negatively correlated with years of training in the gymnasts. Classification analyses indicated FA in deep WM hold higher potential to distinguish the gymnasts from the controls. Overall, our findings provide a more complete picture of training induced plasticity in brain WM. PMID- 29250705 TI - Cognitive functioning following stabilisation from first episode mania. AB - BACKGROUND: The purpose of this study was to examine cognitive functioning in people following first-episode mania relative to a demographically similar healthy control group. METHODS: Forty-one patients, who had recently stabilised from a first manic episode, and twenty-one healthy controls, were compared in an extensive cognitive assessment. RESULTS: First-episode mania participants had significantly lower Full-Scale IQ (FSIQ) relative to healthy controls; however, this finding could be driven by premorbid differences in intellectual functioning. There were no significant differences between groups in Verbal IQ (VIQ) and Performance IQ (PIQ). First-episode mania participants performed significantly poorer than healthy controls in processing speed, verbal learning and memory, working memory, and cognitive flexibility with medium-to-large effects. There were no group differences in other measures of cognition. CONCLUSIONS: Participants following first-episode mania have poorer global intelligence than healthy controls, and have cognitive difficulties in some, but not all areas of cognitive functioning. This highlights the importance of early intervention and cognitive assessment in the early course of the disorder. PMID- 29250704 TI - Telomere chromatin establishment and its maintenance during mammalian development. AB - Telomeres are specialized structures that evolved to protect the end of linear chromosomes from the action of the cell DNA damage machinery. They are composed of tandem arrays of repeated DNA sequences with a specific heterochromatic organization. The length of telomeric repeats is dynamically regulated and can be affected by changes in the telomere chromatin structure. When telomeres are not properly controlled, the resulting chromosomal alterations can induce genomic instability and ultimately the development of human diseases, such as cancer. Therefore, proper establishment, regulation, and maintenance of the telomere chromatin structure are required for cell homeostasis. Here, we review the current knowledge on telomeric chromatin dynamics during cell division and early development in mammals, and how its proper regulation safeguards genome stability. PMID- 29250706 TI - Acid-induced experimental knee pain and hyperalgesia in healthy humans. AB - Inflammation and the related acidity in peri-articular structures may be involved in pain generation and hyperalgesia in knee osteoarthritis. This study investigated pain and associated hyperalgesia provoked by infusion of acidic saline into the infrapatellar fat pad. Twenty-eight subjects participated in two sessions in which acidic saline (AS, pH 5) or neutral saline (NS, pH 7.4) were infused into the infrapatellar fat pad for 15 min. Pain intensity, pain area, mechanical and thermal sensitivity, and maximal voluntary knee extension force were recorded. Repeated infusions were performed in 14 subjects. Infusion of AS caused significantly higher pain intensity, larger pain areas, induced hyperalgesia around the infused knee, and reduced extension force. No significant pain facilitation or spreading of hyperalgesia was found after repeated infusions as compared with single infusions. Acidic saline infused into the infrapatellar fat pad provoked pain and localized mechanical hyperalgesia. Thus, this acid induced pain model may mimic the early-stage responses to tissue injury of knee osteoarthritis. PMID- 29250707 TI - Non-invasive estimation of muscle oxygen uptake kinetics with pseudorandom binary sequence and step exercise responses. AB - PURPOSE: The aim of the study was to test for significant differences in non invasively estimated muscle oxygen uptake ([Formula: see text]) kinetics, assessed by a square-wave exercise protocol (STEP) as well as by a time series approach with pseudorandom binary sequence (PRBS) work rate (WR) changes. METHODS: Seventeen healthy and active individuals (10 women, 7 men; 23 +/- 2 years old; height 175 +/- 11 cm; body mass 73 +/- 14 kg [mean +/- SD]) completed five repetitions of WR transitions from 30 to 80 W for the STEP approach and two sequences of pseudorandom binary WR changes between 30 and 80 W for the PRBS approach. Pulmonary oxygen uptake ([Formula: see text]) was measured breath by breath. [Formula: see text] kinetics were estimated during phase II [Formula: see text] in the STEP approach and during the pseudorandom binary sequence WR changes in the PRBS approach. RESULTS: No significant differences were observed between different models of the STEP and the PRBS approach for estimation of [Formula: see text] kinetics (p > 0.05). In addition, a very high variability between the models was determined for [Formula: see text] kinetics [mean time constants (tau) difference: - 2.5 +/- 11.4 s]. A significant correlation for tau of [Formula: see text] between the STEP approach with experimentally determined phase I [Formula: see text] lengths and the PRBS approach was noticed (r = 0.536; p < 0.05). CONCLUSIONS: Both approaches (STEP and PRBS) are not significantly different for estimating the [Formula: see text] kinetics, but the very high variability impairs the predictability between the models. However, the determination of the length of phase I [Formula: see text] should be as appropriate as possible because predefined duration lengths can result in overestimations in [Formula: see text] kinetics. PMID- 29250708 TI - Identification, characterization, expression profiling, and virus-induced gene silencing of armadillo repeat-containing proteins in tomato suggest their involvement in tomato leaf curl New Delhi virus resistance. AB - Armadillo repeat family is well-characterized in several plant species for their involvement in multiple regulatory processes including growth, development, and stress response. We have previously shown a three-fold higher expression of ARM protein-encoding in tomato cultivar tolerant to tomato leaf curl New Delhi virus (ToLCNDV) compared to susceptible cultivar upon virus infection. This suggests the putative involvement of ARM proteins in defense response against virus infection; however, no comprehensive investigation has been performed to address this inference. In the present study, we have identified a total of 46 ARM-repeat proteins (SlARMs), and 41 U-box-containing proteins (SlPUBs) in tomato. These proteins and their corresponding genes were studied for their physicochemical properties, gene structure, domain architecture, chromosomal localization, phylogeny, and cis-regulatory elements in the upstream promoter region. Expression profiling of candidate genes in response to ToLCNDV infection in contrasting tomato cultivars showed significant upregulation of SlARM18 in the tolerant cultivar. Virus-induced gene silencing of SlARM18 in the tolerant tomato cultivar conferred susceptibility, which suggests the involvement of this gene in resistance mechanism. Further studies are underway to functionally characterize SlARM18 to delineate its precise role in defense mechanism. PMID- 29250709 TI - Folic acid inhibits homocysteine-induced cell apoptosis in human umbilical vein endothelial cells. AB - Homocysteine may be responsible for vascular endothelial cell injury, which occurs early in the pathology of cardiovascular disease. Homocysteine metabolism requires enzymatic interaction with vitamins such as folic acid, vitamin B12, and vitamin B6. We hypothesized that folic acid alleviated homocysteine-induced vascular injury by regulating the metabolic pathway of apoptosis. Human umbilical vein endothelial cells were incubated for 48 h with folic acid at the concentrations of 0-1000 nmol/L, in combination with either 1000 MUmol/L homocysteine or vehicle for the first 24 h. We then assessed cell viability and apoptosis by methyl thiazolyl tetrazolium assay and flow cytometry, respectively. To further investigate how folic acid influenced cell apoptosis, we also analyzed the activities of caspase-3/7 and the mRNA and protein expressions of BCL2, BAX, TP53, CASP3, and CASP8 in human umbilical vein endothelial cells. We showed that folic acid increased cell viability and decreased apoptosis in a dose-dependent manner, and that this effect was mediated by decreased caspase-3/7 activity, upregulated BCL2/BAX ratio, and downregulated TP53, CASP3, and CASP8 expressions. Thus, we conclude that folic acid inhibits cell apoptosis and ameliorates homocysteine toxicity by regulating the expression of apoptosis-related genes in human umbilical vein endothelial cells. PMID- 29250710 TI - A review of monochromatic light devices for the treatment of alopecia areata. AB - There are many laser technologies that are being tested that claim to support hair regrowth for patients with alopecia areata (AA). In this paper, we will determine whether the body of evidence supports the use of devices using monochromatic light sources to treat AA. Articles were gathered from PubMed, Embase, and the Cochrane database using these keywords: lasers, excimer laser, low-level laser therapy (LLLT), low-level light therapy, alopecia, alopecia areata, and hair loss with a category modifier of English. Ten clinical trials and seven case reports/abstracts were assessed. Eight clinical trials and two case reports demonstrated hair regrowth with the 308-nm excimer laser/light in men, women, and children. One case report demonstrated hair regrowth with the ALBA 355(r) laser. One clinical trial and two case reports demonstrated hair regrowth with LLLT. While two case reports demonstrated hair regrowth with fractional laser therapy, one clinical trial showed no improvement. The 308-nm excimer laser is a safe and effective treatment for men, women, and children with refractory AA of the scalp and beard. Larger, double-blinded clinical trials should be conducted to compare excimer laser therapy to standard treatments. More data is needed to determine the efficacy of LLLT and fractional laser therapy in the treatment of AA. PMID- 29250711 TI - Objective evaluation of the effects of intense pulsed light treatment on Asian skin by reflectance confocal microscopy analysis. AB - This study aimed to evaluate the effect of IPL treatment on Asian skin by reflectance confocal microscopy (RCM) analysis. Ten Asian female volunteers (39~54 years old, Fitzpatrick skin type III~IV) received five monthly IPL treatments. RCM skin images were evaluated, and several skin physiological parameters including thickness of stratum corneum, minimal thickness of epidermis, thickness of basal layer, density of dermal papillae, and mean diameter of papillae capillaries were measured both at baseline and 1 month after the last treatment. Transepidermal water loss (TEWL) was evaluated, as well. Thickness of stratum corneum was 4.80 +/- 1.48 MUm before IPL treatment and 5.50 +/- 1.35 MUm after treatment (p = 0.322). Both minimal thickness of epidermis and thickness of basal layer were significantly increased (p = 0.002 and 0.018, respectively) after IPL treatment. Dermal papillae density was significantly increased (p = 0.035), whereas mean capillary diameter was reduced significantly (p = 0.035). TEWL was slightly increased after treatment, while the difference was not significant on either T-zone or U-zone (p = 0.085 on T-zone and p = 0.114 on U-zone). RCM imaging is a feasible method to evaluate the effect of IPL effect on human skin. Moreover, IPL treatment serves to be highly safe in skin rejuvenation. PMID- 29250713 TI - Influence of a strictly perioperative antibiotic prophylaxis vs a prolonged postoperative prophylaxis on surgical site infections in maxillofacial surgery. AB - PURPOSE: The adequate perioperative antibiotic prophylaxis in maxillofacial surgery is still under discussion due to the wide range of hard and soft tissue procedures as well as contaminated, semi-contaminated and clean surgical sides. Perioperative antibiosis is an easy applicable tool that can be used to decrease nosocomial morbidity and mortality by reducing the rate of infections. We compared strictly perioperative antibiosis with an extended postoperative prophylactic antibiosis. MATERIALS AND METHODS: In this study, 901 consecutive patients, from a tertiary care maxillofacial surgery department were included and distributed into two groups: The first group received peri- and postoperative antibiotic prophylaxis (PP; n = 365) from the day of operation until the fifth day postoperatively. The second group was treated with single shot prophylaxis with intraoperative repetition as needed (SSP; n = 536) only. Furthermore, the patients were grouped according to their main diagnosis and surgical procedure. For comparison, general anamnestic data, cultured bacteria and resistances, number of surgical site infections and duration of hospitalization were compared. RESULTS: There were no statistically significant differences in general diseases or extent of surgery between the groups. There was no statistical difference in the surgical site infections between the groups regardless of their diagnosis. There were significant correlations between tracheotomised patients (p < 0.001) as well as patients with a higher BMI (p = 0.009) and the incidence of surgical site infections. Most common cultured bacteria were staphylococci. CONCLUSION: Based on the findings of the study, we believe that a perioperative antibiosis delivers a sufficient prophylaxis for patients undergoing maxillofacial surgery procedures. PMID- 29250714 TI - Age-Related Upregulation of Carboxyl Terminal Modulator Protein Contributes to the Decreased Brain Ischemic Tolerance in Older Rats. AB - Stroke remains one of the leading causes of death worldwide. The underlying neuropathology for stroke is ischemic brain injury. Carboxyl terminal modulator protein (CTMP), an endogenous inhibitor of the prosurvival Akt, may increase brain ischemic injury in young animals. Aging decreases brain ischemic tolerance. We hypothesize that CTMP is increased with aging and that this increase contributes to the decreased brain ischemic tolerance. To address these hypotheses, we determined the expression of CTMP and its downstream proteins in the brain of various ages of rats (Fischer 344 and Sprague-Dawley rats). The role of CTMP in ischemic brain injury was investigated by RNA interference. Here, we showed that CTMP in the brain was increased with aging in rats. The phosphorylated/activated Akt was decreased with aging. Six- and 20-month-old rats had poorer neurological outcome than did 2-month-old rats after brain ischemia. The neurological outcome of 2-month-old rats was worsened by LY294002, an Akt inhibitor. The poor neurological outcome in 6-month-old rats was improved by silencing CTMP. CTMP was increased in ischemic penumbral brain tissues. Silencing this increase activated Akt. These results suggest that CTMP increase with aging contributes to the aging-dependent decrease of brain ischemic tolerance. PMID- 29250712 TI - Photostimulation of osteogenic differentiation on silk scaffolds by plasma arc light source. AB - Low-level laser therapy (LLLT) has been used for more than 30 years to heal wounds. In recent years, LLLT or photostimulation has been indicated as an effective tool for regenerative and dental medicine by using monochromatic light. The aim of this study is to indicate the usability of plasma arc light source for bone regeneration. This is why we used polychromatic light source providing effective wavelengths in the range of 590-1500 nm for cellular response and investigated photostimulation effects on osteogenic differentiation of human mesenchymal stem cells (hMSCs) seeded on 3D silk scaffolds. Cellular responses were examined by using cell culture methods in terms of proliferation, differentiation, and morphological analyses. The results showed that photostimulation with a polychromatic light source (applied for 5 min from the 3rd day after seeding up to the 28th day in 2-day intervals with 92-mW/cm2 power from 10-cm distance to the cells) enhanced osteogenic differentiation of hMSCs according to higher alkaline phosphatase (ALP) activity, collagen and calcium content, osteogenic gene expressions, and matrix mineralization. In conclusion, we suggest that the plasma arc light source that was used here has a great potential for bone regeneration. PMID- 29250715 TI - Long-Term Regular Eccentric Exercise Decreases Neuropathic Pain-like Behavior and Improves Motor Functional Recovery in an Axonotmesis Mouse Model: the Role of Insulin-like Growth Factor-1. AB - Although training programs with regular eccentric (ECC) exercise are more commonly used for improving muscular strength and mobility, ECC exercise effects upon functional recovery of the sciatic nerve has not yet been determined. After sciatic nerve crush, different mice groups were subjected to run on the treadmill for 30 min at a speed of 6, 10, or 14 m/min with - 16 degrees slope, 5 days per week, over 8 weeks. During the training time, neuropathic pain-like behavior (mechanical and cold hyperalgesia) was assessed and functional recovery was determined with the grip strength test and the Sciatic Functional and Static indexes (SFI and SSI). After 9 weeks, triceps surae muscle weight and morphological alterations were assessed. Tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-4 (IL-4), interleukin-1Ra (IL-1Ra), insulin-like growth factor-1 (IGF-1) levels, and markers pro- and anti inflammatory and regeneration, respectively, were quantified in the muscle and sciatic nerve on day 14 post-crushing. Exercised groups presented less neuropathic pain-like behavior and better functional recovery than non-exercised groups. Biochemically, ECC exercise reduced TNF-alpha increase in the muscle. ECC exercise increased sciatic nerve IGF-1 levels in sciatic nerve crush-subjected animals. These findings provide new evidence indicating that treatment with ECC might be a potential approach for neuropathy induced by peripheral nerve injury. PMID- 29250717 TI - Correction to: No difference between manual and different power toothbrushes with and without specific instructions in young, oral healthy adults-results of a randomized clinical trial. AB - The type of used rotating-oscillating toothbrush was incorrectly assigned; correct used rotating-oscillating toothbrush is Pro1000 Precision Clean, Procter&Gamble GmbH, Schwalbach, Germany. PMID- 29250718 TI - Vertical skeletal changes after extraction and non-extraction treatment in matched class I patients identified by a discriminant analysis: cephalometric appraisal and Procrustes superimposition. AB - BACKGROUND: In the long-lasting debate of extraction versus non-extraction treatment, the impact of extractions on the skeletal vertical dimension remains rather unclear. The aim of this retrospective research study was to obtain a bias free sample of morphologically similar borderline patients treated with or without extraction of the four first premolars and to retrospectively evaluate the vertical changes that occurred. METHODS: A borderline sample of 83 patients, 41 treated with four first premolar extractions and 42 treated without, was obtained by means of discriminant analysis applied to a previously investigated parent sample of 542 class I patients. The pretreatment and posttreatment cephalometric radiographs were analyzed digitally, and seven measurements were assessed for vertical skeletal changes. Also, average tracings between the two treatment groups were evaluated using the Procrustes superimposition method. RESULTS: The variables of SN to Go-Gn and Y-axis showed adjusted intergroup differences of - 0.91 degrees and - 1.11 degrees (P = 0.04). Comparing the mean intra-group differences of all the variables simultaneously, a significant difference was found between the two treatment groups (overall P value = 0.04). In the extraction group, only the gonial angle showed a significant decrease (P = 0.01) while the overall P value evaluating the intra-group differences between pre- and posttreatment was significant (overall P value < 0.01). In the non extraction group, the variable of N-ANS/N-Me showed a significant decrease (P = 0.02) and the overall P value evaluating the intra-group differences between pre- and posttreatment was also significant (overall P value < 0.01). Differences in treatment duration were assessed using a log-normal model and showed that extraction treatment lasted significantly longer than non-extraction treatment (P < 0.01). CONCLUSIONS: The borderline group of patients identified by the discriminant analysis exhibited similar morphological characteristics at treatment's onset; therefore, the posttreatment changes could safely be attributed to the choice of extraction or non-extraction treatment and not to pre existing differences. Treatment choice had an impact on the patients' vertical skeletal dimensions. Patients treated with four first premolar extractions showed a slight decrease in the vertical skeletal measurements, whereas non-extraction patient treatment showed a slight increase. The treatment time was also significantly higher in the extraction group. PMID- 29250716 TI - Evaluation of accuracy in implant site preparation performed in single- or multi step drilling procedures. AB - OBJECTIVES: Dental implant failure and insufficient osseointegration are proven results of mechanical and thermal damage during the surgery process. We herein performed a comparative study of a less invasive single-step drilling preparation protocol and a conventional multiple drilling sequence. Accuracy of drilling holes was precisely analyzed and the influence of different levels of expertise of the handlers and additional use of drill template guidance was evaluated. MATERIAL AND METHODS: Six experimental groups, deployed in an osseous study model, were representing template-guided and freehanded drilling actions in a stepwise drilling procedure in comparison to a single-drill protocol. Each experimental condition was studied by the drilling actions of respectively three persons without surgical knowledge as well as three highly experienced oral surgeons. Drilling actions were performed and diameters were recorded with a precision measuring instrument. RESULTS: Less experienced operators were able to significantly increase the drilling accuracy using a guiding template, especially when multi-step preparations are performed. Improved accuracy without template guidance was observed when experienced operators were executing single-step versus multi-step technique. CONCLUSION: Single-step drilling protocols have shown to produce more accurate results than multi-step procedures. The outcome of any protocol can be further improved by use of guiding templates. Operator experience can be a contributing factor. CLINICAL RELEVANCE: Single-step preparations are less invasive and are promoting osseointegration. Even highly experienced surgeons are achieving higher levels of accuracy by combining this technique with template guidance. Hereby template guidance enables a reduction of hands-on time and side effects during surgery and lead to a more predictable clinical diameter. PMID- 29250719 TI - Selenium nanoparticles in poultry feed modify gut microbiota and increase abundance of Faecalibacterium prausnitzii. AB - The poultry industry aims to improve productivity while maintaining the health and welfare of flocks. Pathogen control has been achieved through biosecurity, vaccinations and the use of antibiotics. However, the emergence of antibiotic resistance, in animal and human pathogens, has prompted researchers and chicken growers alike to seek alternative approaches. The use of new and emerging approaches to combat pathogen activity including nanotechnology, in particular, silver nanoparticles (NPs), has been found to not only eradicate pathogenic bacteria but also include issues of toxicity and bioaccumulation effects. Other novel metal nanoparticles could provide this pathogen reducing property with a more tailored and biocompatible nanomaterial for the model used, something our study represents. This study investigated the benefits of nanomaterial delivery mechanisms coupled with important health constituents using selenium as a biocompatible metal to minimise toxicity properties. Selenium NPs were compared to two common forms of bulk selenium macronutrients already used in the poultry industry. An intermediate concentration of selenium nanoparticles (0.9 mg/kg) demonstrated the best performance, improving the gut health by increasing the abundance of beneficial bacteria, such as Lactobacillus and Faecalibacterium, and short-chain fatty acids (SCFAs), in particular butyric acid. SCFAs are metabolites produced by the intestinal tract and are used as an energy source for colonic cells and other important bodily functions. Selenium nanoparticles had no significant effect on live weight gain or abundance of potentially pathogenic bacteria. PMID- 29250721 TI - Annotation and characterization of Cd-responsive metal transporter genes in rapeseed (Brassica napus). AB - In higher plants, heavy metal transporters are responsible for metal uptake, translocation and homeostasis. These metals include essential metals such as zinc (Zn) or manganese (Mn) and non-essential metals like cadmium (Cd) or lead (Pb). Although a few heavy metal transporters have been well identified in model plants (e.g. Arabidopsis and rice), little is known about their functionality in rapeseed (Brassica napus). B. napus is an important oil crop ranking the third largest sources of vegetable oil over the world. Importantly, B. napus has long been considered as a desirable candidate for phytoremediation owning to its massive dry weight productivity and moderate to high Cd accumulation. In this study, 270 metal transporter genes (MTGs) from B. napus genome were identified and annotated using bioinformatics and high-throughput sequencing. Most of the MTGs (74.8%, 202/270) were validated by RNA-sequencing (RNA-seq) the seedling libraries. Based on the sequence identity, nine superfamilies including YSL, OPT, NRAMP, COPT, ZIP, CDF/MTP, HMA, MRP and PDR have been classified. RNA-sequencing profiled 202 non-redundant MTGs from B. napus seedlings, of which, 108 MTGs were differentially expressed and 62 genes were significantly induced under Cd stress. These differentially expressed genes (DEGs) are dispersed in the rapeseed genome. Some of the genes were well confirmed by qRT-PCR. Analysis of the genomic distribution of MTGs on B. napus chromosomes revealed that their evolutional expansion was probably through localized allele duplications. PMID- 29250722 TI - Micro, macro, but what about meso? The institutional context of health inequalities. PMID- 29250723 TI - Innovation in neurosurgery response to: "Ideal", the operating microscope, and the parachute. PMID- 29250724 TI - Cognitive improvement following repair of a basal encephalocele. AB - We report the case of a 55-year-old woman presenting with progressive memory impairment secondary to a transsphenoidal encephalocele involving her dominant medial temporal lobe. Her clinical deterioration was accompanied by radiological progression in the encephalocele's size and associated encephalomalacia. Through a temporal craniotomy, her encephalocele was resected and the defect closed. Baseline neuropsychological assessment indicated global cognitive impairment, but post-operatively, she reported improved memory and concentration. Standardized assessment reflected an improvement in perceptual skills and an associated improved recall of a complex figure. This is the first case report to date of a patient's memory improving following treatment of a basal encephalocele. PMID- 29250725 TI - Angelman Syndrome Due to UBE3A Gene Mutation. AB - A 12-y-old boy presented with developmental delay, autism, epilepsy, limb tremors and behavioral problems which posed a diagnostic challenge. Though his clinical profile and electroencephalogram were suggestive of Angelman syndrome, initial genetic tests were unyielding. Exome sequencing revealed a previously unreported mutation of Ubiquitin Protein Ligase E3A (UBE3A) gene, confirming the diagnosis of Angelman syndrome. The case is aimed to sensitize pediatricians about Angelman syndrome and to highlight the role of sequential investigations in establishing the diagnosis. PMID- 29250726 TI - Benign Infantile Epilepsy Mimicking Reflex Anoxic Seizures in an Infant with PRRT2 Gene Mutation. PMID- 29250728 TI - Autism: Hard to Switch from Details to the Whole. AB - It has long been proposed that individuals with autism exhibit a superior processing of details at the expense of an impaired global processing. This theory has received some empirical support, but results are mixed. In this research we have studied local and global processing in ASD and Typically Developing children, with an adaptation of the Navon task, designed to measure congruency effects between local and global stimuli and switching cost between local and global tasks. ASD children showed preserved global processing; however, compared to Typically Developing children, they exhibited more facilitation from congruent local stimuli when they performed the global task. In addition, children with ASD had more switching cost than Typically Developing children only when they switched from the local to the global task, reflecting a specific difficulty to disengage from local stimuli. Together, results suggest that ASD is characterized by a tendency to process local details, they benefit from the processing of local stimuli at the expense of increasing cost to disengage from local stimuli when global processing is needed. Thus, this work demonstrates experimentally the advantages and disadvantages of the increased local processing in children with ASD. PMID- 29250727 TI - Green synthesis of silver nanoparticles using Holarrhena antidysenterica (L.) Wall.bark extract and their larvicidal activity against dengue and filariasis vectors. AB - The present study was carried out to evaluate the larvicidal potential of methanol, hexane, acetone, chloroform, and aqueous bark extracts of Holarrhena antidysenterica (L.) Wall. and silver nanoparticles (AgNPs) synthesized using aqueous bark extract against the third instar larvae of Aedes aegypti L. and Culex quinquefasciatus Say. AgNPs were prepared by adding 10 ml of aqueous bark extract in 90 ml of 1 mM silver nitrate (AgNO3) solution. After 5 min of mixing, a change in color from yellow to dark brown occurred indicating the synthesis of AgNPs. Their further characterization was done through ultraviolet-visible spectroscopy (UV-Vis), X-ray diffraction analysis (XRD), field emission scanning electron microscope (FE-SEM), transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FT-IR). UV-Vis spectrum of synthesized AgNPs showed a maximum absorption peak at 420 nm wavelength. Crystalline nature of AgNPs was confirmed by the presence of characteristic Bragg reflection peaks in XRD pattern. TEM images have shown that most of the AgNPs were spherical in shape with an average size of 32 nm. FT-IR spectrum of AgNPs showed prominent absorbance peaks at 1012.2 (C-O) and 3439.44 cm-1 (O-H) which represent the major constituents of phenolics, terpenoids, and flavonoids compounds. LC-MS analysis of the bark extract confirmed the presence of carbonyl and hydroxyl functional groups which were directly correlated with FT-IR results. These AgNPs were assayed against different mosquito vectors, and the maximum mortality was recorded against the larvae of A. aegypti with LC50 and LC90 values being 5.53 and 12.01 ppm, respectively. For C. quinquefasciatus, LC50 and LC90 values were 9.3 and 19.24 ppm, respectively, after 72 h of exposure. Bark extracts prepared in different solvents such as methanol, chloroform, hexane, acetone, and water showed moderate larvicidal activity against A. aegypti their respective LC50 values being 71.74, 94.25, 102.25, 618.82, and 353.65 ppm and LC90 values being 217.36, 222.24, 277.82, 1056.36, and 609.37 ppm. For C. quinquefasciatus, their LC50 values were 69.43, 112.39, 73.73, 597.74, and 334.75 ppm and LC90 values of 170.58, 299.76, 227.48, 1576.98, and 861.45 ppm, respectively, after 72 h of treatment. AgNPs proved to be nontoxic against the non-target aquatic organism, Mesocyclops thermocyclopoides Harada when exposed for 24, 48, and 72 h. The results showed that bark extract-derived AgNPs have extremely high larvicidal potential compared to other organic solvents as well as aqueous bark extract alone. These AgNPs, therefore, can be used safely for the control of dengue and filarial vectors that cause severe human health hazards. PMID- 29250729 TI - Validity and reliability of the Turkish version of the Jenkins Sleep Scale in psoriatic arthritis. AB - OBJECTIVE: The aim of this study is to investigate the validity and reliability of the Turkish version of Jenkins Sleep Scale (JSS) in psoriatic arthritis (PsA). METHODS: Patients with PsA according to Classification Criteria for Psoriatic Arthritis (CASPAR) were included in the study. Data about age, sex, body mass index (BMI), disease duration (month) and joint symptom duration (month) were noted. Psoriatic Arthritis Quality of Life (PsAQoL) Scale was used to assess the quality of life, Multidimensional Assessment of Fatigue (MAF) Scale was used to evaluate fatigue, and Pittsburgh Sleep Quality Index (PSQI) was used to evaluate sleep quality. The reliability of JSS scale was determined by internal consistency (Cronbach's alpha coefficient). Face validity and construct validity (convergent and divergent validities) were evaluated. The correlation of the JSS with the PSQI, MAF scale, and PsAQoL scale was assessed for convergent validity. The correlation of the JSS with age, body mass index (BMI), duration of joint symptoms and disease duration were assessed for divergent validity. RESULTS: The mean age of 56 patients was 42.71 +/- 11.79. The Cronbach's alpha of the JSS was 0.862. The JSS had significant correlations with PSQI (rho = 0.653, P < 0.001), MAF (rho = 0.457, P < 0.001), PsAQoL (rho = 0.496, P < 0.001). There were no significant correlations between JSS and age (rho = - 0.052, P = 0.716), BMI (rho = - 0.085, P = 0.550), disease duration (rho = 0.161, P = 0.276) and duration of joint symptoms (rho = 0.107, P = 0.474). CONCLUSION: The Turkish version of JSS is a valid and reliable instrument in PsA. PMID- 29250730 TI - Nanoemulsion of Dill essential oil as a green and potent larvicide against Anopheles stephensi. AB - Indiscriminate use of industrial larvicides causes environment pollution and resistance against the larvicides in mosquitoes. Essential oils (EOs) have many biological activities such as larvicidal effects which have been proposed as new alternatives for industrial ones. Many components of EOs are volatile, thus, should be formulated to retain their activity. Components of Dill EO were identified by GC-MS analysis. Larvicidal activity (LA) of bulk Dill EO (non formulated) was evaluated against Anopheles stephensi in line with WHO guideline for lab tests. For the first time, nanoemulsions of Dill EO were prepared. Various nanoemulsions having fixed amounts of Dill EO 1.2%, comparable with lethal concentration (LC) at 90% of bulk Dill EO, were prepared having tween 20 (5-30%) with/out ethanol (5-30%). LA of two selected nanoemulsions were then evaluated and compared with that of bulk Dill EO. Five ingredients of oil, with high amounts, were identified as p-Cymenealpha (20.81%), alpha-Phellandrene (20.75%), Carvone (10.97%), Dill ether (9.88%), and cis-Sabinol (3.61%). LC of Dill EO at 50 and 90% were found as 38.8 and 65 ppm, respectively, against 3rd and 4th instar larvae of An. stephensi (Beech-Lab strain). Particle size (PS) ranges of nanoemulsions were 10.7-1880.0 nm. LA of optimum nanoemulsion (PS: 10.7 nm) was significantly better than that of bulk Dill EO. The preparation showed stability against 200 times dilution during larvicidal tests and performed significantly better than the nanoemulsion which was not stable after dilution. To obtain improved efficiency against larvae using nanoemulsions of EOs, the nanoemulsion should be resistant against dilution. Such a stable and green nanoemulsion may be used as alternative to industrial larvicides. PMID- 29250731 TI - Potential contributions of dissolved organic matter to monomethylmercury distributions in temperate reservoirs as revealed by fluorescence spectroscopy. AB - The monomethylmercury (MMHg) concentrations, water quality parameters (e.g., pH, suspended particles, total phosphorus, sulfate, and chlorophyll-a), and compositions of dissolved organic matter (DOM) were analyzed to understand how the quality of DOM is related to the MMHg distributions in the surface waters of 14 reservoirs. The excitation-emission matrix (EEM) fluorescence spectroscopy identified six fluorescence peaks, and a parallel factor analysis (PARAFAC) of EEM spectra identified three components of DOM: microbial humic-like (C1), terrestrial humic-like (C2), and protein-like DOM (C3). Using the observation data, the principal component analysis (PCA) were carried out to understand the relative importance of the fluorescence properties of DOM, representing DOM quality, on the MMHg distribution. The loading plot of PCA showed a strong positive correlation between the MMHg and protein regions of the EEM spectra and no correlation between MMHg and the terrestrial humic regions of the EEM, suggesting that autochthonous DOM production is a key factor in increasing MMHg concentration in reservoir water. The preliminary mass flux estimation, which was carried out to identify the major sources of MMHg in Okjeong reservoir, revealed that the major sources are sediment diffusion and water column methylation. Because the studied reservoirs are located remotely from a large-sized river and industrial region, most MMHg in reservoir water is likely diffused from the surface sediment or produced in the water column, and these sources tend to increase in reservoirs enriched with autochthonous DOM. It is suggested that EEM fluorescence can improve our ability to trace the major sources of MMHg in diverse reservoirs. PMID- 29250732 TI - Residue characteristics of sludge from a chemical industrial plant by microwave heating pyrolysis. AB - Sludge from biological wastewater treatment procedures was treated using microwave heating pyrolysis to reduce the environmental impact of a chemical plant. In this study, major elements, trace elements, PAHs and nitro-PAHs in raw sludge, and pyrolysis residues were investigated. The contents of major element from raw sludge were carbon 46.7 +/- 5.9%, hydrogen 5.80 +/- 0.58%, nitrogen 6.81 +/- 0.59%, and sulfur 1.34 +/- 0.27%. Trace elemental concentrations including Zn, Mn, Cr, Cd, As, and Sn were 0.410 +/- 0.050, 0.338 +/- 0.008, 0.063 +/- 0.006, 0.019 +/- 0.001, 0.004 +/- 0.001, and 0.003 +/- 0.002 mg/g, respectively. For various pyrolysis temperatures, Ca, Fe, Sr, Cr, and Sn contents remained at almost the same level as those in raw sludge. Results indicated that these elements did not easily volatilize. The content of 16 PAH species was about 4.78 MUg/g in the raw sludge and 23-65 MUg/g for pyrolysis residues associated with various temperatures. The content of ten nitro-PAHs was about 58 ng/g for the raw sludge and 141-744 ng/g for pyrolysis residues. The total nitro-PAH content was highest at 600 degrees C and then decreased when the temperature was over 600 degrees C. Total nitro-PAH content was about 247 ng/g at 800 degrees C. PMID- 29250733 TI - Effect of plants in constructed wetlands for organic carbon and nutrient removal: a review of experimental factors contributing to higher impact and suggestions for future guidelines. AB - Constructed wetland is a proven technology for water pollution removal, but process mechanisms and their respective contribution are not fully understood. The present review details the effect of plants on removal efficiency of constructed wetlands by focusing on literature that includes experiments with unplanted controls for organic carbon and nutrient (N and P) removal. The contribution of plant direct uptake is also assessed. Although it was found that several studies, mostly at laboratory or pilot scales, showed no statistical differences between planted and unplanted controls, some factors were found that help maximize the effect of plants. This study intends to contribute to a better understanding of the significance of the effect of plants in a constructed wetland, as well as to suggest a set of experimental guidelines in this field. PMID- 29250734 TI - Acquisition of Uropygial Gland Microbiome by Hoopoe Nestlings. AB - Mutualistic symbioses between animals and bacteria depend on acquisition of appropriate symbionts while avoiding exploitation by non-beneficial microbes. The mode of acquisition of symbionts would determine, not only the probability of encountering but also evolutionary outcomes of mutualistic counterparts. The microbiome inhabiting the uropygial gland of the European hoopoe (Upupa epops) includes a variety of bacterial strains, some of them providing antimicrobial benefits. Here, the mode of acquisition and stability of this microbiome is analyzed by means of Automated rRNA Intergenic Spacer Analysis and two different experiments. The first experiment impeded mothers' access to their glands, thus avoiding direct transmission of microorganisms from female to offspring secretions. The second experiment explored the stability of the microbiomes by inoculating glands with secretions from alien nests. The first experiment provoked a reduction in similarity of microbiomes of mother and nestlings. Interestingly, some bacterial strains were more often detected when females had not access to their glands, suggesting antagonistic effects among bacteria from different sources. The second experiment caused an increase in richness of the microbiome of receivers in terms of prevalence of Operational Taxonomic Units (OTUs) that reduced differences in microbiomes of donors and receivers. That occurred because OTUs that were present in donors but not in receivers incorporated to the microbiome of the latter, which provoked that cross inoculated nestlings got similar final microbiomes that included the most prevalent OTUs. The results are therefore consistent with a central role of vertical transmission in bacterial acquisition by nestling hoopoes and support the idea that the typical composition of the hoopoe gland microbiome is reached by the incorporation of some bacteria during the nestling period. This scenario suggests the existence of a coevolved core microbiome composed by a mix of specialized vertically transmitted strains and facultative symbionts able to coexist with them. The implications of this mixed mode of transmission for the evolution of the mutualism are discussed. PMID- 29250736 TI - Chronic Exposure to Water of Lake Qaroun Induced Metal-Related Testicular Damage and Endocrine Disruption in Male Fish. AB - The uncontrolled releasing of hazardous wastes into Lake Qaroun was adversely impacting the aquatic environment and its biota. Therefore, this approach was designed to investigate the impact of these discharges on the reproductive and testicular function of Oreochromis niloticus. Several biomarkers were applied on the testicular tissues as metal bioaccumulation levels, histological examination with recording the ovotestis appearance and antioxidant status after 45 days of exposure to 0, 10, 20, & 30% of Lake Qaroun water (LQW). The bioaccumulated Cu, Mn, Fe, Pb, and Cd were unequally distributed in the testes but all these metals showed a significant concentration-dependent elevation among the studied groups. The exposure to LQW significantly increased the histological alterations in the testicular tissues as vacuolar degeneration, loss of tubular organization, and degeneration of Leydig cell. Based on the frequent appearance of histopathological abnormalities and ovotestis recording, the most deformed testicular tissues were observed in the 30% LQW-exposed groups. The ovotestis severity index (OSI) was significantly raised in LQW-exposed groups compared to the control group. The activities of superoxide dismutase, catalase as well as glutathione-reduced levels were significantly (p < 0.05) decreased in testes after chronic exposure to LQW. On the other pole, the activities of glutathione peroxidase enzyme and malondialdehyde formation were sharply increased. In view of the above, the exposure to LQW induced metal-related oxidative damage to the testicular tissues and impaired the male reproductive health. This study showed strong correlations between the anthropogenic activities around Lake Qaroun and the reproductive dysfunction in fish. PMID- 29250737 TI - A prospective observational study of problematic oral cannabinoid use. AB - BACKGROUND: Despite evidence supporting the benefits of cannabinoids for symptom control across a wide range of medical conditions, concerns have been raised regarding the potential misuse and/or problematic use of cannabinoids (CBs). OBJECTIVE: The first objective of this study was to examine the incidence of problematic prescription cannabinoid use (PPCBU) over a 12-month period among patients initiating cannabinoid therapy. The second objective was to examine the factors associated with PPCBU. A total of 265 patients who were prescribed oral cannabinoid therapy as part of usual medical practice were enrolled into this prospective observational study. Patients first completed a series of baseline questionnaires assessing demographic, clinical, and substance use variables. Three measures designed to assess PPCBU were then administered at 3, 6, and 12 months after initiation of cannabinoid therapy. RESULTS: At each of the follow-up assessment time points, a significantly greater number of patients scored below (vs above) cutoff scores on the three main PPCBU outcomes (all p's < .001). At any follow-up time point, a maximum of roughly 25% of patients demonstrated PPCBU. Heightened odds of PPCBU were observed among patients with a history of psychiatric problems, tobacco smokers, and recreational cannabis users (all p's < .05). Results indicated that past-year substance abuse, assessed using the DAST 20, was the strongest predictor of PPCBU (p < .005). CONCLUSION: Findings from the present study could have implications for clinicians considering the use of cannabinoids for the management of patients with medical conditions. Although results indicated that the majority of patients included in this study did not reach cutoff scores on the three main PPCBU outcomes, our findings suggest that PPCBU should be routinely assessed and monitored over the course of cannabinoid therapy, particularly among patients with a history of psychiatric or substance use problems. PMID- 29250738 TI - Effects of muscarinic M1 and M4 acetylcholine receptor stimulation on extinction and reinstatement of cocaine seeking in male mice, independent of extinction learning. AB - RATIONALE: Stimulating muscarinic M1/M4 receptors can blunt reinforcing and other effects of cocaine. A hallmark of addiction is continued drug seeking/craving after abstinence and relapse. OBJECTIVES: We tested whether stimulating M1 and/or M4 receptors could facilitate extinction of cocaine seeking, and whether this was mediated via memory consolidation. METHODS: Experimentally naive C57BL/6J mice were allowed to acquire self-administration of intravenous cocaine (1 mg/kg/infusion) under a fixed-ratio 1 schedule of reinforcement. Then, saline was substituted for cocaine until responding extinguished to <=30% of cocaine reinforced responding. Immediately after each extinction session, mice received saline, the M1/M4 receptor-preferring agonist xanomeline, the M1 receptor selective allosteric agonist VU0357017, the M4 receptor-selective positive allosteric modulator VU0152100, or VU0357017 + VU0152100. In additional experiments, xanomeline was administered delayed after the session or in the home cage before extinction training began. In the latter group, reinstatement of responding by a 10-mg/kg cocaine injection was also tested. RESULTS: Stimulating M1 + M4 receptors significantly expedited extinction from 17.2 sessions to 8.3 using xanomeline or 7.8 using VU0357017 + VU0152100. VU0357017 alone and VU0152100 alone did not significantly modify rates of extinction (12.6 and 14.6 sessions). The effect of xanomeline was fully preserved when administered delayed after or unpaired from extinction sessions (7.5 and 6.4 sessions). Xanomeline treated mice showed no cocaine-induced reinstatement. CONCLUSIONS: These findings show that M1/M4 receptor stimulation can decrease cocaine seeking in mice. The effect lasted beyond treatment duration and was not dependent upon extinction learning. This suggests that M1/M4 receptor stimulation modulated or reversed some neurochemical effects of cocaine exposure. PMID- 29250739 TI - Prediction of Tumor-to-Plasma Ratios of Basic Compounds in Subcutaneous Xenograft Mouse Models. AB - BACKGROUND: Predicting target site drug concentrations is of key importance for rank ordering compounds before proceeding to chronic pharmacodynamic models. We propose generic tumor-specific correlation-based regression equations to predict tumor-to-plasma ratios (tumor-Kps) in slow- and fast-growing xenograft mouse models. METHODS: Disposition of 14 basic small molecules was investigated extensively in mouse plasma, tissues and tumors after a single oral dose administration. Linear correlation was assessed and compared between tumor-Kp and normal tissue-to-plasma ratio (tissue-Kps) separately for each tumor xenograft. The developed regression equations were validated by leave-one-out cross validation (LOOCV) method. RESULT: Both slow- and fast-growing tumor-Kps showed good correlation (r 2 >= 0.7) with majority of the normal tissue-Kps. Substantial difference was observed in the slopes of developed equations between two xenografts, which was in line with observed difference in tumor distribution. The linear correlations between tumor-Kp and skin- or spleen-Kp were within the acceptable statistical criteria (LOOCV) across xenografts and the class of compounds evaluated. Since > 70% of tumor-Kps from the test data sets were predicted within a factor of twofold for both slow- and fast-growing xenograft mouse models, the results validate the applicability of the developed equations across xenografts. CONCLUSION: Tumor-specific correlation-based regression equations were developed and their applicability was adequately validated across xenografts. These equations could be successfully translated to predict tumor concentrations in order to preclude experimental tumor-Kp determination. PMID- 29250741 TI - Everolimus induced mood changes in breast cancer patients: a case-control study. AB - Introduction The PI3K/Akt/mTOR pathway plays a critical role in cancer cell growth, proliferation and angiogenesis, but also in brain homeostasis and the pathophysiology of mood disorders. The impact of the mTOR inhibitor everolimus on the mood of breast cancer patients is unknown. Materials and methods Consecutive, post-menopausal metastatic breast cancer patients receiving hormone therapy +/- everolimus were prospectively followed-up using the Beck Depression Inventory (BDI) and the MADRS (Montgomery and Asberg Depression Rating Scale) questionnaires. Results Post hoc tests comparing everolimus + hormonotherapy to hormonotherapy alone demonstrated a significant effect of everolimus after 6 weeks of treatment on BDI scores (t(1,38) = -2.0716, p < 0.05), and after 3 weeks (t(1,38) = -3.9165, p < 0.001) and 6 weeks of treatment (t(1,38) = -2.0373, p < 0.05) on MADRS scores. Analysis within each treatment group showed that the effect of time since treatment initiation on BDI and MADRS scores was specifically observed in the everolimus + hormonotherapy group (F(2,34) = 11.875, p < 0.001 and F(2,34) = 7.820, p < 0.01 respectively), but not in the hormonotherapy alone group (F(2,34) = 1.671, p > 0.2 and F(2,34) = 0.830, p > 0.2 respectively). Conclusions The mTOR inhibitor everolimus induces significant mood alterations in breast cancer patients. The evaluation of psychiatric symptoms is not only mandatory in the context of phase 1, dose-finding studies of PI3K/Akt/mTOR inhibitors, but is also clinically relevant in daily practice. PMID- 29250740 TI - Blockade of Bradykinin receptors worsens the dystrophic phenotype of mdx mice: differential effects for B1 and B2 receptors. AB - The Kallikrein Kinin System (KKS) is a vasoactive peptide system with known functions in the maintenance of tissue homeostasis, renal function and blood pressure. The main effector peptide of KKS is Bradykinin (BK). This ligand has two receptors: a constitutive B2 receptor (B2R), which has been suggested to have anti-fibrotic effects in renal and cardiac models of fibrosis; and the inducible B1 receptor (B1R), whose expression is induced by damage and inflammation. Inflammation and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), therefore we hypothesized that the KKS may play a role in this disease. To evaluate this hypothesis we used the mdx mouse a model for DMD. We blocked the endogenous activity of the KKS by treating mdx mice with B2R antagonist (HOE-140) or B1R antagonist (DesArgLeu8BK (DALBK)) for four weeks. Both antagonists increased damage, fibrosis, TGF-beta and Smad-dependent signaling, CTGF/CCN-2 levels as well as the number of CD68 positive inflammatory cells. B2R blockade also reduced isolated muscle contraction force. These results indicate that the endogenous KKS has a protective role in the dystrophic muscle. The KKS may be a new target for future therapies to reduce inflammation and fibrosis in dystrophic muscle. PMID- 29250742 TI - A randomized phase 2 study of a HSP27 targeting antisense, apatorsen with prednisone versus prednisone alone, in patients with metastatic castration resistant prostate cancer. AB - Purpose Heat shock protein 27 (Hsp27) is implicated in prostate cancer progression. Apatorsen is a second generation phosphorothioate antisense inhibitor of Hsp27 expression. We evaluated apatorsen in patients with metastatic castration resistant prostate cancer (mCRPC). Experimental design Eligible patients were randomized 1:1 to receive intravenous apatorsen (3 loading doses of 600 mg within 5-9 days followed by weekly doses of 1000 mg) with oral prednisone 5 mg twice daily or prednisone alone. The primary endpoint was disease progression at 12 weeks. Crossover from prednisone alone was allowed after radiographic progression. Results 74 patients received apatorsen + prednisone (n = 36) or prednisone alone (n = 38). Twenty-five patients crossed-over to receive apatorsen + prednisone. Apatorsen treated patients received a median of 19 infusions. 50% of apatorsen + prednisone patients (95% CI: 32.9%, 67.1%) compared with 42% of prednisone patients (95% CI: 26.3%, 59.2%) did not have disease progression at week 12 (P = 0.33). A PSA decline of >=50% was observed in 47% of apatorsen + prednisone and 24% of prednisone patients (P = 0.04), with a median duration of response of 24.1 weeks (95% CI: 12.0, 52) and 14.0 weeks (95% CI: 4.0, 44.4), respectively. A PSA decline of >=50% was observed in 5 patients (20%) that received cross-over apatorsen. Infusion reactions were the most commonly reported adverse event occurring in 77% of apatorsen-treated patients. Conclusions Apatorsen + prednisone did not change the proportion of CRPC patients without disease progression at 12 weeks compared to prednisone but was associated with significant PSA declines. Further evaluation of Hsp27 targeting in prostate cancer is warranted. PMID- 29250743 TI - Early tapering of immunosuppressive agents after HLA-matched donor transplantation can improve the survival of patients with advanced acute myeloid leukemia. AB - Disease recurrence is the most important obstacle to achieve long-term survival for patients with advanced acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to reduce the relapse risk and improve the survival, the strategy of early tapering of immunosuppressive agents was prospectively evaluated. Thirty-one patients with advanced AML received early tapering of immunosuppressive drugs, while 32 patients with AML in complete remission (CR) were given the routine tapering of immunosuppressive agents after HLA-matched donor transplantation. All advanced AML patients achieved CR after allo-HSCT. At 24 months after transplantation, relapse incidences were 22% in advanced group and 16% in CR group (P = 0.553); disease-free survival (DFS) and overall survival (OS) were 57.7 and 57.8% in advanced group, while in CR group were 66.6% (P = 0.388) and 66.2% (P = 0.423); immunosuppressive agent-free DFS (IDFS) were similar between two groups (P = 0.407). Acute graft-versus-host disease (aGvHD) incidences were similar between two groups (P = 0.311). Chronic GvHD (cGvHD) incidence was much higher in advanced group than in CR group (70.4 vs 38.7%, P = 0.02), but severe cGvHD had no difference. In multivariate analysis, cGvHD was an independent prognostic factor for lower risk of relapse and better DFS and OS; early tapering of immunosuppressive agents was an independent prognostic factor for cGvHD. The study suggested that advanced AML patients could be directly treated with allo HSCT and its survival could be improved through the strategy of early tapering of immunosuppressive agents without significant adverse effects ( Clinicaltrials.org NCT03150134). PMID- 29250745 TI - Effective Treatment of Cytotoxic Agent Refractory Alpha-Fetoprotein-Producing Gastric Cancer with Ramucirumab: a Case Report and Review of the Literature. PMID- 29250744 TI - History Matters: Oviposition Resource Acceptance in an Exploiter of a Nursery Pollination Mutualism. AB - In the fig-fig wasp nursery pollination system, parasitic wasps, such as gallers and parasitoids that oviposit from the exterior into the fig syconium (globular, enclosed inflorescence) are expected to use a variety of chemical cues for successful location of their hidden hosts. Behavioral assays were performed with freshly eclosed naive galler wasps. Syconia with different oviposition histories, i.e. with or without prior oviposition, were presented to wasps in no-choice assays and the time taken to the first oviposition attempt was recorded. The wasps exhibited a preference for syconia previously exposed to conspecifics for oviposition over unexposed syconia. Additionally, syconia exposed to oviposition by heterospecific wasps were also preferred for oviposition over unexposed syconia indicating that wasps recognise and respond to interspecific cues. Wasps also aggregated for oviposition on syconia previously exposed to oviposition by conspecifics. We investigated chemical cues that wasps may employ in accepting an oviposition resource by analyzing syconial volatile profiles, chemical footprints left by wasps on syconia, and syconial surface hydrocarbons. The volatile profile of a syconium is influenced by the identity of wasps developing within and may be used to identify suitable host syconia at long range whereas close range preference seems to exploit wasp footprints that alter syconium surface hydrocarbon profiles. These cues act as indicators of the oviposition history of the syconium, thereby helping wasps in their oviposition decisions. PMID- 29250746 TI - Neutrophils in the lung: "the first responders". AB - Neutrophils, constituting the first line of defense, perform vital functions during immune surveillance. A key feature that assists in their prompt response to an inflammatory signal is rapid migration to the affected site. They are normally short-lived but can be activated to live longer under the influence of an inflammatory stimulus. They can, thereby, release their toxic granule contents that are differentially housed inside the cytoplasm. Although these events are well characterized in the peripheral circulation, we are still far from fully understanding their recruitment in lungs. Lungs are a reservoir of neutrophils under steady-state. In the event of an infection or injury, they promptly activate and recruit to the alveolar compartment as well as the airways. Lung intravital microscopy has revealed that neutrophils display novel features during steady- and activated-state highlighting key differences in the lung vasculature compared to peripheral sites. This review will discuss neutrophil biology in lung inflammation and will highlight the role of angiostatin, an anti-angiogenic molecule, as well as vitronectin, an acute phase secreted plasma protein, in lung neutrophil recruitment. PMID- 29250747 TI - Septo-hippocampal interaction. AB - The septo-hippocampal pathway adjusts CA1 network excitability to different behavioral states and is crucially involved in theta rhythmogenesis. In the medial septum, cholinergic, glutamatergic and GABAergic neurons form a highly interconnected local network. Neurons of these three classes project to glutamatergic pyramidal neurons and different subsets of GABAergic neurons in the hippocampal CA1 region. From there, GABAergic neurons project back to the medial septum and form a feedback loop between the two remote brain areas. In vivo, the firing of GABAergic medial septal neurons is theta modulated, while theta modulation is not observed in cholinergic neurons. One prominent feature of glutamatergic neurons is the correlation of their firing rates to the animals running speed. The cellular diversity, the high local interconnectivity and different activity patterns of medial septal neurons during different behaviors complicate the functional dissection of this network. New technical advances help to define specific functions of individual cell classes. In this review, we seek to highlight recent findings and elucidate functional implications of the septo hippocampal connectivity on the microcircuit scale. PMID- 29250750 TI - Improved medical image fusion based on cascaded PCA and shift invariant wavelet transforms. AB - PURPOSE: In the medical field, radiologists need more informative and high quality medical images to diagnose diseases. Image fusion plays a vital role in the field of biomedical image analysis. It aims to integrate the complementary information from multimodal images, producing a new composite image which is expected to be more informative for visual perception than any of the individual input images. The main objective of this paper is to improve the information, to preserve the edges and to enhance the quality of the fused image using cascaded principal component analysis (PCA) and shift invariant wavelet transforms. METHODS: A novel image fusion technique based on cascaded PCA and shift invariant wavelet transforms is proposed in this paper. PCA in spatial domain extracts relevant information from the large dataset based on eigenvalue decomposition, and the wavelet transform operating in the complex domain with shift invariant properties brings out more directional and phase details of the image. The significance of maximum fusion rule applied in dual-tree complex wavelet transform domain enhances the average information and morphological details. RESULTS: The input images of the human brain of two different modalities (MRI and CT) are collected from whole brain atlas data distributed by Harvard University. Both MRI and CT images are fused using cascaded PCA and shift invariant wavelet transform method. The proposed method is evaluated based on three main key factors, namely structure preservation, edge preservation, contrast preservation. The experimental results and comparison with other existing fusion methods show the superior performance of the proposed image fusion framework in terms of visual and quantitative evaluations. CONCLUSION: In this paper, a complex wavelet based image fusion has been discussed. The experimental results demonstrate that the proposed method enhances the directional features as well as fine edge details. Also, it reduces the redundant details, artifacts, distortions. PMID- 29250751 TI - Changes in Frequency Intake of Foods in Patients Undergoing Sleeve Gastrectomy and Following a Strict Dietary Control. AB - PURPOSE: Dietary intake and food preferences change after bariatric surgery, secondary to gastrointestinal symptoms and dietitian counseling. The aim of this study was to evaluate the changes in the frequency intake of different foods in patients undergoing sleeve gastrectomy and following a strict dietary control. PATIENTS AND METHODS: A prospective observational study of all the morbidly obese patients undergoing laparoscopic sleeve gastrectomy as bariatric procedure between 2007 and 2012 was performed. Dietary assessment was performed using the Alimentary Frequency Questionnaire 1991-2002, developed and validated by the Department of Epidemiology of Miguel Hernandez University (Elche, Alicante Spain). RESULTS: Ninety-three patients were included for analysis, 73 females and 20 males, with a mean preoperative BMI of 46.4 +/- 7.9 kg/m2. One year after surgery, excess weight loss was 81.1 +/- 8.3% and 5 years after surgery, 79.9 +/- 6.4%. Total weight loss at 1 year was 38.8 +/- 5.3% and at 5 years, 35.4 +/- 4.9%. Postoperatively, a reduction in the intake of dairy products, red meat, deli meat products, shellfish, fried potatoes, sweets, rice, pasta, beer, and processed foods was observed. Vegetables, fruits, and legumes intake increased after surgery. In the first postoperative year, there was a slight intolerance to red meat, fruits, vegetables and legumes, dairy products, pasta, and rice that mostly disappeared 5 years after surgery. CONCLUSION: One year after sleeve gastrectomy, calibrated with a 50-French bougie, there are not important problems in the intake of foods a priori difficult to digest. These problems mostly disappeared 5 years after surgery. The decrease intake of other unhealthy foods is mostly based on the dietary counseling. PMID- 29250752 TI - The Dynamic Relationship between Unhealthy Weight Control and Adolescent Friendships: A Social Network Approach. AB - Although adolescence marks a vulnerable stage for peer influence on health behavior, little is known about the longitudinal and dynamic relationship between adolescent friendship and weight control. The current study aims to explain these dynamic processes among a sample of 1156 American adolescents in grades 9-11 (48.6% girls, 23.4% European American, 25.2% African American) from the National Longitudinal Study of Adolescent Health. Stochastic actor-oriented models were fit to examine changes in friendship networks and unhealthy weight control across two waves. The findings support a bidirectional relationship where weight control predicts future friendship seeking and friendship seeking predicts future weight control. The findings also indicate that adolescents prefer friends with similar weight control patterns. Taken together, the results of the current study indicate that adolescent friendships play an integral role in the development of unhealthy weight control and thus can be used to identify adolescents at risk and serve as targets within preventive interventions. PMID- 29250748 TI - Age is the work of art? Impact of neutrophil and organism age on neutrophil extracellular trap formation. AB - Neutrophil extracellular traps or NETs are released by highly activated neutrophils in response to infectious agents, sterile inflammation, autoimmune stimuli and cancer. In the cells, the nuclear envelop disintegrates and decondensation of chromatin occurs that depends on peptidylarginine deiminase 4 (PAD4) and neutrophil elastase (NE). Subsequently, proteins from neutrophil granules (e.g., NE, lactoferrin and myeloperoxidase) and the nucleus (histones) bind to decondensed DNA and the whole structure is ejected from the cell. The DNA decorated with potent antimicrobials and proteases can act to contain dissemination of infection and in sterile inflammation NETs were shown to degrade cytokines and chemokines via serine proteases. On the other hand, overproduction of NETs, or their inadequate removal and prolonged presence in vasculature or tissues, can lead to bystander damage or even initiation of diseases. Considering the pros and cons of NET formation, it is of relevance if the stage of neutrophil maturation (immature, mature and senescent cells) affects the capacity to produce NETs as the cells of different age-related phenotypes dominate in given (pathological) conditions. Moreover, the immune system of neonates and elderly individuals is weaker than in adulthood. Is the same pattern followed when it comes to NETs? The overall importance of individual and neutrophil age on the capacity to release NETs is reviewed in detail and the significance of these facts is discussed. PMID- 29250753 TI - The Purification and Characterization of Lipases from Lasiodiplodia theobromae, and Their Immobilization and Use for Biodiesel Production from Coconut Oil. AB - The coconut kernel-associated fungus, Lasiodiplodia theobromae VBE1, was grown on coconut cake with added coconut oil as lipase inducer under solid-state fermentation conditions. The extracellular-produced lipases were purified and resulted in two enzymes: lipase A (68,000 Da)-purified 25.41-fold, recovery of 47.1%-and lipase B (32,000 Da)-purified 18.47-fold, recovery of 8.2%. Both lipases showed optimal activity at pH 8.0 and 35 degrees C, were activated by Ca2+, exhibited highest specificity towards coconut oil and p-nitrophenyl palmitate, and were stable in iso-octane and hexane. Ethanol supported higher lipase activity than methanol, and n-butanol inactivated both lipases. Crude lipase immobilized by entrapment within 4% (w/v) calcium alginate beads was more stable than the crude-free lipase preparation within the range pH 2.5-10.0 and 20 80 degrees C. The immobilized lipase preparation was used to catalyze the transesterification/methanolysis of coconut oil to biodiesel (fatty acyl methyl esters (FAMEs)) and was quantified by gas chromatography. The principal FAMEs were laurate (46.1%), myristate (22.3%), palmitate (9.9%), and oleate (7.2%), with minor amounts of caprylate, caprate, and stearate also present. The FAME profile was comparatively similar to NaOH-mediated transesterified biodiesel from coconut oil, but distinctly different to petroleum-derived diesel. This study concluded that Lasiodiplodia theobromae VBE1 lipases have potential for biodiesel production from coconut oil. PMID- 29250754 TI - High-Level Production of DNA-Specific Endonuclease AsEndI with Synonymous Codon and its Potential Utilization for Removing DNA Contamination. AB - Endonuclease I is a widely distributed periplasmic or extracellular enzyme. A method for the high-level production of recombinant AsEndI (endonuclease I from Aliivibrio salmonicida) in Escherichia coli with secretion expression is investigated. The coding sequence of AsEndI gene was assembled according to the E. coli codon usage bias, and AsEndI was expressed in the periplasm of E. coli TOP10 with a C-terminal 6* His-tagged fusion. The recombinant AsEndI (His-AsEndI) was purified by Ni-NTA resin with a yield of 1.29 * 107 U from 1-L LB medium. His AsEndI could be classified into Ca2+/Mg2+-dependent nucleases and showed highest nuclease activity to dsDNA at pH 8.0 and 37 degrees C. His-AsEndI is highly active in a broad range of salt concentration range up to 1.0 M with optimal NaCl concentration at 0.4 M. His-AsEndI can effectively remove DNA contamination in RNA sample or in PCR reagents to the level that cannot be detected by highly sensitive nested PCR and without adverse effects on the subsequent PCR reaction. His-AsEndI can remove DNA contamination at high salt conditions, especially for the DNA that may be shielded by DNA-binding protein at low salt conditions. PMID- 29250755 TI - Extracorporeal lung support for advanced lung failure: a new era in thoracic surgery and translational science. AB - For the patients with progressively decompensating acute or acute-on-chronic respiratory failure, the first-choice treatment remains as mechanical ventilation. Despite the consistent value of mechanical ventilation, the majority of lung specialists are aware of its limitations, in particular for the patients with advanced lung failure, and inherent drawbacks that augment disease progression. More recently, the concept of allowing the lungs to 'rest and recover' has been supported by quite a few clinical studies. The pressure and volume of gas delivered to the lungs are reduced compared with mechanical ventilation. Based on recent remarkable evidence and experiences using extracorporeal lung support (ECLS) before, during and after lung transplant, there is growing interest in and expectations for the use of ECLS beyond lung transplant to encompass the entire field of pulmonary medicine. The purpose of this review article is to provide an update on evolving ECLS technologies and their effectiveness and discuss the future of ECLS for advanced lung failure as a new subspecialty in cardiothoracic surgery. PMID- 29250756 TI - Sporadic Nocturnal Frontal Lobe Epilepsy--Report on Two Cases and Review of the First Taiwanese Series of 10 Cases. AB - PURPOSE: To report two additional cases of sporadic (i.e. non-familial) Nocturnal Frontal Lobe Epilepsy (NFLE) and integrate these two cases within the first series of 10 cases of sporadic NFLE reported in Taiwanese patients, and compare the findings with familial NFLE and with findings from Caucasian NFLE patients. METHODS: Clinical interviews, neurological examinations, EEG, brain MRI, and overnight videopolysomnographic (vPSG) monitoring with EEG seizure montage, and treatment outcome. RESULTS: The two additional patients were 12 and 29 year old females manifesting their sporadic NFLE with paroxysmal arousals (PAs) and nocturnal paroxysmal dystonia (NPD), respectively, and also hypermotor seizure behavior in one of these patients. In the series of 10 Taiwanese cases, 3 were classified with PAs, and 7 with NPD. No patient had combined PA/NPD seizure types. Furthermore, 4 cases also demonstrated hypermotor seizure behavior. Gender ratio was four males to six females. Mean age of NFLE onset was 9.6 yrs (range, 1 23), mean age at initial presentation was 16.1 yrs (range,2-41), and mean age at latest follow-up was 23.1 yrs (range 11-45). Premorbid history was negative for any neurologic, medical or psychiatric disorder. MRI brain scan abnormalities with clinical correlates were found in two patient. During vPSG studies, four of ten patients with NFLE seizure events had concurrent epileptiform EEG activity, and two patients had interictal epileptiform EEG activity during their vPSG studies. No case had a spontaneous remission. Anticonvulsant therapy was highly effective in all ten cases (>75% reduction in seizure frequency). CONCLUSION: The two newly reported cases that were integrated into the first series of 10 Taiwanese patients with sporadic NFLE corresponds closely to previously reported sporadic and familial NFLE among Caucasian patients in Europe and North America. There was a high rate of sustained anticonvulsant treatment efficacy, particularly with carbamazepine, oxcarbamazepine, and topiramate. Also, 4 of the 10 patients had hypermotor manifestations (in part) of their NFLE (including one of the two newly reported cases), which are discussed in regards to the newly published entity of "Sleep-Related Hypermotor Epilepsy(1)." PMID- 29250757 TI - Acute Onset of Parkinsonism an End-Stage Renal Disease Patient. AB - PURPOSE: The osmotic demyelination syndrome (ODS) has been identified as a neurological complication of the rapid correction of hyponatremia. In recent years, however, various medical conditions have been associated with the development of ODS, irrelevant to changes in serum sodium. We present a rare case of a eunatremic patient who developed ODS with manifestation of parkinsonism. CASE: A 55 years old woman who has hypertension, type 2 diabetes nephropathy in end-stage renal disease under maintenance hemodialysis came to us with complaint about newly developed resting tremor of bilateral upper limbs, slowness of movements and small shuffling steps. Brain magnetic resonance imaging (MRI) showed bilateral lentiform nuclei demyelination. ODS was diagnosed concerning the comorbidities and her medical history. Her neurological deficits improved dramatically after treatment of Ropinirole. CONCLUSION: ODS may develop in patient with risk factors regardless of change in serum sodium concentration. Brain MRI could help in early detection of the demyelination. Secondary parkinsonism may occur as a rare manifestation of ODS. Supportive treatment, monitoring of vital signs and neurological deficits are warranted. Dopaminergic agent may be beneficial in symptomatic control. PMID- 29250758 TI - Refractory Facial Paralysis: A Case Report. AB - PURPOSE: To present a case of salivary gland malignancy initially mimicking Bell's palsy. CASE REPORT: A 75-year-old woman with hypertension visited our neurological outpatient department,complaining of persistent right facial paralysis for more than a year after oral glucocorticoid therapy with recent development of vertigo and unsteady gait. She was previously diagnosed as having Bell's palsy and was prescribed oral glucocorticoid. However, her right facial muscles were still completely paralyzed, with no signs of improvement. The patient visited the outpatient department of neurology for 3 weeks, seeking treatment for the recent onset of vertigo and ataxia. Brain contrast magnetic resonance imaging (MRI) revealed the right mastoid air cells to be filled with high T2 signal intensity and low T1 signal, with destruction of the bony structure of mastoid, extending to the right jugular bulb. Results obtained from excisional biopsy and pathological analyses were used to diagnose the patient with adenoid cystic carcinoma of the salivary gland. The patient then received a thorough cancer workup and chemoradiotherapy, with the malignancy being under control. However, after a 1-year follow-up, the patient still had permanent right facial palsy. CONCLUSION: Salivary gland malignancy should be considered in patients with acute and subacute facial nerve paralysis, in addition to Bell's palsy. Brain imaging with contrast agents should be performed for differential diagnosis. PMID- 29250759 TI - Orbital Cellulitis Presenting as Giant Cell Arteritis: A Case Report. AB - PURPOSE: To present a case of orbital cellulitis initially mimicking giant cell arteritis. CASE REPORT: An 80-year-old man with a history of hypertension and type 2 diabetes mellitus was referred with a prominent progressive headache over the right temporal and periorbital areas. Non-contrast brain CT results were normal, but ESR was elevated. Giant cell arteritis was suspected initially. However, the symptoms progressed under oral corticosteroid therapy. The subsequent brain MRI with contrast revealed extensive contrast enhancement along the right optic nerve and optic canal with a rim-enhancing lesion in the posterior aspect of the optic nerve. Treatment included intravenous antibiotics and surgical drainage. Culture of the drainage revealed growth of Pseudomonas aeruginosa. CONCLUSION: Orbital cellulitis should be considered in patients with progressive headache over the unilateral temporal and periorbital areas, in addition to giant cell arteritis. Brain imaging with contrast should be performed for detecting occult orbital infection or other intracranial etiologies. PMID- 29250760 TI - Rapid Progression of Vertebral Artery Occlusion After Radiotherapy for Nasopharyngeal Carcinoma. PMID- 29250761 TI - Medical Treatment Guidelines for Acute Migraine Attacks. AB - In 2015, the American Headache Society (AHS) amended the treatment guideline of acute migraine based on evidence-based medicine (EBM) that all triptans in any form of preparations, acetaminophen, and non-steroid anti-inflammation drugs NSAID (aspirin, diclofenac, ibuprofen, naproxen), sumatriptan/naproxen, combined acetaminophen/aspirin/caffeine are considered effective (Level A). Previously effective drugs as prochlorperazine, and dihydroergotamine-DHE (excluded inhaled form) were downrated to probable effective (Level B). Taiwan Headache Society published its treatment guideline for acute migraine attack in 2007. It should be updated based on the new available evidence. The Treatment Guideline Subcommittee of Taiwan Headache Society reviewed the recent trials, evaluated the grade of evidence, and appraised the clinical efficacy to reach a new consensus. We also referred to the guidelines from United States, Europe, Canada and other countries to make this one meets our needs and feasible. Acute medications currently available in Taiwan can be categorized into "migraine-specific"and"migraine nonspecific" groups. Migraine-specific triptans and migraine-nonspecific nonsteroidal antiinflammatory drugs (NSAIDs) have the best levels of evidence, and are recommended as the first-line medications for acute migraine attacks. The administration should follow the concept of "stratified care". For mild to moderate migraine attacks, oral NSAIDs are the first choice; with oral aspirin, combination analgesics, intravenous/intramuscular NSAIDs as alternatives. For moderate to severe attacks, oral or nasal spray triptans and ergotamine/caffeine compounds are recommended and should be administered in the early stage of migraine attacks. Antiemetics can be used as supplement to alleviate nausea and vomiting. Notably, a combination of a triptan and a NSAID yielded a better efficacy compared with either therapy alone. Parenteral steroid and fluid supply are the first choice in treatment of status migrainosus. Acetaminophen is suitable for mild to moderate migraine attacks and remains the first choice for children and pregnant women. Opiates are not recommended for acute migraine treatment at the present time because of serious adverse events. To prevent medication-overuse headache, the use of acute treatment should be limited to a maximum of ten days a month. PMID- 29250762 TI - Evaluation the result of warm normal saline irrigation in ureteral endoscopic surgeries. AB - PURPOSE: Transurethral lithotripsy (TUL) is a major modality for the endoscopic management of ureteral stones. Ureteral spasm makes access for ureters difficult, which causes impaction of the ureteroscope, ureteral dislodge, and a low success rate of endoscopic surgeries. This study described the outcomes of a new endoscopic surgical experience by use of 40-degree warm saline irrigation during TUL compaired with routine ambient air irrigation in TUL. MATERIALS AND METHODS: In this randomized clinical trial from 2014 to 2015, 150 patients with ureteral stone with balanced randomization were divided into two parallel groups. Patients underwent TUL in the first group with 20-25 degree saline irrigation and in the second group with 40-degree saline irrigation. One surgical team with the same semi-rigid instrument performed all TULs and the other steps were similar in both groups. Complete stone fragmentation was measured as the primary outcome and the duration of procedure, retrograde stone migration and all and any intraoperative complications were the secondary measurements. RESULT: While comparing warm saline irrigation with cold saline irrigation, the rate of access to upper ureter was 95% versus 72%, stone retropulsion frequency was 10.7% versus 30.7% and the stone-free rate was 96% versus 76% respectively (P < .05). There was no ureteroscope impaction and ureteral dislodge in both groups. CONCLUSION: Using warm saline irrigation in endoscopic surgeries results in better surgical outcomes including a lower ureteral spasm rate, greater ureteral muscle relaxation and better access to the upper ureteral zone, and a lower rate of complications, such as ureteroscope impaction, ureteral dislodge and stone retropulsion. PMID- 29250763 TI - Transplantation of Spermatogonial Stem Cells Suspension into Rete Testis of Azoospermia Mouse Model. AB - PURPOSE: The loss of spermatogonia following chemo-or radiotherapy leading to temporary or permanent infertility of the patient is a well known and unwanted side effect of many oncological therapies. MATERIALS AND METHODS: In this study, germ cells were isolated from 4 days old mouse testis cells. Busulfan treatment was used to the eliminate proliferating cells in the testis of recipient mice. The donor cells suspended in DMEM, were introduced into the rete testis of recipient mice via microinjection method. To distinguish the progeny of the transplanted donor stem cells from endogenous germ cells, BrdU-labeled cells were used. In addition, real time PCR was performed to determine expression levels of ngn3 and LIN28 (spermatogonia stem cells markers)before and after transplantation. Western blot analysis was further performed to detect an increase in - ngn3 expression after transplantation. RESULTS: Transplantations of stem cells into rete testis of the recipients was done. Our results clearly showed a significant increase in spermatozoa number in epididymal luman Spermatogonial stem cells (SSCs) did not show alkaline phosphatase activities while ngn3 and LIN28 were clearly expressed. Ngn3 and LIN28 expression were reduced after busulfan treatment compared to untreatmented mice. However, the expression of ngn3 and LIN28 increased after transplantation . BrdU-labeled testis cells were successfully transplanted into rete testis of recipient mice. These cells remained in rete testis of all recipient mice up to two months after transplantation. CONCLUSION: The present study clearly confirme that a regeneration after cytotoxic treatment was based on morphological criteria. We demonstrated the increase in stem cell numbers during regeneration and after transplantation. Transplantation of spermatogonial stem cells suspension by the injection of cells via the rete testis of recipient azoospermia model considerably enhances the efficiency of this procedure. PMID- 29250764 TI - The Effect of Tunica Albuginea Incision on Testicular Tissue After Detorsion in the Experimental Model of Testicular Torsion. AB - PURPOSE: Testis torsion is a surgical emergency, and sometimes we cannot sufficiently prevent injury even surgical detorsion of the testis is performed in the appropriate time period due to some reasons such as tissue edema. In this experimental study, we investigated the effect of tunica albuginea incision (TAI) on testicular torsion-detorsion model (TDM). MATERIALS AND METHODS: Twenty four male rats were used. The rats were randomly divided into three groups. In Group I, testicular torsion (TT) of 720 degrees was created. After 4 hours of torsion period, the testis was detorsioned. Then three longitudinal incisions were made on tunica albuginea of the testis. In Group II, torsion and detorsion was created by the same way as in Group I, but TAI was not added to the procedure. Group III was Sham group. At the end of the first week, rats in the experimental groups were sacrificed and the testes were harvested for histological, immunohistological examinations and for the assessment of apoptotic activity. RESULTS: In Group I, the procedures led to partial improvement in color of the testes. Modified Johnsen Scores in Groups I, II and III were detected as 7.8, 4.3 and 9.6 respectively (P = .001). In Group I, immunoreactivity of anti-APAF-1 was moderate in 7 rats, and strong in 1 rat. Immunoreactivity of anti-cytochrome C and anti-caspase3 were moderate in 6 rats, and strong in 2 rats. Immunoreactivity of anti-caspase 8 and 9 were moderate in 5 rats, and strong in 3 rats. The differences of immunoreactivity between the groups were statistically significant. TUNEL percentages were detected as 40, 62% in Group I, 60% in Group II and 11,75% in Group III respectively (P = .001). CONCLUSION: As a result, multiple incisions made on tunica albuginea after detorsion in the TDM in rats, decrease the amount of ischemia- reperfusion injury. This effect might be related with the decrease in testicular edema and free oxygen radicals together with increase in tissue perfusion. Moreover, the decreased apoptotic activity seems to play a role in the decrease in inflammatory response and preservation of tissue parenchyma consequently. PMID- 29250765 TI - A Simple, Non - Biological Model for Percutaneous Renal Access Training. AB - PURPOSE: Percutaneous renal puncture (PRP) is one of the most important and critical step of urology, especially while performing percutaneous nephrostomy and percutaneous nephrolithotomy (PCNL). In the learning period of this procedures, there is a need for validated, effective, economical models for such training. This study describes a simple non - biological model for learning PRP. The aim was to determine the effectivity of this model as a training and assessment tool, and to assess its cost relative to other models. MATERIALS AND METHODS: We designed a training box, made of foam and rubber with two open sides and performed radiopaque pelvicalyceal system maquettes to insert inside it. Experts in PCNL (i.e., > 100 cases) andnovices (i.e., pediatric surgeons and urologists without PCNL experience) performed percutaneous renal puncture. Novices performed a pre -test and a post - test (i.e., after 2 hour training). Data recorded were total procedure time, X - ray exposure time, and number of puncture attempts. Experts who performed PRP successfully were asked torate the model using a questionnaire. RESULTS: Five experts and 21 novices completed the study. Four experts rated the model as an "excellent" (score 5) training and assessment tool; one expert rated these as "very good" (score 4). Comparisons of novices' pre - and post - test median results revealed significant skill acquisition with shorter procedure time, less X - ray exposure, and fewer attempts for successful puncture (all P < .001). CONCLUSION: This new non - biological training model is an effective training tool that helps learners improve skills in PRP. The model is simple to construct, economical, and highly re-useable compared to others. It provides good visibility and imaging, is portable, and could be used widely in training centres. PMID- 29250766 TI - Expression of miRNA-146a, miRNA-155, IL-2, and TNF-alpha in inflammatory response to Helicobacter pylori infection associated with cancer progression. AB - miRNAs appear to play an important role in controlling the expression of several genes, and they are a potential biomarker and prognostic tool in gastric diseases. We analyzed 53 controls, 86 patients with gastritis, and 19 patients with gastric cancer. Real-time-PCR was used to determine the expression levels of miRNA-146a, miRNA-155, IL-2, and TNF-alpha. The subsequent analysis of the target genes was performed using the bioinformatics approach. There was no difference in IL-2 expression between the groups. However, there was a significant increase in TNF-alpha expression in the gastritis group relative to the control and a significant decrease in the gastric cancer group relative to the control. There was also a statistically significant increase in miRNA-146a and miRNA-155 expression in the gastritis group relative to the control, but not in the gastric cancer group. Similar results were found when the presence of H. pylori was considered. The data revealed an increase in miRNA-146a and miRNA-155 expression but not enough to control the expression of TNF-alpha. The presence of H. pylori was found to affect increases in TNF-alpha and microRNA expression, and miRNA 146a and miRNA-155 alone were not able to eliminate bacteria or restore tissue homeostasis. PMID- 29250767 TI - Fast permutation tests and related methods, for association between rare variants and binary outcomes. AB - In large-scale genetic studies, a primary aim is to test for an association between genetic variants and a disease outcome. The variants of interest are often rare and appear with low frequency among subjects. In this situation, statistical tests based on standard asymptotic results do not adequately control the type I error rate, especially if the case : control ratio is unbalanced. In this article, we propose the use of permutation and approximate unconditional tests for testing association with rare variants. We use novel analytical calculations to efficiently approximate the true type I error rate under common study designs, and in numerical studies show that the proposed classes of tests significantly improve upon standard testing methods. We also illustrate our methods in data from a recent case-control study for genetic causes of a severe side effect of a common drug treatment. PMID- 29250768 TI - Critical involvement of atypical chemokine receptor CXCR7 in allergic airway inflammation. AB - Trafficking and recruitment of immune cells to the site of inflammation with spatial and temporal synchronization is crucial for the development of allergic airway inflammation. Particularly, chemokines are known to be key players in these processes. Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signalling or modulated CXCR4-mediated signalling. In the present study, we detected the expression of CXCR7 in airway epithelial cells. Use of a lentiviral delivery system to knock down the expression of CXCR7 in the lung of sensitized mice abrogated the cardinal features of asthma, indicating that CXCR7 plays a role in regulating allergic airway inflammation. The activation of mitogen-activated protein kinase and Akt signalling in response to CXCL12 in the mouse epithelial cell line MLE-12 was reduced when CXCR7 expression was knocked down. However, either knockdown or overexpression of CXCR7 in MLE-12 did not affect CXCL12-mediated calcium influx, indicating that CXCR7 does not modulate CXCR4-mediated signalling, and that it functions as a signalling receptor rather than a decoy receptor. Finally, we found that the expression of chemokine CCL2 is regulated by CXCR7/CXCL12-mediated signalling through beta arrestin in airway epithelial cells. Hence, regulating the expression of CCL2 in airway epithelial cells may be one mechanism by which CXCR7 participates in regulating allergic airway inflammation. PMID- 29250769 TI - A prospective investigation of perceived stress, infertility-related stress, and cortisol levels in women undergoing in vitro fertilization: influence on embryo quality and clinical pregnancy rate. AB - INTRODUCTION: Women undergoing fertility treatment experience high levels of stress. However, it remains uncertain if and how stress influences in vitro fertilization (IVF) cycle outcome. This study aimed to investigate whether self reported perceived and infertility-related stress and cortisol levels were associated with IVF cycle outcomes. MATERIAL AND METHODS: A prospective cohort of 485 women receiving fertility treatment was recruited from September 2011 to December 2013 and followed until December 2014. Data were collected by online questionnaire prior to IVF start and from clinical charts. Salivary cortisol levels were measured. Associations between stress and cycle outcomes (clinical pregnancy and indicators of oocyte and embryo quality) were measured by logistic or linear regression, adjusted for age, body mass index, education, smoking, alcohol and caffeine consumption, shiftwork and night work. RESULTS: Ultrasound verified pregnancy rate was 26.6% overall per cycle started and 32.9% per embryo transfer. Stress measures were not associated with clinical pregnancy: when compared with the lowest categories, the adjusted odds ratio (OR) and 95% confidence interval (CI) for the highest categories of the perceived stress score was 1.04 (95% CI 0.58-1.87), infertility-related stress score was OR = 1.18 (95% CI 0.56-2.47), morning and evening cortisol was OR = 1.18 (95% CI 0.60-2.29) and OR = 0.66 (95% CI 0.34-1.30), respectively. CONCLUSIONS: Perceived stress, infertility-related stress, and cortisol levels were not associated with IVF cycle outcomes. These findings are potentially reassuring to women undergoing fertility treatment with concerns about the influence of stress on their treatment outcome. PMID- 29250771 TI - The synergistic effect of prosociality and physical attractiveness on mate desirability. AB - Mate selection requires a prioritization and joint evaluation of different traits present or absent in potential mates. Herein, we focus on two such traits - physical attractiveness and prosociality - and examine how they jointly shape impressions of overall desirability. We report on two related experiments which make use of an innovative methodology combining large samples of raters and target persons (i.e., stimuli) and information on targets' behaviour in economic games representing altruistic behaviour (Experiment 1) and trustworthiness (Experiment 2), two important facets of prosociality. In accordance with predictions derived from a cognitive perspective on mate choice and sexual strategies theory, the results show that the impact of being prosocial on an individual's overall desirability was increased further by them also being physically attractive, but only in long-term mating contexts. Furthermore, we show that men's mate preferences for certain prosocial traits (i.e., trustworthiness) were more context-dependent than women's due to differential evolutionary pressures for ancestral men and women. PMID- 29250770 TI - Racial Disparities in Hospice Outcomes: A Race or Hospice-Level Effect? AB - OBJECTIVES: To determine whether there is racial variation in hospice enrollees in rates of hospitalization and hospice disenrollment and, if so, whether systematic differences in hospice provider patterns explain the variation. DESIGN: Longitudinal cohort study. SETTING: Hospice. PARTICIPANTS: Medicare beneficiaries (N = 145,038) enrolled in a national random sample of hospices (N = 577) from the National Hospice Survey and followed until death (2009-10). MEASUREMENTS: We used Medicare claims data to identify hospital admissions, emergency department (ED) visits, and hospice disenrollment after hospice enrollment. We used a series of hierarchical models including hospice-level random effects to compare outcomes of blacks and whites. RESULTS: In unadjusted models, black hospice enrollees were significantly more likely than white enrollees to be admitted to the hospital (14.9% vs 8.7%, odds ratio (OR) = 1.84, 95% confidence interval (CI) = 1.74-1.95), visit the ED (19.8% vs 13.5%, OR = 1.58, 95% CI = 1.50-1.66), and disenroll from hospice (18.1% vs 13.0%, OR = 1.48, 95% CI = 1.40-1.56). These results were largely unchanged after accounting for participant clinical and demographic covariates and hospice-level random effects. In adjusted models, blacks were at higher risk of hospital admission (OR = 1.75, 95% CI = 1.64-1.86), ED visits (OR = 1.61, 95% CI = 1.52-1.70), and hospice disenrollment (OR = 1.54, 95% CI = 1.45-1.63). CONCLUSION: Racial differences in intensity of care at the end of life are not attributable to hospice-level variation in intensity of care. Differences in patterns of care between black and white hospice enrollees persist within the same hospice. PMID- 29250772 TI - Adjunctive perampanel in partial-onset seizures: Asia-Pacific, randomized phase III study. AB - OBJECTIVES: To evaluate the efficacy, safety, and tolerability of perampanel, a selective, non-competitive, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as an adjunctive treatment for patients with refractory partial-onset seizures (POS) from Asia-Pacific. MATERIALS & METHODS: This multicenter, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT01618695) involved patients aged >=12 years with refractory POS (receiving 1-3 antiepileptic drugs). Patients were randomized (1:1:1:1) to receive once-daily placebo or perampanel 4, 8, or 12 mg over a 6 week titration and 13-week maintenance double-blind period. Enzyme-inducing antiepileptic drugs were equally stratified between groups. The primary efficacy endpoint was percent change in POS frequency per 28 days (double-blind phase vs baseline). Other efficacy endpoints included >=50% responder rate and seizure freedom. Treatment-emergent adverse events (TEAEs) were also monitored. RESULTS: Of 710 randomized patients, seizure frequency data were available for 704 patients. Median percent changes in POS frequency per 28 days indicated dose proportional reductions in seizure frequency: -10.8% with placebo and -17.3% (P = .2330), -29.0% (P = .0003), and -38.0% (P < .0001) with perampanel 4, 8, and 12 mg, respectively. In total, 108 (15.3%) patients discontinued treatment; 44 (6.2%) due to TEAEs. TEAEs occurring in >=5% of patients, and reported at least twice as frequently with perampanel vs placebo, included dizziness and irritability. CONCLUSIONS: Adjunctive perampanel (8 and 12 mg/d) significantly improved seizure control in patients with refractory POS. Safety and tolerability were acceptable at daily doses of perampanel 4-12 mg. PMID- 29250773 TI - Physiological and pathological relevance of cell competition in fly to mammals. AB - In multicellular organisms, incidentally emerging suboptimal cells are removed to maintain homeostasis of tissues. The unfavorable cells are excluded by a process termed cell competition whereby the resident normal cells actively eliminate the unfit cells of the identical lineage. Although the phenomenon of cell competition was originally discovered in Drosophila, a number of recent studies have provided implications of cell competition in tissue regeneration, development and oncogenesis in mammals. Here the roles of cell competition in fly to mammals are discussed. PMID- 29250774 TI - Facial first impressions and partner preference models: Comparable or distinct underlying structures? AB - Given the frequency of relationships nowadays initiated online, where impressions from face photographs may influence relationship initiation, it is important to understand how facial first impressions might be used in such contexts. We therefore examined the applicability of a leading model of verbally expressed partner preferences to impressions derived from real face images and investigated how the factor structure of first impressions based on potential partner preference-related traits might relate to a more general model of facial first impressions. Participants rated 1,000 everyday face photographs on 12 traits selected to represent (Fletcher, et al. 1999, Journal of Personality and Social Psychology, 76, 72) verbal model of partner preferences. Facial trait judgements showed an underlying structure that largely paralleled the tripartite structure of Fletcher et al.'s verbal preference model, regardless of either face gender or participant gender. Furthermore, there was close correspondence between the verbal partner preference model and a more general tripartite model of facial first impressions derived from a different literature (Sutherland et al., 2013, Cognition, 127, 105), suggesting an underlying correspondence between verbal conceptual models of romantic preferences and more general models of facial first impressions. PMID- 29250775 TI - Most impactful factors on the health-related quality of life of a geriatric population with cancer. AB - BACKGROUND: As the population of older adults with cancer continues to grow, the most important factors contributing to their health-related quality of life (HRQOL) remain unclear. METHODS: A total of 1457 older adults (aged >=65 years) with cancer participated in a telephone survey. Outcomes were measured using the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores of the 12-Item Short Form Survey (SF-12) from the Medical Outcomes Study (version 2). Statistical techniques used to identify factors in 4 domains (physical, psychological, social, and spiritual) most strongly associated with HRQOL included linear models, recursive partitioning, and random forests. Models were developed in a training data set (920 respondents) and performance was assessed in a validation data set (537 respondents). RESULTS: Respondents were a median of 19 months from diagnosis, and 28.1% were receiving active treatment. The most relevant factors found to be associated with PCS were symptom severity, comorbidity scores, leisure-time physical activity, and having physical support needs. The most relevant factors for MCS were having emotional support needs, symptom severity score, and the number of financial hardship events. Results were consistent across modeling techniques. Symptoms found to be strongly associated with PCS included fatigue (adjusted proportion of summary score's variance [R2 ] = 0.34), pain (adjusted R2 = 0.32), disturbed sleep (adjusted R2 = 0.16), and drowsiness (adjusted R2 = 0.16). Symptoms found to be strongly associated with MCS included fatigue (adjusted R2 = 0.23), problems remembering things (adjusted R2 = 0.17), disturbed sleep (adjusted R2 = 0.16), and lack of appetite (adjusted R2 = 0.16). CONCLUSIONS: The findings of the current study support the importance of addressing persistent symptoms, managing comorbidities, promoting leisure-time physical activity, and addressing financial challenges. A long-term comprehensive approach is needed to ensure the well-being of older adults with cancer. Cancer 2018;124:596-605. (c) 2017 American Cancer Society. PMID- 29250776 TI - The alternatively spliced exon of COL5A1 is mutated in autosomal recessive classical Ehlers-Danlos syndrome. PMID- 29250777 TI - An effective HPLC-based approach for the evaluation of the content of total phenolic compounds transferred from olives to virgin olive oil during the olive milling process. AB - BACKGROUND: Several studies demonstrate a strong interest in learning more about phenolic transfer during oil extraction, with the main goal of increasing the phenolic concentration in olive oils. We aimed to propose and apply a new methodological approach for evaluating phenolic transfer from olives into oil during milling, based on the quantification of phenolic content in whole lyophilized fruits and the corresponding oils and considering the oil extraction yields. RESULTS: We investigated the phenols transferred into the oil during olive milling in continuous extraction systems in Tuscany. In 2012, oils were extracted from cultivar Frantoio by a two-phase extraction system; in 2016, oils were extracted from cultivars Leccio del Corno and Arbequina by a three-phase extraction system. Results highlighted very low percentages of extracted phenols: up to 0.40% by the two-phase system and up to 0.19% by the three-phase system (0.08% for cultivar Arbequina and 0.19% for cultivar Leccio del Corno). CONCLUSION: The usefulness of a simple and effective methodological approach for evaluating the extracted phenols was highlighted. Values of extracted phenols were up to 25 times lower than previous literature data. The proposed approach is applicable in all types of milling processes. (c) 2017 Society of Chemical Industry. PMID- 29250778 TI - News & ISN December 2017. AB - The 2016 Mark Smith Award winner is Sunmin Jung (Seoul National University), for the pa per Dual-specificity phosphatase 26 (DUSP26) stimulates Abeta42 generation by promoting amyloid precursor protein axonal transport during hypoxia. Journal of Neurochemistry (2016) 137(5): 770-781, Sunmin Jung, Jihoon Nah, Jonghee Han, Seon-Guk Choi, Hyunjoo Kim, Jaesang Park, Ha-Kyung Pyo, Yong-Keun Jung. https://doi.org/10.1111/jnc.13597. PMID- 29250779 TI - Risk factors for HPV persistence and cytology anomalies at follow-up after treatment for cervical dysplasia. AB - OBJECTIVE: To evaluate predictor factors of persistent cytologic dysplasia and/or high-risk human papillomavirus (hrHPV) infection at 6-month follow-up and at 3-5 years during routine cervical smear testing. METHODS: The present retrospective study included data from women treated for cervical dysplasia by large loop excision of the transformation zone (LLETZ) at Ipswich Hospital, UK, between January 1 and December 31, 2012. Age, parity, smoking, status of resection margins, and previous LLETZ treatment were evaluated by multivariate analyses. RESULTS: There were 192 patients included in the study. There was no association between age (relative risk [RR] 1.0, 95% confidence interval [CI] 0.80-1.23; P>0.99), smoking (RR 1.12, 95% CI 0.79-1.59; P=0.516), or parity (RR 1.10, 95% CI 0.88-1.38; P=0.382) and abnormal cytology and/or persistent hrHPV infection at 6 months. There was an association between positive margins (RR 1.64, 95% CI 1.20 2.24; P=0.003), previous LLETZ (RR 3.48, 95% CI 1.69-7.15; P<0.001), and dyskaryosis and/or hrHPV infection at 6 months. Only previous LLETZ treatment remained associated with abnormal cytology and persistent hrHPV infection at 3-5 years (RR 6.37, 95% CI 3.56-11.3; P<0.001). CONCLUSION: Clinical factors, including age, smoking, treatment history, and status of surgical margins, could help to determine the risk of dysplasia recurrence and facilitate patient follow up based on risk stratification. PMID- 29250780 TI - An analysis on the fate of a selection of blood products derived from cytomegalovirus-seronegative donors at three tertiary referral hospitals in Australia. AB - BACKGROUND: Supply of cytomegalovirus (CMV)-seronegative blood products in Australia is an ongoing challenge. Requests for CMV-negative products are increasing with prediction that the demand will exceed supply by 2019. Clinical information evaluating how these products are being utilized by health providers within Australia is limited. This study aimed to identify indications for use of CMV-negative blood products and gather data to support possible practice change. STUDY DESIGN AND METHODS: All CMV-negative products issued to three tertiary Australian hospitals from May 1, 2016, to May 31, 2016, were identified (n = 1219). This equated to 1044 red blood cell units and 175 platelet units. Data were collected on the fate of each unit. Information collected included the indication and urgency of transfusion, reason for discard, product age, and recipient CMV immunoglobulin G status. RESULTS: Of the units issued during the audit period, 32 (2.6%) were discarded by the hospitals. Transfusion data were collected on 411 units. Of these, 136 (33.1%) were transfused to CMV-positive recipients, in most cases for hematology indications, and 67 units (16.3%) were transfused to CMV-negative requiring recipients. A total of 144 (35%) CMV negative units were selected based on their irradiation status. Other reasons for the selection of CMV-negative units included product close to expiry (n = 134, 32.6%) or specific patient phenotype requirements (n = 31, 7.5%). CONCLUSION: In this study, the majority of CMV-negative blood products were not used for CMV negative requiring recipients. Alterations to inventory management would be advantageous to ensure continued supply for CMV-negative requiring recipients. PMID- 29250781 TI - Blood donor deferral for men who have sex with men: still room to move. AB - BACKGROUND: Like a number of other countries, Australia mandates that a man who has had sex with men is deferred from donation until 12 months has elapsed since the sexual activity. This review examined whether this deferral period is justified by current evidence. STUDY DESIGN AND METHODS: Databases (Medline, EMBASE, Scopus) were searched using terms "blood donation" and "gay" or "MSM" and "HIV risk" from the mid-1980s to the present to investigate the history of donor deferral policy and its rationale in Australia. RESULTS: Gay and bisexual men in Australia face a higher risk of human immunodeficiency virus and other blood borne viruses (BBVs) than other populations. All blood donations, however, are tested for BBVs, and with current testing technologies the window period during which infection may be present but not detected is now less than 1 week. While there is a moral imperative to maintain blood safety, there is also a moral imperative to ensure that differential treatment of population groups with regard to donation eligibility is scientifically justified. Potential social harms that may flow from a dissonance between deferral policy and its evidence base include loss of trust and increased nonadherence to policy. CONCLUSIONS: A 12-month deferral for gay and bisexual men exceeds what is required to maintain blood safety. This disparity potentially causes social harm without any additional benefit to public health. Reducing the deferral period to 3 months will not increase health risk to recipients and may have the social benefit of increasing inclusiveness. PMID- 29250782 TI - Fresh stillborn and severely asphyxiated neonates share a common hypoxic-ischemic pathway. AB - OBJECTIVE: To characterize, among non-breathing flaccid neonates at delivery, immediate heartrate and responses to ventilation in relation to the clinical diagnosis of fresh stillbirth (FSB) or early neonatal death (END) within 24 hours. METHODS: The present cross-sectional study included all deliveries at Haydom Hospital in rural Tanzania between July 1, 2013, and July 31, 2016. Ventilation parameters and heartrate were recorded by monitors with ventilation and dry-electrocardiography sensors. Perinatal characteristics were recorded on data forms by trained research assistants. RESULTS: Among 12 789 neonates delivered, 915 were ventilated; among ventilated neonates, there were 53 (6%) FSBs and 64 (7%) ENDs. Electrocardiography was used in 46 FSBs and 55 ENDs, and these neonates were included in a subanalysis. Initial heartrate was detected in 27 (59%) of 46 FSBs and 52 (95%) of 55 ENDs, and was lower in FSBs (52 +/- 19 vs 76 +/- 37 bpm; P=0.003). More ENDs responded to ventilation (53% vs 9%; P<0.001), with heartrate increasing above 100 bpm. Heartrate at ventilation discontinuation was higher among ENDs (115 +/- 49 vs 52 +/- 33 bpm; P<0.001). CONCLUSION: Progression to FSB or END after intrapartum hypoxia/anoxia is probably part of the same circulatory end-process. Distinguishing FSB from severely asphyxiated newborns is clinically difficult and probably influences estimated global perinatal mortality rates. PMID- 29250783 TI - Risk of suicide within 1 year of cancer diagnosis. AB - The association of the risk of suicide with cancer at different time points after a new cancer diagnosis is unclear. This study explored the suicide hazard at different time points after a first cancer diagnosis during the 1-year period before suicide. This case-crossover study included 2,907 suicide cases from 2002 to 2012 in Taiwan and compared the odds of suicide risk at different time points during one year after any cancer diagnosis with self-matched periods. The 13th month preceding the suicide date was used as the control period, and the hazard period was the duration from the 1st to 12th month in the conditional logistic regression for case-crossover comparisons. Among major groups of cancers, group of lip, oral cavity and pharynx cancers tended to have higher risk of suicide than other groups of cancers. The first month of cancer diagnosis was associated with the highest risk of suicide compared with the 13th month before suicide. The odds ratio (OR) of suicide were significantly in the first six months after cancer diagnosis but declined afterwards. For example, the adjusted OR was 3.47 [95% confidence interval (CI) = 2.60-4.62] in the first month and 1.53 (95% CI = 1.11-2.12) in the sixth month following cancer diagnosis. These findings provide clinicians with a vital reference period during which sufficient support and necessary referral to mental health support should be provided to reduce the risk of suicide among patients with newly diagnosed cancer morbidity. PMID- 29250784 TI - Survey for the presence of a vitronectin-like protein in micro- and macroalgae and cyanobacteria. AB - Vitronectin (Vn) is a glycoprotein that serves a wide variety of roles in multicellular organisms. It was first identified in multicellular animals but has also been isolated from land plants and some algae, where it appears to serve as an extracellular adhesive molecule. In order to further elucidate presence and localization of a Vn-like protein and its potential role in algae, we surveyed different morphological regions of 24 species of macro- and microalgae and three species of cyanobacteria for the presence of a Vn-like protein. Vn-like proteins were not detected in any of the species of cyanobacteria, microalgae or Rhodophyta investigated. They were detected in several species of the Phaeophyceae and Chlorophyta where their localization was limited to the holdfast and rhizoids of these organisms, respectively. Detection of a Vn-like protein (between 0.0125 and 0.097 MUg . MUL-1 protein extract) was therefore limited to locations associated with substrate attachment. PMID- 29250785 TI - Laminaria digitata phlorotannins decrease protein degradation and methanogenesis during in vitro ruminal fermentation. AB - BACKGROUND: Phlorotannins (PhTs) are marine tannins consisting of phloroglucinol subunits connected via carbon-carbon and ether linkages. These have non-covalent protein binding properties and are, therefore, expected to be beneficial in protecting protein from hydrolysis during ruminal fermentation. In this study, the effectiveness of a methanolic PhTs extract from Laminaria digitata (10, 20, 40, 50, 75 and 100 g kg-1 tannin-free grass silage, with or without addition of polyethylene glycol (PEG), was investigated in vitro on protection of dietary protein and reduction of methane (CH4 ) in ruminal fluid. RESULTS: Addition of PhTs had linear (P < 0.0001) and quadratic (P = 0.0003) effects on gas and CH4 production, respectively. Optimal dosage of PhTs was 40 g kg-1 as at this point CH4 decreased (P < 0.0001) from 24.5 to 15.2 mL g-1 organic matter (OM), without affecting gas production (P = 0.3115) and total volatile fatty acids (P = 1.000). Ammonia trended (P = 0.0903) to decrease from 0.49 to 0.39 mmol g-1 OM, indicating protection of protein. Addition of PEG inhibited the effect of tannins at all dosage levels, and none of the fermentation parameters differed from the control. CONCLUSION: PhTs effectively protected protein from fermentation and reduced ruminal methanogenesis. (c) 2017 Society of Chemical Industry. PMID- 29250787 TI - Metagenomics in pooled plasma, with identification of potential emerging infectious pathogens. AB - BACKGROUND: Many emerging infectious pathogens are well known for existing in healthy blood donors and could be transmitted via blood transfusion or plasma derivatives usage. Therefore, there is an urgent need to discover the pathogens in qualified blood donation to avoid potential threats to blood safety. STUDY DESIGN AND METHODS: The objective of this study was to investigate the microbiome that existed in pooled plasma from different manufacturers in Chengdu and Guiyang. Random polymerase chain reaction, large-scale clone sequencing, and bioinformatics were used to investigate the metagenomics and microbiome structure of pooled plasma. Among detected microbiomes, potential pathogens were subsequently identified. RESULT: After host DNA cleaning, 551 clones were classified as bacteria; 88 clones were classified as viruses, and four clones were considered to be parasites, respectively. Thirteen kinds of bacteria and two kinds of parasites that might potentially threaten blood safety were identified along with six kinds of nonpathogenic viruses. The infection status of one identified pathogen Coxiella burnetii was evaluated in 1638 plasma samples. The reactive rate of immunoglobulin (Ig)G1 was 1.10% (18/1638), the reactive rate of IgG2 was 0.85% (14/1638), and the reactive rate of IgM was 0.98% (16/1638). CONCLUSION: Some pathogens that were already considered as threats to blood safety were discovered in those pooled plasma such as C. burnetii, Orientia tsutsugamushi, and Plasmodium sp. As a result, we should initiate some specific tests in the endemic area on plasma donors to enhance the blood safety in China. PMID- 29250786 TI - Neuroblastoma among children in Southern and Eastern European cancer registries: Variations in incidence and temporal trends compared to US. AB - Neuroblastoma comprises the most common neoplasm during infancy (first year of life). Our study describes incidence of neuroblastoma in Southern-Eastern Europe (SEE), including - for the first time - the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST)/Greece, compared to the US population, while controlling for human development index (HDI). Age-adjusted incidence rates (AIR) were calculated for 1,859 childhood (0-14 years) neuroblastoma cases, retrieved from 13 collaborating SEE registries (1990-2016), and were compared to those of SEER/US (N = 3,166; 1990-2012); temporal trends were assessed using Poisson regression and Joinpoint analyses. The overall AIR was significantly lower in SEE (10.1/million) compared to SEER (11.7 per million); the difference was maximum during infancy (43.7 vs. 53.3 per million, respectively), when approximately one-third of cases were diagnosed. Incidence rates of neuroblastoma at ages <1 and 1-4 years were positively associated with HDI, whereas lower median age at diagnosis was correlated with higher overall AIR. Distribution of primary site and histology was similar in SEE and SEER. Neuroblastoma was slightly more common among males compared to females (male-to female ratio: 1.1), mainly among SEE infants. Incidence trends decreased in infants in Slovenia, Cyprus and SEER and increased in Ukraine and Belarus. The lower incidence in SEE compared to SEER, especially in infants living in low HDI countries possibly indicates a lower level of overdiagnosis in SEE. Hence, increases in incidence rates in infancy noted in some subpopulations should be carefully monitored to avoid the unnecessary costs health impacts of tumors that could potentially spontaneously regress. PMID- 29250789 TI - Plant-microbe interactions: organelles and the cytoskeleton in action. AB - Contents Summary 1012 I. Introduction 1012 II. The endomembrane system in plant microbe interactions 1013 III. The cytoskeleton in plant-microbe interactions 1017 IV. Organelles in plant-microbe interactions 1019 V. Inter-organellar communication in plant-microbe interactions 1022 VI. Conclusions and prospects 1023 Acknowledgements 1024 References 1024 SUMMARY: Plants have evolved a multilayered immune system with well-orchestrated defense strategies against pathogen attack. Multiple immune signaling pathways, coordinated by several subcellular compartments and interactions between these compartments, play important roles in a successful immune response. Pathogens use various strategies to either directly attack the plant's immune system or to indirectly manipulate the physiological status of the plant to inhibit an immune response. Microscopy based approaches have allowed the direct visualization of membrane trafficking events, cytoskeleton reorganization, subcellular dynamics and inter-organellar communication during the immune response. Here, we discuss the contributions of organelles and the cytoskeleton to the plant's defense response against microbial pathogens, as well as the mechanisms used by pathogens to target these compartments to overcome the plant's defense barrier. PMID- 29250788 TI - Sensitivity and specificity of a new automated system for the detection of hepatitis B virus, hepatitis C virus, and human immunodeficiency virus nucleic acid in blood and plasma donations. AB - BACKGROUND: Use of nucleic acid testing (NAT) in donor infectious disease screening improves transfusion safety. Advances in NAT technology include improvements in assay sensitivity and system automation, and real-time viral target discrimination in multiplex assays. This article describes the sensitivity and specificity of cobas MPX, a multiplex assay for detection of human immunodeficiency virus (HIV)-1 Group M, HIV-2 and HIV-1 Group O RNA, HCV RNA, and HBV DNA, for use on the cobas 6800/8800 Systems. STUDY DESIGN AND METHODS: The specificity of cobas MPX was evaluated in samples from donors of blood and source plasma in the United States. Analytic sensitivity was determined with reference standards. Infectious window periods (WPs) before NAT detectability were calculated for current donor screening assays. RESULTS: The specificity of cobas MPX was 99.946% (99.883%-99.980%) in 11,203 blood donor samples tested individually (IDT), 100% (99.994%-100%) in 63,012 donor samples tested in pools of 6, and 99.994% (99.988%-99.998%) in 108,306 source plasma donations tested in pools of 96. Seven HCV NAT-yield donations and one seronegative occult HBV infection were detected. Ninety-five percent and 50% detection limits in plasma (IU/mL) were 25.7 and 3.8 for HIV-1M, 7.0 and 1.3 for HCV, and 1.4 and 0.3 for HBV. The HBV WP was 1 to 4 days shorter than other donor screening assays by IDT. CONCLUSION: cobas MPX demonstrated high specificity in blood and source plasma donations tested individually and in pools. High sensitivity, in particular for HBV, shortens the WP and may enhance detection of occult HBV. PMID- 29250790 TI - Stability evaluation of quality parameters for palm oil products at low temperature storage. AB - BACKGROUND: Palm oil is one of the major oils and fats produced and traded worldwide. The value of palm oil products is mainly influenced by their quality. According to ISO 17025:2005, accredited laboratories require a quality control procedure with respect to monitoring the validity of tests for determination of quality parameters. This includes the regular use of internal quality control using secondary reference materials. Unfortunately, palm oil reference materials are not currently available. To establish internal quality control samples, the stability of quality parameters needs to be evaluated. RESULTS: In the present study, the stability of quality parameters for palm oil products was examined over 10 months at low temperature storage (6 +/- 2 degrees C). The palm oil products tested included crude palm oil (CPO); refined, bleached and deodorized (RBD) palm oil (RBDPO); RBD palm olein (RBDPOo); and RBD palm stearin (RBDPS). The quality parameters of the oils [i.e. moisture content, free fatty acid content (FFA), iodine value (IV), fatty acids composition (FAC) and slip melting point (SMP)] were determined prior to and throughout the storage period. The moisture, FFA, IV, FAC and SMP for palm oil products changed significantly (P < 0.05), whereas the moisture content for CPO, IV for RBDPO and RBDPOo, stearic acid composition for CPO and linolenic acid composition for CPO, RBDPO, RBDPOo and RBDPS did not (P > 0.05). The stability study indicated that the quality of the palm oil products was stable within the specified limits throughout the storage period at low temperature. CONCLUSION: The storage conditions preserved the quality of palm oil products throughout the storage period. These findings qualify the use of the palm oil products CPO, RBDPO, RBDPOo and RBDPS as control samples in the validation of test results. (c) 2017 Society of Chemical Industry. PMID- 29250791 TI - Successful management of severe red blood cell alloimmunization in pregnancy with a combination of therapeutic plasma exchange, intravenous immune globulin, and intrauterine transfusion. AB - BACKGROUND: Antibodies to Rhesus and Kell antigens have been associated with severe hemolytic disease of the fetus and newborn (HDFN) necessitating intrauterine transfusion (IUT) of red blood cells (RBCs). We report a case series of five women with severe HDFN secondary to maternal RBC alloimmunization who were successfully managed with therapeutic plasma exchange (TPE), intravenous immune globulin (IVIG), and IUT. STUDY DESIGN AND METHODS: This is a retrospective case series of five women with severe HDFN who underwent a total of three TPE procedures during Weeks 10 to 13 of pregnancy, followed by weekly IVIG infusions. They were followed with serial middle cerebral artery peak systolic velocity studies beginning at 16 weeks' gestation to detect fetal anemia. For IUT, fetuses were administered RBC units that fully matched the maternal phenotype to D, C, E, K, Fy, Jk, and S antigen groups. The delivery outcomes and newborn information were followed. RESULTS: Anti-D and anti-K alloantibodies were implicated in HDFN. A two- to fourfold dilution reduction in anti-D and anti-K titers was observed after TPE. IUT was initiated between 21 to 27 weeks' gestation. The total number of IUTs for each patient ranged from four to seven. All five women delivered healthy infants at 33 to 38 weeks' gestation. CONCLUSION: A combined regimen of TPE and IVIG early in pregnancy and IUT later in pregnancy results in successful management of severe maternal RBC alloimmunization and HDFN. IUT with fully phenotypically matched RBC units may help prevent further RBC alloimmunization in complex cases of HDFN. PMID- 29250793 TI - Dietary synbiotic incorporation as an alternative to antibiotic improves growth performance, intestinal morphology, immunity and antioxidant capacity of broilers. AB - BACKGROUD: The present study aimed to investigate the effects of dietary synbiotic supplementation as an alternative to antibiotics on growth performance, intestinal morphology, immunity and oxidative status of broilers. One-day-old male chicks were allocated to three treatments and given a basal diet free from antibiotic (Control group) and a basal diet supplemented with either chlortetracycline or synbiotic for 42 days, respectively. RESULTS: Compared to the control group, the supplementation of synbiotic increased the average daily gain and gain:feed ratio of broilers from 22 to 42 days and 1 to 42 days of age, as well as the relative weight of the thymus and the secretory immunoglobulin A level in the jejunum and ileum at 42 days of age, with the values of these parameters being similar to the antibiotic group. Dietary synbiotic inclusion promoted the ratio of ileal villus height to crypt depth of broilers at 21 days of age. The supplementation of synbiotic also reduced the ileal malondialdehyde accumulation of broilers at 42 days of age to a level comparable with that of the antibiotic group. CONCLUSION: Dietary synbiotic supplementation as an alternative to antibiotic could exert beneficial consequences on growth performance, intestinal morphology, immunity and the antioxidant capacity of broilers. (c) 2017 Society of Chemical Industry. PMID- 29250792 TI - Increased acetylcholine and glutamate efflux in the prefrontal cortex following intranasal orexin-A (hypocretin-1). AB - Orexin/hypocretin neurons of the lateral hypothalamus and perifornical area are integrators of physiological function. Previous work from our laboratory and others has shown the importance of orexin transmission in cognition. Age-related reductions in markers of orexin function further suggest that this neuropeptide may be a useful target for the treatment of age-related cognitive dysfunction. Intranasal administration of orexin-A (OxA) has shown promise as a therapeutic option for cognitive dysfunction. However, the neurochemical mechanisms of intranasal OxA administration are not fully understood. Here, we use immunohistochemistry and in vivo microdialysis to define the effects of acute intranasal OxA administration on: (i) activation of neuronal populations in the cortex, basal forebrain, and brainstem and (ii) acetylcholine (ACh) and glutamate efflux in the prefrontal cortex (PFC) of Fischer 344/Brown Norway F1 rats. Acute intranasal administration of OxA significantly increased c-Fos expression, a marker for neuronal activation, in the PFC and in subpopulations of basal forebrain cholinergic neurons. Subsequently, we investigated the effects of acute intranasal OxA on neurotransmitter efflux in the PFC and found that intranasal OxA significantly increased both ACh and glutamate efflux in this region. These findings were independent from any changes in c-Fos expression in orexin neurons, suggesting that these effects are not resultant from direct activation of orexin neurons. In total, these data indicate that intranasal OxA may enhance cognition through activation of distinct neuronal populations in the cortex and basal forebrain and through increased neurotransmission of ACh and glutamate in the PFC. PMID- 29250795 TI - Sweet cherry softening accompanied with moisture migration and loss during low temperature storage. AB - BACKGROUND: Hardness is one of the important qualities influencing consumer appeal and marketing of fresh sweet cherry (Prunus avium L.). Moisture loss is one of the main causative factors of cherry softening. In this work, moisture loss and softening process of sweet cherry during postharvest storage at 0 and 4 degrees C were studied. In addition, low-field 1 H nuclear magnetic resonance (LF NMR) was used to analyze water distribution and migration in sweet cherry during storage at 4 degrees C. RESULTS: Moisture content correlated significantly (p < 0.01) with both skin and flesh hardness of cherry fruit at the two storage temperatures. According to the transverse relaxation curve, relaxation time, as T21 (0.01-10 ms), T22 (10-150 ms), and T23 (150-1000 ms) were ascribed to cell wall protons, cytoplasmic water, and vacuolar water respectively. Contents of cytoplasmic (p < 0.05) and vacuolar water (p < 0.01) changed significantly with storage time. Magnetic resonance imaging results illustrated that water distributes uniformly in fresh tissue. With prolonged storage time, free water content increased gradually, and then internal damage occurred. CONCLUSION: Sweet cherry softening closely correlated with moisture loss during low-temperature storage. LF-NMR is a useful technique to investigate moisture migration of fruits and vegetables. (c) 2017 Society of Chemical Industry. PMID- 29250794 TI - Blood use in hematologic malignancies: a nationwide overview in Sweden between 2000 and 2010. AB - BACKGROUND: Patients with hematologic malignancies receive large numbers of blood transfusions, and transfusion practices for this patient group are increasingly being scrutinized by randomized controlled trials. However, no studies so far have presented current transfusion statistics on a population level for this patient group. STUDY DESIGN AND METHODS: A retrospective descriptive study was conducted that was based on the Scandinavian Donations and Transfusions Database (SCANDAT2), which includes data on all blood donations and transfusions in Sweden and Denmark since the 1960s. Incident cases of hematologic malignancies were identified in the Swedish Cancer Register between 2000 and 2010. Cases were divided into nine patient groups based on diagnosis. RESULTS: A total of 28,693 patients were included in the cohort. Overall, the transfusion pattern varied depending on diagnosis and age. Patients with aggressive and acute diagnoses generally received more transfusions with immediate decline in transfusion incidence after diagnosis, whereas chronic diagnoses generally maintained more stable, but lower, transfusion incidence. In general, patients with leukemia received more transfusions than patients with lymphoma, and patients with acute leukemia as well as patients that had undergone allogeneic stem cell transplantations received the most transfusions. Within 2 years after diagnosis, patients with acute myeloid leukemia diagnosed at ages 0 to 65 years received on average between 30 to 40 red blood cell transfusions and platelet transfusions, respectively, corresponding to direct material costs close to 200,000 SEK (23,809 USD). CONCLUSION: Results from this population-based overview of blood use in hematologic malignancies showed high variability depending on diagnosis and age. PMID- 29250798 TI - Effects of microwave-assisted hot water treatments designed against Mexican fruit fly (Anastrepha ludens) on grapefruit (Citrus paradisi) quality. AB - BACKGROUND: Hot water treatment (HWT) against Anastrepha ludens was developed achieving 48 degrees C in the core of grapefruits and holding it for 6 min. After heating, the grapefruits were hydro-cooled and stored at 23 degrees C and analyzed for 16 days. The effect of microwave-assisted HWT (MW-HWT) on grapefruit quality was analyzed and compared with the quality of fruits treated with HWT and control fruits (without treatment). The physicochemical properties and chemical composition of essential oil were analyzed. RESULTS: MW-HWT was equivalent to HWT according to accumulated heat calculations, with the advantage of being shorter. Treatments significantly affected the weight, color, maturity index, juice content, firmness, titratable acidity, pH, and ascorbic acid content of the grapefruits (P < 0.05), but had no effect on the total soluble solids (P > 0.05). The major components identified in the essential oil were d-limonene and beta myrcene, compounds responsible of the scent of the grapefruits. CONCLUSION: MW HWT was shorter (130 min) and had a lesser effect on the quality of the grapefruit when compared with fruits under HWT (188 min duration). Thus, this treatment could be considered as an alternative method against the Mexican fruit fly in grapefruit. (c) 2017 Society of Chemical Industry. PMID- 29250797 TI - Short-term effect of preoperative intravenous iron therapy in colorectal cancer patients with anemia: results of a cohort study. AB - BACKGROUND: In the treatment of preoperative anemia, which is associated with increased postoperative morbidity, iron supplementation can replace blood transfusion and erythropoiesis-stimulating agents. The aim of this study was to assess the efficacy of preoperative intravenous (IV) iron infusion in optimizing hemoglobin (Hb) levels in anemic colorectal cancer patients. STUDY DESIGN AND METHODS: A retrospective cohort study was performed on patients who underwent surgery for colorectal cancer between 2010 and 2016 in a single teaching hospital. The primary outcome measure, the change in Hb level, was assessed by comparing anemic patients receiving usual care (UC; i.e. no iron therapy and no blood transfusion) with anemic patients receiving IV iron therapy (no blood transfusion). RESULTS: A total of 758 patients with colorectal cancer were eligible, of whom 318 (41.9%) had anemia. The IV and the UC groups included 52 and 153 patients with mean Hb levels at diagnosis of 6.3 and 6.9 mmol/L, respectively. In the IV group, preoperative Hb level was significantly increased compared to the UC group (0.65 mmol/L vs. 0.10 mmol/L, p < 0.001). High increase in Hb level after iron infusion was associated with initial higher transferrin and lower ferritin levels (high vs. poor responders: median transferrin 2.9 g/L vs. 2.7 g/L, median ferritin 12 ug/L vs. 27 ug/L). CONCLUSION: Implementation of IV iron therapy in anemic colorectal cancer patients leads to a distinct increase of preoperative Hb level. IV iron therapy is most effective in patients presenting with more severe anemia, and with higher transferrin and lower ferritin levels, markers for an absolute iron deficiency (ID), compared to functional ID. PMID- 29250796 TI - XIAP overexpression promotes bladder cancer invasion in vitro and lung metastasis in vivo via enhancing nucleolin-mediated Rho-GDIbeta mRNA stability. AB - Our recent studies demonstrate that X-linked inhibitor of apoptosis protein (XIAP) is essential for regulating colorectal cancer invasion. Here, we discovered that RhoGDIbeta was a key XIAP downstream effector mediating bladder cancer (BC) invasion in vitro and in vivo. We found that both XIAP and RhoGDIbeta expressions were consistently elevated in BCs of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-treated mice in comparison to bladder tissues from vehicle treated mice and human BCs in comparison to the paired adjacent normal bladder tissues. Knockdown of XIAP attenuated RhoGDIbeta expression and reduced cancer cell invasion, whereas RhoGDIbeta expression was attenuated in BBN-treated urothelium of RING-deletion knockin mice. Mechanistically, XIAP stabilized RhoGDIbeta mRNA by its positively regulating nucleolin mRNA stability via Erks dependent manner. Moreover, ectopic expression of GFP-RhoGDIbeta in T24T(shXIAP) cells restored its lung metastasis in nude mice. Our results demonstrate that XIAP-regulated Erks/nucleolin/RhoGDIbeta axis promoted BC invasion and lung metastasis. PMID- 29250799 TI - Comparison of sensory and chemical evaluation of lager beer aroma by gas chromatography and gas chromatography/mass spectrometry. AB - BACKGROUND: Although the evaluation of beer is conducted by sensory experts, we cannot neglect the influence of human factors and subjectivity. This problem could be solved by the chemical analysis of the volatile part of beer aroma and, from this, we can build a database for the construction of a model that classifies samples in a comparable manner to sensory assessment. RESULTS: Twenty two batches of the same beer brand were assessed by sensory evaluation and described chemically in terms of the contents of alcohols and esters (n = 9), hop essential oil compounds (n = 15) using gas chromatography (GC) and other aroma volatiles (n = 33) as analysed by head space solid-phase microextraction (SPME) GC/mass spectrometry. The best match of 91% with respect to sample classification on the basis of chemical analyses to sensory scores was achieved with a dataset of results from headspace-SPME and analyses of higher alcohols and esters by regularized discriminant analysis. CONCLUSION: The results of the present study show that deviations in beer aroma are not a consequence of a permanent repeatable error in brewing process, nor are they influenced by raw materials, but, instead, they are a consequence of alcoholic fermentation. Sensory analysis could be replaced with chemical/statistical analysis on an appropriate data set and for a distinct beer brand. The good results achieved confirm our approach; however, for different beer brands or types, this method should be optimised. (c) 2017 Society of Chemical Industry. PMID- 29250800 TI - Postoperative outcomes in vedolizumab-treated Crohn's disease patients undergoing major abdominal operations. AB - BACKGROUND: Up to 80% of patients with Crohn's disease require an abdominal operation in their lifetime. As the use of vedolizumab is increasing for the treatment of Crohn's disease, it is important to understand its potential association with post-operative complications. AIM: We sought to compare 30-day postoperative infectious complication rate among vedolizumab-treated Crohn's disease patients vs those who had received TNFalpha inhibitors or no biologic therapy. METHODS: A retrospective review of all Crohn's disease patients who received vedolizumab within 12 weeks of a major abdominal or pelvic operation was performed. Two control cohorts consisted of Crohn's disease patients treated with TNFalpha inhibitors or no biologic therapy. RESULTS: One hundred Crohn's disease patients received vedolizumab within 12 weeks of an abdominal operation. Vedolizumab-treated patients underwent an equivalent rate of laparoscopic surgery (P = .25), had fewer anastomoses performed (P = .0002), and had equally frequent diversion in the setting of anastomoses (P = .47). Thirty-two vedolizumab-treated patients experienced postoperative infectious complications (32%), 26 of which were surgical site infections (26%). The vedolizumab-treated group experienced no difference in nonsurgical site infections (6% vs 5% anti-TNFalpha and 2% nonbiologic; P = .34), but significantly higher rates of surgical site infections (26% vs 8% and 11%; P < .001). On univariate and multivariate analysis, exposure to vedolizumab remained a significant predictor of postoperative surgical site infection (P < .001 and P = .002). CONCLUSIONS: Twenty-six per cent of Crohn's disease patients who received vedolizumab within 12 weeks prior to a major abdominal operation experienced a 30-day postoperative surgical site infection, significantly higher than that of patients receiving TNFalpha inhibitors or no biologic therapy. Vedolizumab within 12 weeks of surgery remained a predictor of 30-day postoperative surgical site infection on multivariable analysis. While vedolizumab-treated Crohn's disease patients may be a sicker cohort of patients, it is important to consider these findings with regard to preoperative counselling, operative timing and primary closure of wounds. PMID- 29250801 TI - Endocrine disrupting chemicals, 4-nonylphenol, bisphenol A and butyl benzyl phthalate, impair metabolism of estradiol in male and female rats as assessed by levels of 15alpha-hydroxyestrogens and catechol estrogens in urine. AB - Bisphenol A (BPA), 4-nonylphenol (NP) and butyl benzyl phthalate (BBP), termed endocrine-disrupting chemicals, are known to mimic estrogen activity. The effects of these chemicals on 17beta-estradiol (E2 ) metabolism in vivo in rats were examined. Male and female rats were given NP (250 mg kg-1 day-1 ), BPA (250 MUg kg-1 day-1 ) or BBP (500 mg kg-1 day-1 ) by gavage for 14 days, followed by a single intraperitoneal injection of E2 (5 mg kg-1 ) on the final day. The urinary excretion over 72 hours of 2-hydroxyestrone 1-N-acetylcysteine thioether, 2 hydroxyestrone 4-N-acetylcysteine thioether, 4-hydroxyestrone 2-N-acetylcysteine thioether, 2-hydroxy-17beta-estradiol (2-OHE2 ), 2-hydroxyestrone (2-OHE1 ), 4 hydroxy-17beta-estradiol, 4-hydroxyestrone, 15alpha-hydroxyestriol (E4 ), 15alpha hydroxy-17beta-estradiol and 15alpha-hydroxyestrone was measured. Increases in urinary excretion of 2-OHE1 and decreases in E4 were observed in males treated with NP or BBP. Decreases in urinary excretion of 2-OHE2 and E4 were observed in males treated with BPA. Decreases in urinary excretion of 2-OHE1 and 2-OHE2 were observed in females treated with BBP. Normalized liver and weights were increased in both sexes treated with NP or BBP. Histologic observations revealed marked changes in the distal tubules and collecting ducts in the kidneys of rats exposed to NP and BBP, and hypertrophy in the hepatocytes of the centrilobular zone of the liver. No BPA-related effects on organ weight and on liver or kidney histopathology were found. These results suggest that the 14 day oral dosing of NP and BBP disrupted E2 metabolism, resulting from marked morphological and functional alterations in the liver and kidneys. In addition, BPA could induce metabolic and endocrine disruption. PMID- 29250802 TI - Occurrence of enteropathogenic bacteria in birds of prey in Italy. AB - : The importance of wild birds as potential vectors of disease has received recent renewed empirical interest, especially regarding human health although information regarding the enteropathogenic bacteria in birds of prey continue to be scant. This study was performed with the aim to evaluate the occurrence of enteropathogenic bacteria (i.e. Campylobacter spp. Escherichia coli, Salmonella spp.) in birds of prey carcasses in Southern Italy. The results of the present study showed a prevalence of 33.1% (49/148) for Campylobacter spp. where all positive isolates (49/49) were identified as Campylobacter jejuni, and among these positive 12/49 were also identified as Campylobacter coli. Thus, 12/49 birds of prey showed mixed infections for both Campylobacter species. Differences in Campylobacter spp. prevalence between diurnal and nocturnal birds were statistically significant (P = 0.016). Escherichia coli showed a prevalence of 6.8% (10/148) and were serogrouped as O26 (n = 3), O55 (n = 2), O145 (n = 5). Salmonella spp. showed a prevalence of 6.8% (10/148) and were serotyped as S. Napoli (n = 4), Salmonella salamae (n = 3) and S. Typhimurium (n = 3). Although wildlife disease outbreaks have often been underreported in the broader context of global epidemiology, results of the present study suggest that birds of prey may serve as a reservoir of pathogens for livestock and human health, acting at the animal-human-ecosystem interface. SIGNIFICANCE AND IMPACT OF THE STUDY: This study confirms the role of birds of prey as a reservoir of enteropathogenic bacteria (i.e. Campylobacter spp., Escherichia coli, Salmonella spp.). Wild birds can contaminate environment with their faeces and play a crucial role in the transmission of pathogens to poultry and livestock farms and aquifers supplying water to humans. Furthermore, wild birds could disseminate pathogens within rescue and rehabilitation centres where they are admitted. PMID- 29250804 TI - Nonredundant functions of Arabidopsis LecRK-V.2 and LecRK-VII.1 in controlling stomatal immunity and jasmonate-mediated stomatal closure. AB - Stomatal immunity restricts bacterial entry to leaves through the recognition of microbe-associated molecular patterns (MAMPs) by pattern-recognition receptors (PRRs) and downstream abscisic acid and salicylic acid signaling. Through a reverse genetics approach, we characterized the function of the L-type lectin receptor kinase-V.2 (LecRK-V.2) and -VII.1 (LecRK-VII.1). Analyses of interactions with the PRR FLAGELLIN SENSING2 (FLS2) were performed by co immunoprecipitation and bimolecular fluorescence complementation and whole-cell patch-clamp analyses were used to evaluate guard cell Ca2+ -permeable cation channels. The Arabidopsis thaliana LecRK-V.2 and LecRK-VII.1 and notably their kinase activities were required for full activation of stomatal immunity. Knockout lecrk-V.2 and lecrk-VII.1 mutants were hyper-susceptible to Pseudomonas syringae infection and showed defective stomatal closure in response to bacteria or to the MAMPs flagellin and EF-Tu. By contrast, Arabidopsis over-expressing LecRK-V.2 or LecRK-VII.1 demonstrated a potentiated stomatal immunity. LecRK-V.2 and LecRK-VII.1 are shown to be part of the FLS2 PRR complex. In addition, LecRK V.2 and LecRK-VII.1 were critical for methyl jasmonate (MeJA)-mediated stomatal closure, notably for MeJA-induced activation of guard cell Ca2+ -permeable cation channels. This study highlights the role of LecRK-V.2 and LecRK-VII.1 in stomatal immunity at the FLS2 PRR complex and in MeJA-mediated stomatal closure. PMID- 29250805 TI - Innovative modeling of naturalistic driving data: Inference and prediction. AB - Naturalistic driving studies provide opportunities for investigating the effects of key driving exposures on risky driving performance and accidents. New technology provides a realistic assessment of risky driving through the intensive monitoring of kinematic behavior while driving. These studies with their complex data structures provide opportunities for statisticians to develop needed modeling techniques for statistical inference. This article discusses new statistical modeling procedures that were developed to specifically answer important analytical questions for naturalistic driving studies. However, these methodologies also have important applications for the analysis of intensively collected longitudinal data, an increasingly common data structure with the advent of wearable devises. To examine the sources of variation between- and within-participants in risky driving behavior, we explore the use of generalized linear mixed models with autoregressive random processes to analyzing long sequences of kinematic count data from a group of teenagers that have measurements at each trip over a 1.5-year observation period starting after receiving their license. These models provide a regression framework for examining the effects of driving conditions and exposures on risky driving behavior. Alternatively, generalized estimating equations approaches are explored for the situation where we have intensively collected count measurements on a moderate number of participants. In addition to proposing statistical modeling for kinematic events, we explore models for relating kinematic events with crash risk. Specifically, we propose both latent variable and hidden Markov models for relating these 2 processes and for developing dynamic predictors of crash risk from longitudinal kinematic event data. These different statistical modeling techniques are all used to analyze data from the Naturalistic Teenage Driving Study, a unique investigation into how teenagers drive after licensure. PMID- 29250806 TI - Paraquat and MPTP alter microRNA expression profiles, and downregulated expression of miR-17-5p contributes to PQ-induced dopaminergic neurodegeneration. AB - Recent evidence indicates that microRNAs (miRNAs) play a key role in neurodegenerative diseases. However, the toxic effects of paraquat (PQ) and 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on miRNA expression profiles in dopaminergic neurons have not been investigated. In the present study, we used microarray analysis to show that PQ and MPTP induce alterations of miRNA expression in neuro-2a cells. The results reveal that treatment with 300 MUm PQ caused miRNA deregulation, such that 60 miRNAs were upregulated and 228 miRNAs were downregulated. Following treatment with 300 MUm MPTP, a total of 576 miRNAs were dysregulated, of which 506 were upregulated and 70 were downregulated. Alterations in the expression of miR-17-5p, miR-210-3p, miR-374-5p, miR-378-3p and miR-503-5p were verified by real-time quantitative reverse transcriptase polymerase chain reaction. Moreover, overexpression of miR-17-5p in Neuro-2a cells enhanced cell proliferation, suppressed apoptosis and promoted S phase transition of the cell cycle after PQ treatment. Taken together, our study demonstrates that characteristic changes in miRNA expression profiles occur after PQ and MPTP treatment, which suggests that miRNAs may be involved in the development of PQ- and MPTP-induced neurodegeneration. Downregulated miR-17-5p expression contributes to PQ-induced dopaminergic neurodegeneration. PMID- 29250807 TI - The Wnt Transcriptional Switch: TLE Removal or Inactivation? AB - Many targets of the Wnt/beta-catenin signaling pathway are regulated by TCF transcription factors, which play important roles in animal development, stem cell biology, and oncogenesis. TCFs can regulate Wnt targets through a "transcriptional switch," repressing gene expression in unstimulated cells and promoting transcription upon Wnt signaling. However, it is not clear whether this switch mechanism is a general feature of Wnt gene regulation or limited to a subset of Wnt targets. Co-repressors of the TLE family are known to contribute to the repression of Wnt targets in the absence of signaling, but how they are inactivated or displaced by Wnt signaling is poorly understood. In this mini review, we discuss several recent reports that address the prevalence and molecular mechanisms of the Wnt transcription switch, including the finding of Wnt-dependent ubiquitination/inactivation of TLEs. Together, these findings highlight the growing complexity of the regulation of gene expression by the Wnt pathway. PMID- 29250803 TI - Impact of vedolizumab therapy on extra-intestinal manifestations in patients with inflammatory bowel disease: a multicentre cohort study nested in the OBSERV-IBD cohort. AB - BACKGROUND: The effectiveness of vedolizumab as a treatment for extraintestinal manifestations (EIM) is questionable due to its gut-specificity. AIM: To assess effectiveness of vedolizumab for EIM in patients with inflammatory bowel disease (IBD) in a large real-life experience cohort. METHODS: Between June and December 2014, 173 patients with Crohn's disease and 121 with ulcerative colitis were treated with vedolizumab. Patients were followed until week 54. EIM activity was assessed at weeks 0, 6, 14, 22, 30 and 54 by using a 3-step scale: complete remission, partial response and no response. RESULTS: At baseline, 49 (16.7%) patients had EIMs of which 47 had inflammatory arthralgia/arthritis, four had cutaneous lesions and two had both rheumatologic and skin EIM. At week 54, 21 (44.7%) patients had complete remission for inflammatory arthralgia/arthritis and three (75%) for cutaneous EIM. In multivariate analysis, complete remission of inflammatory arthralgia/arthritis was associated with clinical remission of IBD (OR = 1.89, IC95% [1.05-3.41], P = .03) and recent onset of inflammatory arthralgia/arthritis (OR = 1.99, IC95% [1.12-3.52], P = .02). During the follow up period, 34 (13.8%) patients without any EIM at baseline, developed incident cases of inflammatory arthralgia/arthritis consisting mostly of peripheral arthralgia without evidence of arthritis and 14 (4.8%) incident cases of paradoxical skin manifestation. CONCLUSION: Vedolizumab therapy is commonly associated with improvement in EIM. This was associated with quiescent IBD and recent EIM. However, paradoxical skin manifestation and inflammatory arthralgia/arthritis may occur upon vedolizumab therapy. PMID- 29250808 TI - Safety and efficacy of sofosbuvir-based treatment of acute hepatitis C in end stage renal disease patients undergoing haemodialysis. AB - BACKGROUND: Hepatitis C virus (HCV) infection in patients undergoing haemodialysis is prevalent and aggressive. The treatment of chronic hepatitis C has been revolutionised by the advent of direct-acting antivirals (DAAs). However, the safety, efficacy, and tolerance of DAAs in the treatment of acute HCV infection in patients with end-stage renal disease who are on haemodialysis are unknown. AIM: To evaluate the safety and efficacy of sofosbuvir plus daclatasvir in this specific, difficult-to-treat population. METHODS: We conducted a prospective and observational study of end-stage renal disease patients who were undergoing haemodialysis and were acutely infected with HCV. Patients received a half dose of sofosbuvir (200 mg) and a full dose of daclatasvir (60 mg) daily. The primary endpoint was the proportion of patients with sustained virological responses (SVRs); the other primary outcomes were safety and tolerability. RESULTS: Thirty-three patients were enrolled in the study. The median HCV RNA viral load at baseline was 6.8 log10 IU/mL. Twenty-four patients were infected with HCV genotype 2a, seven patients with 1b, and two patients with 2a+1b. All patients achieved a SVR at 12 weeks after the end of treatment. The treatment was well tolerated, and there were no drug-related serious adverse events. CONCLUSION: A half dose of sofosbuvir (200 mg once daily) plus a full dose of daclatasvir (60 mg once daily) were suitable for the treatment of acute HCV-infected patients who were undergoing end-stage renal disease and were on haemodialysis. PMID- 29250809 TI - Prostate tumors downregulate microseminoprotein-beta (MSMB) in the surrounding benign prostate epithelium and this response is associated with tumor aggressiveness. AB - BACKGROUND: Microseminoprotein-beta (MSMB) is a major secretory product from prostate epithelial cells. MSMB synthesis is decreased in prostate tumors in relation to tumor grade. MSMB levels are also reduced in the circulation and MSMB is therefore used as a serum biomarker for prostate cancer. We hypothesized that cancers induce a reduction in MSMB synthesis also in the benign parts of the prostate, and that the magnitude of this response is related to tumor aggressiveness. Reduced levels of MSMB in the circulation could therefore be a consequence of reduced MSMB expression not only in tumor tissue but also in the benign prostate tissue. METHODS: MSMB expression was analyzed in prostatectomy specimens from 36 patients using immunohistochemistry and qRT-PCR. MSMB expression in the benign prostate tissue was analyzed in relation to Gleason score, tumor stage, and distance to the tumor. Furthermore, Dunning rat prostate tumors with different aggressiveness were implanted into the prostate of Copenhagen rats to study if this affected the MSMB expression in the tumor adjacent benign rat prostate tissue. RESULTS: In prostatectomy specimens, MSMB expression was reduced in prostate tumors but also in the tumor-adjacent benign parts of the prostate. The reduction in tumor MSMB was related to tumor grade and stage, and the reduction in the benign parts of the prostate to tumor grade, stage, and distance to the tumor. Implantation of Dunning cancer cells into the rat prostate resulted in reduced MSMB protein levels in the tumor-adjacent benign prostate tissue. Rapidly growing and metastatic MatLyLu tumors had a more pronounced effect than slow-growing non-metastatic G tumors. CONCLUSION: Our data suggest that aggressive prostate tumors suppress MSMB synthesis in the benign prostate and that this could explain why serum levels of MSMB are decreased in prostate cancer patients. This study suggests that markers for aggressive cancer can be found among factors altered in parallel in prostate tumors and in the adjacent benign tissue. PMID- 29250810 TI - Complementary version of fermion coupled coherent states method and gram-schmidt algorithm: Theory and applications for electronic states of H2 and H2. AB - In our previous report, we introduced a new version of Fermion coupled coherent states method (FCCS) which was especially suited for simulating the first symmetric spatial electronic state of two-electron systems. In this manuscript, we report a complementary version for FCCS method to simulate both of the first symmetric and antisymmetric spatial electronic states of two-electron systems. Moreover, the Gram-Schmidt orthogonalization process is employed to reach the excited states of the system. We apply this FCCS method and the original coupled coherent state method to simulate the energy of different electronic states of H2 and H2+, respectively. The results for the energy of computed electronic states of H2 and H2+ show a pretty good consistency with the exact values. (c) 2017 Wiley Periodicals, Inc. PMID- 29250811 TI - Injury, illness, and disability risk in American seafarers. AB - BACKGROUND: Seafarers are an understudied and essential workforce, isolated from medical care. This study describes injuries, illness, and risk factors for resultant disability in one shipping company with a majority of American seafarers. METHODS: The study used a telemedicine database of injury and illness incidence in seafarers, and applied descriptive statistical methods and logistic regression modeling. RESULTS: Illnesses were more frequently reported than injuries (860 vs 479). The overall injury rate was 113 per 1000 person-years, and the overall illness rate was 211 per 1000 person-years. Seafarer ratings had higher risk for disability compared to officers (OR = 1.60; 95%CI 1.17, 2.18), and incidents on dry cargo ships (OR = 2.70; 95%CI 1.49, 4.91) and articulated tug-barges (ATBs) (OR = 2.21; 95%CI 1.26, 3.86) had higher disability risk compared to container vessels. CONCLUSION: Additional research in this vital American workforce may be useful to confirm these findings forming a basis for preventive interventions. PMID- 29250812 TI - A multiple-model generalisation of updating clinical prediction models. AB - There is growing interest in developing clinical prediction models (CPMs) to aid local healthcare decision-making. Frequently, these CPMs are developed in isolation across different populations, with repetitive de novo derivation a common modelling strategy. However, this fails to utilise all available information and does not respond to changes in health processes through time and space. Alternatively, model updating techniques have previously been proposed that adjust an existing CPM to suit the new population, but these techniques are restricted to a single model. Therefore, we aimed to develop a generalised method for updating and aggregating multiple CPMs. The proposed "hybrid method" re calibrates multiple CPMs using stacked regression while concurrently revising specific covariates using individual participant data (IPD) under a penalised likelihood. The performance of the hybrid method was compared with existing methods in a clinical example of mortality risk prediction after transcatheter aortic valve implantation, and in 2 simulation studies. The simulation studies explored the effect of sample size and between-population-heterogeneity on the method, with each representing a situation of having multiple distinct CPMs and 1 set of IPD. When the sample size of the IPD was small, stacked regression and the hybrid method had comparable but highest performance across modelling methods. Conversely, in large IPD samples, development of a new model and the hybrid method gave the highest performance. Hence, the proposed strategy can inform the choice between utilising existing CPMs or developing a model de novo, thereby incorporating IPD, existing research, and prior (clinical) knowledge into the modelling strategy. PMID- 29250813 TI - Using threshold regression to analyze survival data from complex surveys: With application to mortality linked NHANES III Phase II genetic data. AB - The Cox proportional hazards (PH) model is a common statistical technique used for analyzing time-to-event data. The assumption of PH, however, is not always appropriate in real applications. In cases where the assumption is not tenable, threshold regression (TR) and other survival methods, which do not require the PH assumption, are available and widely used. These alternative methods generally assume that the study data constitute simple random samples. In particular, TR has not been studied in the setting of complex surveys that involve (1) differential selection probabilities of study subjects and (2) intracluster correlations induced by multistage cluster sampling. In this paper, we extend TR procedures to account for complex sampling designs. The pseudo-maximum likelihood estimation technique is applied to estimate the TR model parameters. Computationally efficient Taylor linearization variance estimators that consider both the intracluster correlation and the differential selection probabilities are developed. The proposed methods are evaluated by using simulation experiments with various complex designs and illustrated empirically by using mortality linked Third National Health and Nutrition Examination Survey Phase II genetic data. PMID- 29250814 TI - Investigation of 2-stage meta-analysis methods for joint longitudinal and time-to event data through simulation and real data application. AB - BACKGROUND: Joint modelling of longitudinal and time-to-event data is often preferred over separate longitudinal or time-to-event analyses as it can account for study dropout, error in longitudinally measured covariates, and correlation between longitudinal and time-to-event outcomes. The joint modelling literature focuses mainly on the analysis of single studies with no methods currently available for the meta-analysis of joint model estimates from multiple studies. METHODS: We propose a 2-stage method for meta-analysis of joint model estimates. These methods are applied to the INDANA dataset to combine joint model estimates of systolic blood pressure with time to death, time to myocardial infarction, and time to stroke. Results are compared to meta-analyses of separate longitudinal or time-to-event models. A simulation study is conducted to contrast separate versus joint analyses over a range of scenarios. RESULTS: Using the real dataset, similar results were obtained by using the separate and joint analyses. However, the simulation study indicated a benefit of use of joint rather than separate methods in a meta-analytic setting where association exists between the longitudinal and time-to-event outcomes. CONCLUSIONS: Where evidence of association between longitudinal and time-to-event outcomes exists, results from joint models over standalone analyses should be pooled in 2-stage meta-analyses. PMID- 29250815 TI - Current and Emerging Pharmacotherapies for Cessation of Tobacco Smoking. AB - Tobacco use disorder is a chronic illness. With its high comorbidity rate, it is a major cause of years of life lost or years lived with disability; however, it is also considered the most preventable cause of death in developed countries. Since the development of nicotine replacement therapy (NRT) in 1978, treatment options have continued to evolve and expand. Despite this, currently available treatments remain insufficient, with less than 25% of smokers remaining abstinent 1 year after treatment. In this article, we review existing and emerging smoking cessation pharmacotherapies, with a special emphasis on the most promising agents that are currently being investigated. A search of the Cochrane Database of Systematic Reviews and the PubMed, Ovid, and ClinicalTrials.gov databases (August 2 to September 1, 2017) was undertaken for articles on smoking cessation pharmacotherapies, applying no language restrictions. More than 40 pharmacotherapies were reviewed including conventional pharmacotherapies-NRT, bupropion, and varenicline (all approved by the U.S. Food and Drug Administration as first-line treatment of smoking cessation)-and novel therapies: cytisine, N acetylcysteine, cycloserine, memantine, baclofen, topiramate, galantamine, and bromocriptine. Studies of combination NRT and varenicline showed the greatest smoking cessation rates. Clonidine and nortriptyline are second-line treatments used when first-line treatments fail or are contraindicated, or by patient preference. Some novel therapies, especially acetylcholinesterase inhibitors, cytisine, and N-acetylcysteine, display promising results. Because the results of randomized clinical trials were reported using varied end points and outcome measures, direct comparisons between different pharmacotherapies cannot easily be evaluated. Additional high-quality randomized double-blind placebo-controlled trials with long-term follow-up, using validated sustained abstinence measures, are needed to find more effective smoking cessation aids. PMID- 29250816 TI - Bartlett-type corrections and bootstrap adjustments of likelihood-based inference methods for network meta-analysis. AB - In network meta-analyses that synthesize direct and indirect comparison evidence concerning multiple treatments, multivariate random effects models have been routinely used for addressing between-studies heterogeneities. Although their standard inference methods depend on large sample approximations (eg, restricted maximum likelihood estimation) for the number of trials synthesized, the numbers of trials are often moderate or small. In these situations, standard estimators cannot be expected to behave in accordance with asymptotic theory; in particular, confidence intervals cannot be assumed to exhibit their nominal coverage probabilities (also, the type I error probabilities of the corresponding tests cannot be retained). The invalidity issue may seriously influence the overall conclusions of network meta-analyses. In this article, we develop several improved inference methods for network meta-analyses to resolve these problems. We first introduce 2 efficient likelihood-based inference methods, the likelihood ratio test-based and efficient score test-based methods, in a general framework of network meta-analysis. Then, to improve the small-sample inferences, we developed improved higher-order asymptotic methods using Bartlett-type corrections and bootstrap adjustment methods. The proposed methods adopt Monte Carlo approaches using parametric bootstraps to effectively circumvent complicated analytical calculations of case-by-case analyses and to permit flexible application to various statistical models network meta-analyses. These methods can also be straightforwardly applied to multivariate meta-regression analyses and to tests for the evaluation of inconsistency. In numerical evaluations via simulations, the proposed methods generally performed well compared with the ordinary restricted maximum likelihood-based inference method. Applications to 2 network meta-analysis datasets are provided. PMID- 29250817 TI - A Bayesian semiparametric latent variable approach to causal mediation. AB - In assessing causal mediation effects in randomized studies, a challenge is that the direct and indirect effects can vary across participants due to different measured and unmeasured characteristics. In that case, the population effect estimated from standard approaches implicitly averages over and does not estimate the heterogeneous direct and indirect effects. We propose a Bayesian semiparametric method to estimate heterogeneous direct and indirect effects via clusters, where the clusters are formed by both individual covariate profiles and individual effects due to unmeasured characteristics. These cluster-specific direct and indirect effects can be estimated through a set of regression models where specific coefficients are clustered by a stick-breaking prior. To let clustering be appropriately informed by individual direct and indirect effects, we specify a data-dependent prior. We conduct simulation studies to assess performance of the proposed method compared to other methods. We use this approach to estimate heterogeneous causal direct and indirect effects of an expressive writing intervention for patients with renal cell carcinoma. PMID- 29250818 TI - Trithorax-group proteins ARABIDOPSIS TRITHORAX4 (ATX4) and ATX5 function in abscisic acid and dehydration stress responses. AB - Trithorax-group proteins (TrxGs) play essential regulatory roles in chromatin modification to activate transcription. Although TrxGs have been shown to be extensively involved in the activation of developmental genes, how the specific TrxGs function in the dehydration and abscisic acid (ABA)-mediated modulation of downstream gene expression remains unknown. Here, we report that two evolutionarily conserved Arabidopsis thaliana TrxGs, ARABIDOPSIS TRITHORAX4 (ATX4) and ATX5, play essential roles in the drought stress response. atx4 and atx5 single loss-of-function mutants showed drought stress-tolerant and ABA hypersensitive phenotypes during seed germination and seedling development, while the atx4 atx5 double mutant displayed further exacerbation of the phenotypes. Genome-wide RNA-sequencing analyses showed that ATX4 and ATX5 regulate the expression of genes functioning in dehydration stress. Intriguingly, ABA HYPERSENSITIVE GERMINATION 3 (AHG3), an essential negative regulator of ABA signaling, acts genetically downstream of ATX4 and ATX5 in response to ABA. ATX4 and ATX5 directly bind to the AHG3 locus and trimethylate histone H3 of Lys 4 (H3K4). Moreover, ATX4 and ATX5 occupancies at AHG3 are dramatically increased under ABA treatment, and are also essential for RNA polymerase II (RNAPII) occupancies. Our findings reveal novel molecular functions of A. thaliana TrxGs in dehydration stress and ABA responses. PMID- 29250819 TI - An exploration of factors associated with older persons' perceptions of the benefits of and satisfaction with a preventive home visit service. AB - BACKGROUND: Preventive home visits (PHVs) are healthcare services aimed at promoting the health of home-dwelling older people and to support their abilities to live independently. To enhance effectiveness, studies that explore older persons' experiences of PHVs are needed. OBJECTIVE: To assess older persons' perceived benefits and opinions of a PHV service and explore associations between perceived benefits from PHV and relevant sociodemographic/health-related factors. THEORY: The study was based on a comprehensive understanding of health, as including objective health/disease, subjective health/well-being and coping ability. METHODS: A cross-sectional survey was administered during spring 2013 in a Norwegian municipality where nurses had offered annual PHVs to residents aged 75 years and older since 1999. We invited a stratified random sample of 393 PHV users to participate; of these, 161 volunteered. The main outcome variables in the questionnaire were perceived benefits from PHV. Logistic regression models were used to analyse the associations between each benefit and sociodemographic/health-related background variables. RESULTS: Approximately 39% of the respondents reported that PHVs added to their feelings of safety; 66% reported support for ability to live at home; 72% reported support for having a good life, 83% were satisfied with the service, and 90% stated that PHVs are important for older people. Each benefit was associated with different sociodemographic/health-related factors. Support for feelings of safety increased with age. More support for living at home was associated with poor physical health and not living alone. Those without children perceived more support for a good life. Satisfaction with PHV increased with increasing scores on the Life Orientation Scale. Persons with poor mental health and those not living alone more often perceived PHV as important. CONCLUSIONS: Annual, comprehensive PHVs to a general older population may support older persons' health and independence. Low response rate restricts the possibility to generalise the results. PMID- 29250820 TI - A computational method for the design of nested proteins by loop-directed domain insertion. AB - The computational design of novel nested proteins-in which the primary structure of one protein domain (insert) is flanked by the primary structure segments of another (parent)-would enable the generation of multifunctional proteins. Here we present a new algorithm, called Loop-Directed Domain Insertion (LooDo), implemented within the Rosetta software suite, for the purpose of designing nested protein domain combinations connected by flexible linker regions. Conformational space for the insert domain is sampled using large libraries of linker fragments for linker-to-parent domain superimposition followed by insert to-linker superimposition. The relative positioning of the two domains (treated as rigid bodies) is sampled efficiently by a grid-based, mutual placement compatibility search. The conformations of the loop residues, and the identities of loop as well as interface residues, are simultaneously optimized using a generalized kinematic loop closure algorithm and Rosetta EnzymeDesign, respectively, to minimize interface energy. The algorithm was found to consistently sample near-native conformations and interface sequences for a benchmark set of structurally similar but functionally divergent domain-inserted enzymes from the alpha/beta hydrolase superfamily, and discriminates well between native and nonnative conformations and sequences, although loop conformations tended to deviate from the native conformations. Furthermore, in cross-domain placement tests, native insert-parent domain combinations were ranked as the best scoring structures compared to nonnative domain combinations. This algorithm should be broadly applicable to the design of multi-domain protein complexes with any combination of inserted or tandem domain connections. PMID- 29250821 TI - A model of well-being for children with neurodevelopmental disorders: Parental perceptions of functioning, services, and support. AB - BACKGROUND: Both child function and supports and services have been found to impact the well-being of parents of children with neurodevelopmental disorders (NDD). The relationship between function and services and the well-being of children with NDD is less well-understood and is important to clarify in order to effect program and service change. METHODS: The current project assessed whether child function as well as the adequacy of formal supports and services provided to children and their families were predictive of child well-being. Well-being was assessed using a measure of quality of life developed for use with children with NDD. Data from 234 parents were analysed using structural equation modelling. RESULTS: Each predictor was found to load significantly on the overall outcome variable of well-being. Parent concerns about child function were significantly related to child well-being; parents who reported more concerns about their children's functioning reported lower levels of child well-being. Unmet needs for formal supports and services were also significantly related to child well-being; parents who reported that more of their children's and family's service needs were unmet reported lower child well-being. An indirect relationship was also found between child function and child well-being. When parents reported that their formal support needs were adequately met, their children's functional difficulties had a lower impact on parent perceptions of their children's overall well-being. CONCLUSIONS: Taken together, the results of the current study enrich our understanding of well-being for children with NDD. Discussion focuses on the service implications for children with NDD and their families. PMID- 29250822 TI - Anatomy of the lower respiratory tract in domestic birds, with emphasis on respiration. AB - This manuscript describes the anatomy of the lower respiratory tract in domestic bird species including the chicken and pigeon. The here described anatomical structures play a major role avian respiration, which is fundamentally different from respiration in mammals. During inspiration and expiration, a continuous caudocranial airflow is present within the tertiary bronchi of the Paleopulmo, while the Neopulmo, which is only present in phylogenetically recent species, is characterized by tidal respiration. Various anatomical structures and aerodynamic mechanisms have been described in an attempt to explain the proposed mechanism of respiration. The air sac system that is essential for avian respiration usually comprises an unpaired clavicular air sac and paired cervical, cranial and caudal thoracic, and abdominal air sacs. The latter are by far the larger and are interwoven with the abdominal organs. PMID- 29250823 TI - Transcriptome analysis of ultraviolet A-induced photoaging cells with deep sequencing. AB - Gene expression changes associate with many biological processes. However, the relative consequences of the genetic alterations induced by ultraviolet (UV)-A radiation on skin photoaging are still not clear. Here, we performed deep sequencing of the transcriptome and explored altered genes related to biological changes in repeated UV-A-irradiated human dermal fibroblasts (HDF) to better understand the skin photoaging mechanisms. The repeatedly UV-A-irradiated group (HDF were induced by 10 J/cm2 UV-A twice daily for 7 days) and the control group (HDF without irradiation) were evaluated. Expression genes profile was measured and compared using high-throughput sequencing on an Illumina HiSeq 2500 platform and DEGseq. Functional annotation and metabolic pathway analysis of genes with altered expression were preformed via National Center for Biotechnology Information, Uniprot, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. Genes related to skin photoaging were verified by quantitative reverse transcription polymerase chain reaction. Transcriptome comparison revealed that 607 genes exhibited significant changes (P < 0.05), of which 238 genes were upregulated and 369 downregulated in UV-A-irradiated HDF. Functional annotations showed that genes altered by UV-A irradiation took part in a variety of biological process, cellular component synthesis, molecular function and metabolic pathway. Photoaging-related genes encoding elastin, sprout, cathepsin K, cathepsin D, cathepsin B ribose-phosphate diphosphokinase and phosphoglucomutase were identified to be changed. We obtained the comprehensive transcriptome and altered genes in repeated UV-A-irritated HDF and identified that the modulated genes were related to a wide panel of pathways and functions. Our results provide new insights into photoaging molecular mechanisms and suggest some novel targets for interfering in skin photoaging. PMID- 29250824 TI - ABCB1 and CYP2D6 polymorphisms and treatment response of psychotic patients in a naturalistic setting. AB - OBJECTIVES: The aim of our study was to examine the association between ABCB1 polymorphisms G2677T/A (rs2032582) and C3435T (rs1045642) and common CYP2D6 variants, with the response to antipsychotic treatment of psychotic patients, in a naturalistic setting, in Greece. METHODS: One hundred patients suffering from schizophrenia and other psychotic disorders were included in the study. Dosages were normalized to chlorpromazine equivalents. Response following 1 month of treatment was assessed as either a continuous variable, using the distribution of the corrected Positive and Negative Syndrome Scale percent change, or as a dichotomous variable defined as the number of patients scoring >=30% from the corrected baseline Positive and Negative Syndrome Scale score. Genotyping was achieved with established polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: With response treated as a continuous variable, the homozygous recessive rs2032582 genotypes (TT) who were simultaneously carriers of a loss-of-function CYP2D6 allele (*4 or *5) responded significantly worse than the rest of the patients. Comparison of genotype frequencies revealed a statistically significant association of the above combination. No significant association between chlorpromazine equivalents and the tested genotypes was detected. CONCLUSION: We have detected a possible interaction between ABCB1 and CYP2D6 in affecting response of psychotic patients to drug treatment, in a naturalistic setting. PMID- 29250826 TI - Enhanced neurogenesis and possible synaptic reorganization in the piriform cortex of adult rat following kainic acid-induced status epilepticus. AB - Epileptic seizure has been reported to enhance adult neurogenesis and induce aberrant synaptic reorganization in the human dentate gyrus in the hippocampal formation. However, adult neurogenesis in the extrahippocampal regions has not been well studied. To investigate seizure-enhanced neurogenesis in the extrahippocampal regions, we performed histological and immunohistochemical as well as western blot analyses on the cerebrum of Sprague-Dawley rats (n = 51, male, 7 weeks old, body weight 250-300 g) treated with intraperitoneal injection of kainic acid (KA, 10 mg/kg) to induce status epilepticus (SE) (n = 36) or normal saline solution (n = 15) followed by 5'-bromo-2-deoxyuridine (BrdU) injection to label newborn cells. Even though severe neuronal damage was found in the piriform cortex of rats having SE, immunohistochemistry for double cortin (DCX) revealed an increase in the number of immature neurons in the piriform cortex. Double immunofluorescence staining demonstrated that DCX-positive cells in the piriform cortex were positive for both BrdU and neuronal nuclear antigen. Immunohistochemistry and western blotting revealed increased expressions of synaptophysin and postsynaptic density protein 95 in the piriform cortex of rat having SE. These results suggested the enhanced neurogenesis and possible synaptic reorganization in the piriform cortex of the KA-treated rat. PMID- 29250827 TI - Predictive coding in auditory perception: challenges and unresolved questions. AB - Predictive coding is arguably the currently dominant theoretical framework for the study of perception. It has been employed to explain important auditory perceptual phenomena, and it has inspired theoretical, experimental and computational modelling efforts aimed at describing how the auditory system parses the complex sound input into meaningful units (auditory scene analysis). These efforts have uncovered some vital questions, addressing which could help to further specify predictive coding and clarify some of its basic assumptions. The goal of the current review is to motivate these questions and show how unresolved issues in explaining some auditory phenomena lead to general questions of the theoretical framework. We focus on experimental and computational modelling issues related to sequential grouping in auditory scene analysis (auditory pattern detection and bistable perception), as we believe that this is the research topic where predictive coding has the highest potential for advancing our understanding. In addition to specific questions, our analysis led us to identify three more general questions that require further clarification: (1) What exactly is meant by prediction in predictive coding? (2) What governs which generative models make the predictions? and (3) What (if it exists) is the correlate of perceptual experience within the predictive coding framework? PMID- 29250829 TI - Low bilirubin kernicterus in OTC deficiency. PMID- 29250828 TI - CD4+CD25Hi FoxP3+ regulatory T cells in long-term cardiac xenotransplantation. AB - BACKGROUND: CD4+CD25Hi FoxP3+ T (Treg) cells are a small subset of CD4+ T cells that have been shown to exhibit immunoregulatory function. Although the absolute number of Treg cells in peripheral blood lymphocytes (PBL) is very small, they play an important role in suppressing immune reactivity. Several studies have demonstrated that the number of Treg cells, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of transplanted grafts. In this study, we analyzed Treg cells in PBL of long-term baboon recipients who have received genetically modified cardiac xenografts from pig donors. METHODS: Heterotopic cardiac xenotransplantation was performed on baboons using hearts obtained from GTKO.hCD46 (n = 8) and GTKO.hCD46.TBM (n = 5) genetically modified pigs. Modified immunosuppression regimen included antithymocyte globulin (ATG), anti-CD20, mycophenolate mofetil (MMF), cobra venom factor (CVF), and costimulation blockade (anti-CD154/anti-CD40 monoclonal antibody). FACS analysis was performed on PBLs labeled with anti-human CD4, CD25, and FoxP3 monoclonal antibodies (mAb) to analyze the percentage of Treg cells in six baboons that survived longer than 2 months (range: 42-945 days) after receiving a pig cardiac xenograft. RESULTS: Total WBC count was low due to immunosuppression in baboons who received cardiac xenograft from GTKO.hCD46 and GTKO.hCD46.hTBM donor pigs. However, absolute numbers of CD4+CD25Hi FoxP3 Treg cells in PBLs of long-term xenograft cardiac xenograft surviving baboon recipients were found to be increased (15.13 +/- 1.50 vs 7.38 +/- 2.92; P < .018) as compared to naive or pre-transplant baboons. Xenograft rejection in these animals was correlated with decreased numbers of regulatory T cells. CONCLUSION: Our results suggest that regulatory T (Treg) cells may contribute to preventing or delaying xenograft rejection by controlling the activation and expansion of donor-reactive T cells, thereby masking the antidonor immune response, leading to long-term survival of cardiac xenografts. PMID- 29250830 TI - Suppressive activities and mechanisms of ugonin J on vascular smooth muscle cells and balloon angioplasty-induced neointimal hyperplasia. AB - Neointimal hyperplasia (or restenosis) is primarily attributed to excessive proliferation and migration of vascular smooth muscle cells (VSMCs). In this study, we investigated the inhibitory effects and mechanisms of ugonin J on VSMC proliferation and migration as well as neointimal formation. Cell viability and the cell-cycle distribution were, respectively, analyzed using an MTT assay and flow cytometry. Cell migration was examined using a wound-healing analysis and a transwell assay. Protein expressions and gelatinase activities were, respectively, measured using Western blot and gelatin zymography. Balloon angioplasty-induced neointimal formation was induced in a rat carotid artery model and then examined using immunohistochemical staining. Ugonin J induced cell cycle arrest at the G0 /G1 phase and apoptosis to inhibit VSMC growth. Ugonin J also exhibited marked suppressive activity on VSMC migration. Ugonin J significantly reduced activations of focal adhesion kinase, phosphoinositide 3 kinase, v-akt murine thymoma viral oncogene homolog 1, and extracellular signal regulated kinase 1/2 proteins. Moreover, ugonin J obviously reduced expressions and activity levels of matrix metalloproteinase-2 and matrix metalloproteinase-9. In vivo data indicated that ugonin J prevented balloon angioplasty-induced neointimal hyperplasia. Our study suggested that ugonin J has the potential for application in the prevention of balloon injury-induced neointimal formation. PMID- 29250831 TI - Injectable simvastatin gel for minimally invasive periosteal distraction: In vitro and in vivo studies in rat. AB - OBJECTIVES: To evaluate whether the subperiosteal injection of simvastatin (SIM) with a novel in situ gel-forming system, SrHA/Alg (strontium hydroxyapatite/alginate), can stimulate vertical bone augmentation in a rat calvarial model. MATERIAL AND METHODS: The SrHA/Alg solution was synthesized and combined with different doses of SIM (0.01, 0.02, 0.1, and 0.2 mg) to form the following groups: (1) SrHA/Alg only, (2) SrHA/Alg/0.01, (3) SrHA/Alg/0.02, (4) SrHA/Alg/0.1, and (5) SrHA/Alg/0.2. The SIM release pattern was analyzed, and rat primary periosteum-derived cell (PDC) responses were investigated. Twenty male Wistar rats were enrolled in the calvarial subperiosteal injection experiment with each animal receiving a 200-MUl single subperiosteal injection of SrHA/Alg with different amounts of SIM (0, 0.01, 0.02, and 0.1 mg) incorporated (n = 5). The 0.2 mg dose group was not tested in vivo due to the severe toxicity found in vitro. The new bone formation was assessed histologically and radiologically at 8 weeks. RESULTS: The slow release of SIM was confirmed, and PDC viability decreased in the SrHA/Alg/0.2 group. Alkaline phosphatase positive areas and mineralization areas were significantly greater in the SrHA/Alg/0.01 and SrHA/Alg/0.02 groups (p < .05). The mRNA expression level of Runx2 significantly increased in the SrHA/Alg/SIM-0.02 group by day 7 (p < .05) and significantly higher levels of VEGF were found in the SrHA/Alg/0.01 and SrHA/Alg/0.02 groups at different time points (p < .05). In vivo, no prominent clinical sign of inflammation was observed, and the most significant bone gain was shown in the SrHA/Alg/0.02 group (p < .05). The osteoclast formation within the newly formed bone area was reduced in the SrHA/Alg/0.1 group (p < .05). CONCLUSIONS: When combined with SrHA/Alg system, the 0.02 mg SIM seemed to be the optimal dose to stimulate subperiosteal bone formation without inducing inflammation. This combination may hold potential therapeutic benefits for clinical bone augmentation in a minimally invasive manner. PMID- 29250832 TI - The Self-Assembly of Cellulose Nanocrystals: Hierarchical Design of Visual Appearance. AB - By controlling the interaction of biological building blocks at the nanoscale, natural photonic nanostructures have been optimized to produce intense coloration. Inspired by such biological nanostructures, the possibility to design the visual appearance of a material by guiding the hierarchical self-assembly of its constituent components, ideally using natural materials, is an attractive route for rationally designed, sustainable manufacturing. Within the large variety of biological building blocks, cellulose nanocrystals are one of the most promising biosourced materials, primarily for their abundance, biocompatibility, and ability to readily organize into photonic structures. Here, the mechanisms underlying the formation of iridescent, vividly colored materials from colloidal liquid crystal suspensions of cellulose nanocrystals are reviewed and recent advances in structural control over the hierarchical assembly process are reported as a toolbox for the design of sophisticated optical materials. PMID- 29250833 TI - A rigid, stand-off hybrid dipole, and birdcage coil array for 7 T body imaging. AB - PURPOSE: To design a robust and patient friendly radiofrequency coil array (8 channel transmit and 16-channel receive) for cross-sectional body imaging at 7 T, and to improve our understanding of the combination of dipole and loop like elements for ultra high field strengths. METHODS: The hybrid coil array was optimized in eletromagnetic simulations. Considered array candidates were the dipole, loop and birdcage array. The winning design was constructed and the signal-to-noise (SNR) was compared to a close fitting array at 3 T. Transmit and receive properties for different body sizes were assessed, and multi-parametric maps were acquired with the Plug-and-Play MRF method. RESULTS: The winning design consists of a dipole array for transceive combined with a birdcage array for receive only. The central SNR improved by a factor of 3 as compared to a 3 T system with a local receive array. A transmit efficiency between 2.4 and 3.9 MUT/kW, a specific absorption rate efficiency of 0.25 to 0.53 MUT/W/kg, and a high SNR was achieved in the center for the targeted patient population. CONCLUSION: The constructed coil array is easy to handle, safe, and patient friendly, allowing further development of abdominal imaging at 7 T. Quantitative MRI in the abdomen is possible with Plug-and-Play MRF using the designed coil array. Magn Reson Med 80:822-832, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29250834 TI - Comparison of drug eluting balloon angioplasty to infrapopliteal artery critical lesions with or without additional pedal artery angioplasty in patients with diabetes mellitus and critical limb ischemia. AB - BACKGROUND: The purpose of this study is to investigate the feasibility and outcome of balloon angioplasty for the treatment of below the ankle (BTA) lesions in addition to below the knee (BTK) lesions in diabetic patients with critical limb ischemia (CLI). METHODS: Inclusion criteria are diabetes mellitus (DM), CLI (Rutherford class 4 or higher) and revascularized significant stenosis or occlusion of at least 1 below-the-knee vessel with incomplete or no pedal loop. Target BTK vessel restenosis and reocclusion at 1-year follow-up was the primary end point whereas minor or major amputation at 1-year follow-up was the secondary end point. RESULTS: From July 2012 to June 2016, 48 diabetic patients identified with BTK with additionally BTA lesions were identified. Three patients were lost to follow-up, leaving 45 patients. In 20 patients both BTK and BTA lesion (BTA group) was revascularized whereas only BTK lesion was treated in 25 patients (BTK group). The primary end point is 15.8% in BTA group and 47.8% in BTK group (p:0.059; P > 0.05). Minor or major amputation rate at 1-year follow-up was 15.8% in BTA group and 34.8% in BTA group (p:0.190; P > 0.05). CONCLUSION: Our study shows that additional BTA angioplasty to BTK intervention may improve the primary patency rate and have higher event free rate, which slightly missed the margin of statistically significance. RBC decreased significantly more in BTA group compared to BTK group, which reflected that the outcome of intervention is better with additional BTA angioplasty. PMID- 29250835 TI - EM algorithm estimation of a structural equation model for the longitudinal study of the quality of life. AB - Health-related quality of life (HRQoL) data are measured via patient questionnaires, completed by the patients themselves at different time points. We focused on oncology data gathered through the use of European Organization for Research and Treatment of Cancer questionnaires, which decompose HRQoL into several functional dimensions, several symptomatic dimensions, and the global health status (GHS). We aimed to perform a global analysis of HRQoL and reduce the number of analyses required by using a two-step approach. First, a structural equation model (SEM) was used for each time point; in these models, the GHS is explained by two latent variables. Each latent variable is a factor that summarizes, respectively, the functional dimensions and the symptomatic dimensions to the global measurement. This is achieved through the maximization of the likelihood of each SEM using the EM algorithm, which has the advantage of giving an estimation of the subject-specific factors and the influence of additional explanatory variables. Then, to consider the longitudinal aspect, the GHS variable and the two factors were concatenated for each patient visit at which the questionnaire was completed. The GHS and the two factors estimated in the first step can then be explained by additional explanatory variables using a linear mixed model. PMID- 29250837 TI - Abstracts of the 17th Annual Congress of the French Speaking Society of Transplantation, La Rochelle, France, 12-15 December 2017. PMID- 29250836 TI - MR scanning, tattoo inks, and risk of thermal burn: An experimental study of iron oxide and organic pigments: Effect on temperature and magnetic behavior referenced to chemical analysis. AB - BACKGROUND: Tattooed persons examined with magnetic resonance imaging (MRI) can develop burning sensation suggested in the literature to be thermal burn from the procedure. MRI-induced thermal effect and magnetic behavior of known tattoo pigments were examined ex vivo. MATERIALS AND METHODS: Magnetic resonance imaging effects on 3 commonly used commercial ink stock products marketed for cosmetic tattooing was studied. A main study tested 22 formulations based on 11 pigment raw materials, for example, one line of 11 called pastes and another called dispersions. Samples were spread in petri dishes and tested with a 0.97 T neodymium solid magnet to observe visual magnetic behavior. Before MRI, the surface temperature of the ink was measured using an infrared probe. Samples were placed in a clinical 3T scanner. Two scans were performed, that is, one in the isocenter and one 30 cm away from the center. After scanning, the surface temperature was measured again. Chemical analysis of samples was performed by mass spectroscopy. RESULTS: Mean temperature increase measured in the isocenter ranged between 0.14 and 0.26 degrees C (P < .01) and in the off-center position from -0.16 to 0.21 degrees C (P < .01). Such low increase of temperature is clinically irrelevant. Chemical analysis showed high concentrations of iron, but also nickel and chrome were found as contaminants. High concentration of iron was not associated with any increase of temperature or any physical draw or move of ink. CONCLUSION: The study could not confirm any clinically relevant temperature increase of tattoo pigments after MRI. PMID- 29250838 TI - Artificial Muscles: Mechanisms, Applications, and Challenges. AB - The area of artificial muscle is a highly interdisciplinary field of research that has evolved rapidly in the last 30 years. Recent advances in nanomaterial fabrication and characterization, specifically carbon nanotubes and nanowires, have had major contributions in the development of artificial muscles. However, what can artificial muscles really do for humans? This question is considered here by first examining nature's solutions to this design problem and then discussing the structure, actuation mechanism, applications, and limitations of recently developed artificial muscles, including highly oriented semicrystalline polymer fibers; nanocomposite actuators; twisted nanofiber yarns; thermally activated shape-memory alloys; ionic-polymer/metal composites; dielectric elastomer actuators; conducting polymers; stimuli-responsive gels; piezoelectric, electrostrictive, magnetostrictive, and photostrictive actuators; photoexcited actuators; electrostatic actuators; and pneumatic actuators. PMID- 29250839 TI - Comments on "Marginalized multilevel hurdle and zero-inflated models for overdispersed and correlated count data with excess zeros". PMID- 29250840 TI - Preface. PMID- 29250841 TI - Corrections to effect size variances for continuous outcomes of crossover clinical trials. PMID- 29250842 TI - Phytotherapeutic effects of the fruits of Poncirus trifoliata (L.) Raf. on cancer, inflammation, and digestive dysfunction. AB - Poncirus trifoliata (L.) Raf. belongs to the family Rutaceae in the genus Poncirus. Its fruits are widely used to alleviate symptoms of various disorders. The mature fruit (MF) possesses anticancer and antiinflammatory activities. Extracts of the dried, immature fruit, Poncirus fructus (PF) are widely used as a traditional medicine for ameliorating symptoms of digestive dysfunction in East Asia. Molecular and cellular mechanisms underlying the effects of MF and PF extracts on cancer, inflammation, and gastrointestinal disorders have been extensively studied in the past decade. This review summarizes recent findings on the anticancer and antiinflammatory effects of MF and the prokinetic effects of PF. Although the therapeutic effects of MF and PF have been clearly elucidated, in-depth further clinical studies are still required to completely verify the clinical efficacy and safety of the fruits of P. trifoliata (L.) Raf. PMID- 29250843 TI - Insulin resistance improvement by cinnamon powder in polycystic ovary syndrome: A randomized double-blind placebo controlled clinical trial. AB - Our aim is to assess the effect of cinnamon powder capsules on insulin resistance, anthropometric measurements, glucose and lipid profiles, and androgens of women with polycystic ovarian syndrome (PCOS). Out of 80 women that were diagnosed as PCOS by Rotterdam Criteria, 66 were enrolled in this randomized double-blind placebo-controlled clinical trial. All of the PCOS women were taking medroxy progesterone acetate 10 mg/day for the last 10 days of their menstrual cycles. The cases were randomly allocated to 2 groups. The women in the first group were treated by cinnamon powder capsules 1.5 g/day in 3 divided doses for 12 weeks and the second group by similar placebo capsules. Anthropometric measurements, fasting blood sugar, fasting insulin, blood glucose 2 hr after taking 75 g oral glucose, HbA1c, testosterone, dehydroepiandrosterone sulphate, homeostatic model assessment for insulin resistance, triglyceride, and cholesterol (low-density lipoprotein, high-density lipoprotein, and total) before and after the intervention were evaluated and compared as outcome measures. Fasting insulin (p = .024) and homeostatic model assessment for insulin resistance (p = .014) were reduced after 12 weeks in the cinnamon group compared with the placebo. There was also a significant decrease in low-density lipoprotein in cinnamon group (p = .004) as compared with baseline that caused significant difference with placebo (p = .049). However, changes in other outcome measurements did not lead to statistically significant difference with placebo. The present results suggest that complementary supplementation of cinnamon significantly reduced fasting insulin and insulin resistance in women with PCOS. PMID- 29250844 TI - Intractable epilepsy due to a rosette-forming glioneuronal tumor with a dysembryoplastic neuroepithelial background. AB - A rosette-forming glioneuronal tumor (RGNT) was initially reported as an infratentorial tumor that comprised both small neurocytic rosettes and astrocytic components. However, a few studies have reported supratentorial RGNTs arising in the cerebral hemispheres. Here, we report an unusual case involving a 9-year-old boy with a supratentorial RGNT who presented with intractable epilepsy and behavioral changes. Brain MRI revealed a well-circumscribed space-occupying lesion with septae in the right inferomedial parietal lobe. Electroencephalography showed multifocal spikes over the right frontal, temporal and parietal regions. The seizure frequency decreased dramatically after tumorectomy. Histopathological examination revealed prominent neurocytic rosette formation appearing with the specific glioneuronal element of a dysembryoplastic neuroepithelial tumor (DNT). Although the pathogenesis has not been elucidated, a supratentorial RGNT presenting with epilepsy may exhibit a rosette component, which is the major feature of this tumor, against the background of a specific glioneuronal element mimicking DNT. However, RGNT arising in regions other than the fourth ventricle is rare, and the pathogenesis of epilepsy due to RGNT has not been fully elucidated. Further clinical and histological studies are required to understand the pathology underlying epilepsy caused by RGNT. PMID- 29250845 TI - Fitness-related differences in the rate of whole-body total heat loss in exercising young healthy women are heat-load dependent. AB - NEW FINDINGS: What is the central question of this study? Aerobic fitness modulates heat loss, albeit the heat load at which fitness-related differences occur in young healthy women remains unclear. What is the main finding and its importance? We demonstrate using direct calorimetry that fitness modulates heat loss in a heat-load dependent manner, with differences occurring between young women of low and high fitness and matched physical characteristics when the metabolic heat load is at least 400 W in hot, dry conditions. Although fitness has been known for some time to modulate heat loss, our findings define the metabolic heat load at which fitness-related differences occur. ABSTRACT: Aerobic fitness has recently been shown to alter heat loss capacity in a heat-load dependent manner in young men. However, given that sex-related differences in heat loss capacity exist, it is unclear whether this response is consistent in women. We therefore assessed whole-body total heat loss in young (21 +/- 3 years old) healthy women matched for physical characteristics, but with low (low-fit; 35.8 +/- 4.5 ml O2 kg-1 min-1 ) or high aerobic fitness (high-fit; 53.1 +/- 5.1 ml O2 kg-1 min-1 ; both n = 8; indexed by peak oxygen consumption), during three 30 min bouts of cycling performed at increasing rates of metabolic heat production of 250 (Ex1), 325 (Ex2) and 400 W (Ex3), each separated by a 15 min recovery, in hot, dry conditions (40 degrees C, 11% relative humidity). Whole body total heat loss (evaporative +/- dry heat exchange) and metabolic heat production were measured using direct and indirect calorimetry, respectively. Body heat content was measured as the temporal summation of heat production and loss. Total heat loss did not differ during Ex1 (low-fit, 215 +/- 16 W; high-fit, 231 +/- 20 W; P > 0.05) and Ex2 (low-fit, 278 +/- 15 W; high-fit, 301 +/- 20 W; P > 0.05), but was lower in the low-fit (316 +/- 21 W) compared with the high-fit women (359 +/- 32 W) during Ex3 (P < 0.01). Consequently, the low-fit group stored 1.3-fold more heat (429 +/- 61 kJ) throughout the three exercise bouts relative to the high-fit group (330 +/- 113 kJ; P < 0.05). We show that aerobic fitness independently modulates heat loss capacity during exercise in hot, dry conditions in women separated by a peak oxygen consumption of ~17 ml O2 kg-1 min-1 starting at a metabolic heat load of 400 W. PMID- 29250846 TI - Realizing Efficient Lead-Free Formamidinium Tin Triiodide Perovskite Solar Cells via a Sequential Deposition Route. AB - Recently, the evolved intermediate phase based on iodoplumbate anions that mediates perovskite crystallization has been embodied as the Lewis acid-base adduct formed by metal halides (serve as Lewis acid) and polar aprotic solvents (serve as Lewis base). Based on this principle, it is proposed to constitute efficient Lewis acid-base adduct in the SnI2 deposition step to modulate its volume expansion and fast reaction with methylammonium iodide (MAI)/formamidinium iodide (FAI) (FAI is studied hereafter). Herein, trimethylamine (TMA) is employed as the additional Lewis base in the tin halide solution to form SnY2 -TMA complexes (Y = I- , F- ) in the first-step deposition, followed by intercalating with FAI to convert into FASnI. It is shown that TMA can facilitate homogeneous film formation of a SnI2 (+SnF2 ) layer by effectively forming intermediate SnY2 TMA complexes. Meanwhile, its relatively larger size and weaker affinity with SnI2 than FA+ ions will facilitate the intramolecular exchange with FA+ ions, thereby enabling the formation of dense and compact FASnI3 film with large crystalline domain (>1 um). As a result, high power conversion efficiencies of 4.34% and 7.09% with decent stability are successfully accomplished in both conventional and inverted perovskite solar cells, respectively. PMID- 29250847 TI - Calix[4]arene-Based Dynamic Covalent Gels: Marriage of Robustness, Responsiveness, and Self-Healing. AB - Herein, the report on a new class of self-healing and pH/temperature responsive mixed solvent (ethanol and water) gels shows unusual mechanical properties to resist slicing, sustain high compression, and withstand stretching as evidenced by the cutting breaking stress, the fracture compressive stress, and the stretching ratio of one of the gels as obtained can reach or exceed 26.4 MPa, 9.2 MPa, and ~5 times, respectively. The gels are designed by introducing dynamic covalent bond, acylhydrazone, which is believed to combine the merits of conventional chemical bonds and those of supramolecular interactions. Specifically, a hydrazide-modified calix[4]arene derivative and linear benzaldehyde-terminated poly(ethylene glycol)s are synthesized and used as reactive components to build gel networks. Interestingly, acid-degradable hydrogel can be obtained via natural drying of the mixed solvent gel first and then swelling in pure water. PMID- 29250848 TI - Informal caregivers' views on the division of responsibilities between themselves and professionals: A scoping review. AB - This scoping review focuses on the views of informal caregivers regarding the division of care responsibilities between citizens, governments and professionals and the question of to what extent professionals take these views into account during collaboration with them. In Europe, the normative discourse on informal care has changed. Retreating governments and decreasing residential care increase the need to enhance the collaboration between informal caregivers and professionals. Professionals are assumed to adequately address the needs and wishes of informal caregivers, but little is known about informal caregivers' views on the division of care responsibilities. We performed a scoping review and searched for relevant studies published between 2000 and September 1, 2016 in seven databases. Thirteen papers were included, all published in Western countries. Most included papers described research with a qualitative research design. Based on the opinion of informal caregivers, we conclude that professionals do not seem to explicitly take into account the views of informal caregivers about the division of responsibilities during their collaboration with them. Roles of the informal caregivers and professionals are not always discussed and the division of responsibilities sometimes seems unclear. Acknowledging the role and expertise of informal caregivers seems to facilitate good collaboration, as well as attitudes such as professionals being open and honest, proactive and compassionate. Inflexible structures and services hinder good collaboration. Asking informal caregivers what their opinion is about the division of responsibilities could improve clarity about the care that is given by both informal caregivers and professionals and could improve their collaboration. Educational programs in social work, health and allied health professions should put more emphasis on this specific characteristic of collaboration. PMID- 29250849 TI - Percutaneous endoscopic colostomy for adults with chronic constipation: Retrospective case series of 12 patients. AB - BACKGROUND: Percutaneous endoscopic colostomy (PEC) is a technique derived from percutaneous endoscopic gastrostomy. When conservative treatment of chronic obstipation fails, colon irrigation via PEC seems less invasive than surgical interventions. However, previous studies have noted high complication rates of PEC, mostly related to infections. Our aim was to report our experiences with PEC in patients with chronic refractory constipation. METHODS: Retrospective analysis of all patients who underwent PEC for refractory constipation in our secondary referral hospital between 2009 and 2016. KEY RESULTS: Twelve patients received a PEC for chronic, refractory constipation. Short-term efficacy for relief of constipation symptoms was good in 8 patients and moderate in 4 patients. Two patients had the PEC removed because of spontaneous improvement of constipation. Three patients, who initially noticed a positive effect, preferred an ileostomy over PEC after 1-5 years. One PEC was removed because of an abscess. Long-term efficacy is 50%: 6 patients still use their PEC after 3.3 years of follow-up. No mortality occurred. CONCLUSIONS AND INTERFERENCES: PEC offers a technically easily feasible and safe treatment option for patients with chronic constipation not responding to conventional therapy. Long-term efficacy of PEC in our patients is 50%. PMID- 29250850 TI - Intraoperative thermographic imaging-A potential "solution" to Del Nido cardioplegia. PMID- 29250851 TI - Administrative databases for outcomes research-quick, easy, but dirty. PMID- 29250854 TI - Predictive cues for auditory stream formation in humans and monkeys. AB - Auditory perception is improved when stimuli are predictable, and this effect is evident in a modulation of the activity of neurons in the auditory cortex as shown previously. Human listeners can better predict the presence of duration deviants embedded in stimulus streams with fixed interonset interval (isochrony) and repeated duration pattern (regularity), and neurons in the auditory cortex of macaque monkeys have stronger sustained responses in the 60-140 ms post-stimulus time window under these conditions. Subsequently, the question has arisen whether isochrony or regularity in the sensory input contributed to the enhancement of the neuronal and behavioural responses. Therefore, we varied the two factors isochrony and regularity independently and measured the ability of human subjects to detect deviants embedded in these sequences as well as measuring the responses of neurons the primary auditory cortex of macaque monkeys during presentations of the sequences. The performance of humans in detecting deviants was significantly increased by regularity. Isochrony enhanced detection only in the presence of the regularity cue. In monkeys, regularity increased the sustained component of neuronal tone responses in auditory cortex while isochrony had no consistent effect. Although both regularity and isochrony can be considered as parameters that would make a sequence of sounds more predictable, our results from the human and monkey experiments converge in that regularity has a greater influence on behavioural performance and neuronal responses. PMID- 29250853 TI - Participation in school-related activities that require hand use for children with and without developmental disabilities. AB - BACKGROUND: Children with developmental disabilities (DD) may experience limited participation in school activities. Little is known about whether school participation of children with DD who attend special schools is impacted. This study specifically focused on physical engagement in school-related activities that require hand use for the comparison between this group of children with DD and typically developing children. METHODS: The sample consisted of 97 children with DD who attended special schools (mean age 8.2 +/- 2.9 years; 60 boys and 37 girls) and 105 typically developing children who attended mainstream schools/kindergartens (mean age 8.6 +/- 2.4 years; 48 boys and 57 girls). Parents completed the Children's Assessment of Participation with Hands, one of the domains of which captures participation in eight school-related activities involving hand use. RESULTS: Parents of children with DD reported that their children participated less, in terms of the number (chi2 = 8.45-14.97, P <= 0.004) and frequency (t = 4.00-6.47, P < 0.001), in four activities than typically developing children. Parents of children with DD also reported that more assistance was needed for their children's participation in all activities (t = 6.93-11.92, P < 0.001), and they wanted their children to participate in most activities more often and more independently (chi2 = 18.46-59.34, P < 0.001). CONCLUSIONS: Differences in participation in school-related activities requiring hand use between children with DD and typically developing children were revealed generally across all participation dimensions (does participate, frequency, independence, and desired change). This study provides information on the areas in which greater efforts are needed to support children's school participation. PMID- 29250855 TI - Functional connectivity based parcellation of early visual cortices. AB - Human brain can be divided into multiple brain regions based on anatomical and functional properties. Recent studies showed that resting-state connectivity can be utilized for parcellating brain regions and identifying their distinctive roles. In this study, we aimed to parcellate the primary and secondary visual cortices (V1 and V2) into several subregions based on functional connectivity and to examine the functional characteristics of each subregion. We used resting state data from a research database and also acquired resting-state data with retinotopy results from a local site. The long-range connectivity profile and three different algorithms (i.e., K-means, Gaussian mixture model distribution, and Ward's clustering algorithms) were adopted for the parcellation. We compared the parcellation results within V1 and V2 with the eccentric map in retinotopy. We found that the boundaries between subregions within V1 and V2 were located in the parafovea, indicating that the anterior and posterior subregions within V1 and V2 corresponded to peripheral and central visual field representations, respectively. Next, we computed correlations between each subregion within V1 and V2 and intermediate and high-order regions in ventral and dorsal visual pathways. We found that the anterior subregions of V1 and V2 were strongly associated with regions in the dorsal stream (V3A and inferior parietal gyrus), whereas the posterior subregions of V1 and V2 were highly related to regions in the ventral stream (V4v and inferior temporal gyrus). Our findings suggest that the anterior and posterior subregions of V1 and V2, parcellated based on functional connectivity, may have distinct functional properties. PMID- 29250852 TI - Temporal coupling of field potentials and action potentials in the neocortex. AB - The local field potential (LFP) is an aggregate measure of group neuronal activity and is often correlated with the action potentials of single neurons. In recent years, investigators have found that action potential firing rates increase during elevations in power high-frequency band oscillations (50-200 Hz range). However, action potentials also contribute to the LFP signal itself, making the spike-LFP relationship complex. Here, we examine the relationship between spike rates and LFP in varying frequency bands in rat neocortical recordings. We find that 50-180 Hz oscillations correlate most consistently with high firing rates, but that other LFP bands also carry information relating to spiking, including in some cases anti-correlations. Relatedly, we find that spiking itself and electromyographic activity contribute to LFP power in these bands. The relationship between spike rates and LFP power varies between brain states and between individual cells. Finally, we create an improved oscillation based predictor of action potential activity by specifically utilizing information from across the entire recorded frequency spectrum of LFP. The findings illustrate both caveats and improvements to be taken into account in attempts to infer spiking activity from LFP. PMID- 29250856 TI - Simultaneous bilateral-knee MR imaging. AB - PURPOSE: To demonstrate and evaluate the scan time and quantitative accuracy of simultaneous bilateral-knee imaging compared with single-knee acquisitions. METHODS: Hardware modifications and safety testing was performed to enable MR imaging with two 16-channel flexible coil arrays. Noise covariance and sensitivity-encoding g-factor maps for the dual-coil-array configuration were computed to evaluate coil cross-talk and noise amplification. Ten healthy volunteers were imaged on a 3T MRI scanner with both dual-coil-array bilateral knee and single-coil-array single-knee configurations. Two experienced musculoskeletal radiologists compared the relative image quality between blinded image pairs acquired with each configuration. Differences in T2 relaxation time measurements between dual-coil-array and single-coil-array acquisitions were compared with the standard repeatability of single-coil-array measurements using a Bland-Altman analysis. RESULTS: The mean g-factors for the dual-coil-array configuration were low for accelerations up to 6 in the right-left direction, and minimal cross-talk was observed between the two coil arrays. Image quality ratings of various joint tissues showed no difference in 89% (95% confidence interval: 85-93%) of rated image pairs, with only small differences ("slightly better" or "slightly worse") in image quality observed. The T2 relaxation time measurements between the dual-coil-array configuration and the single-coil configuration showed similar limits of agreement and concordance correlation coefficients (limits of agreement: -0.93 to 1.99 ms; CCC: 0.97 (95% confidence interval: 0.96-0.98)), to the repeatability of single-coil-array measurements (limits of agreement: -2.07 to 1.96 ms; CCC: 0.97 (95% confidence interval: 0.95 0.98)). CONCLUSION: A bilateral coil-array setup can image both knees simultaneously in similar scan times as conventional unilateral knee scans, with comparable image quality and quantitative accuracy. This has the potential to improve the value of MRI knee evaluations. Magn Reson Med 80:529-537, 2018. (c) 2017 International Society for Magnetic Resonance in Medicine. PMID- 29250857 TI - Theta oscillations reflect conflict processing in the perception of the McGurk illusion. AB - The McGurk illusion is one of the most famous illustrations of cross-modal integration in human perception. It has been often used as a proxy of audiovisual (AV) integration and to infer the properties of the integration process in natural (congruent) AV conditions. Nonetheless, a blatant difference between McGurk stimuli and natural, congruent, AV speech is the conflict between the auditory and the visual information in the former. Here, we hypothesized that McGurk stimuli (and any AV incongruency) engage brain responses similar to those found in more general cases of perceptual conflict (e.g., Stroop), and propose that the McGurk illusion arises as a result of the resolution of such conflict. We used electroencephalography to measure variations in the power of theta, a well-known marker of the brain response to conflict. The results showed that perception of AV McGurk stimuli, just like AV incongruence in general, induces an increase in activity in the theta band. This response was similar to that evoked by Stroop stimuli, as measured in the same participants. This finding suggests that the McGurk illusion is mediated by general-purpose conflict mechanisms, and calls for caution in generalizing findings obtained using the McGurk illusion, to the general case of multisensory integration. PMID- 29250858 TI - Structural and sequence variants in patients with Silver-Russell syndrome or similar features-Curation of a disease database. AB - Silver-Russell syndrome (SRS) is a clinically and molecularly heterogeneous disorder involving prenatal and postnatal growth retardation, and the term SRS like is broadly used to describe individuals with clinical features resembling SRS. The main molecular subgroups are loss of methylation of the distal imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 (50%) and maternal uniparental disomy of chromosome 7 (5%-10%). Through a comprehensive literature search, we identified 91 patients/families with various structural and small sequence variants, which were suggested as additional molecular defects leading to SRS/SRS-like phenotypes. However, the molecular and phenotypic data of these patients were not standardized and therefore not comparable, rendering difficulties in phenotype-genotype comparisons. To overcome this challenge, we curated a disease database including (epi)genetic phenotypic data of these patients. The clinical features are scored according to the Netchine-Harbison clinical scoring system (NH-CSS), which has recently been accepted as standard by consensus. The structural and sequence variations are reviewed and where necessary redescribed according to recent recommendations. Our study provides a framework for both research and diagnostic purposes through facilitating a standardized comparison of (epi)genotypes with phenotypes of patients with structural/sequence variants. PMID- 29250859 TI - Multitemperature Responsive Self-Folding Soft Biomimetic Structures. AB - Untethered, millimeter-scale, stimuli-responsive shape change structures are critical to the function of autonomous devices, smart materials, and soft robotics. Temperature in a range compatible with physiological or ambient environmental conditions is an excellent cue to trigger actuation of soft structures for practical biomimetic applications. Previously, a range of thermally responsive self-folding soft structures has been described and utilized in a variety of applications from tissue engineering to minimally invasive surgery. In order to extend these concepts to more complex devices, thermally responsive bilayer structures composed of poly[oligo (ethylene glycol) methyl ether methacrylate] (POEGMA) gels that swell at three different temperatures are described. The lower critical solution temperature and volume transition temperature of POEGMA are tuned by varying the side chain length and the extent of copolymerization. The swelling properties of the POEGMA gels are characterized and a multilayer photopatterning process is described that is used to create soft biomimetic structures that change shape in a sequential manner while displaying multistate behaviors. PMID- 29250860 TI - Effect of organic acids or probiotics alone or in combination on growth performance, nutrient digestibility, enzyme activities, intestinal morphology and gut microflora in broiler chickens. AB - A feeding trial was conducted to determine the effect of organic acids or probiotics alone or in combination on growth performance, nutrient digestibility, enzyme activity, intestinal morphology and gut microflora in broiler chickens (Ross308). A completely randomized design was used, with 1,440 broiler chicks across four treatments and five replications of 72 chicks each. The chicks in the control treatment were fed on a control diet (CD), whereas for the other treatment groups, the CD was supplemented with 0.2 g/kg organic acids (CDOA), probiotics (CDP) or a combination of organic acids and probiotics (CDOAP). All the chicks were fed ad libitum during the feeding trial throughout 35 days. A total of 20 chicks were randomly allotted to individual metabolic cages to measure the nutrient digestibility (35-42 days) and the digestive enzyme activities (42 days). The intestinal morphology and gut microflora of 80 chicks were examined at the end of experiment. There were no significant (p > .05) differences in the feed intake, body weight gain or feed conversion ratio of the chicks across the four dietary treatments. The crude fibre digestibility was significantly increased in chicks fed on CDOA or CDOAP relative to CD (p < .05). Nutrient utilization, in terms of digestive enzyme activities and excreta thermal property, was unchanged by any supplementation. The chicks fed on the CDOAP had significantly higher duodenal villi height and crypt depth than the chicks fed on CDOA (p < .05). This dietary treatment dramatically improved gut microflora by decreasing the population of Escherichia coli and increasing the Lactobacillus spp.:E. coli ratio. Based on our investigations, supplementation of organic acids and probiotics in chick diets can increase the ability to digest crude fibre and villus height and decrease intestinal E. coli without impairing growth performance. PMID- 29250861 TI - Cortical stimulation relieves parkinsonian pathological activity in vitro. AB - Previously, we have shown that chemical excitatory drives such as N-methyl-d aspartate (NMDA) are capable of activating the striatal microcircuit exhibiting neuronal ensembles that alternate their activity producing temporal sequences. One aim of this work was to demonstrate whether similar activity could be evoked by delivering cortical stimulation. Dynamic calcium imaging allowed us to follow the activity of dozens of neurons with single-cell resolution in mus musculus brain slices. A train of electrical stimuli in the cortex evoked network activity similar to the one induced by bath application of NMDA. Previously, we have also shown that the dopamine-depleted striatal microcircuit increases its spontaneous activity generating dominant recurrent ensembles that interrupt the temporal sequences found in control microcircuits. This activity correlates with parkinsonian pathological activity. Several cortical stimulation protocols such as transcranial magnetic stimulation reduce motor signs of Parkinsonism. Here, we show that cortical stimulation in vitro temporarily eliminates the pathological activity from the dopamine-depleted striatal microcircuit by turning off some neurons that sustain this activity and recruiting new ones that allow transitions between network states, similar to the control circuit. When cortical stimulation is given in the presence of L-DOPA, parkinsonian activity is eliminated during the whole recording period. The present experimental evidence suggests that cortical stimulation such as that generated by transcranial magnetic stimulation, or otherwise, may allow reduce L-DOPA dosage. PMID- 29250862 TI - Azathioprine monotherapy in autoimmune blistering diseases: A feasible option for mild to moderate cases. AB - Azathioprine (AZP) is used as a corticosteroid (CS)-sparing medication to treat autoimmune blistering diseases. In this study, we examined the efficacy of AZP and the feasibility of using AZP monotherapy (without CS) to treat pemphigus and pemphigoid. We performed a retrospective study of 10 Japanese patients (seven with pemphigus and three with pemphigoid) with mild to moderate disease activity who had been treated using AZP. The treatment efficacy was evaluated based on decreases in the disease activity scores and autoantibody titers. The results demonstrate that seven out of 10 cases (70%) were treated successfully using AZP monotherapy with no severe adverse effects. The disease activity scores of the successfully-treated patients decreased to zero after 1-37.5 months (average, 11.9) and the average disease activity scores in these cases decreased significantly at 2 months (38.2 +/- 36.6%) compared with the scores of the three patients who required additional systemic CS therapy (77.5 +/- 3.5%) (P < 0.05). Additionally, the autoantibody titers of five cases treated successfully using AZP decreased by half at 6 months. In conclusion, our findings suggest that AZP monotherapy is a viable treatment option for mild to moderate pemphigus and pemphigoid. PMID- 29250864 TI - Small bowel fed response as measured by wireless motility capsule: Comparative analysis in healthy, gastroparetic, and constipated subjects. AB - BACKGROUND: Small bowel fed response is an increased contractile activity pattern following the ingestion of a meal. Postprandial motility is traditionally evaluated using small bowel manometry. Wireless motility capsule (WMC) is an ingestible wireless capsule that measures pH, temperature, and intraluminal pressure. The primary aim of the study was to assess small bowel fed response captured with the non-invasive WMC. The secondary aim was to compare the fed response patterns between healthy subjects and patients with motility disorders of gastroparesis and constipation. METHODS: All subjects had 250 cc Ensure(r) meal 6 hours after WMC ingestion. Frequency of contractions (Ct), area under the curve (AUC), and motility index (MI) were analyzed during 30 minutes of pre prandial baseline and 60 minutes postprandially in 20-minute windows. KEY RESULTS: One hundred and eighty-eight subjects (107 healthy, 23 gastroparetics, 58 constipated) were analyzed. Healthy: Ct, AUC, and MI all increased significantly immediately after meal ingestion (P < .01). Motility parameters peak at 20-40 minutes postmeal. The motor activity decreased at the end of postprandial hour, but was still significantly higher than the fasting baseline (P < .01). Gastroparetics: All motility parameters failed to increase significantly compared to the baseline throughout the entire postprandial hour. Constipated: The fed response was similar to healthy subjects. CONCLUSIONS AND INFERENCES: The small bowel fed response was readily observed in healthy and chronic constipation subjects with WMC but is blunted in gastroparetics. A blunted small bowel fed response suggests neuropathic changes outside the stomach and may contribute to postprandial symptoms. PMID- 29250863 TI - Cyclobutanone Mimics of Intermediates in Metallo-beta-Lactamase Catalysis. AB - The most important resistance mechanism to beta-lactam antibiotics involves hydrolysis by two beta-lactamase categories: the nucleophilic serine and the metallo-beta-lactamases (SBLs and MBLs, respectively). Cyclobutanones are hydrolytically stable beta-lactam analogues with potential to inhibit both SBLs and MBLs. We describe solution and crystallographic studies on the interaction of a cyclobutanone penem analogue with the clinically important MBL SPM-1. NMR experiments using 19 F-labeled SPM-1 imply the cyclobutanone binds to SPM-1 with micromolar affinity. A crystal structure of the SPM-1:cyclobutanone complex reveals binding of the hydrated cyclobutanone through interactions with one of the zinc ions, stabilisation of the hydrate by hydrogen bonding to zinc-bound water, and hydrophobic contacts with aromatic residues. NMR analyses using a 13 C labeled cyclobutanone support assignment of the bound species as the hydrated ketone. The results inform on how MBLs bind substrates and stabilize tetrahedral intermediates. They support further investigations on the use of transition-state and/or intermediate analogues as inhibitors of all beta-lactamase classes. PMID- 29250865 TI - Measuring health care workers' perceptions of what constitutes a compassionate organisation culture and working environment: Findings from a quantitative feasibility survey. AB - INTRODUCTION: Health care organisation cultures and working environments are highly complex, dynamic and constantly evolving settings. They significantly influence both the delivery and outcomes of care. AIM: Phase 1 quantitative findings are presented from a larger three phase feasibility study designed to develop and test a Cultural Health Check toolkit to support health care workers, patients and organisations in the provision of safe, compassionate and dignified care. METHODOLOGY: A mixed methods approach was applied. The Cultural Health Check Healthcare Workers Questionnaire was distributed across two National Health Service Hospitals in England, UK. Both hospitals allocated two wards comprising of older people and surgical specialities. FINDINGS: The newly devised Cultural Health Check Staff Rating Scale Version 1 questionnaire was distributed to 223 health care workers. Ninety eight responses were returned giving a response rate of 44%. The Cultural Health Check Staff Rating Scale Version 1 has a significant Cronbach alpha of .775; this reliability scaling is reflected in all 16 items in the scale. Exploratory factor analysis identified two significant factors "Professional Practice and Support" and "Workforce and Service Delivery." These factors according to health care workers significantly impact on the organisation culture and quality of care delivered by staff. CONCLUSION: The Cultural Health Check Staff Rating Scale Version 1 questionnaire is a newly validated measurement tool that could be used and applied to gauge health care workers perceptions of an organisations level of compassion. Historically we have focused on identifying how caring and compassionate nurses, doctors and related allied health professionals are. This turns the attention on employers of nurses and other related organisations. IMPLICATIONS FOR NURSING MANAGEMENT: The questionnaire can be used to gauge the level of compassion with a health care organisation culture and working environment. Nurse managers and leaders should focus attention regarding how these two factors are supported and resourced in the future. PMID- 29250866 TI - Hyperbranched Aliphatic Polyester via Cross-Metathesis Polymerization: Synthesis and Postpolymerization Modification. AB - A novel postpolymerization modification methodology is demonstrated to achieve selective functionalization of hyperbranched polymer (HBP). Terminal and internal acrylates of HBP derived from cross-metathesis polymerization (CMP) are functionalized in a chemoselective fashion using the thiol-Michael chemistries. Model reactions between different thiols (benzyl mercaptan and methyl thioglycolate) and acrylates (n-hexyl acrylate and ethyl trans-2-decenoate) by using dimethylphenylphosphine or amylamine as the catalyst are investigated to optimize the modification protocol for HBP. High-molecular-weight HBP P0 is generated through CMP of AB2 monomer 2, a compound containing one alpha-olefin and two acrylate metathetically polymerizable groups. CMP kinetics is monitored by NMR and gel permeation chromatography (GPC). Accordingly, microstructural analysis is conducted in detail, and CMP procedure is optimized. Postpolymerization modification of HBP P0 is performed via two distinguished strategies, namely one-step complete modification and sequential modification, to generate terminally and/or internally functionalized HBPs P1-P3 in a chemoselective fashion by using phosphine-initiated and/or base-catalyzed thiol Michael chemistries. Finally, thermal stability and glass transition behaviors of HBPs P0-P3 are studied by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC), respectively. PMID- 29250867 TI - Through your eyes or mine? The neural correlates of mental state recognition in Huntington's disease. AB - Huntington's disease (HD) can impair social cognition. This study investigated whether patients with HD exhibit neural differences to healthy controls when they are considering mental and physical states relating to the static expressions of human eyes. Thirty-two patients with HD and 28 age-matched controls were scanned with fMRI during two versions of the Reading the Mind in the Eyes Task: The standard version requiring mental state judgments, and a comparison version requiring judgments about age. HD was associated with behavioral deficits on only the mental state eyes task. Contrasting the two versions of the eyes task (mental state > age judgment) revealed hypoactivation within left middle frontal gyrus and supramarginal gyrus in HD. Subgroup analyses comparing premanifest HD patients to age-matched controls revealed reduced activity in right supramarginal gyrus and increased activity in anterior cingulate during mental state recognition in these patients, while manifest HD was associated with hypoactivity in left insula and left supramarginal gyrus. When controlling for the effects of healthy aging, manifest patients exhibited declining activation within areas including right temporal pole. Our findings provide compelling evidence for a selective impairment of internal emotional status when patients with HD appraise facial features in order to make social judgements. Differential activity in temporal and anterior cingulate cortices may suggest that poor emotion regulation and emotional egocentricity underlie impaired mental state recognition in premanifest patients, while more extensive mental state recognition impairments in manifest disease reflect dysfunction in neural substrates underlying executive functions, and the experience and interpretation of emotion. PMID- 29250868 TI - A Mechanoresponsive Phase-Changing Electrolyte Enables Fabrication of High-Output Solid-State Photobioelectrochemical Devices from Pigment-Protein Multilayers. AB - Exploitation of natural photovoltaic reaction center pigment proteins in biohybrid architectures for solar energy harvesting is attractive due to their global abundance, environmental compatibility, and near-unity quantum efficiencies. However, it is challenging to achieve high photocurrents in a device setup due to limitations imposed by low light absorbance by protein monolayers and/or slow long-range diffusion of liquid-phase charge carriers. In an attempt to enhance the photocurrent density achievable by pigment proteins, here, an alternative solid-state device architecture enabled by a mechanoresponsive gel electrolyte that can be applied under nondenaturing conditions is demonstrated. The phase-changing electrolyte gel provides a pervading biocompatible interface for charge conduction through highly absorbing protein multilayers that are fabricated in a simple fashion. Assembled devices exhibit enhanced current stability and a maximal photoresponse of ~860 uA cm-2 , a fivefold improvement over the best previous comparable devices under standard illumination conditions. Photocurrent generation is enhanced by directional energy transfer through extended layers of light-harvesting complexes, mimicking the modular antenna/transducer architecture of natural photosystems, and by metastable radical pair formation when photovoltaic reaction centers are embedded throughout light-harvesting regions of the device. PMID- 29250869 TI - Stepping Stones to Resiliency following a community-based two-generation Canadian preschool programme. AB - Early intervention programmes are designed to address complex inequities for Canadian families living with low income, affecting social relationships, well being and mental health. However, there is limited understanding of resiliency and change in families living with low income over time. We conducted a mixed methods study with recent immigrant, other Canadian-born, and Aboriginal families living with low income, who attended a two-generation preschool programme (CUPS One World) between 2002 and 2008. The aim of this study was to develop an understanding of the processes of change. We included 134 children and their caregivers living with low income, and experiencing mental health problems, addiction or social isolation. Children's receptive language, a proxy for school readiness, was measured at programme intake, exit, and age 10 years using the Peabody Picture Vocabulary Test 3rd Edition (PPVT-III). In Phase I (quantitative), we identified children with receptive language scores in the top and bottom 25th percentile, informing participant selection for Phase II. In Phase II (qualitative), we engaged in constructivist grounded theory to explore experiences of 14 biological mothers, after their children (n = 25) reached age 10 years. Interviews were conducted between June and September 2015. The core category, Stepping Stones to Resiliency, encompassed Perceptions of Family, Moving Forward, Achieving Goals, and Completely Different. Perceptions of Family influenced families' capabilities to move across the Stepping Stones to Resiliency. Stepping Stones to Resiliency provides a lens from which to view others in their daily challenges to break free of painful intergenerational cycles. It is a reminder of our struggle, our shared humanness, and that movement towards resiliency is more difficult for some than others. Our findings challenge traditional episodic, biomedical treatment paradigms for low-income families also experiencing intergenerational cycles of mental health problems, addictions, social isolation, and family violence. PMID- 29250870 TI - Uric acid and cardiovascular risk: What genes can say. AB - BACKGROUND: Although the relationship of elevated serum uric acid levels and cardiovascular disease has been established in a great number of studies, the causal relevance of this finding remains ambiguous. An approach to evaluate the causal relevance of biomarkers is to exploit the natural randomised allocation of allelic variation in genes affecting their level, also known as Mendelian randomisation. AIM: The aim of this paper is to review the current literature regarding serum uric acid levels and cardiovascular and renal disease risk in Mendelian randomisation studies. METHODS: PubMed and Scopus databases were searched to retrieve Mendelian studies regarding uric acid, hyperuricaemia and cardiovascular risk. CONCLUSIONS: Genetic evidence based on conventional and novel Mendelian randomisation approaches suggest a modest, if any, causal effect of serum uric acid concentration on the development of cardiovascular disease, suggesting that further study of uric acid genes is needed in order to elucidate the relationship of serum uric acid levels and cardiovascular disease. PMID- 29250871 TI - Selective copying of the majority suggests children are broadly "optimal-" rather than "over-" imitators. AB - Human children, in contrast to other species, are frequently cast as prolific "over-imitators". However, previous studies of "over-imitation" have overlooked many important real-world social dynamics, and may thus provide an inaccurate account of this seemingly puzzling and potentially maladaptive phenomenon. Here we investigate this topic using a cultural evolutionary approach, focusing particularly on the key adaptive learning strategy of majority-biased copying. Most "over-imitation" research has been conducted using consistent demonstrations to the observer, but we systematically varied the frequency of demonstrators that 4- to 6-year-old children observed performing a causally irrelevant action. Children who "over-imitate" inflexibly should copy the majority regardless of whether the majority solution omits or includes a causally irrelevant action. However, we found that children calibrated their tendency to acquire the majority behavior, such that copying did not extend to majorities that performed irrelevant actions. These results are consistent with a highly functional, adaptive integration of social and causal information, rather than explanations implying unselective copying or causal misunderstanding. This suggests that our species might be better characterized as broadly "optimal-" rather than "over-" imitators. PMID- 29250872 TI - The social functions of babbling: acoustic and contextual characteristics that facilitate maternal responsiveness. AB - What is the social function of babbling? An important function of prelinguistic vocalizing may be to elicit parental behavior in ways that facilitate the infant's own learning about speech and language. Infants use parental feedback to their babbling to learn new vocal forms, but the microstructure of parental responses to babbling has not been studied. To enable precise manipulation of the proximal infant cues that may influence maternal behavior, we used a playback paradigm to assess mothers' responsiveness to prerecorded audiovisual clips of unfamiliar infants' noncry prelinguistic vocalizations and actions. Acoustic characteristics and directedness of vocalizations were manipulated to test their efficacy in structuring social interactions. We also compared maternal responsiveness in the playback paradigm and in free play with their own infants. Maternal patterns of reactions to babbling were stable across both tasks. In the playback task, we found specific vocal cues, such as the degree of resonance and the transition timing of consonant-vowel syllables, predicted contingent maternal responding. Vocalizations directed at objects also facilitated increased responsiveness. The responses mothers exhibited, such as sensitive speech and vocal imitation, are known to facilitate vocal learning and development. Infants, by influencing the behavior of their caregivers with their babbling, create social interactions that facilitate their own communicative development. PMID- 29250873 TI - The entry of Salmonella in a distinct tight compartment revealed at high temporal and ultrastructural resolution. AB - Salmonella enterica induces membrane ruffling and genesis of macropinosomes during its interactions with epithelial cells. This is achieved through the type three secretion system-1, which first mediates bacterial attachment to host cells and then injects bacterial effector proteins to alter host behaviour. Next, Salmonella enters into the targeted cell within an early membrane-bound compartment that matures into a slow growing, replicative niche called the Salmonella Containing Vacuole (SCV). Alternatively, the pathogen disrupts the membrane of the early compartment and replicate at high rate in the cytosol. Here, we show that the in situ formed macropinosomes, which have been previously postulated to be relevant for the step of Salmonella entry, are key contributors for the formation of the mature intracellular niche of Salmonella. We first clarify the primary mode of type three secretion system-1 induced Salmonella entry into epithelial cells by combining classical fluorescent microscopy with cutting edge large volume electron microscopy. We observed that Salmonella, similarly to Shigella, enters epithelial cells inside tight vacuoles rather than in large macropinosomes. We next apply this technology to visualise rupturing Salmonella containing compartments, and we use extended time-lapse microscopy to establish early markers that define which Salmonella will eventually hyper replicate. We show that at later infection stages, SCVs harbouring replicating Salmonella have previously fused with the in situ formed macropinosomes. In contrast, such fusion events could not be observed for hyper-replicating Salmonella, suggesting that fusion of the Salmonella entry compartment with macropinosomes is the first committed step of SCV formation. PMID- 29250874 TI - Children retain implicitly learned phonological sequences better than adults: a longitudinal study. AB - Whereas adults often rely on explicit memory, children appear to excel in implicit memory, which plays an important role in the acquisition of various cognitive skills, such as those involved in language. The current study aimed to test the assertion of an age-dependent shift in implicit versus explicit learning within a theoretical framework that explains the link between implicit sequence memory and word-form acquisition, using the Hebb repetition paradigm. We conducted a one-year, multiple-session longitudinal study in which we presented auditory sequences of syllables, co-presented with pictures of aliens, for immediate serial recall by a group of children (8-9 years) and by an adult group. The repetition of one Hebb sequence was explicitly announced, while the repetition of another Hebb sequence was unannounced and, therefore, implicit. Despite their overall inferior recall performance, the children showed better offline retention of the implicit Hebb sequence, compared with adults who showed a significant decrement across the delays. Adults had gained more explicit knowledge of the implicit sequence than children, but this could not explain the age-dependent decline in the delayed memory for it. There was no significant age effect for delayed memory of the explicit Hebb sequence, with both age groups showing retention. Overall performance by adults was positively correlated with measures of post-learning awareness. Performance by children was positively correlated with vocabulary knowledge. We conclude that children outperform adults in the retention over time of implicitly learned phonological sequences that will gradually consolidate into novel word-forms. The findings are discussed in the light of maturational differences for implicit versus explicit memory systems that also play a role in language acquisition. A video abstract of this article can be viewed at: https://youtu.be/G5nOfJB72t4. PMID- 29250876 TI - Levels of supplementation of inorganic selenium and vitamin E for meat quail aged 0 to 14 and 14 to 35 days. AB - Two experiments were carried out to determine the levels of supplementation of inorganic selenium (Se) and vitamin E (VE) in diets of quails aged 0-14 and 14-35 days old. A completely randomized design was used in a factorial design (Se = 0.1125; 0.2250; 0.3375 and 0.4500 mg kg-1 diet-1 * VE = 10; 23; 36 and 49 IU kg 1 diet-1 ). In experiment 1, quail (n = 2,400) were aged 0-14 days and were divided into 16 treatments, with three replicates of 50 birds. In experiment 2, quail (n = 1,680) were aged 14-35 days and were divided into the same treatments, with three replicates of 35 birds. At age 0-14 days, the levels of VE did not affect performance (p > .05); however, the feed conversion (FC) was influenced by a quadratic effect (p = .0515), according to the level of Se, with a higher level estimated at 0.29 mg Se kg-1 diet-1 . At age 14-35 days, there was a linear effect with interaction (Se * VE), for FC (p = .0150) and weight gain (WG; p = .0266). FC (Se, p = .0048 and VE, p = .0019) and WG (Se, p = .0049 and VE, p = .0068) improved linearly with increasing levels of Se and VE. The feed intake (FI) decreased linearly (p = .0582) as a function of VE. The carcass yield showed a quadratic effect (p = .0056) on the levels of VE, with a higher yield estimation of 27.24 IU VE/kg of diet. It can be concluded that the optimum level of supplementation at age 0-14 days was 0.29 mg Se kg-1 diet-1 and 10 IU VE kg-1 diet-1 and at age 14-35 days, it was 0.4500 mg Se kg-1 diet-1 and 49 IU of VE kg-1 diet-1 . PMID- 29250877 TI - Charges and resource utilization for pediatric heart transplantation across a positive virtual and/or cytotoxicity crossmatch. AB - There is growing acceptance of transplantation across a positive crossmatch for highly allosensitized pediatric HT candidates. While survival may be similar to patients transplanted across a negative crossmatch, costs are unknown. Among 60 HT recipients at our center from 5/07 to 6/12, we analyzed hospital charges and length of stay from the day of HT to discharge and through the first year after transplant. Median age at HT was 6.2 years (15 days-20.5 years). Charges in the first year post-HT were greater for crossmatch-positive patients ($907 678 vs $549 754; P = .017), with a trend toward higher charges for the HT hospitalization ($537 640 vs $407 374; P = .07). Plasmapheresis was more common in crossmatch-positive patients during the HT hospitalization (80% vs 4%, P < .001). In the first year after HT, crossmatch-positive patients had a greater number of endomyocardial biopsies (10 vs 7.5, P = .03) and episodes of treated rejection (2 vs 0, P = .004). Pediatric HT across a positive crossmatch is associated with higher first-year costs, including increased use of plasmapheresis and care around an increased number of rejections. These novel data will help inform decision and policymaking regarding care practices for the growing population of highly sensitized pediatric HT candidates. PMID- 29250879 TI - Editorial IJPD January 2018. PMID- 29250880 TI - The Editor recommends this issue's article to the reader: A systematic review of the effects of supervised toothbrushing on caries incidence in children and adolescents. PMID- 29250878 TI - Precise editing of CLAVATA genes in Brassica napus L. regulates multilocular silique development. AB - Multilocular silique is a desirable agricultural trait with great potential for the development of high-yield varieties of Brassica. To date, no spontaneous or induced multilocular mutants have been reported in Brassica napus, which likely reflects its allotetraploid nature and the extremely low probability of the simultaneous random mutagenesis of multiple gene copies with functional redundancy. Here, we present evidence for the efficient knockout of rapeseed homologues of CLAVATA3 (CLV3) for a secreted peptide and its related receptors CLV1 and CLV2 in the CLV signalling pathway using the CRISPR/Cas9 system and achieved stable transmission of the mutations across three generations. Each BnCLV gene has two copies located in two subgenomes. The multilocular phenotype can be recovered only in knockout mutations of both copies of each BnCLV gene, illustrating that the simultaneous alteration of multiple gene copies by CRISPR/Cas9 mutagenesis has great potential in generating agronomically important mutations in rapeseed. The mutagenesis efficiency varied widely from 0% to 48.65% in T0 with different single-guide RNAs (sgRNAs), indicating that the appropriate selection of the sgRNA is important for effectively generating indels in rapeseed. The double mutation of BnCLV3 produced more leaves and multilocular siliques with a significantly higher number of seeds per silique and a higher seed weight than the wild-type and single mutant plants, potentially contributing to increased seed production. We also assessed the efficiency of the horizontal transfer of Cas9/gRNA cassettes by pollination. Our findings reveal the potential for plant breeding strategies to improve yield traits in currently cultivated rapeseed varieties. PMID- 29250884 TI - Intracanal cryotherapy in endodontics. PMID- 29250887 TI - Response to the letter to the editor from Ishwarya Gurucharan. PMID- 29250891 TI - Physical neglect during childhood alters white matter connectivity in healthy young males. AB - BACKGROUND: Childhood adversity (CA) leads to greater vulnerability for psychopathology by causing structural as well as functional brain abnormalities. Recent findings on gray matter effects point towards the importance of identifying CA outcome as a function of different CA types, varying in the dimensions of threat and deprivation. Using diffusion tensor imaging, we investigate whether different forms of CA impact differently on white matter connectivity in a healthy cohort not confounded by other aspects of disease. METHODS: In 120 healthy young males, we assessed different forms of maltreatment during childhood with the Childhood Trauma Questionnaire (CTQ). Fractional anisotropy (FA) and mean diffusivity (MD) images were generated and projected onto a white matter skeleton using tract-based spatial statistics. Correlational analysis between FA, MD, and CTQ subscores was then performed using voxelwise statistics. RESULTS: Of all CTQ-subscores, only physical neglect (PN) predicted a decrease of FA but not MD in the bilateral anterior thalamic radiation around the middle frontal gyrus and the right inferior fronto-occipital fasciculus, the inferior longitudinal fasciculus, the cingulum and precuneus. Reduced FA in the posterior cingulum was related to the effects of PN during childhood on anxiety levels at trend level. CONCLUSIONS: PN may have severe consequences and should be considered equally important to more active forms of abuse. FA changes, particularly in the cingulum, actually appear to a functional consequence and are linked to trait anxiety, a personality dimension that is suggested to be a transdiagnostic risk factor of affective disorders. Potentially this reveals a mechanistic chain that forms one pathyway from CA to disease. PMID- 29250892 TI - Implementing team huddles in small rural hospitals: How does the Kotter model of change apply? AB - AIMS: To examine how the process of change prescribed in Kotter's change model applies in implementing team huddles, and to assess the impact of the execution of early change phases on change success in later phases. BACKGROUND: Kotter's model can help to guide hospital leaders to implement change and potentially to improve success rates. However, the model is under studied, particularly in health care. METHODS: We followed eight hospitals implementing team huddles for 2 years, interviewing the change teams quarterly to inquire about implementation progress. We assessed how the hospitals performed in the three overarching phases of the Kotter model, and examined whether performance in the initial phase influenced subsequent performance. RESULTS: In half of the hospitals, change processes were congruent with Kotter's model, where performance in the initial phase influenced their success in subsequent phases. In other hospitals, change processes were incongruent with the model, and their success depended on implementation scope and the strategies employed. CONCLUSIONS: We found mixed support for the Kotter model. It better fits implementation that aims to spread to multiple hospital units. When the scope is limited, changes can be successful even when steps are skipped. IMPLICATIONS FOR NURSING MANAGEMENT: Kotter's model can be a useful guide for nurse managers implementing changes. PMID- 29250894 TI - VACTERL phenotype with mosaic trisomy 5 and uniparental disomy 5. PMID- 29250893 TI - Atypical Hemolytic Uremic Syndrome: A Meta-Analysis of Case Reports Confirms the Prevalence of Genetic Mutations and the Shift of Treatment Regimens. AB - Atypical hemolytic uremic syndrome (aHUS) is a rare life-threatening thrombotic microangiopathy (TMA) affecting multiple organ systems. Recently, aHUS has been shown to be associated with uncontrolled complement activation due to mutations in the alternative pathway of complement components paving the way for targeted drug therapy. By meta-analysis of case reports, we discuss the impact of new treatment strategies on the resolution time of aHUS symptoms and mortality, and the distribution of genetic mutations. A PubMed/Medline search was conducted for "atypical hemolytic uremic syndrome" case reports published between November 2005 and November 2015. R Version 3.2.2 was used to calculate descriptive statistics and perform univariate analyses. Wilcoxon rank-sum test was used to compare time to symptoms resolution, creatinine and platelet count normalization across the treatment and mutation carrier groups. A total of 259 aHUS patients were reported in 176 articles between 2005 and 2015. In the last 5-year period compared to the precedent, there was an increase in the number of aHUS cases reported (180 vs. 79 cases) and the use of eculizumab also increased (6.3% to 46.1%, P < 0.000), although plasma exchange usage did not change (P = 0.281). CFH antibodies were present in a significantly higher number of patients treated with plasma exchange therapy (19.1%, P = 0.000) while none of the non-plasma exchange therapy group had CFH antibodies. Most common mutation was CFH (50%, 69/139) followed by CFHR1 (35%, 30/85), MCP (22.8%, 23/101) and CFI (16.6%, 17/102). Time to symptoms resolution and serum creatinine or platelet count normalization were not significantly different between eculizumab and non-eculizumab group (P = 0.166, P = 0.361, P = 0.834), and between plasma exchange and non-plasma exchange group (P = 0.150, P = 0.135, P = 0.784). However, both eculizumab and plasma exchange groups had early platelet recovery (22 vs. 30 days and 25.5 vs. 32.5 days), faster creatinine normalization (27 vs. 30.5 days and 27 vs. 37 days) and interestingly, a longer period for symptoms resolution (45.5 vs. 21 days and 30 vs. 18.5 days) compared to non-eculizumab and non-plasma exchange groups. Mortality rate decreased with the use of eculizumab significantly (P = 0.045) compared to non-eculizumab group and there was no change in mortality rate with the use of plasma exchange therapy (P = 0.760) compared to non-plasma exchange group. Plasma exchange continues to be the initial treatment of choice for aHUS. Although significant reduction in the mortality rate was noted with the use of eculizumab, there were no differences in time to resolution of symptoms or serum creatinine or platelet normalization with the use of either eculizumab or plasma therapy. Atypical HUS is acute and life-threatening, so plasma exchange may be initiated before the confirmed diagnosis and in patients positive for CFH antibodies. Eculizumab therapy should be considered once aHUS is confirmed by genetic testing. PMID- 29250895 TI - Soybean seed coat chitinase as a defense protein against the stored product pest Callosobruchus maculatus. AB - BACKGROUND: Chitinases (EC 3.2.1.14) are enzymes involved in the breaking of the beta-1,4-glycosidic linkages of chitin. In insects, chitin is present mainly in the cuticle and in peritrophic membranes and peritrophic gel. Enzymes with the potential to damage peritrophic membranes and gel, such as chitinase, have been associated with plant defense systems. Identification and characterization of seed coat chitinase as a plant defense molecule may indicate a more effective target for manipulation strategies, which may lead to the prevention of consumption of embryonic tissues by larvae and consequently minimization of seed damage. RESULTS: We studied the efficiency of soybean seed coat chitinase as a defense molecule against the insect Callosobruchus maculatus. The seed coat chitinase was isolated and identified by mass spectrometry, immunoreacted with an anti-chitinase antibody and shown to have activity against chitin azure and 4 methylumbelliferyl beta-D-N,N',N''-triacetylchitotrioside. A chitinase fraction incorporated in artificial cotyledons at 0.1% reduced larval survival by approximately 77%, and at 0.5%, the reduction in larval mass was 60%. Fluorescein isothiocyanate (FITC)-labeled chitinase was detected in the guts and feces of larvae. At 25% in thick artificial seed coats, chitinase showed a high toxicity to larvae, with mortality of 90% and a reduction of larval mass of 87%. CONCLUSION: Seed coat chitinase is an important seed defense molecule not only in the cotyledons but also in seed coats, acting as part of the array of defense mechanisms against Callosobruchus maculatus. (c) 2017 Society of Chemical Industry. PMID- 29250896 TI - Changes in neuronal activity of cortico-basal ganglia-thalamic networks induced by acute dopaminergic manipulations in rats. AB - The basal ganglia are thought to be particularly sensitive to changes in dopaminergic tone, and the realization that reduced dopaminergic signaling causes pronounced motor dysfunction is the rationale behind dopamine replacement therapy in Parkinson's disease. It has, however, proven difficult to identify which neurophysiological changes that ultimately lead to motor dysfunctions. To clarify this, we have here recorded neuronal activity throughout the cortico-basal ganglia-thalamic circuits in freely behaving rats during periods of immobility following acute dopaminergic manipulations, involving both vesicular dopamine depletion and antagonism of D1 and D2 type dopamine receptors. Synchronized and rhythmic activities were detected in the form of betaband oscillations in local field potentials and as cortical entrainment of action potentials in several basal ganglia structures. Analyses of the temporal development of synchronized oscillations revealed a spread from cortex to gradually also include deeper structures. In addition, firing rate changes involving neurons in all parts of the network were observed. These changes were typically relatively balanced within each structure, resulting in negligible net rate changes. Animals treated with D1 receptor antagonist showed a rapid onset of hypokinesia that preceded most of the neurophysiological changes, with the exception of these balanced rate changes. Parallel rate changes in functionally coupled ensembles of neurons in different structures may therefore be the first step in a cascade of neurophysiological changes underlying motor symptoms in the parkinsonian state. We suggest that balanced rate changes in distributed networks are possible mechanism of disease that should be further investigated in conditions involving dopaminergic dysfunction. PMID- 29250897 TI - A Systematic Study of Isomorphically Substituted H-MAlPO-5 Materials for the Methanol-to-Hydrocarbons Reaction. AB - Substituting metals for either aluminum or phosphorus in crystalline, microporous aluminophosphates creates Bronsted acid sites, which are well known to catalyze several key reactions, including the methanol to hydrocarbons (MTH) reaction. In this work, we synthesized a series of metal-substituted aluminophosphates with AFI topology that differed primarily in their acid strength and that spanned a predicted range from high Bronsted acidity (H-MgAlPO-5, H-CoAlPO-5, and H-ZnAlPO 5) to medium acidity (H-SAPO-5) and low acidity (H-TiAlPO-5 and H-ZrAlPO-5). The synthesis was aimed to produce materials with homogenous properties (e.g. morphology, crystallite size, acid-site density, and surface area) to isolate the influence of metal substitution. This was verified by extensive characterization. The materials were tested in the MTH reaction at 450 degrees C by using dimethyl ether (DME) as feed. A clear activity difference was found, for which the predicted stronger acids converted DME significantly faster than the medium and weak Bronsted acidic materials. Furthermore, the stronger Bronsted acids (Mg, Co and Zn) produced more light alkenes than the weaker acids. The weaker acids, especially H-SAPO-5, produced more aromatics and alkanes, which indicates that the relative rates of competing reactions change upon decreasing the acid strength. PMID- 29250898 TI - Protein identification before and after glyphosate exposure in Lolium multiflorum genotypes. AB - BACKGROUND: Weeds reduce crop yields, and among the methods used to control these plants, the use of chemicals is preferred. However, the repeated application of herbicides with the same mechanism of action selects for resistant populations. The aim of this study was to evaluate glyphosate resistance in Lolium multiflorum (Lam.) and relate the resistance to protein expression in the absence and presence of the herbicide using a metabolic-proteomic approach. RESULTS: Glyphosate resistance was confirmed, with a sevenfold difference in resistance between susceptible and resistant genotypes. Among the possible mechanisms affecting resistance, mutations in the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), herbicide differential translocation and overexpression of EPSPS are suggested. Susceptible plants had higher growth than did resistant plants in the absence of the herbicide, in addition to greater expression of protein groups related to photosynthesis and to tolerance to biotic and abiotic stresses. With application of glyphosate, resistant plants maintained their metabolism and began to express EPSPS and other candidate proteins related to herbicide resistance. CONCLUSIONS: In the absence of glyphosate, the susceptible plants would replace the resistant plants over time, and abiotic or biotic stresses would accelerate this process. Resistance in plants resulted from a combination of target-site and non-target-site resistance mechanisms. We identified several candidate proteins that could be investigated in future studies on glyphosate resistance. (c) 2017 Society of Chemical Industry. PMID- 29250899 TI - An uncommon localization of black heels in a free climbing instructor. AB - Black heels, also known as talon noir or calcaneal petechiae, are asymptomatic superficial cutaneous haemorrhages of the feet, mostly seen as post-traumatic lesions in young athletic individuals who practice sports such as tennis, football, or gymnastics. Here, we present a case of black heels in a young male rock climber. PMID- 29250900 TI - Complications of botulinum toxin injection for masseter hypertrophy: Incidence rate from 2036 treatments and summary of causes and preventions. AB - BACKGROUND: Masseter hypertrophy is a common, prominent feature in many Asian patients, and correction procedures are often requested for esthetic reasons. Toxin masseter injections have a high efficacy and safety profile, but the risks of a variety of side effects or complications remain. OBJECTIVES: The categorization of various complications was based on etiology, with a presentation of the author's own incidence rates for consideration and comparison. METHODS: Six hundred and eighty patients received a total of 2036 sessions of toxin injection for masseter hypertrophy from 2011 to 2016, and complications or complaints were recorded through follow-up on a by-treatment basis. Complications were grouped together based on etiology and discussed. RESULTS: Of 2036 sessions, temporary mastication force decrease was reported after 611 (30%), bruising after 51 (2.5%), headaches after 12 (0.58%), smile limitation after 3 (0.15%), paradoxical bulging after 10 (0.49%), sunken cheeks (subzygomatic volume loss) after 9 (0.44%), and sagging after 4 (0.20%). CONCLUSIONS: Masseter injections remain very safe. To further decrease the incidence rate, injections should only be inside the recommended safety zone, a quadrilateral within the muscle that avoids most important local structures. Keeping injections inside the safe zone, and ideally in 3-4 different locations at least 1 cm from any border, is crucial for the prevention of complications. PMID- 29250901 TI - Enhanced Intracellular Delivery of siRNA by Controlling ATP-Responsivity of Phenylboronic Acid-Functionalized Polyion Complex Micelles. AB - Intracellular delivery of small interfering RNA (siRNA) is a long-standing challenge in oligonucleotide therapeutics. Herein, adenosine triphosphate (ATP) responsive polyion complex micelles assembled from poly(ethylene glycol)-block poly(l-lysine) (PEG-PLys) bearing 4-carboxy-3-fluorophenylboronic acid (FPBA) moiety in the PLys side chains (FPBA micelle) for the delivery of cholesterol modified siRNA (Chol-siRNA) are described. The pKa of FPBA moiety is 7.2 and, therefore, it exists in equilibrium between negatively charged tetravalent and noncharged hydrophobic trivalent forms in physiological pH conditions. Each form cooperatively stabilizes the micelle in distinct modes, that is, a covalent ester linkage between charged boronate and ribose functionality at 3' ends of Chol siRNA and a hydrophobic interaction between noncharged boronic acid and Chol siRNA. When exposed to ATP at a concentration associated with the intracellular environment, the Chol-siRNA/boronate linkage is readily cleaved to facilitate the release of Chol-siRNA into cytoplasm. In order to further optimize this switching capability, the effect of FPBA modification rate is studied for the resulting ATP responsive behavior of the micelles. As a result, the range of 23-35% in the modification rate is found suitable to maximize the gene silencing efficiency, demonstrating the potential of the FPBA-modified micelles as ATP-responsive smart siRNA carrier systems. PMID- 29250902 TI - Biochemical Characterization and Mechanistic Analysis of the Levoglucosan Kinase from Lipomyces starkeyi. AB - Levoglucosan kinase (LGK) catalyzes the simultaneous hydrolysis and phosphorylation of levoglucosan (1,6-anhydro-beta-d-glucopyranose) in the presence of Mg2+ -ATP. For the Lipomyces starkeyi LGK, we show here with real time in situ NMR spectroscopy at 10 degrees C and pH 7.0 that the enzymatic reaction proceeds with inversion of anomeric stereochemistry, resulting in the formation of alpha-d-glucose-6-phosphate in a manner reminiscent of an inverting beta-glycoside hydrolase. Kinetic characterization revealed the Mg2+ concentration for optimum activity (20-50 mm), the apparent binding of levoglucosan (Km =180 mm) and ATP (Km =1.0 mm), as well as the inhibition by ADP (Ki =0.45 mm) and d-glucose-6-phosphate (IC50 =56 mm). The enzyme was highly specific for levoglucosan and exhibited weak ATPase activity in the absence of substrate. The equilibrium conversion of levoglucosan and ATP lay far on the product side, and no enzymatic back reaction from d-glucose-6-phosphate and ADP was observed under a broad range of conditions. 6-Phospho-alpha-d-glucopyranosyl fluoride and 6-phospho-1,5-anhydro-2-deoxy-d-arabino-hex-1-enitol (6-phospho-d glucal) were synthesized as probes for the enzymatic mechanism but proved inactive with the enzyme in the presence of ADP. The pyranose ring flip 4 C1 ->1 C4 required for 1,6-anhydro-product synthesis from d-glucose-6-phosphate probably presents a major thermodynamic restriction to the back reaction of the enzyme. PMID- 29250903 TI - Effects of ambient conditions on the risk of pressure injuries in bedridden patients-multi-physics modelling of microclimate. AB - Scientific evidence regarding microclimate and its effects on the risk of pressure ulcers (PU) remains sparse. It is known that elevated skin temperatures and moisture may affect metabolic demand as well as the mechanical behaviour of the tissue. In this study, we incorporated these microclimate factors into a novel, 3-dimensional multi-physics coupled model of the human buttocks, which simultaneously determines the biothermal and biomechanical behaviours of the buttocks in supine lying on different support surfaces. We compared 3 simulated thermally controlled mattresses with 2 reference foam mattresses. A tissue damage score was numerically calculated in a relevant volume of the model, and the cooling effect of each 1 degrees C decrease of tissue temperature was deduced. Damage scores of tissues were substantially lower for the non-foam mattresses compared with the foams. The percentage tissue volume at risk within the volume of interest was found to grow exponentially as the average tissue temperature increased. The resultant average sacral skin temperature was concluded to be a good predictor for an increased risk of PU/injuries. Each 1 degrees C increase contributes approximately 14 times as much to the risk with respect to an increase of 1 mmHg of pressure. These findings highlight the advantages of using thermally controlled support surfaces as well as the need to further assess the potential damage that may be caused by uncontrolled microclimate conditions on inadequate support surfaces in at-risk patients. PMID- 29250904 TI - Assessing a composite end point for new tocolytics in clinical trials: Data from 4 US integrated delivery networks. AB - PURPOSE: A composite end point (CE) measuring neonatal benefit was created for use in tocolytic randomized controlled trials with rates assessed using data from one referral hospital. The goal of this study was to assess wider generalizability of the CE, using data from multiple integrated delivery networks, creating a cohort of linked mother-neonate pairs to understand neonatal outcomes in a broad population. METHODS: Retrospective data on births (2001-2012) were collected from 4 US integrated delivery networks in the COMparative effectiveness PAtient Safety and Surveillance (COMPASS) Research Network, and linked mother-neonate pairs were identified. The CE was analyzed for all in hospital singleton neonates at >=24 weeks of gestational age (GA) born to mothers aged <=45 years at a referral hospital or hospital with >2000 annual births. RESULTS: The CE analyses included 56 485 eligible mother-neonate pairs; frequency of the CE decreased from 89% to 66% between GA weeks 24 and 29 and further decreased to <14% for infants born >34 weeks of GA. Composite end point rates were 20% to 30% lower at 24 to 30 weeks of GA in COMPASS compared with Medical University of South Carolina but were similar by 31 weeks. CONCLUSIONS: The COMPASS Network enabled evaluation of the CE across a large population demonstrating that the CE findings could be replicated beyond a single hospital and the potential for lower CE frequency. Based on this, an adaptive design was adopted for randomized controlled trials, specifically sample size reestimation to mitigate against the risk of lower outcome rates, highlighting the use of real world data in drug development. PMID- 29250905 TI - Validity of diagnostic codes to identify hospitalizations for infections among patients treated with oral anti-diabetic drugs. AB - PURPOSE: Identification of hospitalizations for infection is important for post marketing surveillance of drugs, but the validity of using diagnosis codes to identify these events is unknown. Differentiating between hospitalization for and with infection is important, as the latter is common and less likely to arise from pre-admission exposure to drugs. We determined positive predictive values (PPVs) of diagnostic coding-based algorithms to identify hospitalization for infection among patients prescribed oral anti-diabetic drugs (OADs). METHODS: We identified patients initiating OADs within 2 United States claims databases (Medicare, HealthCore Integrated Research DatabaseSM [HIRDSM ]) and 2 United Kingdom electronic medical record databases (Clinical Practice Research Datalink [CPRD], The Health Improvement Network [THIN]) from 2009 to 2014. To identify potential hospitalizations for infection, we selected patients with a hospital diagnosis of infection and, within 7 days prior to hospitalization, either an outpatient/emergency department visit with an infection diagnosis or outpatient antimicrobial treatment. Hospital records were reviewed by infectious disease specialists to adjudicate hospital admissions for infection. PPVs for confirmed outcomes were determined for each database. RESULTS: Code-based algorithms to identify hospitalization for infection had PPVs exceeding 80% within Medicare (PPV, 83% [90/109]; 95% CI, 74-89%), HIRDSM (PPV, 89% [73/82]; 95% CI, 80-95%), and THIN (PPV, 86% [12/14]; 95% CI, 57-98%) but not within CPRD (PPV, 67% [14/21]; 95% CI, 43-85%). CONCLUSIONS: Algorithms identifying hospitalization for infection utilizing hospital diagnoses along with antecedent outpatient/emergency infection diagnoses or antimicrobial therapy had sufficiently high PPVs for confirmed events within Medicare, HIRDSM , and THIN to enable their use for pharmacoepidemiologic research. PMID- 29250906 TI - Opportunities for training for nutritional professionals in nutritional genomics: What is out there? AB - AIM: To identify and profile training courses available to dietitians and nutritionists in the area of nutritional genomics. Genetic technology is progressing quickly, leading to increased public interest and requests from the public for personalised nutrition advice based on genetic background. Tertiary courses often lack specific curriculum in nutritional genomics, preventing graduates from discussing confidently with their clients the relationships between genetics, nutrition and health. This has increased the demand for professional development in this field. METHODS: The search strategy was intended to replicate real-life practice. Google and snowball searches were conducted using terms related to education and nutritional genomics. Results included online or face-to-face courses in any country providing content on nutritional genomics. One-off courses and those courses no longer accessible were excluded. A descriptive analysis of characteristics of courses was undertaken, reporting on mode of delivery, cost, duration, content, qualification awarded, target audience and affiliations. RESULTS: In total, 37 courses varying in duration, content and cost were identified: 4 postgraduate university degrees, 5 university course units, 4 recurring face-to-face workshops, 15 online short courses, 8 pre recorded presentations and 1 service offering regular live webinars. Affiliations with food and pharmaceutical industry (e.g. genetic testing companies), professional organisations and research/education institutes were observed. CONCLUSIONS: Training courses identified were predominantly delivered online, enabling nutrition professionals worldwide to upskill in nutritional genomics and personalised nutrition. Additional courses exist. Those seeking training should scrutinise and compare cost, duration, mode, content and affiliations of course providers to ensure learning needs are met. PMID- 29250907 TI - Patient perspectives on the use of categories of conditions for decision making about genomic carrier screening results. AB - As expanded genome-scale carrier screening becomes increasingly prevalent, patients will face decisions about whether to receive results about a vast number of genetic conditions. Understanding patient preferences is important to meaningfully demonstrate the ethical goal of respect and support patient autonomy. We explore one possible way to elicit preferences by sorting conditions into categories, which may support patient decision making, but the extent to which categories are helpful is unknown. In the context of a randomized trial of genome sequencing for preconception carrier screening compared to usual care (single disease carrier testing), we interviewed 41 participants who had genome sequencing about their experience using a taxonomy of conditions to select categories of results to receive. We then conducted interviews with an additional 10 participants who were not randomized to genome sequencing, asking them about the taxonomy, their reasons for selecting categories, and alternative ways of presenting information about potential results to receive. Participants in both groups found the categories helpful and valued having a meaningful opportunity to choose which results to receive, regardless of whether they opted to receive all or only certain categories of results. Additionally, participants who received usual care highlighted preparedness as a primary motivation for receiving results, and they indicated that being presented with possible reasons for receiving or declining results for each category could be helpful. Our findings can be used to develop approaches, including the use of categories, to support patient choices in expanded carrier screening. Further research should evaluate and optimize these approaches. PMID- 29250908 TI - The Independent Gradient Model: A New Approach for Probing Strong and Weak Interactions in Molecules from Wave Function Calculations. AB - Extraction of the chemical interaction signature from local descriptors based on electron density (ED) is still a fruitful field of development in chemical interpretation. In a previous work that used promolecular ED (frozen ED), the new descriptor, deltag , was defined. It represents the difference between a virtual upper limit of the ED gradient (?rhoIGM , IGM=independent gradient model) that represents a noninteracting system and the true ED gradient (?rho ). It can be seen as a measure of electron sharing brought by ED contragradience. A compelling feature of this model is to provide an automatic workflow that extracts the signature of interactions between selected groups of atoms. As with the noncovalent interaction (NCI) approach, it provides chemists with a visual understanding of the interactions present in chemical systems. ?rhoIGM is achieved simply by using absolute values upon summing the individual gradient contributions that make up the total ED gradient. Hereby, we extend this model to relaxed ED calculated from a wave function. To this end, we formulated gradient based partitioning (GBP) to assess the contribution of each orbital to the total ED gradient. We highlight these new possibilities across two prototypical examples of organic chemistry: the unconventional hexamethylbenzene dication, with a hexa-coordinated carbon atom, and beta-thioaminoacrolein. It will be shown how a bond-by-bond picture can be obtained from a wave function, which opens the way to monitor specific interactions along reaction paths. PMID- 29250909 TI - A web-based survey to identify current practice in skeletal pin site management. AB - Infections associated with percutaneous pins and wires are common complications which can have a significant impact on patient outcomes. A survey was undertaken to identify current practice and gain insight into variations of clinical practice. Invitations were sent by email to complete an electronic questionnaire using SurveyMonkey. The survey was left open for 100 days. The single largest group of respondents (37.4%, n = 120) cleansed pin sites daily, with significant differences identified between medical and nursing professions (P = 0.02), and country of practice (P < 0.001). Significant differences were also identified in the use of different cleansing solutions between medical and nursing professions (P < 0.001) and country (P < 0.001). The majority group preferences were saline 30% (n = 96) and alcoholic chlorhexidine 29.6% (n = 95). Pin site crusts were routinely removed by 57.9% (n = 186). Pin sites were left exposed by 50.3% (n = 160). Dry gauze was identified as the most common dressing used to dress pin sites, however, substantial variation was identified in the types of dressings used. Compression was not routinely applied to pin sites by 51.6% (n = 165). There remains considerable diversity of practice when caring for pin sites. Further research is required to identify the most effective methods in preventing pin site infection. PMID- 29250910 TI - Dynamics of widespread foot-and-mouth disease virus serotypes A, O and Asia-1 in southern Asia: A Bayesian phylogenetic perspective. AB - Foot-and-mouth disease (FMD) is, arguably, the animal disease with the most devastating global economic impact owing in part, to the severe trade restrictions imposed upon affected countries and regions. South Asia is one of the regions where widespread lineages of the FMDV virus (FMDV) have emerged. Here, we performed an integrative phylogenetic analysis of all FMDV serotypes (A, O and Asia-1) circulating in southern Asia, including viral sequences collected until 2013. Our results describe the occurrence of FMD caused by different serotypes and lineages, focusing in the cycles where a specific lineage predominates within a region for a protracted period and then are rapidly or progressively replaced by an emergent or re-emergent strain that is introduced from an adjacent region. Transmission between the two main regions in southern Asia (the Indian subcontinent and the region comprised by Afghanistan, Iran and Pakistan) has been limited. Results of time divergence estimation of lineages that currently circulate in this region indicate that the most recent common ancestor of endemic lineages are: 1992 [1989-1995] for lineage O/PanAsia; 1997 [1995-1999] for PanAsia2; 2001 [1998-2004] for O/Ind2001; 2001 [2000-2002] for A/Iran-05; 1990 [1988-1991] for A/G-18 (G-VII); 2003 [2000-2006] for Asia-1 Sindh08 and 2002 [1999-2004] for Asia-1 G-VIII. We estimated the mean of the overall substitution rate of the VP1 coding region (substitution/site/year) for serotype O (5.95 * 10-3 ), serotype A (1.19 * 10-2 ) and serotype Asia-1 (3.08 * 10-3 ). The potential factors driving the lineage turnover are discussed. Our results provide insights into the ecological and evolutionary factors driving the emergence of FMDV. PMID- 29250911 TI - Management of intracranial hemorrhage in severe factor V deficiency and definitive treatment with liver transplantation. AB - FV is primarily produced in the liver, and congenital FV deficiency is a disorder with an incidence of one in 1 million. Standard care is to treat severe bleeding phenotypes with FFP as there is no recombinant or plasma-derived FV concentrate. We present a case of a neonate with known severe FV deficiency diagnosed after prolonged bleeding after circumcision who represented at age 2 months with a large left intraparenchymal hemorrhage. His bleed was treated with FFP, platelet transfusion, recombinant VIIa, and emergent evacuation. He was maintained on plasma infusions but was unable to space his infusions beyond 48 hours. Liver transplantation was considered as a definitive treatment for this condition. While awaiting a suitable liver, his FV trough levels occasionally dropped below 5%, and he suffered from a second acute intracranial bleed. He received an orthotopic liver transplant at age 5 months, resulting in correction of his FV levels. He has not required any plasma infusions post-transplantation and has had no further bleeding episodes. Liver transplantation should be considered as definitive treatment early in the course for patients with severe FV deficiency and first time life-threatening bleed. PMID- 29250912 TI - Acid-Catalyzed Conversion of Carbohydrates into Value-Added Small Molecules in Aqueous Media and Ionic Liquids. AB - Biomass is the only realistic major alternative source (to crude oil) of hydrocarbon substrates for the commercial synthesis of bulk and fine chemicals. Within biomass, terrestrial sources are the most accessible, and therein lignocellulosic materials are most abundant. Although lignin shows promise for the delivery of certain types of organic molecules, cellulose is a biopolymer with significant potential for conversion into high-volume and high-value chemicals. This review covers the acid-catalyzed conversion of lower value (poly)carbohydrates into valorized organic building-block chemicals (platform molecules). It focuses on those conversions performed in aqueous media or ionic liquids to provide the reader with a perspective on what can be considered a best case scenario, that is, that the overall process is as sustainable as possible. PMID- 29250913 TI - Brain responses to stimuli mimicking dental treatment among non-phobic individuals: A meta-analysis. AB - Numerous neuroimaging studies have attempted to identify how the brain responds to stimuli mimicking dental treatment in normal non-phobic individuals. However, results were sometimes inconsistent due to small sample sizes and methodological variations. This meta-analysis employs standardized procedures to summarize data from previous studies to identify brain regions that were consistently activated across studies, elicited by stimuli such as pictures, sounds, or audiovisual footage mimicking those encountered during dental treatments. A systematic literature search was carried out using PubMed and Scopus. The meta-analysis analyzed data from 120 healthy subjects from seven neuroimaging studies. We assessed the risk of bias among the included studies with the Risk of Bias Assessment Tool for Nonrandomized Studies. One study appeared to have a high risk of selection bias, whereas the others were considered to have a low risk of bias. Results revealed three clusters of activation with cluster sizes ranging from 768 mm3 to 1,424 mm3 . Stimuli mimicking dental treatment consistently activated the bilateral anterior insula; right dorsal anterior cingulate, putamen, and medial prefrontal cortex; and left claustrum. This study confirmed that audio and/or visual stimuli mimicking dental treatment consistently activated the fear-related brain regions among healthy subjects, mostly consistent with activations from general anxiety but without the involvement of the amygdala. PMID- 29250914 TI - Risk of exposure to Coxiella burnetii from ruminant livestock exhibited at Iowa agricultural fairs. AB - Coxiella burnetii is a zoonotic pathogen typically associated with clinical and asymptomatic infection in ruminant livestock. A re-emerging pathogen of significant public health importance, C. burnetii has caused recent epidemics in the United States and Europe, and public livestock exhibitions are increasingly scrutinized as a potential source of C. burnetii exposure. Although C. burnetii prevalence data among North American domestic ruminants are extremely limited, contemporary studies suggest that this pathogen is both geographically widespread and highly prevalent on a herd basis, especially in dairy cattle and goat populations. We utilized a real-time PCR assay to detect C. burnetii faecal shedding by clinically normal, non-periparturient beef cattle, meat goats and sheep exhibited at Iowa agricultural fairs. Individual faecal samples were collected from beef cattle, meat goats and sheep exhibited at twelve Iowa county fairs during the summer of 2009. The sample pool was blocked by species and fair, and ten samples from each block were randomly selected for the diagnostic assay; this test pool is considered sufficient to identify with 95% confidence a shedding animal in a population prevalence of 2.85% (cattle and sheep) and 6.25% (goats). Detection of C. burnetii DNA was determined through use of a real-time PCR assay validated for use in bovine, ovine and caprine faeces; threshold of detection is one DNA copy per PCR (sensitivity 95.8%, specificity 100%). All tested samples were negative for C. burnetii DNA. We conclude that non-dairy, non periparturient ruminants exhibited at Iowa fairs are unlikely to shed C. burnetii in their faeces and that this population should not be considered to be a significant exposure risk to other livestock or fair attendees. PMID- 29250915 TI - Anti-PLA2R antibody in a secondary cause of membranous nephropathy. PMID- 29250916 TI - Erratum. PMID- 29250917 TI - Spinal meningeal cysts in autosomal dominant polycystic kidney disease. PMID- 29250919 TI - Cabozantinib-induced renal thrombotic microangiopathy. PMID- 29250920 TI - Successful removal of stuck and infected haemodialysis catheter via endoluminal balloon dilatation after unsuccessful surgical cut-down. PMID- 29250918 TI - Cross-sectional associations of albuminuria among Aboriginal and Torres Strait Islander adults: the eGFR Study. AB - OBJECTIVE: To describe the detailed associations of albuminuria among a contemporary cohort of Aboriginal and Torres Strait Islander people to inform strategies for chronic kidney disease prevention and management. METHODS: A cross sectional analysis of Indigenous participants of the eGFR Study. MEASURES: Clinical, biochemical and anthropometric measures were collected (including body circumferences, blood pressure (BP); triglycerides, HbA1c, liver function tests, creatinine; urine- microscopic-haem, albumin: creatinine ratio (ACR), prescriptions- angiotensin converting enzyme inhibitor or angiotensin receptor II antagonist (ACEI/ARB). Albuminuria and diabetes were defined by an ACR>3.0 mg/mmol, and HbA1c>=48 mmol/mol or prior history respectively. Waist: hip ratio (WHR), and estimated glomerular filtration rate (eGFR) were calculated. ACR was non-normally distributed; a logarithmic transformation was applied (in base 2), with each unit increase in log2-albuminuria representing a doubling of ACR. RESULTS: 591 participants were assessed (71% Aboriginal, 61.6% female, mean age 45.1 years, BMI 30.2 kg/m2 , WHR 0.94, eGFR 99.2 ml/min/1.73m2 ). The overall prevalence of albuminuria, diabetes, microscopic-haem and ACEI/ARB use was 41.5%, 41.5%, 17.8% and 34.7% respectively; 69.3% of adults with albuminuria and diabetes received an ACEI/ARB. Using multivariable linear regression modelling, the potentially modifiable factors independently associated with log2-albuminuria were microscopic-haem, diabetes, WHR, systolic BP, alkaline phosphatase (all positive) and eGFR (inverse). CONCLUSION: Albuminuria is associated with diabetes, central obesity and haematuria. High ACEI/ARB prescribing for adults with diabetes and albuminuria was observed. Further understanding of the links between fat deposition, haematuria and albuminuria is required. PMID- 29250921 TI - Determination of sugars and cyclitols isolated from various morphological parts of Medicago sativa L. AB - Plant research interest has increased all over the world, and a large body of evidence has been collected to show the huge potential of medicinal plants in various disease treatments. Medicago sativa L., known as alfalfa, is a rich source of biologically active components and secondary metabolites and was frequently used from the ancient times both as fodder crop and as a traditional medicine in the treatment of various diseases. Cyclitols, naturally occurring in this plant, have a particular interest for us due to their significant anti diabetic, antioxidant, anti-inflammatory, and anti-cancer properties. In the present study we revealed the isolation, the identification, and the quantification of some cyclitols and sugars extracted from different morphological parts of alfalfa plant. Soxhlet extraction and solid phase extraction were used as extraction and purification methods, while for the analyses derivatization followed by gas chromatography with mass spectrometry was involved. The obtained results showed significant differences in the quantities of cyclitols and sugars found in the investigated morphological parts, ranging between 0.02 and 13.86 mg/g of plant in case of cyclitols, and in the range of 0.09 and 40.09 mg/g of plant for sugars. However, roots have the richest part of cyclitols and sugars in contrast to the leaves. PMID- 29250923 TI - New Members of the Editorial Board and International Advisory Board. PMID- 29250922 TI - Impact of pregnancy on autograft dilatation and aortic valve function following the Ross procedure. AB - OBJECTIVE: The effects of pregnancy on autograft dilatation and neoaortic valve function in patients with a Ross procedure have not been studied. We sought to evaluate the effect of pregnancy on autograft dilatation and valve function in these patients with the goal of determining whether pregnancy is safe after the Ross procedure. DESIGN: A retrospective chart review of female patients who underwent a Ross procedure was conducted. PATIENTS: Medical records for 51 patients were reviewed. Among the 33 patients who met inclusion criteria, 11 became pregnant after surgery and 22 did not. OUTCOME MEASURES: Echocardiographic reports were used to record aortic root diameter and aortic insufficiency before, during, and after pregnancy. Patient's charts were reviewed for reinterventions and complications. Primary endpoints included reinterventions, aortic root dilation of >=5 cm, aortic insufficiency degree >= moderate, and death. RESULTS: There were 18 pregnancies carried beyond 20 weeks in 11 patients. There was no significant difference in aortic root diameter between nulliparous patients and parous patients prior to their first pregnancy (3.53 +/- 0.44 vs 3.57 +/- 0.69 cm, P = .74). There was no significant change in aortic root diameter after first pregnancy (3.7 +/- 0.4 cm, P = .056) although there was significant dilatation after the second (4.3 +/- 0.7 cm, P = .009) and third (4.5 +/- 0.7 cm, P = .009) pregnancies. Freedom from combined endpoints was significantly higher for patients in the pregnancy group than those in the nonpregnancy group (P = .002). CONCLUSIONS: Pregnancy was not associated with significantly increased adverse events in patients following the Ross procedure. Special care should be taken after the first pregnancy, as multiparity may lead to increased neoaortic dilatation. PMID- 29250924 TI - Non-tuberculous Mycobacteria isolated from lymph nodes and faecal samples of healthy slaughtered cattle and the abattoir environment. AB - Infections caused by non-tuberculous mycobacteria (NTM) are reported as emerging disease in many countries worldwide. The occurrence of NTM in different hosts and their implication as obligate or opportunistic pathogen remain largely unclear. Lymph nodes and faecal samples of clinically healthy Swiss cattle at slaughter were analysed for the presence of NTM. Based on the examined lymph nodes, NTM were detected in 20% of 108 cattle originating from different premises. The 22 isolates belonged to five different species of Mycobacteria (M. avium subsp. hominissuis, M. kansasii, M. persicum, "M. lymphaticum" and M. europaeum). M. avium subsp. hominissuis (63%) and M. kansasii (18%) thereby predominated and were found in lymph nodes with and without macroscopic changes. Moreover, M. persicum found in two cattle has recently been described as a human pathogen and is closely related to M. kansasii. Amongst cattle with lymph nodes positive for mycobacteria, viable NTM were occasionally also detected in bovine faeces. However, the isolated NTM species from lymph nodes and respective faecal samples (M. hassiacum, M. phlei and M. vaccae) did not coincide. Moreover, NTM species identified amongst isolates from the slaughterhouse environment clearly differed from those from lymph nodes and faecal samples, excluding cross-contamination of the tissue specimens through the environment or laboratory processing. Assuming that some NTM interfere with the detection of bovine tuberculosis (bTB), the present findings in healthy animals emphasize the need of more specific diagnostic tools for bTB eradication programs. PMID- 29250925 TI - Cucurbitacin-B attenuates CCl4 -induced hepatic fibrosis in mice through inhibition of STAT-3. AB - Liver fibrosis is a major health concern worldwide. Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3) have been reported to attenuate experimental liver fibrosis. Therefore, the aim of this study was to investigate the potential ameliorative effect of cucurbitacin-B (Cucu-B) against CCl4 -induced liver fibrosis in mice. Treatment with Cucu-B (5 mg/kg) preserved hepatocellular membrane integrity and amended the metabolic function as indicated by preventing the rise of serum liver function markers. This was confirmed histologically. CCl4 -induced oxidative stress was improved by Cucu-B treatment (1 and 5 mg/kg). Furthermore, Cucu-B treatment ameliorated the fibrotic state as evidenced by inhibiting the rise of hydroxyproline liver content and mitigating the overexpressions of collagen-1alpha, alpha-smooth muscle actin (alpha-SMA) and transforming growth factor beta (TGF-beta) as well as the downexpression of matrix metalloproteinase-2 (MMP-2) mRNA. Importantly, STAT3 activity was inhibited by Cucu-B as confirmed by decreased phosphorylation of STAT3 without changing total STAT3 expression. This was substantiated by the reduced Bcl-2 together with increased Bax mRNA expressions with subsequent elevation of Bax/Bcl 2 ratio. In conclusion, Cucu-B hampers CCl4 -induced liver fibrosis in mice. This can be attributed-at least partly-to inhibition of oxidative stress, inflammation and STAT3 signalling. PMID- 29250927 TI - Possible role of interleukin-17 and macrophage migration inhibitory factor in cutaneous warts. AB - BACKGROUND/OBJECTIVES: Cutaneous warts (CW), or verrucae, are benign proliferation of skin that result from infection with human papilloma viruses. Cellular immune reactivity plays a significant role in wart regression. The aim of this study was to elucidate the cellular immune status of patients with CW through measurements of their serum levels of interleukin-17 (IL-17) and macrophage migration inhibitory factor (MIF,) and, identify the possible role of IL-17 and MIF in CW. We assessed serum IL-17 and MIF levels in patients with different forms of CW and compare the results with controls. PATIENT AND METHODS: Serum levels of IL-17 and MIF were measured using commercially available ELISA assay kits in 60 patients with CW and 20 healthy controls. RESULTS: Serum levels of IL-17 and MIF were significantly lower in patients with CW when compared with the controls (P-value <.01, <.05, respectively). There was nonsignificant correlation between IL-17 and MIF. CONCLUSION: Low IL-17 and MIF levels may have a contributory role in occurrence, maintenance, severity, and recurrence of different types of CW which depend mainly on the defect of cell-mediated immunity. This may shed new light on nontraditional strategies for the future medical treatments of CW through regulation of IL-17 and MIF. PMID- 29250926 TI - Subepidermal moisture detection of heel pressure injury: The pressure ulcer detection study outcomes. AB - We examined subepidermal moisture (SEM) and visual skin assessment of heel pressure injury (PrI) among 417 nursing home residents in 19 facilities over 16 weeks. Participants were older (mean age 77 years), 58% were female, over half were ethnic minorities (29% African American, 12% Asian American, 21% Hispanic), and at risk for PrI (mean Braden Scale Risk score = 15.6). Blinded concurrent visual assessments and SEM measurements were obtained at heels weekly. Visual skin damage was categorised as normal, erythema, stage 1 PrI, deep tissue injury (DTI) or stage 2 or greater PrI. PrI incidence was 76%. Off-loading occurred with pillows (76% of residents) rather than heel boots (21%) and often for those with DTI (91%). Subepidermal moisture was measured with a device where higher readings indicate greater moisture (range: 0-70 tissue dielectric constant), with normal skin values significantly different from values in the presence of skin damage. Subepidermal moisture was associated with concurrent damage and damage 1 week later in generalised multinomial logistic models adjusting for age, diabetes and function. Subepidermal moisture detected DTI and differentiated those that resolved, remained and deteriorated over 16 weeks. Subepidermal moisture may be an objective method for detecting PrI. PMID- 29250928 TI - Longitudinal interplays of estrogen receptor alpha gene rs9340799 with social environmental factors on post-traumatic stress disorder in Chinese Han adolescents after Wenchuan earthquake. AB - Indirect evidences suggested associations of estrogen receptor alpha (ESR1) with post-traumatic stress disorder (PTSD). However, the relationship between rs9340799 on ESR1 gene and PTSD has not been reported yet. The present study was to explore the longitudinal changes of prevalence and severity of PTSD in adolescents with different genotypes of rs9340799 after the 2008 Wenchuan earthquake. Social-environmental factors were collected by questionnaires in 465 high school students. Variants of rs9340799 were determined by polymerase chain reaction-restriction fragment length polymorphism analyses and verified by DNA sequencing. PTSD symptoms were assessed by PTSD Checklist-Civilian Version (PCL C) at 6, 12, and 18 months after the earthquake. The female AA homozygotes had a trend of higher prevalence of PTSD and significantly higher PCL-C scores than the female G allele carriers at 6 months after the earthquake. The female students had higher prevalence of PTSD and higher PCL-C scores than the male subjects at 6 months in the AA homozygotes, but not in the G allele carriers. Consecutive decreases in PCL-C scores were observed only in the female AA homozygotes. Only in the female, the AA genotype was the risk factor and predictor of PCL-C scores at 6 months. Potential factors of PTSD prevalence and predictors of PCL-C scores were different between the AA homozygotes and G allele carriers at different time during the follow-up. These results suggest gene-environment interactions may occur among rs9340799 and social-environmental factors, and influence the development and natural rehabilitation of PTSD in the course after stressed by the earthquake. PMID- 29250929 TI - Prior exposure to non-pathogenic calicivirus RCV-A1 reduces both infection rate and mortality from rabbit haemorrhagic disease in a population of wild rabbits in Australia. AB - Mortality caused by rabbit haemorrhagic disease virus (RHDV) in wild rabbits is reduced in parts of Australia where the related, non-pathogenic calicivirus RCV A1 is endemic. Laboratory experiments previously showed that prior infection with RCV-A1 enabled rabbits to better withstand subsequent infection with highly virulent RHDV, and this was assumed to explain higher survival. Here, we analyse serological data from the field suggesting that reduced mortality rates among wild rabbits may also result from rabbits previously infected with RCV-A1 having a reduced likelihood of RHDV infection. We discuss the possible mechanisms underlying this finding and its implications. The methods we describe for analysing field data gave far greater insights into epidemiological processes and virus interactions than gained from reporting basic seroprevalence rates alone. PMID- 29250930 TI - Management of high risk chronic lymphocytic leukaemia (CLL) patients in Australia. AB - BACKGROUND: Chronic lymphocytic leukaemia (CLL) frequently responds to chemoimmunotherapy combining cytotoxic chemotherapy and monoclonal antibodies. However, CLL is associated with significant genetic heterogeneity, and some high risk forms are known to be chemo-resistant and associated with early relapse. AIMS: To review the current treatment paradigm of patients with high-risk disease, in particular those with del(17p) and TP53 variants. RESULTS: A 'watch and wait' approach is recommended for all patients who are asymptomatic. When symptomatic, fluorescence in situ hybridisation testing should be performed and gene sequencing considered subsequently to identify del(17p) and TP53 variants respectively. In the front-line setting, treatment within a clinical trial is the preferred option. In the relapsed or refractory setting, patients with del(17p) or TP53 aberrations should be offered treatment with a novel agent, such as ibrutinib, idelalisib-rituximab or venetoclax. However, of note, at the date of this publication venetoclax is not PBS reimbursed, and ibrutinib will not be reimbursed until 1 December 2017. CONCLUSION: Testing for del(17p) and TP53 variants identifies high-risk CLL that requires specialist management. PMID- 29250931 TI - Cis-acting DNA elements flanking the variable major protein expression site of Borrelia hermsii are required for murine persistence. AB - In Borrelia hermsii, antigenic variation occurs as a result of a nonreciprocal gene conversion event that places one of ~60 silent variable major protein genes downstream of a single, transcriptionally active promoter. The upstream homology sequence (UHS) and downstream homology sequence (DHS) are two putative cis-acting DNA elements that have been predicted to serve as crossover points for homologous recombination. In this report, a targeted deletion/in cis complementation technique was used to directly evaluate the role for these elements in antigenic switching. The results demonstrate that deletion of the expression site results in an inability of the pathogen to relapse in immunocompetent mice, and that the utilized technique was successful in producing complemented mutants that are capable of antigenic switching. Additional complemented clones with mutations in the UHS and DHS of the expressed locus were then generated and evaluated for their ability to relapse in immunocompetent mice. Mutation of the UHS and inverted repeat sequence within the DHS rendered these mutants incapable of relapsing. Overall, the results establish the requirement of the inverted repeat of the DHS for antigenic switching, and support the importance of the UHS for B. hermsii persistence in the mammalian host. PMID- 29250932 TI - Synthesis, Characterization, and Photoelectrochemical Catalytic Studies of a Water-Stable Zinc-Based Metal-Organic Framework. AB - Metal-organic frameworks (MOFs) are class of porous materials that can be assembled in a modular manner by using different metal ions and organic linkers. Owing to their tunable structural properties, these materials are found to be useful for gas storage and separation technologies, as well as for catalytic applications. A cost-effective zinc-based MOF ([Zn(bpcda)(bdc)]n ) is prepared by using N,N'-bis(pyridin-4-ylmethylene)cyclohexane-1,4-diamine [N,N'-bis(pyridin-4 ylmethylene)cyclohexane-1,4-diamine] and benzenedicarboxylic acid (bdc) linkers. This new material exhibits remarkable photoelectrochemical (PEC) catalytic activity in water splitting for the evolution of oxygen. Notably, this non-noble metal-based MOF, without requiring immobilization on other supports or containing metal particles, produced a highest photocurrent density of 31 MUA cm-2 at 0.9 V, with appreciable stability and negligible photocorrosion. Advantageously for the oxygen evolution process, no external reagents or sacrificial agents are required in the aqueous electrolyte solution. PMID- 29250933 TI - Diagnostic potential of the peptide-mediated magnetic separation (PMS)-phage assay and PMS-culture to detect Mycobacterium avium subsp. paratuberculosis in bovine milk samples. AB - Controlling the spread of Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), in domestic livestock is challenging. Current diagnostic methods lack sufficient sensitivity to detect subclinically infected animals, and thus, better diagnostic methods are needed. This study was carried out to investigate the diagnostic potential of two novel peptide-mediated magnetic separation (PMS)-based tests-a PMS-phage assay and PMS-culture-both of which have been developed and optimized to detect viable MAP cells in bovine milk. Individual milk samples (50 ml) were obtained from 105 "non-infected" and 40 "MAP infected" animals (classified as such on the basis of prior faecal culture and serum-ELISA results) in three dairy herds and tested in parallel by the PMS-phage assay and PMS-culture. Diagnostic sensitivity (DSe) and specificity (DSp) of the PMS-phage and PMS-culture methods were determined relative to the MAP infection status of the animal contributing the milk sample. The PMS-based tests applied individually showed moderate DSe (PMS-culture 0.250 and PMS-phage assay 0.325) and high DSp (0.962 and 1.000, respectively). When results of the two PMS-based tests were combined, DSe increased substantially to 0.525, and the DSp was calculated to be 0.962. It was concluded that combined application of the PMS phage assay and PMS-culture provided the most complete picture regarding the presence of viable MAP in bovine milk samples. A comprehensive validation of the PMS-based assays relative to currently used diagnostic methods (faecal culture and serum-ELISA) would be the next step in assessment of the diagnostic potential of these novel PMS-based methods. PMID- 29250934 TI - ALLO: A tool to discriminate and prioritize allosteric pockets. AB - Allosteric proteins make up a substantial proportion of human drug targets. Thus, rational design of small molecule binders that target these proteins requires the identification of putative allosteric pockets and an understanding of their potential activity. Here, we characterized allosteric pockets using a set of physicochemical descriptors and compared them to pockets that are found on the surface of a protein. Further, we trained predictive models capable of discriminating allosteric pockets from orthosteric pockets and models capable of prioritizing allosteric pockets in a set of pockets found on a given protein. Such models might be useful for identifying novel allosteric sites and in turn, potentially new allosteric drug targets. Datasets along with a Python program encapsulating the predictive models are available at http://github.com/fibonaccirabbits/allo. PMID- 29250935 TI - Identifying risk factors associated with infection in patients with chronic leg ulcers. AB - Leg ulcers are hard to heal. Infection causes delayed healing, negatively impacting patients' quality of life, the healthcare system, and society. Early recognition of patients at high risk of infection is essential to prevent complications and reduce negative impacts. However, at present, factors associated with infection in this population are not yet clearly understood. The study aimed to identify factors that were significantly associated with infection in chronic leg ulcers. A sample of 561 patients with chronic leg ulcers, who were previously recruited at outpatient clinics and community settings within Australia between 2008 and 2015, were selected for the current analysis. The prevalence of infection in the sample at study recruitment was 7.8%. A multivariate logistic regression model was used to identify factors associated with infection. The study identified 7 factors that were significantly independently associated with infection, including depression, chronic pulmonary disease, anti-coagulant use, calf ankle circumference ratio < 1.3, ulcer area >= 10 cm2 , slough in the wound bed tissue, and ulcers with heavy exudate. These findings could assist clinicians in the early recognition of patients at risk of infection and individualise treatment for these patients, thereby promoting wound healing. PMID- 29250937 TI - Erratum to article "Mid-childhood outcomes of infant siblings at familial high risk of autism spectrum disorder" Autism Research, 10 (3), 546-557. PMID- 29250938 TI - How to administer an insulin injection. AB - RATIONALE AND KEY POINTS: Effective insulin injection technique is essential to ensure optimal management of diabetes. Those who administer insulin should understand how it works, in particular its link to blood glucose levels. PMID- 29250936 TI - Expression of the arsenite oxidation regulatory operon in Rhizobium sp. str. NT 26 is under the control of two promoters that respond to different environmental cues. AB - Rhizobium sp. str. NT-26 is a Gram-negative facultative chemolithoautotrophic arsenite oxidizer that has been used as a model organism to study various aspects of arsenite oxidation including the regulation of arsenite oxidation. The three regulatory genes, aioX, aioS, and aioR, are cotranscribed when NT-26 was grown in the presence or absence of arsenite. The aioXSR operon is upregulated in stationary phase but not by the presence of arsenite in the growth medium. The two transcription start sites upstream of aioX were determined which led to the identification of two promoters, the housekeeping promoter RpoD and the growth phase-dependent promoter RpoE2. Promoter-lacZ fusions confirmed their constitutive and stationary phase expressions. The involvement of the NT-26 sigma factor RpoE2 in acting on the NT-26 RpoE2 promoter was confirmed in vivo in Escherichia coli, which lacks a rpoE2 homolog, using a strain carrying both the promoter-lacZ fusion and the NT-26 rpoE2 gene. An in silico approach was used to search for other RpoE2 promoters and AioR-binding motifs and led to the identification of other genes that could be regulated by these proteins including those involved in quorum sensing, chemotaxis, and motility expanding the signaling networks important for the microbial metabolism of arsenite. PMID- 29250939 TI - Legal, ethical and professional aspects of duty of care for nurses. AB - Duty of care is a fundamental aspect of nursing, and many nurses consider this to be an important part of their professional duties as a nurse. However, the legal underpinnings of duty of care are often overlooked, and, as such, nurses may be unsure about when to act if they encounter emergency situations or serious incidents, especially when they are off duty. This article examines the legal, ethical and professional aspects of duty of care, what these mean for nurses in practice, and how duty of care is intrinsically linked with standards of care and negligence. PMID- 29250941 TI - Editorial. PMID- 29250940 TI - Role of nursing leadership in providing compassionate care. AB - This article encourages nurses to explore the concept of leadership in the constantly changing field of health and social care. All nurses have an important role in leadership, and they should consider what type of leader they want to be and what leadership skills they might wish to develop. This article examines what leadership might involve, exploring various leadership styles and characteristics and how these could be applied in nurses' practice. A core component of nursing and nursing leadership is the ability to provide compassionate care. This could correspond with the idea of servant leadership, an approach that moves the leader from a position of power to serving the team and supporting individuals to develop their potential. PMID- 29250942 TI - TACKLING GLOBAL ISSUES FOR A BETTER WORLD. AB - It's almost one year since the United Nations General Assembly launched the Sustainable Development Goals (SDGs) to tackle a range of global issues from gender inequality to climate change. PMID- 29250943 TI - RENOWNED NURSING ETHCIST BOWS OUT. AB - Megan-Jane Johnstone was delving into the study of philosophy at New Zealand's Waikato University in the early 80s when her lightbulb moment hit. PMID- 29250944 TI - NURSE PRACTITIONERS -- THE ANSWER FOR AGED CARE. AB - The nurse practitioner role is now well established in Australia, with these nurses driving clinical leadership and innovation, across a diversity of care settings. The aged care sector, however, was slower than other areas to create positions for nurse practitioners. PMID- 29250945 TI - NURSE PRACTITIONERS. THE ROAD LESS TRAVELLED. AB - With the Australian healthcare system struggling to keep up with surging demand, nurse practitioners are ideally placed and suited to fulfill the role for which they were envisioned. Natalie Dragon looks at the challenges to realize the NP potential. PMID- 29250946 TI - Review of global influenza activity, October 2016-October 2017. PMID- 29250947 TI - A 100 kHz Pulse Shaping 2D-IR Spectrometer Based on Dual Yb:KGW Amplifiers. AB - A high-speed, high-sensitivity and compact two-dimensional infrared (2D-IR) spectrometer based on 100 kHz Yb:KGW regenerative amplifier technology is described and demonstrated. The setup is three color, using an independent pump OPA and two separately tunable probe OPAs. The spectrometer uses 100 kHz acousto optic pulse shaping on the pump beam for rapid 2D-IR acquisitions. The shot-to shot stability of the laser system yields excellent signal-to-noise figures (~10 MUOD noise on 5000 laser shots). We show that the reduced bandwidth of the Yb:KGW amplifiers in comparison with conventional Ti:sapphire systems does not compromise the ability of the setup to generate high-quality 2D-IR data. Instrument responses of <300 fs are demonstrated and 2D-IR data presented for several systems of interest to physical chemists, showing spectral diffusion in NaSCN, amide I and II bands of a beta sheet protein and DNA base-pair-backbone couplings. Overall, the increased data acquisition speed, intrinsic stability, and robustness of the Yb:KGW lasers are a significant step forward for 2D-IR spectroscopy. PMID- 29250948 TI - Fine-Tuning the Quasi-3D Geometry: Enabling Efficient Nonfullerene Organic Solar Cells Based on Perylene Diimides. AB - The geometries of acceptors based on perylene diimides (PDIs) are important for improving the phase separation and charge transport in organic solar cells. To fine-tune the geometry, biphenyl, spiro-bifluorene, and benzene were used as the core moiety to construct quasi-three-dimensional nonfullerene acceptors based on PDI building blocks. The molecular geometries, energy levels, optical properties, photovoltaic properties, and exciton kinetics were systematically studied. The structure-performance relationship was discussed as well. Owing to the finest phase separation, the highest charge mobility and smallest nongeminate recombination, the power conversion efficiency of nonfullerene solar cells using PDI derivatives with biphenyl core (BP-PDI4) as acceptor reached 7.3% when high performance wide band gap donor material poly[(2,6-(4,8-bis(5-(2 ethylhexyl)thiophen-2-yl)-benzo[1,2-b:4,5-b']dithiophene))-alt-(5,5-(1',3'-di-2 thienyl-5',7'-bis(2-ethylhexyl)benzo[1',2'-c:4',5'-c']dithiophene-4,8-dione))] was blended. PMID- 29250949 TI - Dissecting the Gold(I)-Catalyzed Carboaminations of N-Allyl Tetrahydro-beta carbolines to Allenes. AB - N-Allyl tetrahydro-beta-carbolines undergo gold-catalyzed cyclizations that lead to tetracyclic compounds, resulting from both ring closure and the transfer of the allylic group from the nitrogen to the carbon backbone. The final skeleton obtained depends on the nature of both the R2 group of the allene and the R3 group of the allylic residue. Mechanistic studies and DFT calculations allowed the determination of all the mechanistic pathways involved in these processes, stemming from a common intermediate that evolves differently according to the substituents nature. PMID- 29250950 TI - Fundamental Study of Facile and Stable Hydrogen Evolution Reaction at Electrospun Ir and Ru Mixed Oxide Nanofibers. AB - Electrochemical hydrogen evolution reaction (HER) has been an interesting research topic in terms of the increasing need of renewable and alternative energy conversion devices. In this article, IrxRu1-xOy (y = 0 or 2) nanofibers with diverse compositions of Ir/IrO2 and RuO2 are synthesized by electrospinning and calcination procedures. Their HER activities are measured in 1.0 M NaOH. Interestingly, the HER activities of IrxRu1-xOy nanofibers improve gradually during repetitive cathodic potential scans for HER, and then eventually reach the steady-state consistencies. This cathodic activation is attributed to the transformation of the nanofiber surface oxides to the metallic alloy. Among a series of IrxRu1-xOy nanofibers, the cathodically activated Ir0.80Ru0.20Oy shows the best HER activity and stability even compared with IrOy and RuOy, commercial Pt and commercial Ir (20 wt % each metal loading on Vulcan carbon), where a superior stability is possibly ascribed to the instant generation of active Ir and Ru metals on the catalyst surface upon HER. Density functional theory calculation results for hydrogen adsorption show that the energy and adsorbate catalyst distance at metallic Ir0.80Ru0.20 are close to those at Pt. This suggests that mixed metallic Ir and Ru are significant contributors to the improved HER activity of Ir0.80Ru0.20Oy after the cathodic activation. The present findings clearly demonstrate that the mixed oxide of Ir and Ru is a very effective electrocatalytic system for HER. PMID- 29250951 TI - Smart Sensing Based on DNA-Metal Interaction Enables a Label-Free and Resettable Security Model of Electrochemical Molecular Keypad Lock. AB - Recently, molecular keypad locks have received increasing attention. As a new subgroup of smart biosensors, they show great potential for protecting information as a molecular security data processor, rather than merely molecular recognition and quantitation. Herein, label-free electrochemically transduced Ag+ and cysteine (Cys) sensors were developed. A molecular keypad lock model with reset function was successfully realized based on the balanced interaction of metal ion with its nucleic acid and chemical ligands. The correct input of "1-2 3" (i.e., "Ag+-Cys-cDNA") is the only password of such molecular keypad lock. Moreover, the resetting process of either correct or wrong input order could be easily made by Cys, buffer, and DI water treatment. Therefore, our system provides an even smarter system of molecular keypad lock, which could inhibit illegal access of unauthorized users, holding great promise in information protection at the molecular level. PMID- 29250952 TI - Marine Antifouling Behavior of Lubricant-Infused Nanowrinkled Polymeric Surfaces. AB - A new family of polymeric, lubricant-infused, nanostructured wrinkled surfaces was designed that effectively retains inert nontoxic silicone oil, after draining by spin-coating and vigorous shear for 2 weeks. The wrinkled surfaces were fabricated using three different polymers (Teflon AF, polystyrene, and poly(4 vinylpyridine)) and two shrinkable substrates (Polyshrink and shrinkwrap), and Teflon on Polyshrink was found to be the most effective system. The volume of trapped lubricant was quantified by adding Nile red to the silicone oil before infusion and then extracting the oil and Nile red from the surfaces in heptane and measuring by fluorimetry. Higher volumes of lubricant induced lower roll-off angles for water droplets, and in turn induced better antifouling performance. The infused surfaces displayed stability in seawater and inhibited growth of Pseudoalteromonas spp. bacteria up to 99%, with as little as 0.9 MUL cm-2 of the silicone oil infused. Field tests in the waters of Sydney Harbor over 7 weeks showed that silicone oil infusion inhibited the attachment of algae, but the algal attachment increased as the silicone oil was slowly depleted over time. The infused wrinkled surfaces have high transparency and are moldable, making them suited to protect the windows of underwater sensors and cameras. PMID- 29250953 TI - Enhanced Switchable Ferroelectric Photovoltaic Effects in Hexagonal Ferrite Thin Films via Strain Engineering. AB - Ferroelectric photovoltaics (FPVs) are being extensively investigated by virtue of switchable photovoltaic responses and anomalously high photovoltages of ~104 V. However, FPVs suffer from extremely low photocurrents due to their wide band gaps (Eg). Here, we present a promising FPV based on hexagonal YbFeO3 (h-YbFO) thin-film heterostructure by exploiting its narrow Eg. More importantly, we demonstrate enhanced FPV effects by suitably exploiting the substrate-induced film strain in these h-YbFO-based photovoltaics. A compressive-strained h YbFO/Pt/MgO heterojunction device shows ~3 times enhanced photovoltaic efficiency than that of a tensile-strained h-YbFO/Pt/Al2O3 device. We have shown that the enhanced photovoltaic efficiency mainly stems from the enhanced photon absorption over a wide range of the photon energy, coupled with the enhanced polarization under a compressive strain. Density functional theory studies indicate that the compressive strain reduces Eg substantially and enhances the strength of d-d transitions. This study will set a new standard for determining substrates toward thin-film photovoltaics and optoelectronic devices. PMID- 29250955 TI - Multifunctional Bi2WO6 Nanoparticles for CT-Guided Photothermal and Oxygen-free Photodynamic Therapy. AB - The consumption of oxygen in photodynamic therapy (PDT) significantly exacerbates the degree of hypoxia in tumors, which not only impedes the therapeutic effect of PDT, but also drives local tumor recurrence. To relieve the PDT-induced hypoxia and improve the therapeutic outcome of PDT in cancer treatment, herein we reported a class of Bi2WO6 nanoparticles (NPs) as a robust multifunctional platform, which integrates the abilities for contrast-enhanced computed tomography (CT) imaging, photothermal therapy, and PDT in an oxygen-free manner. The as-obtained Bi2WO6 NPs with a mean diameter of 5.2 nm are stable in phosphate buffered saline and an in vivo microenvironment-mimicking buffer. The location of the solid tumor could be accurately positioned using Bi2WO6-enhanced CT with higher spatial resolution. After being irradiated with an 808 nm laser, these Bi2WO6 NPs could realize CT-guided local photothermal ablation of the tumor. Meanwhile, *OH radicals were generated simultaneously from the treatment without consuming an oxygen molecule, which enabled these Bi2WO6 NPs to exert photodynamic killing effect in an oxygen-free manner during cancer therapy. Remarkable tumor suppression was observed in mice bearing the HeLa xenograft, supporting the promising application of these multifunctional Bi2WO6 NPs in the combat against cancers through synergistic photothermal and oxygen-free PDT treatment. PMID- 29250954 TI - Single-Step Laser Plasmonic Coloration of Metal Films. AB - Utilization of structural colors produced by nanosized optical antennas is expected to revolutionize the current display technologies based on an inkjet or a pigmentation-based color printing. Meanwhile, the versatile color-mapping strategy combining the fast single-step single-substrate fabrication cycle with low-cost scalable operation is still missing. We propose lithography-free pure optical approach based on a direct local ablative reshaping of the gold film with nanojoule (nJ)-energy femtosecond laser pulses. Plasmon-color printing at a resolution up to 2.5 * 104 dots per inch satisfying the current visualization demands and data storage capacity is achieved. By controlling only the applied pulse energy, wide gamut of colors in scattering regime was reproduced via tuning the size of the printed nanovoids, which have a polarization- and shape-dependent localized plasmon-mediated scattering. Additionally, brightness of a single pixel was gradually adjusted via varying of the spacing between the printed nanovoids. The presented experimental demonstration opens a new direction toward plasmon color printing for various applications where durability is required: low-cost cryptography, security tagging, and ultracompact optical data storage. PMID- 29250956 TI - Integrated Analysis of Protein Abundance, Transcript Level, and Tissue Diversity To Reveal Developmental Regulation of Maize. AB - The differentiation and subsequent development of plant tissues or organs are tightly regulated at multiple levels, including the transcriptional, posttranscriptional, translational, and posttranslational levels. Transcriptomes define many of the tissue-specific gene expression patterns in maize, and some key genes and their regulatory networks have been established at the transcriptional level. In this study, the sequential window acquisition of all theoretical spectra-mass spectrometry technique was employed as a quantitative proteome assay of four representative maize tissues, and a set of high-confidence proteins was identified. Integrated analysis of the proteome and transcriptome revealed that protein abundance was positively correlated with mRNA level with weak to moderate correlation coefficients, but the abundance of key proteins for function or architecture in a given tissue was closely tempospatially regulated at the transcription level. A subset of differentially expressed proteins, specifically tissue-specific highly expressed proteins, was identified, for example, reproductive structure and flower development-related proteins in tassel and ear, lipid and fatty acid biosynthetic process-related proteins in immature embryo, and inorganic substance and oxidation reduction responsive proteins in root, potentially revealing the physiology, morphology, and function of each tissue. Furthermore, we found many new proteins in specific tissues that were highly correlated with their mRNA levels, in addition to known key factors. These proteome data provide new perspective for understanding many aspects of maize developmental biology. Raw proteomics data are available via ProteomeXchange with identifier PXD008464. PMID- 29250957 TI - Nucleolin-Targeting AS1411-Aptamer-Modified Graft Polymeric Micelle with Dual pH/Redox Sensitivity Designed To Enhance Tumor Therapy through the Codelivery of Doxorubicin/TLR4 siRNA and Suppression of Invasion. AB - In this article, a novel graft polymeric micelle with targeting function ground on aptamer AS1411 was synthesized. The micelle was based on chitosan-ss polyethylenimine-urocanic acid (CPU) with dual pH/redox sensitivity and targeting effects. This micelle was produced for codelivering Toll-like receptor 4 siRNA (TLR4-siRNA) and doxorubicin (Dox). In vitro investigation revealed the sustained gene and drug release from Dox-siRNA-loaded micelles under physiological conditions, and this codelivery nanosystem exhibited high dual pH/redox sensitivity, rapid intracellular drug release, and improved cytotoxicity against A549 cells in vitro. Furthermore, the micelles loaded with TLR4-siRNA inhibited the migration and invasion of A549. Excellent tumor penetrating efficacy was also noted in the A549 tumor spheroids and solid tumor slices. In vivo, multiple results demonstrated the excellent tumor-targeting ability of AS1411-chitosan-ss polyethylenimine-urocanic acid (ACPU) micelle in tumor tissues. The micelles exhibited excellent antitumor efficacy and low toxicity in the systemic circulation in lung-tumor-bearing BALB/c mice. These results conclusively demonstrated the great potential of the new graft copolymer micelle with targeting function for the targeted and efficient codelivery of chemotherapeutic drugs and genes in cancer treatment. PMID- 29250958 TI - 4-Phenoxyphenol-Functionalized Reduced Graphene Oxide Nanosheets: A Metal-Free Fenton-Like Catalyst for Pollutant Destruction. AB - Metal-containing Fenton catalysts have been widely investigated. Here, we report for the first time a highly effective stable metal-free Fenton-like catalyst with dual reaction centers consisting of 4-phenoxyphenol-functionalized reduced graphene oxide nanosheets (POP-rGO NSs) prepared through surface complexation and copolymerization. Experimental and theoretical studies verified that dual reaction centers are formed on the C-O-C bridge of POP-rGO NSs. The electron-rich center around O is responsible for the efficient reduction of H2O2 to *OH, while the electron-poor center around C captures electrons from the adsorbed pollutants and diverts them to the electron-rich area via the C-O-C bridge. By these processes, pollutants are degraded and mineralized quickly in a wide pH range, and a higher H2O2 utilization efficiency is achieved. Our findings address the problems of the classical Fenton reaction and are useful for the development of efficient Fenton-like catalysts using organic polymers for different fields. PMID- 29250959 TI - Formation of Ruddlesden-Popper Faults and Their Effect on the Magnetic Properties in Pr0.5Sr0.5CoO3 Thin Films. AB - Epitaxial Pr0.5Sr0.5CoO3 thin films have been grown on single-crystalline (La0.289Sr0.712)(Al0.633Ta0.356)O3(001) substrates by the pulsed laser deposition technique. The magnetic properties and microstructure of these films are investigated. It is found that Ruddlesden-Popper faults (RP faults) can be introduced in the films by changing the laser repetition rate. The segregation of Pr at the RP faults is characterized by atomic-resolution chemical mapping. The formation of the RP faults not only contributes to the epitaxial strain relaxation but also significantly decreases the ferromagnetic long-range order of the films, resulting in lower magnetizations than those of the fault-free films. Our results provide a strategy for tuning the magnetic properties of cobalt-based perovskite films by modifying the microstructure through the film growth process. PMID- 29250960 TI - Interfacial Chemistry in Solid-State Batteries: Formation of Interphase and Its Consequences. AB - Benefiting from extremely high shear modulus and high ionic transference number, solid electrolytes are promising candidates to address both the dendrite-growth and electrolyte-consumption problems inherent to the widely adopted liquid-phase electrolyte batteries. However, solid electrolyte/electrode interfaces present high resistance and complicated morphology, hampering the development of solid state battery systems, while requiring advanced analysis for rational improvement. Here, we employ an ultrasensitive three-dimensional (3D) chemical analysis to uncover the dynamic formation of interphases at the solid electrolyte/electrode interface. While the formation of interphases widens the electrochemical window, their electronic and ionic conductivities determine the electrochemical performance and have a large influence on dendrite growth. Our results suggest that, contrary to the general understanding, highly stable solid electrolytes with metal anodes in fact promote fast dendritic formation, as a result of less Li consumption and much larger curvature of dendrite tips that leads to an enhanced electric driving force. Detailed thermodynamic analysis shows an interphase with low electronic conductivity, high ionic conductivity, and chemical stability, yet having a dynamic thickness and uniform coverage is needed to prevent dendrite growth. This work provides a paradigm for interphase design to address the dendrite challenge, paving the way for the development of robust, fully operational solid-state batteries. PMID- 29250961 TI - Plasmon-Enhanced Electrochemiluminescence for Nucleic Acid Detection Based on Gold Nanodendrites. AB - Gold nanodendrites (Au NDs) exhibit extremely strong electromagnetic field located around multiple tip branches due to a plasmon coupling effect. In this work, a novel LSPR-enhanced ECL emission from CdTe nanocrystals (NCs) by Au NDs for the detection of nucleic acid is reported. This system is composed of a thin film of CdTe NCs on glassy carbon electrode (GCE) as anodic ECL emitter and Au NDs as plasmon enhancer. DNA tetrahedron embedded with a stem-loop hairpin structure on one edge was applied as a switch to regulate the distance between CdTe NCs and Au NDs. At original state, the hairpin structure was closed and DNA tetrahedron played in a relaxed state on CdTe NCs film. The ECL emission of CdTe NCs was quenched by proximal Au NDs due to Forster resonance energy transfer (FRET), which was defined as the "turn-off" mode. After the complementary hybridization with target DNA, the hairpin structure changed to a rodlike configuration, resulting in an increased distance between CdTe NCs and Au NDs, and a significant enhancement of ECL induced by LSPR of Au NDs, which was defined as a "turn-on" mode. Along with the asymmetric modification method, a controllable and versatile pathway for modifying nanomaterials, the ECL sensor performed well with great stability and repeatability for nucleic acid detection in the range from 1.0 to 500 fM. Considering the high sensitivity and selectivity in the serum sample assay, this proposed method indicates a great potential for bioassay application. PMID- 29250962 TI - Pathways to functional outcomes following a first episode of psychosis: The roles of premorbid adjustment, verbal memory and symptom remission. AB - OBJECTIVE: Most studies have investigated either the singular or relative contributions of premorbid adjustment, verbal memory and symptom remission to functional outcomes in first-episode psychosis. Fewer studies have examined the pathways of these factors in impacting functioning. Our study addresses this gap. The objective was to determine whether the relationship between premorbid adjustment and functional outcomes was mediated by verbal memory and symptom remission. METHOD: A total of 334 first-episode psychosis participants (aged 14 35 years) were assessed on premorbid adjustment, verbal memory upon entry, and positive and negative symptom remission and functioning at multiple time points over a 2-year follow-up. RESULTS: Mediation analyses showed that over the first year, the relationship between premorbid adjustment and functioning was mediated by verbal memory and positive symptom remission (beta = -0.18; 95% confidence interval = [-0.51, -0.04]), as well as by verbal memory and negative symptom remission (beta = -0.41; 95% confidence interval = [-1.11, -1.03]). Over 2 years, the relationship between premorbid adjustment and functioning was mediated by verbal memory and only negative symptom remission (beta = -0.38; 95% confidence interval = [-1.46, -0.02]). CONCLUSION: Comparatively less malleable factors (premorbid adjustment and verbal memory) may contribute to functional outcomes through more malleable factors (symptoms). Promoting remission may be an important parsimonious means to achieving better functional outcomes. PMID- 29250964 TI - Phytochemical Analysis, Antioxidant and Antibacterial Properties of Spilanthes mauritiana Used Traditionally in Limpopo Province, South Africa. AB - Spilanthes mauritiana belonging to the family Asteraceae, was screened for biological activity against bacterial pathogen. Antibacterial activity of the plant was investigated using microbroth dilution assay and bioautography. Total phenols and tannins of the extract were 52.47 +/- 2.29 and 23.9 +/- 1.18 as mg of gallic acid equivalents, respectively. Total flavonoid content was 25.1 +/- 0.79 as mg of quercetin equivalents. Free radical scavenging activity of constituents in all the extract, against 2,2-diphenyl-1-picrylhydrazyl showed minimal activity. All extracts contained compounds with antibacterial activity against tested pathogens. Hexane extract had an average minimum inhibitory concentration value of 2.50 mg/mL, followed by methanol extract (1.72 mg/mL), acetone and dichloromethane extracts (1.96 mg/mL). The present study revealed the presence of compounds in S mauritiana with potent antibacterial activity against tested pathogens that are exhibiting the observed activity independent of other constituents contained in the extracts. PMID- 29250963 TI - High prevalence of Staphylococcus aureus nasal carriage among children in Szolnok, Hungary. AB - We collected nasal samples from 1,390 healthy 3-7 years old children in Szolnok city, Hungary, in 2012. We detected 476 Staphylococcus aureus isolates from 474 children. In two occasions, two different S. aureus were isolated, based on hemolysis type and pulsed-field gel electrophoresis pattern. S. aureus carriage rate was calculated to be 34.1% similar to others studies. Male gender was found to be a risk factor for carriage by statistical analysis. Altogether, four methicillin-resistant S. aureus (MRSA) strains were detected by mecA polymerase chain reaction, which means 0.8% community-acquired MRSA prevalence among the S. aureus isolates. All MRSA strains harbored the SCCmec type IV cassette (typical for CA-MRSA) and belonged to ST45 by multilocus sequence typing. During antibiotic susceptibility testing, we measured the following resistance rates: 0.0% for mupirocin, 0.2% for ciprofloxacin, 0.6% for gentamicin and oxacillin, 3.4% for tetracycline, 9.5% for clindamycin, 10.3% for erythromycin, and 91.4% for penicillin, which are generally lower compared with Hungarian clinical isolates. PMID- 29250965 TI - Knowledge, Attitude, and Practice of Complementary and Alternative Medicine Among Residents of Wayu Town, Western Ethiopia. AB - Complementary and alternative medicine covers a wide variety of therapies and practices, which vary from country to country and region to region. The study was conducted to assess the knowledge, attitude, and practice of complementary and alternative medicine among the residents of Wayu town, Western Ethiopia. A descriptive cross-sectional study was carried out on 302 residents. A systematic sampling was used to select households. Data were entered in SPSS (version 20; IBM Corp) and descriptive statistics was carried out. Of 302 participants, 51.65% have a good knowledge, 78.6% were aware of complementary and alternative medicine, and 74.22% used it in the past 2 years. A total of 23.83% believe that complementary and alternative medicine is more effective than modern medicine and 28.8% preferred complementary and alternative medicine to modern medicine. This study revealed that in Wayu town, there is relatively high public interest in complementary and alternative medicine practices and a significant number has a good knowledge but generally the attitude toward complementary and alternative medicine is relatively low. PMID- 29250966 TI - Advancing Research on Traditional Whole Systems Medicine Approaches. AB - While the intention of Integrative Medicine (IM) is whole person medicine, it has for the most part remained driven by individual modalities. Like the practice of IM itself, IM research too has been driven primarily by studies on individual modalities. There are significant challenges to moving research on whole systems medicine forward, with funding being at the top of the list. Historically, NIH has not been receptive to supporting research on whole systems, preferring instead to support studies that are more individual modality driven so that mechanisms can be identified. Purely mechanistic research, however, assumes unidirectional causality and linear responses yet clinical responses to whole systems approaches are more often multidirectional and dynamically unpredictable. The concept of emergence is applicable here. Whole systems approaches suggest that by incorporating therapies into holistic treatment programs we not only treat symptoms but accomplish more by activating the body's inherent self organizing healing mechanisms and treat the root cause of illnesses as well as associated symptoms. Given that interest in integrative therapies with the general public and medical community is steadily increasing, there is need for more research that explores intact whole systems approaches to elucidate the relevant system-wide effects and dynamic interactions related to these practices. PMID- 29250967 TI - [Emergency diagnosis of the acute vestibular syndrome]. AB - INTRODUCTION AND AIM: To diagnose acute vestibular syndrome (AVS) in a prospective study by a new bedside test (providing 1A evidence) based on oculomotor analysis and assessment of hearing loss. To assess the frequency of central and peripheral causes of acute vestibular syndrome in the emergency room. To establish the diagnostic accuracy of acute cranial computed tomography as compared to oculomotor analysis done by video oculography goggles and audiometry. METHOD: Between 1st March 2016 and 1st March 2017 we documented 125 patients (62 women, 63 men, average age 53 years) in the emergency room of the Petz Aladar County Teaching Hospital using the above bedside and instrumental testing. Diagnosis was verified by cranial magnetic resonance imaging. RESULTS: According to the results of the instrumental examination in AVS in 67% we found a peripheral cause and in 33% a central pathology. In 62% isolated posterior circulation stroke manifested itself by isolated vertigo without additional focal signs and the acute cranial computed tomography showed negative results in 96%. The instrumental examination increased diagnostic accuracy by making the diagnosis of isolated inferior semicircular canal vestibular neuritis possible. CONCLUSIONS: The new bedside oculomotor test is suitable for the diagnosis of posterior circulation stroke manifesting with isolated vertigo in early cases, when the routine neuroradiologic methods have a lower sensitivity or are not available. Orv Hetil. 2017; 158(51): 2029-2040. PMID- 29250968 TI - [Ocular surface squamous neoplasia]. AB - To summarize actual knowledge on epidemiology, etiology, pathology, clinical apparence and treatment of ocular surface squamous neoplasias. We summarize up-to date literature on conjunctival intraepithelial neoplasia and invasive squamous cell carcinoma and present some own cases. Ocular surface squamous neoplasia is the most common malignant ocular surface tumor and the third most common ocular malignancy following malignant melanoma and lymphoma. In spite of its low malignant potential, in advanced stages it may reduce visual acuity significantly or even the eye globe has to be removed. In case of metastasis it may also be life-threatening. As local recurrences of ocular surface squamous neoplasias may occur, knowledge of intra- and postoperative adjuvant treatment options are indispensable and regular control examinations are necessary. Identification and adequate treatment of ocular surface squamous neoplasias are necessary in order to avoid its progression and to prevent recurrences. Orv Hetil. 2017; 158(51): 2011-2022. PMID- 29250969 TI - [The role of selective monoamine oxidase B inhibitors in the therapeutic strategy of Parkinson's disease in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital]. AB - INTRODUCTION: Selective monoamine oxidase B inhibitors have an accurate place in therapeutical strategy of Parkinsons's disease. In the early stages of the disease, especially in younger patients with milder symptoms, the introduction of levodopa substitution could be efficacious in delaying; in advanced stages they are mainly used to treat motor complications, as an adjunct to levodopa. AIM: The evaluation of therapeutical strategies used in the neurology clinics of Tirgu Mures County Emergency Clinical Hospital in order to define the role of monoamine oxidase B inhibitors. METHOD: This retrospective study includes all records of patients with Parkinson's disease hospitalized between 1 January 2003 and 31 December 2016. From the 2194 reports we used data focusing on the therapeutic recommendations. Regarding disease duration, we divided the patients in two groups: less than or equal to 5 years and more than 5 years. RESULTS: From the 1183 patients in first group, 243 received monoamine oxidase inhibitors: 12 as monotherapy, 52 together with dopamine agonists, in 61 cases combined with levodopa. In 118 cases monoamine oxidase inhibitors were combined with levodopa and dopamine agonists. From 582 cases whith Parkinson's disease for more than 5 years, 195 received monoamine oxidase B inhibitors (selegiline: 10 cases, rasagiline: 185 cases). In 429 cases we did not find accurate data regarding disease duration (selegiline: 5 cases, rasagiline: 93 cases). CONCLUSION: The use of monoamine oxidase B inhibitors was similar to those found in literature. The treating physicians should utilise more confidently the available therapeutical combinations. Orv Hetil. 2017; 158(51): 2023-2028. PMID- 29250970 TI - [Image-guided radiotherapy for muscle invasive bladder cancer with intravesical lipiodol injection. A new option for bladder sparing treatment]. AB - INTRODUCTION AND AIM: To implement lipiodol as a fiducial marker of the tumor bed for image-guided radiotherapy with simultaneous integrated boost technique as part of radiochemotherapy for muscle invasive bladder tumors. METHOD: Since April 2016, radiochemotherapy was performed in 3 male patients with muscle invasive, transitional cell bladder carcinoma. Prior to radiochemotherapy, tumor bed resection was performed for each patient, at the same time 10 ml of lipiodol solution was injected submucosally into the resection site, thus marking the tumor bed for escalated dose irradiation. During radiochemotherapy 51 Gy (1.7 Gy/die) to the pelvis, 57 Gy (1.9 Gy/die) to the whole bladder, and 63 Gy (2.1 Gy/die) to the lipiodol-labeled tumor bed was delivered with simultaneous integrated boost technique. The accuracy of the irradiation was controlled by daily kilovoltage CT. Early radiogenic urogenital and gastrointestinal side effects were recorded according to Radiation Therapy Oncology Group side-effects grading recommendation. RESULTS: Substantial perioperative side effect or toxicity were not observed during and after the injection of lipiodol. The prescribed dose was successfully delivered in all patients. Radiotherapy duration was 6 weeks. The lipiodol-labeled tumor bed was clearly visible on daily kilovoltage cone beam CT. In one patient grade II cystitis and proctitis was observed, another patient experienced only grade I cystitis. These complaints improved with symptomatic medication. In the third patient no significant side effect occurred. CONCLUSIONS: The injection of lipiodol into the bladder wall is a safe technique, without any perioperative toxicity or complication. The tumor bed demarcated by lipiodol was visible both on treatment planning and kilovoltage CTs. The total treatment time was shortened by 4 days. The treatment was well tolerated, early side effects were moderate, or slight. Orv Hetil. 2017; 158(51): 2041-2047. PMID- 29250972 TI - Mass media exposure and modern contraceptive use among married West African adolescents. AB - PURPOSE: The purpose of this study was to examine whether family planning (FP) messaging is reaching married adolescent women in West Africa, and whether such messaging is associated with increased contraceptive use. MATERIALS AND METHODS: We utilised data from the 2010 Demographic and Health Surveys (DHS) for Burkina Faso and Senegal (women 15-49; N = 17,067 and N = 15,688, respectively). We used chi-square tests to evaluate whether FP messaging exposure (via TV, radio, and/or print) differed according to socio-demographic characteristics. Subsequent analysis focussed on married adolescents (15-19; N = 961 in Burkina Faso, N = 996 in Senegal) which utilised propensity score matching and multivariable logistic regression models to test the association between self-reported FP messaging exposure and modern contraceptive use, knowledge of a modern contraceptive method, and future intention to use contraception. RESULTS: A higher proportion of women 15-49 who reported FP messaging exposure were urban, from higher wealth quintiles, and had higher education levels, compared with unexposed women. A smaller proportion of adolescents reported exposure compared to older age groups. Among married adolescents, there was a positive but non-significant association between FP messaging exposure and use of a modern contraceptive method in Senegal (adjusted odds ratio (aOR) = 2.3; 95% CI: 0.92, 5.73). No such association was found in Burkina Faso (aOR = 0.98; 95% CI: 0.43, 2.26). CONCLUSIONS: Mass media campaigns are not reaching the most vulnerable populations in West Africa, such as adolescents and poorer rural women. Adapting mass media campaigns to address these gaps is important for increasing exposure to FP messaging. PMID- 29250973 TI - Association of low-dose exposure to persistent organic pollutants with E-cadherin promoter methylation in healthy Koreans. AB - BACKGROUND: Persistent organic pollutants (POPs), despite their considerably low levels in humans, are an increasing concern for the general populations given their various adverse health problems, including metabolic and carcinogenic effects. DNA methylation deregulation is thought to be a key mechanism in the development of human chronic diseases including cancer. METHODS: In an attempt to identify biomarkers monitoring low-dose exposure and hazard, we explored whether organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) may influence the methylation of tumour suppressor gene E-cadherin (CDH1) using peripheral blood cells from 364 healthy Korean subjects. RESULTS: CDH1 methylation was observed in 78.3% of study subjects. Serum concentrations of OCPs or PCBs compounds were higher in CDH1 methylation-positive subjects than in methylation-negative ones. After adjusting for various covariates, the odds ratio of CDH1 methylation of the summary measure of PCBs were 1.0, 2.5 (95% confidence interval: 1.2-5.3), 3.6 (1.6-8.1), 3.6 (1.4-8.6), and 2.5 (1.1-5.7) across quintiles of PCBs (Ptrend = 0.01). The values of OCPs were 1.0, 0.9, 1.2, 2.4 (1.0-5.9), and 1.7 (Ptrend = 0.05). CONCLUSIONS: In this exploratory study with a small sample, CDH1 methylation might be served as the epigenetic biomarker associated with POPs exposure and adverse health effect. PMID- 29250974 TI - Moistening the new vaginal misoprostol tablets: does it increase the efficacy of cervical priming before manual vacuum aspiration in first-trimester miscarriage? A randomised clinical trial. AB - OBJECTIVES: The primary objective of our study was to ascertain whether moistening the Brazilian formulation of vaginal misoprostol tablets increases cervical dilation before manual vacuum aspiration (MVA), compared with use of dry misoprostol, in first-trimester miscarriage. The secondary objective was to ascertain whether there was any correlation between vaginal pH and the degree of cervical dilation using a moistened or dry misoprostol tablet. METHODS: In a single-centre, double-blind, randomised trial, 46 patients with first-trimester miscarriage were randomly allocated to treatment with dry or moistened (with 200 ul distilled water) 2 * 200 MUg misoprostol tablets. RESULTS: The median (range) cervical dilation in the wet and dry groups was 8 mm (6-12 mm) and 7 mm (5-10 mm), respectively (p = .06). The median time between misoprostol insertion and carrying out the procedure did not differ between the dry (406 min, range 180-550 min) and wet (448 min, range 180-526 min) groups (p = .1). No correlation was found between vaginal pH and cervical dilation using continuous data (p = .57; r= 0.08; 95% confidence interval -0.02, 0.3) or dichotomous data (pH <=5/>5; cervical dilation >=8 mm or <8 mm; p = .8). CONCLUSION: No difference was observed in cervical dilation between moistened and non-moistened misoprostol use prior to MVA. PMID- 29250975 TI - An update on emerging drugs for fibromyalgia treatment. AB - INTRODUCTION: Fibromyalgia (FM) is a chronic disorder whose symptoms of pain, fatigue, sleep disturbances and depression have a devastating effect on patients' lives as it limits their ability to engage in everyday working and social activities, and make it difficult to maintain normal relationships with family, friends and employers. None of the currently available drugs are fully effective against the whole spectrum of symptoms. The aim of this narrative review is to summarise the data relating to the new therapeutic options that have become available over the last few years. Areas covered: Increasing efforts by the pharmaceutical industry have led to the introduction of new investigational drugs and new formulations of older drugs, and studies have been carried out in order to investigate the possibility of using drugs that are currently used for other diseases. Expert opinion: Slight improvements in the health of FM patients treated with drugs targeting a range of molecular mechanisms have been observed, but there is still no single drug that is capable of offering substantial efficacy against all of the characteristic symptoms of FM. The identification of new and improved therapies for FM requires consideration of the heterogeneity of the condition, which suggests the existence of different patient subgroups, a relationship between central and peripheral aspects of the pathophysiology, and the need for combined treatment with drugs targeting multiple molecular mechanisms. PMID- 29250976 TI - Attenuation of brain mitochondria oxidative damage by Albizia julibrissin Durazz: neuroprotective and antiemetic effects. AB - Medicinal plants, as new drugs, are considered for treatment of insomnia, anxiety, depression, confusion, nausea, and vomiting symptoms. The current study aimed to evaluate the neuroprotective and antiemetic effects of Albizia. julibrissin Durazz. flower extract in the chickens. Emesis was induced by copper sulfate and ipecac (60 and 600 mg/kg, orally, respectively) and the methanolic extract (50, 100, and 200 mg/kg) were injected intraperitoneally (i.p.). Mitochondrial function, lipid peroxidation (LPO), protein carbonyl (PC) content, and catalase activity as biomarkers of oxidative damage were evaluated in the brain mitochondria. All doses of extract showed significant (p < 0.001) antiemetic activity against induced emesis by copper sulfate and ipecac. Brain mitochondria function (by 50, 100, and 200 mg/kg of extract) were increased 48%, 85%, and 90% against emesis induced by ipecac and 32%, 18%, and 24% against emesis induced by copper sulfate, respectively. LPO and PC contents were significantly decreased after the administration of extract in emesis induced by copper sulfate and ipecac. A significant decrease (p < 0.01) of CAT activity was observed in the extract (200 mg/kg) group in emesis induced by copper sulfate in chickens brain mitochondria. The present study suggests that the extract had antiemetic effects against emesis induced by copper sulfate and ipecac in young chickens via peripheral and central mechanisms. Neuroprotective effect of the extract could be due to the increase in bioactive compounds, plasma antioxidants, or direct free radical scavenging that could prevent lipid and protein alteration and impede the formation of oxidative damage. PMID- 29250978 TI - Review: ecotoxicity of organic and organo-metallic antifouling co-biocides and implications for environmental hazard and risk assessments in aquatic ecosystems. AB - Hazard assessments of Irgarol 1051, diuron, 2-(thiocyanomethylthio)benzothiazole (TCMTB), dichloro-octylisothiazolin (DCOIT), chlorothalonil, dichlofluanid, thiram, zinc pyrithione, copper pyrithione, triphenylborane pyridine (TPBP), capsaicin, nonivamide, tralopyril and medetomidine were performed to establish robust environmental quality standards (EQS), based on predicted no effect concentrations (PNECs). Microalgae, zooplankton, fish and amphibians were the most sensitive ecological groups to all the antifoulants evaluated, especially in the early life stages. No differences were identified between freshwater and seawater species. The use of toxicity tests with non-standard species is encouraged because they increase the datasets, allowing EQS to be derived from probabilistic-based PNECs whilst reducing uncertainties. The global ban of tributyltin (TBT) has been heralded as a major environmental success; however, substitute antifoulants may also pose risks to aquatic ecosystems. Environmental risk assessments (ERAs) have driven decision-makings for regulating antifouling products, but in many countries there is still a lack of regulation of antifouling biocides which should be addressed. PMID- 29250979 TI - Pharmacokinetic drug evaluation of ulipristal acetate for the treatment of uterine fibroids. AB - INTRODUCTION: Uterine fibroids are the most common form of benign gynecological tumors in women of reproductive ages. Although surgery is the main option to treat them, alternative pharmacological approaches are being investigated to control their symptoms. Among them, ulipristal acetate (UPA) has been the first selective progesterone-receptor modulator (SPRM) approved for the pre-operative and long-term treatment of uterine fibroids. Areas covered: The aim of this article is to review the literature on the pharmacodynamics, pharmacokinetics (PK), clinical efficacy and safety of UPA for the treatment of uterine fibroids. Expert opinion: UPA has both agonistic and antagonistic activity on progesterone receptor. Results from PK studies have shown that it has good oral bioavailability, and that it is extensively metabolized in the liver by cytochrome (CYP) 3A4. The PEARL I-II showed that the preoperative treatment with UPA decreases uterine bleeding, uterine volume and fibroid size in women with symptomatic uterine leiomyomas. The PEARL III and IV trials demonstrated the efficacy and safety of long-term intermittent treatment with UPA for the control of fibroid-related symptoms. PMID- 29250977 TI - Microencapsulated macrophages releases conditioned medium able to prevent epithelial to mesenchymal transition. AB - Epithelial to mesenchymal transition (EMT) has emerged as a key process in the development of renal fibrosis. In fact, EMT-derived fibroblasts contribute to the progression of chronic renal disease. In addition, anti-inflammatory M2 macrophages have exhibited a great influence on renal fibrosis. However, because of the high impact that the inputs of different environmental cytokines have on their phenotype, macrophages can easily lose this property. We aim to known if microencapsulated macrophages on M2-inducing alginate matrices could preserve macrophage phenotype and thus release factors able to act on epithelial cells to prevent the epithelial differentiation towards mesenchymal cells. We reproduced an in vitro model of EMT by treating adipose-derived stem cells with all-trans retinoic acid (ATRA) and induced their transformation toward epithelia. Dedifferentiation of epithelial cells into a mesenchymal phenotype occurred when ATRA was retired, thus simulating EMT. Results indicate that induction of M2 phenotype by IL-10 addition in the alginate matrix produces anti-inflammatory cytokines and increases the metabolic activity and the viability of the encapsulated macrophages. The released conditioned medium modulates EMT and maintains healthy epithelial phenotype. This could be used for in vivo cell transplantation, or alternatively as an external releaser able to prevent epithelial to mesenchymal transformation for future anti-fibrotic therapies. PMID- 29250980 TI - Piperine-mediated drug interactions and formulation strategy for piperine: recent advances and future perspectives. AB - INTRODUCTION: Piperine has various pharmacological effects and can modulate the functional activity of metabolic enzymes and drug transporters. Consequently, there is a great interest in the application of piperine as an alternative medicine or bioavailability enhancer. Areas covered: This review deals with the effects of piperine on metabolizing enzymes and drug transporters. It provides the readers with an update on transporter-mediated and also metabolic enzyme mediated piperine-drug interactions, with emphasis on its in vivo implications. This article also encompasses recent advances in the formulation approaches and technologies for optimizing the delivery of piperine. Expert opinion: Piperine can influence the pharmacokinetics of coadministered drugs, which may result in a therapeutically beneficial or adverse effect. Given that piperine inhibits or stimulates the activity of metabolic enzymes and transporters depending on the treatment conditions, the clinical significance of piperine-drug interactions should be assessed by varying the dose, dosing frequency, and the duration of treatment. In particular, better understanding the clinical relevance of piperine drug interactions based on long-term assessments will provide a strong basis for the feasibility and applicability of piperine as a bioenhancer or a health promoting agent. The development of effective formulations is also critical to facilitate the therapeutic applications of piperine. PMID- 29250981 TI - Update on treatment for idiopathic hypersomnia. AB - INTRODUCTION: Idiopathic hypersomnia (IH) is a poorly characterized orphan central disorder of hypersomnolence responsible for excessive daytime sleepiness (EDS), prolonged nighttime sleep and sleep inertia that often require long-term symptomatic stimulant medication. To date, no drug has currently the authorization for the treatment of IH patients worldwide. Areas covered: The authors reviewed data on pharmacological treatment of IH obtained from published literature (Medline/PubMed/Web of Science) and Clinicaltrial.gov database from 1997 to 2017. Most of data on treatment of IH derived from observational studies and case series with only three well-designed clinical trials available. Expert opinion: In two recent randomized, double-blind, placebo-controlled trials, modafinil improves EDS in IH. Most of other wakefulness-promoting agents labeled for narcolepsy have similar efficacy in cases series of IH patients. Pitolisant and sodium oxybate show promising results in two retrospective studies. The efficacy of gamma-aminobutyric acid-A receptor antagonists on objective EDS needs to be clarified. All these medications are used off-label for the management of EDS in IH. Specific clinical instruments and objective tests are required in IH to better evaluate the severity of EDS and responsiveness to medications, but also prolonged sleep and sleep inertia, to optimize the whole management of IH patients. PMID- 29250982 TI - Antimicrobial activity of denture adhesive associated with Equisetum giganteum- and Punica granatum-enriched fractions against Candida albicans biofilms on acrylic resin surfaces. AB - Candida biofilms adhere to the internal surface of removable dentures, which is an etiological factor in the pathogenesis of denture stomatitis (DS). Adhesive materials are used at the base of maxillary complete dentures to improve their retention and chewing qualities. This article reports the antimicrobial activity of the enriched fractions of Equisetum giganteum and Punica granatum incorporated into a denture adhesive against C. albicans biofilm. The biofilms were induced on the surface of heat-cured acrylic resin specimens that were previously treated with a mixture of adhesive/herb extracts. The antimicrobial activity was evaluated by CFU counts, XTT reduction, and SEM and CLSM analysis. Both herb extracts amplified the anti-biofilm action of the adhesive on the acrylic resin by up to 12 h. Therefore, when these extracts were combined with COREGA(r), they played a collaborative and innovative role in biofilm control and can be considered alternatives for temporary use in the treatment and/or prevention of DS. PMID- 29250985 TI - Green synthesis of silver nanoparticles using Thymbra spicata L. var. spicata (zahter) aqueous leaf extract and evaluation of their morphology-dependent antibacterial and cytotoxic activity. AB - Silver (Ag) nanoparticles (NPs) were green synthesized at room temperature using different concentrations of the Thymbra spicata L. var. spicata (Zahter) aqueous leaf extracts for the first time. With the synthesis of AgNPs using the leaf extract of Cynara scolymus (Artichoke) and Mentha piperita (Peppermint), the biological activities of the nanoparticles synthesized using leaf extract of three economically significant plants have been studied comparatively. Nanoparticles were characterized by different spectroscopic and microscopic analysis. TEM analysis of the biosynthesized AgNPs revealed that the size and shape of the AgNPs were changed with the plant extract concentration. Biologically synthesized AgNPs from leaf extracts of the three different plants displayed significant differences in antibacterial activity against two different gram-negative and gram-positive bacteria. Also, the results from this study show the shape dependence of the antibacterial and cytotoxic activity of silver nanoparticles synthesized using T. spicata leaf extract. The nanoparticles with different shapes exhibited the strongest antibacterial and cytotoxic activity compared to mostly spherical nanoparticles. Present results clearly indicate that biological activities of silver nanoparticles were affected by nanoparticle shape and the source of the plant extract used in the synthesis. PMID- 29250984 TI - Intensive fibrosarcoma-binding capability of the reconstituted analog and its antitumor activity. AB - Fibrosarcomas are highly aggressive malignant tumors. It is urgently needed to explore targeted drugs and modalities for more effective therapy. Matrix metalloproteinases (MMPs) play important roles in tumor progression and metastasis, while several MMPs are highly expressed in fibrosarcomas. In addition, tissue inhibitor of metalloproteinase 2 (TIMP2) displays specific interaction with MMPs. Therefore, TIMP2 may play an active role in the development of fibrosarcoma-targeting agents. In the current study, a TIMP2-based recombinant protein LT and its enediyne-integrated analog LTE were prepared; furthermore, the fibrosarcoma-binding intensity and antitumor activity were investigated. As shown, intense and selective binding capability of the protein LT to human fibrosarcoma specimens was confirmed by tissue microarray. Moreover, LTE, the enediyne-integrated analog of LT, exerted highly potent cytotoxicity to fibrosarcoma HT1080 cells, induced apoptosis, and caused G2/M arrest. LTE at 0.1 nM markedly suppressed the migration and invasion of HT1080 cells. LTE at tolerated dose of 0.6 mg/kg inhibited the tumor growth of fibrosarcoma xenograft in athymic mice. The study provides evidence that the TIMP2-based reconstituted analog LTE may be useful as a targeted drug for fibrosarcome therapy. PMID- 29250983 TI - The impact of non-genetic heterogeneity on cancer cell death. AB - The goal of cancer chemotherapy is to induce homogeneous cell death within the population of targeted cancer cells. However, no two cells are exactly alike at the molecular level, and sensitivity to drug-induced cell death, therefore, varies within a population. Genetic alterations can contribute to this variability and lead to selection for drug resistant clones. However, there is a growing appreciation for the role of non-genetic variation in producing drug tolerant cellular states that exhibit reduced sensitivity to cell death for extended periods of time, from hours to weeks. These cellular states may result from individual variation in epigenetics, gene expression, metabolism, and other processes that impact drug mechanism of action or the execution of cell death. Such population-level non-genetic heterogeneity may contribute to treatment failure and provide a cellular "substrate" for the emergence of genetic alterations that confer frank drug resistance. PMID- 29250986 TI - Experience with telemedicine in a multi-disciplinary ALS clinic. AB - OBJECTIVE: Telemedicine using video televisits is emerging as a means to provide care directly to patients. Here we report our experience using video televisits to provide follow-up care as a part of the Massachusetts General Hospital (MGH) Telemedicine for People with ALS (TelePALS) initiative. METHODS: This was a retrospective chart review of all video televisit encounters conducted by the MGH ALS clinic between September 2014 and January 2016. RESULTS: A total of 97 distinct ALS patients were seen using video televisits. Twenty-four percent of these patients had more than one video televisit. The median distance of the patients' primary residence to MGH was 211 miles. The average video televisit lasted 32 min (+/-12). About half the patients (54%) were ambulatory at the time of their video televisit. The most commonly addressed issues were medication management (89%), discussion of goals of care (74%), research (55%) and equipment use (50%). Acute care issues were rarely discussed. CONCLUSION: Video televisits are feasible and can be a useful tool to supplement traditional clinic-based multidisciplinary ALS care. PMID- 29250987 TI - The Bobath concept - a model to illustrate clinical practice. AB - BACKGROUND AND PURPOSE: The model of Bobath clinical practice provides a framework identifying the unique aspects of the Bobath concept in terms of contemporary neurological rehabilitation. The utilisation of a framework to illustrate the clinical application of the Bobath concept provides the basis for a common understanding with respect to Bobath clinical practice, education, and research. The development process culminating in the model of Bobath clinical practice is described. CASE DESCRIPTION: The use of the model in clinical practice is illustrated using two cases: a client with a chronic incomplete spinal cord injury and a client with a stroke. DISCUSSION: This article describes the clinical application of the Bobath concept in terms of the integration of posture and movement with respect to the quality of task performance, applying the Model of Bobath Clinical Practice. Facilitation, a key aspect of Bobath clinical practice, was utilised to positively affect motor control and perception in two clients with impairment-related movement problems due to neurological pathology and associated activity limitations and participation restrictions - the outcome measures used to reflect the individual clinical presentation. Implications for Rehabilitation The model of Bobath clinical practice provides a framework identifying the unique aspects of the Bobath-concept. The model of Bobath clinical practice provides the basis for a common understanding with respect to Bobath clinical practice, education, and research. The clinical application of the Bobath-concept highlights the integration of posture and movement with respect to the quality of task performance. Facilitation, a key aspect of Bobath clinical practice, positively affects motor control, and perception. PMID- 29250989 TI - TwiC or treat? Are trials within cohorts ethically defensible? PMID- 29250988 TI - Innovative approaches to informed consent for randomized clinical trials: Identifying the ethical challenges. PMID- 29250990 TI - Ecological momentary assessment and first smoking cessation lapse after an acute cardiac event: A pilot study. AB - This 28-day pilot study assessed the feasibility of cell phone ecological momentary assessment in 40 smokers who received emergency department evaluations for acute coronary syndrome. Ecological momentary assessments used familiar touch tone response technology during a cell phone call to capture ratings of illness perceptions, emotion, behavioral intentions, and smoking. Ecological momentary assessments were conducted 1-8 times/day and took 1-2 minutes to complete. The mean ecological momentary assessment call compliance for all 40 subjects was 56.3 percent (standard deviation = 29.4), and during an ecological momentary assessment, 72.5 percent of participants reported a first lapse. We found that first-week call compliance was significantly correlated with subsequent compliance ( r = 0.55, p < 0.001). PMID- 29250991 TI - Subjecting the ankle-brachial index to timely scrutiny: is it time to say goodbye to the ABI? AB - Although the ankle-brachial index (ABI) has been used as an indicator of peripheral artery disease and vascular supply to the foot for over 50 years, it is now associated with reservations and qualifying empirical evidence to the extent that the provocative step of abandoning it totally might be advisable. In this article, the results of three publications concerning the ABI are initially described in some depth and the results from eight additional publications are then summarized more briefly. Cumulatively, the research indicates that ABIs that seem to be normal, as well as those in the subnormal range, are often inflated by medial arterial calcification and can therefore produce a high proportion of false-negative screening test results for arterial disease as well as a misleadingly high impression of vascular sufficiency to the lower extremity. The toe-brachial index is suggested as being likely to overcome the problems associated with the ABI, and other alternatives to the ABI and TBI are acknowledged. PMID- 29250992 TI - Validation of the Revised Impact of Miscarriage Scale for Swedish conditions and comparison between Swedish and American couples' experiences after miscarriage. AB - INTRODUCTION: There is a lack of knowledge in women's and men's experience of miscarriage. The Revised Impact of Miscarriage Scale (RIMS) has been used in United States to measure the experiences after miscarriage. The first objective was to test the consistency of RIMS for Swedish conditions. The second purpose of this study was to compare Swedish and American couples' experience of miscarriage by use of the RIMS. METHODS: Forward and back translation was used for translating RIMS into Swedish. This is a hospital-based comparative study including Swedish couples (n = 70) and American couples (n = 70). The couples were matched by the women's age, week of miscarriage and number of children. All participants answered socio-demographic, fertility and depression-scale questions in addition to RIMS. RESULTS: Cronbach's alpha analysis was above 0.650, the mean value was 0.824. There was no significant difference between the Swedish and American participants on the factors 'Isolation/Guilt' and 'Devastating event', but the Swedish women and men scored significantly lower on the factor 'Loss of baby' than the American women and men. The men, Swedish and American combined, scored lower than the women in all factors but the correlation within the couples was similar for both Swedish and American couples. CONCLUSIONS: The high consistency between the countries suggests that the RIMS questionnaire is reliable for both women and men to be used in both countries and two of three factors were similar between the two countries. PMID- 29250993 TI - Pharmaceutical care services to people living with dementia in care homes: A qualitative study of community pharmacists' perceptions. AB - There is a paucity of information on the perceptions of community pharmacists about the nature and effectiveness of pharmaceutical care services they provide to people living with dementia in care homes. This paper explores pharmacists' perceptions of the nature and effectiveness of pharmacy services provided, and their experiences when providing these services. Community pharmacists delivering services to care homes with dementia in Thurrock, Essex and in Medway, Kent, England were invited to participate in the study involving face-to-face interviews. Analysis of semi-structured interviews with 15 community pharmacists revealed that the main pharmaceutical service provided by the pharmacists was prescription processing, normally involving the clinical review and supply of medication into monitored dosage systems (dosette boxes) and delivery to the homes. This was coupled with advice to care homes on the appropriate storage and administration of drugs and appliances supplied, which was in line with the NHS Community Pharmacy Contractual Framework Enhanced Service for care homes. A majority of the community pharmacists interviewed acknowledged that the services they were currently commissioned to provide did not meet the pharmaceutical care needs of dementia patients in care homes, including the monitoring of the appropriateness, safety and effectiveness of drug therapy. PMID- 29250994 TI - Posttraumatic growth and parental bonding in young adults of parents with physical disabilites: testing mediation model of resilience. AB - Positive parent-child relationships are associated with positive youth development, but little is known about the relationships between parental bonding, resilience, and posttraumatic growth, which is positive change resulting from the struggle with trauma. This study examined a mediation model among 119 female young adults with disabled parents. The model included resilience as a mediator of the relationship between the paternal Care and posttraumatic growth. The results revealed that resilience did mediate the relationship between the paternal Care and posttraumatic growth. The findings indicate that paternal Care helps to foster female young adults' resilience, which benefits their growth after suffering adversities. PMID- 29250995 TI - Lower back pain in nurses working in home care: linked to work-family conflict, emotional dissonance, and appreciation? AB - In industrial countries home care services for elderly people living in the community are growing rapidly. Home care nursing is intensive and the nurses often suffer from musculoskeletal pain. Time pressure and job control are job related factors linked to the risk of experiencing lower back pain (LBP) and LBP related work impairment. This survey investigated whether work-family conflict (WFC), emotional dissonance and being appreciated at work have incremental predictive value. Responses were obtained from 125 home care nurses (63% response rate). Multiple linear regression showed that emotional dissonance and being appreciated at work predicted LBP intensity and LBP-related disability independently of time pressure and job control. WFC was not a predictor of LBP related disability in multiple regression analyses despite a zero-order correlation with it. Redesigning the working pattern of home care nurses to reduce the emotional demands and improve appreciation of their work might reduce the incidence of LBP in this group. PMID- 29250996 TI - Female condom acceptability in urban India: Examining the role of sexual pleasure. AB - This qualitative study examined the acceptability of female condoms in urban India, with a focus on sexual pleasure. We conducted focus group discussions with 50 women and 19 men, as well as a small number of individual interviews with women ( n = 3), in Chennai and New Delhi. Perceived benefits of female condoms included protection against unintended pregnancy and sexually transmitted infections, increased sense of empowerment for women, and simple clean up. The most common drawback was reduced sensation. Participants suggested structural changes to the female condom to ease insertion and use. Consent and privacy were discussed as increasing sexual pleasure. Pleasure should be acknowledged in design and education efforts to increase female condom use. PMID- 29250997 TI - Resting high-frequency heart rate variability moderates the association between early-life adversity and body adiposity. AB - This study investigates resting high-frequency heart rate variability as a moderator of the association between early-life adversity and two measures of body adiposity. Data were collected from 149 young adults attending a large university in the Midwestern United States ( Mage = 18.8 years; 45% black; 55% white; 56% female). Self-reported early-life adversity was associated with greater waist-to-height ratio and body mass index. The strength of these associations was moderated by high-frequency heart rate variability, such that the link was stronger for individuals with lower heart rate variability. Resting high-frequency heart rate variability thus has potential health significance as a biomarker of stress vulnerability. PMID- 29250998 TI - Experiences of social support among persons seeking HIV testing. AB - We interviewed 15 HIV test seekers to understand how social support acted either as a facilitator or barrier to HIV testing. Participants were recruited at community outreach testing sites in South Africa and participated in qualitative interviews which were then analysed using thematic analysis. We identified three main themes, namely, the social phenomenon of perceived risk as a facilitator to HIV testing, social support as a way of managing distress and the public health service as a supportive environment, which all played a role in test-seeking among participants. The results are integrated with the current debates on HIV testing in South Africa. PMID- 29250999 TI - Pesticides exposure through environment and risk of pre-term birth: a study from Agra city. AB - Pre-term birth is an increasingly prevalent complex condition with multiple risk factors including environmental pollutants. Evidences linking organochlorine pesticides with adverse pregnancy outcomes are inconsistent for link between organochlorine pesticides and adverse pregnancy outcomes. We performed a case control study of 50 cases of full-term births and 40 cases of pre-term births in this study. Placental organochlorine pesticides like metabolites of dichlorodiphenyltrichloroethane that is, (p,p-DDE, p,p-DDT and o,p-DDD) and isomers of hexachlorocyclohexane (alpha, beta, gamma and delta HCH) were analyzed by gas chromatography. Although the mean levels of pesticide were found higher in the placenta of the women with pre-term delivery cases placentas, but only alpha HCH, total-HCH, p,p-DDE and total-DDT were found statistically significant. It was observed that pesticide exposed women were approximately 1.7 times more likely to deliver pre-term baby as compare to pregnant women that were not exposed to any pesticides. We also observed that increasing maternal age reduced the risk of having pre-term birth (OR = 0.99). Among all pesticides, alpha-HCH was found to be strongest isomer to induce premature baby birth (p < 0.001). This study found that pregnant women's age and chronic disease, baby's weight at the time of birth and alpha-HCH were important risk factors for pre-term births. PMID- 29251001 TI - Ongoing initiatives in Azerbaijan to improve the use of antibiotics; findings and implications. AB - BACKGROUND: There have been a numerous initiatives in Azerbiajan in recent years to improve antibiotic utilization including educational programmes among patients, pharmacists and physicians. Consequently, this study aimed to analyse the influence of these multiple initiatives on antibiotic utilization as a basis for suggesting future initiatives. METHODS: Observational retrospective study of total antibiotic utilization from 2011 to 2015 based on import data. The quality of aggregated antibiotic prescribing was assessed against recognised indicators including those of WHO Europe, as well as compared to neighbouring countries as reference points. RESULTS: There was a significant reduction in total antibiotic utilization from 17.1 DIDs in 2011 in Azerbaijan to 8.02 DIDs in 2015, the lowest level compared with similar countries. Beta lactam antibiotics were typically the largest group of antibiotics with low overall use of co-amoxiclav (although relative utilisation rising), macrolides, cephalosporins and fluoroquinolones. There are concerns with rising use of tetracyclines in recent years in place of penicillins with changing pricing policies, as well as high relative use of third generation cephalosporins. CONCLUSIONS: Multiple interventions in Azerbaijan in recent years appear to have resulted in low use of antibiotics when compared with similar countries. However, there are some concerns especially with third generation cephalosporins. There needs to be a closer look at indications to further improve antibiotic use. PMID- 29251002 TI - Mannosylated T/Tn with Freund's adjuvant induces cellular immunity. AB - Inducing cancer-specific cellular immune responses has become an attractive strategy in cancer treatment. In this study, we investigated the role of several adjuvants in eliciting T/Tn-specific cellular immunity and protection against T/Tn expressing tumor challenge. T/Tn (9:1) antigen was purified from blood type "O" erythrocytes donated from healthy Korean volunteers. Immunization was performed using: T/Tn only, T/Tn mixed with Freund's adjuvant (T/Tn + FA), keyhole limpet hemocyanin (KLH)-conjugated T/Tn mixed with FA (KLH-T/Tn + FA), and oxidized mannan-conjugated T/Tn mixed with FA (ox-M-T/Tn + FA). Mice immunized with ox-M-T/Tn + FA generated T/Tn-specific CD3, helper T (Th) cells, major histocompatibility complex (MHC) II, and MHC I; T/Tn presentation was significantly high and tolerogenic CD11b+ was the lowest among the tumor models. To verify Th type, we stained intracellular cytokines (interferon gamma (IFN gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-4, and IL-10) using CD3 co-staining. Th1 (IFN-gamma and GM-CSF) cytokines were highly expressed and showed high FasL/Fas ratios, cytotoxic T lymphocyte (CTL) activity, and cytotoxic T lymphocyte precursor (CTLp) activity in mice immunized with ox-M-T/Tn + FA. Lymphocyte infiltration was highest in mice immunized with ox-M-T/Tn + FA. Additionally, we monitored FasL, MHC I, CD301, and T/Tn expression levels using immunohistochemistry (IHC) on macrophage and tumor sites. The expression of all markers was highest in the ox-M-T/Tn + FA group. Furthermore, tumor retardation and survival rate were highest in the ox-M-T/Tn + FA group. These results demonstrate that a vaccine formulation of T/Tn conjugated with ox-M and mixed with FA-induced cellular immunity and sustained a humoral immune response without over-activating the immune system, thus effectively inhibiting tumor growth. PMID- 29251003 TI - The physiology and toxicology of acute inhalation phosphine poisoning in conscious male rats. AB - Phosphine (PH3) is a toxidrome-spanning chemical that is widely used as an insecticide and rodenticide. Exposure to PH3 causes a host of target organ and systemic effects, including oxidative stress, cardiopulmonary toxicity, seizure like activity and overall metabolic disturbance. A custom dynamic inhalation gas exposure system was designed for the whole-body exposure of conscious male Sprague-Dawley rats (250-350 g) to PH3. An integrated plethysmography system was used to collect respiratory parameters in real-time before, during and after PH3 exposure. At several time points post-exposure, rats were euthanized, and various organs were removed and analyzed to assess organ and systemic effects. The 24 h post-exposure LCt50, determined by probit analysis, was 23,270 ppm * min (32,345 mg * min/m3). PH3 exposure affects both pulmonary and cardiac function. Unlike typical pulmonary toxicants, PH3 induced net increases in respiration during exposure. Gross observations of the heart and lungs of exposed rats suggested pulmonary and cardiac tissue damage, but histopathological examination showed little to no observable pathologic changes in those organs. Gene expression studies indicated alterations in inflammatory processes, metabolic function and cell signaling, with particular focus in cardiac tissue. Transmission electron microscopy examination of cardiac tissue revealed ultrastructural damage to both tissue and mitochondria. Altogether, these data reveal that in untreated, un anesthetized rats, PH3 inhalation induces acute cardiorespiratory toxicity and injury, leading to death and that it is characterized by a steep dose-response curve. Continued use of our interdisciplinary approach will permit more effective identification of therapeutic windows and development of rational medical countermeasures and countermeasure strategies. PMID- 29251000 TI - Presepsin: A potential biomarker of PJI? A comparative analysis with known and new infection biomarkers. AB - There is still no "gold standard" for the diagnosis and prognosis of post operative periprosthetic joint infection (PJI). Among serum biomarkers, an emerging molecule is presepsin, the soluble fraction of CD14, recently described in other settings as a powerful diagnostic tool to detect sepsis at different degrees of severity. The aim of this study was to investigate the diagnostic and prognostic value of presepsin in PJI. A total of 30 patients with PJI and 30 patients without PJI were enrolled. Presepsin, C-reactive protein (CRP), serum interleukin (IL)-6, triggering receptor expressed on myeloid cells 1 (TREM-1), CCL2, matrix metalloproteinase 9 (MMP-9), CD163, osteopontin (OPN), and toll-like receptor 2 (TLR2) were measured at different times after surgery. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were analyzed for each biomarker. Presepsin showed greater diagnostic value than CRP and IL-6; CD163, TREM-1, and MMP-9 had very low diagnostic potential. Presepsin, OPN, CCL2, suPAR, and TLR2 all decreased significantly with increasing time of recovery after surgery in PJI patients. Presepsin can be considered a useful tool for the diagnosis and clinical monitoring of PJI and can be backed by a panel of new inflammatory markers involved in monocyte-/macrophage-mediated inflammatory responses, such as OPN, CCL2, TLR2, and suPAR. PMID- 29251004 TI - A Novel alpha-Thalassemia Nonsense Mutation on the alpha2-Globin Gene: HBA2: c.184A>T. AB - We report a novel mutation on the alpha2-globin gene, HBA2: c.184A>T, detected in a Chinese proband. This mutation resulted in a Lys->Term substitution at position 62 of the alpha2-globin gene, causing a premature termination of translation. This mutation did not cause severe hematological abnormalities in the carriers. From the properties of substituted residues on the alpha2-globin gene, it is generally expected that this mutation causes unstable and truncated protein, thus this mutation should be detected in couples at-risk for alpha-thalassemia (alpha thal). PMID- 29251005 TI - Coinheritance of alpha- and beta-Thalassemia with a Novel Mutation (HBB: c.268_281delAGTGAGCTGCACTG) in a Chinese Family. AB - We report a novel mutation (HBB: c.268_281delAGTGAGCTGCACTG) in a Chinese proband, who was also an alpha-thalassemia (alpha-thal) Southeast Asian (alphaalpha/- -SEA) deletion carrier and displayed characteristic hematological features of beta-thalassemia (beta-thal) traits. The proband and carriers in her family presented hematological abnormalities. This novel mutation results in a frameshift and consequently creates a premature stop codon at codon 90 of the HBB gene. Thus, couples at-risk for beta-thal should also be tested for this mutation. Double heterozygotes for alpha- and beta-thal are easily misdiagnosed as pure beta-thal carriers, which should be noted in the process of risk assessment and counseling. PMID- 29251006 TI - Prevalence of Thalassemia and Glucose-6-Phosphate Dehydrogenase Deficiency in Newborns and Adults at the Ramathibodi Hospital, Bangkok, Thailand. AB - Thalassemias and glucose-6-phosphate dehydrogenase (G6PD) deficiency are the most common inherited blood disorders. They are distributed among populations living in malaria endemic regions resulting in survival advantage from severe malaria disease. The aims of this study were to analyze the prevalence of thalassemias and G6PD deficiency at the Ramathibodi Hospital, Bangkok, Thailand. A total of 616 adult and 174 cord blood samples were collected and analyzed for red blood cell (RBC) parameters, hemoglobin (Hb) typing and DNA analysis for G6PD mutations and alpha-thalassemia (alpha-thal). The two most prominent types of thalassemia were heterozygous Hb E (HBB: c.79G>A), (19.5% in newborns and 35.6% in adults) followed by heterozygous alpha-thal-2 [-alpha3.7 (rightward) deletion] at 18.7% in newborns and 19.5% in adults. After performing G6PD genotyping using multiplex amplification refractory mutation system-polymerase chain reaction (multiplex ARMS-PCR) for 10 G6PD mutations, the prevalence of G6PD mutation was found in 12.0% of newborns and 11.7% of adults. The G6PD Viangchan [871 (G>A)] is the most common G6PD mutation in newborns (42.9%) and adults (52.8%). In addition, coinheritance of various types of thalassemia with G6PD deficiency were found. The results indicated that heterozygous Hb E and G6PD Viangchan are predominant both in newborns and adults in this study. PMID- 29251007 TI - Point-of-care diagnostics for respiratory viral infections. AB - INTRODUCTION: Successful treatment outcomes for viral respiratory tract infections presenting from primary health care to quaternary hospitals will only be achieved with rapid, sensitive and specific identification of pathogens to allow effective pathogen-specific antiviral therapy and infection control measures. Areas covered: This review aims to explore the different point-of-care tests currently available to diagnose viral respiratory tract infections, discuss the advantages and limitations of point-of-care testing, and provide insights into the future of point-of-care tests. The following databases were searched: Medline (January 1996 to 30 September 2017) and Embase (1988 to 30 September 2017), using the following keywords: 'point of care', 'respiratory virus', 'influenza', 'RSV', 'diagnostics', 'nucleic acid test' and 'PCR'. Expert commentary: Viral respiratory tract infections cause significant morbidity and mortality worldwide, and point-of-care tests are facilitating the rapid identification of the pathogen responsible given the similarities in clinical presentation. PMID- 29251008 TI - First Report of the Rare IVS-II-705 (T>G) beta-Thalassemia Mutation in a Chinese Family. AB - We have found an example of the mutation at the intronic region of the second intervening sequence of the beta-globin gene, IVS-II-705 (T>G) (HBB: c.316 146T>G), in a Chinese family. The two subjects heterozygous for this mutation presented with typical beta-thalassemia (beta-thal) trait. PMID- 29251009 TI - Ultrasound measurement of fetal adrenal gland in fetuses with intrauterine growth restriction, an early predictive method for adverse outcomes. AB - OBJECTIVES: Comparing the sonographic measurements of fetal adrenal gland in pregnancies with intrauterine growth restriction (IUGR) versus healthy controls and to assess whether the changes in adrenal gland measurements could predict adverse pregnancy outcomes in IUGR fetuses. METHODS: This prospective cohort study evaluated 97 pregnant women (48 with IUGR pregnancies and 49 healthy controls) during their third gestational trimester. All mothers underwent two dimensional ultrasonography of the fetal adrenal gland, and the fetal zone in transverse, sagittal, and coronal planes. Adrenal gland volume (AGV) and fetal zone volume (FZV) were calculated and corrected (c) for fetal weight. The mothers were then followed until delivery. RESULTS: Fetuses in the IUGR group had larger corrected adrenal gland volume (c_AGV) and smaller corrected fetal zone volume (c_FZV) compared to the fetuses in the control groups (p < .001). In the IUGR group, significantly smaller c_AGV and higher fetal/adrenal were detected in IUGR fetuses who had nonreassuring fetal status before delivery, preterm birth, very low birth weight delivery, and also those who required neonatal intensive care unit admission (p < .01 for all). CONCLUSIONS: Third trimester fetal adrenal gland sonography could potentially be used as an easy noninvasive method for identifying those IUGR fetuses who might have poorer outcomes. PMID- 29251010 TI - Effect of a sequential treatment combining abaloparatide and alendronate for the management of postmenopausal osteoporosis. AB - The recently published results of the sequential treatment of postmenopausal osteoporotic women with subcutaneous abaloparatide (80 ug/day) (ABL) for 18 months followed by 6 months of oral alendronate (70 mg/week) (ALN) support the administration of an anti-resorptive agent after completion of a treatment course with an osteoanabolic agent. The ABL/ALN sequence resulted in greater bone mineral density gains at all skeletal sites and in a reduction of vertebral, non vertebral, major and clinical fractures compared to what is observed after 18 months of placebo followed by 6 months of ALN. Whereas questions remained unanswered about the ideal anti-resorptive agent to be used after ABL, the optimal duration of the administration of the anti-resorptive drug or the potential interest of re-initiating a course of ABL after a limited administration of ALN, these results support the use of the ABL/ALN sequence in the management of postmenopausal osteoporosis. PMID- 29251012 TI - Enhancing Effect of Hydroxyurea on Hb F in Sickle Cell Disease: Ten-Year Egyptian Experience. AB - Patients with sickle cell disease experience hemolytic anemia and vaso-occlusions that result in pain, organ injury, and premature mortality. Several prospective studies have verified the efficacy and tolerability of hydroxyurea (HU), and demonstrated its efficacy in reducing painful vaso-occlusive crises (VOCs) in addition to its ability to increase Hb F levels. We aimed to evaluate the long term effects of HU therapy on Hb F and assess its long term efficacy and safety in sickle cell disease patients. A retrospective study on 60 sickle cell disease patients was conducted. We studied the laboratory changes, frequency of VOCs per year, frequency of hospital admisions per year and number of transfusions per year, both before and after HU therapy. The follow-up period was 4 to 120 months. Hb F levels after HU therapy positively correlated with the duration of HU therapy, baseline Hb F levels and baseline total hemoglobin (Hb) (r = 0.4, p = 0.04; r = 0.45, p = 0.001; r = 0.5, p = 0.019, respectively) and inversely correlated with baseline total leucocyte count (r = -0.33, p = 0.034). Hydroxyurea therapy was associated with an increase in the total Hb and mean corpuscular volume (MCV) (p = 0.009, p = 0.000; respectively) and with a decrease in total leucocyte count, platelet count and reticulocyte count (p = 0.00, p = 0.03, p = 0.02, respectively). Moreover, a significant reduction in the frequency of VOCs, transfusion frequency and hospital admissions per year after HU therapy was shown in the studied subjects. Hydroxyurea induced an increase in Hb F level, which was maintained over time and was associated with clinical efficacy and acceptable safety. PMID- 29251013 TI - Ultrastructure of neurovascular changes in human diabetic retinopathy. AB - The previous concept regarding diabetic retinopathy assigned a primary role to hyperglycemia-induced microvascular alterations, while neuronal and glial abnormalities were considered to be secondary to either ischemia or exudation. The aim of this study was to reveal the potential role of neuronal and glial cells in initial and advanced alterations of the retinopathy in human type 2 diabetes. Electron microscopy and histochemical studies were performed on 38 surgically removed human eyes (28 obtained from diabetic patients and 10 from non diabetic patients). Morphometric analysis of basement membrane material and lipids was performed. An accumulation of metabolic by-products was found in the capillary wall with aging: this aspect was significantly more pronounced in diabetics. Muller glial cells were found to contribute to alterations of the capillary wall and to occlusion, as well as to the development of proliferative retinopathy and cystoid degeneration of the retina. Our results showed morphological evidence regarding the role of neuronal and glial cells in the pathology of diabetic retinopathy, prior and in addition to microangiopathy. These morphological findings support a neurovascular pathogenesis at the origin of diabetic retinopathy, thus the current treatment approach should be completed by neuroprotective measures. PMID- 29251014 TI - Amaranth oil reduces accumulation of 4-hydroxynonenal-histidine adducts in gastric mucosa and improves heart rate variability in duodenal peptic ulcer patients undergoing Helicobacter pylori eradication. AB - Helicobacter pylori-induced oxidative stress in gastric mucosa (GM) is a milieu for the development of chronic gastritis, duodenal peptic ulcer (DPU), gastric cancer, and a number of extragastric diseases. Because our previous study revealed the accumulation of the protein adducts of lipid peroxidation product 4 hydroxynonenal (HNE) in GM, which persists after eradication of H. pylori, the aim of the study was to test whether Amaranth oil supplementation in addition to standard anti-Helicobacter treatment could prevent such accumulation of HNE in GM in H. pylori-positive DPU patients. Seventy-five patients were randomly split into two groups: group 1 - standard treatment (n = 39) and group 2 - standard treatment with additional supplementation of 1 ml of concentrated oil from amaranth seeds (Amaranthus cruenthus L., n = 36). Clinical analysis, including endoscopy with biopsies from antrum and corpus of the stomach were performed before and after the treatment, as was heart rate variability (HRV) recorded, as parameter of systemic, extragastric pathophysiological alterations in DPU patients. Improvement of clinical, endoscopic and histologic manifestations, and successful ulcer healing were observed in both the groups. Moreover, supplementation of amaranth oil in addition to standard anti-H. pylori treatment significantly reduced accumulation of HNE-histidine adducts in GM and increased HRV in DPU patients (p < .05). Therefore, standard treatments of DPU require additional therapeutic approaches, in accordance with integrative medicine principles, aiming to reduce persistence of oxidative stress, as was successfully done in our study by the use of amaranth oil. PMID- 29251015 TI - Prognostic impact of activation-induced cytidine deaminase expression for patients with diffuse large B-cell lymphoma. AB - Activation-induced cytidine deaminase (AID) plays important roles in the development of diffuse large B-cell lymphoma (DLBCL); however, its prognostic value remains controversial. Here, we evaluated AID expression in 71 DLBCL patients treated with R-CHOP by immunohistochemistry and investigated its prognostic significance. AID expression was detected in 40.8% of DLBCL samples and associated with IRF4 expression. Notably, AID expression correlated with shorter progression-free survival and overall survival for patients with high (3 5) international prognostic index (IPI) score. Moreover, it was a strong predictor of poor overall response to salvage therapy after relapse or disease progression, which may suggest its role in promoting the evolution of tumors into highly refractory disease at relapse. Our findings indicate that AID expression effectively discriminates between IPI-high score patients with different survival outcomes, and suggest that initial disease control would be particularly important for the treatment of IPI-high score patients with AID-positive DLBCL. PMID- 29251011 TI - Single-cycle adenovirus vectors in the current vaccine landscape. AB - INTRODUCTION: Traditional inactivated and protein vaccines generate strong antibodies, but struggle to generate T cell responses. Attenuated pathogen vaccines generate both, but risk causing the disease they aim to prevent. Newer gene-based vaccines drive both responses and avoid the risk of infection. While these replication-defective (RD) vaccines work well in small animals, they can be weak in humans because they do not replicate antigen genes like more potent replication-competent (RC) vaccines. RC vaccines generate substantially stronger immune responses, but also risk causing their own infections. To circumvent these problems, we developed single-cycle adenovirus (SC-Ad) vectors that amplify vaccine genes, but that avoid the risk of infection. This review will discuss these vectors and their prospects for use as vaccines. Areas covered: This review provides a background of different types of vaccines. The benefits of gene-based vaccines and their ability to replicate antigen genes are described. Adenovirus vectors are discussed and compared to other vaccine types. Replication-defective, single-cycle, and replication-competent Ad vaccines are compared. Expert commentary: The potential utility of these vaccines are discussed when used against infectious diseases and as cancer vaccines. We propose a move away from replication-defective vaccines towards more robust replication-competent or single-cycle vaccines. PMID- 29251016 TI - Hb A2-Tianhe (HBD: c.323G>A): First Report in a Chinese Family with Normal Hb A2 beta-Thalassemia Trait. AB - Coinheritance of delta-globin variants along with beta-globin gene defects can interfere with correct diagnosis of beta-thalassemia (beta-thal) trait. In this report, we present the coinheritance of a delta-globin variant, Hb A2-Tianhe [delta107(G9)Gly->Asp; HBD: c.323G>A] and a heterozygous beta-thal in a Chinese individual with microcytosis, hypochromia and a normal Hb A2 level. PMID- 29251017 TI - Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study. AB - A new series of 4,6-disubstituted 2-(4-(dimethylamino)styryl)quinoline 4a,b-9a,b was synthesized by the reaction of 2-(4-(dimethylamino)styryl)-6-substituted quinoline-4-carboxylic acids 3a,b with thiosemicarbazide, p-hydroxybenzaldehyde, ethylcyanoacetate, and 2,4-pentandione. In addition, the antitumour activity of all synthesized compounds 3a,b-9a,b was studied via MTT assay against two cancer cell lines (HepG2 and HCT116). Furthermore, epidermal growth factor receptor (EGFR) inhibition, using the most potent antitumour compounds, 3a, 3b, 4a, 4b, and 8a, was evaluated. The interpretation of the results showed clearly that the derivatives 3a, 4a, and 4b exhibited the highest antitumour activities against the tested cell lines HepG2 and HCT116 with IC50 range of 7.7-14.2 ug/ml, in comparison with the reference drugs 5-fluorouracil (IC50 = 7.9 and 5.3 ug/ml, respectively) and afatinib (IC50 = 5.4 and 11.4 ug/ml, respectively). In vitro EGFR screening showed that compounds 3a, 3b, 4a, 4b, and 8a exhibited moderate inhibition towards EGFR with IC50 values at micromolar levels (IC50 range of 16.01-1.11 uM) compared with the reference drugs sorafenib (IC50 = 1.14 uM) and erlotinib (IC50 = 0.1 uM). Molecular docking was performed to study the mode of interaction of compounds 3a and 4b with EGFR kinase. PMID- 29251018 TI - Cardiovascular outcomes with canagliflozin - is it on the CANVAS? AB - INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors (the 'gliflozins') promote the excretion of glucose from the kidney to lower HbA1c. Empagliflozin was the first gliflozin shown to improve cardiovascular and renal outcomes in subjects with type 2 diabetes and cardiovascular disease. Areas covered: In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, there were improvements in the primary cardiovascular and exploratory renal outcomes with canagliflozin, compared to placebo. The safety outcome finding, which was of most interest, was that there was a higher risk of amputation of toes, feet, or legs with canagliflozin than in the placebo group. This program is the subject of this evaluation. Expert opinion: As canagliflozin has small beneficial effects in the treatment of type 2 diabetes in subjects with cardiovascular disease, it is not on the canvas. However, there are still several questions about canagliflozin that need to be answered before it is widely used, especially in comparison with other gliflozins; As amputations have only been reported with canagliflozin in CANVAS, should other gliflozins be preferred? As canagliflozin has not been shown to be beneficial in subjects not taking diuretics, should other gliflozins be preferred in this population? Clarification is also needed as to whether canagliflozin increases the risk of non-fatal stroke, or not. PMID- 29251019 TI - The RORgammat-CCR6-CCL20 axis augments Th17 cells invasion into the synovia of rheumatoid arthritis patients. AB - OBJECTIVES: To clarify the pathogenic role of transcription factor expression of CD4 + T helper (Th) cell subsets in the development of rheumatoid arthritis (RA). METHODS: We collected CD4 + T cells from peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) by magnetic cell sorting. The proportion of Th cell subsets were classified from cell surface markers (CD45RA, CXCR5, CXCR3, CCR6) and the expression of their transcription factors (T bet, GATA3, RORgammat) were analyzed by flow cytometry before and at 24 weeks after anti-rheumatic treatment. Chemotaxis assays quantified migratory ability. RESULTS: The expression of CCR6 and RORgammat in Th17 cells from PBMC of RA patients was significantly higher than in healthy control volunteers and osteoarthritis patients. The proportion of Th17 cells in SFMCs of RA patients was significantly higher than that in PBMCs. Chemotaxis assays revealed that the migration index of Th17 cells towards CCL20 was remarkably enhanced in RA patients. The expression of CCR6 and RORgammat in Th17 cells at 24 weeks post therapeutic intervention was significantly decreased compared to before treatment. CONCLUSION: The high expression of RORgammat might facilitate the migration of Th17 cells to inflamed joints via the enhanced expression of CCR6 and contribute to the pathology of RA. PMID- 29251020 TI - Podophyllotoxin and rutin in combination prevents oxidative stress mediated cell death and advances revival of mice gastrointestine following lethal radiation injury. AB - Intestinal injury is inevitable during exposure to high radiation doses and is a common side effect observed during abdominal/pelvic radiotherapy. Yet, no radiation countermeasures are available for gastrointestine (GI) injury management. The aim of this study is to determine the effects of podophyllotoxin and rutin in combination (G-003M) on ionising radiation induced GI injury. We prophylactically administered G-003M to C57BL/6J mice exposed to 9 Gy total body radiation (TBI) and assessed for morphological changes, loss in absorption, fluid retention, biochemical alterations, immunohistochemical analysis to study cPARP, caspase-3, PCNA expression, and TUNEL staining. The irradiated intestine demonstrated extensive loss in crypts and villi, disrupted mucosal lining with reduced xylose uptake and enhanced fluid level post 7-day radiation. Mice receiving G-003M before radiation showed significant protection to intestinal epithelium, better allocation of secretory goblet cells, recovery in absorption, and reduced intestinal oedema. Additionally, G-003M administration also prevented radiation induced ROS generation, lipid peroxidation (MDA levels) and maintained the intestinal glutathione pool compared to the irradiated animals. G-003M supplementation also resulted in restoration of intestinal mitochondrial membrane potential, which was otherwise depolarised by radiation treatment. Immunohistochemical analysis demonstrated decrease in c-PARP and caspase-3 expression in jejuna cross sections and upregulation of PCNA in G-003M treated crypt cells as compared to 9 Gy irradiated mice. Our findings show that G-003M augment survival of mice against lethal radiation by promoting structural and functional regeneration in intestinal tissue. This combination therefore can be effectively explored for preventing radiation induced GI toxicity. PMID- 29251021 TI - Prostate cancer proteomics: clinically useful protein biomarkers and future perspectives. AB - INTRODUCTION: Although prostate cancer constitutes one of the most important, death-related diseases in the male population, there is still a need for identification of sensitive biomarkers that could precociously detect the disease and differentiate aggressive from indolent cancers, in order to decrease overtreatment. Proteomics research has improved understanding on mechanisms underlying tumorigenesis, cancer cells migration and invasion potential, and castration resistance. This review has focused on proteomic studies of prostate cancer published in the recent years, with a special emphasis on determination of biomarkers for cancer progression and diagnosis. Areas covered: Shotgun and targeted-proteomic studies of prostate cancer in different matrices are reviewed, i.e., prostate tissue, prostate cell lines, blood (serum and plasma), urine, seminal plasma, and exosomes. The most important biomarkers for cancer diagnosis and aggressiveness characterization are highlighted. Expert commentary: In general, results demonstrate alteration in cell cycle control, DNA repair, proteasomal degradation, and metabolic activity. However, these studies suffer from low reproducibility due to heterogeneity of the cancer itself, as well as to techniques utilized for protein identification/quantification. Downstream confirmatory studies in separate cohorts are warranted in order to demonstrate accuracy of these results. PMID- 29251022 TI - Impact of double positive for anti-centromere and anti-SS-a/Ro antibodies on clinicopathological characteristics of primary Sjogren's syndrome: a retrospective cohort study. AB - OBJECTIVES: The purpose of our study was to define the clinical characteristics of anti-centromere antibody and anti-SS-A/Ro antibody (ACA/SS-A) double positive Sjogren's syndrome (SS) and to clarify the clinical impact of these antibodies. METHODS: We examined 108 patients (6 males, mean age 57.9 years) with SS who underwent labial salivary gland biopsy. The patients were divided into four groups by ACA and anti-SS-A/Ro antibody positivity. Symptoms, laboratory and pathological data, and scleroderma-related data were compared among the groups. RESULTS: The cohort consisted of 16 ACA/SS-A double positive, 20 ACA single positive, 67 SS-A single positive, and 5 ACA/SS-A double negative SS. ACA/SS-A double positive SS were significantly older than SS-A single positive SS (mean age 71.1 vs. 53.1 years). They had higher EULAR Sjogren's syndrome disease activity index (ESSDAI) at diagnosis (mean 3.81 vs. 0.50) and higher serum IgG (mean 2009 vs. 1389 mg/dL) than ACA single positive SS. No patients developed skin sclerosis during a mean follow-up period of 45.6 months (range: 1-178). CONCLUSION: These results demonstrate that ACA/SS-A double positive SS is distinct from ACA single positive and SSA single positive SS. The combination of ACA and anti-SS-A/Ro antibody in SS should deserve greater attention in clinical practice. PMID- 29251023 TI - Autologous haematopoietic stem cell transplantation for Japanese patients with systemic sclerosis: Long-term follow-up on a phase II trial and treatment-related fatal cardiomyopathy. AB - OBJECTIVES: The objective of this study is to elucidate the efficacy and safety of autologous haematopoietic stem cell transplantation (HSCT) for Japanese patients with systemic sclerosis (SSc). METHODS: A phase II clinical trial included SSc patients diagnosed within the last three years having at least one of the following clinical features: diffuse skin sclerosis with modified Rodman total thickness skin score (mRSS) >= 15, refractory digital ulcer or interstitial lung disease (ILD). HSCT were performed after conditioning using cyclophosphamide. RESULTS: Fourteen patients were enrolled and underwent HSCT. Median follow-up period was 137 months. Overall survival or event-free survival rate was 93% or 40% at 10 years, respectively. Eight patients (57%) achieved more than a 50% decrease in mRSS from baseline within six months after HSCT. Six patients (43%) required additional immunosuppressive treatments due to progression of diffuse skin sclerosis and/or ILD during follow-up period. Adverse events related to HSCT occurred in six patients (43%). Severe cardiomyopathy occurred in two patients, and one of them had a fatal course. CONCLUSION: HSCT is a feasible treatment bringing favourable results to more than half of our patients with SSc. Careful selection of the patients is essential for whom benefited from HSCT, considering the risk-benefit balance of the treatment. PMID- 29251024 TI - Outcome of transition phase patients with juvenile idiopathic arthritis. AB - OBJECTIVES: Across diagnosis groups, successful transition of adolescent and young adults from children's hospitals to adult care is often associated with decreased treatment adherence and treatment results. The aim of this study was to characterize disease activity and anti-rheumatic medications following transfer of care of juvenile idiopathic arthritis (JIA) patients to the adult clinic. METHOD: All consecutive JIA patients aged 16-20 years who visited the specific transition clinic in the rheumatology outpatient clinic of Helsinki University Hospital between November 2012 and May 2013 and between April 2015 and April 2016 were evaluated. RESULTS: A total of 214 patients were identified, and 23 appeared in both cohorts. Females had higher disease activity scores (DAS) than males (DAS28-CRP 1.9 +/- 0.7 versus 1.6 +/- 0.3, p = .019; and DAS44-CRP 1.0 +/- 0.7 versus 0.7 +/- 0.5, p = .005; respectively) in the latter cohort. Disease modifying antirheumatic drugs (DMARDs) were prescribed to 86% of patients, and 48% were on biological DMARDs (bDMARDs), whereas 14% had no specific treatments. CONCLUSION: Disease activity and clinic attendance remained stable during the transition period. The proportion of transition phase JIA patients on bDMARDs was high and disease activity was low. Reasons for lower disease activity in males in the latter cohort require further investigation. PMID- 29251025 TI - Low molecular weight heparin use during pregnancy and risk of postpartum hemorrhage: a systematic review and meta-analysis. AB - INTRODUCTION: Postpartum hemorrhage (PPH) is the leading cause of maternal mortality worldwide with a prevalence rate of approximately 6%. Although most cases of PPH have no identifiable risk factors, the incidence of PPH has been associated to the thromboprophylaxis in pregnancy with low molecular weight heparin (LMWH). Thus, the aim of the study is to evaluate the risk of PPH in cases of pregnant women exposed to LMWH. MATERIALS AND METHODS: Electronic research was performed in OVID, Scopus, ClinicalTrials.gov, MEDLINE, the PROSPERO International Prospective Register of Systematic Reviews, EMBASE, and the Cochrane Central Register of Controlled Trials through April 2016. We included randomized controlled trials, cohort and case-control studies of women who underwent thromboprophylaxis with LMWH during pregnancy compared to a control group (either placebo or no treatment). The primary outcome was the incidence of PPH. The summary measures were reported as relative risk (RR) or as mean differences (MD) with 95% confidence interval (CI). RESULTS: Eight studies including 22,162 women were analyzed. Of the 22,162 women, 1320 (6%) were administered LMWH, 20,842 (94%) women formed the nonexposed group (control group). Women treated with LMWH had a higher risk of PPH (RR 1.45, 95%CI 1.02 2.05) compared to controls; there was no difference in mean of blood loss at delivery (MD -32.90, 95%CI 68.72-2.93) and in risk of blood transfusion at delivery (RR 1.24, 95%CI 0.62-2.51), respectively. CONCLUSIONS: Women who receive LMWH during pregnancy have a significantly higher risk of developing PPH. Women who receive LMWH during pregnancy have neither significantly higher mean blood loss at delivery nor higher risk of blood transfusion. PMID- 29251026 TI - Comparison of clinical and laboratory features of patients with and without allergic conditions in IgG4-related disease: A single-center experience in Japan. AB - OBJECTIVE: The objective of this study is to compare the clinical and laboratory features of Japanese patients with IgG4-related disease, with and without allergic conditions. METHODS: We retrospectively examined the clinical and laboratory features and clinical courses of 51 patients with definitively diagnosed IgG4-RD, collected from Nagaoka Red Cross Hospital between January 2004 and August 2017, with reference to the presence of allergic conditions. RESULTS: Among these patients, 43% had allergic conditions. In the allergy group, the proportion of females was significantly higher, the age at diagnosis was significantly lower, and upper body organ involvement was predominant in comparison with the non-allergy group. There was no significant inter-group difference in the absolute number of peripheral blood eosinophils, the levels of serum IgG4 and IgE, the response to steroid, or the proportion of patients who relapsed. CONCLUSION: The present findings suggest that there may be some differences in the clinical features of IgG4-RD patients according to the allergic conditions that are present, although eosinophilia and high serum levels of IgE and IgG4 are common features regardless of allergy. PMID- 29251029 TI - Conference Diary. PMID- 29251027 TI - Efficacy and safety of tocilizumab with inhibition of interleukin-6 in adult onset Still's disease: A meta-analysis. AB - OBJECTIVES: Tocilizumab (TCZ) is the only available biologics inhibiting interleukin-6 presently, and emerging evidences have figured that elevated serum level of interleukin-6 is a crucial link of the pathogenesis of adult-onset Still's disease (AOSD). However, evidence about the efficacy and safety of TCZ in AOSD with strong power is still scarce. Thus, this meta-analysis was conducted to synthetically assess the efficacy and safety of TCZ on AOSD. METHODS: PubMed, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure, and Chinese Biological Medical Literature database were comprehensively searched up to 31 July 2017 for the pertinent studies. The pooled remission rates were synthesized by fixed effect model or randomized effects model, depended on heterogeneity. RESULTS: Ten original studies contained 147 individuals were included in our analysis. The overall partial and complete remission rates were 85.38 (95% CI: 69.32-96.88%) and 77.91% (95% CI: 57.91-90.04%), respectively, and the remission rate of refractory patients was 87.92% (95% CI: 56.53-100.00%). CONCLUSION: The use of TCZ could significantly reduce the need of corticosteroids for AOSD patients. Impressive improvements were attained in both clinical and laboratory parameters. Compared with conventional therapy, TCZ treatment was safety. In conclusion, TCZ was effective and well tolerated for the treatment of AOSD. PMID- 29251030 TI - Victor Bonney Society, Spring Weekend Meeting, Down Hall Country House Hotel, Hertfordshire, 21-22 May 1999. PMID- 29251031 TI - Correlation between time lag of arterial-plethysmographic waveforms and systemic vascular resistance: a prospective study. AB - Blood pressure (BP), a surrogate of cardiac output (CO), is also dependent on systemic vascular resistance (SVR). But SVR is not routinely monitored in daily clinical practice. We hypothesise that the time difference between the peripheral arterial waveform and the finger plethysmographic waveform (time lag index - TLi) could indicate the systemic vascular resistance. In this study, we correlated TLi with the systemic vascular resistance measured by minimally invasive CO monitor (pulse contour analysis). SVR changes in response to administration of mannitol were studied. American Society of Anesthesiologists (ASA) class I and II patients undergoing major intracranial surgeries were recruited. Arterial cannulation and pulse-oximetry recordings were done in the same limb. Arterial and plethysmographic waveforms were recorded before mannitol infusion (baseline) and at every 10 minutes for 60 minutes after the termination of mannitol infusion. Simultaneously, SVR was recorded from the Vigileo FLotrac CO monitor. Using custom-made programme, the time difference between both waveforms was calculated and corrected for heart rate (TLi). The correlation between time lag and the systemic vascular resistance was assessed using a mixed effect model, adjusting for the subject. Data of one hundred subjects were analysed. Following mannitol administration, there was a significant decrease in the SVR and the TLi (p < .001). The patient characteristics influenced both the baseline values of SVR (intercept) and the changes in SVR over time (slope). As both the baseline value and the change over time for SVR were different in each patient, we used mixed effect model analysis to assess the relationship between SVR and TLi for different time periods. The effect of TLi on SVR was significant (beta = 877.16, p = .008). The high beta coefficient suggests that when SVR increases, the TLi also increase and vice versa. A strong correlation between SVR and TLi was demonstrated for a given patient. Further studies are needed to explore the possibility of utilising this parameter to follow up changes in SVR in an individual patient at a particular point in time in different clinical scenarios. PMID- 29251032 TI - Safety and effectiveness of subcutaneous tocilizumab in patients with rheumatoid arthritis in a real-world clinical setting. AB - OBJECTIVES: The objective of this study is to evaluate the safety and effectiveness of subcutaneous tocilizumab (TCZ-SC) in a real-world clinical setting in Japan. METHODS: This single arm, 26-week prospective observational study enrolled patients with RA who were either TCZ naive or switched from TCZ-IV to TCZ-SC (TCZ-IV-SC group) (UMIN Clinical Trials Registry UMIN000011102). All patients received TCZ-SC 162 mg every 2 weeks and data were collected until week 26 or discontinuation. RESULTS: Overall 784 (78.1%) were TCZ naive and 219 (21.8%) were in the TCZ-IV-SC group. 70.9% received disease-modifying antirheumatic drugs at baseline. Adverse events (AEs) and serious AEs occurred in 28.2% and 4.9% of patients, respectively (TCZ-naive: 29.5% and 5.2%; TCZ-IV-SC: 23.2% and 4.1%). Infections and infestations were the most common AEs (7.4%) and serious AEs (1.7%). Two TCZ-naive patients died. TCZ-naive patients had an improvement in median Clinical Disease Activity Index (CDAI) score and mean Disease Activity Score in 28 joints as measured by erythrocyte sedimentation rate (DAS28-ESR) from baseline to week 26. The TCZ-IV-SC group had similar median CDAI scores and mean DAS28-ESR over 26 weeks. CONCLUSIONS: There were no unexpected safety signals with TCZ-SC. TCZ-SC was effective in reducing disease activity in TCZ-naive patients and maintaining remission in TCZ-IV-SC patients. PMID- 29251033 TI - Significant improvement of bone mineral density by denosumab without bisphosphonate pre-treatment in glucocorticoid-induced osteoporosis. AB - OBJECTIVE: The aim of this study was to evaluate differences in outcomes of denosumab for a year with or without bisphosphonate (BP) pre-treatment in patients with glucocorticoid-induced osteoporosis (GIO). METHODS: Forty-eight female patients with GIO and low bone mineral density (BMD) (T score of BMD; less than -3.0 SD) were, retrospectively, enrolled and classified into the following two groups: (1) GIO with BP pre-treatment (BP pre-treated group; n = 24) and (2) GIO without BP treatment (BP pre-untreated group; n = 24). We measured serum bone alkaline phosphatase (BAP), N-terminal propeptide of type 1 procollagen (P1NP), and tartrate-resistant acid phosphatase (TRACP)-5b at baseline, and at 3, 6, and 12 months. We also assessed BMD of the lumbar 1-4 vertebrae BMD (L-BMD) and bilateral hip BMD (H-BMD) at baseline, and at 6 and 12 months. RESULTS: TRACP-5b was significantly inhibited at 3 months in both groups and at 6 and 12 months in the BP pre-untreated group compared with pre-treatment levels. Both BAP and P1NP were significantly suppressed at 3, 6, and 12 months in both groups compared with baseline values. L-BMD and H-BMD were significantly increased at 6 (4.2% and 3.4%, respectively) and 12 months (4.7% and 4.7%, respectively) in the BP pre untreated group over pre-treatment levels. There were no significant differences between the groups during the observational period. CONCLUSION: Denosumab significantly improved both L-BMD and H-BMD in the BP pre-untreated group, but not in the BP pre-treated group, suggesting it to be a good option for GIO patients without BP pre-treatment. PMID- 29251034 TI - Residual symptoms and disease burden among patients with rheumatoid arthritis in remission or low disease activity: a systematic literature review. AB - OBJECTIVES: To identify, describe and summarize evidence on residual symptoms and disease burdens in rheumatoid arthritis (RA) patients qualified as being in remission or low disease activity (LDA). METHODS: A systematic literature review (SLR) was conducted according to Cochrane collaboration guidelines. The population of interest was adult patients with RA in remission or LDA. The reported outcomes of interest were any symptoms or burdens. RESULTS: Fifty-one publications were identified through an eDatabase search. Together with 17 articles found through other sources, 68 were included for full text review. The most commonly reported residual symptoms were pain (number of studies = 25), fatigue (n = 21) and morning stiffness (n = 5). Reported disease burdens included mental health (n = 15), sleep disturbances (n = 7) and work productivity (n = 5), impairment in quality of life (n = 21), and functional disability (n = 34). Substantial residual symptoms and disease burdens were found to be present in patients in remission or LDA. CONCLUSION: This is the first SLR to investigate residual symptoms and disease burdens in RA patients in remission or LDA. The results indicate that despite achieving conventional clinical targets, the disease continues to affect patients, suggesting the existence of unmet need under the current treatment paradigm. PMID- 29251036 TI - Motorball: Soccer With a New Kick. PMID- 29251035 TI - Serum soluble interleukin-2 receptor as a biomarker in immunoglobulin G4-related disease. AB - OBJECTIVES: Serum soluble interleukin-2 (IL-2) receptor (sIL-2R) might reflect disease activity in immunoglobulin G4-related disease (IgG4-RD). We aimed to elucidate the clinical significance of blood markers, including sIL-2R, in patients with IgG4-RD. METHODS: We enrolled 59 patients with IgG4-RD and investigated the association between blood markers (white blood cells, C-reactive protein, sIL-2R, IgG, IgG4, IgE, total hemolytic complement), and clinical indices. RESULTS: At baseline, serum sIL-2R (Rs = 0.532, p < .001) and IgG4 (Rs = 0.545, p < .001) levels showed significant correlation to the number of organs involved. During follow-up period (median, 70 months; range, 7-195 months), 40 patients were treated with corticosteroids. Receiver operating characteristic (ROC) analysis showed that baseline sIL-2R levels most accurately predicted patients requiring glucocorticoid treatment (area under the ROC curve, 0.807). Among the 46 patients who improved, sIL-2R and IgG4 levels decreased in 42 and 41 patients, respectively. Among them, serum sIL-2R levels decreased to a normal range in 42 patients (91%), whereas IgG4 levels normalized in 19 (41%). CONCLUSION: The serum sIL-2R level is a potential biomarker for IgG4-RD that may reflect the number of involved organs and may predict patients requiring glucocorticoid treatment. PMID- 29251038 TI - scanning sports. PMID- 29251037 TI - gameplan. PMID- 29251039 TI - For the Problem Knee, Slip on a Sleeve. PMID- 29251041 TI - Golf's Nine Holes of Anxiety - And How to Stay Out of Them. PMID- 29251040 TI - Second Wind - Trying to Catch It in the Lab. PMID- 29251042 TI - editor's notes. PMID- 29251043 TI - When and Where Women Are Injured in Sports. PMID- 29251044 TI - Warning for Millions: Intense Exercise Can Deplete Potassium. PMID- 29251045 TI - Problems in Matching Young Athletes: Baby Fat, Peach Fuzz, Muscle, and Mustache. PMID- 29251047 TI - It's Horrible - It's Beautiful - It's Rowing. PMID- 29251046 TI - sportspages. PMID- 29251049 TI - Memorial Day Madness. PMID- 29251048 TI - Bloody Urine: Don't Panic, Collect a Specimen. PMID- 29251051 TI - Gene Littler: Cancer, Confidence, Comeback. PMID- 29251050 TI - letters. PMID- 29251052 TI - Salt Pills and Leg Cramps. PMID- 29251053 TI - Teamwork in the Hardest Pull in Sports. PMID- 29251054 TI - Women in Sports - Are the 'problems' Real? PMID- 29251055 TI - Validation of a multivariate clinical prediction model for the diagnosis of mild stroke/transient ischemic attack in physician first-contact patient settings. AB - We validate our previously developed (DOI: 10.1101/089227) clinical prediction rule for diagnosing transient ischemic attack on the basis of presenting clinical symptoms and compare its performance with the ABCD2 score in first-contact patient settings. Two independent and prospectively collected patient validation cohorts were used: (a) referral cohort-prospectively referred emergency department and general practitioner patients ( N = 877); and (b) SpecTRA cohort participants recruited as part of the SpecTRA biomarker project ( N = 545). Outcome measure consisted of imaging-confirmed clinical diagnosis of mild stroke/transient ischemic attack. Results showed that our clinical prediction rule demonstrated significantly higher accuracy than the ABCD2 score for both the referral cohort (70.5% vs 59.0%; p < 0.001) and SpecTRA cohort (72.8% vs 68.3%; p = 0.028). We discuss the potential of our clinical prediction rule to replace the use of the ABCD2 score in the triage of transient ischemic attack clinic referrals. PMID- 29251056 TI - A pilot study exploring the relationship between the use of mobile technologies, walking distance, and clinical decision making among rural hospital nurses. AB - Providing evidence-based information at the point of care for time-poor nurses may lead to better clinical care and patient outcomes. Smartphone applications (apps) have the advantage of providing immediate access to information potentially increasing time spent with patients. This small-scale pre-post survey study explored the impact a smartphone app had on the distance nurses walked and their perceived clinical decision-making ability. A total of 20 nurses working in a rural hospital medical/surgical unit participated. The findings suggest that the use of the smartphone app did not decrease nurses' walking distance. Nor did using the app enhances nurses' perception of their clinical decision-making ability. However, there was a statistically significant increase in confidence in the app over time (F(1,16) = 5.416, p = 0.033, partial eta2 = 0.253), suggesting that providing training opportunities including time to learn how to use smartphone applications has the potential to enhance nurses work. PMID- 29251057 TI - Clinical heterogeneity of SAPHO syndrome: Challenge of diagnosis. PMID- 29251058 TI - Abundant expression of BMI1 in follicular lymphoma is associated with reduced overall survival. AB - Although generally indolent, follicular lymphoma (FL) sometimes pursues a more aggressive course leading to early death. B-cell-specific Mo-MLV insertion site-1 (BMI1) is a member of the polycomb group (PcG) proteins that confer stem cell properties through gene silencing. We used multi-channel immunofluorescence and automated image analysis to quantify BMI1 selectively in the nuclei of FL-derived B-cells in routine biopsy specimens. Applying this assay to 109 pretreatment FL biopsy samples demonstrates a significant association between abundant BMI1 and reduced overall survival (p = .001); the statistically significant association with mortality persists in a Cox proportional hazards model that includes Follicular Lymphoma International Prognostic Index (FLIPI) score, histological grade, and the presence of a component of diffuse large B-cell lymphoma in the biopsy sample. Ascertaining BMI1 over-expression may be useful in identifying patients who might benefit from novel therapies directed at reversing the chromatin-modifying functions of BMI1. PMID- 29251059 TI - Epileptic seizure detection using DWT-based approximate entropy, Shannon entropy and support vector machine: a case study. AB - In this work, we have used a time-frequency domain analysis method called discrete wavelet transform (DWT) technique. This method stand out compared to other proposed methods because of its algorithmic elegance and accuracy. A wavelet is a mathematical function based on time-frequency analysis in signal processing. It is useful particularly because it allows a weak signal to be recovered from a noisy signal without much distortion. A wavelet analysis works by analysing the image and converting it to mathematical function which is decoded by the receiver. Furthermore, we have used Shannon entropy and approximate entropy (ApEn) for extracting the complexities associated with electroencephalographic (EEG) signals. The ApEn is a suitable feature to characterise the EEGs because its value drops suddenly due to excessive synchronous discharge of neurons in the brain during epileptic activity in this study. EEG signals are decomposed into six EEG sub-bands namely D1-D5 and A5 using DWT technique. Non-linear features such as ApEn and Shannon entropy are calculated from these sub-bands and support vector machine classifiers are used for classification purpose. This scheme is tested using EEG data recorded from five healthy subjects and five epileptic patients during the inter-ictal and ictal periods. The data are acquired from University of Bonn, Germany. The proposed method is evaluated through 15 classification problems, and obtained high classification accuracy of 100% for two cases and it indicates the good classifying performance of the proposed method. PMID- 29251060 TI - Ethnic density of regions and psychiatric disorders among ethnic minority individuals. AB - BACKGROUND: Ethnic minorities form an increasingly large proportion of Canada's population. Living in areas of greater ethnic density may help protect mental health among ethnic minorities through psychosocial pathways such as accessibility to culturally appropriate provision of mental health care, less discrimination and a greater sense of belonging. Mood and anxiety disorders are common psychiatric disorders. AIM: This study examined whether ethnic density of regions was related to mood and anxiety disorders among ethnic minorities in Canada. METHOD: Responses by ethnic minority individuals to the 2011-2014 administrations of the Canadian Community Health Survey ( n = 33,201) were linked to health region ethnic density data. Multilevel logistic regression was employed to model the odds of having mood and/or anxiety disorders associated with increasing region-level ethnic density and to examine whether sense of community belonging helped explain variance in such associations. Analyses were adjusted for individual-level demographic factors as well as region-level socio economic factors. RESULTS: Higher ethnic density related to lower odds of mood and/or anxiety disorders for Canadian-born (but not foreign-born) ethnic minorities. Sense of community belonging did not help explain such associations, but independently related to lower odds of mood and/or anxiety disorders. These findings remained after adjusting for regional population density and after excluding (rural/remote) regions of very low ethnic density. CONCLUSION: Ethnic density of regions in Canada may be an important protective factor against mental illness among Canadian-born ethnic minorities. It is important to better understand how, and for which specific ethno-cultural groups, ethnic density may influence mental health. PMID- 29251061 TI - Use of Decision Support Software to Titrate Multiple Daily Injections Yielded Sustained A1c Reductions After 1 Year. AB - PURPOSE: The purpose was to improve the quality of care of at-risk patients through the addition of connected BG meters and CDSS to improve workflow and thus provide more efficient titration of patient's insulin regimens remotely between office visits in an attempt to treat them to their glucose targets faster and efficiently, and maintain that improvement over time. METHODS: Hardware and software included a real-time cellular-enabled blood glucose (BG) meter and Glytec's GlucommanderTM clinical decision support software (CDSS). A quality improvement (QI) project with retrospective before-and-after comparison was conducted. The training period was 90 days and then the project ran for another 11 months. A protocol comprised Glytec CDSS software, which recommends titration intervals from 3 to 28 days as a function of glycemic control, specifically, longer intervals for better control. There were 46 clinic patients. RESULTS: A1C decreased from a baseline average of 10.2% to 7.8% at 3 months, 7.8% at 6 months, 7.8% at 9 months, and 7.2% at 12 months. The baseline-to-final A1C decrease shows a P < .00001 by paired t-test. Out of 36 315 BGs, the average number of BG tests per day was 3.03 during the first 3 months and 2.47 during the final 3 months. The percentage of BGs < 54 mg/dL was 0.33% and the percentage of BGs < 40 mg/dL was 0.05%. CONCLUSIONS: This QI project demonstrated the use of CDSS including its built-in feature of titration interval recommendation can safely and effectively lower A1C for at-risk patients, treat patients to target safely, and maintain those improvements over 12 months of follow-up. PMID- 29251062 TI - Overestimation of Hypoglycemia Diagnosis by FreeStyle Libre Continuous Glucose Monitoring in Long-Term Care Home Residents With Diabetes. PMID- 29251063 TI - Decreased Rates of Inpatient Hypoglycemia Following Implementation of an Automated Tool in the Electronic Medical Record for Identifying Root Causes. AB - OBJECTIVE: The objective was to identify root causes of hypoglycemia on medicine inpatient units using an automated tool. Data collected will guide educational interventions aimed at improving patient care and safety by decreasing rates of hypoglycemia. METHODS: A survey was conducted among RNs to identify risk factors for hypoglycemia. Survey data were used to create a hypoglycemia root cause survey tool in the EMR. RNs were prompted to utilize the tool when blood glucose (BG) < 70 mg/dL. Once the most common modifiable cause of hypoglycemia was identified, an educational intervention for safe and effective use of insulin was launched. This strategy was designed to empower the care team to reduce the insulin dose when appropriate to prevent future hypoglycemic episodes. RESULTS: BG data were compared from March and April in 2016 and 2017. Rates of hypoglycemia (BG < 70 mg/dL) decreased from 2.3% to 1.5%; BG values in target range (70-180 mg/dL) increased from 59.4% to 65.7%; hyperglycemia (BG > 180 mg/dL) decreased from 38.3% to 32.8% (all P values < .001). The number of patients with recurrent hypoglycemia (3 or more episodes) decreased from 5.7% to 2.2% ( P = .044). CONCLUSIONS: The two most frequent modifiable causes of hypoglycemia (insulin and nutrition) were identified by an RN survey and confirmed by chart review. A targeted educational intervention addressing safe and effective insulin dosing resulted in a significant decrease in both hypoglycemia and recurrent hypoglycemia. This was associated with an improvement in overall glycemic control. Ongoing clinician education regarding insulin and nutrition accompanied by discussions between RNs and prescribers to address hypoglycemic events in real-time could continue to lower the rate of occurrence. PMID- 29251064 TI - Risk of Hypoglycemia During Insulin Infusion Directed by Paper Protocol Versus Electronic Glycemic Management System in Critically Ill Patients at a Large Academic Medical Center. AB - BACKGROUND: Insulin infusions are commonly utilized to control hyperglycemia in critically ill patients and decrease hyperglycemia associated complications. Safety concerns have been raised in trials evaluating methods of glycemic control regarding the incidence of hypoglycemia and its relationship to increased mortality. Electronic glycemic management systems (eGMS) may result in less variable blood glucose (BG) control and less hypoglycemia. This study aimed to compare BG control, time in target BG range, and the rate of hypoglycemia when critically ill patients were managed with an insulin infusion guided by paper based protocol (PBP) versus eGMS. METHODS: This retrospective review compared critically ill patients >= 18 years old that received insulin infusion from March to May 2015 (PBP group) and October to January 2017 (eGMS group). The primary outcome was the incidence of hypoglycemia. Secondary outcomes included frequency and severity of hypoglycemia, duration in glycemic target, length of insulin therapy, as well as ICU and hospital length of stay. RESULTS: Fifty-four patients were evaluated, 27 in each group. Percentage of days with BG <70 mg/dL was significantly reduced after eGMS implementation (21.5% v 1.3%, P < .0001) including the frequency of severe hypoglycemia (BG < 40 mg/dL) (5.4% v 0.01%, P < .0001). Patients in the eGMS group spent a greater amount of time in target BG range (31.5% v 63.7%, P < .0001). CONCLUSIONS: An eGMS has the potential to address many of the unmet needs of an optimal glycemic control strategy, minimizing hypoglycemia, and glycemic variability in a heterogeneous critically ill population. PMID- 29251067 TI - sportspages. PMID- 29251068 TI - What Causes Second Wind? PMID- 29251065 TI - The potential influence of LED lighting on mental illness. AB - OBJECTIVES: Two recent scientific breakthroughs may alter the treatment of mental illness, as discussed in this narrative review. The first was the invention of white light-emitting diodes (LEDs), which enabled an ongoing, rapid transition to energy-efficient LEDs for lighting, and the use of LEDs to backlight digital devices. The second was the discovery of melanopsin-expressing photosensitive retinal ganglion cells, which detect environmental irradiance and mediate non image forming (NIF) functions including circadian entrainment, melatonin secretion, alertness, sleep regulation and the pupillary light reflex. These two breakthroughs are interrelated because unlike conventional lighting, white LEDs have a dominant spectral wavelength in the blue light range, near the peak sensitivity for the melanopsin system. METHODS: Pertinent articles were identified. RESULTS: Blue light exposure may suppress melatonin, increase alertness, and interfere with sleep in young, healthy volunteers and in animals. Areas of concern in mental illness include the influence of blue light on sleep, other circadian-mediated symptoms, prescribed treatments that target the circadian system, measurement using digital apps and devices, and adolescent sensitivity to blue light. CONCLUSIONS: While knowledge in both fields is expanding rapidly, future developments must address the potential impact of blue light on NIF functions for healthy individuals and those with mental illness. PMID- 29251070 TI - Low Back Pain in Young Athletes. PMID- 29251069 TI - Come and Play. PMID- 29251071 TI - Football Injury Survey: Part 3: Injury Rates Vary With Coaching. PMID- 29251072 TI - Team Physicians. PMID- 29251073 TI - Aerobatic Pilots - Why Do They Fly That Way? PMID- 29251074 TI - Medical Care for Young Athletes: 'Pretty Barbaric, But That's the Way it Is'. PMID- 29251076 TI - winners and losers. PMID- 29251075 TI - Athletic Care - The Limits to Quality. PMID- 29251077 TI - Treating Flat Feet at the Hips. PMID- 29251078 TI - Where the Golfer Meets History I. PMID- 29251079 TI - X-Ray Diagnosis: Cartilage Tears to Pull-Tabs. PMID- 29251081 TI - editor's notes. PMID- 29251080 TI - Power and Swimming. PMID- 29251082 TI - letters. PMID- 29251083 TI - Effects of constraint-induced movement therapy on brain glucose metabolism in a rat model of cerebral ischemia: a micro PET/CT study. AB - PURPOSE: Constraint-induced movement therapy (CIMT) can improve motor functions in stroke patients and ischemic rats. This study examined the effect of CIMT in ischemic rats using positron emission tomography (PET). METHODS: We used middle cerebral artery occlusion (MCAO) procedure to induce cerebral ischemia in rats. Male rats were divided into a negative control group (Normal, n = 4), a sham operated group (Sham, n = 6), an ischemic group (Control, n = 6) and an ischemic CIMT-treated group (CIMT, n = 6). CIMT started at postoperative day 8 (d8) and lasted for 2 weeks. We utilized 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) micro PET/CT imaging to evaluate glucose metabolism in different brain regions at baseline, before, and after treatment, respectively. RESULTS: CIMT improved behavioral performance in the ischemic CIMT group. At the end of treatment, the CIMT group showed lower standardized uptake values (SUVs) in the ipsilateral cingulate, motor and somatosensory cortex, respectively; as well as the anterodorsal hippocampus compared to the Control group (1.80% +/- 0.10% vs. 1.92% +/- 0.08%, 1.32% +/- 0.14% vs. 1.48% +/- 0.09%, 1.18% +/- 0.14% vs. 1.42% +/- 0.15%, 1.68% +/- 0.09% vs. 1.79% +/- 0.06%, P < 0.05). We also observed higher SUVs in the acbcore shell and cortex insular of the contralateral hemisphere compared to the Control group (2.07% group in the acbcore shell and cortex insular of contralateral P < 0.05). CONCLUSION: CIMT improved behavioral outcomes in cerebral ischemic rats and this effect can be attributed to increased glucose utilization in the contralateral hemisphere. PMID- 29251084 TI - Further Evidence for an External Focus of Attention in Running: Looking at Specific Focus Instructions and Individual Differences. AB - Although attentional focusing in sports has been broadly investigated, the findings vary when it comes to endurance sports. This study provides a comparison between relevant foci in the literature of running economy. These include two internal foci-one addressing automated processes (running movement) and the other nonautomated processes (internal body signals and perceived exertion), an external focus (video) and a control condition. Furthermore, we investigated the influence of interoceptive sensitivity on oxygen consumption within the different attention conditions. Thirty recreational runners performed a four 6-min run at moderate intensity consisting of the four counterbalanced conditions. Running economy was assessed by spiroergometry, and interoception was measured using a heartbeat tracking task. Results revealed a significantly better running economy for the external focus of attention compared with all other conditions. No significant correlations were observed between the heartbeat perception score and oxygen consumption in any condition. PMID- 29251086 TI - Pharmacokinetics and distribution of schisandrol A and its major metabolites in rats. AB - 1. Schizandrol A is an active component in schisandra, also the representative component for the identification of schisandra. 2. A rapid resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (RRLC QTOF/MS) was developed to investigate the pharmacokinetics of schizandrol A after itsintragastric administration (50 mg/kg) in rats. 3. Schizandrol A was rapidly absorbed (Tmax=2.07 h), with a longer duration (t1/2=9.48 h) and larger apparent volume of distribution (Vz/F = 111.81 L/kg) in rats. Schizandrol A can be detected in main organs and the order of its distribution was in the liver > kidney > heart > spleen > brain, particularly higher in the liver. 4. Five schizandrol A metabolites were identified, including 2-demethyl-8(R)-hydroxyl schizandrin, 3-demethyl-8(R)-hydroxyl-schizandrin, hydroxyl-schizandrin, demethoxy-schizandrin, 2, 3-demethyl-8(R) -hydroxyl-schizandrin, indicating that the hydroxylation and demethylation may be the major metabolic way of schizandrol A. 5. This study defined the pharmacokinetic characteristics of schizandrol A in vivo, and the RRLC-QTOF/MS is more sensitive and less limited by conditions, and needs less samples, which may be a useful resource for the further research and development of schisandrol A. PMID- 29251085 TI - Radioprotective and radiomitigative effects of BP-C2, a novel lignin-derived polyphenolic composition with ammonium molybdate, in two mouse strains exposed to total body irradiation. AB - PURPOSE: There remains an unmet medical need for radioprotective and mitigative agents. BP-C2 is a novel lignin-derived polyphenolic composition with ammonium molybdate, developed as radioprotector/radiomitigator. OBJECTIVES: The present study evaluated BP-C2 for the mitigation of acute radiation syndrome (ARS). METHODS: A total-body irradiation mouse model (TBI, 4.0-8.0 Gy) was used in the study. RESULTS: In a 30-day survival study, performed in CBA mice, BP-C2, at a dosage of 81.0 mg/kg, improved survival (dose reduction factor (DRF) = 1.1) and increased the formation of endogenous spleen colony-forming units (CFU). In C57BL/6 mice, BP-C2, when administered daily for 7 days, starting 24 hours after TBI, also improved survival. In animals irradiated with 5.0 Gy, BP-C2 increased the number of CFUs (6.7 +/- 5.1) compared to the 5.0 Gy placebo group (2.3 +/- 2.3, p = .0245). The number of surviving intestinal crypts was maintained in the 5.0 Gy BP-C2 group (133.7 +/- 13.9), in contrast to the 5.0 Gy placebo group (124.2 +/- 10.5, p < .0023). BP-C2 also increased the number of LGR5 + positive cells in intestinal crypts. CONCLUSION: BP-C2 mitigates radiation-induced damage in mid-lethal range of radiation doses. Effects are mediated by enhancement of extramedullar hematopoiesis in the spleen and a protective effect on the intestinal epithelium. PMID- 29251088 TI - Is gut microbiome a predictive marker to response to immune checkpoint inhibitors? PMID- 29251089 TI - The Antecedents of Coaches' Interpersonal Behaviors: The Role of the Coaching Context, Coaches' Psychological Needs, and Coaches' Motivation. AB - This study explored how the coaching context influences coaches' psychological needs, motivation, and reported interpersonal behaviors, using self-determination theory. In Study 1, 56 coaches identified how contextual factors influence their coaching experience. Coaches identified administration, athlete motivation, colleagues, parents, professional development, time, and work-life as having the largest impact on them. In Study 2, 424 coaches reported on their perceptions of the factors identified in Study 1 and their psychological needs, motivation, and interpersonal behaviors. Structural equation modeling analyses suggested perceptions of the coaching context supported or thwarted their psychological needs, which positively or negatively predicted their autonomous and controlled motivation. Coaches' autonomous motivation predicted their reported supportive interpersonal behaviors and controlled motivation predicted thwarting behaviors. Overall, the results provided additional support for understanding how the coaching context, coaches' psychological needs, and their motivation for coaching relate to their coaching behaviors. PMID- 29251087 TI - The clinical significance of neutrophil-to-lymphocyte ratio and monocyte-to lymphocyte ratio in Guillain-Barre syndrome. AB - : Purpose/Aim of the study: Guillain Barre syndrome (GBS) is a severe peripheral nervous disease that leads to muscle weakness and areflexia. We now commonly accept a synthesis that inflammation and immunity play key role in GBS pathogenesis. Many studies pointed out that neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) are novel promising markers of inflammation or immunity. Our study aimed to evaluate whether the NLR and the MLR were associated to GBS or not. MATERIALS AND METHODS: We measured blood cell count in 334 individuals including 117 GBS and 217 healthy controls. RESULTS: Our findings demonstrated that the GBS patients had higher levels of NLR and MLR than the healthy controls. The severe group also had higher levels of NLR and MLR compared to the mild group. We took the method of receiver-operating characteristic curve to find out the cut-off value of NLR for GBS occurrence and severity; it was 2.295 and 3.05, respectively. The cut-off values of MLR for GBS incidence and severity were the same, it was 0.235. CONCLUSION: In the setting of GBS, the NLR and MLR were significantly increased and they may be pathophysiologically and clinically relevant in GBS. The NLR and MLR would be new biomarkers of medical application. PMID- 29251091 TI - gameplan. PMID- 29251090 TI - a need to know. PMID- 29251092 TI - world at play. PMID- 29251094 TI - winners and losers. PMID- 29251093 TI - Diagnosing Kidney Injuries in Athletes. PMID- 29251095 TI - sportspages. PMID- 29251096 TI - Preventive Maintenance for Athletes. PMID- 29251097 TI - Athletes Need a Family Practitioner. PMID- 29251098 TI - Certain Basketball Injuries. PMID- 29251099 TI - Blood Doping - Does It Really Help Athletes? PMID- 29251100 TI - Hockey Injuries: How, Why, Where, and When? PMID- 29251101 TI - lockerroom. PMID- 29251102 TI - letters. PMID- 29251104 TI - editor's notes. PMID- 29251103 TI - Racquetball: Long on Exercise, Short on Time. PMID- 29251105 TI - Orthotic Foot Control and the Overuse Syndrome. PMID- 29251106 TI - The Sportsman's Kidney. PMID- 29251107 TI - Multicenter Assessment of Animal-free Collagenase AF-1 for Human Islet Isolation. AB - Animal-free (AF) SERVA Collagenase AF-1 and Neutral Protease (NP) AF GMP Grade have recently become available for human islet isolation. This report describes the initial experiences of 3 different islet transplant centers. Thirty-four human pancreases were digested using 1 vial of the 6 different lots of Collagenase AF-1 (2,000-2,583 PZ-U/vial) supplemented with 4 different lots of NP AF in a range of 50 to 160 DMC-U per pancreas. Isolation, culture, and quality assessment were performed using standard techniques as previously described. All data are presented as mean +/- standard error of the mean (SEM). Variability of pancreas weight was associated with a wide range of collagenase and NP activities, ranging from 12.7 to 46.6 PZ-U/g (26.0 +/- 1.5 PZ-U/g) and 0.4 to 3.0 DMC-U/g (1.5 +/- 0.1 DMC-U/g), respectively. Postpurification islet yield was 296,494 +/- 33,620 islet equivalents (IEQ) equivalent to 3,274 +/- 450 IEQ/g with a purity of 55.9% +/- 3.2%. Quality assessment performed after 2 to 4 d of culture demonstrated a viability of 88.1% +/- 1.5% and a stimulation index of 3.7 +/- 0.7. Eighteen of the 34 preparations were transplanted into type 1 diabetic patients equivalent to a transplantation rate of 52.9%. Six preparations, which were infused into patients as first transplant, could be analyzed and increased the fasting C-peptide level from 0.11 +/- 0.08 pretransplant to 1.23 +/- 0.24 and 2.27 +/- 0.31 ng/mL 3 and 6 mo posttransplant ( P < 0.05), respectively. Insulin requirements were simultaneously reduced at the same time from 39.2 +/- 3.8 IU/d before transplantation to 10.8 +/- 4.1 and 4.0 +/- 2.3 IU/d, after 3 and 6 mo posttransplant ( P < 0.05), respectively. This study demonstrates the efficiency of AF SERVA Collagenase AF-1 and NP AF for clinical islet isolation and transplantation. The new plant-based production process makes these products a safe new option for the islet field. PMID- 29251108 TI - Sertoli Cells Loaded with Doxorubicin in Lipid Micelles Reduced Tumor Burden and Dox-Induced Toxicity. AB - The toxic side effects of doxorubicin (Dox) limit its long-term use as a lung cancer chemotherapeutic. Additionally, drug delivery to the deep lung is challenging. To address these challenges, isolated rat Sertoli cells (SCs) were preloaded with Dox conjugated to lipid micelle nanoparticles (SC-DLMNs) and delivered to mouse lungs. These immunocompetent cells, when injected intravenously, travel to the lung, deliver the payload, and get cleared by the system quickly without causing any adverse reaction. We observed that SC-DLMNs effectively treated Lewis lung carcinoma 1-induced lung tumors in mice and the drug efficacy was comparable to SC-Dox treatment. Mice treated with SC-DLMNs also showed significantly less toxicity compared to those treated with SC-Dox. The encapsulation of Dox in lipid micelle nanoparticles reduced the toxicity of Dox and the SC-based delivery method ensured drug delivery to the deep lung without evoking any immune response. Taken together, these results provide a novel SC based nanoparticle drug delivery method for improved therapeutic outcome of cardiotoxic antilung cancer drugs. PMID- 29251109 TI - Human Olfactory Ensheathing Cell Transplantation Improves Motor Function in a Mouse Model of Type 3 Spinocerebellar Ataxia. AB - Spinocerebellar ataxia (SCA) is a progressive neurodegenerative disease that affects the cerebellum and spinal cord. Among the 40 types of SCA, SCA type 3 (SCA3), also referred to as Machado-Joseph disease, is the most common. In the present study, we investigated the therapeutic effects of intracranial transplantation of human olfactory ensheathing cells (hOECs) in the ATXN3-84Q mouse model of SCA3. Motor function begins to decline in ATXN3-84Q transgenic mice at approximately 13 weeks of age. ATXN3-84Q mice that received intracranial hOEC transplantation into the dorsal raphe nucleus of the brain exhibited significant improvements in motor function, as measured by the rotarod performance test and footprint pattern analysis. In addition, intracranial hOEC transplantation alleviated cerebellar inflammation, prohibited Purkinje cells from dying, and enhanced the neuroplasticity of cerebellar Purkinje cells. The protein levels of tryptophan hydroxylase 2, the rate-limiting enzyme for serotonin synthesis in the cerebellum, and ryanodine receptor (RYR) increased in mice that received intracranial hOEC transplantation. Because both serotonin and RYR can enhance Purkinje cell maturation, these effects may account for the therapeutic benefits mediated by intracranial hOEC transplantation in SCA3 mice. These results indicate that intracranial hOEC transplantation has potential value as a novel strategy for treating SCA3. PMID- 29251110 TI - Aortic Graft at Coronary Artery Bypass Surgery as a Source of Human Aortic Smooth Muscle Cells. AB - One of the serious obstacles of the aortopathies research is a considerable shortage of human aortic smooth muscle cells (SMCs), which can be used to model the disease. SMC in most cases come from the whole aorta of transplant donors, which are rather difficult to access. In the course of coronary artery bypass graft (CABG) surgery, a fragment of aortic tissue is excised to make a bypass root. In this study, we show a possibility to use CABG leftover fragments of thoracic aorta as a source of human SMC for in vitro research. We isolated SMC from the fragments of aortic tissues obtained during CABG procedure and compared these cells to the cells that were isolated from aortic tissue of transplant donors. The content of key SMC contractile markers (SMA, SM22alpha, and vimentin) as well as proliferation and migration rates, metalloproteases MMP-2 and MMP-9 activities were similar in CABG-derived SMC and in transplant donor-derived SMC. In conclusion, leftovers of ascending thoracic aorta obtained during CABG can be used as a source of human aortic SMCs for in vitro research. PMID- 29251111 TI - Fully Dedifferentiated Chondrocytes Expanded in Specific Mesenchymal Stem Cell Growth Medium with FGF2 Obtains Mesenchymal Stem Cell Phenotype In Vitro but Retains Chondrocyte Phenotype In Vivo. AB - Given recent progress in regenerative medicine, we need a means to expand chondrocytes in quantity without losing their regenerative capability. Although many reports have shown that growth factor supplementation can have beneficial effects, the use of growth factor-supplemented basal media has widespread effect on the characteristics of chondrocytes. Chondrocytes were in vitro cultured in the 2 most widely used chondrocyte growth media, conventional chondrocyte culture medium and mesenchymal stem cell (MSC) culture medium, both with and without fibroblast growth factor-2 (FGF2) supplementation. Their expansion rates, expressions of extracellular matrix-related factors, senescence, and differentiation potentials were examined in vitro and in vivo. Our results revealed that chondrocytes quickly dedifferentiated during expansion in all tested media, as assessed by the loss of type II collagen expression. The 2 basal media (chondrocyte culture medium vs. MSC culture medium) were associated with distinct differences in cell senescence. Consistent with the literature, FGF2 was associated with accelerated dedifferentiation during expansion culture and superior redifferentiation upon induction. However, chondrocytes expanded in FGF2 containing conventional chondrocyte culture medium showed MSC-like features, as indicated by their ability to direct ectopic bone formation and cartilage formation. In contrast, chondrocytes cultured in FGF2-supplemented MSC culture medium showed potent chondrogenesis and almost no bone formation. The present findings show that the chosen basal medium can exert profound effects on the characteristics and activity of in vitro-expanded chondrocytes and indicate that right growth factor/medium combination can help chondrocytes retain a high-level chondrogenic potential without undergoing hypertrophic transition. PMID- 29251112 TI - In Vivo Long-Term Tracking of Neural Stem Cells Transplanted into an Acute Ischemic Stroke model with Reporter Gene-Based Bimodal MR and Optical Imaging. AB - Transplantation of neural stem cells (NSCs) is emerging as a new therapeutic approach for stroke. Real-time imaging of transplanted NSCs is essential for successful cell delivery, safety monitoring, tracking cell fate and function, and understanding the interactions of transplanted cells with the host environment. Magnetic resonance imaging (MRI) of magnetic nanoparticle-labeled cells has been the most widely used means to track stem cells in vivo. Nevertheless, it does not allow for the reliable discrimination between live and dead cells. Reporter gene based MRI was considered as an alternative strategy to overcome this shortcoming. In this work, a class of lentiviral vector-encoding ferritin heavy chain (FTH) and enhanced green fluorescent protein (EGFP) was constructed to deliver reporter genes into NSCs. After these transgenic NSCs were transplanted into the contralateral hemisphere of rats with acute ischemic stroke, MRI and fluorescence imaging (FLI) were performed in vivo for tracking the fate of transplanted cells over a long period of 6 wk. The results demonstrated that the FTH and EGFP can be effectively and safely delivered to NSCs via the designed lentiviral vector. The distribution and migration of grafted stem cells could be monitored by bimodal MRI and FLI. FTH can be used as a robust MRI reporter for reliable reporting of the short-term viability of cell grafts, whereas its capacity for tracking the long-term viability of stem cells remains dependent on several confounding factors such as cell death and the concomitant reactive inflammation. PMID- 29251113 TI - Microarray Expression Profile of lncRNAs and mRNAs in Rats with Traumatic Brain Injury after A2B5+ Cell Transplantation. AB - Traumatic brain injury (TBI) may cause neurological damage, but an effective therapy and the associated mechanisms of action have not yet been elucidated. A TBI model was established using the modified Feeney method. A2B5+ cells, an oligodendroglial progenitor, were acquired from induced pluripotent stem cells (iPSCs) by mouse embryonic fibroblasts and were transplanted into the injured site. The neurological severity score (NSS) was recorded on 3 d, 7 d, 11 d, 15 d, and 19 d. Seven days after transplantation, oligodendrocytes 2 (Olig2) and myelin basic protein (MBP) were detected by immunohistochemistry (IHC) and Western blot (WB), and long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) were screened by microarray technology. Moreover, we took an intersection of the differentially expressed lncRNAs or mRNAs and scanned 10 kb upstream and downstream of the common lncRNAs. Meanwhile, Gene Ontology (GO) and pathway analysis on mRNAs was performed in the A2B5+ iPSC group. A2B5+ iPSCs survived and migrated around the injury site and differentiated into oligodendrocytes. Meanwhile, the increase in Olig2 and MBP were higher in A2B5+ cell-engrafted rats than that in TBI rats. However, the NSSs in the A2B5+ iPSC group were lower than that in the TBI group. Between the TBI and sham groups, 270 lncRNAs and 1,052 mRNAs were differently expressed ( P < 0.05, fold change (FC) > 2), while between the A2B5+ iPSC and TBI groups, 83 lncRNAs and 360 mRNAs were differently expressed ( P < 0.05, FC > 2). Meanwhile, 37 lncRNAs and 195 mRNAs were simultaneously changed in the 2 parts. Using bioinformatic analysis, we found the crucial lncRNA and mRNA were ENSRNOT00000052577 and Kif2c in the TBI brain with cell transplantation. This study demonstrated that A2B5+ iPSC grafts effectively improved neurological function, and the mechanism of action was associated with lncRNA and mRNA expression. Therefore, A2B5+ iPSC transplantation could be considered as a new method for the treatment of TBI, and ENSRNOT00000052577 and Kif2c may be new molecular targets or markers for functional improvement. PMID- 29251116 TI - Welcome to Future Medicinal Chemistry volume 10. PMID- 29251117 TI - The era of GWAS is over - No. PMID- 29251115 TI - Nano-Encapsulation of Bilirubin in Pluronic F127-Chitosan Improves Uptake in beta Cells and Increases Islet Viability and Function after Hypoxic Stress. AB - Pancreatic islet transplantation is the only curative, noninvasive treatment for type 1 diabetes mellitus; however, high rates of cell death in the immediate postimplantation period have limited the success of this procedure. Bilirubin, an endogenous antioxidant, can improve the survival of murine pancreatic allografts during hypoxic stress but has poor solubility in aqueous solutions. We hypothesized that nano-encapsulation of bilirubin in pluronic 127-chitosan nanoparticle bilirubin (nBR) would improve uptake by murine pancreatic islet cells and improve their viability following hypoxic stress. Nano-bilirubin was synthesized, and drug release characteristics were studied in vitro. Cellular uptake of nBR was compared to free bilirubin (fBR) in an insulinoma cell line (INS-R3) model using confocal-like structured illumination microscopy. Next, C57BL/6 mouse islets were treated with concentrations of 0 to 20 MUM of nBR, fBR, or empty nanoparticle (eNP), prior to incubation under standard or hypoxic conditions. Islet viability and function were compared between treatment groups. Release of bilirubin was greatest from nBR suspended in protein-rich solution. Increased, selective uptake of nBR by INS-R3 cells was demonstrated. Cell death after hypoxic stress was significantly decreased in murine islets treated with 5 MUM nBR (18.5% +/- 14.1) compared to untreated islets (33.5% +/- 17.5%; P = 0.019), with reduction in central necrosis. Treatment group had a significant effect on glucose stimulation index [SI], ( P = 0.0137) and islets treated with 5 MUM nBR had the highest SI overall. Delivery of bilirubin using pluronic F127 chitosan NP improves uptake by murine islets compared to fBR and offers dose dependent protective effects following hypoxic stress. PMID- 29251118 TI - Neurosymptomatic cerebrospinal fluid escape in HIV-2: a case report. AB - Cerebrospinal fluid (CSF) escape phenomenon is widely studied and documented in HIV-1. However, hardly anything is known about progressive neurologic disease in otherwise well-controlled HIV-2 infection. We present a case of neurosymptomatic CSF escape in HIV-2 infection from India. PMID- 29251114 TI - S-allylcysteine Improves Blood Flow Recovery and Prevents Ischemic Injury by Augmenting Neovasculogenesis. AB - Studies suggest that a low level of circulating human endothelial progenitor cells (EPCs) is a risk factor for ischemic injury and coronary artery disease (CAD). Consumption of S-allylcysteine (SAC) is known to prevent CAD. However, the protective effects of SAC on the ischemic injury are not yet clear. In this study, we examined whether SAC could improve blood flow recovery in ischemic tissues through EPC-mediated neovasculogenesis. The results demonstrate that SAC significantly enhances the neovasculogenesis of EPCs in vitro. The molecular mechanisms for SAC enhancement of neovasculogenesis include the activation of Akt/endothelial nitric oxide synthase signaling cascades. SAC increased the expression of c-kit, beta-catenin, cyclin D1, and Cyclin-dependent kinase 4 (CDK4) proteins in EPCs. Daily intake of SAC at dosages of 0.2 and 2 mg/kg body weight significantly enhanced c-kit protein levels in vivo. We conclude that dietary consumption of SAC improves blood flow recovery and prevents ischemic injury by inducing neovasculogenesis in experimental models. PMID- 29251120 TI - Sportsview. PMID- 29251121 TI - Fencing: Conversations in Steel. PMID- 29251119 TI - Association of TNF-alpha rs1799964 and IL-1beta rs16944 polymorphisms with multiple system atrophy in Chinese Han population. AB - BACKGROUND: Recent evidence suggested that several single nucleotide polymorphisms (SNPs) of inflammation-related genes (TNF-alpha rs1799964, IL 1alpha rs1800587, IL-1beta rs16944, IL-8 rs4073, ICAM-1 rs5498) were associated with multiple system atrophy (MSA). Herein, we conducted this case-control study to evaluate the possible correlation between the five SNPs related to inflammation and MSA in Chinese Han population. METHODS AND PATIENTS: We recruited 154 sporadic patients with MSA and 223 health controls in this study. All subjects were genotyped for the five SNPs using polymerase chain reaction amplification and Sanger sequencing. RESULTS: TNF-alpha rs1799964, genotype distribution and minor allele frequency (MAF) showed significant differences between patients and controls, which might illustrate the minor allele C may increase the risk for MSA (genotype, P = 0.006, OR = 1.245, 95% CI = [1.066 1.455]; allele, P = 0.001, OR = 1.887, 95% CI = [1.303-2.733]). For rs16944, patients carrying AA genotype showed a nearly 5-year early age at onset (AAO) than GG genotype (50.52 +/- 7.45 years vs. 54.90 +/- 7.21 years, P = 0.037). No differences were found in genotype distribution and MAF of the five SNPs between patients with MSA with predominant cerebellar ataxia (MSA-C) and with predominant Parkinsonism (MSA-P). CONCLUSION: Our study suggests that rs1799964 of TNF-alpha may act as a risk factor for MSA and the IL-1beta rs16944 might be a genetic factor that modifies the AAO in MSA. Moreover, the exact mechanism of neuroinflammatory response in MSA deserves further exploration. PMID- 29251122 TI - Throwing or Swinging, the Shoulder Pays. PMID- 29251123 TI - Exercise: The New Miracle Drug. PMID- 29251124 TI - Changing Patterns in Ski Injuries. PMID- 29251125 TI - Muscular Strength and the Knee. PMID- 29251126 TI - Are Ski Injuries Decreasing? PMID- 29251127 TI - Fencing - A Sport for All Ages. PMID- 29251128 TI - letters. PMID- 29251129 TI - World at play. PMID- 29251130 TI - Immediate Management of Soft Tissue Tear. PMID- 29251131 TI - When Skates Are Too Tight. PMID- 29251132 TI - Case History: Baltimore Orioleosis. PMID- 29251133 TI - Sportspages. PMID- 29251134 TI - Brain Trauma Inside a Football Helmet. PMID- 29251135 TI - The Preparticipation Physical Examination. PMID- 29251136 TI - When Shoulder Complaints Limit Athletic Performance. PMID- 29251137 TI - Ear and Sinus Barotrauma in Diving. PMID- 29251138 TI - Radiologist Fits Out as Foredeck Hand. PMID- 29251139 TI - Examining the Qualifying Exam. PMID- 29251141 TI - editor's notes. PMID- 29251140 TI - winners and losers. PMID- 29251142 TI - Bicycle Ergometer for Injured Athletes. PMID- 29251143 TI - letters. PMID- 29251145 TI - Men Under the Sea - Shaking the Great Hand of Nature. PMID- 29251144 TI - sportspages. PMID- 29251146 TI - Can Blacks Float? PMID- 29251147 TI - A New Look in Heroes. PMID- 29251148 TI - Aging, Exercise, and Longevity. PMID- 29251149 TI - special report. PMID- 29251150 TI - editor's notes. PMID- 29251151 TI - Does a 'Threshold Age' Cancel Longevity Hopes of Exercisers? PMID- 29251152 TI - Mixing Science and Serves, Youthful AMTA Keeps Growing. PMID- 29251153 TI - Want to Get Into Tennis? Here's How. PMID- 29251154 TI - Weight Training for Adolescents. PMID- 29251155 TI - For Fat Freddy and Typical Tillie: HOPE. PMID- 29251156 TI - Let Me Do My Thing - And You Can Do Yours. PMID- 29251157 TI - Margaret Court: Championships and Children. PMID- 29251158 TI - letters. PMID- 29251160 TI - sportspages. PMID- 29251159 TI - A Top Tennis Vet on Aching Elbows. PMID- 29251161 TI - Which Cardiovascular 'Problems' Should Disqualify Athletes? PMID- 29251163 TI - Round Table: Tennis Elbow: Who's Most Likely to Get It, and How. PMID- 29251162 TI - Coping With Killing Cold. PMID- 29251164 TI - Value of HCC-MELD Score in Patients With Hepatocellular Carcinoma Undergoing Liver Transplantation. AB - CONTEXT: Liver transplantation (LT) is considered the ideal therapy for patients with hepatocellular carcinoma (HCC) having cirrhosis but the shortage of liver donors and the risk of dropout from the wait list due to tumor progression severely limit transplantation. A new prognostic score, the HCC-model for end stage liver disease (HCC-MELD), was developed by combining alpha-fetoprotein (AFP), MELD, and tumor size, to improve risk stratification of dropout in patients with HCC. OBJECTIVES: In this study, we investigated the ability of the HCC-MELD score in predicting the posttransplant for patients fulfilling Milan criteria (MC). DESIGN: Two hundred patients with stage II tumor were retrospectively reviewed from a total of 1290 transplants performed at our institution from October 1997 through April 2015. Cox regression analysis was performed to identify the prognostic factors impacting the posttransplant survival. RESULTS: Overall survival at 1, 5, and 10 years was 89.3%, 71.1%, and 67.2%, whereas disease-free survival was 86.4%, 66.5%, and 52.4%, respectively. Multivariate analysis showed HCC-MELD score (hazard ratio [HR] 39.6, P < .001) and microvascular invasion (HR 2.41, P = .002) to be independent risk factors for recurrence, whereas HCC diameter (HR 1.15, P = .041), HCC-MELD (HR 15.611, P = .006), and grading (HR 2.17, P = .03) proved to be predictive factors of poor overall survival. CONCLUSION: Our study showed the validity of the HCC-MELD equation in the evaluation of patients undergoing LT for HCC. This score offers a reliable method to assess the risk of waiting list dropout and predict posttransplantation outcomes. PMID- 29251165 TI - Prostate cancer high dose-rate brachytherapy: review of evidence and current perspectives. AB - INTRODUCTION: Patients with intermediate to high risk disease (prostate specific antigen (PSA) >= 10, Gleason score >= 7, or clinical stage >= T2b) suffer from poorer long-term biochemical control (freedom from an increasing prostate specific antigen level) when treated with external beam radiation (EBRT) alone. In order to improve biochemical control while limiting long-term complications, brachytherapy has been incorporated into radiotherapy treatment, either alone or in combination with EBRT. Areas covered: Current literature regarding the use of high dose-rate (HDR) brachytherapy for localized prostate cancer, including as a boost and monotherapy. The efficacy and toxicities of various approaches are evaluated including comparisons to low dose-rate (LDR) brachytherapy. Expert commentary: Prostate HDR brachytherapy has higher conformality than EBRT, potentially improving the therapeutic ratio by allowing higher doses per fraction to tumor cells. The improved biochemical control shown in trials have resulted in EBRT plus brachytherapy to be included as a standard treatment option supported by the NCCN and ASCO guidance documents for intermediate to high risk prostate cancer. PMID- 29251166 TI - Expression of multiple leukemic stem cell markers is associated with poor prognosis in de novo acute myeloid leukemia. AB - Leukemic stem cells (LSCs) play a crucial role in chemotherapy resistance in acute myeloid leukemia (AML). Although the association between the expression of individual LSC markers and poor prognosis has been reported, few studies have evaluated the prognostic effect of multiple LSC markers in patients with AML. Herein, we examined three LSC markers (CD25, CD96, and CD123) and the combined effect of their expression on clinical outcome. We retrospectively analyzed 80 adult patients with de novo AML who received intensive chemotherapy. Multiple LSC marker expression was significantly associated with shorter three-year overall survival (OS), compared with single or no LSC marker expression (18.2 vs. 65.0%, p < .001). Multivariate analysis showed that the expression of multiple LSC markers remained significant in terms of three-year OS (hazard ratio: 3.80, p = .001). Therefore, the combined evaluation of several LSC markers can predict the clinical outcome in patients with AML. PMID- 29251167 TI - Influence of conformity on the wear of total knee replacement: An experimental study. AB - Wear of total knee replacement continues to be a significant factor influencing the clinical longevity of implants. Historically, failure due to delamination and fatigue directed design towards more conforming inserts to reduce contact stress. As new generations of more oxidatively stable polyethylene have been developed, more flexibility in bearing design has been introduced. The aim of this study was to investigate the effect of insert conformity on the wear performance of a fixed bearing total knee replacement through experimental simulation. Two geometries of insert were studied under standard gait conditions. There was a significant reduction in wear with reducing implant conformity. This study has demonstrated that bearing conformity has a significant impact on the wear performance of a fixed bearing total knee replacement, providing opportunities to improve clinical performance through enhanced material and design selection. PMID- 29251168 TI - Lateral collapse of the tarsal navicular in patients with rheumatoid arthritis: Implications for pes planovarus deformity. AB - OBJECTIVES: In patients with rheumatoid arthritis (RA), the talonavicular joint is commonly involved and midfoot collapse can lead to progressive flattening of the arch. Despite a general awareness of the important structural role of the talonavicular joint in rheumatoid foot disease, details of its destructive pattern have not been elucidated. METHODS: We cross-sectionally investigated 176 RA patients (342 feet) and classified their feet into the following five groups according to radiographic findings: arthritis (RA changes with normal navicular shape), Muller-Weiss Disease (MWD) (collapse of the lateral aspect of the tarsal navicular), flat (flattened navicular), ankylosis (ankylosis of the talonavicular joint), and normal. We compared medical histories and radiographic measurements among all five groups. RESULTS: The arthritis group comprised 91 feet, 36 in the MWD group, nine in the flat group, 12 in the ankylosis group, and 194 classified as normal. The MWD group demonstrated a trend towards pes planovarus deformity in contrast to pes planovalgus deformity in the arthritis group. Corticosteroid use and the mean daily dosage were the highest in the MWD group. CONCLUSIONS: This report revealed a high prevalence of MWD-like changes to the navicular in RA patients and its association with pes planovarus deformity and corticosteroid usage. PMID- 29251169 TI - Prevalence of functional gastrointestinal disorders in adults with systemic lupus erythematosus. AB - Objective (a) to assess the prevalence of functional gastrointestinal disorders (FGIDs) in female Mexican systemic lupus erythematosus (SLE) patients using the Rome III criteria and (b) to examine the effect of disease duration on FGID prevalence. Methods Female SLE outpatients aged >=18 years with no organic gastrointestinal disorder were included. Participants were invited to upper gastrointestinal endoscopy screening and a faecal immunochemical test. FGID symptoms were evaluated using the Rome III questionnaire. Results Eighty-six SLE patients with median age of 45 (interquartile range 34-54) years were included. At least one FGID was found in 76.7% (66/88) of patients with SLE. The most prevalent domains of FGID diagnosed were functional oesophageal, gastroduodenal disorders and bowel disorders, of which functional dyspepsia (72.7%), functional heartburn (68.1%) and bloating (63.8%) were the most frequent. Fifty-nine per cent of patients had overlapping FGIDs. The most prevalent overlap was the combination of functional dyspepsia and functional heartburn. Patients with longer disease duration had a higher prevalence of FGID than those with shorter disease duration. Conclusions There was a high prevalence of FGIDs in Mexican SLE women with low disease activity. Overlapping FGIDs were frequent. Longer disease duration may be associated with FGIDs in SLE patients. PMID- 29251170 TI - Coxiella burnetii infection (Q fever) mimicking systemic lupus erythematosus: two cases. AB - Q fever has extremely polymorphic features, and has been reported to be associated with positivity of several autoimmune antibodies. We report two cases of atypical Q fever with a clinical presentation highly suggestive of an inflammatory systemic disease with positivity of autoimmune antibodies, mimicking systemic lupus erythematosus. PMID- 29251171 TI - Predictors of disability in a childhood-onset systemic lupus erythematosus cohort: results from the CARRA Legacy Registry. AB - Objective Few descriptions of physical disability in childhood-onset SLE (cSLE) exist. We sought to describe disability in a large North American cohort of patients with cSLE and identify predictors of disability. Methods Sociodemographic and clinical data were obtained from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry for patients with cSLE enrolled between May 2010 and October 2014. The Childhood Health Assessment Questionnaire (CHAQ) was used to assess disability and physical functioning. Chi square tests were used for univariate analyses, and multivariate logistic regression was used to assess predictors of disability. Results We analyzed data for 939 patients with cSLE. The median and mean CHAQ scores were 0 and 0.25, respectively, and 41% of the cohort had at least mild disability. Arthritis and higher pain scores were significantly associated with disability as compared to those without disability ( p < 0.001). In multivariate logistic regression analysis, low annual income, arthritis, and higher pain scores were associated with disability at baseline. Conclusions Disability as measured by baseline CHAQ was fairly common in cSLE patients in the CARRA Legacy Registry, and was associated with low household income, arthritis, and higher pain scores. In addition to optimal disease control, ensuring psychosocial supports and addressing pain may reduce disability in cSLE. Further study is needed of disability in cSLE. PMID- 29251172 TI - A method of gene expression data transfer from cell lines to cancer patients for machine-learning prediction of drug efficiency. AB - Personalized medicine implies that distinct treatment methods are prescribed to individual patients according several features that may be obtained from, e.g., gene expression profile. The majority of machine learning methods suffer from the deficiency of preceding cases, i.e. the gene expression data on patients combined with the confirmed outcome of known treatment methods. At the same time, there exist thousands of various cell lines that were treated with hundreds of anti cancer drugs in order to check the ability of these drugs to stop the cell proliferation, and all these cell line cultures were profiled in terms of their gene expression. Here we present a new approach in machine learning, which can predict clinical efficiency of anti-cancer drugs for individual patients by transferring features obtained from the expression-based data from cell lines. The method was validated on three datasets for cancer-like diseases (chronic myeloid leukemia, as well as lung adenocarcinoma and renal carcinoma) treated with targeted drugs - kinase inhibitors, such as imatinib or sorafenib. PMID- 29251173 TI - Plasmatic carbonic anhydrase IX as a diagnostic marker for clear cell renal cell carcinoma. AB - Carbonic anhydrase (CA, EC 4.2.1.1) IX is regarded as a tumour hypoxia marker and CA inhibitors have been proposed as a new class of antitumor agents, with one such agent in Phase II clinical trials. The expression of some CAs, in particular the isoforms CA IX and CA XII, has been correlated with tumour aggressiveness and progression in several cancers. The aim of this study was to evaluate the possibility that CA IX could represent a marker related to clear cell Renal Cell Carcinoma (ccRCC). Bcl-2 and Bax, and the activity of caspase-3, evaluated in tissue biopsies from patients, were congruent with resistance to apoptosis in ccRCCs with respect to healthy controls, respectively. In the same samples, the CA IX and pro-angiogenic factor VEGF expressions revealed that both these hypoxia responsive proteins were strongly increased in ccRCC with respect to controls. CA IX plasma concentration and CA activity were assessed in healthy volunteers and patients with benign kidney tumours and ccRCCs. CA IX expression levels were found strongly increased only in plasma from ccRCC subjects, whereas, CA activity was found similarly increased both in plasma from ccRCC and benign tumour patients, compared to healthy volunteers. These results show that the plasmatic level of CA IX, but not the CA total activity, can be considered a diagnostic marker of ccRCCs. Furthermore, as many reports exist relating CA IX inhibition to a better outcome to anticancer therapy in ccRCC, plasma levels of CA IX could be also predictive for response to therapy. PMID- 29251174 TI - Reliability and validity of a modified 3-minute all-out swimming test in elite swimmers. AB - Critical speed (CS) testing is useful in monitoring training in swimmers, however, completing a series of time trials (TTs) regularly is time-consuming. The 3-minute test may be a solution with positive initial findings. This investigation examined whether a modified 3-minute test (12 * 25 m) could assess CS and supra-CS distance capacity (D') in swimmers. A series of 12 * 25 m intervals were completed unpaced at maximal effort, interspersed with 5 s rest periods. The model speed = a ebt + c was fitted to the data and integrated to calculate D'. The slowest two of the last four efforts were averaged to calculate CS. To assess reliability, 15 highly trained swimmers (9 females, 6 males) completed the 12 * 25 m twice within 72 h. Four measures were deemed reliable: peak velocity (0.01 m s-1; 0.5%, typical error and % coefficient of variation), CS (0.02 m s-1; 1.2%), D' (1.22 m; 5.7%) and drop off % (0.70% points; 4.5%). To assess criterion validity, 21 swimmers (9 from reliability, 12 other) completed two competition races within 2 weeks of a 12 * 25 m in the same stroke. Traditional CS and D' measures were calculated from competition performances (TT method). TT CS and 12 * 25 m CS were highly correlated (adj. R2 = 0.92, p < .001). D' values were moderately correlated (adj. R2 = 0.60, p < .01). Two TTs may have been too few to estimate D' accurately. The 12 * 25 m all-out swimming test is a reliable method for assessing CS and D' in swimmers, however, the validity of D' requires further investigation. PMID- 29251175 TI - The role of S100A4 protein in anticancer cytotoxicity: its presence is required on the surface of CD4+CD25+PGRPs+S100A4+ lymphocyte and undesirable on the surface of target cells. AB - S100A4 is a Ca2+-binding protein that performs an important role in metastasis. It is also known for its antitumor functions. S100A4 is expressed by a specialized subset of CD4+CD25+ lymphocytes and is present on those cell's membranes along with peptidoglycan recognition proteins (PGRPs). There, by interacting with major heat shock protein Hsp70, S100A4 plays an important cytotoxic role. The resulting stably formed complex of PGRPs, S100A4 and Hsp70 is required for the identification and binding between a lymphocyte and a target cell. Here, we investigated the S100A4 functions in CD4+CD25+PGRPs+S100A4+ lymphocyte cytotoxicity against target cells. We demonstrated that those lymphocytes do not form a stable complex with the tumor target cells that themselves have S1004A on their surface. That observation can be explained by our finding that S100A4 precludes the formation of a stable complex between PGRPs, S100A4 (on the lymphocytes' surface), and Hsp70 (on the target cells' surface). The decrease in S100A4 level in CD4+CD25+PGRPs+S100A4+ lymphocytes inhibits their cytotoxic activity, while the addition of S100A4 in the medium restores it. Thus, the resistance of target cells to CD4+CD25+PGRPs+ S100A4+ lymphocyte cytotoxicity depends on their S100A4 expression level and can be countered by S100A4 antibodies. PMID- 29251176 TI - How and when immersion and distancing are useful in emotion focused therapy for depression. AB - OBJECTIVE: The potential benefit or harm of immersion (egocentric perspective) and distancing (observer perspective) on negative experiences are unclear and have not been empirically investigated in therapy. This is a first exploratory study aimed to analyze and compare the perspectives adopted on reflection (immersion and distancing) of negative experiences across therapy and the relationship between them and depressive symptoms in contrasting therapeutic outcomes of emotion-focused therapy (EFT). METHOD: Three good-outcomes cases and three poor-outcomes cases of EFT, diagnosed with mild to moderate depression at the beginning of therapy, were randomly selected. Immersion and distancing on negative experiences were analyzed using the measure of immersed and distanced speech. The depressive symptoms were assessed by the Beck Depression Inventory II. RESULTS: Significant differences across sessions were only found in the good outcome cases which showed a significant decrease of immersion and an increase of distancing, and this evolution pattern was found related to the reduction of symptoms. Moreover, at the beginning of therapy, distancing was higher in the poor-outcome cases rather than in the good-outcome cases. CONCLUSION: The progressive and significant evolution from higher immersion at the initial phase to higher distancing in the final phase may be helpful in EFT for depression. PMID- 29251177 TI - Co-expression of RelA/p65 and ACTN4 induces apoptosis in non-small lung carcinoma cells. AB - Alpha-actinin 4 (ACTN4) is an actin-binding protein of the spectrin superfamily. ACTN4 is found both in the cytoplasm and nucleus of eukaryotic cells. The main function of cytoplasmic ACTN4 is stabilization of actin filaments and their binding to focal contacts. Nuclear ACTN4 takes part in the regulation of gene expression following by activation of certain transcription factors, but the mechanisms of regulation are not completely understood. Our previous studies have demonstrated the interaction of ACTN4 with the RelA/p65 subunit of NF-kappaB factor and the effect on its transcriptional activity in A431 and HEK293T cells. In the present work, we investigated changes in the composition of nuclear ACTN4 interacting proteins in non-small cell lung cancer cells H1299 upon stable RELA overexpression. We showed that ACTN4 was present in the nuclei of H1299 cells, regardless of the RELA expression level. The presence of ectopic RelA/p65 in H1299 cells increased the number of proteins interacting with nuclear ACTN4. Stable expression of RELA in these cells suppressed cell proliferation, which was further affected by simultaneous ACTN4 overexpression. We detected no significant effect on cell cycle but the apoptosis rate was increased in cells with a double RELA/ACTN4 overexpression. Interestingly, when expressed individually ACTN4 promoted proliferation of lung cancer cells. Furthermore, the bioinformatics analysis of gene expression in lung cancer patients suggested that overexpression of ACTN4 correlated with poor survival prognosis. We hypothesize that the effect of RELA on proliferation and apoptosis of H1299 cells can be mediated via affecting the interactome of ACTN4. PMID- 29251178 TI - Putamen Volume Differences Among Older Adults: Depression Status, Melancholia, and Age. AB - BACKGROUND: Individuals with major depressive disorder (MDD) may exhibit smaller striatal volumes reflecting deficits in the reward circuit. Deficits may change with age and be more pronounced among the melancholic subtype. Limited research has investigated striatal volume differences in older adults and by depression subtypes. METHOD: We used baseline data from the Neurocognitive Outcomes of Depression in the Elderly study. We examined volumetric differences in the putamen and caudate nucleus among older adults (60 years and older), comparing healthy control participants (n = 134) to depressed participants (n = 226), and comparing nonmelancholic depressed participants (n = 93) to melancholic depressed participants (n = 133). Group-by-age interactions were examined. RESULTS: There were no significant group differences for the caudate nucleus. For the left putamen, investigation of the significant group-by-age interaction revealed that volume size was greater for the healthy controls compared to the depressed participants but only at younger ages (60-65 years); group differences diminished with increasing age. Examining volume by depression subtype revealed that the melancholic depressed participants had a smaller left putamen compared to the nonmelancholic depressed participants. Anhedonia symptoms were related to both smaller left and right putamen. CONCLUSION: Structural abnormalities in reward regions may underlie the anhedonic phenotype. Volume loss associated with MDD may attenuate in older age. PMID- 29251179 TI - Testamentary Capacity Assessment: Legal, Medical, and Neuropsychological Issues. AB - INTRODUCTION: The increase in the aging population and the number of patients with dementia led to the research in older adults' capacity assessment over the last 3 decades. Many cases of contested wills occur due to lack of testamentary capacity (TC), especially in cases of dementia. AIM: Purpose of the present study was to overview the legal, medical, and neuropsychological aspects of TC as well as the instruments used for TC assessment. FINDINGS: The testator/testatrix with intact TC has realistic perception of his or her property value, lack of psychopathology affecting contact with reality, and intact intention of how and to whom he or she will dispose his or her assets. It is frequent for the health practitioners to serve as "gold standards assessors" by examining an individual's ability to make a valid will and giving evidence to the court to support or not a will contest. The TC assessment is a complex process of clinical and legal practice requiring usually a variety of methods, that is, interviews, evaluation of clinical records, and administration of neuropsychological instruments. CONCLUSION: The evaluation of TC is a multidimensional process that integrates both the legal and medical field, requiring a collaborative approach to its definition and assessment. PMID- 29251180 TI - Maternal steroid therapy for fetuses with immune-mediated complete atrioventricular block: a systematic review and meta-analysis. AB - INTRODUCTION: To explore the effect of maternal fluorinated steroid therapy on fetuses affected by immune-mediated complete atrio-ventricular block (CAVB) in utero. MATERIAL AND METHODS: Pubmed, Embase, Cinahl, and ClinicalTrials.gov databases were searched. Only studies reporting the outcome of fetuses with immune CAVB diagnosed on prenatal ultrasound without any cardiac malformations and treated with fluorinated steroids compared to those not treated were included. The primary outcome observed was the regression of CAVB; secondary outcomes were need for pacemaker insertion, overall mortality, defined as the occurrence of either intrauterine (IUD) or neonatal (NND) death, IUD, NND, termination of pregnancy (TOP). Furthermore, we assessed the occurrence of all these outcomes in hydropic fetuses compared to those without hydrops at diagnosis. Meta-analyses of proportions using random effect model and meta analyses using individual data random-effect logistic regression were used to combine data. RESULTS: Eight studies (162 fetuses) were included. The rate of regression was 3.0% (95%CI 0.2-9.1) in fetuses treated and 4.3% (95%CI 0.4-11.8) in those not treated, with no difference between the two groups (odds ratio (OR): 0.9, 95%CI 0.1-15.1). Pacemaker at birth was required in 71.5% (95%CI 56.0-84.7) of fetuses-treated and 57.8% (95%CI 40.3-74.3) of those not treated (OR: 9, 95%CI 0.4-3.4). There was no difference in the overall mortality rate (OR: 0.5, 95%CI 0.9-2.7) between the two groups; in hydropic fetuses, mortality occurred in 76.2% (95%CI 48.0-95.5) of the treated and in 23.8% (95%CI 1.2-62.3) of the untreated group, while in those without hydrops the corresponding figures were 8.9% (95%CI 2.0-20.3) and 12% (95%CI 8.7-42.2), respectively. Improvement or resolution of hydrops during pregnancy occurred in 76.2% (95%CI 48.0-95.5) of cases treated and in 23.3% (95%CI 1.2-62.3) of those nontreated with fluorinated steroids. CONCLUSIONS: The findings from this systematic review do not suggest a potential positive contribution of antenatal steroid therapy in improving the outcome of fetuses with immune CAVB. PMID- 29251181 TI - Assessment of geriatric predictors of adherence to Zoledronic acid treatment for osteoporosis: a prospective follow-up study. AB - Objectives Discontinuation of bisphosphonate treatment remains high even with the long acting parenteral options. Whether there are some unidentified causes of noncompliance more specific to aged individuals is unknown. The aim of this study was to investigate baseline predictors of adherence to Zoledronic acid (ZOL) infusions among non-demented older adults with osteoporosis. Methods Patients aged >= 65 years who received a first ever ZOL infusion for osteoporosis were prospectively enrolled. Risk factors for osteoporosis and fractures, comorbidities, geriatric assessment measures, including depression, and anticholinergic burden were determined at baseline. Adherence was defined as taking the next ZOL infusion at 12 months. Results A total of 187 participants were included (mean age: 75.7 +/- 6.3 years, female: 77.5%). Adherence to the next ZOL infusion was 66.8% (n = 125). Non-adherent participants (n = 62, 33.2%) had significantly higher frequency of historical height decrease and depression at baseline. Poor adherence was associated with height decrease, presence of depression, and higher anticholinergic burden in univariate analysis. After adjustment for relevant confounders, fragility fracture history (OR: 0.38, 95%CI: 0.17-0.86, p = 0.020), depression (OR: 0.32, 95%CI: 0.12-0.82, p = 0.018), and higher anticholinergic burden (OR: 0.67, 95%CI: 0.49-0.93, p = 0.017) were the predictors of lower adherence to ZOL infusion. Conclusions The rate of adherence to the next ZOL infusion was still suboptimal among older women and men in this study. Past osteoporotic fractures, depression, and higher anticholinergic drug burden predicted poor ZOL adherence. It was a novel finding that drug-related anticholinergic side effects adversely influenced adherence to another medication without anticholinergic properties. PMID- 29251182 TI - Comparison of labour induction with misoprostol and dinoprostone and characterization of uterine response based on electrohysterogram. AB - OBJECTIVE: The objective of this study is to compare the uterine activity response between women administered dinoprostone (prostaglandin E2) and misoprostol (prostaglandin E1) for induction of labour (IOL) by analysing not only the traditional obstetric data but also the parameters extracted from uterine electrohysterogram (EHG). METHODS: Two cohorts were defined: misoprostol (25-ug vaginal tablets; 251 women) and dinoprostone cohort (10 mg vaginal inserts; 249 women). All the mothers were induced by a medical indication of a Bishop Score < = 6. RESULTS: The misoprostol cohort was associated with a shorter time to achieve active labour (p = .017) and vaginal delivery (p = .009) and with a higher percentage of vaginal delivery in less than 24 h in mothers with a very unfavourable cervix score (risk ratio (RR): 1.41, IC95% 1.17-1.69, p = .002). Successful inductions with misoprostol showed EHG parameter values significantly higher than basal state for amplitude and pseudo Montevideo units (PMU) 60' after drug administration, while spectral parameters significantly increased after 150'. This response was not observed in failed inductions. In the successful dinoprostone group, the duration and number of contractions increased significantly after 120', PMU did so after 180', and no significant differences were found for spectral parameters, possibly due to the slower pharmacokinetics of this drug. CONCLUSION: Successful inductions of labour by misoprostol are associated with earlier effective contractions than in labours induced by dinoprostone. PMID- 29251183 TI - The era of GWAS is over - Commentary. PMID- 29251184 TI - Influence of spontaneous fetal reduction on dichorionic diamniotic twin pregnancy outcomes after in vitro fertilization: a large-sample retrospective study. AB - OBJECTIVE: To examine the incidence of spontaneous fetal reduction during dichorionic diamniotic (DCDA) twin pregnancy after in vitro fertilization and embryo transfer (IVF-ET) and its influence on pregnancy outcomes. METHODS: This was a retrospective cohort study of 4447 DCDA twin pregnancies and 14,551 singleton pregnancies after IVF-ET at a single center between 2009 and 2015. The spontaneous pregnancy reduction (SPR) group included 759 women. The remaining 3688 women with DCDA twins showing no spontaneous reduction were included in the non-SPR group. Outcomes were compared to a singleton group (n = 14,551) treated over the same period. The overall rate of spontaneous reduction and frequency distribution across gestational epochs were determined and pregnancy outcomes were compared among the three groups. Further regression analysis was conducted to investigate whether spontaneous reduction was an independent risk factor for decreased take-home baby rate. RESULTS: The overall rate of spontaneous DCDA twin reduction after IVF-ET was 17.1%, with most cases (89.8%) occurring in the first trimester. Pregnancy outcome measures, including miscarriage rate, premature delivery rate, live birth rate, take-home baby rate, gestational age of delivery, and neonatal birth weight, were significantly better in the SPR group than the non-SPR group. Live birth rate, take-home baby rate, neonatal birth weight, and other primary outcome measures in the SPR group were not inferior to the singleton group. Multivariate regression analysis showed that the take-home baby rate was significantly lower in the non-SPR group (OR =0.73, 95%CI: 0.44-0.92, p = .008) and that SPR did not decrease the take-home baby rate. CONCLUSIONS: Spontaneous pregnancy reduction is common in DCDA twin pregnancy after IVF-ET, but has little adverse influence on pregnancy outcomes and does not reduce the probability of taking home live babies. PMID- 29251185 TI - Homicide concealed strangulation after bobbing reins in sexually sadistic homicide. AB - This case of sexually motivated homicide combined the perpetrator's obliteration of his victim's identity along with his attempt at concealment of the corpse and sexual gratification following ligature strangulation of a young unidentified female from a minority Indian state. Sexual bondage was evident with characteristic body tying in a typical posture to fuel the killer's sexual arousal and gratification before, during and then after strangling his victim with a scarf. The victim's body was left in a sack packed with vegetables and transported from the crime site and found abandoned in a park. PMID- 29251187 TI - Shin Splints in the Young Athlete: A Nonspecific Diagnosis. PMID- 29251188 TI - When the Athlete's Life Is Threatened. PMID- 29251186 TI - HIV and the menopause: A review. AB - Effective antiretroviral therapy has resulted in a close to normal life expectancy for people living with HIV. This has led to a shift in the age distribution of women living with HIV in the UK, with one in three attending for HIV care estimated to be aged 45-56 years in 2014. The lack of experience of many HIV physicians in managing menopause, and the perceived complexity of managing menopause in women living with HIV by general practitioners means that many women are unable to access appropriate care and support. This is aggravated by the relative paucity of data on menopause in women living with HIV and conflicting results in this field, for example with regard to age of onset of menopause and symptomatology experienced. Furthermore, women living with HIV have unique considerations such as potential interactions between antiretroviral therapy and menopause hormone therapy (previously called hormone replacement therapy) and other physiological concerns such as a multifactorial propensity towards decreased bone mineral density and potentially increased cardiovascular risk. On the whole, menopause hormone therapy is probably underutilised in this group of women due to perceived concerns around drug-drug interactions, as well as fears shared with women in the general population about menopause hormone therapy. Menopausal women should be given adequate information on symptomatology, lifestyle modification and treatment options including menopause hormone therapy. Furthermore, a holistic approach which considers the increased burden of poor mental health in this population is essential. PMID- 29251189 TI - Character: 'I'd Rather Be One than Have it'. PMID- 29251190 TI - trainer's corner. PMID- 29251191 TI - Decompression Sickness in Sport Scuba Diving. PMID- 29251193 TI - Confidentiality and the Athlete. PMID- 29251192 TI - Legal, Moral, and Ethical Questions in Sports Medicine. PMID- 29251194 TI - Treating Thigh Contusions With Ice. PMID- 29251195 TI - sportspages. PMID- 29251196 TI - world at play. PMID- 29251197 TI - The Pain of the High Jumper. PMID- 29251198 TI - Charter a Boat and Sail the Smiling Caribbean. PMID- 29251199 TI - lockerroom. PMID- 29251201 TI - Officiating in the NBA: 'A Never-Ending Challenge'. PMID- 29251200 TI - letters. PMID- 29251202 TI - CD15 as a marker of fetoplacental endothelial immaturity in IUGR placentas. AB - BACKGROUND: Structural or functional defects in the placenta, are the primary cause of growth restriction of the fetus. Morphological examination of such placentas from intrauterine growth restricted (IUGR) fetuses often appears deceptively normal. Evaluation of angiogenesis and fetoplacental vasculature is critical to understand the underlying pathogenesis of fetal growth restriction in both idiopathic as well as cases where it is thought to be secondary to complications like preeclampsia (PE). We analyzed the immaturity of fetoplacental vasculature using CD15, which is a stage specific embryonic antigen known to be expressed in immature endothelium. MATERIAL AND METHODS: One hundred and twelve placentas (81 from IUGR and 31 from gestationally appropriate samples (appropriate for gestational age (AGA)) were collected based on stringent inclusion criteria, and subjected to detailed examination of morphology and microscopy along with immunostaining for CD15. IUGR placentas known to have villous immaturity such as those associated with gestational diabetes, Rh negative pregnancies and anemia were excluded. The time of clinical onset of IUGR, associated complications like PE and oligohydramnios along with clinical variables were recorded. CD15 expression was scored in both distal and proximal vasculature and the values in IUGR and AGA pregnancies were compared and correlated with clinical variables. RESULTS: The mean CD 15 scores in both proximal vasculature (PV) as well as distal (DV) vasculature were significantly higher in the IUGR group compared to AGA (17.7 versus 5.16 in PV and 50.8 versus 23.7 in distal vasculature (DV)). Gestational age had no influence on CD15 staining in PV or DV in IUGR group, whereas preterm AGAs expressed higher CD15 only in the distal vessels. PE, oligohydramnios and the time of onset of IUGR did not influence the fetal vascular immaturity, as measured by CD15 scores. Although none of the clinical or obstetric factors influenced CD15 staining in AGA, fetal vessel immaturity in the IUGR group remained high even after adjusting for confounding variables like maternal age, gestational age and birth weight. Histological features suggestive of chronic hypoxia were significantly higher in IUGR placentas, compared to AGA and correlated positively with CD15 expression. CONCLUSION: Fetoplacental endothelium in both PV and DV is immature in IUGR irrespective of the gestational age or any other associated factors and CD15 immunodetection is a valuable marker for assessment of immaturity. PMID- 29251203 TI - Combining blinatumomab with targeted therapy for BCR-ABL mutant relapsed/refractory acute lymphoblastic leukemia. PMID- 29251204 TI - Directional Atherectomy With Antirestenotic Therapy vs Drug-Coated Balloon Angioplasty Alone for Common Femoral Artery Atherosclerotic Disease. AB - PURPOSE: To report an experience using directional atherectomy (DA) with antirestenotic therapy (DAART) in the form of drug-coated balloon (DCB) angioplasty vs DCB angioplasty alone in common femoral artery (CFA) occlusive lesions. METHODS: A retrospective review was conducted of 47 consecutive patients (mean age 71 years; 26 men) treated between October 2011 and July 2016 using either DCB angioplasty alone (n=26) or DAART (n=21) for CFA lesions. The majority of patients had lifestyle-limiting claudication (14 DCB and 15 DAART). Mean lesion length (39+/-14 mm DCB and 34+/-16 mm DAART) and vessel calcification (17/26 DCB and 11/21 DAART) were comparable between the groups. There were 4 chronic total occlusions, all in the DAART group. The main outcome measure was primary patency. Key secondary outcomes were technical success, secondary patency, and freedom from clinically-driven target lesion revascularization (TLR). RESULTS: Technical success rates were 89% following DCB angioplasty and 95% for DAART (p=0.41). The 88% 12-month primary patency and 89% freedom from TLR for DAART were higher than the 68% and 75% estimates following DCB angioplasty alone, but neither difference was statistically significant. However, the secondary patency estimate at 12 months was significantly higher in the DAART group (100% vs 81% for DCB, p=0.03). Bailout stenting (1 DCB vs 1 DAART), vessel perforation (1 DCB vs 0 DAART), access site complications (4 DCB vs 3 DAART), and distal embolization (0 DCB vs 1 DAART) were comparable, whereas DCB angioplasty had more non-flow-limiting dissections (8 vs 1 for DAART, p=0.02). CONCLUSION: Preparation of the atherosclerotic CFA with directional atherectomy was not associated with statistically significantly higher primary patency or freedom from TLR compared to DCB angioplasty alone at 12 months. Nonetheless, both modalities had promising outcomes in a primarily surgically treated vascular territory. PMID- 29251205 TI - Novel Endovascular Approach Using the Gore Iliac Branch Endograft for Short Iliac Anatomy. AB - PURPOSE: To report the use of a branched iliac endograft to maintain internal iliac artery (IIA) patency in a patient with an infrarenal aortic aneurysm and short common iliac arteries (CIA). CASE REPORT: A 74-year-old man presented with an asymptomatic, fusiform, 67-mm infrarenal aortic aneurysm confirmed on computed tomography. The right CIA was funnel shaped and only 15 mm in length, providing no appropriate stent-graft landing zone. The left CIA measured 14 mm in diameter and 25 mm in length. Endovascular repair of the aneurysm with preservation of the IIAs was achieved using a Gore Iliac Branch Endoprosthesis for the short right CIA and a conventional limb to land in the left CIA. Follow-up scans to 24 months have shown continued patency of the IIA and no evidence of endoleak. CONCLUSION: The Gore Iliac Branch Endograft can be used to successfully treat patients with short CIA anatomy while preserving flow to the ipsilateral IIA, with maintained early patency of the IIA limb. PMID- 29251206 TI - Temporal Changes in Intraluminal Thrombus Volume Within Abdominal Aortic Aneurysms: Implications for Planning Endovascular Aneurysm Sealing. AB - PURPOSE: To explore whether or not there are temporal changes in the abdominal aortic aneurysm (AAA) and intraluminal thrombus (ILT) volumes between planning and implantation of the endovascular aneurysm sealing (EVAS) device and how these changes influence lumen volume. METHODS: A retrospective review was conducted of 51 AAA patients (mean age 76+/-7.1 years; 36 men) in whom 2 serial preoperative computed tomography angiograms (CTAs) had been performed within 1 to 18 months before fenestrated endovascular repair. The 2 preoperative CTAs were analyzed to identify changes in total sac, ILT, and lumen volumes. RESULTS: Over a median 7.0 months (interquartile range 4, 10), 46 (90%) of 51 AAAs increased in volume between the 2 CTAs. ILT volume increased in 44 aneurysms. In contrast, lumen volume increased in 31 and decreased in 20 AAAs. There was a strong correlation between changes in AAA volume and ILT volume (rs=0.859, p<0.001), which remained significant after adjustment for initial volumes (rs=0.815; p<0.001). There was no correlation between the time interval separating the 2 CTAs and changes in AAA volume (rs=0.115; p=0.421), changes in ILT volume (rs=0.084; p=0.599), or changes in lumen volume (rs=0.060; p=0.676). The AAA growth rate (defined as the change in AAA size/days between CTAs) showed a weak correlation with ILT volume (rs=0.272, p=0.054), which disappeared after adjustment for initial AAA size (rs= 0.002, p=0.991). Between the 2 CTAs, 12 aneurysms crossed the new <1.4 Nellix maximum aorta/lumen diameter ratio. CONCLUSION: As AAAs grow, the increase in aortic volume is largely occupied by additional ILT formation, with minimal change in lumen volume. These changes may alter the suitability of the aneurysm for the Nellix device and could have implications for EVAS planning and device deployment. PMID- 29251208 TI - Choosing a Running Shoe: Science or Subjectivity? AB - Choosing a pair of running shoes in today's market is enough to boggle anyone's mind. Here are some suggestions from people who have lived through it. PMID- 29251207 TI - Perioperative Outcomes From the Prospective Multicenter Least Invasive Fast-Track EVAR (LIFE) Registry. AB - PURPOSE: To determine the feasibility, perioperative resource utilization, and safety of a fast-track endovascular aneurysm repair (EVAR) protocol in well selected patients. METHODS: Between October 2014 and May 2016, the LIFE (Least Invasive Fast-track EVAR) registry ( ClinicalTrials.gov identifier NCT02224794) enrolled 250 patients (mean age 73+/-8 years; 208 men) in a fast-track EVAR protocol comprised of bilateral percutaneous access using the 14-F Ovation stent graft, no general anesthesia, no intensive care unit (ICU) admission, and next day discharge. The primary endpoint was major adverse events (MAE) through 30 days. The target performance goal for the MAE endpoint was 10.4%. RESULTS: Vascular access, stent-graft delivery, and stent-graft deployment success were 100%. A total of 216 (86%) patients completed all elements of the fast-track EVAR protocol. Completion of individual elements was 98% for general anesthesia avoidance, 97% for bilateral percutaneous access, 96% for ICU avoidance, and 92% for next-day discharge. Perioperative outcomes included mean procedure time of 88 minutes, median blood loss of 50 mL, early oral nutrition (median 6 hours), early mobilization (median 8 hours), and short hospitalization (median 26 hours). Fast track EVAR completers had shorter procedure time (p<0.001), less blood loss (p=0.04), faster return to oral nutrition (p<0.001) and ambulation (p<0.01), and shorter hospital stay (p<0.001). With 241 (96%) of the 250 patients returning for the 30-day follow-up, the MAE incidence was 0.4% (90% CI 0.1% to 1.8%), significantly less than the 10.4% performance goal (p<0.001). No aneurysm rupture, conversion to surgery, or aneurysm-related secondary procedure was reported. There were no type III endoleaks and 1 (0.4%) type I endoleak. Iliac limb occlusion was identified in 2 (0.8%) patients. The 30-day hospital readmission rate was 1.6% overall. CONCLUSION: A fast-track EVAR protocol was feasible in well-selected patients and resulted in efficient perioperative resource utilization with excellent safety and effectiveness. PMID- 29251210 TI - brief reports. PMID- 29251211 TI - The Neglected Art of Massage. PMID- 29251213 TI - The Moral Equivalent of War. PMID- 29251212 TI - a need to know. PMID- 29251214 TI - Hazards of Snow Shoveling. AB - Snow shovelers often complain about muscular aches and pains, but the demands on their metabolic and cardiovascular systems may be more significant. PMID- 29251216 TI - Case Report: Spontaneous Pneumothorax in a Jogger. AB - Athletes with a high pain tolerance may delay medical treatment for idiopathic spontaneous pneumothorax, even when significant symptoms are present. PMID- 29251215 TI - The Underweight Female. AB - Thin is in-but are underweight women healthy? These researchers categorize three types, ranging from sedentary malnourished women to lean athletes who often have menstrual irregularities. PMID- 29251218 TI - scanning sports. PMID- 29251217 TI - Returning to Athletic Activity After Infectious Mononucleosis. AB - More objective criteria are needed to determine when an athlete can safely return to sports after infectious mononucleosis. PMID- 29251219 TI - Percent Body Fat Testing: 'A Two-Edged Sword'. AB - Weight is the most common characteristic used to describe an athlete. But percentage of fat is what should concern physicians and coaches. PMID- 29251220 TI - letters. PMID- 29251221 TI - Changes in serum lipid levels after laparoscopic sleeve gastrectomy in morbidly obese dyslipidemic and normolipidemic patients. AB - BACKGROUND: This study investigated the effect of laparoscopic sleeve gastrectomy (LSG) performed for morbid obesity on serum lipid levels of dyslipidemic and normolipidemic patients. METHODS: 141 patients who underwent LSG between September 2014 and January 2016 were included in the study. RESULTS: The patients' mean body mass index was 46.27 +/- 6.79 kg/m2 preoperatively, 31.60 +/- 5.37 kg/m2 in the 6th month postoperatively and 27.80 +/- 4.25 kg/m2 in the 12th month (p < .001). Preoperatively and 12 months after the operation, mean total cholesterol (TC) levels and mean LDL cholesterol, mean HDL cholesterol, and mean triglyceride (TG) levels were statistically significantly decreased (p < .01). Comparing TC levels in the 12th month with preoperative levels, dyslipidemic patients showed a statistically more significant decrease than normolipidemic patients. LDL cholesterol levels were significantly decreased in both the groups. HDL cholesterol levels increased significantly in both groups while mean TG levels decreased significantly in patients with high preoperative TG levels, but not in patients with normal preoperative TG levels. CONCLUSIONS: Although this technique exerts its effect primarily by reducing gastric volume, besides its metabolic and hormonal effects, it also improves serum lipid levels (decreasing TC, LDL cholesterol and TG levels, and increasing HDL cholesterol levels). It therefore contributes to decreasing cardiovascular diseases. PMID- 29251222 TI - Dietary polydextrose and galactooligosaccharide increase exploratory behavior, improve recognition memory, and alter neurochemistry in the young pig. AB - OBJECTIVES: Previous studies have shown that dietary prebiotics have the potential to improve memory, alter social behavior, and reduce anxiety-like behaviors in rodents. The present research sought to expand upon such results and describe the effects of feeding prebiotics early in life on cognition and neurochemistry using a translational piglet model. METHODS: Pigs were provided customized milk replacer containing 2 g/L each of polydextrose (PDX) and galactooligosaccharide (PDX/GOS) or 0 g/L (Control) from postnatal day (PND) 2 33. Beginning on PND 25, pigs were tested on the novel object recognition (NOR), novel location recognition (NLR), and backtest tasks to measure recognition memory and response to restraint stress. At study conclusion pigs were euthanized and intestine, blood, and brain tissues were collected and analyzed. RESULTS: PDX/GOS-fed pigs demonstrated recognition memory on the NOR task (P < 0.001) whereas Control pigs did not (P = 0.184). Additionally, PDX/GOS-fed pigs visited the novel and sample objects more frequently (all P < 0.05) while spending less time per visit exploring the sample object (P = 0.028) than Control pigs. Volatile fatty acids (VFAs) were decreased in the ascending colon (P < 0.012), whereas butyrate tended to be higher in blood (P = 0.080) and lower in the hippocampus (P = 0.061) of PDX/GOS-fed pigs. PDX/GOS-fed pigs exhibited lower serotonin (P = 0.016) in the hippocampus. CONCLUSION: These findings suggest that early life consumption of PDX/GOS supports recognition memory as measured by NOR while modulating the concentrations of VFAs in the colon, blood, and brain, as well as hippocampal serotonin. PMID- 29251223 TI - Research on the hepatotoxicity mechanism of citrate-modified silver nanoparticles based on metabolomics and proteomics. AB - Citrate-modified silver nanoparticles (AgNP-cit) have received extensive attention due to their excellent antimicrobial properties. However, these particles tend to migrate in vivo, thereby entering the blood circulatory system in granular form and accumulating in the liver, causing toxic reactions. However, the mechanism underlying AgNP-cit toxicity is not yet clear. Thus, we adopted a tandem mass tag (TMT)-labeled quantitative proteomics and metabolomics approach to identify proteins and small molecule metabolites associated with AgNP-cit induced liver damage and constructed interaction networks between the differentially expressed proteins and metabolites to explain the AgNP-cit toxicity mechanism. AgNP-cit resulted in abnormal purine metabolism mainly by affecting xanthine and other key metabolites along with pyruvate kinase and other bodily proteins, leading to oxidative stress. AgNP-cit regulated the metabolism of amino acids and glycerol phospholipids through glycerol phospholipids, CYP450 enzymes and other key proteins, causing liver inflammation. Via alanine, isoleucine, L-serine dehydratase/L-threonine deaminase and other proteins, AgNP cit altered the metabolism of glycine, serine and threonine, cysteine and methionine, affecting oxidation and deamination, and ultimately leading to liver damage. This work clearly explains toxic reactions induced by AgNP-cit from three perspectives, oxidative stress, inflammatory response, and oxidation and deamination, thus providing an experimental basis for the safe application of nanomaterials. PMID- 29251224 TI - Corrigendum. AB - Dekker I, Sombekke, MH, Birgit, IW, et al. Asymptomatic spinal cord lesions do not predict the time to disability in patients with early multiple sclerosis. Mult Scler. Epub ahead of print 6 November 2017. DOI: 10.1177/1352458517736147. In the initial Online First version of this article, the Funding statement was incomplete. The correct statement is below: Funding The author(s) declared receipt of the following financial support for the research, authorship and/or publication of this article: The MS Centre Amsterdam is supported by the Dutch MS Research Foundation (grant number 14-358e). Frederik Barkhof (FB) is supported by the NIHR UCLH biomedical research centre. The online version of this article has been updated to reflect the correct declarations. Subsequent versions of the article will also be corrected. The authors apologise for this error and any confusion it may have caused. PMID- 29251225 TI - Associations between snus use, body mass index and general health in a cross sectional population-based sample of women. AB - BACKGROUND: In Norway, snus use among women has increased substantially over the last decade, particularly in younger age groups. Snus use is associated with increased morbidity among men, but few studies have addressed health consequences of snus use among women. AIM: To investigate the associations between body mass index (BMI) and female snus use, and between self-rated general health and female snus use. METHODS: A nationally representative net sample of 13,756 women in Norway, aged 18-45 years, participated in a survey on lifestyle and health. Ordinal logistic regression was applied to address associations between snus use and BMI/general health, adjusting for age and lifestyle factors. RESULTS: Compared to never users of snus, daily snus users had a lower likelihood of high BMI (OR: 0.83, 95% CI: 0.68-1.00), a higher likelihood of low BMI (OR: 1.63, 95% CI: 1.14-2.33), and a higher likelihood of poor/fair health (OR: 1.43, 95% CI: 1.08-1.90). Former and occasional snus users did not differ from never users in terms of BMI or general health in multiply adjusted models. Daily smokers had the highest likelihood of reporting poor/fair health (OR: 2.18, 95% CI: 1.8-2.63) relative to never smokers. CONCLUSIONS: Daily female snus use was associated with a lower likelihood of being overweight, and a higher likelihood of being underweight. Moreover, daily snus use was associated with a higher likelihood of worse general health. Former and occasional female snus use was not associated with BMI or general health. PMID- 29251226 TI - Infusing fundamental cause theory with features of Pierre Bourdieu's theory of symbolic power. AB - The theory of fundamental causes is one of the more influential attempts to provide a theoretical infrastructure for the strong associations between indicators of socioeconomic status (education, income, occupation) and health. It maintains that people of higher socioeconomic status have greater access to flexible resources such as money, knowledge, prestige, power, and beneficial social connections that they can use to reduce their risks of morbidity and mortality and minimize the consequences of disease once it occurs. However, several key aspects of the theory remain underspecified, compromising its ability to provide truly compelling explanations for socioeconomic health inequalities. In particular, socioeconomic status is an assembly of indicators that do not necessarily cohere in a straightforward way, the flexible resources that disproportionately accrue to higher status people are not clearly defined, and the distinction between socioeconomic status and resources is ambiguous. I attempt to address these definitional issues by infusing fundamental cause theory with features of a well-known theory of socioeconomic stratification in the sociological literature-Pierre Bourdieu's theory of symbolic power. PMID- 29251227 TI - Long working hours and stroke among employees in the general workforce of Denmark. AB - AIMS: A systematic review and meta-analysis have found that long working hours were prospectively associated with an increased risk of overall stroke. The primary aim of the present study was to test if this finding could be reproduced in a sample that has been randomly selected from the general workforce of Denmark. A secondary aim was to estimate the association for haemorrhagic and ischaemic stroke separately. METHODS: Individual participant data on 20- to 64 year-old employees were drawn from the Danish Labour Force Survey, 1999-2013, and linked to data on socio-economic status (SES), migrations, hospitalisations and deaths from national registers. The participants were followed from the time of the interview until the end of 2014. Poisson regression was used to estimate age , sex- and SES-adjusted rate ratios for stroke as a function of weekly working hours. RESULTS: With 35-40 working hours per week as reference, the estimated rate ratios for overall stroke were 0.97 (95% confidence interval (CI) 0.83-1.13) for 41-48 working hours, 1.10 (95% CI 0.86-1.39) for 49-54 working hours and 0.89 (95% CI 0.69-1.16) for >=55 working hours. The estimated rate ratios per one category increase in working hours were 0.99 (95% CI 0.93-1.06) for overall stroke, 0.96 (95% CI 0.88-1.05) for ischaemic stroke and 1.15 (95% CI 1.02-1.31) for haemorrhagic stroke. CONCLUSIONS: Our analysis does not support the hypothesis that long working hours are associated with increased rates of overall stroke. It suggests, however, that long working hours might be associated with increased rates of haemorrhagic stroke. PMID- 29251229 TI - Marathon Running and Immunity to Heart Disease. PMID- 29251228 TI - letters. PMID- 29251230 TI - overtime. PMID- 29251231 TI - editor's notes. PMID- 29251232 TI - a need to know. PMID- 29251233 TI - world at play. PMID- 29251235 TI - gameplan. PMID- 29251234 TI - On the Run, But Not in a Hurry. PMID- 29251236 TI - Treating an Energetic Epileptic. PMID- 29251237 TI - sportspages. PMID- 29251238 TI - Everything You Always Wanted to Know About Running. PMID- 29251239 TI - The Case for Mandatory Mouth Protectors. PMID- 29251240 TI - Should Epileptics Be Athletes? PMID- 29251241 TI - How Good Is Bike Riding As Primary Exercise? PMID- 29251242 TI - 'Athlete's Foot'-Scratching Beneath Surface of Fungal Ailments. PMID- 29251243 TI - Running into trouble. PMID- 29251244 TI - MicroRNA-200a induces apoptosis by targeting ZEB2 in alcoholic liver disease. AB - ABSTRAT Alcoholic liver disease (ALD) and its complication continued to be a major health problem throughout the world. Increasing evidence suggests that microRNA (miRNA) that regulate apoptosis, inflammation and lipid metabolism are affected by alcohol in ALD. MiR-200a has emerged as a major regulator in several liver diseases, but its role in ALD has not been elucidated. The aim of this study is to figure out the biological function of miR-200a in ALD and to explore its underlying mechanism. The expression pattern of miR-200a were analyzed in vitro and in vivo, we showed that miR-200a was up-regulated in ALD in AML-12 and primary hepatocyte. We then examined it's effect on cell apoptosis and identified zinc finger E-box binding homeobox 2 (ZEB2; also known as SIP1) as a direct target gene of miR-200a. Furthermore, reintroduction of ZEB2 could reverse the pro-apoptosis of miR-200a on AML-12. Taken together, our study demonstrated that miR-200a regulates the apoptosis of hepatocyte in ALD by directly target ZEB2, both of which could serve as new therapeutic targets for ALD. PMID- 29251245 TI - Telemonitoring in patients with heart failure: Is there a long-term effect? AB - Introduction Evidence suggests that telemonitoring decreases mortality and heart failure (HF)-related hospital admission in patients with HF. However, most studies follow their patients for only several months. Little is known about the long-term effects of telemonitoring after a period of application. Methods In 2007, the TEHAF study was initiated to compare tailored telemonitoring with usual care with respect to time until first HF-related hospital admission. In total, 301 patients completed the study after a follow-up period of one year. No differences could be found in time to first HF-related admission between intervention and control groups. Here, we performed a retrospective analysis in order to investigate potential long-term effects of telemonitoring. The primary endpoint was time to first HF-related hospital admission. Secondary endpoints were, amongst others, all-cause mortality, hospital admission due to HF and days alive and out of hospital (DAOOH). Electronic files of all included patients were reviewed between October 2007 and September 2015. Result Mean follow-up duration was 1652 days (standard deviation: 1055 days). No significant difference in time to first HF-related hospital admission (log-rank test, p = 0.15), all-cause mortality (log-rank test, p = 0.43), or DAOOH (two-sample t-test, p = 0.87) could be found. However, patients that underwent telemonitoring had significantly fewer HF-related hospital admissions (incident rate ratio 0.54, 95% confidence interval 0.31-0.88). Discussion Telemonitoring did not significantly influence the long term outcome in our study. Therefore, extending the follow-up period of telemonitoring studies in HF patients is probably not beneficial. PMID- 29251246 TI - Interventions Highlighting Hypocrisy Reduce Collective Blame of Muslims for Individual Acts of Violence and Assuage Anti-Muslim Hostility. AB - Collectively blaming groups for the actions of individuals can license vicarious retribution. Acts of terrorism by Muslim extremists against innocents, and the spikes in anti-Muslim hate crimes against innocent Muslims that follow, suggest that reciprocal bouts of collective blame can spark cycles of violence. How can this cycle be short-circuited? After establishing a link between collective blame of Muslims and anti-Muslim attitudes and behavior, we used an "interventions tournament" to identify a successful intervention (among many that failed). The "winning" intervention reduced collective blame of Muslims by highlighting hypocrisy in the ways individuals collectively blame Muslims-but not other groups (White Americans, Christians)-for individual group members' actions. After replicating the effect in an independent sample, we demonstrate that a novel interactive activity that isolates the psychological mechanism amplifies the effectiveness of the collective blame hypocrisy intervention and results in downstream reductions in anti-Muslim attitudes and anti-Muslim behavior. PMID- 29251247 TI - The Reputational Consequences of Generalized Trust. AB - The present research examines the reputational consequences of generalized trust. High-trust individuals are seen as moral and sociable, but not necessarily competent. When controlling for other traits, there is a negative relationship between trust and perceived competence (Studies 1 and 2). Compared with optimism, generalized trust has stronger effects on morality and sociability (Study 2). Furthermore, people judge those who do not discriminate between trustworthy and untrustworthy groups (unconditional trustors) more negatively than those who only trust groups that are, in fact, trustworthy (conditional trustors). Unconditional trust and unconditional distrust are both viewed negatively (Study 3), even after controlling for attitudinal similarity (Study 4). Critically, both generalized trust and discriminant ability (i.e., conditional trust) have independent reputational benefits (Study 5). These studies suggest that generalized trust plays an important role in how we perceive and judge others. PMID- 29251249 TI - Cultivation of different microalgae with pentose as carbon source and the effects on the carbohydrate content. AB - In the search for alternative carbon sources for microalgae cultivation, pentoses can be considered interesting alternatives since the most abundant global source of renewable biomass is lignocellulosic waste, which contains significant quantities of pentoses. However, the use of pentoses (C5) in the cultivation of microalgae is still not widely studied and only recently the first metabolic pathway for pentose absorption in microalgae was proposed. So, the objective of this work was to evaluate if the use of pentoses affects the growth and carbohydrates content of Chlorella minutissima, Chlorella vulgaris, Chlorella homosphaera and Dunaliella salina. The kinetic parameters, carbohydrate and protein content and the theoretical potential for ethanol production were estimated for all strains. The highest cellular concentrations (1.25 g L-1) were obtained for D. salina with 5% of pentoses. The addition of pentoses leads to high levels of carbohydrates for C. minutissima (58.6%) cultured with 5% of pentoses, and from this biomass, it is possible to determine a theoretical production of ethanol of 38 mL per 100 g of biomass. The pentoses affect the growth and the biomass composition of the studied strains, generating biomass with potential use for bioethanol production. PMID- 29251250 TI - The era of GWAS is over - Yes. PMID- 29251248 TI - The E3 ubiquitin ligase NEDD4 enhances killing of membrane-perturbing intracellular bacteria by promoting autophagy. AB - The E3 ubiquitin ligase NEDD4 has been intensively studied in processes involved in viral infections, such as virus budding. However, little is known about its functions in bacterial infections. Our investigations into the role of NEDD4 in intracellular bacterial infections demonstrate that Mycobacterium tuberculosis and Listeria monocytogenes, but not Mycobacterium bovis BCG, replicate more efficiently in NEDD4 knockdown macrophages. In parallel, NEDD4 knockdown or knockout impaired basal macroautophagy/autophagy, as well as infection-induced autophagy. Conversely, NEDD4 expression promoted autophagy in an E3 catalytic activity-dependent manner, thereby restricting intracellular Listeria replication. Mechanistic studies uncovered that endogenous NEDD4 interacted with BECN1/Beclin 1 and this interaction increased during Listeria infection. Deficiency of NEDD4 resulted in elevated K48-linkage ubiquitination of endogenous BECN1. Further, NEDD4 mediated K6- and K27- linkage ubiquitination of BECN1, leading to elevated stability of BECN1 and increased autophagy. Thus, NEDD4 participates in killing of intracellular bacterial pathogens via autophagy by sustaining the stability of BECN1. PMID- 29251251 TI - Apoptosis inhibitor 5: Role in the inhibition of caspase-2. PMID- 29251252 TI - The clinical significance of FLT3 ITD mutation on the prognosis of adult acute promyelocytic leukemia. AB - BACKGROUND AND AIMS: To explore the relationship between FLT3 (encoding Fms related tyrosine kinase 3) internal tandem duplication (ITD) mutations with the prognosis of acute promyelocytic leukemia. The PubMed database, the Cochrane Library, conference proceedings, the EMBASE databases, and references of published trials and review articles were searched. Two reviewers independently assessed the quality of the trials and extracted the data. Odd ratios (ORs) for complete remission (CR) rate after induction therapy, 5-year overall survival (OS), and 5-year disease free survival (DFS) were pooled using the STATA package. MAIN RESULTS: Seventeen trials involving 2252 patients were ultimately analyzed. The pooled OR showed that the FLT3 ITD mutation group had a poor prognosis in terms of CR rate (OR = 0.53, 95% confidence interval (CI), 0.30-0.95, P = 0.03), 5-year OS (OR = 0.47, 95% CI, 0.29-0.75, P = 0.002), and as 5-year DFS (OR = 0.48, 95% CI, 0.29-0.78; p = 0.003). CONCLUSIONS: The results suggested that FLT3 ITD mutations could become an indicator of poor prognosis of APL, and these patients should receive more intensive therapy according to current guidelines. PMID- 29251253 TI - Permutations of functional magnetic resonance imaging classification may not be normally distributed. AB - A fundamental question that often occurs in statistical tests is the normality of distributions. Countless distributions exist in science and life, but one distribution that is obtained via permutations, usually referred to as permutation distribution, is interesting. Although a permutation distribution should behave in accord with the central limit theorem, if both the independence condition and the identical distribution condition are fulfilled, no studies have corroborated this concurrence in functional magnetic resonance imaging data. In this work, we used Anderson-Darling test to evaluate the accordance level of permutation distributions of classification accuracies to normality expected under central limit theorem. A simulation study has been carried out using functional magnetic resonance imaging data collected, while human subjects responded to visual stimulation paradigms. Two scrambling schemes are evaluated: the first based on permuting both the training and the testing sets and the second on permuting only the testing set. The results showed that, while a normal distribution does not adequately fit to permutation distributions most of the times, it tends to be quite well acceptable when mean classification accuracies averaged over a set of different classifiers is considered. The results also showed that permutation distributions can be probabilistically affected by performing motion correction to functional magnetic resonance imaging data, and thus may weaken the approximation of permutation distributions to a normal law. Such findings, however, have no relation to univariate/univoxel analysis of functional magnetic resonance imaging data. Overall, the results revealed a strong dependence across the folds of cross-validation and across functional magnetic resonance imaging runs and that may hinder the reliability of using cross-validation. The obtained p-values and the drawn confidence level intervals exhibited beyond doubt that different permutation schemes may beget different permutation distributions as well as different levels of accord with central limit theorem. We also found that different permutation schemes can lead to different permutation distributions and that may lead to different assessment of the statistical significance of classification accuracy. PMID- 29251254 TI - Direct and flexible marginal inference for semicontinuous data: Response. PMID- 29251255 TI - Effects of genetic factors to inhaled corticosteroid response in children with asthma: a literature review. AB - Numerous studies have examined the association between pharmacogenetic effects and the response to inhaled corticosteroids (ICS) in patients with asthma. In fact, several single nucleotide polymorphisms of a number of candidate genes have been identified that might influence the clinical response to ICS in children with asthma. Their direct or indirect effects depend on their role in the inflammatory process in asthma or the anti-inflammatory action of corticosteroids, respectively. Among the genes identified, variants in T-box 21 ( TBX21) and Fc fragment of IgE receptor II ( FCER2) contribute indirectly to the variability in the response to ICS by altering the inflammatory mechanisms in asthma, while other genes such as corticotropin releasing hormone receptor 1 ( CRHR1), nuclear receptor subfamily 3 group C member 1 ( NR3C1), stress induced phosphoprotein 1 ( STIP1), dual specificity phosphatase 1 (DUSP1), glucocorticoid induced 1 (GLCCI1), histone deacetylase 1 (HDAC), ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3), and vascular endothelial growth factors (VEGF) directly affect this variability through the anti-inflammatory mechanisms of ICS. The results to date indicate various potential genetic factors associated with the response to ICS, which could be utilized to predict the individual therapeutic response of children with asthma to ICS. Clinical trials are underway and their results are greatly anticipated. Further pharmacogenetic studies are needed to fully understand the effects of genetic variation on the response to ICS in children with asthma. PMID- 29251256 TI - Screening of Sceptridium ternatum for antitussive and antiasthmatic activity and associated mechanisms. AB - Objectives Sceptridium ternatum is an expectorant in traditional Chinese medicine and is prescribed for the treatment of asthma. The study aim was to screen Sceptridium ternatum for ingredients with antitussive and antiasthmatic effects and to study their associated mechanisms. Methods Cough in mice was induced using ammonia. Cough latency and the number of coughs within 3 minutes were determined. Airway responsiveness was assessed using ovalbumin as a sensitizer and characteristic asthma indicators were measured. Results Chloroform and ethyl acetate extracts significantly reduced the number of coughs within 3 minutes, tidal volume, and the percentage of eosinophilic granulocytes, lymphocytes and neutrophils. All extracts decreased airway responsiveness in asthmatic mice compared with the untreated group. Petroleum ether, chloroform and n-butanol extracts lowered the Penh values of asthmatic mice. Petroleum ether and ethyl acetate extracts greatly reduced interleukin-4 expression and the interleukin 4/interferon gamma ratio. Compared with the model group, all extracts reduced mRNA expression of the cysteinyl leukotriene receptor-1 (CysLT1). Conclusions Chloroform extract and ethyl acetate extract displayed obvious antitussive effects and reduced airway inflammation. Thus, these two extracts contain the effective ingredients of Sceptridium ternatum. The active mechanism was ascribed to inhibition of mRNA expression of the CysLT1 receptor in mice with bronchial asthma. PMID- 29251257 TI - Evaluation of the dosing strategies of biologic agents and the theoretical impact of dose rounding. AB - Introduction Monoclonal antibodies possess unique pharmacokinetic properties that permit flexible dosing. Increased use and high costs of these medications have led to the development of cost-containing strategies. This study aims to quantify the cost savings and clinical impact associated with dose rounding monoclonal antibodies to the nearest vial size. Methods This study was a single-arm, retrospective chart review assessing all monoclonal antibody doses dispensed at an outpatient community infusion center associated with an academic medical center between August 2014 and August 2015. All monoclonal antibody doses were reviewed to determine the cost of drug wasted using two methods. The waste-cost analysis described the amount of drug disposed of due to the use of partial vials. The theoretical dose savings described potential cost avoidance based on rounding the ordered dose to the nearest vial size. The theoretical rounded dose was compared to the actual ordered dose to explore clinical implications. Results A total of 436 doses were included. Of these, 237 were not rounded to the nearest vial size and included in the analysis. The cost of waste associated with these doses was $108,013.64 using actual wholesale price. The potential cost avoidance associated with the theoretical dose calculation was $83,595.53. Rounding these doses to the nearest vial size resulted in a median 6.7% (range, 1.4-20%) deviation from ordered dose. Conclusions Rounding monoclonal antibodies to the nearest vial size could lead to significant cost and waste savings with minimal deviation from the actual ordered dose. PMID- 29251258 TI - Characteristics and Predictors of Occupational Injury Among Career Firefighters. AB - The purpose of this study was to assess occupational injury characteristics and predictors among career firefighters. A total of 249 firefighters from central Texas and northern California participated in this Internet-based survey. Approximately 27% of firefighters had reported an occupational injury within the previous 12 months. The majority of injuries occurred on the scene of a non-fire call while performing an activity that required lifting, pushing, or pulling. Firefighters' backs were most frequently injured. Of the reported injuries, approximately 18% returned to work on modified duty, but 46% were not allowed to work due to their occupational injuries. Firefighters who reported occupational injuries were more likely to be older and experiencing occupational stress compared with their coworkers who did not report occupational injuries. Injured firefighters were also more likely to report fewer job rewards (money/salary), overcommitment, less esteem (respect and support), and fewer promotional prospects. These injury factors should be incorporated into interventions to reduce or prevent workplace injuries. PMID- 29251259 TI - Health Issues and Injury Risks Associated With Prolonged Sitting and Sedentary Lifestyles. AB - Using a case study, this article reviews the health risks associated with prolonged sitting and the reasons sedentary workers are at risk for musculoskeletal injuries. Other health issues associated with prolonged sitting or sedentary behavior as well as the benefits of exercise are also explored. Finally, evidence-based interventions to reduce health risks associated with prolonged sitting may increase productivity. PMID- 29251260 TI - Clinical Profile of Persons with Multiple Sclerosis Across the Continuum of Care. AB - BACKGROUND: This study is part of the Innovations in Data, Evidence and Applications for Persons with Neurological Conditions project to understand the strengths, preferences, and needs of persons with neurological conditions living in Canada. OBJECTIVE: To estimate the prevalence and describe the sociodemographic and clinical characteristics of persons with multiple sclerosis in Canadian home care, nursing home, Complex Continuing Care hospitals, and inpatient mental health care settings. METHODS: Cross-sectional study of adults aged 18 years and older with multiple sclerosis (MS; n=11,250) across Canada from 1996 through 2011 using interRAI Resident Assessment Instrument (RAI) comprehensive health assessments (RAI Minimum Data Set 2.0, RAI-Home Care, RAI Mental Health). Comparisons were made to adults with Alzheimer's disease and related dementias (n=260,910), other neurological conditions (n=163,578) and non neurological conditions (n=571,567). RESULTS: The prevalence of MS was highest in Complex Continuing Care hospitals (4125 cases per 100,000 patients), followed by home care (2020 cases per 100,000 patients), nursing homes (1424 cases per 100,000 patients), and mental health settings (138 cases per 100,000 patients). Persons with MS experienced greater impairment in the completion of activities of daily living, pain, pressure ulcers, swallowing difficulty, depression, and anxiety compared with peers within care settings. There were also significant differences between settings, particularly the degree of physical and cognitive impairment experienced by persons with MS. CONCLUSIONS: Except for mental health care settings, the prevalence of MS in community, institutional and hospital based care settings exceeded that of the general population. These data describing the sociodemographic and clinical characteristics of persons with MS may be used to inform clinical practice and policy decisions for persons with MS across the continuum of care. PMID- 29251262 TI - Hemin immobilized into metal-organic frameworks as an electrochemical biosensor for 2,4,6-trichlorophenol. AB - Hemin immobilized into copper-based metal-organic frameworks was successfully prepared and used as a new electrode material for sensitive electrochemical biosensing. X-ray diffraction patterns, Fourier transform infrared spectra, scanning electron microscopy, UV-vis absorption spectroscopy, and cyclic voltammetry were used to characterize the resultant composites. Due to the interaction between the copper atom groups and hemin, the constrained environment in Cu-MOF-74 acts as a matrix to avoid the dimerization of enzyme molecules and retain its biological activity. The hemin/Cu-MOF composites demonstrated enhanced electrocatalytical activity and high stability towards the oxidation of 2,4,6 trichlorophenol. Under optimum experimental conditions, the sensor showed a wide linear relationship over the range of 0.01-9 MUmol L-1 with a detection limit (3sigma) of 0.005 MUmol L-1. The relative standard deviations were 4.6% and 3.5% for five repeated measurements of 0.5 and 5 MUmol L-1 2,4,6-trichlorophenol, respectively. The detection platforms for 2,4,6-trichlorophenol developed here not only indicate that hemin/Cu-MOF-74 possesses intrinsic biological reactivity, but also enable further work to be conducted towards the application of enzyme containing metal-organic frameworks in electrochemical biosensors. PMID- 29251263 TI - 4D tracking with ultra-fast silicon detectors. AB - The evolution of particle detectors has always pushed the technological limit in order to provide enabling technologies to researchers in all fields of science. One archetypal example is the evolution of silicon detectors, from a system with a few channels 30 years ago, to the tens of millions of independent pixels currently used to track charged particles in all major particle physics experiments. Nowadays, silicon detectors are ubiquitous not only in research laboratories but in almost every high-tech apparatus, from portable phones to hospitals. In this contribution, we present a new direction in the evolution of silicon detectors for charge particle tracking, namely the inclusion of very accurate timing information. This enhancement of the present silicon detector paradigm is enabled by the inclusion of controlled low gain in the detector response, therefore increasing the detector output signal sufficiently to make timing measurement possible. After providing a short overview of the advantage of this new technology, we present the necessary conditions that need to be met for both sensor and readout electronics in order to achieve 4D tracking. In the last section, we present the experimental results, demonstrating the validity of our research path. PMID- 29251261 TI - Diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for screening patients with imported malaria in a non-endemic setting. AB - BACKGROUND: Sensitive and easy-to-perform methods for the diagnosis of malaria are not yet available. Improving the limit of detection and following the requirements for certification are issues to be addressed in both endemic and non endemic settings. The aim of this study was to test whether loop-mediated isothermal amplification of DNA (LAMP) may be an alternative to microscopy or real-time PCR for the screening of imported malaria cases in non-endemic area. RESULTS: 310 blood samples associated with 829 suspected cases of imported malaria were tested during a one year period. Microscopy (thin and thick stained blood slides, reference standard) was used for the diagnosis. Real-time PCR was used as a standard of truth, and LAMP (Meridian Malaria Plus) was used as an index test in a prospective study conducted following the Standards for Reporting Diagnosis Accuracy Studies. In the 83 positive samples, species identification was P. falciparum (n = 66), P. ovale (n = 9), P. vivax (n = 3) P. malariae (n = 3) and 2 co-infections with P. falciparum + P.malariae. Using LAMP methods, 93 samples gave positive results, including 4 false-positives. Sensitivity, specificity, positive predictive value and negative predictive value for LAMP tests were 100%, 98.13%, 95.51%, and 100% compared to PCR. CONCLUSION: High negative predictive value, and limit of detection suggest that LAMP can be used for screening of imported malaria cases in non-endemic countries when expert microscopists are not immediately available. However, the rare occurrence of non valid results and the need for species identification and quantification of positive samples preclude the use of LAMP as a single reference method. PMID- 29251264 TI - Ultra-high-frequency microwave response from flexible transparent Au electromagnetic metamaterial nanopatterned antenna. AB - Flexible transparent materials are a hot spot in current research but also a key technical difficulty in industry. They are playing an increasingly important role in flexible transparent display applications such as organic light-emitting diodes, transparent electrodes, and so on. On the other hand, the present research on nanopatterned antennas is mainly concentrated on the optical frequency but rarely on the microwave (such as 3G, 4G, and 5G) and terahertz frequency band communications, where nanopatterned antennas can have many novel applications. To the authors' knowledge, this is the first paper that presents a method for preparing a flexible transparent Au electromagnetic metamaterial nanopatterned antenna. We study its free-space performance at ultra-high frequency and its application in electronic products such as smartphones, tablets, personal computers, and wearable devices (such as smart watches) which have the function of mobile communication. The experimental results showed that the transparency of the antenna designed and fabricated in this work can be as high as 94%, and its efficiency can reach 74.5%-91.9% of antennas commonly seen at present in academia and industry. By adjusting the capacitive and inductive reactance of the nanopatterned antenna's matching circuit, combined with its measured efficiency and 3D electromagnetic simulation results, we speculate on the mechanism of the Au electromagnetic metamaterial nanopatterned antenna with good performance. PMID- 29251265 TI - Investigation of transition from thermal- to solutal-Marangoni flow in dilute alcohol/water mixtures using nano-plasmonic heaters. AB - We experimentally investigated Marangoni flows around a microbubble in diluted 1 butanol/water, 2-propanol/water, and ethanol/water mixtures using the thermoplasmonic effect of gold nanoisland film. A laser spot on the gold nanoisland film acted as a highly localized heat source that was utilized to generate stable air microbubbles with diameters of 32-48 MUm in the fluid and to induce a steep temperature gradient on the bubble surface. The locally heated bubble has a flow along the bubble surface, with the flow direction showing a clear transition depending on the alcohol concentrations. The fluid is driven from the hot to cold regions when the alcohol concentration is lower than the transition concentration, whereas it is driven from the cold to hot regions when the concentration is higher than the transition concentration. In addition, the transition concentration increases as the carbon number of the alcohol decreases. The observed flow direction transition is explained by the balance of the thermal and solutal-Marangoni forces that are cancelled out for the transition concentration. The selective evaporation of the alcohol at the locally heated surface allows us to generate stable and rapid thermoplasmonic solutal-Marangoni flows in the alcohol/water mixtures. PMID- 29251266 TI - A study on the resistance switching of Ag2Se and Ta2O5 heterojunctions using structural engineering. AB - The resistive random access memory (RRAM) devices with heterostuctures have been investigated due to cycling stability, nonlinear switching, complementary resistive switching and self-compliance. The heterostructured devices can modulate the resistive switching (RS) behavior appropriately by bilayer structure with a variety of materials. In this study, the bipolar resistive switching characteristics of the bilayer structures composed of Ta2O5 and Ag2Se, which are transition-metal oxide (TMO) and silver chalcogenide, were investigated. The bilayer devices of Ta2O5 deposited on Ag2Se (Ta2O5/Ag2Se) and Ag2Se deposited on Ta2O5 (Ag2Se/Ta2O5) were fabricated for investigation of the RS characteristics by stacking sequence of Ta2O5 and Ag2Se. All operating voltages were applied to the Ag top electrode with the Pt bottom electrode grounded. The Ta2O5/Ag2Se device showed that a negative voltage sweep switched the device from high resistance state (HRS) to low resistance state (LRS) and a positive voltage sweep switched the device from LRS to HRS. On the contrary, for the Ag2Se/Ta2O5 device a positive voltage sweep switched the device from HRS to LRS, and a negative voltage sweep switched it from LRS to HRS. The polarity dependence of RS was attributed to the stacking sequence of Ta2O5 and Ag2Se. In addition, the combined heterostructured device of both bilayer stacks, Ta2O5/Ag2Se and Ag2Se/Ta2O5, exhibited the complementary switching characteristics. By using threshold switching devices, sneak path leakage can be reduced without additional selectors. The bilayer heterostructures of Ta2O5 and Ag2Se have various advantages such as self-compliance, reproducibility and forming-free stable RS. It confirms the possible applications of TMO and silver chalcogenide heterostructures in RRAM. PMID- 29251267 TI - Template-assisted electrodeposition of Ni and Ni/Au nanowires on planar and curved substrates. AB - We present a variant of the template-assisted electrodeposition method that enables the synthesis of large arrays of nanowires (NWs) on flat and curved substrates. This method uses ultra-thin (50 nm-10 MUm) anodic aluminum oxide membranes as a template. We have developed a procedure that uses a two-polymer protective layer to transfer these templates onto almost any surface. We have applied this technique to the fabrication of large arrays of Ni and segmented composition Ni/Au NWs on silicon wafers, Cu tapes, and thin (0.2 mm) Cu wires. In all cases, a complete coverage with NWs is achieved. The magnetic properties of these samples show an accentuated in-plane anisotropy which is affected by the form of the substrate (flat or curve) and the length of the NWs. Unlike current lithography techniques, the fabrication method proposed here allows the integration of complex nanostructures into devices, which can be fabricated on unconventional surfaces. PMID- 29251268 TI - Retrievable puncture anchor-assisted gallbladder drainage: Throwing the gallbladder a lifeline. PMID- 29251269 TI - II Brazilian consensus statement on endoscopic ultrasonography. AB - BACKGROUND AND OBJECTIVES: At the time of its introduction in the early 80s, endoscopic ultrasonography (EUS) was indicated for diagnostic purposes. Recently, EUS has been employed to assist or to be the main platform of complex therapeutic interventions. METHODS: From a series of relevant new topics in the literature and based on the need to complement the I Brazilian consensus on EUS, twenty experienced endosonographers identified and reviewed the pertinent literature in databases. The quality of evidence, strength of recommendations, and level of consensus were graded and voted on. RESULTS: Consensus was reached for eight relevant topics: treatment of gastric varices, staging of nonsmall cell lung cancer, biliary drainage, tissue sampling of subepithelial lesions (SELs), treatment of pancreatic fluid collections, tissue sampling of pancreatic solid lesions, celiac neurolysis, and evaluation of the incidental pancreatic cysts. CONCLUSIONS: There is a high level of evidence for staging of nonsmall cell lung cancer; biopsy of SELs as the safest method; unilateral and bilateral injection techniques are equivalent for EUS-guided celiac neurolysis, and in patients with visible ganglia, celiac ganglia neurolysis appears to lead to better results. There is a moderate level of evidence for: yield of tissue sampling of pancreatic solid lesions is not influenced by the needle shape, gauge, or employed aspiration technique; EUS-guided and percutaneous biliary drainage present similar clinical success and adverse event rates; plastic and metallic stents are equivalent in the EUS-guided treatment of pancreatic pseudocyst. There is a low level of evidence in the routine use of EUS-guided treatment of gastric varices. PMID- 29251271 TI - Can endoscopic ultrasound-guided needle-based confocal laser endomicroscopy replace fine-needle aspiration for pancreatic and mediastinal diseases? AB - New applications of confocal laser endomicroscopy (CLE) have been developed, such as needle-based CLE (nCLE) for pancreatic masses, pancreatic cystic tumors, and lymph nodes. nCLE is feasible during endoscopic ultrasound (EUS) examination, and preliminary results are very encouraging and suggest this technology may be used in future as a useful adjunct in cases of inconclusive EUS-guided fine-needle aspiration. The aim of this paper is to give an update in this new technology and to define its place in the diagnosis of pancreatic masses and mediastinal diseases. PMID- 29251270 TI - Practice guidelines for endoscopic ultrasound-guided celiac plexus neurolysis. AB - OBJECTIVES: The objective of guideline was to provide clear and relevant consensus statements to form a practical guideline for clinicians on the indications, optimal technique, safety and efficacy of endoscopic ultrasound guided celiac plexus neurolysis (EUS-CPN). METHODS: Six important clinical questions were determined regarding EUS-CPN. Following a detailed literature review, 6 statements were proposed attempting to answer those questions. A group of expert endosonographers convened in Chicago, United States (May 2016), where the statements were presented and feedback provided. Subsequently a consensus group of 35 expert endosonographers voted based on their individual level of agreement. A strong recommendation required 80% voter agreement. The modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria were used to rate the strength of recommendations and the quality of evidence. RESULTS: Eighty percent agreement was reached on 5 of 6 consensus statements, 79.4% agreement was reached on the remaining one. CONCLUSIONS: EUS CPN is efficacious, should be integrated into the management of pancreas cancer pain, and can be considered early at the time of diagnosis of inoperable disease. Techniques may still vary based on operator experience. Serious complications exist, but are rare. PMID- 29251272 TI - Endoscopic ultrasound-guided fine-needle aspiration from ascites and peritoneal nodules: A scoping review. AB - The peritoneum is involved in many diseases such as primary malignancy (mesothelioma), infectious disease (tuberculosis), and disseminated malignancy (peritoneal carcinomatosis). The peritoneal disease may manifest as ascites and/or peritoneal masses or nodules. Endoscopic ultrasound (EUS), due to its ability to provide high-resolution images, has revolutionized the imaging and diagnosis of pancreaticobiliary diseases among other gastrointestinal conditions. EUS can not only help in imaging of various lesions close to the gastrointestinal lumen but also aspirate/biopsy them. We conducted a systematic search to identify published literature on the value of EUS in detection and diagnosis of peritoneal disorders. This review aims to summarize the available literature on the use of EUS-guided paracentesis and fine-needle aspiration from peritoneal nodules. PMID- 29251273 TI - A retrospective study evaluating endoscopic ultrasound-guided drainage of pancreatic fluid collections using a novel lumen-apposing metal stent on an electrocautery enhanced delivery system. AB - OBJECTIVES: To report the safety and clinical efficacy with the novel lumen apposing metal stent (LAMS) with an electrocautery enhanced delivery system for the drainage of pancreatic fluid collections (PFCs). METHODS: This was a retrospective analysis of all consecutive patients with PFCs who underwent endoscopic ultrasound (EUS)-guided drainage using the LAMS with an electrocautery enhanced delivery system in 2 US centers. RESULTS: Thirteen patients with PFCs (69% with walled-off necrosis [WON]) underwent drainage using the study device. Successful stent placement was accomplished in all patients. Direct endoscopic necrosectomy was carried out in all nine patients with WON complete resolution of the PFC was obtained in all 13 cases, with no recurrence during follow-up. There was one procedure-related adverse event. In one patient, the LAMS was dislodged immediately after deployment, falling into the stomach where it was removed. A second electrocautery enhanced LAMS was placed in this patient immediately afterward. CONCLUSIONS: EUS-guided drainage using the LAMS with the electrocautery-enhanced delivery system is a safe, easily performed, and a highly effective for the drainage of PFCs. PMID- 29251276 TI - Malignant melanoma metastatic to the gallbladder diagnosed by endoscopic ultrasonography-guided fine-needle aspiration. PMID- 29251274 TI - Interventional endoscopic ultrasound: A new promising way for intrahepatic portosystemic shunt with portal pressure gradient. AB - BACKGROUND AND OBJECTIVES: Interventional endoscopic ultrasound (EUS) is a promising novel approach for intravascular interventions. The aim of this study was to assess the feasibility and safety of a EUS-guided intrahepatic portosystemic shunt (EGIPS) with portal pressure gradient measurement in a live porcine model. METHODS: The left hepatic vein (LHV) or the inferior vena cava (IVC) was punctured with a needle that advanced into the portal vein (PV). A guidewire was then inserted into the PV, and a needle knife was used to create an intrahepatic fistula between LHV and PV. Portal pressure was recorded. The fistula was dilated with a balloon and a biliary metal stent was deployed between LHV and PV under sonographic and fluoroscopic observation. A portocavography validated the patency of the stent. Necropsies were realized after euthanasia. RESULTS: Portosystemic stenting was achieved in 19/21 pigs. Final portocavography confirmed stent patency between PV and LHV or IVC in 17 pigs (efficacy of 81%): Four stents were dysfunctional as two were thrombosed and two were poor positioned. Portal pressure was documented before and after shunting in 20/21 pigs. Necropsies revealed that 19/21 procedures were transesophageal and two were transgastric. Hemoperitoneum and pneumothorax were found in one pig and hemothorax was found in two pigs. Morbidity was 14.2% (3/21 animals). CONCLUSION: EGIPS was feasible in 91% of cases, functional in 81%, with 14.2% per procedure morbidity. EGIPS still needs to be assessed in portal hypertension pig models with longer follow-up before being considered as an alternative when the transjugular intrahepatic portosystemic shunt fails. PMID- 29251277 TI - Endoscopic ultrasound to diagnose pneumatosis cystoides intestinalis (with video). PMID- 29251275 TI - Low diagnostic yield of transduodenal endoscopic ultrasound-guided fine needle biopsy using the 19-gauge Flex needle: A large multicenter prospective study. AB - BACKGROUND AND OBJECTIVES: Previous limited experiences have reported the 19 gauge flexible needle to be highly effective in performing endoscopic ultrasound guided fine needle biopsy (EUS-FNB) for transduodenal lesions. We designed a large multicenter prospective study with the aim at evaluating the performance of this newly developed needle. PATIENTS AND METHODS: Consecutive patients with solid lesions who needed to undergo EUS sampling from the duodenum were enrolled in 6 tertiary care referral centers. Puncture of the lesion was performed with the 19-gauge flexible needle (ExpectTM and Slimline ExpectTM 19 Flex). The feasibility, procurement yield, and diagnostic accuracy were evaluated. RESULTS: Totally, 246 patients (144 males, mean age 65.1 +/- 12.7 years) with solid lesions (203 cases) or enlarged lymph nodes (43 cases) were enrolled, with a mean size of 32.6 +/- 12.2 mm. The procedure was technically feasible in 228 patients, with an overall procurement yield of 76.8%. Two centers had suboptimal procurement yields (66.7% and 64.2%). Major complications occurred in six cases: two of bleeding, two of mild acute pancreatitis, one perforation requiring surgery, and one duodenal hematoma. Considering malignant versus nonmalignant disease, the sensitivity, specificity, positive/negative likelihood ratios, and diagnostic accuracy were 70.7% (95% confidence interval [CI]: 64.3-76.6), 100% (95% CI: 79.6-100), 35.3 (95% CI: 2.3-549.8)/0.3 (95% CI: 0.2-0.4), and 73.6% (95% CI: 67.6-79). On multivariate analysis, the only determinant of successful EUS-FNB was the center in which the procedure was performed. CONCLUSIONS: Our results suggest that the use of the 19-gauge flexible needle cannot be widely advocated and its implementation should receive local validation after careful evaluation of both the technical success rates and diagnostic yield. PMID- 29251278 TI - Autoinoculation as a treatment modality for molluscum contagiosum: A preliminary uncontrolled trial. PMID- 29251279 TI - A brief biographic sketch of Dr. Bhau Daji Lad (1822-1874): A forgotten figure of Indian dermatology. PMID- 29251280 TI - Total dystrophic onychomycosis caused by Talaromyces marneffei in a patient with Acquired immunodeficiency syndrome on combined anti-retroviral therapy. PMID- 29251281 TI - [Cobatest network: users' characteristics of community-based voluntary,counselling and testing centres in Spain.] AB - OBJECTIVE: The COBATEST network (European network of community-based voluntary, counselling and testing centers) allows standardized collection of information to monitor HIV testing at these centers. The objective was to describe the performance of the Spanish centers of the COBATEST network and the epidemiological profile of its users, and to analyze the factors associated with having an earlier HIV test. METHODS: Descriptive analysis of the data collected in the 19 Spanish centers that used the common information collection tools during the year 2015. A multivariate logistic regression model was used to identify factors associated with having an earlier test. RESULTS: A total of 6,077 HIV rapid tests were performed and 1.8% were reactive (3.0% MSM, 3.1% SW, 2.3% PWID, 0.6% heterosexual). 82.1% of the reactives were referred to perform a confirmatory test and 94 (97.9%) were HIV positive, of whom 54% were diverted to the health system. 38% said they had never been tested for HIV. Factors associated with having a previous HIV test were: being over 20 years old; being HSH, SW, or PWID; being foreign; having used condoms at the last penetration; having had an STI in the last year; and having been in jail. CONCLUSIONS: The results show the great potential of these services to reach people who have never been tested for HIV. The HIV cases are concentrated in vulnerable groups. It is necessary to improve the linkage of diagnosed people to health care services. PMID- 29251283 TI - Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice. AB - Transcriptome-based drug discovery has identified new treatments for some complex diseases, but has not been applied to alcohol use disorder (AUD) or other psychiatric diseases, where there is a critical need for improved pharmacotherapies. High Drinking in the Dark (HDID-1) mice are a genetic model of AUD risk that have been selectively bred (from the HS/Npt line) to achieve intoxicating blood alcohol levels (BALs) after binge-like drinking. We compared brain gene expression of HDID-1 and HS/Npt mice, to determine a molecular signature for genetic risk for high intensity, binge-like drinking. Using multiple computational methods, we queried LINCS-L1000 (Library of Integrated Network-Based Cellular Signatures), a database containing gene expression signatures of thousands of compounds, to predict candidate drugs with the greatest potential to decrease alcohol consumption. Our analyses predicted novel compounds for testing, many with anti-inflammatory properties, providing further support for a neuroimmune mechanism of excessive alcohol drinking. We validated the top 2 candidates in vivo as a proof-of-concept. Terreic acid (a Bruton's tyrosine kinase inhibitor) and pergolide (a dopamine and serotonin receptor agonist) robustly reduced alcohol intake and BALs in HDID-1 mice, providing the first evidence for transcriptome-based drug discovery to target an addiction trait. Effective drug treatments for many psychiatric diseases are lacking, and the emerging tools and approaches outlined here offer researchers studying complex diseases renewed opportunities to discover new or repurpose existing compounds and expedite treatment options. PMID- 29251282 TI - Dopamine Receptor-Specific Contributions to the Computation of Value. AB - Dopamine is thought to play a crucial role in value-based decision making. However, the specific contributions of different dopamine receptor subtypes to the computation of subjective value remain unknown. Here we demonstrate how the balance between D1 and D2 dopamine receptor subtypes shapes subjective value computation during risky decision making. We administered the D2 receptor antagonist amisulpride or placebo before participants made choices between risky options. Compared with placebo, D2 receptor blockade resulted in more frequent choice of higher risk and higher expected value options. Using a novel model fitting procedure, we concurrently estimated the three parameters that define individual risk attitude according to an influential theoretical account of risky decision making (prospect theory). This analysis revealed that the observed reduction in risk aversion under amisulpride was driven by increased sensitivity to reward magnitude and decreased distortion of outcome probability, resulting in more linear value coding. Our data suggest that different components that govern individual risk attitude are under dopaminergic control, such that D2 receptor blockade facilitates risk taking and expected value processing. PMID- 29251284 TI - Prevention and management of adverse events of Novel agents in multiple myeloma: A consensus of the european myeloma network. AB - During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.Leukemia accepted article preview online, 18 December 2017. doi:10.1038/leu.2017.353. PMID- 29251286 TI - Mitigating Cardiovascular Dysfunction Across the Cancer Continuum?. AB - The mechanisms and outcomes of cancer treatment-related cardiovascular dysfunction are complex and influenced by cardiotoxic treatment exposure, preexisting heart disease, and lifestyle factors. Establishing and implementing evidence to prevent, detect, and manage cancer treatment-related cardiotoxicity requires engagement by the nursing science community.?. PMID- 29251285 TI - Use of a Smartphone Application for Prompting Oral Medication Adherence Among Adolescents and Young Adults With Cancer?. AB - OBJECTIVES: To explore the feasibility and acceptability of use of a smartphone medication reminder application to promote adherence to oral medications among adolescents and young adults (AYAs) with cancer.?. SAMPLE & SETTING: 23 AYAs with cancer from a Children's Oncology Group-affiliated children's hospital and a National Cancer Institute-designated comprehensive cancer center in Salt Lake City, UT.?. METHODS & VARIABLES: Participants were asked to use the application for eight weeks. Data on application usage were obtained from a cloud based server hosted by the application developers. Weekly self-report questionnaires were completed. Feasibility was assessed through participants' usage and responses. Acceptability was assessed through participants' perceived ease of use and usefulness.?. RESULTS: Almost all participants used the application at least once. More than half reported that they took their medications immediately when they received reminders. Participants also reported that the application was easy to set up and use, and that it was useful for prompting medication taking.?. IMPLICATIONS FOR NURSING: Nurses could continue to test the efficacy of integrating e-health modalities, such as smartphone applications, into efforts to promote medication adherence. PMID- 29251287 TI - A Nursing Intervention for Reducing Symptom Burden During Chemotherapy?. AB - OBJECTIVES: To evaluate the efficacy of an individually tailored nursing intervention for reducing chemotherapy-related symptom distress in adult patients with cancer. ?. SAMPLE & SETTING: A control group (n = 71) received usual care and an intervention group (n = 72) received usual care and the CHEMO-SUPPORT intervention, all at the University Hospitals of Leuven in Belgium.?. METHODS & VARIABLES: The intervention effect was evaluated by measuring the difference in outcomes between the two groups. The primary outcome, overall symptom distress, and other symptom-related outcomes were self-reported at the start of treatment (baseline) and at 3, 6, and 12 weeks.?. RESULTS: The CHEMO SUPPORT intervention showed significantly less worsening of overall symptom distress and severity. Self-efficacy and outcome expectations (measured at six weeks) were significantly higher in the intervention group. Self-care (measured at 12 weeks) was statistically similar between the two groups. The results emphasize the importance of nurses in coaching patients to adequately self-manage their symptoms at home.?. IMPLICATIONS FOR NURSING: Providing goal-directed self management support using motivational interviewing as well as tailoring are promising areas for reducing chemotherapy-related symptom distress. PMID- 29251288 TI - New Year, New Look?. AB - For those of you holding this issue of the Oncology Nursing Forum (ONF) in your hands, the change should be tactile. We have changed the paper stock, and I hope you can feel that change. The pages are thicker and matte, and should feel more substantial against your palms. You might have noticed another change when you looked at the cover-we have updated the design and included titles of articles to entice readers to read what we have published. PMID- 29251289 TI - Smoking Prevalence and Management Among Cancer Survivors?. AB - PROBLEM IDENTIFICATION: Continued smoking after a cancer diagnosis can lead to development of potential treatment interactions, secondary cancers, and comorbid conditions. The purpose of this article is to examine the prevalence of smoking after diagnosis and present current management strategies.?. LITERATURE SEARCH: The terms cancer, survivorship, behavior, smoking, and quitlines were searched in PubMed and CINAHL(r) from the start of the databases to December 2016. Statistics, guidelines, and background information were obtained from websites of organizations such as the American Cancer Society, National Cancer Institute, National Institutes of Health, and Centers for Disease Control and Prevention.?. DATA EVALUATION: Of 17 relevant articles, 12 were analyzed to identify variables among survivors who continued to smoke versus those who successfully quit. Five articles were analyzed to identify characteristics of successful smoking cessation interventions.?. SYNTHESIS: Survivors who are younger, female, and not partnered and those who report less socioeconomic and psychosocial support may be at greater risk for continued smoking. Peer counseling, cognitive behavioral therapy exercises, and use of frameworks to guide interventions are unique properties of successful cessation interventions.?. IMPLICATIONS FOR RESEARCH: Continued research on cancer-specific tobacco cessation interventions and exploration of why current evidence-based therapies are not working in this population are warranted. PMID- 29251290 TI - Comparing Outcomes of Genetic Counseling Options in Breast and Ovarian Cancer: An Integrative Review?. AB - PROBLEM IDENTIFICATION: Genetic counseling is vital in helping people at high risk for hereditary breast and ovarian cancer (HBOC) make informed decisions to undergo BRCA testing. Many people, particularly those in rural locations, lack access to these services. This review examines evidence to determine if remotely delivered genetic counseling via telephone or telemedicine is an effective alternative to in-person counseling for people who are at high risk for HBOC.?. LITERATURE SEARCH: A literature review was completed by searching PubMed, SCOPUS, and CINAHL(r) databases.?. DATA EVALUATION: 151 articles were identified from the search, and 7 were included in the review.?. SYNTHESIS: Patients' BRCA knowledge acquisition, cancer-specific distress, anxiety, depression, and satisfaction with mode of counseling delivery were equivalent between in-person and remotely delivered counseling groups. Genetic testing rates were significantly higher in participants receiving in-person counseling. Remotely delivered genetic counseling was more convenient and less expensive. Mixed outcomes existed regarding counselor-patient communication. ?. IMPLICATIONS FOR PRACTICE: The demand for genetic counseling will grow as advances in cancer genomics reveal genes that may contribute to cancer predisposition. Innovative delivery models are necessary to ensure that all people have access to care. PMID- 29251291 TI - The Relationship Between ?Body Mass Index and Sexual Function in Endometrial Cancer?. AB - OBJECTIVES: To explore the association between pretreatment body mass index (BMI) and post-treatment sexual function in women treated for endometrial cancer. ?. SAMPLE & SETTING: 28 postmenopausal women treated with vaginal brachytherapy (VBT) took part in this multisite exploratory secondary analysis at the University of Pennsylvania and Northwestern University. ?. METHODS & VARIABLES: Secondary data analysis was used to determine if pretreatment BMI is associated with post-VBT sexual function in postmenopausal women treated for endometrial cancer at baseline and at six months post-treatment. Because of small sample size, participants were dichotomized according to enrollment BMI. RESULTS: Both groups had poor sexual function at baseline. Although improved function was observed with time, neither group reached a score indicating healthy sexual function.?. IMPLICATIONS FOR NURSING: Understanding factors that influence sexual health in patients with gynecologic cancer can improve post-treatment quality of life. ?. PMID- 29251292 TI - Chemotherapy-Induced Nausea and Vomiting Mitigation With Music Interventions?. AB - PROBLEM IDENTIFICATION: Despite three decades of studies examining music interventions as a mitigant of chemotherapy-induced nausea and vomiting (CINV), to date, no systematic review of this literature exists.?. LITERATURE SEARCH: PubMed, Scopus, PsycInfo(r), CINAHL(r), Cochrane Library, and Google Scholar were searched. Keywords for all databases were music, chemotherapy, and nausea.?. DATA EVALUATION: All studies were appraised for methodology and results.?. SYNTHESIS: 10 studies met inclusion criteria for review. Sample sizes were generally small and nonrandomized. Locus of control for music selection was more often with the investigator rather than the participant. Few studies controlled for the emetogenicity of the chemotherapy administered, nor for known patient-specific risk factors for CINV.?. IMPLICATIONS FOR RESEARCH: The existing data have been largely generated by nurse scientists, and implications for nursing practice are many, because music interventions are low-cost, easily accessible, and without known adverse effects. However, this specific body of knowledge requires additional substantive inquiry to generate clinically relevant data. PMID- 29251293 TI - Impact of a Barcode Medication Administration System on Patient Safety?. AB - OBJECTIVES: To determine the impact of barcode medication administration (BCMA) on the incidence of medication administration errors among patients in an onco hematology day hospital and to identify the characteristics of medication errors in that setting.?. SAMPLE & SETTING: 715 patients treated in the onco hematology day unit at the Principe de Asturias University Hospital in Madrid, Spain.?. METHODS & VARIABLES: A between-groups, pre-/postintervention study was conducted. Administration errors observed in patients with solid tumors (intervention group) were compared with those in patients with hematologic cancer (control group) before and after the introduction of BCMA. Error incidence, type, and severity were assessed, as was length of stay for treatment.?. RESULTS: Use of a BCMA system reduced the incidence and severity of errors in medication administration in the onco-hematology day hospital.?. IMPLICATIONS FOR NURSING: BCMA is a useful technology to check the five rights of medication administration in the onco-hematology day hospital and could help nurses increase the time spent on direct patient care activities. ?. PMID- 29251294 TI - Comparison of Legacy Fatigue Measures With the PROMIS Pediatric Fatigue Short Form?. AB - OBJECTIVES: To compare Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Fatigue Short Form measures and legacy patient-reported outcome fatigue measures to capture cancer-related fatigue change in pediatric patients with cancer. ?. SAMPLE & SETTING: 96 racially diverse children and adolescents with cancer. The study occurred in a 32-bed inpatient unit and three regional outpatient clinics.?. METHODS & VARIABLES: The Fatigue Scale-Child, Fatigue Scale-Adolescent, and the PROMIS Pediatric Fatigue Short Form measures were administered at three time points during chemotherapy. Descriptive, correlational, psychometric, and receiver operating characteristic (ROC) curve analyses were conducted. The variable was pediatric patient-reported fatigue.?. RESULTS: All measures were positively correlated at each time point. ROC curves were not statistically different from each other at any data point. ?. IMPLICATIONS FOR NURSING: Nurses have psychometrically strong options for measuring cancer-related fatigue in pediatric patients with cancer, but the PROMIS Pediatric Fatigue Short Form is applicable to more age groups. PMID- 29251295 TI - Shared Attributes of Responsibility and Emotion in Patients With Lung Cancer and Family Caregivers?. AB - OBJECTIVES: To compare the attributions and emotions held by patients with lung cancer (affected individuals) and family caregivers in their management of the disease. ?. SAMPLE & SETTING: A secondary data analysis of 304 affected individuals and 304 family caregivers. Participants were selected from five oncology outpatient settings.?. METHODS & VARIABLES: Comparative analysis and regression modeling. Variables include responsibility, anger, and pride in managing lung cancer.?. RESULTS: Affected individuals reported higher self oriented blame, fault, and anger than did family caregivers. Family caregivers reported more blame, fault, and anger toward the affected individual than toward themselves. Current smoking behavior of either the affected individual or family caregiver was associated with increased reports of self-oriented blame, fault, and anger. Additional research is needed to understand the attributional and emotional responses affected by the type of lung cancer, gender differences, and characteristics of the caregiving dyad.?. IMPLICATIONS FOR NURSING: Nurses should be aware of the potential for affected individuals to experience internal (self) and external (family caregiver) sources of blame, fault, and anger. Knowledge of the reasons for current smoking behavior is important for understanding emotional responses and determining interventions. PMID- 29251296 TI - A Distress Thermometer Intervention for Patients With Head and Neck Cancer?. AB - OBJECTIVES: To investigate the feasibility of an intervention using the National Comprehensive Cancer Network Distress Thermometer and Problem List with nurse guided follow-up and the effect on depressive symptoms, health-related quality of life, and worry of cancer in patients with head and neck cancer.?. SAMPLE & SETTING: 110 patients with head and neck cancer in a two-arm randomized, controlled trial in an outpatient clinic of a university hospital. ?. METHODS & VARIABLES: Patients were randomized to usual care (n = 57) or the intervention group (n = 53), which consisted of screening with the Distress Thermometer and Problem List plus nurse-guided follow-up lasting about 20 minutes three to four times during 12 months. Intention-to-treat analysis was performed using linear mixed models with outcomes at 6 and 12 months and baseline adjustment.?. RESULTS: The intervention showed moderate compliance and acceptable session duration. Intervention participants were satisfied with nurses' care. Depressive symptoms, health-related quality of life, and worry of cancer were not significantly different in the two treatment groups. The intervention seemed feasible in clinical practice, but no effects on patient outcomes were seen.?. IMPLICATIONS FOR NURSING: Patients with head and neck cancer appreciated the opportunity to discuss their problems and challenges with a nurse. Nurses supported patients with basic psychosocial care, minor interventions, and referral possibilities. PMID- 29251297 TI - Not a Death Sentence: Perspectives of African American Women Living With Lung Cancer?. AB - PURPOSE: To conduct a descriptive, qualitative study to describe the experience of female African American lung cancer survivors, their perception of living with lung cancer, and their desire and ability to adopt positive health-related behaviors. ?. PARTICIPANTS & SETTING: The sample consisted of 18 African American women with a history of stages I-IIIa lung cancer. Three focus groups were conducted in a private conference center in two community hospitals in the southeastern United States.?. METHODOLOGIC APPROACH: A 20-item questionnaire was used to collect demographic, health status, and behavior information. A trained moderator led the audio-recorded focus group discussions using a semistructured interview guide. ?. FINDINGS: Thematic analysis of the professionally transcribed data resulted in identification of four major themes. In addition, participants experienced stigma that influenced their perspectives on living with lung cancer. ?. IMPLICATIONS FOR NURSING: Healthcare professionals should provide culturally tailored communication and support for female African American lung cancer survivors. Additional research is needed to inform the development of interventions focused on health behavior change to enhance lung cancer survivorship in this vulnerable and understudied group. PMID- 29251298 TI - FREE INVENTORY PLATFORM MANAGES CHEMICAL RISKS, ADDRESSES CHEMICAL ACCOUNTABILITY, AND MEASURES COST-EFFECTIVENESS. AB - To develop best practices for laboratory safety and for chemical product and supplies management accountability, the freely-available online platform, Quartzy, was integrated within an interdisciplinary science department at a small Mid-Atlantic liberal-arts college. This was done to ensure the accuracy of purchase records, the appropriate use of storage and handling protocols, and for a continually updated chemical inventory system. Quartzy also facilitated the digital tracking and dispersal of the College's hazardous waste inventory. Since the implementation of the Quartzy platform, the science department achieved significant cost-savings during the procurement of laboratory supplies and equipment, and it developed a sense of ownership towards the common goal of lowering the College's environmental impact as it relates to its managing of laboratory-generated hazardous wastes. PMID- 29251299 TI - Photofading in cotton fibers dyed using red, yellow, and blue direct dyes during examination with microspectrophotometry (MSP). AB - Microspectrophotometry (MSP) is a rapid, nondestructive technique for the analysis of color in textile fibers. This technique combines microscopy and ultraviolet (UV)/visible (Vis) spectroscopy, allowing for very small colored samples, like dyed textile fibers, to be analyzed directly and thereby eliminates the need for time consuming and destructive extractions. While MSP is generally accepted to be a nondestructive evaluation method, a loss of color during analysis, or photofading can occur. In this work, cotton fabric dyed with blue, yellow, and red direct dyes at different concentrations. Dye photofading during MSP examination was investigated by measuring the absorbance at a specific position on the fibers from these fabrics, periodically over the course of 30 minutes. Visible color loss and a reduction in absorbance was observed for all three colors, but was most pronounced for the fibers dyed red. A major goal of this study is to increase awareness of the photofading phenomenon when analyzing cotton fibers using MSP. PMID- 29251300 TI - Rapid detection of fentanyl, fentanyl analogues, and opioids for on-site or laboratory based drug seizure screening using thermal desorption DART-MS and ion mobility spectrometry. AB - Fentanyl and fentanyl analogues represent a current and emerging threat in the United States as pure illicit narcotics and in mixtures with heroin. Because of their extreme potency, methods to safely and rapidly detect these compounds are of high interest. This work investigates the use of thermal desorption direct analysis in real time mass spectrometry (TD-DART-MS) and ion mobility spectrometry (IMS) as tools for the rapid and sensitive (nanogram to picograms) detection of fentanyl, 16 fentanyl analogues, and five additional opioids. Competitive ionization studies highlight that detection of these compounds in the presence of heroin is readily achievable, down to 0.1% fentanyl by mass with TD DART-MS. With IMS, detection of nanogram levels of fentanyl in a binary fentanyl and heroin mixture is possible but can be complicated by decreased resolution in certain commercial instrument models. Modifications to the alarm windows can be used to ensure detection of fentanyl in binary mixtures. Additionally, three complex background matrices (fingerprint residue, dirt, and plasticizers) are shown to have a minimal effect of the detection of these compounds. Wipe sampling of the exterior of bags of questioned powders is shown to be a safe alternative method for field screening and identification, removing the need to handle potentially lethal amounts of material. PMID- 29251301 TI - Contributors to the emerging investigators issue 2018. PMID- 29251303 TI - Role of local response in manipulating the elastic properties of disordered solids by bond removal. AB - We explore the range over which the elasticity of disordered spring networks can be manipulated by the removal of selected bonds. By taking into account the local response of a bond, we demonstrate that the effectiveness of pruning can be improved so that auxetic (i.e., negative Poisson's ratio) materials can be designed without the formation of cracks even while maintaining the global isotropy of the network. The bulk modulus and shear modulus scale with the number of bonds removed and we estimate the exponents characterizing these power laws. We also find that there are spatial correlation lengths in the change of bulk modulus and shear modulus upon removing different bonds that diverge as the network approaches the isostatic limit where the excess coordination number DeltaZ -> 0. PMID- 29251304 TI - Photochromism into nanosystems: towards lighting up the future nanoworld. AB - The ability to manipulate the structure and function of promising nanosystems via energy input and external stimuli is emerging as an attractive paradigm for developing reconfigurable and programmable nanomaterials and multifunctional devices. Light stimulus manifestly represents a preferred external physical and chemical tool for in situ remote command of the functional attributes of nanomaterials and nanosystems due to its unique advantages of high spatial and temporal resolution and digital controllability. Photochromic moieties are known to undergo reversible photochemical transformations between different states with distinct properties, which have been extensively introduced into various functional nanosystems such as nanomachines, nanoparticles, nanoelectronics, supramolecular nanoassemblies, and biological nanosystems. The integration of photochromism into these nanosystems has endowed the resultant nanostructures or advanced materials with intriguing photoresponsive behaviors and more sophisticated functions. In this Review, we provide an account of the recent advancements in reversible photocontrol of the structures and functions of photochromic nanosystems and their applications. The important design concepts of such truly advanced materials are discussed, their fabrication methods are emphasized, and their applications are highlighted. The Review is concluded by briefly outlining the challenges that need to be addressed and the opportunities that can be tapped into. We hope that the review of the flourishing and vibrant topic with myriad possibilities would shine light on exploring the future nanoworld by encouraging and opening the windows to meaningful multidisciplinary cooperation of engineers from different backgrounds and scientists from the fields such as chemistry, physics, engineering, biology, nanotechnology and materials science. PMID- 29251305 TI - Dissolution of oligo(tetrafluoroethylene) and preparation of poly(tetrafluoroethylene)-based composites by using fluorinated ionic liquids. AB - Fluorophilic ionic liquids (ILs) showing enhanced compatibility with poly(tetrafluoroethylene) (PTFE) have been newly synthesised. The as-designed ILs contributed both to the dissolution of PTFE oligomers and to the preparation of composites with PTFE with no fear of bleed-out of the ILs. PMID- 29251306 TI - Electron transport shuttle mechanism via an Fe-N-C bond derived from a conjugated microporous polymer for a supercapacitor. AB - A new innovative electrode material (Fe-P800) consisting of a metal complex anchored on carbon via the utilization of iron-porphyrin conjugated microporous polymer (Fe-CMP) was prepared after pyrolyzing at 800 degrees C. The usage of the polymer with iron-porphyrin repeating units maximized the possible formation of Fe-Nx coordination within the bulk of the sample while the thermal treatment rendered the carbon framework to form a distinct arrangement between metal, nitrogen and carbon with a high surface area of 450 m2 g-1. The formation of the M-N-C bond, confirmed through XPS analysis, established a direct interaction between metal and carbon material. Thus, an indisputable synergistic effect was observed leading to a high capacitance of 182 F g-1 at a current density of 1 A g 1 despite its low metal loading of ~1%. It also exhibited a highly robust cycling stability of ~100% capacitance retention even after 5000 cycles (10 A g-1). In this study, a new mechanism was proposed wherein the metal (iron) center features an electron access point via its highly reversible redox reactivity, providing a shuttle effect for charge transfer to the conductive graphitic carbon matrix. PMID- 29251307 TI - Retraction: Alterations in lipid metabolism due to a protein-restricted diet in rats during gestation and/or lactation. AB - Retraction of 'Alterations in lipid metabolism due to a protein-restricted diet in rats during gestation and/or lactation' by T. C. Sosa-Larios, et al., Food Funct., 2017, DOI: 10.1039/c7fo01513e. PMID- 29251308 TI - In vitro assessment of sex steroids and related compounds in water and sediments a critical review. AB - Detection of endocrine disrupting compounds in water and sediment samples has gained much importance since the evidence of their effects was reported in aquatic ecosystems in the 1990s. The aim of this review is to highlight the advances made in the field of in vitro analysis for the detection of hormonally active compounds with estrogenic, androgenic and progestogenic effects in water and sediment samples. In vitro assays have been developed from yeast, mammalian and in a few cases from fish cells. These assays are based either on the hormone mediated proliferation of sensitive cell lines or on the hormone-mediated expression of reporter genes. In vitro assays in combination with various sample enrichment methods have been used with limits of detection as low as 0.0027 ng L 1 in water, and 0.0026 ng g-1 in sediments for estrogenicity, 0.1 ng L-1 in water, and 0.5 ng g-1 in sediments for androgenicity, and 5 ng L-1 in water for progestogenicity expressed as equivalent concentrations of standard reference compounds of 17beta-estradiol, dihydrotestosterone and progesterone, respectively. The experimental results and limits of quantification, however, are influenced by the methods of sample collection, preparation, and individual laboratory practices. PMID- 29251309 TI - In situ electrochemical development of copper oxide nanocatalysts within a TCNQ nanowire array: a highly conductive electrocatalyst for the oxygen evolution reaction. AB - It is highly desired to develop efficient earth-abundant electrocatalysts for the oxygen evolution reaction (OER) in alkaline media. In this communication, we report the in situ electrochemical conversion of a nanoarray of Cu(tetracyanoquinodimethane), Cu(TCNQ), an inorganic-organic hybrid, on Cu foam into CuO nanocrystals confined in a highly conductive nanoarray via anode oxidation. As a 3D catalyst electrode, the resulting CuO-TCNQ/CF shows high OER activity and demands an overpotential of only 317 mV to drive a geometrical catalytic current density of 25 mA cm-2. Notably, this catalyst also demonstrates strong long-term electrochemical durability. This study provides us with a universal strategy toward topotactic room-temperature preparation of conductive nanoarrays with confined transition metal nanocatalysts for practical applications. PMID- 29251310 TI - Free-standing single-crystalline NiFe-hydroxide nanoflake arrays: a self activated and robust electrocatalyst for oxygen evolution. AB - Free-standing single-crystalline NiFe-hydroxide nanoflake arrays grown in situ on nickel foam are synthesized using a simple hydrothermal method and they exhibit remarkable activity and durability for oxygen evolution in 1.0 M KOH, achieving a decreased overpotential of 235 mV to produce 10 mA cm-2 current density after long-term operation up to 100 h. PMID- 29251311 TI - Macromolecular 'size' and 'hardness' drives structure in solvent-swollen blends of linear, cyclic, and star polymers. AB - In this paper, we apply molecular simulation and liquid state theory to uncover the structure and thermodynamics of homopolymer blends of the same chemistry and varying chain architecture in the presence of explicit solvent species. We use hybrid Monte Carlo (MC)/molecular dynamics (MD) simulations in the Gibbs ensemble to study the swelling of ~12 000 g mol-1 linear, cyclic, and 4-arm star polystyrene chains in toluene. Our simulations show that the macroscopic swelling response is indistinguishable between the various architectures and matches published experimental data for the solvent annealing of linear polystyrene by toluene vapor. We then use standard MD simulations in the NPT ensemble along with polymer reference interaction site model (PRISM) theory to calculate effective polymer-solvent and polymer-polymer Flory-Huggins interaction parameters (chieff) in these systems. As seen in the macroscopic swelling results, there are no significant differences in the polymer-solvent and polymer-polymer chieff between the various architectures. Despite similar macroscopic swelling and effective interaction parameters between various architectures, the pair correlation function between chain centers-of-mass indicates stronger correlations between cyclic or star chains in the linear-cyclic blends and linear-star blends, compared to linear chain-linear chain correlations. Furthermore, we note striking similarities in the chain-level correlations and the radius of gyration of cyclic and 4-arm star architectures of identical molecular weight. Our results indicate that the cyclic and star chains are 'smaller' and 'harder' than their linear counterparts, and through comparison with MD simulations of blends of soft spheres with varying hardness and size we suggest that these macromolecular characteristics are the source of the stronger cyclic-cyclic and star-star correlations. PMID- 29251312 TI - Arsenolipid biosynthesis by the unicellular alga Dunaliella tertiolecta is influenced by As/P ratio in culture experiments. AB - The influence of arsenate and phosphate levels in water on the formation of arsenic-containing lipids (arsenolipids) and water-soluble arsenicals by a unicellular marine alga was investigated by exposing Dunaliella tertiolecta to five regimes of arsenic and phosphate, and determining the biosynthesized organoarsenicals with HPLC/mass spectrometry. Under all conditions, the major arsenolipid produced by D. tertiolecta was the novel phytyl 5-dimethylarsinoyl-2 O-methyl-ribofuranoside (AsSugPhytol546) representing ca. 35-65% of total arsenolipids. The new compound contains a phytol aglycone and a methoxy group replacing a sugar hydroxyl - two structural features not previously observed for arsenolipids. Minor arsenolipids were several previously reported arsenosugar phospholipids (AsSugPLs, in particular AsSugPL958 and the previously unknown AsSugPL978), the relative quantities of which increased with increasing phosphate exposure, and an arsenic-containing hydrocarbon (AsHC360), which remained unaffected by the different treatments. The relative amount of total arsenolipids produced by D. tertiolecta remained remarkably constant (ca. 45% of total As) and independent of the culture conditions. In contrast, with rising As-concentrations we observed an increase of hydrophilic arsenicals, which were dominated by arsenate and arsenosugars. The results highlight a possible major difference in arsenic biochemistry between macroalgae and unicellular algae with potential implications for how various algae handle their natural arsenic exposure in the world's oceans. PMID- 29251313 TI - Activation volumes for cis-to-trans isomerisation reactions of azophenols: a clear mechanistic indicator? AB - The thermal cis-to-trans isomerisation reaction of a series of hydroxy substituted azo derivatives was studied kinetico-mechanistically as a function of temperature and pressure in order to investigate the possible role of the solvent in controlling the isomerisation mechanism, viz. inversion versus rotation. The variation of the observed first order rate constants for kinetic runs carried out at different temperatures and pressures was used to determine the thermal activation parameters DeltaH? and DeltaS?, and the pressure activation parameter DeltaV?. In addition, some experiments with deuterated species or solvents were also performed. The reported results could be interpreted as indicative of a changeover from an inversion mechanism for non-polar solvents to a rotational mechanism for polar solvents, capable of hydrogen bonding, for some of the systems studied. However, the operation of a rotational mechanism in all studied cases can account more consistently for the data observed. PMID- 29251314 TI - Periodontal ligament-associated protein-1 delays rat periodontal bone defect repair by regulating osteogenic differentiation of bone marrow stromal cells and osteoclast activation. AB - The aim of the present study was to assess the roles of periodontal ligament associated protein-1 (PLAP-1) in the osteogenic differentiation of rat bone marrow stromal cells (rBMSCs) and in osteoclast activation during the repair of rat periodontal bone defects. Male, 6-week-old, Wistar rats treated with periodontal bone defects were randomly assigned to 3 groups: The PLAP-1 transfected rBMSC group (PLAP-1 group), the empty vector-transfected rBMSC group (vector group) and the normal rBMSC group (control group). Specimens were obtained at 2, 4 and 6 weeks post-surgery. Histological observation and micro computed tomography were applied to evaluate the repair effect. The bone defect areas of the mandible were dissected for western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Osteogenesis associated proteins, including alkaline phosphatase (ALP), bone sialoprotein (BSP), runt-related transcription factor 2 (Runx2), Osterix (Osx) and osteocalcin (OC), as indicators of rBMSC-induced osteogenesis, were examined by RT-qPCR and western blotting. Osteoclasts were identified and quantified using tartrate resistant acid phosphatase staining. Meanwhile, the receptor activator of nuclear factor kappaBeta ligand (RANKL)/omicronsteoprotegerin (OPG) ratio was quantified to assess osteoclast activation by western blotting. Tauhe repair effect of the PLAP-1 group was significantly worse than that of the vector and control groups. In the PLAP-1 group, newly formed and mineralized bones were significantly less in quantity than that in the other two groups (P<0.05), and the expression of osteogenic proteins (ALP, BSP, Runx2, Osx and OC) was also reduced (P<0.01). However, there was no significant difference between the vector and control groups. The RANKL/OPG ratio was upregulated in the PLAP-1 group due to decreased OPG protein expression and a simultaneous increase in RANKL protein expression (P<0.01), and more osteoclasts were activated in the PLAP-1 group (P<0.01). In conclusion, the present study found that PLAP-1 delays rat periodontal bone defect repair by inhibiting osteogenic differentiation and promoting osteoclast activation, mainly dependent on the upregulation of the RANKL/OPG ratio. PMID- 29251315 TI - Hepatic recruitment of CD11b+Ly6C+ inflammatory monocytes promotes hepatic ischemia/reperfusion injury. AB - Monocytes infiltrate damaged liver tissue during noninfectious liver injury and often have dual roles, perpetuating inflammation and promoting resolution of inflammation and fibrosis. However, how monocyte subsets distribute and are differentially recruited in the liver remain unclear. In the current study, the subpopulations of infiltrating monocytes were examined following liver ischemia/reperfusion (I/R) injury in mice using flow cytometry. CD11b+Ly6C high (Ly6Chi) cells (inflammatory monocytes) and CD11b+Ly6C low cells (reparative monocytes) were recruited into the liver following I/R injury. Treatment with clodronate-loaded liposomes, which transiently deplete systemic macrophages, alleviated hepatic damage. Mice genetically deficient in C-C motif chemokine ligand 2 (CCL2), or its receptor C-C chemokine receptor 2 (CCR2), exhibited diminished hepatic damage compared with wild-type mice following I/R, by controlling intrahepatic inflammatory Ly6Chi monocyte accumulation. In addition, the CCR2 specific inhibitor RS504393 alleviated hepatic I/R injury. The results suggest that the CCR2/CCL2 axis has an important role in monocyte infiltration and may represent a novel target for the treatment of liver I/R injury. PMID- 29251316 TI - Co-expression network analysis of lncRNAs and mRNAs in OPTN-silenced cells. AB - The aim of the present study was to reveal the role of long noncoding RNAs (lncRNAs) in the regulation of the pathogenesis of optineurin (OPTN)-silenced cells. The microarray data set GSE12452 was re-annotated using the non-coding RNA function annotation server to identify differentially expressed lncRNAs. Weighted correlation network analysis was used to construct an lncRNA-lncRNA co-expression network and identify co-expression modules. Three OPTN small interfering RNAs (siRNAs) were transiently transfected into HeLa cells. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect OPTN expression and select the most effective OPTN siRNA to construct stably transfected cells. RT-qPCR was used to quantify the identified lncRNAs in the OPTN-silenced cells. The potential functions of these modules were explored by the functional enrichment of the corresponding co-expressed genes. A total of 3,495 lncRNAs were re-annotated. Of these, matrix metalloprotease 12 and RP11-169D4.1 were upregulated, and RP1-212P9.2 was downregulated. The results of the RT-qPCR analysis of RP1-212P9.2 and RP11-169D4.1 were consistent with the re annotated data in the OPTN-silenced cells. Gene Ontology analyses indicated that the biological functions of the mRNAs co-expressed with these lncRNAs were associated with gene product regulation, and neuronal migration, polarity and differentiation. In addition, Kyoto Encyclopedia of Genes and Genomes analysis indicated that the two validated lncRNAs were associated with the transforming growth factor-beta signaling pathway and the apoptosis pathway, respectively. In conclusion, the abnormal lncRNAs identified in OPTN-silenced cells indicate that lncRNAs may contribute to the molecular pathogenesis of OPTN-associated diseases. PMID- 29251317 TI - Ethanol extract of Patrinia scabiosaefolia induces the death of human renal cell carcinoma 786-O cells via SIRT-1 and mTOR signaling-mediated metabolic disruptions. AB - Recently, natural plant extracts have shown tremendous potential as novel antitumor drugs. Patrinia scabiosaefolia, a traditional prescription for inflammatory diseases, has been reported to effectively suppress various types of cancers. However, the mechanisms underlying its antitumor properties remain elusive. In the present study, we investigated the antitumor effects of an ethanol extract of Patrinia scabiosaefolia (EPS) on human renal cell carcinoma 786-O cells. After 24 h of incubation with EPS, the cell viability and colony number of 786-O cells were significantly decreased in a concentration-dependent manner as compared to the control group as determined by MTT and colony formation assays, respectively. The necrotic rate and apoptotic rate in the EPS exposure group were significantly higher than these rates noted in the control group as revealed by LDH release assay and Hoechst 33342/ PI double staining, respectively. At the concentration of 1.0 mg/ml, the necrotic and apoptotic rates reached 41.7+/-6.6 and 7.8+/-1.4%, respectively (P<0.01). However, the fluorescence intensity of intracellular calcium concentration ([Ca2+]i) was markedly elevated from 0.029+/-0.0007 to 0.060+/-0.003 (P<0.001) after the intervention of EPS. Moreover, the fluorescence intensity of intracellular ROS in the EPS exposure group was significantly higher (0.074+/-0.005) compared to that observed in the control group (0.033+/-0.001, P<0.001), which was partly attenuated by the specific antioxidant N-acetylcysteine (NAC). Furthermore, our results demonstrated that EPS significantly downregulated the expression of SIRT 1 and obviously induced the dephosphorylation of mTOR. Moreover, combined treatment with the SIRT-1 inhibitor nicotinamide and EPS was able to significantly enhance the induction of necrosis and reduction in cell viability of 786-O cells noted following treatment with EPS alone. In summary, we conclude that EPS induced the death of 786-O cells via SIRT-1 and mTOR signaling-mediated metabolic disruptions, which provide novel insight into the application of natural plant extracts for the treatment of cancers. PMID- 29251318 TI - MIG7 is involved in vasculogenic mimicry formation rendering invasion and metastasis in hepatocellular carcinoma. AB - Migration-inducing gene 7 (MIG7) is highly expressed and is implicated in multiple malignant tumors with vasculogenic mimicry (VM) which renders possible routes without the endothelium for invasion and metastasis. However, there are few reports in the literature describing the relationship between MIG7 expression and VM formation in hepatocellular carcinoma (HCC). In the present study, we found a significantly positive correlation between MIG7 expression and VM in 40 HCC specimens. Three-dimensional (3D) culture showed that VM formation in the HCC cell line MHCC-97H with high metastatic potential was enhanced to a greater extent than that of MHCC-97L and Huh-7 with low and non-metastatic potential. There was no VM formation in human normal hepatocyte line L-02. Moreover, MIG7 expression was higher in MHCC-97H than in MHCC-97L and Huh-7 cells and non detectable in L-02 cells. MIG7 knockdown in MHCC-97H cells reduced VM formation, and weakened the invasive properties accompanying the enhanced cellular adhesion. Notably, there was no significant effect of endostatin (ES), a broad-spectrum angiogenesis inhibitor applied to clinical treatment, on both MIG7 expression and VM formation. Thus, the present study presents a causal link between MIG7 expression and VM formation in HCC, suggesting a potential treatment target for invasion and metastasis. PMID- 29251319 TI - delta-Catenin promotes tumorigenesis and metastasis of lung adenocarcinoma. AB - delta-Catenin coded by gene CTNND2 has been found to be overexpressed in various types of cancers, including prostate, breast, lung and ovarian cancers. However, the function of delta-catenin in lung carcinoma remains largely unknown. In the present study, we revealed that delta-catenin acts as an oncogene promoting the malignancy of lung adenocarcinoma. When delta-catenin proteins of Lewis lung cells were depleted by knocking out Ctnnd2 via CRISPR/Cas9 technology, the cells lost the tumorigenic and metastatic abilities in vivo. Consistently, overexpression of Ctnnd2 enhances the subcutaneous tumorigenesis and distant metastasis of Lewis lung cells in vivo. However, delta-catenin promotes cell proliferation and cell cycle progression of Lewis lung cells. Mechanistically, delta-catenin enhances G1-S phase transition in cooperation with canonical Wnt signaling in Lewis lung cells. Moreover, delta-catenin promotes oncosphere formation of lung adenocarcinoma cells and is associated with the expression of cancer stem cell markers, which indicates delta-catenin enhances colonization and invasion via cancer stem cell maintenance. Taken together, our data suggest that delta-catenin may serve an important role in the malignancy of lung adenocarcinoma through activating canonical Wnt signaling and cancer stem cell maintenance. Our research indicates that delta-catenin can be a new potential target for the treatment of lung adenocarcinoma. PMID- 29251320 TI - Mechanism of endogenous digitalis-like factor-induced vascular endothelial cell damage in patients with severe preeclampsia. AB - Although endogenous digitalis-like factor (EDLF) is associated with the development of various physical disorders, the role in preeclampsia remains unclear. This study investigated the effects of EDLF on vascular endothelial cell damage in patients with preeclampsia and the potential mechanisms. From July 2014 to July 2015, 120 singleton pregnancy cases underwent a prenatal examination, inpatient delivery and had normal blood pressure were included in the study, either as patients with severe preeclampsia or the control patients. Serum EDLF levels were compared in these two groups, and an in vitro hypoxic trophocyte induced vascular endothelial cell damage model was established to explore the changes in hypoxic trophocyte EDLF level and the subsequent effects on human umbilical vein endothelial cells (HUVECs). Nuclear factor-kappaB (NF-kappaB) p65 gene expression was silenced in hypoxic trophocytes, and EDLF levels and HUVEC damage were subsequently assessed. Serum EDLF levels were significantly higher in the severe preeclampsia cases than in the controls at the same gestational week (P<0.001). EDLF levels in hypoxic trophocytes increased with the increasing co culture duration. Damage to the biofunctions of HUVECs co-cultured with hypoxic trophocytes also increased with co-culture duration. However, silencing of NF kappaB p65 in the hypoxic trophocytes reduced the EDLF levels. Annexin A2 was highly expressed in HUVECs, and no biofunctions were significantly damaged (P<0.05) compared with the group without receiving NF-kappaB p65 silencing. Serum EDLF levels were significantly higher in patients with severe preeclampsia compared with the controls. The results of the current study indicate that NF kappaB p65 has a role in regulating EDLF production in hypoxic trophocytes. PMID- 29251321 TI - Antitumor potential of a novel camptothecin derivative, ZBH-ZM-06. AB - Camptothecin (CPT) is a cytotoxic quinoline alkaloid that is used clinically as an anticancer drug. However, the clinical application of CPT is limited due to its low solubility as well as serious and unfathomable side-effects. In the present study, we created a novel 10-hydroxy CPT prodrug, ZBH-ZM-06. Its cellular cytotoxic activity was analyzed in terms of cellular viability, acetylcholinesterase (AchE) inhibition, DNA relaxation, cellular cycling and apoptosis properties. Our results showed that the AchE inhibition rate of 10 umol/l ZBH-ZM-06 was 12.5%, compared to 96.5% for carbonyl-oxycamptothecin (CPT 11). In a chemical stability assay, only 4.9% of ZBH-ZM-06 remained after 4 h at pH 7.4. In addition, 10 umol/l ZBH-ZM-06 significantly inhibited the tumor cell viability of nine tumor cell lines, compared to CPT-11 and the CPT active ingredient, 7-ethyl-10-hydroxy-camptothecin (SN38) (p<0.01-0.05). In the apoptosis assay, ZBH-ZM-06 increased the ratio of annexin V+/propidium iodide (PI)-/+ cells by flow cytometric analysis (p<0.05). Moreover, ZBH-ZM-06 activated caspase-3 and poly(ADP-ribose)polymerase (PARP) expression by immunoblotting. Furthermore, ZBH-ZM-06 induced a greater G2/M phase arrest ratio, compared to CPT 11 and SN38. These results indicated that ZBH-ZM-06 had higher antitumor activity than CPT-11 and SN38, which was shown by its: i) release of the effective ingredient; ii) growth inhibition of a broad spectrum of tumor cells; iii) inhibition of DNA topoisomerase (Topo-1); and iv) promotion of apoptosis through an intrinsic signaling pathway. Thus, ZBH-ZM-06 may be applied in the preclinic study for cancer treatment. PMID- 29251322 TI - miR-29a inhibits human retinoblastoma progression by targeting STAT3. AB - Retinoblastoma (RB) is the most common malignancy that occurs during childhood. Growing evidence supports a crucial role for microRNAs (miRNAs) in regulating the initiation and progression of RB. Aberrant expression of microRNA-29a (miR-29a) has been found in many types of cancers, but not including RB. Therefore, the aims of the present study were to evaluate the regulatory role and underlying mechanism of miR-29a in human RB. In the present study, we found that miR-29a expression was significantly downregulated in RB tissues and cell lines. Overexpression of miR-29a in RB cells significantly inhibited cell proliferation, migration, and invasion and promoted cell apoptosis in vitro. Additionally, signal transducer and activator of transcription 3 (STAT3) was identified as a direct target of miR-29a in RB cells. miR-29a overexpression in RB cells not only inhibited STAT3 expression but also altered expression of its downstream genes, including, Bcl2, cyclin D1 and matrix metalloproteinase 2 (MMP-2). STAT3 mRNA expression was upregulated in RB tissues and negatively correlated with miR-29a expression. Reintroduction of STAT3 without 3'-untranslated region (3'UTR) reversed the inhibitory effects of miR-29a on cell proliferation, migration and invasion. In vivo study confirmed that overexpression of miR-29a also inhibited tumor formation of RB in a nude mouse model by repressing STAT3. Collectively, these data suggest that miR-29a exerts a tumor suppressor effect on RB by repressing STAT3, supporting the targeting of miR-29a as a potentially effective therapeutic method for RB. PMID- 29251323 TI - Investigation of the role of tumor necrosis factor-like weak inducer of apoptosis in non-small cell lung cancer. AB - Several of the soluble inflammatory molecules such as cytokines and chemokines are involved in the regulation of cancer behaviors. Tumor necrosis factor (TNF) like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily and is a ligand of fibroblast growth factor inducible 14 (Fn14). TWEAK/Fn14 signaling pathways promote tumor progression in several types of human cancer. In the present study, we investigated the role of TWEAK through bioinformatic assay, in vitro experiments, and serum levels in patients with non-small cell lung cancer (NSCLC). Our results indicated that TWEAK expression in normal tissues was higher than that in lung cancer tissues. In contrast, relatively higher Fn14 expression was detected in lung cancer tissues compared to normal tissues. Recombinant TWEAK treatment did not enhance and inhibit the proliferation and migration of human NSCLC cell lines including A549, H1299, CL1-0 and CL1-5. In addition, the serum concentration of TWEAK in normal controls was significantly higher than that in NSCLC patients. However, the TWEAK levels did not show significant difference in regards to TNM stage, cell type and metastasis status in the sera of NSCLC patients. In summary, the present study suggests that a low serum level of TWEAK may be a feature of NSCLC, and the role of TWEAK-mediated pathways warrant further investigation. PMID- 29251324 TI - MicroRNA-505 is downregulated in human osteosarcoma and regulates cell proliferation, migration and invasion. AB - Recent studies have demonstrated that microRNAs (miRNAs/miRs) are involved in osteosarcoma tumorigenesis, progression, invasion and metastasis. For example, miR-505 plays important roles in human carcinogenesis; however, its exact function in osteosarcoma remains unclear. MicroRNA profiles of osteosarcoma and normal tissues were obtained by miRNA microarray assays, which were validated by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Then, high-mobility group box 1 (HMGB1) expression was evaluated by qRT-PCR and western blot analysis. The correlation between miR-505 and HMGB1 was analyzed by Pearson correlation. In vitro, the biological functions of miR-505 were examined by wound healing, MTT and Transwell assays and western blot analysis in MG63 cells transfected with miRNA mimics or empty vector. Luciferase assay was utilized to assess whether HMGB1 is a target of miR-505. miRNA microarrays revealed 26 aberrant miRNAs in osteosarcoma tissues; miR-505 showed the most pronounced decrease (P<0.01), which was significantly associated with TNM stage and metastasis status (P<0.05). In addition, HMGB1 was highly expressed in osteosarcoma tissues (P<0.01), with a significantly negative correlation with miR 505 (r=-0.6679, P<0.001). Furthermore, miR-505 inhibited proliferation, migration and invasion abilities of MG63 cells (P<0.01). Moreover, luciferase activity of the HMGB1-3'-UTR plasmid was suppressed following miR-505 binding (P<0.01). Finally, HMGB1 overexpression partly reversed the effects of miR-505 on MG63 cells. In conclusion, miR-505 levels are decreased in osteosarcoma tissues, and reduced miR-505 expression is significantly associated with poorer clinical prognosis in patients with osteosarcomas. miR-505 inhibits osteosarcoma cell proliferation, migration and invasion by regulating HMGB1. PMID- 29251326 TI - Isoliquiritigenin inhibits the proliferation and induces the differentiation of human glioma stem cells. AB - Glioma stem cells (GSCs) have been proven to be resistant to various therapeutic strategies, such as temozolomide chemotherapy and radiotherapy, leading to glioma recurrence. Isoliquiritigenin (ISL), a menber of the flavonoids isolated from liquorice has been found to be a potent stimulator of cell differentiation and has potential application for treating various types of cancer including human brain glioma. However, the antitumor activity of ISL on GSCs and the signaling pathway underlying its therapeutic effects are poorly understood. In the present study, GSCs were isolated from SHG44 human glioma cells by serum-free culture and treated with ISL or DAPT (a Notch/gamma-secretase inhibitor). It was found that ISL dose-dependently inhibited GSC growth after 72 h of treatment and decreased the formation of tumor spheres. Meanwhile, GSCs differentiated into astrocytes and neurons. Furthermore, these therapeutic effects were accompanied by downregulation of Notch1 and Hes1 at the protein and mRNA levels. Taken together, our results demonstrated that ISL exhibits antitumor effects on GSCs by inhibiting proliferation and inducing differentiation. The therapeutic effect may be related to downregulation of the Notch1 signaling pathway. Application of ISL presents potential benefits for the treatment of human brain glioma. PMID- 29251325 TI - CD90 promotes cell migration, viability and sphere-forming ability of hepatocellular carcinoma cells. AB - Cluster of differentiation (CD)90 (Thy-1) was proposed as a marker for the liver cancer stem cells that are responsible for tumorigenic activity, however its involvement in the progression of hepatocellular carcinoma (HCC) remains unknown. The aim of the present study was to determine the effect of CD90 on the biological functions of HCC and to investigate the associated circular RNA (circRNA) involved in this process. The analysis of the in vitro data demonstrated that CD90+ cells isolated from SK-Hep-1 cells exhibited increased viability, migration and invasive abilities compared with CD90- cells. In addition, circRNA expression profiles in CD90+ and CD90- cells were screened using a microarray assay and hsa_circ_0067531 and hsa_circ_0057096 were identified to be expressed at significantly different levels. It was additionally demonstrated that the expression of hsa_circ_0067531 in HCC tissues was significantly decreased compared with normal adjacent tissues. Overall, the results of the present study suggested that CD90 may be used as a potential biomarker for HCC. Furthermore, it was demonstrated that hsa_circ_0067531 may affect the biological functions of CD90+ HCC cells and may be a promising candidate to aid in the diagnosis and therapy of HCC. PMID- 29251327 TI - Survival pathway of cholangiocarcinoma via AKT/mTOR signaling to escape RAF/MEK/ERK pathway inhibition by sorafenib. AB - Cholangiocarcinoma (CCC) is a strongly aggressive malignancy for which surgical resection is the only potential curative therapy. Sorafenib, a multikinase inhibitor of the RAF/MEK/ERK pathway, is a molecular-targeted drug that is approved for hepatocellular carcinoma (HCC) but not for CCC. The differences in signaling pathway characteristics under sorafenib treatment between HCC (HLF, Huh7, PLC/PRF/5) and CCC (RBE, YSCCC, Huh28) cell lines were therefore investigated using cell proliferation, western blotting, and apoptosis analyses. Sorafenib inhibited cell growth significantly less in CCC cells than in HCC cells, with lower suppression of ERK phosphorylation. Significantly decreased AKT Ser473 phosphorylation in HCC cells, and conversely enhanced phosphorylation of AKT Ser473 and mTORC2 in CCC cells, were observed with sorafenib treatment. Disassembly of the mTORC2 complex in RBE cells with siRNA targeting Rictor resulted in the downregulation of AKT Ser473 phosphorylation and enhanced apoptosis presumably via increased FOXO1, which consequently suppressed RBE cell proliferation. Phosphorylation of mTORC1 and autophagy were not influenced by sorafenib in CCC cells. Simultaneous administration of everolimus to suppress activated mTORC1 in RBE cells revealed that combined everolimus and sorafenib treatment under mTORC2 disassembly could enhance growth inhibition through the suppression of both sorafenib- and everolimus-dependent AKT Ser473 phosphorylation in addition to the inhibition of mTORC1 phosphorylation. Prevention of escape by AKT/mTOR signaling from the RAF/MEK/ERK pathway in sorafenib treatment by suppressing mTORC2 activity may lead to promising new approaches in CCC therapy. PMID- 29251328 TI - miR-141-3p suppresses proliferation and promotes apoptosis by targeting GLI2 in osteosarcoma cells. AB - MicroRNAs (miRNAs) have been reported as key regulators in numerous diseases including osteosarcoma. The function of microRNA-141-3p (miR-141-3p) and whether this function is achieved by regulation of GLI family zinc finger 2 (GLI2) in osteosarcoma remain unclear. In the present study, we found decreased expression of miR-141-3p, but increased expression of GLI2 in osteosarcoma tissues and cell lines. In addition, we demonstrated a negative correlation between miR-141-3p and GLI2. Furthermore, we revealed that elevation of miR-141-3p resulted in a marked inhibition of proliferation and promotion of apoptosis as well as an obviously decrease in GLI2 in osteosarcoma cell lines. Furthermore, we determined that GLI2 is a target of miR-141-3p by a constructed luciferase assay. In addition, we showed that miR-141-3p could negatively regulate GLI2 and its downstream parathyroid hormone-related protein 1 (PTHRP1). Finally, through a series of antisense experiments we confirmed that the effect of miR-141-3p on proliferation and apoptosis was achieved through the GLI2 pathway in osteosarcoma cells. The findings of the present study may provide a new target for treating osteosarcoma. PMID- 29251329 TI - BET bromodomain inhibitor JQ1 modulates microRNA expression in thyroid cancer cells. AB - Anaplastic thyroid carcinoma (ATC) represents the most lethal thyroid cancer sub type, currently unresponsive to standard treatments. Recently, bromodomain and extra-terminal (BET) proteins have emerged as attractive therapeutic targets in several diseases, including cancer. In different cancer models, the anti neoplastic activity of BET inhibitors such as JQ1, I-BET762 and I-BET151 have already been established, due to both direct and indirect effects. miRNAs are 20 22 nucleotide transcriptional regulators which play important roles in proliferation, differentiation and apoptosis. Hitherto, the relationship between JQ1 and miRNAs has not been explored. The goal of this study was to delineate JQ1 associated miRNA regulation in ATC cells. Two ATC-derived cell lines (SW1736 and 8505c) were treated with either 5 uM JQ1 or vehicle for 48 or 72 h. A non tumorigenic thyroid cell line (Nthy-ori 3-1) was used as a control. miRNome analysis displayed a JQ1-related dysregulation of several miRNAs, 7 of which turned out to be commonly dysregulated in both cell lines at both time-points. Furthermore, miR-4516 turned out to be downregulated in both ATC cell lines, when compared to the non-tumorigenic ones and notably, JQ1 treatment in both ATC cell lines induced its upregulation, restoring, in some way, its basal expression levels. We, therefore, focused on miR-4516 expression and STAT3 levels, since it was previously predicted to be a putative target of this microRNA. Consistently, phospho-STAT3 and its target p21Waf1/Cip1 turned out to be downregulated and upregulated in both JQ1-treated ATC cell lines, respectively. Thus, our data revealed that modulation of miRNA expression is one of the multiple mechanisms of the effect of JQ1 in thyroid cancer cells. PMID- 29251330 TI - STMN1, a prognostic predictor of esophageal squamous cell carcinoma, is a marker of the activation of the PI3K pathway. AB - The esophageal squamous cell carcinoma (ESCC) subtype with STMN1 overexpression has a high likelihood of lymphatic metastatic recurrence. However, the underlying mechanism remains to be further elucidated. We assessed the expression level of STMN1 and PTEN in 96 pN0 ESCC patient tissues using immunohistochemistry and western blot analysis. Then, the association between STMN1 overexpression and postoperative lymphatic metastatic recurrence was evaluated. In addition, the relationship between STMN1 and PTEN was also assessed. The results showed that STMN1 expression was significantly higher in tumor tissues (P=0.013). STMN1 overexpression was related to tumor length (P=0.003) and depth of invasion (P=0.019). In addition, STMN1 overexpression was significantly associated with postoperative lymphatic metastatic recurrence in pN0 ESCC patients. Patients with STMN1-overexpressing tumors had a higher 3-year lymphatic metastatic recurrence rate (P=0.024). Furthermore, in laboratory experiments, STMN1 expression was stably silenced using lentiviral vector delivery of shRNA in Eca109 and EC9706 cell lines to assess the functional effect of STMN1 in vitro. The results indicated that stable silencing of STMN1 expression significantly inhibited cell proliferation, migration and invasion. Moreover, we inactivated the PI3K pathway in ESCC cell lines with the PI3K inhibitor LY294002 and then detected STMN1 expression by western blot analysis. STMN1 levels were robustly reduced consistent with the downregulation of p-Akt (S473) by PI3K pathway inhibition. STMN1 can act as a marker to quantitatively measure the activation of the PI3K pathway and stratify patients accordingly. PMID- 29251331 TI - Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells. AB - Ovarian cancer (OC), of which epithelial ovarian cancer (EOC) is the most common, is the deadliest gynecological tumor because of the difficulties in detection at early stages, and metastasis and chemoresistance at advanced stages. Tumor associated macrophages (TAMs) differentiate through alternative pathways and play important roles in tumor growth and metastasis. However, the underlying mechanism remains unclear. Here, we established a mouse TAM model using bone marrow monocytes and conditioned medium (CM) of TAMs to culture ID8 mouse EOC cells. The results showed that TAM CM accelerated the proliferation and migration of ID8 cells. In a previous study, gene chip analysis showed that human TAMs expressed significantly higher levels of insulin-like growth factor-1 (IGF1) than undifferentiated M0 myeloid cells. In the present study, we observed that the IGF1 level was higher in human EOC specimens than that in benign ovarian tumor specimens, and further analysis showed that a higher level of IGF1 was related to more advanced clinical stage and liver metastasis. Therefore, we hypothesized that TAMs may accelerate the proliferation and migration of EOC cells by upregulating IGF1. As expected, increased IGF1 expression at both the mRNA and protein levels was observed in ID8 cells cultured with TAM CM, whereas blockade of the IGF1 pathway in ID8 cells with an IGF1 neutralizing antibody effectively reversed the promotion of proliferation and migration. Finally, we inhibited the phosphorylation of insulin-like growth factor-1 receptor (IGF1R) and its downstream molecules Akt and Erk with the IGF1R inhibitor linsitinib, and observed that the treatment effectively suppressed the proliferation and migration of ID8 cells exposed to TAM CM. Thus, we demonstrated that TAMs may promote the growth and metastasis of EOC via the activation of the IGF1 pathway; thus, targeting the IGF1 pathway may be promising for EOC therapy. PMID- 29251332 TI - Suppression of Kpnbeta1 expression inhibits human breast cancer cell proliferation by abrogating nuclear transport of Her2. AB - Breast cancer (BC) is one of the most fatal diseases and poses critical health problems worldwide. However, its mechanisms remain unclear. Consequently, there is an urgency to investigate the mechanisms involved in BC initiation and progression and identify novel therapeutics for its prevention and treatment. In this study, we identified karyopherin beta-1 (Kpnbeta1) as a possible novel therapeutic target for BC. Western blotting was used to evaluate the expression of Kpnbeta1 in four pairs of tumorous and adjacent non-tumorous tissues. The results revealed that the protein level of Kpnbeta1 was higher in the cancer samples compared with those in the corresponding normal samples. Immunohistochemistry was performed on 140 BC cases and indicated that Kpnbeta1 was significantly associated with clinical pathological variables. Kaplan-Meier curve revealed that high expression of Kpnbeta1 was related to poor BC patient prognosis. A starvation and re-feeding assay was used to imitate the cell cycle using the SKBR-3 cell line, indicating that Kpnbeta1 plays a critical role in cell proliferation. The Cell Counting Kit-8 assay revealed that SKBR-3 cells treated with Kpnbeta1-siRNA (siKpnbeta1) grew more slowly than the control cells, while flow cytometry revealed that low-Kpnbeta1 expressing SKBR-3 cells exhibited increased BC cell apoptosis. Furthermore, the interaction between Kpnbeta1 and Her2 was clearly observed by immunoprecipitation, indicating that Kpnbeta1 knockdown abrogated nuclear transport of Her2. In summary, our findings revealed that Kpnbeta1 is involved in the progression of BC and may be a useful therapeutic target. PMID- 29251334 TI - Niclosamide acts as a new inhibitor of vasculogenic mimicry in oral cancer through upregulation of miR-124 and downregulation of STAT3. AB - Tumors require nutrients and oxygen for growth and metastasis. Vasculogenic mimicry (VM) has been found as a new manner of blood supply, which is characterized as the formation of tumor cell-lined vessels instead of endothelial vessels. This is why angiogenesis agents targeted to endothelial cells show a limited efficacy. Up to this point, there is no effective drug reported for inhibiting VM formation. Niclosamide is an oral anti-helminthic drug used to treat human tapeworms. Recent studies have indicated that niclosamide has broad applications for cancer and other diseases. In this study, we found that niclosamide could not only inhibit proliferation and promote apoptosis of oral cancer cells, but also inhibited VM formation in vitro and in vivo through downregulation of the expression of VM-related genes VEGFA, MMP2, ROCK1 and Cdc42. In addition, niclosamide upregulated miR-124 and downregulate phosphorylated (p)-STAT3 expression. Further studies showed that, the stable highly expressing miR-124 cell line HN6-miR-124, such as niclosamide, could downregulate p-STAT3 expression. Moreover, HN6-miR-124 showed lower mobility, invasiveness and VM formation ability than control cells. Taken together, our study suggests that niclosamide functions as a new inhibitor of VM in oral cancer through upregulation of miR-124 and downregulation of STAT3, providing a new and safe potential drug candidate for anti-VM therapy. PMID- 29251333 TI - Efficacy of ribavirin against malignant glioma cell lines: Follow-up study. AB - Ribavirin, a nucleic acid analog, has been employed as an antiviral agent against RNA and DNA viruses and has become the standard agent used for chronic hepatitis C in combination with interferon-alpha2a. Furthermore, the potential antitumor efficacy of ribavirin has attracted increasing interest. Recently, we demonstrated a dose-dependent antitumor effect of ribavirin for seven types of malignant glioma cell lines. However, the mechanism underlying the antitumor effect of ribavirin has not yet been fully elucidated. Therefore, the main aim of the present study was to provide further relevant data using two types of malignant glioma cell lines (U-87MG and U-138MG) with different expression of MGMT. Dotted accumulations of gammaH2AX were found in the nuclei and increased levels of ATM and phosphorylated ATM protein expression were also observed following ribavirin treatment (10 uM of ribavirin, clinical relevant concentration) in both the malignant glioma cells, indicating double-strand breaks as one possible mechanism underlying the antitumor effect of ribavirin. In addition, based on assessements using FACS, ribavirin treatment tended to increase the G0/G1 phase, with a time-lapse, indicating the induction of G0/G1 phase arrest. Furthermore, an increased phosphorylated p53 and p21 protein expression was confirmed in both glioma cells. Additionally, analysis by FACS indicated that apoptosis was induced following ribavirin treatment and caspase cascade, downstream of the p53 pathway, which indicated the activation of both exogenous and endogenous apoptosis in both malignant glioma cell lines. These findings may provide an experimental basis for the clinical treatment of glioblastomas with ribavirin. PMID- 29251335 TI - In vitro and in vivo anticancer effects of marmesin in U937 human leukemia cells are mediated via mitochondrial-mediated apoptosis, cell cycle arrest, and inhibition of cancer cell migration. AB - Leukemia is one of the highly lethal cancers among all pediatric cancers. With limited drug options and the severe side effects associated with the current chemotherapy, there is pressing need to look for new and novel anticancer agents. Against this backdrop, in the present study we evaluated the anticancer activity of a natural coumarin, marmesin against human leukemia cell line U937 and normal human monocytes It was observed that marmesin exhibited an IC50 value of 40 uM and exerted its cytotoxic effects in a dose-dependent manner. However, the cytotoxic effects of marmesin were comparatively lower for the normal human monocytes as evident from the IC50 of 125 uM. Our results indicated that marmesin inhibits colony formation and induces apoptosis dose-dependently. We also investigated the effect of marmesin on the expression of Bax and Bcl-2 proteins. It was observed that marmesin treatment triggered upregulation of Bax and downregulation of Bcl-2 causing significant increase in the Bax/Bcl-2 ratio, marmesin could also induce ROS mediated alterations in mitochondrial membrane potential. Additionally, marmesin induced G2/M cell cycle arrest and significantly inhibited cell migration potential of leukemia cells at the IC50. Remarkably, marmesin prevent tumor growth significantly in vivo at the dosage of 30 mg/kg in vivo. These results strongly indicate that marmesin may prove to be a novel anticancer lead for the management of leukemia. PMID- 29251336 TI - [Bilateral two-stage implantation for deep brain stimulation in the treatment of bilateral idiopathic Parkinson's disease: clinical outcomes]. AB - AIMS: Simultaneous bilateral implantation of electrodes in the subthalamic nucleus for idiopathic Parkinson's disease (IPD) is associated with long surgery time, language disorders and post-operative confusion. Moreover, there is evidence of ipsilateral improvement after stimulation of the subthalamic nucleus. In order to optimise perioperative management a prospective study is conducted with deep brain stimulation (DBS) in the subthalamic nucleus in two consecutive unilateral procedures. PATIENTS AND METHODS: We conducted a prospective study of 41 patients with bilateral IPD, with DBS implantation in two unilateral surgical phases. Its clinical outcomes are analysed according to the Unified Parkinson's Disease Rating Scale (UPDRS), the Hoehn and Yahr, and the Schwab and England scales, together with their complications. RESULTS: The mean age was 61 +/- 7 years old, 23 males. Five patients (12%) did not undergo surgery of the contralateral subthalamic nucleus due to good control. The mean on the motor UPDRS and the Hoehn and Yahr in preoperative pharmacological off was 44 +/- 14 and 3, respectively, and 19 +/- 8 and 1.8 at six months' follow-up. The mean improvement on the Schwab and England scale in the pre-operative period and at six months was 39%. Two patients suffered post-operative confusion, and one of them had transient dysarthria. CONCLUSIONS: Bilateral DBS in two unilateral stages was an effective option with few complications in our series of patients with IPD. 10% of the patients did not require contralateral electrodes. It would be necessary to conduct a randomised study in patients who underwent bilateral surgery in one and two stages in order to confirm these results. PMID- 29251337 TI - [Analysis of the direct costs associated with mechanical thrombectomy and intravenous fibrinolysis in the Hospital Universitario Central de Asturias]. AB - INTRODUCTION: The increase in the indications for mechanical thrombectomy and its implementation in Spanish hospitals makes it necessary to determine the costs related to this treatment so as to be able to streamline economic resources and allow them to be distributed in an appropriate manner. AIMS: To analyse the direct costs associated with patients with acute ischaemic stroke who are treated with intravenous fibrinolysis and with mechanical thrombectomy, and to assess the effectiveness and safety of both treatments during the first 90 days of progression in the Hospital Universitario Central de Asturias. PATIENTS AND METHODS: A retrospective analysis was performed that included 44 patients who received intravenous fibrinolysis and 61 patients treated with mechanical thrombectomy, in whom a series of clinical and economic variables were analysed. RESULTS: The mean final total cost per patient was 16,059 euros in treatments with thrombectomy and 8,169 euros in those in which intravenous fibrinolysis was administered. The percentage of patients with a good functional prognosis at 90 days was 63.93% in those treated by endovascular means and 56.82% in those who received intravenous fibrinolysis. Mortality rates were 18.03 and 11.36%, respectively. CONCLUSIONS: The mean cost of treatment with mechanical thrombectomy, as well as the total mean cost per patient during the acute phase of the disease associated with this technique, is higher than in the case of intravenous fibrinolysis. In our setting, both intravenous fibrinolysis and mechanical thrombectomy are considered to be effective and safe. PMID- 29251338 TI - [Pharmacological treatment compliance and a description of its associated factors in patients with myasthenia gravis]. AB - INTRODUCTION: Medication adherence is a public health problem and this has not been previously studied in myasthenia gravis patients. AIM: To determine if patients with myasthenia gravis are adherent to treatment and to describe the clinical factors of patients who are non-adherent to treatment. PATIENTS AND METHODS: Cross-sectional study of patients with myasthenia gravis followed at Padre Hurtado Hospital, Santiago de Chile, who received their medication through the hospital and therefore were on the pharmacy's list. Patients' participation was voluntary and anonymous. Medication adherence was assessed with the Morisky Green-Levine survey (4 items). Patients were assessed for myasthenia gravis severity with the Manual Muscle Test, and myasthenia gravis-related quality of life with the MG-QOL15. Finally, patients were screened for depression with the 12-Item General Health Questionnaire. RESULTS: 26 patients were enrolled and 15 (57.7%) were women. Only 10 (38.5%) of patients were adherent to treatment. Patients who were not adherent to medication had more weakness (p = 0.06), worse quality of life (p = 0.008), were taking a greater number of myasthenia gravis drugs (p = 0.003) and had a higher risk of depression (p = 0.03). CONCLUSIONS: In this cohort of myasthenia gravis patients, three out of five patients were not adherent to treatment. These patients tended to have more weakness, worse quality of life and higher risk of depression. Medication adherence should be assessed routinely in patients with myasthenia gravis. PMID- 29251339 TI - [Extramedullary intradural tuberculosis: a case report and review of the literature]. AB - INTRODUCTION: Central nervous system tuberculosis is a common chronic infection in developing countries, being the most frequent forms: tuberculous meningitis and intracranial tuberculosis. Extramedullary intradural tuberculosis is a rare entity with few cases described in the world literature, and is usually associated with a history of tuberculous meningitis or during antituberculosis treatment. CASE REPORT: A 17 years-old male patient, without history of tuberculosis, with subacute onset and progressive course of compressive myelopathy. Spinal magnetic resonance imaging revealed an intradural extramedullary mass lesion between the C4 and T8 spinal levels. Surgical resection of tuberculoma was realized, followed by chemotherapy. The histopathological study confirmed the diagnostic. CONCLUSIONS: Tuberculosis of the central nervous system is an entity of high incidence in developing countries, and intradural extramedullary tuberculoma should be included in the differential diagnosis of expansive spinal cord injuries, especially if the patient is young and there is a history of pulmonary tuberculosis or tuberculous meningitis. It is also important to take it into account as part of a paradoxical reaction after the initiation of specific treatment. Although surgical resection improves compressive medullary symptoms, medical therapy remains the mainstay in the treatment of tuberculomas. PMID- 29251340 TI - [Rituximab: its efficacy, effectiveness and safety in the treatment of multiple sclerosis]. AB - INTRODUCTION: There is increasing evidence that B cells and humoral immunity play key roles in the pathogenesis of multiple sclerosis (MS). Ocrelizumab, an anti CD20 monoclonal antibody, has been shown to be effective in controlling the disease and has recently been aproved by the Food and Drug Administration for the treatment of primary progressive and relapsing MS. While awaiting its marketing authorization, the use of rituximab, with a similar mechanism of action, has expanded widely in the area of demyelinating diseases. AIM: To address the main aspects of efficacy, effectiveness and safety of rituximab in the treatment of MS. DEVELOPMENT: PubMed review of placebo-controlled clinical trials, prospective open label studies, retrospective observational studies, and case series using rituximab in adult MS affected populations were performed. Its impact on the clinical and radiological control of the disease was evaluated, as well as any relevant safety issues. CONCLUSIONS: In all of the studies reviewed, rituximab demonstrated a consistent benefit in controlling inflammatory activity, both clinically, reducing the incidence of relapses, and radiologically, avoiding the appearance of new and/or active lesions. On the contrary, with regards to the progression of disability, its effect is more controversial. Safety profile appears acceptable. Rituximab seems to be an effective and safe drug in the treatment of MS. PMID- 29251341 TI - [Isolated dysarthria and dysphagia as the presenting symptoms of simultaneous bilateral acute lagunar ischaemic stroke]. PMID- 29251342 TI - [Morphological study with ultrasound imaging in meralgia paraesthetica: in search of therapeutic efficiency]. PMID- 29251343 TI - Evaluating Food Policy Councils Using Structural Equation Modeling. AB - At least 282 Food Policy Councils (FPCs) are currently working to improve access to healthy foods in their communities by connecting food system sectors, gathering community input, and advising food policy. Empirical research on FPCs is limited. This study empirically evaluates FPCs to better understand the relationships between Organizational Capacity, Social Capital, and Council Effectiveness by testing a FPC Framework adapted from Allen and colleagues (2012). Members of all FPCs in the U.S., Canada, and Native American Tribes and First Nations were invited to complete the Food Policy Council Self-Assessment Tool (FPC-SAT). Structural equation modeling was used to test the FPC Framework. Three hundred and fifty-four FPC members from 95 councils completed the FPC-SAT. After slight modification, a revised FPC Framework was a good fit with the data (chi2 = 40.085, df = 24, p-value = .021, comparative fit index = 0.988, Tucker Lewis index = 0.982, root mean squared error of approximation = 0.044, p-close = .650). A moderation analysis revealed that community context influences the relationship between Social Capital and Council Effectiveness within the FPC Framework. The FPC Framework can guide capacity building interventions and FPC evaluations. The empirically tested framework can help FPCs efficiently work toward achieving their missions and improving their local food system. PMID- 29251344 TI - Understanding Systems Change in Early Implementation of Housing First in Canadian Communities: An Examination of Facilitators/Barriers, Training/Technical Assistance, and Points of Leverage. AB - We present interim findings of a cross-site case study of an initiative to expand Housing First (HF) in Canada through training and technical assistance (TTA). HF is an evidence-based practice designed to end chronic homelessness for consumers of mental health services. We draw upon concepts from implementation science and systems change theory to examine how early implementation occurs within a system. Case studies examining HF early implementation were conducted in six Canadian communities receiving HF TTA. The primary data are field notes gathered over 1.5 years and evaluations from site-specific training events (k = 5, n = 302) and regional network training events (k = 4, n = 276). We report findings related to: (a) the facilitators of and barriers to early implementation, (b) the influence of TTA on early implementation, and (c) the "levers" used to facilitate broader systems change. Systems change theory enabled us to understand how various "levers" created opportunities for change within the communities, including establishing system boundaries, understanding how systems components can function as causes of or solutions to a problem, and assessing and changing systems interactions. We conclude by arguing that systems theory adds value to existing implementation science frameworks and can be helpful in future research on the implementation of evidence-based practices such as HF which is a complex community intervention. Implications for community psychology are discussed. PMID- 29251346 TI - Highlighting the Way Forward: A Review of Community Mental Health Research and Practice Published in AJCP and JCP. AB - Articles published in the two most prominent journals of community psychology in North America, the American Journal of Community Psychology (AJCP) and Journal of Community Psychology (JCP), provide a clear indicator of trends in community research and practice. An examination of community psychology's history and scholarship suggests that the field has reduced its emphasis on promoting mental health, well-being, and liberation of individuals with serious mental illnesses over the past several decades. To further investigate this claim, the current review presents an analysis of articles relevant to community mental health (N = 307) published in the American Journal of Community Psychology (AJCP) and Journal of Community Psychology (JCP) from 1973 to 2015. The review focuses on article characteristics (e.g., type of article and methods employed), author characteristics, topic areas, and theoretical frameworks. Results document a downward trend in published articles from the mid-1980s to mid-2000s, with a substantial increase in published work between 2006 and 2015. A majority of articles were empirical and employed quantitative methods. The most frequent topic area was community mental health centers and services (n = 49), but the past three decades demonstrate a clear shift away from mental health service provision to address pressing social issues that impact community mental health, particularly homelessness (n = 42) and community integration of adults with serious mental illnesses (n = 40). Findings reflect both the past and present state of community psychology and suggest promising directions for re-engaging with community mental health and fostering well-being, inclusion, and liberation of adults experiencing serious mental health challenges. PMID- 29251345 TI - The mutagenesis of a type IV secretion system locus of Piscirickettsia salmonis leads to the attenuation of the pathogen in Atlantic salmon, Salmo salar. AB - Piscirickettsiosis is a threatening infectious disease for the salmon industry, due to it being responsible for significant economic losses. The control of outbreaks also poses considerable environmental challenges. Despite Piscirickettsia salmonis having been discovered as the aetiological agent of the disease more than 25 years ago, its pathogenicity remains poorly understood. Among virulence factors identified so far, type four secretion systems (T4SS) seem to play a key role during the infection caused by the bacterium. We report here the genetic manipulation of P. salmonis by means of the transference of plasmid DNA in mating assays. An insertion cassette was engineered for targeting the icmB gene, which encodes a putative T4SS-ATPase and is carried by one of the chromosomal T4SS clusters found within the genome of P. salmonis PM15972A1, a virulent representative of the EM-90-like strain. The molecular characterization of the resulting mutant strain demonstrated that the insertion interrupted the target gene. Further in vitro testing of the icmB mutant showed a dramatic drop in infectivity as tested in CHSE-214 cells, which is in agreement with its attenuated behaviour observed in vivo. Altogether, our results demonstrate that, similar to other facultative intracellular pathogens, P. salmonis' virulence relies on an intact T4SS. PMID- 29251347 TI - Engineering tunable biosensors for monitoring putrescine in Escherichia coli. AB - Biosensors can be a powerful tool for real-time monitoring of specific small molecules and for precise control of gene expression in biological systems. Thus, biosensors have attracted much attention for monitoring increasing number of molecules. However, strategies to tune the properties of biosensors remain less explored, which might restrict their wide applicability. Here we report the development of tunable biosensors for monitoring putrescine, an important member of biological polyamines, in Escherichia coli. The native putrescine-responsive PuuR repressor protein was employed as a sensing component, and its cognate operator was installed in engineered promoters to control the expression of downstream green fluorescent protein (GFP) mut3 as a reporter protein. The engineered biosensors were specific for putrescine, and the response time could be modulated by altering growth medium of the biosensor strains. In addition, the response dynamics and detection ranges of the biosensors can be tuned at the genetic level by modulation of PuuR expression, and by manipulation of the chromosomal genes involved in putrescine biosynthesis. To demonstrate utility of the biosensors, we were able to monitor the changes of endogenous putrescine levels caused by genetic manipulations. Furthermore, a link between the excretory putrescine titer and intracellular GFP fluorescence was established for an E. coli strain that was engineered for improved putrescine biosynthesis and excretion. This study provides a strategy for engineering synthetic biosensor circuit for monitoring and tuning the dynamics in sensing putrescine, which can be generally applicable for monitoring other chemicals through taking a similar approach in circuit design. PMID- 29251348 TI - Using Geospatial Research Methods to Examine Resource Accessibility and Availability as it Relates to Community Participation of Individuals with Serious Mental Illnesses. AB - Greater community participation among individuals with serious mental illnesses is associated with better psychosocial and health outcomes. Typically, studies examining community participation have utilized self-report measures and been conducted in limited settings. The introduction of methodological advances to examining community participation of individuals with serious mental illnesses has the potential to advance the science of community mental health research and invigorate the work of community psychologists in this area. This study employed an innovative geospatial approach to examine the relationship between community participation and resource accessibility (i.e., proximity) and availability (i.e., concentration) among 294 individuals utilizing community mental health services throughout the United States. Findings suggest small but significant associations between community participation and the accessibility and availability of resources needed for participation. Furthermore, findings demonstrate the importance of car access for individuals residing in both urban and non-urban settings. The methods and results presented in this study have implications for community mental health research and services and provide an illustration of ways that geospatial methodologies can be used to investigate environmental factors that impact community inclusion and participation of individuals with serious mental illnesses. PMID- 29251349 TI - Hypoxia and transforming growth factor-beta1 pathway activation promote Chinese Hamster Ovary cell aggregation. AB - Suspension cultivation is the preferred mode of operation for the large-scale production of many biologics. Chinese Hamster Ovary (CHO) cells are anchorage dependent in origin, but they have been widely adapted to suspension culture. In suspension culture, formation of CHO cell aggregates is a common phenomenon and compromises cell culture performance in multiple ways. To better understand the underlying mechanisms that regulate cell aggregation, we utilized CHO-specific transcriptome profiling as a screening tool and demonstrated that many genes encoding extracellular matrix (ECM) proteins were upregulated in the cultures with increased cell aggregation. Significantly, hypoxia was identified to be a cause for promoting CHO cell aggregation, and transforming growth factor beta1 (TGFbeta1) pathway activation served as an intermediate step mediating this biological cascade. These transcriptomics findings were confirmed by cell culture experiments, and it was further demonstrated that adding recombinant TGFbeta1 to the culture significantly increased ECM protein fibronectin expression and cell aggregation. The results of this study emphasize the importance of adequate mixing and oxygen supply for suspension cultures from a new angle, and regulating the TGFbeta1 pathway is proposed as a new strategy for mitigating cell aggregation to improve cell culture performance. PMID- 29251350 TI - Engineered cell migration to lesions linked to autoimmune disease. AB - The damaging and degenerative effects in autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and Crohn's disease often manifests as the formation of lesions that feature a high local concentration of granulocyte macrophage colony-stimulating factor (GM-CSF). GM-CSF along with other pro inflammatory factors form a positive feedback loop that ultimately perpetuate the lesions. Hence, to engineer chemotaxis to GM-CSF, we created a new chimeric GM CSF receptor alpha subunit (GMRchi) that was coupled with a previously engineered Ca2+ -activated RhoA. When these proteins were expressed in mammalian cells, it allowed migration to chemical and cellular sources of GM-CSF. As a possible therapeutic intervention, we further implemented the mechanism of cell-cell membrane fusion and subsequent death. Since the microenvironment of lesions is more than just GM-CSF secretion, the further ability to recognize a combination of other features such as tissue markers will be needed for greater specificity. Nonetheless, this work represents a first step to enable cell-based therapy of autoimmune lesions. PMID- 29251351 TI - 3D stromal tissue equivalent affects intestinal epithelium morphogenesis in vitro. AB - Current in vitro models of human intestine commonly fail to mimic the complex intestinal functions and features required for drug development and disease research. Here, we deeply investigate the interaction existing between epithelium and the underneath stroma, and its role in the epithelium morphogenesis. We cultured human intestinal subepithelial myofibroblasts (ISEMFs) in two different 3D configurations: 3D-collagen gel equivalent (3D-CGE) and 3D cell-synthetized stromal equivalent (3D-CSSE). The 3D-CGEs were obtained by means of the traditional collagen-based cell technique and the 3D-CSSE were obtained by bottom up tissue engineering strategy. The biophysical properties of both 3D models with regard to cell growth and composition (via histological analysis, immunofluorescence, and multiphoton imaging) were assessed. Then, human colorectal adenocarcinoma cell line (CaCo-2) was cultured on both the 3D constructs in order to produce the intestinal model. We identified higher levels of matrix-associated proteins from ISEMFs cultured in 3D-CSSE compared to 3D-CGE. Furthermore, multiphoton investigation revealed differences in the collagen network architecture in both models. At last, the more physiologically relevant stromal environment of the 3D-CSSE drove the CaCo-2 cell differentiation toward the four different type of intestinal epithelial cells (absorptive, mucus secretory, enteroendocrine, and Paneth) phenotype and promotes, in contrast to the 3D-CGE, the production of the basement membrane. Taken together, these results highlight a fundamental role of the 3D stromal environment in addressing a correct epithelium morphogenesis as well as epithelial-stromal interface establishment. PMID- 29251353 TI - Uniform magnetic targeting of magnetic particles attracted by a new ferromagnetic biological patch. AB - A new non-toxic ferromagnetic biological patch (MBP) was designed in this paper. The MBP consisted of two external layers that were made of transparent silicone, and an internal layer that was made of a mixture of pure iron powder and silicon rubber. Finite-element analysis showed that the local inhomogeneous magnetic field (MF) around the MBP was generated when MBP was placed in a uniform MF. The local MF near the MBP varied with the uniform MF and shape of the MBP. Therefore, not only could the accumulation of paramagnetic particles be adjusted by controlling the strength of the uniform MF, but also the distribution of the paramagnetic particles could be improved with the different shape of the MBP. The relationship of the accumulation of paramagnetic particles or cells, magnetic flux density, and fluid velocity were studied through in vitro experiments and theoretical considerations. The accumulation of paramagnetic particles first increased with increment in the magnetic flux density of the uniform MF. But when the magnetic flux density of the uniform MF exceeded a specific value, the magnetic flux density of the MBP reached saturation, causing the accumulation of paramagnetic particles to fall. In addition, the adsorption morphology of magnetic particles or cells could be improved and the uniform distribution of magnetic particles could be achieved by changing the shape of the MBP. Also, MBP may be used as a new implant to attract magnetic drug carrier particles in magnetic drug targeting. Bioelectromagnetics. 39:98-107, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29251352 TI - Microfluidic platforms for the study of neuronal injury in vitro. AB - Traumatic brain injury (TBI) affects 5.3 million people in the United States, and there are 12,500 new cases of spinal cord injury (SCI) every year. There is yet a significant need for in vitro models of TBI and SCI in order to understand the biological mechanisms underlying central nervous system (CNS) injury and to identify and test therapeutics to aid in recovery from neuronal injuries. While TBI or SCI studies have been aided with traditional in vivo and in vitro models, the innate limitations in specificity of injury, isolation of neuronal regions, and reproducibility of these models can decrease their usefulness in examining the neurobiology of injury. Microfluidic devices provide several advantages over traditional methods by allowing researchers to (1) examine the effect of injury on specific neural components, (2) fluidically isolate neuronal regions to examine specific effects on subcellular components, and (3) reproducibly create a variety of injuries to model TBI and SCI. These microfluidic devices are adaptable for modeling a wide range of injuries, and in this review, we will examine different methodologies and models recently utilized to examine neuronal injury. Specifically, we will examine vacuum-assisted axotomy, physical injury, chemical injury, and laser-based axotomy. Finally, we will discuss the benefits and downsides to each type of injury model and discuss how researchers can use these parameters to pick a particular microfluidic device to model CNS injury. PMID- 29251354 TI - Sensitivity assessment of sea lice to chemotherapeutants: Current bioassays and best practices. AB - Traditional bioassays are still necessary to test sensitivity of sea lice species to chemotherapeutants, but the methodology applied by the different scientists has varied over time in respect to that proposed in "Sea lice resistance to chemotherapeutants: A handbook in resistance management" (2006). These divergences motivated the organization of a workshop during the Sea Lice 2016 conference "Standardization of traditional bioassay process by sharing best practices." There was an agreement by the attendants to update the handbook. The objective of this article is to provide a baseline analysis of the methodology for traditional bioassays and to identify procedures that need to be addressed to standardize the protocol. The methodology was divided into the following steps: bioassay design; material and equipment; sea lice collection, transportation and laboratory reception; preparation of dilution; parasite exposure; response evaluation; data analysis; and reporting. Information from the presentations of the workshop, and also from other studies, allowed for the identification of procedures inside a given step that need to be standardized as they were reported to be performed differently by the different working groups. Bioassay design and response evaluation were the targeted steps where more procedures need to be analysed and agreed upon. PMID- 29251355 TI - Identification of anti-inflammatory active ingredients from Tumuxiang by ultra performance liquid chromatography/quadrupole time-of-flight-MSE. AB - The dried roots of Inula helenium L. (IH) and Inula racemosa Hook f. (IR) are used commonly as folk medicine as 'tumuxiang' (TMX). The mixing and sharing of IH and IR in clinical use is a universal phenomenon. Modern pharmacological studies confirmed that IH and IR display anti-inflammatory activities. However, the difference in anti-inflammatory pharmacodynamic substances between these two herbs is still unknown. In the present study, the fingerprints of 18 IH and nine IR samples were established using UPLC/QTOF-MSE . A dimethylbenzene-induced mouse ear vasodilation model was applied in evaluating the anti-inflammatory properties of all 27 samples. Then, the spectrum-efficacy model between chemical characteristic peaks and anti-inflammatory activities was investigated using principal component regression and partial least squares. Finally, the combination of UNIFI Scientific Information System with a library search of traditional Chinese medicines was employed to automatically characterize the peaks. UNIFI identified a total of 80 chemical components. Among the components, the 53 characteristic peaks showed correlation with anti-inflammatory activities, pointing to phenolic and organic acids as primary anti-inflammatory ingredients of TMX. This approach can efficiently and intelligently facilitate the identification of bioactive components from traditional Chinese medicine. PMID- 29251356 TI - HPLC-MS/MS analysis of anthocyanins in human plasma and urine using protein precipitation and dilute-and-shoot sample preparation methods, respectively. AB - A high-performance liquid chromatography tandem-mass spectrometry (HPLC-MS/MS) method has been developed to analyze anthocyanins in urine and plasma to further understand their absorption, distribution, metabolism and excretion. The method employed a Synergi RP-Max column (250 * 4.6 mm, 4 MUm) and an API 4000 mass spectrometer. A gradient elution system consisted of mobile phase A (water-1% formic acid) and mobile phase B (acetonitrile) with a flow rate of 0.60 mL/min. The gradient was initiated at 5% B, increased to 21% B at 20 min, and then increased to 40% B at 35 min. The analysis of anthocyanins presents a challenge because of the poor stability of anthocyanins during sample preparation, especially during solvent evaporation. In this method, the degradation of anthocyanins was minimized using protein precipitation and dilute-and-shoot and sample preparation methods for plasma and urine, respectively. No interferences were observed from endogenous compounds. The method has been used to analyze anthocyanin concentrations in urine and plasma samples from volunteers administered saskatoon berries. Cyanidin-3-galactoside, cyanidin-3-glucoside, cyanidin-3-arabinoside, cyanidin-3-xyloside and quercetin-3-galactoside, the five major flavonoid components in saskatoon berries, were identified in plasma and urine samples. PMID- 29251357 TI - Epigenetic and Transcriptional Variability Shape Phenotypic Plasticity. AB - Epigenetic and transcriptional variability contribute to the vast diversity of cellular and organismal phenotypes and are key in human health and disease. In this review, we describe different types, sources, and determinants of epigenetic and transcriptional variability, enabling cells and organisms to adapt and evolve to a changing environment. We highlight the latest research and hypotheses on how chromatin structure and the epigenome influence gene expression variability. Further, we provide an overview of challenges in the analysis of biological variability. An improved understanding of the molecular mechanisms underlying epigenetic and transcriptional variability, at both the intra- and inter individual level, provides great opportunity for disease prevention, better therapeutic approaches, and personalized medicine. PMID- 29251358 TI - Acute kidney injury post-transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) is a treatment option in high-risk patients with severe aortic stenosis who are not surgical candidates. In light of emerging evidence, it is being increasingly performed even in intermediate-risk patients in recent years. Patients who develop acute kidney injury (AKI) following TAVR are known to have worse outcomes. The objective of this concise review was to identify the prevalence and the impact of AKI following TAVR on patient outcomes by including the most recent literature in our search. After a thorough search on MEDLINE, Google Scholar, and PubMed, we included all literature relevant to AKI following TAVR. We found that AKI was caused by a variety of reasons, such as hemodynamic instability during rapid pacing, blood transfusion, periprocedural embolization, and use of contrast medium, to name a few. In patients who developed AKI following TAVR, 30-day and 1-year mortality were increased. Further, in these patients, length and cost of hospital stay were increased as well. Preventive measures such as optimal periprocedural hydration, careful contrast use, and techniques to prevent embolization during device implantation have been tried with limited success. Given that TAVR is expected to be increasingly performed, this review aimed to summarize the rapidly expanding currently available literature in an effort to reduce procedural complications and thereby improve patient outcomes. PMID- 29251360 TI - Laboratory characteristics of ischemic stroke patients with atrial fibrillation on or off therapeutic warfarin. AB - BACKGROUND: In patients with atrial fibrillation (AF), despite adequate anticoagulation, ischemic stroke (IS) is an uncommon yet concerning occurrence. HYPOTHESIS: Specific laboratory parameters may affect the efficacy of warfarin despite therapeutic international normalized ratio (INR) in patient with AF who present with IS. METHODS: We used the database from a multicenter clinical trial to identify AF patients who presented with IS. We trichotomized the cohort into patients with therapeutic INR on warfarin, subtherapeutic INR on warfarin, and on no anticoagulants. We then compared baseline laboratory characteristics and other baseline features among the groups. RESULTS: Patients with therapeutic INR presented with higher serum creatinine (P = 0.01) and blood urea nitrogen (P = 0.02) and lower glomerular filtration rates (P = 0.001) compared with other groups. Other laboratory parameters were not different among the 3 groups. Patients with therapeutic INR also presented with milder stroke symptoms (P = 0.01). Medical history of the 3 groups was not different, except for history of valvular heart disease, which was more prevalent in patients with therapeutic INR (P = 0.004). In-hospital mortality rates and 90-day disability were not different among the 3 groups. CONCLUSIONS: AF patients who presented with IS on therapeutic warfarin had higher average serum creatinine and blood urea nitrogen, and lower glomerular filtration rates, compared with others. Impaired renal function may be a factor contributing to occurrence of IS in AF patients despite adequate anticoagulation. Larger, targeted studies are needed to confirm these findings. PMID- 29251361 TI - Pulsed electromagnetic field improves subchondral bone microstructure in knee osteoarthritis rats through a Wnt/beta-catenin signaling-associated mechanism. AB - Pulsed electromagnetic field (PEMF) is often used for management of osteoarthritis (OA). The aim of the study was to determine whether PEMF can successfully improve subchondral bone microstructure through a Wnt/beta-catenin signaling-associated pathway in rats with knee OA induced by low-dose monosodium iodoacetate (MIA). Seventy-two 12-week-old male Sprague-Dawley rats were randomly assigned to three groups: OA (n = 24), PEMF (n = 24), and Control (n = 24). OA was induced (OA and PEMF groups) by injecting 0.2 mg MIA in rats' right knee joint. The control rats received a single sterile saline injection in the right knee. Rats in the PEMF group were exposed to daily 2 h PEMF exposure with 75 Hz, 1.6 mT for 4 weeks. After 4 weeks, micro-computed tomography (micro-CT), real time PCR, and immunohistochemistry staining were performed. The PEMF group increased bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and suppressed bone surface/bone volume (BS/BV) and trabecular separation (Tb.Sp) levels in micro-CT analysis. Real-time PCR analysis showed that PEMF promoted tibial subchondral bone's gene expressions of Wnt3a, beta catenin, and OPG, but did not alter LRP5 and RANKL mRNA levels. Similar results involved tibial subchondral bone's protein expressions that were observed in immunohistochemistry staining. These results suggest that PEMF preserved the structural integrity of subchondral bone in knee OA rats by promoting the activation of Wnt/beta-catenin signaling and OPG/RANKL/RANK signaling. Bioelectromagnetics. 39:89-97, 2018. (c) 2017 Wiley Periodicals, Inc. PMID- 29251363 TI - Photoredox-Switchable Resorcin[4]arene Cavitands: Radical Control of Molecular Gripping Machinery via Hydrogen Bonding. AB - Semiquinones (SQ) are generated in photosynthetic organisms upon photoinduced electron transfer to quinones (Q). They are stabilized by hydrogen bonding (HB) with the neighboring residues, which alters the properties of the reaction center. We designed, synthesized, and investigated resorcin[4]arene cavitands inspired by this function of SQ in natural photosynthesis. Cavitands were equipped with alternating quinone and quinoxaline walls bearing hydrogen bond donor groups (HBD). Different HBD were analyzed that mimic natural amino acids, such as imidazole and indole, along with their analogues, pyrrole and pyrazole. Pyrroles were identified as the most promising candidates that enabled the cavitands to remain open in the Q state until strengthening of HB upon reduction to the paramagnetic SQ radical anion provided stabilization of the closed form. The SQ state was generated electrochemically and photochemically, whereas properties were studied by UV/Vis spectroelectrochemistry, transient absorption, and EPR spectroscopy. This study demonstrates a photoredox-controlled conformational switch towards a new generation of molecular grippers. PMID- 29251364 TI - After neoadjuvant chemotherapy platelet/lymphocyte ratios negatively correlate with prognosis in gastric cancer patients. AB - INTRODUCTION: Circulating predictors prognostic factors of neoadjuvant chemotherapy, which identify the patients who are potential possibly to benefit from it are limited at present. In this research, we aimed to compare the prognostic significance of neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) in patients with locally advance gastric carcinoma who were treated with neoadjuvant chemotherapy (NAC) followed by D2 gastrectomy. MATERIALS AND METHODS: From 2007 to 2015, 91 patients with locally advanced gastric cancer treated with NAC followed by D2 gastrectomy included in this retrospective cohort study. The correlation of clinical data, including tumor regression, response evaluation, tumor location, pathological type, systemic therapy, tumor size (cm), neural invasion, lymphatic-vascular invasion, ypTNM stage, and survival prognosis were analyzed. RESULTS: Platelet/lymphocyte ratio and neutrophil/lymphocyte ratio in gastric cancer patients were higher than in matched normal volunteers. PLR levels higher after neoadjuvant chemotherapy are associated with worse OS. Multivariate Cox proportional analysis showed that pre-neoadjuvant chemotherapy PLR was an independent prognostic factor. CONCLUSIONS: Pre-neoadjuvant chemotherapy PLR may be a feasible biomarker for survival prognosis in patients with locally advanced gastric cancer. PLR and NLR were reduced after neoadjuvant chemotherapy. After neoadjuvant chemotherapy, PLR level was negatively correlated with survival prognosis. PMID- 29251365 TI - Investigations of the Copper-Catalyzed Oxidative Cross-Coupling of Tetrahydroisoquinolines with Diethylzinc by a Combination of Mass Spectrometric and Electrochemical Methods. AB - The aerobic oxidative cross-coupling of tetrahydroisoquinolines (THIQs) with diethylzinc catalyzed by CuCl2 has been examined by means of electrospray mass spectrometry (ESI-MS). Substrates, intermediates, and the product were readily detected. Particular emphasis has been placed on the role of CuCl2 . Formation of the intermediate iminium species has been investigated in more detail by ESI-MS, electrochemistry-coupled ESI mass spectrometry (EC-MS), and cyclic voltammetry (CV). Our experiments have consistently revealed strong influences of the N substituent of the THIQ derivative and its oxidation stability with respect to CuCl2 . The results may help to expand the synthetic scope of the reaction, while also further establishing EC-MS as a valuable technique for linking mass spectrometry with cyclic voltammetry in mechanistic studies of organic redox reactions. PMID- 29251366 TI - Liquid chromatographic separation and thermodynamic investigation of lorcaserin hydrochloride enantiomers on immobilized amylose-based chiral stationary phase. AB - A novel liquid chromatographic method was developed for enantiomeric separation of lorcaserin hydrochloride on Chiralpak IA column containing chiral stationary phase immobilized with amylose tris (3.5-dimethylphenylcarbamate) as chiral selector. Baseline separation with resolution greater than 4 was achieved using mobile phase containing mixture of n-hexane/ethanol/methanol/diethylamine (95:2.5:2.5:0.1, v/v/v/v) at a flow rate of 1.2 mL/min. The limit of detection and limit of quantification of the S-enantiomer were found to be 0.45 and 1.5 MUg/mL, respectively; the developed method was validated as per ICH guideline. The influence of column oven temperatures studied in the range of 20 degrees C to 50 degrees C on separation was studied; from this, retention, separation, and resolution were investigated. The thermodynamic parameters DeltaH degrees , DeltaS degrees , and DeltaG degrees were evaluated from van't Hoff plots,(Ink' versus 1/T) and used to explain the strength of interaction between enantiomers and immobilized amylose-based chiral stationary phase. PMID- 29251367 TI - Thyroid FNA diagnostics in a real-life setting: Experiences of the implementation of the Bethesda system in Finland. AB - INTRODUCTION: The Bethesda system is widely accepted for thyroid FNA diagnostics, but has scarcely been analysed in relation to clinical background data. Our aim was to analyse the thyroid FNA diagnostic process in view of clinical data, and to assess the validity of the Bethesda system during the first year of implementation. METHODS: There were 415 thyroid FNAs taken from 363 patients during October 2011-September 2012 in the Pirkanmaa Hospital District, Finland. The median age of the patients was 59 years, and the female-to-male ratio 4:1. Clinical data were collected from patient registries, and thyroid FNA and histopathological data from the pathology registry. RESULTS: The Bethesda categories were represented as follows: 94 non-diagnostic cases (26%); 177 benign (49%); 32 atypia of undetermined significance/follicular lesion of undetermined significance (9%); 31 follicular neoplasm (9%); 20 suspicious for malignancy (5%); and nine malignant cases (2%). Only 23 (24%) of the non-diagnostic samples and 18 (56%) of the atypia of undetermined significance/follicular lesion of undetermined significance led to repeat FNA. Thyroid cancer was histopathologically diagnosed in 28 cases (8%). When the categories requiring surgical treatment were considered true positive findings, the sensitivity of the Bethesda system was 90%, and specificity was 70%. Interobserver accuracy was 86%. CONCLUSIONS: Already during the first year of implementation, the Bethesda system proved reliable in evaluating the risk of thyroid malignancy. Nevertheless, the clinical judgement of the indication of ultrasound/FNA and management according to the FNA findings need improvement. The relatively high proportion of non diagnostic FNAs could be diminished by obtaining the samples by radiologists experienced in ultrasound-guided FNA techniques. PMID- 29251368 TI - The Paris System for urine cytology in upper tract urothelial specimens: A comparative analysis with biopsy and surgical resection. AB - INTRODUCTION: The Paris System (TPS) has recently been used in classification of urinary tract cytological specimens. Upper urinary tract (UUT) specimens are cytologically challenging. The utility of TPS was investigated in evaluating UUT specimens and its correlation with subsequent histological follow-up. METHOD: From 2014 to 2017, 324 cytology cases of UUT from 179 patients were retrieved. Concurrent or subsequent biopsy or resection within a 2-month period was available in 125 cases from 74 patients. RESULT: None of the cases with a cytology of low-grade urothelial neoplasm was found to have a high-grade urothelial carcinoma (HGUC) on biopsy. Among the 19 atypical urothelial cells (AUC) cytology cases, the histology is heterogeneous (seven benign, one atypia, five low-grade lesion, and six HGUC). The risk of HGUC for each cytological diagnostic category are 0% for non-diagnostic/unsatisfactory, 6% for negative for HGUC, 27.3% for AUC, 0% for low-grade urothelial neoplasm, 48% for suspicious for HGUC and 95% for positive HGUC. When we considered cytology cases with suspicious or positive for HGUC interpretations as positive, the performance of TPS in predicting high grade urothelial carcinoma on histology had values of: 78.6% sensitivity, 86% specificity, 80.5% positive predictive value and 84.5% negative predictive value. CONCLUSION: More than one-third of the UUT cytological cases were classified as AUC and approximately 1/15 as suspicious or positive for HGUC. Based on UUT cytology specimens, the risk of malignancy of each cytological diagnostic category of TPS was comparable to those reported in the literature. The use of TPS in evaluating UUT cytology specimens was specific and sensitive in identifying patients with HGUC by histology. PMID- 29251369 TI - Association of polymorphism in the VEGFA gene 3'-UTR +936T/C with susceptibility to biliary atresia in a Southern Chinese Han population. AB - BACKGROUND: Biliary atresia (BA) is a neonatal disease characterized by chronic inflammation of the bile ducts and progressive aggravation of jaundice, but with a poor prognosis and high mortality. The etiology of BA is still uncertain which may be related to gene defect, virus infection, immune disorder, gene polymorphism. As a proinflammatory cytokine, VEGFA gene polymorphism (rs3025039) has been shown to be related to the pathogenesis of BA in Taiwanese population. METHODS: We investigated the association between VEGFA gene polymorphism (rs3025039) and BA susceptibility using the largest case-control cohort, totaling with 506 BA patients and 1473 healthy controls in a Southern Chinese Han population. VEGFA gene polymorphism (rs3025039) was genotyped using the MassARRAY iPLEX Gold system (Sequenom). Odds ratios (OR) and 95% confidence intervals (CIs) were used to access the association between the VEGFA gene polymorphism (rs3025039) and BA risk. RESULTS: No significant association was found between the VEGFA gene polymorphism (rs3025039) and BA risk in the overall analysis. CONCLUSION: These results suggest that VEGFA gene polymorphism (rs3025039) may not be associated with the risk of BA in the Southern Chinese Han population. PMID- 29251370 TI - Barriers and facilitators to birth without epidural in a tertiary obstetric referral center: Perspectives of health care professionals and patients. AB - BACKGROUND: Epidural rates are high in tertiary obstetric referral centers, even though many patients in tertiary settings might not want or need epidural analgesia. Epidural rates are influenced by factors including labor support and routine medical intervention. This study aimed to identify barriers and facilitators to birth without epidural in a Canadian tertiary center, from the perspectives of doctors, nurses, and patients. METHODS: In this qualitative exploratory study, individual, semi-structured interviews were conducted in 2016 with 5 doctors, 5 nurses, and 4 patients who intended to birth without epidural. Interviews were audio-recorded, transcribed, and analyzed using inductive qualitative thematic analysis. RESULTS: Several contextual factors in the tertiary center facilitated or were barriers to birth without epidural. The following themes emerged: (1) differing perceptions of pain, (2) being ready for things to go wrong, (3) labor support is more labor intensive, and (4) having insufficient resources for birth without epidural. CONCLUSIONS: Reconciling patient birth goals with staff focus on patient safety is challenging in the tertiary context. Discrepancies between health care professional and patient attitudes about childbirth pain may influence decision-making about epidural use. Maintaining labor support skills is challenging for health care professionals who have limited exposure to birth without epidural. There is a need to allocate dedicated resources to better support birth without epidural. Specifically, support could be improved through the implementation of guidelines for assessment and management of labor pain, provision of a variety of pain management options, and labor support training for health care professionals. PMID- 29251371 TI - Stimulus-Responsive Assembly of Nanoparticles using Host-Guest Interactions of Cyclodextrins. AB - The design of multifunctional nanomaterials that respond to external stimuli and mimic the capacity of biological materials to respond and adapt to their environment has become a focus of interest in nanotechnology. In this Concept, we describe the development of supramolecular nanoparticle assemblies constructed by use of host-guest interactions between cyclodextrins and suitable guest molecules. The nanoparticle assembly is reversible and can be directed by applying different stimuli that act either on the guest molecules or the nanoparticles. This strategy can be extended to mesoscale assembly of microparticles. We highlight the newest research work in this field of nanochemistry and point out future perspectives and opportunities. PMID- 29251373 TI - Altered erector spinae activity and trunk motion occurs with moderate and severe unilateral hip OA. AB - People with hip osteoarthritis (OA) demonstrate altered movement patterns in the hip joint, as well as the pelvis and spine. While kinematic changes have been described in the literature, little is known about the associated erector spinae (ES) activity. Increased or prolonged ES activity may contribute to the low back pain often associated with hip OA. Using a cross-sectional cohort study, 3D trunk motions and ES surface electromyography were recorded on 19 individuals with severe OA (SOA), 20 with moderate hip OA (MOA), and 19 asymptomatic (ASYM) individuals during treadmill walking, using standardized collection and processing procedures. Principal component analysis was used to derive electromyographic amplitude and temporal waveform features. Three-dimensional thoracic motion in a global system, and thoraco-lumbar motion was calculated. Various statistical analyses determined between group differences (alpha = 0.05). In the sagittal plane, thoracic motion was greater in the SOA group (p < 0.001), whereas the ASYM group used less thoraco-lumbar motion than either OA group (p <= 0.002). Greater frontal plane angular excursion during early stance was found in the thoracic region in the SOA group (p <= 0.001) . With increasing OA severity, bilateral ES activity increased during the swing phase of gait (p < 0.001), whereas during stance, the SOA ipsilateral ES activity was higher than other groups (p < 0.001). Statement of clinical significance: with moderate and severe OA, sagittal, and frontal trunk motion increases during gait. ES activity during the entire gait cycle is more sustained with increased disease severity, which may aide our understanding of low back pain associated with hip OA. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1826-1832, 2018. PMID- 29251372 TI - Synthesis and Biological Evaluation of a Degradable Trehalose Glycopolymer Prepared by RAFT Polymerization. AB - There is a significant need for new biodegradable protein stabilizing polymers. Herein, the synthesis of a polymer with trehalose side chains and hydrolytically degradable backbone esters and its evaluation for protein stabilization and cytotoxicity are described. Specifically, an alkene-containing parent polymer is synthesized by reversible addition-fragmentation chain transfer polymerization, and thiolated trehalose is installed using a radical-initiated thiol-ene reaction. The stabilizing properties of the polymer are investigated by thermally stressing granulocyte colony-stimulating factor (G-CSF), which is expressed and purified using a custom-designed G-CSF fusion protein with a polyhistidine-tagged maltose binding protein. The degradable polymer is shown to stabilize G-CSF to 66% after heating at 40 degrees C. Poly(5,6-benzo-2-methylene-1,3-dioxepane (BMDO)-co-butyl methacrylate-trehalose) is degraded and its cellular compatibility is investigated. While the polymer is noncytotoxic, cytotoxic effects are observed from the degraded products in fibroblasts and murine myeloblasts. These data provide important information for future use of BMDO containing trehalose glycopolymers for biomedical applications. PMID- 29251374 TI - Synthesis and elastase inhibition activities of novel aryl, substituted aryl, and heteroaryl oxime ester derivatives. AB - Fifteen novel aryl, substituted aryl and heteroaryl gamma-hydroxy- (2a-e), gamma methoxyimino- (3a-e), and gamma-benzyloxyimino- (4a-e) butyric acid methyl esters were investigated for their enzyme inhibition, and the synthesis of 10 compounds (3a-e, 4a-e) is given in this study. The other five compounds (2a-e) were synthesized before in another study. Compounds 3a-e and 4a-e were synthesized in this work as original compounds and characterized by 1 H and 13 C NMR, IR, mass, and elemental analyses. Their (E/Z)-isomerisation ratios were analyzed by 1 H and 13 C NMR. All of them are of pure (E)-configuration. Due to the literature survey, the elastase inhibition activity was not studied for these compounds. Elastase inhibition ability was investigated in this work for five gamma-hydroxy- (2a-e), five gamma-methoxy- (3a-e), and five gamma-benzyloxyimino- (4a-e) butyric acid methyl esters. All these 15 compounds showed elastase inhibition activity. Compound 2b was the best one and exhibited a better activity than the standard ursolic acid whereas compound 2a worked like the standard. All these compounds can be novel elastase inhibitor agents in the pharmaceutical and cosmetic industries. PMID- 29251375 TI - Subchondral bone fragility with meniscal tear accelerates and parathyroid hormone decelerates articular cartilage degeneration in rat osteoarthritis model. AB - The aims of this study were to investigate the influence of subchondral bone fragility (SBF) on the progression of the knee osteoarthritis by using a novel rat model, and to examine the preventive effect of parathyroid hormone (PTH) on cartilage degeneration. First, 40 rats were assigned to the following four groups: Sham, SBF, Medial meniscal tear (MMT), and MMT + SBF groups. In SBF and MMT + SBF groups, we induced SBF by microdrilling the subchondral bone. Second, 10 additional rats were randomly assigned to the following two groups: MMT + SBF + saline and MMT + SBF + PTH groups. Osteoarthritic changes in the articular cartilage and subchondral bone were evaluated using safranin-O/fast green staining, matrix metalloproteinase-13 (MMP-13), and type X collagen immunohistochemistry, toluidine blue staining, and micro-CT scanning. The combination of SBF and meniscal tear increased the number of mast cells in the subchondral bone, and led to the abnormal subchondral bone microarchitecture, such as abnormally decreased trabecular number and increased trabecular thickness, compared with meniscal tear alone. Moreover, SBF with meniscal tear enhanced articular cartilage degeneration and increased the expression of MMP-13 and type X collagen, compared with meniscal tear alone. The administration of PTH decreased the number of mast cells in the subchondral bone and improved the microstructural parameters of the subchondral bone, and delayed the progression of articular cartilage degeneration. These results suggest that SBF is one of the factors underlying the osteoarthritis development, especially in knees with traumatic osteoarthritis, and that the administration of PTH is a potential therapeutic treatment for preventing OA progression. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1959-1968, 2018. PMID- 29251376 TI - What are the risk factors associated with hospital birth among women planning to give birth in a birth center in Washington State? AB - BACKGROUND: Few studies have evaluated risk factors associated with hospital birth among women planning to give birth in a birth center in the United States. This study describes the obstetrical risk factors for hospital birth among women intending to deliver in a birth center in Washington State. METHODS: We performed a retrospective cohort study of Washington State birth certificate data for women with singleton, term pregnancies planning to give birth at a birth center from 2004 to 2011. We assessed risk factors for hospital birth including demographic, obstetrical, and medical characteristics. We used multivariable logistic regression to estimate the odds ratio (OR) and 95% confidence interval (CI) of the association between risk factors and hospital birth. RESULTS: Among the 7118 women planning to give birth at a birth center during the study period, 7% (N = 501) had a hospital birth, and 93% delivered at a birth center (N = 6617). The strongest risk factors for hospital transfer included nulliparity (OR 7.2 [95% CI 5.3-9.8]), maternal age >40 years (OR 3.7 [95% CI 2.1-6.7]), inadequate prenatal care (OR 3.7 [95% CI 2.7-5.0]), body mass index >=30 (OR 2.1 [95% CI 1.6-3.0]), government health insurance (OR 9.3 [95% CI 5.0-17.1]), and hypertension (10.1 [95% CI 5.7-18.1]). Among nulliparous women, all of these demographic and obstetrical factors remained strongly associated with hospital birth. CONCLUSIONS: This information may be useful for counseling women who plan a birth center birth about the risk of hospital birth. PMID- 29251377 TI - The incidence and predictive factors for leptomeningeal spread after stereotactic radiation for breast cancer brain metastases. PMID- 29251378 TI - The physiological differentiation along the midgut of Bombyx mori - inspirations from proteomics and gene expression patterns of the secreted proteins in the ectoperitrophic space. AB - The ectoperitrophic space (EcPS) between the insect midgut epithelial cells and the peritrophic matrix is an unexplored, clean resource for concentrated proteins secreted by the midgut epithelial cells, which offers an ideal opportunity to uncover the midgut functions. In this study, we used Bombyx mori as a model organism and performed comparative proteomic analyses of the secreted proteins in the EcPS at the feeding and wandering stages. A total of 372 proteins were identified from both stages and 70 proteins were predicted to be secreted. Amongst these proteins, 17 secreted digestive proteins were identified and their temporal and spatial transcriptional expression patterns demonstrated that all these proteins were up-regulated at the feeding stage and differentially expressed in different parts of the midgut. Proteins with nutrient reservoir activity and defence activity were found to be up-regulated at the wandering stage. This work is the first to show the presence of digestive enzymes in the EcPS of the insect midgut using a proteomic approach, which provides evidence that suggests a physiological functional differentiation of the insect midgut. It is very clear that the EcPS undergoes dynamic changes in its composition of proteins in response to the changing needs of the insect at different developmental stages. PMID- 29251379 TI - Towards High-Throughput Modelling of Copper Reactivity Induced by Structural Disorder in Amyloid Peptides. AB - Transition metal ions often interact with disordered proteins. The affinity is high enough to compete with structured proteins, but the catalytic activity of the metal centre is often out of control and, therefore, potentially dangerous for cells. An example is a single copper ion interacting with the amyloid-beta (Abeta) peptide and triplet dioxygen, an interaction that is fundamental in producing reactive oxygen species in neurodegeneration. High-throughput modelling of the Cu-Abeta-O2 system was performed with the aim of providing a tool to dissect the structural features that characterise dangerous Cu-based catalysts in neurodegeneration. This study showed that the production of superoxide is a process with low-energy intermediate species, once a small population of high energy CuI -Abeta complex is formed. This population is enhanced when Cu bridges two different peptides in 1:1 Cu:Abeta dimers. Despite the bias for high-energy reduced reactant species, the reduction of CuII -Abeta product by superoxide can also occur, in addition to that by ascorbate, because the structural disorder produces a small population of oxidant species characterised by unstable CuII coordination, coexisting with the most abundant reductant species, characterised by stable CuII coordination. PMID- 29251380 TI - The relationship between DSM-5 PTSD symptom clusters and alcohol misuse among military veterans. AB - BACKGROUND AND OBJECTIVES: Prior research has revealed a strong relationship between Posttraumatic Stress Disorder (PTSD) and alcohol misuse. However, previous attempts to understand nuanced associations between PTSD symptom clusters and alcohol misuse within military veteran samples have produced mixed results. In an attempt to better understand the associations between PTSD and alcohol misuse, the current study examined the unique relationships between the newly classified Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) PTSD symptom clusters and alcohol misuse in an outpatient sample of military veterans seeking treatment for PTSD and Substance Use Disorders. METHODS: Veterans (N = 100) were administered a brief battery of self-report questionnaires prior to receiving psychological services to aid in diagnostic assessment and treatment planning. RESULTS: Hierarchical regression analyses revealed that PTSD intrusions (cluster B), negative alterations in cognition and mood (cluster D), and arousal/reactivity (cluster E) symptoms were associated with alcohol misuse. DISCUSSION AND CONCLUSIONS: The positive association between alcohol misuse and PTSD symptom severity is consistent with a broader body of literature demonstrating the co-occurrence of these disorders, particularly in military samples. SCIENTIFIC SIGNIFICANCE: Increased alcohol consumption may interfere with current front-line treatments for PTSD, which encourages patients to experience a full range of emotions. As such, future research should explore the impact of substance use on the effectiveness of trauma focused treatments in the alleviation of DSM-5 PTSD symptoms. (Am J Addict 2018;27:23-28). PMID- 29251381 TI - Inhibitors and facilitators of compassion-focused imagery in personality disorder. AB - BACKGROUND: Compassion-focused therapy (CFT) has potential to benefit clients with a personality disorder (PD), given the inflated levels of shame and self criticism in this population. However, clinical observation indicates that clients with PD may find techniques from this approach challenging. AIMS: The aim of this study is to trial one aspect of CFT, compassion-focused imagery (CFI), with this population, and identify factors that predict clients' ability to generate CFI and experience self-compassion during the task, including type of CFI exercise and, second, to establish whether CFI outcomes increase with practice. METHOD: In Study 1, 53 participants with a diagnosis of PD completed measures of self-compassion, self-reassurance, shame, self-criticism, fear of self-compassion, affect, anxious and avoidant attachment, and mental imagery abilities. Participants were assigned to trial CFI from memory (n = 25) or from imagination (n = 28), then rated their image's vividness, its compassionate traits, and ease of experiencing compassion. A negative mood manipulation was carried out, and CFI tasks and outcome measures were repeated. For Study 2, self compassion and self-criticism were measured before and after 1 week of daily CFI practice. RESULTS: Study 1 found that negative mood and low mental imagery ability are significant inhibitors to generating compassionate images and affect. The 2 CFI exercises were equally effective. Study 2 suffered from high attrition, but regular practice was associated with significant improvement in self compassion (though not self-criticism). CONCLUSIONS: CFI appears to be effective in improving self-compassion for some clients. However, it is less effective in the presence of negative affect. Clients with low mental imagery ability may benefit more from alternative CFT techniques. PMID- 29251382 TI - Robotic da Vinci Xi-assisted nipple-sparing mastectomy: First clinical report. AB - Nipple-sparing mastectomy (NSM) is increasingly popular for the treatment of selected breast cancers and prophylactic mastectomy. Surgical scarring and esthetic outcomes are important patient-related cosmetic considerations. Today, the concept of minimally invasive surgery has become popular, especially using robotic surgery. The authors report the first case of NSM using the latest version of the da Vinci Xi surgical system (Xi). The final incision used to remove the entire mammary gland was located behind the axillary line. In this position, hidden by the arm of the patient, the incision was not visible and was compatible with immediate breast reconstruction. PMID- 29251383 TI - Therapeutic Considerations and Conjugated Polymer-Based Photosensitizers for Photodynamic Therapy. AB - Conjugated polymers have recently attracted a great deal of attention for applications in photodynamic therapy (PDT) because of their light-harvesting capability, efficient energy transfer, and singlet oxygen generation properties. This review describes recent advances in PDT development, including therapeutic mechanisms of PDT in cancer treatments, light excitation methods, and especially recent advances of conjugated polyelectrolytes and conjugated polymer nanoparticles as photosensitizers. The future direction on PDT and further development of conjugated polymer photosensitizers are discussed. The aim of this review is to stimulate innovative ideas to synthesize a new generation of conjugated polymer photosensitizers and promote their translation to clinical applications of PDT. PMID- 29251384 TI - Aspartate transaminase to platelet ratio index and gamma-glutamyl transpeptidase to-platelet ratio outweigh fibrosis index based on four factors and red cell distribution width-platelet ratio in diagnosing liver fibrosis and inflammation in chronic hepatitis B. AB - BACKGROUND: The benefits of using serum markers to diagnose stages of liver disease in chronic hepatitis B (CHB) patients are controversial. We conducted a study to compare the clinical significance of four markers in evaluating liver inflammation and fibrosis in CHB patients. METHODS: A total of 323 treatment naive CHB patients who received a liver biopsy and routine laboratory testing were enrolled in our study. We used the Scheuer scoring system as a pathological standard for diagnosing liver inflammation and fibrosis. The diagnostic performance of the fibrosis index based on four factors (FIB-4), the aspartate transaminase to platelet ratio index (APRI), the gamma-glutamyl transpeptidase-to platelet ratio (GPR), and the red cell distribution width-platelet ratio (RPR) were analyzed with receiver-operating characteristic curves (ROC). RESULTS: No significant differences among the four indexes for diagnosing significant fibrosis (S >= 2) was found, while APRI and GPR were superior to FIB-4 and RPR in diagnosing moderate (G >= 2), severe (G >= 3) inflammation, and severe fibrosis (S >= 3). The AUROCs for diagnosing G >= 2 and G >= 3 were 0.732 and 0.861 for APRI, 0.726 and0.883 for GPR, 0.703 and0.705 for FIB-4, and 0.660 and 0.747 for RPR, respectively. The AUROCs for diagnosing S >= 2 and S >= 3 were0.724 and 0.799 for APRI, 0.714 and0.801 for GPR, 0.683 and0.730 for FIB-4, and 0.643 and 0.705 for RPR, respectively. CONCLUSION: APRI and GPR were more effective than FIB-4 and RPR at diagnosing liver inflammation and fibrosis. PMID- 29251385 TI - Supramolecular Polymers Based on Non-Coplanar AAA-DDD Hydrogen-Bonded Complexes. AB - Non-coplanar triple-hydrogen-bond arrays are connected as telechelic groups to alkyl chains and their properties as AA/BB type supramolecular polymers are examined. Viscosity studies at three temperatures are used to study the ring chain equilibrium and determine the critical concentrations where polymer chains are formed. It is observed that neither the temperature range studied nor the alkyl chain length of one component significantly affect the polymerization properties in this system. PMID- 29251386 TI - A Zeolite Family Nonjointly Built from the 1,3-Stellated Cubic Building Unit. AB - From a technological point of view, the synthesis of new high-silica zeolites is of prime importance owing to their high potential as industrial catalysts and catalyst supports. Two such materials have been synthesized which are made up of the 1,3-stellated cubic unit (hexahedral ([42 54 ]) bre unit) as a secondary building unit, with the aid of existing imidazolium-based structure-directing agents under "excess fluoride" conditions. One of them, denoted PST-21, is the first aluminosilicate zeolite consisting of 9-ring apertures solely; it displays exceptional activity towards steering the skeletal isomerization of 1-butene to isobutene and bridges the gap between small- and medium-pore structures. A series of hypothetical structures are also described that are nonjointly built from the bre unit; all of these structures are chemically feasible and will thus be helpful in designing the synthesis of novel zeolites containing 9-ring and/or 10 ring channels. PMID- 29251387 TI - Utilization of multiple SAVI SCOUT surgical guidance system reflectors in the same breast: A single-institution feasibility study. AB - SAVI SCOUT Surgical Guidance System has been shown to be a reliable and safe alternative to wire localization in breast surgery. This study evaluated the feasibility of using multiple reflectors in the same breast. We performed an IRB approved, HIPAA-compliant, single-institution retrospective review of 183 patients who underwent breast lesion localization and excision using SAVI SCOUT Surgical Guidance System (Cianna Medical) between June 2015 and January 2017. We performed a subset analysis in 42 patients in whom more than one reflector was placed. Specimen radiography, pathology, distance between reflectors, target removal, margin positivity, and complications were evaluated. Among 183 patients, 42 patients had more than one reflector placed in the same breast to localize 68 lesions. Benign (n = 6, 8.8%), high-risk (n = 23, 33.8%), and malignant (n = 39, 57.4%) lesions were included. Thirty-six patients (85.7%) had a total of 2 reflectors placed and 6 patients had a total of 3 reflectors placed (14.3%). The indications for multiple reflector placement in the same breast included multiple separate lesions (n = 23) and bracketing of large lesions (n = 19). The mean distance between the reflectors was 42 mm (22-93 mm). All lesions were successfully targeted and retrieved. Of 39 malignant lesions, 10.3% (n = 4) had positive margins and 10.3% (n = 4) had close (<1 mm) margins at surgery. All patients with positive margins underwent re-excision. No complications occurred preoperatively, intra-operatively, or postoperatively. The use of multiple SAVI SCOUT reflectors for localizing multiple lesions in the same breast or bracketing large lesions is feasible and safe. PMID- 29251388 TI - New n-Type Solution Processable All Conjugated Polymer Network: Synthesis, Optoelectronic Characterization, and Application in Organic Solar Cells. AB - The efficient synthesis of a new solution-processable n-type conjugated polymer network (PNT1) is reported through palladium-catalyzed Stille cross-coupling reaction conditions following the A3 + B2 synthetic approach. A benzo[1,2-b:3,4 b':5,6-b"]trithiophene derivative is used as the A3 knot and an alkyl functionalized naphthalenediimide is utilized as the B2 linker. The thermal, optical, and electrochemical properties are examined in detail, showing high thermal stability, absorbance in the visible part of the solar spectrum, and reversible reduction characteristics similar to those of the fullerene derivative [6,6]-phenyl-C71 -butyric acid methyl ester (PC71 BM). PNT1 is employed as the electron acceptor in solution-processed bulk heterojunction organic solar cells, demonstrating the potential of this new type of materials for optoelectronic applications. PMID- 29251389 TI - Water-Stable Nanoporous Polymer Films with Excellent Proton Conductivity. AB - Achieving high values for proton conductivity in a material critically depends on providing hopping sites arranged in a regular fashion. Record values reported for regular, molecular crystals cannot yet be reached by technologically relevant systems, and the best values measured for polymer membranes suited for integration into devices are almost two orders of magnitude lower. Here, an alternative polymer membrane synthesis strategy based on the chemical modification of surface-mounted, monolithic, crystalline metal-organic framework thin films is demonstrated. Due to chemical crosslinking and subsequent removal of metal ions, these surface-mounted gels (SURGELs) are found to exhibit high proton conductivity (0.1 S cm-1 at 30 degrees C and 100% RH (relative humidity). These record values are attributed to the highly ordered polymer network structure containing regularly spaced carboxylic acid side groups. These covalently bound organic frameworks outperform conventional, ion-conductive polymers with regard to ion conductivity and water stability. Pronounced water induced swelling, which causes severe mechanical instabilities in commercial membranes, is not observed. PMID- 29251390 TI - Pupil occluding intraocular lens insertion for intractable diplopia: a case series and management of post-insertion light perception. PMID- 29251391 TI - Separation of Linear and Branched Alkanes Using Host-Guest Complexation of Cyclic and Branched Alkane Vapors by Crystal State Pillar[6]arene. AB - Activated crystals of pillar[6]arene produced by removing the solvent upon heating were able to take up branched and cyclic alkane vapors as a consequence of their gate-opening behavior. The uptake of branched and cyclic alkane vapors by the activated crystals of pillar[6]arene induced a crystal transformation to form one-dimensional channel structures. However, the activated crystals of pillar[6]arene hardly took up linear alkane vapors because the cavity size of pillar[6]arene is too large to form stable complexes with linear alkanes. This shape-selective uptake behavior of pillar[6]arene was further utilized for improving the research octane number of an alkane mixture of isooctane and n heptane: interestingly, the research octane number was dramatically improved from a low research octane number (17 %) to a high research octane number (>99 %) using the activated crystals of pillar[6]arene. PMID- 29251392 TI - Impact of 2013 ASCO/CAP HER2 reporting guidelines in breast cancer: An assessment study from Indian oncology centre that primarily performs HER2 IHC testing with special emphasis on IHC equivocal category. AB - The ASCO/CAP guidelines for HER2 reporting in breast cancer published in 2007 and were updated in 2013 to assure that the right patient receives the targeted therapy. The updated guidelines have lowered the threshold for HER2 positivity criteria and altered the equivocal category for both IHC and FISH. This first study from India addresses the impact of these updated guidelines in the various reporting categories at a tertiary care centre. We compared the trend of HER2 IHC reporting 1 year before (Period A) and 1 year after (Period B) the implementation of updated 2013 ASCO/CAP guidelines. All HER2 equivocal IHC cases of post 2013 guidelines were reclassified as per 2007 guidelines to detect additional number of cases that have been put into equivocal category. Reflex FISH correlation was also assessed to detect any additional cases eligible for anti HER2 therapy with implementation of these updated guidelines. With implementation of updated 2013 guidelines, there was significant decrease in the number of cases scored as 1+ (from 30.7% to 20.6%; P value: .0001) while significant increase in number of 2+ cases (from 20.2% to 27.3%; P value: .004). Post 2013 guidelines, 39% (64 cases) of tumors were additionally put into the equivocal category which would have been considered as negative (score 1+) as per 2007 guidelines. The reflex FISH testing in these equivocal cases resulted in detection of only 1.5% of additional cases eligible for anti HER2 therapy. With implementation of updated 2013 guidelines, there is no significant increase in HER2 positivity trend. However, there is appreciable increase in IHC equivocal cases which subsequently led to increased reflex FISH testing without significantly contributing to the detection of additional eligible cases for anti HER2 therapy, but resulted in delaying of definite HER2 status along with financial implications. PMID- 29251393 TI - An investigation into the bacterial contamination of goniolenses in use in clinical practice. AB - Objectives To report the incidence and evaluate the clinical significance of goniolens bacterial contamination in clinical use in dogs with three different usage protocols and one with an added cleaning protocol. Animals Studied and Methods Three groups of twenty dogs undergoing gonioscopy at a private practice in the UK had the goniolenses swabbed for bacteriology culture and identification prior to placement on the cornea. Three protocols of lens use, with 2 different types of goniolens, were studied. One protocol was then repeated with 21 dogs with a lens cleaning protocol prior to storage. Results Low levels of bacterial contamination were found in all 3 initial groups (10-15%). No correlation was found between usage protocol used and rate of contamination and no correlation was found between length of storage between use and contamination. All bacteria cultured were considered naturally occurring commensals for the canine eye and environment. The group with a cleaning protocol had a 4.7% contamination rate. This was not statistically different from the non-cleaning groups. Conclusions The rate of bacterial contamination of goniolenses in clinical practice is low and the bacterial contaminants consist of commensal bacteria, unlikely to be of detriment to the eye. Minimal contamination of the goniolenses was found and this did not appear to be of clinical significance. The introduction of a simple cleaning protocol did not produce a statistically significant reduction in bacterial contamination. PMID- 29251394 TI - Optic neuritis in dogs: 96 cases (1983-2016). AB - OBJECTIVE: To characterize ocular and neurologic findings, causes, and treatment outcomes of dogs with optic neuritis. PROCEDURE: Medical records from dogs with a diagnosis of optic neuritis at North Carolina State University, College of Veterinary Medicine, Veterinary Hospital between 1983 and 2016 were reviewed. RESULTS: Ninety-six cases (20 unilateral, 76 bilateral), comprised of 38 males and 58 females with a mean age of 6.1 +/- 3.0 years (range 0.5-13), were identified. Seventy-four cases were presented for vision loss, and 42 had other concurrent neurologic abnormalities. Funduscopic findings included optic nerve head elevation (n = 92), peripapillary retinal edema or separation (n = 37), retinal hemorrhage or dilation of retinal vasculature (n = 23), and multiple inflammatory foci in the peripapillary region (n = 13). Retrobulbar optic neuritis was diagnosed in four cases. The final diagnoses included the following: multifocal meningoencephalitis of unknown etiology (MUE, n = 35), isolated optic neuritis (I-ON, n = 42), neoplasia (n = 10), microbial infection (n = 6), orbital inflammation (n = 2), and suspected ivermectin toxicosis (n = 1). Dogs with I-ON were more commonly male, and medium-to-large breed, when compared to dogs with MUE. Follow-up was available in 72 cases, 50 of which remained blind, 10 had partial visual improvement, and 12 were assessed as having normal vision in the affected eye(s). CONCLUSION: Optic neuritis was most commonly associated with multifocal MUE or was isolated as the sole neurologic finding, with a similar incidence between the two groups. Findings suggest that a clinical syndrome of isolated optic neuritis, distinct from multifocal MUE, occurs in dogs. PMID- 29251395 TI - A Dipleiadiene-Embedded Aromatic Saddle Consisting of 86 Carbon Atoms. AB - This study presents a new type of negatively curved nanographene (C86 H32 ) that contains an unprecedented pattern of heptagons. A tert-butylated derivative of C86 H32 was successfully synthesized using tetrabenzodipleiadiene as a key building block. This synthesis involved a ring expansion reaction as a key step to form the seven-membered rings in the framework of tetrabenzodipleiadiene. The single-crystal structure reveals a saddle-shaped molecule with a highly bent naphthalene moiety at the center of the polycyclic backbone. As found from the DFT calculations, this aromatic saddle is flexible at room temperature and has a saddle-shaped geometry as the dominant conformation. The DFT calculations along with experimental results show that the attachment of t-butyl groups to the central tetrabenzodipleiadiene moiety of nanographene C86 H32 can stabilize the saddle conformation and make this nanographene less flexible. PMID- 29251396 TI - Co-morbidity and mortality among patients with interstitial lung diseases: A population-based study. AB - BACKGROUND AND OBJECTIVE: Co-morbidities are frequent among patients with interstitial lung diseases (ILD). The objective of this study was to investigate their impact on mortality. METHODS: We used the Danish National Patient Registry (DNPR) to identify all patients with a first-time diagnosis of ILD between 1998 and 2010. Patients with ILD were matched 1:4 with controls from the background population. The burden of co-morbidity was assessed using the Deyo-Charlson co morbidity score (DCcs). Mortality risks were assessed using Kaplan-Meier survival curves, and hazard rate ratios (HRR) for death were estimated using Cox proportional hazards regression models. RESULTS: We identified 10 629 patients with ILD with a corresponding incidence estimate of ILD in Denmark of 17.6 per 100 000 inhabitants (95% CI: 16.5-18.7). Mean age was 72 years and 45.6% of the patients were females. Co-morbidity (DCcs >= 1) was present in 30% of the ILD patients and 12% of the controls (P < 0.001). The 5-year survival was 56.0% (95% CI: 54.6-56.6) among ILD patients and 84.0% (95% CI: 83.7-84.4) among controls. HRR for death among patients with ILD was 3.82 for males (95% CI: 3.63-4.02) and 3.85 for females (95% CI: 3.62-4.09) with matched controls as reference. Decreasing survival was seen with increasing DCcs for both groups. The 5-year survival for DCcs = 0 was 61% for ILD and 87% for controls compared with 41% versus 58% for DCcs = 2. CONCLUSION: Survival was impaired for patients with ILD for all levels of the DCcs, although increasing burden of co-morbidity tended to close the mortality gap. PMID- 29251397 TI - Keeping the right track in the treatment of patients with type 2 diabetes. PMID- 29251398 TI - Relation between electrical and mechanical dyssynchrony in patients with left bundle branch block: An electro- and vectorcardiographic study. AB - BACKGROUND: Current guidelines select patients for cardiac resynchronization therapy (CRT) mainly on electrocardiographic parameters like QRS duration and left bundle branch block (LBBB). However, among those LBBB patients, heterogeneity in mechanical dyssynchrony occurs and might be a reason for nonresponse to CRT. This study assesses the relation between electrocardiographic characteristics and presence of mechanical dyssynchrony among LBBB patients. METHODS: The study included patients with true LBBB (including mid-QRS notching) on standard 12-lead electrocardiograms. Left bundle branch block-induced mechanical dyssynchrony was assessed by the presence of septal flash on two dimensional echocardiography. Previously reported electro- and vectorcardiographic dyssynchrony markers were analyzed: global QRS duration (QRSDLBBB ), left ventricular activation time (QRSDLVAT ), time to intrinsicoid deflection (QRSDID ), and vectorcardiographic QRS areas in the 3D vector loop (QRSA3D ). RESULTS: The study enrolled 545 LBBB patients. Septal flash (SF) is present in 52% of patients presenting with true LBBB. Patients with SF are more frequent female, have less ischemic heart disease and smaller left ventricular dimensions. In multivariate analysis longer QRSDLBBB , QRSDLVAT and larger QRSA3D were independently associated with SF. Of all parameters, QRSA3D has the best accuracy to predict SF, although overall accuracy remains moderate (59% sensitivity, 58% specificity). The predictive value of QRSA3D remained constant in both sexes, irrespective of ischemic heart disease, ejection fraction and even when categorizing for QRSDLBBB . CONCLUSION: In LBBB patients, large QRS areas correlate better with mechanical dyssynchrony compared to wide QRSD intervals. However, the overall accuracy to predict mechanical dyssynchrony by electrocardiographic dyssynchrony markers, even when using complex vectorcardiographic parameters, remains low. PMID- 29251399 TI - Computerized pediatric oncology prescriptions review by pharmacist: A descriptive analysis and associated risk factors. AB - BACKGROUND: Systematic prescription analyses by clinical pharmacists result in pharmacist interventions (PIs) to reduce prescription errors and improve medication safety. PIs are particularly critical in oncology, because antineoplastic drugs are highly toxic with low therapeutic indexes especially in a pediatric population. The aim of this study is to describe PIs in a pediatric oncology department and to identify potential risk factors associated with prescription errors. PROCEDURE: We conducted a 20-month observational study in a pediatric oncology department concerning electronic prescription of injectable chemotherapies was conducted. PIs were analyzed for drug-related problems (DRPs), type of intervention, population characteristics, involved drugs, and the potential risk factors. RESULTS: Clinical pharmacists made 90 PIs for 10,214 antineoplastic prescriptions for a rate of 88 PIs per 10,000 prescriptions. The majority of DRPs were dosage errors (61.8%), imputable to measurements (weight and/or height) in 47.4% or unreported dose reduction. The most common patient ages were in the range 1-10 years and the most common time for medical double checks was 2-9 pm. There were statistically more prescription errors in standardized protocols (P < 0.001). CONCLUSIONS: Not surprisingly, PIs were predominantly to correct dose errors, half of which related to height and weight measurements that were not updated. No significant risk factors for errors were identified for errors except in the standardized status of prescription, which appears to be linked in part to our software that did not automatically reflect dose reduction from one course to the next. Medical double-checking followed by a clinical pharmacist's double check were effective in order to prevent prescription errors. PMID- 29251400 TI - Ophthalmic examination findings and intraocular pressures in wild-caught African giant pouched rats (Cricetomys spp.). AB - PURPOSE: To report ophthalmic examination findings and intraocular pressures (IOPs) in wild-caught African giant pouched rats (Cricetomys ansorgei and gambianus) from Tanzania and Ghana. PROCEDURES: After being placed under general anesthesia for examination, slit-lamp biomicroscopy before and after pharmacologic mydriasis and indirect ophthalmoscopy was performed. Eyes were fluorescein stained and IOPs measured by rebound tonometry using the TonoVet(r) . RESULTS: Thirty-two sexually mature pouched rats (64 eyes) were examined, including 16 males and 16 females. The mean IOP (+/- standard deviation) was 7.7 (+/-2.9) mmHg. Fluorescein staining was negative in all eyes. One or more ocular abnormalities were detected in 21 pouched rats (35 eyes). These ocular lesions included the following: lens opacities (n = 23 eyes), persistent pupillary membranes (n = 5), chorioretinal scarring (n = 3), corneal vascularization (n = 2), palpebral margin defect with focal trichiasis (n = 2), phthisis bulbi (n = 1), and posterior synechiae (n = 1). Lens opacities included incipient anterior cortical opacities (n = 7), immature cataract (n = 6), incipient nuclear opacities (n = 5), punctate pigment on anterior lens capsule (n = 2 eyes), incipient suture tip opacities (n = 2), and hypermature cataract (n = 1). CONCLUSIONS: Ocular abnormalities were common in the evaluated population of giant pouched rats; however, most of the detected lesions were mild and believed to have minimal impact on vision. Rebound tonometry with the TonoVet(r) was a reliable and simple technique to measure IOPs in the anesthetized pouched rats. PMID- 29251401 TI - Corneal hysteresis and anterior segment optical coherence tomography anatomical parameters in primary angle closure suspects. AB - IMPORTANCE: Corneal hysteresis (CH) is a dynamic marker of structural and functional changes in the cornea associated with intraocular pressure (IOP) and central corneal thickness, but its utility in assessing primary angle closure suspects (PACS) has not been fully elucidated. BACKGROUND: This study assesses if anterior segment measurements correlate with CH in PACS patients. DESIGN: IRB approved retrospective review of imaging and records at a university practice. PARTICIPANTS: Sixty-three eyes from 37 patients diagnosed as PACS, without other ocular pathology. METHODS: Every eye underwent measurements including: ocular response analyzer (ORA), anterior segment optical coherence tomography (OCT) and a clinical evaluation. ORA measurements were correlated with other anatomic parameters using a mixed effects multivariable linear regression framework. MAIN OUTCOME MEASURES: ORA measurements included: CH, corneal resistance factor, Goldmann IOP (IOPg ) and corneal compensated IOP (IOPcc ). Anterior segment OCT measurements included: central corneal thickness (CCTOCT ), nasal and temporal peripheral corneal thicknesses (PCT1 and PCT2), anterior chamber depth (ACD), nasal angle to temporal angle distance (ATA) and temporal and nasal angle measurements. Clinical measurements included: central corneal thickness via pachymetry, IOP measured by Goldmann applanation, axial length by A-scan ultrasound and spherical equivalent. RESULTS: CH was negatively correlated with IOPcc, and ACD CH was positively correlated with CCTOCT , CCTp , CRF, PCT1 and PCT2. Females were found to have lower CH. In multivariable regression controlling for gender, CCT, PCT, IOP and ACD, no correlation was seen between CH and anatomic measurements. CONCLUSIONS AND RELEVANCE: CH values in PACS do not correlate with anterior segment anatomy. PMID- 29251402 TI - Left ventricular ejection fraction in heart failure: a clinician's perspective about a dynamic and imperfect parameter, though still convenient and a cornerstone for patient classification and management. PMID- 29251403 TI - Rebamipide suppresses TNF-alpha production and macrophage infiltration in the conjunctiva. AB - PURPOSE: To evaluate the anti-inflammatory effect of rebamipide during corneal epithelial wound healing using a mouse wound repair model. METHODS: A 2-mm circular disc of the central cornea was demarcated in the right eye of C57BL/6 mice and the epithelium removed. Rebamipide 2% eyedrop was instilled onto the wounded eye 5 times a day (n = 26). Phosphate-buffered saline (PBS) was used in the control group (n = 26). Corneal and conjunctival IL-1beta and TNF-alpha levels were measured at 6 h and 24 h postinjury by ELISA. The wounded area was evaluated by fluorescein staining at 24 h postinjury. Macrophage infiltration was assessed immunohistochemically, and TNF-alpha secretion from macrophages was examined in vitro. RESULTS: Conjunctival IL-1beta and corneal IL-1beta levels were not significantly different between PBS-treated and rebamipide-treated groups. However, conjunctival TNF-alpha level was significantly lower in the rebamipide-treated group compared with the PBS-treated group. Macrophage migration into the conjunctiva, but not into the cornea, was suppressed by rebamipide treatment. In addition, TNF-alpha secretion from cultured macrophages was suppressed by rebamipide in a concentration-dependent manner. Rebamipide treatment significantly accelerated corneal epithelial wound healing at 24 h postinjury. CONCLUSIONS: In a mouse corneal epithelial wound model, rebamipide suppressed TNF-alpha secretion and macrophage infiltration in the conjunctiva, which might have contributed to accelerated corneal epithelial wound healing in the first 24 h following injury. PMID- 29251404 TI - Number of retained radiopaque markers on a colonic transit study does not correlate with symptom severity or quality of life in chronic constipation. AB - BACKGROUND: Ingestion of radiopaque markers (ROM) is frequently used to determine colonic transit in chronic constipation. Although >=20% of retained markers at 5 days defines slow-transit constipation, some clinicians use the number of retained markers to determine disease severity. METHODS: We assembled a cross sectional cohort of patients presenting for evaluation of chronic constipation who underwent transit testing by ROM and completed validated symptom severity and quality-of-life (QOL) measures. We performed a correlation analysis to determine whether there was an association between number of retained markers and symptom severity and QOL. KEY RESULTS: Among 159 patients undergoing evaluation for chronic constipation, there was poor correlation between the number of retained markers and symptom severity (R = .09, P = .25) and QOL. Among the 55 patients with slow-transit constipation defined by >=5 retained markers retained on day 5, there were similarly poor correlations between symptom severity (R = .17, P = .21) and QOL (R = .07, P = .60). Excluding patients with irritable bowel syndrome and outlet obstruction by balloon expulsion testing did not materially alter our results, nor did a multivariable analysis controlling for demographic and psychiatric confounders. CONCLUSIONS AND INFERENCES: Among patients with chronic constipation, number of retained markers on a ROM colonic transit study does not correlate with measures of symptom severity or QOL. Clinicians should be cautious about overinterpreting ROM transit testing. PMID- 29251405 TI - Germline APC mutations in hepatoblastoma. AB - BACKGROUND: Conflicting reports on the frequency of germline adenomatous polyposis coli (APC) gene mutations in patients with hepatoblastoma (HB) have called into question the clinical value of APC mutation testing on apparently sporadic HB. METHODS: An Institutional Review Board approved retrospective review of clinical data collected from patients with HB who received APC testing at our institution was conducted. All HB patients seen at Cincinnati Children's Hospital Medical Center were eligible for testing. Potential genotype/phenotype correlations were assessed. RESULTS: As of July 2015, 29 patients with HB had received constitutional APC testing. Four (14%) were found to have APC pathogenic truncations of the APC protein and in addition two (7%) had APC missense variants of unknown clinical significance. Two patients (7%) had family histories indicative of familial adenomatous polyposis (FAP). Response to chemotherapy tracked differently in APC pathogenic cases, with a slower imaging response despite an equivalent or slightly faster alpha-fetoprotein (AFP) response. CONCLUSION: The prevalence of pathogenic APC variants in apparently sporadic HB may be higher than previously detected. Differences in time to imaging response, despite similar AFP response, may impact surgical planning. All patients with HB warrant germline APC mutation testing for underlying FAP. PMID- 29251406 TI - Response Evaluation Criteria in Solid Tumors (RECIST) following neoadjuvant chemotherapy in osteosarcoma. AB - BACKGROUND: In osteosarcoma, patient survival has not changed in over 30 years. Multiple phase II trials have been conducted in osteosarcoma using the Response Evaluation Criteria in Solid Tumors (RECIST) as a primary endpoint; however, none of these have revealed new treatment strategies. We investigated RECIST in newly diagnosed patients who received neoadjuvant chemotherapy proven to be beneficial. METHODS: Patients treated from 1986 to 2011 for newly diagnosed osteosarcoma with paired tumor imaging before and after adequate neoadjuvant chemotherapy were included in this retrospective study. Two radiologists performed independent, blinded (to image timing) RECIST measurements of primary tumor and lung metastases at diagnosis and post-neoadjuvant chemotherapy. Association between RECIST and histological necrosis and outcome were assessed. RESULTS: Seventy-four patients met inclusion criteria. Five-year overall survival and progression-free survival (PFS) were 77 +/- 7% and 61 +/- 8%, respectively. No patients had RECIST partial or complete response in the primary tumor. Sixty-four patients (86%) had stable disease, and 10 (14%) had progressive disease (PD). PD in the primary tumor was associated with significantly worse PFS in localized disease patients (P = 0.02). There was no association between RECIST in the primary tumor and necrosis. There were an insufficient number of patients with lung nodules >=1 cm at diagnosis to evaluate RECIST in pulmonary metastases. CONCLUSIONS: PD by RECIST predicts poor outcome in localized disease patients. In bone lesions, chemotherapy proven to improve overall survival does not result in radiographic responses as measured by RECIST. Further investigation of RECIST in pulmonary metastatic disease in osteosarcoma is needed. PMID- 29251407 TI - Exploration of interaction of canthaxanthin with human serum albumin by spectroscopic and molecular simulation methods. AB - The interaction between the food colorant canthaxanthin (CA) and human serum albumin (HSA) in aqueous solution was explored by using fluorescence spectroscopy, three-dimensional fluorescence spectra, synchronous fluorescence spectra, UV-vis absorbance spectroscopy, circular dichroism (CD) spectra and molecular docking methods. The thermodynamic parameters calculated from fluorescence spectra data showed that CA could result in the HSA fluorescence quenching. From the KSV change with the temperature dependence, it was concluded that HSA fluorescence quenching triggered by CA is the static quenching and the number of binding sites is one. Furthermore, the secondary structure of HSA was changed with the addition of CA based on the results of synchronous fluorescence, three-dimensional fluorescence and CD spectra. Hydrogen bonds and van der Waals forces played key roles in the binding process of CA with HSA, which can be obtained from negative standard enthalpy (DeltaH) and negative standard entropy (DeltaS). Furthermore, the conclusions were certified by molecular docking studies and the binding mode was further analyzed with Discovery Studio. These conclusions can highlight the potential of the interaction mechanism of food additives and HSA. PMID- 29251408 TI - Odontogenic parakeratinized cyst resulting in exophthalmos and palatine, maxillary, and zygomatic bone erosion in a dog. AB - A novel case of a canine odontogenic parakeratinized cyst (COPC) that resulted in exophthalmos and palatine, maxillary, and zygomatic bone erosion in a 5-year-old Chihuahua dog is reported. Final diagnosis was aided by cross-sectional imaging (magnetic resonance imaging and computed tomography) and confirmed with histologic examination of the cyst wall. PMID- 29251409 TI - Rational Construction of Hollow Core-Branch CoSe2 Nanoarrays for High-Performance Asymmetric Supercapacitor and Efficient Oxygen Evolution. AB - Metal selenides have great potential for electrochemical energy storage, but are relatively scarce investigated. Herein, a novel hollow core-branch CoSe2 nanoarray on carbon cloth is designed by a facile selenization reaction of predesigned CoO nanocones. And the electrochemical reaction mechanism of CoSe2 in supercapacitor is studied in detail for the first time. Compared with CoO, the hollow core-branch CoSe2 has both larger specific surface area and higher electrical conductivity. When tested as a supercapacitor positive electrode, the CoSe2 delivers a high specific capacitance of 759.5 F g-1 at 1 mA cm-2 , which is much larger than that of CoO nanocones (319.5 F g-1 ). In addition, the CoSe2 electrode exhibits excellent cycling stability in that a capacitance retention of 94.5% can be maintained after 5000 charge-discharge cycles at 5 mA cm-2 . An asymmetric supercapacitor using the CoSe2 as cathode and an N-doped carbon nanowall as anode is further assembled, which show a high energy density of 32.2 Wh kg-1 at a power density of 1914.7 W kg-1 , and maintains 24.9 Wh kg-1 when power density increased to 7354.8 W kg-1 . Moreover, the CoSe2 electrode also exhibits better oxygen evolution reaction activity than that of CoO. PMID- 29251410 TI - Adolescent patient involvement in discussions about relapsed or refractory cancer with oncology clinicians. AB - BACKGROUND: Adolescents with cancer report a strong desire to be actively involved in personal healthcare decision making. The purpose of this study was to examine adolescent cancer patients' involvement in conversations about relapsed and refractory disease, to characterize the content of patient-clinician communication, and to identify opportunities for improved patient-clinician communication. DESIGN/METHOD: We analyzed audiotaped conversations between clinicians, parents, and adolescents with relapsed or refractory cancer. Of 36 conversations audiotaped for a larger study, 11 included adolescents ages 12 through 17 years. RESULTS: Adolescents were responsible for a mean 3.5% of total words spoken (range 0.6-10.0) in each discussion about relapsed or refractory cancer, whereas clinicians were responsible for 66.9% of total words spoken (range 39.5-87.1) and parents were responsible for 30.4% of total words spoken (range 10.9-59.1). Most clinician communication directed at the adolescent involved giving information (27.5%), engaging in social/personal conversation (21.2%), asking about medical history questioning (15.6%), and performing a clinical examination (15.4%). Adolescent communication directed at the clinician was predominantly classified as giving information in response to physician questioning (61.9%). In four of the 11 cases, clinicians sought adolescent opinions or preferences regarding next steps of care; adolescents only shared their preferences when asked directly. CONCLUSIONS: Adolescent patient involvement in conversations about relapsed or refractory cancer is limited and often focused on responding to questions and participating in the history questioning and physical examination. Adolescents play a more active role in conversations about their cancer care when clinicians direct communication toward them. This study highlights opportunities for clinicians to actively engage adolescents in discussions about their medical care. PMID- 29251411 TI - Integrating Sub-3 nm Plasmonic Gaps into Solid-State Nanopores. AB - Plasmonic nanopores combine the advantages of nanopore sensing and surface plasmon resonances by introducing confined electromagnetic fields to a solid state nanopore. Ultrasmall nanogaps between metallic nanoantennas can generate the extremely enhanced localized electromagnetic fields necessary for single molecule optical sensing and manipulation. Challenges in fabrication, however, hamper the integration of such nanogaps into nanopores. Here, a top-down approach for integrating a plasmonic antenna with an ultrasmall nanogap into a solid-state nanopore is reported. Employing a two-step e-beam lithography process, the reproducible fabrication of nanogaps down to a sub-1 nm scale is demonstrated. Subsequently, nanopores are drilled through the 20 nm SiN membrane at the center of the nanogap using focused-electron-beam sculpting with a transmission electron microscope, at the expense of a slight gap expansion for the smallest gaps. Using this approach, sub-3 nm nanogaps can be readily fabricated on solid-state nanopores. The functionality of these plasmonic nanopores for single-molecule detection is shown by performing DNA translocations. These integrated devices can generate intense electromagnetic fields at the entrance of the nanopore and can be expected to find applications in nanopore-based single-molecule trapping and optical sensing. PMID- 29251412 TI - Antifibrotic effects of D-limonene (5(1-methyl-4-[1-methylethenyl]) cyclohexane) in CCl4 induced liver toxicity in Wistar rats. AB - This study was designed to assess the potential antifibrotic effect of D-Limonene a component of volatile oils extracted from citrus plants. D-limonene is reported to have numerous therapeutic properties. CCl4 -intduced model of liver fibrosis in Wistar rats is most widely used model to study chemopreventive studies. CCl4 intoxication significantly increased serum aminotransferases and total cholesterol these effects were prevented by cotreatment with D-Limonene. Also, CCl4 -intoxication caused depletion of glutathione and other antioxidant enzymes while D-Limonene preserved them within normal values. Hydroxyproline and malondialdehyde content was increased markedly by CCl4 treatment while D-Limonene prevented these alterations. Levels of TNF-alpha, TGF-beta, and alpha-SMA were also assessed; CCl4 increased the expression of alpha-SMA, NF-kappaB and other downstream inflammatory cascade while D-Limonene co-treatment inhibited them. Collectively these findings indicate that D-Limonene possesses potent antifibrotic effect which may be attributed to its antioxidant and anti inflammatory properties. PMID- 29251413 TI - Serological, genetic and clinical associations with increased health-care resource utilization in inflammatory bowel disease. AB - OBJECTIVE: Inflammatory bowel diseases (IBD) are associated with significant morbidity and economic burden. The variable course of IBD creates a need for predictors of clinical outcomes and health resource utilization (HRU) to guide treatment decisions. We aimed to identify clinical, serological or genetic markers associated with inpatient resource utilization in patients with ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Patients with IBD with available genetic and serological data who had at least one emergency department visit or hospitalization in a 3-year period were included. The primary outcome measure was HRU, as measured by the All Patient Refined Diagnosis Related Group classification system. Univariate and multivariate linear and logistic regression models were used to identify the associations with HRU. RESULTS: Altogether 858 (562 CD and 296 UC) patients were included. Anti-CBir1 seropositivity (P = 0.002, effect size [ES]: 0.762, 95% confidence interval [CI] 0.512-1.012) and low socioeconomic status (P = 0.005, ES: 1.620 [95% CI 1.091-2.149]) were independently associated with a high HRU. CD diagnosis (P = 0.006, ES: -0.701 [95% CI -0.959 to -0.443]) was independently associated with a low inpatient HRU. CONCLUSION: In patients with IBD who required at least one emergency department visit or hospitalization, anti-CBir1 antibody status may be a useful biomarker of HRU when formulating management strategies to reduce disease complications and resource utilization. PMID- 29251414 TI - Generalized Scheme for High Performing Photodetectors with a p-Type 2D Channel Layer and n-Type Nanoparticles. AB - A generalized scheme for the fabrication of high performance photodetectors consisting of a p-type channel material and n-type nanoparticles is proposed. The high performance of the proposed hybrid photodetector is achieved through enhanced photoabsorption and the photocurrent gain arising from its effective charge transfer mechanism. In this paper, the realization of this design is presented in a hybrid photodetector consisting of 2D p-type black phosphorus (BP) and n-type molybdenum disulfide nanoparticles (MoS2 NPs), and it is demonstrated that it exhibits enhanced photoresponsivity and detectivity compared to pristine BP photodetectors. It is found that the performance of hybrid photodetector depends on the density of NPs on BP layer and that the response time can be reduced with increasing density of MoS2 NPs. The rising and falling times of this photodetector are smaller than those of BP photodetectors without NPs. This proposed scheme is expected to work equally well for a photodetector with an n type channel material and p-type nanoparticles. PMID- 29251415 TI - Specific T Cell Responses against Minor Histocompatibility Antigens Cannot Generally Be Explained by Absence of Their Allelic Counterparts on the Cell Surface. AB - Allogeneic stem cell transplantation has emerged as immunotherapy in the treatment of a variety of hematological malignancies. Its efficacy depends on induction of graft versus leukemia by donor lymphocytes. Both graft versus leukemia and graft versus host disease are induced by T cells reactive against polymorphic peptides, called minor histocompatibility antigens (MiHA), which differ between patient and donor and are presented in the context of self-HLA (where HLA is human leukocyte antigen). The allelic counterpart (AC) of the MiHA is generally considered to be absent at the cell surface, based on the absence of immune responses directed against the AC. To study this in detail, we evaluate the recognition, HLA-binding affinity, and cell surface expression of three selected MiHA. By quantitative MS, we demonstrate the similarly abundant expression of both MiHA and AC at the cell surface. We conclude that the absent recognition of the AC cannot generally be explained by insufficient processing and presentation at the cell surface of the AC. PMID- 29251416 TI - Doping of Ni and Zn Elements in MnCO3 : High-Power Anode Material for Lithium-Ion Batteries. AB - Herein, Ni and Zn elements are doped simultaneously in MnCO3 and microspheric Mnx Niy Znz CO3 is successfully obtained. Atomic mapping images reveal that the Ni and Zn elements have been successfully doped in MnCO3 and thus the prepared sample is not a mixture of MnCO3 , NiCO3 , and ZnCO3 . It is the first time that the atomic mapping images of ternary transition metal carbonates have been demonstrated so far. The scanning transmission electron microscopy - annular bright field (STEM-ABF) image successfully confirms the formation of oxygen vacancies in Mnx Niy Znz CO3 , which is beneficial to improve the electrical conductivity. The evolution of the microstructure from crystal to amorphization during cycling process confirmed by the fast Fourier transform patterns effectively lowers the overpotential of the conversion reaction and accelerates the conversion between Mn2+ and much higher valence of Mn element, contributing to the superior capacity of Mnx Niy Znz CO3 electrode. As anode material for lithium-ion batteries, the prepared Mnx Niy Znz CO3 exhibits excellent long-term cycling stability and outstanding rate performance, delivering the superior reversible discharge capacities of 1066 mA h g-1 at 500 mA g-1 after 500 cycles and 760 mA h g-1 at 1 A g-1 after 1000 cycles. It is the first time that Mnx Niy Znz CO3 has been synthesized and used as anode for lithium-ion batteries so far. PMID- 29251417 TI - STED-TEM Correlative Microscopy Leveraging Nanodiamonds as Intracellular Dual Contrast Markers. AB - Development of fluorescent and electron dense markers is essential for the implementation of correlative light and electron microscopy, as dual-contrast landmarks are required to match the details in the multimodal images. Here, a novel method for correlative microscopy that utilizes fluorescent nanodiamonds (FNDs) as dual-contrast probes is reported. It is demonstrated how the FNDs can be used as dual-contrast labels-and together with automatic image registration tool SuperTomo, for precise image correlation-in high-resolution stimulated emission depletion (STED)/confocal and transmission electron microscopy (TEM) correlative microscopy experiments. It is shown how FNDs can be employed in experiments with both live and fixed cells as well as simple test samples. The fluorescence imaging can be performed either before TEM imaging or after, as the robust FNDs survive the TEM sample preparation and can be imaged with STED and other fluorescence microscopes directly on the TEM grids. PMID- 29251418 TI - A High-Performance Top-Gated Graphene Field-Effect Transistor with Excellent Flexibility Enabled by an iCVD Copolymer Gate Dielectric. AB - A high-performance top-gated graphene field-effect transistor (FET) with excellent mechanical flexibility is demonstrated by implementing a surface-energy engineered copolymer gate dielectric via a solvent-free process called initiated chemical vapor deposition. The ultrathin, flexible copolymer dielectric is synthesized from two monomers composed of 1,3,5-trimethyl-1,3,5-trivinyl cyclotrisiloxane and 1-vinylimidazole (VIDZ). The copolymer dielectric enables the graphene device to exhibit excellent dielectric performance and substantially enhanced mechanical flexibility. The p-doping level of the graphene can be tuned by varying the polar VIDZ fraction in the copolymer dielectric, and the Dirac voltage (VDirac ) of the graphene FET can thus be systematically controlled. In particular, the VDirac approaches neutrality with higher VIDZ concentrations in the copolymer dielectric, which minimizes the carrier scattering and thereby improves the charge transport of the graphene device. As a result, the graphene FET with 20 nm thick copolymer dielectrics exhibits field-effect hole and electron mobility values of over 7200 and 3800 cm2 V-1 s-1 , respectively, at room temperature. These electrical characteristics remain unchanged even at the 1 mm bending radius, corresponding to a tensile strain of 1.28%. The formed gate stack with the copolymer gate dielectric is further investigated for high frequency flexible device applications. PMID- 29251419 TI - Surface Engineering of Nanoparticles for Targeted Delivery to Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated deaths worldwide. There is a lack of efficient therapy for HCC; the only available first-line systemic drug, sorafenib, can merely improve the average survival by two months. Among the efforts to develop an efficient therapy for HCC, nanomedicine has drawn the most attention, owing to its unique features such as high drug-loading capacity, intrinsic anticancer activities, integrated diagnostic and therapeutic functionalities, and easy surface engineering with targeting ligands. Despite its tremendous advantages, no nanomedicine can be effective unless it successfully targets the tumor site, which is a challenging task. In this review, the features of HCC are described, and the physiological hurdles that prevent nanoparticles from targeting HCC are discussed. Then, the surface physicochemical factors of nanoparticles that can influence targeting efficiency are discussed. Finally, a thorough description of the physiological barriers that nanomedicine must conquer before uptake by HCC cells if possible is provided, as well as the surface engineering approaches to nanomedicine to achieve targeted delivery to HCC cells. The physiological hurdles and corresponding solutions summarized in this review provide a general guide for the rational design of HCC targeting nanomedicine systems. PMID- 29251420 TI - High Performance of N-Doped Graphene with Bubble-like Textures for Supercapacitors. AB - Nitrogen-doped graphene (NG) with wrinkled and bubble-like texture is fabricated by a thermal treatment. Especially, a novel sonication-assisted pretreatment with nitric acid is used to further oxidize graphene oxide and its binding with melamine molecules. There are many bubble-like nanoflakes with a dimension of about 10 nm appeared on the undulated graphene nanosheets. The bubble-like texture provides more active sites for effective ion transport and reversible capacitive behavior. The specific surface area of NG (5.03 at% N) can reach up to 438.7 m2 g-1 , and the NG electrode demonstrates high specific capacitance (481 F g-1 at 1 A g-1 , four times higher than reduced graphene oxide electrode (127.5 F g-1 )), superior cycle stability (the capacitance retention of 98.9% in 2 m KOH and 99.2% in 1 m H2 SO4 after 8000 cycles), and excellent energy density (42.8 Wh kg-1 at power density of 500 W kg-1 in 2 m KOH aqueous electrolyte). The results indicate the potential use of NG as graphene-based electrode material for energy storage devices. PMID- 29251421 TI - Recognition of Oxidized 5-Methylcytosine Derivatives in DNA by Natural and Engineered Protein Scaffolds. AB - Methylation of genomic cytosine to 5-methylcytosine is a central regulatory element of mammalian gene expression with important roles in development and disease. 5-methylcytosine can be actively reversed to cytosine via oxidation to 5 hydroxymethyl-, 5-formyl-, and 5-carboxylcytosine by ten-eleven-translocation dioxygenases and subsequent base excision repair or replication-dependent dilution. Moreover, the oxidized 5-methylcytosine derivatives are potential epigenetic marks with unique biological roles. Key to a better understanding of these roles are insights into the interactions of the nucleobases with DNA binding protein scaffolds: Natural scaffolds involved in transcription, 5 methylcytosine-reading and -editing as well as general chromatin organization can be selectively recruited or repulsed by oxidized 5-methylcytosines, forming the basis of their biological functions. Moreover, designer protein scaffolds engineered for the selective recognition of oxidized 5-methylcytosines are valuable tools to analyze their genomic levels and distribution. Here, we review recent structural and functional insights into the molecular recognition of oxidized 5-methylcytosine derivatives in DNA by selected protein scaffolds. PMID- 29251422 TI - Cobalt Iron Hydroxide as a Precious Metal-Free Bifunctional Electrocatalyst for Efficient Overall Water Splitting. AB - Highly efficient and stable electrocatalysts from inexpensive and earth-abundant elements are emerging materials in the overall water splitting process. Herein, cobalt iron hydroxide nanosheets are directly deposited on nickel foam by a simple and rapid electrodeposition method. The cobalt iron hydroxide (CoFe/NF) nanosheets not only allow good exposure of the highly active surface area but also facilitate the mass and charge transport capability. As an anode, the CoFe/NF electrocatalyst displays excellent oxygen evolution reaction catalytic activity with an overpotential of 220 mV at a current density of 10 mA cm-2 . As a cathode, it exhibits good performance in the hydrogen evolution reaction with an overpotential of 110 mV, reaching a current density of 10 mA cm-2 . When CoFe/NF electrodes are used as the anode and the cathode for water splitting, a low cell voltage of 1.64 V at 10 mA cm-2 and excellent stability for 50 h are observed. The present work demonstrates a possible pathway to develop a highly active and durable substitute for noble metal electrocatalysts for overall water splitting. PMID- 29251423 TI - In Situ Disinfection through Photoinspired Radical Oxygen Species Storage and Thermal-Triggered Release from Black Phosphorous with Strengthened Chemical Stability. AB - Photodynamic therapy (PDT) utilizing light-induced reactive oxygen species (ROS) is a promising alternative to combat antibiotic-resistant bacteria and biofilm. However, the photosensitizer (PS)-modified surface only exhibits antibacterial properties in the presence of light. It is known that extended photoirradiation may lead to phototoxicity and tissue hypoxia, which greatly limits PDT efficiency, while ambient pathogens also have the opportunity to attach to biorelevant surfaces in medical facilities without light. Here, an antimicrobial film composed of black phosphorus nanosheets (BPSs) and poly (4 pyridonemethylstyrene) endoperoxide (PPMS-EPO) to control the storage and release of ROS reversibly is introduced. BPS, as a biocompatible PS, can produce high singlet oxygen under the irradiation of visible light of 660 nm, which can be stably stored in PPMS-EPO. The ROS can be gradually thermally released in the dark. In vitro antibacterial studies demonstrate that the PPMS-EPO/BPS film exhibits a rapid disinfection ability with antibacterial rate of 99.3% against Escherichia coli and 99.2% against Staphylococcus aureus after 10 min of irradiation. Even without light, the corresponding antibacterial rate reaches 76.5% and 69.7%, respectively. In addition, incorporating PPMS significantly improves the chemical stability of the BPS. PMID- 29251424 TI - Inadequate sunlight exposure in patients with inflammatory bowel disease. AB - OBJECTIVE: Inadequate sun exposure impairs vitamin D activity and favors low bone density, especially in patients at increased risk for osteoporosis, such as those affected by inflammatory bowel disease (IBD). In this study, sun exposure was investigated in a large series of patients with IBD in a Mediterranean country, Italy, where this risk is considered less likely to occur than in higher latitudes. METHODS: This is a case-control study of 292 patients with IBD [132 with Crohn's disease (CD) and 160 with ulcerative colitis (UC)], 80 diseased and 540 healthy controls, conducted via a validated questionnaire to quantify sunlight exposure. Data were also compared with controls matched by age and gender. RESULTS: In total 78 of the 292 patients with IBD had low, 169 had moderate and 45 had high exposure to sunlight, significantly differing from controls (P < 0.001). The 132 patients with CD were more likely to have abnormal levels of sunlight exposure (49 low, 72 moderate and 11 high) than those with UC (29 low, 97 moderate and 34 high) (P < 0.001). The controls were significantly more exposed to sunlight than both men and women with IBD (P < 0.001 and 0.004, respectively). CONCLUSIONS: IBD patients are significantly less exposed to sunlight than matched controls in Italy, often to an extent that may impair vitamin D activation. Increasing responsible sunlight exposure, thus promoting adequate vitamin D concentrations, may prove beneficial in IBD, in geographical areas in which this risk factor is not generally taken into consideration. PMID- 29251425 TI - Regular Aligned 1D Single-Crystalline Supramolecular Arrays for Photodetectors. AB - Solution-processed semiconductor single-crystal patterns possess unique advantages of large scale and low cost, leading to potential applications toward high-performance optoelectronic devices. To integrate organic semiconductor micro/nanostructures into devices, various patterning techniques have been developed. However, previous patterning techniques suffer from trade-offs between precision, scalability, crystallinity, and orientation. Herein, a patterning method is reported based on an asymmetric-wettability micropillar-structured template. Large-scale 1D single-crystalline supramolecular arrays with strict alignment, pure crystallographic orientation, and precise position can be obtained. The wettability difference between tops and sidewalls of micropillars gives rise to the confinement of organic solutions in discrete capillary tubes followed by dewetting and formation of capillary trailing. The capillary trailing enables unidirectional dewetting, regulated mass transport, and confined crystal growth. Owing to the high crystallinity and pure crystallographic orientation with Pt atomic chains parallel to the substrate, the photodetectors based on the 1D arrays exhibit improved responsivity. The work not only provides fundamental understanding on the patterning and crystallization of supramolecular structures but also develops a large-scale assembly technique for patterning single crystalline micro/nanostructures. PMID- 29251426 TI - Development of Dual-Pore Coexisting Branched Silica Nanoparticles for Efficient Gene-Chemo Cancer Therapy. AB - Various strategies for combination therapy to overcome current limitations in cancer therapy have been actively investigated. Among them, simultaneous delivery of multiple drugs is a subject of high interest due to anticipated synergistic effect, but there have been difficulties in designing and developing effective nanomaterials for this purpose. In this work, dual-pore coexisting hybrid porous silica nanoparticles are developed through Volmer-Weber growth pathway for efficient co-delivery of gene and anticancer drug. Based on the different pore sizes (2-3 and 40-45 nm) and surface modifications of the core and branch domains, loading and controlled release of gene and drug are achieved by appropriate strategies for each environment. With excellent loading capacity and low cytotoxicity of the present platform, the combinational cancer therapy is successfully demonstrated against human cervical cancer cell line. Through a series of quantitative analyses, the excellent gene-chemo combinational therapeutic efficiency is successfully demonstrated. It is expected that the present nanoparticle will be applicable to various biomedical fields that require co-delivery of small molecule and nucleic acid. PMID- 29251427 TI - A novel wheat NAC transcription factor, TaNAC30, negatively regulates resistance of wheat to stripe rust. AB - NAC transcription factors are widespread in the plant kingdom and play essential roles in the transcriptional regulation of defense responses. In this study, we isolated a novel NAC transcription factor gene, TaNAC30, from a cDNA library constructed from wheat (Triticum aestivum) plants inoculated with the stripe rust pathogen Puccinia striiformis f. sp. tritici (Pst). TaNAC30 contains a typical NAM domain and localizes to the nucleus. Yeast one-hybrid assays revealed that TaNAC30 exhibits transcriptional activity and that its C-terminus is necessary for the activation of transcription. Expression of TaNAC30 increased when host plants were infected with a virulent race (CYR31) of the rust fungus Pst. Silencing of TaNAC30 by virus-induced gene silencing inhibited colonization of the virulent Pst isolate CYR31. Moreover, detailed histological analyses showed that silencing of TaNAC30 enhanced resistance to Pst by inducing a significant increase in the accumulation of H2 O2 . Finally, we overexpressed TaNAC30 in fission yeast and determined that cell viability was severely reduced in TaNAC30 transformed cells grown on medium containing H2 O2 . These results suggest that TaNAC30 negatively regulates plant resistance in a compatible wheat-Pst interaction. PMID- 29251429 TI - A Very Highly Efficient Magnetic Nanomaterial for the Removal of PAHs from Aqueous Media. AB - Two new hybrid magnetic recyclable nanomaterials are developed. These new materials are based on bisimide perylene dopamine or bisimide perylene 3 aminopropyltriethoxysilane and iron oxide nanoparticles. One of them, the bisimide perylene dopamine, has proven to be very efficient in the removal, by magneto filtration, of 15 carcinogenic polycyclic aromatic compounds (PAHs), especially naphthalene, acenaphthene, anthracene, phenanthrene, and fluorene. These compounds are known to be common contaminants of drinking and underground water. This nanomaterial presents a high dispersivity and stability in an aqueous media, and it is capable of forming supramolecular fluorescent magnetic nanofibers with benzo-alpha-pyrene or benzo[k]fluoranthene, BKF. This strong association is due to hydrophobic forces and the pi-pi interaction, between the bisimide perylene motif and the polycyclic aromatic compounds. The resilience of this material is tested in different media. No good results are obtained in ethanol, acetone, or acetonitrile, but an 85% recovery is achieved using toluene or hexane. Once washed, nanoparticles are shown to retain their ability to continue capturing PAHs. PMID- 29251428 TI - Epidemiology of obscure gastrointestinal bleeding in China: A single-center series and comprehensive analysis of literature. AB - OBJECTIVE: To determine the etiologies of obscure gastrointestinal bleeding (OGIB) in a Chinese population using a retrospective case series and a systematic analysis of the literatures on OGIB in Chinese patients. METHODS: A large enteroscopy database in a tertiary endoscopic center was searched to identify patients with OGIB from 2010 to 2016. The patients' characteristics and diagnostic findings were collected and analyzed. A comprehensive search of the literature was carried out to harvest all relevant studies published from 2004 to 2016. RESULTS: In total, 708 patients were included in the case series. The most common causes of OGIB were inflammatory diseases (36.3%), non-small bowel lesions (10.2%) and neoplasms (10.0%). A systematic analysis of the literatures included 39 studies providing relevant data for 3145 patients with a pooled detection rate of 84.2%. Inflammatory lesions (27.4%), neoplasms (18.5%), vascular lesions (16.1%) and diverticula or intestinal duplication (11.9%) were the most common causes of OGIB. CONCLUSIONS: Inflammatory lesions, neoplasms, vascular lesions and diverticula or intestinal duplication are the most common in Chinese OGIB patients, while in pediatric patients diverticula or intestinal duplication, vascular lesions and Crohn's disease are prevalent. Furthermore, the etiologies of OGIB distribute differently across different areas in China. PMID- 29251430 TI - Response to Comment on "Retinal pulse wave velocity measurement using spectral domain optical coherence tomography". AB - Spahr et al. recently commented on our latest paper "Retinal pulse wave velocity measurement using spectral-domain optical coherence tomography" with a conclusion that the measured retinal pulse wave velocity (rPWV) in our paper was contradictory to theoretical predictions and previously published results. However, the theoretical predictions by Spahr et al. based on Moens-Korteweg equation are questionable, since the Moens-Korteweg equation should not be used for small arteries like retinal arteries. Previously, various measurements of rPWV using different technologies have been reported. The results on human and rats are not consistent. As the rPWV is an unknown value, we argue that the time delay derived between 2 arterial sites should be verified to see if the delay truly represents the pulse wave transit time. In the future, special emphasis should be placed on demonstration of the reproducibility of technologies and data analysis of large samples. PMID- 29251431 TI - The 10th Joint Meeting on Medicinal Chemistry (JMMC 2017) Held in Dubrovnik, Croatia. AB - The Croatian Chemical Society was established in 1926 and has developed over the decades into a society that actively supports all chemical activities in Croatia. The Society has eight divisions, the youngest of which, the Division of Medicinal and Pharmaceutical Chemistry, was established in 2012 and immediately became a member of the European Federation of Medicinal Chemistry (EFMC). The mission of the Medicinal and Pharmaceutical Chemistry Division is the promotion and development of scientific, professional, and educational activities within the medicinal chemistry community in Croatia, as well as to build partnerships and collaborations with other primarily EU-based medicinal chemistry societies. In Croatia, medicinal chemistry research is ongoing at several institutes, including the University of Zagreb (Faculty of Science, Faculty of Pharmacy and Biochemistry, and Faculty of Chemical Engineering and Technology), national institutes of science (Ruder Boskovic Institute), and private-sector drug discovery companies (CRO Fidelta Ltd.). In order to effectively exchange knowledge, ideas, and scientific results, Croatian medicinal chemists meet twice annually. PMID- 29251432 TI - Graphene-Based Inverted Planar Perovskite Solar Cells: Advancements, Fundamental Challenges, and Prospects. AB - Metal halide based perovskite solar cells (PSCs) are considered among the most promising photovoltaic technologies, and already present certified efficiencies that surpass 22 %. The high performance and low fabrication cost make this technology competitive with that of state-of-the-art thin-film photovoltaics. However, PSCs present some striking disadvantages that hinder their commercialization, including short operational lifetimes, high toxicity, and hysteresis effects, which lower both the performance and long-term stability of the devices. Herein, work conducted within the last two years is summarized with regard to addressing the challenges of low-temperature-processed planar inverted PSCs composed of graphene-based materials. In addition, critical challenges and the prospects of this field are discussed and some prospects for future research directions are proposed. PMID- 29251434 TI - Macrophage p38 kinase inhibition for liver regeneration. AB - In this issue, Ying et al. show that p38alpha kinase (MAPK14) controls macrophage polarization following acute liver injury. Myeloid cell-specific depletion of p38alpha promotes polarization to anti-inflammatory M2 macrophages and prevents pro-inflammatory cytokine secretion that ameliorate acute liver injury and promotes hepatocyte proliferation. Therapeutic targeting of macrophage p38alpha is an attractive strategy not only to suppress inflammation, but also to support liver regeneration. PMID- 29251433 TI - Predictors of timely linkage-to-ART within universal test and treat in the HPTN 071 (PopART) trial in Zambia and South Africa: findings from a nested case control study. AB - INTRODUCTION: HPTN 071 (PopART) is a three-arm community randomized trial in Zambia and South Africa evaluating the impact of a combination HIV prevention package, including universal test and treat (UTT), on HIV incidence. This nested study examined factors associated with timely linkage-to-care and ART initiation (TLA) (i.e. within six-months of referral) in the context of UTT within the intervention communities of the HPTN 071 (PopART) trial. METHODS: Of the 7572 individuals identified as persons living with HIV (PLWH) (and not on antiretroviral treatment (ART)) during the first year of the PopART intervention provided by Community HIV-care Providers (CHiPs) through door-to-door household visits, individuals who achieved TLA (controls) and those who did not (cases), stratified by gender and community, were randomly selected to be re-contacted for interview. Standardized questionnaires were administered to explore factors potentially associated with TLA, including demographic and behavioural characteristics, and participants' opinions on HIV and related services. Odds ratios comparing cases and controls were estimated using a multi-variable logistic regression. RESULTS: Data from 705 participants (333 cases/372 controls) were analysed. There were negligible differences between cases and controls by demographic characteristics including age, marital or socio-economic position. Prior familiarity with the CHiPs encouraged TLA (aOR of being a case: 0.58, 95% CI: 0.39 to 0.86, p = 0.006). Participants who found clinics overcrowded (aOR: 1.51, 95% CI: 1.08 to 2.12, p = 0.006) or opening hours inconvenient (aOR: 1.63, 95% CI: 1.06 to 2.51, p = 0.02) were less likely to achieve TLA, as were those expressing stronger feelings of shame about having HIV (ptrend = 0.007). Expressing "not feeling ready" (aOR: 2.75, 95% CI: 1.89 to 4.01, p < 0.001) and preferring to wait until they felt sick (aOR: 2.00, 95% CI: 1.27 to 3.14, p = 0.02) were similarly indicative of being a case. Worrying about being seen in the clinic or about how staff treated patients was not associated with TLA. While the association was not strong, we found that the greater the number of self-reported lifetime sexual partners the more likely participants were to achieve TLA (ptrend = 0.06). There was some evidence that participants with HIV-positive partners on ART were less likely to be cases (aOR: 0.75, 95% CI: 0.53 to 1.06, p = 0.07). DISCUSSION: The lack of socio-demographic differences between cases and controls is encouraging for a "universal" intervention that seeks to ensure high coverage across whole communities. Making clinics more "patient-friendly" could enhance treatment uptake further. The finding that those with higher risk behaviour are more actively engaging with UTT holds promise for treatment-as-prevention. PMID- 29251435 TI - Announcing the winners of our 50th Anniversary Science Communication Competition. AB - The FEBS Journal is pleased to announce the three winners of its 50th Anniversary Science Communication Competition. Read on to see their prize-winning entries! PMID- 29251437 TI - 50 years of The FEBS Journal: looking back as well as ahead. AB - In this last issue of 2017, we're celebrating the 50th anniversary of The FEBS Journal. This Editorial considers how the journal has grown and changed from volume 1, issue 1 and outlines our exciting plans for the future. PMID- 29251439 TI - Corrigendum. PMID- 29251440 TI - Building an ACT-R Reader for Eye-Tracking Corpus Data. AB - Cognitive architectures have often been applied to data from individual experiments. In this paper, I develop an ACT-R reader that can model a much larger set of data, eye-tracking corpus data. It is shown that the resulting model has a good fit to the data for the considered low-level processes. Unlike previous related works (most prominently, Engelmann, Vasishth, Engbert & Kliegl, ), the model achieves the fit by estimating free parameters of ACT-R using Bayesian estimation and Markov-Chain Monte Carlo (MCMC) techniques, rather than by relying on the mix of manual selection + default values. The method used in the paper is generalizable beyond this particular model and data set and could be used on other ACT-R models. PMID- 29251441 TI - Monitoring of the Conformational Space of Dipeptides by Generative Topographic Mapping. AB - This work describes a procedure to build generative topographic maps (GTM) as 2D representation of the conformational space (CS) of dipeptides. GTMs with excellent propensities to support highly predictive landscapes of various conformational properties were reported for three dipeptides (AA, KE and KR). CS monitoring via GTMproceeds through the projection of conformer ensembles on the map, producing cumulated responsibility (CR) vectors characteristic of the CS areas covered by the ensemble. Overlap of the CS areas visited by two distinct simulations can be expressed by the Tanimoto coefficient Tc of the associated CRs. This idea was used to monitor the reproducibility of the stochastic evolutionary conformer generation process implemented in S4MPLE. It could be shown that conformers produced by <500 S4MPLE runs reproducibly cover the relevant CS zone at given setup of the driving force field. The propensity of a simulation to visit the native CS zone can thus be quantitatively estimated, as the Tc score with respect to the "native" CR, as defined by the ensemble of dipeptide geometries extracted from PDB proteins. It could be shown that low energy CS regions were indeed found to fall within the native zone. The Tc overlap score behaved as a smooth function of force field parameters. This opens the perspective of a novel force field parameter tuning procedure, bound to simultaneously optimize the behavior of the in Silico simulations for every possible dipeptide. PMID- 29251442 TI - The use of van Kaam's psychophenomenological method to interpret the meaning of resilience in the experiences of people with schizophrenia. AB - BACKGROUND: Phenomenology is a suitable method for investigating people's experiences and van Kaam's psychophenomenological model (PPM) is increasingly being used in nursing research. AIM: To describe the use of PPM to interpret the meaning of resilience in the experiences of people with schizophrenia. DISCUSSION: Semi-structured interviews were conducted with a purposive sample of 14 people with schizophrenia. Analysis of data conformed to van Kaam's PPM. This asserts that while people experience phenomena differently, there will be essential structures of an experience that are the same for individuals sharing it and aims to identify these common elements. The elements must be explicitly expressed by some of the sample, be implicitly or explicitly expressed by most, and be compatible with the whole. CONCLUSION: An embedded dynamic of support and challenge in 11 important elements was identified. IMPLICATIONS FOR PRACTICE: PPM is a suitable model for interpreting experiences. However, it is hard for researchers wanting to use the method to find examples of using PPM for analysis. This paper contributes to building original research examples of PPM. PMID- 29251443 TI - The use of phenomenology in mental health nursing research. AB - BACKGROUND: Historically, mental health research has been strongly influenced by the underlying positivism of the quantitative paradigm. Quantitative research dominates scientific enquiry and contributes significantly to understanding our natural world. It has also greatly benefitted the medical model of healthcare. However, the more literary, silent, qualitative approach is gaining prominence in human sciences research, particularly mental healthcare research. AIM: To examine the qualitative methodological assumptions of phenomenology to illustrate the benefits to mental health research of studying the experiences of people with mental illness. DISCUSSION: Phenomenology is well positioned to ask how people with mental illness reflect on their experiences. Phenomenological research is congruent with the principles of contemporary mental healthcare, as person centred care is favoured at all levels of mental healthcare, treatment, service and research. CONCLUSION: Phenomenology is a highly appropriate and suitable methodology for mental health research, given it includes people's experiences and enables silent voices to be heard. IMPLICATIONS FOR PRACTICE: This overview of the development of phenomenology informs researchers new to phenomenological enquiry. PMID- 29251444 TI - A framework for an asset-informed approach to service mapping. AB - BACKGROUND: Asset-informed approaches are increasingly emphasised in public health, but transferring this approach to planning health services requires prospective systematic methods. Asset-informed approaches to service-mapping have started to develop, but there are no standardised guidelines. These methods are becoming of particular interest, as nurses engage in population health activities. AIM: To identify methods of asset-informed mapping for addressing health problems and develop a framework to support the methodological rigour of service-mapping. DISCUSSION: The authors undertook an integrative literature review using a systematic approach and narrative synthesis. Ten articles met the inclusion criteria. Reported methods included the formation of a core team to drive the process, as well as varying detail about methods of collecting data and forming maps. Challenges and solutions included the effectiveness of the core team depending on having a designated leader, frequent meetings and previous partnerships, using community 'cultural brokers', and determining aims and scope. CONCLUSION: Results of the review can be used to modify existing generic resources for asset-informed mapping to their application in health services. Four main stages seem especially applicable and important: defining the parameters of the service-mapping process; identifying services; mapping services; and consultation and implementation. IMPLICATIONS FOR PRACTICE: The shift towards asset-informed approaches in community and public health is an important step in realising the potential of existing assets in communities to influence health outcomes. The framework offered in this paper is intended to assist in developing an evidence base, by promoting the systematic and rigorous reporting of methods used in asset-informed approaches to service-mapping. PMID- 29251445 TI - Emotion work in qualitative research: interviewing parents about neonatal care. AB - BACKGROUND: 'Emotion work' is a term used to describe the emotional responses that may arise in qualitative research exploring difficult experiences. Parents' experiences of neonatal care can raise sensitive issues during interviews, which may lead to emotional responses. AIM: To reflect on an interpretive study involving narrative interviews with parents of preterm neonates, to inform researchers about the potential emotive issues that may arise in such work. DISCUSSION: Reflection on interviews with parents of preterm neonates revealed areas for discussion relating to emotion work, the role of the researcher, emotional connections and empathic interviewing. Consideration of these areas highlights the importance of reflexivity for researchers. CONCLUSION: Qualitative researchers undertaking narrative interviews should be prepared for emotive issues that arise and recognise the need for emotional intelligence. Achieving a balance between being an empathic, emotionally aware interviewer and remaining objective can be challenging. IMPLICATIONS FOR PRACTICE: Strategies that researchers can use to address this balance and to manage the emotion work involved in research of this nature are provided. PMID- 29251446 TI - Maximising nurses' and midwives' response rates to surveys. AB - BACKGROUND: Low response rates to surveys have been a long-standing issue in research. This includes research involving nurses and midwives. To gain representative samples, appropriate measures to maximise response rates need to be used. AIM: To explore ways to maximise response rates from nurses and midwives, using a hospital-wide survey as an example. DISCUSSION: All nurses and midwives at the study hospital were invited to participate in a survey. To encourage participation and elicit an adequate response rate, several strategies were used. A total of 1,000 surveys were distributed and 319 (32%) were returned. All the required age groups, levels of experience and types of nursing registration were represented in the responses and data saturation was achieved. CONCLUSION: It is important to pay attention to obtaining a representative sample. Further investigation of response rates to surveys by nurses and midwives is warranted. IMPLICATIONS FOR PRACTICE: Strategies to maximise response rates from a target population should be used when conducting surveys. PMID- 29251447 TI - Social media as a recruitment strategy: using Twitter to explore young people's mental health. AB - BACKGROUND: The development of a recruitment strategy requires nurse researchers to consider the avenues available to them to fully investigate a phenomenon. In many cases, this will mean that they invite members of the public to be participants in their research. Successfully advertising the research project to potential participants requires a targeted approach, so that the participants will contribute to a data set that is sufficiently representative and analysis will elicit answers to the research questions. Societal changes in communication patterns and in media consumption have led to a downturn in traditional forms of media, such as television, radio and printed newspapers, magazines and newsletters. Increasingly, the public is using social media instead of traditional media. This change has implications for the design of research and researchers will have to adapt their recruitment strategies to include social media, if they are to collect representative rich data that can be analysed and reliably inform the findings of research. AIM: To discuss the importance of rigorous research designs and to provide an example of a study that demonstrates how mental health researchers, investigating help and support for young people's mental health, can adapt their traditional recruitment practices and applied this new knowledge to recruitment using social media. DISCUSSION: A carefully designed social media recruitment process was particularly useful in attracting informative participant respondents who were able to provide meaningful and rich data relevant when responding to particular research questions. Engineering the participant user experience, such as using a minimum number of keyboard clicks to enter the online survey, mitigated the risk of drop out or incomplete responses. CONCLUSION: Recruitment to a research study requires a strategy that matches the dynamics of the communication media used by potential participants. Nurse researchers need to be adept in the use of social media applied to health research contexts to ensure that data sets obtain representative samples and to reveal trustworthy, reliable, dependable and valid evidence to support clinical research and practice. IMPLICATIONS FOR PRACTICE: The general popularity of social media has led to the public expectation that health information, and in some cases treatment, will be available online. Such a change in communication dynamics in recent times requires that nurse researchers develop new researcher skills and expertise in the proficient use of social media for the purpose of ethical recruitment of participants to health research projects. PMID- 29251448 TI - How helpful are mnemonics in the development of a research question? AB - BACKGROUND: The formulation of a research question is a vital first step in the research process and the significance of this is well reported in the literature; a well-structured question increases the outcome of useable findings. To aid the development of a research question, a number of frameworks in the form of mnemonics have been identified. It is suggested that the application of these mnemonics may result in confusion rather than provide helpful guidance. AIM: To present an overview of some of the mnemonically identified frameworks and consider how they may support the development of a research question. DISCUSSION: The use of mnemonics can help to develop questions for empirical research or to identify published evidence. The oldest and most commonly cited mnemonic is PICO, which is most often discussed in association with quantitative approaches. Other mnemonics share similarities with PICO, although may be more aligned to particular research approaches. Along with a flexible approach to their use, the characteristics required to establish an effective research question may support the application of published mnemonics. CONCLUSION: The availability of frameworks in the form of mnemonics can help in the development of a research question, but their use and limitations must be fully understood. A flexible approach to their use is vital and this may also be helped by considering the characteristics of an effective research question. IMPLICATIONS FOR PRACTICE: When developing research questions, nurse researchers and nurses with a role in academic supervision should use the available mnemonics as a guide rather than rigidly adhering to them. They should also be aware of the characteristics of a good research question and advise students accordingly. PMID- 29251449 TI - Determining the optimal cut-off scores for the Workplace Bullying Inventory. AB - BACKGROUND: Over the past two decades, there has been considerable research into workplace bullying. One area that remains poorly developed is a tool with the capacity to accurately differentiate between exposed and unexposed employees. AIM: To determine optimal cut-off scores for the Workplace Bullying Inventory (WBI) that accurately classify cases of exposure to workplace bullying. DISCUSSION: Secondary analysis of data collected from Australian public sector employees ( n =2,197) was conducted. Receiver operator characteristic (ROC) curve analysis was used with a minimum sensitivity of 80%, to determine those scores on the WBI that corresponded with the highest accuracy of the tool to distinguish cases from non-cases. The results suggest using a cut score of 29 from the total score on the WBI (possible range: 18-90). When compared to a sum-score from a single dichotomous self-report variable, the cut-off score estimated a more conservative bullying rate. The single-item rate was potentially inflated by misconceptions about what constitutes bullying in the workplace. CONCLUSION: Employing validated cut-off points for exposure provides an objective threshold for establishing exposure to workplace bullying. The results of the analysis provide a more rigorous approach to quantifying exposure to workplace bullying, in a tool that has been designed and tested in the nursing workforce. This is the first such tool with empirically-derived, discriminant accuracy. IMPLICATIONS FOR PRACTICE: It is common for nurse researchers to employ sum-scores from single items to identify exposure to workplace bullying. By providing reliable cut-off points for exposure, this study offers standardised, diagnostic accuracy for researchers, clinicians and managers. PMID- 29251450 TI - Correspondence between fiber post and drill dimensions for post canal preparation. AB - PURPOSE: To compare fiber posts of several calibers and trademarks to their corresponding root canal preparation drills. METHODS: Three widely used endodontic post brands and their drills were evaluated: Exacto, ParaPost Taper Lux, and Macro-Lock Illusion X-RO. Fiber posts and drills were microphotographed with a scanning electron microscope and images were analyzed using ImageJ image processing software. Fiber post diameter on apical extreme (Pd0), fiber post diameter at 5 mm from the apical extreme (Pd5), drill diameter on apical extreme (Dd0) and drill diameter at 5 mm from the apical extreme (Dd5) were analyzed. The data were statistically analyzed using student t-test. RESULTS: Exacto posts 0.5 showed larger dimensions than their corresponding drills (P< 0.05) at Pd0. Macro Lock posts showed no significant differences vs. their drills at Pd0 in any of the studied groups. ParaPost drills 4.5, 5 and 5.5 were statistically significantly larger than their posts at Dd0 (P< 0.05). Exacto posts 0.5 and 1 showed larger dimensions than their drills measured at Pd5 (P< 0.05). Exacto posts number 2 showed smaller calibers than their corresponding drills at Pd5 (P< 0.05). Macro-Lock drills number 4 and ParaPost drills number 5 were larger than their posts at Dd5 (P< 0.05). CLINICAL SIGNIFICANCE: Poor spatial correspondence between post and drill dimensions can adversely affect the film thickness of the resin cement, diminishing bond strength due to polymerization shrinkage. The lack of correspondence in size between posts and drills may lead to the formation of empty chambers between the post and endodontic obturation with excessive luting cement thickness, thus inducing critical C-Factor stresses. PMID- 29251451 TI - CAD/CAM post-and-core using different esthetic materials: Fracture resistance and bond strengths. AB - PURPOSE: To evaluate the fracture resistance (FR), and push-out bond strengths (BS) of custom-made CAD/CAM post-and-cores manufactured with different esthetic materials. METHODS: 90 single-rooted extracted teeth were selected, endodontically treated and prepared to receive the posts. The specimens were randomly divided into three equal groups according to the material: hybrid ceramic Vita Enamic (HC); nano-ceramic resin composite Lava Ultimate (RC); and experimental epoxy-resin reinforced by glass-fiber (FG). The post-and-cores were manufactured using CAD/CAM and cemented using a self-adhesive resin cement (Rely X Unicem2). A subgroup of 30 specimens (n=10) was subjected to fatigue (1,000,000 cycles at 5 Hz) and then to the FR test. Another subgroup with 60 specimens was submitted to the BS test, with and without fatigue. Data were submitted to analysis of variance (FR - one-way ANOVA; BS - two-way ANOVA) and Tukey's test (alpha= 0.05). RESULTS: The FR values (mean+/-SD, in Newtons) were 414.5+/-83.9 (HC), 621.3+/-100.3 (RC), and 407.6+/-109.0 (FG), with RC showing significantly higher FR values (P< 0.05). For BS, there was no statistically significant difference among the materials, with and without fatigue (P> 0.05). The type of material used to obtain the CAD/CAM-customized post-and-cores had a significant effect on the FR, but not on the BS of the specimens. Fatigue did not influence the BS for the tested materials. CLINICAL SIGNIFICANCE: CAD/CAM custom-made esthetic post-and-cores showed good performance relative to fracture resistance and bond strength to root canal dentin walls. The CAD/CAM materials tested could be used as an alternative to restore wide flared root canals in esthetically compromised teeth. PMID- 29251452 TI - Fluoride release and re-release from a bioactive restorative material. AB - PURPOSE: To compare the amount of fluoride release and re-release of three different restorative materials. METHODS: The three restorative materials included a resin-based composite (Z100TM, 3M-ESPE), a resin-modified glass ionomer cement (VitremerTM, 3M-ESPE) and a bioactive material (Activa Bioactive RestorativeTM, Pulpdent,). Ten disks were fabricated from each material. The disks were immersed in deionized water and stored. Samples were taken from each vial on Days 1, 7, 14 and 30 for fluoride ion analysis. Each disk was then exposed to 2.0% neutral sodium fluoride gel (0.9% fluoride ion, Dentsply), immersed in deionized water and stored. Samples were taken on Days 1, 7, 14 and 30 for fluoride ion analysis utilizing a fluoride-specific ion-analyzer. RESULTS: Z100 released less fluoride on Days 1 (P< 0.001), 7 (P= 0.001) and 14 (P< 0.022) for Phase I (initial release) than Phase II (re-release). Vitremer and Activa released less fluoride on Days 7, 14 and 30 (P< 0.001) for Phase II than Phase I. For all intervals of Phase I, Vitremer released the most fluoride, Activa released the second most, and Z100 released the least. These results were the same for Days 7, 14 and 30 of Phase II. The level of fluoride release from Activa was less than that of Vitremer, and greater than that of Z100 for all intervals of Phase I. The results were the same for all but one interval of Phase II. CLINICAL SIGNIFICANCE: This in vitro study evaluated the fluoride release and subsequent re-release of fluoride following a topical fluoride treatment to analyze if the materials were truly bioactive. The results indicate the bioactive material does uptake fluoride and re-release it which could offer inhibition to caries at restoration margins. PMID- 29251453 TI - An induced extrinsic tooth stain prevention model to investigate whitening potential of sugar-free chewing gums. AB - PURPOSE: To establish an accelerated clinical test method to evaluate the effectiveness of sugar-free gums in prevention of the formation of extrinsic stains when chewed over a 2-week period in conjunction with daily tooth brushing. A secondary objective was to compare three methods for measuring extrinsic stain. METHODS: 25 healthy adult volunteers were enrolled in a single center, examiner blind, randomized 4-way crossover clinical study. Starting with a stain-free baseline, subjects rinsed five times daily with freshly brewed black tea, followed either by chewing one of three different gums for 12 minutes or not chewing (negative control). Extrinsic stain was measured at 1 and 2 weeks by modified Lobene Stain Index (MLSI), digital imaging, and a Vita EasyShade spectrophotometer. RESULTS: At 2 weeks, MLSI scores showed a statistically significant mean reduction of 43% or greater versus no-gum control for all three gum treatments. Digital image analysis and Vita EasyShade measurement showed reductions of yellowness (measured by difference in ?b* values between the three gums and the non-gum control treatment) ranging from 0.28 to 0.34 and 3.52 to 4.18 Deltab* units, respectively, for subjects using the chewing gums versus no gum control (P< 0.05) after 2 weeks. This clinical study demonstrated that sugar free gum can effectively reduce new stain formation along with daily tooth brushing in as little as 2 weeks when used in conjunction with tea rinsing to help promote more rapid stain formation. All three test methods confirmed the results, albeit with different levels of statistical significance. A minor modification of gum base polymer, or change of flavors, did not significantly impact the prevention of new stain formation. CLINICAL SIGNIFICANCE: Regular consumption of sugar-free chewing gum helps prevent extrinsic dental stain accumulation and provides a simple and enjoyable means for consumers to maintain their natural tooth color. PMID- 29251454 TI - Effects of cigarette smoking on color stability of dental resin composites. AB - PURPOSE: To study the effects of cigarette smoke (CS) on the discoloration of dental resin composite compared with the aerosol from a heat-not-burn tobacco product, the Tobacco Heating System 2.2 (THS2.2). METHODS: A total of 60 discs were prepared from three commercial resin composites: Durafill VS (DVS), Filtek Supreme Ultra (FSU) and Tetric EvoCeram BulkFill (TEC). Twenty discs of each composite were divided into two groups and exposed to CS from 20 reference cigarettes (3R4F) or aerosol from 20 THS2.2 tobacco sticks per day for 3 weeks. Color, gloss and surface roughness of the composite discs were measured at baseline and after exposure and brushing with toothpaste at 1, 2 and 3 weeks. RESULTS: Color differences from the baseline (DeltaE) were on average 27.1 (+/ 3.6) in 3R4F and 3.9 (+/-1.5) in the THS2.2 group after 3 weeks of exposure (P< 0.0001). TEC (30.4+/-1.4 and FSU (28.0 +/-2.5) exhibited more discoloration than DVS (23.0+/-1.2) in the 3R4F group (P< 0.0001). FSU (2.6 +/-0.5) showed significantly less discoloration than TEC (5.3+/-1.5) in the THS2.2 group (P< 0.0001). Surface roughness of resin composites was not affected by either CS or THS2.2 aerosol, while surface gloss increased in the composite discs with more severe discoloration. CLINICAL SIGNIFICANCE: Cigarette smoke caused significant discoloration of dental composite resins. Reducing or eliminating the deposits derived from combustion of tobacco has the potential to minimize the impact of smoking on the color of composite resin restorations. PMID- 29251455 TI - Effect of various teas on color stability of resin composites. AB - PURPOSE: To investigate the effect of various teas on color stability of resin composites. METHODS: Two methacrylate-based (Arabesk Top, Grandio) and a silorane based (Filtek Silorane) resin composites were used. 110 cylindrical samples of each resin composite were prepared (2 mm thickness and 8 mm diameter), polished and stored in distilled water (37 degrees C for 24 hours). They were randomly divided into 11 groups (n= 10) and color measurements were taken. Then the samples were immersed in tap water (control), a black tea, a green tea or one of the eight herbal-fruit teas (37 degrees C for 1 week) and subsequently subjected to the final color measurements. The color change of samples (DeltaE*) was calculated, data were subjected to two-way ANOVA and Tukey's HSD tests. RESULTS: Teas, resin composites and their interactions were significant (P= 0.000). All the teas and control caused color changes in all three resin composites. Rosehip tea caused the most color changes, while tap water showed the least in all resin composites. Arabesk Top had the most staining potential in all the teas and control, whereas Filtek Silorane was the most stain resistant except Grandio immersed in sage tea. Color stability of all resin composites used were affected from both structure of resin materials and constituents of teas used. All resin composites were susceptible to staining by all teas especially rosehip tea. Arabesk Top composite showed the greatest color susceptibility in all teas and Filtek Silorane the least with one exception. CLINICAL SIGNIFICANCE: Color of resin composites can be negatively affected from teas consumed. Clinicians should advise patients that drinking different kind of teas could intensify surface staining of resin based restorations. PMID- 29251456 TI - Efficacy of different protocols for at-home bleaching: A randomized clinical trial. AB - PURPOSE: To evaluate the efficacy of two products used for at-home bleaching with different application times. METHODS: 80 participants were enrolled and divided into four groups, (1) 10% carbamide peroxide 1 hour a day; (2) 10% carbamide peroxide overnight; (3) 7.5% hydrogen peroxide 1 hour a day; and (4) 7.5% hydrogen peroxide overnight. The duration of treatment was 14 days. Color measurement was performed using a dental spectrophotometer on the right maxillary central incisor and the canine, at baseline and 2 weeks after. Participants recorded daily tooth sensitivity. To evaluate the influence of concentration and time on bleaching results (DeltaE) the one-way ANOVA with Bonferroni post-hoc test and the Student's t-test were used. RESULTS: Group 2 showed the highest value of DeltaE (DeltaE = 10.59 +/- 2.68), followed by Group 4 (DeltaE = 8.95 +/- 2.32), Group 1 (DeltaE = 8.05 +/- 3.86), and Group 3 (DeltaE = 7.08 +/- 1.99). There were differences between Groups 2 and 3 (P= 0.001) and between Groups 2 and 1 (P= 0.032). The same product applied overnight was more effective than applied 1 hour a day (P< 0.05). Different concentrations during the same application time achieved similar results. The reported tooth sensitivity was mild. CLINICAL SIGNIFICANCE: At-home bleaching is time but not concentration dependent and its secondary effects depend on the active agent concentration; therefore, there is no need to use high concentration products. The most effective protocol is low concentrations (10% carbamide peroxide) with overnight use. PMID- 29251457 TI - Efficacy of an experimental 3% potassium nitrate mouthwash in providing long-term relief from dentin hypersensitivity: An 8-week randomized controlled study (Study 2). AB - PURPOSE: To evaluate the efficacy of an experimental mouthwash containing 3% potassium nitrate (KNO3) in the relief of dentin hypersensitivity when used as an adjunct to brushing with fluoride toothpaste compared with the use of the same toothpaste alone. METHODS: This was a randomized, two-treatment, examiner-blind, parallel-design single-center, 8-week study in healthy subjects with self reported and clinically diagnosed dentin hypersensitivity. Subjects were randomized to receive either fluoride toothpaste plus 3.0% KNO2 mouthwash or the same fluoride toothpaste alone, and instructed to use their allocated treatment twice daily for the next 8 weeks. Dentin hypersensitivity was evaluated at baseline and following 4 and 8 weeks of treatment through assessment of responses to evaporative (air) and tactile stimuli [measured by the Schiff sensitivity scale/a visual rating scale (VRS) and tactile threshold, respectively], and using the Dentin Hypersensitivity Experience Questionnaire (DHEQ, a validated quality of-life instrument for dentin hyper-sensitivity). RESULTS: A total of 135 subjects were randomized and all completed the study. Both treatment groups demonstrated statistically significant improvements in sensitivity from baseline for each clinical measure of sensitivity (P< 0.0001) at Week 4 and Week 8. The toothpaste plus mouthwash group showed greater reductions in sensitivity at both timepoints for all clinical measures; between-treatment differences were only statistically significant for responses to an evaporative (air) stimulus (Schiff sensitivity score and VRS) at Week 4. There was evidence of an improvement in dentin hypersensitivity-associated quality of life as measured by changes from baseline in several DHEQ parameters for both treatment groups, but there were no statistically significant differences between treatments. CLINICAL SIGNIFICANCE: Although in the current study adjunctive use of a 3% KNO2 mouthwash did not provide statistically significant improvements in dentin hypersensitivity for all clinical measures at all timepoints compared with use of fluoride toothpaste alone, the reductions in sensitivity observed in this study are compatible with the findings of a previous study that showed adjunctive use of a 3% KNO2 mouthwash to be effective in providing relief from dentin hypersensitivity after 8 weeks' twice-daily use. PMID- 29251458 TI - Effect of instruction, light curing unit, and location in the mouth on the energy delivered to simulated restorations. AB - PURPOSE: To determine the amount of energy (Joules/cm2) delivered by students to simulated restorations in a patient simulator based on the restoration location, the curing light unit used, and before vs. after instruction on how to improve their light curing technique. METHODS: 30 dental students "light cured" two simulated restorations (that were 1-mm deep anterior and 4-mm deep posterior) using three light-curing units (LCUs) : VALO, Bluephase G2, and Optilux 401. A MARC Patient Simulator was used to measure the irradiance (mW/cm2) received by the restorations in real-time to calculate the radiant exposure (J/cm2) delivered during a 20-second exposure. At first, students were asked to use the light curing technique that they had been previously taught. They were then given 5 minutes of additional verbal instructions and a practical demonstration on proper curing technique using the patient simulator. They then light cured the restorations again. Based on a literature review, 16 J/cm2 was considered the minimum acceptable radiant exposure. RESULTS: Before receiving instruction using the simulator, some students delivered as little as 4 J/cm2 to the restoration. A mixed model test determined that the radiant exposure delivered to the anterior restoration was significantly greater than that delivered to the posterior restoration (Plt; 0.001). Additionally, when the locations were compared for each LCU individually, a paired t-test determined that before the students received the additional instruction, the anterior restoration received a significantly greater radiant exposure than the posterior restoration, for all three LCUs. Further paired t-tests and Wilcoxon signed-rank tests determined that after instruction, the radiant exposure improved significantly at both the anterior and posterior locations, for all three LCUs. The Bluephase G2 and the VALO each individually delivered 45% more radiant exposure than the Optilux 401 (P< 0.001 for both). The Bluephase G2 and VALO lights delivered similar mean radiant exposures (25.4 J/cm2 and 25.7 J/cm2, respectively). This difference was not significant. Depending on the light unit used, at the posterior location, there was a 24 to a 52% increase in the mean radiant exposure that was delivered after instruction compared to before instruction. CLINICAL SIGNIFICANCE: Prior to using the patient simulator, students and their instructors thought that the students were delivering an adequate amount of energy when light curing. This was not always the case. The location of the restoration, the curing light output, its size and shape and how it is used all affected the amount of energy delivered to a restoration. Dental professionals and educators should be aware that appropriate training can improve the amount of energy delivered, and that restorations in posterior teeth will require longer exposure times than those in anterior teeth. PMID- 29251459 TI - Phosphate buffer-stabilized 0.1% chlorine dioxide oral rinse for managing medication-related osteonecrosis of the jaw. AB - PURPOSE: This is a review of the literature on nonsurgical treatment of non healing medication related osteonecrosis of the jaw (MRONJ) utilizing a phosphate buffer-stabilized 0.1% chlorine dioxide mouthrinse. METHODS: A literature search in PubMed revealed only six case reports. MRONJ lesion site description, patient's medication history, the healing time, and the MRONJ treatment protocol followed by those authors were recorded. Additional literature review of the scientific mechanism, risks and benefits, safety and efficacy of the phosphate buffer-stabilized 0.1% chlorine dioxide mouthrinse was also performed and discussed. RESULTS: Many of the authors of the published case reports utilized 0.12% chlorhexidine as the initial mouthrinse, but the lesions did not decrease in size. After switching to a phosphate buffer-stabilized 0.1% chlorine dioxide mouthrinse for a duration ranging from 1-12 months, there was complete healing of the MRONJ lesions in all of the cases. The phosphate buffer-stabilized 0.1% chlorine dioxide mouthrinse can be helpful in the management of active MRONJ lesions as well as the prevention of recurrent MRONJ lesions in the susceptible patient population. CLINICAL SIGNIFICANCE: This literature review supports the use of phosphate buffer-stabilized 0.1% chlorine dioxide mouthrinse in the management of MRONJ lesions either as a first line of therapy or after 0.12% chlorhexidine had not been effective. PMID- 29251461 TI - UNDERSTANDING EBOLA VIRUS. AB - The ANMF's Body Systems Training Room is the most comprehensive library of anatomy and physiology online education programs for all health professionals. Currently we have 55 topics to choose from and the excerpt below is from the Understanding Ebola Virus Disease. PMID- 29251460 TI - NURSE PRACTITIONERS TAKING URGENT CARE OF PERTH. AB - From chronic disease management to emergency care, Nurse Practitioners (NPs) have been redefining the face of health care in Australia since 2000. While the role continues to remain a largely untapped health solution, two endorsed nurse practitioners are treading their own career path with an innovative venture. PMID- 29251462 TI - THE IMPORTANCE OF A SPECIFIC CONSENT. AB - Healthcare practitioners are generally aware of the need to obtain a patient's consent before providing treatment to avoid legal liability. When practitioners fail to obtain a lawful consent it is possible that they could be subject to criminal and or civil proceedings. PMID- 29251463 TI - FALLS AND FALL INJURY IN MENTAL HEALTH INPATIENT UNITS FOR OLDER PEOPLE. AB - Older people in Mental Health Inpatient Units for Older People (MHUOP) are a serious 'at risk' group, both for falling and osteoporotic injury post fall (Stubbs, 2010), as well as prolonged length of stay (Greene et al. 2001). PMID- 29251464 TI - CHALLENGING ASSUMPTIONS ABOUT MEN: PROPOSITIONS FOR MENTAL HEALTH NURSING. AB - There are many assumptions when it comes to how men view and seek treatment for their own mental health. This article highlights some of the assumptions and proposes how healthcare providers can address them. PMID- 29251465 TI - Extension of Expiration Dates for Four Body System Listings. Final rule. AB - We are extending the expiration dates of the following body systems in the Listing of Impairments (listings) in our regulations: Musculoskeletal System, Cardiovascular System, Digestive System, and Skin Disorders. We are making no other revisions to these body systems in this final rule. This extension ensures that we will continue to have the criteria we need to evaluate impairments in the affected body systems at step three of the sequential evaluation processes for initial claims and continuing disability reviews. PMID- 29251466 TI - DON'T FORGET DAD: MEN'S PERINATAL MENTAL HEALTH. AB - The news that a couple is expecting a baby brings excitement. Pregnancy is often an exhilarating time in an expectant parent's life. PMID- 29251467 TI - Radionuclides and heavy metals concentrations in traditional medicinal plants used in Saudi Arabia. AB - Traditional medicinal plants are widely used for the treatment of various diseases in Saudi Arabia. Knowledge of chemical composition of these materials is important as it pertains to health. The activity concentrations of 232Th, 226Ra and 40K were measured in twenty-six medicinal plant samples purchased from different local Saudi markets using gamma- spectrometry with a NaI[Tl] detector. They ranged between 0.50?0.04 to 13.72?1.15 Bq kg-1, 0.45?0.04 to 12.73?1.02 Bq kg-1and 7.00?0.50 to 327.06?11.0 Bq kg-1, respectively. The radium equivalent activity and absorbed dose rate in the studied samples varied from 1.21 to 54.45 Bq kg-1 and from 0.55 to 28.24 nGyh-1, respectively. Intake of radionuclides in samples was insignificant. Consequently, these samples were considered safe in terms of radiological health hazards. The concentration of six heavy metals: Cd, Pb, As, Cu, Mn and Zn were monitored by inductively coupled plasma optical emission and some of them were found above permissible limit. PMID- 29251468 TI - MEN'S HEALTH -- THE MAN WITH PROSTATE CANCER. PMID- 29251469 TI - Evaluation of Pseudomonas fluorescens for the management of tomato early blight disease and fruit borer. AB - Early blight disease and fruit damage by Helicoverpa armigera are serious problems of tomato causing heavy losses in the yield. An experiment was conducted to evaluate the efficacy of talc based formulation of antagonist Pseudomonas flourescens (Psf) delivered through two different forms of substrate, farmyard manure (FYM) and vermicompost, for the management of tomato early blight disease. Two treatments of Psf, were selected Solarization of nursery soil + seeds and seedlings root dip treatment with Psf formulation + Use of FYM colonized with Psf formulation; Solarization of nursery soil + seed and seedlings root dip treatment with Psf formulation + Use of vermicompost colonized with Psf formulation. These were compared with farmer's practice and untreated control. The impact of all these treatments on tomato fruit borer, H. armigera was also studied. There was not much variation in plant growth parameters (plant height and canopy width) between all the treatments. Both biocontrol treatments (17.69% and 141.3 q acre 1; 15.70% and 139.4 q acre-1, respectively), as well as farmer's practice (10.25% and 208.5 q acre-1) were found to be better than untreated control (29.21% and 94.6 q acre-1) in reducing the incidence of early blight disease in tomato and increasing the marketable yield of tomato fruits. However, the farmer's practice was found to be significantly better than both biocontrol treatments of Psf in controlling fruit damage due to disease, as well as fruit borer. The effect of both bioagents enriched formulations i.e. FYM+Psf and vermicompost+Psf with respect to disease was significantly at par with each other, whereas they had no impact on the fruit borer incidence. The results indicated that either of biocontrol treatments of P. flourescens using farmyard manure and vermicompost, as delivery substrates, can be considered as one of the component along with chemical control in developing IPM programme for the management of early blight disease in tomato. PMID- 29251470 TI - Effect of saline irrigation water on gas exchange and proline metabolism in ber (Ziziphus). AB - An experiment was conducted in pots of 25 kg capacity to study the effect of saline irrigation (EC 0,5,10,15 and 20 dSm-1) prepared by mixing NaCl, NaSO4, CaCl and MgCl2 in 3:1 ratio of chloride and sulphate on gas exchange traits, membrane stability, chlorophyll stability index and osmolytic defense mechanism in Ziziphus rotundifolia and Ziziphus nummularia species of Indian jujube (Z.mauritiana). Result showed that net photosynthetic rate (PN), transpiration (e) and stomatal conductance were comparatively lower in Ziziphus nummularia, which further declined with increasing level of saline irrigation water. Chlorophyll stability and membrane stability also declined significantly in salt stress, with higher magnitude in Ziziphus nummularia. The activity of proline anabolic enzymes; Delta1-Pyrrolline-5-carboxylate reductase, Delta1-Pyrrolline-5 carboxylate synthetase and Ornithine-delta-aminotransferase were recorded higher in Ziziphus rotundifolia with decrease in proline dehydrogenase. The sodium content was observed higher in roots of Ziziphus rotundifolia and leaves of Ziziphus nummularia. Therefore, it is suggested that salt tolerance mechanism was more efficiently operative in Ziziphus rotundifolia owing to better management of physiological attributes, osmolytic defense mechanism and restricted translocation of sodium from root to leaves along with larger accumulation of potassium in its leaves. PMID- 29251471 TI - SUPPORTIVE CARE NEEDS OF PROSTATE CANCER SURVIVORS. AB - Recent advances in detection combined with increasingly effective treatment for prostate cancer has led to significant improvements in life expectancy. More men are living longer with the significant physical and emotional after-effects of prostate cancer treatment. PMID- 29251472 TI - PERINATAL MENTAL HEALTH AND MINDFULNESS FOR MEN WITH PREGNANT PARTNERS, PILOT PROJECT. AB - Currently an online pilot project is underway through the University of Newcastle examining the benefits of an online mindfulness program for men with pregnant partners at www.mindfulnessfordads.com. PMID- 29251473 TI - Effects of Transgenic Bt+CpTI cotton on the abundance and diversity of rhizosphere ammonia oxidizing bacteria and archaea. AB - Genetically modified crops (GMCs) hold great promise for improving agricultural output, but at the same time present challenges in terms of environmental safety assessment. Ammonia oxidizers, including ammonia oxidizing bacteria (AOB) and archaea (AOA), are very important functional microbial groups in nitrogen cycle. The abundance and diversity of AOA and AOB in the rhizosphere of genetically modified cotton (SGK321) and non-GM cotton (SY321) across growth stages were investigated using real time quantitative PCR (qPCR) and terminal restriction fragment length polymorphism (T-RFLP). Results showed that cotton genotype had a significant effect on the change in abundance of AOA and AOB, as indicated by amoA copy number. Variations in AOB abundance in rhizosphere of SY321 differed from those in SGK321. The number of AOB in the rhizosphere of SY321 fluctuated considerably: It dramatically decreased from 1.2?106 copies g-1 dry soil to 3?105 copies g-1 dry soil during the flowering stage and then increased to 1.1?106 copies g-1 and 1.5?106 copies g-1 at the belling and boll opening stages, respectively. However, abundance of AOB in the rhizosphere of SGK321 was relatively stable during all the stages of growth. The effect of SGK321 and SY321 on AOA number was quite similar to that of AOB: AOA abundance in SGK321 increased smoothly from 1.0 ?105 copies g-1 dry soil to 1.4?106 copies g-1 dry soil during growth, but that in SY321 fluctuated. Correspondence analysis (CA), canonical CA (CCA), and partial CCA (pCCA) of T-RFLP profiles of AOA and AOB showed that AOB community changed across growth stages in both cotton genotypes, and cotton genotype was the most important factor affecting the AOA community. In conclusion, the current findings indicated no adverse effect of GM cotton on functional microorganisms. PMID- 29251474 TI - SCREENING DADS FOR DEPRESSION IN AUSTRALIAN EARLY PARENTING CENTRES. AB - For the majority of men, becoming a father is a time of joy that enhances their personal growth and wellbeing. However, similar to the experience of some women, this time can be overwhelming when adjusting to the necessary demands of parenthood and can undermine men's mental health. PMID- 29251475 TI - PSYCHS ON BIKES -- NURSES REVVING UP FOR MEN'S MENTAL HEALTH. AB - How do you reach blokes in the bush who don't use health services? Show them your motorcycle. PMID- 29251476 TI - Role of growth media on the phytopromotional potential of symbiotic fungus Piriformospoira indica. AB - Piriformospora indica biomass generated in different growth media Rose Bengal medium, Kaefer's Medium, Enriched Soil Medium, Malt extract Medium and Czapek Dox was quantified and? their bioinoculum potential was compared using? moong bean (Vigna radiata) as? test plant. Plant chlorophyll content in response to inoculations was lowest in Rose Bengal medium (2.772mg plant-1) and highest due to inoculum produced on Enriched soil Medium (3.694 mg plant-1). The highest nitrogen content (19.260 mg plant-1) was recorded by inoculum produced on Kaefer's Medium followed by Enriched Soil Medium (19.123 mg plant-1), ME (18.19 mg plant-1) and CD medium (17.71 mg plant-1). The highest plant phosphorus uptake was registered in Enriched Soil Medium (17.153 mg plant-1) followed by Kaefer's Medium (17.023 mg plant-1). Maximum dry weight of plants was observed by inoculation with fungus cultured in Kaefer's Medium (3.416 g pot-1) and Enriched Soil Medium (3.349 g pot-1). Thus, growth medium used for the culture of fungus can influence its bioefficacy as plant growth promoting agent and Piriformospora indica can be grown on cost effective and simple mass multiplication medium which could augment its usage for commercial purposes. PMID- 29251477 TI - GUIDING HEALTH CONSULTATIONS WITH MEN. AB - In Australia, health areas of concern for men include: average shorter life expectancy; higher levels of avoidable mortality; and higher mortality from almost all common causes of death including heart disease, cancer, respiratory disease and suicide (AIWH, 2014; DHHS, 2015). PMID- 29251478 TI - INCLUDINGMEN IN THE GLOBAL HEALTH AGENDA: AN INVESTMENT IN FAMILIES. AB - Male health outcomes continue to be significantly poorer than females in many parts of the world. By 2010, women were generally outliving men by six years, with a life expectancy at birth approximately 5.3 years less (Baker et al. 2014). PMID- 29251479 TI - Isolation of marine fungi Aspergillus sp. and its in vitro antifouling activity against marine bacteria. AB - Biofouling is considered as a main issue of concern in aquatic environment causing severe economic loss and pollution. The aim of the present study was to isolate marine fungus antagonistic to biofouling bacteria and to define antifouling compounds present in it. Using standard plate method five predominant biofouling bacteria viz., Methylococcus sp., Flavobacterium sp., Marinococcus sp., Serratia sp. and Pseudomonas sp. were isolated from marine solid substances on Zobell's agar. Tolerance range of these bacteria to NaCl was 2-10%. Isolation of fungi from mangrove and estuarine sediments and their screening identified Aspergillus sp. EF4 as a potential isolate. This isolate caused inhibition of all the five test bacterial cultures measuring zone diameters respectively of 11, 16, 12, 13 and 11mm.? Subsequent to submerged fermentation using shaking flask method this fungus produced bioactive compounds within 5 days. The culture parameters optimized were raffinose as carbon source, yeast extract as lone nitrogen source, pH up to 9.0 and temperature up to 40?C. Antifouling compounds of culture filtrate were separated and detected by a three-step procedure involving thin layer chromatography, bioautography and preparative TLC. The in vitro assay involving glass slide-wooden stick-biofilm method revealed that these compounds could cause inhibition and destruction of bacteria to an extent of 2.16 x 104 CFU ml-1 and 2.46 x 104 CFU ml-1 respectively while growth of bacteria in control beaker was enumerated to be 4.41 x 104 CFU ml-1. High performance liquid chromatography of culture filtrate indicated probable principal antifouling compound as Fumonisin B2. Isolation of antagonistic marine fungus from Indian coast and detection of its antifouling compound would help in planning effective strategies for controlling biofouling in marine environment. PMID- 29251480 TI - HEALTH IN CAPTIVITY, A NURSE-LED WELLBEING CLINIC FOR MALE PRISONERS. AB - It is traditionally hard to engage men in preventive healthcare, and it is no easier in a custodial environment. PMID- 29251481 TI - GIS based evaluation of crop suitability for agricultural sustainability around Kolaghat thermal power plant, India. AB - Fly ash exhaust from Kolaghat thermal power plant, West Bengal, India,?? affects the areas within the radius of 3 - 4 km. Land information system indicated that surface texture within 4 km was silty loam and clay content increased with increase of distance. Soil pH was alkaline (7.58-8.01) in affected circles, whereas soil was acidic (5.95-6.41) in rest of block. Organic carbon (OC) is roving from 0.36 to 0.64% in the nearer circles which is lesser from others. The present Crop suitability analysis revealed that 96.98 % area was suitable (S1) for maize, sesame, jute, whereas these were cultivated in less than 1% of land. Flowers are the best suitable (S1) in 88.9 % but it was grown in 6.02 % area.? The present rice area within 4 km of KTPP is showing moderately suitable (S2) and S1 for the rest. Wheat is moderately suitable (S2) in the almost all the circles.? Cultivation of vegetable crops is limited in the affected circles while the highly suitable (S1) comprises 67.49 % for the remaining areas though it covered only 6.01 % of the block.? This evaluation precisely improves more than 300% from the earlier cropping intensity of 177.95 %. Suitability based land use allocation serves as stepping stone to promote agricultural sustainability. Geographic information system (GIS) model has been developed to assess site specific crop suitability for sustainable agricultural planning. PMID- 29251482 TI - CHALLENGES IN THE PREVENTION OF HIV AMONG THAI HOMOSEXUAL MALES IN THE ERA OF DIVERSITY AND FREEDOM OF CULTURE. AB - Undeniably, Thai society has changed dramatically, the way of life, values, beliefs and practices have shifted from what they were previously. Exposure to western culture, values and lifestyles are responsible for changes in the way of life of Thai people and their society. PMID- 29251483 TI - The protective role of phytochemicals on TiO2 nanoparticles-induced DNA damage in lymphocytes. AB - The adverse health effect of nanoparticles is of concern for humans and environment. In the present study, TiO2-nanoparticles (TiO2-NPs)-induced oxidative DNA damage in lymphocytes was measured by comet assay. 80 mg ml-1 TiO2 NPs induced approximately 3-fold increase in DNA damage than in the PBS-control group as measured by olive tail moment. However, on treating vitamin C and N acetylcysteine, DNA damage was effectively protected in a concentration dependent manner. Moreover, the protective effect of several phytochemicals including berberine, resveratrol, sulforaphane, and curcumin on DNA damage caused by TiO2 NPs was manifested. The increased olive tail moment induced by TiO2-NPs was effectively inhibited by treatment with these phytochemicals. Especially, olive tail moment of 5 mg ml-1 berberine-treated group was significantly reduced down to the level of control group, showing almost complete protection. Taken together, the protective effect of phytochemicals against DNA damage by TiO2-NPs may be applied for the development of antidote for TiO2 toxicity. PMID- 29251484 TI - Kinetic and isotherm studies on adsorption of fluoride by limonite with batch technique. AB - Fluoride in drinking water has an intense effect on bones and teeth. The concentration of fluoride >1.5 mg l-1 in drinking water is harmful for human health. In the present study the naturally occurring geomaterial limonite (Iron Ore) has been used as the adsorbent for the investigation of defluoridation capacity by Batch adsorption technique in aqueous condition. Various parameters such as contact time, adsorbent dose, adsorbate concentration, adsorbent particle size and agitation speed at room temperature (298K) and pH (7?0.3), has been optimization for the adsorption of F- onto limonite. The initial rate of the adsorption was very fast and after 120 minutes it attained equilibrium. Three known Isotherm Models (Langmuir, Freundlich and Temkin) used to study the mechanism and nature of adsorption onto the surface of limonite. The experimental results are best fitted into the Langmuir and Temkin isotherm models (R2> 0.99). The average monolayer adsorption capacity (Qm) obtained for limonite is 0.269 mg g-1. The experimental data highlights that surface sites of adsorbent (limonite) are heterogeneous in nature and fits into a heterogeneous site binding model. The kinetic study revealed that the adsorption process followed Pseudo 2nd order model. The removal efficiency of limonite for the naturally high F- water sample (4.12 mg l-1) under optimized condition obtained 66.9%. The maximum adsorption capacity Qe (F- adsorbed) at equilibrium is calculated 2.208 mg g-1. The isotherm and kinetic studies reveal that limonite can be used as an adsorbent for fluoride removal. The OH-group of limonite acts as ion exchange with F- ion confirm by Fourier Transmission-IR spectroscopy analysis (FT-IR). XRD (X-ray Refraction Dispersive) peaks also give good evidence of surface adsorption onto limonite and surface morphology by Scanning electron microscopy (SEM) image. In the future we can use this technology for fluoride removal in large scale by using limonite which is cost-effective, eco-friendly, minimal processing and easily available in the study area. PMID- 29251485 TI - Editorial. PMID- 29251486 TI - Branched High Molecular Weight Glycopolypeptide With Broad-Spectrum Antimicrobial Activity for the Treatment of Biofilm Related Infections. AB - There are few therapeutic options to simultaneously tackle Staphylococcus aureus and Pseudomonas aeruginosa, two of the most relevant nosocomial and antibiotic resistant pathogens responsible for implant, catheters and wound severe infections. The design and synthesis of polymers with inherent antimicrobial activity have gained increasing attention as a safe strategy to treat multi-drug resistant microbes. Here, we tested the activity of a new polymeric derivative with glycopolypeptide architecture (PAA-VC) bearing l-arginine, vancomycin, and colistin as side chains acting against multiple targets, which give rise to a broad spectrum antimicrobial activity favorably combining specific and nonspecific perturbation of the bacterial membrane. PAA-VC has been tested against planktonic and established biofilms of reference strains S. aureus ATCC 25923 and P. aeruginosa ATCC 15442 and susceptible or antibiotic resistant clinical isolates of the above-mentioned microorganisms. MIC values observed for the conjugate (48-190 and 95-190 nM for P. aeruginosa and S. aureus strains, respectively) showed higher efficacy if compared with the free vancomycin (MICs within 1.07-4.28 MUM) and colistin (MICs within 0.63-1.33 MUM). Additionally, being highly biocompatible (IC50 > 1000, 430, and 250 MUg mL-1 for PAA-VC, vancomycin and colistin respectively) high-dosage can be adopted for the eradication of infections in patients. This positively influences the anti biofilm activity of the conjugate leading to a quasi-total eradication of established clinically relevant biofilms (inhibition >90% at 500 MUg mL-1). We believe that the in vitro presented data, especially the activity against established biofilms of two relevant pathogens, the high biocompatibility and the good mucoadhesion properties, would allow the use of PAA-VC as promising candidate to successfully address emerging infections. PMID- 29251487 TI - Evaluation of the H2 Evolving Activity of Benzenehexathiolate Coordination Frameworks and the Effect of Film Thickness on H2 Production. AB - The design of earth-abundant catalysts for the electrochemical production of H2 from water is important for the realization of a sustainable energy future. Incorporation of molecular catalysts into extended frameworks has emerged as a viable strategy for improving catalytic performance and durability while maintaining a high degree of control over the structure and properties of the catalytic active site. Here, we investigate benzenehexathiolate (BHT) coordination frameworks as electrocatalysts for the hydrogen evolution reaction (HER) in pH 1.3 aqueous solutions. The electrocatalytic HER activity of BHT-based coordination frameworks follows the order of CoBHT > NiBHT > FeBHT. CoBHT operates at an overpotential of 185 mV, the lowest observed overpotential of the reported metal dithiolene-based metal organic frameworks and coordination polymers to date. To further understand the properties that dictate electrocatalytic activity, the effect of film thickness on the HER performance of CoBHT, a parameter that has not been extensively explored for electrocatalytic coordination frameworks, was examined. As the thickness was increased to ~1 MUm, charge and proton transfer through CoBHT was hindered, the number of electrochemically accessible active sites decreased, and the mechanical robustness of the modified electrode was diminished. The observed thickness dependent HER activity of CoBHT highlights the importance of practical electrode construction and offers insight into how to optimize proton and electron transfer properties and active site densities within coordination frameworks without reducing the mechanical robustness of the immobilized catalysts. PMID- 29251488 TI - Toward a Rational Design to Regulate beta-Amyloid Fibrillation for Alzheimer's Disease Treatment. AB - The last decades have witnessed a growing global burden of Alzheimer's disease (AD). Evidence indicates that the onset and progression of AD is associated with beta-amyloid (Abeta) peptide fibrillation. As such, there is a strong passion with discovering potent Abeta fibrillation inhibitors that can be developed into anti-amyloiddogenic agents for AD treatment. Current challenges that have arisen with this development involve with Abeta oligomer toxicity suppression and Blood Brain Barrier penetration capability. Considering most natural or biological events, one would observe that there is usually a "seed" to direct natural materials to assemble in response to a certain stimulation. Inspired by this, several materials or compounds, including nanoparticle, peptide or peptide mimics, and organic molecules, have been designed for the purpose of redirecting or impeding Abeta aggregation. Achieving these tasks requires comprehensive understanding on (1) initial Abeta assembly into insoluble deposits, (2) main concerns with fibrillation inhibition, and (3) current major methodologies to disrupt the aggregation. Herein, the objective of this review is to address these three areas, and enable the pathway for a promising therapeutic agent design for AD treatment. PMID- 29251489 TI - Fragility of the Dirac Cone Splitting in Topological Crystalline Insulator Heterostructures. AB - The "double Dirac cone" 2D topological interface states found on the (001) faces of topological crystalline insulators such as Pb1-xSnxSe feature degeneracies located away from time reversal invariant momenta and are a manifestation of both mirror symmetry protection and valley interactions. Similar shifted degeneracies in 1D interface states have been highlighted as a potential basis for a topological transistor, but realizing such a device will require a detailed understanding of the intervalley physics involved. In addition, the operation of this or similar devices outside of ultrahigh vacuum will require encapsulation, and the consequences of this for the topological interface state must be understood. Here we address both topics for the case of 2D surface states using angle-resolved photoemission spectroscopy. We examine bulk Pb1-xSnxSe(001) crystals overgrown with PbSe, realizing trivial/topological heterostructures. We demonstrate that the valley interaction that splits the two Dirac cones at each X is extremely sensitive to atomic-scale details of the surface, exhibiting non monotonic changes as PbSe deposition proceeds. This includes an apparent total collapse of the splitting for sub-monolayer coverage, eliminating the Lifshitz transition. For a large overlayer thickness we observe quantized PbSe states, possibly reflecting a symmetry confinement mechanism at the buried topological interface. PMID- 29251490 TI - Hierarchical Self-Assembly of an Alkynylplatinum(ll) Bzimpy-Functionalized Metallacage via Pt...Pt and pi-pi Interactions. AB - A new discrete supramolecular metallacage functionalized with an alkynylplatinum(ll) 2,6-bis(benzimidazole-2'-yl)-pyridine (bzimpy) moiety has been successfully constructed via coordination-driven self-assembly. A study on the hierarchical self-assembly behavior of the obtained metallacage revealed that it displayed a solvent-induced emission switch accompanied by enhancement of the emission intensity as a result of the change in intermolecular Pt...Pt and pi-pi interactions. More interestingly, the metallacage has been found to spontaneously self-assemble into a transparent metallogel at room temperature without a heating cooling process. PMID- 29251491 TI - Glycosylation Promotes the Random Coil to Helix Transition in a Region of a Protist Skp1 Associated with F-Box Binding. AB - Cullin-ring-ligases mediate protein polyubiquitination, a signal for degradation in the 26S proteasome. The CRL1 class consists of Skp1/cullin-1/F-box protein/Rbx1 (SCF) complexes that cyclically associate with ubiquitin-E2 to build the polyubiquitin chain. Within the SCF complex, the 162-amino acid DdSkp1 from Dictyostelium bridges cullin-1 with an F-box protein (FBP), the specificity factor for substrate selection. The hydroxylation-dependent glycosylation of Pro143 of DdSkp1 by a pentasaccharide forms the basis of a novel O2-sensing mechanism in the social amoeba Dictyostelium and other protists. Previous evidence indicated that glycosylation promotes increased alpha-helical content correlating with enhanced interaction with three F-box proteins. To localize these differences, we used nuclear magnetic resonance (NMR) methods to compare nonglycosylated DdSkp1 and a glycoform with a single GlcNAc sugar (Gn-DdSkp1). We report NMR assignments of backbone 1HN, 15N, 13Calpha, and 13CO nuclei as well as side-chain 13Cbeta and methyl 13C/1H nuclei of Ile(delta1), Leu, and Val in both unmodified DdSkp1 and Gn-DdSkp1. The random coil index and 15N{1H} HNOE indicate that the C-terminal region, which forms a helix-loop-helix motif centered on Pro143 at the crystallographically defined binding interface with F-box domains, remains dynamic in both DdSkp1 and Gn-DdSkp1. Chemical shifts indicate that the variation of conformation in Gn-DdSkp1, relative to DdSkp1, is limited to this region and characterized by increased helical fold. Extension of the glycan chain results in further changes, also limited to this region. Thus, glycosylation may control F-box protein interactions via a local effect on DdSkp1 conformation, by a mechanism that may be general to many unicellular eukaryotes. PMID- 29251493 TI - cGMP Binding Domain D Mediates a Unique Activation Mechanism in Plasmodium falciparum PKG. AB - cGMP-dependent protein kinase from Plasmodium falciparum ( PfPKG) plays a crucial role in the sexual as well as the asexual proliferation of this human malaria causing parasite. However, function and regulation of PfPKG are largely unknown. Previous studies showed that the domain organization of PfPKG significantly differs from human PKG ( hPKG) and indicated a critical role of the cyclic nucleotide binding domain D (CNB-D). We identified a novel mechanism, where the CNB-D controls activation and regulation of the parasite specific protein kinase. Here, kinase activity is not dependent on a pseudosubstrate autoinhibitory sequence (IS), as reported for human PKG. A construct lacking the putative IS and containing only the CNB-D and the catalytic domain is inactive in the absence of cGMP and can efficiently be activated with cGMP. On the basis of structural evidence, we describe a regulatory mechanism, whereby cGMP binding to CNB-D induces a conformational change involving the alphaC-helix of the CNB-D. The inactive state is defined by a unique interaction between Asp597 of the catalytic domain and Arg528 of the alphaC-helix. The same arginine (R528), however, stabilizes cGMP binding by interacting with Tyr480 of the phosphate binding cassette (PBC). This represents the active state of PfPKG. Our results unveil fundamental differences in the activation mechanism between PfPKG and hPKG, building the basis for the development of strategies for targeted drug design in fighting malaria. PMID- 29251494 TI - Fe5Mo Cluster with Iron-Carbide and Molybdenum-Carbide Bonding Motifs: Structure and Selective Alkyne Reductions. AB - Herein we report the synthesis, X-ray structure, and characterization of the title pentairon (molybdo)carbido cluster. The reaction of the pentairon (MU5 carbido) dianion [Fe5(MU6-C)(MU2-CO)2(CO)12]2- (1) with [Mo(CO)3(chpt)] (chpt = cycloheptatriene) forms the heterohexanuclear cluster [K(benzo-18-crown 6)]2[Fe5Mo(MU6-C)(MU2-CO)3(CO)14] (2). The dianion exhibits a Fe5Mo(MU6-C) core structure supported by three bridging (nuCO = 1788 cm-1) and terminal (nuCO = 1943 cm-1) CO ligands. Cluster 2 provides the selective reduction of diphenylacetylene to cis-diphenylethylene via a spectroscopically observed cluster-hydride intermediate (1H NMR: delta -26). PMID- 29251492 TI - Probing Conformational States of the Finger and Thumb Subdomains of HIV-1 Reverse Transcriptase Using Double Electron-Electron Resonance Electron Paramagnetic Resonance Spectroscopy. AB - The configurational space sampled by the finger and thumb subdomains of the p66 subunit of HIV-1 reverse transcriptase was investigated by Q-band double electron electron resonance pulsed electron paramagnetic resonance spectroscopy, a method for determining long-range distances between pairs of nitroxide spin-labels introduced via surface-engineered cysteine residues. Four constructs were examined, each containing two spin-labels in the p66 subunit, one in the finger subdomain and the other in the thumb subdomain. In the unliganded state, open and closed configurations for the finger and thumb subdomains are observed with the distribution between these states modulated by the spin-labels and associated mutations, in contrast to crystallographic data in which the unliganded state crystallizes in the closed conformation. Upon addition of double-stranded DNA, all constructs adopt open conformations consistent with previous crystallographic data in which the position of the thumb and finger subdomains is determined by contacts with the bound oligonucleotide duplex (DNA or DNA/RNA). Likewise, binary complexes with five different non-nucleoside reverse transcriptase inhibitors are in open or partially open conformations, indicating that binding of the inhibitor to the palm subdomain indirectly restricts the conformational space sampled by the finger and thumb subdomains. PMID- 29251495 TI - A High-Valent Metal-Oxo Species Produced by Photoinduced One-Electron, Two-Proton Transfer Reactivity. AB - Described herein is a photochemical approach to the generation of a high-valent metal-oxo species that utilizes a chromophore or "sensitizer", a semiconducting electron acceptor, and a redox buffer that poises a catalyst's initial protonation and oxidation state. The photoexcited sensitizer injects an electron into the semiconductor and then oxidizes the catalyst whose reactivity occurs in kinetic competition with back electron transfer. Core-shell SnO2/TiO2 semiconductor nanocrystallites inhibited charge recombination relative to TiO2 acceptors. With low sensitizer-catalyst surface coverages, a novel trapping process is exploited that enables catalysis reactivity to be quantified on time scales ranging from nanoseconds to minutes. A proof-of-principle example provides the demonstration of a light-initiated, (1e-, 2H+)-transfer reaction, with an inverse isotope effect of kH/kD = 0.63, to generate a Ru(IV) oxo species. PMID- 29251496 TI - Electron-Poor Polar Intermetallics: Complex Structures, Novel Clusters, and Intriguing Bonding with Pronounced Electron Delocalization. AB - Intermetallic compounds represent an extensive pool of candidates for energy related applications stemming from magnetic, electric, optic, caloric, and catalytic properties. The discovery of novel intermetallic compounds can enhance understanding of the chemical principles that govern structural stability and chemical bonding as well as finding new applications. Valence electron-poor polar intermetallics with valence electron concentrations (VECs) between 2.0 and 3.0 e /atom show a plethora of unprecedented and fascinating structural motifs and bonding features. Therefore, establishing simple structure-bonding-property relationships is especially challenging for this compound class because commonly accepted valence electron counting rules are inappropriate. During our efforts to find quasicrystals and crystalline approximants by valence electron tuning near 2.0 e-/atom, we observed that compositions close to those of quasicrystals are exceptional sources for unprecedented valence electron-poor polar intermetallics, e.g., Ca4Au10In3 containing (Au10In3) wavy layers, Li14.7Mg36.8Cu21.5Ga66 adopting a type IV clathrate framework, and Sc4MgxCu15-xGa7.5 that is incommensurately modulated. In particular, exploratory syntheses of AAu3T (A = Ca, Sr, Ba and T = Ge, Sn) phases led to interesting bonding features for Au, such as columns, layers, and lonsdaleite-type tetrahedral frameworks. Overall, the breadth of Au-rich polar intermetallics originates, in part, from significant relativistics effect on the valence electrons of Au, effects which result in greater 6s/5d orbital mixing, a small effective metallic radius, and an enhanced Mulliken electronegativity, all leading to ultimate enhanced binding with nearly all metals including itself. Two other successful strategies to mine electron poor polar intermetallics include lithiation and "cation-rich" phases. Along these lines, we have studied lithiated Zn-rich compounds in which structural complexity can be realized by small amounts of Li replacing Zn atoms in the parent binary compounds CaZn2, CaZn3, and CaZn5; their phase formation and bonding schemes can be rationalized by Fermi surface-Brillouin zone interactions between nearly free-electron states. "Cation-rich", electron-poor polar intermetallics have emerged using rare earth metals as the electropositive ("cationic") component together metal/metalloid clusters that mimic the backbones of aromatic hydrocarbon molecules, which give evidence of extensive electronic delocalization and multicenter bonding. Thus, we can identify three distinct, valence electron-poor, polar intermetallic systems that have yielded unprecedented phases adopting novel structures containing complex clusters and intriguing bonding characteristics. In this Account, we summarize our recent specific progress in the developments of novel Au-rich BaAl4-type related structures, shown in the "gold-rich grid", lithiation-modulated Ca-Li-Zn phases stabilized by different bonding characteristics, and rare earth-rich polar intermetallics containing unprecedented hydrocarbon-like planar Co-Ge metal clusters and pronounced delocalized multicenter bonding. We will focus mainly on novel structural motifs, bonding analyses, and the role of valence electrons for phase stability. PMID- 29251497 TI - The Mineral Stutzite: a Zintl-Phase or Polar Intermetallic? A Case Study Using Experimental and Quantum-Chemical Techniques. AB - Differing reports regarding the structural features of the mineral stutzite, Ag5 xTe3 (-0.25 <= x <= 1.44), and the quest for tellurides with low-dimensional fragments stimulated our impetus to review this system by employing experimental as well as quantum-chemical methods. Determination of the crystal structures for three samples with compositions Ag4.72(3)Te3 (I), Ag4.66(1)Te3 (II), and Ag4.96(2)Te3 (III) revealed considerable positional disorders for the Ag and Te sites and previously unknown structure models for I and II, which differ from that of III through the stacking sequences of honeycomb-fashioned Te layers. The crystal structures comprise [Te@Ag9]@Te14 units in the forms of bicapped hexagonal Te antiprisms that enclose Te-centered tricapped trigonal Ag prisms, while each Te atom is encapsulated by Ag atoms assembling diverse types of coordination polyhedra. The vibrational and electronic properties were determined for three models approximating the actual crystal structure of stutzite by means of techniques based on first principles. From analyses of the electronic structures and projected crystal orbital Hamilton populations (pCOHP), it is clear that the amounts and distributions of the Ag atoms within the Te network should be influenced by the subtle interplay between the attempts to achieve an electronically favorable situation with a gap at EF and minimize the occupations of antibonding states. PMID- 29251499 TI - Incorporation of Metals into Calcite in a Deep Anoxic Granite Aquifer. AB - Understanding metal scavenging by calcite in deep aquifers in granite is of importance for deciphering and modeling hydrochemical fluctuations and water-rock interaction in the upper crust and for retention mechanisms associated with underground repositories for toxic wastes. Metal scavenging into calcite has generally been established in the laboratory or in natural environments that cannot be unreservedly applied to conditions in deep crystalline rocks, an environment of broad interest for nuclear waste repositories. Here, we report a microanalytical study of calcite precipitated over a period of 17 years from anoxic, low-temperature (14 degrees C), neutral (pH: 7.4-7.7), and brackish (Cl: 1700-7100 mg/L) groundwater flowing in fractures at >400 m depth in granite rock. This enabled assessment of the trace metal uptake by calcite under these deep seated conditions. Aquatic speciation modeling was carried out to assess influence of metal complexation on the partitioning into calcite. The resulting environment-specific partition coefficients were for several divalent ions in line with values obtained in controlled laboratory experiments, whereas for several other ions they differed substantially. High absolute uptake of rare earth elements and U(IV) suggests that coprecipitation into calcite can be an important sink for these metals and analogousactinides in the vicinity of geological repositories. PMID- 29251500 TI - Fourier Transform Fluorescence-Encoded Infrared Spectroscopy. AB - While time-resolved infrared (IR) vibrational spectroscopy provides insight on structural dynamics of solution-phase systems, current techniques are limited to high concentrations. Fluorescence-encoded infrared spectroscopy (FEIR) can be used to encode IR-driven vibrational excitations into excited electronic states that fluoresce, which can be detected at lower concentrations than a coherently detected IR signal. Here, we report on the development of Fourier transform FEIR as an alternate approach for high-sensitivity IR spectroscopy. Upon driving vibrational excitation with a pair of IR fields with a variable time delay, an interferometric component was observed in the encoded fluorescence. This signal can be Fourier transformed to obtain a vibrational spectrum. By additionally varying the time delay of the encoding pulse following the second IR pulse, we observed frequency-difference oscillations, allowing us to construct a 2D correlation spectrum of coupled vibrations. Response functions for this experiment have been modeled, which reproduce the observed spectral features and relate them to excitation pathways using diagrammatic perturbation theory. The pathways observed in a 2D FEIR spectrum arise from the excitation of vibrational populations and coherences between coupled vibrations. PMID- 29251501 TI - Energy Selection in Nonadiabatic Transitions. AB - In this work we investigate whether and how a molecule undergoing a nonadiabatic transition can show different energy mean values and distributions in the two electronic states that are populated. We analyze three models, of which models I and II mimick the limiting cases of almost adiabatic and almost diabatic regimes, respectively, and are solvable by first-order perturbation theory. Model III represents realistically the photodissociation of a diatomic molecule and is treated numerically. The three models provide a consistent picture of the energy selection effect. For a typical avoided crossing, the wavepacket component that undegoes the transition between the two adiabatic states has a larger mean value of energy than the other component, both for upward and for downward transitions. The analysis of model II shows that the Landau-Zener rule can be deduced in a fully quantum mechanical way. We believe that the energy selection effect can be observed experimentally in the photodissociation of diatomic molecules. The effect should be particularly relevant for wavepackets endowed with a broad energy spectrum, as the result of excitation with ultrashort light pulses. PMID- 29251498 TI - Protein Inhibitors of CRISPR-Cas9. AB - Bacteria are under constant predation from viruses, called bacteriophages (phages). This threat has driven the evolution of multiple defense systems, including the CRISPR-Cas (clustered regularly interspaced short palindromic repeats and CRISPR associated genes) immune pathway. Phages are not passive bystanders in their CRISPR-mediated demise, however, as many have developed potent protein inhibitors of the bacterial adaptive immune system. Here, I review the work that led to the discovery of many distinct "anti-CRISPR" proteins. Furthermore, I outline how understanding their mechanisms of action has provided a suite of specific and high-affinity reagents to modulate and study CRISPR-Cas applications. PMID- 29251502 TI - Copper Selective Polymeric Extractant Synthesized by Ring-Opening Metathesis Polymerization. AB - Novel polymers bearing pendant picolinic acid functionalities have been synthesized by ring-opening metathesis polymerization (ROMP) for applications in separations-based purification protocols. These polymers and their corresponding monomer were shown to be selective for Cu2+ over a variety of other divalent metal cations as inferred from pH dependent studies carried out under both liquid liquid and solid-liquid extraction conditions. The polymer system of this study also showed high selectivity for Cu2+ over Ni2+ in mock protocols that could be relevant to the purification of Cu radioisotopes. Separation factors as high as 290 were achieved for extractions from solutions containing a 100-fold excess of Ni2+ relative to Cu2+. PMID- 29251504 TI - Cellulosic Nanomaterials in Food and Nutraceutical Applications: A Review. AB - Cellulosic nanomaterials (CNMs) are organic, green nanomaterials that are obtained from renewable sources and possess exceptional mechanical strength and biocompatibility. The associated unique physical and chemical properties have made these nanomaterials an intriguing prospect for various applications including the food and nutraceutical industry. From the immobilization of various bioactive agents and enzymes, emulsion stabilization, direct food additives, to the development of intelligent packaging systems or pathogen or pH detectors, the potential food related applications for CNMs are endless. Over the past decade, there have been several reviews published covering different aspects of cellulosic nanomaterials, such as processing-structure-property relationship, physical and chemical properties, rheology, extraction, nanocomposites, etc. In this critical review, we have discussed and provided a summary of the recent developments in the utilization of cellulosic nanomaterials in applications related to food and nutraceuticals. PMID- 29251503 TI - Preparation of a Strong Gelatin-Short Linear Glucan Nanocomposite Hydrogel by an in Situ Self-Assembly Process. AB - Gelatin hydrogels exhibit excellent biocompatibility, nonimmunogenicity, and biodegradability, but they have limited applications in the food and medical industries because of their poor mechanical properties. Herein, we first developed an in situ self-assembly process for the preparation of gelatin-short linear glucan (SLG) nanocomposite hydrogels with enhanced mechanical strength. The microstructure, dynamic viscoelasticity, compression behavior, and thermal characteristics of the gelatin-SLG nanocomposite hydrogels were determined using scanning electron microscopy (SEM), dynamic rheological experiments, compression tests, and texture profile analysis tests. The SEM images revealed that nanoparticles were formed by the in situ self-assembly of SLG in the gelatin matrix and that the size of these nanoparticles ranged between 200 and 600 nm. The pores of the nanocomposite hydrogels were smaller than those of the pure gelatin hydrogels. Transmission electron microscopy images and X-ray diffraction further confirmed the presence of SLG nanoparticles with spherical shapes and B type structures. Compared with pure gelatin hydrogels, the nanocomposite hydrogels exhibited improved mechanical behavior. Notably, the hardness and maximum values of the compressive stress of gelatin-SLG nanocomposites containing 5% SLG increased by about 2-fold and 3-fold, respectively, compared to the corresponding values of pure gelatin hydrogels. PMID- 29251505 TI - Modulation of Cyclodextrin Particle Amphiphilic Properties to Stabilize Pickering Emulsion. AB - Cyclodextrins have been proven to form complexes with linear oil molecules and stabilize emulsions. Amphiphilic properties of cyclodextrin particles were modulated through esterification reaction between beta-cyclodextrin (beta-CD) and octadecenyl succinic anhydride (ODSA) under alkaline conditions. ODS-beta-CD particles with degree of substitution (DS) of 0.003, 0.011, and 0.019 were obtained. The introduced hydrophobic long chain that was linked within beta-CD cavity led to the change of ODS-beta-CD in terms of morphological structure, surface charge density, size, and contact angle, upon which the properties and stability of the emulsions stabilized by ODS-beta-CD were highly dependent. The average diameter of ODS-beta-CD particles ranged from 449 to 1484 nm. With the DS increased from 0.003 to 0.019, the contact angle and absolute zeta potential value of these ODS-beta-CD particles improved from 25.7 degrees to 47.3 degrees and 48.1 to 62.8 mV, respectively. The cage structure of beta-CD crystals was transformed to channel structure, then further to amorphous structure after introduction of the octadecenyl succinylation chain. ODS-beta-CD particles exhibited higher emulsifying ability compared to beta-CD. The resulting Pickering emulsions formed by ODS-beta-CD particles were more stable during storage. This study investigates the ability of these ODS-beta-CD particles to stabilize oil-in water emulsions with respect to their amphiphilic character and structural properties. PMID- 29251507 TI - Synthesis of Polysubstituted Isoquinolines and Related Fused Pyridines from Alkenyl Boronic Esters via a Copper-Catalyzed Azidation/Aza-Wittig Condensation Sequence. AB - An efficient and straightforward synthesis of isoquinolines is reported from internal alkenyl boronic esters, easily prepared from the corresponding 1,2 bis(boronates), via a sequential copper-catalyzed azidation/aza-Wittig condensation. This synthetic method has been used to synthesize quinisocaine, a topical anesthetic used for the treatment of pain and pruritus, and further extended to thieno[2,3-c]pyridines by using 2-thiophenecarboxaldehyde as coupling partner in the first step. PMID- 29251508 TI - Palladium-Catalyzed Site-Selective sp3 C-H Bond Thiocyanation of 2-Aminofurans. AB - Alkyl thiocyanates are prevalent in natural products, drugs, and biologically active compounds. We report here a novel, mild, and efficient Pd-catalyzed site selective sp3 C-H bond thiocyanation of 2-aminofurans. Using Na2S2O8 as the oxidant and readily available NaSCN as the thiocyanation reagent, the kinetically favorable 2-amino-4-thiocyanatomethylfurans are selectively synthesized in promising yields with a broad substrate scope. This reaction represents the first example of transition-metal-catalyzed site-selective sp3 C-H bond thiocyanation, thus offering a novel strategy for the step- and atom-economic synthesis of alkyl thiocyanates. PMID- 29251509 TI - Ru(II)-Catalyzed Cross-Coupling of Cyclopropenes with Diazo Compounds: Formation of Olefins from Two Different Carbene Precursors. AB - Formal carbene dimerization is a convergent method for the synthesis of alkenes. Herein, we report a Ru(II)-catalyzed carbene dimerization of cyclopropenes and diazo compounds. The yields are up to 97% and the stereoselectivity are up to >20:1. Mechanistically, it has been experimentally demonstrated that the catalyst reacts with cyclopropene first to generate a Ru(II)-carbene species, which is attacked by nucleophilic diazo substrate, followed by dinitrogen extrusion to form the double bond. PMID- 29251510 TI - Fluoroethylene Carbonate as a Directing Agent in Amorphous Silicon Anodes: Electrolyte Interface Structure Probed by Sum Frequency Vibrational Spectroscopy and Ab Initio Molecular Dynamics. AB - Fluorinated compounds are added to carbonate-based electrolyte solutions in an effort to create a stable solid electrolyte interphase (SEI). The SEI mitigates detrimental electrolyte redox reactions taking place on the anode's surface upon applying a potential in order to charge (discharge) the lithium (Li) ion battery. The need for a stable SEI is dire when the anode material is silicon as silicon cracks due to its expansion and contraction upon lithiation and delithiation (charge-discharge) cycles, consequently limiting the cyclability of a silicon based battery. Here we show the molecular structures for ethylene carbonate (EC): fluoroethylene carbonate (FEC) solutions on silicon surfaces by sum frequency generation (SFG) vibrational spectroscopy, which yields vibrational spectra of molecules at interfaces and by ab initio molecular dynamics (AIMD) simulations at open circuit potential. Our AIMD simulations and SFG spectra indicate that both EC and FEC adsorb to the amorphous silicon (a-Si) through their carbonyl group (C?O) oxygen atom with no further desorption. We show that FEC additives induce the reorientation of EC molecules to create an ordered, up-right orientation of the electrolytes on the Si surface. We suggest that this might be helpful for Li diffusion under applied potential. Furthermore, FEC becomes the dominant species at the a-Si surface as the FEC concentration increases above 20 wt %. Our finding at open circuit potential can now initiate additive design to not only act as a sacrificial compound but also to produce a better suited SEI for the use of silicon anodes in the Li-ion vehicular industry. PMID- 29251511 TI - Fabrication of Electrospun Eugenol/Cyclodextrin Inclusion Complex Nanofibrous Webs for Enhanced Antioxidant Property, Water Solubility, and High Temperature Stability. AB - In this study, inclusion complexes (IC) of three cyclodextrin derivatives (HP beta-CD, HP-gamma-CD, and M-beta-CD) with eugenol (essential oil compound) were formed in highly concentrated aqueous solutions and then transformed into self standing functional nanofibrous webs by electrospinning. The improved aqueous solubility of eugenol was confirmed by phase solubility diagrams, in addition, the phase solubility tests also revealed 1:1 molar ratio complexation between host:guest molecules; CD:eugenol. Even though eugenol has a volatile nature, a large amount of eugenol (~70-95%) was preserved in eugenol/cyclodextrin inclusion complex nanofibrous webs (eugenol/CD/IC-NW). Moreover, enhanced thermal stability of eugenol was recorded for eugenol/CD/IC-NW (up to ~310 degrees C) when compared to pure form of eugenol (up to ~200 degrees C). The eugenol/CD/IC-NW exhibited fast dissolving behavior in water, contrary to poorly water-soluble eugenol. It was observed that the complexation between M-beta-CD and eugenol was the strongest when compared to other two host CD molecules (HP-beta-CD and HP gamma-CD) for eugenol/CD/IC-NW samples. The electrospun eugenol/CD/IC-NW samples have shown enhanced antioxidant activity compared to pure form of eugenol. In summary, cyclodextrin inclusion complexes of essential oil compounds, such as eugenol, in the form of self-standing nanofibrous webs may have potentials for food and oral-care applications due to their particularly large surface area along with fast-dissolving character, improved water solubility, high temperature stability, and enhanced antioxidant activity. PMID- 29251506 TI - Scanning Quadrupole Data-Independent Acquisition, Part B: Application to the Analysis of the Calcineurin-Interacting Proteins during Treatment of Aspergillus fumigatus with Azole and Echinocandin Antifungal Drugs. AB - Calcineurin is a critical cell-signaling protein that orchestrates growth, stress response, virulence, and antifungal drug resistance in several fungal pathogens. Blocking calcineurin signaling increases the efficacy of several currently available antifungals and suppresses drug resistance. We demonstrate the application of a novel scanning quadrupole DIA method for the analysis of changes in the proteins coimmunoprecipitated with calcineurin during therapeutic antifungal drug treatments of the deadly human fungal pathogen Aspergillus fumigatus. Our experimental design afforded an assessment of the precision of the method as demonstrated by peptide- and protein-centric analysis from eight replicates of the study pool QC samples. Two distinct classes of clinically relevant antifungal drugs that are guideline recommended for the treatment of invasive "aspergillosis" caused by Aspergillus fumigatus, the azoles (voriconazole) and the echinocandins (caspofungin and micafungin), which specifically target the fungal plasma membrane and the fungal cell wall, respectively, were chosen to distinguish variations occurring in the proteins coimmunoprecipitated with calcineurin. Novel potential interactors were identified in response to the different drug treatments that are indicative of the possible role for calcineurin in regulating these effectors. Notably, treatment with voriconazole showed increased immunoprecipitation of key proteins involved in membrane ergosterol biosynthesis with calcineurin. In contrast, echinocandin (caspofungin or micafungin) treatments caused increased immunoprecipitation of proteins involved in cell-wall biosynthesis and septation. Furthermore, abundant coimmunoprecipitation of ribosomal proteins with calcineurin occurred exclusively in echinocandins treatment, indicating reprogramming of cellular growth mechanisms during different antifungal drug treatments. While variations in the observed calcineurin immunoprecipitated proteins may also be due to changes in their expression levels under different drug treatments, this study suggests an important role for calcineurin-dependent cellular mechanisms in response to antifungal treatment of A. fumigatus that warrants future studies. PMID- 29251512 TI - Three new 3,4-seco-cycloartane triterpenes from Gardenia sootepensis. AB - The plants in the genus Gardenia (Rubiaceae) have long been used as traditional medicines in China. In this study, two new 3,4-seco-cycloartane triterpenes, sootepin J (1) and sootepin K (2), and a novel nor-3,4-seco-cycloartane triterpenes, sootepin L (3), together with two known compounds (4-5), were isolated from the methanolic extract of the leaves and twigs of Gardenia sootepensis. The structures of the new compounds were elucidated by combinations of 1D, 2D NMR experiments and HR-MS data, while the known compounds were identified by comparison of the NMR data with previously published data. PMID- 29251513 TI - Combination of PedCAT Weightbearing CT With Pedography Assessment of the Relationship Between Anatomy-Based Foot Center and Force/Pressure-Based Center of Gravity. AB - BACKGROUND: A customized pedography sensor (Pliance; Novel, Munich, Germany) was inserted into a pedCAT (Curvebeam, Warrington, PA). The aim of this study was to analyze the relative position of the anatomical foot center (FC) and the pedographic center of gravity (COG). The hypothesis was that FC should be a good predictor of mediolateral position of COG but not longitudinal since hindfoot anatomy allows free anteroposterior movement but limited mediolateral movement. METHODS: In 90 patients (180 feet), a pedCAT scan with simultaneous pedography with full weightbearing in a standing position was performed. The morphology based definition of the FC was performed with the pedCAT data following the Torque Ankle Lever Arm System (TALAS) algorithm. The force/pressure-based COG was defined with the pedography data using a software-based algorithm. The distance between FC and COG and the direction of a potential shift (distal-proximal, mediolateral) was measured and analyzed. COG motion during data acquisition was recorded and analyzed. Mean age of patients was 53.8 (range, 17-84) years, and 57 (63%) were female. RESULTS: The distance between FC and COG was 28.7 mm on average (range, 0-60). FC was distal to COG in 175 feet (97%; mean, 27.5 mm; range, -15 to 60) and lateral in 112 feet (62%; mean, 2.0 mm; range, -18 to 20). CONCLUSIONS: There was a constant and major distal longitudinal shift of COG relative to FC and an inconstant minor mediolateral shift. CLINICAL RELEVANCE: The data might be taken into consideration for planning and follow-up in foot and ankle surgery. PMID- 29251514 TI - Validity of a Novel Touch Screen Tablet-Based Assessment for Mild Cognitive Impairment and Probable AD in Older Adults. AB - This study aimed to develop a psychometrically valid touch screen tablet-based cognitive test battery to identify early cognitive impairment due to dementia in older adults. The battery includes eight tests with 13 subscores, evaluating visual attention, auditory attention, information processing speed, visual memory, motor control, and visuospatial perception. Among the participants, 43 had been diagnosed with mild cognitive impairment (MCI) and 36 with probable Alzheimer's disease (AD); 41 had no cognitive impairment. The average time to administer the tablet-based tests was 10 minutes. Significant correlations with the Mini-Mental State Examination were found in 9 out of 13 subscores. Patients with probable AD scored significantly lower than controls in 8 out of 13 subscores, whereas those with MCI scored significantly lower in 4 out of 13 subscores. Confirmatory factor analysis using Promax rotation showed that four factors caused lower subscores in the MCI group compared with the controls: information processing speed, memory, visuospatial perception, and motor control. All four factors significantly discriminated the controls from the MCI and probable AD groups, and in the expected direction. The touch screen tablet-based cognitive test battery is psychometrically valid for evaluating cognition in older adults. PMID- 29251515 TI - Two new compounds from Nigrospora sphaerica ZMT05, a fungus derivated from Oxya chinensis Thunber. AB - A new pyrrolidinone derivative named nigrosporamide A (1), and a new acetophenone derivative, 4-prenyloxyclavatol (2), were isolated from an endophytic fungus Nigrospora sphaerica (collection No. ZMT05) isolated from Oxya chinensis Thunberg. Their chemical structures were established on the basis of the interpretation of spectroscopic data. In primary in vitro bioassay, nigrosporamide A (1) exhibited strong antifungal activity against Colletotrichum gloeosporioides and high inhibitory activity towards alpha-glucosidase. PMID- 29251516 TI - A technique to assess perineuronal mediators. AB - Perineural activity of a variety of inflammatory and immune system mediators can activate peripheral nerves leading to the perception of pain. One example of such effects includes the activity of interleukin 1 beta (IL-1beta); this inflammatory mediator, upon binding to IL-1R1 neuronal membrane receptors will rapidly induce protein kinases in damage-sensing neurons, consequently altering heat-activated ionic inward currents leading to increased neuronal sensitivity to harmful heat. The ability to detect such mediators in proximity to sensory nerves is therefore crucial to investigating the contributing roles of inflammation in human chronic pain. To date there is no recognized method to assess mediator profiles around human sensory nerve roots in vivo. A novel method is described that can assess these mediators in the human trigeminal system where the nerve leaves the brain stem in its pre-ganglionic portion. Mediator levels are shown to change between sample locations on the trigeminal nerve root in patients with trigeminal neuralgia. This methodology may therefore be used to shed insights as to the pathophysiology of trigeminal neuralgia, which may in turn influence clinical decisions concerning the natural history, and treatment options. PMID- 29251517 TI - Yttrium-90 resin microspheres and their use in the treatment of intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is a severe and rapidly progressive hepatic tumor. Surgery is often impracticable due to locally advanced presentation. On the other hand, chemotherapy has demonstrated only limited effectiveness. For these reasons, liver-directed therapies have been successfully applied for treating ICC. In particular, radioembolization with Yttrium-90 (90Y)-labeled spheres has been reported to be a promising therapeutic approach for this neoplasia. Two commercial forms of 90Y-labeled spheres are available: glass (TheraSphere(r)) and resin (SIR-Spheres(r)) microspheres. The aim of the present paper is to review the existing literature on the use of the resin microspheres for the treatment of unresectable and chemorefractory ICC, focusing on the methodology, clinical applications and side effects. PMID- 29251518 TI - Evaluation of the targeted delivery of 5-fluorouracil and ascorbic acid into the brain with ultrasound-responsive nanobubbles. AB - Recently, ultrasound-induced drug delivery into the brain using bubble formulations has been developed. After the brain delivery, however, the information on pharmacokinetics of hydrophilic drugs in the brain is lacking. In this study, to clarify the time-course pharmacokinetics of hydrophilic drugs, we used a brain microdialysis method. Using ultrasound-responsive nanobubbles (bubble liposomes (BLs)) with ultrasound irradiation, two hydrophilic drugs, 5 fluorouracil (5-FU) and ascorbic acid, were delivered into the brain of mice and rats and their time-course pharmacokinetics were evaluated with microdialysis. The results indicated that the time-course pharmacodynamics of ascorbic acid evaluated by examining its antioxidant capacity supported the time-course pharmacokinetics. Additionally, to strengthen the evidences of our evaluation, we varied the effect of BLs dose and duration and intensity of ultrasound irradiation on drug delivery. Among them, when the dose of BLs was changed, the trend of 5-FU intracerebral migration was consistent with other report. In conclusion, we succeeded in clarifying the time-course pharmacokinetics of the two hydrophilic drugs after the brain delivery with bubble formulations and ultrasound irradiation using mice and rats. PMID- 29251519 TI - Impairment of amyloid precursor protein alpha-processing in cerebral microvessels of type 1 diabetic mice. AB - The mechanisms underlying dysfunction of cerebral microvasculature induced by type 1 diabetes (T1D) are not fully understood. We hypothesized that in cerebral microvascular endothelium, alpha-processing of amyloid precursor protein (APP) is impaired by T1D. In cerebral microvessels derived from streptozotocin (STZ) induced T1D mice protein levels of APP and its alpha-processing enzyme, a disintegrin and metalloprotease 10 (ADAM10) were significantly decreased, along with down-regulation of adenylate cyclase 3 (AC3) and enhanced production of thromboxane A2 (TXA2). In vitro studies in human brain microvascular endothelial cells (BMECs) revealed that knockdown of AC3 significantly suppressed ADAM10 protein levels, and that activation of TXA2 receptor decreased APP expression. Furthermore, levels of soluble APPalpha (sAPPalpha, a product of alpha-processing of APP) were significantly reduced in hippocampus of T1D mice. In contrast, amyloidogenic processing of APP was not affected by T1D in both cerebral microvessels and hippocampus. Most notably, studies in endothelial specific APP knockout mice established that genetic inactivation of APP in endothelium was sufficient to significantly reduce sAPPalpha levels in the hippocampus. In aggregate, our findings suggest that T1D impairs non-amyloidogenic processing of APP in cerebral microvessels. This may exert detrimental effect on local concentration of neuroprotective molecule, sAPPalpha, in the hippocampus. PMID- 29251520 TI - Local drug delivery in the urinary tract: current challenges and opportunities. AB - Drug delivery is an important consideration in disease treatment. There are many opportunities for novel methods and technologies to hold promising roles in overcoming traditional obstacles. Delivery systems functionalised to boast synergistic antimicrobial effects, specific targeting, and enhanced bioavailability allow for improved therapeutic potential and better patient outcomes. Many of these delivery modalities find clinical practicality in the field of urology, specifically in the treatment of urinary tract infections (UTIs) and offer advantages over conventional methods. The aim of this review article is to discuss the current modalities of treatment for UTIs and the recent technological advancements for optimising drug delivery. We focus on challenges that persist in drug delivery during UTIs including barriers to antimicrobial penetration, drug resistance, biofilm formation and specific targeting limitations. With a discussion on how emerging methods combat these concerns, we present an overview of potential therapies with special emphasis on nanoparticle based applications. PMID- 29251521 TI - Development and characterisation of levosulpiride-loaded suppositories with improved bioavailability in vivo. AB - The purpose of this study was to develop and characterize levosulpiride loaded liquid suppository with improved bioavailability. The content of levosulpiride loaded liquid suppositories were optimized in a series of experiments using various weight ratios of P188, P407, Tween 80, and drug. The suppositories were liquid at room temperature, however, when rectally administered, they became gel at body temperature. Their rheological properties and release characteristics were determined in vitro while pharmacokinetic study was performed after its rectal administration in rats and compared with drug suspension. Poloxamer 188 and Twee 80 decreased the gelation temperature and gelation time, but increased the gel strength and mucoadhesive force of liquid suppositories. Liquid suppository composed of [Levosulpiride/P 188/P 407/Tween 80 (1/15/17/3%)] with a gelation temperature of about 30.7 degrees C remained liquid at 25 degrees C, but converted to gel at 30-36.5 degrees C, resulting in easy administration and rapid gelation inside the body. This liquid suppository gave a considerably increased dissolution rate reflected in a meaningfully higher plasma concentration and 7.1-fold AUC values of levosulpiride in rats as compared to the drug suspension. Hence, liquid suppository system could be used for enhanced bioavailability of levosulpiride-loaded pharmaceutical products. PMID- 29251522 TI - Docetaxel-carboxymethylcellulose nanoparticles ameliorate CCl4-induced hepatic fibrosis in mice. AB - Chronic liver diseases have recently garnered substantial attention as a leading cause of death around the world. During the progression of liver fibrosis/cirrhosis induced by chronic liver injury, hepatic stellate cells (HSCs) play key roles in the regulation of liver fibrogenesis and can even accelerate the progression of hepatocellular carcinoma (HCC). Thus, inhibition of HSC activation or suppression of inflammatory cytokine secretion by HSCs may be an efficient therapeutic strategy to ameliorate liver fibrosis/cirrhosis. In this study, we demonstrated that Cellax NPs (Carboxymethylcellulose - docetaxel conjugated nanoparticles), which are nanoscale Pegylated carboxymethylcellulose - DTX conjugates, selectively target activated HSCs and abrogate their fibrogenic properties in vitro. Furthermore, Cellax NPs alleviated CCl4-induced hepatic fibrosis and suppressed HCC progression in a clinically relevant HCC model associated with underlying liver fibrosis in vivo. Taken together, Cellax NPs demonstrate great therapeutic promise as a treatment for liver fibrosis and cancer. PMID- 29251523 TI - Perivascular neurotransmitters: Regulation of cerebral blood flow and role in primary headaches. AB - In order to understand the nature of the relationship between cerebral blood flow (CBF) and primary headaches, we have conducted a literature review with particular emphasis on the role of perivascular neurotransmitters. Primary headaches are in general considered complex polygenic disorders (genetic and environmental influence) with pathophysiological neurovascular alterations. Identified candidate headache genes are associated with neuro- and gliogenesis, vascular development and diseases, and regulation of vascular tone. These findings support a role for the vasculature in primary headache disorders. Moreover, neuronal hyperexcitability and other abnormalities have been observed in primary headaches and related to changes in hemodynamic factors. In particular, this relates to migraine aura and spreading depression. During headache attacks, ganglia such as trigeminal and sphenopalatine (located outside the blood-brain barrier) are variably activated and sensitized which gives rise to vasoactive neurotransmitter release. Sympathetic, parasympathetic and sensory nerves to the cerebral vasculature are activated. During migraine attacks, altered CBF has been observed in brain regions such as the somatosensory cortex, brainstem and thalamus. In regulation of CBF, the individual roles of neurotransmitters are partly known, but much needs to be unraveled with respect to headache disorders. PMID- 29251524 TI - Macrophages as an active tumour-targeting carrier of SN38-nanoparticles for cancer therapy. AB - Taking advantage of their enhanced permeability and retention (EPR) effect, nanomedicines have been extensively studied for targeted drug delivery to tumour tissues. However, tumour heterogeneity restricts the EPR effect and drug penetration into tumours, and nanoformulations only generate a limited therapeutic improvement in clinical settings. Macrophages have the inherent ability of tumour homing, stealth in blood circulation, and phagocytosis of particles. In this study, we used peritoneal macrophages as carriers for the delivery of SN38 nanoparticles (SN38-NPs) for cancer treatment. SN38-NPs were internalised by macrophages without any obvious effect on viability and migration, and not only induced apoptosis of tumour cells in vitro, but also accumulated in tumour tissues in vivo. In addition, the macrophage-based delivery system for SN38-NPs showed improved therapeutic effect than an equivalent dose of CPT-11 in an A549 subcutaneous tumour model. PMID- 29251525 TI - The importance of the initial response to cancer treatment in predicting longer overall survival. PMID- 29251526 TI - Inadequate vocal hygiene habits associated with the presence of self-reported voice symptoms in telemarketers. AB - AIM: The aim of this study is to determine possible associations between vocal hygiene habits and self-reported vocal symptoms in telemarketers. PATIENTS AND METHODS: A cross-sectional study that included 79 operators from call centres in Chile was carried out. Their vocal hygiene habits and self-reported symptoms were investigated using a validated and reliable questionnaire created for the purposes of this study. RESULTS: Forty-five percent of telemarketers reported having one or more vocal symptoms. Among them, 16.46% reported that their voices tense up when talking and 10.13% needed to clear their throat to make their voices clearer. Five percent mentioned that they always talk without taking a break and 40.51% reported using their voices in noisy environments. The number of working hours per day and inadequate vocal hygiene habits were associated with the presence of self-reported symptoms. Additionally, an interaction between the use of the voice in noisy environments and not taking breaks during the day was observed. Finally, the frequency of inadequate vocal hygiene habits was associated with the number of symptoms reported. CONCLUSIONS: Using the voice in noisy environments and talking without taking breaks were both associated with the presence of specific vocal symptoms. This study provides some evidence about the interaction between these two inadequate vocal hygiene habits that potentiates vocal symptoms. PMID- 29251527 TI - Decision tree models to classify nanomaterials according to the DF4nanoGrouping scheme. AB - To keep pace with its rapid development an efficient approach for the risk assessment of nanomaterials is needed. Grouping concepts as developed for chemicals are now being explored for its applicability to nanomaterials. One of the recently proposed grouping systems is DF4nanoGrouping scheme. In this study, we have developed three structure-activity relationship classification tree models to be used for supporting this system by identifying structural features of nanomaterials mainly responsible for the surface activity. We used data from 19 nanomaterials that were synthesized and characterized extensively in previous studies. Subsets of these materials have been used in other studies (short-term inhalation, protein carbonylation, and intrinsic oxidative potential), resulting in a unique data set for modeling. Out of a large set of 285 possible descriptors, we have demonstrated that only three descriptors (size, specific surface area, and the quantum-mechanical calculated property 'lowest unoccupied molecular orbital') need to be used to predict the endpoints investigated. The maximum number of descriptors that were finally selected by the classification trees (CT) was very low- one for intrinsic oxidative potential, two for protein carbonylation, and three for NOAEC. This suggests that the models were well constructed and not over-fitted. The outcome of various statistical measures and the applicability domains of our models further indicate their robustness. Therefore, we conclude that CT can be a useful tool within the DF4nanoGrouping scheme that has been proposed before. PMID- 29251528 TI - Pendant HDAC inhibitor SAHA derivatised polymer as a novel prodrug micellar carrier for anticancer drugs. AB - Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACi) approved by FDA for the treatment of cutaneous T cell lymphoma, is a promising anticancer drug for various cancers with a unique mode of action. However, it demonstrates limited clinical benefits in solid tumours as a single drug. In order to achieve enhanced and synergistic co-delivery of SAHA and doxorubicin (DOX), a cleavable SAHA-based prodrug polymer (POEG-b-PSAHA), consisting of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) blocks and hydrophobic SAHA segments, has been developed. POEG-b-PSAHA prodrug polymer was able to form spherical micelles with a diameter around 60 nm and well retained the pharmacological activity of SAHA in either inhibiting the proliferation of tumour cells or inducing histone acetylation. DOX formulated in POEG-b-PSAHA based micelles showed a sustained release profile. DOX-loaded POEG-b-PSAHA exhibited more potent cytotoxicity towards tumour cells than free DOX and DOX loaded in a pharmacologically 'inert' nanocarrier, POEG-b-POM. Consistently, DOX/POEG-b-PSAHA formulation resulted in an improved therapeutic effect in vivo compared to free DOX, Doxil or DOX formulated in POEG-b-POM micelles. These results suggest that SAHA-based prodrug micelles may serve as a dual functional carrier for combination strategies in epigenetic-oriented anticancer therapy. PMID- 29251529 TI - Infectious complications in patients on treatment with Ruxolitinib: case report and review of the literature. AB - BACKGROUND: Primary myelofibrosis is a chronic myeloproliferative neoplasm that may cause debilitating symptoms, which can be improved with the use of Ruxolitinib, a Janus kinase 2 inhibitor. However, this agent has significant immunomodulatory effects which may increase the risk for infections. METHODS: We searched the literature and our institutional electronic medical record for reported cases of infections in adult patients on ruxolitinib treatment. RESULTS: We found 28 cases in our literature search and 4 cases from our Institution for a total of 32 cases. The most common infection was tuberculosis in 11/32 cases (34%), followed by cryptococcal infection in 3/32 (9%) and hepatitis B virus reactivation in 3/32 (9%). CONCLUSION: Opportunistic infections associated with ruxolitinib use are increasingly reported in the literature; further studies should investigate the role of systematic screening and prophylaxis against infections in this subset of patients. PMID- 29251530 TI - Instrument Development of Integrative Health and Wellness AssessmentTM. AB - The nurse coach role was developed to address the needs of our nation and the world for health and wellbeing. The Theory of Integrative Nurse Coaching provides a foundation for coaching interventions supporting health promotion, and a framework for the development of the Integrative Health and Wellness Assessment (IHWA) short form. This 36-question Likert-type scale self-reporting tool assists participants in assessing healthy behaviors through a self-reflection process, provides information for the coaching relationship, and may be an outcome measurement. This article describes the history of the IHWA tool and the development and pilot testing of the IHWA short form using guidelines provided by DeVellis. Results of the Kaiser-Meyer-Olkin test yielded a value of .520, and the Bartlett's test of sphericity was significant. Cronbach's alpha overall scale internal consistency was .88 ( n = 36). Pilot study results indicate that the scale could be improved through additional revision, and an ongoing study is in progress. PMID- 29251531 TI - Micellar formulations of Crizotinib and Dasatinib in the management of glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) defies the currently practiced management of radiotherapy, chemotherapy and surgery and hence, it is associated with a high fatality rate with a median survival of 14.6 months. In our previous work investigating different tyrosine kinase inhibitors (TKIs), we established that a combination of Crizotinib and Dasatinib exerted the most potent effect on different GBM cell lines. In this work, to improve targeted therapy at the site of the tumour and avoid systemic toxicity, we exploited the enhanced permeability and retention effect by designing micellar formulations of these two TKIs. Crizotinib and Dasatinib were successfully encapsulated in poly(styrene-co-maleic acid) (SMA) micelles which were then evaluated for their physicochemical characteristics, anti-proliferative effect, mode of cell death, efficacy in spheroid models, effect on cell signalling, antiangiogenic potential and in vivo anticancer activity. Our results showed that this combination had induced a potent anti-proliferative effect in four GBM cell lines grown as a monolayer and as a spheroid. The combination was also efficacious in in vitro models of angiogenesis and vascular mimicry. In vivo data showed the enhanced activity of the micellar TKIs compared to free drugs. In conclusion, we proved that micellar formulations of Crizotinib and Dasatinib carry promising in vitro and in vivo efficacy that warrant further investigation. PMID- 29251532 TI - Metabolism and pharmacokinetics studies of allyl methyl disulfide in rats. AB - 1. Allyl methyl disulfide (AMDS) is one of the main compounds in garlic, whereas its metabolism has not been studied yet. 2. In this work, we first identified the metabolites of AMDS in rat erythrocytes and rats using GC-MS. The transformation mechanism study among different metabolites was then conducted. The apparent kinetics of AMDS in rat erythrocytes and pharmacokinetics of AMDS by oral administration in rats were also studied. 3. The metabolic pathway study showed that AMDS was mainly metabolized in rats to allyl methyl sulfoxide (AMSO) and allyl methyl sulfone (AMSO2) through mechanisms of reduction, methylation and oxidation. The transformation mechanism study indicated that AMDS was firstly reduced to allyl mercaptan (AM) in rat erythrocytes, and then methylated to allyl methyl sulfide (AMS) by S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), and finally oxidized to AMSO and AMSO2 by liver microsomes. The half-life of AMDS in rat erythrocytes was 6.285 +/- 0.014 min while the half-lives of its active metabolites AMSO and AMSO2 in vivo were 18.17 and 17.50 h, respectively. Also, the large AUCs of the two active metabolites were observed, indicating potential applications of AMDS for certain pharmacological effects. PMID- 29251533 TI - The Functional Movement Screen as a Predictor of Injury in National Collegiate Athletic Association Division II Athletes. AB - CONTEXT: The Functional Movement Screen (FMS) is a tool used to assess the quality of human movement. Previous FMS researchers reported a difference between the comprehensive and individual FMS test scores of injured and uninjured participants. OBJECTIVE: To evaluate the accuracy of the FMS for predicting injury in National Collegiate Athletic Association Division II athletes and to evaluate how an injury definition may affect the prognostic values. DESIGN: Cross-sectional study. SETTING: University preparticipation examinations. PATIENTS OR OTHER PARTICIPANTS: A total of 257 collegiate athletes (men = 176, women = 81) between the ages of 18 and 24 years. MAIN OUTCOME MEASURE(S): The athletes were prospectively screened with the FMS and monitored for subsequent injury. The ability of the FMS to accurately predict musculoskeletal injuries, overall injuries, and severe injuries was determined. RESULTS: The receiver operating characteristic curve provided the FMS cut score of <=15 for the study sample. The areas under the curve were 0.53, 0.56, and 0.53 for musculoskeletal injury, overall injury, and severe injury, respectively. Sensitivity was 0.63 (0.62, 0.61, 0.65), whereas specificity was below 0.50 (0.49, 0.49, 0.45) for all 3 injury definitions of musculoskeletal injury, overall injury, and severe injury, respectively. Relative risk was 1.25 for musculoskeletal injuries, 1.24 for overall injuries, and 1.45 for severe injuries. CONCLUSIONS: The overall prognostic accuracy of the FMS offered a slightly better than 50/50 chance of correctly classifying those most at risk for injury. As such, the FMS did not provide discriminatory prediction of musculoskeletal injury, overall injury, or severe injury in National Collegiate Athletic Association Division II athletes. Using the identified optimal cut score produced inadequate validity, regardless of the injury definition. We recommend using the FMS to assess movement quality rather than as a standalone injury-prediction tool until additional research suggests otherwise. Clinicians screening for injury risk should consider multiple risk factors identified in the literature. PMID- 29251534 TI - The Organizational Climate in Collegiate Athletics: An Athletic Trainer's Perspective. AB - CONTEXT: An organizational climate is largely based on an employee's perceptions of the working conditions in which he or she engages regularly. A multifaceted concept, the organizational climate is often formed by perceptions of employee welfare, rewards, and support. Achieving work-life balance is also a part of the climate. OBJECTIVE: To learn collegiate athletic trainers' perceptions of organizational climate and specifically how it may pertain to their work-life balance. DESIGN: Phenomenologic study. SETTING: Collegiate practice setting. PATIENTS OR OTHER PARTICIPANTS: Thirty athletic trainers working in the collegiate athletics setting took part in 1-on-1 phone interviews. The participants were 30.5 (interquartile range [IQR] = 7.75) years old and had been certified for 7 (IQR = 5) years and at their current position for 4 (IQR = 3) years. DATA COLLECTION AND ANALYSIS: Participants completed a phone interview that followed a semistructured framework. All transcribed interviews were analyzed using a phenomenologic approach. Researcher triangulation, expert review, and data saturation were used to establish credibility. RESULTS: Athletic trainers working in the collegiate athletics setting who had positive perceptions of their work-life balance described their organizational climate as family friendly. Our participants' supervisors allowed for autonomy related to work scheduling, which provided opportunities for work-life balance. These athletic trainers believed that they worked in a climate that was collegial, which was helpful for work-life balance. In addition, the importance of placing family first was part of the climate. CONCLUSIONS: The perceptions of our participants revealed a climate of family friendliness, supervisor support, and collegiality among staff members, which facilitated the positive climate for work life balance. The mindset embraced the importance of family and recognized that work did not always have to supersede personal priorities. PMID- 29251535 TI - Validation of the Professional Identity and Values Scale Among an Athletic Trainer Population. AB - CONTEXT: Forming a professional identity is a process by which an individual achieves an awareness of his or her own self-concept in the context of the profession. Identity in relation to an individual's profession includes the ability to articulate one's role as a professional and professional philosophy. Professional identity has been studied extensively in other fields, but currently no professional identity scales have been validated within the athletic training profession. OBJECTIVE: To validate the Professional Identity and Values Scale (PIVS) among an athletic trainer population. DESIGN: Cross-sectional study. SETTING: Web-based questionnaire. PATIENTS OR OTHER PARTICIPANTS: Athletic trainers employed in National Collegiate Athletic Association Division I, II, III, or National Association of Intercollegiate Athletics colleges or universities (n = 299, 56.5% female, 43.5% male). The average age of the participants was 33.6 +/- 8.3 years, and they had 10.3 +/- 7.6 years of experience. MAIN OUTCOME MEASURE(S): Participants were asked to complete a demographic questionnaire and the 32-item PIVS. The variables included demographics and the PIVS (Professional Orientation and Values subscale [18 items] and the Professional Development subscale [14 items]). RESULTS: Exploratory factor analysis reduced the survey from 32 to 20 items and revealed 6 factors. Three factors emerged from the Professional Development subscale and emphasized professional insecurities during the early career stages, the importance of mentors during the intermediate stages, and self-confidence and awareness during the later stages of professional development. An additional 3 factors emerged from the Professional Orientation and Values subscale: (1) patient care and advocacy, (2) professional engagement and collaboration, and (3) personal wellness and values. A Cronbach alpha of 0.80 indicated good internal consistency. CONCLUSIONS: A modified PIVS is a valid and reliable measure of professional identity among athletic trainers employed in the collegiate setting. PMID- 29251537 TI - Public Health and Law Enforcement Joint Investigation of Unknown Suspicious Substances and Potential Threat Evaluations, Minnesota, 2007-2016. AB - From the Field is a semi-regular column that explores what it means to be a local health professional on the front lines of an emergency. Typically, National Association of County and City Health Officials (NACCHO) members share their stories of preparing for and responding to disasters, epidemics, and other major health issues. This month's column features a submission from a state health department that describes their experience in investigating white powder incidents. Through exploring the analysis of the challenges faced and the solutions developed, readers can learn how these public health champions keep their communities safe even in extreme situations. Readers may submit topics of interest to the column's editor, Meghan McGinty, PhD, MPH, MBA, at mmcginty@naccho.org. PMID- 29251536 TI - Collegiate Athletic Trainers' Knowledge of the Female Athlete Triad and Relative Energy Deficiency in Sport. AB - CONTEXT: The female athlete triad (Triad) and relative energy deficiency in sport (RED-S) specify the consequences of energy imbalance. Athletic trainers (ATs) are positioned to identify athletes who are fueling themselves inadequately and experiencing related health and performance consequences. OBJECTIVE: To assess the knowledge of collegiate ATs about the Triad and RED-S and to examine variability in related screening and referral behaviors among National Collegiate Athletic Association divisions. DESIGN: Cross-sectional study. SETTING: Collegiate athletic training departments. PATIENTS OR OTHER PARTICIPANTS: Head ATs at National Collegiate Athletic Association member institutions (n = 285, response rate = 33%). MAIN OUTCOME MEASURE(S): An electronic survey was administered. The number of Triad components that were correctly identified and screening and referral behaviors related to Triad components were measured. RESULTS: Nearly all respondents (98.61% [n = 281]) had heard of the Triad; a smaller proportion (32.98% [n = 94]) had heard of RED-S. On average, respondents correctly identified 2 components of the Triad. We observed differences by sex, with women correctly identifying more components than men ( U = 12.426, P = .003). More than half (59.93% [n = 163]) indicated that athletes at their institutions were screened for eating disorders. Nearly three-quarters (70.55% [n = 115]) of respondents indicated that all female athletes at their institutions were screened annually for menstrual dysfunction. More comprehensive referral behaviors for athletes identified as experiencing menstrual dysfunction or a bone injury (eg, athlete referred to a nutritionist, dietitian, or counselor) occurred at Division I institutions than at Division II and III institutions. CONCLUSIONS: Continuing education for ATs about the Triad and RED-S may encourage a more comprehensive approach to referral and screening after a diagnosis of menstrual dysfunction or bone-stress injury. Using institutional opportunities, such as preparticipation screening, for identifying components of the Triad or RED-S and specifying protocols for referring athletes who screen positive for 1 of these components should also be explored. PMID- 29251539 TI - Keystone-Designed Perforator Island Flaps for the Coverage of Traumatic Pretibial Defects in Patients With Comorbidities. AB - Reconstruction of pretibial skin and soft-tissue defects remains a challenge because this area has less underlying tissues and limited tissue mobility. Here, we present a retrospective review of our experience with pretibial reconstruction using the keystone-designed perforator island flap (KDPIF) in patients with comorbidities. All defects resulted from nononcological causes. We describe the expanding versatility of KDPIF reconstruction for pretibial defects and suggest a simple algorithmic approach. The medical records of 9 patients who underwent reconstruction with a KDPIF to cover a pretibial defect between May 2016 and June 2017 were reviewed. Clinical and operative data were collected. All 9 KDPIFs fully survived. The defect size varied from 3 * 2 cm2 to 8 * 6 cm2. The flap size varied from 5 * 3 to 20 * 10 cm2. The mean operative time was 90.4 minutes (range = 37-127 minutes). No postoperative complications occurred. The cosmetic results were favorable, and all patients were satisfied with the final outcomes. Thus, the KDPIF is a good reconstruction modality with few complications and provides an alternative to free flaps for pretibial defect reconstruction in patients with comorbidities. PMID- 29251540 TI - Any Advances in Nutritional Supplementation for Lower Extremity Wounds? PMID- 29251541 TI - ImageJ: A Free, Easy, and Reliable Method to Measure Leg Ulcers Using Digital Pictures. AB - Wound measurement to document the healing course of chronic leg ulcers has an important role in the management of these patients. Digital cameras in smartphones are readily available and easy to use, and taking pictures of wounds is becoming a routine in specialized departments. Analyzing digital pictures with appropriate software provides clinicians a quick, clean, and easy-to-use tool for measuring wound area. A set of 25 digital pictures of plain foot and leg ulcers was the basis of this study. Photographs were taken placing a ruler next to the wound in parallel with the healthy skin with the iPhone 6S (Apple Inc, Cupertino, CA), which has a camera of 12 megapixels using the flash. The digital photographs were visualized with ImageJ 1.45s freeware (National Institutes of Health, Rockville, MD; http://imagej.net/ImageJ ). Wound area measurement was carried out by 4 raters: head of the department, wound care nurse, physician, and medical student. We assessed intra- and interrater reliability using the interclass correlation coefficient. To determine intraobserver reliability, 2 of the raters repeated the measurement of the set 1 week after the first reading. The interrater model displayed an interclass correlation coefficient of 0.99 with 95% confidence interval of 0.999 to 1.000, showing excellent reliability. The intrarater model of both examiners showed excellent reliability. In conclusion, analyzing digital images of leg ulcers with ImageJ estimates wound area with excellent reliability. This method provides a free, rapid, and accurate way to measure wounds and could routinely be used to document wound healing in daily clinical practice. PMID- 29251542 TI - Nutritional Supplementation for Diabetic Foot Ulcers: The Big Challenge. AB - Diabetic foot ulcers remain difficult to heal and nutritional supplementation may be an important complementary therapeutic measure. However, we need to clarify many issues before such supplementation is more widely used. Indeed, improvements are needed in the following areas: evaluation of nutritional inadequacy, completion of randomized controlled trials, understanding of patient and ulcer characteristics that favor response to nutritional supplementation, optimal duration of supplementation therapy, and evaluation of patient adherence. The challenge is now to acquire more knowledge in the aforementioned areas. PMID- 29251543 TI - The transpulmonary ratio of endothelin 1 is elevated in patients with preserved left ventricular ejection fraction and combined pre- and post-capillary pulmonary hypertension. AB - Pulmonary hypertension complicating left heart disease (PH-LHD) is associated with increased morbidity and mortality, especially in patients who develop combined pre- and post-capillary PH (Cpc-PH). Mechanisms underlying PH-LHD are incompletely understood, particularly for individuals with preserved left ventricular ejection fraction (LVEF). We hypothesized that transpulmonary concentrations of biomarkers representing signaling pathways with known effects on the pulmonary circulation could provide insight into the molecular etiology of PH-LHD in patients with preserved LVEF. Blood samples were collected from the pulmonary artery (PA) and wedge positions of outpatients with normal LVEF referred for right heart catheterization. Hemodynamic tracings were reviewed to classify patients as "no PH" (n = 23) or "PH-LHD" (n = 22). A biomarker's transpulmonary ratio (TPR) was calculated as the quotient of wedge and PA concentrations. The TPR of endothelin 1 (ET-1) was elevated in Cpc-PH (n = 10) compared to no PH or isolated post-capillary PH (Ipc-PH, n = 12); cAMP and cGMP TPRs were not different among groups. Higher ET-1 TPR in Cpc-PH was due to increased wedge ET-1 concentration. Pulmonary vascular resistance (PVR) strongly correlated with wedge ET-1 exclusively in Cpc-PH patients. In patients with normal LVEF and Cpc-PH, ET-1 TPR is higher, due to elevated wedge ET-1, compared to those without PH or with Ipc-PH. Strong correlation between PVR and wedge ET 1, observed only in the Cpc-PH group, may suggest increased pulmonary vascular responsiveness to ET-1 in these patients. These findings implicate elevated pulmonary ET-1 as a marker of, and a potential contributor to, development of Cpc PH in this population. PMID- 29251544 TI - Consensus recommendations for managing osteoarthritic pain with topical NSAIDs in Asia-Pacific. AB - Osteoarthritis prevalence is expected to increase markedly in the Asia-Pacific region due to rapid population aging. Identifying effective and safe therapeutic options to manage osteoarthritic pain is viewed as a priority. The Asia-Pacific Experts on Topical Analgesics Advisory Board developed consensus statements for use of topical NSAIDs in musculoskeletal pain. Evidence supporting these statements in osteoarthritic pain was reviewed. Best available evidence indicates that topical NSAIDs have a moderate effect on relief of osteoarthritic pain, comparable to that of oral NSAIDs but with a better risk-to-benefit ratio. International clinical practice guidelines recommend topical NSAIDs on par with or ahead of oral NSAIDs for pain management in patients with knee and hand osteoarthritis, and as the first-line choice in persons aged >=75 years. PMID- 29251545 TI - Multicenter mortality and morbidity associated with pulmonary hypertension in the pediatric intensive care unit. AB - Despite advances in the diagnosis and management of pediatric pulmonary hypertension (PH), children with PH represent a growing inpatient population with significant morbidity and mortality. To date, no studies have described the clinical characteristics of children with PH in the pediatric intensive care unit (PICU). A retrospective multicenter cohort study of 153 centers in the Virtual PICU Systems database who submitted data between 1 January 2009 and 31 December 2015 was performed. A total of 14,880/670,098 admissions (2.2%) with a diagnosis of PH were identified. Of these, 2190 (14.7%) had primary PH and 12,690 (85.3%) had secondary PH. Mortality for PH admissions was 6.8% compared to 2.3% in those admitted without PH (odds ratio = 3.1; 95% confidence interval = 2.9-3.4). Compared to patients admitted to the PICU without PH, those with PH were younger, had longer length of stay, higher illness severity scores, were more likely to receive invasive mechanical ventilation, cardiopulmonary resuscitation, extracorporeal membrane oxygenation, and more likely to have co-diagnoses of sepsis, heart failure, and respiratory failure. In a multivariate model, factors significantly associated with mortality for children with PH included age < 6 months or > 16 years, invasive mechanical ventilation, and co-diagnoses of heart failure, sepsis, hemoptysis, disseminated intravascular coagulation, stroke, and multi-organ dysfunction syndrome. Despite therapeutic advances, the disease burden and mortality of children with PH remains significant. Further investigation of the risk factors associated with clinical deterioration and mortality in this population could improve the ability to prognosticate and inform clinical decision-making. PMID- 29251546 TI - Examining Anosognosia of Neglect. AB - Unilateral neglect (neglect) and anosognosia often co-occur post stroke. It is unknown whether anosognosia of neglect varies for different types of daily activities. The objective is to examine the frequency of anosognosia of neglect for items on the Catherine Bergego Scale (CBS) and to determine the level of agreement between participant/assessor item ratings and total scores. Secondary analysis of data was carried out. We conducted descriptive analyses and interrater reliability analyses (Cohen's kappa) to determine the level of agreement between assessor and participant item ratings. A paired t test was conducted to compare assessor and participant total scores. The frequency of anosognosia among items varied (29.2%-83.3%) and Kappa statistics ranged from 0.07 (no agreement) to 0.23 (fair agreement) for item ratings. There was a significant difference- t(36) = 3.02, p <= .01)-between assessor ( M = 8.0, SD = 5.2) and participant-rated ( M = 5.3, SD = 4.5) total CBS scores. Anosognosia is prevalent among those with neglect. Findings highlight the importance of assessing for anosognosia. PMID- 29251547 TI - Riociguat, a soluble guanylate cyclase stimulator, ameliorates right ventricular contraction in pulmonary arterial hypertension. AB - Riociguat is a soluble guanylate cyclase stimulator used for pulmonary hypertension (PH) treatment. We evaluated right ventricular (RV) contractile function in 27 PH patients receiving riociguat. A comparison of pre- and post administration echocardiographic studies demonstrated significantly improved RV strain after riociguat treatment, even after adjusting for RV afterload. PMID- 29251548 TI - Rural Aging in America: Proceedings of the 2017 Connectivity Summit. AB - Rural Aging in America: Proceedings of the 2017 Connectivity Summit Alexis Skoufalos, EdD, Janice L. Clarke, RN, BBA, Dana Rose Ellis, BA, Vicki L. Shepard, MSW, MPA, and Elizabeth Y. Rula, PhD Editorial: Creating a Movement to Transform Rural Aging David B. Nash, MD, MBA, with Donato J. Tramuto, and Joseph F. Coughlin, PhD S-3 Introduction S-4 Summit Proceedings S-5 Roundtable 1: The Power of Community - Enabling Social Connections and Access to Health Resources Through Community-Based Programs S-5 Roundtable 2: Technology and Rural Health: Innovative Solutions to Bridge the Distance, Improve Care, and Deliver Programs S-7 Roundtable 3: An Integrated Experience: The Exponential Potential of a Collaborative Approach to Rural Aging S-8 General Discussion and Recommendations S-8 Post-Summit Debriefing S-9 Strategy and objectives S-9 6-12 month action plan S-9 Conclusion S-9. PMID- 29251549 TI - Acute and chronic dissection of pulmonary artery: new challenges in pulmonary arterial hypertension? AB - Right ventricular failure is a leading cause of mortality in patients with pulmonary arterial hypertension (PAH). However, up to 25% of such patients die unexpectedly, without warning signs of hemodynamical decompensation. We previously documented that pulmonary artery (PA) dilatation significantly increases the risk of those deaths. Some of them may be due to dissection of PA resulting in cardiac tamponade. However, direct confirmation of this mechanism is difficult as most of such deaths occur outside hospitals. We present 4 patients with severe PAH and PA dilatation in whom PA dissection has been confirmed. Three patients had IPAH, one had PAH associated with congenital heart disease. All patients had mean pulmonary artery pressure (PAP) > 50 mmHg at diagnosis and dissection occurred late in the course of apparently well controlled disease (6 to 14 years). Several clinical elements were common to our patients - high systolic PAP, long lasting PH, progressive dilatation of PA to more than 50 mm with chest pain prior to dissection. However, clinical course followed three different patterns: sudden death due to cardiac tamponade, hemopericarditis caused by blood leaking from dissected aneurysm with imminent but not immediate cardiac tamponade, or chronic asymptomatic PA dissection. Indeed, two of our patients are alive and on lung transplantation waiting list for more than 2 years now. Further research is needed to suggest optimal management strategies for patients with stable PAH but significantly dilated proximal pulmonary arteries or confirmed PA dissection depending on the clinical presentation and expected outcome. PMID- 29251550 TI - MRI Study on the Changes of Bone Marrow Microvascular Permeability and Fat Content after Total-Body X-Ray Irradiation. AB - In this study, we investigated microvascular perfusion status, changes to fat content and fatty acid composition in the bone marrow of rat femurs after total body irradiation by quantitative permeability parameters of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and ex vivo high-resolution magic angle spinning (HRMAS) 1H nuclear magnetic resonance spectroscopy (NMRS). Thirty six Sprague-Dawley rats were randomly assigned to either an irradiated or nonirradiated control group. Permeability imaging using DCE-MRI and HRMAS 1H NMRS was performed before irradiation, as well as at days 4 and 7 postirradiation. The volume transfer constant (Ktrans) values increased to 2.219 +/- 0.418/min ( P < 0.01) at day 4 and to 2.760 +/- 0.217/min at day 7 ( P < 0.01) postirradiation. The plasma fraction (vp) values gradually decreased. The proportion of (n-6) polyunsaturated fatty acids (PUFA) gradually reached a peak at day 7, the proportion of (n-3) PUFA gradually decreased and the proportion of saturated fatty acids gradually increased. After irradiation, Ktrans at different times showed significant negative correlation with (n-3) PUFA ( r = -0.6393, P < 0.01) and significant positive correlation with (n-6) PUFA ( r = 0.6841, P < 0.05). These findings indicate that bone marrow microcirculation perfusion and vascular permeability correlated with fat content at an early time point after irradiation. A pathophysiological mechanism may exist based on fat-vascular permeability in the case of injury to bone marrow microcirculation. PMID- 29251551 TI - Cherenkov-excited Multi-Fluorophore Sensing in Tissue-Simulating Phantoms and In Vivo from External Beam Radiotherapy. AB - In this work, Cherenkov-excited molecular sensing was used to assess the potential for simultaneous quantitative sensing of two NIR fluorophores within tissue-simulating phantoms through spectral separation of signals. Cherenkov emissions induced by external beam gamma photon radiation treatment to tissues/tissue-simulating phantoms were detectable over the 500-900-nm wavelength range. The presence of blood was demonstrated to reduce the integrated intensity of detected Cherenkov emissions by nearly 50%, predominantly at wavelengths below 620 nm. The molecular dyes, IRDye 680RD and IRDye 800CW, have excitation and emission spectra at longer wavelengths than the strongest blood absorption peaks, and also where the intensity of Cherenkov light is at its lowest, so that the emission signal relative to background signal is maximized. Tissue phantoms composed of 1% intralipid and 1% blood were used to simulate human breast tissue, and vials containing fluorophore were embedded in the media, and irradiated with gamma photons for Cherenkov excitation. We observed that fluorescence emissions excited by the Cherenkov signal produced within the phantom could be detected at 5-mm depth into the media within a 0.1-25 MU M fluorophore concentration range. The detected fluorescence signals from these dyes showed linear relationships with radiation doses down to the cGy level. In vivo tests were successful only within the range near a MU M, suggesting that these could be used for metabolic probes in vivo where the local concentrations are near this range. PMID- 29251552 TI - Unraveling the Mobilization of Memory in Research With Refugees. AB - In this article, we explore how narrative accounts of trauma are co-constructed through the interaction between researcher and participant. Using a narrative multiple-case study with Kurdish refugee families, we address how this process takes place, investigating how researcher and participants were engaged in relational, moral, collective, and sociopolitical dimensions of remembering, and how this led to the emergence of particular ethical questions. Case examples indicate that acknowledging the multilayered co-construction of remembering in the research relationship profoundly complicates existing deontological guidelines that predominantly emphasize the researcher's responsibility in sensitively dealing with participants' alleged autobiographical trauma narratives. Instead, our analysis invites qualitative researchers to engage in a continued, context-specific ethical reflection on the potential risks and benefits that are invoked in studies with survivors of collective violence. PMID- 29251553 TI - Genetic characterization of bovine respiratory syncytial virus strains isolated in Italy: evidence for the circulation of new divergent clades. AB - Bovine respiratory syncytial virus (BRSV) is circulating in cattle in Europe. Although vaccination helps control the disease, its prevalence within and among herds remains high. Previous genetic characterization studies revealed a strict geographic correlation between viral variants; on the other hand, they showed the emergence of new variants in northern Europe. Few studies have described BRSV distribution, and little is known about the genetic features of BRSV strains circulating in Italy. We studied sample-positive tests for BRSV, and sequenced the coding regions of the G and N proteins to determine the presence of divergent variants. Two different sets of sequences were found, including in samples from animals from vaccinated herds. The 2 groups of sequences correspond to 2 time periods and suggest an active role of herd immunity in preventing the spread of infection. Our findings that different strains of BRSV are circulating in Italy and that the virus is evolving rapidly highlight the importance of updating vaccination strategies. PMID- 29251554 TI - Alkali pretreatment of wheat straw followed by microbial hydrolysis for bioethanol production. AB - The combination of NaOH pretreatment and microorganisms isolated from termite was used for releasing wrapped polysaccharides from wheat straw biomass matrix. Different concentrations of NaOH (1%, 3%, 5%, 7% and 10%) were considered to remove lignin and to release polysaccharides as a pretreatment method at 80 degrees C for 4 h before subjecting it to microbial hydrolysis. Data obtained from compositional analysis of pretreated wheat straws show that a significant amount of cellulose and lignin were released after NaOH pretreatments. The amount of cellulose and lignin released was increased with increasing concentration of NaOH in the pretreatment solution. Further analysis of X-Ray diffraction, field emission scanning electron microscope and Fourier transform infrared spectroscopy confirms the removal of lignin and release of cellulose. About 69.5% of lignin was solubilized and 72.67% of cellulose was released after 10% NaOH pretreatment which was the maximum. Data from spectrophotometric analysis of reducing sugar by the 3,5-dinitrosalycilic acid method show that 83.68% (0.706 g/100 ml) of polysaccharides were converted to glucose and xylose by isolated bacteria after the 15th day of hydrolysis. PMID- 29251555 TI - Reconstruction of the Thoracic Wall With Biologic Mesh After Resection for Chest Wall Tumors: A Presentation of a Case Series and Original Technique. AB - INTRODUCTION: Synthetic materials have traditionally been used for tissue reconstruction in thoracic surgery. New biomaterials have been tested in other areas of surgery with good results. Non-cross-linked swine dermal collagen prosthesis has been used to reconstruct musculofascial defects in the trunk with low infection and herniation rate. MATERIAL AND METHODS: Retrospectively, we analyze our initial experience of chest wall reconstruction on large defects using a non-cross-linked swine dermal collagen matrix mesh with a thickness of 1.4 mm. A total of 11 consecutive patients were included. Preoperative, intraoperative, and postoperative data were taken into consideration. RESULTS: Eleven sarcoma patients with a mean age of 58.25 +/- 12.9 years underwent chest wall resections. Complete thoracic wall defects ranged from 6 . 9 to 16 . 25 cm in size. In all cases, we used a porcine collagen matrix mesh, and in all patients, it was covered by transposition of myocutaneous flap. The complications occurred in 5 (45%) patients, 1 (9%) pneumonia, 1 atrial fibrillation (9%), and 3 (27%) wound healing difficulty because of hematoma or infection. There was no respiratory impairment, and the pulmonary function (total lung capacity, vital capacity, and forced expiratory volume in 1 second) was not statistically different before and after surgery. The 30-day mortality was 0%, 1-year mortality and 2-year mortality was 27.2%. The collagen material resulted in a durable and good to excellent chest wall stability in clinical follow-ups, and on computer tomography scans spanning over 2 years. CONCLUSION: Non-cross-linked acellular porcine dermal collagen matrix is a feasible and reliable biological patch material for reconstruction of the thoracic wall. Excellent wound healing, long term stability, low complication, and good pulmonary function are achieved even in large defects. PMID- 29251556 TI - The impact of ambrisentan and tadalafil upfront combination therapy on cardiac function in scleroderma associated pulmonary arterial hypertension patients: cardiac magnetic resonance feature tracking study. AB - The aim of this study was to evaluate the effect of upfront combination therapy with ambrisentan and tadalafil on left ventricular (LV) and right ventricular (RV) function in patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). LV and RV peak longitudinal and circumferential strain and strain rate (SR), which consisted of peak systolic SR (SRs), peak early diastolic SR (SRe), and peak atrial-diastolic SR (SRa) were analyzed using cardiac magnetic resonance imaging (CMRI) data from the recently published ATPAHSS-O trial (ambrisentan and tadalafil upfront combination therapy in SSc PAH). Twenty-one patients completed the study protocol. Measures of RV systolic function (RV free wall [RVFW] peak longitudinal strain [pLS], RVFW peak longitudinal SRs [pLSRs]) and RV diastolic function (RVFW peak longitudinal SRa [pLSRa], RVFW peak circumferential SRe) were improved after treatment. LV systolic function (LV peak global longitudinal strain [pGLS]) and diastolic function (LV peak global longitudinal SRe [pGLSRe]) were also significantly improved at follow-up. Increased 6-min walk distance was significantly correlated with RVFW pLS and pLSRs, while the decrease in N-terminal pro-brain natriuretic peptide was correlated with LV pGLS. Increased cardiac index was associated with improved LV pGLSRe, and reduction in mean right atrial pressure was correlated with improved RVFW pLS and pLSRa. Combination therapy was associated with a significant improvement in both RV and LV function as assessed by CMR-derived strain and SR. Importantly, the improvement in RV and LV strain and SR correlated with improvements in known prognostic markers of PAH. (Approved by clinicaltrials.gov [NCT01042158] before patient recruitment.). PMID- 29251557 TI - Systemic delivery of MicroRNA mimics with polyethylenimine elevates pulmonary microRNA levels, but lacks pulmonary selectivity. AB - Reversing pathologic alterations in vascular microRNA (miRNA) expression represents a potential therapeutic strategy for pulmonary hypertension. While polyethylenimine (PEI) has previously been shown to be an effective vehicle for vascular lung-directed delivery of plasmid DNA, it remains unclear whether this utility is generalizable to miRNAs. Here we show that despite elevated lung levels, the intravenous infusion of PEI-miRNA mimic complexes fails to provide lung-selective delivery in rats. PMID- 29251558 TI - Validity of the Turkish Occupational Self Assessment for Elderly Individuals. AB - Occupational therapy practices in Turkey are increasing each year, but rehabilitation practitioners working in the occupational therapy field have limited instruments. The aim of this study was to analyze the validity of the Turkish version of the Occupational Self Assessment (OSA), which is based on the Model of Human Occupation. The data were analyzed using exploratory and confirmatory factor analyses to determine construct validity. The Turkish OSA was administered with the World Health Organization Quality of Life-Old (WHOQOL-OLD) and the Functional Autonomy Measurement System (SMAF) to 117 elderly individuals to determine convergent validity. The Turkish OSA has acceptable construct validity scores (exploratory and confirmatory factor analyses). SMAF and WHOQOL OLD Scales showed a moderately significant relationship with OSA competence total scores ( p < .01). The results indicate that the OSA is a valid instrument for determining occupational competence and values in elderly Turkish individuals. PMID- 29251559 TI - Structural refinement and prediction of potential CCR2 antagonists through validated multi-QSAR modeling studies. AB - Chemokines trigger numerous inflammatory responses and modulate the immune system. The interaction between monocyte chemoattractant protein-1 and chemokine receptor 2 (CCR2) may be the cause of atherosclerosis, obesity, and insulin resistance. However, CCR2 is also implicated in other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, asthma, and neuropathic pain. Therefore, there is a paramount importance of designing potent and selective CCR2 antagonists despite a number of drug candidates failed in clinical trials. In this article, 83 CCR2 antagonists by Jhonson and Jhonson Pharmaceuticals have been considered for robust validated multi-QSAR modeling studies to get an idea about the structural and pharmacophoric requirements for designing more potent CCR2 antagonists. All these QSAR models were validated and statistically reliable. Observations resulted from different modeling studies correlated and validated results of other ones. Finally, depending on these QSAR observations, some new molecules were proposed that may exhibit higher activity against CCR2. PMID- 29251560 TI - Rational antibiotic design: in silico structural comparison of the functional cavities of penicillin-binding proteins and beta-lactamases. AB - The class of beta-lactam antibiotics has proven highly efficient in targeting bacterial penicillin-binding proteins (PBP) leading to the blocking of the bacterial cell wall synthesis. However, the benefit of these drugs is limited because of bacterial resistance mechanisms; the most widespread resistance involves beta-lactamase enzymes (betaLACT) that inactivate beta-lactam-based molecules. We focused on PBPs and betaLACTs from enterobacteria, and performed a detailed in silico study of PBPs whose inactivation is lethal for the bacteria and of betaLACTs that have a PBP-type catalytic mechanism. The comparison of the sequences and structures of PBPs and betaLACTs shows an almost perfect conservation of the catalytic site, and a high spatial resemblance of the whole functional cavity despite a very low overall sequence identity. Some notable differences in the functional cavity were observed in the vicinity of the catalytic site: four tyrosines are well conserved in the PBPs, whereas the residues occurring at equivalent positions in the betaLACT families present other physicochemical properties. These tyrosines are thus good candidates to be targeted in designing new antibiotic molecules with increased affinity and specificity for PBPs, with the goal of overcoming drug resistance. Our analysis also identified residues that have similar characteristics in most betaLACT families and different properties in PBPs; these are interesting targets for new ligands that specifically inhibit betaLACT proteins. The in silico approach presented here can be extended to other protein systems in view of guiding and improving rational drug design. PMID- 29251561 TI - Lipopolysaccharide acutely suppresses right-ventricular strain in rats with pulmonary artery hypertension. AB - Worsening right ventricular (RV) dysfunction in the presence of pulmonary artery hypertension (PAH) increases morbidity and mortality in this patient population. Transthoracic echocardiography (TTE) is a non-invasive modality to evaluate RV function over time. Using a monocrotaline-induced PAH rat model, we evaluated the effect of acute inflammation on RV function. In this study, both PAH and control rats were injected with Escherichia coli lipopolysaccharide (LPS) to induce an acute inflammatory state. We evaluated survival curves, TTE parameters, and inflammatory markers to better understand the mechanism and impact of acute inflammation on RV function in the presence of PAH. The survival curve of the PAH rats dropped sharply within 9 h after LPS treatment. Several echocardiographic parameters including left ventricular (LV) stroke volume, RV tricuspid annular plane systolic excursion, RV longitudinal peak systolic strain, and strain rate decreased significantly in PAH rats before LPS injection and 2 h after LPS injection. The expression of phospholamban (PLB) and tumor necrosis factor-alpha (TNF-alpha) significantly increased and the expression of SERCA2a significantly decreased in PAH rats after LPS administration. LPS suppressed the RV longitudinal peak systolic strain and strain rate and cardiac function deteriorated in PAH rats. These effects may be associated with the signal pathway activity of SERCA2a/PLB. PMID- 29251562 TI - Pneumatically Actuated Soft Micromold Device for Fabricating Collagen and Matrigel Microparticles. AB - Collagen microparticles have recently gained more attention as viable cell confinement blocks in many biomedical research fields. Small volume and high surface area of collagen structure improve cell confinement, viability, and proliferation. Moreover, dense collagen fiber structure can protect cells from immune destruction. The ability to produce collagen microparticles in an accurate and reliable way is of upmost importance to the advancement of many biomedical researches, especially cancer research and tissue engineering. Currently, no such fabrication technique exists due to inherent fragility of collagen. Herein, we report the very first platform, pneumatically actuated soft micromold (PASMO) device, which addresses challenges in collagen microparticle production. Our new platform uses a soft micromold with a pneumatic actuator that can produce arbitrary shapes of collagen microstructures precisely from 100 MUm to over 2 mm in range and can encapsulate cells inside without damaging the shape. The duplication accuracy of more than 96% in dimensions and 90% in depth has been demonstrated. The density of collagen fiber distribution is determined to be 86.57%, which is higher than that of collagen microparticles produced by other methods. We have confirmed cell viability in collagen microparticles. We also produce MatrigelTM particles as tool to develop a xenograft cancer model. The results demonstrate that Matrigel particles created by the PASMO device can reduce cell scattering for the xenograft model and the uniformity of tumors developed in mice is 12-fold improved, which can lead to an increased accuracy of cancer metastasis studies and drug screening research. These breakthroughs in the production of modular microparticles will push the boundaries of cancer research in the near future. PMID- 29251563 TI - A Biologically Inspired, Functionally Graded End Effector for Soft Robotics Applications. AB - Soft robotic actuators offer many advantages over their rigid counterparts, but they often are unable to apply highly localized point loads. In contrast, many invertebrates have not only evolved extremely strong "hybrid appendages" that are composed of rigid ends that can grasp, puncture, and anchor into solid substrates, but they also are compliant and resilient, owing to the functionally graded architecture that integrates rigid termini with their flexible and highly extensible soft musculatures. Inspired by the design principles of these natural hybrid appendages, we demonstrate a synthetic hybrid end effector for soft-bodied robots that exhibits excellent piercing abilities. Through the incorporation of functionally graded interfaces, this design strategy minimizes stress concentrations at the junctions adjoining the fully rigid and soft components and optimizes the bending stiffness to effectively penetrate objects without interfacial failure under shear and compressive loading regimes. In this composite architecture, the radially aligned tooth-like elements apply balanced loads to maximize puncturing ability, resulting in the coordinated fracture of an object of interest. PMID- 29251564 TI - Novel Variable-Stiffness Robotic Fingers with Built-In Position Feedback. AB - Despite the increasing popularity of soft robotic research, the application of soft robots is hindered by their limited ability to change compliance and acquire force and position feedback. In this article, both the controllability of compliance and the acquisition of position feedback are achieved in soft robotic fingers in the novel design of a three-dimensional (3D)-printed multismart material substrate. The substrate is composed of shape memory polymer (SMP) and conductive elastomer thermoplastic polyurethane (TPU). The SMP material is utilized to modulate the finger stiffness through its elastic modulus change around glass transition temperature (Tg). The conductive TPU has two functions: one is to tune SMP temperature by producing Joule heat when electrical power is supplied and the other is to provide position feedback of the finger by utilizing the piezoresistive effect of the conductive TPU. Theoretical modeling of finger position feedback and stiffness modulation are conducted. The theoretical analysis has been experimentally validated by a prototype robotic finger built from the proposed concept. PMID- 29251565 TI - On the Potential of Hydrogen-Powered Hydraulic Pumps for Soft Robotics. AB - To perform untethered operations, soft robots require mesoscale power units (10 1000 W) with high energy densities. In this perspective, air-breathing combustion offers an interesting alternative to battery-powered systems, provided sufficient overall energy conversion efficiency can be reached. Implementing efficient air breathing combustion in mesoscale soft robots is notoriously difficult, however, as it requires optimization of very small combustion actuators and simultaneous minimization of fluidic (e.g., hydraulic) losses, which are both inversely impacted by actuations speeds. To overcome such challenges, this article proposes and evaluates the potential of hydrogen-powered, hydraulic free-piston pump architecture. Experimental data, taken from two combustion-driven prototypes, reveal (1) the fundamental role of using hydrogen as the source of fuel to reduce heat losses, (2) the significant impact of compression ratio, equivalence ratio, and surface-to-volume ratio on energy conversion efficiency, and (3) the importance of load matching between combustion and fluidic transmission. In this work, a small-bore combustion actuator demonstrated a 20% efficiency and a net mean output power of 26 W, while a big-bore combustion actuator reached a substantially higher efficiency of 35% and a net mean output power of 197 W. Using the small-bore combustion actuator, the hydrogen-powered, hydraulic free piston pump provided a 4.6% overall efficiency for a 2.34 W net mean output power, thus underlying the potential of the approach for mesoscale soft robotic applications. PMID- 29251566 TI - Soft Dielectric Elastomer Oscillators Driving Bioinspired Robots. AB - Entirely soft robots with animal-like behavior and integrated artificial nervous systems will open up totally new perspectives and applications. To produce them, we must integrate control and actuation in the same soft structure. Soft actuators (e.g., pneumatic and hydraulic) exist but electronics are hard and stiff and remotely located. We present novel soft, electronics-free dielectric elastomer oscillators, which are able to drive bioinspired robots. As a demonstrator, we present a robot that mimics the crawling motion of the caterpillar, with an integrated artificial nervous system, soft actuators and without any conventional stiff electronic parts. Supplied with an external DC voltage, the robot autonomously generates all signals that are necessary to drive its dielectric elastomer actuators, and it translates an in-plane electromechanical oscillation into a crawling locomotion movement. Therefore, all functional and supporting parts are made of polymer materials and carbon. Besides the basic design of this first electronic-free, biomimetic robot, we present prospects to control the general behavior of such robots. The absence of conventional stiff electronics and the exclusive use of polymeric materials will provide a large step toward real animal-like robots, compliant human machine interfaces, and a new class of distributed, neuron-like internal control for robotic systems. PMID- 29251567 TI - Nonparametric Online Learning Control for Soft Continuum Robot: An Enabling Technique for Effective Endoscopic Navigation. AB - Bioinspired robotic structures comprising soft actuation units have attracted increasing research interest. Taking advantage of its inherent compliance, soft robots can assure safe interaction with external environments, provided that precise and effective manipulation could be achieved. Endoscopy is a typical application. However, previous model-based control approaches often require simplified geometric assumptions on the soft manipulator, but which could be very inaccurate in the presence of unmodeled external interaction forces. In this study, we propose a generic control framework based on nonparametric and online, as well as local, training to learn the inverse model directly, without prior knowledge of the robot's structural parameters. Detailed experimental evaluation was conducted on a soft robot prototype with control redundancy, performing trajectory tracking in dynamically constrained environments. Advanced element formulation of finite element analysis is employed to initialize the control policy, hence eliminating the need for random exploration in the robot's workspace. The proposed control framework enabled a soft fluid-driven continuum robot to follow a 3D trajectory precisely, even under dynamic external disturbance. Such enhanced control accuracy and adaptability would facilitate effective endoscopic navigation in complex and changing environments. PMID- 29251568 TI - Integrated Simultaneous Detection of Tactile and Bending Cues for Soft Robotics. AB - Soft robots should move in an unstructured environment and explore it and, to do so, they should be able to measure and distinguish proprioceptive and exteroceptive stimuli. This can be done by embedding mechanosensing systems in the body of the robot. Here, we present a polydimethylsiloxane block sensorized with an electro-optical system and a resistive strain gauge made with the supersonic cluster beam implantation (SCBI) technique. We show how to integrate these sensing elements during the whole fabrication process of the soft body and we demonstrate that their presence does not change the mechanical properties of the bulk material. Exploiting the position of both sensing systems and a proper combination of the output signals, we present a strategy to measure simultaneously external pressure and positive/negative bending of the body. In particular, the optical system can reveal any mechanical stimulation (external from the soft block or due to its own deformation), while the resistive strain gauge is insensitive to the external pressure, but sensitive to the bending of the body. This solution, here applied to a simple block of soft material, could be extended to the whole body of a soft robot. This approach provides detection and discrimination of the two stimuli (pressure and bending), with low computational effort and without significant mechanical constraint. PMID- 29251569 TI - Wet-Spun Biofiber for Torsional Artificial Muscles. AB - The demands for new types of artificial muscles continue to grow and novel approaches are being enabled by the advent of new materials and novel fabrication strategies. Self-powered actuators have attracted significant attention due to their ability to be driven by elements in the ambient environment such as moisture. In this study, we demonstrate the use of twisted and coiled wet-spun hygroscopic chitosan fibers to achieve a novel torsional artificial muscle. The coiled fibers exhibited significant torsional actuation where the free end of the coiled fiber rotated up to 1155 degrees per mm of coil length when hydrated. This value is 96%, 362%, and 2210% higher than twisted graphene fiber, carbon nanotube torsional actuators, and coiled nylon muscles, respectively. A model based on a single helix was used to evaluate the torsional actuation behavior of these coiled chitosan fibers. PMID- 29251570 TI - Stronger at Depth: Jamming Grippers as Deep Sea Sampling Tools. AB - In this work we experimentally demonstrate (a) that the holding strength of universal jamming grippers increases as a function of the jamming pressure to greater than three atmospheres, and (b) that jamming grippers can be operated in the deep sea in ambient pressures exceeding one hundred atmospheres, where such high jamming pressures can be readily achieved. Laboratory experiments in a pressurized, water-filled test cell are used to measure the holding force of a "universal" style jamming gripper as a function of the pressure difference between internal membrane pressure and ambient pressure. Experiments at sea are used to demonstrate that jamming grippers can be installed on, and operated from, remotely operated vehicles at depths in excess of 1200 m. In both experiments, the jamming gripper consists of a latex balloon filled with a mixture of fresh water and ~200 MUm glass beads, which are cheaply available in large quantities as sand blasting media. The use of a liquid, rather than a gas, as the fluid media allows operation of the gripper with a closed-loop fluid system; jamming pressure is controlled with an electrically driven water hydraulic cylinder in the laboratory and with an oil hydraulic-driven large-bore water hydraulic cylinder at sea. PMID- 29251571 TI - Shape Memory Alloy-Based Soft Gripper with Variable Stiffness for Compliant and Effective Grasping. AB - Soft pneumatic actuators and motor-based mechanisms being concomitant with the cumbersome appendages have many challenges to making the independent robotic system with compact and lightweight configuration. Meanwhile, shape memory actuators have shown a promising alternative solution in many engineering applications ranging from artificial muscle to aerospace industry. However, one of the main limitations of such systems is their inherent softness resulting in a small actuation force, which prevents them from more effective applications. This issue can be solved by combining shape memory actuators and the mechanism of stiffness modulation. As a first, this study describes a shape memory alloy-based soft gripper composed of three identical fingers with variable stiffness for adaptive grasping in low stiffness state and effective holding in high stiffness state. Each finger with two hinges is fabricated through integrating soft composite actuator with stiffness changeable material where each hinge can approximately achieve a 55-fold changeable stiffness independently. Besides, each finger with two hinges can actively achieve multiple postures by both selectively changing the stiffness of hinges and actuating the relevant SMA wire. Based on these principles, the gripper is applicable for grasping objects with deformable shapes and varying shapes with a large range of weight where its maximum grasping force is increased to ~10 times through integrating with the stiffness changeable mechanism. The final demonstration shows that the finger with desired shape retained configurations enables the gripper to successfully pick up a frustum shaped object. PMID- 29251572 TI - A Soft Gripper with Rigidity Tunable Elastomer Strips as Ligaments. AB - Like their natural counterparts, soft bioinspired robots capable of actively tuning their mechanical rigidity can rapidly transition between a broad range of motor tasks-from lifting heavy loads to dexterous manipulation of delicate objects. Reversible rigidity tuning also enables soft robot actuators to reroute their internal loading and alter their mode of deformation in response to intrinsic activation. In this study, we demonstrate this principle with a three fingered pneumatic gripper that contains "programmable" ligaments that change stiffness when activated with electrical current. The ligaments are composed of a conductive, thermoplastic elastomer composite that reversibly softens under resistive heating. Depending on which ligaments are activated, the gripper will bend inward to pick up an object, bend laterally to twist it, and bend outward to release it. All of the gripper motions are generated with a single pneumatic source of pressure. An activation-deactivation cycle can be completed within 15 s. The ability to incorporate electrically programmable ligaments in a pneumatic or hydraulic actuator has the potential to enhance versatility and reduce dependency on tubing and valves. PMID- 29251573 TI - Commentary on Some Recent Theses Relevant to Combating Aging: December 2017. PMID- 29251575 TI - Enhancing Hepatic Microcirculation in Postoperative Hepatic Failure With Intra arterial Recombinant Tissue Plasminogen Activator Treatment. AB - Postoperative hepatic failure is one of the most severe complications after liver resection. Treatment protocols have varied from medical support to liver transplant. Here, we describe the clinical course of an 18-year-old female patient with postoperative hepatic failure. The combined use of intra-arterial tissue plasminogen activator infusion and concurrent liver support facilities resulted in successful treatment of postoperative hepatic failure. The role of thrombolytic treatment for postoperative hepatic failure may include future placement in routine treatment protocols, as seen in liver transplant. PMID- 29251576 TI - Pretransplant HbA1c and Glucose Metabolism Parameters in Predicting Posttransplant Diabetes Mellitus and Their Course in the First 6 Months After Living-Donor Renal Transplant. AB - OBJECTIVES: Posttransplant diabetes mellitus is a common and serious metabolic complication after renal transplant. Patients with uremia are known to have abnormal glucose metabolism characterized by insulin resistance and defects in insulin secretion, which are ameliorated to some extent with renal replacement therapy and more so with renal transplant. However, the diabetogenicity of calcineurin inhibitors compounds this state of dysglycemia and promotes the development of diabetes in some patients. It is not clear whether pretransplant dysglycemia is a risk factor for posttransplant diabetes mellitus and, if so, which between insulin resistance and pancreatic beta-cell dysfunction is a major determinant in predicting posttransplant diabetes mellitus. Here, we examined the roles of the pretransplant oral glucose tolerance test, glycated hemoglobin (HbA1c) levels, and homeostatic model assessment-derived insulin resistance and beta-cell function in the prediction of posttransplant diabetes mellitus and the course of these indexes posttransplant. Our aim was to examine the correlations between these factors and their changes posttransplant with the development of posttransplant diabetes mellitus. MATERIALS AND METHODS: Pretransplant fasting blood was drawn from patients for plasma glucose, insulin, C-peptide, and HbA1c levels, which was followed by a 2-hour oral glucose tolerance test. After transplant, patients were followed for 6 months to detect posttransplant diabetes mellitus. Serum insulin, C-peptide, and glycated hemoglobin levels were reexamined in patients with posttransplant diabetes mellitus at 1 and 6 months. RESULTS: Twenty-one patients (29%) developed posttransplant diabetes mellitus. Pretransplant HbA1c was associated with development of posttransplant diabetes mellitus (odds ratio 27.04) on logistic regression. Homeostatic model assessment derived insulin resistance improved significantly at 6 months posttransplant, whereas beta-cell function remained lower than pretransplant levels in patients with posttransplant diabetes mellitus. CONCLUSIONS: Pretransplant HbA1c may be used as a predictive marker for posttransplant diabetes mellitus. Insulin resistance but not beta-cell function improves in patients with posttransplant diabetes mellitus at 6 months posttransplant. PMID- 29251577 TI - Serum and Urinary Levels of Tumor Necrosis Factor-Alpha in Renal Transplant Patients. AB - OBJECTIVES: Allograft rejection is an important cause of early and long-term graft loss in kidney transplant recipients. Tumor necrosis factor-alpha promotes T-cell activation, the key reaction leading to allograft rejection. Here, we investigated whether serum and urinary tumor necrosis factor-alpha levels can predict allograft rejection. MATERIALS AND METHODS: This study included 65 living related-donor renal transplant recipients with mean follow-up of 26 +/- 9 months. Serum and urinary tumor necrosis factor-alpha levels were measured at pretransplant and at posttransplant time points (days 1 and 7 and months 3 and 6); serum creatinine levels were also monitored during posttransplant follow-up. Standard enzyme-linked immunoabsorbent assay was used to detect tumor necrosis factor-alpha levels. Clinical variables were monitored. RESULTS: Nine of 65 patients (13.8%) had biopsy-proven rejection during follow-up. Preoperative serum and urinary tumor necrosis factor-alpha levels were not significantly different when we compared patients with and without rejection. Serum tumor necrosis factor alpha levels (in pg/mL) were significantly higher in the allograft rejection versus nonrejection group at day 7 (11.5 +/- 4.7 vs 15.4 +/- 5.8; P = .029) and month 1 (11.1 +/- 4.8 vs 17.8 +/- 10.9; P =.003). Urinary tumor necrosis factor alpha levels (in pg/mL) were also elevated in the allograft rejection versus the nonrejection group at days 1 (10.2 +/- 2.5 vs 14.1 +/- 6.8; P = .002) and 7 (9.8 +/- 2.2 vs 14.5 +/- 2.7; P < .001) and at months 1 (8.0 +/- 1.7 vs 11.8 +/- 2.4; P < .001), 3 (7.7 +/- 1.6 vs 9.6 +/- 1.7; P = .002), and 6 (7.4 +/- 1.6 vs 8.9 +/ 0.9; P = .005). CONCLUSIONS: Our preliminary findings suggest that tumor necrosis factor-alpha has a role in diagnosing renal transplant rejection. Serum and urinary tumor necrosis factor-alpha levels may be a possible predictor for allograft rejection. PMID- 29251578 TI - Risk Factors for Abnormal Cervical Cytology in Women Undergoing Kidney Transplant Evaluation. AB - OBJECTIVES: Cervical cytology screening has been successful in reducing deaths from cervical cancer. We sought to determine risk factors for abnormal Pap test results in women undergoing kidney transplant evaluation. MATERILAS AND METHODS: We retrospectively examined women undergoing kidney transplant evaluations from 2008 to 2011. Patients were stratified based on normal cytology and atypical/malignant cytology. RESULTS: Of 404 patients, 293 patients (72.5%) had normal cytologic findings, whereas 111 (27.5%) had abnormal findings. On univariate logistic regression analyses, patients who had chronic kidney disease with an autoimmune cause (odds ratio = 2.71 [95% confidence interval, 1.41-5.19]; P = .003), previous renal transplants (odds ratio = 2.64 [95% confidence interval, 1.20-5.82], P = .016), or age <= 50 years (odds ratio = 1.68 [95% confidence interval, 1.08-2.61], P = .022) were more likely to have abnormal findings. Patients with normal and abnormal findings had similar rates of dialysis use. On multivariate logistic regression, patients who had chronic kidney disease with autoimmune causes (odds ratio = 2.48 [95% confidence interval, 1.26-4.88]; P = .008) and who had previous renal transplants (odds ratio = 2.67 [95% confidence interval, 1.20-5.95]; P = .017) were more likely to have abnormal findings. CONCLUSIONS: Previous kidney transplant, autoimmune disease, and age <= 50 years were associated with abnormalities on cervical cancer screening in our female group of patients. Patients with these characteristics may benefit more from routine cervical cancer screening than other patients evaluated for kidney transplant. PMID- 29251579 TI - Bone Marrow Versus Peripheral Blood Stem Cell Transplant in Lymphoma: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: The choice of whether to use bone marrow or peripheral blood in autologous transplantation remains controversial. Posttransplant relapse and long term survival are critical issues. MATERIALS AND METHODS: Studies that compared bone marrow transplant versus peripheral blood stem cell transplant in lymphoma patients were searched. Our search resulted in 15 studies. RESULTS: Pooled data showed contradictory results with no conclusive differences in overall survival (for randomized controlled trials vs nonrandomized controlled trials: hazard ratio = 0.69 vs 1.17; 95% confidence interval, 0.44-1.10 vs 0.90-1.51; and P = .12 vs P = .25), progression-free survival (for randomized controlled trials vs nonrandomized controlled trials: hazard ratio = 0.89 vs 1.14; 95% confidence interval, 0.57-1.38 vs 0.82-1.58; and P = .60 vs P = .43), and relapse rates. However, we observed an overall trend toward lower relapse rate after bone marrow transplant. Lower relapse rate was likely associated with better progression-free survival (P = .052), and lower transplant-related mortality was associated with better overall survival (P = .043). CONCLUSIONS: Autologous bone marrow transplant with mobilization should be reconsidered for lymphoma patients to reduce recurrence and improve quality of life. More powered randomized controlled trials are warranted to update our findings. PMID- 29251580 TI - Successful Treatment of Lung Aspergillus terreus Infection After a Second Hematopoietic Stem Cell Transplant in a Patient With Myelodysplastic Syndrome. AB - A 24-year-old man was diagnosed with myelodysplastic syndrome and received a haploidentical hematopoietic stem cell transplant. The patient experienced graft failure posttransplant. Analysis of specific antibodies revealed that the patient had strongly positive donor-specific antibodies; therefore, we changed the donor to the patient's mother and added a single unit of cord blood to perform the second transplant. Corresponding treatments targeting donor-specific antibodies were administered to reverse the graft rejection and to reduce the antibody load. The grafts were implanted successfully, but the patient developed an invasive fungal infection. A lung biopsy was performed, and the pathogen was confirmed to be Aspergillus terreus via gene sequencing and analysis. The combined treatment of micafungin and posaconazole had good efficacy in this case, and this patient now receives close follow-up and receives oral posaconazole for antifungal maintenance treatment. PMID- 29251581 TI - Efficacy and Safety of Febuxostat in Kidney Transplant Patients. AB - OBJECTIVES: Febuxostat, a nonpurine xanthine oxidase, is known to be effective and safe, even in patients with chronic kidney disease. However, there are insufficient data about the efficacy and safety of febuxostat in kidney transplant patients. MATERIALS AND METHODS: We reviewed medical records of all kidney transplant patients who were prescribed febuxostat between August 2012 and May 2015 at Asan Medical Center in Seoul, Korea. The efficacy and safety results of febuxostat in transplant patients were evaluated. To compare the efficacy of febuxostat, results of kidney transplant patients who were prescribed benzbromarone or allopurinol for more than 1 year during the same period were also reviewed. RESULTS: Thirty-one patients were included in this study. The initial serum uric acid level of 481.83 +/- 143.36 MUmol/L decreased to 302.18 +/ 150.50 MUmol/L after 1 month of febuxostat use. Only 1 patient had altered sense of taste after taking febuxostat, but this symptom quickly improved and he continued treatment. No other adverse events were reported. In addition, at 12 months, mean serum uric acid levels were 280.77 +/- 78.52 MUmol/L in the febuxostat, 332.52 +/- 72.57 MUmol/L in the benzbromarone, and 363.45 +/- 60.08 MUmol/L in the allopurinol group. However, we found no apparent effect on estimated glomerular filtration rate (P = .344). The mean doses of febuxostat, benzbromarone, and allopurinol were 52.31 +/- 5.33 mg/day, 42.19 +/- 1.69 mg/day, and 146.67 +/- 16.52 mg/day. CONCLUSIONS: Febuxostat reduced serum uric acid levels effectively in kidney transplant patients without severe adverse events. PMID- 29251582 TI - Association Between Cytotoxic T-Lymphocyte Antigen 4 Gene Polymorphisms and Torque Teno Virus Infection After Hematopoietic Stem Cell Transplantation. AB - OBJECTIVES: An association between costimulatory molecule gene polymorphisms and viral infection after hematopoietic stem cell transplantation may be related to clinical outcomes, especially acute graft-versus-host disease. Cytotoxic T lymphocyte antigen 4 has been suggested as a crucial negative regulator of the immune system. In this study, our objective was to investigate the association between cytotoxic T-lymphocyte antigen-4 gene polymorphisms (including -1722 T/C, -1661 A/G, -318 C/T, and +49 A/G) and torque teno virus infection after hematopoietic stem cell transplantation in patients with and without acute graft versus-host disease. MATERIALS AND METHODS: Our study included 71 recipients. We evaluated cytotoxic T-lymphocyte antigen 4 gene polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: Our results showed that the GG genotype of the cytotoxic T-lymphocyte antigen 4 +49 A/G was significantly more frequent in transplanted patients infected with torque teno virus, whereas the AG genotype was more common in transplanted patients who did not have this infection. In addition, the -1661 AA and GA genotypes and -318 TC genotypes were significantly more frequent in transplanted patients infected with the virus and who had low-grade (grades I and II) acute graft-versus-host disease. Among those with grade I graft-versus-host disease, the GG genotype of the cytotoxic T-lymphocyte antigen 4+49 A/G was more frequent in transplanted patients with torque teno virus infection, whereas the AG genotype was higher in transplanted patients who did not have this infection. CONCLUSIONS: This is the first report indicating that cytotoxic T-lymphocyte antigen 4 gene polymorphism may be implicated in prevalence of torque teno virus infection after stem cell transplant. Further larger studies and evaluation of other costimulatory molecules are suggested. PMID- 29251583 TI - Improvements in Outcomes for Ethnic Minorities During the Share 35 Era Are Not Due to Decreased Rates of Early Graft Loss. AB - OBJECTIVES: Our aim was to investigate the effects of the Share 35 policy on outcomes in ethnic minorities and recipients who experienced early graft failure. MATERIALS AND METHODS: We analyzed donor and recipient data from the United Network for Organ Sharing database before (June 6, 2011 to June 18, 2013) and after (June 18, 2013 to June 30, 2015) implementation of Share 35. Graft and patient survival outcomes were compared. RESULTS: There were significant differences in 1- and 2-year graft and patient survival rates between ethnicities pre-Share 35 (P = .03, P < .001, P = .01, P < .001, respectively). There were no significant differences in 1- and 2-year graft and patient survival between ethnicities post-Share 35 (P = .268, P = .09, P = .343, P = .087, respectively). There were no differences in early graft failure rates pre- and post-Share 35 at 7 days (2.1% vs 2.0; P = .71) and 30 days (4.0% vs 3.8%; P = .47) after transplant, with a decreased early graft failure rate shown at 90 days after transplant (6.8% vs 5.8%; P = .003). When analyzed separately, the low Model for End-Stage Liver Disease (score of < 35) and the high Model for End-Stage Liver Disease recipients (score of >= 35) both exhibited reduced early graft failure rates post-Share 35 (6.1% vs 5.3% and 10.8% vs 7.8%, respectively; P < .05). CONCLUIONS: Share 35 was associated with a short-term reduction in ethnic disparities. Most ethnic groups experienced improved survival in the Share 35 era. Share 35 was not associated with an increase in early graft failure and is an efficacious policy with regard to short-term outcomes. PMID- 29251584 TI - Awareness Regarding Eye Donation in an Urban Slum Population: A Community-Based Survey. AB - OBJECTIVES: Our objective was to assess the awareness of eye donation in an urban slum population and willingness to donate eyes after death. MATERIALS AND METHODS: A cross-sectional, population-based study was undertaken in 20 urban slum clusters of the Indian capital, New Delhi. A total of 2004 individuals aged 18 years and older were recruited. After written, informed consent was obtained, knowledge regarding eye donation was assessed through a predesigned close-ended questionnaire. The questionnaire was framed so as to understand the sociodemographic factors influencing the willingness to donate and the awareness of eye donation in this distinct population. RESULTS: The mean age of the recruited individuals was 36.53 +/- 13.68 years. Age did not have any significant effect on awareness regarding eye donation. We observed that 34.3% of the study population had no knowledge of eye donation and that 7.78% of the study population had excellent knowledge. Education seemed to be an important determining factor regarding knowledge of eye donation. Multivariable logistic regression demonstrated better awareness among the Hindu population (81.1%) and those belonging to a higher caste (P < .05). The younger age group (those 18-30 years old) showed significant willingness to donate their eyes versus older age groups (P < .001). In our study population, male participants (P = .006), those classified as literate (P < .001), and those classified as Hindu (P < .001) were more willing to pledge their eyes for donation. CONCLUSIONS: Although there is substantial awareness about eye donation, willingness to pledge eyes was very low in the urban slum population. Additional efforts are needed to translate this awareness into actual eye donation in the urban poor population. PMID- 29251585 TI - Complications and Their Prevention in Experimental Renal Transplantation in Rats. AB - OBJECTIVES: Experimental rat models of renal transplant have played a pivotal role in renal transplant research. Both intraoperative and postoperative complications during donor nephrectomy and implantation in the recipient can be associated with significant morbidity and mortality. The aim of this paper is to discuss the incidence, pathophysiology, and prevention of complications that occurred in the process of establishment of a rat model of chronic allograft injury at our institution. MATERIALS AND METHODS: The complications observed while performing 67 consecutive donor nephrectomies and 61 renal transplants were recorded prospectively, and appropriate measures were taken to prevent these complications in the subsequent transplant procedures. RESULTS: Donor-related complications included failure of the kidney to clear of blood by the kidney perfusion solution and intraoperative deaths. The recipient-related complications included intraoperative hemorrhage, inadequately perfused kidneys with dusky appearance, congested and paralyzed hind limbs, urine leak, necrosis of the kidneys, renal and bladder calculi formation, and death during and after kidney transplant. CONCLUSIONS: Complications during donor nephrectomy and renal transplant can lead to significant loss of kidneys and animals. Proper recognition can allow appropriate measures to be taken to prevent these complications, thus achieving high-quality transplants and prolonged graft and animal survival. PMID- 29251586 TI - Knowledge of the Concept of Brain Death Among the Latin-American Population Residing in Spain. AB - OBJECTIVES: The knowledge of brain death is fundamental for being able to understand the organ donation process and for ensuring its acceptance or rejection. Here, we analyzed the level of knowledge of the concept of brain death among Latin-American individuals who are residents of Spain to determine the factors affecting this knowledge. MATERIALS AND METHODS: Our patient group was a sample of 1314 Latin-American residents of Spain, obtained randomly and stratified according to the respondent's nationality, age, and sex. Their attitude was assessed using a validated questionnaire. The survey was self administered and completed anonymously. RESULTS: The questionnaire completion rate was 94% (n = 1237). Of total respondents, 25% (n = 313) knew the concept of brain death, which they considered to be an individual's death, 56% (n = 697) did not know the term, and 19% (n = 227) believed that it did not mean death. The variables related to knowledge of the brain death concept included (1) country of origin, with a better knowledge among those with Mexican nationality (P < .001); (2) male sex (30% vs 23%; P = .003); (3) having university-level education (35% vs 23%; P = .044); (4) having discussed the matter within the family (29% vs 23%; P = .044); (5) having a partner with a favorable attitude toward donation (39% vs 21%; P = .001); and (6) the respondent's religion (47% vs 7%; P < .001). The following factors persisted in the multivariate analysis: country of origin (odds ratio of 2.972), sex (odds ratio of 1.416), education level (odds ratio of 2.228), attitude of the respondent's partner (odds ratio of 1.835), and religion (odds ratio of 4.490). CONCLUSIONS: Knowledge of the concept of brain death is limited among Latin-American residents of Spain, with marked differences among country of origin and other socio-personal factors. PMID- 29251587 TI - Spinal Dural Arteriovenous Fistula and Concomitant Intramedullary Spinal Lesion. PMID- 29251588 TI - Flavobacterium phocarum sp. nov., isolated from soils of a seal habitat in Antarctica. AB - A Gram-stain-negative, yellow-pigmented, non-flagellated, gliding, rod-shaped, oxidase-negative and catalase-positive bacterium, designated SE14T, was isolated from soil on King George Island, South Shetland Islands, Antarctica. Strain SE14T grew at 4-25 degrees C (optimum, 20 degrees C), at pH 6.0-9.0 (optimum, pH 7.0 7.5) and with 0-3.0 % NaCl (optimum, 1.0-1.5 %), and could not produce flexirubin type pigments. 16S rRNA gene sequence analysis showed the the isolate belonged to the genus Flavobacterium. Strain SE14T had the highest 16S rRNA gene sequence similarity to Flavobacterium antarcticum, F. tegetincola and F. degerlachei with 95.8, 95.5 and 95.2 %, respectively. The strain SE14T consisted of a clade with Flavobacteriumnoncentrifugens (16S rRNA gene sequence similarity 94.9 %) and F. qiangtangense (16S rRNA gene sequence similarity 94.2 %) and simultaneously formed a distinct phyletic lineage in the neighbour-joining phylogenetic tree. Polar lipids of the strain included phosphatidylethanolamine and four unidentified aminolipids. Strain SE14T contained anteiso-C15 : 0, iso-C15 : 0 and a mixture of iso-C15 : 0 2-OH and/or C16 : 1omega7c as the main fatty acids, and the only respiratory quinone was menaquinone-6. The genomic DNA G+C content was 42.3 mol%. The polyphasic taxonomic study revealed that strain SE14T belongs to a novel species within the genus Flavobacterium , and the name Flavobacterium phocarum sp. nov. is proposed. The type strain is SE14T (=CCTCC AB 2017225T=KCTC 52612T). PMID- 29251589 TI - ICTV Virus Taxonomy Profile: Chrysoviridae. AB - The Chrysoviridae is a family of small, isometric, non-enveloped viruses (40 nm in diameter) with segmented dsRNA genomes (typically four segments). The genome segments are individually encapsidated and together comprise 11.5-12.8 kbp. The single genus Chrysovirus includes nine species. Chrysoviruses lack an extracellular phase to their life cycle; they are transmitted via intracellular routes within an individual during hyphal growth, in asexual or sexual spores, or between individuals via hyphal anastomosis. There are no known natural vectors for chrysoviruses. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Chrysoviridae, which is available at www.ictv.global/report/chrysoviridae. PMID- 29251590 TI - Spirosoma metallilatum sp. nov., isolated from an automotive air conditioning system. AB - A Gram-stain-negative, aerobic, rod-shaped and yellow-pigmented bacterial strain, designated TX0405T, was isolated from an automotive air conditioning system. Colonies were circular, convex, semi-translucent, smooth and yellow. The strain grew at 20-28 degrees C (optimum, 28 degrees C), at pH 6.0-7.5 (optimum, pH 6.5) and in the presence of 0-1 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequence indicated that the strain was grouped with the members of the genus Spirosoma, with the sequence similarities of 93.0 and 92.3 % with Spirosoma panaciterrae DSM 21099T and Spirosoma swuense JBM2-3T, respectively. The major fatty acids of the strain were summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) (33.2 %), C16 : 1omega5c (25.4 %), iso-C15 : 0 (15.0 %), C16 : 0 (6.5 %) and iso-C17 : 0 3-OH (6.2 %). The predominant menaquinone was MK-7. The polar lipids were phosphatidylethanolamine, an unidentified aminolipid, two unidentified aminophospholipids and three unidentified lipids. The DNA G+C content of the type strain was 51.9 mol%. On the basis of the data presented, strain TX0405T represents a novel species of the genus Spirosoma, for which the name Spirosomametallilatum sp. nov. (=KACC 19012T=NBRC 112493T) is proposed. PMID- 29251591 TI - Free-living human cells reconfigure their chromosomes in the evolution back to uni-cellularity. AB - Cells of multi-cellular organisms evolve toward uni-cellularity in the form of cancer and, if humans intervene, continue to evolve in cell culture. During this process, gene dosage relationships may evolve in novel ways to cope with the new environment and may regress back to the ancestral uni-cellular state. In this context, the evolution of sex chromosomes vis-a-vis autosomes is of particular interest. Here, we report the chromosomal evolution in ~ 600 cancer cell lines. Many of them jettisoned either Y or the inactive X; thus, free-living male and female cells converge by becoming 'de-sexualized'. Surprisingly, the active X often doubled, accompanied by the addition of one haploid complement of autosomes, leading to an X:A ratio of 2:3 from the extant ratio of 1:2. Theoretical modeling of the frequency distribution of X:A karyotypes suggests that the 2:3 ratio confers a higher fitness and may reflect aspects of sex chromosome evolution. PMID- 29251593 TI - Culture shock. AB - Many different human cell lines, including both normal and cancer cells, appear to converge to a state that contains an unusual number of chromosomes when they are grown in culture. PMID- 29251592 TI - The role of microglia and their CX3CR1 signaling in adult neurogenesis in the olfactory bulb. AB - Microglia play important roles in perinatal neuro- and synapto-genesis. To test the role of microglia in these processes during adulthood, we examined the effects of microglia depletion, via treatment of mice with the CSF-1 receptor antagonist PLX5622, and abrogated neuronal-microglial communication in CX3C receptor-1 deficient (Cx3cr1-/-) mice. Microglia depletion significantly lowered spine density in young (developing) but not mature adult-born-granule-cells (abGCs) in the olfactory bulb. Two-photon time-lapse imaging indicated that microglia depletion reduced spine formation and elimination. Functionally, odor evoked responses of mitral cells, which are normally inhibited by abGCs, were increased in microglia-depleted mice. In Cx3cr1-/- mice, abGCs exhibited reduced spine density, dynamics and size, concomitantly with reduced contacts between Cx3cr1-deficient microglia and abGCs' dendritic shafts, along with increased proportion of microglia-contacted spines. Thus, during adult neurogenesis, microglia regulate the elimination (pruning), formation, and maintenance of synapses on newborn neurons, contributing to the functional integrity of the olfactory bulb circuitry. PMID- 29251594 TI - LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair. AB - Low-density lipoprotein receptor-related protein-1 (LRP1) is a large endocytic and signaling molecule broadly expressed by neurons and glia. In adult mice, global inducible (Lrp1flox/flox;CAG-CreER) or oligodendrocyte (OL)-lineage specific ablation (Lrp1flox/flox;Pdgfra-CreER) of Lrp1 attenuates repair of damaged white matter. In oligodendrocyte progenitor cells (OPCs), Lrp1 is required for cholesterol homeostasis and differentiation into mature OLs. Lrp1 deficient OPC/OLs show a strong increase in the sterol-regulatory element-binding protein-2 yet are unable to maintain normal cholesterol levels, suggesting more global metabolic deficits. Mechanistic studies revealed a decrease in peroxisomal biogenesis factor-2 and fewer peroxisomes in OL processes. Treatment of Lrp1-/- OPCs with cholesterol or activation of peroxisome proliferator-activated receptor gamma with pioglitazone alone is not sufficient to promote differentiation; however, when combined, cholesterol and pioglitazone enhance OPC differentiation into mature OLs. Collectively, our studies reveal a novel role for Lrp1 in peroxisome biogenesis, lipid homeostasis, and OPC differentiation during white matter development and repair. PMID- 29251595 TI - Natural variation in stochastic photoreceptor specification and color preference in Drosophila. AB - Each individual perceives the world in a unique way, but little is known about the genetic basis of variation in sensory perception. In the fly eye, the random mosaic of color-detecting R7 photoreceptor subtypes is determined by stochastic on/off expression of the transcription factor Spineless (Ss). In a genome-wide association study, we identified a naturally occurring insertion in a regulatory DNA element in ss that lowers the ratio of SsON to SsOFF cells. This change in photoreceptor fates shifts the innate color preference of flies from green to blue. The genetic variant increases the binding affinity for Klumpfuss (Klu), a zinc finger transcriptional repressor that regulates ss expression. Klu is expressed at intermediate levels to determine the normal ratio of SsON to SsOFF cells. Thus, binding site affinity and transcription factor levels are finely tuned to regulate stochastic expression, setting the ratio of alternative fates and ultimately determining color preference. PMID- 29251596 TI - Two-photon imaging in mice shows striosomes and matrix have overlapping but differential reinforcement-related responses. AB - Striosomes were discovered several decades ago as neurochemically identified zones in the striatum, yet technical hurdles have hampered the study of the functions of these striatal compartments. Here we used 2-photon calcium imaging in neuronal birthdate-labeled Mash1-CreER;Ai14 mice to image simultaneously the activity of striosomal and matrix neurons as mice performed an auditory conditioning task. With this method, we identified circumscribed zones of tdTomato-labeled neuropil that correspond to striosomes as verified immunohistochemically. Neurons in both striosomes and matrix responded to reward predicting cues and were active during or after consummatory licking. However, we found quantitative differences in response strength: striosomal neurons fired more to reward-predicting cues and encoded more information about expected outcome as mice learned the task, whereas matrix neurons were more strongly modulated by recent reward history. These findings open the possibility of harnessing in vivo imaging to determine the contributions of striosomes and matrix to striatal circuit function. PMID- 29251599 TI - Three-parent baby: Is it ethical? AB - The UK was the first country to legalise mitochondrial donation in October 2015 (1). In 2016, the first three-parent baby was born in Mexico (2) and the US Food and Drug Administration declared that further research on mitochondrial donation is ethically permissible (3). It has now become an important issue, raising as it does, the spectre of "genetically modified designer babies". PMID- 29251597 TI - Activation of the dopaminergic pathway from VTA to the medial olfactory tubercle generates odor-preference and reward. AB - Odor-preferences are usually influenced by life experiences. However, the neural circuit mechanisms remain unclear. The medial olfactory tubercle (mOT) is involved in both reward and olfaction, whereas the ventral tegmental area (VTA) dopaminergic (DAergic) neurons are considered to be engaged in reward and motivation. Here, we found that the VTA (DAergic)-mOT pathway could be activated by different types of naturalistic rewards as well as odors in DAT-cre mice. Optogenetic activation of the VTA-mOT DAergic fibers was able to elicit preferences for space, location and neutral odor, while pharmacological blockade of the dopamine receptors in the mOT fully prevented the odor-preference formation. Furthermore, inactivation of the mOT-projecting VTA DAergic neurons eliminated the previously formed odor-preference and strongly affected the Go-no go learning efficiency. In summary, our results revealed that the VTA (DAergic) mOT pathway mediates a variety of naturalistic reward processes and different types of preferences including odor-preference in mice. PMID- 29251600 TI - A few shades fairer, please. AB - This piece critically reflects on the growing Indian desire for fairer shades of skin. While skin-whitening products vanish off store shelves, notwithstanding protests against such products, the event that generated a storm some time ago in the media was the Garbha Sanskar workshops. In these workshops, women were allegedly taught methods to purify their wombs and beget fairer (and taller) children. In this article I argue that not only is it simplistic to label this ideology regressive, but that it becomes rather difficult to criticise the sanskaris because of the "register" they employ, ie the language they use to rationalise and explain their actions. The sanskaris use the rhetoric of modern medical science to justify their methods, while the same science tells us that their logic is not scientific; consequently, we are stranded between a paradox and a dead-end. A step-wise, critical look at this discourse reveals how complex its nature is, especially its attempt to lay simultaneous claims to different (and contradictory) epistemologies. I offer no easy solution, for there is none. I map some of the complexities and contradictions of the scenario as a first step. PMID- 29251598 TI - Ratiometric sensing of BiP-client versus BiP levels by the unfolded protein response determines its signaling amplitude. AB - Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves ER homeostatic readjustment is poorly investigated, as in most studies the ER stress that is elicited cannot be overcome. Here we show that a proteostatic insult, provoked by persistent expression of the secretory heavy chain of immunoglobulin M (us), is well-tolerated in HeLa cells. Upon us expression, its levels temporarily eclipse those of the ER chaperone BiP, leading to acute, full geared UPR activation. Once BiP is in excess again, the UPR transitions to chronic, submaximal activation, indicating that the UPR senses ER stress in a ratiometric fashion. In this process, the ER expands about three-fold and becomes dominated by BiP. As the UPR is essential for successful ER homeostatic readjustment in the HeLa-us model, it provides an ideal system for dissecting the intricacies of how the UPR evaluates and alleviates ER stress. PMID- 29251601 TI - Walking blood banks: an immediate solution to rural India's blood drought. AB - The current system of blood banks in India is such that rural patients are deprived of timely access to an adequate volume of life-saving blood, adding to preventable mortality. On the basis of an academic framework for a blood transfusion system, we describe an alternative approach in which rural practitioners utilise unbanked blood transfusions from a voluntary pool of pre screened donors. This system would provide safe blood - as evidenced by international experience and limited projected increase in transfusion transmissible infection in India - at a fraction of the financial cost imposed by the current system. Given the failing status quo and the undue burden placed on rural clinicians and patients to procure blood, it is imperative that policy makers further explore the use of unbanked, direct blood transfusion for patients facing emergent, life-threatening haemorrhage. PMID- 29251602 TI - Controlled human infection models for vaccine development: Zika virus debate. AB - An ethics panel, convened by the National Institute of Health and other research bodies in the USA, disallowed researchers from the Johns Hopkins University and University of Vermont from performing controlled human infection of healthy volunteers to develop a vaccine against Zika virus infection. The members published their ethical analysis and recommendations in February 2017. They have elaborated on the risks posed by human challenge with Zika virus to the volunteers and other uninvolved third parties and have systematically analysed the social value of such a human challenge experiment. They have also posited some mandatory ethical requirements which should be met before allowing the infection of healthy volunteers with the Zika virus. This commentary elaborates on the debate on the ethics of the human challenge model for the development of a Zika virus vaccine and the role of systematic ethical analysis in protecting the interests of research participants. It further analyses the importance of this debate to the development of a Zika vaccine in India. PMID- 29251603 TI - Medical ethics in times of conflict - why silence is not an option. AB - In this commentary we argue that medical ethics has a key role in discussing the effects of conflicts and other violent human rights abuses. Contemporary medical ethics is an emerging academic discipline without clearly defined boundaries and we have no desire to impose them. We are seeking instead to indicate the kinds of issues that naturally and ordinarily arise within its purview. Recent history has seen a closer relationship and interdependency between medicine and the state. This has led, at times, to tension between professional obligations and state interests. Many would prefer medical ethics to step aside from sectarian politics and focus on the doctor-patient relationship and the objective and neutral medical sciences that underpin it. However, given the role that social inequities play in health outcomes, doctors have been obliged to speak out against such inequities or even against state practices which directly contribute to poor health. For those committed to the impartial practice of medicine, and to the promotion of human wellbeing, silence during times of conflict is seldom an option. PMID- 29251604 TI - Social media and physicians: the Indian scenario. PMID- 29251605 TI - Henry Molaison's operation for epilepsy: a case study in medical ethics. AB - Dr. William Beecher Scoville, an eminent American neurosurgeon of the 1940s, offered to treat Mr Molaison for his intractable epilepsy. During the operation, he removed large portions of both of Mr. Molaison's temporal lobes. Such an operation had never been performed earlier as the function of these parts of the brain was not clearly understood and neurosurgeons such as Dr. Wilder Penfield of Canada feared they could cause grave damage to the patient. Mr. Molaison developed severe loss of memory to the extent that a few minutes after meeting someone, he had no recollection of the meeting and he could not find his way to his own home. Mr. Dittrich, grandson of Dr. Scoville, has analysed the operation on Mr. Molaison's brain against the background of neurosurgery in the 1940s. This essay discusses the ethical aspects of Dr. Scoville's operation in the light of current understanding and practice. PMID- 29251606 TI - Issues in access to end-of-life care in low-resource areas. AB - Even though 1% of people require palliative and end-of-life care in low-resource situations, it remains an uncharted arena. Yet it is as important as curative care to alleviate suffering. Palliative care is not only a need in cancer and HIV disease; but is needed in a diverse group of illnesses ranging from tuberculosis, renal failures, paraplegia to chronic lung diseases. In a lower resource setting, the gaps in palliation may be the need for more technology and interventions or more healthcare professionals. Thus, palliative care will initially mean ensuring that life-prolonging treatment that most patients do not get is ensured to them. It is morally unacceptable to focus on comfort care as an alternative to advocating for patients' rights for appropriate life-prolonging treatments. If organised well and standard protocols are developed to support health workers, appropriate care can be provided for all people. Ethical principles of autonomy, nonmaleficence and benevolence will have to guide this development. We will have to prioritise for high value care which means choosing cheaper alternatives that are just as effective as more expensive diagnostic or therapeutic modalities. There is a need to settle the priorities between palliative and disease-modifying or curative treatments. Major roadblocks that limit access of the rural poor to palliative care relate mainly to the misconceptions among policy-makers and physicians, large gaps in health worker training and cultural mindsets of care providers. A specific example of misplaced policies and regulations is the poor availability of opiates, which can make end-of-life care so much more dignified in illnesses that have chronic pain or breathlessness. A three-tiered structure is proposed with a central palliative care unit which will oversee several physicians and specially trained nurses for noncommunicable diseases, who will oversee primary healthcare centre-based nurses, who in turn, will oversee village health workers. PMID- 29251607 TI - Revisiting New Zealand's "Unfortunate Experiment": Is medical ethics ever a thing done? AB - An experiment dating from the 1960s in New Zealand has eerie similarities to research begun in 1976 in India. In both cases, women with evidence of early cervical cancer or pre-cancer went untreated, despite known treatments that could have prevented their condition from worsening. This Comment on carcinoma cervix research grew out of my reading of a new book by Ronald W Jones about the New Zealand experiment. Jones, a recently retired obstetrician/gynaecologist, worked at the hospital where the controversial research took place and was a whistleblower in the case. His book provides a meticulous account of internal struggles within the hospital over what has been called "the unfortunate experiment." Readers might fairly ask whether a detailed examination of a decades old research scandal in New Zealand can usefully inform ethics debate in India today, where conditions are so different. I argue that Jones's account does indeed provide valuable insights for understanding research wrongdoing in other contexts, including low-income countries. Jones challenges some widespread assumptions about why such cases occur and how to combat them, as do several other recent analyses of research scandals. PMID- 29251608 TI - Manufacturing the truth: From designing clinical trials to publishing trial data. AB - This paper expands on some of the points made by Deepak Natarajan on techniques used in designing clinical trials of new drugs to ensure favourable outcomes. It also considers the nexus between the manufacturers of new drugs and the publishers of medical journals in which edited versions of these favourable outcomes are presented to the medical fraternity. The argument will be illustrated by referring to the clinical trials of rofecoxib (Vioxx(r)) and etoricoxib (Arcoxia(r)). Both these drugs are COX-2 selective non-steroidal anti inflammatory drugs (NSAIDs) manufactured by Merck and Co. Because of the unparalleled access to Merck's internal confidential documents, due to the subpoenaing of these documents by government and private individuals in civil and criminal actions, we are still learning about the company's unconscionable acts. What we learn can inform our judgement concerning published reports of both new and old drugs. PMID- 29251609 TI - [The role of micro-RNA in the regulation of signal pathways in gliomas]. AB - Gliomas are invasive brain tumors with high rates of recurrence and mortality. Glioblastoma multiforme (GBM) is the most deadly form of glioma with nearly 100% rate of recurrence and unfavorable prognosis in patients. Micro-RNAs (miR) are the class of wide-spread short non-coding RNAs that inhibit translation via binding to the mRNA of target genes. The aim of the present review is to analyze recent studies and experimental results concerning aberrant expression profiles of miR, which target components of the signaling pathways Hedgehog, Notch, Wnt, EGFR, TGFb, HIF1a in glioma/glioblastoma. Particularly, the interactions of miR with targets of 2-hydroxyglutarate (the product of mutant isocytrate dehydrogenase, R132H IDH1, which is specific for the glioma pathogenesis) have been considered in the present review. Detecting specific miRNAs in tissue and serum may serve as a diagnostic and prognostic tool for glioma, as well as for predicting treatment response of an individual patient, and potentially serving as a mechanism for creating personalized treatment strategies. PMID- 29251610 TI - [Bacterial TEM-type serine beta-lactamases: structure and analysis of mutations]. AB - Beta-lactamases (EC 3.5.2.6) represent a superfamily containing more than 2,000 members: it includes genetically and functionally different bacterial enzymes capable to destroy the beta-lactam antibiotics. The most common are beta lactamases of molecular class A with serine in the active center. Among them, TEM type beta-lactamases are of particular interest from the viewpoint of studying the mechanisms of the evolution of resistance due to their broad polymorphism. To date, more than 200 sequences of TEM-type beta-lactamases have been described and more than 60 structures of different mutant forms have been presented in Protein Data Bank. We have considered the main structural features of the enzymes of this type with particular attention to the analysis of key drug resistance and the secondary mutations, their location relative to the active center and the surface of the protein globule. We have developed the BlaSIDB database (www.blasidb.org) which is an open information resource combining available data on 3D structures, amino acid sequences and nomenclature of the corresponding forms of beta lactamases. PMID- 29251611 TI - [Bioinformatics analysis of antimicrobial resistance genes and prophages colocalized in human gut metagenomes]. AB - The constant increase of antibiotic-resistant strains of bacteria is caused by extensive uses of antibiotics in medicine and animal breeding. It was suggested that the gut microbiota serves as a reservoir for antibiotics resistance genes that can be carried from symbiotic bacteria to pathogenic ones, in particular, as a result of transduction. In the current study, we have searched for antibiotics resistance genes that are located inside prophages in human gut microbiota using PHASTER prophage predicting tool and CARD antibiotics resistance database. After analysing metagenomic assemblies of eight samples of antibiotic treated patients, lsaE, mdfA and cpxR/cpxA genes were identified inside prophages. The abovementioned genes confer resistance to antimicrobial peptides, pleuromutilin, lincomycins, streptogramins and multidrug resistance. Three (0.46%) of 659 putative prophages predicted in metagenomic assemblies contained antibiotics resistance genes in their sequences. PMID- 29251612 TI - [Interstitial collagenase and their endogenous regulators in squamous cell cervical carcinoma]. AB - Interstitial collagenase (MMP-1) belongs to the family of matrix metalloproteinases (MMP), which play a key role in generalization processes of invasion and metastasis, which determine the degree of tumor malignancy. MMP-1 refers to secreted, inducible MMP, the expression of which in normal tissues is not defined. Induction of expression of MMP in CSS in the tumor occurs under the action of oncogenes of HPV, and in areas adjacent to the tumor normal tissue under the action of the inductor expression of MMP - EMMPRIN (CD147), which expressively on the surface of tumor cells. The aim of this study is to determine the possibility of expression ofMMP-1 and its regulators (tissue inhibitors TIMP 1 and activator - plasminogen activator - ADF) in morphologically normal body of the uterus during CSS. The study was carried out using on a tissue "tape" - postoperative specimens of the uterus when the diagnosis of CSS. All of the samples was expressed HPV16 gene E7. It was shown that: 1. The increase of MMP-1 expression, low expression (or lack thereof) of its inhibitors TIMP-1 and a very clear expression of the activator take place in the tumor when CSS that lead to increased activity of MMP-1, and aims to increase the destructive (invasive) potential of the tumor. 2. In morphologically normal tissue of the uterus during CSS the expression of MMP-1 can occur from the vaginal wall to the bottom of the uterine cavity, but at a much lower level than in the tumor. 3. These data indicate the possibility of development of a destructive process in morphologically normalnyh body tissues of the uterus during CSS, important for understanding the mechanism of tumor progression, and suggest participation in the process of expression of MMP-1 signaling by the type of epithelial mesenchymal interaction . PMID- 29251613 TI - [Participation of melatonin in regulation of blood oxygen-transport function in oxidative stress induced by injection of lipopolisaccharide]. AB - The contribution of melatonin to the regulatoin of the blood oxygen transport function was studied during oxidative stress induced by a triple injection of lipopolysaccharide (at a dose of 5 mg/kg) in conditions of erythropoietin and gasetransmitters (nitrogen monoxide, hydrogen sulfide) action. In the experimental groups, intraperitoneal injections of melatonin (5 mg/kg), erythropoietin (1000 U/kg), hydrogen sulfide donor (NaHS 5 mg/kg), and L-arginine (100 mg/kg), were performed. The use of melatonin alone or in combination with erythropoietin, sodium hydrosulfide or L-arginine led to a decrease in lipid peroxidation products and an increase in the antioxidant protection. Melatonin, during lipopolysaccharide administration, caused changes of blood oxygen transport function: blood oxygen saturation increased, hemoglobin oxygen affinity increased. The modifying effect of melatonin on the blood oxygen transport function in combination with erythropoietin and gastransmitters did not exceed the effect of melatonin alone. PMID- 29251614 TI - [Disorders in structural-functional properties of erythrocytes in experimental acute destructive pancreatitis of alcohol etiology and their correction]. AB - The effects of various combinations of pharmacological agents on parameters characterizing red blood cell (RBC) membrane proteins and lipids have been investigated in RBC isolated from Wistar male rats with acute destructive pancreatitis induced under conditions of forced alcoholization for 60 days. Administration of a combination of Hepon, Hypoxenum, and Phosphogliv normalized 22.5% of parameters altered change during development of acute destructive pancreatitis under conditions of chronic alcoholization of parameters, corrected towards normal values 42.5% of parameters (35% of parameters remained unchanged). Administration of Glutoxim, Mexidol and Heptral, was more effective: this combination normalized 50.0% of parameters studied, corrected towards normal values 37.5% of parameters, leaving unchanged only 12.5% of parameters studied. PMID- 29251615 TI - [The association of the mitochondrial DNA oriB variants with metabolic syndrome]. AB - Different genes are involved in the development of pathology and formation the metabolic syndrome (MS) phenotype. In the literature, there is a data connection to the site oriB polymorphisms of mitochondrial DNA (mtDNA), known as 16184-16193 polycytosine tract, with insulin resistance, type 2 diabetes (T2DM) and other metabolic abnormalities in different ethnic populations. It is supposed that for certain polymorphisms at this site decreases mtDNA copy number in the cells. In this study, we have identified different allelic variants of the mtDNA oriB site in MS patients (n=106) and healthy individuals (n=71) using capillary sequencing, and determined the amount of mtDNA copy blood leukocytes by droplet digital polymerase chain reaction (ddPCR). The continuous polycytosine tract was significantly more common in MS patients, and such a link was particularly strong in MS patients with type 2 diabetes (p<0.01). No significant correlation has been found between mtDNA copy number and the oriB site variants, but in general there is a tendency to decreased mtDNA copy number in MS patients. PMID- 29251616 TI - [The influence of chorionic gonadotropin on phenotype conversion and hTERT gene expression by T-lymphocytes of different degrees of differentiation]. AB - The effects of chorionic gonadotropin (hCG) on the expression of the hTERT gene in combination with the conversion of the phenotype of naive T-cells and T-cells of immune memory in vitro were studied. hCG inhibited expression of hTERT mRNA in naive T-cells (CD45RA+) and immune memory T cells (CD45RO+), causing a decrease in the replicative potential of the cells. The presence of hCG in the culture led to the conversion of the phenotype of T-lymphocytes. hCG reduced the number of proliferating T-cells of immune memory, estimated by phenotypic signs by differential gating. hCG (10 IU/ml and 100 IU/ml) inhibited expression of CD25 by the studied populations, but did not modulate expression of the CD71 proliferation marker. Thus, hCG inhibited the functional activity of naive T cells and T-cells of immune memory, which, in the context of pregnancy, can contribute to the formation of immune tolerance to the semi-allogenic fetus. PMID- 29251617 TI - [Oxoprolinic short peptides - potential pharmacological means of hypolidemic and antitrombotic actions]. AB - One of the most urgent and important tasks of modern biological and medical research is the search and research of pharmacological agents that combine lipid lowering and antithrombotic effects in the organism. The unique effects of the regulatory peptides of the oxoproline series (5-oxo-Pro-His-Pro-NH2, 5-oxo-Pro Trp-Pro and 5-oxo-Pro-Arg-Pro or 5-oxo-Pro-His-Pro-NH2, Pyr-Trp-Pro and Pyr-Arg Pro) have been found in rats with hypercholesterolemia (metabolic syndrome). Multiple intranasal of these peptides to animals with developed hypercholesterolemia increased anticoagulant, fibrinolytic and antiplatelet potential of the blood and simultaneously lowered increased concentrations of total cholesterol, low-density lipoprotein cholesterol and triglycerides. In addition, they contributed to the normalization of blood glucose levels. A week after the last admistration of these peptides, the hypocholesterolemic, normoglycemic and anticoagulant effects persisted. The relationship between the structure of peptides of the oxoproline series and their functional properties is discussed. A conclusion is made about the prospects of further studies of oxoproline peptides as drugs that combine antithrombotic effects with the improvement of fat metabolism in the body. PMID- 29251618 TI - [Evaluation of adjuvant effects of fucoidane from brown seaweed Fucus evanescens and its structural analogues for the strengthening vaccines effectiveness]. AB - The use of sulfated polysaccharides from brown seaweed Fucus evanescens as adjuvants (native fucoidan in combination with polyphenols, fucoidan without polyphenols, a product of enzymatic hydrolysis of fucoidan) stimulated the formation of specific antibodies to the surface antigen of the hepatitis B virus (HBs-AG). Immunization of mice with vaccine compositions containing HBs-AG and fucoidan samples resulted in increasing the serum level of the pro-inflammatory (TNF-a, IFN-g, IL-2) cytokines. Increased production of these cytokines was detected in the culture of splenocytes additionally stimulated in vitro by fucoidans or phytohemagglutinin. The adjuvant effect of fucoidan and its structural modifications was comparable to that of the traditional licensed adjuvant aluminum hydroxide. The obtained results indicate a promising use of sulfated polysaccharides from F. evanescens as vaccine adjuvants. PMID- 29251619 TI - [The influence of enzymatic removal of chlorpyrifos from feed grain-mixture on the biochemical parameters of rat blood]. AB - Organophosphorus pesticides (OP) are used to protect crops from pests. Treatment of plants and animals with pesticides can be done during their growth or creation of conditions necessary for the long-shelf life of the agricultural products. Currently, there are many remedies for prevention and removal of intoxication consequences developed under the action of OP in living organisms. The development of biologics for the degradation of OP and biotechnologies for their application in agriculture is relevant. New biologics based on the stabilized forms of such enzyme as hexahistidine-tagged organophosphorus hydrolase (His6 OPH) in the form of nano-sized particles were tried for OP detoxification. These biologics (enzyme-polyelectrolyte complexes, EPC) were obtained in accordance to previously developed procedure by mixing solutions of His6-OPH and polyanion under certain conditions. The main purpose of this work was to evaluate the usage efficiency of EPC based on His6-OPH and polyglutamic acid for OP detoxification by analyzing biochemical blood parameters of rats consumed the grain-mixture containing chlorpyrifos. The experiment was conducted using female Sprague Dawley albino rats. Treatment of feeding grain-mixture initially containing chlopyrifos (48 mg/kg of the mixture) with EPC based on His6-OPH (1000 U/kg of the mixture) for 24 h was the most effective. The results showed that rats from the group consuming food after enzymatic removal of chlorpyrifos, had comparable acetyl cholinesterase activity in blood of rats consuming pure food (without any OP intoxication). PMID- 29251620 TI - [Effect of afobazole and levodopa on the activity of proline-specific proteinases and adenosine deaminase in blood serum and brain structures of rats with experimental Parkinson's syndrome induced by systemic administration of rotenone]. AB - Rats with experimental Parkinson's syndrome induced by seven-day intraperitoneal administration of rotenone at a dose of 2.75 mg/kg have an increased activity of prolylendopeptidase (EC 3.4.21.26, PREP) in blood serum and a decreased activity of adenosine deaminase (EC 3.5.4.4, ADA) in serum and in the prefrontal cortex. PREP and ADA activity in other brain structures (in the striatum, hypothalamus and hippocampus) did not change; dipeptidyl peptidase IV activity (EC 3.4.14.5, DPP-4, CD26) also remained constant in serum and in all the brain structures investigated. Afobazole and levodopa, which exhibit antiparkinsonian activity in this model of Parkinson's syndrome, decrease elevated PREP activity in serum and increase reduced ADA activity in the prefrontal cortex of rats with the experimental pathology. Meanwhile, treatment with the study drugs was associated with a decrease of ADA activity in the other brain structures. PMID- 29251621 TI - [Donor chimerism and minimal residual disease monitoring in leukemia patients after allo-HSCT]. AB - In present research the comparative analysis of donor chimerism (DC) using different tests was performed to improve the diagnostic tool in patients with malignant hematological disorders after allo-HSCT. The RBC antigen typing, identification of ABO blood type and quantitative analysis of InDel-, STR-, Y polymorphisms were carried out for detection of DC. In addition, the expression of well-known oncogenes and CD-markers for monitoring MRD was evaluated to predict relapse and clinical outcome. According to our research, the analysis of InDel polymorphism using AlleleSEQR-PCR is more sensitive test for estimation of DC as compared with other assays. Moreover, the sensitivity of AlleleSEQR-PCR may be increased after isolation of the CD34 cell population in bone marrow. Nevertheless, observation of high levels in DC (395%) in some leukemia patients (ALL, Ph+, bcr-abl/p190+) during first 6 months after HSCT cannot exclude the possibility of relapse. Thus, the combined monitoring of both DC (InDel) and MRD (oncogenes, WT1 and CD-markers) is a more advisable and useful test in managing hematologic malignancies and predicting relapse risk after allo-HSCT. PMID- 29251622 TI - [The chemerin production changes in obese patients with different carbohydrate metabolism state]. AB - Chemerin is a mediator of adipose tissue involved in the regulation of many processes, including lipogenesis, and inflammatory response. The role of chemerin in the development of insulin resistance has been insufficiently studied and needs detailed understanding. The aim of the study was to investigate chemerin production in obese patients with different states of carbohydrate metabolism. The study included 155 patients with a diagnosis of obesity; 34 patients with overweight. The control group 1 consisted of 43 conditionally healthy donors who did not have obesity. For comparison of the results of a study to determine the levels of tissue-specific mRNA expression of the genes IL-6, TNF-a, RARRES2, (encoding IL-6, TNF-a and chemerin) in adipose tissue introduced a control group 2 - 30 patients without obesity. Study on the relative level of mRNA expression of the genes IL-6, TNF-a and RARRES2 (encoding IL-6, TNF-a and chemerin) was carried out using real time PCR. Concentrations of IL-6, TNF-a, and chemerin were measured in serum/plasma using an enzyme-linked immunosorbent assay (ELISA). We found significant differences in the plasma level of chemerin and tissue-specific features of RARRES2 gene expression in obese patients, depending on the degree of obesity and the state of carbohydrate metabolism. Multidirectional associations of RARRES2 gene expression with TNF-a and IL-6 genes in adipose tissues of different localization are shown: in obese patients (BMI L40 kg/m2) without type 2 diabetes - negative, and type 2 diabetes - positive. Identified relationship chemerin plasma content and the expression level of its gene in biopsies with various parameters of carbohydrate and lipid metabolism, proinflammatory molecules indicate chemerin involved in metabolic and immune processes in obesity. PMID- 29251623 TI - Automated contour analysis of multi-cellular spheroids spreading through high content imaging. AB - The morphology of 2D cell colonies has been studied to understand tumor metastasis in the past decades. However, 2D cell cultures are lacking many features of 3D tissues, and their physiological behaviors are quite different from solid tumors in vivo. In this work, we studied the multi-cellular tumor spheroid (MCTS) spreading on the substrate, which keeps parts of 3D tissue characteristics and facilitates cell tracking through 2D imaging. By using a high content imaging system (HCS), we tracked multiple spheroids in one single 96-well plate for 36 h. An automated algorithm based on Otsu's method was developed to investigate the morphological details of spheroids through the quantification of radius length and its coefficients of variation. Spheroid spreading is altered by the PIP-platin, which was a novel platinum based drug previously reported by us with an inhibitory effect on cell migration. All parameters showed dose dependent decreases when PIP-platin concentration increased, indicating the inhibition of spheroid expansion by this compound. To investigate the surface roughness of spheroids affected by the drug, we applied the Fourier parameter beta and the normalized standard deviation of the radius STD r / [Formula: see text], which were found inversely proportional to the concentrations of PIP-platin. Particularly at the low drug concentrations, the indices of contour roughness appeared to be more sensitive than spheroid sizes, which could be the potential morphological markers for high content screening of drugs. PMID- 29251624 TI - Hydrodynamics of electrons in graphene. AB - Generic interacting many-body quantum systems are believed to behave as classical fluids on long time and length scales. Due to rapid progress in growing exceptionally pure crystals, we are now able to experimentally observe this collective motion of electrons in solid-state systems, including graphene. We present a review of recent progress in understanding the hydrodynamic limit of electronic motion in graphene, written for physicists from diverse communities. We begin by discussing the 'phase diagram' of graphene, and the inevitable presence of impurities and phonons in experimental systems. We derive hydrodynamics, both from a phenomenological perspective and using kinetic theory. We then describe how hydrodynamic electron flow is visible in electronic transport measurements. Although we focus on graphene in this review, the broader framework naturally generalizes to other materials. We assume only basic knowledge of condensed matter physics, and no prior knowledge of hydrodynamics. PMID- 29251625 TI - PDB-NMA of a protein homodimer reproduces distinct experimental motility asymmetry. AB - We have extended our analytically derived PDB-NMA formulation, Atomic Torsional Modal Analysis or ATMAN (Tirion and ben-Avraham 2015 Phys. Rev. E 91 032712), to include protein dimers using mixed internal and Cartesian coordinates. A test case on a 1.3 [Formula: see text] resolution model of a small homodimer, ActVA ORF6, consisting of two 112-residue subunits identically folded in a compact 50 [Formula: see text] sphere, reproduces the distinct experimental Debye-Waller motility asymmetry for the two chains, demonstrating that structure sensitively selects vibrational signatures. The vibrational analysis of this PDB entry, together with biochemical and crystallographic data, demonstrates the cooperative nature of the dimeric interaction of the two subunits and suggests a mechanical model for subunit interconversion during the catalytic cycle. PMID- 29251626 TI - Zn x Cd1-x S tunable band structure-directing photocatalytic activity and selectivity of visible-light reduction of CO2 into liquid solar fuels. AB - A series of Zn x Cd1-x S monodispersed nanospheres were successfully synthesized with tunable band structures. As-prepared Zn x Cd1-x S solid solutions show much enhanced photocatalytic efficiency for CO2 photoreduction in aqueous solutions under visible light irradiation, relative to pure CdS analog. Methanol (CH3OH) and acetaldehyde (CH3CHO) are the major products of CO2 photoreduction for the solid solutions with x = 0, 0.2, and 0.5. Interestingly, Zn0.8Cd0.2S photocatalyst with a wide band gap can also additionally generate ethanol (CH3CH2OH) besides CH3OH and CH3CHO. The balance between the band structure directing redox capacity and light absorption should be considered to influence both product yield and selectivity of CO2 photoreduction. The possible photoreduction mechanism was tentatively proposed. PMID- 29251627 TI - PBX transcription factors drive pulmonary vascular adaptation to birth. AB - A critical event in the adaptation to extrauterine life is relaxation of the pulmonary vasculature at birth, allowing for a rapid increase in pulmonary blood flow that is essential for efficient gas exchange. Failure of this transition leads to pulmonary hypertension (PH), a major cause of newborn mortality associated with preterm birth, infection, hypoxia, and malformations including congenital diaphragmatic hernia (CDH). While individual vasoconstrictor and dilator genes have been identified, the coordination of their expression is not well understood. Here, we found that lung mesenchyme-specific deletion of CDH implicated genes encoding pre-B cell leukemia transcription factors (Pbx) led to lethal PH in mice shortly after birth. Loss of Pbx genes resulted in the misexpression of both vasoconstrictors and vasodilators in multiple pathways that converge to increase phosphorylation of myosin in vascular smooth muscle (VSM) cells, causing persistent constriction. While targeting endothelin and angiotensin, which are upstream regulators that promote VSM contraction, was not effective, treatment with the Rho-kinase inhibitor Y-27632 reduced vessel constriction and PH in Pbx-mutant mice. These results demonstrate a lung intrinsic, herniation-independent cause of PH in CDH. More broadly, our findings indicate that neonatal PH can result from perturbation of multiple pathways and suggest that targeting the downstream common effectors may be a more effective treatment for neonatal PH. PMID- 29251628 TI - Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage. AB - Macrophages are a source of both proinflammatory and restorative functions in damaged tissue through complex dynamic phenotypic changes. Here, we sought to determine whether monocyte-derived macrophages (MDMs) contribute to recovery after acute sterile brain injury. By profiling the transcriptional dynamics of MDMs in the murine brain after experimental intracerebral hemorrhage (ICH), we found robust phenotypic changes in the infiltrating MDMs over time and demonstrated that MDMs are essential for optimal hematoma clearance and neurological recovery. Next, we identified the mechanism by which the engulfment of erythrocytes with exposed phosphatidylserine directly modulated the phenotype of both murine and human MDMs. In mice, loss of receptor tyrosine kinases AXL and MERTK reduced efferocytosis of eryptotic erythrocytes and hematoma clearance, worsened neurological recovery, exacerbated iron deposition, and decreased alternative activation of macrophages after ICH. Patients with higher circulating soluble AXL had poor 1-year outcomes after ICH onset, suggesting that therapeutically augmenting efferocytosis may improve functional outcomes by both reducing tissue injury and promoting the development of reparative macrophage responses. Thus, our results identify the efferocytosis of eryptotic erythrocytes through AXL/MERTK as a critical mechanism modulating macrophage phenotype and contributing to recovery from ICH. PMID- 29251631 TI - Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation in the United States: A Multicenter Survey. AB - The clinical use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (LTx) has greatly increased in recent years. However, clinical practices for ECMO as a bridge to LTx vary widely between LTx centers. To better define the current practice of ECMO as a bridge to LTx, we surveyed pre LTx ECMO practices among all adult LTx programs in the United States. All US LTx centers were surveyed (n = 57) between January and December 2014. Responses were received from 33 of 57 centers (58%). Of 33 responding centers, six (18%) performed >=50 LTxs per year (defined as high volume) and two (6%) performed <10 LTxs per year (low volume). Two-third of responding centers, 22/33 (67%), reported use of ECMO as a bridge to LTx. Of these 22 centers, 18 (82%) successfully used venovenous (VV) ECMO as a bridge to LTx using the dual-lumen Avalon cannula. Patient >65 years of age was judged an ECMO contraindication in 15/33 (45%) of responding centers, but 12/33 (36%) centers, including the six high-volume centers, had no official age cutoff for ECMO candidacy. There was no consensus on the maximum acceptable duration of pre-LTx ECMO therapy; although 18/33 (55%) of programs had no defined maximal duration of ECMO pre-LTx, 10/33 (30%) considered >10 days on ECMO support contraindicated. Our survey suggests that in the United States, ECMO is used frequently pre-LTx, particularly VV ECMO at high-volume centers. However, criteria for ECMO initiation, age eligibility, bedside care, and maximum duration of support varied significantly between survey respondents. PMID- 29251629 TI - HIF-1alpha promotes autophagic proteolysis of Dicer and enhances tumor metastasis. AB - HIF-1alpha, one of the most extensively studied oncogenes, is activated by a variety of microenvironmental factors. The resulting biological effects are thought to depend on its transcriptional activity. The RNAse enzyme Dicer is frequently downregulated in human cancers, which has been functionally linked to enhanced metastatic properties; however, current knowledge of the upstream mechanisms regulating Dicer is limited. In the present study, we identified Dicer as a HIF-1alpha-interacting protein in multiple types of cancer cell lines and different human tumors. HIF-1alpha downregulated Dicer expression by facilitating its ubiquitination by the E3 ligase Parkin, thereby enhancing autophagy-mediated degradation of Dicer, which further suppressed the maturation of known tumor suppressors, such as the microRNA let-7 and microRNA-200b. Consequently, expression of HIF-1alpha facilitated epithelial-mesenchymal transition (EMT) and metastasis in tumor-bearing mice. Thus, this study uncovered a connection between oncogenic HIF-1alpha and the tumor-suppressive Dicer. This function of HIF-1alpha is transcription independent and occurs through previously unrecognized protein interaction-mediated ubiquitination and autophagic proteolysis. PMID- 29251630 TI - Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance. AB - The molecular mechanism by which cancer-associated fibroblasts (CAFs) confer chemoresistance in ovarian cancer is poorly understood. The purpose of the present study was to evaluate the roles of CAFs in modulating tumor vasculature, chemoresistance, and disease progression. Here, we found that CAFs upregulated the lipoma-preferred partner (LPP) gene in microvascular endothelial cells (MECs) and that LPP expression levels in intratumoral MECs correlated with survival and chemoresistance in patients with ovarian cancer. Mechanistically, LPP increased focal adhesion and stress fiber formation to promote endothelial cell motility and permeability. siRNA-mediated LPP silencing in ovarian tumor-bearing mice improved paclitaxel delivery to cancer cells by decreasing intratumoral microvessel leakiness. Further studies showed that CAFs regulate endothelial LPP via a calcium-dependent signaling pathway involving microfibrillar-associated protein 5 (MFAP5), focal adhesion kinase (FAK), ERK, and LPP. Thus, our findings suggest that targeting endothelial LPP enhances the efficacy of chemotherapy in ovarian cancer. Our data highlight the importance of CAF-endothelial cell crosstalk signaling in cancer chemoresistance and demonstrate the improved efficacy of using LPP-targeting siRNA in combination with cytotoxic drugs. PMID- 29251632 TI - Ventricular Assist Device Self-Management Issues: The Patient and Caregiver Perspectives. AB - Despite technological advancements, ventricular assist device (VAD) self management (SM) remains complex. Using a descriptive mixed-method research, we examined the VAD care issues reported by nondyadic sample of 102 patients and 116 caregivers in the United States. Participants (mean age, 50.0 +/- 13.1 years) were predominantly white (80%), female (59%), and married (77%). Quantitative and qualitative data revealed the patients/caregivers' need for competency assessment and reassessment of VAD care after discharge. Competent home-care registered nurses (RNs) and on-going communications with VAD care team are needed in support for VAD SM. PMID- 29251633 TI - Prevalence of Anemia and Iron Deficiency in Pediatric Patients on Ventricular Assist Devices. AB - The prevalence and characteristics of anemia and iron deficiency in children supported by a ventricular assist device (VAD) are unknown. Patients <21 years of age on durable VAD support for >=7 days at Texas Children's Hospital from 2006 to 2015 were retrospectively reviewed. Red blood cell (RBC) and iron deficiency indices in pulsatile VAD (P-VAD) and continuous-flow VAD (CF-VAD) were evaluated. Anemia, iron deficiency, and iron therapy regimens were identified. Seventy-six VAD implants in 74 patients were included: 45 P-VAD and 31 CF-VAD. Overall, 48% (36/75) of patients were anemic at VAD implant, with 67% of CF-VAD and 34% of P VAD affected. Iron deficiency was seen in 52% (39/75) of patients at implant (similar in both groups). At explant, 71% (53/75) had anemia (similar in both groups). No patients had microcytosis. Iron supplementation was given to 20 patients, with four receiving target replacement therapy (2-6 mg/kg/d * 90 days). Red blood cell transfusion volumes were higher for P-VAD versus CF-VAD. We concluded that anemia and iron deficiency are common in pediatric VAD patients. Pulsatile VAD patients tend to develop anemia over the course of VAD support. Lack of microcytosis, likely masked by high RBC transfusions, suggests that specific iron studies are necessary to identify iron deficiency. PMID- 29251634 TI - The Clinical Implication of Transcranial Doppler Detection of Microembolic Signals in Patients with Heartmate II. AB - We aimed to elucidate the clinical relevance of transcranial Doppler (TCD) in the detection of microembolic signals in patients with Heartmate II (HM-II). Twenty patients with HM-II underwent TCD examinations, and microembolic signals were rarely detected in stable patients. However, they were detected in patients with hemolysis and/or thromboembolic events. Further, TCD examination under oxygen inhalation revealed that, both, solid emboli and gaseous emboli exist in patients with HM-II. PMID- 29251635 TI - CE: Oral Care for Head and Neck Cancer Symptom Management. AB - : An evidence-based practice change at a radiation oncology center in a large academic medical center was designed to reduce the severity of oral mucositis in adults receiving radiation treatment for head and neck cancer. In the intervention described, patients were given newly created oral care kits and educational materials to improve their oral hygiene. Evaluations were conducted at three points during the project (before radiation treatment, during week 4 to 5 of treatment, and one month after treatment). At week 4 to 5-when the severity of oral mucositis is expected to peak-patients reported improved oral hygiene practices and reduced oral mucositis severity. The authors conclude that the use of these oral care kits and educational materials lessened the effects of oral mucositis during and after radiation treatment. PMID- 29251637 TI - Biomarker-guided Intervention to Prevent AKI or KDIGO Care Bundle to Prevent AKI in High-risk Patients Undergoing Major Surgery? PMID- 29251636 TI - CE: Managing Postoperative Pain. AB - : Acute postoperative pain remains undertreated despite the dramatic increase in opioid prescribing in the United States over the past 20 years. Inadequately relieved postoperative pain may be a risk factor for persistent postoperative pain, chronic pain, and disability. In an effort to promote evidence-based strategies for optimal postoperative pain management, the American Pain Society published a new postoperative pain management guideline in 2016. Its 32 recommendations for interdisciplinary and multimodal postoperative pain management are stratified according to risks and benefits, based on varying levels of evidence. This article aims to help nurses translate the recommendations into clinical practice, while providing the historical context in which the guidelines emerged and describing current events that may affect guideline implementation. PMID- 29251638 TI - Correlation of Reflectance Confocal Microscopy and Dermatopathology Findings in a Case of Acrodermatitis Chronica Atrophicans. AB - Acrodermatitis chronica atrophicans (ACA) that is characterized by thin, papery dry, translucent, and alopecic patches with visible superficial veins is a late cutaneous manifestation of Lyme borreliosis. Clinical findings, a history of exposure to tick bite, and serology are helpful for the diagnosis of ACA and sometimes a biopsy is performed to rule out other infectious or inflammatory processes. In this study, we report reflectance confocal microscopy (RCM) findings in a case of ACA. RCM examination revealed a flattened surface with broadened skin folds, a flattened dermoepidermal junction with few papillae and less bright basal cells and multiple small bright reflecting spots in the dermis. To the best of our knowledge, this is the first description of the RCM findings in this disorder. PMID- 29251639 TI - Mammary Analog Secretory Carcinoma With ETV6 Rearrangement Arising in the Conjunctiva and Eyelid. AB - Mammary analog secretory carcinoma (MASC) of salivary gland is a recently described neoplasm that morphologically and immunohistochemically resembles secretory carcinoma of the breast. Genetically, both of them harbor ETV-6-NTRK-3 fusion rearrangement. One case of primary MASCs arising from the eyelid is reported. The patient was a 52-year-old man. Microscopically, the tumor exhibited nodular aggregation of solid, tubular, and microcystic/macrocystic structures. Characteristic "colloid-like" eosinophilic secretory material was present within intraluminal spaces. Immunohistochemically, the tumor cells were positive for mammaglobin, S-100, STAT5a, vimentin, GCDFP-15, AE1/AE3, EMA, and CK7 and were negative for DOG-1, CK5/6, and SMA. A dual color break-apart fluorescence in situ hybridization probe identified rearrangement of the ETV6 gene locus on chromosome 12. The patient had no history of breast or salivary gland tumor. The tumor was completely excised, and the patient has no evidence of recurrent disease or metastasis after 1-year follow-up. A diagnosis of primary MASC was rendered. MASC has never been reported occurring in ocular region. This type of secretory carcinoma probably originates from sweat glands or accessory lacrimal glands, Wolfring and Krause. This unique case expands the clinicopathologic landscape of MASCs for better characterization of this rare entity. PMID- 29251640 TI - A novel factor X mutation Cys81 by Arg and a reported factor VII polymorphism Arg353 replaced by Gln co-occured in a patient. AB - : Coagulation factor X and factor VII (FVII) are both very important components in blood coagulation. To study the molecular pathogenic mechanism of the inherited factor X and FVII deficiency, the factor X activity (FX:C) and FVII activity were tested with one-stage clotting methods. The factor X antigen and factor FVII antigen were tested with ELISA. All the exons, intron-exon boundaries and 5',3'-flanking regions of F10 and F7 genes were amplified by PCR with direct sequencing. The ClustalX software was used to analyze the conservative property of the mutation sites. The PolyPhen-2 and Sorting Intolerant From Tolerant (SIFT) online bioinformatics softwares were taken to predict whether the point mutation could affect protein function. The software Swiss-pdb Viewer was brought to analyze the impact of mutations on the structure and function of the protein. The thrombin generation tests were applied to evaluate whether there were obstacles in producing thrombin about the mutant protein. The FX:C and FVII activity of the proband were reduced to 35 and 42%, and the factor X antigen and factor FVII antigen were decreased to 43 and 55%, simultaneously. Correspondingly, a FX:Cys81Arg (Cys81 by Arg) mutation and a FVII:Arg353 replaced by Gln polymorphism were detected in the proband. The Cys81 of factor X was conserved among homologous species, but the Arg353 of FVII was not. All softwares analysis results indicated protein features and structures might be affected by the mutation and the polymorphism. And the thrombin generation tests showed that the mutant protein had obstacles in thrombin generation. We identified a FX:Cys81Arg mutation and a FVII:Arg353 replaced by Gln polymorphism in the proband. And they accounted for the decrease of the activity and antigen of factor X and FVII. Of note, the Cys81Arg of factor X was first reported in the world. PMID- 29251641 TI - Effect of the BASIC Examination on Knowledge Acquisition during Anesthesiology Residency. AB - BACKGROUND: The American Board of Anesthesiology recently introduced the BASIC Examination, a component of its new staged examinations for primary certification, typically offered to residents at the end of their first year of clinical anesthesiology training. This analysis tested the hypothesis that the introduction of the BASIC Examination was associated with an acceleration of knowledge acquisition during the residency training period, as measured by increments in annual In-Training Examination scores. METHODS: In-Training Examination performance was compared longitudinally among four resident cohorts (n = 6,488) before and after the introduction of the staged system using mixed effects models that accounted for possible covariates. RESULTS: Compared with previous cohorts in the traditional examination system, the first resident cohort in the staged system had a greater improvement in In-Training Examination scores between the first and second years of clinical anesthesiology training (by an estimated 2.0 points in scaled score on a scale of 1 to 50 [95% CI, 1.7 to 2.3]). By their second year, they had achieved a score similar to that of third-year clinical anesthesiology residents in previous cohorts. The second cohort to enter the staged system had a greater improvement of the scores between the clinical base year and the first clinical anesthesiology year, compared with the previous cohorts. CONCLUSIONS: These results support the hypothesis that the introduction of the BASIC Examination is associated with accelerated knowledge acquisition in residency training and provides evidence for the value of the new staged system in promoting desired educational outcomes of anesthesiology training. PMID- 29251642 TI - L-arginine and Arginase Products Potentiate Dexmedetomidine-induced Contractions in the Rat Aorta. AB - BACKGROUND: The alpha2-adrenergic sedative/anesthetic agent dexmedetomidine exerts biphasic effects on isolated arteries, causing endothelium-dependent relaxations at concentrations at or below 30 nM, followed by contractions at higher concentrations. L-arginine is a common substrate of endothelial nitric oxide synthase and arginases. This study was designed to investigate the role of L-arginine in modulating the overall vascular response to dexmedetomidine. METHODS: Isometric tension was measured in isolated aortic rings of Sprague Dawley rats. Cumulative concentrations of dexmedetomidine (10 nM to 10 MUM) were added to quiescent rings (with and without endothelium) after previous incubation with vehicle, N-nitro-L-arginine methyl ester hydrochloride (L-NAME; nitric oxide synthase inhibitor), prazosin (alpha1-adrenergic antagonist), rauwolscine (alpha2 adrenergic antagonist), L-arginine, (S)-(2-boronethyl)-L-cysteine hydrochloride (arginase inhibitor), N-hydroxy-L-arginine (arginase inhibitor), urea and/or ornithine. In some preparations, immunofluorescent staining, immunoblotting, or measurement of urea content were performed. RESULTS: Dexmedetomidine did not contract control rings with endothelium but evoked concentration-dependent increases in tension in such rings treated with L-NAME (Emax 50 +/- 4%) or after endothelium-removal (Emax 74 +/- 5%; N = 7 to 12). Exogenous L-arginine augmented the dexmedetomidine-induced contractions in the presence of L-NAME (Emax 75 +/- 3%). This potentiation was abolished by (S)-(2-boronethyl)-L-cysteine hydrochloride (Emax 16 +/- 4%) and N-hydroxy-L-arginine (Emax 18 +/- 4%). Either urea or ornithine, the downstream arginase products, had a similar potentiating effect as L-arginine. Immunoassay measurements demonstrated an upregulation of arginase I by L-arginine treatment in the presence of L-NAME (N = 4). CONCLUSIONS: These results suggest that when vascular nitric oxide homeostasis is impaired, the potentiation of the vasoconstrictor effect of dexmedetomidine by L arginine depends on arginase activity and the production of urea and ornithine. PMID- 29251643 TI - Then It Was Dark and Cold. PMID- 29251644 TI - Pharmacodynamics and Pharmacokinetics of Lidocaine in a Rodent Model of Diabetic Neuropathy. AB - BACKGROUND: Clinical and experimental data show that peripheral nerve blocks last longer in the presence of diabetic neuropathy. This may occur because diabetic nerve fibers are more sensitive to local anesthetics or because the local anesthetic concentration decreases more slowly in the diabetic nerve. The aim of this study was to investigate both hypotheses in a rodent model of neuropathy secondary to type 2 diabetes. METHODS: We performed a series of sciatic nerve block experiments in 25 Zucker Diabetic Fatty rats aged 20 weeks with a neuropathy component confirmed by neurophysiology and control rats. We determined in vivo the minimum local anesthetic dose of lidocaine for sciatic nerve block. To investigate the pharmacokinetic hypothesis, we determined concentrations of radiolabeled (C) lidocaine up to 90 min after administration. Last, dorsal root ganglia were excised for patch clamp measurements of sodium channel activity. RESULTS: First, in vivo minimum local anesthetic dose of lidocaine for sciatic nerve motor block was significantly lower in diabetic (0.9%) as compared to control rats (1.4%). Second, at 60 min after nerve block, intraneural lidocaine was higher in the diabetic animals. Third, single cell measurements showed a lower inhibitory concentration of lidocaine for blocking sodium currents in neuropathic as compared to control neurons. CONCLUSIONS: We demonstrate increased sensitivity of the diabetic neuropathic nerve toward local anesthetics, and prolonged residence time of local anesthetics in the diabetic neuropathic nerve. In this rodent model of neuropathy, both pharmacodynamic and pharmacokinetic mechanisms contribute to prolonged nerve block duration. PMID- 29251645 TI - Dopamine D2-receptor Antagonist Droperidol Deepens Sevoflurane Anesthesia. AB - BACKGROUND: Although midbrain dopaminergic pathways are known to contribute to arousal and emergence from anesthesia, few reports exist regarding the anesthetic effects of dopamine D2 receptor antagonism in humans. This study examined the effect of the D2 receptor antagonist droperidol on sevoflurane anesthesia by examining alpha and slow wave electroencephalogram oscillations. METHODS: Forty five patients, age 20 to 60 yr, were enrolled. Frontal electroencephalograms were continuously collected for offline analysis via Bispectral Index monitoring. After induction of anesthesia, end-tidal sevoflurane concentration was deliberately maintained at 1%, and intravenous droperidol (0.05 mg/kg bolus) was administered. Electroencephalogram changes were examined in power spectrum and bicoherence, before and 10 min after droperidol injection, then compared using the Wilcoxon signed-ranks test and/or paired t test. RESULTS: Droperidol significantly augmented the alpha-bicoherence peak induced by sevoflurane from 30.3% (24.2%, 42.4%) to 50.8% (41.7%, 55.2%) (median [25th, 75th percentiles]; P < 0.0001), Hodges-Lehman median difference, 15.8% (11.3 to 21.4%) (95% CI). The frequency of the alpha-bicoherence peak was simultaneously shifted to the lower frequency; from 11.5 (11.0, 13.0) to 10.5 (10.0, 11.0) Hz (median [25th, 75th percentiles], P < 0.0001). Averaged bicoherence in the delta-theta area increased conspicuously from 17.2% (15.6 to 18.7%) to 25.1% (23.0 to 27.3%) (mean [95% CI]; P < 0.0001), difference, 8.0% (6.0 to 9.9%). CONCLUSIONS: Droperidol augments both alpha and delta-theta bicoherences while shifting the alpha-bicoherence peaks to lower frequencies, and enhances the effect of sevoflurane anesthesia on the electroencephalogram via gamma-aminobutyric acid-mediated oscillatory network regulation. PMID- 29251646 TI - Use of Uncrossmatched Erythrocytes in Emergency Bleeding Situations. PMID- 29251648 TI - Smartphone Use by Nurses in Acute Care Settings. AB - The use of smartphones in acute care settings remains controversial due to security concerns and personal use. The purposes of this study were to determine (1) the current rates of personal smartphone use by nurses in acute care settings, (2) nurses' preferences regarding the use of smartphone functionality at work, and (3) nurse perceptions of the benefits and drawbacks of smartphone use at work. An online survey of nurses from six acute care facilities within one healthcare system assessed the use of personal smartphones in acute care settings and perceptions of the benefits and drawbacks of smartphone use at work. Participants (N = 735) were primarily point-of-care nurses older than 31 years. Most participants (98%) used a smartphone in the acute care setting. Respondents perceived the most common useful and beneficial smartphone functions in acute care settings as allowing them to access information on medications, procedures, and diseases. Participants older than 50 years were less likely to use a smartphone in acute care settings and to agree with the benefits of smartphones. There is a critical need for recognition that smartphones are used by point-of care nurses for a variety of functions and that realistic policies for smartphone use are needed to enhance patient care and minimize distractions. PMID- 29251649 TI - Zolpidem Overdose: A Dilemma in Mental Health. AB - Sleeping pills are one of the most common drugs taken by adults when afflicted by insomnia. Adverse effects of pharmacotherapy, however, should not be overlooked, and monitoring is needed to check for an overdose of sleeping pills. We reviewed zolpidem overdose and patient suicide with benefits and disadvantages of pharmacotherapy. Cases of adverse effects concerning the central nervous system, including delirium and hallucination, as well as abnormal behavior during sleep, are commonly reported among patients who have taken zolpidem for more than 1 year. The serious problem of long-term prescription to medication can lead to a higher mortality rate of insomniac patients. An alternative to medication for treating insomnia is cognitive behavioral therapy, which can improve sleeping habits. Cognitive behavioral therapy induces patients to recognize and change the negative thoughts that affect their sleep. Medical providers should be aware of the adverse effects of sleep inducers and provide sufficient information to their patients about them. When establishing treatment plans, they should encourage patients to make the proper decisions and try to reduce the adverse effects of any medication as much as possible. PMID- 29251647 TI - Pretreatment 18F-Fluorodeoxyglucose Positron Emission Tomography Standardized Uptake Values and Tumor Size in Medically Inoperable Nonsmall Cell Lung Cancer Is Prognostic of Overall 2-Year Survival After Stereotactic Body Radiation Therapy. AB - OBJECTIVE: The aim of this study was to determine prognostic value of tumor size and metabolic activity on survival for patients with early stage nonsmall cell lung cancer receiving stereotactic body radiation therapy. METHODS: We retrospectively evaluated the patients who underwent positron emission tomography computed tomography scan before stereotactic body radiation therapy treatment. Tumor diameter, tumor volume, maximum standardized uptake value (SUVmax), standardized uptake value (SUV) average, and SUV volume were obtained. Cox regression analyses were performed to determine the associations between tumor characteristics and survival. RESULTS: The patients with large tumors and high SUVmax have worse survival than patients with small tumors and low SUVmax (hazard ratio [HR] = 3.47, P = 0.007). Patients with small tumors and high SUVmax (HR = 1.80; P = 0.24) and large tumors and low SUVmax (HR = 1.55; P = 0.43) had increased risk of death compared with patients with small tumors and low SUVmax. CONCLUSIONS: Both increased tumor size and metabolic activity are associated with increased risk of death. Combining size and metabolic activity together is superior for predicting 2-year survival and identifying patients for whom survival is statistically worse. PMID- 29251650 TI - Duration of Dual Antiplatelet Therapy in the Post-Acute Coronary Syndrome Patient. AB - BACKGROUND: After acute coronary syndrome, guidelines recommend dual antiplatelet therapy with aspirin and a P2Y12 inhibitor for a period of 12 months for the prevention of secondary cardiovascular events. However, the risk of recurrent ischemic events can persist beyond 12 months, and there has been much debate regarding the benefits of prolonging dual antiplatelet therapy in certain patient populations. PURPOSE: The purpose of this review was to investigate the optimal duration of dual antiplatelet therapy in the post-acute coronary syndrome patient. CONCLUSION: Extended dual antiplatelet therapy has been associated with an increased risk of bleeding, which must be considered along with the anti ischemic benefits of dual antiplatelet therapy when deciding on the optimal treatment duration for individual patients. CLINICAL IMPLICATIONS: Treatment duration must be tailored to the patient after a thorough evaluation of individual ischemic and bleeding risk factors. PMID- 29251651 TI - The robust error meta-regression method for dose-response meta-analysis. AB - AIM: Dose-response meta-analysis has been widely employed in evidence-based decision-making. Currently, the most popular approach is the one or two-stage generalized least squares for trend model. This approach however has some drawbacks, and therefore, we compare the latter with a one-stage robust error meta-regression (REMR) model, based on inverse variance weighted least squares regression and cluster robust error variances for dealing with the synthesis of correlated dose-response data from different studies. METHODS AND RESULTS: We apply both methods to three examples (alcohol and lung cancer, alcohol and colorectal cancer, and BMI and renal cancer). The analysis of the three datasets reveals that the one-stage REMR approach may result in better error estimation and a better visual fit to the data than the generalized least squares approach with the added benefit of not needing to impute covariances from the data. CONCLUSION: The one-stage REMR approach is easily executed in Stata with codes given in this article. We therefore recommend that REMR models be considered for dose-response meta-analysis and suggest further comparison of these two methods in future studies to conclusively determine the benefits and pitfalls of each. PMID- 29251652 TI - Postdischarge Light-Intensity Physical Activity Predicts Rehospitalization of Older Japanese Patients With Heart Failure. AB - PURPOSE: Regular physical activity (PA) is recommended for patients with heart failure (HF). However, the clinical and social characteristics of older HF patients with low-level PA and the impact of light-intensity PA on 6-mo postdischarge adverse cardiovascular events are still unclear. METHODS: Forty-one older patients who had been admitted because of decompensated HF (American College of Cardiology [ACC]/American Heart Association [AHA] HF classification stage C/D: 76 +/- 5 y) were prospectively enrolled. Light-intensity (1.5-2.9 metabolic equivalents [METs]) and moderate-intensity (>=3 METs) PAs were determined by triaxial accelerometry for at least 7 d postdischarge. Six-min walk distance and 36-item Short Form questionnaire (SF-36) score were evaluated at discharge. HF patients were stratified into either the HFPA-high or HFPA-low group according to median daily PA. Twenty-nine older ACC/AHA stage A/B outpatients (HF-risk), who were at risk for HF but no symptoms of HF had developed, also completed these assessments. Clinical predictors for 6-mo postdischarge HF rehospitalization were assessed. RESULTS: HF patients were anemic and less active. HFPA-low patients were less likely to engage in household work, took fewer steps, and had less light and moderate-intensity PA than HFPA high patients. There were no differences in 6-min walk distance, SF-36 score, or left ventricular ejection fraction between HFPA-low and HFPA-high patients. Postdischarge PA, especially light-intensity PA, was independently associated with HF rehospitalization. CONCLUSION: Low volume of PA postdischarge, especially at 1.5 to 2.9 METs, predicts 6-mo postdischarge HF rehospitalization in older HF patients. PMID- 29251653 TI - Static and Dynamic Balance Performance and Balance Confidence in Individuals With and Without Pulmonary Arterial Hypertension. AB - PURPOSE: Assessment of balance performance is important for both diagnostic and therapeutic reasons in clinical practice. Although the ideal exercise prescription is unknown for patients with pulmonary arterial hypertension (PAH), balance training may be effective for this population if they have balance impairments, such as other patients with cardiopulmonary diseases. The present study aimed to evaluate static and dynamic balance performance and balance confidence in individuals with and without PAH. METHODS: Eighteen participants with PAH and 12 apparently healthy volunteers were included in this cross sectional study. Balance performance was assessed by Balance Master System. Static balance performance was assessed by the modified Clinical Test of Sensory Interaction on Balance and unilateral stance test. Limits of stability was used for the assessment of dynamic balance performance. Balance confidence was determined using the Activities Balance Confidence scale. RESULTS: There was no significant difference in age, gender, and body mass index between the 2 groups. There was no significant difference in modified Clinical Test of Sensory Interaction on Balance and unilateral stance variables between the patients and healthy controls. Reaction time (forward), movement velocity (backward), directional control (backward), endpoint excursion (backward), and maximum excursion (backward) variables that were the subgroups of limits of stability were significantly different between the 2 groups (P < .05). Balance confidence was significantly lower in patients with PAH (P < .001). CONCLUSION: This study suggests that although static balance performance was preserved, patients with PAH had decreased dynamic balance performance and balance confidence without a significant fall history compared with healthy controls. PMID- 29251654 TI - 4-Meter Gait Speed Test in Chronic Obstructive Pulmonary Disease: INTERRATER RELIABILITY USING A STOPWATCH. AB - PURPOSE: 4-meter gait speed (4MGS) is increasingly used to assess functional performance in patients with chronic obstructive pulmonary disease. However, the current literature lacks information regarding some technical standards for this test. Therefore, the purpose of this study was to compare and to evaluate the interrater reliability between a stopwatch and video recording used as timing systems for the 4MGS in patients with chronic obstructive pulmonary disease, as well as to verify the interrater reliability between 2 observers measuring the 4MGS time using a manual stopwatch. METHODS: Fifty-one patients performed the 4MGS using 4 different protocols (random order): walking at the usual and maximum speed in a 4-meter course and walking at the same 2 speeds on an 8-m course using a 2-m acceleration zone, a 4-meter timing area, and a 2-m deceleration zone. Gait speed was measured simultaneously using a stopwatch and a video recording. In a subanalysis (n = 24), 2 independent observers timed the 4MGS using a stopwatch. RESULTS: There was no significant difference in comparison between the 2 timing methods (P > .05 for all), and the reliability between video recording and stopwatch was excellent in all 4MGS studied protocols (intraclass correlation coefficient >= 0.91). Moreover, when comparing gait speed measured by 2 observers using a stopwatch, no significant difference was found among all proposed protocols (P > .05 for all), and there was also excellent reliability between the 2 independent observers (intraclass correlation coefficient >= 0.94). CONCLUSION: The stopwatch, a low-cost and feasible tool, is reliable as a timing device for the 4MGS in patients with chronic obstructive pulmonary disease. PMID- 29251655 TI - Moving Pulmonary Rehabilitation Into the Home: A CLINICAL REVIEW. AB - Pulmonary rehabilitation (PR) is the standard of care for persons with chronic, symptomatic lung disease. The availability of PR is limited, particularly in rural areas. In addition, barriers to PR include the lack of transportation, patient inconvenience, inadequate insurance coverage, and cost. Technology has the potential to overcome several barriers to PR by enhancing the availability and uptake of PR principles through the development of technology-supported, home based PR programs. For technology-supported, home-based PR, or telehealth PR, to be effective, key components of traditional PR must be present including appropriate individualized exercise prescription, self-management education, outcome measurements, and patient support. This clinical review summarizes the current practice of PR, describes limitations to the availability of PR, describes key principles that technology should feature to ensure best practices are met, and proposes current and future technology options as an emerging strategy for home delivery of PR and its components. PMID- 29251656 TI - Rhythmic Auditory Music Stimulation Enhances Walking Distance in Patients With Claudication: A FEASIBILITY STUDY. AB - PURPOSE: Patients with claudication have altered gait, characterized by slower pace and shorter stride length, compared with matched controls. Rhythmic auditory music stimulation has been used successfully to reduce symptoms of pain and improve walking ability in patients with neurological gait alterations. The purpose of this study was to test the hypothesis that rhythmic auditory music stimulation via increased tempo and bass would immediately increase total walking distance in patients with claudication compared with music-without rhythm enhancement condition or a no-music condition (standard). METHODS: Fourteen patients with claudication (mean age = 66.1 +/- 7.7 y; ankle-brachial index = 0.63 +/- 17) underwent three 6-min walk tests on the same day in random order. One with music-without rhythm enhancement with the tempo set at the usual walking cadence of the patient, one without music, and one with rhythmically enhanced music with the tempo increased 10 to 15 beats/min above the usual walking cadence of the patient. This increase in tempo is considered imperceptible to the untrained ear. RESULTS: The paired t test indicated an increase in total walking distance by 22.1 +/- 25.4 m (P = .006) during the rhythmic auditory stimulation condition compared with the no-music condition and by 20.7 +/- 24.4 m compared with the music-without enhancement condition (P = .007). Functional claudication distance increased by 40.0 +/- 49.0 m during the rhythmically enhanced music condition (P = .009) compared with the no-music condition. CONCLUSIONS: These results suggest that rhythmic auditory stimulation immediately increases total walking distance in patients with claudication due to peripheral artery disease. This technology may provide a tool for clinicians to use when prescribing exercise, improve motivation, and increase adherence to exercise rehabilitation programs. PMID- 29251657 TI - Transcatheter Aortic Valve Replacement: OPTIMIZING OUTCOMES FOR HEALTHY RECOVERY. AB - Transcatheter aortic valve replacement (TAVR) has been approved in the United States for intermediate and high-risk patients with severe symptomatic aortic stenosis. More than 80 000 TAVR procedures have been performed in the United States and the number is growing every year. Two valve designs are approved in the United States including the balloon expandable Edwards Sapien prosthesis and self-expanding CoreValve prosthesis. The PARTNER trial of the Sapien valve, involving patients who were considered inoperable, reported a 19% absolute risk reduction in mortality compared with medical therapy, with a number needed to treat of 5. Randomized controlled trials in patients with high and intermediate risk of inhospital mortality based on the Society of Thoracic Surgeons score showed noninferiority of TAVR compared with surgical aortic valve replacement. Major complications associated with TAVR include a 2% to 3% risk of stroke at 30 d, 8% to 25% risk of permanent pacemaker implantation depending on valve design, and 6% risk of major vascular complications. There are some concerns regarding valve durability as this technology is extended to younger patients with lower risk. Five-year follow-up data from the initial PARTNER trials noted appropriate valve performance and hemodynamics in survivors; however, longer follow-up is required to assess the true incidence of structural deterioration. Approximately one-third of TAVR patients are transferred to a transitional care facility after TAVR, and more than 50% of the patients are frail. Cardiac rehabilitation has been reported to be safe in post-TAVR patients and was associated with significant improvements in exercise capacity, functional independence, and frailty. PMID- 29251658 TI - A Patient-Centered Antipsychotic Medication Adherence Intervention: Results From a Randomized Controlled Trial. AB - The purpose of this study was to develop and test a patient-centered and sustainable antipsychotic medication adherence intervention. The study design was a randomized controlled trial. Data from 61 patients diagnosed with schizophrenia or schizoaffective disorder were analyzed. The intervention included a checklist of barriers, facilitators, and motivators (BFM) for taking antipsychotic medications. The results of the checklist were summarized and a note was placed in the electronic medical record (EMR) and a hard copy was given to the patient. However, less than half of the BFM progress notes were placed in the EMR before the clinician visit as planned. The intervention significantly improved adherence at 6 months but not at 12 months and the intervention's effect on total Positive and Negative Syndrome Scale scores was not statistically significant. The BFM intervention is promising, but future studies are needed to improve the integration of the BFM intervention into typical clinic workflow. PMID- 29251659 TI - Exercise in the management of knee and hip osteoarthritis. AB - PURPOSE OF REVIEW: This review focuses on studies published during July 2001 to August 2017 of exercise as an intervention in knee and hip osteoarthritis, including its influence on an array of patient outcomes. RECENT FINDINGS: Studies continue to illustrate the efficacy of exercise in treating and managing osteoarthritis, with current literature more focused on the knee compared with the hip joint. Both traditional (e.g. strength, aerobic, flexibility) and more nontraditional (e.g. yoga, Tai Chi, aquatic) training modes improve patient outcomes related to joint symptoms, mobility, quality of life, psychological health, musculoskeletal properties, body composition, sleep, and fatigue. Exercise that is adequately dosed (e.g. frequency, intensity) and progressive in nature demonstrated the greatest improvements in patient outcomes. Supervised, partially supervised, and nonsupervised interventions can be successful in the treatment of osteoarthritis, but patient preference regarding level of supervision and mode of exercise may be key predictors in exercise adherence and degree of outcome improvement. A topic of increasing interest in osteoarthritis is the supplementary role of behavior training in exercise interventions. SUMMARY: Osteoarthritis is a complex, multifactorial disease that can be successfully managed and treated through exercise, with minimal risk for negative consequences. However, to have greatest impact, appropriate exercise prescription is needed. Efforts to achieve correct exercise doses and mitigate patient nonadherence are needed to lessen the lifelong burden of osteoarthritis. PMID- 29251661 TI - New urate-lowing therapies. AB - PURPOSE OF REVIEW: To discuss recent studies of lesinurad and arhalofenate. RECENT FINDINGS: Lesinurad acts by blocking urate reabsorption channels URAT-1 and OAT-4. It has urate-lowering effect when used alone and in combination with xanthine oxidase inhibitors (XOIs). Its uricosuric activity depends on glomerular filtration, and its' efficacy is impaired at eGFR less than 30 ml/min. Lesinurad monotherapy (400 mg/day) associates with serum creatinine elevations. However, this risk is substantially attenuated with coprescription of a XOI and when prescribed at a dose of 200 mg/day. Given its' modest urate-lowering effect, and the risk of serum creatinine elevation when used alone, it is licenced for use in combination with XOI for people unable to achieve target serum uric acid with XOI alone. Lesinurad does not have the drug interactions associated with probenecid, however, it is metabolized by CYP2C9, and should be used with caution if CYP2C9 inhibitors are coprescribed. Arhalofenate also acts by blocking URAT-1; however, it also blocks the NALP-3 inflammasome providing gout-specific anti-inflammatory effect. Arhalofenate has a weaker urate-lowering effect than lesinurad and further phase III evaluation is planned. SUMMARY: Lesinurad provides an additional option for people with gout unable to achieve target serum uric acid with XOI alone. PMID- 29251660 TI - Epidemiology of systemic lupus erythematosus: an update. AB - PURPOSE OF REVIEW: Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease with a significant disease burden across the world among different ethnic, racial, and age groups. The pathophysiological understanding of SLE is constantly evolving and with it, the need for a better definition of the disease itself, for understanding the risk among the different affected populations, and for identifying the factors responsible for the damage accrual through the years. RECENT FINDINGS: More accurate estimates of incidence and prevalence of SLE among different ethnicities and minority groups not only in the USA, but also in Europe, Middle East, and Asia have provided new insights into the disease burden around the world. Despite advances in treatment, mortality among SLE patients remains high with significant ethnic and geographic variations. SUMMARY: Sex, race, and ethnicity significantly affect SLE incidence, prevalence, and mortality. PMID- 29251662 TI - What's New in SHOCK, January 2018? PMID- 29251664 TI - LONG-TERM OBSERVATION OF MULTIFOCAL METASTATIC INTRAOCULAR CARCINOID WITH ACQUIRED IRIS HETEROCHROMIA. AB - BACKGROUND/PURPOSE: To report a unique case of a pulmonary carcinoid tumor unilaterally metastatic to the iris and ciliary body and bilaterally to the choroid that was conservatively followed. METHODS: A 46-year-old woman presented with bilateral choroidal lesions and a left iris tumor. Ultrasound biomicroscopy disclosed a ciliary body component. A diagnosis of metastatic carcinoid tumor was made based on the clinical features. Rather than an excision, photodynamic therapy, or radiation treatment, as has been reported in all previous cases of carcinoid tumor metastatic to the iris, the patient was observed. RESULTS: Excellent vision was maintained for 8 years. The iris tumor gradually enlarged, but the choroidal lesions remained unchanged. The iris with the carcinoid tumor gradually acquired a brown pigmentation; this is the first reported case of acquired iris heterochromia in the setting of carcinoid tumor. CONCLUSION: We conclude, in cases of metastatic carcinoid in which visual acuity is excellent and the patient is asymptomatic, that observation of the ocular lesions is an acceptable course of action. The iris heterochromia is believed to have been caused by secretory factors produced by the tumor. PMID- 29251665 TI - Molecular pathology of lung cancer: current status and perspectives. AB - PURPOSE OF REVIEW: In this article, we summarize the current knowledge on molecular alterations in lung cancer that are targets for therapy, and provide an outlook on the future development of molecular pathology in precision oncology. RECENT FINDINGS: Lung cancer has become a paradigm for the success of molecular targeted therapies in solid tumors. Tyrosine kinase inhibitors are effective treatment options in adenocarcinoma patients with an EGFR, ALK, ROS1 or B-Raf Proto-Oncogene, Serine/Threonine kinase mutation. Additional molecular targets that are addressed in clinical trials include ERBB2, MET, RET, NTRK1 and FGFR. Therapies with antibodies that block the interaction of PD-L1 with PD-1 and thereby liberate an antitumor immune response have introduced a new era in cancer therapy with impressive therapeutic benefits. The high financial burden, treatment failures and therapeutic side effects of immunotherapies have prompted a search for biomarkers beyond PD-L1 expression, for example, tumor mutation load or immune cell profiling, that might more reliably identify patients that are likely to respond. SUMMARY: The discoveries of cancer research have been translated into the clinical management of lung cancer patients. So far, the approach of targeted therapy that is directed towards certain molecular alterations in a given tumor has been successful for adenocarcinomas, but not yet for squamous or small cell carcinomas. Further clinical progress will require a better understanding of the molecular interactions within cancer cells that will subsequently enable innovative drug designs. Diagnostic molecular pathology will be a provider of information on a tumor's features and thus, navigate precision cancer therapy. PMID- 29251663 TI - Pain or nociception? Subjective experience mediates the effects of acute noxious heat on autonomic responses. AB - Nociception reliably elicits an autonomic nervous system (ANS) response. Because pain and ANS circuitry interact on multiple spinal, subcortical, and cortical levels, it remains unclear whether autonomic responses are simply a reflexive product of noxious stimulation regardless of how stimulation is consciously perceived or whether the experience of pain mediates ANS responses to noxious stimulation. To test these alternative predictions, we examined the relative contribution of noxious stimulation and individual pain experience to ANS responses in healthy volunteers who underwent 1 or 2 pain assessment tasks. Participants received 8 seconds of thermal stimulation of varied temperatures and judged pain intensity on every trial. Skin conductance responses and pupil dilation responses to stimulation served as measures of the heat-evoked autonomic response. We used multilevel modelling to examine trial-by-trial relationships between heat, pain, and ANS response. Although both pain and noxious heat stimulation predicted skin conductance response and pupil dilation response in separate analyses, the individual pain experience statistically mediated effects of noxious heat on both outcomes. Furthermore, moderated mediation revealed that evidence for this process was stronger when stimulation was perceived as painful compared with when stimulation was perceived as nonpainful. These findings suggest that pain appraisal regulates the heat-evoked autonomic response to noxious stimulation, documenting the flexibility of the autonomic pain response to adjust to perceived or actual changes in environmental affordances above and beyond nociceptive input. PMID- 29251666 TI - Advanced PET imaging in oncology: status and developments with current and future relevance to lung cancer care. AB - PURPOSE OF REVIEW: This review highlights the status and developments of PET imaging in oncology, with particular emphasis on lung cancer. We discuss the significance of PET for diagnosis, staging, decision-making, monitoring of treatment response, and drug development. The PET key advantage, the noninvasive assessment of functional and molecular tumor characteristics including tumor heterogeneity, as well as PET trends relevant to cancer care are exemplified. RECENT FINDINGS: Advances of PET and radiotracer technology are encouraging for multiple fields of oncological research and clinical application, including in depth assessment of PET images by texture analysis (radiomics). Whole body PET imaging and novel PET tracers allow assessing characteristics of most types of cancer. However, only few PET tracers in addition to F-fluorodeoxyglucose have sufficiently been validated, approved, and are reimbursed for a limited number of indications. Therefore, validation and standardization of PET parameters including tracer dosage, image acquisition, post processing, and reading are required to expand PET imaging as clinically applicable approach. SUMMARY: Considering the potential of PET imaging for precision medicine and drug development in lung and other types of cancer, increasing efforts are warranted to standardize PET technology and to provide evidence for PET imaging as a guiding biomarker in nearly all areas of cancer treatment. PMID- 29251667 TI - Procalcitonin and Presepsin as Prognostic Markers After Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: Patients resuscitated from cardiac arrest commonly develop an inflammatory response called post-cardiac arrest syndrome that clinically resembles septic shock.Procalcitonin and presepsin are associated with inflammation. We hypothesized that these biomarkers reflect the severity of post cardiac arrest syndrome and predict short-term hemodynamical instability and long term neurological outcome after cardiac arrest. METHODS: As a subcohort analysis of a prospective, observational, multicenter study "FINNRESUSCI," we obtained plasma from 277 intensive care unit (ICU) patients treated following out-of hospital cardiac arrest (OHCA). Procalcitonin and presepsin levels were measured 0 to 6 h from ICU admission and 24, 48, and 96 h thereafter. We defined poor outcome as a 12-month Cerebral Performance Category of 3 to 5. We tested statistical associations between biomarkers and hemodynamical parameters and outcome with regression models. RESULTS: Plasma procalcitonin had best predictive value for 12-month poor outcome at 96 h (AUC 0.76; 95% CI 0.68-0.83) and presepsin at ICU admission (AUC 0.72; 95% CI 0.65-0.78). Elevated procalcitonin concentration at ICU admission predicted unstable hemodynamics in the following 48 h in a linear regression model. In a multivariate logistic regression model with clinical variables, only procalcitonin at 96 h had independent prognostic value for poor 12-month neurological outcome. CONCLUSIONS: Elevated procalcitonin is associated with hemodynamical instability and worsened long-term outcome in OHCA patients. The association is not strong enough for it to be used as a single predictor. Presepsin did not provide clinically relevant information for risk stratification after OHCA. PMID- 29251668 TI - Perioperative Fluid Accumulation Impairs Intestinal Contractility to a Similar Extent as Peritonitis and Endotoxemia. AB - BACKGROUND: Perioperative resuscitation with large amounts of fluid may cause tissue edema, especially in the gut, and thereby impairing its functions. This is especially relevant in sepsis where capillaries become leaky and fluid rapidly escapes to the pericapillary tissue. We assessed the effects of endotoxemia and peritonitis, and the use of high and moderate volume fluid resuscitation on jejunal contractility. We hypothesized that both endotoxemia and peritonitis impair jejunum contractility and relaxation, and that this effect is aggravated in peritonitis and with high fluid administration. METHODS: Pigs were randomized to endotoxin (n = 16), peritonitis (n = 16), or sham operation (n = 16), and either high (20 mL/kg/h) or moderate volume (10 mL/kg/h) fluid resuscitation for 24 h or until death. At the end of the experiment, jejunal contractility and relaxation were measured in vitro using acetylcholine and sodium nitroprusside reactivity, and the effect of nitric oxide synthase inhibition (NOS-I) was assessed. RESULTS: Mortality in the respective groups was 88% (peritonitis high), 75% (endotoxemia high), 50% (peritonitis moderate), 13% (endotoxemia moderate and sham operation high), and 0% (sham operation moderate volume resuscitation). Although gut perfusion was preserved in all groups, jejunal contractility was impaired in the two peritonitis and two endotoxemia groups, and similarly also in the sham operation group treated with high but not with moderate volume fluid resuscitation (model-fluid-contraction-interaction, P = 0.036; maximal contractility 136 +/- 28% [average of both peritonitis, both endotoxemia and sham operation high-volume groups) vs. 170 +/- 74% of baseline [sham operation moderate-volume group]). NOS-I reduced contractility (contraction-inhibition interaction, P = 0.011) without significant differences between groups and relaxation was affected neither by peritonitis and endotoxemia nor by the fluid regimen. CONCLUSIONS: Intestinal contractility is similarly impaired during peritonitis and during endotoxemia. Moreover, perioperative high-volume fluid resuscitation in sham-operated animals also decreases intestinal contractility. This may have consequences for postoperative recovery. PMID- 29251669 TI - Noninvasive Assessment of Intra-Abdominal Pressure Using Ultrasound-Guided Tonometry: A Proof-of-Concept Study. AB - BACKGROUND: Intra-abdominal hypertension jeopardizes abdominal organ perfusion and venous return. Contemporary recognition of elevated intra-abdominal pressure (IAP) plays a crucial role in reducing mortality and morbidity. We evaluated ultrasound-guided tonometry in this context hypothesizing that the vertical chamber diameter of this device inversely correlates with IAP. METHODS: IAP was increased in six 5 mmHg steps to 40 mmHg by instillation of normal saline into the peritoneal cavity of eight anesthetized pigs. Liver and renal blood flows (ultrasound transit time), intravesical, intraperitoneal, and end-inspiratory plateau pressures were recorded. For ultrasound-based assessment of IAP (ultrasound-guided tonometry), a pressure-transducing, compressible chamber was fixed at the tip of a linear ultrasound probe, and the system was applied on the abdominal wall using different predetermined levels of external pressure. At each IAP level (reference: intravesical pressure), two investigators measured the vertical diameter of this chamber. RESULTS: All abdominal flows decreased (by 39% 58%), and end-inspiratory plateau pressure increased from 15 mbar (14-17 mbar) to 38 mbar (33-42 mbar) (median, range) with increasing IAP (all P < 0.01). Vertical chamber diameter decreased from 14.9 (14.6-15.2) mm to12.8 (12.4-13.4) mm with increasing IAP. Coefficients of variations between and within observers regarding change of the vertical tonometry chamber diameter were small (all <4%), and the results were independent of the externally applied pressure level on the ultrasound probe. Correlation of IAP and vertical pressure chamber distance was highly significant (r = -1, P = 0.0004). Ultrasound-guided tonometry could discriminate between normal (baseline) pressure and 15 mmHg, between 15 and 25 mmHg) and between 25 and 40 mmHg IAP (all P <= 0.18). Similar results were obtained for end-inspiratory plateau pressures. CONCLUSIONS: In our model, values obtained by ultrasound-guided tonometry correlated significantly with IAPs. The method was able to discriminate between normal, moderately, and markedly increased IAP values. PMID- 29251670 TI - The road to 11th edition of the International Classification of Diseases: trajectories of scientific consensus and contested science in the classification of intellectual disability/intellectual developmental disorders. AB - PURPOSE OF REVIEW: To increase the expert knowledge-base on intellectual developmental disorders (IDDs) by investigating the typology trajectories of consensus formation in the classification systems up to the 11th edition of the International Classification of Diseases (ICD-11). This expert review combines an analysis of key recent literature and the revision of the consensus formation and contestation in the expert committees contributing to the classification systems since the 1950s. RECENT FINDINGS: Historically two main approaches have contributed to the development of this knowledge-base: a neurodevelopmental clinical approach and a psychoeducational-social approach. These approaches show a complex interaction throughout the history of IDD and have had a diverse influence on its classification. Although in theory Diagnostic and Statistical Manual (DSM)-5 and ICD adhere to the neurodevelopmental-clinical model, the new definition in the ICD-11 follows a restrictive normality approach to intellectual quotient and to the measurement of adaptive behaviour. On the contrary DSM-5 is closer to the recommendations made by the WHO 'Working Group on Mental Retardation' for ICD-11 for an integrative approach. SUMMARY: A cyclical pattern of consensus formation has been identified in IDD. The revision of the three major classification systems in the last decade has increased the terminological and conceptual variability and the overall scientific contestation on IDD. PMID- 29251671 TI - Heart failure following oncological treatment. AB - PURPOSE OF REVIEW: The aim of this review is to give the reader an up-to-date overview of the progress made in the burgeoning field of cardio-oncology, encompassing oncological treatments conferring risk, prediction strategies to identify patients at risk, imaging and biomarker monitoring for emergent or subclinical toxicity and prevention in primary and secondary settings with a focus on heart failure. RECENT FINDINGS: The rapid recent advances in cancer management, particularly with the expansion of targeted and immunotherapies, have led to substantial improvements in outcome, but have also added to the potential causes of cardiac toxicity, which can lead to heart failure. Against this, there has been progression in the field of imaging for cardiac toxicity, identification of at-risk individuals and the clarification of the role of therapy for prevention and treatment of cardiac toxicity. SUMMARY: The findings described in this review provide guidance to clinicians in order to direct monitoring strategy and therapy choice, both in the individual with preexisting cardiac comorbidities and in those predicted to be at the highest risk of cardiac toxicity wherever therapy elements carrying cardiac risk are considered oncologically appropriate. PMID- 29251672 TI - The role of omadacycline in skin and soft tissue infections. AB - PURPOSE OF REVIEW: Skin and soft tissue infections (SSTIs) are among the most frequent infections, contributing to significant morbidity and healthcare costs. Although numerous antibiotics are available for this indication, several medical needs remain unmet, especially for treating methicillin-resistant Staphylococcus aureus (MRSA) or mixed infections. This review summarizes the results achieved in the development of omadacycline, a new aminomethylcycline, which could have useful properties for the treatment of SSTIs. RECENT FINDINGS: The antimicrobial activity of omadacycline against the micro-organisms most frequently cultured in SSTIs has been confirmed in worldwide panels of clinical isolates, including MRSA, Gram-negative aerobes and some anaerobes. Pharmacokinetic data demonstrate interesting characteristics, allowing intravenous and oral administration. The Phase 3 OASIS-1 trial assessed the clinical efficacy and safety of omadacycline versus linezolid in SSTIs and demonstrated noninferiority and a good safety profile especially with regard to gastrointestinal effects. Analyses of subgroups of patients from this trial showed similar activity to that of the comparator drug, good safety and no dosage adjustments for age, sex or hepatic or renal impairment. SUMMARY: Because of its microbiological activities and pharmacokinetic profile, omadacycline may be particularly suitable for the treatment of SSTIs, whether managed in hospital or on an outpatient basis. PMID- 29251673 TI - Recent epidemiology of sexually transmissible enteric infections in men who have sex with men. AB - PURPOSE OF REVIEW: Sexual transmission of enteric pathogens in men who have sex with men (MSM) has been described since the 1970s. Recently, an increasing number of enteric infection outbreaks have been reported in MSM. This article summarizes recent outbreaks and discusses the key issues for prevention and control. RECENT FINDINGS: Sexually transmissible enteric infections (STEIs) can spread rapidly and internationally within highly connected MSM populations and are often associated with antimicrobial resistance (AMR). The infections often cluster in high-risk groups of HIV-positive MSM who are more likely to engage in diverse sexual practices and chemsex, and to have multiple other sexually transmitted infections (STIs). SUMMARY: The roles of asymptomatic and/or persistent infection and other contextual factors in STEI transmission are not well described. STEI associated AMR is increasing and has potential to spread rapidly in MSM, warranting further public health attention. A better understanding of the factors associated with sexual transmission will enable the development of more effective control measures. A holistic approach that promotes health and wellbeing as well as infection prevention and management is needed. PMID- 29251674 TI - The prevalence of occult leiomyosarcoma in women undergoing presumed fibroid surgery and outcomes after morcellation. AB - PURPOSE OF REVIEW: To review the data-derived prevalence rates for occult leiomyosarcoma (LMS), and outcomes for women who have these tumors inadvertently morcellated. RECENT FINDINGS: In 2014, the Food and Drug Administration presented data showing the prevalence rates of occult LMS at 2.02/1000 surgeries for presumed benign fibroids. They also attributed poorer outcomes for women undergoing power morcellation of these tumors. Two more recent meta-analyses have shown much lower rates, as low as one in 8300 surgeries when including only prospective studies, and one in 1428 surgeries when including both prospective and retrospective studies. When looking at outcomes, both studies show no difference in outcomes when comparing power or any other type of morcellation. The most recent data suggest that even intact removal has no advantage when looking at mortality rates. SUMMARY: Prevalence of occult LMS remains quite rare, but outcomes after intact removal or any type of morcellation appear to be no different. PMID- 29251675 TI - Hormone receptor positive breast cancer: state of the art. AB - PURPOSE OF REVIEW: Hormone receptor (HR) positive breast cancer represents the vast majority of breast cancer cases. Treatment for these patients has been 5 years of endocrine therapy in the localized setting and endocrine therapy alone in the metastatic setting until progression of disease and switch to chemotherapy until quite recently. RECENT FINDINGS: The current article will review recent data on role of extended endocrine therapy with tamoxifen and aromatase inhibitors and adjuvant bisphosphonates in the localized disease setting. It will then review the role of targeted agents such as cyclin dependent kinases 4/6 inhibitors, two of which were FDA approved in 2017 in the metastatic setting and are now standard of care. SUMMARY: Landscape of HR positive breast cancer is changing with doubling of progression-free survival with drugs approved in the last 2 years. Although antiestrogen therapy remains the backbone of therapy, we are continuing to improve outcome for patients by changes and additions to this therapy. PMID- 29251676 TI - Frontline therapy of ovarian cancer: trials and tribulations. AB - PURPOSE OF REVIEW: The current article reviews the advances and challenges in the fight with cancer and the hope for cure, with a focus on clinical trials, at the one time with the best outcomes; first-line therapy. RECENT FINDINGS: To date there have been four great stories that bridge inception to development of new drugs in ovarian cancer: Serendipitous insight into the role of platinum, discovery of taxanes, understanding the microenvironment and angiogenesis, and following the science in the development of Poly (ADP-Ribose) Polymerase (PARP) inhibitors. There is a fundamental difference between overall survival (OS), simply living longer; and eradicating disease, cure. The scientific underpinning of both our understanding and the recent developments encourages an optimistic view of the remaining hurdles. SUMMARY: There has been an unprecedented explosion in the number of new drugs approved for the treatment of ovarian cancer with three new classes of agent, and five new drugs receiving food and drug administration approval in the last 3 years (Fig. 2). Getting the right drug truly transforms patients' experience with the seminal event being the development of imatinib in CML. In 1980, an average patient would have lived only 3 years, and now they only live 3 years less than a full lifespan [Bower et al. (2016). J Clin Oncol 34:2851]. PMID- 29251677 TI - Indications for morcellation in gynecologic surgery. AB - PURPOSE OF REVIEW: Minimally invasive gynecologic procedures, in particular laparoscopic hysterectomy and myomectomy, often require tissue morcellation. RECENT FINDINGS: Whether morcellated or not, myometrial cells can be found in the abdomen and pelvis after either laparoscopic or open myomectomy. Following morcellation, careful inspection for and removal of tissue fragments and copious irrigation and suctioning of fluid can remove residual tissue and cells without the use of containment bags. The dogma of not 'cutting-through' cancer is not correct for many surgical specialties and irrelevant with regards to leiomyosarcoma (LMS) and minimally invasive gynecologic surgery. Eliminating residual disease in the pelvis and abdomen should be the goal of myomectomy or hysterectomy. SUMMARY: Morcellation of excised tissue is necessary for many women with symptomatic fibroids who choose to undergo laparoscopic myomectomy or hysterectomy. LMS is an uncommon disease, with a poor prognosis due to early hematogenous metastasis to lung, bone and liver. Preoperatively, it is often difficult to differentiate from benign fibroids. LMS has a high propensity for local recurrence despite performance of total hysterectomy. Efforts to remove all tissue and cells from the pelvis and abdomen should be the goal of minimally invasive surgery with morcellation. PMID- 29251678 TI - Novel poly-ADP-ribose polymerase inhibitor combination strategies in ovarian cancer. AB - PURPOSE OF REVIEW: The recent United States Food and Drug Administration approvals of niraparib and olaparib as maintenance monotherapy for platinum sensitive, high-grade ovarian cancers independent of BRCA status reflect a willingness to seek indications for poly-ADP-ribose polymerase (PARP) inhibitors beyond cancers with deleterious breast cancer 1 and breast cancer 2 mutations. In this review, I describe the rationale behind current PARP combination clinical trials with chemotherapies, angiogenesis inhibitors, cell cycle checkpoint inhibitors, and inhibitors of the phosphoinositide 3-kinase/AK thymoma/mechanistic target of rapamycin pathway. RECENT FINDINGS: PARP inhibitors have primarily been studied as monotherapy in cancers with homologous recombination repair defects based on an early understanding of PARP-1 as a base excision repair enzyme and the idea that abrogation of two DNA repair pathways cripples rapidly dividing cancer cells. It is now known that PARP-1 is a DNA damage sensor with much wider reaching roles in DNA repair processes and normal cellular functions, opening possibilities for PARP inhibitor use in other clinical contexts. SUMMARY: PARP inhibitor combination clinical trials are in the early stages, but will deepen our understanding of DNA repair mechanisms, cancer biology, and targeted therapies, thus contributing to the next iteration of therapeutic options for our patients. PMID- 29251679 TI - Morcellation in gynecologic oncology. AB - PURPOSE OF REVIEW: Morcellation of uteri with unsuspected malignancies has been the focus of reports for decades. More intensive evaluation of clinical outcomes and evaluation of impact of changes in practice has occurred since the release of FDA statement advising against the use of power morcellators. The review summarizes some of the most relevant publications on this topic. RECENT FINDINGS: The Society of Gynecologic Oncology and the American College of Obstetricians and Gynecologists concur that symptomatic women should undergo appropriate evaluation, morcellation should not be performed whenever malignancy is suspected or diagnosed, and acknowledge the limitations of diagnostic testing currently available to detect leiomyosarcoma. Accurate incidence of occult leiomyosarcoma in women undergoing hysterectomy for symptomatic myomas is not known because of poor quality of data. Increased complication rates, including death, with abdominal procedures and increased societal costs have been reported. The FDA safety communication has resulted in decreased laparoscopic hysterectomy rates. SUMMARY: Clinical judgement and practice in accordance to clinical guidelines, based on best current scientific evidence, is recommended. Women should be aware of the limitation of current data regarding the incidence of occult leiomyosarcoma or other malignancies whenever consenting to any form of therapy for symptomatic myomas, including surgical, medical and expectant management. If surgical treatment is selected, morcellation should not be performed if a malignancy diagnosis is known or suspected. A minimally invasive surgical approach is associated with a decreased complication rate and an increased quality of life years. Research efforts should focus on improving diagnostic accuracy and efficacy of therapeutic interventions. PMID- 29251680 TI - Iranian Women's Breast Health-Seeking Behaviors: Husband's Role. AB - BACKGROUND: Breast cancer has become the most common cancer among Yazdi women in Iran. Thus, it is necessary to encourage these women to participate in breast health-seeking behaviors. In this regard, husbands can play an effective role. OBJECTIVE: The aim of this study was to explore women's perceptions about the effect of their husband's role on breast health-seeking protection motivation. METHODS: This study used a directed qualitative content analysis approach based on the Protection Motivation Theory. Participants were selected using purposive sampling; in-depth semistructured interviews with 14 Yazdi women were completed. RESULTS: One major category named "motivator role of husband" emerged from the analysis. The following subcategories underlying this category were "indifference and a lack of support as long as the women can continue with expected duties," "what women want for support," "facilitating and restrictive factors of husband's supportive role," "public health education needed," and "husband's agreement with preventive actions." CONCLUSIONS: Voluntary participation in breast health seeking behaviors is a culturally sensitive topic. The qualitative methodology allowed this sensitive topic and its different aspects to be explored. The findings indicated that the major source of support for women was their husband's behavior toward breast health-seeking actions. Family cohesion and love among couples were identified as strong determinant factors pertaining to husband's supportive behaviors. IMPLICATIONS FOR PRACTICE: The study findings provided deeper understanding about the effective factors related to a husband's role in motivating a wife to practice breast cancer prevention. These new findings are relevant for health educators and practitioners to develop culturally based interventions. PMID- 29251681 TI - Rising Rates of Contralateral Prophylactic Mastectomy as a Treatment for Early Stage Breast Cancer. AB - BACKGROUND: The rate of contralateral prophylactic mastectomy (CPM) in women with unilateral mastectomy is increasing with no plateau. OBJECTIVES: The aim of this study was to improve the understanding of patient- and tumor-related factors that influenced the choice of mastectomy with CPM as treatment for early-stage breast cancer at an academic medical center in New Jersey. METHODS: This was a retrospective analysis of 10 years of breast cancer data including 1556 women aged 40 to 80 years treated for breast cancer at an academic medical center. Logistic regression models identified possible associations between type of surgery and various patient- and tumor-related characteristics. RESULTS: Women most likely to be treated with CPM were younger (P < .0001), white (P = .003), and privately insured (P < .0001). Factors that increased the odds of receiving CPM included year of surgery (odds ratio, 1.441; confidence interval, 1.328 1.564) and residing in a relatively wealthy community (odds ratio, 11.159; confidence interval, 3.467-35.917). CONCLUSIONS: The rate of CPM as a treatment for unilateral breast cancer continues to rise, and this treatment decision seems to be relatively independent of tumor-related factors and clinical evidence of efficacy. More research is needed to ascertain why women are choosing this surgical option. IMPLICATIONS FOR PRACTICE: The large majority who are choosing CPM are doing so regardless of the lack of clinical efficacy, yet there are few articles in the nursing literature preparing nurses to understand and counsel these women who may be asking for advice. Nurses are well situated to provide unbiased and fact-based information to help women making potentially life altering decisions in response to a cancer diagnosis. PMID- 29251683 TI - Menopause 25th anniversary: past success and future direction. PMID- 29251682 TI - Follow the Yellow Brick Road: Self-management by Adolescents and Young Adults After a Stem Cell Transplant. AB - BACKGROUND: Stem cell transplant (SCT) is a major life event that can have long term psychosocial consequences for the entire family. It is unknown the degree to which the psychosocial characteristics associated with SCT influence self management behaviors and health outcomes in adolescents and young adults (AYAs). OBJECTIVE: The study had the following aims: (1) to describe how AYAs manage their care regimen post-SCT and (2) to explore self-management facilitators, barriers, processes, and behaviors within individual, family, community, and healthcare system domains. INTERVENTIONS/METHODS: A grounded theory study was conducted to understand the process AYAs use to manage their care after SCT. Semistructured individual interviews were conducted, digitally recorded, and transcribed verbatim. Data were coded to consensus and analyzed using constant comparison methods. RESULTS: A sample of 17 AYAs (13-25 years old at transplant) and 13 caregivers (dyads) participated in the study. Initially, the participants experienced a tornado of activities, information, and emotions. Support from family, friends, and healthcare providers empowered families to manage their care, maintain a positive attitude, and approach a "normal" life. CONCLUSIONS: Monotony, managing symptoms, and isolation were the hardest obstacles for AYAs throughout the process. Families discussed managing their care activities by developing routines that got easier with time. IMPLICATIONS FOR PRACTICE: Nurses play an instrumental role in AYA self-management practices by providing information, education, and social support. Psychosocial issues were prominent in the self-management process and should be addressed in future research and interventions with AYAs and caregivers. PMID- 29251684 TI - Editorial. PMID- 29251685 TI - A New Condition in McArdle Disease: Poor Bone Health-Benefits of an Active Lifestyle. AB - INTRODUCTION-PURPOSE: McArdle disease (muscle glycogen phosphorylase deficiency) is a genetic condition associated with exercise intolerance, but how it affects lean mass (LM) and bone mineral content (BMC) and density (BMD) in patients is unknown. We compared these variables between McArdle patients and age-/sex matched healthy controls and assessed their potential association with physical activity levels in patients. METHODS: A case-control, cross-sectional design was used to examine LM, BMC, and BMD by using dual-energy x-ray absorptiometry in 136 young adults of both sexes (36 McArdle patients (33 +/- 15 yr) and 103 controls (34 +/- 11 yr)). Physical activity was assessed using the International Physical Activity Questionnaire. RESULTS: McArdle patients had significantly lower LM values in whole-body and regional sites compared with their corresponding controls, whereas no differences were found (except for the trunk) when physically active patients (n = 23) were compared with controls. All bone-related variables were significantly lower in patients than in controls (average difference of 13% for BMC and 7.6% for BMD). By contrast, no significant differences at the lumbar spine, pelvis, and femur sites were found between physically active patients and controls. CONCLUSIONS: We report on a previously undescribed condition in McArdle patients, poor bone health, which warrants further attention because it can occur in relatively young adults. An active lifestyle can at least partly alleviate this disorder presumably because of its beneficial effect on LM. PMID- 29251686 TI - Nil Whey Protein Effect on Glycemic Control after Intense Mixed-Mode Training in Type 2 Diabetes. AB - : Although intense endurance and resistance exercise training and whey protein supplementation have both been shown to independently improve glycemic control, no known studies have examined the effect of high-intensity mixed-mode interval training (MMIT) and whey supplementation in adults with Type 2 diabetes (T2D). PURPOSE: This study aimed to determine if peritraining whey protein supplementation combined with MMIT can improve glycemic control. METHODS: In a double-blind, randomized, placebo-controlled trial, 24 men (55.7 +/- 5.6 yr) with T2D performed MMIT with whey (20 g) or placebo control for 10 wk. Glycemic control was assessed via glucose disposal rate during a euglycemic insulin clamp, fasting blood glucose concentration, and homeostatic model assessment of insulin resistance. Changes in peak oxygen consumption, 1-repetition maximum strength, vastus lateralis muscle, and subcutaneous adipose thicknesses, and waist circumference were also assessed. RESULTS: Ten weeks of MMIT substantially improved glucose disposal rate by 27.5% (90% confidence interval, 1.2%-60.7%) and 24.8% (-5.4% to 64.8%) in the whey and control groups, respectively. There were likely and possible reductions in fasting blood glucose by -17.4% (-30.6% to 1.6%) and homeostatic model assessment of insulin resistance by -14.1% (-25.3% to 1.08%) in the whey group; however, whey effects were not clearly beneficial to glycemic outcomes relative to the control. MMIT also clearly substantially improved 1-repetition maximum by 20.6% (16.3%-24.9%) and 22.7% (18.4%-27.2%), peak oxygen consumption by 22.6% (12.0%-26.2%) and 18.5% (10.5%-27.4%), and vastus lateralis muscle thickness by 18.9% (12.0%-26.2%) and 18.6% (10.5%-27.4%) and possibly reduced waist circumference by -2.1% (-3.1% to -1.0%) and -1.9% ( 3.7% to -0.1%) in the control and whey groups, respectively, but the whey-control outcome was trivial or unclear. CONCLUSIONS: A clinically meaningful enhancement in glycemic control after 10 wk of MMIT was not clearly advanced with peritraining whey protein supplementation in middle-age men with T2D. PMID- 29251687 TI - Implementing Resistance Training in Secondary Schools: A Cluster Randomized Controlled Trial. AB - PURPOSE: Guidelines recommend that young people engage in muscle-strengthening activities on at least 3 d.wk. The purpose of this study was to examine the effect of a school-based intervention focused on resistance training (RT) for adolescents. METHODS: The "Resistance Training for Teens" intervention was evaluated using a cluster-randomized, controlled trial with 607 adolescents (50.1% girls; 14.1 +/- 0.5 yr) from 16 secondary schools. Teachers were trained to deliver the intervention, which included the following: (i) an interactive student seminar; (ii) a structured physical activity program, focused on RT; (iii) lunchtime fitness sessions; and (iv) Web-based smartphone apps. The primary outcome was muscular fitness (MF) and secondary outcomes included body mass index, RT skill competency, flexibility, physical activity, self-efficacy, and motivation. Assessments were conducted at baseline, 6 months (postprogram; primary end point), and 12 months (follow-up). Outcomes were assessed using linear mixed models, with three potential moderators tested using interaction terms (and subgroup analyses where appropriate). RESULTS: For the primary outcome (MF), a group-time effect was observed at 6 months for the upper body (2.0 repetitions; 95% confidence interval (CI), 0.8-3.2), but not the lower body (-1.4 cm; 95% CI, -4.7-1.9). At 6 months, there were intervention effects for RT skill competency and self-efficacy, but no other secondary outcomes. Effects for upper body MF and RT skill competency were sustained at 12 months. Despite overall no effect for body mass index, there was a group-time effect at 12 months among students who were overweight/obese at baseline (-0.55 kg.m; 95% CI, -1.01 to 0.08). CONCLUSIONS: The school-based RT intervention resulted in immediate and sustained improvements in upper body MF and RT skill competency, demonstrating an effective and scalable approach to delivering RT within secondary schools. PMID- 29251688 TI - Melanopsin retinal ganglion cells are not labeled in Thy-1YFP-16 transgenic mice. AB - Retinal ganglion cells (RGCs) that express the photopigment melanopsin (mRGCs) are photosensitive and initiate the non-image-forming pathway, where the majority of their axons terminate in the suprachiasmatic nucleus (SCN). RGCs only make up approximately half of the cells in the ganglion cell layer of the retina; therefore, it is important to be able to distinguish them from other cell types. The transgenic Thy-1 YFP mouse line 16 (Thy-1 YFP-16) expresses yellow fluorescent protein (YFP) in projection neurons, including RGCs. Our objective was to determine whether mRGCs are labeled with YFP in Thy-1 YFP-16 transgenic mice. Paraformaldehyde-fixed retinal wholemounts and frozen vertical sections were prepared from Thy-1 YFP-16 mice and fluorescently labeled with rabbit anti melanopsin and guinea-pig anti-RNA binding protein with multiple splicing to identify mRGCs and total RGCs, respectively. Thy-1 YFP-16 mouse brains were sectioned coronally and imaged to view RGC axonal projections to the SCN. Confocal images of retinal preparations show that the majority (~89%) of mRGCs are not YFP-positive in Thy-1 YFP-16 mice, where ~11% expressed a weak fluorescent signal. In addition, there are almost no YFP-positive axons present in the SCN of coronal brain sections. We conclude that the majority of mRGC somas and axons are not labeled with YFP in the transgenic Thy-1 YFP-16 mouse line; therefore, this mouse model may not suitable for research involving mRGC visual pathways. PMID- 29251689 TI - The Summating Potential Is a Reliable Marker of Electrode Position in Electrocochleography: Cochlear Implant as a Theragnostic Probe. AB - OBJECTIVE: For the increasing number of cochlear implantations in subjects with residual hearing, hearing preservation, and thus the prevention of implantation trauma, is crucial. A method for monitoring the intracochlear position of a cochlear implant (CI) and early indication of imminent cochlear trauma would help to assist the surgeon to achieve this goal. The aim of this study was to evaluate the reliability of the different electric components recorded by an intracochlear electrocochleography (ECochG) as markers for the cochleotopic position of a CI. The measurements were made directly from the CI, combining intrasurgical diagnostics with the therapeutical use of the CI, thus, turning the CI into a "theragnostic probe." DESIGN: Intracochlear ECochGs were measured in 10 Dunkin Hartley guinea pigs of either sex, with normal auditory brainstem response thresholds. All subjects were fully implanted (4 to 5 mm) with a custom six contact CI. The ECochG was recorded simultaneously from all six contacts with monopolar configuration (retroauricular reference electrode). The gross ECochG signal was filtered off-line to separate three of its main components: compound action potential, cochlear microphonic, and summating potential (SP). Additionally, five cochleae were harvested and histologically processed to access the spatial position of the CI contacts. Both ECochG data and histological reconstructions of the electrode position were fitted with the Greenwood function to verify the reliability of the deduced cochleotopic position of the CI. RESULTS: SPs could be used as suitable markers for the frequency position of the recording electrode with an accuracy of +/-1/4 octave in the functioning cochlea, verified by histology. Cochlear microphonics showed a dependency on electrode position but were less reliable as positional markers. Compound action potentials were not suitable for CI position information but were sensitive to "cochlear health" (e.g., insertion trauma). CONCLUSIONS: SPs directly recorded from the contacts of a CI during surgery can be used to access the intracochlear frequency position of the CI. Using SP monitoring, implantation may be stopped before penetrating functioning cochlear regions. If the technique was similarly effective in humans, it could prevent implantation trauma and increase hearing preservation during CI surgery. Diagnostic hardware and software for recording biological signals with a CI without filter limitations might be a valuable add on to the portfolios of CI manufacturers. PMID- 29251690 TI - Cost-Effective Hearing Conservation: Regulatory and Research Priorities. AB - Hearing conservation programs (HCPs) mandated by the US Occupational Safety and Health Administration (OSHA) cost about $350/worker/year. Are they cost effective? A cross-sectional model of the US adult population with and without HCPs incorporates (1) the American Medical Association's method for estimating binaural hearing impairment and whole-person impairment; (2) the model of the International Organization for Standardization (ISO) for estimating both age related and noise-induced hearing loss; and (3) an acceptable cost of $50,000 per quality-adjusted life year. The ISO model's outputs were audiometric thresholds for groups of people with different age, sex, and noise exposure history. These thresholds were used to estimate cost per quality-adjusted life year saved for people in HCPs with different noise exposure levels. Model simulations suggest that HCPs may be cost-effective only when time-weighted average (TWA) noise exposures are >= 90 dBA. Enforcing existing regulations, requiring engineering noise control at high exposure levels, and using new methods that can document hearing protection device performance could improve cost-effectiveness. If the OSHA action level remains at 85 dBA-TWA, reducing the permissible exposure limit to the same level would simplify management and slightly improve cost effectiveness. Research should evaluate employer compliance across industries, determine whether workers currently excluded from HCP regulations are at risk of noise-induced hearing loss, and develop cost-effective HCPs for mobile workers in construction, agriculture, and oil and gas drilling and servicing. Research on HCP cost-effectiveness could be extended to incorporate sensitivity analyses of the effects of a wider range of assumptions. PMID- 29251692 TI - Is refeeding syndrome relevant for critically ill patients? AB - PURPOSE OF REVIEW: To summarize recent relevant studies regarding refeeding syndrome (RFS) in critically ill patients and provide recommendations for clinical practice. RECENT FINDINGS: Recent knowledge regarding epidemiology of refeeding syndrome among critically ill patients, how to identify ICU patients at risk, and strategies to reduce the potential negative impact on outcome are discussed. SUMMARY: RFS is a potentially fatal acute metabolic derangement that ultimately can result in marked morbidity and even mortality. These metabolic derangements in ICU patients differ from otherwise healthy patients with RFS, as there is lack of anabolism. This is because of external stressors inducing a hypercatabolic response among other reasons also reflected by persistent high glucagon despite initiation of feeding. Lack of a proper uniform definition complicates diagnosis and research of RFS. However, refeeding hypophosphatemia is commonly encountered during critical illness. The correlations between risk factors proposed by international guidelines and the occurrence of RFS in ICU patients remains unclear. Therefore, regular phosphate monitoring is recommended. Based on recent trials among critically ill patients, only treatment with supplementation of electrolytes and vitamins seems not sufficient. In addition, caloric restriction for several days and gradual increase of caloric intake over days is recommendable. PMID- 29251691 TI - Nutritional metabolomics in critical illness. AB - PURPOSE OF REVIEW: Disruption of metabolic homeostasis is universal in the critically ill. Macronutrients and micronutrients are major environmental regulators of metabolite production through their gene regulation effects. The study of large numbers of circulating metabolites is beginning to emerge through the comprehensive profiling of the critically ill. In the critically ill, metabolomic studies consistently show that changes in fatty acids, lipids and tryptophan metabolite pathways are common and are associated with disease state and outcomes. RECENT FINDINGS: Metabolomics is now being applied in research studies to determine the critical illness response to nutrient deficiency and delivery. Nutritional metabolomics approaches in nutrient deficiency, malnutrition and nutrient delivery have included single time point studies and dynamic studies of critically ill patients over time. Integration of metabolomics and clinical outcome data may create a more complete understanding of the control of metabolism in critical illness. SUMMARY: The integration of metabolomic profiling with transcription and genomic data may allow for a unique window into the mechanism of how nutrient deficiency and delivery alters cellular homeostasis during critical illness and modulates the regain of cellular homeostasis during recovery. The progress and the challenges of the study of nutritional metabolomics are reviewed here. PMID- 29251693 TI - The fear of cancer recurrence literature continues to move forward: a review article. AB - PURPOSE OF REVIEW: The volume of literature addressing fear of cancer recurrence (FCR) is rapidly increasing. A summary of key developments in the research and treatment of FCR was published by Sharpe et al. in 2017, and the current review focuses on works published thereafter. RECENT FINDINGS: A comprehensive literature review was conducted to provide an up-to-date summary of peer-reviewed publications focusing on FCR. The search consisted of the most recent FCR reports published between 2016 and 2017, which can be broadly categorized as: methods of assessment; associations with FCR; FCR and caregivers; and FCR interventions. SUMMARY: FCR assessments continue to undergo revisions, which may have positive implications for clinicians and researchers seeking shorter measures to assess the FCR of their patients and study participants. However, research is needed to determine if a shorter FCR measure could be created using items that measure the construct alone, yet still retaining optimal sensitivity and specificity, or also with its determinants and consequences. Doing so would result in either unidimensional or multidimensional measure of FCR. Notwithstanding these matters in FCR assessment, the state of the literature continues to advance our understanding about characteristics of survivors with highest FCR, which is useful to identify patients in need of FCR interventions. These empirical results are useful to further investigate the theoretical distinctions of FCR. PMID- 29251694 TI - Existential distress and meaning-focused interventions in cancer survivorship. AB - PURPOSE OF REVIEW: Cancer can challenge fundamental assumptions about security, controllability and life priorities, which may lead to clinically relevant existential distress. We review recent studies on the prevalence of existential distress in cancer survivors, its distinctness from other distress concepts and interventions to address cancer-specific existential challenges. We further describe psychological mechanisms that may underlie change resulting from such interventions. RECENT FINDINGS: One-third to one-half of cancer survivors experienced existential fears and concerns related to reduced control, identity and uncertainty about the future. Clinically relevant levels of demoralization (a state comprising loss of meaning and a sense of poor coping) were found in one in four to five cancer patients in mixed samples. Existential interventions have shown positive effects in facilitating personal meaning and promoting psychological adaptation. SUMMARY: Existential distress can be understood as a distinct dimension of cancer-related distress requiring attention from healthcare professionals. Psychosocial interventions can facilitate dealing with existential challenges during and while transitioning to longer term survivorship. Such interventions can effectively support survivors to manage uncertainty, link cancer to their life story and engage in meaningful activity despite an uncertain and potentially foreshortened future. PMID- 29251695 TI - Association of change in 5-year N-terminal fragment of the prohormone brain-type natriuretic peptide with left ventricular structure and function in stable coronary disease. AB - AIMS: We sought to characterize the association between long-term changes in the N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP) and changes in left ventricular (LV) structure and function in patients with stable coronary artery disease. METHODS: We included 593 participants without significant valvular disease enrolled in the Heart and Soul Study. We evaluated the association of 5-year change in NT-proBNP (DeltaNT-proBNP) with changes in echocardiography-determined LV ejection fraction (LVEF), LV systolic dysfunction (LVSD; LVEF < 50%), LV mass index, incident LV hypertrophy (LVH) (LV mass index >102 g/m for men and >88 g/m for women), and LV diastolic dysfunction (LVDD) using linear and logistic regression. RESULTS: Over 5 years, the prevalence of LVH declined from 36 to 32% (P < 0.001), the prevalence of LVDD increased from 11 to 14% (P = 0.035), mean LVEF decreased from 63 +/- 9% to 62 +/- 10% (P = 0.07), and the prevalence of LVSD increased from 9 to 11% (P = 0.12). Compared with the lowest DeltaNT-proBNP quartile (>=8 ng/l decrease) the highest quartile (>218 ng/l increase) had significantly more incident LVH and LVSD (P < 0.001 for both), with a trend toward increased incidence of LVDD. In logistic regression models adjusted for demographics, cardiac comorbidities, baseline LV structure and function, medication use, kidney function, and baseline NT-proBNP, log transformed DeltaNT-proBNP was associated only with incident LVSD (odds ratio 2.48 * 10, 95% confidence interval 224.53-2.73 * 10, P = 0.002). CONCLUSION: A DeltaNT-proBNP is independently associated with incident LVSD in patients with stable coronary artery disease. This suggests that a long-term rise in NT-proBNP levels may warrant evaluation for incident LVEF less than 50%. PMID- 29251696 TI - Arterial hypertension and atrial fibrillation: standard and advanced echocardiography from diagnosis to prognostication. AB - : Structural changes in left and right cardiac chambers that occur in arterial hypertension (AH) may lead to an increased risk of atrial fibrillation. Considering that AH is currently the most common cardiovascular disease in the general population, it represents a major risk factor for atrial fibrillation development. This review explores the complex relationship between atrial fibrillation and AH, starting from its pathophysiological basis. It focuses on the role of echocardiography in the management of hypertensive and atrial fibrillation patients, with emphasis on what should be evaluated about left ventricular remodeling, diastolic and systolic function, left atrial (LA) size and function and right ventricular deformation in patients with AH. PMID- 29251697 TI - Adherence to proprotein convertase subtilisin/kexin 9 inhibitors in high cardiovascular risk patients: an Italian single-center experience. PMID- 29251698 TI - Echo-navigation to guide challenging transseptal puncture during transfemoral repair of mitral and tricuspid valve. PMID- 29251699 TI - Artificial intelligence in diagnosis of obstructive lung disease: current status and future potential. AB - PURPOSE OF REVIEW: The application of artificial intelligence in the diagnosis of obstructive lung diseases is an exciting phenomenon. Artificial intelligence algorithms work by finding patterns in data obtained from diagnostic tests, which can be used to predict clinical outcomes or to detect obstructive phenotypes. The purpose of this review is to describe the latest trends and to discuss the future potential of artificial intelligence in the diagnosis of obstructive lung diseases. RECENT FINDINGS: Machine learning has been successfully used in automated interpretation of pulmonary function tests for differential diagnosis of obstructive lung diseases. Deep learning models such as convolutional neural network are state-of-the art for obstructive pattern recognition in computed tomography. Machine learning has also been applied in other diagnostic approaches such as forced oscillation test, breath analysis, lung sound analysis and telemedicine with promising results in small-scale studies. SUMMARY: Overall, the application of artificial intelligence has produced encouraging results in the diagnosis of obstructive lung diseases. However, large-scale studies are still required to validate current findings and to boost its adoption by the medical community. PMID- 29251700 TI - Post-discharge adherence with venous thromboembolism prophylaxis after orthopedic trauma: Results from a randomized controlled trial of aspirin versus low molecular weight heparin. AB - BACKGROUND: Orthopedic trauma patients are often treated with venous thromboembolism (VTE) chemoprophylaxis with aspirin or low molecular weight heparin (LMWH) after discharge from their index admission, but adherence patterns are not known. We hypothesized that overall adherence would be moderate and greater with aspirin compared to LMWH. METHODS: We conducted a randomized controlled trial of adult trauma patients with an operative extremity fracture or any pelvic/acetabular fracture requiring VTE prophylaxis. Patients were randomized to receive either LMWH 30 mg BID or aspirin 81 mg BID. Patients prescribed outpatient prophylaxis were contacted between 10 and 21 days after discharge to assess adherence measured by the validated Morisky Medication Adherence Scale (MMAS-8). Adherence scores were compared between the two treatment arms with similar results for intention-to-treat and as-treated analyses. As-treated multivariable logistic regression was performed to determine factors associated with low-medium adherence scores. RESULTS: One hundred fifty patients (64 on LMWH, 86 on aspirin) on chemoprophylaxis at time of follow-up completed the questionnaire. As-treated analysis showed that adherence was high overall (mean MMAS 7.2 out of 8, SD 1.5) and similar for the two regimens (LMWH: 7.4 vs. aspirin: 7.0, p = 0.13). However, patients on LMWH were more likely to feel hassled by their regimen (23% vs. 9%, p = 0.02). In a multivariable model, low-medium adherence was associated with taking LMWH as the prophylaxis medication (aOR 2.34, CI 1.06-5.18, p = 0.04), having to self-administer the prophylaxis (aOR 4.44, CI 1.45-13.61, p < 0.01), being of male sex (aOR 2.46, CI 1.10-5.49, p = 0.03), and of younger age (aOR 0.72 per additional 10 years of age, CI 0.57-0.91, p < 0.01). CONCLUSIONS: Overall post-discharge adherence with VTE prophylaxis was high. Several factors, including prophylaxis by LMWH, were associated with decreased adherence. These factors should be considered when managing patients and designing efficacy trials. LEVEL OF EVIDENCE: Therapeutic, level II. PMID- 29251701 TI - Lower emergency general surgery (EGS) mortality among hospitals with higher quality trauma care. AB - BACKGROUND: Patients undergoing emergency general surgery (EGS) procedures are up to eight times more likely to die than patients undergoing the same procedures electively. This excess mortality is often attributed to nonmodifiable patient factors including comorbidities and physiologic derangements at presentation, leaving few targets for quality improvement. Although the hospital-level traits that contribute to EGS outcomes are not well understood, we hypothesized that facilities with lower trauma mortality would have lower EGS mortality. METHODS: Using the Nationwide Inpatient Sample (2008-2011), we calculated hospital-level risk-adjusted trauma mortality rates for hospitals with more than 400 trauma admissions. We then calculated hospital-level risk-adjusted EGS mortality rates for hospitals with more than 200 urgent/emergent admissions for seven core EGS procedures (laparotomy, large bowel resection, small bowel resection, lysis of adhesions, operative intervention for ulcer disease, cholecystectomy, and appendectomy). We used univariable and multivariable techniques to assess for associations between hospital-level risk-adjusted EGS mortality and hospital characteristics, patient-mix traits, EGS volume, and trauma mortality quartile. RESULTS: Data from 303 hospitals, representing 153,544 admissions, revealed a median hospital-level EGS mortality rate of 1.21% (interquartile range, 0.86% 1.71%). After adjusting for hospital traits, hospital-level EGS mortality was significantly associated with trauma mortality quartile as well as patients' community income-level and race/ethnicity (p < 0.05 for all). Mean risk-adjusted EGS mortality was 1.09% (95% confidence interval, 0.94-1.25%) at hospitals in the lowest quartile for risk-adjusted trauma mortality, and 1.64% (95% confidence interval, 1.48-1.80%) at hospitals in the highest quartile of trauma mortality (p < 0.01). Sensitivity analyses limited to (1) high-mortality procedures and (2) high-volume facilities; both found similar trends (p < 0.01). CONCLUSIONS: Patients at hospitals with lower risk-adjusted trauma mortality have a nearly 33% lower risk of mortality after admission for EGS procedures. The structures and processes that improve trauma mortality may also improve EGS mortality. Emergency general surgery-specific systems measures and process measures are needed to better understand drivers of variation in quality of EGS outcomes. LEVEL OF EVIDENCE: Epidemiological, level III; Care management, level IV. PMID- 29251702 TI - Safety and efficacy of brain injury guidelines at a Level III trauma center. AB - BACKGROUND: Patients with mild to moderate traumatic brain injury (TBI) are often primarily managed by emergency medicine and trauma/acute care physicians. The Brain Injury Guidelines (BIG) were developed at an American College of Surgeons accredited Level 1 trauma center to triage mild to moderate TBI patients and help identify patients who warrant neurosurgical consultation. The BIG have not been validated at a Level III trauma center. We hypothesized that BIG criteria can be safely adapted to an American College of Surgeons-accredited Level III trauma center to guide transfers to a higher echelon of care. METHODS: We reviewed the trauma registry at a Level III trauma center to identify TBI patients who presented with an Abbreviated Injury Severity-Head score greater than zero. Demographic data, injury details, and clinical outcomes were abstracted with primary outcome measures of worsening on second computed tomography of the head, neurosurgical intervention, transfer to a Level I trauma center, and in-hospital mortality. Patients were classified using the BIG criteria. After validating the BIG in our cohort, we reclassified patients using updated BIG criteria. Updated criteria included mechanism of injury, reclassification of anticoagulation or antiplatelet use, and replacement of the neurologic examination component with stratification by admission Glasgow Coma Scale (GCS) score. RESULTS: From July 2013 to June 2016, 332 TBI patients were identified: 115 BIG-1, 25 BIG-2, and 192 BIG-3. Patients requiring neurosurgical intervention (n = 30) or who died (n = 29) were BIG-3 with one exception. Patients with GCS score of less than 12 had worse outcomes than those with a GCS score of 12 or greater, regardless of BIG classification. Anticoagulant or antiplatelet use was not associated with worsened outcomes in patients not meeting other BIG-3 criteria. The updated BIG resulted in more patients in BIG-1 (n = 109) and BIG-2 (n = 100) without negatively affecting outcomes. CONCLUSION: The BIG can be applied in the Level III trauma center setting. Updated BIG criteria can aid triage of mild to moderate TBI patients to a Level I trauma center and may reduce secondary overtriage. LEVEL OF EVIDENCE: Care management, level IV. PMID- 29251703 TI - A pilot registry of trauma surgeons willing and ready to respond to disasters. AB - BACKGROUND: A well-defined means of organizing surgeons based on functional capabilities in disaster response has been lacking. We sought to create a pilot registry of surgeons, organized by functional capacities, available to respond to disasters in conjunction with the American College of Surgeons Operation Giving Back and to better understand their participation in disaster medicine training. METHODS: The authors conducted a survey of the members of the American Association for the Surgery of Trauma and the Eastern Association for the Surgery of Trauma aimed at establishing a pilot registry of qualified trauma surgeons available to respond to disasters. Data from the surveys were analyzed retrospectively for surgical and subspecialty training, board certification, disaster response training, and military or civilian disaster experience to better understand the respondents' functional capacities and disaster training backgrounds. RESULTS: Of 211 respondents, 96% self-identified as trauma surgeons, whereas 87% and 89% reported active practice in acute care surgery and/or critical care. Nearly all had primary board certifications in general surgery (93%), and many had additional certifications in surgical critical care (65%). While many reported participation in American College of Surgeons-sponsored trauma courses, only 30% of those surveyed received disaster-specific training in Federal Emergency Management Agency courses, and even fewer received training in the Disaster Management and Emergency Preparedness course. Few had military (26%) or civilian (19%) experience in disaster response. CONCLUSIONS: This initiative complements efforts to organize a registry of trauma surgeons who are qualified and willing to respond in all aspects of disaster response. While trauma surgeons are optimally positioned to provide a wide range of surgical expertise in a disaster, this study further demonstrated the lack of a universally accepted disaster training program for surgeons willing to respond to mass casualty incidents. Standardized disaster response training for surgeons remains a challenge for the future. LEVEL OF EVIDENCE: Care management, level IV. PMID- 29251704 TI - Improved outcomes in elderly trauma patients with the implementation of two innovative geriatric-specific protocols-Final report. AB - BACKGROUND: Elderly trauma care is challenging owing to the unique physiology and comorbidities prevalent in this population. To improve the care of these patients, two practice management guidelines (PMGs) were implemented: high-risk geriatric protocol (HRGP), which triages patients based on injury patterns and comorbid conditions for occult hypotension, and the anticoagulation and trauma (ACT) alert, which is designed to streamline the care of geriatric trauma patients on anticoagulants. We hypothesized that both HRGP and ACT would decrease mortality and complications in geriatric trauma patients. METHODS: Geriatric blunt trauma patients (aged >=65) presenting to our Level II center from January 2000 to July 2016 were extracted from the trauma registry. Do-not-resuscitate patients were excluded. The study period was divided into three phases: Phase 1, no PMGs in place (2000 to January 2006); Phase 2, HRGP only (February 2006 to February 2012); and Phase 3, HRGP + ACT (March 2012 to July 2016). Multivariate logistic regression models assessed adjusted mortality and complications during these phases to quantify the impact of these protocols. Statistical significance was set at p < 0.05. RESULTS: A total of 8,471 geriatric trauma patients met inclusion criteria. Overall mortality rate was 5.6% (Phase 1, 7.2%; Phase 2, 6.1%; Phase 3, 4.0%). No significant change in mortality was observed during Phase 2 with the HRGP only (adjusted odds ratio (OR), 0.98; 95% confidence interval, 0.73-1.34; p = 0.957); however, a significantly reduced OR of mortality was found during Phase 3 with the combination of both the HRGP and ACT (adjusted OR, 0.67; 95% confidence interval, 0.47-0.94; p = 0.021). No significant changes in incidence of complications was observed over the study duration. CONCLUSIONS: Geriatric trauma patients are not simply older adults. Improved outcomes can be realized with specific PMGs tailored to the geriatric trauma patients' needs. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 29251705 TI - Human adipose-derived stem cell treatment modulates cellular protection in both in vitro and in vivo traumatic brain injury models. AB - BACKGROUND: Traumatic brain injury (TBI) is a common cause of morbidity and mortality in the civilian population. The purpose of this study was to examine the effect(s) of adipose-derived stem cell (ASC) treatment on cellular and functional recovery in TBI via both in vitro and in vivo methods. METHODS: Cultured neuroblastoma cells, SH-SY5Y, were scratched to mimic TBI in an in vitro model. The effect of ASC-conditioned medium (CM) on cell death, mitochondrial function, and expression of inflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin 1beta [IL-1beta], and IL-6), as well as apoptosis marker FAS, was measured. In our in vivo model, Sprague-Dawley rats underwent TBI via a frontal, closed-head injury model. Animals randomly received either intravenous human-derived ASCs or intravenous saline within 3 hours of injury and were compared with a sham group. Functional recovery was evaluated via accelerating Rotarod method. On post-TBI Day 3, brain tissue was harvested and assessed for cellular damage via enzyme-linked immunosorbent assay for TNF-alpha, as well as immunohistochemical staining for beta-amyloid precursor protein (beta-APP). RESULTS: Our in vitro data show that ASC treatment imparted reduced cell death (ratio to control: 1.21 +/- 0.066 vs. 1.01 +/- 0.056, p = 0.017), increased cell viability (ratio to control: 0.86 +/- 0.009 vs. 1.09 +/- 0.01, p = 0.0001), increased mitochondrial function (percentage of control: 78 +/- 6% vs. 68 +/- 3%), and significantly decreased levels of inflammatory cytokine IL-1beta. In our in vivo study, compared with TBI alone, ASC-treated animals showed no difference in functional recovery, lower levels of expressed TNF-alpha (ratio to total protein, 0.47 +/- 0.01 vs. 0.67 +/- 0.04; p < 0.01), and lower levels of beta amyloid precursor protein (fluorescence ratio, 0.43 +/- 0.05 vs. 0.69 +/- 0.03; p < 0.01). CONCLUSIONS: Adipose-derived stem cell treatment results in improved cell survival, decreased inflammatory marker release, and decreased evidence of neural injury. No difference in functional recovery was seen. These data suggest the potential for ASC treatment to aid in cellular protection and recovery in neural cells following TBI. PMID- 29251706 TI - Valproic acid induces prosurvival transcriptomic changes in swine subjected to traumatic injury and hemorrhagic shock. AB - BACKGROUND: Valproic acid (VPA) is a histone deacetylase inhibitor that improves outcomes in large animal models of trauma. However, its protective mechanism of action is not completely understood. We sought to characterize the genetic changes induced by VPA treatment following traumatic injuries. METHODS: Six female Yorkshire swine were subjected to traumatic brain injury (controlled cortical impact), polytrauma (liver and splenic laceration, rib fracture, rectus crush), and hemorrhagic shock (HS, 40% total blood volume). Following 2 hours of HS, animals were randomized to resuscitation with normal saline (NS) or NS + 150 mg/kg of intravenous VPA (n = 3/cohort, 18 samples total). Blood samples were collected for isolation of peripheral blood mononuclear cells at three distinct time points: baseline, 6 hours following injuries, and on postinjury day 1. RNA was extracted from peripheral blood mononuclear cells and sequenced. Differential expression analysis (false discovery rate < 0.001 and p value <0.001) and gene set enrichment (Panther Gene Ontology and Ingenuity Pathway Analysis) was used to compare VPA to non-VPA-treated animals. RESULTS: A total of 628 differentially expressed RNA transcripts were identified, 412 of which were used for analysis. There was no difference between treatment groups at baseline. The VPA-induced genetic changes were similar at 6 hours and on postinjury day 1. Upregulated genes were associated with gene expression (p 2.13E-34), cellular development (1.19E-33), cellular growth and proliferation (1.25E-30), and glucocorticoid receptor signaling (8.6E-21). Downregulated genes were associated with cell cycle checkpoint regulation (3.64E-22), apoptosis signaling (6.54E-21), acute phase response signaling (5.84E-23), and the inflammasome pathway (1.7E-19). CONCLUSION: In injured swine, VPA increases the expression of genes associated with cell survival, proliferation, and differentiation and decreases those associated with cell death and inflammation. These genetic changes could explain the superior clinical outcomes in VPA-treated animals, including smaller brain lesion size and improved neurologic recovery. PMID- 29251707 TI - Transcriptomic changes following valproic acid treatment promote neurogenesis and minimize secondary brain injury. AB - BACKGROUND: Early treatment with valproic acid (VPA) has demonstrated benefit in preclinical models of traumatic brain injury, including smaller brain lesion size, decreased edema, reduced neurologic disability, and faster recovery. Mechanisms underlying these favorable outcomes are not fully understood. We hypothesized that VPA treatment would upregulate genes involved in cell survival and proliferation and downregulate those associated with cell death and the inflammatory response. METHODS: Ten female swine were subjected to a protocol of traumatic brain injury and hemorrhagic shock. They were assigned to two groups (n = 5): normal saline (NS; 3* volume of shed blood), or NS + VPA (150 mg/kg). Following 6 hours of observation, brain tissue was harvested to evaluate lesion size and edema. Brain tissue was processed for RNA sequencing. Gene set enrichment and pathway analysis was performed to determine the differential gene expression patterns following injury. RESULTS: Animals treated with VPA were noted to have a 46% reduction in brain lesion size and a 57% reduction in ipsilateral brain edema. Valproic acid significantly upregulated genes involved in morphology of the nervous system, neuronal development and neuron quantity. The VPA treatment downregulated pathways related to apoptosis, glial cell proliferation, and neuroepithelial cell differentiation. Ingenuity Pathway Analysis identified VPA as the top upstream regulator of activated transcription, supporting it as a direct cause of these transcriptional changes. Master transcriptional regulator NEUROD1 was also significantly upregulated, suggesting that VPA may induce additional transcription factors. CONCLUSION: Administration of VPA attenuated brain lesion size, reduced brain edema, and induced significant changes in the transcriptome of injured brain within 6 hours. Patterns of differential expression were consistent with the proposed neurogenic and prosurvival effects of VPA treatment. PMID- 29251708 TI - Speed is not everything: Identifying patients who may benefit from helicopter transport despite faster ground transport. AB - BACKGROUND: Helicopter emergency medical services (HEMS) have demonstrated survival benefits over ground emergency medical services (GEMS) for trauma patient transport. While HEMS speed is often-cited, factors such as provider experience and level of care may also play a role. Our objective was to identify patient groups that may benefit from HEMS even when prehospital time for helicopter utilization is longer than GEMS transport. METHODS: Adult patients transported by HEMS or GEMS from the scene of injury in the Pennsylvania State Trauma Registry were included. Propensity score matching was used to match HEMS and GEMS patients for likelihood of HEMS, keeping only pairs in which the HEMS patient had longer total prehospital time than the matched GEMS patient. Mixed effects logistic regression evaluated the effect of transport mode on survival while controlling for demographics, admission physiology, transfusions, and procedures. Interaction testing between transport mode and existing trauma triage criteria was conducted and models stratified across significant interactions to determine which criteria identify patients with a significant survival benefit when transported by HEMS even when slower than GEMS. RESULTS: From 153,729 eligible patients, 8,307 pairs were matched. Helicopter emergency medical services total prehospital time was a median of 13 minutes (interquartile range, 6-22) longer than GEMS. Patients with abnormal respiratory rate (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.26-4.55; p = 0.01), Glasgow Coma Scale score of 8 or less (OR, 1.61; 95% CI, 1.16-2.22; p < 0.01), and hemo/pneumothorax (OR, 2.25; 95% CI, 1.06-4.78; p = 0.03) had a significant survival advantage when transported by HEMS even with longer prehospital time than GEMS. Conversely, there was no association between transport mode and survival in patients without these factors (p > 0.05). CONCLUSION: Patients with abnormal respiratory rate, Glasgow Coma Scale score of 8 or less, and hemo/pneumothorax benefit from HEMS transport even when GEMS transport was faster. This may indicate that these patients benefit primarily from HEMS care, such as advanced airway and chest trauma management, rather than simply faster transport to a trauma center. LEVEL OF EVIDENCE: Therapeutic, level III. PMID- 29251710 TI - Mesenchymal stem cell-derived extracellular vesicles attenuate pulmonary vascular permeability and lung injury induced by hemorrhagic shock and trauma. AB - BACKGROUND: Mesenchymal stem cells (MSCs) have been shown to mitigate vascular permeability in hemorrhagic shock (HS) and trauma-induced brain and lung injury. Mechanistically, paracrine factors secreted from MSCs have been identified that can recapitulate many of the potent biologic effects of MSCs in animal models of disease. Interestingly, MSC-derived extracellular vesicles (EVs), contain many of these key soluble factors, and have therapeutic potential independent of the parent cells. In this study we sought to determine whether MSC-derived EVs (MSC EVs) could recapitulate the beneficial therapeutic effects of MSCs on lung vascular permeability induced by HS in mice. METHODS: Mesenchymal stem cell EVs were isolated from human bone marrow-derived MSCs by ultracentrifugation. A mouse model of fixed pressure HS was used to study the effects of shock, shock + MSCs and shock + MSC EVs on lung vascular endothelial permeability. Mice were administered MSCs, MSC EVs, or saline IV. Lung tissue was harvested and assayed for permeability, RhoA/Rac1 activation, and for differential phosphoprotein expression. In vitro, human lung microvascular cells junctional integrity was evaluated by immunocytochemistry and endothelial cell impedance assays. RESULTS: Hemorrhagic shock-induced lung vascular permeability was significantly decreased by both MSC and MSC EV infusion. Phosphoprotein profiling of lung tissue revealed differential activation of proteins and pathways related to cytoskeletal rearrangement and regulation of vascular permeability by MSCs and MSC EVs. Lung tissue from treatment groups demonstrated decreased activation of the cytoskeletal GTPase RhoA. In vitro, human lung microvascular cells, MSC CM but not MSC-EVs prevented thrombin-induced endothelial cell permeability as measured by electrical cell-substrate impedance sensing system and immunocytochemistry of VE-cadherin and actin. CONCLUSION: Mesenchymal stem cells and MSC EVs modulate cytoskeletal signaling and attenuate lung vascular permeability after HS. Mesenchymal stem cell EVs may potentially be used as a novel "stem cell free" therapeutic to treat HS-induced lung injury. PMID- 29251709 TI - Benchmarking clinical outcomes and the immunocatabolic phenotype of chronic critical illness after sepsis in surgical intensive care unit patients. AB - BACKGROUND: A growing number of patients survive sepsis but remain chronically critically ill. We sought to define clinical outcomes and incidence of chronic critical illness (CCI) after sepsis and to determine whether selected biomarkers of inflammation, immunosuppression, and catabolism differ between these patients and those that rapidly recover (RAP). METHODS: This 3-year prospective observational cohort study (NCT02276417) evaluated 145 surgical intensive care unit patients with sepsis for the development of CCI (>=14 days of intensive care unit resource utilization with persistent organ dysfunction). Patient clinical demographics, outcomes, and serial serum/urine samples were collected for plasma protein and urinary metabolite analyses. RESULTS: Of 145 sepsis patients enrolled, 19 (13%) died during their hospitalization and 71 (49%) developed CCI. The CCI patients were significantly older (mean, 63 +/- 15 vs. 58 +/- 13 years, p = 0.006) and more likely to be discharged to long-term acute care facilities (32% vs. 3%, p < 0.0001), whereas those with RAP were more often discharged to home or a rehabilitation facility. Six-month mortality was significantly higher in CCI as compared with RAP cohort (37% vs. 2%; p < 0.01). Multivariate logistic regression modeling revealed delayed onset sepsis (>48 hours after admission; odds ratio [OR], 10.93; 95% confidence interval [CI], 4.15-28.82]), interfacility transfer (OR, 3.58; 95% CI, 1.43-8.96), vasopressor-dependent septic shock (OR, 3.75; 95% CI, 1.47-9.54), and Sequential Organ Failure Assessment score of 5 or greater at 72 hours (OR, 5.03; 95% CI, 2.00-12.62) as independent risk factors for the development of CCI. The CCI patients also demonstrated greater elevations in inflammatory cytokines (IL-6, IL-8, IL-10), and biomarker profiles are consistent with persistent immunosuppression (absolute lymphocyte count and soluble programmed death ligand 1) and catabolism (plasma insulin-like growth factor binding protein 3 and urinary 3-methylhistidine excretion). CONCLUSION: The development of CCI has become the predominant clinical trajectory in critically ill surgical patients with sepsis. These patients exhibit biomarker profiles consistent with an immunocatabolic phenotype of persistent inflammation, immunosuppression, and catabolism. LEVEL OF EVIDENCE: Prognostic, level II. PMID- 29251711 TI - Beta blockers in critically ill patients with traumatic brain injury: Results from a multicenter, prospective, observational American Association for the Surgery of Trauma study. AB - BACKGROUND: Beta blockers, a class of medications that inhibit endogenous catecholamines interaction with beta adrenergic receptors, are often administered to patients hospitalized after traumatic brain injury (TBI). We tested the hypothesis that beta blocker use after TBI is associated with lower mortality, and secondarily compared propranolol to other beta blockers. METHODS: The American Association for the Surgery of Trauma Clinical Trial Group conducted a multi-institutional, prospective, observational trial in which adult TBI patients who required intensive care unit admission were compared based on beta blocker administration. RESULTS: From January 2015 to January 2017, 2,252 patients were analyzed from 15 trauma centers in the United States and Canada with 49.7% receiving beta blockers. Most patients (56.3%) received the first beta blocker dose by hospital day 1. Those patients who received beta blockers were older (56.7 years vs. 48.6 years, p < 0.001) and had higher head Abbreviated Injury Scale scores (3.6 vs. 3.4, p < 0.001). Similarities were noted when comparing sex, admission hypotension, mean Injury Severity Score, and mean Glasgow Coma Scale. Unadjusted mortality was lower for patients receiving beta blockers (13.8% vs. 17.7%, p = 0.013). Multivariable regression determined that beta blockers were associated with lower mortality (adjusted odds ratio, 0.35; p < 0.001), and propranolol was superior to other beta blockers (adjusted odds ratio, 0.51, p = 0.010). A Cox-regression model using a time-dependent variable demonstrated a survival benefit for patients receiving beta blockers (adjusted hazard ratio, 0.42, p < 0.001) and propranolol was superior to other beta blockers (adjusted hazard ratio, 0.50, p = 0.003). CONCLUSION: Administration of beta blockers after TBI was associated with improved survival, before and after adjusting for the more severe injuries observed in the treatment cohort. This study provides a robust evaluation of the effects of beta blockers on TBI outcomes that supports the initiation of a multi-institutional randomized control trial. LEVEL OF EVIDENCE: Therapeutic/care management, level III. PMID- 29251712 TI - Prediction of traumatic carotid-cavernous sinus fistula via noncontrast computed tomography by fracture pattern and abnormality of venous system. AB - BACKGROUND: Traumatic carotid-cavernous sinus fistula (tCCF) is infrequent but with high morbidity if delayed diagnosed or managed. Because of the lack of screening criteria and requirement of advanced and invasive radiological examinations, diagnosis is often delayed or underdiagnosed. METHODS: A matched case-control study with univariate and multivariate analyses was conducted to predict tCCFs. Forty-six patients diagnosed with tCCFs were included and matched with 138 patients of craniofacial trauma without tCCF as control at a ratio of 1:3. RESULTS: The diagnostic diameter of superior ophthalmic vein (SOV) in tCCF was 4 mm with area under curve of 0.89. In multivariate analysis, engorgement of SOV and cavernous sinus (odds ratio [OR], 35.39; 95% confidence interval [CI], 13.56-104.84; p < 0.001) and lateral impact (ipsilateral temporal and sphenoid sinus fractures) (OR, 3.96; 95% CI, 1.10-14.91; p = 0.028) were identified significant, whereas basilar skull fracture (OR, 1.58; 95% CI, 0.53-4.75; p = 0.300) and injuries to ocular nerves (cranial nerves III, IV, and VI) (OR, 1.77; 95% CI, 0.38-7.88; p = 0.055) were insignificant. CONCLUSION: Presence of SOV or cavernous sinus engorgement on noncontrast computed tomography and lateral impact were demonstrated as independent predictors to tCCF and warrant further radiological evaluation. Injury to ocular nerves is not predictive but as an essential differential diagnosis with reversible outcome. LEVEL OF EVIDENCE: Diagnostic, level III. PMID- 29251714 TI - Early identification of patients requiring massive transfusion, embolization or hemostatic surgery for traumatic hemorrhage: A systematic review and meta analysis. AB - BACKGROUND: Delays in appropriate triage of bleeding trauma patients result in poor outcomes. Clinical gestalt is fallible and objective measures of risk stratification are needed. The objective of this review is to identify and assess prediction models and predictors for the early identification of traumatic hemorrhage patients requiring massive transfusion, surgery, or embolization. METHODS: We searched electronic databases through to September 31, 2016, for studies describing clinical, laboratory, and imaging predictors available within the first hour of resuscitation for identifying patients requiring major intervention for hemorrhage within the first 24 hours. RESULTS: We included 84 studies describing any predictor-outcome association, including 47 multivariable models; of these, 26 (55%) were specifically designed for prediction. We identified 35 distinct predictors of which systolic blood pressure, age, heart rate, and mechanism of injury were most frequently studied. Quality of multivariable models was generally poor with only 21 (45%) meeting a commonly recommended sample size threshold of 10 events per predictor. From 21 models meeting this threshold, we identified seven predictors that were examined in at least two models: mechanism of injury, systolic blood pressure, heart rate, hemoglobin, lactate, and focussed abdominal sonography for trauma. Pooled odds ratios were obtained from random-effects meta-analyses. CONCLUSION: The majority of traumatic hemorrhagic prediction studies are of poor quality, as assessed by the Prognosis Research Strategy recommendations and Critical Appraisal and Data Extraction for Systematic Reviews of Modeling Studies checklist. There exists a need for a well-designed clinical prediction model for early identification of patients requiring intervention. The variables of clinical importance identified in this review are consistent with recent expert guideline recommendations and may serve as candidates for future derivation studies. PMID- 29251713 TI - Microparticles formed during storage of red blood cell units support thrombin generation. AB - BACKGROUND: Intact red blood cells (RBCs) appear to support thrombin generation in in vitro models of blood coagulation. During storage of RBC units, biochemical, structural, and physiological changes occur including alterations to RBC membranes and release of microparticles, which are collectively known as storage lesion. The clinical consequences of microparticle formation in RBC units are unclear. This study was performed to assess thrombin generation via the prothrombinase complex by washed RBCs and RBC-derived microparticles as a function of RBC unit age. METHODS: Well-characterized kinetic and flow cytometric assays were used to quantify and characterize microparticles isolated from leukocyte-reduced RBC units during storage for 42 days under standard blood banking conditions. RESULTS: Stored RBCs exhibited known features of storage lesion including decreasing pH, cell lysis, and release of microparticles demonstrated by scanning electron microscopy. The rate of thrombin formation by RBC units linearly increased during storage, with the microparticle fraction accounting for approximately 70% of the prothrombinase activity after 35 days. High-resolution flow cytometric analyses of microparticle isolates identified phosphatidylserine-positive RBC-derived microparticles; however, their numbers over time did not correlate with thrombin formation in that fraction. CONCLUSION: Red blood cell-derived microparticles capable of supporting prothrombinase function accumulate during storage, suggesting an increased potential of transfused units as they age to interact in unplanned ways with ongoing hemostatic processes in injured individuals, especially given the standard blood bank practice of using the oldest units available. PMID- 29251715 TI - A retrospective analysis of the respiratory adjusted shock index to determine the presence of occult shock in trauma patients. AB - BACKGROUND: The shock index (SI), calculated as hear rate/systolic blood pressure, is a simple hemodynamic marker that may be used to assess for the presence of occult shock in trauma patients. The normal range for a healthy adult patient is 0.5 to 0.7. Recently, studies have demonstrated that tachypnea is the most important predictor of cardiac arrest in hospital wards and is an important indicator of derangements across multiple organ systems. As such, we have sought to determine whether the inclusion of the patient's respiratory rate (RR) to the already existing SI (called the Respiratory Adjusted Shock Index [RASI]), calculated as hear rate/systolic blood pressure*(RR/10), will improve the overall diagnostic accuracy of detecting patients in early occult shock. METHODS: A retrospective chart review over a 4-year period (2012-2016) at an urban, Level I trauma center was performed. All patients admitted to hospital for trauma were included in the study. Exclusion criteria were patients in traumatic arrest or in overt shock. Charts were reviewed for triage vital signs and point of care lactate drawn within 30 minutes of presentation. A lactate greater than 2 mmol/L was used to determine presence of hypoperfusion. The upper limit of normal for the RASI was calculated by multiplying the upper limit of the SI by 1.9 (RR of 19 divided by 10) and validated internally. RESULTS: A total of 3,093 patients were included in this study. There was no difference in SI for patients discharged versus patients admitted, 0.6 (95% CI, 0.5-0.7) versus 0.7 (95% CI, 0.5-0.8) and a significant difference between the same groups of patients (discharged vs. admitted) for the RASI, 1.1 (95% CI, 1.04-1.18) versus 1.46 (95% CI, 1.35-1.55), respectively. Area under the curve for SI was 0.58 and for the RASI score was 0.94. CONCLUSION: The RASI score improves diagnostic accuracy for detecting early occult shock in trauma patients when compared to the SI. LEVEL OF EVIDENCE: Diagnostic, level II. PMID- 29251717 TI - Glycolysis gatekeeper PDK1 reprograms breast cancer stem cells under hypoxia. AB - This corrects the article DOI: 10.1038/onc.2017.368. PMID- 29251716 TI - Weekend Surgical Care and Postoperative Mortality: A Systematic Review and Meta Analysis of Cohort Studies. AB - BACKGROUND: An association between weekend health care delivery and poor outcomes has become known as the "weekend effect." Evidence for such an association among surgery patients has not previously been synthesized. OBJECTIVE: To systematically review associations between weekend surgical care and postoperative mortality. METHODS: We searched PubMed, EMBASE, and references of relevant articles for studies that compared postoperative mortality either; (1) according to the day of the week of surgery for elective operations, or (2) according to weekend versus weekday admission for urgent/emergent operations. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for postoperative mortality (<=90 d or inpatient mortality) were pooled using random effects models. RESULTS: Among 4027 citations identified, 10 elective surgery studies and 19 urgent/emergent surgery studies with a total of >6,685,970 and >1,424,316 patients, respectively, met the inclusion criteria. Pooled odds of mortality following elective surgery rose in a graded manner as the day of the week of surgery approached the weekend [Monday OR=1 (reference); Tuesday OR=1.04 (95% CI=0.97-1.11); Wednesday OR=1.08 (95% CI=0.98-1.19); Thursday OR=1.12 (95% CI=1.03-1.22); Friday OR=1.24 (95% CI=1.10-1.38)]. Mortality was also higher among patients who underwent urgent/emergent surgery after admission on the weekend relative to admission on weekdays (OR=1.27; 95% CI=1.08-1.49). CONCLUSIONS: Postoperative mortality rises as the day of the week of elective surgery approaches the weekend, and is higher after admission for urgent/emergent surgery on the weekend compared with weekdays. Future research should focus on clarifying underlying causes of this association and potentially mitigating its impact. PMID- 29251718 TI - A role for 2-Cys peroxiredoxins in facilitating cytosolic protein thiol oxidation. AB - Hydrogen peroxide (H2O2) acts as a signaling messenger by triggering the reversible oxidation of redox-regulated proteins. It remains unclear how proteins can be oxidized by signaling levels of H2O2 in the presence of peroxiredoxins, which are highly efficient peroxide scavengers. Here we show that the rapid formation of disulfide bonds in cytosolic proteins is enabled, rather than competed, by cytosolic 2-Cys peroxiredoxins. Under the conditions tested, the combined deletion or depletion of cytosolic peroxiredoxins broadly frustrated H2O2-dependent protein thiol oxidation, which is the exact opposite of what would be predicted based on the assumption that H2O2 oxidizes proteins directly. We find that peroxiredoxins enable rapid and sensitive protein thiol oxidation by relaying H2O2-derived oxidizing equivalents to other proteins. Although these findings do not rule out the existence of Prx-independent H2O2 signaling mechanisms, they suggest a broader role for peroxiredoxins as sensors and transmitters of H2O2 signals than hitherto recognized. PMID- 29251719 TI - Expression system for structural and functional studies of human glycosylation enzymes. AB - Vertebrate glycoproteins and glycolipids are synthesized in complex biosynthetic pathways localized predominantly within membrane compartments of the secretory pathway. The enzymes that catalyze these reactions are exquisitely specific, yet few have been extensively characterized because of challenges associated with their recombinant expression as functional products. We used a modular approach to create an expression vector library encoding all known human glycosyltransferases, glycoside hydrolases, and sulfotransferases, as well as other glycan-modifying enzymes. We then expressed the enzymes as secreted catalytic domain fusion proteins in mammalian and insect cell hosts, purified and characterized a subset of the enzymes, and determined the structure of one enzyme, the sialyltransferase ST6GalNAcII. Many enzymes were produced at high yields and at similar levels in both hosts, but individual protein expression levels varied widely. This expression vector library will be a transformative resource for recombinant enzyme production, broadly enabling structure-function studies and expanding applications of these enzymes in glycochemistry and glycobiology. PMID- 29251720 TI - Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation. AB - Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition. PMID- 29251721 TI - Ultralow-loss polaritons in isotopically pure boron nitride. AB - Conventional optical components are limited to size scales much larger than the wavelength of light, as changes to the amplitude, phase and polarization of the electromagnetic fields are accrued gradually along an optical path. However, advances in nanophotonics have produced ultrathin, so-called 'flat' optical components that beget abrupt changes in these properties over distances significantly shorter than the free-space wavelength. Although high optical losses still plague many approaches, phonon polariton (PhP) materials have demonstrated long lifetimes for sub-diffractional modes in comparison to plasmon polariton-based nanophotonics. We experimentally observe a threefold improvement in polariton lifetime through isotopic enrichment of hexagonal boron nitride (hBN). Commensurate increases in the polariton propagation length are demonstrated via direct imaging of polaritonic standing waves by means of infrared nano-optics. Our results provide the foundation for a materials-growth directed approach aimed at realizing the loss control necessary for the development of PhP-based nanophotonic devices. PMID- 29251722 TI - Isotope engineering of van der Waals interactions in hexagonal boron nitride. AB - Hexagonal boron nitride is a model lamellar compound where weak, non-local van der Waals interactions ensure the vertical stacking of two-dimensional honeycomb lattices made of strongly bound boron and nitrogen atoms. We study the isotope engineering of lamellar compounds by synthesizing hexagonal boron nitride crystals with nearly pure boron isotopes (10B and 11B) compared to those with the natural distribution of boron (20 at% 10B and 80 at% 11B). On the one hand, as with standard semiconductors, both the phonon energy and electronic bandgap varied with the boron isotope mass, the latter due to the quantum effect of zero point renormalization. On the other hand, temperature-dependent experiments focusing on the shear and breathing motions of adjacent layers revealed the specificity of isotope engineering in a layered material, with a modification of the van der Waals interactions upon isotope purification. The electron density distribution is more diffuse between adjacent layers in 10BN than in 11BN crystals. Our results open perspectives in understanding and controlling van der Waals bonding in layered materials. PMID- 29251723 TI - A sol-gel monolithic metal-organic framework with enhanced methane uptake. AB - A critical bottleneck for the use of natural gas as a transportation fuel has been the development of materials capable of storing it in a sufficiently compact form at ambient temperature. Here we report the synthesis of a porous monolithic metal-organic framework (MOF), which after successful packing and densification reaches 259 cm3 (STP) cm-3 capacity. This is the highest value reported to date for conformed shape porous solids, and represents a greater than 50% improvement over any previously reported experimental value. Nanoindentation tests on the monolithic MOF showed robust mechanical properties, with hardness at least 130% greater than that previously measured in its conventional MOF counterparts. Our findings represent a substantial step in the application of mechanically robust conformed and densified MOFs for high volumetric energy storage and other industrial applications. PMID- 29251724 TI - Safe and recyclable lithium-ion capacitors using sacrificial organic lithium salt. AB - Lithium-ion capacitors (LICs) shrewdly combine a lithium-ion battery negative electrode capable of reversibly intercalating lithium cations, namely graphite, together with an electrical double-layer positive electrode, namely activated carbon. However, the beauty of this concept is marred by the lack of a lithium cation source in the device, thus requiring a specific preliminary charging step. The strategies devised thus far in an attempt to rectify this issue all present drawbacks. Our research uncovers a unique approach based on the use of a lithiated organic material, namely 3,4-dihydroxybenzonitrile dilithium salt. This compound can irreversibly provide lithium cations to the graphite electrode during an initial operando charging step without any negative effects with respect to further operation of the LIC. This method not only restores the low CO2 footprint of LICs, but also possesses far-reaching potential with respect to designing a wide range of greener hybrid devices based on other chemistries, comprising entirely recyclable components. PMID- 29251725 TI - Broad-spectrum non-toxic antiviral nanoparticles with a virucidal inhibition mechanism. AB - Viral infections kill millions yearly. Available antiviral drugs are virus specific and active against a limited panel of human pathogens. There are broad spectrum substances that prevent the first step of virus-cell interaction by mimicking heparan sulfate proteoglycans (HSPG), the highly conserved target of viral attachment ligands (VALs). The reversible binding mechanism prevents their use as a drug, because, upon dilution, the inhibition is lost. Known VALs are made of closely packed repeating units, but the aforementioned substances are able to bind only a few of them. We designed antiviral nanoparticles with long and flexible linkers mimicking HSPG, allowing for effective viral association with a binding that we simulate to be strong and multivalent to the VAL repeating units, generating forces (~190 pN) that eventually lead to irreversible viral deformation. Virucidal assays, electron microscopy images, and molecular dynamics simulations support the proposed mechanism. These particles show no cytotoxicity, and in vitro nanomolar irreversible activity against herpes simplex virus (HSV), human papilloma virus, respiratory syncytial virus (RSV), dengue and lenti virus. They are active ex vivo in human cervicovaginal histocultures infected by HSV-2 and in vivo in mice infected with RSV. PMID- 29251727 TI - Labeling and identifying cell-specific proteomes in the mouse brain. AB - We develop an approach to tag proteomes synthesized by specific cell types in dissociated cortex, brain slices, and the brains of live mice. By viral-mediated expression of an orthogonal pyrrolysyl-tRNA synthetase-tRNAXXX pair in a cell type of interest and providing a non-canonical amino acid with a chemical handle, we selectively label neuronal or glial proteomes. The method enables the identification of proteins from spatially and genetically defined regions of the brain. PMID- 29251726 TI - Orthologous CRISPR-Cas9 enzymes for combinatorial genetic screens. AB - Combinatorial genetic screening using CRISPR-Cas9 is a useful approach to uncover redundant genes and to explore complex gene networks. However, current methods suffer from interference between the single-guide RNAs (sgRNAs) and from limited gene targeting activity. To increase the efficiency of combinatorial screening, we employ orthogonal Cas9 enzymes from Staphylococcus aureus and Streptococcus pyogenes. We used machine learning to establish S. aureus Cas9 sgRNA design rules and paired S. aureus Cas9 with S. pyogenes Cas9 to achieve dual targeting in a high fraction of cells. We also developed a lentiviral vector and cloning strategy to generate high-complexity pooled dual-knockout libraries to identify synthetic lethal and buffering gene pairs across multiple cell types, including MAPK pathway genes and apoptotic genes. Our orthologous approach also enabled a screen combining gene knockouts with transcriptional activation, which revealed genetic interactions with TP53. The "Big Papi" (paired aureus and pyogenes for interactions) approach described here will be widely applicable for the study of combinatorial phenotypes. PMID- 29251728 TI - Viruses leave their stamp on single cells. PMID- 29251730 TI - Biotech's pale shadow. PMID- 29251731 TI - Mentoring for diversity in technology. PMID- 29251729 TI - Virus stamping for targeted single-cell infection in vitro and in vivo. AB - Genetic engineering by viral infection of single cells is useful to study complex systems such as the brain. However, available methods for infecting single cells have drawbacks that limit their applications. Here we describe 'virus stamping', in which viruses are reversibly bound to a delivery vehicle-a functionalized glass pipette tip or magnetic nanoparticles in a pipette-that is brought into physical contact with the target cell on a surface or in tissue, using mechanical or magnetic forces. Different single cells in the same tissue can be infected with different viruses and an individual cell can be simultaneously infected with different viruses. We use rabies, lenti, herpes simplex, and adeno-associated viruses to drive expression of fluorescent markers or a calcium indicator in target cells in cell culture, mouse retina, human brain organoid, and the brains of live mice. Virus stamping provides a versatile solution for targeted single cell infection of diverse cell types, both in vitro and in vivo. PMID- 29251732 TI - Aligning stars of all colors. PMID- 29251733 TI - Parabiosis reveals leukocyte dynamics in the kidney. AB - The immune cellular compartment of the kidney is involved in organ development and homeostasis, as well as in many pathological conditions. Little is known about the mechanisms that drive intrarenal immune responses in the presence of renal tubular and interstitial cell death. However, it is known that tissue resident leukocytes have the potential to have distinct roles compared with circulating cells. We used a parabiosis model in C57BL/6 CD45 congenic and green fluorescent protein transgenic mice to better understand the dynamics of immune cells in the kidney. We found F4/80Hi intrarenal macrophages exhibit minimal exchange with the peripheral circulation in two models of parabiosis, whether mice were attached for 4 or 16 weeks. Other intrarenal inflammatory cells demonstrate near total exchange with the circulating immune cell pool in healthy kidneys, indicating that innate and adaptive immune cells extensively traffic through the kidney interstitium during normal physiology. Neutrophils, dendritic cells, F4/80Low macrophages, T cells, B cells, and NK cells are renewed from the circulating immune cell pool. However, a fraction of double-negative T (CD4- CD8 ) and NKT cells are long-lived or tissue resident. This study provides direct evidence of leukocyte sub-populations that are resident in the renal tissue, cells which demonstrate minimal to no exchange with the peripheral blood. In addition, the data demonstrate continual exchange of other sub-populations through uninflamed tissue. PMID- 29251734 TI - Ligation-dependent RT-PCR: a new specific and low-cost technique to detect ALK, ROS, and RET rearrangements in lung adenocarcinoma. AB - Detection of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and rearranged during transfection (RET) gene rearrangements in lung adenocarcinoma is usually performed by immunohistochemistry (IHC) screening followed by fluorescence in situ hybridization (FISH), which is an expensive and difficult technique. Ligation-dependent reverse transcription polymerase chain reaction (RT PCR) multiplex technique can detect gene rearrangements using probes specifically hybridized to either side of the break point. PCR products are then sequenced by pyrosequencing or high throughput sequencing in order to identify the two genes involved. The reagent cost is <15 dollars per patient and results are available in 2 days. We have developed a 47-probe LD-RT-PCR kit especially for lung adenocarcinomas. Thirty-nine lung adenocarcinomas were studied: 24 ALK+, 14 ROS1+, and 1 RET+. ALK+ and ROS1+ were IHC+ (D5F3 Ventana for ALK and D4D6 Cell Signaling Technology for ROS1) and all cases were FISH+ (Vysis ALK Breakapart Probe Abbott for ALK, Zytolight SPEC ROS1 Dualcolor Breakapart Probe for ROS1 and Zytolight SPEC RET Dual Color Breakapart for RET); 14 wild type samples were included as negative controls. Using LD-RT-PCR, 15 rearrangements (63%) were detected in the ALK cases (gene partner: EML4 in all cases), 9 rearrangements (64%) in the ROS1 cases (gene partners: CD74 in 8 cases and SLC34A2 in 1 case) and 1 (100%) in the single RET case (gene partner: KIF5B). No rearrangement was found in the 14 negative control cases. Negative cases using LD-RT-PCR could be explained by the fact that some partner genes were not included in our assay and therefore could not be detected. Because it is an affordable, fast, and very simple technique, we propose using LD-RT-PCR when ALK immunostaining is positive. For LD-RT-PCR-negative cases, samples should then be analyzed by FISH. PMID- 29251735 TI - Microscale characterization of prostate biopsies tissues using optical coherence elastography and second harmonic generation imaging. AB - Photonics, especially optical coherence elastography (OCE) and second harmonic generation (SHG) imaging are novel high-resolution imaging modalities for characterization of biological tissues. Following our preliminary experience, we hypothesized that OCE and SHG imaging would delineate the microstructure of prostate tissue and aid in distinguishing cancer from the normal benign prostatic tissue. Furthermore, these approaches may assist in characterization of the grade of cancer, as well. In this study, we confirmed a high diagnostic accuracy of OCE and SHG imaging in the detection and characterization of prostate cancer for a large set of biopsy tissues obtained from men suspected to have prostate cancer using transrectal ultrasound (TRUS). The two techniques and methods described here are complementary, one depicts the stiffness of tissues and the other illustrates the orientation of collagen structure around the cancerous lesions. The results showed that stiffness of cancer tissue was ~57.63% higher than that of benign tissue (Young's modulus of 698.43+/-125.29 kPa for cancerous tissue vs 443.07+/-88.95 kPa for benign tissue with OCE. Using histology as a reference standard and 600 kPa as a cut-off threshold, the data analysis showed sensitivity and specificity of 89.6 and 99.8%, respectively. Corresponding positive and negative predictive values were 99.5 and 94.6%, respectively. There was a significant difference noticed in terms of Young's modulus for different Gleason scores estimated by OCE (P-value<0.05). For SHG, distinct patterns of collagen distribution were seen for different Gleason grade disease with computed quantification employing a ratio of anisotropic to isotropic (A:I ratio) and this correlated with disease aggressiveness. PMID- 29251736 TI - PGE2 EP1 receptor inhibits vasopressin-dependent water reabsorption and sodium transport in mouse collecting duct. AB - PGE2 regulates glomerular hemodynamics, renin secretion, and tubular transport. This study examined the contribution of PGE2 EP1 receptors to sodium and water homeostasis. Male EP1-/- mice were bred with hypertensive TTRhRen mice (Htn) to evaluate blood pressure and kidney function at 8 weeks of age in four groups: wildtype (WT), EP1-/-, Htn, HtnEP1-/-. Blood pressure and water balance were unaffected by EP1 deletion. COX1 and mPGE2 synthase were increased and COX2 was decreased in mice lacking EP1, with increases in EP3 and reductions in EP2 and EP4 mRNA throughout the nephron. Microdissected proximal tubule sglt1, NHE3, and AQP1 were increased in HtnEP1-/-, but sglt2 was increased in EP1-/- mice. Thick ascending limb NKCC2 was reduced in the cortex but increased in the medulla. Inner medullary collecting duct (IMCD) AQP1 and ENaC were increased, but AVP V2 receptors and urea transporter-1 were reduced in all mice compared to WT. In WT and Htn mice, PGE2 inhibited AVP-water transport and increased calcium in the IMCD, and inhibited sodium transport in cortical collecting ducts, but not in EP1 /- or HtnEP1-/- mice. Amiloride (ENaC) and hydrochlorothiazide (pendrin inhibitor) equally attenuated the effect of PGE2 on sodium transport. Taken together, the data suggest that EP1 regulates renal aquaporins and sodium transporters, attenuates AVP-water transport and inhibits sodium transport in the mouse collecting duct, which is mediated by both ENaC and pendrin-dependent pathways. PMID- 29251737 TI - Integrated tumor identification and automated scoring minimizes pathologist involvement and provides new insights to key biomarkers in breast cancer. AB - Digital image analysis (DIA) is becoming central to the quantitative evaluation of tissue biomarkers for discovery, diagnosis and therapeutic selection for the delivery of precision medicine. In this study, automated DIA using a new purpose built software platform (QuPath) is applied to a cohort of 293 breast cancer patients to score five biomarkers in tissue microarrays (TMAs): ER, PR, HER2, Ki67 and p53. This software is able to measure IHC expression following fully automated tumor recognition in the same immunohistochemical (IHC)-stained tissue section, as part of a rapid workflow to ensure objectivity and accelerate biomarker analysis. The digital scores produced by QuPath were compared with manual scores by a pathologist and shown to have a good level of concordance in all cases (Cohen's kappa>0.6), and almost perfect agreement for the clinically relevant biomarkers ER, PR and HER2 (kappa>0.86). To assess prognostic value, cutoff thresholds could be applied to both manual and automated scores using the QuPath software, and survival analysis performed for 5-year overall survival. DIA was shown to be capable of replicating the statistically significant stratification of patients achieved using manual scoring across all biomarkers (P<0.01, log-rank test). Furthermore, the image analysis scores were shown to consistently lead to statistical significance across a wide range of potential cutoff thresholds, indicating the robustness of the method, and identify sub populations of cases exhibiting different expression patterns within the p53 and Ki67 data sets that warrant further investigation. These findings have demonstrated QuPath's suitability for fast, reproducible, high-throughput TMA analysis across a range of important biomarkers. This was achieved using our tumor recognition algorithms for IHC-stained sections, trained interactively without the need for any additional tumor recognition markers, for example, cytokeratin, to obtain greater insight into the relationship between biomarker expression and clinical outcome applicable to a range of cancer types. PMID- 29251739 TI - Bis(alkylidynyl)tellurides and ditellurides. AB - The tellurocarbonylates [M(CTe)(CO)2(Tp*)]- (M = Mo, W; obtained from [M([triple bond, length as m-dash]CBr)(CO)2(Tp*)] and Li2Te or [M([triple bond, length as m dash]CLi)(CO)2(Tp*)] and Te) react with an additional equivalent of [M([triple bond, length as m-dash]CBr)(CO)2(Tp*)] to give bis(alkylidynyl)tellurides, [M2(MU CTeC)(CO)4(Tp*)2], whilst oxidation with [Fe(eta-C5H5)2]PF6 affords the corresponding ditellurides [M2(MU-CTe2C)(CO)4(Tp*)2]. The unprecedented M[triple bond, length as m-dash]CTeC[triple bond, length as m-dash]M and M[triple bond, length as m-dash]CTe2C[triple bond, length as m-dash]M bridges are discussed with reference to more conventional but rare alkylidynyltelluroethers [M([triple bond, length as m-dash]CTeR)(CO)2(Tp*)] (R = Me, nBu, Ph). PMID- 29251740 TI - The role of catalytic residue pKa on the hydrolysis/transglycosylation partition in family 3 beta-glucosidases. AB - beta-Glucosidases (betagls) primarily catalyze the hydrolysis of the terminal glycosidic bond at the non-reducing end of beta-glucosides, although glycosidic bond synthesis (called transglycosylation) can also occur in the presence of another acceptor. In the final reaction step, the glucose product or another substrate competes with water for transfer to the glycosyl-enzyme intermediate. The factors governing the balance between the two pathways are not fully known; however, the involvement of ionizable residues in binding and catalysis suggests that their pKa may play a role. Through constant pH molecular dynamics simulations of a glycoside hydrolase Family 3 (GH3) betagl, we showed that the pKa of the catalytic acid/base residue, E441, is low (~2) during either reaction due to E441-R125-E128 and E441-R125-E166 hydrogen bond networks. The low basicity of E441 would reduce its ability to deprotonate the acceptor. This may be less critical for transglycosylation because sugars have a lower deprotonation enthalpy than water. Moreover, their acidity would be increased by hydrogen bonding with R169 at the acceptor binding site. In contrast, no such interaction was observed for catalytic water. The results are likely applicable to other GH3 betagls because R125, E128, E166, and R169 are conserved. As these enzymes are commonly used in biomass degradation, there is interest in developing variants with enhanced hydrolytic activity. This may be accomplished by elevating the acid/base residue pKa by disrupting its hydrogen bond networks and reducing the affinity and reactivity of a sugar acceptor by mutating R169. PMID- 29251738 TI - NM23 proteins: innocent bystanders or local energy boosters for CFTR? AB - NM23 proteins NDPK-A and -B bind to the cystic fibrosis (CF) protein CFTR in different ways from kinases such as PKA, CK2 and AMPK or linkers to cell calcium such as calmodulin and annexins. NDPK-A (not -B) interacts with CFTR through reciprocal AMPK binding/control, whereas NDPK-B (not -A) binds directly to CFTR. NDPK-B can activate G proteins without ligand-receptor coupling, so perhaps NDPK B's binding influences energy supply local to a nucleotide-binding site (NBD1) needed for CFTR to function. Curiously, CFTR (ABC-C7) is a member of the ATP binding cassette (ABC) protein family that does not obey 'clan rules'; CFTR channels anions and is not a pump, regulates disparate processes, is itself regulated by multiple means and is so pleiotropic that it acts as a hub that orchestrates calcium signaling through its consorts such as calmodulin/annexins. Furthermore, its multiple partners make CFTR dance to different tunes in different cellular and subcellular locations as it recycles from the plasma membrane to endosomes. CFTR function in airway apical membranes is inhibited by smoking which has been dubbed 'acquired CF'. CFTR alone among family members possesses a trap for other proteins that it unfurls as a 'fish-net' and which bears consensus phosphorylation sites for many protein kinases, with PKA being the most canonical. Recently, the site of CFTR's commonest mutation has been proposed as a knock-in mutant that alters allosteric control of kinase CK2 by log orders of activity towards calmodulin and other substrates after CFTR fragmentation. This link from CK2 to calmodulin that binds the R region invokes molecular paths that control lumen formation, which is incomplete in the tracheas of some CF-affected babies. Thus, we are poised to understand the many roles of NDPK-A and -B in CFTR function and, especially lumen formation, which is defective in the gut and lungs of many CF babies. PMID- 29251741 TI - Alzheimer's Disease Prevention: Reality or Utopia? PMID- 29251742 TI - Brain Donation by Proxy: Are There Predictors in Neurodegenerative Dementia? AB - OBJECTIVES: To describe the frequency and predictors of brain donation by relatives in patients with neurodegenerative dementia. DESIGN: Database review and quantitative analysis. SETTING: The Alzheimer Center Reina Sofia Foundation (ACRSF), a center devoted to the care and research of patients with neurodegenerative dementia. PARTICIPANTS: Patients with signed consent for participation in the ACRSF research program. MEASUREMENTS: A set of 38 demographic, clinical, and social variables related to patient and closest relative, which were collected by the ACRSF multidisciplinary team upon patient admission. RESULTS: Admission data were available for 198 patients who entered the ACRSF research program; 85 of them (42.9%) died during follow-up. Mean age (SD) at admission was 82.3 (6.8) years and 80.8% of the patients were female. Family link between patient and closest relative was spouse or partner (12.0%), son or daughter (74.9%), or other link (13.1%). Brain was obtained from 56 patients (65.9%). Consent by legal representative and patient's depressive symptoms were more frequent in the donors (p<0.05, corrected) and trend was observed for more aberrant motor symptoms in the donors (p<0.05, uncorrected). CONCLUSION: A high rate of brain donation was achieved, probably due to the unique characteristics of the ACRSF and consent for research policy. Wish of alleviating suffering, as well as general interest in dementia research, possibly exerted an influence in brain donation. More research is needed to ascertain the values, motivations, and circumstances that may lead to brain donation by proxy in neurodegenerative dementia. PMID- 29251743 TI - Cereal Intake Increases and Dairy Products Decrease Risk of Cognitive Decline among Elderly Female Japanese. AB - BACKGROUND: If cognitive decline can be prevented through changes in daily diet with no medical intervention, it will be highly significant for dementia prevention. OBJECTIVES: This longitudinal study examined the associations of different food intakes on cognitive decline among Japanese subjects. DESIGN: Prospective cohort study. SETTING: The National Institute for Longevity Sciences Longitudinal Study of Aging, a community-based study. PARTICIPANTS: Participants included 298 males and 272 females aged 60 to 81 years at baseline who participated in the follow-up study (third to seventh wave) at least one time. MEASUREMENTS: Cognitive function was assessed with the Mini-Mental State Examination (MMSE) in all study waves. Nutritional intake was assessed using a 3 day dietary record in the second wave. Cumulative data among participants with an MMSE >27 in the second wave were analyzed using a generalized estimating equation. Multivariate adjusted odds ratios (OR) and 95% confidence intervals (CI) for an MMSE score <=27 in each study wave according to a 1 standard deviation (SD) increase of each food intake at baseline were estimated, after adjusting for age, follow-up time, MMSE score at baseline, education, body mass index, annual household income, current smoking status, energy intake, and history of diseases. RESULTS: In men, after adjusting for age, and follow-up period, MMSE score at baseline, the adjusted OR for a decline in MMSE score was 1.20 (95% CI, 1.02-1.42; p=0.032) with a 1-SD increase in cereal intake. After adjusting for education and other confounding variables, the OR for a decrease in MMSE score did not reach statistical significance for this variable. In women, multivariate adjusted OR for MMSE decline was 1.43 (95% CI, 1.15-1.77; p=0.001) with a 1-SD increase in cereal intake and 0.80 (95% CI, 0.65-0.98; p=0.034) with a 1-SD increase in milk and dairy product intake. CONCLUSIONS: This study indicates that a 1-SD (108 g/day) decrease in cereal intake and a 1-SD (128 g/day) increase in milk and dairy product intake may have an influence of cognitive decline in community-dwelling Japanese women aged 60 years and older. Further studies are needed in order to explore the potential causal relationship. PMID- 29251744 TI - Update on Prevention Trials in Alzheimer's Disease. AB - An evolving consensus about the need to treat AD in the presymptomatic phase has emerged following the disappointing results of several trials that enrolled subjects with mild to moderate disease, as well as accumulating research demonstrating that AD pathologic process begins decades before the appearance of symptoms. Several lessons can be learned from past prevention trials. The targeted populations were too diverse, the interventions probably not strong enough, and the time of exposure was most likely too short. We have learned from these trials that future prevention trials must be targeted, use strong interventions with known biological activity, and must be sustained with a long term intervention. In this paper, we focus on three prevention trial approaches: A. Targeted therapy: Preventing AD by targeting a specific population with a specific intervention. Such preventive approaches and trials must be based on biomarkers and imaging to select a study population in accordance with the mechanism of the specific intervention; B. Multi-domain interventions targeting a larger, more diverse population over a longer time period with long-term exposure to non-specific, multi-domain intervention. The rationale for this approach stems from studies showing that several environmental factors are associated with the risk of developing dementia. These factors may include educational level, vascular and metabolic risk factors, physical activity, cognitive stimulation, and nutritional status. It may also be possible to identify healthy adults at high risk of AD and likely to benefit from intervention based on subjective memory complaint, ApoEepsilon4 carriage, family history of AD, or the presence of frailty; and use multidomain interventions to compensate for low specificity; C. What will be probably the future of clinical practice: A preventive approach, integrated into primary care settings that begins with longitudinal monitoring of memory function in a general population to identify decliners, followed by a specific intervention based on biomarkers and imaging discussed case by case. Finally, preventing AD will require new and improved infrastructure. PMID- 29251745 TI - Three Cardinal Lessons from ADAPT - 10 Years on. AB - The Alzheimer's Disease Anti-inflammatory Prevention Trial was a placebo controlled three-arm pharmaco-prevention trial of the non-steroidal anti inflammatory drugs naproxen sodium and celecoxib for prevention of incident Alzheimer's disease (AD) dementia in older (aged 70 and over) adults. Although subjects were at increased risk of symptoms because of a firstdegree family history, they were meant to be cognitively healthy at enrollment. ADAPT encountered several problems that resulted in the termination of its treatments after only two years on average. Interim results were complex but potentially interesting. In the end, however, the results were null. We describe the complications that prevented ADAPT from achieving conclusive results, and suggest that these could have been avoided if the trial design and execution had been better guided by preliminary data. We believe such data should be available before beginning further ambitious phase III trials of this sort, and we suggest a broad method by which such data can be accumulated with reasonable economy. PMID- 29251746 TI - [Lifelong learning]. PMID- 29251747 TI - [Inpatient dialectical behaviour therapy for borderline personality disorder: effect on symptoms, coping, attachment and quality of life]. AB - BACKGROUND: Dialectical behaviour therapy (dbt) is an effective treatment for patients suffering from borderline personality disorder (bpd). When outpatient treatment is ineffective, patients are often referred to inpatient (group) treatment. As of yet, little is known about the effectiveness of inpatient (group) dbt. An altered style of attachment is one of the presumed components of inpatient (group) treatment. At present, this supposition has not yet been examined in inpatient dbt programs. AIM: To examine the treatment outcome of an inpatient group dbt program for patients suffering from bpd, evaluating symptoms, coping, attachment style and quality of life. Whether an improvement in attachment style during treatment is a predictor of psychological wellbeing at the end of treatment will also be examined. METHOD: An inpatient group dbt population, comprising of 64 patients diagnosed with bpd, was evaluated. Self report questionnaires assessed symptoms, coping, attachment style and quality of life at the start of treatment, after 19 weeks and at the end of treatment. RESULTS: The mentioned variables significantly improved in the inpatients of the group dbt program (treatment lasting on average 7.2 months). Furthermore, positive changes in secure and preoccupied attachment style were a significant predictor of psychological wellbeing at the end of the treatment. CONCLUSION: We conclude that patients diagnosed with bpd may benefit from an inpatient dbt (group) program. Improvements in attachment style during inpatient treatment may contribute to this benefit. PMID- 29251748 TI - [Disturbances of the body image: a cultural and historical comparison between the glass delusion and body dysmorphic disorder]. AB - : background Research on body dysmorphic disorder (bdd) shows that many debates in the field of psychology, sociology and philosophy already focus on the ways 'ideals of the perfect body' influence this disorder. However, more work needs to be done on the question in what ways bdd is culturally, historically and technologically mediated. AIM: To argue that norms and values of the perfect body and the ways a society prescribes how body and mind should be related, are technologically mediated through different time frames, which influence disorders of disturbances of the body image. METHOD: Literature study. RESULTS: A cultural and historical comparison between the glass delusion and body dysmorphic disorder. CONCLUSION: It's impossible to state that the glass delusion and bdd are similar disorders regarding the types of patients or their symptoms. However, by comparing the relationships between the notion of a disturbed body image, and the technological mediation of cultural norms and values of the perfect body, both diseases in fact do have something in common. PMID- 29251749 TI - [The future of ROM: computerised adaptive testing]. AB - BACKGROUND: Measurement instruments that are used for monitoring patients in mental health care are developed according to the principles of classical test theory. Because the assumptions underlying this theory are outdated, this is a good time to work towards a new method of measurement known as computerised adaptive testing (CAT), the method being based on item response theory. AIM: To introduce the CAT-methodology into Dutch mental health care, and provide an overview of the current and desirable developments. METHOD: We explain what CAT is and why mental health care should warmly welcome this new development. We also outline the limitations of CAT, summarise the developments that have already been made nationally and internationally and consider some developments we think are desirable. RESULTS: PROMIS item banks for anxiety and depression for adults show that CAT is more efficient than instruments currently in use and is able to produce very precise outcomes. CONCLUSION: The first CATs for anxiety and depression will be available late 2017 or early 2018 for adults receiving mental health care in the Netherlands. Recent results are very impressive and CAT technology will increase the efficiency of symptom measurements, bringing these measurements to a higher level. PMID- 29251750 TI - [Electroconvulsive therapy in the Netherlands: the practice in 2015 compared to that in 2008]. AB - BACKGROUND: The most recent information about the use of ECT in the Netherlands dates from 2008. An update version of the guideline for the use of ECT in the Netherlands was issued in 2010. AIM: To obtain insight into the practice of ECT in the Netherlands five years after implementation of the guideline. METHOD: Our study is based on a questionnaire about the use of ECT by psychiatrists in all Dutch institutions (n=33). Questions concerned the use and availability of ECT as well as the implementation of the updated guideline; they also served as a check on the expertise and training of ECT-psychiatrists. RESULTS: All institutions responded. The total number of ECT-sessions performed in 2015 was 15,633, a 16% increase compared to 2008. In 2015 more institutions were using 7x24 ECT and more had an ECT-nurse available. Nearly all psychiatrists were acquainted at the time with the revised guideline of 2010 and nearly 50% of them had adjusted the way they practised ECT. However, just under 40% of psychiatrists did not have the correct knowledge about some technical details regarding ECT. CONCLUSION: The revised guideline on ECT and its implementation have most likely improved the practice of ECT in the Netherlands. PMID- 29251751 TI - [Idiopathic normal pressure hydrocephalus]. AB - Idiopathic normal pressure hydrocephalus (INPH) is a syndrome that can be characterised by the following triad of symptoms: gait disturbances, cognitive impairment and urinary incontinence. The suspected diagnosis can be confirmed by cerebral ventriculomegaly and by a positive result of cerebrospinal fluid drainage. The frequent occurrence of comorbidity and a unflinching firm belief in the significance of the triad of clinical symptoms can hinder a correct diagnosis, leading to a delay in treatment and a poor prognosis. To illustrate this thesis we describe a 77-year-old patient with INPH and severe neuropsychiatric comorbidity. PMID- 29251753 TI - ? PMID- 29251752 TI - [Psychosis in a patient with Prader-Willi syndrome]. AB - Prader-Willi syndrome (pws) is a genetic disorder characterised by specific physical and behavioural abnormalities. Recent studies indicate that patients suffering from this syndrome have an increased risk of psychiatric disorders, including psychosis. We describe the development and the psychiatric condition of a 31-year-old patient with pws who had a first psychotic episode at age 14 and subsequently experienced a highly variable course of recovery and relapse. PMID- 29251754 TI - [2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS.] PMID- 29251755 TI - Zero-fluoroscopy catheter ablation of symptomatic pre-excitation from non coronary cusp during pregnancy. PMID- 29251756 TI - Typical and atypical aspects of cardiac myxomas in a single patient. PMID- 29251757 TI - Cerebellar stroke and aortic arch thrombosis. PMID- 29251758 TI - A case of tuberculous pericarditis on cardiac magnetic resonance. PMID- 29251759 TI - Ventricular tachycardia successfully treated with wearable cardioverter defibrillator. PMID- 29251760 TI - Quantitative oedema analysis using cardiac magnetic resonance T2-mapping techniques in diagnosis of takotsubo cardiomyopathy. PMID- 29251761 TI - Single-pill combinations (SPCs) and treatment of arterial hypertension in Poland. Expert consensus statement of the Polish Society of Hypertension and Polish Cardiac Society Working Group on Cardiovascular Pharmacotherapy. AB - The reasons for the publication of current expert consensus statement after 4 years from the previous one are: the growing number of evidence on the benefits of the use of single-pill combinations (SPCs) in hypertension (also with concomitant dyslipidaemia), the extension of indications for their use in the hypertension management algorithm and the emergence in recent years after the publication of Polish Society of Hypertension experts' position statement in 2013 of new types of SPCs available to doctors in Poland, including triple-drug combinations of antihypertensives and the so-called "hybrids" SPCs containing not only antihypertensive drugs but also statins. The current position statement of experts summarizes the progress of knowledge and practical application of SPCs of antihy-pertensives in Poland. It seems that there will be a long gap in the introduction of new classes of antihypertensive drugs. The only noticeable progress in the pharmacotherapy of hypertension in the last 15 years, which may explain some increase in the effectiveness of blood pressure control in patients, is more common use of SPCs of antihypertensive drugs. Analysis of European Society of Hypertension (ESH) experts' lectures during this year's ESH 2017 Annual Meeting in Milan suggests that the next edition of the 2018 ESH Guidelines may include major changes in the antihypertensive therapy algorithm, suggesting the need for initiation of pharmacologic treatment with combination therapy, i.e. SPCs, in most patients with hypertension. Combination of an angiotensin converting enzyme (ACE) inhibitor + calcium antagonist should be considered optimal in patients with high and very high cardiovascular risk. Undoubtedly, the position of this combination is due to the ACCOM-PLISH trial in which such SPCs werefound to be more effective in reducing cardiovascular risk than SPCs composed of an ACE-inhibitor + thiazide diuretic. As a result of gradually increasing popularity of combined drugs, further SPCs that meet the criteria for optimal combination of antihypertensive drugs emerged in Poland between 2012 and 2017. Two of them provided the possibility of using SPCs in patients who do not need or should not use renin-angiotensin-aldosterone inhibitors. An interesting alternative is the SPC which contains antihypertensive agents along with other drugs used in cardiovascular prevention: statins and acetylsalicylic acid. This direction in the evolution of pharmacotherapy of hypertension is approaching the concept of "polypill". In the opinion of the authors, the use of SPCs in antihypertensive therapy will increase in Poland, which may contribute to further improvement of pressure control in our country. At present, almost all useful anti-hypertensive agents are available in the form of two-drug SPCs. The combination of a sartan with beta-blocker for hypertensive patients with cardiac hypertrophy who do not tolerate ACE inhibitors and a "hybrid" SPCs of an ACE inhibitor + statin are still expected. Three-drug combinations: ACE inhibitor + beta-blocker + calcium antagonist, for patients with hypertension and coronary artery disease requiring intensive therapy, and ACE inhibitor + beta-blocker + statin, which will enable SPCs therapy for most patients, would also be useful. PMID- 29251762 TI - Drug action(s), drug marketing, and clinical medicine. Suppression of ventricular arrhythmogenicity with If blockade in human heart failure: emerging clinical evidence for ivabradine treatment benefit beyond heart rate control. PMID- 29251763 TI - De novo variants in KLF7 are a potential novel cause of developmental delay/intellectual disability, neuromuscular and psychiatric symptoms. AB - Due to small numbers of reported patients with pathogenic variants in single genes, the phenotypic spectrum associated with genes causing neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder is expanding. Among these genes is KLF7 (Kruppel-like factor 7), which is located at 2q33.3 and has been implicated in several developmental processes. KLF7 has been proposed to be a candidate gene for the phenotype of autism features seen in patients with a 2q33.3q34 deletion. Herein, we report 4 unrelated individuals with de novo KLF7 missense variants who share similar clinical features of developmental delay/ID, hypotonia, feeding/swallowing issues, psychiatric features and neuromuscular symptoms, and add to the knowledge about the phenotypic spectrum associated with KLF7 haploinsufficiency. PMID- 29251764 TI - Xom induces proteolysis of beta-catenin through GSK3beta-mediated pathway. AB - The dorsal cell fate determination factor beta-catenin and its antagonist, the ventral cell fate determination factor Xom, are expressed and distributed in a polarized fashion during early vertebrate embryogenesis. Ubiquitin-mediated proteolysis has been shown to control the abundance of both beta-catenin and Xom. However, the mechanism of ubiquitin-mediated proteolysis in regulating dorsoventral patterning remains largely unclear. Our current study shows that Xom induces proteolysis of beta-catenin through GSK3-mediated phosphorylation of Ser33/37 of beta-catenin. Our findings reveal a novel pathway that regulates beta catenin stability, and suggest, for the first time, a critical function of ubiquitin-mediated proteolysis in balancing the integration of dorsal-ventral signals and the polarized distribution of beta-catenin and Xom during dorsoventral axis formation. PMID- 29251765 TI - The structure of BrlR reveals a potential pyocyanin binding site. AB - The transcriptional regulator BrlR from Pseudomonas aeruginosa is a member of the MerR family of multidrug transport activators. Studies have shown that BrlR plays an important role in the drug tolerance of P. aeruginosa in biofilms. The tolerance to drugs can be enhanced by 3',5'-cyclic diguanylic acid (c-di-GMP). In the present study, we analyze the apo structure of BrlR and the direct binding between GyrI-like domain of BrlR and P. aeruginosa toxin pyocyanin. Furthermore, we show that pyocyanin can enhance the binding between BrlR and DNA in vitro. These findings suggest that BrlR can serve as the binding partner for both c-di GMP and pyocyanin. PMID- 29251767 TI - Study finds link between inflammation and colorectal cancer. PMID- 29251766 TI - Handing Off the Older Patient: Improved Documentation of Geriatric Assessment in Transitions of Care. AB - OBJECTIVES: To improve assessment and documentation of function, cognition, and advance care planning (ACP) in admission and discharge notes on an Acute Care of the Elderly (ACE) unit. DESIGN: Continuous quality improvement intervention with episodic data review. SETTING: ACE unit of an 866-bed academic tertiary hospital. PARTICIPANTS: Housestaff physicians rotating on the ACE unit (N = 31). INTERVENTION: Introduction of templated notes, housestaff education, leadership outreach, and posted reminders. MEASUREMENTS: Documentation of function, cognition, and ACP were assessed through chart review of a weekly sample of the ACE unit census and scored using predefined criteria. RESULTS: Medical records (N = 172) were reviewed. At baseline, 0% of admission and discharge notes met minimum documentation criteria for all 3 domains (function, cognition, ACP). Documentation of function and cognition was completely absent at baseline. After the intervention, there was marked improvement in all measures, with 64% of admission notes and 94% of discharge notes meeting minimum documentation criteria or better in all 3 domains. CONCLUSION: A quality improvement intervention using geriatric-specific note templates, housestaff training, and reminders increased documentation of function, cognition and ACP for postacute care. PMID- 29251768 TI - Evolving detection and treatment methods change approaches to prostate cancer: US Preventive Services Task Force draft recommendations now align more closely with others. PMID- 29251770 TI - Human viperin catalyzes the modification of GPP and FPP potentially affecting cholesterol synthesis. AB - Viperin is a radical SAM enzyme that possesses antiviral properties against a broad range of enveloped viruses. Here, we describe the activity of human viperin with two molecules of the mevalonate pathway, geranyl pyrophosphate, and farnesyl pyrophosphate, involved in cholesterol biosynthesis. We postulate that the radical modification of these two molecules by viperin might lead to defects in cholesterol synthesis, thereby affecting the composition of lipid rafts and subsequent enveloped virus budding. PMID- 29251771 TI - Inactivation of cardiolipin synthase triggers changes in mitochondrial morphology. AB - Mitochondrial tubular structures are maintained by a balance between membrane fusion and fission that is regulated by various factors, including Drp1 and mitofusin/fzo-1. Here we report the role of cardiolipin (CL) synthase in the regulation of mitochondrial morphology. Knockdown of CL synthase induced mitochondrial elongation in nematode and human cells. Knockdown of both nematode cardiolipin synthase and drp-1 or fzo-1 suggested that knocking down CL synthase decreases mitochondrial division. Mass spectrometric analysis of human CL synthase-knocked down cells revealed a decreased amount of CL and an accumulation of phosphatidylglycerol, a CL precursor. Knockdown of other genes involved in CL synthesis did not influence mitochondrial morphology. Thus, mitochondrial elongation may result from the accumulation of phosphatidylglycerol rather than decreased CL. PMID- 29251769 TI - Incidence of thromboembolic and bleeding events in patients with newly diagnosed nonvalvular atrial fibrillation: An Asian multicenter retrospective cohort study in Singapore. AB - BACKGROUND: Real-world effectiveness and safety of antithrombotics in nonvalvular atrial fibrillation (NVAF) patients in Singapore has not been thoroughly studied. HYPOTHESIS: Users of various antithrombotics experience a significantly different risk of stroke and major bleed compared with warfarin users. METHODS: This multicenter retrospective cohort study included patients age >= 21 years newly diagnosed with NVAF between July 2012 and September 2015. Using electronic medical records, data on patients' demographics, antithrombotics prescribed, and CHA2 DS2 -VASc and HAS-BLED risk factors were collected. Patients were followed for 1 year from diagnosis for the primary effectiveness and safety endpoints of incident stroke or systemic embolism and major bleed, respectively. The secondary safety endpoint was overall bleed. Hazard ratios (HR) were determined from Cox regression. RESULTS: Of 743 patients included, 224 were on warfarin, 156 on direct oral anticoagulants (DOACs), 277 on single antiplatelet therapy (SAPT), 28 on dual antiplatelet therapy (DAPT), and 58 on no therapy. Mean age (+/-SD) was 68.7 +/- 13.0 years. Compared with warfarin users, SAPT (adjusted [adj.] HR: 3.70, 95% confidence interval [CI]: 1.21-11.3) and DAPT users (adj. HR: 10.1, 95% CI: 1.51-67.2) were more likely to develop thromboembolic outcomes. Also, DOAC users (adj. HR: 0.304, 95% CI: 0.158-0.585), SAPT users (adj. HR: 0.142, 95% CI: 0.0680-0.295), and DAPT users (adj. HR: 0.112, 95% CI: 0.0146-0.857) were less likely to experience any bleed compared with warfarin users. CONCLUSIONS: SAPT and DAPT are less effective than warfarin in NVAF patients. DOACs may be considered in view of lower risk of overall bleed. PMID- 29251772 TI - Population Pharmacokinetic- Pharmacodynamic Analysis to Characterize the Effect of Empagliflozin on Renal Glucose Threshold in Patients With Type 1 Diabetes Mellitus. AB - Sodium glucose cotransporter 2 inhibitors increase urinary glucose excretion (UGE) by lowering the renal threshold for glucose (RTG ). We aimed to quantify the effect of the sodium glucose cotransporter inhibitor empagliflozin on renal glucose reabsorption in patients with type 1 diabetes mellitus (T1DM) using a mechanistic population pharmacokinetic-pharmacodynamic (PK-PD) model and to compare results with analyses in patients with type 2 diabetes mellitus (T2DM). The PK-PD model was developed using data from a randomized phase 2 study in which patients with T1DM received oral once-daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as an adjunct to insulin. The model assumed that UGE was dependent on plasma glucose and renal function and that empagliflozin lowered RTG . The final model was evaluated using visual predictive checks and found to be consistent with observed data. Calculated RTG with placebo was 181 mg/dL, and with empagliflozin (steady state) 1 mg and 2.5 mg was 53.4 mg/dL and 12.5 mg/dL, respectively. Empagliflozin 10 mg and 25 mg yielded negative RTG values, implying RTG was reduced to a negligible value. Although estimated PK-PD parameters were generally comparable between patients with T1DM and patients with T2DM, slight differences were evident, leading to lower RTG and higher UGE in patients with T1DM compared with patients with T2DM. In conclusion, the model provided a reasonable description of UGE in response to administration of empagliflozin and placebo in patients with T1DM. PMID- 29251773 TI - Insights into the uptake, metabolization, and translocation of four non-steroidal anti-inflammatory drugs in cress (Lepidium sativum) by HPLC-MS2. AB - The metabolization of four non-steroidal anti-inflammatory drugs by cress (Lepidium sativum) was investigated using a HPLC-MS2 method. Cress was grown hydroponically in water containing 0.1 mg/L of each drug for investigations on the kinetics of drug uptake and metabolization over a growing period of 12 days. It could be shown that the parent drugs are metabolized and the abundance of both the parent drug and the metabolites formed, varies over time. Furthermore the distribution of the investigated substances within the different plant parts changed throughout the duration of the experiment due to translocation. Finally cress was cultivated in a solution containing the four drugs in concentrations as low as 0.001 mg/L to resemble the situation in real reclaimed wastewaters. Employing a QuEChERS approach for sample extraction and HPLC-MS2 in the multiple reaction monitoring mode allowed detecting nine metabolites in this cress sample. PMID- 29251775 TI - How practical experiences, educational routes and multidisciplinary teams influence genetic counselors' clinical practice in Europe. AB - The main objective of our study was to explore whether, and to what extent, genetic counselors' characteristics impact on their tasks in practice. Specifically, we explored the complementariness between genetic counselors and medical geneticists and therefore looked at the most relevant tasks of genetic counselors, according to genetic counselors themselves and according to the medical geneticists they work with. A total of 104 genetic counselors and 29 medical geneticists from 15 countries completed a purposefully designed questionnaire. Results showed that most genetic counselors in Europe perform similar tasks, irrespective of their backgrounds. When looking at the factors influencing genetic counselors' roles data showed that the type of tasks performed by genetic counselors is associated with the years of experience in the field, not with their background or education. Of particular interest was the consensus between genetic counselors and medical geneticists regarding the genetic counselor's role. Not surprisingly, tasks with more psychosocial implications were seen as genetic counselors' eligibility while tasks with more medical implications were seen as medical geneticists' attribution. Our study shows that most genetic counselors work in tune with international recommendations and seem to be supportive of multidisciplinary teams. Corroborating our data with previous research, we discuss potential implications for practice and training in genetic counseling. PMID- 29251776 TI - Structural basis for Ufm1 recognition by UfSP. AB - Ubiquitin and ubiquitin-like proteins (Ubls) are involved in a variety of cellular functions, and dysfunction of these proteins often leads to disease, thus requiring the precise molecular recognition of the partner. Here, we report a structural basis for the recognition of Ufm1 by the Ufm1-specific protease (UfSP), both from Caenorhabditis elegans. Ufm1 functions in endoplasmic reticulum homeostasis, cell cycle regulation, and dysfunctions of this protein can result in breast cancer and neurological disorders. The structure reveals that in addition to the extended beta-structure at the C-terminus of cUfm1, the interactions made by the completely conserved residues in Ufm1 orthologs, Pro88 Val92, corresponding to P6-P2 positions from the cleavage site, seem to be important for the specific recognition of Ufm1 by cUfSP. PMID- 29251774 TI - Altered toll-like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice. AB - Systemic lupus erythematosus is a debilitating autoimmune disease in which autoantibodies and autoreactive T cells destroy kidneys and other organs. Disease is clinically and genetically heterogeneous, suggesting that underlying mechanisms vary between patients. We previously used an autoantibody transgenic mouse reporter system to examine the effect of different autoimmune backgrounds on B-cell tolerance, failure of which is a fundamental defect in lupus. We identified a defect consistent with reversible anergy induced by endotoxin stimulation of B cells from Ig transgenic New Zealand Black (NZB) mice. Herein we report that the tolerance defect is revealed by TLR7 and TLR9 as well as TLR4 ligands, with additive effect, and is partially reversed by Mek inhibition. Gene expression analysis reveals significant differences in transcription of multiple TLR pathway genes and ptpn22 in stimulated NZB compared to B6 B cells. Additionally, the defect is detected in Ig transgenic NZB F1 hybrid strains (NZBxNZW)F1 and (B6xNZB)F1. These results implicate an inherited defect wherein NZB anergic B cells maintain coordinated TLR/BCR signaling that permits autoantibody production. Agents targeting these pathways may have therapeutic benefit in the subset of lupus patients that manifest similar defects in B-cell regulation. PMID- 29251777 TI - An adaptive motion regularization technique to support sliding motion in deformable image registration. AB - PURPOSE: Isotropic smoothing has been conventionally used to regularize deformation vector fields (DVFs) in deformable image registration (DIR). However, the isotropic smoothing method enforces global smoothness and therefore cannot accurately model the complex tissue deformation, such as sliding motion at organ boundaries. To accurately model and estimate sliding tissue motion, an adaptive direction-dependent DVF regularization technique was developed in this study. METHODS: A DVF is computed and updated iteratively by minimizing the intensity differences between the images. In each iteration, the DVF was smoothed using an adaptive direction-dependent filter which enforces different motion propagation mechanisms along the primary normal and tangential directions of soft tissue local structures. A Gaussian isotropic filter was used along the normal direction while a bilateral filter was used along the tangential direction. To support large sliding motion, an automatic method was developed to delineate sliding surfaces, such as the chest wall and abdominal wall, where large organ sliding motion occurs. Parameters of the DVF regularization were adjusted adaptively based on a distance map to the sliding surfaces. The proposed method was tested on 14 4D-CT datasets at End-Inhalation (EI) and End-Exhalation (EE) phases of a respiratory cycle (10 public lung datasets, 3 upper abdomen datasets and 1 digital phantom dataset). TRE results of the 10 lung datasets were compared to results from six other existing DIR methods. For the three upper abdomen patient datasets, DIR accuracy was evaluated using manually defined landmarks across the lung and the abdomen. For the digital phantom dataset, DIR accuracy was evaluated using the ground truth displacement of a total 40,000 points that were evenly distributed across the phantom. RESULTS: The results showed that the sliding motion was preserved near the surface of chest wall and abdominal wall. The average target registration error (TRE) was reduced by 35.1% using the proposed method in comparison with five other methods on the 10 lung datasets. The sum of squared difference (SSD) after registration using the proposed method was 4.4% and 11.4% smaller than the SSDs obtained using isotropic smoothing and bilateral smoothing respectively. On the digital phantom, the average TRE was reduced by 59.6% near the surface of liver and by 53.7% near the surface of spleen using the proposed method. Contour propagation and Jacobian determinant analysis of DVF suggested an overall improved accuracy using the proposed method. CONCLUSION: An adaptive direction-dependent DVF regularization method has been developed to model the sliding tissue motion of the thoracic and abdominal organs. The overall motion estimation accuracy has been improved especially near the chest wall and abdominal wall where large organ sliding motion occurs. PMID- 29251778 TI - Advance care planning (ACP) for specialists managing cirrhosis: A focus on patient-centered care. AB - : Advance care planning (ACP) and goals of care designation (GCD) are being integrated into modern health care. In cirrhosis, uptake and adoption of these practices have been limited with physicians citing many perceived barriers and limitations. Recognizing the many tangible benefits of ACP and GCD processes in patients with life-limiting chronic diseases, the onus is on health practitioners to initiate and direct these conversations with their patients and surrogates. Drawing upon the literature and our experiences in palliative care and cirrhosis, we provide an actionable framework that can be readily implemented into a busy clinical setting by a practitioner. Conversation starters, visual aids, educational resources (for patients and practitioners), and videos of mock physician-patient scenarios are presented and discussed. Importantly, we have customized each of these tools to meet the unique health care needs of patients with cirrhosis. The inherent flexibility of our approach to ACP discussions and GCD can be further modified to accommodate practitioner preferences. CONCLUSION: In our clinics, this assemblage of "best practice tools" has been well received by patients and surrogates enabling us to increase the number of outpatients with cirrhosis who have actively contributed to their GCD before acute health events and are supported by well-informed surrogates. (Hepatology 2018;67:2025-2040). PMID- 29251779 TI - Selective regulation of type II interferon-inducible genes by NPM1/nucleophosmin. AB - Nucleophosmin (NPM1) is a multifunctional nucleolar protein. Here, we analyze the role of NPM1 in gene expression using our previous microarray data and find a relationship between NPM1 and interferon (IFN)-gamma-inducible genes. We show that NPM1 selectively regulates the expression of a subset of IFN-gamma-inducible genes and directly binds to two important transcription factors in the type II IFN pathway: signal transducer and activator of transcription 1 and interferon regulatory factor 1 (IRF1). Furthermore, NPM1 is found to regulate the IFN-gamma inducible promoter activity of major histocompatibility complex class II transactivator (CIITA), and mutation of the IRF1-binding site on the CIITA promoter abolishes the effect of NPM1. Our results suggest a novel mechanism for IFN-gamma-mediated gene expression by NPM1. PMID- 29251780 TI - Exploring the link between perfectionism and depressive symptoms: Contribution of rumination and defense styles. AB - OBJECTIVE: This study investigated the mediating and moderating roles of emotion focused coping strategies (rumination and immature defenses) in the relationship between perfectionism and depressive symptoms in a Spanish community sample. METHOD: 438 participants (67.4% female; mean age = 36.94 years) completed self reports assessing perfectionism, rumination, immature defenses and depression. Multiple mediation, moderation and moderated mediation analyses were conducted. RESULTS: Brooding-rumination and immature defenses mediated the relationship between perfectionism and depressive symptoms. Also, brooding-rumination moderated the impact of perfectionism on depressive symptoms. The mediating effect of brooding in the relationship between perfectionism and depressive symptoms turned out to be moderated by immature defenses, such that the vulnerability link between perfectionism and depressive symptoms through brooding was stronger in individuals scoring high on immature defenses. CONCLUSION: Brooding-rumination and immature defenses may be essential mechanisms to explain the paths and conditions whereby maladaptive perfectionism gives rise to depression. PMID- 29251781 TI - The reciprocal associations between identity disturbance, relationship disturbance, and suicidal ideation among Chinese adolescents: A three-wave cross lag study. AB - OBJECTIVE: Adolescence is a developmental period associated with a heightened risk for suicidal ideation. During this phase of life, individuals tend to focus on both intrapersonal self and interpersonal relationships. Thus, it is of much significance to understand the roles of intrapersonal and interpersonal factors in the development of suicidal ideation among adolescents. The present study examined the reciprocal associations between identity disturbance, relationship disturbance, and suicidal ideation by using a three-wave cross-lag model in a sample of adolescents. METHOD: A number of 3,600 Chinese adolescents (56.6% females, mean age = 14.58 years) completed questionnaires assessing the three main study variables as well as depressive symptoms, anxiety, and suicidal attempts three times at 6-month intervals. RESULTS: After controlling for gender, age, depressive symptoms, anxiety, and suicidal attempts, relationship disturbance significantly predicted suicidal ideation over time, and vice versa. Suicidal ideation significantly predicted identity disturbance over time, but not vice versa. We also found the mediating effect of relationship disturbance in the path from identity disturbance to suicidal ideation. CONCLUSION: The results suggested the important role of previous relationship disturbance in predicting later suicidal ideation. Theoretical and clinical implications of these findings were discussed. PMID- 29251782 TI - The association between self-compassion and treatment outcomes: Session-level and treatment-level effects. AB - OBJECTIVE: Self-compassion (SC) has been consistently linked to less psychopathology; however, the link between changes in client's SC levels and psychotherapy outcomes has yet to be explored. METHOD: Clients at a university based community clinic completed SC and outcome measures session by session (N = 112) as well as pre- to posttreatment (N = 70). RESULTS: Increases in clients' SC levels across the entire therapeutic process were associated with improvement in all posttreatment outcomes. Additionally, session-to-session increases in SC levels predicted improved symptoms and functioning at the session level; these effects were significant above and beyond the effects of the therapeutic alliance. CONCLUSION: The results of the current study highlight SC as a possible process variable in psychotherapy. PMID- 29251783 TI - Effect of Metformin on Hypothalamic-Pituitary-Thyroid Axis Activity in Elderly Antipsychotic-Treated Women With Type 2 Diabetes and Subclinical Hypothyroidism: A Preliminary Study. AB - Metformin was found to reduce elevated serum thyrotropin levels, and this effect was partially determined by endogenous dopaminergic tone. The aim of this study was to compare the effect of metformin treatment on hypothalamic-pituitary thyroid axis activity in elderly women with subclinical hypothyroidism treated with antipsychotic agents and not receiving this drug. The study population consisted of 34 elderly women with subclinical hypothyroidism, 16 of whom received antipsychotic drugs. Because of coexistent type 2 diabetes, these women were treated with metformin (2.55-3 g daily). Glucose homeostasis markers as well as serum levels of thyrotropin, free thyroid hormones and prolactin were measured at the beginning of the study and 6 months later. Thirty women completed the study. With the exception of prolactin, baseline serum levels of the assessed hormones were comparable in both study groups. Although metformin reduced serum thyrotropin levels in both groups, this effect was more pronounced in the antipsychotic-treated than in the antipsychotic-naive patients. The effect on serum prolactin was observed only in antipsychotic-treated patients. The impact on serum thyrotropin levels correlated with improvement in insulin sensitivity and with a reduction in prolactin levels. Free thyroxine and free triiodothyronine remained at a similar level throughout the study. The obtained results indicate that metformin reduces serum thyrotropin levels in elderly women, and this effect is particularly pronounced in women with diminished dopaminergic transmission. PMID- 29251784 TI - Synthesis of AgCl/Ag3 PO4 Composite Photocatalysts and Study on Photodegradation Activity Based on a Continuous Reactor. AB - Novel AgCl/Ag3 PO4 photocatalysts were synthesized by a simple precipitation method, in which AgCl was coated onto Ag3 PO4 particles, as uncovered by X-ray diffractometry, transmission electron microscopy and ultraviolet-visible spectrometry. Different from previous research on photocatalytic degradation, we studied the performance of methyl orange photodegradation on a small continuous flow reactor. The highest degradation activity of 97% was achieved by the 2 wt.% AgCl/Ag3 PO4 after 8 min of visible light irradiation, while pure Ag3 PO4 degraded only 71% methyl orange under same conditions. The degradation rate constant of the 2 wt.% AgCl/Ag3 PO4 was 1.36 times higher than that of pure Ag3 PO4 . The AgCl/Ag3 PO4 maintained high photocatalytic activity after five cycles, without any significant decrease. PMID- 29251785 TI - Delafloxacin Pharmacokinetics in Subjects With Varying Degrees of Renal Function. AB - Delafloxacin, a fluoroquinolone, has activity against gram-positive organisms including methicillin-resistant Staphylococcus aureus and fluoroquinolone susceptible and -resistant gram-negative organisms. This study was conducted to determine delafloxacin pharmacokinetics after a single intravenous infusion or oral dose administration in subjects with varying degrees of renal function. The study was an open-label, parallel-group crossover study in subjects with normal renal function or with mild, moderate, or severe renal impairment. Subjects received 300 mg delafloxacin intravenously, placebo intravenously, and 400 mg delafloxacin orally in 3 periods separated by >=14-day washouts. Blood and urine pharmacokinetic parameters were calculated using noncompartmental methods. Delafloxacin total clearance decreased with decreasing renal function, with a corresponding increase in AUC0-infinity . After intravenous administration, mean total clearance was 13.7 and 7.07 L/h, and mean AUC0-infinity was 22.6 and 45.0 MUg.h/mL in normal and severe renal subjects, respectively. Mean renal clearance as determined by urinary excretion was 6.03 and 0.44 L/h in normal and severe renal impairment subjects, respectively. Total clearance exhibited linear relationships to eGFR and CLCR . Similar observations were found after oral administration of delafloxacin. Single doses of delafloxacin 300 mg intravenously and 400 mg orally were well tolerated in all groups. In conclusion, renal insufficiency has an effect on delafloxacin clearance; a dosing adjustment for intravenous dosing is warranted for patients with severe renal impairment (eGFR < 30 mL/min). PMID- 29251786 TI - Multipoint scanning dual-detection confocal microscopy for fast 3D volumetric measurement. AB - We propose a multipoint scanning dual-detection confocal microscopy (MS-DDCM) system for fast 3D volumetric measurements. Unlike conventional confocal microscopy, MS-DDCM can accomplish surface profiling without axial scanning. Also, to rapidly obtain 2D images, the MS-DDCM employs a multipoint scanning technique, with a digital micromirror device used to produce arrays of effective pinholes, which are then scanned. The MS-DDCM is composed of two CCDs: one collects the conjugate images and the other collects nonconjugate images. The ratio of the axial response curves, measured by the two detectors, provides a linear relationship between the height of the sample surface and the ratio of the intensity signals. Furthermore, the difference between the two images results in enhanced contrast. The normalising effect of the MS-DDCM provides accurate sample heights, even when the reflectance distribution of the surface varies. Experimental results confirmed that the MS-DDCM achieved high-speed surface profiling with improved image contrast capability. PMID- 29251787 TI - Thwart your destiny; effect of nonacoholic fatty liver disease genes on steatosis, liver injury and cirrhosis varies by body mass index. PMID- 29251789 TI - HCC risk in patients with HBV-related cirrhosis receiving nucleos(t)ide analogues therapy: Is HCC prevented or delayed? PMID- 29251788 TI - Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks. AB - : Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in duck HBV (DHBV)-infected ducks and in patients with chronic HBV or HBV/hepatitis D virus infection. In this preclinical study, a combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV-infected duck groups were treated as follows: normal saline (control); REP 2139 TDF; REP 2139 + TDF; and REP 2139 + TDF + ETV. After 4 weeks of treatment, all animals were followed for 8 weeks. Serum DHBsAg and anti-DHBsAg antibodies were monitored by enzyme-linked immunosorbent assay and viremia by qPCR. Total viral DNA and covalently closed circular DNA (cccDNA) were quantified in autopsy liver samples by qPCR. Intrahepatic DHBsAg was assessed at the end of follow-up by immunohistochemistry. On-treatment reduction of serum DHBsAg and viremia was more rapid when REP 2139 was combined with TDF or TDF and ETV, and, in contrast to TDF monotherapy, no viral rebound was observed after treatment cessation. Importantly, combination therapy resulted in a significant decrease in intrahepatic viral DNA (>3 log) and cccDNA (>2 log), which were tightly correlated with the clearance of DHBsAg in the liver. CONCLUSION: Synergistic antiviral effects were observed when REP 2139 was combined with TDF or TDF + ETV leading to control of infection in blood and liver, associated with intrahepatic viral surface antigen elimination that persisted after treatment withdrawal. Our findings suggest the potential of developing such combination therapy for treatment of chronically infected patients in the absence of pegylated interferon. (Hepatology 2018;67:2127-2140). PMID- 29251790 TI - Capicua suppresses hepatocellular carcinoma progression by controlling the ETV4 MMP1 axis. AB - : Hepatocellular carcinoma (HCC) is developed by multiple steps accompanying progressive alterations of gene expression, which leads to increased cell proliferation and malignancy. Although environmental factors and intracellular signaling pathways that are critical for HCC progression have been identified, gene expression changes and the related genetic factors contributing to HCC pathogenesis are still insufficiently understood. In this study, we identify a transcriptional repressor, Capicua (CIC), as a suppressor of HCC progression and a potential therapeutic target. Expression of CIC is posttranscriptionally reduced in HCC cells. CIC levels are correlated with survival rates in patients with HCC. CIC overexpression suppresses HCC cell proliferation and invasion, whereas loss of CIC exerts opposite effects in vivo as well as in vitro. Levels of polyoma enhancer activator 3 (PEA3) group genes, the best-known CIC target genes, are correlated with lethality in patients with HCC. Among the PEA3 group genes, ETS translocation variant 4 (ETV4) is the most significantly up-regulated in CIC-deficient HCC cells, consequently promoting HCC progression. Furthermore, it induces expression of matrix metalloproteinase 1 (MMP1), the MMP gene highly relevant to HCC progression, in HCC cells; and knockdown of MMP1 completely blocks the CIC deficiency-induced HCC cell proliferation and invasion. CONCLUSION: Our study demonstrates that the CIC-ETV4-MMP1 axis is a regulatory module controlling HCC progression. (Hepatology 2018;67:2287-2301). PMID- 29251791 TI - Chitinase 3-like-1 promotes intrahepatic activation of coagulation through induction of tissue factor in mice. AB - : Coagulation is a critical component in the progression of liver disease. Identification of key molecules involved in the intrahepatic activation of coagulation (IAOC) will be instrumental in the development of effective therapies against liver disease. Using a mouse model of concanavalin A (ConA)-induced hepatitis, in which IAOC plays an essential role in causing liver injury, we uncovered a procoagulant function of chitinase 3-like 1 (Chi3l1). Chi3l1 expression is dramatically elevated after ConA challenge, which is dependent on ConA-induced T cell activation and the resulting interferon gamma and tumor necrosis factor alpha productions. Compared with wild-type mice, Chi3l1-/- mice show less IAOC, reduced tissue factor (TF) expression, and attenuated liver injury. Reconstituting Chi3l1-/- mice with recombinant TF triggers IAOC and augments liver injury. CONCLUSION: Our data demonstrate that Chi3l1, through induction of TF via mitogen-activated protein kinase activation, promotes IAOC and tissue injury. (Hepatology 2018;67:2384-2396). PMID- 29251793 TI - A contribution of CAD/CAM treatment of a dental trauma in a special care patient. AB - After a dental trauma, difficulties of communication and the consequences of the complex clinical situation often make regular chairside oral care long and complicated for special needs patients. The aim of this case report is to show how CAD/CAM technology may help in the prosthetic treatment of a clinical situation by keeping the number and duration of clinical sessions to a minimum while enabling a good aesthetic and functional result to be achieved in the long term. PMID- 29251792 TI - Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation through heat shock protein 90. AB - : A salient feature of alcoholic liver disease (ALD) is Kupffer cell (KC) activation and recruitment of inflammatory monocytes and macrophages (MOs). These key cellular events of ALD pathogenesis may be mediated by extracellular vesicles (EVs). EVs transfer biomaterials, including proteins and microRNAs, and have recently emerged as important effectors of intercellular communication. We hypothesized that circulating EVs from mice with ALD have a protein cargo characteristic of the disease and mediate biological effects by activating immune cells. The total number of circulating EVs was increased in mice with ALD compared to pair-fed controls. Mass spectrometric analysis of circulating EVs revealed a distinct signature for proteins involved in inflammatory responses, cellular development, and cellular movement between ALD EVs and control EVs. We also identified uniquely important proteins in ALD EVs that were not present in control EVs. When ALD EVs were injected intravenously into alcohol-naive mice, we found evidence of uptake of ALD EVs in recipient livers in hepatocytes and MOs. Hepatocytes isolated from mice after transfer of ALD EVs, but not control EVs, showed increased monocyte chemoattractant protein 1 mRNA and protein expression, suggesting a biological effect of ALD EVs. Compared to control EV recipient mice, ALD EV recipient mice had increased numbers of F4/80hi cluster of differentiation 11b (CD11b)lo KCs and increased percentages of tumor necrosis factor alpha positive/interleukin 12/23-positive (inflammatory/M1) KCs and infiltrating monocytes (F4/80int CD11bhi ), while the percentage of CD206+ CD163+ (anti inflammatory/M2) KCs was decreased. In vitro, ALD EVs increased tumor necrosis factor alpha and interleukin-1beta production in MOs and reduced CD163 and CD206 expression. We identified heat shock protein 90 in ALD EVs as the mediator of ALD EV-induced MO activation. CONCLUSION: Our study indicates a specific protein signature of ALD EVs and demonstrates a functional role of circulating EVs containing heat shock protein 90 in mediating KC/MO activation in the liver. (Hepatology 2018;67:1986-2000). PMID- 29251795 TI - The association between nonalcoholic fatty liver disease and metabolic comorbidities. PMID- 29251794 TI - 11Beta-hydroxysteroid dehydrogenase-1 deficiency or inhibition enhances hepatic myofibroblast activation in murine liver fibrosis. AB - : A hallmark of chronic liver injury is fibrosis, with accumulation of extracellular matrix orchestrated by activated hepatic stellate cells (HSCs). Glucocorticoids limit HSC activation in vitro, and tissue glucocorticoid levels are amplified by 11beta-hydroxysteroid dehydrogenase-1 (11betaHSD1). Although 11betaHSD1 inhibitors have been developed for type 2 diabetes mellitus and improve diet-induced fatty liver in various mouse models, effects on the progression and/or resolution of liver injury and consequent fibrosis have not been characterized. We have used the reversible carbon tetrachloride-induced model of hepatocyte injury and liver fibrosis to show that in two models of genetic 11betaHSD1 deficiency (global, Hsd11b1-/- , and hepatic myofibroblast specific, Hsd11b1fl/fl /Pdgfrb-cre) 11betaHSD1 pharmacological inhibition in vivo exacerbates hepatic myofibroblast activation and liver fibrosis. In contrast, liver injury and fibrosis in hepatocyte-specific Hsd11b1fl/fl /albumin-cre mice did not differ from that of controls, ruling out 11betaHSD1 deficiency in hepatocytes as the cause of the increased fibrosis. In primary HSC culture, glucocorticoids inhibited expression of the key profibrotic genes Acta2 and Col1alpha1, an effect attenuated by the 11betaHSD1 inhibitor [4-(2-chlorophenyl-4 fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone. HSCs from Hsd11b1 /- and Hsd11b1fl/fl /Pdgfrb-cre mice expressed higher levels of Acta2 and Col1alpha1 and were correspondingly more potently activated. In vivo [4-(2 chlorophenyl-4-fluoro-1-piperidinyl][5-(1H-pyrazol-4-yl)-3-thienyl]-methanone administration prior to chemical injury recapitulated findings in Hsd11b1-/- mice, including greater fibrosis. CONCLUSION: 11betaHSD1 deficiency enhances myofibroblast activation and promotes initial fibrosis following chemical liver injury; hence, the effects of 11betaHSD1 inhibitors on liver injury and repair are likely to be context-dependent and deserve careful scrutiny as these compounds are developed for chronic diseases including metabolic syndrome and dementia. (Hepatology 2018;67:2167-2181). PMID- 29251797 TI - An ecophysiological perspective on likely giant panda habitat responses to climate change. AB - Threatened and endangered species are more vulnerable to climate change due to small population and specific geographical distribution. Therefore, identifying and incorporating the biological processes underlying a species' adaptation to its environment are important for determining whether they can persist in situ. Correlative models are widely used to predict species' distribution changes, but generally fail to capture the buffering capacity of organisms. Giant pandas (Ailuropoda melanoleuca) live in topographically complex mountains and are known to avoid heat stress. Although many studies have found that climate change will lead to severe habitat loss and threaten previous conservation efforts, the mechanisms underlying panda's responses to climate change have not been explored. Here, we present a case study in Daxiangling Mountains, one of the six Mountain Systems that giant panda distributes. We used a mechanistic model, Niche Mapper, to explore what are likely panda habitat response to climate change taking physiological, behavioral and ecological responses into account, through which we map panda's climatic suitable activity area (SAA) for the first time. We combined SAA with bamboo forest distribution to yield highly suitable habitat (HSH) and seasonal suitable habitat (SSH), and their temporal dynamics under climate change were predicted. In general, SAA in the hottest month (July) would reduce 11.7% 52.2% by 2070, which is more moderate than predicted bamboo habitat loss (45.6% 86.9%). Limited by the availability of bamboo and forest, panda's suitable habitat loss increases, and only 15.5%-68.8% of current HSH would remain in 2070. Our method of mechanistic modeling can help to distinguish whether habitat loss is caused by thermal environmental deterioration or food loss under climate change. Furthermore, mechanistic models can produce robust predictions by incorporating ecophysiological feedbacks and minimizing extrapolation into novel environments. We suggest that a mechanistic approach should be incorporated into distribution predictions and conservation planning. PMID- 29251796 TI - Lipotoxicity induces hepatic protein inclusions through TANK binding kinase 1 mediated p62/sequestosome 1 phosphorylation. AB - : Obesity commonly leads to hepatic steatosis, which often provokes lipotoxic injuries to hepatocytes that cause nonalcoholic steatohepatitis (NASH). NASH, in turn, is associated with the accumulation of insoluble protein aggregates that are composed of ubiquitinated proteins and ubiquitin adaptor p62/sequestosome 1 (SQSTM1). Formation of p62 inclusions in hepatocytes is the critical marker that distinguishes simple fatty liver from NASH and predicts a poor prognostic outcome for subsequent liver carcinogenesis. However, the molecular mechanism by which lipotoxicity induces protein aggregation is currently unknown. Here, we show that, upon saturated fatty acid-induced lipotoxicity, TANK binding kinase 1 (TBK1) is activated and phosphorylates p62. TBK1-mediated p62 phosphorylation is important for lipotoxicity-induced aggregation of ubiquitinated proteins and formation of large protein inclusions in hepatocytes. In addition, cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING), upstream regulators of TBK1, are involved in lipotoxic activation of TBK1 and subsequent p62 phosphorylation in hepatocytes. Furthermore, TBK1 inhibition prevented formation of ubiquitin-p62 aggregates not only in cultured hepatocytes, but also in mouse models of obesity and NASH. CONCLUSION: These results suggest that lipotoxic activation of TBK1 and subsequent p62 phosphorylation are critical steps in the NASH pathology of protein inclusion accumulation in hepatocytes. This mechanism can provide an explanation for how hypernutrition and obesity promote the development of severe liver pathologies, such as steatohepatitis and liver cancer, by facilitating the formation of p62 inclusions. (Hepatology 2018). PMID- 29251798 TI - Lateral ventricular volume measurement by 3D MR hydrography in fetal ventriculomegaly and normal lateral ventricles. AB - BACKGROUND: In fetuses with prenatal ventriculomegaly (VM), ventricular volume on MRI has been shown to correlate with poor postnatal outcomes and in utero death. 3D magnetic resonance hydrography (MRH) has been widely used for MR cholangiopancreatography. PURPOSE: To investigate the reliability of 3D MRH for lateral ventricular volume measurement in fetuses with VM and normal lateral ventricles, using manual multisection planimetry (MSP) as a reference standard. STUDY TYPE: Prospective study. POPULATION: Thirty-five fetuses with VM at 24-37 gestational weeks (GA) and 35 fetuses with normal lateral ventricles at 24-38 GA. FIELD STRENGTH/SEQUENCE: 1.5T MRI with 3D MRH and T2 -weighted single-shot fast spin echo sequence. ASSESSMENT: Left, right, and total lateral ventricle volumes in fetuses were acquired from 3D MRH and manual MSP. All image analysis was performed by a radiologist twice and another radiologist once, blindly. STATISTICAL TESTS: Analysis of linear regression analysis, Pearson's correlation coefficient, Bland-Altman plots, intraclass correlation coefficient (ICC), and independent samples t-test were used for statistical analyses. RESULTS: There were highly significant relationships between all 3D MRH and manual MSP measurements of lateral ventricular volumes (rVM = 0.92-0.98; rN = 0.95-0.98; all P < 0.0001; VM: VM group, N: normal group), although left, right, and total lateral ventricular volumes measured by 3D MRH tended to be slightly larger than MSP (biasVM 0.1 +/- 0.95, 0.26 +/- 0.63, and 0.3 +/- 0.68 mL, respectively; biasN 0.1 +/- 0.95, 0.26 +/- 0.63, and 0.3 +/- 0.68 mL, respectively). Interrater agreement and intrarater repeatability were also excellent for 3D MRH (ICCVM = 0.994-0.99, ICCN = 0.989-0.992; ICCVM = 0.975-0.987, ICCN = 0.958-0.971, respectively). 3D MRH showed significantly reduced measurement time (VM: 3.55 +/- 0.42 vs. 11.81 +/- 0.13 min; N: 3.08 +/- 0.39 vs. 12.12 +/- 0.11 min; all P < 0.0001). DATA CONCLUSION: Lateral ventricular volume measurement by 3D MRH was comparable to manual MSP. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage 1 J. Magn. Reson. Imaging 2017. PMID- 29251799 TI - Atrioventricular junction ablation in patients with atrial fibrillation treated with cardiac resynchronization therapy: positive impact on ventricular arrhythmias, implantable cardioverter-defibrillator therapies and hospitalizations. AB - AIMS: We sought to determine whether atrioventricular junction ablation (AVJA) in patients with cardiac resynchronization therapy (CRT) implantable cardioverter defibrillator (ICD) and with permanent atrial fibrillation (AF) has a positive impact on ICD shocks and hospitalizations compared with rate-slowing drugs. METHODS AND RESULTS: This is a pooled analysis of data from 179 international centres participating in two randomized trials and one prospective observational research. The co-primary endpoints were all-cause ICD shocks and all-cause hospitalizations. Out of 3358 CRT-ICD patients (2720 male, 66.6 years), 2694 (80%) were in sinus rhythm (SR) and 664 (20%) had permanent AF-262 (8%) treated with AVJA (AF + AVJA) and 402 (12%) treated with rate-slowing drugs (AF + Drugs). Median follow-up was 18 months. The mean (95% confidence intervals) annual rate of all-cause ICD shocks per 100 patient years was 8.0 (5.3-11.9) in AF + AVJA, 43.6 (37.7-50.4) in AF + Drugs, and 34.4 (32.5-36.5) in SR patients, resulting in incidence rate ratio (IRR) reductions of 0.18 (0.10-0.32) for AF + AVJA vs. AF + Drugs (P < 0.001) and 0.48 (0.35-0.66) for AF + AVJA vs. SR (P < 0.001). These reductions were driven by significant reductions in both appropriate ICD shocks [IRR 0.23 (0.13-0.40), P < 0.001, vs. AF + Drugs] and inappropriate ICD shocks [IRR 0.09 (0.04-0.21), P < 0.001, vs. AF + Drugs]. Annual rate of all-cause hospitalizations was significantly lower in AF + AVJA vs. AF + Drugs [IRR 0.57 (0.41-0.79), P < 0.001] and SR [IRR 0.85 (073-0.98), P = 0.027]. CONCLUSION: In AF patients treated with CRT, AVJA results in a lower incidence and burden of all cause, appropriate and inappropriate ICD shocks, as well as to fewer all-cause and heart failure hospitalizations. CLINICAL TRIAL REGISTRATION: NCT00147290, NCT00617175, NCT01007474. PMID- 29251800 TI - Challenging a 15-year-old claim: The North Atlantic Oscillation index as a predictor of spring migration phenology of birds. AB - Many migrant bird species that breed in the Northern Hemisphere show advancement in spring arrival dates. The North Atlantic Oscillation (NAO) index is one of the climatic variables that have been most often investigated and shown to be correlated with these changes in spring arrival. Although the NAO is often claimed to be a good predictor or even to have a marked effect on interannual changes in spring migration phenology of Northern Hemisphere breeding birds, the results on relations between spring migration phenology and NAO show a large variety, ranging from no, over weak, to a strong association. Several factors, such as geographic location, migration phase, and the NAO index time window, have been suggested to partly explain these observed differences in association. A combination of a literature meta-analysis, and a meta-analysis and sliding time window analysis of a dataset of 23 short- and long-distance migrants from the constant-effort trapping garden at Helgoland, Germany, however, paints a completely different picture. We found a statistically significant overall effect size of the NAO on spring migration phenology (coefficient = -0.14, SE = 0.054), but this on average only explains 0%-6% of the variance in spring migration phenology across all species. As such, the value and biological meaning of the NAO as a general predictor or explanatory variable for climate change effects on migration phenology of birds, seems highly questionable. We found little to no definite support for previously suggested factors, such as geographic location, migration phenology phase, or the NAO time window, to explain the heterogeneity in correlation differences. We, however, did find compelling evidence that the lack of accounting for trends in both time series has led to strongly inflated (spurious) correlations in many studies (coefficient = -0.13, SE = 0.019). PMID- 29251802 TI - Stepwise Introduction of Cyano Groups into nido- and closo-Undecaborate Clusters. AB - Eleven-vertex closo and nido boron clusters with one or two exo-cyano groups were obtained by a series of consecutive cage-opening and cage-closure reactions starting from K2 [closo-B11 H11 ] (K2 1). In the first step, K2 1 reacts with KCN in water at elevated temperatures to yield [7-NC-nido-B11 H12 ]2- (5 a). Oxidation of 5 a with PbO2 gives [NC-closo-B11 H10 ]2- (2). In analogous subsequent reactions, dianion 2 was converted with KCN regioselectively to [7,9 (NC)2 -nido-B11 H11 ]2- (6 a), which was further oxidized to [(NC)2 -closo-B11 H9 ]2- (3). The {nido-B11 } dianions 5 a and 6 a were protonated to yield [7-NC-nido B11 H13 ]- (5 b) and [7,9-(NC)2 -nido-B11 H12 ]- (6 b). All anions were studied by NMR spectroscopy and, except for 6 b, salts of all anions were characterized by IR and Raman spectroscopy and by elemental analysis. The position of the cyano group(s) in 5 a and 6 a were confirmed by NMR data and single-crystal X-ray diffraction studies on [Ph4 P]2 5 a?CH2 Cl2 and [Et4 N]2 6 a. The {closo-B11 } clusters are fluxional in solution. In the crystal of [EMIm]2 2 the BCN vertex is in the 2-position. Two isomers of dianion 3, [2,3-(NC)2 -closo-B11 H9 ]2- and [2,6-(NC)2 -closo-B11 H9 ]2- , were identified in the crystal of its [Et4 N]+ salt. The peak oxidation potentials Epa of anions 1-3, 5 a, 6 a, 5 b, and [nido B11 H14 ]- (4 b), determined by cyclic voltammetry, increase with increasing number of cyano groups. Increasing Epa in the order 1<2<3 parallels the increasing reactivity toward cyanide anions. PMID- 29251801 TI - The role of replay and theta sequences in mediating hippocampal-prefrontal interactions for memory and cognition. AB - Sequential activity is seen in the hippocampus during multiple network patterns, prominently as replay activity during both awake and sleep sharp-wave ripples (SWRs), and as theta sequences during active exploration. Although various mnemonic and cognitive functions have been ascribed to these hippocampal sequences, evidence for these proposed functions remains primarily phenomenological. Here, we briefly review current knowledge about replay events and theta sequences in spatial memory tasks. We reason that in order to gain a mechanistic and causal understanding of how these patterns influence memory and cognitive processing, it is important to consider how these sequences influence activity in other regions, and in particular, the prefrontal cortex, which is crucial for memory-guided behavior. For spatial memory tasks, we posit that hippocampal-prefrontal interactions mediated by replay and theta sequences play complementary and overlapping roles at different stages in learning, supporting memory encoding and retrieval, deliberative decision making, planning, and guiding future actions. This framework offers testable predictions for future physiology and closed-loop feedback inactivation experiments for specifically targeting hippocampal sequences as well as coordinated prefrontal activity in different network states, with the potential to reveal their causal roles in memory-guided behavior. PMID- 29251804 TI - A study of neurite orientation dispersion and density imaging in wilson's disease. AB - BACKGROUND: Previous studies have indicated that neurite orientation dispersion and density imaging (NODDI) could be used as a biomarker for detecting microstructural changes of brain. PURPOSE: To quantitatively evaluate the changes in basal ganglia (BG) and thalamus in Wilson's disease (WD) by NODDI and assess the correlation between parameters and disease severity. STUDY TYPE: Prospective case-control study. POPULATION: In total, 24 WD patients and 25 age- and sex matched normal controls were involved in this study. FIELD STRENGTH/SEQUENCE: EPI diffusion-weighted MR images (b-values = 0, 1000, and 2000 with 30 diffusion gradient directions) were acquired on a 3T scanner. ASSESSMENT: Diffusion data were analyzed using voxel-based analysis. NODDI indices including intracellular volume fraction (Vic), orientation dispersion index (ODI), and isotropic volume fraction (Viso) were estimated from the BG and thalamus. The disease severity was assessed by two experienced neurologists based on the Global Assessment Scale (GAS). The relative importance of NODDI indices in diagnosing WD and predictive accuracy were also analyzed. STATISTICAL TESTING: The Shapiro-Wilk test, Student's t-test, chi2 test, Mann-Whitney-Wilcoxon test, Spearman rank correlation coefficient analysis and random-forest analysis were used for statistical analyses. RESULTS: The Vic and ODI in the BG and thalamus were significantly lower in WD patients than normal controls, while the Viso in the BG and thalamus were significantly higher (P < 0.01). The Vic in the putamen and ODI in the globus pallidus were negatively correlated with clinical severity (rvic = 0.727, P < 0.001; rodi = -0.705, P < 0.001). The Vic in the putamen was the most valuable predictor for diagnosing WD and the prediction accuracy of NODDI was 95.92%. DATA CONCLUSION: NODDI can effectively evaluate the changes of microstructure and metabolism during copper deposition in WD, and thus, it is likely to be useful in detecting the changes in the brain of this disease and assessing its progression. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2018;48:423-430. PMID- 29251805 TI - Fawcettimine-Type Lycopodium Alkaloids as a Driving Force for Discoveries in Organic Synthesis. AB - Ever since the pioneering synthetic work reported by both Inubushi and Heathcock back in 1980s, the fawcettimine-type Lycopodium alkaloids have continuously served as a driving force for discoveries in organic synthesis. In this personal account, we summarized our recent synthetic efforts towards the total synthesis of fawcettimine-type Lycopodium alkaloids, along with a brief summary of relevant syntheses reported by others. Our discussions focus mainly on the key reactions applied during the synthesis of fawcettimine-type Lycopodium alkaloids. PMID- 29251803 TI - Light modulates hippocampal function and spatial learning in a diurnal rodent species: A study using male nile grass rat (Arvicanthis niloticus). AB - The effects of light on cognitive function have been well-documented in human studies, with brighter illumination improving cognitive performance in school children, healthy adults, and patients in early stages of dementia. However, the underlying neural mechanisms are not well understood. The present study examined how ambient light affects hippocampal function using the diurnal Nile grass rats (Arvicanthis niloticus) as the animal model. Grass rats were housed in either a 12:12 h bright light-dark (brLD, 1,000 lux) or dim light-dark (dimLD, 50 lux) cycle. After 4 weeks, the dimLD group showed impaired spatial memory in the Morris Water Maze (MWM) task. The impairment in their MWM performance were reversed when the dimLD group were transferred to the brLD condition for another 4 weeks. The results suggest that lighting conditions influence cognitive function of grass rats in a way similar to that observed in humans, such that bright light is beneficial over dim light for cognitive performance. In addition to the behavioral changes, grass rats in the dimLD condition exhibited reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, most notably in the CA1 subregion. There was also a reduction in dendritic spine density in CA1 apical dendrites in dimLD as compared to the brLD group, and the reduction was mostly in the number of mushroom and stubby spines. When dimLD animals were transferred to the brLD condition for 4 weeks, the hippocampal BDNF and dendritic spine density significantly increased. The results illustrate that not only does light intensity affect cognitive performance, but that it also impacts hippocampal structural plasticity. These studies serve as a starting point to further understand how ambient light modulates neuronal and cognitive functions in diurnal species. A mechanistic understanding of the effects of light on cognition can help to identify risk factors for cognitive decline and contribute to the development of more effective prevention and treatment of cognitive impairment in clinical populations. PMID- 29251806 TI - Tools for protein science. PMID- 29251807 TI - Proteomic diversity of high-density lipoprotein explains its association with clinical outcome in patients with heart failure. AB - AIMS: Previously, low high-density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in-depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome. METHODS AND RESULTS: We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT-CHF. A novel optimised protocol for selective enrichment of lipoproteins was used to prepare plasma. Enriched lipoprotein content of samples was analysed using high resolution nanoscale liquid chromatography-mass spectrometry-based proteomics, utilising a label free approach. Within the HDL proteome, 49 proteins significantly differed between deaths and survivors. An optimised model of 12 proteins predicted death with 76% accuracy (Nagelkerke R2 =0.37, P < 0.001). The strongest contributors to this model were filamin-A (related to crosslinking of actin filaments) [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.15-0.61, P = 0.001] and pulmonary surfactant-associated protein B (related to alveolar capillary membrane function) (OR 2.50, 95% CI 1.57-3.98, P < 0.001). The model predicted mortality with an area under the curve of 0.82 (95% CI 0.77-0.87, P < 0.001). Internal cross validation resulted in 73.3 +/- 7.2% accuracy. CONCLUSION: This study shows marked differences in composition of the HDL proteome between HF survivors and deaths. The strongest differences were seen in proteins reflecting crosslinking of actin filaments and alveolar capillary membrane function, posing potential pathophysiological mechanisms underlying the association between HDL and clinical outcome in HF. PMID- 29251808 TI - Prognostic significance of global longitudinal strain in chronic kidney disease: the evidence is building. PMID- 29251809 TI - Novel Sensing Strategies Based on Monolayer Protected Gold Nanoparticles for the Detection of Metal Ions and Small Molecules. AB - Monolayer protected gold nanoparticles (AuNPs) have a huge potential for the development of innovative sensing systems for the detection of metal ions and small molecules. The organic ligand shell, primarily utilized to stabilize the gold core, can be rationally designed to promote selective interactions with a desired analyte. In addition, the outstanding physical and optical properties of AuNPs can be exploited to obtain analytically useful signals upon analyte binding. In this account, we review recent advances in AuNP-based sensing systems emphasizing on the rational design of the ligand shell for detection of heavy metal ions and small molecules. We examine various strategies of detection by evaluating their improvements in terms of sensitivity, selectivity and applicability to real samples. PMID- 29251810 TI - Congestion in acute heart failure with reduced vs. preserved left ventricular ejection fraction: differences, similarities and remaining gaps. PMID- 29251813 TI - Building Peptide Bonds in Haifa: The Seventh Chemical Protein Synthesis (CPS) Meeting. AB - The power of CPS, live! More than 90 attendees from around the world came together in Haifa to present and hear about cutting-edge science in protein chemistry, from advances in synthetic methods to applications in biology and medicine. The meeting was a powerful demonstration that chemical protein synthesis can provide otherwise unattainable insights into protein structure and function. PMID- 29251812 TI - The physical spacing between the von Willebrand factor D'D3 and A1 domains regulates platelet adhesion in vitro and in vivo. AB - : Essentials The role of von Willebrand factor (VWF) domains in regulating platelet adhesion was studied in vivo. Multimeric VWF with spacers at the N- and C-terminus of VWF-A1 were systematically tested. N-terminal modified VWF avidly bound platelet GpIbalpha, causing VWD Type2B like phenotype in mice. Novel anti D'D3 mAbs suggest that changes at the D'D3-A1 interface may be biologically relevant. SUMMARY: Background Previous ex vivo studies using truncated VWF (von Willebrand factor) suggest that domain-level molecular architecture may control platelet-GpIbalpha binding function. Objective We determined if this is the case with multimeric VWF in vivo. Methods Full-length human VWF ('hV') was modified with a 22-amino acid mucinous stretch at either the N-terminus of VWF-A1 to create 'hNV' or C-terminus to yield 'hCV'. This extends the physical distance between VWF-A1 and the adjacent domains by ~6 nm. Similar mucin inserts were also introduced into a human-murine chimera ('h[mA1]V') where murine-A1 replaced human A1 in hV. This yielded 'h[mA1]NV' and 'h[mA1]CV', with N- and C-terminal inserts. The constructs were tested ex vivo and in vivo. Results Mucin insertion at the N terminus, but not C-terminus, in both types of constructs resulted in >50-fold increase in binding to immobilized GpIbalpha. N-terminal insertion also resulted in greater shear-induced platelet activation, more thrombus formation on collagen, enhanced platelet accumulation and slower platelet translocation on immobilized VWF in microfluidics assays. Hydrodynamic injection-based expression of h[mA1]NV, but not h[mA1]V or h[mA1]CV, in VWF-/- mice caused profound thrombocytopenia, reduced plasma VWF concentrations, lower multimer distribution, and incessant tail bleeding that is reminiscent of von Willebrand disease type 2B. Platelet plugs were noted in the portal veins and hepatic arteries. An anti D'D3 mAb DD3.3 that displays enhanced binding to VWF containing the N-terminal mucin insert also exhibited increased binding to wild-type VWF under shear and upon ristocetin addition. Conclusion Conformation changes at the VWF D'D3-A1 interface may be a key regulator of thrombosis in vivo. Structural features at the A1-A2 interface are likely of less significance. PMID- 29251811 TI - Impact of adolescent stress on the expression of stress-related receptors in the hippocampus of animals exposed to alcohol prenatally. AB - Many functions of the hippocampus are affected by prenatal alcohol exposure (PAE). In particular, dysregulation of the stress response is especially important because individuals with PAE carry increased risks for exposure to stressful environments throughout life. Little is known, though, about how adolescent stress in the context of PAE-related stress system dysregulation may further alter hippocampal development. Here, we investigate the short- and long term effects of adolescent chronic mild stress (CMS) on mRNA expression of stress related mineralocorticoid (MR), glucocorticoid (GR), and type 1 CRH (CRHR1) receptors in the dorsal and ventral hippocampal formation of PAE and control rats. Our results indicate that PAE affects the expression of stress-related receptors in the hippocampus; however, PAE effects were more prominent during adolescence, as MR and CRHR1 mRNA expression were altered in both male and female PAE animals, with GR mRNA expression alterations observed only in PAE female. In adulthood, the effects of PAE were restricted to alterations in CRHR1 mRNA expression in females, while there were no effects in males. In contrast, the effects of adolescent CMS were more pronounced in adulthood, long after stress exposure termination. Importantly, PAE animals were less responsive to adolescent CMS, with effects only on CRHR1 in PAE animals compared to the altered MR, GR, and CRHR1 mRNA expression observed in controls. Together, our results show that PAE and adolescent CMS induce dynamic alterations in the expression of stress related receptors in the hippocampal formation that manifest differently depending on the age and sex of the animal. PMID- 29251814 TI - Early visual outcomes and optical quality after femtosecond laser small-incision lenticule extraction for myopia and myopic astigmatism correction of over -10 dioptres. AB - PURPOSE: To investigate early visual and refractive outcomes, corneal stability and optical quality after femtosecond laser small-incision lenticule extraction (SMILE) for treating myopia and myopic astigmatism over -10 D. METHODS: Thirty eyes (30 patients) with myopia and myopic astigmatism of over -10 D were treated with VisuMax(r) femtosecond laser (version 3.0; Carl Zeiss Meditec AG, Jena, Germany). Six months postoperative safety, efficacy and predictability were evaluated. Corneal Scheimpflug topography was measured preoperatively, 1 day, 3 months and 6 months postoperatively. Wavefront aberrations were measured preoperatively, 3 months and 6 months postoperatively. RESULTS: Six months postoperatively, LogMAR uncorrected and corrected distance visual acuity (CDVA) were -0.013 +/- 0.086 and -0.073 +/- 0.069, respectively. 73% (97%) of eyes were within 0.5 (1) D of target refraction. No eyes lost CDVA, 43% (13 eyes) gained one line and 7% (two eyes) gained two lines. Mean corneal back curvature (KMB) and posterior central elevation (PCE) did not change significantly comparing preoperative and 6 months postoperative data (p = 0.91 and 0.77, respectively). Comparing 1 day with 6 months postoperative data, central corneal thickness (CCT), mean corneal front curvature (KMF), KMB and PCE did not change significantly (p = 0.27, 0.07, 0.52, 0.71, respectively). Total higher-order aberration (HOA), spherical aberration and coma increased significantly (p < 0.01) but trefoil remained stable (p = 0.49). CONCLUSION: Our results indicate that SMILE can correct myopia and myopic astigmatism of over -10 D predictably. No early ectasia was observed. Long-term changes in visual quality and corneal stability require further investigation. PMID- 29251815 TI - Peripheral Templation-Modulated Interconversion between an A4 L6 Tetrahedral Anion Cage and A2 L3 Triple Helicate with Guest Capture/Release. AB - An anion-coordination-based A4 L6 ("A" denotes anion and "L" is ligand) tetrahedral cage was constructed by a C2 -symmetric bis-bis(urea) ligand and phosphate anion, which showed reversible interconversion with the A2 L3 triple helicate as a response to the template, concentration, or solvent. Notably, an unusual "peripheral" templation was found to be critical to stabilize the tetrahedral structure. This peripheral effect was utilized to assemble an "empty" A4 L6 cage that allows the multi-stimuli-controlled capture/release of biologically important species such as choline and acetylcholine. PMID- 29251816 TI - Interaction of antivirals with a heptameric bundle model of the p7 protein of hepatitis C virus. AB - A series of ligands are known experimentally to affect the infectivity cycle of the hepatitis C virus. The target protein for the ligands is proposed to be p7, a 63 amino acid polytopic channel-forming protein, with possibly two transmembrane domains. Protein p7 is found to assemble into functional oligomers of various sizes, depending on the genotype (GT). Nine ligands are docked to various sites of a computationally derived heptameric bundle of p7 of GT1a. The energy of interaction, here binding energy, is calculated using three different docking programs (Autodock, MOE, LeadIT). Three protein regions are defined to which the ligands are placed, the loop region and the site with the termini as well as the mid-region which is supposed to track poses inside the putative pore. A common feature is that the loop sites and poses either within the pore or at the intermonomer space of the bundle are preferred for all ligands with proposed binding energies smaller than -10 kJ/mol. BIT225, benzamine, amantadine, and NN DNJ show good overall scoring. PMID- 29251817 TI - Mitigation of nitrous oxide emissions from acidic soils by Bacillus amyloliquefaciens, a plant growth-promoting bacterium. AB - Nitrous oxide (N2 O) is a long-lived greenhouse gas that can result in the alteration of atmospheric chemistry and cause accompanying changes in global climate. To date, many techniques have been used to mitigate the emissions of N2 O from agricultural fields, which represent one of the most important sources of N2 O. In this study, we designed a greenhouse pot experiment and a microcosmic serum bottle incubation experiment using acidic soil from a vegetable farm to study the effects of Bacillus amyloliquefaciens (BA) on plant growth and N2 O emission rates. The addition of BA to the soil promoted plant growth enhanced the soil pH and increased the total nitrogen (TN) contents in the plants. At the same time, it decreased the concentrations of ammonium (NH4+ ), nitrate (NO3- ) and TN in the soil. Overall, the addition of BA resulted in a 50% net reduction of N2 O emissions compared with the control. Based on quantitative PCR and the network analysis of DNA sequencing, it was demonstrated that BA partially inhibited the nitrification process through the significant reduction of ammonia oxidizing bacteria. Meanwhile, it enhanced the denitrification process, mainly by increasing the abundance of N2 O-reducing bacteria in the treatment with BA. The results of our microcosm experiment provided evidence that strongly supported the above findings under more strictly controlled laboratory conditions. Taken together, the results of our study evidently demonstrated that BA has dual effects on the promotion of plant growth and the dramatic reduction of greenhouse emissions, thus suggesting the possibility of screening beneficial microbial organisms from the environment that can promote plant growth and mitigate greenhouse trace gases. PMID- 29251819 TI - Direct Transformation of Esters into Heterocyclic Fluorophores. AB - Despite the manifold use of heterocyclic fluorophores, only a fraction of the desired dye diversity can be accessed by contemporary synthetic approaches. Herein, we describe a modular method that converts various carboxylic acid esters directly into a broad spectrum of heteroanthrylium fluorophores. The double addition of heteroatom-bridged 1,5-bifunctional organomagnesium reagents to esters leads to the formation of acridinium, xanthylium, and SiR fluorophores after dehydrative acidic work-up. This one-step synthetic method provides access to organophotoredox catalysts for dual catalysis with nickel and dyes amenable to fluorescence enhancement. PMID- 29251818 TI - Acutely decompensated heart failure with preserved and reduced ejection fraction present with comparable haemodynamic congestion. AB - AIMS: Congestion is a central feature of acute heart failure (HF) and its assessment is important for clinical decisions (e.g. tailoring decongestive treatments). It remains uncertain whether patients with acute HF with preserved ejection fraction (HFpEF) are comparably congested as in acute HF with reduced EF (HFrEF). This study assessed congestion, right ventricular (RV) and renal dysfunction in acute HFpEF, HFrEF and non-cardiac dyspnoea. METHODS AND RESULTS: We compared echocardiographic and circulating biomarkers of congestion in 146 patients from the MEDIA-DHF study: 101 with acute HF (38 HFpEF, 41 HFrEF, 22 HF with mid-range ejection fraction) and 45 with non-cardiac dyspnoea. Compared with non-cardiac dyspnoea, patients with acute HF had larger left and right atria, higher E/e', pulmonary artery systolic pressure and inferior vena cava (IVC) diameter at rest, and lower IVC variability (all P < 0.05). Mid-regional pro atrial natriuretic peptide (MR-proANP) and soluble CD146 (sCD146), but not B-type natriuretic peptide (BNP), correlated with echocardiographic markers of venous congestion. Despite a lower BNP level, patients with HFpEF had similar evidence of venous congestion (enlarged IVC, left and right atria), RV dysfunction (tricuspid annular plane systolic excursion), elevated MR-proANP and sCD146, and renal impairment (estimated glomerular filtration rate; all P > 0.05) compared with HFrEF. CONCLUSION: In acute conditions, HFpEF and HFrEF presented in a comparable state of venous congestion, with similarly altered RV and kidney function, despite higher BNP in HFrEF. PMID- 29251820 TI - Staphylococcus aureus, master manipulator of the human hemostatic system. AB - The coagulation system does not only offer protection against bleeding, but also aids in our defense against invading microorganisms. The hemostatic system and innate immunity are strongly entangled, which explains why so many infections are complicated by either bleeding or thrombosis. Staphylococcus aureus (S. aureus), currently the most deadly infectious agent in the developed world, causes devastating intravascular infections such as sepsis and infective endocarditis. During these infections S. aureus comes in close contact with the host hemostatic system and proves to be a master in manipulating coagulation. The coagulases of S. aureus directly induce coagulation by activating prothrombin. S. aureus also manipulates fibrinolysis by triggering plasminogen activation via staphylokinase. Furthermore, S. aureus binds and activates platelets and interacts with key coagulation proteins such as fibrin(ogen), fibronectin and von Willebrand factor. By manipulating the coagulation system S. aureus gains a significant advantage over the host defense mechanisms. Studying the interplay between S. aureus and the hemostatic system can therefore lead to new innovative therapies for battling S. aureus infections. PMID- 29251821 TI - Intracellular Delivery of Native Proteins Facilitated by Cell-Penetrating Poly(disulfide)s. AB - Intracellular delivery of therapeutic proteins is highly challenging and in most cases requires chemical or genetic modifications. Herein, two complementary approaches for endocytosis-independent delivery of proteins to live mammalian cells are reported. By using either a "glycan" tag naturally derived from glycosylated proteins or a "traceless" tag that could reversibly label native lysines on non-glycosylated proteins, followed by bioorthogonal conjugation with cell-penetrating poly(disulfide)s (CPDs), we achieved intracellular delivery of proteins (including antibodies and enzymes) which, upon spontaneous degradation of CPDs, led to successful release of their "native" functional forms with immediate bioavailability. PMID- 29251822 TI - Proteochemometric modeling of the origin of thymidylate synthase inhibition. AB - Due to its crucial role in DNA synthesis, thymidylate synthase (TS) has been considered as a potential therapeutic target. Inhibition of the enzyme is a promising strategy for the treatment of some hyperproliferative diseases, including infections. As TS species-specific inhibitors would be able to distinguish between the host and the pathogens, developing highly selective inhibitors is of great clinical importance. TS is among the most highly conserved enzymes over evolutionary history, making the design of its species-selective inhibitor significantly challenging. The chemical interaction space, governed by a set of non-selective TS inhibitors, has been explored for human TS and its homologous proteins in both Toxoplasma gondii and Escherichia coli using proteochemometrics modeling (PCM). Validity, robustness, and prediction power of the PCM model have been assessed applying a diverse set of internal/external validation approaches. Our PCM model has provided major structural information, which is indeed of great help to design new TS species-specific inhibitors with the simultaneous inhibition ability toward both T. gondii and E. coli. To show applicability of the PCM model, new compounds have been designed based on structural information provided by the constructed model. Final results have been very promising with regard to selectivity ratios of the designed compounds for different TS isoforms, confirming the applicability of the PCM model. PMID- 29251823 TI - Yellow-green laser-based flow cytometry for CD34+ progenitor cell counting. PMID- 29251825 TI - Synthesis and Structure Revision of Dichrocephones A and B. AB - Herein, we report the first enantioselective synthesis of dichrocephones A and B, which are cytotoxic triquinane sesquiterpenes with a dense array of stereogenic centers within a strained polycyclic environment. Key features include the application of a catalytic asymmetric Wittig reaction, followed by stereoselective functionalization of the propellane core into a pentacyclic intermediate. Double reductive ring cleavage yielded the proposed structure of dichrocephone A. Mismatched spectroscopic data for our synthetic material compared to the natural isolate led us to revise the previously proposed configuration based on biosynthetic considerations and NMR calculations. Implementation of these findings culminated in the synthesis of dichrocephones A and B. PMID- 29251824 TI - Dual drive coexistence of EML4-ALK and TPM3-ROS1 fusion in advanced lung adenocarcinoma. AB - We report a case of concomitant EML4-ALK and TPM3-ROS1 fusion in non-small cell lung cancer (NSCLC) in a 47-year-old Chinese man and review the clinical characteristics of this type double of fusion. The patient presented with a local tumor of the left upper lobe and underwent thoracoscopy. Postoperative surgical pathologic staging revealed T1a N0 M0 stage IA. Histological examination of the tumor showed lung adenocarcinoma. Ventana ALK (D5F3) assay of the left lung tissue was ALK negative; however, immunohistochemical assay was positive for ROS1 protein. Using next generation sequencing, we found that the tumor had concomitant EML4-ALK and TPM3-ROS1 fusion. No recurrence was observed during seven months of follow-up. Precise diagnostic techniques allow the detection of concomitant ROS1 fusion and other driver genes, including ALK or EGFR; therefore oncologists should consider this rare double mutation in NSCLC patients. Further exploration of treatment models is required to provide additional therapeutic options. PMID- 29251826 TI - Digging Deep into Peptidomics Applied to Body Fluids. AB - Peptidomics techniques have allowed the identification of thousands of peptides that are derived from proteins in body fluids, despite the considerable challenges behind sample handling, MS-based identification, data analysis, and integration with bioinformatics tools. Body fluids' naturally occurring peptides are known to perform a variety of local and systemic functions; however, its knowledge is limited. Even so, the biological meaning that can be retrieved from peptidomics applied to the identification of disease markers and to the development of therapies using peptides has driven the progresses made in this field. In this review, a comparative analysis of body fluids' peptidome data retrieved from databases and from scientific papers is performed to identify the biological processes modulated by naturally occurring peptides. This integrative analysis highlights several interesting facts, such as the small overlap between blood-derived serum and plasma, which illustrates the impact of sample handling on these fluids peptidome. Urine is the body fluid with more naturally occurring peptides identified so far, most of which are derived from collagens. In saliva, the majority of peptides are originated from extracellular matrix proteins. Cerebrospinal fluid presents a high number of peptides derived from distinct proteins, mostly involved in the regulation of nervous system homeostasis. The lowest number of endogenous peptides was found in tears, most of which present antimicrobial activity. Collectively, data analysis highlights a peptidome signature for each body fluid, which comprehension will certainly help to improve disease management. PMID- 29251827 TI - Quantitative Proteomics Identified TTC4 as a TBK1 Interactor and a Positive Regulator of SeV-Induced Innate Immunity. AB - TBK1, STING, and MDA5 are important players within the antiviral innate immune response network. We mapped the interactome of endogenous TBK1, STING, and MDA5 by affinity enrichment MS in virally infected or uninfected THP-1 cells. Based on quantitative data of more than 2000 proteins and stringent statistical analysis, 58 proteins were identified as high-confidence interactors for at least one of three bait proteins. Our data indicated that TBK1 and MDA5 mostly interacted within preexisting protein networks, while STING interacted with different proteins with different viral infections. Functional analysis was performed on 17 interactors, and six were found to have functions in innate immune responses. We identified TTC4 as a TBK1 interactor and positive regulator of sendai virus induced innate immunity. PMID- 29251828 TI - ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and related disorders part 4 - assay validation and quality assurance. AB - Over the past six years, a diverse group of stakeholders have put forth recommendations regarding the analytical validation of flow cytometric methods and described in detail the differences between cell-based and traditional soluble analyte assay validations. This manuscript is based on these general recommendations as well as the published experience of experts in the area of PNH testing. The goal is to provide practical assay-specific guidelines for the validation of high-sensitivity flow cytometric PNH assays. Examples of the reports and validation data described herein are provided in Supporting Information. (c) 2017 International Clinical Cytometry Society. PMID- 29251829 TI - Decreased cerebral Irp-1B limits impact of social isolation in wild type and Alzheimer's disease modeled in Drosophila melanogaster. AB - Environmental factors, such as housing conditions and cognitively stimulating activities, have been shown to affect behavioral phenotypes and to modulate neurodegenerative conditions such as Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder affecting cognitive functions. Epidemiological evidence and experimental studies using rodent models have indicated that social interaction reduces development and progression of disease. Drosophila models of Abeta42-associated AD lead to AD-like phenotypes, such as long-term memory impairment, locomotor and survival deficits, while effects of environmental conditions on AD-associated phenotypes have not been assessed in the fly. Here, we show that single housing reduced survival and motor performance of Abeta42 expressing and control flies. Gene expression analyses of Abeta42 expressing and control flies that had been exposed to different housing conditions showed upregulation of Iron regulatory protein 1B (Irp-1B) in fly brains following single housing. Downregulating Irp-1B in neurons of single housed Abeta42 expressing and control flies rescued both survival and motor performance deficits. Thus, we provide novel evidence that increased cerebral expression of Irp-1B may underlie worsened behavioral outcome in socially deprived flies and can additionally modulate AD-like phenotypes. PMID- 29251830 TI - Patterns of altered neural synchrony in the default mode network in autism spectrum disorder revealed with magnetoencephalography (MEG): Relationship to clinical symptomatology. AB - : Disrupted neural synchrony may be a primary electrophysiological abnormality in autism spectrum disorders (ASD), altering communication between discrete brain regions and contributing to abnormalities in patterns of connectivity within identified neural networks. Studies exploring brain dynamics to comprehensively characterize and link connectivity to large-scale cortical networks and clinical symptoms are lagging considerably. Patterns of neural coherence within the Default Mode Network (DMN) and Salience Network (SN) during resting state were investigated in 12 children with ASD (MAge = 9.2) and 13 age and gender-matched neurotypicals (NT) (MAge = 9.3) with magnetoencephalography. Coherence between 231 brain region pairs within four frequency bands (theta (4-7 Hz), alpha, (8-12 Hz), beta (13-30 Hz), and gamma (30-80 Hz)) was calculated. Relationships between neural coherence and social functioning were examined. ASD was characterized by lower synchronization across all frequencies, reaching clinical significance in the gamma band. Lower gamma synchrony between fronto-temporo-parietal regions was observed, partially consistent with diminished default mode network (DMN) connectivity. Lower gamma coherence in ASD was evident in cross-hemispheric connections between: angular with inferior/middle frontal; middle temporal with middle/inferior frontal; and within right-hemispheric connections between angular, middle temporal, and inferior/middle frontal cortices. Lower gamma coherence between left angular and left superior frontal, right inferior/middle frontal, and right precuneus and between right angular and inferior/middle frontal cortices was related to lower social/social-communication functioning. Results suggest a pattern of lower gamma band coherence in a subset of regions within the DMN in ASD (angular and middle temporal cortical areas) related to lower social/social-communicative functioning. Autism Res 2018, 11: 434-449. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Communication between different areas of the brain was observed in children with ASD and neurotypical children while awake, but not working on a task. Magnetoencephalography was used to measure tiny magnetic fields naturally generated via brain activity. The brains of children with ASD showed less communication between areas that are important for social information processing compared to the brains of neurotypical children. The amount of communication between these areas was associated with social and social communication difficulties. PMID- 29251831 TI - A longitudinal study in learning preferences and academic performance in first year medical school. AB - This is a longitudinal study of first year medical students that investigates the relationship between the pattern change of the learning preferences and academic performance. Using the visual, auditory, reading-writing, and kinesthetic inventory at the beginning of the first and second year for the same class, it was found that within the first year, 36% of the class remained unimodal (single) modality learners (SS), 14% changed from unimodal to multimodality learners (SM), 27% changed from multimodality to unimodal modality learners (MS) and 21% remained as multimodality learners (MM). Among the academic performance through subsequent didactic blocks from Clinical Anatomy, Cell and Subcellular Processes to Medical Neuroscience during first year, the SM group made more significant improvement compared to the SS group. Semi-structured interview results from the SM group showed that students made this transition between the Clinical Anatomy course and the middle of the Medical Neuroscience course, in an effort to improve their performance. This study suggests that the transition from unimodal to multimodality learning among academically struggling students improved their academic performance in the first year of medical school. Therefore, this may be considered as part of academic advising tools for struggling students to improve their academic performances. Anat Sci Educ 11: 488-495. (c) 2017 American Association of Anatomists. PMID- 29251832 TI - A role for activity-dependent epigenetics in the development and treatment of major depressive disorder. AB - Chronic stressors, during developmental sensitive periods and beyond, contribute to the risk of developing psychiatric conditions, including major depressive disorder (MDD). Epigenetic mechanisms including DNA methylation and histone modifications, at key stress response and neurotrophin genes, are increasingly implicated in mediating this risk. Although the exact mechanisms through which stressful environmental stimuli alter the epigenome are still unclear, research from the learning and memory fields indicates that epigenomic marks can be altered, at least in part, through calcium-dependent signaling cascades in direct response to neuronal activity. In this review, we highlight key findings from the stress, MDD, and learning and memory fields to propose a model where stress regulates downstream cellular functioning through activity-dependent epigenetic changes. Furthermore, we suggest that both typical and novel antidepressant treatments may exert positive influence through similar, activity-dependent pathways. PMID- 29251833 TI - Population Pharmacokinetics of Levofloxacin in Plasma and Bone of Patients Undergoing Hip or Knee Surgery. AB - Patients undergoing hip or knee replacement therapy are routinely pretreated with antibiotics before they enter the operation theater. This treatment intends to reduce the incidence of peri- or postsurgical infections. Here, we calculated the uptake kinetics of levofloxacin into bone to see whether levofloxacin could be obtained from the trabecular and cortical bone and at what time concentrations are sufficiently high to inhibit the usual hospital infections. Patients (n = 42) undergoing routine surgery were treated with 500 mg levofloxacin intravenously immediately prior to the operation. Plasma samples were taken before and at 3 points after termination of drug infusion. After replacement of the bones, extracts were obtained from them. Levofloxacin was quantified using high performance liquid chromatography. The kinetics of levofloxacin and its distribution into bone were analyzed using a population approach (ADAPT5). Clearance was 14.0 L/h, and distribution volume was 77 L. Bone uptake t1/2 was calculated as 4.2 and 5.4 hours for cortical bone and trabecular bone, respectively. In knee samples (but not in hip samples), we noted that the cortical bone contained higher levels of levofloxacin than the trabecular bone. From our data, we can conclude that levofloxacin might be useful for prophylactic use in bone surgery. PMID- 29251834 TI - Impact and educational outcomes of a small group self-directed teaching strategy in a clinical neuroscience curriculum. AB - The complexity of the material being taught in clinical neuroscience within the medical school curriculum requires creative pedagogies to teach medical students effectively. Many clinical teaching strategies have been developed and are well described to address these challenges. However, only a few have been evaluated to determine their impact on the performance of students studying clinical neuroscience. Interactive, 2-hour, self-directed small-group interactive clinical case-based learning sessions were conducted weekly for 4 weeks to integrate concepts learned in the corresponding didactic lectures. Students in the small groups analyzed cases of patients suffering from neurological disease that were based on eight learning objectives that allowed them to evaluate neuroanatomical data and clinical findings before presenting their case analysis to the larger group. Students' performances on the formative quizzes and summative tests were compared to those of first-year medical students in the previous year for whom the self-directed, small-group interactive clinical sessions were not available. There was a significant improvement in the summative performance of first-year medical students with self-directed clinical case learning in the second year (Y2) of teaching clinical neuroscience (P < 0.05) when compared with first-year students in the first year (Y1) for whom the self-directed learning approach was not available. Student performance in the formative assessments between Y1 and Y2 was not significantly different (P = 0.803). A target of >=70% student scoring above 80% in the final summative examination was met. The current study revealed evidence for the impact and educational outcomes of a self-directed, clinical teaching strategy in a clinical neuroscience curriculum for first-year medical students. Anat Sci Educ 11: 478-487. (c) 2017 American Association of Anatomists. PMID- 29251835 TI - Child and family characteristics moderate agreement between caregiver and clinician report of autism symptoms. AB - : Rates of autism spectrum disorder (ASD) and age at first diagnosis vary considerably across the United States and are moderated by children's sex, race, ethnicity, and availability of services. We additionally suggest that degree of caregiver-clinician agreement on ASD symptoms may play a role in ASD assessment. Since gold standard ASD assessment integrates caregiver-reported developmental history with clinician observations, differential agreement between reporters across demographic groups may contribute to a host of detrimental outcomes. Here, we investigate whether caregiver-clinician agreement on ASD symptoms varies according to child and family characteristics. Comprehensive data from 2,759 families in the Simons Simplex Collection were analyzed. Linear models were created with caregiver reports predicting clinician reports, and moderating effects of child characteristics and family factors were examined. Poorer reporter correspondence was observed when children had higher IQ scores, stronger adaptive behavior, and more behavioral difficulties. Greater disagreement was also associated with African American racial status (for younger children), lower household income, and paternal social difficulties (for older children). Children's biological sex did not moderate caregiver-clinician agreement. Marked disagreement between caregivers and clinicians could lead to suboptimal or insufficient intervention services and negative experiences for families throughout development. Such families may also be less likely to qualify for research studies, and therefore be underrepresented in the ASD literature. Modified assessment procedures may be required to improve assessment accuracy and family experiences. Autism Res 2018, 11: 476-487. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Evaluation of autism spectrum disorder (ASD) incorporates both caregiver and clinician perspectives of symptoms, and disagreement between these perspectives could lead to poorer outcomes for families. Using data from 2,759 families, we show that caregiver clinician agreement on ASD symptoms is poorer for children with higher cognitive and adaptive skills, more behavioral difficulties, lower household income, and African American racial status. These children may be at higher risk for misdiagnosis, poorer family experiences during evaluations, and poorer representation in ASD research. PMID- 29251837 TI - AFOB Special Issue on Stem Cells in Tissue Engineering and Regenerative Medicine. PMID- 29251836 TI - Longitudinal development of thalamic and internal capsule microstructure in autism spectrum disorder. AB - : The thalamus is a key sensorimotor relay area that is implicated in autism spectrum disorder (ASD). However, it is unknown how the thalamus and white-matter structures that contain thalamo-cortical fiber connections (e.g., the internal capsule) develop from childhood into adulthood and whether this microstructure relates to basic motor challenges in ASD. We used diffusion weighted imaging in a cohort-sequential design to assess longitudinal development of the thalamus, and posterior- and anterior-limbs of the internal capsule (PLIC and ALIC, respectively) in 89 males with ASD and 56 males with typical development (3-41 years; all verbal). Our results showed that the group with ASD exhibited different developmental trajectories of microstructure in all regions, demonstrating childhood group differences that appeared to approach and, in some cases, surpass the typically developing group in adolescence and adulthood. The PLIC (but not ALIC nor thalamus) mediated the relation between age and finger tapping speed in both groups. Yet, the gap in finger-tapping speed appeared to widen at the same time that the between-group gap in the PLIC appeared to narrow. Overall, these results suggest that childhood group differences in microstructure of the thalamus and PLIC become less robust in adolescence and adulthood. Further, finger-tapping speed appears to be mediated by the PLIC in both groups, but group differences in motor speed that widen during adolescence and adulthood suggest that factors beyond the microstructure of the thalamus and internal capsule may contribute to atypical motor profiles in ASD. Autism Res 2018, 11: 450-462. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Microstructure of the thalamus, a key sensory and motor brain area, appears to develop differently in individuals with autism spectrum disorder (ASD). Microstructure is important because it informs us of the density and organization of different brain tissues. During childhood, thalamic microstructure was distinct in the ASD group compared to the typically developing group. However, these group differences appeared to narrow with age, suggesting that the thalamus continues to dynamically change in ASD into adulthood. PMID- 29251838 TI - The teenage brain issue. PMID- 29251840 TI - Blood-brain barrier development: Systems modeling and predictive toxicology. AB - The blood-brain barrier (BBB) serves as a gateway for passage of drugs, chemicals, nutrients, metabolites, and hormones between vascular and neural compartments in the brain. Here, we review BBB development with regard to the microphysiology of the neurovascular unit (NVU) and the impact of BBB disruption on brain development. Our focus is on modeling these complex systems. Extant in silico models are available as tools to predict the probability of drug/chemical passage across the BBB; in vitro platforms for high-throughput screening and high content imaging provide novel data streams for profiling chemical-biological interactions; and engineered human cell-based microphysiological systems provide empirical models with which to investigate the dynamics of NVU function. Computational models are needed that bring together kinetic and dynamic aspects of NVU function across gestation and under various physiological and toxicological scenarios. This integration will inform adverse outcome pathways to reduce uncertainty in translating in vitro data and in silico models for use in risk assessments that aim to protect neurodevelopmental health. PMID- 29251839 TI - Exercise, cognition, and the adolescent brain. AB - BACKGROUND: Few adolescents engage in the recommended levels of physical activity, and daily exercise levels tend to drastically decrease throughout adolescence. Beyond physical health benefits, regular exercise may also have important implications for the teenage brain and cognitive and academic capabilities. METHODS: This narrative review examines how physical activity and aerobic exercise relate to school performance, cognition, and brain structure and function. RESULTS: A number of studies have found that habitual exercise and physical activity are associated with academic performance, cognitive function, brain structure, and brain activity in adolescents. We also discuss how additional intervention studies that examine a wide range of neurological and cognitive outcomes are necessary, as well as characterizing the type, frequency, and dose of exercise and identifying individual differences that contribute to how exercise may benefit the teen brain. CONCLUSIONS: Routine exercise relates to adolescent brain structure and function as well as cognitive performance. Together, these studies suggest that physical activity and aerobic exercise may be important factors for optimal adolescent brain development. PMID- 29251841 TI - The impact of junk foods on the adolescent brain. AB - Adolescence is a significant period of physical, social, and emotional development, and is characterized by prominent neurobiological changes in the brain. The maturational processes that occur in brain regions responsible for cognitive control and reward seeking may underpin excessive consumption of palatable high fat and high sugar "junk" foods during adolescence. Recent studies have highlighted the negative impact of these foods on brain function, resulting in cognitive impairments and altered reward processing. The increased neuroplasticity during adolescence may render the brain vulnerable to the negative effects of these foods on cognition and behavior. In this review, we describe the mechanisms by which junk food diets influence neurodevelopment during adolescence. Diet can lead to alterations in dopamine-mediated reward signaling, and inhibitory neurotransmission controlled by gamma-aminobutyric acid (GABA), two major neurotransmitter systems that are under construction across adolescence. We propose that poor dietary choices may derail the normal adolescent maturation process and influence neurodevelopmental trajectories, which can predispose individuals to dysregulated eating and impulsive behaviors. PMID- 29251843 TI - Alcohol consumption during adolescence: A link between mitochondrial damage and ethanol brain intoxication. AB - Adolescence is a period of multiple changes where social behaviors influence interpersonal-relations. Adolescents live new experiences, including alcohol consumption which has become an increasing health problem. The age of onset for consumption has declined in the last decades, and additionally, the adolescents now uptake greater amounts of alcohol per occasion. Alcohol consumption is a risk factor for accidents, mental illnesses or other pathologies, as well as for the appearance of addictions, including alcoholism. An interesting topic to study is the damage that alcohol induces on the central nervous system (CNS) in the young population. The brain undergoes substantial modifications during adolescence, making brain cells more vulnerable to the ethanol toxicity. Over the last years, the brain mitochondria have emerged as a cell organelle which is particularly susceptible to alcohol. Mitochondria suffer severe alterations which can be exacerbated if the amount of alcohol or the exposure time is increased. In this review, we focus on the changes that the adolescent brain undergoes after drinking, placing particular emphasis on mitochondrial damage and their consequences against brain function. Finally, we propose the mitochondria as an important mediator in alcohol toxicity and a potential therapeutic target to reduce or treat brain conditions associated with excessive alcohol consumption. PMID- 29251842 TI - Taurine, caffeine, and energy drinks: Reviewing the risks to the adolescent brain. AB - Energy drinks are emerging as a major component of the beverage market with sales projected to top $60 billion globally in the next five years. Energy drinks contain a variety of ingredients, but many of the top-selling brands include high doses of caffeine and the amino acid taurine. Energy drink consumption by children has raised concerns, due to potential caffeine toxicity. An additional risk has been noted among college-aged consumers of energy drinks who appear at higher risk of over-consumption of alcohol when the two drinks are consumed together. The differential and combinatorial effects of caffeine and taurine on the developing brain are reviewed here with an emphasis on the adolescent brain, which is still maturing. Key data from animal studies are summarized to highlight both reported benefits and adverse effects reported following acute and chronic exposures. The data suggest that age is an important factor in both caffeine and taurine toxicity. Although the aged or diseased brain might benefit from taurine or caffeine supplementation, it appears that adolescents are not likely to benefit from supplementation and may, in fact, suffer ill effects from chronic ingestion of high doses. Additional work is needed though to address gaps in our understanding of how taurine affects females, since the majority of animal studies focused exclusively on male subjects. PMID- 29251845 TI - Melatonin, adolescence, and the brain: An insight into the period-specific influences of a multifunctional signaling molecule. AB - Melatonin is a neurohormone that is involved in the modulation of a wide range of physiological processes, including maintenance of the circadian rhythm, mediation of photoperiodic information, regulation of the sleep-wake cycle, synchronization of cell physiology, antioxidant defense, and immune-modulation. Although there are reports of increasing use of melatonin in the management of a number of health conditions, evidence exists that is suggestive of deleterious effects of melatonin administration on brain and reproductive development in the prepubertal and pubertal periods that are within the teenage years. In this review, we examine the influences of endogenous and exogenous melatonin on the adolescent brain, with specific reference to its involvement in the evolution of brain functions, brain structure, sleep regulation, and modulation of behaviors in health or disease. PMID- 29251844 TI - Convergent neurobiological predictors of emergent psychopathology during adolescence. AB - The adolescent brain undergoes significant structural and functional development. Through the use of magnetic resonance imaging in adolescents, it has been demonstrated that the prefrontal cortex, pertinent for executive control, demonstrates protracted development compared to limbic structures, active during emotion and reward processing. This asynchronous development creates a sensitive window during adolescence, in which many psychopathological disorders (i.e., mental health and substance use) emerge. This review outlines longitudinal studies that use magnetic resonance imaging to identify neurobiological predictors of emergent psychopathology (depression, anxiety, and substance use), during adolescence. Studies identifying neurobiological markers that predict onset and escalation of these disorders, as well as those that predict successful treatment outcomes are explored. An emphasis is placed on frontolimbic brain structures, a convergent neurobiological target for both emergent mental health issues and emergent substance use. The literature reviewed herein suggests that reduced volume and cortical thickness in frontolimbic regions, as well as reduced functional activation (particularly during task involving reward or emotional stimuli) in these regions, may serve as a neurobiological predictors of emergent psychopathology in adolescence. This knowledge is crucial, as it may be used to develop neurobiologically targeted prevention and intervention strategies for youth who are at-risk for developing these psychopathologies. PMID- 29251847 TI - COMMUNITY OUTREACH SERVICE TAKES FLIGHT. AB - Heading out into the community to provide healthcare for older people in their homes keeps Clinical Nurse Consultant (CNC) Diane Gellatly on her toes. PMID- 29251848 TI - TESTED TO THE LIMITS. AB - For nurses and midwives, every new round of collective bargaining for the next enterprise agreement involves another series of tough negotiations and, more often than not, members take some form of industrial action in support of their claims to achieve a fair and reasonable outcome. PMID- 29251849 TI - Occurrence and characterization of hitherto unknown Streptomyces species in semi arid soils. AB - Streptomyces the predominant genus of Actinobacteria and plays an important role in the recycling of soil organic matter and production of important secondary metabolites. The occurrence and diversity assessment of Streptomyces species revealed alkaline and poor nutrient status of soils of semi-arid region of Jodhpur, Rajasthan. The morphological and biochemical characterization of 21 Streptomyces isolates facilitated Genus level identification but were insufficient to designate species. Species designation based on 16S rRNA gene delineated 21 isolates into 14 Streptomyces species. Upon BLAST search, the test isolates exhibited 98 to 100% identities with that of the best aligned sequences of the NCBI database. The GC content of 16S rRNA gene sequences of all the Streptomyces isolates tested ranged from 59.03% to 60.94%. The multiple sequence alignment of all the 21 Streptomyces isolates generated a phylogram with high bootstrap values indicating reliable grouping of isolates based on nucleotide sequence variations by way of insertion, deletion and substitutions and 16S rRNA length polymorphism. Some of the Streptomyces species molecularly identified under present study are reported for the first time from semi-arid region of Jodhpur. PMID- 29251850 TI - Study of commercial effective microorganism on composting and dynamics of plant essential metal micronutrients. AB - The present study addresses the problem of organic farmers' that needs local organic resources with their enhanced quality to effectively fertilize their agriculture crops. In accordance with the objective of the experiment that is about enhancing quality of compost, a blend of organic resources, comprising cow manure (CM), poultry manure (PM) and kitchen waste (KW) (2:1:1 ratio by volume) was composted with effective microorganisms (EM.1) (CompostEM.1) and without (Compostplain). During composting, temperature, pH, carbon, nitrogen, C/N ratio, total and diethylene triamine pentaacetic acid (DTPA)-extractable essential metal micronutrient (Fe3+, Cu2+, Zn2+, and Mn2+) contents of both the composts were recorded following the standard procedures. Low temperature range (24-24), low pH (6.7-7.2) and higher N-content (1.15-1.40) were recorded for CompostEM.1 as compared to Compostplain. Carbon degradation was also faster in CompostEM.1 than in Compostplain. Consequently, C/N ratio stabilization took 6 weeks in CompostEM.1 as compared to 18 weeks in Compostplain, leading to rapid completion of composting. Total concentration of micronutrients increased while their DTPA extractable content decreased during the composting. Total micronutrient concentration was augmented more in Compostplain samples than in CompostEM.1. However, decrease in DTPA-extractable content was similar in both the composts. Increase in micronutrient content was attributed to decrease in organic matter weight, whereas decrease in metal micronutrients was attributed to the formation of organic matter-metal complexes during decomposition. Findings of the study indicated that effective micro-organisms enhanced composting process, however, further studies are required to evaluate its quality, especially effect on plant and soil. PMID- 29251851 TI - Estimation of age and longevity of freshwater fish Salmophasia balookee from otoliths, scales and vertebrae. PMID- 29251852 TI - Death AND DIGNITY. WHY VOLUNTARY EUTHANASIA IS A QUESTION OF CHOICE. AB - The prospect of voluntary euthanasia has created strong debate for decades and provoked passionate opinions from both sides of the fence. While not legal in Australia, a recent revived push for national voluntary euthanasia legislation has once again opened up the conversation and nurses have been encouraged to join the debate. Robert Fedele investigates the latest thinking and why more people are supporting voluntary euthanasia and the right to die with dignity. PMID- 29251846 TI - Neurobiology of substance use in adolescents and potential therapeutic effects of exercise for prevention and treatment of substance use disorders. AB - Substance use (e.g., alcohol, marijuana, opioids, cocaine., etc,) use often initiates during adolescence, a critical period of physiological and social development marked by an increase in risk-taking due, in part, to heightened motivation to obtain arousal from rewards. Substance use during adolescence has been associated with a greater risk of substance use disorders (SUD) in adulthood. Although use rates for most substances have remained relatively stable, the frequency of marijuana use and the perception that regular marijuana use is not harmful has increased in adolescents. Furthermore, the nonmedical use of opioids has increased, particularly in the South, Midwest, and rural low income communities. Substance use in adolescence has been associated with adverse structural and functional brain changes and, may exacerbate the natural "imbalance" between frontal/regulatory and cortical-subcortical circuits, leading to further heightened impulsive and reward-driven behaviors. Exercise increases growth and brain-derived neurotrophic factors that stimulate endogenous dopaminergic systems that, in turn, enhance general plasticity, learning, and memory. Exercise may help to reinforce the "naive" or underdeveloped connections between neurological reward and regulatory processes in adolescence from the "bottom up" and "offset" reward seeking from substances, while concomitantly improving cardiovascular health, as well as academic and social achievement. In this review, we provide an overview of the current state of substance use in adolescents and rationale for the utilization of exercise, particularly "assisted" exercise, which we have shown increases neural activity in cortical subcortical regions and may modulate brain dopamine levels during adolescence, a unique window of heightened reward sensitivity and neural plasticity, for the prevention and adjunctive treatment of SUD. PMID- 29251876 TI - Do emissions from thermal power plants affect crop productivity? A study from the vicinity of Bellary Thermal Power Station, Karnataka, India. AB - In the present study, ambient air quality was monitored during July to November 2013 in the vicinity of Bellary Thermal Power Station (BTPS), Karnataka to assess the impact of pollutants emitted from power plant on the productivity of maize (Zea mays L.). Atmospheric pollutant load were measured in five different villages at varying distances and directions from thermal power plant, with the village farthest away from BTPS (Yelubenchi) as control. Maize yield was also estimated in these locations and correlated to the pollutant concentrations. It was found that, both particulate matter and SO2 which are indicators of emissions from coal-fueled power plants were highest in Thimmalapur village located in the predominant down wind direction. A significant reduction in maize yield was noticed (8197 to 6509 kg ha-1 for seed and 14041 to 9933 kg ha-1 for stover) across the gradient in distance and direction from BTPS which might be influenced by the pollutants emitted. The implications of these observations are further discussed in the paper. PMID- 29251877 TI - MORAL DISTRESS. AB - Australia has an ageing nursing workforce with many nurses due to retire (Health Workforce Australia, 2014). Coupled with increasing service demands, the need for workers will outstrip the supply (CEPAR - ARC Centre of Excellence in Population Ageing Research, 2014). PMID- 29251878 TI - Effects of heavy metal exposure on the morphological and microscopical characteristics of the paddy plant. AB - The objective of the study was to determine the effects of heavy metal exposure on the morphology and anatomy of paddy plant (Oryza sativa L.). Paddy plants were treated with single and combined close of Cd and Pb (5, 10, 15, 20 and 25 ppm) at 35 days after germination. The results showed leaf chlorosis, decrease in number of roots and shoot height under both single and combined treatment. Heavy metal content in paddy was in the order of root>stem>grain>leaf and was highest at reproductive stage. A positive correlation was obtained between Cd, Pb and Cd-Pb concentrations in paddy plant parts with the concentrations of these metals in the soil. Scanning Electron Microscopic studies showed changes in the microscopic features due to accumulation of heavy metal and these included cell degeneration and thickening of cell walls, as well as increase in the number of treacherous elements in vascular cylinder and as residue in cells. Light microscope studies showed that Cd exposure caused dark deposits in the endodermal cells and vascular cylinder, as well as rupturing of parenchyma tissue. Results of the study indicated that paddy plants seemed to have some degree of tolerance to heavy metals. PMID- 29251879 TI - NURSE'S ROLE IN A FOREIGN LAND. AB - For many years a team of specialist Gynaecologists and Anaesthetists from The Women's Hospital in Melbourne have travelled to the beautiful, nomadic land of Mongolia. They have helped train Mongolian doctors in advanced practices related to laparoscopic-gynaecological surgery and anaesthesia, facilitating a number of ground-breaking 'firsts' in hospitals across several regions of the country. The role of nurses in this expedition was never established, and in 2015 a team of perioperative clinical nurse specialists joined the medical team to Mongolia for the first time. PMID- 29251880 TI - ? PMID- 29251882 TI - ? PMID- 29251881 TI - THE ETHICS OF 'NUDGING'. AB - Over the past several years increasing attention has been given to the social engineering process of 'nudging' (also called 'choice architecture') and its impact as a mechanism designed to deliberately manipulate and incentivise people to think and act in a presumably beneficial direction. PMID- 29251883 TI - Spatio-temporal study of carbon sequestration through piscicultural practice at East Kolkata Wetland. AB - The present study focus the variation of carbon concentrations within three trophic level i.e., primary producer (phytoplankton), primary consumers (zooplankton) and secondary consumers (fish) in three selected ponds at East Kolkata Wetland area. Depending on the amount and frequency of wastewater input, physico-chemical characteristics of pond, species richness, predator-prey interactions and pond wise different piscicultural practices, the amount of carbon sequestration varied spatially. Significant temporal variations were also observed in each trophic level of these three selected East Kolkata Wetland pond ecosystems. On average primary producers were sequestered 2038.6 +/- 244.8mg C m 3 d-1 whereas 307 +/- 19.3 mg C m-3 and 11531.4 +/- 318.2mg C m-3 was sequestered by primary and secondary consumers, respectively. In Kolkata and its nearby districts over 90% of the production was marked from the East Kolkata Wetland area. Consequently, a significant amount of sequestered carbon was exported from the East Kolkata Wetland ecosystem in the form of fish and this continuous system might increase the carbon sequestration efficiency of the aquatic ecosystem. PMID- 29251884 TI - A BALANCING ACT: MAINTAINING ACCURATE FLUID BALANCE CHARTING. AB - Fluid balance charting is not a new practice based issue in nursing (Chung et al. 2002; Jeyapala et al. 2015). Evidence reveals that fluid balance charts have been poorly and inaccurately maintained since 1985 (Chung et al, 2002; Scales & Pilsworth, 2008). PMID- 29251885 TI - NOVEL TECHNIQUE AIMS TO TRANSFORM BREASTFEEDING. AB - A Queensland midwife has developed a simple breastfeeding technique that will be piloted at a Brisbane hospital with new mothers, their babies, and midwives next year. With AIHW statistics showing only 15% of babies are breastfed after six months despite a 96% initial breastfeeding rate, it's hoped the project will change the way midwives help women to breastfeed. PMID- 29251886 TI - Micronutrient fortification in a crop to enhance growth, yield and quality of aromatic rice. AB - A field trial comprising of 3 levels of Zn-0, 5 and 10 kg ha-1, 3 levels of Fe-0, 15 and 30 kg ha-1 and 3 levels of Mn-0, 5 and 10 kg ha-1 was carried out during the two consecutive rainy seasons of 2008 and 2009 to study their effect on growth, yield and quality of aromatic rice cv. HUBR 2-1. The experiment was conducted in 33 partial confounding with three replications. All the micronutrients (Zn, Fe and Mn) were applied as basal and rest half doses were applied through foliar application at different intervals of crop growth. Application of 10 kg Zn ha-1 recorded significantly higher growth attributes i.e. plant height, tiller hill-1, dry weight and leaf area index (LAI) as compared to preceding doses. Significant increase in growth attributes was also observed with the application of 15 kg Fe ha-1, but it was statistically similar to 30 kg Fe ha 1. Similarly, incorporation of 5 kg Mn ha-1 significantly increased the growth attributes of rice but further increase in Mn levels decreased the response. Application of 10 kg Zn ha-1 (51.33 q ha-1) and 15 kg Fe ha-1 (51.09 q ha-1) resulted in significantly higher grain yield over control. Whereas, application of 5 kg Mn ha-1 produced the highest grain yield (49.91 q ha-1), but was at par with 10 kg Mn ha-1 (49.18 q ha-1).In respect of quality traits, application of 10 kg Zn ha-1 and 15 kg Fe ha-1 recorded maximum values of hulling, milling, head rice recovery, kernel length and breadth, which remained significantly superior to rest of the doses. Hence, to achieve the maximum productivity, profitability, as well as, quality of aromatic rice cv. HUBR 2-1 was grown with application of 10 kg Zn and 15 kg Fe along with 5 kg Mn ha-1. PMID- 29251887 TI - TAKING ACTION TO IMPROVE OUTCOMES FOR MEN LIVING WITH AND BEYOND PROSTATE CANCER. AB - In Australia prostate cancer is the most commonly diagnosed cancer in men, with around 20,000 diagnosed each year (AIHW 2013, 2014). The many who survive it often battle with significant side-effects from treatment such as incontinence, loss of sexual function, fatigue and psychology issues. PMID- 29251888 TI - NEONATAL ABSTINENCE SYNDROME AND INFANT MENTAL HEALTH. AB - Neonatal Abstinence Syndrome (NAS) is a term used to describe withdrawal symptoms of infants who became physically dependent on drugs of addiction while in utero (Prabhakar, 2014). PMID- 29251889 TI - STUDENT KNOWLEDGE OF PROVIDING CARE FOR WOMEN WHO EXPERIENCE ALCOHOL-USE DISORDERS. AB - Harmful alcohol consumption is associated with detrimental health and social consequences, yet this modifiable and preventable risk factor for serious non communicable diseases remains an unmet challenge (Spanagel et al. 2013; WHO, 2014, 2016). PMID- 29251890 TI - POLYSUBSTANCE USE IN A TERTIARY HOSPITAL EMERGENCY DEPARTMENT IN AUSTRALIA. AB - Alcohol and Other Drug (AOD) presentations are common in the Emergency Department (ED) especially on weekends (Parkinson et al. 2016) and the presence of AOD use can account for substantial healthcare costs (Butler et al. 2016). PMID- 29251891 TI - Adsorption capacity of Curcuma longa for the removal of basic green 1 dye- equilibrium, kinetics and thermodynamic study. AB - In the present study, Curcuma longa (turmeric plant) was used as an adsorbent to remove Basic Green 1 (BG) dye. Batch study was carried out to evaluate the adsorption potential of C. longa and influencing factors such as pH (4-10), adsorbent dose (0.2-5 g l-1), initial dye concentration (50-250 mg l-1) and temperature (30-50 degrees C) on dye removal were analysed. The characterisation of adsorbent was carried out using fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) and Brunauer, Emmett and Teller (BET) method. Isotherm models that included Langmuir, Freundlich, Tempkin and Dubinin-Radushkevich, and kinetic models such as pseudo first order, pseudo second-order, Elovich and intraparticle diffusion models were studied. A maximum removal percentage (82.76%) of BG dye from aqueous solution was obtained with optimum conditions of pH 7, 1g l-1 adsorbent dose and 30 degrees C temperature, for 100 mg l-1 initial dye concentration. The equilibrium and kinetic study revealed that the experimental data fitted suitably the Freundlich isotherm and Pseudo second order kinetic model. Thermodynamic analysis proved that adsorption system in this study was spontaneous, feasible and endothermic in nature. PMID- 29251892 TI - ALCOHOL, TOBACCO AND OTHER DRUGS NURSING WITHIN A CORRECTIONAL SETTING. AB - In Australia 67% of prisoners report previous illicit drug use (AIHW, 2015) with 39% reporting high risk of alcohol-related harm. The links between effective ATOD health programs and outcomes are clearly linked to reduced recidivism (Ombudsman report, 2015) and better biopsychosocial determinates. Correctional nurses' work in challenging environments but their adaptability and passion are key to the provision of community equivalent care. PMID- 29251893 TI - NURSING ATTITUDES TOWARDS PEOPLE WITH COMORBID SUBSTANCE ABUSE: A BRIEF REVIEW OF LITERATURE. AB - A new study in Melbourne aims to assess knowledge, skills and attitudes of mental health nurses employed in a large mental health service. The study will use an observation as well as surveys and interviews to explore knowledge, skills, and attitude of nurses towards consumers with comorbid substance use. PMID- 29251894 TI - OPIOID DEPENDENCY IN PREGNANCY. AB - Substance use (illicit and licit) in pregnant women has consistently increased over the past 50 years, more recently with an escalation of opioid use. PMID- 29251895 TI - NEONATAL ABSTINENCE SYNDROME AND THE ATTACHMENT RELATIONSHIP. AB - Approximately 4.2% of pregnant women consume illicit drugs during pregnancy (AIHW, 2011). Drug exposed infants are more likely to be born small for gestational age, be pre-term, and be admitted to special care or intensive care nurseries (AIHW, 2007). PMID- 29251896 TI - WHERE THERE'S SMOKE: UNCOVERING THE BENEFITS OF A NON-RESIDENTIAL CANNABIS WITHDRAWAL. AB - Drug and alcohol dependence continues to ignite the interest of the media. The 'epidemic' of methamphetamine use, the controversy of private residential rehabs and the burden of substance use on the healthcare system are prominent in the news and across social media. PMID- 29251897 TI - Assessment of natural radioactivity level and radiation hazards in soil samples of Wadi Al-Rummah Qassim province, Saudi Arabia. AB - The present work deals with estimation and distribution of natural radionuclides in 40 soil samples collected from Wadi Al-Rummah (Qassim part) Central Saudi Arabia. Estimations were carried out using NaI (Tl) gamma-ray spectrometer. Activity concentrations ranged from 5.3 to 45.0 Bq kg-1, from 4.3 to 33.8 Bq kg-1 and from 38 Bq kg-1 to 273.1 Bq kg-1 for 226Ra, 232Th and 40K, respectively. The average activity concentrations of 226Ra, 232Th and 40K in soil samples was 15.5 Bq kg-1, 14.1 Bq kg-1 and 143.1 Bq kg-1. The results of this study were compared with other studies around the world. Radiation hazard parameters such as radium equivalent activity, annual dose, external hazard were calculated and compared with the recommended levels quoted from International Commission on Radiological Protection (ICRP-60) and United Nations Scientific Committee on the Effects of Atomic Radiation UNSCEAR reports. PMID- 29251898 TI - LITERATURE SEARCH: STI SCREENING AND DRUG USE IN YOUNG PEOPLE. AB - Alcohol and other drug use are almost synonymous with increased risky sexual activity in young people (12-25 years). There is a direct correlation between initiation into methamphetamine use and an increase in sexual risk behaviours (Hoenigl et al. 2015). PMID- 29251899 TI - Effect of soil cadmium on growth, photosynthesis and quality of Raphanus sativus and Lactuca sativa. AB - Cadmium (Cd) raises serious concerns as its accumulation in the plant not only affect the growth and quality of plant but also threaten the health of consumers. In this research, two vegetables, i.e., radish (Raphanus sativus L.) and lettuce (Lactuca sativa L), were planted in pots having soil treated with Cd as Cd (NO3)2 at different doses (25, 50, 100 and 200 mg Cd kg-1 soil ) to investigate the influence of cadmium on their growth, photosynthetic attributes and quality. Cadmium retarded plant growth as dry weight of radish roots decline by 87% and leaves by 83% following 200 mg Cd kg-1 soil application and the corresponding values for lettuce were 64 and 69% respectively. Significant reductions in various photosynthetic parameters viz., leaf area per plant, total chlorophyll, Chl a and Chl b content were also recorded with Cd applications. The Cd treatments resulted in loss of membrane integrity as revealed by significant increase in electrolyte leakage in leaves of both vegetables. There was significant increase in Cd accumulation in radish and lettuce with all applications but no visual symptoms of Cd toxicity were noticed with 25 and 50 mg Cd kg-1 soil application except for yield differences, illustrating that Cd accumulate in this crop without visual evidence of its presence. However, toxicity symptoms in the form of interveinal chlorosis of the leaf lamina, followed by necrosis and leaf rolling, were clearly evident with 100 and 200 mg Cd kg-1 soil application. Apparently, Cd causes harm due to its phytotoxic effects and high accumulation in edible parts of radish and lettuce without any visible symptoms that constitutes a substantial hazard to human health. PMID- 29251900 TI - Study on improvement of continuous hydrogen production by photosynthetic biofilm in interior illuminant reactor. AB - In the present study, a new type of interior optical fiber illuminating reactor was developed for H2 production to solve the problem of luminous intensity attenuation at the center portion of a reactor, and an immobilization technique was used to enhance the stability of a continuous hydrogen production process with attached photosynthetic bacteria, using glucose as a sole carbon substrate for the indigenous photosynthetic bacteria (PSB) Rhodopseudomonas palustris SP-6. Results of the experiments showed that the interior optical fiber illuminating reactor produces H2 more efficiently and productively than the exterior light source reactor, with the cumulative H2 production, the maximum H2 production rate and H2 yield increased by 813ml, 11.3ml l-1 h-1 and 22.3%, respectively. The stability of the product of continuous hydrogen was realized by immobilizing PSB on the surface of powder active carbon(PAC). After adding the dosage of 2.0g l-1 PAC, the continuous steady operation of H2 production gave a high H2 yield of 1.398 mol H2 mol-1 glucose and an average H2 production rate of 35.1ml l-1 h-1 illuminating with a single interior optical fiber light source. Meanwhile, a higher H2 yield of 1.495 mol H2 mol-1 glucose and an average H2 production rate of 38.7ml l-1 h-1 were attained illuminating with a compound lamp in the continuous H2 production for 20 days. PMID- 29251901 TI - Research on the experiment of reservoir water treatment applying ultrafiltration membrane technology of different processes. AB - The processes and effects of coagulation-ultrafiltration (C-UF) and coagulation sedimentation-ultrafiltration (CS-UF) process used in the treatment of Dalangdian Reservoir water were compared. The experiment data indicated that 99% of turbidity removal and basically 100% of microorganism and algae removal were achieved in both C-UF and CS-UF process. The organic removal effect of CS-UF? process was slightly better than C-UF process. However, the organic removal effect under different processes was not obvious due to limitation of ultrafiltration membrane aperture. Polyaluminium chloride was taken as a coagulant in water plant. The aluminum ion removal result revealed that coagulant dosage was effectively saved by using membrane technology during megathermal high algae laden period. Within the range of certain reagent concentration and soaking time, air-water backwashing of every filtration cycle of membrane was conducted to effectively reduce membrane pollution. Besides, maintenance cleaning was conducted every 60 min. whether or not restorative cleaning was conducted depends on the pollution extent. After cleaning, recovery of membrane filtration effect was obvious. PMID- 29251902 TI - Multiplex Analysis on a Single Porous Hydrogel Bead with Encoded SERS Nanotags. AB - Bead-based assays have drawn more and more attention in biomedical fields. Herein, we proposed a novel approach to achieve multiplex analysis on a single porous hydrogel bead (PHB) with Raman dyes (RDs) encoded core-shell surface enhanced Raman scattering (SERS) nanotags. Because of the amplified signal of RDs by core-shell metal structure of the nanotag and the high surface area to volume ratio (SVR) of the PHB, the sensitivity and linear dynamic range (LDR) of the as proposed multiplex analysis method are significantly improved. We anticipate this approach to be widely used in the multiplex assays and biosensors. PMID- 29251903 TI - Organic-Dye-Modified Upconversion Nanoparticle as a Multichannel Probe To Detect Cu2+ in Living Cells. AB - The development of an inorganic-organic hybrid probe to more accurately detect ions in living systems is very challenging but highly desirable. Here we combined upconversion nanoparticles with the electrically active ferrocene group to detect Cu2+ in living cells. The as-prepared probe displays three different signal changes in absorption, emission, and electrochemical behavior, respectively, during Cu2+ ion detection. Moreover, this new probe has been demonstrated to show high stability and adaptability. In addition, bioimaging testing reveals that this probe is suitable for detecting and visualizing Cu2+ in A549 cells with low cytotoxicity. PMID- 29251904 TI - New Metal-Organic Frameworks for Chemical Fixation of CO2. AB - A novel series of two zirconium- and one indium-based metal-organic frameworks (MOFs), namely, MOF-892, MOF-893, and MOF-894, constructed from the hexatopic linker, 1',2',3',4',5',6'-hexakis(4-carboxyphenyl)benzene, were synthesized and fully characterized. MOF-892 and MOF-893 are two new exemplars of materials with topologies previously unseen in the important family of zirconium MOFs. MOF-892, MOF-893, and MOF-894 exhibit efficient heterogeneous catalytic activity for the cycloaddition of CO2, resulting in a cyclic organic carbonate formation with high conversion, selectivity, and yield under mild conditions (1 atm CO2, 80 degrees C, and solvent-free). Because of the structural features provided by their building units, MOF-892 and MOF-893 are replete with accessible Lewis and Bronsted acid sites located at the metal clusters and the non-coordinating carboxylic groups of the linkers, respectively, which is found to promote the catalytic CO2 cycloaddition reaction. As a proof-of-concept, MOF-892 exhibits high catalytic activity in the one-pot synthesis of styrene carbonate from styrene and CO2 without preliminary synthesis and isolation of styrene oxide. PMID- 29251905 TI - Carbon Dots/Prussian Blue Satellite/Core Nanocomposites for Optical Imaging and Photothermal Therapy. AB - Integration of optical imaging modality with photothermal therapy (PTT) for simultaneously providing oncotherapy and bioimaging enables an optimized therapeutic efficacy and higher treatment accuracy and therefore has emerged as a prospective cancer treatment. However, it remains challenging to develop biocompatible PTT nanoagents capable of imaging, monitoring, and diagnosis. Carbon dots (CDs) possess unique photoluminescent (PL) properties and intrinsic biocompatibility; while Prussian blue nanoparticles (PBNPs) are nontoxic with efficient photothermal conversion capacity for PTT. Herein, a simple, cost effective, and environmentally benign method was developed to strategically fabricate CD-decorated PBNP (CDs/PBNP) nanocomposites with satellite/core structure. The CDs/PBNPs possess distinct green PL emission and near-infrared photoabsorption with high efficiency and photothermal stability. In vitro and in vivo toxicity tests prove the biocompatibility of the CDs/PBNPs. Moreover, the applicability of CDs/PBNPs as nanotheranostic agents was tested, which suggests that CDs/PBNPs possess promising imaging and effective tumor ablation properties. PMID- 29251906 TI - Solvent Transport Behavior of Shear Aligned Graphene Oxide Membranes and Implications in Organic Solvent Nanofiltration. AB - Solvent transport in membranes composed of stacked sheets of graphene oxide (GO) with molecular scale channels and a complex arrangement of hydrophobic and hydrophilic domains is not well understood. Here, we observe that the interlayer space between GO sheets expands in different solvents without disturbing the membrane integrity and is typically larger in aqueous media compared to nonaqueous media. However, the membranes have a tighter molecule sieving feature in aqueous media as demonstrated by lower permeance and higher solute rejection arising from interfacial water layers "sticking" to charged polar groups. As a result of this polar interaction, the permeance of polar solvents in GO membrane scales inversely to the polarity of the solvent, which is contrary to other polymeric and ceramic hydrophilic membranes and also scales inversely to the viscosity of solvents as per continuum expectations. We highlight the extended solvent-handling space of GO membranes, such as in polar protic, polar aprotic, and nonpolar solvents, demonstrating versatility over a commercial nanofiltration membrane, and we predict exciting new applications in advanced separation engineering. PMID- 29251907 TI - A Molecular Rotor-Based Halo-Tag Ligand Enables a Fluorogenic Proteome Stress Sensor to Detect Protein Misfolding in Mildly Stressed Proteome. AB - Cellular stress leads to disruption of protein homeostasis (proteostasis) that is associated with global misfolding and aggregation of the endogenous proteome. Monitoring stress-induced proteostasis deficiency remains one of the major technical challenges facing established sensors of this process. Available sensors use solvatochromic fluorophores to detect protein aggregation in forms of soluble oligomers or insoluble aggregates when cells are subjected to severe stress conditions. Misfolded monomers induced by mild stresses, however, remain largely invisible to these sensors. Here, we describe a fluorogenic proteome stress sensor by conjugating a fluorescent molecular rotor with a metastable Halo tag protein domain that contains a K73T mutation (named AgHalo hereinafter). In nonstressed cells, the AaHalo sensor remains largely folded and the AgHalo*ligand conjugate is fluorescent dark in the folded state. Under various stress conditions, the AgHalo sensor has been established to form both soluble and insoluble aggregates along with metastable proteins of the endogenous cellular proteome. Thus, the AgHalo*ligand conjugate fluoresces strongly when the sensor forms misfolded monomers (a 16-fold increase) or aggregates in both soluble and insoluble forms (a 20-fold increase). Compared to the solvatochromic fluorophore based sensor, we demonstrate that the molecular rotor-based sensor not only is more effective in detecting mild proteome stress that induces primarily misfolding conformations, but also exhibits a higher fluorescence signal in detecting more severe proteome stress that involves protein aggregates. Thus, the conjugation of a fluorescent molecular rotor to AgHalo further improves the capacity of this sensor to detect conditions of proteome stress. This work highlights the utility of molecular rotor-based fluorophores in direct visualization of the protein aggregation cascade in live cells, providing new methodologies for real-time analyses of cellular proteostasis upon exposure to different types of stress conditions. PMID- 29251908 TI - Laser Direct Writing and Selective Metallization of Metallic Circuits for Integrated Wireless Devices. AB - Portable and wearable devices have attracted wide research attention due to their intimate relations with human daily life. As basic structures in the devices, the preparation of high-conductive metallic circuits or micro-circuits on flexible substrates should be facile, cost-effective, and easily integrated with other electronic units. In this work, high-conductive carbon/Ni composite structures were prepared by using a facile laser direct writing method, followed by an electroless Ni plating process, which exhibit a 3-order lower sheet resistance of less than 0.1 ohm/sq compared to original structures before plating, showing the potential for practical use. The carbon/Ni composite structures exhibited a certain flexibility and excellent anti-scratch property due to the tight deposition of Ni layers on carbon surfaces. On the basis of this approach, a wireless charging and storage device on a polyimide film was demonstrated by integrating an outer rectangle carbon/Ni composite coil for harvesting electromagnetic waves and an inner carbon micro-supercapacitor for energy storage, which can be fast charged wirelessly by a commercial wireless charger. Furthermore, a near-field communication (NFC) tag was prepared by combining a carbon/Ni composite coil for harvesting signals and a commercial IC chip for data storage, which can be used as an NFC tag for practical application. PMID- 29251909 TI - Characterization of Metal-Organic Frameworks: Unlocking the Potential of Solid State NMR. AB - An exciting advance in materials science is the discovery of hybrid organic inorganic solids known as metal-organic frameworks (MOFs). Although they have numerous important applications, the local structures, specific molecular-level features, and guest behaviors underpinning desirable properties and applications are often unknown. Solid-state nuclear magnetic resonance (SSNMR) is a powerful tool for MOF characterization as it provides information complementary to that from X-ray diffraction (XRD). We describe our novel pursuits in the three primary applications of SSNMR for MOF characterization: interrogating the metal center, targeting linker molecules, and probing guests. MOFs have relatively low densities, and the incorporated metals are often quadrupolar nuclei, making SSNMR detection difficult. Recently, we examined the local structures of metal centers (i.e., 25Mg, 47/49Ti, 63/65Cu, 67Zn, 69/71Ga, 91Zr, 115In, 135/137Ba, 139La, 27Al) in representative MOFs by SSNMR at a high magnetic field of 21.1 T, addressing several important issues: (1) resolving chemically and crystallographically nonequivalent metal sites; (2) exploring the origin of disorder around metals; (3) refining local metal geometry; (4) probing the effects of activation and adsorption on the metal local environment; and (5) monitoring in situ phase changes in MOFs. Organic linkers can be characterized by 1H, 13C, and 17O SSNMR. Although the framework structure can be determined by X ray diffraction, hydrogen atoms cannot be accurately located, and thus the local structure about hydrogen is poorly characterized. Our work demonstrates that magic-angle spinning (MAS) experiments at very high magnetic field along with ultrafast spinning rates and isotope dilution enables one to obtain ultrahigh resolution 1H MAS spectra of MOFs, yielding structural information truly complementary to that obtained from single-crystal XRD. Oxygen is a key constituent of many important MOFs but 17O SSNMR work on MOFs is scarce due to the low natural abundance of 17O. 17O enriched MOFs can now be prepared in an efficient and economically feasible manner using solvothermal approaches involving labeled H217O water; the resulting 17O SSNMR spectra provide distinct spectral signatures of various key oxygen species in representative MOFs. MOFs are suitable for the capture of the greenhouse gas CO2 and the storage of energy carrier gases such as H2 and CH4. A better understanding of gas adsorption obtained using 13C, 2H, and 17O SSNMR will enable researchers to improve performance and realize practical applications for MOFs as gas adsorbents and carriers. The combination of SSNMR with XRD allows us to determine the number of adsorption sites in the framework, identify the location of binding sites, gain physical insight into the nature and strength of host-guest interactions, and understand guest dynamics. PMID- 29251910 TI - Porous Au@Pt Nanoparticles: Therapeutic Platform for Tumor Chemo-Photothermal Co Therapy and Alleviating Doxorubicin-Induced Oxidative Damage. AB - Nanoparticle-based systems explore not only the delivery efficacy of drugs or contrast agents, but also additional capabilities like reducing the systemic toxicity, especially during cancer chemotherapy. Since some of the noble metal nanoparticles exhibit the catalysis properties which can scavenge the reactive oxygen species (ROS), they can be used as a promising drug delivery platform for reducing the oxidative stress damage in normal tissues caused by some chemotherapy drugs. Herein, in this study, we construct porous Au@Pt nanoparticles and further explore the properties of porous Au@Pt nanoparticles in relieving the oxidative stress damage as well as in tumor growth inhibition by chemo-photothermal co-therapy. The tunable surface pore structure of Au@Pt nanoparticle provides space for Doxorubicin (DOX) loading. cRGD peptide modification enable the DOX-loaded Au@Pt nanoparticles to improve drug delivery properties. The constructed nanocarrier (DOX/Au@Pt-cRGD) shows controlled drug release behavior. Meanwhile, the absorbance peak of the Au@Pt structure in the near-infrared (NIR) portion provides the capacity for in vivo photoacoustic imaging and the high photoconversion efficiency, which make Au@Pt nanoparticle a suitable carrier for photothermal therapy (PTT). Combined with chemotherapy, the nanosystem DOX/Au@Pt-cRGD shows enhanced anticancer therapeutic effects. More importantly, ROS-scavenging activity of Au@Pt alleviates the DOX-induced oxidative stress damage, especially the cardiomyopathy during chemotherapy. Herein, this nanosystem DOX/Au@Pt-cRGD could be explored as reactive oxygen scavenger and drug delivery system for side effects relieving chemo-photothermal combinational therapy. PMID- 29251911 TI - Carboxylate-Selective Chemical Cross-Linkers for Mass Spectrometric Analysis of Protein Structures. AB - Chemical cross-linking coupled with mass spectrometry (CXMS) facilitates structural analysis of proteins. As current CXMS applications are almost exclusively limited to lysine residues, they can only retrieve a small portion of the structural information theoretically accessible to CXMS. Chemical cross linkers targeting the acidic residues Asp/Glu could greatly enhance the power of CXMS. However, it has been difficult to develop chemistries that offer selectivity and efficiency under physiological conditions. Here, we report a class of carboxylate-selective diazo-containing cross-linkers (Diazoker) of which Diazoker 1, with a spacer arm consisting of two ethan-1,2-diol units, is the best example. Unlike previously developed carboxylate-selective cross-linkers like pimelic acid dihydrazide (PDH), Diazoker 1 does not require a coupling reagent. We tested Diazoker 1 on nine model proteins and found that Diazoker 1 generated an average of 73 cross-linked peptide pairs per protein. Although this is 32% fewer than the number generated by PDH, the Diazoker 1 cross-links have a higher rate of compatibility with protein crystal structures. From a more complex protein mixture, Diazoker 1 and PDH identified 75 and 76 cross-linked peptide pairs, respectively. The Asp/Glu residues cross-linked by Diazoker 1 are not the same as those cross-linked by PDH. Diazoker 1 favors acidic residues that are less exposed to solvent. In conclusion, Diazoker 1 is complementary to existing cross-linkers and expands the toolkit of CXMS for structural analysis of proteins. PMID- 29251912 TI - Application of omega-Transaminases in the Pharmaceutical Industry. AB - Chiral amines are valuable building blocks for the pharmaceutical industry. omega TAms have emerged as an exciting option for their synthesis, offering a potential "green alternative" to overcome the drawbacks associated with conventional chemical methods. In this review, we explore the application of omega-TAms for pharmaceutical production. We discuss the diverse array of reactions available involving omega-TAms and process considerations of their use in both kinetic resolution and asymmetric synthesis. With the aid of specific drug intermediates and APIs, we chart the development of omega-TAms using protein engineering and their contribution to elegant one-pot cascades with other enzymes, including carbonyl reductases (CREDs), hydrolases and monoamine oxidases (MAOs), providing a comprehensive overview of their uses, beginning with initial applications through to the present day. PMID- 29251914 TI - Paper-Based Microfluidic Device with Integrated Sputtered Electrodes for Stripping Voltammetric Determination of DNA via Quantum Dot Labeling. AB - This work reports a microfabricated electrochemical paper-based analytical device (ePAD) for the voltammetric determination of DNA. The device is patterned by wax printing on paper and features a circular assay zone connected to an inlet zone and a sink via grooved microfluidic channels for accelerated flow rate. An electrochemical cell with integrated electrodes is formed on the reverse side of the paper by sputtering of thin metal films (Sn, Pt and Ag as the working, counter and reference electrode, respectively). Proof-of-principle of the ePAD for biosensing is demonstrated for a DNA assay involving attachment of capture DNA, hybridization with biotinylated target oligonucleotide and labeling with streptavidin-conjugated CdSe/ZnS quantum dots (QDs). After the acidic dissolution of the QDs, the released Cd(II) is quantified by anodic stripping voltammetry (ASV) at the Sn-film working electrode. Thanks to the synergistic effects of QDs amplification, the inherent sensitivity of ASV and the excellent detection capabilities of the Sn-film working electrode for Cd(II), the target DNA can be detected at levels as low as 0.11 pmol L-1 using sample volumes as low as 1 MUL. The developed microfluidic ePAD costs only 0.11$ and presents favorable fabrication and operational features that make it an excellent candidate biosensor for simple and ultrasensitive point-of-need testing. PMID- 29251913 TI - Role of Oxygen in Ionic Liquid Gating on Two-Dimensional Cr2Ge2Te6: A Non-oxide Material. AB - Ionic liquid gating can markedly modulate a material's carrier density so as to induce metallization, superconductivity, and quantum phase transitions. One of the main issues is whether the mechanism of ionic liquid gating is an electrostatic field effect or an electrochemical effect, especially for oxide materials. Recent observation of the suppression of the ionic liquid gate-induced metallization in the presence of oxygen for oxide materials suggests the electrochemical effect. However, in more general scenarios, the role of oxygen in the ionic liquid gating effect is still unclear. Here, we perform ionic liquid gating experiments on a non-oxide material: two-dimensional ferromagnetic Cr2Ge2Te6. Our results demonstrate that despite the large increase of the gate leakage current in the presence of oxygen, the oxygen does not affect the ionic liquid gating effect on the channel resistance of Cr2Ge2Te6 devices (<5% difference), which suggests the electrostatic field effect as the mechanism on non-oxide materials. Moreover, our results show that ionic liquid gating is more effective on the modulation of the channel resistances compared to the back gating across the 300 nm thick SiO2. PMID- 29251915 TI - Beyond Transcription: Roles of Transcription Factors in Pre-mRNA Splicing. AB - Whereas individual steps of protein-coding gene expression in eukaryotes can be studied in isolation in vitro, it has become clear that these steps are intimately connected within cells. Connections not only ensure quality control but also fine-tune the gene expression process, which must adapt to environmental changes while remaining robust. In this review, we systematically present proven and potential mechanisms by which sequence-specific DNA-binding transcription factors can alter gene expression beyond transcription initiation and regulate pre-mRNA splicing, and thereby mRNA isoform production, by (i) influencing transcription elongation rates, (ii) binding to pre-mRNA to recruit splicing factors, and/or (iii) blocking the association of splicing factors with pre-mRNA. We propose various mechanistic models throughout the review, in some cases without explicit supportive evidence, in hopes of providing fertile ground for future studies. PMID- 29251916 TI - Biomimetic Graphene-Based 3D Scaffold for Long-Term Cell Culture and Real-Time Electrochemical Monitoring. AB - Current achievements on electrochemical monitoring of cells are often gained on two-dimensional (2D) substrates, which fail in mimicking the cellular environments and accurately reproducing the cellular functions within a three dimensional (3D) tissue. In this regard, 3D scaffold concurrently integrated with the function of cell culture and electrochemical sensing is conceivably a promising platform to monitor cells in real time under their in vivo-like 3D microenvironments. However, it is particularly challenging to construct such a multifunctional scaffold platform. Herein, we developed a 3-aminophenylboronic acid (APBA) functionalized graphene foam (GF) network, which combines the biomimetic property of APBA with the mechanical and electrochemical properties of GF. Hence, the GF network can serve as a 3D scaffold to culture cells for a long period with high viability and simultaneously as an electrode for highly sensitive electrochemical sensing. This allows monitoring of gaseous messengers H2S released from the cells cultured on the 3D scaffold in real time. This work represents considerable progress in fabricating 3D cell culture scaffold with electrochemical properties, thereby facilitating future studies of physiologically relevant processes. PMID- 29251917 TI - Environmentally Relevant Concentrations of Carbamazepine Caused Endocrine Disrupting Effects on Nontarget Organisms, Chinese Rare Minnows (Gobiocypris rarus). AB - In the present study, Chinese rare minnows (Gobiocypris rarus) were exposed to 1, 10, and 100 MUg/L of carbamazepine (CBZ) under flow-through conditions for 28 d. A hepatic-specific custom microarray identified 111 and 71 differentially expressed genes in the livers of females and males, respectively, exposed to 100 MUg/L of CBZ (ratio >= 2, p <= 0.05). The levels of five differentially expressed genes associated with the hypothalamic-pituitary-gonadal (HPG) axis were quantified by qPCR, and the results indicated the feasibility of screening endocrine-disrupting chemicals using a custom microarray. The mRNA levels of genes related to the HPG axis differed significantly in different organs of Chinese rare minnows (p < 0.05). Significant differences were observed in the 11 ketotestosterone and plasma vitellogenin levels in all treatments and in the 17beta-estradiol (E2) levels in the 100 MUg/L CBZ treatment. In contrast, the gonadosomatic index was significantly higher in females and slightly higher in males without significant differences. A pathological analysis determined that 10 and 100 MUg/L of CBZ could lead to ova-testis in males and significantly promoted ovum maturation in females. Therefore, our results demonstrate that environmentally relevant concentrations of CBZ have homologous estrogenic activity and induce reproductive toxicity in Chinese rare minnows. PMID- 29251918 TI - Iridium-Catalyzed Aerobic alpha,beta-Dehydrogenation of gamma,delta-Unsaturated Amides and Acids: Activation of Both alpha- and beta-C-H bonds through an Allyl Iridium Intermediate. AB - Direct aerobic alpha,beta-dehydrogenation of gamma,delta-unsaturated amides and acids using a simple iridium/copper relay catalysis system is described. We developed a new strategy that overcomes the challenging issue associated with the low alpha-acidity of amides and acids. Instead of alpha-C-H metalation, this reaction proceeds by beta-C-H activation, which results in enhanced alpha acidity. Conjugated dienamides and dienoic acids were synthesized in excellent yield with this reaction, which uses a simple reaction protocol. Mechanistic experiments suggest a catalyst resting state mechanism in which both alpha-C-H and beta-C-H cleavage is accelerated. PMID- 29251919 TI - Spin-Crossover Iron(II) Coordination Polymer with Fluorescent Properties: Correlation between Emission Properties and Spin State. AB - A spin-crossover coordination polymer [Fe(L1)(bipy)]n (where L = a N2O22- coordinating Schiff base-like ligand bearing a phenazine fluorophore and bipy = 4,4'-bipyridine) was synthesized and exhibits a 48 K wide thermal hysteresis above room temperature (T1/2? = 371 K and T1/2? = 323 K) that is stable for several cycles. The spin transition was characterized using magnetic measurements, Mossbauer spectroscopy, and DSC measurements. T-dependent X-ray powder diffraction reveals a structural phase transition coupled with the spin transition phenomenon. The dimeric excerpt {(MU-bipy)[FeL1(MeOH)]2}.2MeOH of the coordination polymer chain crystallizes in the triclinic space group P1 and reveals that the packing of the molecules in the crystal is dominated by hydrogen bonds. Investigation of the emission properties of the complexes with regard to temperature shows that the spin crossover can be tracked by monitoring the emission spectra, since the emission color changes from greenish to a yellow color upon the low spin-to-high spin transition. PMID- 29251921 TI - Monoclinic Lu2-xSmxWO6-Based White Light-Emitting Phosphors: From Ground-Excited States Calculation Prediction to Experiment Realization. AB - Through ground state and constrained density function calculations, Sm3+ ions luminescence in self-activated monoclinic Lu2WO6 was originated from intra 4f -> 4f transitions, not inter 5d -> 4f transitions. Theoretically the white luminescence was obtained by combining red and blue-green emissions of 4f energy levels and W-O charge transfer transitions. Experimentally, pure and Sm3+ doping Lu2WO6 powders were synthesized using solid phase reaction calcined in air atmosphere. By the analysis of X-ray photoelectron spectroscopy and Rietveld refinement, element Sm charge state was trivalent, and Sm3+ doping was concentration-dependent selectively doping in three Lu sites. With the increase of Sm3+ concentrations, the color coordinates changed gradually from blue (0.17, 0.17) through white light (0.33, 0.25) toward orange (0.44, 0.32) in the visible spectral under 325 nm excitation. On the basis of the theoretical prediction and experimental preparation, a white emission LED lamp was produced using a 365 nm ultraviolet chip and Lu1.99Sm0.01WO6 phosphor. The present design method can be applied to select excellent activators from a large number of rare-earth (Re) ions like Sm3+ and Eu3+/2+ or non-Re ions like Bi3+ and Mn4+ in various matrixes. PMID- 29251922 TI - Membrane Fouling and Rejection of Organics during Algae-Laden Water Treatment Using Ultrafiltration: A Comparison between in Situ Pretreatment with Fe(II)/Persulfate and Ozone. AB - In this study, in situ pretreatments with ozone and Fe(II)/persulfate were employed to suppress membrane fouling during the filtration of algae-laden water and to improve the rejection of metabolites. Both ozonation and Fe(II)/persulfate pretreatments negatively impacted the cell integrity, especially ozonation. Fe(II)/persulfate pretreatment improved the removal of dissolved organic carbon and microcystin-LR, but ozonation resulted in a deterioration in the quality of the filtered water. This suggests that the Fe(II)/persulfate oxidation is selective for organic degradation over cell damage. With ozonation, 2 methylisoborneol and geosmin were detected in the filtered water, and the irreversible fouling increased. The intracellular organic release and generation of small organic compounds with ozonation may be the reason for the increased membrane fouling. Fe(II)/persulfate oxidation substantially mitigated the membrane-fouling resistance at concentrations over 0.2 mM compared to the membrane-fouling resistance without oxidation. The combined effect of oxidation and coagulation is likely the reason for the excellent fouling control with Fe(II)/persulfate pretreatment. Membrane fouling during the filtration of algae laden water is successively governed by complete-blocking and cake-filtration mechanisms. Ozonation caused a shift in the initial major mechanism to intermediate blocking, and the Fe(II)/persulfate pretreatment (>0.2 mM) converted the dominant mechanism into single-standard blocking. PMID- 29251920 TI - Inhibit or Evade Multidrug Resistance P-Glycoprotein in Cancer Treatment. AB - Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for its association with MDR due to overexpression in cancer cells. Several P-gp inhibitors or modulators have been investigated in clinical trials in hope of circumventing MDR, with only limited success. Alternative strategies are actively pursued, such as the modification of existing drugs, development of new drugs, or combination of novel drug delivery agents to evade P-gp-dependent efflux. Despite the importance and numerous studies, these efforts have mostly been undertaken without a priori knowledge of how drugs interact with P-gp at the molecular level. This review highlights and discusses progress toward and challenges impeding drug development for inhibiting or evading P-gp in the context of our improved understanding of the structural basis and mechanism of P-gp-mediated MDR. PMID- 29251923 TI - Computational Design of a Photocontrolled Cytosine Deaminase. AB - There is growing interest in designing spatiotemporal control over enzyme activities using noninvasive stimuli such as light. Here, we describe a structure based, computation-guided predictive method for reversibly controlling enzyme activity using covalently attached photoresponsive azobenzene groups. Applying the method to the therapeutically useful enzyme yeast cytosine deaminase, we obtained a ~3-fold change in enzyme activity by the photocontrolled modulation of the enzyme's active site lid structure, while fully maintaining thermostability. Multiple cycles of switching, controllable in real time, are possible. The predictiveness of the method is demonstrated by the construction of a variant that does not photoswitch as expected from computational modeling. Our design approach opens new avenues for optically controlling enzyme function. The designed photocontrolled cytosine deaminases may also aid in improving chemotherapy approaches that utilize this enzyme. PMID- 29251924 TI - Targeting Transcriptional Enhanced Associate Domains (TEADs). AB - Transcriptional enhanced associate domain (TEAD) proteins are the downstream effectors of the Hippo signaling pathway that regulate cell proliferation and stem cell functions. TEADs are unable to activate transcription and require the help of coactivators such as YAP, TAZ, VgLL, and p160 proteins. The expression of TEAD family is up-regulated in many cancer types including gastric, colorectal, breast, and prostate cancers, which is correlated with poor survival in patients. Pharmacological modulators of TEADs could therefore find application in cancer treatment and regenerative medicine. In this review, we present the very recent available structures of TEADs with or without coactivators or inhibitors and discuss the potential therapeutic application of their ligands. PMID- 29251925 TI - Active-Site Environment of Copper-Bound Human Amylin Relevant to Type 2 Diabetes. AB - Type 2 diabetes mellitus (T2Dm) is characterized by reduced beta cell mass and amyloid deposits of human islet amyloid polypeptide (hIAPP) or amylin, a 37 amino acid containing peptide around pancreatic beta cells. The interaction of copper (Cu) with amylin and its mutants has been studied in detail using absorption, circular dichroism, electron paramagnetic resonance spectroscopy, and cyclic voltammetry. Cu binds amylin in a 1:1 ratio, and the binding domain lies within the first 19 amino acid residues of the peptide. Depending on the pH of the medium, Cu-amylin shows the formation of five pH-dependent components (component IV at pH 4.0, component III at pH 5.0, component II at pH 6.0, component I at pH 8.0, and another higher pH component above pH 9.0). The terminal amine, His18, and amidates are established as key residues in the peptide that coordinate the Cu center. The physiologically relevant components I and II can generate H2O2, which can possibly account for the enhanced toxicity of amylin in the presence of Cu, causing damage of the beta cells of the pancreas via oxidative stress. PMID- 29251926 TI - Unique Spectroscopic Properties of the H-Cluster in a Putative Sensory [FeFe] Hydrogenase. AB - Sensory type [FeFe] hydrogenases are predicted to play a role in transcriptional regulation by detecting the H2 level of the cellular environment. These hydrogenases contain the hydrogenase domain with distinct modifications in the active site pocket, followed by a Per-Arnt-Sim (PAS) domain. As yet, neither the physiological function nor the biochemical or spectroscopic properties of these enzymes have been explored. Here, we present the characterization of an artificially maturated, putative sensory [FeFe] hydrogenase from Thermotoga maritima (HydS). This enzyme shows lower hydrogen conversion activity than prototypical [FeFe] hydrogenases and a reduced inhibition by CO. Using FTIR spectroelectrochemistry and EPR spectroscopy, three redox states of the active site were identified. The spectroscopic signatures of the most oxidized state closely resemble those of the Hox state from the prototypical [FeFe] hydrogenases, while the FTIR spectra of both singly and doubly reduced states show large differences. The FTIR bands of both the reduced states are strongly red-shifted relative to the Hox state, indicating reduction at the diiron site, but with retention of the bridging CO ligand. The unique functional and spectroscopic features of HydS are discussed with regard to the possible role of altered amino acid residues influencing the electronic properties of the H cluster. PMID- 29251927 TI - Electrostatic Self-Assembly: Understanding the Significance of the Solvent. AB - The electrostatic deposition of particles has become a very effective route to the assembly of many nanoscale materials. However, fundamental limitations to the process are presented by the choice of solvent, which can either suppress or promote self-assembly depending on specific combinations of nanoparticle/surface/solvent properties. A new development in the theory of electrostatic interactions between polarizable objects provides insight into the effect a solvent can have on electrostatic self-assembly. Critical to assembly is the requirement for a minimum charge on a surface of an object, below which a solvent can suppress electrostatic attraction. Examples drawn from the literature are used to illustrate how switches in behavior are mediated by the solvent; these in turn provide a fundamental understanding of electrostatic particle surface interactions applicable to many areas of materials science and nanotechnology. PMID- 29251929 TI - Lewis Acid-Mediated Ring-Opening Reactions of trans-2-Aroyl-3-styrylcyclopropane 1,1-dicarboxylates: Access to Cyclopentenes and E,E-1,3-Dienes. AB - The ring-opening reaction of trans-2-aroyl-3-styrylcyclopropane-1,1 dicarboxylates was investigated with different Lewis acids. With SnCl4, the cyclopropane dicarboxylates afforded cyclopentene derivatives through ring opening followed by cyclization (vinylcyclopropane-cyclopentene rearrangement). With TiCl4, they furnished E,E-1,3-diene derivatives stereoselectively via ring opening followed by proton elimination. PMID- 29251928 TI - Comprehensive Synthesis of Amino Acid-Derived Thiazole Peptidomimetic Analogues to Understand the Enigmatic Drug/Substrate-Binding Site of P-Glycoprotein. AB - A novel set of 64 analogues based on our lead compound 1 was designed and synthesized with an initial objective of understanding the structural requirements of ligands binding to a highly perplexing substrate-binding site of P-glycoprotein (P-gp) and their effect on modulating the ATPase function of the efflux pump. Compound 1, a stimulator of P-gp ATPase activity, was transformed to ATPase inhibitory compounds 39, 53, and 109. The ATPase inhibition by these compounds was predominantly contributed by the presence of a cyclohexyl group in lieu of the 2-aminobenzophenone moiety of 1. The 4,4-difluorocyclohexyl analogues, 53 and 109, inhibited the photolabeling by [125I]-IAAP, with IC50 values of 0.1 and 0.76 MUM, respectively. Selected compounds were shown to reverse paclitaxel resistance in HEK293 cells overexpressing P-gp and were selective toward P-gp over CYP3A4. Induced-fit docking highlighted a plausible binding pattern of inhibitory compounds in the putative-binding pocket of P-gp. The current study underscores the stringent requirement by P-gp to bind to chemically similar molecules. PMID- 29251931 TI - Modeling Photoelectron Spectra of CuO, Cu2O, and CuO2 Anions with Equation-of Motion Coupled-Cluster Methods: An Adventure in Fock Space. AB - The experimental photoelectron spectra of di- and triatomic copper oxide anions have been reported previously. We present an analysis of the experimental spectra of the CuO-, Cu2O-, and CuO2- anions using equation-of-motion coupled-cluster (EOM-CC) methods. The open-shell electronic structure of each molecule demands a unique combination of EOM-CC methods to achieve an accurate and balanced representation of the multiconfigurational anionic- and neutral-state manifolds. Analysis of the Dyson orbitals associated with photodetachment from CuO- reveals the strong non-Koopmans character of the CuO states. For the lowest detachment energy, a good agreement between theoretical and experimental values is obtained with CCSD(T) (coupled-cluster with single and double excitations and perturbative account of triple excitations). The (T) correction is particularly important for Cu2O-. Use of a relativistic pseudopotential and matching basis set improves the quality of results in most cases. EOM-DIP-CCSD analysis of the low-lying states of CuO2- reveals multiple singlet and triplet anionic states near the triplet ground state, adding an extra layer of complexity to the interpretation of the experimental CuO2- photoelectron spectrum. PMID- 29251930 TI - Synthesis of a Nonhydrolyzable Nucleotide Phosphoroimidazolide Analogue That Catalyzes Nonenzymatic RNA Primer Extension. AB - We report the synthesis of guanosine 5'-(4-methylimidazolyl)phosphonate (ICG), the third member of a series of nonhydrolyzable nucleoside 5'-phosphoro-2 methylimidazolide (2-MeImpN) analogues designed for mechanistic studies of nonenzymatic RNA primer extension. The addition of a 2-MeImpN monomer to a primer is catalyzed by the presence of a downstream activated monomer, yet the three nonhydrolyzable analogues do not show catalytic effects under standard mildly basic primer extension conditions. Surprisingly, ICG, which has a pKa similar to that of 2-MeImpG, is a modest catalyst of nonenzymatic primer extension at acidic pH. Here we show that ICG reacts with 2-MeImpC to form a stable 5'-5'-imidazole bridged guanosine-cytosine dinucleotide, with both a labile nitrogen-phosphorus and a stable carbon-phosphorus linkage flanking the central imidazole bridge. Cognate RNA primer-template complexes react with this GC-dinucleotide by attack of the primer 3'-hydroxyl on the activated N-P side of the 5'-5'-imidazole bridge. These observations support the hypothesis that 5'-5'-imidazole-bridged dinucleotides can bind to cognate RNA primer-template duplexes and adopt appropriate conformations for subsequent phosphodiester bond formation, consistent with our recent mechanistic proposal that the formation of activated 5'-5'-imidazolium-bridged dinucleotides is responsible for 2-MeImpN-driven primer extension. PMID- 29251932 TI - Discovery of 4-[(2R,4R)-4-({[1-(2,2-Difluoro-1,3-benzodioxol-5 yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2 yl]benzoic Acid (ABBV/GLPG-2222), a Potent Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Corrector for the Treatment of Cystic Fibrosis. AB - Cystic fibrosis (CF) is a multiorgan disease of the lungs, sinuses, pancreas, and gastrointestinal tract that is caused by a dysfunction or deficiency of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an epithelial anion channel that regulates salt and water balance in the tissues in which it is expressed. To effectively treat the most prevalent patient population (F508del mutation), two biomolecular modulators are required: correctors to increase CFTR levels at the cell surface, and potentiators to allow the effective opening of the CFTR channel. Despite approved potentiator and potentiator/corrector combination therapies, there remains a high need to develop more potent and efficacious correctors. Herein, we disclose the discovery of a highly potent series of CFTR correctors and the structure-activity relationship (SAR) studies that guided the discovery of ABBV/GLPG-2222 (22), which is currently in clinical trials in patients harboring the F508del CFTR mutation on at least one allele. PMID- 29251933 TI - Predicting Hydride Donor Strength via Quantum Chemical Calculations of Hydride Transfer Activation Free Energy. AB - We propose a method to approximate the kinetic properties of hydride donor species by relating the nucleophilicity (N) of a hydride to the activation free energy DeltaG? of its corresponding hydride transfer reaction. N is a kinetic parameter related to the hydride transfer rate constant that quantifies a nucleophilic hydridic species' tendency to donate. Our method estimates N using quantum chemical calculations to compute DeltaG? for hydride transfers from hydride donors to CO2 in solution. A linear correlation for each class of hydrides is then established between experimentally determined N values and the computationally predicted DeltaG?; this relationship can then be used to predict nucleophilicity for different hydride donors within each class. This approach is employed to determine N for four different classes of hydride donors: two organic (carbon-based and benzimidazole-based) and two inorganic (boron and silicon) hydride classes. We argue that silicon and boron hydrides are driven by the formation of the more stable Si-O or B-O bond. In contrast, the carbon-based hydrides considered herein are driven by the stability acquired upon rearomatization, a feature making these species of particular interest, because they both exhibit catalytic behavior and can be recycled. PMID- 29251934 TI - High Accuracy ab Initio Calculations of Rotational-Vibrational Levels of the HCN/HNC System. AB - Highly accurate ab initio calculations of vibrational and rotational-vibrational energy levels of the HCN/HNC (hydrogen cyanide/hydrogen isocyanide) isomerising system are presented for several isotopologues. All-electron multireference configuration interaction (MRCI) electronic structure calculations were performed using basis sets up to aug-cc-pCV6Z on a grid of 1541 geometries. The ab initio energies were used to produce an analytical potential energy surface (PES) describing the two minima simultaneously. An adiabatic Born-Oppenheimer diagonal correction (BODC) correction surface as well as a relativistic correction surface were also calculated. These surfaces were used to compute vibrational and rotational-vibrational energy levels up to 25 000 cm-1 which reproduce the extensive set of experimentally known HCN/HNC levels with a root-mean-square deviation sigma = 1.5 cm-1. We studied the effect of nonadiabatic effects by introducing opportune radial and angular corrections to the nuclear kinetic energy operator. Empirical determination of two nonadiabatic parameters results in observed energies up to 7000 cm-1 for four HCN isotopologues (HCN, DCN, H13CN, and HC15N) being reproduced with sigma = 0.37 cm-1. The height of the isomerization barrier, the isomerization energy and the dissociation energy were computed using a number of models; our best results are 16 809.4, 5312.8, and 43 729 cm-1, respectively. PMID- 29251935 TI - Dynamics of Patchy Particles in and out of Equilibrium. AB - We combine particle-based simulations, mean-field rate equations, and Wertheim's theory to study the dynamics of patchy particles in and out of equilibrium, at different temperatures and densities. We consider an initial random distribution of nonoverlapping three-patch particles, with no bonds, and analyze the time evolution of the breaking and bonding rates of a single bond. We find that the asymptotic (equilibrium) dynamics differs from the initial (out of equilibrium) one. These differences are expected to depend on the initial conditions, temperature, and density. PMID- 29251936 TI - Revisiting the Role of Xanthophylls in Nonphotochemical Quenching. AB - Photoprotective nonphotochemical quenching (NPQ) of absorbed solar energy is vital for survival of photosynthetic organisms, and NPQ modifications significantly improve plant productivity. However, the exact NPQ quenching mechanism is obscured by discrepancies between reported mechanisms, involving xanthophyll-chlorophyll (Xan-Chl) and Chl-Chl interactions. We present evidence of an experimental artifact that may explain the discrepancies: strong laser pulses lead to the formation of a novel electronic species in the major plant light-harvesting complex (LHCII). This species evolves from a high excited state of Chl a and is absent with weak laser pulses. It resembles an excitonically coupled heterodimer of Chl a and lutein (or other Xans at site L1) and acts as a de-excitation channel. Laser powers, and consequently amounts of artifact, vary strongly between NPQ studies, thereby explaining contradicting spectral signatures attributed to NPQ. Our results offer pathways toward unveiling NPQ mechanisms and highlight the necessity of careful attention to laser-induced artifacts. PMID- 29251937 TI - Controlling Mobility in Perovskite Oxides by Ferroelectric Modulation of Atomic Scale Interface Structure. AB - Coherent and epitaxial interfaces permit the realization of electric field driven devices controlled by atomic-scale structural and electronic effects at interfaces. Compared to conventional field effect devices where channel conductivity is modulated by carrier density modification, the propagation of atomic-scale distortions across an interface can control the atomic scale bonding, interatomic electron tunneling rates and thus the mobility of the channel material. We use first-principles theory to design an atomically abrupt epitaxial perovskite heterostructure involving an oxide ferroelectric (PbZr0.2Ti0.8O3) and conducting oxide channel (LaNiO3) where coupling of polar atomic motions to structural distortions can induce large, reversible changes in the channel mobility. We fabricate and characterize the heterostructure and measure record values, larger than 1000%, for the conductivity modulation. Our results describe how purely interfacial effects can be engineered to deliver unique electronic device properties and large responses to external fields. PMID- 29251938 TI - Drastic Swelling of Lipid Oligobilayers by Polyelectrolytes: A Potential Molecular Model for the Internal Structure of Lubricating Films in Mammalian Joints. AB - Osteoarthritis is the most common arthropathy in western civilization. It is primarily caused by the degeneration of lipid-coated cartilage, leading to increased friction in joints. Hyaluronic acid (HA), a negatively charged polysaccharide and the main component of the synovial fluid, is held responsible for joint lubrication. It is believed that HA, adsorbed to the lipid-coated cartilage, forms a protective layer against wear. Studies have shown that the concentration and molecular weight (MW) of HA are reduced in joints suffering from osteoarthritis. On the basis of these observations, local joint injections of HA or mixtures of HA and surface-active phospholipids (SAPLs) have been applied as medical cures to restore the functionality of the joints in a procedure called viscosupplementation. However, this cure is still disputed, and no consensus has been reached with respect to optimum HA concentration and MW. To provide detailed insight in the structural rearrangement of lipid films upon contact with HA or polymeric analogues, we studied the interaction of the polyelectrolyte poly(allylamine hydrochloride) (PAH) with surface-bound oligobilayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) by neutron reflectivity (NR) and ellipsometry. Using this model system, we found a drastic swelling of the lipid films as a function of PAH concentration, whose strength compares to that in previous studies on HA incubation. In contrast, no significant dependence of film thickness on PAH MW was observed. A detailed picture of the film architecture was developed which inter alia shows that charged PAH is adsorbed to the lipid headgroups, leading to electrostatic repulsion. The swelling behavior is well explained by the equilibrium of Coulomb and van der Waals interactions in a DLVO-based model. Our detailed structural analysis of the PAH/lipid interfacial layer may help to elucidate the mechanisms of viscosupplementation and derive a structure-function relationship for the lubricating interface in mammalian joints. PMID- 29251939 TI - (H, Li)Br and LiOH Solvation Bonding Dynamics: Molecular Nonbond Interactions and Solute Extraordinary Capabilities. AB - We resolved the O:H-O bond transition from the mode of ordinary water to its hydration in terms of its phonon stiffness (vibration frequency shift Deltaomega), order of fluctuation (line width), and number fraction (phonon abundance), fx(C) = Nhyd/Ntotal. The fx(C) follows fH(C) = 0, fLi(C) ? fOH(C) ? C, and fBr(C) ? 1 - exp(-C/C0) toward saturation with C being the solute concentration. The invariant dfx(C)/dC suggests that the solute forms a constantly sized hydration droplet without responding to interference of other ions because its hydrating H2O dipoles fully screen its electric field. However, the number inadequacy of the highly ordered hydration H2O dipoles partially screens the large Br-. The Br- then interacts repulsively with other Br- anions, which weakens its electric field and the fBr(C) approaches saturation at higher solute concentration. The consistency in the concentration trend of the fLiBr(C), the Jones-Dole viscosity eta(C), and the surface stress of LiBr solution clarifies their common origin of ionic polarization. The resultant energy of the solvent H-O exothermic elongation by O: <=> :O repulsion and the solute H-O endothermic contraction by bond-order deficiency heats up the LiOH solution. An estimation of at least 0.15 eV (160% of the O:H cohesive energy of 0.1 eV) suggests that the H-O elongation is the main source heating up the solution, while the molecular motion, structure fluctuation, or even evaporation dissipates energy caped at 0.1 eV. PMID- 29251940 TI - Metal Halide Perovskite Supercrystals: Gold-Bromide Complex Triggered Assembly of CsPbBr3 Nanocubes. AB - Using nanocrystals as "artificial atoms" to construct supercrystals is an interesting process to explore the stacking style of nanoscale building blocks and corresponding collective properties. Various types of semiconducting supercrystals have been constructed via the assembly of nanocrystals driven by the entropic, electrostatic, or van der Waals interactions. We report a new type of metal halide perovskite supercrystals via the gold-bromide complex triggered assembly of newly emerged attractive CsPbBr3 nanocubes. Through introducing gold bromide (Au-Br) complexes into CsPbBr3 nanocubes suspension, the self-assembly process of CsPbBr3 nanocubes to form supercrystals was investigated with the different amount of Au-Br complexes added to the suspensions, which indicates that the driven force of the formation of CsPbBr3 supercrystals included the van der Waals interactions among carbon chains and electrostatic interactions between Au-Br complexes and surfactants. Accordingly, the optical properties change with the assembly of CsPbBr3 nanocubes and the variation of mesoscale structures of supercrystals with heating treatment was revealed as well, demonstrating the ionic characteristics of CsPbBr3 nanocrystals. The fabricated CsPbBr3 supercrystal presents a novel type of semiconducting supercrystals that will open an avenue for the assembly of ionic nanocrystals. PMID- 29251941 TI - Reduction in Brain Heparan Sulfate with Systemic Administration of an IgG Trojan Horse-Sulfamidase Fusion Protein in the Mucopolysaccharidosis Type IIIA Mouse. AB - Mucopolysaccharidosis Type IIIA (MPSIIIA), also known as Sanfilippo A syndrome, is an inherited neurodegenerative disease caused by mutations in the lysosomal enzyme, N-sulfoglucosamine sulfohydrolase (SGSH), also known as sulfamidase. Mutations in the SGSH enzyme, the only mammalian heparan N-sulfatase, cause accumulation of lysosomal inclusion bodies in brain cells comprising heparan sulfate (HS) glycosaminoglycans (GAGs). Treatment of MPSIIIA with intravenous recombinant SGSH is not possible because this large molecule does not cross the blood-brain barrier (BBB). BBB penetration by SGSH was enabled in the present study by re-engineering this enzyme as an IgG-SGSH fusion protein, where the IgG domain is a chimeric monoclonal antibody (mAb) against the mouse transferrin receptor (TfR), designated the cTfRMAb. The IgG domain of the fusion protein acts as a molecular Trojan horse to deliver the enzyme into brain via transport on the endogenous BBB TfR. The cTfRMAb-SGSH fusion protein bound to the mouse TfR with high affinity, ED50 = 0.74 +/- 0.07 nM, and retained high SGSH enzyme activity, 10 043 +/- 1003 units/mg protein, which is comparable to recombinant human SGSH. Male and female MPSIIIA mice, null for the SGSH enzyme, were treated for 6 weeks with thrice-weekly intraperitoneal injections of vehicle, 5 mg/kg of the cTfRMAb alone, or 5 mg/kg of the cTfRMAb-SGSH fusion protein, starting at the age of 2 weeks, and were euthanized 1 week after the last injection. Brain and liver HS, as determined by liquid chromatography-mass spectrometry, were elevated 30-fold and 36-fold, respectively, in the MPSIIIA mouse. Treatment of the mice with the cTfRMAb-SGSH fusion protein caused a 70% and 85% reduction in brain and liver HS, respectively. The reduction in brain HS was associated with a 28% increase in latency on the rotarod test of motor activity in male mice. The mice exhibited no injection related reactions, and only a low titer end of study antidrug antibody response was observed. In conclusion, substantial reductions in brain pathologic GAGs in a murine model of MPSIIIA are produced by chronic systemic administration of an IgG-SGSH fusion protein engineered to penetrate the BBB via receptor mediated transport. PMID- 29251942 TI - Monoclonal Antibody Interfaces: Dilatation Mechanics and Bubble Coalescence. AB - Monoclonal antibodies (mAbs) are proteins that uniquely identify targets within the body, making them well-suited for therapeutic applications. However, these amphiphilic molecules readily adsorb onto air-solution interfaces where they tend to aggregate. We investigated two mAbs with different propensities to aggregate at air-solution interfaces. The understanding of the interfacial rheological behavior of the two mAbs is crucial in determining their aggregation tendency. In this work, we performed interfacial stress relaxation studies under compressive step strain using a custom-built dilatational rheometer. The dilatational relaxation modulus was determined for these viscoelastic interfaces. The initial value and the equilibrated value of relaxation modulus were larger in magnitude for the mAb with a higher tendency to aggregate in response to interfacial stress. We also performed single-bubble coalescence experiments using a custom built dynamic fluid-film interferometer (DFI). The bubble coalescence times also correlated to the mAbs aggregation propensity and interfacial viscoelasticity. To study the influence of surfactants in mAb formulations, polyethylene glycol (PEG) was chosen as a model surfactant. In the mixed mAb/PEG system, we observed that the higher aggregating mAb coadsorbed with PEG and formed domains at the interface. In contrast, for the other mAb, PEG entirely covered the interface at the concentrations studied. We studied the mobility of the interfaces, which was manifested by the presence or the lack of Marangoni stresses. These dynamics were strongly correlated with the interfacial viscoelasticity of the mAbs. The influence of competitive destabilization in affecting the bubble coalescence times for the mixed mAb/PEG systems was also studied. PMID- 29251943 TI - Controlling Directional Liquid Motion on Micro- and Nanocrystalline Diamond/beta SiC Composite Gradient Films. AB - In this Article, we report the synthesis of micro- and nanocrystalline diamond/beta-SiC composite gradient films, using a hot filament chemical vapor deposition (HFCVD) technique and its application as a robust and chemically inert means to actuate water and hazardous liquids. As revealed by scanning electron microscopy, the composition of the surface changed gradually from pure nanocrystalline diamond (hydrophobic) to a nanocrystalline beta-SiC surface (hydrophilic). Transmission electron microscopy and Raman spectroscopy were employed to determine the presence of diamond, graphite, and beta-SiC phases. The as-prepared gradient films were evaluated for their ability to actuate water. Indeed, water was transported via the gradient from the hydrophobic (hydrogen terminated diamond) to the hydrophilic side (hydroxyl-terminated beta-SiC) of the gradient surface. The driving distance and velocity of water is pivotally influenced by the surface roughness. The nanogradient surface showed significant promise as the lower roughness combined with the longer gradient yields in transport distances of up to 3.7 mm, with a maximum droplet velocity of nearly 250 mm/s measured by a high-speed camera. As diamond and beta-SiC are chemically inert, the gradient surfaces can be used to drive hazardous liquids and reactive mixtures, which was signified by the actuation of hydrochloric acid and sodium hydroxide solution. We envision that the diamond/beta-SiC gradient surface has high potential as an actuator for water transport in microfluidic devices, DNA sensors, and implants, which induce guided cell growth. PMID- 29251944 TI - Improved Protease-Targeting and Biopharmaceutical Properties of Novel Prodrugs of Ganciclovir. AB - The prodrug strategy has been frequently employed as a chemical approach for overcoming the disadvantages of existing parent drugs. In this report, we synthesized four monoester prodrugs of ganciclovir, an anticytomegalovirus drug, and demonstrated their potential advantages in protease-targeted activation and biopharmaceutical profiles over the parent compound. We demonstrated that these four prodrugs of ganciclovir, i.e., N-benzyloxycarbonyl-(L)-alanine-ganciclovir (CbzAlaGCV), N-benzyloxycarbonyl-(alpha,l)-aminobutyric acid-ganciclovir (CbzAbuGCV), N-acetyl-(l)-phenylalanine-(l)-alanine-ganciclovir (AcPheAlaGCV), and N-acetyl-(l)-phenylalanine-(alpha,l)-aminobutyric acid-ganciclovir (AcPheAbuGCV), are hydrolytically activated by the protease of human cytomegalovirus (hCMV), a serine protease that possesses intrinsic esterase activities. CbzAlaGCV and AcPheAlaGCV were found to be activated at a higher rate by the hCMV protease than CbzAbuGCV and AcPheAbuGCV. These ganciclovir prodrugs could potentially be targeted to selective activation by the hCMV protease which is only present at the viral infection sites, thereby achieving higher efficacy and lower systemic toxicity. The tissue stability, cellular uptake, and trans epithelial transport of these ganciclovir prodrugs were also characterized. The N acetylated dipeptide prodrugs of ganciclovir were found to be generally more stable than Cbz-amino acid prodrugs in various tissue matrices. Among the four prodrug candidates, AcPheAbuGCV was the most stable in human cell homogenates, plasma, and pooled liver microsomes. AcPheAbuGCV also possessed a superior cellular uptake profile and permeability across epithelial cell monolayers. Since the targeting and selective activation of a prodrug is determined by not only its rate of hydrolysis catalyzed by the hCMV protease target but also its biopharmaceutical properties, i.e., oral absorption and systemic availability, AcPheAbuGCV is considered the best overall candidate among the four ganciclovir prodrugs for further research and development for treatment of hCMV infection. PMID- 29251945 TI - Cascarinoids A-C, a Class of Diterpenoid Alkaloids with Unpredicted Conformations from Croton cascarilloides. AB - Cascarinoids A-C (1-3), a new class of diterpenoid alkaloids with unpredicted conformations, were isolated and structurally characterized from Croton cascarilloides. It was demonstrated that the dispersion interaction might be one of the main contributors that stabilized the folded conformations for compounds 1 3. Compounds 2 and 3 showed moderate immunosuppressive activity against T and/or B lymphocyte cells. PMID- 29251946 TI - Wealth, poverty, and happiness: Social class is differentially associated with positive emotions. AB - Is higher social class associated with greater happiness? In a large nationally representative U.S. sample (N = 1,519), we examined the association between social class (household income) and self-reported tendencies to experience 7 distinct positive emotions that are core to happiness: amusement, awe, compassion, contentment, enthusiasm, love, and pride. Consistent with past research indicating that social class underlies differential patterns of attending to the self versus orienting to others, higher social class was associated with greater self-oriented feelings of contentment and pride, and with greater amusement. In contrast, lower social class was associated with more other oriented feelings of compassion and love, and with greater awe. There were no class differences in enthusiasm. We discuss that individuals from different social class backgrounds may exhibit different patterns of emotional responding due to their distinct social concerns and priorities. Whereas self-oriented emotions may follow from, foster, and reinforce upper class individuals' desire for independence and self-sufficiency, greater other-oriented emotion may enable lower class individuals to form more interdependent bonds to cope with their more threatening environments. (PsycINFO Database Record PMID- 29251947 TI - Closing your eyes to follow your heart: Avoiding information to protect a strong intuitive preference. AB - Rationally, people should want to receive information that is costless and relevant for a decision. But people sometimes choose to remain ignorant. The current paper identifies intuitive-deliberative conflict as a driver of information avoidance. Moreover, we examine whether people avoid information not only to protect their feelings or experiences, but also to protect the decision itself. We predict that people avoid information that could encourage a more thoughtful, deliberative decision to make it easier to enact their intuitive preference. In Studies 1 and 2, people avoid learning the calories in a tempting dessert and compensation for a boring task to protect their preferences to eat the dessert and work on a more enjoyable task. The same people who want to avoid the information, however, use it when it is provided. In Studies 3-5, people decide whether to learn how much money they could earn by accepting an intuitively unappealing bet (that a sympathetic student performs poorly or that a hurricane hits a third-world country). Although intuitively unappealing, the bets are financially rational because they only have financial upside. If people avoid information in part to protect their intuitive preference, then avoidance should be greater when an intuitive preference is especially strong and when information could influence the decision. As predicted, avoidance is driven by the strength of the intuitive preference (Study 3) and, ironically, information avoidance is greater before a decision is made, when the information is decision relevant, than after, when the information is irrelevant for the decision (Studies 4 and 5). (PsycINFO Database Record PMID- 29251948 TI - The development of narcissistic admiration and Machiavellianism in early adulthood. AB - We investigated the development of narcissistic admiration (i.e., the assertive or extraverted dimension of narcissism; Back et al., 2013) and Machiavellianism (Mach) in early adulthood. Specifically, we examined (a) mean-level changes in narcissistic admiration and Mach during early adulthood and (b) how studying economics and experiencing any of 30 life events were related to individual differences in changes in narcissistic admiration and Mach. We used longitudinal data from 2 cohorts of young adults in Germany (N1 = 4,962 and N2 = 2,572). The mean levels of narcissistic admiration remained stable over time. Life events analyses indicated that narcissistic admiration increased among people who experienced a positively evaluated change in their eating or sleeping habits, a positively evaluated romantic break-up, or a negatively evaluated failure on an important exam. The mean levels of Mach decreased during early adulthood in both cohorts. Life events analyses showed that Mach decreased for only the 91% of young adults who had started a new job and evaluated it positively, suggesting that mastering occupational roles mitigates Mach in early adulthood. The results will be discussed in the light of previous longitudinal studies on narcissism and the Big Five and cross-sectional studies on how age is related to narcissism and Mach. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29251949 TI - Understanding the positive effect of financial compensation on trust after norm violations: Evidence from fMRI in favor of forgiveness. AB - Norm violations are ubiquitous in organizations and often result in tangible harm and a loss of trust. One possible response to enhance trust involves the provision of financial compensation. Unfortunately, little is known about the processes that underlie the effect of such a tangible response to increase trust. We employed techniques in cognitive neuroscience (functional magnetic resonance imaging) to examine these processes. Participants placed in the scanner played the role of recipient in a series of dictator games with different allocators who (unknown to them) were preprogrammed. An unequal division of resources was used as a norm violation that resulted in a financial loss. Afterward the inflicted harm was restored through equal financial compensation. Our neuroimaging data indicate that financial compensation activates forgiveness-related brain areas and that this activation mediates the positive effect of financial compensation on trust. We discuss the theoretical and managerial implications of using tangible responses to increase trust in organizational settings. (PsycINFO Database Record PMID- 29251950 TI - Peer norms and susceptibility mediate the effect of movie alcohol exposure on alcohol initiation in adolescents. AB - Movie alcohol exposure is a known and consistent predictor of adolescent alcohol use initiation and escalation. Nearly 90% of the top U.S. movies contain alcohol content. Social-cognitive theory posits reciprocal links among environmental influences (e.g., movie alcohol exposure), social-cognitive processes (e.g., perceived norms, susceptibility, alcohol outcome expectancies), and behavior (alcohol use), but these links have been tested in only 1 direction. In the current study, we assessed movie alcohol exposure, alcohol cognitions, and alcohol initiation among adolescents (N = 1,023; 52% female, mean age = 13.7 years) in 4 annual survey waves. Cross-lagged panel models tested bidirectional relations between cognitions and movie alcohol exposure. Finally, we tested bidirectional mediation effects in the prospective prediction of alcohol initiation. Movie alcohol exposure prospectively predicted increases in descriptive norms, injunctive norms, and susceptibility but not positive or negative alcohol outcome expectancies. All factors predicted subsequent alcohol initiation. Close friend injunctive and descriptive norms, peer descriptive norms, and susceptibility mediated the effect of earlier movie alcohol exposure on subsequent alcohol initiation. Movie alcohol exposure mediated the effect of earlier close friend descriptive norms on subsequent alcohol initiation. Movie alcohol exposure and social-cognitive processes are interrelated facets that impact alcohol initiation. Permissive cognitions infrequently predicted higher subsequent exposure to movie alcohol. Clinical and preventative implications of this work are discussed. (PsycINFO Database Record PMID- 29251952 TI - The importance of problem-focused treatments: A meta-analysis of anxiety treatments. AB - One explanation for differences in treatment effectiveness for targeted symptoms is that more-effective treatments are more focused on patients' problems than are less-effective treatments. This conjecture was examined meta-analytically. Comparisons of two treatments of adults with anxiety disorders were included. Effect sizes for targeted symptoms, nontargeted symptoms, and global outcomes (e.g., quality of life and well-being) as well as the relative focus on patients' problems and researcher allegiance were coded. Metaregressions were conducted to predict effect sizes from (a) variables related to the focus on patients' problems and (b) researcher allegiance. For symptom measures, the relative focus on patients' problems predicted the relative effectiveness of the treatments, with the expectations created by explanation appearing more predictive than specific therapeutic actions focused on patients' problems, although conclusions about relative importance were difficult to determine given collinearity of predictors. Researcher allegiance also predicted the effects of the comparisons. For global outcomes, both the focus on patients' problems and researcher allegiance seemed to have smaller roles. A focus on patients' problems appears to be important for the reductions of symptoms. Clinical trials comparing treatments need to balance the focus on patients' problems and reduce researcher allegiance. (PsycINFO Database Record PMID- 29251951 TI - The social networks of smokers attempting to quit: An empirically derived and validated classification. AB - Social relationships play an important role in the uptake, maintenance, and cessation of smoking behavior. However, little is known about the natural co occurrence of social network features in adult smokers' networks and how multidimensional features of the network may connect to abstinence outcomes. The current investigation examined whether qualitatively distinct subgroups defined by multiple characteristics of the social network could be empirically identified within a sample of smokers initiating a quit attempt. Egocentric social network data were collected from 1571 smokers (58% female, 83% white) engaged in a 3-year smoking cessation clinical trial. Using nine indicator variables reflecting both risk and protective network features, finite mixture models identified five social network subgroups: High Stress/High Contact, Large and Supportive, Socially Disconnected, Risky Friends and Low Contact, and High Contact with Smokers and Light Drinkers. External variables supported the validity of the identified subgroups and the subgroups were meaningfully associated with baseline demographic, psychiatric, and tobacco measures. The Socially Disconnected subgroup was characterized by little social interaction, low levels of stress, and low exposure to social environmental smoking cues, and had the highest probability of successful cessation at 1 week compared with all other social network subgroups. At 6 months posttreatment its members had higher abstinence rates than members of the High Stress/High Contact subgroup and the Risky Friends and Low Contact subgroup. The present study highlights the heterogeneity of smokers' social milieus and suggests that network features, especially those entailing exposure to smoking cues and contexts, heighten risk for smoking cessation failure. (PsycINFO Database Record PMID- 29251953 TI - Partner-related attachment as a moderator of outcome in patients with social anxiety disorder-a comparison between short-term cognitive-behavioral and psychodynamic therapy. AB - This study investigated whether partner-related attachment characteristics differentially predict premature treatment termination as well as posttreatment and 1-year follow-up outcome in patients with social anxiety disorder treated with a manualized cognitive-behavioral therapy (CBT) or short-term psychodynamic therapy (PDT) in the SOPHO-NET (Social Phobia Psychotherapy Network) trial. Participants were 412 patients with social anxiety disorder (57% female) with a mean age of 35.4 years (SD = 12.1) who were randomized to either CBT or PDT. Partner-related attachment characteristics were measured using the revised Experiences in Close Relationships Questionnaire (ECR-R) at pretreatment. The Liebowitz Social Anxiety Scale was administered at pretreatment, posttreatment, and a 1-year follow-up. To address our research questions, linear regression models were applied. Furthermore, we compared CBT versus PDT patients within ECR R quartiles. Treatment dropout did not differ between CBT and PDT and was not predicted by pretreatment attachment. In both treatment conditions, there was a trend for higher attachment anxiety to be associated with a more limited reduction in symptoms if controlling for pretreatment Liebowitz Social Anxiety Scale scores. Exploratory analyses showed that patients assigned to the highest quartile of the ECR-R-Avoidance distribution showed more benefit within the CBT condition posttreatment and at follow-up than the PDT condition. Our findings suggest that it may be useful to assess attachment characteristics in patients with social anxiety disorder before psychotherapeutic treatment. Patients characterized by very high pretreatment attachment avoidance (ECR-R-Avoidance >3.87) may specifically benefit more from CBT than from PDT. However, replication studies are needed that also should investigate nonlinear effects of pretreatment attachment. (PsycINFO Database Record PMID- 29251954 TI - Internet-based affect-focused psychodynamic therapy for social anxiety disorder: A randomized controlled trial with 2-year follow-up. AB - Social anxiety disorder (SAD) is associated with considerable individual suffering and societal costs. Although there is ample evidence for the efficacy of cognitive behavior therapy, recent studies suggest psychodynamic therapy may also be effective in treating SAD. Furthermore, Internet-based psychodynamic therapy (IPDT) has shown promising results for addressing mixed depression and anxiety disorders. However, no study has yet investigated the effects of IPDT specifically for SAD. This paper describes a randomized controlled trial testing the efficacy of a 10-week, affect-focused IPDT protocol for SAD, compared with a wait-list control group. Long-term effects were also estimated by collecting follow-up data, 6, 12, and 24 months after the end of therapy. A total of 72 individuals meeting diagnostic criteria for DSM-IV social anxiety disorder were included. The primary outcome was the self-report version of Liebowitz Social Anxiety Scale. Mixed model analyses using the full intention-to-treat sample revealed a significant interaction effect of group and time, suggesting a larger effect in the treatment group than in the wait-list control. A between-group effect size Cohen's d = 1.05 (95% [CI]: [0.62, 1.53]) was observed at termination. Treatment gains were maintained at the 2-year follow-up, as symptom levels in the treated group continued to decrease significantly. The findings suggest that Internet-based affect-focused psychodynamic therapy is a promising treatment for social anxiety disorder. (PsycINFO Database Record PMID- 29251955 TI - Emotion-focused therapy for generalized anxiety disorder: An exploratory study. AB - Among psychological therapies for generalized anxiety disorder (GAD), cognitive behavioral therapy has a dominant position as the most studied therapy. However, some researchers have recommended that to increase treatment options and broaden choice for clients, non-cognitive-behavioral therapy models for GAD should be examined. The present study was an exploratory study, assessing pre-post outcomes and 6-month follow-up of emotion-focused therapy for GAD, supplemented by qualitative posttherapy client accounts of helpful and unhelpful aspects of therapy and changes reported since therapy started. Fourteen clients were assessed on several measures focusing on GAD symptoms, depressive symptoms, and general psychological functioning. Quantitative pre-post and 6-month follow-up data indicated large effect sizes. Qualitative data captured changes in emotional functioning, anxiety, self-acceptance, self-confidence, and self-understanding. Clients reported as helpful both relational aspects of the work and in-depth experiential tasks, although some found the experiential aspect of the work difficult. The findings suggest that there may be value in assessing emotion focused therapy as a treatment for GAD in a randomized controlled trial. (PsycINFO Database Record PMID- 29251956 TI - An introduction to the special section on psychotherapy for pregnancy loss: Review of issues, clinical applications, and future research direction. AB - This introduction article to the special section on psychotherapy for pregnancy loss reviews important societal and psychological issues, key clinical processes and recommendations, and future research directions. Differences and similarities among the articles in the special section are discussed along with each article's contribution to the higher order goal of viewing pregnancy loss through a psychological rather than solely medical lens. Each article in this section reviews different therapeutic modalities, interventions, and key clinical process issues when working with patients who have suffered the loss of a pregnancy. The important role that psychotherapy can play in helping parents to mourn the loss of a pregnancy is explored in this introductory article and throughout the special section. (PsycINFO Database Record PMID- 29251957 TI - Reproductive trauma: Psychotherapy for pregnancy loss and infertility clients from a reproductive story perspective. AB - The reproductive story offers a unique way to conceptualize pregnancy loss and infertility. This article describes the development of the reproductive story from early childhood on, and focuses on the devastating losses when the story does not unfold as originally hoped. Regardless of the type of reproductive trauma that clients experience, the underlying psychological constructs of grief are the same. The goal is to help clients work through their grief and loss, accept that their story can be edited and rewritten, and come away with a positive new ending. This paper illustrates how to utilize the reproductive story with infertility and pregnancy loss clients in psychotherapy. Using clinical illustrations, interventions for the treatment of perinatal grief, particularly in the context of infertility, are discussed. Specific suggestions are offered to help clients rethink past ideals, cope with their current trauma, and make constructive decisions in their effort to build their future family. (PsycINFO Database Record PMID- 29251958 TI - Therapeutic educational support for families pregnant after loss (PAL): A continued bond/attachment perspective. AB - Pregnancy following the loss of a baby is a complex journey that often requires supportive intervention to support attachment to a baby that follows. This article offers guidance in supporting parents during their pregnancy that follows a perinatal loss. Content is based on using the continued bond/attachment theories in a therapeutic educational group setting and in individual therapy sessions in clinical practice. Practical guidelines in working with parents to support their parenting relationship with a deceased baby while risking attachment to a new unborn baby are offered. This educational intervention can be useful in both a psychotherapeutic group setting and with individual clients. (PsycINFO Database Record PMID- 29251959 TI - Empathic psychotherapy for pregnancy termination for fetal anomaly. AB - Pregnancy termination for fetal anomaly is a unique reproductive loss with many issues distinct from spontaneous pregnancy loss, as typically addressed in the current literature. After providing a brief overview of this loss and the impact of stigma, some of the therapeutic tasks particular to this loss will be identified, including absorbing the impact of learning about the anomaly, defining what or who has been lost, deciding whether to continue or terminate the pregnancy, and deciding who to tell what. These therapeutic tasks are discussed using the available research literature, but primarily illustrated through clinical vignettes and therapist-client dialogue. Therapeutic empathy will be demonstrated as both an instrument of healing in itself, as well as a means of realizing other therapeutic goals and interventions such as empowerment, normalization, validation and processing grief and trauma, all crucial elements of doing therapy with this population. Contrasting perspectives of this loss in therapy and the role of the therapist are discussed. (PsycINFO Database Record PMID- 29251960 TI - Cognitive behavioral therapy for pregnancy loss. AB - Cognitive-behavioral therapy (CBT) is a system of psychotherapy in which an individualized case formulation drives the strategic delivery of therapeutic interventions that target cognition, emotion, behavior, and the therapeutic relationship. It has the potential to be effective for women who have experienced pregnancy loss, as pregnancy loss often carries profound meaning that disrupts many layers of a woman's belief system, and the associated emotional consequences cannot always be managed using their typical repertoire of coping skills. The distinctive features of CBT are described, as well as 3 typical intervention strategies (i.e., behavioral activation, cognitive restructuring, and mindfulness and acceptance) that are often delivered during the course of CBT with patients who have experienced pregnancy loss. Throughout the article, emphasis is placed on balancing attention to the therapeutic relationship and affective experiencing with the implementation of cognitive and behavioral change strategies. (PsycINFO Database Record PMID- 29251961 TI - A theoretical framework for treating perinatal depression using couple-based interventions. AB - Between 10% and 20% of women will experience depression in the perinatal period, which begins during pregnancy and extends into the first year after delivery. Perinatal depression (PD) is associated with significant emotional and social impairments that impact women, their children, and their partners. Although the majority of women with PD do not seek treatment, a considerable proportion of those who engage in treatment do not achieve remission. The couples and depression literature suggests that interpersonal processes are central in the development and maintenance of depressive disorders and thus, as researchers seek safe and effective treatments for perinatal populations, there may be therapeutic benefit in examining the role that partners play in women's recovery. The primary goal of this practice review is to highlight the utility of including partners in treatment for maternal PD and propose a model for practitioners to guide their work with couples within this domain. Specifically, this model involves three key components of treatment: psychoeducation, communication training, and behavioral activation. Each component addresses distinct risk factors for women and couples in the perinatal period in hopes of offering guidance to practitioners for how to address PD symptomology through a dyadic lens. (PsycINFO Database Record PMID- 29251962 TI - Children's helping behavior in an ethnic intergroup context: Evidence for outgroup helping. AB - Two studies examined when and why children (10-13 years) help ethnic in-group and out-group peers. In Study 1 (n = 163) children could help an out-group or in group peer with a word-guessing game by entering codes into a computer. While children evaluated the out-group more negatively than the in-group, they helped out-group peers more than in-group peers. Study 2 (n = 117) conceptually replicated the findings of Study 1. Additionally the results suggest that when children endorsed the stereotype that the out-group is "less smart," this increased their intention to help out-group peers and it decreased their intention to enter codes for in-group peers. The results suggest that the specific content of a negative stereotype can guide helping responses toward out group and in-group members. (PsycINFO Database Record PMID- 29251963 TI - Identifying differences in early literacy skills across subgroups of language minority children: A latent profile analysis. AB - Despite acknowledgment that language-minority children come from a wide variety of home language backgrounds and have a wide range of proficiency in their first (L1) and second (L2) languages, it is unknown whether differences across language minority children in relative and absolute levels of proficiency in L1 and L2 predict subsequent development of literacy-related skills. The purpose of this study was to identify subgroups of language-minority children and evaluate whether differences in level and rate of growth of early literacy skills differed across subgroups. Five-hundred and twenty-six children completed measures of Spanish and English language and early literacy skills at the beginning, middle, and end of the preschool year. Latent growth models indicated that children's early literacy skills were increasing over the course of the preschool year. Latent profile analysis indicated that language-minority children could be classified into nine distinct groups, each with unique patterns of absolute and relative levels of proficiency in L1 and L2. Results of three-step mixture models indicated that profiles were closely associated with level of early literacy skills at the beginning of the preschool year. Initial level of early literacy skills was positively associated with growth in code-related skills (i.e., print knowledge, phonological awareness) and inversely associated with growth in language skills. These findings suggest that language-minority children are a diverse group with regard to their L1 and L2 proficiencies and that growth in early literacy skills is most associated with level of proficiency in the same language. (PsycINFO Database Record PMID- 29251965 TI - When preferences are in the way: Children's predictions of goal-directed behaviors. AB - Across three studies, we examined 4- to 7-year-olds' predictions of goal-directed behaviors when goals conflict with preferences. In Study 1, when presented with stories in which a character had to act against basic preferences to achieve an interpersonal goal (e.g., playing with a partner), 6- and 7-year-olds were more likely than 4- and 5-year-olds to predict the actor would act in accordance with the goal to play with the partner, instead of fulfilling the basic preference of playing a favored activity. Similar results were obtained in Study 2 with scenarios that each involved a single individual pursuing intrapersonal goals that conflicted with his or her basic preferences. In Study 3, younger children's predictions of goal-directed behaviors did not increase for novel goals and preferences, when the influences of their own preferences, future thinking, or a lack of impulse control were minimized. The results suggest that between ages 4 and 7, children increasingly integrate and give more weight to other sources of motivational information (e.g., goals) in addition to preferences when predicting people's behaviors. This increasing awareness may have implications for children's self-regulatory and goal pursuit behaviors. (PsycINFO Database Record PMID- 29251964 TI - The role of identity commitments in depressive symptoms and stressful life events in adolescence and young adulthood. AB - The formation of a stable identity, consisting of a strong set of commitments, is a key developmental task in adolescence and young adulthood. Not resolving this task and lacking strong identity commitments is related to difficulties like depressive symptoms and stressful life events. However, the exact role of identity commitments in these negative experiences has remained unclear. In two longitudinal studies in the Netherlands spanning 8 and 6 years, respectively, we examined the associations between career and interpersonal commitments, depressive symptoms, and the number of experienced stressful life events over time. Study 1 included 683 adolescents (11 to 15 years at T1) and 268 adolescents and young adults (16 to 20 years at T1). Study 2 included 960 adolescents (12 to 17 years at T1) and 944 young adults (18 to 24 years at T1). Both studies indicated that stronger identity commitments predicted relative decreases in negative experiences. In Study 2, stronger interpersonal commitments predicted relative decreases in depressive symptoms. In both studies, stronger career commitments predicted a relative decrease in stressful life events. Furthermore, only career commitments weakened after negative experiences. Interpersonal commitments did not weaken after negative experiences, possibly because of the importance of interpersonal relationships during difficult times. Moreover, identity commitments did not buffer the effect of stressful life events on depressive symptoms in either study. These findings underscore the importance of identity commitments in adolescence and young adulthood, but provide crucial nuances regarding their role in different life domains. (PsycINFO Database Record PMID- 29251966 TI - Test-retest reliability and predictive validity of the Implicit Association Test in children. AB - The Implicit Association Test (IAT) is increasingly used in developmental research despite minimal evidence of whether children's IAT scores are reliable across time or predictive of behavior. When test-retest reliability and predictive validity have been assessed, the results have been mixed, and because these studies have differed on many factors simultaneously (lag-time between testing administrations, domain, etc.), it is difficult to discern what factors may explain variability in existing test-retest reliability and predictive validity estimates. Across five studies (total N = 519; ages 6- to 11-years-old), we manipulated two factors that have varied in previous developmental research lag-time and domain. An internal meta-analysis of these studies revealed that, across three different methods of analyzing the data, mean test-retest (rs of .48, .38, and .34) and predictive validity (rs of .46, .20, and .10) effect sizes were significantly greater than zero. While lag-time did not moderate the magnitude of test-retest coefficients, whether we observed domain differences in test-retest reliability and predictive validity estimates was contingent on other factors, such as how we scored the IAT or whether we included estimates from a unique sample (i.e., a sample containing gender typical and gender diverse children). Recommendations are made for developmental researchers that utilize the IAT in their research. (PsycINFO Database Record PMID- 29251967 TI - Economic hardship during infancy and U.S. Latino preschoolers' sociobehavioral health and academic readiness. AB - We tested a culturally integrative model examining the associations among economic hardship during infancy and Latino children's later sociobehavioral problems and academic skills prior to kindergarten entry, whether mothers' mental health problems and positive parenting behaviors mediated those associations, and whether they varied by mothers' acculturation levels. Participants were 714 low income Latino mothers (M age at enrollment = 24 years; 82% Mexican American; 59% foreign-born) and children (M age at enrollment = 4 months; 53% boys) in the Early Head Start Research and Evaluation Project (EHSREP). Data were gathered across five time points: when the families enrolled in the EHSREP, when the children were 14, 24, and 36 months of age, and just prior to their kindergarten entry. The results revealed an inverse relation between economic hardship during infancy and academic skills prior to kindergarten entry, with the association mediated through maternal mental health problems and positive parenting behaviors. The association between economic hardship and children's sociobehavioral problems via maternal mental health problems and positive parenting behaviors, however, was not statistically significant. Instead, the positive relation between mothers' mental health problems and children's sociobehavioral problems was mediated by maternal positive parenting behaviors. The findings highlight key family processes by which economic hardship in infancy may be associated with Latino preschoolers' academic skills prior to entering school. (PsycINFO Database Record PMID- 29251968 TI - Maternal employment stability in early childhood: Links with child behavior and cognitive skills. AB - Although many studies have investigated links between maternal employment and children's wellbeing, less research has considered whether the stability of maternal employment is linked with child outcomes. Using unique employment calendar data from the Fragile Families and Child Wellbeing Study (N = 2,011), an urban birth cohort study of largely low-income families, this paper investigates whether the stability of maternal employment in early childhood (birth to age 5) is linked with child behavior and cognitive skills at ages 5 and 9. Employment stability (continuous employment over all 5 years, low levels of job churning, longer job tenure) was linked with less child externalizing behavior, but there was little evidence to suggest stability was particularly important for PPVT and Woodcock-Johnson scores. Rather, for PPVT and Woodcock-Johnson scores, an increase in maternal employment in early childhood more generally was associated with higher scores. (PsycINFO Database Record PMID- 29251969 TI - The development of externalizing symptoms from late childhood through adolescence: A longitudinal study of Mexican-origin youth. AB - Youth who exhibit externalizing problems during childhood and adolescence are at an increased risk for a wide range of detrimental life outcomes. Despite the profound consequences of externalizing problems for children, their families, and their communities, we know less about the precise trajectory of externalizing symptoms across late childhood and adolescence, because of the paucity of fine grained longitudinal research. The present study examined the development of externalizing symptoms in a large sample (N = 674) of Mexican-origin youth, assessed annually from age 10 to 17. Specifically, we conducted analyses to better understand the trajectories of attention-deficit-hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) symptoms (and their codevelopment), as well as how gender and cultural factors influence symptom trajectories. On average, ADHD symptoms slowly declined from age 10 to 17; ODD symptoms increased until age 13 and then declined thereafter; and, CD symptoms slowly increased until age 15 and then leveled off. ADHD, ODD, and CD symptoms predicted change in each other, indicating youth may accumulate multiple forms of externalizing problems over time. Boys reported fewer externalizing problems than girls, contrary to expectations. Consistent with the Immigrant Paradox, we found that 2nd + generation youth, youth who endorsed fewer traditional Mexican cultural values (traditional gender roles, traditional family values, and religiosity), and youth who engaged in less Spanish/more English language use were at increased risk for exhibiting ADHD, ODD, and CD symptoms from childhood through adolescence. We discuss the theoretical and practical implications of these developmental patterns among Mexican-origin youth. (PsycINFO Database Record PMID- 29251970 TI - Personality change among newlyweds: Patterns, predictors, and associations with marital satisfaction over time. AB - The early years of marriage are a time of significant personal and relational changes as partners adjust to their new roles, but the specific ways that spouses' personalities may change in early marriage and how these changes are associated with spouses' marital satisfaction trajectories have been overlooked. Using 3 waves of data collected over the first 18 months of marriage (N = 338 spouses, or 169 heterosexual newlywed marriages), we examined changes in spouses' self-reported Big 5 personality traits over time and the association between initial levels and changes in personality and spouses' concurrent marital satisfaction trajectories. Results indicated significant changes in personality over time, including declines in agreeableness for husbands and for wives, declines in extraversion for husbands, declines in openness and neuroticism for wives, and increases in conscientiousness for husbands. These results did not differ by spouses' age, demographics, relationship length prior to marriage, cohabitation prior to marriage, initial marital satisfaction, or parenthood status. Initial levels of personality as well as changes in personality over time were associated with spouses' marital satisfaction trajectories. Taken together, these findings indicate that newlywed spouses' personalities undergo meaningful changes during the newlywed years and these changes are associated with changes in spouses' marital satisfaction. Further research is needed to understand the processes underlying changes in personality early in marriage and to examine the mechanisms linking changes in personality and changes in marital satisfaction. (PsycINFO Database Record PMID- 29251971 TI - Children's learning and memory of an interactive science lesson: Does the context matter? AB - Children often learn information in a context that is vastly different to the one in which they are asked to recall or use that information. Despite this, little is known about the effect of context change on children's recall of educational information. Here, 197 5- and 6-year-olds were taught the same interactive lesson in their classroom or on a field trip and were tested after a 1- to 2-day and 6 month delay. The effect of learning context was more pronounced for older children, wherein the field trip yielded more autobiographically rich memories than the classroom, but they learned a similar amount of scientific content in both contexts. Furthermore, especially for older children who learned in their classrooms, their autobiographical memory was predictive of the amount of scientific information they recalled. The opportunity to mentally reinstate the learning context generally facilitated children's recollection of autobiographical information, but older children were more adept at effectively utilizing the mental reinstatement prompt to retrieve scientific information. (PsycINFO Database Record PMID- 29251972 TI - Remifentanil maintains lower initial delayed nonmatching-to-sample accuracy compared to food pellets in male rhesus monkeys. AB - Emerging human laboratory and preclinical drug self-administration data suggest that a history of contingent abused drug exposure impairs performance in operant discrimination procedures, such as delayed nonmatching-to-sample (DNMTS), that are hypothesized to assess components of executive function. However, these preclinical discrimination studies have exclusively used food as the reinforcer and the effects of drugs as reinforcers in these operant procedures are unknown. The present study determined effects of contingent intravenous remifentanil injections on DNMTS performance hypothesized to assess 1 aspect of executive function, working memory. Daily behavioral sessions consisted of 2 components with sequential intravenous remifentanil (0, 0.01-1.0 MUg/kg/injection) or food (0, 1-10 pellets) availability in nonopioid dependent male rhesus monkeys (n = 3). Remifentanil functioned as a reinforcer in the DNMTS procedure. Similar delay dependent DNMTS accuracy was observed under both remifentanil- and food maintained components, such that higher accuracies were maintained at shorter (0.1-1.0 s) delays and lower accuracies approaching chance performance were maintained at longer (10-32 s) delays. Remifentanil maintained significantly lower initial DNMTS accuracy compared to food. Reinforcer magnitude was not an important determinant of DNMTS accuracy for either remifentanil or food. These results extend the range of experimental procedures under which drugs function as reinforcers. Furthermore, the selective remifentanil-induced decrease in initial DNMTS accuracy is consistent with a selective impairment of attentional, but not memorial, processes. (PsycINFO Database Record PMID- 29251973 TI - A novel concurrent pictorial choice model of mood-induced relapse in hazardous drinkers. AB - This study tested whether a novel concurrent pictorial choice procedure, inspired by animal self-administration models, is sensitive to the motivational effect of negative mood induction on alcohol-seeking in hazardous drinkers. Forty-eight hazardous drinkers (scoring >=7 on the Alcohol Use Disorders Inventory) recruited from the community completed measures of alcohol dependence, depression, and drinking coping motives. Baseline alcohol-seeking was measured by percent choice to enlarge alcohol- versus food-related thumbnail images in two alternative forced-choice trials. Negative and positive mood was then induced in succession by means of self-referential affective statements and music, and percent alcohol choice was measured after each induction in the same way as baseline. Baseline alcohol choice correlated with alcohol dependence severity, r = .42, p = .003, drinking coping motives (in two questionnaires, r = .33, p = .02 and r = .46, p = .001), and depression symptoms, r = .31, p = .03. Alcohol choice was increased by negative mood over baseline (p < .001, etap2 = .280), and matched baseline following positive mood (p = .54, etap2 = .008). The negative mood-induced increase in alcohol choice was not related to gender, alcohol dependence, drinking to cope, or depression symptoms (ps >= .37). The concurrent pictorial choice measure is a sensitive index of the relative value of alcohol, and provides an accessible experimental model to study negative mood-induced relapse mechanisms in hazardous drinkers. (PsycINFO Database Record PMID- 29251974 TI - Exposure to male sexual scents (androstenone) influences women's drinking. AB - In a demonstration of a heretofore unknown motivational pathway for alcohol consumption, we recently showed that exposure to scents emitted by human females during the fertile phase of their menstrual cycle could increase men's drinking. The current study examined the reverse: whether exposure to male sexual scents (androstenone) would increase women's drinking. One hundred three female participants were primed with either androstenone or a control prime (plain water) camouflaged as a men's "cologne." They then completed a laboratory assessment of beer consumption and related measures. (Nonalcoholic beer was used for methodological and safety reasons.) Results indicated that females exposed to the androstenone prime drank significantly more than those exposed to the control prime. Social and sexual expectancies taken subsequent to drinking (to avoid unwanted manipulation influences) were correlated with drinking in the primed group but not in the neutral group, supporting the idea that information processing pathways related to alcohol use had been engaged in the primed group. Few females were ovulating, precluding assessment of the effects of fertility on this process. Because of the centrality of sexual signaling to fundamental evolutionary/biological forces, these results indicate a potentially powerful influence on alcohol consumption that calls for continued investigation. (PsycINFO Database Record PMID- 29251975 TI - Contingency management targeting abstinence is effective in reducing depressive and anxiety symptoms among crack cocaine-dependent individuals. AB - Although contingency management (CM) is effective in promoting abstinence and treatment retention among crack cocaine users who meet the criteria for cocaine dependence, less is known about its off-target effects. In this secondary analysis, we evaluated the impact of CM on depressive and anxiety symptoms in a sample of cocaine-dependent individuals under treatment. Sixty-five crack cocaine users who met the criteria for cocaine dependence were randomly assigned to receive 12 weeks of standard treatment alone (STA; n = 32) or 12 weeks of standard treatment plus CM (STCM; n = 33). The outcome measures of the secondary analysis were depressive and anxiety symptoms assessed with the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI). At baseline, 59 (90.8%) of the participants reported at least mild depressive symptoms and 47 (72.5%) reported at least mild anxiety symptoms. The mean BDI-II (24.5 +/- 12.1) and BAI (20.7 +/- 13.5) scores in the sample as a whole was moderate. After treatment, the reported levels of depressive symptoms (beta = -9.6, p < .05) and anxiety symptoms (beta = -9.9, p < .05) were lower among the individuals receiving STCM than among those receiving STA. This study provides evidence that an STCM intervention targeting crack cocaine abstinence also produces significant reductions in depressive and anxiety symptoms. This low cost intervention also demonstrated significant promise and optimization potential for crack cocaine users in a setting of scarce resources and high mental health comorbidity. Relevance Statement: We found that the prevalence of depressive and anxiety symptoms were extremely high among crack cocaine users, and that, among such individuals, contingency management (CM) reduced depressive and anxiety symptomatology to a greater degree than did standard treatment. Our results suggest that CM targeting crack cocaine abuse can have off-target effects on psychiatric symptomatology. (PsycINFO Database Record PMID- 29251976 TI - Preliminary validity of the modified Cigarette Evaluation Questionnaire in predicting the reinforcing effects of cigarettes that vary in nicotine content. AB - Validity studies evaluating self-report measures in relation to behavioral preference of cigarettes varying in nicotine content are needed. The current study examined the relationship between ratings on the modified Cigarette Evaluation Questionnaire (mCEQ) and the relative reinforcing effects of Spectrum research cigarettes (15.8, 5.2, 2.4, 0.4 mg per gram of tobacco). Data for this secondary analysis were obtained from a double-blind study (Higgins et al., 2017) evaluating the subjective and reinforcing effects of Spectrum cigarettes under acute smoking abstinence. Current smokers (N = 26) were recruited from three vulnerable smoking populations (economically disadvantaged women of reproductive age, opioid-maintained individuals, individuals with affective disorders). In Phase 1 (five sessions), the mCEQ (Satisfaction, Psychological Reward, Enjoyment of Respiratory Tract Sensations, Craving Reduction, Aversion subscales) was administered following ad lib smoking of Spectrum cigarettes and subscale differences scores were calculated by subtracting ratings of the 15.8 mg/g cigarette from ratings of the reduced nicotine content cigarettes. In Phase 2 (six sessions), participants completed six 2-dose concurrent choice tests. The relationship between mCEQ subscale difference scores from Phase 1 and nicotine dose choice from Phase 2 was examined using mixed-model repeated-measures analyses of variance. Higher Satisfaction and lower Aversion subscale difference scores were associated with choosing the 15.8 mg/g cigarette more than the 5.2, 2.4, and 0.4 mg/g cigarettes. Scores on the other mCEQ subscales were not associated with nicotine choice. These results provide support for validity of the mCEQ Satisfaction and Aversion subscales predicting the relative reinforcing effects and abuse liability of varying nicotine content cigarettes. (PsycINFO Database Record PMID- 29251977 TI - On how patients with multiple sclerosis weigh side effect severity and treatment efficacy when making treatment decisions. AB - Although effective disease-modifying treatments (DMTs) are available for individuals suffering from multiple sclerosis (MS), many patients fail to take their recommended medications. Unlike medications that provide immediate relief from existing symptoms, DMTs decrease the probability of future symptoms (i.e., a probabilistic benefit) while concurrently carrying an appreciable risk of immediate side effects (i.e., a probabilistic cost). Prior research has shown that both the probability of reducing disease progression and the probability of experiencing side effects impact patients' likelihood of taking a hypothetical DMT. The role that side effect severity plays in treatment decisions remains unexplored. The present study examined how probability of medication efficacy and side effect severity impact patients' likelihood of taking hypothetical DMTs. Patients' likelihood of taking a DMT systematically decreased as medication efficacy decreased and side effect severity increased. Because side effect severity appears to impact decision-making processes in unique ways, the present results suggest that providers should present information on severe (which are typically rare) and mild to moderate side effects (which are more common) separately. (PsycINFO Database Record PMID- 29251978 TI - Customized recommendations and reminder text messages for automated, computer based treatment during methadone. AB - The Recovery Line is an automated, computer-based intervention based on cognitive behavioral therapy (CBT) designed to provide real-time assistance by phone for patients in methadone maintenance. Preliminary efficacy findings were promising, however, as with other computer-based systems for substance use disorder, patient system use was less than recommended. Development and evaluation of system functions to increase patient engagement and use is needed. Thus, we conducted two randomized trials to evaluate system functions designed to increase patient use of the Recovery Line among methadone-maintained patients with continued illicit drug use. In Trial 1 (n = 60), patients received customized, system use recommendations or no recommendations on each Recovery Line call. Ratings of system usability were higher for customized recommendations (CR), but number of calls and total call time did not differ by condition. Trial 2 evaluated characteristics of reminder messages (message frame and reminder latency). Participants (N = 67) received gain- and loss-frame reminder messages, and were randomly assigned to immediate, short, or long term message latency. Although message framing had no effect, gender interacted with latency condition such that females did not differ by message latency, while males had significantly greater total contact time in the short latency conditions. Number of calls differed by condition over time such that the shorter latencies led to greater calls initially, but dissipated over time. Overall the study indicates that computer based self-management systems can be adapted to increase patient engagement and use. (PsycINFO Database Record PMID- 29251979 TI - Measuring heightened attention to alcohol in a naturalistic setting: A validation study. AB - Attentional bias to alcohol-related stimuli is believed to be an important contributor to the development and maintenance of drug abuse. There is a considerable body of research examining attentional bias, much of which has typically utilized image-display tasks as a means to assess the phenomenon. Little, however, is known about the nature of this bias in an individual's natural environment. The current study sought to implement a novel approach to assessing attentional bias in vivo. Participants wore portable eye-tracking glasses that recorded video from their point of view and measured fixation time to objects they observed. They entered a room that was designed to represent a recreational setting in which both alcohol- and nonalcoholic-neutral beverages were placed along with other stimuli. In two different testing sessions, participants were free to visually explore the room. Participants showed similar fixation times to alcohol and neutral beverages during Session 1. Attentional bias to alcoholic beverages was observed in Session 2 because fixation time decreased to neutral but not to alcoholic beverages. The magnitude of attentional bias was positively associated with drinking habits, with heavier drinkers demonstrating a higher degree of bias to alcohol. These findings provide an ecological model of how attentional bias can develop as the net result of attention being sustained to alcoholic stimuli while diminishing to other stimuli over time. (PsycINFO Database Record PMID- 29251980 TI - Environmental context effects on craving among consumers of caffeinated alcohol beverages: Associations with aspects of impulsivity. AB - The present study primarily sought to (a) determine the effects of environmental context on subjective ratings of craving for alcohol and caffeinated alcohol beverages (CAB) and (b) test inhibitory control, a state behavioral aspect of impulsivity, as a mediator of the association between context and craving in a sample of consumers of CAB. A secondary aim was to examine the associations between trait impulsivity and subjective craving for alcohol and CAB. Participants were 143 (67.1% female) college CAB drinkers. Participants were randomized into either a simulated bar context condition or neutral context condition and completed measures of alcohol use, CAB use, trait impulsivity, inhibitory control on a go/no-go task, and subjective craving for alcohol and CAB. Findings revealed that participants in the simulated bar condition, as compared with those in the neutral condition, reported more subjective craving for alcohol and for CAB; however, alcohol and CAB-specific craving were not different overall or as a function of context. The association between context and subjective craving for alcohol was not mediated by inhibitory control. Trait impulsivity was positively associated with alcohol and CAB-specific craving at baseline and post context exposure, and this finding was similar across both conditions. Therefore, the current investigation suggests that consumers of CAB may be sensitive to alcohol contexts as indicated by greater responses in alcohol and CAB-specific craving. However, inhibitory control did not explain this association. Future research may benefit from examining other potential mechanisms that explain the relationship between context and craving among CAB consumers. (PsycINFO Database Record PMID- 29251982 TI - The dimensionality of impulsivity: Perspectives and implications for emerging adult drinking. AB - Heightened impulsivity is a risk factor for problematic alcohol use among emerging adults. However, recent literature suggests that impulsivity is comprised of several facets that have shown differential relationships with alcohol use versus alcohol-related problems. Previous reviews have noted the bivariate associations between facets and alcohol use outcomes, but have not honed in on which facets may explain more variance in alcohol-related outcomes once other facets are accounted for. As such, certain facets may be more relevant than others in predicting alcohol-related harms among emerging adults. Consequently, the purpose of this review was to support the validity of discrete impulsivity facets and to identify specific facets that may pose most risk for alcohol-related harms. Based on previous research, the present review focused on five facets from the self-report impulsivity literature (i.e., sensation seeking, negative urgency, positive urgency, premeditation, and perseverance) and two facets from the behavioral impulsivity literature (i.e., impulsive action and impulsive choice). Conceptual and empirical evidence were provided to support the distinction of these self-report and behavioral facets, and literature comparing each of their relative contributions to alcohol use and alcohol-related problems, while controlling for the influence of other facets, is summarized. Overall, it is suggested that among emerging adults, sensation seeking is the strongest predictor of alcohol use whereas positive and negative urgency are the strongest predictors of alcohol-related problems. Implications and directions for future research were proposed. (PsycINFO Database Record PMID- 29251983 TI - On the prospect of knowing: Providing solutions can reduce persistence. AB - Our willingness to persist in problem solving is often held up as a critical component in being successful. Allied against this ability, however, are a number of situational factors that undermine our persistence. In the present investigation, the authors examine 1 such factor-knowing that the answers to a problem are easily accessible. Does having answers to a problem available reduce our willingness to persist in solving it ourselves? Across 4 experiments, participants (university students from a large Canadian University) solved multisolution anagrams and were either provided the answers after giving up (and knew they would receive the answers) or not. Results demonstrated that individuals persisted for less time in the former condition. In addition, participants did not seem to be aware of the effect that answers had on their decisions to quit. Implications for our understanding of the role that access to answers has on persistence across a number of domains (e.g., education, Internet) are discussed. (PsycINFO Database Record PMID- 29251981 TI - Hierarchical investigation of genetic influences on response inhibition in healthy young adults. AB - Poor inhibitory control is a known risk factor for substance use disorders, making it a priority to identify the determinants of these deficits. The aim of the current study was to identify genetic associations with inhibitory control using the stop signal task in a large sample (n = 934) of healthy young adults of European ancestry. We genotyped the subjects genome-wide and then used a hierarchical approach in which we tested seven a priori single nucleotide polymorphisms (SNPs) previously associated with stop signal task performance, approximately 9,000 SNPs designated as high-value addiction (HVA) markers by the SmokeScreen array, and approximately five million genotyped and imputed SNPs, followed by a gene-based association analysis using the resultant p values. A priori SNP analyses revealed nominally significant associations between response inhibition and one locus in HTR2A (rs6313; p = .04, dominance model, uncorrected) in the same direction as prior findings. A nominally significant association was also found in one locus in ANKK1 (rs1800497; p = .03, uncorrected), although in the opposite direction of previous reports. After accounting for multiple comparisons, the HVA, genome-wide, and gene-based analyses yielded no significant findings. This study implicates variation in serotonergic and dopaminergic genes while underscoring the difficulty of detecting the influence of individual SNPs, even when biological information is used to prioritize testing. Although such small effect sizes suggest limited utility of individual SNPs in predicting risk for addiction or other impulse control disorders, they may nonetheless shed light on complex biological processes underlying poor inhibitory control. (PsycINFO Database Record PMID- 29251985 TI - Modulating action duration to establish nonconventional communication. AB - In many joint actions, knowledge about the precise task to be performed is distributed asymmetrically such that one person has information that another person lacks. In such situations, interpersonal coordination can be achieved if the knowledgeable person modulates basic parameters of her goal-directed actions in a way that provides relevant information to the co-actor with incomplete task knowledge. Whereas such sensorimotor communication has frequently been shown for spatial parameters like movement amplitude, little is known about how co-actors use temporal parameters of their actions to establish communication. The current study investigated whether systematic modulations of action duration provide a sufficient basis for communication. The results of 3 experiments demonstrate that knowledgeable actors spontaneously and systematically adjusted the duration of their actions to communicate task-relevant information if the naive co-actor could not access this information in other ways. The clearer the communicative signal was the higher was the benefit for the co-actor's performance. Moreover, we provide evidence that knowledgeable actors have a preference to separate instrumental from communicative aspects of their action. Together, our findings suggest that generating and perceiving systematic deviations from the predicted duration of a goal-directed action can establish nonconventionalized forms of communication during joint action. (PsycINFO Database Record PMID- 29251984 TI - Unconscious conditioning: Demonstration of existence and difference from conscious conditioning. AB - Unpronounceable strings of 4 consonants (conditioned stimuli: CSs) were consistently followed by familiar words belonging to 1 of 2 opposed semantic categories (unconditioned stimuli: USs). Conditioning, in the form of greater accuracy in rapidly classifying USs into their categories, was found when visually imperceptible (to most subjects) CSs occupied >=58 ms of a 75-ms CS-US interval. When clearly visible CSs were presented in a 375 ms CS-US interval, conditioning was strongly correlated with measures of contingency awareness, and did not occur in the absence of that awareness. These experiments delineated 2 forms of conditioning: Unconscious conditioning occurred with a brief CS-US interval, with an effectively masked conditioned stimulus (CS), and with no reportable knowledge of the contingent CS-US relation. Conscious conditioning occurred with a substantially longer CS-US interval, a perceptible CS, and with subjects' reportable knowledge of the contingent CS-US relation. (PsycINFO Database Record PMID- 29251986 TI - "Sex differences in the spatial representation of number": Correction to Bull et al. (2013). AB - Reports an error in "Sex differences in the spatial representation of number" by Rebecca Bull, Alexandra A. Cleland and Thomas Mitchell (Journal of Experimental Psychology: General, 2013[Feb], Vol 142[1], 181-192). In the article, there was an error in the Results section of Experiment 2. The t value incorrectly repeated the beta weight ( .25). The correct value is t(39) = 3.38, p = .002. There was also an error in the Discussion section of Experiment 2. The reported result of F(1, 94) = 4.27, should read F(1, 94) = 4.72, p = .032. Finally, there was an error in the Results section of Experiment 4. The t value for was incorrectly reported as t(50) = 1.56, p = .05. It should be t(50) = 1.98. These typographical errors do not change the overall pattern of results or interpretation of the findings. (The following abstract of the original article appeared in record 2012 10822-001.) There is a large body of accumulated evidence from behavioral and neuroimaging studies regarding how and where in the brain we represent basic numerical information. A number of these studies have considered how numerical representations may differ between individuals according to their age or level of mathematical ability, but one issue rarely considered is whether the representational acuity or automaticity of using numerical representations differs between the sexes. We report 4 studies that suggest that male participants show a stronger influence of the spatial representation of number as revealed through the spatial numerical association of response codes (SNARC) effect, through the numerical distance effect (NDE), and through number-line estimations. Evidence for a sex difference in processing number was present for parity decisions (Experiment 1), color decisions (Experiment 2), number-line estimations (Experiment 3), and magnitude decisions (Experiment 4). We argue that this pattern of results reflects a sex difference in either the acuity of representation or reliance upon spatial representations of number, and that this difference may arise due to differences in the parietal lobes of men and women. (PsycINFO Database Record PMID- 29251987 TI - Top-down structure influences learning of nonadjacent dependencies in an artificial language. AB - Because of the hierarchical organization of natural languages, words that are syntactically related are not always linearly adjacent. For example, the subject and verb in the child always runs agree in person and number, although they are not adjacent in the sequences of words. Since such dependencies are indicative of abstract linguist structure, it is of significant theoretical interest how these relationships are acquired by language learners. Most experiments that investigate nonadjacent dependency (NAD) learning have used artificial languages in which the to-be-learned dependencies are isolated, by presenting the minimal sequences that contain the dependent elements. However, dependencies in natural language are not typically isolated in this way. We report the first demonstration to our knowledge of successful learning of embedded NADs, in which silences do not mark dependency boundaries. Subjects heard passages of English with a predictable structure, interspersed with passages of the artificial language. The English sentences were designed to induce boundaries in the artificial languages. In Experiment 1 & 3 the artificial NADs were contained within the induced boundaries and subjects learned them, whereas in Experiment 2 & 4, the NADs crossed the induced boundaries and subjects did not learn them. We take this as evidence that sentential structure was "carried over" from the English sentences and used to organize the artificial language. This approach provides several new insights into the basic mechanisms of NAD learning in particular and statistical learning in general. (PsycINFO Database Record PMID- 29251988 TI - Hedonic nondurability revisited: A case for two types. AB - Hedonic durability refers to the extent to which the hedonic impact of a change lasts, that is, how long the unhappiness from a loss (or happiness from a gain) will endure over time. The lesson from previous research on this topic has been that the long-term effect of most changes (e.g., larger incomes, bigger houses, shorter commutes) is negligible. The present research shows something different. Consistent with previous research, we observed a pattern of hedonic nondurability in which the impact of a change did not endure over time. However, we also observed a pattern of hedonic durability in which the impact of a change does endure over time. We demonstrate differential rates of hedonic durability for losses, both across variables (Experiment 1) and within different ranges of the same variable (Experiment 2). We also extend our research to show differential rates for gains (Experiment 3). To explain our results, we propose a distinction between preference types, arguing that comparison-independent (i.e., absolute) preference types are hedonically more durable than comparison-dependent (i.e., relative) preference types. This research offers a method for validating preference-type categorization as well as a novel paradigm for testing hedonic durability in the laboratory. Moreover, it yields theoretical insights for affective forecasting and adaptation as well as practical implications for the hedonic treadmill and the joyless economy. (PsycINFO Database Record PMID- 29251989 TI - Ockham's razor cuts to the root: Simplicity in causal explanation. AB - When evaluating causal explanations, simpler explanations are widely regarded as better explanations. However, little is known about how people assess simplicity in causal explanations or what the consequences of such a preference are. We contrast 2 candidate metrics for simplicity in causal explanations: node simplicity (the number of causes invoked in an explanation) and root simplicity (the number of unexplained causes invoked in an explanation). Across 4 experiments, we find that explanatory preferences track root simplicity, not node simplicity; that a preference for root simplicity is tempered (but not eliminated) by probabilistic evidence favoring a more complex explanation; that committing to a less likely but simpler explanation distorts memory for past observations; and that a preference for root simplicity is greater when the root cause is strongly linked to its effects. We suggest that a preference for root simpler explanations follows from the role of explanations in highlighting and efficiently representing and communicating information that supports future predictions and interventions. (PsycINFO Database Record PMID- 29251990 TI - Comprehensive Analysis of Gene Expression Profiles of Sepsis-Induced Multiorgan Failure Identified Its Valuable Biomarkers. AB - Sepsis is an inflammatory-related disease, and severe sepsis would induce multiorgan dysfunction, which is the most common cause of death of patients in noncoronary intensive care units. Progression of novel therapeutic strategies has proven to be of little impact on the mortality of severe sepsis, and unfortunately, its mechanisms still remain poorly understood. In this study, we analyzed gene expression profiles of severe sepsis with failure of lung, kidney, and liver for the identification of potential biomarkers. We first downloaded the gene expression profiles from the Gene Expression Omnibus and performed preprocessing of raw microarray data sets and identification of differential expression genes (DEGs) through the R programming software; then, significantly enriched functions of DEGs in lung, kidney, and liver failure sepsis samples were obtained from the Database for Annotation, Visualization, and Integrated Discovery; finally, protein-protein interaction network was constructed for DEGs based on the STRING database, and network modules were also obtained through the MCODE cluster method. As a result, lung failure sepsis has the highest number of DEGs of 859, whereas the number of DEGs in kidney and liver failure sepsis samples is 178 and 175, respectively. In addition, 17 overlaps were obtained among the three lists of DEGs. Biological processes related to immune and inflammatory response were found to be significantly enriched in DEGs. Network and module analysis identified four gene clusters in which all or most of genes were upregulated. The expression changes of Icam1 and Socs3 were further validated through quantitative PCR analysis. This study should shed light on the development of sepsis and provide potential therapeutic targets for sepsis induced multiorgan failure. PMID- 29251991 TI - Numerical identification of the rupture locations in patient-specific abdominal aortic aneurysmsusing hemodynamic parameters. AB - The rupture of an abdominal aortic aneurysm (AAA) is generally an unexpected event. Up to now, there is no agreement on an accurate criteria to predict the rupture risk of AAAs. This paper aims to numerically investigate the hemodynamics of three ruptured and one non-ruptured patient-specific AAA models to correlate local hemodynamic parameters with the rupture sites, and for the first time, this study introduced helicity as a potential index for the rupture potential of AAAs.3D reconstructions from CT scans were done. The simulation revealed that all the rupture sites were in regions of stagnation with near zero wall shear stress (WSS) but large WSS gradient (WSSG), which may explain the observation by the former researchers that the rupture site in the ruptured AAA has the lowest recorded wall thickness compared to other non-ruptured regions. Moreover, all the ruptures occurred at regions of zero helicity which represents a purely axial or circumferential flow. In addition, this study revealed that the double low region for the non-ruptured AAA was present with a thick layer of plaques, it suggests that the AAA rupture and the formation of atherosclerotic plaques may share a lot common physiological features. However, the fact that there are no plaques present in the walls of three RAAAs also indicates that AAA is not always a result of atherosclerosis. The current computational study may complement the maximum diameter, peak wall stress and other clinically relevant factors in AAA ruptures to identify the rupture sites of AAAs. PMID- 29251992 TI - The Development of Mood Repair Response Repertories: I. Age-Related Changes Among 7- to 14-Year-Old Depressed and Control Children and Adolescents. AB - The purpose of this study was to test developmentally informed hypotheses about regulatory responses to sadness that attenuate versus exacerbate it (adaptive versus maladaptive mood repair responses, respectively) across late childhood, early adolescence, and mid-adolescence. In a multi-site study in Hungary, clinic based, 7- to 14-year-olds with Diagnostic and Statistical Manual of Mental Disorders' (4th ed., text rev.) depressive disorders (N = 697; 55% male) and age/sex matched (at 1:2) nondepressed, school-based controls (N = 1,394) reported on their usual responses to sadness/dysphoria; parental reports were obtained separately. Adaptive and maladaptive response repertoire scores were compared across ages within and across subject groups, and by informant, controlling for confounds. Contrary to Hypothesis 1, older (vs. younger) youths in both groups reported fewer adaptive regulatory responses. Maladaptive response repertoires were unrelated to age among controls but significantly increased with age among depressed youths, particularly the girls. Partially supporting Hypothesis 2, subject groups differed in age-related trajectories of mood repair repertories, but not as expected (e.g., younger depressed children reported larger adaptive response repertoires than did controls). Parental reports revealed no developmental changes in offspring's mood repair repertories. Parent-offspring reports were most discordant for younger (vs. older) offspring, tended to converge around age 11, and were consistently and significantly larger in the depressed sample. Self-reported adaptive mood repair repertories appear to have been laid down by late childhood and then undergo "trimming" across ages 7-14 years. The extensive maladaptive mood repair response repertoires of depressed youths, which increased with age, distinguish them primarily from controls. Therefore, reducing maladaptive regulatory responses to sadness should be a priority when treating depressed youths. PMID- 29251993 TI - Structure elucidation of sweet-tasting cycloartane-type saponins from ginseng oolong tea and Abrus precatorius L. leaves. AB - The composition of ginseng oolong a widely used tea product was investigated. A new sweet-tasting cycloartane-type saponin 3beta-O-[beta-D-glucuronopyranosyl(1 >2)]-beta-D-6-acetylglucopyranosyl)-(20S,22S)-3beta,22-dihydroxy-9,19-cyclolanost 24-en-26,29-oic acid (9), along with five new compounds, was identified in the methanolic extract of the ginseng oolong tea. Structural elucidation was conducted by spectroscopic methods, including 1D- and 2D-NMR, HR-MS, HPLC LITMS/MS. It was shown that these compounds have different sugar chains connected to the abrusogenin molecule. Then saponin profiles of four commercially available ginseng oolong samples and Abrus precatorius L. leaves were compared and the presence of three known abrusosides and six new acetyl and malonyl abrusogenin derivatives was proved. The original ginsenosides were not detected in the extract, therefore, abrusosides could serve as a replacement responsible for the sweet taste of the tea. PMID- 29251994 TI - Flaviviruses Produce a Subgenomic Flaviviral RNA That Enhances Mosquito Transmission. AB - Mosquito-borne flaviviruses (MBFVs) are a global public health burden. MBFVs have several unique 3'UTR structures that inhibit the host RNA decay machinery to produce subgenomic flaviviral RNAs (sfRNAs). Number of sfRNA species and their relative quantities are dependent on the 3'UTR tertiary structures and can vary between tissues. Two recent in vivo studies demonstrated that sfRNA enhances mosquito transmission, resulting in increased infection rate of saliva. Transmission efficiency is determined by the immune response. First evidence points to sfRNA interference with the Toll and RNAi immune pathways. However, a more complex picture that includes flexibility in sfRNA production and interaction with immune-related proteins remains to be explored. PMID- 29251995 TI - Larvicidal potential of Juglans regia male flower against Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus. AB - The diseases vectored by mosquitoes continue to be a main cause of illnesses and death throughout the world. The methanol extract of Juglans regia male flower was screened for larvicidal activity against three therapeutically important mosquito vectors viz., malarial vector, Anopheles stephensi; dengue vector, Aedes aegypti and the filarial vector, Culex quinquefasciatus. The larvicidal activity was assayed against the early fourth-instar larvae of tested mosquito species at a concentration ranging from 12.5 to 200 ppm under laboratory conditions. The methanol extract recorded significant mortality against the early fourth-instar larvae of the tested species. After 12 and 24 h of exposure period, the highest effect was recorded in An. stephensi with LC50 values of 139.87 and 59.80 ppm and LC90 values of 288.96 and 166.73 ppm, respectively, followed by Ae. aegypti and Cx. quinquefasciatus. The results could be useful in search for newer, safer and more effective natural larvicidal agents. PMID- 29251996 TI - Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists. AB - Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell carcinoma patients for high-risk HPV, either from the primary tumor or from cervical nodal metastases, using p16 immunohistochemistry with a 70% nuclear and cytoplasmic staining cutoff, and (2) not routinely testing nonsquamous oropharyngeal carcinomas or nonoropharyngeal carcinomas for HPV. Pathologists are to report tumors as HPV positive or p16 positive. Guidelines are provided for testing cytologic samples and handling of locoregional and distant recurrence specimens. Conclusions Based on the systematic review and on expert panel consensus, high-risk HPV testing is recommended for all new oropharyngeal squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas. PMID- 29251997 TI - Pathology and Professionalism in the Age of Social Media. PMID- 29251998 TI - Examining a novel performance validity task for the detection of feigned attentional problems. AB - Attention Deficit Hyperactivity Disorder (ADHD) is a diagnosis of particular significance for college students, as when present it can significantly compromise academic achievement. However, because high-stakes decisions may be riding on the outcome of an ADHD evaluation (such as access to educational accommodations or stimulant medication), the diagnosis is vulnerable to exaggeration or feigning of symptoms or impairment. This study evaluates a novel procedure, the Tests of Attentional Distraction (TOAD), which is a computer-based performance validity measure involving a low difficulty continuous performance task that directly and obviously targets attentional function. A group of college student simulators (n = 115) feigning ADHD were compared to 32 individuals diagnosed with ADHD and 221 control participants on the TOAD, as well as on symptom validity indicators from the Personality Assessment Inventory (PAI). Moderate to large effects differentiating the feigning group from control participants, both ADHD and non-ADHD, were observed for both the TOAD and PAI indicators. Incremental validity analyses indicated that the two approaches to validity assessment contributed independently to the detection of suspect responding. PMID- 29251999 TI - Biotransformation of 20(R)-panaxatriol by the fungus Aspergillus flavus Link AS 3.3950. AB - Microbial transformation of 20(R)-panaxatriol by the fungus Aspergillus flavus Link AS 3.3950 was performed. Four new (1-4), along with two previously reported metabolites (5 and 6), were obtained. Their chemical structures were elucidated on the basis of extensive spectroscopic analyses. Furthermore, the inhibitory effects of those compounds on K562/ADR, Du-145, Hela, MCF-7 and HepG2 cell lines were evaluated by MTT assay. Among them, compound 15beta-hydroxy-20(R) panaxatriol (4) exhibited selective inhibitory effects on human leukaemic progenitor cells K562/ADR through arresting cell cycle, which was associated with obvious decrease of cyclin B1, cyclin D1 and cyclin-dependent kinase (CDK) 1/2/4/6 protein expression. PMID- 29252001 TI - Evaluation of Maryland's state police impaired driving reduction effort (SPIDRE). AB - OBJECTIVE: Alcohol-impaired driving is a significant factor in fatal and serious injury-producing crashes in the United States and many other countries. In 2013, the State of Maryland implemented an anti-driving under the influence (DUI) enforcement program, called the State Police Impaired Driving Reduction Effort (SPIDRE). This enforcement effort consisted of a select team of 7 police officers from the Maryland State Police who engaged in high-intensity driving under the influence (DUI) enforcement. The purpose of this evaluation was to determine the impact of the SPIDRE program on impaired-driving crashes, DUI arrests, DUI adjudicative outcomes, and public perceptions of DUI enforcement. METHODS: Data from alcohol-related crashes, arrests, and adjudicative outcomes of those arrests were used, along with data obtained from public opinion and bar patron surveys, to compare counties where the SPIDRE program operated and non-SPIDRE counties where it did not. The evaluation period extended from 2010 to 2016 in monthly intervals. Autoregressive integrated moving average (ARIMA) methods were used for the data analyses of crashes and arrests. RESULTS: There was no significant reduction in alcohol-related crashes as reported by the police associated with the SPIDRE program. However, there was a statistically significant decrease in the ratio of single-vehicle nighttime to multiple-vehicle daytime crashes in the SPIDRE counties but not in any other counties, suggesting a positive effect using this surrogate measure of impaired-driving crashes. The specific comparison counties as well as the other non-SPIDRE counties in Maryland experienced a statistically significant decrease in DUI arrests during the evaluation period, whereas the SPIDRE counties did not show such a decrease. Further, the arrests made by the SPIDRE team resulted in a significantly higher rate of positive adjudicative outcomes than arrests made by non-SPIDRE officers in those counties where the SPIDRE team operated. There was no evidence that the public was more aware of DUI enforcement efforts in the SPIDRE counties than in the non-SPIDRE counties. CONCLUSIONS: The SPIDRE program appeared able to prevent a downward trend in DUI arrests, experienced by the rest of the state, and achieved higher quality arrests resulting in more positive adjudicative outcomes. The way in which the SPIDRE team was deployed may have lacked sufficient duration and intensity (e.g., only 2-3 months of activity in any given county) to achieve a reduction in alcohol-impaired-driving crashes as reported by the police. It is recommended that the SPIDRE team increase its enforcement activities for at least 9-12 consecutive months in the county where they are employed. PMID- 29252002 TI - miR-124 inhibits progression of hepatocarcinoma by targeting KLF4 and promises a novel diagnostic marker. AB - Hepatocarcinoma is one of the most lethal malignancy haunting the Chinese population, which is partially due to the difficulties in diagnosis at an early stage. The search for a biomarker that could signify the presence and progress of hepatocarcinoma is never ended. MicroRNAs are 22-nt RNAs that could bind to 3' UTR of target mRNAs, mediating degradation of mRNAs or inhibiting the translation. Although much has been investigated, the role of miR-124 in hepatocarcinoma remained elusive. We first detected aberrant expression level of miR-124 in HCC tissues of 112 patients. By exploring the clinical parameters, we found a significantly inverse correlation between miR-124 level and TNM stages. Consistent with this, the survival analysis indicated the association of low miR 124 with longer survival time. Subsequent forced expression miR-124 resulted in reduced cell viability of Hep3B and SMMC-7221, which cell lines have high and low background expression of miR-124, respectively. TargetScan prediction rendered a subset of target candidates, which were selected for experimental validation, KLF4 was subject to luciferase assay. Ectopic expression of KLF4 increased the sphere formation ability and CD44/133-positive cell numbers, which can be reversed by abundant expression of miR-124, suggesting that KLF4 is a functional target of miR-124 in tumourigenesis and cancer progression of HCC. PMID- 29252003 TI - A novel phenylspirodrimane dimer from cultures of the fungus Stachybotrys chartarum. AB - Stachartone A (1), a novel phenylspirodrimane dimer, was isolated from cultures of the tin mine tailings-associated fungus Stachybotrys chartarum. Its structure was elucidated by means of spectroscopic methods. At the same time, compound (1) was tested for its cytotoxicity against five human cancer cell lines. PMID- 29252004 TI - Chemical composition and antioxidant activities of essential oil of Hedychium greenii and Hedychium gracile from India. AB - The chemical constituents of the essential oils hydrodistilled from rhizome parts of Hedychium greenii W.W. Sm. and Hedychium gracile Roxb, of family Zingiberaceae, growing in India, were analysed for the first time by GC-FID and GC-MS, respectively. A total of 30 and 29 components representing 99.62 and 96.74% of the total oil were identified in the essential oils of H. greenii and H. gracile, respectively. The major components of H. greenii were bornyl acetate (31.32%), alpha-pinene (14.49%), camphene (12.81%) and limonene (10.55%), whereas H. gracile was dominated by beta-pinene (25.24%), gamma-terpinene (24.62%), terpinen-4-ol (14.87%) and 1,8-cineole (7.51%). Essential oils were assessed for antioxidant potential using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2'-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging assay. H. greenii oil exhibited stronger antioxidant potential as compared to H. gracile oil and butylated hydroxytoluene (BHT). Thus, H. greenii rhizome oil has the potential to be used as an alternative source of antioxidant. PMID- 29252005 TI - A finite element model of myocardial infarction using a composite material approach. AB - Computational models are effective tools to study cardiac mechanics under normal and pathological conditions. They can be used to gain insight into the physiology of the heart under these conditions while they are adaptable to computer assisted patient-specific clinical diagnosis and therapeutic procedures. Realistic cardiac mechanics models incorporate tissue active/passive response in conjunction with hyperelasticity and anisotropy. Conventional formulation of such models leads to mathematically-complex problems usually solved by custom-developed non-linear finite element (FE) codes. With a few exceptions, such codes are not available to the research community. This article describes a computational cardiac mechanics model developed such that it can be implemented using off-the-shelf FE solvers while tissue pathologies can be introduced in the model in a straight-forward manner. The model takes into account myocardial hyperelasticity, anisotropy, and active contraction forces. It follows a composite tissue modeling approach where the cardiac tissue is decomposed into two major parts: background and myofibers. The latter is modelled as rebars under initial stresses mimicking the contraction forces. The model was applied in silico to study the mechanics of infarcted left ventricle (LV) of a canine. End-systolic strain components, ejection fraction, and stress distribution attained using this LV model were compared quantitatively and qualitatively to corresponding data obtained from measurements as well as to other corresponding LV mechanics models. This comparison showed very good agreement. PMID- 29252006 TI - Is the speech-language pathology profession prepared for an ageing population? An Australian survey. AB - PURPOSE: This study profiled the demographic characteristics and practice patterns of speech-language pathologists working with older Australians to inform future workforce planning and service development in response to an ageing population and aged care sector reform. METHOD: Data were collected through snowball distribution of an online survey comprising six sections: demographic details; caseload and service delivery practices, degree of inter-professional practice; engagement with professional development and support; and assessment and management of swallowing, mealtime and communication difficulties. All data were analysed using descriptive statistics and chi-square to determine the independence of key variables. RESULT: Data from 145 speech-language pathologists highlight the need for increased numbers of clinicians working outside of metropolitan areas and greater workforce diversity, along with increased incentive, supervision and inter-professional support for new graduate and early career clinicians considering working outside of hospital settings. To ensure evidence-based practice, further research into the validity of current assessment and intervention methods used across aged care settings is needed. CONCLUSION: The findings highlight the need for an extended scope of practice and improved models of support for speech-language pathologists working with older people to better respond to the needs of an ageing population and on-going aged care sector reform. PMID- 29252007 TI - A review of capecitabine-based adjuvant therapy for gastric cancer in the Chinese population. AB - In China, the treatment of locally advanced gastric cancer (AGC) faces unique challenges. Chinese patients may harbor more unfavorable prognostic factors than western populations and, in comparison with other Asian populations such as Japan and South Korea, a higher proportion of Chinese patients are diagnosed with AGC due to inadequate early diagnosis of the malignancy. This review summarizes the use of combination chemotherapy regimens with capecitabine as adjuvant therapy in the Chinese AGC population. Based on the available domestic data in China, the review concludes that capecitabine-based chemotherapy regimens, especially XELOX, offer good efficacy following radical gastrectomy in patients with AGC, with a low incidence of adverse events, acceptable tolerance, greater patient convenience and a lower overall cost than other regimens. PMID- 29252009 TI - The Use of Traditional Media for Public Communication about Medicines: A Systematic Review of Characteristics and Outcomes. AB - A systematic review was conducted to identify, appraise, and synthesize data from original research investigating the use of traditional media for public communication about medicines. Databases were searched for studies conducting quantitative or qualitative analyses between the years 2007 and 2017. Data extraction and assessment of the quality of the resulting studies was conducted by one reviewer and checked for accuracy by a second reviewer. A total of 57 studies met the inclusion criteria. Studies were grouped as follows: "newspapers and other print media" (n = 42), "television" (n = 9), and "radio and a combination of media" (n = 6). Content analysis (n = 34) was the most frequent research design, followed by surveys or interviews (n = 14) and randomized controlled trials (RCTs) (n = 9). Advertising, public awareness, and health administration were the most common themes, and the medicines most analyzed were vaccines, particularly human papillomavirus (HPV) and influenza. Studies conducted in the United States were the most frequent, followed by other high income countries such as Canada and the United Kingdom. The lack of consistent studies of the effects of media campaigns stresses the importance of the use of standardized research methodologies. Theoretical and practical implications of the findings for further research are discussed. PMID- 29252010 TI - Nudging at the checkout counter - A longitudinal study of the effect of a food repositioning nudge on healthy food choice. AB - Objective The current study is a longitudinal conceptual replication and aimed to investigate the effect of a food repositioning nudge on healthy food choice in a kiosk. Design During eight weeks, sales data were collected. The former four weeks formed the baseline phase and the latter four weeks formed the nudge phase where healthy food products were repositioned at the checkout counter display, while unhealthy alternatives remained available elsewhere in the store. Main Outcome Measures The main variable of interest was the proportion of healthy food products (selected to be repositioned) sold per day. Also exit interviews were administered to gather individual level data about purchases, and awareness and opinions of the nudge. Results Results showed that the proportion of selected healthy food products in total food sales was higher in all four nudge weeks than in all four baseline weeks. Individual level data showed that more customers had bought a selected healthy food product in the nudge phase and that customers generally approved of the nudge. Conclusion The current study strengthened the empirical evidence base of repositioning healthy food products as an effective and well-accepted nudge. PMID- 29252008 TI - The Coevolution of Life and Environment on Mars: An Ecosystem Perspective on the Robotic Exploration of Biosignatures. AB - Earth's biological and environmental evolution are intertwined and inseparable. This coevolution has become a fundamental concept in astrobiology and is key to the search for life beyond our planet. In the case of Mars, whether a coevolution took place is unknown, but analyzing the factors at play shows the uniqueness of each planetary experiment regardless of similarities. Early Earth and early Mars shared traits. However, biological processes on Mars, if any, would have had to proceed within the distinctive context of an irreversible atmospheric collapse, greater climate variability, and specific planetary characteristics. In that, Mars is an important test bed for comparing the effects of a unique set of spatiotemporal changes on an Earth-like, yet different, planet. Many questions remain unanswered about Mars' early environment. Nevertheless, existing data sets provide a foundation for an intellectual framework where notional coevolution models can be explored. In this framework, the focus is shifted from planetary scale habitability to the prospect of habitats, microbial ecotones, pathways to biological dispersal, biomass repositories, and their meaning for exploration. Critically, as we search for biosignatures, this focus demonstrates the importance of starting to think of early Mars as a biosphere and vigorously integrating an ecosystem approach to landing site selection and exploration. Key Words: Astrobiology-Biosignatures-Coevolution of Earth and life-Mars. Astrobiology 18, 1-27. PMID- 29252011 TI - Parent and Adolescent Motivational Enhancement Intervention for Substance-Using, Truant Adolescents: A Pilot Randomized Trial. AB - The purpose of this article is to present the results of a treatment development study designed to examine the feasibility, acceptability, and preliminary efficacy of motivational enhancement therapy (MET) for substance using, truant adolescents plus the Family Check-Up (FCU) for parents. A randomized controlled trial was used to test the hypothesis that MET plus the FCU (MET/FCU) would lead to greater reductions in alcohol and marijuana use as well as truant behavior compared to a psychoeducation (PE) condition delivered to both adolescents and parents. Participants (n = 69; M age = 15.8 years) were 39% female, 59% White, and 31% Hispanic/Latino. Adolescents were referred from family court, from school truancy courts, from school counselors, or after presentations in high school health classes. Eligible participants reported using marijuana at least 3 times in the prior 90 days and a history of school truancy in the prior school year. The MET/FCU condition was found to be feasible to implement and was acceptable to both adolescents and parents. The PE condition was also found to be an acceptable and credible comparison condition by participants. Results at the 6-month follow up favored MET/FCU over PE on days of marijuana use and number of times marijuana was smoked per day (medium effect), high volume drinking days and other drug use (small to medium effects), truancy indicators (small effects), parental monitoring (medium to large effects), and parent-teen problem solving (medium to large effects). A larger study to test the efficacy of the MET/FCU appears warranted based on these promising findings. PMID- 29252014 TI - A Response to "A Novel Treatment Approach to Over-Pronation Dysfunction: A Follow Up". PMID- 29252012 TI - What do speech-language pathologists describe as most important when trying to achieve client participation during aphasia rehabilitation? A qualitative focus group interview study. AB - PURPOSE: The aim of this study was to investigate what speech-language pathologists describe as most important when trying to achieve client-oriented participation during aphasia rehabilitation. METHOD: A qualitative study including semi-structured focus group interviews with 11 speech-language pathologists. Interviews were analysed with the use of systematic text condensation. RESULT: Four main themes emerged from the analysis. (1) It is important to take the vulnerability of the client group into account. (2) It is important to address the client's process of realisation by navigating around unrealistic wishes and goals. (3) It is challenging to involve clients when the evidence-base for clinical practice is limited. (4) It is crucial to make therapy meaningful to the client. CONCLUSION: This study showed that speech-language pathologists perceived prediction of a clinical course in aphasia rehabilitation as challenging due to the vulnerable client group and the perceived need to guide the clients through the rehabilitation process. They talked about how unrealistic client goals, and the lack of a solid evidence-base to guide their clinical practice, made collaborative goal setting and treatment planning challenging. Due to these barriers, the speech-language pathologists struggled to achieve client participation, and thereby aphasia rehabilitation could not be described as fully client-oriented. PMID- 29252016 TI - Periungual Eccrine Poroma Masquerading as Ingrown Toenails A Case Report with Dermoscopic Findings. AB - Eccrine poroma is a rare benign adnexal neoplasm originating from a portion of the intraepidermal eccrine sweat gland duct and the acrosyringium. Typically, the lesions are asymptomatic, slow-growing nodules, which may be found in any sweat gland-bearing area. Multiple red lacunae, glomerular vessels, hairpin vessels, flower- and leaf-like vascular patterns, a polymorphic vascular pattern, globule/lacunae-like structures, a frog egg-like appearance, and comedo-like openings have been defined as characteristic dermoscopic patterns of the disease. We report a case of eccrine poroma in an unusual periungual and subungual location mimicking ingrown toenails. The dermoscopic findings of the lesions were compatible with those of eccrine poromas located in areas other than the periungual area. Recurrence was observed after the first excisional biopsy. There was no recurrence 10 months after the second surgical intervention, and near complete regrowth of the nail plate was achieved. Eccrine poroma should be considered as a differential diagnosis in the presence of slow-growing, erythematous, painful, hemorrhagic papular lesions located in the periungual area in conjunction with a prediagnosis of ingrown toenails and malignant processes. PMID- 29252017 TI - An Overview of the Percutaneous Antibiotic Delivery Technique for Osteomyelitis Treatment and a Case Study of Calcaneal Osteomyelitis. AB - BACKGROUND: A percutaneous antibiotic delivery technique (PAD-T) used for the adjunctive management of osteomyelitis is presented. METHODS: This surgical technique incorporates a calcium sulfate and hydroxyapatite (calcium phosphate) bone void filler acting as a carrier vehicle with either an antibiotic or an antifungal medicine, delivering this combination directly into the area of osteomyelitis. RESULTS: The benefit of the PAD-T is reviewed with a case presentation of a successfully treated calcaneal osteomyelitis. CONCLUSIONS: No previously reported PAD-T using a simple bone cortex incision in the adjunctive treatment of osteomyelitis has been reported. The PAD-T safely and effectively uses a calcium sulfate and hydroxyapatite bone void filler carrier vehicle to deliver either an antibiotic or an antifungal medicine directly into the area of osteomyelitis. PMID- 29252018 TI - Health and Safety in Podiatric Medicine Findings from a National Survey of Irish Podiatric Physicians. AB - BACKGROUND: Much of the research into health and safety in podiatric medicine to date has focused on measuring particular hazards. This study examines legislative awareness and compliance in Irish podiatric medical practices and aspects of health and safety practice. METHODS: Podiatric physicians practicing in Ireland completed a cross-sectional questionnaire survey that included measures of health and safety knowledge and awareness, compliance with legislative requirements, perceived risks, and health status. RESULTS: Of 250 podiatric physicians who were contacted, 101 completed the survey (response rate, 40%). Legislative knowledge and compliance were low among respondents. A Student t test revealed that the use of safety control measures was more frequent among podiatric physicians in practice for less than 20 years ( P < .05). Musculoskeletal disorders and back injuries were the most frequently reported health concerns. CONCLUSIONS: This study demonstrates the need for interventions to increase awareness of legislative requirements among podiatric physicians as a first step to increase levels of regulatory compliance. PMID- 29252019 TI - Reversible Secondary Osteolysis in Diabetic Foot Infection. AB - Osteolysis, caused by active resorption of bone matrix by osteoclasts, can be primary or can develop secondary to a variety of disease processes. An elevated level of inflammatory cytokines in the local milieu and increased blood flow secondary to infection or autonomic neuropathy stimulate the osteoclasts and cause bone loss in the diabetic foot. Charcot's neuroarthropathy and osteomyelitis are well-known foot complications of diabetes, and secondary osteolysis has largely been underappreciated and, hence, underreported. Plain radiographs, an initial component in the evaluation of the diabetic foot, may not successfully differentiate secondary osteolysis from osteomyelitis. We describe a patient with phalangeal osteolysis secondary to soft-tissue infection in whom a correct and timely diagnosis helped avoid unnecessary surgical interventions. PMID- 29252020 TI - The Rare Lesser Metatarsal Bipartite Sesamoid A Case Report. AB - Sesamoid bones and accessory ossicles are common incidental findings on radiographs. These can occasionally become symptomatic, usually after a precipitating event such as an injury or overuse, or they can be incidental findings unrelated to the presenting pathology. The aim of this study was to highlight a rare case of a bipartite fifth metatarsal sesamoid bone and to review previous literature regarding sesamoid bones and accessory ossicles. PMID- 29252022 TI - Web-Based Patient Experience Surveys to Enhance Response Rates A Prospective Study. AB - BACKGROUND: Patient experience is a critical component of continuous quality improvement and value-based health-care delivery. This study aimed to identify a simple, cost-effective means of administering a validated patient experience survey in ambulatory-care settings. METHODS: Patients were randomly assigned to groups to complete the validated Consumer Assessment of Healthcare Providers and Systems (CAHPS) clinician and group patient satisfaction survey using a Web-based platform. The response rate was assessed for in-clinic and e-mail distribution and was compared with the historical response rates. Patients were able to change groups after randomization to assess effect on response rate and potential bias. The cost of survey administration was compared. RESULTS: Of 132 participants, 87 completed surveys (65.9%), with no significant differences among distribution methods. Twenty-three participants self-selected the in-clinic survey after being randomized to the e-mail cohort. Survey responses were statistically significantly different in only three of 34 questions. Web-based survey administration costs two to four times less than standard mail, phone, and mixed modal survey administration. CONCLUSIONS: We recommend that ambulatory clinics use Web-based technology to administer CAHPS clinician and group surveys, using both e-mail and in-clinic distribution to enhance the response rate. PMID- 29252023 TI - Risk Factors for Infection with Pseudomonas aeruginosa in Diabetic Foot Infections. AB - BACKGROUND: Selecting empirical therapy for a diabetic foot infection (DFI) requires knowing how likely infection with Pseudomonas aeruginosa is in a particular patient. We designed this study to define the risk factors associated with P aeruginosa in DFI. METHODS: We performed a preplanned microbiological subanalysis of data from a study assessing the effects of treatment with intralesional epidermal growth factor for diabetic foot wounds in patients in Turkey between January 1, 2012, and December 31, 2013. Patients were screened for risk factors, and the data of enrolled individuals were recorded in custom designed patient data forms. Factors affecting P aeruginosa isolation were evaluated by univariate and multivariate logistic regression analyses, with statistical significance set at P < .05. RESULTS: There were 174 patients enrolled in the main study. Statistical analysis was performed in 90 evaluable patients for whom we had microbiological assessments. Cultures were sterile in 19 patients, and 89 bacterial isolates were found in the other 71. The most frequently isolated bacteria were P aeruginosa (n = 23, 25.8%) and Staphylococcus aureus (n = 12, 13.5%). Previous lower-extremity amputation and a history of using active wound dressings were the only statistically significant independent risk factors for the isolation of P aeruginosa in these DFIs. CONCLUSIONS: This retrospective study provides some information on risk factors for infection with this difficult pathogen in patients with DFI. We need prospective studies in various parts of the world to better define this issue. PMID- 29252024 TI - Extraskeletal Chondroma with Concomitant Arthrosis of the Foot at the First Metatarsophalangeal Joint A Case Report. AB - Extraskeletal chondroma is a benign tumor that is found most often in the fingers but can be found in the feet as well. A symptom of this lesion is pressure from the slow-growing mass. We present the case of a 58-year-old woman who presented with an extraskeletal chondroma in the plantar aspect of the left first metatarsophalangeal joint with concomitant symptomatic arthrosis at the joint. Operative treatment was excision of the lesion in addition to arthrodesis of the joint attributable to the presence of symptomatic arthrosis. The patient was seen approximately 1 year postoperatively and had no postoperative complications. Distinction between extraskeletal chondromas and other lesions, such as extraskeletal myxoid chondrosarcomas, is critical because delayed treatment of the latter has the propensity to lead to detriment to the patient. Therefore, proper diagnosis is critical. PMID- 29252025 TI - Ultrasound-Guided Platelet-Rich Plasma Injection in a Patient with a Plantar Fascia Tear. AB - We report the case of a 40-year-old female patient presenting with resistant heel pain attributable to plantar fascia rupture. She was treated with ultrasound guided platelet-rich plasma injection, and her pain was decreased. Additionally, ultrasound was useful for diagnosis, intervention and follow-up of the patient. PMID- 29252027 TI - Arthroscopic Debridement of a Talar Cyst and Bone Grafting with the Osteochondral Autograft Transfer System A Case Report. AB - Simple bone cysts compose approximately 3% of all primary bone tumors and most commonly occur in the metaphyseal regions of the proximal humerus and femur. The percentage of the talus with suspected bone tumors is reported to be 0.003%. Therefore, talar cysts are rare but sometimes present as aggressive lesions, and they can affect any of the tarsal bones. Recently, an arthroscopic approach to these lesions has been developed that is less invasive than conventional open surgery. In the present case study, we profile a 65-year-old female patient who received arthroscopic debridement of a bone cyst from the medial aspect of the talus with the osteochondral autograft transfer system (OATS). By using the OATS core harvester, we penetrated into the tumor. After the cylindrical bone plug was pulled out, the tumor was removed and artificial bone granules were firmly packed into the cavity with intralesional arthroscopy. Then, the cylindrical bone plug previously harvested by OATS was implanted at the site with careful precision. This intervention resulted in a relative restoration of talar dome anatomy and ultimately restored the patient to activity with minimal discomfort. Therefore, arthroscopic debridement with OATS has the potential to be a useful option in dealing with debilitating osteochondral cystic lesions. PMID- 29252028 TI - Mechanical Stress Redistribution in the First Metatarsal Bone After Autologous Bone Harvesting. AB - BACKGROUND: The first metatarsal bone is a viable source for autologous bone grafting in foot and ankle surgery and may serve as another convenient graft site to correct a flail toe deformity. We aimed to determine how progressive bone removal from the first metatarsal affects the mechanical redistribution of the foot and whether this bone removal increases the risk of fracture. METHODS: A three-dimensional finite element model developed from computed tomographic images obtained from a healthy man were used to evaluate traction stresses on the first metatarsal bone as a function of applied loads on the talus and Achilles tendon at two phases of the gait cycle (and according to the depth of bone removal). RESULTS: Simulations indicated that when maximum load was applied to the Achilles tendon, tensile stress increased from 2.049 MPa in the intact foot to 5.941 MPa in the area of maximum bone harvest during the stance phase. Furthermore, as the volume of bone extracted from the first metatarsal increased, there was a redistribution of stress that differed significantly from that of the intact foot. CONCLUSIONS: Although the maximum stress on the first metatarsal was not significantly affected by increasing the volume of bone harvested, the ankle should be splinted in plantarflexion during the postoperative period to eliminate the stance phase of gait and reduce the risk of metatarsal fracture. PMID- 29252029 TI - A Novel Treatment Approach to Over-Pronation Dysfunction A Follow-Up. PMID- 29252030 TI - Isolated Cuboid-Lateral Cuneiform Coalition A Rare Cause of Foot Pain. AB - Tarsal coalitions represent a cohort of conditions characterized by bony, cartilaginous, or fibrous union of two or more tarsal bones. These disorders are often poorly understood by medical professionals, often leading to delays in diagnosis and treatment. They may be asymptomatic or cause hindfoot pain, stiffness, decreased range of motion, and foot deformities. Coalitions can be investigated by an ascending sequence of imaging including radiography, computed tomography, and magnetic resonance imaging. They may be managed conservatively with orthoses, activity modification, physiotherapy, anti-inflammatory medications, or definitive surgical intervention. To our knowledge, cuboid lateral cuneiform coalition has not been reported in the orthopedic literature. We describe a 40-year-old woman with this condition who reported a 1-year history of left foot pain and stiffness. She was definitively diagnosed with magnetic resonance imaging and was managed conservatively with an aircast boot and hydrocortisone injection. PMID- 29252031 TI - Advances in the treatment of HIV/HCV coinfection in adults. AB - INTRODUCTION: Direct-acting antivirals (DAA) have revolutionized the modern treatment of chronic hepatitis C (HCV). These highly efficacious, well-tolerated, all-oral HCV regimens allow cure of HCV in over 95% of HCV-monoinfected as well as HIV/HCV-coinfected patients with short treatment durations of 8-12 weeks. Areas covered: This review will address recent developments of DAA-therapy in HIV/HCV-coinfected patients in clinical trials and real life cohorts and evaluate remaining challenges, particularly resistance, drug-drug interactions, acute HCV infection and liver transplantation focusing on HIV/HCV-coinfected patients. Expert opinion: Indeed, all available data have shown that HIV/HCV-coinfection has no impact on HCV-treatment outcome. Management, indication of therapy and follow-up of HCV-infection are now the same for both patient populations. HIV/HCV coinfected patients however, require careful evaluation of potential drug-drug interactions between HCV drugs and HIV antiretroviral therapy, medication for substance abuse and other comedications. The few remaining gaps in DAA-therapy in particular treatment of cirrhotic treatment-experienced genotype 3 infections, decompensated cirrhosis, chronic kidney disease and patients with prior DAA treatment failure have mostly been overcome by the development of new HCV agents recently licensed. Clearly, the biggest challenge globally remains the access to treatment and the inclusion of all patient populations affected in particular people who inject drugs (PWID). PMID- 29252032 TI - Breast Cancer Association with Cytomegalo Virus-A Tertiary Center Case-Control Study. AB - PURPOSE: Cytomegalo virus is a ubiquitous virus often associated with congenital infections. Some studied have claimed an association between infection with this virus and development of breast cancer. The aim of this prospective research was to study the difference in Cytomegalo virus sero-positivity among patients with breast cancer and benign breast diseases, and thereby to prove any association. MATERIALS AND METHODS: This was a hospital based Case-Control study conducted at the General Surgery wards of our hospital, a tertiary level public sector health care institution. This study was done on 130 patients with breast swellings who underwent surgical excision of their lumps over a 1-year period. Patients with histologically proven malignancies were selected as cases while proven benign cases were deemed to be the controls. IgG and IgM antibodies to Cytomegalo virus were checked in the patients from both groups. RESULTS: All of the studied patients turned out to be positive for Immunoglobulin G against Cytomegalo virus while all the patients were found to be negative for Immunoglobulin M. There was no difference in the antibody titers among the benign and malignant cases in the study. Logistic regression calculation was also carried out including the study parameters and other known risk factors. CONCLUSIONS: We conclude that there is no association between Cytomegalo virus sero-positivity and breast cancer. Another conclusion is that the studied adult population has been exposed to Cytomegalo virus in some point of their lives. Further studies of a larger magnitude are essential to confirm our results. PMID- 29252033 TI - Sociodemographic associations of the dietary proportion of ultra-processed foods in First Nations peoples in the Canadian provinces of British Columbia, Manitoba, Alberta and Ontario. AB - We investigated the food types consumed by 3276 First Nations citizens from the First Nations Food Nutrition and Environment Study (FNFNES) living on-reserve in Canada. Data from 24-h dietary recalls were classified into NOVA categories: fresh or minimally processed foods (MPF), processed culinary ingredients, processed foods, and ultra-processed foods (UPF). Individuals were classified as traditional food (TF) eaters if they ate MPF of their First Nations culture. UPF accounted for 54.0% of energy intake; 23% of participants ate TF. Increasing age and household size, living in British Columbia and TF eating were associated with a lower intake of energy from UPF. Eating TF appeared to be protective against intake of UPF. PMID- 29252034 TI - Effect of anti IL-12/23 on body composition: results of bioelectrical impedance analysis in Caucasian psoriatic patients. AB - BACKGROUND: Bioelectrical impedance analysis (BIA) is an inexpensive, non invasive and fast method to assess body composition. Little is known of the interaction between anti IL 12/23 treatment and body composition. The aim of this study was to evaluate 6- and 12-month changes in body weight, Body Mass Index (BMI) and body composition assessed by BIA in psoriatic patients treated with anti-IL-12/23. RESEARCH DESIGN AND METHODS: Demographic and clinical data were collected for each enrolled patient. Physical examination, anthropometric assessment, Psoriasis Area and Severity Index (PASI) assessment and body composition by BIA (single-frequency 50 kHz), were assessed at baseline and at 6 and 12 months of treatment. RESULTS: A significant decrease in body weight, compared to baseline, in BMI, Fat Mass at month 6 and a significant increase at month 12 for body cellular mass (BCM) and Phase Angle (PhA) were observed. In addition, a significant increase was found for intracellular water. CONCLUSION: At baseline, psoriatic patients showed a lower BCM and a lower mean PhA score. During ustekinumab treatment, the mean PhA and BCM scores increased with an improvement in psoriatic disease. Thus, ustekinumab can be an effective drug for improving not only psoriasis but also the general clinical status of patients. PMID- 29252035 TI - Characterization of fructans and dietary fibre profiles in raw and steamed vegetables. AB - Dietary fibre (DF) has many positive effects on human health associated with its functionality in the gastrointestinal tract. These benefits vary according to the type of DF. Vegetables can be a natural source of DF in the diet. However, to provide adequate nutritional advice, the content and profile of their various DF types must be characterised. This study aimed to determine the DF profile of 29 vegetables cultivated in Wallonia (Belgium) and the impact of steaming on these profiles. Using a combination of enzymatic, gravimetric and chromatographic methods, fructans, total dietary fibre (TDF), low- and high-molecular-weight soluble dietary fibre (SDF), and insoluble dietary fibre (IDF) were analysed. Results show that the DF content varies considerably among the 29 investigated vegetable varieties and species, but the influence of steaming is limited to a shift from IDF to high-molecular-weight SDF for 18 of the 29 tested vegetables, while fructans are preserved with not actual reduction in the DP. PMID- 29252036 TI - PI3K inhibition to overcome endocrine resistance in breast cancer. AB - INTRODUCTION: Activation of the phosphatidylinositol-3 kinase (PI3K) pathway is a critical step in oncogenesis and plays a role in the development of treatment resistance for both estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) positive breast cancers. Hence, there have been efforts to therapeutically inhibit this pathway. Areas covered: Several inhibitors of PI3K are now progressing through clinical trials with varying degrees of efficacy and toxicity to date. Numerous unresolved questions remain concerning the optimal isoform selectivity of PI3K inhibitors and use of predictive biomarkers. This review examines the most important PI3K inhibitors in ER positive breast cancer to date, with a particular focus on their role in overcoming endocrine therapy resistance and the possible use of PIK3CA mutations as a predictive biomarker. Expert opinion: We discuss some of the emerging challenges and questions encountered during the development of PI3K inhibitors from preclinical to phase III studies, including other novel biomarkers and future combinations to overcome endocrine resistance. PMID- 29252037 TI - Electron spin-labelling of the EutC subunit in B12-dependent ethanolamine ammonia lyase reveals dynamics and a two-state conformational equilibrium in the N terminal, signal-sequence-associated domain. AB - The B12 (adenosylcobalamin)-dependent ethanolamine ammonia-lyase (EAL) is a product of the ethanolamine utilisation (eut) gene cluster, that is involved in human gut microbiome homeostasis and in disease conditions caused by pathogenic strains of Salmonella and Escherichia coli. Toward elucidation of the molecular basis of EAL catalysis, and its intracellular trafficking and targeting to the Eut biomicrocompartment (BMC), we have applied electron spin-labelling and electron paramagnetic resonance spectroscopy to wild-type (wt) EAL from Salmonella typhimurium, by using the sulphydryl-specific, 4-maleimido-TEMPO (4MT) spin label. One cysteine residue per active site displays exceptional reactivity with 4MT. This site is identified as betaC37 on the EutC subunit, by using 4MT labeling of site-specific cysteine-to-alanine mutants, enzyme kinetics, and accessible surface area calculations. Electron paramagnetic resonance (EPR) spectra of 4MT-labelled wt EAL are collected over 200-265 K in frozen, polycrystalline water-only, and 1% v/v DMSO solvents. EPR simulations reveal two mobility components for each condition. Detectable spin probe reorientational motion of the two components occurs at 215 and 225 K with 1% v/v DMSO, relative to the water-only condition, consistent with formation of an aqueous-DMSO solvent mesodomain around EAL. Parallel trends in fast- and slow-reorientational correlation times and interconversion of the two populations with increasing temperature, indicate 4MT labelling of a single site (betaC37). A two-state model is proposed, in which the fast and slow motional populations represent EAL-bound and free conformations of the EutC N-terminal domain. The approximately equal proportion of each state may represent a balance between EutC and EAL protein stability and efficient targeting to the BMC. PMID- 29252038 TI - Quality-by-design approach for the development of telmisartan potassium tablets. AB - A quality-by-design approach was adopted to develop telmisartan potassium (TP) tablets, which were bioequivalent with the commercially available Micardis(r) (telmisartan free base) tablets. The dissolution pattern and impurity profile of TP tablets differed from those of Micardis(r) tablets because telmisartan free base is poorly soluble in water. After identifying the quality target product profile and critical quality attributes (CQAs), drug dissolution, and impurities were predicted to be risky CQAs. To determine the exact range and cause of risks, we used the risk assessment (RA) tools, preliminary hazard analysis and failure mode and effect analysis to determine the parameters affecting drug dissolution, impurities, and formulation. The range of the design space was optimized using the face-centered central composite design among the design of experiment (DOE) methods. The binder, disintegrant, and kneading time in the wet granulation were identified as X values affecting Y values (disintegration, hardness, friability, dissolution, and impurities). After determining the design space with the desired Y values, the TP tablets were formulated and their dissolution pattern was compared with that of the reference tablet. The selected TP tablet formulated using design space showed a similar dissolution to that of Micardis(r) tablets at pH 7.5. The QbD approach TP tablet was bioequivalent to Micardis(r) tablets in beagle dogs. PMID- 29252039 TI - Effects of Whey Protein Supplementation Associated With Resistance Training on Muscular Strength, Hypertrophy, and Muscle Quality in Preconditioned Older Women. AB - The purpose of this study was to investigate the effect of whey protein (WP) supplementation on muscular strength, hypertrophy, and muscular quality in older women preconditioned to resistance training (RT). In a randomized, double-blind, and placebo (PLA)-controlled design, 31 older women (67.4 +/- 4.0 years, 62.0 +/- 6.9 kg, 155.9 +/- 5.7 cm, and 25.5 +/- 2.4 kg/m2) received either 35 g of WP (n = 15) or 35 g of PLA (n = 16) over a 12-week study period while performing an RT program three times a week. Dietary intake, one-repetition maximum test, and skeletal muscle mass by dual-energy X-ray absorptiometry were assessed before and after the intervention period. Both groups showed significant (p < .05) improvements in skeletal muscle mass and total strength, and the WP group realized greater increases (p < .05) in these measures compared with PLA (skeletal muscle mass: WP = +4.8% vs. PLA = +2.3%; strength: WP = +8.7% vs. PLA = +4.9%). Muscular quality increased (p < .05) in both groups (WP = +2.9% vs. PLA = +1.5%) without statistical differences (p > .05) noted between conditions. We conclude that WP supplementation in combination with RT induces higher increases in both strength and hypertrophy in older women preconditioned to RT. PMID- 29252040 TI - Influence of low versus moderate glycemic index of diet on substrate oxidation and energy expenditure during incremental exercise in endurance athletes: a randomized counterbalanced cross-over trial. AB - The study was aimed at assessing the influence of 3-week low glycemic index (LGI) versus moderate glycemic index (MGI) diet on substrate oxidation during incremental exercise. 17 runners completed two 3-week trials of either LGI or MGI diet in a randomised counterbalanced manner. Before and after each trial the incremental cycling test was performed. Metabolic alternations were observed only within tested diets and no significant differences in fat and carbohydrate (CHO) oxidation were found between MGI and LGI diets. Following MGI diet CHO oxidation rate increased. The AUC of fat oxidation decreased after both diets. Percent contribution of fat to energy yield declined, whereas contribution of CHO was augmented following MGI diet. This study indicates that the 3-week MGI diet increased the rate of carbohydrate oxidation during incremental cycling test and improved performance in acute intense exercise test, while both high-carbohydrate diets downregulated fat oxidation rate. PMID- 29252041 TI - The effect of fish oil supplementation on brain DHA and EPA content and fatty acid profile in mice. AB - Supplementation with omega-3 (n-3) fatty acids may improve cognitive performance and protect against cognitive decline. However, changes in brain phospholipid fatty acid composition after supplementation with n-3 fatty acids are poorly described. The purpose of this study was to feed increasing n-3 fatty acids and characterise the changes in brain phospholipid fatty acid composition and correlate the changes with red blood cells (RBCs) and plasma in mice. Increasing dietary docosahexaenoic (DHA) and eicosapentaenoic acid (EPA) did not alter brain DHA. Brain EPA increased and total n-6 polyunsaturated fatty acids decreased across treatment groups, and correlated with fatty acid changes in the RBC (r > 0.7). Brain cis-monounsaturated fatty acids oleic and nervonic acid (p < .01) and saturated fatty acids arachidic, behenic, and lignoceric acid (p < .05) also increased. These brain fatty acid changes upon increasing n-3 intake should be further investigated to determine their effects on cognition and neurodegenerative disease. PMID- 29252042 TI - Decreased performance of live attenuated, oral rotavirus vaccines in low-income settings: causes and contributing factors. AB - INTRODUCTION: Numerous studies have shown that the oral rotavirus vaccines are less effective in infants born in low income countries compared to those born in developed countries. Identifying the specific factors in developing countries that decrease and/or compromise the protection that rotavirus vaccines offer, could lead to a path for designing new strategies for the vaccines' improvement. Areas covered: We accessed PubMed to identify rotavirus vaccine performance studies (i.e., efficacy, effectiveness and immunogenicity) and correlated performance with several risk factors. Here, we review the factors that might contribute to the low vaccine efficacy, including passive transfer of maternal rotavirus antibodies, rotavirus seasonality, oral polio vaccine (OPV) administered concurrently, microbiome composition and concomitant enteric pathogens, malnutrition, environmental enteropathy, HIV, and histo blood group antigens. Expert commentary: We highlight two major factors that compromise rotavirus vaccines' efficacy: the passive transfer of rotavirus IgG antibodies to infants and the co-administration of rotavirus vaccines with OPV. We also identify other potential risk factors that require further research because the data about their interference with the efficacy of rotavirus vaccines are inconclusive and at times conflicting. PMID- 29252043 TI - What influences a sustainable implementation of evidence-based interventions in community mental health services? Development and pilot testing of a tool for mapping core components. AB - BACKGROUND: An important aspect of research regarding the implementation of evidence-based practice is the sustainability and long-term stability of a programme. There is a need to measure these critical components for establishing successful programmes. AIM: The aim was to develop and pilot test the sustainable implementation scale (SIS) for measuring the critical components in the sustainable implementation of community mental health services. METHOD: The scale was based on implementation research and consisted of three subscales regarding (1) the organisational level, (2) the team level and (3) continuous support. Data from interviews and documents were collected from 14 programmes implementing the Individual Placement and Support model of supported employment. RESULTS: Internal consistency was acceptable for all subscales and for the scale as a whole. Regarding the scale, an analysis of the differences between fully established programmes and the programmes that were not established or were or only partially established after three years showed statistically significant differences, indicating that a greater number of implementation components were present in the fully established programmes. CONCLUSIONS: SIS showed both good reliability and acceptable internal consistency as well as the ability to predict programme survival. PMID- 29252044 TI - Interlocking Intramedullary Nailing Versus Locked Dual-Plating Fixation for Femoral Shaft Fractures in Patients with Multiple Injuries: A Retrospective Comparative Study. AB - PURPOSE: Intramedullary nailing (IMN) is a popular method in the management of femoral shaft fractures (FSFs). However, whether the association of IMN with pulmonary fat emboli can compromise the pulmonary and nervous systems is debatable. The purpose of this study is to compare IMN with the locked dual plating (LDP) method by assessing the clinical outcomes of FSF patients with head or chest injury. METHOD: A total of 126 FSF patients were included in this study between January 2010 and July 2016 and divided into LDP and IMN groups. Patient demographic characteristics, operative time, blood loss, Harris Hip Score, Lysholm Knee Score, radiological outcomes, and systemic complications were collected and compared between the two treatment groups. Patients were followed up for at least 12 months. RESULTS: The LDP group performed better than IMN in terms of operative time, estimated blood loss amount, and malunion rate. Differences in function scores, fracture union rate, overall pulmonary complication rate, and in-hospital mortality between the two groups were not significant. Average radiographic union time was significantly longer in the LDP group (36.3 weeks) than in the IMN group (32.5 weeks). One case of fixation failure occurred postoperatively in the LDP group, whereas one case of fracture nonunion took place in the IMN group. CONCLUSION: Our findings suggest that dual plating fixation is a promising method for FSFs with multiple injuries. However, the retrospective nature of this study necessitates high-quality trials to be performed to assess the clinical efficiency of dual plating. PMID- 29252045 TI - Isolated Capsulorhexis Flap Technique in Femtosecond Laser-Assisted Cataract Surgery to Protect the Corneal Endothelial Cells. AB - PURPOSE: To present a novel technique that using capsulorhexis flap to protect corneal endothelial cells during femtosecond laser-assisted cataract surgery. METHODS: During the procedure, an isolated capsulorhexis flap was used to lift it up carefully by using OVD until the flap attached to the corneal inner layer. It kept steady during the phaco phase, and been removed by I/A tip after intraocular lens implantation. RESULTS: In our pilot study, the damage to the corneal endothelial cells from the phacoemulsification procedure were no more than the traditional phaco procedure, even femtosecond laser assisted cataract surgery. CONCLUSION: Isolated capsulorhexis flap technique initiate a new approach to protect the endothelial cell. It is a simple technique with a short learning curve, but still need a further investigation to prove the protection of corneal endothelial cells. PMID- 29252046 TI - Nutrition Knowledge Among Young Finnish Endurance Athletes and Their Coaches. AB - The nutrition knowledge of athletes and coaches is often inadequate. However, athletes need sufficient knowledge of this subject to understand the importance of food choices for their athletic performance, recovery, and overall health. Adequate nutrition knowledge and skills are important for coaches because they are often the most significant source of nutrition knowledge for their athletes. Most previous nutrition knowledge studies have been carried out in team sports and outside Scandinavia. The aim of this study, therefore, was to evaluate the nutrition knowledge of Finnish endurance athletes (156 males and 156 females; age = 17.9 +/- 1.2 years) and their coaches (69 males and 25 females; age = 44.3 +/- 12.3 years). The three main sports among the participants were cross-country skiing (n = 53 coaches and n = 111 athletes), orienteering (n = 13 and n = 110), and biathlon (n = 6 and n = 38). On average, the coaches (N = 94) answered 81% +/ 9% of the 79 nutrition questionnaire items correctly, whereas the respective result was 73% +/- 9% among the athletes (N = 312). The coaches had significantly (p < .001) better nutrition knowledge of all the five subcategories of the questionnaire, whereas the "dietary supplements" and "nutrition recommendations for endurance athletes" subcategories appeared particularly difficult for the athletes. The average nutrition knowledge score of athletes was relatively low. As nutrition knowledge may have a positive association with athletes' food choices and subsequent dietary intake, Finnish endurance athletes and coaches would benefit from enhanced nutrition education. PMID- 29252047 TI - The Effect of Beetroot Juice Supplementation on Dynamic Apnea and Intermittent Sprint Performance in Elite Female Water Polo Players. AB - Nitrate-rich beetroot juice is thought to have ergogenic effects, particularly in conditions where oxygen availability is limited. Whether these effects also apply to elite athletes is currently unknown. The aim of this study was to assess the effects of beetroot juice supplementation on dynamic apnea and intermittent sprint performance in elite female water polo players. In a double-blinded, randomized, crossover manner, the Dutch National female water polo team (N = 14) was subjected to two 6-day supplementation periods (1 and 2), with either 140 ml/day of nitrate-rich (BR; ~800 mg/day nitrate) or nitrate-depleted (PLA) beetroot juice. Following blood sampling on Day 6, the athletes performed a maximal-distance front crawl swimming test without breathing (dynamic apnea test). In addition, intermittent sprint performance was assessed by performing 16 swim sprints of 15 m, in a 4 * 4 block with 30-s recovery between blocks (intermittent test). Distance covered during the dynamic apnea test did not differ between BR (49.5 +/- 7.8 m) and PLA (46.9 +/- 9.1 m, p = .178). However, when correcting for test order, the distance covered was significantly larger in BR versus PLA when BR was ingested in Period 2 (50.1 +/- 8.5 vs. 42.8 +/- 5.7 m, p = .002), whereas no difference was observed when BR was ingested in Period 1 (48.8 +/- 7.4 vs. 52.3 +/- 10.4 m, p = .10). The time to complete the intermittent test was not different between BR and PLA (316.0 +/- 7.9 vs. 316.3 +/- 6.9 s, p = .73). In conclusion, beetroot juice supplementation does not improve intermittent performance in elite female water polo players, but there may be a potential for ergogenic effects during dynamic apnea. PMID- 29252048 TI - Associations between the peer support relationship, service satisfaction and recovery-oriented outcomes: a correlational study. AB - BACKGROUND: The working alliance between non-peer providers and mental health consumers is associated with positive outcomes. It is hypothesized that this factor, in addition to other active support elements, is also positively related to peer support service outcomes. AIMS: This study evaluates correlates of the peer-to-peer relationship and its unique association with service satisfaction and recovery-oriented outcomes. METHOD: Participants were 46 adults with serious mental illnesses taking part in a peer-brokered self-directed care intervention. Pearson correlation analyses examined associations among peer relationship factors, services-related variables and recovery-oriented outcomes (i.e. empowerment, recovery and quality of life). Hierarchical multiple regression analyses evaluated associations between relationship factors and outcomes over time, controlling for other possible intervention effects. RESULTS: The peer relationship was not related to number of contacts. There were robust associations between the peer relationship and service satisfaction and some recovery-oriented outcomes at 24-months, but not at 12-months. These associations were not explained by other possible intervention effects. CONCLUSION: This study contributes to a better understanding of the positive, unique association between the peer-to-peer relationship and outcomes, similar to what is found in non-peer delivered interventions. Implications for program administrators and policymakers seeking to integrate peer specialists into mental health service systems are discussed. PMID- 29252049 TI - Assessment of Nutrient Status in Athletes and the Need for Supplementation. AB - Nutrition assessment is a necessary first step in advising athletes on dietary strategies that include dietary supplementation, and in evaluating the effectiveness of supplementation regimens. Although dietary assessment is the cornerstone component of the nutrition assessment process, it should be performed within the context of a complete assessment that includes collection/evaluation of anthropometric, biochemical, clinical, and environmental data. Collection of dietary intake data can be challenging, with the potential for significant error of validity and reliability, which include inherent errors of the collection methodology, coding of data by dietitians, estimation of nutrient composition using nutrient food tables and/or dietary software programs, and expression of data relative to reference standards including eating guidance systems, macronutrient guidelines for athletes, and recommended dietary allowances. Limitations in methodologies used to complete anthropometric assessment and biochemical analysis also exist, as reference norms for the athlete are not well established and practical and reliable biomarkers are not available for all nutrients. A clinical assessment collected from history information and the nutrition-focused physical exam may help identify overt nutrient deficiencies but may be unremarkable in the well-trained athlete. Assessment of potential food drug interactions and environmental components further helps make appropriate dietary and supplement recommendations. Overall, the assessment process can help the athlete understand that supplement intake cannot make up for poor food choices and an inadequate diet, while a healthy diet helps ensure maximal benefit from supplementation. Establishment of reference norms specifically for well trained athletes for the nutrition assessment process is a future research priority. PMID- 29252050 TI - Low Energy Availability Is Difficult to Assess but Outcomes Have Large Impact on Bone Injury Rates in Elite Distance Athletes. AB - We aimed to (a) report energy availability (EA), metabolic/reproductive function, bone mineral density, and injury/illness rates in national/world-class female and male distance athletes and (b) investigate the robustness of various diagnostic criteria from the Female Athlete Triad (Triad), Low Energy Availability in Females Questionnaire, and relative energy deficiency in sport (RED-S) tools to identify risks associated with low EA. Athletes were distinguished according to benchmarks of reproductive function (amenorrheic [n = 13] vs. eumenorrheic [n = 22], low [lowest quartile of reference range; n = 10] versus normal testosterone [n = 14]), and EA calculated from 7-day food and training diaries (< or >30 kcal.kg-1 fat-free mass.day-1). Sex hormones (p < .001), triiodothyronine (p < .05), and bone mineral density (females, p < .05) were significantly lower in amenorrheic (37%) and low testosterone (40%; 15.1 +/- 3.0 nmol/L) athletes, and bone injuries were ~4.5-fold more prevalent in amenorrheic (effect size = 0.85, large) and low testosterone (effect size = 0.52, moderate) groups compared with others. Categorization of females and males using Triad or RED-S tools revealed that higher risk groups had significantly lower triiodothyronine (female and male Triad and RED-S: p < .05) and higher number of all-time fractures (male Triad: p < .001; male RED-S and female Triad: p < .01) as well as nonsignificant but markedly (up to 10-fold) higher number of training days lost to bone injuries during the preceding year. Based on the cross-sectional analysis, current reproductive function (questionnaires/blood hormone concentrations) appears to provide a more objective and accurate marker of optimal energy for health than the more error-prone and time-consuming dietary and training estimation of EA. This study also offers novel findings that athlete health is associated with EA indices. PMID- 29252052 TI - The Culture of Mental Illness and Psychiatric Practice in Africa. PMID- 29252051 TI - Eye-Tracking Technology in Surgical Training. AB - The aim of this review was to amalgamate literature on the use of eye tracking methodology as an adjunct to surgical training. The PRISMA Guidelines were used to undertake this systematic review. Our review studies has shown that recording a surgeon's eye movements; time to first fixation and gaze pattern through the use of eye tracking technology would be beneficial for surgical training. PMID- 29252053 TI - Renal risk stratification in left ventricular assist device therapy. AB - INTRODUCTION: Left ventricular assist device (LVAD) therapy has greatly reduced mortality for patients with advanced heart failure (HF), both as a bridge to heart transplantation and as destination therapy. However, among other comorbidities, LVAD recipients face a risk of renal dysfunction, related to either the residual effects of HF or to LVAD support, which complicates the management of these patients and increases the risk of an adverse clinical outcome, including death. Areas covered: The authors summarize the current understanding of pre-LVAD predictors of post-LVAD renal dysfunction and need for renal replacement therapy (RRT), including emerging data about the risk conferred by proteinuria. The authors also discuss dynamics changes in renal function after LVAD placement, the importance of perioperative hemodynamic management in lowering renal risk, and the challenges of managing LVAD patients requiring chronic RRT. Expert commentary: A requirement for RRT before or after LVAD placement portends a high risk of mortality, suggesting a need to identify patients at high risk for post-LVAD RRT. Proteinuria and reduced renal function prior to LVAD placement predict RRT and should be included in the risk assessment of patients being considered for LVAD therapy. PMID- 29252054 TI - Jollity and the "Santa Claus" effect: bah humbug? PMID- 29252055 TI - Commentary on "Assessment of Risk Factors of Intrauterine Adhesions in Patients with Induced Abortion and the Curative Effect of Hysteroscopic Surgery". PMID- 29252056 TI - Nutritional Supplements and the Brain. AB - Cognitive function plays an important role in athletic performance, and it seems that brain functioning can be influenced by nutrition and dietary components. Thus, the central nervous system might be manipulated through changes in diet or supplementation with specific nutrients including branched-chain amino acids, tyrosine, carbohydrates, and caffeine. Despite some evidence that branched chained amino acids can influence ratings of perceived exertion and mental performance, several well-controlled studies have failed to demonstrate a positive effect on exercise performance. Evidence of an ergogenic benefit of tyrosine supplementation during prolonged exercise is limited. There is evidence that mild dehydration can impair cognitive performance and mood. The beneficial effect of carbohydrate supplementation during prolonged exercise could relate to increased substrate delivery for the brain, with numerous studies indicating that hypoglycemia affects brain function and cognitive performance. Caffeine can enhance performance and reduce perception of effort during prolonged exercise and will influence specific reward centers of the brain. Plant products and herbal extracts such as polyphenols, ginseng, ginkgo biloba, etc. are marketed as supplements to enhance performance. In several animal studies, positive effects of these products were shown, however the literature on their effects on sports performance is scarce. Polyphenols have the potential to protect neurons against injury induced by neurotoxins, suppress neuroinflammation, and to promote memory, learning, and cognitive function. In general, there remains a need for controlled randomized studies with a strong design, sufficient statistical power, and well defined outcome measures before "claims" on its beneficial effects on brain functioning can be established. PMID- 29252057 TI - Decreased survival in hepatitis C patients with monomorphic post-transplant lymphoproliferative disorder after liver transplantation treated with frontline immunochemotherapy. AB - Post-transplant lymphoproliferative disorder (PTLD) develops in 1-3% of liver transplant recipients and no consensus exists about therapeutic management. From 2006 to 2016, 1489 liver transplants were performed at our institution with 20 patients (incidence 1.3%) developing PTLD. Hepatitis C virus (HCV) was the leading cause (n = 10) of liver transplant in PTLD patients. Diffuse large B-cell lymphoma was the most frequent histologic subtype (n = 17), and we report our experience in the management of these patients. Patients were treated with frontline immunochemotherapy without immunosuppression reduction. All evaluable patients achieved a complete remission. Statistically significant decreased survival was identified in HCV-positive patients. Six patients (60%) exhibited increases in HCV RNA levels during therapy. Four patients (40%) developed graft failure and three of them (30%) died from liver dysfunction. This is the first study providing evidence of decreased survival in HCV-positive PTLD patients after liver transplant receiving immunochemotherapy. PMID- 29252058 TI - Case Study: Physical Capacity and Nutritional Status Before and After a Single Handed Yacht Race. AB - During solitary sailing, the sailor is exposed to sleep deprivation and difficulties in consuming regular meals. Sailor weight loss is often reported. In the present case study, we describe changes in the physical capacity and nutritional status of an athlete attempting a single-handed yacht race around the globe. An Italian male ocean racer (Gaetano Mura) asked for our help to reach an optimum level of physical and nutritional preparation. We planned his diet after assessing his anthropometric parameters and body composition, as well as his usual energy intake and nutritional expenditure. The diet consisted of 120 meals stored in sealed plastic bags. Before his departure, GM performed two incremental exercise tests (cycle ergometry and arm crank ergometry) to assess his physical capacity. Cardiac functions were also estimated by Doppler echocardiography. All measures and exercise tests were repeated 10 days after GM finished the race, which lasted 64 days. Anthropometric measures did not change significantly, with the exception of arm fat area and thigh muscle area, which decreased. There were evident increments in maximum oxygen intake and maximum workload during arm cranking after the race. On the contrary, maximum oxygen uptake and maximum workload decreased during cycling. Finally, end-diastolic and stroke volume decreased after the race. It was concluded that nutritional counseling was useful to avoid excessive changes in nutritional status and body composition due to 64 days of solitary navigation. However, a reduction in physical leg capacity and cardiovascular functions secondary to leg disuse were present. PMID- 29252059 TI - Identifying and Localizing of the In-depth Pulmonary Nodules Using Electrical Bio Impedance. AB - Intraoperative localization of small and in-depth pulmonary nodules particularly during video-assisted thoracoscopic surgery (VATS), is one of the main challenges for Thoracic surgeons. Failure to determine the location of nodules may lead to a large incision in the normal lung tissue or the conversion of the minimally invasive surgery to an open thoracotomy. The aim of this study is to evaluate the use of electrical bio-impedance measurement to precisely determine the position of in-depth pulmonary nodules and tumors, which are not visible during thoracoscopic surgeries or even are not palpable during open thoracic surgeries. With this regard, a suitable bio-impedance sensor similar to a biopsy forceps has been designed in order to measure the lung tissue bio-impedance. Using the available data on the electrical properties recorded from lung tissue during inhalation and exhalation, combined with the tumor modeling in COMSOL software, the effect of different parameters including the size and depth of tumor and the relative difference of electrical properties between healthy and tumoral tissue has been assessed. Furthermore, the geometric characteristics of the proposed sensor are considered. The results generally verify that larger size of nodules results in an easier distinguishing process. Additionally, it is worthy to note that applying a larger geometrically sensor is essential to detect the small and in-depth nodules. PMID- 29252060 TI - Reliability of the Load-Velocity Relationship Obtained Through Linear and Polynomial Regression Models to Predict the 1-Repetition Maximum Load. AB - This study aimed to compare the between-session reliability of the load-velocity relationship between (1) linear versus polynomial regression models, (2) concentric-only versus eccentric-concentric bench press variants, as well as (3) the within-participants versus the between-participants variability of the velocity attained at each percentage of the 1-repetition maximum. The load velocity relationship of 30 men (age: 21.2 [3.8] y; height: 1.78 [0.07] m, body mass: 72.3 [7.3] kg; bench press 1-repetition maximum: 78.8 [13.2] kg) were evaluated by means of linear and polynomial regression models in the concentric only and eccentric-concentric bench press variants in a Smith machine. Two sessions were performed with each bench press variant. The main findings were: (1) first-order polynomials (coefficient of variation: 4.39%-4.70%) provided the load-velocity relationship with higher reliability than the second-order polynomials (coefficient of variation: 4.68%-5.04%); (2) the reliability of the load-velocity relationship did not differ between the concentric-only and eccentric-concentric bench press variants; and (3) the within-participants variability of the velocity attained at each percentage of the 1-repetition maximum was markedly lower than the between-participants variability. Taken together, these results highlight that, regardless of the bench press variant considered, the individual determination of the load-velocity relationship by a linear regression model could be recommended to monitor and prescribe the relative load in the Smith machine bench press exercise. PMID- 29252061 TI - The Effect of Training Loads on Performance Measures and Injury Characteristics in Rugby League Players: A Systematic Review. AB - PURPOSE: To conduct a systematic review into the effect of training load (TL) on both performance measures and injury characteristics in rugby league players. METHODS: Based on PRISMA guidelines, a systematic search of electronic databases was performed from the earliest record to December 2016. Five electronic databases (MEDLINE, SPORTDiscus, CINAHL, Web of Science, and AusSportMed) were searched using keywords within the subcategories of population (rugby league players), intervention (training quantification), and outcomes (performance or injury). Original peer-reviewed published manuscripts were considered if they had a clear quantification of TL (eg, session rating of perceived exertion), clear measures of performance (tests of physiological parameters relative to rugby league players [eg, agility]), and/or injury characteristics (eg, injury incidence). RESULTS: Twelve studies met the inclusion criteria. The highest TL was observed in preseason training phases. Higher TL elicited greater improvements in maximal aerobic power, vertical jump (in cm), and agility scores (in s). Higher TL was associated with higher incidence of muscular strains and joint sprains, lower-limb injuries, and overexertion and overuse injuries. CONCLUSIONS: Findings suggest a dose-response relationship between TL, physical performance, and injury characteristics. However, due to study and methodological limitations, the precise nature of this relationship is, as yet, inconclusive. Therefore, the development of uniform TL definition and quantification and further research is warranted. PMID- 29252062 TI - A Carbohydrate Ingestion Intervention in an Elite Athlete Who Follows a Low Carbohydrate High-Fat Diet. AB - This case study documents the performance of an elite-level, exceptionally well fat-adapted endurance athlete as he reintroduced carbohydrate (CHO) ingestion during high-intensity training. He had followed a strict low-CHO high-fat (LCHF) diet for 2 y, during which he ate approximately 80 g of CHO per day and trained and raced while ingesting only water. While following this diet, he earned numerous podium finishes in triathlons of various distances. However, he approached the authors to test whether CHO supplementation during exercise would further increase his high-intensity performance without affecting his fat adaptation. This 7-wk n = 1 investigation included a 4-wk habitual LCHF diet phase during which he drank only water during training and performance trials and a 3-wk habitual diet plus CHO ingestion phase (LCHF + CHO) during which he followed his usual LCHF diet but ingested 60 g/h CHO during 8 high-intensity training sessions and performance trials. After each phase, rates of fat oxidation and 30-s sprint, 4-min sprint, 20-km time trial (TT), and 100-km TT performances were measured. Compared with LCHF, 20-km TT time improved by 2.8% after LCHF + CHO, which would be a large difference in competition. There was no change in 30-s sprint power, a small improvement in 4-min sprint power (1.6%), and a small reduction in 100-km TT time (1.1%). The authors conclude that CHO ingestion during exercise was likely beneficial for this fat-adapted athlete during high-intensity endurance-type exercise (4-30 min) but likely did not benefit his short-sprint or prolonged endurance performance. PMID- 29252063 TI - Characteristics of platelet count and size and diagnostic accuracy of mean platelet volume in patients with venous thromboembolism. A systematic review and meta-analysis. AB - The purpose of this study was to evaluate the association between platelet (PLT) count and mean platelet volume (MPV) and venous thromboembolism (VTE). Thus, this study reviewed and performed a quantitative synthesis on data from the literature. This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 18 studies were included in this paper. A random-effect meta-analysis was conducted for the assessment of heterogeneity using thrombosis place, type of analyzer, type of anticoagulant and incubation time of samples as covariates. A mixed effect meta-regression was performed based on the subgroup for the whole samples using thrombosis place and method of measurement as moderators for MPV and PLT, respectively. The cumulative estimates and 95% confidence interval (95%CI) of specificity, sensitivity, area under the receiver operator characteristic curve (AUC) and diagnostic odds ratio (DOR) for MPV were calculated using a random effect model. The quality assessments were evaluated according to the quality assessment and diagnostic accuracy tool-2 (QUADAS-2). The primary outcome was the occurrence of VTE. Secondary outcomes included PLT and MPV. Patient with deep vein thrombosis is likely to have a higher value of MPV than control group (P < 0.001). The presence of pulmonary embolism (PE) had no significant effect on the standardized mean difference of MPV between patients and controls. Patients are likely to have less PLT than the control group regarding all studies. However, subgroup analysis demonstrated that this effect was significant for patients with PE (P < 0.05). The summary receiver operating characteristic (SROC) curve indicated that AUC was 0.745 (95% CI: 0.672-0.834). The DOR for MPV was 4.76 (95%CI: 2.3-9.85), with diagnostic accuracy of 0.66. PMID- 29252065 TI - Adrian R.L. Gear 1939-2017. PMID- 29252064 TI - Temporomandibular disorders in growing patients after treatment of class II and III malocclusion with orthopaedic appliances: a systematic review. AB - OBJECTIVE: To determine if the use of orthopaedic appliances in growing patients applied to correct Class II and III malocclusion is related to the development of temporomandibular disorders (TMD). MATERIAL AND METHODS: A systematic review was conducted between 1960 and July 2017, based on electronic databases: PubMed, Cochrane Library, Embase, Medline, Scopus, EBSCOhost, Scielo, Lilacs and Bireme. Controlled clinical trials (CCTs) and randomized controlled trials (RCTs) were identified. The articles were selected and analyzed by two authors independently. The quality of the evidence was determined according to the guidelines of the Cochrane Risk Bias Assessment Tool and the Cochrane Quality Study Guide. RESULTS: Seven articles were included, four CCTs and three RCTs. The studies were grouped according to malocclusion treatment in (a) class II appliances (n = 4) and (b) class III appliances (n = 3). The quality of evidence was low due to the high risk of bias, independent of the association reported. All studies concluded that the use of orthopaedic appliances would not contribute to the development of TMD. CONCLUSIONS: The quality of evidence available is insufficient to establish definitive conclusions, since the studies were very heterogeneous and presented a high risk of bias. However, it is suggested that the use of orthopaedic appliances to correct class II and III malocclusion in growing patients would not be considered as a risk factor for the development of TMD. High-quality RCTs are required to draw any definitive conclusions. PMID- 29252066 TI - Night Games and Sleep: Physiological, Neuroendocrine, and Psychometric Mechanisms. AB - CONTEXT: Night games are a regular occurrence for team-sport athletes, yet sleep complaints following night competitions are common. The mechanisms responsible for reported sleep difficulty in athletes are not understood. METHODS: An observational crossover design investigating a night netball game and a time matched rest day in 12 netball athletes was conducted to ascertain differences in physiological (core temperature), psychometric (state and trait), and neuroendocrine (adrenaline, noradrenaline, and cortisol) responses. RESULTS: Following the night game, athletes experienced reduced sleep durations, lower sleep efficiency, early awakenings, and poorer subjective sleep ratings compared with the rest day. No differences were found between core temperature, state psychometric measures, and cortisol at bedtime. Adrenaline and noradrenaline concentrations were elevated compared with the time-matched rest day prior to (26.92 [15.88] vs 12.90 [5.71] and 232.6 [148.1] vs 97.83 [36.43] nmol/L, respectively) and following the night game (18.67 [13.26] vs 11.92 [4.56] and 234.1 [137.2] vs 88.58 [54.08] nmol/L, respectively); however, the concentrations did not correlate to the sleep variables (duration, efficiency, and sleep-onset latency). A correlation (rs = -.611) between sleep efficiency and hyperarousal (trait psychometric measure) was found. CONCLUSIONS: Athletes experienced poor sleep following a night game. Furthermore, results suggest that athletes who have a tendency toward a high trait arousal may be more susceptible to sleep complaints following a night game. These data expand knowledge and refute frequently hypothesized explanations for poor sleep following night competition. The results may also help support staff and coaches target strategies for individual athletes at a higher risk of sleep complaints. PMID- 29252067 TI - Lower Limb Sports Compression Garments Improve Muscle Blood Flow and Exercise Performance During Repeated-Sprint Cycling. AB - PURPOSE: Evidence supporting the use of lower-limb compression garments during repeated-sprint exercise (RSE) with short rest periods, where performance will rely heavily on aerobic metabolism, is lacking. METHODS: A total of 20 recreationally active participants completed 2 cycling RSE sessions, with and without lower-limb compression tights. The RSE session consisted of 4 sets of 10 * 6-s maximal sprints on a wind-braked cycle ergometer, interspaced by 24 s of recovery between bouts and 2 min of recovery between sets. Muscle oxygen consumption ([Formula: see text]) of, and blood flow (mBF) to, the right vastus lateralis muscle was measured during exercise using near-infrared spectroscopy and venous/arterial occlusions of the right lower limb. Cycling performance, oxygen consumption ([Formula: see text]), heart rate, and capillary blood samples (lactate, pH, bicarbonate, and base excess) were also measured/taken throughout the session. RESULTS: Compared with control, peak power (40.7 [19.9] W; mean +/- 95% confidence intervals) and mBF (0.101 [0.061] mL.min-1.100 g-1) were higher, and heart rate (2 [1] beats/min) was lower, when participants wore compression (P < .05). [Formula: see text], [Formula: see text], blood lactate, and heart rate increased as a result of exercise (P < .05), with no differences between conditions. Similarly, blood pH, bicarbonate, and base excess decreased as a result of exercise (P < .05), with no difference between conditions. CONCLUSIONS: Wearing lower-limb compression tights during RSE with short intervals of rest improved cycling performance, vastus lateralis mBF, and heart rate. These results provide novel data to support the notion that lower-limb compression garments aid RSE performance, which may be related to local and/or central blood flow. PMID- 29252068 TI - Relation between dynamic changes of platelet counts and 30-day mortality in severely burned patients. AB - Thrombocytopenia is a common event in severely burned patients and associated with adverse outcome. The underlying relationship between the dynamic changes of platelet counts and mortality has not been well defined. We performed a 6-year retrospective chart of adult patients with a burn index of 50 or greater admitted to two burn centers and collected data on patient demographics, laboratory results, and patient outcomes. The mean daily increase in the platelet count (?PC/?t) from day 3 to day 10 was calculated, and 30-day mortality was determined. For the study, 141 survivors and 65 nonsurvivors were enrolled. The sequential changes in PCs presented a biphasic pattern after admission, with a slump to the nadir during the first 3 days and a subsequent recovery. With respect to 30-day mortality, compared with the AUC of APACHE-II score (0.841), no significant difference was noted between DeltaPC/DeltaT and APACHE-II score (p = 0.0648). The DeltaPC/DeltaT associated with the best discrimination between survivors and nonsurvivors was 20.57 * 109/L due to the cutoff with optimal Youden index (0.453). By multiple logistic regression, DeltaPC/DeltaT < 20.57 * 109/L was one of the prognostic predictors of 30-day mortality. Furthermore, Kaplan-Meier estimates of hospital survival according to the size of DeltaPC/DeltaT revealed that a blunted increase with DeltaPC/DeltaT < 20.57 * 109/L was associated with increased 30-day mortality. A blunted daily increase in PCs, especially DeltaPC/DeltaT < 20.57 * 109/L, is associated with increased 30 day mortality, which provides prognostic information for mortality risk assessment in severely burned patients. PMID- 29252069 TI - Acting One's Age in Physical Exercise: Do Perceived Age Norms Explain Autonomous Motivation Among Older Adults? AB - BACKGROUND: The social identity approach proposes that the more older adults identify with the social group of "older adults," the more they will conform to what they perceive as being normative exercising for their group. However, so far, it remains unclear why older adults adhere to these norms. OBJECTIVE: This study evaluated whether perceived exercise norms are associated with higher levels of autonomous motivation according to the self-determination theory and actual exercise participation. METHODS: A cross-sectional survey, either by regular mail or online, was conducted among 409 older adults in Flanders (Belgium). RESULTS: Our analyses revealed that older adults who perceived more positive older adult norms for exercising were more autonomously motivated to exercise. In explaining 24% of their exercise motivation, older adults' perceptions of the exercise norms for older adults predicted 6% of their exercise participation. CONCLUSION: Our findings suggest that social identity approach and self-determination theory can be meaningfully integrated. PMID- 29252070 TI - Variations in Choroidal and Macular Thickness Maps after Uneventful Phacoemulsification. AB - OBJECTIVE: To investigate changes in retinal and choroidal thickness maps following uncomplicated phacoemulsification using enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: A prospective study was done on 66 eyes. EDI-OCT was performed preoperative, 1 week, 1 month, and 3 months postoperative measuring retinal and choroidal thickness at the fovea and the 9 ETDRS subfields. RESULTS: Subfoveal choroidal thickness (SFCT) showed statistically insignificant increase after 1 week (P = 0.473), but the increase was statistically significant after 1 month (P = 0.014). However, after 3 months, there was non-significant difference from baseline (P = 0.073). Foveal retinal thickness (FT) demonstrated statistically insignificant increase after 1 week (P = 0.094), but statistically significant increase was noted after 1 and 3 months (P = 0.000). CONCLUSION: Uneventful phaco induced statistically significant increases in FT and SFCT from the first postoperative month; however, 3 months postoperative the increase in retinal thickness was maintained but the increase in choroidal thickness became statistically insignificant. PMID- 29252071 TI - The role of CaMK4 in immune responses. AB - Calcium/calmodulin-dependent protein kinase IV (CaMK4) is a multifunctional serine/threonine kinase that regulates gene expression by activating transcription factors in a wide range of immune cells including T cells and antigen-presenting cells. The function of CaMK4 is suggested to be abnormal mainly in systemic lupus erythematosus (SLE), which is characterized by autoantibody production, immune complex formation, and immune dysregulation. Although accumulating evidence indicates that CaMK4 plays important roles in the immune responses, the precise molecular mechanisms underlying the development of autoimmune diseases and inflammatory disorders have not been established. In this review, we briefly summarize the role of CaMK4 in immune responses. We also discuss T-cell signaling pathways that control interleukin (IL)-17 production in patients with lupus nephritis and in glomerulonephritis in lupus-prone mice. A better understanding of the signaling and gene regulation of CaMK4 will lead to the identification of novel therapeutic targets in Th17 driven-autoimmune diseases. PMID- 29252072 TI - Older Adults' Needs and Preferences for Open Space and Physical Activity in and Near Parks: A Systematic Review. AB - Major gaps exist in the literature regarding the link between open space and physical activity promotion for older adults. This study conducted a systematic review on older adults, open space, and physical activity to identify their needs and preferences in and near parks. We identified 48 peer-reviewed journal articles. All articles focused on older adults but not necessarily exclusively. Most studies were descriptive and correlational. Findings suggest that older adults have specific open space and physical activity needs in and near parks that partly overlap with younger people. Framed by the biopsychosocial framework, open space and physical activity in and near parks can benefit older adults' physical health and psychologically well-being to stay socially engaged. Framed within the person-environment and life span perspectives, open space and physical activity in and near parks can facilitate an optimum fit between older adults and their environment as they continue to develop over time. PMID- 29252073 TI - The role of gut in type 2 diabetes mellitus during whole body gamma irradiation in high-fat diet Wistar rats. AB - PURPOSE: The effects of a low rate (100 mGy/min) fractionated whole body gamma irradiation (FWBGI) at different doses were assessed using a real-time PCR technique on the expression of some target genes implicated in the development of type 2 diabetes mellitus in high-fat diet (HFD) Wistar rats. METHOD: HFD Wistar rats were exposed to different doses (12, 24 and 48 Gy) divided into 24 fractions (three times a week for two months), thus, the daily doses were 0.5, 1, 2 Gy, respectively. Total RNA was extracted and the expression of target genes was measured in the four intestinal segments (duodenum, jejunum, ileum and colon). RESULTS: The pre-diabetic state already induced by HFD was found to be improved by irradiation exposure. This irradiation effect occurs mainly via altered anti diabetic gene expressions (mRNA and protein levels) of the incretin glucagon-like peptide-1 (GLP-1) overall bowel segments except the colon which has its own specific response to irradiation exposure by the induction of the insulin receptor substrate 4 (IRS-4) and the uncoupling protein 3 (UCP3). CONCLUSIONS: Results could be of great importance suggesting for the first time, a protective role for FWBGI on HFD animal models by increasing GLP-1 and UCP3 levels. PMID- 29252076 TI - Bidirectional Association Between Psoriasis and Obesity: Benefits and Risks. AB - Psoriasis is a chronic, immune-mediated inflammatory skin disease that is associated with several comorbidities such as obesity. This study was designed to estimate the possibility of utilizing psoriasin, nestin, keratin-16 (Krt16), and interleukin-21 (IL-21) as biochemical markers of psoriasis, to correlate these candidate psoriatic markers with biomarkers of obesity [body mass index (BMI), leptin, and resistin], and to elucidate the bidirectional association between obesity and psoriasis. Blood samples were collected from all participants (n = 108) who were classified according to their BMI into 4 groups: healthy control, obese, psoriatic, and obese psoriatic group. Plasma psoriasin, nestin, Krt16, IL 21, leptin, and resistin were estimated for all subjects. Psoriasin, nestin, Krt16, IL-21, leptin, and resistin were significantly elevated in psoriatic and obese psoriatic groups. However, only leptin, resistin, IL-21, and Krt16 were significantly increased in the obese group compared with the control group. Leptin and resistin showed significant positive correlations with psoriasis area and severity index score, psoriasin, nestin, Krt16, and IL-21. Cutoff values for psoriasin, nestin, Krt16, and IL-21 were 187.5 ng/mL, 1825 pg/mL, 33.1 ng/mL, and 128.6 ng/L, respectively. In conclusion, psoriasin, nestin, Krt16, and IL-21 can be utilized as biochemical markers of psoriasis; these psoriatic markers are significantly positively correlated with obesity biomarkers, and obesity can be considered a risk factor and/or consequence of psoriasis. PMID- 29252074 TI - Murine model of oropharyngeal gastric fluid aspiration-A new assessment method for intrapulmonary liquid distribution using digital pixel calculation. AB - AIM OF THE STUDY: The aim of this study was to investigate a new method for visualization and quantification of intrapulmonary liquid distribution after oropharyngeal gastric fluid aspiration in mice. MATERIAL AND METHODS: Eleven mice received oropharyngeal aspiration with a gastric fluid, India ink, and saline solution. Digital imaging and pixel calculation were used to analyze intrapulmonary fluid distribution selectively. RESULTS: Digital pixel analysis and orophanryngeal aspiration are both safe techniques in mice and deliver reproducible/valid results. Analysis revealed an average aspirate distribution of 86.8% of the total lung area. The proportional amount of the left lung was significantly greater than that of the right lung (P = 0.023). The lobe with the lowest mean distribution was the right lower lobe (79.2% +/- 4.4%). CONCLUSION: Digital pixel calculation is a reliable method for quantitative, macroscopic evaluation of fluid distribution in the lung. This method is a useful tool for training purposes and it can be used to ensure interinvestigator reproducibility. PMID- 29252077 TI - Field-Based Simplified Approach of Evaluating Knee Extensor Muscle Strength and Size in University Freshmen Women. AB - CONTEXT: Periodic assessment of knee extensor muscle strength and size is important for all ages to evaluate the functional status of individuals and to identify and treat those at risk for mobility problems and frailty; however, it is not fully understood whether these field-based simplified approaches correspond to evaluation in knee extensor muscle strength or size. OBJECTIVE: To examine the relationship between field-based simplified evaluation approaches and knee extensor muscle strength or size in young women. DESIGN: Experimental. SETTING: University research laboratory. SUBJECTS: 62 university freshmen women volunteered to participate in this study. MAIN OUTCOME MEASURES: Knee extensor muscle thickness was measured at the anterior half of thigh length; muscle strength was measured when subjects performed knee extension. Field-based simplified approaches [sit-to-stand, standing long jump, handgrip and upper-leg 50% (thigh) girth] were also measured. RESULTS: Maximal strength was correlated with thigh girth, handgrip and standing long jump, but not with the sit-to-stand test. Muscle thickness was correlated with thigh girth and handgrip, but not with standing long jump or the sit-to-stand test. A stepwise multiple-regression analysis was calculated using the predictor thigh girth and standing long jump to predict knee extensor maximal strength (R2 = 0.295). To predict knee extensor muscle thickness, the predictor thigh girth was calculated (R2 = 0.381). CONCLUSIONS: Knee extensor muscle strength and size could be evaluated by the field-based simplified approaches, in particular by the thigh girth measurement, which may be a major determinant to maintain activities of daily living for healthy young women. However, the 4 field-based simplified approaches appear to be still not of high impact. PMID- 29252078 TI - An optimized protocol for the in vitro generation and functional analysis of human PD1/PD-L1 signal. AB - Programmed cell death-1 (PD1) is an inhibitory receptor expressed on the activated T and B cells. Binding of PD1 to its ligands, PD-L1 and PD-L2 has led to deliver an inhibitory signal into the activated T cells. Recently, blocking PD1/PD-L1 pathway has emerged as a new treatment paradigm across a broad spectrum of malignancies. Remarkable clinical responses of monoclonal antibodies specific for PD-1 or its ligands in patients with many different types of cancer, attracted several pharmaceutical companies and researchers to investigate the agents that block PD1/PD-L1 signal. The safety and efficacy of the agents are needed to examine in the preclinical studies. In this study, we optimized a facile and cost-effective protocol for in vitro generation and functional analysis of human PD1/PD-L1 pathway. Activation of CD8 + CD279 + T cell was performed by anti-CD3 and D28 antibodies and the recombinant PD-L1 was used for inactivation of T cells through PD1/PD-L1 pathway. In this protocol, T-cell cytokine production (IL-2 and IFN-gamma) and proliferation assay confirmed that a measurable PD1/PD-L1 signal was generated. We expected that in vitro PD1/PD-L1 signal that has been optimized in this study will serve as a valuable protocol for preclinical studies involving PD1/PD-L1 pathway. PMID- 29252079 TI - eHealth in Wound Care: from conception to implementation. AB - Executive summary Purpose This document aims to provide wound care clinicians with a rapid and structured overview of the key issues related to use of eHealth applications (telemedicine and telehealth) within wound care. This includes: An overview of terminology and available literature Guidance on the methodology for evaluation of eHealth solutions An introduction to and discussion of the potential benefits of eHealth technologies in wound care, and the possible barriers to their implementation Recommendations for ensuring a good implementation process and supporting involvement of wound care professionals in safeguarding that eHealth solutions meet the needs of the patients. Methodology The document sections lean on the structure and focus areas of the Model for ASsessment of Telemedicine (MAST) which defines crucial items to evaluate an eHealth application. The content of the document is developed on the basis of a literature review, identifying available documentation for use of eHealth solutions in wound care. Furthermore, it draws on various key documents recently published on the general development, evaluation and implementation of eHealth solutions. These include valuable up-to-date information relevant for any group of clinicians wishing to follow and influence the way eHealth solutions are integrated into clinical practice. Findings and conclusions The literature review revealed that the amount and level of evidence for use of eHealth applications in wound care is still limited. Some MAST domains are not examined in any of the available studies. Thus, more research is required to identify the potential benefits and harms to patients, and the possible challenges related to implementation of eHealth solutions in wound care. Potential barriers and facilitators for the implementation of eHealth applications into wound care practice are identified in the document, and these may all either enhance or impede the process. However, the available research does demonstrate patient satisfaction, improved access to health services for all client cohorts, and increased job satisfaction for clinicians. The document recommends that wound management clinicians, considering the use of eHealth applications in their clinical practice, consult widely and conduct regular evaluation of the outcomes to ensure efficient implementation of these services. To support this approach, steps to ensure a good implementation process within a given organisation have been proposed. These are synthesised into a three circle model. PMID- 29252080 TI - Sedentary Behavior in Patients With Knee Osteoarthritis Before and After Total Knee Arthroplasty: A Systematic Review. AB - OBJECTIVE: The objective of this systematic review is to integrate the available evidence on changes in sedentary behavior (SB) in patients with knee osteoarthritis after total knee arthroplasty (TKA). METHODS: A systematic literature search from January 2002 to October 31, 2017, was performed for studies assessing objectively and/or subjectively measured SB following TKA. The Scottish Intercollegiate Guidelines Network Methodology appraisal tool was used to critically appraise the methodological quality of the included studies. RESULTS: Ten studies reporting on SB with a total of 1,028 participants were included in the review. Three studies reported changes in SB with two showing a reduction in SB and one (with high risk of bias) an increase in SB after TKA. Seven studies showed no change in SB following TKA. CONCLUSION: Currently, there is insufficient evidence which suggests that SB time improves following TKA. Detailed assessments of SB after TKA are needed. PMID- 29252081 TI - The Mediating Effects of Resilience, Morale, and Sense of Coherence Between Physical Activity and Perceived Physical/Mental Health Among Japanese Community Dwelling Older Adults: A Cross-Sectional Study. AB - The aim of this study was to examine the mediating effects of resilience, morale, and sense of coherence on the relationship between physical activity and respondents' perceived physical/mental health and depression among community dwelling older adults in Japan. The study included 369 participants with an average age of 74 years from Kasuishimohara District in Fukuoka Prefecture, Japan. They completed a survey that included the Resilience Scale, the Sense of Coherence Scale, the Medical Outcomes Short Form 8, the Philadelphia Geriatric Center Morale Scale, the Geriatric Depression Scale (Short Form), and a demographic questionnaire. The results of the path mediation analyses revealed that resilience and morale fully mediated the relationship between physical activity and perceived physical/mental health and depression. However, sense of coherence was not a significant mediator. Some intervention programs are suggested to maximize the effects of physical activity on one's well-being. At risk populations who need such programs are also discussed. PMID- 29252082 TI - There's a New Alphabet in Town: ESSA and Its Implications for Students, Schools, and School Nurses. AB - The 2015 passage of the Every Student Succeeds Act (ESSA) provides state education agencies with more local control over educational planning, requires development of state accountability plans, and provides opportunities for advocacy surrounding school nursing-sensitive indicators of student success. Federal Title I, II, and IV funds are available for state and local education agency utilization in meeting educational needs of impoverished students and for development of high-quality instructional and support personnel. As Specialized Instructional Support Personnel, school nurses can utilize ESSA Title funding to positively impact chronic absenteeism, school climate, and school nurse staffing. ESSA can be a resource for funding school health services and professional education. This article will assist school nurses in better understanding ESSA and how funding is allocated to states and local education agencies. PMID- 29252083 TI - Effect of Trunk Segment Boundary Definitions on Frontal Plane Segment Inertial Calculations. AB - When defining trunk body segment parameters, such as segment length, mass, center of mass location, and radius of gyration, it is necessary to understand and define consistent, anatomically relevant segment boundaries. In addition to the differences in reported trunk parameters due to different data collection and analysis methods (such as cadaver studies and imaging methods), many previous publications have also used differing definitions of the trunk segment. The objective of this study was to determine the effect of differences in trunk segment definitions and obesity on the calculated mass, center of mass, and radius of gyration using dual-energy X-ray absorptiometry anthropometry calculations. Twenty-three participants were recruited in normal weight and morbidly obese body mass index categories. A frontal plane dual-energy X-ray absorptiometry scan was taken of each participant, and 3 trunk segment delineations used by Chambers, de Leva, and Zatsiorsky were used to calculate the trunk parameters. The results showed statistically significant effects of segmentation definition and obesity on the trunk parameters calculated. Because of the potential impacts on static modeling and inverse dynamics calculations, it is important to determine which trunk segmentations are most appropriate for specific applications and to account for the impact of obesity within individuals. PMID- 29252085 TI - North American Society for the Psychology of Sport and Physical Activity. PMID- 29252084 TI - Hyperglycemia during first-line R-CHOP or dose adjusted R-EPOCH chemotherapy for non-Hodgkin lymphoma is prevalent and associated with chemotherapy alteration - a retrospective study. AB - High-dose glucocorticoids such as prednisone are combined with cytotoxic chemotherapy in the R-CHOP or dose adjusted R-EPOCH regimens used for non-Hodgkin lymphoma (NHL). In this retrospective study, our primary objective was to evaluate the incidence of hyperglycemia during first-line R-CHOP or DA-EPOCH-R. The secondary objectives were to evaluate the incidence of chemotherapy alteration and overall survival in those with and without hyperglycemia. One hundred and sixty patients were eligible. We found that 47% of all patients had at least one hyperglycemic episode and hyperglycemia was associated with chemotherapy alteration (p = .028). Multivariate analysis revealed international prognostic index (IPI) >= 3 (p = .045) and chemotherapy alteration (p = .001) were associated with decreased overall survival. We conclude that hyperglycemia is common during first-line NHL treatment with R-CHOP or DA-EPOCH-R, even in the absence of known diabetes and is associated with alterations of chemotherapy. Baseline pre-PET scan fasting blood glucose of 100 mg/dL or higher may predict hyperglycemia during therapy. PMID- 29252086 TI - First and Second Step Characteristics of Amputee and Able-Bodied Sprinters. AB - CONTEXT: In sprint events, the first 2 steps are used to accelerate the center of mass horizontally and vertically. Amputee athletes cannot actively generate energy with their running-specific prosthesis. It is likely that sprint acceleration mechanics, including step asymmetry, are altered compared with able bodied athletes. PURPOSE: To investigate spatiotemporal and kinetic variables of amputee compared with able-bodied sprinters. METHODS: Kinematic and kinetic data of the first and second stance were collected from 15 able-bodied and 7 amputee sprinters (2 unilateral transfemoral, 4 unilateral transtibial, and 1 bilateral transtibial) with a motion-capture system (250 Hz) and 2 force plates (1000 Hz). In addition, bilateral asymmetry was quantified and compared between groups. RESULTS: Compared with able-bodied athletes, amputee athletes demonstrated significantly lower performance values for 5- and 10-m times. Step length, step velocity, and step frequency were decreased and contact times increased. Peak horizontal force and relative change of horizontal velocity were decreased in both stances. Peak vertical force and relative change of vertical velocity were lower for the amputee than the able-bodied group during the first stance but significantly higher during the second stance. During the first stance, able bodied and amputee sprinters displayed a similar orientation of the ground reaction-force vector, which became more vertically orientated in the amputee group during second stance. Amputee sprinters showed significantly greater asymmetry magnitudes for vertical force kinetics compared with able-bodietd athletes. CONCLUSION: A running-specific prosthesis does not replicate the function of the biological limb well in the early acceleration phase. PMID- 29252088 TI - Partially linear mixed-effects joint models for skewed and missing longitudinal competing risks outcomes. AB - Longitudinal competing risks data frequently arise in clinical studies. Skewness and missingness are commonly observed for these data in practice. However, most joint models do not account for these data features. In this article, we propose partially linear mixed-effects joint models to analyze skew longitudinal competing risks data with missingness. In particular, to account for skewness, we replace the commonly assumed symmetric distributions by asymmetric distribution for model errors. To deal with missingness, we employ an informative missing data model. The joint models that couple the partially linear mixed-effects model for the longitudinal process, the cause-specific proportional hazard model for competing risks process and missing data process are developed. To estimate the parameters in the joint models, we propose a fully Bayesian approach based on the joint likelihood. To illustrate the proposed model and method, we implement them to an AIDS clinical study. Some interesting findings are reported. We also conduct simulation studies to validate the proposed method. PMID- 29252087 TI - Temozolomide renders murine cancer cells susceptible to oncolytic adenovirus replication and oncolysis. AB - The preclinical evaluation of oncolytic adenoviruses (OAds) has been limited to cancer xenograft mouse models because OAds replicate poorly in murine cancer cells. The alkylating agent temozolomide (TMZ) has been shown to enhance oncolytic virotherapy in human cancer cells; therefore, we investigated whether TMZ could increase OAd replication and oncolysis in murine cancer cells. To test our hypothesis, three murine cancer cells were infected with OAd (E1b-deleted) alone or in combination with TMZ. TMZ increased OAd-mediated oncolysis in all three murine cancer cells tested. This increased oncolysis was, at least in part, due to productive virus replication, apoptosis, and autophagy induction. Most importantly, murine lung non-cancerous cells were not affected by OAd+TMZ. Moreover, TMZ increased Ad transduction efficiency. However, TMZ did not increase coxsackievirus and adenovirus receptor; therefore, other mechanism could be implicated on the transduction efficiency. These results showed, for the first time, that TMZ could render murine tumor cells more susceptible to oncolytic virotherapy. The proposed combination of OAds with TMZ presents an attractive approach towards the evaluation of OAd potency and safety in syngeneic mouse models using these murine cancer cell-lines in vivo. PMID- 29252089 TI - Effects of Hip Abduction Fatigue on Trunk and Shoulder Kinematics During Throwing and Passive Hip Rotational Range of Motion. AB - CONTEXT: Hip abductor musculature contributes to the stability of the pelvis, which is needed for efficient energy transfer from the lower extremity to the upper extremity during overhead throwing. OBJECTIVE: The purpose of this study was to examine the effects of a hip abduction fatigue protocol on overhead throwing kinematics and hip passive range of motion. DESIGN: Prospective cohort study. SETTING: Laboratory setting. PARTICIPANTS: A convenience sample of nineteen collegiate female softball players (20.6 +/- 1.9 years; 169.3 +/- 9.7 cm; 73.2 +/- 11.2 kg). MAIN OUTCOME MEASURES: Repeated hip abduction on an isokinetic dynamometer to fatigue was performed on three consecutive days. Trunk and shoulder kinematics and hip internal and external range of motion were analyzed prior to fatigue on day one and after the fatigue protocol on day three. RESULTS: Repeated measures analysis of variance revealed no statistically significant differences in trunk and shoulder kinematics pre- and post-fatigue. A statistically significant time by side by direction interaction (F2,36=5.462, p=0.018, n2p=0.233) was observed in hip passive range of motion. Post hoc simple effects tests determined a decrease in throwing side hip internal rotation pre- to post-fatigue (mean difference = -2.284; 95%CI = -4.302, -0.266; p=0.029). CONCLUSION: The hip abductor fatigue protocol utilized in this study did not significantly alter trunk and upper extremity throwing kinematics. The lack of changes may indicate that fatigue of the hip abductors does not contribute to trunk and shoulder kinematics during throwing or the protocol may not have been sport-specific enough to alter kinematics. PMID- 29252090 TI - Validity and Reliability of a Digital Inclinometer to Assess Knee Joint Position Sense in an Open Kinetic Chain. AB - CONTEXT: New methods are being validated to easily evaluate the knee joint position sense (JPS) due to its role in sports movement and the risk of injury. However, no studies to date have considered the open kinetic chain (OKC) technique, despite the biomechanical differences compared to closed kinetic chain movements. OBJECTIVE: To analyze the validity and reliability of a digital inclinometer to measure the knee JPS in the OKC movement. DESIGN: The validity, inter-tester and intra-tester reliability of a digital inclinometer for measuring knee JPS were evaluated. SETTING: Sports research laboratory. PARTICIPANTS: Eighteen athletes (11 males and 7 females; 28.4 +/- 6.6 years; 71.9 +/- 14.0 kg; 1.77 +/- 0.09 m; 22.8 +/- 3.2 kg/m2) voluntary participated in this study. MAIN OUTCOMES MEASURES: Absolute angular error (AAE), relative angular error (RAE) and variable angular error (VAE) of knee JPS in an OKC. RESULTS: Intraclass correlation coefficient (ICC) and standard error of the mean (SEM) were calculated to determine the validity and reliability of the inclinometer. Data showed excellent validity of the inclinometer to obtain proprioceptive errors compared to the video analysis in JPS tasks (AAE: ICC = 0.981, SEM = 0.08; RAE: ICC = 0.974, SEM = 0.12; VAE: ICC = 0.973, SEM = 0.07). Inter-tester reliability was also excellent for all the proprioceptive errors (AAE: ICC = 0.967, SEM = 0.04; RAE: ICC = 0.974, SEM = 0.03; VAE: ICC = 0.939, SEM = 0.08). Similar results were obtained for intra-tester reliability (AAE: ICC = 0.861, SEM = 0.1; RAE: ICC = 0.894, SEM = 0.1; VAE: ICC = 0.700, SEM = 0.2). CONCLUSIONS: The digital inclinometer is a valid and reliable method to assess the knee JPS in OKC. Sport professionals may evaluate the knee JPS to monitor its deterioration during training or improvements throughout the rehabilitation process. PMID- 29252091 TI - Half-Fluence Photodynamic Therapy for Chronic Central Serous Chorioretinopathy: Predisposing Factors for Visual Acuity Outcomes. AB - BACKGROUND: Central serous chorioretinopathy (CSC) is characterised by a serous detachment of the neurosensory retina in the macula. Chronic CSC tends to affect older individuals with a less favourable visual outcome. Photodynamic therapy (PDT) with verteporfin is a possible therapeutic approach in cases of CSC with no tendency for spontaneous resorption. PDT has shown good anatomic and functional results in treating chronic CSC. For the purpose of diminishing side effects, modifications of the standard protocol were used. MATERIALS AND METHODS: This is a retrospective study of 32 eyes with CSC of 32 patients treated by half-fluence PDT. The patients underwent complete ophthalmology examination. On optical coherence tomography (OCT) we measured central retinal thickness (CRT), the outer nuclear layer (ONL), presence of subfoveolar detachment of retinal pigment epithelium (PED), disturbance of external limiting membrane (ELM), morphological changes in the inner segment/outer segment (IS/OS) line and retinal pigment epithelium (RPE) atrophy. We evaluated at baseline, 3 and 12 months after PDT. RESULTS: The mean BCVA at baseline was 0.41 +/- 0.23 log MAR, the mean BCVA at 3 months was 0.24 +/- 0.20 and at the end of the follow-up it was 0.23 +/- 0.200. We observed statistically significant improvements of visual acuity after 3 and 12 months (p < 0.001, Wilcoxon test). The mean central retinal thickness at baseline was 373 +/- 87 um, the mean CRT after 3 months was 234 +/- 42 um and after 12 months 223 +/- 39 um. A significant reduction from baseline was seen after 3 months and 12 months (p < 0.001, Wilcoxon test). Baseline ONL reached 80 +/- 27 um, after 3 months it was 78 +/- 20 and after 12 months it was 74 +/- 20 um. We observed a statistically significant change in diminishing the amount of PED after PDT after 3 months and after 12 months (p = 0.021, McNemar's test). We observed that in patients with RPE ablation, there is lower chance for the restitution of the IS/OS layer (p = 0.045, Mann-Whitney test). We observed a negative association between the improvement of visual acuity after 12 months and the presence of RPE ablation (p = 0.031, Mann-Whitney test). Restitution of ELM was significantly more often in patients with shorter duration of symptoms, (p = 0.027 after 3 months, p = 0.033 after 12 months after PDT, Spearman correlation). Neither ocular nor systemic adverse effects were observed during the follow-up period. CONCLUSIONS: Half-fluence PDT treatment has shown to be a usually safe and often effective therapy in patients with chronic CSC. This study suggests that the most important predictive factor is baseline visual acuity. The important anatomical change detected using OCT is a thinning of the outer nuclear layer. Nonetheless, other studies with a larger number of patients and a longer follow-up are required. PMID- 29252092 TI - Validity and Reliability of a Virtual Reality Game in Evaluating the Projected Frontal Plane Knee Angle When Landing From a Drop Vertical Jump. AB - OBJECTIVES: To determine the validity and reliability of the peak frontal plane knee angle evaluated by a virtual reality (VR) netball game when landing from a drop vertical jump. STUDY DESIGN: Laboratory. METHODS: Forty participants performed 3 drop vertical jumps evaluated by 3-dimensional motion analysis and 3 drop vertical jumps evaluated by the VR game. Limits of agreement for the peak projected frontal plane knee angle and peak knee abduction were determined. Participants were given a consensus category of "above threshold" or "below threshold" based on a prespecified threshold angle of 9 degrees during landing. Classification agreement was determined using kappa coefficient, and accuracy was determined using specificity and sensitivity. Ten participants returned 1 week later to determine intrarater reliability, standard error of the measure, and typical error. RESULTS: The mean difference in detected frontal plane knee angle was 3.39 degrees (95% confidence interval [CI], 1.03 degrees to 5.74 degrees ). Limits of agreement were -10.27 degrees (95% CI, -14.36 degrees to -6.19 degrees ) to 17.05 degrees (95% CI, 12.97 degrees to 21.14 degrees ). Substantial agreement, specificity, and sensitivity were observed for the threshold classification (kappa = .66; 95% CI, .42 to .88; specificity = 0.96; 95% CI, 0.78 to 1.0; and sensitivity = 0.75; 95% CI, 0.43 to 0.95). The game exhibited acceptable reliability over time (intraclass correlation coefficient, ICC3,1 = .844), and error was approximately 2 degrees . CONCLUSION: The VR game reliably evaluated a projected frontal plane knee angle. Although the knee angle detected by the VR game is strongly related to peak knee abduction, the accuracy of detecting the exact angle was limited. A threshold approach may be a more accurate approach for gaming technology to evaluate frontal plane knee angles when landing from a jump. PMID- 29252093 TI - Risk factors for abnormal hepatic enzyme elevation by methotrexate treatment in patients with rheumatoid arthritis: A hospital based-cohort study. AB - OBJECTIVES: Methotrexate (MTX) is used as first-line treatment of rheumatoid arthritis (RA) worldwide. Large interindividual differences in MTX effectiveness and safety occur, and the most frequent adverse reaction is hepatotoxicity, although the main cause remains unknown. We investigated factors associated with MTX-induced hepatic enzyme elevation in a hospital-based cohort study. METHODS: Study participants were 114 Japanese adult RA outpatients prescribed MTX. Sixteen types of single-nucleotide polymorphisms were investigated using real-time PCR. Patient characteristics were collected from the electronic medical records. The onset of MTX-induced abnormal hepatic enzyme elevation was defined according to deviation from normal liver enzyme reference values during treatment. The observation period was 1 year after beginning MTX. Associations between MTX induced hepatic enzyme elevation and patient characteristics were evaluated using the multivariate logistic regression model. RESULTS: Thirty-two patients experienced MTX-induced abnormal hepatic enzyme elevation. In multivariate analysis, MTX dosage, estimated glomerular filtration rate (eGFR), and genetic polymorphisms of ABCB1 3435C>T and ATIC 347C>G were associated with abnormal hepatic enzyme elevation. CONCLUSIONS: MTX-induced abnormal hepatic enzyme elevation in Japanese RA patients was associated with dosage and eGFR as nongenetic factors, and with ABCB1 3435C>T and ATIC 347C>G as genetic factors in this hospital-based cohort study. PMID- 29252094 TI - Evaluation of potentially achievable vaccination coverage of the second dose of measles containing vaccine with simultaneous administration and risk factors for missed opportunities among children in Zhejiang province, east China. AB - OBJECTIVES: This study aimed to evaluate the potential achievable coverage of the second dose of measles containing vaccine (MCV2) when the protocol of simultaneous administration of childhood vaccines was fully implemented. Risk factors for missed opportunity (MO) for simultaneous administration of MCV2 were also investigated. METHODS: Children born from 1 January 2005 to 31 December 2014 and registered in Zhejiang provincial immunization information system were enrolled in this study. The MO of simultaneous administration of MCV2, the actual age-appropriate coverage (AAC) of MCV2 and the potentially achievable coverage (PAC) of MCV2 were evaluated and compared across different birth cohorts, by different socio-demographic variables. For the 2014 birth cohort, logistic regression model was used to detect the risk factors of MOs, from both socio demographic and vaccination service providing aspects. RESULTS: Compared to the AAC, the PAC of MCV2 increased significantly from 2005 birth cohort to 2014 birth cohort (p<0.001), with a median of 12.7 percentage points. Higher birth order of children, resident children, higher maternal education background, higher socio economic development level of resident areas, less frequent vaccination service, and shorter vaccination service time were significant risk factors of MO for simultaneous administration of MCV2, with all p-value < 0.05. CONCLUSION: The findings in this study suggest that fully utilization of all opportunities for simultaneous administration of all age-eligible vaccine doses at the same vaccination visit is critical for achieving the coverage target of 95% for MCV2. Future interventions focusing on the group with risk factors observed could substantially eliminate MOs for simultaneous administration of MCV2, further to improve the coverage of fully immunization of MCV, and finally achieve the goal of eliminating measles. PMID- 29252095 TI - Brassinosteroids regulate vacuolar morphology in root meristem cells of Arabidopsis thaliana. AB - Brassinosteroids (BRs) are plant hormones that regulate plant development and environmental response. Brz-insensitive-long hypocotyl4 (BIL4) was identified as a positive regulator of BR signaling that interacts with the BR receptor, BRASSINOSTEROID INSENSITIVE 1 (BRI1), and inhibits vacuolar degradation of BRI1 in Arabidopsis thaliana. Although BIL4 also localizes to the vacuolar membrane, the possible vacuolar function of BIL4 remains unknown. Here, we studied the effect of BIL4 and BR signaling on vacuole shape in root meristem cells using genetic and pharmacological approaches. In BIL4-deficient plants, vacuoles assumed a smaller luminal structure. Treatment with brassinolide (BL), the most active BR, resulted in visibly larger vacuoles, whereas treatment with the BR biosynthesis inhibitor Brz resulted in substantially smaller luminal vacuolar structures. In the bri1 mutant, vacuolar shapes exhibited small and fragmented structures. Our results suggest that BR signaling impacts vacuolar shape. PMID- 29252096 TI - Hamstring Stiffness Returns More Rapidly After Static Stretching Than Range of Motion, Stretch Tolerance, and Isometric Peak Torque. AB - CONTEXT: Hamstring injuries are common, and lack of hamstring flexibility may predispose to injury. Static stretching increases range of motion (ROM) but also results in reduced muscle strength after stretching. The effects of stretching on the hamstring muscles and the duration of these effects remain unclear. OBJECTIVE: To determine the effects of static stretching on the hamstrings and the duration of these effects. DESIGN: Randomized crossover study. SETTING: University laboratory. PARTICIPANTS: Twenty-four healthy volunteers. INTERVENTIONS: We measured the torque-angle relationship (ROM, passive torque (PT) at the onset of pain, and passive stiffness) and isometric muscle force using an isokinetic dynamometer. After a 60-minute rest, the ROM of the dynamometer was set at maximum tolerable intensity; this position was maintained for 300 seconds while static passive torque (SPT) was measured continuously. We remeasured the torque-angle relationship and isometric muscle force after rest periods of 10, 20, and 30 minutes. MAIN OUTCOME MEASURES: Change in SPT during stretching; changes in ROM, PT at the onset of pain, passive stiffness, and isometric muscle force before stretching compared with 10, 20, and 30 minutes after stretching. RESULTS: SPT decreased significantly during stretching. Passive stiffness decreased significantly 10 and 20 minutes after stretching, but there was no significant pre- vs. post-stretching difference after 30 minutes. PT at the onset of pain and ROM increased significantly after stretching at all rest intervals, while isometric muscle force decreased significantly after all rest intervals. CONCLUSIONS: The effect of static stretching on passive stiffness of the hamstrings was not maintained as long as the changes in ROM, stretch tolerance, and isometric muscle force. Therefore, frequent stretching is necessary to improve the viscoelasticity of the muscle-tendon unit. Muscle force was decreased for 30 minutes after stretching; this should be considered prior to activities requiring maximal muscle strength. PMID- 29252097 TI - Eight-season epidemiological study of injuries in men's international Under-20 rugby tournaments. AB - The aim of this study was to define the incidence and nature of match injuries sustained in men's international under-20 rugby. The study comprised an 8-season prospective study of 16 international under-20 rugby tournaments. Procedures complied with the consensus statement for epidemiological studies in rugby. Outputs included players' mean age, stature and body mass and incidence, severity, location, type and cause of match injuries. The overall incidence of injury was 49.7 injuries/1000 player-match-hours (backs: 48.3; forwards: 50.9) with a mean severity of 32.2 days-absence (backs: 29.4; forwards: 34.4). There were no significant changes in incidence or severity of injury over the study period. Shoulder/clavicle (18.3%), head/face (16.4%), knee (13.7%) and ankle (13.7%) were the most common injury locations and ligament sprain (35.4%), haematoma/bruise (15.9%), concussion (12.5%) and muscle strain (11.2%) the most common types of injury. Being-tackled (29.2%), tackling (24.0%) and collisions (14.3%) were the most common events leading to injury. The results confirm that international under-20 rugby has a high incidence and severity of injury but the incidence is half that reported for senior international players. There was no significant change in the overall incidence of injury at the Under-20 level in the period 2008 to 2016. PMID- 29252099 TI - A Soft Parallel Kinematic Mechanism. AB - In this article, we describe a novel holonomic soft robotic structure based on a parallel kinematic mechanism. The design is based on the Stewart platform, which uses six sensors and actuators to achieve full six-degree-of-freedom motion. Our design is much less complex than a traditional platform, since it replaces the 12 spherical and universal joints found in a traditional Stewart platform with a single highly deformable elastomer body and flexible actuators. This reduces the total number of parts in the system and simplifies the assembly process. Actuation is achieved through coiled-shape memory alloy actuators. State observation and feedback is accomplished through the use of capacitive elastomer strain gauges. The main structural element is an elastomer joint that provides antagonistic force. We report the response of the actuators and sensors individually, then report the response of the complete assembly. We show that the completed robotic system is able to achieve full position control, and we discuss the limitations associated with using responsive material actuators. We believe that control demonstrated on a single body in this work could be extended to chains of such bodies to create complex soft robots. PMID- 29252100 TI - Intra- and Inter-Rater Reliability of Bioimpedance in the Evaluation of Lymphedema Secondary to Treatment of Breast Cancer. AB - The objective of the study was to evaluate the intra- and inter-rater reliability of bioimpedance in determining upper limb volume in women with lymphedema resulting from breast cancer treatment, as well as its correlation with the upper limb volume calculated by circumferential measurement. A blind cross-sectional study was performed in which 27 women (62.59 +/- 10.50 years) were evaluated with upper limb lymphedema secondary to breast cancer treatment. Two examiners performed assessments in the same volunteers independently and twice, with an interval of 1 week between assessments. The collections were performed by the direct tetrapolar multifrequency segmental bioimpedance and by the circumference of the upper limb homolateral to the breast cancer. The results of the circumference showed that the homolateral limb had lymphedema. The intra- and inter-rater analysis showed excellent reliability with intraclass correlation coefficient (ICC) values ranging from 0.954 to 0.999 for the amount of liquid and excellent reliability with ICC values ranging from 0.852 to 0.999 for the electrical impedance of the upper limb with lymphedema. The correlation was strong and negative (p < 0.05) between intracellular, extracellular, and total water when associated with electrical impedance and moderate and positive (p < 0.05) when associated with upper limb volume for all frequencies. The correlations between upper limb volume and water quantities were moderate and positive (p < 0.05). The results indicate that bioimpedance is a reliable method for the evaluation of lymphedema, and the volume of the homolateral upper limb is associated with the amount of water in women with lymphedema secondary to the treatment of breast cancer. PMID- 29252098 TI - The establishment of surrogates and correlates of protection: Useful tools for the licensure of effective influenza vaccines? AB - The search for a test that can predict vaccine efficacy is an important part of any vaccine development program. Although regulators hesitate to acknowledge any test as a true 'correlate of protection', there are many precedents for defining 'surrogate' assays. Surrogates can be powerful tools for vaccine optimization, licensure, comparisons between products and development of improved products. When such tests achieve 'reference' status however, they can inadvertently become barriers to new technologies that do not work the same way as existing vaccines. This is particularly true when these tests are based upon circularly-defined 'reference' or, even worse, proprietary reagents. The situation with inactivated influenza vaccines is a good example of this phenomenon. The most frequently used tests to define vaccine-induced immunity are all serologic assays: hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization (MN). The first two, and particularly the HI assay, have achieved reference status and criteria have been established in many jurisdictions for their use in licensing new vaccines and to compare the performance of different vaccines. However, all of these assays are based on biological reagents that are notoriously difficult to standardize and can vary substantially by geography, by chance (i.e. developing reagents in eggs that may not antigenitically match wild-type viruses) and by intention (ie: choosing reagents that yield the most favorable results). This review describes attempts to standardize these assays to improve their performance as surrogates, the dangers of over-reliance on 'reference' serologic assays, the ways that manufacturers can exploit the existing regulatory framework to make their products 'look good' and the implications of this long-established system for the introduction of novel influenza vaccines. PMID- 29252101 TI - Correlation of trastuzumab-based treatment with clinical characteristics and prognosis in HER2-positive gastric and gastroesophageal junction cancer: A retrospective single center analysis. AB - Attempts for identifying targeted therapy strategies in metastatic gastric and gastroesopheal junction cancer (upper-GI) revealed that the inhibition of human epidermal growth factor receptor-2 (HER2) by monoclonal antibody trastuzumab improves survival of these patients. Hence, adding trastuzumab to doublet chemotherapy has become the standard treatment in this setting. Although the patient survival is extended among clinical trials, the knowledge on the real time setting is limited. With this retrospective, single center analysis of the patient data of the Medical University of Vienna, we sought to investigate the clinical characteristics and outcome of patients, who received trastuzumab-based chemotherapy for metastatic upper-GI tumor. All patients, who received trastzumab at least once were included to the analysis. Clinical and pathological data were recorded. This search revealed 33 patients. The demographic data was comparable with that of the previous clinical trials. Progression free survival (PFS) was 11 months, whereas overall survival (OS) was 21 months. OS was significantly associated with initially favorable response to treatment. Thirteen patients (39%) received trastuzumab as maintenance treatment with a median cycle number of 6. Toxicity profile was acceptable with only one patient detected to have cardiotoxicity. Taken together, trastuzumab based treatment induced a considerable PFS and OS in metastatic or advanced upper-GI tumors with acceptable toxicity profile. The maintenance therapy with trastuzumab was safe and effective in patients who had initially a favorable response to chemotherapy. The optimal duration of the maintenance therapy should be tested in future clinical trials. PMID- 29252103 TI - Physical Activity With and Without Arm Sleeves: Compliance and Quality of Life After Breast Cancer Surgery-A Randomized Controlled Trial. AB - BACKGROUND: After breast cancer surgery patients are at higher risk of lymphedema development and decreasing physical activity (PA), as well as decreasing health related quality of life (HRQOL). The aim of the study was to compare the level of PA and HRQOL in women after breast cancer surgery using light arm compression with women not using compression 1 year after oncological treatment. METHODS AND RESULTS: Forty-five women were preoperatively randomly assigned to a compression group (CG, n = 23) or to no compression group (NCG, n = 22). Arm volumes were measured before surgery and 12 months thereafter. The CG received circular-knit sleeves in compression class 1 for daily wearing in the postoperative period up to 1 year. Both groups underwent a standardized physical exercise program. PA with the short version of International Physical Activity Questionnaire (IPAQ), compliance, and HRQOL by EORTC QLQ-C30 and QLQ-BR23 questionnaires was assessed in both groups 1 year after surgery. After 1 year observation the CG showed significantly lower mean affected arm volume compared to NCG. The total PA (calculated as the sum of vigorous moderate exercises and walking) was markedly higher within the CG, with no difference in particular IPAQ items. There were no correlations between reported PA items and observed arm/edema volume or body mass index changes. The QLQ-BR23 revealed only better sexual functioning (p = 0.014) and greater upset by hair loss in NCG (p = 0.01). CONCLUSIONS: The available data indicate that wearing compression sleeves neither interfere with the level of PA nor decrease quality of life 1 year after breast cancer surgery. PMID- 29252104 TI - Hydrogen peroxide-assisted photocatalytic degradation of textile wastewater using titanium dioxide and zinc oxide. AB - The present work investigated the degradation of a dyeing factory effluent by advanced oxidative process under UV irradiation. TiO2 and ZnO were used as catalysts and the influence of different concentrations of H2O2 added to the system was studied. The catalysts were characterized in terms of crystal structure (X-ray diffraction), textural properties (Brunauer-Emmett-Teller area and pore volume) and point of zero charge, which indicated the semiconductors had a positively charged surface in an acidic medium. After 8 h of irradiation at pH 3.0 and catalyst concentration of 0.0625 g L-1, the effect of H2O2 was evaluated by means of kinetic efficiency (rate constants), absorbance reduction (at 284, 621 e 669 nm), total organic carbon reduction and mineralization (in terms of the formation of ions such as [Formula: see text] and [Formula: see text]). Adding H2O2 to the photocatalytic system significantly increased pollutants' removal, highlighting tests with 1.0 * 10-2 mol L-1, showing higher absorbance reduction and rate constants at 621 and 669 nm for TiO2 and best mineralization rates for ZnO. Ecotoxicity bioassays using Artemia salina L confirmed the treatment efficacy, with effluent lethal concentration (LC50) increasing from 65.68% (in natura) to over 100% after photocatalysis treatment. PMID- 29252102 TI - The Vibrio alginolyticus T3SS effectors, Val1686 and Val1680, induce cell rounding, apoptosis and lysis of fish epithelial cells. AB - Vibrio alginolyticus is a Gram-negative bacterium that is an opportunistic pathogen of both marine animals and people. Its pathogenesis likely involves type III secretion system (T3SS) mediated induction of rapid apoptosis, cell rounding and osmotic lysis of infected eukaryotic cells. Herein, we report that effector proteins, Val1686 and Val1680 from V. alginolyticus, were responsible for T3SS mediated death of fish cells. Val1686 is a Fic-domain containing protein that not only contributed to cell rounding by inhibiting Rho guanosine triphosphatases (GTPases), but was requisite for the induction of apoptosis because the deletion mutant (Deltaval1686) was severely weakened in its ability to induce cell rounding and apoptosis in fish cells. In addition, Val1686 alone was sufficient to induce cell rounding and apoptosis as evidenced by the transfection of Val1686 into fish cells. Importantly, the Fic-domain essential for cell rounding activity was equally important to activation of apoptosis of fish cells, indicating that apoptosis is a downstream event of Val1686-dependent GTPase inhibition. V. alginolyticus infection likely activates JNK and ERK pathways with sequential activation of caspases (caspase-8/-10, -9 and -3) and subsequent apoptosis. Val1680 contributed to T3SS-dependent lysis of fish cells in V. alginolyticus, but did not induce autophagy as has been reported for its homologue (VopQ) in V. parahaemolyticus. Together, Val1686 and Val1680 work together to induce apoptosis, cell rounding and cell lysis of V. alginolyticus-infected fish cells. These findings provide new insights into the mechanism of cell death caused by T3SS of V. alginolyticus. PMID- 29252105 TI - Who Uses eConsult? Investigating Physician Characteristics Associated with Usage (and Nonusage). AB - BACKGROUND: The Champlain BASETM eConsult Service was developed in a Local Health Integration Network (LHIN) in Ontario, Canada in 2010 to reduce wait times and improve access to specialist care. The service allows primary care providers to receive advice from specialists via a secure electronic platform without necessarily requiring a face-to-face consultation. INTRODUCTION: As of 2015, over half of the LHIN's family physicians were registered and trained to use the service. However, 24% of registrants never went on to submit a case. The purpose of this study is to examine the demographic characteristics associated with usage. MATERIALS AND METHODS: Usage data for the pool of physicians registered between January 1, 2011 and September 30, 2015 were linked to physician characteristics retrieved from the College of Physicians and Surgeons of Ontario database. Probit regressions were estimated to determine characteristics associated with usage. RESULTS: Neither sex, being an international medical school graduate-documented predictors of electronic medical records adoption-nor proximity to specialists were found to explain usage. Only length of time in practice was found to be predictive. Being out of medical school an additional 10 years was estimated to decrease the probability of ever using eConsult by five percentage points (p < 0.01). CONCLUSION: Lower use by veteran physicians may reflect their lower need for services like eConsult given their well-established specialist networks, or their greater confidence in practicing medicine. Future work should explore the reasons and barriers for not registering, or not using eConsult, with an aim toward increasing the appropriate use of this cost effective and innovative service. PMID- 29252106 TI - The Effect of Small-Sided Game Formats on Physical and Technical Performance in Wheelchair Basketball. AB - PURPOSE: To examine the effects of different small-sided games (SSGs) on physical and technical aspects of performance in wheelchair basketball (WB) players. DESIGN: Observational cohort study. METHODS: Fifteen highly trained WB players participated in a single 5v5 (24-s shot clock) match and three 3v3 SSGs (18-s shot clock) on a (1) full court, (2) half-court, and (3) modified-length court. During all formats, players' activity profiles were monitored using an indoor tracking system and inertial measurement units. Physiological responses were monitored via heart rate and rating of perceived exertion. Technical performance, that is, ball handling, was monitored using video analysis. Repeated-measures analysis of variance and effect sizes (ESs) were calculated to determine the statistical significance and magnitude of any differences between game formats. RESULTS: Players covered less distance and reached lower peak speeds during half court (P <= .0005; ES >= very large) compared with all other formats. Greater distances were covered, and more time was spent performing moderate- and high speed activity (P <= .008; ES >= moderate) during full court compared with all other formats. Game format had little bearing on physiological responses, and the only differences in technical performance observed were in relation to 5v5. Players spent more time in possession, took more shots, and performed more rebounds in all 3v3 formats compared with 5v5 (P <= .028; ES >= moderate). CONCLUSIONS: Court dimensions affect the activity profiles of WB players during 3v3 SSGs yet had little bearing on technical performance when time pressures (shot clocks) were constant. These findings have important implications for coaches to understand which SSG format may be most suitable for physically and technically preparing WB players. PMID- 29252107 TI - Estimation of Arm Adipose Tissue Quotient Using Segmental Bioimpedance Spectroscopy. AB - BACKGROUND: Breast cancer-related lymphedema (BCRL) is a chronic condition characterized by accumulation of lymph fluid that may subsequently become fibrotic with infiltration of adipose tissue. Bioimpedance spectroscopy (BIS) is the preferred method for early detection of lymphedema as it can estimate extracellular lymph fluid. This study developed a modified impedance technique that concurrently estimates both lymph accumulation and increases in adipose tissue. METHODS AND RESULTS: BIS was used to estimate the adipose tissue volume in a cohort of healthy women (n = 171), which was found to be highly correlated (r > 0.87) with measurements of adipose tissue obtained using the reference method of dual-energy X-ray absorptiometry (DXA). In a separate cohort of women with BCRL (n = 16), adipose volumes measured by BIS and reference method, respectively, were 2452.9 +/- 933.3 mL and 2109.1 +/- 824 6 mL for affected arms; 1770.9 +/- 747.8 mL and 1801.4 +/- 775.7 mL for unaffected arms; and comparable values for a group of age-matched controls were 1862.5 +/- 661.6 mL and 1657.0 +/ 641.1 mL for age-matched control arms. The increase in adipose tissue in affected arms was significant irrespective of the method of measurement, p < 0.02 and p < 0.001 for BIS and DXA, respectively. CONCLUSIONS: An impedance method is described that can estimate increase both in lymph accumulation and adipose tissue in breast cancer-related lymphedema. PMID- 29252109 TI - Premarital sex, contraceptive use among unmarried women migrant workers in industrial parks in Vietnam, 2015. AB - Most of internal female migrants are young, at risk of unintended pregnancy, unsafe abortion. This paper aims to describe premarital sexual behaviors and contraceptive use among unmarried female migrant workers in industrial parks, Vietnam. A cross-sectional survey was completed with a sample of 2,996 workers aged 18-49 years. We found that premarital sex rate was 12.6%. Most of them were inconsistent contraceptive users. About 27.8% did not use any contraception in the last 6/months. Condom was the most popular contraceptive used (61.3%) and obtained through pharmacies, kiosk systems. Contraceptive use was significantly associated with age, education, private companies, and income. PMID- 29252108 TI - Imported African schistosomiasis and the potential risk of transmission in China. PMID- 29252110 TI - Internet Use and Technology-Related Attitudes of Veterans and Informal Caregivers of Veterans. AB - BACKGROUND: Healthcare systems are interested in technology-enhanced interventions to improve patient access and outcomes. However, there is uncertainty about feasibility and acceptability for groups who may benefit but are at risk for disparities in technology use. Thus, we sought to describe characteristics of Internet use and technology-related attitudes for two such groups: (1) Veterans with multi-morbidity and high acute care utilization and (2) informal caregivers of Veterans with substantial care needs at home. MATERIALS AND METHODS: We used survey data from two ongoing trials, for 423 Veteran and 169 caregiver participants, respectively. Questions examined Internet use in the past year, willingness to communicate via videoconferencing, and comfort with new technology devices. RESULTS: Most participants used Internet in the past year (81% of Veterans, 82% of caregivers); the majority of users (83% of Veterans, 92% of caregivers) accessed Internet at least a few times a week, and used a private laptop or computer (81% of Veterans, 89% of caregivers). Most were willing to use videoconferencing via private devices (77-83%). A majority of participants were comfortable attempting to use new devices with in-person assistance (80% of Veterans, 85% of caregivers), whereas lower proportions were comfortable "on your own" (58-59% for Veterans and caregivers). Internet use was associated with comfort with new technology devices (odds ratio 2.76, 95% confidence interval 1.70-4.53). CONCLUSIONS: Findings suggest that technology-enhanced healthcare interventions are feasible and acceptable for Veterans with multi-morbidity and high healthcare utilization, and informal caregivers of Veterans. In-person assistance may be important for those with no recent Internet use. PMID- 29252111 TI - Experimental investigation of biodynamic human body models subjected to whole body vibration during a vehicle ride. AB - In this study, responses of biodynamic human body models to whole-body vibration during a vehicle ride were investigated. Accelerations were acquired from three different body parts, such as the head, upper torso and lower torso, of 10 seated passengers during a car ride while two different road conditions were considered. The same multipurpose vehicle was used during all experiments. Additionally, by two widely used biodynamic models in the literature, a set of simulations were run to obtain theoretical accelerations of the models and were compared with those obtained experimentally. To sustain a quantified comparison between experimental and theoretical approaches, the root mean square acceleration and acceleration spectral density were calculated. Time and frequency responses of the models demonstrated that neither of the models showed the best prediction performance of the human body behaviour in all cases, indicating that further models are required for better prediction of the human body responses. PMID- 29252112 TI - Program Evaluation of Group-based Cognitive Behavioral Therapy for Insomnia: a Focus on Treatment Adherence and Outcomes in Older Adults with Co-morbidities. AB - OBJECTIVE: To describe a program evaluation of the interrelationship of adherence and treatment outcomes in a sample of veteran older adults with co-morbidities who participated in group-based cognitive behavioral therapy for insomnia. METHODS: Retrospective data extraction was performed for 14 older adults. Adherence measures and sleep outcomes were measured with sleep diaries and Insomnia Severity Index. Demographic and clinical information was extracted through chart review. RESULTS: Adherence with prescribed time in bed, daily sleep diaries, and maintaining consistent time out of bed and time in bed was generally high. There were moderate, though not significant, improvements in consistency of time in bed and time out of bed over time. Adherence was not significantly associated with sleep outcomes despite improvements in most sleep outcomes. CONCLUSIONS: The non-significant relationship between sleep outcomes and adherence may reflect the moderating influence of co-morbidities or may suggest a threshold effect beyond which stricter adherence has a limited impact on outcomes. CLINICAL IMPLICATIONS: Development of multi-method adherence measures across all treatment components will be important to understand the influence of adherence on treatment outcomes as monitoring adherence to time in bed and time out of bed had limited utility for understanding treatment outcomes in our sample. PMID- 29252113 TI - Short-Term Effects of the Kinesio Taping(r) on Early Postoperative Hip Muscle Weakness in Male Patients With Hamstring Autograft or Allograft Anterior Cruciate Ligament Reconstruction. AB - OBJECTIVE: Kinesio Taping(r) (KT) is a widely used treatment method in musculoskeletal rehabilitation. Little is known about the KT treatment and hip strength in patients with anterior cruciate ligament reconstruction (ACLR). The purpose of this study was to investigate the effectiveness of the KT treatment on hip muscle weakness in early rehabilitation of ACLR and the possible determinants of the ACLR-hip strength deficit (HSD). DESIGN: Double-blind sham controlled study. SETTING: Rehabilitation department. PATIENTS: 26 male patients who underwent unilateral ACLR using hamstring autograft or allograft 4 days before. INTERVENTIONS: The patients were randomised to receive the knee KT treatment (n = 13) with lymphatic correction plus muscle (biceps/rectus femoris) facilitation or sham KT (n = 13) for 10 days. Additionally, the same ACLR rehabilitation program was applied to all the patients. MAIN OUTCOME MEASURES: The baseline data included demographic and clinical characteristics, postoperative swelling, knee motion loss and knee pain, and bilateral strength of the knee and hip muscle groups except for rotator. Then, percent values of hip HSD and knee strength limb symmetry index (LSI) were calculated. The hip strength measurements in ACLR operated leg were repeated on 5-10th days of KT. RESULTS: Changes in all hip strength values over time were significant in both groups (p < 0.001). In inter group analysis of 15th and 10th days, improvements in the flexor (only 10th day), extensor and adductor hip strength on operated leg were in favour of KT group (p < 0.05). Additionally, the postoperative thigh swelling and knee strength LSI values were correlated with the HSD outcomes in baseline data (p < 0.05). CONCLUSIONS: ACLR-HSD can be caused by postoperative increased swelling and reduced knee strength. The KT treatment with lymphatic correction and muscle facilitation that can be used in treatment of postoperative hip muscle weakness after ACLR. PMID- 29252114 TI - Psychosocial risk factors and processes impeding adaptive capacities and contributing to psychosocial distress among later-life Egyptian immigrants. AB - This qualitative study explores and describes the transactional and cumulative psychosocial stressors that later-life Egyptian immigrants encounter upon coming to the United States, and how they impede their adaptive capacities, hinder their adjustment efforts, and impact their psychosocial well-being. Such stressors are more pronounced among those who immigrated to the United States from Egypt after reaching the retirement age of 60 for two reasons. First, they experience pre immigration stressors that force or expedite their departure from Egypt under duress, thus incurring numerous financial and symbolic losses. Secondly, in the last developmental stage, when age-related losses are triggered, they are concomitantly exposed to a starkly different lifestyle, language, cultural norms, living and financial arrangements, roles, and relationships. All such circumstances contribute to a sense of confusion, guilt, shame, and being a burden on others, which culminate in withdrawal, isolation, and distress. The findings of this study can be used to inform psychosocial and therapeutic interventions and guide the development of appropriate social work programs, services, and policies for later-life Egyptian immigrants in particular and older Arabic-speaking immigrants in general. PMID- 29252115 TI - Practitioners preferences of care coordination for older people: A discrete choice experiment. AB - These findings demonstrate the importance of organisations providing care coordination for older people receiving long-term funding. Further research is required to investigate the influence of service setting on practitioner preferences. This study explored practitioner preferences about the relative value of attributes of care coordination services for older people. A Discrete Choice Experiment (DCE) survey was used to identify the views of 120 practitioners from 17 services in England in 2015. The survey design was informed by an analysis of standards of care coordination, a postal survey and a consultation with carers of older people. Results of the DCE survey were supplemented by a content analysis of qualitative comments and fieldwork notes. Most respondents were over 30 years of age, female and almost half worked part time. Continuity of care (care provided by the same care coordinator) and the ability to access the range of services outlined in the care plan were the most important service attributes. Service setting influenced practitioner preferences. Those in specialist services for people with dementia identified the length of time a service was provided as another important attribute. The DCE methodology has provided the opportunity to systematically canvas practitioner preferences. PMID- 29252116 TI - Using Home-Program Adherence App in Pediatric Therapy: Case Study of Sensory Processing Disorder. AB - BACKGROUND: Pediatric therapies adopt a family-centered approach that encourages a caregiver's involvement in therapy. Contextual interventions in the child's natural environment have been effective in generalization of skills and increasing of child participation in daily activities. The use of home programs is common across a variety of conditions, but adherence has been challenging. Apps have been demonstrated to promote medication adherence and physical activity maintenance. INTRODUCTION: This study suggested and tested a construct for features required for caregivers' behavioral modification during home programs in pediatric therapy. MATERIALS AND METHODS: SensoryTreat is an adherence promoting app for home-program treatments of children with sensory processing disorders. The app was evaluated by testing availability of desired features, usage frequency, impact on adherence with home programs, and parental sense of competence. RESULTS: Results suggest a strong significant correlation between SensoryTreat usage frequency and families' adherence with home programs, as well as a strong significant correlation between relevancy and usefulness of SensoryTreat's interventional content, and parental competence and their adherence with home programs. DISCUSSION: Using SensoryTreat twice or more per week increases parental adherence with home programs. Content plays an important role in promoting adherence and parental sense of competence, yet, as usage frequency grows the interventional content habituates, and other features as goal setting and feedback logs have significant impact on parental competence and adherence with home programs over time. CONCLUSIONS: These findings indicate that the content and features of SensoryTreat app have the potential to promote adherence of families with pediatric therapy home programs. PMID- 29252117 TI - Live Attenuated Influenza Vaccines engineered to express the nucleoprotein of a recent isolate stimulate human influenza CD8+ T cells more relevant to current infections. AB - Live attenuated influenza vaccines (LAIV) induce CD8+ T lymphocyte responses that play an important role in killing virus-infected cells. Despite the relative conservation of internal influenza A proteins, the epitopes recognized by T cells can undergo drift under immune pressure. The internal proteins of Russian LAIVs are derived from the master donor virus A/Leningrad/134/17/57 (Len/17) isolated 60 years ago and as such, some CD8+ T cell epitopes may vary between the vaccine and circulating wild-type strains. To partially overcome this issue, the nucleoprotein (NP) gene of wild-type virus can be incorporated into LAIV reassortant virus, along with the HA and NA genes. The present study compares the human CD8+ T cell memory responses to H3N2 LAIVs with the Len/17 or the wild-type NP using an in vitro model. PMID- 29252118 TI - Mapping the Barriers and Facilitators of HCV Treatment Initiation in Methadone Maintenance Therapy Patients: Implications for Intervention Development. AB - An estimated 70-90% of current methadone users have Hepatitis C (HCV). Current treatments have few side effects and can cure infection in 8-12 weeks, but less than 10% of methadone patients initiate treatment. Engaging this group in treatment is an important strategy to lower both morbidity and mortality from liver disease and eliminate a significant reservoir of HCV in communities. To understand how to address this treatment gap we used commercial marketing techniques called perceptual mapping and vector message modeling to analyze survey data from 100 HCV+ methadone patients from four centers in Philadelphia. Results were used to understand barriers and facilitators to treatment initiation and to devise targeted message strategies to adapt to a mobile health communication intervention. Results indicate that focusing on how treatment can make one feel "in charge", positive interactions with healthcare providers, the positive attributes of the new vs. old HCV treatments, and providing strategies to address tangible barriers to getting treatment, would be important to address in a communication intervention. These marketing methods allow for focusing on specific variables to "move" the group toward a treatment decision, making them an innovative technique to use in developing highly targeted health communication messages. PMID- 29252119 TI - Telemedicine in Pediatric Critical Care: A Retrospective Study in an International Extracorporeal Membrane Oxygenation Program. AB - INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) is an invaluable rescue technique for critically ill children with imminent or present cardiopulmonary collapse. However, medical team expertise to optimize results and decrease complications is scarce. Telemedicine can be used to enhance the delivery of quality interventions. MATERIALS AND METHODS: This is a retrospective review of pediatric patients assisted with ECMO in the cardiac intensive care unit (CICU) at Fundacion Cardiovascular de Colombia from July 2011 to June 2015 (telemedicine) compared with similar patients from a previous period (pretelemedicine). Collected information included demographic data, cardiac diagnosis, risk adjustment for congenital heart surgery (RACHS-1), hospital mortality, CICU and hospital length of stay (LOS), ECMO type, and ECMO run hours as well as specific telemedicine information. RESULTS: Fifty-seven patients in the pretelemedicine and 109 in the telemedicine periods were included in the analysis. Forty-nine teleconsulted patients received 218 teleconsultations, with a recommendation for diagnostic or interventional catheterization in 38 patients (77.5%). A surgical procedure for significant residual lesions was recommended in 30 patients (61.2%). Patients in the telemedicine period were older (4.7 months vs. 1.6 months, p = 0.006), more likely to receive operating room ECMO (43.1% vs. 24.6%, p = 0.02), and had a higher proportion of patients with two-ventricle physiology (73.4% vs. 54.4%, p = 0.013). Hospital survival was higher during the telemedicine period (54.1% vs. 29.8%, p = 0.002), with a longer hospital LOS (67 days vs. 28 days, p < 0.001). CONCLUSION: The implementation of telemedicine assisted interventions in a pediatric ECMO program delivered valuable diagnostic and therapeutic advice, was associated with significant changes in selection criteria and model of care, and an increased hospital survival. PMID- 29252120 TI - Mental Health News: How Frames Influence Support for Policy and Civic Engagement Intentions. AB - Depression accounts for nearly 400 million disability days per year, and has been identified as the definitive public health priority in the decades to come (Greenberg et al., 2015). Despite the passage of the 2008 Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act, which requires coverage of mental health services, behavioral health and substance-use disorders to be equal to physical health coverage, individuals face numerous barriers when seeking help for depression. This research tests whether changing the way stories frame depression affects how audience members attribute responsibility for depression and their intentions to participate in civic engagement activities supporting policy solutions. Findings from this study contradict earlier scholarship and have implications for how information about depression and policy solutions are framed for the public including how to develop health policy messaging when working with the news media. Suggestions for future research are included. PMID- 29252121 TI - What Behavioral and Psychological Symptoms of Dementia Affect Caregiver Burnout? AB - OBJECTIVES: Patients' irritability and aggression have been linked to caregiver depression, but the behaviors that most burden caregivers are not yet definitively identified. This study examines the connection between behavioral and psychological symptoms of dementia (BPSD) and the burnout of caregivers caring for home-dwelling elders with dementia symptoms in Japan. METHODS: 80 Japanese rural and urban family caregivers completed detailed questionnaires about their experiences in caring for demented family members. We statistically analyzed the results for correlations between types of dementia, Pines Burnout, and Caregiver Distress. RESULTS: BPSD symptom severity significantly correlated with caregiver distress. The dementia symptoms most strongly correlated with caregiver burnout were: aggression, irritability, abnormal motor behavior, and hallucinations. CONCLUSIONS: Among the commonest symptoms, apathy, anxiety, and depression did not seriously aggravate caregiver burnout. Caregivers displayed higher burnout facing agitation/aggression, irritability, aberrant motor behavior, and hallucinations. Caregivers' reported distress was surprisingly dissimilar to their burnout scores; patients' delusions and anxiety led to higher distress reporting but not to burnout. CLINICAL IMPLICATIONS: Advance diagnosis of BPSD symptoms should be helpful to support nurses and caregivers of dementia patients. Particular support should be considered for caregivers and nurses of patients expressing aggression, irritability, abnormal motor behavior, and hallucination. PMID- 29252122 TI - Cognitive Functioning After Hematopoietic Cell Transplantation for Hematologic Malignancy: Results From a Prospective Longitudinal Study. AB - Purpose Cognitive impairment is well-recognized after myeloablative allogeneic hematopoietic cell transplantation (HCT). However, cognitive functioning after reduced-intensity allogeneic or autologous HCT remains unclear. Methods A total of 477 HCT recipients (236 autologous, 128 reduced-intensity allogeneic, 113 myeloablative allogeneic) underwent standardized neuropsychologic testing before HCT and at 6 months and 1, 2, and 3 years after HCT. Ninety-nine frequency matched healthy controls underwent testing at commensurate time points. Primary outcomes of the study were practice effect-adjusted domain-specific T scores and global deficit scores. Piecewise generalized estimating equation models were used to compare groups and to identify associated variables and post-HCT trends of cognitive impairment. Results Median age was 52 years (range, 18 to 74 years) for HCT recipients and 55 years (range, 19 to 73 years) for controls. Post-HCT scores were comparable between controls and autologous and reduced-intensity HCT recipients. Myeloablative HCT recipients had significantly lower ( P < .001) post HCT scores than controls for executive function, verbal speed, processing speed, auditory memory, and fine motor dexterity. Pre-HCT to 6 months post-HCT scores did not change after reduced-intensity HCT but declined significantly for fine motor dexterity ( P < .001) after myeloablative HCT. However, pre-HCT to 3 years post-HCT scores declined significantly ( P < .003) in reduced-intensity HCT recipients for executive function, verbal fluency, and working memory. Older age, male sex, and lower education, income, and cognitive reserve were associated with post-HCT cognitive impairment. At 3 years post-HCT, global cognitive impairment was present in 18.7% of autologous and 35.7% of allogeneic HCT recipients. Conclusion Myeloablative allogeneic HCT recipients showed significant cognitive decline compared with healthy controls. Reduced-intensity allogeneic HCT recipients showed evidence of delayed decline. Cognitive functioning in autologous HCT recipients generally was spared. The study identified vulnerable subpopulations that could benefit from targeted interventions. PMID- 29252123 TI - Risk of Hematologic Malignancies After Radioiodine Treatment of Well Differentiated Thyroid Cancer. AB - Purpose To investigate the risk and outcomes of second hematologic malignancies (SHMs) in a population-based cohort of patients with well-differentiated thyroid cancer (WDTC) treated or not with radioactive iodine (RAI). Methods Patients with WDTC were identified from SEER registries. Competing risk regression analysis was performed to calculate the risks of SHMs that occurred after WDTC treatment and outcomes after SHM development were assessed. Results Of 148,215 patients with WDTC, 53% received surgery alone and 47% received RAI. In total, 783 patients developed an SHM after a median interval of 6.5 years (interquartile range, 3.3 to 11.2 years) from WDTC diagnosis. In multivariable analysis, compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing acute myeloid leukemia (AML; hazard ratio, 1.79; 95% CI, 1.13 to 2.82; P = .01) and chronic myeloid leukemia (CML; hazard ratio, 3.44; 95% CI, 1.87 to 6.36; P < .001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. Occurrence of AML but not CML in patients with WDTC was associated with shorter median overall survival compared with matched controls (8.0 years v 31.0 years; P = .001). In addition, AML developing after RAI trended toward inferior survival compared with matched controls with de novo AML (median overall survival, 1.2 years v 2.9 years; P = .06). Conclusion Patients with WDTC treated with RAI had an increased early risk of developing AML and CML but no other hematologic malignancies. AML that arises after RAI treatment has a poor prognosis. RAI use in patients with WDTC should be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance. PMID- 29252126 TI - Leptin Levels and Insulin Dependence in Latent Autoimmune Diabetes in Adults. AB - Latent autoimmune diabetes in adults (LADA) is an autoimmune type of diabetes accounting for up to 10% of all cases of diabetes initially diagnosed as type 2 diabetes mellitus. It has been demonstrated that LADA patients with a lower body mass index (BMI) undergo a faster depletion of beta cell function and require insulin therapy earlier. In this study, we assayed a panel of adipokines (leptin, adiponectin, omentin, resistin, visfatin) and proinflammatory cytokines (interleukin 2, interleukin 6, tumor necrosis factor-alpha) in 71 LADA patients and tested the association with a number of clinical and immunological features. Among men, leptin was positively and significantly correlated with BMI and fat mass (r = 0.487 and r = 0.664, respectively), resistin was positively and significantly correlated with total and low-density lipoprotein cholesterol (r = 0.644 and r = 0.746, P < 0.0001) and with interleukin 2 (r = 0.688, P < 0.01). Omentin showed an inverse correlation with systolic blood pressure in women (r = 0.359, P < 0.001) and a positive correlation with interleukin 2 in both genders (r = 0.395, P < 0.01). The Cox regression analysis showed that leptin levels were inversely and significantly related with the risk of early insulin dependence. Higher leptin secretion may exert a direct effect on beta cell function leading to more insulin sensitivity. PMID- 29252124 TI - Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors. AB - Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (>= 18 months, >= 7 months) and seven stable disease responses >= 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, >= 6, and >= 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing. PMID- 29252127 TI - Expression Pattern of Individual IFNA Subtypes in Chronic HIV Infection. AB - Interferon-alpha (IFN-alpha) plays an important role in HIV pathogenesis. IFN alpha consists of 13 individual IFN-alpha subtypes, which exhibit individual antiviral and immunomodulatory activities in HIV infection. Here, we determined the expression profiles of all IFN-alpha subtypes in treated and treatment-naive HIV+ patients and their impact on the induction of distinct HIV restriction factors. We collected blood samples of chronic HIV+ patients, which underwent antiretroviral therapy or were treatment-naive, and determined the individual expression levels of different IFN-alpha subtypes and HIV restriction factors. HIV infection transiently enhanced the expression of IFNA mRNA. The IFN-alpha response was dominated by the most abundantly expressed subtypes IFNA4, A5, A7, and A14 in all individuals. HIV infection affected the expression pattern of the IFN-alpha response, in particular for IFNA2 and IFNA16, which were elevated by chronic HIV infection. Elevated expression of HIV restriction factors was observed in chronically HIV-infected patients, which partly decreased during successful antiretroviral treatment. In vitro stimulation of peripheral blood mononuclear cells revealed that IFN-alpha6, -alpha14, and -alpha21 were most effective in inducing the expression of HIV restriction factors. These results indicate that HIV infection induces a specific expression pattern of IFN-alpha subtypes, which in turn induce the expression of various HIV restriction factors. PMID- 29252128 TI - Gravity-Related Immunological Changes in Human Whole Blood Cultured Under Simulated Microgravity Using an In Vitro Cytokine Release Assay. AB - Although immune dysfunction by space conditions has been reported postflight, as well as during ground-based experiments, the cause(s) and nature of the immunological changes are not completely understood. Microgravity has been suggested as one of the factors responsible for the observed immune dysregulation. The goal of this study was to assess immune changes in simulated microgravity (s-MUG) using an in vitro cytokine release assay. The effect of s MUG provided by the desktop random positioning machine on cell-mediated immunity was examined by analyzing interleukin 2 (IL-2), interferon-gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 10 (IL-10), in response to immune cell stimulation in whole blood samples (n = 10). Stimuli used were bacterial recall antigens, pokeweed mitogen (PWM), lipopolysaccharide (LPS), or heat-killed Listeria monocytogenes (HKLM). S-MUG caused an overall inhibition of the IL-2 and IFN-gamma responses to recall antigen and mitogen stimulation. More specifically, s-MUG most strongly influenced the levels of all four cytokines elicited by bacterial recall antigen stimulation. In contrast, HKLM-induced TNF alpha secretion was elevated. The average concentrations of TNF-alpha in response to PWM and LPS and IL-10 release stimulated by PWM, LPS, and HKLM were not significantly altered by s-MUG. However, a variable response between individual subjects could be observed. In conclusion, our results demonstrate that the in vitro cytokine release assay can detect gravity-related immune alterations. Furthermore, the use of multiple stimuli and the associated changes in cytokine secretion has the potential to reveal information on the underlying mechanisms affected by s-MUG. PMID- 29252129 TI - From Infections to Anthropogenic Inflicted Pathologies: Involvement of Immune Balance. AB - A temporal trend can be seen in recent human history where the dominant causes of death have shifted from infectious to chronic diseases in industrialized societies. Human influences in the current "Anthropocene" epoch are exponentially impacting the environment and consequentially health. Changing ecological niches are suggested to have created health transitions expressed as modifications of immune balance from infections inflicting pathologies in the Holocene epoch (12,000 years ago) to human behaviors inflicting pathologies beginning in the Anthropocene epoch (300 years ago). A review of human immune health and adaptations responding to environmental (biological, chemical, physical, and psychological) stresses, which are influenced by social conditions, emphasize the involvement of fluctuations in immune cell subsets affecting influential gene environment interactions. The literature from a variety of fields (anthropological, immunological, and environmental) is incorporated to present an expanded perspective on shifts in diseases within the context of immune balance and function and environmental immunology. The influences between historical and contemporary human ecology are examined in relation to human immunity. Several examples of shifts in human physiology and immunity support the premise that increased incidences of chronic diseases are a consequence of human modification of environment and lifestyle. Although the development of better health care and a broader understanding of human health have helped with better life quality and expectancy, the transition of morbidity and mortality rates from infections to chronic diseases is a cause for concern. Combinations of environmental stressors/pollutants and human behaviors and conditions are modulating the immune neuroendocrine network, which compromises health benefits. PMID- 29252130 TI - Patient Needs for an Ambulant Dislocation Alert System Following Total Hip Arthroplasty. AB - INTRODUCTION: One of the major complications in total hip arthroplasty (THA) is dislocation of the prosthesis. To prevent early dislocation, patients are instructed with movement restrictions. The first goal in this development is to obtain insight in the movement restrictions that are reported to have low levels of self-efficacy during activities of daily life. The second goal is to reveal the design needs for an ambulant hip dislocation alert system (HipDas) and the third goal is to explore its usability among patients. METHODS: Patient-centered experiences with THA were explored by the use of a questionnaire and a semistructured focus group. The questionnaire was administered among n = 32 THA patients at 1 week preoperative and at 3 and 6 weeks postoperative. The questions addressed self-efficacy, performance and effort expectancy, and usefulness and social influence. The focus group consisted of patient journeys and scenario composition. The usability of a prototype version of the HipDas system was evaluated (n = 5). RESULTS: Flexion of the hip >90 degrees , bending over while sitting in a chair, and sleeping in a supine position are the restrictions that have the lowest self-efficacy. The majority of patients (>86.6%) believe that a future HipDas is useful. Focus group outcomes suggest there is a gradual decrease in the threshold for feedback. The system is preferably used in the first 6 weeks after surgery and appeared to be usable and highly clinically relevant. DISCUSSION: HipDas is considered an interesting concept that can accelerate functional recovery of patients following THA by providing support on how to properly apply postoperative movement restrictions to prevent a dislocation. PMID- 29252131 TI - Assessing the Potential Use of Narrative and the Entertainment Education Strategy In an mHealth Text-Message Intervention. AB - As the use of mobile phones for health promotion continues to grow, more work needs to be done to determine which health communication strategies are influential on mobile devices. In two studies conducted with college women in the United States, we assessed the potential for the use of narratives, a strategy found successful in a number of communication channels, in a text-message intervention. The first study consisted of seven focus groups with young women (n = 31) about their perceptions of narrative storylines in a text-message intervention about alcohol and casual sexual encounters. In a second study, we then used an experiment (n = 137) to test the potential of narrative messages to influence transportation, counter-arguing, identification, attitudes toward the intervention type, and attitudes toward the messages. Results showed that women were interested in the possibility of receiving health messages, including narrative health messages, via text message. However, the experiment found limited differences between narrative, non-narrative, and control conditions. Transportation was greater in the narrative condition than in the control, but did not significantly differ from the non-narrative condition. Counter-arguing was also greater in the narrative condition than in the non-narrative condition. Participants who viewed the narrative messages had more positive attitudes toward the messages. Based on both studies, we found that the use of narratives in text messages may be a promising strategy, but it may be a challenge to craft effective content. PMID- 29252132 TI - Experimental determination of the dispersion of ions from a point source in the environment. AB - The dispersion of ions from a point source has been extensively modelled but there have been very few attempts to experimentally verify the theoretical findings. The main reason for this has been the difficulty of discriminating between cluster ion and charged particle concentrations in the air. In this paper, we describe a novel technique for the experimental determination of the dispersion of ions from a point source in air. Laboratory experiments showed that the lifetime of cluster ions in an aerosol cloud was of the order of minutes. However, once they attached to aerosols, the particles retained the charge for at least 30 min, suggesting that they may be carried long distances in natural winds. A negative air ionizer was used to produce ions and charged particles in an open field in the presence of a steady horizontal wind. A neutral cluster and air ion spectrometer was used to measure cluster ion and charged particle concentrations as a function of downwind distance from the source. The results are broadly consistent with the Gaussian dispersion model for a continuous point source. We estimate that cluster ions can be carried up to a distance of several hundred metres before they fully attach to particles which can then be carried as far as 3-4 km. Therefore, these observations have important bearing on exposure to cluster ions and charged particles downwind of ion sources such as high voltage power lines and busy roads. PMID- 29252137 TI - MPMI Acknowledgment of Reviewers 2017. PMID- 29252133 TI - Legislation governing tobacco use in Ontario's retirement homes. AB - Legislation banning smoking in public places is a key component of comprehensive tobacco control programs, yet residential facilities for aging adults are often exempt from such legislation. In Ontario, Canada, provincial legislation does not comprehensively safeguard retirement homes' residents and staff from tobacco related health and safety concerns. This study provides a descriptive analysis of municipal-level bylaws in order to begin understanding the regulatory context of tobacco use in retirement homes in the Province. A stratified random sample of retirement homes (n = 75) was selected. A rubric was developed highlighting various components that a model policy would include, to allow for the independent review of municipal-level bylaws governing these 75 homes. Results indicate that 75% of retirement homes were located in areas without municipal level tobacco legislation that addressed retirement homes. The remaining 25% (n = 19 retirement homes) were governed by eight different municipal-level bylaws, all of which lacked in overall comprehensiveness. Amending Ontario's regulatory framework to eliminate loopholes and include retirement homes, as well as the creation and modification of municipal-level legislation, will aid in safeguarding smokers and nonsmokers from the dangers of tobacco-related risks, including secondhand smoke, fires, igniting cigarettes while connected to oxygen, burns to skin, and damage to clothing and property. PMID- 29252138 TI - Lymphatic Medicine: Paradoxically and Unnecessarily Ignored. PMID- 29252139 TI - Temporal Dynamics of the Rat Thoracic Duct Contractility in the Presence of Imposed Flow. AB - BACKGROUND: The initial periods of increased flow inside lymphatic vessels demonstrate specific temporary patterns of self-tuning of lymphatic vessel contractility that are heterogeneous across regional lymphatic networks. The current literature primarily refers to the immediate and fast reactions of the lymphangions to increases in basal flow. Until now, there were no available data on how the lymphatic vessels react to comparatively longer periods of imposed flow. METHODS AND RESULTS: In this study, we measured and analyzed the contractility of the rat thoracic duct segments, isolated, cannulated, and pressurized at 3 cm H2O at no imposed flow conditions and during 4 hours of imposed flow (constant transaxial pressure gradient of 2 cm H2O). We found the development of a progressing lymphatic tonic relaxation and inhibition of the lymphatic contraction frequency over 4 hours of imposed flow. After a short initial decrease, lymphatic phasic contraction amplitude rose significantly during the first hour of imposed flow, and it demonstrated a trend to return toward control levels after 3 hours of imposed flow. As a result, the fractional pump flow (active lymph pumping per minute) of isolated thoracic duct segments reached and maintained a statistically significant decrease (from control no-flow conditions) at the end of the third hour of imposed flow. CONCLUSIONS: Our new findings provide a better understanding of how lymphatic contractility changes during the development of prolonged periods of steady lymph flow. The latter may occur during the initial phases of development of an inflammatory-related tissue edema. PMID- 29252140 TI - An Auto-Adjustable Night Garment to Control Early Rebound Effect of Edema Volume After Intensive Phase of Decongestive Lymphedema Therapy. AB - BACKGROUND: Lymphedema of the arm and/or hand is a well-established complication of breast cancer therapy. The objective of the study was to determine the interest of auto-adjustable MOBIDERM(r) Autofit night arm sleeve in controlling edema rebound effect in breast cancer-related lymphedema patients just after a successful intensive phase of decongestive lymphedema therapy (DLT). MATERIALS AND METHODS: This is a subgroup analysis of MARILYN Study, conducted on 40 patients after completion of intensive DLT. Patients were randomized in Night user group (fitted with MOBIDERM Autofit device) or No night-user group (no night compression). For subgroups analysis, patients were defined as high responders (HR) if their lymphedema volume reduction during DLT was >=35% or as low responders (LR) if it was below 35%. RESULTS: In HR subgroups (n = 16), the mean lymphedema volume variation between Day 0 and 30 was 28.4 mL in the night-user group versus 181.4 mL in the no night-user group. When adjusted to the loss of volume during DLT, 89% of the DLT benefit is maintained in HR night-user versus 54% in no night-user group. Between LR (24 patients), this mean volume variation was by 65.1 mL versus 54.9 mL in night-user and no night-user groups respectively between Day 0 and 30. CONCLUSION: Wearing MOBIDERM Autofit, on top of the day time hosiery, appears a promising way to control the early rebound effect during the maintenance phase especially in DLT-HR. PMID- 29252141 TI - Update December 2017. PMID- 29252143 TI - A scoping review of intimate partner violence educational programs for health care professionals. AB - BACKGROUND: Multiple intimate partner violence (IPV) educational programs have been developed for health care professionals (HCPs); however, program content and effectiveness vary substantially. The purpose of this scoping review was to identify and synthesize the literature evaluating IPV education programs for HCPs to identify key areas for potential evidence-based recommendations and focus future research priorities. METHODS: We conducted a systematic literature search using broad eligibility criteria to identify studies published between January 2000 and July 2015 that evaluated the effectiveness of IPV education programs in health care settings. All potentially eligible references were screened independently by two reviewers. Data extraction was completed independently by two reviewers for all eligible studies. Descriptive statistics were used to summarize all data. RESULTS: We identified 65 eligible studies, 55% of which reported positive program effectiveness. Effective programs often reported the use of online training components, delivery by an IPV educator/expert or physician/surgeon, the inclusion of a treatment protocol and resources for patients and HCPs, and included more than five training sessions lasting no more than one hours each. CONCLUSIONS: Our results demonstrate that IPV educational programs are heterogeneous and that a wide variety of methodologies have been used to evaluate their effectiveness. PMID- 29252144 TI - Whole Grain Nutrition Education Program Improves Whole Grain Knowledge and Behaviors Among Community-Residing Older Adults. AB - U.S. older adults are not meeting the recommendation for whole grain (WG) intake. This pilot study determined the influence that a WG nutrition education program for community-residing adults aged 60 + years has on WG knowledge and behaviors. The program included WG education and discussion, participation in hands-on activities and taste testing. Participants were mostly white, females. Total grain and WG dietary intake frequencies (WG frequency; p <= 0.001), and "knowledge score" increased from PRE to POST (p <= 0.001). Participants in PowerPoint-based classes had a higher "knowledge scores" at POST (p = 0.002). Nearly all (n = 139, 88.5%) intended to eat more WG foods, with almost two-thirds (n = 93, 59.3%) reporting a "strong" intention to do so. There was a positive association between strength of intention to eat WG foods and "WG frequency" at POST (r = 0.435, p <= 0.001). Results suggest that this WG program is an effective strategy for improving WG knowledge and behaviors among older adults. PMID- 29252142 TI - Experimental Models Used to Assess Lymphatic Contractile Function. AB - Recent years have seen a renewed interest in studies of the lymphatic system. This review addresses the differences between in vivo and ex vivo methods for visualization and functional studies of lymphatic networks, with an emphasis on studies of collecting lymphatic vessels. We begin with a brief summary of the historical uses of both approaches. For the purpose of detailed comparisons, we subdivide in vivo methods into those visualizing lymphatic networks through the intact skin and those using surgically opened skin. We subdivide ex vivo methods into isobaric studies (using a pressure myograph) or isometric studies (using a wire myograph). For all four categories, we compile a comprehensive list of the advantages, disadvantages, and limitations of each preparation, with the goal of informing the research community as to the appropriate kinds of experiments best suited, and ill suited, for each. PMID- 29252145 TI - Perceived Barriers to Increased Whole Grain Consumption by Older Adults in Long Term Care. AB - Many older adults fail to consume adequate amounts of dietary fiber from food sources, including whole grains. Little information is available about consumption of dietary fiber and whole grains by residents of long-term care facilities. Surveys were mailed to 3,000 randomly selected US members of the Academy of Nutrition and Dietetics who worked in practice groups related to elder care. Net response rate was 22.7% (n = 681). Cost was a barrier to whole grain use for 27.1% of respondents, followed by dietary needs (22.1%), contracts in place (20.3%), and overall nutritional content (20.1%). Over 75% of respondents stated their patients require dietary fiber supplementation. Nutrition professionals most frequently (23.6%) reported spending $11-20 monthly per patient on dietary fiber supplements. Although a majority of facilities served whole grain foods daily, 89.5% of respondents would like to serve more whole grains. Ready-to-eat cereals, bread, bagels, and hot cereals were the most common whole grain products served at the facilities where survey respondents worked. An economic analysis of the benefits of increased consumption of whole grains and other high-fiber foods versus the use of laxative supplements may be helpful to administrators of long-term care facilities. PMID- 29252147 TI - Response by Costa et al. to Letter Regarding Article: "Nutritional Risk is Associated with Chronic Musculoskeletal Pain in Community-dwelling Older Persons: The PAINEL Study". PMID- 29252148 TI - Nutrition Support Team Intervention Improves Activities of Daily Living in Older Patients Undergoing In-Patient Rehabilitation in Japan: A Retrospective Cohort Study. AB - The effect of nutrition support on activities of daily living (ADL) in individuals aged >=75 years requiring rehabilitation is unknown. This study aimed to investigate the effect of nutrition support on ADL improvement in older patients undergoing in-patient rehabilitation in Japan. This retrospective cohort study was performed in 175 patients aged >=75 years. The nutrition support team (NST) intervened in 85 cases. ADL was evaluated by the functional independence measure (FIM). We analyzed the effects of NST intervention on FIM efficiency. Multiple linear regression analysis revealed that NST intervention (standard partial regression coefficient, beta = 0.164; 95% confidence interval [CI] 0.003 0.229; P = 0.044), energy intake at admission (beta = 0.179; 95% CI, 0.000-0.016; P = 0.043), body mass index (BMI) at admission (beta = 0.227; 95% CI, 0.005 0.046; P = 0.014), and cerebrovascular disease (beta = -0.238; 95% CI, -0.298 to 0.063; P = 0.003) were independently associated with FIM efficiency. NST intervention, energy intake, and BMI on admission may affect ADL improvement in older patients undergoing in-patient rehabilitation. PMID- 29252149 TI - Letter to the Editor: RE: Costa et al. (''Nutritional Risk is Associated with Chronic Musculoskeletal Pain in Community-Dwelling Older Persons: The PAINEL Study''). AB - We read Costa and colleagues' report1 in 2016 in the Journal of Nutrition in Gerontology and Geriatrics with great interest. In this article, the authors reported a statistically significant association between chronic musculoskeletal pain and nutritional risk after controlling for age, gender, body mass index (BMI), depression (GDS, geriatric depression scale), and diabetes in a Brazilian community-dwelling older adult's population (the PAINEL study, see Table 2 in Costa et al. 1 . However, in their study, Costa and colleagues used the DETERMINE 2 Questionnaire, a questionnaire in which 3 out of the 10 questions are directly or indirectly related to pain (i.e., presence of an illness, tooth or mouth problems, and physical disability). The purpose of this letter is to discuss the potential drawbacks of including pain-related questions in nutrition risk screening tool when these tools are used to investigate the relationship between pain and nutritional risk. PMID- 29252150 TI - Whey Protein Supplementation Improves Rehabilitation Outcomes in Hospitalized Geriatric Patients: A Double Blinded, Randomized Controlled Trial. AB - Whey protein supplementation (WPS) has been shown to improve functional outcomes in populations that are able to participate in high-intensity resistance training. The purpose of the study was to evaluate the efficacy of WPS on rehabilitation outcomes in a frail, hospitalized elderly population. Men and women (n = 47) were randomly assigned to either a control group or WPS group for the length of their hospital stay. Several functional and serum measures were determined pre- and post-intervention. WPS significantly increased average daily protein intake and was well tolerated. The WPS group exhibited significant improvements in grip strength and knee extensor force over the control group, and a significant positive correlation was found between change in prealbumin and percent-increase knee extensor force. These findings support the use of WPS to improve protein nutritional status and rehabilitation outcomes in a clinical setting involving a frail, elderly population. PMID- 29252151 TI - Developing a Palliative Radiation Oncology Service Line: The Integration of Advance Care Planning in Subspecialty Oncologic Care. AB - Within radiation oncology, there is often minimal attention on radiotherapy with palliative benefits due to the overlying focus on curative treatments. Historically at the University of Pennsylvania, advanced-stage patients are cared for by cancer site-specific teams rather than a more rapid treatment service model that focuses on patients' symptom needs and larger clinical issues within a palliative framework. Thus, the University of Pennsylvania created a designated palliative radiation oncology team to focus on the complex medical and relational issues of metastatic cancer patients. Social workers play a critical role in patient and family conversations about advance directives, care needs, and end-of life goals and fears as treatment regimens and outcomes continue to unfold. The palliative radiation oncology social worker developed and instituted a new, formalized assessment tool called the "palliative radiation oncology psychosocial care plan" in the electronic medical record. A retrospective analysis of 26 palliative radiation oncology patients under treatment between February and August 2016 was conducted. Of these patients treated with palliative radiation, 19% completed an advance directive after the social work intervention. This model highlights advance care planning as a best practice and encourages end-of-life discussions as a routine part of the oncology workflow. PMID- 29252152 TI - Digital Storytelling: Families' Search for Meaning after Child Death. AB - Bereaved families that collectively make meaning of their grief experiences often function better than those that do not, yet most social work bereavement interventions target individuals rather than family units. In this article, authors describe an innovative social work intervention that employs digital storytelling. This is a narrative technique that combines photography, music, and spoken word to help families bereaved by child death make meaning of their loss and envision a future without their deceased child. PMID- 29252154 TI - Evidence-Based Treatment with Older Adults: Theory, Practice and Research. PMID- 29252153 TI - Burnout Among Iowa Hospice Workers: A Test of the Job Demands-Resources Model. AB - Burnout is a critical problem for hospice care system, particularly given the potential increase in hospice utilization because of the increasing older adult population. Hospice care requires social workers and other professionals to work in interdisciplinary settings under conditions of prolonged stress. Guided by the Job Demands-Resources (JDR) model, this study sought to: (1) understand Iowa hospice workers' level of burnout, indicated by emotional exhaustion (EE); (2) identify organizational and personal determinants of EE. This web-based study used a cross-sectional survey administered to hospice staff across Iowa. Seventeen hospice organizations participated as study sites, and 244 out of 825 employees, consisting of interdisciplinary clinical workers and administrative personnel, completed the survey. Descriptive, correlational, and regression statistics were used to test study hypotheses. Regarding EE levels, 59% of participants were experiencing low EE, while the other 41% had moderate or high EE. Those lacking empathy, working full-time, and working for larger hospice organizations had greater EE. While findings largely support the JDR model, interactions between demands and resources offer only partial support. Results indicate the importance of hospices fostering supportive work environments and providing employee education about emotional benefits of respect, strategies for displaying workplace respect, and evaluation of respect-related initiatives. PMID- 29252155 TI - Grieving the Loss of a Pet Needs the Health System Recognition. AB - Globally there is increased presence of pets in the households. This non-human relationship, with its dimensions of physical and emotional bonds, can get severely jolted on the death of the companion animal. It sets a feeling, 'our life is now left with a void and the house feels utterly empty'. Unlike the loss of a child, spouse or parent which become a shared tragedy; others may not understand the depth of sadness and a sense of void in a grieving pet owner. Emotional pain and physical distress due to the loss of a companion animal are likely to be pronounced. A big challenge for the medical community is to anticipate, identify and address physical and psychosocial symptom burdens in a timely manner. PMID- 29252156 TI - End-of-Life Preparations among Lesbian, Gay, Bisexual, and Transgender People: Integrative Review of Prevalent Behaviors. AB - Proactively making end-of-life (EOL) preparations is important to ensure high quality EOL care. Critical to preparation is the discussion of preferences with one's primary health care providers. Lesbian, gay, bisexual, and transgender (LGBT) people often experience discrimination from health care providers that will detrimentally affect their ability to communicate their care preferences. Structural barriers, such as those based on sexual orientation and gender identity, may impede timely and quality care when one is most in need. The aim of this study was to examine the prevalence of EOL preparatory behaviors among LGBT people, with particular focus on transgender individuals. Eight survey instruments with 30 prevalence estimates found in the literature were analyzed. EOL discussions between LGBT people and their primary health care providers were rare (10%). Transgender people were found to be even less prepared for EOL; they were 50-70% less likely than their LGB counterparts to have a will, a living will or to have appointed a healthcare proxy. A need exists for future mixed-methods research focused on LGBT populations accompanied by the cultural sensitivity needed to ensure their wishes are honored at the EOL. PMID- 29252158 TI - Would You. PMID- 29252159 TI - Editor's Introduction. PMID- 29252160 TI - Fathers Facing Advanced Cancer: An Exploratory Study. AB - Adults who are living with cancer while raising young children are faced with distinct challenges particularly when that cancer is advanced. While the literature examining parental cancer continues to grow, very little has focused on families facing advanced cancer and the father's perspective is nearly absent. To address these gaps, grounded theory methods were used to study the experiences of 11 fathers living with advanced cancer while raising minor children. The participants were all married with between one and six children living in their household. Semistructured, in-person interviews revealed concerns for their children permeated the "ordeal" and these fathers described the ongoing challenge of "teeter-tottering between hope and despair." The fathers used key protective strategies to counterbalance the weight of the barriers to achieve resilience throughout the cancer experience. Primary barriers were characterized as physical impairments, uncertainty, and financial strain. Fathers described relying on flexibility in their roles as fathers, open communication patterns, use of supportive resources, and the ability to find meaning in their experiences as crucial to fostering resilience. Recommendations include interdisciplinary family centered interventions that consider gendered parental roles as well as financial burden. PMID- 29252161 TI - Culture as an ingredient of personalized medicine. PMID- 29252163 TI - Cardiorespiratory concerns shape brain responses during automatic panic-related scene processing in patients with panic disorder. AB - BACKGROUND: Increased automatic processing of threat-related stimuli has been proposed as a key element in panic disorder. Little is known about the neural basis of automatic processing, in particular to task-irrelevant, panic-related, ecologically valid stimuli, or about the association between brain activation and symptomatology in patients with panic disorder. METHODS: The present event related functional MRI (fMRI) study compared brain responses to task-irrelevant, panic-related and neutral visual stimuli in medication-free patients with panic disorder and healthy controls. Panic-related and neutral scenes were presented while participants performed a spatially nonoverlapping bar orientation task. Correlation analyses investigated the association between brain responses and panic-related aspects of symptomatology, measured using the Anxiety Sensitivity Index (ASI). RESULTS: We included 26 patients with panic disorder and 26 heatlhy controls in our analysis. Compared with controls, patients with panic disorder showed elevated activation in the amygdala, brainstem, thalamus, insula, anterior cingulate cortex and midcingulate cortex in response to panic-related versus neutral task-irrelevant stimuli. Furthermore, fear of cardiovascular symptoms (a subcomponent of the ASI) was associated with insula activation, whereas fear of respiratory symptoms was associated with brainstem hyperactivation in patients with panic disorder. LIMITATIONS: The additional implementation of measures of autonomic activation, such as pupil diameter, heart rate, or electrodermal activity, would have been informative during the fMRI scan as well as during the rating procedure. CONCLUSION: Results reveal a neural network involved in the processing of panic-related distractor stimuli in patients with panic disorder and suggest an automatic weighting of panic-related information depending on the magnitude of cardiovascular and respiratory symptoms. Insula and brainstem activations show function-related associations with specific components of panic symptomatology. PMID- 29252162 TI - Mindfulness-based treatments for posttraumatic stress disorder: a review of the treatment literature and neurobiological evidence. AB - Mindfulness-based treatments for posttraumatic stress disorder (PTSD) have emerged as promising adjunctive or alternative intervention approaches. A scoping review of the literature on PTSD treatment studies, including approaches such as mindfulness-based stress reduction, mindfulness-based cognitive therapy and metta mindfulness, reveals low attrition with medium to large effect sizes. We review the convergence between neurobiological models of PTSD and neuroimaging findings in the mindfulness literature, where mindfulness interventions may target emotional under- and overmodulation, both of which are critical features of PTSD symptomatology. Recent emerging work indicates that mindfulness-based treatments may also be effective in restoring connectivity between large-scale brain networks among individuals with PTSD, including connectivity between the default mode network and the central executive and salience networks. Future directions, including further identification of the neurobiological mechanisms of mindfulness interventions in patients with PTSD and direct comparison of these interventions to first-line treatments for PTSD are discussed. PMID- 29252164 TI - Always on guard: emotion regulation in women with borderline personality disorder compared to nonpatient controls and patients with cluster-C personality disorder. AB - BACKGROUND: Borderline personality disorder (BPD) is characterized by emotion dysregulation; however, it is unclear whether this is restricted to negative emotional stimuli or to what degree this is specific to BPD. We investigated neural correlates of hypothesized increased emotional sensitivity and impaired emotion regulation in patients with BPD. METHODS: During functional MRI (fMRI) scanning, patients with BPD, nonpatient controls and patients with cluster-C personality disorder completed an emotion regulation task, including negative, positive and erotic social pictures. RESULTS: We included 55 patients with BPD, 42 nonpatient controls and 24 patients with cluster-C personality disorder in our analyses. Passive viewing of negative stimuli resulted in greater activity in the anterior insula, temporoparietal junction and dorsolateral prefrontal cortex in patients with BPD than in nonpatient controls. The increased activity in the anterior insula and temporoparietal junction was also present when patients with BPD viewed positive stimuli. During regulation of negative stimuli compared with passive viewing, nonpatient controls showed greater activity in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, middle temporal gyrus and bilateral inferior parietal lobule. Patients with BPD did not show this increase in activity. LIMITATIONS: Findings cannot be generalized to men, and patients represented a heterogeneous group regarding comorbid diagnoses and medication. CONCLUSION: When looking at emotional stimuli, patients with BPD showed a unique pattern of activity, suggesting an increase in brain activity involved in emotion generation. In the case of negative stimuli this is accompanied by increased activity in regulation areas. In contrast, increase of regulation processes seems absent when patients with BPD are explicitly instructed to regulate. Results of diagnosis specificity support a dimensional rather than a dichotomous differentiation between BPD and cluster-C personality disorder regarding emotional sensitivity and emotional regulation of social stimuli. PMID- 29252165 TI - Disrupted coupling of large-scale networks is associated with relapse behaviour in heroin-dependent men. AB - BACKGROUND: It is unknown whether impaired coupling among 3 core large-scale brain networks (salience [SN], default mode [DMN] and executive control networks [ECN]) is associated with relapse behaviour in treated heroin-dependent patients. METHODS: We conducted a prospective resting-state functional MRI study comparing the functional connectivity strength among healthy controls and heroin-dependent men who had either relapsed or were in early remission. Men were considered to be either relapsed or in early remission based on urine drug screens during a 3 month follow-up period. We also examined how the coupling of large-scale networks correlated with relapse behaviour among heroin-dependent men. RESULTS: We included 20 controls and 50 heroin-dependent men (26 relapsed and 24 early remission) in our analyses. The relapsed men showed greater connectivity than the early remission and control groups between the dorsal anterior cingulate cortex (key node of the SN) and the dorsomedial prefrontal cortex (included in the DMN). The relapsed men and controls showed lower connectivity than the early remission group between the left dorsolateral prefrontal cortex (key node of the left ECN) and the dorsomedial prefrontal cortex. The percentage of positive urine drug screens positively correlated with the coupling between the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex, but negatively correlated with the coupling between the left dorsolateral prefrontal cortex and dorsomedial prefrontal cortex. LIMITATIONS: We examined deficits in only 3 core networks leading to relapse behaviour. Other networks may also contribute to relapse. CONCLUSION: Greater coupling between the SN and DMN and lower coupling between the left ECN and DMN is associated with relapse behaviour. These findings may shed light on the development of new treatments for heroin addiction. PMID- 29252167 TI - Pharmacological management of neuropsychiatric symptoms in patients with major neurocognitive disorders. PMID- 29252166 TI - Meta-analysis of central and peripheral gamma-aminobutyric acid levels in patients with unipolar and bipolar depression. AB - BACKGROUND: Many studies have measured central and peripheral gamma-aminobutyric acid (GABA) levels in patients with depression. We performed a meta-analysis to provide an objective overview of GABA changes in those with unipolar or bipolar depression. METHODS: After a systematic database search, original data were extracted with the help of seminal authors to calculate standardized mean differences. We compared GABA levels between patients with current major depressive episodes and controls, between euthymic patients and controls, and in patients before and after treatment. We performed meta-regressions to explore the influence of demographic and clinical variables on GABA significant mean differences. RESULTS: For unipolar depression, central and peripheral GABA levels were diminished in currently depressed patients, but normal in euthymic patients, compared with the healthy controls. For bipolar disorder, GABA levels were diminished in medication-free patients, but seemed to be normalized in medicated patients, compared with the healthy controls. We found no significant association with demographic or clinical variables. LIMITATIONS: There was a great heterogeneity across studies, probably because of the substantial variation of clinical characteristics in the included samples. Many subanalyses were performed to assess how the diagnosis, medications, or the type of measurements of peripheral or central GABA levels may affect the main results. CONCLUSION: The GABA levels evolved differentially in patients with unipolar and bipolar disorders. Our results suggest that GABA levels could represent a biomarker of symptomatic states in patients with unipolar disorder and would be normalized by mood stabilizers in those with bipolar disorder. PMID- 29252168 TI - Clozapine, elevated heart rate and QTc prolongation. PMID- 29252169 TI - Epidemiology of Pemphigus in Turkey: One-year Prospective Study of 220 Cases. AB - Pemphigus is a group of rare and life-threatening autoimmune blistering diseases of the skin and mucous membranes. Although they occur worldwide, their incidence shows wide geographical variation, and prospective data on the epidemiology of pemphigus are very limited. Objective of this work is to evaluate the incidence and epidemiological and clinical features of patients with pemphigus in Turkey. All patients newly diagnosed with pemphigus between June 2013 and June 2014 were prospectively enrolled in 33 dermatology departments in 20 different provinces from all seven regions of Turkey. Disease parameters including demography and clinical findings were recorded. A total of 220 patients were diagnosed with pemphigus during the 1-year period, with an annual incidence of 4.7 per million people in Turkey. Patients were predominantly women, with a male to female ratio of 1:1.41. The mean age at onset was 48.9 years. Pemphigus vulgaris (PV) was the commonest clinical subtype (n=192; 87.3%), followed by pemphigus foliaceus (n=21; 9.6%). The most common clinical subtype of PV was the mucocutaneous type (n=83; 43.2%). The mean Pemphigus Disease Area Index was 28.14+/-22.21 (mean +/- Standard Deviation). The incidence rate of pemphigus in Turkey is similar to the countries of South-East Europe, higher than those reported for the Central and Northern European countries and lower than the countries around the Mediterranean Sea and Iran. Pemphigus is more frequent in middle-aged people and is more common in women. The most frequent subtype was PV, with a 9-fold higher incidence than pemphigus foliaceus. PMID- 29252170 TI - HLA-E*0101/0103X is Associated with Susceptibility to Pemphigus Vulgaris: A Case control Study. AB - Pemphigus vulgaris (PV) is a life-threatening, autoimmune blistering disease of the skin and mucous membranes. The relationship between PV and human leukocyte antigen (HLA) has been studied in several reports. Previous reports have demonstrated that HLA-E polymorphisms may have a role in the susceptibility to various autoimmune diseases. Our aim was to evaluate the role of HLA-E gene polymorphisms in the pathogenesis of PV in a Turkish population. A total of 49 patients with PV and 50 healthy subjects were enrolled into the study. We sequenced and analyzed the HLA-E gene from genomic DNA obtained from peripheral blood samples of the study groups. HLA-E haplotyping was performed by Sanger sequencing of PCR products of the HLA-E gene and HLA-E alleles determined by using SeqScape(r) software according to the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System. The frequency of the HLA E*0101/*0103X genotype in male patients with PV was found to be significantly higher than in men in the control group (P=0.023). In addition, the frequency of the HLA-E*0103X/*0103X genotype was significantly lower in patients with PV than the control group (P=0.040). We also detected that the frequency of the HLA E*0101/*0103X genotype in patients with mucocutaneous type PV and the frequency of the HLA-E*0101/*0101 genotype in patients with mucosal type PV was significantly higher than those in other types of PV (P=0.001 and P=0.006). The results of this study indicate that carrying the HLA-E*0101/0103X genotype may increase the risk of PV in male patients. PMID- 29252171 TI - Spectrum of Autoimmune Bullous Diseases in Northern Greece. A 4-year Retrospective Study and Review of the Literature. AB - Bullous Diseases Unit at the 2nd Department of Dermatology and Venereology, Aristotle University of Thessaloniki was founded with the aim to provide the optimal diagnostic approach and treatment of patients with autoimmune bullous diseases (AIotaBD). We processed all AIBD files of patients diagnosed from 2011 to 2014 in order to record all epidemiological data and therapeutic manipulations during monitoring. 57 patients were diagnosed with intraepidermal and 62 with subepidermal bullous diseases. There were 51 cases (89%) of pemphigus vulgaris (PV) and 6 (11%) of pemphigus foliaceus (PF), whereas 45 (73%) patients were diagnosed with bullous pemphigoid (BP), 9 (14%) with mucous membrane pemphigoid (MMP), 3 (5%) with pemphigoid gestationis (PG), 3 (5%) with linear IgA dermatosis (LAD), 1 (2%) with epidermolysis bullosa aquisita (EBA), and 1 patient with an undefined subepidermal AIBD. The mean age of patients within the pemphigus spectrum was 57 years. In the pemphigoid spectrum, the mean age was 72 years. Comorbidities were reported with increasing frequency, as well as treatment options other than systemic corticosteroids, such as adjuvant immunosuppressive agents, which were used to achieve complete remission. This is a report from a tertiary AIBD Referral Center in northern Greece. Our data from a 4-year period contribute to the completion of the global geographic incidence map of AIBD. PMID- 29252172 TI - The Value of the BIOCHIP Mosaic-based Indirect Immunofluorescence Technique in the Diagnosis of Pemphigus and Bullous Pemphigoid in Turkish Patients. AB - Autoimmune bullous diseases (ABD) are a rarely seen group of diseases, of which pemphigus and bullous pemphigoid (BP) are the major groups. Diagnosis is generally based on the combination of clinical features, histopathologic and immunofluorescence (IF) findings, and/or enzyme-linked immunosorbent assay (ELISA). Aims of the work were to determine the value of the innovative BIOCHIP mosaic-based indirect IF technique in the diagnosis of pemphigus and BP in Turkish patients. A total of 63 patients (45 pemphigus and 18 BP) in the active phase of the disease alongside 35 healthy controls were included in the study. All sera from patients and controls were tested using the BIOCHIP technique, and the results were compared with direct IF and/or ELISA. The sensitivity and specificity of this new technique were calculated for validity. The sensitivity and specificity of BIOCHIP in the diagnosis of pemphigus was found to be 91.1% and 97.1%, respectively. In detection of anti-Dsg1 and anti-Dsg3 autoantibodies, the correlation between BIOCHIP and ELISA was statistically significant (P<0.01). The sensitivity and specificity of BIOCHIP in the diagnosis of BP was found to be 94.4% and 94.3%, respectively. In detection of anti-BP180 autoantibodies, the correlation between the BIOCHIP and ELISA was statistically significant (P<0.01). The main limitations are the relatively low number of samples and testing with only one dilution. Direct IF was not performed in all patients, and the low rate of DIF positivity also can be a bias in comparison with BIOCHIP. The new BIOCHIP technique is a highly sensitive and specific tool in the diagnosis of pemphigus and BP. PMID- 29252173 TI - Risk of Attention-Deficit/Hyperactivity Disorder in Children with Atopic Dermatitis. AB - Atopic dermatitis (AD) is a common, chronic, inflammatory, pruritic skin disorder that affects up to 20% of the children in Western countries. Attention Deficit/Hyperactivity disorder (ADHD) has been reported to be more frequent in children with AD. The purpose of this study was to explore the risk for ADHD in our population of patients with AD. A population-based case-control study, using the medical database of Clalit Health Services (CHS), the largest healthcare provider organization in Israel. The study included 840 patients with AD between the age of 0-18 years and 900 age and gender frequency-matched patients without AD. The proportion of ADHD in patients with AD was 7.1% as compared to 4.1% in controls. ADHD was more frequent in boys with AD (9.6% vs. 5.2%, odds ratio (OR) 1.9, 95% confidence interval (CI) 1.1-3.2) but not in girls with AD (4.6% vs. 2.9% OR 1.5). In multivariate analyses, AD was associated with ADHD (OR 2.1, 95% CI 1.3-3.4). The current study demonstrated an association between AD and ADHD. This report and earlier observations emphasize the need for detection and treatment of ADHD in atopic patients. PMID- 29252174 TI - The Impact of Changes in Psoriasis Area and Severity Index by Body Region on Quality of Life in Patients with Psoriasis. AB - Psoriasis severity varies by body region, with each affected region having a different impact on patient quality of life (QoL). The aim of this study was to assess the impact of changes in the Psoriasis Area and Severity Index (PASI) scores by body region on QoL in patients with psoriasis after treatment. A total of 100 patients with psoriasis were recruited to the study. All patients completed the generic EuroQol-5D instrument and two specific QoL measures, Dermatology Life Quality Index (DLQI) and Psoriasis Disability Index (PDI) at the beginning of the study, and 50 patients successfully completed the same questionnaires four weeks after the end of the treatment. Clinical severity was assessed using PASI total score and PASI body region (head, trunk, arms, and legs) scores. QoL improved after treatment, and PASI improvements on visible body regions (head, legs, and arms) showed significant correlation with the most sub areas of the Visual Analog Scale (EQ VAS), DLQI, and PDI. Multiple linear regression analysis revealed that PASI improvement (particularly on the head), sex, age, and disease duration were predictors of QoL score changes for most domains of the three instruments. Improvement of psoriasis in visible body regions has an appreciable influence on QoL improvement, and may positively affect treatment success in patients with psoriasis. PMID- 29252175 TI - Real-Time Investigation of Skin Blood Flow Changes Induced by Topical Capsaicin. AB - Capsaicin induces a localized inflammatory process known as neurogenic inflammation upon its topical administration on the skin, due to the release of various neuropeptides from the cutaneous sensory nerve endings. In this study, we investigated real-time skin blood flow changes that occur in neurogenic inflammation induced by topical capsaicin by means of in vivo reflectance confocal microscopy. 27 healthy subjects (15 women and 12 men, mean age +/- Standard Deviation: 22.62+/-4.47) were administered topical capsaicin solution (Capsaicin group) or immersion oil (Control group) on the dorsal side of their non-dominant hand. At different time intervals during administration (0, 10, 25, and 40 minutes), cutaneous blood flow was evaluated using reflectance confocal microscopy and compared between the two groups. Blood flow values were higher during topical capsaicin, with significant increase after 25 (P=0.0160, Dunn's multiple comparisons test) and 40 minutes (P=0.0132, Dunn's multiple comparisons test) after its administration when compared with the initial 0 min value. Furthermore, the differences in the blood flow changes between the two groups were significant at 25 min (P=0.0182, Dunn's multiple comparisons test) and 40 min (P=0.0296, Dunn's multiple comparisons test) after capsaicin administration. Reflectance confocal microscopy allows in vivo, real-time evaluation of cutaneous blood flow changes within the capsaicin-induced inflammation, and this method might serve as a research model to test neurovascular reactivity. PMID- 29252176 TI - Bilateral Sacroiliitis Confirmed with Magnetic Resonance Imaging during Isotretinoin Treatment: Assessment of 11 Patients and a Review of the Literature. AB - In recent years, several cases pointing at sacroiliitis due to isotretinoin treatment have been reported, but a causal association remains unproven. The aim of this study was to assess the characteristics of patients in whom bilateral sacroiliitis was detected while using isotretinoin treatment for acne and to review previous sacroiliitis cases treated with isotretinoin. In total, 11 patients who were diagnosed with sacroiliitis during isotretinoin treatment were identified, and patient characteristics were noted. Patients were classified according to magnetic resonance imaging (MRI) findings. The 11 patients (3 men and 8 women) ranged in age from 16 to 37 years (mean age 24.27 years). All the 11 (100.00%) patients presented with hip pain, which in 3 (27.27%) patients started in the first month, in 3 (27.27%) in the second, in 2 (18.18%) in the third, in 2 (18.18%) in the fourth, and in 1 (9%) in the fifth. HLA-B27 (human leucocyte antigen) was negative in all cases. MRI findings confirmed mild bilateral sacroiliitis in 5 (45.45%) patients, moderate in 3 (27.27%), and severe in 2 (18.18%). Although our study included a small number of cases, it indicates a strong association between isotretinoin and sacroiliitis. PMID- 29252177 TI - Aquagenic Urticaria: A Perplexing Physical Phenomenon. AB - Aquagenic urticaria (AQ) is a rare physical urticaria induced by contact with water. It may be distinctive clinically, evident as 1-2 mm folliculopapular urticaria, a pattern also characteristic of cholinergic urticaria. AQ has a truncal and upper extremity distribution within 20-30 minutes after contact with water, regardless of its temperature or source. AQ is usually symptomatic with mild to severe pruritus and a burning sensation. The mechanism by which water produces mast cell degranulation and histamine release remains unclear. We review its clinical presentation, diagnostic parameters, differential diagnosis, and treatment. PMID- 29252178 TI - Long Lasting Allergic Patch Test Reactions: A Literature Review. AB - Long-lasting allergic patch test reactions (LLAPTR) are those in which the clinical features of palpable erythema are still present at the site of a positive allergic patch test reaction 14 or more days after application of the allergen. LLAPTR have been described for a wide range of contact allergens, many of these included in the baseline patch test series. LLAPTR are far from uncommon; they occur in consecutive patients with positive patch tests to baseline allergens with frequency up to 17.9% of the total reactions. Patch test reactions persisting for a very long time (up to several months after the test) have been described, the most frequent ones being those induced by gold salts. The pathomechanisms of LLAPTR have not been clarified, but may hypothetically involve a constant antigen stimulation and/or a defect in cell-mediated immunity down-regulation. Host-related factors significantly associated with LLAPTR are, according to some studies, a strong initial patch test response, older age, and atopy. No significant sex differences have been observed in the frequency of LLAPTR. PMID- 29252179 TI - Bevacizumab-associated Sudden Onset of Multiple Monomorphic Comedones on the Scalp Successfully Treated with 30% Salicylic Acid Peels. AB - Bevacizumab is a humanized monoclonal antibody against vascular endothelial factor (VEGF) that targets tumor cell angiogenesis and proliferation. Although it is usually well tolerated, many side-effects have been reported. These include hypertension, bleeding, and thromboembolic events among others. Drug-associated cutaneous adverse effects are less common and include itching, exfoliative dermatitis, and acneiform eruptions. A man with bevacizumab-associated monomorphic skin eruption successfully was treated with 30% salicylic acid peels. To the author's knowledge, this is the first report of open comedones with no further inflammatory acne lesions that developed in a patient treated with bevacizumab. Complete remission of the rash was achieved after performing 30% salicylic peels, and the patient continued the chemotherapy as planned with no need of either dose reduction or discontinuation of bevacizumab. PMID- 29252180 TI - Folliculotropic Mycosis Fungoides Associated with Autoimmune Hepatitis. AB - Dear Editor, the association between lymphomas and autoimmune manifestations, as well as the prevalence of the cases of coexistent lymphomas and autoimmune conditions, has not been completely established (1-3). Since cutaneous T-cell lymphoma (CTCL) cases are rare, any hypothesis can only be based on case reports or small case series. We present the case of a male patient with folliculotropic mycosis fungoides (FMF) and synchronous autoimmune hepatitis (AIH) with extremely high levels of cancer antigen 19-9 (CA 19-9). The patient was under the supervision of a multidisciplinary team consisting of dermatologists, hepatologists, and hematologists. The patient died 15 months after the diagnoses of FMF and AIH were established and 3.5 years after the first skin changes. Based on our knowledge and search of medical databases, this is the first case of AIH in a patient with CTCL, i.e. with MF. A 53-year-old male patient was admitted to our Dermatology Clinic in September 2014 after being briefly treated with acitretin. During hospitalization, he was diagnosed with FMF, autoimmune hepatitis, and newly developed diabetes mellitus. At the time of hospital admission, about 70 percent of the surface of the skin was affected, infiltrated with numerous cysts on the face, neck, and upper thorax. The patient also presented with alopecia affecting most of the scalp, loss of eyebrows and eyelashes (Figure 1), and complained of intensive itching. The clinical presentation suggested the diagnosis of FMF, which was later confirmed based on histological (Figure 2) and immunohistochemical (Figure 3) findings. The histochemical staining method PAS-Alcian did not reveal mucin deposits. Immunohistochemical findings revealed tumor cells to show aberrant T immunophenotypes - CD3+, CD2+, CD5-, CD7-, CD4+, CD8-, CD30-. Due to elevated serum conjugated bilirubin and extremely high levels of hepatocellular and cholestatic liver enzymes, the patient was transferred to the Gastroenterology Department. Diagnosis of AIH was established based on the liver biopsy (highly active autoimmune hepatitis) and the exclusion of viral etiology, drug-induced hepatotoxicity, and inherited metabolic disorders of the liver. CA 19-9 level was extremely high (4475.0; RR <37.0 ug/L). In March 2015, CA 19-9 decreased to 365.3. In April 2015, erythroderma and small isolated tumors on the trunk and extremities developed. The patient was treated with RE-PUVA and radio-therapy. In June 2015, due to systemic symptoms, the patient was started on PUVA with IFNalpha. In November 2015, erythroderma persisted together with larger and ulcerated tumors. The patient was treated at the Hematological Department with two cycles of cyclophosphamide, vincristine, doxorubicin, and methylprednisolone. From March 2015, the patient was continuously treated with ursodeoxycholic acid, prednisolone, azathioprine, analog insulin, and allopurinol. MSCT revealed lymphoma infiltrates in the liver, spleen, and peritoneum (gross tumors). The immunophenotypic analysis of the cells in ascites revealed atypical lymphocytes with convoluted nuclei - LCA+, CD3+, CD20-. The patient died in December 2015 due to sepsis with febrile neutropenia. Before death, he suffered from candidiasis and toxic liver damage due to fluconazole. FMF is an aggressive MF variant with infiltration of lymph nodes, visceral involvement at an earlier stage, and decreased life expectancy (4). Autoimmune hepatitis (AIH) is still an unclear progressive liver disease of unknown etiology which features hypergammaglobulinemia, detectable autoantibodies, and interface hepatitis (5). Being exposed to xenobiotic (acitretin) with consequent liver damage could lead to the formation of self-antigens to which the patient's immune system might have sensitized, and the autoimmune attack continued (6). Slightly elevated CA 19-9 levels in autoimmune hepatitis were reported by other authors (7-9). It should be noted that the liver involvement with atypical lymphocytes can be diffuse without any detectable nodules on a CT scan (4). Soluble liver antigen and liver-pancreas antibodies, together with CA 19-9, need to be implemented as routine diagnostic tools to rationalize the usage of tumor markers in day-to-day practice as well in diagnosis of AIH (10). PMID- 29252181 TI - Nicolau's syndrome: A rare but preventable iatrogenic disease. AB - Dear Editor, Nicolau's syndrome, also called embolia cutis medicamentosa or livedoid dermatitis, is a rare injection site reaction characterized by immediate intense pain at the injection site followed by erythema and a hemorrhagic patch with a livedoid reticular pattern after injections of non-steroidal anti inflammatory drugs (NSAIDS), antiepileptics, antibiotics, antihistaminics, corticosteroids, etc. (1). To the best of our knowledge, only one case of Nicolau's syndrome has been reported after the use of triamcinolone acetonide. Herein we report two cases of Nicolau's syndrome caused by intramuscular injections of triamcinolone acetonide and diclofenac sodium, respectively. CASE 1 A 24-year-old male patient presented with severe pain and bluish discoloration of the right arm for 2 days, which he had noticed shortly after receiving an intramuscular injection of triamcinolone for recurrent episodes of urticaria by a local practitioner in the right deltoid region. On examination, there was a livedoid pattern of non-blanchable, violaceous discoloration extending from the deltoid area to the distal third of the forearm with associated induration (Figure 1, a, b). The local area was warm and tender to the touch. There was no regional lymphadenopathy, and the rest of the examination was normal. The patient's platelet count, bleeding and clotting times, prothrombin time, and international normalized ratio (INR) were unremarkable. There was no previous history of any bleeding disorder. The patient denied any intake of drugs like aspirin, warfarin, etc. Subsequently, the patient developed an ulcer on the forearm, which was managed by topical and systemic antibiotics to prevent any secondary infection of the wound. CASE 2 A 40-year-old female patient presented with complaints of pain and discoloration of the left gluteal region after receiving an intramuscular injection of diclofenac sodium for her arthralgia. A large ecchymotic patch with reticular borders was found on the gluteal region, extending to the lateral aspect of thigh (Figure 2). It was tender to the touch, non-indurated, and the local temperature was raised. There was no regional lymphadenopathy. No other abnormality was detected on examination. All routine investigations were within normal limits. Platelet count, bleeding, clotting and prothrombin times, and international normalized ratio (INR) were within normal limits. The lesions resolved within few weeks without any complications. Nicolau syndrome was first described in the early 1920s by Freudenthal and Nicolau as an adverse effect of using intramuscular injections of bismuth salts in the treatment of syphilis. Since then, several case reports of this disease occurring after intramuscular, intra-articular, intravenous, and subcutaneous injections have appeared in the literature associated with a variety of drugs like NSAIDs, vitamin K, penicillin, antihistamines, corticosteroids, local anesthetics, vaccines, polidocanol, and pegylated interferon alpha (1). The pathogenesis of Nicolau syndrome is unknown, though intra and periarterial injection of the drug is a possible cause. Stimulation of the sympathetic nerve due to periarterial injection causes spasms and consequent ischemia. Inadvertent intra-arterial injections may cause emboli and occlusion. A lipophilic drug may penetrate the vessel and produce physical occlusion like fat embolism. Cytotoxic drugs may produce perivascular inflammation and ischemic necrosis. NSAIDs are believed to additionally induce ischemic necrosis due to their inhibition of cyclooxygenase and, consequently, prostaglandins (2). The clinical features of the disease have been divided into three phases in a review by Kim et al. (3). The authors describe an initial phase characterized by intense pain with subsequent erythema. This is followed 1-3 days later by an acute phase, when an indurated, tender plaque with livedoid pattern develops. The final phase occurs between 5 days and 2 weeks later. Necrosis ensues in this stage, with possible ulceration. Diagnosis is chiefly clinical, and histopathology shows necrotic changes and vascular thrombosis. However, a biopsy was not performed in our cases because both lesions were painful. Management strategies are variable and range from conservative management with analgesics and antibiotics to active surgical debridement (4). Complications include deformities, contractures or even death. The patient in our first case developed ulceration which healed normally, while the second case resolved without any complications. Nicolau syndrome can be avoided by precautions such as aspirating the needle before injecting to check for blood, use of Z-track injection technique, proper site of injection, avoiding large doses at a single site, and regular change of sites if multiple injections are to be given (5). Nicolau syndrome is a rare disease. There are a few case reports of it occurring after diclofenac injection (1-5). We could only find one case report of this syndrome after intramuscular injection (IM) of triamcinolone in a patient with lichen planus (3), and our case is the second reported case of this syndrome as a result of triamcinolone acetonide injection, which adds to the significance to the present article. PMID- 29252182 TI - Heart Rate Variability in Patients with Psoriasis Treated with Etanercept Therapy. AB - In their article, Potenza et al. evaluated the influence of etanercept therapy on autonomic cardiovascular regulation in young patients with moderate-to-severe psoriasis without cardiovascular risk factors by measuring the time domain and frequency domain heart rate variability (HRV) parameters from 5-minute electrocardiogram (ECG) recordings (1). The authors used low frequency (LF), high frequency (HF) power, and LF/HF ratio as indices of frequency domain HRV and standard deviation of normal-to-normal intervals (SDNN); the mean root square of the sum of the squares of differences between consecutive R-R intervals (RMSSD) was used as the index of time domain HRV. The authors found that 12-week etanercept therapy resulted in non-significant alterations in LF, HF, LF/HF ratio, SDNN, and RMSSD values. They concluded that treatment with etanercept in patients with moderate-to-severe psoriasis does not affect cardiovascular autonomic regulation and cardiovascular risk. HRV is a well-established, rapid, and noninvasive tool for the evaluation of the modulation of the cardiac autonomic nervous system. HRV may also be a sensitive test for the detection of the cardiotoxicity of some chemotherapeutic agents (2). Methods for quantifying HRV are categorized as time domain and spectral or frequency domain. Traditionally, spectral parameters such as LF, HF, and total power have been analyzed from standard 5-minute ECG segments, whereas most laboratories require at least 18 hours of valid data to measure time domain parameters such as SDNN and RMSSD in a 24-hour recording. In addition, the measurement of LF and HF power components is usually given in absolute values of power (milliseconds squared) or percentage. LF and HF can also be calculated in normalized units, which represent the relative value of each power component in proportion to the total power. The representation of LF and HF in normalized units underlies the controlled and balanced behavior of the two branches of the autonomic nervous system. Moreover, the normalization tends to minimize the effect of the changes in total power on the values of LF and HF components. Thus, unnormalized units should be presented in conjunction with normalized versions of the same variables whenever possible in order to completely describe the distribution of power in spectral components (2). PMID- 29252183 TI - Bullous Pemphigoid Masquerading as Erythema Annulare Centrifugum. AB - Dear Editor, Bullous pemphigoid (BP), a relatively common autoimmune blistering disease in the elderly, is characterized by large, tense bullae on urticarial, erythematous, or normal skin. However, atypical BP with polymorphic clinical presentations is rarely encountered, leading to misdiagnosis and delayed treatments (1). BP with lesions resembling erythema gyratum repens or figurate erythema has been regarded as a paraneoplastic phenomenon (1). Herein we report a case with erythema annulare centrifugum-like presentation of BP without evidence of underlying malignancy. A 64-year-old woman first presented with multiple large, tense bullae on the trunk and four extremities. She was diagnosed with BP according to the typical clinical, histopathological, and direct immunofluorescence findings. There were no annular lesions at that time. After a treatment course of systemic corticosteroids and azathioprine, the cutaneous symptoms were controlled. One year after discontinuing her medications, a pruritic bullous eruption reappeared with several annular erythematous plaques (Figure 1, a). The patient reported no mucosal involvement and took no new medications before the onset of skin lesions. On physical examination, multiple circular and arcuate erythematous lesions with slightly raised borders were seen on the trunk and both legs. Some erosions and tiny vesicles were noted on the erythematous edges. There were no other systemic symptoms or abnormalities. Laboratory studies, including complete blood count, liver and renal function tests, electrolytes, antinuclear antibody, complement levels, anti-Ro and anti-La antibodies, urine routine, stool routine, and chest X-ray, were normal. The biopsy specimen obtained from the rim of the annular lesions revealed slight vacuolar change at the dermoepidermal junction and perivascular and interstitial lymphocytic infiltration with numerous eosinophils in the upper dermis (Figure 1, b). Direct immunofluorescence showed linear deposits of immunoglobulin G (IgG) and C3 along the basement membrane (Figure 1, c). Histopathological features and immunofluorescence examinations were consistent with BP. There was no evidence of hematological or solid malignancy from further imaging and laboratory testing. The patient was started on oral prednisolone 30 mg/day and azathioprine 150 mg/day, with significant improvement over the following month. Complete regression of all skin lesions was achieved two months later, so the prednisolone dose was gradually tapered and then ceased. Under maintenance monotherapy of azathioprine 100 mg/day, there were no signs of BP recurrence or malignant disease during the one-year follow-up period. The annular erythema variant of BP is extremely rare. Therefore, in this case, erythema multiforme, subacute cutaneous lupus erythematosus, erythema annulare centrifugum, and urticarial vasculitis should be considered in the clinical differential diagnoses. Pathological features and immunofluorescence results can clearly rule out these possibilities. Until now, only 13 cases of BP presenting as annular erythema had been documented in the English literature, described as figurate erythema-like, erythema gyratum repens-like, or erythema annulare centrifugum-like manifestations (1-3). An association with internal malignancy in patients with these types of lesions had been reported (1). Nevertheless, as in most previous case reports (3), malignant diseases were not found in our patient. The precise mechanism of the annular erythema form of BP is unknown. Some authors considered it a variant of pre-bullous phase lesions, usually presenting as itchy erythematous patches or urticarial plaques (4). Based on this case, however, this assumption is less likely because the annular, erythema annulare centrifugum-like skin lesions appeared one year after the initial onset of bullous eruption, and simultaneously with the exacerbation of the bullous phase of BP. The exact pathogenesis of annular BP may be similar to that in erythema annulare centrifugum. Further investigations are warranted to clarify this issue. It should be noted that an erythema annulare centrifugum-like or figurate erythema like manifestation in the absence of underlying malignancy can occasionally be a feature of BP. Making the correct diagnosis may be difficult if there is no concurrent bullous presentation. Clinicians should be vigilant for the development of this type of BP. The histological and direct immunofluorescence findings and the detection of circulating autoantibodies by indirect immunofluorescence or enzyme-linked immunosorbent assay remain crucial tools for establishing a definitive diagnosis. PMID- 29252185 TI - LncRNA KCNQ1OT1 ameliorates particle-induced osteolysis through inducing macrophage polarization by inhibiting miR-21a-5p. AB - This study aimed to investigate the mechanism of lncRNA-KCNQ1OT1 on macrophage polarization to ameliorate particle-induced osteolysis. We used polymethylmethacrylate (PMMA) to induce primary bone marrow-derived macrophages (BMMs) obtained from mice and the RAW264.7 cell line, and found that the tumor necrosis factor-alpha (TNF-alpha) concentration and inducible nitric oxide synthase (iNOS) expression was increased, while interleukin (IL)-10 concentration and Arg1 expression were decreased in PMMA-induced cells. KCNQ1OT1 and IL-10 expression were both suppressed and miR-21a-5p expression was promoted in PMMA induced cells. Overexpression of KCNQ1OT1 reversed the effect of PMMA on RAW264.7 cells, such as the reduced TNF-alpha concentration and iNOS expression, and increased IL-10 concentration and Arg1 expression in PMMA-induced cell transfected with pcDNA-KCNQ1OT1. The luciferase assay confirmed that IL-10 is a target of miR-21a-5p. RNA immunoprecipitation (RIP) and RNA pull-down experiments demonstrated that KCNQ1OT1 functions as a miR-21a-5p decoy. Thus, lncRNA KCNQ1OT1 induces M2 macrophage polarization to ameliorate particle-induced osteolysis by inhibiting miR-21a-5p. PMID- 29252184 TI - Quiescence unveils a novel mutational force in fission yeast. AB - To maintain life across a fluctuating environment, cells alternate between phases of cell division and quiescence. During cell division, the spontaneous mutation rate is expressed as the probability of mutations per generation (Luria and Delbruck, 1943; Lea and Coulson, 1949), whereas during quiescence it will be expressed per unit of time. In this study, we report that during quiescence, the unicellular haploid fission yeast accumulates mutations as a linear function of time. The novel mutational landscape of quiescence is characterized by insertion/deletion (indels) accumulating as fast as single nucleotide variants (SNVs), and elevated amounts of deletions. When we extended the study to 3 months of quiescence, we confirmed the replication-independent mutational spectrum at the whole-genome level of a clonally aged population and uncovered phenotypic variations that subject the cells to natural selection. Thus, our results support the idea that genomes continuously evolve under two alternating phases that will impact on their size and composition. PMID- 29252186 TI - How human serum albumin recognizes DNA and RNA. AB - We show here for the first time that HSA possesses two nucleic acid-(NA) binding sites and we estimated the relative contributions of the nucleotide links of (pN)n to their total affinity for these binding sites with higher and lower affinity for NAs. The minimal ligands of these binding sites are orthophosphate (Kd=3.0 and 20.0 mm), various dNMPs (5.6-400 MUm and 0.063-18 mm) and different rNMPs (4.9-30 MUm and 14-250 MUm). Maximal contribution to the total affinity of all NAs to the first and second sites was observed for one nucleotide and was remarkably lower for three additional nucleotide units of (pN)n (n=1-4) with a significant decrease in the contribution at n=5-6, and at n>=7-8 all dependencies reached plateaus. For d(pA)n and r(pA)n a relatively gradual decrease in the contribution to the affinity at n=1-6 was observed, while several d(pN)n, demonstrated a sharp increase in the contribution at n=2-4. Finally, all (pN)n>10 demonstrated high affinity for the first (1.4-150 nm) and the second (80-2400 nm) sites of HSA. Double-stranded NAs showed significantly lower affinity comparing with single-stranded ligands. The thermodynamic parameters characterizing the specific contribution of every nucleotide link of all (pN)1-9 (DeltaG degrees ) to their total affinity for HSA were estimated. PMID- 29252187 TI - Bone plate-screw constructs for osteosynthesis - recommendations for standardized mechanical torsion and bending tests. AB - This paper follows up on a recent systematic review of test methods and parameters for biomechanical testing of bone plates and it is the first study that contains recommendations for standardized mechanical testing of bone plate screw constructs for osteosynthesis. Following the testing philosophy of ASTM F382 and ISO 9585, we have developed standardized quasi-static and dynamic testing methods for straight linear and anatomically shaped plates, including locked type and conventional systems. The test specification comprises torsion and bending tests along the implant axis and therefore modifies and extends the methods proposed by ASTM F382. We present specific test setups in order to determine product-specific characteristics of the mechanical construct, consisting of the bone plate with corresponding screws (such as construct stiffness, yield strength, ultimate strength and fatigue properties) under the condition that it is rigidly fixed to "healthy bone". We also address specific testing requirements that are important for the purpose of standardization, such as the positioning of the construct for testing or the number of screws in the diaphysis and metaphysis. Finally, we define the outcome parameters and associated failure criteria related to quasi-static and dynamic testing for comparative purposes. This paper does not intend to replace biomechanical testing of those devices under physiological loading conditions. PMID- 29252188 TI - Serum exosomal hnRNPH1 mRNA as a novel marker for hepatocellular carcinoma. AB - BACKGROUND: Distinctive exosomal contents could be useful for cancer diagnosis and prognosis. However, little is known about whether serum exosomal heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) mRNA is a satisfactory biomarker for hepatocellular carcinoma (HCC). METHODS: Two hundred and ninety-one participants divided into four age- and gender-matched groups, including a HCC group (n=88), a liver cirrhosis (LC) group (n=67), a chronic hepatitis B (CHB) group (n=68) and a healthy control group (n=68), were enrolled. Serum exosomal hnRNPH1 mRNA and GAPDH mRNA were measured using TaqMan real-time PCR, and the relative expression levels were calculated. Receiver operating characteristic (ROC) curves were constructed to evaluate the effectiveness of hnRNPH1 mRNA alone and in combination with alpha-fetoprotein (AFP) in the diagnosis of HCC. The correlation between hnRNPH1 mRNA levels and clinicopathological characteristics and overall survival (OS) in HCC was determined. RESULTS: The serum exosomal hnRNPH1 mRNA levels in HCC patients were remarkably higher than in the other groups (p<0.05). The hnRNPH1 mRNA discriminated HCC from CHB with an area under the ROC curve (AUC) of 0.865, with sensitivity of 85.2% and specificity of 76.5% at cut-off value of 0.670. The AUC for hnRNPH1 mRNA in combination with AFP was further improved. The exosomal hnRNPH1 mRNA levels in HCC patients were associated with the Child-Pugh classification, portal vein tumor emboli, lymph node metastasis, TNM stage and OS (p<0.05). CONCLUSIONS: These findings suggested that serum exosomal hnRNPH1 mRNA could be an effective marker for HCC in high HBV prevalence areas. PMID- 29252189 TI - Gender-partitioned patient medians of serum albumin requested by general practitioners for the assessment of analytical stability. AB - BACKGROUND: Recently, the use of separate gender-partitioned patient medians of serum sodium has revealed potential for monitoring analytical stability within the optimum analytical performance specifications for laboratory medicine. The serum albumin concentration depends on whether a patient is sitting or recumbent during phlebotomy. We therefore investigated only examinations requested by general practitioners (GPs) to provide data from sitting patients. METHODS: Weekly and monthly patient medians of serum albumin requested by GP for both male and female patients were calculated from the raw data obtained from three analysers in the hospital laboratory on examination of samples from those >18 years. The half-range of medians were applied as an estimate of the maximum bias. Further, the ratios between the two medians were calculated (females/males). RESULTS: The medians for male and female patients were closely related despite considerable variation due to the current analytical variation. This relationship was confirmed by the calculated half-range for the monthly ratio between the genders of 0.44%, which surpasses the optimum analytical performance specification for bias of serum albumin (0.72%). The weekly ratio had a half range of 1.83%, which surpasses the minimum analytical performance specifications of 2.15%. CONCLUSIONS: Monthly gender-partitioned patient medians of serum albumin are useful for monitoring of long-term analytical stability, where the gender medians are two independent estimates of changes in (delta) bias: only results requested by GP are of value in this application to ensure that all patients are sitting during phlebotomy. PMID- 29252190 TI - Spuriously low lymphocyte count associated with pseudoerythroblastemia in a patient with chronic lymphocytic leukemia treated with ibrutinib. PMID- 29252191 TI - Extra-analytical quality indicators - where to now? AB - A large body of evidence collected in recent years demonstrates the vulnerability of the extra-analytical phases of the total testing process (TTP) and the need to promote quality and harmonization in each and every step of the testing cycle. Quality indicators (QIs), which play a key role in documenting and improving quality in TTP, are essential requirements for clinical laboratory accreditation. In the last few years, wide consensus has been achieved on the need to adopt universal QIs and common terminology and to harmonize the management procedure concerning their use by adopting a common metric and reporting system. This, in turn, has led to the definition of performance specifications for extra analytical phases based on the state of the art as indicated by data collected on QIs, particularly by clinical laboratories attending the Model of Quality Indicators program launched by the Working Group "Laboratory Errors and Patient Safety" of the International Federation of Clinical Chemistry and Laboratory Medicine. Harmonization plays a fundamental role defining not only the list of QIs to use but also performance specifications based on the state of the art, thus providing a valuable interlaboratory benchmark and tools for continuous improvement programs. PMID- 29252192 TI - Scientific publishing in the "predatory" era. PMID- 29252194 TI - Preventing overdiagnosis in mammography screening - a public health perspective. AB - Prevention and management of breast cancer in order to provide high quality health care is an important public health issue. The existence of overdiagnosis for breast-cancer was controversial for a long time but is now broadly accepted. Overdiagnosis is defined as the diagnosis of "disease" that will never cause symptoms or death during a patient's ordinarily expected lifetime. Estimates of the overdiagnosis rate for breast cancer range up to 54% of screen-detected localized tumors. New approaches, such as the identification of high risk groups or primary prevention approaches could be more relevant from the public health perspective. PMID- 29252193 TI - Role of CYP4F2, CYP2C19, and CYP1A2 polymorphisms on acenocoumarol pharmacogenomic algorithm accuracy improvement in the Greek population: need for sub-phenotype analysis. AB - BACKGROUND: We have earlier developed a pharmacogenomic algorithm for acenocoumarol dose prediction in Greek patients that included CYP2C9/VKORC1 genetic information. This study aims at analyzing the potential effect of CYP4F2, CYP2C19, and CYP1A2 gene polymorphisms on acenocoumarol dose requirements and at further improving the Greek-specific pharmacogenomic algorithm. METHODS: A total of 205 Greek patients taking acenocoumarol (140 who reached and 65 who did not reach stable dose), participants of acenocoumarol EU-PACT trial, were included in the study. CYP4F2, CYP2C19, and CYP1A2 polymorphisms were genotyped by use of the PCR-RFLP method. All patients were previously genotyped for CYP2C9/VKORC1 polymorphisms. RESULTS: In the pooled sample, CYP4F2, CYP2C19, and CYP1A2 polymorphisms do not affect independently acenocoumarol dose requirements. For CYP4F2, significant effects were found on patients' ability to reach stable dose and on acenocoumarol dose requirements when CYP2C9/VKORC1 sub-phenotypes were analyzed. Specifically, when the patients were stratified according to their CYP2C9/VKORC1 functional bins, in sensitive responders, CYP4F2*3 allele carriers (CYP4F2 *1/*3 and *3/*3 genotypes) were more frequent in the patient group who reached stable dose (p=0.049). Additionally, in CYP2C9 intermediate metabolizers (IMs), after adjusting for age, weight, and VKORC1 genotypes, CYP4F2 genotypes were significantly associated with acenocoumarol stable dose (beta: 0.07; 95% CI: 0.006-0.134; p=0.033). CONCLUSIONS: CYP4F2 gene shows a prominent weak association with acenocoumarol dose requirements. Sub-phenotype analysis is potentially important in determining additional gene polymorphisms that are associated with acenocoumarol dose requirements. PMID- 29252195 TI - Interest of systematic tomosynthesis (3D mammography) with synthetic 2D mammography in breast cancer screening. AB - Full field digital mammography (FFDM) is the current pillar of breast cancer screening program. However, the emerging technique digital breast tomosynthesis (DBT) has demonstrated a significant increase in the sensibility of cancer detection in several large cohort trials. DBT is particularly helpful for young patients, dense breasts and soft masses due to its ability to reduce overlapping of tissue. In such a population of women, radiologists are more confident and the recall rates are reduced together with a higher positive predictive value. To reduce the breast absorbed doses of screened women and facilitate the workflow, a synthetized two-dimensional (2D) digital mammography (sDM) is obtained from DBT to replace the FFDM. No significant differences regarding detection of anomalies have been reported with respect to FFDM. These results validate a modern strategy for breast cancer screening supported by two views of DBT with sDM. In terms of mean absorbed doses, this strategy is around 1.5 mGy/view and almost equivalent to FFDM. In Europe, major limitations to such evolution are public health policies especially agreements and reimbursement for the technique being used in organized screening. PMID- 29252196 TI - Sibling cigarette smoking and peer network influences on substance use potential among adolescent: a population based study. AB - Background Peer and parental substance use are established predictors for substance use among adolescent, little is known about influence of sibling cigarette smoking and its interaction with peer network on substance use potential that can introduce an important way for substance use prevention programs. Objective The aim of present study was to explore the association of sibling cigarette smoking and peer network with substance use potential among high school students in Tehran. Subjects Data were drawn from the population based cross-sectional study of among 650 high schools students. Methods Multiple linear regression was used in order to determine the adjusted association between cigarette smoking among family members, peer network, their interaction and substance use potential. Result Having a sister who smokes (B = 3.19; p < 0.01) and peer network quality were associated with substance use potential (B = -0.1; p < 0.05). The increase in mean of substance use potential associated with decreases in peer network quality score is much more than in who have a sister with a cigarette smoking habit. Conclusion Having a sister who smokes interacts with peer network quality; appears to be one of the important mechanisms for adolescents' tendency to substance use. These findings can help in a better understanding of substance use potential mechanisms, screening efforts and the formulation of prevention programs. PMID- 29252197 TI - Vaginal bleeding and a giant ovarian cyst in an infant with 21-hydroxylase deficiency. AB - BACKGROUND: Increased adrenal androgen hormones in congenital adrenal hyperplasia (CAH) can rarely cause giant ovarian cysts in the neonatal period. Although the exact mechanism of the development of ovarian cysts is unknown, it is thought that increased androgen levels stimulate folicle development by increasing follicle stimulating hormone (FSH) levels. CASE PRESENTATION: A 16-day-old newborn with ambiguous genitalia was presented to our clinic. Laboratory test results were as follows: sodium: 126 mEq/L, potassium: 5.4 mEq/L, renin: 132 pg/mL, adrenocorticotropic hormone (ACTH): 207 pg/mL, cortisole: 7.8 MUg/dL, basal 17OH progesterone: 21 ng/mL, androstenedione: 5.1 ng/mL, testosterone: 1188 ng/dL and dehydroepiandrosterone sulfate (DHEAS)>1500 MUg/dL. Karyotype analysis resulted in 46,XX. A homozygous mutation of R356W was detected in the CYP21A2 gene. The classical severe form of salt wasting 21 hydroxylase deficiency was diagnosed and treatment was started with hydrocortisone and fludrocortisone. Good metabolic control was ensured by monthly visits but the baby presented with vaginal bleeding as soiling at 4 months. The cystic lesion which extended to the epigastric area from the pelvis in the midline abdomen, had a size of 90*80*60 mm and medially, thin ovarian parenchyma was detected in ultrasonography. CONCLUSIONS: The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels and the giant cyst is developed by activation of gonadotropin cascade and increased gonadotropin receptors, instead of androgens. PMID- 29252198 TI - Addison's disease presenting with perimyocarditis. AB - BACKGROUND: Polyglandular autoimmune syndrome (PGA) and eosinophilic granulomatosis with polyangiitis (EGPA) do not seem to represent a coincidental association. CASE PRESENTATION: A case of a 15-year-old boy is reported who presented with severe systemic inflammation, perimyocarditis and cardiogenic shock, in whom EGPA was initially suspected and later diagnosed with autoimmune adrenalitis with PGA. CONCLUSIONS: The severity of the systemic inflammation and perimyocarditis suggests a more widespread autoimmune-mediated process. Autoimmune adrenal insufficiency should be considered in all cases of pericarditis and perimyocarditis, especially when the severity of clinical manifestations exceeds the expected for the severity of the cardiac findings, as timely identification and prompt treatment may be life-saving. PMID- 29252199 TI - Molecular basis and clinical presentation of classic galactosemia in a Croatian population. AB - BACKGROUND: Classic galactosemia is an autosomal recessive disorder of galactose metabolism caused by severely decreased activity of galactose-1-phosphate uridylyltransferase (GALT) due to pathogenic mutations in the GALT gene. To date more than 330 mutations have been described, with p.Q188R and p.K285N being the most common in Caucasian populations. Although acute manifestations can be fully avoided by a galactose-restricted diet, chronic complications, such as neurological ones, cannot be prevented in a significant number of patients despite compliance with the dietary treatment. METHODS: A cohort of 16 galactosemic Croatian patients, including one pair of siblings, was studied. Molecular characterization was performed by direct sequence analysis of the GALT gene. RESULTS: Sixteen patients were analyzed and only four different mutations were detected. As expected, p.Q188R and p.K285N were common, accounting for 40% and 37% of unrelated alleles, respectively. The third mutation accounting for 20% of mutant alleles was p.R123X causing a premature stop codon, is thus considered to be severe, which is in accordance with the phenotype presented by the homozygous patient described here. The fourth mutation p.E271D was found in a single allele. More than half of our patients manifested some chronic neurological complications. CONCLUSIONS: This is the first report on mutational and phenotypic spectra of classic galactosemia in Croatia that expands the knowledge on the mutational map of the GALT gene across Europe and reveals the genetic homogeneity of the Croatian population. PMID- 29252200 TI - Insulin-mediated pseudoacromegaly: a report of two pediatric patients. AB - BACKGROUND: Insulin-mediated pseudoacromegaly is a rarely described pediatric phenotype. We present two patients displaying excessive growth associated with marked acanthosis nigricans, hyperinsulinemia and metabolic dysregulation. CASE PRESENTATION: Both patients, of First Nations descent, presented with excessive growth - patient one at 3.92 years (height z-score +3.75) and patient two at 9.0 years (height z-score 5.15). Insulin-like growth factor-1 (IGF-1) levels were normal with appropriate growth hormone suppression, yet marked hyperinsulinemia. Prepubescent growth velocities exceeded 9 cm/year, resulting in final adult height predictions exceeding 3 standard deviations (SDs) of predicted. Clinical courses were complicated by type 2 diabetes, marked acanthosis nigricans and long standing psychosocial distress. CONCLUSIONS: Pediatric patients with insulin mediated pseudoacromegaly are at risk of significant physical, metabolic and psychosocial comorbidities. Unlike adults, the implications in childhood prompt consideration for therapies to decelerate linear growth and avert progression to metabolic dysregulation. Increased recognition of this condition may improve pathophysiological understanding, diagnostic criteria and therapeutic options. PMID- 29252201 TI - Early usage of Bakri postpartum balloon in the management of postpartum hemorrhage: a large prospective, observational multicenter clinical study in South China. AB - AIM: To evaluate the success rate and protocol of the Bakri balloon for postpartum hemorrhage (PPH) in the course of a prospective observational multicenter cohort study in South China. METHODS: At 20 hospitals in South China, women with postpartum bleeding who failed to respond to the first-line conservative management and received the Bakri balloon were recruited for the study. Maternal characteristics, PPH characteristics, PPH management and outcomes in regard to the Bakri balloon use were recorded. RESULTS: A total of 472 women had a Bakri balloon tamponade and 407 (86.23%) women were enrolled (67 after vaginal delivery and 340 either during or after cesarean delivery). The success rate of the Bakri balloon in this study was 91.65% (373/407 women). During vaginal deliveries, the group with a hemorrhage >2000 mL before balloon insertion had significantly more blood loss (551.67+/-635.17 mL vs. 242.06+/-313.69 mL, P=0.039) and lower maternal hemoglobin (73+/-21.77 g/L vs. 92.06+/-19.60 g/L, P=0.029) after using Bakri balloon than the group with a hemorrhage <1000 mL. Similar data were found during cesarean deliveries. The blood loss before and after balloon insertion were significantly higher in the Bakri balloon failure group (1700+/-1429.88 mL before and 1209.58+/-1139.72 mL after using the balloon) than those in the success group [918+/-493.92 mL before (P=0.002) and 266.57+/ 361.60 mL after using the balloon (P=0.001)]. CONCLUSION: Rapid diagnosis or prognosis of PPH, in combination with early usage of the Bakri postpartum balloon is more effective for the management of PPH. PMID- 29252202 TI - Neuroanatomy of conversion disorder: towards a network approach. AB - The pathophysiology of conversion disorder is not well understood, although studies using functional brain imaging in patients with motor and sensory symptoms are progressively increasing. We conducted a systematic review of the literature with the aim of summarising the available data on the neuroanatomical features of this disorder. We also propose a general model of the neurobiological disturbance in motor conversion disorder. We systematically searched articles in Medline using the Medical Subject Headings terms '(conversion disorder or hysterical motor disorder) and (neuropsychology or cognition) or (functional magnetic resonance imaging or positron emission tomography or neuroimaging) or (genetics or polymorphisms or epigenetics) or (biomarkers or biology)', following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two authors independently reviewed the retrieved records and abstracts, assessed the exhaustiveness of data abstraction, and confirmed the quality rating. Analysis of the available literature data shows that multiple specialised brain networks (self-agency, action monitoring, salience system, and memory suppression) influence action selection and modulate supplementary motor area activation. Some findings suggest that conceptualisation of movement and motor intention is preserved in patients with limb weakness. More studies are needed to fully understand the brain alterations in conversion disorders and pave the way for the development of effective therapeutic strategies. PMID- 29252204 TI - 18F-FDG production procedures as a source of the eye lens exposure. AB - Decreasing the individual dose limit for the eye lens means verifying the need for routine monitoring of the eye lens of workers exposed to ionizing radiation, including those employed in facilities producing radiopharmaceuticals based on short-lived isotopes. This work analyses the exposure of the eye lenses of employees of centres that produce the isotopes for positron emission tomography, in particular fluorine-18. It takes into account the employment structure and work system of the discussed centres, including in terms of changing the dose limit value for the eye lens. The work complements the Part I, which examines the hand exposure of workers in the radiopharmaceutical production centres. Measurements were carried out by using high-sensitivity thermoluminescence detectors (LiF: Mg, Cu, P - MCP-N). The measurements covered 17 employees. Our results show that the highest values of personal dose equivalent Hp(3) were recorded for the 18F-FDG quality control personnel and nurses who injected the radiopharmaceutical to the patients. In the group of nurses, the maximum daily Hp(3) reaches a value close to 200 MUSv. For staff who performed the quality control of 18F-FDG, the maximum daily dose of Hp(3) exceeds 200 MUSv. Estimated annual exposure of eye lenses of workers in these two occupational groups may exceed the new dose limit (20 mSv/year). Results of this study indicate the need for optimization in the procedures related to quality control of radiopharmaceuticals and injection the 18F-FDG to the patients. PMID- 29252203 TI - The association between physical symptoms and depression among medical students in Bahrain. AB - Objectives: To examine the association between depression and physical symptoms among medical students in Bahrain. Methods: The present study employed a cross sectional design. A total of 160 students were recruited, 41.3% were male and 58.8% female, using a convenience sampling approach. Participants completed the validated Patients Health Questionnaires (PHQs) in which they provided information about demographics, physical symptoms, and depression. Results were considered significant if p <0.05. Results: Nearly nineteen percent of the participants have moderate to severe depression, and 42.2% has moderate to severe physical symptoms. Participants reported different physical symptoms, sleep problems, 40%; lethargy, 31.9%; and headaches, 23.8%. The results of the logistic regression showed that there was a significant association between age and gender (chi2(3) = 32.28, p < 0.001). Sleep and gastrointestinal symptoms were the most associated with depression, respectively (chi2(3)=49.77, p<0.001) and (chi2(3)=49.77, p< 0.05). Conclusions: The association between depression and physical symptoms are considerably high among medical students in Bahrain. Medical educators should take such symptoms seriously among medical students as it may have serious consequences on the mental health of medical students. In practice, adequate awareness initiatives should be organized and provided for medical students to help them overcome their challenges they face. Additionally, incorporating screening self-screening strategies in the medical curriculum can be beneficial for early detections of mental health problems. The Implications and limitations of the study are discussed. PMID- 29252205 TI - A nano continuous variable transmission system from nanotubes. AB - A nano continuous variable transmission (nano-CVT) system is proposed by means of carbon nanotubes (CNTs). The dynamic behavior of the CNT-based nanosystem is assessed using molecular dynamics simulations. The system contains a rotary CNT motor and a CNT-bearing. The tube axes of the nanomotor and the rotor in the bearing are laid in parallel, and the distance between them is known as the eccentricity of the rotor with a diameter of d. By changing the eccentricity (e) of the rotor from 0 to d, some interesting rotation transmission phenomena are discovered, whose procedures can be used to design various nanodevices. This might include the failure of rotation transmission-i.e. the rotor has no rotation when e >= d at an extremely low temperature, or when the edges of the two tubes are orthogonal at their intersections in any condition. This hints that the state of the nanosystem can be used as an on/off switch or breaker. For a system with e = d and a high temperature, the rotor rotates in the reverse direction of the motor. This means that the output signal (rotation) is the reverse of the input signal. When changing the eccentricity from 0 to d continuously, the output signal gradually decreases from a positive value to a negative value; as a result a nano-CVT system is obtained. PMID- 29252206 TI - The Effects of Item Placement in the Young Schema Questionnaire. AB - The Young Schema Questionnaire (YSQ) was developed to measure Early Maladaptive Schemas (EMS), a construct central to Schema Therapy (ST). Traditionally YSQ items were placed in a grouped format for each schema but in recent versions of the questionnaire, items are presented in a random order. This study investigates the effect of item placement on the psychometric properties of the questionnaire. On different occasions, participants completed two versions of the YSQ short form, one with items grouped according to schemas and another where items were placed in a random order. Responses were analysed using the polytomous Rasch model of measurement (partial credit parameterization). Results show that the two versions are not psychometrically equivalent. There were greater differences between the clinical and non-clinical group means for the grouped format than the random format and greater person separation. There was more response dependence between items in the grouped format which has been linked to inflated reliability indices. PMID- 29252207 TI - Stability of INFIT and OUTFIT Compared to Simulated Estimates in Applied Setting. AB - Residual-based fit statistics are commonly used as an indication of the extent to which the item response data fit the Rash model. Fit statistic estimates are influenced by sample size and rules-of thumb estimates may result in incorrect conclusions about the extent to which the model fits the data. Estimates obtained in this analysis were compared to 250 simulated data sets to examine the stability of the estimates. All INFIT estimates were within the rule-of-thumb range of 0.7 to 1.3. However, only 82% of the INFIT estimates fell within the 2.5th and 97.5th percentile of the simulated item's INFIT distributions using this 95% confidence-like interval. This is a 18 percentage point difference in items that were classified as acceptable. Fourty-eight percent of OUTFIT estimates fell within the 0.7 to 1.3 rule- of-thumb range. Whereas 34% of OUTFIT estimates fell within the 2.5th and 97.5th percentile of the simulated item's OUTFIT distributions. This is a 13 percentage point difference in items that were classified as acceptable. When using the rule-of- thumb ranges for fit estimates the magnitude of misfit was smaller than with the 95% confidence interval of the simulated distribution. The findings indicate that the use of confidence intervals as critical values for fit statistics leads to different model data fit conclusions than traditional rule of thumb critical values. PMID- 29252208 TI - Approximate Functional Relationship between IRT and CTT Item Discrimination Indices: A Simulation, Validation, and Practical Extension of Lord's (1980) Formula. AB - Lord (1980) presented a purely conceptual equation to approximate the nonlinear functional relationship between classical test theory (CTT; aka true score theory) and item response theory (IRT) item discrimination indices. The current project proposes a modification to his equation that makes it useful in practice. The suggested modification acknowledges the more common contemporary CTT discrimination index of a corrected item-total correlation and incorporates item difficulty. We simulated slightly over 768 trillion individual item responses to uncover a best-fitting empirical function relating the IRT and CTT discrimination indices. To evaluate the effectiveness of the function, we applied it to real world test data from 16 workforce and educational tests. Our modification results in shifted functional asymptotes, slopes, and points of inflection across item difficulties. Validation with the workforce and educational tests suggests good prediction under common assumption testing conditions (approximately normal distribution of abilities and moderate item difficulties) and greater precision than Lord's (1980) formula. PMID- 29252209 TI - Social Desirability Amongst Chinese Teachers. AB - Research has suggested that self-reported responses on surveys can be affected by a participant's tendency toward social desirability, which would prevent them from revealing their true feelings or behaviors. Researchers should provide evidence that their results have not been affected by socially desirable responses using the Marlowe-Crowne Social Desirability Scale (MC-SDS). Past research has used the 33-item original form and 13-item short form of the MC-SDS, although a few researchers have found questionable validation of the 13 item MC SDS in several populations. Traditional factor analysis failed to converge on a factor structure. Therefore, the current research was conducted using a Rasch dichotomous model analysis on the original 33-item MC-SDS, a 20-item MC-SDS, and the 13-item MC-SDS. Findings indicated that the 33-item MC-SDS had several overlapping items, the 20-item MC-SDS provided a somewhat meaningful measure of social desirability, and the 13-item MC-SDS did not provide sufficient item distribution or separation to produce a meaningful measure. A researcher should check on the factor structure of the MC-SDS when using it in their research, especially with different cultural populations. PMID- 29252210 TI - I'm scared to go to School! Capturing the Effects of Chronic Daily Fears on Students' Concept of Self. AB - Students may experience considerable fear and stress in school settings, and based on Dweck's (2006) notion of "mindset" we hypothesized that fear introduces qualitative changes in students' self-concepts. Hypotheses were tested on 3847 third-grade students from nine Iberoamerican countries (Bolivia, Chile, Colombia, Cuba, Ecuador, Panama, Peru, Spain, and Venezuela), who completed Murillo's (2007) adaptation of Marsh' (1988) SDQ-I. Rasch scaling indicated that the information-content of High-Fear students' ratings was more localized across the latent dimension than was that of Low-Fear students, and their ratings also showed less cognitive variety. The resulting measurement distortions could be captured via logistic regression over the ratings' residuals. Also, using training and validation samples (with respectively 60 and 40% of all cases), it proved possible to predict students' fear levels and their gender. We see the present findings as a first step towards implementing an online warning and detection system for signs of bullying among students. PMID- 29252211 TI - Confidence to Perform in the Global Marketplace: Constructing and Validating a Survey Instrument for Community College Students. AB - This article discusses the construction and validation of an instrument to gauge community college students' confidence to perform in the global marketplace. The instrument was designed to capture students' beliefs in their own abilities to successfully carry out job-related tasks in cross-cultural work environments that are globally-interconnected and constantly at flux. The instrument items emerged from a comprehensive review of literature, nationwide workforce skills initiatives, rounds of expert panel analyses, and focus groups. Items were formulated within Bandura's framework of self-efficacy, and the instrument was analyzed with Rasch measurement. The Rasch analysis, conducted on a sample of 741 students, provided evidence of the content validity of the items, the generalizability of the measure, and its external validity. The instrument can offer useful feedback to community college internationalization-focused staff in their efforts to assess outcomes of international initiatives for community college students, thus supporting program assessment, evaluation of student growth, and institutional decision-making. PMID- 29252212 TI - Measuring Anger Types among Malaysian Adolescents using the Rasch Model. AB - Adolescences is an important transitional phase in human development where they experience physiological as well as psychological changes. Nevertheless, these changes are often understood by teachers, parents, and even the adolescents themselves. Thus, conflicts exist and adolescents are affected from the conflict physically and emotionally. An important state of emotions that result from this conflict is anger. This article describes the development and validation of the 34-item Adolescent Anger Inventory (AAI) to measure types of anger among Malaysian adolescents. A sample of 2,834 adolescents in secondary school who provide responses that were analyzed using Rasch model measurement framework. The 4 response category worked satisfactorily for the scale developed. A total of 11 items did not fit to the model's expectations, and thus dropped from the final scale. The scale also demonstrated satisfactory reliability and separation evidence. Also, items in the AAI depicted no evidence of DIF between 14- and 16 year-old adolescents. Nevertheless, the AAI did not have sufficient items to target adolescents with a high level of physical aggressive anger. PMID- 29252213 TI - Micro(glial)-managing executive function: white matter inflammation drives catatonia. AB - White matter abnormalities are prevalent in neuropsychiatric disorders such as schizophrenia, but it is unclear whether these abnormalities represent a cause or consequence of these disorders. Reduced levels of the myelin protein 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNP) are associated with the schizophrenic symptom catatonia in both humans and mouse models. In this issue of the JCI, Janova et al. show that reduced CNP levels correlate with catatonia and white matter inflammation in human subjects. Furthermore, they demonstrate that microglial ablation prevents and alleviates catatonic signs in Cnp-/- mice, indicating that microglial-mediated inflammation causes catatonia. Together, this study identifies a cellular mechanism by which subtle myelin abnormalities cause low-grade neuroinflammation and catatonic behavior. PMID- 29252215 TI - Pelvic Ring Disruption in a Patient with Bladder Exstrophy: A Case Report. PMID- 29252216 TI - Knee Arthroplasty in Alkaptonuric Arthropathy: A Case Report. PMID- 29252217 TI - Treatment of Iatrogenic Chyloretroperitoneum with Octreotide Following Spinal Deformity Correction: A Case Report. PMID- 29252214 TI - Microglia ablation alleviates myelin-associated catatonic signs in mice. AB - The underlying cellular mechanisms of catatonia, an executive "psychomotor" syndrome that is observed across neuropsychiatric diseases, have remained obscure. In humans and mice, reduced expression of the structural myelin protein CNP is associated with catatonic signs in an age-dependent manner, pointing to the involvement of myelin-producing oligodendrocytes. Here, we showed that the underlying cause of catatonic signs is the low-grade inflammation of white matter tracts, which marks a final common pathway in Cnp-deficient and other mutant mice with minor myelin abnormalities. The inhibitor of CSF1 receptor kinase signaling PLX5622 depleted microglia and alleviated the catatonic symptoms of Cnp mutants. Thus, microglia and low-grade inflammation of myelinated tracts emerged as the trigger of a previously unexplained mental condition. We observed a very high (25%) prevalence of individuals with catatonic signs in a deeply phenotyped schizophrenia sample (n = 1095). Additionally, we found the loss-of-function allele of a myelin-specific gene (CNP rs2070106-AA) associated with catatonia in 2 independent schizophrenia cohorts and also associated with white matter hyperintensities in a general population sample. Since the catatonic syndrome is likely a surrogate marker for other executive function defects, we suggest that microglia-directed therapies may be considered in psychiatric disorders associated with myelin abnormalities. PMID- 29252218 TI - Atypical Subtrochanteric Fracture Through a Cephalomedullary Implant: A Case Report. PMID- 29252219 TI - Basilar Invagination Caused by Langerhans Cell Histiocytosis of the Atlas in an Adult: A Case Report. PMID- 29252220 TI - Spinal Epidural Hematoma Following Epidural Steroid Injection in a Patient Treated with Dabigatran: A Case Report. PMID- 29252221 TI - Biomarker-guided Intervention to Prevent AKI or KDIGO Care Bundle to Prevent AKI in High-risk Patients Undergoing Major Surgery? PMID- 29252222 TI - Prevent the Bleed: How Surgeons Can Lead the National Conversation About Firearm Safety Forward. AB - : In the 5 years since the Sandy Hook elementary school shooting that claimed the lives of 20 children and 6 of their teachers, we have witnessed intolerably more mass shooting events. In the intervening years, over 150,000 Americans have died because of firearm violence, 3 times the number who lost their lives during the Revolutionary war. In the last 2 months, we have been left reflecting on 2 more tragedies. The first came on October 1 in Las Vegas, at the Route 91 music festival where 58 were killed and over 500 injured by a single gunman. The second, on November 5, took place in Sutherland Springs, Texas (population 600) near San Antonio and claimed the lives of 26 men women and children while they prayed. As was witnessed in Orlando and San Bernardino, these most recent mass casualty incidents strained first responders, law enforcement, and the state's trauma systems to their breaking point.Once again, we were left searching for the reasons behind these tragedies asking predictable questions: who did this and why? Was it part of a terrorist plot or a lone psychopath with a grudge? Were the weapons obtained legally, and why would anyone need so many? How can we stop this from happening again? PMID- 29252223 TI - Thoracoscopic Revision of Staple Dislodgment in an Adolescent with Scoliosis: A Case Report. PMID- 29252224 TI - Asymptomatic Bilateral Patella Alta After Surgical Repair of Traumatic, Sequential Bilateral Patellar Tendon Rupture: A Case Report. PMID- 29252225 TI - Mucormycotic Polyarthritis in an Immunocompetent Patient: A Case Report. PMID- 29252226 TI - Periprosthetic Propionibacterium granulosum Joint Infection After Direct Anterior Total Hip Arthroplasty: A Case Report. PMID- 29252227 TI - Brachial Venous Pseudoaneurysm with High Median Nerve Palsy Following Cardiac Catheterization: A Case Report. PMID- 29252228 TI - Massive Spontaneous Acute-on-Chronic Subdural Hematoma Following Coumadin Administration: A Case Report. PMID- 29252229 TI - Rhabdomyolysis and Acute Renal Failure Resulting from the Prone Position on the Jackson Spine Table: A Case Report. PMID- 29252230 TI - Peripheral Primitive Neuroectodermal Tumor of the Chest Wall in a Neonate: A Case Report. PMID- 29252231 TI - Arterial Missile Embolus Resulting from a Novel Mechanism: A Case Report. PMID- 29252232 TI - Cryoamputation as a Lifesaving Intervention: A Case Report, Description of Technique, and Review of the Literature. PMID- 29252233 TI - Posterior Spinal Fusion for Friedreich Ataxia-Related Scoliosis in Twin Girls: A Case Report. PMID- 29252234 TI - Acute Compartment Syndrome of the Upper Extremity Secondary to Blunt Trauma That Resulted in Closed Disruption of an Arteriovenous Fistula in the Absence of Fracture: A Case Report. PMID- 29252235 TI - Intra-Articular Metastasis of Lung Carcinoma Presenting as Pigmented Villonodular Synovitis of the Knee: A Case Report. PMID- 29252236 TI - Leg Constriction by Electronic Security Bracelets That Are Obscured by a Pavlik Harness: A Report of Two Cases. PMID- 29252238 TI - Retrieval Analysis of an Early Fracture of a Vitamin E-Stabilized Tibial Liner in Total Knee Arthroplasty: A Case Report. PMID- 29252237 TI - An Atypical Type-II Monteggia Fracture Equivalent Lesion: A Case Report. PMID- 29252239 TI - Septic Prepatellar Bursitis Caused by Traumatic Inoculation of Nocardia Nova: Case Report and Literature Review. PMID- 29252240 TI - Intraosseous Inflammatory Myofibroblastic Tumor of the Twelfth Thoracic Vertebra: Report of a Rare Case with Histological Diagnosis and Surgical Treatment. PMID- 29252241 TI - Systemic Complications of ACL Reconstruction. PMID- 29252242 TI - Shearing of a Continuous Interscalene Catheter with Lancinating Symptoms After an Interscalene Block: A Case Report. PMID- 29252243 TI - Pyoderma Gangrenosum Following Orthopaedic Surgery: A Case Report and Literature Review. PMID- 29252244 TI - Acute Postoperative Bisphosphonate-Associated Atypical Periprosthetic Femoral Fracture: A Case Report. PMID- 29252245 TI - Lymphoma as a Mimicker of Femoroacetabular Impingement: A Case Report. PMID- 29252246 TI - Surgical Excision of an Omovertebral Bone in an Adult with Untreated Sprengel Deformity: A Case Report. PMID- 29252247 TI - An Undiagnosed Fracture of the Radial Neck in a Young Child: The Radial Neck Fleck Sign: A Case Report. PMID- 29252248 TI - Successful Manubriosternal Fusion Following Failure of Open Reduction and Internal Fixation of a Traumatic Manubriosternal Dislocation: A Case Report. PMID- 29252250 TI - Pediatric Fractures: Patient Factors and Imaging Challenges Can Delay Diagnosis. PMID- 29252249 TI - Tissue Necrosis Resulting from Vascular Injury Due to Failed Hardware in Revision Total Hip Arthroplasty: A Case Report. PMID- 29252251 TI - Neurovascular Injury Following Traumatic Posterior Shoulder Dislocation in an Adolescent Contact Athlete: A Case Report. PMID- 29252252 TI - Fulminant Clostridium Difficile Colitis After Surgical Treatment of Cervical Destructive Spondyloarthropathy: A Case Report. PMID- 29252253 TI - Pyogenic Sacroiliac Arthritis Resulting in Septic Shock in a Postpartum Patient: A Rare Problem with a Rare Organism: A Case Report. PMID- 29252254 TI - Metastatic Lung Cancer Presenting During the Treatment Interval of an Acute Lumbar Disc Herniation: A Case Report. PMID- 29252255 TI - Septic Arthritis of Two Joints Following Blunt Trauma: A Case Report and Review of the Literature. PMID- 29252256 TI - Osteomyelitis of the Atlantooccipital Joint in an Intravenous Drug User: A Case Report and Review of the Literature. PMID- 29252257 TI - Intradural Extramedullary Spinal Tuberculosis Diagnosed Eight Years After Treatment of the Primary Infection: A Case Report. PMID- 29252258 TI - Fracture of a Cemented, Highly Polished, Collarless, Triple-Tapered, High Nitrogen Stainless Steel Femoral Stem: A Case Report. PMID- 29252259 TI - Acute Thoracic Aortic Dissection After Chiropractic Intervention: A Case Report. PMID- 29252260 TI - Heterotopic Ossification Excision Improves Kinetic and Kinematic Gait Parameters as Demonstrated by Computerized Motion Analysis: A Case Report. PMID- 29252261 TI - Recurrent Anterior Instability Manifesting as Luxatio Erecta Humeri: A Case Report. PMID- 29252262 TI - "Floating Fibula" Secondary to Traumatic Dislocation of the Ankle Joint, Ankle Syndesmosis, and the Proximal Tibiofibular Joint: A Case Report. PMID- 29252263 TI - Dominant-Sided First-Rib Stress Fracture in a Collegiate Baseball Pitcher: A Case Report. PMID- 29252264 TI - Ischemic Optic Neuropathy Following Surgical Fixation of Multiple Ipsilateral Upper-Extremity Fractures: A Case Report. PMID- 29252265 TI - An Open Distal Radius Fracture Inflicted by a Bear Mauling: A Case Report and Literature Review. PMID- 29252266 TI - External Iliac Artery Injury from Migrated Antibiotic Hip Spacer: A Case Report. PMID- 29252267 TI - Nonunion of the Radius After Elastic Stable Intramedullary Nailing of a Midshaft Forearm Fracture in a Seven-Year-Old Child: A Case Report. PMID- 29252268 TI - Segmental Bone Transport with the Monorail Technique in Reconstructing a Bone Defect in the Forearm: A Case Report. PMID- 29252269 TI - Ewing Sarcoma of the Distal Part of the Thumb: Allograft Reconstruction to Preserve Function: A Case Report. PMID- 29252270 TI - Multiple Femoral and Tibial Avulsion Fractures in a Skeletally Mature Patient Secondary to Knee Dislocation: A Case Report. PMID- 29252271 TI - A Pulseless Extremity Following an Apparently Nondisplaced Proximal Humeral Physeal Fracture: A Case Report. PMID- 29252272 TI - Heterotopic Ossification Excision Improves Kinetic and Kinematic Gait Parameters as Demonstrated by Computerized Motion Analysis: A Case Report. PMID- 29252273 TI - Natural History of Untreated Osteoblastoma: A Case Report. PMID- 29252274 TI - Elbow Reconstruction Following an Extensive Resection of the Proximal Part of the Ulna in a Patient with Ewing Sarcoma: A Case Report. PMID- 29252275 TI - Smith-Petersen Vitallium Mold Arthroplasty: Case Report with a Fifty-One-Year Follow-Up and Histopathologic Analysis. PMID- 29252276 TI - A Novel Posterior Arthrotomy Approach for the Treatment of a Large Osteochondral Defect of the Posterior Aspect of the Lateral Femoral Condyle of the Knee: A Case Report and Technical Note. PMID- 29252277 TI - Late Developmental Dysplasia of the Hip That Was Sonographically Determined to Be Stable at First Examination: A Case Report. PMID- 29252278 TI - Late Abnormal Skin Changes Overlying Total Knee Arthroplasty: A Case Report. PMID- 29252279 TI - Nonsurgical Extraction of a Needle in the Foot with Use of a Magnet: A Case Report. PMID- 29252280 TI - Congenital Extrarenal Extra-Central Nervous System Malignant Rhabdoid Tumor of the Upper Extremity: A Case Report. PMID- 29252281 TI - Surgical Reconstruction of a Severe Crush Injury of the Lateral Part of the Forefoot with Use of a Cross-Leg Osteocutaneous Pedicled Fibular Graft: A Case Report. PMID- 29252282 TI - Tumor-Induced Osteomalacia Caused by a Bone Tumor in the Ulna: A Case Report. PMID- 29252283 TI - Mirror Hand Deformity: A Report of Two Cases. PMID- 29252284 TI - Tubercular Popliteal Cyst as a Primary Presentation in an Adult: A Case Report and Review of the Literature. PMID- 29252285 TI - Elbow Hemiarthroplasty for Late Reconstruction of a Traumatic Elbow Bone Defect in a Young Patient: A Case Report. PMID- 29252286 TI - Some Skin Abnormalities Around Metal Implants Are Not Serious. PMID- 29252287 TI - Secondary Chondrosarcoma of the Proximal Part of the Humerus Arising in a Four Year-Old Boy with Ollier Disease: A Case Report. PMID- 29252288 TI - Pulmonary Embolism After Vertebroplasty with Use of Hydroxyapatite Blocks: A Case Report. PMID- 29252289 TI - Extra-Articular Pigmented Villonodular Synovitis of the Deep Infrapatellar Bursa: A Case Report. PMID- 29252290 TI - Delayed Acute Sciatic Nerve Palsy as a Complication of Bridging Chemothromboprophylaxis Following Hip Hemiarthroplasty: A Case Report. PMID- 29252291 TI - An Unusual Cause for Noninfectious Subcutaneous Emphysema of the Upper Extremity: A Case Report. PMID- 29252292 TI - Paraparesis as the Presenting Form of a Lumbar Hemorrhagic Synovial Cyst: A Case Report and Review of the Literature. PMID- 29252293 TI - Chronic (Ten Years) Ischial Tuberosity Avulsion Fracture Nonunion Treated with Fragment Excision and Simultaneous Primary Repair of the Hamstring Tendon: A Case Report. PMID- 29252294 TI - Implant Failure in Slipped Capital Femoral Epiphysis: A Report of Two Cases. PMID- 29252295 TI - Histoplasmosis Masquerading as a Rheumatoid Nodule in an Immunocompromised Host: A Case Report. PMID- 29252296 TI - Intraosseous Fifth Carpometacarpal Dislocation Associated with a Coronal Hamate Fracture: A Case Report. PMID- 29252297 TI - Humeral Shaft Fracture with Ipsilateral Anterior Shoulder Dislocation and Posterior Elbow Dislocation: A Case Report and Review of the Literature. PMID- 29252298 TI - Anterior Sacroiliac Dislocation: A Case Report and Review of the Literature. PMID- 29252299 TI - Tumor-Induced Rickets Presenting in an Adolescent: A Case Report and Review of the Literature. PMID- 29252300 TI - Distal Phalanx Osteomyelitis Complicating Zone I Flexor Tendon Repair with a Non Pullout Suture Tied Over a Dorsal Button: A Report of Two Cases. PMID- 29252301 TI - Atypical Subtrochanteric Femoral Fracture Below an Arthritic Hip: A Case Report. AB - CASE: We present a case of a sixty-nine-year-old woman with an atypical subtrochanteric femoral fracture below an arthritic hip; the patient had a history of long-term bisphosphonate treatment. We performed a one-stage total hip arthroplasty with a plate and cables because the healing of atypical femoral fractures in patients with a history of bisphosphonate use can be prolonged. CONCLUSION: The combined use of a plate and total hip arthroplasty is a potential intervention for atypical proximal femoral fractures associated with hip arthritis. PMID- 29252302 TI - Reverse Total Shoulder Arthroplasty for Recurrent Shoulder Dislocation in an Elderly Patient: A Case Report. AB - CASE: We present a case of a seventy-one-year-old woman with recurrent anterior dislocation of the shoulder in the setting of an irreparable rotator cuff tear and degenerative joint disease. CONCLUSION: In an elderly patient with recurrent anterior shoulder dislocation and an irreparable rotator cuff tear, reverse total shoulder arthroplasty (RTSA) is a viable surgical intervention. In the case presented here, RTSA resulted in the patient exhibiting increased range of motion, reporting an improved quality of life, and having no additional dislocation events as of the two-year follow-up. PMID- 29252303 TI - Positional Occlusion of an Interposition Vein Graft for Brachial Artery Reconstruction Following Open Elbow Dislocation in a Pediatric Patient: A Case Report. AB - CASE: We present a case of positional occlusion of the brachial artery after open elbow dislocation and vein graft reconstruction in a pediatric patient. Two years after reconstruction, arterial Doppler studies demonstrated occlusion of the artery; however, an angiogram revealed a widely patent artery. Given the clinical findings of pain and cold intolerance, the patient underwent surgical exploration. Arterial occlusion was found to coincide with elbow flexion. The redundant segment of the basilic vein graft was resected and repaired end-to-end. CONCLUSIONS: Vein graft reconstruction of the brachial artery should be checked for patency in flexion prior to closing the incision. Vein grafts with lengths in excess of a defect may kink in flexion due to redundant graft and the relatively thin walls of veins compared to arteries. This case report emphasizes that an understanding of routine tests is invaluable when eliciting the etiology of contradictory test results. PMID- 29252305 TI - Central Nervous System Complications Following Spine Surgery. PMID- 29252304 TI - A Unique Treatment for Talar Osteonecrosis: Placement of an Internal Bone Stimulator: A Case Report. AB - CASE: There are many treatment options for talar osteonecrosis without collapse, ranging from restricted weight-bearing to arthrodesis. We present a patient with talar osteonecrosis without evidence of collapse. After conservative treatment had failed, she was treated successfully with arthroscopic drilling, bone grafting, and placement of an internal bone stimulator. CONCLUSION: Talar osteonecrosis is a challenging entity to treat. Despite our increased knowledge of the complex talar vascular anatomy, etiologies, and treatment options, poor outcomes remain all too common. A combination of bone-grafting and an internal bone stimulator was effective for relief of symptoms in our patient in the short term. PMID- 29252306 TI - Iatrogenic Hip Subluxation After Surgical Dislocation Successfully Treated with Periacetabular Osteotomy: A Case Report. PMID- 29252307 TI - Missed Pediatric Traumatic Hip Dislocation: A Case Report. PMID- 29252308 TI - Bilateral Congenital Posterior Cruciate Ligament Hypoplasia: A Case Report. PMID- 29252309 TI - The Effect of High-Dose Corticosteroids on Cervical Spinal Fusion: A Report of Two Cases. PMID- 29252310 TI - Spondyloptosis of the Cervical Spine in a Patient with Neurofibromatosis Type 1: A Case Report and Review of the Literature. PMID- 29252311 TI - Extraskeletal Osteosarcoma of the Hand in an Adolescent: A Case Report. PMID- 29252312 TI - A Late Fracture of the Femur Through an External Fixator Pin Site: A Case Report. PMID- 29252313 TI - Transphyseal Fracture of the Distal Part of the Femur in a Newborn: A Case Report. PMID- 29252314 TI - Neglected Idiopathic Bilateral Clubfoot Successfully Treated with the Ponseti Method: A Case Report. PMID- 29252315 TI - "Residual Osteocytic Lesion": Effect of Denosumab (AMG 162) Treatment on the Morphology and Immunophenotype of Giant-Cell Tumor: A Report of Two Cases. PMID- 29252316 TI - Ruptured Pseudoaneurysm After Percutaneous Achilles Tenotomy During Ponseti Treatment for Congenital Clubfoot Deformity: A Case Report. PMID- 29252317 TI - Antecubital Venipuncture Resulting in Compartment Syndrome of the Anterior Brachium: A Case Report. PMID- 29252318 TI - Fresh Osteochondral Allograft Transplantation for Treatment of Chondroblastoma of the Femoral Head: A Case Report. PMID- 29252319 TI - Growth Stimulation Following an All-Epiphyseal Anterior Cruciate Ligament Reconstruction in a Child: A Case Report. PMID- 29252320 TI - Open Dislocation of the Knee with Draining Urine: A Case Report. PMID- 29252321 TI - Postpartum Enterobacter Pyogenic Sacroiliitis: A Case Report and Literature Review. PMID- 29252322 TI - Dynamic MRI Reveals Soft-Tissue Compression Causing Progressive Myelopathy in Postlaminectomy Patients: A Report of Three Cases. PMID- 29252323 TI - Elevated Serum Metal Levels from Vitamin Supplementation: A Case Report. PMID- 29252324 TI - Open Ligamentous Disruption of the Lateral Aspect of the Ankle without Associated Fracture or Dislocation: A Case Report. PMID- 29252325 TI - Compartment Syndrome After Intraosseous Infusion Associated with a Fracture of the Tibia: A Case Report. PMID- 29252326 TI - Vitamin K-Dependent Coagulopathy in Pediatric Osteomyelitis: A Case Report. PMID- 29252327 TI - A Lesson from the Failure of Intramedullary Fixation of Atypical Subtrochanteric Fractures: A Report of Two Cases. PMID- 29252328 TI - Multicentric Giant Cell Tumor of Bone and Paraganglioma: A Case Report. PMID- 29252329 TI - Fatal Air Embolus During Internal Fixation of the Clavicle: A Case Report. PMID- 29252330 TI - T2 Spinal Cord Injury Caused by Noncontiguous Traumatic C1-C2 Ligamentous Injury in a Young Child: A Case Report. PMID- 29252331 TI - Continuous Thoracocervical Epidural Analgesia for Management of Perioperative Pain in an Adolescent with Osteosarcoma: A Case Report. PMID- 29252332 TI - Knee Arthrodesis in Navajo Familial Neurogenic Arthropathy: A Case Report and Review of the Literature. PMID- 29252333 TI - Metaphyseal Screw Migration After Medial Patellofemoral Ligament Reconstruction in a Skeletally Immature Patient: A Case Report. PMID- 29252334 TI - Osteonecrosis of the Lunate Following Low-Energy Trauma: A Case Report. PMID- 29252336 TI - Concern About Early Intraprosthetic Dislocation in Dual-Mobility Implants. PMID- 29252335 TI - Extra-Articular Lipoma Arborescens of the Dorsal Aspect of the Wrist with Invasion of the Extensor Tendons: A Case Report. PMID- 29252337 TI - A Fatal Shewanella algae Infection After an Open Tibial Fracture Following a Tropical Storm: A Case Report. PMID- 29252338 TI - Vertebral Artery Pseudoaneurysm Resulting in Embolic Stroke as a Complication of Posterior C1 Lateral Mass Screw Fixation: A Case Report. PMID- 29252339 TI - Complete Dissociation of the Polyethylene Component in a Newly Available Dual Mobility Bearing Used in Total Hip Arthroplasty: A Case Report. PMID- 29252341 TI - Treating Atypical Femoral Fractures Related to Bisphosphonates. PMID- 29252340 TI - Early Failure of Metal-on-Metal Large-Diameter Head Total Hip Arthroplasty Revised with a Dual-Mobility Bearing: A Case Report. PMID- 29252342 TI - Overlapping Dislocation of the Pubic Symphysis with an Open Reduction and Anterior and Posterior Pelvic Ring Fixation: A Case Report. AB - CASE: We present a case of a patient who sustained overlapping dislocation of the pubic symphysis (ODPS), which required an open reduction as well as anterior and posterior pelvic ring fixation. CONCLUSION: This case report is a valuable addition to the current literature on ODPS because we believe it to be the first report describing a patient who required both anterior and posterior fixation because of pelvic instability. PMID- 29252343 TI - Hydatid Disease of the Femur Treated with a Total Femoral Replacement: A Case Report. AB - CASE: A thirty-one-year-old woman presented with symptoms of worsening left knee and thigh pain. Radiographs and magnetic resonance imaging demonstrated extensive lytic and cystic changes throughout the femur. A biopsy demonstrated necrosis, chronic granulomatous inflammation, and laminations suggestive of an echinococcal cyst. Serology confirmed an Echinococcus granulosus infection. Treatment with anthelmintic agents was initiated, but reconstruction with a total femoral endoprosthesis was implemented as definitive management. The patient tolerated surgery well and returned for a one-year postoperative visit without evidence of recurrence of infection. CONCLUSION: Osseous hydatidosis is a rare disease, but it should be included in the differential diagnosis of patients with extensive destructive bone processes. PMID- 29252344 TI - A Traumatic Partial Through-the-Elbow Amputation with Disarticulation of the Humerus: A Case Report and Review of the Literature. AB - CASE: A fifty-two-year-old fisherman sustained a severely mangled open elbow dislocation; the distal part of the humerus was protruding from the wound. Although all of the soft tissue attached to the distal part of the humerus was stripped off the bone, no neurovascular structures were damaged. A hinged external fixator was applied and a lateral collateral ligament repair was performed. At the final follow-up, the range of elbow motion was -10 degrees in extension and 125 degrees in flexion, with no instability. CONCLUSION: Despite the near amputation of the limb, a good functional outcome was achieved because the neurovascular structures remained intact. PMID- 29252345 TI - Calcific Tendinopathy of the Abductor Hallucis Tendon in an Adolescent Gymnast: A Case Report. AB - CASE: A fifteen-year-old gymnast presented with right foot pain, noting tenderness to palpation about the right medial metatarsophalangeal joint prominence. Radiographs and magnetic resonance imaging raised concerns for a possible avulsion fracture of the head of the first metatarsal. Surgical exposure of the presumed fragment revealed chalklike material that was easily friable and seemed to emanate from the capsule. Pathologic evaluation confirmed dense fibrous tissue with calcification, consistent with a diagnosis of calcific tendinopathy. CONCLUSION: Calcific tendinopathy may occur in unusual anatomic locations, and must remain on the differential diagnosis for pediatric patients with the appropriate clinical picture. PMID- 29252346 TI - Allograft Reconstruction of a Chronic Quadriceps Tendon Rupture with Use of a Novel Technique. PMID- 29252347 TI - Bilateral Total Knee Arthroplasty with Extensor Mechanism Allografts and Flap Reconstructions After Soft-Tissue Joint Destruction from Purpura Fulminans: A Case Report. PMID- 29252348 TI - Traumatic Hemipelvectomy: A Rare and Catastrophic Injury: A Case Report. PMID- 29252349 TI - Closed Rupture of the Flexor Hallucis Longus Tendon with Evaluation of the Mechanism of Injury: A Case Report. PMID- 29252350 TI - Parameniscal Cyst with Associated Extensive Proximal Tibial Bone Erosion: A Case Report and Literature Review. PMID- 29252351 TI - Lateral Tibial Plateau Fracture with a Displaced Posterolateral Fragment and Fibular Head Entrapment: A Case Report. PMID- 29252352 TI - Magnetic Resonance Imaging Diagnosis of Rib Fracture in a Competitive Collegiate Rower: A Case Report. PMID- 29252353 TI - Pulmonary Edema from Intravasation of Irrigation Fluid During Hip Arthroscopy in a Child: A Case Report. PMID- 29252354 TI - Acute Dynamic Thoracic Outlet Syndrome After Midshaft Clavicular Osteosynthesis for Nonunion: A Case Report. PMID- 29252355 TI - Bilateral Acute Calcium Pyrophosphate Crystal Arthritis After Bilateral Total Knee Arthroplasty: A Case Report. PMID- 29252356 TI - Phenotypic Differences in Multiple Osteochondromas in Monozygotic Twins: A Case Report. PMID- 29252357 TI - Traumatic Divergent Elbow Dislocation in an Adult with an Associated Fracture of the Distal Part of the Humeral Shaft and an Open Perilunate Dislocation: A Case Report. PMID- 29252358 TI - Septic Arthritis of the Hip Caused by Group B Streptococcus in a Postpartum Patient: A Case Report. PMID- 29252359 TI - Free Vascularized Iliac Crest Bone Graft for the Treatment of a Pediatric Lateral Humeral Condyle Fracture Nonunion: A Case Report. PMID- 29252360 TI - An Unusual Neurological Complication Twenty Years After a Modified Bristow Latarjet Procedure: A Case Report. PMID- 29252361 TI - Open Resection of a Subchondral Acetabular Osteoid Osteoma Guided by Combined CT Navigation and Hip Arthroscopy: A Case Report. PMID- 29252362 TI - Twenty-one Years with Congenital Insensitivity to Pain: A Case Report. PMID- 29252363 TI - Traumatic Sternomanubrial Instability and Arthrosis: A Case Report and Review. PMID- 29252364 TI - Arthroscopy-Associated Complications in Osteosarcoma: A Case Report and Review of the Literature. PMID- 29252365 TI - Irreducible Tibial Pilon Fracture Secondary to Posterior Tibial Tendon Entrapment: A Case Report. PMID- 29252366 TI - Periprosthetic Epithelioid Hemangioma of the Proximal Part of the Tibia: A Case Report. PMID- 29252367 TI - Correction of a Femoral Head Fracture Malunion with Surgical Dislocation of the Hip: A Case Report. PMID- 29252368 TI - Posterior Interosseous Nerve Palsy Associated with Radial Neck Nonunion: A Case Report. PMID- 29252369 TI - Immune-Mediated Coagulopathy Complicating Elective Orthopaedic Knee Surgery: A Report of Three Cases. PMID- 29252370 TI - Enhanced Callus Formation After Six Weeks of Parathyroid Hormone Treatment in a Man with Multiple Pelvic Fractures and Osteogenesis Imperfecta Type IV: A Case Report. PMID- 29252371 TI - Improvement in the Contractility and Muscle Stem Cell Density of the Rotator Cuff Following Surgical Repair: A Case Report. PMID- 29252372 TI - Torn Flexor Digitorum Longus Tendon and Lacerated Posterior Tibial Artery Associated with an Open Hawkins Type-III Talar Neck Fracture: A Case Report. PMID- 29252373 TI - Reconstruction of Congenital Pseudarthrosis of the Clavicle with Use of the Masquelet Technique: A Case Report. PMID- 29252374 TI - Anterior Subluxation of the Talus: A Complication of Malreduction of the Ankle Syndesmosis: A Report of Three Cases. PMID- 29252375 TI - Posteriorly Displaced Fragment in a Juvenile Tillaux Fracture: A Case Report. PMID- 29252376 TI - Caveat Emptor: Adverse Inflammatory Soft-Tissue Reactions in Total Hip Arthroplasty with Modular Femoral Neck Implants: A Report of Two Cases. PMID- 29252377 TI - Acute Bilateral Exertional Lateral Leg Compartment Syndrome with Delayed Presentation: A Case Report. PMID- 29252378 TI - Fixation of a Chondral Fragment of the Knee in an Adult: A Case Report. PMID- 29252379 TI - Fracture of a Tapered Femoral Neck After Total Hip Arthroplasty: A Case Report. PMID- 29252380 TI - Cutaneous B-Cell Lymphoma Presenting as a Hand Mass: A Case Report. PMID- 29252381 TI - Multidisciplinary Reconstructive Approach to Traumatic Extensor Mechanism Disruption: A Case Report. PMID- 29252382 TI - Intraligamentous Synovial Chondromatosis of the Anterior Cruciate Ligament: A Case Report. PMID- 29252383 TI - Formation of Abdominal Heterotopic Bone Following the Utilization of Bone Morphogenetic Protein in Anterior Lumbar Spinal Fusion: A Case Report. PMID- 29252384 TI - Reconstruction of an Extensive Plantar Defect with Two Simultaneous Free Flaps: A Case Report. PMID- 29252385 TI - Sinus Tract Formation After Arthroplasty of the Shoulder Secondary to Tuberculosis: A Case Report and Review of the Literature. PMID- 29252386 TI - An Unexpected Foreign Body in the Knee: A Case Report. PMID- 29252387 TI - Metachronous Aneurysmal Bone Cysts in a Fourteen-Year-Old Girl: A Case Report and Review of the Literature. PMID- 29252388 TI - Congenital Cervicothoracic Scoliosis Treated with Hemiepiphysiodesis and Placement of Distraction-Based Instrumentation: A Case Report. PMID- 29252389 TI - Pseudoaneurysm Formation from a Prominent Orthopaedic Implant: Case Report and Literature Review. PMID- 29252390 TI - Nontraumatic Proximal Junctional Kyphosis with Catastrophic Neurologic Deficits After Instrumented Arthrodesis in an Adolescent with Cerebral Palsy: Case Report and Review of the Literature. PMID- 29252391 TI - Central Nervous System Complications Following Spine Surgery. PMID- 29252392 TI - Intracortical or Transcortical Chondroma: A Report of Two Cases. PMID- 29252393 TI - Open Anterior Transverse (Divergent) Dislocation of the Elbow Joint: A Case Report and Review of the Literature. PMID- 29252394 TI - Stress Fracture of the Lateral Cuneiform Bone in a Lacrosse Player: A Case Report. PMID- 29252395 TI - Stage-IV Medial Femoral Condyle Osteochondritis Dissecans Treated with Unicompartmental Arthroplasty and Trabecular Metal Augmentation: A Case Report. PMID- 29252396 TI - Anterior Hoffa Fracture of the Lateral Femoral Condyle: A Case Report. PMID- 29252397 TI - Acetabular Refracture Through Posterior Wall Malunion Treated with Sciatic Neuroplasty and Open Reduction and Internal Fixation: A Report of Two Cases. PMID- 29252398 TI - Bilateral Scapular Fracture and Triceps Tendon Rupture After a Grand Mal Seizure: A Case Report. PMID- 29252399 TI - Distant Subdural and Epidural Hematomas: A Case Report. PMID- 29252400 TI - Mechanical Failure of the OrthoPediatrics PediPlate in Late-Onset Tibia Vara with Moderate Deformity: A Report of Three Cases. PMID- 29252401 TI - Reticular Telangiectatic Erythema After Total Knee Replacement Surgery: A Report of Two Cases. PMID- 29252402 TI - Bilateral Double-Layered Patella: MRI Findings and Fusion with Multiple Headless Screws: A Case Report. PMID- 29252403 TI - Implant Retrieval Analysis of Bilateral Hip Resurfacings Obtained at Autopsy: A Case Report. PMID- 29252404 TI - Locked Elbow Joint Due to a Cartilage Flap Caused by Osteonecrosis of the Humeral Trochlea: A Case Report. PMID- 29252405 TI - Cardiovascular Monitoring During Video Urodynamic Studies in Persons With Spinal Cord Injury. AB - OBJECTIVE: The aims of the study were to observe cardiovascular responses during video urodynamic studies and to identify correlations between autonomic dysreflexia events and video urodynamic study findings in spinal cord injuries. DESIGN: Thirty-four persons with spinal cord injury were enrolled and investigated using continuous cardiovascular monitoring during video urodynamic studies. Associations between cardiovascular responses and video study variables were analyzed. RESULTS: Bladder type-specific cardiovascular responses occurred during the study. The incidence of overactive detrusor during urodynamic study and bladder trabeculation on voiding cystourethrogram was significantly higher in autonomic dysreflexia persons with spinal cord injury (P < 0.05). Systolic blood pressure changes showed moderate negative correlation (r = -0.402, P = 0.020) with bladder compliance and high positive correlation (r = 0.810, P = 0.000) with maximum detrusor pressure. However, no significant differences in neurological level of injury, injury completeness, autonomic dysreflexia symptoms, and voiding type were found. Spinal cord injury increase at each section was significantly higher in overactive detrusor group (P < 0.05). Significant bradycardia or tachycardia correlating with autonomic dysreflexia during urodynamic studies was not observed. CONCLUSIONS: Unpredictable cardiovascular reactions during urodynamic study should be considered carefully in persons with a spinal cord injury above T6. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Describe limitations of previous cardiovascular monitoring during urodynamic study to observe changes in cardiovascular responses; (2) Identify factors contributing to autonomic dysreflexia during urodynamic testing; and (3) Discuss the effect of morphologic features in voiding cystourethrogram including trabeculation and vesicourethral reflux on autonomic dysreflexia. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 29252406 TI - Mobility Functional Outcomes of Neurofibromatosis Patients: A Preliminary Report. AB - OBJECTIVE: The aim of the study was to describe the mobility outcomes of neurofibromatosis (NF) patients who received acute inpatient rehabilitation. DESIGN: This is a retrospective study of 62 consecutive neurofibromatosis patients of any age who received physical medicine and rehabilitation consultations at a comprehensive cancer center. Postoperative, inpatient rehabilitation admission and discharge functional independence measures (FIM scores) of transfers and gait and length of hospital stay were obtained from 37 patients who were transferred to inpatient rehabilitation (acute rehabilitation) and 25 who had an alternative disposition (consultation only). RESULTS: Mean age was 34 yrs. Both groups had similar postoperative FIM transfer and gait scores; however, at approximately postoperative day 10, the consultation only group was discharged with median FIM of 5 (supervision level) as compared with the acute rehabilitation group FIM of 4 (P = 0.000). The acute rehabilitation group had improved mobility FIM scores from postoperative to rehabilitation admission and again from rehabilitation admission to discharge (P < 0.0001). At discharge, the acute rehabilitation group ambulated a significantly longer distance (500 f. vs. 300 ft) (P = 0.04). The median length of hospital stay for the acute rehabilitation and consultation only groups was 20 and 10 days, respectively (P = 0.004). CONCLUSIONS: Acute inpatient rehabilitation leads to improvement in mobility-associated FIM scores for neurofibromatosis patients minimizing caregiver needs at home. PMID- 29252408 TI - Technical Complications of ACL Reconstruction. PMID- 29252409 TI - Preventing and Treating Complications After Hip Arthroscopy. PMID- 29252407 TI - Cytotoxicity of Local Anesthetics in Mesenchymal Stem Cells. AB - Cell therapy based on the trophic, mitogenic, and immunomodulatory capacity of mesenchymal stem cells is a promising treatment modality for degenerative musculoskeletal conditions. Local anesthetics have been commonly used in interventional procedures for alleviating pain, but local anesthetics may have negative impact on MSC dosing because of cytotoxicity or other biological effects. Because previous studies have not reached consensus yet on the potential complications of local anesthetics in cell therapy, we reviewed 11 studies that involve in vitro experimentation with MSCs using aminoamide-type anesthetics including lidocaine, ropivacaine, mepivacaine, bupivacaine, articaine, and prilocaine. Three studies that compare the effects of different types of local anesthetic agents showed that ropivacaine has the least detrimental effects on mesenchymal stem cell populations, whereas lidocaine seems to have the most significant effects on stem cell viability. Concentration- and time-dependent effects on cell viability were reported with bupivacaine, ropivacaine, lidocaine, and mepivacaine. We conclude that local anesthetic agents have time- and concentration-dependent detrimental effects on MSCs. However, in vivo studies will be required to understand the interactions of these agents with MSCs, because in vitro studies cannot replicate the pharmacokinetics of anesthetics in vivo or the recovery of MSCs in a more physiological environment. PMID- 29252410 TI - Delayed Candida albicans Septic Arthritis in a Pediatric Patient with Cerebral Palsy: A Case Report and Review of the Literature. PMID- 29252411 TI - Anterolateral Proximal Tibial Opening Wedge Osteotomy to Treat Symptomatic Genu Recurvatum with Valgus Alignment: A Case Report. PMID- 29252412 TI - Salvage of a Through-Knee Amputation by Performing a Femoral Shortening Osteotomy: A Case Report. PMID- 29252413 TI - Posterior Migration of a Pediatric Coronoid Fracture: A Case Report. PMID- 29252414 TI - Ultrasound-Guided Pulse Lavage for Heterotopic Ossification After Prior Hip Arthroscopy: A Case Report. PMID- 29252415 TI - Partial Hip Resurfacing for an Osteochondral Defect of the Femoral Head: A Case Report. PMID- 29252416 TI - Intrapelvic Dislocation of the Proximal Part of the Femur with Fracture of the Acetabulum: A Case Report. PMID- 29252417 TI - Surgical Treatment of Anterior Sacral Meningoceles in Patients with Marfan Syndrome: A Report of Three Cases. PMID- 29252418 TI - Acute Tetraparesis Caused by a Cervical Spine Synovial Cyst Associated with an Os Odontoideum: A Case Report. PMID- 29252419 TI - Traumatic Femoral Vein Rupture Resulting in Compartment Syndrome with Concomitant Closed Femoral Diaphyseal Fracture: A Case Report. PMID- 29252420 TI - Development of Scoliosis Following Complex Combat-Related Lower-Extremity Amputations: Two Case Reports. PMID- 29252421 TI - Anchorage of Partial Avulsion of the Heel Pad with Use of Multiple Kirschner Wires: A Report of Four Cases. PMID- 29252422 TI - Periprosthetic Fracture of the Femur After Long-Term Bisphosphonate Use: A Case Report. PMID- 29252423 TI - Iliopsoas Tendon Impingement After Total Hip Arthroplasty with Use of a Large Diameter Femoral Head: A Case Report. PMID- 29252424 TI - Fatal Cerebral Swelling Associated with Scoliosis Surgery in Two Patients with Neuromuscular Scoliosis and Congenital Hydrocephalus: A Report of Two Cases. PMID- 29252425 TI - Subcutaneous Internal-External Fixation for Pelvic Fracture Fixation: A Novel Approach for Open Fracture Fixation: A Case Report. PMID- 29252426 TI - Early Failure of a Ceramic-on-Metal Total Hip Arthroplasty: A Case Report. PMID- 29252427 TI - Compressive Brachial Plexopathy After Fixation of a Clavicular Fracture Nonunion: A Case Report. PMID- 29252428 TI - Chlorhexidine-Gluconate-Related Burns Under a Tourniquet: A Report of Two Cases. PMID- 29252429 TI - Enthesopathy of the Distal Biceps Femoris Tendon Insertion: An Unusual Case of Posterolateral Knee Pain: A Case Report. PMID- 29252430 TI - Reactive Myeloproliferative Syndrome Secondary to Tumor-Related Inflammation in Giant-Cell Tumor of the Scapula: A Case Report. PMID- 29252431 TI - A Rare Technical Complication Causing ACL Graft Failure: Aberrant Femoral Tunnel Trajectory and Posterolateral Corner Compromise: A Case Report. PMID- 29252432 TI - Complete Femoral Nerve Palsy Following Traumatic Iliacus Hematoma: A Case Report and Literature Review. PMID- 29252433 TI - Prophylactic Free Flap for Chronic Lower-Extremity Soft-Tissue Defect Prior to Total Knee Arthroplasty: A Case Report. PMID- 29252434 TI - Symptomatic Aseptic Hydrogen Pneumarthrosis as a Sign of Crevice Corrosion Following Total Hip Arthroplasty with a Modular Neck: A Case Report. PMID- 29252435 TI - Severe Thoracic Kyphosis with Neuropathy in a Three-Year-Old Child: A Case Report. PMID- 29252436 TI - Masquelet Technique for Midfoot Reconstruction Following Osteomyelitis in Charcot Diabetic Neuropathy: A Case Report. AB - CASE: We describe a case of ulcerative midfoot osteomyelitis in a patient with Charcot diabetic neuropathy. After debridement, an extensive osseous defect led to staged reconstruction in an attempt to salvage the foot. We describe the presentation, the treatment, and the technical points of this challenging case. CONCLUSION: We reconstructed the midfoot defect with use of the induced-membrane Masquelet technique, successfully reestablishing a stable, well-aligned, plantigrade, ulcer-free foot. PMID- 29252437 TI - Severe Wear and Pseudotumor Formation Due to Taper Mismatch in a Total Hip Arthroplasty: A Case Report. AB - CASE: We describe the case of a seventy-six-year-old woman who had undergone bilateral total hip arthroplasty with Zweymuller-Metasul prostheses in 1996. After a fall sixteen years after the index procedures, radiographs suggested a taper fracture of the left total hip arthroplasty. However, revision surgery showed pseudotumor formation, with no evidence of taper fracture. Analysis of the prosthesis showed massive wear of the male stem taper caused by a mismatch between the stem taper and the head taper. CONCLUSION: This case vividly demonstrates how taper size mismatch can cause dramatic metal wear and increased release of metal ions, resulting in pseudotumor formation. PMID- 29252438 TI - Ciprofloxacin-Induced Extensor Tendon Rupture in the Hand: A Case Report. AB - CASE: An eighty-one-year-old man had begun taking ciprofloxacin one week prior to the sudden inability to extend the metacarpophalangeal joint of the ring finger of the dominant right hand. He presented to us three months after he initially noticed this finding. CONCLUSION: Ciprofloxacin-induced tendon rupture appears to be possible in the extensor digitorum communis tendons of the hand. Our patient was managed operatively and had a good functional outcome. PMID- 29252439 TI - Trephine Use During Revision Total Hip Arthroplasty Resulting in Diaphyseal Osteonecrosis and Stress Fracture: A Case Report. AB - CASE: A fifty-three-year-old woman presented with a fracture of an extensively porous-coated femoral component. Revision was performed with use of trephine reamers to remove the distal portion of the stem. Despite radiographs that showed an acceptable position of the revision stem, she experienced substantial thigh pain at four months postoperatively, which persisted at twelve months. A technetium-99m bone scan demonstrated a 5-cm photopenic region, suggestive of thermal osteonecrosis. Two months later, there was evidence of callus formation, which is consistent with a stress fracture. The fracture was treated with protected weight-bearing; it healed with nonoperative management and resolution of the pain. CONCLUSION: A diaphyseal stress fracture secondary to thermal osteonecrosis associated with trephine use developed after removal of a broken femoral component; it healed without surgical intervention. PMID- 29252440 TI - Unusual Complications Associated with Gout. PMID- 29252441 TI - Stress Fracture of the Femoral Neck Through Previously Inserted Metallic Hardware: A Case Report. PMID- 29252442 TI - Spondylodiscitis After Ingestion of a Lithium Button Battery: A Case Report. PMID- 29252443 TI - Proximal Tibial Epiphyseal Fracture in a Newborn Following Cesarean Section: A Case Report. PMID- 29252444 TI - Acute Comminuted Pathologic Fracture of a Hallucal Sesamoid with Tophaceous Gout: A Case Report. PMID- 29252445 TI - Posterior Shoulder Instability with a Reverse Hill-Sachs Defect: Repair with Use of Combined Arthroscopic Labral Repair and Fracture Disimpaction: A Case Report. PMID- 29252446 TI - Bisphosphonate-Associated Subtrochanteric Femoral Fracture with Profound Proximal Cortical Thickening and Canal Narrowing Requiring Blade-Plate Fixation: A Report of Two Cases. PMID- 29252447 TI - Severe and Strange Consequences of Arthroplasty Component Wear. PMID- 29252448 TI - Interferon-Induced Transmembrane Protein 5 Mutation Causing Type-V Osteogenesis Imperfecta: A Case Report. AB - CASE: We report a case of heterozygous mutation of c.-14C>T in the 5' untranslated region of the interferon-induced transmembrane protein 5 in a nine year-old girl. She was diagnosed with type-V osteogenesis imperfecta based on the classic features of bone fragility, radial head dislocation, forearm interosseous membrane calcification, limited forearm rotation, hyperplastic callus formation, and radiodense metaphyseal bands, as well as absent blue sclerae, absence of hearing loss, and absence of dentinogenesis imperfecta. CONCLUSION: Although the differential diagnosis may include infantile cortical hypertrophy, child abuse, or a malignant tumor (e.g., osteosarcoma), the presence of typical clinical and radiographic features and characteristic gene mutation helps confirm the diagnosis of type-V osteogenesis imperfecta. PMID- 29252449 TI - Acute Decompression for Peroneal Nerve Palsy Following Primary Total Knee Arthroplasty: A Report of Two Cases. AB - CASE: Two cases of peroneal nerve palsy following primary total knee arthroplasty are presented. Treatment included acute decompression of the peroneal nerve, with full neurological recovery. CONCLUSION: Acute peroneal nerve decompression is a viable option for patients with peroneal nerve palsy after primary total knee arthroplasty. PMID- 29252450 TI - Atypical Osteomyelitis Caused by Mycobacterium chelonae in a Nonimmunocompromised Patient: A Case Report. AB - CASE: A previously healthy fifty-seven-year-old woman presented with an acute atypical mycobacterial infection of the first metatarsal bone of the left foot. Despite antimicrobial treatment, the infection was not controlled. First-ray amputation was performed, and antimicrobial treatment was continued for a total of six months. The patient was fitted with an orthotic (insole) and followed for eighteen months; there was no recurrence of infection. CONCLUSION: To the best of our knowledge, this is the first case report describing Mycobacterium chelonae osteomyelitis of the first metatarsal ray in an immunocompetent individual. This diagnosis should be considered in patients with osteomyelitis that persists despite the use of broad-spectrum antibiotics, even in healthy individuals. PMID- 29252451 TI - Alternative Bone Graft Sources and Techniques for Tibiofibular Synostosis Creation Following Transtibial Amputation: A Report of Two Cases. AB - CASE: Alternative methods of the modified Ertl osteomyoplasty with use of two different tibial grafts for synostosis are presented in two patients who underwent revision transtibial amputation. CONCLUSION: These two techniques spare residual limb length relative to other described local techniques, avoid the morbidity of remote autograft harvest, and may be attempted in patients with inadequate residual limb lengths or in those who have tibiofibular length mismatch to achieve stable bridge synostosis. PMID- 29252452 TI - Acute Multifocal Osteomyelitis Following Acupuncture: A Case Report. PMID- 29252453 TI - Functional Gait Analysis Before and After Delayed Military Trauma-Related Amputation: A Report of Three Cases. PMID- 29252454 TI - Pseudogout Mimicking Infection Following Total Knee Arthroplasty: A Report of Two Cases. PMID- 29252455 TI - Acrometastasis: First Metatarsophalangeal Joint Pain Due to Metastatic Lung Cancer: A Case Report. PMID- 29252456 TI - Acute Intraoperative Ventriculoperitoneal Shunt Failure in a Child with Myelomeningocele: A Case Report. PMID- 29252457 TI - An Anterolateral Thigh Perforator Flap for the Treatment of Defects After Resection of an Arteriovenous Malformation of the Foot: A Case Report. PMID- 29252458 TI - Myositis Ossificans Traumatica Secondary to Fracture of the Odontoid in a Five Month-Old Infant: A Case Report. PMID- 29252459 TI - Late Neurovascular Compromise Secondary to a Malunited Clavicular Fracture in a Preadolescent: A Case Report. PMID- 29252460 TI - Fracture of the Sesamoid Bone of the Index Finger: A Case Report. PMID- 29252461 TI - Jaffe-Campanacci Syndrome: A Case Report and Review of Literature. PMID- 29252462 TI - Bilateral Peroneal Nerve Palsy After Bilateral Hip Osteotomy in a Patient with Multiple Hereditary Exostosis: A Case Report and Review of the Literature. PMID- 29252463 TI - Acute Postoperative Renal Failure Following Insertion of an Antibiotic Impregnated Cement Spacer in Revision Total Joint Arthroplasty: Two Case Reports. PMID- 29252464 TI - Recognition of Small Bowel Entrapment in the Pubic Symphysis Following Combat Related Traumatic Pelvic Fracture: A Case Report and Literature Review. PMID- 29252465 TI - Diaphyseal Femoral Fracture After Long Unlocked Cephalomedullary Nailing of an Intertrochanteric Fracture of the Femur: A Case Report and Review of the Literature. PMID- 29252466 TI - Backflow from a Metallosis-Induced Intrapelvic Mass into a Revision Hip Arthroplasty: A Case Report. PMID- 29252467 TI - Coloarticular Fistula Associated with a Pseudotumor After Metal-on-Metal Hip Resurfacing Arthroplasty: A Case Report. PMID- 29252468 TI - Bilateral Proximal Fifth Metatarsal Nonunion Treated with Gastrocnemius-Soleus Recession: A Case Report. PMID- 29252469 TI - Isolated Distal Posterior Interosseous Nerve Palsy Mimicking Extensor Pollicis Longus Tendon Rupture: A Case Report and Review of the Literature. PMID- 29252470 TI - Sacral Foraminal Osteochondroma Causing Radiculopathy: A Case Report. PMID- 29252471 TI - A Different Kind of Open Mind: The Current State of Depth of Anesthesia Monitoring. PMID- 29252472 TI - To Clot or Not to Clot: Understanding Coagulopathy in Liver Disease. PMID- 29252473 TI - Anesthesia & Analgesia: Update and a Year in Review. PMID- 29252474 TI - Inadvertent Perioperative Hypothermia Induced by Spinal Anesthesia for Cesarean Delivery Might Be More Significant Than We Think: Are We Doing Enough to Warm Our Parturients? PMID- 29252475 TI - Efficiency, Paths, Goals, and Frontiers in Graduate Education: New Uses for Old Concepts. PMID- 29252476 TI - Are You Down With TPP? Considering Transpulmonary Pressures as Opposed to Ventilator-Measured Pressures. PMID- 29252477 TI - "However Beautiful the Strategy, You Should Occasionally Look at the Results": Sir Winston Churchill and Medical Checklists. PMID- 29252478 TI - Postoperative Atrial Fibrillation and Maslow's Hammer. PMID- 29252479 TI - The Pediatric Elephant in the Room. PMID- 29252480 TI - The Eye of the Beholder. PMID- 29252481 TI - Insight Into Our Technologies: A New Series of Manuscripts in Anesthesia & Analgesia. PMID- 29252483 TI - Writing Research Reports. AB - Clear writing makes manuscripts easier to understand. Clear writing enhances research reports, increasing clinical adoption and scientific impact. We discuss styles and organization to help junior investigators present their findings and avoid common errors. PMID- 29252484 TI - Does the Risk Scale Predict Emergence Agitation in Children? PMID- 29252485 TI - In Response. PMID- 29252486 TI - Stress Fracture of the Lateral Cuneiform Bone in a Lacrosse Player. PMID- 29252487 TI - Stage-IV Medial Femoral Condyle Osteochondritis Dissecans Treated with Unicompartmental Arthroplasty and Trabecular Metal Augmentation. PMID- 29252488 TI - Anterior Hoffa Fracture of the Lateral Femoral Condyle. PMID- 29252489 TI - Acetabular Refracture Through Posterior Wall Malunion Treated with Sciatic Neuroplasty and Open Reduction and Internal Fixation. PMID- 29252491 TI - Ultrasound Can Help Solve Orthopaedic Mysteries. PMID- 29252490 TI - Bilateral Scapular Fracture and Triceps Tendon Rupture After a Grand Mal Seizure. PMID- 29252492 TI - Overcoming Growth-Plate Disturbances Around the Knee. PMID- 29252493 TI - Hip Osteonecrosis: Some Mysterious Etiologies. PMID- 29252494 TI - Aneurysmal Bone Cyst of the Patella Mimicking Patellofemoral Syndrome: A Case Report. PMID- 29252495 TI - Intraneural Synovial Sarcoma of the Digital Nerve in a Hand: A Case Report and Review of the Literature. PMID- 29252496 TI - Bullet Extraction from the Sacroiliac Joint with an Arthroscopically Assisted Dual Guidewire Technique: A Case Report. PMID- 29252497 TI - Avoiding Complications from Arthroplasty and Anticoagulation. PMID- 29252498 TI - Spontaneous Dural Tear Presenting as an Acute-Onset Headache After a Minor Fall: A Case Report. PMID- 29252499 TI - Warfarin-Induced Skin Necrosis After Total Knee Arthroplasty: A Case Report. PMID- 29252500 TI - Total Hip Arthroplasty in a Patient with a Left Ventricular Assist Device: A Case Report. PMID- 29252501 TI - Ipsilateral Patellar Distal Pole and Tibial Tubercle Avulsion Fractures in an Adolescent: A Case Report and Review of the Literature. PMID- 29252502 TI - Successful Limb Salvage of a "Too-Short Segment" of the Proximal Part of the Femur with Use of a Compression Osseointegration Implant: A Case Report. PMID- 29252503 TI - Extraskeletal Osteochondroma of the Leg: A Case Report. PMID- 29252504 TI - Bone Marrow Edema Syndrome of the Proximal Part of the Femur Following Gastric Bypass Surgery: A Case Report. PMID- 29252505 TI - Acral Dedifferentiated Chondrosarcoma of a Toe Phalanx: A Case Report. PMID- 29252506 TI - Os Acromiale Rupture Associated with a Massive Rotator Cuff Tear Causing Deltoid Insufficiency and Superior Escape of the Humeral Head: A Case Report. PMID- 29252507 TI - Spinal Column Injury at T11-T12 Causing C8 Tetraplegia Misdiagnosed as Spinal Cord Injury without Radiographic Abnormality in an Adult: A Case Report. PMID- 29252508 TI - Abuse-deterrent Opioid Formulations. AB - Abuse-deterrent opioid formulations have been suggested as one way to decrease the abuse, addiction, and overdose of orally prescribed opioids. Ten oral opioid formulations have received abuse-deterrent labeling by the U.S. Food and Drug Administration (FDA). Their properties consist of physical and/or chemical means by which the pills resist manipulation and create a barrier to unintended administration, such as chewing, nasal snorting, smoking, and intravenous injection. In this review, we describe the mechanisms of abuse-deterrent technology, the types of premarketing studies required for FDA approval, the pharmacology of the currently approved abuse-deterrent opioid formulations, and the evidence for and against their influence on opioid abuse. We conclude that there is currently insufficient evidence to indicate that the availability of abuse-deterrent opioid formulations has altered the trajectory of opioid overdose and addiction; however, postmarketing studies are in their infancy, and novel deterrent formulations are continually being developed and submitted for marketing approval. PMID- 29252509 TI - Dexmedetomidine Prevents Cognitive Decline by Enhancing Resolution of High Mobility Group Box 1 Protein-induced Inflammation through a Vagomimetic Action in Mice. AB - BACKGROUND: Inflammation initiated by damage-associated molecular patterns has been implicated for the cognitive decline associated with surgical trauma and serious illness. We determined whether resolution of inflammation mediates dexmedetomidine-induced reduction of damage-associated molecular pattern-induced cognitive decline. METHODS: Cognitive decline (assessed by trace fear conditioning) was induced with high molecular group box 1 protein, a damage associated molecular pattern, in mice that also received blockers of neural (vagal) and humoral inflammation-resolving pathways. Systemic and neuroinflammation was assessed by proinflammatory cytokines. RESULTS: Damage associated molecular pattern-induced cognitive decline and inflammation (mean +/- SD) was reversed by dexmedetomidine (trace fear conditioning: 58.77 +/- 8.69% vs. 41.45 +/- 7.64%, P < 0.0001; plasma interleukin [IL]-1beta: 7.0 +/- 2.2 pg/ml vs. 49.8 +/- 6.0 pg/ml, P < 0.0001; plasma IL-6: 3.2 +/- 1.6 pg/ml vs. 19.5 +/- 1.7 pg/ml, P < 0.0001; hippocampal IL-1beta: 4.1 +/- 3.0 pg/mg vs. 41.6 +/- 8.0 pg/mg, P < 0.0001; hippocampal IL-6: 3.4 +/- 1.3 pg/mg vs. 16.2 +/- 2.7 pg/mg, P < 0.0001). Reversal by dexmedetomidine was prevented by blockade of vagomimetic imidazoline and alpha7 nicotinic acetylcholine receptors but not by alpha2 adrenoceptor blockade. Netrin-1, the orchestrator of inflammation-resolution, was upregulated (fold-change) by dexmedetomidine (lung: 1.5 +/- 0.1 vs. 0.7 +/- 0.1, P < 0.0001; spleen: 1.5 +/- 0.2 vs. 0.6 +/- 0.2, P < 0.0001), resulting in upregulation of proresolving (lipoxin-A4: 1.7 +/- 0.2 vs. 0.9 +/- 0.2, P < 0.0001) and downregulation of proinflammatory (leukotriene-B4: 1.0 +/- 0.2 vs. 3.0 +/- 0.3, P < 0.0001) humoral mediators that was prevented by alpha7 nicotinic acetylcholine receptor blockade. CONCLUSIONS: Dexmedetomidine resolves inflammation through vagomimetic (neural) and humoral pathways, thereby preventing damage-associated molecular pattern-mediated cognitive decline. PMID- 29252510 TI - Astrocytic N-Myc Downstream-regulated Gene-2 Is Involved in Nuclear Transcription Factor kappaB-mediated Inflammation Induced by Global Cerebral Ischemia. AB - BACKGROUND: Inflammation is a key element in the pathophysiology of cerebral ischemia. This study investigated the role of N-Myc downstream-regulated gene-2 in nuclear transcription factor kappaB-mediated inflammation in ischemia models. METHODS: Mice (n = 6 to 12) with or without nuclear transcription factor kappaB inhibitor pyrrolidinedithiocarbamate pretreatment were subjected to global cerebral ischemia for 20 min. Pure astrocyte cultures or astrocyte-neuron cocultures (n = 6) with or without pyrrolidinedithiocarbamate pretreatment were exposed to oxygen-glucose deprivation for 4 h or 2 h. Astrocytic nuclear transcription factor kappaB and N-Myc downstream-regulated gene-2 expression, proinflammatory cytokine secretion, neuronal apoptosis and survival, and memory function were analyzed at different time points after reperfusion or reoxygenation. Proinflammatory cytokine secretion was also studied in lentivirus transfected astrocyte lines after reoxygenation. RESULTS: Astrocytic nuclear transcription factor kappaB and N-Myc downstream-regulated gene-2 expression and proinflammatory cytokine secretion increased after reperfusion or reoxygenation. Pyrrolidinedithiocarbamate pretreatment significantly reduced N-Myc downstream regulated gene-2 expression and proinflammatory cytokine secretion in vivo and in vitro, reduced neuronal apoptosis induced by global cerebral ischemia/reperfusion (from 65 +/- 4% to 47 +/- 4%, P = 0.0375) and oxygen-glucose deprivation/reoxygenation (from 45.6 +/- 0.2% to 22.0 +/- 4.0%, P < 0.001), and improved memory function in comparison to vehicle-treated control animals subjected to global cerebral ischemia/reperfusion. N-Myc downstream-regulated gene-2 lentiviral knockdown reduced the oxygen-glucose deprivation-induced secretion of proinflammatory cytokines. CONCLUSIONS: Astrocytic N-Myc downstream regulated gene-2 is up-regulated after cerebral ischemia and is involved in nuclear transcription factor kappaB-mediated inflammation. Pyrrolidinedithiocarbamate alleviates ischemia-induced neuronal injury and hippocampal-dependent cognitive impairment by inhibiting increases in N-Myc downstream-regulated gene-2 expression and N-Myc downstream-regulated gene-2 mediated inflammation. PMID- 29252511 TI - Pseudotumor After Bilateral Ceramic-on-Metal Total Hip Arthroplasty: A Case Report. PMID- 29252512 TI - Nonreducible Shoulder Due to Acute Posterior Dislocation of the Long Head of the Biceps Tendon: A Case Report and Review of the Literature. PMID- 29252513 TI - Failure of a Ceramic-on-Ceramic Hip Resurfacing Due to Metallosis: A Case Report. PMID- 29252514 TI - Multifocal Osteonecrosis of the Capitella and Femoral Condyles After Stem Cell Transplantation and Corticosteroid Treatment for Acute Lymphocytic Leukemia: A Case Report. PMID- 29252515 TI - Hybrid Fixation Utilizing a Custom Stem Extension for the Treatment of Periprosthetic Femoral Nonunions Around Well-Fixed Cylindrical Femoral Stems: A Report of Two Cases. PMID- 29252516 TI - Nonoperative Treatment of Congenital Hallux Valgus: A Case Report. PMID- 29252517 TI - Periosteal Mesenchymal Chondrosarcoma in the Distal Part of the Tibia of a Four Year-Old Boy: A Case Report. PMID- 29252518 TI - An Eleven-Year Follow-up of a Custom Talar Prosthesis After Open Talar Extrusion in an Adolescent Patient: A Case Report. PMID- 29252519 TI - Eight-Year Natural Course of a Femoral Neck Deformity Secondary to an Osteoid Osteoma Discovered at Fourteen Months of Age: A Case Report. PMID- 29252520 TI - Intraosseous Epidermoid Cyst in the Femur After an Open Fracture: A Case Report. PMID- 29252521 TI - Lipoma Arborescens and Coexisting Psoriatic Arthritis: A Case Report and Review of the Literature. PMID- 29252522 TI - Ewing Sarcoma After Treatment of a Unicameral Bone Cyst of the Proximal Part of the Humerus. PMID- 29252523 TI - Traumatic Rupture of the Coracobrachialis Muscle: A Case Report. PMID- 29252524 TI - Cystic Angiomatosis: A Rare Cause of Thoracic Radiculopathy: A Case Report. PMID- 29252525 TI - Bilateral Transient Osteoporosis of the Hip: A Case Report. PMID- 29252526 TI - Material Properties of a Highly Anteverted Vitamin E-Stabilized Polyethylene Liner After Sixteen Months In Vivo: A Case Report. PMID- 29252527 TI - Anterior Dislocation of a Total Knee Prosthesis with Vascular Compromise: A Case Report. PMID- 29252528 TI - Staged Arthroscopic Rotator Cuff Repair with a Bridging Acellular Human Dermal Graft in the Treatment of Infection Following Open Rotator Cuff Repair: A Case Report. PMID- 29252529 TI - Not All Hip Pain Is Impingement: Femoral Neck Osteoid Osteoma in a Patient with a Coexisting Cam Deformity: A Case Report. PMID- 29252530 TI - Mortality from Intrathecal Baclofen Withdrawal Following Posterior Spinal Fusion: A Case Report. PMID- 29252531 TI - Slipped Capital Femoral Epiphysis in a Child with Pycnodysostosis: A Case Report. PMID- 29252532 TI - A Sixty-One-Year-Old Woman with Ischemia After Total Knee Arthroplasty: A Case Report. PMID- 29252533 TI - Biplanar Osteotomy for the Correction of Symptomatic Foot Ectrodactyly (Split Foot Deformity): A Report of Two Cases. PMID- 29252534 TI - Atrial Myxoma with Disseminated Osteolytic Embolic Lesions: A Case Report. PMID- 29252535 TI - Near Complete Necrosis of a Giant Cell Tumor After Treatment with Denosumab: A Case Report. PMID- 29252536 TI - Functional Outcome of Replantation of the Leg in an Infant: A Case Report with Six-Year Follow-up. PMID- 29252537 TI - Use of the Vertical Rectus Abdominis Muscle Flap for an Open Pelvic Fracture Secondary to a Blast Injury: A Case Report. PMID- 29252538 TI - Tuberculous Osteomyelitis of the Metatarsals: A Report of Two Cases and Literature Review. PMID- 29252539 TI - Subclinical Chronic Atlanto-Occipital Rotatory Fixation: A Case Report. PMID- 29252540 TI - A Transphyseal Fracture of the Nonossified Proximal Femoral Epiphysis as a Result of Child Abuse: A Case Report. PMID- 29252541 TI - Tuberculous Pyomyositis Masquerading as Pyogenic Infection: A Case Report. PMID- 29252542 TI - Infection in Closed Fractures: A Case Report and Literature Review. PMID- 29252543 TI - Distraction Phenomenon After Lengthening of Spinal Growing Rods: A Case Report. PMID- 29252544 TI - Proximal Tibiofibular Synostosis in a Professional Soccer Player: A Case Report. PMID- 29252545 TI - Minocycline-Induced Bone Discoloration: A Case Report. PMID- 29252546 TI - Reimplantation of an Extruded Humeral Segment into an Intact Periosteal Envelope in a Child: A Case Report. PMID- 29252547 TI - Bulk Allograft Using the Proximal Part of the Femur for a Posterosuperior Acetabular Defect: A Case Report. PMID- 29252548 TI - Effective Treatment of Posttraumatic Osteonecrosis of the Body of the Talus by Subtalar Fusion in a Child: A Case Report. PMID- 29252549 TI - Ischioplasty for Femoroischial Impingement: A Case Report. PMID- 29252550 TI - Trichinellosis Masquerading as a Soft-Tissue Mass: A Case Report. PMID- 29252551 TI - Lipoma Arborescens of the Knee Treated with Arthroscopic Synovectomy: A Case Report and Review of the Literature. PMID- 29252552 TI - Custom Reconstruction of the Distal Part of the Humerus Using Compressive Osseointegration: A Report of Three Cases. PMID- 29252553 TI - Concern About Femoral Neck Fractures in Long-Necked Modular Implants. PMID- 29252554 TI - Bilateral Iliac Fracture: An Unusual Sequela of Osteoporosis and Spinal Fusion: A Case Report. PMID- 29252555 TI - Monostotic Fibrous Dysplasia of the Lumbar Vertebra: A Case Report and Review of the Literature. PMID- 29252556 TI - Verrucous Hemangioma of the Plantar Surface of the Foot: A Case Report. PMID- 29252557 TI - Cyclic Sciatica Due to Endometriosis of the Sciatic Nerve: Neurolysis with Combined Laparoscopic and Transgluteal Approaches: A Case Report. PMID- 29252558 TI - Bilateral Compartment Syndrome of the Thigh in a College Football Athlete: A Case Report. PMID- 29252559 TI - Treatment of a Large Bone Defect of the Distal Part of the Radius After Intralesional Excision of Stage-III Recurrent Giant Cell Tumor by Bone Regeneration. PMID- 29252560 TI - Surgical Approaches to Deficient Knee Extensor and Collateral Mechanisms. PMID- 29252561 TI - Timothy Syndrome: A Life-Threatening Syndactyly Association: A Case Report. PMID- 29252562 TI - Myositis Ossificans Circumscripta Occurring in the Subacromial Space with Severe Mechanical Blocking of the Shoulder Joint: A Case Report. PMID- 29252563 TI - Sequential Ipsilateral Avulsion of the Anterior Inferior Iliac Spine and the Anterior Superior Iliac Spine in an Adolescent Patient: A Case Report. PMID- 29252564 TI - Fracture of the Cam Mechanism of a Posterior-Stabilized Total Knee Femoral Component: A Previously Unrecognized Mode of Failure: A Case Report. PMID- 29252566 TI - Atypical Femoral Fractures: An Update. PMID- 29252565 TI - A Scaphoid Osteochondral Autograft for Reconstruction of the Lunate Fossa of the Distal Part of the Radius After a Complex Open Fracture: A Case Report. PMID- 29252567 TI - Bernese Periacetabular Osteotomy in a Young Adult with an Ipsilateral Renal Transplant: A Case Report. AB - CASE: An eighteen-year-old woman was referred to our center because of left groin pain and was diagnosed with acetabular dysplasia. The proposed treatment was a Bernese periacetabular osteotomy (PAO). The patient had undergone two renal transplants due to polycystic kidney disease; the current, functional kidney was at the lateral inguinal fossa on the left side. The patient was on chronic immunosuppressants and antihypertensive therapy. CONCLUSION: The present case shows that PAO can be a safe procedure with good outcomes even in patients who have undergone renal transplantation. PMID- 29252568 TI - Intrathoracic Glenohumeral Dislocation without Fracture of the Humerus: A Case Report and Review of the Literature. AB - CASE: A fifty-three-year-old man presented with an intrathoracic glenohumeral dislocation (ITGHD) and associated hemothorax, rib fracture, massive rotator cuff tear, and axillary nerve palsy following an ice hockey injury. Treatment consisted of closed reduction and staged open rotator cuff repair. Despite a substantial injury, the patient recovered nearly normal use of the arm two years postoperatively. CONCLUSION: ITGHD is an extremely rare entity. This injury should be managed by a multidisciplinary team with anticipation of associated thoracic and vascular injuries. In cases with repairable pathology (e.g., an acute rotator cuff tear), good functional outcomes can be obtained. PMID- 29252569 TI - A Pseudoaneurysm of a Peripheral Artery Arising Four Years After Trauma to a Limb: A Case Report. AB - CASE: A young woman who underwent plate fixation for a radial shaft fracture had an uneventful recovery for four years. Subsequently, over a four-month period, a slowly progressing swelling appeared in the forearm with no features of vascular insufficiency, bruits, or pulsatility. Doppler ultrasonography and computed tomography revealed a pseudoaneurysm arising from the ulnar artery. The patient was treated with exploration, evacuation of the clot, aneurysm repair, and implant removal. CONCLUSION: To our knowledge, this is the longest period of quiescence reported for a posttraumatic pseudoaneurysm. A late pseudoaneurysm is possible in previously operated limbs, even after years of recovery and the absence of the typical features of vascular lesions. PMID- 29252570 TI - Postoperative Blindness Due to Posterior Reversible Encephalopathy Syndrome Following Spine Surgery: A Case Report and Review of the Literature. PMID- 29252571 TI - Unusual Late Metastasis of Adamantinoma Presenting Thirty Years After Resection of Original Tumor. PMID- 29252572 TI - Soft-Tissue Gas Can Signify Life-Threatening Conditions. PMID- 29252573 TI - Failure of Primary Total Hip Arthroplasty Secondary to New Onset of Paget Disease: A Case Report. AB - CASE: Paget disease of bone occurs in 3% to 4% of the population over fifty years of age, more often in men than in women. There is no known genetic basis for the disease, which is often diagnosed via incidental radiographic findings. We present a seventy-seven-year-old man with new-onset Paget disease after total hip arthroplasty, leading to loosening of the femoral stem and necessitating revision. CONCLUSION: This case emphasizes the need for thoughtful evaluation of patients with failed arthroplasty and proposes steps for an appropriate workup prior to revision surgery. PMID- 29252574 TI - Initial Treatment of "Pelvic Injuries" with Commercially Available Pelvic Binders Results in Displacement of Acetabular Fractures: A Report of Three Cases. AB - CASES: Three hemodynamically stable patients with displaced acetabular fractures were treated with commercially available pelvic binders after blunt trauma. In two of the patients, placement of the binder corresponded with transfer from a community hospital to a tertiary care facility. CONCLUSION: The pelvic binder is an increasingly utilized portable device that can provide lifesaving tamponade in patients with hemodynamically unstable pelvic injuries. However, incorrect application of the device may expose patients to unnecessary morbidity. This report demonstrates the need to establish appropriate guidelines and provide training for first responders and community physicians who are likely to encounter these fractures in the acute setting. PMID- 29252575 TI - Checkrein Deformity Associated with Intra-Articular Talar Fracture: A Report of Three Cases. AB - CASES: We present three cases of checkrein deformity associated with intra articular talar fracture. Two of the cases were secondary to entrapment of the flexor hallucis longus (FHL) tendon between fracture fragments, and one was related to the increased pathway of the FHL tendon around the dislocated talar body. All cases were diagnosed and treated on the day of injury. CONCLUSION: Physicians should suspect the entrapment of the FHL tendon in cases of flexion deformity of the hallux associated with talar fracture. Proper examination of the forefoot when a patient presents with a hindfoot injury will help to avoid missing such deformities. PMID- 29252576 TI - Necrotizing Soft-Tissue Infection of the Thumb: A Case Report. AB - CASE: We present the case of a fifty-three-year-old man who presented with a necrotizing soft-tissue infection (NSTI) of the thumb, which tracked along the flexor pollicis longus tendon into the space of Parona. In this case report, we review the clinical and laboratory findings diagnostic of NSTI as well as the appropriate initial treatment for this challenging problem. CONCLUSION: NSTI is a rare, life-threatening condition that must be identified and treated promptly for optimal results. In our patient, although we amputated the necrotic thumb, we were able to salvage the remaining hand and wrist despite more proximal involvement. PMID- 29252577 TI - Severe Dry Eye in CD25 Deficiency Syndrome. AB - CD25 deficiency (Interleukin-2 receptor alpha deficiency) is a rare subtype of combined B- and T-cell immunodeficiency. Recurrent infections and lymphocyte infiltration of multiple tissues are the main clinical presentations. Only four patients have been reported in whom ophthalmological findings were not described. In this article, ocular findings of CD25 deficiency in a 12-year-old child are highlighted. PMID- 29252578 TI - Slipped Capital Femoral Epiphysis: Preventing and Managing Complications. PMID- 29252579 TI - Iatrogenic Meniscus Posterior Root Injury Following Reconstruction of the Posterior Cruciate Ligament: A Report of Three Cases. PMID- 29252580 TI - Displaced Insufficiency Femoral Neck Stress Fracture in the Setting of Ochronosis: A Case Report. PMID- 29252581 TI - Tumor-Induced Osteomalacia Secondary to a Fibroblast Growth Factor 23-Secreting Phosphaturic Mesenchymal Tumor in the Foot. PMID- 29252582 TI - Staged Management of Osteonecrosis with Open Reduction and Hinged Distraction After a Slipped Capital Femoral Epiphysis: A Case Report. PMID- 29252583 TI - Thoracic Extradural Intraspinal Synovial Cyst Causing Progressive Myelopathy: A Case Report. PMID- 29252584 TI - Restoring Cartilage: The Holy Grail of Orthopaedics. PMID- 29252585 TI - Locked Metacarpophalangeal Joint of the Middle Finger Caused by a Lipoma in the Flexor Tenosynovium: A Case Report. PMID- 29252586 TI - Metal Hypersensitivity Mimicking Periprosthetic Erysipelas-Like Infection: A Case Report. PMID- 29252587 TI - Fracture of an Exeter Stem: A Case Report. PMID- 29252588 TI - Aspirin Versus Heparin for Management of Cerebellar Stroke After Vertebral Artery Dissection Following C1-C2 Fracture-Dislocation: A Case Report. PMID- 29252589 TI - Femoral Lengthening Over an Intramedullary Nail: A Case of Failed Distraction: A Case Report. PMID- 29252590 TI - Dislocation After Hip Arthroscopy for Cam-Type Femoroacetabular Impingement Leading to Progressive Arthritis: A Case Report. AB - CASE: We present the case of a fifty-two-year-old man who underwent hip arthroscopy for cam-type femoroacetabular impingement and had an anterior hip dislocation three weeks postoperatively. The patient did not have any of the previously identified risk factors for instability after hip arthroscopy. He underwent revision involving capsular repair and removal of loose bodies but progressed to needing total hip arthroplasty within two years. CONCLUSION: This case illustrates that even patients without the previously reported risk factors for hip instability are at risk of dislocation after hip arthroscopy and this can lead to rapid joint degeneration necessitating arthroplasty. PMID- 29252591 TI - Brachial Plexopathy Following Use of Recombinant Human BMP-2 for Treatment of Atrophic Delayed Union of the Clavicle. AB - CASE: Although recombinant human bone morphogenetic protein-2 (rhBMP-2) is approved for treatment of open tibial fractures and anterior lumbar interbody fusion, off-label use has been associated with complications such as local inflammation, osteolysis, and dysphagia. This case report describes a patient treated with rhBMP-2 for an atrophic delayed union of a clavicular fracture who subsequently developed a profound motor and sensory brachial plexopathy. CONCLUSION: Use of rhBMP-2 near peripheral nerves may cause neuropathy. This should be considered prior to its use in surgical sites with peripheral nerves in proximity. PMID- 29252592 TI - Single-Stage Corrective Osteotomies for Multiple Angular Deformities Around the Knee Joint with Patellar Instability in a Patient with Multiple Epiphyseal Dysplasia: A Case Report. AB - CASE: It is rare to find a case report on combined recurvatum and valgus deformity of the knee with associated patellar instability due to a depressed lateral tibial plateau in a young adult with multiple epiphyseal dysplasia. We treated such a patient with single-stage osseous and soft-tissue procedures and achieved a stable, well-aligned, pain-free, and mobile joint. CONCLUSION: Patellar instability with genu recurvatum and genu valgum leading to reduced range of motion of the knee in multiple epiphyseal dysplasia shows mechanical and functional improvement following single-stage surgical intervention, thereby improving quality of life. PMID- 29252594 TI - Lymphoma's Musculoskeletal Manifestations. PMID- 29252593 TI - Emphysematous Cystitis Found Incidentally in a Patient Undergoing Hip Arthroplasty: A Case Report. AB - CASE: Emphysematous cystitis is a rare, complicated urinary tract infection that is potentially life-threatening if left untreated. We present the case of an eighty-one-year-old woman with left hip pain from a low-energy fall with no associated urinary symptoms. Pelvic computed tomography revealed a left femoral neck fracture and an air-fluid level in the bladder. Bipolar hemiarthroplasty was delayed for three weeks to allow for the potentially serious urinary tract infection to resolve. CONCLUSION: Increased awareness is required for early diagnosis and treatment of asymptomatic emphysematous cystitis in a patient presenting with musculoskeletal symptoms. PMID- 29252595 TI - Combined Volar Hamate Dislocation and Scapholunate Ligament Rupture: A Case Report. AB - CASE: A twenty-two-year-old male patient presented to our trauma center after a motor-vehicle accident in which he sustained multiple injuries, including a volar dislocation of the hamate and ipsilateral scapholunate dissociation. Following closed reduction of the hamate dislocation, open reduction and stabilization of these carpal injuries was undertaken two days post-injury via a dorsal approach. Percutaneous Kirschner wires were used as well as two mini suture anchors to repair the scapholunate ligament. The patient was immobilized for six weeks and Kirschner wires were removed at twelve weeks postoperatively. CONCLUSION: To our knowledge, hamate dislocation with scapholunate dissociation and its surgical treatment have not previously been described. Successful surgical treatment for this injury pattern may be performed dorsally via direct reduction and repair of the scapholunate ligament with percutaneous pinning of the affected carpal bones. PMID- 29252596 TI - Primary Lymphoma of Bone Complicating Total Knee Arthroplasty: An Unexpected Mode of Prosthesis Failure: A Case Report. AB - CASE: Primary lymphoma of bone is a rare musculoskeletal malignancy that typically arises in long bones. Few cases of bone lymphoma occurring alongside orthopaedic implants have been reported in the literature. We describe the complex case of a seventy-eight-year-old woman who developed diffuse large B-cell lymphoma of the proximal part of the tibia five years after a successful total knee arthroplasty. CONCLUSION: Several studies have suggested a link between orthopaedic implants and genomic instability, although true carcinogenesis remains questionable. Lymphoma complicating joint arthroplasty poses a unique problem for orthopaedic physicians due to diagnostic challenges and the unique implications of disease and treatment-related complications. PMID- 29252597 TI - Femoral Head-Trunnion Dissociation Secondary to Corrosion of a Modular Total Hip Replacement: A Case Report. AB - CASE: We report a rare case of modular femoral head-trunnion dissociation. The patient presented with a sudden onset of groin pain and an inability to bear weight. Intermittent clunking was reported to have started around five years after implantation of the hip replacement. The duration of symptoms, radiographic findings, and analysis of the retrieved components support the theory of chronic trunnion failure due to corrosion. CONCLUSION: This is, to our knowledge, the first case of dissociation of the femoral head from the trunnion in which substantial macroscopic wear of the trunnion was observed and likely contributed to the dissociation. A new onset of clicking or clunking should be investigated as it may be a harbinger of head-neck dissociation. PMID- 29252598 TI - Bilateral Atypical Femoral Fracture in a Man on Long-Term Bisphosphonate and Glucocorticoid Therapy: A Case Report. AB - CASE: We present here, to our knowledge, the first case of a male patient with a sequential bilateral atypical femoral fracture associated with long-term use of bisphosphonates to treat glucocorticoid-induced osteoporosis. CONCLUSIONS: Given the known effectiveness of bisphosphonates, both their use and the potential complication of rare atypical femoral fractures have increased. These fractures are understood to occur when there is an alteration in the bone quality and its resistance to fatigue fracture in a subgroup of patients receiving bisphosphonates or denosumab. PMID- 29252599 TI - Laminoplasty is the Preferred Procedure for a Posteriorly Based Multilevel Surgery in a Patient With a Neutral Spine and Cervical Spondylotic Myelopathy: True or False? PMID- 29252601 TI - A Plethora of Complications from Paget Disease. PMID- 29252602 TI - A Rare Presentation of Sciatic Palsy Due to Hematoma After Use of the Kocher Langenbeck Approach to the Acetabulum. AB - CASE: A delayed sciatic palsy caused by compression due to hematoma formation is a rare complication of total hip arthroplasty. We report the case of a twenty seven-year-old man who underwent open reduction and internal fixation of transverse and posterior wall acetabular fractures with posterior hip dislocation and had development of a delayed sciatic palsy due to the formation of a hematoma five days after the procedure. CONCLUSION: A patient who presents with a delayed onset sciatic palsy with signs and symptoms of a hematoma after an acetabular surgery represents a surgical emergency. Early recognition and urgent decompression offers the best chance of nerve recovery. PMID- 29252603 TI - Heterotopic Transarticular Replantation: A Functional Reconstruction Design for a Mutilated Hand with Multiple Digit Involvement. AB - CASE: A patient sustained a high-energy trauma that resulted in amputation of the middle and ring fingers, along with injuries to the thumb and the index finger. The amputations were not clean; therefore, heterotopic replantation of the best amputated part of the finger to the most functional stump was undertaken. Transarticular replantation was done at the level of the proximal interphalangeal joint without osseous fixation. Early active motion was initiated the next day. The replanted finger had excellent function. CONCLUSION: Whenever possible, designing a heterotopic transarticular replantation can minimize the functional drawbacks resulting from the prolonged immobilization often associated with fracture fixation. PMID- 29252600 TI - Vitamin D, parathyroid hormone and cardiovascular risk: the good, the bad and the ugly. AB - : 25-Hydroxyvitamin D insufficiency and increased cardiovascular risk (CVR) association is still debated. The vitamin D (VitD)-dependent parathyroid hormone (PTH) is considered as the possible actuator of VitD effects on CVR. To investigate the association of CVR, PTH and VitD, we carried out blood pressure measurements and blood samples and collected information on dietary habits, anamnestic, clinical and metabolic data of 451 participants in the Salerno area (Southern Italy) during the World Hypertension Day (17 May). CVR was calculated according to the Framingham CVR charts. The overall population mean age was 51.6 +/- 0.7 years, and female sex was slightly prevalent (55%). VitD deficiency (<20 ng/ml) was most frequent (59.7%). In this population, VitD and CVR did not correlate. VitD and PTH inversely correlated (r = -0.265, P < 0.001) as expected. PTH was in direct correlation (r = 0.225, P < 0.001) with CVR. Elevated PTH (75 percentile; >=49.5 pg/ml) levels identify a population with higher CVR (11.8 +/- 0.5 vs. 8.5 +/- 0.3, P < 0.001). In a multivariate analysis, both age and PTH correlate to CVR, but not VitD. In conclusion, VitD does not directly affect CVR in the overall population. Rather, increased PTH might be a better predictor of CVR. PMID- 29252604 TI - Intraprosthetic Dislocation of Dual-Mobility Bearings Associated with Closed Reduction. AB - CASE: We present two patients with dual-mobility total hip arthroplasty components who underwent closed reduction of posterior dislocations with conscious sedation in the emergency room. Following closed reduction, both patients had immediate pain, clicking, and grinding of the hip. Radiographs identified intraprosthetic dislocation of the dual-mobility components, and revision surgery was required. CONCLUSION: When dislocation of a dual-mobility bearing occurs, the surgeon should consider performing a careful closed reduction with muscle paralysis and use of fluoroscopic guidance in the operating room to avoid intraprosthetic dislocation. PMID- 29252605 TI - Long-Term Results of Carpal Tunnel and Trigger Finger Releases in a Patient with Hurler Syndrome. AB - CASE: Prior to the emergence of bone marrow transplantation as a treatment for Hurler syndrome, most individuals with this syndrome did not survive into their teenage years. We describe a twenty-three-year-old patient with Hurler syndrome who had been treated with bone marrow transplantation; we focus on the presentation and treatment of the associated carpal tunnel syndrome and trigger digits. After initial trigger digit release and revision bilateral carpal tunnel release with a tenosynovectomy, he maintained symptom-free hand function. CONCLUSION: Surgical treatment of median nerve compression and trigger digits due to Hurler syndrome is effective in the long term. PMID- 29252606 TI - Posterior Tibial Artery Perforator-Based Fascial Flap for Skin Necrosis and Exposed Extensor Tendon After Revision Total Ankle Replacement. AB - CASE: Delayed wound-healing of anterior ankle incisions can be problematic for patients who have undergone total ankle replacement. We describe the case of a patient in whom a posterior tibial artery perforator-based fascial flap was effectively used to cover skin necrosis and to repair the extensor retinaculum in a wound following revision total ankle replacement. CONCLUSION: When a tendon is exposed in the ankle, a skin flap is generally required. The creation of a perforator-based fascial flap is a useful technique for covering a wound with an exposed tendon and is an alternative to a musculocutaneous flap. PMID- 29252607 TI - Length-Preserving Intramedullary Femoral Fixation for Traumatic Leg Amputation. AB - CASE: We present the case of a twenty-one-year-old woman with a traumatic left leg amputation, substantial proximal skin degloving, and an ipsilateral femoral fracture treated with revision amputation distal to the fracture site and retrograde femoral nailing through the amputation site. CONCLUSION: A short retrograde femoral nail is a surgical option to fix a femoral shaft fracture proximal to a traumatic amputation in order to preserve limb length for effective prosthetic fit and ambulation. PMID- 29252608 TI - Progression and Treatment of Bilateral Knee Bone Marrow Edema Syndrome. AB - CASE: We report the case of a patient with bilateral multicompartmental bone marrow edema syndrome of the knee, which responded favorably to subchondral core decompression after failing to respond to nonoperative treatment. CONCLUSION: This case demonstrates that subchondral core decompression can be effective for the treatment of bone marrow edema syndrome. PMID- 29252609 TI - Vascular Malformations Corresponding to Sclerotomes in Multifocal Melorheostosis: Painful Hip and Knee Contractures Treated with Total Joint Arthroplasty. AB - CASE: A forty-three-year-old male patient complained of difficulty walking due to severe hip and knee pain and stiffness, which had persisted for twenty years. He was found to have multifocal melorheostosis involving the axial skeleton and the entire left lower limb, along with complex vascular and lymphatic malformations corresponding to the sclerotomes related to the skeletal anomalies. Total hip and knee arthroplasties were performed. He was eventually free of pain during walking, and joint motion of the hip and knee was substantially improved after surgery. CONCLUSION: Hip and knee pain and contracture resulting from multifocal melorheostosis were successfully treated with total hip and knee arthroplasty. PMID- 29252610 TI - Reliability and performance of the Swiss Emergency Triage Scale used by paramedics. AB - OBJECTIVES: No general emergency department triage scale has been evaluated for prehospital triage. The objective of this study was to evaluate the reliability and the performance of the Swiss Emergency Triage Scale (SETS) used by paramedics to determine the emergency level and orientation of simulated patients. PATIENTS AND METHODS: In a prospective cross-sectional study, 23 paramedics evaluated 28 clinical scenarios with the SETS using interactive computerized triage software simulating real-life triage. The primary outcome was inter-rater reliability regarding the triage level among participants measured by intraclass correlation coefficient (ICC). Secondary outcomes were the accuracy of triage level and the reliability and accuracy of orientation of patients of at least 75 years to a dedicated geriatric emergency centre. RESULTS: Twenty-three paramedics completed the evaluation of the 28 scenarios (644 triage decisions). Overall, ICC for triage level was 0.84 (95% confidence interval: 0.77-0.99). Correct emergency level was assigned in 89% of cases, overtriage rate was 4.8%, and undertriage was 6.2%. ICC regarding orientation in the subgroup of simulated patients of at least 75 years was 0.76 (95% confidence interval: 0.61-0.89), with 93% correct orientation. CONCLUSION: Reliability of paramedics rating simulated emergency situations using the SETS was excellent, and the accuracy of their rating was very high. This suggests that in Switzerland, the SETS could be safely used in the prehospital setting by paramedics to determine the level of emergency and guide patients to the most appropriate hospital.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/. PMID- 29252611 TI - Reactive Myeloproliferative Syndrome Secondary to Tumor-Related Inflammation in Giant-Cell Tumor of the Scapula: A Case Report. PMID- 29252612 TI - A Rare Technical Complication Causing ACL Graft Failure: Aberrant Femoral Tunnel Trajectory and Posterolateral Corner Compromise: A Case Report. PMID- 29252613 TI - Complete Femoral Nerve Palsy Following Traumatic Iliacus Hematoma: A Case Report and Literature Review. PMID- 29252614 TI - Prophylactic Free Flap for Chronic Lower-Extremity Soft-Tissue Defect Prior to Total Knee Arthroplasty: A Case Report. PMID- 29252615 TI - Symptomatic Aseptic Hydrogen Pneumarthrosis as a Sign of Crevice Corrosion Following Total Hip Arthroplasty with a Modular Neck: A Case Report. PMID- 29252616 TI - Severe Thoracic Kyphosis with Neuropathy in a Three-Year-Old Child: A Case Report. PMID- 29252617 TI - Diagnosis, Treatment, and Outcome of Stenotrophomonas maltophilia Discitis and Cervical Osteomyelitis: A Case Report and Review of the Literature. AB - CASE: A fifty-six-year-old man presented with a three-month history of worsening neck pain and weakness of the right arm. Magnetic resonance imaging revealed C5 C6 osteomyelitis and discitis and a prevertebral abscess from C3 to C7. He underwent staged instrumented anterior and posterior spinal fusion from C5 to C7, with an anterior C5-C6 cervical discectomy and a C6 corpectomy. Intraoperative cultures exhibited growth of Stenotrophomonas maltophilia. The patient subsequently received five months of oral trimethoprim/sulfamethoxazole therapy. At twelve months postoperatively, he had full recovery of motor strength bilaterally. CONCLUSION: Osteomyelitis with S. maltophilia is associated with agricultural-machinery-related injuries. Surgical intervention for cervical osteomyelitis should be considered if the patient presents with a neurologic deficit or a paravertebral abscess. PMID- 29252618 TI - Avulsion Fracture of the Medial Head of the Gastrocnemius Muscle Associated with Posterior Dislocation of the Knee: A Case Report. AB - CASE: We present an extremely rare case of an avulsion fracture of the medial head of the gastrocnemius muscle associated with posterior dislocation of the knee. The patient was a fifty-one-year-old man who was hit by a car while riding a motorcycle. The avulsed fragment was reduced and fixed with a screw, which resulted in maintenance of joint reduction despite residual instability due to the multiligamentous injuries. CONCLUSION: Reduction and fixation of the bone fragment attached to the medial head of the gastrocnemius muscle is important to restore tension of the gastrocnemius muscle, which serves as an important posterior joint stabilizer. PMID- 29252619 TI - Decompressive Laminectomy Complicated by Postoperative Mycoplasma hominis Epidural Abscess and Meningitis in a Young Woman: A Case Report. AB - CASE: A twenty-eight-year-old woman underwent decompressive laminectomy and placement of an interlaminar stabilizer due to L4/L5 disc herniation. Thirteen days later she developed a fever unresponsive to meropenem and vancomycin, along with signs of meningitis. A Mycoplasma hominis epidural abscess was identified. She had no preoperative risk factors for extragenital M. hominis infection, but had had a urinary catheter inserted intraoperatively. CONCLUSION: M. hominis postoperative surgical site infection is a rarely identified complication of spinal surgery. Seeding from the genitourinary tract is the most likely source. PMID- 29252620 TI - Minimally Invasive Screw Fixation of Inferior Pubic Ramus Stress Fracture Nonunion in a Runner: A Case Report. AB - CASE: A fifty-one-year-old female runner developed a stress fracture of the inferior pubic ramus. Nonoperative treatment was initiated, but the symptoms persisted and she was diagnosed with a nonunion. After eleven months of symptoms and ten months of nonoperative treatment, including four months of complete avoidance of running, percutaneous screw fixation was performed, with radiographic and clinical healing of the fracture. CONCLUSION: While inferior pubic ramus stress fractures are usually successfully treated nonoperatively, instances of nonunion and delayed union have been described. In the present report, we describe the case of a patient in whom an inferior pubic ramus stress fracture nonunion was successfully treated with minimally invasive screw fixation. PMID- 29252621 TI - Pseudotumors After Non-MoM Hip Replacements. PMID- 29252622 TI - Failure of a Ceramic-on-Ceramic Hip Resurfacing Due to Metallosis: A Case Report. PMID- 29252623 TI - Multifocal Osteonecrosis of the Capitella and Femoral Condyles After Stem Cell Transplantation and Corticosteroid Treatment for Acute Lymphocytic Leukemia: A Case Report. PMID- 29252624 TI - Intracortical or Transcortical Chondroma: A Report of Two Cases. PMID- 29252625 TI - Open Anterior Transverse (Divergent) Dislocation of the Elbow Joint: A Case Report and Review of the Literature. PMID- 29252626 TI - Osteonecrosis in Adolescent Girls Involved in High-Impact Activities: Could Repetitive Microtrauma Be the Cause?: A Report of Three Cases. PMID- 29252627 TI - Carbon Fiber Arrow Injuries to the Wrist: More Than Meets the Eye: A Case Report. PMID- 29252628 TI - An Osteochondritis Dissecans Lesion of the Glenoid in an Adult: A Case Report. PMID- 29252629 TI - Reconstruction of Extensor Tendon Dislocation Due to Chronic Sagittal Band Rupture of the Thumb Metacarpophalangeal Joint: A Case Report. AB - CASE: We report a case of recurrent dislocation of the extensor pollicis longus and extensor pollicis brevis tendons due to chronic rupture of the radial sagittal band of the metacarpophalangeal joint of the thumb. CONCLUSION: Successful restabilization of these tendons was achieved by transferring a half slip of the abductor pollicis brevis tendon. PMID- 29252630 TI - Bilateral Discoid Medial Menisci: A Case Report. AB - CASE: We present the case of a 37-year-old man with features of a meniscal tear in 1 symptomatic knee and radiographic findings of discoid menisci in both knees. A provisional diagnosis of bilateral discoid medial menisci was made. Magnetic resonance imaging confirmed the discoid nature of the medial menisci in both knees. The symptomatic knee was managed with good results by partial meniscectomy using a routine arthroscopic procedure. CONCLUSION: Discoid medial meniscus is a relatively rare pathology of the knee joint, and bilateral cases are extremely rare. A high index of suspicion is necessary for diagnosis; only symptomatic knees should be treated surgically. PMID- 29252631 TI - Enchondroma Protuberans of the Ulna in a Pediatric Patient: A Case Report. AB - CASE: We report the case of a 3-year-old boy who presented with a distal ulnar fracture through a mixed sclerotic and lytic expansile lesion. The underlying lesion, an enchondroma protuberans, can mimic either benign or malignant bone tumors. It was successfully treated with casting and intralesional treatment. CONCLUSION: Enchondroma protuberans is a rare entity that mimics enchondroma, osteochondroma, periosteal chondroma, or chondrosarcoma. Diagnosis is typically made through both radiographic and histologic means. In this case, the pathologic fracture was successfully treated with casting followed by intralesional curettage and bone-grafting. There was no evidence of recurrence at 18 months. PMID- 29252632 TI - Successful Treatment of Mycobacterium gordonae Sacroiliitis Using a Novel Minimally Invasive Sacroiliac Joint Arthrodesis: A Case Report. AB - CASE: A 43-year-old man with a history of well-controlled HIV (human immunodeficiency virus) infection presented with sacroiliac joint destruction from a Mycobacterium gordonae infection. A sacroiliac joint arthrodesis was performed using a minimally invasive technique utilizing both biologic fusion (allograft bone with rhBMP-2 [recombinant human bone morphogenetic protein-2]) and fixation with titanium ingrowth rods. CONCLUSION: To our knowledge, this is the first reported case of infectious sacroiliitis from a nontubercular mycobacterium (M. gordonae) treated with a combination of joint debridement, biologic fusion with bone graft, and nonbiologic functional fusion using titanium ingrowth rods, all performed in a minimally invasive fashion. This strategy effectively alleviated pain and preserved function at 2 years of follow-up. PMID- 29252633 TI - Congenital Agenesis of the Posterior Elements of the Axis (C2), Occipitalization of the Atlas (C1), and Basilar Invagination in an Adult Woman: A Case Report. AB - CASE: A 55-year-old woman presented with chronic neck pain. Physical and neurological examination results were normal. Radiographs revealed absence of the posterior elements of C2 with hypertrophy of the spinous process of C3. A computed tomography scan showed occipitalization of the atlas with basilar invagination. Magnetic resonance imaging did not reveal any soft-tissue abnormalities. The patient was treated with a short course of a nonsteroidal anti inflammatory drug and physiotherapy. CONCLUSION: Agenesis of the posterior elements of C2 should be considered in patients with hypertrophy of the spinous process of C3. Patients may have a varied presentation ranging from neck pain to myelopathy. Dynamic (flexion and extension) lateral cervical spine radiographs should be obtained, as cases reported in the literature involved instability of the cervical spine. PMID- 29252634 TI - Wrong-Way Wrist Bones. PMID- 29252635 TI - Scaphoid and Lunate Dislocation with Complete Soft-Tissue Avulsion: A Case Report. AB - CASE: We describe an intercarpal dislocation with proximal and rotatory displacement of the lunate and with volar and radial dislocation of the scaphoid; both bones were stripped of soft tissue. Treatment involved ORIF (open reduction and internal fixation). Three years postoperatively, the patient had a DASH (Disabilities of the Arm, Shoulder and Hand) score of 10, equivalent grip strength and 50% wrist palmar flexion and 98% wrist dorsiflexion compared with the uninjured side, and radiographic evidence of posttraumatic arthritis. CONCLUSION: Treatment of simultaneous divergent lunate and scaphoid dislocation with loss of nearly all soft-tissue attachments and vascular supply by means of ORIF and repair of soft-tissue structures can result in a favorable intermediate term functional outcome and may be superior to other salvage procedures such as proximal row carpectomy. PMID- 29252636 TI - Synovial Ganglion of the Hip as a Rare Cause of L5 Radiculopathy: A Case Report. AB - CASE: We report a rare case of a dorsal synovial ganglion of the left hip causing L5 radiculopathy in a 48-year-old woman. After a 12-month history of intermittent pain in the groin, left buttock, and left lower limb, magnetic resonance imaging (MRI) of the pelvis revealed a 10-cm-long cystic ganglion. The lesion originated from the posterior aspect of the hip joint capsule and extended through the sciatic notch toward the L5 nerve root, causing severe nerve compression. Open resection of the ganglion via surgical hip subluxation was performed. CONCLUSION: Combined presentation of symptoms attributable to intrinsic hip disease and peripheral radiculopathy should raise suspicion for a shared cause of these entities. PMID- 29252637 TI - Pediatric Intra-Articular Localized Tenosynovial Giant Cell Tumor Presenting as an Acutely Irritable Hip: A Case Report. AB - CASE: An otherwise healthy 9-year-old girl developed a fever and atraumatic right hip pain with inability to bear weight and exquisite pain with any motion. Her peripheral white blood-cell count was 9.85 * 10/MUL, erythrocyte sedimentation rate was 18 mm/hr, and C-reactive protein level was 7.56 mg/L. Aspiration yielded bloody fluid with 611,932 red blood cells/MUL, 49,529 white blood cells/MUL (92% neutrophils), negative Gram stain, and no crystals. Magnetic resonance imaging revealed an intracapsular lesion anterior to the femoral neck. The joint was irrigated and the lesion was excised. Microscopic examination showed neutrophils interspersed within an otherwise histologically classic tenosynovial giant cell tumor. CONCLUSION: Tenosynovial giant cell tumor may rarely present as an acutely irritable hip. PMID- 29252638 TI - Transcondylar Fracture-Dislocation of the Elbow: A Case Report. AB - CASE: Transcondylar fracture of the distal part of the humerus with associated dislocation (Posadas fracture) is rare. Stabilization of this fracture is often difficult because the distal fragments are small and are predominantly composed of impacted articular cartilage. CONCLUSION: We report the case of a patient in whom this rare fracture, which was associated with a brachial artery injury, was successfully treated with internal fixation. PMID- 29252639 TI - Adolescent Hip Fracture-Dislocation: Transphyseal Fracture with Posterior Dislocation of the Proximal Femoral Epiphysis: A Case Report. AB - CASE: A 13-year-old male patient sustained a posterior transphyseal hip fracture dislocation while playing football. A surgical hip dislocation with a trochanteric flip osteotomy, as described by Ganz and colleagues, was performed. Drilling of the dislocated epiphysis demonstrated no blood flow. Transepiphyseal and transphyseal fracture fixation with screws was performed. Two years after the injury, the patient had no evidence of osteonecrosis or functional limitations. CONCLUSION: Traumatic transepiphyseal fracture-dislocations are rare injuries that commonly result in osteonecrosis. Application of the Ganz surgical hip dislocation technique to a difficult pediatric hip fracture-dislocation achieved an excellent result. PMID- 29252640 TI - Forty-three-Year Follow-up of Salvage Knee Reconstruction Using the Patella to Replace Lost Tibial Articular Surface: A Case Report. AB - CASE: A 19-year-old soldier presented with sudden onset of left knee pain and giving-way while running. Evaluation showed a pathologic fracture through a radiolucent lesion of the tibial metaphysis. Excision of a giant cell tumor of bone entailed removal of much of the lateral tibial articular surface. The joint surface was replaced by transposition of the patella, which was transfixed in position with an ASIF (Association for the Study of Internal Fixation) condylar blade plate. This technique resulted in satisfactory knee function that has persisted for 43 years. CONCLUSION: When excision of a tumor of the tibia results in removal of a substantial portion of the articular surface, the defect can be replaced by transposition of the patella to provide long-lasting satisfactory knee function. PMID- 29252641 TI - Lumbar Posterior Apophyseal Ring Fracture Combined with Spondylolysis in Pediatric Athletes: A Report of Three Cases. AB - CASE: Lumbar posterior apophyseal ring fracture is an uncommon finding in children, but lumbar spondylolysis is a common disorder. Both disorders are prevalent in young athletes. We describe 3 adolescent athletes who showed both lumbar spondylolysis and lumbar posterior apophyseal ring fracture. Because lumbar spondylolysis is comparatively easy to diagnose, a concurrent posterior lumbar apophyseal ring fracture is likely to be overlooked. CONCLUSION: In patients with severe low back and radicular pain in whom spondylolysis is suspected, it is important to perform not only magnetic resonance imaging and radiography but also computed tomography for identifying posterior apophyseal ring fractures. PMID- 29252642 TI - The Induced Membrane Technique for Bone Defects of Critical Size After Infection in Children: A Report of 3 Consecutive Cases. AB - CASE: We report 3 consecutive cases of bone defects of critical size after chronic osteomyelitis in children that were treated with the induced membrane technique, in 2 girls and a boy 7 months to 7 years old. All defects were diaphyseal. The length of resection was from 4 to 12 cm (35% to 55% of the total bone length). Resection of the infected bone, filling of the defect with a cement spacer, and intramedullary fixation were followed by autologous bone-grafting 60 to 90 days later. All defects healed. At the latest follow-up, which ranged from 21 months to 6 years, no recurrence or complication had occurred. CONCLUSION: The induced membrane technique is an attractive option for bone defects of critical size after chronic osteomyelitis in children. PMID- 29252643 TI - Systemic Blastomyces Infection Presenting as a Soft-Tissue Infection of the Finger: A Case Report. AB - CASE: A thirty-eight-year-old male patient presented with fusiform swelling of the left ring finger after minor trauma. After medical evaluation by the emergency department, primary care service, and rheumatology service, he was referred to the orthopaedic service, where he underwent 2 surgical debridements. Cultures from the second surgery revealed a diagnosis of blastomycosis, and the patient was treated with intravenous amphotericin B followed by oral itraconazole. CONCLUSION: Our case report demonstrates a rare presentation and diagnosis of blastomycosis. Knowledge of atypical infections such as this can allow for earlier diagnosis and more appropriate treatment. PMID- 29252644 TI - Masquelet Induced Membrane Technique Helps Fill Many Bone Voids. PMID- 29252645 TI - Hematoma of the Flexor Tendon Sheath Mimicking Acute Septic Tenosynovitis: A Case Report. AB - CASE: We report a case of a 65-year-old woman receiving chronic anticoagulation who presented with acute onset of severe long finger pain and was supratherapeutic on Coumadin. Her examination was consistent with early septic flexor tenosynovitis. She was treated with antibiotics and tendon sheath incision and drainage. Intraoperatively, she was found to have a hematoma in the flexor tendon sheath with no purulence. Her symptoms resolved with decompression. After 2 months, she had regained full range of motion with no deficits. CONCLUSION: Flexor tendon sheath hematoma warrants consideration in the differential diagnosis of patients presenting with the signs and symptoms of acute septic flexor tenosynovitis. PMID- 29252646 TI - Immunoglobulin G Deficiency-Associated Septic Arthritis Identified Following Corticosteroid Injection and Knee Arthroscopy: A Case Report. AB - CASE: We present the case of a patient who had worsening pain following intra articular knee corticosteroid injection and who subsequently underwent arthroscopic partial meniscectomy with positive intraoperative cultures for Staphylococcus lugdunensis. He was treated with multiple irrigation and debridements, and subsequent work-up yielded a diagnosis of immunoglobulin G (IgG) deficiency. We believe that it is critical to maintain a high index of suspicion for underlying immune deficiency when faced with atypical presentations of infections or atypical bacteria in otherwise healthy patients. CONCLUSION: Knee arthroscopy for the treatment of meniscal tears is one of the most common procedures performed by orthopaedic surgeons in the United States. Patients with an antibody deficiency may have a limited or reduced immune response when presented with a pathogen foreign to the body. This may place the patient at an increased risk of infection and should be addressed through referral to the appropriate subspecialists when recurrent or atypical infection presents to the orthopaedic surgeon. PMID- 29252647 TI - Large Skin Ulcer Due to a Subcutaneous Orthopaedic Implant After Bevacizumab Therapy: A Case Report. AB - CASE: Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor that is involved in the inhibition of vasculogenesis and angiogenesis. We report the case of a patient who developed a severe skin ulcer at the site of the surgical incision 5 years after clavicular fracture fixation with a titanium plate. This ulcer represents an adverse event of bevacizumab therapy for sigmoid colon cancer. CONCLUSION: Bevacizumab therapy is widely used, particularly for the treatment of metastatic colon cancer and other solid tumors, although it is associated with several adverse events, including delayed wound-healing and skin ulcers. However, to our knowledge, orthopaedic-related adverse events have not previously been reported. PMID- 29252649 TI - Posterior Tibial Arterial System Deficiency Mimicking Chronic Exertional Compartment Syndrome: A Case Report. AB - CASE: A 15-year-old female competitive high school basketball player presented as an outpatient with a 3-month history of bilateral exertional calf pain. Patient history and compartment pressure measurements were consistent with the diagnosis of chronic exertional compartment syndrome, and the patient underwent bilateral fasciotomies. Postoperatively, her symptoms recurred and she was found to have a deficient posterior tibial arterial system bilaterally, as confirmed on advanced imaging. CONCLUSION: We advocate the careful consideration of vascular etiologies in athletes who present with exertional leg pain. PMID- 29252648 TI - Synovial Chondromatosis of the Knee in a 2-Year-Old Child: A Case Report and Review of the Literature. AB - CASE: We describe a rare case of synovial chondromatosis of the knee of a 2-year old child. The diagnosis was based on the history, physical examination, and complementary examinations (radiography and magnetic resonance imaging). Anterior and posterior approaches were used for total synovectomy and resection of loose bodies. CONCLUSION: Physicians should keep this condition in mind, even in young children, because early identification prevents future secondary degenerative changes in the knee joint. As far as we know, this is the youngest child with synovial chondromatosis of the knee reported in the English-language literature. PMID- 29252650 TI - Rim Fracture of a Tibial Base-Plate Due to Retained Cement as a Cause of Catastrophic Failure of Unicompartmental Knee Arthroplasty: A Case Report. AB - CASE: We report a case of catastrophic implant failure due to fatigue fracture of a well-functioning unicompartmental knee arthroplasty at 7 years in an active 55 year-old man, who presented with sudden onset of atraumatic knee pain and effusion. The patient underwent revision to total knee arthroplasty. Intraoperative findings included a metallic fragment fractured off the rim of the tibial base-plate and cement retained in the tibial tray. CONCLUSION: Retained cement in the tibial tray resulted in increased tibial tray contact stresses and fatigue fracture of the rim of the tray, creating a free metallic loose body that produced symptoms. PMID- 29252651 TI - Morphological Transformation of Giant-Cell Tumor of Bone After Treatment with Denosumab: A Case Report. AB - CASE: Denosumab, an inhibitor of RANKL (receptor activator of nuclear factor kappa-B ligand), was recently introduced for the treatment of giant-cell tumor of bone (GCTB). We describe the clinical, radiographic, and histological features of a GCTB of the spine in a 24-year-old woman that progressed after neoadjuvant treatment with denosumab. Disappearance of the multinuclear osteoclastic giant cells was accompanied by newly formed woven bone, which was deposited in interconnected strands with a prominent fibrovascular stroma that was histologically and radiographically similar to that of an osteoblastoma. CONCLUSION: Pathologists, radiologists, and surgeons should be aware of this post treatment transformation to avoid misdiagnosis. PMID- 29252652 TI - Traumatic Rupture of Posterior Tibial Tendon Following Closed Supination Adduction Ankle Fracture: A Case Report. AB - CASE: A 25-year-old man with no known comorbidities presented with pain and swelling of the left ankle following a twisting injury that had occurred during a road traffic accident. On examination, a 1 * 1-cm abrasion was noted on the medial malleolus and tenderness was noted over the medial and lateral malleoli. A radiograph of the left ankle revealed a fracture of the medial malleolus and an infrasyndesmotic avulsion fracture of the lateral malleolus (a supination adduction injury). Immediate surgery was performed for the treatment of the medial malleolar fracture. On exploration, the posterior tibial tendon was found to be severed and frayed 2 cm proximal to the medial malleolar fracture. The medial malleolus was fixed with 2 parallel malleolar screws. The ruptured tendon was explored proximally, and the ends were debrided and repaired. CONCLUSION: At 1 year of follow-up, the ankle had good union and function of the tendon was restored. Posterior tibial tendon ruptures, although rare, should be suspected in cases of closed ankle fracture, irrespective of the mechanism of injury. PMID- 29252653 TI - Pins in the Shoulder Girdle: Beware Wayward Wires. PMID- 29252654 TI - Asymptomatic Migration of a Kirschner Wire from the Proximal Aspect of the Humerus to the Thoracic Cavity: A Case Report. AB - CASE: A 78-year-old man presented with an open fracture of the proximal aspect of the humerus and an axillary artery laceration; the fracture was treated provisionally with Kirschner wires (K-wires). Forty-five days postoperatively, he presented with pin prominence at the lateral aspect of the arm, and was incidentally noted to have migration of a separate K-wire to the left lung. He underwent successful thoracotomy and lung wedge resection for wire removal. CONCLUSION: K-wires used in the fixation of fractures of the proximal aspect of the humerus may migrate into the thoracic cavity. No modification of this technique, including the use of threaded, terminally bent, or external pins that are visibly secured, eliminates the potential for devastating complications. PMID- 29252655 TI - Malignant Transformation of a Giant Cell Tumor of Bone Treated with Denosumab: A Case Report. AB - CASE: Giant cell tumor (GCT) of bone was first described almost 200 years ago, but the optimal treatment continues to evolve. We present a patient with a pelvic GCT who was treated with embolization, 20 months of denosumab therapy, and resection. Histologically, the tumor consisted of degenerated GCT, bone, and fibrous tissue. After 7 months, the patient was found to have osteosarcoma at the site of the initial lesion as well as pulmonary metastases. CONCLUSION: The apparent malignant transformation of a GCT of bone treated initially with denosumab indicates that close follow-up is warranted. PMID- 29252656 TI - Cervical Spinal Epidural Abscess Due to Mycobacterium tuberculosis without Osseous Involvement: A Case Report. AB - CASE: We present a rare case of cervical spinal epidural abscess due to Mycobacterium tuberculosis without osseous involvement that was treated with decompression and arthrodesis in a 2-stage procedure. CONCLUSION: Spinal epidural abscess due to Mycobacterium tuberculosis is the least common of the various forms of spinal tuberculosis. This abscess represents a severe infection of the epidural space that can compromise neural elements and can require urgent surgical intervention to avoid permanent neurological deficits. Early diagnosis and early decompression remain the 2 most important predictors of a successful neurological outcome. PMID- 29252657 TI - An Intramedullary Osteolipoma of the Upper Thoracic Spinal Cord: A Case Report. AB - CASE: We present a rare case of an intramedullary osteolipoma without any extramedullary connections or coexisting spinal dysraphism. A 48-year-old woman presented with back pain and pain around the lateral aspect of the left thigh. Magnetic resonance imaging (MRI) revealed a heterogeneous hyperintense and hypointense region on T1 and T2-weighted imaging. A cavernous hemangioma was suspected, and the patient was admitted for surgical resection. The histological diagnosis was an intramedullary osteolipoma. CONCLUSION: MRI with fat suppression and computed tomography are recommended for the diagnosis of an intramedullary osteolipoma, but a definitive diagnosis requires histological examination. PMID- 29252658 TI - Return to Sport After Short-Stem Total Hip Arthroplasty. AB - OBJECTIVES: Information about sport activity after short-stem total hip arthroplasty (THA) is scarce in the literature. We therefore aimed to evaluate the rate of return to sport after short-stem THA. METHODS: We evaluated the sport pattern, rate of return to sport, activity level, extent of sport activity, and subjective rating and sense of well-being in 137 patients (137 hips) after short stem THA. The minimum follow-up time was 18 months. All results were analyzed according to gender (male and female) and age (<=60, >60-<=70, and >70 years). RESULTS: Ninety-two percent of all patients practiced sport before surgery, and 91% of the patients returned to sport. Most patients returned to sport within the first 6 months after surgery. There was a decline in the number of sport disciplines from preoperatively to postoperatively, which was from 2.9 to 2.6 (P = 0.025). High-impact activities decreased postoperatively, but most low-impact activities did not change significantly. Eighty percent of all patients were involved in recreational sports. CONCLUSION: In this study, we observed an excellent rate of return to sport after short-stem THA. Most patients returned to the same level of sport activity that they had before the onset of restricting symptoms, with the majority of patients having a great sense of well-being during and after sports, and almost no pain in the affected hip. PMID- 29252659 TI - Not-So-Run-of-the-Mill Running Injuries. PMID- 29252660 TI - More Arthroscopic Solutions to Ornery Orthopaedic Problems. PMID- 29252661 TI - The Clinical Challenges of Necrotizing Fasciitis. PMID- 29252662 TI - Exertional Compartment Syndrome with Amniotic Band Disruption Sequence: A Report of Two Cases. AB - CASES: We report the cases of two female patients who presented with symptoms of lower-extremity exertional compartment syndrome years after initial amniotic band reconstruction. These patients underwent extensive fascial release for treatment of amniotic band disruption sequence (ABDS) of the lower extremity, with resolution of their symptoms. We describe our current technique that is now performed at the time of initial reconstruction for addressing all layers of the deformity. CONCLUSION: The surgical reconstruction of ABDS requires addressing all layers of the deformity. Failure to do so may lead to long-term sequelae. Both patients in this report had exertional compartment syndrome following incomplete fascial release at their primary surgery, requiring subsequent fasciotomies. PMID- 29252663 TI - Not as Straight(forward) as an Arrow: Ultrasound Use to Detect a Carbon-Fiber Foreign Body: A Case Report. AB - CASE: A fifteen-year-old boy sustained an archery injury when a carbon-fiber arrow shaft embedded in the volar aspect of his left forearm. The shaft was removed, but at a follow-up visit he still felt the sensation of a retained foreign body in the tissue. Although radiographs were negative, ultrasound examination found three foreign bodies of various lengths still located in the soft tissue. Further surgery removed the objects without difficulty. CONCLUSION: Ultrasound examination can be a valuable diagnostic tool when radiographs yield inconclusive results after penetrating wounds due to radiolucent foreign bodies. PMID- 29252664 TI - Metachondromatosis without Enchondromas: A Case Report and Review of the Literature. AB - CASE: A nine-year-old boy had multiple osteochondromas in the hands, feet, and tibiae, many of which pointed toward the adjacent joint. Although several were treated surgically, others resolved spontaneously. A heterozygous mutation in the PTPN11 gene was identified by genetic analysis of peripheral blood, so the patient was diagnosed with metachondromatosis despite the absence of enchondromatous lesions. CONCLUSION: To the best of our knowledge, this is the first reported case of a patient with metachondromatosis without any enchondromatous lesions. PMID- 29252665 TI - Clavicular Fracture Associated with Life-Threatening Hemorrhage: A Case Report. AB - CASE: A sixty-four-year-old woman sustained a displaced midshaft clavicular fracture. Shortly after admission to the hospital, she developed symptoms of hypovolemic shock as well as neurologic compromise of the ipsilateral upper extremity. Her workup demonstrated a large periclavicular hematoma. She underwent surgical exploration, during which a subclavian artery laceration was identified and repaired. CONCLUSION: This case serves as a reminder to the treating physician to maintain an appropriate index of suspicion for associated injuries when treating clavicular fractures. PMID- 29252666 TI - Late Amputation Following Refracture After Removal of Multiplanar Circular External Fixator for Treatment of Severe Combat-Related Tibial Fracture: A Case Report. AB - CASE: The multiplanar circular external fixator is commonly used in the treatment of severe combat-related tibial fractures. We present the case of a patient who sustained a refracture after removal of such a fixator. This complication contributed to failure of the limb salvage and ultimately resulted in the patient undergoing transtibial amputation. CONCLUSION: The choice to pursue limb salvage or amputation must be a shared decision between the patient and provider. This discussion must now include the possibility of refracture if limb salvage is pursued using multiplanar circular external fixation. Further study is also required to define fracture stability after the removal of a multiplanar circular external fixator. PMID- 29252667 TI - Rupture of the Long Head of the Biceps Tendon in a Pediatric Athlete: A Case Report. AB - CASE: We report a case of an adolescent athlete who sustained an isolated rupture of the long head of the biceps tendon and was subsequently treated with subpectoral biceps tenodesis. CONCLUSION: Provided that there is no damage to the rotator cuff, an open biceps tenodesis may be performed in this young patient population with good short-term outcomes and return to full activity. PMID- 29252668 TI - Late Partial Dissociation of a Humeral Head Morse Taper Associated with Periprosthetic Proximal Humeral Fracture: A Case Report. AB - CASE: A fifty-two-year-old man who had undergone total shoulder arthroplasty ten years previously presented following a mechanical fall onto his operatively treated shoulder, resulting in a periprosthetic humeral fracture and partial dissociation of the humeral head from the stem. CONCLUSION: Shoulder surgeons should consider late disengagement of the Morse taper as a potential cause of surgical failure. Partial late dissociation of the humeral head from the stem after shoulder arthroplasty is possible and can be associated with a fracture. The shoulder surgeon should be aware of this potential complication when evaluating periprosthetic proximal humeral fractures, emphasizing the importance of attention to detail when evaluating patients. PMID- 29252669 TI - Autologous Chondrocyte Implantation Using a Bilayer Collagen Membrane with Bone Graft and Anteromedialization of the Tibial Tubercle for the Treatment of a Large Osteochondral Defect in the Lateral Knee Trochlea: A Case Report. AB - CASE: Autologous chondrocyte implantation (ACI) is an established technique for the treatment of osteochondral lesions of the knee. For larger lesions with a substantial amount of bone loss, ACI using a bilayer collagen membrane with bone grafting has been demonstrated to offer good to excellent results in the tibiofemoral joint, but little has been reported on its use in the patellofemoral joint. We report on the 2-year follow-up of this technique of ACI with bone grafting used for the treatment of a large osteochondral defect in the lateral aspect of the trochlea of the knee in an 18-year-old, active female patient. CONCLUSION: This case illustrates that ACI with bone-grafting using such a "sandwich" technique can be an effective treatment option for osteochondral lesions of the trochlea in the knee. PMID- 29252670 TI - Periprosthetic Femoral Stress Fracture After Bisphosphonate Treatment Resulting in Nonunion Successfully Treated with Teriparatide: A Case Report. AB - CASE: We present the case of a postmenopausal osteoporotic woman, treated with bisphosphonates, who developed a stress fracture at the tip of a revision femoral component, resulting in nonunion after several operative treatment attempts. The nonunion healed after 7 months of subcutaneous injections of 20 MUg/day of teriparatide. CONCLUSION: Teriparatide treatment should be considered for use in recalcitrant stress fractures after total hip arthroplasty. PMID- 29252671 TI - Traumatic Conus Medullaris Syndrome: A Case Report and Review of the Literature. AB - CASE: A twenty-six-year-old man was diagnosed with conus medullaris syndrome (CMS) after sustaining a traumatic L1 burst fracture. Surgical decompression and stabilization was performed within ninety-six hours of admission; postoperatively, normal bladder function rapidly returned. CONCLUSION: CMS is difficult to diagnose because of the clinically variable presentation. There is no consensus regarding the natural history of conus medullaris injury or regarding the necessity, approach, or timing for decompression. Higher-level evidence is needed to guide treatment for acute traumatic CMS. PMID- 29252672 TI - Popliteal Artery Thrombosis After Open Reduction and Internal Fixation of the Patella: A Case Report. AB - CASE: A 31-year-old man presented with a right patellar fracture after a motor vehicle accident. He had a history of a myocardial infarction and cerebrovascular accident, for which he reported taking aspirin and clopidogrel daily. One hour after surgery, an acute popliteal artery thrombosis was detected. The patient was ultimately successfully managed with endovascular placement of a catheter and a 14-hour infusion of tissue plasminogen activator. The patient had no further known thromboembolic events after 11 months of follow-up. CONCLUSION: High suspicion must be maintained for acute thromboembolic events in patients with a history of such events. PMID- 29252673 TI - Arthroscopic Repair of an Isolated Teres Minor Tear: A Case Report. AB - CASE: Isolated avulsion of the teres minor tendon is exceedingly uncommon and, to our knowledge, the presentation and arthroscopic repair of this type of injury have not been described. Known musculotendinous avulsions about the shoulder frequently involve the supraspinatus, long head of the biceps, and pectoralis major. CONCLUSION: We present the case of a patient with an isolated teres minor avulsion and an otherwise intact rotator cuff. The patient underwent successful arthroscopic repair and rehabilitation, allowing for a return to the pre-injury level of function. PMID- 29252674 TI - Management of a Dermocutaneous Black Mold Abscess of the Finger with Flexor Sheath Involvement. AB - CASE: We present the case of a 76-year-old man with a black mold infection of the index finger. This granulomatous abscess uncharacteristically invaded the flexor sheath compartment, threatening proximal spread. Treatment consisted of excision of the abscess and drainage of the flexor sheath. The patient recovered unremarkably, maintaining digital function without recurrent infection. CONCLUSION: The members of the fungal genus Exophiala are dark-pigmented mycoses commonly termed "black mold." Previously reported atraumatic black mold infections of the hand have been limited to subcutaneous involvement. To our knowledge, this is the first report of the successful treatment of a flexor sheath infection caused by the species E. jeanselmei. PMID- 29252675 TI - Multiple Bone Lesions in an 8-Month-Old Child Presenting with Pathologic Fracture: A Rare Case of Solely Osseous Multicentric Infantile Myofibromatosis. AB - CASE: An otherwise healthy 8-month-old boy presented with a pathologic fracture of the distal aspect of the radius. Further work-up demonstrated widespread osseous lesions of the axial and the appendicular skeleton with no soft-tissue or visceral involvement. CONCLUSION: Infantile myofibromatosis has a spectrum of severity that demands a careful and complete work-up. In rare cases such as the present one, it can manifest as multiple osseous lesions. The patient in the present case was managed conservatively, with no morbidity demonstrated at 1 year of follow-up. PMID- 29252676 TI - Chronic Recurrent Multifocal Osteomyelitis: A Diagnostic Dilemma: A Case Report and Review of the Literature. AB - CASE: Chronic recurrent multifocal osteomyelitis, a misnomer in itself, is a rare disorder that presents infrequently to orthopaedic units. The differential diagnosis is wide, including neoplastic lesions and infection, which may lead to unnecessary interventional and surgical procedures. We present a case that exhibited the hallmark features of this condition-recurrent, multifocal, aseptic osteitis in a 9-year-old girl-and our rationalized management including imaging, nonsteroidal anti-inflammatory drugs, and bisphosphonates. CONCLUSION: With increased awareness by orthopaedic surgeons, patients may be diagnosed and managed appropriately, enabling a benign course and limiting morbidity. PMID- 29252677 TI - Necrotizing Fasciitis of the Thigh and Calf: A Reminder to Exclude a Perforated Intra-Abdominal Viscus: A Case Report. AB - CASE: Diverticular disease and its associated complications are an increasing problem among Western populations. Perforated diverticulitis results in intra abdominal sepsis, which rarely causes a life-threatening necrotizing soft-tissue infection. We present the case of a 70-year-old man with a sigmoid diverticulitis perforation presenting as necrotizing fasciitis of the thigh and calf requiring serial debridement and major limb reconstruction. CONCLUSION: Clinicians should be aware of index presentations of diverticulitis and its recognized complications in this demographic group. For the orthopaedic and the general surgeon, knowledge of the dangers of the concomitant presence of these 2 conditions will substantially reduce morbidity and mortality. PMID- 29252678 TI - Explant Analysis from a Patient Exhibiting Rapid Acceleration of Parkinson Disease Symptoms and Hypercobaltemia Following Metal-on-Metal Total Hip Arthroplasty: A Case Report. AB - CASE: A 46-year-old man developed rapidly progressing Parkinson disease symptoms after metal-on-metal total hip arthroplasty, worsening to the extent that he underwent implantation of a right subthalamic deep brain stimulator (DBS). A serum cobalt level of 116 MUg/L was measured shortly after DBS implantation, and revision arthroplasty was performed using ceramic-on-polyethylene bearings. After revision, the patient's serum cobalt level fell below 1 MUg/L, the Parkinson disease symptoms improved, and he reduced the DBS to its lowest setting. Explant analysis showed substantial material loss from the bearing surfaces of one hip. CONCLUSION: Future studies should evaluate the possible link between Parkinson disease symptoms and prosthesis wear-induced hypercobaltemia. PMID- 29252679 TI - Apophyseal Avulsion of the Greater Trochanter in an Adolescent: Treatment with Abduction Bracing: A Case Report. AB - CASE: We describe a case of an adolescent athlete who sustained a greater trochanteric avulsion fracture. After conservative management with abduction bracing, the patient made a full recovery, with no signs of osteonecrosis at 12 months. We describe the presentation, the course of recovery, and the literature regarding treatment and outcomes. CONCLUSION: Isolated fracture of the greater trochanteric apophysis is a rare but possibly devastating injury to the adolescent hip when complicated by osteonecrosis. We describe the successful conservative treatment of this injury in what we believe to be the second such report in the English-language literature. PMID- 29252680 TI - Fracture at the Modular Junction of a Cementless Revision Hip System: A Case Report. AB - CASE: Multiple cases of modular femoral component failure involving fatigue at the modular stem junction have been reported following revision total hip arthroplasty. In the present report, we describe what we believe to be the first case of catastrophic failure involving the Biomet Arcos revision system. The failure involved a young patient with an elevated body mass index and proximal bone deficiency. CONCLUSION: The possibility of this failure mechanism must be weighed against the potential advantages of modular cementless stems when planning for complex hip arthroplasty, especially in the young, active patient. PMID- 29252681 TI - Aneurysmal Bone Cyst of the Scaphoid: A Case Report. AB - CASE: We report the case of a 14-year-old girl with an aneurysmal bone cyst of the scaphoid successfully treated with curettage, phenol adjuvant therapy, and bone-grafting. CONCLUSION: Aneurysmal bone cysts rarely arise in the carpal bones, especially the scaphoid. This lesion may represent a rare yet treatable cause of wrist dysfunction in some patients. Curettage, phenol adjuvant therapy, and bone-grafting resulted in a good clinical outcome for our patient. PMID- 29252682 TI - Joint Instability After Anatomic Reconstruction of Severe, Chronic Slipped Capital Femoral Epiphysis: A Report of 3 Cases, with High Femoral Anteversion in 1 and Adaptive Acetabular Roof Deformation in 3. AB - CASES: Joint instability after slipped capital femoral epiphysis (SCFE) reorientation through the physis has been attributed to a combination of capsulotomy and chondrolabral rim damage. We report on 3 hips with severe SCFE with closed physes, in which anatomic correction with femoral neck osteotomy led to joint instability. All 3 had acetabular roof flattening; 1 showed slight additional acetabular retroversion but also increased femoral anteversion. CONCLUSION: We speculate that the slight roof flattening in all 3 cases and/or the high femoral anteversion in 1 case had contributed to joint instability. Femoral derotation osteotomy was performed in 1 and periacetabular osteotomy was performed in 2 for joint restabilization. PMID- 29252683 TI - Emphysematous Septic Arthritis of the Knee Caused by Citrobacter freundii: A Case Report and Review of the Literature. AB - CASE: A 50-year-old diabetic woman presented with painful swelling of the right knee and proximal part of the calf. A radiograph revealed gas shadows in the suprapatellar pouch and soft tissues of the posteromedial aspect of the proximal part of the calf. An arthrotomy was performed to evacuate pus and debride the synovium. The collection in the calf was approached through a separate posteromedial incision. Citrobacter freundii was isolated on culture, and the patient was given antibiotics to which it was sensitive. CONCLUSION: The constellation of signs, symptoms, and radiographic features was characteristic of emphysematous septic arthritis. The patient recovered well following surgery and treatment with antibiotics. To our knowledge, this is the first reported case of such arthritis caused by C. freundii. PMID- 29252684 TI - Trends in Hospitalization, Acute Kidney Injury, and Mortality in Patients With Spontaneous Bacterial Peritonitis. AB - GOALS: The purpose of our study was to evaluate trends of hospitalization, acute kidney injury (AKI) and mortality in cirrhotic patients with spontaneous bacterial peritonitis (SBP). BACKGROUND: SBP is a frequent bacterial infection in cirrhotic patients leading to increased morbidity and mortality. MATERIALS AND METHODS: A total of 4,840,643 patients hospitalized with cirrhosis from 2005 to 2014 were identified using the Nationwide Inpatient Sample database, of which 115,359 (2.4%) had SBP. We examined annual trends and used multivariable mixed effects logistic regression analyses to obtain adjusted odds ratios by accounting for hospital level and patient level variables. RESULTS: We identified a striking increase in hospitalizations for SBP in cirrhotic patients (0.45% to 3.12%) and AKI in SBP patients (25.6% to 46.7%) from 2005 to 2014. Inpatient mortality decreased over the study period in patients with SBP (19.1% to 16.1%) and in patients with SBP plus AKI (40.9% to 27.6%). Patients with SBP had a higher inpatient mortality rate than those without SBP [15.5% vs. 6%, adjusted odd ratio (aOR): 2.02, P<0.001]. AKI was 2-fold more prevalent in cirrhotics with SBP than those without SBP (42.8% vs. 17.2%, aOR: 1.91, P<0.001) and concomitant AKI was associated with a 6-fold mortality increase (aOR: 5.84, P<0.001). Cirrhotic patients with SBP had higher hospitalization costs and longer length of stays than patients without SBP. CONCLUSIONS: Despite a higher hospitalization rate and prevalence of concomitant AKI, mortality in patients with SBP decreased during the study period. SBP is associated with high likelihood of development of AKI, which in turn, increases mortality. PMID- 29252685 TI - Osteonecrosis in Adolescent Girls Involved in High-Impact Activities: Could Repetitive Microtrauma Be the Cause?: A Report of Three Cases. PMID- 29252686 TI - Carbon Fiber Arrow Injuries to the Wrist: More Than Meets the Eye: A Case Report. PMID- 29252687 TI - An Osteochondritis Dissecans Lesion of the Glenoid in an Adult: A Case Report. PMID- 29252688 TI - Patent Foramen Ovale and Elective Posterior Fossa Craniotomy in the Park-bench Position: How Should We Proceed? PMID- 29252689 TI - Rehabilitation of Visual Loss: Where We Are and Where We Need to Be. AB - BACKGROUND: Spontaneous recovery of visual loss resulting from injury to the brain is variable. A variety of traditional rehabilitative strategies, including the use of prisms or compensatory saccadic eye movements, have been used successfully to improve visual function and quality-of-life for patients with homonymous hemianopia. More recently, repetitive visual stimulation of the blind area has been reported to be of benefit in expanding the field of vision. EVIDENCE ACQUISITION: We performed a literature review with main focus on clinical studies spanning from 1963 to 2016, including 52 peer-reviewed articles, relevant cross-referenced citations, editorials, and reviews. RESULTS: Repetitive visual stimulation is reported to expand the visual field, although the interpretation of results is confounded by a variety of methodological factors and conflicting outcomes from different research groups. Many studies used subjective assessments of vision and did not include a sufficient number of subjects or controls. CONCLUSIONS: The available clinical evidence does not strongly support claims of visual restoration using repetitive visual stimulation beyond the time that spontaneous visual recovery might occur. This lack of firm supportive evidence does not preclude the potential of real benefit demonstrated in laboratories. Additional well-designed clinical studies with adequate controls and methods to record ocular fixation are needed. PMID- 29252690 TI - Optical Coherence Tomography in Optic Nerve Hypoplasia: Correlation With Optic Disc Diameter, Nerve Fiber Layer Thickness, and Visual Function. AB - BACKGROUND: The correlation between optic disc diameters (DDs) with average retinal nerve fiber layer thickness (RNFLT) and visual function in children with optic nerve hypoplasia (ONH) having nystagmus is unknown. METHODS: Data were obtained from a retrospective review of 28 children (mean age: 9.4 years; +/ 5.1). Optic DD was defined as the maximal horizontal opening of Bruch membrane with spectral optical coherence tomography combined with a confocal laser ophthalmoscope. Average RNFLT was obtained from circumpapillary b-scans. RNFLT was also remeasured at eccentricities that were proportionate with DD to rule out potential sampling artifacts. Visual function was assessed by visual acuity at last follow-up and by visual evoked potentials (VEP) in 11 patients. The eye with the larger DD, which had better visual acuity, was analyzed to exclude potential effects of amblyopia. RESULTS: DD was correlated with average RNFLT (r = 0.61), visual acuity (r = 0.32), and VEPs (r = 0.66). The relationship between RNFLT and DD was as follows: average RNFLT (MUm) = 0.074 * DD (MUm) - 18.8. RNFLT also correlated with the ratio of horizontal optic DD to macula-disc-margin distance (DD:DM; r = 0.59). RNFLT measured at eccentricities proportionate with DD showed progressive decrease in thickness only for DDs <1,100 MUm. All patients with DD <1,000 MUm had subnormal visual acuity, whereas those with DD <1,200 MUm had subnormal VEPs. CONCLUSIONS: DD correlates with average RNFLT and with visual function in children with ONH. Using OCT imaging, DD can be obtained in children with nystagmus and provides objective information. PMID- 29252691 TI - In Reply: The Quantitative Measurements of Vascular Density and Flow Area of Optic Nerve Head Using Optical Coherence Tomography Angiography. PMID- 29252692 TI - Posterior Tibial Artery Perforator-Based Fascial Flap for Skin Necrosis and Exposed Extensor Tendon After Revision Total Ankle Replacement: A Case Report. AB - CASE: Delayed wound-healing of anterior ankle incisions can be problematic for patients who have undergone total ankle replacement. We describe the case of a patient in whom a posterior tibial artery perforator-based fascial flap was effectively used to cover skin necrosis and to repair the extensor retinaculum in a wound following revision total ankle replacement. CONCLUSION: When a tendon is exposed in the ankle, a skin flap is generally required. The creation of a perforator-based fascial flap is a useful technique for covering a wound with an exposed tendon and is an alternative to a musculocutaneous flap. PMID- 29252693 TI - Length-Preserving Intramedullary Femoral Fixation for Traumatic Leg Amputation: A Case Report. AB - CASE: We present the case of a twenty-one-year-old woman with a traumatic left leg amputation, substantial proximal skin degloving, and an ipsilateral femoral fracture treated with revision amputation distal to the fracture site and retrograde femoral nailing through the amputation site. CONCLUSION: A short retrograde femoral nail is a surgical option to fix a femoral shaft fracture proximal to a traumatic amputation in order to preserve limb length for effective prosthetic fit and ambulation. PMID- 29252694 TI - Progression and Treatment of Bilateral Knee Bone Marrow Edema Syndrome: A Case Report. AB - CASE: We report the case of a patient with bilateral multicompartmental bone marrow edema syndrome of the knee, which responded favorably to subchondral core decompression after failing to respond to nonoperative treatment. CONCLUSION: This case demonstrates that subchondral core decompression can be effective for the treatment of bone marrow edema syndrome. PMID- 29252695 TI - Vascular Malformations Corresponding to Sclerotomes in Multifocal Melorheostosis: Painful Hip and Knee Contractures Treated with Total Joint Arthroplasty: A Case Report. AB - CASE: A forty-three-year-old male patient complained of difficulty walking due to severe hip and knee pain and stiffness, which had persisted for twenty years. He was found to have multifocal melorheostosis involving the axial skeleton and the entire left lower limb, along with complex vascular and lymphatic malformations corresponding to the sclerotomes related to the skeletal anomalies. Total hip and knee arthroplasties were performed. He was eventually free of pain during walking, and joint motion of the hip and knee was substantially improved after surgery. CONCLUSION: Hip and knee pain and contracture resulting from multifocal melorheostosis were successfully treated with total hip and knee arthroplasty. PMID- 29252696 TI - Gas-Containing Paralabral Ganglion Cyst of the Shoulder: A Case Report. AB - CASE: A thirty-three-year-old woman presented with right shoulder pain and moderate atrophy of the infraspinatus muscle, with grade-4 (of 5) external rotation strength. Magnetic resonance imaging showed a gas-containing ganglion cyst. Surgical excision and arthroscopic evaluation were performed. The extra articular arthroscopic view of the ganglion showed bubbles within the mucous material. One year after surgery, she had pain-free, normal range of motion and normal strength of the affected shoulder. CONCLUSION: We report a rare case of a gas-containing ganglion cyst that originated in the posterosuperior glenohumeral capsule and caused entrapment of the suprascapular nerve. PMID- 29252697 TI - Segmental Forearm Fracture Due to Grip-Lock Injury in Male Gymnast: A Case Report. AB - CASE: A fifteen-year-old male gymnast sustained a segmental forearm fracture with physeal involvement as the result of a grip-lock injury. CONCLUSION: Grip lock occurs when a leather grip becomes caught around a bar while the athlete is rotating around it. This may lead to physeal injuries, extensor tendon injuries, and fractures of the hand, wrist, or forearm. Proper grip fit and maintenance as well as education of coaches, parents, and athletes is important to prevent this type of injury. PMID- 29252698 TI - Atypical Vancouver Type-C Periprosthetic Fracture Complicated by Nonunion: A Case Report. AB - CASE: In recent years, atypical femoral fractures (AFFs) associated with bisphosphonate use have increasingly been reported, but current definitions limit their diagnosis to native femora. Atypical periprosthetic fractures are rare. We present a case of a Vancouver type-C periprosthetic fracture that was recognized as an AFF following nonunion. CONCLUSION: Bisphosphonate-associated AFFs can present as periprosthetic fractures. Delayed recognition of the role of bisphosphonates in a periprosthetic fracture may lead to a worse outcome, including a delay in diagnosis, delayed union, and failure of fixation. PMID- 29252699 TI - Deltoid Compartment Syndrome After Prolonged Lateral Decubitus Positioning: A Case Report. AB - CASE: A thirty-six-year-old man fell off a ladder and sustained an open fracture of the distal end of the left humerus. He was taken to the operating room for irrigation, debridement, and fixation of the fracture and was placed in the right lateral decubitus position for over seven hours. He subsequently developed right deltoid compartment syndrome, necessitating emergency compartment release. One year later, he had limited function, with a Disabilities of the Arm, Shoulder and Hand score of 81.3 points. CONCLUSION: Deltoid compartment syndrome can occur from operative positioning, with poor long-term outcomes as a result. Expeditious surgery, additional padding, and repeat checks are necessary for at-risk patients. PMID- 29252700 TI - Percutaneous Transluminal Angioplasty for Axillary Artery Dissection After Open Reduction of Shoulder Fracture-Dislocation: A Case Report. AB - CASE: Injury of the axillary artery after shoulder-joint fracture or dislocation is uncommon. We describe the clinical outcome of an elderly patient with a dissecting aneurysm of the axillary artery following open reduction of a fracture dislocation of the shoulder. The arterial dissection was successfully managed with percutaneous transluminal balloon angioplasty. CONCLUSION: This case report highlights the need for careful vascular examination of all elderly patients with a fracture or dislocation of the shoulder and the possible use of percutaneous transluminal angioplasty for the management of arterial dissection prior to proceeding with surgical exploration. PMID- 29252701 TI - Carpal Tunnel Syndrome Associated with Klippel-Trenaunay-Weber Syndrome: A Case Report. AB - CASE: A fourteen-year old patient with Klippel-Trenaunay-Weber syndrome presented with an eleven-year history of pain and subjective weakness in the median nerve distribution of the hand. Electromyography studies demonstrated chronic denervation, and magnetic resonance imaging ruled out vascular malformations as a cause of extrinsic compression. Despite the chronic compression of the median nerve within the carpal tunnel and known complications associated with Klippel Trenaunay-Weber syndrome, a surgical release was performed. CONCLUSION: Postoperatively, the patient noted immediate pain relief. At the time of the three-year follow-up, the subjective strength and function of the hand were greatly improved compared with the preoperative status. Even with symptoms suggesting decade-long compression, carpal tunnel release can be a safe and beneficial treatment for patients with Klippel-Trenaunay-Weber syndrome. PMID- 29252702 TI - Coexisting Upper Lumbar-Disc Herniation and Lumbosacral Radiculoplexus Neuropathy: A Diagnostic Challenge: A Case Report. AB - CASE: An elderly man presented with nontraumatic, acute onset of paralysis of the right quadriceps and the hip flexors, adductors, and abductors without backache or signs of nerve-root tension. Magnetic resonance imaging showed evidence of upper lumbar-disc extrusion with foraminal stenosis as well as right-sided inflammatory lumbar plexitis involving the L2, L3, and L4 nerve roots. However, the pattern of neurological involvement and relatively rapid and full recovery following treatment with parenteral corticosteroids suggested a diagnosis of chemical radiculitis. CONCLUSION: It is important to differentiate chemical radiculitis from both lumbar plexopathy and a herniated nucleus pulposus because it can be treated nonoperatively, with the expectation of a relatively rapid and full recovery. PMID- 29252703 TI - Extensive Lower-Extremity Deep Venous Thrombosis Following Arthroscopic Anterior Cruciate Ligament Reconstruction Related to May-Thurner Syndrome: A Case Report. AB - CASE: An extensive iliofemoral-popliteal deep venous thrombosis following arthroscopic anterior cruciate ligament reconstruction presented on the ninth postoperative day as the result of underlying May-Thurner syndrome. The patient was managed with therapeutic anticoagulation and mechanical disruption of the thrombus. The focal stenosis of the left common iliac vein was addressed with angioplasty and stent placement. Repeat venography demonstrated no residual stenosis of the vein. CONCLUSION: A multidisciplinary approach remains necessary for treating and reducing the risk of post-thrombotic syndrome. The present case further emphasizes the need for aggressive workup and response when a patient presents with left-sided deep venous thrombosis associated with underlying May Thurner syndrome. PMID- 29252704 TI - Bilateral Crush Injury of the Proximal Tibial Physis in an Adolescent Gymnast: A Case Report. AB - CASE: A thirteen-year-old female gymnast experienced bilateral knee pain after landing from a jump off a vault during a competition. Initial radiographs revealed negative findings, but magnetic resonance imaging demonstrated periphyseal osseous edema of the proximal parts of the tibiae. The patient later developed an anterior physeal bar on the right side, with recurvatum deformity. CONCLUSION: Despite similar initial imaging findings bilaterally and identical mechanisms of injury, only the injury on the right side met the strict criteria for classification as a Salter-Harris type-V injury. This case illustrates the difficulty encountered with current diagnostic criteria for type-V injuries. PMID- 29252705 TI - Septic Arthritis of the Ankle Caused by Group-B Streptococci Following Blunt Trauma: A Case Report. AB - CASE: A healthy young adult underwent irrigation and debridement after experiencing minimal blunt trauma involving the ankle. Culture of synovial fluid demonstrated growth of group-B streptococci. Magnetic resonance imaging of the joint at three months of follow-up demonstrated synovitis without signs of osteomyelitis. At one year of follow-up, the patient reported resolution of pain and return of range of motion to normal baseline. CONCLUSION: Septic arthritis of the ankle can lead to joint destruction if not immediately diagnosed and treated. Empiric antimicrobial therapy should be administered while awaiting bacterial identification on the basis of culture of synovial fluid. Group-B streptococci are a more common cause of septic arthritis in the pediatric and peripartum populations; however, hematogenous spread can translocate these bacteria from the genitourinary tract to joints in all age groups. PMID- 29252706 TI - Development of Bilateral Cam Deformity After Dunn Procedure and Contralateral Prophylactic Fixation: A Periosteal Reaction?: A Case Report. AB - CASE: We present the case of a fourteen-year-old male athlete with a slipped capital femoral epiphysis who was managed with a unilateral Dunn procedure and contralateral prophylactic screw fixation. Even though the cartilaginous epiphyseal growth plate was removed on one side, cam deformities subsequently developed on both sides in the postoperative period. CONCLUSION: This case suggests that structures other than the growth plate are also capable of inducing cam deformity of the hip. PMID- 29252707 TI - Atraumatic Dislocation of Constrained Total Scapular Endoprosthesis: A Report of Two Cases. AB - CASE: Two patients undergoing constrained endoprosthetic reconstruction following scapulectomy for the treatment of neoplasm sustained atraumatic glenohumeral dissociation. To our knowledge, this complication had not been observed in association with anatomic-orientation constrained designs prior to 2014. CONCLUSION: Despite the improved stability associated with constrained total scapular endoprosthesis designs, every effort should be made to reconstruct the joint capsule and consideration should be given to augmentation with use of a synthetic sleeve. However, even when these measures are taken, dislocations of the constrained glenohumeral articulation may occur. Treatment of dislocations should be based on patient-specific factors, and nonoperative treatment may be appropriate. In the setting of dislocation associated with constrained liner wear, limited revision may be considered. Reassessment of periprosthetic tissue balancing and potential augmentation should be considered. PMID- 29252708 TI - Necrotizing Dermatosis of the Arm Following Cubital Tunnel Release: Pyoderma Gangrenosum, the Great Mimic: A Case Report. AB - CASE: We report the case of a fifty-one-year-old woman who underwent an uneventful cubital tunnel release and was admitted five days after surgery with a diagnosis of infection. Despite multiple surgical debridements and prolonged intravenous antibiotic treatment, the wound edges continued to slough and necrose. A delayed diagnosis of postsurgical pyoderma gangrenosum (PG) was made, and corticosteroid and immunosuppressive treatment was administered, with immediate clinical improvement. CONCLUSION: When apparent postoperative infections fail to improve with debridement and antimicrobial treatment, and when accompanied by a fever and severe local pain, nonspecific histopathological findings, and negative microbiological cultures, postsurgical PG should be considered. PMID- 29252710 TI - Getting a Good Grip Is Key to All-Inside Meniscal Repair. PMID- 29252709 TI - Arthroscopic Management of a Glenohumeral Osteochondral Defect Using Particulated Juvenile Cartilage Allograft: A Case Report. AB - CASE: A sixteen-year-old high school varsity quarterback was referred to us for evaluation of right shoulder pain two months after an injury sustained during a football tackle. The patient reported being substantially limited in his ability to perform vigorous activity because of pain and the sensation that his shoulder was about to dislocate. Evaluation showed a Bankart tear and a focal full thickness glenoid osteochondral defect. The tear was treated with Bankart repair, and the osteochondral defect was filled arthroscopically with particulated juvenile cartilage graft. The patient returned to full sports activity without restriction at nine months after surgery and, at two years of follow-up, remained pain free with full range of motion and strength and no symptoms of instability. CONCLUSION: The current case suggests that particulated juvenile cartilage may be effective in the treatment of osteochondral lesions of the glenoid. PMID- 29252711 TI - Concomitant Total Ankle Replacement and Open Reduction and Internal Fixation for a Comminuted Distal Tibial Pilon Fracture: A Case Report. PMID- 29252712 TI - Premature Consolidation with Resultant Implant Failure Using PRECICE Femoral Nail Lengthening: A Case Report. AB - CASE: Posttraumatic limb-length discrepancies secondary to femoral malunion can be treated with a variety of external or internal lengthening systems. The PRECICE nail is an intramedullary device featuring an external remote control to activate a magnetically driven internal distraction mechanism. While this intramedullary system avoids the soft-tissue complications common to external lengthening, it has unique mechanisms of failure that are difficult to diagnose and that require a systematic approach. CONCLUSION: In this case report, we describe a failure to lengthen with the PRECICE femoral nail and the subsequent steps taken to determine the root cause. We believe that this failure represents the first reported case of malfunction of the PRECICE femoral nail distraction mechanism since its 2013 redesign. PMID- 29252714 TI - Unrecognized Isolated Medial Trochlear Fracture Leading to Malunion: A Case Report. AB - CASE: A twenty-year-old woman presented with an isolated intra-articular fracture of the medial part of the trochlea twelve weeks after a traumatic fall. The fracture had gone undetected during the initial twelve weeks following injury, resulting in an anteriorly and superiorly displaced malunion and severe range-of motion restrictions of the elbow. CONCLUSION: Vigilant clinical examination is imperative to avoid missing this uncommon fracture pattern and complication. Prompt surgical management is necessary to ensure that adequate healing is achieved and to avoid unnecessary complications. This case report demonstrates that an excellent clinical outcome can be achieved with intra-articular osteotomy and anatomic fixation of the malunited segment. PMID- 29252713 TI - Bilateral Hemiarthroplasty in a Patient with Below-Knee and Above-Knee Amputations: A Case Report. AB - CASE: This case involved a sixty-two-year-old male patient with bilateral femoral neck fractures that occurred six months apart in the setting of bilateral lower extremity amputation. Hemiarthroplasty was performed at each presentation, with the use of a standard femoral stem on the right side and a short stem on the left. At the time of follow-up, the patient had returned to his preoperative ambulatory status. CONCLUSION: This case report illustrates successful bilateral hemiarthroplasty in a patient who had previously undergone bilateral lower extremity amputation, with use of an implant with a short stem for the limb with above-knee amputation. PMID- 29252715 TI - Injury to the Obturator Artery During Periacetabular Osteotomy: A Case Report. AB - CASE: We describe a middle-aged woman who had undergone periacetabular osteotomy (PAO) on both hips successively within a two-year period. Although the first PAO was successfully performed on the right hip without any complications, injury to the obturator artery occurred during the subsequent PAO on the left hip. In this case, the obturator artery seemed to be injured at the medial base of the iliopectineal eminence during osteotomy. CONCLUSION: PAO has been employed as a reconstructive surgery for acetabular dysplasia. However, given the proximity of intrapelvic vascular structures, there is a risk of iatrogenic vascular injury. PMID- 29252716 TI - Diagnosing and Treating Intra-Articular Fractures. PMID- 29252717 TI - Fusobacterium nucleatum Osteomyelitis of the Femur in a Patient with Hereditary Hemorrhagic Telangiectasia: A Case Report. AB - CASE: Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber Rendu syndrome, is an often overlooked cause of orthopaedic-related infections despite a well-accepted association in the literature. We present the case of a forty-seven-year-old man with HHT who developed femoral osteomyelitis and a subsequent pathologic femoral fracture from a rare bacterial species associated with HHT. CONCLUSION: Patients with HHT and extremity pain should be carefully evaluated for orthopaedic infections. If an orthopaedic infection is suspected, fastidious organisms should be considered as a possible etiologic agent. PCR (polymerase chain reaction) is helpful when organisms cannot be isolated from traditional culture media. PMID- 29252718 TI - Volatile Hypertension Following Anterior Cervical Discectomy and Fusion: A Case Report. AB - CASE: A sixty-one-year-old man underwent anterior cervical discectomy and fusion (ACDF) from C4 to C7 for the treatment of cervical spondylosis. Postoperatively, the patient experienced paroxysmal surges in blood pressure with associated diaphoresis and anxiety that were difficult to control. He had additional episodes after discharge, requiring a second hospital admission. He was ultimately diagnosed with baroreflex failure syndrome and was managed with a three-drug regimen. He gradually improved and was symptom-free at seven months. CONCLUSION: Baroreflex failure syndrome should be considered in the setting of volatile hypertension following ACDF. Prompt recognition of this condition can lead to early referral to a specialist and may reduce patient morbidity. PMID- 29252720 TI - Intraoperative Catastrophic Failure of a Mizuho OSI Orthopedic Trauma Table Top: A Case Report. AB - CASE: During orthopaedic open reduction and internal fixation, early fatigue failure of a Mizuho OSI Orthopedic Trauma Table Top occurred. The patient fell toward the ground but was uninjured. A material failure characterized by a crack in the spar tube leading to complete table component separation was identified. To our knowledge, this report is the first of its kind to specifically highlight surgical table device failure intraoperatively. CONCLUSION: Although rare, early fatigue failure of operating tables is possible, leading to hazardous intraoperative situations and the potential for serious patient injury or death. Operating tables and equipment should be inspected rigorously and with proper documentation to prevent such events. PMID- 29252719 TI - Twenty-nine-Year Follow-up of Nonoperatively Treated Three-Level Lumbar Spondylolysis: A Case Report and Review of the Literature. AB - : This article was updated on May 25, 2016, because of a previous error. On page 4, in the address block, one of the e-mail addresses was incorrectly identified. The line had previously read "E-mail address for Y.-Y. Chen: yugangg@163.com." The sentence now reads "E-mail address for Y. Chen: yugangg@163.com." CASE: Multilevel spondylolysis, especially involving more than two levels, is rarely encountered in clinical practice. We present a case of three-level spondylolysis with two-level spondylolisthesis followed for twenty-nine years after nonoperative treatment. The patient was a forty-six-year-old man who presented with stabbing pain in the lower left portion of his back without radiating symptoms or neurological deficit. Lumbar radiographs showed bilateral pars defects at L3, L4, and L5 and grade-I spondylolisthesis at L4/L5 and L5/S1, but flexion and extension views showed no obvious translation. Review of medical records showed that the patient had already had three-level bilateral spondylolysis at L3, L4, and L5 almost thirty years ago. The patient had no history of lumbar surgery during the intervening years. Nonsteroidal anti inflammatory drugs were initially prescribed. Physical therapy was prescribed for eight weeks, and the low back pain improved. CONCLUSION: For patients with multilevel lumbar spondylolysis without neurological symptoms and with slippage of <25%, we recommend conservative treatment with regular follow-up. PMID- 29252721 TI - C1 Lateral Mass Screw Migration Causing a Delayed Unilateral Hypoglossal Nerve Lesion: A Case Report. AB - CASE: We present the case of a fifty-eight-year-old woman who was initially treated with a C1 to C7 anterior-posterior cervical decompression and fusion for an epidural abscess and returned two years postoperatively with four days of progressive dysphagia and tongue deviation. She was diagnosed with a unilateral hypoglossal nerve (cranial nerve XII) palsy secondary to compression from a C1 lateral mass screw. CONCLUSION: This is the first reported case that we are aware of describing a delayed cranial nerve palsy secondary to cutout and cephalad migration of a C1 lateral mass screw resulting in a neurologic deficit due to impingement on the hypoglossal nerve. PMID- 29252722 TI - Rib Stress Fracture in a Collegiate Softball Pitcher: A Case Report. AB - CASE: We present the case of a twenty-one-year-old right-hand-throwing, right hand-batting female softball pitcher who presented with a three-month history of right rib pain. A bone scan showed increased uptake in the lateral aspect of the right seventh rib, consistent with a stress fracture. The patient was managed nonoperatively and made a full recovery. CONCLUSION: The forces created by the attachment of the serratus anterior during underhand throwing are the likely etiology of the injury in our patient. Physicians should maintain a high clinical index of suspicion for stress fracture in underhand athletes with lateral rib pain. PMID- 29252723 TI - OR Table Fracture Puts Spotlight on Equipment-Failure Communication Challenges. PMID- 29252724 TI - Clavicular Stress Fracture Following Reverse Total Shoulder Arthroplasty: A Case Report. AB - CASE: We describe the case of a ninety-year-old woman with a clavicular stress fracture that occurred ten months following reverse total shoulder arthroplasty. Conservative treatment was preferred by the patient, given her age and comorbidities. There was an important loss of function but a decrease in pain at four months after diagnosis. CONCLUSION: Clavicular stress fracture following reverse total shoulder arthroplasty is rare, but shoulder surgeons should be aware of the possibility of this complication. The cause of stress fracture of the clavicle rather than the acromion remains unclear. PMID- 29252725 TI - Management of Pipkin Type-III Femoral Head Fracture and Ipsilateral Open Floating Knee with Extensor Apparatus Injury: A Case Report. AB - CASE: A twenty-eight-year-old man presented with a Pipkin type-III femoral head fracture and open floating knee injury. Initially debridement was performed, during which the extensor apparatus could not be salvaged. The top priority in management of the floating knee was achievement of adequate soft-tissue coverage followed by skeletal stabilization as staged procedures. Because the femoral head was split, dislocated, comminuted, and deemed nonreconstructible, arthroplasty was considered the best option. The extensor mechanism damage was addressed by reconstruction using an iliotibial tract flap. CONCLUSION: This case report is presented for its uniqueness, the management protocol, and the difficulties encountered during the multistage treatment. PMID- 29252726 TI - Hemoptysis Due to Anterior Scoliosis Implants: A Case Report. AB - CASE: A twenty-five-year-old man presented with recurrent episodes of hemoptysis requiring hospitalization and interventional embolization. Instrumentation that had been implanted ten years previously for anterior spinal correction and fusion to treat adolescent idiopathic scoliosis adjoined the medial border of the right lung. The instrumentation eroded the lung during respiration, which prompted the formation of adhesions and fibrosis. Because of the risk of additional hemoptysis events, we performed revision thoracotomy, removal of the spinal instrumentation, and partial lobectomy. CONCLUSION: This rare and serious complication underscores the importance of meticulous surgical technique to ensure proper implant placement and of vigilant monitoring for late iatrogenic injury. PMID- 29252727 TI - Primary Psoas Pyomyositis Presenting as Subluxation of the Hip: A Case Report. AB - CASE: An eight-year-old girl presented with a septic subluxation of the right hip secondary to spontaneous drainage of a psoas pyomyositis. The course of the infection was protracted, and the symptoms were mild relative to the magnitude of the psoas abscess and the volume of purulence in the hip that caused subluxation of the femoral head. At the time of surgical drainage, the hip capsule directly communicated with the psoas abscess along the course of the iliopsoas tendon sheath. Methicillin-sensitive Staphylococcus aureus (MSSA) was the microorganism that was isolated from the abscess and from the hip joint. CONCLUSION: Drainage of the psoas abscess and septic arthritis coupled with antibiotic treatment eliminated the infection, and the child returned to normal activities. At the five-year follow-up, she was asymptomatic, but the subtle changes in the sphericity of the femoral head as well as the slight joint-space narrowing may be associated with problems in the future. PMID- 29252728 TI - Combined Glenoid and Humeral Head Reconstruction with Allografts: A Report of Two Cases and the Midterm Outcomes. AB - CASE: We present two cases of anterior glenohumeral instability in which both the humeral head and the glenoid were reconstructed concurrently with use of allografts; we discuss the midterm outcomes at four and one-half and five years of follow-up, respectively. CONCLUSION: In our experience, concomitant glenoid and humeral head allograft reconstruction for anterior glenohumeral instability with severe combined humeral head and glenoid pathology yielded good midterm clinical, functional, and radiographic outcomes. This treatment approach may be a viable option for young and active patients presenting with severe combined glenoid and humeral pathology and warrants additional investigation. PMID- 29252729 TI - The Ice and Salt Challenge: An Atypical Presentation of a Cold Injury: A Case Report. AB - CASE: We present a case of a healthy seventeen-year-old adolescent with a cold injury to the hands from a new phenomenon known as the "ice and salt challenge," where adolescents hold an ice cube and salt against their skin in competition to see which participant can withstand the discomfort the longest. This competition results in a characteristic injury pattern to the hands. The patient was treated with local wound care and had no long-term deficits. CONCLUSION: It is important for orthopaedic surgeons to be aware of the ice and salt challenge because they may be the first health-care providers to witness its effects. A high index of suspicion is critical in order to properly diagnose, treat, and counsel these patients against risk-taking behaviors. PMID- 29252730 TI - Complete Wear-Through of a Polyethylene Liner and Metal-Backed Acetabular Cup Resulting in a Unique Form of Catastrophic Total Hip Arthroplasty Failure: A Case Report. AB - CASE: We describe a case of total hip arthroplasty failure where a cobalt-chrome femoral head completely wore through the polyethylene liner and the titanium acetabular cup. The patient subsequently underwent revision total hip arthroplasty with acetabular revision and femoral head exchange. CONCLUSION: This case illustrates the natural history of catastrophic failure in a metal-on polyethylene total hip arthroplasty design. If recognized earlier, this patient may have been a candidate for isolated liner and head exchange. Additionally, this case represents a unique complication in using mixed metals in total hip arthroplasty, where the harder cobalt-chrome femoral head wore completely through the much softer titanium component. PMID- 29252731 TI - Subscapular Abscess in a Nine-Year-Old Female Patient: A Case Report. AB - CASE: The subscapular space is a clinically concealed anatomic space where soft tissue abscesses can form. To our knowledge, five cases of a subscapular abscess have been reported in the past thirty-four years, so there is little evidence available to guide treatment. We present a unique case of a spontaneous, subscapular abscess due to methicillin-resistant Staphylococcus aureus in a pediatric host, and we describe a surgical approach for adequate debridement. CONCLUSION: The effective treatment of a subscapular abscess depends on an accurate, rapid diagnosis and effective surgical debridement. A modified Judet approach provides adequate access to the subscapular space for debridement. PMID- 29252732 TI - Intraprosthetic Dislocation of Dual-Mobility Bearings Associated with Closed Reduction: A Report of Two Cases. AB - CASE: We present two patients with dual-mobility total hip arthroplasty components who underwent closed reduction of posterior dislocations with conscious sedation in the emergency room. Following closed reduction, both patients had immediate pain, clicking, and grinding of the hip. Radiographs identified intraprosthetic dislocation of the dual-mobility components, and revision surgery was required. CONCLUSION: When dislocation of a dual-mobility bearing occurs, the surgeon should consider performing a careful closed reduction with muscle paralysis and use of fluoroscopic guidance in the operating room to avoid intraprosthetic dislocation. PMID- 29252733 TI - Long-Term Results of Carpal Tunnel and Trigger Finger Releases in a Patient with Hurler Syndrome: A Case Report. AB - CASE: Prior to the emergence of bone marrow transplantation as a treatment for Hurler syndrome, most individuals with this syndrome did not survive into their teenage years. We describe a twenty-three-year-old patient with Hurler syndrome who had been treated with bone marrow transplantation; we focus on the presentation and treatment of the associated carpal tunnel syndrome and trigger digits. After initial trigger digit release and revision bilateral carpal tunnel release with a tenosynovectomy, he maintained symptom-free hand function. CONCLUSION: Surgical treatment of median nerve compression and trigger digits due to Hurler syndrome is effective in the long term. PMID- 29252734 TI - Peculiar Problems Affecting the Sciatic Nerve. PMID- 29252735 TI - Osteochondritis Dissecans: Baseball and Familial Connections. PMID- 29252736 TI - Radial Head Arthroplasty Understuffing in the Setting of Longitudinal Radioulnar Dissociation: A Case Report. AB - CASE: We present a case in which underlengthening of the radius allowed proximal migration of the radius and ulnocarpal abutment in a patient with a comminuted radial head fracture and concomitant longitudinal forearm instability. CONCLUSION: Radial head arthroplasty is a common treatment for comminuted, displaced radial head fractures. Ideally, the dimensions of the radial head implant should match the native anatomy to restore elbow stability and kinematics. Underlengthening the radius by placing a small radial head implant can lead to carpal abutment at the wrist level. PMID- 29252737 TI - Entrapment Neuropathy of the Sciatic Nerve Caused by a Paralabral Cyst: Three Cases Treated Arthroscopically: A Case Report. AB - CASE: Three patients with sciatica were referred to our outpatient clinic between 2007 and 2012. Magnetic resonance imaging (MRI) of the hip showed compression of the sciatic nerve by a perineural cyst arising from a paralabral cyst. All 3 patients underwent arthroscopic decompression. Upon follow-up, the mean visual analog scale scores for pain had improved from 7.3 to 0.3. MRI showed no evidence of recurrence of the cyst in any of the patients. CONCLUSION: Arthroscopic treatment for entrapment neuropathy of the sciatic nerve caused by a paralabral cyst was effective for improving symptoms; at the final follow-up, none of the patients had experienced recurrence of the cyst. PMID- 29252738 TI - Radialization of the Ulnar Component During Revision Total Elbow Arthroplasty: A Case Report. AB - CASE: Revision total elbow arthroplasty (TEA) is becoming more common. Revision of a failed total elbow prosthesis requires implant removal and replacement. With implant removal, substantial damage to the distal part of the humerus or the proximal part of the ulna can occur. Therefore, reconstruction may require special or custom implants with bone augmentation (e.g., allograft bone graft). This report describes the 9-year follow-up of a man who underwent revision TEA with placement of the ulnar component into the proximal part of the radial shaft (radialization) instead of into the proximal part of the ulnar shaft. CONCLUSION: Radialization of the ulnar component is a viable reconstruction option for the ulnar component during revision TEA. PMID- 29252739 TI - Traumatic Inferior Dislocation (Luxatio Erecta) of the Hip: A Rare Presentation: A Case Report. AB - CASE: Inferior dislocation of the hip is rare, and very few cases have been reported in the English-language literature. This case report describes a patient who presented with an acutely flexed hip, with the thigh almost parallel to the long axis of the trunk, the knee flexed with slight abduction of the hip, and the patella facing upward and slightly laterally. The dislocation was treated successfully with closed reduction. Follow-up after 6, 12, and 18 months revealed no postreduction complications. CONCLUSION: Inferior dislocation of the hip is rare and can be treated successfully with closed reduction. Orthopaedic surgeons must be able to diagnose this type of dislocation and provide optimal management. PMID- 29252740 TI - Atypical Tumoral Presentation of Calcium Pyrophosphate Deposition Disease: A Case Report. AB - CASE: A 55-year-old man presented with a history of forefoot pain and swelling. Radiographs revealed a mass with internal calcifications and osseous erosion of the fifth metatarsophalangeal bone. The mass was isointense to muscle on T1 weighted magnetic resonance imaging (MRI) and hyperintense on T2-weighted MRI. A biopsy was performed, and intraoperatively, the lesion appeared as chalky white material, which under polarized light microscopy was composed of weakly positively birefringent rhomboid crystals, leading to a diagnosis of tophaceous pseudogout. CONCLUSION: Tophaceus pseudogout should be included in the differential diagnosis of neoplastic-appearing lesions in the foot, and polarized light microscopy should be used when examining biopsy specimens. PMID- 29252741 TI - A Novel Complication of the Dall-Miles Cable Grip System Mimicking Recurrent Synovial Chondromatosis: A Case Report and Review of the Literature. AB - CASE: A 25-year-old man with synovial chondromatosis of the hip was treated with a synovectomy through a transtrochanteric approach; the repair was made with use of a Dall-Miles cable. Approximately 13 years later, the patient returned with a massive bursal reaction and a cyst containing "rice bodies." Although the physical examination and imaging were suggestive of recurrent synovial chondromatosis, the bursal reaction actually represented a novel complication of the Dall-Miles system. CONCLUSION: When a patient who has had prior orthopaedic instrumentation presents with pain and imaging that demonstrates formation of a bursal cyst, a cyst containing rice bodies secondary to bursal irritation by the implant should be considered. PMID- 29252742 TI - Management of a Combined Femoral Head and Neck Fracture: A Case Report. AB - CASE: A 19-year-old woman sustained a traumatic hip injury with dislocation and fractures of the femoral head and neck. A modified Gibson approach with trochanteric flip osteotomy was performed. We describe the management technique used to reduce and stabilize the femoral head and neck fractures during surgical hip dislocation. The stabilization of the femoral head to the femoral neck was performed primarily in a retrograde manner. CONCLUSION: Retrograde fixation of combined femoral head and neck fractures can be safely performed during surgical hip dislocation with satisfactory results. PMID- 29252743 TI - Acetabular Osteoarticular Allograft After Ewing Sarcoma Resection: A 15-Year Follow-up: A Case Report. AB - CASE: A 4-year-old girl with Ewing sarcoma of the periacetabular region had been treated with neoadjuvant chemotherapy followed by resection and osteoarticular allograft reconstruction with an adult hemipelvis. At 15 years postoperatively, she remained disease-free with remarkable functionality. She had minimal groin pain and could walk an unlimited distance. Radiographs demonstrated union at the anastomotic junctions. The allograft, which had been considerably oversized 15 years ago, was now identical in size to the contralateral ilium. CONCLUSION: Osteoarticular allograft remains one of the best reconstructive options following hemipelvectomy in the pediatric population because of its potential durability and its capacity to restore pelvic stability and preserve functionality. PMID- 29252744 TI - Chondrocyte Viability 3.5 Years Following a Vascularized Medial Femoral Trochlea Osteocartilaginous Free Flap. AB - CASE: A 30-year-old woman underwent arthroscopy for wrist pain 3.5 years following a medial femoral trochlea (MFT) osteocartilaginous free flap for Kienbock disease, which provided the opportunity to examine the transferred cartilage in vivo. Arthroscopy revealed no evidence of chondrolysis, and histologic examination revealed uniformly viable chondrocytes within a matrix consistent with fibrocartilage. CONCLUSION: To the best of our knowledge, the long-term viability of chondrocytes following an MFT free flap has not been previously documented. This case provides early evidence that free tissue transfer based on the descending genicular artery can provide a durable solution for osteocartilaginous defects. PMID- 29252745 TI - Bilateral Salmonella Septic Arthritis of the Hip in a Patient with Crohn Disease: A Case Report. AB - CASE: A 27-year-old immunocompromised man with Crohn disease presented with bilateral septic hip arthritis due to Salmonella enterica serotype Typhi. The diagnosis was confirmed by synovial membrane and effusion culture specimens that were obtained during arthroscopic debridement of both hips. CONCLUSION: Prolonged antimicrobial therapy, bilateral femoral head resection, and placement of cement spacers for 5 months, followed by bilateral total hip arthroplasty, was a radical and effective treatment for a patient with Crohn disease and bilateral Salmonella septic arthritis of the hip. PMID- 29252746 TI - Indicative Knee Posture in Children with Osteomyelitis of the Proximal Part of the Tibia with or without an Associated Subperiosteal Abscess: A Report of 3 Cases. AB - CASE: Three patients with documented osteomyelitis of the proximal part of the tibia are described. On examination, all of the patients had an indicative finding of knee flexion to 90 degrees . Because of the concern for septic arthritis, each patient underwent knee aspiration as part of the evaluation.All recovered with conventional infection treatment protocols. CONCLUSION: High knee flexion beyond what is typical in patients with septic arthritis may indicate osteomyelitis of the proximal part of the tibia. Consideration of this diagnosis may lead to more expedient and efficient care. PMID- 29252747 TI - Nonsurgical Treatment of Aseptic Periprosthetic Gout Flare of the Knee: A Report of 2 Cases. AB - CASE: Gout is a rarely reported cause of a painful knee following total knee arthroplasty, but it can mimic infection in its symptomatology and workup. Two individuals who had previously undergone a knee replacement and had a history of gout had symptoms of infection. These patients presented with knee warmth and effusion, and they had elevated inflammatory markers and synovial cell counts. In both cases, there was a good response to medication, and surgery was avoided. CONCLUSION: Although simultaneous infection can occur, aseptic periprosthetic gout should be considered in individuals with a known history of gout, in those with a good response to anti-gout medication, and when there is an otherwise negative workup for infection. PMID- 29252748 TI - Nonoperative Treatment of a Completely Displaced Pediatric Type-I Open Fracture of the Proximal Part of the Humerus: A Case Report. AB - CASE: Most pediatric closed fractures of the proximal part of the humerus are treated nonoperatively. However, with open fractures of the proximal part of the humerus, nonoperative treatment typically is not indicated, and no such cases previously have been reported in the literature. We describe a 10-year-old boy with a completely displaced type-I open fracture of the proximal part of the humerus who was treated definitively in the emergency department with local irrigation and debridement, antibiotics, and the application of a hanging arm cast. One year later, he had complete radiographic union, no infectious sequelae, and no functional impairment of the shoulder. CONCLUSION: Nonoperative treatment of a pediatric type-I open fracture of the proximal part of the humerus can be successful. PMID- 29252749 TI - Ewing Sarcoma in the Fifth Metacarpal of an Adult Woman: A Case Report. AB - CASE: Atypical presentations of Ewing sarcoma (ES) can lead to misdiagnosis and delays in treatment. We present a rare case of ES in the hand of an adult woman who underwent multiple interventions prior to referral to our institution. At 22 months after definitive treatment, the patient remained pleased with the result and had no evidence of recurrence. CONCLUSION: To our knowledge, ES of the hand in an adult woman has not yet been reported in the literature, and a lack of recognition of this condition might be secondary to the absence of features traditionally associated with malignant bone neoplasms. A broader differential diagnosis after intervention failures offers the opportunity for diagnosis and appropriate treatment. PMID- 29252750 TI - Gross Trunnion Failure of a Cobalt-Chromium Femoral Head on a Titanium Stem at Midterm Follow-up: A Report of 3 Cases. AB - CASE: Three patients underwent uncomplicated primary total hip arthroplasty with cobalt-chromium femoral heads (36+5 mm) on titanium V40 tapers. At 6 to 9 years of follow-up, severe effects of corrosion at the trunnion were noted in all 3 patients, along with elevated levels of serum cobalt ions and normal levels of serum chromium ions. Gross trunnion failure, apparently caused by corrosion, required femoral stem revision in all of the patients. CONCLUSION: Decreased neck diameter, longer trunnion length, and large-sized cobalt-chromium heads are possible contributors to early failure after primary total hip arthroplasty due to trunnionosis. Surgeons should be mindful of trunnionosis as a cause of pain and a mechanism of failure following total hip arthroplasty, and serum metal ions should be monitored in these patients. PMID- 29252751 TI - Vocal Cord Paresis After Posterior Spinal Fusion to Treat Adolescent Idiopathic Scoliosis: A Case Report. AB - CASE: A 15-year-old girl with adolescent idiopathic scoliosis with a 50 degrees curve underwent posterior spinal fusion from T3 to T11. After discharge from the hospital, the patient reported dysphonia and dysphagia. Flexible nasendoscopy confirmed left vocal cord paresis. Stretch injury to the recurrent laryngeal nerve from the left T5 pedicle screw or intubation may have caused the vocal cord paresis. The pedicle screw was removed during revision surgery. Postsurgically, the patient demonstrated immediate and ultimately full recovery and no longer had any symptoms. CONCLUSION: To our knowledge, this is the first case report of vocal cord paresis most likely caused by pedicle screw position after posterior spinal fusion. PMID- 29252752 TI - Morel-Lavallee Lesion: Presenting Etiology of Chronic Myelogenous Leukemia in an Adolescent Athlete: A Case Report. AB - CASE: A 16-year-old boy presented with a concealed degloving lesion of the knee, a Morel-Lavallee lesion, 3 weeks after an injury to the right knee while playing basketball. An incidental hematologic finding led to the additional diagnosis of chronic myelogenous leukemia. CONCLUSION: Morel-Lavallee lesions often can be overlooked and appear to be subcutaneous hematomas. This case was complicated further by a leukemic condition that was likely the causative mechanism for the recalcitrant nature of the lesion in this athlete. PMID- 29252753 TI - Osteochondritis Dissecans of the Glenoid in a Major League Baseball Prospect: A Case Report. AB - CASE: A 16-year-old Major League Baseball prospect presented with persistent shoulder pain associated with throwing. Magnetic resonance imaging (MRI) demonstrated a large osteochondritis dissecans lesion in the posterosuperior aspect of the glenoid. The patient was restricted from throwing and underwent therapy to improve range of motion and throwing mechanics. Eight months after initiating nonoperative treatment, an MRI arthrogram demonstrated a healed lesion. At follow-up 2 years after treatment, full relief of symptoms had persisted. CONCLUSION: Osteochondritis dissecans lesions of the glenoid are extremely rare, but have the potential to heal in overhead-throwing athletes. To our knowledge, this is the only case reported in the literature that demonstrates a healed osteochondritis dissecans lesion of the glenoid following nonoperative treatment. PMID- 29252754 TI - Arthroscopic Excision of a Solitary Acetabular Osteochondroma in an Adult: A Case Report. AB - CASE: A 43-year-old woman presented with localized pain of the right hip 2 months after a trivial trauma. Physical examination revealed a positive Patrick (FABER [Flexion, Abduction, and External Rotation]) test. Radiographs showed a radiopaque lesion at the acetabular fossa, and magnetic resonance imaging revealed a mass with adjacent bone marrow edema. Arthroscopic excision of the lesion was performed; histopathologic examination demonstrated that it was an osteochondroma. CONCLUSION: A solitary intra-articular osteochondroma is a possible cause of localized hip pain. Hip arthroscopy can be a good diagnostic and therapeutic option. PMID- 29252756 TI - A Terrible Quartet Injury of the Elbow: A Terrible Triad Variant with a Capitellar Shear Fracture: A Case Report. PMID- 29252755 TI - Ruptured Pseudoaneurysm of the Dorsalis Pedis Artery Following Ankle Arthroscopy: A Case Report. AB - CASE: We describe the case of a pseudoaneurysm of the dorsalis pedis artery that developed following a repeat ankle arthroscopy for persistent osseous impingement. The patient underwent attempted fluid aspiration for a presumed effusion, and ultimately experienced rupture of the pseudoaneurysm with substantial blood loss, which required emergency vascular repair. CONCLUSION: Anterior tibial artery and dorsalis pedis artery pseudoaneurysms are relatively rare, but they are well-documented complications of ankle arthroscopy; however, their clinical importance is poorly understood. To our knowledge, this is the first reported case of a ruptured pseudoaneurysm of the dorsalis pedis artery following ankle surgery, and it highlights the need for timely diagnosis. PMID- 29252757 TI - Successful Spinal Fixation Surgery Following Teriparatide Treatment in an Adolescent Boy with Severe Osteoporosis and Progressive Kyphoscoliosis: A Case Report. PMID- 29252758 TI - Fibrocartilaginous Dysplasia of the Proximal Part of the Femur with a Pathological Fracture in a Child: A Case Report. PMID- 29252759 TI - Distal Femoral Subchondral Metastasis Mistaken for an Insufficiency Fracture and Treated with Total Knee Arthroplasty: A Case Report. AB - CASE: A seventy-three-year-old woman who had been given the tentative diagnosis of spontaneous osteonecrosis presented to our clinic for a second opinion. Additional imaging and evaluation revealed the lesion to be a subchondral metastasis consistent with breast cancer. She received proper oncologic treatment and subsequent total knee arthroplasty. CONCLUSION: Orthopaedic surgeons should be aware of the possibility of metastatic disease manifesting itself in the form of an isolated subchondral lesion about the knee. For patients with such lesions, treatment in the form of total knee arthroplasty is a viable option that can provide excellent pain relief and function. PMID- 29252760 TI - Painful Ununited Fracture of the Posterior Process of the Talus in an Adolescent Dancer: A Case Report. AB - CASE: Fractures of the talus in children and adolescents are uncommon and generally involve the body or neck of the talus. We present a thirteen-year-old dancer with an ununited fracture of the posterior process of the talus that was initially thought to be a painful os trigonum. CONCLUSION: This injury was confused with a painful os trigonum. We found that the size of the fragment, the extent to which the fracture line undercut the tibial plafond, and the findings on magnetic resonance imaging were helpful in clarifying the diagnosis of the fracture. PMID- 29252762 TI - Avoiding Flexible Reamer Breakage During Anatomic ACL Reconstruction. PMID- 29252761 TI - Metachronous Bilateral Chondroblastoma of the Proximal Part of the Femur with a Pathologic Fracture: A Case Report. AB - CASE: A twenty-two-year-old man presented with metachronous bilateral chondroblastoma of the proximal part of the femur with a pathologic fracture. The pathologic fracture on the right side was treated with tumor resection and total hip arthroplasty. Within forty-three months, the chondroblastoma in the left femoral head was detected and treated with the same protocol as the chondroblastoma on the right side. No metastatic lesion was evident at this time; because of its benign appearance histologically, the lesion was diagnosed as a metachronous lesion. CONCLUSION: In a patient who has been previously diagnosed with and treated for chondroblastoma, skeletal pain at another site may represent a metachronous lesion. PMID- 29252763 TI - Pitfalls in Single-Bundle Anterior Cruciate Ligament Reconstruction with the Flexible Reamer System: A Report of Two Cases and Review of the Literature. AB - CASE: We present two cases of anterior cruciate ligament reconstruction with use of the flexible reamer system. In both patients, the starting reamers were broken during femoral reaming. The location of the breaks was approximately 60 mm from the tip of the reamer, which is the transitional zone between the proximal and distal portions of the reamer. CONCLUSION: We believe that several conditions could have resulted in abnormal stress concentration on the flexible reamers, including engagement of the flexible reamer with a physeal scar or the posterior cortex, an inappropriate flexion angle of the knee, and acute bending of the flexible pin. PMID- 29252764 TI - A Modified Transtibial Pull-Out Repair for Posterior Root Avulsions of the Lateral Meniscus with Concomitant Anterior Cruciate Ligament Reconstruction: A Report of Two Cases. AB - CASE: This case series describes the surgical technique for and outcomes after a modified transtibial pull-out repair for posterior root avulsions of the lateral meniscus. This modified technique is designed to prevent tunnel convergence during a concomitant or staging of an anterior cruciate ligament (ACL) reconstruction. Promising short-term clinical outcomes were seen at the two-year follow-up for both patients. On second-look arthroscopy, one patient also demonstrated excellent healing. CONCLUSION: Results provide preliminary evidence suggesting that this technique may (1) facilitate anatomic healing of the root and (2) allow for concomitant or staged ACL reconstruction tunnel reaming. PMID- 29252765 TI - Fracture of a BIOLOX Delta Ceramic Femoral Head Articulating Against a Polyethylene Liner: A Case Report. AB - CASE: A forty-five-year-old woman underwent primary total hip arthroplasty with a 36-mm BIOLOX delta ceramic femoral head articulating against a polyethylene liner. She presented with hip pain at eighteen months postoperatively, two months after being in a bicycle accident; fracture of the femoral head was diagnosed. CONCLUSION: The possibility of a ceramic femoral head fracture should be decreased with use of the latest generation of ceramic material, a ceramic-on polyethylene articulation rather than a ceramic-on-ceramic articulation, and a larger head size, all of which applied to this case. Taper-trunnion compatibility and correct intraoperative handling of the components are also essential. PMID- 29252766 TI - Staged Placement of Growing Rods for Metabolic Bone Disease and Insufficient Bone Quality: A Report of Two Cases. AB - CASE: We present two cases of successful staged placement of standard growing-rod instrumentation for early-onset scoliosis in children with metabolic bone disease and poor bone quality. CONCLUSION: Because use of growing-rod surgery is increasing throughout the world, we propose that a staged approach to placement of growing rods is a practical and safe option for surgeons who encounter patients with early-onset scoliosis and concomitant poor bone quality. PMID- 29252767 TI - Osteomyelitis as a Late Complication of Percutaneous Pinning of a Supracondylar Fracture of the Distal Part of the Humerus. AB - CASE: We report a case of an eleven-year-old boy who presented to our clinic with a draining wound from the left elbow. He had a history of a left closed supracondylar humeral fracture that had been treated with closed reduction and percutaneous pinning at five years of age, and he subsequently developed late onset osteomyelitis. The patient was successfully treated with surgical irrigation and debridement, followed by intravenous and oral antibiotics. CONCLUSION: Dormant osteomyelitis should be considered in the differential diagnosis for any child who presents with elbow symptoms with a prior history of a supracondylar humeral fracture that has been treated with closed reduction and percutaneous pinning. PMID- 29252768 TI - Entrapment of the Flexor Hallucis Longus Tendon by Direct Impalement in the Osseofibrous Tunnel Under the Sustentaculum Tali: An Extremely Rare Complication of a Calcaneal Fracture: A Case Report. AB - CASE: This article presents a case of entrapment of the flexor hallucis longus tendon in the osseofibrous tunnel under the sustentaculum tali due to a bone fragment from a calcaneal fracture. Despite good visualization with computed tomography, we did not recognize this complication preoperatively. Limited motion of the hallux was the key to recognition of this rare pathogenic situation. CONCLUSION: We emphasize the importance of careful physical examination of the forefoot when there is a hindfoot injury. PMID- 29252769 TI - Hodgkin Lymphoma Presenting as Severe Shoulder Pain Following Small Quantities of Alcohol Ingestion: A Case Report. AB - CASE: Shoulder pain is a common symptom. We report a case of a twenty-two-year old man who had shoulder pain that was induced by small quantities of alcohol ingestion, which is an unusual presenting sign of Hodgkin lymphoma. The history, physical examination of the shoulder, and imaging revealed no noteworthy findings. Chest computed tomography and subsequent biopsy led to the diagnosis of Hodgkin lymphoma. CONCLUSION: This report emphasizes the need to consider Hodgkin lymphoma as part of the differential diagnosis in a patient presenting with shoulder pain that is precipitated by alcohol ingestion. PMID- 29252770 TI - Treatment of a Chronic Multidrug-Resistant Cutaneous Mycobacterium chelonae Infection of the Hand with Wide Debridement and Skin-Grafting: A Case Report. AB - CASE: We present a case of a healthy thirty-seven-year-old woman with a chronic cutaneous Mycobacterium chelonae infection of the hand recalcitrant to antibiotics and excisional biopsies. She was treated with wide excision of the lesion and staged full-thickness skin-grafting. At the sixth-month follow-up, she reported no activity limitations and demonstrated full painless digital motion without evidence of recurrent infection. CONCLUSION: The technique presented offers the advantage of early digital range of motion with temporary soft-tissue coverage prior to definitive coverage with a full-thickness skin graft while laboratory analysis is performed. PMID- 29252771 TI - A Custom Trabecular Metal Implant in Revision Total Hip Replacement with a Paprosky Type-IV Femoral Defect: A Case Report. AB - CASE: Treatment for severe femoral bone defects involving loss of the supporting isthmus is limited. Techniques are based on surgeon experience and patient related factors. Revision arthroplasty can be challenging depending on bone loss and quality. Highly porous metals, such as trabecular metal, are ideal alternatives for complex reconstruction; however, little has been written about trabecular metal for reconstruction of the proximal part of the femur. CONCLUSION: We report the five-year midterm results of a custom trabecular metal implant for a Paprosky type-IV femoral defect. This novel construct provides durable midterm survivorship and excellent function for Paprosky type-IV femoral bone loss. PMID- 29252772 TI - Anterior Tibial Artery Injury Following Tibiotalocalcaneal Retrograde Intramedullary Nailing: A Case Report. AB - CASE: We report the case of a patient who sustained injury to the anterior tibial artery during tibiotalocalcaneal retrograde nailing and developed an acutely ischemic foot. CONCLUSION: Vascular injury during tibiotalocalcaneal arthrodesis with retrograde nailing is a rare but serious complication. While retrograde tibiotalocalcaneal arthrodesis nailing for end-stage ankle and subtalar arthritis has shown encouraging results, a high index of suspicion for postoperative complications is necessary in patients with risk factors for poor posterior collateral circulation. PMID- 29252773 TI - Late-Emerging Lethal Exacerbation of Cardiomyopathy in a Patient with Mitochondrial Myopathy After Total Hip Arthroplasty: A Case Report. AB - CASE: Mitochondrial myopathy comprises heterogeneous neuromuscular disorders caused by mitochondrial dysfunction. Acute exacerbation of mitochondrial myopathy infrequently occurs sequentially after perioperative stress. We present an unusual case of a late-emerging and lethal exacerbation of mitochondrial myopathy after total hip arthroplasty. Despite special attention paid to perioperative control, the patient's condition drastically deteriorated on postoperative day thirteen, and she died later as a result of cardiomyopathy. CONCLUSION: When performing surgery on a patient with mitochondrial myopathy, the merits of surgery must always surpass the possible grave risk of this condition. PMID- 29252774 TI - Acute Compartment Syndrome in the Forearm with Extensor and Flexor Tendon Ruptures: A Case Report. AB - CASE: While working in a factory, a thirty-five-year-old man injured his right forearm and was then diagnosed with acute compartment syndrome. Ruptures of the flexor and extensor tendons were revealed via single volar and dorsal incisions. End-to-side transfer with use of the remaining extensor tendons was performed; the end of the extensor indicis proprius tendon was sutured to the side of the extensor digitorum communis tendon of the middle finger, and the extensor pollicis longus tendon was sutured to the extensor pollicis brevis tendon. CONCLUSION: In cases of high-energy injuries, associated tendon rupture should be considered. PMID- 29252775 TI - Arthroscopy Helps Solve Some Unusual Orthopaedic Problems. PMID- 29252776 TI - Rapid-Onset Diffuse Skeletal Fluorosis from Inhalant Abuse: A Case Report. AB - CASE: A thirty-year-old man presented with severely debilitating left hip pain and stiffness. Radiographs demonstrated diffuse osteosclerosis and heterotopic bone formation with near ankylosis of the left hip. The patient underwent successful joint-preserving surgery to restore hip range of motion. After disclosing a history of inhalant abuse, which was confirmed by elevated serum fluoride levels, he was diagnosed with diffuse skeletal fluorosis. CONCLUSIONS: To the best of our knowledge, we present the first reported case of diffuse skeletal fluorosis caused by inhalant abuse of 1,1-difluoroethane. Skeletal fluorosis is uncommon in the United States but is important to consider in the differential diagnosis when a patient presents with otherwise unexplained joint pain and osteosclerosis. PMID- 29252777 TI - Arthroscopy-Assisted Fixation of an Intra-Articular Medial Femoral Condyle (Hoffa) Fracture of the Knee: A Case Report. AB - CASE: A thirty-one-year-old woman was diagnosed with a minimally displaced medial femoral condyle (Hoffa) fracture. Reduction and retrograde percutaneous screw fixation were performed under arthroscopic visualization. At three months postoperatively, she was able to walk without support, had no pain, and had full range of movement of the knee. CONCLUSION: In Hoffa fractures, arthroscopy assisted fixation is an option for treatment. It is advantageous because it allows the ability to evaluate other intra-articular structures, decreases blood loss, shortens surgical time, decreases soft-tissue dissection, and facilitates a shorter postoperative rehabilitation period. PMID- 29252778 TI - An Osteochondral Lesion of the Lateral Femoral Condyle with Arthroscopic Appearance Resembling a Fried Egg: A Case Report. AB - CASE: We encountered an unusual case of an osteochondral lesion of the lateral femoral condyle with a detached osteochondral fragment that was reversed and became reattached to its bed; examination by arthroscopy depicted this lesion with a unique resemblance to a fried egg. Because the excised osteochondral fragment showed little damage or degeneration and had relatively good compatibility with the site of origin, we selected the treatment option of reduction and suture fixation. CONCLUSION: The pathological presentation of this osteochondral lesion that resembled a fried egg was an unusual and rare occurrence. PMID- 29252779 TI - Early Postoperative Intratunnel Migration of an EndoButton After Anatomic Double Bundle Anterior Cruciate Ligament Reconstruction: A Case Report. AB - CASE: We report a rare case of early postoperative migration of an EndoButton following anatomic double-bundle anterior cruciate ligament reconstruction with use of the EndoButton for femoral fixation. Although secure fixation of the EndoButton was confirmed during the operation, one-week postoperative radiographs revealed an intratunnel displacement of the posterolateral EndoButton. We performed a reoperation and refixed the EndoButton to the surface of the femoral cortex; we also hooked and tied both ends of the sutures to make a knot in order to prevent remigration. CONCLUSION: Orthopaedic surgeons should be aware that EndoButton displacement and migration could arise at an early postoperative stage. PMID- 29252780 TI - Use of Extracorporeal Membrane Oxygenation to Stabilize a Polytrauma Patient During Intramedullary Nailing of a Femoral Fracture: A Case Report. AB - CASE: An eighteen-year-old polytrauma patient sustained multiple nonorthopaedic and orthopaedic injuries, including a closed femoral shaft fracture. She was started on extracorporeal membrane oxygenation (ECMO) for respiratory failure. After added resuscitation and stabilization, she underwent intramedullary nailing of the femoral fracture while on ECMO on the third day after the injury. She remained stable throughout the case and recovered after a prolonged hospital course. At the most recent clinical follow-up, she was walking without assistance and had union of the fracture. CONCLUSIONS: ECMO successfully stabilized and mitigated any potential pulmonary complications during intramedullary nailing of a femoral shaft fracture in an unstable patient with polytrauma. PMID- 29252781 TI - Total Bodily Extrusion of the Lunate: An Extreme Inferior Arc Injury: A Case Report. AB - CASE: A fifty-six-year-old man had an open radiocarpal and intercarpal dislocation with a radial styloid fracture, an open triangular fibrocartilage complex tear, and complete bodily extrusion of the lunate. We performed irrigation and debridement and an immediate total wrist arthrodesis. One year postinjury, the fusion had healed without infection, and the patient had functional digital range of motion, 80 degrees of active pronation, and 60 degrees of active supination without distal radioulnar joint instability; he had only mild pain with strenuous activities. CONCLUSION: In this severe case, we believed that total wrist arthrodesis was the most reliable treatment option, and it produced an acceptable result. PMID- 29252782 TI - Complicated Open Supracondylar Fracture of the Femur Managed Primarily with an Autogenous Split Fibular Graft in Conjunction with an Intramedullary Nail: A Case Report. AB - CASE: A thirty-two-year-old man presented with an open type-IIIA Muller type-C2 supracondylar fracture of the femur and an ipsilateral segmental fracture of the tibia. An external fixator was used for initial stabilization. After ten days, the fractured femur was stabilized with a retrograde intramedullary nail along with an autogenous split fibular graft placed on either side of the nail; intramedullary nail fixation of the tibia was also performed. At the two-year follow-up, both fractures had united. CONCLUSION: An autogenous split fibular graft in conjunction with an intramedullary nail is a viable option to manage bone defects in complicated supracondylar fractures of the femur. PMID- 29252783 TI - A Unique Rectus Femoris Injury in an Adolescent Professional Soccer Player: A Case Report. AB - CASE: A sixteen-year-old professional soccer player presented with persistent pain in the right thigh of two years' duration and the inability to return to play. Evaluation revealed a chronic rupture of the rectus femoris muscle. Because physiotherapy and rehabilitation failed to help, a surgical repair was performed. He returned to his previous activity level within nine months after surgery. CONCLUSION: Rupture of the proximal part of the rectus femoris should be acknowledged in the differential diagnosis, especially when presenting with persistent pain in the anterior aspect of the thigh lasting more than one year. Delayed repair might be recognized as a reasonable option for chronic rupture of the proximal part of the rectus femoris. PMID- 29252784 TI - Malakoplakia of Bone: A Case Report and Review of the Literature. AB - CASE: A sixty-one-year-old woman presented with right knee pain. Imaging demonstrated osteonecrosis, pathologic fracture, and a permeative lesion. A biopsy with irrigation and debridement was performed. Cultures grew Escherichia coli, and histology showed features of malakoplakia, a rare lesion of uncertain etiology usually found in the genitourinary tract. The patient was treated successfully with antibiotics. CONCLUSION: Malakoplakia, although rare, should be included in the differential diagnosis of permeative bone lesions, especially in an immunocompromised patient. PMID- 29252785 TI - Open Complete Medial Talar Dislocation without Fracture of the Talus or the Malleoli: A Case Report. AB - CASE: A twenty-three-year-old man presented with an open complete medial talar dislocation without fracture of the talus or the malleoli; this was associated with an injury to the posterior tibial artery and the tibial nerve. It was difficult to reduce because of entrapment of the tendons of the flexor digitorum, the flexor hallucis longus, and the tibialis posterior, as well as entrapment of the posterior tibial artery and the tibial nerve. At the twelve-month follow-up, the talus did not show osteonecrosis. CONCLUSION: After a complete medial talar dislocation, the patient was found to have no arthritis or osteonecrosis, and he had return of normal sensation at one year postinjury. PMID- 29252786 TI - Unusual Orthopaedic Injuries from the World's Most Popular Sport. PMID- 29252787 TI - Isolated Irreducible Chronic Volar Dislocation of the Distal Radioulnar Joint: A Case Report. AB - CASE: We report a case of a fifty-eight-year-old woman who sustained a chronic dislocation of the distal radioulnar joint (DRUJ) with extensive secondary cartilage damage and bone loss. We performed an open reduction to restore normal alignment of the distal part of the radius and the distal part of the ulna while preserving the structures that provide stability to the DRUJ. CONCLUSION: At eighteen months postoperatively, the patient had regained 60 degrees of pronation and 60 degrees of supination and did not have any pain. We found that even in a chronic injury, a simple anatomic reduction can restore the stability of the DRUJ. PMID- 29252788 TI - A Left Nonrecurrent Inferior Laryngeal Nerve in a Patient with Vascular and Atlantoaxial Abnormalities: A Case Report. AB - CASE: We present a case of a fifty-eight-year-old woman with chronic occipital headaches and neck pain who underwent C2-C3 anterior and posterior fusion for cervical instability. Perioperative discovery of multiple cervical anomalies, including a left nonrecurrent inferior laryngeal nerve, greatly complicated the approach. CONCLUSION: A left nonrecurrent inferior laryngeal nerve is a rare anatomical anomaly that may co-occur with other cervical abnormalities. It is an important anatomical variant to consider during an anterior approach to the cervical spine, especially when preoperative images of the cervical region show vascular and cervical spine anatomical anomalies. PMID- 29252789 TI - Bilateral Calcaneal Avulsion Fracture Complicated with a Delayed Achilles Tendon Rupture in a Patient with Diabetes: A Case Report. AB - CASE: A sixty-five-year-old man with diabetes mellitus had bilateral calcaneal avulsion fracture without a history of trauma. Both fractures were treated surgically with modified tension-band wiring, cerclage wiring, and screws. Six months after the surgery on the left side, the patient had a left Achilles tendon rupture proximal to its insertion into the calcaneus. CONCLUSION: Calcaneal avulsion fractures are rare but often have complications. Even if these fractures are managed by well-established treatment methods, an unanticipated complication, namely a delayed Achilles tendon rupture, can occur in patients with diabetes. PMID- 29252790 TI - Use of a Hinged Antibiotic-Loaded Cement Spacer for an Infected Periprosthetic Fracture in a Total Elbow Arthroplasty: A Novel Construct Utilizing Ilizarov Rods: A Case Report. AB - CASE: After a fall, a seventy-seven-year-old woman had been treated at an outside institution with a right total elbow arthroplasty (TEA), which was complicated by subsequent infection and a periprosthetic fracture. After referral to our institution for definitive management, we confirmed chronic periprosthetic infection. The patient underwent a two-stage revision with interval use of a hinged antibiotic-loaded cement spacer created with Ilizarov rods. One year postrevision, she had no pain, no signs of infection, and an elbow active range of motion of 10 degrees to 110 degrees . CONCLUSION: A two-stage revision of an infected TEA with a periprosthetic fracture can be managed successfully with our novel hinged antibiotic-loaded cement spacer. PMID- 29252791 TI - Limb Deformity Caused by Distal Femoral and Proximal Tibial Growth Arrest After ACL Reconstruction in a Child: A Case Report. AB - CASE: We report the case of a twelve-year-old boy with limb deformity caused by physeal closure after transphyseal intra-articular reconstruction of the anterior cruciate ligament of the left knee at the age of seven years. We treated premature closure of the physis with a Langenskiold procedure. Lengthening and correction of the deformity were accomplished with use of the Ilizarov method. Although gross instability remained, reasonable limb alignment was attained with prolonged treatment. CONCLUSION: We document growth arrest and severe limb deformity after transepiphyseal anterior cruciate ligament reconstruction with an artificial polyester ligament and successful surgical correction. PMID- 29252792 TI - Over-Tightening of the Syndesmosis After Ankle Fracture: A Case Report. AB - CASE: An eighteen-year-old patient sustained a fracture-dislocation of the left ankle while playing rugby. The fracture was treated in the emergency department with closed reduction and splinting, followed by open reduction and internal fixation. Subsequently, increased tibiotalar clear space was noted radiographically. Coronal computed tomography images confirmed distal distraction of the talus. This was determined to have resulted from "over-tightening" the syndesmosis. Our surgical treatment consisted of minute manual repositioning of the talus. CONCLUSION: We advise meticulous scrutiny of intraoperative radiographs to evaluate potential talar distraction. Additionally, comparison radiographs of the contralateral ankle can be an essential component of preoperative and intraoperative assessment of ankle fractures with syndesmotic disruption. PMID- 29252793 TI - Sternoclavicular Joint Infection Treated with Debridement, Vancomycin-Loaded Calcium Sulfate, and Partial Pectoralis Muscle Flap: A Case Report. AB - CASE: We report the case of a forty-six-year-old man with a left sternoclavicular joint infection that was treated effectively with surgical debridement, the implantation of vancomycin-loaded calcium sulfate, a partial pectoralis major muscle flap, and two weeks of intravenous antibiotics. CONCLUSION: Sternoclavicular joint infection is a rare problem that has received little attention in the orthopaedic literature. The combined surgical procedure detailed here provided good soft-tissue coverage, avoided the potential toxic effect of prolonged systemic antibiotic therapy, and resulted in a good clinical outcome. PMID- 29252794 TI - Nontuberculous Mycobacterial Osteomyelitis of the Thumb: Successful Treatment with Serial Debridement, Antimicrobial Therapy, External Fixation, and Interphalangeal Arthrodesis: A Case Report. AB - CASE: We present the case of a fifty-seven-year-old woman treated for persistent inflammation of her thumb initially thought to be due to tuberculous osteomyelitis but which ultimately proved to be due to infection caused by a novel nontuberculous mycobacterial species. The establishment of this diagnosis and her treatment are described. CONCLUSION: Indolent hand infections caused by atypical mycobacterial species may occur even in immunocompetent hosts, and their diagnosis remains challenging and often elusive. Surgeons should have a low threshold of suspicion for nontuberculous mycobacteria in cases refractory to treatment by standard protocols. The miniature external fixator provides stability and allows for soft-tissue healing in the setting of hand infections. PMID- 29252795 TI - Osteochondral Lesions at the Interphalangeal Joint of the Hallux. AB - CASE: A case of bilateral osteochondral lesions of the first phalanx of the hallux is reported. Despite this, only one foot was symptomatic. We resected the lesion and tightened the capsule without bone-graft interposition with good clinical results. CONCLUSION: This case suggests that not all osteochondral lesions of the first phalanx of the hallux manifest clinically and that less aggressive treatments seem to be effective. PMID- 29252796 TI - Hemodialysis-Associated Spondylodiscitis of the Cervical Spine: A Case Report. AB - CASE: A fifty-seven-year-old, hemodialysis-dependent man presented with a one month history of progressive neck pain and paresthesias of the upper extremities. Radiographic examination demonstrated collapse of the C5 and C6 vertebrae with resultant kyphosis and spinal cord compression. CONCLUSION: The patient underwent a staged anterior debridement with C5 and C6 corpectomies, cage placement, and plate fixation of C4 to C7, followed by a posterior arthrodesis from C4 to C7. He completed a six-week course of intravenous antibiotics for the treatment of Staphylococcus epidermidis spondylodiscitis, followed by suppressive oral antibiotics. At one year of follow-up, he had no residual neck pain or neurological signs or symptoms. PMID- 29252797 TI - Myxoid Liposarcoma of the Thigh with Metastasis to the Left Ventricle of the Heart: A Case Report. AB - CASE: This report describes a sixty-one-year old man who was diagnosed with a myxoid liposarcoma of the left thigh that was resected and then treated with radiation therapy. He underwent yearly surveillance imaging but presented seventeen years after initial resection with symptoms of heart failure. He was found to have a cardiac abnormality that was first thought to be a pseudoaneurysm but was later shown to be a myxoid liposarcoma, presumably metastatic. CONCLUSION: Myxoid liposarcoma can present with late metastasis, including to the heart. PMID- 29252798 TI - Extreme Cobalt Toxicity: Bearing the Brunt of a Failed Ceramic Liner: A Case Report. AB - CASE: We present a case of systemic cobalt toxicity secondary to third-body wear of a cobalt-chromium (CoCr) femoral head following revision of a fractured ceramic bearing. Removal of the CoCr head was followed by resolution of much of the systemic symptoms. CONCLUSION: This case supports previous reports of cobalt toxicity secondary to catastrophic third-body wear of a CoCr femoral head following a fractured ceramic bearing. It also demonstrates the potential reversibility of many systemic sequelae associated with cobalt toxicity. To our knowledge, this case represents the highest documented blood cobalt level (45,840 nmol/L). PMID- 29252799 TI - Cuboid-Navicular Tarsal Coalition in an Adolescent Female Athlete: A Case Report. AB - CASE: A fourteen-year-old female shot-putter developed midfoot pain with activity that initially responded to nonoperative care. However, the symptoms subsequently returned and became persistent. Advanced imaging demonstrated a fibrous cuboid navicular tarsal coalition. Surgical resection of the tarsal coalition was performed when the patient was seventeen years old, and she returned to sports activities postoperatively with no pain. CONCLUSION: Although fibrous cuboid navicular tarsal coalition is a very rare condition, it should be considered as one cause of persistent midfoot pain in an adolescent athlete. Surgical resection of the tarsal coalition can lead to a resolution of symptoms. PMID- 29252800 TI - Like Father, Like Son: Cleidocranial Dysplasia: A Case Report. AB - CASE: We present the case of a six-year-old boy who was referred to the pediatric orthopaedics division of our academic medical center by his primary care physician for a concern regarding possible fractured clavicles. He was diagnosed with cleidocranial dysplasia, a genetic condition characterized by skeletal and dental anomalies, primarily delayed ossification of midline osseous structures. On radiographs, cleidocranial dysplasia has been linked to both coxa vara and a characteristic "chef's hat" appearance of the femoral head. CONCLUSION: Cleidocranial dysplasia has multiple potential orthopaedic complications, and an awareness of this condition, its presentations, and its diagnosis is useful for all physicians. PMID- 29252801 TI - Anterior Percutaneous Hemiepiphysiodesis of the Distal Aspect of the Femur: A New Technique: A Case Report. AB - CASE: Anterior distal femoral hemiepiphysiodesis for knee flexion deformity in children is typically done using staples or plate-and-screw constructs. Staple migration and postoperative knee pain are common complications associated with these procedures. The authors describe a new technique of percutaneous epiphysiodesis using transphyseal screws (PETS) for anterior hemiepiphysiodesis of the distal aspect of the femur that was used to treat recurrent knee flexion deformity in a child with cerebral palsy who had recurrent crouch gait after hamstring lengthening. CONCLUSION: The technique has the advantage of being less expensive than plate-and-screw constructs, and it has the potential for causing less postoperative knee pain. PMID- 29252802 TI - Alkaptonuria-Associated Changes in Disc Degeneration: A Case Report. AB - CASE: A thirty-nine-year-old man with alkaptonuria presented with low back pain. Imaging demonstrated lumbar scoliosis, extensive irregularities of end-plate vertebral margins, and Thompson Grade-V disc degeneration. Six months later, the patient returned with a herniated L2-L3 disc. Minimally invasive disc surgery was performed, and harvested disc tissue showed marked extracellular matrix changes and ochronotic pigment deposits. CONCLUSION: Scattered previous literature is available regarding disc changes in alkaptonuria. Although rare, alkaptonuria appears to severely impact the disc as reflected by cellular and matrix inclusions that contribute to disc-cell pathology. PMID- 29252803 TI - Delayed Erosion of a Pelvic Reconstruction Plate into the Bladder Causing Recurrent Urinary Tract Infections: A Case Report. AB - CASE: A forty-seven-year-old woman presented with recurrent urinary tract infections eleven years after open fixation of a pelvic ring injury. Cystoscopy revealed that the pelvic reconstruction plate had eroded into the bladder, likely the source of the recurrent infections. Following removal of the involved pelvic hardware and repair of the bladder, the patient had no further urinary tract infections. CONCLUSION: Operative fixation of osseous pelvic injuries places metal implants in proximity to the bladder. Late erosion of hardware into the bladder can occur. A low threshold for urological work-up should be maintained for recurrent genitourinary symptoms in these patients. PMID- 29252805 TI - "Happy Endings" to Unusual Cervical Spine Injuries. PMID- 29252804 TI - A Variant Rockwood-Type Traumatic Inferior Acromioclavicular Joint Separation without Concomitant Fracture: A Case Report. AB - CASE: A left inferior acromioclavicular joint separation, which followed a fall from a mountain bicycle resulting in a violent axial thrust to the shoulder, was treated with open reduction and internal fixation. Results at thirteen months of follow-up were good, with a Constant shoulder score of 97 of 100 and a Western Ontario Rotator Cuff Index of 97.5%. Radiographs showed no signs of recurrent instability. CONCLUSION: Operative treatment of this rare shoulder girdle injury can yield good results. PMID- 29252806 TI - Survival without Neurological Impairment After Complete Dislocation of the C7 Vertebral Body: A Case Report. AB - CASE: We report a case of a forty-one-year-old woman who sustained a C7/T1 fracture-dislocation due to a vehicle rollover accident. Despite complete dislocation of the C7 vertebral body, no subsequent injury-related neurological deficit occurred. After the initial survey, injury evaluation with computed tomography and magnetic resonance imaging was performed. Immediate open reduction and internal fixation included anterior plating and interbody arthrodesis from C6 to T1 with an iliac crest bone graft. The patient was discharged home ten days postoperatively. Sufficient osseous consolidation was confirmed after two months. CONCLUSION: Immediate surgical treatment in this case resulted in an excellent short-term clinical outcome. Other treatment alternatives are discussed. PMID- 29252807 TI - Idiopathic Intervertebral Disc Calcification in a Child: An Atypical Case Involving Many Segments. AB - CASE: A seven-year-old girl presented to the emergency department with severe neck pain and restricted movement of sudden onset. A basic neurological examination supplemented by radiography showed calcification within the intervertebral disc at the C6-C7 level. Computed tomography and magnetic resonance imaging of the spine confirmed the diagnosis and revealed additional calcification within the spine at the C3-C4, C7-T1, T1-T2, T4-T5, and T5-T6 levels. CONCLUSION: Idiopathic intervertebral disc calcification is a rare condition in children, and its etiology remains unclear. In this report, we present a rare case of idiopathic intervertebral disc calcification at numerous levels in a seven-year-old girl. The clinical and radiographic findings, laboratory examination, and follow-up are discussed. PMID- 29252808 TI - Scapular Malunion in a Vietnam War Veteran: Superior Medial Angle of the Scapula Impinging on the Clavicle: A Case Report. AB - CASE: Scapular malunion can be overlooked as a source of substantial upper extremity pain and dysfunction and can generate unnecessary studies or treatments. We present the case of a Vietnam War veteran who sustained a projectile injury in the left shoulder and had persistent symptoms limiting his activity and quality of life for a number of years until surgical resection was performed. CONCLUSION: Scapular malunion should be considered in the differential diagnosis of a patient presenting with persistent upper-extremity pain and weakness following scapular fracture. Making the correct diagnosis based on the history, examination, and imaging will prevent unnecessary studies and invasive procedures. PMID- 29252809 TI - An Atypical Case of Tuberculosis of the Posterior Elements of T2 and T3 without Involvement of the Vertebral Bodies. AB - CASE: Isolated Mycobacterium tuberculosis (TB) infection of the posterior element of a vertebra is rare, but timely diagnosis affords an opportunity for treatment before spinal cord compression occurs. A twenty-eight-year-old woman presented with bilateral weakness of the lower extremities. The clinical findings correlated with compressive myelopathy, for which the most likely causes include a primary tumor and infection. The diagnosis of TB was based on the magnetic resonance imaging findings, along with ultrasound-guided aspiration showing necrotizing granulomatous inflammation in a patient at high risk for TB. She was managed conservatively with an antitubercular treatment and achieved a good response at the latest follow-up at one and a half years. CONCLUSION: Even with symptoms of spinal cord compression, some patients with TB infection of the posterior elements of vertebrae can be managed medically without surgery. PMID- 29252810 TI - Conventional Chondrosarcoma Diagnosed After Total Knee Arthroplasty: A Case Report. AB - CASE: Three years after a total knee arthroplasty, the patient presented with persistent pain and an enlarging intra-articular periprosthetic mass. Attempts at nonoperative treatment and arthroscopic debridement were unsuccessful. A biopsy revealed a large, intermediate-grade chondrosarcoma involving the joint space. The patient was treated with an above-the-knee amputation, but eventually died as a result of widespread metastatic disease. CONCLUSION: To our knowledge, this is the first reported case of chondrosarcoma involving the joint space that was diagnosed after total knee arthroplasty. This case demonstrates the need for increased awareness when there are suspicious clinical findings and the importance of diagnosing and/or treating tumors prior to or shortly after total joint arthroplasty. PMID- 29252811 TI - Articular Sinus Tract with Mycobacterium fortuitum Osteomyelitis After Anterior Cruciate Ligament Reconstruction: A Case Report. AB - CASE: Three weeks after transphyseal anterior cruciate ligament reconstruction with a hamstring autograft, a fourteen-year-old boy presented with fevers, joint effusion, and elevated inflammatory markers. Cultures from an operative debridement grew Mycobacterium fortuitum, for which he received six months of antibiotics. Continued drainage prompted magnetic resonance imaging, which revealed osteomyelitis of the tibial tunnel. CONCLUSION: This case report describes a postoperative infection with an atypical organism that had a protracted course despite early diagnosis. Complete resolution was achieved following tibial tunnel debridement with a high-speed burr and bone-grafting with an antibiotic-laden allograft. PMID- 29252812 TI - Painful Hips and a Nodular Neck: Bilateral Slipped Capital Femoral Epiphysis Leading to the Diagnosis of Multiple Endocrine Neoplasia: A Case Report. AB - CASE: A twelve-year-old slender white girl underwent pinning of a slipped capital femoral epiphysis (SCFE) on both the right and left sides. The bilateral nature of the disease and her slender build prompted consideration of an underlying predisposition. She was referred for medical evaluation, which resulted in the identification of medullary thyroid carcinoma. CONCLUSION: This report highlights the importance of recognizing atypical presentations of SCFE and the necessity for investigation of associated comorbid diagnoses. As with this case, atypical SCFE may represent the sentinel event leading to identification of underlying systemic illness and therefore may present an opportunity for early intervention. PMID- 29252813 TI - Revision Total Knee Arthroplasty in a Patient with Bilateral Below-the-Knee Amputation: A Case Report. AB - UPDATE: This article was updated on January 27, 2016. The byline, which had previously read "M.G. Williams, MBChB, and J. Phillips, MBBS, FRCS," now reads "M.G. Williams, MBChB, J. Phillips, MBBS, FRCS, and K. Eyres, MD, FRCS(Tr&Orth)." In addition, the name, address, and e-mail address for Dr. Eyres have been added to the address block at the end of the article.An erratum has been published: JBJS Case Connect. 2016 Mar 23;6(1):e22. CASE: We report the case of a patient with bilateral below-the-knee amputation who had a periprosthetic fracture around a total knee arthroplasty. The fracture was managed with a revision total knee arthroplasty. We discuss the rationale for revision surgery, the surgical techniques, and the postoperative rehabilitation. Follow-up at one year demonstrated maintenance of the pretrauma functional status. CONCLUSION: In selected patients with a periprosthetic fracture, we believe that revision of a total knee arthroplasty may be considered as an option rather than an above-the knee amputation or an arthrodesis. PMID- 29252814 TI - A Novel, Minimally Invasive Resection of a Pediatric Cervical Spine Osteoblastoma: A Case Report. AB - CASE: An eleven-year-old girl with a left C6 pedicle mass consistent with an osteoblastoma was treated with a minimally invasive procedure with use of intraoperative imaging to guide intralesional curettage and grafting. CONCLUSION: Intraoperative navigation allowed localization of the tumor. We used a muscle splitting approach and avoided the muscle stripping and blood loss associated with a standard midline incision. Performing tumor resection with minimally invasive methods enabled us to avoid a spinal fusion; this eliminated the additional risks associated with fusion, including nonunion, loss of motion, and future revisions related to the instrumentation. PMID- 29252815 TI - Pain After Total Knee Arthroplasty Due to Unrecognized 180 degrees Rotation of the Mobile-Bearing Tibial Insert: A Case Report. AB - CASE: A woman presented with continuously worsening right knee pain and stiffness six years after a total knee arthroplasty. During revision total knee arthroplasty, we discovered that the rotating-platform tibial component was rotated 180 degrees . This likely occurred during a minor bedside fall on postoperative day one after the index procedure. CONCLUSION: This case demonstrates that a 180 degrees rotation of the rotating tibial insert can occur with minimal trauma, resulting in persistent pain and stiffness. This cause of pain should be added to the differential diagnosis of patients with pain after total knee arthroplasty with a rotating-platform tibial insert. PMID- 29252816 TI - Intraosseous Pseudotumor After Knee Viscosupplementation: A Case Report. AB - CASE: A sixty-eight-year-old woman with osteoarthritis in the right knee who had received a single injection of a commercial hyaluronic acid preparation presented with an intraosseous mass that had not appeared in previous imaging studies. Open biopsy and curettage was performed, and a reactive pseudotumor related to viscosupplementation was diagnosed. At the last follow-up fourteen months after surgery, the patient had experienced no recurrence of the lesion. CONCLUSION: Viscosupplementation is considered a conservative treatment option for early stage knee osteoarthritis. To the best of our knowledge, this complication, namely an intraosseous mass, has not been described previously in the literature. PMID- 29252817 TI - Ceramic-on-Poly Femoral Head Fractures: What's Going On? PMID- 29252818 TI - Atraumatic Fracture of a BIOLOX Delta Ceramic Femoral Head Articulating with a Polyethylene Liner: A Case Report. AB - CASE: We describe the case of a forty-one-year-old man who underwent total hip arthroplasty with a 32-mm BIOLOX delta ceramic head articulating with a polyethylene liner. The patient did not suffer any trauma postoperatively, and his only symptom was of a "clicking" noise from the operatively treated hip. At his six-week postoperative review, fracture of the femoral head was diagnosed. CONCLUSION: Fracture of a ceramic femoral head is a rare but catastrophic complication. This case report highlights the importance of vigilance on the part of the surgeon when reviewing patients after hip arthroplasty with ceramic-on polyethylene bearing couples, even with limited symptoms associated with the hip and no reported trauma. PMID- 29252819 TI - Pyoderma Gangrenosum in Revision Total Hip Arthroplasty: Clinical and Histopathological Findings with a Seven-Year Follow-up: A Case Report. AB - CASE: We describe the clinical and histopathological findings associated with a case of pyoderma gangrenosum (PG) after revision total hip arthroplasty. The patient developed an expanding purple-red, necrotic, ulcerative lesion at the surgical site, which was initially suspected to be either a surgical-site infection or warfarin-induced skin necrosis. After treatment with empiric intravenous antibiotics, surgical debridement, and vacuum-assisted closure of the wound, the patient had a painless hip with a remodeled scar and was asymptomatic at the seven-year follow-up. CONCLUSION: Confirmation of the diagnosis of surgical-site PG requires clinical-pathological correlation and familiarity with the PG skin lesion. Treatment of PG differs from treatment of infection; therefore, misdiagnosis and surgical treatment may exacerbate the clinical findings in PG. PMID- 29252820 TI - A New Approach for Complex Upper Limb Revisions Utilizing the Clavicula Pro Humero Technique: A Case Report. AB - CASE: A complex case is described involving limb salvage using a combination of the clavicula pro humero technique with a free vascularized fibular graft to span the defect following a failed megaprosthetic reconstruction. This is believed to be the first description of this approach for a very difficult problem. CONCLUSION: In the setting of infection and minimal bone stock, conventional reconstruction options for the proximal aspect of the humerus were unsatisfactory. This new technique provides a biologic, immunocompetent option for limb salvage. PMID- 29252821 TI - Spontaneous Ruptures of the Distal Biceps and Rotator Cuff Tendons Secondary to Syringomyelia: A Case Report. AB - CASE: We present a case of ipsilateral spontaneous ruptures of the distal biceps and rotator cuff tendons secondary to syringomyelia of the cervical spine. The distal biceps tendon ruptured first and underwent successful repair. Six months postoperatively, the patient was found to have an ipsilateral massive acute-on chronic rotator cuff tear following minimal trauma, with a well-maintained glenohumeral joint space. He was subsequently diagnosed with a syrinx and underwent neurosurgical decompression. Five months later, a successful lower trapezius transfer was performed. CONCLUSION: Orthopaedic surgeons should maintain a high index of suspicion for a neurologic etiology in the setting of relatively atraumatic tendon ruptures in otherwise healthy young patients. PMID- 29252822 TI - Turn-up Plasty for Salvage of Transtibial Amputations: An Illustrated Description of the Surgical Technique: A Case Report. AB - CASE: We present the operative technique for turn-up plasty with a transtibial amputation in three patients with combat-related open tibial fractures who ultimately required amputation. Unaugmented amputation would have resulted in residual limbs of 7 cm; however, with use of the turn-up plasty technique, resultant limbs averaged 14 cm. All three patients achieved union at the osteosynthesis site and regular ambulation with a below-the-knee prosthesis. CONCLUSION: Transtibial turn-up plasty for length and level salvage is a sound option to provide robust, sensate soft-tissue coverage with additional osseous length when limb salvage fails and primary amputation would result in either an extremely short transtibial amputation or a more proximal level amputation. PMID- 29252823 TI - Effect of Electronic Video Education on Patient's Self-Assessed Knowledge About Obesity and Pelvic Floor Disorders: A Randomized Controlled Trial. AB - OBJECTIVE: The objective of this study was to study the effect of electronic video education on patient's self-assessed perception of knowledge about pelvic floor disorders in relation to obesity in a prospective randomized controlled trial. METHODS: From June to July 2015, women with a body mass index of 25 kg/m or higher seeking care at a single urogynecology center were recruited and randomized into either a standard visit with an 8-minute video (group A) or a standard visit control (group B). Randomization was performed with computer generated number blocks of 4. Allocation sequence was concealed from the caregiver, in sequentially numbered, opaque, and sealed envelopes. Immediately after their visit, patients answered a series of 3 questionnaires, which were statistically analyzed using unpaired t tests, Wilcoxon rank sum and analysis of variance tests, presented as mean and standard deviation. Primary outcome was a difference in self-assessed perception of knowledge questionnaire scores. Secondary outcome was a difference in motivation to lose weight. RESULTS: Forty eight women enrolled, and 40 completed all questionnaires, 20 in each group. Representation in both groups was demographically similar. The mean (SD) answers for the postvisit survey measuring participant's self-assessed perception of knowledge was 3.9 (0.8) for group A and 3.5 (1.1) for group B (P = 0.002). Ninety percent of women in group A reported motivation to lose weight, compared with 75% in group B (P = 0.4). CONCLUSIONS: Participants who received electronic video education scored significantly higher on self-assessed perception of knowledge questionnaire about pelvic floor disorders in relation to obesity. The video did not increase motivation to lose weight. PMID- 29252824 TI - Ninety-Day Reimbursements for Primary Single-Level Posterior Lumbar Interbody Fusion From Commercial and Medicare Data. AB - STUDY DESIGN: Retrospective, economic analysis. OBJECTIVE: To analyze the distribution of 90-day payments for a primary single-level posterior lumbar interbody fusion from Commercial payers and Medicare. SUMMARY OF BACKGROUND DATA: Episode-based bundled payments aim to align incentives of all health care providers toward the common goal of high quality and economic health care. Understanding the evolving reimbursement models for spine surgery will require knowledge on existing payments, distribution, and variation. Also, it will help identify areas for cost reduction. This is currently not known for a primary single-level posterior lumbar interbody fusion. METHODS: Administrative claims data were used to study reimbursements from Commercial payers (2007-Q3 2015), Medicare Advantage (2007-Q3 2015), and Medicare (2005-2012) for a primary single level posterior lumbar interbody fusion. Distribution of payments among various service providers was studied. In addition to descriptive analysis, variation between regions and payers was studied by a one-way analysis of variance and post hoc Tukey test. RESULTS: Average hospital costs comprise 74.2% to 77% of the total payments, followed by surgeon's fees which accounted for 12.8% to 13.7%. Overall burden of readmissions/revisions was 2.1% to 2.7%, but for the readmitted patient it constitutes 25% to 54% of the 90-day payment. Inpatient surgery had significantly higher facility costs than outpatient surgery (P = 0.02). The average 90-day payment amount was $51,465, $26,234, and $25,501 for Commercial payers, Medicare Advantage, and Medicare, respectively. There was some regional variation, however not consistent among different payers. CONCLUSION: Hospital costs constitute the majority share of 90-day payments, which can be reduced by performing surgery in the outpatient setting. Reducing hospital costs and readmissions can lower the financial burden associated with this common spine procedure. LEVEL OF EVIDENCE: 3. PMID- 29252825 TI - Service to the Greater Good. PMID- 29252826 TI - Power Mobility Training Methods for Children: A Systematic Review. AB - PURPOSE: To summarize and critically appraise the existing evidence related to power mobility training methods used in research studies conducted with children 21 years or younger. METHODS: A systematic review was conducted using 16 electronic databases to identify primary source quantitative studies published in peer-reviewed journals. Data extraction, determination of level of evidence, evaluation of methodological rigor, and assessment of the risk of bias were completed. The Evidence Alert Traffic Light Grading System (EATLS) was used. RESULTS: Twenty-seven studies were included in the review. Levels of evidence were II to V; scientific rigor scores were 2 to 7. CONCLUSIONS: An overall Yellow EATLS level of evidence was found indicating that therapists should use caution when providing power mobility training interventions and measure outcomes related to established goals in areas such as development, functional skills, or use of a power mobility device. PMID- 29252827 TI - Commentary on "Power Mobility Training Methods for Children: A Systematic Review". PMID- 29252828 TI - Interrelationships of Functional Status and Health Conditions in Children With Cerebral Palsy: A Descriptive Study. AB - PURPOSE: To examine the relationship among the Gross Motor Function Classification System (GMFCS), the Manual Ability Classification System (MACS), and the Communication Function Classification System (CFCS) in children with cerebral palsy (CP) and to determine the average number and effect of health conditions. METHODS: Participants were 671 children with CP aged 2 to 12 years from Canada and the United States. Cross-tabulation of functional classifications and averages were computed for the number and impact of health conditions and comparisons among groups. RESULTS: A total of 78 of the 125 possible classification combinations were recorded. Most frequent were GMFCS I, MACS I, CFCS I; GMFCS I, MACS II, CFCS I; and GMFCS II, MACS II, CFCS I. With lower levels of function, the average number and average impact of associated health conditions increased. CONCLUSIONS: The use of functional profiles across classification systems, with data on the associated health conditions, provides a more comprehensive picture of CP than any single classification or measure. PMID- 29252829 TI - Commentary on "Interrelationships of Functional Status and Health Conditions in Children With Cerebral Palsy: A Descriptive Study". PMID- 29252830 TI - Thirty-Second Walk Test: Expansion of Normative Data. AB - PURPOSE: To collect 30-second walk test (30sWT) normative data on a large, diverse sample of school children developing typically, ages 5 to 13 years, and describe the influences of gender, body mass index, and path shape on distance walked. METHODS: Five physical therapists administered the 30sWT on 1223 children developing typically (boys = 517, girls = 706) from 20 urban schools. RESULTS: Average distances (standard deviation) ranged from 139.1 (20.3) to 163.0 (18.6) ft; children aged 10 years walked the farthest and those aged 5 years the shortest. Distance steadily increased from ages 5 to 10 years, steadily decreased from ages 11 to 13 years; children aged 8, 9, and 10 years had statistical but not functionally meaningful gender differences. Body mass index and path shape had no meaningful effects. Distance and velocities are similar to prior studies. CONCLUSION: This study updated 30sWT normative values with a large, ethnically diverse, urban sample developing typically. Norms may be useful as part of a comprehensive examination. PMID- 29252831 TI - Commentary on "Thirty-Second Walk Test: Expansion of Normative Data". PMID- 29252832 TI - Facilitators and Barriers to Performing Activities and Participation in Children With Cerebral Palsy: Caregivers' Perspective. AB - PURPOSE: To investigate contextual factors that were facilitators and barriers to performing activity and participation for children with cerebral palsy from the caregivers' perspective. METHODS: Qualitative in-depth interview with primary caregivers of children with cerebral palsy aged 4 to 12 years was conducted in the metropolitan area of Thailand. Semistructured questions related to environmental and personal factors were recorded. Interviews were transcribed verbatim and analyzed for main themes on the basis of the International Classification of Functioning, Disability, and Health-Children and Youth Version (ICF-CY) classification. RESULTS: Twenty-seven caregivers participated. Facilitators were appropriateness of assistive devices, support and acceptance from family, friends, and society, health services, willingness, and self acceptance. Barriers were inappropriate design and facilities, overprotection of family, nonacceptance from family, friends, and society, inconvenient transportation, financial problems, limited health services, limited access to education, frustration, and being an introvert. CONCLUSIONS: Contextual factors that can be facilitators and barriers to perform activities and participation should be considered for improving lives of children with cerebral palsy. PMID- 29252833 TI - Commentary on "Facilitators and Barriers in Performing Activities and Participation in Children With Cerebral Palsy: Caregivers' Perspective". PMID- 29252834 TI - Number of Synergies Is Dependent on Spasticity and Gait Kinetics in Children With Cerebral Palsy. AB - PURPOSE: Children with cerebral palsy have motor dysfunctions, which are mainly associated with the loss of motor coordination. For the assessment of motor coordination, muscle synergies calculated by nonnegative matrix factorization have been investigated. However, the characteristics of muscle synergies in children with cerebral palsy are not understood. METHODS: This study compared the number of muscle synergies during gait between children with cerebral palsy and children with typical development and clarified whether certain clinical parameters differed according to the number of synergies. RESULTS: Children with cerebral palsy had significantly fewer synergies than children developing typically. The extent of spasticity and gait kinetics differed according to the number of synergies. CONCLUSION: Increases in the number of synergies are limited by severe spasticity. The muscle synergies calculated by nonnegative matrix factorization have the potential to enable the quantification of motor coordination during gait. PMID- 29252835 TI - Commentary on "Number of Synergies Is Dependent on Spasticity and Gait Kinetics in Children With Cerebral Palsy". PMID- 29252836 TI - Trends in Attitudes and Practice Patterns of Physical Therapists in Addressing Childhood Obesity in Schools. AB - PURPOSE: This study investigated trends in attitudes of school physical therapists about intervention for childhood obesity. METHODS: A survey was developed to quantify attitudes. Two cases investigated the influence of attitudes on choices in treatment frequency. Factor analysis further delineated reasons for treatment frequency recommendations. RESULTS: Attitudes did not change. Variability in responses decreased. Personal characteristics had evolving influence. In 2008, the perception of the PT's role in childhood obesity intervention had a greater influence on the choice to treat, but in 2015 the perception of the seriousness had a bigger effect on that decision. DISCUSSION: Changing demographics of the therapists, increasing prevalence of obesity, and recent attention to the problem may have contributed to the trends. CONCLUSION: There is no consensus as to the role of school physical therapy with intervention for obesity, but influential variables are emerging and practice patterns are evolving. PMID- 29252837 TI - Commentary on "Trends in Attitudes and Practice Patterns of Physical Therapists in Addressing Childhood Obesity in Schools". PMID- 29252838 TI - Modified Ride-On Car Use by Young Children With Disabilities. AB - PURPOSE: The purpose of this single-subject case series study is to determine the effect of modified ride-on car use in natural environments on mobility. METHOD: Three children younger than 2 years diagnosed with various disabilities participated in this 24-week study using a modified ride-on car in their home and community. RESULTS: All 3 children demonstrated an ability to independently use the modified ride-on car and enjoyed doing so. Two of the 3 children demonstrated clinically significant gains in mobility skills as measured by the Pediatric Evaluation of Disability Inventory. CONCLUSIONS: Modified ride-on car use is an emerging powered mobility device option for children younger than 2 years. Further research is needed to demonstrate the potential long-term gains of early powered mobility access to young children with disabilities. PMID- 29252839 TI - Commentary on "Modified Ride-On Car Use by Young Children With Disabilities". PMID- 29252840 TI - Comparison of Hand Function Between Children With Type 1 Diabetes Mellitus and Children Without Type 1 Diabetes Mellitus. AB - PURPOSE: This study compared the hand function of children between the ages of 8 and 12 years with type 1 diabetes mellitus (T1DM) with that of children without diabetes. METHODS: The Modified Jebsen-Taylor Hand Function Test and the Purdue Pegboard Test were used to assess hand function. The Pediatric Quality of Life Inventory 4.0 was used for evaluating health-related quality of life. RESULTS: Duration of writing was found to be significantly longer on the dominant side of the T1DM group compared with the children without T1DM. The durations of card turning, moving large, light objects, and large, heavy objects on the nondominant side of the T1DM group were also found to be significantly longer than those in the children without T1DM. The total scale score of health-related quality of life was significantly lower in the T1DM group compared with the children without T1DM. CONCLUSIONS: T1DM affects hand function, particularly the dominant side for writing and nondominant side for card turning and moving large objects. PMID- 29252841 TI - Commentary on "Comparison of Hand Function Between Children With Type 1 Diabetes Mellitus and Children Without Type 1 Diabetes Mellitus". PMID- 29252843 TI - Trunnion Troubles in Modular Hip Implants. PMID- 29252842 TI - Effect of Transcranial Direct Current Stimulation of Motor Cortex in Cerebral Palsy: A Study Protocol. AB - PURPOSE: To assess the best electrode position of transcranial direct current stimulation combined with treadmill training in children with unilateral spastic cerebral palsy. METHODS: Thirty children with cerebral palsy were randomly allocated to 3 groups: (1) treadmill training combined with anodal electrode positioned over the primary motor cortex in the region of the dominant hemisphere and the cathode positioned in the supraorbital region contralateral to anode; (2) sham anodal transcranial direct current stimulation over the primary motor cortex and sham cathode over the contralateral supraorbital region combined with treadmill training; (3) treadmill training combined with the anodal electrode positioned over the primary motor cortex in the region of the injured hemisphere and the cathode positioned contralateral to anode over the primary motor cortex. Evaluations of gait, balance, quality of life, and electromyographic activity were performed. DISCUSSION: This is the protocol for an intervention study investigating electrode position to achieve improved function. PMID- 29252844 TI - Strange and Dangerous Spinal Infections. PMID- 29252845 TI - Atypical Femoral Fracture Despite Prophylactic Intramedullary Nailing: A Case Report. AB - CASE: A forty-three-year-old woman on bisphosphonate therapy sustained an atypical femoral fracture that was successfully treated with an intramedullary nail. After she developed radiographic and clinical signs of an impending stress fracture of the contralateral femur, prophylactic nailing was performed. However, seven months postoperatively, she sustained a spontaneous, complete fracture of the prophylactically nailed femur at the site of the lateral cortical stress lesion. CONCLUSION: To our knowledge, progression of a bisphosphonate-associated stress lesion to a complete fracture months after initially successful prophylactic intramedullary nailing has not been previously reported. Implications regarding treatment and prognosis are discussed. PMID- 29252846 TI - Treatment of an Acute Fracture of the Femoral Neck in a Young Female Adult with a Transfemoral Amputation: A Case Report. AB - INTRODUCTION: Fracture of the femoral neck in a young adult with an ipsilateral transfemoral amputation is uncommon, and there is no consensus regarding the best treatment. METHODS: We present a unique case of a displaced right femoral neck fracture treated with closed reduction and percutaneous screw fixation in a twenty-eight-year-old woman with a preexisting ipsilateral transfemoral amputation. RESULTS: We observed satisfactory healing of the fracture with a slight varus deformity and no radiographic signs of osteonecrosis at one year. CONCLUSION: In a young adult with a preexisting transfemoral amputation and an acute femoral neck fracture, reduction and fixation of the fracture may be a reasonable treatment option. PMID- 29252847 TI - Spinal Dural Arteriovenous Fistula Presenting as a Recurrent Nucleus Pulposus Herniation: A Case Report and Literature Review. AB - CASE: Of the many potential causes of nerve compression that lead to radiculopathy, vascular etiologies remain among the most infrequent, with an estimated prevalence of only five to ten per million cases of radiculopathy. In this case report, we outline the clinical presentation, imaging, intraoperative findings, and pathologic findings for a fifty-four-year old patient with an intradural, extramedullary form of a spinal dural arteriovenous fistula at the L1 L2 level who presented only with axial back pain and radiculopathy. The radiologist and surgeon initially diagnosed the patient with a herniated nucleus pulposus. However, the intraoperative findings and angiogram were suggestive of an arteriovenous fistula. Methods to identify this rare entity are described for the orthopaedic spine community. CONCLUSION: The potential for a missed diagnosis is particularly important as many partial discectomy procedures are performed at small surgical centers with limited blood products available and no vascular surgeon on staff. For patients with preoperative magnetic resonance imaging (MRI) that is suggestive of vascular malformations (T2 hyperintensity in the lower spinal cord and conus medullaris), we recommend that MR angiography be performed as a secondary diagnostic evaluation. MR angiography has a 95% positive predictive value for specifically diagnosing an arteriovenous fistula. PMID- 29252848 TI - Propionibacterium acnes Infection in the Native Hip: A Case Report. AB - CASE: A sixty-five-year-old immunocompetent man with bilateral osteonecrosis of the hip and no prior surgical procedures or trauma was found to have a subacute Propionibacterium acnes infection of the femoral head. To our knowledge, this is the first reported case of Propionibacterium acnes infection in a native hip in the orthopaedic literature. CONCLUSION: Diagnosing a subacute P. acnes infection can be challenging because of nonspecific clinical findings, normal laboratory values, and delayed growth of this organism on culture. Clinicians should maintain a high degree of suspicion as these infections are frequently missed. PMID- 29252849 TI - Complications Associated with FAST-FIX All-Inside Meniscal Repair: A Report of Two Cases. AB - CASE: We describe the cases of two patients with a previously unreported complication associated with the all-inside FAST-FIX meniscal repair system. In both cases, anchors came loose postoperatively. CONCLUSION: Surgeons need to be aware of this potential complication in the event that a patient presents with pain and mechanical symptoms after meniscal repair. PMID- 29252850 TI - Retained Surgical Drain After Total Knee Arthroplasty: An Eight-Year Follow-up: A Case Report. AB - CASE: This report describes a patient in whom the intra-articular portion of a suction drain broke during total knee arthroplasty. The broken portion of the drain could not be removed, but the patient experienced no major complications over an eight-year follow-up period. CONCLUSION: The presence of a retained surgical drain needs to be carefully assessed but is not an absolute indication for removal. PMID- 29252851 TI - Perioperative Takotsubo Cardiomyopathy: A Rare Cardiac Complication Following Orthopaedic Surgery: A Case Report. AB - CASE: We present a case of Takotsubo cardiomyopathy associated with cardiogenic shock following reverse total shoulder arthroplasty in an eighty-three-year-old man with no history of cardiopulmonary medical problems. Takotsubo cardiomyopathy was diagnosed with emergency cardiac catheterization and angiography. The patient was managed with supportive measures that included the placement of a ventricular assist device. CONCLUSION: The patient recovered without any permanent cardiac sequelae. We review the pathogenesis, diagnosis, and treatment of Takotsubo cardiomyopathy. PMID- 29252852 TI - Early Fracture of a Vitamin-E-Infused, Highly Cross-Linked Polyethylene Liner After Total Hip Arthroplasty: A Case Report. AB - CASE: A vitamin-E-infused, highly cross-linked ultra-high molecular weight polyethylene (HXLPE) acetabular liner fractured without trauma less than twelve months after its implantation in a seventy-one-year-old woman. CONCLUSION: The remelting process utilized in the production of many commercially available HXLPE acetabular liners causes an immediate reduction in the fracture toughness of the material; however, it provides the benefit of oxidative stability, which prevents the loss of beneficial mechanical properties over time. Vitamin-E-infused HXLPE avoids the immediate decrease in fracture toughness by avoiding the remelting process. The case of our patient demonstrates that this material still can experience catastrophic failure despite acceptable component positioning. PMID- 29252853 TI - Extensive Heterotopic Ossification After Arthroscopic Rotator Cuff Repair: A Case Report. AB - CASE: A sixty-three-year-old woman who underwent routine arthroscopic rotator cuff repair developed extensive heterotopic ossification postoperatively. She required a reoperation for excision. CONCLUSION: Heterotopic ossification should be included in the differential diagnosis for postoperative stiffness after an arthroscopic rotator cuff repair. PMID- 29252854 TI - Compressive Ulnar Neuropathy Due to a Ganglion Cyst and Thickened Cubital Tunnel Retinaculum Fifty Years After Osteomyelitis Variolosa of the Elbow: A Case Report. AB - CASE: Ulnar neuropathy developed acutely in a fifty-four-year-old man with an arthritic and deformed elbow as the result of osteomyelitis variolosa, a complication of smallpox, which he contracted at the age of five years. Intraoperatively, a ganglion cyst arising from the joint and a pathologically thick cubital tunnel retinaculum were found to be compressing the nerve. Surgical excision of the ganglion, release of the cubital tunnel retinaculum, and anterior transposition of the ulnar nerve resulted in substantial clinical improvement at one year. CONCLUSION: The deformity and limited motion that can develop in the elbow over time following osteomyelitis variolosa may predispose the patient to ulnar neuropathy caused by a ganglion cyst arising in the compromised cubital tunnel. PMID- 29252855 TI - Do Osteoblastoma and Osteoid Osteoma Represent the Same Pathologic Entity?: A Case Report and Review of the Recent Literature. AB - CASE: We present the case of a fourteen-year-old boy with a benign diaphyseal femoral lesion that initially fulfilled the diagnostic criteria for osteoid osteoma but rapidly progressed and was finally diagnosed as osteoblastoma. CONCLUSION: Clinical and radiographic criteria provide imperfect and somewhat arbitrary distinguishing features between osteoid osteoma and osteoblastoma. Although previous work highlighted the importance of histologic interpretation in this regard, recent comparative histologic and immunohistochemical evaluations failed to differentiate the two. We conclude that consideration should be given to the classification of osteoid osteoma and osteoblastoma as the same pathologic entity, with treatment based on presentation along a continuum of aggressiveness, and that future directions for study may include identification of factors predictive of progression and/or recurrence. PMID- 29252856 TI - Septic Arthritis of the Hip in the Setting of Hemophagocytic Lymphohistiocytosis: A Case Report. AB - CASE: A twenty-two-month-old boy with septic hip arthritis had persistent elevated inflammatory markers and daily fevers despite multiple antibiotic regimens and repeated surgical debridements yielding negative cultures. After exhaustive work-up for other infectious, rheumatologic, and immunologic etiologies, he met diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) and developed cultures positive for fungal hip arthritis. Following treatment for HLH and fungal hip arthritis, he improved and was discharged. CONCLUSION: No previous report in the literature specifically associates HLH with septic hip arthritis, to our knowledge. Surgeons should suspect underlying immunologic deficiencies and atypical infectious causes of septic arthritis when usual treatment modalities have failed. PMID- 29252857 TI - Catastrophic Head-Neck Dissociation of a Modular Cementless Femoral Component. AB - CASE: We report two cases of modular head-neck junction failure involving the Stryker Accolade TMZF stem leading to sudden dissociation of the femoral head from the stem. Both patients presented with mechanical symptoms in the hip followed by pain and hip dysfunction. Disassembly of the head and deformation of the male taper were seen on preoperative radiographs. Intraoperatively, both patients had substantial metallosis with a markedly damaged taper requiring stem revision. CONCLUSION: We recommend regular clinical and radiographic surveillance of patients with the Stryker Accolade TMZF stem, especially those patients with pain and/or mechanical symptoms. PMID- 29252858 TI - Extrusion of the Hamate: A Case Report with Proposed Classification Amendment. AB - CASE: A thirteen-year-old right-hand-dominant girl sustained a right hamate fracture-extrusion with associated pisiform dislocation and volar degloving injury with open fractures of the scaphoid, capitate, lunate, and trapezoid following an all-terrain-vehicle rollover. She was noted to have paresthesias in the median nerve distribution. Treatment involved irrigation and debridement of the right wrist and internal fixation of the hamate, capitate, and scaphoid. At fifteen months of follow-up, she had returned to competitive softball as a pitcher. Radiographs demonstrated fully healed fractures. CONCLUSION: Complete extrusion of the hamate through an open wound can be treated with good functional outcomes. PMID- 29252859 TI - Arthroscopic Posterior Knee Capsulotomy for a Fixed Flexion Contracture in a Ten Year-Old Boy Due to a Hypertrophied Ligamentum Mucosum: A Case Report. AB - CASE: Knee flexion contractures are difficult to treat effectively. We present the case of a ten-year-old boy with a flexion contracture due to a hypertrophied ligamentum mucosum treated with an arthroscopic posterior capsular release. The patient obtained full extension and maintained it at the time of final follow-up. CONCLUSION: This case represents a unique cause of an impinging ligamentum mucosum and provides anecdotal support to the concept of an arthroscopic posterior capsular release as a safe and effective option for flexion contractures. PMID- 29252860 TI - Intrameniscal Gouty Tophi in the Knee: A Case Report. AB - CASE: We report a case of recurrent acute arthritis and restricted range of motion in the knee joint, with magnetic resonance imaging subsequently detecting a nodular lesion within the lateral meniscus. Knee arthroscopy and histology revealed that the lesion was intrameniscal gouty tophi. After arthroscopic synovectomy and excision of the tophi, the symptoms resolved and the patient remained symptom-free at two years of follow-up. CONCLUSION: Surgeons should be aware of the presence of such pathology and consider arthroscopic surgery if the mechanical symptoms persist. PMID- 29252861 TI - Anterior Transverse Divergent Dislocation of the Elbow in a Child: A Case Report. AB - CASE: A five-year-old boy injured his right elbow. Radiography revealed an anterior dislocation of the elbow with an olecranon fracture and a proximal radioulnar joint dissociation. Computed tomography (CT) confirmed the disruption of the proximal radioulnar joint, and a diagnosis of anterior transverse divergent dislocation of the elbow was established. Open reduction and fixation of the ulna was performed with good clinical results. CONCLUSION: We document a rare type of anterior divergent dislocation of the elbow. It is important to use CT to evaluate a proximal radioulnar joint dissociation to determine the correct diagnosis to aid in surgical planning. PMID- 29252862 TI - Intradural Extension of a Pyogenic Epidural Abscess: A Case Report. AB - CASE: Few cases of spinal epidural abscess involving an extradural abscess with an intradural extension have been reported. A unique complication with extension of pus from the epidural space through multiple perforations into the dura is described. Due to a proximal meningeal inflammatory reaction, which served as a proximal plug, no cerebrospinal fluid leak was encountered. CONCLUSION: Intradural extension of pus through multiple dural perforations is a rare complication of spinal epidural abscess and a treatment challenge. Early diagnosis enabling prompt surgical decompression, along with subsequent aggressive debridements and prolonged intravenous antibiotic treatment, can lead to a favorable outcome. PMID- 29252863 TI - A Novel Technique for the Surgical Treatment of Chronic Osteomyelitis of Long Bones: A Case Report. AB - CASE: A twenty-eight-year-old man sustained an open, comminuted tibial plateau fracture from a gunshot wound. Treatment included external fixation, serial debridements, and subsequent open reduction and internal fixation. Five months later, he developed chronic osteomyelitis of the proximal part of the tibia. Intraosseous debridement and irrigation with an arthroscope and arthroscopic tools was performed through existing bone screw holes. At the time of the final follow-up, he had resolution of pain and no recurrent infection. CONCLUSION: This minimally invasive technique may be considered for the treatment of chronic osteomyelitis of long bones to prevent structural destabilization and minimize disability. PMID- 29252864 TI - Low-Intensity Pulsed Ultrasound Bone Stimulator Treatment for Symptomatic Distal Phalangeal Shaft Fracture Nonunion. AB - CASE: Two cases of symptomatic distal phalangeal fracture nonunion that were treated with a course of digital splinting and daily external low-intensity pulsed ultrasound (LIPUS) treatment are presented. Osseous union, symptom resolution, and full range of motion were successfully achieved in both cases without surgery. CONCLUSION: Digital splinting and daily LIPUS should be considered as a treatment option for symptomatic nonunion of the distal phalanx in cases that do not require correction of bone deformity. PMID- 29252866 TI - Latin American Consensus for Pediatric Cardiopulmonary Resuscitation 2017: Latin American Pediatric Critical Care Society Pediatric Cardiopulmonary Resuscitation Committee. AB - OBJECTIVES: To develop a Latin American Consensus about Pediatric Cardiopulmonary Resuscitation. To clarify, reinforce, and adapt some specific recommendations for pediatric patients and to stimulate the implementation of these recommendations in clinical practice. DESIGN: Expert consensus recommendations with Delphi methodology. SETTING: Latin American countries. SUBJECTS: Experts in pediatric cardiopulmonary resuscitation from 19 Latin American countries. INTERVENTIONS: Delphi methodology for expert consensus. MEASUREMENTS AND MAIN RESULTS: The goal was to reach consensus with all the participating experts for every recommendation. An agreement of at least 80% of the participating experts had to exist in order to deliver a recommendation. Two Delphi voting rounds were sent out electronically. The experts were asked to score between 1 and 9 their level of agreement for each recommendation. The score was then classified into three groups: strong agreement (score 7-9), moderate agreement (score 4-6), and disagreement (score 1-3). Nineteen experts from 19 countries participated in both voting rounds and in the whole process of drafting the recommendations. Sixteen recommendations about organization of cardiopulmonary resuscitation, prevention, basic resuscitation, advanced resuscitation, and postresuscitation measures were approved. Ten of them had a consensus of 100%. Four of them were agreed by all the participants except one (94.7% consensus). One recommendation was agreed by all except two experts (89.4%), and finally, one was agreed by all except three experts (84.2%). All the recommendations reached a level of agreement. CONCLUSIONS: This consensus adapts 16 international recommendations to Latin America in order to improve the practice of cardiopulmonary resuscitation in children. Studies should be conducted to analyze the effectiveness of the implementation of these recommendations. PMID- 29252865 TI - Effect of Location on Tracheal Intubation Safety in Cardiac Disease-Are Cardiac ICUs Safer? AB - OBJECTIVES: Evaluate differences in tracheal intubation-associated events and process variances (i.e., multiple intubation attempts and oxygen desaturation) between pediatric cardiac ICUs and noncardiac PICUs in children with underlying cardiac disease. DESIGN: Retrospective cohort study using a multicenter tracheal intubation quality improvement database (National Emergency Airway Registry for Children). SETTING: Thirty-six PICUs (five cardiac ICUs, 31 noncardiac ICUs) from July 2012 to March 2016. PATIENTS: Children with medical or surgical cardiac disease who underwent intubation in an ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Our primary outcome was the rate of any adverse tracheal intubation associated event. Secondary outcomes were severe tracheal intubation-associated events, multiple tracheal intubation attempt rates, and oxygen desaturation. There were 1,502 tracheal intubations in children with underlying cardiac disease (751 in cardiac ICUs, 751 in noncardiac ICUs) reported. Cardiac ICUs and noncardiac ICUs had similar proportions of patients with surgical cardiac disease. Patients undergoing intubation in cardiac ICUs were younger (median age, 1 mo [interquartile range, 0-6 mo]) compared with noncardiac ICUs (median 3 mo [interquartile range, 1-11 mo]; p < 0.001). Tracheal intubation-associated event rates were not different between cardiac ICUs and noncardiac ICUs (16% vs 19%; adjusted odds ratio, 0.74; 95% CI, 0.54-1.02; p = 0.069). However, in a sensitivity analysis comparing cardiac ICUs with mixed ICUs (i.e., ICUs caring for children with either general pediatric or cardiac diseases), cardiac ICUs had decreased odds of adverse events (adjusted odds ratio, 0.71; 95% CI, 0.52-0.97; p = 0.033). Rates of severe tracheal intubation-associated events and multiple attempts were similar. Desaturations occurred more often during intubation in cardiac ICUs (adjusted odds ratio, 1.61; 95% CI, 1.04-1.15; p = 0.002). CONCLUSIONS: In children with underlying cardiac disease, rates of adverse tracheal intubation-associated events were not lower in cardiac ICUs as compared to noncardiac ICUs, even after adjusting for differences in patient characteristics and care models. PMID- 29252868 TI - Efficacy and Safety Outcome Domains and Outcome Measures in Systematic Reviews of Neuropathic Pain Conditions. AB - OBJECTIVES: Heterogeneity of outcome domains, used in interventional trials and systematic reviews (SRs) for neuropathic pain (NeuP), makes decisions on the comparative effectiveness of available treatments difficult. This study analyzed outcome domains and measures used in SRs of randomized controlled trials on efficacy and safety of interventions for NeuP and compared them with the core outcome set (COS) and core outcome measures (COMs) for chronic pain recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). METHODS: Five electronic databases were searched to find SRs of interventions for NeuP. Outcome domains and measures were independently extracted by 2 authors, and compared against the IMMPACT-recommended COS and COMs. Outcome domains specified in the methods and reported in the results were also compared. RESULTS: Ninety-seven SRs were analyzed. The 2 core domains most frequently specified in the methods and reported in the results of SRs were pain and symptoms and adverse events. Pain intensity was mostly assessed with Visual Analog Scale (n=59) and Numerical Rating Scale (n=29). The incidence (n=70) and severity (n=60) were most commonly reported for adverse events. There were 240 different outcome measures used for the assessment of treatment efficacy and safety. CONCLUSIONS: Authors of SRs in the field of NeuP insufficiently use relevant recommended COS and COMs for chronic pain. More effort should be put into the implementation of COS to ensure that the study results can be compared and combined. There is a need for defining core outcome domains and measures specific for NeuP. PMID- 29252870 TI - Breaking the Barriers in Resident Education: A Quality Improvement Initiative. AB - INTRODUCTION: In 2013, the American College of Cardiology and American Heart Association updated the cholesterol guideline. Despite strong evidence supporting the recommendations, a discernible gap exists in the number of residents who practice them. Our study aimed to identify barriers hindering residents from guideline implementation. METHODS: Twenty eight residents were administered a preintervention and postintervention questionnaire to identify barriers in guideline application. The questionnaire was categorized into three barriers: knowledge, attitude, and behavior. A multifaceted educational intervention consisting of directed teaching sessions and supervised patient encounters was conducted. RESULTS: Our analysis showed that our residents lacked awareness, familiarity, and self-efficacy in using the cholesterol guideline. The intervention led to significant improvements in awareness (79% vs. 43%, p = .0129), familiarity (61% vs. 29%, p = .0306), and self-efficacy (65% vs. 16%, p = .0018) and achieved a 31% increase in knowledge (p = .0001), 38% in attitude (p = .0001), and 20% in behavior (p = .019). The overall improvement in scores averaged 30% (p = .0001). CONCLUSION: Our quality improvement initiative successfully improved our resident's comprehension and applicability of the 2013 ACC/AHA cholesterol guideline. We recommend a multifaceted educational approach tailored toward addressing specific barriers to improve the practice of evidence based medicine. PMID- 29252869 TI - Altered Spontaneous Brain Activity in Patients With Idiopathic Trigeminal Neuralgia: A Resting-state Functional MRI Study. AB - OBJECTIVES: To identify the changes of local coherence and intrinsic brain activity in resting-state idiopathic trigeminal neuralgia (ITN) patients by using regional homogeneity (ReHo) and fractional aptitude of low-frequency fluctuation (fALFF) analysis. METHODS: ReHo and fALFF were analyzed in 23 ITN patients and 23 age-matched and sex-matched pain-free controls to detect the functional abnormality in the brains of ITN patients. Correlations between ReHo and fALFF were analyses. ITN pain intensity were also assessed in the ITN group. RESULTS: Compared with pain-free controls, ITN patients exhibited significantly abnormal ReHo and fALFF in several brain regions, including the cerebellum, cingulate cortex, temporal lobe, putamen, occipital lobe, limbic lobe, precuneus, insula, medial, and superior frontal gyrus compared with healthy controls. Correlation analysis showed that ReHo values of several altered brain areas positively correlated with visual analog scale values. But no correlation was found between fALFF and visual analog scale. DISCUSSION: Our results showed that ITN patients exhibited significantly abnormal spontaneous brain activity in several brain regions that are involved in pain modulation and perception. The present study reflects the maladaptive process of daily pain attacks and may enhance the understanding of how chronic pain affects local intrinsic brain activity. PMID- 29252871 TI - Differences in Patient Experience Between Hispanic and Non-Hispanic White Patients Across U.S. Hospitals. AB - INTRODUCTION: Despite the increased emphasis on patient experience, little is known about whether there are meaningful differences in hospital satisfaction between Hispanic and non-Hispanic whites. METHODS: To determine if satisfaction differs, we used Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey data (2009-2010) reported by hospitals to compare responses between Hispanic and non-Hispanic white patients. Clustered logistic regression models identified within-hospital and between-hospital differences in satisfaction. RESULTS: Of the 3,864,938 respondents, 6.2% were Hispanics, who were more often younger and females and less likely to have graduated from high school. Hispanics were overall more likely to recommend their hospital (74.1% vs. 70.9%, p < .001) and to rate it 9 or 10 (72.5% vs. 65.9%, p < .001) than whites. Increased satisfaction among Hispanics was more pronounced when compared with whites within the same hospitals, with significantly higher ratings on all HCAHPS measures. However, hospitals serving a higher percentage of Hispanics had lower satisfaction scores for both Hispanic and white patients than other hospitals. CONCLUSION: There were significant but only modest-sized differences in patient experience between Hispanic and white patients across U.S. hospitals. Hispanics tended to be more satisfied with their care but received care at lower-performing hospitals. PMID- 29252872 TI - Atypical Acute Compartment Syndrome. PMID- 29252873 TI - Kinematic Characteristics of an Osteotomy of the Proximal Aspect of the Fibula During Walking: A Case Report. AB - CASE: A 51-year-old patient with medial compartment osteoarthritis of the left knee underwent an osteotomy of the proximal aspect of the fibula. Gait kinematic data were collected before and after the surgery with use of an optical tracking system during level walking. A sharp increase of approximately 5 degrees to 7 degrees in femoral abduction and a 5 degrees to 8 degrees increase in femoral external rotation were exhibited at 3 months postsurgery. At 1 year postsurgery, femoral external rotation had increased by 3 degrees to 5 degrees . There was also an increase of distal femoral translation (approximately 2 to 10 mm). CONCLUSION: An osteotomy of the proximal aspect of the fibula altered the kinematics by increasing valgus, femoral external rotation, and distal translation of the knee. These alterations may help reduce knee pain and improve early functional recovery. PMID- 29252874 TI - Bilateral Osteochondritis Dissecans of the Capitellum in Fraternal Twins: A Case Report. AB - CASE: We report the cases of 15-year-old male fraternal twins with bilateral osteochondritis dissecans (OCD) of the capitellum in the absence of syndromic features. At the time of presentation, they had been actively engaged in competitive rhythmic gymnastics for 3 years. Both patients had chronic symptoms in the right elbow, and both underwent arthroscopic evaluation and management. CONCLUSION: The cases of these 2 patients provide evidence to support the theory that the etiology of OCD may have a genetic background. PMID- 29252875 TI - Arthroscopic Management of a Rare Case of Melioidotic Septic Arthritis of the Ankle in a New Endemic Area on the Southwest Coast of India: A Case Report. AB - CASE: We report a case of melioidotic septic arthritis of the ankle and secondary osteomyelitis of the talus in a 64-year-old farmer with diabetes mellitus. Arthroscopic drainage and debridement, followed by 6 months of appropriate antibiotic therapy, resulted in a good short-term outcome. CONCLUSION: Melioidotic septic arthritis of the ankle is extremely rare. This case report highlights the possibility of this disease occurring on the Indian subcontinent. PMID- 29252876 TI - Percutaneous Nailing and Cementoplasty for Palliative Management of Supra Acetabular Iliac Wing Metastases: A Case Report. AB - CASE: A 48-year-old woman was unable to walk due to an extensive osteolytic supra acetabular iliac wing metastatic lymphoma involving the arcuate line. A minimally invasive technique that combined percutaneous nailing of the iliac bone with a customized nail and cementoplasty (intraosseous injection of polymethylmethacrylate) was performed. At the 1-year follow-up, she was able to walk without crutches, and computed tomography (CT) showed a stable iliac bone fixation. CONCLUSION: Osteolytic metastasis is a common cause of bone weakening, especially in load-bearing areas. With osteolytic metastases involving the acetabulum, intraosseous injection of bone cement into the weakened acetabulum may reduce pain and prevent fracture. Nailing combined with cementoplasty may be proposed for extensive destruction of the iliac bone involving the arcuate line to relieve pain and allow for resumed walking. PMID- 29252877 TI - Scoliosis Secondary to Dystonia: A Case Report and Review of the Literature. AB - CASE: An adolescent girl presented with an atypical scoliotic curve, pelvic obliquity, back pain, and lower-extremity paresthesias. A workup revealed generalized primary torsion dystonia. The condition was refractory to medical treatment and necessitated implantation of a deep brain stimulator. The scoliosis required operative correction, and the patient underwent posterior spinal arthrodesis with hook-rod instrumentation, which resulted in successful correction through 7 years of follow-up. CONCLUSION: The differential diagnosis for adolescent scoliosis should include dystonia as a potential cause, especially when a patient presents with muscular contractures, an atypical scoliotic curve, pelvic obliquity, or changing curve characteristics. PMID- 29252878 TI - Candida albicans Sacral Osteomyelitis Causing Necrosis of a Sacral Nerve Root: A Case Report. AB - CASE: A 31-year-old immunocompetent woman presented with a large sacral mass on the left side, concerning for a neoplastic process. A biopsy specimen demonstrated fungal osteomyelitis. Intraoperatively, the left S1 sacral nerve root was found to be necrotic, consistent with the symptoms of numbness and weakness. The infection was resolved with aggressive surgical debridement and long-term therapy with antifungal medication. CONCLUSION: Fungal osteomyelitis of the sacrum is rare, especially in an immunocompetent patient, and untreated infections can cause nerve root necrosis. We recommend aggressive surgical and antifungal management to avoid neurologic compromise. PMID- 29252879 TI - Spontaneous Compartment Syndrome in a Patient with McArdle Disease: A Case Report and Review of the Literature. AB - CASE: McArdle disease, a glycogen storage disorder, often manifests as exercise intolerance secondary to muscle ischemia. Few authors have reported on rhabdomyolysis or compartment syndrome following inciting events among patients with McArdle disease. We present the case of a 40-year-old woman who developed spontaneous compartment syndrome of the right forearm and subsequently underwent emergency fasciotomy. CONCLUSION: On the basis of the present case and our review of the current literature, we advocate a high level of suspicion for compartment syndrome in patients with a history of McArdle disease. PMID- 29252880 TI - Pathologic Tuft Fracture in a Thumb: A Rare Presentation of Metastatic Endometrioid Ovarian Carcinoma: A Case Report and Review of the Literature. AB - CASE: A 51-year-old woman with a medical history noteworthy for endometrioid ovarian carcinoma presented with progressive left thumb swelling in the absence of trauma or injury. Radiographs revealed a lytic lesion in the distal phalanx. Inflammatory markers and white blood-cell count were mildly elevated. The thumb was amputated at the interphalangeal joint, and pathologic examination identified the lesion as an adenocarcinoma, consistent with the known endometrioid ovarian carcinoma. CONCLUSION: The similar presentation of tumor and infection can present a diagnostic challenge. Despite the rare incidence of osseous metastases to the hand, orthopaedic surgeons must consider metastatic bone lesions in patients presenting with swollen or painful fingers. PMID- 29252881 TI - Fracture of the Ankylosed Spine Following a Direct Anterior Approach for Total Hip Arthroplasty on a Fracture Table: A Case Report. AB - CASE: An 85-year-old man with diffuse idiopathic skeletal hyperostosis underwent total hip arthroplasty (THA) through a direct anterior approach. Postoperatively, persistent blood loss and worsening abdominal and back pain prompted computed tomography, which identified an L1 hyperextension fracture-dislocation. The patient underwent staged posterior and anterior instrumented fusion. At the 5 year follow-up, he had persistent dorsal column dysfunction. CONCLUSION: Fracture dislocation of the ankylosed spine is a rare complication following THA. We recommend lateral decubitus positioning, pelvic and back support, careful limb manipulation, and an in situ femoral neck osteotomy to avoid excessive loads on the stiff spine during THA. PMID- 29252882 TI - Traumatic Hemipelvectomy with a Contralateral Unstable Pelvis and Acetabular Fracture: A Case Report and Review of the Literature. AB - CASE: A traumatic hemipelvectomy (THP) is a rare life-threatening injury, with limited reports in the civilian population. We present the case of a patient who sustained a massive pelvic injury with an incomplete unilateral THP, a contralateral unstable pelvis, and a fracture of the acetabulum. CONCLUSION: With advancements in resuscitative techniques, carefully timed and planned surgical interventions, and a coordinated multidisciplinary approach, a greater number of patients may be able to survive a massive pelvic injury. PMID- 29252883 TI - Epidural Pneumorrhachis Causing Intraoperative Loss of Motor Potentials During Instrumented Fusion for Scoliosis: A Case Report. AB - CASE: In a patient who underwent a thoracoscopic anterior release combined with a posterior spinal fusion for juvenile idiopathic scoliosis, unilateral loss of neuromonitoring signals was noted during the posterior instrumentation, and epidural pneumorrhachis was identified by intraoperative O-arm imaging. An immediate laminectomy and decompression of epidural fat and air were performed, resulting in return of the neuromonitoring signals. The patient had no clinical motor or neurological deficits postoperatively, and the posterior spinal fusion was completed successfully 3 days later. CONCLUSION: Epidural pneumorrhachis is a possible complication of scoliosis surgery with pedicle screw fixation, which can result in the intraoperative loss of neuromonitoring signals; however, rapid identification and intervention can result in an excellent outcome. PMID- 29252884 TI - Pregnancy-Related Ligamentous Laxity Mimicking Dynamic Scapholunate Instability: A Case Report. AB - CASE: A 29-year-old woman presented with spontaneous, isolated, total palmar scaphoid subluxation in the left hand approximately 6 weeks postpartum. She had a positive Watson scaphoid shift test, with an easily subluxable and reducible scaphoid unilaterally. She was diagnosed with scapholunate ligamentous laxity with dynamic instability. Approximately 4 months after stopping lactation, she had complete resolution of the scapholunate subluxation; there was no recurrence of symptoms over the next 5 years of follow-up. CONCLUSION: Women can have manifestations of pregnancy and lactation-related ligamentous laxity, including scapholunate instability, which may spontaneously resolve upon cessation of lactation. PMID- 29252885 TI - A Rare Case of Isolated Salmonella Species Group B Sacroiliitis in a Healthy Collegiate-Level Swimmer: A Case Report. AB - CASE: We present a case of isolated Salmonella species group B sacroiliitis in a healthy 19-year-old collegiate-level swimmer with no known risk factors. To our knowledge, there are no similar cases described in the current literature. CONCLUSION: Pyogenic sacroiliitis (PS) is a rare form of septic arthritis, especially in adults. PS is most commonly seen in the setting of intravenous drug use or in an immunocompromised patient. If a patient does not fit either of these demographics, PS initially can be a difficult diagnosis because of its rarity and vague symptomatology. PMID- 29252886 TI - Mycobacterium abscessus Osteomyelitis of the Calcaneus Presenting as Tumor Mimicking Lesions: A Case Report. AB - CASE: We present the case of a 51-year-old immunocompetent man with refractory heel pain who initially had been treated for plantar fasciitis. However, the pain was proven to be caused by a Mycobacterium abscessus infection of the calcaneus. The process of diagnosis and treatment is described. CONCLUSION: Although rare, chronic heel pain can be caused by an atypical mycobacterial infection of the calcaneus. Because of its indolent clinical course, misdiagnosis is not uncommon with calcaneal osteomyelitis. Physicians should note that this rare infection should be considered in patients with refractory heel pain. PMID- 29252887 TI - A Posterolateral Approach to the Scapula for Evacuation of a Subscapular Abscess: A Case Report. AB - CASE: We present the case of a subscapular abscess that was drained via a posterolateral approach to the scapula. Complete evacuation of the abscess was achieved, and the incisions healed without difficulty. There were no immediate postoperative complications from this approach. CONCLUSION: To our knowledge, a posterolateral approach for evacuating a subscapular abscess has not been described previously in the literature. Utilizing the internervous plane between the teres major and latissimus dorsi muscles, along with medial counterincisions, allows for safe drainage of this rare type of abscess. PMID- 29252888 TI - Osteonecrosis of the Femoral Head and Hip Arthritis in an Adolescent Following an Isolated Fracture of the Greater Trochanter: A Case Report and Review of the Literature. AB - CASE: A healthy adolescent sustained an isolated fracture of the greater trochanter after falling from a height. He was treated nonoperatively. After 10 weeks of improvement, the pain recurred, and osteonecrosis of the femoral head was diagnosed. Core decompression and a bone-marrow injection were performed. Transient relief was achieved, followed by deterioration to end-stage hip arthritis. CONCLUSION: To our knowledge, 19 other cases of isolated fractures of the greater trochanter in adolescents have been reported since 1905. All high energy injuries (10 cases) progressed to osteonecrosis, independent of the intervention; none of the low-energy cases progressed to osteonecrosis. We advocate vigilance and early magnetic resonance imaging for these injuries to detect and treat osteonecrosis in its early stages. PMID- 29252889 TI - Delayed Profunda Femoris Artery Bleeding After Intramedullary Nailing of an Unstable Intertrochanteric Fracture: A Case Report. AB - CASE: A 75-year-old man underwent intramedullary nailing for an unstable intertrochanteric fracture of the left hip. After surgery and postoperative recovery, he was transferred to a rehabilitation ward. He was able to mobilize at 2 days postoperatively; at 2 weeks postoperatively, he developed the sudden onset of tachycardia, hypotension, and a large hematoma on the left thigh. Following immediate resuscitation, a computed tomography (CT) angiogram demonstrated a bleed from a branch of the profunda femoris artery. The 3-dimensional CT reconstruction implicated the displaced lesser trochanter osseous fragment as the cause of the hemorrhage. CONCLUSION: Surgeons should be aware of this rare complication and the possible etiology of fracture displacement as the cause of a delayed-onset bleed after intramedullary nailing, and they should also be cognizant of the subsequent optimal management. PMID- 29252890 TI - A Zone-II Flexor Tendon Injury Secondary to a Catfish Spine: A Case Report. AB - CASE: We present the case of a 17-year-old man who sustained a delayed rupture of a zone-II flexor tendon injury in the long finger from a catfish spine, which caused local envenomization and a likely secondary bacterial infection. He underwent surgical exploration and irrigation and debridement of the finger. The flexor digitorum profundus tendon was found to be lacerated and was primarily repaired. CONCLUSION: Catfish spines can cause traumatic disruption of anatomic structures and can envenomate the area of injury, which can lead to a secondary bacterial infection. We review the literature regarding catfish spine injuries and describe a basic treatment algorithm for patients who are injured by catfish spines. PMID- 29252891 TI - Use of the S3 Corridor for Iliosacral Fixation in a Dysmorphic Sacrum: A Case Report. AB - CASE: The S1 and S2 corridors are the typical osseous pathways for iliosacral screw fixation of posterior pelvic ring fractures. In dysmorphic sacra, the S1 screw trajectory is often different from that in normal sacra. We present a case of iliosacral screw placement in the third sacral segment for fixation of a complex lateral compression type-3 pelvic fracture in a patient with a dysmorphic sacrum. CONCLUSION: In patients with dysmorphic sacra and unstable posterior pelvic ring fractures or dislocations, the S3 corridor may be a feasible osseous fixation pathway that can be used in a manner equivalent to the S2 corridor in a normal sacrum. PMID- 29252892 TI - Arthroscopic Osteochondral Autograft Transfer for Juvenile Osteochondritis Dissecans of the Humeral Head: A Case Report. AB - CASE: Osteochondritis dissecans (OCD) rarely affects the humeral head. We describe a 14-year-old adolescent who, despite conservative treatment, had persistent pain in the left shoulder as well as limited function. Radiographs and a computed tomography (CT) arthrogram revealed an osteochondral defect of the humeral head. He was managed with an arthroscopic osteochondral autograft transfer from the knee, which provided a satisfactory outcome. CONCLUSION: Arthroscopic osteochondral autograft transfer is an effective option for the treatment of OCD of the humeral head. PMID- 29252893 TI - Arterial Thoracic Outlet Syndrome and Cerebellar Infarction Following a Stress Fracture of the First Rib and Extensive Callus Formation: A Case Report. AB - CASE: Stress fractures of the first rib rarely have been reported in association with sports activities. We report a case of a cerebellar infarction that possibly was associated with arterial thoracic outlet syndrome (aTOS) that developed as a result of extensive callus formation in a young baseball player with a stress fracture of the first rib. CONCLUSION: According to the literature, almost all cases of stress fracture in the first rib have a relatively good prognosis, and there are only a few reports of TOS occurring as a rare late complication. To our knowledge, there have been no prior reports of cerebellar infarction associated with aTOS following a stress fracture of the first rib. PMID- 29252894 TI - Methotrexate-Related Lymphoproliferative Disorder Presenting with Severe Swelling of the Elbow Joint: A Case Report. AB - CASE: A patient with rheumatoid arthritis (RA) who was being treated with methotrexate (MTX) therapy presented with severe swelling of the left elbow. Magnetic resonance imaging showed a tumor-like lesion around the elbow joint. Fluorodeoxyglucose positron emission tomography indicated multiple lesions in the lung and the lymph nodes. An open biopsy of a cervical lymph node was performed, and MTX-related lymphoproliferative disorder (MTX-LPD) was diagnosed. After cessation of the MTX therapy, the elbow swelling regressed, and the patient was in remission of MTX-LPD. CONCLUSION: MTX-LPD should be considered in the differential diagnosis when a patient with RA develops severe joint swelling while on MTX therapy. PMID- 29252896 TI - Standing on the Shoulders of Giants. PMID- 29252895 TI - The Natural History of the Development of Trevor Disease of the Hip and Subsequent Arthroplasty: A Case Report. AB - CASE: Trevor disease (dysplasia epiphysealis hemimelica [DEH]) is a rare, intra articular anomaly of cartilaginous overgrowth of the epiphysis. The usual presentation is on 1 side of the body and on 1 side of the epiphysis. The natural history of this disease is not clear because the lesions often are treated during childhood. Additionally, hip involvement is relatively uncommon; to our knowledge, total hip arthroplasty in a patient with DEH has not been reported previously. Our patient presented with previously untreated DEH of the hip joint, which had developed into a very unusual shape. He was treated with a total hip arthroplasty and had satisfactory functioning 2.5 years postsurgery. CONCLUSION: Untreated DEH of the hip can lead to a very misshapen hip with a deformed femoral head and loss of the shape of the acetabulum, as well as stiffness due to an unusual shape and osteoarthritic changes. A total hip arthroplasty can give satisfactory functional results. PMID- 29252897 TI - Editors' Recognition Awards for Distinction in Reviewing in 2017. PMID- 29252898 TI - Reinventing Radiology: Big Data and the Future of Medical Imaging. AB - PURPOSE: Today, data surrounding most of our lives are collected and stored. Data scientists are beginning to explore applications that could harness this information and make sense of it. MATERIALS AND METHODS: In this review, the topic of Big Data is explored, and applications in modern health care are considered. RESULTS: Big Data is a concept that has evolved from the modern trend of "scientism." One of the primary goals of data scientists is to develop ways to discover new knowledge from the vast quantities of increasingly available information. CONCLUSIONS: Current and future opportunities and challenges with respect to radiology are provided with emphasis on cardiothoracic imaging. PMID- 29252899 TI - Lung Cancer Radiogenomics: The Increasing Value of Imaging in Personalized Management of Lung Cancer Patients. AB - Radiogenomics provide a large-scale data analytical framework that aims to understand the broad multiscale relationships between the complex information encoded in medical images (including computational, quantitative, and semantic image features) and their underlying clinical, therapeutic, and biological associations. As such it is a powerful and increasingly important tool for both clinicians and researchers involved in the imaging, evaluation, understanding, and management of lung cancers. Herein we provide an overview of the growing field of lung cancer radiogenomics and its applications. PMID- 29252900 TI - Accommodation in Early Presbyopes Fit with Bilateral or Unilateral Near Add. AB - SIGNIFICANCE: When fit with monovision, most early presbyopes (aged 40 to 50 years) accommodated to near objects by focusing the distance corrected eye, leaving the near corrected eye myopically defocused with reduced image quality. A few were able to switch focus to the near corrected eye retaining a consistently focused image in one eye over a wider range of distances. PURPOSE: The aim of this study was to examine accommodation behavior, pupil responses, and resultant image quality of early presbyopes fit with either bilateral or unilateral (monovision) near adds. METHODS: Accommodative response and pupil size of 19 subjects (27 to 60 years), including 13 early presbyopes (40 to 50 years), were measured using an aberrometer as a binocularly viewed 20/40 letter E was moved from 2 m to 20 cm. Each subject was fit with different refractive strategies: bilateral distance correction, bilateral +2 diopters (D) near add, and unilateral +2 D near add placed over the measured right eye or unmeasured left eye. Monochromatic image quality was quantified using the Visual Strehl ratio metric. RESULTS: With bilateral +2 D near add, all early presbyopes mostly refrained from accommodating (gain = 0.22 D/D) until the target approached closer than the 50-cm far point, and they then accommodated accurately until their maximum accommodative amplitude was reached. With monovision, most (10 of 13 early presbyopes) accommodated to focus the distance corrected eye, leaving the near corrected eye myopically defocused with reduced image quality. As stimulus distance became closer than their distance corrected eye's near point, they continued to exert maximum accommodation. Only two early presbyopes relaxed their accommodation to "switch" focus to the near corrected eye as target distance was reduced, and these two did not experience bilateral drop in image quality as stimulus distance became closer than the near point of the distance corrected eye. CONCLUSIONS: Our data suggest that many early presbyopes will not initially adopt an accommodation strategy that optimizes image quality with monovision, but consistently accommodate to focus the distance corrected eye. PMID- 29252901 TI - Mechanisms of Image Stabilization in Central Vision Loss: Smooth Pursuit. AB - SIGNIFICANCE: In addition to understanding the adaptive mechanisms of eccentric viewing during smooth pursuit, the ocular motor adaptations of patients with central vision loss give us a better understanding of the basic mechanisms of smooth pursuit in the healthy visual system. PURPOSE: For patients with age related macular degeneration and controls with normal vision, we examined the closed-loop gain of horizontal and vertical smooth pursuit eye movements as a function of stimulus speed and direction. We hypothesized that pursuit gain functions would be affected by stimulus speed and the location of the preferred retinal locus (PRL) in relation to the scotoma as determined by a fixation stability task using a microperimeter. Specifically, that a PRL on the left of the scotoma in the visual field would decrease the rightward gain relative to the leftward gain and a PRL below the scotoma in the visual field would decrease the upward gain. METHODS: Ten patients and 15 controls were tested in a step-ramp procedure with direction (left/right for horizontal motion; up/down for vertical motion), speed (5, 10, 15, 20, and 30 deg/s), and five replication conditions randomized and blocked by orientation (horizontal vs. vertical). RESULTS: Horizontal pursuit had a higher gain than vertical pursuit. The two eyes of the patients moved conjugately with similar smooth pursuit gains. For horizontal pursuit, all patients, regardless of PRL location, showed significantly better pursuit of leftward motion. For vertical pursuit, downward pursuit had a higher gain than upward pursuit for most patients. CONCLUSIONS: PRL location was not predictive of the directional preponderance of pursuit performance. These results imply that patients may not use the PRL that was initially found during a static fixation task; they may adapt to the task by using a PRL that appears more suitable. PMID- 29252902 TI - Factors Influencing Visual Acuity in Fuchs' Endothelial Corneal Dystrophy. AB - SIGNIFICANCE: In eyes with mild Fuchs' endothelial corneal dystrophy without significant corneal edema, objective scattering index has the strongest influence on distance visual acuity, followed by the anterior corneal densitometry. Our findings suggest that distance visual acuity deteriorates in eyes with higher forward light scatter. PURPOSE: To evaluate the factors affecting distance visual acuity in patients with Fuchs' endothelial corneal dystrophy. METHODS: This retrospective study comprised 31 eyes of 31 patients with mild Fuchs' dystrophy without corneal edema and 25 eyes of 25 age-matched healthy subjects. Stepwise multiple regression analysis was used to assess the relationship between distance acuity with age, sex, forward light scatter, corneal backward scatter, anterior and posterior corneal higher-order aberrations, endothelial cell density, central corneal thickness, and corneal astigmatism. RESULTS: The forward light scatter, corneal backward scatter, and corneal higher-order aberrations were significantly larger in the Fuchs' dystrophy group than those in the control group (P <= .004). In a univariate analysis, with higher forward light scatter, anterior corneal backward scatter, corneal higher-order aberrations, and age, the distance acuity significantly deteriorated in eyes with Fuchs' dystrophy. In a multiple linear regression analysis, explanatory variables relevant to the distance acuity were the forward light scatter (P < .001, partial regression coefficient B = 0.035) and anterior corneal backward scatter (P = 0.2, B = 0.008) (adjusted R = 0.694). CONCLUSIONS: Eyes with higher light scatter, especially forward light scattering, showed deteriorated visual acuity. Results suggest that forward light scatter and corneal backward scatter play a more important role in visual performance than corneal higher-order aberrations in Fuchs' endothelial corneal dystrophy. PMID- 29252903 TI - Case Series: Overnight Wear of Scleral Lens for Persistent Epithelial Defects. AB - SIGNIFICANCE: This case series demonstrates successful use of PROSE (Prosthetic Replacement of the Ocular Surface Ecosystem) for overnight wear among patients with persistent epithelial defects, while exploring the efficacy of using PROSE reservoir for autologous hematopoietic products during treatment. PURPOSE: This case series proposes a strategic approach to the treatment of refractory cases of persistent epithelial defect via overnight PROSE device wear. CASE REPORTS: We followed three patients with persistent epithelial defect treated with PROSE devices and observed expedited defect resolution and improvement in best corrected visual acuity over the course of 2 to 4 weeks. In addition to moxifloxacin and preservative-free saline, autologous hematopoietic products were added to the reservoir of two patient's PROSE devices. Patients were advised to wear their PROSE device at all times except for lens cleaning and replacement of reservoir contents every 12 hours. CONCLUSIONS: Together, these cases demonstrated the safety and efficacy of overnight wear of PROSE devices in the treatment of refractory persistent epithelial defect (PED). PMID- 29252904 TI - Assessment of Tear Film Using Videokeratoscopy Based on Fractal Dimension. AB - SIGNIFICANCE: The proposed automated approach for estimating the quality of the tear film closes the gap between the manual and automated assessment, translating the high-speed videokeratoscopy technology from scientific laboratories to a clinical practice. PURPOSE: To develop and test a new method for characterizing Tear Film Surface Quality with high-speed videokeratoscopy utilizing a fractal dimension approach. METHODS: The regularity of the reflected pattern in high speed videokeratoscopy (E300; Medmont) depends on tear film stability. Thus, determining tear film stability can be addressed by estimating the fractal dimension of the reflected pattern. The method is tested on 39 normal subjects. The results of the fractal dimension approach are compared with those obtained using previously proposed automated method, based on a gray-level co-occurrence matrix approach, and with subjective results obtained by two operators that were assessing the video recordings in ideal conditions. RESULTS: Fractal dimension method was less affected by eye movements and changes in the videokeratoscopic image background than gray-level co-occurrence matrix method. Median difference of the noninvasive break-up time between manual and automated methods was 0.03 s (IQR = 4.47 s) and 0.0 s (IQR = 2.22 s) for gray-level co-occurrence matrix and fractal dimension approaches, respectively. Correlation coefficient with manual noninvasive break-up time was r = 0.86 (P < 0.001) for gray-level co-occurrence matrix approach, and r = 0.82 (P < 0.001) for fractal dimension approach. Significant statistical difference was found between noninvasive break-up measurements of manual and gray-level co-occurrence matrix method (P = 0.008). CONCLUSIONS: The proposed method has the potential to characterize tear film dynamics in more detail compared to previous methods based on high-speed videokeratoscopy. It showed good correlation with manual assessment of tear film. PMID- 29252905 TI - Higher-Order Aberrations in Children and Adolescents of Southwest China. AB - SIGNIFICANCE: This study provides a descriptive characterization of higher-order optical aberrations for the eyes of a larger number of Chinese children and adolescents. PURPOSE: To determine the distribution of higher-order aberrations (HOAs) of Han Chinese young subjects with normal vision and their relationship to age. METHODS: Children and adolescents, aged from 3 to 17 years, with normal visual acuity were enrolled, and their wavefront aberrations for a 6-mm pupil were evaluated by the Zywave II aberrometer. Their correlations with age were analyzed, and the 95% statistical reference ranges were computed for each Zernike term. RESULTS: A total of 1634 eyes (287 for preschool-age children, 897 for school-age children, and 450 for adolescents) were analyzed. There was a significant correlation with age and the root mean square (RMS) of total HOAs (r = 0.256, P < .0001), third-order aberrations (r = 0.062, P = .029), fourth-order aberrations (r = 0.197, P < .0001), fifth-order aberrations (r = 0.067, P = .017), and trefoil-like aberrations (r = 0.100, P < .0001) in the myopic group. There were significant differences in RMS values (except coma-like aberrations, chi = 4.179, P = .124) as well as the Zernike coefficients among three different age groups. Therefore, the 95% statistical normal reference values were calculated separately for three age groups. CONCLUSIONS: The RMS value of total HOAs, coma-like, trefoil-like, third-order, fourth-order, and fifth-order aberrations are correlated with age, and the RMS values and Zernike coefficients of aberrations were different in different age stages of the subjects. This study described the distribution of HOAs in children and adolescents and established 95% statistical normal values of HOAs for different ages of children and adolescents by analyzing the HOAs in a large number of the Han Chinese clinical population. PMID- 29252906 TI - Tear-Film Evaporation Rate from Simultaneous Ocular-Surface Temperature and Tear Breakup Area. AB - SIGNIFICANCE: A corneal heat-transfer model is presented to quantify simultaneous measurements of fluorescein tear-breakup area (TBA) and ocular-surface temperature (OST). By accounting for disruption of the tear-film lipid layer (TFLL), we report evaporation rates through lipid-covered tear. The modified heat transfer model provides new insights into evaporative dry eye. PURPOSE: A quantitative analysis is presented to assess human aqueous tear evaporation rate (TER) through intact TFLLs from simultaneous in vivo measurement of time dependent infrared OST and fluorescein TBA. METHODS: We interpret simultaneous OST and TBA measurements using an extended heat-transfer model. We hypothesize that TBAs are ineffectively insulated by the TFLL and therefore exhibit higher TER than does that for a well-insulting TFLL-covered tear. As time proceeds, TBAs increase in number and size, thereby increasing the cornea area-averaged TER and decreasing OST. Tear-breakup areas were assessed from image analysis of fluorescein tear-film-breakup video recordings and are included in the heat transfer description of OST. RESULTS: Model-predicted OSTs agree well with clinical experiments. Percent reductions in TER of lipid-covered tear range from 50 to 95% of that for pure water, in good agreement with literature. The physical picture of noninsulating or ruptured TFLL spots followed by enhanced evaporation from underlying cooler tear-film ruptures is consistent with the evaporative driven mechanism for local tear rupture. CONCLUSIONS: A quantitative analysis is presented of in vivo TER from simultaneous clinical measurement of transient OST and TBA. The new heat-transfer model accounts for increased TER through expanding TBAs. Tear evaporation rate varies strongly across the cornea because lipid is effectively missing over tear-rupture troughs. The result is local faster evaporation compared with nonruptured, thick lipid-covered tear. Evaporative driven tear-film ruptures deepen to a thickness where fluorescein quenching commences and local salinity rises to uncomfortable levels. Mitigation of tear film rupture may therefore reduce dry eye-related symptoms. PMID- 29252907 TI - Case Report: Acute Hydrops with Descemet Membrane Schisis in Corneal Ectasia after Radial Keratotomy. AB - SIGNIFICANCE: As patients with previous radial keratotomy (RK) are still occasionally encountered, recognition of the anatomy of post-RK corneas and management of their complications remain relevant. High-definition anterior segment optical coherence tomography (AS-OCT) is a very useful tool to assess these postsurgical corneas. PURPOSE: To describe a case of acute corneal hydrops with Descemet membrane schisis after RK with observation by AS-OCT. CASE REPORT: A 43-year-old woman presented with a 9-day history of sudden vision loss, foreign body sensation, and photophobia in her left eye. She had undergone bilateral RK 25 years ago at her local hospital. Slit-lamp examination revealed marked corneal edema and stromal clefts in the central cornea along with radial surgical scars in her left eye. Pentacam imaging showed the typical pattern of a post-RK cornea with ectasia in her right eye. Multiple dilacerations of collagen lamellae and fluid-filled intrastromal cysts together with epithelial edema were observed in her left eye using AS-OCT. A Descemet membrane detachment with schisis was also shown by AS-OCT. After 5 months of medication with topical 0.1% fluorometholone eye drops four times daily together with 3% ofloxacin eye ointment once daily, the corneal edema, Descemet membrane detachment, and Descemet membrane schisis had completely resolved resulting in pan-stromal scarring. CONCLUSIONS: This report describes acute corneal hydrops with Descemet membrane schisis after RK imaged using high-definition AS-OCT. The acute hydrops was possibly caused by corneal ectasia or underlying keratoconus, which was aggravated by RK. High definition AS-OCT is a useful tool to demonstrate the details of different corneal layers and to observe the resolving process of acute hydrops. Topical medications consisting of antibiotic, lubrication, and corticosteroid can be used to treat the acute event effectively. PMID- 29252908 TI - Expect the Unexpected. PMID- 29252909 TI - Operative Management for Pediatric and Adolescent Scaphoid Nonunions: A Meta analysis. AB - INTRODUCTION: Scaphoid fractures in the pediatric population represent ~3% of all hand and carpal fractures. Cast immobilization has been shown to yield excellent results in the acute phase, however some patients develop nonunions. Currently, there is no consensus regarding the best surgical treatment after development of a pediatric/adolescent scaphoid nonunion. METHODS: A comprehensive literature review was performed utilizing Medline, Ovid, and Embase databases to compare surgical techniques for adolescent scaphoid nonunions on the basis of union rates, functional outcomes, and operative complications. Our initial search returned 2110 publications. Inclusion criteria consisted of a scaphoid fracture with >3 months of no clinical or radiographic improvement after cast immobilization and age less than 18 years. Ultimately, 11 studies met our criteria and were included in the final analysis. RESULTS: A total of 176 surgically treated pediatric/adolescent scaphoid nonunions were identified from the 11 studies, including 157 nonvascularized bone graft procedures and 19 nongrafted rigid fixation procedures. Patients treated with a nongrafted method achieved union with a total random effects model revealing a union rate of 94.6%, whereas the grafted cohort had a union rate of 94.8%. Functional outcomes including range of motion and grip strength were significantly improved in both cohorts. Patients managed operatively with bone graft had 4 complications, in contrast those without bone grafting did not report complications (P=0.9). CONCLUSION: Surgical treatment of pediatric/adolescent scaphoid fracture nonunions produce excellent union rates and functional outcomes after surgical intervention, using both grafted and nongrafted techniques. Future prospective studies are needed to assess if the outcomes of a specific technique are more favorable, as well as to determine if differences exist based on fracture location. LEVEL OF EVIDENCE: Level III. This study is a meta-analysis of studies containing level of evidence of III or greater. PMID- 29252910 TI - Validation of the "Pain Block" concrete ordinal scale for children aged 4 to 7 years. AB - Pain scales using faces are commonly used tools for assessing pain in children capable of communicating. However, some children require other types of pain scales because they have difficulties in understanding faces pain scales. The goal of this study was to develop and validate the "Pain Block" concrete ordinal scale for 4- to 7-year-old children. This was a multicenter prospective observational study in the emergency department. Psychometric properties (convergent validity, discriminative validity, responsivity, and reliability) were compared between the "Pain Block" pain scale and the Faces Pain Scale Revised (FPS-R) to assess the validity of the "Pain Block" scale. A total of 163 children (mean age, 5.5 years) were included in this study. The correlation coefficient between the FPS-R and the Pain Block scale was 0.82 for all participants which increased with age. Agreement between the 2 pain scales was acceptable, with 95.0% of the values within the predetermined limit. The differences in mean scores between the painful group and nonpainful group were 3.3 (95% confidence interval, 2.6-4.1) and 3.8 (95% confidence interval, 3.1-4.6) for FPR-S and Pain Block, respectively. The pain scores for both pain scales were significantly decreased when analgesics or pain-relieving procedures were administered (difference in Pain Block, 2.4 [1.4-3.3]; and difference in FPS-R, 2.3 [1.3-3.3]). The Pain Block pain scale could be used to assess pain in 4- to 7 year-old children capable of understanding and counting up to the number 5, even if they do not understand the FPS-R pain scale. PMID- 29252911 TI - Pain as a risk factor for common mental disorders. Results from the Netherlands Mental Health Survey and Incidence Study-2: a longitudinal, population-based study. AB - Pain might be an important risk factor for common mental disorders. Insight into the longitudinal association between pain and common mental disorders in the general adult population could help improve prevention and treatment strategies. Data were used from the first 2 waves of the Netherlands Mental Health Survey and Incidence Study-2, a psychiatric epidemiological cohort study among the Dutch general population aged 18 to 64 years at baseline (N = 5303). Persons without a mental disorder 12 months before baseline were selected as the at-risk group (n = 4974 for any mood disorder; n = 4979 for any anxiety disorder; and n = 5073 for any substance use disorder). Pain severity and interference due to pain in the past month were measured at baseline using the Short Form Health Survey. DSM-IV mental disorders were assessed at both waves using the Composite International Diagnostic Interview version 3.0. Moderate to very severe pain was associated with a higher risk of mood (odds ratio [OR] = 2.10, 95% confidence interval [CI] = 1.33-3.29) or anxiety disorders (OR = 2.12, 95% CI = 1.27-3.55). Moderate to very severe interference due to pain was also associated with a higher risk of mood (OR = 2.14, 95% CI = 1.30-3.54) or anxiety disorders (OR = 1.92, 95% CI = 1.05-3.52). Pain was not significantly associated with substance use disorders. No interaction effects were found between pain severity or interference due to pain and a previous history of mental disorders. Moderate to severe pain and interference due to pain are strong risk factors for first-incident or recurrent mood and anxiety disorders, independent of other mental disorders. Pain management programs could therefore possibly also serve as a preventative program for mental disorders. PMID- 29252912 TI - REOPENING OF MACULAR HOLE AFTER INTRAVITREAL AFLIBERCEPT FOR NEOVASCULAR AGE RELATED MACULAR DEGENERATION. AB - PURPOSE: To describe the clinical course and surgical outcome of a patient with full-thickness macular hole recurrence after aflibercept injections for wet age related macular degeneration. METHODS: Case report with spectral domain optical coherence tomography retinal imaging. RESULTS: An 84-year-old patient, with a successfully closed full-thickness macular hole by vitrectomy and internal limiting membrane (ILM) peel 4 years ago in the right eye, developed neovascular age-related macular degeneration (AMD) of the same eye. After 6 intravitreal aflibercept injections, visual acuity was 20/50, with minimal subretinal fluid (SRF). Four days after the seventh aflibercept injection, visual acuity decreased to 20/200. Spectral domain optical coherence tomography demonstrated a reopened full-thickness macular hole of diameter 430 MUm, associated with a reduction in pigment epithelial detachment height, increase in SRF, and an epiretinal membrane (ERM). A 23-gauge pars plana vitrectomy with indocyanine green-assisted removal of residual ILM and ERM, and sulfur hexafluoride (SF6) 20% tamponade was performed. At 1 month postoperatively, the full-thickness macular hole was successfully closed and visual acuity improved to 20/80. CONCLUSION: In wet AMD eyes with previously closed macular holes, hole reopening may occur as a rare complication of aflibercept therapy.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29252913 TI - PARACENTRAL ACUTE MIDDLE MACULOPATHY IN PREGNANCY. AB - PURPOSE: To describe a case of paracentral acute middle maculopathy (PAMM) during the first trimester of pregnancy without other ocular or systemic comorbidities. METHODS: Case report. RESULTS: A 31-year-old woman in her first trimester of pregnancy presented with a paracentral scotoma in the absence of other retinal pathology or systemic associations. Optical coherence tomography showed a classic acute PAMM lesion, and optical coherence tomography angiography showed preservation of vascular flow in the area of the PAMM lesion 1 week after symptom onset. Subsequent workup for underlying systemic disease that can affect the retinal vasculature was negative. CONCLUSION: Paracentral acute middle maculopathy lesions have been described in eyes with retinal vascular disease and in people with systemic vascular diseases or events. This is the first described case of a PAMM lesion in the absence of associated factors other than an uncomplicated pregnancy. PMID- 29252914 TI - Significance of Immune-related Lipase Increase Induced by Antiprogrammed Death-1 or Death Ligand-1 Antibodies: A Brief Communication. AB - Antiprogrammed death-1 (anti-PD1) and antiprogrammed death ligand-1 (anti-PD-L1) antibodies are effective checkpoint inhibitors that stimulate the immune system against many types of cancers. The flip side of these immunotherapies is the generation of immune-related adverse events, which can theoretically affect all organs. Among these side effects, lipase increase is frequently observed; however the meaning of this biological abnormality remains poorly understood. We investigate in this case study all the lipase increases greater or equal to grade 2 that occurred in patients receiving anti-PD-1 or anti-PD-L1 treatments, to determine their biological and clinical significance. Twenty-one patients were retained with lipase increase related to the immune checkpoint inhibitor. Most of them (71%) were treated for a metastatic melanoma. The peak of lipase increase was observed at a median of 2.8 (range, 0.4-11.4) months after the initiation of the anti-PD1 or anti-PD-L1 treatment, which correlates with cycle 5 of treatment. Three of 21 patients (14%) had a clinical or radiologic immune-related pancreatitis that led to a permanent discontinuation of the treatment. In 15 of 21 (71%) patients, the lipase increase was not considered as clinically significant, and the treatment was continued without complications. The 3 remaining patients discontinued the treatment for progressive disease. These data indicate that lipase increase related to anti-PD1 or anti-PD-L1 is not associated with a significant clinical event in most cases. On the basis of these data, we propose that lipase increase in an asymptomatic patient and without radiographic abnormalities of the pancreas can be reasonably regarded as a not clinically significant event, allowing the continuation of the anti-PD-1 or anti-PD-L1 treatment. PMID- 29252915 TI - Cholesterol Esterification Enzyme Inhibition Enhances Antitumor Effects of Human Chimeric Antigen Receptors Modified T Cells. AB - Chimeric antigen receptor-modified T cell (CART) therapy has been demonstrated to have significant effect on hematologic tumor in patients. However, many persistent obstacles and challenges still limit the application. It is known that CD8 T cells are a key component of antitumor immunity. An avasimibe-induced inhibition of cholesterol esterification has been shown to improve the antitumor response of CD8 T cells in mice. In this study, using human CD19-directed CART cells as effector cells and CD19-overexpressing K562 cells as target cells, we detected whether cholesterol acyltransferase inhibition by avasimibe can enhance the antitumor effect of human CART cells. After avasimibe treatment, the infection rate was dropped by up to 50% (P<0.05). The cytotoxic effect of CART cells was significantly increased than the control group in a dose-dependent manner. Moreover, the level of secreted interferon-gamma increased in almost half of the cases (P<0.05); the ratio of CD8CD4 T cells was increased among the total T cells and the CART cells in some of cases (P<0.05). Our study suggests that inhibition of cholesterol acyltransferase can promote the antitumor effect of CART cells, and provides a new option for a combination therapy by regulating T cell metabolism to enhance antitumor effects. PMID- 29252917 TI - Depressive Symptomatology, Presenteeism Productivity, and Quality of Life: A Moderated Mediation Model. AB - : In this study, we intend to test if presenteeism productivity influences the relationship between depressive symptoms and quality of life and also if this relation is conditional upon levels of information processing speed. Data were collected from 231 participants who completed a neuropsychological test and self reported measures. Results revealed a significant indirect effect and a significant moderation effect. The association between depressive symptoms and presenteeism productivity was moderated by information processing speed only in their medium and high levels. Our findings suggest that individuals with higher levels of processing speed may have more difficulty in focusing on work without being distracted by health problems. The present investigation has made a significant contribution to the existing literature about cognitive function and productivity in workers with depressive symptomatology and its effects on their quality of life. PMID- 29252916 TI - Pembrolizumab Utilization and Outcomes for Advanced Melanoma in US Community Oncology Practices. AB - The programmed death-1 inhibitor pembrolizumab has demonstrated efficacy and safety in clinical trials for treating advanced (unresectable/metastatic) melanoma. We investigated the real-world utilization of pembrolizumab and associated patient outcomes for advanced melanoma in US community oncology practices. This retrospective, observational study used deidentified data from electronic health records for adult patients with advanced melanoma who received pembrolizumab at The US Oncology Network sites from September 2014 through December 2015, with follow-up through September 2016. Patients enrolled in clinical trials were excluded. Overall survival (OS) and physician-stated progression-free survival (PFS) were analyzed from pembrolizumab initiation using Kaplan-Meier, and associations between pembrolizumab therapy and OS/PFS, using multivariable Cox regression. Of 168 patients studied, 110 (65%) were male; the median age was 66 years (range, 26-over 90). Pembrolizumab was prescribed as first-line, second-line, and third-line/later for 39 (23%), 87 (52%), and 42 (25%) patients, respectively. In total, 41 patients (24%) had brain metastases. At pembrolizumab initiation, 21/129 (16%) had Eastern Cooperative Oncology Group performance status (ECOG PS) >1; 51/116 (44%) had elevated lactate dehydrogenase. Median follow-up was 10.5 months (range, 0-25.1); median OS was 19.4 months (95% confidence interval, 14.0-not reached); median PFS was 4.2 months (95% confidence interval, 2.9-5.3). Brain metastases, ECOG PS>1, elevated lactate dehydrogenase, and third-line/later (vs. first-line) pembrolizumab were significant predictors (P<0.01) of decreased survival. Treatment-related toxicity was a discontinuation reason for 25% (29/117) of patients, and for 10 of these 29 patients (6% of the full-study cohort) treatment-related toxicity was the only reported reason. The real-world effectiveness and safety of pembrolizumab for advanced melanoma are consistent with clinical trial findings. PMID- 29252918 TI - Usage of Sit-Stand Workstations and Associations Between Work and Nonwork Sitting Time: An Observational Study. AB - OBJECTIVE: No studies have objectively measured habitual usage of sit-stand workstations. METHODS: Eighteen full-time office workers participated (47.9 +/- 9.2 years, 61% female). Sitting time was objectively measured (activPAL, 24 h/7 days), and time at desk, desk position, and perceptions of desk use were self reported. RESULTS: Participants sat for 39% of their daily workstation time, and changed workstation position twice daily. The most common reasons for standing included back pain (44%) and tiredness (22%). The majority of participants received no workstation occupational health (72%) or educational (61%) information. Workstation standing time had a significant moderate correlation with total daily standing time (P = 0.02). CONCLUSION: Office workers with sit stand workstations rarely change desk position, and there is no relationship between the time spent sitting at the workstation, and total daily sitting time. Education about the workstations was limited. PMID- 29252919 TI - Association Between Employment Status and Objectively Measured Physical Activity and Sedentary Behavior-The Maastricht Study. AB - OBJECTIVE: To examine the association between employment status and physical activity and sedentary behavior. METHODS: We included 2045 participants from The Maastricht Study, who used a thigh-worn accelerometer. We compared time spent sedentary, standing, stepping, and higher intensity physical activity between participants with different employment status (non-employed or low-, intermediate or high-level occupation) with analysis of variance. RESULTS: Participants in low-level occupations were less sedentary and standing and stepping more than those in other occupational categories and non-employed participants. Among the employed, the differences were mostly observed on weekdays, whereas the differences in sedentary time and standing between those in low-level occupations and non-employed participants were evident both on weekdays and weekend days. CONCLUSIONS: Those in low-level occupational category were less sedentary and more active than non-employed and those in other occupational categories, especially on weekdays. PMID- 29252920 TI - Occupational Hazard Exposures and Depressive Symptoms of Pregnant Workers. AB - OBJECTIVES: The aim of this study was to explore the prevalence of exposure to occupational hazards and depressive mood with associated underlying risk factors among pregnant workers. METHODS: Women at 12 weeks of gestation (n = 172) were recruited during regular prenatal screening. Data were obtained via questionnaires that explored job details and Edinburgh Postnatal Depression Scale. RESULTS: The most commonly encountered hazard was prolonged standing. The majority of women reported that the workplace provided no information on the safety or rights of pregnant women, but those exposed to at least four hazards had more access to such services (P < 0.05). Thirteen percent may have suffered from depressive symptomatology. Higher-level work-related burnout, lower job control, and reduced workplace support were significantly associated with possible antenatal depressive symptoms. CONCLUSION: Pregnant workers are exposed to substantial levels of occupational hazards and may experience depressive symptoms; thus, their work conditions require monitoring and improvement. PMID- 29252921 TI - Responsibilities of the Occupational and Environmental Medicine Provider in the Treatment and Prevention of Climate Change-Related Health Problems. AB - : Workers are uniquely susceptible to the health hazards imposed by environmental changes. Occupational and environmental medicine (OEM) providers are at the forefront of emerging health issues pertaining to working populations including climate change, and must be prepared to recognize, respond to, and mitigate climate change-related health effects in workers. This guidance document from the American College of Occupational and Environmental Medicine focuses on North American workers health effects that may occur as a result of climate change and describes the responsibilities of the OEM provider in responding to these health challenges. PMID- 29252922 TI - A Systematic, Thematic Review of Social and Occupational Factors Associated With Psychological Outcomes in Healthcare Employees During an Infectious Disease Outbreak. AB - OBJECTIVE: To conduct a systematic literature review to identify social and occupational factors affecting the psychological wellbeing of healthcare workers involved in the severe acute respiratory syndrome (SARS) crisis. METHODS: Four literature databases were searched and data extracted from relevant papers. RESULTS: Eighteen thousand five papers were found and 22 included in the review. The psychological impact of SARS on employees appeared to be associated with occupational role; training/preparedness; high-risk work environments; quarantine; role-related stressors; perceived risk; social support; social rejection/isolation; and impact of SARS on personal or professional life. CONCLUSIONS: To minimize the psychological impact of future outbreaks of infectious diseases, healthcare workers should be prepared for the potential psychological impact; employers should encourage a supportive environment in the workplace and ensure that support is in place for those most at risk, for example, those with the most patient contact. PMID- 29252923 TI - Management of Hepatitis B Infection in Pregnancy. AB - In many parts of the world, perinatal transmission is the most common route of infection for hepatitis B virus. In the United States, sexual contact is the most common source of hepatitis B virus infection. As a result, it is essential that women's health care providers become aware of the recommended strategies used to identify women infected with hepatitis B and to subsequently reduce perinatal transmission, particularly now that immigration and globalization is more common and reproductive science makes pregnancy more possible for women with liver disease. This article reviews evidence-based strategies for management of hepatitis B infection during pregnancy. PMID- 29252924 TI - Cervical Cancer Screening. AB - Cervical cancer screening has significantly reduced the incidence of cervical cancer in the United States. National recommendations have evolved to keep pace with advancement in our understanding of human papilloma virus (HPV) biology as well as improvements in HPV testing. This chapter summarizes present national screening guidelines, reviews information regarding recent development in HPV biology and testing, discusses some of the controversies related to screening and provides clinicians with talking points for their patients. PMID- 29252925 TI - Setting the Threshold for Surgical Prevention in Women at Increased Risk of Ovarian Cancer. AB - The number of ovarian cancer cases is predicted to rise by 14% in Europe and 55% worldwide over the next 2 decades. The current absence of a screening program, rising drug/treatment costs, and only marginal improvements in survival seen over the past 30 years suggest the need for maximizing primary surgical prevention to reduce the burden of ovarian cancer. Primary surgical prevention through risk reducing salpingo-oophorectomy (RRSO) is well established as the most effective method for preventing ovarian cancer. In the UK, it has traditionally been offered to high-risk women (>10% lifetime risk of ovarian cancer) who have completed their family. The cost-effectiveness of RRSO in BRCA1/BRCA2 carriers older than 35 years is well established. Recently, RRSO has been shown to be cost effective in postmenopausal women at lifetime ovarian cancer risks of 5% or greater and in premenopausal women at lifetime risks greater than 4%. The acceptability, uptake, and satisfaction with RRSO at these intermediate-risk levels remain to be established. Prospective outcome data on risk-reducing salpingectomy and delayed-oophorectomy for preventing ovarian cancer is lacking, and hence, this is best offered for primary prevention within the context and safe environment of a clinical trial. An estimated 63% of ovarian cancers occur in women with greater than 4% lifetime risk and 53% in those with 5% or greater lifetime-risk. Risk-reducing salpingo-oophorectomy can be offered for primary surgical prevention to women at intermediate risk levels (4%-5% to 10%). This includes unaffected women who have completed their family and have RAD51C, RAD51D, or BRIP1 gene mutations; first-degree relatives of women with invasive epithelial ovarian cancer; BRCA mutation-negative women from high-risk breast-and ovarian cancer or ovarian-cancer-only families. In those with BRCA1, RAD51C/RAD51D/MMR mutations and the occasional families with a history of ovarian cancer in their 40s, surgery needs to be considered at younger than 45. In other moderate-risk gene mutation carriers and those with polygenic risk, RRSO needs be considered at 50. There is need for establishment/expansion of well-defined pathways to increase clinical access to RRSO. It is time to lower the risk threshold for RRSO to enable introduction of a targeted primary prevention approach, which could significantly impact the future burden of ovarian cancer. PMID- 29252926 TI - Do Groin Drains Reduce Postoperative Morbidity in Women Undergoing Inguinofemoral Lymphadenectomy for Vulvar Cancer? AB - OBJECTIVE: Sentinel lymph node biopsy has been widely adopted in the surgical management of women with early-stage vulvar cancer, but many patients require inguinofemoral lymphadenectomy (IFL). Following IFL, many surgeons drain the groin to prevent lymphocyst formation despite a lack of evidence to support this practice. Our objective was to investigate whether groin drains after IFL are associated with reduced postoperative morbidity in women undergoing surgery for vulvar cancer. METHODS: A retrospective cohort study of women diagnosed as having primary vulvar cancer who underwent vulvectomy/radical local excision and unilateral or bilateral IFL was conducted. Cases were ascertained from the weekly outcome reports of a statewide tertiary gynecologic oncology tumor board. Data including postoperative outcomes were abstracted from medical records. Patients were stratified into 1 of 2 groups according to whether a groin drain had been used. RESULTS: Seventy-one patients were included. Inguinal drains were used in 48 patients (67.6%) and 23 patients (32.4%) did not have their groin wound(s) drained. The most common postoperative complications recorded were wound infection (59.2%), groin lymphocyst (32.4%), and cellulitis (25.4%). The mean length of hospital admission was 11.5 days (2-40 days). Compared with patients in whom inguinal drains were placed, those in the "no drain" group had a significantly lower incidence of postoperative groin cellulitis (8.7% vs 25.4% P = 0.039). No significant differences were observed between patients in the "drain" and "no drain" groups in lymphocyst formation, wound infection, return to the operating room, duration of hospital stay, readmission post-discharge, and lower-limb lymphedema. CONCLUSIONS: In this study of patients undergoing inguinofemoral dissection for primary vulvar cancer, postoperative cellulitis occurred less frequently in patients without an inguinal drain. The incidence of other postoperative complications was no different whether or not a groin drain was used. Prospective studies may be warranted. PMID- 29252927 TI - Premature Termination of Psychotherapy in Patients With Borderline Personality Disorder: A Cluster-Analytic Study. AB - The goal of the present study was to establish profiles of patients with borderline personality disorder (BPD) who dropped out early from an outpatient psychotherapy program. From a sample of 56 BPD patients who dropped out after the first of a three-year program, a TwoStep cluster analysis procedure was performed, using the five factors of the Treatment Attrition-Retention Scale for Personality Disorders (Gamache et al., J Pers Disord 1-21, 2017) and the Global Assessment of Functioning score (Spitzer et al., Global Assessment of Functioning [GAF] Scale. In Sederer LI, Dickey B [Eds], Outcomes assessment in clinical practice [pp 76-78]. Baltimore, MD: Walter and Williams) as clustering variables. Four clusters emerged: Higher-functioning, Narcissistic features/entitlement, Pseudo-normality, and Highly dysfunctional. Differences between the clusters were found on sex, occupational status, and presence of antisocial features. These findings could help both identify BPD patients at potential risk of dropping out of psychotherapy and adjust interventions accordingly to reduce premature termination. PMID- 29252928 TI - Sources of Parent-Child Transmission of Drug Abuse: Path Analyses of Not-Lived With Parental, Stepparental, Triparental, and Adoptive Families. AB - To clarify the origins of parent-child resemblance for drug abuse (DA), using national Swedish data, we fit path models to information on DA in parents and children from six informative family types: i) not-lived-with father, ii) not lived-with mother, iii) stepfather, iv) stepmother, v) triparental, and vi) adoptive. From these families, we estimated parent-offspring resemblance reflecting the effects of genes + rearing, genes only, and rearing only. The estimates of parent-offspring correlations were statistically homogenous across family types. The weighted estimate of the father-offspring correlation for DA for genes + rearing, genes-only, and rearing-only relationships were, respectively, +0.26, +0.19, and +0.06. Parallel figures for mother-offspring relationships were +0.19, +0.13, and +0.09. In both genes + rearing and genes only parent-offspring relationships, DA correlations were stronger for fathers than for mothers. Both genetic and environmental factors contribute substantially to parent-offspring resemblance for DA and seem to be additive. PMID- 29252929 TI - Endotype Transitions During the Acute Phase of Pediatric Septic Shock Reflect Changing Risk and Treatment Response. AB - OBJECTIVE: We previously identified septic shock endotypes A and B based on 100 genes reflecting adaptive immunity and glucocorticoid receptor signaling. The endotypes differ with respect to outcome and corticosteroid responsiveness. We determined whether endotypes change during the initial 3 days of illness, and whether changes are associated with outcomes. DESIGN: Observational cohort study including existing and newly enrolled participants. SETTING: Multiple PICUs. PATIENTS: Children with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured the 100 endotyping genes at day 1 and day 3 of illness in 375 patients. We determined if endotype assignment changes over time, and whether changing endotype is associated with corticosteroid response and outcomes. We used multivariable logistic regression to adjust for illness severity, age, and comorbidity burden. Among the 132 subjects assigned to endotype A on day 1, 56 (42%) transitioned to endotype B by day 3. Among 243 subjects assigned to endotype B on day 1, 77 (32%) transitioned to endotype A by day 3. Assignment to endotype A on day 1 was associated with increased odds of mortality. This risk was modified by the subsequent day 3 endotype assignment. Corticosteroids were associated with increased risk of mortality among subjects who persisted as endotype A. CONCLUSIONS: A substantial proportion of children with septic shock transition endotypes during the acute phase of illness. The risk of poor outcome and the response to corticosteroids change with changes in endotype assignment. Patients persisting as endotype A are at highest risk of poor outcomes. PMID- 29252930 TI - Effect of Boarding on Mortality in ICUs. AB - OBJECTIVES: Hospitals use a variety of strategies to maximize the availability of limited ICU beds. Boarding, which involves assigning patients to an open bed in a different subspecialty ICU, is one such practice employed when ICU occupancy levels are high, and beds in a particular unit are unavailable. Boarding disrupts the normal geographic colocation of patients and care teams, exposing patients to nursing staff with different training and expertise to those caring for nonboarders. We analyzed whether medical ICU patients boarding in alternative specialty ICUs are at increased risk of mortality. DESIGN: Retrospective cohort study using an instrumental variable analysis to control for unmeasured confounding. A semiparametric bivariate probit estimation strategy was employed for the instrumental model. Propensity score matching and standard logistic regression (generalized linear modeling) were used as robustness checks. SETTING: The medical ICU of a tertiary care nonprofit hospital in the United States between 2002 and 2012. PATIENTS: All medical ICU admissions during the specified time period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The study population consisted of 8,429 patients of whom 1,871 were boarders. The instrumental variable model demonstrated a relative risk of 1.18 (95% CI, 1.01 1.38) for ICU stay mortality for boarders. The relative risk of in-hospital mortality among boarders was 1.22 (95% CI, 1.00-1.49). GLM and propensity score matching without use of the instrument yielded similar estimates. Instrumental variable estimates are for marginal patients, whereas generalized linear modeling and propensity score matching yield population average effects. CONCLUSIONS: Mortality increased with boarding of critically ill patients. Further research is needed to identify safer practices for managing patients during periods of high ICU occupancy. PMID- 29252931 TI - Legislating Medicine: The Need for Evidence, Argument, and Alliance. PMID- 29252932 TI - Assessment of Mobility in Older People Hospitalized for Medical Illness Using de Morton Mobility Index and Cumulated Ambulation Score-Validity and Minimal Clinical Important Difference. AB - BACKGROUND AND PURPOSE: Older adults acutely hospitalized for medical illness typically have comorbidity and disability, and inhospital physical inactivity greatly increases the likelihood of developing new disability. Thus, assessment of the patients' mobility status is crucial for planning and carrying out targeted interventions that ensure mobilization during hospital admission. The aim of this study was to determine convergent validity, known group validity, floor and ceiling effects, and anchor-based minimal clinically important difference (MCID) of the more time-consuming de Morton Mobility Index (DEMMI) and the less time-consuming Cumulated Ambulation Score (CAS) in older adults acutely hospitalized for medical illness. METHODS: In this multicenter cohort study, 235 older hospitalized adults, with a mean (standard deviation) age of 84.8 (7.1) years, were consecutively included. Assessments of mobility using the DEMMI (score range 0-100), the CAS (score range 0-6), and the Barthel Index (BI, score range 0-100) were performed by physical or occupational therapists at hospital admission and discharge. In addition, at discharge patients and therapists were independently asked to assess the patients' current mobility status compared with their mobility status at hospital admission using the Global Rating of Change scale. RESULTS AND DISCUSSION: Complete data sets were obtained for 155 patients. Baseline characteristics of those with complete data sets did not differ from those with incomplete data sets, except for the number of secondary diagnoses, which was lower in the latter. Significant and moderate relationships existed both at admission and at discharge between scores in the DEMMI and the BI (rs = 0.68, P < .0001, and rs = 0.71, P < .0001), and between scores in the CAS and the BI (rs = 0.60, P < .0001, and rs = 0.57, P < .0001). Use of a gait aid and discharge to inpatient rehabilitation or nursing home were associated with significantly lower DEMMI and CAS scores. No floor or ceiling effects were present in the DEMMI, while a ceiling effect was present in the CAS. The MCID scores based on patients' assessments were 10.7 points for the DEMMI and 0.67 for the CAS. CONCLUSIONS: These data show that the DEMMI is valid and responsive to changes in mobility and can be considered to have the required properties for measuring mobility in older adults who are hospitalized in medical and geriatric wards. In contrast, the CAS appears to be appropriate to identify whether a patient is independently mobile or needs assistance, while the measure is less suitable for measuring improvements in mobility.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29252933 TI - Does Robot Overcome Obesity-related Limitations of Minimally Invasive Rectal Surgery for Cancer? AB - BACKGROUND: Adoption of laparoscopic surgery for cancers requiring partial or total proctectomy has been slow due to difficulty of achieving oncologically adequate resection. Obesity is a factor complicating use and outcomes of laparoscopic technique for rectal surgery. Impact of obesity on the outcomes of robotic rectal surgery for cancer is not well defined. This study is designed to assess whether if the robotic technique has potential to overcome the limitations of obesity and to improve outcomes of minimally invasive rectal surgery for cancer. PATIENTS AND METHODS: Patients undergoing robotic sphincter-saving radical resection with da Vinci Xi System between December 2014 and December 2016 were included. Patients were divided into 2 groups as obese and nonobese. Patient demographics, perioperative outcomes and short-term results were compared between the groups. RESULTS: The study included 101 patients (30 were obese). Sex (female: 35 vs. 37%, P=0.89), American Society of Anesthesiologists score (2 vs. 2, P=0.41), number of patients undergoing neoadjuvant chemoradiation (39% vs. 23%, P=0.12) and history of prior abdominal surgery (28% vs. 23%, P=0.62) were comparable between the groups. Operative time was longer in the obese group (311 vs. 332 min. P=0.01). Overall complication rates (27% vs. 23%, P=0.72), length of hospital stay (6 vs. 7, P=0.10) and pathologic outcomes were similar between the groups. Conversion to laparoscopy was not required in any operation. Two nonobese patients required conversion to open surgery. CONCLUSION: Robotic rectal surgery for cancer in obese patients is equally safe and effective as in nonobese patients. The new robotic platform can facilitate to overcome obesity-related limitations of rectal surgery. PMID- 29252934 TI - Efficacy and Safety of Therapeutic ERCP in the Elderly: A Single Center Experience. AB - BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has been an important therapeutic measure for the treatment of pancreatobiliary diseases in the elderly, but limited data on the use of ERCP in the super-aged elderly are available. This study aimed to evaluate the efficacy and safety of ERCP in patients 80 years of age or older. METHODS: All therapeutic ERCPs performed from January 2012 to December 2015 at our endoscopy unit were retrospectively reviewed to evaluate the clinical outcomes and ERCP-related complications in patients 80 years of age or older (group A) and in patients younger than 65 years of age (group B). RESULTS: A total of 141 patients (182 procedures) were 80 years of age or older (group A), and 513 patients (610 procedures) were 65 years old or younger (group B). Chronic concomitant diseases (73.05% vs. 31.19%, P<0.01) and the use of antithrombotic drugs (25.53% vs. 15.01%, P<0.01) were more frequent in group A than in group B. Common bile duct (CBD) stones were the most common indication for ERCP in both groups. The rate of a difficult cannulation was higher in group A than in group B (23.63% vs. 16.56%, P<0.01). The mean procedure time was longer, and second ERCPs were performed more frequently in group A than in group B. In addition, periampullary diverticulum was observed significantly more frequently in group A (30.22% vs. 20%, P<0.01) than in group B. The overall success rate (92.31% vs. 93.93%, P>0.05) and the complication rate (6.59% vs. 5.25%, P>0.05) were not significantly different between the 2 groups. CONCLUSIONS: ERCP is a safe and effective intervention in patients 80 years of age or older, although elderly patients had a high rate of concomitant chronic diseases and used antithrombotic drugs more frequently. PMID- 29252935 TI - The Surgical Outcomes of Totally Laparoscopic Stomach-partitioning Gastrojejunostomy for Gastric Outlet Obstruction: A Retrospective, Cohort Study. AB - BACKGROUND: We have reported the effectiveness of laparoscopy-assisted stomach partitioning gastrojejunostomy Roux-en-Y reconstruction (LASPGJ-RY) for gastric outlet obstruction (GOO). The aim of this study was to evaluate the surgical outcomes of totally laparoscopic stomach-partitioning gastrojejunostomy Roux-en-Y reconstruction (TLSPGJ-RY) for GOO. MATERIALS AND METHODS: This retrospective study enrolled 19 consecutive patients with GOO. Surgical outcomes of LASPGJ-RY (LA group; n=8) and TLSPGJ-RY (TL group; n=11) between January 2004 and 2015 were compared. The patients' background characteristics, operative findings, postoperative complications, and period to starting postoperative chemotherapy were examined. RESULTS: Eligible cases included 6 patients with gastric cancer, 4 with pancreatic cancer, 4 with duodenal cancer, 4 with urologic malignancies, and 1 with benign duodenal stenosis. The patients' background characteristics were not significantly different. In surgical outcomes, there were no significant differences in operating time, bleeding, complications (>=Clavien-Dindo grade IIIA), and postoperative hospital stay between the groups. The time to resume diet was significantly shorter in the TL group (median, 3 d; range, 3 to 6 d) than in the LA group (median, 5 d; range, 3 to 7 d; P=0.0093), and the number of patients who could receive chemotherapy after surgery was significantly higher in the TL group (P=0.039). CONCLUSIONS: TLSPGJ-RY was a safe and feasible gastrojejunostomy procedure for GOO. TLSPGJ-RY might be useful for early resumption of oral intake after surgery. PMID- 29252936 TI - Artificial Neural Networking Model for the Prediction of Early Occlusion of Bilateral Plastic Stent Placement for Inoperable Hilar Cholangiocarcinoma. AB - BACKGROUND: This study aimed to determine whether the back-propagation artificial neural network (BP-ANN) model could be constructed to accurately in predicting early occlusion of bilateral plastic stent placement for inoperable hilar cholangiocarcinoma (HCA). METHODS: A total of 288 patients from the An Hui provincial Hospital were randomly divided into the training cohort (80%) and the internal testing cohort (20%). The predictive accuracy of the BP-ANN for predicting early occlusion of bilateral plastic stent placement of inoperable HCA was measured by the area under the curve (AUC) on receiver operating characteristic (ROC) curve analysis. The results were compared with those obtained using the conventional multivariate logistic regression analysis. RESULTS: Multivariate analysis revealed that cancer stage (P=0.005) and Bismuth stage (P=0.003) were independently and significantly associated with early stent occlusion. In the training cohort, BP-ANN had larger AUC than the multivariate logistic regression model (P=0.00049). In the internal testing cohort, the AUC of the BP-ANN had larger AUC than the multivariate logistic regression model (P=0.02142). CONCLUSIONS: This study showed that the BP-ANN model is a good predictive tool. It performed better than the conventional and commonly used statistical model in predicting early occlusion of bilateral plastic stent placement for inoperable HCA. PMID- 29252937 TI - Cooperation in emergency medicine in Europe: the bright side of the medal. PMID- 29252938 TI - Signs and symptoms in adult patients with acute dyspnea: a systematic review and meta-analysis. AB - INTRODUCTION: Rapid and accurate diagnosis of patients with a new episode of acute dyspnea is a common challenge for Primary Care or Emergency Physicians. OBJECTIVE: To determine the diagnostic accuracy of signs and symptoms in adult patients with a new episode of acute dyspnea presenting to a GP or an Emergency Physician (EP). PATIENTS AND METHODS: This was a diagnostic systematic review. Using MEDLINE, Cumulative Index to Nursing and Allied Health Literature, EMBASE, tracing references, and by contacting experts, studies were identified on the diagnostic accuracy of additional signs and symptoms in adult patients with acute or suddenly worsening dyspnea, presenting to a GP or an EP. Study quality was assessed using QUADAS and results were pooled using a random-effects model. Sensitivity, specificity, positive and negative likelihood ratio (NLR), and positive and negative predictive values for a diagnosis of heart failure (HF) were calculated for the combination of acute dyspnea and each additional sign or symptom in the selected studies. RESULTS: Eight of the 24 identified studies were carried out in the ED and provided us with all the required data, including 4737 patients. All publications reported HF; two studies additionally investigated pulmonary embolism, acute exacerbations of chronic obstructive pulmonary disease or asthma, acute pulmonary infectious diseases, or acute coronary syndrome. The prevalence of HF in patients with acute dyspnea ranged from 25 to 59%. Heterogeneity was present in all analyses.Comparing signs and symptoms, sensitivity was very poor for the presence of fever (0.05) and sputum production (0.06), and poor for fatigue (0.36-0.76), orthopnea (0.2-0.76), paroxysmal nocturnal dyspnea (0.23-0.70), elevated jugular venous pressure (0.19-0.70), rales (0.32-0.88), and peripheral edema (0.29-0.77). Specificity was poor for fatigue (0.28-0.69), moderate for the presence of fever (0.76-0.88), sputum production (0.73-0.89), orthopnea (0.49-0.92), paroxysmal nocturnal dyspnea (0.52 0.93), and rales (0.31-0.98), and good for elevated jugular venous pressure (0.75 0.97) and peripheral edema (0.67-0.89).For all other signs and symptoms, sensitivities varied between 0.20 and 0.43; specificities for symptoms varied widely between 0.37 and 0.91 and those of signs between 0.20 and 1.0.The pooled sensitivities, however, remained poor: below 0.55. Pooled specificity of most signs ranged between 0.69 and 0.88. The positive likelihood ratio was between 0.64 and 4.11 and the NLR was between 0.59 and 1.29 with one outlier: rales (pooled NLR=0.35). CONCLUSION: This systematic review, which only included patients from ED settings, did not identify any single sign or symptom that had acceptable sensitivity to be useful in ruling out a diagnosis of HF, chronic obstructive pulmonary disease, asthma, or pulmonary embolism. Elevated jugular venous pressure (0.88, pooled odds ratio: 7), added third heart sound (0.97), and lung crepitations (0.77, pooled odds ratio: 11) are useful in ruling in HF. PMID- 29252939 TI - Effects of Sanguinate(r) on Systemic and Microcirculatory Variables in a Model of Prolonged Hemorrhagic Shock. AB - BACKGROUND: Hemorrhage and its complications are the leading cause of preventable death from trauma in young adults, especially in remote locations. To address this, deliverable, shelf-stable resuscitants that provide therapeutic benefits throughout the time course of hemorrhagic shock and the progressive ischemic injury it produces are needed. SANGUINATE is a novel bovine PEGylated carboxyhemoglobin-based oxygen carrier, which has desirable oxygen-carrying and oncotic properties as well as a CO moiety to maintain microvascular perfusion. OBJECTIVES: To compare the crystalloid (Lactated Ringer's Solution; LRS), and the colloid (Hextend) standards of care with SANGUINATE in a post "golden hour" resuscitation model. METHODS: Rats underwent a controlled, stepwise blood withdrawal (45% by volume), were maintained in untreated hemorrhagic shock state for > 60 min, resuscitated with a 20% bolus of one of the three test solutions, and observed till demise. Parameters of tissue oxygenation (PISFO2), arteriolar diameters, and mean arterial pressure (MAP) were collected. RESULTS: SANGUINATE treated animals survived significantly longer than those treated with Hextend and LRS. SANGUINATE also significantly increased tissue PISFO2 two hours after resuscitation, whereas LRS and Hextend did not. SANGUINATE also produced a significantly higher MAP, which was hypotensive compared to baseline, that endured until demise. CONCLUSIONS: Resuscitation with SANGUINATE after PHS improves survival, MAP, and PISFO2 compared to standard of care plasma expanders. Since the pathologies of hemorrhagic shock and the associated systemic ischemia are progressive, preclinical studies of this nature are essential to determine efficacy of new resuscitants across the range of possible times to treatment.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 29252940 TI - A Standardized Clinical Pathway to Decrease Hospital Admissions Among Febrile Children With Sickle Cell Disease. AB - BACKGROUND AND OBJECTIVE: Recurrent hospital admissions for patients with sickle cell disease (SCD) are costly and contribute to a low quality of life for patients. We implemented a clinical pathway to safely discharge SCD patients with fever who are evaluated in the emergency department (ED) of a large tertiary care center. METHODS: An interdisciplinary team of ED and hematology physicians, nurses, and an improvement advisor developed a clinical pathway that identified febrile SCD patients at low risk of serious bacterial infection based on historical, clinical, and laboratory criteria who could be discharged from the ED. Phone follow-up was planned through the use of an automated electronic notification that was sent to an established hematology follow-up pool at the time of ED discharge. We conducted two "fake front end" trials in the ED to receive feedback on our process before full implementation. A postpathway implementation quality improvement team monitored discharge rates, phone follow up rates and adverse events. RESULTS: In the first 9 weeks postpathway implementation, 100 SCD patients were evaluated for fever; 84 (24%) met low-risk criteria and were discharged home. This reduction in admission rate has been maintained throughout the 3 years postimplementation. Successful phone follow-up was achieved in all discharged patients within 24 hours and no adverse events were identified. CONCLUSIONS: Low-risk febrile patients with SCD can be safely discharged from the ED. An automated notification system within the electronic medical record system can facilitate patient follow-up after ED discharge. Future quality improvement efforts aimed to further reduce admissions in this population should target patients with modifiable risk factors for serious bacterial infection. PMID- 29252941 TI - Necessities for the Assessment and Delivery of Value-Based Critical Care: Empirical Evidence and Systemic Considerations. PMID- 29252942 TI - Embracing Enrichment and Unknown Unknowns. PMID- 29252943 TI - A Self-Fulfilling Hypothesis. PMID- 29252944 TI - Inhaled Antibiotics: Do as We Say Not as We Study. PMID- 29252945 TI - The Challenges Faced With Early Mobilization of Patients on Extracorporeal Membrane Oxygenation. PMID- 29252946 TI - Connecting the Dots: The Influence of Risk Perception on Patient Safety. PMID- 29252947 TI - Next Steps for Confirming Bronchoalveolar Lavage Amlyase as an Useful Biomarker for Ventilator-Associated Pneumonia. PMID- 29252948 TI - Gazing Into the Crystal Ball or Looking Through the Rear View Mirror? Prediction of Neurologic Outcome in Survivors of Pediatric Critical Illness. PMID- 29252949 TI - Reading the Smoke Signals: What Is the Meaning of Burnout Among Pediatric Critical Care Physicians? PMID- 29252950 TI - Sedation and Analgesia Following Pediatric Heart Surgery-Less May Be More. PMID- 29252951 TI - Responsible Precision Medicine in Pediatric Acute Respiratory Distress Syndrome: The Challenge of Searching for Biomarker-Driven Earlier Diagnosis, Effective Treatment, and Stratified Outcomes. PMID- 29252952 TI - Escalations in Care: Do Interhospital Transfers Lead to Greener Pastures? PMID- 29252954 TI - Propofol Related Infusion Syndrome: Ultrastructural Evidence for a Mitochondrial Disorder. AB - OBJECTIVE: The objective of this report of a fatal propofol-related infusion syndrome in a young adult was to present-to our knowledge for the first time direct ultrastructural evidence for the central role of mitochondrial damage in the pathogenesis of this syndrome. DATA SOURCES: Histological and electron microscopical analysis of liver, skeletal, and heart muscle obtained by autopsy and blood obtained from patient. STUDY SELECTION: Case report. DATA EXTRACTION: In addition to conventional macroscopical and histological investigations, electron-microscopical analysis of myocardial- and skeletal muscle and liver tissue obtained at autopsy from a young man was performed in order to search for ultrastructural changes of mitochondria. Acylcarnitine concentrations of his blood were determined by ultra-high performance liquid chromatography mass spectrometry. DATA SYNTHESIS: A 19-year-old male was admitted with acute left side hemiparesis. The patient was intubated, then propofol infusion started, and a craniotomy was performed to remove an intracerebral hematoma. In the postoperative period, the patient presented with elevated intracranial pressure and brain edema. After repeat surgery, the patient showed impaired systolic left ventricular function, increasing fever, anuria, hyperkalemia, and metabolic acidosis, and he finally expired. Electron microscopy revealed dark, electron dense amorphous structures associated with mitochondria in heart muscle and liver tissue obtained at autopsy. Peripheral blood analysis revealed increased levels of acetyl-, propionyl-, butyryl-, malonyl-, and valeryl-carnitine as an indicator for propofol-related infusion syndrome, as well as for propofol-mediated inhibition of free fatty acid uptake into mitochondria, affecting beta-oxidation. CONCLUSIONS: Electron dense bodies found in association with mitochondria in muscle and liver cells probably correspond to accumulation of free fatty acid provide direct morphological evidence for the mitochondrial damage in propofol related infusion syndrome. PMID- 29252955 TI - The Healthy User Effect in Studies of Statins in the Critically Ill. PMID- 29252956 TI - The author replies. PMID- 29252957 TI - Could Polymerase Chain Reaction-Based Methods Differentiate Pneumonitis From Bacterial Aspiration Pneumonia? PMID- 29252958 TI - The authors reply. PMID- 29252959 TI - Calcium Channel Blockers and Sepsis Outcomes. PMID- 29252960 TI - The authors reply. PMID- 29252961 TI - Hyperoxemia and Veno-Arterial Extracorporeal Membrane Oxygenation: Do Not Forget the Gut. PMID- 29252962 TI - The authors reply. PMID- 29252963 TI - Hyponatremic Encephalopathy. PMID- 29252964 TI - The authors reply. PMID- 29252965 TI - Sexual Harassment in Academic Medicine: It Is Time to Break the Silence. PMID- 29252966 TI - Patient Safety in Hospitals: What We Do and What We Need-Focus Groups With Stakeholders of Hospitals in Southern Germany. AB - OBJECTIVES: To provide the basis for designing an interprofessional patient safety training for medical treatment teams, the current situation regarding patient safety and existing training programs in southern German hospitals should be explored. Moreover, need-based content regarding the subject areas teamwork, safety culture, and patient involvement should be derived, a conducive learning format suggested, and wishes and concerns regarding the training explored. METHODS: Qualitative design (focus groups) in five hospitals with different levels of care involving a total of 39 members of interprofessional teams, administration, and quality management team. Structured contents analysis was used for evaluation. RESULTS: The need for training to improve patient safety was highlighted. Related contents regarding the subject areas were derived: teamwork (team-building exercises, interprofessional teamwork, interprofessional communication), safety culture (dealing with criticism, appraisals, open handling of errors/proactive error reporting), and patient involvement (inclusion of patients and/or relatives, question types). The combination of e-learning and interprofessional in-person training was emphasized as a conducive learning format. The desire for practical tips, Continuing Medical Education credits, and intuitive review of theories was expressed. CONCLUSIONS: The study initially presents the current situation regarding patient safety, existing training, teamwork, safety culture, and patient involvement in southern German hospitals and gives recommendations for related content and learning format. Based on our results, we recommend to develop a combination of e-learning and interprofessional in-person training. This training should systematically link all three subject areas and address the derived content from the focus groups to improve patient safety. PMID- 29252967 TI - Evaluation of the Effects of Radio-Frequency Identification Technology on Patient Tracking in Hospitals: A Systematic Review. AB - OBJECTIVE: The aim of this study was to systematically review all studies that evaluated the effects of using radio-frequency identification (RFID) for tracking patients in hospitals. METHODS: The PubMed and Embase databases were searched (to August 2015) for relevant English language studies, and those that evaluated the effects of a real-time locating systems with RFID for patient tracking in hospitals were identified and extracted. RESULTS: Of the 652 studies found, the 17 relevant studies were extracted for inclusion. Five of the extracted studies used RFID systems in operating theaters, two in emergency departments, one in a magnetic resonance imaging department, one in a radiology room, and the remaining eight studies were in other wards. In these studies, features such as the feasibility, accuracy, precision, reliability, security, level of satisfaction, cost of care, and time efficiency of the RFID systems were reported. Of all the extracted studies, seven evaluated the accuracy of the systems in crowded and unattended areas, and five of these were satisfied with their accuracy. Six evaluated the reliability of the systems, and all of these found the systems to be reliable. Six evaluated time-savings, and all of them reported the systems to be time effective. Two focused on the cost of care, and both of these reported the systems to be cost effective. CONCLUSIONS: Although most studies reported a positive impact on the accuracy and precision of patient identification, there is insufficient good evidence to show that RFID systems can accurately localize patients in crowded settings. PMID- 29252968 TI - Application of a Healthcare Failure Modes and Effects Analysis to Identify and Mitigate Potential Risks in the Implementation of a National Prehospital Pediatric Rapid Sequence Intubation Program. AB - INTRODUCTION: Rapid sequence intubation (RSI) has become the de facto airway method of choice in the emergency airway management of adult and pediatric patients. There is significant controversy regarding pediatric RSI in the prehospital setting, given not only the complexities inherent in both the procedure and patient population, but in variations in emergency medical service models, prehospital qualifications, scope of practice, and patient exposure too. METHODS: A Healthcare Failure Mode and Effects Analysis was conducted to identify and mitigate potential hazards in the national implementation of a prehospital pediatric RSI program. A process map and potential failure points were developed and identified. Probabilities, severity, and hazards scores were calculated for each failure point, and actions items developed to address these. RESULTS: One hundred four potential failure points were identified among 44 subprocesses, divided between nine major processes. In terms of severity, most were classified as either major (n = 39 [37.5%]) or catastrophic (n = 35 [33.7%]) with just more than half falling within the uncommon category (n = 56 [53.9%]) in terms of probability. Five strategic actions items were identified to mitigate against the failure points meeting criteria for action. To monitor the success of these, 11 quality and performance indicators were developed for concurrent implementation. CONCLUSIONS: The Healthcare Failure Mode and Effects Analysis represents a simple yet comprehensive first step toward risk analysis of complex procedures within the prehospital emergency care setting. Application of the methodology provided guidance for the consensus identification of hazards associated with prehospital pediatric RSI and appropriate actions to mitigate them. PMID- 29252969 TI - Differences in Hip and Knee Running Moments across Female Pubertal Development. AB - PURPOSE: This study aimed to investigate whether knee and hip running moments differ across stages of female pubertal development. METHODS: This was a cross sectional study comparing the barefoot running moments of 91 prepubertal (n = 31, Tanner stage I), early/midpubertal (n = 30, Tanner stages II and III), and late/postpubertal (n = 30, Tanner stages IV and V) girls. External peak moments for knee abduction (KAbM), knee adduction (KAM), knee flexion (KFM), and knee internal rotation (KIRM) were analyzed. Secondary measures of hip adduction moment at the time of peak KAbM and hip flexion moment at the time of peak KFM were also derived. Between-group differences were analyzed using a series of one way ANOVAs and ANCOVAs. RESULTS: At the knee, the late/postpubertal girls displayed a higher peak KFM and KAM compared with the prepubertal group (P < 0.05), and the early/midpubertal group exhibited a higher peak KFM than the prepubertal group (P = 0.034). No between-group differences were found for peak KAbM or KIRM (P > 0.05). At the hip, both the late/postpubertal (P = 0.03) and early/midpubertal girls (P = 0.039) ran with a lower hip adduction moment at the time of peak KAbM than the prepubertal girls. The hip flexion moment at the time of peak KFM in late/postpubertal girls was also significantly lower than both the early/mid- and prepubertal girls (P < 0.001). CONCLUSION: Girls at the latter stages of puberty exhibit higher peak external knee flexion and adduction moments, but not abduction or internal rotation moments. This may be partly attributed to a lower hip flexion but higher hip abduction moment at the time of peak knee moments. Future research should examine whether these differences in knee kinetics between pubertal stages have implications for knee injuries such as patellofemoral pain syndrome. PMID- 29252970 TI - Physical Education Classes, Physical Activity, and Sedentary Behavior in Children. AB - PURPOSE: This study aimed to examine the associations between participation frequency in physical education (PE) classes and objective measures of physical activity (PA) and sedentary behavior (SB) in children from 12 countries at different levels of development. METHODS: This multinational, cross-sectional study included 5874 children 9-11 yr old from sites in Australia, Brazil, Canada, China, Colombia, Finland, India, Kenya, Portugal, South Africa, the United Kingdom, and the United States. PA and SB were monitored for seven consecutive days using a waist-worn accelerometer. PA and SB data were presented for weekdays (times in and out of school) and weekend days. Participation frequency in PE classes was determined by questionnaire. Multilevel modeling analyses stratified by sex were used. RESULTS: Overall, 24.8% of children self-reported participation in PE classes >=3 times per week (25.3% in high-income countries [HIC] and 24.3% in low- and middle-income countries [LMIC]). After adjusting for age, sex, parental education, and body mass index z-score, results showed that children from low- and middle-income countries who took PE classes one to two times per week were more likely to present better indicators of PA and shorter time in SB in and out of school. In HIC, boys that participated in PE classes were more likely to meet the moderate-to-vigorous PA recommendations and to present better indicators of PA (in school) and shorter time in SB in and out of school. For girls in HIC, attending PE classes increased the likelihood of spending more time in moderate-to-vigorous PA, especially if they attended >=3 times per week. CONCLUSION: Attending PE classes is associated with a higher level of PA and a lower level of SB in and out of school during weekdays in children from countries at various levels of development. PMID- 29252971 TI - Lower-Extremity Injury Increases Risk of First-Time Low Back Pain in the US Army. AB - : Low back pain (LBP) and lower-extremity injuries (LEI) are primary reasons for lost duty days and disability among military populations. PURPOSE: This study examined acute LEI as a risk factor for developing LBP and examined the time to incident LBP between individuals with and without a history of LEI. METHODS: This retrospective cohort study examined U.S. Army medical and personnel data from the Total Army Injury and Health Outcomes Database for the years 2007 to 2011. Andersen-Gill Cox regression methods were used to examine the change in LEI status over time and changes in demographic covariates. Adjusted hazard ratios (HR) for LBP after LEI were calculated from the Cox regression model for each calendar year. An accelerated failure time (AFT) model was used to describe time to LBP, and mean time to event and adjusted time ratios (TR) after LEI were calculated from the AFT model for each year. Overall HR and TR for LBP after LEI were calculated over the five calendar years using variance-based weighted averages. RESULTS: Each yearly analysis included an average of 213,307 soldiers; on average for each year 8.44% of soldiers developed LBP and 11.54% had previous LEI. The pooled TR showed soldiers with a LEI had a 10% decrease in mean survival times to LBP compared to those without a LEI (TR, 0.901; 95% confidence interval, 0.897-0.905). The weighted average HR showed that soldiers with a LEI had 1.7 times the hazard of LBP compared with those without LEI (HR, 1.70; 95% confidence interval, 1.66-1.74). CONCLUSIONS: These findings suggest that a potential second order effect of LEI is an increased short-term risk for developing LBP, which should be considered during rehabilitation planning. PMID- 29252972 TI - OPTICAL DENSITY RATIO OF THE SUBRETINAL FLUID IN CHOROIDAL MELANOMA AND METASTASIS. AB - PURPOSE: To investigate the optical density (OD) characteristics and clinical relevance of subretinal fluid in choroidal melanoma and choroidal metastasis. METHODS: Medical records of patients with choroidal melanoma and choroidal metastasis who underwent optical coherence tomography examinations at diagnosis before any intervention and whose optical coherence tomography scans showed sufficient subretinal fluid for sampling were reviewed. The highest quality B scan containing subretinal fluid was analyzed. Optical density measurements obtained using ImageJ and optical density ratios (ODRs) were calculated as subretinal fluid OD divided by vitreous OD. Patient details and diagnosis were masked during measurements. Nonparametric tests for independent samples were used to detect differences in ODR between groups. RESULTS: Of the 39 cases of choroidal tumors that met the inclusion criteria, 14 were diagnosed as metastases and 25 as malignant melanoma. There were no significant differences between the groups in age, optical coherence tomography acquisition and parameters of quality, and vitreous OD. Optical density ratio values were significantly lower in metastases cases (mean 0.68, SD +/-0.18) than in melanoma cases (0.95 +/- 0.33, P = 0.006). Receiver operating characteristic curve analysis yielded an optimal cutoff of ODR = 0.771 (sensitivity = 78.6%, specificity = 72.0%). CONCLUSION: Optical density ratio can serve as an additional test to differentiate between choroidal melanoma and choroidal metastases. PMID- 29252973 TI - SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY ASSESSMENT OF FELLOW EYES IN COATS DISEASE. AB - PURPOSE: To assess foveal and parafoveal vasculature at superficial capillary plexus (SCP), deep capillary plexus, and choriocapillaris using optical coherence tomography angiography in the fellow eyes of patients with Coats disease. METHODS: Observational and prospective case series. Thirteen patients with unilateral Coats and 14 healthy age- and sex-matched controls were consecutively recruited at Manchester Royal Eye Hospital and the Department of Ophthalmology of San Raffaele Hospital. Both groups underwent complete ophthalmologic examination, including optical coherence tomography angiography (Topcon Corp) 3 mm * 3 mm scans. Images were imported into ImageJ software and binarized; foveal avascular zone area was manually outlined and vessel density analyzed in inner (foveal) and outer (parafoveal) areas of SCP, deep capillary plexus, and choriocapillaris. RESULTS: Fellow eyes disclosed a significant increase in the foveal vessel density of SCP (P = 0.04); in particular, superior and temporal quadrants showed more marked alterations (P = 0.02 and 0.04, respectively). Analysis of foveal avascular zone area revealed a significant enlargement in the SCP (P = 0.04). No correlation was found between fellow eyes and the stage of affected eyes. CONCLUSION: Fellow eyes of Coats patients carry quantitative foveal vascular alterations at SCP. These may represent markers of altered inner blood-retinal barrier, due to a bilateral defect in midcapillary angiogenesis. PMID- 29252974 TI - SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING OF THE MACULA AND VITREOMACULAR INTERFACE IN PERSISTENT FETAL VASCULATURE SYNDROME WITH POSTERIOR INVOLVEMENT. AB - PURPOSE: To describe the microstructural features of the macula and vitreomacular interface in persistent fetal vasculature syndrome (PFVS) with posterior involvement managed with early vitrectomy or with observation, with functional correlation. METHODS: We retrospectively identified 45 consecutive pediatric patients with PFVS with posterior involvement treated from 2005 to 2016. The eyes that could be imaged with spectral domain optical coherence tomography were included, and images were correlated with best-corrected visual acuity. RESULTS: Thirty-eight imaging sessions were performed on 10 eyes from 9 patients, including 7 that had been managed with vitrectomy for PFVS-related tractional retinal detachment, and 3 that had been observed. Mean age of the patients who were imaged was 9.1 years and their average length of follow-up was 5.9 years. Best-corrected visual acuities of the eyes imaged ranged from 20/30 to count fingers, with mean best-corrected visual acuity 20/163. All eyes imaged had microstructural anomalies identified. The main anomalous features included posterior hyaloidal organization, vitreoretinal traction, vitreopapillary traction, diminished foveal contour, foveal displacement, and disruption of the ellipsoid zone. Posterior hyaloidal organization (P = 0.043), diminished foveal contour (P = 0.019), and disruption of the ellipsoid zone (P = 0.014) were associated with worse best-corrected visual acuity. CONCLUSION: Macular and vitreomacular interface anomalies were identified in all pediatric patients with posterior PFVS imaged with spectral domain optical coherence tomography. These microstructural findings, together with functional measures, may inform the diagnosis and management of PFVS with posterior involvement. PMID- 29252975 TI - TRAFFIC ACCIDENT-RELATED OPEN GLOBE INJURIES. AB - PURPOSE: To evaluate the clinical characteristics and visual outcomes of patients with traffic accident-related open globe injuries, and to examine preoperative factors influencing the visual prognosis after pars plana vitrectomy, as compared with common open globe injuries. METHODS: Patients with open globe injuries, who underwent pars plana vitrectomy, were identified. Patients' demographic and clinical data were entered into a computerized database for review and analysis; data included age, sex, initial visual acuity, duration between onset of injury and surgery, information about the type and cause of injury, wound location and length, presence of ocular complications, and final visual acuity. RESULTS: Of the 355 open globe injuries, 14 were sustained during a traffic-related accident; the average age was 50.4 years (range: 20-85) and most (78.6%) were men. Of these 14 patients, 9 (64.3%) presented with rupture and 5 (35.7%) with laceration. Injuries were caused while driving (6 eyes; 42.9%), riding a bicycle (5 eyes; 35.7%), involved in car accident while walking (2 eyes; 14.3%), and riding a motorbike (1 eye; 7.1%). Initial visual acuity was significantly related to final visual acuity (P = 0.003, R = 0.80). The final visual acuity in patients with traffic accident-related open globe injuries was significantly better than that of the total group (P = 0.01). CONCLUSION: Traffic accident-related open globe injuries had better visual outcomes than common open globe injuries. Visual outcomes in patients with traffic accident-related open globe injuries were related to the initial visual acuity. No eyes developed endophthalmitis in patients with traffic accident-related open globe injuries. PMID- 29252976 TI - TREATMENT OF EXUDATIVE CIRCUMSCRIBED CHOROIDAL HEMANGIOMA: Efficacy of Fractionated Proton Therapy (20 Gray Relative Biological Effectiveness in 8 Fractions). AB - PURPOSE: To evaluate treatment of circumscribed choroidal hemangioma by hyperfractionated proton beam therapy protocol (20 gray relative biological effectiveness in 8 fractions) on tumor control, attachment of retina and visual function. METHODS: Retrospective review of patients treated between January 2010 and April 2015 with at least 6 months of follow-up. RESULTS: Forty-three patients with exudative and symptomatic circumscribed choroidal hemangioma were included. Before treatment, 41 (95%) presented an exudative retinal detachment, median visual acuity was 20/63 and median tumor thickness was 3.3 mm. Mean follow-up was 26 months (7-62). At last follow-up, all patients presented regression of ultrasound tumor thickness and 23/43 (53.5%) a totally flat scar. The mean time to achieve a flat scar was 20 months. Retina was reattached in all patients except one with 9 months of follow-up. Visual acuity was improved or stabilized in 37 patients (86%) and final median visual acuity was 20/25. No patient presented radiation maculopathy or papillopathy. CONCLUSION: Proton beam therapy with a dose of 20 gray relative biological effectiveness delivered in 8 fractions provides excellent anatomical and functional results and are comparable with those obtained with the same dose delivered in 4 fractions. Longer follow-up is required to determine the long-term radiation sequelae. PMID- 29252977 TI - Evaluating the Performance of a Visually Guided Hearing Aid Using a Dynamic Auditory-Visual Word Congruence Task. AB - OBJECTIVES: The "visually guided hearing aid" (VGHA), consisting of a beamforming microphone array steered by eye gaze, is an experimental device being tested for effectiveness in laboratory settings. Previous studies have found that beamforming without visual steering can provide significant benefits (relative to natural binaural listening) for speech identification in spatialized speech or noise maskers when sound sources are fixed in location. The aim of the present study was to evaluate the performance of the VGHA in listening conditions in which target speech could switch locations unpredictably, requiring visual steering of the beamforming. To address this aim, the present study tested an experimental simulation of the VGHA in a newly designed dynamic auditory-visual word congruence task. DESIGN: Ten young normal-hearing (NH) and 11 young hearing impaired (HI) adults participated. On each trial, three simultaneous spoken words were presented from three source positions (-30, 0, and 30 azimuth). An auditory visual word congruence task was used in which participants indicated whether there was a match between the word printed on a screen at a location corresponding to the target source and the spoken target word presented acoustically from that location. Performance was compared for a natural binaural condition (stimuli presented using impulse responses measured on KEMAR), a simulated VGHA condition (BEAM), and a hybrid condition that combined lowpass filtered KEMAR and highpass-filtered BEAM information (BEAMAR). In some blocks, the target remained fixed at one location across trials, and in other blocks, the target could transition in location between one trial and the next with a fixed but low probability. RESULTS: Large individual variability in performance was observed. There were significant benefits for the hybrid BEAMAR condition relative to the KEMAR condition on average for both NH and HI groups when the targets were fixed. Although not apparent in the averaged data, some individuals showed BEAM benefits relative to KEMAR. Under dynamic conditions, BEAM and BEAMAR performance dropped significantly immediately following a target location transition. However, performance recovered by the second word in the sequence and was sustained until the next transition. CONCLUSIONS: When performance was assessed using an auditory-visual word congruence task, the benefits of beamforming reported previously were generally preserved under dynamic conditions in which the target source could move unpredictably from one location to another (i.e., performance recovered rapidly following source transitions) while the observer steered the beamforming via eye gaze, for both young NH and young HI groups. PMID- 29252978 TI - Social Development in Children With Early Cochlear Implants: Normative Comparisons and Predictive Factors, Including Bilateral Implantation. AB - OBJECTIVES: There are mixed results regarding psychosocial development in children with cochlear implants (CIs) compared with children with normal hearing (NH), and the effect of bilateral CIs has not yet been investigated. This study aimed to investigate whether social development differed between NH children and those with early CIs, and to identify new predictors of psychosocial development in children with early CIs. DESIGN: The psychosocial development, cognitive and language abilities of 159 children were measured as part of a longitudinal outcomes study of children with CIs. Parental involvement was also assessed. RESULTS: The children in this study did not differ significantly from their peers with NH in terms of their psychosocial development, except with regard to Prosocial Behavior, with parents reporting significantly poorer development in this area. Having bilateral CIs predicted significantly fewer difficulties with psychosocial development, with earlier age at implantation increasing the effect size of the second CI for Emotional Symptoms and Peer Problems. Receptive language ability, higher parent education, later birth order, high parent involvement, and female gender predicted significantly fewer parent reports of psychosocial problems. Higher child cognitive ability and greater screen time predicted significantly greater reported psychosocial difficulties. Marginal effects modeling quantified the effects of changes in the predictive factors examined. CONCLUSIONS: Psychosocial development in these children with early CIs was found to be similar to that for peers with NH, with the exception of delayed Prosocial Behavior development. Having bilateral CIs predicted significantly better emotional outcomes. A number of new predictive factors were found for psychosocial development. The results of the marginal effects modeling should be shared with parents and professionals to increase their understanding of the impact of changes in predictive factors, particularly in terms of their own contribution to psychosocial outcomes for children with CIs. PMID- 29252979 TI - Looking Behavior and Audiovisual Speech Understanding in Children With Normal Hearing and Children With Mild Bilateral or Unilateral Hearing Loss. AB - OBJECTIVES: Visual information from talkers facilitates speech intelligibility for listeners when audibility is challenged by environmental noise and hearing loss. Less is known about how listeners actively process and attend to visual information from different talkers in complex multi-talker environments. This study tracked looking behavior in children with normal hearing (NH), mild bilateral hearing loss (MBHL), and unilateral hearing loss (UHL) in a complex multi-talker environment to examine the extent to which children look at talkers and whether looking patterns relate to performance on a speech-understanding task. It was hypothesized that performance would decrease as perceptual complexity increased and that children with hearing loss would perform more poorly than their peers with NH. Children with MBHL or UHL were expected to demonstrate greater attention to individual talkers during multi-talker exchanges, indicating that they were more likely to attempt to use visual information from talkers to assist in speech understanding in adverse acoustics. It also was of interest to examine whether MBHL, versus UHL, would differentially affect performance and looking behavior. DESIGN: Eighteen children with NH, eight children with MBHL, and 10 children with UHL participated (8-12 years). They followed audiovisual instructions for placing objects on a mat under three conditions: a single talker providing instructions via a video monitor, four possible talkers alternately providing instructions on separate monitors in front of the listener, and the same four talkers providing both target and nontarget information. Multi-talker background noise was presented at a 5 dB signal-to noise ratio during testing. An eye tracker monitored looking behavior while children performed the experimental task. RESULTS: Behavioral task performance was higher for children with NH than for either group of children with hearing loss. There were no differences in performance between children with UHL and children with MBHL. Eye-tracker analysis revealed that children with NH looked more at the screens overall than did children with MBHL or UHL, though individual differences were greater in the groups with hearing loss. Listeners in all groups spent a small proportion of time looking at relevant screens as talkers spoke. Although looking was distributed across all screens, there was a bias toward the right side of the display. There was no relationship between overall looking behavior and performance on the task. CONCLUSIONS: The present study examined the processing of audiovisual speech in the context of a naturalistic task. Results demonstrated that children distributed their looking to a variety of sources during the task, but that children with NH were more likely to look at screens than were those with MBHL/UHL. However, all groups looked at the relevant talkers as they were speaking only a small proportion of the time. Despite variability in looking behavior, listeners were able to follow the audiovisual instructions and children with NH demonstrated better performance than children with MBHL/UHL. These results suggest that performance on some challenging multi-talker audiovisual tasks is not dependent on visual fixation to relevant talkers for children with NH or with MBHL/UHL. PMID- 29252980 TI - Analysis of Pre- and Postoperative Pain Variation in Osteoporotic Vertebral Compression Fracture Patients Undergoing Kyphoplasty. AB - BACKGROUND Balloon kyphoplasty (KP) has been widely applied in the treatment of elderly patients with osteoporosis vertebral compression fracture (OVCF), but there has been little research on the pain relief effect. Therefore, we performed this study of patients who received KP. The study included a set of fluoroscopy tests and follow-up evaluation, which aimed to verify the effectiveness of kyphoplasty in controlling back pain associated with OVCFs. MATERIAL AND METHODS Forty-three OVCF patients underwent kyphoplasty: 21 were allocated to an intervention group and 22 were allocated to a control group, and the 2 groups received treatment with different KP instruments. The variation of vertebral height was measured on X-ray and change of signal of MRI was recorded. The pain was assessed by VAS score and diagram, and physical function was evaluated by ODI. The complications after surgery were recorded and collated during 2 years of follow-up. RESULTS The intervention group showed no significant difference on the VAS and ODI compared to the control group (p>0.05). There was no difference in the VAS with different degrees of radiological change (p>0.05). Signal change on MRI imaging was rare. CONCLUSIONS Kyphoplasty is a positive way to alleviate early-onset OVCF pain. The change of BME extent in the treated level is unrelated to the relief of back pain after KP. PMID- 29252981 TI - Total brain, cortical, and white matter volumes in children previously treated with glucocorticoids. AB - BackgroundPerinatal exposure to glucocorticoids and elevated endogenous glucocorticoid levels during childhood can have detrimental effects on the developing brain. Here, we examined the impact of glucocorticoid treatment during childhood on brain volumes.MethodsA total of 30 children and adolescents with rheumatic or nephrotic disease previously treated with glucocorticoids and 30 controls matched on age, sex, and parent education underwent magnetic resonance imaging (MRI) of the brain. Total cortical gray and white matter, brain, intracranial volume, and total cortical thickness and surface area were derived from MRI scans.ResultsPatients had significantly smaller gray and white matter and total brain volumes relative to healthy controls. Brain volume differences disappeared when accounting for intracranial volume, as patients had relatively smaller intracranial volumes. Group differences were mainly driven by the children with rheumatic disease. Total cortical thickness and cortical surface area did not significantly differ between groups. We found no significant associations between glucocorticoid-treatment variables and volumetric measures.ConclusionObserved smaller total brain, cortical gray, and white matter volumes in children and adolescents previously treated with glucocorticoids compared with that in healthy controls may reflect both developmental and degenerative processes. Prospective longitudinal studies are warranted to clarify whether findings are related to treatment or disease. PMID- 29252982 TI - Regulating toxic chemicals for public and environmental health. PMID- 29252983 TI - Efficacy and safety of Descemet's membrane endothelial keratoplasty versus Descemet's stripping endothelial keratoplasty: A systematic review and meta analysis. AB - PURPOSE: Based on current evidence, the efficiency and safety of Descemet's membrane endothelial keratoplasty (DMEK) was compared with that of Descemet's stripping endothelial keratoplasty (DSEK). METHODS: Pubmed, Embase, Web of Science, the Cochrane Database and conference abstracts were comprehensively searched for studies that compared the efficacy and safety of DMEK and DSEK. The efficacy outcome was the postoperative best-corrected visual acuity (BCVA). The safety outcomes included the postoperative endothelial cell density (ECD) and complications such as graft detachment, graft rejection, graft failure, postoperative elevated intraocular pressure (IOP), tissue loss, etc. The outcomes were pooled using random-effects models with Stata 13.0 software. Heterogeneity was qualified with Q statistic and I2/H2 statistic. Publication bias was assessed using funnel plot, Begg rank correlation test, and Egger or Horbard linear regression. RESULTS: 19 articles were eligible, and 1124 eyes and 1254 eyes were included in the DMEK and DSEK groups, respectively. The overall pooled estimates showed a significantly better postoperative BCVA, a comparable ECD and an increased graft detachment rate in the DMEK group compared with the DSEK group (BCVA: mean difference (MD) = -0.15, 95% CI = -0.19 to -0.11, P<0.001; ECD: MD = 14.88, 95% CI = -181.50 to 211.27, P = 0.882; graft detachment rate: OR = 4.56, 95% CI = 2.43 to 8.58, P<0.001). Except for the postoperative ECD, which was changed to be higher in the DSEK group than the DMEK group, the learning curve did not have a marked effect on the comparison outcome of the BCVA and graft detachment rate based on the estimates pooled from studies that collected data during the DMEK learning phase (ECD (learning curve): MD = -361.24, 95% CI = 649.42 to -73.07, P = 0.014). CONCLUSION: Although DMEK is a more technically difficult and challenging procedure, it may represent a safe and more efficient alternative to DSEK for the treatment of corneal endothelial diseases, even during its learning curve. PMID- 29252984 TI - Predictors of non-adherence to antiretroviral therapy among HIV infected patients in northern Tanzania. AB - BACKGROUND: Antiretroviral therapy (ART) has been shown to reduce HIV-related morbidity and mortality amongst those living with HIV and reduce transmission of the virus to those who are yet to be infected. However, these outcomes depend on maximum ART adherence, and HIV programs around the world make efforts to ensure optimal adherence. Predictors of ART non-adherence vary considerably across populations and settings with respect to demographic, psychological, behavioral and economic factors. The objective of this study is to investigate risk factors that predict non-adherence to antiretroviral treatment among HIV-infected individuals in northern Tanzania. METHODS: At Kilimanjaro Christian Medical Centre (KCMC), a tertiary and referral hospital in northern Tanzania, we used an existing ART database to randomly select HIV-infected patients above 18 years of age who have been on triple ART for at least two years. We used interviewer administered structured questionnaires to cross-sectionally determine predictors of ART non-adherence. We determined non-adherence through retrospective review of pharmacy drug refill (PDR) records of the interviewed participants using a pharmacy database. RESULTS: Non-adherence was defined as collecting less than 95% of expected monthly refills in the previous 2 years. Multivariable logistic regression model was used to determine the predictors of non-adherence. Of the 256 patients enrolled mean age was 44 years (SD +/- 11) and median CD4 count was 499 cells per microliter (IQR 332-690). Median PDR adherence was 71% (IQR 58% 75%). Non-adherence was associated with younger age and unemployment. CONCLUSION: In this setting, adherence strategies could be adapted to address issues facing young adults, and those with household challenges such as unemployment. Further research is required to better understand the potential roles of these factors in suboptimal adherence. PMID- 29252985 TI - Which climate change path are we following? Bad news from Scots pine. AB - Current expectations on future climate derive from coordinated experiments, which compile many climate models for sampling the entire uncertainty related to emission scenarios, initial conditions, and modelling process. Quantifying this uncertainty is important for taking decisions that are robust under a wide range of possible future conditions. Nevertheless, if uncertainty is too large, it can prevent from planning specific and effective measures. For this reason, reducing the spectrum of the possible scenarios to a small number of one or a few models that actually represent the climate pathway influencing natural ecosystems would substantially increase our planning capacity. Here we adopt a multidisciplinary approach based on the comparison of observed and expected spatial patterns of response to climate change in order to identify which specific models, among those included in the CMIP5, catch the real climate variation driving the response of natural ecosystems. We used dendrochronological analyses for determining the geographic pattern of recent growth trends for three European species of trees. At the same time, we modelled the climatic niche for the same species and forecasted the suitability variation expected across Europe under each different GCM. Finally, we estimated how well each GCM explains the real response of ecosystems, by comparing the expected variation with the observed growth trends. Doing this, we identified four climatic models that are coherent with the observed trends. These models are close to the highest range limit of the climatic variations expected by the ensemble of the CMIP5 models, suggesting that current predictions of climate change impacts on ecosystems could be underestimated. PMID- 29252986 TI - Indoor residual spraying with a mixture of clothianidin (a neonicotinoid insecticide) and deltamethrin provides improved control and long residual activity against pyrethroid resistant Anopheles gambiae sl in Southern Benin. AB - INTRODUCTION: There is an urgent need for new insecticides for indoor residual spraying (IRS) which can provide improved and prolonged control of malaria vectors that have developed resistance to existing insecticides. The neonicotinoid, clothianidin represents a class of chemistry new to public health. Clothianidin acts as an agonist on nicotinic acetyl choline receptors. IRS with a mixture of Clothianidin and another WHO approved insecticide such as deltamethrin could provide improved control of insecticide resistant malaria vector populations and serve as a tool for insecticide resistance management. METHODS: The efficacy and residual activity of a novel IRS mixture of deltamethrin and clothianidin was evaluated against wild pyrethroid resistant An. gambiae sl in experimental huts in Cove, Benin. Two application rates of the mixture were tested and comparison was made with clothianidin and deltamethrin applied alone. To assess the residual efficacy of the treatments on different local wall substrates, the inner walls of the experimental huts were covered with either cement, mud or plywood. RESULTS: Clothianidin demonstrated a clear delayed expression in mortality of wild pyrethroid resistant An. gambiae sl in the experimental huts which reached its full effect 120 hours after exposure. Overall mortality over the 12-month hut trial was 15% in the control hut and 24-29% in the deltamethrin-treated huts. The mixture of clothianidin 200mg/m2 and deltamethrin 25mg/m2 induced high overall hut mortality rates (87% on mud walls, 82% on cement walls and 61% on wooden walls) largely due to the clothianidin component and high hut exiting rates (67-76%) mostly due to the deltamethrin component. Mortality rates remained >80% for 8-9 months on mud and cement walls. The residual activity trend was confirmed by results from monthly in situ cone bioassays with laboratory susceptible An. gambiae Kisumu strain. CONCLUSION: IRS campaigns with the mixture of clothianidin plus deltamethrin have the potential to provide prolonged control of malaria transmitted by pyrethroid resistant mosquito populations. PMID- 29252987 TI - Roles of claudin-2, ZO-1 and occludin in leaky HK-2 cells. AB - BACKGROUND: Claudin-2, ZO-1, and occludin are major components of tight junctions (TJs) in the proximal tubule. However, their roles in maintaining paracellular permeability as leaky epithelia have yet to be defined. METHODS: To investigate the contributory role of TJ proteins in the leaky proximal tubule, we xamined the effect of inhibiting claudin-2, occludin, and ZO-1 expression on transepithelial electrical resistance (TER) and paracellular permeability using the immortalized human proximal tubule epithelial cell line HK-2. For this, small-interfering RNAs (siRNAs) against claudin-2, occludin and ZO-1 were transfected into HK-2 cells. TER and transepithelial flux rates of dextrans (4 and 70 kDa) were determined after 24 h. RESULTS: Transfection of siRNAs (25 nM) knocked down TJ protein expression. Control HK-2 monolayers achieved a steady-state TER of 6-8 Omega.cm2 when grown in 12-well Transwell filters, which are compatible with leaky epithelia. Knockdown of claudin-2 decreased in TER and increased occludin expression. Transfection with siRNA against either occludin or ZO-1 increased TER and decreased claudin-2 expression. TER was decreased by co-inhibition of claudin 2 and ZO-1 but increased by co-inhibition of claudin-2 and occludin. TER was suppressed when claudin-2, occludin, and ZO-1 were all inhibited. Dextran flux rate was increased by claudin-2, occludin, or ZO-1 siRNA transfection. Increased dextran flux was enhanced by co-transfection of claudin-2, ZO-1, and occludin siRNA. CONCLUSIONS: The depletion of claudin-2, occludin and ZO-1 in HK-2 cells had differential effects on TER and macromolecule flux. We demonstrated that integration of claudin-2, occludin and ZO-1 is necessary for maintaining the function of the proximal tubular epithelium. PMID- 29252988 TI - Overload-based cascades on multiplex networks and effects of inter-similarity. AB - Although cascading failures caused by overload on interdependent/interconnected networks have been studied in the recent years, the effect of overlapping links (inter-similarity) on robustness to such cascades in coupled networks is not well understood. This is an important issue since shared links exist in many real world coupled networks. In this paper, we propose a new model for load-based cascading failures in multiplex networks. We leverage it to compare different network structures, coupling schemes, and overload rules. More importantly, we systematically investigate the impact of inter-similarity on the robustness of the whole system under an initial intentional attack. Surprisingly, we find that inter-similarity can have a negative impact on robustness to overload cascades. To the best of our knowledge, we are the first to report the competition between the positive and the negative impacts of overlapping links on the robustness of coupled networks. These results provide useful suggestions for designing robust coupled traffic systems. PMID- 29252989 TI - Chinese version of the Perceived Stress Scale-10: A psychometric study in Chinese university students. AB - Chinese university students often suffer from acute stress, which can affect their mental health. We measured and evaluated perceived stress in this population using the Simplified Chinese version of the 10-item Perceived Stress Scale (SCPSS-10). The SCPSS-10, Patient Health Questionnaire (PHQ), and Generalized Anxiety Disorder 7-item scale (GAD-7) were conducted in 1096 university students. Two weeks later, 129 participants were re-tested using the SCPSS-10. Exploratory factor analysis yielded two factors with Eigen values of 4.76 and 1.48, accounting for 62.41% of the variance. Confirmatory factor analysis demonstrated good fit of this two-factor model. The internal consistency reliability, as measured by Cronbach's alpha, was 0.85. The test-retest reliability coefficient was 0.7. The SCPSS-10 exhibited high correlation with the PHQ-9 and GAD-7, indicating an acceptable concurrent validity. The SCPSS-10 exhibited satisfactory psychometric properties in Chinese university students. PMID- 29252990 TI - Genetic and antigenic divergence in the influenza A(H3N2) virus circulating between 2016 and 2017 in Thailand. AB - Influenza virus evolves rapidly due to the accumulated genetic variations on the viral sequence. Unlike in North America and Europe, influenza season in the tropical Southeast Asia spans both the rainy and cool seasons. Thus, influenza epidemiology and viral evolution sometimes differ from other regions, which affect the ever-changing efficacy of the vaccine. To monitor the current circulating influenza viruses in this region, we determined the predominant influenza virus strains circulating in Thailand between January 2016 and June 2017 by screening 7,228 samples from patients with influenza-like illness. During this time, influenza A(H3N2) virus was the predominant influenza virus detected. We then phylogenetically compared the hemagglutinin (HA) gene from a subset of these A(H3N2) strains (n = 62) to the reference sequences and evaluated amino acid changes in the dominant antigenic epitopes on the HA protein structure. The divergence of the circulating A(H3N2) from the A/Hong Kong/4801/2014 vaccine strain formed five genetic groups (designated I to V) within the 3C.2a clade. Our results suggest a marked drift of the current circulating A(H3N2) strains in Thailand, which collectively contributed to the declining predicted vaccine effectiveness (VE) from 74% in 2016 down to 48% in 2017. PMID- 29252991 TI - Change in blood pressure variability in patients with acute ischemic stroke and its effect on early neurologic outcome. AB - BACKGROUND: How short-term blood pressure variability (BPV) is affected in the acute stage of ischemic stroke and whether BPV is associated with early neurologic outcomes remains unclear. METHODS: Patients who admitted for ischemic stroke within 24 h of symptom onset were consecutively identified between January 2010 and January 2015. BP profiles measured in real-time were summarized into short-term, 24-h time intervals, based on standard deviation (SD) and mean of systolic BP (SBPSD) during the first 3 days. The primary outcome was daily assessment of early neurological deterioration (END). The associations between short-term SBPSD values and the secular trend for primary outcome were examined. RESULTS: A total of 2,545 subjects (mean age, 67.1 +/- 13.5 years old and median baseline National Institutes of Health Stroke Scale score, 3) arrived at the hospital an average of 6.1 +/- 6.6 h after symptom onset. SBPSD values at day 1 (SD#D1), SD#D2, and SD#D3 were 14.4 +/- 5.0, 12.5 +/- 4.5, and 12.2 +/- 4.6 mmHg, respectively. Multivariable analyses showed that SD#D2 was independently associated with onset of END at day 2 (adjusted odds ratio, 1.08; 95% confidence interval, 1.03-1.13), and SD#D3 was independently associated with END#D3 (1.07, 1.01-1.14), with adjustments for predetermined covariates, SBPmean, and interactions with daily SBPSD. CONCLUSION: Short-term BPV changed and stabilized from the first day of ischemic stroke. Daily high BPV may be associated with neurological deterioration independent of BPV on the previous day. PMID- 29252992 TI - High prevalence of Angiostrongylus cantonensis (rat lungworm) on eastern Hawai'i Island: A closer look at life cycle traits and patterns of infection in wild rats (Rattus spp.). AB - The nematode Angiostrongylus cantonensis is a zoonotic pathogen and the etiological agent of human angiostrongyliasis or rat lungworm disease. Hawai'i, particularly east Hawai'i Island, is the epicenter for angiostrongyliasis in the USA. Rats (Rattus spp.) are the definitive hosts while gastropods are intermediate hosts. The main objective of this study was to collect adult A. cantonensis from wild rats to isolate protein for the development of a blood based diagnostic, in the process we evaluated the prevalence of infection in wild rats. A total of 545 wild rats were sampled from multiple sites in the South Hilo District of east Hawai'i Island. Adult male and female A. cantonensis (3,148) were collected from the hearts and lungs of humanely euthanized Rattus rattus, and R. exulans. Photomicrography and documentation of multiple stages of this parasitic nematode in situ were recorded. A total of 45.5% (197/433) of rats inspected had lung lobe(s) (mostly upper right) which appeared granular indicating this lobe may serve as a filter for worm passage to the rest of the lung. Across Rattus spp., 72.7% (396/545) were infected with adult worms, but 93.9% (512/545) of the rats were positive for A. cantonensis infection based on presence of live adult worms, encysted adult worms, L3 larvae and/or by PCR analysis of brain tissue. In R. rattus we observed an inverse correlation with increased body mass and infection level of adult worms, and a direct correlation between body mass and encysted adult worms in the lung tissue, indicating that larger (older) rats may have developed a means of clearing infections or regulating the worm burden upon reinfection. The exceptionally high prevalence of A. cantonensis infection in Rattus spp. in east Hawai'i Island is cause for concern and indicates the potential for human infection with this emerging zoonosis is greater than previously thought. PMID- 29252993 TI - Geometric and mechanical evaluation of 3D-printing materials for skull base anatomical education and endoscopic surgery simulation - A first step to create reliable customized simulators. AB - INTRODUCTION: Endoscopic skull base surgery allows minimal invasive therapy through the nostrils to treat infectious or tumorous diseases. Surgical and anatomical education in this field is limited by the lack of validated training models in terms of geometric and mechanical accuracy. We choose to evaluate several consumer-grade materials to create a patient-specific 3D-printed skull base model for anatomical learning and surgical training. METHODS: Four 3D printed consumer-grade materials were compared to human cadaver bone: calcium sulfate hemihydrate (named Multicolor), polyamide, resin and polycarbonate. We compared the geometric accuracy, forces required to break thin walls of materials and forces required during drilling. RESULTS: All materials had an acceptable global geometric accuracy (from 0.083mm to 0.203mm of global error). Local accuracy was better in polycarbonate (0.09mm) and polyamide (0.15mm) than in Multicolor (0.90mm) and resin (0.86mm). Resin and polyamide thin walls were not broken at 200N. Forces needed to break Multicolor thin walls were 1.6-3.5 times higher than in bone. For polycarbonate, forces applied were 1.6-2.5 times higher. Polycarbonate had a mode of fracture similar to the cadaver bone. Forces applied on materials during drilling followed a normal distribution except for the polyamide which was melted. Energy spent during drilling was respectively 1.6 and 2.6 times higher on bone than on PC and Multicolor. CONCLUSION: Polycarbonate is a good substitute of human cadaver bone for skull base surgery simulation. Thanks to short lead times and reasonable production costs, patient-specific 3D printed models can be used in clinical practice for pre-operative training, improving patient safety. PMID- 29252994 TI - Screening for cervical cancer in imprisoned women in Brazil. AB - CONTEXT AND OBJECTIVE: Incarcerated women are more vulnerable to developing cervical cancer than women in general; therefore, screening and intervention programs must be included in their healthcare provision. We therefore aimed to investigate the state of cervical cancer screening for imprisoned women in Mato Grosso do Sul, and to analyze the interventions geared toward the control of cervical cancer. MATERIALS AND METHODS: This was a cross-sectional study with analysis of primary and secondary data. Interviews were held with 510 women in seven prisons in the Brazilian state of Mato Grosso do Sul. The data for 352 medical records were analyzed statistically with the significance level set at 5%. Associations were assessed by the chi-squared test, adjusted by the Bonferroni correction. RESULTS: Most female prisoners had limited education, used tobacco, and had key risk factors for the development of cervical cancer. Half of the women interviewed (n = 255) stated that they had received a Papanicolaou (Pap) test in prison, but 134 (52.5%) of these did not know the result. Of those who had not received a Pap test, 149 (58.4%) stated that this was because of a lack of opportunity. There was no information regarding the provision of Pap tests or subsequent treatment in the medical records of 211 (59.9%) women. No protocols were in place for the provision of Pap tests in prison. There were statistical differences between prisons in terms of test frequency, the information provided to women, and how information was recorded in medical records. CONCLUSION: The screening of cervical cancer in prisons is neither systematic nor regular, and the results are not communicated to women in a significant number of cases. It is necessary to organize health services within the prison environment, ensuring that tests are done and that there is investigation for human papillomavirus. This could increase the diagnosis of cervical cancer at less advanced stages of the disease. PMID- 29252995 TI - Identifying volatile metabolite signatures for the diagnosis of bacterial respiratory tract infection using electronic nose technology: A pilot study. AB - OBJECTIVES: New point of care diagnostics are urgently needed to reduce the over prescription of antimicrobials for bacterial respiratory tract infection (RTI). We performed a pilot cross sectional study to assess the feasibility of gas capillary column ion mobility spectrometer (GC-IMS), for the analysis of volatile organic compounds (VOC) in exhaled breath to diagnose bacterial RTI in hospital inpatients. METHODS: 71 patients were prospectively recruited from the Acute Medical Unit of the Royal Liverpool University Hospital between March and May 2016 and classified as confirmed or probable bacterial or viral RTI on the basis of microbiologic, biochemical and radiologic testing. Breath samples were collected at the patient's bedside directly into the electronic nose device, which recorded a VOC spectrum for each sample. Sparse principal component analysis and sparse logistic regression were used to develop a diagnostic model to classify VOC spectra as being caused by bacterial or non-bacterial RTI. RESULTS: Summary area under the receiver operator characteristic curve was 0.73 (95% CI 0.61-0.86), summary sensitivity and specificity were 62% (95% CI 41-80%) and 80% (95% CI 64-91%) respectively (p = 0.00147). CONCLUSIONS: GC-IMS analysis of exhaled VOC for the diagnosis of bacterial RTI shows promise in this pilot study and further trials are warranted to assess this technique. PMID- 29252996 TI - The EQ-5D-5L is a valid approach to measure health related quality of life in patients undergoing bariatric surgery. AB - Bariatric surgery is considered an effective treatment for individuals with severe and complex obesity. Besides reducing weight and improving obesity related comorbidities such as diabetes, bariatric surgery could improve patients' health related quality of life. However, the frequently used instrument to measure quality of life, the EQ-5D has not been validated for use in bariatric surgery, which is a major limitation to its use in this clinical context. Our study undertook a psychometric validation of the 5 level EQ-5D (EQ-5D-5L) using clinical trial data to measure health-related quality of life in patients with severe and complex obesity undergoing bariatric surgery. Health-related quality of life was assessed at baseline (before randomisation) and six months later in 189 patients in a randomised controlled trial of bariatric surgery. Patients completed two generic health-related quality of life instruments, the EQ-5D-5L and SF-12, which were used together for the validation using data from all patients in the trial as the trial is ongoing. Psychometric analyses included construct and criterion validity and responsiveness to change. Of the 189 validation patients, 141 (75%) were female, the median age was 49 years old (range 23-70 years) and body mass index ranged from 33-70 kg/m2. For construct validity, there were significant improvements in the distribution of responses in all EQ-5D dimensions between baseline and 6 months after randomisation. For criterion validity, the highest degree of correlation was between the EQ-5D pain/discomfort and SF-12 bodily pain domain. For responsiveness the EQ-5D and SF 12 showed statistically significant improvements in health-related quality of life between baseline and 6 months after randomisation. The EQ-5D-5L is a valid generic measure for measuring health-related quality of life in bariatric surgery patients. PMID- 29252997 TI - The unsteady state and inertia of chemical regulation under the US Toxic Substances Control Act. AB - After 40 years, the 1976 US Toxic Substances Control Act (TSCA) was revised under the Frank R. Lautenberg Chemical Safety for the 21st Century Act. Its original goals of protecting the public from hazardous chemicals were hindered by complex and cumbersome administrative burdens, data limitations, vulnerabilities in risk assessments, and recurring corporate lawsuits. As a result, countless chemicals were entered into commercial use without toxicological information. Few chemicals of the many identified as potential public health threats were regulated or banned. This paper explores the factors that have worked against a comprehensive and rational policy for regulating toxic chemicals and discusses whether the TSCA revisions offer greater public protection against existing and new chemicals. PMID- 29252998 TI - Near-zero methane emission from an abandoned boreal peatland pasture based on eddy covariance measurements. AB - Although estimates of the annual methane (CH4) flux from agriculturally managed peatlands exist, knowledge of controls over the variation of CH4 at different time-scales is limited due to the lack of high temporal-resolution data. Here we present CH4 fluxes measured from May 2014 to April 2016 using the eddy covariance technique at an abandoned peatland pasture in western Newfoundland, Canada. The goals of the study were to identify the controls on the seasonal variations in CH4 flux and to quantify the annual CH4 flux. The seasonal variation in daily CH4 flux was not strong in the two study years, however a few periods of pronounced emissions occurred in the late growing season. The daily average CH4 flux was small relative to other studies, ranging from -4.1 to 9.9 nmol m-2 s-1 in 2014-15 and from -7.1 to 12.1 nmol m-2 s-1 in 2015-16. Stepwise multiple regression was used to investigate controls on CH4 flux and this analysis found shifting controls on CH4 flux at different periods of the growing season. During the early growing season CH4 flux was closely related to carbon dioxide fixation rates, suggesting substrate availability was the main control. The peak growing season CH4 flux was principally controlled by the CH4 oxidation in 2014, where the CH4 flux decreased and increased with soil temperature at 50 cm and soil water content at 10 cm, but a contrasting temperature-CH4 relation was found in 2015. The late growing season CH4 flux was found to be regulated by the variation in water table level and air temperature in 2014. The annual CH4 emission was near zero in both study years (0.36 +/- 0.30 g CH4 m-2 yr-1 in 2014-15 and 0.13 +/- 0.38 g CH4 m-2 yr-1 in 2015-16), but fell within the range of CH4 emissions reported for agriculturally managed peatlands elsewhere. PMID- 29252999 TI - Distinct kinetics of inhibitory currents in thalamocortical neurons that arise from dendritic or axonal origin. AB - Thalamocortical neurons in the dorsal lateral geniculate nucleus (dLGN) transfer visual information from retina to primary visual cortex. This information is modulated by inhibitory input arising from local interneurons and thalamic reticular nucleus (TRN) neurons, leading to alterations of receptive field properties of thalamocortical neurons. Local GABAergic interneurons provide two distinct synaptic outputs: axonal (F1 terminals) and dendritic (F2 terminals) onto dLGN thalamocortical neurons. By contrast, TRN neurons provide only axonal output (F1 terminals) onto dLGN thalamocortical neurons. It is unclear if GABAA receptor-mediated currents originating from F1 and F2 terminals have different characteristics. In the present study, we examined multiple characteristics (rise time, slope, halfwidth and decay tau) of GABAA receptor-mediated miniature inhibitory postsynaptic synaptic currents (mIPSCs) originating from F1 and F2 terminals. The mIPSCs arising from F2 terminals showed slower kinetics relative to those from F1 terminals. Such differential kinetics of GABAAR-mediated responses could be an important role in temporal coding of visual signals. PMID- 29253000 TI - Variations in eco-enzymatic stoichiometric and microbial characteristics in paddy soil as affected by long-term integrated organic-inorganic fertilization. AB - To investigate the effects of different nutrient management regimes on the soil chemical, eco-enzymatic stoichiometric and microbial characteristics, soil samples were collected from a 30-year, long-term field experiment with six plots growing rice. The results showed that as integrated fertilization increased, so did the concentrations of soil total or available nutrients and microbial biomass carbon (MBC). Our results also found enhanced soil basal respiration and cumulative carbon mineralization compared to chemical fertilization alone at the same nutrient doses. The activities of soil protease (Pro), beta-glucosidase (betaG), N-acetyl-glucosaminidase (NAG) and acid phosphatase (AP) from the integrated fertilization treatments were significantly higher than those of the treatments without organic manure, so did the activities of soil leucyl aminopeptidase (LAP) and urease (Ure) from the treatment with organic manure in addition to farmer practise fertilization (NPKM2). The stoichiometric ratios, expressed as lnbetaG/ln(NAG+LAP)/lnPro/lnUre/lnAP, ranged from 1:0.94:1.04:0.67:1.01 to 1:0.98:1.10:0.78:1.25, indicating that the acquisition of C, N and P changed consistently and synchronously under different nutrient management strategies. Integrated fertilization was more beneficial to the acquisition and utilization of soil organic carbon compared to low-molecular weight organic nitrogen. We concluded that protease and urease should be considered in eco-enzymatic stoichiometric assessments for the hydrolysis of proteins, amino acids, carbohydrates and phosphomonoesters in soil, and integrated fertilization with chemical fertilizers and organic manure should be recommended as a preferable nutrient management system for intensive rice cultivation. PMID- 29253001 TI - Five-year study of the effects of simulated nitrogen deposition levels and forms on soil nitrous oxide emissions from a temperate forest in northern China. AB - Few studies have quantified the effects of different levels and forms of nitrogen (N) deposition on soil nitrous oxide (N2O) emissions from temperate forest soils. A 5-year field experiment was conducted to investigate the effects of multiple forms and levels of N additions on soil N2O emissions, by using the static closed chamber method at Xi Mountain Experimental Forest Station in northern China. The experiment included a control (no N added), and additions of NH4NO3, NaNO3, and (NH4)2SO4 that each had two levels: 50 kg N ha-1 yr-1 and 150 kg N ha-1 yr-1. All plots were treated to simulate increased N deposition on a monthly schedule during the annual growing season (March to October) and soil N2O emissions were measured monthly from March 2011 to February 2016. Simultaneously, the temperature, moisture, and inorganic N contents of soil were also measured to explore how the main factors may have affected soil N2O emission. The results showed that the types and levels of N addition significantly increased soil inorganic N contents, and the accumulation of soil NO3--N was significantly higher than that of soil NH4+-N due to N addition. The three N forms significantly increased the average N2O emissions (P < 0.05) in the order of NH4NO3 > (NH4)2SO4 > NaNO3 by 355.95%, 266.35%, and 187.71%, respectively, compared with control. The promotion of N2O emission via the NH4+-N addition was significantly more than that via the NO3--N addition, while N addition at a high level exerted a stronger effect than at the low-level. N addition exerted significantly stronger effects on cumulative N2O emissions in the initial years, especially the third year when the increased cumulative N2O emission reached their maximum. In the later years, the increases persisted but were weakened. Increasing inorganic N concentration could change soil from being N-limited to N rich, and then N-saturated, and so the promotion on soil available N effect increased and then decreased. Moreover, the soil NH4+-N, NO3--N, temperature, and water-filled pore space were all positively correlated with soil N2O emissions. These findings suggest that atmospheric N deposition can significantly promote soil N2O emission, and that exogenous NH4+-N and NO3--N inputs into temperate forests can have synergic effects on soil N2O emission. In future research, both aspects should be better distinguished in the N cycle and balance of terrestrial ecosystems by using 15N tracer methods. PMID- 29253002 TI - Incidence and progression of myopia and associated factors in urban school children in Delhi: The North India Myopia Study (NIM Study). AB - AIM: To evaluate the incidence and progression of myopia and factors associated with progression of myopia in school going children in Delhi. METHODS: Prospective longitudinal study of 10,000 school children aged 5 to 15 years screened after an interval of 1 year to identify new myopes (Spherical Equivalent<= -0.5D) and progression of myopia in previously diagnosed myopic children. Association between risk factors and progression was analyzed using adjusted odds ratio. RESULTS: Of the 9,616 children re-screened (97.3% coverage), annual incidence of myopia was 3.4%with mean dioptric change of -1.09 +/- 0.55. There was a significant higher incidence of myopia in younger children compared to older children (P = 0.012) and among girls compared to boys (P = 0.002). Progression was observed in 49.2%children with mean dioptric change of -0.27 +/- 0.42 diopters. The demographic and behavioral risk factors were analyzed for children with progression (n = 629) and adjusted odds ratio values were estimated. Hours of reading-writing/week (p<0.001), use of computers/ video games (P<0.001) and watching television (P = 0.048) were significant risk factors for progression of myopia. Outdoor activities / time spent outdoors> 2 hours in a day were protective with an inverse association with progression of myopia (P< 0.001). CONCLUSION: Myopia is an important health issue in India and is associated with long hours of reading and screen time with use of computers and video games. An annual eye vision screening should be conducted, and outdoor activities be promoted to prevent the increase of myopia among school children. PMID- 29253003 TI - Aedes aegypti resistance development to commonly used insecticides in Jakarta, Indonesia. AB - Aedes aegypti is the primary vector of various relevant arthropod-borne viral infectious diseases worldwide. The mosquito control is still mainly performed by using insecticides but their effectiveness is increasingly questioned nowadays. We here conducted a study on Ae. aegypti resistance development towards several commonly used insecticides in the capital city of Jakarta, Indonesia. In order to achieve this goal, Ae. aegypti eggs from Jakarta were collected with ovitraps and hatched in the insectary of the Gadjah Mada University, Indonesia. The F0 generations were used for WHO resistance tests and knockdown resistance (kdr) assays. Presented results clearly showed that there was resistance development of Ae. aegypti populations to the here tested pyrethroid insecticides (i. e. permethrin). Observed mortalities were less than 90% with highest resistance against 0.75% permethrin concentrations. Furthermore, a significant association of V1016G gene mutations with resistance phenotypes to 0.75% permethrin was observed. Nevertheless, the F1534C mutation did not show a significant correlation to resistance development. In conclusion, our results show that populations of Ae. aegypti mosquitoes within the city of Jakarta have developed resistance against several routinely used pyrethroid insecticides in local performed control programs. Thus, the regular verification/assessment of resistance development status will hopefully help in the future to assist local public health authorities in their mosquito control programs by recommending and managing the rotation of different routinely used insecticides with diverse effector mechanisms in order to delay Ae. aegypti resistance development. PMID- 29253004 TI - Driving anger and its relationships with type A behavior patterns and trait anger: Differences between professional and non-professional drivers. AB - The present study examined the types of situations that caused Chinese professional and non-professional drivers to become angry and investigated the differences in driving-elicited anger, considering the influences of type A behavior pattern and trait anger between the two groups. The 20-item revised Driving Anger Scale (DAS) was used to assess a sample of 232 drivers (57% professional, 43% non-professional). The non-professional drivers reported significantly higher levels of anger than the professional drivers on the overall Driving Anger Scale (DAS) and the traffic obstructions and discourtesy subscales. In both groups, the preferred driving speeds were positively related to driving anger. Furthermore, drivers with a type A personality exhibited higher overall driving anger scores and higher anger scores in response to traffic obstructions and slow driving than drivers with a type B personality. Trait anger was significantly related to driving anger in both groups. In the non-professional group, type A behavior patterns (TABPs) and time hurry (TH) were positively correlated with anger evoked by slow driving. In the professional group, TABPs, TH and competitive hostility (CH) were positively related to driving anger, and the TABPs exerted an indirect effect on driving anger by mediating the influence of trait anger. Overall, these findings provide a theoretical basis for implementing targeted interventions for driving anger in both professional and non-professional drivers. PMID- 29253005 TI - Association between osteoprotegerin gene T950C polymorphism and osteoporosis risk in the Chinese population: Evidence via meta-analysis. AB - Osteoporosis has been reported to be at least partially developed in response to functional polymorphisms of the osteoprotegerin (OPG). However, conflicting results have been found. This meta-analysis aimed to provide an assessment of the relationship between the risk for developing osteoporosis and OPG T950C polymorphism in the Chinese population. Studies to be analyzed were identified with the literature search in PubMed, Embase, Web of Science, the Cochrane Library, and the Chinese National Knowledge Infrastructure during May 2017. Seven case-control studies that included a total of 1850 osteoporosis cases and 3074 controls were assessed in this meta-analysis. Overall, no significant associations could be detected between OPG T950C polymorphism and osteoporosis when all included studies were pooled into this meta-analysis. In a subgroup analyses, OPG T950C polymorphism was significantly associated with the osteoporosis risk in South China (CC+TC vs. TT: OR = 1.34, 95% CI = 1.17-1.54; CC vs. TC+TT: OR = 0.79, 95% CI = 0.69-0.95) and for studies that included postmenopausal osteoporosis (CC vs. TC+TT: OR = 0.78, 95% CI = 0.64-0.94) or hospital-based controls (CC vs. TC+TT: OR = 0.81, 95% CI = 0.68-0.96). In conclusion, the results of this meta-analysis suggest that OPG T950C polymorphism might be associated with an increased osteoporosis risk in the Chinese population. PMID- 29253006 TI - Linear distributed source modeling of local field potentials recorded with intra cortical electrode arrays. AB - Planar intra-cortical electrode (Utah) arrays provide a unique window into the spatial organization of cortical activity. Reconstruction of the current source density (CSD) underlying such recordings, however, requires "inverting" Poisson's equation. For inter-laminar recordings, this is commonly done by the CSD method, which consists in taking the second-order spatial derivative of the recorded local field potentials (LFPs). Although the CSD method has been tremendously successful in mapping the current generators underlying inter-laminar LFPs, its application to planar recordings is more challenging. While for inter-laminar recordings the CSD method seems reasonably robust against violations of its assumptions, is it unclear as to what extent this holds for planar recordings. One of the objectives of this study is to characterize the conditions under which the CSD method can be successfully applied to Utah array data. Using forward modeling, we find that for spatially coherent CSDs, the CSD method yields inaccurate reconstructions due to volume-conducted contamination from currents in deeper cortical layers. An alternative approach is to "invert" a constructed forward model. The advantage of this approach is that any a priori knowledge about the geometrical and electrical properties of the tissue can be taken into account. Although several inverse methods have been proposed for LFP data, the applicability of existing electroencephalographic (EEG) and magnetoencephalographic (MEG) inverse methods to LFP data is largely unexplored. Another objective of our study therefore, is to assess the applicability of the most commonly used EEG/MEG inverse methods to Utah array data. Our main conclusion is that these inverse methods provide more accurate CSD reconstructions than the CSD method. We illustrate the inverse methods using event-related potentials recorded from primary visual cortex of a macaque monkey during a motion discrimination task. PMID- 29253007 TI - Hypertonic saline attenuates the cytokine-induced pro-inflammatory signature in primary human lung epithelia. AB - Trauma/hemorrhagic shock is a complex physiological phenomenon that leads to dysregulation of many molecular pathways. For over a decade, hypertonic saline (HTS) has been used as an alternative resuscitation fluid in the setting of trauma/hemorrhagic shock. In addition to restoring circulating volume within the vascular space, studies have shown a positive immunomodulatory effect of HTS. Targeted studies have shown that HTS affects the transcription of several pro inflammatory cytokines by inhibiting the NF-kappaB-IkappaB pathway in model cell lines and rats. However, few studies have been undertaken to assess the unbiased effects of HTS on the whole transcriptome. This study was designed to interrogate the global transcriptional responses induced by HTS and provides insight into the underlying molecular mechanisms and pathways affected by HTS. In this study, RNA sequencing was employed to explore early changes in transcriptional response, identify key mediators, signaling pathways, and transcriptional modules that are affected by HTS in the presence of a strong inflammatory stimulus. Our results suggest that primary human small airway lung epithelial cells (SAECS) exposed to HTS in the presence and absence of a strong pro-inflammatory stimulus exhibit very distinct effects on cellular response, where HTS is highly effective in attenuating cytokine-induced pro-inflammatory responses via mechanisms that involve transcriptional regulation of inflammation which is cell type and stimulus specific. HTS is a highly effective anti-inflammatory agent that inhibits the chemotaxis of leucocytes towards a pro-inflammatory gradient and may attenuate the progression of both the innate and adaptive immune response. PMID- 29253008 TI - Molecular dynamics simulation unveils the conformational flexibility of the interdomain linker in the bacterial transcriptional regulator GabR from Bacillus subtilis bound to pyridoxal 5'-phosphate. AB - GabR from Bacillus subtilis is a transcriptional regulator belonging to the MocR subfamily of the GntR regulators. The structure of the MocR regulators is characterized by the presence of two domains: i) a N-terminal domain, about 60 residue long, possessing the winged-Helix-Turn-Helix (wHTH) architecture with DNA recognition and binding capability; ii) a C-terminal domain (about 350 residue) folded as the pyridoxal 5'-phosphate (PLP) dependent aspartate aminotransferase (AAT) with dimerization and effector binding functions. The two domains are linked to each other by a peptide bridge. Although structural and functional characterization of MocRs is proceeding at a fast pace, virtually nothing is know about the molecular changes induced by the effector binding and on how these modifications influence the properties of the regulator. An extensive molecular dynamics simulation on the crystallographic structure of the homodimeric B. subtilis GabR has been undertaken with the aim to envisage the role and the importance of conformational flexibility in the action of GabR. Molecular dynamics has been calculated for the apo (without PLP) and holo (with PLP bound) forms of the GabR. A comparison between the molecular dynamics trajectories calculated for the two GabR forms suggested that one of the wHTH domain detaches from the AAT-like domain in the GabR PLP-bound form. The most evident conformational change in the holo PLP-bound form is represented by the rotation and the subsequent detachment from the subunit surface of one of the wHTH domains. The movement is mediated by a rearrangement of the linker connecting the AAT domain possibly triggered by the presence of the negative charge of the PLP cofactor. This is the second most significant conformational modification. The C terminal section of the linker docks into the "active site" pocket and establish stabilizing contacts consisting of hydrogen-bonds, salt-bridges and hydrophobic interactions. PMID- 29253009 TI - Crystal structures of H-2Db in complex with the LCMV-derived peptides GP92 and GP392 explain pleiotropic effects of glycosylation on antigen presentation and immunogenicity. AB - Post-translational modifications significantly broaden the epitope repertoire for major histocompatibility class I complexes (MHC-I) and may allow viruses to escape immune recognition. Lymphocytic choriomeningitis virus (LCMV) infection of H-2b mice generates CD8+ CTL responses directed towards several MHC-I-restricted epitopes including the peptides GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL), both with a N-glycosylation site. Interestingly, glycosylation has different effects on the immunogenicity and association capacity of these two epitopes to H-2Db. To assess the structural bases underlying these functional results, we determined the crystal structures of H-2Db in complex with GP92 (CSANNSHHYI) and GP392 (WLVTNGSYL) to 2.4 and 2.5 A resolution, respectively. The structures reveal that while glycosylation of GP392 most probably impairs binding, the glycosylation of the asparagine residue in GP92, which protrudes towards the solvent, possibly allows for immune escape and/or forms a neo-epitope that may select for a different set of CD8 T cells. Altogether, the presented results provide a structural platform underlying the effects of post-translational modifications on epitope binding and/or immunogenicity, resulting in viral immune escape. PMID- 29253010 TI - Phenotypic characterization of adenomyosis occurring at the inner and outer myometrium. AB - OBJECTIVE: To estimate the phenotypic characterization of fibrotic process in adenomyosis occurring at the inner or the outer myometrium. METHODS: Eight cases of adenomyosis occurring at the inner myometrium (Subtype I) and 10 cases of adenomyosis occurring at the outer myometrium (Subtype II), and 10 normal counterparts were used in this study. A immunohistochemical study for smooth muscle cells (SMCs) was performed using cytoskeletal proteins, Type I and III collagen, TGF-beta and its signaling molecules. RESULTS: An increased expression of Type I collagen was observed in the extracellular matrix of adenomyotic foci. In normal uteri, immunostaining of SMC differentiation marker proteins (Desmin, Smoothelin, Myosin heavy chain (MHC)) were absent or only found in low numbers at the inner myometrium, while all of these marker proteins were clearly stained at the outer myometrium. In both types of adenomyotic foci, Desmin, Smoothelin, and MHC commonly showed a negative staining at the adjacent area to the glands. A significant staining of Non-muscle myosin IIB, TGF-beta, and phosphorylated TGF beta type I receptors were found only at the SMCs of Subtype II adenomyosis. The Smad3/2 ratio of Subtype II adenomyosis was significantly higher than that of Subtype I. CONCLUSIONS: The inner myometrium of normal uteri was composed of undifferentiated phenotypes of SMCs, while the outer myometrium was composed of terminally differentiated SMCs. Various fibrotic processes have been suggested in the development of uterine adenomyosis. Distinct expression patterns of fibrosis related proteins have been shown to be implicated with differences in the subtypes of adenomyosis. PMID- 29253011 TI - An exploration of needs and preferences for dietary support in colorectal cancer survivors: A mixed-methods study. AB - PURPOSE: To describe the proportion of colorectal cancer (CRC) survivors who perceive a need for dietary support; to examine which socio-demographic, cancer related, and health-related characteristics are associated with this need; to explore reasons for (not) needing support; and to explore CRC survivors' specific needs and preferences with regard to lifestyle (i.e., dietary, exercise, and/or weight management) support. METHODS: This mixed-methods study comprised a cross sectional survey among 1774 Dutch CRC survivors and three focus groups (n = 16). To examine associations, logistic regression analyses were conducted. Focus groups were audio-taped, transcribed verbatim, and analyzed using a thematic approach. RESULTS: Of 1458 respondents (82%), 1198 (67.5%) were included for analyses. 17.5% reported a need for dietary support. Characteristics associated with this need were: being younger, living without a partner, having a stoma, having diabetes, and being overweight or obese. The main reason for needing support was being unable to initiate and maintain lifestyle changes without support. CRC survivors preferred receiving information soon after diagnosis to make an autonomous, informed decision on improving their lifestyle. They preferred to receive individually-tailored lifestyle support in an autonomy supportive environment, preferably with involvement of their family and fellow sufferers. CONCLUSIONS: This study has provided knowledge on appropriate support for CRC survivors in need for dietary support to improve health outcomes by promoting adherence to lifestyle and body weight recommendations. Findings can be used to better identify CRC survivors in need for dietary support, and to tailor lifestyle support to their needs and preferences in order to promote uptake, adherence, and effectiveness. PMID- 29253012 TI - Synchrotron macro ATR-FTIR microspectroscopic analysis of silica nanoparticle embedded polyester coated steel surfaces subjected to prolonged UV and humidity exposure. AB - Surface modification of polymers and paints is a popular and effective way to enhance the properties of these materials. This can be achieved by introducing a thin coating that preserves the bulk properties of the material, while protecting it from environmental exposure. Suitable materials for such coating technologies are inorganic oxides, such as alumina, titania and silica; however, the fate of these materials during long-term environmental exposure is an open question. In this study, polymer coatings that had been enhanced with the addition of silica nanoparticles (SiO2NPs) and subsequently subjected to environmental exposure, were characterized both before and after the exposure to determine any structural changes resulting from the exposure. High-resolution synchrotron macro ATR-FTIR microspectroscopy and surface topographic techniques, including optical profilometry and atomic force microscopy (AFM), were used to determine the long term effect of the environment on these dual protection layers after 3 years of exposure to tropical and sub-tropical climates in Singapore and Queensland (Australia). Principal component analysis (PCA) based on the synchrotron macro ATR-FTIR spectral data revealed that, for the 9% (w/w) SiO2NP/polymer coating, a clear discrimination was observed between the control group (no environmental exposure) and those samples subjected to three years of environmental exposure in both Singapore and Queensland. The PCA loading plots indicated that, over the three year exposure period, a major change occurred in the triazine ring vibration in the melamine resins. This can be attributed to the triazine ring being very sensitive to hydrolysis under the high humidity conditions in tropical/sub-tropical environments. This work provides the first direct molecular evidence, acquired using a high-resolution mapping technique, of the climate induced chemical evolution of a polyester coating. The observed changes in the surface topography of the coating are consistent with the changes in chemical composition. PMID- 29253013 TI - Impact of optic disc hemorrhage on subsequent glaucoma progression in mild-to moderate myopia. AB - PURPOSE: To investigate optic disc hemorrhage (DH)'s clinical implications to subsequent progression of primary open-angle glaucoma (POAG) in cases of mild-to moderate myopia. DESIGN: Retrospective comparative study. PARTICIPANTS: (1) Fifty nine (59) myopic (26.5 mm > axial length [AXL] >= 24.0 mm) POAG patients with DH and (2) 59 age-, AXL-, and mean deviation (MD) of visual field (VF)-matched controls without DH were evaluated over the course of a minimum 3.5 years of follow up. For clear assessment of the effect of DH on progression of glaucoma, the patients selected for inclusion in the study were those with stable IOP (i.e., those showing an at least 20% reduction relative to the baseline IOP) whose IOP-lowering medication was not increased, supplemented or changed during the follow-up period. METHODS: The patients' optic disc/retinal nerve fiber layer (RNFL) photographs were independently evaluated by three glaucoma specialists for structural progression of glaucoma. Event-based analysis with Guided Progression Analysis (GPA) software was used to determine their functional progression. The durations of structural and functional progression were compared by Kaplan-Meier life survival analyses. MAIN OUTCOME MEASURES: Optic disc/RNFL progression and VF progression. RESULTS: The mean follow-up periods between the DH and non-DH groups were not significantly different: in the DH group, 5.6+/-2.7 years; in the non-DH group, 5.4+/-2.6 years (P = 0.588). In the DH group, 30 (50.8%) of 59 eyes manifested optic disc/RNFL deterioration; in the non-DH group, however, only 17 (28.8%) of 59 eyes showed structural progression. For the DH group, the cumulative probability of structural glaucoma progression was significantly greater than for the non-DH group (P = 0.001; log rank test). Interestingly, the two groups did not significantly differ in the cumulative probability of functional progression (P = 0.79; log rank test): in the DH group, VF progression was observed in 14 eyes (23.7%); in the non-DH group, in 12 eyes (20.3%). CONCLUSIONS: DH was associated with a greater probability of structural progression in medically well-controlled-IOP POAG eyes with mild-to-moderate myopia. However, the relevance of DH to VF progression was not clear over the course of the average 5.5-year duration of the study. PMID- 29253014 TI - Socioeconomic status and biomedical risk factors in migrants and native tuberculosis patients in Italy. AB - Action on social determinants is a main component of the World Health Organization End Tuberculosis (TB) Strategy. The aim of the study was to collect information on socioeconomic characteristics and biomedical risk factors in migrant TB patients in Italy and compare it with data collected among Italian TB patients. A cross-sectional study was conducted among TB patients aged >=18 years over a 12-months enrolment period in 12 major Italian hospitals. Information on education, employment, housing and income was collected, and European Union Statistics on Income and Living Conditions index was used to assess material deprivation. Among migrants, we also analyzed factors associated with severe material deprivation. Migrants were compared with younger (18-64 years) and older (65+ years) Italians patients. Out of 755 patients enrolled (with a median age of 42 years, interquartile range: 31-53), 65% were migrants. Pulmonary, microbiologically confirmed, and new cases were 80%, 73%, and 87% respectively. Prevalence of co-morbidities (i.e. diabetes, chronic kidney disease, neoplastic diseases and use of immunosuppressive drugs) was lower among migrants compared to Italian TB patients, while indicators of socioeconomic status, income and housing conditions were worst in migrants. Forty-six percent of migrants were severely deprived vs. 9% of Italians (p<0.0001, 11.3% and 5.5% among younger and older Italians, respectively). Among migrants, being male, older, irregular, unemployed, with a shorter time spent in Italy, a lower education level, and without a co-morbidity diagnosis were factors associated with severe material deprivation at multi-variable logistic regression. Moreover, socioeconomic indicators for Italian patients did not differ from those reported for the general Italian population, while migrant TB patients seem to have a higher prevalence of severe material deprivation than other migrants residing in Italy. Intervention to address the needs of this population are urgent. PMID- 29253015 TI - Genetic variability of environmental sensitivity revealed by phenotypic variation in body weight and (its) correlations to physiological and behavioral traits. AB - Adaptive phenotypic plasticity is a key component of the ability of organisms to cope with changing environmental conditions. Fish have been shown to exhibit a substantial level of phenotypic plasticity in response to abiotic and biotic factors. In the present study, we investigate the link between environmental sensitivity assessed globally (revealed by phenotypic variation in body weight) and more targeted physiological and behavioral indicators that are generally used to assess the sensitivity of a fish to environmental stressors. We took advantage of original biological material, the rainbow trout isogenic lines, which allowed the disentangling of the genetic and environmental parts of the phenotypic variance. Ten lines were characterized for the changes of body weight variability (weight measurements taken every month during 18 months), the plasma cortisol response to confinement stress (3 challenges) and a set of selected behavioral indicators. This study unambiguously demonstrated the existence of genetic determinism of environmental sensitivity, with some lines being particularly sensitive to environmental fluctuations and others rather insensitive. Correlations between coefficient of variation (CV) for body weight and behavioral and physiological traits were observed. This confirmed that CV for body weight could be used as an indicator of environmental sensitivity. As the relationship between indicators (CV weight, risk-taking, exploration and cortisol) was shown to be likely depending on the nature and intensity of the stressor, the joint use of several indicators should help to investigate the biological complexity of environmental sensitivity. PMID- 29253016 TI - Skeletal muscle IL-6 regulates muscle substrate utilization and adipose tissue metabolism during recovery from an acute bout of exercise. AB - An acute bout of exercise imposes a major challenge on whole-body metabolism and metabolic adjustments are needed in multiple tissues during recovery to reestablish metabolic homeostasis. It is currently unresolved how this regulation is orchestrated between tissues. This study was undertaken to clarify the role of skeletal muscle derived interleukin 6 (IL-6) in the coordination of the metabolic responses during recovery from acute exercise. Skeletal muscle specific IL-6 knockout (IL-6 MKO) and littermate Control mice were rested or ran on a treadmill for 2h. Plasma, skeletal muscle, liver and adipose tissue were obtained after 6 and 10h of recovery. Non-exercised IL-6 MKO mice had higher plasma lactate and lower plasma non-esterified fatty acids than Controls. The activity of pyruvate dehydrogenase in the active form was, in skeletal muscle, higher in IL-6 MKO mice than Controls in non-exercised mice and 6h after exercise. IL-6 MKO mice had lower glucose transporter 4 protein content in inguinal adipose tissue (WAT) than Control in non-exercised mice and 10h after treadmill running. Epididymal WAT hormone sensitive lipase phosphorylation and inguinal WAT mitogen activated kinase P38 phosphorylation were higher in IL-6 MKO than Control mice 6h after exercise. These findings indicate that skeletal muscle IL-6 may play an important role in the regulation of substrate utilization in skeletal muscle, basal and exercise-induced adaptations in adipose tissue glucose uptake and lipolysis during recovery from exercise. Together this indicates that skeletal muscle IL-6 contributes to reestablishing metabolic homeostasis during recovery from exercise by regulating WAT and skeletal muscle metabolism. PMID- 29253017 TI - Investigation on the morphological and optical evolution of bimetallic Pd-Ag nanoparticles on sapphire (0001) by the systematic control of composition, annealing temperature and time. AB - Multi-metallic alloy nanoparticles (NPs) can offer additional opportunities for modifying the electronic, optical and catalytic properties by the control of composition, configuration and size of individual nanostructures that are consisted of more than single element. In this paper, the fabrication of bimetallic Pd-Ag NPs is systematically demonstrated via the solid state dewetting of bilayer thin films on c-plane sapphire by governing the temperature, time as well as composition. The composition of Pd-Ag bilayer remarkably affects the morphology of alloy nanostructures, in which the higher Ag composition, i.e. Pd0.25Ag0.75, leads to the enhanced dewetting of bilayers whereas the higher Pd composition (Pd0.75Ag0.25) hinders the dewetting. Depending on the annealing temperature, Pd-Ag alloy nanostructures evolve with a series of configurations, i.e. nucleation of voids, porous network, elongated nanoclusters and round alloy NPs. In addition, with the annealing time set, the gradual configuration transformation from the elongated to round alloy NPs as well as size reduction is demonstrated due to the enhanced diffusion and sublimation of Ag atoms. The evolution of various morphology of Pd-Ag nanostructures is described based on the surface diffusion and inter-diffusion of Pd and Ag adatoms along with the Ag sublimation, Rayleigh instability and energy minimization mechanism. The reflectance spectra of bimetallic Pd-Ag nanostructures exhibit various quadrupolar and dipolar resonance peaks, peak shifts and absorption dips owing to the surface plasmon resonance of nanostructures depending on the surface morphology. The intensity of reflectance spectra is gradually decreased along with the surface coverage and NP size evolution. The absorption dips are red shifted towards the longer wavelength for the larger alloy NPs and vice-versa. PMID- 29253019 TI - Detection and validation of predictors of successful extubation in critically ill children. AB - INTRODUCTION: Availability of objective criteria for predicting successful extubation could avoid unnecessary prolongation of mechanical ventilation and/or inadvertent premature extubation, but the predictors of successful extubation in children are unclear. This study was performed to detect and validate respiratory function predictors of successful extubation in children admitted to the pediatric critical care unit. METHODS: A retrospective chart review from 2010 to 2012 identified 463 patients, who were divided into a derivation cohort (n = 294) and a validation cohort (n = 169). RESULTS: The incidence rate of failed extubation was 5% and 9% in the derivation and validation cohorts, respectively. The optimal cut-off values of crying vital capacity (CVC), peak inspiratory flow rate (PIFR), and maximum inspiratory pressure (MIP) were 17 ml/kg, 3.5 ml/sec/cm, and 50 cmH2O, respectively. The pass rates of CVC, PIFR, and MIP were 54.2%, 92.7%, and 55.5%, respectively. In the validation cohort, the successful extubation rate was 97.9% for patients who passed all 3 respiratory tests, 88.8% for those who passed at least one test, and 66.7% for those who failed all of the tests. Extubation failed in 5 patients who passed all three respiratory tests and failure was due to postoperative respiratory muscle fatigue or upper airway impairment. CONCLUSIONS: We detected and validated predictors of successful extubation in critically ill children. A combination of CVC, PIFR, and MIP may be used to predict successful extubation for critically ill children. It is necessary to pay attention when extubating patients with postoperative respiratory muscle fatigue or upper airway impairment due to disturbance of consciousness and/or glottal edema even if they pass the respiratory function tests. PMID- 29253018 TI - New roles for nuclear EGFR in regulating the stability and translation of mRNAs associated with VEGF signaling. AB - Cell membrane-associated epidermal growth factor receptor (EGFR) translocates into a perinuclear/nuclear location upon stimulation, where it complexes with mRNAs. Treatment with radiation and cisplatin decreases the amounts of mRNAs present within this complex. Gene array analyses of mRNAs in complex with immunoprecipitated nEGFR revealed significant enrichment of different mRNA species compared to the control immunoprecipitation. Functional annotation with help of DAVID Gene Ontology Analysis identified under other terms the HIF-1A/VEGF signaling pathway as one of the top scoring KEGG pathways. RT-PCR and western blots revealed the radiation-induced expression of mRNAs and proteins involved in HIF-1A/VEGF signaling. Simultaneously, the levels of the corresponding validated miRNAs within the complex containing nEGFR and mRNAs were decreased. This finding argues that an mRNA/miRNA/nEGFR complex regulates protein expression. Indeed, we detected the GW182, AGO2, PABPC1 and cNOT1 proteins, which belong to the deadenylase complex, in a complex with nuclear EGFR. Erlotinib-mediated inhibition of EGFR kinase reduced the radiation-induced increase in mRNA expression. In this context, erlotinib reduced AGO2 phosphorylation by the EGFR kinase at residue Y393, which was associated with increased cNOT1 deadenylase activity and reduced mRNA stability. To prove the roles of miRNAs in this context, we transfected cells with an inhibitor of Hsa-mir-1180p5, which targets the NFATC4 mRNA, an mRNA associated with VEGF signaling, or pretreated cells with erlotinib. Indeed, Hsa-mir-1180p5 knockdown increased and the erlotinib treatment decreased the expression of the NFATC4 protein. The expression of the NFATC4 protein controlled the cloning efficiency and radiosensitivity of A549 and FaDu tumor cells. Thus, this study is the first to show that a membrane-located tyrosine kinase receptor, such as EGFR, is internalized to a nuclear/perinuclear location upon exposure to stress and modulates the stability and translation of miRNA-selected mRNAs. This mechanism enables cells to directly express proteins in response to EGFR activation and may contribute to treatment resistance in EGFR overexpressing tumors. PMID- 29253020 TI - Abnormal neural activation patterns underlying working memory impairment in chronic phencyclidine-treated mice. AB - Working memory impairment is a hallmark feature of schizophrenia and is thought be caused by dysfunctions in the prefrontal cortex (PFC) and associated brain regions. However, the neural circuit anomalies underlying this impairment are poorly understood. The aim of this study is to assess working memory performance in the chronic phencyclidine (PCP) mouse model of schizophrenia, and to identify the neural substrates of working memory. To address this issue, we conducted the following experiments for mice after withdrawal from chronic administration (14 days) of either saline or PCP (10 mg/kg): (1) a discrete paired-trial variable delay task in T-maze to assess working memory, and (2) brain-wide c-Fos mapping to identify activated brain regions relevant to this task performance either 90 min or 0 min after the completion of the task, with each time point examined under working memory effort and basal conditions. Correct responses in the test phase of the task were significantly reduced across delays (5, 15, and 30 s) in chronic PCP-treated mice compared with chronic saline-treated controls, suggesting delay-independent impairments in working memory in the PCP group. In layer 2-3 of the prelimbic cortex, the number of working memory effort-elicited c Fos+ cells was significantly higher in the chronic PCP group than in the chronic saline group. The main effect of working memory effort relative to basal conditions was to induce significantly increased c-Fos+ cells in the other layers of prelimbic cortex and the anterior cingulate and infralimbic cortex regardless of the different chronic regimens. Conversely, this working memory effort had a negative effect (fewer c-Fos+ cells) in the ventral hippocampus. These results shed light on some putative neural networks relevant to working memory impairments in mice chronically treated with PCP, and emphasize the importance of the layer 2-3 of the prelimbic cortex of the PFC. PMID- 29253021 TI - Correction: HLA Class I and Class II Associations with ESRD in Saudi Arabian Population. AB - [This corrects the article DOI: 10.1371/journal.pone.0111403.]. PMID- 29253022 TI - Identification of ?-amino acid-containing peptides in human serum. AB - Biologically uncommon d-aspartate (d-Asp) residues have been shown to accumulate in proteins associated with age-related human disorders, such as cataract and Alzheimer disease. Such d-Asp-containing proteins are unlikely to be broken down completely because metabolic enzymes recognize only proteins or peptides composed exclusively of l-amino acids. Therefore, undigested d-Asp-containing peptides may exist in blood and, if detectable, may be a useful biomarker for associated diseases. In this study, we investigated d-amino acid-containing peptides in adult human serum by a qualitative d-amino acid analysis based on a diastereomer method and LC-MS/MS method. As a result, two d-Asp-containing peptides were detected in serum, both derived from the fibrinogen beta-chain, a glycoprotein that helps in the formation of blood clots. One of the peptides was fibrinopeptide B, which prevents fibrinogen from forming polymers of fibrin, and the other was same peptide with C-terminal Arginine missing. To our knowledge, this is the first report of the presence of d-amino acid-containing peptides in serum and the approach described will provide a new direction on the serum proteome and fragmentome. PMID- 29253023 TI - Antiepileptic drug use among women from the Taiwanese Registry of Epilepsy and Pregnancy: Obstetric complications and fetal malformation outcomes. AB - To investigate antiepileptic drugs (AEDs) prescription and pregnancy outcomes in pregnancies with epilepsy in Taiwan between 2004 and 2015. We retrospectively reviewed data from the Taiwanese Registry of Epilepsy and Pregnancy (TREP). The TREP registry is a voluntary prospective cohort registry, which tracks pregnant women with epilepsy and AED prescription throughout pregnancy, delivery, and early childhood development. All TREP pregnancies (n = 318) that had completed questionnaires up until delivery or had had an unsuccessful pregnancy were analyzed. Over 94.7% of women had been prescribed AEDs during pregnancy, with 69.0% and 25.7% having received monotherapy, or polytherapy, respectively. Among live births, 12 (3.9%) reported malformation. Cesarean section rate was reported higher than usual (54.5%). In 2004, 73.3% of AEDs prescribed were 1st generation, with 1st generation prescription rates falling to only 8.3% of total prescribed in 2015. AED polytherapy also fell during the study period (40.0% to 20.0%). Cesarean sections were found to be higher for women over 35 years, who had generalized epilepsy, or had experienced an obstetric complication during pregnancy term. Binary logistic regression revealed that Cesarean section was associated with maternal complications (OR = 5.11, CI 95% = 1.11-23.51, p = 0.036), while malformations were associated with obstetric complication (OR = 20.46, CI 95% = 4.80-87.21, p<0.001). Both AED risk types were not associated with complications or malformations. Our sample provides a unique insight into the women with epilepsy with AED use during pregnancy. Cesarean section rate was observed to be higher than usual, but malformation rates remained low. Results indicate a decrease in both 1st generation AEDs and proportion of patients receiving polytherapy over the study period. Obstetric complications were associated with Cesarean section. Fetal malformations were significantly associated with obstetric complications. AED risk factors were not significantly associated with either complications or malformations. PMID- 29253024 TI - Complementarity determining regions and frameworks contribute to the disulfide bond independent folding of intrinsically stable scFv. AB - CyDisCo is a system facilitating disulfide bond formation in recombinant proteins in the cytoplasm of Escherichia coli. Previously we screened for soluble expression of single chain antibody fragments (scFv) in the cytoplasm of E. coli in the presence and absence of CyDisCo, with >90% being solubly expressed. Two scFv, those derived from natalizumab and trastuzumab, were solubly produced in high amounts even in the absence of folding catalysts i.e. disulfide bond formation is not critical for their folding. Here we investigate the contribution of the framework and the complementarity determining regions (CDRs) of scFv to the disulfide-independence of folding. We swapped CDRs between four scFv that have different properties, including two scFv that can efficiently fold independently from disulfide bonds and two more disulfide-dependent scFv. To confirm disulfide-independence we generated cysteine to alanine mutants of the disulfide-independent scFv. All of the scFv were tested for soluble expression in the cytoplasm of E. coli in the presence and absence of the oxidative folding catalysts Erv1p and PDI. Eight of the hybrid scFv were solubly produced in the presence of CyDisCo, while seven were solubly produced in the absence of CyDisCo, though the yields were often much lower when CyDisCo was absent. Soluble expression was also observed for scFv natalizumab and trastuzumab containing no cysteines. We compared yields, thermal stability and secondary structure of solubly produced scFv and undertook binding studies by western blotting, dot blotting or surface plasmon resonance of those produced in good yields. Our results indicate that both the CDRs and the framework contribute to the disulfide dependence of soluble production of scFv, with the CDRs having the largest effect. In addition, there was no correlation between thermal stability and disulfide-dependence of folding and only a weak correlation between the yield of protein and the thermal stability of the protein. PMID- 29253025 TI - The statistical mechanics of human weight change. AB - Over the past 35 years there has been a near doubling in the worldwide prevalence of obesity. Body Mass Index (BMI) distributions in high-income societies have increasingly shifted rightwards, corresponding to increases in average BMI that are due to well-studied changes in the socioeconomic environment. However, in addition to this shift, BMI distributions have also shown marked changes in their particular shape over time, exhibiting an ongoing right-skewed broadening that is not well understood. Here, we compile and analyze the largest data set so far of year-over-year BMI changes. The data confirm that, on average, heavy individuals become lighter while light individuals become heavier year-over-year, and also show that year-over-year BMI evolution is characterized by fluctuations with a magnitude that is linearly proportional to BMI. We find that the distribution of human BMIs is intrinsically dynamic-due to the short-term variability of human weight-and its shape is determined by a balance between deterministic drift towards a natural set point and diffusion resulting from random fluctuations in, e.g., diet and physical activity. We formulate a stochastic mathematical model for BMI dynamics, deriving a theoretical shape for the BMI distribution and offering a mechanism that may explain the right-skewed broadening of BMI distributions over time. An extension of the base model investigates the hypothesis that peer-to-peer social influence plays a role in BMI dynamics. While including this effect improves the fit with the data, indicating that correlations in the behavior of individuals with similar BMI may be important for BMI dynamics, testing social transmission against other plausible unmodeled effects and interpretations remains the subject of future work. Implications of our findings on the dynamics of BMI distributions for public health interventions are discussed. PMID- 29253026 TI - Genetic variation and factors affecting the genetic structure of the lichenicolous fungus Heterocephalacria bachmannii (Filobasidiales, Basidiomycota). AB - Heterocephalacria bachmannii is a lichenicolous fungus that takes as hosts numerous lichen species of the genus Cladonia. In the present study we analyze whether the geographical distance, the host species or the host secondary metabolites determine the genetic structure of this parasite. To address the question, populations mainly from the Southern Europe, Southern Finland and the Azores were sampled. The specimens were collected from 20 different host species representing ten chemotypes. Three loci, ITS rDNA, LSU rDNA and mtSSU, were sequenced. The genetic structure was assessed by AMOVA, redundance analyses and Bayesian clustering methods. The results indicated that the host species and the host secondary metabolites are the most influential factors over the genetic structure of this lichenicolous fungus. In addition, the genetic structure of H. bachmannii was compared with that of one of its hosts, Cladonia rangiformis. The population structure of parasite and host were discordant. The contents in phenolic compounds and fatty acids of C. rangiformis were quantified in order to test whether it had some influence on the genetic structure of the species. But no correlation was found with the genetic clusters of H. bachmannii. PMID- 29253027 TI - A computational study on outliers in world music. AB - The comparative analysis of world music cultures has been the focus of several ethnomusicological studies in the last century. With the advances of Music Information Retrieval and the increased accessibility of sound archives, large scale analysis of world music with computational tools is today feasible. We investigate music similarity in a corpus of 8200 recordings of folk and traditional music from 137 countries around the world. In particular, we aim to identify music recordings that are most distinct compared to the rest of our corpus. We refer to these recordings as 'outliers'. We use signal processing tools to extract music information from audio recordings, data mining to quantify similarity and detect outliers, and spatial statistics to account for geographical correlation. Our findings suggest that Botswana is the country with the most distinct recordings in the corpus and China is the country with the most distinct recordings when considering spatial correlation. Our analysis includes a comparison of musical attributes and styles that contribute to the 'uniqueness' of the music of each country. PMID- 29253028 TI - The JAK2/STAT3 inhibitor pacritinib effectively inhibits patient-derived GBM brain tumor initiating cells in vitro and when used in combination with temozolomide increases survival in an orthotopic xenograft model. AB - PURPOSE: The prognosis for patients diagnosed with glioblastoma multiforme (GBM) remains dismal, with current treatment prolonging survival only modestly. As such, there remains a strong need for novel therapeutic strategies. The janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 pathway regulates many cellular processes in GBM, including survival, proliferation, invasion, anti-apoptosis, and immune evasion. Here, we evaluated the preclinical efficacy of pacritinib, a novel compound targeting JAK2, using a collection of diverse patient-derived brain tumor initiating cells (BTICs). EXPERIMENTAL DESIGN: The effects of pacritinib on BTIC viability and sphere forming capacity were evaluated in vitro using the alamarBlue and neurosphere assays, respectively. On-target inhibition of JAK2/STAT3 signaling was investigated using western blotting. The efficacy of pacritinib was tested in vivo in pharmacokinetic analyses, liver microsome analyses, and Kaplan-Meier survival studies. RESULTS: In vitro, pacritinib decreased BTIC viability and sphere forming potential at low micromolar doses and demonstrated on-target inhibition of STAT3 signaling. Additionally, pacritinib was found to improve the response to temozolomide (TMZ) in TMZ-resistant BTICs. In vivo, systemic treatment with pacritinib demonstrated blood-brain barrier penetration and led to improved overall median survival in combination with TMZ, in mice orthotopically xenografted with an aggressive recurrent GBM BTIC culture. CONCLUSION: This preclinical study demonstrates the efficacy of pacritinib and supports the feasibility of testing pacritinib for the treatment of GBM, in combination with the standard of care TMZ. PMID- 29253029 TI - Sleep-wake functions and quality of life in patients with subthalamic deep brain stimulation for Parkinson's disease. AB - OBJECTIVES: Sleep-wake disturbances (SWD) are frequent in Parkinson's disease (PD). The effect of deep brain stimulation (DBS) on SWD is poorly known. In this study we examined the subjective and objective sleep-wake profile and the quality of life (QoL) of PD patients in the context of subthalamic DBS. PATIENTS AND METHODS: We retrospectively analyzed data from PD patients and candidates for DBS in the nucleus suthalamicus (STN). Pre-DBS, sleep-wake assessments included subjective and objective (polysomnography, vigilance tests and actigraphy) measures. Post-DBS, subjective measures were collected. QoL was assessed using the Parkinson's Disease Questionnaire (PDQ-39) and the RAND SF-36-item Health Survey (RAND SF-36). RESULTS: Data from 74 PD patients (62% male, mean age 62.2 years, SD = 8.9) with a mean UPDRS-III (OFF) of 34.2 (SD = 14.8) and 11.8 (SD = 4.5) years under PD treatment were analyzed. Pre-DBS, daytime sleepiness, apathy, fatigue and depressive symptoms were present in 49%, 34%, 38% and 25% of patients respectively but not always as co-occurring symptoms. Sleep-wake disturbances were significantly correlated with QoL scores. One year after STN DBS, motor signs, QoL and sleepiness improved but apathy worsened. Changes in QoL were associated with changes in sleepiness and apathy but baseline sleep-wake functions were not predictive of STN DBS outcome. CONCLUSION: In PD patients presenting for STN DBS, subjective and objective sleep-wake disturbances are common and have a negative impact on QoL before and after neurosurgery. Given the current preliminary evidence, prospective observational studies assessing subjective and objective sleep-wake variables prior to and after DBS are needed. PMID- 29253030 TI - Comparisons of auditory brainstem response and sound level tolerance in tinnitus ears and non-tinnitus ears in unilateral tinnitus patients with normal audiograms. AB - OBJECTIVE: Recently, "hidden hearing loss" with cochlear synaptopathy has been suggested as a potential pathophysiology of tinnitus in individuals with a normal hearing threshold. Several studies have demonstrated that subjects with tinnitus and normal audiograms show significantly reduced auditory brainstem response (ABR) wave I amplitudes compared with control subjects, but normal wave V amplitudes, suggesting increased central auditory gain. We aimed to reconfirm the "hidden hearing loss" theory through a within-subject comparison of wave I and wave V amplitudes and uncomfortable loudness level (UCL), which might be decreased with increased central gain, in tinnitus ears (TEs) and non-tinnitus ears (NTEs). SUBJECTS AND METHODS: Human subjects included 43 unilateral tinnitus patients (19 males, 24 females) with normal and symmetric hearing thresholds and 18 control subjects with normal audiograms. The amplitudes of wave I and V from the peak to the following trough were measured twice at 90 dB nHL and we separately assessed UCLs at 500 Hz and 3000 Hz pure tones in each TE and NTE. RESULTS: The within-subject comparison between TEs and NTEs showed no significant differences in wave I and wave V amplitude, or wave V/I ratio in both the male and female groups. Individual data revealed increased V/I amplitude ratios > mean + 2 SD in 3 TEs, but not in any control ears. We found no significant differences in UCL at 500 Hz or 3000 Hz between the TEs and NTEs, but the UCLs of both TEs and NTEs were lower than those of the control ears. CONCLUSIONS: Our ABR data do not represent meaningful evidence supporting the hypothesis of cochlear synaptopathy with increased central gain in tinnitus subjects with normal audiograms. However, reduced sound level tolerance in both TEs and NTEs might reflect increased central gain consequent on hidden synaptopathy that was subsequently balanced between the ears by lateral olivocochlear efferents. PMID- 29253031 TI - Gender-specific factors associated with the use of mental health services for suicidal ideation: Results from the 2013 Korean Community Health Survey. AB - This study examined gender-specific factors associated with the use of mental health services (MHS) for suicidal ideation (SI). We included data on 6,768 males and 12,475 females who had experienced SI over the past year from the nationwide 2013 Korean Community Health Survey. These individuals were grouped as MHS users for SI if they had received professional counseling at medical institutions, professional counseling agencies, or community health centers for SI-related problems. Their information on sociodemographic factors, socio-familial relationships, health behaviors, and health status were included as exposures in a logistic regression analysis. Of the 19,243 individuals, 7.0% of the males and 10.5% of the females used MHS for SI treatment. For males with SI, living in an urban area, being a widower, and having unhealthy behaviors (frequent alcohol consumption and infrequent walking) were associated with underuse of MHS. For females with SI, frequent contact with friends, low level of religious activity, and good self-rated health were associated with underuse of MHS. For both males and females, those who were younger, completed higher education, and experienced depression/suicide attempts in the past year were more likely to use MHS for SI. These findings suggest that gender-specific factors should be used to inform suicide prevention strategies. PMID- 29253032 TI - Estimates of insulin sensitivity and beta-cell function in children and adolescents with and without components of the metabolic syndrome. AB - INTRODUCTION: The accumulation of components of the metabolic syndrome (MetS) is associated with a disturbed glucose metabolism in obese children. AIM OF STUDY: The aim of the present study was to evaluate the association between MetS and estimates of insulin sensitivity and beta-cell function obtained from oral glucose tolerance test (OGTT)-derived indices in lean and obese children. MATERIAL AND METHODS: A 2-hour OGTT was administered in 83 children aged 7-17 years. 47 children were obese and recruited from a childhood obesity clinic and 36 were lean age- and sex-matched controls. Surrogate measures of insulin sensitivity and beta-cell function were assessed by the OGTT-derived indices: the Matsuda index, the insulinogenic index, and the oral disposition index. The severity of MetS was assessed by measures of waist circumference, blood pressure, and fasting levels of triglycerides, high-density lipoprotein cholesterol, and glucose. RESULTS: The 83 children were allocated to one of three groups according to the number of components of MetS: the median body mass index standard deviation score was 0.2 (range -0.6-2.9) in the low MetS risk group (n=36), 2.8 (0.1-4.1) in the high MetS risk group (n=25), and 2.9 (2.1-4.4) in the MetS group (n=22). An increasing number of MetS components were associated with a lower insulin sensitivity and an altered beta-cell function according to the Matsuda index (p<0.0001), the insulinogenic index (p<0.0001), and the oral disposition index (p=0.005). CONCLUSIONS: Children burdened by the accumulation of components of MetS exhibited a disturbed glucose metabolism as expressed by lowered peripheral insulin sensitivity and beta-cell function. PMID- 29253033 TI - Assessment of preservation of beta-cell function in children with long-standing type 1 diabetes with "ultrasensitive c-peptide" method. AB - INTRODUCTION: Type 1 diabetes mellitus is a disease caused by the autoimmune destruction of pancreatic beta-cells. It was previously believed that the loss of the endocrine function of the pancreas is total and inevitable. With the rise of new knowledge and new methods allowing to reliably measure c-peptide in the low plasma concentration range, we have learned otherwise. Some residual function of the beta-cells can be present even after decades of the course of the disease. The aim of the study was to evaluate the c-peptide level with routine laboratory and ultrasensitive methods in children with long-standing type 1 diabetes in relation to clinical characteristics. METHODS: We recruited 178 consecutive children with type 1 diabetes mellitus lasting at least 1 year, mean diabetes duration was 5.6 years. Basic anthropometric measurements were performed and blood samples were drawn. From patients history records we gathered data regarding the course of the disease and laboratory results previously acquired. Laboratory tests performed on the blood samples included HbA1c levels and c peptide level measurement using classic (n=178) and ultrasensitive (n=160) method (Mercodia). Clinically relevant c-peptide level was set at 0.23 ng/ml according to the DCCT recommendations. RESULTS: Clinically relevant c-peptide was found in 54 of 160 (33.75%) patients. Patients with preserved c-peptide were older at the time of diagnosis, had longer clinical remission, and required lower total and basal doses of insulin. Significantly lower mean HbA1c from the last year, but higher HbA1c at the time of the diabetes diagnosis were found in the group with higher c-peptide levels. The comparison of the classic and ultrasensitive c peptide tests revealed that both yield similar results. CONCLUSIONS: Our observation shows that 34% of young patients with long-standing type 1 diabetes have prolonged c-peptide secretion. We confirm the long-standing assumption that residual beta-cell function is beneficial for metabolic control of the patients. Classic method of the c-peptide measurement can be just as useful in clinical practice as the ultrasensitive one. PMID- 29253034 TI - Coexisting psoriasis affects the clinical course of type 1 diabetes in children. AB - INTRODUCTION: Literature reports link psoriasis with insulin resistance characteristic for type 2 diabetes. However, this condition may also affect the clinical course of type 1 diabetes (T1D). AIM: To investigate whether children with type 1 diabetes mellitus (T1D) and psoriasis have a different course of diabetes. METHODS: We evaluated patients diagnosed with T1D in the years 2002 2011 for the presence of psoriasis and matched them 1:10 with T1D-only patients by sex and duration of diabetes using propensity score. We collected T1D-onset parameters and metabolic control surrogates from six months after T1D diagnosis. RESULTS: We identified 14 patients with psoriasis and matched 140 controls, of whom 129 (68 boys) were eligible for the analysis. At onset T1D+psoriasis patients showed higher concentration of C-peptide than controls (median: 0.38ng/ml vs 0.15ng/ml, p=0.02). Six months later, they had non-significantly lower HbA1c (6.0 vs 6.6%, p=0.11), TC (143mg/dl vs 159mg/dl, p=0.14) HDL (54.5mg/dl vs 59mg/dl, p=0.11). CONCLUSIONS: Patients with T1D and psoriasis present higher endogenous insulin secretion at T1D onset and a tendency for better glycemic control during the first 6 months. PMID- 29253035 TI - History of endocrinology in the world and in Poland. AB - Endocrinology is a branch of medicine dealing with the functioning of endocrine glands. Theain role of the endocrine glands is to control various functions and to adopt internal environment to changes in the external environment. Glands manage to do this by regulating the metabolism of target cells by hormones. One of the earliest connections with endocrinology is found in theHippocratic humoral hypothesis dating about 400 years BC. The author of the first endocrinological observations was Aristotle, who noticed changes in behavior and appearance in castrated roosters. In the Middle Ages winners of battles ate their enemies organs, such as the heart, brain, or gonads, believing that they were a source of special power.However, the last two centuries were a time of intensive development of the research in this field. Certainly, we can now look to the future awaiting the next breakthroughs that will revolutionize today's perception of endocrinology. PMID- 29253036 TI - [Prevention of overweight and obesity in children and adolescents in European countries]. AB - In the 21st century the occurrence of overweight and obesity in children and adolescents reaches the size of a global epidemic. It is recommended to promote a healthy lifestyle and, above all, to educate children, adolescents and adults about the dangerous consequences of being overweight or obese. It is crucial for prevention programs to comprise educational activities so that the participants are encouraged to change their lifestyle for better. However, it must be borne in mind that the overall effectiveness of such activities is determined by the commitment of both the obese child and the environment - the school or kindergarten and the media. Only integrated efforts can increase patients' awareness and reverse the growing trend in incidence of obesity around the world. This work discusses the current knowledge of overweight and obesity in children and adolescents, as well as the methods of prevention applied in various European countries. The analysis was based on up-to-date epidemiological data available in PubMed, Scopus, and Google Scholar databases. PMID- 29253037 TI - [Myasthenia gravis, Graves-Basedow disease and other autoimmune diseases in patient with diabetes type 1 - APS-3 case report, therapeutic complications]. AB - Diabetes type 1(T1D) is the most frequent form of diabetes in children and young people, which essence is autoimmune destruction of pancreatic B cells islet. Co occurrence of other autoimmune diseases is observed in children with T1D, the most often are: Hashimoto disease or coeliac disease. We report the case of the patient, who presents coincidence of T1D with other rare autoimmune diseases such as: Graves - Basedow disease, myasthenia gravis, vitiligo and IgA deficiency. All mentioned diseases significantly complicated both endocrine and diabetic treatment of our patient and they negatively contributed her quality of life. The clinical picture of the case allows to recognize one of the autoimmune polyendocrine syndromes: APS-3 and is associated with still high risk of developing another autoimmune disease. PMID- 29253038 TI - [Difficulties of the therapy in a boy with coexisting type 1 diabetes mellitus and idiopathic thrombocytopenic purpura]. AB - Idiopathic thrombocytopenic purpura (ITP) is an acquired autoimmune disease, caused by antibodies against platelet glycoproteins, which provoke platelet destruction and inhibit platelet production in bone marrow. Type 1 Diabetes Mellitus (T1DM) is an acquired autoimmune disease in witch beta cells are destroyed by autoantibodies. Patient with T1DM since the age of 6, was treated by intensive functional insulin therapy by insulin pump. At the age of 14,5 he was also diagnosed with ITP. Due to the short effect of immunoglobulin therapy, glucocorticoids were introduced. After 3 months of glucocorticotherapy the platelet count was 46 G/l. Patient developed various adverse effects of glucocorticoids, among others stretch marks covering all surface of his abdomen, buttocks, arms and thighs and raise in the daily requirement of insulin by 200%. Adverse effects of glucocorticotherapy made impossible the therapy by insulin pump and imposed urgent revision of the ITP therapy. Side effects of the glucocorticotherapy can make impossible the treatment by insulin pump of T1DM in children. PMID- 29253039 TI - The Research of Dishevelled-2 in Dental Implant Osseointegration of Hyperlipidemic Rats. AB - PURPOSE: To investigate the influence of dishevelled-2 (Dvl2) protein and the phosphorylation and ubiquitination of Dvl2 on dental implant osseointegration in hyperlipidemic rats. MATERIALS AND METHODS: Thirty-six Wistar rats were divided equally into two groups: an experimental group fed with a high-fat diet for 8 weeks and a control group fed with a normal diet for 8 weeks. Serum lipids were detected, and titanium implants were placed into bilateral proximal metaphysis of rats' femurs. At 1, 3, and 5 days after implantation, rats were sacrificed, and 1 mm of bone around each implant was obtained. Real-time polymerase chain reaction of runt-related transcription factor 2 (Runx2), Cathepsin K, and Dvl2 was performed. Western blot of Dvl2, phosphorylation, and ubiquitination of Dvl2 was also performed. RESULTS: In the experimental group, the expressions of Runx2, Dvl2, and phosphorylation of Dvl2 were lower (P < .05), while that of Cathepsin K and ubiquitination of Dvl2 were higher than those in the control group (P < .05). CONCLUSION: Hyperlipidemia suppressed the dental implant osseointegration. This inhibition may be modulated by downregulated Dvl2, phosphorylation of Dvl2, and upregulated ubiquitination of Dvl2. PMID- 29253040 TI - The Feasibility of Flapless Approach to Sinus Augmentation Using an Implant Device Designed According to Residual Alveolar Ridge Height. AB - Hydraulic sinus lift and augmentation may be successfully performed using a dedicated implant device designed according to residual bone height (RBH). The aim of this study was to evaluate whether a flapless surgical approach might negatively influence the outcome. A total of 40 consecutive patients (16 men and 24 women) were included in the study, 20 in each group (minimal flap/control versus flapless/study). Inclusion criteria were >= 3 mm RBH, >= 6 mm width of the residual alveolar ridge according to preoperative cone beam computerized tomography, and >= 8 mm buccopalatal keratinized gingiva for the flapless group. Primary outcome parameters included intraoperative membrane perforation. Secondary outcome parameters included postoperative infection, soft tissue healing, bone gain, and short-term dental implant survival. Mean RBH was 4.6 mm. No intraoperative membrane perforations and no postoperative infections were observed. Mean bone gain height was similar for both groups, at 11 mm. Soft tissue healing was observed within 2 months. In all cases, second-stage surgery allowed generation of at least 2 mm of keratinized gingiva buccally. All implants were osseointegrated at second-stage surgery. The use of a flapless approach to maxillary sinus augmentation using an implant device based on RBH yields predictable results. PMID- 29253041 TI - The Use of CAD/CAM Cobalt-Chromium Framework to Optimize Subgingival Prosthetic Contours and Improve Esthetics: Anterior Mandibular Case Reports. AB - Although implant therapy in esthetically relevant areas is currently based on a prosthetically driven philosophy, anatomical and technical factors may impair ideal implant placement. In these scenarios, the clinician is frequently asked to solve the discrepancy between the implant emergence and the ideal coronal anatomy of the final restoration. This report describes how changes of the implant abutment-crown contour in specific locations may be intentionally promoted to determine improvements of the peri-implant soft tissues and overall esthetic integration. Cobalt-chromium alloys together with computer-aided design/computer assisted manufacture technologies are critical factors in achieving this goal. Case reports for the mandibular anterior dentition demonstrated the ability to enhance biologic and esthetic results of malpositioned implants. PMID- 29253042 TI - A farewell from the Editor. PMID- 29253043 TI - Heterotopic pancreas located in the ileum. PMID- 29253044 TI - Pancreatic gangliocytic paraganglioma - CEUS appearance. PMID- 29253045 TI - Pneumatosis cystoides intestinalis in a patient with ulcerative colitis. PMID- 29253046 TI - Intubation failure during gastroscopy: incidence, predictors and follow-up findings. AB - BACKGROUND: Intubation failure (IF) occurs when an endoscopist is unable to progress via the oropharynx into the upper oesophagus. AIM: To assess incidence and aetiology of IF and predictors of structural pharyngeal abnormalities in patients with IF. METHODS: All gastroscopies (n=26,130) performed in our centre, between August 2010 and August 2016 were retrospectively reviewed. Barium radiology and repeat gastroscopy findings were evaluated for structural causes of IF. Patients were categorised into 'failure to tolerate' and 'failure to progress' based on endoscopy reports. RESULTS: The incidence of IF was 0.95%. Rates of IF varied with endoscopist specialty (p=0.021), but not with patient age, sex or sedation dose. Among cases of IF, structural pharyngeal abnormalities were detected on barium radiology in 28.9%, consisting of cricopharyngeal hypertrophy and/or Zenker's diverticulum in 73.2%. 'Failure to progress' predicted pharyngeal pathology in 55.6%. Predictors of structural causes on barium radiology following IF included: age >/=65 (OR 4.0, 95% CI: 1.8-8.9, p<0.001); indication of dysphagia (OR 5.5, 95% CI: 2.5-11.8, p<0.001), and failure of endoscopic progression (OR 5.2, 95% CI: 2.3-12.0, p<0.001). CONCLUSION: Patients with IF should be investigated owing to the high risk of underlying pathology, particularly if associated with age >/=65, dysphagia, and failure of endoscopic progression. We propose that IF rates of <1% could be used as a quality indicator in gastroscopy. PMID- 29253047 TI - Adherence to an acotiamide therapeutic regimen improves long-term outcomes in patients with functional dyspepsia. AB - BACKGROUND AND AIMS: Long-term outcomes in patients with functional dyspepsia remain elusive. Acotiamide, a prokinetic drug, has been available in Japan since 2013. The aim of this study was to assess long-term outcomes in patients with functional dyspepsia treated with acotiamide. METHODS: We retrospectively reviewed 79 consecutive patients with functional dyspepsia whose symptoms improved with acotiamide therapy and who were followed for more than one year. All patients underwent esophagogastroduodenoscopy prior to acotiamide therapy. The mean follow-up was 1.9 (range, 1.0-3.3) years. We assessed the patients' symptom severity using the Izumo scale, which reflects changes in various abdominal symptoms. RESULTS: At one year, dyspepsia symptoms recurred in 25% (20/79) of the patients. In multivariate analysis, severe dyspepsia was significantly associated with increased recurrence (odds ratio [OR] 15.04, 95% confidence interval [CI] 1.73-130.47, p=0.013). Continued use of acotiamide for one year diminished the recurrence of dyspepsia symptoms significantly (OR 0.16, 95%CI 0.04-0.61, p=0.006). The influence of these significant predictors on long term outcomes was analyzed using the Kaplan-Meier method. Patients with severe dyspepsia before starting acotiamide had significantly more recurrences than those with mild symptoms (p=0.004, log-rank test). Patients who continued acotiamide therapy throughout the follow-up period had significantly fewer recurrences than those who stopped therapy (p<0.001). CONCLUSIONS: Over the long term, patients with functional dyspepsia have a considerable rate of recurrence of dyspepsia. Severe dyspepsia before treatment increases the recurrence rates, while adherence to an acotiamide therapeutic regimen decreases recurrence rate. PMID- 29253048 TI - The Orientation of Gastric Biopsy Samples Improves the Inter-observer Agreement of the OLGA Staging System. AB - BACKGROUND AND AIMS: Evaluation of severity and extension of gastric atrophy and intestinal metaplasia is recommended to identify subjects with a high risk for gastric cancer. The inter-observer agreement for the assessment of gastric atrophy is reported to be low. The aim of the study was to evaluate the inter observer agreement for the assessment of severity and extension of gastric atrophy using oriented and unoriented gastric biopsy samples. Furthermore, the quality of biopsy specimens in oriented and unoriented samples was analyzed. METHODS: A total of 35 subjects with dyspeptic symptoms addressed for gastrointestinal endoscopy that agreed to enter the study were prospectively enrolled. The OLGA/OLGIM gastric biopsies protocol was used. From each subject two sets of biopsies were obtained (four from the antrum, two oriented and two unoriented, two from the gastric incisure, one oriented and one unoriented, four from the gastric body, two oriented and two unoriented). The orientation of the biopsy samples was completed using nitrocellulose filters (Endokit(r), BioOptica, Milan, Italy). The samples were blindly examined by two experienced pathologists. Inter-observer agreement was evaluated using kappa statistic for inter-rater agreement. The quality of histopathology specimens taking into account the identification of lamina propria was analyzed in oriented vs. unoriented samples. The samples with detectable lamina propria mucosae were defined as good quality specimens. Categorical data was analyzed using chi-square test and a two-sided p value <0.05 was considered statistically significant. RESULTS: A total of 350 biopsy samples were analyzed (175 oriented / 175 unoriented). The kappa index values for oriented/unoriented OLGA 0/I/II/III and IV stages have been 0.62/0.13, 0.70/0.20, 0.61/0.06, 0.62/0.46, and 0.77/0.50, respectively. For OLGIM 0/I/II/III stages the kappa index values for oriented/unoriented samples were 0.83/0.83, 0.88/0.89, 0.70/0.88 and 0.83/1, respectively. No case of OLGIM IV stage was found in the present case series. Good quality histopathology specimens were described in 95.43% of the oriented biopsy samples, and in 89.14% of the unoriented biopsy samples, respectively (p=0.0275). CONCLUSION: The orientation of gastric biopsies specimens improves the inter-observer agreement for the assessment of gastric atrophy. PMID- 29253049 TI - A Comparative Study of White Light Endoscopy, Chromoendoscopy and Magnifying Endoscopy with Narrow Band Imaging in the Diagnosis of Early Gastric Cancer after Helicobacter pylori Eradication. AB - BACKGROUND AND AIM: Early-stage gastric cancer (EGC) found after H. pylori eradication often has non-tumorous epithelium on the tumorous tissue and/or surface differentiation of tumors, which may confuse endoscopic and histologic diagnosis. We investigated the diagnostic reliability of EGC using conventional white light endoscopy (WLE), chromoendoscopy (CE) using indigo carmine, and magnifying endoscopy with narrow band imaging (ME-NBI) in patients with EGC with or without history of prior H. pylori eradication therapy. METHODS: Diagnostic reliability of EGC by using the WLE, CE and ME-NBI was investigated in 71 EGC lesions diagnosed after successful H. pylori eradication (eradication group) and 115 EGC lesions with current H. pylori infection (control group). RESULTS: Diagnostic reliability of EGC was lower in the eradication group than in the control group using all three modalities. In particular, the diagnostic accuracy of CE in the eradication group was especially lower compared to that of the control group (WLE: 74.6% vs. 86.1%, P=0.05; CE: 64.8% vs. 91.3%, P<0.0001; ME NBI: 88.7% vs. 98.2%, P=0.01). The ME-NBI scored better in comparison with WLE and CE in the eradication group (both P<0.05). The indistinct EGC lesions in the eradicated group by using CE were associated with the presence of histological changes such as non-tumorous epithelium on the tumor and/or surface differentiation of tumors (P=0.005). CONCLUSIONS: It should be noted that the diagnostic reliability of EGC after H. pylori eradication becomes lower especially using CE. Indistinguishable cases using CE are associated with histological findings such as non-tumorous epithelium on the tumor and/or surface differentiation of tumors. PMID- 29253050 TI - Risk Factors for Delayed Ulcer Healing after Endoscopic Submucosal Dissection of Gastric Neoplasms. AB - BACKGROUND AND AIMS: With improved technology, the size of artificial ulcers after endoscopic submucosal dissection (ESD) has increased. The aim of our study was to examine the risk factors for delayed gastric ulcer healing after ESD, including the possible benefit of potassium-competitive acid blocker (P-CAB) treatment. METHODS: The primary outcome was the rate of healing of the artificial ulcers induced by ESD at 8 weeks post intervention. Design - retrospective case series. Setting - Aichi Medical University Hospital. Patients - patients who underwent ESD for gastric neoplasm, between April 2015 and March 2017. Intervention - ESD, with a follow-up endoscopic examination at 8 weeks post-ESD. Univariate and multivariate analyses were used to identify the independent risk factors for delayed healing. RESULTS: Of the 73 gastric neoplasms included in the analysis, delayed ulcer healing was identified in 21.9%. Dyslipidemia (p=0.04), ESD procedure time (p=0.003) and artificial ulcer size (p<0.001) were identified as risk factors for delayed healing, with location in the lower third of the stomach [Odds ratio (OR) 6.76; p=0.016] and artificial ulcer size (OR, 1.18; p=0.024) retained as independent risk factors. A cut-off ulcer size of 854 mm2 was predictive of delayed healing, with a sensitivity of 29.8% and specificity of 87.5%. For large ulcers, the rate of healing of 70% with vonoprazan was higher than the rate of 47.6% with proton pump inhibitors (PPIs), although this difference was not significant. CONCLUSION: For artificial ulcers after ESD with a resection diameter >35 mm, it might be desirable to use PPIs for >8 weeks or P CAB. PMID- 29253051 TI - Refractory Anaemia Secondary to Small Bowel Angioectasias - Comparison between Endotherapy Alone versus Combination with Somatostatin Analogues. AB - BACKGROUND AND AIMS: Patients with small bowel angioectasias (SBAs) can be difficult to manage as they are generally elderly with multiple co-morbidities. Angioectasias are multiple and tend to recur. Argon plasma coagulation (APC), despite being a commonly used method to treat these patients has an associated persistent rate of re-bleeding necessitating additional treatment to manage these patients. METHODS: All patients with refractory iron deficiency anaemia secondary to SBAs were retrospectively subdivided into two groups. Patients in group 1 were managed with double balloon enteroscopy (DBE) and APC alone and those in group 2 received Lanreotide in addition to DBE and APC. RESULTS: A total of 49 patients were included in this study: group 1: 37 patients (75.5%), group 2: 12 patients (24.5%). All had significant comorbidities and the mean duration of anaemia was 114.3, SD 307.0 months. Significant improvements in haemoglobin (Hb) (11g/L vs 3.2g/L p=0.043), transfusion requirements per month (0.8 vs 4.7 p=0.052) and mean bleeding episodes (1.08 vs 2.6 p=0.032) were demonstrated in group 2 when compared to group 1. One patient developed symptomatic gallstone disease and one patient stopped Lanreotide due to a lack of response. CONCLUSIONS: This is the first study comparing endotherapy to a combination of endotherapy and pharmacotherapy. It shows a significantly better outcome in patients receiving a combination of endotherapy and Lanreotide. Lanreotide can be a safe additional treatment in patients not responding to APC alone. PMID- 29253052 TI - Managing Successful Pregnancies in Patients with Chronic Intestinal Failure on Home Parenteral Nutrition: Experience from a UK National Intestinal Failure Unit. AB - BACKGROUND AND AIM: There are minimal reports of pregnancy in the chronic intestinal failure (CIF)/ home parenteral nutrition (HPN) population, with some concern relating to the risk associated with such pregnancies. The aim of this retrospective observational study was to evaluate pregnancy experience and outcomes in patients with CIF requiring HPN in a national UK CIF referral centre. METHOD: All known pregnancies in patients treated with HPN for CIF between 1982 and 2016 were identified retrospectively from a prospectively maintained database. Maternal and foetal outcomes were collated, along with PN requirements before and during pregnancy. RESULTS: There were 5 pregnancies in 5 mothers in our cohort consisting of over 700 patients, males and females. The median age at conception was 28 years (range 24-33 years). The median duration on HPN prior to pregnancy was 26 months (range 4-85 months). One patient had Crohn's disease, another had pan-enteric dysmotility and the other three patients had ischaemic complications leading to short bowel syndrome (SBS). All mothers were intensively monitored in an obstetric clinic and a dedicated CIF multi-disciplinary clinic throughout pregnancy. There were 2/5 preterm deliveries. One of the preterm deliveries was associated with spontaneous labour and the other had a planned induction as a result of maternal clinical need. Neonatal complications were seen in both prenates. There were no recorded maternal catheter related line infections during the 5 pregnancies. CONCLUSION: Successful pregnancy whilst receiving HPN is feasible but requires close, intensive monitoring and dedicated optimisation of PN in order to minimise maternal and foetal complications. All women of child-bearing age on HPN should be counselled about pregnancy. PMID- 29253053 TI - New Epidemiologic Data Regarding Hepatitis C Virus Infection in Romania. AB - BACKGROUND AND AIMS: Literature data suggest that HCV genotype-1b is present in 93-99% of the Romanian patients infected with hepatitis C virus (HCV). We present the genotyping tests recently performed on patients with HCV and advanced fibrosis eligible for the Direct-Acting Antiviral (DAA) therapy, as well as the prevalence of these cases across Romania. METHODS: The genotyping method was performed on 7,421 HCV patients with advanced fibrosis. The detection method was automatic real time PCR platform M2000 (Abbott). Every subject was introduced into a database including age, sex, county and address. RESULTS: Genotype 1b was almost exclusively present: 7,392/7,421 (99.6%). Genotype 1b patients were 19.6% from Bucharest, 49% were males, with a median age of 60 years. Genotype non-1b was encountered in 29/7,421 subjects (0.4%), 62% were males, 69% from Bucharest and the median age was 52 years. Most of the subjects (75%) were in the 6th and 7th age decade. The prevalence of these cases varied significantly across Romanian counties: the highest was in Bucharest (61.3/105), Bihor (47/105), Iasi (46/105) and Constanta (43/105), and the lowest in Ilfov (2.8/105), Harghita (3.7/105), Covasna (5.4/105) and Maramures (8.8/105) (p<0.001). CONCLUSIONS: Genotype 1b is encountered in 99.6% of patients with chronic hepatitis C and advanced fibrosis from Romania. The presence of genotypes non-1b is more common in Bucharest, in males and at a younger age. There are significant differences regarding the distribution of these cases across Romania: the highest rates are in Bucharest, Bihor, Iasi and Constanta. PMID- 29253054 TI - Nodule-in-Nodule Imaging Pattern in Hepatocellular Carcinoma Treated by Transarterial Chemoembolization - a Multiparametric Magnetic Resonance Imaging Study. AB - BACKGROUND AND AIMS: Emerging minimally invasive treatments for hepatocellular carcinoma (HCC) can significantly improve a patient's prognosis, but they may alter the imaging features of the treated nodules. This study focuses on a series of patients presenting with a rare pathology, the nodule-in-nodule imaging pattern of HCC, analyzes the imaging features and discusses possible approaches for the diagnosis of tumoral recurrence. METHOD: Nine patients recruited over two years, having HCC with nodule-in-nodule imaging pattern on diagnosis, and treated by transarterial chemoembolization were monitored by magnetic resonance imaging (MRI). Nodule morphology, dynamic contrast behavior and size progression were followed in this study. RESULTS: All patients showed tumor recurrence. In 7 nodules, a T2 weighted-imaging hyperintense signal of the HCC foci was found, with isointensity of the background nodule. Restricted diffusion within the HCC foci was found in 6 cases but with no statistical significance. Dynamic contrast images evaluation showed a "classical" enhancement pattern in five patients. All nodules had hypointense HCC foci in the hepatobiliary phase. Four patients demonstrated progressive disease according to the mRECIST criteria. CONCLUSIONS: Due to the particularly challenging nodule characteristics, the sensitivity in diagnosing HCC foci in these nodules is about 77% when using conventional imaging criteria related to nodule morphology. Contrast media uptake curves may be altered by changes in nodule hemodynamics caused by embolization. The diagnostic rate may be significantly increased by considering the tumoral size increase in follow-up studies and completing the study with a hepatobiliary phase using Acidum Gadoxeticum. PMID- 29253055 TI - PPIs Prevent Aspirin-Induced Gastrointestinal Bleeding Better than H2RAs. A Systematic Review and Meta-analysis. AB - BACKGROUND AND AIMS: Aspirin is one of the most widely used medication for its analgesic and anti-platelet properties and thus a major cause for gastrointestinal (GI) bleeding. This study compared the preventive effect of histamine-2 receptor antagonists (H2RAs) and proton-pump inhibitors (PPIs) against chronic low-dose aspirin (LDA)-related GI bleeding and ulcer formation. METHODS: Electronic databases of Pubmed, Embase and Cochrane Central Register of Controlled Trials were searched for human observations (randomised controlled trials and observational studies) comparing the long term effects of PPIs and H2RAs treatment in the prevention of GI bleeding or ulcer formation in patients on chronic LDA treatment listed up till September 30, 2016. Two independent authors searched databases using PICO questions (aspirin, H2RA, PPI, GI bleeding or ulcer), and reviewed abstracts and articles for comprehensive studies keeping adequate study quality. Data of weighted odds ratios were statistically evaluated using Comprehensive Metaanalysis (Biostat, Inc., Engelwood, MJ, USA), potential bias was checked. RESULTS: Nine studies for GI bleeding and eight studies for ulcer formation were found meeting inclusion criteria, altogether 1,879 patients were included into review. The H2RAs prevented less effectively LDA-related GI bleeding (OR= 2.102, 95% CI: 1.008-4.385, p<0.048) and ulcer formation (OR= 2.257, 95% CI: 1.277-3.989, p<0.005) than PPIs. CONCLUSION: The meta-analysis showed that H2RAs were less effective in the prevention of LDA-related GI bleeding and ulcer formation suggesting the preferable usage of PPIs in case of tolerance. PMID- 29253056 TI - Hepatocellular Carcinoma Occurrence and Recurrence after Antiviral Treatment in HCV-Related Cirrhosis. Are Outcomes Different after Direct Antiviral Agents? A Review. AB - Hepatitis C virus (HCV) infection is one of the major causes of hepatocellular carcinoma (HCC) worldwide. In the last decades, several studies have showed a lower rate of HCC occurrence or recurrence in patients with HCV-related cirrhosis after interferon-based antiviral therapies compared to untreated controls, even without reaching viral clearance. Unfortunately, interferon regimens could only yield viral clearance in approximately half of the patients. The recent development of new all-oral regimens with direct-acting antivirals (DAAs) has radically improved the cure rate to above 90%. In respect to these findings, many would have thought that interferon-free regimens would decrease the development and recurrence of HCC. Literature data have unexpectedly reported high rates of both the occurrence and recurrence of HCC after therapy with DAAs. However, it is probably too early to express some concerns. More recent data showed that both occurrence and recurrence of HCC are decreased by the DAAs. Interferon-free therapy is definitely not without limits. Together with the initial thoughts of an increased risk of HCC, these may lead to an unwanted restricted access to interferon-free regimens in specific subpopulations. This issue should be settled as soon as possible because millions of hepatitis C patients are and will be using DAAs in the present and future. Our purpose is to review the existing literature and to offer a more precise and rational interpretation of the existing data. PMID- 29253057 TI - A Challenging Diagnosis of Jejunal Adenocarcinoma in a Celiac Patient: Case Report and Systematic Review of the Literature. AB - Celiac disease (CD) is a common and chronic disorder requiring a long-life gluten free diet. There is evidence that asymptomatic or subclinical presentation of CD has increased in the last decades, so that several cases are diagnosed during adulthood or even in the elderly. Celiac disease patients are at an increased risk of developing malignancies, particularly when the disease is diagnosed in the elderly. We describe a case of a challenging diagnosis of small bowel adenocarcinoma which developed in a patient with CD discovered only in the elderly. We also performed a systematic review of the literature. A tailored follow-up in a sub-group of CD patients at an increased risk of developing intestinal adenocarcinoma could be implemented. PMID- 29253058 TI - Rare Primary Esophageal Paget's Disease Diagnosed on a Large Bloc Specimen Obtained by Endoscopic Mucosal Resection. AB - Primary esophageal Paget's disease is rare. Only a few case reports have described the intraepithelial papillary capillary loop (IPCL) pattern obtained by magnified Narrow Band Imaging (M-NBI) endoscopy in this rare pathology. This report highlights the usefulness of M-NBI and the successful diagnosis using a large bloc specimen obtained by endoscopic mucosal resection with the cap method (EMR-c). A 53-year-old man was referred to endoscopic examination for dysphagia. The endoscopic image revealed a ring-shaped scarring of the esophagus suggestive for eosinophilic esophagitis. The IPCL pattern by M-NBI endoscopy showed an inflammatory pattern, and the entire epithelium of the esophagus was not stained by Lugol iodine spraying. Based on six biopsies randomly performed, a poorly differentiated adenocarcinoma was diagnosed. Since the M-NBI pattern and the histology were completely different, EMR-c was performed to obtain large bloc specimens for a more detailed diagnosis. The pathological findings revealed extensive Paget's cells infiltration into the epithelium and multifocal invasion from the mucosa to the submucosal layer with adenocarcinoma. In conclusion, a large bloc specimen by EMR-c might be more useful than a small biopsy for an accurate diagnosis of the rare esophageal Paget's disease. PMID- 29253059 TI - A Rare Association between Left Lobe Secondary Biliary Cirrhosis and Budd-Chiari Syndrome Secondary to Hepatocellular Carcinoma in the Non-Cirrhotic Right Liver Lobe. AB - Liver cirrhosis is a diffuse chronic liver disease affecting the entire liver. The fibrosis accumulation and distribution in the liver are known to be heterogeneous. "Localized" or "focal" cirrhosis is only anecdotically reported. Acute hepatitis E virus (HEV) infection is uncommon in western countries, especially in temperate climate areas and is very often missed or underdiagnosed. However, it may be responsible of up to 15% of acute-on-chronic liver failure cases. We present the case of a 35-year-old patient with a very uncommon association of Budd-Chiari syndrome secondary to hepatocellular carcinoma (HCC) developed on a non-cirrhotic right liver lobe and secondary biliary cirrhosis of the left liver lobe, that further complicated with acute HEV infection leading to acute-on-chronic liver failure and death. PMID- 29253060 TI - High Resolution Manometry and pH step-up method on the localisation of the lower esophageal sphincter. PMID- 29253061 TI - Gallstone ileus - a rare finding in the era of laparoscopic cholecystectomy. PMID- 29253063 TI - Uses and limitations of IgG4 positive plasma cells in evaluating ulcerative colitis. PMID- 29253062 TI - UGT1A1*33 (TA)5 is more common in Romania and Northern Sweden than previously believed. PMID- 29253067 TI - Testing Pneumonia Vaccines in the Elderly: Determining a Case Definition for Pneumococcal Pneumonia in the Absence of a Gold Standard. AB - Clinical assessments of vaccines to prevent pneumococcal community-acquired pneumonia (CAP) require sensitive and specific case definitions, but there is no gold standard diagnostic test. To develop a new case definition suitable for vaccine efficacy studies, we applied latent class analysis (LCA) to the results from 7 diagnostic tests for pneumococcal etiology on clinical specimens from 323 elderly persons with radiologically confirmed pneumonia enrolled in the Finnish Community-Acquired Pneumonia Epidemiology study during 2005-2007. Compared with the conventional use of LCA, which is mainly to determine sensitivities and specificities of different tests, we instead used LCA as an appropriate instrument to predict the probability of pneumococcal etiology for each CAP case based on individual test profiles, and we used the predictions to minimize the sample size that would be needed for a vaccine efficacy trial. When compared with the conventional laboratory criteria of encapsulated pneumococci in culture, in blood culture or high-quality sputum culture, or urine antigen positivity, our optimized case definition for pneumococcal CAP resulted in a trial sample size that was almost 20,000 subjects smaller. We believe that the novel application of LCA detailed here to determine a case definition for pneumococcal CAP could also be similarly applied to other diseases without a gold standard. PMID- 29253068 TI - Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial. AB - Background: Patients with diffuse large B-cell lymphoma (DLBCL) with an International Prognostic Index (IPI) >=3 are at higher risk for relapse after a complete response (CR) to first-line rituximab-based chemotherapy (R-chemo). Everolimus has single-agent activity in lymphoma. PILLAR-2 aimed to improve disease-free survival (DFS) with 1 year of adjuvant everolimus. Patients and methods: Patients with high-risk (IPI >=3) DLBCL and a positron emission tomography/computed tomography-confirmed CR to first-line R-chemo were randomized to 1 year of everolimus 10 mg/day or placebo. The primary end point was DFS; secondary end points were overall survival, lymphoma-specific survival, and safety. Results: Between August 2009 and December 2013, 742 patients were randomized to everolimus (n = 372) or placebo (n = 370). Median follow-up was 50.4 months (range 24.0-76.9). Overall, 47% of patients were >=65 years, 50% were male, and 42% had an IPI of 4 or 5. 48% and 67% completed everolimus and placebo, respectively. Primary reasons for everolimus discontinuation versus placebo were adverse events (AEs; 30% versus 12%) and relapsed disease (6% versus 13%). Everolimus did not significantly improve DFS compared with placebo (hazard ratio 0.92; 95% CI 0.69-1.22; P = 0.276). Two-year DFS rate was 77.8% (95% CI 72.7 82.1) with everolimus and 77.0% (95% CI 72.1-81.1) with placebo. Common grade 3/4 AEs with everolimus were neutropenia, stomatitis, and decreased CD4 lymphocytes. Conclusions: Adjuvant everolimus did not improve DFS in patients already in PET/CT-confirmed CR. Future approaches should incorporate targeted agents such as everolimus with R-CHOP rather than as adjuvant therapy after CR has been obtained. ClinicalTrials.gov: NCT00790036. PMID- 29253069 TI - European Society for Medical Oncology (ESMO) position paper on supportive and palliative care. AB - Oncology has come a long way in addressing patients' quality of life, together with developing surgical, radio-oncological and medical anticancer therapies. However, the multiple and varying needs of patients are still not being met adequately as part of routine cancer care. Supportive and palliative care interventions should be integrated, dynamic, personalised and based on best evidence. They should start at the time of diagnosis and continue through to end of-life or survivorship. ESMO is committed to excellence in all aspects of oncological care during the continuum of the cancer experience. Following the 2003 ESMO stand on supportive and palliative care (Cherny N, Catane R, Kosmidis P. ESMO takes a stand on supportive and palliative care. Ann Oncol 2003; 14(9): 1335-1337), this position paper highlights the evolving and growing gap between the needs of cancer patients and the actual provision of care. The concept of patient-centred cancer care is presented along with key requisites and areas for further work. PMID- 29253070 TI - fMLC: fast multi-level clustering and visualization of large molecular datasets. AB - Motivation: Despite successful applications of data clustering and visualization techniques in molecular sequence identification, current technologies still do not scale to large biological datasets. Results: We address this problem by a new multi-threaded tool, fMLC, primarily developed to cluster DNA sequences, that is supplemented with an interactive web-based visualization component, DiVE. fMLC enabled to compare, cluster and visualize 350K ITS fungal sequences at the species level. It took less than two hours to compare and cluster the dataset, which is twelve times faster than the time reported previously. Availability and implementation: https://github.com/FastMLC/fMLC (doi: 10.5281/zenodo.926820). Contact: d.vu@westerdijkinstitute.nl or v.robert@westerdijkinstitute.nl. PMID- 29253071 TI - Patient Experience With Care and Its Association With Adherence to Hypertension Medications. AB - BACKGROUND: Medication adherence is crucial to effective chronic disease management, yet little is known about the influence of the patient-provider interaction on medication adherence to hypertensive regimens. We aimed to examine the association between the patient's experience with care and medication adherence. METHODS: We collected 2,128 surveys over 4 years from a convenience sample of hypertensive patients seeking care at three urban safety-net practices in upstate New York. The survey collected adherence measures using the Morisky Medication Adherence Scale (MMAS-8) and patient experience measures. We used regression models to adjust for age, gender, race/ethnicity, self-reported health status, and clustering by patients. The primary outcome was reporting of medium to-high adherence (MMAS >= 6) vs. low adherence. RESULTS: A total of 62.5% of respondents reported medium-to-high medication adherence. The concern the provider demonstrated for patient questions or worries (adjusted odds ratio [AOR] 1.4; 95% confidence interval [CI] 1.1-1.7), provider efforts to include the patient in decisions (AOR 1.5; 95% CI 1.8-1.9), information given (AOR 1.3; 95% CI 1.0-1.6), and the overall rating of care received (AOR 1.4; 95% CI 1.1-1.8) were associated with higher medication adherence. The amount of time the provider spent was not associated with medication adherence (AOR 1.2; 95% CI 0.9-1.4). Medium-to-high medication adherence was in turn associated with increased hypertension control rates. CONCLUSIONS: Overall, better experiences with care were associated with higher adherence to hypertension regimens. However, the amount of time the provider spent with the patient was not statistically associated with medication adherence, suggesting that the quality of communication may be more important than the absolute quantity of time. PMID- 29253072 TI - K2 and K2*: efficient alignment-free sequence similarity measurement based on Kendall statistics. AB - Motivation: Alignment-free sequence comparison methods can compute the pairwise similarity between a huge number of sequences much faster than sequence-alignment based methods. Results: We propose a new non-parametric alignment-free sequence comparison method, called K2, based on the Kendall statistics. Comparing to the other state-of-the-art alignment-free comparison methods, K2 demonstrates competitive performance in generating the phylogenetic tree, in evaluating functionally related regulatory sequences, and in computing the edit distance (similarity/dissimilarity) between sequences. Furthermore, the K2 approach is much faster than the other methods. An improved method, K2*, is also proposed, which is able to determine the appropriate algorithmic parameter (length) automatically, without first considering different values. Comparative analysis with the state-of-the-art alignment-free sequence similarity methods demonstrates the superiority of the proposed approaches, especially with increasing sequence length, or increasing dataset sizes. Availability and implementation: The K2 and K2* approaches are implemented in the R language as a package and is freely available for open access (http://community.wvu.edu/daadjeroh/projects/K2/K2_1.0.tar.gz). Contact: yueljiang@163.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29253073 TI - Adherence to Antihypertensive Therapy: A Missing Link Between Treatment and Outcomes. PMID- 29253075 TI - A novel approach based on KATZ measure to predict associations of human microbiota with non-infectious diseases. PMID- 29253074 TI - Analyzing large scale genomic data on the cloud with Sparkhit. AB - Motivation: The increasing amount of next-generation sequencing data poses a fundamental challenge on large scale genomic analytics. Existing tools use different distributed computational platforms to scale-out bioinformatics workloads. However, the scalability of these tools is not efficient. Moreover, they have heavy run time overheads when pre-processing large amounts of data. To address these limitations, we have developed Sparkhit: a distributed bioinformatics framework built on top of the Apache Spark platform. Results: Sparkhit integrates a variety of analytical methods. It is implemented in the Spark extended MapReduce model. It runs 92-157 times faster than MetaSpark on metagenomic fragment recruitment and 18-32 times faster than Crossbow on data pre processing. We analyzed 100 terabytes of data across four genomic projects in the cloud in 21 h, which includes the run times of cluster deployment and data downloading. Furthermore, our application on the entire Human Microbiome Project shotgun sequencing data was completed in 2 h, presenting an approach to easily associate large amounts of public datasets with reference data. Availability and implementation: Sparkhit is freely available at: https://rhinempi.github.io/sparkhit/. Contact: asczyrba@cebitec.uni-bielefeld.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29253076 TI - Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer. PMID- 29253078 TI - A greater risk of premature death in residential respite care: a national cohort study. AB - Background: the demand for residential respite care for older persons is high yet little is known about the occurrence of harm, including death in this care setting. Objective: to compare the prevalence and nature of deaths among residential respite to permanent nursing home residents. Design: retrospective cohort study. Setting: australian accredited nursing homes between 1 July 2000 and 30 June 2013. Subjects: respite and permanent residents of Australian accredited nursing homes, whose deaths were investigated by Australian coroners. Methods: prevalence of deaths of nursing home residents were calculated using routinely generated coronial data stored in the National Coronial Information System. Odds ratios (OR) were calculated to examine residency (respite or permanent) by cause of death. Results: of the 21,672 residents who died during the study period, 172 (0.8%) were in respite care. The majority of deaths were due to natural causes. A lower proportion occurred in respite (n = 119, 69.2%) than permanent (n = 18,264, 84.9%) residents. Falls-related deaths in respite as a proportion (n = 41, 23.8%) was almost double that in permanent care (n = 2,638, 12.3%). Deaths from other injury-related causes (such as suicide and choking) were significantly more likely in respite residents (OR = 2.0; 95% confidence interval: 1.1-3.6; P = 0.026). Conclusions: this is the first national cohort study examining mortality among respite residents. It established that premature, injury-related deaths do occur during respite care. This is the first step towards better understanding and reducing the risk of harm in respite care. PMID- 29253077 TI - DeepSynergy: predicting anti-cancer drug synergy with Deep Learning. AB - Motivation: While drug combination therapies are a well-established concept in cancer treatment, identifying novel synergistic combinations is challenging due to the size of combinatorial space. However, computational approaches have emerged as a time- and cost-efficient way to prioritize combinations to test, based on recently available large-scale combination screening data. Recently, Deep Learning has had an impact in many research areas by achieving new state-of the-art model performance. However, Deep Learning has not yet been applied to drug synergy prediction, which is the approach we present here, termed DeepSynergy. DeepSynergy uses chemical and genomic information as input information, a normalization strategy to account for input data heterogeneity, and conical layers to model drug synergies. Results: DeepSynergy was compared to other machine learning methods such as Gradient Boosting Machines, Random Forests, Support Vector Machines and Elastic Nets on the largest publicly available synergy dataset with respect to mean squared error. DeepSynergy significantly outperformed the other methods with an improvement of 7.2% over the second best method at the prediction of novel drug combinations within the space of explored drugs and cell lines. At this task, the mean Pearson correlation coefficient between the measured and the predicted values of DeepSynergy was 0.73. Applying DeepSynergy for classification of these novel drug combinations resulted in a high predictive performance of an AUC of 0.90. Furthermore, we found that all compared methods exhibit low predictive performance when extrapolating to unexplored drugs or cell lines, which we suggest is due to limitations in the size and diversity of the dataset. We envision that DeepSynergy could be a valuable tool for selecting novel synergistic drug combinations. Availability and implementation: DeepSynergy is available via www.bioinf.jku.at/software/DeepSynergy. Contact: klambauer@bioinf.jku.at. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29253079 TI - Curatr: a web application for creating, curating and sharing a mass spectral library. AB - Summary: We have developed a web application curatr for the rapid generation of high quality mass spectral fragmentation libraries from liquid-chromatography mass spectrometry datasets. Curatr handles datasets from single or multiplexed standards and extracts chromatographic profiles and potential fragmentation spectra for multiple adducts. An intuitive interface helps users to select high quality spectra that are stored along with searchable molecular information, the providence of each standard and experimental metadata. Curatr supports exports to several standard formats for use with third party software or submission to repositories. We demonstrate the use of curatr to generate the EMBL Metabolomics Core Facility spectral library http://curatr.mcf.embl.de. Availability and implementation: Source code and example data are at http://github.com/alexandrovteam/curatr/. Contact: palmer@embl.de. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29253085 TI - JASPAR RESTful API: accessing JASPAR data from any programming language. AB - Summary: JASPAR is a widely used open-access database of curated, non-redundant transcription factor binding profiles. Currently, data from JASPAR can be retrieved as flat files or by using programming language-specific interfaces. Here, we present a programming language-independent application programming interface (API) to access JASPAR data using the Representational State Transfer (REST) architecture. The REST API enables programmatic access to JASPAR by most programming languages and returns data in eight widely used formats. Several endpoints are available to access the data and an endpoint is available to infer the TF binding profile(s) likely bound by a given DNA binding domain protein sequence. Additionally, it provides an interactive browsable interface for bioinformatics tool developers. Availability and implementation: This REST API is implemented in Python using the Django REST Framework. It is accessible at http://jaspar.genereg.net/api/ and the source code is freely available at https://bitbucket.org/CBGR/jaspar under GPL v3 license. Contact: aziz.khan@ncmm.uio.no or anthony.mathelier@ncmm.uio.no. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29253082 TI - Comprehensive review and empirical analysis of hallmarks of DNA-, RNA- and protein-binding residues in protein chains. AB - Proteins interact with a variety of molecules including proteins and nucleic acids. We review a comprehensive collection of over 50 studies that analyze and/or predict these interactions. While majority of these studies address either solely protein-DNA or protein-RNA binding, only a few have a wider scope that covers both protein-protein and protein-nucleic acid binding. Our analysis reveals that binding residues are typically characterized with three hallmarks: relative solvent accessibility (RSA), evolutionary conservation and propensity of amino acids (AAs) for binding. Motivated by drawbacks of the prior studies, we perform a large-scale analysis to quantify and contrast the three hallmarks for residues that bind DNA-, RNA-, protein- and (for the first time) multi-ligand binding residues that interact with DNA and proteins, and with RNA and proteins. Results generated on a well-annotated data set of over 23 000 proteins show that conservation of binding residues is higher for nucleic acid- than protein-binding residues. Multi-ligand-binding residues are more conserved and have higher RSA than single-ligand-binding residues. We empirically show that each hallmark discriminates between binding and nonbinding residues, even predicted RSA, and that combining them improves discriminatory power for each of the five types of interactions. Linear scoring functions that combine these hallmarks offer good predictive performance of residue-level propensity for binding and provide intuitive interpretation of predictions. Better understanding of these residue level interactions will facilitate development of methods that accurately predict binding in the exponentially growing databases of protein sequences. PMID- 29253084 TI - Enhanced Recovery After Surgery: The Plastic Surgery Paradigm Shift. AB - Background: With a focus on providing high quality care and reducing facility based expenses there has been an evolution in perioperative care by way of enhanced recovery after surgery (ERAS). ERAS allows for a multidisciplinary and multimodal approach to perioperative care which not only expedites recovery but maximizes patient outcomes. This paradigm shift has been generally accepted by most surgical specialties, including plastic surgery. Objectives: The goal of this study was to evaluate the impact of ERAS on outcomes in cosmetic plastic surgery. Methods: A prospective study consisting of phone call questionnaires was designed where patients from two senior plastic surgeons (N.H.R. and J.D.F.) were followed. The treatment group (n = 10) followed an ERAS protocol while the control group (n = 12) followed the traditional recovery after surgery which included narcotic usage. Patients were contacted on postoperative days (POD) 0 through 7+ and surveyed about a number of outcomes measures. Results: The ERAS group demonstrated a significant reduction in postoperative pain on POD 0, 1, 2, and 3 (all P < 0.01). There was also statistically less nausea/vomiting, fatigue/drowsiness, constipation, and hindrance on ambulation compared to the control group (all P < 0.05). Significance was achieved for reduction in fatigue/drowsiness on POD 0 and 1 (P < 0.01), as well as ability to ambulate on POD 0 and 3 (P = 0.044). Lastly, opioid use (P < 0.001) and constipation (P = 0.003) were decreased. Conclusions: ERAS protocols have demonstrated their importance within multiple surgical fields, including cosmetic plastic surgery. The utility lies in the ability to expedite patient's recovery while still providing quality care. This study showed a reduction in postoperative complaints by avoiding narcotics without an increase in complications. Our findings signify the importance of ERAS protocols within cosmetic plastic surgery. Level of Evidence 4: PMID- 29253088 TI - Cardiovascular Research: new challenges and new horizons. PMID- 29253095 TI - A Systematic Review of Safety and Immunogenicity of Influenza Vaccination Strategies in Solid Organ Transplant Recipients. AB - Immunogenicity from seasonal inactivated influenza vaccine (IIV) remains suboptimal in solid organ transplant recipients (SOTRs). We conducted a systematic review that compared the safety and immunogenicity of nonstandard influenza vaccination strategies with single-dose IIV in SOTRs. Booster doses and possibly high-dose (HD) influenza vaccination strategies seem to hold promise for improving vaccination immunogenicity in SOTRs. Administration of intradermal and MF59-adjuvanted trivalent IIV (IIV3) did not improve vaccine immunogenicity compared with single-dose intramuscular IIV. Alternative vaccine strategies were generally well tolerated; SOTRs who received HD, intradermal or adjuvanted IIV3 had a higher frequency of infection site reactions, while systemic adverse events were more frequent in SOTRs who received HD IIV3. Allograft rejection rates were similar in both groups. SOTRs should continue to receive standard-dose IIV annually in accordance with current recommendations, pending future studies to determine the optimal timing, frequency, and dosage of IIV using the booster-dose strategy. PMID- 29253083 TI - Circulating cell-free DNA as predictor of treatment failure after neoadjuvant chemo-radiotherapy before surgery in patients with locally advanced rectal cancer. AB - Background: Treatment of patients with locally advanced rectal cancer (LARC) is based on a combination of chemo-radiotherapy (CRT) and surgery. The rate of distant recurrences remains over 25%. Circulating cell-free DNA (cfDNA) in plasma is a mixture of normal and cancer-specific DNA segments and is a promising biomarker in patients with colorectal cancer. The aim of our study was to investigate plasma cfDNA as a prognostic marker for outcome in patients with LARC treated with neoadjuvant CRT and surgery. Patients and methods: In total, 123 patients with LARC were included in 2 biomarker studies. Patients were treated with neoadjuvant CRT before TME surgery. Fifty-two (42%) of the patients received induction chemotherapy with capecitabine + oxaliplatin. Total cfDNA was measured by direct fluorescent assay in EDTA plasma samples obtained at baseline, after induction chemotherapy, and after CRT. Serial samples 5 years after surgery were collected in 51 patients (41%). Results: Median follow-up was 55 months. Distant or local recurrence was seen in 30.9% of the patients. Patients with baseline cfDNA levels above the 75th quartile had a higher risk of local or distant recurrence and shorter time to recurrence compared with patients with plasma cfDNA below the 75th percentile (HR = 2.48, 95% CI: 1.3-4.8, P = 0.007). The same applied to disease-free survival (DFS) (HR = 2.43, 95% CI: 1.27-4.7, P = 0.015). In multivariate analysis, a high cfDNA level was significantly associated with time to progression and DFS. During follow-up, the association remained significant regardless of time point for sample analysis. Conclusion: We have demonstrated an association between a high baseline plasma level of cfDNA and increased risk of recurrence, shorter time to recurrence, and shorter DFS in patients with LARC. Consequently, cfDNA could potentially improve pre- and post treatment risk assessment and facilitate individualized therapy for patients with LARC. PMID- 29253094 TI - Chromatographic Methods for Quantitative Determination of Ampicillin, Dicloxacillin and Their Impurity 6-Aminopenicillanic Acid. AB - Two accurate, precise and sensitive high-performance thin layer chromatography (HPTLC) and high-performance liquid chromatography (HPLC) methods were developed for assay of ampicillin (AMP) and dicloxacillin (DX) in the presence of their impurity, 6-aminopenicillanic acid (APA). Method (A) is HPTLC method; using silica gel HPTLC F254 plates as a stationary phase with methanol: chloroform: acetic acid (1:9: 0.2, by volume) as a developing system. All the bands were scanned at 220 nm. Method (B) is reversed phase- HPLC which depended on isocratic elution using C18 column and mobile phase consisting of acetonitrile: water (60:40, v/v), pH adjusted to 4 with orthophosphoric acid, at a flow rate of 1 mL min-1 and ultraviolet detection at 240 nm. The proposed methods were validated as per ICH guidelines and their linearity was evident in the ranges of 0.5-2 MUg band-1, 0.4-2 MUg band-1 and 0.2-1.2 MUg band-1 for method (A) and 5-40 MUg mL-1, 5-40 MUg mL-1 and 2-16 MUg mL-1 for method (B) for AMP, DX and APA, respectively. The proposed methods were successfully used for assay of AMP and DX in pure form and in pharmaceutical formulation where no interference from the excipients was detected. PMID- 29253091 TI - The incorporated aortomitral homograft for double-valve endocarditis: the 'hemi Commando' procedure. Early and mid-term outcomes. AB - OBJECTIVES: Surgical management of invasive double-valve infective endocarditis (IE) involving the intervalvular fibrosa (IVF) is a technical challenge that requires extensive debridement followed by complex reconstruction. In this study, we present the early and mid-term outcomes of the hemi-Commando procedure and aortic root replacement with reconstruction of IVF using an aortomitral allograft. METHODS: From 2010 to 2017, 37 patients with IE involving the IVF underwent the hemi-Commando procedure. Postoperative clinical data and echocardiograms were reviewed for the assessment of cardiac structural integrity and clinical outcomes. RESULTS: Twenty-nine (78%) cases were redo surgery and 15 (41%) were emergency surgery. Preoperatively, 70% (n = 26) of patients were admitted to the intensive care unit and 11% (n = 4) of patients were in septic shock. Ten (27%) patients had native aortic valve IE, while 27 (73%) patients had prosthetic valve IE. Hospital death occurred in 8% (n = 3) of patients due to multisystem organ failure. Postoperative echocardiogram showed no aortic regurgitation in 86% (n = 32) and mild regurgitation in 14% (n = 5) of patients, while mitral regurgitation prevalence was none/trivial in 62% (n = 23), mild in 32% (n = 12) and moderate in 5%. Intact IVF reconstruction was confirmed in all patients with no abnormal communication between the left heart chambers. One-year survival was 91%, while 3-year survival was 82%. Mid-term follow up revealed 1 death secondary to recurrent IE. CONCLUSIONS: Compared to double-valve replacement with IVF reconstruction ('Commando operation'), the early and mid term outcomes of the hemi-Commando procedure proved to be a feasible treatment option for IVF reconstruction, enabling preservation of the mitral valve and the subvalvular apparatus in high-risk patients with invasive double-valve IE. PMID- 29253093 TI - Minimal incision palatoplasty with or without muscle reconstruction in patients with isolated cleft palate: a cast and medical records analysis. AB - Objectives: To compare the minimal incision (MI) technique with the minimal incision including muscle reconstruction (MMI) technique regarding surgical complications and dentoalveolar status at 5 years of age. Subjects and method: A consecutive series of 202 Caucasian non-syndromic children (apart from Pierre Robin Sequence) born with isolated cleft palate between 1987 and 2007 and treated with MI (n = 78) or MMI (n = 102) palatoplasty at a mean age of 12.7 (SD = 1.43) months in Stockholm. Twenty-two patients did not fulfill the inclusion criteria. The patients were divided into two subgroups: clefts within the soft palate only (small cleft, n = 50) and clefts within the hard and soft palate (big cleft, n = 130). Dental relations, structure of the palatal mucosa, and height of the palatal vault at 5 (mean age 5.3, range: 4.4-6.9) years of age were studied using plaster models. Time for surgery, blood loss, complications in the immediate postoperative period, frequency of fistulas, and additional pharyngeal flap surgery were evaluated. Student's t-test, chi-square test and 95 per cent confidence intervals were calculated. Results: MMI compared to MI technique result in statistically significant increased operation time, less need for pharyngeal flap surgery, and to shallower palatal vault. Big clefts result in statistically significant increased operation time and need for pharyngeal flap surgery. Dental relations were the same in all groups. Limitations: Retrospective single centre study, limited sample size, more than one surgeon. Conclusions: The muscle reconstruction results in a reduced subsequent need for pharyngeal flap surgery, but to shallower palatal vault and demand for almost double operation time. The dental relations were the same in all groups. PMID- 29253086 TI - Reduced LRRK2 in association with retromer dysfunction in post-mortem brain tissue from LRRK2 mutation carriers. AB - Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenic for familial Parkinson's disease. However, it is unknown whether levels of LRRK2 protein in the brain are altered in patients with LRRK2-associated Parkinson's disease. Because LRRK2 mutations are relatively rare, accounting for approximately 1% of all Parkinson's disease, we accessioned cases from five international brain banks to investigate levels of the LRRK2 protein, and other genetically associated Parkinson's disease proteins. Brain tissue was obtained from 17 LRRK2 mutation carriers (12 with the G2019S mutation and five with the I2020T mutation) and assayed by immunoblot. Compared to matched controls and idiopathic Parkinson's disease cases, we found levels of LRRK2 protein were reduced in the LRRK2 mutation cases. We also measured a decrease in two other proteins genetically implicated in Parkinson's disease, the core retromer component, vacuolar protein sorting associated protein 35 (VPS35), and the lysosomal hydrolase, glucocerebrosidase (GBA). Moreover, the classical retromer cargo protein, cation-independent mannose-6-phosphate receptor (MPR300, encoded by IGF2R), was also reduced in the LRRK2 mutation cohort and protein levels of the receptor were correlated to levels of LRRK2. These results provide new data on LRRK2 protein expression in brain tissue from LRRK2 mutation carriers and support a relationship between LRRK2 and retromer dysfunction in LRRK2-associated Parkinson's disease brain. PMID- 29253092 TI - A case of CLIPPERS challenging the new diagnostic criteria. PMID- 29253089 TI - A Double-Blind, Randomized Trial of High-Dose vs Standard-Dose Influenza Vaccine in Adult Solid-Organ Transplant Recipients. AB - Background: The annual standard-dose (SD) influenza vaccine has suboptimal immunogenicity in solid organ transplant recipients (SOTRs). Influenza vaccine that contains higher doses of antigens may lead to greater immunogenicity in this population. Methods: We conducted a randomized, double-blind trial to compare the safety and immunogenicity of the 2016-2017 high-dose (HD; FluzoneHD, Sanofi) vs SD (Fluviral, GSK) influenza vaccine in adult SOTRs. Preimmunization and 4-week postimmunization sera underwent strain-specific hemagglutination inhibition assay. Results: We enrolled 172 patients who received study vaccine, and 161 (84 HD; 77 SD) were eligible for analysis. Seroconversion to at least 1 of 3 vaccine antigens was present in 78.6% vs 55.8% in HD vs SD vaccine groups (P < .001), respectively. Seroconversions to A/ H1N1, A/H3N2, and B strains were 40.5% vs 20.5%, 57.1% vs 32.5%, and 58.3% vs 41.6% in HD vs SD vaccine groups (P = .006, P = .002, P = .028, respectively). Post-immunization geometric mean titers of A/H1N1, A/H3N2, and B strains were significantly higher in the HD group (P = .007, P = .002, P = .033). Independent factors associated with seroconversion to at least 1 vaccine strain were the use of HD vaccine (odds ratio [OR], 3.23; 95% confidence interval [CI], 1.56-6.67) and use of mycophenolate doses <2 g daily (OR, 2.76; 95% CI, 1.12-6.76). Conclusions: HD vaccine demonstrated significantly better immunogenicity than SD vaccine in adult transplant recipients and may be the preferred influenza vaccine for this population. Clinical Trials Registration: NCT03139565. PMID- 29253096 TI - Reply to Suciu et al. PMID- 29253090 TI - Burden of Respiratory Syncytial Virus Infection in South African Human Immunodeficiency Virus (HIV)-Infected and HIV-Uninfected Pregnant and Postpartum Women: A Longitudinal Cohort Study. AB - Background: Limited data exist on the burden of respiratory syncytial virus (RSV) illness among pregnant women, to determine their potential benefit from RSV vaccination. We evaluated the incidence of RSV illness from midpregnancy until 24 weeks postpartum in human immunodeficiency virus (HIV)-uninfected and HIV infected women and their infants. Methods: Mother-infant dyads were enrolled in maternal influenza vaccine efficacy trials. These included 1060 and 1056 HIV uninfected pregnant women in 2011 and 2012, respectively, 194 HIV-infected pregnant women in 2011, and their infants. Upper respiratory tract samples obtained at illness visits were tested for RSV. Results: The incidence (per 1000 person-months) of RSV illness (n = 43 overall) among HIV-uninfected women was lower in 2011 (1.2; 95% confidence interval [CI], .6-2.2) than in 2012 (4.0; 95% CI, 2.8-5.6). The incidence of RSV illness (n = 5) in HIV-infected women was 3.4 (95% CI, 1.4-8.1). Maternal RSV infection was associated with respiratory symptoms including cough (72.1%), rhinorrhea (39.5%), sore throat (37.2%), and headache (42%), but fever was absent. RSV infection during pregnancy was not associated with adverse pregnancy outcomes. Postpartum, RSV infection in mothers (n = 27) was associated with concurrent infection among 51.9% of their infants and, conversely, 29.8% of mothers investigated within 7 days of their infants having an RSV illness also tested positive for RSV. Conclusions: RSV infection is associated with respiratory illness during pregnancy and postpartum. Vaccination of pregnant women against RSV could benefit the mother, albeit primarily against nonfebrile illness, and her infant. Clinical Trial Registration: NCT01306669 and NCT01306682. PMID- 29253087 TI - Role of up-front autologous stem-cell transplantation in peripheral T-cell lymphoma for patients in response after induction: an analysis of patients from LYSA centers. AB - Background: Peripheral T-cell lymphoma (PTCL) remains a therapeutic challenge. Due to the rarity and the heterogeneity of PTCL, no consensus has been achieved regarding even the type of first-line treatment. The benefit of autologous stem cell transplantation (ASCT) is, therefore, still intensely debated. Patients and methods: In the absence of randomized trials addressing the role of ASCT, we performed a large multicentric retrospective study and used both a multivariate proportional hazard model and a propensity score matching approach to correct for sample selection bias between patients allocated or not to ASCT in intention-to treat (ITT). Results: Among 527 patients screened from 14 centers in France, Belgium and Portugal, a final cohort of 269 patients <=65 years old with PTCL-not otherwise specified (NOS) (N = 78, 29%), angioimmunoblastic T-cell lymphoma (AITL) (N = 123, 46%) and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK-ALCL) (N = 68, 25%) with partial (N = 52, 19%) or complete responses (N = 217, 81%) after induction was identified and information about treatment allocation was carefully collected before therapy initiation from medical records. One hundred and thirty-four patients were allocated to ASCT in ITT and 135 were not. Neither the Cox multivariate model (HR = 1.02; 95% CI: 0.69 1.50 for PFS and HR = 1.08; 95% CI: 0.68-1.69 for OS) nor the propensity score analysis after stringent matching for potential confounding factors (logrank P = 0.90 and 0.66 for PFS and OS, respectively) found a survival advantage in favor of ASCT as a consolidation procedure for patients in response after induction. Subgroup analyses did not reveal any further difference for patients according to response status, stage disease or risk category. Conclusions: The present data do not support the use of ASCT for up-front consolidation for all patients with PTCL NOS, AITL, or ALK-ALCL with partial or complete response after induction. PMID- 29253080 TI - The structural variability of the influenza A hemagglutinin receptor-binding site. AB - Hemagglutinin (HA) is a transmembrane protein of the influenza A virus and a key component in its life cycle. The protein allows the virus to enter a host cell by recognizing specific glycans attached to transmembrane proteins of the host, which leads to viral endocytosis. In recent years, significant progress has been made in understanding the structural relationship between changes in the HA receptor-binding site (RBS) and the sialylated glycans that bind them. Several mutations were identified in the HA RBS that allows the virus to change host tropism. Their impact on binding the analogs of human and avian receptors was determined with X-ray crystallography. In this article, we provide a short overview of the HA protein structure and briefly discuss the adaptive mutations introduced to different HA subtypes. PMID- 29253081 TI - Pertuzumab, trastuzumab, and standard anthracycline- and taxane-based chemotherapy for the neoadjuvant treatment of patients with HER2-positive localized breast cancer (BERENICE): a phase II, open-label, multicenter, multinational cardiac safety study. AB - Background: Anti-HER2 therapies are associated with a risk of increased cardiac toxicity, particularly when part of anthracycline-containing regimens. We report cardiac safety of pertuzumab, trastuzumab, and chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer. Patients and methods: BERENICE (NCT02132949) is a nonrandomized, phase II, open-label, multicenter, multinational study in patients with normal cardiac function. In the neoadjuvant period, cohort A patients received four cycles of dose-dense doxorubicin and cyclophosphamide, then 12 doses of standard paclitaxel plus four standard trastuzumab and pertuzumab cycles. Cohort B patients received four standard fluorouracil/epirubicin/cyclophosphamide cycles, then four docetaxel cycles with four standard trastuzumab and pertuzumab cycles. The primary end point was cardiac safety during neoadjuvant treatment, assessed by the incidence of New York Heart Association class III/IV heart failure and of left ventricular ejection fraction declines (>=10 percentage-points from baseline and to a value of <50%). The main efficacy end point was pathologic complete response (pCR, ypT0/is ypN0). Results are descriptive. Results: Safety populations were 199 and 198 patients in cohorts A and B, respectively. Three patients [1.5%; 95% confidence interval (CI) 0.31% to 4.34%] in cohort A experienced four New York Heart Association class III/IV heart failure events. Thirteen patients (6.5%; 95% CI 3.5% to 10.9%) in cohort A and four (2.0%; 95% CI 0.6% to 5.1%) in cohort B experienced at least one left ventricular ejection fraction decline. No new safety signals were identified. pCR rates were 61.8% and 60.7% in cohorts A and B, respectively. The highest pCR rates were in the HER2-enriched PAM50 subtype (75.0% and 73.7%, respectively). Conclusion: Treatment with pertuzumab, trastuzumab, and common anthracycline-containing regimens for the neoadjuvant treatment of early breast cancer resulted in cardiac and general safety profiles, and pCR rates, consistent with prior studies with pertuzumab. Clinical Trial Information: NCT02132949. PMID- 29253100 TI - Swimming Training Improves Myocardial Mechanics, Prevents Fibrosis, and Alters Expression of Ca2+ Handling Proteins in Older Rats. AB - Exercise training effects on the contractility of aged myocardium have been investigated for more than 20 years, but the data are still unclear. This study evaluated the hypothesis that a swimming training (ST) may improve myocardial inotropism in older rats. Male Wistar rats aged 4 (young)-and 21 (old)-months-old were divided into young untrained (YNT), old untrained (ONT), and old trained (OTR; 6 weeks of ST) groups. Echocardiography and hemodynamic were employed to assess left ventricular morphology and function. Myocardial mechanics was evaluated on papillary muscles. Histological and immunoblotting were carried out to evaluate fibrosis and proteins that modulate the myocardial function and calcium handling. We found that older rats did not show cardiac dysfunction, but ONT group showed lower physical performance during a swimming test (YNT: 5 +/- 2; ONT: -16 +/- 0.4; OTR: 51 +/- 3; Delta%, sec). Moreover, ONT group showed worse myocardial inotropism, in which it was reversed by ST (Peak developed tension: YNT: 6.2 +/- 0.7; ONT: 3.9 +/- 0.3; OTR: 6.9 +/- 0.9; g/mm2). The ST was associated with preserved collagen content (YNT: 0.38 +/- 0.05; ONT: 0.78 +/- 0.12; OTR: 0.34 +/- 0.09; %). Exercise partially mitigated the effects of aging on intracellular Ca2+-regulating protein (eg, L-Ca2+ channel and phospholamban) and beta-isoform of myosin. Thus, we propose that these molecular alterations together with inhibition of collagen increase contribute to improved myocardial performance in older rats. PMID- 29253097 TI - ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)-infected Participants With HIV-1 RNA <500000 Copies/mL. AB - Background: Limited data exist on initial human immunodeficiency virus type 1 (HIV-1) treatment with dolutegravir plus lamivudine. Methods: A5353 is a phase 2, single-arm, pilot study of once-daily dolutegravir (50 mg) plus lamivudine (300 mg) in treatment-naive participants with HIV-1 RNA >=1000 and <500000 copies/mL. Exclusion criteria included active hepatitis B or major protease, reverse transcriptase, or integrase resistance. The primary efficacy measure was the proportion with HIV-1 RNA <50 copies/mL (FDA [US Food and Drug Administration] Snapshot) at week 24. Virologic failure (VF) was confirmed HIV-1 RNA >400 copies/mL at week 16/20 or >200 copies/mL at or after week 24. Dolutegravir levels and drug resistance testing were performed at VF. Results: One hundred and twenty participants (87% male, median age 30 years, 37 (31%) HIV-1 RNA >100000 copies/mL) initiated study treatment. Median entry HIV-1 RNA and CD4 count were 4.61 log10 copies/mL and 387 cells/mm3. Virologic efficacy at week 24 was 108/120 (90%, confidence interval [83%, 95%]), with comparable results in the >100000 copies/mL and <=100000 copies/mL strata, that is, 89% (75%, 97%) and 90% (82%, 96%), respectively. Three participants with VF, had undetected plasma dolutegravir at >=1 time points; the M184V and R263R/K mutations developed in 1 participant. Two participants experienced grade 3 possible/probable treatment related adverse events; none discontinued treatment due to adverse events. Conclusions: Dolutegravir plus lamivudine demonstrated efficacy in individuals with pretreatment HIV-1 RNA up to 500000 copies/mL in this pilot trial, but a participant developed resistance mutations. Clinical Trials Registration: NCT02582684. PMID- 29253098 TI - Video-assisted thoracoscopic surgery yields better outcomes than thoracotomy for anatomical lung resection in Brazil: a propensity score-matching analysis using the Brazilian Society of Thoracic Surgery database. AB - OBJECTIVES: The use of video-assisted anatomical lung resection is increasingly widespread for lung cancer and non-neoplastic diseases, showing excellent results. Nonetheless, a comparative analysis of the benefits of this technique has yet to be conducted in Latin America, a region with a completely different case mix from the USA or Europe. The purpose of this study was to compare the outcomes of video-assisted thoracoscopic surgery (VATS) and open thoracotomy (OT) for anatomical lung resection in patients included on the Brazilian Society of Thoracic Surgery (BSTS) database. METHODS: Using propensity score matching, we conducted an analysis of 1355 patients who underwent anatomical lung resection (704 OT and 651 VATS) registered in the BSTS database between August 2015 and December 2016. Propensity score matching was performed using the following baseline characteristics: age at surgery, gender, comorbidities, pulmonary lung function, type of resection and cancer and non-cancer diagnosis. The propensity score-matched sample comprised a well-matched group of 890 patients. The main outcomes tested were mortality, complications and major cardiopulmonary complications based on the European Society of Thoracic Surgeons (ESTS) database definitions and terminology. RESULTS: Standardized differences of means and proportions suggested that an adequate balance had been achieved. Major cardiopulmonary complications were shown to be more frequent in patients who underwent OT (16.0% compared with 9.2% in VATS patients; odds ratio = 1.87, 95% confidence interval 1.25-2.80) and the overall complications rate was higher among patients who underwent OT (30.1% compared with 21.8% in VATS patients; odds ratio = 1.55, 95% confidence interval 1.17-2.05). No statistically significant difference in mortality rate was observed between OT (2.5%) and VATS (1.8%) (odds ratio = 1.38, 95% confidence interval 0.54-3.50). CONCLUSIONS: In Brazil, the rate of complications associated with minimally invasive surgery (VATS) for anatomical lung resection is significantly lower than that of conventional OT. PMID- 29253105 TI - Is there any correlation between the occurrence of spontaneous pneumothorax and changes in the weather conditions worldwide? PMID- 29253106 TI - Nasal high-flow oxygen therapy improves arterial oxygenation during one-lung ventilation in non-intubated thoracoscopic surgery. AB - OBJECTIVES: Intraoperative hypoxaemia during one-lung ventilation (OLV) remains a major concern in thoracic surgery. Non-intubated video-assisted thoracic surgery (VATS) involves a greater risk of consequent emergent conversion to endotracheal intubation. Transnasal humidified rapid-insufflation ventilatory exchange (THRIVE) has recently been reported to be beneficial for higher oxygen reserves during difficult intubations and for enhancing postoperative recovery after thoracic surgery. However, the effects of THRIVE on oxygenation and carbon dioxide elimination before and during OLV in non-intubated VATS have not been investigated. METHODS: Between September 2016 and October 2016, 30 patients underwent non-intubated VATS for lung tumour and were maintained with THRIVE at a flow of 20 l/min. These patients were compared with a historical control group comprising 30 patients who were maintained with oxygen masks at an oxygen flow of 10 l/min using a propensity score matching algorithm between September 2015 and July 2016. RESULTS: The preoperative arterial oxygen tension was significantly higher in patients maintained with THRIVE than it was in patients maintained with oxygen masks (mean 416.0 vs 265.9 mmHg, P < 0.01). During OLV, arterial oxygen tension remained significantly higher in the THRIVE group than in the oxygen mask group (mean 207.0 vs 127.8 mmHg, P = 0.01). The arterial carbon dioxide tension was comparable before and during OLV. CONCLUSIONS: The results indicated that THRIVE effectively increases the oxygen reserve both during OLV and after anaesthesia. Furthermore, non-intubated VATS is safer if THRIVE with flow adjustment is incorporated into a minimally invasive surgical approach, although carbon dioxide elimination is not facilitated. PMID- 29253108 TI - Embolic protection devices for transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) is a major advancement in the treatment of severe aortic valve stenosis in elderly high-risk patients. Implementing TAVR also in younger intermediate- or low-risk patients increases interest in the possibility of further lowering the risk of perioperative cerebrovascular events. To this aim, some embolic protection devices (EPDs) have been developed, some of which have already been approved for clinical use. Nevertheless, the cause of cerebrovascular events after TAVR is multifactorial, and selection of patients who would benefit from EPD is crucial to further improve outcomes, survival rate and quality of life. We reviewed the available literature in order to assess the incidence of and the mechanisms responsible for neurological events that can occur during TAVR, and we analysed clinical results and imaging findings following EPD use. Clinical trials for Embrella, TriGuard, Sentinel and Embol-X devices were designed to test their safety and their ability to prevent neurological complications in patients having TAVR. So far, published results showed that EPD may help in reducing the volume and size of periprocedural silent ischaemic brain lesions identified on magnetic resonance images but not in reducing the incidence of new lesions and new neurological events. The clinical impact of EPD in lowering the number of transient ischaemic attacks/strokes during TAVR needs to be further investigated in randomized trials. PMID- 29253101 TI - A novel human pain insensitivity disorder caused by a point mutation in ZFHX2. AB - Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs.awx326media15680039660001. PMID- 29253102 TI - A fingerprint of the epileptogenic zone in human epilepsies. AB - Defining a bio-electrical marker for the brain area responsible for initiating a seizure remains an unsolved problem. Fast gamma activity has been identified as the most specific marker for seizure onset, but conflicting results have been reported. In this study, we describe an alternative marker, based on an objective description of interictal to ictal transition, with the aim of identifying a time frequency pattern or 'fingerprint' that can differentiate the epileptogenic zone from areas of propagation. Seventeen patients who underwent stereoelectroencephalography were included in the study. Each had seizure onset characterized by sustained gamma activity and were seizure-free after tailored resection or laser ablation. We postulated that the epileptogenic zone was always located inside the resection region based on seizure freedom following surgery. To characterize the ictal frequency pattern, we applied the Morlet wavelet transform to data from each pair of adjacent intracerebral electrode contacts. Based on a visual assessment of the time-frequency plots, we hypothesized that a specific time-frequency pattern in the epileptogenic zone should include a combination of (i) sharp transients or spikes; preceding (ii) multiband fast activity concurrent; with (iii) suppression of lower frequencies. To test this hypothesis, we developed software that automatically extracted each of these features from the time-frequency data. We then used a support vector machine to classify each contact-pair as being within epileptogenic zone or not, based on these features. Our machine learning system identified this pattern in 15 of 17 patients. The total number of identified contacts across all patients was 64, with 58 localized inside the resected area. Subsequent quantitative analysis showed strong correlation between maximum frequency of fast activity and suppression inside the resection but not outside. We did not observe significant discrimination power using only the maximum frequency or the timing of fast activity to differentiate contacts either between resected and non-resected regions or between contacts identified as epileptogenic versus non-epileptogenic. Instead of identifying a single frequency or a single timing trait, we observed the more complex pattern described above that distinguishes the epileptogenic zone. This pattern encompasses interictal to ictal transition and may extend until seizure end. Its time-frequency characteristics can be explained in light of recent models emphasizing the role of fast inhibitory interneurons acting on pyramidal cells as a prominent mechanism in seizure triggering. The pattern clearly differentiates the epileptogenic zone from areas of propagation and, as such, represents an epileptogenic zone 'fingerprint'.awx306media15687076823001. PMID- 29253107 TI - Respiratory Syncytial Virus During Pregnancy. PMID- 29253110 TI - Delta: a new web-based 3D genome visualization and analysis platform. AB - Summary: Delta is an integrative visualization and analysis platform to facilitate visually annotating and exploring the 3D physical architecture of genomes. Delta takes Hi-C or ChIA-PET contact matrix as input and predicts the topologically associating domains and chromatin loops in the genome. It then generates a physical 3D model which represents the plausible consensus 3D structure of the genome. Delta features a highly interactive visualization tool which enhances the integration of genome topology/physical structure with extensive genome annotation by juxtaposing the 3D model with diverse genomic assay outputs. Finally, by visually comparing the 3D model of the beta-globin gene locus and its annotation, we speculated a plausible transitory interaction pattern in the locus. Experimental evidence was found to support this speculation by literature survey. This served as an example of intuitive hypothesis testing with the help of Delta. Availability and implementation: Delta is freely accessible from http://delta.big.ac.cn, and the source code is available at https://github.com/zhangzhwlab/delta. Contact: zhangzhihua@big.ac.cn. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29253109 TI - Induction of Complete Remission by Azacitidine in a Patient with Myelodysplastic Syndrome-Associated Inflammatory Bowel Disease. AB - Myelodysplastic syndrome [MDS] is a clonal disorder of bone marrow [BM] cells, caused by acquired chromosomal abnormalities and gene mutations. Pro-inflammatory antigen-presenting cells [APCs] originating from BM cells bearing chromosomal abnormalities and gene mutations can cause immune-mediated disorders including inflammatory bowel disease [IBD]. Here, we report the first case with MDS associated IBD that was successfully treated with the DNA methyltransferase inhibitor, azacitidine [AZA]. A 75-year-old man with a 5-year history of MDS was admitted for examination of diarrhoea and high fever. Blood examination revealed pancytopenia and a marked elevation of C-reactive protein. Colonoscopy revealed multiple round ulcers from the terminal ileum to the sigmoid colon. Pathological examination of the endoscopic biopsy specimens showed destruction of crypt architecture and infiltration of CD3+ T cells and CD68+ macrophages. Surprisingly, administration of AZA, which has been approved for the treatment of high-risk MDS, improved the symptoms, and the multiple round ulcers disappeared. AZA treatment markedly decreased the expressions of tumour necrosis factor-alpha, interleukin-12 (IL-12)/23p40 and IL-17 in colonic biopsy samples, as assessed by quantitative reverse transcription polymerase chain reaction. In contrast, AZA treatment did not change the expression of forkhead box P3, a master regulator of regulatory T cells. These data suggest that AZA treatment led to complete remission in MDS-associated IBD through suppression of pro-inflammatory cytokine responses. PMID- 29253103 TI - Characteristics and outcomes of hospitalised patients with vertebral fragility fractures: a systematic review. AB - Background: the complex management for patients presenting to hospital with vertebral fragility fractures provides justification for the development of specific services for them. A systematic review was undertaken to determine the incidence of hospital admission, patient characteristics and health outcomes of vertebral fragility fracture patients to inform the development of such a service. Methods: non-randomised studies of vertebral fragility fracture in hospital were included. Searches were conducted using electronic databases and citation searching of the included papers. Results: a total of 19 studies were included. The incidence of hospital admission varied from 2.8 to 19.3 per 10,000/year. The average patient age was 81 years, the majority having presented with a fall. A diagnosis of osteoporosis or previous fragility fracture was reported in around one-third of patients. Most patients (75% men and 78% women) had five or more co-pathologies. Most patients were managed non-operatively with a median hospital length of stay of 10 days. One-third of patients were started on osteoporosis treatment. Inpatient and 1-year mortality was between 0.9 and 3.5%, and 20 and 27%, respectively, between 34 and 50% were discharged from hospital to a care facility. Many patients were more dependent with activities of daily living on discharge compared to their pre-admission level. Older age and increasing comorbidities was associated with longer hospital stay and higher mortality. Conclusion: these findings indicate that specific hospital services for patients with vertebral fragility fractures should take into consideration local hospitalisation rates for the condition, and should be multifaceted providing access to diagnostic, therapeutic, surgical and rehabilitation interventions. PMID- 29253111 TI - Morbid obesity is not a contraindication to transport on extracorporeal support. AB - OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) transport has not been described in morbidly obese patients, a population that can pose significant challenges in obtaining vascular access, indexed flows and transport logistics. We sought to study the feasibility and safety of transporting obese and morbidly obese patients during extracorporeal support. METHODS: We conducted a retrospective review of all patients transported to our institution while receiving ECMO from September 2008 to September 2016. Survival to decannulation and survival to discharge were the primary outcomes. Obesity and morbid obesity were defined as a body mass index of greater than 30 kg/m2 and greater than 40 kg/m2, respectively. RESULTS: From 2008 to 2016, 222 patients were transported to our institution while receiving ECMO. Among these included patients, 131 were non obese (interquartile range 22-27 kg/m2), 63 were obese (interquartile range 31-35 kg/m2) and 28 were morbidly obese (interquartile range 41-49 kg/m2), with 6 patients having a body mass index greater than 50 kg/m2 (range 52.3-79 kg/m2). Pre-ECMO arterial blood gases, disease severity indices, cannulation strategies and transport distances were similar between these 3 groups. There was no mortality of patients during transport, and survival to discharge was 66% (n = 87) in non-obese patients, 56% (n = 35) in obese patients and 82% (n = 23) in morbidly obese patients (P = 0.042). On multivariable logistic regression analysis, body mass index was not a predictor of in-hospital mortality (odds ratio 0.99, 95% confidence interval 0.95-1.03; P = 0.517). CONCLUSIONS: Transport of morbidly obese patients receiving ECMO may be performed safely and with excellent results in the setting of a dedicated ECMO transport programme with well-established management protocols. PMID- 29253112 TI - Metabolite profiles of healthy aging index are associated with cardiovascular disease in African Americans: the Health, Aging, and Body Composition Study. AB - Background: Metabolic dysfunction is a hallmark of differential aging, specifically in African-Americans. Investigation of systemic metabolic state, multi-organ aging, and long-term cardiovascular outcome in African-Americans has not been reported. Methods: We studied 291 African-American males in the Health, Aging, and Body Composition (Health ABC) study to identify circulating metabolites related to the Newman healthy aging index (HAI; a multi-parametric score comprised of blood pressure, blood glucose, neurocognitive function, creatinine, and forced vital capacity). We examined the relationship of selected metabolites differential abundant at the extremes of HAI with long-term survival from cardiovascular mortality. Results: The median age was 73 years. We identified 19 metabolites differentially expressed in blood in 86 study participants at the extremes of HAI (HAI 0-3: N=30; vs. 8-10: N=56). At a median follow-up of 10 years, 78 participants (27%) died from cardiovascular causes. After adjustment for age, body mass index, presence of prevalent cardiovascular disease, creatinine, and HAI, 6 of these 19 metabolites were associated with long term cardiovascular mortality. While several metabolites had been previously reported in Caucasians (e.g., isocitrate), we identified several metabolites with unreported association with cardiac disease. Metabolites associated with HAI and cardiac death in African-Americans specified pathways relevant to nitric oxide, oxidative stress, mitochondrial function, urea cycle, and gut microbial metabolism. Conclusions: Metabolite profiling in African-Americans identified known and novel metabolic pathways linked to HAI and cardiovascular death. Further investigation in larger patient cohorts is required to uncover race-based signatures of cardiovascular disease with aging. PMID- 29253099 TI - Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. AB - See Josephs (doi:10.1093/brain/awx367) for a scientific commentary on this article.In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration (FTLD) were found in the microtubule-associated protein tau (MAPT) gene on chromosome 17 in families with frontotemporal degeneration and parkinsonism (FTDP-17). However, it was soon discovered that 50% of these families had a nearby mutation in progranulin. Regardless, the original FTDP-17 nomenclature has been retained for patients with MAPT mutations, with such patients currently classified independently from the different sporadic forms of FTLD with tau-immunoreactive inclusions (FTLD-tau). The separate classification of familial FTLD with MAPT mutations implies that familial forms cannot inform on the pathogenesis of the different sporadic forms of FTLD-tau. To test this assumption, this study pathologically assessed all FTLD-tau cases with a known MAPT mutation held by the Sydney and Cambridge Brain Banks, and compared them to four cases of four subtypes of sporadic FTLD-tau, in addition to published case reports. Ten FTLD tau cases with a MAPT mutation (K257T, S305S, P301L, IVS10?+?16, R406W) were screened for the core differentiating neuropathological features used to diagnose the different sporadic FTLD-tau subtypes to determine whether the categorical separation of MAPT mutations from sporadic FTLD-tau is valid. Compared with sporadic cases, FTLD-tau cases with MAPT mutations had similar mean disease duration but were younger at age of symptom onset (55 +/- 4 years versus 70 +/- 6 years). Interestingly, FTLD-tau cases with MAPT mutations had similar patterns and severity of neuropathological features to sporadic FTLD-tau subtypes and could be classified into: Pick's disease (K257T), corticobasal degeneration (S305S, IVS10?+?16, R406W), progressive supranuclear palsy (S305S) or globular glial tauopathy (P301L, IVS10?+?16). The finding that the S305S mutation could be classified into two tauopathies suggests additional modifying factors. Assessment of our cases and previous reports suggests that distinct MAPT mutations result in particular FTLD-tau subtypes, supporting the concept that they are likely to inform on the varied cellular mechanisms involved in distinctive forms of sporadic FTLD-tau. As such, FTLD-tau cases with MAPT mutations should be considered familial forms of FTLD-tau subtypes rather than a separate FTDP-17 category, and continued research on the effects of different mutations more focused on modelling their impact to produce the very different sporadic FTLD-tau pathologies in animal and cellular models. PMID- 29253117 TI - Cancer immunotherapy full speed ahead. PMID- 29253119 TI - Advance Care Planning for Patients with End-Stage Renal Disease. PMID- 29253116 TI - Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy. PMID- 29253120 TI - Long-term outcome of epicardial implantable cardioverter-defibrillator systems in children: results justify its preference in paediatric patients. AB - Aims: The question of whether transvenous or epicardial implantable cardioverter defibrillator (ICD) system is more beneficial in children and adolescents is controversially discussed. We sought to analyse the long-term outcome after implantation of ICDs using epicardial pacing/sensing and pleural shock leads. Methods and results: Retrospective analysis of 31 consecutive patients undergoing a total of 55 implantations of epicardial/pleural ICD systems below 20 years of age. Median age at implantation was 11.4 years (range 2.2-20) and median follow up 57 months (range 0.4-127). The ICDs were implanted for primary (n = 17) and for secondary prevention (n = 14). The first defibrillation threshold at implantation was <=25 J in 94% of the implant procedures. Appropriate shocks occurred in 6 of 31 patients. Inappropriate shocks occurred in 4 of 31 patients triggered by lead fracture, T-wave oversensing, sinus tachycardia, and atrial fibrillation. Freedom from first ICD discharge was 81, 71, and 71% at 3, 6, and 9 years, respectively. Reoperation was indicated in 16 of 31 patients for lead failure (n=11), end of battery life (n=10), generator migration (n=1) and recall (n=1); freedom from reoperation was 74 and 55% at 3 and 6 years. Conclusion: Paediatric epicardial/pleural ICD therapy is feasible, effective, and safe both in the short-term as well as in the long-term perspective at the price of relatively frequent surgical revisions. They do not generally result in an increased burden of inappropriate shocks. This ICD system meets the needs of the paediatric population and can be recommended as a first choice in this age group. PMID- 29253121 TI - Implementing a Nationally Recognized Pediatric-to-Adult Transitional Care Approach in a Major Children's Hospital. PMID- 29253118 TI - Long-term follow-up after ventricular septal defect repair in children: cardiac autonomic control, cardiac function and exercise capacity. AB - OBJECTIVES: Survival after surgical repair of a ventricular septal defect (VSD) is good, but, as in almost all congenital heart diseases, late complications are frequent in adulthood. The exact mechanisms, timing and who is at risk are not fully understood. Altered cardiac autonomic nervous system (ANS) activity might play a role in these long-term sequelae. The aim of this study was to extensively evaluate children late after VSD repair including their cardiac ANS activity, cardiac function and exercise capacity. METHODS: Thirty-three patients after surgical VSD repair and 66 healthy age-matched controls underwent 24-h monitoring of ANS control and cardiac output using impedance cardiography, detailed echocardiography and cardiopulmonary exercise testing. RESULTS: Ambulatory cardiac ANS control was not different between the patients and the controls. Right ventricular function, exercise capacity and ambulatory cardiac output were decreased in patients compared with the controls. No relationships were found between cardiac ANS activity and cardiac function. CONCLUSIONS: Long (average time after repair was 9.9 years) after successful surgical correction of a VSD, cardiac ANS control is not different from the controls. Right ventricular function and exercise capacity are impaired in VSD patients. Post-surgical outcome in these patients may be less benign than presently assumed; therefore, follow-up should be continued into adulthood to detect adverse outcomes in a timely fashion. PMID- 29253125 TI - Improving the quality of point-of-care testing. AB - Background: It is suggested that new models of primary care should have better access to test results through the use of point-of-care testing (POCT). Objective: To determine whether quality management of POCT leads to better results. Methods: A comprehensive search of the literature on quality management of POCT in primary care, where the impact of participation in quality management programmes had been investigated with relevant outcome measures. Results: Three databases were systematically searched using key words relevant to POCT and quality management, covering from 1945 to January 2017. Titles and abstracts were reviewed for relevance and papers selected for review and data extraction. Five observational studies were found in which the performance of POCT for specific analytes in external quality assurance (EQA) programmes was used to assess improvement over a period of time, varying from 3.5 to 15 years. The tests monitored were HbA1c, urine albumin, C-reactive protein, glucose and haemoglobin. In each case, the performance of the test against defined analytical criteria was used to judge improvement in performance. Different summary performance criteria were used, including the imprecision of results over a period of time (two studies) and meeting defined target values for bias and imprecision of measurement (three studies). Performance improved with time and was associated with regular participation in EQA schemes and with the use of internal quality control (IQC) procedures. Conclusions: These findings indicate that adoption of quality management for POCT, including participation in IQC and EQA, with the support of laboratory medicine professionals, will improve the quality of the results 'produced'. PMID- 29253115 TI - Intratumoral immunotherapy: using the tumor as the remedy. AB - Immune checkpoint-targeted monoclonal antibodies directed at Programmed Death Receptor 1 (PD-1), Programmed Death Ligand 1 (PD-L1) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4) are currently revolutionizing the prognosis of many cancers. By blocking co-inhibitory receptors expressed by antitumor T cells, these antibodies can break the immune tolerance against tumor cells and allow the generation of durable cancer immunity. Benefits in overall survival over conventional therapies have been demonstrated for patients treated with these immunotherapies, leading to multiple approvals of such therapies by regulatory authorities. However, only a minority of patients develop an objective tumor response with long-term survival benefits. Moreover, the systemic delivery of immunotherapies can be responsible for severe auto-immune toxicities. This risk increases dramatically with anti-PD(L)1 and anti-CTLA-4 combinations and currently hampers the development of triple combination immunotherapies. In addition, the price of these novel treatments is probably too high to be reimbursed by health insurances for all the potential indications where immunotherapy has shown activity (i.e. in more than 30 different cancer types). Intratumoral immunotherapy is a therapeutic strategy which aims to use the tumor as its own vaccine. Upon direct injections into the tumor, a high concentration of immunostimulatory products can be achieved in situ, while using small amounts of drugs. Local delivery of immunotherapies allows multiple combination therapies, while preventing significant systemic exposure and off-target toxicities. Despite being uncertain of the dominant epitopes of a given cancer, one can therefore trigger an immune response against the relevant neo-antigens or tumor-associated antigens without the need for their characterization. Such immune stimulation can induce a strong priming of the cancer immunity locally while generating systemic (abscopal) tumor responses, thanks to the circulation of properly activated antitumor immune cells. While addressing many of the current limitations of cancer immunotherapy development, intratumoral immunotherapy also offers a unique opportunity to better understand the dynamics of cancer immunity by allowing sequential and multifocal biopsies at every tumor injection. PMID- 29253126 TI - Joking about cancer as an avoidance strategy among US adults. AB - Findings from years of research on fear appeals suggest that individuals with low efficacy utilize avoidance strategies when they perceive a significant threat-a process called fear control. Some research suggests that joking could be an avoidance strategy. The current study identifies conditions in which people are more likely to joke about colorectal cancer and explores how this behavior may be associated with screening avoidance. Older adults (N = 209) recruited from eight different worksites completed a survey measuring fear appeal constructs and enactment of colorectal cancer-related joking. Results of a moderated mediation analysis suggest that men were more likely to joke about colorectal cancer than women, particularly if they perceived significant threat but had limited self efficacy, signifying fear control. Results support prior fear appeal research, suggesting that an increase in joking behavior concerning colorectal cancer may be indicative of screening avoidance, and describe belief-based mechanisms that explain differences between biological sex and joking. PMID- 29253122 TI - Risk and benefit of neoadjuvant therapy among patients undergoing resection for non-small-cell lung cancer. AB - OBJECTIVES: Neoadjuvant therapy has emerged as a favoured treatment paradigm for patients with clinical N2 disease undergoing surgical resection for non-small cell lung cancer. It is unclear whether such a treatment paradigm affects perioperative outcomes. We sought to examine the National Cancer Database (NCDB) to assess the impact of neoadjuvant therapy on perioperative outcomes and long term survival in these patients. METHODS: All patients with a history of non small-cell lung cancer undergoing anatomical resection between 2004 and 2014 were included. Thirty-day and 90-day mortality of all patients having neoadjuvant therapy versus those who did not were compared. In addition, the impact of neoadjuvant therapy on the overall survival of patients with clinical N2 disease was examined. RESULTS: Of the 134 428 selected patients, 9896 (7.4%) patients had neoadjuvant chemotherapy. Patients undergoing neoadjuvant therapy had a higher 30 day (3% vs 2.6%; P < 0.01) and 90-day mortality (6.5% vs 4.9%; P < 0.01). This association remained after adjusting for covariates. Among patients with clinical N2 disease (n = 10 139), 42.3%, 35.3% and 22.4% of patients had neoadjuvant, adjuvant and no chemotherapy, respectively. Univariable, multivariable and propensity score-weighted analyses indicated no difference in survival between patients receiving neoadjuvant and adjuvant chemotherapy. CONCLUSIONS: Neoadjuvant therapy may adversely affect perioperative outcomes without providing a survival advantage compared with adjuvant therapy in clinical N2 stage patients. Randomized controlled trials need to be conducted to examine this issue further. PMID- 29253123 TI - Free margin length and coaptation surface area in normal tricuspid aortic valve: an anatomical study. AB - OBJECTIVES: Aortic cusp free margins are a central target in most aortic valve repair operations to optimize valve coaptation. The objective of this anatomical study was to analyse the normal dimensions of free margin length (FML) and coaptation surface and to analyse their relationship with other valve and root dimensions in normal tricuspid aortic valves. METHODS: We analysed 25 aortic root homografts. Eight valve and root measurements were obtained from fresh specimens including the length of the free margin while applying appropriate tension on the structures. The valves were then fixed with formalin in the diastolic position under pressure to allow measurement of the coaptation surface. In addition to normal values, we analysed the correlations and ratios between the different measures. RESULTS: The mean FML was 34.3 +/- 3.1 mm. The FML was similar between the 3 cusps and correlated with all other valve and root measures. The ratio of the FML to the geometric height was 1.81, and the free edge length/sinotubular junction was 1.29. The mean coaptation surface was 122 +/- 21 mm2 per cusp and corresponded to 41% of the cusp surface. The central coaptation length was 3.3 +/ 0.8 mm, and the lateral coaptation length was 5.9 +/- 0.6 mm. The total coaptation surface per specimen was 184 +/- 32 mm2. CONCLUSIONS: We described the normal dimensions of the FML and coaptation surface in the tricuspid aortic valve. These measurements will serve in the further development of an objective method of free margin shortening based on intraoperative measurements of the FML to treat cusp prolapse and low coaptation after valve-sparing surgery. PMID- 29253127 TI - Isolation and evaluation of cocktail phages for the control of multidrug resistant Escherichia coli serotype O104: H4 and E. coli O157: H7 isolates causing diarrhea. AB - Escherichia coli serotype O157: H7 and E. coli O104: H4 are well known foodborne pathogens causing sever enteric illness. Using bacteriophages as biocontrol agents of some foodborne pathogens and multidrug-resistant (MDR) bacteria has a great attention nowadays. This study aims to test the effect of cocktail phages on the growth of some foodborne pathogens and MDR E. coli. Routine conventional PCR was used to confirm the identification of E. coli isolates. Double-layered culture technique was used to isolate phages from sewage water. Morphology of bacteriophage was described using transmission electron microscopy, and spot test was performed to determine host range of the phage cocktail. Phage cocktail of Siphoviridae and Podoviridae family infecting E. coli O157: H7, E. coli O104: H4 and untypeable E. coli (neither O157 nor O104) has been isolated from sewage water. Phage cocktail showed both lytic and lysogenic activity. Lytic activity was observed against E. coli O157: H7, E. coli O104: H4 isolates, Staphylococcus. aureus ATCC6538 and Pseudomonas aeruginosa ATCC 10145, while the lysogenic activity was observed against the untypeable strain. The tested phage cocktail showed a promising inhibitory action on E. coli O157: H7 and O104: H4, S. aureus ATCC6538 and P. aeruginosa ATCC 10145, suggesting the possibility of its use as a biocontrol tool or as natural food preservatives for many food products. PMID- 29253124 TI - Baicalin alleviates osteomyelitis by regulating TLR2 in the murine model. AB - Osteomyelitis is an inflammation of bone caused by invading organisms. TLR2, inflammatory cytokines and mitogen-activated protein kinase (MAPK) signaling pathway are involved in osteomyelitis. Baicalin, the major active constituent of the isolated root of Scutellaria lateriflora Georgi, has been shown to have anti inflammatory effects. In this study, the potentials of baicalin against osteomyelitis were evaluated. We treated mice and MC3T3-E1 cells with baicalin together with Staphylococcus aureus infection, and then analyzed the mice bone destruction, the expressions of TLR2 and osteogenic marker, the serum levels of proinflammatory factors and activation of MAPK signaling pathway. We also knocked down TLR2 by shRNA in MC3T3-E1 cells and detected the role of TLR2 in baicalin mediated inhibition of osteomyelitis. It was found that baicalin alleviated bone destruction in osteomyelitis. Baicalin decreased TLR2, alkaline phosphatase, osteopontin and collagen type I expressions. Baicalin decreased serum levels of proinflammatory factors IL-1beta, IL-6 and CRP. Baicalin inhibited activation of MAPK signaling pathway. The inhibition of osteomyelitis by baicalin depended on TLR2 inhibition. In summary, baicalin is able to alleviate osteomyelitis by regulating TLR2. PMID- 29253128 TI - A Transgenic Mouse Model for Detection of Tissue-Specific Thyroid Hormone Action. AB - Thyroid hormone (TH) is present in the systemic circulation and thus should affect all cells similarly in the body. However, tissues have a complex machinery that allows tissue-specific optimization of local TH action that calls for the assessment of TH action in a tissue-specific manner. Here, we report the creation of a TH action indicator (THAI) mouse model to study tissue-specific TH action. The model uses a firefly luciferase reporter readout in the context of an intact transcriptional apparatus and all elements of TH metabolism and transport and signaling. The THAI mouse allows the assessment of the changes of TH signaling in tissue samples or in live animals using bioluminescence, both in hypothyroidism and hyperthyroidism. Beyond pharmacologically manipulated TH levels, the THAI mouse is sufficiently sensitive to detect deiodinase-mediated changes of TH action in the interscapular brown adipose tissue (BAT) that preserves thermal homeostasis during cold stress. The model revealed that in contrast to the cold induced changes of TH action in the BAT, the TH action in this tissue, at room temperature, is independent of noradrenergic signaling. Our data demonstrate that the THAI mouse can also be used to test TH receptor isoform-specific TH action. Thus, THAI mouse constitutes a unique model to study tissue-specific TH action within a physiological/pathophysiological context and test the performance of thyromimetics. In conclusion, THAI mouse provides an in vivo model to assess a high degree of tissue specificity of TH signaling, allowing alteration of tissue function in health and disease, independently of changes in circulating levels of TH. PMID- 29253113 TI - Preclinical and clinical development of neoantigen vaccines. AB - Cancer neoantigens are antigens that result from somatic mutations present in individual cancers. Neoantigens are considered important targets for cancer immunotherapy because of their immunogenicity and lack of expression in normal tissues. Next-generation sequencing technologies and computational analysis have recently made neoantigen discovery possible. Although neoantigens are important targets of checkpoint blockade therapy, neoantigen vaccines are currently being investigated in preclinical models and early-phase human clinical trials. Preliminary results from these clinical trials demonstrate that dendritic cell, synthetic long peptide, and RNA-based neoantigen vaccines are safe, and capable of inducing both CD8+ and CD4+ neoantigen-specific T-cell responses. We and others are testing neoantigen vaccines in melanoma, breast cancer, non-small-cell lung cancer and other cancer types. Since cancers have evolved mechanisms to escape immune control, it is particularly important to study the efficacy of neoantigen vaccines in combination with other immunotherapies including checkpoint blockade therapy, and immune therapies targeting the immunosuppressive tumor microenvironment. PMID- 29253134 TI - Theorizing a model information pathway to mitigate the menstrual taboo. AB - The impact of menstruation on the society is directly seen in the educational opportunities, quality of life and professional endeavors of females. However, lack of menstrual hygiene management has indirect implication on the balance and development of the society and nation. This study is set in the Indian context. The researcher identifies actors with a potential of mitigating menstrual taboo and then theorizes an optimal information pathway to mitigate menstrual taboo. Diffusion of innovation, framing and agenda setting theories contribute as frameworks in the creation of an optimal pathway to dissolve the menstrual taboo. The actors identified in this model are scholars, health activists, students, NGOs, media, government, corporations and villages or communities. The determinants for the direction and the order of the pathway to diffuse knowledge and confidence among these actors are the ultimate goal and sustainability of the model, strengths and weaknesses of actors, and actors' extent of influence. Considering the absence of an existing alternate, this model pathway provides a solid framework purely from a theoretical perspective. Theoretically, this model pathway is possible, practical and optimal. PMID- 29253130 TI - Things are not always what they seem: pacemaker dysfunction or just a technical limitation? PMID- 29253131 TI - Identification of capillary rarefaction using intracoronary wave intensity analysis with resultant prognostic implications for cardiac allograft patients. AB - Aims: Techniques for identifying specific microcirculatory structural changes are desirable. As such, capillary rarefaction constitutes one of the earliest changes of cardiac allograft vasculopathy (CAV) in cardiac allograft recipients, but its identification with coronary flow reserve (CFR) or intracoronary resistance measurements is hampered because of non-selective interrogation of the capillary bed. We therefore investigated the potential of wave intensity analysis (WIA) to assess capillary rarefaction and thereby predict CAV. Methods and results: Fifty two allograft patients with unobstructed coronary arteries and normal left ventricular (LV) function were assessed. Adequate aortic pressure and left anterior descending artery flow measurements at rest and with intracoronary adenosine were obtained in 46 of which 2 were lost to follow-up. In a subgroup of 15 patients, simultaneous RV biopsies were obtained and analysed for capillary density. Patients were followed up with 1-3 yearly screening angiography. A significant relationship with capillary density was noted with CFR (r = 0.52, P = 0.048) and the backward decompression wave (BDW) (r = -0.65, P < 0.01). Over a mean follow-up of 9.3 +/- 5.2 years patients with a smaller BDW had an increased risk of developing angiographic CAV (hazard ratio 2.89, 95% CI 1.12-7.39; P = 0.03). Additionally, the index BDW was lower in those who went on to have a clinical CAV-events (P = 0.04) as well as more severe disease (P = 0.01). Conclusions: Within cardiac transplant patients, WIA is able to quantify the earliest histological changes of CAV and can predict clinical and angiographic outcomes. This proof-of-concept for WIA also lends weight to its use in the assessment of other disease processes in which capillary rarefaction is involved. PMID- 29253137 TI - Mid-term results and risks of isolated tricuspid valve reoperation following left sided valve surgery. AB - OBJECTIVES: Tricuspid valve reoperation (TVR) following left-sided valve surgery (LSVS) is a high-risk procedure. This study was conducted to analyse the mid-term results and risks of isolated TVR following LSVS. METHODS: From May 2007 to December 2016, 91 patients who underwent isolated TVR following LSVS were enrolled in this study. RESULTS: The patients comprised 23 men and 68 women with a mean age of 57.5 +/- 8.0 years (range 33-75 years). The in-hospital mortality rate was 2.2% (2 of 91 patients). Fourteen (15.4%) procedures were performed through a median sternotomy, whereas 77 (84.6%) were performed through a right thoracotomy. One patient underwent tricuspid valve repair, while the others underwent valve replacement including 16 (17.6%) cases involving mechanical valves and 74 (81.3%) involving tissue valves. Eight (9.0%) deaths occurred during the follow-up at 9.21 +/- 18.8 months (range 1-108 months), including 5 cardiac deaths. The Kaplan-Meier survival rates at 1 year and 5 years were 97.7% and 90.0%, respectively. Previous aortic and mitral valve replacement [odds ratio (OR) 0.161, P = 0.0015], preoperative central venous pressure (OR 1.202, P = 0.0353), pulmonary artery pressure (OR 1.075, P = 0.0134) and left ventricular end-systolic diameter (OR 1.13, P = 0.0155) were the risk factors for a longer intensive care duration. The valve type had no significant effect on the survival of patients who had undergone valve replacement. CONCLUSIONS: Isolated TVR is a safe and effective surgery for tricuspid valve lesions following LSVS, and right thoracotomy may be a reasonable choice. PMID- 29253135 TI - Obesity and Nursing Home Care in the United States: A Systematic Review. AB - Background and Objectives: Obesity is increasing among people residing in nursing homes, and resident obesity substantially affects services needed, equipment and facilities provided, and morbidity in this setting. The purpose of this article is to describe the scope and depth of evidence regarding the impact of obesity among nursing home residents in the United States. Research Design and Methods: A systematic literature review was performed in PubMed, EMBASE, CINAHL, and Web of Science databases as well as additional hand-searched documents. Included articles were published from 1997 to March 2017. The characteristics and content of the included articles were systematically reviewed and reported. Results: Twenty-eight studies met inclusion criteria for review. The median study size was 636 residents (interquartile range 40-11,248); 18 (64%) studies were retrospective and 10 (36%) were prospective in nature. Ten (36%) studies examined medical and functional morbidity, 10 (36%) examined health system effects, and 5 (18%) examined the risk of admission to nursing homes. Most studies found that obesity poses serious issues to resident health and the provision of health care, as well as broad health system and nursing challenges in the provision of high quality nursing home care and services. Discussion and Implications: Although obesity affects about one in four nursing home residents in the United States, relatively limited evidence exists on the complex challenges of obesity for their residents and their care. A continued focus on resident quality of life, health system improvement, and nursing best practices for properly caring for individuals with obesity is needed. PMID- 29253132 TI - Bracing For Hurricanes: A Qualitative Analysis of the Extent and Level of Preparedness Among Older Adults. AB - Background and Objectives: Older adults are at greater risk than other age groups throughout all stages of a disaster. To date, the bulk of empirical disaster research concerning older adults has centered on the consequences of a disaster. This study focuses on older residents in a hurricane-prone community and investigates the extent and level of their reported preparedness for hurricanes, which takes place prior to a disaster. Research Design and Methods: This study engaged year-round older residents of Sarasota County, Florida. Semi-structured interviews were conducted for 30 older individuals of 60-90 years of age. Transcripts were analyzed by qualitative content analysis integrating both inductive and deductive coding approaches. Results: Older respondents overwhelmingly practiced survival preparedness by only storing water and food supplies, but lacked efforts in planning and structural preparedness due to insufficient awareness and financial resources. Most respondents asserted hurricane readiness despite the shortage of preparation practices because "being prepared" is defined differently for different individuals. Many respondents claimed hurricane experience and subjective interpretation rather than objective nature of prior exposure appeared to have a greater influence over respondents' reported preparedness behavior. Discussion and Implications: This study adds to the emerging, but highly limited body of work specifically addressing disaster preparedness among older adults. The interview data inclusive of respondents' voices and values suggest that expectations by emergency managers that older individuals will follow hurricane preparedness recommendations may be misplaced. More practical and age-specific interventions are needed to promote disaster preparedness of older adults. PMID- 29253140 TI - Biochemical and clinical comparisons of segmental maxillary posterior tooth distal movement between two different force magnitudes. AB - Background/objectives: Maxillary tooth distal movement is a treatment option for Class II malocclusion. This prospective clinical study (split-mouth design) was aimed to compare chondroitin sulphate (CS) levels in gingival crevicular fluid (GCF), the rates of tooth movement, and patient pain and discomfort during segmental maxillary posterior tooth distal movement using either 120 or 180 g of retraction force. Materials and methods: Twenty patients (6 males and 14 females; aged 18.85 +/- 4.38 years) with Class II malocclusion were recruited. The force magnitudes were controlled at 120 or 180 g, randomly assigned to either the right or left five-tooth segments. Gingival crevicular fluid samples were collected with Periopaper(r) strips. Competitive ELISA with monoclonal antibody was used to measure CS levels in GCF. The rates of segmental maxillary posterior tooth distal movement, and the amount of pain and discomfort were evaluated. Results: The median CS levels during the segmental distal movement period were significantly greater than those before the segmental distal movement period (P < 0.05). At each 1-week period during segmental distal movement, the differences between the median CS levels induced by the two different force magnitudes were not significantly different. The rates of segmental distal movement induced by the two different force magnitudes were not significantly different. The mean visual analog scale scores for pain and discomfort with 180 g of retraction force was significantly greater than that with 120 g (P < 0.05). Conclusions: One hundred and twenty grams of retraction force was sufficient to cause segmental distal movement, as indicated by biochemically assessed bone remodeling activity and a similar rate of tooth movement to that caused by 180 g of retraction force; it also produced less patient pain and discomfort. Trial Registration: The study has been registered as TCTR20170728001. PMID- 29253136 TI - Cost-effectiveness of health systems strengthening interventions in improving maternal and child health in low- and middle-income countries: a systematic review. AB - Health systems strengthening (HSS) interventions are increasingly being implemented to improve maternal and child health (MCH) services in low- and middle-income countries (LMICs). This study reviews global literature on cost effectiveness of HSS interventions in improving MCH. A systematic review was conducted. Keywords, based on World Health Organization framework on health systems and prior studies, were applied to search in bibliographic databases and on the web. Articles that estimated cost-effectiveness of HSS interventions in LMICs were included in the analysis. Each of the 24 selected studies from 15 countries was assessed in terms of quality and biases using Cochrane's criteria. Review Manager and an Excel template were used to extract data and synthesize findings. HSS interventions concentrated on the components of service delivery, health financing, human resources and quality improvement. Within each component, there existed diverse strategies to strengthen health systems. Among the 24 studies, 15 were rated as high quality, 5 as medium and 4 as low quality. A majority of studies reported cost per disability-adjusted life year (DALY) averted or cost per quality-adjusted life year (QALY) gained; other studies reported cost per life saved or life year gained. However, studies used mixed perspectives of analyses. Compared with gross domestic product per capita, interventions in studies reporting cost per DALY averted or QALY gained were all cost-effective, including performance-based financing, health insurance and quality improvement. This review shows the diversity of HSS interventions in improving MCH, and their potential cost-effectiveness. However, the different perspectives employed in the studies, costing components included in the analyses, and heterogeneous measures of effectiveness and outputs, made it challenging to compare cost-effectiveness across all studies, calling for more and standardized cost-effectiveness studies. For policy making, it is critical to examine long-term cost-effectiveness of programs and cost-effectiveness of synergistic demand- and supply-side interventions. PMID- 29253139 TI - Impact of Targeted Tuberculosis Vaccination Among a Mining Population in South Africa: A Model-Based Study. AB - Optimizing the use of new tools, such as vaccines, may play a crucial role in reaching global targets for tuberculosis (TB) control. Some of the most promising candidate vaccines target adults, although high-coverage mass vaccinations may be logistically more challenging among this population than among children. Vaccine delivery strategies that target high-risk groups or settings might yield proportionally greater impact than do those that target the general population. We developed an individual-based TB transmission model representing a hypothetical population consisting of people who worked in South African gold mines or lived in associated labor-sending communities. We simulated the implementation of a postinfection adult vaccine with 60% efficacy and a mean effect duration of 10 years. We then compared the impact of a mine-targeted vaccination strategy, in which miners were vaccinated while in the mines, with that of a community-targeted strategy, in which random individuals within the labor-sending communities were vaccinated. Mine-targeted vaccination averted an estimated 0.37 TB cases per vaccine dose compared with 0.25 for community targeted vaccination, for a relative efficacy of 1.46 (95% range, 1.13-1.91). The added benefit of mine-targeted vaccination primarily reflected the disproportionate demographic burden of TB among the population of adult males as a whole. As novel vaccines for TB are developed, venue-based vaccine delivery that targets high-risk demographic groups may improve both vaccine feasibility and the impact on transmission. PMID- 29253138 TI - Success factors for implementing and sustaining a mature electronic medical record in a low-resource setting: a case study of iSante in Haiti. AB - Electronic health information systems, including electronic medical records (EMRs), have the potential to improve access to information and quality of care, among other things. Success factors and challenges for novel EMR implementations in low-resource settings have increasingly been studied, although less is known about maturing systems and sustainability. One systematic review identified seven categories of implementation success factors: ethical, financial, functionality, organizational, political, technical and training. This case study applies this framework to iSante, Haiti's national EMR in use in more than 100 sites and housing records for more than 750 000 patients. The author group, consisting of representatives of different agencies within the Haitian Ministry of Health (MSPP), funding partner the Centers for Disease Control and Prevention (CDC) Haiti, and implementing partner the International Training and Education Center for Health (I-TECH), identify successes and lessons learned according to the seven identified categories, and propose an additional cross-cutting category, sustainability. Factors important for long-term implementation success of complex information systems are balancing investments in hardware and software infrastructure upkeep, user capacity and data quality control; designing and building a system within the context of the greater eHealth ecosystem with a plan for interoperability and data exchange; establishing system governance and strong leadership to support local system ownership and planning for system financing to ensure sustainability. Lessons learned from 10 years of implementation of the iSante EMR system are relevant to sustainability of a full range of increasingly interrelated information systems (e.g. for laboratory, supply chain, pharmacy and human resources) in the health sector in low-resource settings. PMID- 29253129 TI - Potentiating tangle formation reduces acute toxicity of soluble tau species in the rat. AB - Tauopathies are neurodegenerative diseases characterized by the aggregation of tau protein. These pathologies exhibit a wide variety of clinical and anatomo pathological presentations, which may result from different pathological mechanisms. Although tau inclusions are a common feature in all these diseases, recent evidence instead implicates small oligomeric aggregates as drivers of tau induced toxicity. Hence in vivo model systems displaying either soluble or fibrillary forms of wild-type or mutant tau are needed to better identify their respective pathological pathways. Here we used adeno-associated viruses to mediate gene transfer of human tau to the rat brain to develop models of pure tauopathies. Two different constructs were used, each giving rise to a specific phenotype developing in less than 3 months. First, hTAUWT overexpression led to a strong hyperphosphorylation of the protein, which was associated with neurotoxicity in the absence of any significant aggregation. In sharp contrast, its co-expression with the pro-aggregation peptide TauRD-DeltaK280 in the hTAUProAggr group strongly promoted its aggregation into Gallyas-positive neurofibrillary tangles, while preserving neuronal survival. Our results support the hypothesis that soluble tau species are key players of tau-induced neurodegeneration. PMID- 29253142 TI - Surgical treatment in Takayasu's arteritis with patch reconstruction of the left anterior descending coronary artery. PMID- 29253133 TI - Coaching to create a smoke-free home in a brief secondhand smoke intervention. AB - Few community interventions exist to reduce secondhand exposure to tobacco smoke in the home. This study presents the coaching process of a larger intervention to promote smoke-free homes across an efficacy and 2 effectiveness trials. It furthers assesses the coaching call's reach and participants' satisfaction with the call across three intervention sites. The sources of the data were from baseline and 3-month follow-up surveys, coaching forms or online tracking system and interviews with coaches. Reach for the coaching call across trials was fairly high from 72% to 92%. Overall, the majority of participants were highly satisfied with the intervention (M = 3.76) and found it useful in creating a smoke-free home (M = 3.63). Common goals set were changing the environment to support a home smoking ban (e.g. putting up signs, removing ashtrays) (82%) or picking a date (60%). Challenges to a smoke-free home were consistent with other literature on barriers related to household smoking restrictions, including need for assistance in quitting, outside weather and smokers who do not want to quit. Additional research is needed to explore differential reach and reactions to the coaching call as it is disseminated and the impact of coaching call on the outcome of a smoke-free home. PMID- 29253143 TI - Effects of word-of-mouth on the behavior of Austrian blood donors: a case study of the Red Cross Blood Donation Service. AB - The procurement of blood is an essential challenge of today's health care. Current studies emphasize the influence of word-of-mouth (WOM) on health care behavior, including blood donation. Still, there exists no study which systematically investigates how WOM affects the behavior of blood donors. Therefore, this paper aims to contribute to this lack of research by focusing on Austrian blood donors as possible receivers and senders of WOM. A survey was distributed to 300 donors of the Austrian Red Cross with a return of 245 surveys. The results highlight the strong influence of WOM on the awareness of the blood service and the willingness to donate blood. Further, structured and organized procedures, friendly employees and respectful interaction were found to be important factors determining willingness to recommend blood donation. Family members as well as friends are the preferred WOM-receivers and the personal face to-face contact is the favored channel of communication. The results also show that WOM-behavior is strongly influenced by factors such as age, gender and donation frequency. By helping blood bank managers to better understand how WOM affects donation intention and behavior, this study provides a new approach to attract blood donors. PMID- 29253141 TI - The causes of human variability: a Darwinian view. PMID- 29253146 TI - Funding sources of practice-changing trials. PMID- 29253144 TI - Polymorphisms in the Wilms Tumor Gene Are Associated With Interindividual Variations in Rubella Virus-Specific Cellular Immunity After Measles-Mumps Rubella II Vaccination. AB - Rubella vaccination induces widely variable immune responses in vaccine recipients. While rubella vaccination is effective at inducing immunity to rubella infection in most subjects, up to 5% of individuals do not achieve or maintain long-term protective immunity. To expand upon our previous work identifying genetic polymorphisms that are associated with these interindividual differences in humoral immunity to rubella virus, we performed a genome-wide association study in a large cohort of 1843 subjects to discover single nucleotide polymorphisms (SNPs) associated with rubella virus-specific cellular immune responses. We identified SNPs in the Wilms tumor protein gene (WT1) that were significantly associated (P < 5 * 10-8) with interindividual variations in rubella-specific interleukin 6 secretion from subjects' peripheral blood mononuclear cells postvaccination. No SNPs were found to be significantly associated with variations in rubella-specific interferon-gamma secretion. Our findings demonstrate that genetic polymorphisms in the WT1 gene in subjects of European ancestry are associated with interindividual differences in rubella virus-specific cellular immunity after measles-mumps-rubella II vaccination. PMID- 29253150 TI - Immunology of cystic echinococcosis (hydatid disease). AB - Background: The neglected disease cystic echinococcosis is caused by larval Echinococcus granulosus flatworms, which form bladder-like hydatid cysts in liver, lungs, and other organs. Sources of data: Published literature. Areas of agreement: Establishing larvae are susceptible to antibody-dependent killing, as attested by successful animal vaccination, whereas once established they are partially protected by the so-called laminated layer. Host responses are Th2 dominated, with a Th1 component. Diagnostic antigens from cyst fluid are known, but responses appear absent in one-fifth of patients. Areas of controversy: Is evasion mainly based on induction of Th2 or regulatory responses by the parasite? Growing points: The parasite induces regulatory responses. The laminated layer has immune-regulatory properties. Areas timely for developing research: Develop tools for functional genomics; characterize immunologically interesting proteins suggested by genomic information; analyse infection in broader context of granulomatous responses; identify molecules secreted/excreted by intact larvae/cysts towards their outside, including diffusible immune-regulators. PMID- 29253149 TI - Adipose-derived stem cells in orthopaedic pathologies. AB - Introduction: To examine the current literature regarding the clinical application of adipose-derived stem cells (ADSCs) for the management of orthopaedic pathologies. Sources of data: MEDLINE,SCOPUS, CINAHL and EMBASE (1950 to April 14, 2017) were searched by two independent investigators for articles published in English. Reviews, meta-analyses, expert opinions, case reports, mini case series and editorials were excluded. Furthermore, we excluded animal studies, cadaveric studies and in vitro studies. Areas of agreement: ADSCs seem to produce excellent clinical results. However, the length and modalities of follow-up in the different conditions are extremely variable. Nevertheless, it appears that the use of adipose-derived stem cells is associated with subjective and objective clinical improvements and minimal complication rates. Areas of controversy: None of the studies identified is a randomized double-blinded trial, and most of the selected studies present major limitations, and different methods, confounding the results of our review. Growing points: It is necessary to conduct more and better studies to ascertain whether ADSCs really play a role in orthopaedic surgery with particular attention to ADSCs harvesting method, type of administration and the conditions treated. Areas timely for developing research: The current literature regarding the use of ADSCs for orthopaedic pathologies is limited. At present, long-term safety is the biggest challenge of ADSCs based regenerative medicine. Level of evidence: Level IV-Study of Level I, II, III, IV. PMID- 29253148 TI - Changing Patterns of Emerging Zoonotic Diseases in Wildlife, Domestic Animals, and Humans Linked to Biodiversity Loss and Globalization. AB - The fundamental human threats to biodiversity including habitat destruction, globalization, and species loss have led to ecosystem disruptions altering infectious disease transmission patterns, the accumulation of toxic pollutants, and the invasion of alien species and pathogens. To top it all, the profound role of climate change on many ecological processes has affected the inability of many species to adapt to these relatively rapid changes. This special issue, "Zoonotic Disease Ecology: Effects on Humans, Domestic Animals and Wildlife," explores the complex interactions of emerging infectious diseases across taxa linked to many of these anthropogenic and environmental drivers. Selected emerging zoonoses including RNA viruses, Rift Valley fever, trypanosomiasis, Hanta virus infection, and other vector-borne diseases are discussed in detail. Also, coprophagous beetles are proposed as important vectors in the transmission and maintenance of infectious pathogens. An overview of the impacts of climate change in emerging disease ecology within the context of Brazil as a case study is provided. Animal Care and Use Committee requirements were investigated, concluding that ecology journals have low rates of explicit statements regarding the welfare and wellbing of wildlife during experimental studies. Most of the solutions to protect biodiversity and predicting and preventing the next epidemic in humans originating from wildlife are oriented towards the developed world and are less useful for biodiverse, low-income economies. We need the development of regional policies to address these issues at the local level. PMID- 29253153 TI - Fosfomycin efficacy and emergence of resistance among Enterobacteriaceae in an in vitro dynamic bladder infection model. AB - Background: Urinary tract infections (UTIs) are among the most common bacterial infections and a frequent indication for antibiotic use. Fosfomycin, an important oral antibiotic for outpatient UTIs, remains a viable option for MDR uropathogens. We aimed to perform pharmacodynamic profiling simulating urinary concentrations to assess the adequacy of the current dosing regimen. Methods: A dynamic in vitro bladder infection model was developed, replicating urinary fosfomycin concentrations after gastrointestinal absorption, systemic distribution and urinary elimination. Concentrations were measured by LC-MS/MS. Twenty-four Enterobacteriaceae strains (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae; MIC range 0.25-64 mg/L) were examined. Pathogen kill and emergence of resistance was assessed over 72 h. Results: Observed in vitro fosfomycin concentrations accurately simulated urinary fosfomycin exposures (Tmax 3.8 +/- 0.5 h; Cmax 2630.1 +/- 245.7 mg/L; AUC0-24 33 932.5 +/- 1964.2 mg.h/L). Fifteen of 24 isolates regrew, with significant rises in fosfomycin MIC (total population MIC50 4 to 64 mg/L, MIC90 64 to > 1024 mg/L, P = 0.0039; resistant subpopulation MIC50 128 to > 1024 mg/L, MIC90 >1024 mg/L, P = 0.0020). E. coli and E. cloacae isolates were killed with pharmacokinetic/pharmacodynamic EI50 of fAUC0-24/MIC = 1922, fCmax/MIC = 149 and fTime>4*MIC = 44 h. In contrast, K. pneumoniae isolates were not reliably killed. Conclusions: Using dynamic in vitro simulations of urinary fosfomycin exposures, E. coli and E. cloacae isolates with MIC >16 mg/L, and all K. pneumoniae isolates, were not reliably killed. Emergence of resistance was significant. This challenges fosfomycin dosing and clinical breakpoints, and questions the utility of fosfomycin against K. pneumoniae. Further work on in vitro dose optimization is required. PMID- 29253151 TI - Management of Zika virus in pregnancy: a review. AB - Introduction/background: Since 2015, an epidemic of Zika virus spread across the Americas. This coincided with an increased incidence of microcephaly reported at birth in Brazil, with subsequent evidence of a causal association. Sources of data: Systemic reviews, observational studies, public health organizations. Areas of agreement: Zika virus causes microcephaly and brain abnormalities in infants born to mothers infected during or shortly before pregnancy. Zika virus is a trigger for Guillain Barre Syndrome. Whilst mosquito bite is the main route of transmission, sexual transmission is another confirmed route. Areas of controversy: Uncertainty remains regarding the proportion of Zika-infected pregnancies that will give rise to a significantly affected infant. Growing points: The development of a vaccine remains a priority whilst public health efforts continue to educate at risk populations on reducing transmission. Areas timely for developing research: Follow-up studies of affected infants are vital to inform on prognosis and guide screening programmes of the future. PMID- 29253145 TI - Noncommunicable Diseases in People Living With HIV: Time for Integrated Care. PMID- 29253147 TI - Single-molecule sequencing and optical mapping yields an improved genome of woodland strawberry (Fragaria vesca) with chromosome-scale contiguity. AB - Background: Although draft genomes are available for most agronomically important plant species, the majority are incomplete, highly fragmented, and often riddled with assembly and scaffolding errors. These assembly issues hinder advances in tool development for functional genomics and systems biology. Findings: Here we utilized a robust, cost-effective approach to produce high-quality reference genomes. We report a near-complete genome of diploid woodland strawberry (Fragaria vesca) using single-molecule real-time sequencing from Pacific Biosciences (PacBio). This assembly has a contig N50 length of ~7.9 million base pairs (Mb), representing a ~300-fold improvement of the previous version. The vast majority (>99.8%) of the assembly was anchored to 7 pseudomolecules using 2 sets of optical maps from Bionano Genomics. We obtained ~24.96 Mb of sequence not present in the previous version of the F. vesca genome and produced an improved annotation that includes 1496 new genes. Comparative syntenic analyses uncovered numerous, large-scale scaffolding errors present in each chromosome in the previously published version of the F. vesca genome. Conclusions: Our results highlight the need to improve existing short-read based reference genomes. Furthermore, we demonstrate how genome quality impacts commonly used analyses for addressing both fundamental and applied biological questions. PMID- 29253157 TI - Antibiotic susceptibility of Francisella tularensis subsp. holarctica strains isolated from tularaemia patients in France between 2006 and 2016. AB - Objectives: To determine the in vitro susceptibility to 18 antibiotics of human strains of Francisella tularensis isolated in France between 2006 and 2016, to check the absence of acquired resistance and to evaluate potential therapeutic alternatives. Methods: Fifty-nine clinically unrelated F. tularensis subsp. holarctica strains identified at the French National Reference Centre for Francisella as belonging to the phylogenetic subclade B.FTNF002-00 were used. MICs were determined in CAMHB medium supplemented with 2% PolyViteX(r), using the CLSI broth microdilution method. Results: All strains were susceptible to fluoroquinolones (ofloxacin, ciprofloxacin, levofloxacin and moxifloxacin; MIC range: 0.016-0.25 mg/L), aminoglycosides (gentamicin and tobramycin; MIC range: <=0.03-0.25 mg/L), doxycycline (MIC range: 0.125-0.25 mg/L) and chloramphenicol (MIC range: 0.5-2 mg/L). The erythromycin MIC range (0.5-2 mg/L) confirmed that all isolates belonged to biovar I of F. tularensis subsp. holarctica. Azithromycin and telithromycin displayed lower MIC ranges (0.25-1 and 0.03-0.5 mg/L, respectively). The tigecycline MIC range (0.25-1 mg/L) was slightly higher than that of doxycycline. All strains were resistant to ampicillin, meropenem, daptomycin, clindamycin and linezolid. Conclusions: F. tularensis strains isolated in France remain susceptible to antibiotic classes recommended for tularaemia treatment. Because fluoroquinolones display the lowest MIC90, have bactericidal activity and have lower therapeutic failure rates compared with doxycycline, they may be advocated as first-line treatment of mild cases of tularaemia, predominant in Europe. MIC data also indicate that azithromycin or telithromycin may be possible therapeutic options against biovar I strains from Western Europe in case of contraindication to first-line antibiotics. PMID- 29253158 TI - The Impact of Global Environmental Changes on Infectious Disease Emergence with a Focus on Risks for Brazil. AB - Environmental changes have a huge impact on the emergence and reemergence of certain infectious diseases, mostly in countries with high biodiversity and serious unresolved environmental, social, and economic issues. This article summarizes the most important findings with special attention to Brazil and diseases of present public health importance in the country such as Chikungunya, dengue fever, yellow fever, Zika, hantavirus pulmonary syndrome, leptospirosis, leishmaniasis, and Chagas disease. An extensive literature review revealed a relationship between infectious diseases outbreaks and climate change events (El Nino, La Nina, heatwaves, droughts, floods, increased temperature, higher rainfall, and others) or environmental changes (habitat fragmentation, deforestation, urbanization, bushmeat consumption, and others). To avoid or control outbreaks, integrated surveillance systems and effective outreach programs are essential. Due to strong global and local influence on emergence of infectious diseases, a more holistic approach is necessary to mitigate or control them in low-income nations. PMID- 29253152 TI - Whole genome analysis of cephalosporin-resistant Escherichia coli from bloodstream infections in Australia, New Zealand and Singapore: high prevalence of CMY-2 producers and ST131 carrying blaCTX-M-15 and blaCTX-M-27. AB - Objectives: To characterize MDR Escherichia coli from bloodstream infections (BSIs) in Australia, New Zealand and Singapore. Methods: We collected third generation cephalosporin-resistant (3GC-R) E. coli from blood cultures in patients enrolled in a randomized controlled trial from February 2014 to August 2015. WGS was used to characterize antibiotic resistance genes, MLST, plasmids and phylogenetic relationships. Antibiotic susceptibility was determined using disc diffusion and Etest. Results: A total of 70 3GC-R E. coli were included, of which the majority were ST131 (61.4%). BSI was most frequently from a urinary source (69.6%), community associated (62.9%) and in older patients (median age 71 years). The median Pitt score was 1 and ICU admission was infrequent (3.1%). ST131 possessed more acquired resistance genes than non-ST131 (P = 0.003). Clade C1/C2 ST131 predominated (30.2% and 53.5% of ST131, respectively) and these were all ciprofloxacin resistant. All clade A ST131 (n = 6) were community associated. The predominant ESBL types were blaCTX-M (80.0%) and were strongly associated with ST131 (95% carried blaCTX-M), with the majority blaCTX-M-15. Clade C1 was associated with blaCTX-M-14 and blaCTX-M-27, whereas blaCTX-M-15 predominated in clade C2. Plasmid-mediated AmpC genes (mainly blaCMY-2) were frequent (17.1%) but were more common in non-ST131 (P < 0.001) isolates from Singapore and Brisbane. Two strains carried both blaCMY-2 and blaCTX-M. The majority of plasmid replicon types were IncF. Conclusions: In a prospective collection of 3GC-R E. coli causing BSI, community-associated Clade C1/C2 ST131 predominate in association with blaCTX-M ESBLs, although a significant proportion of non-ST131 strains carried blaCMY-2. PMID- 29253156 TI - A life-threatening infection due to Corynebacterium striatum: a lesson learned. AB - Because the genus Corynebacterium colonize the human skin, detection of Corynebacterium striatum in a sterile blood specimen is sometimes considered as contamination. An 80-year-old man who underwent cardiovascular operation presented with high-grade fever postoperatively. Corynebacterium striatum was detected in the blood and wound exudate, and the patient was diagnosed with mediastinitis due to Corynebacterium striatum. One month earlier, a patient with similar symptoms due to C. striatum-related mediastinitis died in our care. The Corynebacterium striatum isolates from both patients had identical biochemical and genetic characteristics, suggesting that Corynebacterium striatum was acquired nosocomially. We have learnt a lesson from this negative experience: early diagnosis of Corynebacterium striatum-related infection and early administration of glycopeptide antibiotics could have saved this patient. It is notable that C. striatum can cause life-threatening infection after cardiovascular operation. PMID- 29253162 TI - Comment on: Benznidazole treatment safety: the Medecins Sans Frontieres experience in a large cohort of Bolivian patients with Chagas' disease. PMID- 29253159 TI - Cardiac optogenetics: a novel approach to cardiovascular disease therapy. AB - Optogenetics is a cell-type specific and high spatial-temporal resolution method that combines genetic encoding of light-sensitive proteins and optical manipulation techniques. Optogenetics technology provides a novel approach for research on cardiac arrhythmia treatment, including pacing, recovering the conduction system, and achieving cardiac resynchronization with precise and low energy optical control. Photosensitive proteins, which usually act as ion channels, pumps, or receptors, are delivered to target cells, where they respond to light pulses of specific wavelengths, evoke transient flows of transmembrane ion currents, and induce signal transmission. With the development of gene technology, the in vivo efficiency of optogenetics in cardiology has been trialed, and in vitro experiments have been performed to test its potential in cardiac electrophysiology. Challenges for applying optogenetics in large animals and humans include the effectiveness, safety, and long-term expression of photosensitive proteins, unscattered and unattenuated exogenous light stimulation, and the need for implantable miniature light stimulators. Photosensitive proteins, genetic engineering technology, and light equipment are essential for experiments in cardiac optogenetics. Optogenetics may provide an alternative method for evaluating the mechanism of cardiac arrhythmias, testing hypotheses, and treating cardiovascular diseases. PMID- 29253160 TI - A comparison of methods to correct for misclassification bias from administrative database diagnostic codes. AB - Background: In administrative database research, misclassification bias can result from diagnostic codes that imperfectly represent the condition being studied. It is unclear how to correct for this bias. Methods: Severe renal failure and Colles' fracture status were determined in two distinct cohorts using gold standard methods. True disease prevalence and disease association with other covariables were measured and compared with results when disease status was determined using diagnostic codes. Differences ('misclassification bias') were then adjusted for using two methods: quantitative bias analysis (QBA) with bias parameters (code sensitivity and specificity) of varying accuracy; and disease status imputation using bootstrap methods and disease probability models. Results: Prevalences of severe renal failure (n = 50 074) and Colles' fracture (n = 5680) were 7.5% and 37.0%, respectively. Compared with true values, important bias resulted when diagnostic codes were used to measure disease prevalence and disease-covariable associations. QBA increased bias when population-based (vs strata-specific) bias parameters were used. QBA's ability to account for misclassification bias was most dependent upon deviations in code specificity. Bootstrap imputation accounted for misclassification bias, but this depended on disease model calibration. Conclusions: Extensive bias can result from using inaccurate diagnostic codes to determine disease status. This bias can be addressed with QBA using accurate bias parameter measures, or by bootstrap imputation using well-calibrated disease prediction models. PMID- 29253155 TI - Mendelian randomization with Egger pleiotropy correction and weakly informative Bayesian priors. AB - Background: The MR-Egger (MRE) estimator has been proposed to correct for directional pleiotropic effects of genetic instruments in an instrumental variable (IV) analysis. The power of this method is considerably lower than that of conventional estimators, limiting its applicability. Here we propose a novel Bayesian implementation of the MR-Egger estimator (BMRE) and explore the utility of applying weakly informative priors on the intercept term (the pleiotropy estimate) to increase power of the IV (slope) estimate. Methods: This was a simulation study to compare the performance of different IV estimators. Scenarios differed in the presence of a causal effect, the presence of pleiotropy, the proportion of pleiotropic instruments and degree of 'Instrument Strength Independent of Direct Effect' (InSIDE) assumption violation. Based on empirical plasma urate data, we present an approach to elucidate a prior distribution for the amount of pleiotropy. Results: A weakly informative prior on the intercept term increased power of the slope estimate while maintaining type 1 error rates close to the nominal value of 0.05. Under the InSIDE assumption, performance was unaffected by the presence or absence of pleiotropy. Violation of the InSIDE assumption biased all estimators, affecting the BMRE more than the MRE method. Conclusions: Depending on the prior distribution, the BMRE estimator has more power at the cost of an increased susceptibility to InSIDE assumption violations. As such the BMRE method is a compromise between the MRE and conventional IV estimators, and may be an especially useful approach to account for observed pleiotropy. PMID- 29253163 TI - Prevalence of carbapenem resistance and carbapenemase production among Enterobacteriaceae isolated from urine in the UK: results of the UK infection Carbapenem Resistance Evaluation Surveillance Trial (iCREST-UK). AB - Objectives: Although carbapenem susceptibility testing has been recommended for all Enterobacteriaceae from clinical specimens, for practical reasons a carbapenem is not included in many primary antibiotic panels for urine specimens. The 'iCREST' study sought carbapenemase-producing Enterobacteriaceae (CPE) in routine urine specimens yielding Gram-negative growth in five diagnostic laboratories in the UK. We sought also to compare locally and centrally determined MICs of meropenem and ceftazidime/avibactam. Methods: Positive growth from up to 2000 urine specimens per laboratory was plated onto chromID(r) CARBA SMART agar. Suspected CPE colonies were tested locally by Etest for susceptibility to meropenem and ceftazidime/avibactam, and referred to central laboratories for PCR confirmation of CPE status and microbroth MIC determination. Results: Twenty-two suspected CPE were identified from 7504 urine specimens. Ten were confirmed by PCR to have NDM (5), IMP (2), KPC (2) or OXA-48-like (1) carbapenemases. Locally determined ceftazidime/avibactam MICs showed complete categorical agreement with those determined centrally by microbroth methodology. The seven ceftazidime/avibactam-resistant isolates (MICs >=256 mg/L) had NDM or IMP metallo-carbapenemases. Conclusions: The frequency of confirmed CPE among Gram-negative urinary isolates was low, at 0.13% (10/7504), but CPE were found in urines at all five participating sites and the diversity of carbapenemase genes detected reflected the complex epidemiology of CPE in the UK. These data can inform local policies about the cost-effectiveness and clinical value of testing Gram-negative bacteria from urine specimens routinely against a carbapenem as part of patient management and/or infection prevention and control strategies. PMID- 29253161 TI - Surgery for metachronous second primary lung cancer versus surgery for primary lung cancer: a propensity score-matched comparison of postoperative complications and survival outcomes. AB - OBJECTIVES: Surgical treatments for metachronous second primary lung cancer (MSPLC) may be increasing. It was thought that surgery for MSPLC is associated with high mortality and morbidity. However, recent diffusion of minimally invasive surgical procedures may improve the safety of surgery for MSPLC. The aim of this study was to clarify the safety and prognosis of surgery for MSPLC compared with that for primary lung cancer (PLC). METHODS: We reviewed medical records of 1340 patients who underwent pulmonary resection for non-small-cell lung cancer between 2006 and 2013. We identified patients with PLC and those with MSPLC, and surgical parameters and survival outcome were compared. To eliminate selection bias between the MSPLC group and the PLC group, propensity score matched analysis on the basis of clinicopathological factors was performed. RESULTS: Fifty-three patients underwent resection for MSPLC. Propensity score matching identified 50 patients from each treatment group. Of the 50 MSPLC patients, 41 (82.0%) underwent segmentectomy or wedge resection, 44 (82.0%) had clinical Stage I tumour and 36 (72.0%) received resection via video-assisted thoracoscopic surgery approach. Postoperative complications with a severity of Grade II or more occurred in 11 (22.0%) patients. The incidence of postoperative complications in the MSPLC group was not different from that of the PLC group (P = 0.4894). The 5-year overall survival rates were 68.7% and 83.0% in the PLC and the MSPLC groups, respectively. There was no significant difference between the PLC and the MSPLC groups in terms of overall survival (P = 0.2018, log-rank test). CONCLUSIONS: Pulmonary resection for MSPLC was safely performed with low short-term morbidity similar to that of PLC, and its long-term overall survival was acceptable. PMID- 29253166 TI - Erratum to: Synthea: An approach, method, and software mechanism for generating synthetic patients and the synthetic electronic health care record. PMID- 29253165 TI - Childbirth and Trauma, 1940s-1980s. AB - This article analyzes trauma in mid-twentieth century hospital births, focusing on the United States, but with additional evidence drawn from Great Britain and France. As many as half of women today experience childbirth as traumatic and no evidence suggests that the figure was lower a half-century ago. Drawing on women's birth narratives and psychiatric literature, this article highlights the striking consistency over time in how women describe their experiences of traumatic birth. By the 1970s, however, women proved less ready to accept their trauma as the product of their own psychological shortcomings. Under the sway of second-wave feminism, they pushed back against care they defined as inhumane in both conventional maternity care and in natural childbirth. Psychiatry too demonstrates change over time. Hegemonic at midcentury, Freudian thinking began to yield to critiques that questioned gender norms and the preeminence of the subconscious. Based on private letters to maternity caregivers and between physicians, as well as a wide array of medical journal articles, popular magazines, and newsletters from childbirth education and birth advocacy organizations, this article argues that, despite different approaches to trauma in birth and clarity about how best to minimize it, contemporary maternity care has to date proven unable to heed the lessons of history. PMID- 29253171 TI - Phillippe Menasche MD PhD. PMID- 29253164 TI - Ebola Virus Neutralizing Antibodies Detectable in Survivors of theYambuku, Zaire Outbreak 40 Years after Infection. AB - The first reported outbreak of Ebola virus disease occurred in 1976 in Yambuku, Democratic Republic of Congo. Antibody responses in survivors 11 years after infection have been documented. However, this report is the first characterization of anti-Ebola virus antibody persistence and neutralization capacity 40 years after infection. Using ELISAs we measured survivor's immunological response to Ebola virus Zaire (EBOV) glycoprotein and nucleoprotein, and assessed VP40 reactivity. Neutralization of EBOV was measured using a pseudovirus approach and plaque reduction neutralization test with live EBOV. Some survivors from the original EBOV outbreak still harbor antibodies against all 3 measures. Interestingly, a subset of these survivors' serum antibodies could still neutralize live virus 40 years postinitial infection. These data provide the longest documentation of both anti-Ebola serological response and neutralization capacity within any survivor cohort, extending the known duration of response from 11 years postinfection to at least 40 years after symptomatic infection. PMID- 29253170 TI - Trials and Technology: Robert Califf speaks on innovation in healthcare. PMID- 29253173 TI - PANPACH: The First Independent Paediatric Workshop of the Pan African Network for Paediatric and Congenital Heart (PANPACH). PMID- 29253175 TI - Peter Schwartz, new EHJ International Associate Editor. PMID- 29253172 TI - The story of carotid body resection for HF: How an intriguing pathophysiology concept became a valid target for intervention. PMID- 29253167 TI - Studying third-parties and environments: New Zealand sun-safety research. AB - Wearable cameras have been used to study health behaviours, but their utility in assessing third-party behaviours and the built environment is uncertain. This paper reports on the feasibility of using wearable cameras for this purpose in a study of sun-protective behaviours and shade availability during school lunch breaks. The Kids'Cam study provided 168 children (aged 11-13 years), recruited from 16 randomly selected schools in the Wellington region of New Zealand, with wearable cameras. The devices automatically captured images every 7 s from the child's perspective. Images captured during school lunch-breaks by a random sample of 15 children who took part during terms 4 and 1 (October 2014-April 2015) were selected and assessed for usability. The feasibility of studying third party sun-protective behaviours and school shade availability was assessed for a subset of 320 images. Of the 3492 eligible lunch-break images, 96.4% were useable; the remainders were excluded due to obstruction, blurriness or unsuitable camera position. Overall, 1278 children and 108 shade structures were observed in the sample images. The use of shade, hats, sleeves, collars and sunglasses could be determined for 97.0%, 77.2%, 74.4%, 47.6% and 54.9% of children, respectively. All shade structures could be classified according to type, and canopy composition could be assessed for 95.4% of structures. Wearable cameras are a feasible tool for assessing sun-safety, particularly shade availability, hat wearing and shade use. This methodology could be used to objectively study other third-party health-related behaviours, and other features of the built environment. PMID- 29253168 TI - Genomic analysis reveals different mechanisms of fusidic acid resistance in Staphylococcus aureus from Danish atopic dermatitis patients. AB - Background: Staphylococcus aureus skin colonization is common in patients with atopic dermatitis (AD) and is associated with risk of skin infections. AD patients therefore often receive antibiotic treatments, including topical treatment with fusidic acid, which have been associated with resistance development. Objectives: To examine the prevalence of antibiotic resistance in S. aureus isolated from Danish AD patients, with a primary focus on fusidic acid resistance and the genetic mechanisms that underlie it. Methods: One hundred and thirty-eight S. aureus isolates collected from lesional skin (n = 54), non lesional skin (n = 27) and anterior nares (n = 57) from 71 adult AD patients were included in the study. Isolates were tested for susceptibility to 17 selected antibiotics. S. aureus whole-genome sequences were used to examine the genetic determinants of fusidic acid resistance (fusA or fusE mutations or carriage of fusB or fusC genes). Results: One hundred and nine isolates (79%) were resistant to at least one of the tested antibiotics, with the most prevalent resistances being to penicillin (55%), fusidic acid (41%) and erythromycin (11%). The primary genetic mechanisms of fusidic acid resistance were carriage of fusC (57%) or mutations in fusA (38%). The most prevalent S. aureus lineage was ST1 (23%). All ST1 isolates carried fusC. Conclusions: S. aureus fusidic acid resistance, caused by either fusA mutations or fusC gene carriage, is a major concern among AD patients. Resistant S. aureus might spread from the patients to the community, indicating the need to reduce the use of fusidic acid in the treatment of AD. PMID- 29253154 TI - The Effect of Testosterone on Cardiovascular Biomarkers in the Testosterone Trials. AB - Context: Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. Objective: To determine the effect of testosterone treatment on cardiovascular biomarkers in older men with low testosterone. Design: Double blind, placebo-controlled trial. Setting: Twelve academic medical centers in the United States. Participants: In all, 788 men >=65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials. Intervention: Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcome Measures: Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage. Results: Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, -6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, -2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, -2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, 1.7 uIU/mL; P = 0.02) and homeostatic model assessment-insulin resistance (adjusted mean difference, -0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo. Conclusions and Relevance: Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes. PMID- 29253174 TI - Pacemakers reused: Mexican doctors have safely reused donated pacemakers after sterilisation. PMID- 29253176 TI - Does high body mass index have any impact on survival of patients undergoing oesophagectomy for oesophageal cancer? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'Does high body mass index (BMI) have any impact on survival of patients undergoing oesophagectomy for oesophageal cancer?' A total of 232 papers were found using the reported search, of which 8 papers represented the best evidence to answer the clinical question, which included 1 meta-analysis and 7 cohort studies. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. One meta-analysis and 4 cohort studies provided the evidence that high BMI was significantly correlated with a better survival of oesophageal cancer patients undergoing oesophagectomy, while the other 3 cohort studies found that high BMI had no impact on the survival of those patients. We conclude that patients with high BMI may have a better prognosis than those with normal BMI undergoing oesophagectomy for oesophageal cancer. PMID- 29253180 TI - Comparing Active and Passive Distraction-Based Music Therapy Interventions on Preoperative Anxiety in Pediatric Patients and Their Caregivers. AB - Background: Young children who experience high levels of preoperative anxiety often exhibit distress behaviors, experience more surgical complications, and are at a higher risk for developing a variety of negative postoperative consequences. A significant factor in pediatric preoperative anxiety is the level of anxiety present in their caregivers. Active and passive music therapy interventions addressing anxiety prior to invasive procedures have been met with success. Objective: The purpose of this study was to investigate the comparative effectiveness of two distraction-based music therapy interventions on reducing preoperative anxiety in young pediatric surgical patients and their caregivers. Methods: A total of 40 pediatric patient and caregiver dyads undergoing ambulatory surgery were included in this study. Pediatric preoperative anxiety was measured pre- and post-intervention using the modified Yale Pediatric Anxiety Scale, while caregiver anxiety was measured through self-report using the short form Strait-Trait Anxiety Inventory-Y6. Participants were randomized to either an active or passive intervention group for a preoperative music therapy session. Results: Results indicated a significant reduction in preoperative anxiety for both patients and their caregivers regardless of intervention type. Neither active nor passive music therapy interventions were significantly more effective than the other. Conclusions: For future studies, the researchers recommend an increased sample size, controlling for various factors such as sedative premedication use, and testing interventions with patients in various stages of development. PMID- 29253177 TI - Incidence and outcomes of emergent cardiac surgery during transfemoral transcatheter aortic valve implantation (TAVI): insights from the European Registry on Emergent Cardiac Surgery during TAVI (EuRECS-TAVI). AB - Aims: Life-threatening complications occur during transcatheter aortic valve implantation (TAVI) which can require emergent cardiac surgery (ECS). Risks and outcomes of patients needing ECS during or immediately after TAVI are still unclear. Methods and results: Incidence, risk factors, management, and outcomes of patients requiring ECS during transfemoral (TF)-TAVI were analysed from a contemporary real-world multicentre registry. Between 2013 and 2016, 27 760 patients underwent TF-TAVI in 79 centres. Of these, 212 (0.76%) patients required ECS (age 82.4 +/- 6.3 years, 67.5% females, logistic EuroSCORE: 17.1%, STS-score 5.8%). The risk of ECS declined from 2013 (1.07%) to 2014 (0.70%) but remained stable since. Annual TF-TAVI numbers have more than doubled from 2013 to 2016. Leading causes for ECS were left ventricular perforation by the guidewire (28.3%) and annular rupture (21.2%). Immediate procedural mortality (<72 h) of TF-TAVI patients requiring ECS was 34.6%. Overall in-hospital mortality was 46.0%, and highest in case of annular rupture (62%). Independent predictors of in-hospital mortality following ECS were age > 85 years [odds ratio (OR) 1.87, 95% confidence interval (95% CI) (1.02-3.45), P = 0.044], annular rupture [OR 1.96, 95% CI (0.94 4.10), P = 0.060], and immediate ECS [OR 3.12, 95% CI (1.07-9.11), P = 0.037]. One year of survival of the 114 patients surviving the in-hospital period was only 40.4%. Conclusion: Between 2014 and 2016, the need for ECS remained stable around 0.7%. Left ventricular guidewire perforation and annular rupture were the most frequent causes, accounting for almost half of ECS cases. Half of the patients could be salvaged by ECS-nevertheless, 1 year of all-cause mortality was high even in those ECS patients surviving the in-hospital period. PMID- 29253178 TI - PolyC-binding proteins enhance expression of the CDK2 cell cycle regulatory protein via alternative splicing. AB - The PolyC binding proteins (PCBPs) impact alternative splicing of a subset of mammalian genes that are enriched in basic cellular functions. Here, we focus our analysis on PCBP-controlled cassette exon-splicing within the cell cycle control regulator cyclin-dependent kinase-2 (CDK2) transcript. We demonstrate that PCBP binding to a C-rich polypyrimidine tract (PPT) preceding exon 5 of the CDK2 transcript enhances cassette exon inclusion. This splice enhancement is U2AF65 independent and predominantly reflects actions of the PCBP1 isoform. Remarkably, PCBPs' control of CDK2 ex5 splicing has evolved subsequent to mammalian divergence via conversion of constitutive exon 5 inclusion in the mouse CDK2 transcript to PCBP-responsive exon 5 alternative splicing in humans. Importantly, exclusion of exon 5 from the hCDK2 transcript dramatically represses the expression of CDK2 protein with a corresponding perturbation in cell cycle kinetics. These data highlight a recently evolved post-transcriptional pathway in primate species with the potential to modulate cell cycle control. PMID- 29253169 TI - A value set for documenting adverse reactions in electronic health records. AB - Objective: To develop a comprehensive value set for documenting and encoding adverse reactions in the allergy module of an electronic health record. Materials and Methods: We analyzed 2 471 004 adverse reactions stored in Partners Healthcare's Enterprise-wide Allergy Repository (PEAR) of 2.7 million patients. Using the Medical Text Extraction, Reasoning, and Mapping System, we processed both structured and free-text reaction entries and mapped them to Systematized Nomenclature of Medicine - Clinical Terms. We calculated the frequencies of reaction concepts, including rare, severe, and hypersensitivity reactions. We compared PEAR concepts to a Federal Health Information Modeling and Standards value set and University of Nebraska Medical Center data, and then created an integrated value set. Results: We identified 787 reaction concepts in PEAR. Frequently reported reactions included: rash (14.0%), hives (8.2%), gastrointestinal irritation (5.5%), itching (3.2%), and anaphylaxis (2.5%). We identified an additional 320 concepts from Federal Health Information Modeling and Standards and the University of Nebraska Medical Center to resolve gaps due to missing and partial matches when comparing these external resources to PEAR. This yielded 1106 concepts in our final integrated value set. The presence of rare, severe, and hypersensitivity reactions was limited in both external datasets. Hypersensitivity reactions represented roughly 20% of the reactions within our data. Discussion: We developed a value set for encoding adverse reactions using a large dataset from one health system, enriched by reactions from 2 large external resources. This integrated value set includes clinically important severe and hypersensitivity reactions. Conclusion: This work contributes a value set, harmonized with existing data, to improve the consistency and accuracy of reaction documentation in electronic health records, providing the necessary building blocks for more intelligent clinical decision support for allergies and adverse reactions. PMID- 29253114 TI - Informatics for cancer immunotherapy. AB - The rapid development of immunomodulatory cancer therapies has led to a concurrent increase in the application of informatics techniques to the analysis of tumors, the tumor microenvironment, and measures of systemic immunity. In this review, the use of tumors to gather genetic and expression data will first be explored. Next, techniques to assess tumor immunity are reviewed, including HLA status, predicted neoantigens, immune microenvironment deconvolution, and T-cell receptor sequencing. Attempts to integrate these data are in early stages of development and are discussed in this review. Finally, we review the application of these informatics strategies to therapy development, with a focus on vaccines, adoptive cell transfer, and checkpoint blockade therapies. PMID- 29253179 TI - The interaction of lncRNA EZR-AS1 with SMYD3 maintains overexpression of EZR in ESCC cells. AB - EZR, a member of the ezrin-radixin-moesin (ERM) family, is involved in multiple aspects of cell migration and cancer. SMYD3, a histone H3-lysine 4 (H3-K4) specific methyltransferase, regulates EZR gene transcription, but the molecular mechanisms of epigenetic regulation remain ill-defined. Here, we show that antisense lncRNA EZR-AS1 was positively correlated with EZR expression in both human esophageal squamous cell carcinoma (ESCC) tissues and cell lines. Both in vivo and in vitro studies revealed that EZR-AS1 promoted cell migration through up-regulation of EZR expression. Mechanistically, antisense lncRNA EZR-AS1 formed a complex with RNA polymerase II to activate the transcription of EZR. Moreover, EZR-AS1 could recruit SMYD3 to a binding site, present in a GC-rich region downstream of the EZR promoter, causing the binding of SMYD3 and local enrichment of H3K4me3. Finally, the interaction of EZR-AS1 with SMYD3 further enhanced EZR transcription and expression. Our findings suggest that antisense lncRNA EZR-AS1, as a member of an RNA polymerase complex and through enhanced SMYD3-dependent H3K4 methylation, plays an important role in enhancing transcription of the EZR gene to promote the mobility and invasiveness of human cancer cells. PMID- 29253181 TI - Control of proline accumulation under drought via a novel pathway comprising the histone methylase CAU1 and the transcription factor ANAC055. AB - Proline plays a crucial role in the drought stress response in plants. However, there are still gaps in our knowledge about the molecular mechanisms that regulate proline metabolism under drought stress. Here, we report that the histone methylase encoded by CAU1, which is genetically upstream of P5CS1 (encoding the proline biosynthetic enzyme Delta1-pyrroline-5-carboxylate synthetase 1), plays a crucial role in proline-mediated drought tolerance. We determined that the transcript level of CAU1 decreased while that of ANAC055 (encoding a transcription factor) increased in wild-type Arabidopsis under drought stress. Further analyses showed that CAU1 bound to the promoter of ANAC055 and suppressed its expression via H4R3sme2-type histone methylation in the promoter region. Thus, under drought stress, a decreased level of CAU1 led to an increased transcript level of ANAC055, which induced the expression of P5CS1 and increased proline level independently of CAS. Drought tolerance and the level of proline were found to be decreased in the cau1 anac055 double-mutant, while proline supplementation restored drought sensitivity in the anac055 mutant. Our results reveal the details of a novel pathway leading to drought tolerance mediated by CAU1. PMID- 29253182 TI - Findings of Thyroid Ultrasound Examination Within 3 Years After the Fukushima Nuclear Power Plant Accident: The Fukushima Health Management Survey. AB - Context: Childhood thyroid cancer is of great concern after the Fukushima nuclear power plant accident. Baseline analytical data on thyroid ultrasound examination (TUE) in children are important for future studies. Objective: We analyzed the age and sex distribution of findings from the TUEs of children and adolescents in the Fukushima Health Management Survey (FHMS). Design, Setting, and Participants: From October 2011 through March 2014, 294,905 participants aged 18 years or younger at the time of the earthquake voluntarily had TUEs in the first round of the FHMS. A secondary confirmatory examination was performed in 2032 subjects. Age- and sex-dependent prevalence and size of thyroid cysts, nodules, and cancers were analyzed. Main Outcome Measures: Age, sex, and size distribution of findings were analyzed. Results: Thyroid cysts, nodules, and cytologically suspected cancers were detected in 68,009, 1415, and 38 male subjects and in 73,014, 2455, and 74 female subjects, respectively. There was an age-dependent increase in the detection rate of thyroid nodules and cancer, but that of cysts reached a peak at 11 to 12 years. Sex affected the prevalence of thyroid nodules and cancers after the onset of puberty, but only a small difference was exhibited in that of cysts. Conclusions: The thyroid cancer detection rate in Fukushima was clarified, and the proportion of individuals with thyroid nodules and cysts varied substantially by age. The results of this study will contribute to future epidemiological research on nodular thyroid diseases in children and adolescents. PMID- 29253185 TI - Nature of events and alcohol-related content in marketing materials at a university freshers' fair: a summative content analysis. AB - Introduction: The transition to university is a potentially influential time upon students' drinking behaviour. This study explored the nature of activities and alcohol-related content in marketing materials from student-led societies and local businesses provided to students, at a university freshers' fair in the UK. Methods: All marketing materials handed out at the fair were collected across the 5-day event in September 2015. Written and visual content was analysed using a summative qualitative content analysis. Results: Most student-led societies promoted social events they were hosting (n = 530), most of which took place in a drinking venue or referred to drinking (n = 335). Only four explicitly alcohol free events were promoted. Student-led societies also promoted activities relating to their interest, e.g. sports training (n = 519), a small proportion of which had references to drinking and drinking venues (n = 54). Three societies provided promotional handouts from local bars or nightclubs. Local bars, pubs and nightclubs promoted events they hosted (n = 81) as well as alcoholic drink promotions (n = 79) and alcohol branded advertising (n = 22), albeit infrequently for the latter. Conclusions: In the first week of university, students are exposed to alcohol-related events, promotions and advertising, which may act as an incentive to participate in drinking. PMID- 29253184 TI - AtCSLD3 and GhCSLD3 mediate root growth and cell elongation downstream of the ethylene response pathway in Arabidopsis. AB - CSLD3, a gene of the cellulose synthase-like D family, affects root hair elongation, but its interactions with ethylene signaling and phosphate-starvation are poorly understood. Here, we aim to understand the role of CSLD3 in the context of the ethylene signaling and phosphate starvation pathways in Arabidopsis plant growth. Therefore, we performed a comparative analysis of the csld3-1 mutant, CSLD3-overexpressing lines, and ethylene-response mutants, such as the constitutive ethylene-response mutant i-ctr1. We found that CSLD3 overexpression enhanced root and hypocotyl growth by increasing cell elongation, and that the root growth was highly sensitive to ethylene treatment (1 uM ACC), in particular under phosphate starvation. However, the CSLD3-mediated hypocotyl elongation occurred independently of the ethylene signaling pathway. Notably, the typical induction of root hair and root elongation by ethylene and phosphate starvation was completely abolished in the csld3-1 mutant. Furthermore, i-ctr1 csld3-1 double-mutants were hairless like the csld3-1 parent, confirming that CSLD3 acts downstream of the ethylene signaling pathway during root growth. Moreover, the CSLD3 levels positively correlated with cellulose levels, indicating a role of CSLD3 in cellulose synthesis, which may explain the observed growth effects. Our results establish how CSLD3 works in the context of the ethylene signaling and phosphate-starvation pathways during root hair growth, cell elongation, and cell wall biosynthesis. PMID- 29253183 TI - Nuclear poly(A)-binding protein 1 is an ATM target and essential for DNA double strand break repair. AB - The DNA damage response (DDR) is an extensive signaling network that is robustly mobilized by DNA double-strand breaks (DSBs). The primary transducer of the DSB response is the protein kinase, ataxia-telangiectasia, mutated (ATM). Here, we establish nuclear poly(A)-binding protein 1 (PABPN1) as a novel target of ATM and a crucial player in the DSB response. PABPN1 usually functions in regulation of RNA processing and stability. We establish that PABPN1 is recruited to the DDR as a critical regulator of DSB repair. A portion of PABPN1 relocalizes to DSB sites and is phosphorylated on Ser95 in an ATM-dependent manner. PABPN1 depletion sensitizes cells to DSB-inducing agents and prolongs the DSB-induced G2/M cell cycle arrest, and DSB repair is hampered by PABPN1 depletion or elimination of its phosphorylation site. PABPN1 is required for optimal DSB repair via both nonhomologous end-joining (NHEJ) and homologous recombination repair (HRR), and specifically is essential for efficient DNA-end resection, an initial, key step in HRR. Using mass spectrometry analysis, we capture DNA damage-induced interactions of phospho-PABPN1, including well-established DDR players as well as other RNA metabolizing proteins. Our results uncover a novel ATM-dependent axis in the rapidly growing interface between RNA metabolism and the DDR. PMID- 29253186 TI - A study of the learning curve for robotic oesophagectomy for oesophageal cancer. AB - OBJECTIVES: Robot-assisted minimally invasive oesophagectomy (RAMIE) enables radical, meticulous dissection of the oesophagus and lymph nodes. Our goal was to identify the effect of the learning curve for RAMIE when performing radical upper mediastinal dissection in patients with oesophageal cancer. METHODS: We conducted a retrospective review of a prospectively maintained database of patients who underwent RAMIE for oesophageal cancer between May 2008 and July 2016. The gain in proficiency for each postoperative outcome measure was presented using observed-expected cumulative sum (O-E CUSUM) curves. The change points were defined at the maximal distance from the zero axis. RESULTS: A total of 140 patients were included. Squamous cell carcinoma (n = 131, 93.6%) was the dominant type. Thirty-day and 90-day deaths occurred in 1 and 5 patients (0.7% and 3.6%, respectively). The change points of the risk-adjusted O-E CUSUM curves were similar to those of the unadjusted O-E CUSUM curves with the exception of those for thoracic procedure time and vocal cord palsy. The number of harvested lymph nodes increased from 25 to 45 before and after 30 cases. The vocal cord palsy rate decreased from 36% to 17% before and after 60 cases. The total operation time decreased from 496 min to 431 min; the length of the hospital stay decreased from 24 days to 14 days; and the anastomotic leakage rate decreased from 15% to 2% before and after 80 cases. CONCLUSIONS: Our study demonstrated a temporal improvement in postoperative outcomes based on accumulated experience with RAMIE. The risk-adjusted O-E CUSUM curves were similar to the unadjusted O-E CUSUM curves, which represents the significant impact of the effect of a learning period on the postoperative outcomes of RAMIE in patients with oesophageal cancer. PMID- 29253187 TI - The GhmiR157a-GhSPL10 regulatory module controls initial cellular dedifferentiation and callus proliferation in cotton by modulating ethylene mediated flavonoid biosynthesis. AB - MicroRNAs (miRNAs) modulate many biological processes through inactivation of specific mRNA targets such as those encoding transcription factors. A delicate spatial/temporal balance between specific miRNAs and their targets is central to achieving the appropriate biological outcomes. Somatic embryogenesis in cotton (Gossypium hirsutum), which goes through initial cellular dedifferentiation, callus proliferation, and somatic embryo development, is of great importance for both fundamental research and biotechnological applications. In this study, we characterize the function of the GhmiR157a-GhSPL10 miRNA-transcription factor module during somatic embryogenesis in cotton. We show that overexpression of GhSPL10, a target of GhmiR157a, increases free auxin and ethylene content and expression of associated signaling pathways, activates the flavonoid biosynthesis pathway, and promotes initial cellular dedifferentiation and callus proliferation. Inhibition of expression of the flavonoid synthesis gene F3H in GhSPL10 overexpression lines (35S:rSPL10-7) blocked callus initiation, while exogenous application of several types of flavonol promoted callus proliferation, associated with cell cycle-related gene expression. Inhibition of ethylene synthesis by aminoethoxyvinylglycine treatment in the 35S:rSPL10-7 line severely inhibited callus initiation, while activation of ethylene signaling through 1 aminocyclopropane 1-carboxylic acid treatment, EIN2 overexpression, or inhibition of the ethylene negative regulator CTR1 by RNA interference promoted flavonoid related gene expression and flavonol accumulation. These results show that an up regulation of ethylene signaling and the activation of flavonoid biosynthesis in GhSPL10 overexpression lines were associated with initial cellular dedifferentiation and callus proliferation. Our results demonstrate the importance of a GhmiR157a-GhSPL10 gene module in regulating somatic embryogenesis via hormonal and flavonoid pathways. PMID- 29253188 TI - From carotenoids to strigolactones. AB - Strigolactones are phytohormones that regulate various plant developmental and adaptation processes. When released into soil, strigolactones act as chemical signals, attracting symbiotic arbuscular mycorrhizal fungi and inducing seed germination in root-parasitic weeds. Strigolactones are carotenoid derivatives, characterized by the presence of a butenolide ring that is connected by an enol ether bridge to a less conserved second moiety. Carotenoids are isopenoid pigments that differ in structure, number of conjugated double bonds, and stereoconfiguration. Genetic analysis and enzymatic studies have demonstrated that strigolactones originate from all-trans-beta-carotene in a pathway that involves the all-trans-/9-cis-beta-carotene isomerase DWARF27 and carotenoid cleavage dioxygenase 7 and 8 (CCD7, 8). The CCD7-mediated, regiospecific and stereospecific double-bond cleavage of 9-cis-beta-carotene leads to a 9-cis configured intermediate that is converted by CCD8 via a combination of reactions into the central metabolite carlactone. By catalyzing repeated oxygenation reactions that can be coupled to ring closure, CYP711 enzymes convert carlactone into tricyclic-ring-containing canonical and non-canonical strigolactones. Modifying enzymes, which are mostly unknown, further increase the diversity of strigolactones. This review explores carotenogenesis, provides an update on strigolactone biosynthesis, with emphasis on the substrate specificity and reactions catalyzed by the different enzymes, and describes the regulation of the biosynthetic pathway. PMID- 29253189 TI - Rapidly increasing body mass index among children, adolescents and young adults in a transitioning population, South Africa, 2008-15. AB - Background: There is a global epidemic of overweight and obesity; however, this rate of increase is even greater in some low- and middle-income countries (LMIC). South Africa (SA) is undergoing rapid socioeconomic and demographic changes that have triggered a rapid nutrition transition. The paper focuses on the recent rate of change of body mass index (BMI) among children, adolescents and young adults, further stratified by key sociodemographic factors. Methods: We analysed mean BMI of 28 247 individuals (including children) from 7301 households by age and year, from anthropometric data from four national cross-sectional (repeated panel) surveys using non-linear fitted curves and associated 95% confidence intervals. Results: From 2008 to 2015, there was rapid rise in mean BMI in the 6-25 age band, with the highest risk (3-4+ BMI unit increase) among children aged 8-10 years. The increase was largely among females in urban areas and of middle-high socioeconomic standing. Prominent gains were also observed in certain rural areas, with extensive geographical heterogeneity across the country. Conclusions: We have demonstrated a major deviation from the current understanding of patterns of BMI increase, with a rate of increase substantially greater in the developing world context compared with the global pattern. This population-wide effect will have major consequences for national development as the epidemic of related non communicable disease unfolds, and will overtax the national health care budget. Our refined understanding highlights that risks are further compounded for certain groups/places, and emphasizes that urgent geographical and population targeted interventions are necessary. These interventions could include a sugar tax, clearer food labelling, revised school feeding programmes and mandatory bans on unhealthy food marketing to children.The scenario unfolding in South Africa will likely be followed in other LMICs. PMID- 29253193 TI - Corrigendum. PMID- 29253191 TI - Beyond the genetic code in leaf senescence. AB - Leaf senescence is not only genetically programmed but also induced by exogenous stress to ensure completion of the plant life cycle, successful reproduction and environmental adaptability. Genetic reprogramming is a major aspect of leaf senescence, and the senescence signaling that follows is controlled by a complex regulatory network. Recent studies suggest that the activity of transcription factors together with epigenetic mechanisms ensures the robustness of this network, with the latter including chromatin remodeling, DNA modification, and RNA-mediated control of transcription factors and other senescence-associated genes. In this review, we provide an overview of the relevant epigenetic mechanisms and summarize recent findings of epigenetic regulators of plant leaf senescence involved in DNA methylation and histone modification along with the functions of small RNAs in this process. PMID- 29253197 TI - Genetic Mapping Reveals an Anthocyanin Biosynthesis Pathway Gene Potentially Influencing Evolutionary Divergence between Two Subspecies of Scarlet Gilia (Ipomopsis aggregata). AB - Immense floral trait variation has likely arisen as an adaptation to attract pollinators. Different pollinator syndromes-suites of floral traits that attract specific pollinator functional groups-are repeatedly observed across closely related taxa or divergent populations. The observation of these trait syndromes suggests that pollinators use floral cues to signal the underlying nectar reward, and that complex trait combinations may persist and evolve through genetic correlations. Here, we explore pollinator preferences and the genetic architecture of floral divergence using an extensive genetic mapping study in the hybrid zone of two Ipomopsis aggregata subspecies that exhibit a hummingbird and a hawkmoth pollinator syndrome. We found that natural selection acts on several floral traits, and that hummingbirds and hawkmoths exhibited flower color preferences as predicted by their respective pollinator syndromes. Our quantitative trait loci (QTL) analyses revealed 46 loci affecting floral features, many of which colocalize across the genome. Two of these QTL have large effects explaining >15% of the phenotypic variance. The strongest QTL was associated with flower color and localized to a SNP in the anthocyanin biosynthesis pathway gene, dihydroflavonol-4-reductase (DFR). Further analysis revealed strong associations between DFR SNP variants, gene expression, and flower color across populations from the hybrid zone. Hence, DFR may be a target of pollinator-mediated selection in the hybrid zone of these two subspecies. Together, our findings suggest that hummingbirds and hawkmoths exhibit contrasting flower color preferences, which may drive the divergence of several floral traits through correlated trait evolution. PMID- 29253198 TI - The Island of Alternatives: Power, Medical Science, and "Gentle Birthing" in Socialist Czechoslovakia. AB - Beginning in the early 1980s, medical experts and birthing women increasingly voiced criticism of what had long been the technocratic, depersonalized nature of obstetric treatment in Czechoslovakia, despite the limited opportunities for them to do so publicly. A few maternity hospitals responded to the complaints by introducing radically different regimens of care. This article examines the history of one reformist project that took place in the small town of Ostrov nad Ohri. Ostrov means "island" in Czech and, during the last decade of Communist rule in Czechoslovakia, the Ostrov hospital became an island of alternative obstetric care, embracing Leboyer's method of "gentle birthing," acupuncture, fathers in delivery rooms, and assorted technological innovations that aimed to spark fundamental change in familial and social relationships, and humanize childbirth. While many medical professionals decried these reforms as nonsensical and dangerous, a number of parents-to-be flocked to Ostrov to give birth, circumventing the official rules mandating that they receive healthcare in their area of residence. This proactive consumerist behavior among expectant parents, in tandem with the call of some physicians for more attention to individual and family needs, despite the opposing official political discourse, is evidence of a grassroots movement for market-oriented principles in healthcare that reflected broader societal change during the last decade of the Communist regime. PMID- 29253200 TI - Bone marrow-derived mesenchymal stem cells transplantation alters the course of experimental paracoccidioidomycosis by exacerbating the chronic pulmonary inflammatory response. AB - Several studies have shown the potential use of bone marrow mesenchymal stem cells (BM-MSCs) as a therapeutic approach to infectious diseases. Since BM-MSCs can exert antimicrobial properties and influence the immune response against pathogens, our aim was to study the antimicrobial therapeutic potential of BM MSCs in an experimental model of paracoccidioidomycosis (PCM). BM-MSCs were isolated from BALB/c donor mice. Paracoccidioides brasiliensis-infected male BALB/c mice were injected with purified BM-MSCs at 8th week post-infection. Mice were sacrificed at 12th week post-infection. Homing of BM-MSCs was confirmed by cellular labeling with fluorescent lipophilic dye and detected by flow cytometry. We found that, in comparison with nontransplanted infected animals, BM-MSCs treated and P. brasiliensis-infected mice showed a significant increase in (i) fungal burdens, (ii) neutrophils, eosinophils and M2 macrophages counts, and (iii) interleukin (IL)-6, IL-9, GM-CSF, CXCL1, CXCL9, and CCL5 levels, while presenting a decrease in M1 macrophages and Treg cells in lungs. In addition, the histopathological analysis of the lungs showed an increased inflammatory process. This is the first study to our knowledge that evaluates the effects of BM-MSCs treatment in PCM. Our results indicate that the immunoregulatory function of BM MSCs may be triggered by the interaction with P. brasiliensis, which exacerbates chronic pulmonary inflammatory response. PMID- 29253199 TI - Transformation From a Conventional Clinical Microbiology Laboratory to Full Automation. AB - Background: To validate the performance, reproducibility, and reliability of BD automated instruments in order to establish a fully automated clinical microbiology laboratory. Methods: We used control strains and clinical samples to assess the accuracy, reproducibility, and reliability of the BD Kiestra WCA, the BD Phoenix, and BD Bruker MALDI-Biotyper instruments and compared them to previously established conventional methods. The following processes were evaluated: sample inoculation and spreading, colony counts, sorting of cultures, antibiotic susceptibility test, and microbial identification. Results: The BD Kiestra recovered single colonies in less time than conventional methods (e.g. E. coli, 7h vs 10h, respectively) and agreement between both methodologies was excellent for colony counts (kappa=0.824) and sorting cultures (kappa=0.821). Antibiotic susceptibility tests performed with BD Phoenix and disk diffusion demonstrated 96.3% agreement with both methods. Finally, we compared microbial identification in BD Phoenix and Bruker MALDI-Biotyper and observed perfect agreement (kappa=1) and identification at a species level for control strains. Together these instruments allow us to process clinical urine samples in 36h (effective time). Conclusion: The BD automated technologies have improved performance compared with conventional methods, and are suitable for its implementation in very busy microbiology laboratories. PMID- 29253194 TI - Chemotherapy for hepatocellular carcinoma: current status and future perspectives. AB - Chemotherapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC). On the basis of the results of two pivotal Phase III placebo-controlled studies, sorafenib is currently acknowledged worldwide as the standard therapeutic agent for advanced HCC. Following the introduction of sorafenib for the treatment of HCC, Phase III trials of numerous other agents as first-line or second-line chemotherapy have been conducted to determine if any of these agents might offer superior survival benefit to sorafenib. In 2016, a clear survival benefit of regorafenib over placebo was demonstrated in HCC patients showing disease progression after sorafenib treatment. A year later, in 2017, lenvatinib has been shown to be non-inferior to sorafenib, in terms of the overall survival, in chemo-naive patients with advanced HCC. More recently, promising outcomes have also been reported with new agents, such as nivolumab and cabozantinib. At present, various novel combination regimens including these agents are currently under development. Hepatic arterial infusion chemotherapy (HAIC) is frequently adopted for the treatment of locally advanced HCC in Japan, based on reports of high response rates and favorable long-term outcomes. Although some randomized controlled trials of HAIC plus sorafenib vs. sorafenib alone as first-line therapy have been conducted in patients with advanced HCC, no firm evidence of the superiority of one over the other has been established yet. In the future, demonstration of the survival advantage of HAIC and the recognition of HAIC as one of the standard treatments for patients with advanced HCC are expected. PMID- 29253192 TI - Binding of Fibronectin to SsPepO Facilitates the Development of Streptococcus suis Meningitis. AB - Background: SsPepO is an important virulence in Streptococcus suis. Methods: In this study, we showed that SsPepO contributes to the human fibronectin-mediated adherence ability of S. suis to human brain microvascular endothelial cells. Results: The addition of an antifibronectin antibody or an arginine-glycine aspartic acid peptide that blocks fibronectin binding to integrins significantly reduced adherence of the wild-type but not the SspepO mutant strain, indicating the importance of the SsPepO-fibronectin-integrin interaction for S. suis cellular adherence. Conclusions: By analyzing Evans blue extravasation in vivo, we showed that the interaction between SsPepO and human fibronectin significantly increased permeability of the blood-brain barrier. Furthermore, the SspepO mutant caused lower bacterial loads in the brain than wild-type S. suis in models of meningitis. These data demonstrate that SsPepO is a fibronectin-binding protein, which plays a contributing role in the development of S. suis meningitis. PMID- 29253195 TI - TopA, the Sulfolobus solfataricus topoisomerase III, is a decatenase. AB - DNA topoisomerases are essential enzymes involved in all the DNA processes and among them, type IA topoisomerases emerged as a key actor in the maintenance of genome stability. The hyperthermophilic archaeon, Sulfolobus solfataricus, contains three topoisomerases IA including one classical named TopA. SsoTopA is very efficient at unlinking DNA catenanes, grouping SsoTopA into the topoisomerase III family. SsoTopA is active over a wide range of temperatures and at temperatures of up to 85 degrees C it produces highly unwound DNA. At higher temperatures, SsoTopA unlinks the two DNA strands. Thus depending on the temperature, SsoTopA is able to either prevent or favor DNA melting. While canonical topoisomerases III require a single-stranded DNA region or a nick in one of the circles to decatenate them, we show for the first time that a type I topoisomerase, SsoTopA, is able to efficiently unlink covalently closed catenanes, with no additional partners. By using single molecule experiments we demonstrate that SsoTopA requires the presence of a short single-stranded DNA region to be efficient. The unexpected decatenation property of SsoTopA probably comes from its high ability to capture this unwound region. This points out a possible role of TopA in S. solfataricus as a decatenase in Sulfolobus. PMID- 29253202 TI - Right ventricular papillary muscle approximation for functional tricuspid regurgitation associated with severe leaflet tethering. AB - Recurrent tricuspid regurgitation (TR) can occur after tricuspid annuloplasty if severe leaflet tethering persists. To reduce the tethering, we applied right ventricular papillary muscle approximation in 7 patients with severe functional TR associated with significant leaflet tethering. Postoperative echocardiogram revealed mild or less TR and a significant reduction in the tethering effect. In conclusion, this adjunctive technique can improve functional TR associated with leaflet tethering. PMID- 29253204 TI - In vitro activity of isavuconazole against fluconazole-resistant isolates of Histoplasma capsulatum. AB - No clinical trials for histoplasmosis have been performed with the newer azoles, leaving itraconazole as the azole of choice. In vitro studies suggest that Histoplasma capsulatum from patients that relapse on fluconazole has higher minimum inhibitory concentrations (MICs) to fluconazole and voriconazole but not itraconazole and posaconazole. The newest azole, isavuconazole, shares structural similarity to voriconazole, but to date nobody has explored emergence of resistance. In vitro susceptibilities to isavucoanzole and fluconazole were performed on previously obtained isolates from the patients who relapsed on fluconazole therapy. Susceptibilities were determined by NCCLS method M27A developed for yeasts, as modified for H. capsulatum. The change in the MIC from the primary to the relapse isolate was tested using Wilcoxon Rank-Sum for paired data. Among the primary isolates, the median MICs were 1.0 (range 0.25 to 4.0) MUg/ml for fluconazole and <=0.007 (range <=0.007 to 0.015) MUg/ml for isavuconazole. In the group of relapsed isolates, the median MICs rose to 8.0 (range 0.25 to 64.0) MUg/ml for fluconazole and remained unchanged at <=0.007 (range <=0.007 to 0.015) MUg/ml for isavuconazole (P < .001). Only one isolate exhibited a nonsignificant increase in MIC to isavuconazole. Histoplasma isolates from patients who relapsed on fluconazole did not have an elevation in MICs to isavuconazole. This differs from the results previously seen with voriconazole and suggests that despite a closer structural similarity to voriconazole than itraconazole and posaconazole, isavuconazole has a higher barrier to resistance and may be effective as therapy for histoplasmosis. PMID- 29253196 TI - Nuclear miR-122 directly regulates the biogenesis of cell survival oncomiR miR-21 at the posttranscriptional level. AB - Hepatic miR-122 can serve as a pro-apoptotic factor to suppress tumorigenesis. The underlying mechanism, however, remains incompletely understood. Here we present the first evidence that miR-122 promotes hepatocellular carcinoma cell apoptosis through directly silencing the biogenesis of cell survival oncomiR miR 21 at posttranscriptional level. We find that miR-122 is strongly expressed in primary liver cell nucleus but its nuclear localization is markedly decreased in transformed cells particularly in chemoresistant tumor cells. MiRNA profiling and RT-qPCR confirm an inverse correlation between miR-122 and miR-21 in hepatocellular carcinoma tissues/cells, and increasing or decreasing nuclear level of miR-122 respectively reduces or increases miR-21 expression. Mechanistically, nuclear miR-122 suppresses miR-21 maturation via binding to a 19 nt UG-containing recognition element in the basal region of pri-miR-21 and preventing the Drosha-DGCR8 microprocessor's conversion of pri-miR-21 into pre miR-21. Furthermore, both in vitro and in vivo studies demonstrate that nuclear miR-122 participates in the regulation of HCC cell apoptosis through modulating the miR-21-targeted programmed cell death 4 (PDCD4) signal pathway. PMID- 29253190 TI - Addition of Estradiol to Cross-Sex Testosterone Therapy Reduces Atherosclerosis Plaque Formation in Female ApoE-/- Mice. AB - The contributions of estradiol and testosterone to atherosclerotic lesion progression are not entirely understood. Cross-sex hormone therapy (XHT) for transgender individuals dramatically alters estrogen and testosterone levels and consequently could have widespread consequences for cardiovascular health. Yet, no preclinical research has assessed atherosclerosis risk after XHT. We examined the effects of testosterone XHT after ovariectomy on atherosclerosis plaque formation in female mice and evaluated whether adding low-dose estradiol to cross sex testosterone treatments after ovariectomy reduced lesion formation. Six-week old female ApoE-/- C57BL/6 mice underwent ovariectomy and began treatments with testosterone, estradiol, testosterone with low-dose estradiol, or vehicle alone until euthanized at 23 weeks of age. Atherosclerosis lesion progression was measured by Oil Red O stain and confirmed histologically. We found reduced atherosclerosis in the estradiol- and combined testosterone/estradiol-treated mice compared with those treated with testosterone or vehicle only in the whole aorta (-75%), aortic arch (-80%), and thoracic aorta (-80%). Plaque size was similarly reduced in the aortic sinus. These reductions in lesion size after combined testosterone/estradiol treatment were comparable to those obtained with estrogen alone. Testosterone/estradiol combined therapy resulted in less atherosclerosis plaque formation than either vehicle or testosterone alone after ovariectomy. Testosterone/estradiol therapy was comparable to estradiol replacement alone, whereas mice treated with testosterone only fared no better than untreated controls after ovariectomy. Adding low-dose estrogen to cross-sex testosterone therapy after oophorectomy could improve cardiovascular outcomes for transgender patients. Additionally, these results contribute to understanding of the effects of estrogen and testosterone on atherosclerosis progression. PMID- 29253203 TI - A sibling study of whether maternal exposure to different types of natural space is related to birthweight. AB - Background: Birthweight is an important determinant of health across the life course. Maternal exposure to natural space has been linked to higher birthweight, but stronger evidence of a causal link is needed. We use a quasi-experimental sibling study design to investigate if change in the mother's exposure to natural space between births was related to birthweight, in urban Scotland. Methods: Amount (% area) of total natural space, total accessible (public) natural space, parks, woodlands and open water within 100 m of the mother's postcode was calculated for eligible births (n = 40 194; 1991-2010) in the Scottish Longitudinal Study (a semi-random 5.3% sample of the Scottish population). Associations between natural space and birthweight were estimated, using ordinary least squares and fixed effects models. Results: Birthweight was associated with the total amount of natural space around the mother's home (+8.2 g for interquartile range increase), but was unrelated to specific types of natural space. This whole-sample relationship disappeared in the sibling analysis, indicating residual confounding. The sibling models showed effects for total natural space with births to women who already had children (+20.1 g), and to those with an intermediate level of education (+14.1 g). Conclusions: The importance of total natural space for birthweight suggests that benefits can be experienced near to as well as within natural space. Ensuring expectant mothers have good access to high quality neighbourhood natural space has the potential to improve the infant's start in life, and consequently their health trajectory over the life course. PMID- 29253205 TI - Comorbidities Among US Patients With Prevalent HIV Infection-A Trend Analysis. AB - Objective: Quantify proportion of human immunodeficiency virus (HIV)-infected patients with specific comorbidities receiving healthcare coverage from commercial, Medicaid, and Medicare payers. Methods: Data from MarketScan research databases were used to select adult HIV-infected patients from each payer. Treated HIV-infected patients were matched to HIV-negative controls. Cross sectional analyses were performed between 2003 and 2013 among HIV-infected patients to quantify the proportion with individual comorbidities over the period, by payer. Results: Overall, 36298 HIV-infected patients covered by commercial payers, 26246 covered by Medicaid payers, and 1854 covered by Medicare payers were identified between 2003 and 2013. Essential hypertension (31.4%, 39.3%, and 76.2%, respectively), hyperlipidemia (29.2%, 22.1%, and 49.6%), and endocrine disease (21.8%, 27.2%, and 54.0%) were the most common comorbidities. Comparison of data from 2003 to data from 2013 revealed significant increases across payers in the percentage of patients with the comorbidities specified above (P < .05). Across all payers, the proportions of treated HIV-infected patients with deep vein thrombosis, hepatitis C, renal impairment, thyroid disease, and liver disease from 2003 to 2013 was significantly greater (P < .05) than for matched controls. Conclusions: Comorbidities are common among the aging HIV-infected population and have increased over time. There should be a consideration in treatment choices for HIV infection, including the choices of antiretroviral regimens. PMID- 29253207 TI - Breed-related differences in age-dependent down-regulation of the beta1 adrenoceptor and adenylate cyclase activity in atrial and ventricular myocardium of Crollwitzer ("wild-type") turkeys. AB - In conventional meat-type (British United Turkey (B.U.T.) Big 6) turkey hearts, it has been shown that all cardiac chambers exhibit down-regulation of the beta1 adrenoceptors (beta1-AR) and concomitantly cAMP accumulation with increasing age regardless of sex. In this study we proved the hypothesis that breed differences exist in age-dependent alterations in the beta1-AR system. Right (RA) and left (LA) atrial as well as right (RV) and left (LV) ventricular tissues were collected from male and female Crollwitzer "wild-type" turkey poults of increasing age (6 wk, 12 wk, 16 wk, 21 wk). The beta1-AR density and function were quantified by (-)-[125I]-iodocyanopindolol (ICYP) radioligand binding analysis in cell membranes from 4 cardiac chambers. Basal and stimulated cAMP production was determined as indicator of the receptor function. Wild-type turkeys showed significantly higher heart to body weight ratio than the meat-type B.U.T. Big 6 turkeys. In both sexes of Crollwitzer turkey hearts, the beta1-AR density decreased with age but significance was reached in male cardiac chambers. The receptor affinity (KD) and subtype distribution were not altered. Sex had no effect on age-related decrease in receptor density but had an effect on adenylate cyclase (AC) activity and subsequently cAMP production. In male Crollwitzer turkey hearts of all ages, cAMP remained at same level, whereas this was even increased in female cardiac chambers. Thus, breed affected age-related receptor-, G-protein and AC-stimulated cAMP formation in normal ventricles and atria, with females exhibiting pronounced increase with age. This suggests that the receptor signaling in wild-type turkey hearts is not as blunted as in hearts of meat-type turkey poults in which stressful farming conditions and fast growing lead to receptor down-regulation. PMID- 29253201 TI - Impact of the Levonorgestrel-Releasing Intrauterine System on the Progression of Chlamydia trachomatis Infection to Pelvic Inflammatory Disease in a Baboon Model. AB - Background: Understanding the relationship between the levonorgestrel (LNG) releasing intrauterine system (IUS) and sexually transmitted infections (STIs) is increasingly important as use of the LNG-IUS grows to include women at higher risk for STIs. This study assessed the impact of the LNG-IUS on development of Chlamydia trachomatis pelvic inflammatory disease, using a baboon model. Methods: Baboons with and those without the LNG-IUS were cervically inoculated with C. trachomatis and monitored daily, and cervical and fallopian tube swab specimens were collected weekly for C. trachomatis quantitation by nucleic acid amplification testing and culture. Vaginal swab specimens were collected for cytokine analysis, and serum samples were obtained for detection of C. trachomatis antibodies. Results: The LNG-IUS resulted in an increased C. trachomatis burden in the cervix, with the bacterial burden in the LNG-IUS group diverging from that in the non-LNG-IUS group by 6 weeks after infection. One of 7 baboons in the non-LNG-IUS group and 2 of 6 in the LNG-IUS group developed pelvic inflammatory disease, while 3 animals in each group met criteria suggestive of pelvic inflammatory disease. LNG-IUS increased baseline interleukin 8 levels but failed to further upregulate interleukin 8 during infection. In LNG-IUS recipients, early perturbations in the interleukin 1beta axis corresponded to decreased C. trachomatis clearance and increased T-helper type 2 immune responses. Conclusion: LNG-IUS use results in delayed clearance of C. trachomatis and might alter the reproductive tract immune environment. PMID- 29253208 TI - Placing Antismoking Graphic Warning Posters at Retail Point-of-Sale Locations Increases Some Adolescents' Susceptibility to Future Smoking. AB - Objectives: This experiment tested whether introducing graphic antitobacco posters at point-of-sale (POS) had any effect on adolescents' susceptibility to future cigarette smoking and whether these effects were moderated by adolescents' baseline risk of cigarette smoking. Methods: The study was conducted in the RAND StoreLab, a life-sized replica of a convenience store that was developed to experimentally evaluate how changing aspects of tobacco advertising displays in retail POS environments influence tobacco use risk and behavior during simulated shopping experiences. In this study, 441 adolescents were randomized to one of the four conditions in a 2 (graphic antismoking poster placed near the tobacco power wall: no, yes) * 2 (graphic antismoking poster placed near the cash register: no, yes) experimental design. The outcome of interest was susceptibility to future cigarette smoking. Results: The addition of antismoking posters at POS led to a significant increase in future smoking susceptibility among those adolescents who already were at high risk for smoking in the future (p < .045). The introduction of graphic antismoking posters had no impact on committed never smokers, regardless of poster location; never smokers' susceptibility to future smoking was uniformly low across experimental conditions. Conclusions: Introducing graphic antismoking posters at POS may have the unintended effect of further increasing cigarette smoking susceptibility among adolescents already at risk. PMID- 29253215 TI - Perceptions of Financial Incentives for Smoking Cessation: A Survey of Smokers in a Country With an Endgame Goal. AB - Introduction: Financial incentives can support smoking cessation, yet low acceptability may limit the wider implementation of such schemes. Few studies have examined how smokers view financial-incentive interventions aimed at reducing smoking prevalence. Methods: We recruited a sample of 623 smokers from an internet panel to a survey assessing support for, and perceived effectiveness of, financial incentives for smoking cessation. We used descriptive statistics, plus logistic regression, to test associations between demographics and smoking, and support. We used qualitative content analysis to analyze open-ended responses to a question that invited respondents to comment on financial incentives. Results: Financial incentives were supported by 38.4% of smokers; 42.2% did not support and 19.4% had no opinion. Support was higher among heavy (OR = 3.96, 95% CI = 2.39 to 6.58) and moderate smokers (OR = 1.68, 95% CI = 1.13 to 2.49), and those with a recent quit attempt (OR = 1.47, 95% CI = 1.04 to 2.07). Support was strongly associated with perceived effectiveness. A Government-funded reward-only scheme was seen as the most acceptable option (preferred by 26.6% of participants), followed by a Government-funded deposit-based scheme (20.6%); few respondents supported employer-funded schemes. Open-ended responses (n = 301) indicated three overarching themes expressing opposition to financial incentives: smokers' individual responsibility for quitting, concerns about abuse of an incentive scheme, and concerns about unfairness. Conclusion: Even amongst those who would benefit from schemes designed to reward smokers for quitting, support for such schemes is muted, despite the evidence of their effectiveness. Media advocacy and health education could be used to increase the understanding of, and support for, financial incentives for smoking cessation. Implications: Given the absolute effectiveness and cost effectiveness of financial-incentive schemes for smoking cessation amongst pregnant smokers and in workplaces, implementing such schemes at a national-level could help reduce overall smoking prevalence and contribute to endgame goals. Our study found that similar proportions of smokers supported and opposed financial-incentive schemes and suggests that much of the opposition was underpinned by information gaps, which could be addressed using education and media advocacy. PMID- 29253212 TI - Letter to the Editor Regarding a Recent Article: A Novel Chronic Opioid Monitoring Tool to Assess Prescription Drug Steady State Levels in Oral Fluid. PMID- 29253209 TI - Colistin- and carbapenem-resistant Klebsiella pneumoniae carrying mcr-1 and blaOXA-48 isolated at a paediatric hospital in Vietnam. PMID- 29253214 TI - Gender Distribution of Authorship in Pain Publications Is More Balanced than in Other Scientific Fields. PMID- 29253217 TI - Corrigendum. PMID- 29253213 TI - Comparative analysis of structure and strength of vitelline membrane and physical parameters of yolk of ostrich, emu, and greater rhea eggs. AB - In this study, we analyzed selected morphological traits of eggs, as well as structure, strength, and protein composition of the vitelline membrane (VM) of ostrich, emu, and greater rhea eggs. Ninety eggs (30 for species) were analyzed for the following parameters: egg weight, yolk weight, yolk ratio, and yolk index. In addition, pH value, water activity, consistency index, and flow behavior index were determined. The strength of VM was measured using the TA.HDPlus Texture Analyzer. Micrograph images were taken via a scanning electron microscope. Polyacrylamide gel electrophoresis was conducted under denaturing conditions. Ostrich eggs were characterized by the highest egg and yolk weight compared with those of emu and greater rhea eggs, whereas emu eggs had the highest yolk ratio compared with those of ostrich and greater rhea eggs (P > 0.05). Yolk content differed among the species in terms of water activity; it was found to be higher in emu eggs than in ostrich and greater rhea eggs (P > 0.05). Based on flow curves, yolks of the ratites were classified as pseudoplastic non Newtonian fluids. The consistency index was significantly higher in yolks of ostrich and emu than that of greater rhea eggs, whereas the VM of yolks of greater rhea eggs was the most resistant (had the highest breaking force = 26.4 g). All species differed significantly regarding the structure of VM, the outer layer (OL) in particular, which was found to constitute fibers of various thicknesses that were differently arranged. Fibers of the OL of the VM of emu, whose fibers were the least differentiated but formed the most compact network, were the most diverse in characterization. An electropherogram of the VM of ostrich revealed 11 primary protein bands: 6 for the OL and 5 for the inner layer (IL), that of emu revealed 9 bands: 5 for the OL and 4 for the IL, and that of greater rhea revealed 10 bands: 6 for the OL and 4 for the IL. PMID- 29253210 TI - Validity and Reliability of Clinical Examination in the Diagnosis of Myofascial Pain Syndrome and Myofascial Trigger Points in Upper Quarter Muscles. AB - Objectives: To determine whether two independent examiners can agree on a diagnosis of myofascial pain syndrome (MPS). To evaluate interexaminer reliability in identifying myofascial trigger points in upper quarter muscles. To evaluate the reliability of clinical diagnostic criteria for the diagnosis of MPS. To evaluate the validity of clinical diagnostic criteria for the diagnosis of MPS. Design: Validity and reliability study. Setting: Provincial Hospital. Toledo, Spain. Participants: Twenty myofascial pain syndrome patients and 20 healthy, normal control subjects, enrolled by a trained and experienced examiner. Methods: Ten bilateral muscles from the upper quarter were evaluated by two experienced examiners. The second examiner was blinded to the diagnosis group. The MPS diagnosis required at least one muscle to have an active myofascial trigger point. Three to four days separated the two examinations. The primary outcome measure was the frequency with which the two examiners agreed on the classification of the subjects as patients or as healthy controls. The kappa statistic (K) was used to determine the level of agreement between both examinations, interpreted as very good (0.81-1.00), good (0.61-0.80), moderate (0.41-0.60), fair (0.21-0.40), or poor (<=0.20). Results: Interexaminer reliability for identifying subjects with MPS was very good (K = 1.0). Interexaminer reliability for identifying muscles leading to a diagnosis of MPS was also very good (K = 0.81). Sensitivity and specificity showed high values for most examination tests in all muscles, which confirms the validity of clinical diagnostic criteria in the diagnosis of MPS. Conclusions: Interrater reliability between two expert examiners identifying subjects with MPS involving upper quarter muscles exhibited substantial agreement. These results suggest that clinical criteria can be valid and reliable in the diagnosis of this condition. PMID- 29253218 TI - Predictors of outcomes for patients with common mental health disorders receiving psychological therapies in community settings: a systematic review. AB - Background: Psychological therapies are increasingly delivered in community care settings. In existing literature, patient, disorder and service variables are known to have a significant impact on the recovery outcomes for patients undergoing psychological treatment in secondary care. The aim of this review is to establish which predictors have a significant impact on recovery from common mental health disorders in community settings. Methods: A systematic review of the literature was conducted according to PRISMA guidelines to identify variables with a predictive power on psychological therapy outcomes. We searched databases using key words and MeSH terms and a strict scoring system and bias check were used. Results: A total of 486 unique references were identified from the search. Overall, 19 papers met the inclusion criteria. These reported on a total of 34 778 patients from five countries in various community care settings. Predictive factors identified and found to be significant were initial severity and comorbid depression (11/19 studies), which negatively impacted outcome in all studies. Conclusions: We identified key predictors for recovery in a community settings from five countries. The evidence currently available for this setting is limited, so this review serves as a starting point to highlight key factors that warrant further investigation. PMID- 29253211 TI - Lipid profile and quality indices of ostrich meat and giblets. AB - In this study, the lipid profile of 5 different edible tissues (leg, thigh, heart, gizzard, and liver) of ostrich was analyzed. Ostrich edible tissues presented a low fat content (<5 g/100 g wet basis). Gizzard and heart revealed the highest amounts of total cholesterol (1.77 and 1.47 mg/g wet basis, respectively), differing significantly from all other tissues (which averaged 0.95 mg/g wet basis). The main tocochromanol in all tissues was alpha-tocopherol (10.3 MUg/g wet basis in heart and an average of 3.4 MUg/g wet basis for all the remaining tissues). All the samples presented a fatty acid profile, dominated by polyunsaturated fatty acids (PUFA) (>38%), namely, linoleic and arachidonic acids. The leg presented simultaneously the highest PUFA/saturated fatty acids (SFA), the lowest n-6/n-3 ratios, and the most favorable lipid quality indices among all tissues in comparison. PMID- 29253219 TI - SODIUM POTASSIUM ROOT DEFECTIVE1 regulates FLOWERING LOCUS T expression via the microRNA156-SQUAMOSA PROMOTER BINDING PROTEIN-LIKE3 module in response to potassium conditions. AB - To determine flowering time, plants perceive multiple environmental stimuli and integrate these signals in the regulation of a florigen gene, FLOWERING LOCUS T (FT). It has been known that nutrient availability affects flowering time in both laboratories and fields. Nitrogen (N), phosphorus (P) and potassium (K) are the three major macronutrients which are important for plant growth and development. Although N and P stimuli can alter the expression of regulators of FT including microRNA156 (miR156) and miR156-targeted transcription factors of the SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) family, how K+ conditions affect flowering is still unclear. We focused on SODIUM POTASSUIM ROOT DEFECTIVE1 (NaKR1) whose mutant plants showed Na+ and K+ overaccumulation and late flowering. It was reported that NaKR1 is involved in the phloem transport of FT protein. Here we report that NaKR1 is also required for the promotion of FT expression in long-day conditions. NaKR1 affects the accumulation of miR156 and SPL3 expression, suggesting that NaKR1 regulates FT expression in part through the miR156-SPL3 module. The late-flowering phenotype of the nakr1-1 mutant was partially suppressed under low K+ conditions, and miR156 abundance and SPL3 expression in the nakr1-1 mutant and, to a lesser extent, in wild-type plants responded to K+ conditions. Taken together, our findings suggest that the miR156-SPL3 module mediates regulation of FT expression by NaKR1 in response to K+ conditions. Finally, we propose a model in which NaKR1 plays dual roles in regulation of flowering, one in the regulation of florigen production, the other in that of florigen transport. PMID- 29253216 TI - Genome assembly of the Pink Ipe (Handroanthus impetiginosus, Bignoniaceae), a highly valued, ecologically keystone Neotropical timber forest tree. AB - Background: Handroanthus impetiginosus (Mart. ex DC.) Mattos is a keystone Neotropical hardwood tree widely distributed in seasonally dry tropical forests of South and Mesoamerica. Regarded as the "new mahogany," it is the second most expensive timber, the most logged species in Brazil, and currently under significant illegal trading pressure. The plant produces large amounts of quinoids, specialized metabolites with documented antitumorous and antibiotic effects. The development of genomic resources is needed to better understand and conserve the diversity of the species, to empower forensic identification of the origin of timber, and to identify genes for important metabolic compounds. Findings: The genome assembly covers 503.7 Mb (N50 = 81 316 bp), 90.4% of the 557 Mbp genome, with 13 206 scaffolds. A repeat database with 1508 sequences was developed, allowing masking of ~31% of the assembly. Depth of coverage indicated that consensus determination adequately removed haplotypes assembled separately due to the extensive heterozygosity of the species. Automatic gene prediction provided 31 688 structures and 35 479 messenger RNA transcripts, while external evidence supported a well-curated set of 28 603 high-confidence models (90% of total). Finally, we used the genomic sequence and the comprehensive gene content annotation to identify genes related to the production of specialized metabolites. Conclusions: This genome assembly is the first well-curated resource for a Neotropical forest tree and the first one for a member of the Bignoniaceae family, opening exceptional opportunities to empower molecular, phytochemical, and breeding studies. This work should inspire the development of similar genomic resources for the largely neglected forest trees of the mega-diverse tropical biomes. PMID- 29253220 TI - Medical treatment for acute Type A aortic dissection. AB - Six patients with acute Type A aortic dissection were medically treated due to advanced age, patient refusal and comorbidity despite surgical indication. Computed tomography after onset revealed a thrombosed false lumen in 3 patients and a patent false lumen with flap in 3 patients. All patients were stable during admission except 1 patient who presented with shock. After admission, treatment including strict control of systolic blood pressure was started according to a predetermined treatment strategy. All patients had no significant complications during hospitalization. All patients survived and returned to their usual activities. Medical treatment for stable elderly patients is a possible therapeutic option for acute Type A aortic dissection. PMID- 29253223 TI - Big data in nephrology-a time to rethink. PMID- 29253224 TI - Feed habituation alleviates decreased feed intake after feed replacement in broilers. AB - In the present study, 2 experiments were conducted to investigate the effect of replacing a mash diet with a pellet diet on the expression of genes related to appetite in the hypothalamus and gastrointestinal tract (GT) and to evaluate the attenuating effect of feed habituation on the disadvantage influence on feed consumption. In experiment 1, the mash diet of one group of 21-day-old chicks was replaced with a pellet diet (PD) with the same ingredient composition, while the other group of chicks was continued on the mash diet (control). In experiment 2, all the experimental chickens were divided into 3 treatments at 18 d of age. One treatment of birds was provided with feeders with pellet feed scattered on the surface of the mash diet (around one-third of feeder surface, MP) from d 18 to d 20, and they were provided with the PD on d 21. The other 2 treatments of chickens were either fed with the PD (PDF) or continued the mash diet (control) at 21 d of age. The results showed that replacing a mash diet with a PD decreased (P < 0.05) feed consumption. The intestinal morphology was not influenced (P > 0.05). The mRNA levels of cholecystokinin (CCK) in the jejunum were upregulated (P < 0.05) in the PD chickens. The expression of anorexia gene ghrelin, corticotropin-releasing hormone (CRH), and melanocortin receptor 4 (MCR-4) were significantly down-regulated (P < 0.05) in the hypothalamus of the MP and PDF chickens 4 h after feed replacement. The results indicated that feed replacement altered the expression of genes related to appetite in the GT and hypothalamus. Pellet changeover causes a short-term decrease in the feed intake of broilers, and feed habituation relieves the negative effects of feed replacement. PMID- 29253228 TI - Phytase in starter and grower diets of White Pekin ducks. AB - The growth performance and phosphorus utilization responses of ducks to phytase were investigated during the starter and grower phases. Five-hundred-seventy-six one-day-old drakes with an average initial BW of 55 g were grouped by BW into 8 blocks of 6 pens and assigned to 48 pens with 12 ducks per pen. The 6 dietary treatments consisted of: 1) positive control (PC), adequate in all nutrients with 4.5 g non-phytate phosphorus (nPP)/kg starter diet or 3.5 g nPP/kg grower diet; 2) negative control (NC), adequate in all other nutrients except phosphorus with 3.0 g nPP/kg starter diet or 2.0 g nPP/kg grower diet; 3) the NC plus phytase at 500 units/kg diet; 4) the NC plus phytase at 1,000 units/kg diet; 5) the NC plus phytase at 1,500 units/kg diet; and 6) the NC plus phytase at 15,000 units/kg diet. Starter and grower diets were fed from d 1 to 15 and d 15 to 43 post hatching, respectively. Ducks had free access to diets and water during the 42 day study. Feeding the low-P NC diet to ducks reduced (P < 0.01) gain and feed intake compared with the PC diet in both starter and grower phases. Supplementing the NC diet with phytase resulted in both linear and quadratic improvements (P < 0.05) in gain, feed intake, and G: F. Feeding the low-P NC diet to ducks reduced (P < 0.01) tibia ash compared with the PC diet. There were both linear and quadratic increases (P < 0.05) in tibia ash with phytase supplementation. Supplementing the NC diet with phytase resulted in both linear and quadratic increases (P < 0.001) in ileal digestibility and retention of P in both the starter and grower phases. The results of this study showed that phytase was efficacious in hydrolyzing phytate P for bone mineralization and growth of ducks through the starter and grower periods. PMID- 29253221 TI - Directed hydroxyl radical probing reveals Upf1 binding to the 80S ribosomal E site rRNA at the L1 stalk. AB - Upf1 is an SF1-family RNA helicase that is essential for the nonsense-mediated decay (NMD) process in eukaryotes. While Upf1 has been shown to interact with 80S ribosomes, the molecular details of this interaction were unknown. Using purified recombinant proteins and high-throughput sequencing combined with Fe-BABE directed hydroxyl radical probing (HTS-BABE) we have characterized the interaction between Upf1 and the yeast 80S ribosome. We identify the 1C domain of Upf1, an alpha-helical insertion in the RecA helicase core, to be essential for ribosome binding, and determine that the L1 stalk of 25S rRNA is the binding site for Upf1 on the ribosome. Using the cleavage sites identified by hydroxyl radical probing and high-resolution structures of both yeast Upf1 and the human 80S ribosome, we provide a model of a Upf1:80S structure. Our model requires that the L1 stalk adopt an open configuration as adopted by an un-rotated, or classical state, ribosome. Our results shed light on the interaction between Upf1 and the ribosome, and suggest that Upf1 may specifically engage a classical-state ribosome during translation. PMID- 29253222 TI - Differences in intestinal size, structure, and function contributing to feed efficiency in broiler chickens reared at geographically distant locations. AB - The contribution of the intestinal tract to differences in residual feed intake (RFI) has been inconclusively studied in chickens so far. It is also not clear if RFI-related differences in intestinal function are similar in chickens raised in different environments. The objective was to investigate differences in nutrient retention, visceral organ size, intestinal morphology, jejunal permeability and expression of genes related to barrier function, and innate immune response in chickens of diverging RFI raised at 2 locations (L1: Austria; L2: UK). The experimental protocol was similar, and the same dietary formulation was fed at the 2 locations. Individual BW and feed intake (FI) of chickens (Cobb 500FF) were recorded from d 7 of life. At 5 wk of life, chickens (L1, n = 157; L2 = 192) were ranked according to their RFI, and low, medium, and high RFI chickens were selected (n = 9/RFI group, sex, and location). RFI values were similar between locations within the same RFI group and increased by 446 and 464 g from low to high RFI in females and males, respectively. Location, but not RFI rank, affected growth, nutrient retention, size of the intestine, and jejunal disaccharidase activity. Chickens from L2 had lower total body weight gain and mucosal enzyme activity but higher nutrient retention and longer intestines than chickens at L1. Parameters determined only at L1 showed increased crypt depth in the duodenum and jejunum and enhanced paracellular permeability in low vs. high RFI females. Jejunal expression of IL1B was lower in low vs. high RFI females at L2, whereas that of TLR4 at L1 and MCT1 at both locations was higher in low vs. high RFI males. Correlation analysis between intestinal parameters and feed efficiency metrics indicated that feed conversion ratio was more correlated to intestinal size and function than was RFI. In conclusion, the rearing environment greatly affected intestinal size and function, thereby contributing to the variation in chicken RFI observed across locations. PMID- 29253231 TI - Use of In Vivo Imaging System Technology in Leishmania major BALB/c Mouse Ear Infection Studies. AB - Novel treatments for cutaneous leishmaniasis (CL) are needed, due to current lack of effective universal treatments, increasing resistance among the parasite, and toxic effects or impracticality of the current therapeutics. Models of direct infection with high number of Leishmania parasites in the current research of CL involving the BALB/c mouse or Golden Syrian Hamster are considered not suitable for the assessment of antileishmanial drug efficacy because of the lack of disease similarities with humans. The saliva of the sand fly vector is known to affect the host response to infection by the Leishmania parasite. Here, we build upon a previous BALB/c model infected with luciferase-expressing Leishmania major parasites. In the present study, we infect the ear dermis instead of the foot pad or base of the tail, and compare multiple methods of infection, using parasites alone or mixed with either bites from uninfected sand flies (Phlebotomus duboscqi Diptera Psychodidae:Neveu-Lemaire) or salivary gland sonicate from sand flies. Our data show a dose-response of bioluminescent signal (which represents the parasite load at the infection site), dermal lesion development, and Leishmania Donovan Units in liver and spleen. This in vivo L. major ear infection model, once optimized, can be used for assessing the efficacy of drug compounds that have been determined as very effective in the other, high inoculum CL models. PMID- 29253227 TI - Influence of dietary avilamycin on ileal and cecal microbiota in broiler chickens. AB - The mechanisms by which antibiotic growth promoters (AGP) enhance growth rates, feed efficiencies, and disease resistance in poultry need to be understood for designing safer and alternative strategies to replace AGP. Avilamycin has been widely used as an AGP in poultry, but its impact on the structure and function of the gut microbiome of broiler chickens has not been fully elucidated. In this study, we investigated the bacterial communities of the ileum and cecum in broiler chickens fed with an avilamycin-supplemented diet, by high-throughput sequencing of bacterial 16S rRNA genes. Alpha diversity metrics indicated that the ileal bacterial diversity was higher in avilamycin-fed chickens than in the control group, whereas the opposite was true for the cecum. Multivariate analyses revealed that the ileal microbiota of the avilamycin-fed group were clearly distinguished from those of the control group, whereas the cecal bacterial communities were apparently not influenced by feeding diets containing avilamycin. In the ilea, 2 operational taxonomic units (OTU) that matched Lactobacillus reuteri and Clostridium were enriched (P = 0.016 and P = 0.007, respectively) in the avilamycin-fed group, and an OTU belonging to Lactobacillus crispatus was decreased (P = 0.016). In the cecal microbiota showing much higher diversity with 1,286 non-singleton OTU, 12 OTU were decreased, and 3 were increased in response to avilamycin treatment (P = 0.005-0.047). Functional profiling of bacterial communities based on PICRUSt analysis revealed that 10 functional categories were enriched by avilamycin treatments, and 4 functional categories were decreased. In conclusion, our results demonstrated that the influence of avilamycin supplementation on the diversity, taxonomic composition, and functional profiles of the microbiota was evidently different in the ileum and cecum. These results further our understanding of the impact of AGP on the composition and activity of commensal bacteria in the chicken gastrointestinal tract to develop novel feeding strategies for improving animal health and performance. PMID- 29253229 TI - Endogenous viral gene ev21 is not responsible for the expression of late feathering in chickens. AB - The late-feathering (LF) gene K on the Z chromosome is an important gene in the chicken industry, which is frequently utilized for the feather sexing, a type of autosexing, of neonatal chicks. The K gene is closely associated with the endogenous ev21 gene from an avian leukosis virus and the incomplete duplication (ID) of prolactin receptor (PRLR) and sperm flagellar protein 2 (SPEF2) genes, and ev21 has been used as a molecular marker to detect LF birds. In the present study, a comprehensive survey for the presence or absence of ev21 and ID across 1,994 birds from 52 chicken breeds, three commercial hybrid groups, and the Red Jungle Fowl revealed that almost all LF breeds have both ev21 and ID. However, only one LF breed (Ingie) has only ID and no ev21. Moreover, this study revealed that almost all early (normal)-feathering (EF) breeds lack both ev21 and ID, but only one breed (White Plymouth Rock) included EF birds with ev21 but no ID. Therefore, regarding LF expression, the results indicated that ID is responsible, but ev21 is not required. Henceforth, ID should be used as a molecular marker to detect LF birds instead of ev21. Because ev21 contains the full genome of an avian leukosis virus, there is a risk of disease development in breeds with this gene. Therefore, the Ingie breed, which has no ev21 at the K locus, represents excellent material for the establishment of new LF stocks. PMID- 29253226 TI - Sales Trends in Price-Discounted Cigarettes, Large Cigars, Little Cigars, and Cigarillos-United States, 2011-2016. AB - Introduction: Tobacco manufacturers continue to implement a range of pricing strategies to increase the affordability and consumption of tobacco products. To demonstrate the extent of retail- and brand-level price discounts at the point of sale, this study assessed national sales trends in price-discounted cigarettes, large cigars, little cigars, and cigarillos. Methods: Retail scanner data for tobacco product sales were obtained for convenience stores (C-store) and all other-outlets-combined (AOC) from September 25, 2011, to January 9, 2016. The proportion of price-discounted sales, average nondiscounted unit price, and average discounted unit price were examined by product category and brand. JoinPoint regression was used to assess average monthly percentage change. Results: Overall, price-discounted sales accounted for 11.3% of cigarette, 3.4% of large cigar, 4.1% of little cigar, and 3.9% of cigarillo sales. The average difference between nondiscounted and discounted prices was 25.5% (C-store) and 36.7% (AOC) for cigarettes; 11.0% (C-store) and 11.2% (AOC) for large cigars; 19.2% (C-store) and 9.6% (AOC) for little cigars; and 5.3% (C-store) and 14.7% (AOC) for cigarillos. Furthermore, price-discounted sales of top-selling tobacco brands comprised up to 36% of cigarette, 7.4% of large cigar, 7.7% of little cigar, and 4.2% of cigarillo unit sales. Conclusions: These findings highlight the use of price discounts by tobacco manufacturers to reduce the cost of cigarettes, large cigars, little cigars, and cigarillos to consumers. These sales patterns underscore the importance of sustained efforts to implement evidence based strategies to increase prices and reduce availability and consumption of combustible tobacco in the United States. Implications: This study highlights the prevalence and provides a baseline of price-discounted cigarettes, large cigars, little cigars, and cigarillos. Surveillance of tobacco sales data, including state-level trends and additional product types, is critical for informing approaches to reduce tobacco consumption. These approaches include countering tobacco product price-discounting practices and raising and maintaining a high sales price for all tobacco products. The implementation of evidence-based population-level interventions, together with local, state, and federal regulation of tobacco products, could prevent tobacco initiation, increase tobacco cessation, and reduce overall tobacco use among US youth and adults. PMID- 29253230 TI - Correlation between miRNAs and target genes in response to Campylobacter jejuni inoculation in chicken. AB - Campylobacter jejuni (C. jejuni) is one of the main causes of human campylobacteriosis worldwide. Chicken is the main reservoir of C. jejuni. The cecum is the primary site of C. jejuni colonization. Our previous study has shown that the CLOCK gene is important to regulate the response to C. jejuni inoculation and has a cross-talking with immune-related genes. Correlation networks between the CLOCK gene and microRNAs (miRNAs) play vital roles in colorectal tumorigenesis. MiRNAs play crucial roles in bacterial invasion through regulating multiple target genes. To study the regulatory correlation between miRNAs and target genes, 5 miRNAs that regulate the expression of the CLOCK gene (CLOCK-interacted miRNAs) and 5 immune-related target genes predicted through Targetscan and miRDB were selected to analyze the expression pattern in chicken ceca at 4, 8, 12, 16, 20, and 24 h post C. jejuni inoculation using quantitative PCR. The results showed that the expression of gga-miR-148a, gga-miR-1416-5p, gga miR-30b, and gga-miR-30c were significantly up-regulated at 8 hpi, and gga-miR 30a-5p, gga-miR-30b, and gga-miR-30c were significantly down-regulated at 24 hpi, and gga-miR-1416-5p was significantly down-regulated at 20 hpi (P < 0.05). The expression levels of BCL9 (B-cell CLL/lymphoma 9), STX16 (syntaxin16), IL4R (interleukin 4 receptor), and IRF4 (interferon regulatory factor 4) genes were significantly up-regulated at 8 hpi, while SOCS3 (suppressor of cytokine signaling 3) was significantly down-regulated. Furthermore, the expression pattern of gga-miR-30b was consistent with gga-miR-30c. Both miRNAs and mRNAs showed an oscillation expression pattern in both inoculated and non-inoculated groups. The regulatory direction of SOCS3 was contrary to those of gga-miR-148a, gga-miR-1416-5p, gga-miR-30b, and gga-miR-30c at 8 hpi. In summary, MiR-30 and the miR-148/miR-152 family time-dependently regulate the response to C. jejuni inoculation in chicken ceca. BCL9, STX16, IRF4, and IL4R play important roles in the response to C. jejuni inoculation. The CLOCK gene-interacted miRNA and immune related target genes had a correlative response to C. jejuni inoculation. The SOCS3 gene interacts with gga-miR-30b, gga-miR-30c, gga-miR-148a, and gga-miR 1416-5p in response to C. jejuni inoculation at 8 hpi. The correlations between CLOCK-interacted miRNA and immune-related target genes play vital roles in the response to C. jejuni inoculation. The results herein will lay the foundation for further study of a regulatory mechanism of chicken miRNAs and their target genes in response to C. jejuni inoculation. PMID- 29253232 TI - Dynamics of the excised base release in thymine DNA glycosylase during DNA repair process. AB - Thymine DNA glycosylase (TDG) initiates base excision repair by cleaving the N glycosidic bond between the sugar and target base. After catalysis, the release of excised base is a requisite step to terminate the catalytic cycle and liberate the TDG for the following enzymatic reactions. However, an atomistic-level understanding of the dynamics of the product release process in TDG remains unknown. Here, by employing molecular dynamics simulations combined with the Markov State Model, we reveal the dynamics of the thymine release after the excision at microseconds timescale and all-atom resolution. We identify several key metastable states of the thymine and its dominant releasing pathway. Notably, after replacing the TDG residue Gly142 with tyrosine, the thymine release is delayed compared to the wild-type (wt) TDG, as supported by our potential of mean force (PMF) calculations. These findings warrant further experimental tests to potentially trap the excised base in the active site of TDG after the catalysis, which had been unsuccessful by previous attempts. Finally, we extended our studies to other TDG products, including the uracil, 5hmU, 5fC and 5caC bases in order to compare the product release for different targeting bases in the TDG-DNA complex. PMID- 29253225 TI - Single-molecule DNA unzipping reveals asymmetric modulation of a transcription factor by its binding site sequence and context. AB - Most functional transcription factor (TF) binding sites deviate from their 'consensus' recognition motif, although their sites and flanking sequences are often conserved across species. Here, we used single-molecule DNA unzipping with optical tweezers to study how Egr-1, a TF harboring three zinc fingers (ZF1, ZF2 and ZF3), is modulated by the sequence and context of its functional sites in the Lhb gene promoter. We find that both the core 9 bp bound to Egr-1 in each of the sites, and the base pairs flanking them, modulate the affinity and structure of the protein-DNA complex. The effect of the flanking sequences is asymmetric, with a stronger effect for the sequence flanking ZF3. Characterization of the dissociation time of Egr-1 revealed that a local, mechanical perturbation of the interactions of ZF3 destabilizes the complex more effectively than a perturbation of the ZF1 interactions. Our results reveal a novel role for ZF3 in the interaction of Egr-1 with other proteins and the DNA, providing insight on the regulation of Lhb and other genes by Egr-1. Moreover, our findings reveal the potential of small changes in DNA sequence to alter transcriptional regulation, and may shed light on the organization of regulatory elements at promoters. PMID- 29253233 TI - Effect of epigallocatechin gallate on growth performance and serum biochemical metabolites in heat-stressed broilers. AB - This study aims to investigate the effects of epigallocatechin gallate (EGCG) on the growth performance and serum metabolic characteristics of heat-stressed broilers. A total of 192 14-day-old Arbor Acres broilers were divided into 4 groups with 6 replicates per group (8 chickens/cage). Thermoneutral group (Group TN) was fed the basal diet and maintained at 28 degrees C for 24 h/d. The heat stressed groups were housed at 35 degrees C for 12 h/d and 28 degrees C for 12 h/d and fed the basal diet supplemented with EGCG at 0, 300, and 600 mg/kg diet (Groups HS0, HS300, and HS600, respectively). The production performance and serum metabolic characteristics were analyzed at d 21, 28, and 35, respectively. At d 35 of age, heat stress reduced (P < 0.05) the body weight (BW), feed intake (FI) and the contents of serum total protein (TP) and glucose (GLU); inhibited (P < 0.05) alkaline phosphatase (ALP) activity; But increased (P < 0.05) the contents of uric acid (UA), cholesterol (CHOL), triglyceride (TG), and the activities of creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST). Heat-stressed chickens fed EGCG exhibited a linear increase (P < 0.05) in BW, FI, the levels of serum TP, GLU, and ALP activity; and linear decrease (P < 0.05) in the contents of serum UA, CHOL, and TG, as well as the activities of LDH, CK, and AST. Heat stress also reduced (P < 0.05) the activities of serum glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) on d 35 and increased (P < 0.05) the GSH-Px and SOD activity on d 21 and malondialdehyde (MDA) contents. There was a linear increase (P < 0.05) in activities of GSH-Px, SOD and CAT at 35 d of age, and linear decreased (P < 0.05) in MDA contents. In conclusion, EGCG can improve the growth performance of broilers by enhancing antioxidant property and alleviating oxidant damage caused by heat stress. PMID- 29253235 TI - Who Knows Best (Interests)? The Case of Charlie Gard. AB - When baby Charlie Gard was diagnosed with a rare mitochondrial disease, his parents located a Professor of Neurology in the USA willing to provide nucleoside therapy which offered a theoretical chance of improvement and successfully raised L1.3 million through crowd funding. The decision that unproven therapy was contrary to Charlie Gard's best interests and that life-sustaining treatment should be withdrawn was devastating for his parents and difficult for their supporters to comprehend. The decision was upheld at three levels of appeal and Charlie died in July 2017 aged 11 months. This commentary provides a critical analysis of the legal principles surrounding unproven treatment and application of the best interests test in the different contexts of hospital and court. It draws attention to conflicting guidance and explores differences in approach in relation to unproven treatment for adults lacking capacity and children. PMID- 29253236 TI - High Susceptibility of Lrig1 Sebaceous Stem Cells to TCDD in Mice. PMID- 29253234 TI - FANCD2 binding identifies conserved fragile sites at large transcribed genes in avian cells. AB - Common Chromosomal Fragile Sites (CFSs) are specific genomic regions prone to form breaks on metaphase chromosomes in response to replication stress. Moreover, CFSs are mutational hotspots in cancer genomes, showing that the mutational mechanisms that operate at CFSs are highly active in cancer cells. Orthologs of human CFSs are found in a number of other mammals, but the extent of CFS conservation beyond the mammalian lineage is unclear. Characterization of CFSs from distantly related organisms can provide new insight into the biology underlying CFSs. Here, we have mapped CFSs in an avian cell line. We find that, overall the most significant CFSs coincide with extremely large conserved genes, from which very long transcripts are produced. However, no significant correlation between any sequence characteristics and CFSs is found. Moreover, we identified putative early replicating fragile sites (ERFSs), which is a distinct class of fragile sites and we developed a fluctuation analysis revealing high mutation rates at the CFS gene PARK2, with deletions as the most prevalent mutation. Finally, we show that avian homologs of the human CFS genes despite their fragility have resisted the general intron size reduction observed in birds suggesting that CFSs have a conserved biological function. PMID- 29253238 TI - Two-dimensional Gaussian fitting for precise measurement of lattice constant deviation from a selected-area diffraction map. AB - Unlike X-ray diffraction or Raman techniques, which suffer from low spatial resolution, transmission electron microscopy can be used to obtain strain maps of nanoscaled materials and devices. Convergent-beam electron diffraction (CBED) and nanobeam electron diffraction (NBED) techniques detect the deviation of a lattice constant (i.e. an indicator of strain) within 0.01%; however, their use is restricted to beam-insensitive samples. Selected-area electron diffraction (SAED) does not have such limitations but has low spatial resolution and precision. The use of a spherical aberration corrector and a nanosized selected-area aperture improves the spatial resolution, but the precision is still low. In this study, a two-dimensional stage-scanning system is used to acquire arrays of diffraction patterns at different positions of the sample under fixed beam conditions. Data processing with iterative nonlinear least-squares fitting enabled the spot displacement for each point of the scan area to be measured with precision comparable to that of the CBED or NBED technique. The precise strain determination, in combination with the simplicity of the measurement process, makes the nanosized SAED technique competitive with other methods for strain mapping at nanoscale dimensions. PMID- 29253237 TI - Brain Vacuolation Resulting From Administration of the Type II Ampakine CX717 Is An Artifact Related to Molecular Structure and Chemical Reaction With Tissue Fixative Agents. AB - Ampakines are small molecule positive allosteric modulators of the alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). One class II ("low impact") ampakine, CX717, has been implicated to have a neurotoxic effect based on findings in nonclinical, long-term toxicity studies. The neurotoxicity concerns, which halted the clinical development of the molecule, arose due to a finding of extensive white matter vacuolation in multiple brain regions of animals that were administered high doses of CX717 in several test species (unpublished data). This work characterized the features and a potential mechanism by which ampakines induce vacuoles in brain tissue. Brain sections from adult rats given CX717 (750 mg/kg BID by oral gavage) exhibited no vacuoles with acute or short-term dosing. However, after 14 or more days of treatment, vacuoles were prominent in cerebellum, globus pallidus, and hippocampus. Vacuole margins were lined by glial fibrillary acidic protein (GFAP), and by transmission electron microscopy were shown to be astrocyte processes. CX717-associated vacuoles occurred in formaldehyde-fixed specimens but not flash-frozen samples. Time-course experiments showed that brain tissue slices from CX717-treated animals exhibit no vacuoles until immersed in formaldehyde fixative, whereupon vacuoles form and expand in a time-dependent manner. Chemical interactions in test tube experiments have demonstrated that the combination of CX717 and formalin in an aqueous solution produces an exothermic reaction. Taken together, the data indicate that CX717 does not induce vacuoles in vivo, but rather is associated with astrocyte vacuolation post mortem, likely as the ampakine reacts with formalin to produce gas pockets in brain parenchyma. PMID- 29253240 TI - Characteristics and determinants of respiratory event associated leg movements. AB - Study Objectives: To (i) replicate the recently described distribution of respiratory event associated leg movements (rLM) in subjects with mild to moderate obstructive sleep apnea syndrome (OSAS), (ii) explore global and local factors associated with the presence of rLM, and (iii) investigate differences related to OSAS severity and periodic leg movements during sleep (PLMS) status. Methods: We randomly selected six groups of subjects without restless legs syndrome (12-15 subjects in each group), stratified by AHI severity (AHI 10-20, 20-30, and 30-40) and PLMS status (PLMS index < 15/h and > 15/h) from the population based HypnoLaus study that assessed full polysomnography at home in subjects aged 40 to 80 years, randomly selected from the population register of the city of Lausanne, Switzerland. Results: Our results confirmed the distribution of leg movement activity at the end of respiratory events (-2.0 s to +10.25 s). Mixed effects logistic regression modeling rLM-probability showed that rLM were more frequent in high-PLMS subjects, at the end of obstructive apneas (vs. hypopneas) and in the presence of arousals at the end of the events. In high PLMS subjects rLM-probability decreased with time of night and was more reduced during REM sleep (vs. NREM sleep) while the duration of the respiratory event had a significant effect only in low-PLMS subjects. Conclusions: We confirm the previously reported distribution of rLM in subjects with mild to moderate OSAS and our results suggest that rLM are sensitive to both sleep-related and respiratory-related factors in a complex interaction with the PLMS status. PMID- 29253241 TI - Early root growth and architecture of fast- and slow-growing Norway spruce (Picea abies) families differ-potential for functional adaptation. AB - The relationship between the growth rate of aboveground parts of trees and fine root development is largely unknown. We investigated the early root development of fast- and slow-growing Norway spruce (Picea abies (L.) H. Karst.) families at a developmental stage when the difference in size is not yet observed. Seedling root architecture data, describing root branching, were collected with the WinRHIZOTM image analysis system, and mixed models were used to determine possible differences between the two growth phenotypes. A new approach was used to investigate the spatial extent of root properties along the whole sample root from the base of 1-year-old seedlings to the most distal part of a root. The root architecture of seedlings representing fast-growing phenotypes showed ~30% higher numbers of root branches and tips, which resulted in larger root extensions and potentially a better ability to acquire nutrients. Seedlings of fast-growing phenotypes oriented and allocated root tips and biomass further away from the base of the seedling than those growing slowly, a possible advantage in nutrient limited and heterogeneous boreal forest soils. We conclude that a higher long term growth rate of the aboveground parts in Norway spruce may relate to greater allocation of resources to explorative roots that confers a competitive edge during early growth phases in forest ecosystems. PMID- 29253244 TI - Assessing Neonatal Pain, Duration of Crying and Procedure Time following Use of Automatic or Manual Heel Lances: A Randomized Controlled Study. AB - Objective: The objective of this study was to compare neonatal pain, duration of crying and procedure time following use of automatic or manual heel lancets. Methods: This randomized trial was conducted with neonates undergoing heel prick procedures in a neonatal intensive care unit for routine blood bilirubin monitoring. An information form, an observation form and the Neonatal Infant Pain Scale (NIPS) were used. Pain before, during and after (1 and 3 min) was assessed using NIPS scoring. Results: Seventy neonates were included (automatic lancet, n = 35; manual lancet, n = 35); there was no difference between the groups (p > 0.01). Pain scores were significantly lower, with automatic lancets compared with manual lancets (p = 0.001). The duration of crying after the procedure (p = 0.001) and procedure time (p = 0.001) was significantly shorter with automatic lancets compared with manual lancets. Conclusion: Automatic heel lancets in neonates are more effective than manual lancets at reducing pain, and shorten the procedure time and duration of post-procedural crying. PMID- 29253239 TI - OCCUPATIONAL EXPOSURE FROM F-18-FDG PET/CT: IMPLEMENTATION TO ROUTINE CLINICAL PRACTICE. AB - The purpose of this study was to assess the occupational radiation exposure arising from positron emission tomography combined with X-ray computed tomography (PET/CT) procedures. From 2009 through the end of 2014, in a team of six technologists, personal dosimetry was performed using electronic personal dosemeters and film badge dosemeters. The technologists registered the separate exposure after each PET/CT operational step, which included radiopharmaceutical arrival, dispensing in individual syringes, injection and patient positioning.From the total of 3024 PET/CT procedures, 2142 were available for analysis. The personal dose equivalent for the technologists performing PET/CT ranged from 11.5 nSv/MBq to 23.8 nSv/MBq. Whole-body radiation dose originated mainly from radiopharmaceutical injection (41.5%) and patient positioning (51.1%). The sources of occupational exposure were successfully identified for PET/CT procedures. Record keeping using on-site occupational dosimetry is a useful tool for exposure optimisation. PMID- 29253246 TI - Validity, reliability, responsiveness and feasibility of four hand mobility measures in hand osteoarthritis. AB - Objectives: To investigate metric properties of four hand mobility tests in hand OA patients, using the OMERACT filter. Methods: Trained assessors examined the Hand Mobility in Scleroderma test (HAMIS), fingertip-to-palm distance (FPD), modified Kapandji index (MKI) and number of hand joints with limited mobility in participants from two cohorts [Genetics ARthrosis and Progression (n = 207) and Hand OSTeoArthritis in Secondary care (n = 174)]. Validity was appraised by assessment of correlations with other outcome measures, and ability to measure thumb vs finger mobility specifically, using cumulative probability plots. The proportion of participants changing in hand mobility based on the smallest detectable difference was calculated for responsiveness. Intraclass correlation coefficients (ICCs) for intra- and interobserver reliability, and feasibility (time to perform tests) were studied in a random sample (n = 20). Results: Participants displayed large variation in mobility scores. Strongest correlations were observed with structural damage (rs = 0.43-0.52) and bony swelling (rs = 0.46-0.58); correlation patterns were similar among tests. HAMIS, FPD and MKI could all measure finger mobility specifically, but only HAMIS measured thumb mobility particularly. Interobserver reliability was best for HAMIS, ICC 0.90 (95% CI: 0.76, 0.96); intraobserver reliability was excellent for all (ICCs 0.94 0.97). In 2 years, little change was observed; HAMIS was the most sensitive-to change (smallest detectable difference 3.7% of maximum score). The mean performance time ranged from 0.7 (s.d. 0.5, for FPD) to 5.7 (s.d. 1.3, for HAMIS) min. Conclusion: HAMIS, FPD, MKI and number of joints with limited mobility are all valid, reliable and feasible measures for assessing hand mobility in hand OA, although HAMIS had slightly more favourable properties. Studies assessing sensitivity-to-change in a clinical trial setting are warranted. PMID- 29253243 TI - Biomarkers of Potential Harm: Summary of an FDA-Sponsored Public Workshop. AB - Introduction: Since 2009, the United States (U.S.) Food and Drug Administration (FDA) Center for Tobacco Products (CTP) has had the authority to regulate the manufacture, distribution, and marketing of tobacco products in order to reduce the death and disease caused by tobacco use. Biomarkers could play an important role across a number of FDA regulatory activities, including assessing new and modified risk tobacco products and identifying and evaluating potential product standards. Methods: On April 4-5, 2016, FDA/CTP hosted a public workshop focused on biomarkers of potential harm (BOPH) with participants from government, industry, academia, and other organizations. The workshop was divided into five sessions focused on: 1) overview of BOPH; 2) cardiovascular disease (CVD); 3) chronic obstructive pulmonary disease (COPD); 4) cancer; and 5) new areas of research. Results and Conclusions: The deliberations from the workshop noted some promising BOPH but also highlighted the lack of systematic effort to identify BOPH that would have utility and validity for evaluating tobacco products. Research areas that could further strengthen the applicability of BOPH to tobacco regulatory science include the exploration of composite biomarkers as predictors of disease risk, "omics" biomarkers, and examining biomarkers using existing cohorts, surveys and experimental studies. Implications: This paper synthesizes the main findings from the 2016 FDA-sponsored workshop focused on biomarkers of potential harm (BOPH) and highlights research areas that could further strengthen the science around BOPH and their applicability to tobacco regulatory science. PMID- 29253242 TI - Characterization of the impact of rpoB mutations on the in vitro and in vivo competitive fitness of Clostridium difficile and susceptibility to fidaxomicin. AB - Objectives: To establish the role of specific, non-synonymous SNPs in the RNA polymerase beta subunit (rpoB) gene in reducing the susceptibility of Clostridium difficile to fidaxomicin and to explore the potential in vivo significance of rpoB mutant strains. Methods: Allelic exchange was used to introduce three different SNPs into the rpoB gene of an erythromycin-resistant derivative (CRG20291) of C. difficile R20291. The genome sequences of the created mutants were determined and each mutant analysed with respect to growth and sporulation rates, toxin A/B production and cytotoxicity against Vero cells, and in competition assays. Their comparative virulence and colonization ability was also assessed in a hamster infection model. Results: The MIC of fidaxomicin displayed by three mutants CRG20291-TA, CRG20291-TG and CRG20291-GT was substantially increased (>32, 8 and 2 mg/L, respectively) relative to that of the parent strain (0.25 mg/L). Genome sequencing established that the intended mutagenic substitutions in rpoB were the only changes present. Relative to CRG20291, all mutants had attenuated growth, were outcompeted by the parental strain, had lower sporulation and toxin A/B production capacities, and displayed diminished cytotoxicity. In a hamster model, virulence of all three mutants was significantly reduced compared with the progenitor strain, whereas the degree of caecum colonization was unaltered. Conclusions: Our study demonstrates that particular SNPs in rpoB lead to reduced fidaxomicin susceptibility. These mutations were associated with a fitness cost in vitro and reduced virulence in vivo. PMID- 29253247 TI - Atypical Structural Asymmetry of the Planum Temporale is Related to Family History of Dyslexia. AB - Research on the neural correlates of developmental dyslexia indicates atypical anatomical lateralization of the planum temporale, a higher-order cortical auditory region. Yet whether this atypical lateralization precedes reading acquisition and is related to a familial risk for dyslexia is not currently known. In this study, we address these questions in 2 separate cohorts of young children and adolescents with and without a familial risk for dyslexia. Planum temporale surface area was manually labeled bilaterally, on the T1-weighted MR brain images of 54 pre-readers (mean age: 6.2 years, SD: 3.2 months; 33 males) and 28 adolescents (mean age: 14.7 years, SD: 3.3 months; 11 males). Half of the pre-readers and adolescents had a familial risk for dyslexia. In both pre-readers and adolescents, group comparisons of left and right planum temporale surface area showed a significant interaction between hemisphere and family history of dyslexia, with participants who had no family risk for dyslexia showing greater leftward asymmetry of the planum temporale. This effect was confirmed when analyses were restricted to normal reading participants. Altered planum temporale asymmetry thus seems to be related to family history of dyslexia. PMID- 29253245 TI - Nomograms for predicting disease progression in patients of Stage I non-small cell lung cancer treated with stereotactic body radiotherapy. AB - Objective: Non-local progression is a major concern in non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Herein we aimed to create a pre-treatment prognostic nomogram for patients with Stage I NSCLC receiving SBRT. Methods: We retrospectively studied 182 eligible patients. Patients were randomly divided into a model (70%) group and a validation (30%) group. In the model group, thirteen parameters consisting of patient, treatment, and tumor factors were studied and multivariate Cox proportional hazards regression was performed to identify independent predictors for survival outcome, based on which we developed clinical nomogram. The nomogram was externally validated in the validation group. Results: Multivariate analysis showed that tumor size (P = 0.011) was the only factor correlated with 2-year overall survival, whereas 2-year locoregional control (LRC) was significantly related to tumor size (P = 0.024) and the maximum standardized uptake value (SUVmax) (P = 0.044), so does 2-year progression-free survival (PFS) (tumor size: P = 0.026; SUVmax: P = 0.038). Nomogram for 2-year LRC and 2-year PFS were created based on aforementioned results. The C-indexes for the nomograms to predict 2-year LRC and PFS were 0.816 and 0.804, respectively, in model group, and were 0.729 and 0.731, respectively, in the validation group. Calibration plots also showed that the model performed well. Conclusions: Tumor of larger size and higher SUVmax predisposed patients to early onset of locoregional and distant progression. The nomogram developed in our study would be helpful in clinical decision-making and selection of patients who may benefit from more rigorous follow-up and aggressive systemic treatment plan. PMID- 29253256 TI - Effect of cardia banding and improved anaesthetic care on outcome of oesophageal atresia in a developing country. AB - We comparatively analysed cases of oesophageal atresia (OA) managed in Enugu, south-eastern Nigeria from October 2010 to September 2015 to evaluate our short term outcome with management following incorporation of temporary cardia banding to gastrostomy for late presenting cases and improved anaesthesia in 2013. Overall, 19 cases were analysed. The clinical parameters did not differ in the cases managed before (Group A) and after (Group B) these introductions. Four (21.1%) cases had primary repair (2 per group), six (31.6%) had delayed primary repair after treatment of pneumonitis (Group A 5; Group B 1) and nine (47.3%) had delayed primary repair after gastrostomy (Group A 4; Group B 5). Anaesthesia related mortality dropped from 53.8 to 7.7% and survival improved from 9.1 to 62.5% following the introductions. Despite persisting barriers to care, outcome of OA in our setting may improve with better anaesthesia and incorporation of temporary cardia banding to gastrostomy. PMID- 29253251 TI - Primate Ventromedial Prefrontal Cortex Neurons Continuously Encode the Willingness to Engage in Reward-Directed Behavior. AB - To survive in their complex environment, primates must integrate information over time and adjust their actions beyond immediate events. The underlying neurobiological processes, however, remain unclear. Here, we assessed the contribution of the ventromedial prefrontal cortex (VMPFC), a brain region important for value-based decision-making. We recorded single VMPFC neurons in monkeys performing a task where obtaining fluid rewards required squeezing a grip. The willingness to perform the action was modulated not only by visual information about Effort and Reward levels but also by contextual factors such as Trial Number (i.e., fatigue and/or satiety) or behavior in recent trials. A greater fraction of VMPFC neurons encoded contextual information, compared with visual stimuli. Moreover, the dynamics of VMPFC firing was more closely related to slow changes in motivational states driven by these contextual factors rather than rapid responses to individual task events. Thus, the firing of VMPFC neurons continuously integrated contextual information and reliably predicted the monkeys's willingness to perform the task. This function might be critical when animals forage in a complex environment and need to integrate information over time. Its relation with motivational states also resonates with the VMPFC's implication in the "default mode" or in mood disorders. PMID- 29253253 TI - The Basal Radial Glia Occurs in Marsupials and Underlies the Evolution of an Expanded Neocortex in Therian Mammals. AB - A hallmark of mammalian brain evolution is the emergence of the neocortex, which has expanded in all mammalian infraclasses (Eutheria, Marsupialia, Monotremata). In eutherians, neocortical neurons derive from distinct neural stem and progenitor cells (NPCs). However, precise data on the presence and abundance of the NPCs, especially of basal radial glia (bRG), in the neocortex of marsupials are lacking. This study characterized and quantified the NPCs in the developing neocortex of a marsupial, the tammar wallaby (Macropus eugenii). Our data demonstrate that its neocortex is characterized by high NPC diversity. Importantly, we show that bRG exist at high relative abundance in the tammar indicating that this cell type is not specific to the eutherian neocortex and that similar mechanisms may underlie the formation of an expanded neocortex in eutherian and marsupial mammals. We also show that bRG are likely to have been present in the therian ancestor, so did not emerge independently in the eutherian and marsupial lineages. Moreover, our data support the concept that changes in multiple parameters contribute to neocortex expansion and demonstrate the importance of bRG and other NPCs for the development and expansion of the mammalian neocortex. PMID- 29253258 TI - Gangrenous Necrotizing Cutaneous Mucormycosis in an Immunocompetent Neonate: A Case Report from Oman. AB - We describe a case of progressive cutaneous mucormycosis, which caused gangrenous necrotizing fasciitis, in an immunocompetent neonate from Oman. Extensive wound contamination and a favorable environment for the growth of Mucorales were the predisposing factors. Early aggressive management including frequent wound debridement, targeted pharmacotherapy with liposomal amphotericin B and supportive care is pivotal for improved outcomes. PMID- 29253257 TI - Diverse effects of natural antioxidants on cyclosporin cytotoxicity in rat renal tubular cells. PMID- 29253250 TI - Diminished Alpha Lateralization During Working Memory but Not During Attentional Cueing in Older Adults. AB - Aging has been associated with declined performance in tasks that rely on working memory (WM). Because attention and WM are tightly coupled, declined performance on a WM task in older adults could be due to deficits in attention, memory capacity, or both. We used alpha (8-14 Hz) power modulations as an index to assess how changes in attention and memory capacity contribute to decreased WM performance in older adults. We recorded the magnetoencephalogram in healthy older (60-76 years) and younger adults (18-28 years) while they performed a lateralized WM task. At matched difficulty, older adults showed significantly lower memory spans than younger adults. Alpha lateralization during retention was nearly absent in older adults due to a bilateral reduction of alpha power. By contrast, in younger adults alpha power was reduced only contralateral to the attended hemifield. Surprisingly, during the cue interval, both groups showed equal alpha lateralization. The preserved alpha lateralization during attentional cueing, and lack thereof during retention, suggests that reduced WM performance in older adults is due to deficits in WM-related processes, not deficits in attentional orienting, and that a compensatory mechanism in aging permits significant residual WM performance in the absence of alpha lateralization. PMID- 29253248 TI - Inhibitory Modulation of Orbitofrontal Cortex on Medial Prefrontal Cortex Amygdala Information Flow. AB - The amygdala receives cortical inputs from the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) that are believed to affect emotional control and cue-outcome contingencies, respectively. Although mPFC impact on the amygdala has been studied, how the OFC modulates mPFC-amygdala information flow, specifically the infralimbic (IL) division of mPFC, is largely unknown. In this study, combined in vivo extracellular single-unit recordings and pharmacological manipulations were used in anesthetized rats to examine how OFC modulates amygdala neurons responsive to mPFC activation. Compared with basal condition, pharmacological (N-Methyl-D-aspartate) or electrical activation of the OFC exerted an inhibitory modulation of the mPFC-amygdala pathway, which was reversed with intra-amygdala blockade of GABAergic receptors with combined GABAA and GABAB antagonists (bicuculline and saclofen). Moreover, potentiation of the OFC-related pathways resulted in a loss of OFC control over the mPFC-amygdala pathway. These results show that the OFC potently inhibits mPFC drive of the amygdala in a GABA dependent manner; but with extended OFC pathway activation this modulation is lost. Our results provide a circuit-level basis for this interaction at the level of the amygdala, which would be critical in understanding the normal and pathophysiological control of emotion and contingency associations regulating behavior. PMID- 29253254 TI - Dissociated Representations of Deceptive Intentions and Kinematic Adaptations in the Observer's Motor System. AB - Previous studies showed that observing deceptive actions modulates the activity of the observer's motor system. However, it is unclear whether this modulation reflects the coding of deceptive intentions or the mapping of the kinematic adaptations required to attain deceptive actions. Here, we used single-pulse transcranial magnetic stimulation to measure cortico-spinal excitability (CSE) from hand and forearm muscles while participants predicted the weight of cubes lifted by actors who received truthful information on the object weight and provided 1) truthful (truthful actions) or 2) deceptive (deceptive actions) cues to the observers or 3) who received fooling information and were asked to provide truthful cues (deceived actions). This way, we independently manipulated actor's intentions and kinematic adaptations. We found that, as compared to truthful action observation, CSE increased during observation of deceptive actions, but decreased during observation of deceived actions. Importantly, while the CSE enhancement in response to deceptive intentions lacked muscle specificity, perceiving kinematic alterations in the deceived condition affected CSE only for the hand muscle involved in kinematic adaptations to unexpected object weight. This suggests that actor's intentions and movement kinematics may be coded by the observer's motor system at different hierarchical levels of action representation. PMID- 29253255 TI - Low-Beta Oscillations Turn Up the Gain During Category Judgments. AB - Synchrony between local field potential (LFP) rhythms is thought to boost the signal of attended sensory inputs. Other cognitive functions could benefit from such gain control. One is categorization where decisions can be difficult if categories differ in subtle ways. Monkeys were trained to flexibly categorize smoothly varying morphed stimuli, using orthogonal boundaries to carve up the same stimulus space in 2 different ways. We found evidence for category-specific patterns of low-beta (16-20 Hz) synchrony in the lateral prefrontal cortex (PFC). This synchrony was stronger when a given category scheme was relevant. We also observed an overall increase in low-beta LFP synchrony for stimuli that were near the category boundary and thus more difficult to categorize. Beta category selectivity was evident in partial field-field coherence measurements, which measure local synchrony, but the boundary enhancement was not. Thus, it seemed that category selectivity relied on local interactions while boundary enhancement was a more global effect. The results suggest that beta synchrony helps form category ensembles and may reflect recruitment of additional cortical resources for categorizing challenging stimuli, thus serving as a form of gain control. PMID- 29253252 TI - Longitudinal Alterations of Frontoparietal and Frontotemporal Networks Predict Future Creative Cognitive Ability. AB - Creative cognition is important to academic performance and career success during late adolescence and adulthood. However, there is a lack of longitudinal data on whether brain structural development could predict improvements in creative thinking, and how such changes interact with other cognitive abilities to support creative performance. Here we examined longitudinal alterations of brain structure and their relation to creative cognitive ability in a sample of 159 healthy young adults who were scanned using magnetic resonance imaging 2-3 times over the course of 3 years. The most robust predictor of future creative ability was the right dorsolateral prefrontal cortex (DLPFC), which in conjunction with baseline creative capacity showed a 31% prediction rate. Longitudinal analysis revealed that slower decreases in gray matter density within left frontoparietal and right frontotemporal clusters predicted enhanced creative ability. Moreoever, the relationship between longitudinal alterations within frontal-related clusters and improved creative ability was moderated by the right DLPFC and working memory ability. We conclude that continuous goal-directed planning and accumulated knowledge are implemented in the right DLPFC and temporal areas, respectively, which in turn support longitudinal gains in creative cognitive ability. PMID- 29253249 TI - Differential Sources for 2 Neural Signatures of Target Detection: An Electrocorticography Study. AB - Electrophysiology and neuroimaging provide conflicting evidence for the neural contributions to target detection. Scalp electroencephalography (EEG) studies localize the P3b event-related potential component mainly to parietal cortex, whereas neuroimaging studies report activations in both frontal and parietal cortices. We addressed this discrepancy by examining the sources that generate the target-detection process using electrocorticography (ECoG). We recorded ECoG activity from cortex in 14 patients undergoing epilepsy monitoring, as they performed an auditory or visual target-detection task. We examined target-related responses in 2 domains: high frequency band (HFB) activity and the P3b. Across tasks, we observed a greater proportion of electrodes that showed target-specific HFB power relative to P3b over frontal cortex, but their proportions over parietal cortex were comparable. Notably, there was minimal overlap in the electrodes that showed target-specific HFB and P3b activity. These results revealed that the target-detection process is characterized by at least 2 different neural markers with distinct cortical distributions. Our findings suggest that separate neural mechanisms are driving the differential patterns of activity observed in scalp EEG and neuroimaging studies, with the P3b reflecting EEG findings and HFB activity reflecting neuroimaging findings, highlighting the notion that target detection is not a unitary phenomenon. PMID- 29253260 TI - Effects of chicken feet gelatin extracted at different temperatures and wheat fiber with different particle sizes on the physicochemical properties of gels. AB - The objectives of this study were to determine the effects of 1) the extraction temperature (65, 75, 85, and 95 degrees C) of chicken feet gelatin (CFG) and 2) CFG extracted at different temperatures and wheat fiber (WF) with different particle sizes (80, 250, and 500 MUm) on the physicochemical properties of the resultant gels. Raw chicken feet (CF) were swelled by treatment of an acidic solution [i.e., 0.1 N HCl (pH 2)]. The CFG was extracted from the swelled CF at different temperatures. Samples of 4% CFG or a mixture of 3% CFG and 3% WF were prepared using distilled water at 42 +/- 1 degrees C and then cooled to form gels. The physicochemical properties of the prepared CFG or the gel with CFG and WF were then investigated. The results indicate that the extraction yield, protein content, and L* values for the CFG samples significantly increased as the extraction temperature increased, whereas the viscosity, melting point, and a* values decreased. For the gel with CFG and WF, the gel strength, melting point, viscosity, and L* and b* values were significantly affected (P < 0.05) by the extraction temperature of CFG, but they partially were not affected (P > 0.05) by the particle size of WF. The gel with WF and extracted CFG at 65 degrees C had the highest (P < 0.05) gel strength, melting point, viscosity, and a* values. In conclusion, CFG or the gel with CFG and WF could be utilized to prepare gelatins or gel with different physicochemical properties by controlling the extraction temperature or particle size of WF, depending on the specific application. Moreover, with its distinct physicochemical properties, the gel with CFG and WF could possibly be used as a non-meat ingredient for fat replacement. PMID- 29253259 TI - THERMOLUMINESCENT DOSIMETRY IN THE EVALUATION OF NATURAL RADIOACTIVITY INDOOR OF HOMES NEAR THE URANIUM DEPOSIT OF PARAIBA, BRAZIL. AB - High levels of primordial radionuclides have been reported in soils and rocks of Sao Jose de Espinharas, in the state of Paraiba, Brazil. These radionuclides are derived from high concentrations of natural uranium and thorium from a mine in the region. Thus, there is a need for a dosimetric evaluation in the area near the mine and the surrounding cities. In this study, the annual effective dose was analyzed in 178 points of five cities. The measurements were performed using thermoluminescent dosimetry with LiF:Mg, Ti (TLD-100). The annual effective dose from environmental exposure varied from 0.71 to 2.07 mSv, with an arithmetic mean of 0.99 mSv. This average is more than twice the estimated value for indoor environments adopted by the UNSCEAR, which is 0.41 mSv. These results will allow establishing reference values for background radiation of the region and criteria to infer a stochastic risk for the local population. PMID- 29253262 TI - Still neglected? Unprecedented progress and future challenges discussed at the neglected tropical disease summit. PMID- 29253265 TI - Robotic Stereotaxy in Cranial Neurosurgery: A Qualitative Systematic Review. AB - BACKGROUND: Modern-day stereotactic techniques have evolved to tackle the neurosurgical challenge of accurately and reproducibly accessing specific brain targets. Neurosurgical advances have been made in synergy with sophisticated technological developments and engineering innovations such as automated robotic platforms. Robotic systems offer a unique combination of dexterity, durability, indefatigability, and precision. OBJECTIVE: To perform a systematic review of robotic integration for cranial stereotactic guidance in neurosurgery. Specifically, we comprehensively analyze the strengths and weaknesses of a spectrum of robotic technologies, past and present, including details pertaining to each system's kinematic specifications and targeting accuracy profiles. METHODS: Eligible articles on human clinical applications of cranial robotic guided stereotactic systems between 1985 and 2017 were extracted from several electronic databases, with a focus on stereotactic biopsy procedures, stereoelectroencephalography, and deep brain stimulation electrode insertion. RESULTS: Cranial robotic stereotactic systems feature serial or parallel architectures with 4 to 7 degrees of freedom, and frame-based or frameless registration. Indications for robotic assistance are diversifying, and include stereotactic biopsy, deep brain stimulation and stereoelectroencephalography electrode placement, ventriculostomy, and ablation procedures. Complication rates are low, and mainly consist of hemorrhage. Newer systems benefit from increasing targeting accuracy, intraoperative imaging ability, improved safety profiles, and reduced operating times. CONCLUSION: We highlight emerging future directions pertaining to the integration of robotic technologies into future neurosurgical procedures. Notably, a trend toward miniaturization, cost-effectiveness, frameless registration, and increasing safety and accuracy characterize successful stereotactic robotic technologies. PMID- 29253261 TI - Supplementation with curcuminoids and tuna oil influenced skin yellowness, carcass composition, oxidation status, and meat fatty acids of slow-growing chickens. AB - The present study aimed to determine the effects of dietary curcuminoids combined with tuna oil on the growth performance, meat quality, thiobarbituric acid reactive substances (TBARS) values in the plasma and raw meat, and fatty acid profile of chicken meat. A total of 480 21-day-old mixed-sex slow-growing chickens was assigned to a completely randomized design model with 6 treatments and 4 replicates (pens) per treatment. The basal diet based on corn-soybean and 4% tuna oil was used as the negative control. The experimental diets comprised the basal diet supplemented with curcumin removed turmeric oleoresin to provide 20, 40, 60, or 80 mg/kg curcuminoids (CUR-20, CUR-40, CUR-60, and CUR-80, respectively) or dl-alpha-tocopheryl acetate at 200 ppm as the positive control (E-200). Finally, the vacuum-packed carcasses were stored frozen at -20 degrees C for 3 mo to examine the effect of curcuminoids on changes in the TBARS values and fatty acid composition of the breast and thigh meat. Increasing the levels of curcuminoids tended to improve the feed conversion ratio (linear, P = 0.065) and significantly increased the proportion of breast fillet (linear, P = 0.037) and the yellowness of the skin of both the breast (linear, P = 0.016) and the thigh (linear, P = 0.023). The curcuminoids exhibited antioxidant properties, but their effect was not dose dependent. The CUR-20 and CUR-40 treatments increased the linoleic acid content but decreased the C22:6n-3 (DHA) content of the breast meat. The CUR-60 treatment inhibited oxidation (measured by TBARS) in the chicken meat similarly to dl-alpha-tocopheryl acetate but had no effect on the proportion of DHA in the breast or thigh meat. Auto-oxidation occurred in the breast meat but not in the thigh meat during the 3 mo of frozen storage. The present study showed that a suitable level of curcuminoids in the diet of slow-growing chickens was 60 mg/kg. PMID- 29253270 TI - DETERMINATION OF NEUTRON EFFECTIVE DOSES IN WHOLE BODY POINT SOURCE EXPOSURES. AB - The objective of this work is to obtain fluence to effective dose conversion coefficients for neutron point sources, using the GEANT4 toolkit. These calculations aim to investigate the aspects of neutron transport in the human body through Monte Carlo simulation using the International Commission on Radiological Protection (ICRP) voxel phantoms, described in its publication 110. A benchmarking of the code was made for the case of monoenergetic plane parallel neutron beam in the antero-posterior (AP) irradiation geometry and organ absorbed dose conversion coefficients were compared with those found in the ICRP publication 116. The results showed good agreement with ICRP results in the studied energy range. Conversion coefficients were presented for specific conditions with 241Am-Be and 252Cf point neutron sources 1 m away from the phantom in the AP geometry. PMID- 29253267 TI - Awake and (Only Just) Aware? A Typology, Taxonomy, and Holistic Framework for Withdrawing Clinically Assisted Nutrition and Hydration in the Minimally Conscious State. AB - Decisions to withdraw clinically assisted nutrition and hydration (CANH) from people in the minimally conscious state are predicated on the question as to whether it is in the individual's best interests to continue with CANH and determined traditionally using a 'balance sheet' approach. The emerging case law in this area suggests that decisions may appear inconsistent and lack sufficient certainty and clarity of process. Using an analysis of statute, common law and academic commentary we articulate a typology for the elements that tend to engage in these decisions. Next, we construct a taxonomy of overarching legal and ethical issues and then proceed to develop a novel framework for holistic decision-making. We validate this on the principle upon which it is grounded: coherent weighting of elements and theoretical proof of concept. The framework has potentially far-reaching benefits that include consistency and transparency of decision-making, thereby enabling a more uniform judicial approach. We suggest this as a foundational paradigm for decision-making in this context. PMID- 29253266 TI - Drug treatment of scrub typhus: a systematic review and meta-analysis of controlled clinical trials. AB - Scrub typhus, a potentially fatal infection caused by the pathogen Orientia tsutsugamushi, has a wide geographical distribution. This systematic review analyses the evidence from prospective controlled clinical studies for the efficacy of antibiotics in the treatment of scrub typhus. PubMed, Embase, Scopus, Cochrane Library, CINAHL and clinical trial registries in China, India and Sri Lanka were searched for controlled prospective clinical trials (randomized, quasi randomized or non-randomized) enrolling patients with confirmed scrub typhus for treatment with antibiotics. The PROSPERO registration number for this review is CRD42017071374. Eleven studies (from Southeast Asia and China) that enrolled 957 patients into 28 study groups met the inclusion criteria. Doxycycline was the most frequent comparator with other antibiotics. Chloramphenicol, tetracycline and azithromycin (limited evidence for roxithromycin, telithromycin, levofloxacin and rifampicin) had equal efficacy to doxycycline in achieving clinical cure. The cure rates in all studies varied from 64 to 100%. Of the antibiotics frequently used in current practice, azithromycin had the best evidence compared with doxycycline for equal efficacy in clinical cure (three trials, 280 participants, moderate quality evidence) with fewer gastrointestinal adverse events. The preferred choice of antibiotics for each patient depends on the adverse effect profile, personal circumstances (e.g., age, pregnancy), cost and local prescription guidelines. PMID- 29253264 TI - Avian Metapneumovirus circulation in Italian broiler farms. AB - With increasing frequency, avian Metapneumovirus (aMPV) is reported to induce respiratory signs in chickens. An adequate knowledge of current aMPV prevalence among Italian broilers is lacking, with little information available on its economical and health impact on the poultry industry. In order to collect preliminary data on the epidemiological context of aMPV in broiler flocks, a survey was performed in areas of Northern Italy with high poultry density from 2014 to 2016. Upper respiratory tract swabs were collected and processed by A and B subtype-specific multiplex real-time reverse transcription PCR (RT-PCR). Samples were also screened for infectious bronchitis virus (IBV) by generic RT PCR and sequencing. Productive data and respiratory signs were detailed where possible. The high prevalence of aMPV was confirmed in broilers older than 26 d and also attested in IBV-negative farms. All aMPV detections belonged to subtype B. Italian strain genetic variability was evaluated by the partial attachment (G) gene sequencing of selected strains and compared with contemporary turkey strains and previously published aMPV references, revealing no host specificity and the progressive evolution of this virus in Italy. PMID- 29253274 TI - Assessing behavior in Aseel pullets under free-range, part-time free-range, and cage system during growing phase. AB - The objective of this study was to explore the effects of free-range (FR), part time free-range (PTFR), and cage system (CS) on behavioral repertoire in Lakha (LK), Mushki (MS), Peshawari (PW), and Sindhi (SN) varieties of Aseel chicken during the growing phase (9 to 18 wk of age). In total, 144 Aseel pullets were allotted to 12 treatment groups in a 3 * 4 (rearing system * Aseel variety) factorial arrangement, according to a randomized complete block design (RCBD). Each treatment group was replicated 3 times with 4 birds in each replicate (12 birds per treatment group). The pullets were randomly marked weekly for identification, and their behavior was observed through the focal animal sampling method. Time spent on different behavioral activities was recorded and converted to a percentage. The data were analyzed using 2-way ANOVA under a factorial arrangement using SAS 9.1, and the behavioral parameters were evaluated. The results indicated greater (P < 0.05) sitting, standing, drinking, preening, and aggressiveness in CS; walking, running, and jumping in PTFR; and foraging and dustbathing in both FR and PTFR, whereas feather pecking was found to be reduced in FR compared with PTFR and CS. Among varieties, PW showed the least feeding/foraging and feather pecking behavior, and greater standing, running, and jumping behavior (P < 0.05). However, SN spent less time in walking and preening, and more time in sitting, drinking, and aggressiveness. Dustbathing was found to be similar in all Aseel varieties (P = 0.135). In conclusion, the PTFR system could be suggested as a substitute for conventional housing systems because it better accommodates normal behavior in Aseel pullets. PMID- 29253269 TI - Correlation of T follicular helper cells and plasmablasts with the development of organ involvement in patients with IgG4-related disease. AB - Objective: To assess the role of an abnormal immune network in the pathology of IgG4-related disease (IgG4-RD). Methods: Sixteen patients diagnosed with IgG4-RD at our institution were selected. Peripheral immunocompetent cells were immunophenotyped by multicolour flow cytometry to assess the association between clinical manifestation and pathological findings. Results: Compared with healthy controls, IgG4-RD patients showed comparable proportions of Th1 and Th17 cells, but higher proportions of Treg and follicular helper T (Tfh) cells. Further, the proportions of class-switched memory B cells and plasmablasts were higher in patients. Among all phenotypes, in particular, the plasmablast proportion increased from 4.2% (controls) to 16.5% (patients). The serum IgG levels were found to be correlated with the proportions of plasmablasts and Tfh cells, but not with those of other T cell subsets. In patients with extraglandular symptoms, only plasmablasts, Tfh cells and memory Treg cells were increased. Histopathological examination revealed a marked Tfh (CD4+ Bcl6+) cell infiltration; the increase of Tfh cells in the peripheral blood thus reflected the degree of Tfh cell infiltration into the tissue. Although steroid therapy reduced plasmablast and Tfh cell proportions, the memory Treg cell proportion remained unchanged. Conclusion: The association found between Tfh cells and plasmablasts, linked with biological plausibility, suggests that Tfh cells contribute to the pathogenesis of IgG4-RD. Our results also suggested that controlling the Tfh cell-plasmablast axis could be a novel therapeutic strategy for treating IgG4-RD. PMID- 29253272 TI - Effect of mechanical stress on magnetic resonance imaging of the sacroiliac joints: assessment of military recruits by magnetic resonance imaging study. AB - Objective: To assess the baseline condition of the SI joints (SIJs) in healthy individuals without symptoms of back pain and to study the effect of mechanical stress caused by intense physical training on MRI of the SIJs. Methods: Twenty two military recruits underwent an MRI of the SIJs before and after 6 weeks of intense standardized physical training. Bone marrow oedema and structural lesions were scored based on the Spondyloarthritis Research Consortium of Canada (SPARCC) method, by three trained readers blinded for time sequence and clinical findings. Additionally, fulfilment of the Assessment of SpondyloArthritis international Society (ASAS) definition of a positive MRI was evaluated. Results: At baseline, 9/22 recruits (40.9%) already presented a SPARCC score ?1; this number increased to 11/22 (50.0%) at week 6 (P = 0.625). In these patients, the mean (SD) SPARCC score was 2.4 (0.4) at baseline, compared to 3.7 (1.3) at week 6. Overall, the mean (SD) change in SPARCC score over time in all 22 patients was 0.9 (0.6) (P = 0.109). A positive MRI according to the ASAS definition was present in 5/22 recruits (22.7%) at baseline, which increased to 8/22 (36.4%) at follow-up (P = 0.375). Structural lesions were present in 6/22 subjects (27.3%), both at baseline and after 6 weeks of training. Conclusion: A substantial proportion of healthy active individuals without any symptoms of back pain displayed bone marrow oedema lesions on MRI at baseline. However, MRI lesions did not increase significantly after 6 weeks of intensive physical training. Our study underscores the necessity to interpret MRI findings of the SIJs in the appropriate clinical context, even in a young active population. PMID- 29253268 TI - Bacteriophage DNA glucosylation impairs target DNA binding by type I and II but not by type V CRISPR-Cas effector complexes. AB - Prokaryotes encode various host defense systems that provide protection against mobile genetic elements. Restriction-modification (R-M) and CRISPR-Cas systems mediate host defense by sequence specific targeting of invasive DNA. T-even bacteriophages employ covalent modifications of nucleobases to avoid binding and therefore cleavage of their DNA by restriction endonucleases. Here, we describe that DNA glucosylation of bacteriophage genomes affects interference of some but not all CRISPR-Cas systems. We show that glucosyl modification of 5 hydroxymethylated cytosines in the DNA of bacteriophage T4 interferes with type I E and type II-A CRISPR-Cas systems by lowering the affinity of the Cascade and Cas9-crRNA complexes for their target DNA. On the contrary, the type V-A nuclease Cas12a (also known as Cpf1) is not impaired in binding and cleavage of glucosylated target DNA, likely due to a more open structural architecture of the protein. Our results suggest that CRISPR-Cas systems have contributed to the selective pressure on phages to develop more generic solutions to escape sequence specific host defense systems. PMID- 29253271 TI - Effect of an artificial Ascaridia galli infection on egg production, immune response, and liver lipid reserve of free-range laying hens. AB - This study was conducted to determine the effect of Ascaridia galli infection on free-range laying hens. Lohmann Brown laying hens (n = 200) at 17 wk of age were allocated to 4 treatment groups (n = 50 per group), each with 5 replicate pens of 10 hens. Hens in 3 treatment groups were orally inoculated with different doses of embryonated A. galli eggs: low (250 eggs), medium (1,000 eggs), and high (2,500 eggs) levels, whereas hens of the control group were not infected. Infection levels were monitored using excreta egg counts and mature A. galli worm counts in the intestine. Anti A. galli antibody titers (IgY) in the serum were measured prior to infection, and at 6, 11, 15, and 20 wk post infection (PI) and in egg yolk at 11 and 20 wk PI. Parameters evaluated included feed intake, egg production, egg weight, egg mass, FCR, liver weight, liver fat, and intra epithelial immune cell infiltration. The results showed no difference in feed intake, body weight, or FCR among any treatment groups (P > 0.05). Egg production was lower in the low infection group compared to other groups at 20 wk of age (P < 0.01). Serum IgY was higher in the infected groups' hens at 20 wk PI compared to control group hens (P < 0.01). Yolk IgY increased significantly over time and was higher in infected hens compared to hens of the control group at 11 and 20 wk PI (P < 0.001). No differences were observed in liver lipid content or intraepithelial lymphocytes infiltration among treatment groups. Ascaridia galli eggs in the coprodeum content and adult A. galli worm count were higher in infected hens compared to hens of the control group (P < 0.01). In conclusion, the effects of artificial infection with A. galli on the parameters investigated were minor, and egg yolk antibody may be a more reliable indicator of A. galli infection than serum antibody or excreta egg count. PMID- 29253263 TI - The gastrointestinal microbiome and its association with the control of pathogens in broiler chicken production: A review. AB - The microbiome of the broiler chicken gastrointestinal tract (GIT) has been extensively studied, and it has been amply demonstrated that it plays an important role in the health of the host, as it has a positive impact on the immune system, the physiology of the GIT, and productivity. Also, the microbiota is involved in reducing and preventing colonization by enteric pathogens through the process of competitive exclusion and the production of bacteriostatic and bactericidal substances. The taxonomic composition of the microbiota is affected by different factors, such as the organ, the age of the animal, diet and the use of antimicrobials.Different kinds of additives that regulate the microbial community in feed include probiotics (live microorganisms that when administered in adequate amounts confer a health benefit on the host), prebiotics (ingredients that stimulate increased beneficial microbial activity in the digestive system in order to improve the health of the host) and phytobiotics (primary or secondary components of plants that contain bioactive compounds that exert a positive effect on the growth and health of animals). Phages may potentially provide an integrated solution to modulate the intestinal microbiome of chicken intestines, as they reduce specific pathogenic microbial populations, permitting the proliferation of beneficial microbiota. Studies have shown that the use of cocktails of phages, especially in high concentrations and with short lapses of time between exposure to the bacteria and treatment with phages, optimize the reduction of Salmonella in chickens. Each of these technologies has demonstrable positive effects on the health of the host and the reduction of the pathogen load in controlled assays.This paper presents a comprehensive summary of the role of the microbiota in the broiler chicken gastrointestinal tract, and discusses the usefulness of different strategies for its modulation to control pathogens, with a particular emphasis on bacteriophages. PMID- 29253276 TI - Evaluation of recombinant Salmonella vaccines to provide cross-serovar and cross serogroup protection. AB - Historically, Salmonella vaccines have been either live attenuated or killed bacterin vaccines that fail to offer cross-serogroup protection, which limits risk mitigation and protection of consumers. Subunit recombinant vaccines which possess highly conserved antigens offer potential to provide cross-serogroup protection, and the ability to express immune-enhancing molecules that promote recognition by the immune system. Six Salmonella subunit vaccine candidates were developed in either attenuated S. Enteritidis (SE) or S. Typhimurium (ST) that cell-surface express antigenic epitopes of high mobility group box 1 immune enhancing sequence (H), peptidoglycan associated lipoprotein (P), and Omp18 protein Cj0113 (C) in different pattern arrangements for evaluation against S. Heidelberg (SH) challenge in broilers. In exp. 1, chicks were orally vaccinated with SE-CPH, SE-HCP, SE-CHP, ST-CPH, ST-HCP, or ST-CHP at 1 * 107 cfu/chick, or saline on d 1 and d 14. On d 17 all birds were challenged with 6 * 106 cfu/chick SH, and ceca collected on d 23 and d 28. On d 23 only SE-CPH reduced (P < 0.05) SH recovery at 0.34 +/- 0.23 log10 cfu when compared to control at 1.19 +/- 0.26 log10 cfu. On d 28, SE-CPH and ST-HCP reduced SH recovery at 0.40 +/- 0.40 and 0.51 +/- 0.26 log10 cfu, respectively in comparison to control at 1.36 +/- 0.23 log10 cfu. For exp. 2, chicks were orally vaccinated with 1 * 108 cfu/chick SE CPH, SE-HCP, SE-CHP or saline on d 1. At d 7 all chicks were orally challenged with 7 * 106 cfu/chick SH and ceca collected on d 28 and d 35. SE-CPH reduced (P < 0.05) SH recovery on d 28 when compared to control (6.16 +/- 0.13 vs. 4.71 +/- 0.55 log10 cfu). In exp 3, chicks were vaccinated by spray in a commercial vaccination cabinet with SE-CPH vaccination, 1.6 * 107 cfu/chick, or saline. Birds were challenged on d 14 with 3 * 107 cfu/chick SH and ceca collected on d 18 and d 25. SE-CPH reduced SH recovery (P < 0.05) on d 18, 2.75 +/- 0.05 log10 cfu, and d 25, 1.89 +/- 0.43 log10 cfu, as compared to control chickens at 5.6 +/ 0.37 (d 18) and 3.98 +/- 0.5 log10 cfu (d 25). The results of these experiments suggest that cross-serogroup protection is possible using these SE and ST vectored subunit vaccines. PMID- 29253275 TI - Dosimetric and clinical effects of interfraction and intrafraction correlation errors during marker-based real-time tumor tracking for liver SBRT. AB - Correlation model error (CME) between the internal target and the external surrogate, and marker-tumor correlation error (MTCE) between the tumor and the implanted marker occur during marker-based real-time tumor tracking. The effects of these intrafraction and interfraction errors on the dose coverage in the clinical target volume (CTV) and on tumor control probability (TCP) for hepatocellular carcinoma (HCC) were evaluated in this study. Eight HCC patients treated with non-isocentric dose delivery by a robotic radiosurgery system were enrolled. The CMEs were extracted from the treatment log file, and the MTCEs were calculated from the preceding study. The CMEs and MTCEs were randomly added to each beam's robot position, and the changes in the TCP and the 2%, 95% and 99% dose coverage values for the CTV (D2, D95 and D99) were simulated. The data were statistically analyzed as a function of the CTV to planning target volume (PTV) margin, the dose fraction and the marker-tumor distance. Significant differences were observed in the majority of the CTV D2, D95 and D99 values and the TCP values. However, a linear regression revealed that ?CTV D2, D95 and D99 have a weak correlation with ?TCP. A dose-difference metric would be unable to detect a critical error for tumor control if the coverage changes for the CTV and ?TCP were weakly correlated. Because the simulated TCP-based parameter determination was based on the dose simulation, including predicted interfraction and intrafraction errors, we concluded that a 95th percentile TCP-based parameter determination would be a robust strategy for ensuring tumor control while reducing doses to normal structures. PMID- 29253273 TI - Nonhuman Primates and Translational Research: Progress, Opportunities, and Challenges. AB - Nonhuman primates (NHPs) are the closest animal models to humans regarding genetics, physiology and behavior. Therefore, NHPs are usually a critical component in translational research projects aimed at developing therapeutics, vaccines, devices or other interventions aimed at preventing, curing or ameliorating human disease. NHPs are often used in conjunction with other animal models, such as rodents, and results obtained using NHPs must often be used as the final criterion for establishing the potential efficacy of a pharmaceutical or vaccine before transition to human clinical trails. In some cases, NHPs may be the only relevant animal models for a particlular translational study. This issue of the ILAR journal brings together, in one place, articles that discuss the use of NHP models for studying human diseases that are highly prevalent and that cause extraordinary human suffering and financial and social burdens. Topics covered in detail include: tuberculosis; viral hepatitis; HIV/AIDS; neurodegenerative disorders; Substance abuse disorders; vision and prevention of blindness; disorder associated with psychosocial processes, such as anxiety, depression and loneliness; cardiovascular disease; metabolic disease, such as obesity and metabolic syndrome; respiratory disease; and female reproduction, prenatal development and women's health. Proper husbandry of NHPs that reduces stress and maintains animal health is critical for the development of NHP models. This issue of the journal includes a review of procedures for environmental enrichment, which helps assure animal health and wellbeing. Taken together, these articles provide detailed reviews of the use of NHP models for translational investigations and discuss successes, limitations, challenges and opportunities associated with this research. PMID- 29253279 TI - AbbVie Denies Overlapping Patents in Most Recent Adalimumab Litigation. PMID- 29253280 TI - Guidelines for the management of systemic lupus erythematosus: great synthesis of evidence and eminence with limited focus on patient's needs. PMID- 29253281 TI - Global Health Engagement and The Department of Defense as a Vehicle for Security and Sustainable Global Health. AB - The Unites States Department of Defense (DoD) is viewed by many in the general public as a monolithic government entity whose primary purpose is to coordinate this country's ability to make war and maintain a military presence around the world. However, the DoD is in fact a multidimensional organization whose global impact is as expansive as it is varying and is responsible for far-reaching global health interventions. The United States has worked toward providing long term care among host nation populations by providing training in several areas related to medicine, with positive results. These efforts can be built upon with substantial positive effects. Building health infrastructure and capacity around the world is essential. The DoD is the most generously funded agency in the world, and the resources at its disposal provide the opportunity to make great gains in the long term in terms of both health and security worldwide. With efficient and careful use of DoD resources, and partnerships with key non governmental organizations with specialized knowledge and great passion, partnerships can be forged with communities around the world to ensure that public health is achieved in even the most underserved communities. A move toward creating sustainable health systems with long-term goals and measurable outcomes is an essential complement to the already successful disaster and emergency relief that the United States military already provides. By ensuring that communities around the world are both provided with access to the sustainable health care they need and that emergency situations can be responded to in an efficient way, the United States can serve its duty as a leader in sharing expertise and resources for the betterment and security of all humankind. PMID- 29253282 TI - Impact of egg handling and conditions during extended storage on egg quality. AB - The international trade of shell eggs has become more important in recent years in order to feed a growing worldwide population, meet food manufacturing demands, and address supply issues during disease outbreaks or product recalls. The primary barriers for the export and import of shell eggs are: whether to wash eggs and egg storage temperature. The current study was undertaken to compare egg quality factors as influenced by egg washing and storage temperature. Three lots of nest run white shell eggs were collected on consecutive d from a commercial in line egg production facility. The treatment and storage conditions were selected to encompass the primary egg handling and storage conditions utilized throughout the world: washed; washed, oiled; and unwashed stored at 4 degrees C; and unwashed stored at 22 degrees C. Eggs were assessed weekly from 0 to 15 wk. Percent egg weight loss was greatest for the unwashed 22 degrees C eggs (15.72%) and least for washed, oiled 4 degrees C (0.33%, P < 0.0001). Less than 24 h at 22 degrees C had a greater impact on yolk shape measurements decline than 15 wk at 4 degrees C (P < 0.05). After 15 wk, average Haugh unit scores for all refrigerated treatments were still Grade A, and unwashed 22 degrees C dropped from Grade AA to almost Grade B in one week. Room temperature storage of eggs rapidly declines egg quality. Egg treatment did not impact egg quality factors when stored at 4 degrees C. Washing and oiling eggs before refrigerated storage did suppress the rate of egg weight loss. PMID- 29253283 TI - Posterior Quadrant Disconnection: A Fiber Dissection Study. AB - BACKGROUND: Posterior quadrant disconnection can be highly effective in the surgical treatment of selected cases of refractory epilepsy. The technique aims to deafferent extensive areas of epileptogenic posterior cortex from the rest of the brain by isolating the temporoparietooccipital cortex. OBJECTIVE: To describe this procedure and relevant white matter tracts with a specific emphasis on the extent of callosotomy in an anatomic study. METHODS: Twenty hemispheres were dissected according to Klingler's fiber dissection technique illustrating the peri-insular (temporal stem, superior longitudinal fasciculus, corona radiata) and mesial disconnection (mesiotemporal cortex, cingulum, and corpus callosum). RESULTS: Extensive white matter tract disconnection is obtained after posterior quadrant disconnection. Callosal fibers connecting the anterior most part of the parietal cortex invariably ran through the isthmus of the corpus callosum and need to be disconnected, while frontal lobe connections including the corticospinal tract and the anterior two-thirds of the corpus callosum are spared during the procedure. CONCLUSION: Our findings suggest the involvement of both the splenium and the isthmus in interhemispheric propagation in posterior cortex epilepsies. Sectioning the total extent of the posterior one-third of the corpus callosum might therefore be necessary to achieve optimal outcomes in posterior quadrant epilepsy surgery. PMID- 29253284 TI - Lumbar Drains Decrease the Risk of Postoperative Cerebrospinal Fluid Leak Following Endonasal Endoscopic Surgery for Suprasellar Meningiomas in Patients With High Body Mass Index. AB - BACKGROUND: Postoperative cerebrospinal fluid (CSF) leak is a persistent, albeit much less prominent, complication following endonasal endoscopic surgery. The pathology with highest risk is suprasellar meningiomas. A postoperative lumbar drain (LD) is used to decrease the risk of CSF leak but is not universally accepted. OBJECTIVE: To compare the rates of postoperative CSF leak between patients with and without LD who underwent endonasal endoscopic surgical resection of suprasellar meningiomas. METHODS: A consecutive series of newly diagnosed suprasellar meningiomas was drawn from a prospectively acquired database of endonasal endoscopic surgeries at our institution. An intraoperative, preresection LD was placed and left open at 5 cc/h for ~48 h. In a subset of patients, the LD could not be placed. Rates of postoperative CSF leak were compared between patients with and without an LD. RESULTS: Twenty-five patients underwent endonasal endoscopic surgical resection of suprasellar meningiomas. An LD could not be placed in 2 patients. There were 2 postoperative CSF leaks (8%), both of which occurred in the patients who did not have an LD (P = .0033). The average body mass index (BMI) of the patients in whom the LD could not be placed was 39.1 kg/m2, compared with 27.6 kg/m2 for those in whom the LD could be placed (P = .009). In the subgroup of obese patients (BMI > 30 kg/m2), LD placement was protective against postoperative CSF leak (P = .022). CONCLUSION: The inability to place an LD in patients with obesity is a risk factor for postoperative CSF leak. An LD may be useful to prevent postoperative CSF leak, particularly in patients with elevated BMI. PMID- 29253285 TI - Urgent Carotid Artery Stenting for Carotid-Related Stroke-in-Evolution. AB - BACKGROUND: Stroke-in-evolution (SIE) is a major outcome determinant in patients with acute ischemic stroke. The benefit of surgery for treatment of carotid artery-related SIE remains controversial. OBJECTIVE: To retrospectively evaluate the use of carotid artery stenting (CAS) as a possible alternative treatment in patients with carotid-related SIE. METHODS: Ten patients with carotid-related SIE were treated with CAS from May 2005 to December 2014. The mean initial National Institutes of Health Stroke Scale (NIHSS) score was 5.4 +/- 4.4. Two patients had total occlusion of the internal carotid artery, and 8 had severe stenosis. The mean interval from symptom onset to clinical deterioration was 2.9 +/- 2.9 d. The mean NIHSS score after deterioration was 14.3 +/- 4.5. In the hemodynamic assessment using perfusion imaging, the ipsilateral cerebral hemodynamics was impaired in 7 of 8 patients. RESULTS: All patients underwent urgent CAS in the acute phase of SIE. Seven patients underwent CAS using flow reversal with or without distal protection. No procedure-related complications occurred in any patients, although 1 patient developed aspiration pneumonia. The mean NIHSS score 7 d after CAS was 4.8 +/- 2.3. Six patients (60%) had a modified Rankin scale score of 0 to 2 at discharge. CONCLUSION: Urgent CAS for carotid-related SIE with hemodynamic impairment appears to be an effective method for achieving good clinical outcomes. PMID- 29253286 TI - Cross-sectional Area of the Median Nerve Before Revision Carpal Tunnel Release-A Cross-sectional Study. AB - BACKGROUND: High-resolution ultrasound can be used for diagnosis of carpal tunnel syndrome with an equal accuracy to electrodiagnostic studies. Up to date there has been no investigation published that examined the median nerve in a large patient cohort with recurrent or persistent symptoms. Reference and cutoff values are lacking. OBJECTIVE: To provide reference values for detection of ongoing or recurrent compression in patients with recurring or persisting symptoms in carpal tunnel syndrome. METHODS: One hundred and sixteen patients undergoing revision decompression of the median nerve at the carpal tunnel between January 2010 and October 2015 were studied retrospectively to determine the cross-sectional area of the median nerve at the wrist by the technique of neurosonography. RESULTS: In cases of insufficient primary release, the mean cross-sectional area was 20.0 mm2 preop. In cases of scar or synovitis, the mean cross-sectional area was 17.0 mm2 (significantly less than in cases of insufficient primary release, P = .008). Compared to successfully operated patients with de novo carpal tunnel syndrome (n = 74), a cutoff value of 14.5 mm2 yielded a sensitivity of 78% and a specificity of 97% to diagnose ongoing or recurrent compression in case of a typical clinical presentation of ongoing or recurrent symptoms (tested via comparison of patients who are symptom free vs patients with symptoms). CONCLUSION: For the first time, we provide reference values in patients with recurring or persisting symptoms in carpal tunnel syndrome based on a large patient population. Ultrasound can aid in the evaluation of patients with entrapment neuropathy of the median nerve and recurring or persisting symptoms. PMID- 29253287 TI - Microsurgical Clipping of an Anterior Communicating Artery Aneurysm Using a Novel Robotic Visualization Tool in Lieu of the Binocular Operating Microscope: Operative Video. AB - INTRODUCTION: The binocular operating microscope has been the visualization instrument of choice for microsurgical clipping of intracranial aneurysms for many decades. OBJECTIVE: To discuss recent technological advances that have provided novel visualization tools, which may prove to be superior to the binocular operating microscope in many regards. METHODS: We present an operative video and our operative experience with the BrightMatterTM Servo System (Synaptive Medical, Toronto, Ontario, Canada) during the microsurgical clipping of an anterior communicating artery aneurysm. To the best of our knowledge, the use of this device for the microsurgical clipping of an intracranial aneurysm has never been described in the literature. RESULTS: The BrightMatterTM Servo System (Synaptive Medical) is a surgical exoscope which avoids many of the ergonomic constraints of the binocular operating microscope, but is associated with a steep learning curve. The BrightMatterTM Servo System (Synaptive Medical) is a maneuverable surgical exoscope that is positioned with a directional aiming device and a surgeon-controlled foot pedal. While utilizing this device comes with a steep learning curve typical of any new technology, the BrightMatterTM Servo System (Synaptive Medical) has several advantages over the conventional surgical microscope, which include a relatively unobstructed surgical field, provision of high-definition images, and visualization of difficult angles/trajectories. CONCLUSION: This device can easily be utilized as a visualization tool for a variety of cranial and spinal procedures in lieu of the binocular operating microscope. We anticipate that this technology will soon become an integral part of the neurosurgeon's armamentarium. PMID- 29253288 TI - Intracranial Connections of the Vertebral Venous Plexus: Anatomical Study with Application to Neurosurgical and Endovascular Procedures at the Craniocervical Junction. AB - BACKGROUND: Descriptions of intracranial extensions of vertebral venous plexuses are lacking. OBJECTIVE: To identify vertebral venous plexuses at the craniocervical junction in cadavers and describe them. METHODS: The authors dissected 15 ink-injected, formalin-fixed, adult cadaveric heads and measured cranial extensions of the spinal venous plexuses. RESULTS: All specimens had vertebral venous plexuses at the craniocervical junction composed of multiple interwoven vessels concentrated anteriorly (anterior vertebral plexuses), posteriorly (posterior vertebral venous plexuses), and laterally (lateral vertebral venous plexuses). Veins making up the plexus tended to be largest for the anterior internal vertebral venous plexus. On 33%, a previously unnamed lateral internal vertebral venous plexus was identified that connected to the lateral marginal sinus. The anterior external vertebral venous plexus connected to the basilar venous plexus via transclival emissary veins in 13%; remaining veins connected either intracranially via small perforating branches through the anterior atlanto-occipital membrane (33%) or had no direct gross connections inside the cranium (53%). The anterior internal vertebral plexus, which traveled between layers of the posterior longitudinal ligament, connected to the anterior half of the marginal sinus in 33% and anterolateral parts of the marginal sinus in 20%. The posterior internal venous plexus connected to the posterior aspect of the marginal sinus on 80% and into the occipital sinus in 13.3%. The posterior external venous plexus connected to veins of the hypoglossal canal in 20% and into the posterior aspect of the marginal sinus in 13.3%. CONCLUSION: Knowledge of these connections is useful to neurosurgeons and interventional radiologists. PMID- 29253289 TI - Ophthalmic Complications Following Acoustic Neuroma Resection. AB - BACKGROUND: Past studies have shown high rates of ocular complications with the need for ophthalmic surgery following acoustic neuroma resection (ANR). OBJECTIVE: To determine the rates of ophthalmic complications, referrals, and surgery following ANR, and the factors associated with poor outcomes. METHODS: A retrospective study of ophthalmic outcomes in patients who underwent ANR was conducted, following institutional review board approval. Surgical approach, tumor size, tumor characteristics, completeness of resection, postoperative House Brackmann grades, ocular complications, referrals to ophthalmology, and ophthalmic treatments were recorded. RESULTS: Between 2007 and 2012, 174 patients underwent ANR. There were 3 surgical groups: retrosigmoid (n = 97), translabyrinthine (n = 59), and combined retrosigmoid and translabyrinthine (n = 18). Median tumor size was 2.2 cm. Postoperatively, 30% of patients had facial nerve dysfunction (House-Brackmann >=3), which recovered to 19% by 1 mo and 8.6% by 1 yr following ANR. Fifty-six (32.9%) patients experienced ocular complications postoperatively, with lagophthalmos, dry eye, and blurry vision as the most common complications. Thirty-six (67.9%) of the patients who required ophthalmic treatment were managed nonsurgically, with just 13 (7.6%) patients requiring referral to an ophthalmologist. In total, only 9 (5.3%) patients received an ophthalmic procedure. Patients with tumors >2 cm, those undergoing combined retrosigmoid and translabyrinthine resection, and those with severe facial nerve dysfunction which did not improve in the first month following surgery were more likely to have poor ophthalmic outcomes. CONCLUSION: We present lower rates of ophthalmic complications following ANR than previously reported. Improved surgical technique, better postoperative eye care, and facial nerve monitoring most likely accounted for the improved ocular outcomes. PMID- 29253290 TI - Percutaneous Endoscopic Removal of Cervical Foraminal Schwannoma via Interlaminar Approach: A Case Report. AB - BACKGROUND AND IMPORTANCE: Cervical foraminal schwannomas commonly originate from spinal nerves that pass through the intervertebral foramen of the cervical vertebrae. Because of the proximity of this type of tumor to the vertebral artery and spinal nerves, surgical management remains a major challenge. Conventional open spine surgery usually requires the removal of the articular process and is supplemented by a simultaneous posterolateral spine fusion surgery. To decrease the associated risks of surgical complications by further reducing invasiveness, percutaneous spinal endoscopy may be used for resection of foraminal spinal neoplasm. CLINICAL PRESENTATION: A 52-yr-old female who presented with neck pains with duration of 1 yr was admitted to our hospital. Physical examination revealed moderate rigidity in the neck and grade 5 muscle strength in both upper and lower limbs. Preoperative magnetic resonance imaging (MRI) scans demonstrated a left sided lesion at the C3-C4 intervertebral foraminal area. Under C-arm fluoroscopy navigation and neuromonitoring, the endoscope was properly positioned on the same side of the tumor, and a small part of the left C3 inferior and C4 superior lamina were first removed by an endoscopic drill to enlarge the interlaminar space. Next, through an endoscopic working canal, the left intervertebral ligamentum flavum was removed to fully expose the tumor. The tumor mass was finally resected in a piecemeal approach. Postoperative MRI confirmed complete tumor resection. CONCLUSION: This is the first case report of a total removal of a cervical foraminal schwannoma with a percutaneous spinal endoscopic procedure. PMID- 29253291 TI - Retrolabyrinthine Meatotomy as Part of Retrosigmoid Approach to Expose the Whole Internal Auditory Canal: Rationale, Technique, and Outcome in Hearing Preservation Surgery for Vestibular Schwannoma. AB - BACKGROUND: Vestibular schwannoma extending to the fundus of the internal auditory canal is currently considered an unfavorable condition for hearing preservation surgery via a retrosigmoid approach because the lateral end of the canal is hard to view directly during microsurgery. OBJECTIVE: To present an improved retrolabyrinthine meatotomy (RLM) technique that enables the full length of the cochlear and facial nerves to be inspected up to their orifices on the fundus. Long-term results are briefly reported. METHODS: A consecutive series of 100 cases with various degrees of fundus involvement underwent surgery via a retrosigmoid approach and RLM. The follow-up ranged from 4 to 14 yr. Outcomes on hearing and facial nerve function were recorded, and preoperative MRI findings of the tumor on the fundus were correlated with the surgical findings and the long term radicality of the tumor resection. RESULTS: Residual tumor on the fundus was identified in 3 cases, all belonging to the group with tumors adhering to the fundus. The functional results were in line with the best reported outcomes of this surgery. CONCLUSION: RLM via a retrosigmoid approach seemed adequate for the purposes of hearing preservation surgery and enabled the full course of the facial and cochlear nerves through the internal auditory canal to be exposed to direct view. Tumors adhering to the vestibular quadrant of the fundus were more difficult to remove, and there were a few cases of local residual tumor. PMID- 29253292 TI - Bipolar Cutting Method: Another Technique for Harvesting Donor Artery With Histological Investigation. AB - BACKGROUND: Safe and appropriate harvesting of the donor scalp vessel is the first key procedure in any type of bypass surgery. OBJECTIVE: To use the so called bipolar cutting method to harvest donor arteries, in which the donor arteries are skeletonized with bipolar cautery. The surgical procedure and the preparation of the equipment of the bipolar cutting method are described. The surgical results and histological assessment are presented. METHODS: The bipolar generator was set at 50 Malis units in the coagulation mode. Under the surgical microscope, the surrounding tissue of the donor artery was divided and coagulated with the bipolar forceps. The donor artery was completely skeletonized to provide adequate length. After the recipient artery was chosen and the anastomosis site was decided, the distal end of the donor artery was cut to the appropriate length. The remnant fragment of the donor artery was histologically investigated for any damage to the arterial wall. The specimen was cut longitudinally to observe the entire length of the arterial wall and stained with hematoxylin and eosin and elastica van Gieson. RESULTS: A total of 30 bypass surgeries were performed and 38 histological specimens were obtained between February 2015 and June 2016. The success rate of the bypass was 96%. No arterial wall damage such as thermal injury or dissection of the wall was recognized in any of the specimens. CONCLUSION: The bipolar cutting method is a useful and safe method for harvesting donor scalp artery. PMID- 29253293 TI - Intracranial-Intracranial A1 ACA-SVG-M2 MCA+M2 MCA Double Reimplantation Bypass For a Giant Middle Cerebral Artery Aneurysm: 3-Dimensional Operative Video. PMID- 29253294 TI - Macrovascular Decompression of Brainstem and Lower Cranial Nerves: 3-Dimensional Operative Video. PMID- 29253295 TI - Side-to-Side A3-A4 Bypass after Clip Ligation of Recurrent Coiled Anterior Communicating Artery Aneurysm: 3-Dimensional Operative Video. PMID- 29253297 TI - Whether to Ignore the Macular Hole in a Uveitic Patient: A Discussion of the Pros and Cons of Elective Macular Surgery in a Challenging Population. PMID- 29253296 TI - Crowds Replicate Performance of Scientific Experts Scoring Phylogenetic Matrices of Phenotypes. AB - Scientists building the Tree of Life face an overwhelming challenge to categorize phenotypes (e.g., anatomy, physiology) from millions of living and fossil species. This biodiversity challenge far outstrips the capacities of trained scientific experts. Here we explore whether crowdsourcing can be used to collect matrix data on a large scale with the participation of nonexpert students, or "citizen scientists." Crowdsourcing, or data collection by nonexperts, frequently via the internet, has enabled scientists to tackle some large-scale data collection challenges too massive for individuals or scientific teams alone. The quality of work by nonexpert crowds is, however, often questioned and little data have been collected on how such crowds perform on complex tasks such as phylogenetic character coding. We studied a crowd of over 600 nonexperts and found that they could use images to identify anatomical similarity (hypotheses of homology) with an average accuracy of 82% compared with scores provided by experts in the field. This performance pattern held across the Tree of Life, from protists to vertebrates. We introduce a procedure that predicts the difficulty of each character and that can be used to assign harder characters to experts and easier characters to a nonexpert crowd for scoring. We test this procedure in a controlled experiment comparing crowd scores to those of experts and show that crowds can produce matrices with over 90% of cells scored correctly while reducing the number of cells to be scored by experts by 50%. Preparation time, including image collection and processing, for a crowdsourcing experiment is significant, and does not currently save time of scientific experts overall. However, if innovations in automation or robotics can reduce such effort, then large-scale implementation of our method could greatly increase the collective scientific knowledge of species phenotypes for phylogenetic tree building. For the field of crowdsourcing, we provide a rare study with ground truth, or an experimental control that many studies lack, and contribute new methods on how to coordinate the work of experts and nonexperts. We show that there are important instances in which crowd consensus is not a good proxy for correctness. PMID- 29253298 TI - Non-Mydriatic Ultra-Widefield Imaging Compared With Single-Field Imaging in the Evaluation of Peripheral Retinal Pathology. AB - BACKGROUND AND OBJECTIVE: To report clinical feasibility of non-mydriatic ultra widefield (NMUWF) imaging and determine the prevalence of peripheral retinal pathology in comparison to standard single-field imaging in a primary care setting. PATIENTS AND METHODS: Six hundred and thirty-two subjects (1,260 eyes) who underwent NMUWF imaging during annual health screening from October 2015 through March 2016 were retrospectively identified. An automated algorithm processed the raw images into: (1) NMUWF image with mask/grid outline that delineates the center 45 degrees field simulating standard single-field photograph and (2) single-field image comprising 45 degrees posterior pole extracted from the corresponding NMUWF image. RESULTS: Mean age of patients was 59.6 years +/- 7.5 years. Of the 1,260 eyes, 1,238 eyes (98.3%) were considered optimum for grading. NMUWF images detected peripheral retinal pathology in 228 eyes (18.4%) that were not visible on corresponding single-field images. CONCLUSIONS: NMUWF imaging is feasible in a primary care setting, allows improved visualization of peripheral retinal pathology, and may therefore be useful for telemedicine screening. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:962 968.]. PMID- 29253299 TI - Choroidal Thickness Change in Patients With Diabetic Macular Edema. AB - BACKGROUND AND OBJECTIVE: To evaluate subfoveal choroidal thickness (SFCT) in diabetic macular edema (DME) and its relationships. PATIENTS AND METHODS: One hundred and six eyes were included in this prospective, nonrandomized case control study. They were divided into 37 cases of healthy, normal subjects and 69 cases of nonproliferative diabetic retinopathy (NPDR) with DME. Spectral-domain optical coherence tomography was done for all cases and analyzed to measure SFCT and central foveal thickness (CFT). RESULTS: The SFCT was significantly thinner in the DME group (193.4 MUm) than in the control group (282.6 MUm) (P = .001). In the DME group, SFCT was significantly related to CFT and vision (P < .05). The cutoff point for the relationship between SFCT and vision was 228 MUm below the point at which vision is affected. CONCLUSIONS: DME is associated with a significant decrease in SFCT. SFCT is directly related to vision and foveal thickness, but it is inversely correlated to age. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:970-977.]. PMID- 29253300 TI - Outer Retinal Changes on Spectral-Domain Optical Coherence Tomography Pre- and Post-Silicone Oil Removal. AB - BACKGROUND AND OBJECTIVE: To evaluate outer retinal changes present on spectral domain optical coherence tomography (SD-OCT) in eyes pre- and post-silicone oil (SiO) removal (SOR). PATIENTS AND METHODS: Retrospective case series of patients who underwent pars plana vitrectomy with SiO instillation and had SD-OCT completed pre- and post-SOR. SD-OCT parameters included presence of subretinal fluid, epiretinal membrane, ellipsoid zone disruption (EZD), external limiting membrane disruption, central subfield thickness (CST), and choroidal thickness. Visual acuities (VAs) and duration of SiO instillation were recorded. RESULTS: Thirty eyes of 30 patients were included. Mean Snellen VA pre- and post-SOR was 20/762 and 20/206, respectively (P < .001). Eyes with EZD under SiO had significantly longer duration of SiO tamponade (P = .029) along with worse VA post-SOR (P = .002). EZD was noted in 20 eyes with SiO and only 10 eyes post-SOR. Of these 10 eyes with resolution of EZD post-SOR, mean VA was significantly better (Snellen equivalent 20/133) compared to eyes with persistent EZD (Snellen equivalent 20/513; P = .01). CST and choroidal thickness decreased post-SOR (P = .117, P = .07). CONCLUSION: Outer retinal abnormalities on SD-OCT in SiO-filled eyes may improve in some patients following SOR. Some changes may be related to duration of SiO tamponade. EZD in SiO-filled eyes may portend a worse clinical outcome post-SOR despite surgical success. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:978-982.]. PMID- 29253301 TI - Full-Term Neonatal Ophthalmic Screening in China: A Review of 4-Year Outcomes. AB - BACKGROUND AND OBJECTIVE: To report the 4-year outcomes of a neonatal ophthalmic screening program in the Kunming Maternity and Child Care Hospital of Kunming City, Kunming, China. PATIENTS AND METHODS: This was a retrospective, observational case series study. Newborns who underwent neonatal eye screening using the RetCam system (Clarity Medical Systems, Pleasanton, CA) at the authors' hospital from March 2010 to February 2014 were included. RESULTS: Of the 15,284 full-term infants who participated in the program, 21% (3,171 of 15,284) had some ocular abnormalities. Among these abnormalities, retinal hemorrhage was the most frequent finding, accounting for 19% (2,899 of 15,284) of all cases. Other anomalies were found in 2% (272 of 15,284) of the cases. No major ocular or systemic complications were found to be associated with the screening process. CONCLUSION: Overall, 21% of the newborns who underwent the eye screening program were found to have an abnormality. The use of the RetCam for the screening program was both efficient and safe in identifying ocular anomalies. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:983-992.]. PMID- 29253302 TI - Optical Coherence Tomography in Patients With the Subretinal Implant Retina Implant Alpha IMS. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to assess changes in retinal structure and thickness after subretinal implantation of the Retina Implant Alpha IMS (Retina Implant AG, Reutlingen, Germany). PATIENTS AND METHODS: Spectral domain optical coherence tomography (SD-OCT) imaging was performed to assess the structure and thickness of the retina anterior to the microphotodiode array preoperatively, within 6 weeks and 6 months +/- 1 month after implantation. Thickness measurements were performed using the distance tool of the built-in software. Three thickness measurements were performed in each of the four quadrants of the retina on the microchip within 6 weeks and 6 months +/- 1 month after implantation. RESULTS: The mean +/- standard deviation change in retinal thickness from within 6 weeks to 6 months +/- 1 month after implantation in all four quadrants combined was 24 MUm +/- 68 MUm. None of the tested variables (location, time, or their interaction) had a statistically significant effect on the mean retinal thickness (P = .961, P = .131, and P = .182, respectively; n = 19). CONCLUSION: The authors report on qualitative and quantitative findings in retinal structure in 27 patients after subretinal implantation of the Retina Implant Alpha IMS using OCT technology. No significant changes of retinal thickness could be observed in a period of 6 months after surgery. With more patients receiving subretinal implants and with advanced OCT technology, the data set will be extended to study possible changes in retinal structure in finer detail. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:993-999.]. PMID- 29253303 TI - Characteristics of the Choriocapillaris Layer in Optical Coherence Tomography Angiography of Acute Central Serous Chorioretinopathy. AB - BACKGROUND AND OBJECTIVE: To describe the vascular characteristics of the choriocapillaris layer in acute central serous chorioretinopathy (CSC) imaged by optical coherence tomography angiography (OCTA), and to analyze the vascular density. PATIENTS AND METHODS: Retrospective, observational case series. In the study, 20 eyes of patients with acute CSC and 20 normal individuals were selected. All underwent OCTA, and 3 mm * 3 mm scanning mode was chosen for analyzing vascular density and morphological characteristics on the choriocapillaris layer. RESULTS: A dark region with some hyperreflective signal spots on the choriocapillaris layer was found in all affected eyes' OCTA images. The choroidal vascular density (CVD) in the affected eyes was significantly lower than in the normal eyes (P = .000 vs. P < .05). Additionally, the density of affected eyes was much smaller in comparison with the fellow eyes, which was statistically significant (P = .000 vs. P < .05). Fellow eyes' density was also lower than in normal eyes (P = .009 vs. P < .05). CONCLUSION: OCTA could offer a new approach to help understand the mechanisms of changes in the choriocapillary with imaging and provide quantitative analysis, as well. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:1000-1005.]. PMID- 29253304 TI - A Frag Bag for Efficient Removal of Dislocated Nuclear Material. AB - Dislocated nuclear material may be present in the vitreous cavity following complicated cataract surgery, closed globe injury, or spontaneous dislocation of the crystalline lens. The authors report herein a method to remove larger pieces of retained nuclear material during vitrectomy surgery with a retractable basket made from nitinol referred to as the "Frag Bag" (patent pending). Although originally designed for cystoscopic removal of kidney stones, this instrument fits easily through a 23-gauge vitrectomy port. The basket allows for retrieval of larger pieces of retained nuclear material with stabilization of the lens material in the mid-vitreous cavity and softening of the nuclear material to allow efficient and safe removal with the vitreous cutter, away from the retinal surface. Use of the Frag Bag may potentially improve the safety and efficiency of a pars plana lensectomy by obviating the need for a phacofragmatome and decreasing the number of times instruments are brought close to the retinal surface. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:1006-1008.]. PMID- 29253305 TI - A Case of Serious Eye Injury Caused by a Mistaken Injection of Methylrosaniline Chloride During Vitreous Surgery. AB - This case involved a 75-year-old female with left-eye epiretinal membrane (ERM) and cataract who developed serious eye disorders during vitreous surgery due to methylrosaniline chloride (MRC) being mistakenly injected and applied to the retina instead of Brilliant Blue G during internal limiting membrane staining. Once realized, MRC was washed out with intraocular infusion solution, and ERM surgery was successfully completed. Postoperatively, a Descemet's fold and corneal edema, marked reduction in corneal endothelial cell density, and inner retina damage and visual field defect extending from the macula toward the temporal side were observed. MRC was found highly toxic to eye tissues. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:1010-1015.]. PMID- 29253306 TI - Failed Pneumatic Retinopexy for Rhegmatogenous Retinal Detachment Repair in Ocular Albinism: Clues to the Role of Melanin in Retinal Pigment Epithelium Pump Function. AB - The authors report the first case, to their knowledge, of failed pneumatic retinopexy (PR) for rhegmatogenous retinal detachment (RRD) repair in a patient with ocular albinism (OA). The failure of PR to spontaneously resolve the subretinal fluid and reattach the retina in this case is suggestive of a deficiency in subretinal fluid reabsorption by the retinal pigment epithelium (RPE). These findings suggest that in cases of RRD in OA, primary PR should be avoided since this procedure relies on an adequately functioning RPE pump to reabsorb subretinal fluid prior to laser retinopexy. The use of primary vitrectomy or scleral buckling with cryopexy may constitute a more effective strategy for RRD in OA. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:1016 1020.]. PMID- 29253307 TI - Positive Visual Phenomena Following Implantation of the Argus II Retinal Prosthesis. AB - A 62-year-old female who was legally blind secondary to retinitis pigmentosa (RP) developed new positive visual phenomena (PVP) ("visual storms") following implantation of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Sylmar, CA). The potential mechanisms for the exacerbating PVP or hallucinatory release phenomena are proposed. Clinicians should be aware of these visual phenomena in patients with RP and the potential for worsening of or de novo development of PVP in patients considering the Argus II implant. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:1022-1025.]. PMID- 29253308 TI - Chorioretinal Perfusion in Persistent Placoid Maculopathy. AB - Persistent placoid maculopathy (PPM) is a rare clinical entity that has previously been reported in the literature with a characteristic appearance on multimodal imaging, including hypofluorescence observed on fluorescein angiogram (FA) and indocyanine green angiography (ICGA). The leading mechanisms proposed for this hypofluorescence include impaired choroidal vasculature with nonperfusion of the choriocapillaris and/or blockage of choroidal fluorescence by inflammatory deposits. This report demonstrates previously unreported characteristics of chorioretinal perfusion in a case of acute onset PPM in a 58 year-old woman. Optical coherence tomography angiography confirmed hypoperfusion of the choriocapillaris corresponding to the hypoperfusion seen on FA and ICGA. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:1026-1031.]. PMID- 29253309 TI - Enhanced Photocatalytic Activity of Vacuum-activated TiO2 Induced by Oxygen Vacancies. AB - TiO2 (Degussa P25) photocatalysts harboring abundant oxygen vacancies (Vacuum P25) were manufactured using a simple and economic Vacuum deoxidation process. Control experiments showed that temperature and time of vacuum deoxidation had a significant effect on Vacuum P25 photocatalytic activity. After 240 min of visible light illumination, the optimal Vacuum P25 photocatalysts (vacuum deoxidation treated at 330 degrees C for 3 h) reach as high as 94% and 88% of photodegradation efficiency for rhodamine B (RhB) and tetracycline, respectively, which are around 4.5 and 4.9 times as that of pristine P25. The XPS, PL and EPR analyses indicated that the oxygen vacancies were produced in the Vacuum P25 during the vacuum deoxidation process. The oxygen vacancy states can produce vacancy energy level located below the conduction band minimum, which resulting in the bandgap narrowing, thus extending the photoresponse wavelength range of Vacuum P25. The positron annihilation analysis indicated that the concentrations ratio of bulk and surface oxygen vacancies could be adjusted by changing the vacuum deoxidation temperature and time. Decreasing the ratio of bulk and surface oxygen vacancies was shown to improve photogenerated electron-hole pair separation efficiency, which leads to an obvious enhancement of the visible photocatalytic activities of Vacuum P25. PMID- 29253310 TI - Theoretical Insight into the Emission Properties of the Luciferin and Oxyluciferin of Latia. AB - Latia neritoides is a small limpet-like snail that produces a bright green bioluminescence (BL) via a unique light-emitting system. The process, mechanism, and even light emitter of its light emission remain unknown, although this BL has been known for decades. Unlike the other BL systems, neither the luciferin (Luc) nor the oxyluciferin (OxyLuc) of Latia is fluorescent according to the previous experiments. To help to identify its bioluminophore, we studied the geometrical and electronic structures and absorption and fluorescence spectra of Latia Luc and its six analogs as well as its OxyLuc in the gas phase and in water. The calculated results provide clear evidence of the lack of fluorescence in the Luc and OxyLuc of Latia. For the analogs of Latia Luc, the electron-withdrawing or electron-donating ability of the substituted group affects the fluorescence. The results shed new light on the BL mechanism and will likely aid the understanding of Latia BL. PMID- 29253311 TI - Insight Into Malachite Green Degradation, Mechanism and Pathways by Morphology Tuned alpha-NiMoO4 Photocatalyst. AB - The microwave hydrothermal process was used for the synthesis of various morphologies of alpha-NiMoO4 by simply adjusting the pH during experimental conditions. The effect of morphology/size on the photocatalytic performances for degradation of malachite green (MG) has been investigated under UV-Vis/visible light irradiation. Nanorod morphology has strong tendency to degrade (88.18%) the MG as compared to spherical quantum-sized (57.65%) and layered square microsheet (37.98%) under UV-Vis irradiation in 180 min. The active species trapping experiment revealed that active species (OH* , O2*- and h+ ) play a crucial role for MG degradation. The high BET surface area, greater amount of oxygen defect and efficient separation of electron-hole pair are responsible for MG degradation. About seventeen types of organic fragments of MG were confirmed by high resolution-quadruple time of flight electrospray ionization mass spectroscopy (HR-QTOF ESI/MS) technique on the basis of retention time and molecular masses. Degradation mechanism and pathways were proposed that follow the demethylation, nitration, decarboxylation, hydrolysis, decarboxylation and oxidation reaction. The reduction of total organic carbon revealed the mineralization of MG during photocatalytic degradation process. Therefore, this article represents the investigation of MG degradation by various morphology of alpha-NiMoO4 and detailed degradation mechanism and pathways. PMID- 29253312 TI - Biogenic Hierarchical MIL-125/TiO2 @SiO2 Derived from Rice Husk and Enhanced Photocatalytic Properties for Dye Degradation. AB - The hierarchical porous heterostructured MIL-125/TiO2 @SiO2 composites are successfully obtained by biogenic-templated method using rice husk both as biomorphic. The products are characterized by X-ray diffraction, N2 -adsorption desorption analysis, scanning electron microscopy and Fourier transform infrared spectroscopy. The results reveal that MIL-125/TiO2 @SiO2 possesses a hierarchical porous structure in scale from micrometer to nanometer with high Brunauer-Emmett Teller (BET) surface area (385.7-902.7 m2 g-1 ). The photocatalytic mechanism was discussed in detail. Meanwhile, the activity of MIL-125/TiO2 @SiO2 for the photocatalytic degradation of rhodamine B in aqueous medium is significantly higher than that of P25. The current work provides some concept and methods in the development of MOF-based photocatalysts. PMID- 29253314 TI - Regulatory mechanisms of microRNA sorting into extracellular vesicles. PMID- 29253313 TI - Plasmodium yoelii S4/CelTOS is important for sporozoite gliding motility and cell traversal. AB - Gliding motility and cell traversal by the Plasmodium ookinete and sporozoite invasive stages allow penetration of cellular barriers to establish infection of the mosquito vector and mammalian host, respectively. Motility and traversal are not observed in red cell infectious merozoites, and we have previously classified genes that are expressed in sporozoites but not merozoites (S genes) in order to identify proteins involved in these processes. The S4 gene has been described as criticaly involved in Cell Traversal for Ookinetes and Sporozoites (CelTOS), yet knockout parasites (s4/celtos-) do not generate robust salivary gland sporozoite numbers, precluding a thorough analysis of S4/CelTOS function during host infection. We show here that a failure of oocysts to develop or survive in the midgut contributes to the poor mosquito infection by Plasmodium yoelii (Py) s4/celtos- rodent malaria parasites. We rescued this phenotype by expressing S4/CelTOS under the ookinete-specific circumsporozoite protein and thrombospondin related anonymous protein-related protein (CTRP) promoter (S4/CelTOSCTRP ), generating robust numbers of salivary gland sporozoites lacking S4/CelTOS that were suitable for phenotypic analysis. Py S4/CelTOSCTRP sporozoites showed reduced infectivity in BALB/c mice when compared to wild-type sporozoites, although they appeared more infectious than sporozoites deficient in the related traversal protein PLP1/SPECT2 (Py plp1/spect2-). Using in vitro assays, we substantiate the role of S4/CelTOS in sporozoite cell traversal, but also uncover a previously unappreciated role for this protein for sporozoite gliding motility. PMID- 29253315 TI - Biomass sorghum as a novel substrate in solid-state fermentation for the production of hemicellulases and cellulases by Aspergillus niger and A. fumigatus. AB - AIMS: We investigated the role of carbon and nitrogen sources in the production of cellulase and hemicellulase by Aspergillus strains. METHODS AND RESULTS: The strains Aspergillus niger SCBM1 and Aspergillus fumigatus SCBM6 were cultivated under solid-state fermentation (SSF), with biomass sorghum (BS) and wheat bran (WB) as lignocellulosic substrates, in different proportions, along with variable nitrogen sources. The best SSF condition for the induction of such enzymes was observed employing A. niger SCBM1 in BS supplemented with peptone; maximum production levels were achieved as follows: 72 h of fermentation for xylanase and exoglucanase (300.07 and 30.64 U g-1 respectively), 120 h for beta-glucosidase and endoglucanase (54.90 and 41.47 U g-1 respectively) and 144 h for beta xylosidase (64.88 U g-1 ). CONCLUSIONS: This work demonstrated the viability of the use of BS for the production of hemi- and cellulolytic enzymes; the high concentration of celluloses in BS could be associated with the significant production of cellulases, mainly exoglucanase. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study which presents the promising use of biomass sorghum (genetically modified sorghum to increase its biomass content) as an alternative carbon source for the production of enzymes by SSF. PMID- 29253316 TI - Inositol 1,4,5-trisphosphate receptors and neurodegenerative disorders. AB - The inositol 1,4,5-trisphosphate receptor (IP3 R) is an intracellular ion channel that mediates the release of calcium ions from the endoplasmic reticulum. It plays a role in basic biological functions, such as cell division, differentiation, fertilization and cell death, and is involved in developmental processes including learning, memory and behavior. Deregulation of neuronal calcium signaling results in disturbance of cell homeostasis, synaptic loss and dysfunction, eventually leading to cell death. Three IP3 R subtypes have been identified in mammalian cells and the predominant isoform in neurons is IP3 R type 1. Dysfunction of IP3 R type 1 may play a role in the pathogenesis of certain neurodegenerative diseases as enhanced activity of the IP3 R was observed in models of Huntington's disease, spinocerebellar ataxias and Alzheimer's disease. These results suggest that IP3 R-mediated signaling is a potential target for treatment of these disorders. In this review we discuss the structure, functions and regulation of the IP3 R in healthy neurons and in conditions of neurodegeneration. PMID- 29253317 TI - What Do We Know about Risk Factors for Fetal Growth Restriction in Africa at the Time of Sustainable Development Goals? A Scoping Review. AB - BACKGROUND: The reduction in the under-5 year mortality rate to at least as low as 25 per 1000 livebirths by 2030 has been implemented as one of the new Sustainable Development Goals. Fetal growth restriction (FGR) is one of the most important determinants of infant mortality in developing countries. In this review, we assess the extent of the literature and summarize its findings on the main preventable factors of FGR in Africa. METHODS: A scoping review was conducted using the Arksey and O'Malley framework. Five bibliographic databases and grey literature were used to identify studies assessing at least one risk factor for FGR. Aggregate risk estimates for the main factors associated with FGR were calculated. RESULTS: Forty-five of a total of 671 articles were selected for the review. The prevalence of FGR varied between 2.6 and 59.2% according to both the African region and the definition of FGR. The main preventable factors reported were a low maternal nutritional status (aggrerate odds ratio [OR]: 2.28, 95% confidence interval [CI] 1.59, 3.25), HIV infection (aOR 1.86, 95% CI 1.38, 2.50), malaria (aOR 1.95, 95% CI 1.04, 3.66), and gestational hypertension (aOR 2.61, 95% CI 2.42, 2.82). CONCLUSION: FGR is, to a large extent, preventable through existing efficacious interventions dedicated to malaria, HIV and nutrition. Further studies are still needed to assess the influence of risk factors most commonly documented in high-income countries. Improving research on FGR in Africa requires a consensual and standardized definition of FGR-for a higher comparability-between studies and settings. PMID- 29253318 TI - Demodex canis targets TLRs to evade host immunity and induce canine demodicosis. AB - Widespread incidence of Demodex mites throughout the mammalian class and occasional serious and fatal outcomes in dogs warrant an insight into the host parasite interface especially. Therefore, this study was aimed to unravel the interplay between innate immune response and canine demodicosis. The dogs diagnosed to have natural clinical demodicosis were allocated into two groups; dogs with localized demodicosis (LD) and with generalized demodicosis (GD). The expression of toll-like receptors (TLRs) 2, 4 and 6 genes in peripheral blood mononuclear cells of these dogs was quantified by real-time PCR. Significantly increased TLR2 gene expression, while significantly diminished TLR4 and TLR6 gene expressions were observed in demodicosed dogs (LD and GD) as compared with the healthy ones. Even the expression of TLR2 gene was found to differ significantly between the dogs with LD and GD. Therefore, it can be inferred that clinical demodicosis in dogs is coupled with an up-regulation of TLR2 and down-regulation of TLR4 and TLR6 gene expressions. Overexpression of TLR2 gene might be responsible for Demodex-induced clinical manifestations, while TLR4 and TLR6 gene down-regulations could be the paramount strategy of Demodex mites to elude the host-immune interface. PMID- 29253319 TI - Indigenous endophytic seed bacteria promote seedling development and defend against fungal disease in browntop millet (Urochloa ramosa L.). AB - AIMS: This study was conducted to investigate indigenous seed endophyte effects on browntop millet seedling development. We report that seed-inhabiting bacterial endophytes are responsible for promoting seedling development, including stimulation of root hair formation, increasing root and shoot length growth and increasing photosynthetic pigment content of seedlings. Bacterial endophytes also improved resistance of seedlings to disease. METHODS AND RESULTS: A total of four endophytic bacteria were isolated from surface-sterilized seeds and identified by 16S rDNA sequencing as Curtobacterium sp. (M1), Microbacterium sp. (M2), Methylobacterium sp. (M3) and Bacillus amyloliquefaciens (M4). Removal of bacteria with streptomycin treatment from the seeds compromised seedling growth and development. When endophytes were reinoculated onto seeds, seedlings recovered normal development. Strains M3 and M4 were found to be most potent in promoting growth of seedlings. Bacteria were found to produce auxin, solubilize phosphate and inhibit fungal pathogens. Significant protection of seedlings from Fusarium infection was found using strain M4 in microcosm assays. The antifungal lipopeptide genes for surfactin and iturin were detected in M4; culture extracts of M4 showed a positive drop collapse result for surfactins. CONCLUSIONS: This study demonstrates that browntop millet seeds vector indigenous endophytes that are responsible for modulation of seedling development and protection of seedlings from fungal disease. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is significant and original in that it is the first report of seed-inhabiting endophytes of browntop millet that influence seedling development and function in defence against soilborne pathogens. This study suggests that conservation and management of seed-vectored endophytes may be important in development of more sustainable agricultural practices. PMID- 29253320 TI - Novel concepts in sleep regulation. AB - Knowledge regarding the cellular mechanisms of sleep regulation is accumulating rapidly. In addition to neurones, also non-neuronal brain cells (astrocytes and microglia) are emerging as potential players. New techniques, particularly optogenetics and designed receptors activated by artificial ligands (DREADD), have provided also sleep research with important additional tools to study the effect of either silencing or activating specific neuronal groups/neuronal networks by opening or shutting ion channels on cells. The advantages of these strategies are the possibility to genetically target specific cell populations and the possibility to either activate or inhibit them with inducing light signal into the brain. Studies probing circuits of NREM and REM sleep regulation, as well as their role in memory consolidation, have been conducted recently. In addition, fundamentally new thoughts and potential mechanisms have been introduced to the field. The role of non-neuronal tissues in the regulation of many brain functions has become evident. These non-neuronal cells, particularly astrocytes, integrate large number of neurones, and it has been suggested that one of their functions is to integrate the (neural) activity in larger brain areas-a feature that is one of the prominent features of also the state of sleep. PMID- 29253321 TI - Role of capsule endoscopy in alarm features and non-responsive celiac disease: A European multicenter study. AB - BACKGROUND AND AIM: The role of capsule endoscopy (CE) in established celiac disease (CD) remains unclear. Our objective was to analyze the usefulness of CE in the suspicion of complicated CD. METHODS: This was a retrospective multicenter study. One hundred and eighty-nine celiac patients (mean age: 46.6 +/- 16.6, 30.2% males) who underwent CE for alarm symptoms (n = 86, 45.5%) or non responsive CD (n = 103, 54.5%) were included. Diagnostic yield (DY), therapeutic impact and safety were analyzed. RESULTS: Capsule endoscopy was completed in 95.2% of patients (small bowel transit time: 270.5 +/- 100.2 min). Global DY was 67.2%, detecting atrophic mucosa (n = 92, 48.7%), ulcerative jejunoileitis (n = 21, 11.1%), intestinal lymphoma (n = 7, 3.7%) and other enteropathies (n = 7, 3.7%, six Crohn's disease cases and one neuroendocrine tumor). The DY of CE was significantly higher in patients presenting with non-responsive disease compared to patients with alarm symptoms (73.8% vs 59.3%, P = 0.035). The new findings of the CE modified management in 59.3% of the cases. There were no major complications. CONCLUSION: Capsule endoscopy may be a moderately helpful and safe diagnostic tool in the suspicion of complicated CD, modifying the clinical course of these patients. PMID- 29253322 TI - Bisphosphonates in multiple myeloma: an updated network meta-analysis. AB - BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and are used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010 and 2012. OBJECTIVES: To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus non-aminobisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw (ONJ) and hypocalcemia. SEARCH METHODS: We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Issue 7) to identify all randomized controlled trial (RCT) in MM up to July 2017 using a combination of text and MeSH terms. SELECTION CRITERIA: Any randomized controlled trial (RCT) comparing bisphosphonates versus placebo/no treatment/bisphosphonates and observational studies or case reports examining bisphosphonate-related ONJ in patients with MM were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) using a random-effects model. We used meta-regression to explore statistical heterogeneity. Network meta-analysis using Bayesian approach was conducted. MAIN RESULTS: In this update, we included four new studies (601 participants), resulting in a total of 24 included studies.Twenty RCTs compared bisphosphonates with either placebo or no treatment and four RCTs involved another bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 participants. Pooled results showed that there was moderate-quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I2 = 65%) for OS. To explain this heterogeneity we performed a meta-regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low-quality evidence). There is probably a similar risk of non vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate-quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate-quality evidence) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate-quality evidence). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).Bisphosphonates may increase ONJ compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants; low-quality evidence). The results from the network meta-analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.The pooled results showed no evidence for a difference in increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.59; seven studies; 1829 participants; low-quality evidence).The pooled results showed no evidence for a difference in increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74; three studies; 1090 participants; low-quality evidence). The results from network meta-analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used. AUTHORS' CONCLUSIONS: Use of bisphosphonates in participants with MM reduces pathological vertebral fractures, SREs and pain. Bisphosphonates were associated with an increased risk of developing ONJ. For every 1000 participants treated with bisphosphonates, about one patient will suffer from the ONJ. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non-aminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate was found to be better than placebo and first-generation bisposphonate (etidronate) in pooled direct and indirect analyses for improving OS and other outcomes such as vertebral fractures. Direct head-to-head trials of the second-generation bisphosphonates are needed to settle the issue if zoledronate is truly the most efficacious bisphosphonate currently used in practice. PMID- 29253323 TI - Establishment of Photoaging In Vitro by Repetitive UVA Irradiation: Induction of Characteristic Markers of Senescence and its Prevention by PAPLAL with Potent Catalase Activity. AB - To understand a role of UVA radiation in photoaging of the skin, we established a model of photoaging cells using cultured human dermal fibroblasts. Repeated low dose UVA radiation for 10 consecutive days induced senescence in fibroblasts, characterized with (1) increased level of senescence-associated beta galactosidase, (2) flattened large cell shape, (3) accumulation of reactive oxygen species, (4) yellowish coloration and (5) expression of p16. These were also observed in chronologically aged fibroblasts (doubling times >20), whereas none of these were detected in young cells (doubling times <10). Collectively, we propose that fibroblasts exposed to repetitive UVA radiation may be a good model of aged cells to study the mechanism of aging and photoaging and further to search for novel agents preventing cellular senescence. In addition, H2 O2 was produced in the culture medium by a single low dose of UVA irradiation. Further, PAPLAL, a nanoparticle of platinum and palladium having potent catalase-like activity, significantly delayed the onset of H2 O2 -induced cell senescence. The present study strongly indicates that repetitive short-term UVA irradiation induces aging of cells possibly via H2 O2 and may be suppressed by potent anti-H2 O2 agents. PMID- 29253324 TI - Layered metal(IV) phosphonate materials: Solid-state 1 H, 13 C, 31 P NMR spectra and NMR relaxation. AB - Multinuclear solid-state NMR and powder X-ray diffraction data collected for phosphonate materials Zr(O3 PC6 H4 PO3 ) . 3.6H2 O and Sn(O3 PC6 H4 PO3 )0.85 (O3 POH)0.30 . 3.09H2 O have resulted in the layered structure, where the phosphonic acids cross-link the layers. The main structural motif (the 111 connectivity in the PO3 group) has been established by determination of chemical shift anisotropy parameters for phosphorus nuclei in the phosphonate groups. An analysis of the variable-temperature 31 P T1 measurements and the shapes of the phosphorus resonances in the 31 P static NMR spectra have resulted in the dipolar mechanism of the phosphorus spin-lattice relaxation, where the rotating phenylene rings reorient dipolar vectors P... H as a driving force of the relaxation process. It has been found that water protons do not affect the 31 P T1 times. The activation energy of the phenylene rotation in both compounds has been determined as low as 12.5 kJ/mol. The interpretation of the phosphorus relaxation data has been independently confirmed by the measurements of 1 H T1 times for protons of the phenylene rings. PMID- 29253325 TI - Significant improvement of intestinal microbiota of gibel carp (Carassius auratus gibelio) after traditional Chinese medicine feeding. AB - AIMS: Increasing attention has been attracted to intestinal microbiota, due to interactions with nutrition, metabolism and immune defence of the host. Traditional Chinese medicine (TCM) feed additives have been applied in aquaculture to improve fish health, but the interaction with fish gut microbiota is still poorly understood. This study aimed to explore the effect of adding TCM in feed on the intestinal microbiota of gibel carp (Carassius auratus gibelio). METHODS AND RESULTS: Bacterial communities of 16 fish intestinal contents and one water sample were characterized by high-throughput sequencing and analysis of the V4-V5 region of the 16S rRNA gene. The results showed that the composition and structure of the bacterial community were significantly altered by the TCM feeding. Some phyla increased markedly (Proteobacteria, Actinobacteria, Acidobacteria, etc.), while Fusobacteria were significantly reduced. Concurrently, the richness and diversity of the taxonomic units increased, and the microbiota composition of TCM-treated fish was more homogeneous among individuals. At the genus level, the addition of TCM tended to reduce the incidence of potential pathogens (Aeromonas, Acinetobacter and Shewanella), while stimulating the emergence of some potential probiotics (Lactobacillus, Lactococcus, Bacillus and Pseudomonas). CONCLUSIONS: These data suggested that the feed additive could regulate the fish intestinal microbiota by reinforcing the microbial balance. SIGNIFICANCE AND IMPACT OF THE STUDY: This study may provide useful information for further application of TCM for diseases prevention and stress management in aquaculture. PMID- 29253327 TI - A Responsive "Nano String Light" for Highly Efficient mRNA Imaging in Living Cells via Accelerated DNA Cascade Reaction. AB - Nonenzymatic DNA catalytic amplification strategies have greatly benefited bioanalysis. However, long period incubation is usually required due to its relatively low reaction rate and efficiency, which limits its in vivo application. Here we design a responsive DNA nano string light (DNSL) by interval hybridization of modified hairpin DNA probe pairs to a DNA nanowire generated by rolling circle amplification and realize accelerated DNA cascade reaction (DCR) for fast and highly efficient mRNA imaging in living cells. Target mRNA initiates interval hybridization of two paired hairpin probes sequentially along the DNA nanowire and results in instant lighting up of the whole DNA nanowire with high signal gain due to the fast opening of all the self-quenched hairpins. The reaction time is about 6.7 times shorter compared with a regular DNA cascade reaction due to the acceleration based on domino effect. The cell delivery is achieved by modifying one of the hairpin probes with folic acid, and this intracellular imaging strategy is verified using human HeLa cells and intracellular survivin mRNA with a series of suppressed expressions as model, which provides a useful platform for fast and highly efficient detection of low abundance nucleic acids in living cells. PMID- 29253326 TI - Tendinous tissue properties after short- and long-term functional overload: Differences between controls, 12 weeks and 4 years of resistance training. AB - AIM: The potential for tendinous tissues to adapt to functional overload, especially after several years of exposure to heavy-resistance training, is largely unexplored. This study compared the morphological and mechanical characteristics of the patellar tendon and knee extensor tendon-aponeurosis complex between young men exposed to long-term (4 years; n = 16), short-term (12 weeks; n = 15) and no (untrained controls; n = 39) functional overload in the form of heavy-resistance training. METHODS: Patellar tendon cross-sectional area, vastus lateralis aponeurosis area and quadriceps femoris volume, plus patellar tendon stiffness and Young's modulus, and tendon-aponeurosis complex stiffness, were quantified with MRI, dynamometry and ultrasonography. RESULTS: As expected, long-term trained had greater muscle strength and volume (+58% and +56% vs untrained, both P < .001), as well as a greater aponeurosis area (+17% vs untrained, P < .01), but tendon cross-sectional area (mean and regional) was not different between groups. Only long-term trained had reduced patellar tendon elongation/strain over the whole force/stress range, whilst both short-term and long-term overload groups had similarly greater stiffness/Young's modulus at high force/stress (short-term +25/22%, and long-term +17/23% vs untrained; all P < .05). Tendon-aponeurosis complex stiffness was not different between groups (ANOVA, P = .149). CONCLUSION: Despite large differences in muscle strength and size, years of resistance training did not induce tendon hypertrophy. Both short term and long-term overload demonstrated similar increases in high-force mechanical and material stiffness, but reduced elongation/strain over the whole force/stress range occurred only after years of overload, indicating a force/strain specific time-course to these adaptations. PMID- 29253328 TI - Twin Defect Derived Growth of Atomically Thin MoS2 Dendrites. AB - Morphology management for tailoring the properties of monolayer transition-metal dichalcogenides (TMDCs), that is, molybdenum disulfide (MoS2), has attracted great interest for promising applications such as in electrocatalysis and optoelectronics. Nevertheless, little progress has been made in engineering the shape of MoS2. Herein, we introduce a modified chemical vapor deposition method to grow monolayer MoS2 dendrites by pretreating substrates with adhesive tapes. The as-grown MoS2 crystals are featured with hexagonal backbones with fractal shapes and tunable degrees. By characterizing the atomic structure, it is found that these morphologies are mainly initiated from the twin defect derived growth and controlled by the S:Mo vapor ratio. Due to the accumulated sulfur vacancies in the cyclic twin regions, strong enhancement of photoluminescence emission is localized, which determines the shape dependency of optical property. This work not only enriches the understanding of the twin defects derived crystal growth mechanism and extends its applications from nanomaterials to two-dimensional crystals, but also offers a robust and controllable protocol for shape-engineered monolayer TMDCs in electrochemical and optoelectronic applications. PMID- 29253330 TI - Mo-Terminated Edge Reconstructions in Nanoporous Molybdenum Disulfide Film. AB - The catalytic and magnetic properties of molybdenum disulfide (MoS2) are significantly enhanced by the presence of edge sites. One way to obtain a high density of edge sites in a two-dimensional (2D) film is by introducing porosity. However, the large-scale bottom-up synthesis of a porous 2D MoS2 film remains challenging and the correlation of growth conditions to the atomic structures of the edges is not well understood. Here, using molecular beam epitaxy, we prepare wafer-scale nanoporous MoS2 films under conditions of high Mo flux and study their catalytic and magnetic properties. Atomic-resolution electron microscopy imaging of the pores reveals two new types of reconstructed Mo-terminated edges, namely, a distorted 1T (DT) edge and the Mo-Klein edge. Nanoporous MoS2 films are magnetic up to 400 K, which is attributed to the presence of Mo-terminated edges with unpaired electrons, as confirmed by density functional theory calculation. The small hydrogen adsorption free energy at these Mo-terminated edges leads to excellent activity for the hydrogen evolution reaction. PMID- 29253331 TI - Electroless Deposition Metals on Poly(dimethylsiloxane) with Strong Adhesion As Flexible and Stretchable Conductive Materials. AB - A new surface modification method is developed for electroless deposition of robust metal (copper, nickel, silver) layers on poly(dimethylsiloxane) (PDMS) substrate with strong adhesion. Under the synergies of the polydopamine (PDA), the plasma process enhances Ag+ reduction, and a thin Ag film is capable of tightly attaching to the PDMS surface, which catalyzes electroless deposition (ELD) to form robust metal layers on the PDMS surface with strong adhesion. Subsequently, a flexible and stretchable Cu-PDMS conductor is obtained through this method, showing excellent metallic conductivity of 1.2 * 107 S m-1, even at the longest stretch strain (700%). This process provides a successful strategy for obtaining good robust metal layers on PDMS and other polymer substrate surfaces with strong adhesion and conductivity. PMID- 29253329 TI - Characteristics of a PHD Finger Subtype. AB - Although the plant homeodomain (PHD) finger superfamily is known for its site specific readouts of histone tails, the origins of the mechanistic differences in histone H3 readout by different PHD subtypes remain less clear. We show that sequences containing the xCDxCDx motif in the PHD treble clef (xCDxCDx-PHD) constitute a distinct subtype, based on the following observations: (i) the amino acid composition of the binding site is strikingly different from other subtypes due to position-specific enrichment of negatively charged and bulky nonpolar residues, (ii) the binding site positions are mutually and positively correlated, and this correlation is absent in other subtypes, and (iii) there are only small structural deviations, despite low sequence similarity. The xCDxCDx-PHD constitutes ~20% of the PHD family, and the double PHD fingers (DPFs) are 10% of the total number of xCDxCDx-PHDs. This subtype originated early in the evolution of eukaryotes but has diversified within the metazoan lineage. Despite sequence diversification, the positions of the enriched nonpolar residues, in particular, show very small structural deviations, suggesting critical contributions of nonpolar residues in the binding mechanism of this subtype. Using mutagenesis, we probed the contributions of the binding-site positions enriched in nonpolar residues in four xCDxCDx-PHD proteins and found that they contribute to the tight packing of the H3 residues. This effect may potentially be exploited, as we observed affinity enhancement upon substituting a bulky nonpolar residue at the same binding site in another histone reader. Overall, we present a detailed characterization of PHD subtypes. PMID- 29253332 TI - Engineering Elastin-Like Polypeptide-Poly(ethylene glycol) Multiblock Physical Networks. AB - Hybrids of protein biopolymers and synthetic polymers are a promising new class of soft materials, as the advantages of each component can be complementary. A recombinant elastin-like polypeptide (ELP) was conjugated to poly(ethylene glycol) (PEG) by macromolecular coupling in solution to form multiblock ELP-PEG copolymers. The hydrated copolymer preserved the thermoresponsive properties from the ELP block and formed hydrogels with different transition temperatures depending on salt concentration. Small angle scattering indicates that the copolymer hydrogels form sphere-like aggregates with a "fuzzy" interface, while the films form a fractal network of nanoscale aggregates. The use of solutions with different salt concentrations to prepare the hydrogels was found to influence the transition temperature, the mechanical properties, and the size of the nanoscale structure of the hydrogel without changing the secondary structure of the ELP. The salt variation and the addition of a plasticizer also affected the nanoscale structure and the mechanical characteristics of the films. PMID- 29253333 TI - Atom Types Independent Molecular Mechanics Method for Predicting the Conformational Energy of Small Molecules. AB - We previously implemented a well-known qualitative chemical principle into an accurate quantitative model computing relative potential energies of conformers. According to this principle, hyperconjugation strength correlates with electronegativity of donors and acceptors. While this earlier version of our model applies to sigma bonds, lone pairs, disregarded in this earlier version, also have a major impact on the conformational preferences of molecules. Among the well-established principles used by organic chemists to rationalize some organic chemical behaviors are the anomeric effect, the alpha effect, basicity, and nucleophilicity. These effects are directly related to the presence of lone pairs. We report herein our effort to incorporate lone pairs into our model to extend its applicability domain to any saturated small molecules. The developed model H-TEQ 2 has been validated on a wide variety of molecules from polyaromatic molecules to carbohydrates and molecules with high heteroatoms/carbon ratios. Interestingly, this method, in contrast to common force field-based methods, does not rely on atom types and is virtually applicable to any organic molecules. PMID- 29253334 TI - Efficient Red/Green/Blue Tandem Quantum-Dot Light-Emitting Diodes with External Quantum Efficiency Exceeding 21. AB - Highly efficient tandem quantum-dot light-emitting diodes (QLEDs) are developed by using an interconnecting layer (ICL) with the structure of ZnMgO/Al/HATCN/MoO3. The developed ICL exhibits high transparency, efficient charge generation/injection capability, and high robustness to resist solvent damage during deposition of the upper functional layers. With the proposed ICL, full color (red/green/blue, R/G/B) tandem QLEDs are demonstrated with extremely high current efficiency and external quantum efficiency (EQE): 17.9 cd/A and 21.4% for B-QLEDs, 121.5 cd/A and 27.6% for G-QLEDs, 41.5 cd/A and 23.1% for R QLEDs. To the best of our knowledge, these are the highest values ever reported. In addition, the EQEs of R-, G-, and B-QLEDs all exceed 21%. The high efficiency can be well maintained over a wide range of luminance from 102 to 104 cd/m2. For example, even at a high brightness of 20 000 cd/m2, the EQE of R-, G-, and B QLEDs can still sustain its 96%, 99%, and 78% maximum value, respectively. The demonstrated full-color tandem QLEDs, with extremely high efficiency, long operational lifetime, low roll-off efficiency, and high color purity, would be ideal candidates to bring QLEDs into the next generation of full-color displays and the solid-state lighting market. PMID- 29253336 TI - A Minimum Variance Clustering Approach Produces Robust and Interpretable Coarse Grained Models. AB - Markov state models (MSMs) are a powerful framework for the analysis of molecular dynamics data sets, such as protein folding simulations, because of their straightforward construction and statistical rigor. The coarse-graining of MSMs into an interpretable number of macrostates is a crucial step for connecting theoretical results with experimental observables. Here we present the minimum variance clustering approach (MVCA) for the coarse-graining of MSMs into macrostate models. The method utilizes agglomerative clustering with Ward's minimum variance objective function, and the similarity of the microstate dynamics is determined using the Jensen-Shannon divergence between the corresponding rows in the MSM transition probability matrix. We first show that MVCA produces intuitive results for a simple tripeptide system and is robust toward long-duration statistical artifacts. MVCA is then applied to two protein folding simulations of the same protein in different force fields to demonstrate that a different number of macrostates is appropriate for each model, revealing a misfolded state present in only one of the simulations. Finally, we show that the same method can be used to analyze a data set containing many MSMs from simulations in different force fields by aggregating them into groups and quantifying their dynamical similarity in the context of force field parameter choices. The minimum variance clustering approach with the Jensen-Shannon divergence provides a powerful tool to group dynamics by similarity, both among model states and among dynamical models themselves. PMID- 29253335 TI - Antibacterial and Biocompatible Cross-Linked Waterborne Polyurethanes Containing Gemini Quaternary Ammonium Salts. AB - A cross-linked waterborne polyurethane (CPTMGPU) with long-term stability was developed from poly(ethylene glycol) (PEG), polyoxytetramethylene glycol (PTMG), isophorone diisocyanate (IPDI), l-lysine, and its derivative diamine consisting of gemini quaternary ammonium salt (GQAS), using ethylene glycol diglycidyl ether (EGDE) as a cross-linker. Weight loss test, X-ray photoelectron spectroscopy (XPS) measurements, and attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) were performed to prove the surface structure and stability of these CPTMGPU films. Furthermore, the GQAS-bearing CPTMGPUs show repeatable contact-active antibacterial efficacy against both Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) bacteria and do not show any inhibition effect against fibroblasts in vitro. After subcutaneous implantation in rats, the CPTMGPU films manifest good biocompatibility in vivo, despite the presence of a typical foreign body reaction toward surrounding tissues and mild systematic inflammation reaction that could be eliminated after a short implantation period, as demonstrated by histology and immunohistochemistry combined with interleukin (IL)-1beta, IL-4, IL-6, IL-10, and TNF-alpha analysis though enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qRT-PCR). Therefore, these cross-linked waterborne polyurethanes hold great promise for antibacterial applications in vivo. PMID- 29253337 TI - Electrical Neural Stimulation and Simultaneous in Vivo Monitoring with Transparent Graphene Electrode Arrays Implanted in GCaMP6f Mice. AB - Electrical stimulation using implantable electrodes is widely used to treat various neuronal disorders such as Parkinson's disease and epilepsy and is a widely used research tool in neuroscience studies. However, to date, devices that help better understand the mechanisms of electrical stimulation in neural tissues have been limited to opaque neural electrodes. Imaging spatiotemporal neural responses to electrical stimulation with minimal artifact could allow for various studies that are impossible with existing opaque electrodes. Here, we demonstrate electrical brain stimulation and simultaneous optical monitoring of the underlying neural tissues using carbon-based, fully transparent graphene electrodes implanted in GCaMP6f mice. Fluorescence imaging of neural activity for varying electrical stimulation parameters was conducted with minimal image artifact through transparent graphene electrodes. In addition, full-field imaging of electrical stimulation verified more efficient neural activation with cathode leading stimulation compared to anode leading stimulation. We have characterized the charge density limitation of capacitive four-layer graphene electrodes as 116.07-174.10 MUC/cm2 based on electrochemical impedance spectroscopy, cyclic voltammetry, failure bench testing, and in vivo testing. This study demonstrates the transparent ability of graphene neural electrodes and provides a method to further increase understanding and potentially improve therapeutic electrical stimulation in the central and peripheral nervous systems. PMID- 29253338 TI - Superphenylphosphines: Nanographene-Based Ligands That Control Coordination Geometry and Drive Supramolecular Assembly. AB - Tertiary phosphines remain widely utilized in synthesis, most notably as supporting ligands in metal complexes. A series of triarylphosphines bearing one to three hexa-peri-hexabenzocoronene (HBC) substituents has been prepared by an efficient divergent route. These "superphenylphosphines", P{HBC(t-Bu)5}nPh3-n (n = 1-3), form the palladium complexes PdCl2L2 and Pd2Cl4L2 where the isomer distribution in solution is dependent on the number of HBC substituents. The crystalline structures of five complexes all show intramolecular pi-stacking between HBC-phosphines to form a supramolecular bidentate-like ligand that distorts the metal coordination geometry. When n = 2 or 3, the additional HBC substituents engage in intermolecular pi-stacking to assemble the complexes into continuous ribbons or sheets. The phosphines adopt HBC's characteristics including strong optical absorption, green emission, and redox activity. PMID- 29253339 TI - Exciting H2 Molecules for Graphene Functionalization. AB - Hydrogen functionalization of graphene by exposure to vibrationally excited H2 molecules is investigated by combined scanning tunneling microscopy, high resolution electron energy loss spectroscopy, X-ray photoelectron spectroscopy measurements, and density functional theory calculations. The measurements reveal that vibrationally excited H2 molecules dissociatively adsorb on graphene on Ir(111) resulting in nanopatterned hydrogen functionalization structures. Calculations demonstrate that the presence of the Ir surface below the graphene lowers the H2 dissociative adsorption barrier and allows for the adsorption reaction at energies well below the dissociation threshold of the H-H bond. The first reacting H2 molecule must contain considerable vibrational energy to overcome the dissociative adsorption barrier. However, this initial adsorption further activates the surface resulting in reduced barriers for dissociative adsorption of subsequent H2 molecules. This enables functionalization by H2 molecules with lower vibrational energy, yielding an avalanche effect for the hydrogenation reaction. These results provide an example of a catalytically active graphene-coated surface and additionally set the stage for a re interpretation of previous experimental work involving elevated H2 background gas pressures in the presence of hot filaments. PMID- 29253340 TI - Structure-Guided Synthesis and Mechanistic Studies Reveal Sweetspots on Naphthyl Salicyl Hydrazone Scaffold as Non-Nucleosidic Competitive, Reversible Inhibitors of Human Ribonucleotide Reductase. AB - Ribonucleotide reductase (RR), an established cancer target, is usually inhibited by antimetabolites, which display multiple cross-reactive effects. Recently, we discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH or E-3a) of human RR (hRR) binding at the catalytic site (C-site) and inhibiting hRR reversibly. We herein report the synthesis and biochemical characterization of 25 distinct analogs. We designed each analog through docking to the C-site of hRR based on our 2.7 A X-ray crystal structure (PDB ID: 5TUS). Broad tolerance to minor structural variations preserving inhibitory potency is observed. E-3f (82% yield) displayed an in vitro IC50 of 5.3 +/- 1.8 MUM against hRR, making it the most potent in this series. Kinetic assays reveal that E-3a, E-3c, E-3t, and E-3w bind and inhibit hRR through a reversible and competitive mode. Target selectivity toward the R1 subunit of hRR is established, providing a novel way of inhibition of this crucial enzyme. PMID- 29253342 TI - Safe Staphylococcal Platform for the Development of Multivalent Nanoscale Vesicles against Viral Infections. AB - Many viruses often have closely related yet antigenically distinct serotypes. An ideal vaccine against viral infections should induce a multivalent and protective immune response against all serotypes. Inspired by bacterial membrane vesicles (MVs) that carry different protein components, we constructed an agr locus deletion mutant of the Staphylococcus aureus strain (RN4220-Deltaagr) to reduce potential toxicity. Nanoscale vesicles derived from this strain (DeltaagrMVs) carry at least four major components that can deliver heterologous antigens. These components were each fused with a triple FLAG tag, and the tagged proteins could be incorporated into the DeltaagrMVs. The presentation levels were (3.43 +/ 0.73)%, (5.07 +/- 0.82)%, (2.64 +/- 0.61)%, and (2.89 +/- 0.74)% of the total DeltaagrMV proteins for Mntc-FLAG, PdhB-FLAG, PdhA-FLAG, and Eno-FLAG, respectively. With two DENV envelope E domain III proteins (EDIIIconA and EDIIIconB) as models, the DENV EDIIIconA and EDIIIconB delivered by two staphylococcal components were stably embedded in the DeltaagrMVs. Administration of such engineered DeltaagrMVs in mice induced antibodies against all four DENV serotypes. Sera from immunized mice protected Vero cells and suckling mice from a lethal challenge of DENV-2. This study will open up new insights into the preparation of multivalent nanosized viral vaccines against viral infections. PMID- 29253341 TI - Mechanistic Investigations of PoyD, a Radical S-Adenosyl-l-methionine Enzyme Catalyzing Iterative and Directional Epimerizations in Polytheonamide A Biosynthesis. AB - Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a growing family of bioactive peptides. Among RiPPs, the bacterial toxin polytheonamide A is characterized by a unique set of post-translational modifications catalyzed by novel radical S-adenosyl-l-methionine (SAM) enzymes. Here we show that the radical SAM enzyme PoyD catalyzes in vitro polytheonamide epimerization in a C-to-N directional manner. By combining mutagenesis experiments with labeling studies and investigating the enzyme substrate promiscuity, we deciphered in detail the mechanism of PoyD. We notably identified a critical cysteine residue as a likely key H atom donor and demonstrated that PoyD belongs to a distinct family of radical SAM peptidyl epimerases. In addition, our study shows that the core peptide directly influences the epimerization pattern allowing for production of peptides with unnatural epimerization patterns. PMID- 29253343 TI - Next-Generation Hypoxic Cell Radiosensitizers: Nitroimidazole Alkylsulfonamides. AB - Innovations in the field of radiotherapy such as stereotactic body radiotherapy, along with the advent of radio-immuno-oncology, herald new opportunities for classical oxygen-mimetic radiosensitizers. The role of hypoxic tumor cells in resistance to radiotherapy and in suppression of immune response continues to endorse tumor hypoxia as a bona fide, yet largely untapped, drug target. Only nimorazole is used clinically as a radiosensitizer, and there is a dearth of new radiosensitizers in development. Here we present a survey of novel nitroimidazole alkylsulfonamides and document their cytotoxicity and ability to radiosensitize anoxic tumor cells in vitro. We use a phosphate prodrug approach to increase aqueous solubility and to improve tumor drug delivery. A 2-nitroimidazole and a 5 nitroimidazole analogue demonstrated marked tumor radiosensitization in either ex vivo assays of surviving clonogens or tumor regrowth delay. PMID- 29253345 TI - MicroRNA-145, Cystic Fibrosis Transmembrane Conductance Regulator, and Transforming Growth Factor-beta. An (Un)tangled Regulatory Web. PMID- 29253344 TI - Rubbery Chitosan/Carrageenan Hydrogels Constructed through an Electroneutrality System and Their Potential Application as Cartilage Scaffolds. AB - In the present work, the bulk and homogeneous composite hydrogels were successfully constructed from positively charged chitosan (CS) and negatively charged carrageenan (CG) in alkali/urea aqueous solution via a simple one-step approach for the first time. An electroneutral CS solution was achieved in alkali/urea, leading to a homogeneous solution blended by CS and CG, which could not be realized in acidic medium because of the agglomeration caused by polycation and polyanion. Subsequently, the CS/CG composite hydrogels with multiple cross-linked networks were prepared from blend solution by using epichlorohydrin (ECH) as the cross-linking agent. The composite hydrogels exhibited hierarchically porous architecture, excellent mechanical properties as well as pH- and salt-responsiveness. Importantly, the composite hydrogels were successfully applied for spreading ATDC5 cells, showing high attachment and proliferation of cells. The results of fluorescent micrographs and scanning electronic microscope images revealed that the CS/CG composite hydrogels enhanced the adhesion and viability of ATDC5 cells. The alcian blue staining, glycosaminoglycan quantification, and real-time PCR analysis proved that the CS/CG composite hydrogels could induce chondrogenic differentiation of ATDC5 cells in vitro, exhibiting great potential for application in cartilage repair. This work provides a facile and fast fabrication pathway for the construction of ampholytic hydrogel from polycation and polyanion in an electroneutrality system. PMID- 29253346 TI - Do Selective COX-2 Inhibitors Affect Pain Control and Healing After Arthroscopic Rotator Cuff Repair? A Preliminary Study. AB - BACKGROUND: Selective cyclooxygenase (COX)-2 inhibitors are commonly used analgesics that provide similar analgesia as that of other analgesics but with fewer adverse effects. However, few prospective studies have performed comparative analyses in this regard. PURPOSE: To evaluate the efficacy of a selective COX-2 inhibitor in early postoperative pain control, satisfaction with pain management, and incidence of systemic adverse effects in patients undergoing arthroscopic rotator cuff repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: This study included 180 patients who underwent arthroscopic rotator cuff repair between September 2011 and August 2012. The patients were randomly assigned to receive celecoxib, ibuprofen, or tramadol (n = 60 each). Visual analog scale (VAS) scores for pain intensity and satisfaction with medication, incidence of adverse effects, and use of rescue medication were recorded and compared between the 3 groups at 3 days and 2 weeks after surgery. Magnetic resonance and ultrasonography images of 82 patients were retrospectively reviewed at least 24 months after surgery, along with the range of motion and pain VAS and functional scores. RESULTS: There were no significant differences among the 3 groups in terms of pain intensity, incidence of adverse effects, or dosage of rescue medication at 3 days or 2 weeks after surgery. Pain VAS and functional scores at the final follow-up were also comparable among the 3 groups. However, the retear rate in the celecoxib group (11/30 [37%]) was significantly higher than those in the ibuprofen (2/27 [7%]) and tramadol (1/25 [4%]) groups ( P = .009). CONCLUSION: Despite having similar postoperative analgesic effects as other nonsteroidal anti-inflammatory drugs and opioids, selective COX-2 inhibitors should not be used for postoperative analgesia because they might negatively affect tendon-to-bone healing after surgical repair. Registration: NCT02850211 ( ClinicalTrials.gov identifier). PMID- 29253347 TI - We Do Not Appreciate SALT. PMID- 29253348 TI - The Role of Meniscal Tears in Spontaneous Osteonecrosis of the Knee: A Systematic Review of Suspected Etiology and a Call to Revisit Nomenclature. AB - BACKGROUND: The cause of spontaneous osteonecrosis of the knee (SONK) and postarthroscopic osteonecrosis of the knee is unknown, and the mechanisms involved have been poorly characterized. Hypothesis/Purpose: The purpose of this study was to perform a detailed systematic review of the literature to examine proposed etiological mechanisms for SONK in order to establish an improved understanding of the processes involved. We hypothesized that the etiology of SONK would be multifactorial. STUDY DESIGN: Systematic review. METHODS: A systematic review of the literature was performed by searching PubMed, Medline, Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials. Inclusion criteria were all original research articles presented in the English language that reported on the suspected etiology of SONK. Reviews, case reports with fewer than 3 patients, cost-effectiveness studies, technical reports, editorial articles, surveys, special topics, letters to the editor, personal correspondence, and studies that only proposed factors for the progression of SONK were excluded. RESULTS: After a comprehensive review of 255 articles, 26 articles were included for final analysis. Twenty-one (80.7%) of 26 articles implicated the role of the meniscus in the development of SONK, in an association with either meniscal tears or its development after meniscectomy. The medial meniscus and posterior meniscal root tears were implicated more frequently. All 4 studies incorporating histological findings supported the insufficiency fracture hypothesis as a pathological basis of SONK. CONCLUSION: Physicians should be cognizant of the high prevalence of medial meniscus root tears in patients with SONK. Meniscectomy and meniscal tears, particularly of the medial meniscus posterior root, increase contact pressures and create an environment from which insufficiency fractures can emanate. We believe the term SONK is a misrepresentation of the etiology and pathogenesis of the condition and should be replaced with subchondral insufficiency fractures of the knee. Further elucidation of the etiology is required. PMID- 29253349 TI - Differential Motion and Compression Between the Plantaris and Achilles Tendons: A Contributing Factor to Midportion Achilles Tendinopathy? AB - BACKGROUND: The plantaris tendon (PT) has been thought to contribute to symptoms in a proportion of patients with Achilles midportion tendinopathy, with symptoms improving after PT excision. HYPOTHESIS: There is compression and differential movement between the PT and Achilles tendon (AT) during ankle plantarflexion and dorsiflexion. STUDY DESIGN: Descriptive laboratory study. METHODS: Eighteen fresh frozen cadaveric ankles (mean +/- SD age: 35 +/- 7 years, range = 27-48 years; men, n = 9) were mounted in a customized testing rig, where the tibia was fixed but the forefoot could be moved freely. A Steinmann pin was drilled through the calcaneus, enabling a valgus torque to be applied. The soleus, gastrocnemius, and plantaris muscles were loaded with 63 N with a weighted pulley system. The test area was 40 to 80 mm above the os calcis, corresponding to where the injury is observed clinically. Medially, the AT and PT were exposed, and a calibrated flexible pressure sensor was inserted between the tendons. Pressure readings were recorded with the ankle in full dorsiflexion, full plantarflexion, and plantargrade and repeated in these positions with a 5 N.m torque, simulating increased hindfoot valgus. The pressure sensor was removed and the PT and AT marked with ink at the same level, with the foot held in neutral rotation and plantargrade. Videos and photographs were taken to assess differential motion between the tendons. After testing, specimens were dissected to identify the PT insertion. One-way analysis of variance and paired t tests were performed to make comparisons. RESULTS: The PT tendons with an insertion separate from the AT demonstrated greater differential motion through range (14 +/- 4 mm) when compared with those directly adherent to the AT (2 +/- 2 mm) ( P < .001). Mean pressure between the PT and AT rose in terminal plantarflexion for all specimens ( P < .001) and was more pronounced with hindfoot valgus ( P < .001). CONCLUSION: The PT inserting directly into the calcaneus resulted in significantly greater differential motion as compared with the AT. Tendon compression was elevated in terminal plantarflexion, suggesting that adapting rehabilitation tendon-loading programs to avoid this position may be beneficial. CLINICAL RELEVANCE: The insertion pattern of the PT may be a factor in plantaris-related midportion Achilles tendinopathy. Terminal range plantarflexion and hindfoot valgus both increased AT and PT compression, suggesting that these should be avoided in this patient population. PMID- 29253350 TI - Randomized Study of Long-term (15-17 Years) Outcome After Microfracture Versus Mosaicplasty in Knee Articular Cartilage Defects. AB - BACKGROUND: Few comparative randomized long-term studies on microfracture versus mosaicplasty have been published, and only 2 studies reported a follow-up of 10 years. Hypothesis/Purpose: The purpose was to compare the clinical outcome of microfracture versus mosaicplasty/osteochondral autograft transfer in symptomatic cartilage lesions. The null hypothesis was that the outcome was not statistically different at any point of time. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Forty patients with articular cartilage defects were randomized to undergo cartilage repair by either microfracture (n = 20) or mosaicplasty (n = 20). Inclusion criteria were as follows: age 18 to 50 years at the time of surgery, 1 or 2 symptomatic focal full-thickness articular chondral defects on the femoral condyles or trochlea, and size 2 to 6 cm2. The main outcome variable was the Lysholm knee score recorded before the surgery and at 12 months, median 5 years, median 10 years, and minimum 15 years after the surgery. RESULTS: Forty patients were included in the study (28 men, 12 women; median age, 32 years; range, 18-48 years). Defects with a median size of 3.5 cm2 (range, 2-5 cm2) were treated. A significant increase in the Lysholm score was seen for all subjects- from a mean 53 (SD, 16) at baseline to 69 (SD, 21) at the minimum 15 year follow-up ( P = .001). The mean Lysholm score was significantly higher in the mosaicplasty group than the microfracture group at 12 months, median 5 years, median 10 years, and minimum 15 years: 77 (SD, 17) versus 61 (SD, 22), respectively ( P = .01), at the last follow-up. At all follow-up time points, the difference in mean Lysholm score was clinically significant (>10 points). CONCLUSION: At short, medium, and long term (minimum 15 years), mosaicplasty results in a better, clinically relevant outcome than microfracture in articular cartilage defects (2-5 cm2) of the distal femur of the knee in patients aged 18 to 50 years. PMID- 29253351 TI - Short time effect of a single session of intense whole-body electromyostimulation on energy expenditure. A contribution to fat reduction? AB - To determine the underlying mechanisms after 1 session of (intense) whole-body electromyostimulation (WB-EMS) on total energy expenditure (TEE) and resting metabolic rate (RMR), 16 subjects followed a standardized protocol of indirect calorimetry for up to 72 h in 12-h intervals. The single session significantly increased RMR by approximately 25% +/- 10% (p < 0.001) and TEE by approximately 9.5% +/- 1%, a net effect of ~460 +/- 50 kcal (WB-EMS vs. control group). PMID- 29253352 TI - Resistance training-induced decrease in central arterial compliance is associated with decreased subendocardial viability ratio in healthy young men. AB - High-intensity resistance training decreases central arterial compliance (CAC). Subendocardial viability ratio (SEVR) is a useful tool that reflects the balance between coronary perfusion and left ventricular afterload. Animal studies have demonstrated that decreased CAC is associated with SEVR deterioration. Therefore, resistance training-induced decrease in CAC may be associated with changes in SEVR. The objective of the present study was to investigate the association between SEVR and CAC using both cross-sectional and longitudinal (i.e., resistance training) study designs. To achieve this, we first conducted a cross sectional study to investigate the association between SEVR and CAC in 89 young men. Thereafter, a longitudinal study was performed to examine the effects of resistance training on SEVR and CAC in young men. A total of 28 young men were divided into 2 groups: control (n = 13) and training (n = 15). In the training group, subjects underwent supervised resistance training for 4 weeks (5 sets of 10 repetitions at 75% of 1-repetition maximum, 3 times/week). CAC and SEVR were then measured in all subjects. In the cross-sectional study, SEVR was significantly positively correlated with CAC, whereas resistance training significantly decreased both SEVR and CAC. Moreover, training-induced changes in CAC were significantly correlated with changes in SEVR. Thus, these results suggest that resistance training-induced decrease in CAC is associated with decreased SEVR in young men. PMID- 29253354 TI - Emerging branches of the N-end rule pathways are revealing the sequence complexities of N-termini dependent protein degradation. AB - The N-end rule links the identity of the N-terminal amino acid of a protein to its in vivo half-life, as some N-terminal residues confer metabolic instability to a protein via their recognition by the cellular machinery that targets them for degradation. Since its discovery, the N-end rule has generally been defined as set of rules of whether an N-terminal residue is stabilizing or not. However, recent studies are revealing that the N-terminal code of amino acids conferring protein instability is more complex than previously appreciated, as recent investigations are revealing that the identity of adjoining downstream residues can also influence the metabolic stability of N-end rule substrate. This is exemplified by the recent discovery of a new branch of N-end rule pathways that target proteins bearing N-terminal proline. In addition, recent investigations are demonstrating that the molecular machinery in N-termini dependent protein degradation may also target proteins for lysosomal degradation, in addition to proteasome-dependent degradation. Herein, we describe some of the recent advances in N-end rule pathways and discuss some of the implications regarding the emerging additional sequence requirements. PMID- 29253353 TI - Novel Method for Noninvasive Sampling of the Distal Airspace in Acute Respiratory Distress Syndrome. AB - RATIONALE: A major barrier to a more complete understanding of acute respiratory distress syndrome (ARDS) pathophysiology is the inability to sample the distal airspace of patients with ARDS. The heat moisture exchanger (HME) filter is an inline bacteriostatic sponge that collects exhaled moisture from the lungs of mechanically ventilated patients. OBJECTIVES: To test the hypothesis that HME filter fluid (HMEF) represents the distal airspace fluid in patients with ARDS. METHODS: Samples of HMEF were collected from 37 patients with acute pulmonary edema (either from ARDS or hydrostatic causes [HYDRO; control subjects]). Concurrent undiluted pulmonary edema fluid (EF) and HMEF were collected from six patients. HMEF from 11 patients (8 ARDS and 3 HYDRO) were analyzed by liquid chromatography-coupled tandem mass spectometry. Total protein (bicinchoninic acid assay), MMP-9 (matrix metalloproteinase-9), and MPO (myeloperoxidase) (ELISA) were measured in 29 subjects with ARDS and 5 subjects with HYDRO. SP-D (surfactant protein-D), RAGE (receptor for advanced glycation end-products) (ELISA), and cytokines (IL-1beta, IL-6, IL-8, and tumor necrosis factor-alpha) (electrochemiluminescent assays) were measured in six concurrent HMEF and EF samples. MEASUREMENTS AND MAIN RESULTS: Liquid chromatography-coupled tandem mass spectrometry on concurrent EF and HMEF samples from four patients revealed similar base peak intensities and m/z values indicating similar protein composition. There were 21 significantly elevated proteins in HMEF from patients with ARDS versus HYDRO. Eight proteins measured in concurrent EF and HMEF from six patients were highly correlated. In HMEF, total protein and MMP-9 were significantly higher in ARDS than in HYDRO. CONCLUSIONS: These data suggest that HMEF is a novel, noninvasive method to accurately sample the distal airspace in patients with ARDS. PMID- 29253355 TI - Isolation and characterization of two lytic cold-active bacteriophages infecting Pseudomonas fluorescens from the Napahai plateau wetland. AB - As the "kidneys of the Earth", wetlands play important roles as biodiversity reservoirs, in water purification, and in flood control. In this study, 2 lytic cold-active bacteriophages, named VW-6S and VW-6B, infecting Pseudomonas fluorescens W-6 cells from the Napahai plateau wetland in China were isolated and characterized. Electron microscopy showed that both VW-6S and VW-6B had an icosahedral head (66.7 and 61.1 nm, respectively) and a long tail (8.3 nm width * 233.3 nm length and 11.1 nm width * 166.7 nm length, respectively). The bacteriophages VW-6S and VW-6B were classified as Siphoviridae and had an approximate genome size of 30-40 kb. The latent and burst periods of VW-6S were 60 and 30 min, whereas those of VW-6B were 30 and 30 min, respectively. The optimal pH values for the bacteriophages VW-6S and VW-6B were 8.0 and 10.0, respectively, and their activity decreased rapidly at temperatures higher than 60 degrees C. These cold-active bacteriophages provide good materials for further study of cold-adaptation mechanisms and interaction with the host P. fluorescens. PMID- 29253357 TI - When is a medicine unwanted, how is it disposed, and how might safe disposal be promoted? Insights from the Australian population. AB - Objective The aim of the present study was to explore disposal practices of unwanted medicines in a representative sample of Australian adults, compare this with previous household waste surveys and explore awareness of the National Return and Disposal of Unwanted Medicines (RUM) Project.Methods A 10-min online survey was developed, piloted and conducted with an existing research panel of adult individuals. Survey questions recorded demographics, the presence of unwanted medicines in the home, medicine disposal practices and concerns about unwanted medicines. Descriptive statistical analyses and rank-ordered logit regression were conducted.Results Sixty per cent of 4302 respondents reported having unwanted medicines in their household. Medicines were primarily kept just in case they were needed again and one-third of these medicines were expired. Two thirds of respondents disposed of medicines with the household garbage and approximately one-quarter poured medicines down the drain. Only 17.6% of respondents had heard of the RUM Project, although, once informed, 91.7% stated that they would use it. Respondents ranked the risk of unintended ingestion as the most important public health message for future social marketing campaigns.Conclusions Respondents were largely unaware of the RUM Project, yet were willing to use it once informed. Limited awareness could lead to environmental or public health risks, and targeted information campaigns are needed.What is known about the topic? There is a growing international evidence base on how people dispose of unwanted medicines and the negative consequences, particularly the environmental effects of inappropriate disposal. Although insight into variation in disposal methods is increasing, knowledge of how people perceive risks and awareness of inappropriate disposal methods is more limited.What does this paper add? This study provides evidence of inappropriate medicines disposal and potential stockpiling of medicines in Australian households that could contribute to environmental and/or public health risks. It also reveals possible trends towards a higher frequency of inappropriate disposal practices in the Australian context. Insights into respondents' perceptions of associated risks and awareness of a national scheme for appropriate disposal of medicines have not previously been reported.What are the implications for practitioners? The findings of the present study provide important insights for all health professionals as stakeholders in the quality use of medicines. It is important for those health professionals who assist consumers to manage their medicines to have strategies in place that routinely identify potential stockpiling and inform consumers about appropriate methods of medicines disposal. Although the findings of this study are specific to the Australian context, they may usefully inform policy, public health campaigns and the individual practices of health professionals and other stakeholders in promoting the quality use of medicines nationally and internationally. PMID- 29253356 TI - Foot-and-mouth disease virus infection stimulates innate immune signaling in the mouse macrophage RAW 264.7 cells. AB - The innate immune system acts as the first line of defense against invasion by bacterial and viral pathogens. The role of macrophages in innate immune responses to foot-and-mouth disease virus (FMDV) is poorly understood. To determine the mechanism underlying activation of innate immunity after FMDV infection in macrophages, we performed FMDV infection in mouse macrophage RAW 264.7 cells and found that FMDV serotype O infection induced a cytopathic effect. We then evaluated the gene expression profile in macrophage RAW 264.7 cells after FMDV infection using systematic microarray analysis. Gene ontology annotation and enrichment analysis revealed that FMDV promoted expression in a group of genes that are enriched in innate immune response and inflammatory response processes. Further research demonstrated that FMDV serotype O infection enhanced NF-kappaB, Toll-like, and RIG-I-like receptor signaling pathways and proteins expression and increased transcription and expression of a series of cytokines and interferons, as proved by qRT-PCR, Western blot, ELISA, and dual-luciferase reporter assay. Our study concluded that FMDV infection triggers the innate immune response in macrophages after activation of multiple innate immune pathway receptors and proteins by FMDV serotype O, resulting in activation and secretion of a series of cytokines and interferons. PMID- 29253358 TI - Editorial Comment. PMID- 29253359 TI - France: new government, new opportunities for public health. PMID- 29253360 TI - Unravelling the associations between social isolation, loneliness, and mortality. PMID- 29253361 TI - Socioeconomic status and susceptibility to alcohol-related harm. PMID- 29253362 TI - Excess weight and multimorbidity: putting people's health experience in risk factor epidemiology. PMID- 29253363 TI - Explosive remnants of war: a public health threat. PMID- 29253364 TI - A new President in France: an opportunity for public health policy against alcohol-related harms and deaths? PMID- 29253365 TI - Tobacco control in the Sustainable Development Goals: a precarious inclusion? PMID- 29253367 TI - Acute Hyponatremia in Puerperium: Sheehan's Syndrome. PMID- 29253366 TI - The effect of explosive remnants of war on global public health: a systematic mixed-studies review using narrative synthesis. AB - BACKGROUND: Explosive remnants of war (ERW)-landmines, unexploded ordnance (UXO), and abandoned explosive ordnance (AXO)-have been recognised as a threat to health since the 1990s. We aimed to study the effect of ERW on global public health. METHODS: In this systematic mixed-studies review, we searched the Web of Science, Scopus, PubMed, and ProQuest databases, and hand searched relevant websites, for articles published between Jan 1, 1990, and Aug 31, 2015. We used keywords and Medical Subject Headings related to ERW, landmines, UXO, and AXO to locate original peer-reviewed quantitative, qualitative, or mixed-methods studies in English of the direct physical or psychological effects of ERW on direct victims of the explosive device or reverberating social and economic effects on direct victims and indirect victims (their families and the wider at-risk community). We excluded studies if more than 20% of participants were military, if they were of deminers, if they were from high-income countries, or if they were of chemical weapons. We identified no peer-reviewed studies of AXO effects, so we extended the search to include grey literature. We critically appraised study quality using a mixed methods appraisal tool. We used a narrative synthesis approach to categorise and synthesise the literature. We extracted quantitative data and calculated means and percentages. FINDINGS: The initial search identified 10 226 studies, leaving 8378 (82%) after removal of duplicates, of which we reviewed 54 (26 [48%] were quantitative descriptive studies, 20 [37%] were quantitative non randomised studies, four [7%] were mixed-methods studies, and four [7%] were grey literature). The direct psychological effects of landmines or UXO appear high. We identified comorbidity of anxiety and depression in landmine or UXO victims in four studies, more women presented with post-traumatic stress disorder than did men in two studies, and landmine or UXO victims reported a greater prevalence of post-traumatic stress disorder, anxiety, or depression than did control groups in two studies. Overall injury and mortality rates caused by landmines or UXO decreased over time across five studies and increased in one. More men were injured or killed by landmines or UXO than were women (0-30.6% of women), the mean ages of casualties ranged from 18.5 years to 38.1 years, and victims were likely to be doing an activity of economic necessity at the time of injury. The proportion of casualties of landmines or UXO younger than 18 years ranged from 22% to 55% across twelve studies. Landmine or UXO victims who had one or more limbs amputated ranged from 19.5% to 82.6%. Landmines and UXO had a negative effect on internally displaced populations and returning refugees, physical security, economic productivity, child health and educational attainment, food security, and agriculture in studies from seven countries. We could not establish the proportion of casualties caused by AXO from unplanned explosions at munitions sites, although the grey literature suggests that AXO is a substantial problem. INTERPRETATION: Individually, these landmine and UXO results are not new and substantiate findings from existing research. Taken together, however, these findings provide a picture of the effect of landmines and UXO that stretches far beyond injury and mortality prevalence, making landmine and UXO clearance a more favourable option for funders. AXO effects are understudied and warrant further research. FUNDING: King's College London. PMID- 29253368 TI - The environment we live in. PMID- 29253369 TI - Innovative models are needed for equitable abortion access in the USA. PMID- 29253370 TI - Mortality by occupation: the best basis for actionable results? PMID- 29253371 TI - The power of environmental protection: arsenic in drinking water. PMID- 29253372 TI - Hazards of residential exposure to household asbestos. PMID- 29253373 TI - Disparities and change over time in distance women would need to travel to have an abortion in the USA: a spatial analysis. AB - BACKGROUND: Abortion can help women to control their fertility and is an important component of health care for women. Although women in the USA who live further from an abortion clinic are less likely to obtain an abortion than women who live closer to an abortion clinic, no national study has examined inequality in access to abortion and whether inequality has increased as the number of abortion clinics has declined. METHODS: For this analysis, we obtained data on abortion clinics for 2000, 2011, and 2014 from the Guttmacher Institute's Abortion Provider Census. Block groups and the percentage of women aged 15-44 years by census tract were obtained from the US Census Bureau. Distance to the nearest clinic was calculated for the population-weighted centroid of every block group. We calculated the median distance to an abortion clinic for women in each county and the median and 80th percentile distances for each state by weighting block groups by the number of women of reproductive age (15-44 years). FINDINGS: In 2014, women in the USA would have had to travel a median distance of 10.79 miles (17.36 km) to reach the nearest abortion clinic, although 20% of women would have had to travel 42.54 miles (68.46 km) or more. We found substantially greater variation within than between states because, even in mostly rural states, women and clinics were concentrated in urban areas. We identified spatial disparities in abortion access, which were broadly unchanged, at least as far back as 2000. INTERPRETATION: We showed substantial and persistent spatial disparities in access to abortion in the USA. These results contribute to an emerging literature documenting similar disparities in other high-income countries. FUNDING: An anonymous grant to the Guttmacher Institute. PMID- 29253374 TI - Risk of cancer associated with residential exposure to asbestos insulation: a whole-population cohort study. AB - BACKGROUND: The health risks associated with living in houses insulated with asbestos are unknown. Loose-fill asbestos was used to insulate some houses in the Australian Capital Territory (ACT). We compared the incidence of mesothelioma and other cancers in residents of the ACT who did and did not live in these houses. METHODS: Our cohort study included all ACT residents identified using Medicare enrolment data. These data were linked to addresses of affected residential properties in the ACT to ascertain exposure. We followed up residents by linking data to the Australian Cancer Database and National Death Index. Outcomes were diagnosis of mesothelioma and selected other cancers. Effects were estimated for males and females separately using standardised incidence ratios (SIRs), adjusting for age and calendar time of diagnosis. FINDINGS: Between Nov 1, 1983, and Dec 31, 2013, 1 035 578 ACT residents were identified from the Medicare database. Of these, 17 248 (2%) had lived in an affected property, including seven (2%) of 285 people diagnosed with mesothelioma. The adjusted incidence of mesothelioma in males who had lived at an affected property was 2.5 times that of unexposed males (SIR 2.54, 95% CI 1.02-5.24). No mesotheliomas were reported among females who had lived at an affected property. Among individuals who had lived at an affected property, there was an elevated incidence of colorectal cancer in women (SIR 1.73, 95% CI 1.29-2.26) and prostate cancer in men (1.29, 1.07-1.54); colorectal cancer was increased, although not significantly, in males (SIR 1.32, 95% CI 0.99-1.72), with no significant increase in the other cancers studied. INTERPRETATION: Residential asbestos insulation is likely to be unsafe. Our findings have important health, social, financial, and legal implications for governments and communities in which asbestos has been used to insulate houses. FUNDING: ACT Government. PMID- 29253375 TI - A new journal for a new era in public health. PMID- 29253376 TI - Economic opportunity, health behaviours, and health outcomes in the USA: a population-based cross-sectional study. AB - BACKGROUND: Inequality of opportunity, defined as differences in the prospects for upward social mobility, might have important consequences for health. Diminished opportunity can lower the motivation to invest in future health by reducing economic returns to health investments and undermining hope. We estimated the association between county-level economic opportunity and individual-level health in young adults in the general US population. METHODS: In this population-based cross-sectional study, we used individual-level data from the 2009-12 United States Behavioral Risk Factor Surveillance Surveys. Our primary outcomes were current self-reported overall health and the number of days of poor physical and mental health in the last month. Economic opportunity was measured by the county-averaged national income rank attained by individuals born to families in the lowest income quartile. We restricted our sample to adults aged 25-35 years old to match the data used to assign exposure. Multivariable ordinary least squares and probit models were used to estimate the association between the outcomes and economic opportunity. We adjusted for a range of demographic and socioeconomic characteristics, including age, sex, race, education, income, access to health care, area income inequality, segregation, and social capital. FINDINGS: We assessed nearly 147 000 individuals between the ages of 25 years and 35 years surveyed from 2009 to 2012. In models adjusting for individual-level demographics and county-level socioeconomic characteristics, increases in county-level economic opportunity were associated with greater self reported overall health. An interdecile increase in economic opportunity was associated with 0.76 fewer days of poor mental health (95% CI -1.26 to -0.25) and 0.53 fewer days of poor physical health (-0.96 to -0.09) in the last month. The results were robust to sensitivity analyses. INTERPRETATION: Economic opportunity is independently associated with self-reported health and health behaviours. Policies seeking to expand economic opportunities might have important spillover effects on health. FUNDING: Robert Wood Johnson Foundation Health and Society Scholars Program. PMID- 29253378 TI - Economic opportunity: a determinant of health? PMID- 29253377 TI - HPV vaccination in boys should not be discounted. PMID- 29253380 TI - Women's rights: never truly acquired? PMID- 29253379 TI - Population-level impact, herd immunity, and elimination after human papillomavirus vaccination: a systematic review and meta-analysis of predictions from transmission-dynamic models. AB - BACKGROUND: Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions of population-level effectiveness and herd effects. We did a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV-vaccine-type elimination. METHODS: We searched MEDLINE and Embase for transmission-dynamic modelling studies published between Jan 1, 2009, and April 28, 2015, that predicted the population-level impact of vaccination on HPV 6, 11, 16, and 18 infections in high-income countries. We contacted authors to determine whether they were willing to produce new predictions for standardised scenarios. Strategies investigated were girls-only vaccination and girls and boys vaccination at age 12 years. Base-case vaccine characteristics were 100% efficacy and lifetime protection. We did sensitivity analyses by varying vaccination coverage, vaccine efficacy, and duration of protection. For all scenarios we pooled model predictions of relative reductions in HPV prevalence (RRprev) over time after vaccination and summarised results using the median and 10th and 90th percentiles (80% uncertainty intervals [UI]). FINDINGS: 16 of 19 eligible models from ten high-income countries provided predictions. Under base-case assumptions, 40% vaccination coverage and girls-only vaccination, the RRprev of HPV 16 among women and men was 0.53 (80% UI 0.46-0.68) and 0.36 (0.28-0.61), respectively, after 70 years. With 80% girls-only vaccination coverage, the RRprev of HPV 16 among women and men was 0.93 (0.90-1.00) and 0.83 (0.75-1.00), respectively. Vaccinating boys in addition to girls increased the RRprev of HPV 16 among women and men by 0.18 (0.13-0.32) and 0.35 (0.27-0.39) for 40% coverage, and 0.07 (0.00-0.10) and 0.16 (0.01-0.25) for 80% coverage, respectively. The RRprev were greater for HPV 6, 11, and 18 than for HPV 16 for all scenarios investigated. Finally at 80% coverage, most models predicted that girls and boys vaccination would eliminate HPV 6, 11, 16, and 18, with a median RRprev of 1.00 for women and men for all four HPV types. Variability in pooled findings was low, but increased with lower vaccination coverage and shorter vaccine protection (from lifetime to 20 years). INTERPRETATION: Although HPV models differ in structure, data used for calibration, and settings, our population-level predictions were generally concordant and suggest that strong herd effects are expected from vaccinating girls only, even with coverage as low as 20%. Elimination of HPV 16, 18, 6, and 11 is possible if 80% coverage in girls and boys is reached and if high vaccine efficacy is maintained over time. FUNDING: Canadian Institutes of Health Research. PMID- 29253381 TI - US reproductive health and rights: beyond the global gag rule. PMID- 29253382 TI - Value for money in reducing opioid-related deaths. PMID- 29253383 TI - Relative poverty still matters. PMID- 29253384 TI - Interpretation of dementia diagnosis and treatment trends in the UK over time. PMID- 29253385 TI - The price of delaying measles eradication. PMID- 29253386 TI - Effects of naloxone distribution alone or in combination with addiction treatment with or without pre-exposure prophylaxis for HIV prevention in people who inject drugs: a cost-effectiveness modelling study. AB - BACKGROUND: In the USA, an epidemic of opioid overdose deaths is occurring, many of which are from heroin. Combining naloxone distribution with linkage to addiction treatment or pre-exposure prophylaxis (PrEP) for HIV prevention through syringe service programmes has the potential to save lives and be cost-effective. We estimated the outcomes and cost-effectiveness of five alternative strategies: no additional intervention, naloxone distribution, naloxone distribution plus linkage to addiction treatment, naloxone distribution plus PrEP, and naloxone distribution plus linkage to addiction treatment and PrEP. METHODS: We developed a decision analytical Markov model to simulate opioid overdose, HIV incidence, overdose-related deaths, and HIV-related deaths in people who inject drugs in Connecticut, USA. Model input parameters were derived from published sources. We compared each strategy with no intervention, as well as simultaneously considering all strategies. Sensitivity analysis was done for all variables. Linkage to addiction treatment was referral to an opioid treatment programme for methadone. Endpoints were survival, life expectancy, quality-adjusted life-years (QALYs), number and percentage of overdose deaths averted, number of HIV-related deaths averted, total costs (in 2015 US$) associated with each strategy, and incremental cost per QALY gained. FINDINGS: In the base-case analysis, compared with no additional intervention, the naloxone distribution strategy yielded an incremental cost-effectiveness ratio (ICER) of $323 per QALY, and naloxone distribution plus linkage to addiction treatment was cost saving compared with no additional intervention (greater effectiveness and less expensive). The most efficient strategies (ie, those conferring the greatest health benefit for a particular budget) were naloxone distribution combined with linkage to addiction treatment (cost saving), and naloxone distribution combined with PrEP and linkage to addiction treatment (ICER $95 337 per QALY) at a willingness-to-pay threshold of $100 000. In probabilistic sensitivity analysis, the combination of naloxone distribution, PrEP, and linkage to addiction treatment was the optimal strategy in 37% of iterations and the combination of naloxone distribution and linkage to addiction treatment was the optimal strategy in 34% of iterations. INTERPRETATION: Naloxone distribution through syringe service programmes is cost effective compared with syringe distribution alone, but when combined with linkage to addiction treatment is cost saving compared with no additional services. A strategy that combines naloxone distribution, PrEP, and linkage to addiction treatment results in greater health benefits in people who inject drugs and is also cost-effective. FUNDING: State of Connecticut Department of Public Health and the National Institute of Mental Health. PMID- 29253387 TI - The effect of a transition into poverty on child and maternal mental health: a longitudinal analysis of the UK Millennium Cohort Study. AB - BACKGROUND: Whether or not relative measures of income poverty effectively reflect children's life chances has been the focus of policy debates in the UK. Although poverty is associated with poor child and maternal mental health, few studies have assessed the effect of moving into poverty on mental health. To inform policy, we explore the association between transitions into poverty and subsequent mental health among children and their mothers. METHODS: In this longtitudinal analysis, we used data from the UK Millennium Cohort Study, a large nationally representative cohort of children born in the UK between Sept 1, 2000, and Jan 11, 2002, who participated in five survey waves as they progressed from 9 months of age to 11 years of age. Our analysis included all children and mothers who were free from mental health problems and not in poverty when the children were aged 3 years. We only included singletons (ie, not twins or other multiple pregnancies) and children for whom the mother was the main respondent to the study. The main outcomes were child socioemotional behavioural problems (Strengths and Difficulties Questionnaire) at ages 5 years, 7 years, and 11 years and maternal psychological distress (Kessler 6 scale). Using discrete time-hazard models, we followed up families without mental health problems at baseline and estimated odds ratios for subsequent onset of maternal and child mental health problems associated with first transition into poverty, while adjusting for confounders, including employment transitions. We further assessed whether or not change in maternal mental health explained any effect on child mental health. FINDINGS: Of the 6063 families in the UK Millennium Cohort study at 3 years who met our inclusion criteria, 844 (14%) had a new transition into poverty compared with 5219 (86%) who remained out of poverty. After adjustment for confounders, transition into poverty increased the odds of socioemotional behavioural problems in children (odds ratio 1.41 [95% CI 1.02-1.93]; p=0.04) and maternal psychological distress (1.44 [1.21-1.71]; p<0.0001). Controlling for maternal psychological distress reduced the effect of transition into poverty on socioemotional behavioural problems in children (1.30 [0.94-1.79]; p=0.11). INTERPRETATION: In a contemporary UK cohort, first transition into income poverty during early childhood was associated with an increase in the risk of child and maternal mental health problems. These effects were independent of changes in employment status. Transitions to income poverty do appear to affect children's life chances and actions that directly reduce income poverty of children are likely to improve child and maternal mental health. FUNDING: The Wellcome Trust and The Farr Institute for Health Informatics Research (Medical Research Council). PMID- 29253388 TI - Trends in diagnosis and treatment for people with dementia in the UK from 2005 to 2015: a longitudinal retrospective cohort study. AB - BACKGROUND: The objectives of this study were to describe changes in the proportion of people diagnosed with dementia and the pharmacological treatments prescribed to them over a 10 year period from 2005 to 2015 at a time of UK policy strategies and prioritisation of dementia. We aimed to explore the potential impact of policy on dementia care. METHODS: In this longitudinal retrospective cohort study, we included all patients registered at a Clinical Practice Research Datalink (CPRD) practice between July 1, 2005, and June 30, 2015, with a diagnosis of dementia defined using Read codes. The main outcomes were the number and proportion of acceptable patients, who met the CPRD threshold for data quality, in a GP practice defined by the CPRD as contributing up-to-standard data with a diagnosis of dementia and the number and proportion of these with a prescription for an antidementia or antipsychotic medication. We examined the prevalence of dementia diagnosis and prescribing by calendar quarter, and stratified by age, sex, and UK country (England, Scotland, Wales, or Northern Ireland). We investigated the use of antidementia drugs, alone and in combination, antipsychotics, antidepressants, anxiolytics, and hypnotics. The trend in the proportion of patients with a diagnosis of dementia, before and after the introduction of the UK National Dementia Strategy, was estimated using an interrupted time-series analysis. FINDINGS: 8 966 224 patients were identified in the CPRD whose most recent registration period overlapped the study period. Of these, 128 249 (1.4%) had a diagnosis of dementia before the end of the study period. The proportion of people diagnosed with dementia in the UK doubled from 0.42% (19 635 of 4 640 290 participants) in 2005 to 0.82% (25 925 of 3 159 754 participants) in 2015 (chi2 test for trend, p<0.0001), and the proportion of those who received antidementia medication increased from 15.0% (2942 of 19 635) to 36.3% (9406 of 25 925). The interrupted time-series analysis showed a significant acceleration in the rate of diagnosis of dementia after the introduction of the UK National Dementia Strategy (p<0.0001). There was a large reduction in antipsychotic drug prescription in dementia from 22.1% (4347 of 19 635) in 2005 to 11.4% (2943 of 25 925) by 2015. INTERPRETATION: Over the 10 years studied, there is evidence of a sustained positive change in diagnosis rates of dementia and in the quality of drug treatment provided to those diagnosed. The prescription of antidementia drugs more than doubled and the prescription of potentially hazardous antipsychotics halved after the introduction of national dementia strategies. These data support the formulation and delivery of national policy to improve the quality of care for people with dementia. FUNDING: None. PMID- 29253390 TI - Two days in Abidjan: finding the voice of francophone Africa. PMID- 29253389 TI - The effect of a reduction in alcohol consumption on blood pressure: a systematic review and meta-analysis. AB - BACKGROUND: Although it is well established that heavy alcohol consumption increases the risk of hypertension, little is known about the effect of a reduction of alcohol intake on blood pressure. We aimed to assess the effect of a reduction in alcohol consumption on change in blood pressure stratified by initial amount of alcohol consumption and sex in adults. METHODS: In this systematic review and meta-analysis, we searched MedLine, Embase, CENTRAL, and ClinicalTrials.gov from database inception up to July 13, 2016, for trials investigating the effect of a change of alcohol consumption on blood pressure in adults using keywords and MeSH terms related to alcohol consumption, blood pressure, and clinical trials, with no language restrictions. We also searched reference lists of identified articles and published meta-analyses and reviews. We included full-text articles with original human trial data for the effect of a change of alcohol consumption on blood pressure in adults, which reported a quantifiable change in average alcohol consumption that lasted at least 7 days and a corresponding change in blood pressure. We extracted data from published reports. We did random-effects meta-analyses stratified by amount of alcohol intake at baseline. All meta-analyses were done with Stata (version 14.1). For the UK, we modelled the effect of a reduction of alcohol consumption for 50% of the population drinking more than two standard drinks per day (ie, 12 g pure alcohol per drink). FINDINGS: 36 trials with 2865 participants (2464 men and 401 women) were included. In people who drank two or fewer drinks per day, a reduction in alcohol was not associated with a significant reduction in blood pressure; however, in people who drank more than two drinks per day, a reduction in alcohol intake was associated with increased blood pressure reduction. Reduction in systolic blood pressure (mean difference -5.50 mm Hg, 95% CI -6.70 to -4.30) and diastolic blood pressure (-3.97, -4.70 to -3.25) was strongest in participants who drank six or more drinks per day if they reduced their intake by about 50%. For the UK, the results would translate into more than 7000 inpatient hospitalisations and 678 cardiovascular deaths prevented every year. INTERPRETATION: Reducing alcohol intake lowers blood pressure in a dose-dependent manner with an apparent threshold effect. Implementation of effective alcohol interventions in people who drink more than two drinks per day would reduce the disease burden from both alcohol consumption and hypertension, and should be prioritised in countries with substantial alcohol-attributable risk. FUNDING: National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (NIH). PMID- 29253391 TI - Have you herd? Indirect flu vaccine effects are critically important. PMID- 29253392 TI - Promotion of healthy food and beverage purchases: are subsidies and consumer education sufficient? PMID- 29253393 TI - Causal system modelling of cervical cancer screening. PMID- 29253394 TI - Alcohol and blood pressure. PMID- 29253395 TI - 2017: a challenging year for public health in Europe. PMID- 29253396 TI - Let's get more population health out of health systems. PMID- 29253397 TI - Prevention of the causes of premature illness and death: making it happen. PMID- 29253398 TI - 1986: Ottawa and onwards. PMID- 29253399 TI - Advocacy for action and meaningful change in public health in 2017. PMID- 29253400 TI - Correction to Lancet Public Health 2017; 2: e4-5. PMID- 29253401 TI - Effect of a price discount and consumer education strategy on food and beverage purchases in remote Indigenous Australia: a stepped-wedge randomised controlled trial. AB - BACKGROUND: Evidence is mounting that price discounts can be effective in improving diet. This study examined the effectiveness of a 20% price discount on food and drink purchases with and without consumer education in remote Indigenous Australia. METHODS: A 20% discount on fruit, vegetables, water, and artificially sweetened soft drinks was applied for 24 weeks in 20 communities in remote Indigenous Australia where the community store was managed by the Arnhem Land Progress Aboriginal Corporation (ALPA) or Outback Stores (OBS) in a stepped-wedge randomised trial. Communities were randomly allocated to a fixed framework of five sets of four stratified by store association; ten stores (two in each set) were randomly assigned to receive consumer education. A store from each of the ALPA and OBS store groups (contained in separate opaque envelopes) was selected, and stores in turn continued to be consecutively allocated to the fixed store set framework, starting with the first store slot in the first store set, until all stores had been allocated. The effect of the discount on the weight of fruit and vegetables purchased (the primary endpoint) was assessed using weekly store sales data and mixed models per protocol. We did sensitivity analyses by repeating the analyses with the outliers included and repeating the analyses for the primary outcome measure removing each store one at a time. This trial was registered with Australian New Zealand Clinical Trials Registry, number ACTRN12613000694718. FINDINGS: Weekly store sales data on all food and drink products sold in 20 stores were collected from July 1, 2012, to Dec 28, 2014. Price discount alone was associated with a 12.7% (95% CI 4.1-22.1) increase in purchases in grams of fruit and vegetables combined (primary outcome), and a 19.8% (6.2-35.1) increase post discount (after vs before); an effect of 12 g and 18 g per capita per day. Sensitivity analyses did not modify the results for the primary outcome measure. INTERPRETATION: A 20% discount can only increase fruit and vegetable purchases to help protect against obesity and diet related disease to a certain extent. Large discounts might have a greater impact than small discounts. Creative merchandising approaches to consumer education could also be considered alongside fiscal interventions to achieve marked improvements in diet. FUNDING: Australian National Health and Medical Research Council. PMID- 29253403 TI - Public health is local. PMID- 29253404 TI - Health haves, health have nots, and heterogeneity in population health. PMID- 29253402 TI - Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: effectiveness and economic assessment for the National Cervical Screening Program. AB - BACKGROUND: Australia's National Cervical Screening Program currently recommends cytological screening every 2 years for women aged 18-69 years. Human papillomavirus (HPV) vaccination was implemented in 2007 with high population coverage, and falls in high-grade lesions in young women have been reported extensively. This decline prompted a major review of the National Cervical Screening Program and new clinical management guidelines, for which we undertook this analysis. METHODS: We did effectiveness modelling and an economic assessment of potential new screening strategies, using a model of HPV transmission, vaccination, natural history, and cervical screening. First, we evaluated 132 screening strategies, including those based on cytology and primary HPV testing. Second, after a recommendation was made to adopt primary HPV screening with partial genotyping and direct referral to colposcopy of women positive for HPV16/18, we evaluated the final effect of HPV screening after incorporating new clinical guidelines for women positive for HPV. Both evaluations considered both unvaccinated and vaccinated cohorts. FINDINGS: Strategies entailing HPV testing every 5 years and either partial genotyping for HPV16/18 or cytological co testing were the most effective. One of the most effective and cost-effective strategies comprised primary HPV screening with referral of women positive for oncogenic HPV16/18 direct to colposcopy, with reflex cytological triage for women with other oncogenic types and direct referral for those in this group with high grade cytological findings. After incorporating detailed clinical guidelines recommendations, this strategy is predicted to reduce cervical cancer incidence and mortality by 31% and 36%, respectively, in unvaccinated cohorts, and by 24% and 29%, respectively, in cohorts offered vaccination. Furthermore, this strategy is predicted to reduce costs by up to 19% for unvaccinated cohorts and 26% for cohorts offered vaccination, compared with the current programme. INTERPRETATION: Primary HPV screening every 5 years with partial genotyping is predicted to be substantially more effective and potentially cost-saving compared with the current cytology-based screening programme undertaken every 2 years. These findings underpin the decision to transition to primary HPV screening with partial genotyping in the Australian National Cervical Screening Program, which will occur in May, 2017. FUNDING: Department of Health, Australia. PMID- 29253405 TI - Beyond availability and affordability: how access to medicines affects non communicable disease outcomes. PMID- 29253406 TI - Smoke-free policy and child health. PMID- 29253407 TI - Can Healthy Cities be made really healthy? PMID- 29253408 TI - Complex systems and individual-level approaches to population health: a false dichotomy? PMID- 29253409 TI - Smart cities: health and safety for all. PMID- 29253410 TI - Child undernutrition: opportunities beyond the first 1000 days. PMID- 29253411 TI - Variation in life expectancy and mortality by cause among neighbourhoods in King County, WA, USA, 1990-2014: a census tract-level analysis for the Global Burden of Disease Study 2015. AB - BACKGROUND: Health outcomes are known to vary at both the country and local levels, but trends in mortality across a detailed and comprehensive set of causes have not been previously described at a very local level. Life expectancy in King County, WA, USA, is in the 95th percentile among all counties in the USA. However, little is known about how life expectancy and mortality from different causes of death vary at a local, neighbourhood level within this county. In this analysis, we estimated life expectancy and cause-specific mortality within King County to describe spatial trends, quantify disparities in mortality, and assess the contribution of each cause of death to overall disparities in all-cause mortality. METHODS: We applied established so-called garbage code redistribution algorithms and small area estimation methods to death registration data for King County to estimate life expectancy, cause-specific mortality rates, and years of life lost (YLL) rates from 152 causes of death for 397 census tracts from Jan 1, 1990, to Dec 31, 2014. We used the cause list developed for the Global Burden of Disease 2015 study for this analysis. Deaths were tabulated by age group, sex, census tract, and cause of death. We used Bayesian mixed-effects regression models to estimate mortality overall and from each cause. FINDINGS: Between 1990 and 2014, life expectancy in King County increased by 5.4 years (95% uncertainty interval [UI] 5.0-5.7) among men (from 74.0 years [73.7-74.3] to 79.3 years [79.1 79.6]) and by 3.4 years (3.0-3.7) among women (from 80.0 years [79.7-80.2] to 83.3 years [83.1-83.5]). In 2014, life expectancy ranged from 68.4 years (95% UI 66.9-70.1) to 86.7 years (85.0-88.2) for men and from 73.6 years (71.6-75.5) to 88.4 years (86.9-89.9) for women among census tracts within King County. Rates of YLL by cause also varied substantially among census tracts for each cause of death. Geographical areas with relatively high and relatively low YLL rates differed by cause. In general, causes of death responsible for more YLLs overall also contributed more significantly to geographical inequality within King County. However, certain causes contributed more to inequality than to overall YLLs. INTERPRETATION: This census tract-level analysis of life expectancy and cause-specific YLL rates highlights important differences in health among neighbourhoods in King County that are masked by county-level estimates. Efforts to improve population health in King County should focus on reducing geographical inequality, by targeting those health conditions that contribute the most to overall YLLs and to inequality. This analysis should be replicated in other locations to more fully describe fine-grained local-level variation in population health and contribute to efforts to improve health while reducing inequalities. FUNDING: John W Stanton and Theresa E Gillespie. PMID- 29253413 TI - 1986-2016: from Ottawa to Vienna. PMID- 29253414 TI - New evidence for the role of transportation in health. PMID- 29253415 TI - Health effects of the financial crisis: lessons from Greece. PMID- 29253416 TI - Balancing the cost-benefit equation for cervical cancer prevention: a moving target. PMID- 29253417 TI - Traumatic brain injury: an underappreciated public health issue. PMID- 29253418 TI - Total and cause-specific mortality before and after the onset of the Greek economic crisis: an interrupted time-series analysis. AB - BACKGROUND: Greece was one of the countries hit the hardest by the 2008 financial crisis in Europe. Yet, evidence on the effect of the crisis on total and cause specific mortality remains unclear. We explored whether the economic crisis affected the trend of overall and cause-specific mortality rates. METHODS: We used regional panel data from the Hellenic Statistical Authority to assess mortality trends by age, sex, region, and cause in Greece between January, 2001, and December, 2013. We used Eurostat data to calculate monthly age-standardised mortality rates per 100 000 inhabitants for each region. Data were divided into two subperiods: before the crisis (January, 2001, to August, 2008) and after the onset of the crisis (September, 2008, to December, 2013). We tested for changes in the slope of mortality by doing an interrupted time-series analysis. FINDINGS: Overall mortality continued to decline after the onset of the financial crisis ( 0.065, 95% CI -0.080 to -0.049), but at a slower pace than before the crisis ( 0.13, -0.15 to -0.10; trend difference 0.062, 95% CI 0.041 to 0.083; p<0.0001). The trend difference was more evident for females (0.087, 95% CI 0.064-0.11; p<0.0001) than for males (0.040, 0.013-0.066; p=0.007). Those aged at least 75 years experienced more negative effects (trend difference 0.056, 95% CI 0.042 to 0.071; p<0.0001) than did those aged 20-34 years, in whom mortality trends improved (-0.0074, -0.0089 to -0.0059; p<0.0001). Deaths by diseases of the circulatory system declined more slowly after the onset of compared with before the crisis (trend difference 0.043, 95% CI 0.024 to 0.063; p<0.0001), whereas deaths from vehicular accidents declined faster (-0.0062, -0.0090 to -0.0033; p<0.0001), most prominently among men aged 20-34 years (-0.0065, -0.0085 to 0.0044; p<0.0001). Conversely, deaths from suicides (trend difference 0.0021, 95% CI 0.00092-0.0033; p=0.002), diseases of the nervous system (0.0036, 0.0016 0.0056; p=0.002), and mental health problems (0.00073, 0.000047-0.0014 p=0.038) increased after the onset of the crisis. Also, deaths due to adverse events during medical treatment increased significantly after the onset of the crisis (trend difference 0.0020, 95% CI 0.0012-0.0028; p<0.0001). By comparing the expected values of the period after the onset of the crisis with extrapolated values based on the period before the crisis, we estimate that an extra 242 deaths per month occurred after the onset of the crisis. INTERPRETATION: Mortality trends have been interrupted after the onset of compared with before the crisis, but changes vary by age, sex, and cause of death. The increase in deaths due to adverse events during medical treatment might reflect the effects of deterioration in quality of care during economic recessions. FUNDING: None. PMID- 29253419 TI - Cost-effectiveness of the next generation nonavalent human papillomavirus vaccine in the context of primary human papillomavirus screening in Australia: a comparative modelling analysis. AB - BACKGROUND: First generation bivalent and quadrivalent human papillomavirus (HPV) vaccines have been introduced in most developed countries. A next generation nonavalent vaccine (HPV9) has become available, just as many countries are considering transitioning from cytology-based to HPV-based cervical screening. A key driver for the cost-effectiveness of HPV9 will be a reduction in screen detected abnormalities and surveillance tests. We aimed to evaluate the cost effectiveness of HPV9 in Australia, a country with HPV vaccination of both sexes that is transitioning to 5-yearly HPV-based screening. METHODS: We used Policy1 Cervix and HPV-ADVISE-two dynamic models of HPV transmission, vaccination, and cervical screening-to estimate the cost-effectiveness of HPV9 versus quadrivalent vaccine (HPV4), assuming lifelong vaccine protection, two vaccine doses, and that additional costs were incurred in girls only. Policy1-Cervix was used to estimate the lifetime risk of cervical cancer diagnosis and death. Probabilistic sensitivity analysis of the cost-effectiveness outcomes was done with both models, and results are presented as the median and 10th to 90th percentiles of simulation runs (referred to as 80% uncertainty intervals [UIs]). FINDINGS: Compared with cytology-based screening, HPV screening is predicted to reduce lifetime risk of cervical cancer diagnosis by 18% and of death by 20%, even in unvaccinated cohorts. Under base-case assumptions (lifelong protection, full efficacy at two doses), HPV4 will provide a further reduction in diagnosis of 54% and in death of 53% and HPV9 will provide a further reduction in both diagnosis and death of 11%, compared with cytology-based screening in unvaccinated cohorts. For HPV9 to remain a cost-effective alternative to HPV4, the incremental cost per dose in girls should not exceed a median of AUS$35.99 (80% UI 28.47-41.18) with Policy1-Cervix or AUS$22.74 (15.49-34.45) with HPV-ADVISE, at a willingness-to pay threshold of AUS$30 000 per quality-adjusted life-year. INTERPRETATION: Differing methods and assumptions led to some differences in the estimates produced by the two models. However, on the basis of median results, HPV9 will be a cost-effective alternative to HPV4 if the additional cost per dose is AUS$23-36 (US$18-28). These results will be important when determining the optimum price of the vaccine in Australia. FUNDING: National Health and Medical Research Council, Australia. PMID- 29253421 TI - DACA-where social policies meet public health. PMID- 29253420 TI - Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis. AB - INTRODUCTION: Traumatic brain injuries (TBI) are a major medical and socioeconomic problem. We aimed to estimate the hospital-based incidence, population-wide mortality, and the contribution of TBI to injury-related mortalities in European countries, and to provide European summary estimates for these indicators. METHODS: For this cross-sectional analysis, we obtained population data from Eurostat for hospital discharges and causes of death in European countries in 2012. Outcomes of interest were TBIs that required hospital admission or were fatal. We calculated age-adjusted hospital discharge rates and mortality rates and extrapolated data to 28 European Union countries and all 48 states in Europe. We present between-country comparisons, pooled age-adjusted rates, and comparisons with all-injury rates. FINDINGS: In 2012, 1 375 974 hospital discharges (data from 24 countries) and 33 415 deaths (25 countries) related to TBI were identified. The pooled age-adjusted hospital discharge rate was 287.2 per 100 000 (95% CI 232.9-341.5) and the pooled age-adjusted mortality rate was 11.7 per 100 000 (9.9-13.6). TBI caused 37% (95% CI 36-38) of all injury related deaths in the analysed countries. Extrapolating our results, we estimate 56 946 (95% CI 47 286-66 099) TBI-related deaths and 1 445 526 (1 172 996-1 717 039) hospital discharges occurred in 2012 in the European Union (population 508.5 million) and about 82 000 deaths and about 2.1 million hospital discharges in the whole of Europe (population 737 million). We noted substantial between-country differences. INTERPRETATION: TBI is an important cause of death and hospital admissions in Europe. The substantial between-country differences observed warrant further study and suggest that the true burden of TBI in Europe has not yet been captured. Rigorous epidemiological studies are needed to fully quantify the effect of TBI on society. Despite a great degree of consistency in data reporting across countries already being achieved, further efforts in this respect could improve the validity of between-country comparisons. FUNDING: European Union, FP7. PMID- 29253422 TI - Prevention of tuberculosis transmission through medical surveillance systems. PMID- 29253423 TI - Drivers of ethnic disparities in sexual health in the UK. PMID- 29253424 TI - Where next? The emergence of hypervirulent W meningococcus in the Netherlands. PMID- 29253412 TI - Availability and affordability of blood pressure-lowering medicines and the effect on blood pressure control in high-income, middle-income, and low-income countries: an analysis of the PURE study data. AB - BACKGROUND: Hypertension is considered the most important risk factor for cardiovascular diseases, but its control is poor worldwide. We aimed to assess the availability and affordability of blood pressure-lowering medicines, and the association with use of these medicines and blood pressure control in countries at varying levels of economic development. METHODS: We analysed the availability, costs, and affordability of blood pressure-lowering medicines with data recorded from 626 communities in 20 countries participating in the Prospective Urban Rural Epidemiological (PURE) study. Medicines were considered available if they were present in the local pharmacy when surveyed, and affordable if their combined cost was less than 20% of the households' capacity to pay. We related information about availability and affordability to use of these medicines and blood pressure control with multilevel mixed-effects logistic regression models, and compared results for high-income, upper-middle-income, lower-middle-income, and low-income countries. Data for India are presented separately because it has a large generic pharmaceutical industry and a higher availability of medicines than other countries at the same economic level. FINDINGS: The availability of two or more classes of blood pressure-lowering drugs was lower in low-income and middle income countries (except for India) than in high-income countries. The proportion of communities with four drug classes available was 94% in high-income countries (108 of 115 communities), 76% in India (68 of 90), 71% in upper-middle-income countries (90 of 126), 47% in lower-middle-income countries (107 of 227), and 13% in low-income countries (nine of 68). The proportion of households unable to afford two blood pressure-lowering medicines was 31% in low-income countries (1069 of 3479 households), 9% in middle-income countries (5602 of 65 471), and less than 1% in high-income countries (44 of 10 880). Participants with known hypertension in communities that had all four drug classes available were more likely to use at least one blood pressure-lowering medicine (adjusted odds ratio [OR] 2.23, 95% CI 1.59-3.12); p<0.0001), combination therapy (1.53, 1.13-2.07; p=0.054), and have their blood pressure controlled (2.06, 1.69-2.50; p<0.0001) than were those in communities where blood pressure-lowering medicines were not available. Participants with known hypertension from households able to afford four blood pressure-lowering drug classes were more likely to use at least one blood pressure-lowering medicine (adjusted OR 1.42, 95% CI 1.25-1.62; p<0.0001), combination therapy (1.26, 1.08-1.47; p=0.0038), and have their blood pressure controlled (1.13, 1.00-1.28; p=0.0562) than were those unable to afford the medicines. INTERPRETATION: A large proportion of communities in low-income and middle-income countries do not have access to more than one blood pressure lowering medicine and, when available, they are often not affordable. These factors are associated with poor blood pressure control. Ensuring access to affordable blood pressure-lowering medicines is essential for control of hypertension in low-income and middle-income countries. FUNDING: Population Health Research Institute, the Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research Strategy for Patient Oriented Research through the Ontario SPOR Support Unit, the Ontario Ministry of Health and Long-Term Care, pharmaceutical companies (with major contributions from AstraZeneca [Canada], Sanofi Aventis [France and Canada], Boehringer Ingelheim [Germany amd Canada], Servier, and GlaxoSmithKline), Novartis and King Pharma, and national or local organisations in participating countries. PMID- 29253425 TI - An argument for a common-sense global public health agenda. PMID- 29253426 TI - The migrant crisis and health systems: Hygeia instead of Panacea. PMID- 29253428 TI - Immunisation of older adults: where are the frail? PMID- 29253427 TI - Towards population-based health care: students as public health ambassadors. PMID- 29253429 TI - Effectiveness of Canada's tuberculosis surveillance strategy in identifying immigrants at risk of developing and transmitting tuberculosis: a population based retrospective cohort study. AB - BACKGROUND: In Canada, tuberculosis disproportionately affects the foreign-born population. The national tuberculosis medical surveillance programme aims to prevent these cases. Individuals referred for further in-country surveillance (referrals) have a history of active tuberculosis or have features of old, healed tuberculosis on chest radiograph; those not referred (non-referrals) do not undergo surveillance. We aimed to examine the risk of transmission arising from referrals versus non-referrals. METHODS: We did this population-based retrospective cohort study of foreign-born migrants (aged 15-64 years) to Alberta, Canada, between Jan 1, 2002, and Dec 31, 2013. We obtained information about year of arrival and country of citizenship from Immigration, Refugees and Citizenship Canada, and data for tuberculosis cases and their contacts from the Alberta Tuberculosis Registry. The outcome of interest was culture-positive pulmonary tuberculosis. We compared the incidence of pulmonary tuberculosis and the odds of transmission among referrals versus non-referrals. By use of conventional and molecular epidemiological techniques, we defined transmission as either a secondary case or a tuberculin skin-test (TST) conversion among close contacts. We used multivariate logistic regression to determine the independent association between referral for tuberculosis surveillance and transmission. FINDINGS: Between 2002 and 2013, there were 223 225 foreign-born migrants to Alberta, of whom 5500 (2%) were referrals and 217 657 (98%) were non-referrals. 3805 (69%) referrals and 115 226 (53%) non-referrals were from countries with a tuberculosis incidence of more than 150 per 100 000 populations, or sub-Saharan Africa. 234 foreign-born individuals were diagnosed with culture-positive pulmonary tuberculosis between Jan 1, 2004, and Dec 31, 2013. The incidence of culture-positive pulmonary disease was nine times higher in referrals (n=50) than all non-referrals (n=184; incidence rate ratio 9.1, 95% CI 6.7-12.5) and five times higher in referrals than non-referrals from high-risk countries (n=167; 5.0, 3.6-6.8). 71 total transmission events arose from the individuals with culture-positive pulmonary tuberculosis-three (4%) from referrals and 68 (96%) from non-referrals. No secondary cases were attributable to a referral source case, whereas 18 secondary cases were attributable to 11 different non-referral source cases. Three TST conversions were attributable to three different referral source cases compared with 50 conversions from 31 different non-referral source cases. That is, three (6%) referrals transmitted tuberculosis compared with 42 (22%) non-referrals (adjusted odds ratio of 0.19, 95% CI 0.054-0.66; p=0.009). INTERPRETATION: Despite a much higher incidence of pulmonary tuberculosis in referrals than non-referrals, referrals were 80% less likely to transmit tuberculosis. Rather than a focus on referrals, Canada could consider screening and treatment of latent tuberculosis in all migrants from high-risk countries-a group that accounted for 100% of secondary cases. FUNDING: Canadian Institutes of Health Research. PMID- 29253431 TI - Homeless people-their health and their children's health. PMID- 29253430 TI - Temporal associations between national outbreaks of meningococcal serogroup W and C disease in the Netherlands and England: an observational cohort study. AB - BACKGROUND: Since 2009, the incidence of meningococcal serogroup W disease has increased rapidly in the UK because of a single strain (the so-called original UK strain) belonging to the hypervirulent sequence type-11 clonal complex (cc11), with a variant outbreak strain (the so-called 2013 strain) emerging in 2013. Subsequently, the Netherlands has had an increase in the incidence of meningococcal serogroup W disease. We assessed the temporal and phylogenetic associations between the serogroup W outbreaks in the Netherlands and England, and the historical serogroup C outbreaks in both countries. METHODS: For this observational cohort study, we used national surveillance data for meningococcal serogroup W and serogroup C disease in the Netherlands and England for the epidemiological years (July to June) 1992-93 to 2015-16. We also did whole genome sequencing and core genome multilocus sequence typing (1546 loci) on serogroup W disease isolates from both countries for surveillance years 2008-09 to 2015-16. We used Poisson regression to compare the annual relative increase in the incidence of serogroup W and serogroup C between both countries. FINDINGS: In the Netherlands, the incidence of meningococcal serogroup W disease increased substantially in 2015-16 compared with 2014-15, with an incidence rate ratio of 5.2 (95% CI 2.0-13.5) and 11% case fatality. In England, the incidence increased substantially in 2012-13 compared with 2011-12, with an incidence rate ratio of 1.8 (1.2-2.8). The relative increase in the Netherlands from 2014-15 to 2015-16 was 418% (95% CI 99-1248), which was significantly higher than the annual relative increase of 79% (61-99) per year in England from 2011-12 to 2014-15 (p=0.03). Cases due to meningococcal serogroup W cc11 (MenW:cc11) emerged in 2012 13 in the Netherlands. Of 29 MenW:cc11 cases found up to 2015-16, 26 (90%) were caused by the 2013 strain. For both the current serogroup W outbreak and the historical serogroup C outbreak, the increase in incidence started several years later in the Netherlands than in England, the rate of increase was higher in the Netherlands, and age distributions were similar in both countries. INTERPRETATION: Given the historical similarities of meningococcal serogroup W with meningococcal serogroup C emergence, the rapid expansion of the MenW:cc11 2013 strain in the Netherlands, its high case fatality, and the availability of a safe and effective vaccine, urgent consideration is needed for public health interventions in the Netherlands and other affected countries to prevent further serogroup W cases and deaths. FUNDING: National Institute for Public Health and the Environment (Netherlands), Academic Medical Center (Netherlands), and Public Health England. PMID- 29253432 TI - Mental disorders in offspring of parents who have been homeless. PMID- 29253433 TI - Access to primary care and public health. PMID- 29253434 TI - Oil spill clean-up: a trade-off between human health and ecological restoration? PMID- 29253435 TI - Legalisation of non-medical cannabis in Canada: will supply regulations effectively serve public health? PMID- 29253436 TI - Non-attending patients in general practice. PMID- 29253437 TI - Transformation of health systems: contribution of population health intervention research. PMID- 29253438 TI - Social and implementation research for ending AIDS in Africa. PMID- 29253439 TI - Risk of psychiatric disorders in offspring of parents with a history of homelessness during childhood and adolescence in Denmark: a nationwide, register based, cohort study. AB - BACKGROUND: Children and adolescents from deprived backgrounds have high rates of psychiatric problems. Parental and social factors are crucial for children's healthy and positive development, but whether psychiatric morbidity is associated with parental social marginalisation is unknown. We aimed to analyse the association between mother's and father's history of homelessness and the offspring's risk of psychiatric disorders, including substance use disorder, during childhood and adolescence. METHODS: We did a nationwide, register-based cohort study of 1 072 882 children and adolescents aged 0-16 years, who were living or born in Denmark between Jan 1, 1999, and Dec 31, 2015. Parental homelessness was the primary exposure, data on which were obtained from the Danish Homeless Register. The Danish Civil Registration System was used to extract the population and link offspring to parental information, and the outcome, psychiatric disorders in the offspring, was obtained from the Danish Psychiatric Central Research Register and the Danish National Patient Register. We analysed the association between parental history of homelessness and risk of psychiatric disorders in offspring by survival analysis using Poisson regression and incidence rate ratios (IRRs), adjusted for year and offspring characteristics, and additionally adjusted for parental factors (age at offspring's birth and parental psychiatric disorders). FINDINGS: 17 238 (2%) offspring had either one or two parents with a history of homelessness, and 56 330 (5%) children and adolescents were diagnosed with any psychiatric disorder during the study period. The incidence of any psychiatric disorder was 15.1 cases per 1000 person-years (95% CI 14.4-15.8) in offspring with at least one parent with a history of homelessness, compared with 6.0 per 1000 person-years (95% CI 6.0-6.1) in those whose parents had no such history (IRR 2.5 [95% CI 2.3-2.7] for mother homeless, 2.3 [2.2-2.5] for father homeless, and 2.8 [2.4-3.2] for both parents homeless, after adjustment for year and offspring characteristics). This risk remained elevated after additional adjustment for factors including parental psychiatric disorders. IRRs in offspring were increased for most specific psychiatric disorders, with the highest risk for attachment disorder when both parents had a history of homelessness (IRR 32.5 [95% CI 24.6-42.9]) and substance use disorder when only the mother had a history of homelessness (6.9 [4.9-9.7]). In offspring whose mothers had a history of both homelessness and a psychiatric disorder, 35.9% (95% CI 27.1-44.8) had been diagnosed with a psychiatric disorder by the age of 15 years. INTERPRETATION: Parental homelessness was associated with an increased risk of psychiatric disorders in offspring during childhood and adolescence. These findings have important implications for public health and policy because they suggest a need for improvement in the support of socially marginalised families to help prevent psychiatric illness in offspring. FUNDING: University of Copenhagen, The Lundbeck Foundation Initiative for Integrated Psychiatric Research (iPSYCH). PMID- 29253440 TI - Demographic and practice factors predicting repeated non-attendance in primary care: a national retrospective cohort analysis. AB - BACKGROUND: Addressing the causes of low engagement in health care is a prerequisite for reducing health inequalities. People who miss multiple appointments are an under-researched group who might have substantial unmet health needs. Individual-level patterns of missed general practice appointments might thus provide a risk marker for vulnerability and poor health outcomes. We sought to ascertain the contributions of patient and practice factors to the likelihood of missing general practice appointments. METHODS: For this national retrospective cohort analysis, we extracted UK National Health Service general practice data that were routinely collected across Scotland between Sept 5, 2013, and Sept 5, 2016. We calculated the per-patient number of missed appointments from individual appointments and investigated the risk of missing a general practice appointment using a negative binomial model offset by number of appointments made. We then analysed the effect of patient-level factors (including age, sex, and socioeconomic status) and practice-level factors (including appointment availability and geographical location) on the risk of missing appointments. FINDINGS: The full dataset included information from 909 073 patients, of whom 550 083 were included in the analysis after processing. We observed that 104 461 (19.0%) patients missed more than two appointments in the 3 year study period. After controlling for the number of appointments made, patterns of non-attendance could be differentiated, with patients who were aged 16-30 years (relative risk ratio [RRR] 1.21, 95% CI 1.19-1.23) or older than 90 years (2.20, 2.09-2.29), and of low socioeconomic status (Scottish Index of Multiple Deprivation decile 1: RRR 2.27, 2.22-2.31) significantly more likely to miss multiple appointments. Men missed fewer appointments overall than women, but were somewhat more likely to miss appointments in the adjusted model (1.05, 1.04 1.06). Practice factors also substantially affected attendance patterns, with urban practices in affluent areas that typically have appointment waiting times of 2-3 days the most likely to have patients who serially miss appointments. The combination of both patient and practice factors to predict appointments missed gave a higher pseudo R2 value (0.66) than models using either group of factors separately (patients only R2=0.54; practice only R2=0.63). INTERPRETATION: The findings that both patient and practice characteristics contribute to non attendance of general practice appointments raise important questions for both the management of patients who miss multiple appointments and the effectiveness of existing strategies that aim to increase attendance. Addressing these issues should lead to improvements in provision of services and public health. FUNDING: Scottish Government Chief Scientist Office and Data Sharing and Linkage Service of the Scottish Government. PMID- 29253442 TI - The power of a treaty. PMID- 29253441 TI - Mental health indicators associated with oil spill response and clean-up: cross sectional analysis of the GuLF STUDY cohort. AB - BACKGROUND: Adverse mental health effects have been reported following oil spills but few studies have identified specific responsible attributes of the clean-up experience. We aimed to analyse the effects of the 2010 Deepwater Horizon (Gulf of Mexico) disaster on the mental health of individuals involved in oil spill response and clean-up. METHODS: We used data from the Gulf Long-term Follow-up Study, a cohort of workers and volunteers involved in oil spill clean-up after the Deepwater Horizon disaster. We included 8968 workers (hired after completing training for oil spill response and clean-up) and 2225 non-workers (completed training but were not hired) who completed a Patient Health Questionnaire-8 and four-item Primary Care PTSD Screen to assess for probable depression and post traumatic stress disorder (PTSD) indicators. Participants were recruited between March 28, 2011, and March 29, 2013. The mental health indicators were assessed at home visits done between May 12, 2011, and May 15, 2013. We used regression models to analyse the effect of potentially stressful job experiences, job type, and total hydrocarbon exposure on mental health indicators. FINDINGS: Oil spill response and clean-up work was associated with increased prevalence of depression (prevalence ratio [PR] 1.22, 95% CI 1.08-1.37) and PTSD (PR 1.35, 95% CI 1.07 1.71). Among workers, individuals who reported smelling oil, dispersants, or cleaning chemicals had an elevated prevalence of depression (1.56, 1.37-1.78) and PTSD (2.25, 1.71-2.96). Stopping work because of the heat was also associated with depression (1.37, 1.23-1.53) and PTSD (1.41, 1.15-1.74), as was working as a commercial fisherman before the spill (1.38, 1.21-1.57; and 2.01, 1.58-2.55, respectively). An increase in exposure to total hydrocarbons appeared to be associated with depression and PTSD, but after taking into account oil spill job experiences, only the association between the highest amount of total hydrocarbons and PTSD remained (1.75, 1.11-2.76). INTERPRETATION: Oil spill clean up workers with high amounts of total hydrocarbon exposure or potentially stressful job experiences had an increased prevalence of depression and PTSD. These findings provide evidence that response and clean-up work is associated with adverse psychological effects and suggest the need for mental health services both before and after the event. FUNDING: National Institutes of Health (NIH) Common Fund and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. PMID- 29253443 TI - Understanding the association between the WHO Framework Convention on Tobacco Control, adoption of tobacco control policies, and reduction in smoking prevalence. PMID- 29253444 TI - The Deferred Action for Childhood Arrivals programme: a quasi-experiment in giving hope to migrants. PMID- 29253445 TI - eSexual health interventions: promising, but more evidence needed. PMID- 29253446 TI - Record-linkage studies: dates and event-definitions matter hugely. PMID- 29253447 TI - Correction to Lancet Public Health 2017; 2: e133-40. PMID- 29253448 TI - Implementation of key demand-reduction measures of the WHO Framework Convention on Tobacco Control and change in smoking prevalence in 126 countries: an association study. AB - BACKGROUND: The WHO Framework Convention on Tobacco Control (WHO FCTC) has mobilised efforts among 180 parties to combat the global tobacco epidemic. This study examined the association between highest-level implementation of key tobacco control demand-reduction measures of the WHO FCTC and smoking prevalence over the treaty's first decade. METHODS: We used WHO data from 126 countries to examine the association between the number of highest-level implementations of key demand-reduction measures (WHO FCTC articles 6, 8, 11, 13, and 14) between 2007 and 2014 and smoking prevalence estimates between 2005 and 2015. McNemar tests were done to test differences in the proportion of countries that had implemented each of the measures at the highest level between 2007 and 2014. Four linear regression models were computed to examine the association between the predictor variable (the change between 2007 and 2014 in the number of key measures implemented at the highest level), and the outcome variable (the percentage point change in tobacco smoking prevalence between 2005 and 2015). FINDINGS: Between 2007 and 2014, there was a significant global increase in highest-level implementation of all key demand-reduction measures. The mean smoking prevalence for all 126 countries was 24.73% (SD 10.32) in 2005 and 22.18% (SD 8.87) in 2015, an average decrease in prevalence of 2.55 percentage points (SD 5.08; relative reduction 10.31%). Unadjusted linear regression showed that increases in highest-level implementations of key measures between 2007 and 2014 were significantly associated with a decrease in smoking prevalence between 2005 and 2015). Each additional measure implemented at the highest level was associated with an average decrease in smoking prevalence of 1.57 percentage points (95% CI -2.51 to -0.63, p=0.001) and an average relative decrease of 7.09% (-12.55 to -1.63, p=0.011). Controlling for geographical subregion, income level, and WHO FCTC party status, the per-measure decrease in prevalence was 0.94 percentage points (-1.76 to -0.13, p=0.023) and an average relative decrease of 3.18% (-6.75 to 0.38, p=0.079). This association was consistent across all three control variables. INTERPRETATION: Implementation of key WHO FCTC demand reduction measures is significantly associated with lower smoking prevalence, with anticipated future reductions in tobacco-related morbidity and mortality. These findings validate the call for strong implementation of the WHO FCTC in the WHO's Global Action Plan for the Prevention and Control of Non-communicable Diseases 2013-2020, and in advancing the UN's Sustainable Development Goal 3, setting a global target of reducing tobacco use and premature mortality from non communicable diseases by a third by 2030. FUNDING: Health Canada, Canadian Institutes of Health Research, Ontario Institute for Cancer Research and Canadian Cancer Society Research Institute. PMID- 29253449 TI - Health consequences of the US Deferred Action for Childhood Arrivals (DACA) immigration programme: a quasi-experimental study. AB - BACKGROUND: The effects of changes in immigration policy on health outcomes among undocumented immigrants are not well known. We aimed to examine the physical and mental health effects of the Deferred Action for Childhood Arrivals (DACA) programme, a 2012 US immigration policy that provided renewable work permits and freedom from deportation for a large number of undocumented immigrants. METHODS: We did a retrospective, quasi-experimental study using nationally representative, repeated cross-sectional data from the US National Health Interview Survey (NHIS) for the period January, 2008, to December, 2015. We included non-citizen, Hispanic adults aged 19-50 years in our analyses. We used a difference-in differences strategy to compare changes in health outcomes among individuals who met key DACA eligibility criteria (based on age at immigration and at the time of policy implementation) before and after programme implementation versus changes in outcomes for individuals who did not meet these criteria. We additionally restricted the sample to individuals who had lived in the USA for at least 5 years and had completed high school or its equivalent, in order to hold fixed two other DACA eligibility criteria. Our primary outcomes were self-reported overall health (measured on a 5 point Likert scale) and psychological distress (Kessler 6 [K6] scale), the latter was administered to a random subset of NHIS respondents. FINDINGS: Our final sample contained 14 973 respondents for the self-reported health outcome and 5035 respondents for the K6 outcome. Of these individuals, 3972 in the self-reported health analysis and 1138 in the K6 analysis met the DACA eligibility criteria. Compared with people ineligible for DACA, the introduction of DACA was associated with no significant change among DACA eligible individuals in terms of self-reported overall health (b=0.056, 95% CI 0.024 to 0.14, p=0.17) or the likelihood of reporting poor or fair health (adjusted odds ratio [aOR] 0.98, 95% CI 0.66-1.44, p=0.91). However, DACA eligible individuals experienced a reduction in K6 score compared with DACA ineligible individuals (adjusted incident risk ratio 0.78, 95% CI 0.56-0.95, p=0.020) and were less likely to meet screening criteria for moderate or worse psychological distress (aOR 0.62, 95% CI 0.41-0.93, p=0.022). INTERPRETATION: Economic opportunities and protection from deportation for undocumented immigrants, as offered by DACA, could confer large mental health benefits to such individuals. Health consequences should be considered by researchers and policy makers in evaluations of the broader welfare effects of immigration policy. FUNDING: None. PMID- 29253450 TI - The eSexual Health Clinic system for management, prevention, and control of sexually transmitted infections: exploratory studies in people testing for Chlamydia trachomatis. AB - BACKGROUND: Self-directed and internet-based care are key elements of eHealth agendas. We developed a complex online clinical and public health intervention, the eSexual Health Clinic (eSHC), in which patients with genital chlamydia are diagnosed and medically managed via an automated online clinical consultation, leading to antibiotic collection from a pharmacy. Partner notification, health promotion, and capture of surveillance data are integral aspects of the eSHC. We aimed to assess the safety and feasibility of the eSHC as an alternative to routine care in non-randomised, exploratory proof-of-concept studies. METHODS: Participants were untreated patients with chlamydia from genitourinary medicine clinics, untreated patients with chlamydia from six areas in England in the National Chlamydia Screening Programme's (NCSP) online postal testing service, or patients without chlamydia tested in the same six NCSP areas. All participants were aged 16 years or older. The primary outcome was the proportion of patients with chlamydia who consented to the online chlamydia pathway who then received appropriate clinical management either exclusively through online treatment or via a combination of online management and face-to-face care. We captured adverse treatment outcomes. FINDINGS: Between July 21, 2014, and March 13, 2015, 2340 people used the eSHC. Of 197 eligible patients from genitourinary medicine clinics, 161 accessed results online. Of the 116 who consented to be included in the study, 112 (97%, 95% CI 91-99) received treatment, and 74 of those were treated exclusively online. Of the 146 eligible NCSP patients, 134 accessed their results online, and 105 consented to be included. 93 (89%, 95% CI 81-94) received treatment, and 60 were treated exclusively online. In both groups, median time to collection of treatment was within 1 day of receiving their diagnosis. 1776 (89%) of 1936 NCSP patients without chlamydia accessed results online. No adverse events were recorded. INTERPRETATION: The eSHC is safe and feasible for management of patients with chlamydia, with preliminary evidence of similar treatment outcomes to those in traditional services. This innovative model could help to address growing clinical and public health needs. A definitive trial is needed to assess the efficacy, cost-effectiveness, and public health impact of this intervention. FUNDING: UK Clinical Research Collaboration. PMID- 29253452 TI - Ageing: a 21st century public health challenge? PMID- 29253451 TI - Acute myocardial infarction hospital admissions and deaths in England: a national follow-back and follow-forward record-linkage study. AB - BACKGROUND: Little information is available on how primary and comorbid acute myocardial infarction contribute to the mortality burden of acute myocardial infarction, the share of these deaths that occur during or after a hospital admission, and the reasons for hospital admission of those who died from acute myocardial infarction. Our aim was to fill in these gaps in the knowledge about deaths and hospital admissions due to acute myocardial infarction. METHODS: We used individually linked national hospital admission and mortality data for England from 2006 to 2010 to identify all primary and comorbid diagnoses of acute myocardial infarction during hospital stay and their associated fatality rates (during or within 28 days of being in hospital). Data were obtained from the UK Small Area Health Statistics Unit and supplied by the Health and Social Care Information Centre (now NHS Digital) and the Office of National Statistics. We calculated event rates (reported as per 100 000 population for relevant age and sex groups) and case-fatality rate for primary acute myocardial infarction diagnosed during the first physician encounter or during subsequent encounters, and acute myocardial infarction diagnosed only as a comorbidity. We also calculated what proportion of deaths from acute myocardial infarction occurred in people who had been in hospital on or within the 28 days preceding death, and whether acute myocardial infarction was one of the recorded diagnoses in such admissions. FINDINGS: Acute myocardial infarction was diagnosed in the first physician encounter in 307 496 (69%) of 446 744 admissions with a diagnosis of acute myocardial infarction, in the second or later physician encounter in 52 374 (12%) admissions, and recorded only as a comorbidity in 86 874 (19%) admissions. Patients with comorbid diagnoses of acute myocardial infarction had two to three times the case-fatality rate of patients in whom acute myocardial infarction was a primary diagnosis. 135 950 deaths were recorded as being caused by acute myocardial infarction as the underlying cause of death, of which 66 490 (49%) occurred in patients who were in hospital on the day of death or in the 28 days preceding death. AMI was the primary diagnosis in 32 695 (49%) of these 66 490 patients (27 678 [42%] diagnosed in the first physician encounter and 5017 [8%] in a second or subsequent encounter), was a comorbid diagnosis in 12 118 (18%), and was not mentioned at all in the remaining 21 677 (33%). The most common causes of admission in people who did not have an acute myocardial infarction diagnosis but went on to die of acute myocardial infarction as the underlying cause of death were other circulatory conditions (7566 [35%] of 21 677 deaths), symptomatic diagnoses including non-specific chest pain, dyspnoea and syncope (1368 [6%] deaths), and respiratory disorders (2662 [12%] deaths), mainly pneumonia and chronic obstructive airways disease. INTERPRETATION: As many acute myocardial infarction deaths occurring within 28 days of being in hospital follow a non-acute myocardial infarction admission as follow an acute myocardial infarction admission. These people are often diagnosed with other circulatory disorders or symptoms of circulatory disturbance. Further investigation is needed to establish whether there are symptoms and information that can be used to predict the risk of a fatal acute myocardial infarction in such patients, which can contribute to reducing the mortality burden of acute myocardial infarction. FUNDING: Wellcome Trust, Medical Research Council, Public Health England, National Institute for Health Research. PMID- 29253453 TI - The future burden of disability in the UK: the time for urgent action is now. PMID- 29253454 TI - Childhood trauma: psychiatry's greatest public health challenge? PMID- 29253455 TI - Tuberculosis control in New York City: the importance of vulnerable populations. PMID- 29253456 TI - Colorectal cancer screening in Australia. PMID- 29253457 TI - Brexit, the junior doctor contract, and medical student intentions. PMID- 29253458 TI - Long-term evaluation of benefits, harms, and cost-effectiveness of the National Bowel Cancer Screening Program in Australia: a modelling study. AB - BACKGROUND: No assessment of the National Bowel Screening Program (NBCSP) in Australia, which considers all downstream benefits, costs, and harms, has been done. We aimed to use a comprehensive natural history model and the most recent information about cancer treatment costs to estimate long-term benefits, costs, and harms of the NBCSP (2 yearly immunochemical faecal occult blood testing screening at age 50-74 years) and evaluate the incremental effect of improved screening participation under different scenarios. METHODS: In this modelling study, a microsimulation model, Policy1-Bowel, which simulates the development of colorectal cancer via both the conventional adenoma-carcinoma and serrated pathways was used to simulate the NBCSP in 2006-40, taking into account the gradual rollout of NBCSP in 2006-20. The base-case scenario assumed 40% screening participation (currently observed behaviour) and two alternative scenarios assuming 50% and 60% participation by 2020 were modelled. Aggregate year-by-year screening, diagnosis, treatment and surveillance-related costs, resource utilisation (number of screening tests and colonoscopies), and health outcomes (incident colorectal cancer cases and colorectal cancer deaths) were estimated, as was the cost-effectiveness of the NBCSP. FINDINGS: With current levels of participation (40%), the NBCSP is expected to prevent 92 200 cancer cases and 59 000 deaths over the period 2015-40; an additional 24 300 and 37 300 cases and 16 800 and 24 800 deaths would be prevented if participation was increased to 50% and 60%, respectively. In 2020, an estimated 101 000 programme-related colonoscopies will be done, associated with about 270 adverse events; an additional 32 500 and 49 800 colonoscopies and 88 and 134 adverse events would occur if participation was increased to 50% and 60%, respectively. The overall number needed to screen (NNS) is 647-788 per death prevented, with 52-59 colonoscopies per death prevented. The programme is cost-effective due to the cancer treatment costs averted (cost-effectiveness ratio compared with no screening at current participation, AUS$3014 [95% uncertainty interval 1807-5583] per life-year saved) in the cost-effectiveness analysis. In the budget impact analysis, reduced annual expenditure on colorectal cancer control is expected by 2030, with expenditure reduced by a cumulative AUS$1.7 billion, AUS$2.0 billion, and AUS$2.1 billion (2015 prices) between 2030 and 2040, at participation rates of 40%, 50%, and 60%, respectively. INTERPRETATION: The NBCSP has potential to save 83 800 lives over the period 2015-40 if coverage rates can be increased to 60%. By contrast, the associated harms, although an important consideration, are at a smaller magnitude at the population level. The programme is highly cost effective and within a decade of full roll-out, there will be reduced annual health systems expenditure on colorectal cancer control due to the impact of screening. FUNDING: Australia Postgraduate Award PhD Scholarship, Translational Cancer Research Network Top-up scholarship (supported by Cancer Institute NSW) and Cancer Council NSW. PMID- 29253459 TI - Fibrosis in Preeclamptic Placentas Is Associated with Stromal Fibroblasts Activated by the Transforming Growth Factor-beta1 Signaling Pathway. AB - Although fibrosis is one of the most prominent pathologic features of preeclamptic (PE) placentas, its mechanism remains largely unknown. Consistent with previous reports, we observed overexpression of collagen; actin, alpha2, smooth muscle, aorta; connective tissue growth factor; and fibronectin in PE placentas compared with control ones. To investigate the mechanism of fibrosis in PE placentas, placental fibroblasts were isolated from PE placentas or normal pregnancies at delivery. The expression of fibrosis-related factors in fibroblasts was evaluated by real-time RT-PCR, Western blotting, enzyme-linked immunosorbent assay, and gene microarrays. An in vitro collagen gel contraction assay was also performed. Fibroblasts isolated from PE placentas showed higher expression levels of fibrosis-related factors compared with those from control ones. Global gene expression profiling of PE fibroblasts was contrasted with that of control ones and indicated an intimate association with transforming growth factor-beta1 (TGFB1) signaling. Furthermore, the PE fibroblasts expressed abundant phosphorylated SMAD family member 2 and showed higher expression levels of target genes of TGFB1 signaling compared with the control ones. The PE fibroblasts also had a greater ability to contract compared with the control ones. Contractility also depended on TGFB1 signaling. Our results suggest that TGFB1 signaling is activated in the fibroblasts in PE placentas and that these active fibroblasts contribute to fibrosis. PMID- 29253462 TI - Reply. PMID- 29253461 TI - Mechanical Mitral Valve Thrombosis Secondary to Tinzaparin as an Anticoagulation Bridging Strategy. AB - For patients with mechanical heart valves, oral vitamin K antagonists effectively reduce the risk of valve thrombosis. Bridging strategies that use intravenous unfractionated heparin or subcutaneous low molecular weight heparin (LMWH) are required when reversal of anticoagulation is needed for invasive procedures or bleeding complications. There is limited data comparing anticoagulation efficacy between subtypes of LMWH and dosing regimens in this context. This report describes the case of a 45-year-old man with acute mechanical mitral valve thrombosis and suggests that the use of once daily dosing of subcutaneous tinzaparin may be an inappropriate anticoagulation bridging strategy. PMID- 29253460 TI - MicroRNA-31-3p Is Involved in Substance P (SP)-Associated Inflammation in Human Colonic Epithelial Cells and Experimental Colitis. AB - Substance P (SP) mediates colitis. SP signaling regulates the expression of several miRNAs, including miR-31-3p, in human colonocytes. However, the role of miR-31-3p in colitis and the underlying mechanisms has not been elucidated. We performed real-time PCR analysis of miR-31-3p expression in human colonic epithelial cells overexpressing neurokinin-1 receptor (NCM460 NK-1R) in response to SP stimulation and in NCM460 cells after IL-6, IL8, tumor necrosis factor (TNF)-alpha, and interferon-gamma exposure. Functions of miR-31-3p were tested in NCM460-NK-1R cells and the trinitrobenzene sulfonic acid (TNBS) and dextran sodium sulfate (DSS) models of colitis. Targets of miRNA-31-3p were confirmed by Western blot analysis and luciferase reporter assay. Jun N-terminal kinase inhibition decreased SP-induced miR-31-3p expression. miR-31-3p expression was increased in both TNBS- and DSS-induced colitis and human colonic biopsies from ulcerative colitis, compared with controls. Intracolonic administration of a miR 31-3p chemical inhibitor exacerbated TNBS- and DSS-induced colitis and increased colonic TNF-alpha, CXCL10, and chemokine (C-C motif) ligand 2 (CCL2) mRNA expression. Conversely, overexpression of miR-31-3p ameliorated the severity of DSS-induced colitis. Bioinformatic, luciferase reporter assay, and Western blot analyses identified RhoA as a target of miR-31-3p in NCM460 cells. Constitutive activation of RhoA led to increased expression of CCL2, IL6, TNF-alpha, and CXCL10 in NCM460-NK-1R cells on SP stimulation. Our results reveal a novel SP-miR 31-3p-RhoA pathway that protects from colitis. The use of miR-31-3p mimics may be a promising approach for colitis treatment. PMID- 29253464 TI - Reply. PMID- 29253463 TI - Outcomes in 937 Intermediate-Risk Patients Undergoing Surgical Aortic Valve Replacement in PARTNER-2A. AB - BACKGROUND: The Placement of Aortic Transcatheter Valves 2A (PARTNER-2A) randomized trial compared outcomes of transfemoral transcatheter and surgical aortic valve replacement (SAVR) in intermediate-risk patients with severe aortic stenosis. The purpose of the present study was to perform an in-depth analysis of outcomes after SAVR in the PARTNER-2A trial. METHODS: From January 2012 to January 2014, 937 patients underwent SAVR at 57 centers. Mean age was 82 +/- 6.7 years and 55% were men. Less-invasive operations were performed in 140 patients (15%) and concomitant procedures in 198 patients (21%). Major outcomes and echocardiograms were adjudicated by an independent events committee. Follow-up was 94% complete to 2 years. RESULTS: Operative mortality was 4.1% (n = 38, Society of Thoracic Surgeons predicted risk of mortality: 5.2% +/- 2.3%), observed to expected ratio (O/E) was 0.8, and in-hospital stroke was 5.4% (n = 51), twice expected. Aortic clamp and bypass times were 75 +/- 30 minutes and 104 +/- 46 minutes, respectively. Patients having severe prosthesis-patient mismatch (n = 260, 33%) had similar survival to patients without (p > 0.9), as did patients undergoing less-invasive SAVR (p = 0.3). Risk factors for death included cachexia (p = 0.004), tricuspid regurgitation (p = 0.01), coronary artery disease (p = 0.02), preoperative atrial fibrillation (p = 0.001), higher white blood cell count (p < 0.0001), and lower hemoglobin (p = 0.0002). CONCLUSIONS: In this adjudicated prospective study, SAVR in intermediate-risk patients had excellent results at 2 years. However, there were more in-hospital strokes than expected, most likely attributable to mandatory neurologic assessment after the procedure. No pronounced structural valve deterioration was found during 2-year follow-up. Continued long-term surveillance remains important. PMID- 29253465 TI - Reply. PMID- 29253466 TI - Inverted Lobes Have Satisfactory Functions Compared With Noninverted Lobes in Lung Transplantation. AB - BACKGROUND: To overcome the problem of small-for-size grafts in standard living donor lobar lung transplantation (LDLLT), we developed inverted LDLLT, in which a right lower lobe from 1 donor is implanted as a right graft and another right lower lobe from another donor is implanted as a left graft. We retrospectively analyzed the functions of inverted grafts vs noninverted grafts. METHODS: Between 2008 and 2015, 64 LDLLTs were performed. Included were 35 LDLLTs whose recipients were adults and monitored for more than 6 months without developing chronic lung allograft dysfunction. Among them, 65 implanted lobes were eligible for this analysis. There were 31 right lower lobes implanted as right grafts (right-to right group), 7 right lower lobes as inverted left grafts (right-to-left group), and 27 left lower lobes as left grafts (left-to-left group). We evaluated the graft forced vital capacity (G-FVC) and graft volume of the 65 lobes before and 6 months after LDLLT and compared them among the three groups. RESULTS: Preoperatively, G-FVC in the right-to-left group (1,050 mL) was comparable to that in the right-to-right group (1,177 mL) and better than that in the left-to left group (791 mL, p < 0.01). Six months after LDLLT, G-FVC in the right-to-left group (1,015 mL) remained comparable to that in the right-to-right group (1,001 mL) and better than that in the left-to-left group (713 mL, p = 0.047). The ratio of graft volume 6 months after LDLLT to the preoperative value was comparable. CONCLUSIONS: The functions of inverted grafts in inverted LDLLTs were satisfactory compared with those of noninverted grafts. PMID- 29253467 TI - Our greatest untapped resource. PMID- 29253468 TI - Inequality and intergenerational transmission of complex adversity. PMID- 29253469 TI - Seasonal immunisation against respiratory syncytial virus disease. PMID- 29253470 TI - Hypertension in children: from screening to primordial prevention. PMID- 29253471 TI - Ethics of public health surveillance: new guidelines. PMID- 29253472 TI - Mental health and global strategies to reduce NCDs and premature mortality. PMID- 29253473 TI - France: new government, new focus on medical deserts? PMID- 29253474 TI - Alcohol consumption, wealth, and health. PMID- 29253475 TI - Alcohol consumption, wealth, and health - Authors' reply. PMID- 29253476 TI - Mobile phone and handheld microscopes for public health applications. PMID- 29253478 TI - Prevalence of elevated blood pressure in children and adolescents in Africa: a systematic review and meta-analysis. AB - BACKGROUND: Despite substantial attention paid to the threat of elevated blood pressure in children and adolescents in high-income countries and the epidemic of hypertension in African adult populations, data on the burden of elevated blood pressure in African children and adolescents have not yet been synthesised. We did a systematic review and meta-analysis to provide estimates of the prevalence of elevated blood pressure and assess associated factors among children and adolescents in Africa. METHODS: We searched Embase, PubMed, African Journals Online, and African Index Medicus to identify articles published from Jan 1, 1996, to Feb 2, 2017, and searched the reference list of retrieved articles. Each study was independently reviewed for methodological quality. We used a random effects model to estimate the prevalence of elevated blood pressure across studies and heterogeneity (I2) was assessed via the chi2 test on Cochran's Q statistic. This review is registered with PROSPERO, number CRD42015019029. FINDINGS: We included 51 studies in qualitative synthesis and 25 in the meta analysis reporting data of a pooled sample of 54 196 participants aged 2-19 years. Study quality was high with only four medium-quality studies and no low quality studies. Prevalence of elevated blood pressure varied widely across studies (range 0.2-24.8%). The pooled prevalence of elevated blood pressure (systolic or diastolic blood pressure >=95th percentile) was 5.5% (95% CI 4.2 6.9), whereas that of slightly elevated blood pressure (systolic or diastolic blood pressure >=90th percentile and <95th percentile) was 12.7% (2.1-30.4). The prevalence of elevated blood pressure was largely associated with body-mass index (BMI), with a prevalence of elevated blood pressure six times higher in obese (30.8%, 95% CI 20.1-42.6) versus normal-weight children (5.5%, 3.1-8.4; p<0.0001). INTERPRETATION: This study suggests a high prevalence of elevated blood pressure among children and adolescents in Africa, with overweight and obesity being an important risk factor. Efforts to address this burden of elevated blood pressure in children and adolescents should mainly focus on primary prevention at the community level, by promoting healthy lifestyles and avoiding other cardiovascular risk factors, especially overweight and obesity. This study also stresses the need for more elaborate studies using uniform and reliable diagnostic methods to reliably map the burden of elevated blood pressure in children and adolescents in Africa. FUNDING: None. PMID- 29253479 TI - Prospects for public health in a sustainable NHS. PMID- 29253477 TI - The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis. AB - BACKGROUND: A growing body of research identifies the harmful effects that adverse childhood experiences (ACEs; occurring during childhood or adolescence; eg, child maltreatment or exposure to domestic violence) have on health throughout life. Studies have quantified such effects for individual ACEs. However, ACEs frequently co-occur and no synthesis of findings from studies measuring the effect of multiple ACE types has been done. METHODS: In this systematic review and meta-analysis, we searched five electronic databases for cross-sectional, case-control, or cohort studies published up to May 6, 2016, reporting risks of health outcomes, consisting of substance use, sexual health, mental health, weight and physical exercise, violence, and physical health status and conditions, associated with multiple ACEs. We selected articles that presented risk estimates for individuals with at least four ACEs compared with those with none for outcomes with sufficient data for meta-analysis (at least four populations). Included studies also focused on adults aged at least 18 years with a sample size of at least 100. We excluded studies based on high-risk or clinical populations. We extracted data from published reports. We calculated pooled odds ratios (ORs) using a random-effects model. FINDINGS: Of 11 621 references identified by the search, 37 included studies provided risk estimates for 23 outcomes, with a total of 253 719 participants. Individuals with at least four ACEs were at increased risk of all health outcomes compared with individuals with no ACEs. Associations were weak or modest for physical inactivity, overweight or obesity, and diabetes (ORs of less than two); moderate for smoking, heavy alcohol use, poor self-rated health, cancer, heart disease, and respiratory disease (ORs of two to three), strong for sexual risk taking, mental ill health, and problematic alcohol use (ORs of more than three to six), and strongest for problematic drug use and interpersonal and self-directed violence (ORs of more than seven). We identified considerable heterogeneity (I2 of >75%) between estimates for almost half of the outcomes. INTERPRETATION: To have multiple ACEs is a major risk factor for many health conditions. The outcomes most strongly associated with multiple ACEs represent ACE risks for the next generation (eg, violence, mental illness, and substance use). To sustain improvements in public health requires a shift in focus to include prevention of ACEs, resilience building, and ACE-informed service provision. The Sustainable Development Goals provide a global platform to reduce ACEs and their life-course effect on health. FUNDING: Public Health Wales. PMID- 29253480 TI - The costs of overweight. PMID- 29253481 TI - The end of AIDS? PMID- 29253482 TI - Privatisation and mortality in Russia. PMID- 29253483 TI - Burden of hip fracture on disability. PMID- 29253484 TI - Cost-effectiveness estimates: the need for complete reporting. PMID- 29253485 TI - Cost-effectiveness estimates: the need for complete reporting - Authors' reply. PMID- 29253486 TI - Correction to Lancet Public Health 2017; 2: e175-81. PMID- 29253488 TI - Progress and prospects for the control of HIV and tuberculosis in South Africa: a dynamical modelling study. AB - BACKGROUND: In September, 2016, South Africa adopted a policy of providing antiretroviral treatment to everyone infected with HIV irrespective of their CD4 cell count. Studies of universal treatment and expanded prevention of HIV differ widely in their projections of effects and the associated costs, so we did this analysis to attempt to find a consensus. METHODS: We used data on HIV from the Joint UN Programme on HIV and AIDS (UNAIDS) from 1988 to 2013 and from data from WHO on tuberculosis from 1980 to to 2013 to fit a dynamical model to time trends in HIV prevalence, antiretroviral therapy (ART) coverage, and tuberculosis notification rates in South Africa. We then used the model to estimate current trends and project future patterns in HIV prevalence and incidence, AIDS-related mortality, and tuberculosis notification rates, and we used data from the South African National AIDS Council to assess current and future costs under different combinations of treatment and prevention approaches. We considered two treatment strategies: the Constant Effort strategy, in which people infected with HIV continue to start treatment at the rate in 2016, and the Expanded Treatment and Prevention (ETP) strategy, in which testing rates are increased, treatment is started immediately after HIV is detected, and prevention programmes are expanded. FINDINGS: Our estimates show that HIV incidence among adults aged 15 years or older fell from 2.3% per year in 1996 to 0.65% per year in 2016, AIDS related mortality decreased from 1.4% per year in 2006 to 0.37% per year in 2016, and both continue to fall at a relative rate of 17% per year. Our model shows that maintenance of Constant Effort will have a substantial effect on HIV but will not end AIDS, whereas ETP could end AIDS by 2030, with incidence of HIV and AIDs-related mortality rates both at less than one event per 1000 adults per year. Under ETP the annual cost of health care and prevention will increase from US$2.3 billion in 2016 to $2.9 billion in 2018, then decrease to $1.7 billion in 2030 and $0.9 billion in 2050. Over the next 35 years, the expansion of treatment will avert an additional 3.8 million new infections, save 1.1 million lives, and save $3.2 billion compared with continuing Constant Effort up to 2050. Expansion of prevention, including provision of pre-exposure prophylaxis, condom distribution, and male circumcision, could avert a further 150 000 new infections, save 5000 lives, and cost an additional $5.7 billion compared with Constant Effort. INTERPRETATION: Our results suggest that South Africa is on track to reduce HIV incidence and AIDS-related mortality substantially by 2030, saving both lives and money. Success will depend on high rates of HIV testing, ART delivery and adherence, good patient monitoring and support, and data to monitor progress. FUNDING: None. PMID- 29253487 TI - Hospital costs in relation to body-mass index in 1.1 million women in England: a prospective cohort study. AB - BACKGROUND: Excess weight is associated with poor health and increased health care costs. However, a detailed understanding of the effects of excess weight on total hospital costs and costs for different health conditions is needed. METHODS: Women in England aged 50-64 years were recruited into the prospective Million Women Study cohort in 1996-2001 through 60 NHS breast cancer screening centres. Participants were followed up and annual hospital costs and admission rates were estimated for April 1, 2006, to March 31, 2011, in relation to body mass index (BMI) at recruitment, overall and for categories of health conditions defined by the International Classification of Diseases 10th revision chapter of the primary diagnosis at admission. Associations of BMI with hospital costs were projected to the 2013 population of women aged 55-79 years in England. FINDINGS: 1 093 866 women who provided information on height and weight, had a BMI of at least 18.5 kg/m2, and had no previous cancer at recruitment, were followed up for an average of 4.9 years from April 1, 2006 (12.3 years from recruitment), during which time 1.84 million hospital admissions were recorded. Annual hospital costs were lowest for women with a BMI of 20.0 kg/m2 to less than 22.5 kg/m2 (L567 per woman per year, 99% CI 556-577). Every 2 kg/m2 increase in BMI above 20 kg/m2 was associated with a 7.4% (7.1-7.6) increase in annual hospital costs. Excess weight was associated with increased costs for all diagnostic categories, except respiratory conditions and fractures. L662 million (14.6%) of the estimated L4.5 billion of total annual hospital costs among all women aged 55-79 years in England was attributed to excess weight (BMI >=25 kg/m2), of which L517 million (78%) arose from hospital admissions with procedures. L258 million (39%) of the costs attributed to excess weight were due to musculoskeletal admissions, mainly for knee replacement surgeries. INTERPRETATION: Excess body weight is associated with increased hospital costs for middle-aged and older women in England across a broad range of conditions, especially knee replacement surgery and diabetes. These results provide reliable up-to-date estimates of the health-care costs of excess weight and emphasise the need for investment to tackle this public health issue. FUNDING: Cancer Research UK; Medical Research Council; National Institute for Health Research. PMID- 29253489 TI - Burden of hip fracture using disability-adjusted life-years: a pooled analysis of prospective cohorts in the CHANCES consortium. AB - BACKGROUND: No studies have estimated disability-adjusted life-years (DALYs) lost due to hip fractures using real-life follow-up cohort data. We aimed to quantify the burden of disease due to incident hip fracture using DALYs in prospective cohorts in the CHANCES consortium, and to calculate population attributable fractions based on DALYs for specific risk factors. METHODS: We used data from six cohorts of participants aged 50 years or older at recruitment to calculate DALYs. We applied disability weights proposed by the National Osteoporosis Foundation and did a series of sensitivity analyses to examine the robustness of DALY estimates. We calculated population attributable fractions for smoking, body mass index (BMI), physical activity, alcohol intake, type 2 diabetes and parity, use of hormone replacement therapy, and oral contraceptives in women. We calculated summary risk estimates across cohorts with pooled analysis and random effects meta-analysis methods. FINDINGS: 223 880 men and women were followed up for a mean of 13 years (SD 6). 7724 (3.5%) participants developed an incident hip fracture, of whom 413 (5.3%) died as a result. 5964 DALYs (27 per 1000 individuals) were lost due to hip fractures, 1230 (20.6%) of which were in the group aged 75-79 years. 4150 (69.6%) DALYs were attributed to disability. Current smoking was the risk factor responsible for the greatest hip fracture burden (7.5%, 95% CI 5.2-9.7) followed by physical inactivity (5.5%, 2.1-8.5), history of diabetes (2.8%, 2.1-4.0), and low to average BMI (2.0%, 1.4-2.7), whereas low alcohol consumption (0.01-2.5 g per day) and high BMI had a protective effect. INTERPRETATION: Hip fracture can lead to a substantial loss of healthy life-years in elderly people. National public health policies should be strengthened to reduce hip fracture incidence and mortality. Primary prevention measures should be strengthened to prevent falls, and reduce smoking and a sedentary lifestyle. FUNDING: European Community's Seventh Framework Programme. PMID- 29253490 TI - Restricted feeding for 9h in the active period partially abrogates the detrimental metabolic effects of a Western diet with liquid sugar consumption in mice. AB - BACKGROUND: Obesity is a major public health concern that can result from diets high in fat and sugar, including sugar sweetened beverages. A proposed treatment for dietary-induced obesity is time-restricted feeding (TRF), which restricts consumption of food to specific times of the 24-hour cycle. Although TRF shows great promise to prevent obesity and the development of chronic disease, the effects of TRF to reverse metabolic changes and the development of NAFLD in animal models of a Western diet with sugary water consumption is not known. OBJECTIVE: The objective of the current study was to evaluate the role of TRF in the treatment of obesity and NAFLD through examination of changes in metabolic and histopathologic parameters. METHODS: To better understand the role of TRF in the treatment of obesity and NAFLD, we investigated the metabolic phenotype and NAFLD parameters in a mouse model of NAFLD in which obesity and liver steatosis are induced by a Western Diet (WD): a high-fat diet of lard, milkfat and Crisco with sugary drinking water. Mice were subjected to a short-term (4-weeks) and long-term (10-weeks) TRF in which food was restricted to 9h at night. RESULTS: Prior to TRF treatment, the WD mice had increased body mass, and exhibited less activity, and higher average daytime energy expenditure (EE) than chow fed mice. Approximately 4- and 10-weeks following TFR treatment, WD-TRF had moderate but not statistically significant weight loss compared to WD-ad libitum (WD-AL) mice. There was a modest but significant reduction in the inguinal adipose tissue weight in both WD-TRF groups compared to the WD-AL groups; however, there was no difference in epididymal and retroperitoneal adipose tissue mass or adipocyte size distribution. In contrast, the diet-induced increase in normalized liver tissue weight, hepatic triglyceride, and NAFLD score was partially abrogated in the 4-week WD-TRF mice, while systemic insulin resistance was partially abrogated and glucose intolerance was completely abrogated in the 10-week WD-TRF mice. Importantly, WD-induced metabolic dysfunction (substrate utilization, energy expenditure, and activity) was partially abrogated by 4- and 10-week TRF. CONCLUSIONS: Our results support the hypothesis that TRF aids in reducing the detrimental metabolic effects of consuming a WD with sugary drinking water but does not ameliorate obesity. PMID- 29253491 TI - Can bats sense smoke during deep torpor? AB - While torpor is a beneficial energy-saving strategy, it may incur costs if an animal is unable to respond appropriately to external stimuli, which is particularly true when it is necessary to escape from threats such as fire. We aimed to determine whether torpid bats, which are potentially threatened because they must fly to escape, can sense smoke and whether respiration rate (RR), heart rate (HR) and reaction time of torpid bats prior to and following smoke introduction is temperature-dependent. To test this we quantified RR and HR of captive Australian tree-roosting bats, Nyctophilus gouldi (n=5, ~10g), in steady state torpor in response to short-term exposure to smoke from Eucalyptus spp. leaves between ambient temperatures (Ta) of 11 and 23 degrees C. Bats at lower Ta took significantly longer (28-fold) to respond to smoke, indicated by a cessation of episodic breathing and a rapid increase in RR. Bats at lower Ta returned to torpor more swiftly following smoke exposure than bats at higher Ta. Interestingly, bats at Ta<15 degrees C never returned to thermoconforming steady state torpor prior to the end of the experimental day, whereas all bats at Ta>=15 degrees C did, as indicated by apnoeic HR. This shows that although bats at lower Ta took longer to respond, they appear to maintain vigilance and prevent deep torpor after the first smoke exposure, likely to enable fast escape. Our study reveals that bats can respond to smoke stimuli while in deep torpor. These results are particularly vital within the framework of fire management conducted at Ta<15 degrees C, as most management burns are undertaken during winter when bats will likely respond more slowly to fire cues such as smoke, delaying the time to escape from the fire. PMID- 29253492 TI - Modeling the interrelationships between brain activity and trait attention measures to predict individual differences in reaction times in children during a Go/No-Go task. AB - Many researchers are utilizing event-related potentials (ERPs) to better understand brain-behavior relationships across development. The present study demonstrates how structural equation modeling (SEM) techniques can be used to refine descriptions of brain-behavior relationships in a sample of neurotypical children. We developed an exploratory latent variable model in which trait measures of maturation and attention are related to neural processing and task behaviors obtained during a cued Go/No-Go task. Model findings are compared to results of traditional analysis techniques such as bivariate correlations. The data suggest that more sophisticated statistical approaches are beneficial to accurately interpreting the nature of brain-behavior relationships. PMID- 29253493 TI - An approach of the exact linearization techniques to analysis of population dynamics of the mosquito Aedes aegypti. AB - Dengue fever, chikungunya and zika are caused by different viruses and mainly transmitted by Aedes aegypti mosquitoes. These diseases have received special attention of public health officials due to the large number of infected people in tropical and subtropical countries and the possible sequels that those diseases can cause. In severe cases, the infection can have devastating effects, affecting the central nervous system, muscles, brain and respiratory system, often resulting in death. Vaccines against these diseases are still under development and, therefore, current studies are focused on the treatment of diseases and vector (mosquito) control. This work focuses on this last topic, and presents the analysis of a mathematical model describing the population dynamics of Aedes aegypti, as well as present the design of a control law for the mosquito population (vector control) via exact linearization techniques and optimal control. This control strategy optimizes the use of resources for vector control, and focuses on the aquatic stage of the mosquito life. Theoretical and computational results are also presented. PMID- 29253494 TI - Angiopoietin-2 (Ang-2) is a useful serum tumor marker for liver cancer in the Chinese population. AB - BACKGROUND: We estimated the diagnostic and prognostic value of serum angiopoietin-2 (Ang-2) in liver cancer patients. METHODS: Tissue Ang-2 was measured using immunohistochemistry (IHC). Cell localization of Ang-2 was tested using immunofluorescence (IF). Cell viability and apoptosis were evaluated using MTT and caspase3/7 assays, respectively. Colony-formation was measured using a soft agar assay. Serum Ang-2 was examined using enzyme-linked immunosorbent assay (ELISA) and Western blotting. RESULTS: Ang-2 was up-regulated in liver cancer compared to the levels in normal tissues. Serum Ang-2 concentrations were much higher in liver cancer patients than in healthy individuals and those with chronic liver disease (CLD). Inhibitions of Ang-2 using specific shRNA decreased cell proliferation. Serum Ang-2 decreased significantly after surgery. Serum Ang 2 was positively correlated with serum alpha-fetoprotein (AFP; R=0.375, P=0.005). Receiver operating characteristic (ROC) curves suggested that serum Ang-2 could be used with relatively high sensitivity and specificity in differentiating liver cancer patients from CLD patients or healthy controls, with corresponding AUC values of 0.742 and 0.924, respectively. Serum Ang-2 was negatively correlated with overall survival. Subgroup analysis also showed that Ang-2 retained its prognostic value in overall survival prediction in different risk subgroups. CONCLUSION: Serum Ang-2 may be a useful tumor marker in predicting liver cancer prognosis. PMID- 29253495 TI - MRP14 is dispensable for LPS-induced shock in BALB/c mice. AB - Myeloid-related protein (MRP) 14 and MRP8 are abundantly expressed by myeloid cells and are involved in various inflammatory disorders. Although accumulating evidence revealed the roles of MRP14 and MRP8 in inflammatory responses by using MRP14-knockout (KO) mice, the KO mice were only available in the C57BL/6 background. We established BALB/c-background MRP14-KO mice to examine if its biological functions are conserved in mice with a different genetic background. MRP14-KO BALB/c mice showed different phenotypes from the reported MRP14-KO C57BL/6 mice in terms of bone marrow cell response to LPS and peripheral leukocyte population. When an acute lethal dose of LPS was injected, the survival rate was not different between MRP14-KO and WT mice, which was also different from results previously reported on C57BL/6 mice. These results suggest that immunological functions of MRP14, and possibly also the associated molecule MRP8, are different between BALB/c and C57BL/6 mice, at least in the response to LPS. PMID- 29253496 TI - Development of an in vivo infection model to study Mouse papillomavirus-1 (MmuPV1). AB - Preclinical model systems to study multiple features of the papillomavirus life cycle are extremely valuable tools to aid our understanding of Human Papillomavirus (HPV) biology, disease progression and treatments. Mouse papillomavirus (MmuPV1) is the first ever rodent papillomavirus that can infect the laboratory strain of mice and was discovered recently in 2011. This model is an attractive model to study papillomavirus pathogenesis due to the ubiquitous availability of lab mice and the fact that this mouse species is easily genetically modifiable. Several other groups, including ours, have reported that MmuPV1-induced papillomas are restricted to T-cell deficient immunosuppressed mice. In our lab we showed for the first time that MmuPV1 causes skin cancers in UVB-irradiated immunocompetent animals. In this report we describe in detail the MmuPV1-UV infection model that can be adapted to study MmuPV1 biology in immunocompetent animals. PMID- 29253497 TI - Evaluation of clinical applicability of reverse transcription-loop-mediated isothermal amplification assay for detection and subtyping of Influenza A viruses. AB - BACKGROUND: Influenza A viruses (IAVs) have always remain a serious concern for the global economy and public health. A rapid, specific and sensitive detection method is always needed to control the influenza in its early stages by timely intervention of therapy and early clinical management. OBJECTIVES: To develop RT LAMP assays for detection of influenza A viruses, their further subtyping into seasonal (H1N1, H3N2) and novel pandemic H1N1 viruses and to evaluate clinical applicability of optimized RT-LAMP assays on patients' samples. STUDY DESIGN: In this study, we optimized RT-LAMP assay to detect IAVs by using primers against matrix gene and subtyping of IAVs was done by using primers against hemagglutinin gene. Optimized RT-LAMP assays were applied on clinical samples from patients having influenza like illness and results were compared with conventional one step RT-PCR and real-time RT-PCR. RESULTS: RT-LAMP assays successfully detected and differentiated IAVs into H1N1, H3N2 and pdm09/H1N1 subtypes. One hundred and sixty seven clinical swab samples from influenza suspected patients were taken and tested with RT-LAMP assay, detecting 30 (17.9%) samples positive for Influenza A virus. Out of 30 samples, 21, 7 and 2 were found positive for pdm09/H1N1, H3N2 and seasonal H1 respectively. Conventional one-step RT-PCR detected a total of 27 (16.2%) samples for influenza A and further subtyping showed 20 and 7 samples positive for pdm09/H1N1 and H3N2 virus respectively whereas none was found positive for seasonal H1N1. RT-LAMP assay demonstrated higher sensitivity (93.8%) than conventional RT-PCR (84.4%) for influenza A viruses detection in clinical samples. CONCLUSIONS: RT-LAMP assay is rapid, sensitive, specific and cost effective method for detection of influenza A viruses than conventional one-step RT-PCR and it can serve as a good alternate for diagnosis and surveillance studies during influenza outbreaks in resource limited setups of developing countries. PMID- 29253499 TI - Sex differences in the effects of nicotine on contextual fear extinction. AB - Anxiety and stress disorders occur at a higher rate in women compared to men as well as in smokers in comparison to non-smoker population. Nicotine is known to impair fear extinction, which is altered in anxiety disorders. However, nicotine differentially affects fear learning in men and women, which may mean that sex and nicotine-product use can interact to also alter fear extinction. For this study, we examined sex differences in the effects of acute and chronic nicotine administration on fear memory extinction in male and female C57BL/6J mice. To study the acute effects of nicotine, animals trained in a background contextual fear conditioning paradigm were administered nicotine (0.09, 0.18 or 0.36mg/kg) prior to extinction sessions. For chronic nicotine, animals continuously receiving nicotine (12.6, 18, or 24mg/kg/day) were trained in a background contextual fear conditioning paradigm followed by fear extinction sessions. Males exhibited contextual fear extinction deficits following acute and chronic nicotine exposure. Females also exhibited extinction deficits, but only at the highest doses of acute nicotine (0.36mg/kg) while chronic nicotine did not result in extinction deficits in female mice. These results suggest that sex mediates sensitivity to nicotine's effects on contextual fear memory extinction. PMID- 29253498 TI - Enhancing the antiviral potency of ER alpha-glucosidase inhibitor IHVR-19029 against hemorrhagic fever viruses in vitro and in vivo. AB - Targeting host functions essential for viral replication has been considered as a broad spectrum and resistance-refractory antiviral approach. However, only a few host functions have, thus far, been validated as broad-spectrum antiviral targets in vivo. ER alpha-glucosidases I and II have been demonstrated to be essential for the morphogenesis of many enveloped viruses, including members from four families of viruses causing hemorrhagic fever. In vivo antiviral efficacy of various iminosugar-based ER alpha-glucosidase inhibitors has been reported in animals infected with Dengue, Japanese encephalitis, Ebola, Marburg and influenza viruses. Herein, we established Huh7.5-derived cell lines with ER alpha glucosidase I or II knockout using CRISPR/Cas9 and demonstrated that the replication of Dengue, Yellow fever and Zika viruses was reduced by only 1-2 logs in the knockout cell lines. The results clearly indicate that only a partial suppression of viral replication can possibly be achieved with a complete inhibition of ER-alpha-glucosidases I or II by their inhibitors. We therefore explore to improve the antiviral efficacy of a lead iminosugar IHVR-19029 through combination with another broad-spectrum antiviral agent, favipiravir (T-705). Indeed, combination of IHVR-19029 and T-705 synergistically inhibited the replication of Yellow fever and Ebola viruses in cultured cells. Moreover, in a mouse model of Ebola virus infection, combination of sub-optimal doses of IHVR 19029 and T-705 significantly increased the survival rate of infected animals. We have thus proved the concept of combinational therapeutic strategy for the treatment of viral hemorrhagic fevers with broad spectrum host- and viral- targeting antiviral agents. PMID- 29253501 TI - Accuracy of Clinical Tests in Detecting Disk Herniation and Nerve Root Compression in Subjects With Lumbar Radicular Symptoms. AB - OBJECTIVES: To investigate the accuracy of 3 commonly used neurodynamic tests (slump test, straight-leg raise [SLR] test, femoral neurodynamic test) and 2 clinical assessments to determine radiculopathy (radiculopathy I, 1 neurologic sign; radiculopathy II, 2 neurologic signs corresponding to 1 specific nerve root) in detecting magnetic resonance imaging (MRI) findings (extrusion, subarticular nerve root compression, and foraminal nerve root compression). DESIGN: Validity study. SETTING: Secondary care. PARTICIPANTS: We included subjects (N=99; mean age, 58y; 54% women) referred for epidural steroid injection because of lumbar radicular symptoms who had positive clinical and MRI findings. Positive clinical findings included the slump test (n=67), SLR test (n=50), femoral neurodynamic test (n=7), radiculopathy I (n=70), and radiculopathy II (n=33). Positive MRI findings included extrusion (n=27), subarticular nerve compression (n=14), and foraminal nerve compression (n=25). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Accuracy of clinical tests in detecting MRI findings was evaluated using sensitivity, specificity, and receiver operating characteristics analysis with area under the curve (AUC). RESULTS: The slump test had the highest sensitivity in detecting extrusion (.78) and subarticular nerve compression (1.00), but the respective specificity was low (.36 and .38). Radiculopathy I was most sensitive in detecting foraminal nerve compression (.80) but with low specificity (.34). Only 1 assessment had a concurrent high sensitivity and specificity (ie, radiculopathy II) in detecting subarticular nerve compression (.71 and .73, respectively). The AUC for all tests in detecting extrusion, subarticular nerve compression, and foraminal nerve compression showed ranges of .48 to .60, .63 to .82, and .33 to .57, respectively. CONCLUSIONS: In general, the investigated neurodynamic tests or assessments for radiculopathy lacked diagnostic accuracy. The slump test was the most sensitive test, while radiculopathy II was the most specific test. Most interestingly, no relationship was found between any neurodynamic test and foraminal nerve compression (foraminal stenosis) as visualized on MRI. PMID- 29253500 TI - Carnosic acid prevents COL1A2 transcription through the reduction of Smad3 acetylation via the AMPKalpha1/SIRT1 pathway. AB - Carnosic acid (CA), a major bioactive component in rosemary extract, has many biological and pharmaceutical activities. Smad3 acetylation can regulate the transcription of type I alpha2 collagen (COL1A2), which is the major component of the extracellular matrix (ECM). The aim of the current study was to evaluate whether CA inhibits COL1A2 transcription via the reduction of Smad3 acetylation against liver fibrosis. The results showed that CA treatment significantly suppressed COL1A2 transcription and markedly decreased the deposition of ECM induced by dimethylamine (DMN) in rats. Importantly, the suppression of COL1A2 transcription following CA treatment depended on the reduction of Smad3 acetylation via the activation of Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase. SIRT1 siRNA increased the acetylation of Smad3 and blocked CA-down-regulated Smad3 deacetylation. Notably, CA-mediated AMP-activated protein kinase-alpha1 (AMPKalpha1) activation not only increased AMPKalpha1 phosphorylation but also increased SIRT1 expression, thus leading to a significant reduction in Smad3 acetylation. Furthermore, CA-mediated SIRT1 activation was inhibited by AMPKalpha1 siRNA. Collectively, CA can inhibit the transcription of COL1A2 through SIRT1-mediated Smad3 deacetylation, and the activation of SIRT1 by CA involves the AMPKalpha1/SIRT1 pathway in liver fibrosis. PMID- 29253502 TI - Hydrogen-rich saline protects against small-scale liver ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress. AB - AIM: Our research investigated the role of Hydrogen-rich saline (HRS) on the Endoplasmic reticulum stress (ERS) pathway and the effect of HRS on tissue injury in small Bama pig model of hepatic ischemia-reperfusion combined with partial hepatectomy. MAIN METHODS: Eighteen healthy Bama miniature pigs were randomly divided equally into three groups: Sham, IRI, and HRS. Laparoscopic technique was employed to establish the model of hepatic ischemia-reperfusion combined with partial hepatectomy. HRS (10mL/kg) was injected into the portal vein 10min before perfusion. Histological examinations of the liver tissues were performed after HE staining. Additionally, transmission electron microscopy was performed to detect liver cell microstructure. Real-time PCR, Western blotting, and immunohistochemical staining were performed to analyze various ERS molecules including GRP78, p-eIF2alpha, XBP-1s, Full-length ATF6alpha, p-JNK, ATF4, and CHOP. KEY FINDINGS: We observed that HRS visibly improved ischemia-reperfusion injury (IRI) by reducing various parameters of ERS stress as evidenced by down regulation of the mRNA as well as protein levels of GRP78, p-eIF2alpha, XBP-1s, p JNK, and CHOP, and reducing the cleavage of Full-length ATF6alpha. SIGNIFICANCE: Our study demonstrates that HRS protects the liver from IRI by inhibiting ERS. PMID- 29253503 TI - FACS isolation of live mouse eosinophils at high purity via a protocol that does not target Siglec F. AB - Flow cytometry protocols designed to identify mouse eosinophils typically target Siglec F, an alpha-2,3-sialic acid binding transmembrane protein expressed universally on cells of this lineage. While a convenient target, antibody mediated ligation of Siglec F induces eosinophil apoptosis, which limits its usefulness for isolations that are to be followed by functional and/or gene expression studies. We present here a method for FACS isolation which does not target Siglec F and likewise utilizes no antibodies targeting IL5Ralpha (CD125) or CCR3. Single cell suspensions are prepared from lungs of mice that were sensitized and challenged with Aspergillus fumigatus antigens; eosinophils were identified and isolated by FACS as live SSChi/FSChi CD11c-Gr1-/loMHCII- cells. This strategy was also effective for eosinophil isolation from the lungs of IL5tg mice. Purity by visual inspection of stained cytospin preparations and by Siglec F-diagnostic flow cytometry was 98-99% and 97-99%, respectively. Eosinophils isolated by this method (yield, ~4*106/mouse) generated high-quality RNA suitable for gene expression analysis. PMID- 29253504 TI - Lipid-mediated regulation of pore-forming activity of syringomycin E by thyroid hormones and xanthene dyes. AB - The effects of dipole modifiers, thyroid hormones (thyroxine and triiodothyronine) and xanthene dyes (Rose Bengal, phloxineB, erythrosin, eosinY and fluorescein) on the pore-forming activity of the lipopeptide syringomycin E (SRE) produced by Pseudomonas syringae were studied in a model bilayer. Thyroxine does not noticeably influence the steady-state number of open SRE channels (Nop), whereas triiodothyronine decreases it 10-fold at -50mV. Rose Bengal, phloxine B and erythrosin significantly increase Nop by 350, 100 and 70 times, respectively. Eosin Y and fluorescein do not practically affect the pore-forming activity of SRE. Recently, we showed that hormones decrease the dipole potential of lipid bilayers by approximately 60mV at 50MUM, while Rose Bengal, phloxine B and erythrosin at 2.5MUM reduce the membrane dipole potential by 120, 80 and 50mV, respectively. In the present study using differential scanning microcalorimetry, confocal fluorescence microscopy, the calcein release technique and measurements of membrane curvature elasticity, we show that triiodothyronine strongly affects the fluidity of model membranes: its addition leads to a significant decrease in the temperature and cooperativity of the main phase transition of DPPC, calcein leakage from DOPC vesicles, fluidization of solid domains in DOPC/DPPC liposomes, and promotion of lipid curvature stress. Thyroxine exerts a weaker effect. Xanthene dyes do not influence the phase transition of DPPC. Despite the decrease in the dipole potential, thyroid hormones modulate SRE channels predominantly via the elastic properties of the membrane, whereas the xanthene dyes Rose Bengal, phloxine B and erythrosine affect SRE channels via bilayer electrostatics. PMID- 29253506 TI - Evolution of emotional contagion in group-living animals. AB - Emotional contagion refers to an instantaneous matching of an emotional state between a subject and an object. It is believed to form one of the bases of empathy and it causes consistent group behavior in many animals. However, how this emotional process relates to group size remains unclear. Individuals with the ability of emotional contagion can instantaneously copy the emotion of another group member and can take relevant behavior driven by this emotion, but this would entail both cost and benefit to them because the behavior can be either appropriate or inappropriate depending on the situation. For example, emotional contagion may help them escape from a predator but sometimes induce mass panic. We theoretically study how these two aspects of emotional contagion affect its evolution in group-living animals. We consider a situation where an environmental cue sometimes indicates a serious event and individuals have to make a decision whether to react to them. We show that, as the group size increases, individuals with the ability of emotional contagion would evolutionarily weaken their sensitivity to environmental cues. We also show that a larger group yields a larger benefit to them through such evolutionary change. However, larger group size prevents the invasion of mutants with the ability of emotional contagion into the population of residents who react to environmental cues independently of other group members. These results provide important suggestions on the evolutionary relationship between emotional contagion and group living. PMID- 29253507 TI - Long negative feedback loop enhances period tunability of biological oscillators. AB - Oscillatory phenomena play a major role in organisms. In some biological oscillations such as cell cycles and heartbeats, the period can be tuned without significant changes in the amplitude. This property is called (period) tunability, one of the prominent features of biological oscillations. However, how biological oscillators produce tunable oscillations remains largely unexplored. We tackle this question using computational experiments. It has been reported that positive-plus-negative feedback oscillators produce tunable oscillations through the hysteresis-based mechanism. First, in this study, we confirmed that positive-plus-negative feedback oscillators generate tunable oscillations. Second, we found that tunability is positively correlated with the dynamic range of oscillations. Third, we showed that long negative feedback oscillators without any additional positive feedback loops can produce tunable oscillations. Finally, we computationally demonstrated that by lengthening the negative feedback loop, the Repressilator, known as a non-tunable synthetic gene oscillator, can be converted into a tunable oscillator. This work provides synthetic biologists with clues to design tunable gene oscillators. PMID- 29253505 TI - The TGFbeta pathway is a key player for the endothelial-to-hematopoietic transition in the embryonic aorta. AB - The embryonic aorta produces hematopoietic stem and progenitor cells from a hemogenic endothelium localized in the aortic floor through an endothelial to hematopoietic transition. It has been long proposed that the Bone Morphogenetic Protein (BMP)/Transforming Growth Factor beta (TGFbeta) signaling pathway was implicated in aortic hematopoiesis but the very nature of the signal was unknown. Here, using thorough expression analysis of the BMP/TGFbeta signaling pathway members in the endothelial and hematopoietic compartments of the aorta at pre hematopoietic and hematopoietic stages, we show that the TGFbeta pathway is preferentially balanced with a prominent role of Alk1/TgfbetaR2/Smad1 and 5 on both chicken and mouse species. Functional analysis using embryonic stem cells mutated for Acvrl1 revealed an enhanced propensity to produce hematopoietic cells. Collectively, we reveal that TGFbeta through the Alk1/TgfbetaR2 receptor axis is acting on endothelial cells to produce hematopoiesis. PMID- 29253508 TI - Roles of Cdc42 and Rac in Bergmann glia during cerebellar corticogenesis. AB - Bergmann glia (BG) are important in the inward type of radial migration of cerebellar granule neurons (CGNs). However, details regarding the functions of Cdc42 and Rac in BG for radial migration of CGN are unknown. To examine the roles of Cdc42 and Rac in BG during cerebellar corticogenesis, mice with a single deletion of Cdc42 or Rac1 and those with double deletions of Cdc42 and Rac1 under control of the glial fibrillary acidic protein (GFAP) promoter: GFAP Cre;Cdc42flox/flox (Cdc42-KO), GFAP-Cre;Rac1flox/flox (Rac1-KO), and GFAP-Cre; Cdc42flox/flox;Rac1flox/flox (Cdc42/Rac1-DKO) mice, were generated. Both Cdc42-KO and Rac1-KO mice, but more obviously Cdc42-KO mice, had disturbed alignment of BG in the Purkinje cell layer (PCL). We found that Cdc42-KO, but not Rac1-KO, induced impaired radial migration of CGNs in the late phase of radial migration, leading to retention of CGNs in the lower half of the molecular layer (ML). Cdc42 KO, but not Rac1-KO, mice also showed aberrantly aligned Purkinje cells (PCs). These phenotypes were exacerbated in Cdc42/Rac1-DKO mice. Alignment of BG radial fibers in the ML and BG endfeet at the pial surface of the cerebellum evaluated by GFAP staining was disturbed and weak in Cdc42/Rac1-DKO mice, respectively. Our data indicate that Cdc42 and Rac, but predominantly Cdc42, in BG play important roles during the late phase of radial migration of CGNs. We also report here that Cdc42 is involved in gliophilic migration of CGNs, in contrast to Rac, which is more closely connected to regulating neurophilic migration. PMID- 29253509 TI - Two Thyroid Stimulating Hormone assays correlated in clinical practice show disagreement in subclinical hypothyroidism patients. AB - : Thyroid Stimulating Hormone (TSH) levels are related to the pituitary gland's ability to detect thyroid hormone concentration. Many studies have analyzed the correlation between TSH and T4, demonstrating a complex system correlation. This complex system may vary among different TSH levels and patients. OBJECTIVES: The main purpose of this study is to assess the correlation and agreement of serum TSH measured with two assays in different settings. DESIGN & METHODS: We evaluated healthy individuals as well as subclinical or overt hypothyroid patients. Eighty participants had TSH levels measured by Cobas Roche Elecsys 600 (Roche Diagnostics) and Abbott Architect I 2000 (Abbott Diagnostics). The TSH methods correlations were established with Pearson's correlation, and the strength of the agreement was determined by the McBride scale. The paired Student's t-test was applied to evaluate TSH values from both methods. The one sample t-test was used to evaluate the difference between TSH values. The agreement was also assessed by a Bland-Altman plot. A regression analysis was applied to the correlation between TSH and T4. RESULTS: There was a significant difference in TSH values measured by the two methods (p<0.01). Our results demonstrated a poor correlation for TSH in the euthyroid (r: 0.888, p<0.01) and the subclinical hypothyroid (r:0.886, p<0.01) range. The Bland-Altman plot demonstrates that the majority of the TSH values fell between the lines of equality. There were few differences in the values in the normal upper range and slightly above that range (from a TSH: 3.25 to 6.36mUI/L). The level of correlation between TSH assays remains high in all scenarios for age (r>=0.951), BMI (r>=0.962), anti-TPO antibodies (r: 0.977) or levothyroxine use (r: 0.970). CONCLUSIONS: TSH measurement is essential to access thyroid function. Although the overall agreement between the methods is substantial, there was a poor agreement in the normal upper range and close above. The disagreement observed reinforces the difficulty in using different assays in clinical practice. The better correlation with fT4 and the reference range used by Cobas assay allowed the best clinical performance. PMID- 29253510 TI - How to best use high-sensitivity cardiac troponin in patients with suspected myocardial infarction. AB - High-sensitivity cardiac troponin (hs-cTn) assays have been used clinically by thousands of physicians in many countries throughout the world since their clinical introduction seven years ago. In the early diagnosis of myocardial infarction (MI), beyond doubt the most important indication of hs-cTn assays, these simple, inexpensive and highly reproducible tools complement detailed clinical assessment including chest pain characteristics and the electrocardiogram. Hs-cTn assays for the first time allowed the precise quantification of cardiomyocyte injury around the 99th percentile and thereby substantially increased the accuracy of MI detection from blood obtained at presentation to the emergency department (ED). Higher accuracy at ED presentation enabled the development and extensive validation of early hs-cTn-based diagnostic algorithms, which substantially reduced the time required for the safe rule-out or rule-in of MI. This review summarizes key principles underlying the safe and effective use of hs-cTn in the ED in patients with suspected MI. PMID- 29253512 TI - Cardiovascular indexes of threat impair responsiveness in situations of conflicting interests. AB - This research examined how situations in which self- and relationship-interests are misaligned can "get under the skin" to negatively impact cardiovascular and relationship processes. Interdependence theory was integrated with the biopsychosocial model of challenge and threat to better understand the biological processes that underlie relationship behavior in stressful circumstances. Couples engaged in a discussion in which one person (the discloser) revealed s/he had just gotten into her/his dream job or school and the other person (the responder) reacted to the news. Couples were randomly assigned to discuss living apart (self and relationship interests do not align) or together (self and relationships do align). Both responders and disclosers who discussed long-distance relationships and exhibited greater cardiovascular indexes of threat were behaviorally less responsive to their partners. Analyses also revealed that responders (regardless of conversation topic) who exhibited greater cardiovascular indexes of threat were less responsive. In addition to direct consequences for relationship processes and affective dynamics, these data implicate indirect pathways between relationship wellbeing and cardiovascular functioning. PMID- 29253511 TI - Recombinant growth differentiation factor 11 influences short-term memory and enhances Sox2 expression in middle-aged mice. AB - Previous evidence suggests that a significant decline in cognitive ability begins during middle-age and continues to deteriorate with increase in age. Recent work has demonstrated the potential rejuvenation impact of growth differentiation factor-11 (GDF-11) in aged mice. We carried out experiments to evaluate the impact of a single dose of recombinant (rGDF-11) on short-term visual and spatial memory in middle-aged male mice. On the novel object recognition task, we observed middle-aged mice treated rGDF-11 showed improved performance on the novel object recognition task. However, middle-aged mice did not show increased expression of phosphorylated-Smad2/3, a downstream effector of GDF-11. We noted however that the expression of the transcription factor, Sox2 was increased within the dentate gyrus. Our data suggest that a single injection of rGDF-11 contributes to improvements in cognitive function of middle-aged animals, which may be critical in the preservation of short-term memory capacity in old age. PMID- 29253514 TI - Implementing the DF4 in a robust model, allowing for enhanced comparison, prioritisation and grouping of Nanomaterials. AB - It is here shown how partial order can be used to provide a robust and consistent implementation of the DF4 approach which provides unbiased information enabling comparison and open up the possibility for grouping. The approach is based on few assumptions, works well with the data, can include different types of input parameters, and can provide fundamental information about the ranks of tested materials. It is shown that the materials in many cases are below one threshold within a tier, but above another threshold within the same tier. It is also observed that the ranks of the materials can differ between tiers, although this is less relevant for DF4 since parameters evaluation may be hierarchical. PMID- 29253513 TI - Neonatal hyperoxia promotes asthma-like features through IL-33-dependent ILC2 responses. AB - BACKGROUND: Premature infants often require oxygen supplementation and, therefore, are exposed to oxidative stress. Following oxygen exposure, preterm infants frequently develop chronic lung disease and have a significantly increased risk of asthma. OBJECTIVE: We sought to identify the underlying mechanisms by which neonatal hyperoxia promotes asthma development. METHODS: Mice were exposed to neonatal hyperoxia followed by a period of room air recovery. A group of mice was also intranasally exposed to house dust mite antigen. Assessments were performed at various time points for evaluation of airway hyperresponsiveness, eosinophilia, mucus production, inflammatory gene expression, and TH and group 2 innate lymphoid cell (ILC2) responses. Sera from term- and preterm-born infants were also collected and levels of IL-33 and type 2 cytokines were measured. RESULTS: Neonatal hyperoxia induced asthma-like features including airway hyperresponsiveness, mucus hyperplasia, airway eosinophilia, and type 2 pulmonary inflammation. In addition, neonatal hyperoxia promoted allergic TH responses to house dust mite exposure. Elevated IL-33 levels and ILC2 responses were observed in the lungs most likely due to oxidative stress caused by neonatal hyperoxia. IL-33 receptor signaling and ILC2s were vital for the induction of asthma-like features following neonatal hyperoxia. Serum IL-33 levels correlated significantly with serum levels of IL-5 and IL-13 but not IL-4 in preterm infants. CONCLUSIONS: These data demonstrate that an axis involving IL 33 and ILC2s is important for the development of asthma-like features following neonatal hyperoxia and suggest therapeutic potential for targeting IL-33, ILC2s, and oxidative stress to prevent and/or treat asthma development related to prematurity. PMID- 29253515 TI - Cancer-associated fibroblasts promote epithelial-mesenchymal transition and EGFR TKI resistance of non-small cell lung cancers via HGF/IGF-1/ANXA2 signaling. AB - The involvement of the tumor stromal cells in acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism remains unclear. In the present study, we investigated the role and mechanism underlying Cancer-associated fibroblasts (CAFs) in TKI resistance of NSCLCs. In vitro and in vivo experiments showed that HCC827 and PC9 cells, non-small cell lung cancer cells with EGFR-activating mutations, became resistant to the EGFR-TKI gefitinib when cultured with CAFs isolated from NSCLC tissues. Moreover, we showed that CAFs could induce epithelial-mesenchymal transition (EMT) phenotype of HCC827 and PC9 cells, with an associated change in the expression of epithelial to mesenchymal transition markers. Using proteomics-based method, we identified that CAFs significantly increased the expression of the Annexin A2 (ANXA2). More importantly, knockdown of ANXA2 completely reversed EMT phenotype and gefitinib resistance induced by CAFs. Furthermore, we found that CAFs increased the expression and phosphorylation of ANXA2 by secretion of growth factors HGF and IGF-1 and by activation of the corresponding receptors c-met and IGF-1R. Dual inhibition of HGF/c-met and IGF-1/IGF-1R pathways could significantly suppress ANXA2, and markedly reduced CAFs-induced EMT and gefitinib resistance. Taken together, these findings indicate that CAFs promote EGFR-TKIs resistance through HGF/IGF 1/ANXA2/EMT signaling and may be an ideal therapeutic target in NSCLCs with EGFR activating mutations. PMID- 29253516 TI - Inducible overexpression of endothelial proNGF as a mouse model to study microvascular dysfunction. AB - Impaired maturation of nerve growth factor precursor (proNGF) and its accumulation has been reported in several neurodegenerative diseases, myocardial infarction and diabetes. To elucidate the direct impact of proNGF accumulation identified the need to create a transgenic model that can express fully mutated cleavage-resistant proNGF. Using Cre-Lox technology, we developed an inducible endothelial-specific proNGF transgenic mouse (proNGFLoxp) that overexpresses GFP conjugated cleavage-resistant proNGF123 when crossed with VE-cadherin-CreERT2 (Cre). Expression of proNGF, inflammatory mediators, NGF and VEGF was evaluated by PCR, Western blot and immunohistochemistry. EC-proNGF overexpression was confirmed using colocalization of anti-proNGF within retinal vasculature. EC proNGF did not cause retinal neurotoxicity or marked glial activation at 4-weeks. Microvascular preparation from Cre-proNGF mice showed significant imbalance of proNGF/NGF ratio, enhanced expression of TNF-alpha and p75NTR, and tendency to impair TrkA phosphorylation compared to controls. EC-proNGF overexpression triggered mRNA expression of p75NTR and inflammatory mediators in both retina and renal cortex compared to controls. EC-proNGF expression induced vascular permeability including breakdown of BRB and albuminuria in the kidney without affecting VEGF level at 4-weeks. Histopathological changes were assessed after 8 weeks and the results showed that EC-proNGF triggered formation of occluded (acellular) capillaries, hall mark of retinal ischemia. EC-proNGF resulted in glomerular enlargement and kidney fibrosis, hall mark of renal dysfunction. We have successfully created an inducible mouse model that can dissect the contribution of autocrine direct action of cleavage-resistant proNGF on systemic microvascular abnormalities in both retina and kidney, major targets for microvascular complication. PMID- 29253517 TI - Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney. AB - Th1 and Th17 cells, T helper (Th) subtypes, are key inducers of renal fibrosis. The molecular mechanisms of their recruitment into the kidney, however, are not well understood. Here, we show that biglycan, a proteoglycan of the extracellular matrix, acting in its soluble form as a danger signal, stimulates autonomously the production of Th1 and Th17 chemoattractants CXCL10 and CCL20 in macrophages. In the presence of IFNgamma, biglycan synergistically stimulates CXCL9. In macrophages deficient for TLR2, TLR4, and their adaptor molecules MyD88 or TRIF, we identified highly selective mechanisms of biglycan-dependent Th1/17 chemoattraction. Thus, the expression of CXCL9 and CXCL10, common chemoattractants for CXCR3-positive Th1 and Th17 cells, is triggered in a biglycan-TLR4/TRIF-dependent manner. By contrast, biglycan induces CCL20 chemokine production, responsible for CCR6-positive Th17 cell recruitment, in a TLR2/4/MyD88-dependent manner. Importantly, at the onset of diabetes mellitus and lupus nephritis we provide evidence for biglycan-dependent recruitment of Th1 and Th17 cells, IFNgamma and IL-17 production, and development of albuminuria in mice lacking or overexpressing soluble biglycan. Furthermore, by genetic ablation of Cxcl10 we showed in vivo involvement of this chemokine in biglycan-dependent recruitment of Th1 and Th17 cells into the kidney. Finally, a positive correlation of biglycan and CXCL10/CXCL9 levels was detected in plasma from patients with diabetic nephropathy and lupus nephritis. Taken together, we identified biglycan as a novel trigger of Th1 and Th17 cell recruitment into the kidney and we postulate that interfering with biglycan/TLR/TRIF/MyD88-signaling might provide novel therapeutic avenues for renal fibrosis. PMID- 29253518 TI - Small leucine-rich proteoglycans and matrix metalloproteinase-14: Key partners? AB - Small leucine-rich proteoglycans (SLRPs) are important regulators of extracellular matrix assembly and cell signaling. They are a family of proteoglycans that are present in extracellular matrix and that share in common multiple repeats of a leucine-rich structural motif. SLRPs have been identified as inhibitors of cancer progression by affecting MMPs, especially MMP-14 activity. Lumican, a member of the SLRPs family, and its derived peptides were shown to possess anti-tumor activity. Interestingly, it was demonstrated recently that lumican interacts directly with the catalytic domain of MMP-14 and inhibits its activity. The aim of this review was to summarize the interactions between SLRPs and MMPs with a special interest to lumican. PMID- 29253519 TI - Transplastomic plants yield a multicomponent vaccine against cysticercosis. AB - Low cost vaccines against cysticercosis are needed to fight this parasitosis, especially in developing countries. Herein polycistron arrangements were designed to accomplish the simultaneous expression of multiple protective antigens from Taenia solium in the plant cell as an attractive biofactory and delivery vehicle of vaccines. Transplastomic plants carrying synthetic polycistrons were able to simultaneously express the KETc1, KETc7, KETc12, GK1, and TSOL18/HP6-Tsol antigens; which retained their antigenicity and ability to induce humoral responses in BALB/c mice. These clones may be useful for the production of low cost cysticercosis vaccine prototypes. PMID- 29253520 TI - Monaural-driven Functional Changes within and Beyond the Auditory Cortical Network: Evidence from Long-term Unilateral Hearing Impairment. AB - Long-term unilateral hearing impairment (UHI) results in changes in hearing and psychoacoustic performance that are likely related to cortical reorganization. However, the underlying functional changes in the brain are not yet fully understood. Here, we studied alterations in inter- and intra-hemispheric resting state functional connectivity (RSFC) in 38 patients with long-term UHI caused by acoustic neuroma. Resting-state fMRI data from 17 patients with left-sided hearing impairment (LHI), 21 patients with right-sided hearing impairment (RHI) and 21 healthy controls (HCs) were collected. We applied voxel-mirrored homotopic connectivity analysis to investigate the interhemispheric interactions. To study alterations in between-network interactions, we used four cytoarchitectonically identified subregions in the auditory cortex as "seeds" for whole-brain RSFC analysis. We found that long-term imbalanced auditory input to the brain resulted in (1) enhanced interhemispheric RSFC between the contralateral and ipsilateral auditory networks and (2) differential patterns of altered RSFCs with other sensory (visual and somatomotor) and higher-order (default mode and ventral attention) networks among the four auditory cortical subregions. These altered RSFCs within and beyond the auditory network were dependent on the side of hearing impairment. The results were reproducible when the analysis was restricted to patients with severe-to-profound UHI and patients with hearing impairment durations greater than 24 months. Together, we demonstrated that long term UHI drove cortical functional changes within and beyond the auditory network, providing empirical evidence for the association between brain changes and hearing disorders. PMID- 29253521 TI - Longitudinal Diffusion Tensor Imaging Revealed Nerve Fiber Alterations in Aspm Mutated Microcephaly Model Mice. AB - Autosomal recessive primary microcephaly-5 (MCPH5) is characterized by congenital microcephaly and is caused by the mutation in the abnormal spindle-like, microcephaly-associated (ASPM) gene. This study aimed to demonstrate a correlation between radiological and pathological analyses in evaluating postnatal brain development using MCPH5-model mice, ASPM ortholog (Aspm) knockout (KO) mice. In vivo MRI was performed at two time points (postnatal 3 weeks; P3W and P10W) and complementary histopathological analyses of brains were done at P5W and P13W. In the MRI analysis, Aspm KO mice showed significantly decreased brain sizes (average 8.6% difference) with larger ventricles (average 136.4% difference) at both time points. Voxel-based statistics showed that the fractional anisotropy (FA) values were significantly lower in Aspm KO mice in both the cortex and white matter at both time points. Developmental changes in the FA values were less remarkable in the Aspm KO mice, compared with the controls. Histometric analyses revealed that the ratios of the horizontal to the vertical neurites were significantly higher in cortical layers IV, V and VI, with a remarkable increase according to maturation at P13W in the control mice (average 12.7% difference between control and KO), whereas the ratio in layer VI decreased at P13W in the KO mice. The myelin basic protein positive ratio in the white matter significantly decreased in Aspm KO mice at P5W. These results suggest that temporal FA changes are closely correlated with pathological findings such as abnormal neurite outgrowth and differentiation, which may be applicable for analyzing diseased human brain development. PMID- 29253523 TI - Long non-coding RNAs in the regulation of skeletal myogenesis and muscle diseases. AB - Skeletal muscle myogenesis during development and the injury induced regeneration contribute to the formation and maintenance of muscle tissue. Emerging studies have demonstrated that long non-coding RNAs (lncRNAs) participate in the regulation of gene expression during skeletal myogenesis and their aberrant expression is associated with several muscular diseases. In this review, we summarize recent studies of lncRNAs in the regulation of myogenesis and muscle diseases with mechanistic characterization. These findings have greatly enhanced our understanding of gene regulatory mechanisms governing muscle formation and regeneration, which will eventually lead to novel therapeutics against various muscle diseases. PMID- 29253522 TI - Cancer, obesity and immunometabolism - Connecting the dots. PMID- 29253524 TI - Targeted co-delivery of epirubicin and NAS-24 aptamer to cancer cells using selenium nanoparticles for enhancing tumor response in vitro and in vivo. AB - Chemotherapy is a commonly used cancer treatment strategy that causes severe side effects by damaging normal tissue. Therefore, targeted drug delivery systems have attracted great attention for the treatment of cancer in recent years. In this study, epirubicin (EPI)-loaded-NAS-24-functionalized PEI-PEG-5TR1 aptamer coated selenium nanoparticles (SeNPs), known as the ENPPASe complex, were developed and used for targeted delivery of both EPI (anticancer drug) and NAS-24 aptamer (apoptosis induction agent) to MCF7 (human breast carcinoma cell) and C26 (murine colon carcinoma cell) cancer cells using 5TR1 aptamer as the target agent. The ENPPASe complex could significantly reduce the toxicity in non-target cells (HEPG2, hepatocellular carcinoma cell). As with the EPI alone, the ENPPASe complex could significantly reduce cell viability in the target cancer cells (MCF 7 and C26). In addition, the complex significantly reduced the tumor growth in cancer-bearing mice compared to EPI treatment alone. PMID- 29253525 TI - Crosstalk mechanisms in hepatoprotection: Thyroid hormone-docosahexaenoic acid (DHA) and DHA-extra virgin olive oil combined protocols. AB - Normal liver function includes a number of metabolic processes, secretion of cellular mediators and its role in immunobiology; these require a high energy supply, which is further enhanced under adverse conditions triggering hepatic disorders or injury due to the operation of counteracting mechanisms. Alterations in oxygen availability, such as ischemia-reperfusion (IR) leading to liver inflammation and high-fat diet (HFD)-induced hepatic steatosis, are noxious responses encountered in hepatic surgery and obesity, respectively. Several strategies have been developed to attenuate or prevent these disorders, including thyroid hormone (T3), docosahexaenoic acid (DHA) and extra virgin olive oil (EVOO). These hormetic agents that exert beneficial effects in the low dose range were shown to abrogate IR-induced liver injury effectively in the case of T3, DHA, or their combined administration, whereas DHA plus EVOO attenuate HFD induced hepatic steatosis, although they can induce adverse effects in other experimental settings. The use of combined hepatoprotective protocols (DHA + T3 or DHA + EVOO) using low doses or reduced supplementation periods is characterized by the stimulation of different types of molecular defensive mechanisms and similar signaling processes that exhibit synergism, thus constituting suitable experimental liver pharmacological preconditioning strategies with possible future clinical applications. PMID- 29253526 TI - Comparative analysis of high butanol tolerance and production in clostridia. PMID- 29253527 TI - The potential role of the novel hypothalamic neuropeptides nesfatin-1, phoenixin, spexin and kisspeptin in the pathogenesis of anxiety and anorexia nervosa. AB - Due to the dynamic development of molecular neurobiology and bioinformatic methods several novel brain neuropeptides have been identified and characterized in recent years. Contemporary techniques of selective molecular detection e.g. in situ Real-Time PCR, microdiffusion and some bioinformatics strategies that base on searching for single structural features common to diverse neuropeptides such as hidden Markov model (HMM) have been successfully introduced. A convincing majority of neuropeptides have unique properties as well as a broad spectrum of physiological activity in numerous neuronal pathways including the hypothalamus and limbic system. The newly discovered but uncharacterized regulatory factors nesfatin-1, phoenixin, spexin and kisspeptin have the potential to be unique modulators of stress responses and eating behaviour. Accumulating basic studies revelaed an intriguing role of these neuropeptides in the brain pathways involved in the pathogenesis of anxiety behaviour. Nesfatin-1, phoenixin, spexin and kisspeptin may also distinctly affect the energy homeostasis and modulate food intake not only at the level of hypothalamic centres. Moreover, in patients suffered from anxiety and anorexia nervosa a significant, sex-related changes in the plasma neuropeptide levels occurred. It should be therefore taken into account that the targeted pharmacomodulation of central peptidergic signaling may be potentially helpful in the future treatment of certain neuropsychiatric and metabolic disorders. This article reviews recent evidence dealing with the hypothetical role of these new factors in the anxiety-related circuits and pathophysiology of anorexia nervosa. PMID- 29253528 TI - Developing a Healing Environment for Broken Souls of Patients With Life Threatening Illnesses and Their Caregivers. AB - What a privilege it is to be able to touch those sacred spaces in the soul of each person that we encounter everyday. Patients with life-threatening illnesses can struggle with physical, emotional, and existential and spiritual concerns and the suffering of caregivers. A key goal of our supportive and palliative care teams is to alleviate patient and caregiver suffering. When caring for patients with advanced and terminal illness, the spirituality of each member of the palliative care team becomes a single collective spirituality or soul with common goals, values, and belonging, with a main goal of providing the best care for patients and caregivers in the alleviation of suffering. Embracing the spiritual care into our daily practice is a common effort and a service provided by each member of the team. Our role as members of the collective soul is to preserve human dignity and raise up the broken souls of patients living with life threatening illness by creating healing environments. PMID- 29253529 TI - Juvenile hormone-independent function of Kruppel homolog 1 in early development of water flea Daphnia pulex. AB - Elaborate regulation of insect metamorphosis is the consequence of physiological cooperation among multiple endocrine factors such as juvenile hormones (JHs) and ecdysteroids. Hormone-induced transcription factors play important roles in substantive interactions between hormonal signaling pathways. In insects, zinc finger transcription factor Kruppel homolog 1 (Kr-h1) is a key gene of the endocrine signaling pathway in which it is directly upregulated by JH receptor Methoprene-tolerant (Met) in the presence of JH and then regulates multiple downstream factors, including components of the ecdysteroid signaling pathway. Although JH also plays a role in various biological phenomena in other arthropod species, little is known about the molecular basis of the JH signaling pathway. Here we cloned Kr-h1 from a branchiopod crustacean, Daphnia pulex, (DappuKr-h1) and analyzed its expression profile and developmental function together with consideration of its relationship to the JH signaling pathway. We suggest that DappuKr-h1 lacks JH responsiveness and regulatory relationship with the JH receptor. Moreover our loss-of-function analysis revealed that maternal mRNA of DappuKr-h1 plays a critical role in early development independent from the JH signaling pathway. These findings provide insights about whether and how the JH signaling pathway influenced evolution, leading to greater diversity in phylum Arthropoda. PMID- 29253530 TI - Multiple signaling pathways convey central and peripheral signals to regulate pituitary function: Lessons from human and non-human primate models. AB - The anterior pituitary gland is a key organ involved in the control of multiple physiological functions including growth, reproduction, metabolism and stress. These functions are controlled by five distinct hormone-producing pituitary cell types that produce growth hormone (somatotropes), prolactin (lactotropes), adrenocorticotropin (corticotropes), thyrotropin (thyrotropes) and follicle stimulating hormone/luteinizing hormone (gonadotropes). Classically, the synthesis and release of pituitary hormones was thought to be primarily regulated by central (neuroendocrine) signals. However, it is now becoming apparent that factors produced by pituitary hormone targets (endocrine and non-endocrine organs) can feedback directly to the pituitary to adjust pituitary hormone synthesis and release. Therefore, pituitary cells serve as sensors to integrate central and peripheral signals in order to fine-tune whole-body homeostasis, although it is clear that pituitary cell regulation is species-, age- and sex dependent. The purpose of this review is to provide a comprehensive, general overview of our current knowledge of both central and peripheral regulators of pituitary cell function and associated intracellular mechanisms, focusing on human and non-human primates. PMID- 29253532 TI - Molecular phylogeny of Macrosiphini (Hemiptera: Aphididae): An evolutionary hypothesis for the Pterocomma-group habitat adaptation. AB - The aphid tribe Macrosiphini Wilson, 1910 (Hemiptera: Aphididae: Aphidinae) is one of the most controversial groups within Aphididae. We sequenced 2876 bp from one nuclear gene (EF-1alpha) and four mitochondrial genes (COI, tRNA + COII, 16S) from 107 terminal taxa representing 57 genera of Macrosiphini s.l. (the former Macrosiphini + genera in former Pterocommatini), including all of the recognized major genera and outgroups, and reconstructed the phylogeny using maximum likelihood, maximum parsimony and Bayesian methods. The stepping-stone method was used to evaluate various topological hypotheses regarding Macrosiphini s.l. and related groups. Our findings support both the monophyly of Macrosiphini s.l., and of two subordinate groups (Macrosiphini s.str and the Pterocomma-group), as well as the transfer of Capitophorus, Pleotrichophorus, Liosomaphis and Vesiculaphis to the Pterocomma-group-a result not previously suggested by analyses of molecular data. Ancestral state reconstructions for Macrosiphini and the Pterocomma-group suggest an ancestral primary host association with Rosales and Malpighiales, respectively, and other host associations within the tribe. Host transitions independently occurred more than once in Macrosiphini s.str. Furthermore, host-shifts between Rosales and Malpighiales may have occurred at least once in the Pterocomma-group. Additionally, the Macrosiphini phylogeny indicates that host associations are consistent also with host ecology, with a partitioning of aphid-host relationships into riparian and periaquatic habitats versus drier forest/shrubland habitats. PMID- 29253531 TI - RIFM fragrance ingredient safety assessment, 2-methylundecanal dimethyl acetal, CAS Registry Number 68141-17-3. PMID- 29253533 TI - The PM&R Journal Implements a Social Media Strategy to Disseminate Research and Track Alternative Metrics in Physical Medicine and Rehabilitation. AB - Implementation science is an evolving part of translating evidence into clinical practice and public health policy. This report describes how a social media strategy for the journal PM&R using metrics, including alternative metrics, contributes to the dissemination of research and other information in the field of physical medicine and rehabilitation. The primary goal of the strategy was to disseminate information about rehabilitation medicine, including but not limited to new research published in the journal, to health care professionals. Several different types of metrics were studied, including alternative metrics that are increasingly being used to demonstrate impact in academic medicine. A secondary goal was to encourage diversity and inclusion of the physiatric workforce enhancing the reputations of all physiatrists by highlighting their research, lectures, awards, and other accomplishments with attention to those who may be underrepresented. A third goal was to educate the public so that they are more aware of the field and how to access care. This report describes the early results following initiation of PM&R's coordinated social media strategy. Through a network of social media efforts that are strategically integrated, physiatrists and their associated institutions have an opportunity to advance their research and clinical agendas, support the diverse physiatric workforce, and educate the public about the field to enhance patient awareness and access to care. PMID- 29253535 TI - Optimizing combination of liver-enriched transcription factors and nuclear receptors simultaneously favors ammonia and drug metabolism in liver cells. AB - The HepG2 cell line is widely used in studying liver diseases because of its immortalization, but its clinical application is limited by its low expression of the urea synthesis key enzymes and cytochromes P450 (CYPs). On the basis of our previous work, we investigated the transcriptional regulation of arginase 1 (Arg1) and ornithine transcarbamylase (OTC) in HepG2 cells. We also screened for the optimal combination of liver enrichment transcription factors (LETFs) and xenobiotic nuclear receptors that can promote the expression of key urea synthases and five major CYPs in HepG2 cells. Thus, recombinant HepG2 cells were established. Results showed that C/EBPbeta, not C/EBPalpha, could upregulate expression of Arg1 and PGC1alpha and HNF4alpha cooperatively regulate the expression of OTC. The two optimal combinations C/EBPbeta+HNF4alpha+HNF6+PXR and C/EBPbeta+HNF4alpha+HNF6+CAR were selected. Compared with the control cells, the recombinant HepG2 cells modified by the two optimal combinations exhibited enhanced ammonia metabolism and CYP enzyme activity. Moreover, the HepG2/(C/EBPbeta+HNF4alpha+HNF6+PXR) cells more strongly reduced ammonia than any other combination tested in this study. The present work indicated that optimizing the combination of transcription factors will simultaneously promote hepatocyte ammonia metabolism and drug metabolism. The recombinant HepG2 liver cell line constructed by the optimal combination provided an improved alternative means for bioartificial liver applications and drug toxicity testing. PMID- 29253536 TI - By modulating alpha2beta1 integrin signalling, gastrin increases adhesion oF AGS GR gastric cancer cells. AB - Peritoneal metastasis is a major cause of recurrence of gastric cancer and integrins are key molecules involved in gastric cancer cells attachment to the peritoneum. The peptide hormone, gastrin, initially identified for its role in gastric acid secretion is also a growth factor for gastric mucosa. Gastrin has also been shown to contribute to gastric cancers progression. Here, we provide the first evidence that gastrin increases the adhesion of gastric cancer cells. Gastrin treatment induces the expression of alpha2 integrin subunit through a mechanism that involves the ERK pathway. We also observed in response to gastrin an increase in the amount of alpha2 integrin associated with beta1subunit. In addition, gastrin-stimulated cell adhesion was blocked with an anti-alpha2beta1 integrin neutralizing antibody. We also show that gastrin activates the integrin pathway via the phosphorylation of beta1 integrin by a Src family kinase. This mechanism may contribute to the enhancement of cell adhesion observed in response to gastrin since we found an inhibition of gastrin-mediated cell adhesion when cells were treated with a Src inhibitor. By regulating one of the key step of the metastatic process gastrin might contribute to increase the aggressive behaviour of human gastric tumours. PMID- 29253534 TI - Functional role for stable microtubules in lens fiber cell elongation. AB - The process of tissue morphogenesis, especially for tissues reliant on the establishment of a specific cytoarchitecture for their functionality, depends a balanced interplay between cytoskeletal elements and their interactions with cell adhesion molecules. The microtubule cytoskeleton, which has many roles in the cell, is a determinant of directional cell migration, a process that underlies many aspects of development. We investigated the role of microtubules in development of the lens, a tissue where cell elongation underlies morphogenesis. Our studies with the microtubule depolymerizing agent nocodazole revealed an essential function for the acetylated population of stable microtubules in the elongation of lens fiber cells, which was linked to their regulation of the activation state of myosin. Suppressing myosin activation with the inhibitor blebbistatin could attenuate the loss of acetylated microtubules by nocodazole and rescue the effect of this microtubule depolymerization agent on both fiber cell elongation and lens integrity. Our results also suggest that acetylated microtubules impact lens morphogenesis through their interaction with N-cadherin junctions, with which they specifically associate in the region where lens fiber cell elongate. Disruption of the stable microtubule network increased N-cadherin junctional organization along lateral borders of differentiating lens fiber cells, which was prevented by suppression of myosin activity. These results reveal a role for the stable microtubule population in lens fiber cell elongation, acting in tandem with N-cadherin cell-cell junctions and the actomyosin network, giving insight into the cooperative role these systems play in tissue morphogenesis. PMID- 29253538 TI - Anaesthesia management by residents does not alter the incidence of self-reported anaesthesia awareness: A teaching hospital-based propensity score analysis. AB - BACKGROUND: Intraoperative awareness during general anaesthesia is rare but represents one of the major anaesthesia-related complications. Intraoperative awareness may be a result of inadequate anaesthesia management. Therefore, the incidence can be related with the experience of anaesthetists. To assess whether the incidence of intraoperative awareness is related to anaesthetists' experience, we compared the incidence of self-reported intraoperative awareness between patients managed by anaesthesia residents or by experienced anaesthetists. METHODS: This is a retrospective review of an institutional registry containing 21,606 general anaesthesia cases. It was conducted with the ethics board approval. Propensity score analysis was used to generate a set of matched cases (resident managements) and controls (anaesthetist managements), yielding 4940 matched patient pairs. The incidence of self-reported intraoperative awareness compared as primary outcomes. Additionally, a multivariate logistic analysis in the entire cohort, using the incidence of self reported intraoperative awareness as dependent variable, was conducted to confirm the result of the primary outcome. RESULTS: In the unmatched population, contrary to our hypothesis, the incidence of self-reported intraoperative awareness was lower in resident management compared with anaesthetist management (1.1% vs. 1.5%, P=0.028). However, after propensity score matching, there was no difference in incidences of self-reported intraoperative awareness (1.5% vs. 1.3%, 0.38). The multivariate analysis confirmed the result of the primary outcome from the matched pair analysis and showed that ASA physical status (OR=1.40, 95% CI=1.08 to 1.81), emergency case (CI=2.05, 95% CI=1.40 to 3.00), and application of postoperative analgesia (OR=0.70, 95% CI=0.50 to 0.97) were independently associated with incidence of self-reported intraoperative awareness. CONCLUSION: In conclusion, when supervised by an anaesthetist, resident anaesthesia management is not more likely to result in complaints about intraoperative recall than anaesthetist management. PMID- 29253537 TI - Macrophages in keloid are potent at promoting the differentiation and function of regulatory T cells. AB - The mechanistic details of keloid formation are still not understood. Given that the immune system is engaged in skin lesion repair, we examined the CD14+ macrophages and CD3+ T cells in keloid tissues and in the normal skin. Compared to the normal skin, keloid tissues presented significantly elevated infiltration by CD14+ macrophages. Moreover, the transcription and protein expression of iNOS, IL-12, IL-10, and TGF-beta were significantly higher in keloid macrophages than in normal skin macrophages, in which the expression of M2-associated genes were further elevated compared to M1-associated genes in keloid. We also observed that keloid tissues presented higher infiltration by CD3+ T cells, of which the majority was CD4+ T cells. Notably, the frequency of Foxp3+ regulatory T cells (Tregs) in keloid tissues was significantly higher compared to that in the peripheral blood. Furthermore, macrophages from keloid tissues possessed potent capacity to induce Foxp3 expression in circulating CD3+ T cells. Together, this study suggested that macrophages in keloid tissues presented high activation status and were polarized toward the M2 subtype; moreover, these macrophages could promote Treg differentiation by upregulating Foxp3 expression. PMID- 29253539 TI - Continuous ultrasound guided erector spinae plane block for the management of chronic pain. PMID- 29253540 TI - Machine Learning in Detection of Undiagnosed Celiac Disease. PMID- 29253541 TI - Reply. PMID- 29253542 TI - Epigenetic biomarkers in gastrointestinal cancers: The current state and clinical perspectives. AB - Each year, almost 4.1 million people are diagnosed with gastrointestinal (GI) cancers. Due to late detection of this disease, the mortality is high, causing approximately 3 million cancer-related deaths annually, worldwide. Although the incidence and survival differs according to organ site, earlier detection and improved prognostication have the potential to reduce overall mortality burden from these cancers. Epigenetic changes, including aberrant promoter DNA methylation, are common events in both cancer initiation and progression. Furthermore, such changes may be identified non-invasively with the use of PCR based methods, in bodily fluids of cancer patients. These features make aberrant DNA methylation a promising substrate for the development of disease biomarkers for early detection, prognosis and for predicting response to therapy. In this article, we will provide an update and current clinical perspectives for DNA methylation alterations in patients with colorectal, gastric, pancreatic, liver and esophageal cancers, and discuss their potential role as cancer biomarkers. PMID- 29253543 TI - Expression, purification, and characterization of a novel amylosucrase from Neisseria subflava. AB - Amylosucrase (ASase) is a glucosyltransferase, which catalyzes the de novo synthesis of amylose-like polymers from sucrose. In the present study, ASase from Neisseria subflava (NsAS) was cloned, sequenced, and expressed in Escherichia coli. The production of NsAS was achieved by inducting gene expression with 0.2 mM isopropyl-beta-d-thiogalactopyranoside. The molecular mass of the Ni-NTA column purified NsAS analyzed by SDS-PAGE was determined to be 72 kDa. NsAS exhibited maximal activity at 45 degrees C and pH 8.0, and showed strong thermal stability at 40 degrees C with a half-life of 385 h. The reaction pattern of NsAS at [sucrose] range of 0.1-1.0 M showed that at 0.7 M of [sucrose], the production yield of insoluble linear alpha-(1,4)-glucans reached 24% maximum, and any further increase in [sucrose] resulted in a slight decrease in yield. Meanwhile, the production yield of turanose significantly increased from 16 to 29% by increasing [sucrose] from 0.1 to 1.0 M. The synthesized glucan had degrees of polymerization (DP); for 0.1, 0.4, 0.7, and 1.0 M sucrose, the DP values were 77, 49, 39, and 31 respectively. These results suggested that NsAS would be a promising candidate for food industrial production of linear alpha-(1,4)-glucans and turanose as a next generation sweetener. PMID- 29253544 TI - Egg white hybrid nanoflower (EW-hNF) with biomimetic polyphenol oxidase reactivity: Synthesis, characterization and potential use in decolorization of synthetic dyes. AB - In this study, for the first time, we described organic-inorganic hybrid nanoflowers using crude egg white as the organic component and copper (II) ions as the inorganic component under the mild conditions. The synthesized egg white inorganic hybrid nanoflowers (EW-hNFs) were characterized using SEM, EDX, XRD and FTIR analysis. The biomimetic Polyphenol/Peroxidase like activities of synthesized egg white-inorganic hybrid nanoflowers (EW-hNFs) were determined by using various phenolics with or without H2O2. Optimum pH and temperature, kinetic parameters, reusability, pH and thermal stability of EW-hNFs were also studied. The most noteworthy aspect of our study is that synthesized EW-hNFs which consist of only egg white proteins, showed polyphenol oxidase activity. Furthermore, potential use of the EW-hNFs in the discoloration of the some synthetic dyes was also evaluated. PMID- 29253545 TI - Study of chemical characteristics, gelation properties and biological application of calcium pectate prepared using apple or citrus pectin. AB - The most notable and unique property of pectin is the ability to form gel; thus, many biological applications of pectin are based on its gelation properties. Pectin isolated from different plant cell walls may differ in molecular structure and distribution pattern, which may result in different gelling and function properties. In this work, we investigated the chemical characteristics, gelation properties, and biological application of calcium pectate (CaP) prepared using apple (AP) or citrus pectin (CP). These two types of pectins exhibited similar molecular parameters and glycosidic bone structure; however, there was a difference in the composition proportion of single monosaccharide. In addition, it was found that it was relatively easier to form CaP beads with CP compared with AP. Moreover, CP exhibited a higher binding capability with Ca2+. The morphological study suggests that CP-CaP beads have a rough wrinkle structure on the surface, which might benefit mass transfer and cell proliferation. Moreover, although there are some differences in the viability and proliferation of cells encapsulated in the AP-CaP and CP-CaP beads, both can be used for cell encapsulation. PMID- 29253547 TI - Successive grafting of poly(hydroxyethyl methacrylate) brushes and melamine onto chitosan microspheres for effective Cu(II) uptake. AB - Cross-linked chitosan (CCS) microspheres tethered with melamine-conjugated poly(hydroxyethyl methacrylate) (PHEMA) brushes were synthesized by combination of surface-initiated atom transfer radical polymerization (ATRP) of HEMA and subsequent covalent immobilization of melamine onto the chain ends of PHEMA brushes. The as-synthesized CCS microsphere was used as a novel adsorbent for effective uptake of Cu(II) ions from aqueous solution. Success in each functionalization step was ascertained by SEM, ATR-FTIR and XPS characterization. Batch adsorption experimental results demonstrated that the adsorption equilibrium of Cu(II) ions on the melamine-grafted CCS microsphere was rapidly established within 20 min, and the adsorption process was found to be governed by intra-particle diffusion and chemisorption processes. The Langmuir-fitted maximum adsorption capacity of Cu(II) ions on the as-synthesized CCS microspheres was as high as circa 4.67 mmol L-1 (299 mg g-1). The calculated thermodynamic parameters revealed an endothermic and spontaneous adsorption process of Cu(II) ions on the melamine-grafted CCS microspheres. XPS spectra revealed that the adsorption mechanism was attributed to coordination (or chelation) interactions between amino (or hydroxyl) groups with cationic Cu(II) ions. PMID- 29253546 TI - Chitosan stabilized gold nanoparticle mediated self-assembled gliP nanobiosensor for diagnosis of Invasive Aspergillosis. AB - Diagnosis of Invasive Aspergillosis (IA) casused by Aspergillus fumigatus in miniaturized setting is challenging with great importance in human health. In this direction, we have designed a sensitive electrochemical nanobiosensor for diagnosis of IA through detecting the virulent glip target gene (glip-T) in a miniaturized experimetal setting. The sensor probe was fabricated using 1,6 Hexanedithiol and chitosan stabilized gold nanoparticle mediated self-assembly of glip probes (glip-P) on gold electrode. It was characterized by UV-visible spectroscopy, cyclic voltametry and electrochemical impedance spectroscopy. The ability of sensor to detect glip-T was analysed based on the hybridyzation reaction and the signal obtained using toluidine blue as indicator molecule. Analytical parameters were optimized in terms of glip-P concentration, temperature, reaction time, and concentration of toluidine blue. The biosensor showed the dynamic range between 1 * 10-14- 1 * 10-2 M with the detection limit of 0.32 +/- 0.01 * 10-14(RSD < 5.2%). The regeneration of biosensor was evaluated and the interference due to non-target oligonucleotide sequences was evaluated individualy as well as in mixed sample to validate the high selectivity of the designed sensor. The stability of the designed sensor was examined and practical applicability of biosensor was tested by detecting glip-T in real sample environment. PMID- 29253548 TI - Enzymatic degradation of beta-1,4-linked N-acetylglucosaminoglucan prepared from Thiothrix nivea. AB - Thiothrix nivea is a filamentous sulfur-oxidizing bacterium commonly found in activated sludge. The filament of this bacterium is covered with a sheath. The sheath is an assemblage of macromolecular glucosaminoglucan (GG), [4)-beta-d-GlcN (1 -> 4)-beta-d-Glc-(1 -> ]n, modified with an unidentified deoxy-sugar at position 3 of Glc. GG was obtained by dialysis after the partial hydrolysis of the sheath. The GG hydrogel was prepared by drying a GG solution. Then, the hydrogel was N-acetylated to prepare a stable hydrogel of N acetylglucosaminoglucan (NGG), [4)-beta-d-GlcNAc-(1 -> 4)-beta-d-Glc-(1 -> ]n. The NGG hydrogel was stable in phosphate buffer but was disrupted by lysozyme addition, suggesting that NGG is susceptible to lysozyme degradation and has potential for medical use. The GG solution was N-acetylated to prepare a NGG suspension to confirm enzymatic degradation. The turbidity of the NGG suspension was decreased by lysozyme addition. Sugars released in the reaction mixture were derivatized with 4-aminobenzoic acid ethyl ester (ABEE) followed by HPLC analysis. Two major derivatives were detected, and their concentration was increased in reverse proportion to the turbidity of the reaction mixture. The derivatives were identified as GlcNAc-Glc-GlcNAc-Glc-ABEE and GlcNAc-Glc-ABEE by mass spectrometry. Consequently, NGG was found to be degraded by lysozyme via a mechanism similar to that of chitin degradation. PMID- 29253549 TI - Voluntary breath-holding duration in healthy subjects with obesity: Role of peripheral chemosensitivity to carbon dioxide. AB - OBJECTIVE: The present study aimed to explore the peripheral chemoreflex sensitivity in healthy subjects with high body mass index (BMI). METHODS: We studied 26 healthy men with obesity and 23 healthy men without obesity. All participants performed the breath-holding test in the morning, and the single breath carbon dioxide (SB-CO2) test on the next day. RESULTS: The sensitivity of peripheral chemoreceptors to CO2 did not differ between two groups (P = .47). In contrast, the duration of breath-holding was significantly lower in participants with elevated BMI (40.6 +/- 10.5 s versus 47.2 +/- 8.7 s; P < .05). In the multifactor regression model, only differences in waist-to-hip ratio (WHR) and SB CO2 remained statistically significant (R2 for the model = 0.62, P < .001). CONCLUSIONS: The sensitivity of peripheral chemoreflex to CO2 was preserved in healthy men with obesity. The higher sensitivity of peripheral chemoreflex to CO2 and higher WHR were associated with a decrease in the duration of voluntary apnea in subjects with obesity. PMID- 29253550 TI - Long non-coding RNA H19 mediates mechanical tension-induced osteogenesis of bone marrow mesenchymal stem cells via FAK by sponging miR-138. AB - Bone marrow mesenchymal stem cells (BMMSCs) provide the biological basis for bone reconstruction. Mechanical tension stimulation as a potent modulator is able to promote osteogenic capability of BMMSCs. Long non-coding RNAs (LncRNAs) as competing endogenous RNAs (ceRNAs) for microRNAs, are postulated to regulate the osteogenic differentiation of stem cells. However, the mechanism how (whether) lncRNAs mediates tension-induced osteogenesis of BMSCs still remains poor understood. Here, human BMMSCs (hBMMSCs) were subjected to mechanical tension (10%, 0.5Hz). Results showed that mechanical tension could enhance osteogenic differentiation and increase H19 expression. H19 deficiency suppressed tension induced osteogenic differentiation, demonstrating that H19 could mediate tension induced osteogenesis in hBMMSCs. Besides, mechanical tension could suppress miR 138 expression, and down-regulated miR-138 promoted tension-induced osteogenesis in hBMMSCs. Luciferase reporter assays illustrated that H19 had binding sites with miR-138, and H19 deficiency increased miR-138 level, demonstrating that H19 may act as a ceRNA for miR-138 in hBMMSCs. Luciferase reporter assays also showed that miR-138 could target PTK2,a gene encoding focal adhesion kinase (FAK). Up regulated miR-138 impaired increased FAK expression induced by mechanical tension. The relationship among H19, miR-138 and FAK under tension condition was further studied. H19 deficiency inhibited FAK expression, which could be partly rescued by knock-downing miR-138. In addition, suppressed tension-induced osteogenic differentiation in H19 defective cells was partly rescued by miR-138 knockdown. Taken together, this study indicated that H19 is a positive regulator in tension-induced osteogenesis of hBMMSCs through acting as a ceRNA for miR-138 and then up-regulating downstream FAK. PMID- 29253551 TI - Pain and Fatigue Variability Patterns Distinguish Subgroups of Fibromyalgia Patients. AB - : The current study examined between- and within-subject variability in pain related symptoms as predictors of pain and fatigue, and identified patient subgroups on the basis of symptom variability characteristics. Two hundred fifty six fibromyalgia (FM) patients completed daily diaries up to a period of 154 days and reported on symptoms of pain intensity, pain unpleasantness, fatigue, anxiety, and depressed mood. Measures of health status, quality of life, and somatic symptoms were obtained at baseline, and hierarchical linear modeling and cluster analyses were used. Significant intra- and interindividual variability in daily FM symptoms was observed. Higher levels of pain were associated with greater fluctuations in pain unpleasantness, fatigue, and depressed mood. Similar effects were observed for fatigue and individual variability in anxiety also emerged as a robust predictor. Three FM subgroups were revealed: low variability in symptoms (cluster 1), high symptom variability (cluster 2), and a mixed variability group characterized by low fluctuation in pain unpleasantness; moderate pain, fatigue, and depressed mood variability; and high anxiety variability (cluster 3). Cluster 3 exhibited lower social functioning and higher levels of pain, compared with cluster 1. These findings support the dynamic nature of FM pain and suggest the presence of FM subgroups on the basis of variation in mood and pain symptomatology. PERSPECTIVE: FM patients show significant intra- and interindividual variability in pain, mood, and fatigue. Subgroups in mood and pain-related variability emerged, with phenotypic clusters differing across levels of pain intensity and social functioning. Better understanding of the processes affecting pain variability may facilitate targeted treatments for the control of pain. PMID- 29253552 TI - Risk of Exposure to Zika Virus and Impact on Cord Blood Banking and Adult Unrelated Donors in Hematopoietic Cell Transplantation: The Canadian Blood Services Experience. AB - Zika virus has emerged as a potential threat to the Canadian blood supply system. Stem cell donors within Canadian Blood Services' Cord Blood Bank (CBB) and OneMatch Stem Cell and Marrow Network (OM) now undergo screening measures designed to reduce the risk of Zika virus transmission. The impact these screening measures have on cord blood and unrelated adult stem cell donations is currently unknown. Among 146 donor workups initiated by OM between July 2016 and May 2017, 102 were completed and 44 workups were canceled. There were 17 potential donors (11.6%) with a risk of Zika virus exposure identified by the donor questionnaire (13 completed, 4 canceled workups). None of the workups involved a donor diagnosed with confirmed Zika virus within the past 6 months. Only 1 of the 44 canceled workups (and only 1 of 4 cases with a risk of Zika transmission) was canceled because of the risk of Zika transmission, and a backup donor was selected. Canadian Blood Services' CBB identified 25 of 875 cord blood units (2.9%) from women who donated their infants' cord blood and underwent screening that otherwise met the initial cell number thresholds for banking and had at least 1 risk factor for exposure to Zika virus. No women were diagnosed with Zika virus at any point of their pregnancy. All 25 units were discarded. Unrelated donors at OM have a higher incidence of a risk of exposure to Zika virus compared with cord blood donors. Only rarely did transplant centers cancel donor workups due to potential Zika virus exposure. The impact of screening for Zika virus exposure risk on cord blood banking was minor. Continued vigilance and surveillance is recommended. PMID- 29253553 TI - The Risk of TB in Patients With Type 2 Diabetes Initiating Metformin vs Sulfonylurea Treatment. AB - BACKGROUND: Metformin and the sulfonylureas are common initial antidiabetic agents; the former has demonstrated anti-TB action in in vitro and animal studies. The comparative effect of metformin vs the sulfonylureas on TB risk in patients with type 2 diabetes mellitus (T2DM) remains unclear. METHODS: In this retrospective cohort study, patients without chronic kidney disease who received a T2DM diagnosis during 2003 to 2013 were identified from the Taiwan National Health Insurance Research Database. Participants with >= 2 years of follow-up were reviewed and observed for TB until December 2013. Patients receiving metformin >= 60 cumulative defined daily dose (cDDD) and sulfonylureas < 15 cDDD in the initial 2 years were defined as metformin majors; it was the inverse for sulfonylurea majors. The two groups were matched 1:1 by propensity score and compared for TB risk by multivariate Cox regression analysis. RESULTS: Among 40,179 patients with T2DM, 263 acquired TB (0.65%) over a mean follow-up of 6.1 years. In multivariate analysis, the initial 2-year dosage of metformin, but not that of the sulfonylureas, was an independent predictor of TB (60-cDDD increase (adjusted hazard ratio [HR], 0.931; 95% CI, 0.877-0.990) after adjustment by cofactors, including adapted diabetes complication severity index. Metformin majors had a significantly lower TB risk than that of sulfonylurea majors before and after matching (HR, 0.477; 95% CI, 0.268-0.850 and HR, 0.337; 95% CI, 0.169 0.673; matched pairs, n = 3,161). Compared with the reference group (initial 2 year metformin < 60 cDDD), metformin treatment showed a dose-dependent association with TB risk (60-219 cDDD; HR, 0.860; 95% CI, 0.637-1.161; 220-479 cDDD, HR, 0.706; 95% CI, 0.485-1.028; >= 480 cDDD, HR, 0.319; 95% CI, 0.118 0.863). CONCLUSIONS: Metformin use in the initial 2 years was associated with a decreased risk of TB, and metformin users had a reduced risk compared with their sulfonylurea comparators. PMID- 29253554 TI - Heparin-Induced Thrombocytopenia in the Critically Ill Patient. AB - Heparin-induced thrombocytopenia (HIT) is associated with clinically significant morbidity and mortality. Patients who are critically ill are commonly thrombocytopenic and exposed to heparin. Although HIT should be considered, it is not usually the cause of thrombocytopenia in the medical-surgical ICU population. A systematic approach to the patient who is critically ill who has thrombocytopenia according to clinical features, complemented by appropriate laboratory confirmation, should lead to a reduction in inappropriate laboratory testing and reduce the use of more expensive and less reliable anticoagulants. If the patient is deemed as being at intermediate or high risk for HIT or if HIT is confirmed by means of the serotonin-release assay, heparin should be stopped, heparin-bonded catheters should be removed, and a direct antithrombin or fondaparinux should be initiated to reduce the risk of thrombosis. Warfarin is absolutely contraindicated in the acute phase of HIT; if administered, its effects must be reversed by using vitamin K. PMID- 29253555 TI - The Impact of Listening to Music During a High-Intensity Exercise Endurance Test in People With COPD. AB - BACKGROUND: In people with COPD, dyspnea is the primary symptom limiting exercise tolerance. One approach to reducing dyspnea during exercise is through music listening. A constant speed endurance test reflects a high-intensity aerobic exercise training session, but whether listening to music affects endurance time is unknown. This study aimed to determine the effects of listening to music during a constant speed endurance test in COPD. METHODS: Participants with COPD completed two endurance walk tests, one with and one without listening to self selected music throughout the test. The primary outcome was the difference in endurance time between the two conditions. Heart rate, percutaneous oxygen saturation, dyspnea, and rate of perceived exertion were measured before and after each test. RESULTS: Nineteen participants (mean [SD]: age, 71 [8] years; FEV1, 47 [19] % predicted) completed the study. Endurance time was greater (1.10 [95% CI, 0.41-1.78] min) while listening to music (7.0 [3.1] min) than without (5.9 [2.6] min), and reduced end-test dyspnea (1.0 [95% CI, -2.80 to -1.80] units) (with music, 4.6 [1.7] units; vs without music, 5.6 [1.4] units, respectively). There was not a significant difference in heart rate, percutaneous oxygen saturation, or leg fatigue. There were no adverse events under either condition. CONCLUSIONS: In COPD, dyspnea was less while listening to music and was accompanied by an increased tolerance of high-intensity exercise demonstrated by greater endurance time. Practically, the effect was modest but may represent an aid for exercise training of these patients. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry; No. ACTRN12617001217392. PMID- 29253556 TI - Lateral Intercondylar Ridge: Is it a reliable landmark for femoral ACL insertion?: An anatomical study. AB - BACKGROUND: Incorrect femoral tunnel placement is the most common cause of graft failure during Anterior Cruciate Ligament (ACL) Reconstruction. A reliable landmark can minimize errors. AIM: To identify whether the Lateral Intercondylar Ridge (LIR) is a consistent anatomical structure and define its relationship with the femoral ACL insertion. MATERIALS AND METHODS: Phase 1: we studied 23 femoral dry bone specimens macroscopically. Using a digital microscribe, the medial surface of the lateral femoral condyle was reconstructed (3D) to evaluate whether there was an identifiable bony ridge. Phase 2: 7 cadaveric specimens with intact soft tissues were dissected to identify the femoral ACL insertion. A 3D reconstruction of the femoral ACL insertion and the surface allowed us to define the relationship between the LIR and the ACL insertion. RESULTS: All specimens had a defined LIR on the medial surface of the lateral femoral condyle. The ridge was consistently located just anterior to the femoral ACL insertion. The ACL footprint was present in the depression between the ridge and the Inferior Articular Cartilage Margin (IACM). The mean distance from the midpoint of the IACM to the LIR was 10.1 mm. CONCLUSIONS: This is the first study to use the microscribe to digitally reconstruct the medial surface of the lateral femoral condyle. It shows that the LIR is a consistent anatomical structure that defines the anterior margin of the femoral ACL insertion, which guides femoral tunnel placement. Our findings support the ruler technique, which is a commonly used method for anatomic single bundle ACL reconstruction. PMID- 29253557 TI - Ancient duplications and functional divergence in the interferon regulatory factors of vertebrates provide insights into the evolution of vertebrate immune systems. AB - Interferon regulatory factors (IRFs) were first discovered as transcription factors that regulate the transcription of human interferon (IFN)-beta. Increasing evidence shows that they might be important players involved in Adaptive immune system (AIS) evolution. Although numbers of IRFs have been identified in chordates, the evolutionary history and functional diversity of this gene family during the early evolution of vertebrates have remained obscure. Using IRF HMM profile and HMMER searches, we identified 148 IRFs in 11 vertebrates and 4 protochordates. For them, we reconstructed the phylogenetic relationships, determined the synteny conservation, investigated the profile of natural selection, and analyzed the expression patterns in four "living fossil" vertebrates: lamprey, elephant shark, coelacanth and bichir. The results from phylogeny and synteny analysis imply that vertebrate IRFs evolved from three predecessors, instead of four as suggested in a previous study, as results from an ancient duplication followed by special expansions and lost during the vertebrate evolution. The profile of natural selection and expression reveals functional dynamics during the process. Together, they suggest that the 2nd whole genome duplication (2WGD) provided raw materials for innovation in the IRF family, and that the birth of type-I IFN might be an important factor inducing the establishment of IRF-mediated immune networks. As a member involved in the AIS evolution, IRF provide insights into the process and mechanism involved in the complexity and novelties of vertebrate immune systems. PMID- 29253558 TI - Tapasin's protein interactions in the rainbow trout peptide-loading complex. AB - Major histocompatibility complex (MHC) class I receptors play a key role in the immune system by presenting non-self peptides to T cell lymphocytes. In humans, the assembly of the MHC class I with a peptide is mediated by machinery in the endoplasmic reticulum referred as the peptide loading complex (PLC). Although, the identity of the PLC has been widely explored in humans, this complex has not been characterized in fish. Co-immunoprecipitation and mass spectrometry analysis revealed that the protein-protein interactions which exist in the human PLC are conserved in the monocyte/macrophage rainbow trout cell line (RTS11), in particular the interaction of tapasin with the transporter associated with antigen processing (TAP), MHC class I and ERp57. Importantly, a 20 kDa tapasin version that contains an intact C and N terminal domains was found to associate with ERp57 and form a 75 kDa heterodimer. These results suggest a possible novel alternative spliced version of tapasin may regulate the formation of the peptide loading complex in teleosts. PMID- 29253560 TI - Antibody persistence and booster responses 24-36 months after different 4CMenB vaccination schedules in infants and children: A randomised trial. AB - OBJECTIVES: This phase IIIb, open-label, multicentre, extension study (NCT01894919) evaluated long-term antibody persistence and booster responses in participants who received a reduced 2 + 1 or licensed 3 + 1 meningococcal serogroup B vaccine (4CMenB)-schedule (infants), or 2-dose catch-up schedule (2 10-year-olds) in parent study NCT01339923. MATERIALS AND METHODS: Children aged 35 months to 12 years (N = 851) were enrolled. Follow-on participants (N = 646) were randomised 2:1 to vaccination and non-vaccination subsets; vaccination subsets received an additional 4CMenB dose. Newly enrolled vaccine-naive participants (N = 205) received 2 catch-up doses, 1 month apart (accelerated schedule). Antibody levels were determined using human serum bactericidal assay (hSBA) against MenB indicator strains for fHbp, NadA, PorA and NHBA. Safety was also evaluated. RESULTS: Antibody levels declined across follow-on groups at 24 36 months versus 1 month post-vaccination. Antibody persistence and booster responses were similar between infants receiving the reduced or licensed 4CMenB schedule. An additional dose in follow-on participants induced higher hSBA titres than a first dose in vaccine-naive children. Two catch-up doses in vaccine-naive participants induced robust antibody responses. No safety concerns were identified. CONCLUSION: Antibody persistence, booster responses, and safety profiles were similar with either 2 + 1 or 3 + 1 vaccination schedules. The accelerated schedule in vaccine-naive children induced robust antibody responses. PMID- 29253561 TI - A prospective observational treatment study of aerococcal urinary tract infection. AB - OBJECTIVES: Aerococcus urinae and Aerococcus sanguinicola cause urinary tract infections (UTIs) and antibiotic treatment recommendations are solely based on in vitro findings and limited clinical experience. Our objective was to investigate the effectiveness of different treatment strategies in aerococcal UTI through a prospective observational study. METHODS: Urine samples with aerococci were identified and patients were enrolled. The aerococci were subjected to Etests. Information on clinical symptoms, and the treatment given, was collected. Patients were interviewed after the conclusion of treatment to assess clinical cure and a control urine culture assessed the microbiological cure. RESULTS: Of 31,629 urine samples, 144 grew aerococci and fulfilled the inclusion criteria. 91 patients gave consent and the 72 patients with UTI were assessed for treatment outcome. 53 patients had A. urinae UTI, while 19 had A. sanguinicola UTI. Nitrofurantoin was most commonly prescribed, achieving clinical and microbiological success in 71/76% of cases of A. urinae UTI, and 42/50% of cases of A. sanguinicola UTI. Pivmecillinam achieved success in patients with A. urinae cystitis and ciprofloxacin in patients with pyelonephritis. CONCLUSIONS: Our results support that nitrofurantoin is a valid option for the treatment of cystitis caused by A. urinae. PMID- 29253562 TI - Increasing prevalence of non-tuberculous mycobacterial infection from 2004-2009 to 2012-2017: A laboratory-based surveillance in China. PMID- 29253559 TI - Early impact of 13-valent pneumococcal conjugate vaccine on pneumococcal meningitis-Burkina Faso, 2014-2015. AB - OBJECTIVES: We evaluate early impact of 13-valent pneumococcal conjugate vaccine (PCV13) on pneumococcal meningitis in Burkina Faso. METHODS: Nationwide surveillance gathered demographic/clinical information and cerebrospinal fluid (CSF) results for meningitis cases. Pneumococcal cases were confirmed by culture, polymerase chain reaction (PCR), or latex agglutination, and strains serotyped using PCR. We compared incidence (cases per 100,000) in the early post-PCV13 period (2014 and 2015) to average pre-PCV13 incidence (2011-2013). RESULTS: In 2015, age-specific pneumococcal meningitis incidences were 8.7 (<1 year), 2.4 (1 4 years), 6.5 (5-14 years), and 2.6 (>=15 years). Compared to 2011-2013, PCV13 serotype incidence among all ages decreased by 32% (95%CI: 23%-39%), with significant decreases among children aged <1 year (76%; 95%CI: 64%-84%) and 1-4 years (58%, 95%CI: 40%-71%). Among all ages, incidence of PCV13 serotypes besides serotype 1 decreased (68%; 95%CI: 59%-75%), but serotype 1 incidence did not. Incidence of non-PCV13 serotypes also decreased (47%; 95%CI: 29%-60%). Among children aged <1 year, serotypes 12F/12A/12B/44/46 (17%), 1 (12%), and 5 (10%) predominated. CONCLUSIONS: Following PCV13 introduction, PCV13-serotype meningitis incidence in young children significantly decreased. PCV13 impact on serotype 1 and disease in older children and adults requires continued monitoring. PMID- 29253563 TI - A water-soluble precursor for efficient silica polymerization by silicateins. AB - Silicateins, the spicule-forming proteins from marine demosponges capable to polymerize silica, are popular objects of biomineralization studies due to their ability to form particles varied in shape and composition under physiological conditions. Despite the occurrence of the many approaches to nanomaterial synthesis using silicateins, biochemical properties of this protein family are poorly characterized. The main reason for this is that tetraethyl orthosilicate (TEOS), the commonly used silica acid precursor, is almost insoluble in water and thus is poorly available for the protein. To solve this problem, we synthesized new water-soluble silica precursor, tetra(glycerol)orthosilicate (TGS), and characterized biochemical properties of the silicatein A1 from marine sponge Latrunculia oparinae. Compared to TEOS, TGS ensured much greater activity of silicatein and was less toxic for the mammalian cell culture. We evaluated optimum conditions for the enzyme - pH range, temperature and TGS concentration. We concluded that TGS is a useful silica acid precursor that can be used for silica particles synthesis and in vivo applications. PMID- 29253564 TI - LncRNA LOC730101 promotes osteosarcoma cell survival under energy stress. AB - Long non-coding RNAs have been proved in tumorigenesis of various cancers, including osteosarcoma. However, the role of LOC730101 in cancer is rare to be reported, not mention to osteosarcoma. In current study, quantitative real-time PCR, was applied to evaluate the expression of LOC730101 under energy stress. The roles of LOC730101 in cell viability, apoptosis and tumor development under energy stress were analyzed by cell biological assays in vitro and in vivo. AMPK CA (continuously active) and Compound C (AMPK inhibitor) were employed to investigate the mechanism. And we further confirmed that compared with adjacent tissues, LOC730101 is remarkably increased in osteosarcoma in our fresh tissues. In addition, cellular function assays demonstrated that LOC730101 promotes cell viability, tumor development, and deficiency of LOC730101 promotes cell apoptosis under energy stress. Furthermore, we validated that up-regulated LOC730101 enhances cell viability through AMPK under energy stress. Taken together, our findings enlarged the knowledge about the roles of LOC730101 in osteosarcoma progression. PMID- 29253565 TI - Dehydrodiconiferyl alcohol promotes BMP-2-induced osteoblastogenesis through its agonistic effects on estrogen receptor. AB - Estrogen deficiency results in an imbalance between the levels of bone-resorping osteoclasts and bone-forming osteoblasts, eventually leading to overall bone loss. Dehydrodiconiferyl alcohol (DHCA), a lignan compound originally isolated from Cucurbita moschata, has been shown to bind to estrogen receptor, and indeed exhibits various activities of estrogen, such as anti-inflammatory and anti oxidative stress effects. In this study, we tested whether synthetic DHCA could affect the BMP-2-induced osteoblastogenesis in vitro. In MC3T3-E1 cells, DHCA promoted BMP-2-induced differentiation of osteoblasts. Consistently, the expression of three osteoblastogenic genes known to be induced by BMP-2, ALP, osteocalcin and OPG, was up-regulated by DHCA treatment. DHCA was also shown to activate the production of RUNX2 by activating Smad1/5/9 and AMPK. Data from transient transfection assays suggested that DHCA might activate the estrogen receptor signaling pathway. Effects of DHCA on BMP-2-induced osteoblastogenesis were reduced when cells were treated with a specific siRNA to ERalpha or ERbeta. Taken together, our results suggest that DHCA may be developed as an efficient therapeutic for osteoporosis by regulating osteoblastogenesis through its estrogenic effects. PMID- 29253566 TI - NK cell and IFN signatures are positive prognostic biomarkers for resectable pancreatic cancer. AB - To establish prognostic biomarkers and to identify potential novel therapeutic targets, we performed integrative immunomonitoring of blood and tumor in patients with resectable pancreatic cancer. Flow cytometry (FC) was employed for phenotyping immune cells, multiplex bead assays for plasma cytokine and chemokine determination, and RNA-Seq for the analysis of gene expression in the tumor. Nineteen pancreatic cancer patients were stratified into those with longer or shorter than median recurrence-free survival after surgery (median, 426 days). There were no significant differences between the two groups for clinical parameters including age, sex, surgical procedure, stage, or postoperative adjuvant therapy. However, we found that the percentages of NK cells as assessed by FC in peripheral blood mononuclear cells were higher in patients with late recurrence (P = .037). RNA-Seq data indicated no differences in the amount of immune cells or stromal cells between the two groups, although NK cells in the tumor did tend to be higher in patients with late recurrence (P = .058). Type I and II IFN signatures were enriched in late-recurring tumors (FDR q-value <0.001), while genes related to KRAS signaling and the epithelial mesenchymal transition (EMT) were enriched in early recurrence. We conclude that tumor intrinsic properties of metastasis and recurrence influence prognosis, whereas NK cells that might contribute to prevent metastasis are associated with longer recurrence-free survival. Therefore, enhancement of NK cell activity and inhibition of the EMT and KRAS signaling might represent appropriate therapeutic targets following surgical resection of pancreatic cancer. PMID- 29253567 TI - Plakoglobin localization to the cell border restores desmosome function in cells lacking 14-3-3gamma. AB - Desmosomes are cell-cell adhesion junctions that anchor intermediate filaments. Loss of 14-3-3gamma in HCT116 cells led to defects in desmosome assembly due to a decrease in the transport of Plakoglobin (PG) to the cell border thus disrupting desmosome formation. Desmosome formation in cells lacking 14-3-3gamma was restored by artificially localizing PG to the cell border by fusing it to EGFP-f (PG-EGFP-f). These results suggest that a major role of 14-3-3gamma in desmosome assembly is to transport PG to the cell border leading to the initiation of desmosome formation. PMID- 29253569 TI - Activation of KGFR-Akt-mTOR-Nrf2 signaling protects human retinal pigment epithelium cells from Ultra-violet. AB - Ultra-violet (UV) radiation causes oxidative injuries to human retinal pigment epithelium (RPE) cells. We tested the potential effect of keratinocyte growth factor (KGF) against the process. KGF receptor (KGFR) is expressed in ARPE-19 cells and primary human RPE cells. Pre-treatment with KGF inhibited UV-induced reactive oxygen species (ROS) production and RPE cell death. KGF activated nuclear-factor-E2-related factor 2 (Nrf2) signaling in RPE cells, causing Nrf2 Ser-40 phosphorylation, stabilization and nuclear translocation as well as expression of Nrf2-dependent genes (HO1, NOQ1 and GCLC). Nrf2 knockdown (by targeted shRNAs) or S40T mutation almost reversed KGF-induced RPE cell protection against UV. Further studies demonstrated that KGF activated KGFR-Akt-mTORC1 signaling to mediate downstream Nrf2 activation. KGFR shRNA or Akt-mTORC1 inhibition not only blocked KGF-induced Nrf2 Ser-40 phosphorylation and activation, but also nullified KGF-mediated RPE cell protection against UV. We conclude that KGF-KGFR activates Akt-mTORC1 downstream Nrf2 signaling to protect RPE cells from UV radiation. PMID- 29253568 TI - Lack of O-GlcNAcylation enhances exercise-dependent glucose utilization potentially through AMP-activated protein kinase activation in skeletal muscle. AB - O-GlcNAcylation is a post-translational modification that is characterized by the addition of N-acetylglucosamine (GlcNAc) to proteins by O-GlcNAc transferase (Ogt). The degree of O-GlcNAcylation is thought to be associated with glucotoxicity and diabetic complications, because GlcNAc is produced by a branch of the glycolytic pathway. However, its role in skeletal muscle has not been fully elucidated. In this study, we created skeletal muscle-specific Ogt knockout (Ogt-MKO) mice and analyzed their glucose metabolism. During an intraperitoneal glucose tolerance test, blood glucose was slightly lower in Ogt-MKO mice than in control Ogt-flox mice. High fat diet-induced obesity and insulin resistance were reversed in Ogt-MKO mice. In addition, 12-month-old Ogt-MKO mice had lower adipose and body mass. A single bout of exercise significantly reduced blood glucose in Ogt-MKO mice, probably because of higher AMP-activated protein kinase alpha (AMPKalpha) protein expression. Furthermore, intraperitoneal injection of 5 aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, resulted in a more marked decrease in blood glucose levels in Ogt-MKO mice than in controls. Finally, Ogt knockdown by siRNA in C2C12 myotubes significantly increased protein expression of AMPKalpha, glucose uptake and oxidation. In conclusion, loss of O GlcNAcylation facilitates glucose utilization in skeletal muscle, potentially through AMPK activation. The inhibition of O-GlcNAcylation in skeletal muscle may have an anti-diabetic effect, through an enhancement of glucose utilization during exercise. PMID- 29253570 TI - Harmine promotes molar root development via SMAD1/5/8 phosphorylation. AB - Tooth and bone are major tissues involved in physiological calcification in the body, and they use similar molecular pathways for development, homeostasis, and regeneration. Harmine (HMN) is a natural small compound that stimulates osteoblast differentiation in vitro and in vivo. Here we examined the biological effect of HMN on the postnatal development of molar tooth roots and periodontal tissues. HMN supported the formation of tooth roots and periodontal tissues in developing tooth germs. In tooth germ organ culture, HMN promoted the elongation of Hertwig's epithelial root sheath (HERS) and stimulated cell proliferation in HERS and dental follicle-derived tissues, including dental papillae and dental follicles. HMN stimulated cell proliferation and cell movement of HERS-derived cells without mesenchymal cells in vitro and directly induced the phosphorylation of SMAD1/5/8 protein in HERS-derived cells. Our results indicated that HMN was the first natural small compound to stimulate postnatal development of tooth germs. PMID- 29253571 TI - Inhibition of Notch signaling pathway using gamma-secretase inhibitor delivered by a low dose of Triton-X100 in cultured oral cancer cells. AB - How to effectively delivering therapeutic agents, including gamma-secretase inhibitors (GSIs), into live cells, remains a significant challenge. This study assessed the effect of Notch signaling inhibition by examining levels of the Notch1 intracellular domain (N1ICD) in cultured oral cancer cells analyzed with random stitched images (2D) and 3D visualizations using confocal microscopy and quantitative gene analysis. Substantially, we have developed a novel method to assist the delivery of gamma-secretase inhibitor, DAPT, into live cells in the presence of an effective minimum concentration of Triton-X100 (0.001%) without damaging cell activity and membrane integrity assessed with cell proliferation assays. The images obtained in this study showed that DAPT alone could not block the gamma-secretase inhibitor despite inhibiting cell growth. Further analysis of quantitative gene expressions of Notch signaling canonical pathway to verify the effectiveness of the novel method for delivering inhibitor into live cells, displayed deregulation of Notch1, Delta-like ligand 1 (DLL1) and hairy and enhancer of split 1 (Hes1). Our data suggest that Notch1/Hes1 signaling pathway is deactivated using DAPT with a low dose of Triton-X100 in this cancer cells. And the finding also suggests that Notch1 could be engaged by DLL1 to promote differentiation in oral cancer cells. Using this approach, we demonstrate that Triton-X100 is a promising and effective permeabilization agent to deliver gamma secretase inhibitor DAPT into live oral epithelial cells. This strategy has the potential to implicate in the treatment of cancer diseases. PMID- 29253572 TI - Silencing of secretory clusterin sensitizes NSCLC cells to V-ATPase inhibitors by downregulating survivin. AB - Secretory clusterin (sCLU) is a stress-associated protein that confers resistance to therapy when overexpressed. In this study, we observed that the V-ATPase inhibitors bafilomycin A1 and concanamycin A significantly stimulated sCLU protein expression. Knockdown of sCLU with siRNA sensitized non-small cell lung cancer (NSCLC) cells to bafilomycin A1, suggesting that sCLU expression renders cells resistant to V-ATPase inhibitors. The dual PI3K/AKT and mTOR inhibitor BEZ235 suppressed sCLU expression and enhanced cell sensitivity induced by bafilomycin A1. Notably, sCLU knockdown further decreased the expression of the survivin protein by bafilomycin A1, and the ectopic expression of survivin alleviated the cell sensitivity by bafilomycin A1 and sCLU depletion, suggesting that increased sensitivity to sCLU depletion in the cells with V-ATPase inhibitors is due, at least in part, to the down-regulation of survivin. Taken together, we demonstrated that the depletion of sCLU expression enhances the sensitivity of NSCLC cells to V-ATPase inhibitors by decreasing survivin expression. Inhibition of the PI3K/AKT/mTOR pathway enhances the sensitivity of NSCLC cells to V-ATPase inhibitors, leading to decreased sCLU and survivin expression. Thus, we suggest that a combination of PI3K/AKT/mTOR inhibitors with V-ATPase inhibitors might be an effective approach for NSCLC treatment. PMID- 29253573 TI - Acute myeloid leukemia xenograft success prediction: Saving time. AB - Xenograft assay allows functional analysis of leukemia-initiating cells of acute myeloid leukemia primary samples. However, 40% of samples derived from patients with better outcomes fail to engraft in immunodeficient mouse recipients when conventional protocols are followed. At diagnosis, the engraftment of intermediate-risk group samples cannot be anticipated. In this study, we decided to further explore the reasons for xenograft success and failure. No differences in extracellular phenotype, apoptosis, or cell cycle profile could distinguish samples that engraft (engrafter [E]) from samples that do not engraft (nonengrafter [NE]) in NSG mice. In addition, ex vivo long-term culture assay revealed, after 5 weeks, a lower content of leukemic-LTC-initiating cells in the NE samples associated with a lower expansion rate capacity. One-week co-cultures with mesenchymal or osteoblastic or endothelial cells did not influence the proliferation rate, suggesting that E and NE samples are genuinely rapidly or slowly expanding independent of external cue. Engraftment success for some NE samples was consistently observed in recipient mice analyzed 6 months later than the conventional 3-month period. Eventually we implemented a flow cytometry-based assay, which allowed us to predict, in 1 week, the fast or delayed engraftment potential of a noncharacterized acute myeloid leukemia sample. This approach will be especially useful in selecting intermediate-risk-group patient samples and restricting the experimental duration to a 3-month period and, eventually, in reducing the number of animals and the cost and effort of unnecessary xenograft failures. PMID- 29253574 TI - Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. AB - Alzheimer'sdisease(AD) is characterized by deposition of amyloid-beta (Abeta)plaques, neurofibrillary tangles, andneuronal loss, accompaniedbyneuroinflammation. Neuroinflammatoryprocesses are thought to contribute toAD pathophysiology. Metformin has been reported to have anti inflammatory efficacy. However, whether metformin is responsible for the anti neuroinflammationand neuroprotection on APPswe/PS1DeltaE9 (APP/PS1) mice remains unclear. Here we showed that metformin attenuated spatial memory deficit, neuron loss in the hippocampus and enhanced neurogenesis in APP/PS1 mice. In addition, metformin administration decreased amyloid-beta (Abeta)plaque load and chronic inflammation (activated microglia and astrocytes as well as pro-inflammatory mediators) in the hippocampus and cortex. Further study demonstrated that treatment with metformin enhanced cerebral AMPK activation. Meanwhile, metformin notably suppressed the activation of P65 NF-kappaB, mTOR and S6K, reduced Bace1 protein expression. Our data suggest that metformin can exert functional recovery of memory deficits and neuroprotective effect on APP/PS1 mice via triggering neurogenesis and anti-inflammation mediated by regulating AMPK/mTOR/S6K/Bace1 and AMPK/P65 NF-kappaB signaling pathways in the hippocampus, which may contribute to improvement in neurological deficits. PMID- 29253575 TI - Brain extraction in partial volumes T2*@7T by using a quasi-anatomic segmentation with bias field correction. AB - BACKGROUND: Poor brain extraction in Magnetic Resonance Imaging (MRI) has negative consequences in several types of brain post-extraction such as tissue segmentation and related statistical measures or pattern recognition algorithms. Current state of the art algorithms for brain extraction work on weighted T1 and T2, being not adequate for non-whole brain images such as the case of T2*FLASH@7T partial volumes. NEW METHOD: This paper proposes two new methods that work directly in T2*FLASH@7T partial volumes. The first is an improvement of the semi automatic threshold-with-morphology approach adapted to incomplete volumes. The second method uses an improved version of a current implementation of the fuzzy c means algorithm with bias correction for brain segmentation. RESULTS: Under high inhomogeneity conditions the performance of the first method degrades, requiring user intervention which is unacceptable. The second method performed well for all volumes, being entirely automatic. COMPARISON WITH EXISTING METHODS: State of the art algorithms for brain extraction are mainly semi-automatic, requiring a correct initialization by the user and knowledge of the software. These methods can't deal with partial volumes and/or need information from atlas which is not available in T2*FLASH@7T. Also, combined volumes suffer from manipulations such as re-sampling which deteriorates significantly voxel intensity structures making segmentation tasks difficult. The proposed method can overcome all these difficulties, reaching good results for brain extraction using only T2*FLASH@7T volumes. CONCLUSIONS: The development of this work will lead to an improvement of automatic brain lesions segmentation in T2*FLASH@7T volumes, becoming more important when lesions such as cortical Multiple-Sclerosis need to be detected. PMID- 29253576 TI - Simplified adaptor for stereotactic surgery in non-human primates. AB - BACKGROUND: It is challenging for researchers performing stereotactic procedures to transition from small animals to non-human primate (NHP) experiments. The NHP stereotactic atlas is based on ear-bar zero (EBZ), which is an anatomical reference frame that is not visible during surgery. Most current NHP stereotactic systems require high-cost MRI or CT imaging and complex computer processing to determine the stereotactic coordinates, limiting the procedure to those with significant expertise. NEW METHOD: We have designed a simplified adaptor consisting of a circular arc for coronal tilt, a carrier for electrodes or cannulas, and an anchor to attach the adaptor to a conventional stereotactic frame. Our adaptor allows easy identification of the EBZ with the help of an anchor notch, and provides digital distance sensors without the need for imaging data or computer processing. Our system enables the use of trajectories that avoid injury to important structures and vessels. RESULTS: We tested the accuracy of our system using simulated targeting with phantoms, and demonstrated sub millimeter accuracy. Infusion of methylene blue also showed satisfactory staining in target structures deep in the brain. COMPARISON WITH EXISTING METHODS: This system does not require high-cost imaging and extra training to determine EBZ. Once EBZ is set automatically by the system itself, targeting is similar to that in small animal stereotactic procedure. CONCLUSION: Our simple adaptor will aid researchers who plan to conduct experiments involving stereotactic surgery in NHPs. PMID- 29253577 TI - Dynamic footprint based locomotion sway assessment in alpha-synucleinopathic mice using Fast Fourier Transform and Low Pass Filter. AB - BACKGROUND: Sway is a crucial gait characteristic tightly correlated with the risk of falling in patients with Parkinsons disease (PD). So far, the swaying pattern during locomotion has not been investigated in rodent models using the analysis of dynamic footprint recording obtained from the CatWalk gait recording and analysis system. NEW METHODS: We present three methods for describing locomotion sway and apply them to footprint recordings taken from C57BL6/N wild type mice and two different alpha-synuclein transgenic PD-relevant mouse models (alpha-synm-ko, alpha-synm-koxalpha-synh-tg). Individual locomotion data were subjected to three different signal processing analytical approaches: the first two methods are based on Fast Fourier Transform (FFT), while the third method uses Low Pass Filters (LPF). These methods use the information associated with the locomotion sway and generate sway-related parameters. RESULTS: The three proposed methods were successfully applied to the footprint recordings taken from all paws as well as from front/hind-paws separately. Nine resulting sway-related parameters were generated and successfully applied to differentiate between the mouse models under study. Namely, alpha-synucleinopathic mice revealed higher sway and sway itself was significantly higher in the alpha-synm-koxalpha-synh-tg mice compared to their wild-type littermates in eight of the nine sway-related parameters. COMPARISON WITH EXISTING METHOD: Previous locomotion sway index computation is based on the estimated center of mass position of mice. CONCLUSIONS: The methods presented in this study provide a sway-related gait characterization. Their application is straightforward and may lead to the identification of gait pattern derived biomarkers in rodent models of PD. PMID- 29253578 TI - The Effect of Nerve Sparing Status on Sexual and Urinary Function: 3-Year Results from the CEASAR Study. AB - PURPOSE: Nerve sparing contributes to the recovery of sexual and urinary function after radical prostatectomy but it may be ineffective in some patients or carry the risk of a positive surgical margin. We evaluated sexual and urinary function outcomes according to the degree of nerve sparing in patients with prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: The CEASAR (Comparative Effectiveness Analysis of Surgery and Radiation) study is a prospective, population based, observational study of men diagnosed with localized prostate cancer in 2011 to 2012. Patient reported sexual and urinary functions were measured using the 26-item Expanded Prostate Index Composite at baseline within 6 months after diagnosis, and 6, 12 and 36 months after enrollment. Study inclusion criteria included radical prostatectomy as primary treatment, documentation of nerve sparing status and absent androgen deprivation therapy. Nerve sparing status was defined as none, unilateral or bilateral according to the operative report. RESULTS: The final analytical cohort included 991 men. The 11 men treated with unilateral nerve sparing and the 75 treated with a nonnerve sparing procedure were grouped together. In the multivariable model there was a significant difference in the sexual function score 3 years after radical prostatectomy in the bilateral nerve sparing group compared with the unilateral and nonnerve sparing group (6.1 points, 95% CI 2.0-10.3, p = 0.004). This was more pronounced in men with high baseline sexual function (8.23 points, 95% CI 1.6-14.8, p = 0.014) but not in those with low baseline function (4.0 points, 95% CI -0.6-8.7, p = 0.090). Similar effects were demonstrated on urinary incontinence scores. CONCLUSIONS: Bilateral nerve sparing resulted in better sexual and urinary function outcomes than unilateral or nonnerve sparing but the difference was not significant in men with low baseline sexual function. PMID- 29253579 TI - Dusting versus Basketing during Ureteroscopy-Which Technique is More Efficacious? A Prospective Multicenter Trial from the EDGE Research Consortium. AB - PURPOSE: There is scant evidence in the literature to support dusting vs active basket extraction during ureteroscopy for kidney stones. We prospectively evaluated and followed patients to determine which modality produced a higher stone-free rate with the fewest complications. MATERIALS AND METHODS: Members of the Endourologic Disease Group for Excellence research consortium prospectively enrolled patients with a renal stone burden ranging from 5 to 20 mm in this study. A holmium laser was used and all patients were stented postoperatively. Ureteral access sheaths were used in 100% of basketing cases while sheaths were optional when dusting. The primary study outcome was the stone-free rate at 6 weeks as determined by x-ray and ultrasound. RESULTS: A total of 84 and 75 patients were enrolled in the basketing and dusting arms, respectively. Stones in the dusting group were significantly larger (mean +/- SD stone area 96.1 +/- 65.3 vs 63.3 +/- 46.0 mm2, p <0.001). The stone-free rate was significantly higher in the basketing group on univariate analysis (74.3% vs 58.2%, p = 0.04) but not on multivariate analysis (1.9 OR, 95% CI 0.9-4.3, p = 0.11). In patients who underwent a basketing procedure operative time was 37.7 minutes longer than in those treated with a dusting procedure (95% CI 23.8-51.7, p <0.001). There was no statistically significant difference in complication rates, hospital readmissions or additional procedures between the groups. CONCLUSIONS: The stone-free rate was higher for active basket retrieval of fragments at short-term followup on univariate analysis but not on multivariate analysis. There was no difference in postoperative complications or procedures. The 2 techniques should be in the armamentarium of the urologist. PMID- 29253580 TI - Contraceptive use at last intercourse among reproductive-aged women with disabilities: an analysis of population-based data from seven states. AB - OBJECTIVE: To assess patterns of contraceptive use at last intercourse among women with physical or cognitive disabilities compared to women without disabilities. STUDY DESIGN: We analyzed responses to 12 reproductive health questions added by seven states to their 2013 Behavioral Risk Factor Surveillance System questionnaire. Using responses from female respondents 18-50 years of age, we performed multinomial regression to calculate estimates of contraceptive use among women at risk for unintended pregnancy by disability status and type, adjusted for age, race/ethnicity, marital status, education, health insurance status, and parity. RESULTS: Women with disabilities had similar rates of sexual activity as women without disabilities (90.0% vs. 90.6%, p=.76). Of 5995 reproductive-aged women at risk for unintended pregnancy, 1025 (17.1%) reported one or more disabilities. Contraceptive use at last intercourse was reported by 744 (70.1%) of women with disabilities compared with 3805 (74.3%) of those without disabilities (p=.22). Among women using contraception, women with disabilities used male or female permanent contraception more often than women without disabilities (333 [29.6%] versus 1337 [23.1%], p<.05). Moderately effective contraceptive (injection, oral contraceptive, patch, or ring) use occurred less frequently among women with cognitive (13.1%, n=89) or independent living (13.9%, n=40) disabilities compared to women without disabilities (22.2%, n=946, p<.05). CONCLUSIONS: The overall prevalence of sexual activity and contraceptive use was similar for women with and without physical or cognitive disabilities. Method use at last intercourse varied based on presence and type of disability, especially for use of permanent contraception. IMPLICATIONS: Although women with disabilities were sexually active and used contraception at similar rates as women without disabilities, contraception use varied by disability type, suggesting the importance of this factor in reproductive health decision-making among patients and providers, and the value of further research to identify reasons why this occurs. PMID- 29253581 TI - Access to long-acting reversible contraception among US publicly funded health centers. AB - OBJECTIVES: Access to a full range of contraceptive methods, including long acting reversible contraception (LARC), is central to providing quality family planning services. We describe health center-related factors associated with LARC availability, including staff training in LARC insertion/removal and approaches to offering LARC, whether onsite or through referral. STUDY DESIGN: We analyzed nationally representative survey data collected during 2013-2014 from administrators of publicly funded U.S. health centers that offered family planning. The response rate was 49.3% (n=1615). In addition to descriptive statistics, we used multivariable logistic regression to identify health center characteristics associated with offering both IUDs and implants onsite. RESULTS: Two-thirds (64%) of health centers had staff trained in all three LARC types (hormonal IUD, copper IUD, implant); 21% had no staff trained in any of those contraceptive methods. Half of health centers (52%) offered IUDs (any type) and implants onsite. After onsite provision, informal referral arrangements were the most common way LARC methods were offered. In adjusted analyses, Planned Parenthood (AOR=9.49) and hospital-based (AOR=2.35) health centers had increased odds of offering IUDs (any type) and implants onsite, compared to Health Departments, as did Title X-funded (AOR=1.55) compared to non-Title X-funded health centers and centers serving a larger volume of family planning clients. Centers serving mostly rural areas compared to those serving urbans areas had lower odds (AOR 0.60) of offering IUD (any type) and implants. CONCLUSIONS: Variation in LARC access remains among publicly funded health centers. In particular, Health Departments and rural health centers have relatively low LARC provision. IMPLICATIONS: For more women to be offered a full range of contraceptive methods, additional efforts should be made to increase availability of LARC in publicly-funded health centers, such as addressing provider training gaps, improving referrals mechanisms, and other efforts to strengthen the health care system. PMID- 29253582 TI - An exploration of perceived contraceptive coercion at the time of abortion. AB - OBJECTIVE: To explore patient experiences of contraceptive coercion by healthcare providers at time of abortion. STUDY DESIGN: We conducted a qualitative study of English-speaking women seeking abortion services at a hospital-based clinic. We used the Integrated Behavioral Model and the Reproductive Autonomy Scale to inform our semi-structured interview guide; the Scale provides a framework of reproductive coercion as a lack of autonomy or power to decide about and control decisions relating to reproduction. We enrolled participants until thematic saturation was achieved. Two coders used modified grounded theory to analyze transcribed interviews with Nvivo 11.0 (Kappa=0.81). RESULTS: The 31 women we interviewed from June 2016 to March 2017 were all in the first trimester, and predominantly young (mean age 27+/-5 years), non-Hispanic Black (52%) and Medicaid-insured (68%). Some participants (42%) reported feeling "pressured" into choosing some form of contraception. A subset of participants (26%) voiced that providers seemed to prefer LARC methods or were "pushing" a specific method. Several participants perceived pressure to choose any method due to providers' preference to prevent repeat abortions. Conversely, participants who were offered a range of methods through the use of decision aids and who were given time to deliberate demonstrated more reproductive autonomy. CONCLUSIONS: Almost half of participants perceived a form of coercion around their contraceptive counseling. Coercion manifested in perceived provider preference for specific methods or immediate initiation of a method. Participant narratives involving decision aids to offer a range of methods and time for deliberation demonstrated greater reproductive autonomy and less coercion. Abortion stigma may mediate potentially coercive interactions between patients and providers. IMPLICATIONS: This qualitative study explored contraceptive coercion at the time of abortion. Findings highlighted provider pressure to initiate contraception, LARC preference, and abortion stigma. Offering many methods and opportunity for deliberation supported autonomy and satisfaction. Findings inform ongoing efforts to improve contraceptive counseling and promote reproductive autonomy, while addressing unintended pregnancies. PMID- 29253583 TI - Generic patches containing fentanyl: In vitro equivalence and abuse deterrent evaluation according to EMA and FDA guidelines. AB - The aim of this work was to characterize in vitro and ex vivo the performances of Durogesic and of two bioequivalent generic products, by evaluating: (a) fentanyl release; (b) fentanyl permeation across porcine skin and (c) fentanyl ease of extraction. Additional characteristics studied are the effect of temperature and skin integrity, applied individually or combined, to check a possible synergism. The two generic patches resulted equivalent to the originator according to the new Guideline. Nevertheless, the same data reported in a different way, i.e. considering the total amount of drug permeated from the whole patch over the application time, highlight differences among the patches. The additional tests performed showed that skin integrity does not represent a barrier for fentanyl permeation across the skin, regardless of the type and complexity of the patch. The effect of temperature resulted critical for two out of three patches, probably due to the different composition and to the different structure. The combination of skin damage and elevated temperature did not produce a synergistic effect. Fentanyl extraction was different for the different products and variable according to the conditions used. The results reported in the present work underline the influence of patch composition and complexity on fentanyl extraction, release and skin permeation, in particular in conditions that can be critical, such as elevated temperature. In particular, the effect of critical variables, such as skin integrity and temperature, should be addressed to in the development of a new or new generic patch and new discriminant tests should be developed. PMID- 29253584 TI - A drop penetration method to measure powder blend wettability. AB - Water wettability of pharmaceutical blends affects important quality attributes of final products. We investigate the wetting properties of a pharmaceutical blend lubricated with Magnesium Stearate (MgSt) as a function of the mechanical shear strain applied to the blend. We measure the penetration dynamics of sessile drops deposited on slightly compressed powder beds. We consider a blend composed of 9% Acetaminophen 90% Lactose and 1% MgSt by weight. Comparing the penetration time of water and a reference liquid Polydimethylsiloxane (silicon oil) we obtain an effective cosine of the contact angle with water, based on a recently developed drop penetration method. We repeat the experiments for blends exposed to increasing levels of shear strain and demonstrate a significant decrease in water wettability (decrease in the cosine of the contact angle). The results are consistent with the development of a hydrophobic film coating the powder particles as a result of the increased shear strain. Finally, we show that, as expected dissolution times increase with the level of shear strain. Therefore, the proposed drop penetration method could be used to directly assess the state of lubrication of a pharmaceutical blend and act as a quality control on powder blend attributes before the blend is tableted. PMID- 29253585 TI - Development of poloxamer gel formulations via hot-melt extrusion technology. AB - Poloxamer gels are conventionally prepared by the "hot" or the "cold" process. But these techniques have some disadvantages such as high energy consumption, requires expensive equipment and often have scale up issues. Therefore, the objective of this work was to develop poloxamer gels by hot-melt extrusion technology. The model drug selected was ketoprofen. The formulations developed were 30% and 40% poloxamer gels. Of these formulations, the 30% poloxamer gels were selected as ideal gels. DSC and XRD studies showed an amorphous nature of the drug after extrusion. It was observed from the permeation studies that with increasing poloxamer concentration, a decrease in drug permeation was obtained. Other studies conducted for the formulations included in-vitro release studies, texture analysis, rheological studies and pH measurements. In conclusion, the hot melt extrusion technology could be successfully employed to develop poloxamer gels by overcoming the drawbacks associated with the conventional techniques. PMID- 29253586 TI - From benchtop to pilot scale-experimental study and computational assessment of a hot-melt extrusion scale-up of a solid dispersion of dipyridamole and copovidone. AB - The aim of our work was to study and define a computationally-based adiabatic scale-up methodology for a hot-melt extrusion (HME) process to produce an amorphous solid dispersion (ASD). As a drug product becomes commercially viable, there is a need for scaling up the manufacturing process. In the case of HME used for the formation of ASDs, scale-up can be challenging due to the fundamental differences in how heat is generated in extruders of differing scale, i.e. conduction vs. viscous dissipation and the significant role heat generation plays in determining the final product attributes. Using a 30%w/w dipyridamole-in copovidone formulation, 11 mm-, 16 mm- and 24 mm-diameter extruders with L/D 40, solid-state characterization tools, a geometric scaling equation, and Ludovic(r) twin-screw extrusion software, we compared the total imparted material energy, the conducted energy and the difference between barrel and melt temperature at die exit for various feed rates and screw speeds. Numerical simulation identified desirable adiabatic conditions at multiple extruder scales in agreement with the chosen scaling factor. With the use of computational tools, the energetics in an extrusion process can be evaluated and processing conditions can be selected to identify the most efficient scaling of a HME process. PMID- 29253588 TI - Homocysteine pathway and in vitro fertilization outcome. AB - A prospective study investigating whether levels of the homocysteine pathway are associated with pregnancy rate in in vitro fertilization (IVF). Prior to initiate treatments, women gave a blood sample to test serum and red blood cell (RBC) folates, homocysteine and vitamin B12. The main outcome was cumulative clinical pregnancy rate according to basal levels of serum and RBC folates, homocysteine and vitamin B12. Two-hundred-nine women were selected, of whom 56 achieved a clinical pregnancy (27%). Median [interquartile range] levels of RBC and serum folate in women who did and did not become pregnant were 328 and 263 ng/ml (p = 0.018) and 13.6 and 9.4 ng/ml (p = 0.001), respectively. The adjusted ORs (95%CI) of pregnancy in women with RBC and serum folate concentrations in the upper tertile of the distributions were 2.6 (1.4-5.1) and 1.9 (1.0-3.7), respectively. Women undergoing IVF treatments with higher levels of folate have a higher chance of clinical pregnancy. PMID- 29253587 TI - Effect of beta-cypermethrin exposure on embryo implantation in mice. AB - The aim of this study was to investigate the effect of beta-CP on embryo implantation in mice. Forty female mice were randomly assigned to four groups of 10 mice each: one control group and three beta-CP treated groups. The control group was administered corn oil only, while the three beta-CP-treated groups were given corn oil containing 5, 10, and 20 mg/kg bw d beta-CP for 3 months through intragastric administration. The results indicated that the administration of beta-CP decreased the rate of embryo implantation (all p < 0.05), E2 level in the serum, and the expression of Homeobox A10 (HoxA10) protein. In addition, beta-CP significantly increased ERa and PRA protein expression levels. These results suggest that beta-CP can disrupt the balance of E2 and P, influence ERa and PRA expression and their downstream-related molecule Hoxa10, and decrease embryo implantation. PMID- 29253590 TI - Current state of knowledge in Chorea-Acanthocytosis as core Neuroacanthocytosis syndrome. AB - Neuroacanthocytosis (NA) syndromes are a group of rare diseases characterized by neurological disorders and misshaped spiky red blood cells (acanthocytes) including Chorea-Acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington disease like 2 (HDL 2), pantothenate kinase-associated neurodegeneration (PKAN), abeta- and hypobetalipoproteinemia and aceruloplasminemia. This clinically and genetically heterogeneous group of diseases shares main clinical features presenting most often as a hyperkinetic movement disorder. Even though these are long noted disease conditions, we still know only little on the underlying disease mechanisms. The current review focuses upon ChAc as the core entity of NA syndromes caused by mutations in the VPS13A gene. The support of patient organizations and the ERA-NET initiative yielded to different multidisciplinary efforts with significant progress on our understanding of ChAc. Disturbances in two pathways are currently considered to be significantly involved in the pathophysiology of ChAc, namely elevated Lyn kinase phosphorylation and decreased signaling via Phosphoinositide 3-kinase (PI3K). These recent developments may reveal potential drugable targets for causative therapies of ChAc. PMID- 29253589 TI - Mitochondrial CDP-diacylglycerol synthase activity is due to the peripheral protein, TAMM41 and not due to the integral membrane protein, CDP-diacylglycerol synthase 1. AB - CDP diacylglycerol synthase (CDS) catalyses the conversion of phosphatidic acid (PA) to CDP-diacylglycerol, an essential intermediate in the synthesis of phosphatidylglycerol, cardiolipin and phosphatidylinositol (PI). CDS activity has been identified in mitochondria and endoplasmic reticulum of mammalian cells apparently encoded by two highly-related genes, CDS1 and CDS2. Cardiolipin is exclusively synthesised in mitochondria and recent studies in cardiomyocytes suggest that the peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1alpha and beta) serve as transcriptional regulators of mitochondrial biogenesis and up-regulate the transcription of the CDS1 gene. Here we have examined whether CDS1 is responsible for the mitochondrial CDS activity. We report that differentiation of H9c2 cells with retinoic acid towards cardiomyocytes is accompanied by increased expression of mitochondrial proteins, oxygen consumption, and expression of the PA/PI binding protein, PITPNC1, and CDS1 immunoreactivity. Both CDS1 immunoreactivity and CDS activity were found in mitochondria of H9c2 cells as well as in rat heart, liver and brain mitochondria. However, the CDS1 immunoreactivity was traced to a peripheral p55 cross-reactive mitochondrial protein and the mitochondrial CDS activity was due to a peripheral mitochondrial protein, TAMM41, not an integral membrane protein as expected for CDS1. TAMM41 is the mammalian equivalent of the recently identified yeast protein, Tam41. Knockdown of TAMM41 resulted in decreased mitochondrial CDS activity, decreased cardiolipin levels and a decrease in oxygen consumption. We conclude that the CDS activity present in mitochondria is mainly due to TAMM41, which is required for normal mitochondrial function. PMID- 29253591 TI - Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer's disease brain: A meta-analysis in human pathological specimens. AB - Oxidative stress and decreased cellular responsiveness to oxidative stress are thought to influence brain aging and Alzheimer's disease, but the specific patterns of oxidative damage and the underlying mechanism leading to this damage are not definitively known. The objective of this study was to define the pattern of changes in oxidative-stress related markers by brain region in human Alzheimer's disease and mild cognitive impairment brain tissue. Observational case-control studies were identified from systematic queries of PubMed, ISI Web of Science and Scopus databases and studies were evaluated with appropriate quality measures. The data was used to construct a region-by-region meta-analysis of malondialdehyde, 4-hydroxynonenal, protein carbonylation, 8-hydroxyguanine levels and superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase activities. We also evaluated ascorbic acid, tocopherol, uric acid and glutathione levels. The analysis was complicated in several cases by publication bias and/or outlier data. We found that malondialdehyde levels were slightly increased in the temporal and occipital lobes and hippocampus, but this analysis was significantly impacted by publication bias. 4-hydroxynonenal levels were unchanged in every brain region. There was no change in 8-hydroxyguanine level in any brain region and protein carbonylation levels were unchanged except for a slight increase in the occipital lobe. Superoxide dismutase, glutathione peroxidase and reductase and catalase activities were not decreased in any brain region. There was limited data reporting non-enzymatic antioxidant levels in Alzheimer's disease brain, although glutathione and tocopherol levels appear to be unchanged. Minimal quantitative data is available from brain tissue from patients with mild cognitive impairment. While there is modest evidence supporting minor regional changes in markers of oxidative damage, this analysis fails to identify a consistent pattern of pro-oxidative changes and accumulation of oxidative damage in bulk tissue analysis in the setting of Alzheimer's disease, as has been widely reported. PMID- 29253592 TI - WDR26/MIP2 interacts with VDAC1 and regulates VDAC1 expression levels in H9c2 cells. AB - MIP2, one of WDR26 isoforms, encodes a 498 amino acid protein with an amino terminal CTLH domain and five carboxyl-terminal WD40 motifs. MIP2 is localized to the mitochondria and protects cardiomyocytes against oxidative stress; however, nothing is known about how MIP2 confers its cytoprotection. Using co immunoprecipitation (co-IP) method to isolate MIP2-protein complex from Sprague Dawley rat heart, followed by mass spectrometry analysis, we have identified VDAC1, a protein located at mitochondria, as a novel MIP2-interacting protein in the myocardium of rat hearts as well as H9c2 cells. This interaction was further confirmed by co-IP assays in the myocardial tissues and H9c2 cardiomyocytes, and by protein overlay assay (POA) in vitro. It was shown that MIP2 overexpression alleviated the H2O2-induced increase of VDAC1 and cell damage, and MIP2 deficiency aggravated the increase of VDAC1 and cell damage in H2O2 -treated H9c2 cells. Our research suggests that the protective effect of MIP2 on the cardiomyocytes against oxidative stress is partly associated with its interaction with VDAC1 and thus inhibiting its expression. PMID- 29253593 TI - Tumor cell cholesterol depletion and V-ATPase inhibition as an inhibitory mechanism to prevent cell migration and invasiveness in melanoma. AB - BACKGROUND: V-ATPase interactions with cholesterol enriched membrane microdomains have been related to metastasis in a variety of cancers, but the underlying mechanism remains at its beginnings. It has recently been reported that the inhibition of this H+ pump affects cholesterol mobilization to the plasma membrane. METHODS: Inhibition of melanoma cell migration and invasiveness was assessed by wound healing and Transwell assays in murine cell lines (B16F10 and Melan-A). V-ATPase activity was measured in vitro by ATP hydrolysis and H+ transport in membrane vesicles, and intact cell H+ fluxes were measured by using a non-invasive Scanning Ion-selective Electrode Technique (SIET). RESULTS: Cholesterol depletion by 5mM MbetaCD was found to be inhibitory to the hydrolytic and H+ pumping activities of the V-ATPase of melanoma cell lines, as well as to the migration and invasiveness capacities of these cells. Nearly the same effects were obtained using concanamycin A, a specific inhibitor of V-ATPase, which also promoted a decrease of the H+ efflux in live cells at the same extent of MbetaCD. CONCLUSIONS: We found that cholesterol depletion significantly affects the V ATPase activity and the initial metastatic processes following a profile similar to those observed in the presence of the V-ATPase specific inhibitor, concanamycin. GENERAL SIGNIFICANCE: The results shed new light on the functional role of the interactions between V-ATPases and cholesterol-enriched microdomains of cell membranes that contribute with malignant phenotypes in melanoma. PMID- 29253594 TI - Evaluation of immune responses induced by polymeric OMP25-BLS Brucella antigen. AB - Brucellosis is one the serious infectious diseases caused deleterious health and economic losses. Vaccination with subunit vaccines is the efficient alternative way than live attenuated vaccines against infectious diseases. Herein a new chimeric OMP25-BLS antigen emulsified in Chitosan Nanoparticles was designed and its immune responses were compared with control groups. Also, the role of heat shock protein 60 kDa in combination with OMP25-BLS antigen was assessed. Structural and antigenic features of chimeric antigen were predicted using bioinformatics tools. Moreover, the humoral and cellular immune responses were measured by ELISA in seven different groups. Observations showed rOMP25-BLS structure was highly stable and antigenic. Cytokines analysis showed rOMP25 and rOMP25-BLS + rHSP60 induced higher titer of INF-gamma than rHSP60 and rOMP25-BLS. There was no statistically significant difference between positive control group and rOMP25-BLS + rHSP60 in inducing TNF-alpha (p < .05). Additionally, the highest titer of IL-4 was dedicated to rOMP25 among other immunized treatments, while there were no significant differences between positive control group and other immunized groups with recombinant proteins (p < .05). In addition, rOMP25 BLS and rHSP60 induced higher titer of total antibody compared to other groups. Also, rHSP60 could improve IgG2a to IgG1 ratio when it used in combination with chimeric antigen. Moreover, the lymphocyte proliferation index was higher in chimeric rOMP25-BLS + HSP60 antigen. In conclusion, while rOMP25-BLS chimeric antigen unable to induce efficient cellular response than individual injection of rOMP25, its injection in combination with rHSP60 could improve cellular immunity. PMID- 29253595 TI - Aeromonas caviae alters the activities of ecto-enzymes that hydrolyze adenine nucleotides in fish thrombocytes. AB - It is recognized that the purinergic system, through the activities of ectonucleoside triphosphate diphosphohydrolase (E-NTPDase), ecto-5'-nucleotidase (E-5'-nucleotidase), and ecto-adenosine deaminase (E-ADA), is involved in the regulation and modulation of the physiological and pathological events linked to hemostasis. This occurs due to the role of adenosine diphosphate (ADP) in the activation and recruitment of platelets, and the role of adenosine (Ado) in the inhibition of platelet activation. Thus, here we aimed to evaluate whether Aeromonas caviae infection impairs the ecto-enzymes of the purinergic system in fish thrombocytes and the involvement of this system in the hemorrhagic septicemia. The total number of fish thrombocytes decreased in infected animals compared to uninfected animals. Regarding the ecto-enzymes of the purinergic system, the E-NTPDase and E-5'-nucleotidase activities increased in infected animals compared to uninfected animals, while the E-ADA activity decreased. These findings show that adenine nucleotide hydrolysis is modified in the thrombocytes of fish experimentally infected with A. caviae, which impairs the coagulation process due the excessive hydrolysis of ADP, a molecule linked with activation and recruitment of thrombocytes at the site of vascular injury, and augmentation on Ado levels, a molecule linked with inhibitory effects on platelet activation and aggregation. In summary, the purinergic system might contribute to the occurrence of hemorrhagic frames in fish infected with A. caviae. PMID- 29253596 TI - Mechanism of bio molecule stabilized selenium nanoparticles against oxidation process and Clostridium Botulinum. AB - The bio molecules from plant leaf extract utilized in the preparation of selenium material at the nano scale. The selenium ion was reduced to selenium nanoparticles in the presence of molecule residue of the plant leaf extract. The bio molecule stabilized selenium nanoparticles were grown gradually in the reaction mixture. The selenium nanoparticles were characterized using atomic absorption spectroscopy, fourier transform inferred spectroscopy, X-ray diffraction, scanning electronic microscope and transmission electronic microscope. The selenium nanoparticles were synthesized successfully as the nano crystalline pure hexagonal phase and the size range of 26-41 nm with spherical in shape. The activity and mechanism of nanoparticles suggested that the selenium nanoparticles are causes of leakage of reducing sugars and protein of pathogens membrane cell. The selenium nano are responsible for death and fully inhibited the microbial growth of pathogen. The bio molecule stabilized selenium nanoparticles were also investigated for the antioxidant agent. Selenium nanoparticles showed scavenging activity up to 94.48%. These results recommended that the advantages of using this method for synthesis of selenium nanoparticles with excellent antioxidant and antimicrobial mechanism and activity, which can be used as the antioxidant and antibiotic agent. PMID- 29253597 TI - Comparative therapeutic efficacy of Phyllanthus emblica (Amla) fruit extract and procaine penicillin in the treatment of subclinical mastitis in dairy buffaloes. AB - To investigate the comparative therapeutic efficacy of Phyllanthus emblica (Amla) fruit extract and procaine penicillin in the treatment of subclinical mastitis, a total of 30 subclinical mastitis positive buffaloes out of 194 lactating buffaloes were divided into 3 equal groups viz. A, B and C. Group A was treated with procaine penicillin, group B was treated with Phyllanthus emblica fruit extract and group C was served as control for 5 days respectively. The collected milk samples were subjected to the treatment trials before and after the treatment at day 0, 7th and 14th day aseptically. The evaluation parameters were bacteriological cure rate, milk pH, milk yield. The percentage cure rate of sub clinically mastitic quarters in group A, B and C were 80.95%, 64.7% and 22.22% at day 14 respectively. The quarter based bacteriological cure rate was highest in group A (80.95%) followed by group B (64.7%) and group C (22.22%). The pH was significant (P > .05) in group A, B and C at day 0, 7 and 14. It is concluded that Phyllanthus emblica fruit extract is an inexpensive source in the treatment of subclinical mastitis in dairy buffaloes and can be used as an alternative to antibiotic therapy as for procaine penicillin. PMID- 29253598 TI - Antibacterial activity and virtual screening by molecular docking of lycorine from Pancratium foetidum Pom (Moroccan endemic Amaryllidaceae). AB - Lycorine is an alkaloid isolated from bulbs of Pancratium foetidum Pom Amaryllidaceae of the genus Lycoris. It has very strong pharmacodynamics properties and biological effects, among others, antimalarial, antiviral, antitumor, and anti-inflammatory. Lycorine has been identified and characterized by thin layer chromatography, IR and NMR (1H and 13C NMR, COZY, HMBC, HSQC and NOESY). The antibacterial activity of lycorine has been evaluated. Lycorine has a moderate antibacterial activity on the majority of strains studied, nevertheless it is more effective than Streptomycin and Ampicillin against bacteria: P. aeruginosa, En. cloacae. To confirm these results, it is necessary to use qualitative techniques and methods, etc... We performed a virtual docking ligand lycorine protein screening study to predict and characterize their mode of interaction with the LpxC receptor. Docking results have shown that lycorine can interact with target amino residues studied by hydrogen and metal-ion bonds. In addition, the ADME-Tox profile study has shown that lycorine is all in agreement, either with Lipinski's critics or with the toxicity standards. PMID- 29253599 TI - Myxobolus okamurae sp. nov. (Myxosporea: Myxozoa) causing severe gill myxoboliosis in the cyprinid Labeo bata in a cold water wetland, Punjab (India). AB - During the present study on myxozoan parasites infecting gills of cyprinid carps inhabiting Ranjit Sagar Wetland, a new parasite, Myxobolus okamurae sp. nov. infecting gills of Labeo bata has been described based on morphology, histopathology and partial 18S rDNA sequencing. For M. okamurae sp. nov., hundred fish specimens were examined, out of which thirty-three had large cylindrical to round, white plasmodia in gills, each plasmodium measured 0.9-3.0 mm in diameter. The myxospore body was pyriform in shape, measuring 12.25 * 4.93 MUm, with a small intercapsular process at the anterior end. The polar capsules were equal and pyriform in shape, measuring 6.06 * 1.45 MUm having polar filaments forming coils up to 13-14 in number. The intensity of infection was recorded to be heavy as indicated by gill plasmodium index (GPI = 3). Sequence analysis showed that M. okamurae sp. nov. is 91% similar with M. catlae infecting gills of Catla catla from India followed by M. intimus infecting gills of Leuciscus idus from Hungary. The phylogenetic tree based on the final edited alignment (403 bp) with Maximum Likelihood showed the high bootstrap value of 75 and formed two major clades involving M. okamurae sp. nov. with M. pendula M. catlae and M. dispar in one clade with a low bootstrap value of 23 and the rest of the species in a separate clade. The plasmodium was located in the gill lamella and typed as "intralamellar vascular type, LV3". PMID- 29253600 TI - Cadmium induced ROS alters M1 and M3 receptors, leading to SN56 cholinergic neuronal loss, through AChE variants disruption. AB - Cadmium, an environmental neurotoxic compound, produces cognitive disorders, although the mechanism remains unknown. Previously, we described that cadmium induces a more pronounced cell death on cholinergic neurons from basal forebrain (BF). This effect, partially mediated by M1 receptor blockade, triggering it through AChE splices variants alteration, may explain cadmium effects on learning and memory processes. Cadmium has been also reported to induce oxidative stress generation leading to M2 and M4 muscarinic receptors alteration, in hippocampus and frontal cortex, which are necessary to maintain cell viability and cognitive regulation, so their alteration in BF could also mediate this effect. Moreover, it has been reported that antioxidant treatment could reverse cognitive disorders, muscarinic receptor and AChE variants alterations induced by cadmium. Thus, we hypothesized that cadmium induced cell death of BF cholinergic neurons is mediated by oxidative stress generation and this mechanism could produce this effect, in part, through AChE variants altered by muscarinic receptors disruption. To prove this, we evaluated in BF SN56 cholinergic neurons, whether cadmium induces oxidative stress and alters muscarinic receptors, and their involvement in the induction of cell death through alteration of AChE variants. Our results show that cadmium induces oxidative stress, which mediates partially the alteration of AChE variants and M2 to M4 muscarinic receptors expression and blockage of M1 receptor. In addition, cadmium induced oxidative stress generation by M1 and M3 receptors alteration through AChE variants disruption, leading to cell death. These results provide new understanding of the mechanisms contributing to cadmium harmful effects on cholinergic neurons. PMID- 29253601 TI - Association of the AADAC gene and Tourette syndrome in a Han Chinese cohort. AB - Tourette syndrome (TS) is a complex neuropsychiatric disorder with chronic motor and vocal tics. Though the etiology is elusive, strong evidence for a genetic contribution to TS has been established. To date, various chromosomal or genetic alterations have been implicated in its pathogenesis. Recently, the deletion in the arylacetamide deacetylase gene (AADAC) was reported to be associated with TS. To investigate the association between the AADAC gene variants and TS, we conducted genetic analysis of the AADAC gene in 200 Han Chinese patients and 300 ethnicity-matched normal controls. Two variants, including a heterozygous splice site variant, c.361 + 1G > A (rs762169706), and a missense variant, c.744A > T (p.R248S, rs186388618), were identified in two unrelated patients. The c.361 + 1G > A variant, absent in 300 ethnicity-matched controls, led to the deletion of exon 2 in AADAC mRNA, probably associated with development of TS. The c.744A > T variant, predicted to be damaging, was identified in two normal controls. The findings indicate that the AADAC gene c.361 + 1G > A variant may be a potential candidate factor for TS development, though further investigations are warranted. PMID- 29253602 TI - Increased MMN amplitude following passive perceptual learning with LTP-like rapid stimulation. AB - An important feature of perception is plasticity, enabling the acquisition of new perceptual representations to facilitate responding to regular stimuli in the environment. The auditory system has shown capacity for plasticity into adulthood, allowing the perceptual discrimination abilities to be improved by training. It has been suggested that a certain form of passive learning using rapid sensory stimulation can lead to plasticity in the sensory cortex through mechanisms similar to long-term potentiation. Here we demonstrate using electroencephalography that brief rapid auditory stimulation (2 min, 13 Hz) with a sinusoidal tone (1025 Hz) led to increased discriminability of the stimulated tone from a standard tone (1000 Hz) as indexed by mismatch negativity event related potential. This shows that perceptual learning with brief exposure can cause plastic changes similar to long-term training. PMID- 29253603 TI - Region-specific expression of circular RNAs in the mouse brain. AB - Circular RNAs (circRNAs) are abundant in mammalian brain and their expression is regulated in a tissue- and developmental stage-specific manner. Mammalian brain is the most transcriptionally complex organ. While many studies have extensively studied linear transcriptome and its biological functions in the brain, the circular transcriptome remains largely unexplored. This study focused on investigation of circRNA expression patterns in the mammalian brain regions critical for cognitive and memory functions and performed comparative analysis with the linear transcriptome. Altogether our study showed that circular and linear RNAs have independent expression patterns despite being derived from the same genomic locus, and that circular transcriptomes from different brain region have distinct characteristics in terms of transcript abundance and composition. PMID- 29253604 TI - Adults with Specific Language Impairment fail to consolidate speech sounds during sleep. AB - Specific Language Impairment (SLI) is a common learning disability that is associated with poor speech sound representations. These differences in representational quality are thought to impose a burden on spoken language processing. The underlying mechanism to account for impoverished speech sound representations remains in debate. Previous findings that implicate sleep as important for building speech representations, combined with reports of atypical sleep in SLI, motivate the current investigation into a potential consolidation mechanism as a source of impoverished representations in SLI. In the current study, we trained individuals with SLI on a new (nonnative) set of speech sounds, and tracked their perceptual accuracy and neural responses to these sounds over two days. Adults with SLI achieved comparable performance to typical controls during training, however demonstrated a distinct lack of overnight gains on the next day. We propose that those with SLI may be impaired in the consolidation of acoustic-phonetic information. PMID- 29253605 TI - Acute treatment with ketamine and chronic treatment with minocycline exert antidepressant-like effects and antioxidant properties in rats subjected different stressful events. AB - Despite decades of research, the fundamental neurochemical and molecular mechanisms underlying the major depressive disorder (MDD) are still poorly understood, and current antidepressant treatments have limited clinical efficacy. In clinical conditions, the rapprochement between the disease and the corrective actions of drugs in laboratory animals is essential for developing effective therapies. Thus, the aim of this study was to evaluate the antidepressant effects of ketamine (N-metil-d-asparte (NMDA) receptor antagonist), minocycline (tetracycline antibiotic), and amitriptyline (classical antidepressant), on behavior and oxidative stress parameters in animals submitted to the chronic mild stress (CMS) and maternal deprivation protocols. For this aim, male Wistar rats were submitted to maternal deprivation or CMS. To induce maternal deprivation, Wistar rats were deprived of maternal care during the first 10 days of life. To induce CMS, Wistar rats were submitted to the CMS for 40 days. To reverse the effects of stress, treatment was done intraperitoneally with a single dose of ketamine (15 mg/kg), and minocycline (25 mg/kg) and amitriptyline (10 mg/kg) by 20 days. After treatment, the animals were submitted to the forced swimming test and then analyzed oxidative stress parameters in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens (NAc). Treatment with ketamine, minocycline and amitriptyline were able to exert antidepressant effects in the forced swimming test. However, these antidepressant effects were dependent on the stress model by which the animals were exposed. In certain brain regions some treatment strategies had a pro-oxidant effect. Though, most of the strategies used in this study had antioxidant effects, as reported by a decrease on protein and lipid damage, nitrite/nitrate concentration and myeloperoxidase activity. In addition, an increase in the antioxidant superoxide dismutase (SOD) and catalase (CAT) enzymes activities were also evident after treatments. In conclusion, the antidepressant effects of ketamine and minocycline, in the present study, may be associated, at least in part, with its antioxidant and neuroprotective effects in animals subjected to maternal deprivation or CMS. PMID- 29253606 TI - Effects of Xiao Yao San on interferon-alpha-induced depression in mice. AB - BACKGROUND AND OBJECTIVE: Xiao Yao San (XYS) is a traditional Chinese medicine used to treat depression; however, the mechanism underlying its antidepressant properties remains unclear. The objective of the present study was to investigate the effects and action mechanisms of XYS on interferon-alpha-induced depression in mice. METHOD: Mice were divided into six groups: control; model; low-, medium , and high-dose XYS; and escitalopram-treated group. Except for the control mice, all groups of mice were injected with interferon (IFN)-alpha to establish the depression model. XYS and escitalopram were then administered to the respective mice daily for 21 days. Sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) were used to measure behavioral indices. High performance liquid chromatography (HPLC) was used to measure serotonin (5-HT) concentrations, while western blots were used to examine indoleamine-2,3 dioxygenase 1 (IDO1) expression in the dorsal raphe nucleus (DRN). The number of microglia in the DRN was observed using immunofluorescence. RESULTS: Compared with that of the control group, the model group showed a significant decrease in sucrose consumption (P < 0.05) and significant increase in the duration of immobility in the FST and TST (P < 0.05). These parameters improved significantly after XYS or escitalopram treatment. There was also a significantly higher and lower expression of IDO1 protein and 5-HT in the mouse DRN, respectively, which were reversed by administering XYS and escitalopram (P < 0.05). Moreover, the number of microglia in the mouse DRN increased significantly and was reduced by XYS and escitalopram (P < 0.05). CONCLUSION: XYS reduced the number of microglia and expression of IDO1, which increased the levels of 5-HT in the mouse DRN and, thereby, improved the depressive behavior of mice. This may explain, at least in part, the antidepressant properties of XYS in patients. PMID- 29253607 TI - Single-case experimental designs to assess intervention effectiveness in rehabilitation: A practical guide. AB - Single-case experimental designs (SCED) are experimental designs aiming at testing the effect of an intervention using a small number of patients (typically one to three), using repeated measurements, sequential (+/-randomized) introduction of an intervention and method-specific data analysis, including visual analysis and specific statistics. The aim of this paper is to familiarise professionals working in different fields of rehabilitation with SCEDs and provide practical advice on how to design and implement a SCED in clinical rehabilitation practice. Research questions suitable for SCEDs and the different types of SCEDs (e.g., alternating treatment designs, introduction/withdrawal designs and multiple baseline designs) are reviewed. Practical steps in preparing a SCED design are outlined. Examples from different rehabilitation domains are provided throughout the paper. Challenging issues such as the choice of the repeated measure, assessment of generalisation, randomization, procedural fidelity, replication and generalizability of findings are discussed. Simple rules and resources for data analysis are presented. The utility of SCEDs in physical and rehabilitation medicine (PRM) are discussed. PMID- 29253608 TI - Uncovering the molecular organization of unusual highly scattered 5S rDNA: The case of Chariesterus armatus (Heteroptera). AB - One cluster of 5S rDNA per haploid genome is the most common pattern among Heteroptera. However, in Chariesterus armatus, highly scattered signals were noticed. We isolated and characterized the entire 5S rDNA unit of C. armatus aiming to a deeper knowledge of molecular organization of the 5S rDNA among Heteroptera and to understand possible causes and consequences of 5S rDNA chromosomal spreading. For a comparative analysis, we performed the same approach in Holymenia histrio with 5S rDNA restricted to one bivalent. Multiple 5S rDNA variants were observed in both species, though they were more variable in C. armatus, with some of variants corresponding to pseudogenes. These pseudogenes suggest birth-and-death mechanism, though homogenization was also observed (concerted evolution), indicating evolution through mixed model. Association between transposable elements and 5S rDNA was not observed, suggesting spreading of 5S rDNA through other mechanisms, like ectopic recombination. Scattered organization is a rare example for 5S rDNA, and such organization in C. armatus genome could have led to the high diversification of sequences favoring their pseudogenization. PMID- 29253609 TI - Genome-wide analysis of DNA methylation in five tissues of sika deer (Cervus nippon). AB - DNA methylation plays an important role in regulating gene expression during tissue development and differentiation in eukaryotes. In contrast to domestic animals, epigenetic studies have been seldom conducted in wild animals. In the present study, we conducted the genome-wide profiling of DNA methylation for five tissues of sika deer using the fluorescence-labeled methylation-sensitive amplified polymorphism (F-MSAP) technique. Overall, a total of 104,131 fragments were amplified including 41,951 methylated fragments using 32 pairs of selected primers. The average incidence of DNA methylation was approximately 38.18% in muscle, 40.32% in heart, 41.86% in liver, 41.20% in lung, and 41.68% in kidney, respectively. Also, the significant differences of the DNA methylation levels were found between the different tissue types (P<0.05), which indicates that the differences of genome-wide DNA methylation levels may be related to gene expression during tissue development and differentiation. In addition, 37 tissue specific differentially methylated regions (T-DMRs) were identified and recovered by MSAP in five tissues, and were further confirmed by Southern blot analysis. Our study presents the first look at the T-DMRs in sika deer and represents an initial step towards understanding of epigenetic regulatory mechanism underlying tissue development and differentiation in sika deer. PMID- 29253610 TI - Association between single nucleotide polymorphisms in TLR4, TLR2, TLR9, VDR, NOS2 and CCL5 genes with acute viral bronchiolitis. AB - BACKGROUND: Acute viral bronchiolitis is the leading cause of hospitalization among infants during the first year of life. Most infants hospitalized for bronchiolitis do not present risk factors and are otherwise healthy. Our objective was to determine the genetic features associated with the risk and a severe course of bronchiolitis. METHODS: We prospectively evaluated 181 infants with severe bronchiolitis admitted at three hospitals over a 2-year period, who required oxygen therapy. The control group consisted of 536 healthy adults. Patients were evaluated for the presence of comorbidities (premature birth, chronic respiratory disease, and congenital heart disease), underwent nasopharyngeal aspirate testing for virus detection by multiplex-PCR, and SNPs identification in immune response genes. Patient outcomes were assessed. RESULTS: We observed association between SNP rs2107538*CCL5 and bronchiolitis caused by respiratory syncytial virus(RSV) and RSV-subtype-A, and between rs1060826*NOS2 and bronchiolitis caused by rhinovirus. SNPs rs4986790*TLR4, rs1898830*TLR2, and rs2228570*VDR were associated with progression to death. SNP rs7656411*TLR2 was associated with length of oxygen use; SNPs rs352162*TLR9, rs187084*TLR9, and rs2280788*CCL5 were associated with requirement for intensive care unit admission; while SNPs rs1927911*TLR4, rs352162*TLR9, and rs2107538*CCL5 were associated with the need for mechanical ventilation. CONCLUSIONS: Our findings provide some evidence that SNPs in CCL5 and NOS2 are associated with presence of bronchiolitis and SNPs in TLR4, TLR2, TLR9, VDR and CCL5 are associated with severity of bronchiolitis. PMID- 29253611 TI - Biomarker identification in clear cell renal cell carcinoma based on miRNA-seq and digital gene expression-seq data. AB - This study aimed to explore the underlying microRNA (miRNA) targets in clear cell renal cell carcinoma (ccRCC). The expression profile with accession number GSE24952 was downloaded from the Gene Expression Omnibus database. Based on the dataset, the differentially expressed genes (DEGs) and miRNAs in ccRCC tissues and matched normal adjacent tissues were analyzed. The target genes of the differentially expressed miRNAs were then predicted. Expression levels of several key miRNAs and genes were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A total of 168 up- and 288 downregulated DEGs, and 26 up- and 54 downregulated differentially expressed miRNAs were identified. The target genes of miRNA-429 (TGFB1, CCND1, EGFR, and LAMC1) and miRNA-206 (CCND1 and EGFR) were upregulated. Based on the tumor suppressor (TS) gene and tumor-associated gene (TAG) databases, miRNA-142-5p was selected from the upregulated miRNAs. miRNA-429, miRNA-422a, miRNA-206, miRNA-132-3p, and miRNA 184 were selected from the downregulated miRNAs. Moreover, the miRNA regulation network revealed that CCND1 was the common target gene of miRNA-429, miRNA-206, and miRNA-184, and ATP1B1 was the common target gene of miRNA-140-3p and miRNA 142-5p. qRT-PCR revealed that the expression levels of miR-140-3p and CCND1 significantly increased, while that of ATP1B1 significantly decreased in 786-O cells compared with those in human renal tubular epithelial cells, which was in accordance with the predicted results of bioinformatic analysis. In conclusion, miRNA-429, miRNA-206, and miRNA-184 and their target gene CCND1, as well as miRNA 140-3p and miRNA-142-5p and their target gene ATP1B1, might play key roles in ccRCC progression and could be useful biomarkers during ccRCC development. PMID- 29253612 TI - Folk medicinal plant mixtures: Establishing a protocol for further studies. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Most ethnobotanical research bases its analyses on individual taxa catalogues and their uses, rather than on mixtures. However, mixtures constitute an important chapter of our different lines of research and they represent a large volume of information. The relevance of these data in folk medicine could be explained as a response to the cure of multicausal etiology diseases or by a possible polyvalent effect of the mixture as opposed to the effect of each taxon alone. AIMS OF THE STUDY: The main goals are: i) to perform qualitative and quantitative analyses of these mixtures; ii) to carry out a comparison among the mixtures in two Catalan territories and their floristic composition; iii) to assess the worth of families association; and, iv) to evaluate whether the plants claimed to be used in mixtures have contraindications or possible negative interactions according to phytopharmaceutical literature. The ultimate goal is to test a protocol that can be implemented in similar studies. MATERIALS AND METHODS: We have used data on medicinal plant mixtures obtained from two extensive ethnobotanical field studies carried out in two Catalan districts, Alt Emporda and Ripolles. The quantitative analyses by means of descriptive statistics were carried out with Excel. New contributions like the implementation of the Shannon index to quantify the diversity of families in plant combinations, the creation of a new index to calculate the taxon importance in mixtures, or the use of a social network analysis to study the connection between botanical families have been employed in this work. RESULTS: In total, a set of 484 mixtures from Alt Emporda and Ripolles (Catalonia, Iberian Peninsula) have been analysed: 462 for human use and 22 for veterinary. Thymus vulgaris and Rosmarinus officinalis are among the most commonly used species in mixtures. The aerial part of the plant is the most used, and the anticatarrhal usage is the most frequent in both territories. A wide diversity of families has been observed in mixtures and reflects a strong bond between the number of taxa and the number of families in each mixture, being almost equal to one. The Shannon diversity index applied to mixtures has the maximum value at 0.86. No exclusive plants are used in mixtures, as reflected on the index of taxon usefulness in mixtures (ITUM), proposed in the present work. The association of families is strong between Lamiaceae (12.12%) and Asteraceae with Lamiaceae (11.69%). Finally, the informant consensus factor (0.85) reflects the strong consistency of data reported by the interviewees. CONCLUSIONS: The present analysis has confirmed that it is possible to study the data of plants in mixtures as thoroughly as when they are considered in isolation in an ethnofloristic catalogue, and maybe this kind of ethnobotanical investigation could be a first step for future pharmacological studies that may result in a relevant complement to the current phytotherapy market. PMID- 29253613 TI - Neuroprotective effect of He-Ying-Qing-Re formula on retinal ganglion cell in diabetic retinopathy. AB - ETHNOPHARMACOLOGY RELEVANCE: He-Ying-Qing-Re Formula (HF) was empirically modified from Si-Miao-Yong-An Decoction (SD), which was recorded in the literature of Divine Doctor's Secret Transmission, and has been utilized for centuries to treat vasculopathy through clearing heat and accelerating bloodstream. HF has been used as an effective holistic treatment of diabetic retinopathy (DR) for decades and experimentally reported to ameliorate retinal condition in diabetic mice. AIM OF THE STUDY: Our study aims to investigate the effect of HF in preventing sustained hyperglycemia and hyperlipidemia-associated retinal ganglion cell (RGC) cell death and its possible mechanism. MATERIALS AND METHODS: Chromatographic fingerprint of HF was obtained upon the UPLC-based analytic system; Diabetic retinopathy was established in streptozotocin (STZ) injection-induced hyperglycemic mice; Alterations of retinal structure was assayed by H&E staining. Expression of PSD-95 and CHOP in retinae was assessed by immunofluorescence; RGC cell line (mRGC) was used for in vitro study. Cell death was analyzed by flow cytometry; Intracellular reactive oxygen species (ROS) was measured by 2',7'-dichlorofluorescin diacetate (DCFDA); Apoptosis-related proteins and signaling were monitored with immunoblotting and colorimetric assay. RESULTS: Chlorogenic acid, ferulic acid, and rutin were identified in HF. HF attenuates the loss of RGCs, thinning of inner retinal layers in diabetic mice. Furthermore, expressions of Brn3a and PSD-95 were restored while CHOP level was downregulated upon HF treatment. In vitro study, HF alleviates H2O2-induced apoptosis of mRGCs and loss of postsynaptic protein via scavenging ROS and suppressing ATF4/CHOP-mediated endoplasmic reticulum stress and mitochondria related pro-apoptotic factors, probably as cleaved-caspase-3, and phospho-p38 mitogen-activated protein kinase (MARK). Meanwhile, both pro-survival protein levels like Bcl-2/Bcl-xL and postsynaptic protein of PSD-95 were upregulated upon HF treatment. CONCLUSION: HF administration was a valid therapeutic approach for DR treatment, oriented at the blockade of endoplasmic reticulum- and mitochondria dependent oxidative stress-induced retinal neurodegeneration including RGC apoptosis. PMID- 29253614 TI - The hidden mechanism beyond ginger (Zingiber officinale Rosc.) potent in vivo and in vitro anti-inflammatory activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ginger (Zingiber officinale Roscoe) is a well known anti-inflammatory drug in the Egyptian, Indian and Chinese folk medicines, yet its mechanism of action is unclear. AIM OF THE STUDY: To explore its mechanism of action and to correlate it to its biophytochemicals. MATERIALS AND METHODS: Various extracts viz. water, 50%, 70%, 80%, and 90% ethanol were prepared from ginger rhizomes. Fractionation of the aqueous extract (AE) was accomplished using Diaion HP-20. In vitro anti-inflammatory activity of the different extracts and isolated compounds was evaluated using protein denaturation inhibition, membrane stabilization, protease inhibition, and anti lipoxygenase assays. In vivo anti-inflammatory activity of AE was estimated using carrageenan-induced rat paw edema in rats at doses 25, 50, 100 and 200mg/kg b.wt. RESULTS: All the tested extracts showed significant (p< 0.1) in vitro anti inflammatory activities. The strongest anti-lipoxygenase activity was observed for AE that was more significant than that of diclofenac (58% and 52%, respectively) at the same concentration (125MUg/ml). Purification of AE led to the isolation of 6-poradol (G1), 6-shogaol (G2); methyl 6- gingerol (G3), 5 gingerol (G4), 6-gingerol (G5), 8-gingerol (G6), 10-gingerol (G7), and 1-dehydro 6-gingerol (G8). G1, G2 and G8 exhibited potent activity in all the studied assays, while G4 and G5 exhibited moderate activity. In vivo administration of AE ameliorated rat paw edema in a dose-dependent manner. AE (at 200mg/kg) showed significant reduction in production of PGE2, TNF-alpha, IL-6, monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T-cell expressed and secreted (RANTES), myeloperoxidase (MPO) activity by 60%, 57%, 60%, 41%, 32% and 67%, respectively. AE at 100 and 200mg/kg was equipotent to indomethacin in reduction of NOx level and in increasing the total antioxidant capacity (TAC). Histopathological examination revealed very few inflammatory cells infiltration and edema after administration of AE (200mg/kg) prior to carrageenan. CONCLUSIONS: Ginger anti-inflammatory activity is mediated by inhibiting macrophage and neutrophils activation as well as negatively affecting monocyte and leukocyte migration. This was evidenced by the dose-dependent decrease in pro-inflammatory cytokines and chemokines and replenishment the total antioxidant capacity. PMID- 29253615 TI - Immunomodulatory effects of Sceletium tortuosum (TrimesemineTM) elucidated in vitro: Implications for chronic disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sceletium tortuosum, among other Sceletium species, was traditionally used by the Khoisan people of Southern Africa for relief of pain-related ailments. However, the commercial availability of this supplement has greatly expanded due to anecdotal claims of its mood-elevating and anxiolytic properties. Unrelated research has elucidated a significant link between cytokines and the mediation of depression. Therefore, the effect of Sceletium supplementation on immune cell functionality is of interest, since the efficacy of potential depression treatments could, at least in part, rely on downregulation of pro-inflammatory signalling. AIM OF THE STUDY: The current study evaluated the immunomodulatory effects of a Sceletium extract, both basally and in the context of acute endotoxin stimulation. MATERIALS AND METHODS: Primary human monocytes were supplemented with either a 0.01mg/ml or 1mg/ml Sceletium extract dose, with or without E. coli LPS stimulation in vitro, for 24h. Mitochondrial viability, as an indirect measure of cytotoxicity, and cytokine release in response to the treatment intervention were assessed. RESULTS: Sceletium extract treatment was associated with increased mitochondrial viability, as well as up-regulated IL-10 release under basal conditions. LPS exposure significantly decreased mitochondrial viability, but this was prevented completely under Sceletium-treated conditions. The acute inflammatory response to LPS stimulation was not negatively affected. Sceletium treatment conferred most significant effects at a dose of 0.01mg/ml. CONCLUSIONS: Sceletium exerts significant cytoprotective effects in the setting of endotoxin stimulation. Cytokine assessment indicated that Sceletium possesses mild anti-inflammatory properties, but does not hinder the mounting of an adequate immune response to acute immune challenge. These findings indicate that Sceletium may be beneficial for the attenuation of cytokine-induced depression, as well as in systemic low grade inflammation. PMID- 29253616 TI - Extracts of Cordyceps sinensis inhibit breast cancer cell metastasis via down regulation of metastasis-related cytokines expression. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cordyceps sinensis is a traditional Chinese medicine and has been used as adjuvant treatments for cancer and it has been also demonstrated to be effective in cancer patients. AIM OF THE STUDY: The objective of the present study is to investigate the anti-metastasis effects of water extracts of Cordyceps sinensis (WECS) in breast cancer and the potential mechanisms. MATERIALS AND METHODS: The cytotoxicity of WECS on 4T1 breast cancer cells was evaluated in vitro using cell counting kit-8 (CCK8) assay. The in vivo anti-metastatic activity of intraperitoneally administered WECS and its effect on animal survival were measured in a mouse breast cancer metastasis model. To explore the molecular mechanisms of the anti-metastasis effect of WECS, the expression of matrix metalloprotein-9 (MMP-9) in serum was determined by enzyme linked immunosorbent assay (ELISA). In addition, a protein array was used to examine the cytokine expression profiles in lung homogenates. RESULTS: Treatment with WECS (0.10-0.40mg/ml) significantly inhibited 4T1 cell viability in vitro. In animal studies, 50mg/kg WECS significantly reduced the number of metastatic lung nodules and the weight of lung, without affecting body weight of mice. Furthermore, WECS increased the survival rate of 4T1 tumor bearing mice in a dose dependent manner, and at high dose, WECS (50mg/kg) significantly increased the life span of the mice compared to untreated control group. The expression level of MMP-9 in serum was decreased about 50% in 50mg/kg WECS treated group compared to control group. The results of protein array showed that the expression of CC chemokine ligand 17 (CCL17), MMP-9, osteopontin (OPN), interleukin-33 (IL-33), CC chemokine ligand 12 (CCL12) and CC chemokine ligand 6 (CCL6) in the lungs of 4T1 tumor bearing mice was increased more than two fold compared with normal mice. Among them, the expression of CCL17, MMP-9, OPN, IL-33 was significantly reduced by treatment of 50mg/kg WECS. CONCLUSION: Our results demonstrated that WECS has potent anti-metastasis activity in a mouse breast cancer metastasis model possibly by down-regulation the expression of several metastasis-related cytokines. PMID- 29253617 TI - Scaphoid screw fixation perpendicular to the fracture plane: Comparing volar and dorsal approaches. AB - INTRODUCTION: To percutaneously fixate a midwaist scaphoid fracture, both volar and dorsal approaches are considered valid options although they may have different screw insertion angles relative to the scaphoid fracture plane influencing fixation stability. In this virtual simulation study, we investigated the accessibility of placing a screw perpendicularly to the fracture plane in transverse and horizontal oblique scaphoid midwaist fracture models and compared standard volar and dorsal approaches. MATERIAL AND METHODS: Computed tomography scans of 38 healthy wrists were used to obtain virtual 3-dimensional wrist models in flexion and extension. In case the trapezium in volar approach or the distal radius in dorsal approach obstructed the screw axis perpendicular to the fracture plane, an alternative non-obstructed screw axis was chosen as close as possible to the perpendicular axis. The deviation angle between the best possible non obstructed screw placement and true perpendicular screw placement was quantified. RESULTS: For transverse fractures, the average deviation angle (+/-standard deviation) was 8 degrees (+/-5 degrees ) in volar approach, and 0 degrees (+/-0 degrees ) in dorsal approach. For horizontal oblique fractures, these angles were 40 degrees (+/-6 degrees ) and 14 degrees (+/-8 degrees ), respectively. DISCUSSION: In our simulations, compared to the volar approach, the dorsal approach provided the most precise screw placement perpendicular to the fracture plane, with the largest differences for horizontal oblique fractures. When taken in addition to screw purchase, thread engagement and protrusion risk, information about screw orientation may help surgeons in deciding between percutaneous approaches in scaphoid surgery on which there is currently no consensus. LEVEL OF EVIDENCE: N/A. PMID- 29253619 TI - Shortened Basal Internodes Encodes a Gibberellin 2-Oxidase and Contributes to Lodging Resistance in Rice. AB - Breeding semi-dwarf varieties to improve lodging resistance has been proven to be enormously successful in increasing grain yield since the advent of the "green revolution." However, the breeding of the majority of semi-dwarf rice varieties in Asia has been dependent mainly on genetic introduction of the mutant alleles of SD1, which encodes a gibberellin (GA) 20-oxidase, OsGA20ox2, for catalyzing GA biosynthesis. Here, we report a new rice lodging-resistance gene, Shortened Basal Internodes (SBI), which encodes a gibberellin 2-oxidase and specifically controls the elongation of culm basal internodes through deactivating GA activity. SBI is predominantly expressed in culm basal internodes. Genetic analyses indicate that SBI is a semi-dominant gene affecting rice height and lodging resistance. SBI allelic variants display different activities and are associated with the height of rice varieties. Breeding with higher activity of the SBI allele generates new rice varieties with improved lodging resistance and increased yield. The discovery of the SBI provides a desirable gene resource for producing semi-dwarf rice phenotypes and offers an effective strategy for breeding rice varieties with enhanced lodging resistance and high yield. PMID- 29253618 TI - UDP-sugars activate P2Y14 receptors to mediate vasoconstriction of the porcine coronary artery. AB - AIMS: UDP-sugars can act as extracellular signalling molecules, but relatively little is known about their cardiovascular actions. The P2Y14 receptor is a Gi/o coupled receptor which is activated by UDP-glucose and related sugar nucleotides. In this study we sought to investigate whether P2Y14 receptors are functionally expressed in the porcine coronary artery using a selective P2Y14 receptor agonist, MRS2690, and a novel selective P2Y14 receptor antagonist, PPTN (4,7 disubstituted naphthoic acid derivative). METHODS AND RESULTS: Isometric tension recordings were used to evaluate the effects of UDP-sugars in porcine isolated coronary artery segments. The effects of the P2 receptor antagonists suramin and PPADS, the P2Y14 receptor antagonist PPTN, and the P2Y6 receptor antagonist MRS2578, were investigated. Measurement of vasodilator-stimulated phosphoprotein (VASP) phosphorylation using flow cytometry was used to assess changes in cAMP levels. UDP-glucose, UDP-glucuronic acid UDP-N-acetylglucosamine (P2Y14 receptor agonists), elicited concentration-dependent contractions of the porcine coronary artery. MRS2690 was a more potent vasoconstrictor than the UDP-sugars. Concentration dependent contractile responses to MRS2690 and UDP-sugars were enhanced in the presence of forskolin (activator of cAMP), where the level of basal tone was maintained by addition of U46619, a thromboxane A2 mimetic. Contractile responses to MRS2690 were blocked by PPTN, but not by MRS2578. Contractile responses to UDP-glucose were also attenuated by PPTN and suramin, but not by MRS2578. Forskolin-induced VASP-phosphorylation was reduced in porcine coronary arteries exposed to UDP-glucose and MRS2690, consistent with P2Y14 receptor coupling to Gi/o proteins and inhibition of adenylyl cyclase activity. CONCLUSIONS: Our data support a role of UDP-sugars as extracellular signalling molecules and show for the first time that they mediate contraction of porcine coronary arteries via P2Y14 receptors. PMID- 29253621 TI - Antibacterial properties and compressive strength of new one-step preparation silver nanoparticles in glass ionomer cements (NanoAg-GIC). AB - OBJECTIVES: This work aimed (1) to develop polyacid formulations by the one-step photoreduction of silver nanoparticles (AgNP) in a polyacrylate solution of conventional glass ionomer cement (GIC), imparting antibacterial activity; and (2) to evaluate handling and mechanical properties of experimental ionomers in comparison to a commercially available conventional GIC. METHODS: Formulations with increasing sub-stoichiometric amounts of AgNO3 were monitored during continuous UV light exposure by UV-vis spectroscopy and analyzed by transmission electron microscopy. The resulted synthesis of formulations containing small and disperse spherical nanoparticles (~6 nm) were used to design the experimental nano-silver glass ionomer cements (NanoAg-GIC). The cements were characterized as to net setting time and compressive strength according to ISO 9917-1:2007 specifications. The antibacterial activity of these cements was assessed by Ag+ diffusion tests on nutritive agar plates (E. coli) and by MTT assay (S. mutans). RESULTS: The higher concentration of silver (0.50% by mass) in the matrix of NanoAg-GIC allowed viable net setting time and increased in 32% compressive strength of the experimental cement. All groups containing AgNP induced statistically significant E. coli growth inhibition zones (p-value <.05), indicating diffusion of Ag+ ions on the material surroundings. Metabolic activity of S. mutans grown on NanoAg-GIG with higher concentration of silver was significantly affected compared to control (p-value <.01). CONCLUSIONS: Silver nanoparticles one-step preparation in polyacrylate solution allowed the production of highly bioactive water-based cements within suitable parameters for clinical use and with large potential of dental and biomedical application. PMID- 29253620 TI - Molecular characterization and metal induced gene expression of the novel glutathione peroxidase 7 from the chordate invertebrate Ciona robusta. AB - In the present study, we describe the identified and characterized the gene and the transcript of a novel glutathione peroxidase-7 (GPx7) from the solitary ascidian Ciona robusta, an invertebrate chordate widely distributed in temperate shallow seawater. The putative nucleotide and amino acid sequences were compared with those of GPx7 from other metazoans and phylogenetic analysis suggests the presence of a high evolutionary pressure in the contest of neutral evolution. The mRNA of CrGPx7 is located in hemocytes and ovarian follicular cells, as revealed by in situ hybridization. The time course of CrGPx7 mRNA levels in the presence of Cd, Cu and Zn, showed upregulation in the final stages of the experiments, suggesting a role of GPx7 in late protection from oxidative stress. Our in silico analyses of the crgpx7 promoter region revealed putative consensus sequences similar to mammalian metal-responsive elements (MRE) and xenobiotic-responsive elements (XRE), suggesting that the transcription of these genes directly depends on metals. Cell-free extract from C. robusta tissues show the presence of selenium-independent GPx activity that is inhibited by the presence of metals. PMID- 29253623 TI - Virulence patterns of Staphylococcus aureus strains from nasopharyngeal colonization. AB - BACKGROUND: The prevalence of nasopharyngeal colonization with Staphylococcus aureus can reach 20-30% among the population, which can lead to invasive infection. AIM: To investigate the prevalence of colonization among different age groups, and analyse S. aureus strain-specific virulence patterns. METHOD: For analysis of the prevalence of colonization, groups consisting of newborns, healthy volunteers aged 5-60 years, and nursing home residents aged >80 years were examined with nasopharyngeal swabs. After S. aureus was cultured, genetic analysis and phenotypic virulence testing were performed by cell-based assays. FINDINGS: Among 924 volunteers, the overall colonization rate was approximately 30%, with a peak in subjects aged 5-10 years (49%). Neonates and subjects aged >80 years showed different distributions of clonal clusters. Overall, the strains of all age groups exhibited virulence characteristics that can contribute to the development of infection. In particular, the neonatal strains exhibited a high incidence of toxin genes that resulted in increased cytotoxic effects compared with the other strains tested. CONCLUSIONS: Colonizing strains showed a virulence profile in all age groups, which may lead to the establishment of invasive infection. Consequently, decolonization measures could be considered for selected patients depending on the risk of infection. PMID- 29253622 TI - Regional point prevalence study of healthcare-associated infections and antimicrobial use in acute care hospitals in Liguria, Italy. AB - BACKGROUND: Given the importance of monitoring healthcare-associated infections (HCAIs) and the consumption of antibiotics, a regional point prevalence survey was conducted in Liguria between March and April 2016. AIM: To measure the overall prevalence of HCAI and describe the use of antibiotics in all public hospitals. METHODS: Data on risk factors and use of antibiotics were collected for each hospitalized patient. To define the variables significantly associated with HCAI, univariate and multivariate analyses were conducted. Standardized infection ratio and standardized antimicrobial use ratio were measured for each participating hospital. FINDINGS: A total of 3647 patients were enrolled. In all, 429 HCAIs were diagnosed in 376 patients, giving a prevalence of HCAI of 10.3%. Respiratory tract (21.7%) and urinary tract (20%) were the most frequent sites of infection. High rates of meticillin-resistant Staphylococcus aureus (47.4%) and Enterobacteriaceae resistant to carbapenems (26.3%) were isolated. Forty-six percent of patients received at least one antibiotic. Combinations of penicillins including beta-lactamase inhibitors (24.1%) were the most widely used; the main indication (46.7%) was the treatment of a community-acquired infection. CONCLUSION: There was an increase in HCAI prevalence compared to a similar survey conducted in 2007; however, the performance of overlapping investigations will enable more reliable considerations. Nevertheless, data on antimicrobial resistance and use of antibiotics are consistent with the national trend. Despite methodological limitations, prevalence studies are useful to monitor HCAI over time and encourage greater awareness of the problem by all stakeholders. PMID- 29253624 TI - Traffic flow and microbial air contamination in operating rooms at a major teaching hospital in Ghana. AB - BACKGROUND: Current literature examining the relationship between door-opening rate, number of people present, and microbial air contamination in the operating room is limited. Studies are especially needed from low- and middle-income countries, where the risk of surgical site infections is high. AIM: To assess microbial air contamination in operating rooms at a Ghanaian teaching hospital and the association with door-openings and number of people present. Moreover, we aimed to document reasons for door-opening. METHODS: We conducted active air sampling using an MAS 100(r) portable impactor during 124 clean or clean contaminated elective surgical procedures. The number of people present, door opening rate and the reasons for each door-opening were recorded by direct observation using pretested structured observation forms. FINDINGS: During surgery, the mean number of colony-forming units (cfu) was 328 cfu/m3 air, and 429 (84%) of 510 samples exceeded a recommended level of 180 cfu/m3. Of 6717 door openings recorded, 77% were considered unnecessary. Levels of cfu/m3 were strongly correlated with the number of people present (P = 0.001) and with the number of door-openings/h (P = 0.02). In empty operating rooms, the mean cfu count was 39 cfu/m3 after 1 h of uninterrupted ventilation and 52 (51%) of 102 samples exceeded a recommended level of 35 cfu/m3. CONCLUSION: The study revealed high values of intraoperative airborne cfu exceeding recommended levels. Minimizing the number of door-openings and people present during surgery could be an effective strategy to reduce microbial air contamination in low- and middle income settings. PMID- 29253625 TI - Insulin tolerance test predicts non response vs. sustained efficacy of Liraglutide on glycemic control in type 2 diabetes patients: A prospective real world setting study. AB - AIMS: Less than half of type 2 diabetes patients treated with Glucagon-Like Peptide 1 (GLP-1) analogs displays good glycemic control, according to real life studies. Predictive markers of inefficacy/efficacy are therefore needed. The effectiveness of Liraglutide in terms of glycemic control and weight loss was then evaluated according to putative predictive parameters. METHODS: 80 type 2 diabetes patients treated with Liraglutide were included in this prospective study. An Insulin Tolerance test (ITT) was performed at baseline to calculate velocity of C-Peptide decrease (C-peptide T1/2). Several clinical and biological parameters including HbA1c and weight were assessed at baseline and after 12, 24, 52 and 104 weeks of treatment. RESULTS: HbA1c decrease over the follow-up period was highly associated with C-peptide T1/2. A mean fall of 0.7% of HbA1c (7.7 mmol/mol) was predicted with 82% sensitivity and 80% specificity by C-peptide T1/2. In patients with rapid response during ITT (C-peptide T1/2 < 120 min), a HbA1c decrease of 1.5% (16.5 mmol/mol) was constantly found (p = .002) all over the follow-up. HbA1c remained unmodified for the rest of the patients (p = .34) compared to baseline. HbA1c evolution was not predicted by diabetes duration. Weight loss was predicted only by low baseline C-peptide plasma level. CONCLUSIONS: This study suggests ITT as an efficient test to discriminate non response from long-term efficacy before initiating Liraglutide. ITT could therefore help avoiding "try and see" prescription pattern by using a more precise and patient-centered strategy in order to reduce inertia in adapting treatment and so reduce subsequent complications. PMID- 29253626 TI - ATLANTIC DIP: Despite insulin therapy in women with IADPSG diagnosed GDM, desired pregnancy outcomes are still not achieved. What are we missing? AB - AIMS: To assess if pregnancy outcomes for women with GDM treated with insulin (GDM-I) are comparable to outcomes for women with GDM treated with medical nutritional therapy (MNT) (GDM-M). MATERIALS AND METHODS: This retrospective cohort study included 752 women with GDM-I and 567 women with GDM-M. Maternal and foetal outcomes were examined. RESULTS: Women with GDM-I had a greater risk of polyhydramnios (aOR 2.33, 95%CI 1.31-4.14) and were more likely to deliver by caesarean section (CS) (aOR 1.67, 95%CI 1.25-2.23). Their offspring had higher rates of macrosomia (22.2% vs 12.7%; p < .01), large for gestational age (LGA) (19.7% vs 12.5%; p < .01) and were more likely to require neonatal intensive care unit (NICU) admission (aOR 4.88, 95%CI 3.54-6.73). There was no difference between the groups in rates of pre-eclampsia (PET), pregnancy-induced hypertension (PIH), infant mortality, congenital malformations, neonatal hypoglycaemia, prematurity and rates of small for gestational age (SGA). CONCLUSIONS: GDM-I and GDM-M mothers have similar rates of maternal medical morbidities. Despite this, the rate of delivery by CS remains greater, possibly driven by physician choice for elective intervention in the GDM-I group. Despite insulin therapy, offspring of GDM-I mothers experience higher rates of macrosomia, LGA and NICU admissions. This may be related to the higher baseline risk profile in GDM-I women, to sub-optimal glycaemic control, excessive gestational weight gain (GWG) or higher baseline BMI of the mother. Addressing baseline maternal BMI, limiting excessive GWG and tightening glycaemic control in GDM-I women may translate to better pregnancy outcomes. PMID- 29253627 TI - Potential serum biomarkers for early detection of diabetic nephropathy. AB - AIM: Diabetic nephropathy (DN) is considered as one of the diabetic complications affecting up to 40% of patients with type 1 or type 2 diabetes. In clinical practice, the frequently used markers of renal disease and progression are serum creatinine, estimated glomerular filtration rate (eGFR) and albuminuria. The aim of this study is to determine new biomarkers in human serum which are promising for early detection of DN. METHODS: This study included 50 patients with type 2 diabetes mellitus (T2DM) and 25 clinically healthy individuals. The patients were divided into two groups; group I included 25 T2DM patients with normoalbuminuria, and group II consisted of 25 T2DM patients with microalbuminuria. In all groups, neutrophil gelatinase-associated lipocalin (NGAL), beta-trace protein (betaTP) and microRNA- 130b (miR-130b) were estimated. RESULTS: The serum levels of NGAL and betaTP were significantly elevated in T2DM patients with microalbuminuria (group II) compared with T2DM patients with normoalbuminuria (group I) and control subjects but there was no significant difference between group I and control subjects. Serum miR-130b level was significantly decreased in patients with T2DM (groups I and II) compared with healthy control subjects, with a higher decrease in their levels in group II compared with group I. CONCLUSION: Our results suggest that serum NGAL and betaTP as tubular and glomerular markers respectively, together with serum miR-130b may be independent and reliable biomarkers for early detection of DN in patients with T2DM. PMID- 29253628 TI - Multi-scale and multi-physics model of the uterine smooth muscle with mechanotransduction. AB - Preterm labor is an important public health problem. However, the efficiency of the uterine muscle during labor is complex and still poorly understood. This work is a first step towards a model of the uterine muscle, including its electrical and mechanical components, to reach a better understanding of the uterus synchronization. This model is proposed to investigate, by simulation, the possible role of mechanotransduction for the global synchronization of the uterus. The electrical diffusion indeed explains the local propagation of contractile activity, while the tissue stretching may play a role in the synchronization of distant parts of the uterine muscle. This work proposes a multi-physics (electrical, mechanical) and multi-scales (cell, tissue, whole uterus) model, which is applied to a realistic uterus 3D mesh. This model includes electrical components at different scales: generation of action potentials at the cell level, electrical diffusion at the tissue level. It then links these electrical events to the mechanical behavior, at the cellular level (via the intracellular calcium concentration), by simulating the force generated by each active cell. It thus computes an estimation of the intra uterine pressure (IUP) by integrating the forces generated by each active cell at the whole uterine level, as well as the stretching of the tissue (by using a viscoelastic law for the behavior of the tissue). It finally includes at the cellular level stretch activated channels (SACs) that permit to create a loop between the mechanical and the electrical behavior (mechanotransduction). The simulation of different activated regions of the uterus, which in this first "proof of concept" case are electrically isolated, permits the activation of inactive regions through the stretching (induced by the electrically active regions) computed at the whole organ scale. This permits us to evidence the role of the mechanotransduction in the global synchronization of the uterus. The results also permit us to evidence the effect on IUP of this enhanced synchronization induced by the presence of SACs. This proposed simplified model will be further improved in order to permit a better understanding of the global uterine synchronization occurring during efficient labor contractions. PMID- 29253629 TI - Multidimensional mitochondrial energetics: Application to the study of electron leak and hydrogen peroxide metabolism. AB - Oxygen consumption is a valuable tool to link with measurements of mitochondrial electron leakage to form reactive oxygen species (ROS), which in mitochondria is predominantly superoxide and H2O2. However, oxygen consumption may respond differently to changes in conditions than superoxide/H2O2 production does, complicating the use of respiration as a sole indicator of mitochondrial energetics. The same equipment that is valuable for fluorescent monitoring of H2O2 efflux provides a straightforward means of estimating membrane potential (DeltaPsi), thereby an alternative metric of mitochondrial energetics is readily added to complement studies on the link between mitochondrial energetics and electron leak. By combining multiple aspects of mitochondrial energetics a far more detailed picture emerges on why changes in superoxide/H2O2 formation arise with reduced dependence on assumptions. Here we illustrate integration of experimental methods via demonstration of linkages between mitochondrial DeltaPsi, oxygen consumption and superoxide/H2O2 formation (the latter estimated by H2O2 efflux). In doing so we also expand on some pitfalls and cautions for these experimental manipulations of isolated mitochondria and, using these techniques, we raise the possibility that the oxygen affinity for respiration may be higher than the affinity for some sites of electron leak. PMID- 29253630 TI - PREPARE: presurgery physiotherapy for patients with degenerative lumbar spine disorder: a randomized controlled trial. AB - BACKGROUND CONTEXT: Surgery because of disc herniation or spinal stenosis results mostly in large improvement in the short-term, but mild to moderate improvements for pain and disability at long-term follow-up. Prehabilitation has been defined as augmenting functional capacity before surgery, which may have beneficial effect on outcome after surgery. PURPOSE: The aim was to study if presurgery physiotherapy improves function, pain, and health in patients with degenerative lumbar spine disorder scheduled for surgery. STUDY DESIGN: A single-blinded, two arm, randomized controlled trial (RCT). PATIENT SAMPLE: A total of 197 patients were consecutively included at a spine clinic. The inclusion criteria were patients scheduled for surgery because of disc herniation, spinal stenosis, spondylolisthesis, or degenerative disc disease (DDD), 25-80 years of age. OUTCOME MEASURES: Primary outcome was Oswestry Disability Index (ODI). Secondary outcomes were pain intensity, anxiety, depression, self-efficacy, fear avoidance, physical activity, and treatment effect. METHODS: Patients were randomized to either presurgery physiotherapy or standardized information, with follow-up after the presurgery intervention as well as 3 and 12 months post surgery. The study was funded by regional research funds for US$77,342. No conflict of interest is declared. RESULTS: The presurgery physiotherapy group had better ODI, visual analog scale (VAS) back pain, EuroQol-5D (EQ-5D), EQ-VAS, Fear Avoidance Belief Questionnaire-Physical Activity (FABQ-PA), Self-Efficacy Scale (SES), and Hospital Anxiety and Depression Scale (HADS) depression scores and activity level compared with the waiting-list group after the presurgery intervention. The improvements were small, but larger than the study-specific minimal clinical important change (MCIC) in VAS back and leg pain, EQ-5D, and FABQ-PA, and almost in line with MCIC in ODI and Physical Component Summary (PCS) in the physiotherapy group. Post surgery, the only difference between the groups was higher activity level in the physiotherapy group compared with the waiting-list group. CONCLUSIONS: Presurgery physiotherapy decreases pain, risk of avoidance behavior, and worsening of psychological well-being, and improves quality of life and physical activity levels before surgery compared with waiting-list controls. These results were maintained only for activity levelspost surgery. Still, presurgery selection, content, dosage of exercises, and importance of being active in a presurgery physiotherapy intervention is of interest to study further to improve long-term outcome. PMID- 29253632 TI - Radiological morphology variances of osteotomized vertebra-disc complex following pedicle subtraction osteotomy for ankylosing spondylitis with thoracolumbar kyphosis: the incidence, mechanisms, and prognosis. AB - BACKGROUND CONTEXT: Inaccurate osteotomy cut along with incomplete or even subluxated bone-on-bone closure of osteotomy gap following pedicle subtraction osteotomy (PSO) may be disastrous, hampering the lordosing effect and increasing the likelihood of complications. The inelastic yet osteoporotic spine in ankylosing spondylitis (AS) is specially predisposed to such suboptimal osteotomy, while the relevant data concerning this issue are scarce. PURPOSE: This study aimed to analyze the incidence of radiological morphology variances (RMV) of osteotomized vertebra-disc complex (OVDC) following PSO in patients with kyphotic AS, conceptualize the mechanisms of the deviated morphology, and investigate the prognosis. STUDY DESIGN: This is a retrospective radiological data analysis. PATIENT SAMPLE: The sample being screened comprises 71 patients with thoracolumbar kyphotic AS who underwent single-level PSO at our hospital between March 2006 and February 2014. They were stratified by the presence of bridging syndesmophytes (BS) locating within the OVDC. OUTCOME MEASURES: Any irregular radiological configuration of OVDC other than the wedge morphology would be considered as RMV and were studied with care to fully describe and classify the spectrum of deviated morphologic features. Multiple spinopelvic sagittal parameters were measured to assess both the regional lordosing effect and the global realignment of sagittal spinal profile. METHODS: For each selected patient with confirmed RMV, the radiological morphology was assessed, defined, and categorized. The prognosis involving surgical corrections and maintenance of spinopelvic sagittal parameters, as well as the remodeling in disordered osteotomized vertebral shape over time, were also investigated. RESULTS: The incidence of RMV was 21.9% in positive BS group (PG) and 30.8% in negative BS group (NG). Inappropriate angle and range of osteotomy accounted for the largest share (1 pts for PG and 10 pts for NG, 57.9%) of mechanisms responsible for RMV, followed by vertebral subluxation (VS) (5 pts for PG and 2 pts for NG, 36.8%) and failed osteotomy gap closure (1 pts for PG, 5.3%). For these patients, the mean bony lordosing effect per PSO segment was 36.0 degrees +/-8.9 degrees postoperatively, and decreased to 34.7 degrees +/-8.7 degrees by a mean follow up of 3 years (p=.076). The magnitude of neighboring disc opening was significantly higher in NG (10.2 degrees +/-6.5 degrees vs. 2.4 degrees +/-3.2 degrees , p=.009). The global kyphosis and sagittal vertical axis were significantly corrected (77.0 degrees +/-21.2 degrees vs. 24.4 degrees +/-18.8 degrees ; 160.6 degrees +/-72.4 degrees vs. 48.2 degrees +/-38.6 mm, all p<.001) and remained stable by the ultimate follow-up (p>.05). No devastating neurologic deficits were noticed. Patients with VS and failed osteotomy gap closure exclusively showed solid bone healing and adaptive remodeling without rod breakage at final follow-up. CONCLUSIONS: Radiological morphology variances of OVDC were a high occurrence following PSO in AS, being mainly attributed to inaccurate osteotomy cut and VS. Neighboring disc opening and rotational or translational subluxation were major available remedial mechanisms strengthening the lordosing effect when that of vertebral wedging was impaired and insufficient. The bone fusion and remodeling concerning the subluxated or dislocated osteotomized vertebra was utterly favorable, maintaining the kyphosis correction and preventing instrumentation failure. PMID- 29253631 TI - Safety and accuracy of freehand versus navigated C2 pars or pedicle screw placement. AB - BACKGROUND CONTEXT: C2 pedicle and pars screws require accurate placement to avoid injury to nearby neurovascular structures. Freehand, fluoroscopically guided, and computed tomography (CT)-based navigation techniques have been described in the medical literature. PURPOSE: The present study aims to compare the safety and accuracy of the freehand technique versus stereotactic navigation for the placement of C2 pedicle and pars screws. STUDY DESIGN/SETTING: This study was a retrospective review of consecutive patients treated with posterior fixation constructs. PATIENT SAMPLE: A total of 220 consecutive patients were treated with posterior fixation constructs containing C2 pars or pedicle screws placed at our institution. OUTCOME MEASURES: Computed tomography imaging was used to assess the accuracy of screw placement. Intraoperative complications and incidence of stroke or mortality within 30 days of the operation were analyzed. METHODS: A retrospective review was conducted of consecutive patients treated with posterior fixation constructs containing C2 pars or pedicle screws placed by spine surgeons between January 1, 2010, and August 31, 2016. Clinical and radiographic data were collected and analyzed. Screw accuracy was graded independently by two reviewers according to the following criteria: grade A (no breach), grades B-E (breach with transverse foramen obstruction of 1%-25%, 26% 50%, 51%-75%, or 76%-100%, respectively), and grade M (medial breach). Screws were divided into acceptable (grades A and B) and unacceptable (grades C-E and M). RESULTS: A total of 426 C2 pars or pedicle screws (312 freehand, 114 navigated) were placed in 220 patients (160 freehand, 60 navigated). Complications were similar between the groups: three vertebral artery injuries (two [1%] freehand, one [2%] navigated; p>.99), five deaths (four [3%] freehand, one [2%] navigated; p>.99), and one (2%) stroke in the navigated group (p=.61). Computed tomography imaging was available for accuracy grading of 182 screws (131 freehand, 51 navigated). No breaches (grade A) occurred in 113 of the freehand screws (86%) and in 34 of the navigated screws (67%) (p=.006). More screws had acceptable placement in the freehand group (123 of 131, 94%) than in the navigated group (42 of 51, 82%) (p=.02). CONCLUSIONS: In patients with postoperative CT imaging (43%), the freehand technique was found to be more accurate than CT-based navigation for C2 pedicle or pars screw placement. Complication rates did not differ between the two techniques in this study. PMID- 29253633 TI - Investigation of the passive mechanical properties of spine muscles following disruption of the thoracolumbar fascia and erector spinae aponeurosis, as well as facet injury in a rat. AB - BACKGROUND CONTEXT: Muscle tissue is known to remodel in response to changes to its mechanical environment. Alterations in passive mechanical properties of muscles can influence spine stiffness and stability. PURPOSE: This study aimed to determine whether passive muscle elastic moduli and passive muscle stresses increased 28 days following mechanical disruption of the thoracolumbar fascia and erector spinae aponeurosis, and injury induced by facet joint compression. STUDY DESIGN: Male Sprague Dawley rats were randomly assigned to three groups (Incision n=8; Injury n=8; and Control n=6). METHODS: The thoracolumbar fascia and erector spinae aponeurosis were incised in the Incision and Injury groups to expose the left L5-L6 facet joint. In the Injury group, this facet was additionally compressed for three minutes to induce facet injury and cartilage degeneration. Twenty-eight days after surgery, rats were sacrificed and muscle samples were harvested from lumbar and thoracic erector spinae and multifidus for mechanical testing. RESULTS: Histologic staining revealed mild cartilage degeneration and boney remodeling in the Injury group. However, the hypotheses that either (1) disruption of the thoracolumbar fascia and erector spinae aponeurosis (Incision group) or (2) the addition of facet compression (Injury group) would increase the passive elastic modulus and stress of surrounding muscles were rejected. There was no effect of surgery (Incision or Injury) on the passive elastic modulus (p=.6597). Passive muscle stresses were also not different at any sarcomere length between surgical groups (p>.7043). CONCLUSION: Disruption of the thoracolumbar fascia and erector spinae aponeurosis and mild facet damage do not lead to measurable changes in passive muscle mechanical properties within 28 days. These findings contribute to our understanding of how spine muscles are affected by injury and fundamental aspects of the initial stages of spine surgery. PMID- 29253634 TI - Odontoid-sparing transnasal approach for drainage of craniocervical epidural abscess; a novel technique and review of the literature. AB - BACKGROUND CONTEXT: Surgical approaches to the craniovertebral junction (CVJ) are challenging. Available approaches include posterior, transoral, endonasal, and anterior extended retropharyngeal approach. Resection of the odontoid process is necessary to gain access to the pathology posterior to it. The resultant cranio atlanto-axial instability usually necessitates subsequent posterior stabilization. PURPOSE: To describe a new odontoid-sparing approach to the spinal canal at the CVJ. This dens-sparing approach preserves occipito-atlanto-axial stability and avoids the need for occipitocervical stabilization that adds to the extent of surgery and its associated morbidity and mortality. STUDY DESIGN: Describing a novel technique and reporting two cases. PATIENT SAMPLE: Two patients that presented with infection at the CVJ with a retro-odontoid epidural abscess were operated on. OUTCOME MEASURES: Self-reported measures: visual analog scale for neck pain. Physiologic measures: plain x-rays (anteroposterior and lateral views), magnetic resonance imaging with contrast, computed tomography scan, C-reactive protein, and leukocytic count. Functional measures: dynamic flexion-extension views of the cervical spine. METHODS: Two patients were operated on using a combined endoscopic transnasal-transoral approach for drainage of a retro-odontoid epidural abscess and debridement without dens resection. A 4-mm, 30-degree rigid endoscope was used. Preoperative clinical and neurologic status was evaluated. The follow-up period was 12 months. The study received no funding from any organization. None of the authors has any relevant financial disclosures or conflict of interest. RESULTS: Both patients improved clinically after the endonasal transoral abscess drainage. Follow-up contrast magnetic resonance imaging showed complete resolution of the abscess after 3 weeks. Culture-sensitivity tests were positive for Staphylococcus aureus in one patient. Antibiotic therapy with clindamycin and flucloxacillin was continued for 12 weeks postoperatively. There were no intraoperative or postoperative complications. There was no need for posterior occipitocervical stabilization in both cases. CONCLUSION: This represents the first clinical report of accessing the spinal canal at the CVJ without resection of the odontoid or the anterior arch of the atlas. The addition of endoscopic-assisted supra-dental approach to the transoral one improved visibility, and allowed access to the most cranial part of spinal canal without the need for dens resection, a procedure that significantly compromises C0-1-2 stability necessitating stabilization. This novel odontoid-sparing approach showed a favorable outcome in our first two cases with retro-odontoid abscess; however, it would likely pose a high risk in other pathologies including tumors. PMID- 29253635 TI - Modic type 1 change is an autoimmune response that requires a proinflammatory milieu provided by the 'Modic disc'. AB - BACKGROUND CONTEXT: Modic changes (MCs) are magnetic resonance imaging (MRI) evidence of inflammatory and fibrotic vertebral bone marrow lesions that associate with adjacent disc degeneration and end plate damage. Although MC etiology is uncertain, historical data suggest a linkage to an autoimmune response of bone marrow triggered by the nucleus pulposus (NP). PURPOSE: The aim of this study was to test whether bone marrow has an autoimmune response to NP cells that is amplified by an inflammatory milieu and ultimately leads to MC development in vivo. We hypothesized that an inflammatory co-stimulus is required for bone marrow/NP crosstalk to stimulate MC. STUDY DESIGN: This is an in-vitro cell co-culture study plus in-vivo experiments in rat caudal vertebrae. METHODS: In in-vitro study, bone marrow mononuclear cells (BMNCs) and NP cells (NPCs) from rats were co-cultured with and without interleukin (IL)-1alpha stimulation. Cell viability (n=3) of BMNCs and NPCs and gene expression (n=7) were analyzed. In in vivo study, proinflammatory lipopolysaccharide (LPS) and control disc nucleus surrogates (NP micromass pellets) were generated in vitro from rat NPCs and implanted into rat tail vertebrae, and the response was compared with sham surgery (n=12 each). Tissue changes were investigated with T1w and T2w MRI (7T), histology, and immunohistochemistry (tumor necrosis factor, CD3) 1 (n=6) and 2 weeks (n=6) after implantation. RESULTS: BMNC/NPC co-culture significantly increased lymphocyte viability (42%-69%, p<.05) and reduced NPC viability (96% 88%, p<.001), indicating immunogenicity of NPC. However, IL-1alpha was required to cause significant transcriptional upregulation of IL-1, IL-6, IL-10, and tropomyosin receptor kinase A. Therefore, an inflammatory activation is required to amplify the immune response. Immunogenicity of the NP was corroborated in vivo by CD3 cell accumulation around LPS and control disc surrogates at Day 7. However, only the LPS disc surrogate group demonstrated infiltration of CD3 cells at Day 14. Furthermore, end plate defects (p<.05, LPS: n=4/6, Ctrl: n=0/6, sham: n=0/6) and MC1-like MRI changes (T2w hyperintensity, p<.05) were only seen with LPS disc surrogates. CONCLUSIONS: NPCs are immunogenic but cannot trigger MC without an additional proinflammatory stimulus. Our data suggest that MC requires end plate defects that allow marrow/NPC co-mingling plus an adjacent inflammatory "MC disc" that can amplify the immune response. PMID- 29253636 TI - Advanced Training of Gynecologic Surgeons and Incidence of Intraoperative Complications after Total Laparoscopic Hysterectomy: A Retrospective Study of More Than 2000 Cases at a Single Institution. AB - STUDY OBJECTIVE: To investigate whether surgeon factors including level of training undertaken in laparoscopic surgery, time in specialist practice, and case volume were associated with surgical morbidity for total laparoscopic hysterectomy (TLH). DESIGN: A retrospective cohort study (Canadian Task Force classification II-2). SETTING: A tertiary care setting in Western Australia. PATIENTS: Two thousand thirteen patients who underwent TLH for benign or malignant indications. INTERVENTIONS: Women undergoing TLH were allocated to 1 of 3 groups of surgeons: general gynecologists, gynecologic endoscopists, and subspecialists. MEASUREMENTS AND MAIN RESULTS: All patients undergoing elective TLH at St John of God Subiaco Hospital, Subiaco, Perth, Western Australia, between January 1, 2011, and December 31, 2016, were included for analysis. Variables recorded included cystotomy, ureteric injury, enterotomy/colostomy, bowel serosa injury, vascular injury, conversion to laparotomy, return to the operating room, hemorrhage, blood transfusion, operating time, length of stay, and postoperative complications to 42 days. The primary outcome was any major intraoperative complication. The incidence of any major intraoperative complication was 1.8% (36/2013 cases). Forty-five patients (2.2%) had a postoperative complication, and 74 (3.7%) patients were readmitted to the hospital after discharge. The incidence of any major intraoperative complication was significantly higher among general gynecologists compared with subspecialists (3.3% vs 1.1%, p = .002). No association was found between time in specialist practice and the incidence of major intraoperative complications (p = .629). A significant association for major intraoperative complications was observed for surgeons who had performed <100 laparoscopic hysterectomies during the study period (p = .032). CONCLUSION: In this study, despite a higher level of surgical acuity and the performance of additional and more complex procedures, surgical morbidity was lower in patients undergoing TLH by gynecologic surgeons with a higher level of subspecialist training. PMID- 29253637 TI - Comparative study on in vivo behavior of PEGylated gadolinium oxide nanoparticles and Magnevist as MRI contrast agent. AB - PEGylated gadolinium oxide nanoparticles (PEG-Gd2O3 NPs) as MRI nano-contrast agents (nano-CAs) displayed high relaxivity in our previous study. However, their behaviors in vivo have not been studied systematically yet. Herein, with clinically used CA, Magnevist as control, their toxicity, pharmacokinetics, biodistribution, half-life and excretion in vivo were studied. Mouse experiments after PEG-Gd2O3 NP administration, including the analysis of general appearance, histological changes, hepatic and renal functions, were performed to evaluate their toxicity in vivo. MRI and inductively coupled plasma-mass spectrometry (ICP MS) quantification of Gd accumulation in different organs were introduced to investigate their biodistribution and excretion. The results showed that compared with Magnevist, PEG-Gd2O3 NPs presented longer half-life, similar acute toxicity and histological influence, less effect on hepatic and renal functions, and stronger contrast enhancement in tumor, showing their potentials as MRI CA for preclinical applications. Different from kidney clearance of Magnevist, PEG-Gd2O3 NPs were mainly excreted via liver. PMID- 29253638 TI - Antipurinergic therapy for autism-An in-depth review. AB - Are the symptoms of autism caused by a treatable metabolic syndrome that traces to the abnormal persistence of a normal, alternative functional state of mitochondria? A small clinical trial published in 2017 suggests this is possible. Based on a new unifying theory of pathogenesis for autism called the cell danger response (CDR) hypothesis, this study of 10 boys, ages 5-14years, showed that all 5 boys who received antipurinergic therapy (APT) with a single intravenous dose of suramin experienced improvements in all the core symptoms of autism that lasted for 5-8weeks. Language, social interaction, restricted interests, and repetitive movements all improved. Two children who were non-verbal spoke their first sentences. None of these improvements were observed in the placebo group. Larger and longer studies are needed to confirm this promising discovery. This review introduces the concept of M2 (anti-inflammatory) and M1 (pro-inflammatory) mitochondria that are polarized along a functional continuum according to cell stress. The pathophysiology of the CDR, the complementary functions of M1 and M2 mitochondria, relevant gene-environment interactions, and the metabolic underpinnings of behavior are discussed as foundation stones for understanding the improvements in ASD behaviors produced by antipurinergic therapy in this small clinical trial. PMID- 29253639 TI - Eye movement attenuation of intrusive social anxiety imagery: A pilot study. PMID- 29253640 TI - Introducing an EXperimental Paradigm to investigate Expectation Change (EXPEC). AB - BACKGROUND AND OBJECTIVES: Dysfunctional expectations are considered to be core features of various mental disorders. Clinical observations suggest that people suffering from mental disorders such as major depression tend to maintain dysfunctional expectations despite expectation-disconfirming evidence. Surprisingly, this clinically relevant phenomenon has not yet sufficiently been investigated in empirical studies. Therefore, we developed an experimental paradigm to investigate expectation change vs. maintenance, and the first step to test its validity is to apply it in healthy individuals. METHODS: After conducting two pilot studies (n = 28; n = 37), the present study systematically examined whether it is possible to change healthy individuals' (n = 102) task specific and generalized performance expectations through expectation disconfirming experiences. Using a standardized instruction, we initially induced non-positive expectations regarding participants' ability to successfully work on an unknown test. Then, participants received standardized performance feedback that either confirmed or disconfirmed their expectations before assessing participants' expectations again after completing the Test for the Measure of Emotional Intelligence. RESULTS: Results indicate that expectation-disconfirming feedback led to a significant change of both task-specific and generalized performance expectations. There was no expectation change in the expectation confirming condition. LIMITATIONS: As the present study examined expectation change among healthy individuals, the next step is to apply this paradigm in a clinical sample and to examine whether expectation change is less likely among people suffering from depression or other mental disorders characterized by dysfunctional expectations. CONCLUSIONS: Focusing more rigorously on expectation maintenance among people with mental disorders could enable therapists to develop expectation-focused interventions aiming at enhancing expectation change. PMID- 29253641 TI - Mapping the dynamical organization of the cell nucleus through fluorescence correlation spectroscopy. AB - The hierarchical organization of the cell nucleus into specialized open reservoirs and the nucleoplasm overcrowding impose restrictions to the mobility of biomolecules and their interactions with nuclear targets. These properties determine that many nuclear functions such as transcription, replication, splicing or DNA repair are regulated by complex, dynamical processes that do not follow simple rules. Advanced fluorescence microscopy tools and, in particular, fluorescence correlation spectroscopy (FCS) provide complementary and exquisite information on the dynamics of fluorescent labeled molecules moving through the nuclear space and are helping us to comprehend the complexity of the nuclear structure. Here, we describe how FCS methods can be applied to reveal the dynamical organization of the nucleus in live cells. Specifically, we provide instructions for the preparation of cellular samples with fluorescent tagged proteins and detail how FCS can be easily instrumented in commercial confocal microscopes. In addition, we describe general rules to set the parameters for one and two-color experiments and the required controls for these experiments. Finally, we review the statistical analysis of the FCS data and summarize the use of numerical simulations as a complementary approach that helps us to understand the complex matrix of molecular interactions network within the nucleus. PMID- 29253642 TI - Disease tolerance: concept and mechanisms. AB - Two distinct defense strategies provide a host with survival to infectious diseases: resistance and tolerance. Resistance is dependent on the ability of the host to kill pathogens. Tolerance promotes host health while having a neutral to positive impact of pathogen fitness. Immune responses are almost inevitably defined in terms of pathogen resistance. Recent evidence has shown, however, that several effects attributed to activation of innate and adaptive immune mechanisms, cannot be readily explained with the paradigm of immunity as effectors of microbial destruction. This review focuses on integrating the concept of disease tolerance into recent studies of immune system function related to the regulation and resolution of tissue damage, T cell exhaustion, and tolerance to innocuous antigen. PMID- 29253643 TI - Higher low-density lipoprotein cholesterol levels are associated with decreased mortality in patients with intracerebral hemorrhage. AB - BACKGROUND AND AIMS: The relationship between lipoprotein levels, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and clinical outcome after intracerebral hemorrhage (ICH) remains controversial. We sought to evaluate the association of lipoprotein cholesterol levels and statin dosage with clinical and neuroimaging outcomes in patients with ICH. METHODS: Data on consecutive patients hospitalized with spontaneous acute ICH was prospectively collected over a 5-year period and retrospectively analyzed. Demographic characteristics, clinical severity documented by NIHSS-score and ICH score, neuroimaging parameters, pre-hospital statin use and doses, and LDL-C and HDL-C levels were recorded. Outcome events characterized were hematoma volume, hematoma expansion, in-hospital functional outcome, and in-hospital mortality. RESULTS: A total of 672 patients with acute ICH [(mean age 61.6 +/- 14.0 years, 43.6% women, median ICH score 1 (IQR: 0-2)] were evaluated. Statin pretreatment was not associated with neuroimaging or clinical outcomes. Higher LDL-C levels were associated with several markers of poor clinical outcome and in-hospital mortality. LDL-C levels were independently and negatively associated with the cubed root of hematoma volume (linear regression coefficient -0.021, 95% CI: 0.042--0.001; p = 0.049) on multiple linear regression models. Higher admission LDL-C (OR 0.88, 95% CI 0.77-0.99; p = 0.048) was also an independent predictor for decreased hematoma expansion. Higher admission LDL-C levels were independently (p < 0.001) associated with lower likelihood of in-hospital mortality (OR per 10 mg/dL increase 0.68, 95% CI: 0.57-0.80) in multivariable logistic regression models. CONCLUSIONS: Higher LDL-C levels at hospital admission were an independent predictor for lower likelihood of hematoma expansion and decreased in-hospital mortality in patients with acute spontaneous ICH. This association requires independent confirmation. PMID- 29253644 TI - Metabolic phenotyping of human atherosclerotic plaques: Metabolic alterations and their biological relevance in plaque-containing aorta. AB - BACKGROUND AND AIMS: Atherosclerosis is a chronic inflammatory disease characterized by thickening of the arterial wall. However, a limited number of studies have been conducted on metabolic profiling of human aortic tissue. METHODS: We applied liquid chromatography/mass spectrometry to perform global and targeted profiling of plaque-containing aortic tissue. The aorta samples included plaque-containing (n = 18) and control plaque-free (n = 24) aortic tissue from patients undergoing aortic surgery. RESULTS: The metabolic patterns of atherosclerotic and control vessels were significantly different. Metabolites in the purine and glutathione pathways showed dysregulation of oxidative stress in plaques, and levels of glucosylceramide, tryptophan, and kynurenine, which are related to inflammation, were also altered. Interestingly, an increased level of quinic acid was observed in plaques (p < 0.000), and we demonstrated an inhibitory effect of quinic acid on inflammatory activation and oxidative stress in macrophages. CONCLUSIONS: Our study provides insight into the disease mechanism and potential markers of atherosclerosis through comprehensive metabolic profiling of human aortic tissue samples containing plaque. PMID- 29253645 TI - Warning symptoms preceding out-of-hospital cardiac arrest: Do patient delays matter? AB - BACKGROUND: Although increasing patient delays between symptom onset and activation of emergency medical services (EMS) can lead to poorer outcomes following acute myocardial infarction, its effect in out-of-hospital cardiac arrest (OHCA) populations is unclear. METHODS: Between 1st January 2003 and 31st December 2011, we included adult patients with anginal warning symptoms and subsequent EMS witnessed OHCA of presumed cardiac aetiology from the Victorian Ambulance Cardiac Arrest Registry. Multivariable logistic regression was used to assess the impact of patient delay time (i.e. symptom onset to EMS call time) on survival to hospital discharge. RESULTS: A total of 1056 EMS witnessed OHCA were screened, of which 515 (48.8%) reported chest pain or anginal equivalent symptoms. The median patient delay time was 25min (interquartile range [IQR] 9 89min), and did not differ across survivors and non-survivors. However, patients in lowest quartile of patient delay (<=8min) also experienced significantly higher rates of non-shockable arrest rhythms and circulatory compromise. A total of 16 baseline and clinical characteristics were tested in a multivariable model of survival to hospital discharge, of which, only six were retained in the final model, including: age, dyspnoea, vomiting, shockable arrest rhythm, systolic blood pressure, and patient delay time. Every 30min increase in patient delay time was independently associated with a 2.3% (95% CI: 0.4%, 4.1%; p=0.02) reduction in the odds of survival to hospital discharge. Among patients with ST segment deviation on the pre-arrest ECG, every 30min increase in patient delay time was associated with a 3.4% reduction in the odds of survival (OR 0.966, 95% CI: 0.937, 0.996; p=0.03). CONCLUSION: Increasing delays in activating EMS before the onset OHCA may be associated with reduced survival. Future research could explore whether increasing public awareness of the warning symptoms leads to earlier medical contact for OHCA. PMID- 29253646 TI - Coronary lesions in refractory out of hospital cardiac arrest (OHCA) treated by extra corporeal pulmonary resuscitation (ECPR). AB - PURPOSE: Extracorporeal cardiopulmonary resuscitation (ECPR) is a second line treatment for refractory cardiac arrest (R-OHCA). Timing of ECPR before performing coronary angiography (CAG) is still debated. The aim of the study was to describe the clinical and angiographic characteristics of the largest cohort of out-of-hospital cardiac arrest (OHCA) patients undergoing ECPR. METHODS: All refractory OHCA patients with ECPR managed by the prehospital mobile intensive care unit (MoICU of the SAMU) in Paris (France) were prospectively included from October 2014 to December 2016. RESULTS: Among 74 patients included over the period, 54 patients had coronary artery disease (CAD). There is a trend toward the CAD patients being older but it did not meet statistical significance (55.3 +/- 11.8 vs. 50.6 +/- 12.8, p = 0,14). Patients were more frequently men and smokers (p = 0.03 for both). The proportion of initial shockable rhythm tended to be higher in patients with CAD (71% vs. 55%). The rate of 1-, 2-, and 3-vessel disease were 43%, 35% and 22% respectively. The Syntax Score was 18 +/- 9 and the lesions in each epicardial vessel were mainly proximal. Percutaneous coronary intervention was performed ad hoc in 49 patients (91%). Complete revascularization was performed in 64%. Inhospital death was numerically lower (65% vs. 75%) in patients with CAD, especially in patients with initial shockable rhythm. CONCLUSION: In 74 refractory OHCA patients treated with ECPR implanted by a prehospital mobile intensive care unit, the rate of CAD was high (54/74) especially in patients with shockable rhythm. The majority of patients presented with double or triple vessel disease and proximal lesions. The severity and extension of CAD may explain the refractory nature of the cardiac arrest. PMID- 29253647 TI - Metabolomic profiling for outcome prediction in emergency department patients with out-of-hospital cardiac arrest. PMID- 29253649 TI - Letter to the Editor. PMID- 29253648 TI - Hunt-Hess 5 subarachnoid haemorrhage presenting with cardiac arrest is associated with larger volume bleeds. AB - AIMS: The mechanism, effects, and outcomes of cardiac arrest (CA) caused by subarachnoid haemorrhage (SAH) remain unclear. We compared SAH patients presenting with CA to other high-grade SAH patients presenting without CA in order to better understand (1) the cause of CA, (2) cerebral pathophysiology following CA, and (3) outcomes of CA in patients with SAH. METHODS: We performed a retrospective analysis of a prospectively collected observational cohort. 31 Hunt-Hess 5 patients that presented with CA were compared to 146 Hunt-Hess 5 patients that presented without CA. Clinical and imaging findings were predefined and adjudicated. Cerebral physiology measures were available for a subset of patients, matched 1:1 by age. RESULTS: Twenty-two (71%) CA patients had pulseless electrical activity/asystole compared to 2 (6%) with a shockable rhythm. The CA patients were younger (OR 0.96, 95% CI 0.93-0.99, p=0.009), had more SAH on CT (OR 1.07, 95% CI 1.01-1.13, p=0.02), and had higher in-hospital mortality (87% vs. 58%, OR 6.2 (2.1-26.6), p=0.004). There were no differences in aneurysm location, cerebral herniation, or ictal seizures. Despite similar cerebral perfusion pressure, CA patients had pathologically lower brain tissue oxygenation, lower glucose, and higher lactate to pyruvate ratios. CONCLUSIONS: CA in SAH is associated with larger volume bleeds. Despite normal cerebral perfusion pressures, CA patients show compromised cerebral physiology. PMID- 29253650 TI - Olive flounder CD276 (B7-H3) a coinhibitory molecule for T cells: Responses during viral hemorrhagic septicemia virus (VHSV) stimulation. AB - Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis, defense and protect tissue integrity. CD276 (B7 H3) is an important immune checkpoint member of this family, which is induced on antigen-presenting cells (APCs), and plays an important role in the inhibition of T-cell function. We have characterized the CD276 gene of olive flounder, Paralichthys olivaceus. OfCD276 has an ORF of 912 bp that codes for 303 amino acids with a predicted molecular mass of 33 kDa. It is a type I transmembrane protein with a single extracellular V- and C-like Ig domains, a transmembrane region, and a highly diverse cytoplasmic tail. This gene was distinctly expressed in gill, spleen, and skin, and sparsely expressed in other tissues. Pathogen stimulation by VHSV revealed that transcription of OfCD276 was induced on early hours in liver and expressed late in head kidney, spleen, intestine and gill tissues. Flow cytometry analysis of leukocytes revealed the percentage of granulocytes and lymphocytes that expressed OfCD276 molecules on their cell surface was 85.1% and 3.1%, respectively. Our study shows a significant role played by this coinhibitory molecule that participate in the regulation of the cell mediated immune response. PMID- 29253651 TI - Behavioral and neural effects of congruency of visual feedback during short-term motor learning. AB - Visual feedback can facilitate or interfere with movement execution. Here, we describe behavioral and neural mechanisms by which the congruency of visual feedback during physical practice of a motor skill modulates subsequent performance gains. 18 healthy subjects learned to execute rapid sequences of right hand finger movements during fMRI scans either with or without visual feedback. Feedback consisted of a real-time, movement-based display of virtual hands that was either congruent (right virtual hand movement), or incongruent (left virtual hand movement yoked to the executing right hand). At the group level, right hand performance gains following training with congruent visual feedback were significantly higher relative to training without visual feedback. Conversely, performance gains following training with incongruent visual feedback were significantly lower. Interestingly, across individual subjects these opposite effects correlated. Activation in the Supplementary Motor Area (SMA) during training corresponded to individual differences in subsequent performance gains. Furthermore, functional coupling of SMA with visual cortices predicted individual differences in behavior. Our results demonstrate that some individuals are more sensitive than others to congruency of visual feedback during short-term motor learning and that neural activation in SMA correlates with such inter individual differences. PMID- 29253652 TI - What dominates the time dependence of diffusion transverse to axons: Intra- or extra-axonal water? AB - Brownian motion of water molecules provides an essential length scale, the diffusion length, commensurate with cell dimensions in biological tissues. Measuring the diffusion coefficient as a function of diffusion time makes in vivo diffusion MRI uniquely sensitive to the cellular features about three orders of magnitude below imaging resolution. However, there is a longstanding debate, regarding which contribution - intra- or extra-cellular - is more relevant in the overall time-dependence of the MRI-derived diffusion metrics. Here we resolve this debate in the human brain white matter. By varying not just the diffusion time, but also the gradient pulse duration of a standard diffusion MRI sequence, we identify a functional form of the measured time-dependent diffusion coefficient transverse to white matter tracts in 10 healthy volunteers. This specific functional form is shown to originate from the extra-axonal space, and provides estimates of the fiber packing correlation length for axons in a bundle. Our results offer a metric for the outer axonal diameter, a promising candidate marker for demyelination in neurodegenerative diseases. From the methodological perspective, our analysis demonstrates how competing models, which describe different physics yet interpolate standard measurements equally well, can be distinguished based on their prediction for an independent "orthogonal" measurement. PMID- 29253654 TI - Adolescent cannabis use and brain systems supporting adult working memory encoding, maintenance, and retrieval. AB - Given prior reports of adverse effects of cannabis use on working memory, an executive function with a protracted developmental course during adolescence, we examined associations between developmental patterns of cannabis use and adult working memory (WM) processes. Seventy-five adults with longitudinal assessments of cannabis use (60 with reported use, 15 with no reported use) and prenatal drug exposure assessment completed a spatial WM task during fMRI at age 28. All subjects passed a multi-drug urine screen on the day of testing and denied recreational drug use in the past week. A fast event-related design with partial trials was used to separate the BOLD response associated with encoding, maintenance, and retrieval periods of the WM task. Behavioral results showed that subjects who began using cannabis earlier in adolescence had longer reaction times (RT) than those with later initiation. Cannabis age of onset was further associated with reduced posterior parietal cortex (PPC) encoding BOLD activation, which significantly mediated age of onset WM RT associations. However, cannabis age of onset brain-behavior associations did not differ between groups with a single reported use and those with repeated use, suggesting age of onset effects may reflect substance use risk characteristics rather than a developmentally timed cannabis exposure effect. Within repeated cannabis users, greater levels of total cannabis use were associated with performance-related increases in dorsolateral prefrontal cortex (DLPFC) activation during maintenance. This pattern of significant results remained unchanged with inclusion of demographic and prenatal measures as covariates. Surprisingly, however, at the group level, cannabis users generally performed better than participants who reported never using cannabis (faster RT, higher accuracy). We extend previous investigations by identifying that WM associations with cannabis age of onset may be primary to PPC stimulus encoding activity, while the amount of cannabis use is associated with DLPFC maintenance processes. Poorer performance of participants who reported never using cannabis and the consistency of cannabis age of onset associations across single and repeated users limit interpretation of direct developmental effects of cannabis on WM in adulthood. PMID- 29253653 TI - A probabilistic atlas of human brainstem pathways based on connectome imaging data. AB - The brainstem is a critical structure that regulates vital autonomic functions, houses the cranial nerves and their nuclei, relays motor and sensory information between the brain and spinal cord, and modulates cognition, mood, and emotions. As a primary relay center, the fiber pathways of the brainstem include efferent and afferent connections among the cerebral cortex, spinal cord, and cerebellum. While diffusion MRI has been successfully applied to map various brain pathways, its application for the in vivo imaging of the brainstem pathways has been limited due to inadequate resolution and large susceptibility-induced distortion artifacts. With the release of high-resolution data from the Human Connectome Project (HCP), there is increasing interest in mapping human brainstem pathways. Previous works relying on HCP data to study brainstem pathways, however, did not consider the prevalence (>80%) of large distortions in the brainstem even after the application of correction procedures from the HCP-Pipeline. They were also limited in the lack of adequate consideration of subject variability in either fiber pathways or region of interests (ROIs) used for bundle reconstruction. To overcome these limitations, we develop in this work a probabilistic atlas of 23 major brainstem bundles using high-quality HCP data passing rigorous quality control. For the large-scale data from the 500-Subject release of HCP, we conducted extensive quality controls to exclude subjects with severe distortions in the brainstem area. After that, we developed a systematic protocol to manually delineate 1300 ROIs on 20 HCP subjects (10 males; 10 females) for the reconstruction of fiber bundles using tractography techniques. Finally, we leveraged our novel connectome modeling techniques including high order fiber orientation distribution (FOD) reconstruction from multi-shell diffusion imaging and topography-preserving tract filtering algorithms to successfully reconstruct the 23 fiber bundles for each subject, which were then used to calculate the probabilistic atlases in the MNI152 space for public release. In our experimental results, we demonstrate that our method yielded anatomically faithful reconstruction of the brainstem pathways and achieved improved performance in comparison with an existing atlas of cerebellar peduncles based on HCP data. These atlases have been publicly released on NITRIC (https://www.nitrc.org/projects/brainstem_atlas/) and can be readily used by brain imaging researchers interested in studying brainstem pathways. PMID- 29253656 TI - Artificial scotoma estimation based on population receptive field mapping. AB - Population receptive field (pRF) mapping based on functional magnetic resonance imaging (fMRI) is an ideal method for obtaining detailed retinotopic information. One particularly promising application of pRF mapping is the estimation and quantification of visual field effects, for example scotomata in patients suffering from macular dysfunction or degeneration (MD) or hemianopic defects in patients with intracranial dysfunction. However, pRF mapping performance is influenced by a number of factors including spatial and temporal resolution, distribution of dural venous sinuses and patient performance. This study addresses the ability of current pRF methodology to assess the size of simulated scotomata in healthy individuals. The data demonstrate that central scotomata down to a radius of 2.35 degrees (4.7 degrees diameter) visual angle can be reliably estimated in single subjects using high spatial resolution protocols and multi-channel receive array coils. PMID- 29253655 TI - Considering factors affecting the connectome-based identification process: Comment on Waller et al. AB - A recent study by Waller and colleagues evaluated the reliability, specificity, and generalizability of using functional connectivity data to identify individuals from a group. The authors note they were able to replicate identification rates in a larger version of the original Human Connectome Project (HCP) dataset. However, they also report lower identification accuracies when using historical neuroimaging acquisitions with low spatial and temporal resolution. The authors suggest that their results indicate connectomes derived from historical imaging data may be similar across individuals, to the extent that this connectome-based approach may be inappropriate for precision psychiatry and the goal of drawing inferences based on subject-level data. Here we note that the authors did not take into account factors affecting data quality and hence identification rates, independent of whether a low spatiotemporal resolution acquisition or a high spatiotemporal resolution acquisition is used. Specifically, we show here that the amount of data collected per subject and in scanner motion are the predominant factors influencing identification rates, not the spatiotemporal resolution of the acquisition. To do this, we investigated identification rates in the HCP dataset as a function of the amount of data and motion. Using a dataset from the Consortium for Reliability and Reproducibility (CoRR), we investigated the impact of multiband versus non-multiband imaging parameters; that is, high spatiotemporal resolution versus low spatiotemporal resolution acquisitions. We show scan length and motion affect identification, whereas the imaging protocol does not affect these rates. Our results suggest that motion and amount of data per subject are the primary factors impacting individual connectivity profiles, but that within these constraints, individual differences in the connectome are readily observable. PMID- 29253657 TI - Gas-free calibrated fMRI with a correction for vessel-size sensitivity. AB - Calibrated functional magnetic resonance imaging (fMRI) is a method to independently measure the metabolic and hemodynamic contributions to the blood oxygenation level dependent (BOLD) signal. This technique typically requires the use of a respiratory challenge, such as hypercapnia or hyperoxia, to estimate the calibration constant, M. There has been a recent push to eliminate the gas challenge from the calibration procedure using asymmetric spin echo (ASE) based techniques. This study uses simulations to better understand spin echo (SE) and ASE signals, analytical modelling to characterize the signal evolution, and in vivo imaging to validate the modelling. Using simulations, it is shown how ASE imaging generally underestimates M and how this depends on several parameters of the acquisition, including echo time and ASE offset, as well as the vessel size. This underestimation is the result of imperfect SE refocusing due to diffusion of water through the extravascular environment surrounding the microvasculature. By empirically characterizing this SE attenuation as an exponential decay that increases with echo time, we have proposed a quadratic ASE biophysical signal model. This model allows for the characterization and compensation of the SE attenuation if SE and ASE signals are acquired at multiple echo times. This was tested in healthy subjects and was found to significantly increase the estimates of M across grey matter. These findings show promise for improved gas-free calibration and can be extended to other relaxation-based imaging studies of brain physiology. PMID- 29253658 TI - Brain signal variability is modulated as a function of internal and external demand in younger and older adults. AB - Variability in the Blood Oxygen-Level Dependent (BOLD) signal from fMRI is often associated with better cognitive performance and younger age. It has been proposed that neural variability enables flexible responding to uncertainty in a changing environment. However, signal variability reflecting environmental uncertainty may reduce to the extent that a task depends on internally-directed attention and is supported by neural "solutions" that are schematic and relatively stable within each individual. Accordingly, we examined the hypothesis that BOLD variability will be low at rest, higher during internally-directed tasks, and higher still during externally-directed tasks, and that this effect will be reduced with aging. Modulation of BOLD variability across conditions was consistent with these hypotheses, and was associated with faster and more stable behavioral performance in both young and older adults. These data support the idea that brain signal variability may modulate in response to environmental uncertainty, which is presumed to be greater in the external environment than in the internal milieu. Reduced flexibility of signal variability with age may indicate less ability to switch between internal and external brain states. PMID- 29253659 TI - Prevalence and socioeconomic inequalities in indoor exposure to secondhand smoke at home among children 0-5years in Ghana. AB - BACKGROUND: Daily exposure to secondhand smoke (ESHS) among children can be fatal for their health. With increasing prevalence of smoking in low-income countries, particularly among low socioeconomic status (SES) groups amidst poor tobacco legislations, children in these countries can be at risk of ESHS at home. This study investigated the prevalence and socioeconomic inequalities in indoor daily of ESHS at home among children aged 0-5years in Ghana. METHODS: Population-based data collected through interviews in 2014 in 4616 households, 98.5% response rate, were used. Logistic regression analyses were used to investigate socioeconomic inequalities in daily ESHS among children at home. RESULTS: One out of every ten children was exposed to daily secondhand smoke at home. The proportion of children's ESHS by wealth quintile ranges from richest (6.5%) to poorest (46.3%). Children of male-headed households were at higher risk of daily ESHS (OR 1.71, CI 1.27-2.31). A child living in a household where the head had no formal education had four folds the risk of daily ESHS compared with another in a household headed by a person with higher educational attainment. In rural setting, a child living in a poorest household (measured by wealth index) had more than two folds the risk of daily ESHS compared with another in the richest household. Correspondingly, a child living in the poorest household in an urban area had 8 times (OR 8.05, CI 4.03-16.08) the risk of daily ESHS compared with the counterpart in the richest household. CONCLUSIONS: Children from socioeconomically disadvantaged and male-headed households both in rural and urban areas were at higher risk of daily ESHS at homes. However, children in the poorest households in urban areas had the highest concentration of ESHS among socioeconomically disadvantaged children. Interventions to end smoking indoors at home is urgently needed to protect children from its harmful effects. PMID- 29253660 TI - Therapeutic community graduates cluster together in social networks: Evidence for spatial selection as a cooperative mechanism in therapeutic communities. PMID- 29253661 TI - Parents' concordant and discordant alcohol use and subsequent child behavioral outcomes. AB - Alcohol problems have variable outcomes for marital relationships depending on whether drinking patterns are concordant or discordant among the members of the dyad; however, it is unclear what impact these variations in drinking patterns have on children. The current study was designed to explore several gaps and limitations in the parent heavy drinking literature. In particular, the prospective associations over 3years between parent heavy drinking, parenting, and child externalizing behavior were investigated in an integrated model to examine the influence of concordant and discordant drinking within couples on subsequent outcomes for their children. The study consisted of 180 couples recruited by mailings with children primarily between the ages of 4 and 11years old (52% male children). Parent-report of marital conflict, parenting, alcohol use, and child externalizing behavior were measured in a longitudinal study. Actor-Partner Interdependence Model analyses were conducted. Higher levels of maladaptive parenting were associated with higher externalizing for children of concordant drinking couples as opposed to discordant drinking couples. Implications for research and practice are discussed, including investigating mediators and moderators of the current findings such as quality of the parent child relationship. PMID- 29253662 TI - Plasmodium falciparum invasion and intraerythrocytic development are impaired by 2', 3'-dialdehyde adenosine. AB - Purine nucleotide synthesis in protozoa takes place exclusively via the purine salvage pathway and S-adenosyl-l-homocysteine hydrolase (SAHH) is an important enzyme in the Plasmodium salvage pathway which is not present in erythrocytes. Here, we describe the antimalarial effect of 2'3'-dialdehyde adenosine or oxidized adenosine (oADO), inhibitor of SAHH, on in vitro infection of human erythrocytes by P. falciparum. Treatment of infected erythrocytes with oADO inhibits parasite development and reinvasion of new cells. Erythrocytes pre treated with oADO have a reduced susceptibility to invasion. Our results suggest that oADO interferes with one or more parasitic enzymes of the purine salvage pathway. PMID- 29253663 TI - Effective platinum(IV) prodrugs conjugated with lonidamine as a functional group working on the mitochondria. AB - Platinum-based anticancer drugs are one of the most widely used anticancer chemotherapeutics in oncology. Lonidamine (LND) could increase the response of human tumor cells to platinum(II) drugs in preclinical studies by working on the mitochondria. Herein, five platinum(IV) prodrugs conjugated with their potentiator LND are prepared, and most of the target complexes achieve improved anticancer activities compared with their platinum(II) precursors. Notably, Pt(NH3)2(LND)Cl3 (complex 1) derived from cisplatin achieve significantly improved anticancer activities against LNCaP cells and could trigger cancer cell death via an apoptotic pathway and the cell cycle arrest mainly at S phases. And the induction of apoptosis by complex 1 in LNCaP cells is closely associated with mitochondrial function disruption and reactive oxygen species (ROS) accumulation. Moreover, it is possessed of the ability to overcome cisplatin-resistance. Further research revealed that complex 1 could be easily reduced to release its platinum(II) precursor and axial ligand by ascorbic acid. All the results provid evidence to support the design strategy of conjugating platinum complexes with its potentiator to improve their anticancer effect. PMID- 29253665 TI - Effect of storage temperature, nitrogen gassing and sperm concentration on the in vitro semen quality and in vivo fertility of liquid bull semen stored in INRA96. AB - The aim of this study was to assess the effect of storage temperature, nitrogen (N2) gassing and sperm concentration on in vitro characteristics and calving rate (CR) following artificial insemination (AI) of liquid bull semen stored in INRA96. In Experiment 1 the effect of liquid bull semen diluted in either N2 bubbled or non-bubbled INRA96 at a concentration of 5 * 106 sperm per 0.25 mL insemination dose and stored at 5 or 15 degrees C was assessed subjectively for total and progressive motility on Days 0, 1, 2, 3 and 4 post collection. In Experiment 2a, the effect of stored liquid semen at three sperm concentrations (3, 4 or 5 * 106 sperm per 0.25 mL insemination dose) on total and progressive motility was assessed subjectively on Days 0, 1 and 2 post collection. In Experiment 2b, the field fertility of liquid semen stored at ambient temperature at a concentration of 3, 4 or 5 * 106 sperm per 0.25 mL dose and inseminated on Days 1 or 2 post collection was assessed in comparison to frozen-thawed semen (total of n = 5742). In Experiment 1, total and progressive motility decreased with increased duration of storage (P < 0.01); however, there was no effect of N2 bubbling on motility on Days 0, 1, 2, 3 and 4 of storage. There was an effect of temperature on total and progressive motility, regardless of treatment, as semen stored at 15 degrees C recorded higher motility values than semen stored at 5 degrees C (P < 0.01). In Experiment 2a, there was no effect of sperm concentration on total or progressive motility on Days 0, 1 or 2 of storage. There was a linear decrease in motility with increased duration of storage (P < 0.01); however, there was no sperm concentration by day interaction. In Experiment 2b, there was an effect of sperm concentration on CR (P < 0.01); semen diluted to 3 and 4 * 106 sperm per dose resulted in a lower CR after 2 days of storage (41.1 and 44.7%, respectively) in comparison to frozen-thawed semen (55.2%) but did not differ to CR of semen diluted to 5 * 106 sperm per dose on Day 2 of storage. There was an effect of parity, fertility sub-index and days in milk (DIM) at AI on CR (P < 0.01). In conclusion, N2 bubbling and sperm concentration had no effect on in vitro sperm motility of liquid semen, but this study demonstrated a reduction in CR on Day 2 of storage at lower sperm concentrations in comparison to frozen-thawed semen. PMID- 29253664 TI - Efficient bioconversion of organic wastes to high optical activity of l-lactic acid stimulated by cathode in mixed microbial consortium. AB - Lactic acid is one of the emerging top biomass derived platform chemicals that can be fermented from organic wastes. This study evaluated the potential of Cathodic Electro-Fermentation (CEF) as a novel approach to enhance the yield of high optical activity (OA) of l-lactic acid from organic wastes using mixed microbial consortium. The fermentation process was stimulated through the cathode applied with -100 mV versus standard hydrogen electrode (SHE), which contributed to 4.73 times higher lactic acid productivity (0.6578 g L-1 h-1) compared to that in the open circuit control (0.1392 g L-1 h-1), and an improved OA of l-lactic acid was also observed (42.3% vs. 3.6% of the open circuit control). The study elucidated that the optimal voltage at -100 mV promoted the conversion of pyruvate to l-lactate by 77.9% compared to the Blank, which triggered the generation of l-lactic acid to occur rapidly even at low concentration of pyruvate. The significant variation of microbial community in family- and genus level distributions were observed in CEF system. Furthermore, the open-circuit operation test demonstrated that the cathode providing in-situ electron supply was essential to achieve high efficient bioconversion of organic wastes to lactic acid. Our work highlights the feasibility of CEF to steer high value-added fermentation products deriving from organic wastes by the mixed microbial consortium. PMID- 29253666 TI - Simple storage (CO2-free) of porcine morulae for up to three days maintains the in vitro viability and developmental competence. AB - The advancement of porcine embryo transfer (ET) technology is constrained by regulatory hurdles (liquid nitrogen transportation) or, more importantly, the technical obstacles of using vitrified embryos in combination with nonsurgical deep uterine ET technology. Maintaining embryos in culture during transport and prior ET collides with the need of CO2 gassing and the best choice of culture medium. In this work, we describe storage conditions for short-term embryo CO2 free storage that allowed for a majority of in vivo-derived porcine morulae to survive after 3 days of storage in a liquid state, and to develop to the blastocyst stage unhatched, a sanitary prerequisite for ET. The storage conditions included NCSU-23 medium supplemented with bovine serum albumin, where bicarbonate was partially replaced by HEPES to avoid the need for CO2 gassing, and a temperature of 37 degrees C. These conditions were able to maintain the functionality of the stored embryos (hatching capacity after exposure to conventional culture conditions) and their developmental competence after ET (normal fetuses by day 38 of pregnancy). Use of this strategy of CO2-free storage should allow the shipment of fresh embryos worldwide in the absence of liquid nitrogen. PMID- 29253667 TI - Triploid or hybrid tetra: Which is the ideal sterile host for surrogate technology? AB - This work was aimed at developing an effective procedure to obtain sterile ideal host fish in mass scale with no endogenous germ cells in the germinal epithelium, owning permanent stem-cell niches able to be colonized by transplanted germ cells in surrogate technology experiments. Thus, triploids, diploid hybrids, and triploid hybrids were produced. To obtain hybrid offspring, oocytes from a single Astyanax altiparanae female were inseminated by sperm from five males (A. altiparanae, A. fasciatus, A. schubarti, Hyphessobrycon anisitsi, and Oligosarcus pintoi). Triploidization was conducted by inhibition of the second polar body release using heat shock treatment at 40 degrees C for 2 min. At 9-months of age, the offspring from each crossing was histologically evaluated to access the gonadal status of the fish. Variable morphological characteristics of the gonads were found in the different hybrids offspring: normal gametogenesis, gametogenesis without production of gametes, sterile specimens holding germ cells, and sterile specimens without germ cells, which were considered "ideal hosts". However, only in the hybrid derived from crossing between A. altiparanae and A. fasciatus, 100% of the individuals were completely sterile. Among them 83.3% of the male did not present germ cells inside germinal epithelium, having only somatic cells in the gonad. The other 16.7% also presented spermatogonia inside the niches. Such a methodology allows the production of sterile host in mass scale, opening new insights for application of surrogate technologies. PMID- 29253668 TI - The effect of gender, age and product type on the origin induced food product experience among young consumers in Finland. AB - Locally produced and sourced food products are gaining popularity among consumers. The effect of the expectations induced by the origin of the food was studied with 1491 consumers in two separate studies among different age groups. In order to test the consumer response to the product origin neutral, domestic, and local conditions were used. Consumers evaluated the product's pleasantness, their probability to choose it, the overall quality, and their willingness to pay. To gather information on whether the phenomenon was consistent, independent from the product category, three different types of products were tested (meat, bread, and vegetables). Our results show that a closer origin does not necessarily produce a positive response, but that there are several moderating factors such as gender, age, and product type. Female university students responded equally to domestic and local origins in the case of bread, but for meat products, only those of local origin induced a positive reaction. In this study population, the male respondents only reacted to a local origin in the case of bread, while domestic meat products provided similar results to local origins. Among young men consumers in the 7th-9th grades responded to the local origin of vegetables positively, while others among the youngest consumers, the origin did not induce a significant effect. The results indicate that even when the product is not appealing itself, locality can still increase the perceived quality. PMID- 29253670 TI - An overture to overeating: The cross-modal effects of acoustic pitch on food preferences and serving behavior. AB - Billions of dollars are spent annually with the aim of enticing consumers to purchase food. Yet despite the prevalence of such advertising, little is known about how the actual sensation of this advertising media affects consumer behavior, including consequential choices regarding food. This paper explores the effect of acoustic pitch in food advertising, demonstrating in two studies, including a field study in a live retail environment, how the perception of pitch in advertising can impact food desirability and decisions regarding serving size. In study 1, a field study, pitch affects actual serving sizes and purchase behavior in a live, self-serve retail setting, with low pitch leading to larger serving sizes. Study 2 demonstrates how low pitch increases desire for a food product among hungry consumers, and that this effect is mediated by perceptions of size and how filling consumers believe the product will be. We discuss these results in the context of cross-modal correspondence and mental imagery. PMID- 29253669 TI - The role of craving in emotional and uncontrolled eating. AB - This study presents a novel application of the cognitive processing model of alcohol craving (CPMA) from the addictions field to the role of food craving in the well-established restrained eating-overeating relationship associated with binge eating disorder (BED). A community sample (N = 1058, ages 18-66) completed an online survey assessing four core domains: restrained eating, trait food craving, uncontrolled eating, and emotional eating. In accordance with the CPMA, food craving emerged as a significant indirect effect of the association between restrained eating and both uncontrolled and emotional eating. Gender did not significantly moderate any direct or indirect associations, suggesting that gender may not change the pattern of association between restrained eating and different facets of overeating. Results suggest that treatments targeting binge eating behaviors may benefit from 1) explicitly addressing the activation of food craving rather than concentrating on reducing restrained eating and 2) recognizing that food craving may be an important gender-neutral target with the potential to reduce binge and overeating behaviors. Future research should extend these preliminary findings by examining the application of the CPMA to eating behaviors while jointly investigating antecedents and contextual factors. PMID- 29253671 TI - Whole exome sequencing identifies novel mutations of epigenetic regulators in chemorefractory pediatric acute myeloid leukemia. AB - Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML. PMID- 29253672 TI - Emergence of canine parvovirus subtype 2b (CPV-2b) infections in Australian dogs. AB - Tracing the temporal dynamics of pathogens is crucial for developing strategies to detect and limit disease emergence. Canine parvovirus (CPV-2) is an enteric virus causing morbidity and mortality in dogs around the globe. Previous work in Australia reported that the majority of cases were associated with the CPV-2a subtype, an unexpected finding since CPV-2a was rapidly replaced by another subtype (CPV-2b) in many countries. Using a nine-year dataset of CPV-2 infections from 396 dogs sampled across Australia, we assessed the population dynamics and molecular epidemiology of circulating CPV-2 subtypes. Bayesian phylogenetic Skygrid models and logistic regressions were used to trace the temporal dynamics of CPV-2 infections in dogs sampled from 2007 to 2016. Phylogenetic models indicated that CPV-2a likely emerged in Australia between 1973 and 1988, while CPV-2b likely emerged between 1985 and 1998. Sequences from both subtypes were found in dogs across continental Australia and Tasmania, with no apparent effect of climate variability on subtype occurrence. Both variant subtypes exhibited a classical disease emergence pattern of relatively high rates of evolution during early emergence followed by subsequent decreases in evolutionary rates over time. However, the CPV-2b subtype maintained higher mutation rates than CPV-2a and continued to expand, resulting in an increase in the probability that dogs will carry this subtype over time. Ongoing monitoring programs that provide molecular epidemiology surveillance will be necessary to detect emergence of new variants and make informed recommendations to develop reliable detection and vaccine methods. PMID- 29253673 TI - Structural vaccinology considerations for in silico designing of a multi-epitope vaccine. AB - Multi-epitope peptide vaccines, as a kind of fusion proteins, usually possess a string-of-beads structure, consisting of several peptidic epitopes, probably adjuvants and linkers. Very numerous options are possible in selecting the order of different segments and linkers. Such factors can affect the vaccine efficacy through impacting physicochemical characteristics and protein tertiary structure. To investigate such relations, eleven different constructs were designed and studied as a multi-epitope prophylaxis vaccine for human papilloma virus (HPV). The vaccine contained two epitopes from the minor protein of virus capsid (L2) of HPV16, two TLR agonists as adjuvants (flagellin and RS09, as TLR5 and TLR4 agonists, respectively), and two universal T-helper epitopes. Since the used TLR4 agonist was inserted in the middle of the construct, its appropriate interaction with the bulky TLR4 was a serious concern. Thus, beyond evaluating the physicochemical properties, secondary and tertiary structures, and conformational B-cell epitopes of the designed constructs, TLR4 agonist exposability was also studied. Besides, the interaction between TLR4 and its agonist was investigated through docking and MD studies. Consequently, one structure ("D") with proper physicochemical features, a high frequency of conformational B-cell epitopes, and appropriate interactions with TLR4 and TLR5 in docking and MD studies, was selected as a proper candidate. Accordingly, for in silico designing of multi epitope vaccines, structural concerns should be considered, and the linkers and arrangement of epitopes and adjuvants should be optimized. Considering the diversity of the possible structures, devising computational tools for such investigations would be very valuable. PMID- 29253674 TI - Complex patterns of Hepatitis-C virus longitudinal clustering in a high-risk population. AB - We investigated longitudinal viral clustering among and within subjects in a highly networked cohort of people who inject drugs (PWID). All subjects had estimated dates of infection and two or more E1 sequences (bp 943-1288 relative to H77) with 1 to 14years of follow up. Two methods (HIV-TRACE and PhyloPart) were used to determine clusters. Genetic distance thresholds were determined by comparing intra-and inter-host distances. Additional phylogenetic analysis was performed on subjects with complicated viral histories. At the optimal threshold of 3.9%, HIV-TRACE found 77 clusters and PhyloPart found 63 clusters, of which 27 and 32 contained multiple subjects, respectively. Furthermore, 1/3 of the subjects had sequences in different clusters over the course of the study, including some cases in which a later-sampled sequence matched a cluster detected much earlier in the infection, despite being separated by RNA-negative lab visit and detection of sequences in different clusters. A detailed phylogenetic analysis of four subjects with such patterns showed that in all four cases, the earlier and later variants grouped closely on the tree, and did not group with concurrent sequences from any other subject. These observations suggest that subjects are either experiencing rapid and recurring infection-clearance reinfection cycles from the same source, or a single transmission event produces a chronic infection that may go undetected and/or co-circulate with different viruses from separate transmission events. Furthermore, our results show the utility of using longitudinal sampling to obtain a more comprehensive view of the viral linkages in high-risk populations. PMID- 29253675 TI - The clinical impact of integration of magnetoencephalography in the presurgical workup for refractory nonlesional epilepsy. AB - OBJECTIVE: For patients with nonlesional refractory focal epilepsy (NLRFE), localization of the epileptogenic zone is more arduous, and intracranial electroencephalography (EEG) (icEEG) is frequently required. Planning for icEEG is dependent on combined data from multiple noninvasive modalities. We report the negative impact of lack of integration of magnetoencephalography (MEG) in the presurgical workup in NLRFE. METHODS: Observational MEG case series involving 31 consecutive patients with NLRFE in an academic epilepsy center. For various reasons, MEG data were not analyzed in a timely manner to be included in the decision-making process. The presumed impact of MEG was assessed retrospectively. RESULTS: Magnetoencephalography would have changed the initial management in 21/31 (68%) had MEG results been available by reducing the number of intracranial electrodes, modifying their position, allowing for direct surgery, canceling the intracranial study, or providing enough evidence to justify one. Good surgical outcome was achieved in 11 out of 17 patients who proceeded to epilepsy surgery. Nine out of eleven had MEG clusters corresponding to the resection area, and MEG findings would have allowed for direct surgery (avoiding icEEG) in 2/11. Six patients had poor outcome including three patients where MEG would have significantly changed the outcome by modifying the resection margin. Magnetoencephalography provided superior information in 3 patients where inadequate coverage precluded accurate mapping of the epileptogenic zone. CONCLUSION: In this single center retrospective study, MEG would have changed patient management, icEEG planning, and surgical outcome in a significant percentage of patients with NLRFE and should be considered in the presurgical workup in those patients. PMID- 29253676 TI - The electroclinical spectrum, etiologies, treatment and outcome of nonconvulsive status epilepticus in the elderly. AB - BACKGROUND: Nonconvulsive status epilepticus (NCSE) in the elderly is particularly difficult to diagnose, mainly due to subtle clinical manifestations and associated comorbidities. The recently validated electroencephalography (EEG) diagnostic criteria for NCSE and the proposed operational classification of status epilepticus provide tools that can allow an earlier diagnosis and better management of NCSE in this age group, possibly contributing to reduce its high mortality. MATERIAL AND METHODS: we used these tools to identify and characterize a cohort of elderly (>60year-old) patients admitted at our institution in a 3 year period; the video-EEG and clinical files of the patients fulfilling EEG diagnostic criteria for NCSE were reviewed, being in this study described their electroclinical spectrum, etiologies, treatment, inhospital mortality, and status epilepticus severity score (STESS). RESULTS: Fourty patients (23 women; mean age 76.6years) were identified. Although dyscognitive NCSE associated with >2.5Hz of epileptiform discharges (ED) was the most frequent electroclinical phenotype, this was quite heterogeneous, ranging from patients with aura continua to patients in coma, associated with frequent ED or rhythmic slow activities. Acute symptomatic (45%) and multifactorial (27.5%) etiologies were the most common, and associated with the worst prognosis. There was a trend to use newer antiepileptic drugs in the early steps of NCSE treatment. The inhospital mortality was high (22.5%) and predicted by STESS scores >=3. CONCLUSION: In the elderly, NCSE has heterogeneous electroclinical phenotypes and etiologies. In spite of the treatment limitations conditioned by the comorbidities, more aggressive treatments could be justified to reduce mortality in patients with high STESS scores. PMID- 29253677 TI - Internalizing and externalizing symptoms in preschool and school-aged children with epilepsy: Focus on clinical and EEG features. AB - INTRODUCTION: Psychiatric and behavioral problems are frequent comorbidities of epilepsy, although their clinical and electroencephalographic (EEG) correlates remain uncertain. In this study, we have assessed the frequency of psychopathological problems in a cohort of children with epilepsy, and established their main clinical and EEG-associated features. METHODS: One hundred fifty-nine young patients with epilepsy were recruited and assessed through the Child Behavior Checklist for preschool-aged children (CBCL 1 1/2-5) or for school aged children (CBCL 6-18). Child Behavior Checklist (CBCL) results were then correlated to the main clinical and EEG data. RESULTS: We found emotional and behavioral problems in about half of the children in our sample. Internalizing, social, and attention problems were more common than externalizing features. Moderate intellectual disability, a nonidiopathic etiology of epilepsy, a poor control of seizures, and antiepileptic polytherapies, as well as an early age at seizure-onset and a longer duration of the disorder, were all associated with specific behavioral and emotional problems. A temporal site of interictal EEG abnormalities also enhanced the risk for psychiatric comorbidities, especially in the externalizing domain. CONCLUSIONS: Several clinical and EEG features are associated with an increased risk for emotional and behavioral comorbidities in children with epilepsy. Their identification may foster an early diagnosis and appropriate care, limiting the worsening of psychiatric symptoms and their impact on quality of life and health status. A better understanding of the underlying clinical and molecular mechanisms is needed to further improve prevention and treatment interventions. PMID- 29253678 TI - The influence of EEG-detected nocturnal centrotemporal discharges on the expression of core symptoms of ADHD in children with benign childhood epilepsy with centrotemporal spikes (BCECTS): A prospective study in a tertiary referral center. AB - Benign childhood epilepsy with centrotemporal spikes (BCECTS) is the most frequent benign focal epilepsy in childhood. Although it is described as a benign epilepsy syndrome, many studies have revealed that a significant number of patients have some degree of neuropsychological impairment. Thirty-two patients with BCECTS aged 6-11years were included in the study. All patients (without any antiepileptic or psychiatric medication) underwent all-night EEG monitoring and complex neuropsychological testing to diagnose the presence of core symptoms of attention-deficit/hyperactivity disorder (ADHD). The spike index (number of spikes per minute) on awake and asleep EEG, age at seizure onset, family history of epilepsy, and perinatal risks were correlated with the results of neuropsychological testing. Of the 32 patients, 21 patients (65.6%) fulfilled the criteria for ADHD diagnosis. Children who were younger at epilepsy onset demonstrated lower IQ and higher attention deficit (P=0.004) and higher impulsivity (P=0.016). The occurence of epileptiform discharges on nocturnal EEG was positively related to higher attention deficit and higher impulsivity. The findings are discussed in terms of how interictal discharges in the centrotemporal region during sleep affect the development of cognitive functions in children during critical epochs of neuropsychological development. PMID- 29253679 TI - Impact of the modified Atkins diet on cardiovascular health in adults with epilepsy. AB - AIM: The current study investigated biochemical and vascular markers of cardiovascular health in adult patients with epilepsy treated with long-term (greater than 1year) ketogenic diet therapy compared with controls. METHOD: Anthropometric measures, serum fasting lipid panel, apolipoproteins A-1 and B, lipoprotein sub-fractions as well as common carotid intima-media thickness (cIMT), and plaque presence were assessed in 20 adult patients with epilepsy on a modified Atkins diet (MAD) for >1year started as an adult compared with 21 adult patients with epilepsy naive to diet therapy. RESULTS: Patients treated with MAD had significantly lower weight, body mass index, waist and hip circumference, percent body fat, and serum triglyceride levels when compared with control patients. In contrast, they had significantly higher serum levels of small low density-lipoprotein (LDL) particles and were significantly more likely to have LDL pattern B in which small LDL particles predominate when compared with controls. However, there was no significant difference in cIMT or plaque presence between groups. CONCLUSION: Our results provide clinical evidence demonstrating the cardiovascular safety of a high-fat, low-carbohydrate diet used in adults with epilepsy for at least 12months. It also highlights potential markers of cardiovascular risk - small dense LDL particles - that should be closely monitored in adults treated with diet therapy long-term. PMID- 29253680 TI - Effect of lacosamide on depression and anxiety symptoms in patients with focal refractory epilepsy: A prospective multicenter study. AB - INTRODUCTION: Depression is the main psychiatric comorbidity in epilepsy with an estimated prevalence between 20% and 55% and one of the main determinants of quality of life. The aim of this study was to investigate the effect of lacosamide (LCM) on mood and anxiety symptoms in patients with focal onset seizures (FOS). The secondary objective was to evaluate if the potential modifications in variables were related to seizure control or to the intrinsic effect of LCM. MATERIAL AND METHODS: We performed a prospective multicenter study in 8 tertiary epilepsy centers in adults with FOS in which LCM was initiated as add-on therapy. Patients' mood and quality of life were evaluated through questionnaires and scales such as the Beck Depression Inventory-II (BDI-II), the State-Trait Anxiety Inventory (STAI-S/T), the Hospital Anxiety and Depression Scale (HADS), and the Quality of Life in Epilepsy-10 (QOLIE-10). Initiation of psychotropic medication was not allowed during the observation period. Patients with diagnosis of major depression or bipolar disorder were excluded. Evaluations were scheduled before LCM treatment, at 3 and 6months. RESULTS: Forty-nine patients were included (51% female) with an average age of 39.5years (range 18 65). At the start of treatment with LCM, 65.3% of the patients were on treatment with one antiepileptic drug (AED). Based on BDI-II, 38.8% of patients had depressive symptoms and 46.9% according to HADS Depression (HADS-D), 63.3% of patients presented pathological levels of anxiety (STAI-S/T), and 44.9% according to HADS Anxiety (HADS-A). Quality of Life in Epilepsy-10 showed that 57.1% of patients had a relevant reduction in their quality of life. After LCM, the score on the BDI-II depression scale decreased significantly (p<0.001). Based on the STAI and HADS-anxiety scales, patients who had a pathological anxiety at baseline, significantly improved. The QOLIE-10 improved significantly over the observation period (p<0.001). At 6months, 28.3% of patients were seizure-free (67.4% were responders). The improvements on depression and anxiety scores were not statistically related to seizure control. CONCLUSION: Lacosamide seems to have a positive effect on depressive and anxiety symptoms. Although the efficacy of LCM in seizure control was demonstrated, the antidepressant and anxiolytic effect on mood and anxiety seems to be an independent factor. PMID- 29253681 TI - Pre- and long-term postoperative courses of hippocampus-associated memory impairment in epilepsy patients with antibody-associated limbic encephalitis and selective amygdalohippocampectomy. AB - OBJECTIVE: Limbic encephalitis (LE) is defined by mesiotemporal lobe structure abnormalities, seizures, memory, and psychiatric disturbances. This study aimed to identify the long-term clinical and neuropsychological outcome of selective amygdalohippocampectomy (sAH) in drug-resistant patients with temporal lobe epilepsy due to known or later diagnosed subacute LE not responding to immunotherapy associated with neuronal autoantibodies. METHODS: In seven patients with temporal lobe epilepsy due to antibody positive LE (glutamic acid decarboxylase (GAD65): n=5; voltage-gated potassium channel complex (VGKC), N methyl d-aspartate receptor (NMDAR): n=1; Ma-2/Ta: n=1) sAH (6 left, 1 right) was performed. Those patients underwent repeated electroencephalography (EEG) recordings, magnetic resonance imaging (MRI) volumetry of the amygdala and hippocampus, and neuropsychological examinations and were followed up for 6 7years on average. RESULTS: Verbal memory and figural memory were affected in 57% of patients at baseline and 71% at the last follow-up. At the last follow-up, 14% of the patients had declined in verbal memory and figural memory. We observed improved memory in 43% of patients regarding figural memory, but not in a single patient regarding verbal memory. Repeated evaluations across the individual courses reveal cognitive and MRI dynamics that appear to be unrelated to surgery and drug treatment. Three of the seven patients with LE with different antibodies (NMDAR: n=1, Ma-2/Ta: n=1 and GAD65: n=1) achieved persistent seizure freedom along with no accelerated memory decline after surgery. Two of the five GAD65 antibody patients positive with LE showed progressive memory decline and a long term tendency to contralateral hippocampus atrophy. CONCLUSIONS: While memory demonstrated some decline in the long run, what is most important is that a progressive decline in memory is seldom found after sAH in patients with LE. Moreover, the dynamics in performance and MRI before and after surgery reveal disease dynamics independent of surgery. Selective amygdalohippocampectomy can lead to seizure freedom, but should be considered as a last resort treatment option for drug-resistant patients with temporal lobe epilepsy due to LE. Particular caution is recommended in patients with GAD65-LE. PMID- 29253682 TI - Enlarged perivascular spaces in the centrum semiovale are associated with poststroke depression: A 3-month prospective study. AB - BACKGROUND: Enlarged perivascular spaces (EPVS), markers of cerebral small vessel disease, are associated with unfavorable prognosis of stroke. This study explored the relationship between EPVS and poststroke depression (PSD). METHODS: A total of 725 patients with acute ischemic stroke were recruited from the Stroke Unit of a university-affiliated hospital in Hong Kong. PSD was defined as a Geriatric Depression Scale score of >= 7 assessed at three months after stroke. The extent of EPVS in the basal ganglia (BG) and the centrum semiovale (CS) was assessed on axial T2 weighted magnetic resonance imaging using a validated scale. Patients' EPVS status was categorized as either mild or moderate to severe degree. The association between EPVS and PSD was examined with logistic regression. RESULTS: One hundred and fifty-three (21.1%) of the study sample had PSD three month after stroke. 55.6% of the study sample were classified as having a minor stroke. The median scores of CS- and BG-EPVS were 1 (1-2) and 1 (0-2), respectively. After adjusting for demographic, clinical and imaging characteristics in multivariate logistic regression analyses, the CS-EPVS continuous score remained an independent predictor of PSD [odds ratio (OR) = 1.27; 95% confidence interval (CI) = 1.03-1.57]. After dichotomized, moderate to severe CS-EPVS was independently associated with PSD with an OR of 1.68 (95%CI = 1.10-2.57). LIMITATIONS: The diagnosis of PSD was based on GDS score rather than a standardized clinical examination. The study favored the patients with milder stroke. CONCLUSION: CS-EPVS were associated with PSD identified at three months after mild to moderate acute ischemic stroke. PMID- 29253683 TI - A standardized stepwise drug treatment algorithm for depression reduces direct treatment costs in depressed inpatients - Results from the German Algorithm Project (GAP3). AB - BACKGROUND: In a previous single center study we found that a standardized drug treatment algorithm (ALGO) was more cost effective than treatment as usual (TAU) for inpatients with major depression. This report aimed to determine whether this promising initial finding could be replicated in a multicenter study. METHODS: Treatment costs were calculated for two time periods: the study period (from enrolment to exit from study) and time in hospital (from enrolment to hospital discharge) based on daily hospital charges. Cost per remitted patient during the study period was considered as primary outcome. RESULTS: 266 patients received ALGO and 84 received TAU. For the study period, ALGO costs were significantly lower than TAU (ALGO: 7 848 +/- 6 065 ?; TAU: 10 033 +/- 7 696 ?; p = 0.04). For time in hospital, costs were not different (ALGO: 14 734 +/- 8 329 ?; TAU: 14 244 +/- 8 419 ?; p = 0.617). Remission rates did not differ for the study period (ALGO: 57.9%, TAU: 50.0%; p=0.201). Remission rates were greater in ALGO (83.3%) than TAU (66.2%) for time in hospital (p = 0.002). Cost per remission was lower in ALGO (13 554 +/- 10 476 ?) than TAU (20 066 +/- 15 391 ?) for the study period (p < 0.001) and for time in hospital (ALGO: 17 582 +/- 9 939 ?; TAU: 21 516 +/- 12 718 ?; p = 0.036). LIMITATIONS: Indirect costs were not assessed. Different dropout rates in TAU and ALGO complicated interpretation. CONCLUSIONS: Treatment algorithms enhance the cost effectiveness of the care of depressed inpatients, which replicates our prior results in an independent sample. PMID- 29253684 TI - Individual depressive symptoms and all-cause mortality In 6673 patients with myocardial infarction: Heterogeneity across age and sex subgroups. AB - BACKGROUND: Depression predicts poor prognosis in patients with myocardial infarction (MI). However, individual depressive symptoms may have different prognostic value, and age and sex could be important effect modifiers. This study compared the prognostic value of individual depressive symptoms across age and sex subgroups in post-MI patients. METHODS: Individual patient-data were compiled for 6673 post-MI patients from seven studies. Depressive symptoms were measured with 10 items of the Beck Depression Inventory (BDI10). The endpoint was all cause mortality (mean=3.8 years). Multilevel multivariable Cox regression analysis was used to estimate the mortality risk across age groups (<=55, 56-69 and >=70 years) and sex for symptoms that potentially interacted with age and sex. RESULTS: At follow-up, 995 (15%) post-MI patients had died. BDI10 depression scores were associated with an increased mortality risk (HR:1.20;95%CI:1.11 1.28,p<.001). Negative self-image (HR:1.53;1.06-2.21;p=.022) and indecisiveness (HR:1.53;1.15-2.04;p=.003) were associated with increased mortality in men <55. Dissatisfaction was associated with increased mortality in men aged 56-69 (HR:1.35;1.07-1.71;p=. 011), and dissatisfaction (HR:1.34;1.10-1.63;p=.003) and fatigue (HR:1.45;1.20-1.74;p<.001) in men >70. Fatigue was associated with mortality in women aged 56-69 (HR:1.54;1.09-2.15;p=.012), and suicidal ideation in women aged >70 (HR:1.58;1.03-2.43;p=.037). Left-ventricular ejection fraction (LVEF) accounted for much of the associations in men <=55 years and women >=70 years. LIMITATIONS: Findings are sample-specific and need replication in future research; BDI10 items were derived from the original BDI assessment. CONCLUSIONS: There is large heterogeneity in the prognostic value of individual depressive symptoms in post-MI patients across sex and age subgroups. LVEF partially explained the depression-prognosis association in specific subgroups. PMID- 29253685 TI - Exploring the emotional dynamics of subclinically depressed individuals with and without anhedonia: An experience sampling study. AB - BACKGROUND: Anhedonia has been linked to worse prognosis of depression. The present study aimed to construct personalized models to elucidate the emotional dynamics of subclinically depressed individuals with versus without symptoms of anhedonia. METHODS: Matched subclinically depressed individuals with and without symptoms of anhedonia (N = 40) of the HowNutsAreTheDutch sample completed three experience sampling methodology assessments per day for 30 days. For each individual, the impact of physical activity, stress experience, and high/low arousal PA/NA on each other was estimated through automated impulse response function analysis (IRF). These individual IRF associations were combined to compare anhedonic versus non-anhedonic individuals. RESULTS: Physical activity had low impact on affect in both groups. In non-anhedonic individuals, stress experience increased NA and decreased PA and physical activity more strongly. In anhedonic individuals, PA high arousal showed a diminished favorable impact on affect (increasing NA/stress experience, decreasing PA/physical activity). Finally, large heterogeneity in the personalized models of emotional dynamics were found. LIMITATIONS: Stress experience was measured indirectly by assessing level of distress; the timeframe in between measurements was relatively long with 6h; and only information on one of the two hallmarks of anhedonia, loss of interest, was gathered. CONCLUSIONS: Our results suggest different pathways of emotional dynamics underlie depressive symptomatology. Subclinically depressed individuals with anhedonic complaints are more strongly characterized by diminished favorable impact of PA high arousal and heightened NA reactivity, whereas subclinically depressed individuals without these anhedonic complaints seem more characterized by heightened stress reactivity. The automatically generated personalized models may offer patient-specific insights in emotional dynamics, which may show clinical relevance. PMID- 29253687 TI - Removal of emerging contaminants from the environment by adsorption. AB - Emerging contaminants (EC's) are pollutants of growing concern. They are mainly organic compounds such as: pesticides, pharmaceuticals and personal care products, hormones, plasticizers, food additives, wood preservatives, laundry detergents, surfactants, disinfectants, flame retardants, and other organic compounds that were found recently in natural wastewater stream generated by human and industrial activities. A majority of ECs does not have standard regulations and could lead to lethal effects on human and aquatic life even at small concentrations. The conventional primary and secondary water treatment plants do not remove or degrade these toxic pollutants efficiently and hence need cost effective tertiary treatment method. Adsorption is a promising method worldwide for EC removal since it is low initial cost for implementation, highly efficient and has simple operating design. Research has shown that the application of different adsorbents such as, activated carbons(ACs), modified biochars (BCs), nanoadsorbents (carbon nanotubes and graphene), composite adsorbents, and other are being used for EC's removal from water and wastewater. The current review intends to investigate adsorption process as an efficient method for the treatment of ECs. The mechanism of adsorption has also been discussed. PMID- 29253686 TI - Suicidal ideation and suicidal behavior according to the C-SSRS in a European cohort of Huntington's disease gene expansion carriers. AB - BACKGROUND: Huntington's disease (HD) gene expansion carriers are at an increased risk of suicide, but so far, no studies have investigated the full spectrum of suicidality, including suicidal ideation, suicidal behavior and self-injurious behavior. METHODS: We included 1451 HD gene expansion carriers (age 48.4 years (SD 14.0), 54.8% female) of the REGISTRY study of the European Huntington's Disease Network. Lifetime suicidal ideation and suicidal behavior were assessed with the Columbia-Suicidal Severity Rating Scale. Motor symptoms and disease stage were assessed using subscales of the Unified Huntington's Disease Rating Scale, and depressed mood and irritability were assessed by the Problem Behaviors Assessment. RESULTS: Lifetime passive suicidal ideation was reported by 21.2%. Participants in stage II showed the highest prevalence rate of suicidal ideation, while participants in stage IV/V showed the highest prevalence of suicidal behavior. A lifetime suicide attempt was reported by 6.5% of the HD gene expansion carriers. In multivariate regression analyses, both suicidal ideation and suicidal behavior were associated with a depressed mood, and to a lesser extend to irritability. LIMITATIONS: Results may have been affected by denial or recall bias and no conclusions can be made about the temporal and causal relationships with depressed mood and irritability because of the cross-sectional analyses. CONCLUSIONS: Given the high prevalence of suicidal ideation and suicidal behavior in all stages of HD, it is important to screen HD gene expansion carriers for suicidal ideation and suicidal behavior on a regular basis in clinical practice. PMID- 29253688 TI - Secretion, isotopic labeling and deglycosylation of N-acylethanolamine acid amidase for biophysical studies. AB - N-acylethanolamine acid amidase (NAAA) is an N-terminal nucleophile (Ntn) enzyme with a catalytic cysteine residue that has highest activity at acidic pH. The most prominent substrate hydrolyzed is palmitoylethanolamine (PEA), which regulates inflammation. Inhibitors of NAAA have been shown to increase endogenous levels of PEA, and are of interest as potential treatments for inflammatory disorders and other maladies. Currently, there are no X-ray or NMR structures of NAAA available to inform medicinal chemistry. Additionally, there are a limited number of enzyme structures available that are within the Ntn-hydrolase family, have a catalytic cysteine residue, and have a high sequence homology. For these reasons, we developed expression and purification methods for the production of enzyme samples amenable to structural characterization. Mammalian cells are necessary for post-translational processing, including signal sequence cleavage and glycosylation, that are required for a correctly folded zymogen before conversion to active, and mature enzyme. We have identified an expression construct, mammalian cell line, specific media and additives to express and secrete hNAAA zymogen and we further optimized propagation conditions and show this secretion method is suitable for isotopic labeling of the protein. We refined purification methods to achieve a high degree of protein purity potentially suited to crystallography. Glycosylated proteins can present challenges to biophysical methods. Therefore we deglycosylate the enzyme and show that the activity of the mature enzyme is not affected by deglycosylation. PMID- 29253689 TI - Cranial Osteomyelitis: A Comprehensive Review of Modern Therapies. AB - BACKGROUND: Cranial osteomyelitis is a rare but potentially life-threatening condition that requires early diagnosis with prompt and appropriate management by neurosurgeons to prevent further central nervous system complications. METHODS: The literature in the Medline database was comprehensively reviewed with the keywords "cranial osteomyelitis," "skull base osteomyelitis (SBO)," "central skull base osteomyelitis," and "temporal bone osteomyelitis." Items in the reference list of each article relevant to the objective of this study were reviewed. RESULTS: This review produced 183 articles: 13 book chapters, 24 case reports, 17 case series, 98 original articles, 30 review articles, and 1 meta analysis. We classified cranial osteomyelitis as sinorhino-otogenic, including anterior, middle, and posterior skull base osteomyelitis; and non-sinorhino otogenic, including iatrogenic, posttraumatic, hematologic, and osteomyelitis with other causes. CONCLUSIONS: New diagnostic modalities, the introduction of broad-spectrum antibiotics, and recent advances in neurosurgical procedures have led to a decrease in the rate of treatment failure in cranial osteomyelitis. Early recognition of initial nonspecific symptoms is key to diagnosing and managing this treatable but life-threatening condition. Early identification of the causative pathogen, appropriate broad-spectrum antibiotic therapy over a period of 8-20 weeks, and aggressive surgical debridement are essential for managing cranial osteomyelitis. On the other hand, inadequate treatment is responsible for refractory cases and poses a great diagnostic challenge. A new classification dividing cranial osteomyelitis into sinorhino-otogenic versus nonsinorhino-otogenic groups could prove valuable for clinical communication and treatment. PMID- 29253690 TI - Effects of Positive End-Expiratory Pressure on the Risk of Postoperative Pulmonary Complications in Patients Undergoing Elective Craniotomy. AB - BACKGROUND: Intraoperative use of positive end-expiratory pressure (PEEP) has a protective effect in patients with acute lung injury and is recommended during anesthesia to minimize postoperative pulmonary complications. However, high levels of pressure might also cause harm to the lung because of overdistension. This retrospective study was designed to compare the effect of low and high levels of PEEP on the risk of postoperative pulmonary complications in patients with normal lung function who were undergoing an elective craniotomy. METHODS: Two thousand four hundred thirty-seven patients without any pre-existing respiratory disease, who underwent an elective craniotomy, were hospitalized from January 1, 2008, to December 31, 2012. The patients were divided into 2 groups according to the application of an intraoperative PEEP < 5 or >= 5 cm H2O, referred as low and high groups. Primary outcome was the odds of postoperative pneumonia and the requirement for either noninvasive ventilation (NIV) or reintubation and mechanical ventilation (MV). RESULTS: One thousand twenty-three (42%) of 2437 patients were in the low group, and 1414 patients (58%) were in the high group. Patients in the low group did not show any difference in the incidence of postoperative pneumonia (P = 0.523) or the requirement of postoperative reintubation and MV (P = 0.999) compared with those in the high group. The incidence of reintubation and MV is significantly associated with postoperative pneumonia (P < 0.001). CONCLUSIONS: Low and high levels of PEEP show similar incidences of postoperative pneumonia and requirement of postoperative NIV or invasive MV in patients with normal function of the lungs undergoing elective craniotomy. PMID- 29253691 TI - De Novo Spinal Dural Arteriovenous Fistula in a Patient with a Lipomyelomeningocele: Case Report. AB - BACKGROUND: Spinal dural arteriovenous fistula (AVF), the most common type of spinal vascular malformation, tends to manifest as progressive myelopathy over several years. Spinal dural AVFs are considered an acquired lesion and, in contrast to spinal arteriovenous malformations, are not often associated with other anomalies. The presence of a spinal dural AVF in the setting of a lipomyelomeningocele and tethered cord is extremely rare. Both lesions tend to cause similar symptoms, and patients with concomitant lesions generally require surgical intervention for both. CASE DESCRIPTION: A 57-year-old female with lifelong urinary incontinence and mild weakness in the left lower extremity presented with progressive worsening of left lower extremity weakness as well as worsening bowel and bladder incontinence. Magnetic resonance imaging (MRI) performed 4 years before our evaluation revealed a lipomyelomeningocele and a tethered cord; a new MRI demonstrated a new additional finding of flow voids suspicious of an underlying vascular malformation. Diagnostic angiography revealed a dural AVF fed by a left lateral sacral artery. Onyx embolization of the dural AVF was performed, and the patient improved steadily postoperatively without the need for surgically addressing the tethered cord. CONCLUSION: In this case report, we present evidence of de novo development of a spinal dural AVF associated with a lipomyelomeningocele. In addition, this is the second documented patient in the literature with a lipomyelomeningocele and concomitant dural AVF who did not undergo detethering of the cord as part of treatment. PMID- 29253692 TI - Delayed Postoperative Neurologic Deficit After Spine Deformity Surgery: Analysis of 5377 Cases at 1 Institution. AB - BACKGROUND: To our knowledge, few studies have focused on delayed postoperative neurologic deficit (DPND) after spine deformity surgery. OBJECTIVES: This study was intended to investigate the incidence, risk factors, treatments, and outcomes of DPND after corrective surgery for spinal deformity in a single spine center. METHODS: The database of a single spine center was queried for dates from 2002 to 2014 to identify all spinal deformity cases. The variables extracted included patient age, diagnosis, procedure, whether neuromonitoring was used and if so which methods were used, whether neuromonitoring abnormalities were detected, whether new neurologic deficits occurred, whether implants were used, and the degree of recovery from new neurologic deficits (none, partial, complete). The patients were classified as pediatric (<21 years old) or adult (>=21 years old). The rates of DPND were tabulated and stratified on the basis of age, diagnosis, and surgical features. RESULTS: A total of 5377 cases were investigated from 2002 through 2014. Seven cases of DPND were reported (incidence, 0.13%). For adult patients, the overall incidence of DPND was 0.17%, and for pediatric patients, it was 0.10%. The incidence of DPND was 0.35% when osteotomies were performed and 0.05% without osteotomies. After the onset of neurologic deficits, loss of somatosensory evoked potentials occurred in 1 patient, and loss of motor evoked potentials occurred in all 7 patients. Revision surgery was performed for 3 patients. At the last follow-up visit, 1 patient experienced no recovery, 2 partial recovery, and 5 complete recovery. CONCLUSIONS: The incidence of DPND is low. Old age and osteotomies are risk factors for DPND. Most patients with DPND experience varying degrees of recovery. PMID- 29253694 TI - A Novel Functional Magnetic Resonance Imaging Paradigm for the Preoperative Assessment of Auditory Perception in a Musician Undergoing Temporal Lobe Surgery. AB - BACKGROUND: Presurgical evaluation for temporal lobe epilepsy routinely assesses speech and memory lateralization and anatomic localization of the motor and visual areas but not baseline musical processing. This is paramount in a musician. Although validated tools exist to assess musical ability, there are no reported functional magnetic resonance imaging (fMRI) paradigms to assess musical processing. We examined the utility of a novel fMRI paradigm in an 18-year-old left-handed pianist who underwent surgery for a left temporal low-grade ganglioglioma. METHODS: Preoperative evaluation consisted of neuropsychological evaluation, T1-weighted and T2-weighted magnetic resonance imaging, and fMRI. Auditory blood oxygen level-dependent fMRI was performed using a dedicated auditory scanning sequence. Three separate auditory investigations were conducted: listening to, humming, and thinking about a musical piece. RESULTS: All auditory fMRI paradigms activated the primary auditory cortex with varying degrees of auditory lateralization. Thinking about the piece additionally activated the primary visual cortices (bilaterally) and right dorsolateral prefrontal cortex. Humming demonstrated left-sided predominance of auditory cortex activation with activity observed in close proximity to the tumor. CONCLUSIONS: This study demonstrated an fMRI paradigm for evaluating musical processing that could form part of preoperative assessment for patients undergoing temporal lobe surgery for epilepsy. PMID- 29253693 TI - Newly Diagnosed Acquired Hemophilia A Manifesting as Massive Intracranial Hemorrhage Following a Neurosurgical Procedure. AB - OBJECTIVE: Increased attention has been paid to limiting preoperative hemostatic screening because assessment of patient history can be used as an alternative. However, there may be some clinical pitfalls in overlooking acquired coagulopathies. Here, we present a case of newly diagnosed acquired hemophilia A (AHA) that manifested as a massive intracranial hemorrhage without unexplained bleeding history or abnormal hemostatic results. CASE DESCRIPTION: A 58-year-old man, who had a history of surgical clipping of an anterior communicating artery aneurysm 30 years ago, experienced subarachnoid hemorrhage because of a ruptured middle cerebral artery aneurysm. He underwent surgical clipping and external decompressive craniectomy; 30 days later, cranioplasty was performed without preoperative hemostatic screening because of his normal coagulation status at the time of a previous surgery. Persistent wound bleeding and epistaxis suddenly began 6 hours after surgery. Computed tomography (CT) revealed a massive intracranial hematoma in the damaged parenchyma, although the patient was asymptomatic. At that time, laboratory tests showed isolated prolonged activated partial thromboplastin time and the presence of factor VIII inhibitor, which confirmed AHA. To manage the bleeding, fresh frozen plasma was transfused for 4 consecutive days, and hemostasis was finally achieved. Thereafter, the laboratory test results were normalized in 5 weeks. The patient's clinical course has been uneventful for 7 months without recurrence of AHA. CONCLUSIONS: Acquired coagulopathies are relatively rare but life-threatening. Because clinical history is insufficient to predict an acquired coagulopathy, preoperative hemostatic screening should be performed before each neurosurgical procedure. PMID- 29253695 TI - Effect of Epineurial Neurorrhaphy on Restoration of Facial Nerve Injuries with Different Levels of Neurotmesis in a Rat Model: A Pilot Study. AB - BACKGROUND: Different degrees of neurotmesis of the peripheral facial nerve frequently are encountered in clinic, for which the epineurial neurorrhaphy is the preferred technique. However, because of the capability of self-restoration of nerves and the side effects of surgery, neurorrhaphy may not be an optimal choice for various degrees of neurotmesis. In this study, we explored the necessity of epineurial neurorrhaphy for different degrees of neurotmesis, in addition to investigating factors that impact neural functional recovery. METHODS: Rat models were divided into 6 groups: intact, noninjured controls; A, one-third cross-sectional facial nerve disconnected injury after epineurial neurorrhaphy; B, one-third cross-sectional facial nerve disconnected injury without epineurial neurorrhaphy; C, two-thirds cross-sectional facial nerve disconnected injury after epineurial neurorrhaphy; D, two-thirds cross-sectional facial nerve disconnected injury without epineurial neurorrhaphy; and E, two thirds cross-sectional facial nerve disconnection followed by complete transection and neurorrhaphy. Facial functional recovery was assessed with the use of behavioral assessments and electrophysiologic tests. The morphologic changes of trunk of the facial nerve were analyzed by osmium-toluidine blue staining and immunofluorescence. The modification of central nervous system was evaluated by retrograde labeling and Nissl's staining of facial nerve nuclei. RESULTS: Concerning morphologic and functional assessments, there were no statistically significant differences between one-third facial nerve disconnected injury with or without epineurial neurorrhaphy and the intact model. For two thirds facial nerve disconnected injury, direct neurorrhaphy was superior to complete transection followed by neurorrhaphy. For two-thirds facial nerve disconnected injury, the nerves can largely self-restore in neural structure and function without the use of epineurial neurorrhaphy. For the facial nerve nuclei, the number of neurons decreased in the more than two-thirds nerve disconnected models, and models with two-thirds disconnection and without neurorrhaphy had the least number of neurons. For the distribution of neurons in different facial nerve subnuclei, both models with two-thirds nerve disconnection without neurorrhaphy and models with two-thirds nerve disconnection after complete transection and neurorrhaphy demonstrated disorganization of neurons, in which the latter was more serious. CONCLUSIONS: For one-third disconnected facial nerve injury, there's no need to suture the nerve stump, although for residual one third connected nerve injury, direct suture is preferable if permitted than pre performing a complete transection to trim the stump. Residual one-third connected nerve fibers largely can self-restore. The results from this study indicate that neural functional defect may be attributed to the damage and misdirection of peripheral nerve fibers and central neurons. PMID- 29253696 TI - Posterior Rigid Instrumentation of C7: Surgical Considerations and Biomechanics at the Cervicothoracic Junction. A Review of the Literature. AB - BACKGROUND: The cervicothoracic junction is a challenging anatomic transition in spine surgery. It is commonly affected by different types of diseases that may significantly impair stability in this region. The seventh cervical vertebra (C7) is an atypical cervical vertebra with unique anatomic features compared to subaxial cervical spine (C3 to C6). C7 has relatively broader laminae, larger pedicles, smaller lateral masses, and a long nonbifid spinous process. These features allow a variety of surgical methods for performing posterior rigid instrumentation in the form of different types of screws, such as lateral mass screws, pedicle screws, transfacet screws, and intralaminar screws. Many biomechanical studies on cadavers have evaluated and compared different types of implants at C7. METHODS: We reviewed PubMed/Medline by using specific combinations of keywords to summarize previously published articles that examined C7 posterior rigid instrumentation thoroughly in an experimental fashion on patients or cadavers with additional descriptive radiologic parameters for evaluation of the optimum surgical technique for each type. RESULTS: A total of 44 articles were reported, including 22 articles that discussed anatomic considerations (entry points, sagittal and axial trajectories, and features of screws) and another 22 articles that discussed the relevant biomechanical testing at this transitional region if C7 was directly involved in terms of receiving posterior rigid implants. CONCLUSIONS: C7 can accommodate different types of screws, which can provide additional benefits and risks based on availability of bony purchase, awareness of surgical technique, biomechanics, and anatomic considerations. PMID- 29253698 TI - Traumatic and Nontraumatic Spinal Cord Injuries. AB - OBJECTIVE: Owing to the aging of the population in the United States, it is anticipated that injury mechanisms, treatment, and outcomes of spinal cord injuries (SCI) will change. There is a scarcity of literature on nontraumatic SCI. Our goal in this study was to evaluate the causes, management, complications, and outcomes after SCI. METHODS: In a retrospective review, patients with traumatic and nontraumatic SCI admitted to the inpatient rehabilitation unit at a level 1 trauma center from 2003 to 2013 were reviewed. RESULTS: In all, 757 entries were identified, and 685 unique patients met our inclusion criteria; 17.4% were <35 years of age, 51.7% were 35 to 64 years of age, and 30.9% were at least 65 years old. The young adults had the highest proportion of fractures (60.5%) and subluxations (21.8%), whereas the oldest group had the highest rates of stenosis (35.4%), spondylotic myelopathy (16.5%), and cancer (15.1%). In SCI patients <35 years of age, 66.6% of injuries were caused by traumatic mechanisms of injury compared with 30.2% in the geriatric cohort. In the total of all SCI, 61.6% were nontraumatic. Surgical management was more prevalent with increasing age (58.8%, 73.7%, 82.1% from youngest to oldest group), as were overall rates of complications (58.6%, 59.4%, 66.7%). Mortality rates significantly increased with age (2.5%, 18.9%, 40.6% overall mortality rates in the 3 age groups). The overall mortality rate in nontraumatic SCI patients was 27.7% compared with 14.8% in traumatic SCI patients. CONCLUSIONS: Falls caused significantly more SCIs than expected, but most SCIs were predominantly nontraumatic in cause. The epidemiology of SCI is shifting rapidly. PMID- 29253697 TI - Use of Tubular Retractor for Resection of Deep-Seated Cerebral Tumors and Colloid Cysts: Single Surgeon Experience and Review of the Literature. AB - INTRODUCTION: Brain retraction is often required to develop a surgical corridor during the resection of deep-seated intracranial lesions. Traditional blade retractors distribute pressure asymmetrically and may case local tissue damage. Tubular retractors minimize this pitfall by distributing pressure evenly, which has been shown to translate to significant safety and efficacy data. Further qualified reports regarding the use of tubular retractors are of interest. METHODS: We performed a retrospective analysis of 1 surgeon's experience with 20 cases of minimally invasive resection with the ViewSite Brain Access System (n = 7) and BrainPath (n = 13) systems. In addition, a comprehensive review of all published cases of tubular retractor systems used for resection of subcortical neoplastic, cystic, infectious, vascular, and hemorrhagic lesions was conducted. RESULTS: Of the 20 cases analyzed, gross total resection was achieved in 18, with an associated 10% immediate postoperative complication rate and 5% long-term complication rate. A comprehensive review of the literature showed 30 articles describing 536 cases of resection of deep neoplastic or colloid cysts with an overall complication rate of 9.1%. CONCLUSIONS: Tubular retractor systems have a favorable safety profile and are an important tool in the armamentarium of a neurosurgeon for the resection of deep intracranial lesions. PMID- 29253699 TI - Unexpected Persistent Dentocentral Synchondrosis of C2. AB - BACKGROUND: The persistence of synchondrosis in adulthood can confound diagnostic decisions made during patient management. CASE DESCRIPTION: A 59-year-old woman who presented neck pain, acute headache, and acute cervical myelopathy symptoms after suffering whiplash grade 3 in a car rear-end impact underwent a conventional radiologic study that revealed no fracture and no anatomic spine variations. The magnetic resonance imaging study revealed no spinal cord intensity signal changes, but it showed a persistent (remnant) dentocentral synchondrosis that was undetected in a previous conventional radiographic evaluation. CONCLUSIONS: The localization and level of the remnant of the dentocentral synchondrosis are extremely important from the clinical viewpoint because of odontoid and C2 fractures. Neurosurgeons should thus be aware of the possible presence of a persistent (remnant) C2 dentocentral synchondrosis in adult subjects in order to avoid misdiagnosis with C2 fracture. PMID- 29253700 TI - Role of Visuohaptic Surgical Training Simulator in Resident Education of Orthopedic Surgery. AB - OBJECTIVE: We sought to assess the validity of a virtual surgical training system on lumbar pedicle screw placement for residents. METHODS: Ten inexperienced residents were randomly assigned to the simulation training (ST) group (n = 5) and control group (n = 5). The ST group performed the lumbar pedicle screw placement on the virtual surgical training system, and the control group was given an introductory teaching session before the cadaver test. A total of 8 adult fresh cadavers including 5 males and 3 females were collected and randomly allocated to the 2 groups. Each group performed the bilateral L1-L5 pedicle screw instrumentation in the cadaver specimens, respectively. Accuracy was assessed by computed tomography after instrumentation. The screw penetration rates, acceptable rates, and average screw penetration distance of the 2 groups were compared using statistical analysis. RESULTS: The screw penetration rate of the ST group (12.5%) was significantly lower than the control group (37.5%, P < 0.05). The screw acceptable rates in ST and control groups were 100% and 85%, respectively, with statistical differences between each other (P < 0.05). There was also a statistically significant difference of the average screw penetration distance between the ST (1.37 +/- 0.62 mm) group and control group (2.42 +/- 0.51 mm, P < 0.05). CONCLUSIONS: The virtual surgery simulation with greater accuracy is superior to the traditional teaching methods in surgical training of pedicle screw placement and can be used as a promising alternative for training of neurosurgical procedures. PMID- 29253701 TI - Effectiveness of Transpedicular Dynamic Stabilization in Treating Discogenic Low Back Pain. AB - PURPOSE: To assess clinical outcomes after dynamic stabilization in discogenic low back pain. METHODS: From April 2012 to January 2015, 23 patients with discogenic low back pain were treated with dynamic stabilization via the Wiltse approach. Main clinical assessments included visual analog scale, Oswestry Disability Index, and complications. Radiographs were evaluated for lumbar range of motion and intervertebral height. The Woodend classification was determined by magnetic resonance imaging. RESULTS: There were 23 cases evaluated with a mean follow-up time of 39 months. At last follow-up, visual analog scale and Oswestry Disability Index scores improved significantly compared with preoperatively (P < 0.05). At the stabilized segments, the height of intervertebral discs was increased significantly after surgery (P < 0.05). At last follow-up, the height was reduced to the preoperative level. At the operated segment, 47.4% of the flexion/extension range of motion was retained. Six discs showed rehydration with 1 grade improvement on the Woodend classification. CONCLUSIONS: Dynamic stabilization was a safe and effective treatment in carefully selected groups of patients with discogenic low back pain and promoted disc regeneration to some extent. PMID- 29253702 TI - Opioid Prescribing Practices of Neurosurgeons: Analysis of Medicare Part D. AB - OBJECTIVE: The Centers for Disease Control have declared that the United States is amidst a continuing opioid epidemic, with drug overdose-related death tripling between 1999 and 2014. Among the 47,055 overdose-related deaths that occurred in 2014, 28,647 (60.9%) of them involved an opioid. METHODS: The Part D Prescriber Public Use File, which is based on beneficiaries enrolled in the Medicare Part D prescription drug program, was used to query information on prescription drug events incurred by Medicare beneficiaries with a Part D prescription drug plan from 31 June 2014 to 30 June 2015. Only those providers with the specialty description of neurosurgeon, as reported on the provider's Part B claims, were included in this study. RESULTS: A total of 271,502 beneficiaries, accounting for 971,581 claims and 22,152,689 day supplies of medication, accounted for the $52,956,428.40 paid by the Centers for Medicare and Medicaid Services for medication that the 4085 neurosurgeons submitted to the Centers for Medicare and Medicaid Services Part D program in the 2014 calendar year. During the same year, 402,767 (41.45%) claims for 158,749 (58.47%) beneficiaries accounted for 6,458,624 (29.16%) of the day supplies of medications and $13,962,630.11 (26.37%) of the total money spent by the Centers for Medicare and Medicaid Services Part D that year. Nationwide, the ratio of opioid claims to total Medicare Part D beneficiaries was 1.48. No statistically significant regional differences were found. CONCLUSIONS: The opioid misuse epidemic is a complex and national issue with patterns of prescription not significantly different between regions. All neurosurgeons must be cognizant of their prescribing practices so as to best support the resolution of this public health crisis. PMID- 29253703 TI - Risk Factors for Recollapse of the Augmented Vertebrae After Percutaneous Vertebral Augmentation: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND OBJECTIVE: Recollapse of the augmented vertebrae after percutaneous vertebral augmentation treatment for osteoporotic vertebral compression fractures has obtained much attention. Although many potential risk factors have been proposed, they are still disputed. The aim of our study was to identify the characteristics of the augmented vertebrae that had undergone a recollapse according to a systematic review from the earliest available records up to August 2017 and then conduct a meta-analysis based on eligible studies to assess significant potential risk factors for recollapse of the augmented vertebrae. METHODS: Fourteen studies were identified for investigating recollapse of the augmented vertebrae. Of those studies, 9 studies were eligible for meta analysis. RESULTS: Pooled results showed that 5 primary factors were associated with recollapse of the augmented vertebrae, including preoperative intravertebral cleft, the affected vertebrae in the thoracolumbar region, preoperative severe kyphotic deformity, solid lump cement distribution pattern, and higher vertebral height restoration. It was possibly another risk factor that the distance between PMMA and superior end plate was relatively large. CONCLUSIONS: Careful observation of patients with these risk factors and reasonable intervention could be useful to prevent deterioration of their clinical course. PMID- 29253704 TI - High prolactin concentration during lactation period induced disorders of maternal behavioral in offspring. AB - Early-life stress during the perinatal period induces several neuropsychological disorders in adulthood. In animal studies, early-life stress during the perinatal period induces not only behavioral disorders but also other neurofunctional disorders, such as somatosensory functional disorder in adulthood. Furthermore, the offspring of an early-life-stressed parent also show disturbance of brain function in humans. Behavioral and neurological alterations in the offspring of a stressed parent have also been shown in animal studies. However, the mechanisms underlying such behavioral/neurological alterations are not yet fully understood. In this study, we found a disorder of maternal behavior in the offspring of early life-stressed mothers. The stressed mothers showed high concentrations of serum prolactin (PRL) during pregnancy and lactation. The concentration on the day of weaning the offspring significantly correlated with the changes in the concentration of corticosterone and the neurological function of offspring. These findings indicate that PRL may be involved in the induction of transgenerational effects of early-life stress on the brain function of offspring. In addition, maternal PRL can be a good biomarker for predicting the potential risk of neurofunctional alterations in the offspring. PMID- 29253705 TI - Hepatitis C virus deep sequencing for sub-genotype identification in mixed infections: A real-life experience. AB - BACKGROUND: The effectiveness of the new generation of hepatitis C treatments named direct-acting antiviral agents (DAAs) depends on the genotype, subtype, and resistance-associated substitutions present in individual patients. The aim of this study was to evaluate a massive sequencing platform for the analysis of genotypes and subtypes of hepatitis C virus (HCV) in order to optimize therapy. METHODS: A total of 84 patients with hepatitis C were analyzed. The routine genotyping methodology for HCV used at the study institution (Versant HCV Assay, LiPA) was compared with a deep sequencing platform (454/GS-Junior and Illumina MiSeq). RESULTS: The mean viral load in these HCV patients was 6.89*106+/ 7.02*105. Viral genotypes analyzed by LiPA were distributed as follows: 26% genotype 1a (22/84), 55% genotype 1b (46/84), 1% genotype 1 (1/84), 2.5% genotype 3 (2/84), 6% genotype 3a (5/84), 6% genotype 4a/c/d (5/84). When analyzed by deep sequencing, the samples were distributed as follows: 27% genotype 1a (23/84), 56% genotype 1b (47/84), 8% genotype 3a (7/84), 5% genotype 4d (4/84), 2.5% genotype 4f (2/84). Six of the 84 patients (7%) were infected with more than one subtype. Among these, 33% (2/6) failed DAA-based triple therapy. CONCLUSIONS: The detection of mixed infection could explain some treatment failures. Accurate determination of viral genotypes and subtypes would allow optimal patient management and improve the effectiveness of DAA therapy. PMID- 29253706 TI - Clinical utility of an optimised multiplex real-time PCR assay for the identification of pathogens causing sepsis in Vietnamese patients. AB - INTRODUCTION: For the identification of bacterial pathogens, blood culture is still the gold standard diagnostic method. However, several disadvantages apply to blood cultures, such as time and rather large volumes of blood sample required. We have previously established an optimised multiplex real-time PCR method in order to diagnose bloodstream infections. MATERIAL AND METHODS: In the present study, we evaluated the diagnostic performance of this optimised multiplex RT-PCR in blood samples collected from 110 septicaemia patients enrolled at the 108 Military Central Hospital, Hanoi, Vietnam. RESULTS: Positive results were obtained by blood culture, the Light Cylcler-based SeptiFast(r) assay and our multiplex RT-PCR in 35 (32%), 31 (28%), and 31 (28%) samples, respectively. Combined use of the three methods confirmed 50 (45.5%) positive cases of bloodstream infection, a rate significantly higher compared to the exclusive use of one of the three methods (P=0.052, 0.012 and 0.012, respectively). The sensitivity, specificity and area under the curve (AUC) of our assay were higher compared to that of the SeptiFast(r) assay (77.4%, 86.1% and 0.8 vs. 67.7%, 82.3% and 0.73, respectively). Combined use of blood culture and multiplex RT-PCR assay showed a superior diagnostic performance, as the sensitivity, specificity, and AUC reached 83.3%, 100%, and 0.95, respectively. The concordance between blood culture and the multiplex RT-PCR assay was highest for Klebsiella pneumonia (100%), followed by Streptococcus spp. (77.8%), Escherichia coli (66.7%), Staphylococcus spp. (50%) and Salmonella spp. (50%). In addition, the use of the newly established multiplex RT-PCR assay increased the spectrum of identifiable agents (Acintobacter baumannii, 1/32; Proteus mirabilis, 1/32). CONCLUSION: The combination of culture and the multiplex RT-PCR assay provided an excellent diagnostic accomplishment and significantly supported the identification of causative pathogens in clinical samples obtained from septic patients. PMID- 29253708 TI - Splenic tuberculosis. PMID- 29253707 TI - Hyperglycemia during tuberculosis treatment increases morbidity and mortality in a contemporary cohort of HIV-infected patients in Rio de Janeiro, Brazil. AB - BACKGROUND: Hyperglycemia occurs in tuberculosis (TB), but the long-term impact is unknown. We estimated the prevalence of hyperglycemia and compared the TB treatment outcomes and 1-year mortality rate according to the glycemic status noted during TB treatment. METHODS: We conducted a retrospective cohort analysis of adult patients who had TB and HIV coinfection and started receiving TB treatment at the Instituto Nacional de Infectologia Evandro Chagas, Brazil, between 2010-2015. Diabetes Mellitus (DM) and hyperglycemia were defined according to the American Diabetes Association. After excluding for known DM at baseline, the proportion of participants who developed new-onset DM after TB treatment was assessed. TB outcome was classified as successful or adverse (i.e., treatment failure, abandonment, and death). Kaplan-Meier survival curves were compared by the log-rank test based on the glycemic status of patients. Multivariate Cox regression models were used to assess the association between hyperglycemia and 1-year mortality. Two-sided p values <0.05 were considered statistically significant. RESULTS: We identified 414 euglycemic patients (87.5%), 49 hyperglycemic patients (10.3%), and 10 patients with known DM (2.1%). Diabetic patients were older compared to the euglycemic and hyperglycemic patients (47.9 vs. 37 vs. 39.7 years, respectively, p=0.001). Diabetic patients frequently had cavitation on chest image compared to hyperglycemic and euglycemic patients (50% vs. 23.4% vs. 15.3%, p=0.007, respectively). Hyperglycemic patients had more new-onset DM at follow-up compared to euglycemic (22 vs. 1; p<0001). Hyperglycemia was associated with adverse outcomes (71.4% vs. 24.6%, p<0.0001) compared to euglycemia. Crude 1-year mortality was significantly higher in patients with hyperglycemia compared with euglycemia (48.9% vs. 7.9%; unadjusted HR: 5.79 (3.74-8.96)). In the adjusted Cox models, hyperglycemia remained a significant factor for increased 1-year mortality (adjusted HR: 3.72 (2.17 6.38)]. CONCLUSIONS: Hyperglycemia frequently occurs in HIV-infected patients who commence TB treatment, and it increases the risks of adverse TB outcomes and 1 year mortality. Glucose testing during TB treatment detects patients at risk of adverse outcomes. PMID- 29253709 TI - Investigation of a cluster of multi-drug resistant tuberculosis in a high-rise apartment block in Singapore. AB - OBJECTIVE: Between February 2012 and May 2016, six residents of an 11-storey apartment block were diagnosed with MDR-TB. Based on initial tests, all isolates had similar genotypic profiles, although there were no identifiable epidemiological transmission patterns between three cases. We present findings from the cluster investigation and results of a mass screening exercise. DESIGN: Free voluntary TB screening was offered to past and current residents of the apartment block, comprising an interview, Chest X-Ray, and Interferon Gamma Release Assay or Tuberculin skin test. Expected latent TB proportions were calculated using a reference population, and whole genome sequencing (WGS) was performed. RESULTS: The index case was involved in a separate gaming centre outbreak involving five patrons. 241 current (67.9% of 355 residents) and 18 past residents were screened. The latent TB proportion was 19.9%, which was at the higher end of the expected range. WGS confirmed relatedness of cases' MDR-TB isolates- eight of 10 isolates were genetically identical, while the remaining two were one Single Nucleotide Polymorphism apart. CONCLUSION: With WGS, TB clusters not apparent through regular activity-based contact tracing may be detected. Mass screening may help inform the extent of transmission, but is limited by participation and difficulties in interpretation. PMID- 29253710 TI - Mapping of new HIV infections in Morocco and impact of select interventions. AB - OBJECTIVES: The aim of this study was to assess HIV modes of exposure in Morocco at the national level and also for Souss-Massa-Draa, the region most affected by HIV. Another aim was to assess the impact of different scenarios of select intervention packages. METHODS: The Modes of Transmission Model was adapted and used, and was parameterized using quality bio-behavioral surveillance data among key populations, routine data sources, and literature reviews. RESULTS: Nationally in 2013, the largest number of new infections occurred among clients of female sex workers (FSWs) (25%; 95% confidence interval (CI) 14-37%), followed by men who have sex with men (MSM) (22%; 95% CI 12-35%), HIV serodiscordant couples (22%; 95% CI 12-34%), FSWs (11%; 95% CI 6-18%), and people who inject drugs (5%; 95% CI 2-9%). A similar pattern of results was observed in Souss-Massa Draa, but the HIV incidence rate was four-fold that at the national level. Different scenarios of feasible intervention packages reduced HIV incidence by 8 44%. CONCLUSIONS: Commercial heterosexual sex networks continue as the leading driver of the epidemic, with half of HIV incidence. A quarter of new infections occurred among MSM, a third of which in Souss-Massa-Draa. Feasible expanded coverage of interventions could lead to large reductions in incidence. PMID- 29253711 TI - Urine colorimetry for therapeutic drug monitoring of pyrazinamide during tuberculosis treatment. AB - OBJECTIVES: Pyrazinamide is a key drug in the first-line treatment regimen for tuberculosis, with a potent sterilizing effect. Although low pyrazinamide peak serum concentrations (Cmax) are associated with poor treatment outcomes, many resource-constrained settings do not have sufficient laboratory capacity to support therapeutic drug monitoring (TDM). The objective of this study was to determine whether a colorimetric test of urine can identify tuberculosis patients with adequate pyrazinamide exposures, as defined by serum Cmax above a target threshold. METHODS: In the derivation study of healthy volunteers, three dose sizes of pyrazinamide were evaluated, and intensive pharmacokinetic blood sampling was performed over an 8-h period, with a timed urine void at 4h post dosing. Pyrazinamide in urine was isolated by spin column centrifugation with an exchange resin, followed by colorimetric analysis; the absorbance peak at 495nm was measured. The urine assay was then evaluated in a study of 39 HIV/tuberculosis patients in Botswana enrolled in an intensive pharmacokinetic study. Receiver operating characteristics (ROC) curves were used to measure diagnostic accuracy. The guideline-recommended pyrazinamide serum Cmax target of 35mg/l was evaluated in the primary analysis; this target was found to be predictive of favorable outcomes in a clinical study. Following this, a higher serum Cmax target of 58mg/l was evaluated in the secondary analysis. RESULTS: At the optimal cut-off identified in the derivation sample, the urine colorimetric assay was 97% sensitive and 50% specific to identify 35 of 39 HIV/tuberculosis patients with pharmacokinetic target attainment, with an area under the ROC curve of 0.81 (95% confidence interval 0.60-0.97). Diagnostic accuracy was lower at the 58mg/l serum Cmax target, with an area under the ROC curve of 0.68 (95% confidence interval 0.48-0.84). Men were less likely than women to attain either serum pharmacokinetic target. CONCLUSIONS: The urine colorimetric assay was sensitive but not specific for the detection of adequate pyrazinamide pharmacokinetic exposures among HIV/tuberculosis patients in a high-burden setting. PMID- 29253712 TI - Border zone brain lesions due to neurotrichinosis. AB - Trichinosis is a parasitic disease that, due to variable clinical syndromes, is often underrecognized. We present the case of a patient with eosinophilia, focal neurological signs and multiple bilateral brain lesions, distributed mainly in the border zones. The diagnostic workup revealed neurotrichinosis, which should be suspected even without a clear history of consumption of poorly cooked meat. PMID- 29253713 TI - Extensive AIDS-associated Kaposi's sarcoma. PMID- 29253714 TI - Multiscale modeling of glycosaminoglycan structure and dynamics: current methods and challenges. AB - Glycosaminoglycans are long unbranched and complex polysaccharides that are an essential component of mammalian extracellular matrices. Characterization of their molecular structure, dynamics and interactions are essential to understand important biological phenomena in health and disease, and will lead to novel therapeutics and medical devices. However, this has proven to be a challenge experimentally and theoretical techniques are needed to develop new hypotheses, and interpret experiments. This review aims to examine the current theoretical (rather than experimental) methods used by researchers to investigate glycosaminoglycan structure, dynamics and interactions, from the monosaccharide to the macromolecular scale. It will consider techniques such as quantum mechanics, molecular mechanics, molecular dynamics, coarse graining and docking. PMID- 29253715 TI - Detection of copy-move image modification using JPEG compression model. AB - The so-called copy-move forgery, based on copying an object and pasting in another location of the same image, is a common way to manipulate image content. In this paper, we address the problem of copy-move forgery detection in JPEG images. The main problem with JPEG compression is that the same pixels, after moving to a different position and storing in the JPEG format, have different values. The majority of existing algorithms is based on matching pairs of similar patches, which generates many false matches. In many cases they cannot be eliminated by postprocessing, causing the failure of detection. To overcome this problem, we derive a JPEG-based constraint that any pair of patches must satisfy to be considered a valid candidate and propose an efficient algorithm to verify the constraint. The constraint can be integrated into most existing methods. Experiments show significant improvement of detection, especially for difficult cases, such as small objects, objects covered by textureless areas and repeated patterns. PMID- 29253716 TI - Maternal relationship quality and peer social acceptance as mediators between child maltreatment and adolescent depressive symptoms: Gender differences. AB - Childhood maltreatment negatively impacts the development of maternal and peer relationships and may put adolescents at risk for depression. The present study examined gender differences in maternal relationship quality and peer social acceptance as mediators of the association between childhood maltreatment and adolescent depressive symptoms in 342 (151 female, 191 male) maltreated (n = 198) and nonmaltreated (n = 144) youth in the USA. An observer report Q-Scale measure of depressive symptoms was developed and received preliminary support. Social acceptance was a significant mediator for both genders. The significant association between maltreatment and maternal relationship quality was unique to females, and the association between maternal relationship quality and depressive symptoms was significantly stronger for females. Lower maternal relationship quality marginally significantly mediated the association between maltreatment and depressive symptoms for females only. Results have implications for the prevention and intervention of depression in adolescents with a history of childhood maltreatment. PMID- 29253718 TI - Integration of radiation and immunotherapy in breast cancer - Treatment implications. AB - Radiation therapy (RT) has been successfully used in the treatment of breast cancer (BC) for over a century. While historically thought to be immunosuppressive, new data have shown that RT can work together with the immune system to eliminate cancer. It can cause immunogenic cell death and facilitate tumor neoantigen presentation and cross-priming of tumor-specific T-lymphocytes, turning irradiated tumor into an in-situ vaccine. Unfortunately, due to various immune escape mechanism put in place by the tumor, RT alone rarely results in a systemic response of metastatic disease sites (known as the abscopal effect). Immunotherapy, a series of agents designed to stimulate the immune system in order to generate tumor-specific immune response, is showing promise in treatment of various cancers, including BC, and can be an ideal complement to RT in stimulating a systemic immune response to reject the tumor cells. This review discusses the mechanisms in which RT can trigger an immune response for tumor rejection, and provide emerging preclinical and clinical data of combination immunoradiotherapy, and its potential in treating BC. PMID- 29253717 TI - Regulation of ADAM10 by miR-140-5p and potential relevance for Alzheimer's disease. AB - Recent reports in Alzheimer's disease (AD) research suggest that alterations in microRNA (miRNA) expression are associated with disease pathology. Our previous studies suggest that A Disintegrin and Metalloproteinase 10 (ADAM10) expression is important in AD and could be modulated by an extended regulatory region that includes the 3' untranslated region. In this study, we have investigated the role of trans-acting factors in ADAM10 gene regulation. Our study shows that miRNA-140 5p has enhanced expression in the AD postmortem brain hippocampus using high throughput miRNA arrays and quantitative real-time polymerase chain reaction. Interestingly, we have also seen that miRNA-140-5p seed sequence is present on 3' untranslated region of both ADAM10 and its transcription factor SOX2. The specific interaction of miRNA-140-5p with both ADAM10 and SOX2 signifies high regulatory importance of this miRNA in controlling ADAM10 expression. Thus, this investigation unravels mechanisms underlying ADAM10 downregulation by miR-140-5p and suggests that dysfunctional regulation of ADAM10 expression is exacerbated by AD-related neurotoxic effects. These findings underscore the importance of understanding the impact of trans-acting factors in the modulation of AD pathophysiology. PMID- 29253719 TI - Increasing rates of thrombosis in children with congenital heart disease undergoing cardiac surgery. AB - OBJECTIVE: To determine thrombosis incidence, morbidities, and mortality of children with congenital heart disease who develop thrombosis after cardiac surgery. MATERIALS AND METHODS: This retrospective study reviewed patients <18 years old within the Pediatric Health Information System (PHIS) database who underwent cardiac surgery from 2004-2012. Thrombosis rates were compared for each procedure. Mortality was modeled using proportional hazards, adjusting for important clinical and demographic factors. RESULTS: Of 91909 CHD patients who underwent surgery, 2655 (2.9%) developed thrombosis within the ensuing 12 months. The rate of thrombosis increased 253% (p<0.001), from 1.7% in 2004 to 4.4% in 2012. Systemic to pulmonary shunt placement (34.3%) and septostomy (26.1%) had the highest thrombosis percentages. Children <28 days had the highest prevalence (61%). Those with thrombosis had longer lengths of stay than those without [median 27 hospital days and 10 ICU days vs. 6 and 2 (p<0.001)]. Mean risk adjusted cost was higher with thrombosis; $126,257 vs. $40,773 (p<0.001). Thrombosis was also associated with higher rates of bacteremia [8.3% vs. 3.4%, p<0.001], endocarditis [0.7% vs. 0.2%, p<0.001], and mortality [12.3% vs. 0.8%, p<0.001]. The adjusted hazard ratio for mortality in patients with thrombosis was 5.5 (95% CI: 4.6-6.5). CONCLUSIONS: Thrombosis rates in CHD patients after cardiac surgery is increasing. Thrombosis is associated with longer hospital stay, increased ICU days, and cost. CHD patients with thrombosis also have increased bacteremia and mortality rates. More research is needed to understand contributors to thrombosis which may help develop strategies to mitigate morbidity and mortality. PMID- 29253720 TI - Dietary intake of fish and n-3 polyunsaturated fatty acids and risks of perinatal depression: The Japan Environment and Children's Study (JECS). AB - The results of several epidemiological studies and clinical trials investigating the effects of n-3 polyunsaturated fatty acids (PUFAs) on antenatal and postnatal depression remain controversial. We investigated the possible association of dietary intake of fish and n-3 PUFAs with the risks of maternal and paternal psychological distress during pregnancy and of maternal postpartum depression in Japan. From a dataset comprising 104,102 maternal registrations and 52,426 paternal registrations in The Japan Environment and Children's Study, this study analyzed complete data on questionnaires for 75,139, 79,346, and 77,661 women during early pregnancy, mid-late pregnancy, and after pregnancy, respectively, and for 41,506 male partners. Multivariable logistic regression showed reduced risk of psychological distress in the second and third quintiles for fish intake in early pregnancy and in the second to fifth quintile in mid-late pregnancy. No reductions were observed for n-3 PUFA intake in early pregnancy but in the second to fourth quintile in mid-late pregnancy. For postpartum depression, reductions were observed in the second to fourth quintile for fish intake but only in the first quintile for n-3 PUFA intake. As for paternal psychological distress, only the fourth quintile for fish intake showed a significant reduced risk but none were shown for n-3 PUFA intake. In conclusion, fish intake was associated with some reduced risk of psychological distress during pregnancy, even for male partners. The associations were weaker for n-3 PUFA intake than for fish intake. PMID- 29253721 TI - Household water insecurity after a historic flood: Diarrhea and dehydration in the Bolivian Amazon. AB - While 884 million people worldwide lack access to clean water, millions live in flood-prone regions. Unexpected flooding increases risk of diarrheal diseases and is expected to occur with increased frequency in the 21st century. Water insecurity is linked to mental distress in water scarce regions, yet this construct has not been examined closely among populations living in flood-prone regions. This paper examines how differences in water sources and lifestyle among Tsimane' forager-horticulturalists in lowland Bolivia are related to water insecurity after a historic flood in 2014, and in turn, how water insecurity is associated with diarrhea and dehydration. Pre-flood data come from qualitative interviews with 36 household heads, anthropometrics, participant observation, and water quality analysis between September 2013-January 2014 used to create a locally-adapted water insecurity questionnaire. Water insecurity was measured after the historic flood; no pre-flood water insecurity measures are available. Post-flood data were collected through surveys, water quality analysis, and health exams using near-exhaustive sampling in two villages, yielding 118 adults and 115 children (aged 2-12 years) in 62 households between March-April 2014. Overall, 89% of adults reported medium or high water insecurity. Only hand-pumps tested negative for pathogenic bacteria both pre- and post-flood. Tobit regressions suggest that hand-pumps (when available) and adult age were associated with lower water insecurity scores. Multiple logistic regressions suggest that adults with high water insecurity were more likely to report diarrhea than adults with low (Odds Ratio [OR] 9.2; 95% CI: 1.27-67.1). Children from households with medium (OR: 6.8; 95% CI: 1.41-32.5) or high (OR: 14.0; 95% CI: 2.40-81.5) water insecurity had significantly higher odds of dehydration than children in households with low water insecurity. Catastrophic flooding may systematically increase dimensions of household water insecurity. This research suggests an experience-based measure of water insecurity is associated with objective health outcomes. PMID- 29253722 TI - The next Sub Saharan African epidemic? A case study of the determinants of cervical cancer knowledge and screening in Kenya. AB - Early cervical cancer screening has been shown to be beneficial in reducing cervical cancer related deaths. Despite the benefits of early cervical cancer screening, uptake remains limited, with wide disparities in access and uptake in most developing countries. As part of a larger study, this paper uses a socio ecological framework to explain the determinants of cervical cancer knowledge and screening among women of reproductive age (15-49 years) in Kenya. We conducted a multilevel analysis of cervical cancer knowledge (n = 11,138) and screening (n = 10,333) using the 2014 Kenya Demographic and Health Survey (KDHS). Results show regional disparities in cancer knowledge and the utilization of cervical cancer screening services; regions with high wealth inequality (OR = 0.70, 95% CI [0.56 0.87]) emerged as vulnerable regions where women were less likely to screen for cervical cancer. Gender equity, health insurance coverage and education level significantly predicted cervical cancer screening rates. Results further revealed regional as well as rural-urban wealth inequalities in cervical cancer screening. We argue that given that Kenyan women are highly exposed to human papilloma virus (HPV) due to the legacy of human immunodeficiency virus (HIV) in the country, cervical cancer may be the next epidemic if integrated measures are not adopted to increase cervical cancer knowledge and overcome the barriers to utilizing early screening services. The paper concludes with policy recommendations and directions for future research. PMID- 29253723 TI - YAP mediated mechano-homeostasis - conditioning 3D animal body shape. AB - Cells of terrestrial animals are constantly exposed to external forces including gravity. However, the complex 3D structure of the body and its organs form without being flattened. A century ago, the mathematical biologist D'Arcy Thompson predicted in 'On Growth and Form' that terrestrial animal body shapes are entirely conditioned by gravity [1], but the prediction remained to be proved due to the lack of an appropriate animal model. In this review, we outline a new mechanism of morphogenesis which ensures the generation of vertebrate 3D body shape that can withstand gravity and in which Hippo-YAP signaling acts as a mechano-effector controlling mechano-homeostasis. We will highlight the recent papers that advanced the field and discuss the impact of this previously unrecognized function of YAP-mediated signaling on the established concept of organogenesis, tissue homeostasis and disease. PMID- 29253724 TI - Maximizing the use of Special Olympics International's Healthy Athletes database: A call to action. AB - There is a critical need for high-quality population-level data related to the health of individuals with intellectual disabilities. For more than 15 years Special Olympics International has been conducting free Healthy Athletes screenings at local, national and international events. The Healthy Athletes database is the largest known international database specifically on the health of people with intellectual disabilities; however, it is relatively under utilized by the research community. A consensus meeting with two dozen North American researchers, stakeholders, clinicians and policymakers took place in Toronto, Canada. The purpose of the meeting was to: 1) establish the perceived utility of the database, and 2) to identify and prioritize 3-5 specific priorities related to using the Healthy Athletes database to promote the health of individuals with intellectual disabilities. There was unanimous agreement from the meeting participants that this database represents an immense opportunity both from the data already collected, and data that will be collected in the future. The 3 top priorities for the database were deemed to be: 1) establish the representativeness of data collected on Special Olympics athletes compared to the general population with intellectual disabilities, 2) create a scientific advisory group for Special Olympics International, and 3) use the data to improve Special Olympics programs around the world. The Special Olympics Healthy Athletes database includes data not found in any other source and should be used, in partnership with Special Olympics International, by researchers to significantly increase our knowledge and understanding of the health of individuals with intellectual disabilities. PMID- 29253725 TI - A cryostatic, fast scanning, wideband NQR spectrometer for the VHF range. AB - In the search for a novel MRI contrast agent which relies on T1 shortening due to quadrupolar interaction between Bi nuclei and protons, a fast scanning wideband system for zero-field nuclear quadrupole resonance (NQR) spectroscopy is required. Established NQR probeheads with motor-driven tune/match stages are usually bulky and slow, which can be prohibitive if it comes to Bi compounds with low SNR (excessive averaging) and long quadrupolar T1 times. Moreover many experiments yield better results at low temperatures such as 77 K (liquid nitrogen, LN) thus requiring easy to use cryo-probeheads. In this paper we present electronically tuned wideband probeheads for bands in the frequency range 20-120 MHz which can be immersed in LN and which enable very fast explorative scans over the whole range. To this end we apply an interleaved subspectrum sampling strategy (ISS) which relies on the electronic tuning capability. The superiority of the new concept is demonstrated with an experimental scan of triphenylbismuth from 24 to 116 MHz, both at room temperature and in LN. Especially for the first transition which exhibits extremely long T1 times (64 ms) the and low signal the new approach allows an acceleration factor by more than 100 when compared to classical methods. PMID- 29253726 TI - Testing signal enhancement mechanisms in the dissolution NMR of acetone. AB - In cryogenic dissolution NMR experiments, a substance of interest is allowed to rest in a strong magnetic field at cryogenic temperature, before dissolving the substance in a warm solvent, transferring it to a high-resolution NMR spectrometer, and observing the solution-state NMR spectrum. In some cases, negative enhancements of the 13C NMR signals are observed, which have been attributed to quantum-rotor-induced polarization. We show that in the case of acetone (propan-2-one) the negative signal enhancements of the methyl 13C sites may be understood by invoking conventional cross-relaxation within the methyl groups. The 1H nuclei acquire a relative large net polarization through thermal equilibration in a magnetic field at low temperature, facilitated by the methyl rotation which acts as a relaxation sink; after dissolution, the 1H magnetization slowly returns to thermal equilibrium at high temperature, in part by cross relaxation processes, which induce a transient negative polarization of nearby 13C nuclei. We provide evidence for this mechanism experimentally and theoretically by saturating the 1H magnetization using a radiofrequency field pulse sequence before dissolution and comparing the 13C magnetization evolution after dissolution with the results obtained from a conventional 1H-13C cross relaxation model of the CH3 moieties in acetone. PMID- 29253727 TI - Proper name retrieval and structural integrity of cerebral cortex in midlife: A cross-sectional study. AB - There is currently little understanding on whether retrieval of proper names differs in midlife compared to young adulthood and if so, whether the age differences in this ability are associated with differences in structural integrity of the cerebral cortex. To answer these questions, we studied retrieval of proper names in 115 cognitively healthy middle-aged persons (49.7, +/-3.2), comparing their performance on a tip-of-the-tongue (TOT) task with that of 68 young persons (25.4, +/-3.5) from the Cam-Can data repository (http://www.mrc cbu.cam.ac.uk/datasets/camcan/). Grey matter (GM) density and cortical thickness were used as indices of structural integrity of the cerebral cortex. The middle aged (MA) group experienced more TOTs during proper names retrieval than young adults (YA), (t = 3.789, p < .005) and had considerably less GM density and cortical thickness across a range of brain areas bilaterally. Small clusters in left BA 45 and right BA 44 (cortical thickness) and in right BA 40 (volumetry) revealed group differences when accounting for TOTs. However, we observed no correlations between MA's TOT scores and GM volumes or cortical thickness of the brain regions typically reported as implicated in retrieval of proper names: left anterior temporal lobe, left insula, and left superior and middle temporal gyri. PMID- 29253728 TI - Normalized frontal impact biofidelity kinematic corridors using post mortem human surrogates. AB - Due to reducing cost and powerful computing resources and the ability of finite element human body models (FEHBM) to predict human body response more realistically, they are gaining acceptance to be a substitute for mechanical surrogates. Unlike mechanical surrogates, FEHBM can realistically simulate human kinematics and kinetics. Moreover, an array of quantities can be directly measured from FEHBMs. However, similar to Anthropomorphic Test Devices (ATDs), in order to evaluate the biofidelity, these models must be validated using PMHS response corridors. Therefore, availability of such PMHS corridors that can be used to validate both ATD and FEHBM kinematics is of primary importance. The current study presents normalized biofidelity corridors of head CG, T1, T12, and sacrum accelerations using PMHS frontal sled tests that were previously conducted. In addition, rotational accelerations and displacements of the head are also presented. The experimental data were collected using four specimens. Each specimens were tested with non-injurious pulses using two different velocities (low: 3.6m/s and medium: 6.9m/s). These data were normalized using mass-based technique to represent mid-sized United States population. Using the normalized data, average and plus/minus one standard deviation response corridors were generated that can be used to evaluate the biofidelity of ATDs and FEHBMs. PMID- 29253729 TI - Measurement of anisotropic mechanical properties in porcine brain white matter ex vivo using magnetic resonance elastography. AB - The mechanical properties of brain tissue, particularly those of white matter (WM), need to be characterized accurately for use in finite element (FE) models of brain biomechanics and traumatic brain injury (TBI). Magnetic resonance elastography (MRE) is a powerful tool for non-invasive estimation of the mechanical properties of soft tissues. While several studies involving direct mechanical tests of brain tissue have shown mechanical anisotropy, most MRE studies of brain tissue assume an isotropic model. In this study, an incompressible transversely isotropic (TI) material model parameterized by minimum shear modulus (MU2), shear anisotropy parameter (phi), and tensile anisotropy parameter (zeta) is applied to analyze MRE measurements of ex vivo porcine white matter (WM) brain tissue. To characterize shear anisotropy, "slow" (pure transverse) shear waves were propagated at 100, 200 and 300Hz through sections of ex vivo brain tissue including both WM and gray matter (GM). Shear waves were found to propagate with elliptical fronts, consistent with TI material behavior. Shear wave fields were also analyzed within regions of interest (ROI) to find local shear wavelengths parallel and perpendicular to fiber orientation. FE simulations of a TI material with a range of plausible shear modulus (MU2) and shear anisotropy parameters (phi) were run and the results were analyzed in the same fashion as the experimental case. Parameters of the FE simulations which most closely matched each experiment were taken to represent the mechanical properties of that particular sample. Using this approach, WM in the ex vivo porcine brain was found to be mildly anisotropic in shear with estimates of minimum shear modulus (actuation frequencies listed in parenthesis): MU2= 1.04 +/ 0.12 kPa (at 100Hz), MU2= 1.94 +/- 0.29 kPa (at 200Hz), and MU2= 2.88 +/- 0.34 kPa (at 300Hz) and corresponding shear anisotropy factors of phi= 0.27 +/- 0.09 (at 100Hz), phi= 0.29 +/- 0.14 (at 200Hz) and phi= 0.34 +/- 0.13 (at 300Hz). Future MRE studies will focus on tensile anisotropy, which will require both slow and fast shear waves for accurate estimation. PMID- 29253730 TI - Air pollution and occurrence of type 2 diabetes in a large cohort study. AB - The few cohort studies that have investigated the association between exposure to air pollution and occurrence of diabetes have reported conflicting results. We aimed to evaluate the association of long-term exposure to particulate matter (PM), nitrogen oxides (NOx) and ozone (O3), with baseline prevalence and incidence of type 2 diabetes in a large administrative cohort in Rome, Italy. A total of 1,425,580 subjects aged 35+years (January 1st, 2008) were assessed and followed for six years. We estimated PM10, PM2.5-10, PM2.5, NO2, and NOx exposures at residence using land use regression models, and summer O3 exposure using dispersion modeling. To estimate the association between air pollutant exposures and prevalence and incidence of diabetes, we used logistic and Cox regression models, considering individual, environmental (noise and green areas), and contextual characteristics. We identified 106,387 prevalent cases at baseline and 65,955 incident cases during the follow-up period. We found positive associations between nitrogen oxides exposures and prevalence of diabetes with odds ratios (ORs) up to 1.010 (95% CI: 1.002, 1.017) and 1.015 (1.009, 1.021) for NO2 and NOx, respectively, per fixed increases (per 10MUg/m3 and 20MUg/m3, respectively). We also found some evidence of an association between NOx and O3 and incidence of diabetes, with hazard ratios (HRs) of 1.011 (95%CI: 1.003-1.019) and 1.015 (1.002-1.027) per 20 and 10MUg/m3 increases, respectively. The association with O3 with incident diabetes was stronger in women than in men and among those aged <50years. In sum, long-term exposure to nitrogen oxides was associated with prevalent diabetes while NOx and O3 exposures were associated with incident diabetes. PMID- 29253731 TI - An analysis of cumulative risks based on biomonitoring data for six phthalates using the Maximum Cumulative Ratio. AB - The Maximum Cumulative Ratio (MCR) quantifies the degree to which a single chemical drives the cumulative risk of an individual exposed to multiple chemicals. Phthalates are a class of chemicals with ubiquitous exposures in the general population that have the potential to cause adverse health effects in humans. This work used the MCR to evaluate coexposures to six phthalates as measured in biomonitoring data from the most recent cycle (2013-2014) of the National Health and Nutrition Examination Survey (NHANES). The values of MCR, Hazard Index (HI), and phthalate-specific Hazard Quotients (HQs) were determined for 2663 NHANES participants aged six years and older by using reverse dosimetry techniques to calculate steady-state doses consistent with concentrations of metabolites of six phthalates in urine and using Tolerable Daily Intake values. There were 21 participants (0.8% of the NHANES sample) with HI>1. Of those, 43% (9/21) would have been missed by chemical-by-chemical assessments (i.e. all HQs were less than one). The mean MCR value in the 21 participants was 2.1. HI and MCR values were negatively correlated (p<0.001) indicating that most participants, especially those with elevated HI values, had their cumulative risks driven by relatively large doses of a single phthalate rather than doses of multiple phthalates. The dominate phthalate varied across participants. Children (aged 6-17years) had a higher HI values (p<0.01) than adults (18+ years). However, the probability of having HI>1 was not driven by age, gender, or ethnicity. The cumulative exposures of concern largely originated from a subset of three of the fifteen possible pairs of the six phthalates. These findings suggest that cumulative exposures were a potential concern for a small portion of the surveyed participants involving a subset of the phthalates explored. The largest risks tended to occur in individuals whose exposures were dominated by a single phthalate. PMID- 29253732 TI - An apple NAC transcription factor negatively regulates cold tolerance via CBF dependent pathway. AB - Cold stress is an adverse stimulus that affects plant growth and development, and the C-repeat binding factor (CBF) cold-regulatory cascade has been regarded as a master regulator in the plant response to cold stress. Here, we showed that a NAC transcription factor modulated low-temperature tolerance. MdNAC029/MdNAP, an apple NAC gene was isolated and its role in regulating cold tolerance was investigated. MdNAC029 was responsive to low-temperature treatment, and over expression of MdNAC029 reduced cold tolerance in apple calli and Arabidopsis. Furthermore, EMSA assays and transient expression assays demonstrated that MdNAC029 directly repressed the expression of MdCBF1 and MdCBF4 by binding to their promoters. Taken together, our data suggest that MdNAC029 functions as a negative regulator in regulating plant cold tolerance in a CBF-dependent manner, providing a deeper understanding of NAC transcription-factor-mediated cold tolerance. PMID- 29253733 TI - Morphology and molecular phylogeny of Holostichides terrae nov. spec. (Ciliophora: Spirotrichea) with discussion on the possible non-monophyly of Holostichides. AB - In a study to investigate ciliate diversity, we discovered a new soil ciliate. Holostichides terrae nov. spec. was examined and identified based on observations of living cells and stained specimens. In addition, the nuclear SSU rRNA gene along with morphology was analyzed to infer its phylogenetic position. The new species closely resembles H. dumonti, but can be distinguished by the morphology of the pharynx (with rod-shaped structure vs. lacking) and the number of frontoterminal cirri (invariably two vs. usually more than two). Molecular analyses indicate that the genus Holostichides is not monophyletic, and H. terrae is closely related with the genera Birojimia and Hemicycliostyla, both of which have a pharynx with rod-shaped structures, as also seen in H. terrae. PMID- 29253734 TI - Diterpenoids from the roots of Euphorbia ebracteolata and their inhibitory effects on human carboxylesterase 2. AB - A chemical investigation of the roots of Euphorbia ebracteolata identified eighteen diterpenoids and glycosides. On the basis of spectroscopic data, they were determined to be ent-kauranes, ent-atisanes, tigliane derivatives, ingenane, and ent-abietanes, among which were eleven previously undescribed diterpenoids. The inhibitory effects of the isolated compounds against human carboxylesterase 2 (hCE-2) were evaluated in vitro, which revealed moderate inhibitory effects with IC50 values < 50 MUM. Next, the inhibitory kinetics were evaluated for the putative hCE-2 inhibitor 4beta,9alpha,16,20-tetrahydroxy-14(13 -> 12)-abeo 12alphaH-1,6-tigliadiene-3,13-dione (IC50 3.88 MUM), and results indicated competitive inhibition with Ki 4.94 MUM. Additionally, none of the diterpenoids showed cytotoxic effects against five human tumor cell lines as determined by MTT assays. PMID- 29253735 TI - Phenolic chemistry of the seagrass Zostera noltei Hornem. Part 1: First evidence of three infraspecific flavonoid chemotypes in three distinctive geographical regions. AB - The flavonoid content of Zostera noltei leaves was investigated over a broad spatial scale using chromatographic and spectroscopic techniques (HPLC-DAD, LC/MS and NMR). Samples were collected at fifteen localities covering Mediterranean Sea and NE Atlantic coast, and representative of three types of coastal ecosystems: mesotidal bays, coastal lagoons, and open-sea. Three geographically distinct flavonoid chemotypes were identified on the basis of their respective major compound. One is characterized by apigenin 7-sulfate (Eastern part of Gulf of Cadiz), one by diosmetin 7-sulfate (French Atlantic coast and Mediterranean Sea), and the third contained similar quantities of the above two compounds (Mauritania and South Portugal). Our results show that metabolomic profiling using a combination of analytical techniques is a tool of choice to characterize chemical phenotype accurately. This work emphasizes for the first time the spatial variability in the flavonoid chemistry of Z. noltei throughout Atlantic and Mediterranean range, and constitutes the first report of chemical races in the Zosteraceae family. This infraspecific chemical differentiation should be considered when dealing with the role of Z. noltei in coastal ecosystems or in the selection of the best population donor for Z. noltei beds restoration. Combined with molecular identification, phenolic fingerprinting might be helpful to elucidate the evolutionary history of Z. noltei. PMID- 29253736 TI - Polyvinylidene fluoride effects on the electrocatalytic properties of air cathodes in microbial fuel cells. AB - The use of polyvinylidene fluoride (PVDF) as a binder was investigated in order to prepare the active carbon catalyst and carbon black diffusion layers of a microbial fuel cell cathode. Compared with other binders, PVDF performed competitively as it did not require a lengthy curing time and high curing temperature. Results of XRD characterization showed that the typical beta-PVDF was enhanced as PVDF content ratio increased. SEM results indicated that the catalyst layer easily peeled off due to the low binder concentration of binder, but the high binder content was deemed undesirable because the large amount of non-conductive PVDF interrupted the percolation path. The optimum binder concentration was double checked using Tafel and EIS tests. Results indicated that the cathode with 10% PVDF is the optimum operated concentration. The cathode can obtain 180mV of cathode potential and the smallest total impedance of 2500Omega, which are consistent with the SEM analysis. Moreover, the cathode with 10% PVDF concentration produced a maximum power density of 1600mWm-2, suggesting that PVDF can compete with other traditional binders. PMID- 29253737 TI - Effect of postparturient oral calcium administration on serum total calcium concentration in Holstein cows fed diets of different dietary cation-anion difference in late gestation. AB - Minimizing the severity of post parturient hypocalcemia and the incidence of subclinical hypocalcaemia in multiparous dairy cows are important goals of the transition period. The primary objective of this study was to determine whether feeding an acidogenic ration in late gestation combined with oral CaCl2 administration after parturition improved calcium homeostasis when compared to feeding an acidogenic ration prepartum or oral CaCl2 administration postpartum alone. Forty-two Holstein dairy cows were randomly assigned to one of three groups of 14 cows. Group L were fed a low DCAD ration. Groups L+Ca and M+Ca were fed a low or moderate DCAD ration, respectively, and administered 50g Ca as a CaCl2 solution at calving and 12h later by ororuminal intubation in 500mL of water. Mean serum [calcium] was lower immediately after parturition in group M+Ca (7.1mg/dL) than group L+Ca (8.2mg/dL). Oral CaCl2 administration increased mean serum [calcium] at 6h after treatment in groups M+Ca (8.0mg/dL) and L+Ca (8.7mg/dL), but most of this increase had disappeared at 12h after treatment. Group L+Ca had a higher serum [calcium] at time=6h and 12h than the other two groups, and a higher serum [calcium] than group M+Ca at 1 and 2days after treatment. We conclude that feeding an acidogenic ration in late gestation combined with oral CaCl2 administration provided a higher serum [calcium] at 6 and 12h after parturition than feeding an acidogenic ration prepartum or oral CaCl2 administration postpartum alone. PMID- 29253738 TI - The integration of audio-tactile information is modulated by multimodal social interaction with physical contact in infancy. AB - Interaction between caregivers and infants is multimodal in nature. To react interactively and smoothly to such multimodal signals, infants must integrate all these signals. However, few empirical infant studies have investigated how multimodal social interaction with physical contact facilitates multimodal integration, especially regarding audio - tactile (A-T) information. By using electroencephalogram (EEG) and event-related potentials (ERPs), the present study investigated how neural processing involved in A-T integration is modulated by tactile interaction. Seven- to 8-months-old infants heard one pseudoword both whilst being tickled (multimodal 'A-T' condition), and not being tickled (unimodal 'A' condition). Thereafter, their EEG was measured during the perception of the same words. Compared to the A condition, the A-T condition resulted in enhanced ERPs and higher beta-band activity within the left temporal regions, indicating neural processing of A-T integration. Additionally, theta band activity within the middle frontal region was enhanced, which may reflect enhanced attention to social information. Furthermore, differential ERPs correlated with the degree of engagement in the tickling interaction. We provide neural evidence that the integration of A-T information in infants' brains is facilitated through tactile interaction with others. Such plastic changes in neural processing may promote harmonious social interaction and effective learning in infancy. PMID- 29253739 TI - Telomeres and aging. AB - Telomeres (the TTAGGG repetitive DNA at the ends of linear chromosomes) are part of the 3D spatial organization of the nuclear genome. Long-range 3D chromatin interactions also establish specific patterns of regulated gene expression. An emerging area of interest is the role of telomere 3D looping with interstitial telomeric sequences (ITS) through interactions with telomere shelterin proteins. Telomeres form interstitial telomere loops (ITL) that interact with ITS and modify gene expression at distal genomic regions. Human laminopathies and telomeropathies often correlate with short telomeres. Since telomeres progressively shorten with increased turnover and chronological age in dividing somatic cells, ITLs may also change and have functional roles in normal and pathophysiological processes. Overall, telomeres help stabilize the nuclear genome with high fidelity throughout early adult life but diminish in post reproductive age-associated pathology. PMID- 29253741 TI - Self-controlled video feedback on tactical skills for soccer teams results in more active involvement of players. AB - Many studies have shown that self-controlled feedback is beneficial for learning motor tasks, and that learners prefer to receive feedback after supposedly good trials. However, to date all studies conducted on self-controlled learning have used individual tasks and mainly relatively simple skills. Therefore, the aim of this study was to examine self-controlled feedback on tactical skills in small sided soccer games. Highly talented youth soccer players were assigned to a self control or yoked group and received video feedback on their offensive performance in 3 vs. 2 small-sided games. The results showed that the self-control group requested feedback mostly after good trials, that is, after they scored a goal. In addition, the perceived performance of the self-control group was higher on feedback than on no-feedback trials. Analyses of the conversations around the video feedback revealed that the players and coach discussed good and poor elements of performance and how to improve it. Although the coach had a major role in these conversations, the players of the self-control group spoke more and showed more initiative compared to the yoked group. The results revealed no significant beneficial effect of self-controlled feedback on performance as judged by the coach. Overall, the findings suggest that in such a complex situation as small-sided soccer games, self-controlled feedback is used both to confirm correct performance elements and to determine and correct errors, and that self-controlled learning stimulates the involvement of the learner in the learning process. PMID- 29253740 TI - Performance and microbial features of the partial nitritation-anammox process treating fish canning wastewater with variable salt concentrations. AB - The partial nitritation-anammox (PN-AMX) process applied to wastewaters with high NaCl concentration was studied until now using simulated media, without considering the effect of organic matter concentration and the shift in microbial populations. This research work presents results on the application of this process to the treatment of saline industrial wastewater. Obtained results indicated that the PN-AMX process has the capability to recover its initial activity after a sudden/acute salt inhibition event (up to 16 g NaCl/L). With a progressive salt concentration increase for 150 days, the PN-AMX process was able to remove the 80% of the nitrogen at 7-9 g NaCl/L. The microbiological data indicated that NaCl and ammonia concentrations and temperature are important factors shaping PN-AMX communities. Thus, the NOB abundance (Nitrospira) decreases with the increase of the salt concentration, while heterotrophic denitrifiers are able to outcompete anammox after a peak of organic matter in the feeding. PMID- 29253742 TI - In situ examination of decision-making skills and gaze behaviour of basketball players. AB - In this study we examined in situ decision-making skills and gaze behaviour of skilled female basketball players. Players participated as ball carriers in a specific 3 vs 3 pick-and-roll basketball play. Playing both on the right and left side of the court and facing three types of defensive play, they chose and performed one of four options: shoot, drive to the basket, pass to the screener or pass to the corner player. We concurrently measured gaze behaviour to examine the direct relationship between gaze and decision making. As one of the first studies examining decision making and gaze behaviour in situ, this study found support for the embodied choice framework as the results showed that handling the ball with the dominant or non-dominant hand influenced the decisions that were made. Gaze measures suggested that peripheral vision may serve a significant role in decision making in situ, whereas players mainly relied on central vision to execute an action. Furthermore, this study underlined the need for developing and using newer and more informative methods to analyse gaze. PMID- 29253743 TI - Refractory epilepsy following natalizumab associated PML. AB - Natalizumab treatment of multiple sclerosis (MS) is associated with a risk of developing progressive multifocal leukoencephalopathy (PML), a rare opportunistic viral demyelinating disease caused by reactivation of John Cunningham virus (JCV). Herein, we report a case of a 40-year-old woman who developed refractory temporal lobe epilepsy; one year after recovery form Natalizumab-induced PML. Localisation related epilepsy, which may be refractory in nature, as in this case report, is a potential chronic disabling complication of PML. Epilepsy in this context, likely reflects grey matter involvement, which may then act as cortical epileptogenic zone. PMID- 29253744 TI - Severe neutropenia after rituximab-treatment of multiple sclerosis. AB - We present here the first MS-case where rituximab-treatment led to grade IV neutropenia, with hospitalization and treatment of a serious infection with broad spectrum antibiotics. The neutropenia resolved promptly with granulocyte-colony stimulating factor-treatment and the patient recovered well. Due to risk of recurring neutropenia rituximab-treatment was not re-administered. We discuss the mechanisms and occurrence of neutropenia as a side effect to rituximab-treatment of MS, and remind of the importance of monitoring rituximab-treated MS-patients for this rare but potentially dangerous side effect. PMID- 29253745 TI - Supratentorial extraventricular ependymomas: A retrospective study focused on long-term outcomes and prognostic factors. AB - OBJECTIVE: Supratentorial extraventricular ependymomas are relatively rare. Long term outcomes and prognostic factor for this rare tumor have not been well established. The purpose of this study was to demonstrateprogression freesurvival(PFS),overallsurvival(OS), and prognostic factors of such tumor. PATIENTS AND METHODS: Fifty-five patients with supratentorial extraventricular ependymomas from our hospital were included in this study. Epidemiological characteristics, clinical features, treatment,long-term outcomes, and prognostic factors for PFS and OS were reviewed retrospectively. RESULTS: The patients consisted of 30 males and 25 females with mean age of 30.0 +/- 23.6 years (range, 1-74 years). Twenty-nine tumors were located in the right hemisphere, and 26 in the left side. The 2 most common tumor locations were the frontal (n = 19; 35%) and parietal lobe (n = 11; 20%). All patients underwent surgical resection. Gross total resection (GTR) was achieved in 42 cases (76%) and subtotal resection (STR) was performed in 13 patients (24%). According to the WHO classification system, 38 tumors (69%) were Grade III (anaplastic ependymoma), and 17 (31%) were Grade II (ependymoma). Three-,5-, and 10 year PFS rates were 60%, 49%, and 36%, respectively. Three-,5-, and 10 year OS rates were 79%, 64%, and 49%, respectively. EOR and tumor grade were identified as prognostic factors for PFS and OS on univariate analysis, multivariate analysis, and Kaplan-Meierlog-rank testing. Subtotal resection (STR) predicted a worse PFS (HR = 4.808; 95%, 1.942 11.905; P = .001) and OS (HR = 5.650; 95%, 2.114-15.152; P = .001). WHO Grade III tumors also had worse PFS (HR = 3.922; 95%, 1.429-18.182; P = .012) and OS (HR = 6.329; 95%, 1.328-30.303; P = 0.021). For patients with tumor recurrence, reoperation was significant prognostic factors for OS (HR = 2.091; 95%, 0.939 4.654; p = .000). Age, sex, tumor side, and postoperativeradiotherapy were not prognostic factors for PFS and OS. CONCLUSIONS: Most supratentorial extraventricular ependymomas are WHO grade III tumors. STRandWHO Grade III pathology predicted worse PFS and OS. Gross-total resection remains the optimal treatment for patients with supratentorial extraventricular ependymoma. Reoperation should be considered first in cases of recurrence. The role of postoperative radiotherapy as an adjuvant treatment for supratentorial extraventricular ependymoma needs further investigation. PMID- 29253746 TI - Analysis of the risk factors for anterior cruciate ligament injury: an investigation of structural tendencies. AB - OBJECTIVE: The aim of this study was to determine the most important anatomical risk factors for injury of the anterior cruciate ligament (ACL) of the knee. MATERIALS AND METHODS: After study approval by our institutional ethics committee, 3 radiologists reinterpreted the preoperative magnetic resonance (MR) images of 86 patients who had undergone surgery for ACL rupture. The measurements were compared with those for a control group comprising 109 patients with intact ACL who had undergone MR examinations for other reasons, such as meniscal injuries or Baker cyst ruptures. Interobserver differences were calculated after measurement of the notch width (NW), NW index (NWI), medial condyle width (MCW), lateral condyle width (LCW), MCW/LCW ratios, alpha (alpha) angle, NW angle, quadriceps angle (Q angle), posterior medial tibial slope (MTS), posterior lateral tibial slope, coronal tibial slope, and depth of medial tibial plateau for each group. The relationships between these parameters and ACL injury were studied by performing logistic regression and receiver operating characteristic curve analyses in comparison with those in the control group. RESULTS: We found that there were significant differences in the anatomical parameters of the NW, MCW, NWI, alpha angle, and MTS between the ACL injured and noninjured groups (p<0.05). There were also significant differences in the bicondylar width, alpha angle, Q angle, and MTS between the patients with ACL rupture because of noncontact injuries and the control group (p<0.05). The NWI and MTS had the highest predicted relative risk for both the male and female groups. CONCLUSION: We found that the NW, NWI, and MTS were the most important parameters in risk assessment of ACL injuries. PMID- 29253747 TI - Down-regulation of inflammatory signaling pathways despite up-regulation of Toll like receptors; the effects of corticosteroid therapy in brain-dead kidney donors, a double-blind, randomized, controlled trial. AB - BACKGROUND: The brain death of a potential organ donor induces a systemic inflammatory response, resulting in inferior organ quality and function. Our study aimed to evaluate the effects of methylprednisolone (MPN) therapy on pattern recognition receptor (PRR) signaling in potential brain-dead (BD) kidney donors. MATERIAL AND METHODS: To evaluate the effects of MPN therapy on PRR signaling in BD kidney donors we performed a prospective randomized treatment versus-control study. Fifty-one potential kidney donors were randomly divided into three groups: brain-dead donors (BDDs) who received 15 mg/kg/d of methylprednisolone (group T1, n = 17), BDDs who received 15 mg/kg/d of MPN at the time of filling consent for kidney donation and 100 mg/2 h until kidney harvest (group T2, n = 17), and normal donors as controls n = 17. Gene expression for Toll-like receptors (TLRs) 1-9 and their signaling pathway molecules including MYD88, TRIF, NF-KB1, IRAK, IRF3, and IRF7, as well as the inflammatory cytokines RANTES, IL-1beta, TNF-alpha, IL-6, CXCL8, IL-18, IFN-alpha, and IFN-beta was determined by PCR array. Due to the crucial role of TLRs 2 and 4 in pattern recognition, surface expression of these molecules was analyzed by flow cytometry. Plasma levels of inflammatory cytokines were measured by immunoassay. Finally, serum creatinine and cystatin C were measured in 100 kidney recipients one week and one, three, and six months after transplant. RESULT: Polymerase chain reaction (PCR) array gene expression revealed greater expression of TLRs and signaling molecules in group T1 than in the controls. Surface expression of TLRs 2 and 4 were significantly greater in group T2 than in group T1 (P < .05). Plasma concentrations of inflammatory cytokines were significantly greater in group T1 than in controls (P < .05). The recipients that received kidneys from group T1 had significantly higher levels of creatinine and cystatin C than the recipients of kidneys from both group T1 and controls (P<0.05). CONCLUSION: Administration of MPN to BDDs at specified periods until kidney harvest resulted in less systemic inflammation in the BDDs and improved renal function in kidney graft recipients compared with common MPN therapy. PMID- 29253748 TI - Anemia and neutrophil-to-lymphocyte ratio are prognostic in p16-positive oropharyngeal carcinoma treated with concurrent chemoradiation. AB - OBJECTIVES: We investigated the prognostic value of pre-treatment hematological parameters in patients with p16-positive oropharyngeal squamous-cell carcinoma (OPSCC). MATERIAL AND METHODS: Neutrophil count, lymphocyte count, neutrophil-to lymphocyte ratio (NLR), and hemoglobin concentration measurement (Hb), were collected on day one of treatment. Endpoints were overall survival (OS) and progression-free survival (PFS). All patients were planned to receive concurrent chemoradiation. Staging were reviewed according to the recent AJCC 8th edition. RESULTS: We included 167 patients in this study. In multivariate analyses, a smoking history > 30 packyears was associated with decreased OS (p = 0.009; HR, 3.4827) and PFS (p = 0.042; HR, 2.421); Hb < 12g/dL was associated with impaired OS (p = 0.007; HR, 6.527) and PFS (p = 0.014; HR, 4.092); an NLR > 5 before treatment was associated with decreased OS (p = 0.042; HR, 2.945). Hemoglobin concentration and the NLR were not correlated (p = 0.577), nor anemia and an NLR > 5 (p = 0.167). Patients with an NLR > 5 had a significantly higher rate of disease recurrence (30.8% vs. 8.4%, p = 0.0299, RR = 3.922, 95% CI 1.351-11.386). DISCUSSION: We found hemoglobin level and the NLR to be independent prognostic factors in p16-positive OPSCC patients. This approach is to be considered for further clinical investigations, and its significance in treatment decision making should be further explored. PMID- 29253749 TI - Bioconversion of ecotoxic dehydroabietic acid using Rhodococcus actinobacteria. AB - Actinobactrial strains Rhodococcus erythropolis IEGM 267 and R. rhodochrous IEGM 107 were used to study biodegradation of dehydroabietic acid (DHA), a toxic tricyclic diterpenoid. The experiments were carried out in batch cultures of pre grown rhodococci in the presence of 0.1% (v/v) n-hexadecane under aerobic conditions for 7 days. It was shown that R. erythropolis IEGM 267 and R. rhodochrous IEGM 107 partially and completely degraded DHA (500 mg/L), respectively. Characteristic physicochemical (reduced zeta potential) and morphological-physiological (increased average size of single cells and cell aggregates, increased root-mean-square roughness) changes in DHA-exposed actinobacteria were revealed. Products of DHA bioconversion by R. erythropolis IEGM 267 were analyzed and exhibited a previously unidentified metabolite 5alpha hydroxy-abieta-8,11,13-triene-18-oat. The obtained experimental data widen the knowledge on the catalytic activity of rhodococci and their possible contribution to decontamination of natural ecosystems from pollutants. PMID- 29253750 TI - Preparation of water-compatible molecularly imprinted thiol-functionalized activated titanium dioxide: Selective adsorption and efficient photodegradation of 2, 4-dinitrophenol in aqueous solution. AB - A novel water-compatible surface molecularly imprinted thiol-functionalized titanium dioxide (TiO2) material (CMIP-coated TiO2) was prepared in water, using 2, 4-dinitrophenol (2, 4-DNP) as template molecule and o-phenylenediamine (OPDA) as both functional monomer and cross-linker. The as-synthesized materials were characterized by FESEM, FTIR, XRD, BET and UV-vis DRS. Moreover, we have investigated the adsorption capacity, adsorption selectivity and photodegradation activity of the CMIP-coated TiO2 and non-molecular imprinted materials (CNIP coated TiO2). Additionally, the effects of pH and concentration of 2, 4-DNP on the degradation rate of 2, 4-DNP were also investigated. Results showed that CMIP coated TiO2 exhibited higher adsorption capacity, greater selectivity and faster photodegradation activity for 2, 4-DNP compared with the CNIP-coated TiO2. Meanwhile, the specific selectivity to 2, 4-DNP over its structural analogue 4 nitrophenol (4-NP) and the enhanced photodegradation capacity were mainly attributed to the imprinted cavities on the surface of CMIP-coated TiO2. Taking advantage of efficient removal capacity, high reusability and no-additional chemicals in imprinted process, the prepared materials can be potentially applied to "green" removal of 2, 4-DNP in wastewater. PMID- 29253752 TI - A membrane electroflotation process for recovery of recyclable chromium(III) from tannery spent liquor effluent. AB - A two-compartment membrane electroflotation reactor has been demonstrated for recovery of recyclable chromium(III) from tannery spent liquor effluent. Dimensionally stable RuO2/TiO2-Ti and Ti were used as anode and cathode, respectively. The spent liquor effluent was used as catholyte and 0.01 N H2SO4 used as anolyte which was separated by Nafion 117 membrane. About 98% of chromium(III) was recovered and the removal efficiency correlated with the presence of organics in the effluent. The advantage of two-compartment membrane electroflotation process is capable of removing chromium(III) without oxidising it into chromium(VI) in chloride containing tannery spent liquor effluent. The mechanism of chromium(III) removal has been discussed. The recovered Cr(OH)3 was successfully demonstrated for tanning of cowhide. PMID- 29253751 TI - TCE degradation in groundwater by chelators-assisted Fenton-like reaction of magnetite: Sand columns demonstration. AB - Trichloroethylene (TCE) degradation in sand columns has been investigated to evaluate the potential of chelates-enhanced Fenton-like reaction with magnetite as iron source for in situ treatment of TCE-contaminated groundwater. The results showed that successful degradation of TCE in sand columns was obtained by nitrilotriacetic acid (NTA)-assisted Fenton-like reaction of magnetite. Addition of ethylenediaminedisuccinic acid (EDDS) resulted in an inhibitory effect on TCE degradation in sand columns. Similar to EDDS, addition of ethylenediaminetetraacetic acid (EDTA) also led to an inhibition of TCE degradation in sand column with small content of magnetite (0.5 w.t.%), but enhanced TCE degradation in sand column with high content of magnetite (7.0 w.t.%). Additionally, the presence of NTA, EDDS and EDTA greatly decreased H2O2 uptake in sand columns due to the competition between chelates and H2O2 for surface sites on magnetite (and sand). Furthermore, the presented results show that magnetite in sand columns remained stable in a long period operation of 230 days without significant loss of performance in terms of TCE degradation and H2O2 uptake. Moreover, it was found that TCE was degraded mainly to formic acid and chloride ion, and the formation of chlorinated organic intermediates was minimal by this process. PMID- 29253753 TI - Analysis and comparison of safety models using average daily, average hourly, and microscopic traffic. AB - There have been plenty of traffic safety studies based on average daily traffic (ADT), average hourly traffic (AHT), or microscopic traffic at 5 min intervals. Nevertheless, not enough research has compared the performance of these three types of safety studies, and seldom of previous studies have intended to find whether the results of one type of study is transferable to the other two studies. First, this study built three models: a Bayesian Poisson-lognormal model to estimate the daily crash frequency using ADT, a Bayesian Poisson-lognormal model to estimate the hourly crash frequency using AHT, and a Bayesian logistic regression model for the real-time safety analysis using microscopic traffic. The model results showed that the crash contributing factors found by different models were comparable but not the same. Four variables, i.e., the logarithm of volume, the standard deviation of speed, the logarithm of segment length, and the existence of diverge segment, were positively significant in the three models. Additionally, weaving segments experienced higher daily and hourly crash frequencies than merge and basic segments. Then, each of the ADT-based, AHT based, and real-time models was used to estimate safety conditions at different levels: daily and hourly, meanwhile, the real-time model was also used in 5 min intervals. The results uncovered that the ADT- and AHT-based safety models performed similar in predicting daily and hourly crash frequencies, and the real time safety model was able to provide hourly crash frequency. PMID- 29253754 TI - Exploring the relationships between drivers' familiarity and two-lane rural road accidents. A multi-level study. AB - Previous research has suggested that drivers' route familiarity/unfamiliarity (using different definitions of familiarity), and the interactions between familiar and unfamiliar drivers, may affect both the driving performances and the likelihood of road crashes. The purpose of this study is to provide a contribution in the search for relationships between familiarity and crashes by: 1) introducing a measure of familiarity based on the distance from residence; 2) analyzing a traffic and accident dataset referred to rural two-lane sections of the Norwegian highways E6 and E39; 3) using a multi-level approach, based on different perspectives, from a macro analysis to more detailed levels. In the macro analyses, the accident rates computed for different seasons and for different summer traffic variation rates (used as indicators of the share of familiar drivers in the flow) were performed. At the second level, a logistic regression model was used to explain the familiarity/unfamiliarity of drivers (based on their distance from residence), through variables retrieved from the database. In the last step, an in-depth analysis considering also accident types and dynamics was conducted. In the macro analysis, no differences were found between accident rates in the different conditions. Whereas, as emerged from the detailed analyses, the factors: high traffic volume, low summer traffic variation, autumn/winter, minor intersections/driveways, speed limits <80 km/h, travel purposes (commuting/not working) are associated to higher odds of having familiar drivers involved in crashes; while the factors: high traffic volume, high summer traffic variation, summer, head on/rear end-angle crashes, heavy vehicles involved, travel purposes (not commuting), young drivers involved are associated to higher odds of finding unfamiliar drivers involved. To a minor extent, some indications arise from the in-depth analyses about crash types and dynamics, especially for familiar drivers. With regard to the definitions used in this article, the familiarity was confirmed as an influential factor on the accident risk, possibly due to distraction and dangerous behaviors, while the influence of being unfamiliar on the accident proneness has some unclarified aspects. However, crashes to unfamiliar drivers may cluster at sites showing high summer traffic variation and in summer months. PMID- 29253755 TI - Global road fatality trends' estimations based on country-wise micro level data. AB - The global road crash deaths during the past 35 years are estimated and analysed considering micro-level data for 215 countries. The data were gathered from Governmental records, international databases, and personal contacts. The data are adjusted for underreporting, death definition differences and missing data. The study models both reported and adjusted death to forecast future crash trends for each continent. The developed models employed curve fitting regression technique. It took over five years to build-up the database. The global sum of crash deaths showed firm increasing trends between 1980 and 2008. Subsequently, the global deaths tend to slow down. The adjusted death during 2014 ranged between 792,000 and 905,000. The high range showed 40% lesser death than World Health Organization (WHO) estimate. The developed models presented a plateauing transition stage of global road deaths before descending. This is contradicting WHO and The World Bank (TWB) forecasts. The global adjusted death for 2020 and 2030, differed substantially from WHO and TWB forecasts. The results showed inconsistencies in road deaths between various WHO sectors. The trend of crash fatalities in Asia followed closely with that for global trend, and that in Africa it showed fluctuated trend with steep increasing tendency after 1999. In South America, it showed continuous ascending trends, and that in Europe and Oceanic countries showed clear descending patterns. The trend in North and Central America did not change much during the period between 1980 and 2007. While the developed models indicated drops of 33% in North and Central America, 18% in Oceania and 13% in Asia by 2025 compared with 2014, they increase by over 44% in Africa and 32% in South America. The poor safety records in several continents, require careful reading, proper interpretation of the results and extensive research. PMID- 29253756 TI - Non-dependence of nuclear decay rates of 123I and 99mTc on Earth-Sun distance. AB - Recently published studies have suggested an annual fluctuation of the decay rate of several radionuclides, in particular 32Si and 226Ra. Variation of solar neutrino flux caused by variation of Earth-Sun distance has been proposed as the mechanism of this fluctuation. In this study we prospectively look at two radionuclides which have not previously been studied for annual variation, 123I and 99mTc. Half-lives of samples of these radionuclides were measured approximately weekly and semiweekly respectively over a period of 2 years. Spectral analysis using the Lomb-Scargle method demonstrated no significant periodicity, and in particular, no evidence for a period of 1 year. PMID- 29253757 TI - On the ratio distribution of energy windowing algorithms for radiation portal monitors. AB - This paper introduces a windowing algorithm for radiation portal monitors based on a transformation of random variables to calculate the ratio between the radiation intensity in two energy windows. Procedures to evaluate critical limits and establish detection limits are described. Simulations and experimental data illustrate a good agreement between derived and observed ratio distributions. The algorithm was compared with commonly-used algorithms. The results illustrate proper evaluation of critical and detection limits even in the case of shadow shielding by vehicles entering a radiation portal monitor. PMID- 29253758 TI - Highly dispersed Au nanoparticles decorated WO3 nanoplatelets: Laser-assisted synthesis and superior performance for detecting ethanol vapor. AB - Loading of noble metal nanoparticles (NPs) on the surfaces of semiconductor oxides to form a hybrid nanostructure is an effective strategy to improve gas sensing performance. In this study, WO3 nanoplatelets decorated with Au NPs were prepared by laser ablation in liquids (LAL) with subsequent aging and annealing treatments. Results indicated that Au NPs with an average size of 7.8 +/- 2.5 nm were highly dispersed on the surface of WO3 nanoplatelets. As gas-sensing materials, the obtained Au-decorated WO3 nanoplatelets showed lower operating temperature of 320 degrees C and higher response value of 3.5-fold in detecting ethanol molecules compared with pure WO3 nanoplatelets. Moreover, Au-decorated WO3 nanoplatelets displayed good selectivity toward ethanol compared with other tested vapors and excellent stability within several cycled measurements. These results can be ascribed to the supported Au NPs, which promote the adsorption and dissociation of oxygen species, eventually resulting in accelerated electron depletion on the surface of Au-WO3 hybrids. PMID- 29253759 TI - Ultrafast synthesis of bifunctional Er3+/Yb3+-codoped NaBiF4 upconverting nanoparticles for nanothermometer and optical heater. AB - We reported a simple and ultrafast route to synthesize the bifunctional Er3+/Yb3+ codoped NaBiF4 upconverting nanoparticles. It was found that the phase composition and microstructure of the prepared samples were strongly dependent on the NH4F content. When the NH4F content was 14 mmol, after 1 min reaction at room temperature, the resultant compounds exhibited pure single phase and were composed of uniform spherical nanoparticles. Under 980 nm light irradiation, the synthesized nanoparticles emitted visible emissions originating from the intra-4f transitions of Er3+ ions and the involved upconversion luminescence mechanism was associated with the typical two-photon process. With the aid of the fluorescence intensity ratio technique, the optical thermometric behaviors of the studied nanoparticle based on the (2H11/2,4S3/2) thermally-coupled levels in the temperature range of 303-483 K were systematically analyzed and the maximum sensor sensitivity was determined to be about 0.0057 K-1 at 483 K. Furthermore, the internal heating properties of the resultant nanoparticles induced by the laser power source were also studied. With elevating the pump power from 159 to 658 mW, the temperature of the upconverting nanoparticles was improved from 304 to 464 K. These results suggest that the Er3+/Yb3+-codoped NaBiF4 upconverting nanoparticles are promising bifunctional luminescent materials for nanothermometer and optical heater applications. PMID- 29253760 TI - Artemisia capillaris extract AC68 induces apoptosis of hepatocellular carcinoma by blocking the PI3K/AKT pathway. AB - Artemisia capillaris Thunberg (AC) has been widely used to treat various diseases including hepatitis and is known to affect many cellular events such as cell proliferation and apoptosis. Herein a potent ethyl acetate fraction (AC68) was newly extracted from AC, and was assessed for its anti-cancer efficacy in progression and growth of hepatocellular carcinoma (HCC). AC68 dose-dependently inhibited the growth and proliferation of two HCC cell lines. The AC68-induced apoptosis was observed by increased levels of cleaved caspase-3 and decreased survivin, XIAP, and MCL-1 expression via mitochondria membrane potential change, as well as elevated numbers of TUNEL-positive apoptotic cells. AC68 was also found to suppress invasion and migration of HCC cells. Moreover, it inhibited PI3K/AKT signaling pathway in vitro and in vivo. In vivo study showed that AC68 significantly inhibited tumor growth in HCC mouse xenograft model, and induced apoptosis by increasing the expression of cleaved caspase-3. The expression of PCNA was decreased by the treatment of AC68. Taken together, our data demonstrated that AC68 not only induced apoptosis but also inhibited cell growth, migration, and invasion of liver cancer cells by blocking the PI3K/AKT pathway. We suggest that AC68 may be a potent chemotherapeutic candidate for the treatment of HCC. PMID- 29253762 TI - Metformin treatment decreases nitroxidative stress, restores nitric oxide bioavailability and endothelial function beyond glucose control. AB - Reduction of nitric oxide (NO), a potent vasodilator, and an increase in cytotoxic peroxynitrite (ONOO-) may be associated with the uncoupling of NO synthase (eNOS) and endothelial cell (EC) dysfunction. In addition to its effect on glucose control, metformin, may also directly benefit in the restoration of the function of eNOS and EC. Obese Zucker rats were administered vehicle or 300 mg/kg/day metformin for 4 weeks. NO concentration [NO] and ONOO- concentration [ONOO-] were measured in aortic and glomerular endothelial cells from Zucker rats in vitro. Compared with controls, aortic and glomerular endothelial [NO] was reduced by 32% and 41%, while [ONOO-] release increased 79% and 69%, respectively. Metformin treatment increased aortic and glomerular endothelial [NO] by 37% and 57%, respectively, while decreasing [ONOO-] by 32% and 34%, compared with vehicle-treated animals. Treatment with metformin significantly restored the balance in the [NO]/[ONOO-] ratio with 101% and 138% increase for aortic and glomerular endothelial cells, respectively. Fasting glucose levels were not significantly changed. These findings indicate that metformin therapy has a direct and beneficial effect on arterial and renal EC function in obese rats, including enhanced NO release and reduced nitroxidative stress, beyond any effects on fasting glucose levels. PMID- 29253761 TI - Diminazene aceturate alleviated lipopolysaccharide/D-galactosamine-induced fulminant hepatitis in mice. AB - Diminazene aceturate (DIZE) has been widely used as an antiprotozoal agent, but recent studies have revealed its anti-inflammatory activities. In the present study, the potential effects of DIZE on lethal inflammatory disorder were investigated in a mouse model with lipopolysaccharide (LPS)/D-galactosamine (D Gal)-induced fulminant hepatitis. The results indicated that treatment with DIZE suppressed LPS/D-Gal-induced elevation of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alleviated histopathological damage in liver and improved the survival rate of the experimental animals, these effects were accompanied with inhibited expression of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6). Treatment with DIZE also inhibited the activation of caspase-3, -8, -9, reduced the level of cleaved caspase-3, suppressed the phosphorylation of c-jun-N-terminal kinase (JNK) and decreased the count of TUNEL-positive cells. These data suggests that DIZE might have potential value in the prevention of inflammation-based lethal inflammatory liver disorders. PMID- 29253763 TI - Synthesis, characterization and inhibitory effects of crocetin derivative compounds in cancer and inflammation. AB - Crocetin is a natural product possessing extraordinary therapeutic effects for various diseases. However, its extremely low solubility limits its application greatly. Conjugation of organic compounds containing heteroatoms such as N to poor soluble molecules can help the synthesized derivative to form stable hydrogen bonds by lowering the salvation energy, which will improve the solubility of the synthesized compounds. Herein, crocetin was modified by conjugating with piperidyl, diethylin and benzylamine to improve their solubility and bioactivities. In the present study, the conjugation of crocetin with piperidyl, diethylin and benzylamine and their influence on the solubility and the pharmacological effects of crocetin were investigated. With the described strategy, crocetin derivatives were synthesized and their structures were elucidated by 1H NMR, 13C NMR and UPLC-MS spectroscopic analysis. The solubility of crocetin and its derivatives were identified. Upon that, the pharmacological effects of the crocetin derivatives on the tumor and inflammation treatment were investigated. It was shown that, in contrast to crocetin, of which, the solubility and pharmacological effects were low and limited, the synthesized compounds have significantly higher solubility and possess broad spectrum of anticancer effects in multiple tumor cell lines, including B16F10, MCF-7, A549 and SKOV3, as well as enhanced anti-inflammation efficacy in macrophage (RAW264.7) without causing cells damage. Conjugation of piperidyl, diethylin and benzylamine with the crocetin was demonstrated to be a highly efficient strategy to improve the solubility of crocetin. The synthesized crocetin derivatives were shown the promising therapeutics for the tumor and inflammation treatment with high safety. PMID- 29253764 TI - The role of MCM5 expression in cervical cancer: Correlation with progression and prognosis. AB - Minichromosome maintenance protein 5 (MCM5) has been suggested overexpressed in cervical cancer, but the clinical value and biological function of MCM5 in cervical cancer is still unknown. In our study, MCM5 mRNA and protein were significantly overexpressed in cervical cancer tissues and cell lines compared with normal cervical tissues and cell lines, and were obviously increased in cervical adenocarcinoma tissues and cell lines in comparison to cervical squamous cell carcinoma tissues and cell lines. In cervical adenocarcinoma patients, we firstly found that MCM5 expression was closely correlated with clinical stage, lymph node metastasis, distant metastasis and histological grade. Univariate and multivariate analysis showed MCM5 high-expression was an independent unfavorable prognostic factor. In conclusion, MCM5 is associated with the malignant status and poor prognosis in cervical adenocarcinoma patients, and modulates cervical adenocarcinoma cells proliferation. PMID- 29253765 TI - Glucose-dependent growth arrest of leukemia cells by MCT1 inhibition: Feeding Warburg's sweet tooth and blocking acid export as an anticancer strategy. AB - This study aims to investigate the utilization of The Warburg Effect, cancer's "sweet tooth" and natural greed for glucose to enhance the effect of monocarboxylate transporter inhibition on cellular acidification. By simulating hyperglycemia with high glucose we may increase the effectiveness of inhibition of lactate and proton export on the dysregulation of cell pH homeostasis causing cell death or disruption of growth in cancer cells. MCT1 and MCT4 expression was determined in MCF7 and K562 cell lines using RT-PCR. Cell viability, growth, intracellular pH and cell cycle analysis was measured in the cell lines grown in 5 mM and 25 mM glucose containing media in the presence and absence of the MCT1 inhibitor AR-C155858 (1 MUM) and the NHE1 inhibitor cariporide (10 MUM). The MCT1 inhibitor, AR-C155858 had minimal effect on the viability, growth and intracellular pH of MCT4 expressing MCF7 cells. AR-C155858 had no effect on the viability of the MCT1 expressing K562 cells, but decreased intracellular pH and cell proliferation, by a glucose-dependent mechanism. Inhibition of NHE1 on its own had a no effect on cell growth, but together with AR-C155858 showed an additive effect on inhibition of cell growth. In cancer cells that only express MCT1, increased glucose concentrations in the presence of an MCT1 inhibitor decreased intracellular pH and reduced cell growth by G1 phase cell-cycle arrest. Thus we propose a transient hyperglycemic-clamp in combination with proton export inhibitors be evaluated as an adjunct to cancer treatment in clinical studies. PMID- 29253767 TI - Are paravertebral nerve blocks an answer to pain after iliac crest bone marrow biopsy? PMID- 29253766 TI - Protective effect of Coptisine from Rhizoma Coptidis on LPS/D-GalN-induced acute liver failure in mice through up-regulating expression of miR-122. AB - Coptisine (COP), one of the main active ingredients of Rhizoma Coptidis, reportedly has anti-inflammatory, anti-colon cancer properties, but it remains elusive whether COP owns hepatoprotective activity. Mice were pretreated with COP for 7d prior to lipopolysaccharide/d-galactosamine (LPS/D-GalN) administration to detect the hepatic protective effects of COP. The mechanism was explored in using HepG2 cells with low level of miR-122 and LO2 cells with high level of miR-122, combining with miR-122 agomir transfection by means of detecting the expression of miR-122 and proteins, clinical index and apoptosis. COP ameliorated the LPS/D GalN-induced liver failure by lowering serum levels of ALT and AST, raising hepatic GSH and SOD levels, and maintaining the morphology of hepatocytes, along with an increase in miR-122 expression in mice. The results in vitro indicated that, after miR-122 mimic administration, the alone treatment of COP and the co treatment of COP and LPS transfection obviously promoted the apoptosis of HepG2, which was increased by 152.67% and 113.97% compared with NC (P < 0.05 vs NC). LPS significantly induced the apoptosis of L02 cells, but COP treatment attenuated that of L02 cells. Further analysis showed that COP increased the miR-122 level and the expression of Bax, cleaved-casp3 and decreased Bcl-2, Bcl-xL in LPS treated HepG2 cells. COP increased the miR-122 level but decreased the expression of TLR4, Bcl-2, Bcl-xL in LPS-treated L02 cells. COP attenuated LPS/D-GalN induced ALF by up-regulating the level of miR-122, synergistically promoting apoptosis, and suggesting COP which showed a potential protective effect on ALF. PMID- 29253768 TI - Ultrasound guided left interscalene block for the treatment of refractory electrical storm. PMID- 29253769 TI - Pollution characteristics and sources of polybrominated diphenyl ethers in indoor air and dustfall measured in university laboratories in Hangzhou, China. AB - Laboratories at Zhejiang University of Technology in Hangzhou were selected to ascertain the pollution status of polybrominated diphenyl ethers (PBDEs) in indoor city air. Air and dustfall samples were collected during 2015 and analysed using gas chromatography. This study provides important information on the typical indoor pollution of brominated flame retardants in urban areas in China, particularly in university laboratories. The annual geometric mean concentration of PBDEs of passive air samples in the university laboratories was 545.64pg/m3, corresponding to a medium level of air pollution. The highest level was recorded in winter and the lowest in summer. The average concentration of PBDEs in dustfall was 8198.69ng/g, generally higher than that reported in other studies. The annual geometric mean of deposition fluxes of PBDEs was 121.96ng/(m2d). BDE 209 was the main congener of PBDEs in all areas studied, and BDE-47, BDE-66, and BDE-99 also made a significant contribution to the total concentration of PBDEs.The detection rates were 100% for BDE-17, -28, and -66 in air samples, while the detection rates of BDE-17, -28, -71 and -66 were all 100% in dustfall samples. PBDE concentrations and deposition fluxes were unevenly distributed and showed sampling point differences, mainly attributed to differences in the materials used for indoor furnishings, the function of the room, the ventilation systems and the surrounding environment. Seasonal variations of PBDE concentrations in air samples ranged as winter>autumn>spring>summer, while seasonal variations in dustfall samples were winter>summer>autumn>spring. Two significant positive linear relationship were found between the total quantity of electronic equipment (r=0.722, p<0.05) and the quantity of plywood desktop (r=0.745, p<0.05) with the deposition fluxes of PBDEs. PMID- 29253770 TI - Multiple approaches to assess the effects of F-53B, a Chinese PFOS alternative, on thyroid endocrine disruption at environmentally relevant concentrations. AB - A Chinese perfluorooctane sulfonate (PFOS) substitute frequently detected in the environment, 6:2 chlorinated polyfluorinated ether sulfonate (F-53B), has a similar structure to PFOS and it is proposed to cause thyroid dysfunction. To further confirm this hypothesis, the effects of F-53B on the thyroid endocrine system and underlying mechanisms were investigated in vitro and in vivo using rat pituitary GH3 cells and developing zebrafish, respectively. In GH3 cells, F-53B enhanced cell proliferation in a dose-dependent manner, indicative of thyroid receptor agonistic activity. In zebrafish larvae, F-53B exposure induced significant developmental inhibition and increased thyroxine (T4) but not 3,5,3' triiodothyronine (T3) levels accompanied by a decrease in thyroglobulin (TG) protein and transcript levels of most genes involved in the hypothalamic pituitary-thyroid (HPT) axis. Interestingly, T4 levels remained significantly increased while TG protein and gene transcription levels were markedly upregulated after depuration. Molecular docking studies revealed that F-53B binds to transthyretin (TTR) by forming hydrogen bonds with Lys123 and Lys115, thereby interfering with thyroid hormone homeostasis. Our collective in vitro, in vivo and in silico studies provide novel evidence that F-53B disrupts the thyroid endocrine system at environmentally relevant concentrations, which cannot be recovered after depuration. Given the persistence of F-53B in the environment, the long-term consequences of thyroid hormone disruption by this chemical warrant further investigation. PMID- 29253771 TI - Comparative environmental Life Cycle Assessment of integral revalorization of vine shoots from a biorefinery perspective. AB - The use of vine shoots as feedstock in biorefining activities to obtain bioproducts under efficient and optimized conditions could be crucial to make future high added value compounds and processes more sustainable. In this study, five different potential valorization scenarios from vine shoots differing on diverse extraction and delignification steps were assessed from an environmental perspective using the Life Cycle Assessment methodology to identify the most sustainable biorefining route. The main findings from this study reported that an increment on the number of valorization steps involved higher energy and chemical requirements deriving on worse environmental profiles. Scenarios incorporating fermentation of the glucose liquors or organosolv delignification performed the worst profiles. Autohydrolysis, concentration and freeze drying and enzymatic hydrolysis were the main responsible stages of the environmental burdens. Further research should be focused on optimizing chemicals and electricity requirements to develop greener systems. PMID- 29253772 TI - Long-term trends of atmospheric organochlorine pollutants and polycyclic aromatic hydrocarbons over the southeastern Tibetan Plateau. AB - Long-term monitoring in remote regions is essential for revealing pollution trends at the global scale but relevant studies remain limited. In the present study, a six-year continuous monitoring of atmospheric persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons (PAHs) was carried out at Lulang in the southeastern Tibetan Plateau (TP). Average concentrations of hexachlorocyclohexanes (HCHs), hexachlorobenzene (HCB), dichlorodiphenyltrichloroethanes (DDTs), polychlorinated biphenyls (PCBs) and PAHs were 13.5, 8.9, 41.7, 1.8pg/m3 and 6.2ng/m3, respectively. Obvious seasonality was found for all the target compounds. HCHs, DDTs and PCBs had their highest concentrations in summer (monsoon season) and lowest in winter, which is consistent with the fluctuation of the Indian monsoon. Meanwhile, HCB and 5-6 ring PAHs showed opposite variations, possibly induced by local sources and the westerly flow in winter. Declining trends were observed for most of the chemicals, except o,p'-DDE, HCB and PCBs. A declining trend in the alpha/gamma HCH ratio indicated a shift from technical HCHs to lindane. An increasing trend in the o,p'/p,p'-DDT ratio suggested a likely shift from technical DDTs to dicofol. For PAHs, the contribution from high-temperature combustion has increased recently. The half-lives of alpha-HCH, gamma-HCH, o,p'-DDT, p,p'-DDT were 6.1, 108, 77.6 and 14.2years, respectively. The half-lives of gamma-HCH, o,p'-DDT and p,p'-DDT were higher than those in the Arctic, indicating these compounds will persist in the TP for a longer period. The temporal trends in atmospheric POPs were possibly induced by emissions in India and likely driven by wind speed in Lulang. This study contributes toward a better understanding of the behavior and transport of POPs in the TP region. PMID- 29253774 TI - A new method to quantify surface urban heat island intensity. AB - Reliable quantification of urban heat island (UHI) can contribute to the effective evaluation of potential heat risk. Traditional methods for the quantification of UHI intensity (UHII) using pairs-measurements are sensitive to the choice of stations or grids. In order to get rid of the limitation of urban/rural divisions, this paper proposes a new approach to quantify surface UHII (SUHII) using the relationship between MODIS land surface temperature (LST) and impervious surface areas (ISA). Given the footprint of LST measurement, the ISA was regionalized to include the information of neighborhood pixels using a Kernel Density Estimation (KDE) method. Considering the footprint improves the LST-ISA relationship. The LST shows highly positive correlation with the KDE regionalized ISA (ISAKDE). The linear functions of LST are well fitted by the ISAKDE in both annual and daily scales for the city of Berlin. The slope of the linear function represents the increase in LST from the natural surface in rural regions to the impervious surface in urban regions, and is defined as SUHII in this study. The calculated SUHII show high values in summer and during the day than in winter and at night. The new method is also verified using finer resolution Landset data, and the results further prove its reliability. PMID- 29253773 TI - Elevated exposure, uptake and accumulation of polycyclic aromatic hydrocarbons by nestling tree swallows (Tachycineta bicolor) through multiple exposure routes in active mining-related areas of the Athabasca oil sands region. AB - In the Athabasca Oil Sands (OS) Region, the exposure (by air, water, diet), uptake and deposition of polycyclic aromatic compounds (PACs), including parent and alkylated hydrocarbons (PAHs) and dibenzothiophenes (DBTs), was assessed in nestling tree swallows (Tachycineta bicolor) at mining-related (OS1, OS2) and reference (REF) sites. The OS sites did not receive oil-sands processed waters (OSPW) and were >=60km from the reference sites. Most of the 42 PACs (<=98%) were detected in all matrices. Swallows at the OS sites were exposed to higher air and water concentrations of individual PAC congeners, SigmaPACs, Sigmaparent-PAHs, Sigmaalkyl-PAHs and SigmaDBTs. Compared to reference nestlings (SigmaPACs: 13 27ng/g wet weight (ww)), PACs were significantly higher in OS nestlings (31 106ng/gww) that also accumulated higher concentrations of major PAHs (i.e., naphthalene, C1-naphthalene, C2-naphthalene, C1-fluorenes, C2-fluorenes, C1 phenanthrenes) measured in 60% of nestlings. Uptake and deposition of PAHs in the birds' muscle was related to diet (delta15N: C1-naphthalenes, C2-naphthalenes, C1 fluorenes), water (C1-phenanthrenes), and air through inhalation and feather preening (C1-fluorenes), but fecal concentrations were not well explained by diet or environmental concentrations. While PAH concentrations were much higher in muscle than feces, they were highly correlated (p<=0.001 for all). Thus feces may represent a non-lethal method for characterizing PAH exposure of birds, with muscle characterizing accumulation and sources of PAH exposure. Tree swallows in the Athabasca OS Region are exposed to many PACs, accumulating higher concentrations when developing in close proximity to mining activity through diet, aerial deposition and mining-impacted freshwater sources (e.g., wetlands). PMID- 29253775 TI - On the reintroduction of the endangered thick-shelled river mussel Unio crassus: The importance of the river's longitudinal profile. AB - Freshwater mussels of the order Unionida provide important ecosystem functions and services. Unfortunately, some previously widespread species are now seriously endangered. To restore the historical range of the population of Unio crassus in the Biala River, southern Poland, the species was reintroduced into a series of 'stepping stones' joining two remnant populations. During the first phase of the study, the relationships between the abundance of U. crassus, physical habitat, and water quality were studied to assess reintroduction potential. In general, chemical water quality improved upstream from the existing population, favouring the decision for reintroduction, whereas morphological variables worsened. Mussel abundance was correlated negatively with the elevation and slope of channel, organic matter contents, and pH (exceeding 8.0), but positively with silt presence, water conductivity, and concentrations of HCO3-, Ca2+, and NO3-. During the second phase, adult individuals were introduced into one type of functional habitat-marginal channel sectors with still water and fine sediment. Despite the initial very high rate of reproduction in some parts of the upper reach of the river, the juveniles were ultimately recruited only in the lower part of the restored range, resulting in a very rapid change in recruitment at a channel slope of 1.80/00. Recruitment was positively related to silt content, conductivity, and Ca2+ and HCO3- ions, negatively to channel elevation and slope, and water pH. The host fish species showed no correlation with abiotic habitat features within the studied reach. These results imply that most of the habitat traits related to U. crassus occurrence depended on the river's longitudinal profile, not on the chemical water quality, and that final success of introduction should be evaluated after several years. PMID- 29253776 TI - A cost-effective and efficient framework to determine water quality monitoring network locations. AB - A crucial part in designing a robust water quality monitoring network is the selection of appropriate water quality sampling locations. Due to cost and time constraints, it is essential to identify and select these locations in an accurate and efficient manner. The main contribution of the present article is the development of a practical methodology for allocating critical sampling points in present and future conditions of the non-point sources under a case study of the Khoy watershed in northwest Iran, where financial resources and water quality data are limited. To achieve this purpose, the river mixing length method (RML) was applied to propose potential sampling points. A new non-point source potential pollution score (NPPS) was then proposed by the analytic network process (ANP) to classify the importance of each sampling point prior to selecting the most appropriate locations for a river system. In addition, an integrated cellular automata-Markov chain model (CA-Markov) was applied to simulate future change in non-point sources during the period 2026-2036. Finally, by considering anthropogenic activities through land-use mapping, the hierarchy value, the non-point source potential pollution score values and budget deficiency in the study area, the seven sampling points were identified for the present and the future. It is not expected, however, that the present location of the proposed sampling points will change in the future due to the forthcoming changes in non-point sources. The current study provides important insights into the design of a reliable water quality monitoring network with a high level of assurance under certain changes in non-point sources. Furthermore, the results of this study should be valuable for water quality monitoring agencies looking for a cost-effective approach for selecting sampling locations. PMID- 29253777 TI - A dynamic viticultural zoning to explore the resilience of terroir concept under climate change. AB - Climate change (CC) directly influences agricultural sectors, presenting the need to identify both adaptation and mitigation actions that can make local farming communities and crop production more resilient. In this context, the viticultural sector is one of those most challenged by CC due to the need to combine grape quality, grapevine cultivar adaptation and therefore farmers' future incomes. Thus, understanding how suitability for viticulture is changing under CC is of primary interest in the development of adaptation strategies in traditional wine growing regions. Considering that climate is an essential part of the terroir system, the expected variability in climate change could have a marked influence on terroir resilience with important effects on local farming communities in viticultural regions. From this perspective, the aim of this paper is to define a new dynamic viticultural zoning procedure that is able to integrate the effects of CC on grape quality responses and evaluate terroir resilience, providing a support tool for stakeholders involved in viticultural planning (winegrowers, winegrower consortiums, policy makers etc.). To achieve these aims, a Hybrid Land Evaluation System, combining qualitative (standard Land Evaluation) and quantitative (simulation model) approaches, was applied within a traditional region devoted to high quality wine production in Southern Italy (Valle Telesina, BN), for a specific grapevine cultivar (Aglianico). The work employed high resolution climate projections that were derived under two different IPCC scenarios, namely RCP 4.5 and RCP 8.5. The results obtained indicate that: (i) only 2% of the suitable area of Valle Telesina expresses the concept of terroir resilience orientated towards Aglianico ultra quality grape production; (ii) within 2010-2040, it is expected that 41% of the area suitable for Aglianico cultivation will need irrigation to achieve quality grape production; (iii) by 2100, climate change benefits for the cultivation of Aglianico will decrease, as well as the suitable areas. PMID- 29253778 TI - Characterization and quantitative analysis of related substances in Coenzyme A by HPLC and LC-MS/MS. AB - Ten related substances in coenzyme A (CoA) were detected using a newly developed gradient reverse phase high performance liquid chromatographic (HPLC) method. A highly specific and efficient LC-MS/MS method was developed to characterize process-related substances and the major degradation products, and three unknown related substances were further synthesized and characterized by H-NMR and C-NMR spectroscopy. Synthesized samples of the related substances were used for quantitative analysis by HPLC. The method was validated according to ICH guidelines with respect to specificity, precision, accuracy and linearity. The forced degradation studies included acidic, alkaline, oxidative, photolytic and thermal stress conditions. Furthermore, we depicted and speculated the probable mechanism of formation of related substances and the plausible fragmentation mechanism showed that all the related substances came from the manufacturing process. Characterization, synthesis and quantitative analysis of related substances were discussed in detail, and were critical for quality control, manufacturing process optimization and CoA monitoring, all of which were important to ensure the security of CoA. PMID- 29253779 TI - Combination of LC-MS based metabolomics and antioxidant activity for evaluation of bioactive compounds in Fragaria vesca leaves from Italy. AB - Wild strawberry (Fragaria vesca) is recognized as a traditional food of Campania region (Italy). The vegetative parts have a pharmaceutical interest, being used as decoctions for hypertension treatment due their detoxifying, diuretic, stimulant and dermatological protective properties; leaves, that after collection of fruits are generally thrown away, could be an interesting byproduct, source of bioactive compounds for cosmetic and pharmaceutical industry. In the present work, the metabolite profiles of F. vesca leaves coming from populations spontaneously growing in the underwood (wild) and in crop (cultivated) and from autochthonous and non-autochthonous germplasm of Campania region (Italy) were investigated by LC-ESI/LTQOrbitrap/MS analysis. 27 metabolites mainly belonging to organic acids, flavonoids, catechin and its oligomers, and ellagitannins were putatively identified. Antioxidant activity was tested for each sample, in particular cultivated samples and wild samples with autochthonous germplasm of Campania region showed higher antioxidant activity compared to the non autochthonous ones. Moreover, in this study, it was possible to predict antioxidant metabolites, markers of this species, using LC-MS spectra and multivariate regression data analysis. PMID- 29253780 TI - Electron microscopy/energy dispersive X-ray spectroscopy of drug distribution in solid dispersions and interpretation by multifractal geometry. AB - Much contemporary research of poorly water-soluble drugs focuses on amorphous solid dispersions (SDs) for oral drug delivery. Recently, a multifractal formalism has been introduced to describe the distribution of an inorganic carrier in SDs. The present work attempts to directly image model drugs by means of scanning electron microscopy and energy dispersive X-ray spectroscopy. The compounds amlodipine, felodipine, glyburide, and indomethacine, which include halogens to enable sufficient scattering in energy dispersive X-ray spectroscopy, were employed to prepare SDs with hydroxypropyl methylcellulose acetate succinate (HPMCAS) by using a microwave method. Following chemical imaging, it was demonstrated that drug distribution was best described by multifractals, which was clearly superior to a monofractal assumption. The obtained fractal dimensions were influenced by drug loading and it was possible to detect microstructural changes upon addition of the plasticizer urea. Accordingly, the multifractal approach bears much potential to better explore the analytical results of chemical formulation imaging. Insights can be gained from the microstructural organization of SDs, which is interesting to further study formulation and process factors as well as physical stability. PMID- 29253781 TI - Cellulase pretreatment for enhancing cold caustic extraction-based separation of hemicelluloses and cellulose from cellulosic fibers. AB - The effective separations of cellulose and hemicelluloses from cellulosic fibers are the prerequisite for creating high-value to the abundant and green cellulose materials. In this study, the process concept of cellulase pretreatment, followed by a cold caustic extraction (CCE) was investigated for a softwood sulfite pulp. The results showed that the cellulase pretreatment led to favorable fiber morphological changes, including the increases of the specific surface area (SSA), pore volume and diameter, and the water retention value (WVR). These changes can induce more pronounced fiber swelling in the subsequent CCE process so that the hemicelluloses removal is enhanced. After the cellulase pretreatment (cellulase dosage of 1 mg/g) and CCE process, the cellulose purity was as high as 97.49%, while the hemicelluloses removal selectivity reached 76.42%. PMID- 29253782 TI - Biological activities and nitrogen and phosphorus removal during the anabaena flos-aquae biofilm growth using different nutrient form. AB - This work investigated the biological activities and nitrogen and phosphorus removal during the anabaena flos-aquae biofilm growth on the polyvinyl chloride (PVC) carriers, in different nutrient form mediums. The study showed that the production of dehydrogenase activity (DHA) and extracellular polymeric substances (EPS) can reach 40.4 g/(h.m2) and 115 * 10-2 g/m2 in an 11-day period, respectively, indicating that the anabaena flos-aquae biofilm had high biological activities. The results showed that the nitrogen and phosphorus removal reached 94.9 and 96.8%, respectively, in the ammonium form nitrogen group; while 97.7% of phosphorus were removed in the orthophosphate form phosphorous group. A comparison study was conducted and results showed that the present anabaena flos aquae based biofilm provided a better removal of nitrogen and phosphorus than the other microalgae biofilms. PMID- 29253783 TI - Fear processing is differentially affected by lateralized stimulation of carotid baroreceptors. AB - Information processing, particularly of salient emotional stimuli, is influenced by cardiovascular afferent signals. Carotid baroreceptors signal the state of cardiovascular arousal to the brain, controlling blood pressure and heart rate via the baroreflex. Animal studies suggest a lateralization of this effect: Experimental stimulation of the right carotid sinus has a greater impact on heart rate when compared to left-sided stimulation. We tested, in humans, whether the processing of emotional information from faces was differentially affected by right versus left carotid afferents. To achieve so, we used an automated neck suction device to stimulate the carotid mechanoreceptors in the carotid sinus (parasympathetic pathway) synchronously with functional magnetic resonance imaging (fMRI) acquisition whilst participants were engaged in an emotional rating task of fearful and neutral faces. We showed that both right and left carotid stimulation (CS) influenced brain activity within opercular regions, although a stronger activation was observed within left insula during right stimulation compared to left stimulation. As regards the processing of fearful faces, right, but not left carotid stimulation attenuated the perceived intensity of fear, and (albeit to a lesser extent) enhanced intensity ratings of neutral faces. Mirroring the behavioural effects, there was a significant expression-by stimulation interaction for right carotid stimulation only, when bilateral amygdala responses were attenuated to fear faces and amplified to neutral faces. Individual differences in basal heart rate variability (HRV) predicted the extent to which right carotid stimulation attenuated amygdala responses during fear processing. Our study provides unique evidence for lateralized viscerosensory effects on brain systems supporting emotional processing. PMID- 29253785 TI - Physiologically-based pharmacokinetic and toxicokinetic models for estimating human exposure to five toxic elements through oral ingestion. AB - Biological monitoring and physiologically-based pharmacokinetic (PBPK) modelling are useful complementary tools in quantifying human exposure to elements in the environment. In this work, we used PBPK models to determine the optimal time for collecting biological samples in a longitudinal study to determine if participants who consumed allotment produce had been exposed to arsenic, cadmium, chromium, nickel or lead. There are a number of PBPK models for these elements published in the literature, which vary in size, complexity and application, given the differences in physiochemical properties of the elements, organs involved in metabolism and exposure pathways affected. We selected PBPK models from the literature to simulate the oral ingestion pathway from consumption of allotment produce. Some models required modification by reducing or removing selected compartments whilst still maintaining their original predictability. The performance of the modified models was evaluated by comparing the predicted urinary and blood elemental levels with experimental data and other model simulations published in the literature. Overall, the model predictions were consistent with literature data (r > 0.7, p < 0.05), and were influential in predicting when samples should be collected. Our results demonstrate the use of mathematical modelling in informing and optimising the design of longitudinal studies. PMID- 29253784 TI - Smokeless tobacco (SLT) use and cessation in India: Lessons from user and health care provider perspectives. AB - BACKGROUND: The use of smokeless tobacco (SLT) is very common in India and leads to well established adverse health effects, particularly oral cancers. AIM: To understand the perceptions of SLT users and health care providers regarding the prevalence of SLT in the community, awareness about its adverse effects and challenges for cessation METHODS: Key Informant (KI) interviews with SLT users; Focus group discussions (FGDs) with female and male tobacco users and health care providers RESULTS: KI perceptions among users and service providers were more or less similar regarding the extent of SLT use in the community. There was inadequate knowledge of the harm from SLT use, both among SLT users and health care providers. FGD's revealed high positive expectancies from SLT use and low risk perception. Shift from one to the other form of tobacco and a very early age of initiation, particularly among women, was observed. There was a low demand for assistance to quit. CONCLUSIONS: SLT cessation efforts in the country must take cognizance of user perspectives and focus on strategies for demand reduction in all populations, including adolescents. Health care providers need to be trained in SLT cessation. PMID- 29253786 TI - Effects of food contaminated with cadmium and copper on hemocytes of Steatoda grossa (Araneae: Theridiidae). AB - The aim of this study was to evaluate the metabolic condition of Steatoda grossa (Theridiidae) spider, from their hemocytes, after a short-term (four-week) exposure to cadmium and copper in sublethal doses by administering them into the body of the preys. The ultrastructure of the dominant types of hemocytes, such as granulocytes, plasmatocytes and prohemocytes, was evaluated using transmission electron microscope (TEM). Quantitative evaluation of apoptotic and necrotic cells, as well as the ones with depolarized mitochondria in hemolymph, was performed using flow cytometry, while ATP concentration and ADP/ATP ratio in hemocytes were measured by luminescent methods. Cadmium, unlike copper, demonstrated proapoptotic and pronecrotic activity. Low ATP levels and high ADP/ATP ratio in hemocytes indicate a disturbance in the energy metabolism of cells and may account for their qualitative and quantitative degenerative changes. The intensification of death processes in hemocytes after an exposure to cadmium-contaminated food may impair the ability of these cells to fight infectious diseases. Copper at the applied dosage was safe for the spiders without causing visible changes in the hemocyte ultrastructure and in the level of analyzed cell death indices. PMID- 29253787 TI - Optimization of copper, lead and cadmium biosorption onto newly isolated bacterium using a Box-Behnken design. AB - Due to the progressive development of industrial and technological activities, heavy metal contamination is increasing each year and it poses a serious health and environmental risk. Microorganisms are capable of removing heavy metals from a contaminated environment. In this work, 51 microbial strains were isolated from heavy metal contaminated water and soil. The JAW1 strain, identified as Pseudomonas azotoformans, was selected and applied in bioremediation of the specific mixture of metals (Cd, Cu, and Pb) in an aqueous medium. The Box-Behnken design was used to optimize the biosorption process, with three factors: pH, initial metal concentration, concentration of the biosorbent. For the strain P. azotoformans JAW1, the optimal conditions were pH = 6.0, 25mg/L of each metal and 2g/L, following removal levels were achieved: Cd 44,67%; Cu 63,32%; Pb 78,23%. The possible interactions of cell-metal ions were evaluated using FT-IR analysis. The study indicated the presence of groups, which may be responsible for bonding of metal ions. The studies conducted on bioremediation mechanisms indicated that metal accumulation could occur on the cell surface (biosorption) where the amount of adsorbed metals reached: Cd 98,57%, Cu 69,76%, Pb 88,58%. P. azotoformans JAW1 exhibited a potential for application in the bioremediation of mining wastewater with complex metal contaminations. PMID- 29253788 TI - H2S adsorption by municipal solid waste incineration (MSWI) fly ash with heavy metals immobilization. AB - As a byproduct of municipal solid waste incineration (MSWI) plant, fly ash is becoming a challenge for waste management in recent years. In this study, MSWI fly ash (FA) was evaluated for the potential capacity of odorous gas H2S removal. Results showed that fly ash demonstrated longer breakthrough time and higher H2S capacities than coal fly ash and sandy soil, due to its high content of alkali oxides of metals including heavy metals. H2S adsorption capacities of FA1 and FA2 were 15.89 and 12.59 mg H2S/g, respectively for 750 ppm H2S. The adsorption of H2S on fly ash led to formation of elemental sulfur and metal sulfide. More importantly, the formation of metal sulfide significantly reduced the leachability of heavy metals, such as Cr, Cu, Cd and Pb as shown by TCLP tests. The adsorption isotherms fit well with Langmuir model with the correlation coefficient over 0.99. The adsorption of H2S on fly ash features simultaneous H2S removal and stabilization and heavy metals found in most MSWI fly ash, making fly ash the potential low cost recycled sorbent material. PMID- 29253789 TI - Impact of an iron mine and a nickel smelter at the Norwegian/Russian border close to the Barents Sea on surface soil magnetic susceptibility and content of potentially toxic elements. AB - An important problem in soil magnetometry is unraveling the soil contamination signal in areas with multiple emitters. Here, geophysical and geochemical measurements were performed at four sites on a north - south transect along the Pasvik River in the Barents Region (northern Norway). These sites are influenced by depositions from the Bjornevatn iron mine and a Ni-Cu smelter in Nikel, Russia. To relate the degree and type of pollution from these sources to the corresponding magnetic signal, the topsoil concentrations of 12 Potentially Toxic Elements (PTEs) (As, Cd, Co, Cr, Cu, Fe, Mo, Ni, Pb, Se, Ti, Zn), were determined, magnetic hysteresis parameters and thermomagnetic properties were measured. In situ magnetic low-field susceptibility decreases from north to south with increasing distance from the iron mine. Relatively large magnetic multidomain grains of magnetite and/or titanomagnetite are responsible for the strong magnetic signal from the topsoil close to Bjornevatn. These particles are related to increased enrichment factors of As, Mo and Cu, yielding high positive correlation coefficients with susceptibility values. At a site furthest away from the iron mine and located 7 km from the Ni-Cu smelter magnetic susceptibility values are much lower but significant positive correlations on the level of p < .1 with 8 PTEs (Ni, Cu, Co, Se, As, Zn, Cd, Cr) have been observed. The magnetic signal in this area is due to fine-grained primary sulphides and secondary fine grained magnetite and/or maghemite. PMID- 29253790 TI - Electrosorption enhanced electrooxidation of a model organic pollutant at 3D SnO2 Sb electrode in superimposed pulse current mode. AB - In this work, the novel pulse "electrosorption-electrooxidation-electrosorption" (PESO) mode is developed in the superimposed pulse current system for benzoic acid oxidation. Due to the synergistic effect of electrosorption and electrooxidation at TiO2-NTs/3D-SnO2-Sb electrode in PESO mode, the enhancement of removal efficiency, improvement in mass transport and decrease of energy consumption were significantly obvious. The mechanism for the great enhancement of the mode is analyzed in details. The strengthened interaction between electrode and organics, increased instantaneous currents and lower intermediate accumulation contributed to the significant enhancement of electrochemical performance of the superimposed pulse system. The pulse PESO mode was an efficient and promising method for treating organic pollutants. PMID- 29253791 TI - Seawater toilet flushing sewage treatment and nutrients recovery by marine bacterial-algal mutualistic system. AB - Seawater toilet flushing sewage with excess eutrophic and high salinity brought a great barrier on the municipal wastewater treatment plants. Nutrients recovery and biomass production as potential biofuel feedstock with less energy consumption will be a key challenge in wastewater treatment. In the optimal inoculation of algae and bacteria, a marine bacterial-algal mutualistic system was established to treat synthetic seawater toilet flushing sewage without extra carbon and O2 addition. It was showed that 85.5% of total nitrogen (TN) (from 200 mg/L), 91.0% of total phosphorus (TP) (from 40 mg/L) and 98.7% of chemical oxygen demand (COD) (from 1600 mg/L) were removed with 4.28 g/L of biomass yield (biomass productivity 159.3 mg/L/d) containing 16.3% lipid and 62.6% protein, which performance mainly achieved by bacteria during first six days and algae functioned subsequently. Both nitrogen and phosphorus removal of the system were mainly assimilation/accumulation. Algal facultative heterotrophia ensured dissolved organic carbon for bacterial utilization and avoiding excessive organic matter produced. The established algal-bacterial system provided a potential energy-efficient and eco-friendly approach for seawater blackwater treatment and nutrients recovery simultaneously. PMID- 29253792 TI - Case study: Fixture water use and drinking water quality in a new residential green building. AB - Residential plumbing is critical for the health and safety of populations worldwide. A case study was conducted to understand fixture water use, drinking water quality and their possible link, in a newly plumbed residential green building. Water use and water quality were monitored at four in-building locations from September 2015 through December 2015. Once the home was fully inhabited average water stagnation periods were shortest at the 2nd floor hot fixture (90 percentile of 0.6-1.2 h). The maximum water stagnation time was 72.0 h. Bacteria and organic carbon levels increased inside the plumbing system compared to the municipal tap water entering the building. A greater amount of bacteria was detected in hot water samples (6-74,002 gene copy number/mL) compared to cold water (2-597 gene copy number/mL). This suggested that hot water plumbing promoted greater microbial growth. The basement fixture brass needle valve may have caused maximum Zn (5.9 mg/L), Fe (4.1 mg/L), and Pb (23 MUg/L) levels compared to other fixture water samples (Zn <= 2.1 mg/L, Fe <= 0.5 mg/L and Pb <= 8 MUg/L). At the basement fixture, where the least amount of water use events occurred (cold: 60-105, hot: 21-69 event/month) compared to the other fixtures in the building (cold: 145-856, hot: 326-2230 event/month), greater organic carbon, bacteria, and heavy metal levels were detected. Different fixture use patterns resulted in disparate water quality within a single-family home. The greatest drinking water quality changes were detected at the least frequently used fixture. PMID- 29253793 TI - Chronic inflammation and impaired development of the preterm brain. AB - The preterm newborn is at significant risk of neural injury and impaired neurodevelopment. Infants with mild or no evidence of injury may also be at risk of altered brain development, with evidence impaired cell maturation. The underlying causes are multifactorial and include exposure of both the fetus and newborn to hypoxia-ischemia, inflammation (chorioamnionitis) and infection, adverse maternal lifestyle choices (smoking, drug and alcohol use, diet) and obesity, as well as the significant demand that adaptation to post-natal life places on immature organs. Further, many fetuses and infants may have combinations of these events, and repeated (multi-hit) events that may induce tolerance to injury or sensitize to greater injury. Currently there are no treatments to prevent preterm injury or impaired neurodevelopment. However, inflammation is a common pathway for many of these insults, and clinical and experimental evidence demonstrates that acute and chronic inflammation is associated with impaired brain development. This review examines our current knowledge about the relationship between inflammation and preterm brain development, and the potential for stem cell therapy to provide neuroprotection and neurorepair through reducing inflammation and release of trophic factors, which promote cell maturation and repair. PMID- 29253794 TI - Unsaturated fatty acids protect trophoblast cells from saturated fatty acid induced autophagy defects. AB - Dysregulated serum fatty acids are associated with a lipotoxic placental environment, which contributes to increased pregnancy complications via altered trophoblast invasion. However, the role of saturated and unsaturated fatty acids in trophoblastic autophagy has yet to be explored. Here, we demonstrated that prolonged exposure of saturated fatty acids interferes with the invasiveness of human extravillous trophoblasts. Saturated fatty acids (but not unsaturated fatty acids) inhibited the fusion of autophagosomes and lysosomes, resulting in the formation of intracellular protein aggregates. Furthermore, when the trophoblast cells were exposed to saturated fatty acids, unsaturated fatty acids counteracted the effects of saturated fatty acids by increasing degradation of autophagic vacuoles. Saturated fatty acids reduced the levels of the matrix metalloproteinases (MMP)-2 and MMP-9, while unsaturated fatty acids maintained their levels. In conclusion, saturated fatty acids induced decreased trophoblast invasion, of which autophagy dysfunction plays a major role. PMID- 29253795 TI - New insights into early and late onset subgroups of preeclampsia from longitudinal versus cross-sectional analysis of urinary inositol-phosphoglycan P Type. AB - Most pre-eclampsia (PE) studies have used cross-sectional data to derive conclusions regarding the pathophysiology of the condition. This has led to the concept that there exists early (<34 weeks) and late-onset (>34 weeks) disease according to gestational age at diagnosis. Survival time models have predicted that if the pregnancy was to continue indefinitely, all women would develop PE. In this study we have performed a longitudinal analysis of the urinary biomarker, inositol phosphoglycan (IPG), in a cohort of women giving birth in Mauritius (n 920). We have analysed the PE data in the traditional cross-sectional manner for n = 77 women who developed PE and also then looked at the longitudinal data for 71/77 of the same women. The data allows us to use longitudinal values to calculate a date of onset (first presence of biomarker in urine) and compare that to date of clinical diagnosis (cross sectional). We find two populations for both analysis consistent with an early and late stage subgroup. The calculated date of onset had subgroups (early and late) at 28.4 +/- 0.41 weeks and 35.37 +/- 0.26 weeks and for clinical date of diagnosis, 32.3 +/- 0.59 weeks and 37.04 +/- 0.62 weeks, respectively. The presence of the same biomarker in both subgroups and its ability to predict clinical onset 2-4 weeks prior to clinical diagnosis suggest that both groups may have similar aetiology. PMID- 29253796 TI - Prior binge-drinking history promotes the positive affective valence of methamphetamine in mice. AB - An alcohol use disorder is a major predisposing factor for methamphetamine (MA) abuse. Further, MA-alcohol co-abuse is a risk factor for treatment discontinuation and non-compliance in MA-dependent individuals. No effective treatment exists for MA addiction, let alone treatments directed at those suffering from MA-alcohol addiction co-morbidity. Thus, it is imperative that we develop high-throughput animal models to study the biobehavioral interactions between MA and alcohol of relevance to the etiology and treatment of co-abuse. To this end, we reported that a history of binge alcohol-drinking [5,10, 20 and 40% (v/v); 2 h/day for 10-14 days] reduces MA reinforcement and intake, but it augments MA-preference and intake when drug availability is behaviorally non contingent. To reconcile this apparent discrepancy in findings, we employed a comparable 2-week binge-drinking paradigm as that employed in our previous studies followed by place-conditioning procedures (4 pairings of 0.25, 0.5, 1, 2 or 4 mg/kg MA, i.p.). This was meant to determine how a prior binge-drinking history impacts the affective valence of MA and sensitivity to MA-induced psychomotor-activation/sensitization. Prior binge-drinking history blunted spontaneous locomotor activity and shifted the MA dose-place-preference function upwards of water drinking controls. The potentiation of MA-conditioned reward by prior binge-drinking history was independent of any alcohol effects upon the locomotor-activating or -sensitizing effects of MA. Based on these results we propose that the reduced MA reinforcement reported previously by our group likely reflects a compensatory response to an increased sensitivity to MA's positive subjective effects rather than increased sensitivity to the drug's psychomotor activating effects. PMID- 29253798 TI - Severe interpersonal violence against children in sport: Associated mental health problems and quality of life in adulthood. AB - In a recent large-scale prevalence study of interpersonal violence (IV) against child athletes in the Netherlands and Belgium we found that 9% of adult respondents who participated in organized sports before the age of 18 had experienced severe psychological violence, 8% severe physical violence, and 6% severe sexual violence in various sport settings. While the general literature has repeatedly shown that exposure to IV during childhood is associated with mental health problems in adulthood and to a lesser extent with reduced quality of life (QOL), these relationships have not been demonstrated in (former) athletes. Thus, the current study aims to assess the association of severe childhood IV in sport and adult wellbeing. Depression, anxiety, and somatization were assessed in the same general population sample (N = 4043) using the Brief Symptom Inventory (BSI-18) and QOL with the World Health Organization Quality of Life questionnaire (WHOQOL-Bref). The association between severe IV in sport and adult wellbeing was investigated using multiple linear regression while controlling for demographics, recent life events, and relatives' psychological problems. We found severe sexual, physical, and psychological childhood IV in sport to be associated with more adult psychological distress and reduced QOL. Polyvictimization shows the strongest correlation with poorer wellbeing and QOL. Recent life events, relatives' psychological problems, marital status, and level of education were significant covariates in the psychological symptoms and QOL assessed. We hope that these new insights prompt sport administrators to implement broad spectrum child protection measures and raise the awareness of mental health professionals about the necessity to also screen for adverse childhood experiences in the sport context. PMID- 29253797 TI - Neural response to errors is associated with problematic alcohol use over time in combat-exposed returning veterans: An event-related potential study. AB - BACKGROUND: Currently, we do not have biomarkers to help identify individuals at risk for chronic, problematic alcohol use, especially among veteran populations, who have notoriously high rates of alcohol use. One biomarker that may predict individuals at risk for chronic, problematic alcohol use is error-related brain activity. We examined longitudinal associations between the error-related negativity (ERN), an event-related potential observed following the commission of errors, and problematic alcohol use among U.S. military veterans returning from recent conflicts in Iraq and Afghanistan. METHODS: Forty-six military veterans, aged 18-55 years, completed a well-validated flanker task known to elicit the ERN at baseline. Problematic alcohol use and other clinically relevant variables were assessed at baseline, 3-, 6-, 9-, 12-, 15-, 18-, 21-months, and 2 years. RESULTS: Results indicated that the ERN magnitude was associated with problematic alcohol use over time, even after controlling for relevant clinical variables. Specifically, veterans with a smaller ERN magnitude evidenced a decline in problematic alcohol use over time, while veterans with a larger ERN magnitude had no change in their problematic alcohol use across the follow-up. In addition, exploratory analyses found that treatment engagement during the study did not moderate these relationships. CONCLUSIONS: Our findings provide preliminary evidence that ERN can be used as a predictor of problematic alcohol use over time. Therefore, neural response to errors could help to identify individuals at risk for continued problematic alcohol use for intervention efforts and suggests that error processing may be an important therapeutic target within Alcohol Use Disorder intervention efforts. PMID- 29253799 TI - The influence of pelvic rotation on clinical measurements of hip flexion and extension range of motion across sex and age. AB - OBJECTIVE: The purpose of this study was to identify the amount of pelvic rotation associated with hip motion during passive hip flexion and extension goniometric measurements. DESIGN: Cross-sectional study. SETTING: University laboratory. PARTICIPANTS: One hundred healthy adults (males = 45, females = 55) aged 18-66 years participated. OUTCOME MEASURES: Clinical range of motion measurements of hip flexion, and extension during the modified Thomas test, and pelvic sagittal position measured using a device, attached from the PSIS to ASIS, and a fluid-filled inclinometer. RESULTS: When pelvic rotation was subtracted from the clinical measurements, hip flexion measurements were significantly reduced in both sexes (males: 110.8 +/- 7.4 to 93.8 +/- 7.8 degrees , P < 0.001; females: 121.3 +/- 7.2 to 107.3 +/- 8.6 degrees , P < 0.001). However, subtracting pelvic rotation from hip extension measurements only significantly reduced the measurements in females (15.5 +/- 6.0 to 6.2 +/- 6.8 degrees , P < 0.001). No significant differences were found across age groups. CONCLUSIONS: Clinical measurements of hip flexion exaggerated the range of motion in both sexes. The modified Thomas test appeared to control for rotation of the pelvis during hip extension in men. However, in women, hip extension measurements were exaggerated. PMID- 29253800 TI - Difference of proteomics vernalization-induced in bolting and flowering transitions of Beta vulgaris. AB - Sugar beet (Beta vulgaris) is a biennial crop that accounts for 30% sugar production of the world. Vernalization is an essential factor for sugar beet reproductative growth under long days. Although genes association with bolting and flowering were well explored, the difference of proteomics in the two growth stages were still poorly understood. To address the molecular mechanism at the level of proteins, an isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomics approach was employed to the three different growth stages (germination, bolting, flowering) of vernalized samples and the corresponding stage germination (17W weeks), 19W and 20W of nonvernalized samples. A total of 1110 peptides, 842 unique peptides and 570 proteins were identified. Most of them were assigned to phenylpropanoid biosynthesis, hormone metabolism and protein processing pathway. IAA and Gibberellins (GA3) promoted growth and development in a threshold manner at growth stage germination after vernalization. A novel discovery was that IAA biosynthetic pathway of sugar beet was the Trp-dependent. In addition, two predominant pathways of protein processing association with vernalization were also identified in sugar beet at growth stage flowering. This study provided an in-depth understanding of the molecular mechanism of vernalization at the level of proteomics. PMID- 29253801 TI - Concentration of phenolic compounds is increased in lettuce grown under high light intensity and elevated CO2. AB - The present study was focused on lettuce, a widely consumed leafy vegetable for the large number of healthy phenolic compounds. Two differently-pigmented lettuce cultivars, i.e. an acyanic-green leaf cv. and an anthocyanic-red one, were grown under high light intensity or elevated CO2 or both in order to evaluate how environmental conditions may affect the production of secondary phenolic metabolites and, thus, lettuce quality. Mild light stress imposed for a short time under ambient or elevated CO2 concentration increased phenolics compounds as well as antioxidant capacity in both lettuce cvs, indicating how the cultivation practice could enhance the health-promoting benefits of lettuce. The phenolic profile depended on pigmentation and the anthocyanic-red cv. always maintained a higher phenolic amount as well as antioxidant capacity than the acyanic-green one. In particular, quercetin, quercetin-3-O-glucuronide, kaempferol, quercitrin and rutin accumulated under high light or high CO2 in the anthocyanic-red cv., whereas cyanidin derivatives were responsive to mild light stress, both at ambient and elevated CO2. In both cvs total free and conjugated phenolic acids maintained higher values under all altered environmental conditions, whereas luteolin reached significant amounts when both stresses were administered together, indicating, in this last case, that the enzymatic regulation of the flavonoid synthesis could be differently affected, the synthesis of flavones being favored. PMID- 29253802 TI - Long-term exposure to slightly elevated air temperature alleviates the negative impacts of short term waterlogging stress by altering nitrogen metabolism in cotton leaves. AB - Short-term waterlogging and chronic elevated temperature occur frequently in the Yangtze River Valley, yet the effects of these co-occurring environments on nitrogen metabolism of the subtending leaf (a major source leaf for boll development) have received little attention. In this study, plants were exposed to two temperature regimes (31.6/26.5 degrees C and 34.1/29.0 degrees C) and waterlogging events (0 d, 3 d, 6 d) during flowering and boll development. The results showed that the effects of waterlogging stress and elevated temperature in isolation on nitrogen metabolism were quite different. Waterlogging stress not only limited NR (EC 1.6.6.1) and GS (EC 6.3.1.2) activities through the down regulation of GhNR and GhGS expression for amino acid synthesis, but also promoted protein degradation by enhanced protease activity and peptidase activity, leading to lower organ and total biomass (reduced by 12.01%-27.63%), whereas elevated temperature inhibited protein degradation by limited protease activity and peptidase activity, promoting plant biomass accumulation. Furthermore, 2-3 degrees C chronic elevated temperature alleviated the negative impacts of a brief (3 d) waterlogging stress on cotton leaves, with the expression of GhNiR up-regulated, the activities of NR, GS and GOGAT (EC 1.4.7.1) increased and the activities of protease and peptidase decreased, leading to higher protein concentration and enhanced leaf biomass for EW3 relative to AW3. The results of the study suggested that exposure to slightly elevated air temperature improves the cotton plants' ability to recover from short-term (3 d) waterlogging stress by sustaining processes associated with nitrogen assimilation. PMID- 29253803 TI - Childhood maltreatment is associated with attachment insecurities, dissociation and alexithymia in bipolar disorder. AB - Child maltreatment is a public health issue that is a well-established risk factor for many psychological conditions, including bipolar disorder. The current study is one of the first to investigate associations among child maltreatment, dissociative symptomatology, alexithymia, anxiety, depression, and attachment insecurities. 40 patients with bipolar disorder-I and 40 healthy subjects matched for age, gender, and education participated in the study. The Dissociative Experiences Scale (DES), Somatoform Dissociation Questionnaire (SDQ), Childhood Trauma Questionnaire (CTQ-28), Toronto Alexithymia Scale (TAS-20), Depression Anxiety Stress Scale (DASS-21), and Experiences in Close Relationships-Revised (ECR-R) were completed by participants. In comparison to control participants, patients with bipolar disorder-I reported significantly more frequent abusive experiences in childhood, higher levels of attachment insecurities, more severe pathological and somatoform dissociation, as well as higher scores on measures of alexithymia, anxiety, depression and psychological stress. Reports of psychopathology among first-degree relatives (OR = 102.169, 95%IC = 4.596 2271.255; P < 0.01) and childhood emotional trauma (OR = 1.032; 95%CI = 0.782 1.363, P = 0.05) significantly contributed to bipolar disorder-I diagnosis. In contrast, absorption was negatively associated with bipolar illness (OR = 0.852; 95% CI = 0.747-0.973, P < 0.05). Our results showed significant associations between childhood trauma exposure and risk of bipolar disorder. Moreover, the results demonstrate that emotional abuse exposure predicts bipolar illness. PMID- 29253804 TI - The latent nature of prolonged grief - A taxometric analysis: Results from a representative population sample. AB - Individuals suffering from prolonged grief disorder (PGD) show severe grief reactions after the death of a significant other, even beyond a period of grieving that is within a person's cultural and religious context. In addition to this core element, PGD can manifest in various ways. Symptoms may include persistent preoccupation, intense emotional pain, or impairment in important life domains. The symptoms, furthermore, have to be of culturally or religiously inappropriate extent or severity, taking into account different norms of grieving. PGD is discussed as a distinct diagnostic category in the revision of the International Classification of Diseases (ICD-11). Nosology of PGD has been highly debated surrounding the suggested inclusion in the DSM-5, which had been declined due to insufficient evidence. This paper addresses the latent nature of PGD. Using a short form of the Inventory of Complicated Grief-Revised (ICG-R), we applied three popular taxometric methods: MAXEIG, MAMBAC and L-Mode. Data stemmed from a subsample of N = 1445 bereaved individuals that participated in a large representative German population survey (N = 2520). The analysis strongly indicated a dimensional latent structure of PGD. Implications of the conceptualization of PGD on a continuum are discussed, regarding measurement, diagnosis, etiology and future research. PMID- 29253805 TI - Theta-phase gamma-amplitude coupling as a neurophysiological marker in neuroleptic-naive schizophrenia. AB - Theta-phase gamma-amplitude coupling (TGC) was used as an evidence-based tool to reflect the dysfunctional cortico-thalamic interaction in patients with schizophrenia. The aim of the present study was to evaluate the diagnostic utility of TGC. The subjects included 90 patients with schizophrenia and 90 healthy controls. We compared the TGC results between the groups using an analysis of covariance (ANCOVA) to adjust for age and sex and receiver operator characteristic (ROC) curve analyses to examine the discrimination ability of delta to gamma frequency bands and TGC. Patients with schizophrenia showed a significant increase in the resting-state TGC at all 19 electrodes. The analysis of the ROC curves for each frequency band exhibited relatively low classification accuracies for the delta, theta, slow alpha, fast alpha, and beta power. The TGC generated the most accurate results among the electroencephalography (EEG) measures, with an overall classification accuracy of 92.5%. The resting-state TGC value was increased in patients with schizophrenia compared to that in healthy controls and had a higher discriminating ability than the other parameters. These findings may be related to the compensatory hyper-arousal patterns of the dysfunctional default-mode network (DMN) in schizophrenia. Therefore, resting state TGC is a promising neurophysiological marker of schizophrenia. PMID- 29253806 TI - Motivation, health-related lifestyles and depression among university students: A longitudinal analysis. AB - Positive motivational attitudes protect against depressive symptoms in young adults. This study examined the longitudinal relationship between motivation to achieve important life goals and depression in a sample of young adult university students, who are at higher risk of developing psychiatric disorders and adopting unhealthy behaviours than their age peers who are not attending university. The participants were 228 Italian undergraduates who completed an online self-report questionnaire twice during a one-year period. Measures included positive motivational attitudes, depressive feelings, body mass index, smoking, alcohol consumption, cannabis use, subjective family income and satisfaction with academic choice. A cross-lagged longitudinal model demonstrated that higher motivation predicted lower depression after one year. No other covariate effects were observed. The results confirm that motivation protects against mental health problems during higher education and is a better predictor of mental health than health-related risk factors. Encouraging undergraduates to invest effort in achieving important goals may prevent the onset of depressive disorders. PMID- 29253807 TI - Compartmentalization of extracellular polymeric substances (EPS) solubilization and cake microstructure in relation to wastewater sludge dewatering behavior assisted by horizontal electric field: Effect of operating conditions. AB - Sludge treatment and disposal have become important environmental issues in China. Mechanical dewatering is widely used to reduce the amount of sludge to be disposed and relieve the rapid growth pressure of waste sludge. In comparison to traditional sludge dewatering processes, pressure electro-osmotic dewatering has many advantages on sludge dewatering efficiency, low conditioner dosage and concentrated cake are both beneficial to further recycling of waste sludge. In general, complex electrochemical effects (eg. electrochemical oxidation, ohmic heating and pH gradient effect) are accompanied by the pressure electro-osmotic dewatering process. These electrochemical effects will inevitably cause solubilization and/or degradation of key constituents of wastewater sludge - extracellular polymeric substances (EPS). In this study, the effects of voltage, pH and ionic strength on sludge electro-osmotic dewatering performance and electrochemical effects were investigated. The solubilization and degradation of EPS were analyzed by examining the variation of dissolved organic matter (DOM) in the filtrate, and the relationships between microstructural properties of sludge cake and DOM and electro-osmosis dewatering performance in electro-dewatering process was examined. It was found that electro-dewatering properties were improved by raising the operating voltage or decreasing the pH value, while dewatering rate initially increased at low ionic strength it decreases with increased ionic strength. In addition, the porous structure of cathodic cake was more plentiful than that at the anode. At the cathode, the EPS dissolution was mainly related to alkalization, while the oxidation and acidification were responsible for release of EPS at the anode. Meanwhile, electrophoresis effect was able to promote migration of EPS toward the anode. The average electro osmotic dewatering rate at the anode (R2.>0.79, p < 0.02) and at the cathode (R2.>0.87, p < 0.03) strongly correlated with the volume of pore of sludge cake. There was no correlation between the total content of anodic DOM (R2<0.31, p>0.08) and electro-osmotic dewatering rate at the anode, however, the content of cathodic DOM (R2 > 0.62, p < 0.09) negatively correlated with average electro osmosis dewatering rate of cathode. Since cathode is the main water-permeable side in sludge electro-dewatering, and the sticky biopolymers (proteins and humic subtances) could not be converted into small molecules, higher EPS release was associated with worse sludge filterability. As for the anode, the biopolymers were degraded into small molecules due to electrochemical oxidation, which greatly reduced the impact of DOM on dewatering effect. Therefore, the operating conditions (voltage, pH and ionic strength) caused changes in electrochemical effects, which played a crucial role in compartmentalization of sludge EPS dissolution and consequently sludge electro-dewatering behavior. PMID- 29253808 TI - Modest ratios of fast food outlets to supermarkets and green grocers are associated with higher body mass index: Longitudinal analysis of a sample of 15,229 Australians aged 45 years and older in the Australian National Liveability Study. AB - Food purchasing decisions are made within the context of the range of options available, yet most epidemiological studies focus upon single outlet types. Ratios of fast food outlets to supermarkets and green grocers were linked to addresses of 15,229 adults in the 45 and Up Study at baseline (2006-2008) and follow-up (2009-2010). Compared to having no fast food outlet but having healthy food outlets within 3.2km from home, multilevel growth curves revealed that relative exposure>25% fast food outlets were associated with 0.36-1.19kg/m2 higher BMI (p<0.05). These associations were consistent as people aged. No associations were observed for food outlets<0.8km. PMID- 29253809 TI - Effects of plantar hypothermia on quasi-static balance: Two different hypothermic procedures. AB - Inducing hypothermia to examine its effects on balance is performed with various approaches. However, data interpretations of underlying postural mechanisms often do not consider the applied hypothermic protocol. In this context, the effects of diminished plantar mechanoreceptor activity on quasi-static balance performance were investigated, examining the applicability of a continuously cooling thermal platform in comparison with conventional ice pads. Increased instability for the thermal platform compared to cooling with ice pads was hypothesized, since we expected increased temperatures for the ice pad group directly after balance tests. Similar scores on a Visual Analogue Scale (VAS) were predicted regarding subjective pain. Results showed that both cooling procedures successfully induced plantar hypothermia. However, the thermal platform was more effective with respect to reaching and maintaining the desired temperature throughout the trials, especially when comparing temperatures before and after balance tests. Therefore, balance tests indeed demonstrated increased COP parameters exclusively after permanent cooling via the thermal platform as early as after the first 10 min of cooling. Reduced plantar input may result in this postural instability, but without the need of other sensory systems to compensate. The VAS generally demonstrated higher pain scores for the ice pads, rejecting our hypothesis. This is an important finding, since pain is known to influence balance. Therefore, permanent and controllable cooling via the thermal platform should be taken into consideration when conducting related research. PMID- 29253810 TI - A case report of cervical neurofibrosarcoma: Clinical presentation, treatment and outcome. AB - INTRODUCTION: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas in which complete surgical resection is the mainstay of therapy. CLINICAL PRESENTATION: We report a case of MPNST, a 24 year old patient with right neck painful mass of 13 cm of greater dimension, skin spots, lentigos, cutaneous neurofibromas. The neck CT scan revealed a mass with liquid and soft tissues densities. Surgery was performed through right cervical Paul Andre incision and allowed exeresis of a hemorrhagic mass expensing on the cranial nerves X, XI, XII and the cervical sympathetic chain. Pathology analysis revealed a neurofibrosarcoma, the patient received six doses of chemotherapy. A second surgery was performed one year later after the appearance of a rapidly growing neck mass on the same site. The patient deceased in the intensive care unit one day post-op. DISCUSSION: Neurofibrosarcoma is a rare clinical entity most often reported as case report. This tumor takes its origin from nerve structures such as the brachial plexus, the cervical sympathetic chain and the cranial nerves and their branches. The appearance of pain, size modification or signs of nerve root compression should warn us to search for a malignant degeneration. Surgery is the base of treatment, associated to radiotherapy and chemotherapy. Vinblastin and doxorubicin were used by other authors in association to radiotherapy with complete local control of inoperable tumors. The 5-year survival is 50% in patients with a neurofibrosarcoma de novo. CONCLUSION: The prognosis of neurofibrosarcoma is poor, prompting aggressive local (surgery) and systemic treatment (radiotherapy and/or chemotherapy). PMID- 29253811 TI - Snapping wrist due to multiple accessory tendon of first extensor compartment. AB - BACKGROUND: Snapping phenomena result from the sudden impingement between anatomical and/or heterotopical structures with subsequent abrupt movement and noise. Snaps are variously perceived by patients, from mild discomfort to significant pain requiring surgical management. snapping syndrome occurs at various site like hip, knee, shoulder and wrist. There are many cadaveric studies shows accessory tendon in first extensor compartment of wrist. CASE PRESENTATION: We present a 19 year old male presents catching sensation and occasional radial side wrist pain for 6 months. Finkelstein test was negative. Radiograph showed small bony projection over the radial styloid. MRI wrist was reported as normal but retrospective analysis of image shows multiple tendons. Intraopertively we found multiple accessory tendon of extensor pollicis brevis which is causing snapping. Fibrous tunnel release with tenotomy of few accessory tendons done. On table patients catching sensation was assessed and found to be relieved. Patient is not having snapping on his follow up visit and able to carry out his daily activity without difficulties. CONCLUSION: There are various causes for snapping wrist syndrome. Multiple accessory tendon can also cause snapping as shown in this case report. Moreover am presenting this case to highlight the diagnostic failure with non dynamic radiological investigation and to consider multiple accessory tendon as differential diagnosis for snapping wrist syndrome. Also suggest dynamic study could be a better choice of investigation to diagnosis snapping syndrome. First compartment tunnel release with few accessory tendon slip tenotomy gives good result. PMID- 29253813 TI - Susceptibility of Enterococcus faecalis and Propionibacterium acnes to antimicrobial photodynamic therapy. AB - Bacterial resistance to available antibiotics nowadays is a global threat leading researchers around the world to study new treatment modalities for infections. Antimicrobial photodynamic therapy (aPDT) has been considered an effective and promising therapeutic alternative in this scenario. Briefly, this therapy is based on the activation of a non-toxic photosensitizing agent, known as photosensitizer (PS), by light at a specific wavelength generating cytotoxic singlet oxygen and free radicals. Virtually all studies related to aPDT involve a huge screening to identify ideal PS concentration and light dose combinations, a laborious and time-consuming process that is hardly disclosed in the literature. Herein, we describe an antimicrobial Photodynamic Therapy (aPDT) study against Enterococcus faecalis and Propionibacterium acnes employing methylene blue, chlorin-e6 or curcumin as PS. Similarities and discrepancies between the two bacterial species were pointed out in an attempt to speed up and facilitate futures studies against those clinical relevant strains. Susceptibility tests were performed by the broth microdilution method. Our results demonstrate that aPDT mediated by the three above-mentioned PS was effective in eliminating both gram-positive bacteria, although P. acnes showed remarkably higher susceptibility to aPDT when compared to E. faecalis. PS uptake assays revealed that P. acnes is 80 times more efficient than E. faecalis in internalizing all three PS molecules. Our results evidence that the cell wall structure is not a limiting feature when predicting bacterial susceptibility to aPDT treatment. PMID- 29253812 TI - Short-term sustained hyperglycaemia fosters an archetypal senescence-associated secretory phenotype in endothelial cells and macrophages. AB - Diabetic status is characterized by chronic low-grade inflammation and an increased burden of senescent cells. Recently, the senescence-associated secretory phenotype (SASP) has been suggested as a possible source of inflammatory factors in obesity-induced type 2 diabetes. However, while senescence is a known consequence of hyperglycaemia, evidences of SASP as a result of the glycaemic insult are missing. In addition, few data are available regarding which cell types are the main SASP-spreading cells in vivo. Adopting a four-pronged approach we demonstrated that: i) an archetypal SASP response that was at least partly attributable to endothelial cells and macrophages is induced in mouse kidney after in vivo exposure to sustained hyperglycaemia; ii) reproducing a similar condition in vitro in endothelial cells and macrophages, hyperglycaemic stimulus largely phenocopies the SASP acquired during replicative senescence; iii) in endothelial cells, hyperglycaemia-induced senescence and SASP could be prevented by SOD-1 overexpression; and iiii) ex vivo circulating angiogenic cells derived from peripheral blood mononuclear cells from diabetic patients displayed features consistent with the SASP. Overall, the present findings document a direct link between hyperglycaemia and the SASP in endothelial cells and macrophages, making the SASP a highly likely contributor to the fuelling of low-grade inflammation in diabetes. PMID- 29253814 TI - The imprints of the high light and UV-B stresses in Oryza sativa L. 'Kanchana' seedlings are differentially modulated. AB - High light and ultraviolet-B radiation (UV-B) are generally considered to have negative impact on photosynthesis and plant growth. The present study evaluates the tolerance potential of three cultivars of Oryza sativa L. (Kanchana, Mattatriveni and Harsha) seedlings towards high light and UV-B stress on the basis of photosynthetic pigment degradation, chlorophyll a fluorescence parameters and rate of lipid peroxidation, expressed by malondialdehyde content. Surprisingly, it was revealed that Kanchana was the most sensitive cultivar towards high light and at the same time it was the most tolerant cultivar towards UV-B stress. This contrasting feature of Kanchana towards high light and UV-B tolerance was further studied by analyzing photosystem (PS) I and II activity, mitochondrial activity, chlorophyll a fluorescence transient, enzymatic and non enzymatic antioxidant defense system. Due to the occurrence of more PS I and PSII damages, the inhibition of photochemical efficiency and emission of dissipated energy as heat or fluorescence per PSII reaction center was higher upon high light exposure than UV-B treatments in rice seedlings of Kanchana. The mitochondrial activity was also found to be drastically altered upon high light as compared to UV-B treatments. The UV-B induced accumulation of non-enzymatic antioxidants (proline, total phenolics, sugar and ascorbate) and enzymatic antioxidants (ascorbate peroxidase, guaiacol peroxidase, superoxide dismutase and glutathione reductase) in rice seedlings than those subjected to high light exposure afforded more efficient protection against UV-B radiation in rice seedlings. Our results proved that high tolerance of Kanchana towards UV-B than high light treatments, correlated linearly with the protected photosynthetic and mitochondrial machinery which was provided by upregulation of antioxidants particularly by total phenolics, ascorbate and ascorbate peroxidase in rice seedlings. Data presented in this study conclusively proved that rice cultivar Kanchana respond to different environmental signals independently and tolerance mechanisms to individual stress factors was also varied. PMID- 29253815 TI - One-pot biosynthesis of silver nanoparticles using Iboza Riparia and Ilex Mitis for cytotoxicity on human embryonic kidney cells. AB - Plant extracts continue gaining significant prominence in green synthesis of silver nanoparticles (AgNPs), due to their potential applications in nano medicine and material engineering. This work reports on green synthesis of silver nanoparticles (AgNPs) from aqueous extracts of Iboza Riparia leaf and Ilex Mitis root bark with diterpenes (DTPs) and saponins (SPNs) as major components. After TEM, DLS, TGA/DSC, ATR, XRD and UV-Vis characterization, the relevant cytotoxicity studies were conducted with the MTT assay on human embryonic kidney cells (HEK293T) followed by antioxidant activity with ABTS. Overall, the AgNPs DTPs (156nm) were found to be less toxic with 49.7% cell viability, while AgNPs SPNs (50nm) and AgNPs-PVA (44nm) had cell viability of 40.8 and 28.0% respectively at 400MUM. Based on the cytotoxicity and antioxidant activity, it is fair to report that these plant extracts have potential reducing and capping agents as they retain chemical properties on the surface of the nanoparticles. PMID- 29253816 TI - A glucose biosensor based on novel Lutetium bis-phthalocyanine incorporated silica-polyaniline conducting nanobeads. AB - The facile preparation of highly sensitive electrochemical bioprobe based on lutetium phthalocyanine incorporated silica nanoparticles (SiO2(LuPc2)) grafted with Poly(vinyl alcohol-vinyl acetate) itaconic acid (PANI(PVIA)) doped polyaniline conducting nanobeads (SiO2(LuPc2)PANI(PVIA)-CNB) is reported. The preparation of CNB involves two stages (i) pristine synthesis of LuPc2 incorporated SiO2 and PANI(PVIA); (ii) covalent grafting of PANI(PVIA) onto the surface of SiO2(LuPc2). The morphology and other physico-chemical characteristics of CNB were investigated. The scanning electron microscopy images show that the average particle size of SiO2(LuPc2)PANI(PVIA)-CNB was between 180-220nm. The amperometric measurements showed that the fabricated SiO2(LuPc2)PANI(PVIA) CNB/GOx biosensor exhibited wide linear range (1-16mM) detection of glucose with a low detection limit of 0.1mM. SiO2(LuPc2)PANI(PVIA)-CNB/GOx biosensor exhibited high sensitivity (38.53uAmM-1cm-2) towards the detection of glucose under optimized conditions. Besides, the real (juice and serum) sample analysis based on a standard addition method and direct detection method showed high precision for measuring glucose at SiO2(LuPc2)PANI(PVIA)-CNB/GOx biosensor. The SiO2(LuPc2)PANI(PVIA)-CNB/GOx biosensor stored under refrigerated condition over a period of 45 days retains ~ 96.4% glucose response current. PMID- 29253817 TI - A semi-analytical approach for SH guided wave mode conversion from evanescent into propagating. AB - Conversion of evanescent shear horizontal (SH) guided waves into propagating is presented in this paper. The conversion is exemplified by a time-harmonic SH evanescent displacement prescribed on a narrow aperture at an edge of a semi infinite isotropic plate. The conversion efficiency in terms of the amplitude of the propagating SH mode converted from evanescent can be expressed in a very simple compact form. The magnitude of the conversion efficiency can be quantified through a derived semi-analytical form based on the complex reciprocity theorem in conjunction with a two-dimensional (2-D) finite element analysis (FEA). Through power conversion analysis, it can be shown that the power flow generated into the plate due to evanescent incident is complex valued. It is theoretically proved that the real part of the complex power flow is associated with the propagating SH modes, while the imaginary part is confined due to the evanescent modes at the plate edge. The conversion efficiency and converted modes are dependent on the geometric configuration of the aperture as well as the selection of the excitation frequency. PMID- 29253818 TI - ASP49-phospholipase A2-loaded liposomes as experimental therapy in cutaneous leishmaniasis model. AB - This study aimed to evaluate the in vivo anti-Leishmania amazonensis activity of a Phospholipase A2 (Asp49-PLA2), isolated from Bothrops jararacussu venom, encapsulated in liposomes as a modified toxin release system. The activity of the liposomes was evaluated in BALB/c mice, previously infected with 1*105 of the parasite's promastigotes. The size of the paw lesion in Asp49-PLA2-liposomal treated animals, after 21days, was observed as decreasing by 16% relative to the untreated control group and 12% by the Glucantime(r)-treated animals, which was used as a reference drug. At the end of the treatment, the animals were sacrificed and the paw and lymph node tissues were collected. Part of the collection was used to recover amastigotes and another to quantify cytokines and nitrites. In the group treated with Asp49-PLA2-liposomes the parasitic load was observed to be reduced by 73.5% in the macerated lymph node, compared to the control group. Comparatively, in the paw tissue was observed a reduction of 57.1%. The infected groups treated with Asp49-PLA2-liposomes showed significant production in TNF-alpha measured in lymph nodes and paw (43.73pg/mL+/-2.25 and 81.03pg/mL+/-5.52, respectively) and nitrite levels (31.28MUM+/-0.58 and 35.64MUM+/-5.08) also measured in lymph nodes and paw tissues, respectively, compared to untreated groups. These results indicate that the Asp49-PLA2-loaded liposomes were able to activate the production of some cellular components of the protective TH1 response during the infection, constituting a promising tool for inducing the microbicidal activity of the Leishmania-infected macrophages. PMID- 29253819 TI - Mouse beta-defensin-14 for inducing the maturation of dendritic cells. AB - BACKGROUND: beta-defensins are an excellent antimicrobial peptide against microbial infection in which dendritic cells (DCs) play a crucial role by improving the innate and adaptive immune defense. However, it is unclear whether BDs affect DC maturation. This work aimed to study the effects of mouse beta defensin-14 (MBD-14) on DC maturation. METHODS: Via in vitro using mouse bone marrow DCs, the maturation of DCs was evaluated by cell morphological staining, flow cytometry, endocytosis assay, and allogeneic mixed lymphocyte reaction, respectively. And it was also assessed by in vivo establishing a mouse air-pouch model for flow cytometric determination, cytokine analysis, and histological staining. Additionally, CLI-095, an inhibitor of Toll-like receptor-4 (TLR-4), was used to determine whether TLR-4 is possibly involved in DC maturation. RESULTS: It was found MBD-14 promoted DCs to form more filopodia and lamellipodia, increased the expression of DC maturation markers (CD40 and MHC II), decreased their endocytic capacity, and enhanced T-cell proliferation. The analyses of the air-pouch exudates were consistent with the in vitro results of MBD-14 activating DCs. And when CLI-095 was applied, DC maturation was inhibited partly. CONCLUSIONS: This work demonstrates that MBD-14 can promote the maturation of DCs in which TLR-4 is possibly involved. PMID- 29253820 TI - Andrographolide sulfonate reduces mortality in Enterovirus 71 infected mice by modulating immunity. AB - Outbreaks of hand, foot and mouth disease (HFMD), which is caused by Enterovirus 71 (EV71), have erupted in recent years. Andrographolide sulfonate (Trade name: Xiyanping injection) has been recommended to treat severe HFMD in China because of its conventional antithermic and antitoxic activities, but its actual mechanism has not been revealed clearly until now. To explore its therapeutic efficacy and mechanism, a Xiyanping injection treatment mouse model was established. Based on the therapeutic model, routine clinical parameters and histopathologic changes were investigated, in the same time, viral loads, immune cells, inflammatory molecules and cell signaling pathways were determined. Xiyanping injection treatment protected mice from lethal EV71 challenge in a therapeutic regimen-dependent manner, which may mostly depend on its direct immunomodulatory activities on neutrophil and T lymphocyte. Reduced inflammatory molecular production of neutrophil and elevated T lymphocyte activity may result from its marked inhibition of some signaling pathways. Taken together, Xiyanping injection was an effective treatment for severe HFMD by improving hosts' immunity. PMID- 29253821 TI - Iodine excess did not affect the global DNA methylation status and DNA methyltransferase expression in T and B lymphocytes from NOD.H-2h4 and Kunming mice. AB - Dysregulated DNA methylation in lymphocytes has been linked to various autoimmune disorders. Excessive iodine intake leads to lymphocyte dysfunction and contributes to autoimmune thyroiditis (AIT) flares in humans and animals. However, whether excessive iodine modifies the DNA methylation status in lymphocytes is unknown. Twenty NOD.H-2h4 mice and 20 Kunming mice were randomly divided into high iodine and control groups. We scored lymphatic infiltration in the thyroid by hematoxylin and eosin (H&E) staining and assayed serum thyroglobulin antibody (TgAb) levels by an indirect enzyme-linked immunosorbent assay. CD3+ T cells and CD19+ B cells were separated by flow cytometry. Global DNA methylation levels were examined by absorptiometry. Methylation of long interspersed nucleotide element-1 (LINE-1) repeats was detected with bisulfite sequencing PCR. Expression of DNA methyltransferase (DNMT) 1, DNMT3a and DNMT3b mRNA and protein were determined by real-time PCR and Western blot, respectively. We observed evident thyroiditis in the high-iodine-treated NOD.H-2h4 mice, while mice in the other three groups did not develop thyroiditis. No differences were found in the global methylation levels and methylation status of LINE-1 repeats in T and B lymphocytes from high-iodine-treated NOD.H-2h4 mice and Kunming mice compared with those from normal-iodine-supplemented controls. We did not find obvious changes in DNMT mRNA and protein expression levels in T and B lymphocytes among the studied groups. In conclusion, we showed for the first time that excess iodine did not affect the global methylation status or DNMT expression in T and B lymphocytes in NOD.H-2h4 and Kunming mice. PMID- 29253822 TI - Phorbol ester (PMA)-treated U937 cells cultured on type I collagen-coated dish express a lower production of pro-inflammatory cytokines through lowered ROS levels in parallel with cell aggregate formation. AB - The present study is aimed to investigate the effect of collagen I on U937 cells, human monocyte-like histiocytic lymphoma cell line. Differentiation of U937 cells was induced by phorbol ester (PMA) treatment. The cells were cultured on the collagen I-coated plate. PMA-stimulated U937 cells formed multicellular aggregates on collagen I-coated surface, whereas PMA-unstimulated cells kept themselves away off each other. Moreover, the levels of reactive oxygen species (ROS) and productions of pro-inflammatory cytokines such as IL-1beta, TNFalpha and PGE2, pro-inflammatory mediator, were down-regulated in differentiated U937 cells cultured on collagen I-coated dishes. However, collagen I did not influence the capacity of E. coli phagocytosis. Cell aggregation as well as the down regulation of IL-1beta, TNFalpha and PGE2 caused by the culture on collagen I coated surface were suppressed by ROS donor, tert-butylhydroperoxide (tBHP). The sizes of cell aggregates became bigger in differentiated U937 cells by treatment with ROS scavengers such as N-acetylcysteine (NAC), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH). In conclusion, collagen I-coated culture induces the differentiated U937 cells to form cell aggregates and decreases the production of pro-inflammatory cytokines through down-regulating ROS generation. PMID- 29253823 TI - The effect of toxic carbon source on the reaction of activated sludge in the batch reactor. AB - The toxic carbon source can cause higher residual effluent dissolved organic carbon than easily biodegraded carbon source in activated sludge process. In this study, an integrated activated sludge model is developed as the tool to understand the mechanism of toxic carbon source (phenol) on the reaction, regarding the carbon flows during the aeration period in the batch reactor. To estimate the toxic function of phenol, the microbial cells death rate (kdeath) is introduced into the model. The integrated model was calibrated and validated by the experimental data and it was found the model simulations matched the all experimental measurements. In the steady state, the toxicity of phenol can result in higher microbial cells death rate (0.1637 h-1 vs 0.0028 h-1) and decay rate coefficient of biomass (0.0115 h-1 vs 0.0107 h-1) than acetate. In addition, the utilization-associated products (UAP) and extracellular polymeric substances (EPS) formation coefficients of phenol are higher than that of acetate, indicating that more carbon flows into the extracellular components, such as soluble microbial products (SMP), when degrading toxic organics. In the non steady state of feeding phenol, the yield coefficient for growth and maximum specific growth rate are very low in the first few days (1-10 d), while the decay rate coefficient of biomass and microbial cells death rate are relatively high. The model provides insights into the difference of the dynamic reaction with different carbon sources in the batch reactor. PMID- 29253824 TI - Synthesis of submicron silver powder from scrap low-temperature co-fired ceramic an e-waste: Understanding the leaching kinetics and wet chemistry. AB - The current study focuses on the understanding of leaching kinetics of metal in the LTCC in general and silver leaching in particular along with wet chemical reduction involving silver nanoparticle synthesis. Followed by metal leaching, the silver was selectively precipitated using HCl as AgCl. The precipitated AgCl was dissolved in ammonium hydroxide and reduced to pure silver metal nanopowder (NPs) using hydrazine as a reductant. Polyvinylpyrrolidone (PVP) used as a stabilizer and Polyethylene glycol (PEG) used as reducing reagent as well as stabilizing reagent to control size and shape of the Ag NPs. An in-depth investigation indicated a first-order kinetics model fits well with high accuracy among all possible models. Activation energy required for the first order reaction was 21.242 kJ mol-1 for Silver. PVP and PEG 1% each together provide better size control over silver nanoparticle synthesis using 0.4 M hydrazine as reductant, which provides relatively regular morphology in comparison to their individual application. The investigation revealed that the waste LTCC (an industrial e-waste) can be recycled through the reported process even in industrial scale. The novelty of reported recycling process is simplicity, versatile and eco-efficiency through which waste LTCC recycling can address various issues like; (i) industrial waste disposal (ii) synthesis of silver nanoparticles from waste LTCC (iii) circulate metal economy within a closed loop cycle in the industrial economies where resources are scarce, altogether. PMID- 29253825 TI - Transformation of chlorinated paraffins to olefins during metal work and thermal exposure - Deconvolution of mass spectra and kinetics. AB - Chlorinated paraffins (CPs) are high production volume chemicals widely used as additives in metal working fluids. Thereby, CPs are exposed to hot metal surfaces which may induce degradation processes. We hypothesized that the elimination of hydrochloric acid would transform CPs into chlorinated olefins (COs). Mass spectrometry is widely used to detect CPs, mostly in the selected ion monitoring mode (SIM) evaluating 2-3 ions at mass resolutions R < 20'000. This approach is not suited to detected COs, because their mass spectra strongly overlap with CPs. We applied a mathematical deconvolution method based on full-scan MS data to separate interfered CP/CO spectra. Metal drilling indeed induced HCl-losses. CO proportions in exposed mixtures of chlorotridecanes increased. Thermal exposure of chlorotridecanes at 160, 180, 200 and 220 degrees C also induced dehydrohalogenation reactions and CO proportions also increased. Deconvolution of respective mass spectra is needed to study the CP transformation kinetics without bias from CO interferences. Apparent first-order rate constants (kapp) increased up to 0.17, 0.29 and 0.46 h-1 for penta-, hexa- and heptachloro-tridecanes exposed at 220 degrees C. Respective half-life times (tau1/2) decreased from 4.0 to 2.4 and 1.5 h. Thus, higher chlorinated paraffins degrade faster than lower chlorinated ones. In conclusion, exposure of CPs during metal drilling and thermal treatment induced HCl losses and CO formation. It is expected that CPs and COs are co-released from such processes. Full-scan mass spectra and subsequent deconvolution of interfered signals is a promising approach to tackle the CP/CO problem, in case of insufficient mass resolution. PMID- 29253826 TI - This girl can #jointhemovement: Effectiveness of physical functionality-focused campaigns for women's body satisfaction and exercise intent. AB - We tested the effectiveness of exposure to two functionality-focused media campaigns, This Girl Can and #jointhemovement, in improving state appearance and physical functionality satisfaction, exercise intent, and protecting against exposure to idealised imagery. Across two studies, 339 (Mage=24.94, SD=4.98) and 256 (Mage=26.46, SD=5.50) women viewed the campaign or control video, followed by images of models who were posed or physically active, or images of landscapes. State satisfaction and exercise intent was measured at pre-test, post-video, post images, and 1-week follow-up. Social comparison was measured at post-images. Viewing either campaign produced higher appearance satisfaction and exercise intentions than the control video. Effects weren't maintained after viewing idealised imagery or 1 week later. Further, the campaigns did not decrease social comparisons when viewing idealised imagery. Results can inform agencies about campaign effectiveness and suggest that women benefit from campaigns that feature non-idealised depictions of women exercising. PMID- 29253827 TI - Changes of hematological and biochemical parameters revealed genotoxicity and immunotoxicity of neonicotinoids on Chinese rare minnows (Gobiocypris rarus). AB - Adverse impacts of immunity in terrestrial non-target organisms exposed to neonicotinoid insecticides have been reported, but the causal link between insecticide exposure and possible immune alterations in fish remains limited. In the present study, the potential genotoxicity and immunotoxicity of three neonicotinoids (imidacloprid, nitenpyram, and dinotefuran) were assessed in Chinese rare minnows by using a 60-day chronic toxicity test. The hematological and biochemical parameters of juvenile Chinese rare minnows and changes in the transcription of six inflammation-related genes were determined after exposure to neonicotinoids at 0.1, 0.5, or 2.0 mg/L. A clear difference in the frequency of erythrocytes with micronuclei (MN) was observed after treatment with 2.0 mg/L imidacloprid (p < .05). Additionally, exposure to 0.5 or 2.0 mg/L imidacloprid significantly increased the binucleated (BN) erythrocytes and those with notched nuclei (NT) (p < .05). A serum protein electrophoresis (SPE) assay showed significant alterations in the serum protein in all treatments (p < .05), and further analysis indicated decreases in immunoglobulin (Ig) in treatments with 0.5 or 2.0 mg/L imidacloprid or dinotefuran or with 0.1 mg/L nitenpyram (p < .05). Moreover, a biochemical assay confirmed that immunoglobulin M (IgM) levels were indeed significantly decreased upon treatment with imidacloprid or dinotefuran at 0.5 or 2.0 mg/L (p < .05). In addition, the transcriptional levels of the inflammatory cytokines IL-6, INF-alpha, TNF-alpha, and IL-1beta were markedly down-regulated after all imidacloprid treatments (p < .05), whereas the expression levels of only TNF-alpha and IL-1beta were significantly down regulated following the 0.5 and 2.0 mg/L dinotefuran treatments (p < .05). Taken together, our results clearly demonstrate that imidacloprid, rather than nitenpyram and dinotefuran, can induce genotoxicity. The responsiveness of these immune indicators provides new insight into and evidence of the adverse effects of neonicotinoids on aquatic non-target organisms. PMID- 29253828 TI - Prenatal maternal stress is associated with toddler cognitive functioning: The Iowa Flood Study. PMID- 29253829 TI - Additional experimental and epidemiologic studies for evaluating pathogenecity of Kudoa septempunctata should be needed. PMID- 29253830 TI - Dietary exposure to methylmercury affects flight endurance in a migratory songbird. AB - Although there has been much speculation in the literature that methylmercury (MeHg) exposure can reduce songbird fitness, little is known about its effects on migration. Migrating songbirds typically make multiple flights, stopping to refuel for short periods between flights. How refueling at MeHg-contaminated stopover sites would contribute to MeHg bioaccumulation, and how such exposure could affect subsequent flight performance during migration has not been determined. In a dosing experiment we show that migratory yellow-rumped warblers (Setophaga coronata) rapidly accumulate dietary MeHg in blood, brain and muscle, liver and kidneys in just 1-2 weeks. We found that exposure to a 0.5 ppm diet did not affect vertical takeoff performance, but in 2-h wind tunnel flights, MeHg treated warblers had a greater median number of strikes (landing or losing control) in the first 30 min, longer strike duration, and shorter flight duration. The number of strikes in the first 30 min of 0.5 ppm MeHg-exposed warblers was related to mercury concentration in blood in a sigmoid, dose dependent fashion. Hyperphagic migratory songbirds may potentially bioaccumulate MeHg rapidly, which can lead to decreased migratory endurance flight performance. PMID- 29253831 TI - Feasibility of coupled empirical and dynamic modeling to assess climate change and air pollution impacts on temperate forest vegetation of the eastern United States. AB - Changes in climate and atmospheric nitrogen (N) deposition caused pronounced changes in soil conditions and habitat suitability for many plant species over the latter half of the previous century. Such changes are expected to continue in the future with anticipated further changing air temperature and precipitation that will likely influence the effects of N deposition. To investigate the potential long-term impacts of atmospheric N deposition on hardwood forest ecosystems in the eastern United States in the context of climate change, application of the coupled biogeochemical and vegetation community model VSD+PROPS was explored at three sites in New Hampshire, Virginia, and Tennessee. This represents the first application of VSD+PROPS to forest ecosystems in the United States. Climate change and elevated (above mid-19th century) N deposition were simulated to be important factors for determining habitat suitability. Although simulation results suggested that the suitability of these forests to support the continued presence of their characteristic understory plant species might decline by the year 2100, low data availability for building vegetation response models with PROPS resulted in uncertain results at the extremes of simulated N deposition. Future PROPS model development in the United States should focus on inclusion of additional foundational data or alternate candidate predictor variables to reduce these uncertainties. PMID- 29253832 TI - A critical review of selenium biogeochemical behavior in soil-plant system with an inference to human health. AB - Selenium (Se) is an essential trace element for humans and animals, although controversial for different plant species. There exists a narrow line between essential, beneficial and toxic levels of Se to living organisms which greatly varies with Se speciation, as well as the type of living organisms. Therefore, it is crucial to monitor its solid- and solution-phase speciation, exposure levels and pathways to living organisms. Consumption of Se-laced food (cereals, vegetables, legumes and pulses) is the prime source of Se exposure to humans. Thus, it is imperative to assess the biogeochemical behavior of Se in soil-plant system with respect to applied levels and speciation, which ultimately affect Se status in humans. Based on available relevant literature, this review traces a plausible link among (i) Se levels, sources, speciation, bioavailability, and effect of soil chemical properties on selenium bioavailability/speciation in soil; (ii) role of different protein transporters in soil-root-shoot transfer of Se; and (iii) speciation, metabolism, phytotoxicity and detoxification of Se inside plants. The toxic and beneficial effects of Se to plants have been discussed with respect to speciation and toxic/deficient concentration of Se. We highlight the significance of various enzymatic (catalase, peroxidase, superoxide dismutase, ascorbate peroxidase, glutathione peroxidase) and non-enzymatic (phytochelatins and glutathione) antioxidants which help combat Se-induced overproduction of reactive oxygen species (ROS). The review also delineates Se accumulation in edible plant parts from soils containing low or high Se levels; elucidates associated health disorders or risks due to the consumption of Se deficient or Se-rich foods; discusses the potential role of Se in different human disorders/diseases. PMID- 29253833 TI - Gene hypermethylation in blood leukocytes in humans long term after radiation exposure - Validation set. AB - : Hypermethylation of SpG islands in the promoter regions of several genes with basic protective function in blood leukocytes of individuals exposed to ionizing radiation long time ago (2-46 years), and differential effects of age and radiation exposure on hypermethylation was reported in our previous work. To validate these results, epigenetic modifications were assessed in an independent series of 49 nuclear industry workers from the "Mayak" facility (67-84 years old at sampling) with documented individual accumulated doses from the prolonged external gamma-radiation exposure (95.9-409.5 cGy, end of work with radiation:0.3 39 years ago), and in 50 non-exposed persons matched by age. In addition to the genes analyzed before (RASSF1A, p16/INK4A, p14/ARF, GSTP1), four additional loci were analyzed: TP53, ATM, SOD3, ESR1. The frequency of individuals displaying promoter methylation of at least one of the 8 genes (71.4%) was significantly higher in exposed group as compared to the control group (40%), p = .002, OR = 3.75. A significantly elevated frequency of individuals with hypermethylated SpG islands in GSTP1, TP53, SOD3 promoters was revealed among exposed subjects as compared to the control group (p = .012, OR = 8.41; p = .041, OR = 4.02 and p = .009, OR = 3.42, respectively). A similar trend (p = .12, OR = 3.06) was observed for the p16/INK4A gene. As a whole, p16/INK4A and GSTP1 promoter hypermethylation in irradiated subjects from both previously and currently analyzed groups was pronounced. Thus, the direction of the effects was fully confirmed, suggesting the result reproducibility. No statistically significant correlation between promoter methylation and individual radiation dose was found. Further studies are required to create an array of blood epigenetic markers of radiation exposure associating with premature aging and age-related diseases and to accurately evaluate radiation-added effect across the range of doses. SYNTHESIS: The results of studies of epigenetic changes in two independent samples of irradiated subjects indicated the significance of radiation factor in the induction of hypermethylation of CpG islands in gene promoters that is revealed in blood cells years and decades after exposure. PMID- 29253834 TI - Performance evaluation of the Aptima HSV-1 and 2 assay for the detection of HSV in cutaneous and mucocutaneous lesion specimens. AB - BACKGROUND: Timely and precise laboratory diagnosis of Herpes simplex viruses (HSV) is required to guide clinical management. OBJECTIVES: The study evaluated limit of detection (LOD) and performance characteristics of the Aptima HSV 1 & 2 assay in comparison to four assays. STUDY DESIGN: The multi-center study compared qualitative detection of HSV-1 and 2 by the Aptima HSV-1 and 2 assay (Hologic) to ELVIS culture, Lyra Direct (Quidel), AmpliVue (Quidel) and a laboratory developed test (LDT). LOD was performed using VTM and STM diluted viral concentrations and clinical performance was evaluated using 505 swab specimens. RESULTS: The Aptima LOD studies performed showed a lower detection limit for STM specimens as 1450 copies/mL and 430 copies/mL for HSV1 and HSV-2 respectively; the LOD for VTM specimens was 9370 copies/mL and 8045 copies/mL for HSV-1 and HSV-2 respectively. When the assays were analyzed based on the positive consensus result established the Aptima had 95% of percent positive agreement (PPA) and 100% negative percent agreement (NPA) for the HSV-1. For the HSV-2, the PPA and NPA for Aptima were 96% and 100% respectively. AmpliVue had 1.8% invalid rate, while Lyra had no invalid results but an inhibition rate of 0.8%. Aptima and LDT did not have any invalid or inhibited results. CONCLUSION: The results indicate that the Aptima HSV-1 & 2 assay is sensitive and the performance characteristics of the Aptima assay is comparable to the assays analyzed for the detection and differentiation of HSV-1 and 2 from cutaneous and mucocutaneous lesions. PMID- 29253835 TI - Allele frequencies of 15 STR loci (IdentifilerTM kit) in Basque-Americans. AB - Individuals with Basque ancestry form a historically and culturally important minority of the population of the western United States. Allele frequencies for the 15 autosomal STRs in the AmpFlSTR(r) Identifiler(r) PCR Amplification Kit (Applied Biosystems) from 156 unrelated self-identified Basque individuals born in the United States are presented. Allele frequencies were used to calculate parameters commonly used in genetics and forensics including power of discrimination (PD), power of exclusion (PE), polymorphic information content (PIC), and expected heterozygosity (He). The sample population was also compared with the European Basque population and the major American ethnicities. PMID- 29253836 TI - Multi-agent chemotherapy in advanced soft tissue sarcoma (STS) - A systematic review and meta-analysis. AB - BACKGROUND: Despite a lack of improvement in overall survival (OS) with doxorubicin-based combinations over doxorubicin alone in advanced STS, the role of multi-agent chemotherapy remains poorly defined. METHODS: We conducted a systematic review and meta-analysis to evaluate benefits and harms of multi-agent chemotherapy in advanced STS. Eligible studies were randomized trials of chemotherapy in advanced STS comparing single agent to multi-agent therapy. Data from studies reporting a hazard ratio (HR) and 95% confidence intervals (CI) for OS and progression-free survival (PFS) were pooled in a meta-analysis. Meta regression was utilized to explore the association between efficacy (OS and PFS) and both toxicity and dose intensity. RESULTS: We identified 22 trials published between 1974 and April 2016 and comprising 5044 patients. Overall, multi-agent chemotherapy was associated with improved OS (HR:0.79, p = 0.02), and borderline improvement in PFS (HR:0.86, p = 0.05). While the effect on OS was similar in trials with non-anthracycline controls compared to those with anthracycline controls (HR for OS 0.73 vs. 0.82, p for difference = 0.63) there was a non significantly greater effect for multi-agent chemotherapy on PFS in non anthracycline RCT (HR for PFS 0.73 vs. 0.91, p for difference = 0.13). Compared to studies with cytotoxic therapy-based multi-agent therapy, a non-significantly greater magnitude of effect among studies with biological/cytostatic experimental groups was seen (HR for OS 0.64 vs. 0.86, p for difference = 0.37). There was a borderline significant association between dose reductions (which were more common in combination arms) and worse PFS (beta = 0.70, p = 0.053). CONCLUSION: Multi-agent chemotherapy is associated with a modest, but statistically significant improvement in outcomes in STS. Combining chemotherapy with non cytotoxic agents might represent a promising strategy. PMID- 29253837 TI - Aiming for the Insulin-like Growth Factor-1 system in breast cancer therapeutics. AB - Despite the major discoveries occurred in oncology the recent years, breast malignancies remain one of the most common causes of cancer-related deaths for women in developed countries. Development of HER2-targeting drugs has been considered a breakthrough in anti-cancer approaches and alluded to the potential of targeting growth factors in breast cancer (BrCa) therapeutics. More than twenty-five years have passed since the Insulin-like Growth Factor-1 (IGF-1) system was initially recognized as a potential target candidate in BrCa therapy. To date, a growing body of studies have implicated the IGF-1 signaling with the BrCa biology. Despite the promising experimental evidence, the impression from clinical trials is rather disappointing. Several reasons may account for this and the last word regarding the efficacy of this system as a target candidate in BrCa therapeutics is probably not written yet. Herein, we provide the theoretical basis, as well as, a comprehensive overview of the current literature, regarding the different strategies targeting the various components of the IGF-1/IGF-1R axis in several pathophysiological aspects of BrCa, including the tumor micro environment and cancer stemness. In addition, we review the rationale for targeting the IGF-1 system in the different BrCa molecular subtypes and in treatment resistant breast tumors with a focus on both the molecular mechanisms and on the clinical perspectives of such approaches in specific population subgroups. We also discuss the future challenges, as well as, the development of novel molecules and strategies targeting the system and suggest potential improvements in the field. PMID- 29253838 TI - Prognostic significance of disseminated intravascular coagulation in patients with heat stroke in a nationwide registry. AB - PURPOSE: Heat stroke (HS) induces disseminated intravascular coagulation (DIC); however, the prognostic significance of DIC in patients with HS has not yet been fully assessed in large populations. The aim of this study was to examine the prognostic significance of DIC in patients with HS using a nationwide registry. MATERIALS AND METHODS: Data regarding HS were obtained and analyzed from three prospective, observational, multicenter HS registries (HSRs): 2010, 2012, and 2014. Univariate and multivariate analyses were performed to identify independent predictors of hospital death. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) diagnostic criteria, with a total score>=4 implying a DIC diagnosis. RESULTS: In total, 705 (median age, 68years; 501 men) were included in this study. Hospital mortality was 7.1% (50 patients). Multiple regression analysis revealed that hospital mortality was significantly associated with presence of DIC (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.09 4.27; p=0.028). Mortality worsened as the DIC score increased, and increased remarkably to approximately 10% when the DIC score was 2. CONCLUSIONS: Presence of DIC was an independent prognostic factor of hospital mortality in patients with HS. Hematological dysfunction represents potential target for specific therapies in HS. PMID- 29253839 TI - Symptom Signatures and Diagnostic Timeliness in Cancer Patients: A Review of Current Evidence. AB - Early diagnosis is an important aspect of contemporary cancer prevention and control strategies, as the majority of patients are diagnosed following symptomatic presentation. The nature of presenting symptoms can critically influence the length of the diagnostic intervals from symptom onset to presentation (the patient interval), and from first presentation to specialist referral (the primary care interval). Understanding which symptoms are associated with longer diagnostic intervals to help the targeting of early diagnosis initiatives is an area of emerging research. In this Review, we consider the methodological challenges in studying the presenting symptoms and intervals to diagnosis of cancer patients, and summarize current evidence on presenting symptoms associated with a range of common and rarer cancer sites. We propose a taxonomy of cancer sites considering their symptom signature and the predictive value of common presenting symptoms. Finally, we consider evidence on associations between symptomatic presentations and intervals to diagnosis before discussing implications for the design, implementation, and evaluation of public health or health system interventions to achieve the earlier detection of cancer. PMID- 29253840 TI - Muscle recruitment and coordination during upper-extremity functional tests. AB - Performance-based tests, such as the Jebsen Taylor Hand Function Test or Chedoke Arm and Hand Activity Inventory, are commonly used to assess functional performance after neurologic injury. However, the muscle activity required to execute these tasks is not well understood, even for unimpaired individuals. The purpose of this study was to evaluate unimpaired muscle recruitment and coordination of the dominant and non-dominant limbs during common clinical tests. Electromyography (EMG) recordings from eight arm muscles were monitored bilaterally for twenty unimpaired participants while completing these tests. Average signal magnitudes, activation times, and cocontraction levels were calculated from the filtered EMG data, normalized by maximum voluntary isometric contractions (MVICs). Overall, performance of these functional tests required low levels of muscle activity, with average EMG magnitudes less than 6.5% MVIC for all tests and muscles, except the extensor digitorum, which had higher activations across all tasks (11.7 +/- 2.7% MVIC, dominant arm). When averaged across participants, cocontraction was between 25 and 62% for all tests and muscle pairs. Tasks evaluated by speed of completion, rather than functional quality of movement demonstrated higher levels of muscle recruitment. These results provide baseline measurements that can be used to evaluate muscle specific deficits after neurologic injury and track recovery using common clinical tests. PMID- 29253841 TI - Targeting flavin-containing enzymes eliminates cancer stem cells (CSCs), by inhibiting mitochondrial respiration: Vitamin B2 (Riboflavin) in cancer therapy. AB - Here, we performed high-throughput drug-screening to identify new non-toxic mitochondrial inhibitors. This screening platform was specifically designed to detect compounds that selectively deplete cellular ATP levels, but have little or no toxic side effects on cell viability. Using this approach, we identified DPI (Diphenyleneiodonium chloride) as a new potential therapeutic agent. Mechanistically, DPI potently blocks mitochondrial respiration by inhibiting flavin-containing enzymes (FMN and FAD-dependent), which form part of Complex I and II. Interestingly, DPI induced a chemo-quiescence phenotype that potently inhibited the propagation of CSCs, with an IC-50 of 3.2 nano-molar. Virtually identical results were obtained using CSC markers, such as CD44 and CD24. We further validated the effects of DPI on cellular metabolism. At 10 nM, DPI inhibited oxidative mitochondrial metabolism (OXPHOS), reducing mitochondrial driven ATP production by >90%. This resulted in a purely glycolytic phenotype, with elevated L-lactate production. We show that this metabolic inflexibility could be rapidly-induced, after only 1 hour of DPI treatment. Remarkably, the mitochondrial inhibitory effects of DPI were reversible, and DPI did not induce ROS production. Cells maintained in DPI for 1 month showed little or no mitochondrial activity, but remained viable. Thus, it appears that DPI behaves as a new type of mitochondrial inhibitor, which maintains cells in a state of metabolic-quiescence or "suspended animation".In conclusion, DPI treatment can be used to acutely confer a mitochondrial-deficient phenotype, which we show effectively depletes CSCs from the heterogeneous cancer cell population. These findings have significant therapeutic implications for potently targeting CSCs, while minimizing toxic side effects. We also discuss the possible implications of DPI for the aging process. Interestingly, previous studies in C. elegans have shown that DPI prevents the accumulation of lipofuscin (an aging-associated hallmark), during the response to oxidative stress. Our current results are consistent with data showing that flavins (FAD, FMN and/or Riboflavin) are auto fluorescent markers of i) increased mitochondrial "power" (OXPHOS) and ii) elevated CSC activity.Finally, we believe that DPI is one of the most potent and highly selective CSC inhibitors discovered to date. Therefore, our current findings suggest a new impetus to create novel analogues of i) DPI (Diphenyleneiodonium chloride) and ii) DPI-related compounds (Diphenyliodonium chloride), using medicinal chemistry, to optimize this very promising and potent anti-CSC activity. We propose to call these new molecules "Mitoflavoscins".For example, DPI is ~30 times more potent than Palbociclib (IC-50 = 100 nM), which is an FDA-approved CDK4/6 inhibitor, that broadly targets proliferation in any cell type, including CSCs. PMID- 29253842 TI - MicroRNA-939 inhibits cell proliferation via targeting LRSAM1 in Hirschsprung's disease. AB - BackgroundHirschsprung's disease (HSCR) is a common digestive disease caused by impaired development of neural crest cells. Some studies have revealed the roles of microRNA (miRNA) in various diseases. But the function of miRNA in HSCR needs further investigation.MethodsWe adopted qRT-PCR and immunoblot analyses to explore the relative expression of miR-939 and LRSAM1 in 80 HSCR bowel tissues and 80 normal bowel tissues. CCK-8 assay, transwell assay and flow cytometry were used to evaluate the function of miR-939 by overexpression of miR-939 in 293T, SK N-BE(2), SH-SY5Y cell lines. The direct connection between miR-939 and LRSAM1 was validated by dual-luciferase reporter assay. We also investigated the autophagy level via immunoblot analyses.ResultsMir-939 was significantly upregulated in HSCR tissues with decreased expression of LRSAM1. Overexpression of miR-939 suppressed cell proliferation without affecting cell apoptosis, cell cycle or cell migration. And LRSAM1 exerted similar function. Autophagy was impaired in HSCR tissues compared with control samples. Mir-939 did not inhibit the autophagy although it decreased the expression of LRSAM1.ConclusionsOur study shows the potential function of mir-939 through regulating LRSAM1 in HSCR and infers that autophagy may also confer the risk of HSCR. PMID- 29253844 TI - Factors Associated with Chronic Kidney Disease and Their Clinical Utility in Primary Care Clinics in a Multi-Ethnic Southeast Asian Population. AB - BACKGROUND: Chronic kidney disease (CKD) is a major global public health challenge. We investigated determinants of CKD and their clinical utility in an ethnically diverse Southeast Asian population. METHODS: Electronic health records (EHR) of adults >=40 years who visited any one of 4 government polyclinics in Singapore from January 1, 2012 to -December 31, 2015 were analyzed. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2 or 1+ dipstick proteinuria excretion, based on 2 measurements >=3 months apart. CKD associated factors and their clinical utility for predicting odds of CKD were investigated using multiple logistic regression analysis. RESULTS: Based on the study criteria, 25.9% (95% CI 25.6-26.2) of the 88,765 eligible study individuals had CKD. The factors (OR and 95% CI) independently associated with CKD were older age >=65 years (2.54 [2.44-2.64] vs. <=65 years), respectively; men (1.13 [1.09 1.18]); Malay (1.27 [1.20-1.33]) and Indian (0.77 [0.71-0.83]) vs. Chinese ethnicity; overweight (body mass index [BMI] >=27.5 kg/m2; 1.10 [1.04-1.16]) vs. normal weight (BMI 18 to <23 kg/m2); government (1.22 [1.15-1.31]) vs. private housing; and with hypertension (3.32 [3.09-3.56]), diabetes (6.93 [6.67-7.20]) or stroke (1.46 [1.36-1.56]) vs. without each co-morbidity, respectively. The area under the receiver operating characteristic curve (95% CI) for the model to predict the probability of CKD using hypertension, diabetes, and age was 0.808 (0.805-0.811). Only 28.5% (27.9-29.1%) of individuals with CKD had physician documentation of their CKD status. However, documentation of CKD status was associated with age >=65 years (1.11 [1.04-1.20] vs. <65 years), men (1.35 [1.26 1.44]) vs. women, with vs. without hypertension (1.24 [1.07-1.44]), Indian (0.80 [0.69-0.92]) compared to Chinese ethnicity, ever smokers (0.89 [0.81-0.99]) vs. non-smokers, and those with vs. without stroke (0.83 [0.75-0.93]). CONCLUSIONS: CKD prevalence in our Southeast Asian population is high and under-documented even in high-risk patients. Our findings highlight factors associated with CKD, and the predictive value of hypertension, diabetes, and advancing age as EHR based screening targets for CKD. Our results also suggest that complementary educational efforts will be needed to increase physician detection and optimize the management of CKD, especially in high risk and marginalized groups across all clinics in Singapore, and possibly in the region. PMID- 29253843 TI - ICS Use May Modify FEV1 Decline in alpha1-Antitrypsin Deficiency Patients with Relatively High Blood Eosinophils. AB - BACKGROUND: alpha1-Antitrypsin deficiency (AATD) predisposes to chronic obstructive pulmonary disease (COPD). In COPD unrelated to AATD, the role of a higher blood eosinophil count in disease and subsequent personalization of therapy has recently received much attention. We sought to investigate this concept in patients with AATD-associated COPD. OBJECTIVES: The study aims to evaluate eosinophilia status against outcomes including mortality and FEV1 decline in patients with AATD. METHODS: All patients with PiSZ and PiZZ genotypes were identified from the UK AATD registry. The participants were substratified according to inhaled corticosteroid (ICS) use. Blood eosinophil counts were assessed from baseline and annually during follow-up (range 1-18 years). Eosinophilia was defined as a level >0.2 * 109/L, and classified by the frequency of such counts into "always," "intermittent," or "never present." Univariate and multivariate analyses were conducted. RESULTS: In total, 646 participants were included, 53.9% of whom demonstrated intermittent and 7.4% persistent eosinophilia. Survival did not differ according to eosinophilic group (p > 0.05). Those with persistent eosinophilia showed a slower FEV1 decline (p < 0.001). There was no clear association with exacerbation frequency. Patients on ICS at baseline were more likely to be eosinophilic (p = 0.002) and having a lower FEV1 (p < 0.001) and greater pack-year exposure (16.5 vs. 7.8 pack-years, p < 0.001). When the multivariate analyses of FEV1 decline were stratified for baseline ICS use, the association of persistent eosinophilia with slower decline persisted in those on ICS. CONCLUSIONS: Blood eosinophil levels persistently >0.2 * 109/L may be an indication for ICS use in PiZZ AATD in order to reduce FEV1 decline. PMID- 29253845 TI - Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Beta1 Expression in Macrophage. AB - BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment. METHODS: The expression and distribution patterns of PAI-1 and transforming growth factor beta (TGF-beta) were measured in 60 non-small cell lung cancer (NSCLC) tumors. A statistical correlation analysis was performed between PAI-1 and TGF-beta expression and distribution in each tumor. The distribution of tumor-associated macrophages (TAMs) was also measured and its correlation to PAI-1 levels was analyzed. Levels of secreted CCL-17, CCL-22, IL-6 and TGF-beta were measured in cell cultures of human macrophage cell lines THP-1 and U937 treated with PAI-1. Levels of secreted PAI-1 were monitored in cell cultures of human NSCLCs cell lines 95D and A549 treated with TGF-beta. Secreted proteins were measured in cell culture supernatants using ELISA. Changes in downstream signaling pathways were investigated using western blot. RESULTS: PAI-1 and TGF-beta were found to be overexpressed in human NSCLCs. PAI-1 expression was tightly correlated to TGF beta expression as well as the percentage of TAMs. PAI-1 treatment increased the expression of TAM-associated cytokines and chemokines, including CCL-17, CCL-22, and IL-6. PAI-1 treatment was also observed to enhance TGF-beta expression in macrophage cell lines through an IL-6 autocrine/paracrine manner. The effects on TGF-beta expression were blocked by NF-kappaB and STAT3 inhibition. Interestingly, TGF-beta also increased levels of secreted PAI-1 in NSCLC cells through SMAD3-dependent signaling, therefore resulting in a feed-forward loop. However, this loop could be blocked by NF-kappaB, STAT3 and SMAD3 signaling inhibition, as well as treatment with a high concentration of TGF-beta. CONCLUSION: PAI-1 and TGF-beta promote NSCLC tumor cells and TAMs and might be valuable targets for cancer immunosuppression. PMID- 29253847 TI - A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of Nalbuphine ER Tablets for Uremic Pruritus. AB - BACKGROUND: Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at MU and kappa-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a MU-opioid antagonist and kappa-opioid agonist. METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. RESULTS: The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (p = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (p = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. CONCLUSIONS: In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients. PMID- 29253848 TI - Filament turnover tunes both force generation and dissipation to control long range flows in a model actomyosin cortex. AB - Actomyosin-based cortical flow is a fundamental engine for cellular morphogenesis. Cortical flows are generated by cross-linked networks of actin filaments and myosin motors, in which active stress produced by motor activity is opposed by passive resistance to network deformation. Continuous flow requires local remodeling through crosslink unbinding and and/or filament disassembly. But how local remodeling tunes stress production and dissipation, and how this in turn shapes long range flow, remains poorly understood. Here, we study a computational model for a cross-linked network with active motors based on minimal requirements for production and dissipation of contractile stress: Asymmetric filament compliance, spatial heterogeneity of motor activity, reversible cross-links and filament turnover. We characterize how the production and dissipation of network stress depend, individually, on cross-link dynamics and filament turnover, and how these dependencies combine to determine overall rates of cortical flow. Our analysis predicts that filament turnover is required to maintain active stress against external resistance and steady state flow in response to external stress. Steady state stress increases with filament lifetime up to a characteristic time taum, then decreases with lifetime above taum. Effective viscosity increases with filament lifetime up to a characteristic time tauc, and then becomes independent of filament lifetime and sharply dependent on crosslink dynamics. These individual dependencies of active stress and effective viscosity define multiple regimes of steady state flow. In particular our model predicts that when filament lifetimes are shorter than both tauc and taum, the dependencies of effective viscosity and steady state stress on filament turnover cancel one another, such that flow speed is insensitive to filament turnover, and shows a simple dependence on motor activity and crosslink dynamics. These results provide a framework for understanding how animal cells tune cortical flow through local control of network remodeling. PMID- 29253849 TI - Characterization of CobB kinetics and inhibition by nicotinamide. AB - Lysine acetylation has emerged as a global protein regulation system in all domains of life. Sirtuins, or Sir2-like enzymes, are a family of histone deacetylases characterized by their employing NAD+ as a co-substrate. Sirtuins can deacetylate several acetylated proteins, but a consensus substrate recognition sequence has not yet been established. Product inhibition of many eukaryotic sirtuins by nicotinamide and its analogues has been studied in vitro due to their potential role as anticancer agents. In this work, the kinetics of CobB, the main Escherichia coli deacetylase, have been characterized. To our knowledge, this is the first kinetic characterization of a sirtuin employing a fully acetylated and natively folded protein as a substrate. CobB deacetylated several acetyl-CoA synthetase acetylated lysines with a single kinetic rate. In addition, in vitro nicotinamide inhibition of CobB has been characterized, and the intracellular nicotinamide concentrations have been determined under different growth conditions. The results suggest that nicotinamide can act as a CobB regulator in vivo. A nicotinamidase deletion strain was thus phenotypically characterized, and it behaved similarly to the DeltacobB strain. The results of this work demonstrate the potential regulatory role of the nicotinamide metabolite in vivo. PMID- 29253850 TI - Systematic review and meta-analysis of traditional Chinese medicine in the treatment of constipation-predominant irritable bowel syndrome. AB - AIM: This meta-analysis analyzed the efficacy and safety of traditional Chinese medicine (TCM) for the treatment of irritable bowel syndrome with constipation (IBS-C). METHODS: We searched seven electronic databases for randomized controlled trials investigating the efficacy of TCM in the treatment of IBS-C. The search period was from inception to June 1, 2017. Eligible RCTs compared TCM with cisapride and mosapride. Article quality was evaluated with the Cochrane Risk Bias Tool in the Cochrane Handbook by two independent reviewers. Begg's test was performed to evaluate publication bias. Review Manager 5.3 and Stata 12.0 were used for analyses. RESULTS: Eleven eligible studies comprising a total of 906 participants were identified. In the primary outcome, TCM showed significant improvement in overall clinical efficacy compared with cisapride and mosapride (odds ratio [OR] = 4.00; 95% confidence interval [CI]: 2.74,5.84; P < 0.00001). In terms of secondary outcomes, TCM significantly alleviated abdominal pain (OR = 5.69; 95% CI: 2.35, 13.78; P = 0.0001), defecation frequency (OR = 4.38; 95% CI: 1.93, 9.93. P = 0.0004), and stool form (OR = 4.96; 95% CI: 2.11, 11.65; P = 0.0002) in the treatment group as compared to the control group. A lower recurrence rate was associated with TCM as compared to cisapride and mosapride (OR = 0.15; 95% CI: 0.08, 0.27; P < 0.00001). No adverse effects were observed during TCM treatment. CONCLUSIONS: TCM showed greater improvement in terms of clinical efficacy in the treatment of IBS-C than cisapride and mosapride, although it was not possible to draw a definitive conclusion due to the small sample size, high risk, and low quality of the studies. Large multi-center and long-term high-quality randomized control trials are needed. PMID- 29253852 TI - Correction of failure in linear antenna arrays with greedy sparseness constrained optimization technique. AB - This paper proposes the correction of faulty sensors using a synthesis of the greedy sparse constrained optimization GSCO) technique. The failure of sensors can damage the radiation power pattern in terms of sidelobes and nulls. The synthesis problem can recover the wanted power pattern with reduced number of sensors into the background of greedy algorithm and solved with orthogonal matching pursuit (OMP) technique. Numerical simulation examples of linear arrays are offered to demonstrate the effectiveness of getting the wanted power pattern with a reduced number of antenna sensors which is compared with the available techniques in terms of sidelobes level and number of nulls. PMID- 29253853 TI - Familial episodic ataxia in lambs is potentially associated with a mutation in the fibroblast growth factor 14 (FGF14) gene. AB - Familial episodic ataxia of lambs is a congenital transient autosomal dominant disorder of newborn lambs, with varying expressivity. Affected lambs show episodes of an asymmetric ataxic gait, base-wide extensor hypertonia of the thoracic limbs and flexor hypertonia of the pelvic limbs. The aim of the study was to determine the genetic variant causing familial episodic ataxia in lambs. Using whole genome sequencing of two half-sib affected lambs, their sire, and their two normal dams, a heterozygous C>T transition at OAR10:77593415 (Oar_v3.1) in exon 1 of the fibroblast growth factor 14 (FGF14) gene (c.46C>T) was identified. The c.46C>T transition resulted in a premature stop codon at position 16 of the 247 amino acid FGF14 protein (p.Q16*). PCR and Sanger sequencing was used to genotype an additional 20 clinically affected animals, demonstrating all lambs carried the c.46C>T variant but 1 clinically more severely affected inbred lamb was homozygous (TT). A further 11 unrelated normal ewes were positionally sequenced, none of which had the variant, while in 18 lambs of unknown status born over 2 years of breeding trials six lambs were found to have the c.46C>T variant, likely clinically unidentified heterozygotes due to the variable expressivity, while 12 did not. In conclusion, familial episodic ataxia of lambs is potentially associated with a c.46C>T variant in the FGF14 gene. Further research is required into the mechanism behind the apparent recovery of lambs. PMID- 29253851 TI - eCD4-Ig promotes ADCC activity of sera from HIV-1-infected patients. AB - Antibody-dependent cell-mediated cytotoxity (ADCC) can eliminate HIV-1 infected cells, and may help reduce the reservoir of latent virus in infected patients. Sera of HIV-1 positive individuals include a number of antibodies that recognize epitopes usually occluded on HIV-1 envelope glycoprotein (Env) trimers. We have recently described eCD4-Ig, a potent and exceptionally broad inhibitor of HIV-1 entry that can be used to protect rhesus macaques from multiple high-dose challenges with simian-human immunodeficiency virus AD8 (SHIV-AD8). Here we show that eCD4-Ig bearing an IgG1 Fc domain (eCD4-IgG1) can mediate efficient ADCC activity against HIV-1 isolates with differing tropisms, and that it does so at least 10-fold more efficiently than CD4-Ig, even when more CD4-Ig molecules bound cell surface-expressed Env. An ADCC-inactive IgG2 form of eCD4-Ig (eCD4-IgG2) exposes V3-loop and CD4-induced epitopes on cell-expressed trimers, and renders HIV-1-infected cells susceptible to ADCC mediated by antibodies of these classes. Moreover, eCD4-IgG2, but not IgG2 forms of the broadly neutralizing antibodies VRC01 and 10-1074, enhances the ADCC activities of serum antibodies from patients by 100-fold, and significantly enhanced killing of two latently infected T-cell lines reactivated by vorinostat or TNFalpha. Thus eCD4-Ig is qualitatively different from CD4-Ig or neutralizing antibodies in its ability to mediate ADCC, and it may be uniquely useful in treating HIV-1 infection or reducing the reservoir of latently infected cells. PMID- 29253854 TI - Human Neutrophil Peptide 1 as immunotherapeutic agent against Leishmania infected BALB/c mice. AB - Human Neutrophil Peptide 1 (HNP1) produced by neutrophils, is a well-known antimicrobial peptide which plays a role both in innate as well as in adaptive immunity and is under intensive investigation as a potential therapeutic agent. Previous in vitro experiments have indicated the leishmaniacidal effect of recombinant HNP1 on Leishmania major (L. major) promastigotes and amastigotes. In the current study, we further extended the idea to explore the remedial effect of HNP1 in the two modalities of peptide therapy (folded HNP1) and gene therapy in L. major infected BALB/c mice. To this end, mice in five different groups received synthetic folded HNP1 (G1), pcDNA-HNP1-EGFP (G2), pcDNA-EGFP (G3), Amphotericin B (G4) and PBS (G5), which was started three weeks after infection for three consecutive weeks. Footpad swelling was monitored weekly and a day after the therapy ended, IFN-gamma, IL-4, IL-10, IL-6 and nitric oxide produced by splenocytes were analyzed together with the parasite load in draining lymph nodes. Arginase activity and dermal histopathological changes were also analyzed in the infected footpads. We demonstrated that both therapeutic approaches effectively induced Th1 polarization and restricted parasite burden. It can control disease progression in contrast to non-treated groups. However, pcDNA HNP1-EGFP is more promising in respect to parasite control than folded HNP1, but less effective than AmB treatment. We concluded with the call for a future approach, that is, a DNA-based expression of HNP1 combined with AmB as it can improve the leishmaniacidal efficacy. PMID- 29253855 TI - Racism and health service utilisation: A systematic review and meta-analysis. AB - Although racism has been posited as driver of racial/ethnic inequities in healthcare, the relationship between racism and health service use and experience has yet to be systematically reviewed or meta-analysed. This paper presents a systematic review and meta-analysis of quantitative empirical studies that report associations between self-reported racism and various measures of healthcare service utilisation. Data were reviewed and extracted from 83 papers reporting 70 studies. Studies included 250,850 participants and were conducted predominately in the U.S. The meta-analysis included 59 papers reporting 52 studies, which were analysed using random effects models and mean weighted effect sizes. Racism was associated with more negative patient experiences of health services (HSU-E) (OR = 0.351 (95% CI [0.236,0.521], k = 19), including lower levels of healthcare related trust, satisfaction, and communication. Racism was not associated with health service use (HSU-U) as an outcome group, and was not associated with most individual HSU-U outcomes, including having had examinations, health service visits and admissions to health professionals and services. Racism was associated with health service use outcomes such as delaying/not getting healthcare, and lack of adherence to treatment uptake, although these effects may be influenced by a small sample of studies, and publication bias, respectively. Limitations to the literature reviewed in terms of study designs, sampling methods and measurements are discussed along with suggested future directions in the field. PMID- 29253856 TI - Fundamental properties of the mammalian innate immune system revealed by multispecies comparison of type I interferon responses. AB - The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provide an immediate barrier to virus infection. Studies of the type I 'interferome' have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Here, using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species and developed a webserver to mine the dataset. This approach revealed a conserved 'core' of 62 ISGs, including genes not previously associated with IFN, underscoring the ancestral functions associated with this antiviral host response. We show that gene expansion contributes to the evolution of the IFN system and that interferomes are shaped by lineage-specific pressures. Consequently, each mammal possesses a unique repertoire of ISGs, including genes common to all mammals and others unique to their specific species or phylogenetic lineages. An analysis of genes commonly down-regulated by IFN suggests that epigenetic regulation of transcription is a fundamental aspect of the IFN response. Our study provides a resource for the scientific community highlighting key paradigms of the type I IFN response. PMID- 29253857 TI - Forced sexual intercourse and its association with HIV status among people attending HIV Voluntary Counseling and Testing in a healthcare center in Kinshasa (DRC). AB - INTRODUCTION: Sexual violence, an HIV determinant, is an integrated behavior in the D.R.Congo. We aimed to analyze the prevalence of forced sexual intercourse (FSI) among people receiving HIV Voluntary Counseling and Testing in a hospital in Kinshasa, and its association with socio-demographics, behaviors and HIV status. METHODOLOGY: Case-control study (2010-2012). Two-hundred and seventy-four cases with a new HIV+ test and 1,340 controls with an HIV- test were interviewed about HIV-related knowledge, attitudes and behaviors, including FSI. RESULTS: Thirty-four percent of the participants declared having had FSI (38% of women and 32% of men). Being a woman, aged 25-49 and reporting multiple sexual partners were associated with reporting FSI. For men, being single was protective against FSI; and cohabiting, having a high socioeconomic status, and alcohol consumption increased the odds. For women, being single, divorced/separated and widow was associated with reporting FSI. A significant positive association was found between FSI and an HIV positive test. CONCLUSION: Among our Congolese population, FSI was strongly associated with HIV infection and it was also associated with alcohol consumption and multiple sexual partnerships, other key HIV determinants. These behaviors need to be identified as potential risk factors of FSI during counseling interventions. Researchers, practitioners and decision-makers should work together to get violence prevention integrated into health, social and educational policies. PMID- 29253858 TI - A family-based genome-wide association study of chronic rhinosinusitis with nasal polyps implicates several genes in the disease pathogenesis. AB - BACKGROUND: The pathogenesis of chronic rhinosinusitis with nasal polyps is largely unknown. Previous studies have given valuable information about genetic variants associated with this disease but much is still unexplained. Our goal was to identify genetic markers and genes associated with susceptibility to chronic rhinosinusitis with nasal polyps using a family-based genome-wide association study. METHODS: 427 patients (293 males and 134 females) with CRSwNP and 393 controls (175 males and 218 females) were recruited from several Swedish hospitals. SNP association values were generated using DFAM (implemented in PLINK) and Efficient Mixed Model Association eXpedited (EMMAX). Analyses of pathway enrichment, gene expression levels and expression quantitative trait loci were then performed in turn. RESULTS: None of the analysed SNPs reached genome wide significant association of 5.0 x 10-8. Pathway analyses using our top 1000 markers with the most significant association p-values resulted in 138 target genes. A comparison between our target genes and gene expression data from the NCBI Gene Expression Omnibus database showed significant overlap for 36 of these genes. Comparisons with data from expression quantitative trait loci showed the most skewed allelic distributions in cases with chronic rhinosinusitis with nasal polyps compared with controls for the genes HLCS, HLA-DRA, BICD2, VSIR and SLC5A1. CONCLUSION: Our study indicates that HLCS, HLA-DRA, BICD2, VSIR and SLC5A1 could be involved in the pathogenesis of chronic rhinosinusitis with nasal polyps. HLA-DRA has been associated with chronic rhinosinusitis with nasal polyps in previous studies and HLCS, BICD2, VSIR and SLC5A1 may be new targets for future research. PMID- 29253846 TI - The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. AB - BACKGROUND: People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease. METHODS: The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin -versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ~5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate >=30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to <=5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (alpha = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death. CONCLUSION: CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease. TRIAL REGISTRATION: EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791. PMID- 29253859 TI - Association of the urinary sodium to urinary specific gravity ratio with metabolic syndrome in Korean children and adolescents: The Korea National Health and Nutrition Examination Survey 2010-2013. AB - OBJECTIVES: This study aimed to evaluate the association between sodium intake and metabolic syndrome (MetS) in Korean boys. METHODS: A total of 1,738 boys aged 10-18 years were included in this study from the Korea National Health and Nutrition Examination Survey (KNHANES) during the years 2010-2013. Sodium intake was assessed using the urinary sodium excretion to urinary specific gravity ratio (U-Na to U-SG ratio). RESULTS: The median U-Na to U-SG ratio was 133.27 mmol/L (interquartile range: 95.66-178.50 mmol/L). Significant positive associations were found between the U-Na to U-SG ratio and the TG (P = 0.001 for trend) and TG concentrations, and these concentrations were significantly higher in boys with a U-Na to U-SG ratio in the highest quartile compared with those with a ratio in the lowest (P = 0.001) and second (P = 0.033) quartiles, as demonstrated through analysis of covariance (ANCOVA) after adjustment for possible confounders, including age, BMI standard deviation score, ferritin, vitamin D, house income, smoking, alcohol intake, physical activity, season, total intake, total energy intake, protein intake, fat intake, carbohydrate intake, and water intake. Significant inverse associations were found for the U-Na to U-SG ratio with the HDL-C (P = 0.033 for trend) and HDL-C levels, and these values were significantly lower in boys with a ratio in the highest quartile compared with those with a ratio in the second quartile (P = 0.020), as demonstrated through an ANCOVA. Although the trends did not reach statistical significance, a higher U-Na to U-SG ratio tended to be associated with higher SBP (P = 0.086 for trend), DBP (P = 0.063 for trend), and glucose levels (P = 0.099 for trend), as illustrated through ANCOVA. Boys with a ratio in the highest quartile exhibited a 1.73-fold increased risk for elevated TG (95% CI, 1.19-2.51) and a 2.66-fold increased risk for MetS (95% CI, 1.11-6.35) compared with those with a ratio in the lowest quartile, as demonstrated through multivariate logistic regression analyses after adjusting for confounders. CONCLUSIONS: Our results suggest that high sodium intake may be significantly independently associated with MetS in Korean boys aged 10-18 years. PMID- 29253860 TI - New insights into Trypanosoma cruzi evolution, genotyping and molecular diagnostics from satellite DNA sequence analysis. AB - Trypanosoma cruzi has been subdivided into seven Discrete Typing Units (DTUs), TcI-TcVI and Tcbat. Two major evolutionary models have been proposed to explain the origin of hybrid lineages, but while it is widely accepted that TcV and TcVI are the result of genetic exchange between TcII and TcIII strains, the origin of TcIII and TcIV is still a matter of debate. T. cruzi satellite DNA (SatDNA), comprised of 195 bp units organized in tandem repeats, from both TcV and TcVI stocks were found to have SatDNA copies type TcI and TcII; whereas contradictory results were observed for TcIII stocks and no TcIV sequence has been analyzed yet. Herein, we have gone deeper into this matter analyzing 335 distinct SatDNA sequences from 19 T. cruzi stocks representative of DTUs TcI-TcVI for phylogenetic inference. Bayesian phylogenetic tree showed that all sequences were grouped in three major clusters, which corresponded to sequences from DTUs TcI/III, TcII and TcIV; whereas TcV and TcVI stocks had two sets of sequences distributed into TcI/III and TcII clusters. As expected, the lowest genetic distances were found between TcI and TcIII, and between TcV and TcVI sequences; whereas the highest ones were observed between TcII and TcI/III, and among TcIV sequences and those from the remaining DTUs. In addition, signature patterns associated to specific T. cruzi lineages were identified and new primers that improved SatDNA-based qPCR sensitivity were designed. Our findings support the theory that TcIII is not the result of a hybridization event between TcI and TcII, and that TcIV had an independent origin from the other DTUs, contributing to clarifying the evolutionary history of T. cruzi lineages. Moreover, this work opens the possibility of typing samples from Chagas disease patients with low parasitic loads and improving molecular diagnostic methods of T. cruzi infection based on SatDNA sequence amplification. PMID- 29253861 TI - Bicarbonate buffered peritoneal dialysis fluid upregulates angiopoietin-1 and promotes vessel maturation. AB - BACKGROUND: Ultrafiltration decline is a progressive issue for patients on chronic peritoneal dialysis (PD) and can be caused by peritoneal angiogenesis induced by PD fluids. A recent pediatric trial suggests better preservation of ultrafiltration with bicarbonate versus lactate buffered fluid; underlying molecular mechanisms are unknown. METHODS: Angiogenic cytokine profile, tube formation capacity and Receptor Tyrosine Kinase translocation were assessed in primary human umbilical vein endothelial cells following incubation with bicarbonate (BPDF) and lactate buffered (LPDF), pH neutral PD fluid with low glucose degradation product content and lactate buffered, acidic PD fluid with high glucose degradation product content (CPDF). Peritoneal biopsies from age-, PD-vintage- and dialytic glucose exposure matched, peritonitis-free children on chronic PD underwent automated histomorphometry and immunohistochemistry. RESULTS: In endothelial cells angiopoietin-1 mRNA and protein abundance increased 200% upon incubation with BPDF, but decreased by 70% with LPDF as compared to medium control; angiopoietin-2 remained unchanged. Angiopoietin-1/Angiopoietin-2 protein ratio was 15 and 3-fold increased with BPDF compared to LPDF and medium. Time-lapse microscopy with automated network analysis demonstrated less endothelial cell tube formation with BPDF compared to LPDF and CPDF incubation. Receptor Tyrosine Kinase translocated to the cell membrane in BPDF but not in LPDF or CPDF incubated endothelial cells. In children dialyzed with BPDF peritoneal vessels were larger and angiopoietin-1 abundance in CD31 positive endothelium higher compared to children treated with LPDF. CONCLUSION: Bicarbonate buffered PD fluid promotes vessel maturation via upregulation of angiopoietin-1 in vitro and in children on dialysis. Our findings suggest a molecular mechanism for the observed superior preservation of ultrafiltration capacity with bicarbonate buffered PD fluid with low glucose degradation product content. PMID- 29253862 TI - The interruption of Onchocerca volvulus and Wuchereria bancrofti transmission by integrated chemotherapy in the Obongi focus, North Western Uganda. AB - INTERVENTION: Few studies have documented the interruption of onchocerciasis and Lymphatic Filariasis (LF) by integrated chemotherapy in Uganda. The study describes the interruption of transmission of the two diseases co-endemic in Obongi focus, north western Uganda. Base line data for Onchocerciasis and LF were collected in 1994 and 2006, respectively. Annual mass drug administration for onchocerciasis (Ivermectin) and Lymphatic Filariasis (Ivermectin + albendazole) was conducted for 20 and 6 years, respectively. Thereafter, assessments by skin snip, larval searches in rivers and human landing catches were performed. Children <10 years were screened for IgG4 antibodies using Ov16 ELISA technique in 2013. LF Pre-TAS and TAS1 were conducted in sentinel sites. ITN coverage and utilization for the implementation unit was also reported. INTERVENTION COVERAGE: Onchocerciasis treatment coverage was <80% but improved with the introduction of CDTI in 1999. While for LF, effective coverage of >65% was achieved in the six treatment rounds. Household ownership of ITN's and utilization was 96% and 72.4%., respectively. IMPACT: Parasitological examinations conducted for onchocerciasis among 807 adults and children, revealed a reduction in mf prevalence from 58% in 1994 to 0% in 2012. Entomological monitoring conducted at the two sites had no single Simulium damnosum fly caught. Serological analysis using Ov16 ELISA for onchocerciasis revealed that out of the 3,308 children <10 years old screened in 2013, only 3/3308 (0.091%) positive cases were detected. All Ov16 positive children were negative when tested for patent infection by skin snip PCR. A reduction in LF microfilaria prevalence from 2.5% (n = 13/522) in 2006 to 0.0% (n = 602) in 2014 was observed. LF TAS1 conducted in 2015 among 1,532 children 6-7 years, all were negative for antigens of W. bancrofti. CONCLUSION: The results concluded that interruption of onchocerciasis and LF has been achieved. PMID- 29253864 TI - Invariant recognition drives neural representations of action sequences. AB - Recognizing the actions of others from visual stimuli is a crucial aspect of human perception that allows individuals to respond to social cues. Humans are able to discriminate between similar actions despite transformations, like changes in viewpoint or actor, that substantially alter the visual appearance of a scene. This ability to generalize across complex transformations is a hallmark of human visual intelligence. Advances in understanding action recognition at the neural level have not always translated into precise accounts of the computational principles underlying what representations of action sequences are constructed by human visual cortex. Here we test the hypothesis that invariant action discrimination might fill this gap. Recently, the study of artificial systems for static object perception has produced models, Convolutional Neural Networks (CNNs), that achieve human level performance in complex discriminative tasks. Within this class, architectures that better support invariant object recognition also produce image representations that better match those implied by human and primate neural data. However, whether these models produce representations of action sequences that support recognition across complex transformations and closely follow neural representations of actions remains unknown. Here we show that spatiotemporal CNNs accurately categorize video stimuli into action classes, and that deliberate model modifications that improve performance on an invariant action recognition task lead to data representations that better match human neural recordings. Our results support our hypothesis that performance on invariant discrimination dictates the neural representations of actions computed in the brain. These results broaden the scope of the invariant recognition framework for understanding visual intelligence from perception of inanimate objects and faces in static images to the study of human perception of action sequences. PMID- 29253865 TI - Radiation enhanced the local and distant anti-tumor efficacy in dual immune checkpoint blockade therapy in osteosarcoma. AB - Radiation therapy has been long utilized as localized cancer treatment. Recent studies have also demonstrated that it has a distant effect by the enhanced immunity, but it rarely occurs. The purpose of this study was to investigate whether X-ray irradiation combined with anti-PD-L1 and anti-CTLA-4 antibodies (P1C4) provides a higher probability of this distant effect as well as enhanced local antitumor efficacy for osteosarcoma. LM8 mouse osteosarcoma cells were inoculated into both legs of C3H mice assigned to one of four groups, namely no treatment (No Tx), P1C4, X-ray irradiation (RAD) to the leg of one side, and combination (COMB) groups. Survival and treatment-related immune molecular changes were analyzed. Administration of P1C4 produced a tumor growth delay on day 30 in 18% of the mice. In contrast, combination therapy produced the strongest tumor growth inhibition not only at the irradiated tumor but also at unirradiated tumor in 67% of the mice. Accordingly, lung metastasis in the COMB group was strongly reduced by 98%, with a significant survival benefit. Unirradiated tumor in mice in the COMB group significantly recruited CD8 + tumor infiltrating lymphocytes with a moderate reduction of Treg, producing a significant increase in the CD8/Treg ratio. These results suggest that radiation enhances the efficacy of P1C4 treatment against distant metastasis as well as local control in osteosarcoma. Our data suggest that radiation therapy combined with dual checkpoint blockade may be a promising therapeutic option for osteosarcoma. PMID- 29253863 TI - Probing the antigenicity of hepatitis C virus envelope glycoprotein complex by high-throughput mutagenesis. AB - The hepatitis C virus (HCV) envelope glycoproteins E1 and E2 form a non covalently linked heterodimer on the viral surface that mediates viral entry. E1, E2 and the heterodimer complex E1E2 are candidate vaccine antigens, but are technically challenging to study because of difficulties in producing natively folded proteins by standard protein expression and purification methods. To better comprehend the antigenicity of these proteins, a library of alanine scanning mutants comprising the entirety of E1E2 (555 residues) was created for evaluating the role of each residue in the glycoproteins. The mutant library was probed, by a high-throughput flow cytometry-based assay, for binding with the co receptor CD81, and a panel of 13 human and mouse monoclonal antibodies (mAbs) that target continuous and discontinuous epitopes of E1, E2, and the E1E2 complex. Together with the recently determined crystal structure of E2 core domain (E2c), we found that several residues in the E2 back layer region indirectly impact binding of CD81 and mAbs that target the conserved neutralizing face of E2. These findings highlight an unexpected role for the E2 back layer in interacting with the E2 front layer for its biological function. We also identified regions of E1 and E2 that likely located at or near the interface of the E1E2 complex, and determined that the E2 back layer also plays an important role in E1E2 complex formation. The conformation-dependent reactivity of CD81 and the antibody panel to the E1E2 mutant library provides a global view of the influence of each amino acid (aa) on E1E2 expression and folding. This information is valuable for guiding protein engineering efforts to enhance the antigenic properties and stability of E1E2 for vaccine antigen development and structural studies. PMID- 29253866 TI - High proportion of genetic cases in patients with advanced cardiomyopathy including a novel homozygous Plakophilin 2-gene mutation. AB - Cardiomyopathies might lead to end-stage heart disease with the requirement of drastic treatments like bridging up to transplant or heart transplantation. A not precisely known proportion of these diseases are genetically determined. We genotyped 43 index-patients (30 DCM, 10 ARVC, 3 RCM) with advanced or end stage cardiomyopathy using a gene panel which covered 46 known cardiomyopathy disease genes. Fifty-three variants with possible impact on disease in 33 patients were identified. Of these 27 (51%) were classified as likely pathogenic or pathogenic in the MYH7, MYL2, MYL3, NEXN, TNNC1, TNNI3, DES, LMNA, PKP2, PLN, RBM20, TTN, and CRYAB genes. Fifty-six percent (n = 24) of index-patients carried a likely pathogenic or pathogenic mutation. Of these 75% (n = 18) were familial and 25% (n = 6) sporadic cases. However, severe cardiomyopathy seemed to be not characterized by a specific mutation profile. Remarkably, we identified a novel homozygous PKP2-missense variant in a large consanguineous family with sudden death in early childhood and several members with heart transplantation in adolescent age. PMID- 29253867 TI - The coordination of plural logics of action and its consequences: Evidence from plural medical systems. AB - Drawing on the theory of social action in organizational and institutional sociology, this paper examines the behavioral consequences of plural logics of action. It addresses the question based on the empirical case of plural medical systems that are composed of both biomedicine and alternative medicine. Applying mixed methods of a cross-national panel data analysis and a content analysis of medical journal articles, it finds that plural systems affect health outcomes negatively when tensions between biomedicine and alternative medicine are unaddressed. In contrast, plural systems produce tangible health benefits when biomedicine and alternative medicine are coordinated through government policies or by health care organizations/professionals. This paper proposes plurality coordination as an important mechanism that modifies the behavioral consequences of plural logics. This proposition contributes to providing theoretical answers to the sociological puzzle that plural logics of action produce inconsistent behavioral consequences. PMID- 29253869 TI - An error-tuned model for sensorimotor learning. AB - Current models of sensorimotor control posit that motor commands are generated by combining multiple modules which may consist of internal models, motor primitives or motor synergies. The mechanisms which select modules based on task requirements and modify their output during learning are therefore critical to our understanding of sensorimotor control. Here we develop a novel modular architecture for multi-dimensional tasks in which a set of fixed primitives are each able to compensate for errors in a single direction in the task space. The contribution of the primitives to the motor output is determined by both top-down contextual information and bottom-up error information. We implement this model for a task in which subjects learn to manipulate a dynamic object whose orientation can vary. In the model, visual information regarding the context (the orientation of the object) allows the appropriate primitives to be engaged. This top-down module selection is implemented by a Gaussian function tuned for the visual orientation of the object. Second, each module's contribution adapts across trials in proportion to its ability to decrease the current kinematic error. Specifically, adaptation is implemented by cosine tuning of primitives to the current direction of the error, which we show to be theoretically optimal for reducing error. This error-tuned model makes two novel predictions. First, interference should occur between alternating dynamics only when the kinematic errors associated with each oppose one another. In contrast, dynamics which lead to orthogonal errors should not interfere. Second, kinematic errors alone should be sufficient to engage the appropriate modules, even in the absence of contextual information normally provided by vision. We confirm both these predictions experimentally and show that the model can also account for data from previous experiments. Our results suggest that two interacting processes account for module selection during sensorimotor control and learning. PMID- 29253871 TI - Unique double concentric ring organization of light harvesting complexes in Gemmatimonas phototrophica. AB - The majority of life on Earth depends directly or indirectly on the sun as a source of energy. The initial step of photosynthesis is facilitated by light harvesting complexes, which capture and transfer light energy into the reaction centers (RCs). Here, we analyzed the organization of photosynthetic (PS) complexes in the bacterium G. phototrophica, which so far is the only phototrophic representative of the bacterial phylum Gemmatimonadetes. The isolated complex has a molecular weight of about 800 +/- 100 kDa, which is approximately 2 times larger than the core complex of Rhodospirillum rubrum. The complex contains 62.4 +/- 4.7 bacteriochlorophyll (BChl) a molecules absorbing in 2 distinct infrared absorption bands with maxima at 816 and 868 nm. Using femtosecond transient absorption spectroscopy, we determined the energy transfer time between these spectral bands as 2 ps. Single particle analyses of the purified complexes showed that they were circular structures with an outer diameter of approximately 18 nm and a thickness of 7 nm. Based on the obtained, we propose that the light-harvesting complexes in G. phototrophica form 2 concentric rings surrounding the type 2 RC. The inner ring (corresponding to the B868 absorption band) is composed of 15 subunits and is analogous to the inner light-harvesting complex 1 (LH1) in purple bacteria. The outer ring is composed of 15 more distant BChl dimers with no or slow energy transfer between them, resulting in the B816 absorption band. This completely unique and elegant organization offers good structural stability, as well as high efficiency of light harvesting. Our results reveal that while the PS apparatus of Gemmatimonadetes was acquired via horizontal gene transfer from purple bacteria, it later evolved along its own pathway, devising a new arrangement of its light harvesting complexes. PMID- 29253868 TI - Increased autophagic sequestration in adaptor protein-3 deficient dendritic cells limits inflammasome activity and impairs antibacterial immunity. AB - Bacterial pathogens that compromise phagosomal membranes stimulate inflammasome assembly in the cytosol, but the molecular mechanisms by which membrane dynamics regulate inflammasome activity are poorly characterized. We show that in murine dendritic cells (DCs), the endosomal adaptor protein AP-3 -which optimizes toll like receptor signaling from phagosomes-sustains inflammasome activation by particulate stimuli. AP-3 independently regulates inflammasome positioning and autophagy induction, together resulting in delayed inflammasome inactivation by autophagy in response to Salmonella Typhimurium (STm) and other particulate stimuli specifically in DCs. AP-3-deficient DCs, but not macrophages, hyposecrete IL-1beta and IL-18 in response to particulate stimuli in vitro, but caspase-1 and IL-1beta levels are restored by silencing autophagy. Concomitantly, AP-3 deficient mice exhibit higher mortality and produce less IL-1beta, IL-18, and IL 17 than controls upon oral STm infection. Our data identify a novel link between phagocytosis, inflammasome activity and autophagy in DCs, potentially explaining impaired antibacterial immunity in AP-3-deficient patients. PMID- 29253872 TI - Determinants for adherence to continuous positive airway pressure therapy in obstructive sleep apnea. AB - BACKGROUND: Continuous positive airway pressure (CPAP) therapy is an efficacious treatment for patients diagnosed with obstructive sleep apnea (OSA). However, there are only few data on long-term adherence. The aim of this study is to quantify the extent of non-adherence and describe the clinical characteristics. METHODS: A retrospective study including 695 patients with newly diagnosed OSA and prescribed CPAP therapy within an inclusion period of 14 months. All patients were offered free of charge individually adjusted CPAP therapy. Data on comorbidity, medication, BMI and Epworth Sleepiness Score (ESS) were obtained by questionnaires and consultation with an otorhinolaryngeal specialist. RESULTS: The median follow-up time after initiating CPAP therapy was 3.0 (range 2.4-3.6) years. An adherence rate of 89% was found for severe OSA, 71% for moderate OSA and 55% for mild OSA. 18% initiated humidification. Patients adherent to CPAP had a significantly higher Body Mass Index (BMI), Apnea Hypopnea Index (AHI), Oxygen Desaturation Index (ODI) and ESS compared to non-adherent patients. Furthermore, adherence was associated with a higher frequency of observed interrupted breathing, a less frequent use of hypnotic drugs, fewer smokers, and they were more often offered humidification. Age, gender and comorbidity were not significantly associated with adherence. In a Cox model only AHI (Hazard Ratio (HR) 0.963, p < 0.001), ESS (HR 0.939, p = 0.001) and smoking (HR 1.576, p = 0.022) were independently associated with CPAP non-adherence. CONCLUSIONS: The severity of OSA, subjective daytime sleepiness and smoking status are independently related to adherence to CPAP therapy. PMID- 29253870 TI - Downregulation of monocytic differentiation via modulation of CD147 by 3-hydroxy 3-methylglutaryl coenzyme A reductase inhibitors. AB - CD147 is an activation induced glycoprotein that promotes the secretion and activation of matrix metalloproteinases (MMPs) and is upregulated during the differentiation of macrophages. Interestingly, some of the molecular functions of CD147 rely on its glycosylation status: the highly glycosylated forms of CD147 induce MMPs whereas the lowly glycosylated forms inhibit MMP activation. Statins are hydroxy-methylglutaryl coenzyme A reductase inhibitors that block the synthesis of mevalonate, thereby inhibiting all mevalonate-dependent pathways, including isoprenylation, N-glycosylation and cholesterol synthesis. In this study, we investigated the role of statins in the inhibition of macrophage differentiation and the associated process of MMP secretion through modulation of CD147. We observed that differentiation of the human monocytic cell line THP-1 to a macrophage phenotype led to upregulation of CD147 and CD14 and that this effect was inhibited by statins. At the molecular level, statins altered CD147 expression, structure and function by inhibiting isoprenylation and N glycosylation. In addition, statins induced a shift of CD147 from its highly glycosylated form to its lowly glycosylated form. This shift in N-glycosylation status was accompanied by a decrease in the production and functional activity of MMP-2 and MMP-9. In conclusion, these findings describe a novel molecular mechanism of immune regulation by statins, making them interesting candidates for autoimmune disease therapy. PMID- 29253873 TI - Social-ecological factors and preventive actions decrease the risk of dengue infection at the household-level: Results from a prospective dengue surveillance study in Machala, Ecuador. AB - BACKGROUND: In Ecuador, dengue virus (DENV) infections transmitted by the Aedes aegypti mosquito are among the greatest public health concerns in urban coastal communities. Community- and household-level vector control is the principal means of controlling disease outbreaks. This study aimed to assess the impact of knowledge, attitudes, and practices (KAPs) and social-ecological factors on the presence or absence of DENV infections in the household. METHODS: In 2014 and 2015, individuals with DENV infections from sentinel clinics in Machala, Ecuador, were invited to participate in the study, as well as members of their household and members of four neighboring households located within 200 meters. We conducted diagnostic testing for DENV on all study participants; we surveyed heads of households (HOHs) regarding demographics, housing conditions and KAPs. We compared KAPs and social-ecological factors between households with (n = 139) versus without (n = 80) DENV infections, using bivariate analyses and multivariate logistic regression models with and without interactions. RESULTS: Significant risk factors in multivariate models included proximity to abandoned properties, interruptions in piped water, and shaded patios (p<0.05). Significant protective factors included the use of mosquito bed nets, fumigation inside the home, and piped water inside the home (p<0.05). In bivariate analyses (but not multivariate modeling), DENV infections were positively associated with HOHs who were male, employed, and of younger age than households without infections (p<0.05). DENV infections were not associated with knowledge, attitude, or reported barriers to prevention activities. DISCUSSION: Specific actions that can be considered to decrease the risk of DENV infections in the household include targeting vector control in highly shaded properties, fumigating inside the home, and use of mosquito bed nets. Community-level interventions include cleanup of abandoned properties, daily garbage collection, and reliable piped water inside houses. These findings can inform interventions to reduce the risk of other diseases transmitted by the Ae. aegypti mosquito, such as chikungunya and Zika fever. PMID- 29253875 TI - Residual sweeping errors in turbulent particle pair diffusion in a Lagrangian diffusion model. AB - Thomson, D. J. & Devenish, B. J. [J. Fluid Mech. 526, 277 (2005)] and others have suggested that sweeping effects make Lagrangian properties in Kinematic Simulations (KS), Fung et al [Fung J. C. H., Hunt J. C. R., Malik N. A. & Perkins R. J. J. Fluid Mech. 236, 281 (1992)], unreliable. However, such a conclusion can only be drawn under the assumption of locality. The major aim here is to quantify the sweeping errors in KS without assuming locality. Through a novel analysis based upon analysing pairs of particle trajectories in a frame of reference moving with the large energy containing scales of motion it is shown that the normalized integrated error [Formula: see text] in the turbulent pair diffusivity (K) due to the sweeping effect decreases with increasing pair separation (sigmal), such that [Formula: see text] as sigmal/eta -> infinity; and [Formula: see text] as sigmal/eta -> 0. eta is the Kolmogorov turbulence microscale. There is an intermediate range of separations 1 < sigmal/eta < infinity in which the error [Formula: see text] remains negligible. Simulations using KS shows that in the swept frame of reference, this intermediate range is large covering almost the entire inertial subrange simulated, 1 < sigmal/eta < 105, implying that the deviation from locality observed in KS cannot be atributed to sweeping errors. This is important for pair diffusion theory and modeling. PACS numbers: 47.27.E?, 47.27.Gs, 47.27.jv, 47.27.Ak, 47.27.tb, 47.27.eb, 47.11.-j. PMID- 29253874 TI - Optimal number of spacers in CRISPR arrays. AB - Prokaryotic organisms survive under constant pressure of viruses. CRISPR-Cas system provides its prokaryotic host with an adaptive immune defense against viruses that have been previously encountered. It consists of two components: Cas proteins that cleave the foreign DNA and CRISPR array that suits as a virus recognition key. CRISPR array consists of a series of spacers, short pieces of DNA that originate from and match the corresponding parts of viral DNA called protospacers. Here we estimate the number of spacers in a CRISPR array of a prokaryotic cell which maximizes its protection against a viral attack. The optimality follows from a competition between two trends: too few distinct spacers make host vulnerable to an attack by a virus with mutated corresponding protospacers, while an excessive variety of spacers dilutes the number of the CRISPR complexes armed with the most recent and thus most useful spacers. We first evaluate the optimal number of spacers in a simple scenario of an infection by a single viral species and later consider a more general case of multiple viral species. We find that depending on such parameters as the concentration of CRISPR-Cas interference complexes and its preference to arm with more recently acquired spacers, the rate of viral mutation, and the number of viral species, the predicted optimal number of spacers lies within a range that agrees with experimentally-observed values. PMID- 29253876 TI - Temporal and spatial differences between taxonomic and trait biodiversity in a large marine ecosystem: Causes and consequences. AB - Biodiversity is a multifaceted concept, yet most biodiversity studies have taken a taxonomic approach, implying that all species are equally important. However, species do not contribute equally to ecosystem processes and differ markedly in their responses to changing environments. This recognition has led to the exploration of other components of biodiversity, notably the diversity of ecologically important traits. Recent studies taking into account both taxonomic and trait diversity have revealed that the two biodiversity components may exhibit pronounced temporal and spatial differences. These apparent incongruences indicate that the two components may respond differently to environmental drivers and that changes in one component might not affect the other. Such incongruences may provide insight into the structuring of communities through community assembly processes, and the resilience of ecosystems to change. Here we examine temporal and spatial patterns and drivers of multiple marine biodiversity indicators using the North Sea fish community as a case study. Based on long-term spatially resolved survey data on fish species occurrences and biomasses from 1983 to 2014 and an extensive trait dataset we: (i) investigate temporal and spatial incongruences between taxonomy and trait-based indicators of both richness and evenness; (ii) examine the underlying environmental drivers and, (iii) interpret the results in the context of assembly rules acting on community composition. Our study shows that taxonomy and trait-based biodiversity indicators differ in time and space and that these differences are correlated to natural and anthropogenic drivers, notably temperature, depth and substrate richness. Our findings show that trait-based biodiversity indicators add information regarding community composition and ecosystem structure compared to and in conjunction with taxonomy-based indicators. These results emphasize the importance of examining and monitoring multiple indicators of biodiversity in ecological studies as well as for conservation and ecosystem-based management purposes. PMID- 29253877 TI - Formation of large viroplasms and virulence of Cauliflower mosaic virus in turnip plants depend on the N-terminal EKI sequence of viral protein TAV. AB - Cauliflower mosaic virus (CaMV) TAV protein (TransActivator/Viroplasmin) plays a pivotal role during the infection cycle since it activates translation reinitiation of viral polycistronic RNAs and suppresses RNA silencing. It is also the major component of cytoplasmic electron-dense inclusion bodies (EDIBs) called viroplasms that are particularly evident in cells infected by the virulent CaMV Cabb B-JI isolate. These EDIBs are considered as virion factories, vehicles for CaMV intracellular movement and reservoirs for CaMV transmission by aphids. In this study, focused on different TAV mutants in vivo, we demonstrate that three physically separated domains collectively participate to the formation of large EDIBs: the N-terminal EKI motif, a sequence of the MAV domain involved in translation reinitiation and a C-terminal region encompassing the zinc finger. Surprisingly, EKI mutant TAVm3, corresponding to a substitution of the EKI motif at amino acids 11-13 by three alanines (AAA), which completely abolished the formation of large viroplasms, was not lethal for CaMV but highly reduced its virulence without affecting the rate of systemic infection. Expression of TAVm3 in a viral context led to formation of small irregularly shaped inclusion bodies, mild symptoms and low levels of viral DNA and particles accumulation, despite the production of significant amounts of mature capsid proteins. Unexpectedly, for CaMV-TAVm3 the formation of viral P2-containing electron-light inclusion body (ELIB), which is essential for CaMV aphid transmission, was also altered, thus suggesting an indirect role of the EKI tripeptide in CaMV plant-to-plant propagation. This important functional contribution of the EKI motif in CaMV biology can explain the strict conservation of this motif in the TAV sequences of all CaMV isolates. PMID- 29253879 TI - Cold shock treatment extends shelf life of naturally ripened or ethylene-ripened avocado fruits. AB - Avocado is an important tropical fruit with high commercial value, but has a relatively short storage life. In this study, the effects of cold shock treatment (CST) on shelf life of naturally ripened and ethylene-ripened avocado fruits were investigated. Fruits were immersed in ice water for 30 min, then subjected to natural or ethylene-induced ripening. Fruit color; firmness; respiration rate; ethylene production; and the activities of polygalacturonase (PG), pectin methylesterase (PME), and endo-beta-1,4-glucanase were measured. Immersion in ice water for 30 min effectively delayed ripening-associated processes, including peel discoloration, pulp softening, respiration rate, and ethylene production during shelf life. The delay in fruit softening by CST was associated with decreased PG and endo-beta-1,4-glucanase activities, but not PME activity. This method could potentially be a useful postharvest technology to extend shelf life of avocado fruits. PMID- 29253878 TI - Eicosanoyl-5-hydroxytryptamide (EHT) prevents Alzheimer's disease-related cognitive and electrophysiological impairments in mice exposed to elevated concentrations of oligomeric beta-amyloid. AB - Soluble forms of oligomeric beta-amyloid (Abeta) are thought to play a central role in Alzheimer's disease (AD). Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Abeta. In addition, eicosanoyl-5-hydroxytryptamide (EHT), a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson's disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Abeta. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Abeta-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Abeta induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Abeta-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions. PMID- 29253880 TI - The amino-terminus of the hepatitis C virus (HCV) p7 viroporin and its cleavage from glycoprotein E2-p7 precursor determine specific infectivity and secretion levels of HCV particle types. AB - Viroporins are small transmembrane proteins with ion channel activities modulating properties of intracellular membranes that have diverse proviral functions. Hepatitis C virus (HCV) encodes a viroporin, p7, acting during assembly, envelopment and secretion of viral particles (VP). HCV p7 is released from the viral polyprotein through cleavage at E2-p7 and p7-NS2 junctions by signal peptidase, but also exists as an E2p7 precursor, of poorly defined properties. Here, we found that ectopic p7 expression in HCVcc-infected cells reduced secretion of particle-associated E2 glycoproteins. Using biochemical assays, we show that p7 dose-dependently slows down the ER-to-Golgi traffic, leading to intracellular retention of E2, which suggested that timely E2p7 cleavage and p7 liberation are critical events to control E2 levels. By studying HCV mutants with accelerated E2p7 processing, we demonstrate that E2p7 cleavage controls E2 intracellular expression and secretion levels of nucleocapsid-free subviral particles and infectious virions. In addition, our imaging data reveal that, following p7 liberation, the amino-terminus of p7 is exposed towards the cytosol and coordinates the encounter between NS5A and NS2-based assembly sites loaded with E1E2 glycoproteins, which subsequently leads to nucleocapsid envelopment. We identify punctual mutants at p7 membrane interface that, by abrogating NS2/NS5A interaction, are defective for transmission of infectivity owing to decreased secretion of core and RNA and to increased secretion of non/partially-enveloped particles. Altogether, our results indicate that the retarded E2p7 precursor cleavage is essential to regulate the intracellular and secreted levels of E2 through p7-mediated modulation of the cell secretory pathway and to unmask critical novel assembly functions located at p7 amino terminus. PMID- 29253881 TI - Complete hazard ranking to analyze right-censored data: An ALS survival study. AB - Survival analysis represents an important outcome measure in clinical research and clinical trials; further, survival ranking may offer additional advantages in clinical trials. In this study, we developed GuanRank, a non-parametric ranking based technique to transform patients' survival data into a linear space of hazard ranks. The transformation enables the utilization of machine learning base learners including Gaussian process regression, Lasso, and random forest on survival data. The method was submitted to the DREAM Amyotrophic Lateral Sclerosis (ALS) Stratification Challenge. Ranked first place, the model gave more accurate ranking predictions on the PRO-ACT ALS dataset in comparison to Cox proportional hazard model. By utilizing right-censored data in its training process, the method demonstrated its state-of-the-art predictive power in ALS survival ranking. Its feature selection identified multiple important factors, some of which conflicts with previous studies. PMID- 29253883 TI - Patients with chronic peripheral vestibular hypofunction compared to healthy subjects exhibit differences in gaze and gait behaviour when walking on stairs and ramps. AB - OBJECTIVE: The aim of this study was to compare gaze behaviour during stair and ramp walking between patients with chronic peripheral vestibular hypofunction and healthy human subjects. METHODS: Twenty four (24) patients with chronic peripheral vestibular hypofunction (14 unilateral and 10 bilateral) and 24 healthy subjects performed stair and ramp up and down walks at self-selected speed. The walks were repeated five times. A mobile eye tracker was used to record gaze behaviour (defined as time directed to pre-defined areas) and an insole measurement device assessed gait (speed, step time, step length). During each walk gaze behaviour relative to i) detection of first transition area "First TA", ii) detection of steps of the mid-staircase area and the handrail "Structure", iii) detection of second transition area "Second TA", and iv) looking elsewhere "Elsewhere" was assessed and expressed as a percentage of the walk duration. For all variables, a one-way ANOVA followed by contrast tests was conducted. RESULTS: Patients looked significantly longer at the "Structure" (p<0.001) and "Elsewhere" (p<0.001) while walking upstairs compared to walking downstairs (p<0.013). Patients looked significantly longer at the "Structure" (p<0.001) and "Elsewhere" (p<0.001) while walking upstairs compared to walking downstairs (p<0.013). No differences between groups were observed for the transition areas with exception of stair ascending. Patients were also slower going downstairs (p = 0.002) and presented with an increased step time (p = 0.003). Patients were walking faster up the ramp (p = 0.014) with longer step length (p = 0.008) compared to walking down the ramp (p = 0.050) with shorter step length (p = 0.024). CONCLUSIONS: Patients with chronic peripheral vestibular hypofunction differed in time directed to pre-defined areas during stair and ramp walking and looked longer at stair and ramp areas of interest during walking compared to healthy subjects. Patients did not differ in time directed to pre defined areas during the stair-floor transition area while going downstairs, an area where accidents may frequently occur. PMID- 29253882 TI - Host immunity, nutrition and coinfection alter longitudinal infection patterns of schistosomes in a free ranging African buffalo population. AB - Schistosomes are trematode parasites of global importance, causing infections in millions of people, livestock, and wildlife. Most studies on schistosomiasis, involve human subjects; as such, there is a paucity of longitudinal studies investigating parasite dynamics in the absence of intervention. As a consequence, despite decades of research on schistosomiasis, our understanding of its ecology in natural host populations is centered around how environmental exposure and acquired immunity influence acquisition of parasites, while very little is known about the influence of host physiology, coinfection and clearance in the absence of drug treatment. We used a 4-year study in free-ranging African buffalo to investigate natural schistosome dynamics. We asked (i) what are the spatial and temporal patterns of schistosome infections; (ii) how do parasite burdens vary over time within individual hosts; and (iii) what host factors (immunological, physiological, co-infection) and environmental factors (season, location) explain patterns of schistosome acquisition and loss in buffalo? Schistosome infections were common among buffalo. Microgeographic structure explained some variation in parasite burdens among hosts, indicating transmission hotspots. Overall, parasite burdens ratcheted up over time; however, gains in schistosome abundance in the dry season were partially offset by losses in the wet season, with some hosts demonstrating complete clearance of infection. Variation among buffalo in schistosome loss was associated with immunologic and nutritional factors, as well as co-infection by the gastrointestinal helminth Cooperia fuelleborni. Our results demonstrate that schistosome infections are surprisingly dynamic in a free-living mammalian host population, and point to a role for host factors in driving variation in parasite clearance, but not parasite acquisition which is driven by seasonal changes and spatial habitat utilization. Our study illustrates the power of longitudinal studies for discovering mechanisms underlying parasite dynamics in individual animals and populations. PMID- 29253884 TI - Effect of anterior chamber depth on the choice of intraocular lens calculation formula. AB - PURPOSE: To investigate the effect of anterior chamber depth (ACD) on the refractive outcomes of the SRK/T, Holladay 1, Hoffer Q and Haigis formulae in short, normal, long and extremely long eyes. METHODS: This retrospective study involved patients who had uncomplicated cataract surgery. Preoperative axial length (AL) was divided into four subgroups: short (< 22.00 mm), normal (22.00 24.49 mm), long (24.50-25.99 mm), extremely long (>= 26.00 mm). Preoperative ACD was divided into three subgroups: < 2.5, 2.50-3.49, and >= 3.5 mm. Median absolute errors (MedAEs) predicted by the SRK/T, Holladay 1, Hoffer Q and Haigis formulae were compared with the Friedman test. Post-hoc analysis involved the Wilcoxon signed rank test with a Bonferroni adjustment. Correlations between ACD and the predictive refractive errors of the four formulas were analyzed. RESULTS: In short eyes with an ACD < 2.5 mm, the Haigis formula revealed the highest MedAE. The difference in MedAE with the Hoffer Q formula (which had the lowest MedAE) was statistically significant (P = 0.002). In normal eyes, the Haigis formula significantly differed from the Holladay 1 (P = 0.002) and Hoffer Q (P = 0.005) formulae in the ACD < 2.5 mm group. In long eyes and extremely long eyes with an ACD >= 3.5 mm, the differences in MedAEs were statistically significant (P = 0.018, P = 0.001, respectively) and the Haigis formula had the lowest MedAEs in both subgroups (0.29 D, 0.30 D, respectively). In the total of 1,123 eyes, refractive errors predicted by the Haigis formula showed a significant negative correlation with the ACD (R2 = 0.002, P = 0.047). CONCLUSIONS: The Hoffer Q formula is preferred over other formulae in short eyes with an ACD shallower than 2.5 mm. In short and normal eyes with an ACD < 2.5 mm the Haigis formula might underestimate ELP. The Haigis formula is the preferred choice in eyes with an AL >= 24.5 mm and an ACD >= 3.5 mm. PMID- 29253886 TI - Responses of root physiological characteristics and yield of sweet potato to humic acid urea fertilizer. AB - Humic acid (HA), not only promote the growth of crop roots, they can be combined with nitrogen (N) to increase fertilizer use efficiency and yield. However, the effects of HA urea fertilizer (HA-N) on root growth and yield of sweet potato has not been widely investigated. Xushu 28 was used as the experimental crop to investigate the effects of HA-N on root morphology, active oxygen metabolism and yield under field conditions. Results showed that nitrogen application alone was not beneficial for root growth and storage root formation during the early growth stage. HA-N significantly increased the dry weight of the root system, promoted differentiation from adventitious root to storage root, and increased the overall root activity, total root length, root diameter, root surface area, as well as root volume. HA-N thus increased the activity of superoxide dismutase (SOD), peroxidase (POD), and Catalase (CAT) as well as increasing the soluble protein content of roots and decreasing the malondialdehyde (MDA) content. HA-N significantly increased both the number of storage roots per plant increased by 14.01%, and the average fresh weight per storage root increased by 13.7%, while the yield was also obviously increased by 29.56%. In this study, HA-N increased yield through a synergistic increase of biological yield and harvest index. PMID- 29253885 TI - LRSSLMDA: Laplacian Regularized Sparse Subspace Learning for MiRNA-Disease Association prediction. AB - Predicting novel microRNA (miRNA)-disease associations is clinically significant due to miRNAs' potential roles of diagnostic biomarkers and therapeutic targets for various human diseases. Previous studies have demonstrated the viability of utilizing different types of biological data to computationally infer new disease related miRNAs. Yet researchers face the challenge of how to effectively integrate diverse datasets and make reliable predictions. In this study, we presented a computational model named Laplacian Regularized Sparse Subspace Learning for MiRNA-Disease Association prediction (LRSSLMDA), which projected miRNAs/diseases' statistical feature profile and graph theoretical feature profile to a common subspace. It used Laplacian regularization to preserve the local structures of the training data and a L1-norm constraint to select important miRNA/disease features for prediction. The strength of dimensionality reduction enabled the model to be easily extended to much higher dimensional datasets than those exploited in this study. Experimental results showed that LRSSLMDA outperformed ten previous models: the AUC of 0.9178 in global leave-one out cross validation (LOOCV) and the AUC of 0.8418 in local LOOCV indicated the model's superior prediction accuracy; and the average AUC of 0.9181+/-0.0004 in 5 fold cross validation justified its accuracy and stability. In addition, three types of case studies further demonstrated its predictive power. Potential miRNAs related to Colon Neoplasms, Lymphoma, Kidney Neoplasms, Esophageal Neoplasms and Breast Neoplasms were predicted by LRSSLMDA. Respectively, 98%, 88%, 96%, 98% and 98% out of the top 50 predictions were validated by experimental evidences. Therefore, we conclude that LRSSLMDA would be a valuable computational tool for miRNA-disease association prediction. PMID- 29253887 TI - Effects of GABACR and mGluR1 antagonists on contrast response functions of Sprague-Dawley and P23H rat retinal ganglion cells. AB - The GABACR antagonist TPMPA and the mGluR1 antagonist JNJ16259685 have been shown previously to alter the sensitivity of retinal ganglion cells (RGCs) in the Sprague-Dawley (SD) rat and P23H rat (animal model of retinitis pigmentosa) to brief flashes of light. In order to better understand the effects of these antagonists on the visual responses of SD and P23H rat RGCs, I examined the responses of RGCs to a drifting sinusoidal grating of various contrasts. Multielectrode array recordings were made from RGCs to a drifting sinusoidal grating of a spatial frequency of 1 cycle/mm and a temporal frequency of 2 cycles/s. In both SD and P23H rat retinas, contrast response functions were found to have a variable shape across cells. Some cells showed saturation of responses at high contrast levels while others did not. Whereas 49% of SD rat RGCs exhibited response saturation, only 14% of P23H rat RGCs showed response saturation. TPMPA decreased the responses of saturating SD rat RGCs to low (6% to 13%) grating contrasts but increased the response to the highest contrast (83%) tested. JNJ16259685 did not significantly affect the contrast response functions of either saturating or non-saturating SD rat RGCs. In contrast, both TPMPA and JNJ16259685 increased the responses of saturating and non-saturating P23H rat RGCs to all grating contrasts. Neither TPMPA nor JNJ16259685 affected the contrast thresholds of SD rat RGCs, but both antagonists lowered the contrast thresholds of P23H rat RGCs. Overall, the findings show that GABACR and mGluR1 antagonists have differential effects on the contrast response functions of SD and P23H rat RGCs. Notably, these receptor antagonists increase the responsiveness of P23H rat RGCs to both low and high contrast visual stimuli. PMID- 29253888 TI - Burkholderia pseudomallei natural competency and DNA catabolism: Identification and characterization of relevant genes from a constructed fosmid library. AB - Burkholderia spp. are genetically and physiologically diverse. Some strains are naturally transformable and capable of DNA catabolism. Burkholderia pseudomallei (Bp) strains 1026b and K96243 and B. thailandensis strain E264 are able to utilize DNA as a sole carbon source for growth, while only strains 1026b and E264 are naturally transformable. In this study, we constructed low-copy broad-host range fosmid library, containing Bp strain 1026b chromosomal DNA fragments, and employed a novel positive selection approach to identify genes responsible for DNA uptake and DNA catabolism. The library was transferred to non-competent Bp K96243 and B. cenocepacia (Bc) K56-2, harboring chromosomally-inserted FRT flanked sacB and pheS counter-selection markers. The library was incubated with DNA encoding Flp recombinase, followed by counter-selection on sucrose and chlorinated phenylalanine, to select for clones that took up flp-DNA, transiently expressed Flp, and excised the sacB-pheS cassette. Putative clones that survived the counter-selection were subsequently incubated with gfp-DNA and bacteria were visualized via fluorescent microscopy to confirm natural competency. Fosmid sequencing identified several 1026b genes implicated in DNA uptake, which were validated using chromosomal mutants. One of the naturally competent clones selected in Bc K56-2 enabled Bc, Bp and B. mallei to utilize DNA as a sole carbon source, and all fosmids were used to successfully create mutations in non naturally-competent B. mallei and Bp strains. PMID- 29253889 TI - A confidence interval analysis of sampling effort, sequencing depth, and taxonomic resolution of fungal community ecology in the era of high-throughput sequencing. AB - High-throughput sequencing technology has helped microbial community ecologists explore ecological and evolutionary patterns at unprecedented scales. The benefits of a large sample size still typically outweigh that of greater sequencing depths per sample for accurate estimations of ecological inferences. However, excluding or not sequencing rare taxa may mislead the answers to the questions 'how and why are communities different?' This study evaluates the confidence intervals of ecological inferences from high-throughput sequencing data of foliar fungal endophytes as case studies through a range of sampling efforts, sequencing depths, and taxonomic resolutions to understand how technical and analytical practices may affect our interpretations. Increasing sampling size reliably decreased confidence intervals across multiple community comparisons. However, the effects of sequencing depths on confidence intervals depended on how rare taxa influenced the dissimilarity estimates among communities and did not significantly decrease confidence intervals for all community comparisons. A comparison of simulated communities under random drift suggests that sequencing depths are important in estimating dissimilarities between microbial communities under neutral selective processes. Confidence interval analyses reveal important biases as well as biological trends in microbial community studies that otherwise may be ignored when communities are only compared for statistically significant differences. PMID- 29253890 TI - Leaf shedding as an anti-bacterial defense in Arabidopsis cauline leaves. AB - Plants utilize an innate immune system to protect themselves from disease. While many molecular components of plant innate immunity resemble the innate immunity of animals, plants also have evolved a number of truly unique defense mechanisms, particularly at the physiological level. Plant's flexible developmental program allows them the unique ability to simply produce new organs as needed, affording them the ability to replace damaged organs. Here we develop a system to study pathogen-triggered leaf abscission in Arabidopsis. Cauline leaves infected with the bacterial pathogen Pseudomonas syringae abscise as part of the defense mechanism. Pseudomonas syringae lacking a functional type III secretion system fail to elicit an abscission response, suggesting that the abscission response is a novel form of immunity triggered by effectors. HAESA/HAESA-like 2, INFLORESCENCE DEFICIENT IN ABSCISSION, and NEVERSHED are all required for pathogen-triggered abscission to occur. Additionally phytoalexin deficient 4, enhanced disease susceptibility 1, salicylic acid induction-deficient 2, and senescence-associated gene 101 plants with mutations in genes necessary for bacterial defense and salicylic acid signaling, and NahG transgenic plants with low levels of salicylic acid fail to abscise cauline leaves normally. Bacteria that physically contact abscission zones trigger a strong abscission response; however, long-distance signals are also sent from distal infected tissue to the abscission zone, alerting the abscission zone of looming danger. We propose a threshold model regulating cauline leaf defense where minor infections are handled by limiting bacterial growth, but when an infection is deemed out of control, cauline leaves are shed. Together with previous results, our findings suggest that salicylic acid may regulate both pathogen- and drought-triggered leaf abscission. PMID- 29253891 TI - What constitutes responsiveness of physicians: A qualitative study in rural Bangladesh. AB - Responsiveness entails the social actions by health providers to meet the legitimate expectations of patients. It plays a critical role in ensuring continuity and effectiveness of care within people centered health systems. Given the lack of contextualized research on responsiveness, we qualitatively explored the perceptions of outpatient users and providers regarding what constitute responsiveness in rural Bangladesh. An exploratory study was undertaken in Chuadanga, a southwestern Bangladeshi District, involving in-depth interviews of physicians (n = 17) and users (n = 7), focus group discussions with users (n = 4), and observations of patient provider interactions (three weeks). Analysis was guided by a conceptual framework of responsiveness, which includes friendliness, respecting, informing and guiding, gaining trust and optimizing benefits. In terms of friendliness, patients expected physicians to greet them before starting consultations; even though physicians considered this unusual. Patients also expected physicians to hold social talks during consultations, which was uncommon. With regards to respect patients expected physicians to refrain from disrespecting them in various ways; but also by showing respect explicitly. Patients also had expectations related to informing and guiding: they desired explanation on at least the diagnosis, seriousness of illness, treatment and preventive steps. In gaining trust, patients expected that physicians would refrain from illegal or unethical activities related to patients, e.g., demanding money against free services, bringing patients in own private clinics by brokers (dalals), colluding with diagnostic centers, accepting gifts from pharmaceutical representatives. In terms of optimizing benefits: patients expected that physicians should be financially sensitive and consider individual need of patients. There were multiple dimensions of responsiveness- for some, stakeholders had a consensus; context was an important factor to understand them. This being an exploratory study, further research is recommended to validate the nuances of the findings. It can be a guideline for responsiveness practices, and a tipping point for future research. PMID- 29253892 TI - Small molecules targeting LapB protein prevent Listeria attachment to catfish muscle. AB - Listeria monocytogenes is a Gram-positive foodborne pathogen and the causative agent of listeriosis. L. monocytogenes lapB gene encodes a cell wall surface anchor protein, and mutation of this gene causes Listeria attenuation in mice. In this work, the potential role of Listeria LapB protein in catfish fillet attachment was investigated. To achieve this, boron-based small molecules designed to interfere with the active site of the L. monocytogenes LapB protein were developed, and their ability to prevent L. monocytogenes attachment to fish fillet was tested. Results indicated that seven out of nine different small molecules were effective in reducing the Listeria attachment to catfish fillets. Of these, three small molecules (SM3, SM5, and SM7) were highly effective in blocking Listeria attachment to catfish fillets. This study suggests an alternative strategy for reduction of L. monocytogenes contamination in fresh and frozen fish products. PMID- 29253893 TI - Histamine Receptor 3 negatively regulates oligodendrocyte differentiation and remyelination. AB - BACKGROUND: Agents promoting oligodendrocyte precursor cell differentiation have the potential to restore halted and/or delayed remyelination in patients with multiple sclerosis. However, few therapeutic targets have been identified. The objective of this study was to identify novel targets for promotion of remyelination and characterize their activity in vitro and in vivo. METHODS: A high-content screening assay with differentiation of primary rat oligodendrocyte precursor cells was used to screen GSK-proprietary annotated libraries for remyelination-promoting compounds. Compounds were further validated in vitro and in vivo models; clinical relevance of target was confirmed in human post-mortem brain sections from patients with MS. RESULTS: Of ~1000 compounds screened, 36 promoted oligodendrocyte precursor cell differentiation in a concentration dependent manner; seven were histamine receptor-3 (H3R) antagonists. Inverse agonists of H3R but not neutral antagonists promoted oligodendrocyte precursor cell (OPC) differentiation. H3R was expressed throughout OPC differentiation; H3R expression was transiently upregulated on Days 3-5 and subsequently downregulated. H3R gene knockdown in OPCs increased the expression of differentiation markers and the number of mature oligodendrocytes. Overexpression of full-length H3R reduced differentiation marker expression and the number of mature cells. H3R inverse agonist GSK247246 reduced intracellular cyclic AMP (cAMP) and downstream cAMP response element-binding protein (CREB) phosphorylation in a dose-dependent manner. Histone deacetylase (HDAC-1) and Hes 5 were identified as key downstream targets of H3R during OPC differentiation. In the mouse cuprizone/rapamycin model of demyelination, systemic administration of brain-penetrable GSK247246 enhanced remyelination and subsequently protected axons. Finally, we detected high H3R expression in oligodendroglial cells from demyelination lesions in human samples of patients with MS, and validated a genetic association between an exonic single nucleotide polymorphism in HRH3 and susceptibility to multiple sclerosis. CONCLUSIONS: From phenotypic screening to human genetics, we provide evidence for H3R as a novel therapeutic target to promote remyelination in patients with multiple sclerosis. PMID- 29253894 TI - Background sequence characteristics influence the occurrence and severity of disease-causing mtDNA mutations. AB - Inherited mitochondrial DNA (mtDNA) mutations have emerged as a common cause of human disease, with mutations occurring multiple times in the world population. The clinical presentation of three pathogenic mtDNA mutations is strongly associated with a background mtDNA haplogroup, but it is not clear whether this is limited to a handful of examples or is a more general phenomenon. To address this, we determined the characteristics of 30,506 mtDNA sequences sampled globally. After performing several quality control steps, we ascribed an established pathogenicity score to the major alleles for each sequence. The mean pathogenicity score for known disease-causing mutations was significantly different between mtDNA macro-haplogroups. Several mutations were observed across all haplogroup backgrounds, whereas others were only observed on specific clades. In some instances this reflected a founder effect, but in others, the mutation recurred but only within the same phylogenetic cluster. Sequence diversity estimates showed that disease-causing mutations were more frequent on young sequences, and genomes with two or more disease-causing mutations were more common than expected by chance. These findings implicate the mtDNA background more generally in recurrent mutation events that have been purified through natural selection in older populations. This provides an explanation for the low frequency of mtDNA disease reported in specific ethnic groups. PMID- 29253895 TI - Improvement of the catalytic efficiency of a hyperthermophilic xylanase from Bispora sp. MEY-1. AB - Extremophilic xylanases have attracted great scientific and industrial interest. In this study, a GH10 xylanase-encoding gene, Xyl10E, was cloned from Bispora sp. MEY-1 and expressed in Pichia pastoris GS115. Deduced Xyl10E shares the highest identities of 62% and 57% with characterized family GH10 xylanases from Talaromyces leycettanus and Penicillium canescens (structure 4F8X), respectively. Xyl10E was most active at 93 to 95 degrees C and pH 4.0, retained more than 75% or 48% of the initial activity when heated at 80 degrees C or 90 degrees C for 30 min, respectively, and hardly lost activity at pH 1.0 to 7.0, but was completely inhibited by SDS. Two residues, A160 and A161, located on loop 4, were identified to play roles in catalysis. Mutants A160D/E demonstrated higher affinity to substrate with lower Km values, while mutants A161D/E mainly displayed elevated Vmax values. All of these mutants had significantly improved catalytic efficiency. According to the molecular dynamics simulation, the mutation of A160E was able to affect the important substrate binding site Y204 and then improve the substrate affinity, and the mutation of A161D was capable of forming a hydrogen bond with the substrate to promote the substrate binding or accelerate the product release. This study introduces a highly thermophilic fungal xylanase and reveals the importance of loop 4 for catalytic efficiency. PMID- 29253896 TI - Assessment of the distribution, bioavailability and ecological risks of heavy metals in the lake water and surface sediments of the Caohai plateau wetland, China. AB - In this study, selected heavy metals (Hg, As, Cd, Pb, Cr, Cu and Zn) in the lake water and sediments from the Caohai wetland, which is a valuable state reserve for migrant birds in China, were investigated to assess the spatial distribution, sources, bioavailability and ecological risks. The results suggested that most of the higher concentrations were found in the eastern region of the lakeshore. The concentration factor (CF) revealed that Hg, Cd and Zn were present from moderate risk levels to considerable risk levels in this study; thus, based on the high pollution load index (PLI) values, the Caohai wetland can be considered polluted. According to the associated effects-range classification, Cd may present substantial environmental hazards. An investigation of the chemical speciation suggested that Cd and Zn were unstable across most of the sites, which implied a higher risk of quick desorption and release. Principal component analysis (PCA) indicated that the heavy metal contamination originated from both natural and anthropogenic sources. PMID- 29253898 TI - Correction: Mapping and predictive variations of soil bacterial richness across France. AB - [This corrects the article DOI: 10.1371/journal.pone.0186766.]. PMID- 29253897 TI - Increased activated memory B-cells in the peripheral blood of patients with erythema nodosum leprosum reactions. AB - B-cells, in addition to antibody secretion, have emerged increasingly as effector and immunoregulatory cells in several chronic inflammatory diseases. Although Erythema Nodosum Leprosum (ENL) is an inflammatory complication of leprosy, the role of B- cell subsets has never been studied in this patient group. Therefore, it would be interesting to examine the contribution of B-cells in the pathogenesis of ENL. A case-control study design was used to recruit 30 untreated patients with ENL and 30 non-reactional lepromatous leprosy (LL) patient controls at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before, during and after treatment from each patient. Peripheral blood mononuclear cells (PBMCs) were isolated and used for immunophenotyping of B- cell subsets by flow cytometry. The kinetics of B-cells in patients with ENL before, during and after Prednisolone treatment of ENL was compared with LL patient controls as well as within ENL group. Total B-cells, mature B-cells and resting memory B-cells were not significantly different between patients with ENL reactions and LL controls before treatment. Interestingly, while the percentage of naive B-cells was significantly lower in untreated ENL patients than in LL patient controls, the percentage of activated memory B-cells was significantly higher in these untreated ENL patients than in LL controls. On the other hand, the percentage of tissue-like memory B-cells was considerably low in untreated ENL patients compared to LL controls. It appears that the lower frequency of tissue-like memory B-cells in untreated ENL could promote the B-cell/T-cell interaction in these patients through downregulation of inhibitory molecules unlike in LL patients. Conversely, the increased production of activated memory B-cells in ENL patients could imply the scale up of immune activation through antigen presentation to T-cells. However, the generation and differential function of these memory B-cells need further investigation. The finding of increased percentage of activated memory B-cells in untreated patients with ENL reactions suggests the association of these cells with the ENL pathology. The mechanism by which inflammatory reactions like ENL affecting these memory cells and contributing to the disease pathology is an interesting area to be explored for and could lead to the development of novel and highly efficacious drug for ENL treatment. PMID- 29253899 TI - A favorable cardiometabolic profile is associated with the G allele of the genetic variant rs5068 in African Americans: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - In whites, the minor G allele of the atrial natriuretic peptide (ANP) genetic variant rs5068 is associated with higher circulating levels of ANP and B-type natriuretic peptide (BNP), lower risk of hypertension, higher high-density lipoprotein (HDL) cholesterol plasma levels, and lower prevalence of obesity and metabolic syndrome. The observed phenotype is consistent with the blood pressure lowering and metabolic properties of ANP and BNP. The cardiovascular and metabolic phenotype associated with rs5068 genotypes in African Americans is undefined. We genotyped 1631 African Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) for rs5068 and investigated their phenotype. Genotype frequencies of rs5068 were 93.2% AA (n = 1520), 6.7% AG (n = 110) and 0.1% GG (n = 1). All subsequent analyses are AG + GG versus AA genotype. Using a Bonferroni corrected level of significance of 0.005, the prevalence of metabolic syndrome (23% vs 38%, age-sex-adjusted p = 0.002) and triglycerides plasma values (76 vs 90 mg/dl, age-sex-BMI adjusted p = 0.004) were both significantly lower in the AG+GG genotypes. In the AG+GG genotypes, the prevalence of diabetes (8% vs 18%, age-sex-BMI-adjusted p = 0.02) and insulin plasma levels tended to be lower (4.8 vs 5.7 MUU/ml, age-sex-BMI adjusted p = 0.04) whereas HDL-cholesterol levels tended to be higher (55 vs 50 mg/dl, age-sex-BMI-adjusted p = 0.04). No association was found with hypertension. The association between the rs5068 G allele and a favorable metabolic phenotype is now shown in African Americans. The rs5068 AG+GG genotypes are associated with lower prevalence of metabolic syndrome and lower triglycerides values. PMID- 29253900 TI - Association between arterial hypertension and nutritional status in adolescents from Goiania, Goias, Brazil. AB - INTRODUCTION: Adolescents are a population with unique lifestyle challenges, including physical inactivity, inadequate nutrition, and obesity, all of which increase the risk of developing hypertension (HTN). The objective of this study has been to estimate the prevalence of factors associated with hypertension in adolescents in the city of Goiania City, Central Brazil. METHODS: Between 2013and2014, a cross-sectional population study on cardiovascular risk in adolescents, was conducted with the participation of 1,586 adolescents in 108 classes at 36 schools (public and private) in Goiania city. All of the adolescents were interviewed to establish their sociodemographic and behavioral characteristics related to hypertension and nutritional status. Anthropometric and blood pressure data were collected following a protocol. A Poisson regression, stratified by gender, was used to verify the factors associated with HTN. RESULTS: In this mixed-gender group of 1,586 students, the prevalence of HTN was 6.2% (95% CI: 4.6-8.2%) in girls and 14.0% (95% CI: 10.2-18.8%) in boys-about twice as high in boys as in girls (p <0.001). Obesity was independently associated with HTN in both genders. Being overweight was a risk factor for HTN. In addition, there was a positive correlation between the SBP/SBP percentile and the BMI Z-score/Nutritional status (NS)in both genders. A high prevalence of physical inactivity was also observed in the adolescents investigated, especially in the girls. On the other hand, more boys than girls were found to be obese. CONCLUSION: The results of this investigation revealed the need for strategies to prevent and control HTN and its risk factors, especially in Brazil's schools. In addition to the constant surveillance of HTN prevalence and risk factors (in particular, being overweight or obese), information should be distributed to promote beneficial health behaviors among adolescents. PMID- 29253901 TI - Single molecule sequencing of the M13 virus genome without amplification. AB - Next generation sequencing (NGS) has revolutionized life sciences research. However, GC bias and costly, time-intensive library preparation make NGS an ill fit for increasing sequencing demands in the clinic. A new class of third generation sequencing platforms has arrived to meet this need, capable of directly measuring DNA and RNA sequences at the single-molecule level without amplification. Here, we use the new GenoCare single-molecule sequencing platform from Direct Genomics to sequence the genome of the M13 virus. Our platform detects single-molecule fluorescence by total internal reflection microscopy, with sequencing-by-synthesis chemistry. We sequenced the genome of M13 to a depth of 316x, with 100% coverage. We determined a consensus sequence accuracy of 100%. In contrast to GC bias inherent to NGS results, we demonstrated that our single molecule sequencing method yields minimal GC bias. PMID- 29253902 TI - Rapid identification of candidate genes for resistance to tomato late blight disease using next-generation sequencing technologies. AB - Tomato late blight caused by Phytophthora infestans (Mont.) de Bary, also known as the Irish famine pathogen, is one of the most destructive plant diseases. Wild relatives of tomato possess useful resistance genes against this disease, and could therefore be used in breeding to improve cultivated varieties. In the genome of a wild relative of tomato, Solanum habrochaites accession LA1777, we identified a new quantitative trait locus for resistance against blight caused by an aggressive Egyptian isolate of P. infestans. Using double-digest restriction site-associated DNA sequencing (ddRAD-Seq) technology, we determined 6,514 genome wide SNP genotypes of an F2 population derived from an interspecific cross. Subsequent association analysis of genotypes and phenotypes of the mapping population revealed that a 6.8 Mb genome region on chromosome 6 was a candidate locus for disease resistance. Whole-genome resequencing analysis revealed that 298 genes in this region potentially had functional differences between the parental lines. Among of them, two genes with missense mutations, Solyc06g071810.1 and Solyc06g083640.3, were considered to be potential candidates for disease resistance. SNP and SSR markers linking to this region can be used in marker-assisted selection in future breeding programs for late blight disease, including introgression of new genetic loci from wild species. In addition, the approach developed in this study provides a model for identification of other genes for attractive agronomical traits. PMID- 29253903 TI - Cell-to-cell variation and specialization in sugar metabolism in clonal bacterial populations. AB - While we have good understanding of bacterial metabolism at the population level, we know little about the metabolic behavior of individual cells: do single cells in clonal populations sometimes specialize on different metabolic pathways? Such metabolic specialization could be driven by stochastic gene expression and could provide individual cells with growth benefits of specialization. We measured the degree of phenotypic specialization in two parallel metabolic pathways, the assimilation of glucose and arabinose. We grew Escherichia coli in chemostats, and used isotope-labeled sugars in combination with nanometer-scale secondary ion mass spectrometry and mathematical modeling to quantify sugar assimilation at the single-cell level. We found large variation in metabolic activities between single cells, both in absolute assimilation and in the degree to which individual cells specialize in the assimilation of different sugars. Analysis of transcriptional reporters indicated that this variation was at least partially based on cell-to-cell variation in gene expression. Metabolic differences between cells in clonal populations could potentially reduce metabolic incompatibilities between different pathways, and increase the rate at which parallel reactions can be performed. PMID- 29253905 TI - Hidden early-warning signals in scale-free networks. AB - Critical transitions of complex systems can often be predicted by so-called early warning signals (EWS). In some cases, however, such signals cannot be detected although a critical transition is imminent. Observing a relation of EWS detectability and the network topology in which the system is implemented, we simulate and investigate scale-free networks and identify which networks show, and which do not show EWS in the framework of a two state system that exhibits critical transitions. Additionally, we adapt our approach by examining the effective state of the system, rather than its natural state, and conclude that this transformation can reveal hidden EWS in networks where those signals are otherwise obscured by a complex topology. PMID- 29253904 TI - Pathogen-associated molecular patterns alter molecular clock gene expression in mouse splenocytes. AB - Circadian rhythms are endogenous 24-h oscillations that influence a multitude of physiological processes. The pathogen-associated molecular pattern (PAMP), lipopolysaccharide, has been shown to modify the circadian molecular clock. The aim of this study was to determine if other PAMPs alter clock gene expression. Therefore, mRNA levels of clock genes (Per2, Bmal1, Rev-erbalpha, and Dbp) were measured after an ex vivo challenge with several PAMPs and to further test the relevance of PAMP alteration of the molecular clock, an in vivo poly(I:C) challenge was performed. This study revealed that several other PAMPs are also capable of altering clock gene expression. PMID- 29253908 TI - Cytotoxic Deoxypodophyllotoxin Can Be Extracted in High Purity from Anthriscus sylvestris Roots by Supercritical Carbon Dioxide. AB - Deoxypodophyllotoxin is present in the roots of Anthriscus sylvestris. This compound is cytotoxic on its own, but it can also be converted into podophyllotoxin, which is in high demand as a precursor for the important anticancer drugs etoposide and teniposide. In this study, deoxypodophyllotoxin is extracted from A. sylvestris roots by supercritical carbon dioxide extraction. The process is simple and scalable. The supercritical carbon dioxide method extracts 75 - 80% of the total deoxypodophyllotoxin content, which is comparable to a single extraction by traditional Soxhlet. However, less polar components are extracted. The activity of the supercritical carbon dioxide extract containing deoxypodophyllotoxin was assessed by demonstrating that the extract arrests A549 and HeLa cells in the G2/M phase of the cell cycle. We conclude that biologically active deoxypodophyllotoxin can be extracted from A. sylvestris by supercritical carbon dioxide extraction. The method is solvent free and more sustainable compared to traditional methods. PMID- 29253909 TI - Effect of Levetiracetam Monotherapy in Nonlesional Focal Childhood Epilepsy. AB - This article compares the efficacy and tolerability of carbamazepine (CBZ) and levetiracetam (LEV) when used as initial monotherapy in children with nonlesional focal epilepsy. Patients with nonlesional focal epilepsy were subdivided into two groups according to the initial monotherapy: a LEV group administered LEV at an initial dose of 5 mg/kg/day and a CBZ group. Seizure response, adverse events, medication dose, reasons for discontinuing medication, adherence, and random serum levels were recorded. The overall percentage of patients who failed initial treatment and reasons for each treatment failure were determined. Data were analyzed from 183 children who received CBZ monotherapy and 46 children who received LEV monotherapy for >=12 months. Overall, 126 patients (68.9%) became seizure-free with CBZ, compared with 37 patients (80.4%) with LEV. Moreover, four patients in CBZ and four patients in LEV groups showed a >50% reduction in seizure frequency. The efficacy rate was significantly higher and the adverse event rate was significantly lower in the LEV group than in the CBZ group (p = 0.0129 and p = 0.0039, respectively). LEV may offer superior efficacy and a lower risk of adverse effects compared with CBZ. LEV as initial monotherapy may represent a valuable treatment option for children with nonlesional focal childhood epilepsy. PMID- 29253906 TI - A hemolytic-uremic syndrome-associated strain O113:H21 Shiga toxin-producing Escherichia coli specifically expresses a transcriptional module containing dicA and is related to gene network dysregulation in Caco-2 cells. AB - Shiga toxin-producing (Stx) Escherichia coli (STEC) O113:H21 strains are associated with human diarrhea and some of these strains may cause hemolytic uremic syndrome (HUS). The molecular mechanism underlying this capacity and the differential host cell response to HUS-causing strains are not yet completely understood. In Brazil O113:H21 strains are commonly found in cattle but, so far, were not isolated from HUS patients. Here we conducted comparative gene co expression network (GCN) analyses of two O113:H21 STEC strains: EH41, reference strain, isolated from HUS patient in Australia, and Ec472/01, isolated from cattle feces in Brazil. These strains were cultured in fresh or in Caco-2 cell conditioned media. GCN analyses were also accomplished for cultured Caco-2 cells exposed to EH41 or Ec472/01. Differential transcriptome profiles for EH41 and Ec472/01 were not significantly changed by exposure to fresh or Caco-2 conditioned media. Conversely, global gene expression comparison of both strains cultured in conditioned medium revealed a gene set exclusively expressed in EH41, which includes the dicA putative virulence factor regulator. Network analysis showed that this set of genes constitutes an EH41 specific transcriptional module. PCR analysis in Ec472/01 and in other 10 Brazilian cattle-isolated STEC strains revealed absence of dicA in all these strains. The GCNs of Caco-2 cells exposed to EH41 or to Ec472/01 presented a major transcriptional module containing many hubs related to inflammatory response that was not found in the GCN of control cells. Moreover, EH41 seems to cause gene network dysregulation in Caco-2 as evidenced by the large number of genes with high positive and negative covariance interactions. EH41 grows slowly than Ec472/01 when cultured in Caco-2 conditioned medium and fitness-related genes are hypoexpressed in that strain. Therefore, EH41 virulence may be derived from its capacity for dysregulating enterocyte genome functioning and its enhanced enteric survival due to slow growth. PMID- 29253907 TI - Inhibiting DPP4 in a mouse model of HHT1 results in a shift towards regenerative macrophages and reduces fibrosis after myocardial infarction. AB - AIMS: Hereditary Hemorrhagic Telangiectasia type-1 (HHT1) is a genetic vascular disorder caused by haploinsufficiency of the TGFbeta co-receptor endoglin. Dysfunctional homing of HHT1 mononuclear cells (MNCs) towards the infarcted myocardium hampers cardiac recovery. HHT1-MNCs have elevated expression of dipeptidyl peptidase-4 (DPP4/CD26), which inhibits recruitment of CXCR4 expressing MNCs by inactivation of stromal cell-derived factor 1 (SDF1). We hypothesize that inhibiting DPP4 will restore homing of HHT1-MNCs to the infarcted heart and improve cardiac recovery. METHODS AND RESULTS: After inducing myocardial infarction (MI), wild type (WT) and endoglin heterozygous (Eng+/-) mice were treated for 5 days with the DPP4 inhibitor Diprotin A (DipA). DipA increased the number of CXCR4+ MNCs residing in the infarcted Eng+/- hearts (Eng+/- 73.17+/-12.67 vs. Eng+/- treated 157.00+/-11.61, P = 0.0003) and significantly reduced infarct size (Eng+/- 46.60+/-9.33% vs. Eng+/- treated 27.02+/-3.04%, P = 0.03). Echocardiography demonstrated that DipA treatment slightly deteriorated heart function in Eng+/- mice. An increased number of capillaries (Eng+/- 61.63+/-1.43 vs. Eng+/- treated 74.30+/-1.74, P = 0.001) were detected in the infarct border zone whereas the number of arteries was reduced (Eng+/- 11.88+/-0.63 vs. Eng+/- treated 6.38+/-0.97, P = 0.003). Interestingly, while less M2 regenerative macrophages were present in Eng+/- hearts prior to DipA treatment, (WT 29.88+/-1.52% vs. Eng+/- 12.34+/-1.64%, P<0.0001), DPP4 inhibition restored the number of M2 macrophages to wild type levels. CONCLUSIONS: In this study, we demonstrate that systemic DPP4 inhibition restores the impaired MNC homing in Eng+/- animals post-MI, and enhances cardiac repair, which might be explained by restoring the balance between the inflammatory and regenerative macrophages present in the heart. PMID- 29253910 TI - Whole Exon Deletion in the GFAP Gene Is a Novel Molecular Mechanism Causing Alexander Disease. AB - Alexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white-gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease. PMID- 29253911 TI - Comparison of Cervicovaginal Cytopathological Samples Collected in Basic Health Units and in Private Clinics in the Midwest of Santa Catarina. AB - OBJECTIVE: To compare the quality of cervicovaginal samples obtained from basic health units (BHUs) of the Unified Health System (SUS) and those obtained from private clinics to screen precursor lesions of cervical cancer. METHODS: It was an intervention study whose investigated variables were: adequacy of the samples; presence of epithelia in the samples, and cytopathological results. A total of 940 forms containing the analysis of the biological samples were examined: 470 forms of women attended at BHUs of the SUS and 470 forms of women examined in private clinics in January and February of 2016. RESULTS: All the unsatisfactory samples were collected at BHUs and corresponded to 4% of the total in this sector (p < 0.0001). There was a higher percentage of samples containing only squamous cells in the SUS (43.9%). There was squamocolumnar junction (SJC) representativeness in 82.1% of the samples from the private clinics (p < 0.0001). Regarding negative results for intraepithelial lesions and/or malignancies, the percentages obtained were 95.9% and 99.1% (p < 0.0049) in the exams collected in the private system and SUS, respectively. Less serious lesions corresponded to 0.89% of the samples from the SUS and 2.56% of the tests from the private sector; more serious lesions were not represented in the samples obtained from BHUs, whereas the percentage was 1.49% in private institutions. CONCLUSION: Unsatisfactory cervical samples were observed only in exams performed at the SUS. There is a need for guidance and training of professionals who perform this procedure to achieve higher reliability in the results and more safety for women who undergo this preventive test. PMID- 29253912 TI - Vertical Transmission of HIV-1 in the Metropolitan Area of Belo Horizonte, Brazil: 2006-2014. AB - OBJECTIVE: To revise HIV-1 vertical transmission (VT) rates in the metropolitan area of Belo Horizonte, Brazil, from January of 2006 to December of 2014. METHODS: Descriptive study of a prospective cohort of HIV-1-infected pregnant women and their children, monitored by the Maternal and Child HIV/Aids Research Group of Research Group at Faculty of Medicine of Universidade Federal de Minas Gerais, Brazil. RESULTS: The VT general rate was 1.9% (13/673; confidence interval [CI] 95%: 1.0-3.3). The extensive use of combined highly active antiretroviral therapy (HAART) (89.7%; 583/650) strongly impacted the reduction of VT during this period. Maternal viral load (VL) higher than 1,000 copies/mL showed significant association with VT (OR:6.6; CI 95%:1.3-33.3). Maternal breastfeeding was described in 10 cases in this cohort (1.5%; CI 95%: 0.7-2.7), but it was not associated with VT. CONCLUSION: The present cohort data were coherent with the low VT rate described in other global populations, and it was considerably lower in comparison to the results of the same cohort during the period of 1998-2005, when the VT rate was 6.2%. These data confirm the efficiency of the National Guidelines, and emphasize the importance of adopting the international recommended procedures for prevention of mother-to-child transmission (MTCT) of HIV. PMID- 29253913 TI - Body Mass Index Changes during Pregnancy and Perinatal Outcomes - A Cross Sectional Study. AB - OBJECTIVE: To evaluate the relation between changes the body mass index (BMI) percentile, reflected in the Atalah curve, and perinatal outcomes. METHODS: A cross-sectional study with 1,279 women was performed. Data regarding gestational weight, sociodemographic characteristics and perinatal outcomes were collected through medical charts, prenatal card and interviews in the postpartum period. Women could be classified according to the Atalah curve in the following categories: low weight, adequate weight, overweight, and obese. The BMI was calculated at the first and at the last prenatal care visits, and these values were compared. RESULTS: An increase in the BMI category according to the Atalah classification occurred in 19.9% of pregnant women, and an increase of 3.4, 5.8 and 6.4 points of BMI were found for women respectively classified in the adequate weight, overweight and obese categories at the first prenatal visit. Women with high school education presented a lower chance of increasing their BMI (odds ratio [OR] 0:47 [0.24- 0.95]). Women who evolved with an increase in the the Atalah classification were associated with cesarean section (OR 1.97-2.28), fetal macrosomia (OR 4.13-12.54) and large for gestational age newborn (OR 2.88 9.83). CONCLUSION: Pregnant women who gained enough weight to move up in their BMI classification according to the Atalah curve had a higher chance of cesarean section and macrosomia. Women classified as obese, according to the Atalah curve, at the first prenatal visit had a high chance of cesarean section and delivering a large for gestational age newborn. PMID- 29253914 TI - [Preschool Examination in Baden-Wuerttemberg: Results of a Survey by Local Health Authorities]. AB - AIMS: German federal states conduct preschool examinations of children, to assess risks to their success in school. In 2009, step 1 of the preschool examination (ESU) in the German federal state Baden-Wuerttemberg (BaW) was preponed to the second-to-last year of kindergarten (age 4-5) to gain enough time for developmental interventions. Procedures and practice of ESU by local health authorities (HAs) in step 1 and step 2 (last year of kindergarten) were analyzed to infer strengths, weaknesses and requirements for change in the current ESU format. METHODS: The staff of 38 local HAs completed an extensive questionnaire on basic data, resources, acceptance, cooperation, content, methods and effects of ESU and enhanced their responses in free-text comments. The questionnaire was based on the statewide, standardized procedures of the ESU. RESULTS: In step 1, a median number of 2091 children were examined per HA. In step 2, the median number of children was 192. Staff resources were rated as insufficient by some HAs. ESU was rated as indispensable or helpful by most HAs. Much emphasis was placed on communication with parents and kindergarten teachers. ESU was performed completely or largely in accordance with the state-wide standards. Some changes in developmental screening were desired. Ratings of kindergarten teachers and parental questionnaires were regarded as helpful. According to HA estimates, about 20% of children suffer from health or developmental problems that are relevant to success in school, especially language problems. Information on developmental interventions following ESU is often missing. CONCLUSION: According to HAs, conducting step 1 of the ESU earlier, i. e. in the second-to-last year of kindergarten, has been a success and this change is well accepted. It seems sensible to further refine ESU screening methods and questionnaires. Feedback on developmental interventions following ESU should be the rule. Step 2 of the ESU in the last year of kindergarten should focus on children with special needs and their parents and teachers. PMID- 29253915 TI - [Evaluation of a Proactive Health Programme for Insured Persons with Persistent Back Pain: One-year Follow-up of a Randomised Controlled Trial]. AB - Background To facilitate access to evidence-based care for persisting back pain, a private medical insurance developed a health programme and offered it proactively to their members. The aim of this study was to evaluate the feasibility and efficacy of this procedure. Methods The design of the study was a Zelen randomized controlled trial. Adult insured persons with persistent back pain were randomized to the control (CG) or intervention group (IG) prior to giving consent. The IG was invited to participate in the health programme, the CG in a survey. Primary outcomes were back pain intensity and disability (according to von Korff) and health-related quality of life (SF-12). At baseline, 12- and 24 month follow-up, outcomes were documented by identical online questionnaires. Results 552 of 3462 randomized insured persons agreed to participate in the study; 132 of 258 (51.2%) from the IG and 243 of 294 (82.7%) from the CG completed the questionnaires at the 12-month follow-up. Small beneficial effects were seen for 3 of 4 primary outcomes. Compared to the CG, the IG reported less severe pain intensity (38.6 vs 44.5; p=0.001; d=0.36) and less disability (1.6 vs 2.2; p=0.002; d=0.41). The IG scored better at the SF-12 physical health scale (43.6 vs 39.0; p<0.001; d=0.54); no beneficial effect was seen in the SF-12 mental health scale. Conclusions The pro-active health programme seems to be feasible and effective as determined by patient-reported outcomes. Final evaluation awaits cost analysis and the results of the 24-month follow-up. PMID- 29253916 TI - [Consultation of Mushroom Experts As a Part of the Public Health Service in Mecklenburg-West Pomerania]. AB - The consultation of people regarding the edibility of mushrooms is realized by mushroom experts, who are working on behalf of public health authorities. State and district authorities are involved in this process. How does the division of labour works, which legal backgrounds exist and which tasks do have the responsible actors, is content of this work. PMID- 29253917 TI - [Meeting the challenge of Easy-to-Read language - Translating the North Rhine Westphalian Public Health Report 2015 into Easy-to-Read language]. AB - BACKGROUND AND METHODS: The United Nations Convention on the Rights of Persons with Disabilities determines amongst others the right of access to information. Information for the general public must be made accessible for persons with disabilities in formats and technologies appropriate to different kinds of disabilities. The language poses the largest barrier for people with learning difficulties. Therefore, we translated parts of the Public Health Report 2015 of North Rhine-Westphalia into an Easy-to-Read language.The translation was performed by a professional translation agency in cooperation with an assessment group, composed by people with learning problems, and the NRW Centre for Health (LZG.NRW).During the translation the population health monitoring group of the LZG.NRW experienced several challenges. The scope of these challenges and the chosen solutions are described in detail in this paper. RESULTS: 3 challenges were experienced clearly during the translation of the Public Health Report: (1) (Large) numbers and rates are a key element in population health monitoring but they should be avoided in texts in Easy-to-Read language. (2) The translation of the age-standardization approach and the related effects appeared to be difficult. (3) Finding the right balance between the description of lifestyle influences and the influence of the wider health determinants as well as finding a non-discriminatory wording regarding the influence of social health determinants were challenging.The following approaches were chosen to counteract these challenges: (1) We avoided to report numbers and rates. In some cases simple fractions are presented. In addition, all of these fractions were explained and visualized in the introductory section of the translated report. (2) We resigned to describe time trends. In some cases time trends were mentioned as crude rates and an explanation of potential effects (e.g., demographic change) was added. If gender specific differences occurred in the crude and age standardised rates, we described the age-standardised differences. (3) The relativization of direct and striking formulations regarding the influence of the social health determinants and the inclusion of recommendations related to the scope of upstream determinants needed to be recognized and incorporated. CONCLUSION: Translating a public health report into Easy-to-Read language is a challenging process. Continuous and smooth cooperation between translators, the assessment group and the authors of the original report is mandatory to be successful. PMID- 29253918 TI - Motorized spiral colonoscopy: a first single-center feasibility trial. AB - BACKGROUND: Cecal intubation rate represents a key procedural quality parameter in diagnostic colonoscopy. However, even experienced investigators report 10 % of all colonoscopies to be difficult and intubation of the cecum is sometimes impossible. A recently developed novel motorized spiral endoscope might potentially overcome some limitations of standard colonoscopy by actively pleating the bowel onto the endoscope. The study aim was to evaluate the feasibility and safety of motorized spiral colonoscopy (MSC) for diagnostic colonoscopy. METHODS: 30 consecutive patients with an indication for diagnostic colonoscopy were enrolled in a proof-of-concept single-center trial. RESULTS: 13 men and 17 women (mean age 68.9 years, range 30 - 90) were enrolled; 43.3 % had diverticula. Mean procedure time was 20.8 min (range 11.4 - 55.3). Cecal intubation rate was 96.7 %. One incomplete colonoscopy occurred because of an unexpected postinflammatory stricture. Adenoma detection rate was 46.6 %. No severe adverse events occurred. CONCLUSIONS: Results indicate that MSC is safe and effective for diagnostic colonoscopy. It potentially offers advantages in terms of ease and it may facilitate therapeutic interventions. PMID- 29253919 TI - Purse-string transoral outlet reduction (TORe) is effective at inducing weight loss and improvement in metabolic comorbidities after Roux-en-Y gastric bypass. AB - : BACKGROUND AND STUDY AIMS : Transoral outlet reduction (TORe), performed using a traditional interrupted or a recently described purse-string suture pattern, is effective at inducing short- and mid-term weight loss in patients with weight regain after Roux-en-Y gastric bypass (RYGB). We aimed to determine the technical feasibility and safety of purse-string TORe and to assess its impact on weight and metabolic profiles. PATIENTS AND METHODS: RYGB patients undergoing purse string TORe were included. The gastrojejunal anastomosis (GJA) was ablated using argon plasma coagulation or dissected using endoscopic submucosal dissection. A suture was used to place stitches around the GJA in a continuous ring fashion. The suture was cinched over a balloon (8 - 12 mm). The primary outcome was technical feasibility. Secondary outcomes were the percentage of total body weight lost (%TWL), adverse events, impact on comorbidities, and predictors of weight loss. RESULTS: 252 RYGB patients underwent 260 purse-string TORes. They had regained 52.6 +/- 46.4 % of lost weight and weighed 107.6 +/- 24.6 kg. The technical success rate was 100 %. At 6 and 12 months, %TWL was 9.6 +/- 6.3 and 8.4 +/- 8.2. Two serious adverse events (0.8 %) occurred: gastrointestinal bleeding and GJA stenosis. At 12 months, blood pressure, hemoglobin A1c, and ALT had improved. Prior weight regain was associated with %TWL at 12 months (beta = 0.07, P = 0.007) after controlling for BMI, pouch size, and number of purse string rings. CONCLUSION: Purse-string TORe to treat weight regain after RYGB is technically feasible and safe. Additionally, it is associated with improvement in weight and comorbidity profiles up to 12 months post-procedure. PMID- 29253920 TI - Long-acting inhaled bronchodilators for cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is a life-limiting inherited condition which affects one in 2500 newborns in the UK and 70,000 children and adults worldwide. The condition is multifaceted and affects many systems in the body. The respiratory system is particularly affected due to a build up of thickened secretions and a predisposition to infection. Inhaled bronchodilators are prescribed for 80% of people with cystic fibrosis in order to widen the airways and alleviate symptoms. Both short- and long-acting inhaled bronchodilators are used to improve respiratory symptoms. Short-acting inhaled bronchodilators take effect in minutes and typically last for four to eight hours (muscarinic antagonists). Long-acting inhaled bronchodilators also take effect within minutes but typically last for around 12 hours and sometimes longer. This review is one of two which are replacing a previously published review of both long- and short-acting inhaled bronchodilators. OBJECTIVES: This review aims to evaluate long-acting inhaled bronchodilators in children and adults with cystic fibrosis in terms of clinical outcomes and safety. If possible, we aimed to assess the optimal drug and dosage regimen. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books.Date of last search: 10 October 2017.We also carried out a separate search of Embase and the reference lists of included trials. We searched clinical trials registries for any ongoing trials and made contact with pharmaceutical companies for any further trials.Date of Embase search: 11 October 2017. SELECTION CRITERIA: Randomised or quasi-randomised parallel trials comparing long-acting inhaled bronchodilators (beta-2 agonists and muscarinic antagonists) with placebo, no treatment or a different long-acting inhaled bronchodilator in adults and children with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Both authors independently assessed trials for inclusion (based on title, abstract and full text). The authors independently assessed the included trials for quality and risk of bias and extracted data. Discrepancies were resolved by a third party. MAIN RESULTS: The searches identified 195 unique references, of which 155 were excluded on title and abstract. We assessed the full texts of the remaining references, excluded 16 trials (28 references) and included four trials (12 references) in the review with 1082 participants.One trial (n = 16) measuring the effect of beta-2 agonists reported an improvement in forced expiratory volume at one second (FEV1) after treatment (at one month), but the trial was small with an unclear risk of bias so we judged the evidence to be very low quality. The trial did not report on participant-reported outcomes, quality of life or adverse events.Three trials (n = 1066) looked at the effects of the muscarinic antagonist tiotropium at doses of 2.5 ug and 5.0 ug in both the short term (up to 28 days) and the longer term (up to three months). Only one of the trials reported the change in FEV1 (L) after 28 days treatment and showed no significant difference between groups; with 2.5 ug tiotropium, mean difference (MD) -0.02 (95% confidence interval (CI) -0.13 to 0.09), or 5.0 ug tiotropium, MD 0.00 (95% CI -0.10 to 0.10) (moderate-quality evidence). All three trials of muscarinic antagonists provided data on adverse events which were found to differ little from placebo at doses of 2.5 ug, risk ratio (RR) 1.01 (95% CI 0.92 to 1.11) or 5.0 ug, RR 0.98 (95% CI 0.90 to 1.06). Very little participant-reported outcome data or quality of life data were available for analysis. Two of the trials were at low risk of bias overall whilst the remaining trial was at an unclear risk overall. AUTHORS' CONCLUSIONS: Neither long-acting beta-2 agonists nor long-acting muscarinic antagonist bronchodilators demonstrate improvement in our primary outcome of FEV1. No difference was observed between intervention and placebo in terms of quality of life or adverse events. The quality of evidence for the use of beta-2 agonists was very low. The use of a long-acting inhaled bronchodilator may help to reduce the burden of treatment for people with cystic fibrosis as it is taken less often than a short-acting inhaled bronchodilator, but future trials would benefit from looking at the effects on our primary outcomes (spirometric changes from baseline, quality of life and adverse effects) in the longer term. PMID- 29253921 TI - Singing for adults with chronic obstructive pulmonary disease (COPD). AB - BACKGROUND: Singing is a complex physical activity dependent on the use of the lungs for air supply to regulate airflow and create large lung volumes. In singing, exhalation is active and requires active diaphragm contraction and good posture. Chronic obstructive pulmonary disease (COPD) is a progressive, chronic lung disease characterised by airflow obstruction. Singing is an activity with potential to improve health outcomes in people with COPD. OBJECTIVES: To determine the effect of singing on health-related quality of life and dyspnoea in people with COPD. SEARCH METHODS: We identified trials from the Cochrane Airways Specialised Register, ClinicalTrials.gov, the World Health Organization trials portal and PEDro, from their inception to August 2017. We also reviewed reference lists of all primary studies and review articles for additional references. SELECTION CRITERIA: We included randomised controlled trials in people with stable COPD, in which structured supervised singing training of at least four sessions over four weeks' total duration was performed. The singing could be performed individually or as part of a group (choir) facilitated by a singing leader. Studies were included if they compared: 1) singing versus no intervention (usual care) or another control intervention; or 2) singing plus pulmonary rehabilitation versus pulmonary rehabilitation alone. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected trials for inclusion, extracted outcome data and assessed risk of bias. We contacted authors of trials for missing data. We calculated mean differences (MDs) using a random effects model. We were only able to analyse data for the comparison of singing versus no intervention or a control group. MAIN RESULTS: Three studies (a total of 112 participants) were included. All studies randomised participants to a singing group or a control group. The comparison groups included a film workshop, handcraft work, and no intervention. The frequency of the singing intervention in the studies ranged from 1 to 2 times a week over a 6 to 24 week period. The duration of each singing session was 60 minutes.All studies included participants diagnosed with COPD with a mean age ranging from 67 to 72 years and a mean forced expiratory volume in one second (FEV1) ranging from 37% to 64% of predicted values. The sample size of included studies was small (33 to 43 participants) and overall study quality was low to very low. Blinding of personnel and participants was not possible due to the physical nature of the intervention, and selection and reporting bias was present in two studies.For the primary outcome of health related quality of life, there was no statistically significant improvement in the St George's Respiratory Questionnaire total score (mean difference (MD) 0.82, 95% confidence interval (CI) -4.67 to 3.02, 2 studies, n = 58, low-quality evidence). However, there was a statistically significant improvement in the SF 36 Physical Component Summary (PCS) score favouring the singing group (MD 12.64, 95% CI 5.50 to 19.77, 2 studies, n = 52, low-quality evidence). Only one study reported results for the other primary outcome of dyspnoea, in which the mean improvement in Baseline Dyspnoea Index (BDI) score favouring the singing group was not statistically significant (MD 0.40, 95% CI -0.65 to 1.45, 1 study, n = 30, very low-quality evidence).No studies examined any long-term outcomes and no adverse events or side effects were reported. AUTHORS' CONCLUSIONS: There is low to very low-quality evidence that singing is safe for people with COPD and improves physical health (as measured by the SF-36 physical component score), but not dyspnoea or respiratory-specific quality of life. The evidence is limited due to the low number of studies and the small sample size of each study. No evidence exists examining the long-term effect of singing for people with COPD. The absence of studies examining singing performed in conjunction with pulmonary rehabilitation precludes the formulation of conclusions about the effects of singing in this context. More randomised controlled trials with larger sample sizes and long-term follow-up, and trials examining the effect of singing in addition to pulmonary rehabilitation, are required to determine the effect of singing on health-related quality of life and dyspnoea in people with COPD. PMID- 29253922 TI - Prevalence and Genotyping of Torque Teno Virus in HBV/HIV and Chronic HBV Patients in Iran AB - Background: Torque teno virus (TTV) was the first human Anelloviridae detected in a Japanese patient with an unknown type of hepatitis in 1997. TTV is by far the first known single-stranded circular DNA virus infecting human. In spite of its widespread nature in human population, its pathogenesis is still unclear. In addition, information regarding TTV infection in Iranian population is limited. Therefore, we attempted to determine the prevalence and genotype of TTV in three groups: HIV/HBV patients, chronic hepatitis B patients, and healthy individuals. Methods: The presence of TTV DNA in sera was investigated using PCR. The primer sets encompassing two 5?-UTR and N22 regions were used, and the positive products were collected for sequencing. Phylogenetic tree was generated based on N22 region and using the MEGA 7 software. Results: TTV DNA was detected in 452 patients with HIV/HBV and chronic hepatitis B, as well as in healthy control groups. The results from PCR indicated positive rates for these three groups, 48%, 54%, and 49.3% using 5?-UTR primer and 15.1%, 12%, and 8% using N22 primer, respectively. Conclusion: Five genogroups were observed, which the second group was found to be the most frequent. The results of 5?-UTR primer showed more prevalence of TTV DNA comparing to N22 primer in patients and healthy control. PMID- 29253923 TI - IR 780-loaded hyaluronic acid micelles for enhanced tumor-targeted photothermal therapy. AB - In this study, we propose using IR 780-loaded, CD44-targeted hyaluronic acid based micelles (HA-IR 780) for enhanced photothermal therapy (PTT) effects in tumors. Two kinds of HA-C18 micelles were synthesized from different C18 feed ratios with degree of substitution of 3% and 13% respectively. Three different IR 780 weight percentages were used for micelle formation with loading content of 4.6%, 7.9%, and 10.3% respectively. The IC50 value of HA-IR 780 in TC1 cells was 21.89MUgmL-1 (32.81MUM). Upon irradiation of the tumor site with an 808-nm laser (2Wcm-2) for 2min, the temperature in the tumor in the HA-IR 780-treated groups reached 49.9 degrees C which exceeds the temperature threshold to induce irreversible tissue damage. Toxicity studies showed that HA-IR 780 does not cause any adverse effects in organs, including heart, liver, lungs, kidney and spleen, although it selectively caused cell damage in the tumor region upon laser irradiation. Therefore, the present study suggests that HA-IR 780 can cause selective cell death in tumor regions due to its enhanced tumor-targeting and photothermal capabilities. PMID- 29253924 TI - Hyaluronate dots for highly efficient photodynamic therapy. AB - Nanoscale particles, such as quantum dots and carbon dots, are important materials for use in sensing and treating irregular biological events, but their versatility for biomedical applications are usually limited by their undesirable properties such toxicity and non-degradability. Here, we report biofunctional hyaluronic acid (HA) dots containing biodegradable/biocompatible HA. HA dots were prepared by conjugating multiple HA molecules to C60 (used as a base dot) without any hydrothermal treatment. The hydroxyl groups of HA completely linked to all pi pi carbon bonds in C60. The chemically synthesized HA dots (Mn=16.1kDa) were 2nm in diameter, soluble in aqueous solution, and possessed multiple functional (carboxyl) groups. The HA dots were biofunctional, enabling highly efficient binding to CD44 receptors overexpressed on in vitro/in vivo tumors. With light illumination, we demonstrated that the HA dots bearing a photosensitizing model drug (chlorin e6: Ce6) resulted in a significant enhancement in in vitro/in vivo tumor cell ablation. We believe that this approach offers a new strategy to create biopolymer dots. PMID- 29253925 TI - A review on carbohydrate embedded polyurethanes: An emerging area in the scope of biomedical applications. AB - Polyurethanes (PUs) are expanding to newer horizons in the field of biomedical sciences, particularly due to their exceptional set of properties that deem fit for applications in the said field. On the other hand, carbohydrates find increasing attention as components of biomedical devices due to their easy availability from renewable resources. The manipulation of PUs by carbohydrate has solved the major concern of biodegradability, biocompatibility and economy. This review summarizes the recent trends in PUs embedded with carbohydrates ranging from monosaccharide to polysaccharides, including supramolecular host such as cyclodextrin etc. Diverse approaches for embedding them in PUs in various forms have been listed. In recent decade, significant research has been carried out to employ such polymers in biomedical applications such as drug delivery devices, implants, scaffolds for tissue engineering etc. This knowledge could facilitate the selection of more efficient approach for synthesis of polymeric systems based on the biological macromolecules. PMID- 29253926 TI - Effect of guar gum and salt concentrations on drag reduction and shear degradation properties of turbulent flow of water in a pipe. AB - Concentrated solutions of guar gum in water (1000-3000ppm) with and without KCl salt (1000-4000ppm) were injected near the wall for a short period (2.5min) to investigate their effect on drag reduction in turbulent flow of water through a pipe (Re~17000-45000). Relative to bulk solution, the concentrations of polymer and salt were 50-150ppm and 50-200ppm, respectively. A drag reduction of 71.45% was observed for 3000ppm of biopolymer without salt. Guar gum experienced mechanical degradation under high shear conditions and addition of KCl improved shear stability up to 47% (for Re~45000). A polymer concentration of 3000ppm and salt concentration of 2000ppm in the injection fluid were found to be optimum for achieving the highest drag reduction with better shear stability. Results indicated that boundary layer injection shows better drag reduction ability than pre-mixed solutions. PMID- 29253927 TI - Effects of chitosan molecular weight on its antioxidant and antimutagenic properties. AB - Chitosan (300.0kDa) was enzymatically degraded to obtain six degraded chitosans with molecular weights (MWs) of 156.0, 72.1, 29.2, 7.1, 3.3, and 2.2kDa. The antioxidant and antimutagenic properties of all seven chitosan samples were evaluated in vitro. The antioxidant scavenging activities of chitosans on hydrogen peroxide and 2, 2-diphenyl-1-picryl hydrazyl radical, and on chelating ferrous ion were significantly increased with chitosan's decreasing MW, with 2.2 kDa chitosan have the highest impact. All seven chitosan samples exhibited strong anitmutagenic effects against direct (4- nitroquinoline 1-oxide) and indirect (benzo[alpha]pyrene) mutagens in the presence of rat liver enzyme S9 mix in Salmonella typhimurium TA 98 and TA 100. The effect of MW on antimutagenicity was similar to that on antioxidant activity. The underlying mechanism for chitosan antimutagenicity proved to be its desmutagenic effect on mutagens. PMID- 29253928 TI - Activation of Na2S2O8 for dye degradation by Fe complexes fixed on polycarboxylic acids modified waste cotton. AB - Three aliphatic polycarboxylic acids (PCAs) including tartaric acid (TA), citric acid (CA) and 1,2,3,4-butanetetracarboxylic acid (BTCA) were used for the surface modification of waste cotton fiber by an industrialized pad-dry-cure process to introduce carboxyl groups, which then coordinated with Fe3+ ions to obtain three PCA modified cotton fiber Fe complexes. TA modified cotton fiber could easily react with Fe3+ ions to form its complex with high Fe content. Furthermore, TA modified cotton fiber Fe complex showed a better enhanced effect of activated Na2S2O8 to produce free oxygen radicals for the degradation of an azo dye, Reactive Red 195 than the other two complexes. Different critical Fe contents were found for three complexes to obtain the best enhanced effect. PMID- 29253929 TI - Co-encapsulation of curcumin and resveratrol into novel nutraceutical hyalurosomes nano-food delivery system based on oligo-hyaluronic acid-curcumin polymer. AB - In this work, in order to enhance the stability, bioavailability and antioxidant activity of insoluble antioxidants used into juice, yoghourt and nutritional supplements, the oligo-hyalurosomes nano-delivery system (CRHs) based on oligo hyaluronic acid -curcumin (oHC) polymer loaded curcumin(Cur) and resveratrol (Res) was fabricated with new nanotechnolgy. The rosy biodegradable amphiphilic oHC polymer was successfully synthesized and used to fabricate the hyalurosomes containing both Cur and Res, called CRHs. The CRHs can spontaneously self assemble into nano-sized spherical shape of average particle size 134.5+/-5.1nm and Zeta potential -29.4+/-1.2 at pH 7.4 PBS conditions. In vitro gastrointestinal release test showed a perfect stability and outstanding sustained release character. Moreover, compared to the single formulations and liposomes, CRHs showed a dose-dependent manner with a higher radical scavenging activity. Therefore, the novel CRHs nano-food manifested the hopeful properties for the new effective gastrointestinal formulation and promising new nano-food delivery system in the use of juice, yoghourt and nutritional supplements. PMID- 29253930 TI - Isolation and characterization of nanocrystalline cellulose from sugar palm fibres (Arenga Pinnata). AB - Cellulose was extracted from sugar palm fibres (Arenga pinnata) by conducting delignification and mercerization treatments. Subsequently, sugar palm nanocrystalline celluloses (SPNCCs) were isolated from the extracted cellulose with 60wt% concentrated sulphuric acid. The chemical composition of sugar palm fibres were determined at different stages of treatment. Structural analysis was carried out by Brunauer-Emmett-Teller (BET), X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR). Morphological analysis of extracted cellulose and isolated nanocrystalline cellulose (NCCs) was investigated by using field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), and transmission electron microscopy (TEM). The thermal stability of sugar palm fibres at different stages of treatment was investigated by thermogravimetric analysis (TGA). The results showed that lignin and hemicellulose were removed from the extracted cellulose through the delignification and mercerization process, respectively. The isolated SPNCCs were found to have length and diameters of 130+/-30nm and 9+/-1.96nm, respectively. PMID- 29253931 TI - Development of liquid repellent coating on cotton fabric by simple binary silanization with excellent self-cleaning and oil-water separation properties. AB - This paper aims to develop a facile and single step method for the fabrication of superhydrophobic coating on cotton fabric. The coating has been prepared by using two silane trichloro(octadecyl)silane and (pentaflurophenyl)triethoxy silane by solution immersion technique. The wettability, surface topography and chemical compostion of the cotton fabric before and after treatment were charecterized by contact angle measurement, scanning electron microscope, and energy dispersive X ray spectrum, respectively. Additionally, the functional group present in coating was analysed by FT-IR spectra. The coated fabric shows a contact angle of 172.9+/ 3 degrees , 169+/-3 degrees and 167+/-3 degrees for water, ethylene glycol and glycerol, respectively. The chemical stability of the coated sample has been evaluated by immersion of the sample in different pH solutions and different solvents, showing the excellent chemical stability of coating. Ultrasonication with water, detergent and petroleum ether, and water jet impact test reveals the mechanical stability of coating. The thermal stability of the coated fabric has been examined by annealing the sample at different temperature. Additionally, it shows resistance to stain and UV irradiation. Furthermore, the coated cotton fabric exhibits excellent self-cleaning and oil-water separation properties, which makes it suitable for industrial applications. PMID- 29253932 TI - Impact of TEMPO-oxidization strength on the properties of cellulose nanofibril reinforced polyvinyl acetate nanocomposites. AB - Nanocomposites of polyvinyl acetate (PVAc) reinforced with two different TEMPO oxidized cellulose nanofibrils (CNF) were prepared by casting/evaporation method. These two sets of CNF, designed as CNF-O-5min (5min of oxidation) and CNF-O 120min (120min of oxidation), are different by their surface charge, geometrical characteristics and crystallinity index. The weight fraction of CNF was changed from 1 to 10wt%. The mechanical and thermal properties of the nanocomposite films were studied by dynamic mechanical thermal analysis (DMTA), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and tensile tests, and their morphology was investigated by scanning electron microscopy (SEM). For all nanocomposites, increasing amounts of CNF led to a significant increase in the mechanical properties (increase in Young's modulus and tensile strength) and in the water uptake. On the other hand, the lost of transparency became very significant when the weight fraction of CNF exceeded 3wt%. The comparison between the two sets of CNF showed that PVAc/CNF-O-5min nanocomposite films had a tendency to display higher tensile strength and elastic modulus than those of PVAc/CNF-O-120min films. In addition, the water uptake is higher for PVAc/CNF-O 120min. Finally, the thermal stability analyses for PVAc/CNF films show that shorter and more charged fibrils (CNF-O-120min) appear to slightly increase the thermal stability compared to other larger and less charged fibrils (CNF-O-5min). All these results are discussed in connection with the CNFs characteristics. PMID- 29253933 TI - Ultrasound assisted polyacrylamide grafting on nano-fibrillated cellulose. AB - Polyacrylamide has been grafted onto nanofibrillated cellulose (NFC-g-PAM) under mild conditions. This was accomplished by developing and optimizing an ultrasound assisted protocol in the presence of potassium persulfate initiator. The synthesis was optimized on the basis of maximizing grafting percentage and grafting efficiency by varying the initiator and monomer concentration. The data shows that ultrasound has a profound effect in promoting the grafting of PAM onto NFC. The intended grafting was confirmed and the properties of the new co polymers were examined by elemental analyses, Fourier transform infrared spectroscopy, thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). Intrinsic viscosity determinations in 0.1M cupriethylenediamine solutions for the NFC-g-PAM copolymers and the starting NFC and PAM homopolymer revealed that grafting of PAM onto nanofibrillated cellulose has a profound effect on the hydrodynamic characteristics of the graft polymers. PMID- 29253934 TI - The characteristics of konjac glucomannan octenyl succinate (KGOS) prepared with different substitution rates. AB - The characteristics of octenyl succinic anhydride (OSA)-modified polysaccharide could be affected by its degree of reaction. Four konjac glucomannan octenyl succinate (KGOS) samples were prepared with different substitution rates (SRs) of 1.151%, 1.514%, 1.753% and 2.247%. The critical micelle concentration (CMC) of the four KGOS materials decreased with increasing SR. Fourier transform infrared (FT-IR) spectroscopy indicated that the increase in SR had little effect on the type of acyl peak. The viscosity test indicated that with SR increase, the viscosity increased slightly at low rotational speed. The emulsion capacity (EC) and stability (ES) also increased with increasing SR, but the extent of increase was not obvious when the SR exceeded 1.753%. A similar pattern was found in confocal scanning laser microscopy (CSLM) observations and ES tests of KGOS nanoemulsions. Considering the characteristics of KGOS and the economic benefits, it is preferable to prepare KGOS with an SR of 1.514% and additions of alkalizing agent and OSA (in proportion to konjac glucomannan (KGM), w/w) of 2% and 3%, respectively, during the KGOS preparation. PMID- 29253935 TI - Modification of cellulose foam paper for use as a high-quality biocide disinfectant filter for drinking water. AB - Development of a foam-formed cellulose filter paper with high wet strength was carried out for application as a drinking water filter. The wet strength and antimicrobial activity of cellulose foam paper against several bacteria species (Bacillus subtilis MTCC 441 (Gram +ve), B. cereus NCDC 240 (Gram +ve), Pseudomonas aeruginosa NCDC 105 (Gram -ve), Klebsiella pneumonia NCDC 138 (Gram ve), and Escherichia coli MTCC 40 (Gram -ve)) were investigated. The morphology and structure of the cellulose foam paper were characterized using scanning electron microscopy (SEM). The results of our study confirmed that glutaraldehyde solution or 1,2,3,4-butanetetracarboxylic acid (BTCA) added to cellulose foam paper pretreated with cationic polyacrylamide (C-PAM) provided very high and stable wet strength performance together with excellent antimicrobial properties. PMID- 29253936 TI - Curaua and eucalyptus nanofibers films by continuous casting: Mechanical and thermal properties. AB - A wide variety of new green materials such as curaua leaf fibers (CLFs) has potential applications in nanotechnology. This study aims to investigate the thermomechanical properties and morphological structure of cellulose nanocrystals (CNCs) and cellulose nanofibrils (CNFs) films obtained by continuous casting. The CNCs were obtained by acid hydrolysis and CNFs by mechanical shearing from bleached CLFs and eucalyptus pulp. The morphology after continuous casting resulted in oriented nanofibers, and as a consequence there was mechanical anisotropy. CNCs films showed the greatest values of tensile strength (36+/-4MPa) and the more effective fibrillation provided better mechanical strength of eucalyptus CNFs films than curaua CNFs films. Sulfur groups and mechanical shear degradation affected the stability of CNCs and CNFs films, respectively. Thus, the type of nanostructure, the way they interact to each other, the cellulose source and the process interfere significantly on the properties of the films. PMID- 29253938 TI - Simultaneous enhancement of elasticity and strength of Al2O3-based ceramics body from cellulose nanocrystals via gel-casting process. AB - A green gel-casting method was developed by the combination of rod-like cellulose nanocrystals (CNC) and low toxicity monomer N, N-dimethylacrylamide (DMAA), which was proved to be a promising substitute of traditional neurotoxin monomer acrylamide (AM). The hydrophilic nature and homogeneous dispersion of CNC in aqueous suspension ensured the essential compatibility with the hydrosoluble polymerization system, and therefore provided remarkable mechanical enhancement of green body. The bending strength of the green body was highly increased by 68% with the introduction of 0.9 wt0/00 CNC. Meanwhile, the fabricated green body exhibited significant improvement in flexibility and elasticity, with the unique bendable and recovery performances after drying treatment at room temperature for 1h. The computer stimulation by the COMSOL Multiphysics confirmed the special mechanical enhancement effect induced by the presence of highly-crystalline and rigid CNC. PMID- 29253937 TI - Non-leaching antibacterial cellulose triacetate reverse osmosis membrane via covalent immobilization of quaternary ammonium cations. AB - A novel procedure to fabricate quaternized cellulose triacetate reverse osmosis (QCTA-RO) membranes via the etherification procedure between partially hydrolyzed CTA-RO membrane and 3-chloro-2-hydroxypropyl-trimethyl ammonium chloride (CHPTAC) in alkaline solutions (pH=9-11) for different reaction time (1, 2, 3 and 4h) was proposed. The structure and performances of the obtained QCTA-RO membranes were characterized and their antibacterial performances against E. coli and S. aureus were evaluated through colony counting method. The results showed that quaternary amine group was successfully grafted on the surface of membrane via covalently bond without significant damage to morphology, mechanical performance and thermal stability. The permeation flux values increased with prolonging modification time to 3h, while the salt rejection decreased slightly but remained above 92%. QCTA RO membranes displayed good antibacterial activity against Gram-negative E. coli and Gram-positive S. aureus and their bactericidal rates were 78.7-89.0% and 64.7 76.6% respectively at the optimized modification time of 2-3h. PMID- 29253939 TI - Environment-friendly urea-oxidized starch adhesive with zero formaldehyde emission. AB - This study reports on an environment-friendly renewable and zero formaldehyde emission urea-oxidized starch (U-OSt) adhesive based on native corn starch. The adhesive was prepared by polycondensation reaction of oxidized starch and urea. The morphology, molecular structure, crystalline structure, shear strength and viscosity of the adhesive, the native and oxidized starch were instrumentally investigated. The influence of processing factors was studied, such as the oxidizer content, the urea content and the addition of titanium dioxide nanoparticle (nano-TiO2). The results show the adhesive has an excellent comprehensive performance at urea content of 50% (w/w, dry starch basis) while 5.0% (w/w, dry starch basis) KMnO4 as oxidizer. The dry shear strength was increased by 16.9% by adding of nano-TiO2 content of 1.5% (w/w, dry starch basis), and the corresponding viscosity was 4100mPas. It is found appropriate amount of nano-TiO2 played a complementary effect between adhesive and adherend, which enhanced the adhesive property and stability of adhesive. PMID- 29253940 TI - Chitosan-based polymer hybrids for thermo-responsive nanogel delivery of curcumin. AB - The purpose of this study is to design and develop thermoresponsive nano-sized hydrogel particles from a natural polymer, chitosan, as smart material platforms for curcumin delivery. Chitosan was used as the backbone material to be grafted with poly-(N-isopropylacrylamide) (pNIPAM) using an EDC/NHS coupling reaction. The conjugated products were characterized by 1H NMR and TGA. Chitosan-grafted pNIPAM (CS-g-pN) nanogels were prepared by a sonication method. The loading of curcumin into the CS-g-pN nanogels was achieved using an incubation method. Size, morphology of nanogels, amounts of curcumin loaded to the nanogels and cellular uptake were investigated by DLS, TEM, fluorescent spectroscopy and confocal microscopy techniques, respectively. A CellTiter-Blue(r) cell viability assay was performed in NIH-3T3 and HeLa cells to assess the safety while MTT assay was carried out in MDA-231, Caco-2, HepG2, and HT-29 cells for determining cytotoxic effects. Results showed that CS-g-pN with 3-60% degree of modification were simply assembled into spherical nanogel particles with submicron sizes, in which curcumin was encapsulated. The thermoresponsive behavior of each CS-g-pN nanogel formulation differed due to the grafted pNIPAM length and density. The CS-g-pN nanogel formulations were non-toxic towards NIH-3T3 and HeLa cells. Each curcumin loaded CS-g-pN nanogel formulation could be up taken into NIH-3T3 cell lines and showed the dose-dependent cytotoxicity against tested cell lines. Successful development of this curcumin-loaded nanogel will lead to advanced materials that can be functionalized and optimized for targeted therapy and controlled delivery of small molecules and/or biomolecules for biomedical applications. PMID- 29253941 TI - Synergistic effects of graft polymerization and polymer blending on the flexibility of xylan-based films. AB - To develop functional and sustainable films from xylan-based hemicelluloses, beechwood xylan was firstly modified with p-dioxanone (PDO) through ring-opening graft polymerization (ROGP) and then reinforced by poly(vinyl alcohol) (PVA) to fabricate xylan-graft-poly(p-dioxanone)/PVA (XGP/PVA) ternary composite films. FT IR spectra proved the existence of intermolecular hydrogen bonding interactions between the hydroxyl groups of XGP and PVA. SEM analysis outlined the good compatibility between the XGP matrix and the PVA filler in blending films. From DSC data, the miscibility between XGP and PVA led to increase in the glass transition temperature (Tg) and the crystallinity (Xc) of XGP. In addition, XRD analysis also revealed the increased Xc of XGP in the presence of PVA, which was consistent with the DSC results. TGA/DTG curves indicated that the addition of PVA improved the thermal stability of XGP. Tensile testing showed a dramatic increase in the elongation at break of films with the development of weight percent gain (WPG) of XGP. PMID- 29253942 TI - Enzymatic pretreatment for the improvement of dispersion and film properties of cellulose nanofibrils. AB - In the present study, cellulose nanofibrils (CNF) were produced from unbleached eucalyptus pulp, and the effect of enzymatic treatment on the properties of CNF was studied. Moreover, the mechanism of enzymatic treatment on the dispersion and film properties of CNF was speculated. The xylanase pretreatment facilitated the deconstruction of pulp into CNF via mechanical shearing and high-pressure homogenization, while the hemicellulose composition was preserved. Compared to the control, the CNF suspensions made from the xylanase pretreated pulp were more crystalline with higher dispersion, optical and rheological properties. CNF films were produced with a vacuum filtration process. The optical and mechanical strength properties of the CNF films were improved by the removal of hemicellulose. It was found that the carboxyl and hydroxyl groups played key roles in affecting the dispersion and film properties of the CNF. The carboxyl group content increased after the enzymatic pretreatment, which benefits the even distribution of CNF in water. The mechanical strength of the CNF films was further improved by exposing the hydroxyl group when lignin-carbohydrate complexes were de-structured by the enzymes. This study expanded the application of CNF produced from unbleached pulp. The theoretical foundation for stabilizing the CNF suspension and the high-speed dehydration of CNF films were explored for the continuous roll to roll production of CNF film. PMID- 29253943 TI - Budesonide nanocrystal-loaded hyaluronic acid microparticles for inhalation: In vitro and in vivo evaluation. AB - Most inhaled pharmaceutical formulations on the market are intended to exert immediate pharmacological action, even although inhaled sustained-release formulations can be needed to reduce the frequency of dosing. The purpose of this study was to investigate the pulmonary retention and pharmacokinetics of a poorly water-soluble drug after loading its nanocrystal form into inhalable mucoadhesive microparticles composed of hyaluronic acid. It was intended to prolong the pharmacological effect without compromising the dissolution rate of the poorly water-soluble drug. In this study, budesonide, a corticosteroid anti-inflammatory drug, was used as a model poorly water-soluble drug. Submicron budesonide particles were prepared by wet ball milling, and subsequently loaded into hyaluronic acid microparticles by the spray drying process. The ball-milled budesonide particles and the spray-dried microparticles were characterized using dynamic light scattering (DLS), laser diffraction, Scanning electron microscopy (SEM), X-ray powder diffraction (XRD) and differential scanning calorimetry (DSC). Selected formulations were evaluated in terms of their dissolution/release rate, aerosol performance, muco-adhesion and pharmacokinetics in rats. As shown by XRD and DSC analysis, the nanonized budesonide particles in this study were mainly in crystalline form. The dissolution/release study showed that the in vitro release of budesonide from the microparticles was not significantly sustained compared with the dissolution rate of budesonide nanocrystals (BUD-NC). However, the budesonide in the microparticles exhibited prolonged retention on the surface of porcine tracheal tube owing to the muco-adhesion ability of hyaluronic acid. After intratracheal administration to rats, the BUD-NC exhibited a similar pharmacokinetic profile to that of budesonide solution via i.v. injection. In contrast, budesonide loaded in the mucoadhesive microparticles exhibited a significantly prolonged Tmax and increased bioavailability with the animal model. This study demonstrated that inhaled microparticles composed of hyaluronic acid could produce sustained budesonide pharmacological effects. This can be attributed to the mucoadhesion of the polymer that overcame the mucociliary clearance and, consequently, prolonged the retention of the active substance in the lung without necessarily reducing the in vitro dissolution rate. PMID- 29253944 TI - Optimization of enzymatic production of prebiotic galacto/galacto(arabino) oligosaccharides and oligomers from potato rhamnogalacturonan I. AB - A bi-enzymatic system using two multi-enzymatic preparations (Depol 670L and Gamanase 1.5L) was investigated for the production of prebiotic galacto/galacto(arabino)-oligosaccharides and oligomers with well-defined degree of polymerisation (DP) from potato galactan-rich rhamnogalacturonan I. Depending on the reaction condition, yields of low (DP of 2-6) and high-MW oligosaccharides (DP of 7-12) and oligomers (DP of 13-70) varied between 0.1-13.9, 0.0-37.5 and 0.0-75.7%, respectively. Substrate concentration and Depol 670L/Gamanase 1.5L ratio were identified as the most significant linear terms in oligosaccharide and oligomer yield models, respectively. Moreover, interaction between reaction time and substrate concentration had a significant effect on the yield of oligosaccharides, while interaction between reaction time and Depol 670L/Gamanase 1.5L ratio affected significantly the yield of oligomers. Higher yields of both oligosaccharides and oligomers were obtained when equal amount of Depol 670L and Gamanase 1.5L was used in combination. The DP and the monosaccharide composition of the generated galacto/galacto(arabino)-oligosaccharides and oligomers were confirmed. PMID- 29253945 TI - A novel structural fucosylated chondroitin sulfate from Holothuria Mexicana and its effects on growth factors binding and anticoagulation. AB - Fucosylated chondroitin sulfate (FCS), a structurally distinct glycosaminoglycan from the body wall of sea cucumber, possesses many biological properties and pharmacology functions. The refined structure of FCS isolated from sea cucumber Holothuria Mexicana (FCShm) was characterized by NMR spectra and HILIC-FTMS, which demonstrated four types of branches in FCShm. Among these, two branches were alpha-L-Fuc-2S4S (where Fuc is fucose and S is sulfo) and alpha-L-Fuc-4S linked to O-3 of glucuronic acid residues, while others were identified as alpha L-Fuc-4S and alpha-L-Fuc-3S4S attached to O-6 of N-acetylgalactosamine residue. Furthermore, the fucosyl branches were alpha-1,3-linked with different degree of polymerization from 1 to 5. FCShm exhibited high affinity to fibroblast growth factor 1 and 2, growth factors involved in neovascularization. Moreover, FCShm displayed intrinsic anticoagulant activity and inhibited thrombin and factor Xa activation by antithrombin III. Our results proposed a novel structural FCS and demonstrated its favorable application prospects in anti-angiogenesis and anticoagulation. PMID- 29253946 TI - Synthesis and evaluation of chondroitin sulfate based hydrogels of loxoprofen with adjustable properties as controlled release carriers. AB - Mixtures of polymer (chondroitin sulfate) and monomer (AMPS) in the presence of co-monomer (MBA) were employed for the production of hydrogels, with adjustable properties, following free radical copolymerization. The hydrogel's structural properties were assessed by FTIR, DSC, TGA, SEM and XRD which confirmed the development and stability of synthesized structure. The results from FTIR analysis showed that CS react with the AMPS monomer during the polymerization process and confirmed the grafting of AMPS chains onto CS backbone. The surface morphology of CS-co-poly(AMPS) hydrogels, as evident by SEM, corresponds to their improved swelling ability due to high porosity. Thermal analysis showed that crosslinking formed a stable hydrogel network which is thermally more stable than its basic ingredients. The effects of pH revealed an increasing trend in swelling with increasing concentration of either CS or AMPS. In addition, different modalities for drug loading were studied with respect to drug homogeneous distribution; loxoprofen sodium was employed as model drug and was loaded by swelling-diffusion method. In vitro drug release profiles and kinetics were assessed to confirm their reproducibility and reliability. Higuchi model is the best fit model to explain drug release from formed gels indicating diffusion controlled release. Similarly, Korsmeyer-Peppas model yields remarkably good adjustments where release kinetics involves a combination of diffusion in hydrated matrix and polymer relaxation. Conclusively, CS-co-poly(AMPS) hydrogels could be a potential alternate to conventional dosage forms for controlled delivery of loxoprofen sodium for extended period of time. PMID- 29253947 TI - Sugar-based gene delivery systems: Current knowledge and new perspectives. AB - Carbohydrates, one of the most abundant natural compounds and key participants in many biological processes, are relevant in medical and industrial fields. In comparison with synthetic polymers, carbohydrates are biocompatible and have intrinsic targeting properties, enabling them to interact with cell-surface receptors. Among the different carbohydrates, polysaccharides are naturally occurring biological molecules with tremendous potential for biomedical applications. The physicochemical properties of these polysaccharide based nanoparticles, such as excellent biocompatibility, surface charge to interact with nucleic acids, low toxicity and cost effectiveness make them superior carriers for nanomedicine. In addition to variety of physicochemical properties, polysaccharides allow the great ease of chemical modification which enables the preparation of wide range of nanoparticles. In this review, we present the state of-the-art information on the potential of polysaccharides-based polymers as non viral gene delivery vectors in treating various diseases. Then, we discuss the chemical modification and structure/property relationship of carbohydrates. PMID- 29253948 TI - Molecular and functional properties of a xylanase hydrolysate of corn bran arabinoxylan. AB - Enzymatic hydrolysis of arabinoxylans to prepare arabinoxylo-oligosaccharides has been of high interest from the commercial point of view. However, some arabinoxylans, such as those extracted from corn bran, tend to be difficult to hydrolyze into oligosaccharides due to their highly branched structure which limits the action of xylanases. This research presents a new arabinoxylo oligosaccharide preparation by enzymatic treatment of corn bran with an endoxylanase enzyme. The native arabinoxylan had a molecular weight of 253kDa and the hydrolysate polymers ranged from 51.6 to 132kDa. The hydrolyzates showed improved solubility in contrast to the original sample. The molecular properties of the hydrolyzates were related to the enzyme concentration used in the hydrolysis process, with increasing enzyme concentration leading to decreasing molecular weight and size. Solution viscosity of the samples also decreased with increasing enzyme concentration. All of the hydrolyzates showed emulsifying ability that was comparable to the original arabinoxylan. PMID- 29253950 TI - Synthesis, characterisation and application of pyridine-modified chitosan derivatives for the first non-racemic Cu-catalysed Henry reaction. AB - The preparation, characterisation and application of two pyridine-modified chitosan derivatives (C1 and C2) containing Cu(OAc)2 adsorbed as catalysts for the conversion of benzaldehyde into 2-nitro-1-phenylethanol are described. Quantitative solid-state 13C multiple-contact cross-polarization, magic-angle spinning, nuclear magnetic resonance (MC-CP MAS NMR) measurements confirmed the successful grafting of 2-pyridinecarboxaldehyde and 6-methylpyridine-2 carboxaldehyde to the chitosan backbone and indicated that 47(+/-2)% of the NH2 groups were grafted for both C1 and C2. The use of C1-Cu(OAc)2 as a catalyst in the nitroaldol reaction led to 96(+/-1)% conversion and 19(+/-4)% enantiomeric excess (ee), while the use of C2-Cu(OAc)2 as a catalyst also promoted the nitroaldol reaction, affording almost quantitatively the expected 2-nitro-1 phenylethanol (98(+/-1)%) with 14.5(+/-1.5)% ee. PMID- 29253949 TI - Synthesis and characterization of hyaluronic acid hydrogels crosslinked using a solvent-free process for potential biomedical applications. AB - Hyaluronic acid (HA) is a natural linear polysaccharide that has been used extensively in the biomedical field as it is a biocompatible, biodegradable, nontoxic and non-immunogenic polymer with high water affinity. Besides, the presence of multiple acid and hydroxyl groups in the HA molecule makes it an ideal candidate for chemical modification. The present paper describes the synthesis and characterization of HA-based hydrogels. For this purpose, aqueous mixtures containing 5% (w/w) of HA and different concentrations of Gantrez S97 (GAN) (1, 3 and 5% w/w) were used to prepare HA-based hydrogels. The mixtures were dried and the hydrogels were obtained after heating the solid material at 80 degrees C for 24h. GAN is the acid form of an methylvinylether and maleic anhydride copolymer and contains multiple acid groups that can form ester bonds when reacting with the multiple hydroxyl groups present in HA chains. The method described here present potential to be applied for the preparation of HA-based biomaterials with a defined form as the crosslinking reaction between HA and the crosslinker takes place in solid phase. Besides, the method can be considered an environmental-friendly process as no organic solvents or potentially toxic substances were used. The esterification reaction was confirmed by infrared spectroscopy and dynamic scanning calorimetry measurements. The loading and release capabilities of the hydrogels were evaluating by using methylene blue (MB) as a model molecule. The hydrogels showed a high affinity for MB showing loadings up to 0.35mg MB per mg of hydrogel. Moreover, the hydrogels were capable of sustaining the MB release over two days. The use of microwave radiation was evaluated to reduce the crosslinking time from 24h to 1h, but this procedure needs to be optimized in future studies. As the crosslinking procedure takes place in solid state, the HA/GAN hydrogels were used to prepare micro-engineered device, microneedle arrays. Finally, the antimicrobial properties of the hydrogels were evaluated. The results showed that the hydrogels presented anti infective properties. PMID- 29253951 TI - Chitosan derivatives targeting lipid bilayers: Synthesis, biological activity and interaction with model membranes. AB - The antimicrobial activity of chitosan and derivatives to human and plant pathogens represents a high-valued prospective market. Presently, two low molecular weight derivatives, endowed with hydrophobic and cationic character at different ratios were synthesized and characterized. They exhibit antimicrobial activity and increased performance in relation to the intermediate and starting compounds. However, just the derivative with higher cationic character showed cytotoxicity towards human cervical carcinoma cells. Considering cell membranes as targets, the mode of action was investigated through the interaction with model lipid vesicles mimicking bacterial, tumoral and erythrocyte membranes. Intense lytic activity and binding are demonstrated for both derivatives in anionic bilayers. The less charged compound exhibits slightly improved selectivity towards bacterial model membranes, suggesting that balancing its hydrophobic/hydrophilic character may improve efficiency. Observing the aggregation of vesicles, we hypothesize that the "charge cluster mechanism", ascribed to some antimicrobial peptides, could be applied to these chitosan derivatives. PMID- 29253953 TI - Corrigendum to 'Optimization of hyaluronan-based eye drop formulations'[carbohydrate polymers 153 (2016) 275-]. PMID- 29253952 TI - Characterization, antioxidation, anti-inflammation and renoprotection effects of selenized mycelia polysaccharides from Oudemansiella radicata. AB - The present work investigated the characteristics, antioxidative, anti inflammative and renoprotective effects of mycelia selenized polysaccharides (MSPS) from Oudemansiella radicata on lipopolysaccharide (LPS)-induced kidney damaged mice. The results demonstrated that both MSPS and mycelia polysaccharides (MPS) showed potential renoprotective effects reflecting by decreasing the serum levels of CRE, BUN and UA, increasing the nephritic enzyme activities of SOD, GSH Px, CAT and T-AOC, reducing the activities of MPO, as well as down-regulating the contents of MDA and LPO, respectively. And the MSPS showed superior effects. Furthermore, the selenium contents and physical properties of polysaccharides were investigated by FAAS, GC, HPGPC, FT-IR, NMR and AFM analysis, and the results indicated that MSPS was a homogeneous heteropolysaccharide with an average molecular weight of 3.12*104Da. These results may provide theoretical basis in applying natural and functional foods for the prevention and alleviation of kidney damages and its complications. PMID- 29253954 TI - Anthocyanin stabilization by chitosan-chondroitin sulfate polyelectrolyte complexation integrating catechin co-pigmentation. AB - The thermochemical instability of anthocyanins (ATC) presents a challenge to their utilization as natural colorants in many food systems. This is addressed herein with the development of polysaccharide based carriers formed by combined encapsulation and copigmentation approaches which utilize polyelectrolyte complexation between chitosan and chondroitin sulfate (CS). At pH 3, a 1.5mg/mL and 1:1wt ratio mix of both polysaccharides produced hydrophilic and positively charged polyelectrolyte complexes (PECs) with which a maximum ATC encapsulation efficiency of 88% could be achieved using a 1:6 elderberry extract as the ATC source. ATC coupled with EGCG co-pigmentation achieved the highest encapsulation efficiencies. Storage studies showed the combination of polysaccharide encapsulation and EGCG copigmentation improved ATC stability against elevated temperature and ascorbic acid. Copigmented PECs were shown to retain ATC color at a rate more than 3-fold greater than of non-encapsulated ATC, and, furthermore, were shown to improve and preserve ATC anti-oxidant activity and stability during storage. PMID- 29253955 TI - Synthesis of hyaluronan-amikacin conjugate and its bactericidal activity against intracellular bacteria in vitro and in vivo. AB - Aminoglycosides are often subtherapeutic to intracellular infections due to their high hydrophilicity. Here we used hyaluronic acid (HA) as a carbohydrate carrier of the aminoglycoside antibiotic, amikacin (AM) to deal with intracellular bacterial infections. The hyaluronan-amikacin conjugate (HA-AM) was synthesized by 'click' reaction between HA-propargyl amide (HAPA) and AM-azide. This conjugate with little cytotoxicity retained antibiotic effects on planktonic bacteria and showed better intracellular bactericidal activity than the antibiotic did. In addition, this conjugate was more efficient in reducing bacteria burden in an in vivo acute infection model than amikacin did. These results suggested that hyaluronic acid conjugation could reduce the dosage of antibiotic in treatment of intracellular bacterial infection, and further helping to alleviate the emergence of drug resistance in bacteria due to a long-term, high-dosage treatment. PMID- 29253956 TI - Effects of chain length of the cross-linking agent on rheological and swelling characteristics of dextran hydrogels. AB - Rheological characteristics during chemical gelation of semidilute solutions of dextran in the presence of cross-linking agents of different chain length are reported. Effects of cross-linker chain length on the gel point, structure of the gel network, and mechanical properties were investigated. The rheological results disclose that for all systems, the gelation process proceeds over a long time and both the complex viscosity and the power law exponent reveal that solid-like gel structures are formed in the post-gel region. Water absorption behavior of the gels was studied and the results were interpreted by using a kinetic model indicating that the swelling is diffusion controlled. The findings clearly show that the rheological characteristics, such as the time of gelation and gel strength of dextran hydrogels can be tuned by changing the chain length of the cross-linker agent. Furthermore, the swelling results also exposed significant differences between gels cross-linked with the two different cross-linker agents. PMID- 29253957 TI - Conjugation of paclitaxel to C-6 hexanediamine-modified hyaluronic acid for targeted drug delivery to enhance antitumor efficacy. AB - Polymer-based paclitaxel (PTX) conjugates have demonstrated application potentials to improve the water solubility and enhance the efficiency of drug delivery. In this study, a novel HA-based drug conjugate, HA-6-PTX, was designed and successfully synthesized by chemically grafting PTX to the C-6 position of N acetyl-d-glucosamine (GlcNAc) of hyaluronic acid (HA) using hexanediamine as the linker. Leaving the carboxylate of HA chain unaffected, the conjugate with drug loading as high as 21.8% showed an excellent water solubility of 168mg/mL and exhibited increased drug release in the presence of hyaluronidase. Compared to free PTX, HA-6-PTX demonstrated increased cytotoxicity and enhanced apoptosis inducing effect against HepG2 and A549 cells due to the increased cellular uptake of drug via HA-receptor mediated endocytosis. It was concluded that the HA-6-PTX conjugate could be potentially utilized for further exploration as targeted drug delivery to enhance antitumor efficacy. PMID- 29253958 TI - Direct link between specific structural levels of starch and hydration properties. AB - Enhanced water retention capacity (WRC) of physically modified flours is often attributed to a particle size reduction, neglecting potential influences of altered amylose/amylopectin ratio and crystallinity of starch. Therefore, this study aims to investigate the impact of altered amylose/amylopectin ratio and crystallinity on WRC by modifying wheat flour using a cryogenic (CG) and an ultra centrifugal grinder (UCG). With increased grinding time in CG and rotation speed in UCG, WRC rose linearly. Neither for CG nor for UCG modified flours a linear dependency of amylose/amylopectin ratio on WRC was detected. Additionally, no linear relation between crystallinity and WRC of UCG modified flours was determined (R2=0.03). For both modifying methods, however, linear dependency of WRC and starch modification degree was found. Through this systemic approach it was proven that WRC of modified flours can exclusively be attributed to alterations of surface properties. PMID- 29253959 TI - Gum Arabic: A promising candidate for the construction of physical hydrogels exhibiting highly stretchable, self-healing and tensility reinforcing performances. AB - The preparation of tough and healable hydrogels in one step remains a big challenge throughout the field of hydrogel methodology. Herein, we fabricated a series of Poly(N,N-dimethyl acrylamide)-TiO2-gum arabic (PDMAA-TiO2-GA) hybrid hydrogels by simply introducing nanoparticles TiO2 and vinyl-modified gum arabic (GMAGA) into polymer networks. Without complicate molecular design and post treating process, the hydrogel molding process was simple and effective. The hydrogel exhibited highly stretchable, self-healing and tensility reinforcing performances with the optimized compositions of 30% DMAA, 0.6% GMAGA and 0.13% TiO2. The maximum elongation of the hydrogel after self-healing recover could reach nearly 700% after only 20min healing time. The hydrogel could ensure 20 times continuous compressive or tensile tests without obvious deformation. Amazing was the significantly enhanced tensile modulus from 5kPa to 40kPa after 20 stretch-release cycles. The facile preparation and fascinating tensility reinforcing performance benefit the potential application of the carbohydrate GA in hydrogels. PMID- 29253960 TI - Electrospinning of non-ionic cellulose ethers/polyvinyl alcohol nanofibers: Characterization and applications. AB - The morphology of spin-coated films and electrospun fibers of ethyl hydroxy ethyl cellulose (EHEC), hydrophobically modified ethyl hydroxy ethyl cellulose (HM EHEC) and their blends with Poly(vinyl alcohol) (PVA) was examined by AFM, SEM and contact angle measurements. These polysaccharides upon blending with PVA exhibited smooth surface which was evidenced by Atomic Force Microscopy (AFM) observation. The electrospinnability of above polysaccharides with PVA was demonstrated for the first time. The oriented fibers could be obtained using a rotating disc collector. Contact angles of spin-coated films and electrospun fibers were discussed in terms of hydrophobicity and wetting characteristics. Further, The nanofibers of EHEC/PVA were in-situ crosslinked using citric acid and were used for controlled release of an antibacterial drug, Chlorhexidine Digluconate (ChD). In-vitro studies of cytotoxicity, cell growth and cell proliferation were performed using L929 mouse fibroblast cells. These nanofiber mats show potential in drug delivery and as scaffolds in tissue engineering applications. PMID- 29253961 TI - Polyelectrolyte-complex multilayer membrane with gradient porous structure based on natural polymers for wound care. AB - Chitosan and alginate have been considered to be promising natural polymers for biomedical application because of their biocompatibility, biodegradability and similarity to macromolecules recognized by human body, which are extensively used in wounds and burns management. Here a sponge-like polyelectrolyte-complex multilayer membrane (PCMM) was prepared via freeze-drying method. The attenuated total reflectance fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS) and field emission scanning electron microscopy (FE-SEM) analysis revealed that chitosan/alginate layer exhibited gradient porous structure and interpenetrating polymer networks in PCMM. The porosity and swelling ratio of PCMM were evaluated. The results indicate that the prepared PCMM shows porosity up to 90% and equilibrium swelling ratio up to 22.4 in deionized water as well as 21.5 in ion-containing solution. Antibacterial activity evaluated in vitro shows the PCMM appears obviously antibacterial activity towards E. coli. Cytotoxicity study evaluated in vitro illustrates the nontoxic nature of the PCMM, and it is good for the cell attachment, growth, and proliferation. These results strongly support the possibility of using this novel PCMM for wound care. PMID- 29253962 TI - Synthesis and structural features of phosphorylated Artemisia sphaerocephala polysaccharide. AB - Phosphorylation is a key route to achieve varieties of biological activities for polysaccharides. Currently, conventional phosphorylation reagents are characterized by long processing times and high reaction temperatures. Here, we reported phosphorylation of Artemisia sphaerocephala polysaccharides (PASP) with the degrees of substitution (DS) of 0.34-0.54 in mild reaction conditions (3-4h and 25 degrees C) by employing POCl3/pyridine technique. FT-IR spectroscopy and X ray photoelectron spectroscopy (XPS) analysis confirmed the appearance of phosphate ester (P5+) groups in PASP. Size exclusion chromatography combined with multi-angle laser light scattering (SEC-MALLS) result clearly showed temperature dependent increment of weight average molecular mass (MW). High temperature facilitated the reaction of phosphoryl chloride with primary and secondary hydroxyl groups, favoring the crosslinking of polysaccharide chains by phosphate di-esters as further confirmed in 13C NMR determination. Our results provide insight into the relationship between the structure and reaction conditions of phosphorylated polysaccharide, which is important for understanding and exploiting these derivatives in a wide range of applications. PMID- 29253963 TI - Amino acids modified konjac glucomannan as green corrosion inhibitors for mild steel in HCl solution. AB - Konjac glucomannan (KGM) was modified with amino acids to synthesize polysaccharide esters (KGMA and KGMH) which were evaluated as corrosion inhibitor for mild steel in 0.5M HCl solution by weight loss tests, Tafel curves, electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM). The synthetic polymers were found to have the lower water absorbency and the higher water solubility than KGM. Gravimetric measurements showed the maximum efficiencies of KGMA and KGMH for decreasing the corrosion rate of metal at 2000ppm are up to 89.9% and 92.4%, respectively. Polarization curves indicated polysaccharide esters could retard both hydrogen evolution reaction and metal dissolution reaction and that the inhibitory effect was concentration dependent. Besides, EIS studies demonstrated the corrosion resistance of mild steel in hydrochloric acid was enhanced by polymer additives. The observations on mild steel surface by SEM suggested the metallic substrate obtained good protection against corrosion in inhibitor-containing HCl solution. The adsorptive behavior of polymer molecules including physisorption and chemisorption obeyed Langmuir isotherm and UV-vis spectra revealed the formation of inhibitor-ion complex. The better performance of KGMH on corrosion inhibition was attributed to the easier transfer of pi-electron or n-electron, which was confirmed by quantum chemical calculations. PMID- 29253964 TI - Preparation of porous 2,3-dialdehyde cellulose beads crosslinked with chitosan and their application in adsorption of Congo red dye. AB - Micrometer sized 2,3-dialdehyde cellulose (DAC) beads were produced via a recently developed method relying on periodate oxidation of Cladophora nanocellulose. The produced dialdehyde groups and pristine hydroxyl groups provided the DAC beads with a vast potential for further functionalization. The sensitivity of the DAC beads to alkaline conditions, however, limits their possible functionalization and applications. Hence, alkaline-stable and porous cellulose beads were prepared via a reductive amination crosslinking reaction between 2,3-dialdehyde cellulose beads and chitosan. The produced materials were thoroughly characterized with different methods. The reaction conditions, including the amount of chitosan used, conditions for reductive amination, reaction temperature and time, were investigated and the maintained morphology of the beads after exposure to 1M NaOH (aq.) was verified with SEM. Different washing and drying procedures were used and the results were studied by SEM and BET analysis. Furthermore, FTIR, TGA, EDX, XPS, DLS and elemental analysis were performed to characterize the properties of the prepared beads. Finally, the alkaline-stable porous chitosan cross-linked 2,3-dialdehyde cellulose beads were applied as adsorbent for the dye Congo red. The crosslinked beads displayed fast and high adsorption capacity at pH 2 and good desorption properties at pH 12, providing a promising sorption material. PMID- 29253965 TI - Efficient conversion of lignocellulosic biomass to levulinic acid using acidic ionic liquids. AB - In the present research work, dicationic ionic liquids, containing 1,4-bis(3 methylimidazolium-1-yl) butane ([C4(Mim)2]) cation with counter anions [(2HSO4)(H2SO4)0], [(2HSO4)(H2SO4)2] and [(2HSO4)(H2SO4)4] were synthesised. ILs structures were confirmed using 1H NMR spectroscopy. Thermal stability, Hammett acidity, density and viscosity of ILs were determined. Various types of lignocellulosic biomass such as rubber wood, palm oil frond, bamboo and rice husk were converted into levulinic acid (LA). Among the synthesized ionic liquids, [C4(Mim)2][(2HSO4)(H2SO4)4] showed higher % yield of LA up to 47.52 from bamboo biomass at 110 degrees C for 60min, which is the better yield at low temperature and short time compared to previous reports. Surface morphology, surface functional groups and thermal stability of bamboo before and after conversion into LA were studied using SEM, FTIR and TGA analysis, respectively. This one-pot production of LA from agro-waste will open new opportunity for the conversion of sustainable biomass resources into valuable chemicals. PMID- 29253966 TI - Production and characterization of cellulose acetate - titanium dioxide nanotubes membrane fraxiparinized through polydopamine for clinical applications. AB - The present paper introduces a study on the preparation and characterization of cellulose acetate - TiO2 nanotubes membrane. In order to be used as a hemodialysis membrane, fraxiparinized nanotubes have been incorporated into the cellulose matrix. Fraxiparine embedding was performed via strong binding ability of dopamine. Composite membrane was characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and water contact angle measurement. Electrochemical impedance spectroscopy was used to correlate the morphology of composite membrane with its electrochemical properties. Mott Schottky test proved titanium dioxide semiconductor incorporation in composite membrane. Permeation test was made to determine pure water flux. The obtained results showed that addition of nanotubes had a positive impact on membrane permeation compared with a control polymeric membrane. PMID- 29253967 TI - Stability mechanism of O/W Pickering emulsions stabilized with regenerated cellulose. AB - The stability and mechanism of O/W Pickering emulsions stabilized with regenerated cellulose were investigated. The Turbiscan Lab Expert Stabilizer, Particle Size Analyser, and Physica MCR301 Rheometer were used. When the concentration of regenerated cellulose increases, the aggregation of regenerated cellulose, emulsion stability and bulk and interfacial viscoelasticity increase as the diameter of the oil droplets decreases. In addition, the emulsions display a typical gel-like characteristic, and the oil-water interfacial shear rheological behaviour slightly differs from that of the O/W Pickering emulsions. This difference can be attributed to the aggregation of regenerated cellulose in the droplet surface under the shear condition. The emulsions exhibit excellent salt resistance at high salt concentrations. Moreover, the regenerated cellulose displays a better temperature resistance than amphiphilic polymer (AP), which is commonly used in oilfields. Hence, commercially available regenerated cellulose can be used as an ideal candidate for enhanced oil recovery. PMID- 29253968 TI - A novel electrospun hydroxypropyl methylcellulose/polyethylene oxide blend nanofibers: Morphology and physicochemical properties. AB - The objective of this study was to fabricate and characterize Hydroxypropyl methylcellulose (HPMC) -based homogenous nanofibers by using electrospinning method. As the concentrations of the solutions increased, viscosity and electrical conductivity of the solutions increased. The morphology of the fibers changed from the beaded structure to the uniform fiber structure by increasing the concentrations of the solutions. Water vapor permeability (WVP) of electrospun HPMC nanofibers decreased with increasing polymer concentration. The shift in wavelengths, the change in intensity of FTIR peaks and melting point depression were the evidence of miscibility of HPMC/PEO blends. Nanofibers showing both melting temperature (Tm) and glass transition temperature (Tg) had semicrystalline structure. By combining PEO with HPMC, the thermal stability of nanofibers was increased. Hence, this study suggests homogenous biopolymer-based nanofibers with low WVP and high thermal stability which can have potential applications in food packaging field. PMID- 29253969 TI - Post-sulfonation of cellulose nanofibrils with a one-step reaction to improve dispersibility. AB - Cellulose nanofibrils (CNF) were sulfonated and the dispersion quality was compared to unfunctionalized and 2,2,6,6-tetramethylpiperdine-1-oxyl radical (TEMPO) post-oxidation treatment of existing CNF (mechanically fibrillated pulp). A post-sulfonation treatment on existing CNF in chlorosulfonic acid and dimethylformamide (DMF) resulted in sulfonated CNF that retained a fibril-like morphology. There was a small decrease in the cellulose crystallinity index for the sulfonated CNF, but this was much lower than the reported regioselective oxidative bisulfite pretreatment method used to make sulfonated CNF. The current approach was extremely quick, and 5min of reaction time was sufficient to result in significant improvements in dispersibility compared to unfunctionalized CNF. The sulfonated CNF and TEMPO oxidized CNF had better dispersibility compared to the unfunctionalized CNF when dispersed in DMF and water, and in many cases the sulfonated CNF had better dispersibility than the TEMPO CNF. It was found that when CNF was dispersed in DMF the TEMPO CNF formed carboxyl dimethylammonium groups, while the sulfonated CNF formed formate groups. PMID- 29253971 TI - Self-assembled cellulose materials for biomedicine: A review. AB - Cellulose-based materials have reached a growing interest for the improvement of biomedicine, due to their good biocompatibility, biodegradability, and low toxicity. Self-assembly is a spontaneous process by which organized structures with particular functions and properties could be obtained without additional complicated processing steps. This article describes the modifications, properties and applications of cellulose and its derivatives, which including a detailed review of representative types of solvents such as NMMO, DMAc/LiCl, some molten salt hydrates, some aqueous solutions of metal complexes, ionic liquids and NaOH-water system etc. The modifications were frequently performed by esterification, etherification, ATRP, RAFT, ROP and other novel methods. Stimuli responsive cellulose-based materials, such as temperature-, pH-, light- and redox responsive, were synthesized for their superior performance. Additionally, the applications of cellulose-based materials which can self-assemble into micelles, vesicles and other aggregates, for drug/gene delivery, bioimaging, biosensor, are also discussed. PMID- 29253970 TI - Enhancing strength and toughness of cellulose nanofibril network structures with an adhesive peptide. AB - The mechanical properties of cellulose nanofibrils network structure are essential for their applications in functional materials. In this work, an adhesive peptide consisting of just 11 amino acid residues with a hydrophobic core sequence of FLIVI (F - phenylalanine, L - leucine, I - isoleucine, V - valine) flanked by three lysine (K) residues was adsorbed to 2,2,6,6-Tetramethyl 1-piperidinyloxy radical (TEMPO) oxidized cellulose nanofibrils (TO-CNF). Composite films were prepared by solution casting from water suspensions of TO CNF adsorbed with the adhesive peptide. The nanofibrils network structure of the composite was characterized by atomic force microscopy (AFM). The structure of the peptide in the composites and the interactions between TO-CNF and the peptide were studied by Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD). The mechanical properties of the composites were characterized by tensile tests and dynamic mechanical analysis (DMA). With 6.3wt.% adhesive peptide adsorbed onto TO-CNF, the composite showed a modulus of 12.5+/-1.4GPa, a tensile strength of 344.5+/-(15.3)MPa, and a strain to failure of 7.8+/-0.4%, which are 34.4%, 48.8%, and 23.8% higher than those for neat TO-CNF, respectively. This resulted in significantly improved toughness (work to fracture) for the composite, 77% higher than that for the neat TO-CNF. PMID- 29253972 TI - Green synthesis of bioactive polysaccharide-capped gold nanoparticles for lymph node CT imaging. AB - The development of biologically targeted contrast agents for X-ray computed tomography (CT) imaging remains a major challenge. Here, we investigated a green chemistry-based synthesis of lymph node-targeted mannan-capped gold nanoparticles (M-GNPs) as a CT contrast agent. In this study, mannan was used as a reducing and stabilizing agent for gold nanoparticles (AuNPs). M-GNPs were readily internalized by antigen-presenting cells (APCs) through mannose receptors mediated endocytosis. The M-GNPs, which had a spherical morphology, had an average diameter of 9.18+/-0.71nm and surface plasmon resonance (SPR) absorption spectra with maximal absorption at 522nm. The M-GNPs displayed a concentration based X-ray attenuation property with a maximum Hounsfield unit (HU) value of 303.2+/-10.83. The local administration of M-GNPs led to significantly enhanced X ray contrast for the imaging of popliteal lymph nodes. These findings demonstrated that M-GNPs can be used as biologically targeted contrast agents for CT imaging. PMID- 29253973 TI - Polyvinyl alcohol/chitosan hydrogels with enhanced antioxidant and antibacterial properties induced by lignin nanoparticles. AB - Polyvinyl alcohol/chitosan (PVA/Ch) hydrogels containing 1 and 3wt% of lignin nanoparticles (LNPs) were prepared through a freezing-thaw procedure. Results from microstructural, thermal and mechanical characterization of LNPs based PVA/Ch demonstrated that the lowest amount of LNPs (1wt%) was beneficial, whereas the presence of agglomerates at higher LNP content limited the effect. Moreover, a different swelling behaviour was observed for hydrogels containing LNPs with respect of PVA/Ch, due to the formation of a porous honeycomb-like structure. A synergic effect of Ch and LNPs was revealed in terms of antioxidative response by DPPH (1,1-Diphenyl-2-picryl-hydrazyl) activity of migrated substances, whereas results from antimicrobial tests confirmed LNPs as effective against Gram negative bacteria (E. coli) when compared to Gram positive (S.aureus and S. epidermidis) strains. The obtained results suggested the possible use of produced PVA/Ch hydrogels incorporating LNPs in many different sectors, such as drug delivery, food packaging, wound dressing. PMID- 29253974 TI - Polysaccharide metallohydrogel obtained from Salecan and trivalent chromium: Synthesis and characterization. AB - Here, a new kind of Salecan derived polysaccharide metallohydrogel was reported. Successful fabrication of Salecan metallohydrogel was verified by Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and rheological measurements. Scanning electron microscope investigations have been conducted to elucidate the morphology of Salecan/Cr3+ gel (SCgel). We found that the pore size of metallohydrogel can be tailored by adjusting the Cr3+ dose during gel formation. After that, swelling and de-swelling behaviors were systematically studied. The increasing of chromium ion concentration and the presence of saline solutions will cause the decrease of swelling percentage. It is assumed that the decreasing hydrophilicity of Salecan, the increase of crosslinking density, and the complexation of the carboxylate group with saline ions are the main syneresis mechanisms. Altogether, this study opens a new avenue to prapare Salecan-based hydrogel. PMID- 29253975 TI - Effects of divalent anionic catalysts on cross-linking of cellulose with 1,2,3,4 butanetetracarboxylic acid. AB - 1,2,3,4-Butanetetracarboxylic acid (BTCA) can efficiently esterify cellulose with pyrophosphoric acid (PPA) as a catalyst to remove protons of reaction intermediates. However, valence and relative concentration ratio (RCR) of catalyst anions correlating to pH of finishing bath played a critical role in the reactions. Results here indicated that wrinkle recovery angle, tensile strength retention and ester absorbance of fabrics treated at pH of 2.8 showed higher values. It was a competing reaction for BTCA molecules to esterify or depolymerize cellulose. Importantly, divalent PPA anions were more efficient than monovalent ones in catalyzing the esterification between anhydrides and cellulose, which was confirmed by FTIR results and two-dimensional correlation spectroscopy analyses and by the RCRs of PPA anions and their changing rates versus pH. Furthermore, the higher catalytic efficiency of divalent anions was proved by the selected model catalysts. Meaningfully, the fabrics treated at pH<=3.2 presented good durability. PMID- 29253976 TI - Synthesis and characterization of regioselectively substituted curdlan hetero esters with different ester groups on primary and secondary hydroxyl groups. AB - Two kinds of regioselectively substituted curdlan hetero ester, 2,4-di-O-acetyl-6 O-propionyl-curdlan (CD24Ac6Pr) and 2,4-di-O-propionyl-6-O-acetyl-curdlan (CD24Pr6Ac), were synthesized. By repeating detritylation and esterification, a new method to remove trityl group from 6-O-trityl-curdlan without acyl migration was developed. Their molecular structures, thermal and mechanical properties and crystal structures were analyzed by NMR, TGA, DSC, tensile test and WAXD. It was concluded that the ester groups substituted on secondary hydroxyl groups at C2 and C4 positions play the decisive role in the melting behavior and crystalline formation of curdlan esters. Also, the mechanical properties of curdlan esters are controllable by the adjustment on its molecular structures. PMID- 29253977 TI - Multifunctional properties of cotton fabrics coated with in situ synthesis of zinc oxide nanoparticles capped with date seed extract. AB - In situ formation of zinc oxide nanoparticles (ZnO-NPs) was studied within the framework of several factors. variables examined include (i) innovation of a new capping agent; (ii) nature of the cotton fabric related to its processing; (iii) formation of Zinc hydroxide (Zn(OH)2) due to reduction of zinc acetate with sodium hydroxide (iv) treatment of the differently processed cotton fabrics with (Zn(OH)2) functionalized dispersion as per the exhaustion method, (v) further treatment of the cotton fabrics with (Zn(OH)2) dispersion according to the pad dry-cure method and (Vi) conversion of (Zn(OH)2) to ZnO-NPs during the curing step in the latter method. Results depict that the incorporation of the bio extract obtained from date seed waste works effectively as capping material which stabilize ZnO-NPs. Mercerized bleached cotton fabric proves to be a better candidate than mercerized loomstate cotton fabric in conferring sustainable bactericidal and UV blocking. PMID- 29253978 TI - Ascorbic acid- and sodium ascorbate-loaded oxidized potato starch films: Comparative evaluation of physicochemical and antioxidant properties. AB - The purpose of this study was to compare the effects of increasing concentrations of ascorbate ions (AIs, 0-100mM) in the form of ascorbic acid (AA) and sodium ascorbate (SA) on the properties of edible oxidized potato starch films. The browning reactions were faster in the SA-added films than in those of AA-added. In, turn, AA recrystallized faster than its sodium salt. The highest concentration of SA increased the water vapor permeability of the films. The mechanical strength and stiffness of the films gradually decreased with the increase of AI content. Fourier-transform infrared spectroscopy spectra suggested that addition of SA provoked a more intensive structural changes in the films than AA. X-ray diffraction showed that 25 and 50mM AI-added films exhibited higher crystanility than the control. The films with AA and SA did not differ in terms of dissolving behavior, ability to release AI, and consequently, antioxidant activity. PMID- 29253979 TI - Rapid and efficient removal of heavy metal and cationic dye by carboxylate-rich magnetic chitosan flocculants: Role of ionic groups. AB - A multifunctional carboxylate-rich magnetic chitosan flocculant (Mag@PIA-g-CS) was prepared through surface graft copolymerization on magnetite particles. The effect of monomer molar ratio, initiator and pre-neutralized degree on polymerization rate was determined. Various analytical methods were applied to characterize Mag@PIA-g-CS, exhibiting the successful grafting of polymers, good magnetic feature and core-shell structure. The kinetic process of Ni(II) and malachite green (MG) flocculation by Mag@PIA-g-CS reached equilibrium within <60min with the optimal uptake rate of 98.3% and 87.4%, and exhibited satisfactory removal effect in wide pH range (4.0-8.0 for Ni(II), 5.0-10.0 for MG). Mag@PIA-g-CS exhibited superior flocculation performance over chitosan magnetic flocculant (Mag@CS). The pH-dependent behavior, rapid responsiveness and sensitivity to ionic strength in batch flocculation tests indicated the distinct effect of ionic groups. Moreover, sweeping action of linear molecular chains facilitated further flocculation. Mag@PIA-g-CS showed high stability in extreme environments, and can be easily regenerated and separated. PMID- 29253981 TI - Quantification of 1,3-beta-D-glucan from yeast added as a functional ingredient to bread. AB - Due to their immunomodulatory effect, 1,3-beta-G from yeast are used as functional ingredients, but reliable methods for their detection in foods are lacking. We have adapted a method based on fluorescence detection with aniline blue to quantify the amount of five commercial yeast beta-glucan preparations added to crisp or yeast-leavened bread. This assay detected yeast beta-glucan preparations added to different breads with an average recovery of 90, 96, 99 and 105%, while one of the preparations was overestimated, with an average recovery of 157%. The presence of cereal 1,3-1,4-beta-D-glucans did not interfere with assay performance. The addition of 1,3-beta-G at 0.2 and 0.5 g/100g is low compared to the recommended dose of 1,3-beta-G per serving demonstrating assay sensitivity. However, more research is needed to fully understand the effect of 1,3-beta-G conformation/structure on aniline blue interaction as well as the effect of baking on structure and dissolution properties of yeast beta-glucans. PMID- 29253980 TI - Macromolecular structure and film properties of enzymatically-engineered high molar mass dextrans. AB - New alpha(1->2) or alpha(1->3) branched dextrans with high molar masses and controlled architecture were synthesized using a dextransucrase and branching sucrases. Their molecular structure, solubility, conformation, film-forming ability, as well as their thermal and mechanical properties were determined. These new dextrans present structures with low densities from 9,500 to 14,000gm-3 in H2O/DMSO medium, their molar mass, size and dispersity increase with increasing branching degree (weight-average molar mass up to 109gmol-1 and radius of gyration around 500nm). Dextrans exhibit a glass transition between 40.5 and 63.2 degrees C for water content varying from 12.2 to 14.1%. The effect of branching is mainly observed on the ability of dextran to crystallize. They have a good film-forming ability with a storage modulus which varies from 2 to 4GPa within a relative humidity range of 10-50%. PMID- 29253982 TI - Ion-crosslinked wood-derived nanocellulose hydrogels with tunable antibacterial properties: Candidate materials for advanced wound care applications. AB - Development of advanced dressings with antimicrobial properties for the treatment of infected wounds is an important approach in the fight against evolution of antibiotic resistant bacterial strains. Herein, the effects of ion-crosslinked nanocellulose hydrogels on bacteria commonly found in infected wounds were investigated in vitro. By using divalent calcium or copper ions as crosslinking agents, different antibacterial properties against the bacterial strains Staphylococcus epidermidis and Pseudomonas aeruginosa were obtained. Calcium crosslinked hydrogels were found to retard S. epidermidis growth (up to 266% increase in lag time, 36% increase in doubling time) and inhibited P. aeruginosa biofilm formation, while copper crosslinked hydrogels prevented S. epidermidis growth and were bacteriostatic towards P. aeruginosa (49% increase in lag time, 78% increase in doubling time). The wound dressing candidates furthermore displayed barrier properties towards both S. epidermidis and P. aeruginosa, hence making them interesting for further development of advanced wound dressings with tunable antibacterial properties. PMID- 29253983 TI - Nanocomposite films based on CMC, okra mucilage and ZnO nanoparticles: Physico mechanical and antibacterial properties. AB - This work examined the physico mechanical parameters and antibacterial activity of CMC/okra mucilage (OM) blend films containing ZnO nanoparticles (NPs). Different proportions of CMC and okra mucilage (100/0; 70/30; 60/40 and 50/50 respectively), were mixed and casted to posterior analysis of formed films. The more colored films were obtained by higher contents of okra mucilage and adding ZnO nanoparticles. The incorporation of ZnO NPs into CMC film decreased the elongation at the break (EB) value of the films and increased the tensile strength (TS) value of the film. With increase in CMC concentration in the films, higher water vapor permeability and higher solubility in water were achieved. Microstructure analysis using SEM showed a smooth and compact surface morphology, homogeneous structure, and a rough surface for CMC, CMC+ZnO, and CMC/OM30%+ZnO, respectively. Nanocomposite films presented antibacterial activity against tested bacteria. Films contained okra mucilage showed more antibacterial activity. The inhibitory activities of resultant films were stronger against S. aureus than E. coli. PMID- 29253984 TI - Cellulose nanowhiskers improve the methylene blue adsorption capacity of chitosan g-poly(acrylic acid) hydrogel. AB - Cellulose nanowhiskers (CNWs, 90% crystalline) were used to enhance the adsorption capacity of chitosan-g-poly(acrylic acid) hydrogel. The composites up to 20w/w-% CNWs showed improved adsorption capacity towards methylene blue (MB) as compared to the pristine hydrogel. At 5w/w-% CNWs the composite presented the highest adsorption capacity (1968mg/g). The maximum removal of MB (>98% of initial concentration 2000mg/L) was achieved quickly (60min) at room temperature, pH 6, and at low ionic strength (0.1M). Adsorption mechanism was explained with the Langmuir type I model suggesting the formation of a MB monolayer on the adsorbent surface. The interaction between the adsorbent and MB molecules was explained by chemisorption, as suggested by the pseudo-second-order kinetic model. Desorption experiments showed that 75% of loaded-MB could be recovered from the adsorbent by its immersion in a pH 1 solution. Additional experiments showed the post-utilized composite could be regenerated and reused for at least 5 consecutive adsorption/desorption cycles with minimum efficiency loss (~2%). PMID- 29253985 TI - Protective effects of natural and partially degraded konjac glucomannan on Bifidobacteria against antibiotic damage. AB - This study was to evaluate the protective effects of a dietary fiber, konjac glucomannan (KGM) from the plant tuber of Amorphohallus konjac on Bifidobacteria against antibiotic damage. KGM (~8.8*108Da) was partially degraded with high intensity ultrasound to KGM-US (~1.8*106Da) and then hydrolyzed with trifluoroacetic acid (TFA) to KGM-AH (1369Da). KGM-US (at 5g/l) showed the most significant protective effect on most bifidobacterial strains against penicillin and streptomycin inhibition, increasing the minimal inhibitory and bactericidal concentration (MIC and MBC) dramatically, and KGM also showed significant effects on enhancing the MBC of enrofloxacin, penicillin, tetracycline and streptomycin. In addition, the adsorbance ability and biofilm formation effects of KGM and degraded KGM products may be partially responsible for the protective effects. The results suggested that natural KGM and ultrasound treated KGM have protective effects for the human gut probiotic bacteria against the damage caused by specific antibiotics. PMID- 29253986 TI - Cellulose nanocrystals obtained from office waste paper and their potential application in PET packing materials. AB - Annually a tremendous amount of office waste paper (OWP) is discarded creating environmental pollution. Therefore, how to make this paper from waste to wealth and use it in new approaches have become a meaningful and challenging work. In this work, OWP being a cellulose rich biomass was employed for the production of cellulose nanocrystals (CNCs) by acid hydrolysis with different acid concentrations but without subjecting OWP to alkali and bleaching treatments. The testing results showed that CNCs prepared using sulfuric acid concentration of 59% with respect to OWP had the highest crystallinity and this concentration was the transition concentration for the production of opaque CNCs film with convoluted nanofibers to transparent one with orientated nanofibers. Besides, CNCs prepared using acid concentration of 65% coated on PET sheet not only had a better water vapor barrier property but also was on a par with the transparency of PET, which was hopeful to be used as coating materials in packaging materials. PMID- 29253987 TI - Lipopolysaccharides of Pantoea agglomerans 7604 and 8674 with structurally related O-polysaccharide chains: Chemical identification and biological properties. AB - Structurally related O-specific polysaccharide (O-antigen) and lipid A components were obtained by mild acid degradation of the lipopolysaccharides (LPSs) of two strains of bacteria Pantoea agglomerans, 7604 and 8674. Studies by sugar analysis along with 1D and 2D 1H and 13C NMR spectroscopy enabled elucidation of the following structures of the O-polysaccharides, which differ only in the linkage configuration of a side-chain glucose residue: R=alpha-d-Glcp in strain 7604 or beta-d-Glcp in strain 8674 Lipid A samples were studied by GC-MS and high resolution ESI-MS and found to be represented by penta- and tetra-acyl species; lipid A of strain 8674 also included hexaacyl species. A peculiar feature of lipid A of both strains is the presence of the major cis-9-hexadecenoic (palmitoleic) acid, which has not been found in P. agglomerans strains studied earlier. The LPSs of both strains were pyrogenic, reduced the average adhesion and the index of adhesiveness and showed a relatively low level of lethal toxicity. O-antiserum against strain 7604 showed one-way cross-reactivity with the LPS of strain 8674, and O-antisera against both strains cross-reacted with LPSs of some other R. agglomerans strains but more strains were serologically unrelated. These structural and serological data indicate immunochemical heterogeneity of R. agglomerans strains and will find demand in classification of R. agglomerans by O-antigens. PMID- 29253988 TI - Hyaluronan hydrogels modified by glycinated Kraft lignin: Morphology, swelling, viscoelastic properties and biocompatibility. AB - Effects of the addition of water soluble glycinated Kraft lignin (WS/KL) on the mechanical stability and biocompatibility of hyaluronan (NaHy) hydrogels were evaluated in this work. Water soluble lignin was obtained by the modification of Kraft lignin via a Mannich reaction. It was found that WS/KL is highly compatible with hyaluronan due to its improved water solubility, which favours its use in designing new advanced composite hydrogels. The effects of the concentration of WS/KL on morphological, swelling and creep/recovery behaviours of hyaluronan hydrogels were investigated. It was detected that the creep resistance and creep recovery of NaHy hydrogels was improved by the incorporation of up to 3% (w/w) of WS/KL. In contrast, the swelling capacity of hydrogels was decreased. The cytotoxicity tests proved that glycinated KL lignin limits the viability of cells only slightly, and the final hyaluronan/lignin hydrogels were non-toxic materials. PMID- 29253989 TI - Characterization and analysis of motion mechanism of electroactive chitosan-based actuator. AB - In order to analyze the bending mechanism of the electroactive chitosan-based actuator, different amounts of poly(diallyldimethylammonium chloride) (PDAD) were incorporated in chitosan solution. The effects of PDAD concentration on electromechanical performance of chitosan actuator were investigated under various excitation voltages. With the incorporation of PDAD into chitosan solution, crosslinked chitosan film acts as an actuator showing a considerable displacement behavior. However it can be noted that higher incorporation of PDAD into chitosan solution decreased the performance of the actuators. Thermal, viscoelastic, and crystallographic properties of the chitosan films were examined by thermogravimetric analysis, dynamic mechanical analysis, and X-ray diffraction analysis, respectively. The effect of incorporation of PDAD in chitosan-based film on morphological properties of chitosan film was determined by scanning electron microscopy. It was observed that the films involving PDAD have larger pore size than the PDAD free film. PMID- 29253990 TI - Two-step economical welan gum production by Sphingomonas sp. HT-1 from sugar industrial by-products. AB - A two-step fermentation strategy using glucose mother liquor (GML) for cell growth and xylose mother liquor (XML) for welan gum synthesis was used to alleviate uneconomic welan gum fermentation. This study revealed: (1) optimal initial GML concentration was 11.7g/L (10g/L sugars contained); (2) optimal XML feeding strategy was pseudo-exponential fed-batch and feeding time was 12thh 54thh, amounting to 25.7g/L XML (20g/L sugars contained); and (3) in a 7.5-L bioreactor, welan gum concentration was 22.68+/-0.50g/L and its yield reached 0.756g/g sugars with trace residual sugars. Compared with the cost of batch fermentation using glucose as sole carbon source, the final carbon source costs decreased by 61.40% and the welan gum yield increased by 50%. GML and XML can be used as inexpensive carbon sources for welan gum production with higher yield, giving them industrial application potential to produce value-added chemicals. PMID- 29253991 TI - Robust superhydrophobic and superoleophilic filter paper via atom transfer radical polymerization for oil/water separation. AB - Robust superhydrophobic and superoleophilic cellulose-g-PFOEMA filter paper membranes were fabricated via surface grafting of poly(perfluorooctylethyl methacrylate) (PFOEMA) using atom transfer radical polymerization (ATRP). The surface chemical compositions, morphologies and wettability of cellulose-g-PFOEMA with different degree of graft ratio (DG) were investigated using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), and contact angle (CA) measurement. IR and XPS showed that PFOEMA were introduced into surface of filter paper. The superhydrophobicity of filter paper increased with amount of PFOEMA grafted. When DG of grafted PFOEMA was higher than 11.2%, the superhydrophobicity reached a steady state and the measured water contact angle was about 157 degrees . The PFOEMA-grafted filter paper exhibited excellent chemical resistance toward a wide range of pH solution from 1 to 12. Cellulose-g PFOEMA is convenient for oil/water separation with efficiency higher than 95%. The excellent reusability and stability make cellulose-g-PFOEMA filter paper membrane a promising candidate in the applications of oil spillage cleanup and the separation of oil/water mixture. PMID- 29253993 TI - Gum Arabic-silver nanoparticles composite as a green anticorrosive formulation for steel corrosion in strong acid media. AB - A green anticorrosive composite (GA-AgNPs) has been formulated for steel in 15% HCl and 15% H2SO4 media. Characterization of GA-AgNPs is achieved via FTIR, UV vis, EDAX, and SEM. Gravimetric, electrochemical (EIS, EFM, DEIS, & TP), and surface assessment (SEM, EDAX, AFM, & XPS) techniques have been deployed in the anticorrosion studies. Results from all applied methods potray GA-AgNPs as effective anticorrosive agent. Inhibition is by adsorption mechanism and follows Langmuir isotherm. GA-AgNPs acts as mixed type inhibitor in 15% H2SO4 solution but as anodic type in 15% HCl solution. Results from surface techniques confirm adsorption of GA-AgNPs molecules on specimen surface. Oxides, hydroxides, carbonates, and sulphates (H2SO4 medium) or chlorides (HCl medium) are the corrosion products in the free corrodent according to XPS results. In the presence of composite, both ionic and neutral forms of GA-AgNPS are adsorbed. AgNPs are present on the surface in the form: Ag degrees , Ag2O, and AgO. PMID- 29253992 TI - Structural characterization and thermal behavior of a gum extracted from Ferula assa foetida L. AB - The gum asafoetida, an oleo-gum-resin from root of Ferula assa foetida, was extracted through alcoholic procedure followed by water extraction and then biochemically characterized using colorimetric assays, Fourier infrared spectroscopy, gas chromatography coupled to mass spectrometry, and 1D and 2D nuclear magnetic resonance. The gum was mainly composed of carbohydrates (67.39% w/w) with a monosaccharide distribution of 11.5: 5.9: 2.3: 1 between Gal, Ara, Rha and GlcA (molar ratio) and proteins (arabinogalactan protein). The polysaccharide consisted of a (1->3)-beta-d-galactan backbone ramified predominantly from O-6 but also from O-4 and O-4,6. Side chains included terminal alpha-l-Araf, terminal-alpha-l-Rhap, (1->3)-alpha-l-Araf, (1->5)-alpha-l-Araf, terminal-beta-d-Galp, beta-d-GlcA and traces of (1->4)-beta-d-GlcA. X-ray diffraction pattern showed a semi crystalline microstructure. Thermal behavior of the gum was evaluated by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) revealed temperatures below and upper 200 degrees C as dominant regions of weight loss. PMID- 29253994 TI - Structural analysis and biological activity of a highly regular glycosaminoglycan from Achatina fulica. AB - Edible snails have been widely used as a health food and medicine in many countries. A unique glycosaminoglycan (AF-GAG) was purified from Achatina fulica. Its structure was analyzed and characterized by chemical and instrumental methods, such as Fourier transform infrared spectroscopy, analysis of monosaccharide composition, and 1D/2D nuclear magnetic resonance spectroscopy. Chemical composition analysis indicated that AF-GAG is composed of iduronic acid (IdoA) and N-acetyl-glucosamine (GlcNAc) and its average molecular weight is 118kDa. Structural analysis clarified that the uronic acid unit in glycosaminoglycan (GAG) is the fully epimerized and the sequence of AF-GAG is >4)-alpha-GlcNAc (1->4)-alpha-IdoA2S (1->. Although its structure with a uniform repeating disaccharide is similar to those of heparin and heparan sulfate, this GAG is structurally highly regular and homogeneous. Anticoagulant activity assays indicated that AF-GAG exhibits no anticoagulant activities, but considering its structural characteristic, other bioactivities such as heparanase inhibition may be worthy of further study. PMID- 29253995 TI - Microcellular foaming of arabinoxylan and PEGylated arabinoxylan with supercritical CO2. AB - In this study, arabinoxylan extracted from barley husks was reacted with polyethylene glycol (PEG) of various molecular weights to introduce an internal plasticizer into the polymer matrix. A successful PEGylation reaction was identified using FTIR and elemental analysis. Thermal and mechanical properties were studied using dynamic mechanical analysis, which revealed that the attachment of PEG chains reduced the glass transition temperature by up to 25 degrees C. Foaming experiments were conducted under different test conditions in a batch foaming process with supercritical CO2 in a thermoregulated and pressurized cylinder. The foams were evaluated using SEM by studying the morphology of the samples foamed at different temperatures. The unmodified arabinoxylan sample was found to produce the best foam morphology, though the PEGylated samples could be produced at lower temperatures than could the unmodified arabinoxylan. This was interpreted as due to the decrease in the glass transition temperature. PMID- 29253996 TI - Thermo-sensitive and swelling properties of cellouronic acid sodium/poly (acrylamide-co-diallyldimethylammonium chloride) semi-IPN. AB - In current study, cellouronic acid sodium (CAS), obtained from bagasse pith, has been introduced into poly(acrylamide-co-diallyldimethylammonium chloride) (poly(AM-co-DAC)) network to form novel thermo-sensitive semi-IPNs. The structure and morphology of the hydrogels were proved by Fourier transformation infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). The effects of CAS content, initiator charge, cross linker dosage and swelling-medium property on the thermo-responsive water absorptivity were investigated in detail. The results elucidated that the prepared gels exhibited a thermo-sensibility with an upper critical solution temperature (UCST) and a high water-absorbency. And the values of UCST and equilibrium swelling ratio largely depended on the inner structure of the semi IPNs and the external solvent property. It was also revealed that the swelling process conformed to the Schott's pseudo second order model and diffusion type was non-Fickian diffusion. The value of activation energy for this polyelectrolyte was found to be 8.74kJ/mol. PMID- 29253997 TI - Review of direct chemical and biochemical transformations of starch. AB - Starch is an important natural sustainable resource for various industries. Via chemical and biochemical one-step transformations it may be converted into numerous products or promising substances for different applications. All starch based products may be divided into five main groups: carbon based materials, small organic molecules, starch depolymerization products, products with retained polymer chains but changed supramolecular structure, and modified starch. Some of the products are well-known and traditionally manufactured from starch in industrial scale. Other materials, like mesoporous carbon or nanosized starch particles, are just coming to market, and still require more thorough investigation and tuning of the preparation, treatment, and application procedures. Approaches for preparation of the novel greener composite or homogeneous carbon based materials, nanoparticles, heterocycles, organic acids, polyols from starch, are given in details. Recent improvements in starch hydrolysis, molecular or supramolecular modifications are also summarized in this review. PMID- 29253998 TI - N-mercapto acetyl-N'-octyl-O, N"-glycol chitosan as an efficiency oral delivery system of paclitaxel. AB - Herein, thioglycolic acid modified N-octyl-O, N'-glycol chitosan (N-mercapto acetyl-N'-octyl-O, N"-glycol chitosan, abbreviated as SH-OGC) was synthesized to improve the oral bioavailability of paclitaxel (PTX). PTX was readily solubilized into the hydrophobic inner core of SH-OGC. Pharmacokinetic studies demonstrated that the bioavailability of PTX was greatly enhanced when delivered by SH-OGC compared to Taxol(r) or non-sulfhydrylated OGC micelles. Caco-2 cell experiments confirmed PTX or rhodamine-123-loaded SH-OGC demonstrated effective cellular accumulation via caveola-mediated endocytosis along with the inhibition of P-gp efflux. Furthermore, Caco-2 transport studies demonstrated that the mechanistic basis of SH-OGC efficacy was attributed to P-gp inhibition, enhanced permeability of tight junctions and clathrin-mediated transcytosis across the endothelium. In addition, SH-OGC exhibited increased intestinal retention through thiol-mediated mucoadhesion compared with OGC according to results of mucoadhesion evaluation on freshly excised rat intestine. In summary, SH-OGC micelles may present as a promising delivery vehicle for enhancing the oral bioavailability of P-gp substrates. PMID- 29253999 TI - Polyethylene oxide films reinforced by cellulose nanocrystals: Microstructure properties relationship. AB - Composite films of polyethylene oxide/cellulose nanocrystals (PEO/CNCs) comprising up to 75wt.% CNCs were obtained via solution casting. For the first time, investigations of the PEO/CNCs composite films over a wide composition range were carried out. Morphology, crystalline structure, thermal stability and the resulting reinforcing effect on the PEO matrix were studied. Polarizing optical microscopy (POM), scanning electron microscopy (SEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric (TG) analysis, Fourier transform infrared spectroscopy (FTIR), and tensile testing were used to examine the properties of the composites. The revealed extreme dependences of the composite properties refer to the CNCs content of 15-35wt.%. This composition range is characterized by destruction of PEO spherulites and appearance of a pronounced PEO fibrillar structure. PMID- 29254000 TI - One-step coagulation to construct durable anti-fouling and antibacterial cellulose film exploiting Ag@AgCl nanoparticle- triggered photo-catalytic degradation. AB - An anti-fouling and antibacterial surface of cellulose film was obtained by one step coagulation of the cellulose-LiCl/Dimethyl acetamide (DMAc) solution with AgNO3 and polyvinyl pyrrolidone (PVP). The AgCl nanocrystals were embedded on the surface of cellulose film with the assistance of PVP, and the Ag@AgCl was formed due to the partly decomposition of AgCl under the visible-light irradiation. Morphology and size of the Ag@AgCl in cellulose matrix could be regulated by changing the concentration of PVP. From a series of comparative tests, Ag@AgCl could be stably embedded on cellulose film at the concentration of 1wt% PVP, and its photo-degradation efficiency could be still retained 89% after 5-cycle testing. Meanwhile, a dramatic reduction in viable bacteria was also observed within 120min of exposure on this film, and when exposure time was 180min, no active bacteria was observed.This work provided a simple pathway to construct the functional cellulose film which could be applied as packaging materials. PMID- 29254001 TI - Improved thermal stability of cellulose nanofibrils using low-concentration alkaline pretreatment. AB - The thermal stability of cellulose nanofibrils (CNFs) can be improved by converting cellulose crystalline structure to cellulose II using an alkaline treatment method. The conventional method requires around 20wt.% NaOH solutions and causes the cellulose interdigitation and aggregation, making CNFs production difficult. The objective of this study is to develop a new pretreatment method using a low-concentration alkaline solution to produce well-dispersed CNFs with improved thermal stability. CNFs with 90nm diameter were successfully prepared by treating cellulose powder with 2wt.% NaOH solution below 0 degrees C, followed by homogenization through a French pressure cell press. The CNFs had relatively high thermal stability with the mean onset and maximum thermal decomposition temperature of 305 degrees C and 343 degrees C, respectively, compared with the CNFs prepared without the NaOH pretreatment (283 degrees C and 310 degrees C). The increased thermal stability can create new opportunities for the development of CNF-based bio-composites and electronics. PMID- 29254002 TI - Cellulose nanocrystals as carriers in medicine and their toxicities: A review. AB - Cellulose nanocrystals (CNCs) are crystalline nanoparticles that present myriad applications. CNCs are produced from a variety of renewable sources, and they can be chemically modified. Although there are promising perspectives for introducing CNCs into pharmaceutical formulations, prior to achieving commercial products the influence of many parameters such as extraction and toxicity of the resulting products must be revealed. Since there is great physicochemical flexibility in the steps of obtaining and conjugating CNCs, there are uncountable and complex outcomes from the interactions of those parameters. We present a discussion that helps to unveil the whole panorama on the use of CNCs as drug delivery systems. The methods of producing CNCs are correlated to the resulting nanotoxicity from the cellular to organism level. This review points to relevant concerns that must be overcome to attain safe use of these nanostructures. We also discuss the patents and commercially available products based on CNCs. PMID- 29254004 TI - The influence of nanocellulose coating on saffron quality during storage. AB - Since saffron is an added-value product, and the most expensive agricultural product, it is necessary to increase its shelf life, prevent its quality loss during storage, and maintain its organoleptic properties, enabling producers to export saffron with higher quality and better consumer acceptability. So, in this research, saffron samples were coated through applying different carbohydrate biopolymers: maltodextrin with DE=4 or DE=20 (MD4 and MD20) or their combination with nanocellulose fibres (MDC4 and MDC20). Finally, the experiments were carried out to measure rehydration ratio, water activity, crocin content, color values, and sensory properties of saffron samples coated by different materials. MDC4 resulted in the lowest rehydration ratio among coated samples since, first, lower DE degrees of biopolymer complexes decreased moisture adsorption and solubility of maltodextrin and second, crystalline nanocellulose fibres increased tortuous and bended pathways in materials and reduced penetration possibilities of water molecules. MDC4 was the most effective treatment in preventing crocin decrease. Indeed, film forming characteristic of maltodextrin with low hydrolysis degree and special structure of nanocellulose led to the maintenance of crocin bioactive ingredient. SEM observations revealed coating on saffron surfaces as a thin clear and brilliant layer which enhanced saffron acceptability for our panelists. PMID- 29254003 TI - Hierarchical structure and thermal behavior of hydrophobic starch-based films with different amylose contents. AB - This work discloses the multi-level structure and thermal behaviors of hydrophobic, propionylated starch-based films as affected by the amylose contents of starch materials used. Scanning electron microscopy results showed that amylose promoted the formation of more compact structure within the film matrices. Also, small and wide angle X-ray scattering analysis revealed that higher amylose content was preferable for the formation of new orders on nanoscale and crystallites. With these structural changes, the viscoelasticity of amorphous short chains was enhanced and the glass transition temperature was reduced by the increased amylose content; but the depolymerization of macromolecules and the decomposition of molecular bonds were postponed, since the increase in starch crystallites restricted the motion of adjacent amorphous regions. Hence, this work provides valuable information for rational design of hydrophobic starch-based films with desired thermal features by simply regulating the amylose content of starch raw materials. PMID- 29254005 TI - Impact of HPMC on inhibiting crystallization and improving permeability of curcumin amorphous solid dispersions. AB - The purpose of this paper was to elucidate the impacts of hydroxypropylmethyl cellulose E5 as assistant excipient on inhibiting crystallization and improving membrane permeability in curcumin amorphous solid dispersions that formulated by Eudragit E100. Intermolecular interactions formed between curcumin and polymers were probed using in situ Raman imaging and infrared spectroscopy. The abilities of hydroxypropylmethyl cellulose E5 in inhibiting crystallization and improving membrane permeability were confirmed by fluorescence spectroscopy, dynamic light scattering analysis and in vitro permeability experiment. The results demonstrated hydroxypropylmethyl cellulose E5 was significant in maintaining the amorphous drug concentration owing to the hydrogen bond interactions formed with curcumin, rending its ability to inhibit crystallization by reducing drug droplet size. Furthermore, the addition of hydroxypropylmethyl cellulose E5 in curcumin amorphous solid dispersions promoted drug membrane permeability through lowering the order level of phospholipid bilayer layer. PMID- 29254006 TI - Enzyme functionalized electrospun chitosan mats for antimicrobial treatment. AB - This work presents electrospun chitosan mats, functionalized with glucose oxidase (GOX) to implement an in-situ hydrogen peroxide (H2O2) generation system. The as spun CTS-PEO mats exhibited a smooth and homogenous morphology in combination with a high specific surface area (5.4m2/g) providing an excellent basis for further functionalization and subsequent glutaraldehyde crosslinking provided them with superior mechanical stability in aqueous environments. GOX was covalently immobilized, as proven by XPS, and resulted in activity recoveries between 20 and 40%. The functional mats generated a steady state concentration of ~60MUM H2O2 per cm2 which resulted in growth inhibition of E. coli and of S. aureus already after two hours of incubation. Additional cytotoxicity tests of the modified mats against mouse fibroblasts did not show an influence on the viability of the cells which proved it a functional biomaterial of great potential for biomedical applications. PMID- 29254007 TI - Colloid properties of hydrophobic modified alginate: Surface tension, zeta potential, viscosity and emulsification. AB - Micelle properties of hydrophobic modified alginate (HM-alginate) in various dispersion media have been studied by surface tension, zeta-potential, and viscosity measurements. Effect of salt on micelle properties showed that the presence of counter ion weakened the repulsive interaction between surfactant ions, decreased the critical micelle concentration (CMC) value of the HM alginate, reduced the effective volume dimensions of HM-alginate and hence viscosity, which coincide with the corresponding zeta-potential values. Soy oil in-water emulsions, stabilized solely by HM-alginate, were produced in high speed homogenization conditions and their stability properties were studied by visual inspection, optical microscopy and droplet size measurements. The results showed that emulsions (oil-water ratio was 1:7) containing 15mg/mL HM-alginate presented better stability during 15days storage, which stating clearly that HM-alginate is an effective emulsifier to stabilize oil-in-water emulsions. The herein presented homogeneous method for preparation of emulsion has the potential to be used in food industry. PMID- 29254008 TI - Functionalized cellulose beads with three dimensional porous structure for rapid adsorption of active constituents from Pyrola incarnata. AB - In the present study, porous magnetic cellulose beads (CBs) were prepared and further modified using amines. The CBs appeared to have good spherical shape and three-dimensional (3D) porous structure. In the adsorption tests, the modified cellulose beads (MCBs) showed better adsorption capacities and shorter adsorption times on hyperin and 2'-O-galloylhyperin than the commercial resins. The adsorption may be due to the hydrogen bonding between the target compounds and the amine groups of MCBs. After adsorption and desorption, the contents of hyperin and 2'-O-galloylhyperin reached 1.32% and 3.92%, which were 4.08 and 4.23 times higher than those in the Pyrola extracts. Therefore, the prepared MCBs in this study make an excellent adsorbing material of hyperin and 2'-O galloylhyperin, and it may have potential for the separation of other natural compounds. PMID- 29254009 TI - pH-sensitive inulin-based nanomicelles for intestinal site-specific and controlled release of celecoxib. AB - Aiming at a site-specific drug release in the lower intestinal tract, this paper deals with the synthesis and physicochemical/biological characterization of pH sensitive nanomicelles from an inulin (INU) amphiphilic derivative. To allow an intestinal site specific release of the payload, INU-Vitamin E (INVITE) bioconjugates were functionalized with succinic anhydride to provide the system with pH-sensitive groups preventing a premature release of the payload into the stomach. The obtained INVITESA micelles resulted nanosized, with a low critical aggregation concentration and the release studies showed a marked pH-dependent release. The drug loading stabilized the micelles against the acidic hydrolysis. From transport studies on Caco-2 cells, resulted that INVITESA nanomicelles cross the cellular monolayer but are actively re-transported in the secretory (basolateral-apical) direction when loaded in apical side. It suggests that the entrapped drug could not be absorbed before the release from the micelles, enabling so a local release of the active. PMID- 29254011 TI - Highly efficient absorption of cationic dyes by nano composite hydrogels based on kappa-carrageenan and nano silver chloride. AB - Novel nanocomposite hydrogel was synthesized based on kappa-carrageenan and nano silver chloride by a simple method and applied for the removal of cationic dyes in aqueous solution. Inclusion of nano-silver chloride into the superabsorbent hydrogel was utilized for producing the effective dye absorbent. The dye absorption was more than 98% after 5min in a 10ppm aqueous solution at pH=6. The nanocomposite hydrogel was characterized by FT-IR spectroscopy, SEM, TEM, TGA/DTG, and BET analysis. The absorption of crystal violet was investigated by changing the absorbent dosage, contact time, dye concentration, pH, and temperature. Several kinetic models were used to predict the kinetic behavior of the dye absorption. The best result was obtained with the pseudo-second order model. The results demonstrated that the Temkin model has been fitted better than the other models. The reusability experiments showed that the superabsorbent retained more than 60% of initial activity after 9 cycles. PMID- 29254010 TI - Injectable methylcellulose hydrogel containing silver oxide nanoparticles for burn wound healing. AB - A thermo-sensitive methylcellulose (MC) hydrogel containing silver oxide nanoparticles (NPs) was prepared via one-pot synthesis in which a silver acetate precursor salt (CH3COOAg) induces a salt-out effect in the MC solution. The silver oxide NPs were synthesized in situ from Ag+ ions during the MC hydrogelation, and the residual CH3COO- ions decreased the gelation temperature of the MC solution through the salt-out effect. The gelation behavior of the MC solution varied according to the CH3COOAg content and was monitored. Also, the formation and structure of the silver oxide NPs in the MC hydrogel was confirmed. From the results, silver oxide NPs was successfully incorporated in MC hydrogels, simultaneously, acetate ion which was counter ion of Ag was affected gelation behavior of Ag. Finally, the antimicrobial activity and wound healing effect was examined using the shaking flask method and burn wound test, respectively. The MC hydrogel with silver oxide NPs showed excellent antimicrobial activity and burn wound healing. Therefore, this thermo-responsive MC hydrogel has great potential as an injectable hydrogel for wound regeneration. PMID- 29254012 TI - Production of novel palladium nanocatalyst stabilized with sustainable chitosan/cellulose composite and its catalytic performance in Suzuki-Miyaura coupling reactions. AB - In this study, we designed a new palladium nanocatalyst on chitosan/cellulose composite for the first time to increase the use of sustainable polysaccharides, which are cheap, non-toxic, environmental friendly, abundant in nature, and can be used as support materials for metallic nanoparticles. Physicochemical characterization of fabricated palladium nanocatalyst was illuminated with FT-IR, TG/DTG, SEM/EDAX, XRD, and ICP-OES analyses. Pd nanoparticles were found to be almost spherically structured, and the average particle size was 26-30nm. Then catalytic performance of the designed nanocatalyst was investigated in the synthesis of a series of biphenyl compounds via the Suzuki-Miyaura reaction by using the green method which is conducted in a very short-time, under low temperature, and without the presence of any toxic chemical solvents (e.g., 5min treatment in microwave oven at 400W at 50 degrees C). As a result of the tests, palladium nanocatalyst showed excellent catalytic performance with high conversion yields for a wide range of substrates and with a very low catalyst loading for the Suzuki reactions. Sustainability performance of palladium nanocatalyst was also studied, and it is found that the catalyst was able to be recycled for eight successive runs. PMID- 29254013 TI - A study on adsorption behavior of newly synthesized banana pseudo-stem derived superabsorbent hydrogels for cationic and anionic dye removal from effluents. AB - In this work, an environmentally benign superabsorbent hydrogel based on banana pseudo-stem has been synthesized by free radical graft co-polymerization of sodium acrylate (NaAc) and acrylamide (AM) on to modified banana pseudo-stem cellulose backbone using ammonium persulfate (APS) and N,N-methylene-bis acrylamide (MBA) as initiator and crosslinker respectively.The optimum condition for initiator, monomers and crosslinker concentrations was found to be 0.0032molL 1, 0.013molL-1 and 0.00048molL-1 respectively. Structural confirmation of the hydrogel prepared is performed by FT-IR spectroscopy whereas the morphology and thermal properties assessments were performed by SEM and TGA analysis respectively. Swelling behavior in solutions with different pH (2, 4, 7, 9 and 12) and contact time (5-750min) indicated 323.54gg-1 in pH 7 solutions for 570min. The optimized hydrogel was used as adsorbent for methylene blue (MB) and methyl orange (MO) with a maximum adsorption of 333.3 and 124 mgg-1 respectively. Kinetics and Isotherm adsorption studies revealed pseudo second-order and Freundlich isotherm as befitting models. PMID- 29254014 TI - Effect of extraction techniques on properties of polysaccharides from Enteromorpha prolifera and their applicability in iron chelation. AB - The structural characteristics of polysaccharides directly affect their property, function, and application. Enteromorpha prolifera, a resource-rich green alga, contains special sulfated rhamnose-rich polysaccharides. In this study, the physicochemical properties of polysaccharides extracted from E. prolifera using different techniques were compared, and significant differences in yield, molecular weight, and chemical composition were observed. The acid extraction had the highest extraction yield (24.7%), and the obtained polysaccharides (ACP) had a molecular weight of 41.1kDa and sulfate content of 16.2%. ACP showed a good iron(III) chelating capacity, and after response surface optimization, the iron content of ACP-iron(III) complex reached 20.85%. According to the structure analysis, iron(III) was bound with hydroxyl and carboxyl of ACP. Soluble polysaccharides are the main component of E. prolifera tissue, easy to prepare, and with unique properties. The prepared ACP-iron(III) complex may be a powerful candidate for iron supplements. PMID- 29254015 TI - Mannan and phosphomannan from Kuraishia capsulata yeast. AB - Linear mannan and branched phosphomannan were identified as exopolysaccharides produced by Kuraishia capsulata yeast. Their structures were determined using nuclear magnetic resonance spectroscopy. The repeating unit of mannan was found to be a trisaccharide ->6)-alpha-Manp-(1->2)-alpha-Manp-(1->2)-alpha-Manp-(1->, while the phosphomannan was shown to be built of beta-Manp-(1->2)-alpha-Manp-(1 disaccharide blocks linked by phosphodiester bonds via C-1 and C-6 of the reducing unit. The production of both polysaccharides was shown to depend on the phosphate concentration in the culture medium. In the absence of phosphate, only mannan was obtained, while an excess of KH2PO4 led to the exclusive production of phosphomannan. Chemical depolymerisation of phosphomannan led to the formation of disaccharide beta-Manp-(1->2)-(6-P)-Manp, representing the repeating unit of the hydrolysed polysaccharide. The treatment of the disaccharide with alkaline phosphatase resulted in the formation of disaccharide beta-Manp-(1->2)-Manp. The latest products can be transformed into glycosyl donors applicable further in the synthesis of oligosaccharides related to Candida cell wall polysaccharides. PMID- 29254016 TI - Relation between concentration and shear-extensional rheology properties of xanthan and guar gum solutions. AB - The influence of concentration on the shear and extensional rheology properties of aqueous solutions of xanthan and guar gums was studied in this work. Shear rheology involved small amplitude oscillatory shear (SAOS), flow curves and transient flow, while the extensional rheology was analyzed using hyperbolic contraction flow. In addition, the mechanical properties during solutions manufacture were monitored in situ through the evolution of torque with processing time by mixing rheometry. The results showed that the hydrocolloids exert a great influence on the process rheokinetics and on the resulting rheological response. SAOS tests showed that the xanthan gum solutions behaved as weak gels, whereas guar gum solutions suggest the presence of entanglement and the formation of a viscoelastic, gel-like structure. All the systems exhibited shear-thinning behaviour. Guar gum solutions obeyed the Cox-Merz rule, with some divergence at high rates for the more concentrated solutions, while the Cox-Merz rule was not followed for xanthan gum in the range of concentration studied. The extensional viscosity exhibited an extensional-thinning behaviour within the strain range used and all solutions were characterized by a high Trouton ratio. PMID- 29254017 TI - Reactivity of main components and substituent distribution in esterified sugarcane bagasse prepared by effective solid phase reaction. AB - Three main components of lignocellulose (cellulose, hemicellulose, and lignin isolated from sugarcane bagasse (SCB)) as well as holocellulose and SCB were modified with maleic acid by mechanical activation (MA)-assisted solid phase reaction (MASPR) technology. The order of reactivity was found to be lignin>hemicellulose>cellulose. The amorphous structure of lignin and hemicellulose mainly attributed to their better reactivity, and the modified lignin could reach a maximum degree of esterification (DE) of 93.45%. MA improved the accessibility and reactivity of cellulose, as the DE of modified cellulose gradually increased with milling time and reached the maximum value of 57.30% at 120min, which had significant effect on structure changes and DE of modified holocellulose and SCB. MA enhanced the esterification of all three components in lignocellulose with relatively high substituent distribution in them, and maleated SCB with a maximum DE of 64.17% was successfully prepared by this simple, green, and effective MASPR technology. PMID- 29254018 TI - Eco-friendly isolation of cellulose nanoplatelets through oxidation under mild conditions. AB - Agave is recognized as a low recalcitrant material, which makes it a potential source to obtain nanocellulose. Aqueous dispersions (in water, H2O2, H2O2/H2SO4) of agave powder were heated at 120 degrees C under vapor pressure (1kg/cm2). The resultant materials were observed with an optical microscope (OM), a laser scanning microscope (LSM) to obtain the thickness measurement and a scanning electron microscope (SEM) to observe morphology. Raman spectroscopy, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) were used to obtain the chemical structure. Cellulose nanoplatelets (CNPs) from Agave salmiana were successfully isolated under mild conditions. Physicochemical analysis indicates that lignin was removed in a single step oxidation with hydrogen peroxide in presence of sulfuric acid at low concentration (0.17M). The CNPs images revealed the presence of entangled cellulose nanofibrils (O~14nm) along the nanoplatelets (thickness ~80nm). PMID- 29254019 TI - Study on characterization of Furcraea foetida new natural fiber as composite reinforcement for lightweight applications. AB - The exploration of new natural fibers in the field of polymer composites can contribute to increase the invention of natural reinforcements and expand their use in possible applications. In the present work, the physico-chemical, thermal, tensile and morphological properties of Furcraea foetida (FF) fiber are presented for the first time. Chemical analysis results shows that FF has relatively higher cellulose (68.35%) with lower hemicelluloses (11.46%) and lignin (12.32%). Structural analysis of FF was conducted by Fourier transform infrared and 13C (CP MAS) nuclear magnetic resonance spectroscopy. X-ray diffraction (XRD) analysis evidenced that FF has crystallinity index of 52.6% with crystalline size of 28.36nmThe surface morphology of FF was investigated by scanning electron microscopy (SEM), energy dispersive X-ray micro analyzer (EDX) and atomic force microscopy (AFM). The thermogravimetric analysis (TGA) reveals thermal constancy of the fiber upto 320.5 degrees C with the kinetic activation energy of 66.64kJ/mol, which can be used as reinforcements in thermoplastic green composite whose working temperatures is below 300 degrees C. The FF results were compared with those of other natural fibers, and indicated as a suitable alternative source for composite manufacture. PMID- 29254020 TI - Surfactant-stable and pH-sensitive liposomes coated with N-succinyl-chitosan and chitooligosaccharide for delivery of quercetin. AB - Layer-by-layer (LbL) self-assembly of multilayered liposomes is used to improve the stability of conventional liposomes. In this study, the LbL technology was used to prepare novel multilayered liposomes from chitooligosaccharide and N succinyl-chitosan. We propose that this preparation can be used as a transdermal drug delivery system (TDDS) to enhance stability against surfactants and control drug release. Particle size increased with the number of layers in the multilayer and the zeta potential varied between positive and negative values with alternate deposition of polyelectrolytes. Finally, approximately 300-400nm-thick four layered liposomes were prepared. These liposomes were more stable against surfactants and showed a relatively high release of quercetin at pH 5.5 than the uncoated liposomes as assessed via in vitro drug release and skin permeation studies. In summary, the multilayered liposomes showed potential for use as a surfactant-stable TDDS that effectively enhanced the permeation of quercetin, a poorly soluble drug, into the skin. PMID- 29254022 TI - Removal of Cd(??) and phenol using novel cross-linked magnetic EDTA/chitosan/TiO2 nanocomposite. AB - In the present study, a novel cross-linked magnetic EDTA/chitosan/TiO2 (MECT) was prepared as eco-friendly and efficient bioadsorbent for the removal of Cd(II) ions and phenol from aqueous solution. Magnetic chitosan was improved by surface functionalization and cross-linking of it with EDTA and photocatalytic with TiO2. The nanocomposite was characterized by FE-SEM, EDX, FTIR and XRD techniques and Cd(II) ions adsorption and phenol degradation under varied experimental conditions were investigated. Results revealed that MECT nanoparticle with an average diameter of 40nm had the best performance in adsorption of Cd(II) and degradation of phenol at optimum pH values of 5-6. Moreover, the adsorption kinetics proceeded according to the mechanism of the pseudo-second-order model. The maximum adsorption capacity of Cd(II) obtained from Langmuir model was 209.205mgg-1 and phenol degradation efficiency was up to 90%. Reusability of MECT was tested and the adsorption and degradation capacities were not affected after five cycles. The paper suggests that the MECT is a promising recyclable nanocomposite for the removal of hazardous pollutants from contaminated water. PMID- 29254021 TI - Fabrication of photo-crosslinkable glycol chitosan hydrogel as a tissue adhesive. AB - In this work, an in situ gelling system composed of glycol chitosan (GC) was fabricated and evaluated regarding its tissue-adhesive, anti-bacterial and hemostatic properties. GC conjugated with 3-(4-hydroxyphenyl) propionic acid gelled immediately after illumination with blue light in the presence of ruthenium complex. The phenolic GC hydrogel was investigated regarding its mechanical property, hydration, degradation rate, cytotoxicity, tissue adhesiveness, and hemostatic ability. The hydrogel was shown to glue two pieces of tissues tightly in an egg-membrane model. The antibiotic-incorporated hydrogel killed bacteria effectively. When the hydrogel was applied to a wound in a mouse liver model, bleeding was reduced quickly and greatly. All the promising results show that the photo-chemically crosslinkable GC hydrogel could be used as a tissue adhesive, controlled drug release, and a hemostat. PMID- 29254023 TI - Production and characterization of a nanocomposite of highly crystalline nanowhiskers from biologically extracted chitin in enzymatic poly(epsilon caprolactone). AB - A nano-composite from biologically obtained chitin nanofillers homogenously dispersed in a poly(epsilon-caprolactone) matrix was successfully achieved by an ultrasonication-assisted non-toxic and non-aqueous methodology. For this purpose, biological chitin was obtained from lactic acid fermentation of shrimp wastes and converted into chitin whiskers by acidic hydrolysis in a novel process at low temperature (4 degrees C) that enhanced the distribution and yield. Additionally, the polyester matrix was enzymatically produced in a non-toxic compressed fluid (1,1,1,2-tetrafluoroethane at 25bar and 65 degrees C) medium. The homogeneous distribution of the nanofiller in the matrix was corroborated by confocal and atomic force microscopies. Films of the nanocomposite were physicochemically characterized to assess its adequate properties. Additionally, the qualitative viability of human fibroblasts and osteoblasts cells was studied on the produced nanocomposite films showing good biocompatibility. PMID- 29254024 TI - N-[4-(N,N,N-trimethylammonium)benzyl]chitosan chloride: Synthesis, interaction with DNA and evaluation of transfection efficiency. AB - A novel cationic chitosan derivative, N-[4-(N,N,N trimethylammonium)benzyl]chitosan chloride (TMAB-CS), with different degrees of substitution (DS) was synthesized by a chemoselective interaction of 4-formyl N,N,N-trimethylanilinium iodide with chitosan amino groups using a reductive amination method. Several factors (pH, reactant ratio, reaction time, and chitosan structure) were studied for their effects on the DS of the resulting TMAB-CS. The obtained derivatives were characterized by 1H NMR and FTIR spectroscopy. Turbidimetric titration showed enhanced solubility over a wide pH range even for low-substituted TMAB-CS. TMAB-CS provided strong DS-dependent binding of plasmid DNA. Dynamic light scattering measurements revealed the formation of stable polyplexes with hydrodynamic diameters of 200-300nm and zeta potential of 20-30mV. TMAB-CS with relatively low DS (25%) demonstrated more pronounced transfection efficiency (up to 2000 cell/cm2) of plasmid DNA into the HEK293 cell line promoted by free TMAB-CS. The positive effects of lower DS can be related to a better polyplex dissociation within the cell. The cytotoxicity of TMAB-CS was comparable to that of the initial chitosan at concentrations up to 300ng/MUL, even at high DS. PMID- 29254025 TI - Preparation and characterization of acetylated maltodextrin and its blend with poly(butylene adipate-co-terephthalate). AB - Acetylated maltodextrins (AMDs) were synthesized. It was found that maltodextrin (MD) was easily acetylated to form AMDs with high degree of substitution (DS). The DS of the prepared AMDs was much higher than that of acetylated corn starches (ACSs) obtained under the same reaction conditions. The differential scanning calorimetry (DSC) measurements clearly highlighted that AMD underwent a glass transition at about 109 degrees C. Moreover, AMD possessed higher thermal stability than MD. The AMD with DS 2.13 (AMD2.13) was melt-blended with poly(butylene adipate-co-terephthalate) (PBAT) to fabricate novel PBAT/AMD polymer blends. Rheological measurements indicated that AMD2.13 had a plasticizing effect on PBAT. Moreover, scanning electron microscopy (SEM) measurements indicated good interfacial adhesion between PBAT and AMD2.13. The onset temperature of non-isothermal melt crystallization of PBAT increased from 81.95 to 92.19 degrees C due to the favorable heterogeneous nucleation effect. Mechanical tests showed that the yield strength of the PBAT/AMD blends was enhanced. PMID- 29254026 TI - Chitosan coatings crosslinked with genipin for corrosion protection of AZ31 magnesium alloy sheets. AB - In this study, coatings of chitosan crosslinked with genipin were prepared on sheets of AZ31 magnesium alloy and their corrosion protection properties were characterized by means of potentiodynamic polarization and electrochemical impedance spectroscopy (EIS). The coatings were also characterized by means of FTIR and XPS. It was observed that the crosslinking process decreases the corrosion current and shifts the corrosion potential of the alloy to less negative values. The EIS analysis demonstrated that the crosslinking process increases the maximum impedance after short and long exposure times. The superior performance of the crosslinked coatings is related to a lower degree of swelling, as observed in the swelling tests carried out on free-standing films. PMID- 29254027 TI - One pot synthesis of carbon dots decorated carboxymethyl cellulose- hydroxyapatite nanocomposite for drug delivery, tissue engineering and Fe3+ ion sensing. AB - In this work, carbon dots conjugated carboxymethyl cellulose-hydroxyapatite nanocomposite has been synthesized by one-pot synthesis method and used for multiple applications like metal ion sensing, osteogenic activity, bio-imaging and drug carrier. The structure and morphology of the nanocomposite were systematically characterized by FTIR, XRD, TGA, FESEM, TEM and DLS. Results clearly demonstrated the formation of fluorescent enabled carbon dots conjugated nanocomposite from carboxymethyl cellulose-hydroxyapatite nanocomposite by a simple thermal treatment. The synthesized nanocomposite is smaller than 100 nm and exhibits fluorescence emission band around 440 nm upon excitation with 340 nm wavelength. In the meantime, the nanocomposite was loaded with a chemotherapeutic drug, doxorubicin to evaluate the drug loading potential of synthesized nanocomposite. Moreover, the as-synthesized nanocomposite showed good osteogenic properties for bone tissue engineering and also exhibited excellent selectivity and sensitivity towards Fe3+ ions. PMID- 29254028 TI - Rheological characterization of the exopolysaccharide Paenan in surfactant systems. AB - Rheology-controlling agents are of importance for numerous products in a variety of industries. Replacement of synthetic chemicals with natural additives is desired in light of current environmental awareness and limited fossil resources. This study investigates the rheological features of Paenan, an exopolysaccharide produced by Paenibacillus polymyxa. Paenan exhibits highly shear-thinning flow behavior at concentrations >=0.1% in 0.5% NaCl. Because of its pronounced intermolecular network, it forms stable, weak gels, thereby delivering elasticity as well as thixotropy. Application-relevant flow behavior is obtained with 60-65% less polymer as compared to the benchmark commercial products Xanthan and Gellan. In mixtures with surfactants (sodium lauryl ether sulfate, cetrimonium chloride, cocamidopropyl betaine, or lauryl glucoside), Paenan displays outstanding compatibility with every class of surfactant, making it superior to the partially incompatible Xanthan and Gellan. The weak-gel character of Paenan/surfactant systems is retained with three out of four surfactants, rendering Paenan highly interesting for various applications. PMID- 29254029 TI - Development and characterization of novel antimicrobial bilayer films based on Polylactic acid (PLA)/Pickering emulsions. AB - Biodegradable food packaging is sustainable and has a great application prospect. PLA is a promising alternative for petroleum-derived polymers. However, PLA packaging suffers from poor barrier properties compared with petroleum-derived ones. To address this issue, we designed bilayer films based on PLA and Pickering emulsions. The formed bilayer films were compact and uniform and double layers were combined firmly. This strategy enhanced mechanical resistance, ductility and moisture barrier of Pickering emulsion films, and concomitantly enhanced the oxygen barrier for PLA films. Thymol loadings in Pickering emulsion layer endowed them with antimicrobial and antioxidant activity. The release profile of thymol was well fitted with Fick's second law. The antimicrobial activity of the films depended on film types, and Pickering emulsion layer presented larger inhibition zone than PLA layer, hinting that the films possessed directional releasing role. This study opens a promising route to fabricate bilayer architecture creating synergism of each layer. PMID- 29254030 TI - Preparation of cationic konjac glucomannan in NaOH/urea aqueous solution. AB - Cationic derivatives of konjac glucomannan (KGM) were homogeneously synthesized by reacting KGM with 3-chloro-2-hydroxypropyltrimethylammonium chloride (CHPTAC) in NaOH/urea aqueous solutions. The derivatives were characterized by FT-IR, 1H NMR, elemental analysis, thermogravimetric analysis and zeta potential analysis. The results showed that the degree of substitution (DS) of the CKGM with the value of 0.15-0.46 could be obtained by changing the molar ratio between KGM and CHPTAC. The TG/DTG revealed that the thermal stability of KGM after cationization was lower than that of raw KGM. Among a wide range of pH value, the zeta potential in CKGM solution was shown with positive charges. The flocculation capacity of the CKGM was assessed through Kaolin suspension using the light transmission test. The results exhibited that the CKGM had excellent flocculation performance and could be used as an emerging flocculant agent in the wastewater treatment. PMID- 29254031 TI - Alginate and polyethyleneimine dually mediated synthesis of nanosilver-containing composites for efficient p-nitrophenol reduction. AB - Three-dimensional silver/polyethyleneimine/alginate hydrogel beads have been prepared successfully via a facile and simple one-pot assembly method, which can be used efficiently in catalytic hydrogenation reaction of p-nitrophenol under batch and fixed-bed experiment. Polyethyleneimine is used to reduce and limit the growth of nano-silver particle and alginate microsphere is used as the catalyst carrier, leading to form well silver nanoparticles dispersion. Several characterizations were applied to the materials, such as X-ray diffraction, scanning electron microscopy, transmission electron microscopy and X-ray photoelectron spectroscopy. As-prepared catalysts only spent 120s finishing reaction at ambient temperature (20% silver load) and stable catalytic performance with high conversion percentage for p-nitrophenol about 90% at 298K under fixed-bed condition. The relationship between concentration and time was well depicted by Pseudo-first order kinetic model. The catalytic performance for recycled catalyst remained highly efficient, and the conversion efficiency of 96.4% can be maintained after 10 cycles. PMID- 29254032 TI - Characterization, antimicrobial and antioxidant property of exopolysaccharide mediated silver nanoparticles synthesized by Streptomyces violaceus MM72. AB - Green synthesis of silver nanoparticle (SNPs) has gained considerable attention in nano-biotechnology and nano-medicine owing their potency and eco-friendliness. In this, we account the exopolysaccharide and its mediated synthesis of SNPs and their biological activities. Exopolysaccharide of the Streptomyces violaceus composed of total carbohydrate (61.4%), ash (16.1%), moisture content (1.8%) and NMR confirmed their structural composition. SNPs synthesized by the exopolysaccharide, confirmed using UV-vis spectral analysis and characterized by TEM and XRD analyses. Further, the SNPs evaluated for its antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis using disc diffusion method. The SNPs has shown promising antibacterial activity were evaluated for MIC. Furthermore, the SNPs were tested for antioxidant activities and was found to have promising antioxidant activity over the standards. The above results prove that SNPs can be considered as a potent antibacterial and antioxidant drug in future. PMID- 29254033 TI - Preparation and properties of wet-spun agar fibers. AB - Motivated by the extensive application of agar, this work developed a wet spinning process to fabricate micro-scale fibers using the gelation process of agar. The effect of three vital spinning parameters, namely dope concentration, coagulation bath composition, and fiber post-processing on morphological properties, tensile properties and chemical structure of the fiber have been discussed. The concentration of agar was determined by the results of rheological measurement. The addition of barium chloride in the coagulation process improved the mechanical properties of fibers as compared to deionized water as coagulation. The agar fibers immersed in amino silicone demonstrated significantly showed better mechanical properties compared to the agar fibers only immersed in ethanol. The physical and chemical properties of agar fibers were characterized by X-ray diffraction, FTIR, tensile testing, and SEM. The results showed that excellent agar fibers with several potential applications can be produced with amino silicone modification in optimum coagulation bath. PMID- 29254034 TI - Characterization, antioxidativity, and anti-carcinoma activity of exopolysaccharide extract from Rhodotorula mucilaginosa CICC 33013. AB - The water-soluble exopolysaccharide REPS2-A was isolated and characterized from R. mucilaginosa CICC 33013. REPS2-A was composed of galactose, arabinose, glucose, and mannose at a molar ratio of 63.1:0.2:18.3:18.3, respectively, with a molecular weight of 7.125*106Da. Based on FT-IR, NMR, and methylation analysis, REPS2-A was identified to be a highly branched polysaccharide with a backbone of (1->3)-linkedGal with Man, Gal, and Ara terminals. The branches were identified as (1->2)-linked Glc, (1->4)-linked Man, (1->3)-linked Glc, (1->4,6)-linked Man, and (1->2,3,4)-linked Ara. In addition, REPS2-A exhibited excellent free radical scavenging (DPPH, ABTS, and reducing power) and antitumor activities. These results indicate its activity against growth of the human hepatocarcinoma cell HepG2 with IC50 values of 1.0mg/mL, compared to lower cytotoxic effects on normal human hepatocyte cell L02. Studying the underlying mechanisms indicated that REPS2-A induced both dose- and time-dependent cell cycle arrest at the G1/S phase. PMID- 29254035 TI - Direct conversion of lignocellulose to levulinic acid catalyzed by ionic liquid. AB - Acidic ionic liquid (IL) [C3SO3Hmim]HSO4 was applied to catalyze lignocellulose conversion to levulinic acid (LA) in one pot with high selectivity under hydrothermal conditions. Through the optimization of reaction conditions, the highest yield of LA is 96.6mol% (21.6wt%) based on the amount of C6-sugars in the straw. The relationship between IL structure and LA yield was established, disclosing that acidity and hydrogen bonding ability of anions are crucial to the yield of LA. Moreover, the LA product can be readily separated through extraction by methyl isobutyl ketone (MIBK) and IL can be reused over 5 cycles without loss of activity. In addition, the chemical structures and morphologies of the solid residues were investigated by DTG, SEM and IR, demonstrating the gradual conversion process of cellulose and hemicellulose accompanied by the formation of humin byproducts, whereas the lignin fraction of the straw sustains the scaffold structure without modifications during the reaction. PMID- 29254037 TI - Versatile magnetic gel from peach gum polysaccharide for efficient adsorption of Pb2+ and Cd2+ ions and catalysis. AB - In this paper, we report a facile approach to prepare magnetic gel based on the simultaneous formation of Fe3O4 nanoparticles and crosslinking of natural peach gum polysaccharide. The obtained magnetic gel with porous structure, high specific surface area and numerous oxygen-containing functional groups exhibited fast and efficient adsorption capability towards Pb2+ and Cd2+ ions. The adsorption isotherms and kinetics presented good correlation with Langmuir isotherm and pseudo-second-order model, respectively. The maximum adsorption capacity of the magnetic gel for Pb2+ and Cd2+ ions can reach 277.0 and 141.4mgg 1, respectively, which is much higher than many other reported magnetic adsorbents. In addition, the magnetic gel can serve as a magnetic support for in situ growth of Pt nanocatalyst with high catalytic activity, as demonstrated by the reduction of 4-nitrophenol. Moreover, the magnetic gel exhibited excellent magnetic separation capability and superior reusability both for the adsorption and catalysis applications. PMID- 29254036 TI - Hybrid graphene oxide/polysaccharide nanocomposites with controllable surface properties and biocompatibility. AB - Herein, a strong interdependence between the composition of hybrid graphene oxide/hyaluronan/chitosan GO/HA/Chi multilayers and their surface properties and biocompatibility was demonstrated that can be used to build up coatings with desirable and precisely tunable properties. Both the position and the abundance of GO-layers into the polymer matrix were systematically varied to draw interconnection with the growth type, thickness, morphology, roughness, hydrophilicity and biocompatibility. It was found that when deposited in-between the HA and Chi layers GO forms diffusion barrier, hindering the mobility of Chi chains and changing the exponential film growth to linear. Incorporation of GO layers into the biodegradable and highly hydrated HA/Chi matrix does not affect the final thickness, but has a dramatic impact on the surface morphology and roughness, which in turn tunes the hydrophilicity, protein adsorption and platelets adhesion. This provides an opportunity for various biomedical applications of the studied hybrid films as coatings with controllable surface properties. PMID- 29254038 TI - Optimized biosynthesis of xanthan via effective valorization of orange peels using response surface methodology: A kinetic model approach. AB - Herein, an enhanced green production of xanthan gum has been achieved by utilizing orange peels. Response surface methodology and kinetic modeling were adapted for the process optimization and its influence on scale up production respectively. Optimal conditions for the maximum xanthan production were 1.62% acid hydrolysis, 85% carbon source of orange peel hydrolysate and 30.4 degrees C temperature. Furthermore, the optimized treatment was conducted in the batch culture fermentor to observe the associated variations during scale up process. In bio-fermentor, to the first time ever, xanthan production along with reducing sugar conversion and utilization rates reached 30.19g/L, 69.29% and 99.99%, respectively. Employed characterization techniques of FTIR, XRD and HPLC confirmed the fermented product as xanthan gum and obtained an average molecular weight of 1.01*106g/mol. This work on account of optimized process parameters presented maximum xanthan production from a waste material. PMID- 29254040 TI - Synthesis, characterization and antioxidant activity of chitosan-chromone derivatives. AB - In this study, a new chromone-functionalized chitosan Schiff base and its cross linked derivative were synthesized and characterized by FT-IR, UV-vis, 13C CP/MAS solid-state NMR, TGA, XRD-powder and SEM measurements and elemental analysis data. Degrees of substitution (DS) were determined from the elemental analysis by using the C/N ratios. The in vitro antioxidant activity of high molecular chitosan and its chromone derivatives was evaluated as radical scavengers against 1,1-diphenyl-2-picrylhydrazyl radicals (DPPH). The results showed that both of the chitosan-chromone derivatives have good antioxidant potential which might be due to the phenolic group introduced after chemical modification of chitosan with a chromone derivative. Chromone-chitosan Schiff base (CSCH) had a better ability to scavenging DPPH radical (IC50, 0.88mg/mL) than that of its cross-linked derivative (CSCH-TP) obtained by using terephthalaldehyde (IC50, 1.32mg/mL). PMID- 29254039 TI - Characterization of alginate/chitosan-based nanoparticles and mathematical modeling of their SpBMP-9 release inducing neuronal differentiation of human SH SY5Y cells. AB - The incidence of brain degenerative disease such as Alzheimer's disease (AD) will increase as the world population is ageing. While current AD treatments have only a transient effect, there are many evidences indicating that some growth factors, such as BMP-9, may be used to treat AD. However, growth factors cannot readily access the brain because of their size and the presence of the blood brain barrier. We have therefore developed a small peptide derived from BMP-9, SpBMP-9, which can promote the differentiation of cholinergic neurons and inactivate GSK3beta, a Tau kinase. Here, we investigated the potential of a nanoparticle based delivery system of SpBMP-9, made of alginate and chitosan (Alg/Chit NPs), as a new therapeutic strategy against AD. The Alg/Chit NPs size distribution revealed NPs with an average diameter of ~240nm. The encapsulation efficiency of SpBMP-9 was ~70% of the initial peptide mass loading. Release kinetics of SpBMP-9 were performed in physiological conditions and modelled with a mechanistic framework that took into account the size distribution of Alg/Chit NPs. The release of SpBMP-9 revealed to be mostly diffusive, but there were interactions between the peptide and the alginate chains. The Alg/Chit NPs could also increase the viability of SH-SY5Y cells in comparison to the control. Finally, the SpBMP-9 released from Alg/Chit NPs promoted the SH-SY5Y differentiation into mature neurons as demonstrated by a higher neurite outgrowth and an increased expression of the neuronal markers NSE and VAchT. In conclusion, the nano-scale SpBMP-9 delivery system made of Alg/Chit may be a promising therapeutic strategy against AD. PMID- 29254041 TI - Biosynthesis of superparamagnetic polymer microbeads via simple precipitation of enzymatically synthesized short-chain amylose. AB - Here, we report a simple and non-emulsion based approach to prepare starch-based magnetic polymer beads with well-defined size, shape and dispersibility in aqueous environment through co-precipitation of enzymatically synthesized short chain amylose (SCA) and dextran-coated iron oxide nanoparticles (Dex@IONPs). The size and morphology of magnetic polymer beads (MPBs) were controlled by employing Dex@IONPs as a seeding agent. The resulting superparamagnetic amylose microbeads (SAMBs) were readily functionalized with antibody through one step reaction using a linker protein, which showed great capture efficiency (>90%) and specificity for target bacteria present in complicated food matrix. The excellent magnetic sensitivity also enabled the SAMBs readily assembled into ordered 1D arrays by external magnetic field whose structure could permanently be fixed by SCA mediated precipitation process. PMID- 29254042 TI - Preparation and characterization of nanocrystalline cellulose/Eucommia ulmoides gum nanocomposite film. AB - The nanocomposite films were prepared using Eucommia ulmoides gum (EUG) matrix reinforced with nanocrystalline cellulose (NCC) at different concentrations. Subsequently, the obtained films were characterized by Raman spectra, AFM, XRD, TGA, and DSC. Meanwhile, the wettability, mechanical, and water vapor barrier properties of these films were analyzed. AFM noticed that the average sizes of NCC were 81.95*50.17*13.06nm, while the size of molecular chain for EUG was 2530*57.33*1.28nm. In comparison with control film, a certain amount of NCC obviously improved elongation at break and enhanced their crystallinity and DeltaHm. More importantly, NCC/EUG nanocomposite films presented lower thermal stability, glass transition temperature (Tg), melting temperature (Tm), and water vapor permeability (WVP) values, especially the WVP values of 4% NCC film were the lowest as 0.28*10-9, 0.30*10-9, and 0.58*10-9g/m/h/Pa at RH 34%, 55%, and 76%, respectively. PMID- 29254043 TI - Construction of flame retardant coating on polyamide 6.6 via UV grafting of phosphorylated chitosan and sol-gel process of organo-silane. AB - Phosphorylated chitosan (PCS) was synthesized and grafted onto the surface of polyamide 6.6 (PA 6.6) fabrics via UV-induced grafting polymerization in order to improve the flame retardant properties. Subsequently, PCS grafted PA 6.6 fabrics were modified by (3-aminopropyl) triethoxysilane (APTES) through sol-gel process in order to form a cross-linking coating. The results obtained from the vertical burning test indicated that only the PCS grafted and simultaneously sol-gel treated fabrics could stop the melt dripping. A maximum reduction (30%) in the peak heat release rate was achieved for the PA6.6-PCS-4W-SG fabric sample. The optimal flame retardant effect was achieved for the PA6.6 fabrics treated by PCS and APTES simultaneously, which was attributed to the joint effect of thermal shielding exerted by the silica and char-forming effect derived from PCS. PMID- 29254044 TI - pH-responsive selenium nanoparticles stabilized by folate-chitosan delivering doxorubicin for overcoming drug-resistant cancer cells. AB - Herein, we first report pH-responsive SeNPs stabilized with modified folic acid-N trimethyl chitosan (TMC-FA) as nanocarriers for delivery of doxorubicin (DOX) to overcome drug-resistant cancer cells, which could enhance the activity of DOX by approximately 10-fold for a reduced IC50 value compared to free DOX. When nanoparticles were taken up by cells, the DOX-loaded SeNPs@TMC-FA demonstrated a faster release rate under acidic conditions. The cumulative release amount of DOX at pH 5.3 was 54.1% within 2h and 95.5% at 6h, whereas the release rate at pH 7.4 was 12.3% in 2h and 42.2% for 6h; release was not completed at the end of the study, 72h. Mechanistic studies suggested that DOX-SeNPs@TMC-FA induced cell death through the apoptosis pathway by involvement of caspase-3 and PARP proteins. The results demonstrated that pH-responsive SeNPs@TMC-FA, as targeted nanocarriers, promoted the efficacy of DOX and overcame drug resistance in NCI/ADR-RES cells. PMID- 29254045 TI - Quinoa starch: Structure, properties, and applications. AB - Quinoa (Chenopodium quinoa Willd.) has gained popularity worldwide largely due to the attractive nutritional profile. It also has much potential for food security due to the great genetic diversity. Starch is the main component of quinoa grain and makes up to 70% of the dry matter. The starch plays a crucial role in functional properties of quinoa and related food products. The starch granules are rather small (~1-3MUm) with relatively low amylose contents as compared with most of the other starches. Quinoa amylopectin has significant amounts of short chains and super-long chains. These unique features have generated research interest in using the starch for food and other applications such as creating Pickering emulsions. This review summarizes the present knowledge of the isolation, composition, granular and molecular structures, physicochemical properties, modifications, and applications of quinoa starch. It becomes obvious that this starch has great potential for food and nonfood applications. PMID- 29254046 TI - Pervaporation multilayer membranes based on a polyelectrolyte complex of lambda carrageenan and chitosan. AB - A polyelectrolyte complex (PEC) was prepared from chitosan (CS) and lambda carrageenan (lambda-CAR) using a layer-by-layer deposition of polyion solutions on a plated nonporous support. This material was then used as a multilayer membrane for the pervaporation separation of aqueous ethanol solutions. The fabricated complex film (25-30MUm thick) was a multilayer system (lambda-CAR-PEC CS) containing a polycation CS (MW 3.1*105, DDA 0.93), a polyanion lambda-CAR (MW 3.5*105, extracted from the alga Chondrus armatus), and a PEC layer formed between the two polyion layers. X-ray diffraction indicated a significant structuring of the film in the region of the composite PEC-CS bilayer. The structural and morphological characteristics of the CS surface in the multilayer membrane, as revealed by atomic force microscopy, were close to the characteristics of the dense CS film. However, this structure changed following pervaporation (i.e., the distinct spherical structures on the surface disappeared). Similarly, the initially loose surface of lambda-CAR in the composite changed to an ordered domain after pervaporation. The transport properties of the pervaporation membranes were tested by examining the separation of ethanol-water mixtures of different compositions. The flux increased with an increase in the weight percentage of water in the feed mixture, but the separation capacity of the membrane was unchanged. In a range of feed concentrations of 50-94wt%, the membrane mainly releases water with a corresponding concentration in the permeate of 99.9-99.8wt% and substantial fluxes of 0.003-1.130kgm-2h-1 at 40 degrees C. The obtained results indicate significant prospects for the use of non-gelling type CARs for the formation of highly effective pervaporation membranes. PMID- 29254047 TI - Water absorption and viscosity behaviour of thermally stable novel graft copolymer of carboxymethyl cellulose and poly(sodium 1-hydroxy acrylate). AB - A novel thermally stable hydrolysed carboxymethyl cellulose-g-poly(sodium 1 hydroxy acrylate) i.e. CMC-g-PNaHA graft copolymer was synthesized from the CMC and vinyl monomer 5-methylene-2-isopropyl-1,3-dioxolan-4-one (MD) in an aqueous medium using an initiator followed by transformation of resulting CMC-g-PMD via alkaline hydrolysis. The graft copolymerization is confirmed by the Fourier transform infrared spectroscopy (FT-IR), Nuclear magnetic resonance spectroscopy (NMR) and X-ray diffractometer (XRD). The influence of the CMC and PNaHA content on the properties of the resulting hydrolysed CMC-g-PNaHA graft copolymer was investigated. In comparison with the PNaHA polymer, the resulted hydrolysed CMC-g PNaHA grafted copolymer has improved thermal stability, water absorption properties, viscosity and weight-average molecular weight. PMID- 29254048 TI - Insights into the EDC-mediated PEGylation of cellulose nanofibrils and their colloidal stability. AB - EDC-mediated coupling has frequently been utilized to poly(ethylene glycol) functionalize (PEGylate) cellulose-based materials, but no work has previously been reported on the direct N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) mediated PEGylation of cellulose nanofibrils (CNF). Herein, we report the first study where CNF has been directly sterically stabilized with amine-terminated PEG employing N-hydroxysuccinimide (NHS)-assisted EDC-coupling. This work has shown that this coupling reaction is highly sensitive to the reaction conditions and purification procedures, and hence an optimized coupling protocol was developed in order to achieve a reaction yield. Elemental analysis of the nitrogen content also showed the successful PEGylation. It was also shown that a surprisingly low PEGylation (1%) is sufficient to significantly improve the colloidal stability of the PEGylated samples, which reached dispersion-arrested-state-transitions at higher concentrations than neat CNF. The colloidal stability was preserved with increasing ionic strength, when comparably long polymer chains were grafted, targeting only 1% PEGylation. PMID- 29254049 TI - Preparation and characterization of the spherical nanosized cellulose by the enzymatic hydrolysis of pulp fibers. AB - In this work, the pulp fibers were enzymolyzed to prepare the nanosized cellulose (NC). The as-prepared samples were characterized by optical microscopy, electron microscopy, and Raman spectra. The experimental results indicated that enzymatic hydrolysis of pulp fibers could produce the spherical NC with a mean particle size of about 30nm, which had the excellent monodispersity and uniformity. When the concentration of complex enzymes was 20u/mL (cellulase: xylanase=9: 1), the yield of NC was 13.6%. The single cellulase was used, even if the enzyme concentration reached up to 200u/mL, only a mixture of strip and granular flocculation were obtained. The positive synergistic effect between xylanase and cellulase could be due to the enzymolysis of hemicellulose located on the cellulose microfibers to be favorable of cutting and splitting of the microfibers by the endoglucanase in cellulase. PMID- 29254050 TI - Montmorillonite@chitosan-poly (ethylene oxide) nanofibrous membrane enhancing poly (vinyl alcohol-co-ethylene) composite film. AB - A montmorillonite@chitosan-poly (ethylene oxide) nanofibrous membrane (MMT@CPF) enhancing poly (vinyl alcohol-co-ethylene) (EVOH-MMT@CPF) composite film was developed by using a space-filling embedding method. The structure of EVOH MMT@CPF was characterized, and the thermal stability, mechanical and barrier properties of the films were investigated. The CPF was fabricated via electrospinning technique and the self-assembly of MMT nano-platelets on CPF was achieved by the driving of electrostatic interactions between MMT nano-platelet and CPF. The experimental results indicated that the well-kept MMT@CPF after embedding in the EVOH matrix significantly improved the thermal stability and mechanical properties of the film, and also endowed the film with outstanding oxygen barrier (0.2*10-16cm3cmcm-2s-1Pa-1) and good moisture barrier (4.6*10-6gmm 2s-1atm-1 under a relative humidity of 90%) by prolonging the tortuous paths for molecule penetration. The composite film may have a great potential application in food packaging. PMID- 29254051 TI - Structural analysis of Ioncell-F fibres from birch wood. AB - Quite recently, the Ioncell-F process, a novel and promising Lyocell fibre process, has been developed. The ionic liquid 1,5-diazabicyclo[4.3.0]non-5-enium acetate ([DBNH]OAc) utilized in this process, was identified as an excellent cellulose solvent for dry-jet wet fibre spinning. Fibres spun from cellulose [DBNH]OAc solution have shown excellent mechanical properties. Herein, various structural features of these ionic liquid-based fibres were analyzed and correlated with their mechanical properties. The highest slope of tenacity increase of these Ioncell-F fibres (from birch wood) observed at low draw ratios (DRs), while a continuous but slower increase occurs to partly very high draws. The improvements in the mechanical properties do not seem to correlate with changes in the crystallite size or the crystalline orientation based on wide angle X-ray scattering (WAXS) results. More significant differences were seen for the sample crystallinity, the amorphous orientation (measured by birefringence), the orientation of the voids, the specific surface (measured by small-angle X-ray scattering (SAXS)), and the sorption/desorption properties of the fibres. PMID- 29254052 TI - Microwave assisted hydrothermal extraction of polysaccharides from Ulva prolifera: Functional properties and bioactivities. AB - Sulfated polysaccharides from green tide algae Ulva prolifera were effectively extracted by microwave assisted hydrothermal extraction technology. The properties and bioactivities of polysaccharides could be controlled by extraction conditions. While rhamnose, galacturonic acid and glucose were major monosaccharides at 90 degrees C with 0.01M HCl, glucose was the major monomer at 150 degrees C with 0.1M HCl. Sulfur content increased with temperature and acid concentration, while molecular weight decreased with temperature and concentration. Functional property analysis showed that polysaccharides extracted from 90 degrees C, 0.05M HCl had the best water-holding capacity (41.32g/g) and oil-holding capacity (15.09g/g), and polysaccharides extracted from 150 degrees C, 0.05M HCl had the best foaming properties (foaming capacity 143% and foaming stability 113%, respectively). In addition, polysaccharides extracted from 150 degrees C, 0.1M HCl exhibited higher antioxidant activity and pancreatic lipase inhibition activity. The relationship between polysaccharide compositions/molecular weight and properties/bioactivities was discussed. PMID- 29254054 TI - Monitoring succinoglycan production in single Sinorhizobium meliloti cells by Calcofluor white M2R staining and time-lapse microscopy. AB - Here, we describe a simple, non-time consuming and inexpensive method for monitoring of Calcofluor white M2R-binding exopolysaccharides in individual bacterial cells. This method was demonstrated by time-lapse microscopy of succinoglycan-producing cells of the plant-symbiotic alpha-proteobacterium Sinorhizobium meliloti. The method is most likely applicable to other bacteria producing beta-(1->3) and beta-(1->4) linked polysaccharides. PMID- 29254053 TI - Immunostimulatory and anti-metastatic activity of polysaccharides isolated from byproducts of the corn starch industry. AB - Corn steep liquor (CSL) is a major by-product of the corn steeping process that is utilized in the wet milling industry. To develop new physiologically active polysaccharides from CSL, polysaccharides were isolated and their innate immunostimulatory and anti-metastatic activities were investigated. Corn byproduct polysaccharides (CBP) were preferentially isolated from CSL and further separated into supernatant (CBP1S) and precipitate (CBP1P) fractions. The anti complementary activity of CBP1S was more potent than CBP1P and CBP. In addition, CBP1S enhanced production of macrophage-stimulating cytokines (e.g., IL-6 and IL 12) and natural killer (NK) cell-activating substances (e.g., granzyme and interferon-gamma). Further, CBP1S significantly inhibited lung metastasis at a dose of 1000MUg per mouse in an experimental lung metastasis model. These results suggest that CBP1S seems to promote the inhibition of lung metastasis through a mechanism leading to stimulation of the innate immune system, and CBP1S could be used as immunostimulating agents and for industrial applications. PMID- 29254055 TI - Anti-proliferative activity of a purified polysaccharide isolated from the basidiomycete fungus Paxillus involutus. AB - A growth-inhibitory polysaccharide (GIPinv) was purified using size-exclusion and ion-exchange chromatography from the fourth sodium hydroxide extraction step of a fungus found in British Columbia. The fungus was genetically identified as a member of the Paxillus involutus complex. GIPinv has an average molecular weight of 229kDa and is a heteroglycan composed of glucose (65.9%), galactose (20.8%), mannose (7.8%), fucose (3.2%) and xylose (2.3%). GC-MS methylation analysis suggests that GIPinv has mixed linkages in the backbone containing (1->6)-Gal (25.5%), (1->4)-Glc (18.3%), (1->6)-Glc (8.3%), (1->3)-Glc (5.3%) and (1->2)-Xyl (4.5%). GIPinv has branching points at (1->2, 6)-Man (8.6%) and (1->3, 6)-Man (4.9%) having unsubstituted fucose (8.3%) and glucose (16.3%) as terminal sugars. GIPinv had growth-inhibitory activity against several cancer cell lines and triggered apoptosis. GIPinv should be further explored as a potential anti-cancer agent and a unique polysaccharide. PMID- 29254056 TI - Influence of different classes of crosslinkers on alginate polyelectrolyte nanoparticle formation, thermodynamics and characteristics. AB - Complexation of linear alginate polyanions with different classes of crosslinkers (divalent cations, polycations, positively charged surfactants) was investigated, to unravel their effects on nanoparticle formation. The goal was to define the crosslinker-to-alginate molar ratios at which nanoparticles are formed, and to reveal the underlying thermodynamics and molecular interactions using dynamic and electrophoretic light scattering, isothermal titration calorimetry, and infrared spectroscopy. Alginate nanoparticles were formed across a limited range of molar ratios that was specific for each crosslinker, and had different size and stability. Thermodynamic parameters of alginate complexation with crosslinkers showed that nanoparticle formation was in all cases entropy driven, together with a minor enthalpic contribution. The crosslinking mechanism was based on ionic interactions, with accompanying weaker interactions specific for each crosslinker, and involved characteristic macroscopic association constants (Ka1) for complexation of alginate (range, 104-109M-1). Additionally, the ionic strengths of the media influenced the characteristics and stabilities of the polyelectrolyte nanoparticles. PMID- 29254057 TI - Exploring the mechanism of high degree of delignification inhibits cellulose conversion efficiency. AB - This study explored the mechanism that high degree of delignification (DD) inhibits enzymatic hydrolysis. Sample with DD of 86.22% achieved the highest cellulose conversion of 68.26%, and the cell wall exhibited defibrillation of macrofibrils and erosion of microfibrils during enzymatic hydrolysis. Cracks between microfibrils are formed within the cell wall, getting the largest specific surface area, which greatly enhanced cellulose conversion. However, high DD of 96.58% resulted in dramatic reduction of cellulose conversion to 56.60% which was evidenced to be the synergistic effect of internal cell wall collapse and microfibrils reaggregation. These ultrastructural changes dominated upon this condition and induced a more compact surface structure which significantly hinders the accessibility of cellulase. The CrI value increased after delignification but changed little with the increased DD, suggesting limited influence of DD on crystalline structure. The results indicate that certain amount of lignin retained may be essential to enhance cellulose conversion. PMID- 29254058 TI - HPMC granules by wet granulation process: Effect of vitamin load on physicochemical, mechanical and release properties. AB - Due to its versatile properties, hydroxypropyl methylcellulose (HPMC) is largely used in many applications and deeply studied in the various fields such as pharmaceuticals, biomaterials, agriculture, food, water purification. In this work, vitamin B12 loaded HPMC granules were produced to investigate their potential application as nutraceutical products. To this aim the impact of vitamin load on physico-chemical, mechanical and release properties of granules, achieved by wet granulation process, was investigated. In particular, three different loads of B12 (1%, 2.3% and 5% w/w) were assayed. Unloaded granules (used as control) and loaded granules were dried, sieved, and then the suitable fraction for practical uses, 0.45-2mm in size, was fully characterized. Results showed that the vitamin incorporation of 5% reduced the granulation performance in the range size of 0.45-2mm and led granules with higher porosity, more rigid and less elastic structures compared to unloaded granules and those loaded at 1% and 2.3% of B12. Vitamin release kinetics of fresh and aged granules were roughly found the same trends for all the prepared lots; however, the vitamin B12 was released more slowly when added with a load at 1% w/w, suggesting a better incorporation. PMID- 29254059 TI - Use of heparinized bacterial cellulose based scaffold for improving angiogenesis in tissue regeneration. AB - Vascularization is a prerequisite to achieve tissue regeneration especially for long-term survival of a scaffold. During the regeneration process, the delivery of angiogenic factors is very important for developing a vascular network. In this paper, vascular endothelial growth factor (VEGF)-loaded 3D porous bacterial cellulose/gelatin (B/G) scaffolds modified with heparin were firstly prepared. The pro-angiogenic effects of scaffolds towards proliferation and migration of endothelial cells (PIECs) were evaluated as well as in vivo implantation. Results showed that the B/G scaffold modified with heparin could provide a prolonged release of VEGF for two weeks. In vitro cellular assays showed that proliferation and migration were promoted in the presence of VEGF. Subcutaneous implantation demonstrated that angiogenesis was significantly improved for the heparinized scaffolds loaded with VEGF (V-B/G/H), compared to B/G scaffold. The resulting scaffold with sustained delivery of VEGF could be potential and effective tissue engineered candidates in tissue regeneration for future clinical applications. PMID- 29254060 TI - Synthesis of carbohydrate conjugated 6A,6D-bifunctionalized beta cyclodextrin derivatives as potential liver cancer drug carriers. AB - Galactosyl and lactosyl conjugated 6A,6D-bifunctionlized beta cyclodextrin derivatives were designed and synthesized as the potential liver cancer drug carriers through SN2 replacement and click reactions in order to increase liver cancer drug's targeting ability, solubility and stability. The synthetic methods and strategies to obtain the designed compounds were discussed. PMID- 29254061 TI - Thiolated citrus low-methoxyl pectin: Synthesis, characterization and rheological and oxidation-responsive gelling properties. AB - In the present study, citrus low-methoxyl pectin was modified by conjugating cysteine via amide bonds, and the resultant polymer (CYS-PEC) was characterized. CYS-PEC conjugates with thiol contents varying from 77.8MUmol/g to 296MUmol/g were synthesized, and the successful conjugation was evidenced by elemental, and FT-IR analyses. The sulfur in CYS-PEC is predominately in the thiol form, with a minor fraction forming disulfide bonds (~15%), which occur when thiol/disulfide interchange interrupts the intended thiolation. Both native and modified pectin dispersions exhibited strong pseudoplastic properties, and the frequency sweeps revealed them to be dispersions containing microgel particles. Dynamic viscoelastic analysis was used to determine the oxidation-response gelling capacities of polymer dispersions containing H2O2, especially those that are highly thiolated and have cross-linked gel properties. For oxidation-induced CYS PEC gels, their gelation time, hardness, viscosity and elastic moduli and swelling-disintegration ratio are dependent on the thiol group content, H2O2 concentration and polymer concentration. PMID- 29254062 TI - Synthesis and characterization of Locust Bean Gum derivatives and their application in the production of nanoparticles. AB - The development of LBG-based nanoparticles intending an application in oral immunization is presented. Nanoparticle production occurred by mild polyelectrolyte complexation, requiring the chemical modification of LBG. Three LBG derivatives were synthesized, namely a positively charged ammonium derivative (LBGA) and negatively charged sulfate (LBGS) and carboxylate (LBGC) derivatives. These were characterized by Fourier-transform infrared spectroscopy, elemental analysis, nuclear magnetic resonance spectroscopy, gel permeation chromatography, and x-ray diffraction. As a pharmaceutical application was aimed, a toxicological analysis of the derivatives was performed by both MTT test and LDH release assay. Several nanoparticle formulations were produced using LBGA or chitosan (CS) as positively charged polymers, and LBGC or LBGS as negatively charged counterparts, producing nanoparticles with adequate properties regarding an application in oral immunization. PMID- 29254063 TI - Physicochemical properties of black pepper (Piper nigrum) starch. AB - Black pepper (Piper nigrum) is among the most popular spices around the world. Starch is the major component of black pepper. However, little is known about functional properties of this starch. In this study, swelling, solubility, thermal properties, rheology, and enzyme susceptibility of 2 black pepper starches were studied and compared with those of maize starch. Pepper starch had lower water solubility and swelling power than maize starch. It had higher viscosity during pasting event. In dynamic oscillatory analysis, pepper starch had lower storage modulus. Thermal analysis showed that pepper starch had much higher gelatinization temperatures (e.g., conclusion temperature of 94 degrees C) than maize starch. The susceptibility to alpha-amylolysis of pepper starch was not very different from that of maize starch. Overall, the differences in the physicochemical properties of the 2 pepper starches are non-significant. The relationships between structure (especially amylopectin internal molecular structure) and properties of starch components are highlighted. PMID- 29254064 TI - A closer look to cell structural barriers affecting starch digestibility in beans. AB - Isolated bean cells were used to understand the contribution of cell wall and cytoplasmic matrix on starch digestibility. Cotyledon cells were treated enzymatically and mechanically to reduce the level of cell intactness. SEM and chemical characterization revealed that enzymatic treatment modified cell wall thickness and porosity without altering the cytoplasmic matrix, whereas mechanical treatment completely disrupted cell structure. Decreasing cell intactness increased the rate but not the extent of starch digestion in-vitro. It was concluded that cell wall serves as a permeable barrier limiting the access of digestive enzymes. Cytoplasmic matrix, on the other hand, reduced further the accessibility of amylase to starch affecting its hydrolysis rate. In addition, it was proven that cell structural changes, if any, occurring during digestion had no effect on starch hydrolysis. PMID- 29254066 TI - Early improvement and response to antidepressant medications in adults with major depressive disorder. Meta-analysis and study of a sample with treatment-resistant depression. AB - BACKGROUND: Initial improvement in the first weeks of antidepressant (AD) treatment is a useful early predictor of complete AD response. We performed a meta-analysis of AD studies to investigate whether a partial decrease in depressive symptoms by week 4 was associated with response and remission by weeks 6-14 in major depressive disorder (MDD). Finally, we focused on treatment resistant depression (TRD: lack of response to prior AD) to test the impact of early improvement on a second AD treatment outcome and to compare different switching strategies. METHODS: Meta-analysis was conducted on AD naturalistic studies published between 01.01.2000 and 06.30.2017. TRD was an exclusion criterion. TRD was analyzed in 407 MDD patients treated with venlafaxine for 6 weeks. The MADRS was used to define very early improvement (VEI: > 20% decrease at week 2), early improvement (EI: > 30% decrease at week 4) and remission (week 6 MADRS < 10). A theoretical model was used to simulate AD switch in TRD patients who failed to achieve remission (Algorithm A), VEI (Algorithm B) or EI (Algorithm C). RESULTS: Our meta-analysis (9 studies; N = 6185) showed significant associations between early improvement, response (OR: 3.28 95% C.I: 2.06-5.20) and remission (OR: 2.10 95% C.I: 1.53-2.87). 24.6% of TRD sample remitted. VEI was a poor outcome predictor: sensitivity = 0.52 (0.40-0.63); specificity = 0.82 (0.76-0.86); AUC = 0.67 (0.62-0.71). EI had a moderate predictive power: sensitivity = 0.87 (0.77-0.93); specificity = 0.71 (0.66-0.77); AUC = 0.76 (0.71 0.80). The best treatment scenario was Algorithm C (switch after 4 weeks) in which remission rate was marginally increased (35.1% vs 33.7% of Algorithm A). Algorithm B (switch after 2 weeks) led to a 4.3% decrease in remission compared to Algorithm A. LIMITATIONS: Inclusion of a naturalistic sample without a control arm; simulation of treatments. CONCLUSION: Although literature data suggest a correlation between an initial improvement of depressive symptoms and later response and remission during AD treatment, our analysis shows that such an early improvement is not a reliable outcome predictor in TRD. The nature of TRD is complex and different biological mechanisms and treatments might be necessary for TRD patients. PMID- 29254065 TI - A pilot resting-state functional connectivity study of the kynurenine pathway in adolescents with depression and healthy controls. AB - BACKGROUND: The neuroimmunological kynurenine pathway (KP) has been hypothesized to play a role in depressive/anhedonic symptoms and related CNS disturbances. Indoleamine 2,3-dioxygenase (IDO) is the rate limiting enzyme which leads to neurotrophic [kynurenic acid (KA)] and neurotoxic [Quinolinic acid (QUIN)] branches. In this pilot, we sought to examine associations between blood KP neuro toxic/trophic measures and anhedonia/depression associated networks in youth with major depression (MDD) and healthy controls (HC). METHODS: Subjects were 14 psychotropic-medication free adolescents with MDD and 7 HC, ages 12-19 yo. All underwent resting-state functional magnetic resonance imagining (fMRI) scans. Voxel-wise maps were generated indicating correlation strengths among 4 bilateral seeds [(dorsal anterior cingulate cortex (dACC), perigenual ACC (pgACC), subgenual ACC (sgACC) and nucleus accumbens (NAc)] and remaining brain regions. FMRI analyses were family-wise error corrected. KP metabolites were measured using liquid chromatography-tandem mass spectrometry. RESULTS: Connectivity between the right dACC and the right precuneus was positively correlated with KA levels. This same cluster demonstrated an inverse correlation with IDO activity. Exploratory analysis at a more liberal clustering threshold showed the KA/QUIN ratio was positively correlated with connectivity between the pgACC and the right medial prefrontal cortex. Lastly, connectivity between the pgACC and the left inferior temporal gyrus was positively correlated with QUIN levels. LIMITATIONS: Findings are preliminary due to the small sample size. CONCLUSIONS: This pilot study is the first report in depressed adolescents demonstrating associations between the KP and anhedonia/depression-associated brain networks. This pilot adds evidence to the putative role of the KP in MDD. PMID- 29254067 TI - Worry amplifies theory-of-mind reasoning for negatively valenced social stimuli in generalized anxiety disorder. AB - BACKGROUND: Theory-of-mind (ToM) is the ability to accurately infer others' thoughts and feelings. In generalized anxiety disorder (GAD), cognitive and emotion regulation theories allude to the plausibility that ToM is conditional on the degree of individuals' state worry, a hallmark symptom. GAD and state worry may interact to predict ToM constructs. However, no experiments have directly tested such interactional hypotheses, and used ToM as a framework to advance understanding of social cognition in GAD. This study therefore aimed to address this gap. METHODS: 171 participants (69 GAD, 102 Controls) were randomly assigned to either a Worry or Relaxation induction and completed well-validated ToM decoding (Reading the Mind in the Eyes Test) and reasoning (Movie for the Assessment of Social Cognition) tasks. RESULTS: GAD status significantly interacted with state worry to predict accuracy of overall reasoning, cognitive reasoning, positive-reasoning, and negative-reasoning ToM. Worry, as opposed to relaxation, led sufferers of GAD to display more accurate overall reasoning and cognitive-reasoning ToM than controls, especially for negative signals. Participants with GAD who worried, but not relaxed, were also significantly better than the norm at interpreting negative signals. These findings remained after controlling for gender, executive function, social anxiety, and depressive symptoms. For other ToM abilities, mean scores of persons with and without GAD who either worried or relaxed were normative. LIMITATIONS: The ToM reasoning measure lacked self-reference, and these preliminary findings warrant replication. CONCLUSIONS: Theoretical implications, such as the state worry contingent nature of ToM in GAD, and clinical implications are discussed. PMID- 29254068 TI - Developmental timing of trauma exposure and emotion dysregulation in adulthood: Are there sensitive periods when trauma is most harmful? AB - BACKGROUND: This study aimed to determine whether there were sensitive periods when a first exposure to trauma was most associated with emotion dysregulation symptoms in adulthood. METHODS: Adult participants came from a public urban hospital in Atlanta, GA (n = 1944). Lifetime trauma exposure was assessed using the Traumatic Events Inventory (TEI). Multiple linear regression models were used to assess the association between the developmental timing of first trauma exposure, classified as early childhood (ages 0-5), middle childhood (ages 6-10), adolescence (ages 11-18), and adulthood (ages 19+), on adult emotion dysregulation symptoms, measured using the abbreviated Emotion Dysregulation Scale. RESULTS: Participants exposed to trauma at any age had higher emotion dysregulation scores than their unexposed peers. However, participants first exposed to child maltreatment or interpersonal violence during middle childhood had higher emotion dysregulation scores relative to those first exposed during other developmental stages; these developmental timing differences were detected even after controlling for sociodemographic factors, exposure to other trauma, and frequency of exposure to trauma. Further, after controlling for current psychiatric symptoms, the effect of other interpersonal trauma exposure in middle childhood was diminished and first exposure to other interpersonal violence in early childhood was associated with significantly lower emotion dysregulation symptoms. LIMITATIONS: Limitations of this study include the use of retrospective reports and absence of complete information about trauma severity or duration. CONCLUSION: These findings should be replicated in other population-based samples with prospective designs to confirm the importance of developmental timing of trauma on later emotion dysregulation. PMID- 29254069 TI - Rapid identification of oral solid dosage forms of counterfeit pharmaceuticals by discrimination using near-infrared spectroscopy. AB - BACKGROUND: Since it can take an enormous amount of time and cost to discriminate counterfeit medicines by using conventional methods, counterfeit medicines has been spread in the world markets. OBJECTIVE: The purpose of this study was to develop a rapid and simple analytical method to discriminate counterfeit drugs using near infrared (NIR) spectroscopy. METHODS: Seven types of brand name tablet and generic tablets containing atorvastatin calcium sesquihydrate (AT) preparations were used as simulated counterfeit medicines. NIR spectra of 35 AT tablet products were measured using a diffuse reflection method. RESULTS: The NIR spectral data were analyzed by principal component analysis (PCA). The PCA results suggested that the model had sufficient accuracy to discriminate the 7 types for AT tablets. The NIR spectral data were also analyzed using a soft independent modeling of class analogy (SIMCA) method. Predicting the classification of the AT tablet samples was performed based on all the validated AT tablet data using the SIMCA model, and the probability of classification of 7 types was 100%. The discrimination power spectrum of the SIMCA model indicated significant patterns based on diluents. CONCLUSIONS: The PCA and SIMCA classification of the AT tablets were depended on the major excipient combinations. PMID- 29254070 TI - Regulation of periodontal ligament-derived cells by type III collagen-coated hydroxyapatite. AB - BACKGROUND: The periodontal ligament (PDL), which maintains homeostasis in the periodontium, is a group of specialized connective tissue fibers attached to both the cementum and alveolar bone. Regeneration of periodontium with PDL cells has been investigated, and the chemical and molecular structures of scaffolds control the adhesion and differentiation of cells. Therefore, the development of adequate materials for PDL-derived cells is essential to regenerate the periodontium. OBJECTIVE: We evaluated the suitable passage time for PDL-derived cells and investigated the behaviors of PDL-derived cells grown on hydroxyapatite (HAp) scaffolds coated with type I and type III collagen. METHODS: PDL-derived cells were isolated with enzyme from the upper molars of male Wister rats. After characterization of HAp, type I collagen, and type III collagen, PDL-derived cells at passage 2 were seeded onto collagen-coated HAp. Cell adhesion, proliferative potential, and osteoconductivity were analyzed with immunostaining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, Alizarin S staining, and real-time polymerase chain reaction. RESULTS: Type I and III collagens were successfully coated on HAp. Gene expression analysis revealed that passage 2 was suitable for maintaining differentiation potential. Proliferative potential and cell adhesion were significantly higher on type III collagen than on HAp alone or type I collagen. In contrast, the osteoconductivity of type III collagen was significantly lower than those of HAp and type I collagen. CONCLUSION: PDL-derived cells on type I collagen differentiated into osteogenic cells and formed hard tissues. However, type III collagen enhanced the adhesion of PDL-derived cells and inhibited mineralization. PMID- 29254071 TI - Bacterial cellulose membrane used as biological dressings on third-degree burns in rats. AB - INTRODUCTION: Burn injuries represent a high risk of morbidity and mortality. The wound healing process is complex and requires the participation of different types of cells. Therefore, new biomaterials, which innovate the wound healing process, are being investigated. OBJECTIVE: The aim of this study was to investigate the use of bacterial cellulose both in its pure state and enriched with lidocaine in full-thickness burns in rats. METHODS: Thirty rats (Wistar) (260 +/- 20 gramas) divided into control group (CG), bacterial cellulose membrane group (MG) and bacterial cellulose membrane enriched with lidocaine group (MLG) were used. The burns were induced using a 150 degrees C heated soldering iron, held on the animal neck for 10 seconds. The biomaterial was applied immediately after injury and skin samples were collected on the tenth day of the treatment. The level of significance of p?0.05 was used for the conclusion of the statistical analysis. RESULTS: The groups treated with the biomaterials, a histological pattern compatible with a more advanced repair stage showing skin appendages, mild inflammatory infiltrate, better collagen fiber organization and mild immunostaining COX-2 and MMP-9 was observed, when compared to the control group that did not receive any type of treatment. CONCLUSION: Thus, was concluded that the bacterial cellulose-based biomaterial both in its pure state and enriched with lidocaine optimizing the full-thickness burn wound healing in rats. PMID- 29254073 TI - An effective method to identify various factors for denoising wrist pulse signal using wavelet denoising algorithm. AB - BACKGROUND: WPS is a non-invasive method to investigate human health. During signal acquisition, noises are also recorded along with WPS. OBJECTIVE: Clean WPS with high peak signal to noise ratio is a prerequisite before use in disease diagnosis. Wavelet Transform is a commonly used method in the filtration process. Apart from its extensive use, the appropriate factors for wavelet denoising algorithm is not yet clear in WPS application. The presented work gives an effective approach to select various factors for wavelet denoise algorithm. With the appropriate selection of wavelet and factors, it is possible to reduce noise in WPS. METHODS: In this work, all the factors of wavelet denoising are varied successively. Various evaluation parameters such as MSE, PSNR, PRD and Fit Coefficient are used to find out the performance of the wavelet denoised algorithm at every one step. RESULTS: The results obtained from computerized WPS illustrates that the presented approach can successfully select the mother wavelet and other factors for wavelet denoise algorithm. The selection of db9 as mother wavelet with sure threshold function and single rescaling function using UWT has been a better option for our database. CONCLUSION: The empirical results proves that the methodology discussed here could be effective in denoising WPS of any morphological pattern. PMID- 29254072 TI - Absolute quantification of residual DNA in a new extracellular matrix derived from human reticular dermis (HADM) using real-time TaqMan(r) MGB-PCR. AB - BACKGROUND: The development of dermal scaffolds is of major interest in reconstructive surgery. Human Acellular Dermal Matrices (HADMs) provides biomechanical support and elicits new tissue formation. The use of allograft dermis is limited by its immunogenic characteristics. Our research group has focused on the use of human alloplastic glycerolized reticular dermis. OBJECTIVE: The dermal grafts were subjected to two different decellularization protocols in parallel, in order to compare the efficacy in the elimination of residual DNA. METHODS: It was compared the incubation of the dermis in NaOH (0.06 N) and in the standard culture medium "Dulbecco Modified Eagle Medium" (DMEM). The samples were incubated in the specific medium for 8 weeks. The newly developed real-time TaqMan(r) MGB-PCR assay was applied for both the detection and absolute quantification of residual DNA. RESULTS: It was observed that the level of residual DNA decreased until time T3 and remained constant until time T8. Moreover, there was no statistical difference between treatment with DMEM or NaOH 0.06 N as to the amount of residual DNA. CONCLUSIONS: Decellularization methods, DMEM or NaOH 0.06 N do not affect DNA recovery. The proposed approach offers an alternative method to quantify residual DNA in HADM samples. PMID- 29254074 TI - Preparation of poly(lactic acid)/sintered hydroxyapatite composite biomaterial by supercritical CO2. AB - Based on a kind of sintered hydroxyapatite (HA) with a good cytocompatibility, a series of polylactic acid (PLA) and PLA/HA with the various PLA:HA weight ratio (5:5, 4:6, 3:7, 2:8, 1:9) were fabricated by supercritical CO2. The physical and chemical properties were evaluated by pH, degradation, water absorption, porosity, density, mechanical property, and cytotoxicity respectively. With the increase of HA content, the pH value and porosity increased gradually, while weight loss rate and the density showed a gradual downward trend. Existence of HA can drastically improve the hydroscopicity of PLA scaffolds. The compression strength values slightly increased (p>0.05) from 39.96 MPa of PLA to 45.00 MPa of PLA/HA with the ratio of 7:3, subsequently, the values decreased (p<0.05) from 43.29 MPa (8:2) to 19.00 MPa (9:1). While the modulus of elasticity decreased (p<0.05) from 5.89 to 1.84 GPa with increasing HA content. The PLA/HA (8:2) promoted cell proliferation more significantly than any of other groups (p<0.05). Based on the results, the overall properties of porous scaffolds are the optimal when the weight ratio of PLA/HA is 8:2. Its pH, porosity, density, compression strength, and elasticity modulus are 7.39, 83.0%, 0.60g/cm-3, 34.1 MPa and 2.63 GPa, respectively. SEM observation presented a homogeneous distribution of HA in PLA matrix and a foam-like structure comprising interconnected pores. PMID- 29254075 TI - Numerical investigations of the mechanical properties of braided vascular stents. AB - BACKGROUND: Braided stents, such as Pipeline Embolization Device (PED; ev3 Neurovascular, Irvine, CA, USA), are commonly used to treat cerebral aneurysms. However, little information is available on the compression and bending characteristics of such stents. OBJECTIVE: This paper investigates how geometrical parameters of braided stents influence their radial compression and bending characteristics. METHODS: Six groups of braided stent models with different braiding angles, numbers of wires and wire diameters are constructed. Parametric analyses of these models are conducted using Abaqus/Explicit software. The numerical results of a finite element analysis are validated by comparison with data of theoretical analysis. RESULTS: The results show that the radial stiffness is not uniform along the longitudinal direction of the stent. When the braiding angle increases from 30 degrees to 75 degrees , the minimum radial deformation decreases from 0.85 mm to 0.0325 mm (at a pressure of 500 Pa, for 24 braided wires). When the wire diameter increases from 0.026 mm to 0.052 mm, the minimum radial deformation decreases from 0.65 mm to 0.055 mm (at a pressure of 500 Pa and a braiding angle of 60 degrees , for 24 braided wires). Frictions don't affect stent diameter and its axial length when braided stent is crimping, but the friction must be considered when it is related to the radial pressure required for compression the braided stent. CONCLUSIONS: Compared with commonly used intracranial stents, a braided stent with geometrical parameters close to PED stent has a smaller radial stiffness but a considerably greater longitudinal flexibility. The results of this analysis of braided stents can help in the design and selection of flow diverter stents for clinical treatment of cerebral aneurysms. PMID- 29254076 TI - Numerical simulation of low-density lipoprotein mass transport in human arterial stenosis - Calculation of the filtration velocity. AB - Accumulation of cholesterol and other atherogenic lipids such as low-density lipoprotein (LDL) in artery wall causes reduction of vessel diameter and artery stenosis. The study of the mass transfer of these large molecules in the wall with considering effective factors on lumen flow and different physiological factors is the subject considered nowadays. In this paper, results of two dimensional and axi-symmetric simulations of three different models of the artery with 60% stenosis under pulsatile blood flow are presented. Filtration velocity of LDL mass transport in the permeable artery wall and shear stress of blood flow are investigated using ADINA software Three different flow models are considered. In the first and second models, the filtration velocity considered as a given parameter and constant in arterial wall boundary, while in third model arterial wall considered as porous wall, the filtration velocity is calculated from pressure difference as an input parameter of the model. The results show that filtration velocity is strongly depend on geometry and it is not constant along the wall, contrary to simplified models. The results of concentration variations in lumen and wall illustrate the increase in near wall LDL concentration or concentration polarization. PMID- 29254077 TI - Effect of metallographic structure and machining process on the apatite-forming ability of sodium hydroxide- and heat-treated titanium. AB - Although titanium (Ti) is clinically used for hard tissue reconstruction, it has low bone-bonding ability, i.e. bioactivity. Materials able to deposit apatite on their surfaces within the body is considered to exhibit bioactivity. Effects of the metallographic structure and machining process of Ti on its apatite-forming ability remains unclear. In this study, Ti substrates subjected to various preheating and machining processes were then subjected to NaOH and heat treatments. The apatite-forming abilities of resulting Ti were examined in simulated body fluid (SBF). Preheating of the Ti decreased its reactivity with NaOH solution. When quenched or annealed Ti was subjected to NaOH and heat treatments, the induction period for apatite formation in SBF slightly increased. This was attributed to a decrease in sodium titanate and increase in rutile on the Ti surface after the treatments. Substrates subjected to wire-electrical discharge machining did not form apatite. This was attributed to the inhibition of PO43- adsorption on their surfaces following Ca2+ adsorption, which is an essential process for apatite nucleation. Contamination of Ti surface by components of the brass wire used in the machining contributed to the inhibition. The bioactivity of surface-modified Ti was therefore significantly affected by its thermal treatment and machining process. PMID- 29254078 TI - Production and characterization of highly porous biodegradable Mg alloy scaffolds containing Ca, Zn and Co. AB - In this study, highly porous Mg-Ca-Zn-Co alloy scaffolds for tissue engineering applications were prepared by powder metallurgy based space holder method. Mg-Ca Zn-Co alloy foam can be used as a scaffold material for hard tissue generation. Mechanical properties of the porous specimens are close to cancellous bone. Increasing Zn content in the alloy decreased the Mg grain size and enhanced the mechanical properties. Increasing Zn content of the alloy from 1.0 to 8.0 wt.% increased the Young's modulus from 12 GPa to 23 GPa. Ca addition prevented the oxidation of the specimens during sintering. Electrochemical corrosion behaviour of the specimens was examined in the simulated body fluid. Corrosion rate was decreased with Zn addition up to 3.0 wt.% and then increased. Increasing Co content increased the corrosion rate. Weight loss/gain and Mg ion release values were increased with increasing immersion time. Weight loss of the specimen was initially decreased with Zn addition up to about 3% and then increased. PMID- 29254080 TI - Rationale and Design of the Mechanistic Potential of Antihypertensives in Preclinical Alzheimer's (HEART) Trial. AB - Research indicates that certain antihypertensive medications alter Alzheimer's disease (AD) biomarkers in Caucasians. The renin angiotensin system (RAS) regulates blood pressure (BP) in the body and the brain and may directly influence AD biomarkers, including amyloid-beta (Abeta) neuropathology, cerebral blood flow (CBF), and inflammatory markers. This hypothesis is supported by studies, including ours, showing that antihypertensives targeting the RAS reduce the risk and slow the progression of AD in Caucasians. While mounting evidence supports a protective role of RAS medications in Caucasians, this mechanism has not been explored in African Americans. To assess the mechanism by which RAS medications modify the brain RAS, cerebrospinal fluid (CSF) Abeta, CBF, and inflammatory markers in African Americans, we are conducting an eight month, Phase Ib randomized, placebo controlled trial, enrolling 60 middle-aged (45-70 years), non-demented individuals, at risk for AD by virtue of a parental history. Participants include normotensive and treated hypertensives that have never been exposed to a RAS medication. Participants are randomized (1 : 1:1) by gender and BP medication use (yes/no) to one of three groups: placebo, or 20 mg, or 40 mg telmisartan (Micardis), to determine the dose required to penetrate the CNS. Our overarching hypothesis is that, compared to placebo, both doses of telmisartan will penetrate the CNS and produce salutary, dose dependent effects on the brain RAS as well as CSF Abeta, CBF, and CSF inflammatory markers in African Americans, over eight months. This manuscript describes the trial rationale and design. PMID- 29254081 TI - Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer's Disease Development. AB - BACKGROUND: Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies. OBJECTIVE: To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD. METHODS: Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses. RESULTS: The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007). CONCLUSION: The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1 associated AD, possibly via its effects on the immune system. PMID- 29254082 TI - Testamentary Capacity Assessment Tool (TCAT): A Brief Instrument for Patients with Dementia. AB - BACKGROUND: In current practice, it is common for the medical practitioner to assess a person's testamentary capacity (TC) and give evidence to the Courts about a potential will contest. TC is an advanced cognitive activity that is both situation- and task-specific. OBJECTIVE: The aim of the present study was the development of a brief, specialized instrument for TC assessment in patients with dementia. METHOD: We developed a short tool consisting of four subtests, assessing the person's core functions which are required for TC: memory (orientation, autobiographical memory and realistic perception of beneficiaries), absence of serious psychopathology, knowledge of financial parameters (value of assets, everyday life products, bills), and intention (vignettes, theory of mind). For its validation, we examined 64 outpatients from the Cognitive Disorders/Dementia Unit, 2nd Department of Behavioral Neurology, University of Athens. The decision of the expert served as the gold standard for the evaluation of TC. RESULTS: Of the 64 participants, 39 were judged by the expert as capable of TC and the remaining 25 as incapable. For the total scale (maximum score of 48), the best combination of sensitivity (82.6%) and specificity (100%) was obtained for a cut-off score of 32/33. Cronbach's alpha showed high levels of internal reliability for the scale (alpha= 0.86) and the point-biserial correlation coefficients showed high levels of criterion-related validity (rbp = 0.797, p < 0.001). CONCLUSION: The new instrument appears to be a reliable screening tool for the evaluation of TC in dementia, which can be used by both the expert and the non-expert. Further research is needed to confirm these promising findings. PMID- 29254083 TI - Increased Foxo3a Nuclear Translocation and Activity is an Early Neuronal Response to betagamma-Secretase-Mediated Processing of the Amyloid-beta Protein Precursor: Utility of an AbetaPP-GAL4 Reporter Assay. AB - Sequential cleavage of the amyloid-beta protein precursor (AbetaPP) by BACE1 (beta-secretase) followed by thegamma-secretase complex, is strongly implicated in Alzheimer's disease (AD) but the initial cellular responses to these cleavage events are not fully defined. beta-secretase-mediated AbetaPP processing yields an extracellular domain (sAbetaPPbeta) and a C-terminal fragment of AbetaPP of 99 amino acids (C99). Subsequent cleavage by gamma-secretase produces amyloid-beta (Abeta) and an AbetaPP intracellular domain (AICD). A cellular screen based on the generation of AICD from an AbetaPP-Gal4 fusion protein was adapted by introducing familial AD (FAD) mutations into the AbetaPP sequence and linking the assay to Gal4-UAS driven luciferase and GFP expression, to identify responses immediately downstream of AbetaPP processing in neurons with a focus on the transcription factor Foxo3a which has been implicated in neurodegeneration. The K670N/M671L, E682K, E693G, and V717I FAD mutations and the A673T protective mutation, were introduced into the AbetaPP sequence by site directed mutagenesis. When expressed in mouse cortical neurons, AbetaPP-Gal4-UAS driven luciferase and GFP expression was substantially reduced by gamma-secretase inhibitors, lowered by beta-secretase inhibitors, and enhanced by alpha-secretase inhibitors suggesting that AICD is a product of the betagamma-secretase pathway. AbetaPP Gal4-UAS driven GFP expression was exploited to identify individual neurons undergoing amyloidogenic AbetaPP processing, revealing increased nuclear localization of Foxo3a and enhanced Foxo3a-mediated transcription downstream of AICD production. Foxo3a translocation was not driven by AICD directly but correlated with reduced Akt phosphorylation. Collectively this suggests that betagamma-secretase-mediated AbetaPP processing couples to Foxo3a which could be an early neuronal signaling response in AD. PMID- 29254084 TI - Hedonic Assessment of Odors: A Comparison of Two Sensory Scales for Use with Alzheimer's Disease Patients and Elderly Individuals. AB - BACKGROUND: Several clinical studies concerning the olfactory function of patients with cognitive impairment have used sensory scales to investigate hedonic perception. However, no study has focused on the choice of the most appropriate sensory hedonic scale for the individuals with neurodegenerative disorders or other psychiatric diseases involving cognitive deficits. OBJECTIVE: The aim of this study was to investigate the ability of patients with Alzheimer's disease (AD) to use two hedonic scales (category scale and linear scale) and compare their discriminatory capacity, repeatability, and ease of use. This should allow us to identify the most appropriate hedonic scale for patients with AD. METHODS: We recruited 18 patients with mild to moderate AD, and 20 healthy volunteers matched for gender, age, smoking status, and educational level. The participants underwent a clinical assessment and hedonic evaluation of three odorants (pleasant, unpleasant, and neutral), using a five-point category scale and a 10-cm linear scale with a marked mid-point. RESULTS: AD patients were able to use hedonic scales as well as paired healthy elderly subjects. The linear scale performed slightly better in terms of ease of use for both patients and healthy controls and discriminatory capacity for AD patients. The results for AD patients and controls with both scales were repeatable. CONCLUSION: The linear scale may be more appropriate for AD patients pending further studies involving a larger population of patients, using several odorants. PMID- 29254085 TI - Progression of Alzheimer's Disease: A Longitudinal Study in Norwegian Memory Clinics. AB - BACKGROUND: The course of Alzheimer's disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression. OBJECTIVE: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0-18), the cognitive test Mini-Mental State Examination (MMSE, 0-30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1). METHODS: The Progression of AD and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics. RESULTS: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16-37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores. CONCLUSION: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate. PMID- 29254086 TI - Impaired IL-17 Production in Gut-Residing Immune Cells of 5xFAD Mice with Alzheimer's Disease Pathology. AB - Alzheimer's disease (AD) is characterized by accumulation of amyloid-beta plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This study aimed to determine cell composition of GALT in 5xFAD mice, an established model for AD. Immune cells isolated from Peyer's patches (PP) and mesenteric lymph nodes (MLN) were stained with surface and intracellular markers for T helper (Th) subpopulations, B lymphocytes and macrophages and analyzed cytofluorimetrically, while cytokine expression and production were determined by qPCR and ELISA, respectively. Inflammation was detected in GALT of 5xFAD mice with established AD pathology. Although the production of IFN-gamma, IL-4, and IL-10 was comparable between the strains, lower IL-17 production was observed in PP and MLN cells. This phenomenon could not be attributed to a lower abundance of Th17 cells, or cytokines that initiate their formation or propagation (TGF-beta, IL-6, and IL-23). Also, reduced IL-17 production was not a consequence of altered Il-17 mRNA transcription or deficiency of Rorgammat, a key transcription factor for IL-17. However, the expression of miR-155 (a non-coding micro RNA that promotes the development of Th17 cells), was significantly lower in MLN cells of 5xFAD mice. In contrast, mice without AD neuropathology did not have inflammation in GALT or altered Th17 numbers, nor decreased IL-17 production. In conclusion, the observed changes in GALT of 5xFAD mice mirror the disease progression and might reflect inadequate immune surveillance in the gut and lead to enhanced AD pathology. PMID- 29254087 TI - Assessing Working Memory in Mild Cognitive Impairment with Serial Order Recall. AB - BACKGROUND: Working memory (WM) is often assessed with serial order tests such as repeating digits backward. In prior dementia research using the Backward Digit Span Test (BDT), only aggregate test performance was examined. OBJECTIVE: The current research tallied primacy/recency effects, out-of-sequence transposition errors, perseverations, and omissions to assess WM deficits in patients with mild cognitive impairment (MCI). METHODS: Memory clinic patients (n = 66) were classified into three groups: single domain amnestic MCI (aMCI), combined mixed domain/dysexecutive MCI (mixed/dys MCI), and non-MCI where patients did not meet criteria for MCI. Serial order/WM ability was assessed by asking participants to repeat 7 trials of five digits backwards. Serial order position accuracy, transposition errors, perseverations, and omission errors were tallied. RESULTS: A 3 (group)*5 (serial position) repeated measures ANOVA yielded a significant group*trial interaction. Follow-up analyses found attenuation of the recency effect for mixed/dys MCI patients. Mixed/dys MCI patients scored lower than non MCI patients for serial position 3 (p < 0.003) serial position 4 (p < 0.002); and lower than both group for serial position 5 (recency; p < 0.002). Mixed/dys MCI patients also produced more transposition errors than both groups (p < 0.010); and more omissions (p < 0.020), and perseverations errors (p < 0.018) than non MCI patients. CONCLUSIONS: The attenuation of a recency effect using serial order parameters obtained from the BDT may provide a useful operational definition as well as additional diagnostic information regarding working memory deficits in MCI. PMID- 29254088 TI - Physical Activity and Hippocampal Sub-Region Structure in Older Adults with Memory Complaints. AB - BACKGROUND: Physical activity (PA) plays a major role in maintaining cognition in older adults. PA has been shown to be correlated with total hippocampal volume, a memory-critical region within the medial temporal lobe (MTL). However, research on associations between PA and MTL sub-region integrity is limited. OBJECTIVE: To examine the relationship between PA, MTL thickness, and its sub-regions, and cognitive function in non-demented older adults with memory complaints. METHODS: Twenty-nine subjects aged >=60 years, with memory complaints were recruited for this cross-sectional study. PA was tracked for 7 days using accelerometers, and average number of steps/day determined. Subjects were categorized into two groups: those who walked <=4000 steps/day (lower PA) and those with >4000 steps/day (higher PA). Subjects received neuropsychological testing and 3T MRI scans. Nonparametric ANCOVAs controlling for age examined differences between the two groups. RESULTS: Twenty-six subjects aged 72.7(8.1) years completed the study. The higher PA group (n = 13) had thicker fusiform gyrus (median difference = 0.11 mm, effect size (ES) = 1.43, p = 0.001) and parahippocampal cortex (median difference = 0.12 mm, ES = 0.93, p = 0.04) compared to the lower PA group. The higher PA group also exhibited superior performance in attention and information processing speed (median difference = 0.90, ES = 1.61, p = 0.003) and executive functioning (median difference = 0.97, ES = 1.24, p = 0.05). Memory recall was not significantly different between the two groups. CONCLUSION: Older non demented individuals complaining of memory loss who walked >4000 steps each day had thicker MTL sub-regions and better cognitive functioning than those who walked <=4000 steps. Future studies should include longitudinal analyses and explore mechanisms mediating hippocampal related atrophy. PMID- 29254089 TI - Mitochondrial Translocase of the Outer Membrane Alterations May Underlie Dysfunctional Oxidative Phosphorylation in Alzheimer's Disease. AB - BACKGROUND: The translocase of the outer membrane (TOM) is a vital mitochondrial transport system facilitating the importation of nuclear encoded proteins into the organelle. While mitochondrial dysfunction, including perturbation of oxidative phosphorylation (OXPHOS) complex, is evident in Alzheimer's disease (AD), it remains unclear whether the observed OXPHOS deficits may be associated with TOM alterations. OBJECTIVES: To correlate TOM subunits with OXPHOS complex proteins in AD. METHODS: Postmortem neocortex (BA40) from AD and age-matched controls were processed to obtain mitochondrial enriched homogenates for the measurement of Tom20, Tom22, Tom40, and Tom70 as well as components of OXPHOS complex I-V by immunoblotting. RESULTS: Tom20 and Tom70 immunoreactivities were significantly reduced in AD, as were components of OXPHOS complex I and III. Both Tom20 and Tom70 positively correlated with complex III and V, while Tom20 also correlated withcomplex IV. CONCLUSION: Reductions in certain TOM subunits and their correlations with specific OXPHOS complex proteins suggest that an impaired mitochondrial transportation system may contribute to previously observed oxidative phosphorylation deficits in AD. Follow-up studies are needed to corroborate the present correlative study. PMID- 29254090 TI - Executive and Language Subjective Cognitive Decline Complaints Discriminate Preclinical Alzheimer's Disease from Normal Aging. AB - BACKGROUND: There is a need to specify the profile of subjective cognitive decline in preclinical Alzheimer's disease (preAD). OBJECTIVES: To explore specific items of the Subjective Cognitive Decline Questionnaire (SCD-Q) that discriminate preAD from normal aging. METHODS: 68 cognitively normal older adults were classified as controls (n = 52) or preAD (n = 16) according to amyloid-beta (Abeta) levels. An exploratory factor analysis and item analysis of the SCD-Q were performed. Informant reports of the SCD-Q were used to corroborate the findings of self-reports. One-year neuropsychological follow-up was available. RESULTS: Four SCD-Q factors were extracted: EM-factor (episodic memory), A-factor (attention), O-factor (organization), and L-factor (language). PreAD reported a significantly higher decline in L-factor (F(1) = 6.49; p = 0.014) and A-factor (F(1) = 4.04; p = 0.049) compared to controls, and showed a higher frequency of perceived decline in SCD-Q items related with language and executive tasks (Sig items.) Significant discriminative powers for Abeta-positivity were found for L factor (AUC = 0.75; p = 0.003) and A-factor (AUC = 0.74; p = 0.004). Informants in the preAD group confirmed significantly higher scores in L-factor and Sig items. A significant time*group interaction was found in the Semantic Fluency and Stroop tests, with the preAD group showing a decrease in performance at one-year. CONCLUSIONS: Our results suggest that SCD-Q items related with language and executive decline may help in prediction algorithms to detect preAD. Validation in an independent population is needed. PMID- 29254091 TI - Combined Socio-Behavioral Evaluation Improves the Differential Diagnosis Between the Behavioral Variant of Frontotemporal Dementia and Alzheimer's Disease: In Search of Neuropsychological Markers. AB - BACKGROUND: Current diagnostic criteria for behavioral variant of frontotemporal dementia (bvFTD) and typical Alzheimer's disease (AD) include a differential pattern of neuropsychological impairments (episodic memory deficit in typical AD and dysexecutive syndrome in bvFTD). There is, however, large evidence of a frequent overlap in neuropsychological features, making the differential diagnosis extremely difficult. OBJECTIVES: In this retrospective study, we evaluated the diagnostic value of different cognitive and neurobehavioral markers in bvFTD and AD patient groups. METHODS: We included 95 dementia patients with a clinical and biomarker evidence of bvFTD (n = 48) or typical AD (n = 47) pathology. A clinical 2-year follow-up confirmed clinical classification. Performances at basic cognitive tasks (memory, executive functions, visuo spatial, language) as well as social cognition skills and neurobehavioral profiles have been recorded. A stepwise logistic regression model compared the neuropsychological profiles between groups and assessed the accuracy of cognitive and neurobehavioral markers in discriminating bvFTD from AD. RESULTS: Statistical comparison between patient groups proved social cognition and episodic memory impairments as main cognitive signatures of bvFTD and AD neuropsychological profiles, respectively. Only half of bvFTD patients showed attentive/executive deficits, questioning their role as cognitive marker of bvFTD. Notably, the large majority of bvFTD sample (i.e., 70%) poorly performed at delayed recall tasks. Logistic regression analysis identified social cognition performances, Frontal Behavioral Inventory and Mini-Mental State Examination scores as the best combination in distinguishing bvFTD from AD. CONCLUSION: Social cognition tasks and socio-behavioral questionnaires are recommended in clinical settings to improve the accuracy of early diagnosis of bvFTD. PMID- 29254092 TI - Lipid Metabolism and Survival Across the Frontotemporal Dementia-Amyotrophic Lateral Sclerosis Spectrum: Relationships to Eating Behavior and Cognition. AB - BACKGROUND: Patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) exhibit changes in eating behavior that could potentially affect lipid levels. OBJECTIVE: This study aimed to document changes in lipid metabolism across the ALS-FTD spectrum to identify potential relationships to eating behavior (including fat intake), cognitive change, body mass index (BMI), and effect on survival. METHODS: One hundred and twenty-eight participants were recruited: 37 ALS patients, 15 ALS patients with cognitive and behavioral change (ALS-Plus), 13 ALS-FTD, 31 behavioral variant FTD, and 32 healthy controls. Fasting total cholesterol, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglyceride levels were measured and correlated to eating behavior (caloric, fat intake), cognitive change, and BMI; effect on survival was examined using cox regression analyses. RESULTS: There was a spectrum of lipid changes from ALS to FTD with increased triglyceride (p < 0.001), total cholesterol/HDL ratio (p < 0.001), and lower HDL levels (p = 0.001) in all patient groups compared to controls. While there was no increase in total cholesterol levels, a higher cholesterol level was found to correlate with 3.25 times improved survival (p = 0.008). Triglyceride and HDL cholesterol levels correlated to fat intake, BMI, and measures of cognition and disease duration. CONCLUSION: A spectrum of changes in lipid metabolism has been identified in ALS FTD, with total cholesterol levels found to potentially impact on survival. These changes were mediated by changes in fat intake, and BMI, and may also be mediated by the neurodegenerative process, offering the potential to modify these factors to slow disease progression and improve survival. PMID- 29254094 TI - Influence of Butyrylcholinesterase in Progression of Mild Cognitive Impairment to Alzheimer's Disease. AB - BACKGROUND: Several demographic and genetic prognostic factors of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have been recognized so far. The most frequent polymorphism of butyrylcholinesterase (BuChE), the K variant, has been proposed as a risk factor for AD, but data regarding its influence on early disease progression is still limited. OBJECTIVE: To investigate the influence of the BuChE-K variant in MCI progression to AD. METHODS: 96 MCI patients were included in the study and were genotyped for BuChE K variant and Apolipoprotein E (ApoE). Cerebrospinal fluid (CSF) BuChE activity, as well as the levels of AD biomarkers amyloid-beta 42 (Abeta42), total and hyperphosphorylated tau (t-tau and p-tau) were also determined. RESULTS: No significant differences were found in either BuChE-K variant or BuChE activity between MCI patients that progressed to AD (MCI-AD) and patients that remained stable during clinical follow-up (MCI-St). As expected, baseline CSF levels of Abeta42 were significantly lower and t-Tau, p-Tau, and ApoE E4 allele frequency were significantly higher in MCI-AD patients. An association between the ApoE E4 allele and the BuChE-K variant in MCI-AD, but not in MCI-St patients, was found with patients carrying both alleles presenting the highest incidence of progression and the lowest estimated time of progression to AD. CONCLUSION: Although BuChE-K alone does not seem to play a major role in progression to AD in MCI patients, a synergistic effect with the ApoE E4 allele was found, highlighting the importance of assessing these combined genotypes for evaluating risk progression in MCI patients. PMID- 29254097 TI - Aphasia in Progressive Supranuclear Palsy: As Severe as Progressive Non-Fluent Aphasia. AB - BACKGROUND: Adynamic speech is characteristic of progressive supranuclear palsy (PSP), but higher language deficits have been reported inconsistently, in the context of clinical and pathological overlaps with progressive non-fluent aphasia (PNFA). OBJECTIVE: The present study tested two hypotheses: 1) PSP and PNFA display impaired single word repetition, object naming, semantic knowledge, and syntactic comprehension; and 2) PSP have reduced speed on timed cognitive tasks. METHODS: Structured clinical and neuropsychological assessments of language were performed on patients with clinically defined PSP and PNFA. Language was tested using the Sydney Language Battery (SYDBAT) and the Test of Reception of Grammar (TROG). RESULTS: In total, 144 participants were studied (PSP 22, PNFA 29, and Control 93). PSP patients had prominent eye movement abnormalities, parkinsonism, and falls. All 4 PSP patients who underwent postmortem examination had 4-Repeat tauopathy, with PSP pathology in 3. The frequency and severity of impairment on the SYDBAT (naming, word comprehension, semantic association), and TROG (syntactic comprehension) did not differ between PSP and PNFA, but PSP were significantly slower on timed non-language cognitive tests. CONCLUSION: Tested formally, aphasia may be seen in PSP, with a severity similar to that seen in PNFA. PMID- 29254095 TI - Dissecting the Role of 5-Lipoxygenase in the Homocysteine-Induced Alzheimer's Disease Pathology. AB - Alzheimer's disease (AD) affects over 40 million patients around the world and poses a huge economic burden on society since no effective therapy is available yet. While the cause(s) for the most common sporadic form of the disease are still obscure, lifestyle and different environmental factors have emerged as modulators of AD susceptibility. Hyperhomocysteinemia (HHCY), a condition of high circulating levels of homocysteine, is an independent but modifiable risk factor for AD. Studies in AD mouse models have linked HHCY with memory impairment, amyloidosis, tau pathology, synaptic dysfunction, and neuroinflammation. However, the exact mechanism by which HHCY affects AD pathogenesis is unclear. The 5 lipoxygenase (5LO) is a protein upregulated in postmortem AD brains and plays a functional role in AD pathogenesis. Recently, in vitro and in vivo studies showed that HHCY effects on amyloid-beta and tau pathology, synapse and memory impairments are dependent on the activation of the 5LO enzymatic pathway, since its genetic absence or pharmacological inhibition prevents them. HHCY induces 5LO gene upregulation by lowering the methylation of its promoter, which results in increased translation and transcription of its mRNA. Based on these findings, we propose that epigenetic modification of 5LO represents the missing biological link between HHCY and AD pathogenesis, and for this reason it represents a viable therapeutic target to prevent AD development in individuals bearing this risk factor. PMID- 29254093 TI - Memantine for the Treatment of Dementia: A Review on its Current and Future Applications. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-beta protein (Abeta) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Abeta production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered. PMID- 29254098 TI - Vestibular Loss Predicts Poorer Spatial Cognition in Patients with Alzheimer's Disease. AB - The vestibular system is an important contributor to balance control, spatial orientation, and falls risk. Recent evidence has shown that Alzheimer's disease (AD) patients have a higher prevalence of vestibular impairment relative to healthy controls. We sought to evaluate whether vestibular loss is specifically associated with poor spatial cognitive skills among patients with mild cognitive impairment (MCI) and AD. We enrolled 50 patients (22 MCI and 28 AD) from an interdisciplinary Memory Clinic and measured vestibular physiologic function in all patients. Spatial cognitive function was assessed using the Money Road Map Test (MRMT) and the Trail Making Test Part B (TMT-B). General cognitive function was assessed with the Mini-Mental Status Examination (MMSE). In multivariable linear regression analyses adjusted for age, gender, education level, and MMSE, MCI and AD patients with vestibular loss made significantly more errors on the MRMT relative to patients with normal vestibular function (beta= 7.3, 95% CI 2.4, 12.1 for unilateral vestibular loss and beta= 6.4, 95% CI 1.9, 10.9 for bilateral vestibular loss). We further stratified AD patients into "spatially normal" and "spatially impaired" groups based on MRMT performance, and found that the prevalence of vestibular loss was significantly higher in the spatially impaired AD group relative to the spatially normal AD group. These findings support the hypothesis that vestibular loss contributes specifically to a decline in spatial cognitive ability in MCI and AD patients, independently of general cognitive decline, and may predict a "spatially impaired" subtype of AD. PMID- 29254096 TI - Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-beta Burden in Down Syndrome. AB - BACKGROUND: The Down syndrome (DS) population is genetically predisposed to amyloid-beta protein precursor overproduction and Alzheimer's disease (AD). OBJECTIVE: The temporal ordering and spatial association between amyloid-beta, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. METHODS: Twenty four adults (13 male, 11 female; 39+/-7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. RESULTS: Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. CONCLUSIONS: In adults with DS, early amyloid-beta accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-beta, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions. PMID- 29254099 TI - Cerebrospinal Fluid, MRI, and Florbetaben-PET in Cerebral Amyloid Angiopathy Related Inflammation. AB - BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is associated with a cerebrospinal fluid (CSF) biomarker profile similar to that observed in CAA. Few CAA-ri patients have been studied by fibrillar amyloid-beta (Abeta) imaging (using 11C-Pittsburgh compound B and 18F-florbetapir, but not 18F florbetaben). OBJECTIVE: To describe CSF biomarkers, magnetic resonance imaging (MRI), and 18F-florbetaben (FBB)-positron emission tomography (PET) changes in CAA-ri patients. METHODS: CSF levels of total tau, phosphorylated tau, Abeta1-42, and Abeta1-40, MRI (cerebral microbleeds count on susceptibility-weighted imaging and semi-quantitative analysis of fluid-attenuation inversion recovery white matter hyperintensities), and FBB-PET (using both cerebellar cortex and pons to calculate standardized uptake value ratios) were analyzed in nine consecutive CAA ri patients. RESULTS: A median number of 769 cerebral microbleeds/patient were counted on MRI. When using the pons as reference region, amyloid load on FBB-PET was very strongly correlated to CSF Abeta1-40 levels (rho = -0.83, p = 0.008) and moderately correlated to cerebral microbleed numbers in the occipital lobes (rho = 0.59, p = 0.001), while comparisons with other CSF biomarkers were not statistically significant (total tau, rho = -0.63, p = 0.076; phosphorylated tau, rho = -0.68, p = 0.05; Abeta1-42, rho = -0.59, p = 0.09). All correlations were weaker, and not statistically significant, when using the cerebellum as reference region. A non-significant correlation (rho = -0.50, p = 0.18) was observed between CSF Abeta1-40 levels and cerebral microbleed numbers. CONCLUSION: In CAA ri, CSF Abeta1-40 levels correlated well with amyloid load assessed by FBB-PET when the pons was used as reference, and to a lesser degree with cerebral microbleeds count on MRI. This confirms earlier data on CSF Abeta1-40 as an in vivo marker for CAA and CAA-ri. PMID- 29254100 TI - Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppresses iNOS Expression and Ameliorates Neural Impairment in Alzheimer's Disease Mice. AB - BACKGROUND: Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been reported to exhibit therapeutic effects in various animal models of neurological diseases, such as stroke and hypoxic-ischemic brain injury. OBJECTIVE: The present study investigated the potential beneficial effect of MSC derived EVs in an animal model of Alzheimer's disease (AD). METHODS: APP/PS1 mice and their non-transgenic littermates (WT) received intracerebroventricle injection of MSC-derived EVs once per two days for two weeks. Then novel object recognition and water maze tasks were carried out to measure the cognitive behaviors. Electrophysiological tests were carried out to measure hippocampal synaptic plasticity. Inducible nitric oxide synthase (iNOS) mRNA and protein levels were measured by qRT-PCR and western blotting in primary cultured neurons treated with amyloid-beta peptide (Abeta) or prepared from APP/PS1 mice. RESULTS: Treatment with MSC-derived EVs alleviates exogenous Abeta-induced iNOS mRNA and protein expression. In cultured primary neurons prepared from APP/PS1 pups, iNOS mRNA and protein levels were significantly reduced when treated with MSC-derived EVs. MSC-derived EVs improved cognitive behavior, rescued impairment of CA1 synaptic transmission, and long-term potentiation in APP/PS1 mice. CONCLUSION: MSC-derived EVs possessed beneficial effects in a mouse model of AD, probably by suppressing Abeta induced iNOS expression. PMID- 29254101 TI - Nutrition: Review on the Possible Treatment for Alzheimer's Disease. AB - Since its discovery some hundred years ago, Alzheimer's disease (AD), a neurodegenerative disease and an eminent cause of most dementia, continues to pose problems for affected families and society, especially in developed countries. With the approved medications by the Food and Drugs Administration in the United States, effectual treatment of AD apropos to the complete eradication of the disease continues to be elusive due to complexities relating to the pathophysiology of the disease. Nutrition has and continues to play a salient role in the survival of living organisms with no exception for human beings. Herein, we report the connection between nutrition and AD with particular attention to vitamins, curcumin, and the Mediterranean diet. PMID- 29254103 TI - Cognitive Dysfunction Contributes to Mobility Impairments in Huntington's Disease. AB - BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disorder that results in a gradual decline in mobility and balance. Increasing evidence has documented an important role of executive function in the safe ambulation of the elderly and people with a variety of neurological disorders. Little is known about the contribution of cognitive deficits to decline in mobility over time in HD. OBJECTIVE: This study examined the relationships of mobility, motor and cognitive function measures at baseline, and of mobility and cognitive measures over four years. METHODS: A retrospective chart review was performed on 70 patients with genetically confirmed HD (age 20-75 years old) across 121 HD clinic visits. Correlations between Unified Huntington's Disease Rating Scale - Total Motor, Tinetti Mobility Test (TMT), and cognitive measures (Letter Verbal Fluency, Symbol Digit Modalities Test (SDMT), and Stroop Test) were analyzed. Longitudinal relationships between TMT and cognitive measures were examined using mixed effect regression models. RESULTS: Gait and balance measures representing domains of mobility (TMT scores) were significantly correlated with each of the cognitive measures with the exception of the Verbal Fluency score. Mixed effects regression modeling showed that the Stroop Interference sub-test and SDMT were significant predictors (p-values <0.01) of TMT total scores. CONCLUSIONS: Impairments in executive function measures correlate highly with measures of gait, balance and mobility in individuals with HD. Interventions designed to improve mobility and decrease fall risk should also address issues of cognitive impairments with particular consideration given to interventions that may focus on motor-cognitive dual task training. PMID- 29254105 TI - Understanding the emergence of microbial consciousness: From a perspective of the Subject-Object Model (SOM). AB - Microorganisms demonstrate conscious-like intelligent behaviour, and this form of consciousness may have emerged from a quantum mediated mechanism as observed in cytoskeletal structures like the microtubules present in nerve cells which apparently have the architecture to quantum compute. This paper hypothesises the emergence of proto-consciousness in primitive cytoskeletal systems found in the microbial kingdoms of archaea, bacteria and eukarya. To explain this, we make use of the Subject-Object Model (SOM) of consciousness which evaluates the rise of the degree of consciousness to conscious behaviour in these systems supporting the hypothesis of emergence and propagation of conscious behaviour during the pre Cambrian part of Earth's evolutionary history. Consciousness as proto consciousness or sentience computed via primitive cytoskeletal structures substantiates as a driver for the intelligence observed in the microbial world during this period ranging from single-cellular to collective intelligence as a means to adapt and survive. The growth in complexity of intelligence, cytoskeletal system and adaptive behaviours are key to evolution, and thus supports the progression of the Lamarckian theory of evolution driven by quantum mediated proto-consciousness to consciousness as described in the SOM of consciousness. PMID- 29254106 TI - Fish oil and depression: The skinny on fats. AB - Depression is the leading cause of disability worldwide, and even though many forms of therapy exist, about one third of patients treated with conventional antidepressants do not experience a response. For these reasons, new approaches to treat depression, including fish oil, are being investigated. Fish oil is known to have many beneficial side effects, and clinical trials demonstrate that supplementation with fish oil is beneficial in the management of depression. Fish oil contains omega-3 polyunsaturated fatty acids (PUFA), and there are several mechanisms by which PUFAs are thought to induce an antidepressant effect, including anti-inflammatory action and direct effects on membrane properties. This review will analyze and evaluate the clinical trials surrounding fish oil use in the treatment of depression, and will also review the likely sites of action of PUFAs at the cell membrane with special attention being placed on lipid rafts and G-proteins. PMID- 29254107 TI - The Five Dimensions of Parkinson's Disease Genetic Risk. AB - Genome-wide association studies of Parkinson's disease have revealed polymorphic variants associated with closely mapped genes of interest. We propose here that those genes may only represent the tip of an iceberg of regulatory effects and do not necessary reflect disease relevance. To usefully interpret a risk locus, one needs to consider 5 dimensions of information, which represent the three dimensional structure of chromatin (dimensions #1- 3), which is locally variable across time (dimension #4), and, most importantly, dependent on cell type and context (dimension #5). PMID- 29254109 TI - Erratum. PMID- 29254110 TI - Erratum. PMID- 29254108 TI - Using Medical Claims Analyses to Understand Interventions for Parkinson Patients. AB - The scientific evidence to support the value of a range of non-pharmacological interventions for people with Parkinson's disease (PD) is increasing. However, showing unequivocally that specific interventions are better than usual care is not straightforward because of generic drawbacks of clinical trials. Here, we address these challenges, specifically related to the context of evaluating complex non-pharmacological interventions for people with PD. Moreover, we discuss the potential merits of undertaking "real world" analyses using medical claims data. We illustrate this approach by discussing an interesting recent publication in The Lancet Neurology, which used such an approach to demonstrate the value of specialized physiotherapy for PD patients, over and above usual care physiotherapy. PMID- 29254102 TI - Modulating Neurotrophin Receptor Signaling as a Therapeutic Strategy for Huntington's Disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the IT15 gene which encodes the huntingtin (HTT) protein. Currently, no treatments capable of preventing or slowing disease progression exist. Disease modifying therapeutics for HD would be expected to target a comprehensive set of degenerative processes given the diverse mechanisms contributing to HD pathogenesis including neuroinflammation, excitotoxicity, and transcription dysregulation. A major contributor to HD-related degeneration is mutant HTT-induced loss of neurotrophic support. Thus, neurotrophin (NT) receptors have emerged as therapeutic targets in HD. The considerable overlap between NT signaling networks and those dysregulated by mutant HTT provides strong theoretical support for this approach. This review will focus on the contributions of disrupted NT signaling in HD-related neurodegeneration and how targeting NT receptors to augment pro-survival signaling and/or to inhibit degenerative signaling may combat HD pathologies. Therapeutic strategies involving NT delivery, peptidomimetics, and the targeting of specific NT receptors (e.g., Trks or p75NTR), particularly with small molecule ligands, are discussed. PMID- 29254112 TI - Effects of dynamic neuromuscular stabilization on diaphragm movement, postural control, balance and gait performance in cerebral palsy. AB - PURPOSE: To determine the effects of a novel dynamic neuromuscular stabilization (DNS) technique on gross motor function, diaphragm movement, and activation of the external oblique (EO) and internal oblique (IO)/transversus abdominal (TrA) muscles in participants with cerebral palsy (CP). METHOD: Fifteen participants with CP (7 females) underwent DNS intervention for 30 minutes/day, 3 days a week for 4 weeks. Gross motor function, diaphragm movement, and muscle activation were determined using a gross motor function measure (GMFM-88), ultrasound, and electromyography measurements, respectively, before and after the DNS core stabilization intervention. Paired t-tests were used at p < 0.05. DESIGN: A single-arm, pretest-posttest clinical trial. RESULTS: GMFM scores for standing, walking, and jumping domains were significantly improved after the intervention (P < 0.05). Diaphragm descending movement (P = 0.0001) and activation of the internal oblique and transversus abdominals were initially undetectable, but remarkably increased after the intervention (P = 0.012). CONCLUSIONS: DNS is a promising, effective intervention for facilitating deep core muscle activation of the underactive muscle chain comprising the diaphragm, internal oblique, and transversus abdominals, thereby improving age-appropriate standing, walking, and jumping in participants with spastic diplegic CP. PMID- 29254111 TI - Novel multi-pad functional electrical stimulation in stroke patients: A single blind randomized study. AB - BACKGROUND: Foot drop is common gait impairment after stroke. Functional electrical stimulation (FES) of the ankle dorsiflexor muscles during the swing phase of gait can help correcting foot drop. OBJECTIVE: To evaluate efficacy of additional novel FES system to conventional therapy in facilitating motor recovery in the lower extremities and improving walking ability after stroke. METHODS: Sixteen stroke patients were randomly allocated to the FES group (FES therapy plus conventional rehabilitation program) (n = 8), and control group (conventional rehabilitation program) n = 8. FES was delivered for 30 min during gait to induce ankle plantar and dorsiflexion. MAIN OUTCOME MEASURES: gait speed using 10 Meter Walk Test (10 MWT), Fugl-Meyer Assessment (FMA), Berg Balance Scale (BBS) and modified Barthel Index (MBI). RESULTS: Results showed a significant increase in gait speed in FES group (p < 0.001), higher than the minimal detected change. The FES group showed improvement in functional independence in the activities of daily living, motor recovery and gait performance. CONCLUSIONS: The findings suggest that novel FES therapy combined with conventional rehabilitation is more effective on walking speed, mobility of the lower extremity, balance disability and activities of daily living compared to a conventional rehabilitation program only. PMID- 29254113 TI - Association between trunk acceleration during walking and clinically assessed balance in patients with stroke. AB - BACKGROUND: Accelerometers provide information regarding balance and gait, but they are rarely used in clinical settings for stroke patients. Clinically, balance is assessed with simple tests, but their relationships with accelerometry results after stroke are unknown. OBJECTIVE: We examined the relationship between accelerometry-assessed gait indices calculated from trunk acceleration and results of the Timed Up and Go (TUG) and Berg Balance Scale (BBS) tests in stroke patients. METHODS: Twenty-nine stroke patients completed assessments with the TUG, BBS, and trunk acceleration during walking using a tri-axial accelerometer. The root mean square (RMS), stride regularity (SR), and step symmetry (SS), which indicate gait fluctuations, regularity, and symmetry, respectively, were calculated based on trunk acceleration. These were calculated in the vertical (VT), anteroposterior, and mediolateral directions. A multiple linear regression analysis was performed to determine whether these gait indices contributed independently to TUG and BBS results. RESULTS: VT-RMS and VT-SS were significant determinants of TUG, and VT-SS, VT-RMS, and VT-SR were significant determinants of BBS. CONCLUSIONS: This study suggested that the gait indices calculated from trunk acceleration that were relevant to balance were those in the VT direction. These may be useful for evaluating dynamic gait balance in patients with stroke. PMID- 29254114 TI - Application of virtual environments in a multi-disciplinary day neurorehabilitation program to improve executive functioning using the Stroop task. AB - BACKGROUND: Virtual reality (VR) technology has demonstrated usefulness in diagnosis, education, and training. Studies supporting use of VR as a therapeutic treatment in medical rehabilitation settings remain limited. This study examines the use of VR in a treatment capacity, and whether it can be effectively integrated into neurorehabilitation. OBJECTIVE: To determine whether immersive VR treatment interventions improve executive dysfunction in patients with brain injury and whether performance is stronger on a VR version of the Stroop than traditional Stroop formats. METHODS: 15 patients with brain injury admitted to day neurorehabilitation. OUTCOME MEASURES: reaction time, inhibition, and accuracy indices on VR Stroop; Automated Neuropsychological Assessment Metrics (ANAM) Stroop, Delis-Kaplan Executive Function System Stroop, Golden Stroop, and Woodcock-Johnson, 3rd Edition (WJ-III): Pair Cancellation. RESULTS: Participants demonstrated significantly reduced response time on the word-reading condition of VR Stroop and non-significantly reduced response time on the interference condition. Non-significant improvements in accuracy and inhibition were demonstrated on the color-naming condition of VR Stroop. Significantly improved accuracy under time pressure was found for the ANAM, after VR intervention. CONCLUSION: Implementation of immersive VR interventions during neurorehabilitation is effective in improving specific executive functions and information processing speed in brain-injured patients during the subacute period. PMID- 29254115 TI - Short- and medium-term effect of kinesio taping or electrical stimulation in hemiplegic shoulder pain prevention: A randomized controlled pilot trial. AB - OBJECTIVE: To compare the short and medium-term effectiveness of combining Kinesio Tape (KT) or neuromuscular electrical stimulation (NMES) with a conventional approach to prevent shoulder pain after stroke. METHODS: Thirty-one first-time stroke survivors (58.06% females) were recruited and randomly assigned to one group; Control (n = 10), KT (n = 11), or NMES (n = 10). Ten of all participants were lost during follow-up because of death or a second stroke. The control group underwent conventional treatment (careful shoulder handling and daily mobilizations). This approach was combined with KT or NMES over deltoid muscles in the KT and NMES groups respectively. Measurements were taken at baseline, and at weeks 1, 2, 3, 4, 12, and 24 post-stroke. Data collected included self-perceived shoulder pain (Visual Analogue Scale), disability (Barthel Index and Berg scale), and upper limb function (Action Research Arm test). RESULTS: In all groups, shoulder pain did not appear during the first month (p < 0.001), but increased afterwards. In the between-groups analysis, all groups similarly improved disability and function, and no significant differences were observed for any measure (p > 0.05). CONCLUSION: The combination of KT or NMES with conventional treatment is no superior to conventional treatment alone to prevent hemiplegic shoulder pain. PMID- 29254116 TI - Effects of resistance expiratory muscle strength training in elderly patients with dysphagic stroke. AB - BACKGROUND: Recently, resistance expiratory muscle strength training (EMST) has been reported as a remedial treatment for dysphagia. OBJECTIVE: To investigate the effect of resistance EMST on the swallowing function in stroke patients with oropharyngeal dysphagia. METHODS: Forty-two stroke patients with dysphagia were randomly assigned to two groups: an experimental group (n = 13) and a placebo group (n = 13). The experimental group performed EMST using a portable EMST device, while the placebo group performed EMST using a sham EMST device with no loading. The intervention was performed 5 days per week for 4weeks, in five sets of 5 breaths through the device for a total of 25 breaths per day. Both groups underwent conventional dysphagia treatment for 30 minutes/day, 5 days/week, for 4 weeks. Videofluoroscopic dysphagia scale (VDS) and penetration-aspiration scale (PAS) based on a videofluoroscopic swallowing study (VFSS) were assessed to analyze the oropharyngeal swallowing function. RESULTS: The experimental group showed more improvement in pharyngeal phase of the VDS (p = 0.018 and 0.006, respectively) and PAS compared to the placebo group (p = 0.014). CONCLUSIONS: We suggest that EMST could improve the effects of dysphagia observed in post-stroke elderly patients based on swallowing function. PMID- 29254117 TI - Parkinson disease-induced upregulation of apoptotic mediators could be attenuated in the skeletal muscle following chronic exercise training. AB - BACKGROUND: We have shown elevated levels of p53 and active caspase-3 in gastrocnemius skeletal muscle with Parkinson's disease (PD). The main aim of this study is to examine the impact of endurance exercise training on the expression of p53 and active caspase-3 in the skeletal muscle of mouse with induced Parkinsonism. METHODS: Sedentary control (SC), sedentary Parkinson diseased (SPD), and exercised Parkinson diseased (EPD) groups were formed; each consisting of 10 randomly selected normal albino mice. Chronic Parkinson disease was induced in the SPD and EPD animals using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p). The expression of p53 and active caspase-3 was investigated, using immunohistochemistry, in the gastrocnemius muscle in each animal group. RESULTS: Both p53 and active caspase-3 expression was significantly (p value < 0.05) reduced in the PD gastrocnemius skeletal muscle following endurance exercise training. CONCLUSION: Our present data suggest that chronic exercise training reduced Parkinson disease-induced upregulation of p53 and active caspase 3 in gastrocnemius skeletal muscle. Thus, our study suggests that inhibiting p53 and/or active caspase-3 may be considered as a therapeutic approach to ameliorate PD skeletal muscle abnormalities. PMID- 29254119 TI - A spiral, bi-planar gradient coil design for open magnetic resonance imaging. AB - PURPOSE: To design planar gradient coil for MRI applications without discretization of continuous current density and loop-loop connection errors. METHODS: In the new design method, the coil current is represented using a spiral curve function described by just a few control parameters. Using a proper parametric equation set, an ensemble of spiral contours is reshaped to satisfy the coil design requirements, such as gradient linearity, inductance and shielding. RESULTS: In the given case study, by using the spiral coil design, the magnetic field errors in the imaging area were reduced from 5.19% (non-spiral design) to 4.47% (spiral design) for the transverse gradient coils, and for the longitudinal gradient coil design, the magnetic field errors were reduced to 5.02% (spiral design). The numerical evaluation shows that when compared with conventional wire loop, the inductance and resistance of spiral coil was reduced by 11.55% and 8.12% for x gradient coil, respectively. CONCLUSION: A novel spiral gradient coil design for biplanar MRI systems, the new design offers better magnetic field gradients, smooth contours than the conventional connected counterpart, which improves manufacturability. PMID- 29254120 TI - Virtual postural assessment of an assembly work in a small scale submersible pump manufacturing industry. AB - BACKGROUND: Depletion of groundwater has increased the depth of bore wells drilled to meet water requirements. Water from these bore wells are accessed by operating submersible pumps with multi-stages. The number of stages of submersible pump directly depends upon the depth of bore well. Health-related risk such as Musculoskeletal Disorders (MSDs) arises during the manual assembly of these pumps in an awkward posture. OBJECTIVE: The objective of this paper is to eliminate or reduce risk in the manual assembly of submersible pumps using virtual postural analysis. Secondary objective is to redesign the existing workstation incorporating ergonomic interventions. METHODS: It reports a case study in which postural analysis is carried out with the help of Rapid Upper Limb Assessment (RULA) method. RESULTS: It is observed that inserting the stage casing weighing around 1.5 Kg through top end of the shaft is the awkward working posture involving a flexion of the arm about 152 degrees . RULA score (7) indicate a high level of risk exists in the workstation, calling for investigate and change the working posture immediately. In order to reduce this risk, a redesigned workstation has been proposed. CONCLUSION: This study results help in minimizing the awkward postures, thereby reducing the health-related risk. This will also increase the efficiency of the worker and his productivity. PMID- 29254121 TI - Insurance workers' and physiotherapists' perceptions of their roles in the management of workers with injuries in the Western Australian workers' compensation system. AB - BACKGROUND: Insurance workers and physiotherapists are important stakeholders in the rehabilitation of workers with an injury and subsequent musculoskeletal pain. Understanding perceptions of roles may facilitate communication between these stakeholders. OBJECTIVE: Increase knowledge around, (i) the self-perception of and (ii) the external perception of the insurance workers and physiotherapists roles in the management of a worker with an injury in an Australian workers' compensation environment. METHODS: A cross-sectional study assessed the perceptions of insurance workers and physiotherapists related to the roles of these two professions in managing a worker with an injury via questionnaire. Respondents were also asked about potential communication barriers. RESULTS: Insurance workers (n = 48) and physiotherapists (n = 80) reported contrasting role perceptions, with their perception of the other profession leaning towards negative attributes. There was greater alignment of their beliefs of roles in the 'ideal' situation. The perception of barriers to communication also differed between the two professions. Effective and efficient communication was identified as a central component of mismatched role perceptions between stakeholders, but recognised as a critical attribute of 'ideal' stakeholder roles. CONCLUSION: Insurance workers and physiotherapists self-perception of their roles differs from external perceptions. This information highlights the importance of a shared understanding of stakeholder roles in the management of a worker with an injury. PMID- 29254122 TI - The high and low comfort peaks in passengers' flight. AB - BACKGROUND: Knowing the high and low peaks in comfort during a flight could be useful in prioritizing aircraft interior improvements. OBJECTIVE: The first objective of this study was to identify whether there are differences in comfort experiences during different phases of a flight. The second objective of this study was to identify similarities between recalled and real time reported comfort experiences. METHODS: 149 participants were asked to rate the comfort in the different phases of their last flight on a scale from 1-10. Additionally, a combination of a self-reporting design probe and generative interview was used to investigate the appraisal patterns of emotions in nine passengers. RESULTS: The 149 subjects reported the highest comfort after take-off and arriving at the destination, the lowest while stowing the luggage and during the cruise flight. The qualitative long haul inflight study showed after take-off and while arriving at the destination the most positive emotions and during the cruise flight there is a negative experience phase. CONCLUSIONS: Suggestions are given to improve the cruise flight phase, by for example stimulation of movement or better service. PMID- 29254123 TI - Thermal protection study of bladder compensatory suit using a heat transfer model. AB - BACKGROUND: The bladder compensatory suit (BCS) is important individual protective equipment for pilots' activities in a high-flying environment. The layout and thermal diffusion ability of the bladder directly affects the thermal comfort of pilots in flight. OBJECTIVE: (1) Established and verified a human compensatory suit-environment heat transfer model; (2) Used the model to study the human thermal variation of each segment in hot conditions and clothing. METHODS: To verify the two-dimensional heat transfer model, simulated data of body temperature were compared with experimental results under the same conditions (AT: 40/45 degrees C, ordinary clothing). The model could be used to calculate the temperature variation of each body segment in three environments temperature (28 degrees C, 35 degrees C and 40 degrees C) and three types of clothing (naked, ordinary clothing, BCS). RESULTS: The results showed that: (1) the bladder significantly affected sweating speed and skin temperature, as well as core temperature; (2) the skin temperature of the area covered by the bladder was difficult to reduce by the thermal regulation system. It was because sweat secretion was inhibited, thus, to limit evaporation. CONCLUSIONS: The model could be used as a reference for the thermal protection design of bladder compensatory suit. SUMMARY: The bladder compensatory suit (BCS) is important individual protective equipment for pilots activities in a high-flying environment, and its layout directly affects the thermal comfort. Based on a two-dimensional thermal regulation system model, a body-clothing-environment heat transfer model was established. The model was used to calculate the temperature and sweat variation of each body segment in different environments and clothing. PMID- 29254124 TI - Minor long-term effects 3-4 years after the ReDOTM intervention for women with stress-related disorders: A focus on sick leave rate, everyday occupations and well-being. AB - BACKGROUND: The Redesigning Daily Occupations (ReDOTM) work rehabilitation method has been found effective, compared with care as usual (CAU), for women with stress-related disorders. OBJECTIVE: To conduct a long-term follow-up of former ReDOTM and CAU participants with respect to sick leave, well-being and everyday occupations 3-4 years after completed work rehabilitation. METHODS: Forty-two women in each group participated. An index day was decided to estimate sick-leave rate, retrieved from register data. Fifty-five women also participated in a telephone interview addressing well-being, everyday occupations and life events. RESULTS: Both groups had reduced their sick-leave rate further, but no difference between the groups was established. The ReDOTM women perceived a better balance in the work domain of everyday occupations, whereas the CAU group reported more over-occupation. No differences were found on well-being. The groups had experienced similar important life events, affecting the women's work and private lives. Previous stress and anxiety predicted sick leave at the long-term follow up. CONCLUSIONS: Although the ReDOTM intervention had speeded up return to work in the immediate follow-up perspective, the CAU had caught up in the longer term. Still, the ReDOTM women exhibited better balance in the work domain. PMID- 29254125 TI - Effect of a novel workstation device on promoting non-exercise activity thermogenesis (NEAT). AB - BACKGROUND: Strategies to increase non-exercise activity thermogenesis (NEAT) through promotion of movement and energy expenditure at desk stations are needed to help overcome ill effects of prolonged sitting. OBJECTIVE: Examine the metabolic rate during three stages of a workstation: sitting, standing, and use of a device (HOVR(r)) that promotes leg movement while seated. METHODS: Participants (n = 16; mean +/-standard deviation: age 26.1+/-6.0 years; BMI 24.7+/-4.3 kg/m2) were tested for VO2 and VCO2 for 15 min at each stage in this order: sitting only, sitting using the HOVR, and standing. Participants performed the same desk work to keep fine-motor activity consistent for the stages. Data collected during the final 5 min of a stage were averaged and analyzed as steady state data. To evaluate the effect of each stage on cognitive function, the Stroop word-color test was administered after metabolic assessment as the stage continued. One-way ANOVA with repeated measures was used to compare stages for VO2 (L/min), metabolic equivalents (METs), respiratory exchange ratio (RER), and heart rate (p < 0.05). RESULTS: The ANOVA revealed significant differences between the mean values for each stage for each dependent variable (p < 0.05). Post hoc tests indicated VO2 differed for each stage (mean+/-SD in mL/kg/min: sitting, 4.13+/-0.56; sitting with HOVR, 4.82+/-0.74; standing, 4.50+/-0.53; p < 0.05). METs followed a similar pattern (sitting, 1.19+/-0.16; sitting with HOVR, 1.39+/-0.20; standing, 1.29+/-0.16; p < 0.05). An increase in Stroop Test scores was found as the stages progressed (p < 0.05). CONCLUSION: Modest movement while seated, i.e., use of HOVR, elevated metabolic rate by 17.6% compared to sitting and by 7% compared to standing and might be a reasonable strategy to help elevate NEAT during the workday. PMID- 29254126 TI - The association between work-life balance and health status among Korean workers. AB - BACKGROUND: Although the relationship between work-life balance (WLB) and health is well known, it has been poorly studied in Korea. OBJECTIVE: This study investigated factors related to WLB for Korean workers, including working time features and the relationships between WLB and health outcomes. METHODS: Data were obtained from the third Korean Working Conditions Survey, which examined a representative working population. This study investigated general characteristics, working time characteristics, work related health, and WLB. A multivariate logistic regression was used to test the associations between WLB and health outcome variables, including general health status, mental health, work-related risks to health and safety, sickness absenteeism, presenteeism, musculoskeletal disease, headache/eyestrain, and fatigue. RESULTS: General characteristics including gender, age, working sector, occupation, and employment type were found to be related to WLB. Moreover, working time characteristics were found to be strongly related to WLB. In addition, WLB was significantly related to various health outcomes. CONCLUSIONS: Our findings indicate that WLB is strongly related to health outcomes among Korean workers. The results suggest that there is a need for interventions that focus on implementing working time strategies for better health. PMID- 29254127 TI - Analysis of burnout syndrome, musculoskeletal complaints, and job content in middle and senior managers: Case study of manufacturing industries in Ciudad Juarez, Mexico. AB - BACKGROUND: In developing countries such as Mexico, the effects of burnout syndrome (BS) are observed in manufacturing industries. However, the relationships among BS, Job Content (JC), and Musculoskeletal Complaints (MC) are scarcely studied within the manufacturing sector, even though senior and middle managers are exposed to highly demanding and mentally exhausting situations. OBJECTIVES: The objective of this paper is to determine the relationships among the three BS dimensions, MC, and JC among middle and senior managers of the manufacturing industry in Ciudad Juarez, Mexico. METHODS: The Maslach Burnout Inventory-General Survey (MBI-GS), the Job Content Questionnaire (JCQ), and the Body Map assessment were administered as data collection instruments. The sample included 361 participants from six industries located in Ciudad Juarez, Mexico. Also, we proposed structural equations models (SEM) to establish the relationships among variables. RESULTS: The questionnaires and the model showed acceptable reliability and quality indices. Emotional exhaustion was the most relevant latent variable, having significant effects on MC and on professional efficacy, and significantly contributing to increasing levels of cynicism. On the other hand, the variable social support showed a negative direct impact on Job Demands and Emotional Exhaustion. CONCLUSIONS: Actions to reduce emotional exhaustion at work include providing a positive and suitable work environment through social support. These strategies help prevent MC and improve professional efficacy, life quality at work, and productivity. PMID- 29254128 TI - DESperately Seeking Service: A narrative review informing a disability employment services reform framework for Australians with mental illness. AB - BACKGROUND: Notwithstanding efforts by vocational services to assist Australians with mental illness into employment many of these consumers remain unemployed. OBJECTIVE: To inform policymakers and practitioners of a disability employment services reform framework that endeavours to help more consumers who are experiencing mental illness to attain and retain employment. METHODS: Thematic analysis was directed to summarize results obtained from a narrative literature review of disability employment service reforms utilising Scopus, Medline and Pubmed databases and including articles published between 2000 and 2016. RESULTS: Research results reveal a preparative framework covering three levels of disability employment services reform for consumers with mental illness. CONCLUSION: This research makes important theoretical contributions across three areas. First this study reveals individualised, integrated and outcome-oriented services as dimensions of disability employment services reform that warrant greater government investment, practitioner focus and consumer involvement. Second recognising that none of these service reforms are immune from challenges which may hinder their effectiveness, future research is needed to identify evidence-based mitigation measures. Finally with individualised services positioned at the nucleus of the reform framework, integrated services and outcome-oriented reforms should be operationalised in ways that remain sensitive to the principle of strength-based support. PMID- 29254129 TI - The role of occupational medicine in assessing work limitation: A cross-sectional study on construction workers over a five-year period in Croatia. AB - BACKGROUND: Maintaining adequate working ability of construction workers is of considerable importance for society, as the construction sector is burdened with high prevalence of work-related diseases and health-issues. OBJECTIVE: To determine the number and age of construction workers in Croatia with temporary or permanent work limitation status, as well as to identify the most common health causes of such work limitation. METHODS: A retrospective cross-sectional study was performed using the data from 2534 construction workers, aged between 18 and 65 years, who underwent standardized routine occupational health examinations between 2011 and 2015. Thorough medical history and medical record reviews, blood and urine analyses, vision parameters and hearing range evaluation, as well as mental health assessment were conducted on every study participant. RESULTS: A total of 210 construction workers (8.29%) received occupational/work limitation status (either temporary or permanent). Four main categories of work limitation were high blood pressure, disorders of the liver and digestive system, hearing loss and amblyopia, comprising 61.69% of all diagnoses. A total of 37.62% of workers with work limitation status had two or more different diagnoses (i.e. co morbid conditions). Those with work limitation (either temporary or long-term) were significantly older than those fit enough to work (p-value <0.00001). CONCLUSIONS: This type of organized screening represents a significant preventative effort in the construction industry, as workers may become more cognizant of the conditions that may affect their work ability. PMID- 29254130 TI - School-to-work transition for youth with severe physical disabilities: Stakeholder perspectives. AB - BACKGROUND: Multiple challenges await people with severe physical disability when they are preparing to enter the labour market at the end of the school period. OBJECTIVE: This study aims to better understand the multiple factors that influence the course of disabled youth transitioning into the workforce by gathering perceptions from stakeholders. Methods The study used a qualitative descriptive design with an interpretative description approach to analyze the experiences reported by six school staff, six parents, and three employers. RESULTS: Significant facilitators to the workforce transition were the active involvement of the school's staff in multiplying outreach activities between the various external partners. Significant obstacles include the level of help required to complete day-to-day activities at work and student lack of work experience. Government cutbacks were unanimously identified as the prominent obstacle. CONCLUSIONS: The results presented in this study indicate that a successful school to work transition program is dependent on many factors. These factors include the characteristics of the targeted population, the level of involvement from key stakeholders, the willingness of employers to hire this population, as well as program objectives deviating from paid employment. Further development opportunities have proven to be helpful, such as the development of a solid partnership and collaboration between all stakeholders. PMID- 29254131 TI - Predicting return to work following a cardiac event in Malaysia. AB - BACKGROUND: Return to work is an important aspect for cardiac rehabilitation following a major cardiac event. OBJECTIVE: The aim was to understand the local prevalence and factors associated with returning to work in Malaysia after a cardiac event. METHODS: A cross sectional design was used. All patients attending the cardiac rehabilitation program after major cardiac event during an 11-months period (2011-2012) were included. Data relating to socio-demographic, work related, risk factors and acute myocardial infarction were collected. The SF-36 questionnaire was used to assess quality of life. Regression analysis was used to determine the predicting factors to return to work. RESULTS: A total of 398 files were screened, 112 respondents agreed to participate giving a response rate of 47.3%. The prevalence of returned to work (RTW) was 66.1% [95% CI: 57.2-75.0]. Factors associated with work resumption were age (Adj. OR: 0.92 (95% CI: 0.84 0.99), diabetes mellitus (Adj. OR: 3.70, 95% CI: 1.35-10.12), Mental Component Summary (MCS) score (Adj. OR: 1.05 (95% CI: 1.01-1.09) and baseline angiography findings. Patients with single vessel and two vessel disease were 8.9 times and 3.78 times more likely to return to work compared to those with 3 vessels (Adj. OR: 8.90 (95% CI: 2.29-34.64) and Adj. OR: 3.78, (95% CI: 1.12, 12.74). CONCLUSIONS: We proposed a cardiac rehabilitation program to emphasize mental health as it may improve successful return to work after cardiac event. PMID- 29254132 TI - Prevalence and associated factors of work related musculoskeletal disorders among commercial milling machine operators in South-Eastern Nigerian markets. AB - BACKGROUND: Milling machine operators perform physically demanding tasks that can lead to work related musculoskeletal disorders (WRMSDs), but literature on WRMSDs among milling machine operators is scarce. Knowledge of prevalence and risk factors of WRMSDs can be an appropriate base for planning and implementing ergonomics intervention programs in the workplace. OBJECTIVE: This study aimed to determine the prevalence, pattern and associated factors of WRMSDs among commercial milling machine operators in Enugu, Nigeria. METHODS: This cross sectional survey involved 148 commercial milling machine operators (74 hand operated milling machine operators (HOMMO) and 74 electrically-operated milling machine operators (EOMMO)), within the age range of 18-65 years, who were conveniently selected from four markets in Enugu, Nigeria. A standard Nordic questionnaire was used to assess the prevalence of WRMSDs among the participants. Data were summarized using descriptive statistics. RESULTS: There was a significant difference (p = 0.001) related to prevalence of WRMSDs between HOMMOs (77%) and EOMMOs (50%). All body parts were affected in both groups and shoulders (85.1%) and lower back (46%) had the highest percentage of prevalence. Working in awkward and same postures, working with injury, poor workplace design, repetition of tasks, vibratory working equipments, reduced rest, high job demand and heavy lifting were significantly associated with the prevalence of WRMSDs. CONCLUSIONS: WRMSDs are prevalent among commercial milling machine operators with higher occurrence in HOMMOs. Ergonomic interventions, including the re-design of milling machines and appropriate work posture education of machine operators are recommended in the milling industry. PMID- 29254133 TI - Prevalence of musculoskeletal disorders and its relation to depression among workers in kindergarten. AB - BACKGROUND: Working in a closed environment for more than 7-8 hours can affect both psychological and physical health among kindergarten workers. OBJECTIVE: To determine the prevalence of musculoskeletal disorders (MSD) and depression as well as the correlation between them, if any, among kindergarten workers. METHODS: In a cross-sectional observation, one hundred and five healthy female staff members (age: 34.27+/-7.01 year, working duration: 7.42+/-0.81 hr/d, BMI: 24.50+/-2.61 kg/m2 (mean+/-SD)), who have had at least one year of working experience, were selected randomly from 10 kindergartens. The subjects completed both the Cornell musculoskeletal and Patient Health (PHQ-9) questionnaires to enable the assessments of MSD and depression scores accordingly. The correlation between both questionnaires was then measured to find any links. To assess the reliability of Farsi-language versions of the Cornell questionnaire and PHQ-9, the Inter-class Correlation Co-efficient (ICC) was measured through test-retest with 1-week delay and the prevalence of MSD and depression were subsequently assessed as well. RESULTS: The Inter-class Correlation Co-efficient (ICC) illustrated that the Farsi version of MSD instruments showed high levels of repeatability. The ICC coefficient was (0.932-0.987, p < 0.001) for the Cornell questionnaire and the Cronbach alpha for PHQ-9 questionnaire was 0.861. The highest severity of pain was related to lower back (30.5%), and after it, neck (27.6%), right shoulder (27.6%) and left shoulder (25.7%) pain, respectively. The results of PHQ-9 questionnaire indicated that 41.9% (n = 44) of subjects had a severe depression. There was a significant (r = 0.338, p < 0.01) relation between depression and MSD. CONCLUSIONS: Prevalence of depression and severity of physical pain was an issue among staff in kindergartens. More study will be needed to define all aspects of this issue. PMID- 29254134 TI - Identification of influential demographic and work-related risk factors associated to lower extremity pain perception among rice farmers. AB - BACKGROUND: A high prevalence of musculoskeletal disorders and abnormal alignments of the lower extremities (LE) was found for rice farmers. It is important to investigate demographic and work-related risk factors associated with LE pain prior to developing intervention strategies addressing the problematic factors of the highest-risk task. OBJECTIVE: To identify factors associated with LE pain in rice farmers for every stage of the cultivation process. METHODS: Thirty experienced farmers (age of 45.9+/-6.21 (mean+/-SD)) rated LE pain experienced before and after each cultivation stage using the Standardized Nordic Questionnaire. Risk factors of pain were characterized based on expert risk assessment of tasks due to force, posture and motion, in addition to a conventional survey of demographic and other work-related information. RESULTS: Ergonomic risk factors were found to be the strongest predictors of knee and foot pain perception, which induced a substantial increase of pain perception (up to 4.6 times) with varying extent for individual cultivation stages. The highest risk and pain perception was found during the planting performance. Age exhibited significantly positive association with foot pain during planting and harvesting. However, more experienced farmers perceived less foot pain, presumably by developing effective movement strategies. CONCLUSIONS: The findings suggest that the planting process should be subject of further intervention development, especially for older farmers, with focus on reducing force, awkward posture and repetitive movement to minimize risk of LE pain. PMID- 29254135 TI - Work-related stigma and disclosure: A daily challenge for people living with HIV. AB - BACKGROUND: Stigma and disclosure are important work-related issues for people living with HIV (PLWH). To gain better understanding and improve the position of PLWH in the labor market, further insight in these issues is needed. OBJECTIVE: This study reviews the scientific evidence related to work-related stigma and disclosure. METHODS: A sensitive literature search was performed in the databases of Medline, Embase, Cochrane Library, Cinahl and Psychinfo for articles published between 1996 and 2016. All studies on PLWH in western countries and investigating disclosure or stigma in relation to work were included. RESULTS: Of the 866 identified studies, 19 met the inclusion criteria: 4 addressed both disclosure and stigma (2 quantitative), 9 addressed only disclosure (4 quantitative) and 7 studies addressed only stigma (4 quantitative). CONCLUSION: This review provides a unique overview of the research on work-related disclosure and stigma, which will enable health care providers to support PWLH to make well-considered decisions. However, the available literature was heterogeneous and in most studies the topics of our interest were secondary outcomes and provided only basic insight. PMID- 29254136 TI - The effect of shoulder strap width and load placement on shoulder-backpack interface pressure. AB - BACKGROUND: Pressure on the shoulder can be a major limiting factor to backpack use and poor design can lead to pain and injury. OBJECTIVE: To evaluate the effect of shoulder strap width and load placement in a backpack on the shoulder and axilla. METHODS: A manikin fitted with a backpack load of 20 kg mass and four different width straps (5, 6, 7, and 8 cm) was used. The load was placed high or low. Interface pressure sensors were placed over the shoulder and chest wall at the axilla. RESULTS: A significant interaction was observed between shoulder strap width and load placement. The positive effect of wide straps on shoulder pressure is greater with high load placement and the benefit of wide straps on axillary pressure is improved with low load placement. Interface pressure decreased significantly from narrow to wide straps. A large difference was noted between interface pressure on high and low load placement with narrow straps; however, as shoulder strap width increased, the difference between the two load placements decreased. CONCLUSION: The least amount of interface pressure was observed with 8 cm shoulder straps and high load placement. These findings should influence design and use of backpacks. PMID- 29254138 TI - Synthetic lethal genetic interactions between Rad54 and PARP-1 in mouse development and oncogenesis. AB - Mutations in DNA repair pathways are frequent in human cancers. Hence, gaining insights into the interaction of DNA repair genes is key to development of novel tumor-specific treatment strategies. In this study, we tested the functional relationship in development and oncogenesis between the homologous recombination (HR) factor Rad54 and Parp-1, a nuclear enzyme that plays a multifunctional role in DNA damage signaling and repair. We introduced single or combined Rad54 and Parp-1 inactivating germline mutations in Ptc1 heterozygous mice, a well characterized model of medulloblastoma, the most common malignant pediatric brain tumor. Our study reveals that combined inactivation of Rad54 and Parp-1 causes a marked growth delay culminating in perinatallethality, providing for the first time evidence of synthetic lethal interactions between Rad54 and Parp-1 in vivo. Although the double mutation hampered investigation of Rad54 and Parp-1 interactions in cerebellum tumorigenesis, insights were gained by showing accumulation of endogenous DNA damage and increased apoptotic rate in granule cell precursors (GCPs). A network-based approach to detect differential expression of DNA repair genes in the cerebellum revealed perturbation of p53 signaling in Rad54-/-/Parp-1-/-/Ptc1+/-, and MEFs from combined Rad54/Parp-1 mutants showed p53/p21-dependent typical senescent features. These findings help elucidate the genetic interplay between Rad54 and Parp-1 by suggesting that p53/p21-mediated apoptosis and/or senescence may be involved in synthetic lethal interactions occurring during development and inhibition of tumor growth. PMID- 29254139 TI - miR-449a inhibits colorectal cancer progression by targeting SATB2. AB - miR-449a has been reported to act as a tumor suppressor in several cancers, however, it is controversial whether it inhibits tumor growth in colorectal cancer. The mechanisms underlying its expression and functions in colorectal cancers are still largely unknown. SATB2 is a sensitive and specific marker for CRC diagnosis. However, the mechanisms by which the expression and functions of SATB2 are regulated still remain to be clarified. We investigated the expression and functional significance of miR-449a and SATB2 and the mechanisms of their dysregulation in human CRC cells. miR-449a overexpression or SATB2 depletion inhibited tumor growth and promoted apoptosis in colorectal tumor cells in vitro and in xenograft mouse model, partially by downregulating SATB2. Expression of miR-449a was increased epigenetically via knocking down their targets, particularly SATB2. miR-449a was downregulated and STAB2 expression was upregulated in human CRCs. Their expressions were significantly associated with overall survival of CRC patients. Our findings demonstrate the existence of a miR 449a-SATB2 negative feedback loop that maintains low levels of miR-449a as well as high level of SATB2, thereby promoting CRC development. PMID- 29254141 TI - Sociodemographic predictors of patients with brain metastases treated with stereotactic radiosurgery. AB - Background: Patient sociodemographic factors such income, race, health insurance coverage, and rural residence impact a variety of outcomes in patients with cancer. The role of brain metastasis at presentation and its subsequent outcomes have not been well characterized in this patient population. Results: Multivariate analysis revealed that median income lower than $50,000 was associated with higher presenting symptom grade for brain metastasis (mean RTOG grade 1.2 vs 1.0, SE = 0.1, p = 0.04) and higher chronic symptom grade (mean RTOG grade 1.3 vs 0.9, SE = 0.1, p = 0.002). Higher area-level median income was associated with a lower symptom grade at diagnosis of brain metastasis (p = 0.0008) and likelihood of hospitalization (p = 0.004). Other sociodemographic factors were not significantly associated with survival, neurologic death, or patterns of failure after stereotactic radiosurgery for brain metastases. Conclusions: Lower median income was associated with a greater symptom burden at the time of diagnosis and need for hospitalization for patients with brain metastases, suggesting a delayed time to presentation. These differences in symptom burden persisted during treatment. Methods: Between January 2000 and December 2013, we identified 737 patients treated with stereotactic radiosurgery for brain metastases. They were characterized by 4 sociodemographic factors: median income, race, rural-urban residence, and health insurance status. Clinical outcomes included stage at diagnosis, symptom grade at presentation, likelihood of hospitalization from brain metastasis, overall survival, local failure, distant brain failure, and neurologic death. Multivariate cox proportional hazards model for each outcome was performed controlling for age, sex, number of brain metastases, and dose to brain metastases. PMID- 29254140 TI - Differential response to exercise in claudin-low breast cancer. AB - Exposure to exercise following a breast cancer diagnosis is associated with reductions in the risk of recurrence. However, it is not known whether breast cancers within the same molecular-intrinsic subtype respond differently to exercise. Syngeneic mouse models of claudin-low breast cancer (i.e., EO771, 4TO7, and C3(1)SV40Tag-p16-luc) were allocated to a uniform endurance exercise treatment dose (forced treadmill exercise) or sham-exercise (stationary treadmill). Compared to sham-controls, endurance exercise treatment differentially affected tumor growth rate: 1- slowed (EO771), 2- accelerated (C3(1)SV40Tag-p16-luc), or 3- was not affected (4TO7). Differential sensitivity of the three tumor lines to exercise was paralleled by effects on intratumoral Ki 67, Hif1-alpha, and metabolic programming. Inhibition of Hif1-alpha synthesis by the cardiac glycoside, digoxin, completely abrogated exercise-accelerated tumor growth in C3(1)SV40Tag-p16-luc. These results suggest that intratumoral Hif1 alpha expression is an important determinant of claudin-low breast cancer adaptation to exercise treatment. PMID- 29254142 TI - By up-regulating MU- and delta-opioid receptors, neuron-restrictive silencer factor knockdown promotes neurological recovery after ischemia. AB - We investigated the effects of neuron-restrictive silencer factor (NRSF) on proliferation of endogenous nerve stem cells (NSCs) and on MU- and delta-opioid receptor (MOR/DOR) expression in rats after cerebral ischemia. Among 100 rats subjected to cerebral ischemia, 20 rats were transfected with NRSF shRNA, and the remaining 80 were randomly assigned to normal, sham, model, and negative control (NC) groups. On days 7, 14, and 28 after ischemia and reperfusion, neurological function scores were assigned and a step-down passive avoidance test was conducted. Nerve function scores, step-down reaction periods, error times and apoptosis rates, as well as levels of B-cell CLL/lymphoma 2 (Bcl-2), BCL2 associated X protein (Bax), and NRSF expression were lower in the NRSF shRNA group than in the model and NC groups. By contrast, step-down latency, numbers of bromodeoxyuridine-positive cells, MOR/DOR expression, and phosphorylation of extracellular signal regulated protein kinase (ERK) and cAMP response element binding protein (CREB) were higher in the NRSF shRNA group than in the model and NC groups. These results suggest that by up-regulating MOR/DOR expression, NRSF knockdown accelerates recovery of neurological function after cerebral ischemia, at least in part by promoting NSC proliferation and inhibiting apoptosis. PMID- 29254143 TI - Let-7g suppresses both canonical and non-canonical NF-kappaB pathways in macrophages leading to anti-atherosclerosis. AB - Transformation of macrophages to foam cells contributes to atherosclerosis. Here, we report that let-7g reduces macrophage transformation and alleviates foam cell apoptosis by suppressing both canonical and non-canonical NF-kappaB pathways. In the canonical pathway, let-7g inhibits phosphorylation of IKKbeta and IkappaB, down-regulates SREBF2 and miR-33a, and up-regulates ABCA1. In the non-canonical pathway, let-7g directly knocks down MEKK1, IKKalpha and ablates IKKalpha phosphorylation. Let-7g's effects in macrophages can be almost completely blocked by inactivation of NF-kappaB signaling, which suggests that let-7g's effects are primarily mediated through the suppression of NF-kappaB pathways. NF-kappaB has been reported to directly activate lin28 transcription, and lin28 is a well-known negative regulator for let-7 biogenesis. Therefore, there is negative feedback between NF-kappaB and let-7g. Additional macrophages-specific NF-kappaB knockout in the apoE deficiency mice reduces atherosclerotic lesion by 85%. Let-7g also suppresses p53-dependent apoptosis. Altogether, sufficient let-7g levels are important to prevent NF-kappaB over-activation in macrophages and to prevent atherosclerosis. PMID- 29254145 TI - Bile acid and cigarette smoke enhance the aggressive phenotype of esophageal adenocarcinoma cells by downregulation of the mitochondrial uncoupling protein-2. AB - Limited information is available regarding mechanisms that link the known carcinogenic risk factors of gastro-esophageal reflux and cigarette smoking to metabolic alterations in esophageal adenocarcinoma (EAC). In the present study, we utilized a novel in-vitro model to examine whether bile acid and cigarette smoke increase the aggressiveness of EAC and whether these changes are associated with metabolic changes. EAC cells (EACC) were exposed to 10 MUg/ml cigarette smoke condensate (CSC) and/or 100 MUM of the oncogenic bile acid, deoxycholic acid (DCA), for 5 days. These exposure conditions were chosen given their lack of effect on proliferation or viability. DCA and CSC increased invasion, migration, and clonogenicity in EAC cells. These changes were associated with concomitant increases in ATP, ROS, and lactate production indicative of increased mitochondrial respiration as well as glycolytic activity. DCA and CSC exposure significantly decreased expression of uncoupling protein-2 (UCP2), a mitochondrial inner membrane protein implicated in regulation of the proton gradient. Knockdown of UCP2 in EACC phenocopied DCA and CSC exposure as evidenced by increased cell migration, invasion, and clonogenicity, whereas over-expression of UCP2 had an inverse effect. Furthermore, over-expression of UCP2 abrogated DCA and CSC-mediated increases in lactate and ATP production in EACC. DCA and CSC promote the aggressive phenotype of EACC with concomitant metabolic changes occurring via downregulation of UCP2. These results indicate that UCP2 is integral to the aggressive phenotype of EACC. This mechanism suggests that targeting alterations in cellular energetics may be a novel strategy for EAC therapy. PMID- 29254144 TI - RUNX3 regulates renal cell carcinoma metastasis via targeting miR-6780a-5p/E cadherin/EMT signaling axis. AB - Runt-related transcription factor 3 (RUNX3) is a tumor suppressor in many human solid tumors. In this study, renal cell carcinoma (RCC) microarray analysis showed that the level of RUNX3 expression was lower in RCC tissue than in adjacent normal renal tissues, and was correlated with depth of invasion (pT stage) (P<0.001) and Tumor Node Metastasis (TNM) stage (P<0.001). RUNX3 expression was negatively correlated with poor 5-year overall and disease-free patient survival. RUNX3 suppressed RCC metastasis and invasion and increased levels of E-cadherin, an important marker of epithelial-mesenchymal transition, in vitro and in vivo. RUNX3 also inhibited microRNA-6780a-5p, which directly targeted the E-cadherin 3'untranslated region and decreased its expression. We confirmed that miR-6780a-5p mimics abrogated RUNX3-mediated E-cadherin upregulation and RCC metastasis/invasion inhibition. Thus, RUNX3 targeted the miR 6780a-5p/E-cadherin/EMT signaling axis to suppress renal carcinoma cell migration and invasion. This pathway illustrates a new RUNX3 function and provides potential targets for the treatment of RUNX3 mutant and loss-of-function RCC tumors. RUNX3 may also act as an effective prognostic indicator in RCC. PMID- 29254147 TI - Measurement of molecular biomarkers that predict the tumor response in estrogen receptor-positive breast cancers after dose-dense (biweekly) paclitaxel/carboplatin neoadjuvant chemotherapy. AB - The aim of this study was to determine the predictive value of the clinical and histopathological characteristics of estrogen receptor (ER)-positive patients treated with dose-dense paclitaxel/carboplatin neoadjuvant chemotherapy (NCT). Pathological complete response (pCR) and the change in tumor size between pre- and post-NCT were used to evaluate the tumor response.85 ER-positive breast cancer patients who were treated with dose-dense (biweekly) paclitaxel/carboplatin NCT were analyzed with respect to the expression of progesterone receptor (PgR), Tau, Ki67, human epidermal growth factor receptor 2 (HER2), and Bcl-2 by immunohistochemistry (IHC). These data were used to determine whether these biomarkers could predict the tumor response. A univariate analysis showed that the patients who tested positive for HER2 expression (56.00% vs 11.67%, p<0.01), negative for Tau expression (41.94% vs 14.81%, p=0.005), negative for Bcl-2 expression (46.43% vs 14.04%, p<0.01) and had smaller (<=2 cm) tumors (45.00% vs 18.46%, p=0.02) were associated with higher pCR rates. A multivariate analysis showed that a HER2-positive status (OR: 6.244; 95%CI: 1.734 22.487; p=0.005), Bcl-2-negative status (OR: 0.236; 95%CI: 0.064-0.869; p=0.030) and smaller (<=2 cm) tumor sizes (OR: 0.188; 95%CI: 0.046-0.767; p=0.020) are independent predictors of pCRs. The tumor sizes were significantly reduced in patients with HER2-positive, Tau-negative, Bcl-2-negative and high Ki67 index breast cancer. In conclusion, Bcl-2 negative, HER2-positive and smaller (<=2 cm) tumor sizes are independent predictors of pCR in ER-positive patients treated with dose-dense (biweekly) paclitaxel/carboplatin NCT. This study is registered with ClinicalTrials.gov (NCT0205986). PMID- 29254146 TI - cFLIP critically modulates apoptotic resistance in epithelial-to-mesenchymal transition. AB - Epithelial cancers (carcinomas) comprise the top four causes of cancer-related deaths in the United States. While overall survival has been steadily improving, therapy-resistant disease continues to present a major therapeutic challenge. Carcinomas often exploit the normal developmental program, epithelial-to mesenchymal transition (EMT), to gain a mesenchymal phenotype associated with increased invasiveness and resistance to apoptosis. We have previously shown that an isoxazole-based small molecule, ML327, partially reverses TGF-beta-induced EMT in an immortalized mouse mammary epithelial cell line. Herein, we demonstrate that ML327 reverses much of the EMT gene expression program in cultured carcinoma cell lines. The reversal of EMT sensitizes these cancer cells to the apoptosis inducing ligand TRAIL. This sensitization is independent of E-cadherin expression and rather relies on the downregulation of a major anti-apoptotic protein, cFLIPS. Loss of cFLIPS is sufficient to overcome resistance to TRAIL and exogenous overexpression of cFLIPS restores resistance to TRAIL-induced apoptosis despite EMT reversal with ML327. In summary, we have utilized an isoxazole-based small molecule that partially reverses EMT in carcinoma cells to demonstrate that cFLIPS critically regulates the apoptosis resistance phenotype associated with EMT. PMID- 29254149 TI - Association of serum cystatin C levels with mortality in patients with acute type A aortic dissection. AB - Increased serum cystatin C levels are related to the prognosis of cardiovascular diseases. This study aims to investigate the effect of admission serum cystatin C levels on short- and long-term mortality in patients with acute type A aortic dissection (ATAAD). From 2010 to 2014, 136 consecutive patients with ATAAD were enrolled and followed up. Clinical data and laboratory assays including were measured. During a median follow-up of 198.7 days, the short-term mortality (30 days) was 20.6%, whereas the long-term death rate was 10.2%. We identified that the expression of cystatin C and high-sensitivity C-reactive protein (hs-CRP) in the dying patients was higher than in the surviving patients (P < 0.01). Hs-CRP (HR = 1.41, 95% CI: 1.03-2.59, P = 0.037) was an independent risk factor of short term death determined by univariate and multivariate Cox analyses. No impact of cystatin C was observed on the short-term mortality. For long-term mortality, cystatin C (HR = 1.49, 95% CI: 1.10-7.36, P = 0.013) was identified as an independent predictor at above the cut-off value >= 1.10 mg/L. ROC analysis showed the AUC values of cystatin C and hs-CRP were 0.772 (95% CI, 0.692-0.839) and 0.640 (95% CI, 0.574-0.739), respectively, in the prediction of long-term death. The combined AUC value of cystatin C and hs-CRP was 0.883 (95% CI, 0.826 0.935; P < 0.01). Taken together, high cystatin C levels (>= 1.10 mg/L) on admission are independently associated with the long-term mortality in patients with ATAAD. PMID- 29254148 TI - Association between Paraoxonase 1 polymorphisms and risk of esophagogastric junction adenocarcinoma: a case-control study involving 2,740 subjects. AB - Esophagogastric junction adenocarcinoma (EGJA) is a serious public health problem with high mortality in China. In this study, we assessed the association between Paraoxonase 1 (PON-1) rs662 C>T, rs854560 A>T polymorphisms and EGJA risk. This case-control study enrolled 2,740 participants of Asians origin from the Eastern Chinese Han populations. SNPscanTM genotyping assay was harnessed to determine the genotyping of PON1 polymorphisms. The PON-1 rs854560 A>T and rs662 C>T genotypes distribution accorded with Hardy-Weinberg equilibrium. We found that there was no difference in the frequency of PON-1 rs662 C>T, rs854560 A>T genotypes between the overall EGJA cases and controls. In the subgroup analyses, the results indicated that PON-1 rs662 C>T polymorphism might be associated with a significantly decreased risk of EGJA in ever smoking group (TT vs. CC/CT: adjusted OR = 0.58, 95% CI 0.35-0.95, P = 0.029). In conclusion, our study highlights PON-1 rs662 C>T polymorphism may decrease the risk of EGJA, which interacts with the tobacco using. In the future, a fine-mapping case-control study with detailed gene-environmental data is needed to further assess these potential relationship. PMID- 29254150 TI - Novel allylated monocarbonyl analogs of curcumin induce mitotic arrest and apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and inhibition of STAT3. AB - Curcumin is a promising active compound from a natural source and is extensively being tested in clinical trials because of its bio-functional properties. However, poor bioavailability has hampered its clinical application. Numerous attempts have been made in our laboratory to discover analogs of curcumin with enhanced bioavailability and superior pharmacological activity. In this study, we have investigated a new series of allylated monocarbonyl analogs of curcumin (MAC) and tested their effect on gastric cancer cells. Our results show six MAC that selectively targeted cancer cell lines to inhibit growth and induce apoptosis. This activity was achieved by generation of reactive oxygen species (ROS) by MAC. We selected one effective MAC (CA10) for further investigation and show that CA10 inhibits cell growth by causing G2/M cell cycle arrest and induction of apoptotic death. CA10 induced ROS generation and subsequent activation of endoplasmic reticulum (ER) stress and inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation, inhibits cancer cell proliferation. These anti-tumor activities of CA10 were confirmed in gastric cancer xenografts. CA10 induced ROS, activated the ER stress pathway and inhibited STAT3 phosphorylation and gastric xenografts tumor growth in mice. Our studies provide experimental evidence that MAC CA10 effectively targets gastric cancer in preclinical models by enhancing ROS and ROS-mediated signaling. PMID- 29254151 TI - KH-type splicing regulatory protein is involved in esophageal squamous cell carcinoma progression. AB - KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein, which is involved in several post-transcriptional aspects of RNA metabolism, including microRNA (miRNA) biogenesis. It affects distinct cell functions in different tissues and can have an impact on various pathological conditions. In the present study, we investigated the oncogenic functions of KHSRP and their underlying mechanisms in the pathogenesis of esophageal squamous cell carcinoma (ESCC). KHSRP expression levels were elevated in ESCC tumors when compared with those in non-tumorous tissues by immunohistochemistry, and cytoplasmic KHSRP overexpression was found to be an independent prognosticator for worse overall survival in a cohort of 104 patients with ESCC. KHSRP knockdown inhibited growth, migration, and invasion of ESCC cells. KHSRP knockdown also inhibited the maturation of cancer-associated miRNAs, such as miR-21, miR-130b, and miR-301, and induced the expression of their target mRNAs, such as BMP6, PDCD4, and TIMP3, resulting in the inhibition of epithelial-to-mesenchymal transition. Our findings uncover a novel oncogenic function of KHSRP in esophageal tumorigenesis and implicate its use as a marker for prognostic evaluation and as a putative therapeutic target in ESCC. PMID- 29254152 TI - Identification of novel Ack1-interacting proteins and Ack1 phosphorylated sites in mouse brain by mass spectrometry. AB - Ack1 (activated Cdc42-associated tyrosine kinase) is a non-receptor tyrosine kinase that is highly expressed in brain. This kinase contains several protein protein interaction domains and its action is partially regulated by phosphorylation. As a first step to address the neuronal functions of Ack1, here we screened mouse brain samples to identify proteins that interact with this kinase. Using mass spectrometry analysis, we identified new putative partners for Ack1 including cytoskeletal proteins such as Drebrin or MAP4; adhesion regulators such as NCAM1 and neurabin-2; and synapse mediators such as SynGAP, GRIN1 and GRIN3. In addition, we confirmed that Ack1 and CAMKII both co-immunoprecipitate and co-localize in neurons. We also identified that adult and P5 samples contained the phosphorylated residues Thr 104 and Ser 825, and only P5 samples contained phosphorylated Ser 722, a site linked to cancer and interleukin signaling when phosphorylated. All these findings support the notion that Ack1 could be involved in neuronal plasticity. PMID- 29254153 TI - A retrospective study of elevated post-operative parathormone in primary hyperparathyroid patients. AB - We retrospectively analyzed the relationship between normocalcemic parathormone elevation (NPE) and recurrence of primary hyperparathyroidism (pHPT) after surgery, as well as the risk factors of NPE. Out of 309 patients with pHPT that underwent parathyroidectomy. Six months after surgery, 75 patients exhibited NPE with high preoperative serum levels of alkaline phosphatase, calcium and intact parathyroid hormone (iPTH), postoperative day 1 iPTH, and large parathyroid volume. 15 exhibited NPE at 2 years after surgery with low serum vitamin D levels. Postoperative serum iPTH levels gradually normalized in most patients. Multivariate analysis showed that male patients were at greater risk for postoperative NPE (p<0.05). Only 3 of 309 patients showed recurrence during the follow-up period. NPE may not predict recurrent hyperparathyroidism or incomplete parathyroidectomy for benign parathyroid lesions. Postoperative NPE thus appears to be a response to severe hyperparathyroidism and vitamin D deficiency. PMID- 29254154 TI - Macroscopic types of intrahepatic cholangiocarcinoma and the eighth edition of AJCC/UICC TNM staging system. AB - The prognosis of patients with intrahepatic cholangiocarcinoma (ICC) is undefined among the different macroscopic types. This study evaluated the viability of the American Joint Committee on Cancer (AJCC) 8th edition staging classification for different macroscopic types. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we enrolled a total of 2,679 eligible patients with an estimated 199 periductal infiltrating type of ICC (ICC-PI) patients and 2,480 mass-forming type of ICC (ICC-MF) patients. After conducting a multivariate Cox analysis, we found that the AJCC 8th edition staging system was suitable for ICC MF patients but not for ICC-PI patients according to cancer-specific survival (CSS) and overall survival (OS). The main reason was the similar hazard ratio (HR) between the ICC-PI patients with stage I and stage II disease according to CSS (HR:0.969, P = 0.949) and OS (HR:0.832, P = 0.703). Moreover, we found that ICC-PI patients in AJCC stage I had a similar HR as ICC-MF patients in AJCC stage II according to CSS (HR: 1.208, P = 0.475) and OS (HR:1.206, P = 0.456). Therefore, we suggested that ICC-PI patients may be defined as T2, which is classified as stage II disease. This suggestion for the AJCC 8th edition staging system would be more suitable for different macroscopic types of ICC but requires further verification in prospective clinical trials. PMID- 29254155 TI - Casticin inhibits interleukin-1beta-induced ICAM-1 and MUC5AC expression by blocking NF-kappaB, PI3K-Akt, and MAPK signaling in human lung epithelial cells. AB - The compound casticin, isolated from Vitex rotundifolia, exerts anti-inflammatory effects and causes apoptosis of cancer cells. In this study, we explored the anti inflammatory effects of casticin and modulation of cyclooxygenase (COX)-2, intercellular adhesion molecule 1 (ICAM-1), and mucin 5AC (MUC5AC) expression in interleukin-1beta (IL-1beta)-activated A549 human pulmonary epithelial cells. A549 cells were treated with various concentrations of casticin (5-20 MUM), and an inflammatory response was triggered with interleukin (IL)-1beta cytokines. Casticin decreased levels of IL-6, tumor necrosis factor alpha, and IL-8 and suppressed COX-2 expression and prostaglandin E2 production. It also reduced MUC5AC, proinflammatory cytokine, and chemokine gene expression and inhibited ICAM-1 expression for monocyte adhesion in IL-1beta-stimulated A549 cells. In addition, casticin inhibited phosphorylation of Akt, phosphatidylinositol 3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) and blocked nuclear transcription factor kappa-B (NF-kappaB) subunit p65 protein translocation into the nucleus. Co-culture of NF-kappaB, MAPK, and PI3K inhibitors with casticin also led to more significantly suppressed ICAM-1 expression in inflammatory A549 cells. These results provide evidence that casticin has an anti-inflammatory effect by blocking proinflammatory cytokine, chemokine, and ICAM-1 expression via suppression of the PI3K/Akt, NF-kappaB, and MAPK signaling pathways in IL-1beta stimulated inflammatory pulmonary epithelial cells. PMID- 29254156 TI - The clinical significance of circulating GPC1 positive exosomes and its regulative miRNAs in colon cancer patients. AB - Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Recent study found an increased level of glypican-1 positive (GPC1+) plasma exosomes in patients with stage II CRC, but decreased levels of plasma miR-96-5p and miR-149. This study further investigated the clinical significance of plasma GPC1+ exosomes and plasma miR-96-5p and miR-149 levels in stage III CRC patients. To study the effect of these microRNAs on GPC1+ plasma exosomes, we isolated and purified exosomes and overexpressed human GPC1 and the microRNAs miR-96-5p and miR-149 by adenovirus vectors. Overexpression of GPC1 activated epithelial mesenchymal transition (EMT) which then increased invasion and migration in HT29 and HCT-116 colon cancer cells. In contrast, silencing GPC1 expression and overexpressing miR-96-5p and miR-149 significantly inactivated EMT and decreased invasion and migration of HT29 and HCT-116 cells. miR-96-5p and miR-149 inhibitors significantly increased invasion and migration of HT29 and HCT-116 cells. Our results indicate that high levels of circulating GPC1 positive exosomes before and after surgery as well as low circulating miR-96-5p and miR 149 before surgery indicated a severe clinical status and poor prognosis in stage III colon cancer patients. We conclude that GPC1 can be a biomarker for relapse of stage III CRC and may be involved in EMT activation, invasion, and migration of colorectal cancer cells. PMID- 29254157 TI - Cerebrospinal fluid metabolomic profiles can discriminate patients with leptomeningeal carcinomatosis from patients at high risk for leptomeningeal metastasis. AB - Purpose: Early diagnosis of leptomeningeal carcinomatosis (LMC) is necessary to improve outcomes of this formidable disease. However, cerebrospinal fluid (CSF) cytology is frequently false negative. We examined whether CSF metabolome profiles can be used to differentiate patients with LMC from patients having a risk for development of LMC. Results: A total of 10,905 LMIs were evaluated using PCA-DA. The LMIs defined Group 2 with a sensitivity of 85% and a specificity of 91%. After selecting 33 LMIs, including diacetylspermine and fibrinogen fragments, the CSF metabolomics profile had a sensitivity of 100% and a specificity of 93% for discriminating Group 1b from the other groups. After selecting 21 LMIs, including phosphatidylcholine, the CSF metabolomics profile differentiated LMC (Group 2) patients from the high-risk groups of Group 3 and Group 4 with 100% sensitivity and 100% specificity. Materials and Methods: We prospectively collected CSF from five groups of patients: Group 1a, systemic cancer; Group 1b, no tumor; Group 2, LMC; Group 3, brain metastasis; Group 4, brain tumor other than brain metastasis. All metabolites in the CSF samples were detected as low-mass ions (LMIs) using mass spectrometry. Principal component analysis-based discriminant analysis (PCA-DA) and two search algorithms were used to select the LMIs that differentiated the patient groups of interest from controls. Conclusions: Analysis of CSF metabolite profiles could be used to diagnose LMC and exclude patients at high-risk of LMC with a 100% accuracy. We expect a future validation trial to evaluate CSF metabolic profiles supporting CSF cytology. PMID- 29254158 TI - High mobility group protein B1 is a predictor of poor survival in ovarian cancer. AB - High-mobility group protein B1 (HMGB1) has been implicated in numerous tumour types where expression regulates tumour cell growth and survival. We hypothesised that high HMGB1 expression in ovarian tumours would predict poor patient survival. Using tissue microarrays of primary ovarian cancers combined with a comprehensive database of clinicopathological variables, the expression of HMGB1 was assessed by immunohistochemistry in two independent cohorts (n=194 and n=360) using a monoclonal antibody specific for HMGB1. Kaplan-Meier analysis showed an association of HMGB1 expression with progression free survival in the primary cohort (p=0.023). In the validation cohort, expression was associated with overall survival (p=0.002). Low expression of HMGB1 was protective and in a multivariate model HMGB1 expression was shown to be an independent predictor of poor survival in ovarian cancer (p=0.006). The role of HMGB1 in cancer is complex. As high levels of HMGB1 expression are likely to render ovarian cancer cells resistant to chemotherapy, therapies targeting the HMGB1 axis may be appropriate in the treatment of ovarian cancer patients. PMID- 29254159 TI - Separation of low and high grade colon and rectum carcinoma by eukaryotic translation initiation factors 1, 5 and 6. AB - Colorectal cancer (CRC) is the third most common cause of cancer related death worldwide. Furthermore, with more than 1.2 million cases registered per year, it constitutes the third most frequent diagnosed cancer entity worldwide. Deregulation of protein synthesis has received considerable attention as a major step in cancer development and progression. Eukaryotic translation initiation factors (eIFs) are involved in the regulation of protein synthesis and are functionally linked to the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. The identification of factors accounting for colorectal carcinoma (CRC) development is a major gap in the field. Besides the importance of eIF3 subunits and the eIF4 complex, eIF1, eIF5 and eIF6 were found to be altered in primary and metastatic CRC. We observed significant difference in the expression profile between low and high grade CRC. eIF1, eIF5 and eIF6 are involved in translational control in CRC. Our findings also indicate a probable clinical impact when separating them into low and high grade colon and rectum carcinoma. eIF and mTOR expression were analysed on protein and mRNA level in primary low and high grade colon carcinoma (CC) and rectum carcinoma (RC) samples in comparison to non-neoplastic tissue without any disease-related pathology. To assess the therapeutic potential of targeting eIF1, eIF5 and eIF6 siRNA knockdown in HCT116 and HT29 cells was performed. We evaluated the eIF knockdown efficacy on protein and mRNA level and investigated proliferation, apoptosis, invasion, as well as colony forming and polysome associated fractions. These results indicate that eIFs, in particular eIF1, eIF5 and eIF6 play a major role in translational control in colon and rectum cancer. PMID- 29254160 TI - Tumor image-derived texture features are associated with CD3 T-cell infiltration status in glioblastoma. AB - This study analyzed magnetic resonance imaging (MRI) scans of Glioblastoma (GB) patients to develop an imaging-derived predictive model for assessing the extent of intratumoral CD3 T-cell infiltration. Pre-surgical T1-weighted post-contrast and T2-weighted Fluid-Attenuated-Inversion-Recovery (FLAIR) MRI scans, with corresponding mRNA expression of CD3D/E/G were obtained through The Cancer Genome Atlas (TCGA) for 79 GB patients. The tumor region was contoured and 86 image derived features were extracted across the T1-post contrast and FLAIR images. Six imaging features-kurtosis, contrast, small zone size emphasis, low gray level zone size emphasis, high gray level zone size emphasis, small zone high gray level emphasis-were found associated with CD3 activity and used to build a predictive model for CD3 infiltration in an independent data set of 69 GB patients (using a 50-50 split for training and testing). For the training set, the image-based prediction model for CD3 infiltration achieved accuracy of 97.1% and area under the curve (AUC) of 0.993. For the test set, the model achieved accuracy of 76.5% and AUC of 0.847. This suggests a relationship between image derived textural features and CD3 T-cell infiltration enabling the non-invasive inference of intratumoral CD3 T-cell infiltration in GB patients, with potential value for the radiological assessment of response to immune therapeutics. PMID- 29254161 TI - Adipokines in hereditary breast cancer patients and healthy relatives. AB - Background: The role of adipocytokines and ghrelin in hereditary breast cancer syndrome (HBCS) has never been tested. Results: No significant differences in leptin, adiponectin and ghrelin plasma levels between cancer patients and healthy subjects was observed. Conversely, an higher level of adiponectin was shown in healthy subjects with BRCA 1/2 gene mutation vs those without (p < 0.03). Logistic regression analysis demonstrated that Adiponectin plasma level (OR 0.26; 95% CI:0.007-0.81; p < 0.02) and age (OR 5.51; 95% CI:1.78-19.71; p < 0.004) were the only factors independently associated with BMI; furthermore, Leptin plasma level (OR 0.23; 95% CI:0.06-0.76; p < 0.01) and age (OR 0.05; 95% CI:0.05-0.61; p < 0.007) resulted the only factors significantly associated with breast cancer. Materials and Methods: We analyzed blood plasma expression of leptin, adiponectin and ghrelin using Bio-Plex platform in 25 breast cancer patients with HBCS and in 38 healthy relatives. BRCA 1/2 gene status (presence of pathogenic mutations by direct molecular sequencing), clinical-pathological characteristics and Body Mass Index (BMI) of each subject were recorded. Conclusions: Adiponectin confirms to be associated with BMI also in subjects with HBCS. Leptin plasma level seems a direct and independent biomarker of a breast cancer risk. A validation of Leptin as a circulating biomarker of breast cancer development in larger series of HBCS subjects is needed. PMID- 29254162 TI - miR-137 acts as a tumor suppressor via inhibiting CXCL12 in human glioblastoma. AB - Up to date, miR-137 has been demonstrated as a tumor suppressor in many kinds of human malignancies. In the present study, we conducted transfection, western blot and RT-PCR to explore the role of miR-137 in the development of human glioblastoma (GBM). Here, we found that miR-137 expression was obviously down regulated in GBM tissues and cells rather than matched non-tumor tissues and NHA cells. However, the expression of C-X-C motif ligand 12 (CXCL12) mRNA and protein were up-regulated in GBM tissues and cells. In vitro, miR-137 mimics inhibited GBM cell proliferation, migration and invasion, and the 3'-untranslated regions (3'-UTR) of CXCL12 were a direct target of miR-137. In addition, miR-137 mimics also inhibited the expression of EGFR, Bcl-2 and MMP2/9 proteins, but increased the expression of Bax protein. Notably, CXCL12 over-expression attenuated miR-137 inhibited cell proliferation and invasion, while CXCL12 siRNAs promoted miR-137 inhibition effects. In vivo, miR-137 mimics also suppressed tumor growth in nude mice xenograft model. In conclusion, miR-137 serves as a tumor suppressor by inhibition of CXCL12 in human GBM. Thus, miR-137-CXCL12 can be recommended as a useful and effective target for treatment of GBM. PMID- 29254163 TI - The differential diagnostic value of serum homocysteine for white coat hypertension. AB - Objective: To assess the value of serum homocysteine (Hcy) in differential diagnosis of white coat hypertension (WCH). Results: In this retrospective study, serum Hcy levels were elevated in hypertensive patients (P < 0.001) compared to WCH patients. Serum Hcy levels were positively correlated with 24-h mean systolic blood pressure, r = 0.1378, P < 0.001. The results of the receiving operating characteristic (ROC) curve showed that the AUC value of Hcy was 0.80 (95% CI, 0.77-0.83), the cut-off value was 13.8 MUmol/L, the sensitivity was 68.58% and the specificity 87.21%. In the prospective study, the AUC value of Hcy was 0.73 (95% CI: 0.67-0.78), higher than N - terminal pro - brain natriuretic peptide(NT pro-BNP) (0.64, 95% CI:0.58-0.70) and cystatin C (Cys-C) (0.62, 95% CI:0.55 0.68). Hcy, NT-proBNP and Cys-C combined, provided a better indication of a differential diagnosis of WCH, than Hcy alone. Materials and Methods: This investigation involved both a retrospective and a prospective study. Clinical data including blood pressure, age, sex, height, weight, BMI, smoking status, past history, and behavioral electrocardiogram of patients who had undergone 24 hour ambulatory blood pressure monitoring (ABPM) with elevated clinical blood pressure (BP) were recorded. Pearson correlation analysis was used to test the correlation between Hcy and BP. The ROC curve was used to analyze the value of measuring Hcy levels in differential diagnosis of WCH. Conclusions: Serum Hcy was decreased in WCH patients and therefore could be a biomarker for differential diagnosis of WCH. PMID- 29254164 TI - Osteopontin production by TM4SF4 signaling drives a positive feedback autocrine loop with the STAT3 pathway to maintain cancer stem cell-like properties in lung cancer cells. AB - Transmembrane 4 L6 family proteins have been known to promote cancer. In this study, we demonstrated that transmembrane 4 L6 family member 4 (TM4SF4), which is induced by gamma-radiation in non-small cell lung cancer (NSCLC) cells, is involved in epithelial-to-mesenchymal transition (EMT) and cancer stem cell (CSC) properties of NSCLC through the regulation of osteopontin (OPN). Forced TM4SF4 overexpression in A549 cells increased the secretion of OPN, which activates CD44 or integrin signaling and thus maintains EMT-associated CSC-like properties. OPN, known as a downstream target of beta-catenin/T-cell factor 4 (TCF-4), was induced by up-regulated beta-catenin via TM4SF4-driven phosphorylation of glycogen synthase kinase 3b (GSK3beta). TCF4 complexed to promoter regions of OPN in TM4SF4-overexpressing A549 cells was also confirmed by chromatin immunoprecipitation. Knockout of either beta-catenin or TCF4-suppressed OPN expression, demonstrating that both factors are essential for OPN expression in NSCLC cells. OPN secreted by TM4SF4/GSK3beta/beta-catenin signaling activated the JAK2/STAT3 or FAK/STAT3 pathway, which also up-regulates OPN expression in an autocrine manner and consequently maintains the self-renewal and metastatic capacity of cancer cells. Neutralizing antibody to OPN blocked the autocrine activation of OPN expression, consequently weakened the metastatic and self renewal capacity of cancer cells. Collectively, our findings indicate that TM4SF4 triggered OPN expression is involved in the persistent reinforcement of EMT or cancer stemness by creating a positive feedback autocrine loop with JAK2/STAT3 or FAK/STAT3 pathways. PMID- 29254165 TI - A long non-coding RNA expression signature to predict survival of patients with colon adenocarcinoma. AB - Colon cancer is the most common type of gastrointestinal cancer and is still the leading cause of cancer-related mortality worldwide. Long non-coding RNAs (lncRNAs) have been proved to be superior biomarkers in cancer diagnosis and prognosis than miRNAs and protein-coding genes. In the current study, our objective was to detect novel lncRNA biomarkers by analyzing lncRNA expression profiles and clinical data in a large cohort of patients with colon patients from The Cancer Genome Atlas (TCGA). By using Cox regression analysis, we identified two lncRNAs (SNHG6 and CTD-2354A18.1) which could be independent prognostic factors for predicting clinical outcome in colon adenocarcinoma. Then a linear combination of these two lncRNA biomarkers (SNHG6 and CTD-2354A18.1), termed two lncRNA signature, was developed in the training set as a predictor for OS in patients with colon adenocarcinoma, and validated in the testing set and the entire patient set. This two-lncRNA signature demonstrated significant prognostic performance in both the testing set and the entire patient set which classified the patients into two groups with significantly different OS. The multivariate and stratified analysis suggested that the prognostic value of the two-lncRNA signature was independent of other traditional clinical variables. Functional analysis suggested that these two lncRNA biomarkers might be mainly involved in transcription/translation-related or DNA repair-related biological processes. In summary, our results warrant further studies on these lncRNAs that will improve our understanding of the mechanisms associated with pathogenesis and progression of colon adenocarcinoma. PMID- 29254166 TI - Identification of glycerol-3-phosphate dehydrogenase 1 as a tumour suppressor in human breast cancer. AB - In the present study, we found the mRNA expression level of glycerol-3-phosphate dehydrogenase (GPD1) was significantly downregulated in human breast cancer patients. Patients with reduced GPD1 expression exhibited poorer overall metastatic relapse-free survival (p = 0.0013). Further Cox proportional hazard model analysis revealed that the reduced expression of GPD1 is an independent predictor of overall survival in oestrogen receptor-positive (p = 0.0027, HR = 0.91, 95% CI = 0.85-0.97, N = 3,917) and nodal-negative (p = 0.0013, HR = 0.87, 95% CI = 0.80-0.95, N = 2,456) breast cancer patients. We also demonstrated that GPD1 was a direct target of miR-370, which was significantly upregulated in human breast cancer. We further showed that exogenous expression of GPD1 in human MCF-7 and MDA-MB-231 breast cancer cells significantly inhibited cell proliferation, migration, and invasion. Our results, therefore, suggest a novel tumour suppressor function for GPD1 and contribute to the understanding of cancer metabolism. PMID- 29254167 TI - Detection of BRCA1/2 mutations in circulating tumor DNA from patients with ovarian cancer. AB - Approximately 25% of patients with ovarian cancer harbor a pathogenic BRCA1/2 mutation that has been associated with favorable responses for targeted therapy with poly (ADP-ribose) polymerase 1 (PARP1) inhibitors compared to wild-type individuals. The overall frequency of germline and somatic BRCA1/2 alterations is estimated at 13-15% and 3-10%, respectively. A high incidence of BRCA1/2 somatic variants significantly increases the number of patients eligible for treatment with PARP1 inhibitors. Here, we assessed circulating tumor DNA (ctDNA) from 121 patients with ovarian cancer for BRCA1/2 mutational analysis by next generation sequencing. A total number of patients carrying the pathogenic BRCA1/2 variants was 30/121 (24.8%), including 22 and 7 individuals with exclusively germline or somatic mutations, respectively and one patient with variants of both origin. Among this cohort, more than one known pathogenic BRCA1 and/or BRCA2 alterations were identified in 7/30 individuals. The most recurrent mutations were detected in the BRCA1 gene: c.5266dupC (p.Gln1756Profs*74) with the frequency of ~18%, followed by c.3756_3759del (p.Ser1253Argfs*10) and c.181T>G (p.Cys61Gly). In seven (5.8%) patients, coincidence of two or more BRCA1/2 pathogenic mutations have been identified. Our results clearly demonstrate that the detection of both germline and somatic BRCA1/2 mutations in ctDNA from ovarian cancer patients is feasible and may be a valuable complementary tool for identification of somatic alterations when the standard diagnostic procedures are insufficient. Finally, ctDNA can potentially allow to monitor the efficacy of PARP1 inhibitors and to detect a secondary reversion BRCA1/2 mutations. PMID- 29254168 TI - LC-MS-based metabolomics revealed SLC25A22 as an essential regulator of aspartate derived amino acids and polyamines in KRAS-mutant colorectal cancer. AB - SLC25A22, which encodes the mitochondrial glutamate transporter, is overexpressed in colorectal cancer (CRC) and is essential for the proliferation of CRC cells harboring KRAS mutations. However, the role of SLC25A22 on metabolic regulation in KRAS-mutant CRC cells has not been comprehensively characterized. We performed non-targeted metabolomics, targeted metabolomics and isotope kinetic analysis of KRAS-mutant DLD1 cells with or without SLC25A22 knockdown using ultra-high performance liquid chromatography (UHPLC) coupled to Orbitrap mass spectrometry (MS) or tandem MS (MS/MS). Global metabolomics analysis identified 35 altered metabolites, which were attributed to alanine, aspartate and glutamate metabolism, urea cycle and polyamine metabolism. Targeted metabolomics including 24 metabolites revealed that most tricarboxylic acid (TCA) cycle intermediates, aspartate-derived asparagine, alanine and ornithine-derived polyamines were strongly down-regulated in SLC25A22 knockdown cells. Moreover, targeted kinetic isotope analysis showed that most of the 13C-labeled ornithine-derived polyamines were significantly decreased in SLC25A22 knockdown cells and culture medium. Exogenous addition of polyamines could significantly promote cell proliferation in DLD1 cells, highlighting their potential role as oncogenic metabolites that function downstream of SLC25A22-mediated glutamine metabolism. Collectively, SLC25A22 acts as an essential metabolic regulator during CRC progression as it promotes the synthesis of aspartate-derived amino acids and polyamines in KRAS mutant CRC cells. PMID- 29254169 TI - MicroRNA-182 downregulates Wnt/beta-catenin signaling, inhibits proliferation, and promotes apoptosis in human osteosarcoma cells by targeting HOXA9. AB - We investigated the mechanisms by which microRNA (miR)-182 promotes apoptosis and inhibits proliferation in human osteosarcoma (OS) cells. Levels of miR-182 and Homeobox A9 (HOXA9) expression were compared between human OS and normal cells. Subjects were divided into OS and normal groups. We analyzed the target relationship of miR-182 and Homeobox A9 (HOXA9). Cells were then assigned into blank, negative control, miR-182 mimics, miR-182 inhibitors, siRNA-HOXA9, or and miR-182 inhibitors + siRNA-HOXA9 groups. Cell function was assayed by CCK-8, flow cytometry and wound healing assay. Additionally, we analyzed OS tumor growth in a xenograft mouse model. Dual-luciferase reporter assays indicated miR-182 directly targets HOXA9. Reverse transcription quantitative PCR and western blotting revealed elevated expression of miR-182, WIF-1, BIM, and Bax, and reduced expression of HOXA9, Wnt, beta-catenin, Survivin, Cyclin D1, c-Myc, Mcl-1, Bcl xL, and Snail in osteosarcoma cells treated with miR-182 mimic or siRNA-HOXA9 as compared to controls. Osteosarcoma cells also exhibited decreased cell proliferation, migration, and tumor growth, and increased apoptosis when treated with miR-182 mimic or siRNA-HOXA9. Correspondingly, in a xenograft mouse model, osteosarcoma tumor volume and growth were increased when cells were treated with miR-182 inhibitor and decreased by miR-182 mimic or siRNA-HOXA9. These results indicate that miR-182 downregulates Wnt/beta-catenin signaling, inhibits cell proliferation, and promotes apoptosis in osteosarcoma cells by suppressing HOXA9 expression. PMID- 29254170 TI - Propensity score matching analysis of the prognosis for the rare oxyphilic subtype of thyroid cancer (Hurthle cell carcinoma). AB - There is controversy regarding the prognosis of patients with oxyphilic thyroid cancer (OXTC). The present study compared the prognoses of OXTC, papillary thyroid cancer (PTC), and follicular thyroid cancer (FTC), in order to provide a new perspective regarding the treatment guidelines for these diseases. We evaluated data from patients with thyroid cancer who were included in the Surveillance, Epidemiology, and End Results database between 2004 and 2013. Patient mortality was evaluated using Cox proportional hazards regression analyses and Kaplan-Meier analyses with log-rank tests. The multivariate Cox regression analysis revealed that the cancer-specific survival rate for OXTC was similar to that for PTC, but higher than that for FTC. However, after propensity score matching for relevant factors, the cancer-specific survival rate for OXTC was higher than that for PTC and FTC. This unexpected result provides new implications for the treatment of patients with OXTC. PMID- 29254171 TI - Lentivirus-mediated RNA interference targeting FAMLF-1 inhibits cell growth and enhances cell differentiation of acute myeloid leukemia partially differentiated cells via inhibition of AKT and c-MYC. AB - Genetic heterogeneity is the basis of clinical heterogeneity among different subtypes of AML. We have successfully cloned a gene related to AML termed FAMLF from a FAB-M2 patient's sample of a second largest AML pedigree. Then we revealed at least three splice variants, named as FAMLF-1, FAMLF-2 and FAMLF-3, and found miR181a1/b1 in the second intron of FAMLF gene family. Higher expression of FAMLF 1 was related to a higher complete remission (CR) rate, but shorter relapse free survival (RFS) in AML. We further found that the FAMLF-1 single nucleotide polymorphism (SNP) haplotype and its expression were positively correlated to clinical parameters of acute myeloid leukemia partially differentiated (FAB-M2) patients, but not FAB non-M2 patients or Acute Monocytic Leukemia (FAB-M5) patients. GTAGG SNP haplotype of FAMLF gene might increase FAB-M2 susceptibility in Han population and act as a useful candidate biomarker for FAB-M2 screening. We also demonstrated that FAMLF-1 gene silencing in FAB-M2 cells could lead to proliferation inhibition, cell cycle G0/G1 phase arrest, and differentiation promotion independent of its intronic miR-181a1, which might be related to Akt/c Myc pathway. These findings reveal a role of FAMLF-1 as a potential pathogenic gene for FAB-M2. PMID- 29254172 TI - Trastuzumab beyond progression in patients with HER2-positive advanced gastric adenocarcinoma: a multicenter AGEO study. AB - Introduction: Trastuzumab in combination with platinum-based chemotherapy is the standard first-line regimen in HER2-positive advanced gastric cancer. However, there are very few data concerning efficacy of continuing trastuzumab beyond first-line progression. Methods: This retrospective multicenter study included all consecutive patients with HER2-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who received a second-line of chemotherapy with or without trastuzumab after progression on platinum-based chemotherapy plus trastuzumab. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method and compared using log-rank test. The prognostic variables with P values <= 0.05 in univariate analysis were eligible for the Cox multivariable regression model. Results: From May 2010 to December 2015, 104 patients were included (median age, 60.8 years; male, 78.8%; ECOG performance status [PS] 0-1, 71.2%). The continuation (n=39) versus discontinuation (n=65) of trastuzumab beyond progression was significantly associated with an improvement of median PFS (4.4 versus 2.3 months; P=0.002) and OS (12.6 versus 6.1 months; P=0.001. In the multivariate analysis including the ECOG PS, number of metastatic sites and measurable disease, the continuation of trastuzumab beyond progression remained significantly associated with longer PFS (HR, 0.56; 95% CI, 0.35-0.89; P=0.01) and OS (HR, 0.47; 95% CI, 0.28-0.79; P=0.004). Conclusion: This study suggests that continuation of trastuzumab beyond progression has clinical benefit in patients with HER2-positive advanced gastric cancer. These results deserve a prospective randomized validation. PMID- 29254174 TI - Upregulation of long noncoding RNA Xist promotes proliferation of osteosarcoma by epigenetic silencing of P21. AB - Recent studies show that lncRNAs involve in the initiation and progression of various cancers including osteosarcoma (OS). IncRNA Xist has been verified as an oncogene in several human cancers, and its abnormal expression was closely associated with tumor initiation and progression. Nevertheless, the role of Xist in OS remains unclear. Here, we revealed the Xist expression level was up regulated in OS tissues and discovered that Xist knockdown significantly repressed OS cell proliferation. Additionally, mechanistic analysis revealed that Xist can repress P21 expression to regulate OS cell cycle and proliferation by binding to EZH2. Taking all into account, Xist may function in promoting OS cell proliferation and may potentially serve as a novel biomarker and therapeutic target for OS. PMID- 29254173 TI - Blockade of potassium ion transports enhances hypotonicity-induced cytocidal effects in gastric cancer. AB - Background: Peritoneal lavage with distilled water has been used for surgeries of various cancers to reduce peritoneal recurrence. This study examined whether blockade of potassium ion transports enhances hypotonicity-induced cytocidal effects in gastric cancer (GC). Results: A potassium channel blocker inhibited the occurrence of regulatory volume decrease (RVD) induced by mild hypotonic stimulation, and significantly enhanced cytocidal effects on GC cells. Incubating MKN45 cells with hypotonic solutions containing a potassium channel blocker significantly reduced the formation of peritoneal metastases in nude mice. Methods: The three human GC cell lines (HGC-27, Kato III, and MKN45) were exposed to mild hypotonic solutions, and the effects of blockade of potassium ion transports during hypotonic stimulation on cell volume changes and cell viabilities were examined. In the in vivo study, MKN45 cells stimulated with mild hypotonic solutions were intraperitoneally injected into nude mice, and the effects of blockade of potassium ion transports during hypotonic stimulation on the formation of peritoneal metastases were evaluated. Conclusions: Blockade of potassium ion transports enhances hypotonicity-induced cytocidal effects on GC cells, which may contribute to development of a novel lavage method for further reduction of peritoneal recurrence in GC. PMID- 29254175 TI - Targeting viperin improves diet-induced glucose intolerance but not adipose tissue inflammation. AB - Viperin is an interferon-inducible antiviral protein, responsible for antiviral response to a variety of viral infections. Here, we show that silencing viperin by antisense oligonucleotides (ASO) protects against diet-induced glucose intolerance, and yet exacerbates adipose tissue inflammation. In high-fat diet fed mice, viperin ASO improves glucose homeostasis, reduces plasma triglyceride concentrations and ameliorates diet-induced hepatic steatosis. Peripheral delivery of viperin by adeno-associated virus elevates fasting plasma glucose and insulin concentrations and reduces insulin-stimulated glucose uptake in skeletal muscle. Viperin overexpression reduces epinephrine- stimulated lipolysis in white adipose tissue, whereas viperin ASO increases expression of lipolytic genes. Targeting viperin by antisense oligonucleotides promotes reciprocal regulation of hepatic and adipose lipogenesis by reducing hepatic lipid content and increasing triacylglycerol content in adipose tissue. These findings reveal viperin as an important target to improve glucose metabolism, and suggest that suppressing antiviral potential may improve the metabolic adaptability to high-fat diet. PMID- 29254176 TI - Lung cancer mutation testing: a clinical retesting study of agreement between a real-time PCR and a mass spectrometry test. AB - To investigate the clinical validity and utility of tests for detecting Epidermal Growth Factor Receptor (EGFR) gene mutations in non-squamous non-small cell lung cancer patients, tumour DNA extracts from 532 patients previously tested by the cobas EGFR Mutation Test (RT-PCR test) were retested by the Sequenom/Agena Biosciences MassArray OncoFocus mass spectrometry test (MS test). Valid results from both tests were available from 470 patients (88%) for agreement analysis. Survival data were obtained for 513 patients (96%) and 77 patients (14%) were treated with EGFR tyrosine kinase inhibitors (TKIs). Agreement analysis revealed moderately high positive (79.8%), negative (96.9%) and overall percentage agreement (93.2%) for the detection of EGFR mutations. However, EGFR mutations were detected by one test and not by the other test in 32 patients (7%). Retesting of discordant samples revealed false-positive and false-negative results generated by both tests. Despite this, treatment and survival outcomes correlated with the results of the RT-PCR and MS tests. In conclusion, this study provides evidence of the clinical validity and utility of the RT-PCR and MS tests for detection of EGFR mutations that predict prognosis and benefit from EGFR-TKI treatment. However, their false-positive and false-negative test results may have important clinical consequences. PMID- 29254177 TI - MAPK, NFkappaB, and VEGF signaling pathways regulate breast cancer liver metastasis. AB - In this study, we investigated the molecular pathways regulating breast cancer liver metastasis. We identified 48 differentially expressed genes (4 upregulated and 44 downregulated) by analyzing microarray dataset GSE62598 from Gene Expression Omnibus (GEO). We constructed a genetic interaction network with 84 nodes and 237 edges using the String consortium database. The network was reliably robust with a clustering coefficient (cc) of 0.598 and protein-protein interaction (PPI) enrichment p value of zero. Using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases, we identified MAPK, NFkappaB and VEGF signaling pathways as the most critical pathways regulating breast cancer liver metastasis. These results indicate that the distinct breast cancer metastatic stages, including dissemination from the primary breast tumor, transit through the vasculature, and survival and proliferation in the liver, are regulated by the MAPK, NFkappaB, and VEGF signaling pathways. PMID- 29254178 TI - Theophylline exhibits anti-cancer activity via suppressing SRSF3 in cervical and breast cancer cell lines. AB - Caffeine, theophylline, and theobromine are the most well-known members of methylxanthines. Caffeine-induced serine/arginine-rich splicing factor 2, SRSF2, and SRSF3 are required for the alternative splicing of a subset of cancer associated genes. However, it remains to be investigated whether and how theophylline and theobromine as well as caffeine exert their antitumor effects through mediating the alternative splicing process. Here, we reveal that theophylline down-regulated SRSF3 expression and switched p53 from alpha into a beta isoform as caffeine did in HeLa and MCF-7 cells via the reverse transcriptase polymerase chain reaction and Western blot analysis. Further functional studies show that theophylline induced cellular apoptosis, senescence, and decreased colony formation. Interestingly, theophylline had a suppressive effect on cellular proliferation, whereas caffeine enhanced cellular proliferation rates via the 5-bromo-2-deoxyuridine analysis. Theophylline and caffeine had no effect on MCF-10A cells, which is a normal breast cell line. Our results provide an insight that theophylline as well as caffeine could be repurposed as antitumor leading compounds via the downregulation of splicing factor SRSF3 and its target genes. PMID- 29254180 TI - NOD2 maybe a biomarker for the survival of kidney cancer patients. AB - Background: Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) may play an important role in the outcome of kidney cancer patients. To explore the relationship between NOD2 and the prognosis of kidney cancer patients, a databank-based reanalysis was conducted. Materials and Methods: Data related to kidney cancer patients at least with survival information, was obtained mainly from The Cancer Genome Atlas (TCGA). Some clinical data, not available online, was collected by personal email to the author. Then, we reanalyzed all the data in order to make a conclusion about the relationship between NOD2 gene and the prognosis of kidney cancer patients. Results: A total of 1953 samples with NOD2 information from four databanks of The Cancer Genome Atlas (TCGA) were enrolled in this study. The results of KIPAN showed the Kaplan-Meier curve for risk groups, concordance index, and p-value of the log-rank testing equality of survival curves ( Concordance Index = 56.57, Log-Rank Equal Curves p=0.0009006, R^2 = 0.036/0.953, Risk Groups Hazard Ratio = 1.61 (conf. int. 1.21 ~ 2.13), p = 0.001005) , while a box plot across risk groups, including the p-value testing for difference using t-test (or f-test for more than two groups) was shown. There was a statistical significance for the p value of the result (p < 0.01 ). The similar results could be seen in KIRC and the fourth data (including 468 samples). Conclusions: The status of NOD2 gene maybe a biomarker for the survival of kidney cancer patients. PMID- 29254179 TI - Galectin-3 induced by hypoxia promotes cell migration in thyroid cancer cells. AB - Background: The aim of this study is to investigate the role of Galectin-3 in human thyroid cancer migration. Methods: The expression of Galectin-3 in surgical specimens was investigated using immunohistochemistry and western blot. A papillary thyroid cancer cell line (B-cpap) and an anaplastic thyroid cancer cell line (8305c) were transfected with short-hairpin RNA against Galectin-3 (Gal-3 shRNA). Low-molecular citrus pectin (LCP) was also used to antagonize Galectin-3. The migration and invasion of the cell lines were examined. The related signaling pathways were investigated to explore the Galectin-3 mechanism of action. Results: Galectin-3 was highly expressed in metastasized thyroid cancers. Knocking down and antagonizing Galectin-3 significantly suppressed the migration of thyroid cancer cells. Knocking down Galectin-3 inhibited the activity of Wnt, MAPK, Src and Rho signaling pathways. Galectin-3 was up-regulated via HIF-1alpha in a hypoxic environment. Galectin-3 knockdown could reduce cell motility in hypoxic environments. Conclusion: This study suggests that Galectin-3 could act as a modulator of thyroid cancer migration, especially in hypoxic microenvironments. This regulation function of Galectin-3 may work through multiple signaling pathways. PMID- 29254181 TI - Oncological outcomes of neoadjuvant chemotherapy in patients with locally advanced upper tract urothelial carcinoma: a multicenter study. AB - Objective: The clinical impact of neoadjuvant chemotherapy (NAC) on oncological outcomes in patients with locally advanced upper tract urothelial carcinoma (UTUC) remains unclear. We investigated the oncological outcomes of platinum based NAC for locally advanced UTUC. Results: Of 234 patients, 101 received NAC (NAC group) and 133 did not (Control [Ctrl] group). The regimens in the NAC group included gemcitabine and carboplatin (75%), and gemcitabine and cisplatin (21%). Pathological downstagings of the primary tumor and lymphovascular invasion were significantly improved in the NAC than in the Ctrl groups. NAC for locally advanced UTUC significantly prolonged recurrence-free and cancer-specific survival. Multivariate Cox regression analysis using an inverse probability of treatment weighted (IPTW) method showed that NAC was selected as an independent predictor for prolonged recurrence-free and cancer-specific survival. However, the influence of NAC on overall survival was not statistically significant. Materials and Methods: A total of 426 patients who underwent radical nephroureterectomy at five medical centers between January 1995 and April 2017 were examined retrospectively. Of the 426 patients, 234 were treated for a high risk disease (stages cT3-4 or locally advanced [cN+] disease) with or without NAC. NAC regimens were selected based on eligibility of cisplatin. We retrospectively evaluated post-therapy pathological downstaging, lymphovascular invasion, and prognosis stratified by NAC use. Multivariate Cox regression analysis was performed for independent factors for prognosis. Conclusions: Platinum-based NAC for locally advanced UTUC potentially improves oncological outcomes. Further prospective studies are needed to clarify the clinical benefit of NAC for locally advanced UTUC. PMID- 29254182 TI - Metformin induces cell cycle arrest at the G1 phase through E2F8 suppression in lung cancer cells. AB - A target molecule responsible for cell cycle arrest by metformin was discovered using a gene chip array in lung cancer cells and the effect of metformin on E2F8 was assessed. The siRNA-mediated knockdown of E2F8 significantly suppressed G1-S progression while ectopic expression of E2F8 relieved metformin-induced G1 arrest. The mRNA levels of p21 were found to be inversely related to those of E2F8 in lung cancer cells while siRNA-mediated knockdown of p21 partly rescued siE2F8-induced arrest of the cell cycle. Metformin had no effect on degradation of E2F8 mRNA. Activation and inhibition of AMPK by AICAR and Dorsomorphin, respectively, did not affect E2F8 suppression by metformin. The clinical significance of E2F8 was analyzed in The Cancer Genome Atlas (TCGA) data. One hundred six (13%) of 848 TCGA lung cancers overexpressed E2F8 mRNA. The overexpression of E2F8 was associated with poor overall survival (adjusted hazard ratio = 1.58, 95% confidence interval = 1.13-2.22; P = 0.008). The present study suggests that metformin may induce cell cycle arrest at the G1 phase by suppressing E2F8 expression in lung cancer cells. In addition, E2F8 may be associated with poor overall survival in lung cancer patients irrespective of histology. PMID- 29254183 TI - Therapeutic potential of an anti-angiogenic multimodal biomimetic peptide in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. Due to inadequate screening methods and the common coexistence of limited functional liver reserves, curative treatment options are limited. Liver transplantation is the only curative treatment modality for early HCC. There are multidisciplinary treatment options like ablative treatments, radiation and systemic therapy available for more advanced patients or those that are inoperable. Treatment resistance and progression is inevitable for these HCC patients. Newer therapeutics need to be explored for better management of HCC. HCC is a hypervascular tumor and many pro-angiogenic proteins are found significantly overexpressed in HCC. Here we explored the therapeutic potential of the anti-angiogenic, anti-lymphangiogenic, and directly anti-tumorigenic biomimetic collagen IV-derived peptide developed by our group. Human HCC cell lines HuH7, Hep3b and HepG2 showed significant disruption of cell adhesion and migration upon treatment with the peptide. Consistent with previously described multimodal inhibitory properties, the peptide was found to inhibit both c-Met and IGF1R signaling in HepG2 cells and blocked HepG2 conditioned media stimulation of microvascular endothelial cell (MEC) tube formation. Furthermore, the peptide treatment of mouse HepG2 tumor xenografts significantly inhibited growth relative to untreated controls. The peptide was also found to improve the survival of autochthonous Myc-induced HCC in a transgenic mouse model. Mechanistically, we found that the peptide treatment reduced microvascular density in the autochthonous liver tumors with increased apoptosis. This study shows the promising therapeutic potential of our biomimetic peptide in the treatment of HCC. PMID- 29254184 TI - PD-L1 promoter methylation mediates the resistance response to anti-PD-1 therapy in NSCLC patients with EGFR-TKI resistance. AB - The anti-PD-1/PD-L1 therapy has been demonstrated effective and safe for advanced NSCLC patients, especially for EGFR-TKIs (epidermal growth factor receptor - tyrosine kinase inhibitors) resistant NSCLC (non-small cell lung cancer) patients with EGFR mutations. However, whether the anti-PD-1/PD-L1 therapy also promotes drug resistance as EGFR-TKIs treatment remains unclear. Thus, we conducted the present study to investigate the effects of anti-PD-1 therapy on the expression of PD-L1, which is one important factor mediates the efficacy of anti-PD-1 therapy. To address the expression dynamics of PD-L1 after anti-PD-1 therapy, we first divided the patients into three groups according to the EGFR mutation status (wild type, L858R and T790M mutation). The PD-L1 was highly expressed in the NSCLC tissues than the corresponding normal tissues. After cancer recurrence, the PD-L1 was further up-regulated in patients treated with chemotherapy or EGFR TKI therapy but decreased in the patients with anti-PD1 therapy. Promoter methylation analysis showed that the secondary NSCLC after cancer recurrence with anti-PD1 therapy had much higher promoter methylation level than the primary cancer tissue or normal tissues. In the mice model, the anti-PD-1 therapy could induce PD-L1 promoter methylation irrespective of EGFR mutation status. Combining DNA hypomethylating agent azacytidine with anti-PD-1 therapy could significantly further reduce the tumor size when comparing with the anti-PD-1 therapy alone. Our results demonstrated that the anti-PD-1 therapy might promote drug resistance through PD-L1 promoter methylation and down-regulation. And combining DNA hypomethylating agent azacytidine with anti-PD-1 therapy might be a promising approach to overcome the resistance. PMID- 29254185 TI - Hepatoprotective potential of isoquercitrin against type 2 diabetes-induced hepatic injury in rats. AB - Non-alcoholic fatty liver disease is a main complication of type 2 diabetes. Isoquercitrin are employed for antidiabetic therapies, but the effects on liver function and the hepatocytes are unclear. The aim of this study was to investigate the effects of isoquercitrin on the T2DM-induced hepatic injury in rats. Isoquercitrin (10 mg/kg/d, 30 mg/kg/d), sitagliptin phosphate (10 mg/kg/d) was given orally for 21 days. The administration of isoquercitrin at 10 mg/kg/d and 30 mg/kg/d showed a dose dependent. Compare to the negative control (treated with saline), rats medicated with isoquercitrin (30 mg/kg/d) and sitagliptin phosphate (10 mg/kg/d) improved the clinical symptoms, FBG and glucose tolerance, reduced serum ALT, AST and IR, but increased TP, Alb, SOD, GSH, MDA, HDL-C, INS and GLP-1. On histology, Rats of these to groups presented nearly normal liver tissue and Langerhans, degeneration, necrosis and apoptosis were markedly reduced. Instead, hepatocytes showed regenerate. These two groups also showed significant increase in mRNA expression of PKA, AKT, PKCa, InsR and PI3K, and a decrease in DPP-IV mRNA level. These results indicated that treatment with isoquercitrin protects against hepatic injury by T2DM. PMID- 29254186 TI - Association of elevated reactive oxygen species and hyperthermia induced radiosensitivity in cancer stem-like cells. AB - Cancer stem-like cells (CSCs) are the principal causes of tumor radio-resistance, dormancy and recurrence after radiotherapy. Clinical trials show hyperthermia (HT) might be a potent radiation sensitizer. In this study, CSCs were found to be more susceptible to radiation when combined with HT treatment. Treated cells showed significantly reduced self-renewal, cell survival and proliferation in vitro, as well as significant reduced tumor formation in vivo. Further study demonstrated that the radiosensitization effect was associated with increased intracellular reactive oxygen species (ROS) level in CSCs, confirmed by modifying redox status in CSCs bidirectionally. Pharmacologic depletion of glutathione by buthionine sulphoximine mimicked HT induced radiosensitivity in CSCs. Antioxidant N-acetylcysteine could efficiently rescue HT induced radiosensitivity in CSCs. To our knowledge, this may be the first report suggesting the association between elevated intracellular ROS level and HT induced radiosensitization in human breast CSCs and pancreatic CSCs, which might provide new strategy for improving CSCs radiosensitivity. PMID- 29254187 TI - Transcriptomic pathway analysis of urokinase receptor silenced breast cancer cells: a microarray study. AB - Urokinase plasminogen activator receptor (PLAUR) has been implicated in a variety of physiological and pathological conditions. The multi-functionality of PLAUR is due to its capacity to interact with many co-receptors to regulate extracellular proteolysis and intracellular signaling. Recent reports are identifying novel functions of PLAUR which were not evident in the past; however, the molecular mechanisms of PLAUR signaling are not completely understood. Here, we have compared the transcriptomes of silencing control (sicon) and PLAUR silenced (PLAURsi) MDA-MB-231 breast cancer cells on treatment with radiation. We isolated RNA from the cells, synthesized cDNA and measured the gene expression changes by microarray. We identified 24 downregulated and 53 upregulated genes, which were significantly (P-value < 0.005) affected by PLAUR silencing. Our analysis revealed 415 canonical pathways and 743 causal disease networks affected on silencing PLAUR. Transcriptomic changes and predicted pathways supported and consolidated some of the earlier understanding in the context of PLAUR signaling; including our recent observations in DNA damage and repair process. In addition, we have identified several novel pathways where PLAUR is implicated. PMID- 29254188 TI - Molecular characteristics of hepatocellular carcinomas from different age groups. AB - While most patients in Western countries who are diagnosed with HCC are in their 50s and 60s, HCCs diagnosed at extremes of the age spectrum (i.e., < 40 years and >= 75 years) are less common and have been linked with distinct geographic locations and etiologies. Using multiplatform profiling, we identified differences in genetic alterations and protein expression in different age groups within a large cohort of HCC patients (N = 421). Young adult HCC patients (18-39 years' old) were more likely to be female, living in the West and Midwestern United States, and showed decreased androgen receptor, drug resistance and pro angiogenic protein expression compared to older patients. TP53 mutations were the most frequent alteration in young adults (19%), whereas CTNNB1 mutations occurred in 30-33% of patients >= 40 years' old. The overall frequency of pathogenic and presumed pathogenic mutations was observed to increase significantly with advancing age. To our knowledge, these data represent one of the only studies to analyze age-specific molecular profiles in HCC, and provide a basis for further exploration and validation of these findings with respect to their clinical and therapeutic implications. PMID- 29254189 TI - The component formula of Salvia miltiorrhiza and Panax ginseng induces apoptosis and inhibits cell invasion and migration through targeting PTEN in lung cancer cells. AB - Lung cancer still remains the leading cause of cancer-related death worldwide. It is an urgent need for development of novel therapeutic agents to improve current treatment of this disease. Here we investigate whether the effective component formula of traditional Chinese Medicine could serve as new potential therapeutic drugs to treat lung cancer. We optimize the most effective component formula of Salvia miltiorrhiza and Panax Ginseng (FMG), which is composed of Salvianolic acid A, 20(S)-Ginsenoside and Ginseng polysaccharide. We discovered that FMG selectively inhibited lung cancer cell proliferation and induced apoptosis but had no any cytotoxic effects on normal lung epithelial BEAS-2B cells. Moreover, FMG inhibited lung cancer cell migration and invasion. Mechanistically, we found that FMG significantly promoted p-PTEN expression and subsequently inhibited PI3K/AKT signaling pathway. The phosphatase activity of PTEN protein was increased after FMG bound to PTEN protein, indicating that PTEN is one of the FMG targeted proteins. In addition, FMG regulated expression of some marker proteins relevant to cell apoptosis, migration and invasion. Collectively, these results provide mechanistic insight into the anti-NSCLC of FMG by enhancing the phosphatase activity of PTEN, and suggest that FMG could be as a potential option for lung cancer treatment. PMID- 29254190 TI - Mutation spectrum of Chinese patients with Bartter syndrome. AB - Objective: Bartter syndrome (BS) has been rarely reported in Chinese population except for a few case reports. This investigation was aimed to analyze the mutations of the causal genes in sixteen Chinese patients with BS, and review their followup and treatment. Methods: Identify mutations by the next generation sequencing and the multiplex ligation-dependent probe amplification (MLPA). Clinical characteristics and biochemical findings at the first presentation as well as follow-up were reviewed. Results: 15 different CLCNKB gene mutations were identified in fourteen patients with BS, including 11 novel ones. A novel missense mutation and a novel small deletion were found from SLC12A1 gene. A novel gross deletion was found in CLCNKA gene. A recurrent missense mutation was identified from BSND gene. We found that the whole gene deletion mutation of CLCNKB gene was the most frequent mutation (32%), and the rate of gross deletion was up to 50 percent in this group of Chinese patients. Conclusion: The present study has found 19 mutations, including 14 novel ones, which would enrich the human gene mutation database (HGMD) and provide valuable references to the genetic counseling and diagnosis of the Chinese population. PMID- 29254191 TI - Propensity score matching analysis of the prognosis for the rare insular subtype of thyroid cancer based on SEER database. AB - Insular thyroid carcinoma (ITC) is an uncommon thyroid malignancy with an unclear prognosis. The aim of this study was to determine the prognoses of patients with ITC. We investigated a large cohort of patients with differentiated thyroid cancer from the Surveillance, Epidemiology, and End Results (SEER) database who were registered between 2004 and 2013, and compared the prognosis of patients with ITC to those with classic papillary thyroid cancer (CPTC) and follicular thyroid cancer (FTC). Patient mortality was determined using Kaplan-Meier analyses with log-rank tests, as well as Cox proportional hazards regression analyses. The study cohort comprised of 165 patients with ITC, 5419 patients with FTC, and 60739 patients with CPTC. The rate of cancer-specific mortality per 1000 person-years for ITC was higher than that for CPTC or FTC. According to multivariate Cox regression analysis, however, the cancer-specific and all-cause mortality rates of ITC were similar to those of CPTC and FTC. The cancer-specific survival rate in patients with ITC was higher than that in patients with CPTC, but similar to that in patients with FTC, after adjusting for potentially influencing factors using propensity score matching analysis. These findings, which contrast with previously published data, provide new implications for the treatment of patients with ITC. PMID- 29254192 TI - Inhibition of coiled coil domain containing protein 69 enhances platinum-induced apoptosis in ovarian cancer cells. AB - Cisplatin is a platinum-based drug that is used for the treatment of human gynecological cancers. However, molecular mechanisms of chemo-resistance in ovarian cancer are poorly understood. The aim of the study is to examine the role of coiled coil domain containing protein 69 (CCDC69) in the underlying mechanism of chemoresistance. Heavy CpG methylation (73.1% and 74.3%) was found in A2780 and A2780cis cells assessing by bisulfite sequencing. Restoration in the expression of CCDC69 was found in A2780 and A2780cis cells after 5-Aza-dC treatment. In fact, the expression levels of CCDC69 were about 3-4 fold higher in cisplatin-resistant A2780cis cells than its parental cisplatin-sensitive A2780 cells. When knockout CCDC69 in cisplatin-resistant A2780cis and SKOV3 cells by CRISPR/Cas9, the CCDC69 knockout cisplatin-resistant A2780cis and CCDC69 knockout SKOV3 cells were also shown increased sensitive to cisplatin treatment. Moreover, treating CCDC69 knockout A2780cis cells with cisplatin, abrogated G1 and G2/M arrest, increased of cleaved caspase 3&8, greater DeltaPsim loss and higher levels of Bax were observed. When restoring CCDC69 expression in CCDC69 knockout A2780cis cells by transient transfection, it attenuated sensitivity to cisplatin. By immunoblotting, we found that depletion of CCDC69 increased p53 acetylation at K382 site and Bax mitochondrial redistribution. Additionally, inhibition of c-Myc enhanced cisplatin sensitivities in CCDC69 knockout A2780cis cells, overexpression of c-Myc reduced apoptosis in CCDC69 knockout SKOV3 cells. Our results showed that CCDC69 inhibition might interfere with the effectiveness of combination therapy with platinum drugs. PMID- 29254193 TI - MicroRNA-363 inhibits ovarian cancer progression by inhibiting NOB1. AB - In this study, we investigated the role of microRNA-363(miR-363) in ovarian cancer (OC) progression. MiR-363expression was downregulated in OC patient tissues and four OC cell lines (SKOV3, A2780, OVCAR and HO-8910). Low miR-363 levels were associated with advanced stage, lymph node metastasis, and poor prognosis in OC. MiR-363 overexpression decreased growth, colony formation, migration and invasiveness of SKOV3 cells. In addition, miR-363 overexpression in SKOV3 cells also decreased xenograft tumor size and weight in nude mice. Bioinformatics and dual luciferase reporter assays revealed that miR-363 suppresses expression of NIN1/RPN12 binding protein 1 homolog (NOB1) by binding to the 3'-UTR of its transcript. NOB1 expression inversely correlated with miR 363 levels in OC tissues. Thus miR-363 appears to play a tumor suppressor role in OC by inhibiting NOB1. PMID- 29254194 TI - Cardioprotective properties of N-terminal galanin fragment (2-15) in experimental ischemia/reperfusion injury. AB - Background and purpose: Galanin is an endogenous peptide involved in diverse physiological functions in the central nervous system including central cardiovascular regulation. The present study was designed to evaluate the potential effects of the short N-terminal galanin fragment 2-15 (G) on cardiac ischemia/reperfusion (I/R) injury. Experimental Approach: Peptide G was synthesized by the automatic solid phase method and identified by 1H-NMR spectroscopy and mass spectrometry. Experiments were performed on cultured rat cardiomyoblast (H9C2) cells, isolated perfused working rat hearts and anaesthetized open-chest rats. Key Results: Cell viability increased significantly after treatment with 10 and 50 nM of G peptide. In hypoxia and reoxygenation conditions, exposure of H9C2 cells to G peptide decreased cell apoptosis and mitochondrial reactive oxygen species (ROS) production. Postischemic infusion of G peptide reduced cell membrane damage and improved functional recovery in isolated hearts during reperfusion. These effects were accompanied by enhanced restoration of myocardial metabolic state. Treatment with G peptide at the onset of reperfusion induced minor changes in hemodynamic variables but significantly reduced infarct size and plasma levels of necrosis markers. Conclusion and implications: These findings suggest that G peptide is effective in mitigating cardiac I/R injury, thereby providing a rationale for promising tool for the treatment of cardiovascular diseases. PMID- 29254195 TI - Heavy metals and metalloid distribution in different organs and health risk assessment for edible tissues of fish captured from Honghu Lake. AB - Honghu Lake is the seventh largest freshwater lake in China, and fishery is one of the most important economic sources for local inhabitants. Toxic metal concentrations in muscle of all analyzed fish species captured from Honghu Lake were generally below China standards, except Cr in crucian carp. The average concentrations were decreased in the following order, Zn (14.65 mg/kg) > Cr (1.25 mg/kg) > Cu (0.5994 mg/kg) > Pb (0.0884 mg/kg) > Cd (0.0069 mg/kg) > As (0.0007 mg/kg). There was no significant health risk in consuming fish captured from Honghu Lake, based on the analysis results of target hazard quotient (THQ), carcinogenic risk (CR), and estimated weekly intake (EWI). Mixed edible fish tissues consuming brought higher carcinogenic risks than muscle consuming. Pb was regarded as the major contributor of potential non-carcinogenic risk, while As of the potential carcinogenic risk. THQ set the most stringent allowed values of the average consuming amount of fish muscle at 1,316 g/d, while CR set the value of mixed fish tissues at 525 g/d. PMID- 29254196 TI - The expression of cystathionine gamma-lyase is regulated by estrogen receptor alpha in human osteoblasts. AB - Hydrogen sulfide (H2S), generated in the osteoblasts predominantly via cystathionine-gamma-lyase (CSE), is bone protective. Previous studies suggested that the onset of bone loss due to estrogen deficiency is associated to decreased levels of H2S and blunted gene expression of CSE. However, there are still a lot of unknowns on how H2S levels influence bone cells function. The present study aims to explore the mechanisms by which estrogen may regulate CSE expression, in particular the role of estrogen receptor alpha (ERalpha) in human osteoblasts (hOBs). Vertebral lamina derived hOBs were characterized and then assessed for CSE expression by western blot analysis in the presence or absence of ERalpha overexpression. Bioinformatic analysis, luciferase reporter assay and ChIP assay were performed to investigate ERalpha recruitment and activity on hCSE gene promoter. Three putative half Estrogen Responsive Elements (EREs) were identified in the hCSE core promoter and were found to participate in the ERalpha - mediated positive regulation of CSE expression. All osteoblast samples responded to ERalpha over-expression increasing the levels of CSE protein in a comparable manner. Notably, the ERalpha recruitment on the regulatory regions of the CSE promoter occurred predominantly in female hOBs than in male hOBs. The obtained results suggest that CSE/H2S system is in relation with estrogen signaling in bone in a gender specific manner. PMID- 29254197 TI - Apelin13/APJ promotes proliferation of colon carcinoma by activating Notch3 signaling pathway. AB - Background: The link between Apelin (APL)/APL receptor (APJ) and Jagged (JAG)/Notch signaling pathways in colorectal cancer (CRC) has been poorly investigated. APL/APJ system, a potent angiogenic factor, is up-regulated in a variety of cancers. It contributes to tumor angiogenesis, and correlates with progression of malignancy. JAG/Notch signaling also contributes to progression, proliferation and metastasis of multiple cancers, including CRC. Here we tested the hypothesis that APL/APJ system promotes CRC proliferation by up-regulating Notch3, thus allowing further binding of JAG1 to Notch3. Materials and Methods: We used a variety of methods including Western blot, RT-qPCR, gene silencing, ELISA, immunofluorescence staining, to investigate the interaction between APL/APJ system and Notch3 signaling pathway in both surgically-resected specimens and CRC cell line LS180. Results: We show that the expression of APL13, APJ, and Notch3 is elevated in CRC. We further demonstrate that APL13 can be secreted into culture media of LS180 cells, suggesting the existence of autocrine loop in CRC. Moreover, we found that APL13 stimulated expression of Notch3. Finally, we found that inhibition of either APJ or Notch3 prevents proliferation of LS180 cells. Conclusions: Our results suggest that APL13/APJ and JAG1/Notch3 signaling pathways are linked in CRC. These findings provide a new direction to the efforts targeting effective therapeutic and management approaches in the treatment of CRC. PMID- 29254198 TI - Profiling of ribonucleotides and deoxyribonucleotides pools in response to DNA damage and repair induced by methyl methanesulfonate in cancer and normal cells. AB - The absolute and relative pool sizes of deoxyribonucleotides (dRNs) are essential in DNA replication fidelity, DNA damage and repair. We found in this study that although DNA damage induced by methyl methanesulfonate (MMS) seemed similar in cancer (HepG2) and normal (LO2) cells, more extensive alterations in ribonucleotides (RNs) and dRNs pools occurred in HepG2 cells indicating that HepG2 cells were more vigilant to DNA damage. After 10 h repair, RNs pools were still severely perturbed in LO2 cells. Compared to LO2 cells, deoxyribonucleotide triphosphates (dNTPs) pools in HepG2 cells elevated by more folds which could facilitate more efficient DNA repair and improve survival probability following DNA damage, although this should definitely lead to higher mutation rates. DNA repair was more efficient in HepG2 cells at S phase and it partly came to an end while DNA repair was still uncompleted in LO2 cells outside S phase. In conclusion, our results demonstrated that HepG2 and LO2 cells presented many differences in nucleotide metabolism, cell cycle checkpoints and DNA repair pathways in response to DNA damage, which could be potential targets for cancer treatment. PMID- 29254199 TI - NDRG4 promotes myogenesis via Akt/CREB activation. AB - N-Myc downstream-regulated gene 4 (NDRG4) plays an important role in biological processes and pathogenesis, but its function in muscle development is unclear. In this study, we investigated the function of the NDRG4 gene in the regulation of myogenic differentiation. NDRG4 expression is upregulated during muscle regeneration and C2C12 myoblast differentiation. Gain and loss of function studies revealed that NDRG4 dramatically promotes expression of myogenic differentiation factor (MyoD), myogenin (MyoG), and myosin heavy chain (MyHC) genes and myotube formation. Mechanistically, the binding of NDRG4 to carboxyl terminal modulator protein (CTMP) abates the interaction of CTMP and protein kinase B (Akt) and increases the phosphorylation of Akt and cAMP response element binding protein (CREB), which leads to increased expression of myogenic genes. Our results reveal that NDRG4 promotes myogenic differentiation via Akt/CREB activation. PMID- 29254201 TI - Trichostatin A inhibits radiation-induced epithelial-to-mesenchymal transition in the alveolar epithelial cells. AB - Radiation-induced pneumonitis and fibrosis are major complications following thoracic radiotherapy. Epithelial-to-mesenchymal transition (EMT) plays an important role in tissue injury leading to organ fibrosis, including lung. Our previous studies have reported that radiation can induce EMT in the type II alveolar epithelial cells in both in vitro and in vivo. HDAC inhibitors are a new family of anti-cancer agents currently being used in several clinical trials. In addition to their intrinsic anti-tumor properties, HDAC inhibition is also important in other human diseases, including fibrosis and radiation-induced damage. In this study, we evaluated the effect of Trichostatin A (TSA), a HDAC inhibitor, on radiation-induced EMT in type II alveolar epithelial cells (RLE 6TN). Pre-treatment of RLE-6TN cells with TSA inhibited radiation-induced EMT like morphological alterations including elevated protein level of alpha-SMA and Snail, reduction of E-cadherin expression, enhanced phosphorylation of GSK3beta and ERK1/2, increased generation of ROS. Radiation enhanced the protein level of TGF-beta1, which was blocked by N-acetylcysteine, an antioxidant. Treating cells with SB-431542, TGF-beta1 type I receptor inhibitor, diminished radiation-induced alterations in the protein levels of p-GSK-3beta, Snail-1 and alpha-SMA, suggesting a regulatory role of TGF-beta1 in EMT. Pre-incubation of cells with TSA showed significant decrease in the level of TGF-beta1 compared to radiation control. Collectively, these results demonstrate that i] radiation-induced EMT in RLE-6TN cells is mediated by ROS/MEK/ERK and ROS/TGF-beta1 signaling pathways and ii] the inhibitory role of TSA in radiation-induced EMT appears to be due, at least in part, to its action of blocking ROS and TGF-beta1 signaling. PMID- 29254200 TI - Clinical course and outcome of essential thrombocythemia and prefibrotic myelofibrosis according to the revised WHO 2016 diagnostic criteria. AB - The recently revised World Health Organization (WHO) classification of myeloid neoplasms recognizes prefibrotic myelofibrosis (prePMF) as a distinct entity, characterized by well-defined histopathologic features together with minor clinical criteria (leukocytes, anemia, increased LDH, splenomegaly). The aim of the study was to examine the clinical relevance of distinguishing prePMF from essential thrombocythemia (ET). We identified in our database all patients affected with ET, prePMF and primary myelofibrosis (PMF) diagnosed according to 2008 WHO criteria with a bone marrow fibrosis grade 0-1 at diagnosis and one DNA sample to define the mutational status. The bone marrow morphology of all 404 identified patients was reviewed by an expert pathologist and patients were reclassified according to the 2016 WHO criteria. After reclassification, our cohort included 269 ET, 109 prePMF, and 26 myeloproliferative neoplasm unclassificable. In comparison with ET, patients with prePMF had higher leukocyte count, lower hemoglobin level, higher platelet count, higher LDH values, and higher number of circulating CD34-positive cells; they showed more frequently splenomegaly (all P values < .001). CALR mutations were more frequent in prePMF than in ET (35.8% vs 17.8%, P < .001). PrePMF patients had shorter overall survival (P < .001) and a trend to a higher incidence of leukemic evolution (P .067) compared to ET patients, while they did not differ in terms of thrombotic and bleeding complications. In conclusion, ET and prePMF diagnosed according to 2016 WHO criteria are two entities with a different clinical phenotype at diagnosis and a different clinical outcome. PMID- 29254202 TI - MiR-92a promotes stem cell-like properties by activating Wnt/beta-catenin signaling in colorectal cancer. AB - We previously reported the oncogenic function of miR-92a in colorectal cancer. This study identified that miR-92a was upregulated in chemoresistant colorectal cancer cells and tissues. Ectopic expression of miR-92a conferred resistance to 5 fluorouracil-induced apoptosis in vitro, while antagomiR-92a significantly enhanced chemosensitivity in vivo. Moreover, Overexpression of miR-92a promoted the tumor sphere formation and the expression of stem cell markers. MiR-92a overexpression also displayed higher tumourigenesis in vivo. Furthermore, we demonstrated that miR-92a upregulates the Wnt/beta-catenin signaling activity via directly targeting KLF4, GSK3beta and DKK3, which are multiple level negative regulators of the Wnt/beta-catenin signaling cascade. In addition, our results indicate IL-6/STAT3 pathway increases miR-92a expression by directly targeting its promoter, resulting in Wnt/beta-catenin signaling activation and consequent promotion of stem-like phenotypes of colorectal cancer cells. Our present results suggest the essential role of IL-6/STAT3/miR-92a/Wnt/beta-catenin pathway in regulating the stem cell-like traits of colorectal cancer cells and provide a potential target for colorectal cancer therapy. PMID- 29254203 TI - Inhibition of STAT3/VEGF/CDK2 axis signaling is critically involved in the antiangiogenic and apoptotic effects of arsenic herbal mixture PROS in non-small lung cancer cells. AB - Despite the antitumor effects of asrsenic trioxide (As2O3), tetraarsenic hexoxide (As4O6 or PR) and tetraarsenic tetrasulfide (As4S4) in several cancers, their adverse poisoning, toxicity and resistance are still hot issues for effective cancer therapy. Here, antitumor mechanism of arsenic herbal mixture PROS including PR and OS (Oldenlandia diffusa and Salvia miltiorrhiza extract) was elucidated in non-small cell lung cancer cells (NSCLCs), since PR alone showed resistant cytotoxicity in NSCLCs compared to other cancers. PROS exerted significant cytotoxicity, induced sub-G1 phase and S phase arrest, increased apoptotic bodies, and attenuated the expression of pro-PARP, Bcl-2, Cyclin E, Cyclin A, CDK2, E2F1, p-Src, p-STAT3, p-ERK, p-AKT, COX-2 and SOCS-1 in A549 and H460 cells along with disrupted binding of STAT3 with CDK2 or VEGF. Notably, PROS inhibited VEGF induced proliferation, migration and tube formation in HUVECs and suppressed angiogenesis in chorioallantoic membrane (CAM) assay via reduced phosphorylation of VEGFR2, Src and STAT3. Consistently, PROS reduced the growth of H460 cells implanted in BALB/c athymic nude mice via inhibition of STAT3, and VEGF and activation of caspase 3. Overall, these findings suggest that PROS exerts antiangiogenic and apoptotic effects via inhibition of STAT3/ VEGF/ CDK2 axis signaling as a potent anticancer agent for lung cancer treatment. PMID- 29254204 TI - Metformin prevents peritendinous fibrosis by inhibiting transforming growth factor-beta signaling. AB - Injury-induced peritendinous adhesion is a critical clinical problem that leads to tendon function impairment. Therefore, it is very urgent to explore potential approaches to attenuate peritendinous adhesion formation. Recently, several studies have demonstrated the biological effect of metformin in inhibiting multiple tissue fibrosis. In this study, we performed in vitro and in vivo experiments to examine whether metformin prevents injury-induced peritendinous fibrosis. We found that tendon injury induced severe fibrosis formation in rats. However, orally administered metformin significantly alleviated the fibrosis based on macroscopic and histological evaluation. Peritendinous tissue from metformin-treated rats also showed decreased expression of fibrotic genes including col1a1, col3a1, and alpha-smooth muscle actin (alpha-SMA), and inhibition of transforming growth factor (TGF)-beta1 signaling. The cell counting kit (CCK)-8, flow cytometry, and 5-ethynyl-2'-deoxyuridine (EdU) staining analyses showed that treatment of NIH/3T3 fibroblasts with metformin significantly inhibited excessive cell proliferation and promoted cell apoptosis. Metformin treatment also inhibited the expression of fibrotic genes and decreased the phosphorylation of smad2/3 and extracellular signal-regulated kinase (ERK) 1/2. Furthermore, blocking AMP-activated protein kinase (AMPK) signaling abolished the inhibitory effect of metformin on fibrosis. Our findings indicate that metformin has a protective role against peritendinous tissue fibrosis and suggest its clinical use could be a promising therapeutic approach. PMID- 29254205 TI - An important discovery on combination of irreversible electroporation and allogeneic natural killer cell immunotherapy for unresectable pancreatic cancer. AB - Purpose: To study the safety and clinical efficacy on combination of irreversible electroporation and allogeneic natural killer cell therapy for treating Stage III/IV pancreatic cancer, evaluating median progression free survival (PFS), and overall survival (OS). Results: Adverse events of all patients were limited to grades 1 and 2, including local (mainly tussis 13.4%, nausea and emesis 7.1%, pain of puncture point 29.6% and duodenum and gastric retention 4.3%) and systemic (mainly fatigue 22.3%, fever 31.6%, and transient reduction of intraoperative blood pressure 25.1% and white cell count reduction 18.3%) reactions, fever was the most frequent. The serum amylase level at 24 h and 7 d after IRE was not significantly changed compared to those before IRE (P > 0.05). CA19-9 value was lower in IRE-NK group than in IRE at 1 month after treatment (P < 0.05). After a median follow-up of 7.4 months (3.6-11.2 months): in stage III group, median PFS was higher in IRE-NK group (9.3 months) than in IRE group (8.1 months, P = 0.0465), median OS was higher in IRE-NK (13.2 months) than in IRE (11.4 months, P = 0.0411), and median PFS was higher in who received multiple NK than single NK (9.8 months vs.8.1 months, P = 0.0423, respectively), median OS who received multiple NK was higher than single NK (13.9 months vs.12.3 months, P = 0.0524, respectively), the RR in IRE-NK (63.2%) was higher than in IRE (50.0%, P < 0.05); in stage IV group, median OS was higher in IRE-NK (9.8 months) than in IRE (8.7 months, P = 0.0397), the DCR in IRE-NK (66.7%) was higher than in IRE (42.9%, P < 0.05). Materials and Methods: Between July 2016 and May 2017, we enrolled 71 patients who met the enrollment criteria. The patients were divided into stage III (32 patients, 17 patients received only IRE and 15 patients received IRE-NK (Irreversible electroporation- natural killer): 8 patients underwent a course of NK and 7 patients underwent >= 3 courses) and stage IV (39 patients, 22 patients received only IRE and 17 patients received IRE-NK: 9 patients underwent a course of NK and 8 patients underwent >= 3 courses). The safety and short-term effects were evaluated firstly, then the median PFS, median OS, response rate (RR) and disease control rate (DCR) were assessed. Conclusions: Combination of irreversible electroporation and allogeneic natural killer cell immunotherapy significantly increased median PFS and median OS in stage III pancreatic cancer and extended the median OS of stage IV pancreatic cancer. Multiple allogeneic natural killer cells infusion was associated with better prognosis to stage III pancreatic cancer. PMID- 29254207 TI - Treatment outcomes regarding the addition of targeted agents in the therapeutic portfolio for stage II-III rectal cancer undergoing neoadjuvant chemoradiation. AB - Background: To evaluate the impact of targeted agents in stage II-III rectal cancer undergoing neoadjuvant concurrent chemoradiation therapy (CCRT). Method: A retrospective study was performed in 124 consecutive patients with clinically T3N0-2M0-staged rectal cancer incorporating targeted agents in CCRT. Results: Pathologic complete response was detected in 34.2% (n=26) of bevacizumab+FOLFOX treated patients (n=76), which was significantly higher (p=0.019, post-hoc statistical power =35.87%) than that (n=10, 20.8%) of the cetuximab+FOLFOX treated patients (n=48). Patients receiving cetuximab+FOLFOX therapy tended to develop severe liver toxicity (91.7%, n=44 versus 17.1%, n=13, p<0.0001), as evaluated by morphologic grading of hepatic steatosis and sinusoidal dilatation in laparoscopy. In the 57 patients with morphologically severe liver toxicity, 36 (63.2%) retained a normal liver function; for the remaining 21 patients with an abnormal liver function, the abnormality was self-limited in 19 patients, whereas 2 cetuximab-treated patients progressed to hepatic failure and mortality. A subset analysis within bevacizumab+FOLFOX-treated patients with either wild-type (n=36) or mutant (n=40) K-ras status indicated K-ras status did not significantly influence the treatment outcomes. Conclusions: The addition of bevacizumab instead of cetuximab to FOLFOX in the neoadjuvant settings for T3N0-2M0-staged rectal cancer could induce a promising rate of pathologic complete response and lesser hepatotoxicity. PMID- 29254208 TI - VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim. AB - The PI3K/mTOR/AKT pathway is an integral regulator of survival and drug resistance in multiple myeloma (MM). VS-5584 was synthesized with dual-specific and equipotent activity against mTORC1/2 and all four Class I PI3K isoforms so as to durably inhibit this pathway. We show that VS-5584 is highly efficacious against MM cell lines even in the presence of IL-6 and IGF-1 and that this growth inhibition is partially dependent on Bim. Importantly, VS-5584 triggers apoptosis in patient cells with a favorable therapeutic index. Gene expression profiling revealed a VS-5584-induced upregulation of RARRES3, a class II tumor suppressor gene. MM patient databases, UAMS and APEX, show that RARRES3 is under-expressed in 11q13 subsets which correlates with the reduced effectiveness of VS-5584 in 11q13 cell lines. Silencing RARRES3 expression significantly rescues VS-5584 induced cell death and increases cyclin D2 expression but not cyclin D1 or other cyclins implying a role for RARRES3 in cell cycle arrest. In vivo, VS-5584 significantly reduces the tumor burden of MM mouse xenografts. We further identified that VS-5584 synergised with Dexamethasone, Velcade, and exceptionally so with HDAC inhibitor, Panobinostat. Interestingly, this was consistently observed in several patient samples, proposing a promising novel clinical strategy for combination treatment especially in relapsed/refractory patients. PMID- 29254206 TI - Oncogenomics of c-Myc transgenic mice reveal novel regulators of extracellular signaling, angiogenesis and invasion with clinical significance for human lung adenocarcinoma. AB - The c-Myc transcription factor is frequently deregulated in cancers. To search for disease diagnostic and druggable targets a transgenic lung cancer disease model was investigated. Oncogenomics identified c-Myc target genes in lung tumors. These were validated by RT-PCR, Western Blotting, EMSA assays and ChIP seq data retrieved from public sources. Gene reporter and ChIP assays verified functional importance of c-Myc binding sites. The clinical significance was established by RT-qPCR in tumor and matched healthy control tissues, by RNA-seq data retrieved from the TCGA Consortium and by immunohistochemistry recovered from the Human Protein Atlas repository. In transgenic lung tumors 25 novel candidate genes were identified. These code for growth factors, Wnt/beta-catenin and inhibitors of death receptors signaling, adhesion and cytoskeleton dynamics, invasion and angiogenesis. For 10 proteins over-expression was confirmed by IHC thus demonstrating their druggability. Moreover, c-Myc over-expression caused complete gene silencing of 12 candidate genes, including Bmp6, Fbln1 and Ptprb to influence lung morphogenesis, invasiveness and cell signaling events. Conversely, among the 75 repressed genes TNFalpha and TGF-beta pathways as well as negative regulators of IGF1 and MAPK signaling were affected. Additionally, anti angiogenic, anti-invasive, adhesion and extracellular matrix remodeling and growth suppressive functions were repressed. For 15 candidate genes c-Myc dependent DNA binding and transcriptional responses in human lung cancer samples were confirmed. Finally, Kaplan-Meier survival statistics revealed clinical significance for 59 out of 100 candidate genes, thus confirming their prognostic value. In conclusion, previously unknown c-Myc target genes in lung cancer were identified to enable the development of mechanism-based therapies. PMID- 29254209 TI - Long noncoding RNA PVT1 inhibits renal cancer cell apoptosis by up-regulating Mcl 1. AB - Long non-coding RNA plasmacytoma variant translocation 1 (PVT1) is up-regulated in various human cancers, and our results indicated that PVT1 was up-regulated in clear cell renal cell carcinoma tissues. The Cancer Genome Atlas cohort analysis revealed that in clear cell renal cell carcinoma, higher PVT1 expression correlated with advanced TNM stage, histological grade, and poor survival. PVT1 knockdown promoted apoptosis, inhibited renal cancer cell proliferation, decreased Mcl-1, and increased cleaved caspase-3 and cleaved PARP. PVT1 increased Mcl-1 mRNA levels in renal cancer cells by promoting mRNA stability without influencing its transcription. in vitro, the enhanced apoptosis arising from PVT1 suppression was attenuated by overexpressing Mcl-1. In addition, in vivo experiments showed that PVT1 knockdown repressed xenograft tumor growth, while Mcl-1 overexpression partially rescued xenograft tumor growth. These results indicate the PVT1/Mcl-1 pathway inhibits renal cancer cell apoptosis in vitro and in vivo. PVT1 may thus serve as a novel biomarker, and the PVT1/Mcl-1 pathway may be a useful therapeutic target for clear cell renal cell carcinoma. PMID- 29254210 TI - Up-regulation of RNF187 induces hepatocellular carcinoma cell epithelial to mesenchymal transitions. AB - Ring finger protein 187 (RNF187) has been identified to be a co-activator linking c Jun to Ras signaling. However, the expression and function of RNF187 in hepatocellular carcinomas (HCC) remains unclear. Here, we tried to determine the expression and roles of RNF187 in hepatocellular carcinomas (HCC).The expression of RNF187 was determined in HCC tissues and cell lines, and we found that RNF187 expressed highly in HCC tissues compared with the corresponding adjacent liver tissues both in mRNA and protein level, which was consistent with the result of immunohistochemistry on HCC tissue microarrays. In HCC cell lines, the level of RNF187 was positively associated with the HCC cells metastatic potential. By the RNF187 interference and cDNA transfection, we showed that the high level of RNF187 induced the HCC cells invasion and metastasis both in vitro and in vivo, as well as the high ability of colony formation.Mechanistically, we detected the high level of RNF187 promoted cell scatter by inducing epithelial-mesenchymal transition (EMT). Clinically, the high level of RNA187 was significantly correlated with a malignant phenotype, including larger tumor size, multiple tumors, and microvascular invasion. Importantly, high level of RNF187 correlated with HCC patients' shorter OS and lower disease free survival rates than those with low level of RNF187. Our results revealed that elevated expression of RNF187 induced hepatocellular carcinoma cell epithelial to mesenchymal transitions, and represented a novel marker for predicting the poor prognosis of HCC. PMID- 29254211 TI - Multiplexed targeted mass spectrometry assays for prostate cancer-associated urinary proteins. AB - Biomarkers for effective early diagnosis and prognosis of prostate cancer are still lacking. Multiplexed assays for cancer-associated proteins could be useful for identifying biomarkers for cancer detection and stratification. Herein, we report the development of sensitive targeted mass spectrometry assays for simultaneous quantification of 10 prostate cancer-associated proteins in urine. The diagnostic utility of these markers was evaluated with an initial cohort of 20 clinical urine samples. Individual marker concentration was normalized against the measured urinary prostate-specific antigen level as a reference of prostate specific secretion. The areas under the receiver-operating characteristic curves for the 10 proteins ranged from 0.75 for CXL14 to 0.87 for CEAM5. Furthermore, MMP9 level was found to be significantly higher in patients with high Gleason scores, suggesting a potential of MMP9 as a marker for risk level assessment. Taken together, our work illustrated the feasibility of accurate multiplexed measurements of low-abundance cancer-associated proteins in urine and provided a viable path forward for preclinical verification of candidate biomarkers for prostate cancer. PMID- 29254213 TI - Gendermetrics of cancer research: results from a global analysis on lung cancer. AB - Background: Cancer research is critically dependent on a continuous recruitment of junior research staff that devotes its academic life not only to clinical duties but also to basic and translational research. The present study aims to elucidate the success concerning gender equality in cancer research in the last decade (from 2008 to 2016) with lung cancer as the target parameter. Materials and Methods: On the basis of the Gendermetrics Platform, a total of 19,724 articles related to lung cancer research were analyzed. The key method was the combined analysis of the proportion of female authorships and the female-to-male odds ratio for first, co- and last authorships. The distribution of prestigious authorships was measured by the Prestige Index. Results: 31.3% of all authorships and 35.2% of the first, 32.2% of the co- and 22.1% of the last authorships were held by women. The corresponding female-to-male odds ratio is 1.22 (CI: 1.18 1.27) for first, 1.19 (CI: 1.16-1.23) for co- and 0.59 (CI: 0.57-0.61) for last authorships. Women are underrepresented at prestigious authorships compared to men (Prestige Index = -0.22). The female underrepresentation accentuates in articles with many authors that attract the highest citation rates. Conclusions: While the current system promotes early career promotion of women, men still outnumber women in leadership positions. However, this male-female career dichotomy has been narrowed in the last decade and will likely be further reduced in the next decade. PMID- 29254212 TI - Long noncoding RNA TUG1 is a diagnostic factor in lung adenocarcinoma and suppresses apoptosis via epigenetic silencing of BAX. AB - Lung cancer is one of the leading causes of cancer-related mortality, and responds badly to existing treatment. Thus, it is of urgent need to identify novel diagnostic markers and therapeutic targets. Increasing evidences have indicated that long non-coding RNAs (lncRNAs) play an important role in initiation and progression of lung cancer. However, the role of lncRNA Taurine upregulated 1 (TUG1) in lung adenocarcinoma (LAD) progression is not well known. In this study, we determined the diagnostic value of TUG1 in LAD patients, and further uncovered the underlying functional mechanism. Our results showed that TUG1 was significantly upregulated in LAD cells and serum samples. Receiver operator characteristic (ROC) analysis suggested a relatively higher area under the curve (AUC) of TUG1 (0.756) contrast to cyfra21-1 (0.619). In addition, high TUG1 level was associated with enhanced tumor size, degree of differentiation, lymph node metastases, distant metastasis and TNM stage. Cell functional assays showed that knockdown of TUG1 suppressed LAD cell viability and promoted cell apoptosis. We then sought to reveal the underlying regulatory mechanism, and the pro-apoptotic protein BAX was then identified as the downstream target of TUG1. Gain and loss functional assays showed that inhibition of BAX reversed the induced apoptosis by TUG1 knockdown. Finally, RNA immunoprecipitation and Chromatin immunoprecipitation revealed that TUG1 suppressed BAX expression through physically interacting with EZH2. In conclusion, lncRNA TUG1 is a promising diagnostic marker for LAD patients and suppression of TUG1 levels could be a future direction to promote the prognosis of LAD patients. PMID- 29254214 TI - Aberrant expression of translationally controlled tumor protein (TCTP) can lead to radioactive susceptibility and chemosensitivity in lung cancer cells. AB - Translationally controlled tumor protein (TCTP) is an evolutionally highly conserved protein which has been implicated as a biomarker for cancer cell reversion although the mechanism is not very clear. This makes it a potential target for cancer therapy. P53 tumor suppressor protein is important in regulating cell growth, it can induce either growth arrest or programmed cell death (apoptosis). TCTP and P53 has been reported that can regulate the protein level of each other. Here we proved that TCTP is a malignancy state keeper in lung cancer and lower level of TCTP protein made cells more sensitive to stressful condition. No obvious difference has been observed from wildtype and the TCTP knockdown lung cancer cells (A549) when located in the normal circumstances. While under the stressful condition, the existence of higher protein level of TCTP can protect cells from apoptosis. TCTP and P53 formed a feedback signal pathway and through it to regulate the downstream Akt signal pathways to make the lung cancer cells keep a higher metabolism level and protect cancer cells from apoptosis induced by outside stress. PMID- 29254215 TI - Genetic polymorphisms in the ALDH2 gene and the risk of ischemic stroke in a Chinese han population. AB - Background: Previous studies have shown that aldehyde dehydrogenase 2 (ALDH2) plays a role in ischemic stroke progression. In recent years, the activation of the ALDH2 pathway have been reported serving as a useful index in the identification of stroke-prone participants, and the ALDH2 pathway may be a potential target for the therapeutic intervention in ischemic stroke. Materials and Methods: We evaluated six tagging single-nucleotide polymorphisms (SNPs) of the ALDH2 gene in a case-control study from Hainan of China (488 cases, 503 controls). We used SPSS version 17.0 statistical software, Excel software and other analysis software to explore associations between SNPs and the risk of ischemic stroke various genetic models (additive, dominant, and recessive). Results: Through statistical analysis, we found that ALDH2 rs886205 [odds ratio (OR) = 6.39; 95% confidence interval (CI) = 1.19-34.38; p = 0.03] and rs7296651 (OR = 9.29; 95% CI = 1.37-63.21; p = 0.02) were associated with increased risk of ischemic stroke in recessive model analysis. In addition, we established that the "AA" genotype (OR = 5.99; 95% CI = 1.11-32.23; p = 0.037) for rs886205 and the "AA" genotype (OR = 8.93; 95% CI = 1.31-60.78; p = 0.025) for rs7296651 were associated with increased ischemic stroke risk. Conclusions: Our results provide evidence that variants of ALDH2 gene polymorphisms influence the risk of developing ischemic stroke in Han Chinese population. PMID- 29254216 TI - Novel characteristics of alpha-fetoprotein (AFP)-producing gastric cancer. AB - Background: Although serum AFP level is increased in the AFP-producing gastric cancer (GC) patient, AFP-producing GC may become recurrent without re-elevation of serum AFP level. Therefore, novel characteristics of AFP-producing GC such as other biomarkers are to be explored. Results: 35 AFP-GC and 48 non-AFP-GC patients were included. Our present study revealed that blood type O (15 cases, 42.8%) and A (18 cases, 37.5%) were predominantly observed among AFP-GC and non AFP-GC patients, respectively. Intriguingly, the least consistently was blood type AB (8.5%, 14.6%). Among AFP-GC patients, pre-operative serum AFP levels were weakly and reversely associated with pre-operative percentage of lymphocytes in the peripheral blood (R2 = 0.1556). The level of alkaline phosphatase (ALP) was highly correlated with the level of lactate dehydrogenase (LDH) (R2 = 0.6682) and CEA (R2 = 0.6813). The level of CEA was moderately correlated with the level of LDH (R2 = 0.3903). By contrast, no any associations between ALP, LDH, CEA, AFP, and peripheral lymphocytes were observed among those 48 non-AFP-GC patients. Materials and Methods: Retrospective analysis was carried out for 2773 inpatients of gastric cancer from January 2012 to November 2016 in the Second Affiliated Hospital of Zhejiang University School of Medicine. Conclusions: The aggressive biological features of AFP-producing GC are closely associated with abnormality of other tumor biomarkers and decrease of the proportion of peripheral lymphocytes, implying that post-operative increase of peripheral lymphocytes might benefit GC patients. Combined use of multiple biomarkers is of significance in comprehensive evaluation of AFP-producing GC patients and assessment for those with high risk of cancer recurrence. PMID- 29254217 TI - Genipin suppresses colorectal cancer cells by inhibiting the Sonic Hedgehog pathway. AB - Genipin, a major component of Gardenia jasminoides Ellis fruit, has been shown to inhibit the growth of gastric, prostate, and breast cancers. However, the anti proliferative activity of genipin in colorectal cancer (CRC) has not been characterized. Herein, we demonstrated that genipin inhibits the proliferation of CRC cells and that genipin suppressed the Hedgehog pathway. Further investigation showed that p53 and NOXA protein levels were increased during inhibition of Hedgehog pathway-mediated apoptosis in CRC cells. We also showed that p53 modulated the expression of NOXA during genipin-induced apoptosis, and suppression via SMO also played a role in this process. Subsequently, GLI1 was ubiquitinated by the E3 ligase PCAF. In a xenograft tumor model, genipin suppressed tumor growth, which was also associated with Hedgehog inactivation. Taken together, these results suggest that genipin induces apoptosis through the Hedgehog signaling pathway by suppressing p53. These findings reveal a novel regulatory mechanism involving Hedgehog/p53/NOXA signaling in the modulation of CRC cell apoptosis and tumor-forming defects. PMID- 29254219 TI - LncRNA MALAT1 acts as an oncogene in multiple myeloma through sponging miR-509-5p to modulate FOXP1 expression. AB - Previous studies showed that Metastasis associated lung adenocarcinoma transcript 1(MALAT1) acted as an oncogene in Multiple Myeloma (MM). However, the underlying mechanism of MALAT1 in MM remains unclear. Quantitative real time-PCR(qRT-PCR) was used to determine MALAT1 expression in MM samples and cell lines. in vitro function assays were used to determine the function of MALAT1 on MM cells. Bioinformatics tools were used to predict the targets of MALAT1 and miR-509-5p, respectively. Furthermore, rescue experiments were performed to further confirm the regulation of miR-509-5p by MALAT1. In the present study, our data showed that MALAT1 expression was upregulated in MM samples and cell lines. In function assays, we confirmed that MALAT1 inhibition significantly suppressed cells proliferation, induced cells apoptosis, arrested cells in G1/S phase, and inhibited MM cells growth in vivo. Furthermore, MALAT1 was identified to function as a competitive endogenous RNA (ceRNA) for miR-509-5p to promote MM cell viability. Additionally, our results suggested that miR-509-5p targeted the 3' UTR of FOXP1 to suppress MM cells progression. Meanwhile, our results showed that miR-509-5p inhibitors significantly abrogated the decreased expression of FOXP1 induced by MALAT1 suppression, indicating that MALAT1 could positively regulate FOXP1 expression by sponging miR-509-5p. Our findings suggested that MALAT1/miR 509-5p/FOXP1 axis was one of the key signalings in mediating MM cell growth, and further indicated that MALAT1 could act as a novel diagnostic marker and therapeutic target for the treatment of MM. PMID- 29254218 TI - Tomentodione M sensitizes multidrug resistant cancer cells by decreasing P glycoprotein via inhibition of p38 MAPK signaling. AB - In this study, we investigated the mechanism by which tomentodione M (TTM), a novel natural syncarpic acid-conjugated monoterpene, reversed multi-drug resistance (MDR) in cancer cells. TTM increased the cytotoxicity of chemotherapeutic drugs such as docetaxel and doxorubicin in MCF-7/MDR and K562/MDR cells in a dose- and time-dependent manner. TTM reduced colony formation and enhanced apoptosis in docetaxel-treated MCF-7/MDR and K562/MDR cells, and it enhanced intracellular accumulation of doxorubicin and rhodamine 123 in MDR cancer cells by reducing drug efflux mediated by P-gp. TTM decreased expression of both P-gp mRNA and protein by inhibiting p38 MAPK signaling. Similarly, the p38 MAPK inhibitor SB203580 reversed MDR in cancer cells by decreasing P-gp expression. Conversely, p38 MAPK-overexpressing MCF-7 and K562 cells showed higher P-gp expression than controls. These observations indicate that TTM reverses MDR in cancer cells by decreasing P-gp expression via p38 MAPK inhibition. PMID- 29254220 TI - Expression of PD-1/PD-L1 and PD-L2 in peripheral T-cells from non-small cell lung cancer patients. AB - Binding of programmed death-1 (PD-1) with its ligands (PD-L1/2) transmits a co inhibitory signal in activated T-cells that promotes T-cell exhaustion, leading to tumor immune evasion. The efficacy of antibodies targeting PD-1 and PD-L1 has led to a paradigm shift in lung cancer treatment but the prognostic and predictive value of tumor PD-L1 expression remains controversial. Evaluating PD 1, PD-L1/2 expression in peripheral blood cells may serve as a potential biomarker for prognosis and response to therapy. In this prospective observational study, plasma cytokine levels and PD-1, PD-L1 and PD-L2 expression was evaluated in circulating CD3+, CD3+CD4+ and CD3+CD8+ cells from 70 treatment naive patients with advanced NSCLC (Stage IIIB and IV) and from 10 healthy donors. The primary objective was to assess OS according to PD-1, PD-L1, PD-L2 expression status on PBMCs and lymphocyte subsets. Our results indicate that the percentage of PD-L1+CD3+, PD-L1+CD3+CD8+ PD-L2+PBMCs, PD-L2+CD3+, PD-L2+CD3+CD4+ cells was higher in patients than in healthy donors. Survival was decreased among patients with a high percentage of either PD-1+PBMCs, PD-1+CD3+, PD-L1+CD3+, PD L1+CD3+CD8+, PD-L2+CD3+, PD-L2+CD3+CD4+, or PD-L2+CD3+CD8+ cells. IL-2 and TNF alpha showed the strongest association with PD-L1 and PD-L2 expression on specific subsets of T-lymphocytes. Our findings suggest that increased PD-1/PD L1/PDL-2 expression in PBMCs, particularly in T-cells, may be an additional mechanism leading to tumor escape from immune control. This study is registered with ClinicalTrials.gov, number NCT02758314. PMID- 29254221 TI - Long non-coding RNA00364 represses hepatocellular carcinoma cell proliferation via modulating p-STAT3-IFIT2 signaling axis. AB - The effects of long non-coding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) remain largely unclear. In this study, we identified an interferon (IFN)-gamma induced LncRNA, LncRNA00364, in HCC by microarray. LncRNA00364 displays lower expression in HCC tumor samples compared to paired normal controls. Overexpression of LncRNA00364 inhibits cell proliferation, G1/S cell cycle progression and promotes apoptosis in HCC cell lines. Consistently, LncRNA00364 overexpression leads to decreased HCC tumor formation in vivo. Mechanistically, LncRNA00364 specifically binds with STAT3, resulting in inhibition of STAT3 phosphorylation and therefore leads to upregulation of IFIT2. In a clinical setting, LncRNA00364 shows an independent prognostic indicator for overall survival and cumulative recurrence in HCC patients, and correlates with IFIT2. Therefore, our study provides new insights into a novel therapeutic avenue targeting the LncRNA00364 signaling axis in HCC. PMID- 29254222 TI - Proteomics and metabolomics analysis of hepatic mitochondrial metabolism in alcohol-preferring and non-preferring rats. AB - Alcohol preference induced tolerance in humans and animals when their bodily functions adapt to compensate for the disruption caused by alcohol consumption. This was thought to be an important component of the genetic predisposition to alcoholism. To investigate the underlying mechanisms of hepatic metabolic tolerance during alcohol preference, the alcohol preferring and alcohol non preferring rats were used in this study. The liver mitochondria were purified for comparative quantitative proteomics analysis, and the liver metabolite extracts were collected for metabolomics analysis. Our study identified 96 differentially expressed hepatic mitochondrial proteins that associated with alcohol preference, the further gene ontology and protein interaction network analysis suggest a down regulation of amino acid metabolism and up-regulation of lipid metabolism. We found alcohol preference induced a series of enzymes decreased (e.g. SSADH and GABA-T) and several amino acids increased (e.g. glutamate and aspartate) in rat liver, indicating down-regulations of glutamate degradation occurred during alcohol preference. Most of these changes were due to the genetic differences between alcohol preferring and non-preferring animals. Furthermore, this study would provided new insights to further clarify the mechanisms of hepatic metabolic tolerance during alcohol preference. PMID- 29254223 TI - Development and validation of a targeted next generation DNA sequencing panel outperforming whole exome sequencing for the identification of clinically relevant genetic variants. AB - Next generation sequencing (NGS) technologies have revolutionized our approach to genomic research. The use of whole genome sequencing (WGS), whole exome sequencing (WES), transcriptome profiling, and targeted DNA sequencing has exponentially improved our understanding of the human genome and the genetic complexities underlying malignancy. Yet, WGS and WES clinical applications remain limited due to high costs and the large volume of data generated. When utilized to address biological questions in basic science studies, targeted sequencing panels have proven extremely valuable due to reduced costs and higher sequencing depth. However, the routine application of targeted sequencing to the clinical setting is limited to a few cancer subtypes. Some highly aggressive tumor types, like type 2 endometrial cancer (EC), could greatly benefit from routine genomic analysis using targeted sequencing. To explore the potential utility of a mid size panel (~150 genes) in the clinical setting, we developed and validated a custom panel against WGS, WES, and another commercially available targeted panel. Our results indicate that a mid size custom designed panel is as efficient as WGS and WES in mapping variants of biological and clinical relevance, rendering higher coverage, at a lower cost, with fewer variants of uncertain significance. Because of the much higher sequencing depth that could be achieved, our results demonstrate that targeted sequencing outperformed WGS and WES in the mapping of pathogenic variants in a breast cancer case, as well as a case of mixed serous and high-grade endometrioid EC, the most aggressive EC subtype. PMID- 29254224 TI - Modifying glycyrrhetinic acid liposomes with liver-targeting ligand of galactosylated derivative: preparation and evaluations. AB - In this study, novel glycyrrhetinic acid (GA) liposomes modified with a liver targeting galactosylated derivative ligand (Gal) were prepared using a film dispersion method. To characterize the samples, particle size, zeta potential, drug loading, and encapsulation efficiency were performed. Moreover, plasma and tissues were pre-treated by liquid-liquid extraction and analyzed by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that the mean residence times (MRTs) and the area under the curve (AUC) of GA liposomes with Gal (Gal-GA-LP), and GA liposomes (GA-LP) were higher than the GA solution (GA-S) in plasma. The tissue (liver) distribution of Gal-GA LP was significantly different in contrast to GA-LP. The relative intake rate (Re) of Gal-GA-LP and GA-LP in the liver was 4.752 and 2.196, respectively. The peak concentration ratio (Ce) of Gal-GA-LP and GA-LP in the liver was 2.796 and 1.083, respectively. The targeting efficiency (Te) of Gal-GA-LP and GA-LP in the liver was 48.193% and 34.718%, respectively. Taken together, the results indicate that Gal-GA-LP is an ideal complex for liver-targeting, and has great potential application in the clinical treatment of hepatic diseases. Drug loading and releasing experiments also indicated that most liposomes are spherical structures and have good dispersity under physiologic conditions, which could prolong GA release efficiency in vitro. PMID- 29254225 TI - Transplantation of bFGF-expressing neural stem cells promotes cell migration and functional recovery in rat brain after transient ischemic stroke. AB - Cerebrovascular disease such as stroke is one of the most common diseases in the aging population, and neural stem cells (NSCs) transplantation may provide an alternative therapy for cerebral ischemia. However, a hostile microenvironment in the ischemic brain offers is challenging for the survival of the transplanted cells. Considering the neuroprotective role of basic fibroblast growth factor (bFGF), the present study investigated whether bFGF gene-modified NSCs could improve the neurological function deficit after transient middle cerebral artery occlusion (MCAO) in adult male Sprague-Dawley rats. These rats were intravenously injected with modified NSCs (5*106/200 MUL) or vehicle 24 h after MCAO. Histological analysis was performed on days 7 and 28 after tMCAO. The survival, migration, proliferation, and differentiation of the transplanted modified C17.2 cells in the brain were improved. In addition, the intravenous infusion of NSCs and bFGF gene-modified C17.2 cells improved the functional recovery as compared to the control. Furthermore, bFGF promoted the C17.2 cell growth, survival, and differentiation into mature neurons within the infarct region. These data suggested that bFGF gene-modified NSCs have the potential to be a therapeutic agent in brain ischemia. PMID- 29254226 TI - CRISPR-ON-Mediated KLF4 overexpression inhibits the proliferation, migration and invasion of urothelial bladder cancer in vitro and in vivo. AB - Kruppel like factor 4 (KLF4), a transcription factor associated with carcinogenesis and tumor progression, plays an important role in various malignancies. In the present study, we utilized the CRISPR-ON system to upregulate KLF4 expression level and subsequently investigated the effect and mechanism of KLF4 in the carcinogenesis and progression of urothelial bladder cancer (UBC). Immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) were used to evaluate the expression of KLF4. The CpG methylation status of the promoter region was analyzed using bisulfite-sequencing PCR (BSP). CRISPR-ON system comprised sgRNA and dCas9 protein combined with a transcriptional activation domain. The cell proliferation and cell cycle were assessed by CCK-8 assay, flow cytometry and colony formation assay. The cell motility ability was evaluated using trans-well assay. In vivo tumorigenesis assay and lung metastasis model were also performed. The KLF4 expression was significantly downregulated in UBC tissues. The high CpG methylation status in the promoter of KLF4 was confirmed using BSP. KLF4 overexpression was successfully achieved via CRISPR-ON system, which inhibited the proliferation and induced G1-phase arrest in T24 cells through the regulation of AKT/p21 signal. Furthermore, enforced expression of KLF4 also abrogated the migration and invasion of T24 cells by suppressing EMT progression. Finally, in vivo models indicated that the upregulation of KLF4 could inhibit tumorigenesis and lung metastasis in nude mice. In conclusion, KLF4 overexpression mediated by CRISPR-ON inhibits tumorigenesis and EMT progression in UBC cells, representing a potential therapeutic target, and CRISPR-ON system could be a therapeutic strategy for UBC in the future. PMID- 29254227 TI - High Tim-3 expression on AML blasts could enhance chemotherapy sensitivity. AB - T-cell immunoglobulin and mucin domain-containing molecule3 (Tim-3) represents a novel mechanism of T-cell dysfunction and exhaustion. Tim-3 has also been identified in various solid tumors. However, the role of Tim-3 expression on blast cells in acute myeloid leukemia (AML) is not well understood. In this study, we aimed to explore the role of Tim-3 in patients with de novo AML, and the correlation between Tim-3 and clinicopathological prognosis. The study cohort consisted of 76 patients with de novo non-M3 AML. These patients' bone marrow samples were collected and then bone marrow mononuclear cells (BMCs) were isolated for flow cytometry to detect Tim-3 expression on blasts. According to FAB type, 76 diagnosed AML patients included in this study were: M0 (n=2), M1 (n=16), M2 (n=20), M4 (n=20), M5 (n=16), and M6 (n=2). A positive expression (>20%) of Tim-3 was found in 87% (66/76) of patients with AML. The average percentage of Tim-3(+) blasts in these AML patients was 58.26 +/- 29.23%. Moreover, the frequency of Tim-3 high expression was higher in M4 patients than that in other AML patients according to FAB type (P=0.004). Tim-3 high expression was also closely associated with inv(16) (P=0.01) and C/EBPA mutation (P=0.03). The mutations of the following six genes, i.e., FLT3-ITD, NPM1, C-KIT, IDH1/IDH2, DNMT3A, were independent of the Tim-3 expression. Additionally, it is more likely to find higher levels of Tim-3 in the low-risk group than in the intermediate- and high-risk groups (P=0.02). The expression of Tim-3 was positively correlated with CD13 (r=0.36, P=0.001), CD34 (r=0.41, P=0.000), and CD7 (r=0.27, P=0.02) in AML patients. AML patients with high Tim-3 expression achieved significantly high complete remission (CR) rate (P=0.01), while their Tim-3 expression significantly decreased after CR (P=0.01). Blockade of Tim-3 expression on AML blasts significantly reduced the Idarubicin (IDA)-mediated suppression of cell growth and reduction of cell apoptosis in vitro. Collectively, our study suggests that high Tim-3 expression on AML blasts could enhances chemotherapy sensitivity. PMID- 29254228 TI - Hypoxia regulates IL-17A secretion from nasal polyp epithelial cells. AB - Hypoxia creates a microenvironment conducive to polypogenesis by regulating immune responses of the nasal polyp (NP) epithelium. We explored the immunocompetence of NP and control epithelial cells in response to hypoxia, to investigate potential relationships with polypogenesis. Three groups of tissue samples were collected: inferior turbinate (IT)and NP from individuals with chronic rhinosinusitis with NPs (CRSwNP), and control IT. A positive relationship was detected between HIF1alpha, HIF2alpha protein expression in epithelial cells and endoscope score in NP samples, while there was a negative correlation between HIF1alpha expression and degree of eosinophil infiltration. Epithelial IL-17A expression was lower in NPs than in IT samples from either controls or patients with CRSwNP. Primary human nasal epithelial cells were cultured under hypoxic or normoxic conditions. Enzyme-linked immunosorbent assays demonstrated decreased IL 17A expression upon prolonged exposure to hypoxia in both IT and NP samples from patients with CRSwNP, while IL-17A increased in control IT epithelial cells; correlation and time-dependency were observed between HIF1alpha and IL-17A expression in both IT and NP samples from patients with CRSwNP. These observations suggest that hypoxia is involved in the pathogenesis of NPs through regulation of IL-17A secretion and HIF1alpha and HIF2alpha expression in the NP epithelium. PMID- 29254229 TI - Reproductive factors as risk modifiers of breast cancer in BRCA mutation carriers and high-risk non-carriers. AB - This study was conducted to identify the role of reproductive factors as environmental modifiers for breast cancer (BC) risk in clinic-based, East-Asian BRCA1 and BRCA2 mutation carriers and non-carriers with high-risk criteria of BRCA mutations (family history (FH) of BC, early-onset BC (aged <=40 years)). A total of 581 women who were BRCA carriers (222 BRCA1 and 359 BRCA2), 1,083 non carriers with FH, and 886 non-carriers with early-onset BC were enrolled and interviewed to examine the reproductive factors, from 2007 to 2014. The hazard ratio (HR) and its 95% confidence interval (CI) in the weighted Cox regression model were used to calculate the BC risk based on the reproductive factors. Earlier menarche increased BC risk by 3.49-fold in BRCA2 mutation carriers (95%CI=2.03-6.00) and 3.30-fold in non-carriers with FH (95%CI=1.73-6.34), but was insignificantly associated with BRCA1 carriers and non-carriers for early onset BC (P-heterogeneity=0.047). Higher parity decreased BC risk in BRCA carriers and non-carriers with FH, especially in BRCA1 carriers (HR=0.27, 95% CI=0.09-0.83 for two parity; and HR=0.23, 95%CI=0.05-1.00 for >=3 parity), but increased the early-onset BC risk (HR=4.63, 95%CI=2.56-8.51 for >3 parity, p heterogeneity=0.045). Oral contraceptive (OC) use and longer estrogen exposure periods (>=30 years) were associated with an increased risk of early-onset BC (HR=3.99, 95%CI=1.65-9.67; HR=7.69, 95%CI=1.96-25.01), while OC use was not associated with BC risk in other groups and longer estrogen exposure had rather decreased risk for BC risk (both p-heterogeneity<0.001). Several reproductive factors as risk modifiers could heterogeneously be associated with BC among BRCA1/2 mutation carriers, non-carriers with FH, and early-onset BC non-carriers. PMID- 29254230 TI - MiR-29b/TET1/ZEB2 signaling axis regulates metastatic properties and epithelial mesenchymal transition in breast cancer cells. AB - MiR-29b has been reported to be both a suppressor and a promoter in breast cancer (BC) cells proliferation and metastasis. Significant efforts have been made to explain the seemingly contradictory effects of miR-29b on BC, but no answer has yet been clearly verified. In this study, we overexpressed and knocked down miR 29b in BC cell lines, modulated expression of its downstream target gene TET1 and downregulated a downstream target gene of TET1, ZEB2, to explore the regulatory mechanism of miR-29b in BC cell proliferation, migration and epithelial mesenchymal transition (EMT). Our results showed lower expression of miR-29b in BC samples and cell lines. Functional assays showed that miR-29b overexpression resulted in a higher cell proliferation, greater colony formation, higher migration rate and EMT. A dual luciferase assay identified TET1 as a direct target of miR-29b. As the promoting effects of miR-29b in the proliferation and metastasis of MDA-MB-231 and MCF-7, knockdown of TET1 also led to increased proliferation, colony formation, invasion and EMT. Further, we found that TET1 bound to the promoter of ZEB2, and siTET1 enhanced ZEB2 expression. Disruption of ZEB2 expression inhibited BC cells proliferation, colony formation and invasion. Our results establish the miR-29b/TET1/ZEB2 pathway in BC cell proliferation, migration and provide a theoretical basis for further research on the molecular mechanisms and new clinical treatments for BC. PMID- 29254231 TI - Proteomic analysis of affinity-purified extracellular proteasomes reveals exclusively 20S complexes. AB - Proteasome-mediated proteolysis is important for many basic cellular processes. In addition to their functions in the cell, proteasomes have been found in physiological fluids of both healthy and diseased humans including cancer patients. Higher levels of these proteasomes are associated with higher cancer burden and stage. The etiology and functions of these proteasomes, referred to as circulating, plasmatic, or extracellular proteasomes (ex-PSs), are unclear. Here we show that human cancer cell lines, as well as human endometrium-derived mesenchymal stem cells (hMESCs), release proteasome complexes into culture medium (CM). To define ex-PS composition, we have affinity purified them from CM conditioned by human leukemia cell line K562. Using matrix-assisted laser desorption/ionization (MALDI) Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry (MS), we have identified core 20S proteasome subunits and a set of 15 proteasome-interacting proteins (PIPs), all previously described as exosome cargo proteins. Three of them, PPIase A, aldolase A, and transferrin, have never been reported as PIPs. The study provides compelling arguments that ex-PSs do not contain 19S or PA200 regulatory particles and are represented exclusively by the 20S complex. PMID- 29254232 TI - Anti-leukemia activity of NSC-743380 in SULT1A1-expressing acute myeloid leukemia cells is associated with inhibitions of cFLIP expression and PI3K/AKT/mTOR activities. AB - Our recent study showed that acute myeloid leukemia (AML) cells expressing SULT1A1 are highly sensitive to NSC-743380, a small molecule that inhibits STAT3 activity and induces SULT1A1-dependent apoptosis of various cancer cell lines. In this study, we characterized the molecular mechanisms of NSC-743380-mediated anti leukemia activity in AML cell lines and antileukemia activity of NSC-743380 in patient-derived primary leukemia cells from AML patients. Our results showed that treatment with NSC-743380 triggered robust apoptosis in SULT1A1-positive AML cells. Treatment with NSC-743380 did not increase intracellular reactive oxygen species or change of STAT3 activity in AML cells, but did dramatically and rapidly decrease cFLIP expression. Proteomic analysis with reverse phase protein microarray revealed that treatment of U937 and THP-1 AML cells with NSC-743380 led to drastic and time-dependent suppression of phosphorylation of several key nodes in the PI3K/AKT/mTOR pathway, including AKT and mTOR. Moreover, primary AML cells expressed SULT1A1 were highly sensitive to treatment with NSC-743380, which was not affected by co-culture with bone marrow mesenchymal stem cells. Thus, our results provide proof-of-concept evidence that AML cells expressing SULT1A1 can be targeted by small molecules that induce apoptosis through inhibiting the expression or activities of multiple targets. PMID- 29254234 TI - Commensal-infected macrophages induce dedifferentiation and reprogramming of epithelial cells during colorectal carcinogenesis. AB - The colonic microbiome contributes to the initiation of colorectal cancer through poorly characterized mechanisms. We have shown that commensal-polarized macrophages induce gene mutation, chromosomal instability, and endogenous transformation through microbiome-induced bystander effects (MIBE). In this study we show that MIBE activates Wnt/beta-catenin signaling and pluripotent transcription factors associated with dedifferentiation, reprogramming, and the development of colorectal cancer stem cells (CSCs). Exposure of murine primary colon epithelial cells (YAMC) to Enterococcus faecalis-infected macrophages increased Wnt3alpha expression while suppressing Wnt inhibitor factor 1 (Wif1). Wnt/beta-catenin activation was confirmed by increased active beta-catenin and Tcf4. in vivo, active beta-catenin was evident in colon biopsies from E. faecalis colonized Il10 knockout mice compared to sham-colonized mice. This effect was mediated, in part, by 4-hydroxy-2-nonenal and tumor necrosis factor alpha. MIBE also activated pluripotent transcription factors c-Myc, Klf4, Oct4, and Sox2 in YAMC cells and colons from E. faecalis-colonized Il10 knockout mice. These transcription factors are associated with cellular reprogramming, dedifferentiation, and induction of colorectal CSC progenitors. In support of this was an increase in the expression of Dclk1 and CD44, two colorectal CSC markers, in YAMC cells that were exposed to MIBE. Finally, compared to normal colon biopsies and hyperplastic polyps, DCLK1 expression increased in human tubular adenomas and invasive colorectal cancers. Blocking beta-catenin/TCF4 signaling using FH535 and CTNNB1-specific small interfering RNA decreased DCLK1 expression in HCT116 human colon cancer cells. These findings provide mechanism for microbiome-induced colorectal cancer and identify new potential targets for colorectal cancer prevention. PMID- 29254233 TI - A core program of gene expression characterizes cancer metastases. AB - While aberrant expression or splicing of metastasis genes conveys to cancers the ability to break through tissue barriers and disseminate, the genetic basis for organ preference in metastasis formation has remained incompletely understood. Utilizing the gene expression profiles from 653 GEO datasets, we investigate whether the signatures by diverse cancers in various metastatic sites display common features. We corroborate the meta-analysis in a murine model. Metastases are generally characterized by a core program of gene expression that induces the oxidative metabolism, activates vascularization/tissue remodeling, silences extracellular matrix interactions, and alters ion homeostasis. This program distinguishes metastases from their originating primary tumors as well as from their target host tissues. Site-selectivity is accomplished through specific components that adjust to the target micro-environment. The same functional groups of gene expression programs are activated in the metastases of B16-F10 cells to various target organs. It remains to be investigated whether these genetic signatures precede implantation and thus determine organ preference or are shaped by the target site and are thus a consequence of implantation. Conceivably, chemotherapy of disseminated cancer might be more efficacious if selected to match the genetic makeup of the metastases rather than the organ of origin by the primary tumor. PMID- 29254235 TI - Prednisone may induce immunologic tolerance by activating the functions of decidual immune cells in early pregnancy. AB - The objective of this study was to investigate alterations in human first trimester decidual immune cells (DICs) and relevant cytokines after treatment with prednisone. Decidual lymphocytes were treated with prednisone alone, cytokines alone or the combination of prednisone and cytokines. Levels of STAT3, STAT5, RORC and FOXP3 mRNA were assayed using quantitative real-time PCR, proportions of CD4+ T helper 17 (Th17) and CD4+ T regulatory (Treg) cells were measured using flow cytometry, and concentrations of interleukin (IL)-17A and IL 10 were determined using enzyme-linked immunosorbent assay. After treatment with prednisone alone, levels of STAT5 and FOXP3 mRNA were significantly higher than in untreated control cells (both P < 0.01), while levels of RORC mRNA were significantly lower than in controls (P < 0.05). Levels of STAT3 mRNA did not vary significantly with treatment. After treatment with prednisone alone, proportions of Th17/CD4+ cells and levels of IL-17A were significantly lower than in control cells, and proportions of Treg/CD4+ cells and levels of IL-10 significantly higher than in controls (all P < 0.01). Our results suggest that prednisone may improve pregnancy outcomes by restoring immunological homeostasis through up-regulation of STAT5 and FOXP3, induction of DIC differentiation into Treg cells, inhibition of DIC differentiation into Th17 cells, reduction of IL 17A secretion and induction of IL-10 secretion. PMID- 29254236 TI - The ubiquitous 'cancer mutational signature' 5 occurs specifically in cancers with deleted FHIT alleles. AB - The FHIT gene is located at the fragile FRA3B locus where activation by carcinogen-induced and endogenous replication stress causes FHIT deletions even in normal cells over a lifetime. Our lab has shown that loss of FHIT expression causes genome instability and provides single-strand DNA substrates for APOBEC3B hypermutation, in line with evidence that FHIT locus deletions occur in many cancers. Based on these biological features, we hypothesized that FHIT loss drives development of COSMIC mutational signature 5 and here provide evidence, including data mining of >6,500 TCGA samples, that FHIT is the cancer-associated gene with copy number alterations correlating most significantly with signature 5 mutation rate. In addition, tissues of Fhit-deficient mice exhibit a mutational signature strongly resembling signature 5 (cosine similarity value = 0.89). We conclude that FHIT loss is a molecular determinant for signature 5 mutations, which occur in all cancer types early in cancer development, are clock-like, and accelerated by carcinogen exposure. Loss of FHIT caretaker function may be a predictive and preventive marker for cancer development. PMID- 29254237 TI - Constructing an ovarian cancer metastasis index by dissecting medical records. AB - Globally, ovarian cancer (OC) is the leading cause of gynecological cancer associated deaths. Metastasis, especially multi-organ metastasis, determines the speed of disease progression. A multicenter retrospective study was performed to identify the factors that drive metastasis, from medical records of 534 patients with OC. The average number of target organs per patient was 3.66, indicating multi-organ metastasis. The most common sites of metastasis were large intestine and greater omentum, which were prone to co-metastasis. Results indicated that ascites and laterality, rather than age and menopausal status, were the potential drivers for multi-organ metastasis. Cancer antigen (CA) 125 (CA-125) and nine other blood indicators were found to show a significant, but weak correlation with multi-organ metastasis. A neural network cascade-multiple linear regression hybrid model was built to create an ovarian cancer metastasis index (OCMI) by integration of six multi-organ metastasis drivers including CA-125, blood platelet count, lymphocytes percentage, prealbumin, ascites, and laterality. In an independent set of 267 OC medical records, OCMI showed a moderate correlation with multi-organ metastasis (Spearman rho = 0.67), the value being 0.72 in premenopausal patients, and good performance in identifying multi-organ metastasis (area under the receiver operating characteristic curve = 0.832), implying a potential prognostic marker for OC. PMID- 29254238 TI - The association between MAD2 and prognosis in cancer: a systematic review and meta-analyses. AB - This systematic review and meta-analyses investigates the expression of the cell checkpoint regulator, mitotic arrest deficiency protein 2 (MAD2) in cancerous tissue and examines whether an association exists between MAD2 levels and cancer survival and recurrence. Studies investigating MAD2 expression in cancer tissue utilising immunohistochemistry (IHC) were identified by systematic literature searches of Medline, Embase and Web of Science databases by October 2015. Random effects meta-analyses were performed to generate pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of overall and progression-free survival according to MAD2 expression. Forty-three studies were included in the overall review. In 33 studies investigating MAD2 expression by IHC in cancer tissue, a wide range of expression positivity (11-100%) was reported. Higher MAD2 expression was not associated with an increased risk of all-cause mortality in a range of cancers (pooled HR 1.35, 95% CI 0.97-1.87; P = 0.077, n = 15). However, when ovarian cancer studies were removed, a significant pooled HR of 1.59 for risk of all cause mortality in other cancer patients with higher expressing MAD2 tumours was evident (95% CI, 1.17-2.17; P = 0.003, n = 12). In contrast, higher MAD2 expression was associated with significant decreased risk of all-cause mortality in ovarian cancer patients (pooled HR = 0.50, 95% CI, 0.25-0.97; P = 0.04, n = 3). In conclusion, with the exception of ovarian cancer, increased MAD2 expression is associated with increased risk of all-cause mortality and recurrence in cancer. For ovarian cancer, reduced levels of MAD2 are associated with poorer outcome. Further studies are critical to assess the clinical utility of a MAD2 IHC biomarker. PMID- 29254239 TI - Association between CD40 rs1883832 and immune-related diseases susceptibility: A meta-analysis. AB - Background/objective: It has been reported that CD40 rs1883832 might be associated with immune-related diseases susceptibility. Owing to mixed and inconclusive results, we conducted a meta-analysis of case-control studies to summarize and clarify this association. Methods/main results: A systematic search of studies on the association between CD40 rs1883832 and immune-related diseases susceptibility was conducted in databases. Odds ratios and 95% confidence intervals were used to pool the effect size. 40 articles were included in our meta-analysis. Conclusions: CD40 rs1883832 is associated with decreased risk of Graves' disease, especially in Asian; CD40 rs1883832 is associated with increased risk of multiple sclerosis; CD40 -1C>T (rs1883832) is not associated with the susceptibility of Hashimoto's thyroiditis, systemic sclerosis or Asthma; there is insufficient data to fully confirm the association between CD40 rs1883832 and systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Behcet's disease (BD), myasthenia gravis (MG), Crohn's disease (CD), ulcerative colitis (UC), Sarcoidosis, Fuch uveitis syndrome (FUS), Vogt-Koyanagi-Harada syndrome (VKH), Kawasaki disease (KD), giant cell arteritis (GCA) or Immune thrombocytopenia (ITP). PMID- 29254240 TI - Percutaneous endoscopic gastrostomy versus fluoroscopic gastrostomy in amyotrophic lateral sclerosis (ALS) sufferers with nutritional impairment: A meta analysis of current studies. AB - Gastrostomy is recommended for Amyotrophic Lateral Sclerosis (ALS) patients with malnutrition. There are two main methods of gastrostomy insertion: Percutaneous Endoscopic Gastrostomy (PEG) and Fluoroscopic Gastrostomy (FG). The latter included Radiologically Inserted Gastrostomy (RIG) and Per-oral Image-Guided Gastrostomy (PRG). A meta-analysis was conducted to compare these approaches in terms of survival outcomes, pain occurrence and success rate, through the literature search in PubMed, Web of Science and Cochrane Library. A total of 7 studies with 701 cases (322 in PEG, 264 in RIG and 115 in PRG) were enrolled in the final analysis. The lack of differences between the comparisons (PEG vs. PRG, PEG vs. RIG and PEG vs. PRG+RIG) on 30-day mortality and survival length was confirmed. For the pooling analysis of peri- and post-procedural complications, patients with PEG had a lower incidence of pain than cases with PRG and RIG together (P < 0.001). The same trends could be found when compared with PRG and RIG, separately (P < 0.05 and P < 0.001, respectively). And PEG showed a lower rate of successful attempts than PEG and RIG (P < 0.05). For other complications, we didn't find any differences. This meta-analysis demonstrates that PEG, PRG and RIG had their intrinsic advantages. The current evidences could not determine the preference of them. Further investigations should be done to reveal the most appropriate method for ALS patients. PMID- 29254241 TI - Blood transfusion and mortality in myocardial infarction: an updated meta analysis. AB - Background: Several observational and preclinical studies have shown that blood transfusion may modify the mortality of patients with myocardial infarction (MI). The aim of this meta-analysis is to evaluate the recent evidence on the effectiveness of blood transfusion for all-cause mortality in patients with MI. Materials and Methods: PUBMED, EMBASE and the Cochrane central register of controlled trials were searched up to June 2016 by two independent investigators. Studies were considered eligible if they recruited adult MI patients and reported hazard ratio (HR) for all-cause mortality comparing those who received blood transfusion with those who did not receive blood transfusion. We abstracted and calculated pooled HRs using a random-effects model. Results: From 4277 unique reports, we identified 17 studies including 260811 patients with 11 studies examining short-term (in hospital/30-day) all-cause mortality and 9 studies examining long-term (more than 30 days) all-cause mortality. Meta-analysis demonstrated that patients treated with blood transfusion had increased short term all-cause mortality (HR, 2.39, 95% CI 1.81 to 3.15) compared with those without blood transfusion treatment. Similar findings were observed by subgroup analyses. We also find significant association between blood transfusion and long term all-cause mortality (HR 1.90, 95% CI 1.40 to 2.58) for MI patients. Conclusions: In patients with MI, blood transfusion treatment is associated with patient short-term and long-term all-cause mortality. However, further large scale prospective studies are needed to establish its validity of this association. PMID- 29254242 TI - A comprehensive genomic meta-analysis identifies confirmatory role of OBSCN gene in breast tumorigenesis. AB - The giant multifunctional protein "OBSCURIN" is encoded by OBSCN gene and is mostly expressed in cardiac and other skeletal muscles responsible for myofibrils organization. Loss of OBSCURIN affects the entire downstream pathway proteins vital for various cellular functions including cell integration and cell adhesion. The OBSCN gene mutations are more frequently observed in various muscular diseases, and cancers. Nevertheless, the direct role of OBSCN in tumorigenesis remains elusive. Interestingly, in clinical breast cancer samples a significant number of function changing mutations have been identified in OBSCN gene. In this study, we identified a significant role of OBSCN by conducting an integrative analysis of copy number alterations, functional mutations, gene methylation and expression data from various BRCA cancer projects data available on cBioPortal and TCGA firebrowse portal. Finally, we carried out genetic network analysis, which revealed that OBSCN gene plays a significant role in GPCR, RAS, p75 or Wnt signaling pathways. Similarly, OBSCN gene interacts with many cancer associated genes involved in breast tumorigenesis. The OBSCN gene probably regulates breast cancer progression and metastasis and the prognostic molecular signatures such as copy number alterations and gene expression of OBSCN may serve as a tool to identify breast tumorigenesis and metastasis. PMID- 29254243 TI - PPARG c.1347C>T polymorphism is associated with cancer susceptibility: from a case-control study to a meta-analysis. AB - : Recently, several studies suggested that PPARG c.1347C>T polymorphism was correlated with cancer risk. However, past results remained controversial. In this study, we performed a case-control study on the relationship of PPARG c.1347C>T polymorphism with risk of non-small cell lung cancer (NSCLC) and subsequently carried out a meta-analysis to further assess the association between PPARG c.1347C>T and overall cancer. In our case-control study, after adjusting by age, sex, body mass index (BMI), smoking and drinking, a tendency to increased NSCLC risk was noted (CT/TT vs. CC: adjusted OR, 1.21; 95% CI, 0.97 1.51; P = 0.097). In the meta-analysis, we found a significant association between PPARG c.1347C>T polymorphism and overall cancer risk (T vs. C: OR, 1.13; 95% CI, 1.03-1.23; P = 0.006; TT vs. CC: OR, 1.29; 95% CI, 1.07-1.56; P = 0.008, CT/TT vs. CC: OR, 1.11; 95% CI, 1.02-1.21; P = 0.014 and TT vs. CT/CC: OR, 1.26; 95% CI, 1.04-1.52; P = 0.016). In a subgroup analysis by ethnicity, evidence of significant association between PPARG c.1347C>T polymorphism and cancer risk was found among Asians and mixed populations. In a subgroup analysis by cancer type, PPARG c.1347C>T polymorphism was associated with risk of esophageal cancer and glioblastoma. In addition, in a subgroup analysis by origin of cancer cell, evidence of significant association between PPARG c.1347C>T polymorphism and cancer risk was also found among epithelial tumor. In conclusion, the findings indicate PPARG c.1347C>T polymorphism may increase the susceptibility of cancer. PMID- 29254244 TI - Diagnostic efficacy of long non-coding RNA MALAT-1 in human cancers: a meta analysis study. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) is one kind of long non-coding RNAs (lncRNAs) that has been recognized as a hallmark of the onset and development of several carcinomas. This study seek to meta-analyze the overall diagnostic efficacy of elevated MALAT-1 expression profile for human cancers. Studies on the diagnostic performance of MALAT-1 in cancers were retrieved by searching the online databases. The combined effect sizes were summarized using a bivariate meta-analysis model. Impacts of publication bias on the pooled effect sizes were assessed using "Duval and Tweedie nonparametric trim and fill method". Sensitivity analysis and meta-regression test were applied to deeply trace the heterogeneity sources among eligible studies. A total of 14 studies with 1342 cancer cases were included. The combined effect sizes showed that MALAT-1 expression profiling conferred an estimated sensitivity of 0.69 (95% CI: 0.62-0.75) (I2 = 84.01%, P < 0.001), specificity of 0.85 (95% CI: 0.79-0.90) (I2 = 87.95%, P < 0.001) and AUC (area under curve) of 0.83 in distinguishing cancer patients from noncancerous contrasts. Moreover, stratified analysis depending on cancer type manifested that elevated MALAT-1 harbored a promising efficacy in the diagnosis of pulmonary tumors (AUC = 0.90), digestive system tumors (AUC = 0.84), gynecologic cancers (AUC = 0.84) and nasopharyngeal carcinoma (AUC = 0.84), particularly in confirming the subtype of squamous carcinoma (AUC = 0.91) and non-small cell lung carcinoma (AUC = 0.88) in lung cancer. Other analyses based on test matrix and ethnicity also presented robust results. Collectively, elevated MALAT-1 could be developed as an auxiliary molecular marker to aid in cancer diagnosis. PMID- 29254245 TI - NQO1 C609T polymorphism and lung cancer susceptibility: Evidence from a comprehensive meta-analysis. AB - A variety of case-control studies have been performed to assess the correlation between NQO1 C609T polymorphism and the risk of lung cancer, but an explicit consensus has not been reached. We conducted this updated meta-analysis to identify the function of NQO1 C609T polymorphism in lung cancer risk. All relevant literature was retrieved from the PubMed, EMBASE, CNKI, and WanFang databases before April 2017. A total of 37 studies (29 articles) with 8493 cases and 10,999 controls were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of relations. We found that the NQO1 C609T polymorphism did not correlate with the risk of lung cancer in the overall analysis. In addition, no statistical significance was observed in the analysis stratified based on ethnicity, control source, quality score, or smoking status. A significant association was found in the subgroup of small cell lung cancer risk. Despite some limitations, this meta-analysis indicates that the NQO1 C609T polymorphism may not be associated with lung cancer risk. However, more epidemiological studies of larger samples and more ethnicities are needed to confirm these results. PMID- 29254246 TI - Comprehensive assessment of the association between estrogen receptor of alpha polymorphisms and the risk of prostate cancer: evidence from a meta-analysis. AB - We performed a meta analysis to access the relationship of estrogen receptor of alpha (ESRalpha) polymorphisms with the risk of prostate cancer (PC). Twenty-four case-control studies (including 5477 cases and 10708 controls) were recruited for meta-analysis. The strongest association with the risk of PC was observed between ESRalpha rs9340799 and rs2234693 under the two genotypic models of allele and codominance in the overall population (p < 0.05). Under the subgroup analysis of ethnicity, we observed that ESRalpha rs9340799 was significantly associated with the susceptibility to PC in European population (AvsG, p = 0.000; AAvsGG, p = 0.002), while there was no difference in Asian (AvsG, p = 0.493; AAvsGG, p = 0.736) or African population (AvsG, p = 0.800; AAvsGG, p = 0.788). The results also showed that significant association between rs2234693 and the susceptibility to PC in European (CvsT, p = 0.004; CCvsTT, p = 0.001) and Asian population (CvsT, p = 0.004; CCvsTT, p = 0.003), but not in African population (CvsT, p = 0.636; CCvsTT, p = 0.669). The meta-analysis indicated that ESRalpha rs9340799 and rs2234693 might contribute to susceptibility and development of PC in European population. PMID- 29254247 TI - Molecular targeted agents as second-line treatment for hepatocellular carcinoma: a meta-analysis and review. AB - It is unclear whether targeted agents can produce survival advantage in patients with advanced HCC previously treated with sorafenib. We performed this meta analysis of randomized trials and reviewed clinical outcomes of molecular targeted agents in the second-line treatment for advanced HCC. A systematic computerized search of the electronic databases PubMed, Embase, Google Scholar, and Cochrane Library (up to May 2017) was carried out. From six studies, 2,388 patients were included in the meta-analysis. Almost all patients were treated with sorafenib as first-line therapy. Compared with placebo, targeted agents significantly improved time-to-progression (hazard ratio = 0.62, 95% confidence interval: 0.49-0.78, P < 0.0001). In terms of overall survival, targeted therapy tended to improve prognosis (hazard ratio = 0.86, 95% confidence interval: 0.74 1.01, P = 0.06). In conclusion, this meta-analysis indicates that molecular targeted agents have a potential to improve prognosis after failure of first-line treatment with sorafenib in patients with advanced HCC. PMID- 29254248 TI - Lower risk of liver cancer in patients with schizophrenia: a systematic review and meta-analysis of cohort studies. AB - Previous studies regarding the association between schizophrenia and the subsequent risk of liver cancer have shown inconsistent results. We aimed to perform a systematic review and meta-analysis to evaluate the association between schizophrenia and liver cancer incidence. We systematically searched the PubMed and Embase electronic databases for cohort studies reporting the standardized incidence ratio (SIR) for the risk of liver cancer in patents with schizophrenia as compared with the general population. A random-effects model was used to analyze the data. Stratified analyses were performed according to the gender of the patients. Seven studies comprising 312,834 patients with schizophrenia were included. During follow-up, 581 liver cancer cases were confirmed. The meta analysis results showed that schizophrenia was associated with a trend of a lower liver cancer incidence (SIR: 0.83, 95% confidence interval [CI]: 0.66-1.04, p = 0.10) with significant heterogeneity (I2 = 81%). Sensitivity analysis of five cohorts of patients with cancer events before the diagnosis of schizophrenia indicated that schizophrenia was associated with a significantly lower incidence of liver cancer (SIR: 0.76, 95% CI: 0.61-0.96, p = 0.02; I2 = 84%). The reduction of a subsequent incidence of liver cancer was significant in male patients with schizophrenia (SIR: 0.71, p = 0.005), and a trend of a reduced risk of liver cancer was also detected in female patients (SIR: 0.83, p = 0.12). Significant publication bias was detected. However, "trim and fill" analyses by including the imputed unpublished studies showed similar results. In summary, schizophrenia may be protective against the incidence of liver cancer. PMID- 29254249 TI - Quantitation of cell-free DNA in blood is a potential screening and diagnostic maker of breast cancer: a meta-analysis. AB - Introduction: Increased cell-free DNA (cfDNA) levels in circulating blood have been associated with higher possibility of breast cancer, however, researchers have not reached an agreement on its analysis. Materials and Methods: We conducted a meta-analysis of 12 retrospective studies to clarify the value of cfDNA quantification in screening and diagnosis of breast cancer. PubMed, EMBASE, Web of Science and Cochrane library were searched from January, 2000 to October, 2016. Pooled analyses were estimated using a random effects model. Results: In total, 1003 primary breast cancer patients, 283 cases with benign breast disease and 575 healthy individuals were included. Pooled diagnostic odds ratio (DOR) was 27.63 (95% confidence interval [CI]: 10.96~69.61, I2 = 86.2%, P < 0.001) in discriminating between breast cancer and healthy controls; the area under the summary receiver operating characteristic (SROC) curve measured 0.91 (95% CI: 0.17~1.00). Analysis of available data in distinguishing breast cancer and benign breast disease showed a pooled DOR of 35.30 (95% CI: 7.58~164.39, I2 = 79.9%, P = 0.002) with an area under SROC of 0.91 (95% CI: 0.89~0.93). Ethnic group distribution based geographical factors suggested by meta-regression and subgroup analyses explained most of the heterogeneity. Conclusions: Quantification of cfDNA is a promising test in screening and diagnostic of breast cancer, but population-based standardization of test methods require completion prior to clinical use. PMID- 29254250 TI - Long non-coding RNA AFAP1-AS1 is a novel biomarker in various cancers: a systematic review and meta-analysis based on the literature and GEO datasets. AB - Background: Growing evidence indicates that AFAP1-AS1 plays an important role in various cancers, suggesting that it might be a potential cancer biomarker. Materials and Methods: A meta-analysis was performed using microarray data obtained via the Affymetrix Human Genome U133 Plus 2.0 platform (found in the GEO database) and data obtained through a systematic search of PubMed and Web of Science. The pooled odds ratio (OR) and hazard ratio (HR) with 95% CI (confidence interval) were used to judge the value of biomarkers. Results: A total of 30 studies were included in this meta-analysis, comprising a total of 3573 patients. AFAP1-AS1 was significantly linked with overall survival (OS) (HR = 1.58; 95% CI: 1.12-2.23) and recurrence-free survival (RFS) (HR = 2.32, 95% CI: 1.68-3.19). We found that AFAP1-AS1 was a risk factor in the prognoses of lung cancer (pooled HR: 1.54; 95% CI: 1.01-2.34), digestive system cancer (pooled HR: 1.87; 95% CI: 1.45-2.41) and nasopharyngeal carcinoma (HR: 11.82; 95% CI: 5.09-27.46). AFAP1 AS1 was also a risk factor for RFS in breast cancer (pooled HR = 2.90; 95% CI: 1.69-4.98), as well as TNM stage in both esophageal cancer (pooled OR = 1.90; 95% CI: 1.01-3.57) and colorectal cancer (OR = 6.72; 95% CI: 1.92-23.58). AFAP1-AS1 was significantly associated with lymph node metastasis in clear cell carcinoma (OR = 5.04; 95% CI: 2.36-10.78) and distant metastasis in pancreatic cancer (OR = 11.64; 95% CI: 2.13-63.78). Conclusions: AFAP1-AS1 can serve as a novel molecular marker predicting tumor progression, patient prognosis and lymph node metastasis in different types of cancers. PMID- 29254252 TI - The role of anti-EGFR agents in patients with locoregionally advanced head and neck cancer: a meta-analysis of randomized trials. AB - There has been a debate over whether the addition of anti-epidermal growth factor receptor (EGFR) agents to the conventional treatments has beneficial effects in patients with head and neck squamous cell carcinoma (HNSCC). This meta-analysis was performed to investigate the role of anti-EGFR agents in patients with locoregionally advanced HNSCC (LA-HNSCC). A systematic search of the electronic databases was carried out. From eight randomized controlled trials, 2,263 patients were included in the meta-analysis. Compared with chemoradiotherapy (CRT), the addition of an EGFR inhibitor to radiotherapy (RT) or CRT did not improve locoregional control (hazard ratio (HR) = 1.19 [95% confidence interval (CI): 0.99-1.42], P = 0.06), progression-free survival (HR = 1.07 [95% CI: 0.92 1.24], P = 0.37), and overall survival (HR = 1.04 [95% CI, 0.88-1.23], P = 0.65) in patients with LA-HNSCC. Moreover, the addition of anti-EGFR agents increased the risk of skin toxicities (odds ratio = 4.04 [95% CI: 2.51-6.48], P < 0.00001) and mucositis (odds ratio = 1.58 [95% CI: 0.99-2.52], P = 0.06). In conclusion, this meta-analysis indicates that the addition of an anti-EGFR agent to RT or CRT do not improve clinical outcomes compared with CRT in patients with LA-HNSCC. Except for patients with coexisting medical conditions or decreased performance status, concurrent CRT should remain the standard of care for patients with LA HNSCC. PMID- 29254251 TI - Prognostic and clinicopathological value of p53 expression in renal cell carcinoma: a meta-analysis. AB - Background: The prognostic value of p53 expression in renal cell carcinoma (RCC) had been investigated in previous studies; however, the results remain inconsistent. This study was performed to investigate the prognostic and clinicopathological significance of p53 protein expression in RCC. Materials and Methods: Literature was identified from PubMed, Embase, Web of Science, and Cochrane database, which investigated the relationships between p53 expression and outcomes. Hazard ratios (HRs) for survival outcomes and odds ratios (ORs) for clinical parameters associated with p53 were extracted from eligible studies. Heterogeneity was assessed using the I2 value. The fixed-effects model was used if there was no evidence of heterogeneity; otherwise, the random-effects model was used. Publication bias was evaluated using Begg's funnel plots and Egger's regression test. Results: A total of 2,013 patients from 22 studies were included in the meta-analysis. The results showed that p53 positive expression is associated with poor overall survival (OS) (HR = 2.17, 95% confidence [CI]: 1.51 3.13) and cancer-specific survival (CSS) (HR = 1.59, 95% CI: 1.19-2.12) in RCC. In addition, p53 positive expression was closely correlated with TNM stage (III/IV vs. I/II: OR = 2.51, 95% CI: 1.05-6.00), Fuhrman grade (III/IV vs. I/II: OR = 1.80, 95% CI: 1.24-2.63), and distant metastasis (M1 vs. M0: OR = 1.70, 95% CI: 1.16-2.49), but not related to lymph node involvement (N1 vs. N0: OR = 1.32, 95% CI: 0.80-2.18), primary tumor stage (pT3/pT4 vs. pT1/pT2: OR = 1.16, 95% CI: 0.88-1.53), and sex (n = 2, male vs. female, OR = 1.09, 95% CI: 0.70-1.68). Conclusions: This study suggests that p53 positive expression is correlated with poor prognosis and advanced clinicopathological features in patients with RCC, which indicates that p53 is a potentially effective therapeutic target. PMID- 29254253 TI - Benzodiazepine drug use and cancer risk: a dose-response meta analysis of prospective cohort studies. AB - Conflicting results identifying the relationship between benzodiazepine drug use and cancer risk. Therefore, we conducted a dose-response meta-analysis of prospective cohort studies to clarify and quantitative assessed the relationship between benzodiazepine drug use and cancer risk. Up to July 2017, 22 original publications were included in current meta-analysis. Our results showed statistically significant association between benzodiazepine drug use and cancer risk (RR:1.25; 95% CI, 1.15-1.36). Subgroup analysis showed benzodiazepine using was associated with significantly a higher risk of breast cancer (RR:1.15; 95% CI, 1.05-1.26), ovarian cancer (RR:1.17; 95% CI, 1.09-1.25), colon cancer (RR:1.07; 95% CI, 1.02-1.13), renal cancer (RR:1.31; 95% CI, 1.15-1.49), malignant melanoma (RR:1.10; 95% CI, 1.03-1.17), brain cancer (RR:2.06; 95% CI, 1.76-2.43), esophagus cancer (RR:1.55; 95% CI, 1.30-1.85), prostate cancer (RR:1.26; 95% CI, 1.16-1.37), liver cancer (RR:1.22; 95% CI, 1.13-1.31), stomach cancer (RR:1.17; 95% CI, 1.03-1.32), pancreatic cancer (RR:1.39; 95% CI, 1.17 1.64) and lung cancer (RR:1.20; 95% CI, 1.12-1.28). Furthermore, a significant dose-response relationship was observed between benzodiazepine drug use and cancer risk (likelihood ratio test, P < 0.001). Our results showed per 500 mg/year, per 5 year of time since first using, per 3 prescriptions and per 3 year of duration incremental increase in benzodiazepine drug use was associated with a 17%, 4%, 16% and 5% in cancer risk increment. Considering these promising results, increasing benzodiazepine using might be harmful for health. PMID- 29254254 TI - Innovation in endocrine surgery: robotic versus laparoscopic adrenalectomy. Meta analysis and systematic literature review. AB - Several studies in the last years demonstrated the better surgical outcome of laparoscopic approach to adrenal gland. Laparoscopic surgery is more difficult to learn and requires different psychomotor skills than open surgery, especially with regard to complex maneuvers requiring precision and dexterity. The development of robotic platform with three-dimensional vision and increased degrees of freedom of the surgical instruments has the aim to overcome these problems. We performed a systematic literature review with meta-analysis to evaluate preoperative data and surgical outcomes of robotic adrenalectomy compared with laparoscopic technique. In September 2016 we performed a systematic literature review using the Pubmed, Scopus and ISI web of knowledge database with search term "robotic adrenalectomy". We identified 13 studies with eligible criteria that compared surgical outcomes. This present systematic review with meta-analysis includes 798 patients: 379 underwent to robotic adrenalectomy (cases group) and 419 to laparoscopic adrenalectomy (controls group). There were no significant differences between the two groups of patients respect to age, gender, laterality and tumor size. BMI instead was significant lower in the robotic group. In this group we found also patients with higher incidence of previous abdominal surgery. The results from operative time demonstrated lower operative time for laparoscopic group but there were no significant differences with robotic group. Robotic adrenalectomy showed a significant lower blood loss. Robotic adrenalectomy is a safe and feasible technique with reduced blood loss and shorter hospital stay than laparoscopic adrenalectomy. Laparoscopic approach seems to be a more rapid technique when comparing to robotic technique, although recent studies demonstrate a significant operative time reduction in robotic group with the learning curve improvement and the development of new surgical technology. PMID- 29254255 TI - Association between ALDH2 rs671 G>A polymorphism and gastric cancer susceptibility in Eastern Asia. AB - To date, the relationship between the aldehyde dehydrogenases-2 (ALDH2) rs671 G>A (Glu504Lys) polymorphism and gastric cancer (GC) risk has not been thoroughly elucidated. To derive a more precise estimation of the effect of the ALDH2 rs671 G>A polymorphism on GC, we conducted this meta-analysis. We searched for qualified studies in the Embase, PubMed, Wang Fan and China National Knowledge Infrastructure databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the association. A total of 6,421 GC patients and 8,832 control subjects were included in the present study. The pooled results indicated no significant relationship between the ALDH2 rs671 G>A polymorphism and GC susceptibility in all genetic models. A stratified analysis by country showed that the ALDH2 rs671 G>A polymorphism might be a risk factor for GC in Japan (Allele model: Punadjusted = 0.034; Dominant model: Punadjusted = 0.040); however, the result was nonsignificant when the Bonferroni correction and false discovery rate (FDR) were applied. In subgroup analyses by drinking status in the dominant model, our study revealed that the ALDH2 rs671 G>A polymorphism significantly increased the risk of GC for drinkers (dominant model: P < 0.001). No relationship between the ALDH2 rs671 G>A polymorphism and GC risk was observed in any other subgroup. Our present study indicated no association between the ALDH2 rs671 G>A polymorphism and GC risk in Eastern Asian populations. However, the ALDH2 rs671 G>A polymorphism can significantly increase GC risk for drinkers. PMID- 29254256 TI - Dose age affect the efficacy of molecular targeted agents in the treatment of hepatocellular carcinoma: a systematic review and meta-analysis. AB - Currently, whether the impact of age on efficacy of molecular targeted agents (MTAs) in the treatment of hepatocellular carcinoma (HCC) patients remains undetermined. We searched databases and abstracts presented at ASCO meeting to identify relevant studies. The endpoints were overall survival (OS) and progression-free survival (PFS). Data were examined using age cutoffs of 65 years. A total of 4,231 HCC patients from eight RCTs were included for analysis, with 1,607 patients aged >= 65 years and 2,624 patients aged < 65 years. The pooled results demonstrated that the use of MTAs in patients < 65 years significantly improved PFS (HR 0.69, 95% CI: 0.51-0.95, p = 0.023) and OS (HR 0.79, 95% CI: 0.69-0.89, p < 0.001) when compared to controls. For HCC patients aged >= 65 years, the use of MTAs significantly improved PFS (HR 0.66, 95% CI: 0.53-0.84, p = 0.001) but not for OS (HR 0.94, 95% CI: 0.81 -1.09, p = 0.41). No publication bias was detected by Begg's and Egger's tests for OS. Therefore, the treatment effect of MTAs on OS might be different in younger and older HCC patients undergoing first-line or second-line treatment, but not for PFS benefit. PMID- 29254257 TI - The progression in atrial fibrillation patients with COPD: a systematic review and meta-analysis. AB - Aim: Chronic Obstructive Pulmonary Disease (COPD) and atrial fibrillation (AF) share pathophysiological links, as supported by the high prevalence of AF within COPD patients. AF progression and recurrence can increase the risks of mortality, morbidity and adverse cardiovascular events. The present systematic review and meta-analysis aims to assess the risk for AF progression and recurrence for COPD patients, to further demonstrate the risk of COPD in AF patients. Methods and Results: A systematic review was conducted in MEDLINE / PubMed and Cochrane Library and Embase, Web of science. Prospective studies including AF patients with COPD were screened and included if matching inclusion and exclusion criteria. 7 studies were included, adding up to 10761 AF patients (1556 with AF and COPD, 9205 without COPD). Mean age from each study ranged from 51 to 81 years, and 57.2% were male. Hypertension accounted for 75.5% of the population, and 20.7% had the comorbidity of diabetes mellitus. The pool analysis showed that COPD could promote AF progression (OR = 1.90; 95% CI, 1.34-2.68, I2 = 77%, p = 0.0003). For subgroup analysis, we found that COPD could increase the risk of AF recurrence (OR = 2.35; 95% CI, 1.86-2.97, I2 = 0%, p = 0.39). Besides, in the younger group, at the median age of 64, COPD was still a risk factor for AF progression (OR = 2.22; 95% CI, 1.80-2.74, I2 = 0%, p = 0.69). Conclusions: COPD is an independent risk for AF progression and recurrence, COPD patients with AF carry a worse prognosis than those in sinus rhythm (SR). PMID- 29254258 TI - Meta-analysis identifies candidate key genes in endometrium as predictive biomarkers for clinical pregnancy in IVF. AB - Genetic factors in endometrium are likely to be involved in the embryo implantation failure (IF), one of the major limiting factors in the success of in vitro fertilization (IVF). In this study, we aimed to identify critical genes from the transcriptional profile for the establishment of the endometrial receptivity which supporting the normal pregnancy. Three GEO datasets, including 12 samples of IF and 12 samples of controls, were used for the meta-analysis. We identified 182 different expression genes (DEGs) by comparing IF with controls and present here the successful clustering according to sample type, not by the origin. The gene ontology (GO) enriched analysis demonstrated the significant downregulation in activation and regulation of inflammatory and immune response in IF patients. Furthermore, network analysis of down-regulated genes identified the significant hub genes containing GADD45A (growth arrest and DNA damage inducible alpha, Degree = 77), GZMB (granzyme B, Degree = 38) and NLRP2 (NLR family pyrin domain containing 2, Degree = 37). The lower expression of NLRP2, related to inflammatory responses with the most degree in the network, was validatied by other GEO data. Besides, it was confirmed that the NLRP2 could act as a predictor for pregnancy after IVF (AUC = 87.93%; sensitivity, 60.00%; specificity, 91.30% ). Our meta-analysis will help us to better understand the molecular regulation of endometrial receptivity, and guiding further line of treatment for IF during IVF. PMID- 29254259 TI - Prevalence of hepatitis B virus and hepatitis C virus infection in patients with systemic lupus erythematosus: a systematic review and meta-analysis. AB - We attempted to explore the prevalence of HBV and HCV infections in patients with systemic lupus erythematous (SLE) via a systematic review. Articles published before June 2017 and, related to prevalence rates for HBV and HCV infection in SLE patient were identified in PubMed, Embase, CNKI, and Wanfang databases. Based on these searches 22 studies were selected for further analysis. The OR of HBsAg positive rate in SLE patients compared with control population was 0.28, with significant heterogeneity identified among the studies (I2 = 92%, P < 0.00001). Following exclusion of one study, the adjusted OR of HBsAg in patients with SLE was 0.24, and no significant heterogeneity was observed (I2 = 32%, P = 0.15). The adjusted OR of HBcAb positive rate in SLE patients compared with control population was 0.40, with no significant heterogeneity between studies (I2 = 0%, P = 0.56). The risk of having HCV infection by SLE patients was higher compared with the control subjects (OR = 2.91). In conclusion, this meta-analysis suggested that SLE might exert a role of protection against HBV but not for HCV infection. Further epidemiological and experimental studies are necessary to explore the role and mechanisms by which SLE affects HBV/HCV infections. PMID- 29254260 TI - CLPTM1L gene rs402710 (C > T) and rs401681 (C > T) polymorphisms associate with decreased cancer risk: a meta-analysis. AB - Cleft lip and palate transmembrane 1-like (CLPTM1L) gene rs402710 (C > T) and rs401681 (C > T) polymorphisms have been widely studied for their potential relation to cancer risk, but studies have produced conflicting results. To systematically evaluate the association between these two polymorphisms and overall cancer risk, we conducted a comprehensive meta-analysis on all relevant articles found in the PubMed and EMBASE databases published prior to May 1, 2017. There were 26 articles with 28 studies, including 30,770 cases and 34,089 controls, for the rs402710 polymorphism and 38 articles with 48 studies, including 67,849 cases and 328,226 controls, for the rs401681 polymorphism. The pooled results indicated that both rs402710 and rs401681 polymorphisms are significantly associated with decreased overall cancer risk. In our stratification analysis, a significant association of the rs402710 polymorphism with lung and bladder cancers was identified among Asian and Caucasian populations in both hospital-based and population-based studies. The rs401681 polymorphism was significantly associated with a decreased risk of lung cancer, bladder cancer, and basal cell carcinoma in Asians and in hospital-based studies. CLPTM1L gene rs402710 and rs401681 polymorphisms thus have a protective association with various types of cancer, especially lung cancer among Asians. PMID- 29254261 TI - Efficacy and safety of trastuzumab emtansine (T-DM1) in the treatment of HER2 positive metastatic breast cancer (MBC): a meta-analysis of randomized controlled trial. AB - Aims: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate against human epidermal growth factor receptor 2 (HER2), has been used in the treatment of patients with HER2-positive metastatic breast cancer (MBC). We conducted a meta analysis to evaluate the efficacy and toxicity of T-DM1 for the treatment of patients with HER2-positive MBC. Materials and Methods: Randomized controlled trials (RCTs), published in Pubmed, Embase, and Web of Science were systematically reviewed to assess the survival benefits and toxicity profile of HER2-positive patients with MBC who were treated with T-DM1. Outcomes included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and toxicities. Results were expressed as the hazard ratio (HR) with 95% confidence intervals (CIs). Results: A total of 5 RCTs involving 3,720 patients met the inclusion criteria and were included in this meta-analysis. T-DM1 significantly prolonged PFS (HR = 0.73, 95% CI: 0.61, 0.86; P < 0.05), OS (HR = 0.68, 95% CI: 0.62, 0.74; P < 0.05), but it did not increase ORR (RR = 1.25, 95% CI: 0.94, 1.66; P = 0.148). Subgroup analysis indicated that T-DM1 significantly improved PFS when it was used as first-line (HR = 0.86, 95% CI: 0.74, 1.00; P < 0.05) or non-first-line treatment (HR = 0.65, 95% CI: 0.53, 0.81; P < 0.05). T DM1 was associated with more frequent adverse events, including fatigue, elevated ALT, elevated AST, and thrombocytopenia, than other anti-HER2 therapies. Conclusions: Based on the current evidence, T-DM1 significantly prolonged PFS and OS with a tolerated toxicity than other anti-HER2 therapies in patients with HER2 positive MBC. These findings confirm the use of T-DM1 for the treatment of patients with HER2-positive MBC. Further well-designed, multi-center RCTs needed to identify these findings. PMID- 29254262 TI - Dexmedetomidine versus propofol on the sedation of pediatric patients during magnetic resonance imaging (MRI) scanning: a meta-analysis of current studies. AB - Magnetic resonance imaging (MRI) is a widely applied diagnostic approach for detection of pediatric diseases. Sedatives are commonly used to acquire the accurate MRI images. Dexmedetomidine and propofol serve as sole or combined sedatives in pediatric MRI scanning. This meta-analysis aimed to compare the efficacy of dexmedetomidine and propofol in children ubdergoing MRI. Pubmed, Cochrane Library and Web of Science were searched up to June, 2017. Onset of sedation time, recovery time, sedation time, MRI time, MRI quality and emergence delirium were analyzed. 6 studies with 368 subjects were enrolled in this meta analysis. The pooling data showed that propofol had a shorter onset of sedation time (WMD: 6.05, 95% CI: 3.12 - 8.98, P < 0.0001) and recovery time (WMD: 1.01, 95% CI: 0.36-1.67, P < 0.001) than dexmedetomidine. But for sedation time and MRI scanning time, there were no differences between the two groups (sedation time: P = 0.29; MRI scanning time: P = 0.50). There were no significance between dexmedetomidine and propofol on MRI quality (MRI quality 1: P = 1.00; MRI quality 2: P = 0.68; MRI quality 3: P = 0.45). Two studies using Pediatric Anesthesia Emergence Delirium (PAED) to assess emergence delirium 10 minutes after awakening showed that propofol had a lower PAED than dexmedetomidine (WMD: 2.57, 95% CI: 0.15-5.00, P = 0.04). Thus, propofol should be encouraged in pediatric patients undergoing MRI for its better sedative effects and a low incidence of emergence delirium. PMID- 29254263 TI - Clinical significance of sarcopenia in the treatment of patients with primary hepatic malignancies, a systematic review and meta-analysis. AB - Background: The impact of sarcopenia on outcomes following treatment for primary liver tumors remains contentious. Therefore, we performed a systematic literature review and meta-analysis to evaluate the clinical significance of sarcopenia in the treatment of patients with primary liver tumors. Data sources: A systematic literature search was performed in English through February 1, 2017 in databases. Results: There were significant differences between patients with and without sarcopenia in overall 1- and 3-year survival (1 year: OR: 0.43; 95% CI: 0.27 0.68; P=0.0004; 3 year: OR: 0.67; 95% CI: 0.47-0.96; P=0.03). However, overall 5 year survival showed no significant difference between the groups (OR: 0.61; 95% CI: 0.35-1.07; P=0.08). Patients with sarcopenia showed a significant 53% reduction in disease-free survival within 5 years (OR: 0.47; 95% CI: 0.28-0.79; P=0.005). Also, sarcopenia had a significantly negative impact on recurrence in patients with primary liver tumors (RR: 2.71; 95% CI: 1.46-5.05; P=0.002). Regarding complications rate, we concluded that there was a statistically significant difference between two groups in overall complications rate (RR: 2.52; 95% CI: 1.50-4.22; P=0.0005). However, the major complications rate showed no significant difference between the groups (RR: 1.19; 95% CI: 0.65-2.20; P=0.57). Conclusions: Sarcopenia seemed to have a negative effect on overall survival in patients with primary liver tumors in the early phase post-treatment, but further research is needed to investigate the prognostic impact on overall survival over the longer term. Moreover, sarcopenia could significantly increase the incidence rates of post-treatment recurrence and overall complications in patients with primary liver tumors. PMID- 29254264 TI - Association between nonsteroidal anti-inflammatory drugs use and risk of central nervous system tumors: a dose-response meta analysis. AB - Although studies have examined the association between nonsteroidal anti inflammatory drugs (NSAIDs) use and central nervous system (CNS) tumors risk, the results are inconclusive. Here, we conducted a dose-response meta-analysis in order to investigate the correlation between NSAIDs use and CNS tumors risk. Up to July 2017, 12 studies were included in current meta-analysis. NSAIDs use was significantly associated with a lower risk of CNS tumors. Furthermore, non aspirin NSAIDs or aspirin use are significantly associated with a lower risk of CNS tumors. Additionally, NSAIDs use was associated with significantly a lower risk of glioma, glioblastoma but not meningioma. Subgroup analysis showed consistent findings. Furthermore, a significant dose-response relationship was observed between NSAIDs use and CNS tumors risk. Increasing cumulative 100 defined daily dose of NSAIDs use was associated with a 5% decrement of CNS tumors risk, increasing NSAIDs or non-aspirin NSAIDs or aspirin use (per 3 prescriptions increment) was associated with a 7%, 7%, 10% decrement of CNS tumors risk, increasing per 2 year of duration of NSAIDs or non-aspirin NSAIDs or aspirin use was associated with a 6%, 8%, 6% decrement of CNS tumors risk. Considering these promising results, NSAIDs use might provide helpful for reducing CNS tumors risk. Large sample size and different ethnic population are warranted to validate this association. PMID- 29254265 TI - Impact of persistence on survival of patients with breast cancer treated with endocrine therapy in Northeast China: a prospective study. AB - The purpose of this prospective study is to investigate the impact of endocrine treatment persistence on the survival of patients with estrogen receptor-positive breast cancer treated with endocrine therapy and identify the risk factors influencing the treatment persistence. We enrolled 1085 patients from Northeast China who were diagnosed as stage I-III, estrogen receptor-positive breast cancer between January 2007 and December 2010. The prognostic factors for disease-free survival (DFS) and overall survival (OS) of patients were identified using univariate and multivariate Cox proportional hazards regression models. Multiple logistic regression analysis was done to determine the possible risk factors for non-endocrine treatment and treatment discontinuation. Among the patients enrolled, 598 (55.1%) underwent 5 years of endocrine therapy, 278 (25.6%) less than 5 years, and 209 (19.3%) non-endocrine therapy. OS rates in the continuation, discontinuation, and non-endocrine treatment groups were 97.8%, 92.6% and 74.3%, and DFS 97.5%, 86.2% and 69.9%, respectively. After adjusting for pathological and socioeconomic factors, non-endocrine therapy and discontinuation were independent predictors for DFS and OS. Elderly patients (>= 65 years), those living in suburban and rural areas, locally advanced patients, and receiving no radiotherapy and/or chemotherapy were more likely to receive non endocrine therapy and discontinue endocrine treatment. In conclusion, the prospective study demonstrate that the persistence of endocrine treatment is low in estrogen receptor-positive breast cancer patients in Northeast China. Non endocrine treatment and early discontinuation serve as independent prognostic factors for both DFS and OS of breast cancer patients treated with endocrine therapy. PMID- 29254267 TI - Effect of trimetazidine on preventing contrast-induced nephropathy in diabetic patients with renal insufficiency. AB - Background: Our study sought to assess the effect of trimetazidine (TMZ) on preventing contrast-induced nephropathy (CIN) in diabetic patients with renal insufficiency. Materials and Methods: 106 diabetic patients with renal insufficiency who were undergoing coronary angiography (CAG) and/or percutaneous coronary intervention (PCI) were enrolled in this study. Standard hydration was administered to both groups (the TMZ group and the control group). In the TMZ group, patients were orally administered TMZ for 48 hours before and 24 hours after CAG and/or PCI. Serum creatinine (Scr), cystatin C and the glomerular filtration rate (eGFR) were measured before as well as 24 hours, 48 hours and 72 hours after contrast media injection. The incidence of CIN and major cardiovascular events (MACE) was also evaluated in both groups. Results: Scr, cystatin C and the eGRF in the TMZ group were better than those in the control group after 24 hours (OR: 0.78, 95% CI: 0.54-0.82; OR: 0.66, 95% CI: 0.62-0.73; OR: 1.2, 95% CI: 1.02-1.53, respectively), 48 hours (OR: 0.69, 95% CI: 0.52-0.73; OR: 0.76, 95% CI: 0.69-0.84; OR: 1.5, 95% CI: 1.25-1.68, respectively) and 72 hours (OR: 0.82, 95% CI: 0.77-0.91; OR: 0.85, 95% CI: 0.71-0.92; OR: 1.67, 95% CI: 1.33-1.72, respectively). The incidence of CIN (9.26% vs 16.67%) and MACE (7.41% vs 18.51%) in the TMZ group was significantly lower than that in the control group (P < 0.05). Conclusions: Our study suggests that TMZ could reduce the incidence of CIN and MACE in diabetic patients with renal insufficiency who are undergoing CAG and/or PCI. PMID- 29254266 TI - Magnetic resonance imaging of RRx-001 pharmacodynamics in preclinical tumors. AB - RRx-001 is an anticancer agent that subjects cancer cells to reactive oxygen/nitrogen species (ROS/RNS) and acts as an epigenetic modifier. We have used a thiol-bearing MRI contrast agent, Gd-LC7-SH, to investigate the pharmacodynamics of RRx-001 in CHP-100 Ewing's Sarcoma, HT-29 colorectal carcinoma, and PANC-1 pancreatic carcinoma xenografts in SCID mice. Binding of Gd LC7-SH to the Cys34 residue on plasma albumin prolongs retention in the tumor microenvironment and increases tumor enhancement on MRI. Mice were imaged by MRI and in vivo T1 maps acquired 50 min (T150 min) after injection of 0.05 mmol/kg Gd LC7-SH (i.v.) at baseline and 1, 24, and 72 h post-treatment with 10 mg/kg RRx 001 (i.v.). Consistent with an indirect thiol-modifying activity of RRx-001, tumor T150 min at 1 h post-drug was significantly longer than pre-drug tumor T150 min in all three tumor models, with the T150 min remaining significantly longer than baseline through 72 h post-drug in the HT-29 and PANC-1 tumors. The T150 min of CHP-100 tumors recovered to baseline by 24 h post-drug, suggesting a robust anti-oxidant response to the RRx-001 challenge that was presaged by a marked increase in perfusion at 1 h post-drug measured by DCE-MRI. MRI enhanced with Gd LC7-SH provides a mechanistically rational biomarker of RRx-001 pharmacodynamics. PMID- 29254268 TI - A postoperative scoring system for post-hepatectomy early recurrence of colorectal liver metastases. AB - The aims of this study were to assess early recurrence predictive factors and elucidate the best early recurrence management. 255 patients with colorectal liver metastases (CRLM) who underwent hepatectomy were retrospectively analyzed. A total of 87 patients (34.1%) developed early recurrence, defined as recurrence that occurred within 6 months after resection. Multivariate analysis showed that preoperative carcino-embryonic antigen (CEA) level >= 30 ng/ml, primary tumor lymphovascular invasion (LVI), number of metastases >= 4, R1 resection and initially unresectable disease were independent predictors of early recurrence. A predictive scoring system for early recurrence was created by incorporating these factors, and this system showed good discrimination (concordance index of 0.78). In early recurrent patients who underwent salvage treatment, those with 0-2 risk factors demonstrated a significantly longer median survival after recurrence than patients with 3-5 risk factors (33.4 months vs. 20.2 months, p = 0.001). For patients who underwent chemotherapy alone, the median survival after recurrence between two groups was comparable (18.3 months vs. 22.6 months, p = 0.926). Multivariate analysis revealed that primary tumor lymph node metastases (HR = 1.96, p = 0.032), early recurrence (HR = 1.67, p = 0.045), salvage treatment for recurrence (HR = 0.47, p = 0.002) and predictive scores for early recurrence (HR = 1.39, p = 0.004) were independent factors for survival in patients with recurrence. In patients with early recurrence, bilobar distribution of metastases (HR = 2.05, p = 0.025) and salvage treatment for recurrence (HR = 0.46, p = 0.019) were independent factors for survival. In conclusion, we developed a predictive model that is a very useful tool for determining both the likelihood of early recurrence and the necessity for salvage treatment. PMID- 29254269 TI - Trends in the incidence of AIDS and epidemiological features in Tianjin, China from 2005 to 2016. AB - The objective of this study was to assess the epidemiological trends among patients with AIDS in Tianjin, China. A long-term surveillance study was conducted from 2005 to 2016 in Tianjin, China. All patients with AIDS registered in Tianjin from 2005 to 2016 were recruited to this study. Demographic information and clinical features were recorded. A total of 3062 patients with AIDS who were treated with antiretroviral therapy were included in this study. Among AIDS patients, men were more likely to be younger than women (age, 37.84 years vs. 43.27 years; P < 0.001). The incidence of AIDS increased by 39.6% annually over the past 12 years overall. There was the greatest increase (by 44.7%) for homosexual route. Moreover, the proportion of patients aged < 30 years increased considerably over the 12-year study period, while there was a decrease in the proportion of patients aged >= 35 years. The frequency of homosexual transmission increased by 86% from before 2011 to 2016, but the frequency of heterosexual transmission decreased by 49%. The frequency of transmission through intravenous drug use decreased in men and patients aged 25-29 years. For those infected through homosexual transmission, there was a significant increase in the numbers of patients aged 20-24 years and 25-29 years. It is important for developing countries to effectively prevent and control the transmission of HIV/AIDS; in particular, it is crucial to promote disease education and sexual protection among young men. PMID- 29254270 TI - A non-laboratory-based risk score for predicting diabetic kidney disease in Chinese patients with type 2 diabetes. AB - Aim: To construct a simple screening tool for predicting diabetic kidney disease in Chinese patients with type 2 diabetes. Materials and Methods: In the development cohort, the clinical and procedural characteristics of the 4,795 patients were considered as candidate univariate predictors of diabetic kidney disease. The beta-coefficients derived from a multiple logistic regression model predicting the presence of DKD were used to calculate the risk score. The performance of the risk score was validated in a cross-sectional and a prospective cohort population. Results: The risk score included sex, body mass index, systolic blood pressure, and duration of diabetes. The total point ranged from 0 to 39. In the development cohort, compared with participants with risk score < 10, those with risk score between 10 to 20, 21 to 30, and > 30 had ORs of 3.21, 7.92 and 17.55 for developing diabetic kidney disease, respectively. In the prospective cohort, 60.9% patients with risk score over 30 were expected to develop DKD at 72 months of follow-up. Conclusions: Sex, body mass index, systolic blood pressure, and duration of diabetes were independent predictors of diabetic kidney disease, and the derived risk equation was a simple screening tool for screening diabetic kidney disease in Chinese patients with type 2 diabetes. PMID- 29254271 TI - ACTION (acute coronary treatment and intervention outcomes network) registry-GWTG (get with the guidelines) risk score predicts long-term mortality in acute myocardial infarction. AB - This study aimed to test the predictive performance of the updated ACTION, GRACE, and CADILLAC risk scores (RS's) for long-term mortality in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). The study included individuals from 2 independent cohorts: derivation cohort (N = 1901) and validation cohort (N = 728). From the derivation cohort, we used Cox regression analysis to determine that the updated ACTION, GRACE, and CADILLAC RS's were associated with long-term mortality. The concordance (C) statistics of the 3 RS's were 0.682, 0.703 and 0.734, respectively. We used the validation cohort to validate the results. Moreover, the discriminatory performance of the updated ACTION RS for predicting long-term mortality in both the respective derivation and validation cohorts was similar to the discriminatory performance of the GRACE and CADILLAC RS's (ACTION vs. GRACE: z = 0.684, p = 0.494; ACTION vs. CADILLAC: z = 1.638, p = 0.101) and (ACTION vs. GRACE: z = 0.460, p = 0.646; ACTION vs. CADILLAC: z = 0.290, p = 0.772). Despite their development over a decade ago, GRACE and CADILLAC RS's maintain good performance for predicting the long-term mortality of AMI patients undergoing PCI. As a new risk model, the updated ACTION RS also predicts long-term mortality, and its discriminatory performance is similar to that of the GRACE and CADILLAC RS's. PMID- 29254273 TI - Use of magnetic resonance imaging for diagnosis and after treatment of patients with myeloid sarcoma of the brain. AB - The purpose of this retrospective study was to assess the utility of magnetic resonance imaging (MRI) for evaluating post-treatment responses in patients with myeloid sarcoma (MS) of the brain. We evaluated images from both conventional and advanced MR, including diffusion weighted imaging (DWI), arterial spin labeling (ASL) and susceptibility weighted imaging (SWI). Parameters of our qualitative review included lesion location, number, size, morphologic characteristics, surrounding edema, mass effect, pattern and degree of enhancement, +/- restricted diffusion, +/-susceptibility artifact and +/- higher perfusion. Our quantitative assessments were calculated from DW and ASL MR images. The 10 patients had a total of 40 lesions in their brains (mean lesion size of 2.0 +/- 0.8 cm). The majority of cases exhibited restricted diffusion (90%) and mild-to-moderate low perfusion (80%). Follow-up MRI after chemotherapy revealed that most lesions (80%) were significantly alleviated after two chemotherapy courses and further improved after four courses. Only a few lesions (5%) were residual after six courses. These findings demonstrate that brain MS can be characterized by changes in various MRI parameters and that MRI can be a useful and predictive assessment tool for brain MS diagnosis and treatment management. PMID- 29254272 TI - Chemotherapy use and survival in stage II nasopharyngeal carcinoma. AB - Although common, the use of chemotherapy for stage II nasopharyngeal carcinoma (NPC) is controversial due to its undefined clinical benefits. We therefore conducted a retrospective cohort study to investigate whether chemotherapy confers survival gains to stage II NPC patients. A total of 251 stage II (2010 UICC/AJCC staging system) NPC patients treated between January 2007 and December 2014 were retrospectively analyzed. Patients were matched using the propensity score matching method. The primary endpoint was overall survival (OS). Secondary endpoints were locoregional-free survival (LRFS) and distant metastasis-free survival (DMFS). Our analyses revealed no significant differences in OS, LRFS, or DMFS for stage II NPC patients treated with radiotherapy (RT) alone, concurrent chemoradiotherapy (CCRT), or CCRT + adjuvant chemotherapy (AC). T2N1 (OR = 6.690; 95% CI, 3.091-14.481) and T1N1 (OR = 5.857; 95% CI, 2.278-15.061) patients were more likely to receive CCRT than T2N0 patients. Similarly, both T2N1 (OR = 10.513; 95% CI, 3.439-32.137) and T1N1 (OR = 7.321; 95% CI, 1.978-27.098) patients were more likely to receive CCRT + AC than T2N0 patients. The present matched survival analysis suggests potential overuse of chemotherapy in stage II NPC, as the addition of chemotherapy did not provide a survival benefit in this group of patients. PMID- 29254274 TI - Red cell distribution width and homocysteine act as independent risk factors for cardiovascular events in newly diagnostic essential hypertension. AB - Hyperhomocysteinemia and increased red cell distribution width (RDW) are associated with a higher possibility of adverse clinical outcomes of hypertension. The study aims to validate the effect of homocysteine (Hcy) and RDW on cardiovascular events (CVE) and investigate whether RDW is independently associated with serum Hcy in patients with essential hypertension (EH). The study reviewed 804 patients with newly diagnosed EH in our hospital. The clinical characteristics and laboratory results of all subjects were grouped according to the presence/absence of CVE. Patients in the CVE group had higher RDW and Hcy, as compared to the patients in the no CVE group. Multiple Cox regression analysis demonstrated that both RDW (HR = 1.24, 95% CI =1.02-1.56, P = 0.002) and Hcy (HR = 1.37, 95% CI = 1.02-1.80, P < 0.001) resulted significantly related to the CVE. Subsequent analysis found that patients with high RDW had higher Hcy levels as compared with those with low RDW (P = 0.007). Although Pearson's correlation suggested that RDW was positively correlated with Hcy (r = 0.122, P = 0.028), no significant correlation was observed between RDW and Hcy (beta = 0.15, p = 0.126) after adjusted for a series of potential confounders using multiple linear regression analysis. In conclusion, RDW is not correlated with Hcy in patients with EH. Both RDW and Hcy are independent risk factors for CVE in newly diagnostic EH and have the potential to improve risk stratification. PMID- 29254275 TI - Mesenchymal stem cells in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a major cause of respiratory failure in critically ill patients and common outcome of various lung interstitial diseases. Its mortality remains high, and no effective pharmacotherapy, in addition to artificial ventilation and transplantation, exists. As such, the administration of mesenchymal stem or stromal cells (MSCs) is currently investigated as a new therapeutic method for pulmonary fibrosis. Clinical trials on MSC-based therapy as a potential treatment for lung injury and fibrosis are also performed. MSCs can migrate to injured sites and secrete multiple paracrine factors and then regulate endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and inhibit bacterial growth. In this review, recent studies on stem cells, particularly MSCs, involved in alleviating lung inflammation and fibrosis and their potential MSC-induced mechanisms, including migration and differentiation, soluble factor and extracellular vesicle secretion, and endogenous regulatory functions, were summarized. PMID- 29254276 TI - Review: Oncolytic virotherapy, updates and future directions. AB - Oncolytic viruses (OVs) are viral strains that can infect and kill malignant cells while spare their normal counterparts. OVs can access cells through binding to receptors on their surface or through fusion with the plasma membrane and establish a lytic cycle in tumors, while leaving normal tissue essentially unharmed. Multiple viruses have been investigated in humans for the past century. IMLYGICTM (T-VEC/Talimogene Laherparepvec), a genetically engineered Herpes Simplex Virus, is the first OV approved for use in the United States and the European Union for patients with locally advanced or non-resectable melanoma. Although OVs have a favorable toxicity profile and are impressively active anticancer agents in vitro and in vivo the majority of OVs have limited clinical efficacy as a single agent. While a virus-induced antitumor immune response can enhance oncolysis, when OVs are used systemically, the antiviral immune response can prevent the virus reaching the tumor tissue and having a therapeutic effect. Intratumoral administration can provide direct access to tumor tissue and be beneficial in reducing side effects. Immune checkpoint stimulation in tumor tissue has been noted after OV therapy and can be a natural response to viral induced oncolysis. Also for immune checkpoint inhibition to be effective in treating cancer, an immune response to tumor neoantigens and an inflamed tumor microenvironment are required, both of which treatment with an OV may provide. Therefore, direct and indirect mechanisms of tumor killing provide rationale for clinical trials investigating the combination of OVs other forms of cancer therapy, including immune checkpoint inhibition. PMID- 29254277 TI - Apoptosis in the aging liver. AB - Various changes in the liver during aging can reduce hepatic function and promote liver injury. Aging is associated with high morbidity and a poor prognosis in patients with various liver diseases, including nonalcoholic fatty liver disease, hepatitis C and liver cancer, as well as with surgeries such as partial hepatectomy and liver transplantation. In addition, apoptosis increases with liver aging. Because apoptosis is involved in regeneration, fibrosis and cancer prevention during liver aging, and restoration of the appropriate level of apoptosis can alleviate the adverse effects of liver aging, it is important to understand the mechanisms underlying this process. Herein, we elaborate on the causes of apoptosis during liver aging, with a focus on oxidative stress, genomic instability, lipotoxicity, endoplasmic reticulum stress, dysregulation of nutrient sensing, and liver stem/progenitor cell activity. PMID- 29254279 TI - Modeling the process of childhood ETV6-RUNX1 B-cell leukemias. AB - ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. Pre leukaemic clones carrying ETV6-RUNX1 oncogenic lesions are frequently found in neonatal cord blood, but only few ETV6-RUNX1 carriers develop pB-ALL. The highly demanding and pending challenge is to reveal the multistep natural history of ETV6-RUNX1 pB-ALL, because it can offer non-toxic prophylactic interventions to preleukemic carriers. However, the lack of a genetically engineered ETV6-RUNX1 mouse model mimicking the human pB-ALL has hampered our understanding of the pathogenesis of this disease. This rule has now been broken in a study of the effect of the ETV6-RUNX1 oncogene in cancer development in a mouse model in which oncogene expression is restricted to the stem cell compartment. In this article, we review the different attempts to model this disease, including the recent representative success stories and we discuss its potential application to both identify etiologic factors of childhood ETV6-RUNX1 pB-ALL and prevent the conversion of a preleukemic clone in an irreversible transformed state. PMID- 29254278 TI - Molecular hydrogen: a preventive and therapeutic medical gas for various diseases. AB - Since the 2007 discovery that molecular hydrogen (H2) has selective antioxidant properties, multiple studies have shown that H2 has beneficial effects in diverse animal models and human disease. This review discusses H2 biological effects and potential mechanisms of action in various diseases, including metabolic syndrome, organ injury, and cancer; describes effective H2 delivery approaches; and summarizes recent progress toward H2 applications in human medicine. We also discuss remaining questions in H2 therapy, and conclude with an appeal for a greater role for H2 in the prevention and treatment of human ailments that are currently major global health burdens. This review makes a case for supporting hydrogen medicine in human disease prevention and therapy. PMID- 29254280 TI - Ca2+ signaling in HCO3- secretion and protection of upper GI tract. AB - The cytosolic calcium ([Ca2+]cyt) is one of the most important cell signaling that can modulate gastrointestinal (GI) epithelial secretion and promote GI mucosal wound repair. The GI mucosal bicarbonate secretion is the main mechanism of mucosal protection. Our research team has been working in this field and provided solid evidence for the important role of Ca2+ signaling in the regulation of GI epithelial secretion and the underlying molecular mechanisms. In this review, we attempt to systemically review the current status of our knowledge on the role of Ca2+ signaling in the regulation of intestinal bicarbonate secretion and in the upper GI epithelial protection. We expect that novel targets could be identified for drug development to better protect GI mucosa and treat mucosal injury with the advance in this filed. PMID- 29254281 TI - Studies of lncRNAs in DNA double strand break repair: what is new? AB - The 'junk DNA' that has haunted human genetics for a long time now turns out to hold enormous hidden treasures. As species had their genomes and transcriptomes sequenced, there are an overwhelming number of lncRNA transcripts being reported, however, less than 100 of them have been functionally characterized. DNA damage is recognized and quickly repaired by the cell, with increased expression of numerous genes involved in DNA repair. Most of the time the studies have focused only on proteins involved in these signaling pathways. However, recent studies have implied that lncRNAs can be broadly induced by DNA damage and regulate DNA repair processes by various mechanisms. In this paper, we focus on recent advances in the identification and functional characterization of novel lncRNAs participating in DNA double strand break repair. PMID- 29254282 TI - Role of tandospirone, a 5-HT1A receptor partial agonist, in the treatment of central nervous system disorders and the underlying mechanisms. AB - 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter in the modulation of the cognitive, behavioral and psychological functions in animals and humans. Among the fourteen subtypes of 5-HT receptor, 5-HT1A receptor has been extensively studied. Tandospirone, an azapirone derivative with strong and selective agonist effect on 5-HT1A receptor, has been used for the treatment of anxiety disorders especially generalized anxiety disorder for decades. Recently, tandospirone showed the efficacy in relieving the syndromes of social anxiety disorder and post-traumatic stress disorder as well as in potentiating the effect of antidepressants in the treatment of depression in both preclinical and clinical studies. More impressively, the beneficial effect of tandospirone has been revealed on improvement of motor dysfunction of Parkinson's disease and cognitive deficits of schizophrenia either in monotherapy or in combination with other drugs. This review discusses the superiority of tandospirone in the treatment of the disorders and associated mechanisms in central nervous system from the literature. PMID- 29254283 TI - Functions of pancreatic stellate cell-derived soluble factors in the microenvironment of pancreatic ductal carcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with poor prognosis because it is highly resistant to traditional chemotherapy and radiotherapy and it has a low rate of surgical resection eligibility. Pancreatic stellate cells (PSC) have become a research hotspot in recent years, and play a vital role in PDAC microenvironment by secreting soluble factors such as transforming growth factor beta, interleukin-6, stromal cell-derived factor-1, hepatocyte growth factor and galectin-1. These PSC-derived cytokines and proteins contribute to PSC activation, participating in PDAC cell proliferation, migration, fibrosis, angiogenesis, immunosuppression, epithelial-mesenchymal transition, and chemoradiation resistance, leading to malignant outcome. Consequently, targeting these cytokines and proteins or their downstream signaling pathways is promising for treating PDAC. PMID- 29254285 TI - Picroside II attenuates fatty acid accumulation in HepG2 cells via modulation of fatty acid uptake and synthesis. AB - BACKGROUND/AIMS: Hepatic steatosis is caused by an imbalance between free fatty acids (FFAs) uptake, utilization, storage, and disposal. Understanding the molecular mechanisms involved in FFAs accumulation and its modulation could drive the development of potential therapies for Nonalcoholic fatty liver disease. The aim of the current study was to explore the effects of picroside II, a phytoactive found in Picrorhiza kurroa, on fatty acid accumulation vis-a-vis silibinin, a known hepatoprotective phytoactive from Silybum marianum. METHODS: HepG2 cells were loaded with FFAs (oleic acid:palmitic acid/2:1) for 20 hours to mimic hepatic steatosis. The FFAs concentration achieving maximum fat accumulation and minimal cytotoxicity (500 MUM) was standardized. HepG2 cells were exposed to the standardized FFAs concentration with and without picroside II pretreatment. RESULTS: Picroside II pretreatment inhibited FFAs-induced lipid accumulation by attenuating the expression of fatty acid transport protein 5, sterol regulatory element binding protein 1 and stearoyl CoA desaturase. Preatreatment with picroside II was also found to decrease the expression of forkhead box protein O1 and phosphoenolpyruvate carboxykinase. CONCLUSIONS: These findings suggest that picroside II effectively attenuated fatty acid accumulation by decreasing FFAs uptake and lipogenesis. Picroside II also decreased the expression of gluconeogenic genes. PMID- 29254286 TI - Mast cell in innate immunity mediated by proinflammatory and antiinflammatory IL 1 family members. AB - Innate immunity consists of physical and chemical barriers which provide the early defense against infections. Innate immunity orchestrates the defense of the host with cellular and biochemical proteins. Mast cells (MCs) are involved in innate and adaptive immunity and are the first line of defense which generates multiple inflammatory cytokines/chemokines in response to numerous antigens. MC activated antigen receptor Fc-RI provokes a number of important biochemical pathways with secretion of numerous vasoactive, chemoattractant and inflammatory compounds which participate in allergic and inflammatory diseases. MCs can also be activated by Th1 cytokines and generate pre-formed and de novo inflammatory mediators, including TNF. IL-37 is an anti-inflammatory cytokine which binds IL 18R-alpha chain and reduces the production of inflammatory IL-1 family members. IL-37 down-regulates innate immunity by inhibiting macrophage response and its accumulation and reduces the cytokines that mediate inflammatory diseases. Here, we discuss the relationship between MCs, innate immunity, and pro-inflammatory and anti-inflammatory cytokines. PMID- 29254287 TI - Thymoquinone protects against cobalt chloride-induced neurotoxicity via Nrf2/GCL regulated glutathione homeostasis. AB - The prevalence of neurodegenerative diseases worldwide has increased dramatically in the last decades. Hypoxia and oxidative stress play a central role in the pathogenesis of neurodegenerative diseases. Thymoquinone (TQ) is a monoterpenoid hydrocarbon compound that possesses potent antioxidant activity. In the current study, we investigated the neuroprotective effects of TQ against CoCl2, a widely used hypoxia-inducing agent. We found that TQ inhibited CoCl2-indcued cytotoxicity in vitro, as reflected by an increase of cell viability and decrease of apoptosis in CoCl2-treated PC12 cells. TQ exhibited a potent protective effect against CoCl2-induced neurotoxicity in vivo, as evidenced by decreased time spent to find the platform site in the Probe trials, reduced escape latencies, decreased traveling distance and reduction of apoptotic cell death in brains in CoCl2-treated rats. CoCl2-resulted decrease of glutathione (GSH) and increase of malondialdehyde (MDA) levels were significantly inhibited by TQ. Inhibition of GSH synthesis by buthionine sulphoximine (BSO) significantly attenuated TQ induced neuroprotective effects against CoCl2 in rats and in PC12 cells. TQ could upregulate nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/glutamate-cysteine ligase catalytic subunit (GCLc) and Nrf2/glutamate-cysteine ligase modifier subunit (GCLm) pathway which contributed to antioxidant and neuroprotective effects of TQ. In summary, we found that TQ exhibited protective effects against neurotoxicity via upregulation of Nrf2/GCL signaling. Upregulation of Nrf2/GCL signaling promoted the synthesis of GSH and contributed to attenuation of oxidative stress, neuronal cell apoptosis and neurotoxicity. These data have appointed a new path toward the understanding of the neuroprotective activities of TQ. PMID- 29254284 TI - Post-menopausal breast cancer: from estrogen to androgen receptor. AB - In the United States, breast cancer is the second leading cause of death among women, and even though different therapies can treat primary breast tumors, most breast cancer-related deaths (>95%) occur due to metastasis. A majority (~70%) of breast tumors are found to express estrogen receptor, and a significant portion (~90%) of ER-positive (ER+) breast tumors are also androgen receptor-positive (AR+). Although ER is known to promote tumorigenesis, the role and underlying mechanism(s) of AR in these closely knit processes remain controversial. Endocrine therapies are the most commonly used treatment for patients with ER+ breast tumors; but, ~30%-50% of initially responsive patients develop resistance to these therapies. Whereas 70%-90% of all breast tumors are AR+ and AR overexpression is correlated with endocrine resistance, but the precise molecular mechanism(s) for this association is yet to be studied. Multiple mechanisms have been proposed to show AR and ER interactions, which indicate that AR may preferentially regulate expression of a subset of ER-responsive genes and that may be responsible for breast cancer and its progression in affected patients. On the other hand, most of the ER+ breast tumors found in post-menopausal women (~80%); and they have very low 17beta-estradiol and high androgen levels, but how these hormonal changes make someone more prone to cancer phenotype has long been a disputed issue. In this study, we have discussed multiple molecular mechanisms that we believe are central to the understanding of the overall contributions of AR in breast cancer and its metastasis in post-menopausal women. PMID- 29254288 TI - Expression of genes responsible for cell morphogenesis involved in differentiation in porcine buccal pouch mucosal cells during long-term primary culture and real-time proliferation in vitro. AB - Recently, using experimental animal model, we demonstrated that porcine buccal pouch mucosal cells reflect increased proliferation capability during primary cultivation in vitro. Although the histological structure and morphogenesis in oral cavity is well recognized, the molecular mechanisms which regulate this process still need further investigation. This study was aimed to analyze the molecular marker expression profile involved in morphogenesis and differentiation capacity of porcine buccal pouch mucosal cells during their long-term primary cultivation in vitro. The experiment was performed on buccal pouch mucosal cells isolated from 80 pubertal crossbred Landrace gilts. After collection, the cells were treated enzymatically and transferred into a primary in vitro culture (IVC) system and cultured for 30 days. The cells were collected for RNA isolation after 7, 15 and 30 days of IVC and were checked for their real-time proliferative status using the RTCA system. We found an increased expression of FN1 and SOX9 genes when calculated against ACTB after 7, and 30 days of IVC, (P less than 0.01, P less than 0.001, respectively). The CXCL12 mRNA was down-regulated after 7, 15 and 30 days of IVC, but not statistically significant. Similar expression profile was observed when calculated against HPRT, however, DAB2 was found to be higher expressed at day 15 of IVC, (P less than 0.05). The cell index measured during real-time cell proliferation was substantially increased between 96 h and 147h of IVC and reached the log phase. Since FN1 and SOX9 revealed significant increase of expression after long-term culture in vitro, it is suggested that expression of these differentiation and stemness genes is accompanied by cell proliferation. Moreover, FN1 and SOX9 might be recognized as new markers of buccal pouch mucosal cell proliferation and differentiation in pigs in in vitro primary culture model. PMID- 29254289 TI - Tea catechins induce crosstalk between signaling pathways and stabilize mast cells in ulcerative colitis. AB - It is well documented that nutraceuticals, in general, and Green tea catechins, in particular, possess a potential therapeutic value in inflammatory bowel diseases (IBD) due to their anti-oxidative and anti-inflammatory effects. This study aimed to investigate the possible mechanism of action of catechins in a rat model of colitis induced by 2.4.6 trinitrobenzene sulfonic acid (TNBS). Thirty five young adult Sprague-Dawley rats were divided into four groups: normal control (n=5), catechins (n=9), TNBS (n=9) and TNBS plus catechins (n=12) treated. Catechin in the form of Epigallocatechin-3-gallate (EGCG) was administered daily by intraperitoneal injection, 1 week before the induction date of UC. Biopsies of the descending colon were collected on days 3, 10 and 17, and partly frozen for molecular studies or fixed for light microscopy. The status of intestinal tissue alterations and mast cells number were also assessed, as well as the mRNA expressions of IL-6, TNF-a and NF-kB, and determination of ROS expression. Histological data depicted a significant amelioration in the TNBS- and EGCG-treated rats compared to the non-treated animals. Catechin expressed strong anti-inflammatory and anti-oxidant effects, ameliorated ulcerative colitis and stabilized mast cells. The mechanism of action occurred basically through the NF-kB pathway and possibly through a crosstalk with other pathways. PMID- 29254290 TI - Expression and clinical significance of ARTN and MMP-9 in endometrial carcinoma. AB - The aim of this study was to detect the differential expression of Artemin (ARTN) and matrix metallopeptidase protein 9 (MMP-9) in endometrial carcinoma (EC) and to assess their clinical significance in order to provide insight into the pathological mechanism of tumor infiltration and metastasis in EC. A total of 48 patients who had undergone surgery for EC at the School of Medicine and Affiliated Hospital of HeBei University of Engineering between July 2015 and July 2016 were included in the study. The 48 patients were classified into 3 groups according to tumor stage: 27 patients with EC stage I, 12 patients with EC stage II and 9 patients with EC stage III. The samples collected from each patient included fresh normal endometrial tissue, endometrial simple hyperplastic tissue and endometrial atypical hyperplastic tissue. The transcription levels of ARTN and MMP-9 mRNA in each group were investigated using RT-PCR. The expression levels of ARTN and MMP-9 protein in each group were examined using Western blotting. Spearman?s correlation analysis was used to analyze the correlation between the expression levels of ARTN and MMP-9 proteins and EC tissue type. RT PCR and Western blotting assays revealed that the expression levels of ARTN and MMP-9 were increased in normal endometrial tissue, simple hyperplastic tissue, atypical hyperplastic tissue and EC of stages I, II and III. The differences noted were statistically significant (P less than 0.05). Furthermore, Western blot analysis indicated that the expression levels of ARTN and MMP-9 proteins in lymphatic metastatic tissues were higher than those in non-lymphatic metastatic tissues (P less than 0.05). The expression levels in the infiltration tissues of the deep muscular layer were higher than those noted in the light muscular layer (P less than 0.05). The expression levels of ARTN and MMP-9 proteins were positively correlated (P less than 0.05). The data suggest that ARTN and MMP-9 are involved in the occurrence, development, invasion and metastasis of EC, and play a synergistic role in the development of EC and lymphatic metastasis. PMID- 29254291 TI - Tumor potential in rat wounds after short- and long-term administration of platelet-rich plasma. AB - Platelet-rich plasma (PRP) has been recognized as an effective strategy for tissue regeneration, how-ever, the safety of PRP in wound healing in terms of tumorigenicity has not yet been addressed. Therefore, the aim of this study was to examine the impact of PRP administration on the expression of the inflammatory marker, tenascin-C (TnC) and the myofibroblast markers, alpha-smooth muscle actin (alpha-SMA) and vimentin. The immune suppressive response was examined by determining the level of forkhead box protein 3 (Foxp3). PRP was administered for both long-term (two times weekly for four weeks) and short-term (for the fourth week only) post-wounding. Collagen I (col1) and lysyl oxidase (LOX) were used to indicate complete healing, after which any increase in the myofibroblast or in the inflammatory markers would suggest tumor potential. Collagen III (col3), a marker for granulation tissue, was used to remark non-healing. Quantitative real time reverse transcriptase polymerase chain reaction (QRT-PCR) and Western blot showed that after long-term administration of PRP, the expression of TnC, alpha SMA and vimentin was barely detected, while being markedly expressed in the wounded non-treated group and in the short-term administration group. Moreover, the active expression of alpha-SMA in the two groups was associated positively with the expression of col3 and negatively with the expression of col1. The low expression of Foxp3 after short-term administration relative to the control group indicated active immunity against tumor development. In conclusion, these findings indicate that PRP can be safely used in short- and long-term administration without tumorigenesis concern. PMID- 29254292 TI - Characterization of human apical papilla-derived stem cells. AB - Dental tissues represent an alternative and promising source of post-natal Mesenchymal stem cells (MSCs) for tissue engineering. Furthermore, dental stem cells from apical papilla (SCAPs) cells can be obtained from the wisdom tooth which is unnecessary for human masticatory function and frequently extracted for orthodontic reasons or dysodontiasis. More precisely, apical papilla is the immature, mostly uncalcified, precursor of the tooth root, therefore is composed of more undifferentiated cells than dental pulp. In addition, tooth extraction, especially by piezosurgery technique, can be considered less invasive in comparison to bone marrow or other tissues biopsy. Our work is aimed to investigate the safety of and predictable procedure on surgical immature third molar extraction and to provide new insight on SCAP research for future biomedical applications. The isolated cells were examined for stem cell properties by analyzing their colony-forming efficiency, differentiation characteristics and the expression of MSC markers. PMID- 29254293 TI - Human cardiac multipotent adult stem cells in 3D matrix: new approach of tissue engineering in cardiac regeneration post-infarction. AB - Myocardial infarction is the leading cause of morbidity and mortality in developed countries. It causes a left ventricular dysfunction, mainly due to the loss of functional tissue, resulting in heart failure. New therapies are being developed, using a tissue engineering approach, with the ultimate goal of restoring cardiac function by regenerating and repairing the damaged myocardium. In the present study we investigated the behaviour of a specific population of c kit positive human cardiac stem cells, called Multipotent Adult Stem Cells (MASCs), grown within three-dimensional collagen scaffolds (3D), to establish whether they could be used in post-infarction cardiac regeneration. We also evaluated the expression levels of the Granulocyte Macrophage-Colony Stimulating Factor Receptor (GM-CSFR) and endoglin, a component of the Transforming Growth Factor beta (TGF-beta) receptor complex. Finally, we also evaluated the expression of the alpha2beta1integrin. MASCs cultured within 3D collagen matrices are able to proliferate and migrate even in the absence of chemotactic agents and express high levels of factors involved in cell proliferation and migration, such as GM-CSFRalpha chain and integrins. They therefore represent a promising approach to tissue engineering aimed to restore cardiac function. Our results also suggest a role of GM-CSF in cell proliferation, while TGF-beta does not seem to be relevant. PMID- 29254294 TI - Autophagy-related gene expression in colorectal cancer patients. AB - There is evidence that autophagy can play a dual role in tumor cells ? as a tumor suppressor, and a process involved in tumor cell survival. The aim of this work was to assess the expression of the genes engaged in the autophagy process in biopsies taken from the colon, confirmed as adenocarcinoma, and normal tissue and to relate them to the clinical stage of the tumor. A total of 20 pairs of surgically removed tumors and healthy (marginal) tissue samples from colorectal cancer patients at clinical stages (CS) I-IV were analyzed. Gene expression profile analysis was performed using HG-U133A microarrays. Differentially expressed genes were identified, using the PL-Grid Infrastructure. Only for CSI, there were two specific genes: FOXO1 and BNIP1; further in CSII ? LAMP2, MET and BCL2L, in CSIII ? HIF1A and 2 ID mRNAs for HGF and 18 genes were specific for CSIV in comparison to controls. PINK1 is the only gene that differentiates all transcriptome groups from controls. Furthermore, examination of the expression of genes associated with the autophagy process may allow for better knowledge and understanding of the processes occurring during the development of colon cancer. The presented genes may be used as prognostic markers of clinical stages of colorectal cancer, contributing to the development of new lines of therapy focused on reducing metastasis of the primary tumor. PMID- 29254295 TI - Serum levels of ADAM10, ADAM12, ADAM17 AND ADAM28 in colorectal cancer patients. AB - Colorectal cancer is the third most common cancer in the world. Our study analyzed the potential significance of serum levels of selected adamalysines (ADAM10, ADAM12, ADAM17, ADAM28) in colorectal cancer patients. The study was performed on a group of 85 colorectal cancer patients (48 men, 37 women). Serum protein concentrations were measured by ELISA. The ADAMs serum level changes were analyzed according to selected clinical parameters (BMI, sex, age, clinical stage of disease). The following ranges of concentration of analyzed proteins were obtained: ADAM10 min=1.7, max=321.8 [ng/ml]; ADAM12 min=0.6, max=26.7 [ng/ml]; ADAM17 min=0.4, max=9.8 [ng/ml]; ADAM28 min=17.1, max=1545.8 [ng/ml]. In addition, it was stated that there is a relationship between the serum level of ADAM28 and the degree of the clinical stage (p less than 0.04). The obtained results could be the starting point for further research into the role of adamalysines in the development of colorectal cancer, as well as the potential predictive and prognostic value of these proteins. PMID- 29254296 TI - Bioinformatic analysis of pivotal genes associated with septic shock. AB - We aimed to identify important genes associated with septic shock and then explore the possibly significant mechanisms of this disease. We downloaded GSE26440 expression data of samples from 98 children with septic shock and 32 normal controls from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in samples from patients with septic shock were analyzed in comparison with those in samples from normal controls using a limma package. Functional enrichment analysis for DEGs was performed using DAVID, and a protein?protein interaction (PPI) network was constructed. Upstream transcription factors for DEGs were predicted using the CHIPBase database, and a transcriptional regulation network was constructed. A total of 383 significantly DEGs, including 141 downregulated and 242 upregulated genes, were obtained in the sepsis shock group compared with the normal group. The top five nodes in the PPI network were lysine (K)-specific demethylase 6B (KDM6B), histone deacetylase 2 (HDAC2), V-Myc avian myelocytomatosis viral oncogene homolog (MYC), heat-shock protein 90 kDa alpha (cytosolic), class B member 1 (HSP90AB1), and poly (A) binding protein, cytoplasmic 1 (PABPC1). Nuclear factor kappa-light-chain enhancer of activated B cells (NFkB) was the transcription factor targeted by most genes, and it regulated the expression of KDM6B, HDAC2, MYC, HSP90AB1, and PABPC1. In conclusion, KDM6B, HDAC2, MYC, HSP90AB1, and PABPC1 may play important roles in the development of septic shock. Furthermore, NFkappaB may be involved in septic shock by regulating the expression of KDM6B, HDAC2, MYC, HSP90AB1, and PABPC1. PMID- 29254297 TI - Propolis nasal spray effectively improves recovery from infectious acute rhinitis and common cold symptoms in children: a pilot study. AB - Currently, treatment for acute rhinitis (AR) is symptomatic but no clear agreement exists to control its development. Propolis extract may appear as a promising natural treatment for AR, but its beneficial effects have not yet been fully tested. Forty children suffering from AR and common cold symptoms aged between 2-12 years were enrolled in a prospective epidemiological multicentre study. A 7-day treatment with propolis nasal spray (3 times/day) was applied and a comparison of symptomatology, subjective global improvement and quality of life (QoL) between baseline (day 1) and final (day 7) visits were performed. The main goal was to evaluate the changes in symptom intensity using the Jackson?s scoring test. After 7 days of treatment there was a significant decrease of symptoms both in the total score (p less than 0.0001) and in regard to each AR symptom (p less than 0.01). On the whole, the sample reported no symptoms by day 7, and the resolution of symptoms occurred approximately at day 4. Furthermore, there was no need for supplementary treatment. Both the subjective global improvement impression and the QoL of patients appeared to significantly improve after treatment. No adverse events (AEs) were found globally. It can be concluded that propolis nasal spray effectively improves recovery from infectious AR and common cold symptoms in children and is an optimal alternative in the treatment of this disease without need for any adjuvant treatment. PMID- 29254298 TI - Alterations in transaminase activity and serum level of leptin and hepcidin induced by high fat diet in albino rats. AB - Obesity is a commonly growing life-threatening problem of the modern world. The present study was aimed to assess alterations in transaminase levels as well as leptin and hepcidin levels of sera through ELISA after high fat diet consumption for sixteen weeks by albino rats (n=5). Three groups were established: experimental groups 1 and 2 and a control group. Group 1 was fed on a high fat diet having a composition of 33% rat chow +33% sucrose +33% milk powder. Similarly, group 2 was fed with another high fat diet with a mixture of rat chow and milk powder ad libitum. The control group was fed on normal rat chow and water ad libitum. After sixteen weeks, the rats were euthanized and blood was collected for serum separation. Serum levels of alanine aminotransferase showed a positive significant increase (P=0.0325) while a significant negative change (P=0.0006) was noted in aspartate aminotransferase levels in both the experimental groups compared to the control group. Serum leptin levels were found to be increased up to 10.06-fold in Group 1 and 6.11-fold in Group 2 when compared to controls. On the other hand, serum hepcidin levels showed up to 1 fold and 2.59-fold changes in Group 1 and Group 2, respectively, compared to controls. Taken together, from these results it can be concluded that a high fat diet not only disturbs normal metabolism, but it also leads to liver inflammation which is obvious by the changes in transaminase activity as well as leptin and hepcidin levels. PMID- 29254299 TI - Elevated plasma il-8 concentration is related to severity of systemic inflammation in chronic spontaneous urticaria. AB - Chronic spontaneous urticaria (CSU) is associated with activation of acute phase response. Questions arise regarding its association with other inflammatory mediators. To determine plasma IL-8 concentration in CSU patients and its association with C-reactive protein (CRP) concentration, a nonspecific inflammatory marker of the disease activity, concentrations of plasma IL-8 and serum CRP were measured in CSU patients and compared with healthy controls. IL-8 and CRP concentrations were significantly higher in CSU patients as compared with the healthy subjects. In addition, there were significant differences in IL-8 and CRP concentrations between CSU patients with moderate-severe symptoms and the healthy subjects. Plasma IL-8 and serum CRP concentrations showed a significant correlation with urticaria activity score (UAS). Additionally, a significant positive correlation was observed between IL-8 and CRP concentrations. Up regulations of IL-8 and its association with the marker of clinical and inflammatory activity suggest a role of this cytokine in the pathogenesis of CSU. PMID- 29254300 TI - Antimicrobial, antioxidant, cytotoxicity and LC-MS analyses of Aerva javanica: an ethnomedicinally important plant. AB - In this study, Aerva javanica was used to extract the essential oil with notable medicinal activities. The chemical composition was investigated by high performance liquid chromatography (HPLC) and liquid chromatography/mass spectrometry (LC-MS). Ten major chemical compounds were identified as flavonoids derivatives, dihydroxylated and glycosylated metabolites. The antimicrobial, antioxidant, and cytotoxicity activities were tested using agar well-diffusion assay, 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free-radical scavenging and linoleic acid oxidation assays and hemolytic assay against human erythrocytes (RBCs), respectively. Plant extracts exhibited different extents of antimicrobial activities against selected bacterial and fungal strains; however, the essential oil displayed potent antimicrobial activity against all the tested strains. The percentage inhibition of linoleic acid oxidation and inhibitory concentration (IC50) were recorded to be in the range of 42.45-96.21% and 14.21-38.18 MUg/mL, respectively. Cytotoxicity profile of A. javanica extracts and essential oil was found in the range of 5.82 to 14.47%. In conclusion, A. javanica essential oil could be a potential alternative to chemical additives in the food and pharmaceutical industries. PMID- 29254301 TI - Analysis of specialized nursing on respiratory functions in thoracotomy patients. AB - To analyze the nursing effect on the respiratory function of thoracotomy patients, sixty thoracotomy hospitalized patients were studied. The subjects were divided into a normal group (A) and an observation group (B). The patients in group A received routine nursing only, while those in group B received chest physiotherapy as well as routine nursing. Afterwards, the respiratory function indicators of the two groups were compared and a data analysis was performed. The results showed that the partial pressure of oxygen (PO2) value of the patients in group B was greater than that of the patients in group A while the partial pressure of carbon dioxide (PCO2) value in group B was smaller than that in group A, and there was a significant difference between the two groups (p less than 0.05). The vital capacity under normal circumstances and forced breathing of group B were greater than that of group A and the difference was statistically significant (p less than 0.05). The incidence of complications (atelectasis, respiratory infections, pleural effusion) was statistically significant between the two groups (p less than 0.05). The degree of autonomic respiratory dysfunction in group B was lower than that in group A, and there was a significant difference (p less than 0.05), suggesting that the respiratory function in patients receiving chest physiotherapy improved significantly. PMID- 29254302 TI - Inhibition of PAR2 and TRPA1 signals alleviates neuropathic pain evoked by chemotherapeutic bortezomib. AB - Bortezomib (BTZ) is generally used as a chemotherapeutic agent for the treatment of multiple myeloma; however, one of the significant limiting complications of BTZ is painful peripheral neuropathy observed during BTZ therapy. There is a lack of drugs which can prevent and/or treat the painful symptoms induced by BTZ, as the underlying molecular mechanism leading to neuropathic pain remains largely unclear. In the present study, we examined engagement of proteinase-activated receptor 2 (PAR2) and transient receptor potential ankyrin 1 (TRPA1) in neuropathic pain induced by BTZ in rats. Our results demonstrated that systemic injection of BTZ increased mechanical pain and cold sensitivity as compared with control animals (P less than 0.05 vs control rats). Our data further showed that blocking respective PAR2 and TRPA1 attenuated mechanical pain and cold sensitivity observed in control rats and BTZ rats (P less than 0.05 vs vehicle control). Notably, the attenuating effect of blocking PAR2 and TRPA1 on mechanical pain and cold sensitivity was significantly less in BTZ rats than that in control rats. In addition, protein expression of PAR2 and TRPA1 was upregulated in the lumbar dorsal root ganglion of BTZ rats, and inhibition of PAR2 decreased the levels of TRPA1 and attenuated its downstream pathways (namely, PKCE and PKA). Overall, we revealed specific signaling pathways leading to neuropathic pain induced by chemotherapeutic BTZ and that blocking PAR2 and TRPA1 in sensory nerves is beneficial to improve neuropathic pain during BTZ intervention. PMID- 29254303 TI - Dose-dependent acute phase response of aqueous leaf decoction of Nerium oleander in Wistar rats. AB - Many studies have been carried out in order to determine the toxicity of medicinal plants. The objective of this study was to compare and analyze the hepatic response against two doses of Nerium oleander, (N. oleander) ?kaner? leaf decoction. Aqueous leaf decoction was injected intramuscularly into both hind limbs of male rats (200∓10g), assigned into three categories (n=4): control group with no treatment; group I, injected with 5 ml/ kg; and group II injected with 10 ml/ kg of leaf decoction, respectively. Animals were sacrificed 6 h after administration and hepato-histological changes were then observed. The decoction induced an acute phase reaction reflected by a more significant recruitment of inflammatory cells in group II than in group I and controls, as observed by histological studies. These results indicated that both doses can induce an acute-phase condition. Hence, traditional practice of medicinal plants without preliminary dose assessment must not be administered. PMID- 29254304 TI - Coagulation in hindbrain membrane meningioma patients treated with different injections using acute hypervolemic hemodilution. AB - The aim of this study was to analyze the changes in coagulation in meningioma patients treated with different injections using the method of acute hypervolemic hemodilution (AHH). One hundred fifty hindbrain membrane meningioma patients were randomly divided into 5 groups, 30 per group. The first group were injected 40ml/time with Danhong after anesthesia induction; the second group were injected with 40ml~60ml/time Kangai and combined with interventional chemotherapy and embolization procedure; the third group of AHH were injected with polygeline 15ml/kg; the fourth group were injected with hydroxyethyl starch (130/0.4) sodium chloride in doses of 15ml/kg; the control group underwent basic treatment for lowering blood pressure and lowering blood fat. The changes of coagulation index were recorded before and after surgery and before and after the injection of different medications. Compared to the control group, for the first group of AHH, after being treated for 10 days and 30 days, the concentrations of bone specific alkaline phosphatase (BALP), bone Gla protein (BGP) and pro-collagen carboxy terminal propeptide (PICP) were higher than that of the control group, the levels of endotoxin (ET) and C-reactive protein (CRP) were decreased compared to the control group (p less than 0.05); for the second group of AHH, after being treated for 10 days, the index of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg) were not significantly changed, but the related level of vascular endothelial growth factor (VEGF) significantly decreased (p less than 0.05). Comparing the coagulation function index after surgery in the third and fourth groups, there were no significant changes in mean arterial pressure (MAP) level, heart rate (HR) value presented a low decrease, central venous pressure (CVP) level increased and the level of interleukin IL-6 showed a steady state after increasing. Analyzing the levels of interleukin IL-8 and tumor necrosis factor alpha (TNF-alpha) after surgery, it was seen that in the third group they increased and in the fourth group they decreased (p less than 0.05). Danhong injection improved the coagulation function and microcirculation of patients, Kangai injection and interventional chemotherapy and embolization restrained the appearance of tumor angiogenesis, AHH operation with polygeline injection and hydroxyethyl starch (130/0.4) sodium chloride kept blood flow in normal parameters. PMID- 29254305 TI - Age-related changes of bone mineral density in mandible by quantitative computed tomography. AB - Quantitative Computed Tomography (QCT) was used to investigate age-related changes in trabecular bones of the mandible. The volumetric Bone Mineral Density (vBMD) of mandibles was found to be increasing with aging in the 20-29, 30-39, 40 49 age groups, while resulted decreasing in the 50~ years age group in a Chinese population. The aim of this study was to validate QCT as a reliable method to measure the vBMD of the mandible and to assess vBMD of the mandible in a Chinese population. A total of seven hundred and eighteen volunteers (299 males, 419 females), ranging from 20 to 63 years of age, previously enrolled in another study, were included for vBMD measurements by QCT. A total of 50 subjects were enrolled for the validation of QCT measurement. Basic information (age, height and weight), and vBMD of the mandible (middle, body and angle) were recorded. Comparisons among age and sex groups were analyzed using the Mann-Whitney test. Linear correlation analysis between vBMD and age was performed. The mandibular vBMD was twice measured with QCT by one operator and resulted highly repeatable (ICC 0. 97, P 0. 05). The vBMD in the middle of the mandible was the highest, followed by that in the body and at the angle of mandible. In each age group, the mean vBMD increased with aging except for the 50~ years age group (P less than 0.05) in which it decreased. The mean mandibular vBMD was higher in females than males in each age group (P less than 0.05). Correlation between vBMD and age was statistically significant (r=0.15, P less than 0.01). QCT shows high precision for the measurement of BMD in the mandible. The present study provides normative data of the mandible in an age- and sex-stratified manner, which can be helpful in clinical practice. PMID- 29254306 TI - Preoperative evaluation and surgical technique of functional and cosmetic aspects in zygomatic complex fracture patients. AB - The zygomatico-maxillary complex functions as the principle buttress of the face and is the cornerstone to an individual?s aesthetic appearance. Its fracture not only creates cosmetic deformities owing to its position and facial contour, but can also cause disruption of ocular and mandibular functions. The aim of this study was to evaluate the quality, efficacy and impact of internal fixation of zygomatic complex fractures on functional and cosmetic outcomes. A prospective study was carried out on 100 patients who were divided according to the classification and the severity of injury. Subjective evaluation was submitted based on the patient?s perception of signs and symptoms in the preoperative and postoperative periods. Intraoperative and postoperative assessment of bone reduction quality was made according to the type of the fracture and related difficulties; also, the difference between these groups was observed as functional and esthetic outcome. To optimize the treatment of zygomatic bone fractures, a pre-designed questionnaire was used for subjective evaluation of symptoms and treatment outcome. In 70% of cases, ophthalmologic consultation was taken and was most common in type VII fractures (100% cases). Neurosensory disturbance was the most common finding (60%), followed by diplopia (56R%), pain upon mouth opening (54%) and malar depression (50%). Out of all possible 400 fracture sites in 100 patients of zygomatic complex fractures, 266 (66.5%) fractures were detected by clinical examination, in contrast to 330 (82.5%) on radiological examination, which were highest at zygomatic-maxillary buttress (93%) followed by infraorbital rim (91%) and almost equal among fronto-zygomatic site (72%) and zygomatic arch (74%). The scores from the questionnaire for annoyance were significantly higher for paraesthesia (23%) than for trismus (10%), pain (8.5%), or deformity (8.25%). Residual deformity and pain significantly influenced the total satisfaction. Conclusively, there are many treatment modalities available for zygomatic complex fractures, and the preferred methods should be selected on the basis of fracture type, fracture severity, pre operative signs and symptoms. Regarding the requirements of fracture site exposure and actual fixation, one priority should be to minimize postoperative complications, morbidity and residual deformities. PMID- 29254307 TI - Social selection favours offspring prone to the development of androgenetic alopecia. AB - In recent years, dermatologists have observed an increase in the incidence of male androgenetic alopecia (AGA). In a survey of 41 dermatologists, 88% reported an increase in incidence of AGA in men younger than 30 years. This phenomenon has no apparent explanation. However, due to the strong genetic inheritance component of AGA, a social or environmental factor which favours the inheritance of genes that increase the risk of developing AGA is suspected. To date, the strongest predictor of AGA in men has been the length of the CAG repeat located in the androgen receptor gene (AR gene) on the X chromosome. The same genetic variant in women is associated with ovulation at a later age, higher antral follicle count, and lower risk for premature ovarian failure. This led us to theorize that, due to social pressure to conceive later in life, women carriers of the short CAG repeat in the AR gene would have a selective advantage to conceive later in life and would thus favour male offspring exhibiting AGA. PMID- 29254308 TI - Effectiveness of acupuncture in the management of cervical spondylosis: a meta analysis. AB - Cervical spondylosis is the most common type of spinal pathology which is more common in middle-aged or senile populations with a high potential to affect physical and mental health. This study evaluates the effectiveness of acupuncture in the management of cervical spondylosis. After a detailed literature search in electronic databases, the required data were acquired from selected research articles and meta-analyses were performed to obtain the percent cure, failure and total effectiveness rates under random effects model. Meta-regression was performed to identify the factors affecting the efficacy. Twenty-seven studies were selected for data acquisition (2,853 patients; average age 46.2+/-9.5; 51.7+/-12.5% males). Acupuncture alone had 33.41% (25.50, 41.24) cure rate but in combination with other therapies it rose to 53.36% (41.9, 64.8). Similarly, total effectiveness rate was 87.01% (83.40, 90.62) with acupuncture alone and 93.62% (89.85, 97.38) with acupuncture in combination with other therapies. Age was inversely associated with the percent cure rate and the number of combination therapies with acupuncture was positively associated with the cure rate. In conclusion, acupuncture therapy alone can provide cure and total effectiveness rates of 33% and 87%, respectively, but acupuncture with additional therapies can improve the cure and total effectiveness rates to 53% and 94%, respectively. Age inversely affects efficacy and the number of additional therapies improves the efficacy. PMID- 29254309 TI - Association of BCL-2 with oxidative stress and total antioxidant status in pediatric acute lymphoblastic leukemia. AB - B-Cell Lymphoma protein-2 (BCL-2) is one of the most studied proteins with substantial regulatory potential for both apoptosis and autophagy. BCL-2 confer chemoresistance through influencing cancer pathophysiology. Serum level of lactate dehydrogenase (LDH) predicts increased anaerobic glycolysis and is associated with metabolic modulation in cancer cells. In the present research, the interplay of BCL-2, total oxidative status (TOS) and LDH was investigated in patients with acute lymphoblastic leukemia (ALL). The studied parameters, BCL-2 protein (p less than 0.001), TOS (p less than 0.001) and LDH (p less than 0.001) were significantly elevated in the ALL group compared to the normal group (N group). However, the total antioxidant status (TAS) was reduced significantly (p less than 0.01) in ALL patients. In the ALL group, the TOS had significant negative correlation with TAS (p less than 0.01). Furthermore, non-significant positive correlations were found between BCL-2 and LDH, BCL-2 and TAS and LDH and TAS (each with; p>0.05). However, a negative non-significant correlation was observed between BCL-2 and TOS and LDH and TOS (each with; p>0.05). PMID- 29254310 TI - T1 mapping combined with Gd-EOB-DTPA-enhanced magnetic resonance imaging in predicting the pathologic grading of hepatocellular carcinoma. AB - The aim of this study was to investigate the value of Gd-EOB-DTPA-enhanced MRI on hepatobiliary phase (HBP) imaging and T1 mapping sequence in the differentiation of hepatocellular carcinoma (HCC). A total of 45 patients with HCC who were to undergo a resection were enrolled in this study. Gd-EOB-DTPA-enhanced magnetic resonance examination was performed prior to resection. T1 mapping was performed before and 20 min after injection of Gd-EOB-DTPA. T1 values of the lesions were measured on pre-contrast (T1p) and during HBP (T1-HBP) on T1 maps. The signal intensity, the diameter and the margin of HCC lesions on HBP images were analyzed. The reduction in T1 value (T1d) and the reduction rate (DeltaT1%) of T1 mapping between pre-contrast and HBP were calculated. The Edmondson-Steiner classification of each lesion was made after surgery. The SPSS software package was used for statistical analysis and the analysis of receiver operator characteristic (ROC) curve and area under the curve (AUC) were carried out by using MedCalc software package. Mean values of T1p and T1-HBP were 1935.4+/-730.8 ms and 1257.1+/-529.1 ms, respectively. T1p accuracy (AUC = 0.685, p = 0.037) in predicting pathological grading was similar to that of T1-HBP (AUC = 0.751, p = 0.005). A T1p of 1648.2 ms or greater had a sensitivity and specificity of 85.19% and 61.11%, respectively. A T1-HBP of 1006 ms or greater had a sensitivity and specificity of 81.84% and 61.11%, respectively. The number of HCCs with a non smooth tumor margin was 20 (44.4%), and a non-smooth tumor margin correlated moderately with the Edmondson-Steiner grade (Spearman r = 0.491, p = 0.041). There was no significant correlation between T1d, DeltaT1%, HCC signal intensity on HBP image and lesion diameter with pathologic grading. T1 mapping in pre contrast and HBP of Gd-EOB-DTPA-enhanced MRI, a non-smooth tumor margin in the HBP of Gd-EOB-DTPA-enhanced MRI, are useful in predicting the pathologic grading of HCC. PMID- 29254311 TI - Link between cutaneous infection, stress and depression. AB - Depression and mood disorders often develop after dermatological conditions which could be primary or secondary to dermatological pathology. The oxidative and psychological stress cause physiological changes in the body. Shift in the methylation pathway, elevated cortisol, lowered neurotransmitter levels and lowered immune system allow infection to penetrate the body and lead to anxiety and depression. Here, a case report of a 20 year old male patient is presented to show how infectious skin lesions, unresponsive to the usual treatment plan, were treated after using a multipronged approach of addressing systemic infection of Escherichia coli, elevated cortisol levels and nutritional imbalances. PMID- 29254312 TI - p16 gene expression in pancreatic cancer tissue and its importance in diagnosis. AB - The aim of this study was to assess the importance of p16 gene expressions in pancreatic cancer tissue for early diagnosis and treatment. Two groups were included in the study: an experimental group of 35 pancreatic cancer tissue specimens and a control group of 35 pancreatic cancer adjacent tissues collected during surgery. The expression of p16 gene in the two groups was observed using the immunohistochemical streptavidin peroxidase conjugated (S-P) method. The results were statistically interpreted using SPSS22.0 software. The positive expression rate of p16 in the experimental group was lower than that of the control group (p less than 0.05). Comparing the intensity of p16 gene expression, differentiation degree, clinical stage and metastases of nearby lymph nodes the differences had statistical significance (p less than 0.05). The intensity of p16 gene expression in high and medium differentiated pancreatic cancer group was higher than that of the low differentiated group. p16 gene expression in stages III and IV groups was lower than that in stages I and II groups. Differentiation degree, clinical stage, metastases of nearby lymph nodes and distant metastasss were negatively related with p16 gene expression (p less than 0.05). There was no correlation between age or gender and p16 gene expression. The decreased expression of p16 gene in pancreatic cancer tissue was negatively correlated with differentiation degree and clinical stage. Our results indicated that p16 can be used as a cue signal for diagnosing advanced pancreatic cancer. PMID- 29254313 TI - Mechanism of action of minoxidil in the treatment of androgenetic alopecia is likely mediated by mitochondrial adenosine triphosphate synthase-induced stem cell differentiation. AB - Topical minoxidil is the only topical drug approved by the US Food and Drug Administration (FDA) for the treatment of androgenetic alopecia. However, the exact mechanism by which minoxidil stimulates anagen phase and promotes hair growth is not fully understood. In the late telegen phase of the hair follicle growth cycle, stem cells located in the bulge region differentiate and re-enter anagen phase, a period of growth lasting 2-6 years. In androgenetic alopecia, the anagen phase is shortened and a progressive miniaturization of hair follicles occurs, eventually leading to hair loss. Several studies have demonstrated that minoxidil increases the amount of intracellular Ca2+, which has been shown to up regulate the enzyme adenosine triphosphate (ATP) synthase. A recent study demonstrated that ATP synthase, independent of its role in ATP synthesis, promotes stem cell differentiation. As such, we propose that minoxidil induced Ca2+ influx can increase stem cell differentiation and may be a key factor in the mechanism by which minoxidil facilitates hair growth. Based on our theory, we provide a roadmap for the development of a new class of drugs for the treatment of androgenetic alopecia. PMID- 29254314 TI - Expression profile of eukaryotic translation initiation factor and matrix metalloproteinase 9 in endometrial cancer tissue. AB - The aim of the present study was to provide a novel method for the diagnosis, prevention and treatment of endometrial cancer by the determination of the characteristic expression of the eukaryotic translation initiation factor 4E (eIF4E) and the enzyme matrix metalloproteinase 9 (MMP9) in endometrial cancer tissue. Three types of endometrial tissue specimens were selected (including 20 cases of normal endometrial tissue specimens, 15 cases of hyperplastic endometrial tissue specimens and 45 cases of endometrial cancer tissue specimens). The expression of eIF4E and MMP9 in the specimens was examined by immunohistochemistry and their corresponding levels were statistically analyzed. The positive expression rates of eIF4E and MMP9 in endometrial cancer specimens were 64.44% and 66.67% respectively, which were higher than those noted in hyperplastic endometrial tissue specimens and normal endometrial tissue specimens (p less than 0.05). The comparisons between the groups indicated that the expression levels of eIF4E and MMP9 in the endometrial cancer specimens were increased compared with those noted in the normal endometrial tissue specimens (p less than 0.0167). In endometrial cancer specimens, the positive expression rates of eIF4E and MMP9 were related to the endometrial cancer stages as determined by the International Federation of Gynecology and Obstetrics (FIGO), tumor cell differentiation degree and lymphatic metastasis (p less than 0.05) classifications. eIF4E expression was positively related to MMP9 expression in endometrial cancer specimens. High expression levels of eIF4E and MMP9 proteins were noted in endometrial cancer specimens, which were correlated with FIGO stages, histological grade and degree of lymphatic metastasis. Thus, endometrial cancer and malignant biological behavior may be connected to the high expression of eIF4E and MMP9. The positive correlation between eIF4E and MMP9 expression in endometrial cancer specimens suggests their potential up-regulation during carcinogenesis. PMID- 29254315 TI - Tacrolimus induced nephrotoxicity and pulmonary toxicity in Wistar rats. AB - Transplantation has evolved into an accepted treatment for end-stage organ failure. The major limitation for solid organ transplantation is organ rejection, which is an adaptive immune response caused by the activation of T-cells. Immunosuppressant drugs are used to overcome this problem. Tacrolimus is a powerful immunosuppressive drug which is used to minimize the risk of organ rejection. The present study was designed to find the toxic effects of tacrolimus on lungs and kidneys. Wistar rats were divided into 4 experimental groups and one control group (n=9). Each rat of the experimental group was orally given the aqueous suspension of tacrolimus powder (3mg/ml) and dissected after 6, 12, 24 and 48 hours of tacrolimus suspension dose. Lungs and kidneys were excised and processed for histopathological and histochemical alterations. Kidney tissues presented signs of toxic potential on tissue architecture such as increased interstitial spaces, necrosis, especially acute tubular necrosis, glomerular shrinkage, dilated blood vessels and enlargement of Bowman?s capsule. Lung sections also confirmed the toxic potential, characterized by bronchiolar wall thickening, alveolar cells necrosis, collapsing of alveolar spaces and interstitial round cell infiltrate. Results of Prussian blue iron staining showed no iron deposition in kidney architecture while in lung sections, iron accumulation was evident. Taken together from these observations we can conclude that tacrolimus may induce toxicity to a certain extent with structural distortion of the kidneys and lungs. PMID- 29254316 TI - Relationship between transmembrane serine protease expression and prognosis of esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma is the most common type of esophageal cancer in Eastern Europe and Asia, being the 6th most common cause of cancer deaths worldwide. The aim of this study was to analyze the expression of transmembrane serine protein in esophageal squamous cell carcinoma, and to correlate it with the clinical biological features of esophageal cancer. The expression of transmembrane protease serine 4 (TMPRSS4) mRNA and protein in carcinoma tissues and corresponding adjacent tissues and non-tumorous esophageal tissues was determined using PCR (qRT-PCR). The results show that both TMPRSS4 mRNA and protein expression were remarkably lower in adjacent normal tissues than in tumorous tissues. TMPRSS4 protein expression in esophageal carcinoma was correlated with patient demographic characteristics, tumor type, high TNM stages and overall survival (OS). Based on the experimental results, we conclude that TMPRSS4 is closely related to the occurrence, development and metastasis of esophageal squamous cell carcinoma. PMID- 29254317 TI - Quick rehabilitation nursing improves the recovery of colon cancer patients after laparoscopy. AB - Colon cancer is a common malignant tumor with particularly high morbidity and mortality. The aim of this study was to compare the effect of quick rehabilitation nursing and routine nursing in postoperative recovery of patients with colon cancer after laparoscopic surgery. Two hundred forty patients with colon cancer were classified into four random groups (A, B, C and D, with 60 patients in each group). All patients underwent surgery to remove the colon tumor by laparoscopy under general anesthesia. Patients in groups A and B received quick rehabilitation nursing for post-surgery recovery. In group C patients, local anesthesia associated with quick rehabilitation nursing for post-surgery recovery was used. Group D was used as control group and the patients were treated based on routine nursing. Time to get out of bed, first bowel movement time and the average time of hospitalisation in group A was lower than group D (p less than 0.05), postoperative leukocyte level as well as the occurrence rate of nausea and vomiting, ankylenteron and pelvic adhesion was decreased in group A compared to group D (p less than 0.05), but the postoperative albumin and total protein level was higher than group D (p less than 0.05). The serum level of C Reactive Protein (CRP) and interleukin 6 (IL-6) in group A was decreased compared to group D several days after surgery (p less than 0.05); group B had 4 cases of intestinal obstruction after surgery that could be cured through conservative treatment, while group D had 10 cases of intestinal obstruction, 8 of which could be cured through conservative treatment and two needed surgery (p less than 0.05); VAS for pain degree of group C in active state was clearly lower at 1h, 5h, 7h, 15h, 30h and 42h after surgery, and side effects of postoperative analgesia were clearly reduced. Time to get out of bed was obviously decreased, while there was no evident effect on postoperative dosage, chronic pain and complications. Adopting quick rehabilitation nursing can effectively reduce occurrence of complications and postoperative pain, speed up the recovery of gastrointestinal function, shorten the length of stay, and improve patients? satisfaction. PMID- 29254318 TI - Perioperative plasmatic presepsin levels in patients undergoing total hip or knee replacement: a preliminary study. AB - Presepsin (sCD14-ST) is an emerging biomarker in the diagnosis of sepsis. In the field of orthopaedics, it could be useful in the diagnosis and management of periprosthetic joint infections (PJI). The aim of this study is to define the normal perioperative plasmatic levels of presepsin in patients undergoing primary cementless total hip replacement (THR) or primary cemented total knee replacement (TKR). For this purpose, 50 patients (19 male, 31 female, mean age= 64.04+/-8.88) were recruited. The patients were divided into two groups: Group A patients underwent cementless THR, whereas Group B patients underwent cemented TKR. On recruitment, anthropometric data, smocking status, osteoarthritis stage according to Kellgren and Lawrence, Harris Hip Score (HHS) for Group A patients and Knee Society Score (KSS) for Group B patients, drugs assumption and comorbidities were recorded. All the patients underwent serial blood tests, including complete blood count, presepsin (PS), C-reactive protein (CRP) and procalcitonin (PCT) 24 hours before arthroplasty (T0) and at 24 (T1), 48 (T2), 72 (T3) and 96 (T4) hours postoperatively. Body temperature (theta) was recorded every six hours in the time lapse T0-T4. Presepsin plasmatic concentration was comparable at baseline in both groups. After surgery, however, a significant increase of presepsin was observed in Group A, whereas in Group B no significant changes of presepsin were recorded. A comparable trend of this biomarker was found in the two groups, i.e. presepsin increased from T0 to T3, when it reached its maximum value, and its decrease started at T4. Finally, presepsin resulted more accurate than CRP in the evaluation of perioperative inflammatory response in patients undergoing THR or TKR. These data will be helpful in defining a reference interval for presepsin in patients with prosthetic joint implants, and a cut-off of this biomarker for the diagnosis of PJI. PMID- 29254320 TI - Anti-inflammatory steroid use in impacted third molar surgery: a systematic review. AB - Oral surgery procedures involve traumatization of mucosal and bony tissues, and lengthy interventions can lead to inflammatory post-operative sequelae. In the bony tissues in particular, the inflammatory processes can affect healing. Modern drug therapies provide valid support for lowering the risk of occurrence of post operative inflammatory signs. The two main types of agents used are nonsteroidal anti-inflammatory drugs and/or corticosteroids, which act on two different molecular pathways in the inflammatiory process. The aim of this systematic review is to examine the different corticosteroids used in oral surgery procedures, their indications for use, and their route of administration, to provide the clinician with a useful scheme for correct pharmacological management of post-operative inflammation. To identify studies eligible for inclusion in this systematic review, we performed a literature search up to April 2017 of the electronic databases, considering published papers from 2007 to 2017. The search terms included steroids, third molar, oral surgery, RCT [randomized controlled trial], human, and clinical trial. Only articles in English language were considered. PMID- 29254319 TI - Lipid-lowering effect of bergamot polyphenolic fraction: role of pancreatic cholesterol ester hydrolase. AB - Bergamot polyphenolic fraction (BPF) has been shown to positively modulate several mechanisms involved in metabolic syndrome, suggesting its use in therapy. In particular, it is able to induce a significant amelioration of serum lipid profile in hyperlipemic patients at different levels. The purpose of our study was to investigate the effect of BPF on cholesterol absorption physiologically mediated by pancreatic cholesterol ester hydrolase (pCEH). An in vitro activity assay was performed to study the effect of BPF on pCEH, whereas the rate of cholesterol absorption was evaluated through in vivo studies. In particular, male, Sprague-Dawley rats (200?225 g) were fed either normal chow or chow supplemented with 0.5% cholic acid, 5.5% peanut oil, and varying amounts of cholesterol (0 to 1.5%). BPF (10 mg/Kg) was daily administrated by means of a gastric gavage to animals fed with lipid supplemented diet for 4 weeks and, at the end of the study, plasma lipids and liver cholesteryl esters were measured in all experimental groups. Our results show that BPF was able to inhibit pCEH activity and this effect was confirmed, in vivo, via detection of lymphatic cholesteryl ester in rats fed with a cholesterol-rich diet. This evidence clarifies a further mechanism responsible for the hypolipemic properties of BPF previously observed in humans, confirming its beneficial effect in the therapy of hypercholesterolemia and in the treatment of metabolic syndrome. PMID- 29254322 TI - Cytokine expression profile and blood parameter evaluation of patients undergoing cardiac surgery. AB - Cardiac surgery is accompanied by an important immune response that is poorly understood. This inflammatory response is caused by several stimuli: surgical trauma, cardiopulmonary bypass apparatus, aortic-cross clamping, reperfusion injury and hypothermia. The aim of the present study is to investigate the cytokine level profile involved in the inflammatory pathway of patients undergoing cardiac surgery. One hundred and two patients undergoing elective cardiac surgery utilizing cardiopulmonary bypass (CPB) apparatus were enrolled in the study. In the hematological and biochemical profiles investigated, we observed a significant increase of WBC and blood glucose concentration and a strong decrease of RBC, HB, HCT and PLT 24 h post-surgery compared to baseline and immediately after surgery groups. Furthermore, we found a modulation of cytokine levels mostly for IL-10 and an increase of IL-6, detected at 6 h post surgery, IL-8 at 6 and 24 h, and TNFalpha only at 24 h post-surgery. In conclusion, these findings evidence a time course profile on cytokine levels and a balance between pro- and anti-inflammatory cytokine activation during and after cardiac surgery. In fact, IL-6 and IL-10, a pro- and an anti-inflammatory cytokine, respectively, increased immediately after surgery. The plasma level of TNF-alpha could be inhibited by the high concentration of IL-10 up to 6 h post surgery. An IL-10 reduction at baseline level, after 24 h post-surgery, could explain a rise of TNF-alpha plasma concentration. On the other hand, considering the dual role of IL-6 on inflammation acting both as an activator of inflammatory cascade or an anti-inflammatory agent, the increased IL-6 levels 24 h after surgery could be related to the negative feedback action on TNFalpha activity. PMID- 29254323 TI - Anteriorly placed tumors to the conus: removal by interradicular window. AB - Tumors anteriorly situated to the medullary conus are rarely encountered and represent a true surgical challenge. We examined the literature on this topic, concluding that there are no previous reports on alternative surgical techniques different to the traditional one. We report two cases of intradural extramedullary tumor operated on by a technique performed through a window opened between the spinal roots, which allows an easy, effective and useful resection. We describe a new operative technique which ensures a complete removal of these tumors and discuss clinical implications in the light of the available literature on this topic. PMID- 29254321 TI - Colorectal cancer in patients with type 2 diabetes mellitus: a single-center experience. AB - Type 2 diabetes mellitus (T2DM) is associated with an increased risk of colorectal cancer (CRC). The aim of the study is to evaluate the prevalence of CRC in a cohort of Caucasian patients with T2DM and the association with other variables previously known to be related with increased risk of CRC. We retrospectively evaluated the data of 741 consecutive Caucasian patients with T2DM who underwent colonoscopic screening in our tertiary referral center. A control cohort of 333 patients with thyroid disease was selected to evaluate the difference in the incidence of CRC. At a median follow-up of 132.5 months (range 33.3-175.7), 67 cases of cancer (prevalence 9%) occurred; among these, 14 cases of CRC were reported (prevalence 1.88%) among the diabetic patients, while only two case (one of these was a CRC) (overall prevalence 0.006%, prevalence of CRC 0.003%) occurred in the control group; the difference between the prevalence of CRC was statistically significant (chi-square 4.21, p=0.04). The median duration of T2DM to CRC diagnosis was 168 months (range 12-768). At the univariate analysis, older age (p=0.001, r 0.138) and diabetes duration (p=0.001, r 0.138) were related to higher risk of cancer, while metformin seems to be protective towards cancer (p=0.07, r -0.098). In the subset of patients with CRC, the age (RR = 2.25; 95% CI: 0.30 - 17.31; p less than 0.001), the diabetes duration (RR = 1.93; 95% CI: 0.25 ? 14.77; p = 0.001) and the sulphonylureas treatment (RR = 2.33; 95% CI: 0.78 ? 7.38; p = 0.007) were independently correlated with CRC. In our study, the prevalence of CRC in the cohort of patients with T2DM was higher compared to that from the National Tumor Register in 2010 (0.5%). Furthermore, we could speculate that sulphonylureas may play a role in CRC carcinogenesis impairing the physiological insulin secretion. PMID- 29254324 TI - Focal active colitis as a predictor of inflammatory bowel disease: results from a single-center experience. AB - The term focal active colitis (FAC) is conventionally used to describe the presence of isolated cryptitis, characterized by an inflammatory infiltrate consisting of intraepithelial neutrophils and/or neutrophils invading the lumen of the criptae, with no other microscopic alteration of the colonic mucosa and, in particular, without the presence of signs of chronic inflammation. To date, only four studies, including one conducted in a pediatric population, have been performed to evaluate the clinical significance of this disease. The aim of this retrospective study on prospectively-collected data is to evaluate the clinical implications of the focal active colitis, since there still remains a marked uncertainty regarding this topic and about how often such a diagnosis will presage a diagnosis of inflammatory bowel disease (IBD). Clinical, endoscopic, and pathological data were retrospectively reviewed from 30 patients with focal active colitis, who had no other diagnostic findings on colorectal biopsy and no history of chronic inflammatory bowel disease. The histological findings were correlated with clinical diagnoses. Thirty patients (11 males, 19 females; age 24 80 years, median 56 years) (0.5%) out of 5,600 undergoing colonoscopy between January 2012 and December 2016 presented a definitive diagnosis of FAC. Follow-up ranged from 6 to 60 months (median 24 months). At endoscopy, 19 patients (63%) had mild and non-specific changes, such as mild mucosal erythema, while 11 (37%) had normal findings. Eight patients were documented as having irritable bowel syndrome, while nine cases could be attributed to the effects of drugs, five presented FAC as incidental finding, one a diagnosis of infectious colitis, and seven a diagnosis of IBD (4 with Crohn?s disease). FAC was confirmed to be a more significant predictor of IBD than the previous literature would indicate, even if larger prospective studies, targeted to study this relationship, are needed to understand more clearly its clinical significance. PMID- 29254325 TI - Instant loading with intraoral welding technique and PRAMA implants: a new prosthetic approach. AB - When splinting multiple implants passive fit of the framework should be achieved to avoid excessive force distribution on the implants. Recently, a protocol was suggested for immediate loading of multiple implants by welding a titanium bar to implant abutments directly in the oral cavity so as to create a customized, precise and passive metal-reinforced provisional restoration. The intraoral welding technique subsequently proves to be a successful option in the full-arch immediate restorations of the mandible and maxilla. The aim of this article is to present a case report in which a new prosthetic approach, using trans-mucosal implants, is described. Dental implants are instantly loaded with a provisional prosthesis supported by an intraoral welded titanium framework to obtain a precise passive fit of the immediate loaded prosthesis. PMID- 29254326 TI - Altered diurnal cardiac sympathovagal balance correlates with nutritional status indexes in systemic sclerosis patients. AB - Autonomic nervous system is involved in body weight regulation. Gastrointestinal manifestations of systemic sclerosis (SSc) can influence patients? nutritional status and facilitate the development of protein?energy malnutrition. The aim of the study is to assess the nutritional status of SSc patients and to explore its possible correlation with autonomic dysfunction using heart rate variability (HRV). We enrolled 19 SSc subjects and 19 healthy subjects as controls. Body mass index (BMI) and body surface area (BSA) were collected and recorded in all patients. HRV was measured and the domains of low frequencies (LF, index of the sympathetic modulation) and high frequencies (HF, index of the parasympathetic modulation) were recorded. As assessed by the LF/HF RATIO, sympathovagal balance is altered in SSc patients because of increased sympathetic modulation and reduced parasympathetic activity. BMI positively correlates with LF (r=0.57; p less than 0.01) and LF/HF RATIO during daytime (r= 0.46; p less than 0.05). Similarly, BSA positively correlates with LF (r= 0.51; p less than 0.05), LF day time (r= 0.53; p less than 0.05) and LF/HF RATIO night time (r=-0.51; p less than 0.05). In SSc patients the autonomic dysfunction is characterized by increased sympathetic modulation. We observed a correlation between autonomic dysfunction and nutritional status in SSc patients. PMID- 29254327 TI - Safety and tolerability of intra-articular hyaluronic acid (Sinovial(r)/GELSYN 3tm) injections in the treatment of knee osteoarthritis. AB - Osteoarthritis (OA) is a progressively degenerative joint disease, with a very high prevalence rate that is expected to increase worldwide with the ageing of the population. Considering that OA requires long-term treatment, therapies with minimal side effects and which can be repeated as needed are warranted. Hyaluronic acid (HA), a natural glycosaminoglycan with viscoelastic properties, is a major component of synovial fluid and the extracellular matrix of the joint cartilage, and plays key roles in maintaining synovial fluid viscosity and the bio-mechanical integrity of healthy cartilage. Intra-articular administration of exogenous HA has therefore been used to successfully improve the viscoelastic properties of the joint to improve lubrication, modulate inflammation and modify the catabolic micro-environment. Sinovial(r)/GELSYN-3TM is a sterile, non pyrogenic formulation of highly purified, chemically unmodified HA of bio fermentative origin, which has been introduced in several different concentrations in clinical use within the European market. This expert opinion reports on the published data regarding the efficacy and tolerability of first and multiple injection series of Sinovial(r)-based product formulations. The data regarding the tolerability of Sinovial(r) in patients with knee osteoarthritis were analyzed, showing that this formulation, beside favourable therapeutic effects, has a very good tolerability profile, with only mild, transient, and easily managed, local injection-site reactions and absence of systemic reactions. In particular, repetitive cycles of HA have been shown to yield positive results in terms of both efficacy and safety and therefore should be offered to patients who had undergone a successful first course of therapy when their symptoms reoccur. PMID- 29254328 TI - Role of biomarkers in adult sepsis and their application for a good laboratory practice: a pilot study. AB - This study measured Procalcitonin (PCT), Presepsin (PRE-S) and pro-Adrenomedullin (pro-ADM) in intensive care unit (ICU) patient?s blood to assess their contribution to accurate diagnosis of sepsis and potential predictive impact on prognosis. The final aim was to improve the use of infection biomarkers for optimizing the impact of laboratory medicine on clinical outcomes, focusing on the good management of resources designed to produce maximum effectiveness and efficiency. Sixty-four adult patients were studied during their hospitalization in ICU; blood samples were collected and categorized according to their clinical diagnosis and illness severity, and sepsis marker levels were measured on automated immunoassay platforms. PCT, PRE-S and pro-ADM infection markers were significantly lower in controls than in sepsis or septic shock groups. The area under the curve, by ROC curve analysis, was 0.945 for PCT, 0.756 for PRE-S and 0.741 for pro-ADM. Sepsis diagnostic accuracy was not improved by combining PCT, PRE-S and pro-ADM measures. Preliminary data demonstrated that, despite PRE-S and pro-ADM being able to differentiate between septic and non-septic patients with accuracy, PCT remains the most reliable marker available. The results obtained still do not allow us to consider a combination of markers, because it would merely increase laboratory costs without improving diagnostic performance. Furthermore, the results confirm a possible prognostic role of pro-ADM in septic states, but no correlation between biomarker levels and survival at 48 h was detected. Hence PCT, PRE-S, nor pro-ADM can be used to predict short-term prognosis. PMID- 29254329 TI - Positron Emission Tomography Imaging of Prostate Cancer with Ga-68-Labeled Gastrin-Releasing Peptide Receptor Agonist BBN7-14 and Antagonist RM26. AB - Radiolabeled bombesin (BBN) analogs have long been used for developing gastrin releasing peptide receptor (GRPR) targeted imaging probes, and tracers with excellent in vivo performance including high tumor uptake, high contrast, and favorable pharmacokinetics are highly desired. In this study, we compared the 68Ga-labeled GRPR agonist (Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2, BBN7-14) and antagonist (d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) for the positron emission tomography (PET) imaging of prostate cancer. The in vitro stabilities, receptor binding, cell uptake, internalization, and efflux properties of the probes 68Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-Aca-BBN7-14 and 68Ga-NOTA-poly(ethylene glycol)3 (PEG3)-RM26 were studied in PC-3 cells, and the in vivo GRPR targeting abilities and kinetics were investigated using PC-3 tumor xenografted mice. BBN7-14, PEG3-RM26, NOTA-Aca-BBN7-14, and NOTA-PEG3-RM26 showed similar binding affinity to GRPR. In PC-3 tumor-bearing mice, the tumor uptake of 68Ga-NOTA-PEG3-RM26 remained at around 3.00 percentage of injected dose per gram of tissue within 1 h after injection, in contrast with 68Ga-NOTA-Aca-BBN7-14, which demonstrated rapid elimination and high background signal. Additionally, the majority of the 68Ga-NOTA-PEG3-RM26 remained intact in mouse serum at 5 min after injection, while almost all of the 68Ga-NOTA-Aca-BBN7-14 was degraded under the same conditions, demonstrating more-favorable in vivo pharmacokinetic properties and metabolic stabilities of the antagonist probe relative to its agonist counterpart. Overall, the antagonistic GRPR targeted probe 68Ga-NOTA-PEG3 RM26 is a more-promising candidate than the agonist 68Ga-NOTA-Aca-BBN7-14 for the PET imaging of prostate cancer patients. PMID- 29254330 TI - Protective Effects of DHA-PC against Vancomycin-Induced Nephrotoxicity through the Inhibition of Oxidative Stress and Apoptosis in BALB/c Mice. AB - The clinical use of glycopeptide antibiotic vancomycin is usually accompanied by nephrotoxicity, limiting its application and therapeutic efficiency. The aim of this study was to investigate the protection of DHA-enriched phosphatidylcholine (DHA-PC) against nephrotoxicity using a model of vancomycin-induced male BALB/c mice with renal injury by measuring death curves, histological changes, and renal function indexes. The addition of DHA in DHA and DHA-PC groups were 300 mg/kg per day on the basis of human intake level in our study. Results indicated that DHA PC could dramatically extend the survival time of mice, while traditional DHA and PC had no significant effects. Moreover, oral administration of DHA-PC exhibited better effects on reducing vancomycin-induced increases of blood urea nitrogen, creatinine, cystatin C, and kidney injury molecule-1 levels than traditional DHA and PC. DHA-PC significantly delayed the development of vancomycin-induced renal injury, including tubular necrosis, hyaline casts, and tubular degeneration. A further mechanistic study revealed that the protective effect of DHA-PC on vancomycin-mediated toxicity might be attributed to its ability to inhibit oxidative stress and inactivate mitogen-activated protein kinase (MAPK) signaling pathways, which was associated with upregulation of Bcl-2 and downregulation of caspase-9, caspase-3, cytochrome-c, p38, and JNK. These findings suggest that DHA PC may be acted as the dietary supplements or functional foods against vancomycin induced nephrotoxicity. PMID- 29254331 TI - DNA-Stabilized Silver Nanoclusters as Specific, Ratiometric Fluorescent Dopamine Sensors. AB - Neurotransmitters are small molecules that orchestrate complex patterns of brain activity. Unfortunately, there exist few sensors capable of directly detecting individual neurotransmitters. Those sensors that do exist are either unspecific or fail to capture the temporal or spatial dynamics of neurotransmitter release. DNA-stabilized silver nanoclusters (DNA-AgNCs) are a new class of biocompatible, fluorescent nanostructures that have recently been shown to offer promise as biosensors. In this work, we identify two different DNA sequences that form dopamine-sensitive nanoclusters. We demonstrate that each sequence supports two distinct DNA-AgNCs capable of providing specific, ratiometric fluorescent sensing of dopamine concentration in vitro. DNA-Ag nanoclusters therefore offer a novel, low-cost approach to quantification of dopamine, creating the potential for real time monitoring in vivo. PMID- 29254332 TI - Reactivity of Criegee Intermediates toward Carbon Dioxide. AB - Recent theoretical work by Kumar and Francisco suggested that the high reactivity of Criegee intermediates (CIs) could be utilized for designing efficient carbon capture technologies. Because the anti-CH3CHOO + CO2 reaction has the lowest barrier in their study, we chose to investigate it experimentally. We probed anti CH3CHOO with its strong UV absorption at 365 nm and measured the rate coefficient to be <=2 * 10-17 cm3 molecule-1 s-1 at 298 K, which is consistent with our theoretical value of 2.1 * 10-17 cm3 molecule-1 s-1 at the QCISD(T)/CBS//B3LYP/6 311+G(2d,2p) level but inconsistent with their results obtained at the M06-2X/aug cc-pVTZ level, which tends to underestimate the barrier heights. The experimental result indicates that the reaction of a Criegee intermediate with atmospheric CO2 (400 ppmv) would be inefficient (keff < 0.2 s-1) and cannot compete with other decay processes of Criegee intermediates like reactions with water vapor (~103 s 1) or thermal decomposition (~102 s-1). PMID- 29254333 TI - Large Scale Identification of Variant Proteins in Glioma Stem Cells. AB - Glioblastoma (GBM), the most malignant of primary brain tumors, is a devastating and deadly disease, with a median survival of 14 months from diagnosis, despite standard regimens of radical brain tumor surgery, maximal safe radiation, and concomitant chemotherapy. GBM tumors nearly always re-emerge after initial treatment and frequently display resistance to current treatments. One theory that may explain GBM re-emergence is the existence of glioma stemlike cells (GSCs). We sought to identify variant protein features expressed in low passage GSCs derived from patient tumors. To this end, we developed a proteomic database that reflected variant and nonvariant sequences in the human proteome, and applied a novel retrograde proteomic workflow, to identify and validate the expression of 126 protein variants in 33 glioma stem cell strains. These newly identified proteins may harbor a subset of novel protein targets for future development of GBM therapy. PMID- 29254335 TI - Transition from Low to High Iodide and Iodine Concentration States in the Briggs Rauscher Reaction: Evidence on Crazy Clock Behavior. AB - The Briggs-Rauscher reaction containing malonic acid may undergo a sudden transition from low (state I) to high iodide and iodine (state II) concentration states after a well-defined and strongly reproducible oscillatory period. This study clearly shows that even though the time-dependent behavior of the oscillatory state is reproducible, the time lag necessary for the appearance of the state I to state II transition after the system leaves the oscillatory state becomes irreproducible for an individual kinetic run. This crazy clock behavior of the state I to state II transition is identified by repeated experiments in which stirring rate is taken as a control parameter and all other parameters such as initial conditions, temperature, vessel surface, and the age of solution were kept constant. Surprisingly, a better stirring condition does not make the transition reproducible; it simply does not allow the transition to happen at all. The proposed mechanism, additional explanations, and proposals for this irreproducibility of state I to state II transition have been presented. Considering the fact that the number of crazy clock reactions is only a few, this study may contribute to a better understanding of fundaments of this phenomenon. PMID- 29254334 TI - Energetics Underlying Twist Polymorphisms in Amyloid Fibrils. AB - Amyloid fibrils are highly ordered protein aggregates associated with more than 40 human diseases. The exact conditions under which the fibrils are grown determine many types of reported fibril polymorphism, including different twist patterns. Twist-based polymorphs display unique mechanical properties in vitro, and the relevance of twist polymorphism in amyloid diseases has been suggested. We present transmission electron microscopy images of Abeta42-derived (amyloid beta) fibrils, which are associated with Alzheimer's disease, demonstrating the presence of twist variability even within a single long fibril. To better understand the molecular underpinnings of twist polymorphism, we present a structural and thermodynamics analysis of molecular dynamics simulations of the twisting of beta-sheet protofilaments of a well-characterized cross-beta model: the GNNQQNY peptide from the yeast prion Sup35. The results show that a protofilament model of GNNQQNY is able to adopt twist angles from -11 degrees on the left-hand side to +8 degrees on the right-hand side in response to various external conditions, keeping an unchanged peptide structure. The potential of mean force (PMF) of this cross-beta structure upon twisting revealed that only ~2kBT per peptide are needed to stabilize a straight conformation with respect to the left-handed free-energy minimum. The PMF also shows that the canonical structural core of beta-sheets, i.e., the hydrogen-bonded backbone beta-strands, favors the straight conformation. However, the concerted effects of the side chains contribute to twisting, which provides a rationale to correlate polypeptide sequence, environmental growth conditions and number of protofilaments in a fibril with twist polymorphisms. PMID- 29254336 TI - MinGenome: An In Silico Top-Down Approach for the Synthesis of Minimized Genomes. AB - Genome minimized strains offer advantages as production chassis by reducing transcriptional cost, eliminating competing functions and limiting unwanted regulatory interactions. Existing approaches for identifying stretches of DNA to remove are largely ad hoc based on information on presumably dispensable regions through experimentally determined nonessential genes and comparative genomics. Here we introduce a versatile genome reduction algorithm MinGenome that implements a mixed-integer linear programming (MILP) algorithm to identify in size descending order all dispensable contiguous sequences without affecting the organism's growth or other desirable traits. Known essential genes or genes that cause significant fitness or performance loss can be flagged and their deletion can be prohibited. MinGenome also preserves needed transcription factors and promoter regions ensuring that retained genes will be properly transcribed while also avoiding the simultaneous deletion of synthetic lethal pairs. The potential benefit of removing even larger contiguous stretches of DNA if only one or two essential genes (to be reinserted elsewhere) are within the deleted sequence is explored. We applied the algorithm to design a minimized E. coli strain and found that we were able to recapitulate the long deletions identified in previous experimental studies and discover alternative combinations of deletions that have not yet been explored in vivo. PMID- 29254338 TI - 19th SIOI National Congress in Pisa. PMID- 29254339 TI - Has the prevalence and severity of dental erosion in Norway changed during the last 30 years? PMID- 29254340 TI - Microleakage of MTA in primary molar pulpotomies. PMID- 29254337 TI - Land-Sparing Opportunities for Solar Energy Development in Agricultural Landscapes: A Case Study of the Great Central Valley, CA, United States. AB - Land-cover change from energy development, including solar energy, presents trade offs for land used for the production of food and the conservation of ecosystems. Solar energy plays a critical role in contributing to the alternative energy mix to mitigate climate change and meet policy milestones; however, the extent that solar energy development on nonconventional surfaces can mitigate land scarcity is understudied. Here, we evaluate the land sparing potential of solar energy development across four nonconventional land-cover types: the built environment, salt-affected land, contaminated land, and water reservoirs (as floatovoltaics), within the Great Central Valley (CV, CA), a globally significant agricultural region where land for food production, urban development, and conservation collide. Furthermore, we calculate the technical potential (TWh year-1) of these land sparing sites and test the degree to which projected electricity needs for the state of California can be met therein. In total, the CV encompasses 15% of CA, 8415 km2 of which was identified as potentially land-sparing for solar energy development. These areas comprise a capacity-based energy potential of at least 17 348 TWh year-1 for photovoltaic (PV) and 2213 TWh year-1 for concentrating solar power (CSP). Accounting for technology efficiencies, this exceeds California's 2025 projected electricity demands up to 13 and 2 times for PV and CSP, respectively. Our study underscores the potential of strategic renewable energy siting to mitigate environmental trade-offs typically coupled with energy sprawl in agricultural landscapes. PMID- 29254341 TI - Adhesive systems for CAD-CAM customised lingual orthodontic brackets: which one is better? PMID- 29254342 TI - Evaluation of maxillary and mandibular arch forms in an Italian adolescents sample with normocclusion. PMID- 29254343 TI - Early treatment of a severe Class II malocclusion with the Forsus fatigue resistant device. PMID- 29254344 TI - Dental fear among children of foreign background in a multicultural area in Stockholm. PMID- 29254345 TI - Significance of observational studies in clinical paediatric dentistry research. PMID- 29254346 TI - Comparison of single tooth anaesthesia by computer-controlled local anaesthetic delivery system (C-CLADS) with a supraperiosteal traditional syringe injection in paediatric dentistry. PMID- 29254347 TI - Effect of saliva contamination on the sealing properties of glass ionomer sealants placed over Er,Cr:YSGG laser-etched fissures. PMID- 29254348 TI - Factors associated with cooperative levels of Autism Spectrum Disorder children during dental treatments. PMID- 29254349 TI - Pre-surgical orthopedics in newborns affected by clefts of the lip, alveolus and palate. Report of two cases. PMID- 29254350 TI - Flowable composite as a direct restoration technique for primary molars. PMID- 29254351 TI - Paediatric laser dentistry. Part 3: Dental trauma. PMID- 29254352 TI - Cognitive Abilities Explain Wording Effects in the Rosenberg Self-Esteem Scale. AB - There is consensus that the 10 items of the Rosenberg Self-Esteem Scale (RSES) reflect wording effects resulting from positively and negatively keyed items. The present study examined the effects of cognitive abilities on the factor structure of the RSES with a novel, nonparametric latent variable technique called local structural equation models. In a nationally representative German large-scale assessment including 12,437 students competing measurement models for the RSES were compared: a bifactor model with a common factor and a specific factor for all negatively worded items had an optimal fit. Local structural equation models showed that the unidimensionality of the scale increased with higher levels of reading competence and reasoning, while the proportion of variance attributed to the negatively keyed items declined. Wording effects on the factor structure of the RSES seem to represent a response style artifact associated with cognitive abilities. PMID- 29254353 TI - Digit Span Subscale Scores May Be Insufficiently Reliable for Clinical Interpretation: Distinguishing Between Stratified Coefficient Alpha and Omega Hierarchical. AB - The Digit Span subscale (Digit Span Forward, Backward, and Sequencing combined composite) internal inconsistency reliability has been reported at .93, based on a coefficient known as stratified coefficient alpha. With accessible examples, we demonstrate that stratified coefficient alpha can deviate substantially from a model-based internal consistency reliability that represents an underlying dimension, that is, omega hierarchical. Next, we simulated item-level Digit Span subscale data to correspond very closely to the Wechsler Adult Intelligence Scale fourth edition normative sample. Based on omega hierarchical, we estimated the internal consistency reliability associated with the Digit Span subscale scores at .74. In light of the results, clinicians are cautioned against interpreting Digit Span subscale scores. Instead, interpretations should probably be restricted to the Digit Span Forward, Digit Span Backward, and Digit Span Sequencing test scores. Finally, we offer suggestions for improvement to achieve higher levels of Digit Span subscale score reliability. PMID- 29254354 TI - Comparing the Reliability and Validity of Global Self-Report Measures of Subjective Well-Being With Experiential Day Reconstruction Measures. AB - Self-report measures of global well-being are thought to reflect the overall quality of people's lives. However, several scholars have argued that people rely on heuristics, such as current mood, when reporting their global well-being. Experiential well-being measures, such as the day reconstruction method (DRM), have been proposed as an alternative technique to obtain a potentially more accurate assessment of well-being. Across two multimethod, short-term longitudinal studies, we compared the psychometric properties of global self reports and short-form DRM-based assessments of well-being. We evaluated their stability across one month, tested their convergent validity using self-informant agreement, and evaluated correlations with personality traits. Results indicated that global measures of well-being were more stable than DRM-based experiential measures. Self-informant agreement was also either equal across global and DRM measures or higher for global measures. Correlations with personality were similar across approaches. These findings suggest that DRM and global measures of well-being have similar psychometric properties when used to provide an overall assessment of a person's typical level of subjective well-being. PMID- 29254355 TI - New reconstruction algorithm for digital breast tomosynthesis: better image quality for humans and computers. AB - Background The image quality of digital breast tomosynthesis (DBT) volumes depends greatly on the reconstruction algorithm. Purpose To compare two DBT reconstruction algorithms used by the Siemens Mammomat Inspiration system, filtered back projection (FBP), and FBP with iterative optimizations (EMPIRE), using qualitative analysis by human readers and detection performance of machine learning algorithms. Material and Methods Visual grading analysis was performed by four readers specialized in breast imaging who scored 100 cases reconstructed with both algorithms (70 lesions). Scoring (5-point scale: 1 = poor to 5 = excellent quality) was performed on presence of noise and artifacts, visualization of skin-line and Cooper's ligaments, contrast, and image quality, and, when present, lesion visibility. In parallel, a three-dimensional deep learning convolutional neural network (3D-CNN) was trained (n = 259 patients, 51 positives with BI-RADS 3, 4, or 5 calcifications) and tested (n = 46 patients, nine positives), separately with FBP and EMPIRE volumes, to discriminate between samples with and without calcifications. The partial area under the receiver operating characteristic curve (pAUC) of each 3D-CNN was used for comparison. Results EMPIRE reconstructions showed better contrast (3.23 vs. 3.10, P = 0.010), image quality (3.22 vs. 3.03, P < 0.001), visibility of calcifications (3.53 vs. 3.37, P = 0.053, significant for one reader), and fewer artifacts (3.26 vs. 2.97, P < 0.001). The 3D-CNN-EMPIRE had better performance than 3D-CNN-FBP (pAUC-EMPIRE = 0.880 vs. pAUC-FBP = 0.857; P < 0.001). Conclusion The new algorithm provides DBT volumes with better contrast and image quality, fewer artifacts, and improved visibility of calcifications for human observers, as well as improved detection performance with deep-learning algorithms. PMID- 29254356 TI - Biological Response Following Inlay Arthroplasty of the Knee: Cartilage Flow Over the Implant. AB - Objective Inlay arthroplasty (IA) has seen growing interest as a new primary arthroplasty intervention for patients that need to transition from biology to joint replacement. The purpose of this study was to investigate the biological response to this procedure. Design Patients presenting with symptomatic mono- or bicompartmental arthrosis and varus malalignment underwent IA and concurrent medial open wedge high tibial osteotomy (HTO). A subset of patients required hardware removal and consented to second-look arthroscopy without biopsy allowing for assessment of IA components and compartment-specific findings related to implant fixation, cartilage flow, propagation of lesions, and opposing tibial surfaces. Results In a series of 41 knees (35 patients) treated with combined IA and HTO (mean varus >7 degrees ), 26 knees (23 patients, 18 male, 5 female) with a mean age of 52 years (range = 43-67) required HTO plate removal. Concurrent second look arthroscopy was performed at a mean of 14 months (range = 12-19) following the index procedure. On probing, all arthroplasty components showed solid fixation without gap formation. On the medial femoral condyle, 15 mm implants ( n = 14) showed a peripheral cartilage flow of 12% (range = 5% to 25%), 20 mm implants ( n = 12) of 9% (range 5% to 15%), and trochlear implants ( n = 12) of 20% (range 10% to 40%). No progressive deterioration of the index defects or progression of tibial and retropatellar grades were seen. Conclusion Joint surface reconstruction using IA showed stable fixation with peripheral cartilage coverage ranging from 9% to 20% and no further chondral damage on opposing surfaces. Future clinical effectiveness studies are required to support the positive biological integration. PMID- 29254357 TI - Respecting Choices and Related Models of Advance Care Planning: A Systematic Review of Published Evidence. AB - All individuals should receive care consistent with their expressed preferences during serious and chronic illnesses. Respecting Choices (RC) is a well-known model of advance care planning intended to assist individuals consider, choose, and communicate these preferences to health-care providers. In this systematic review, we evaluated the published literature on the outcomes of the RC and derivative models utilizing criteria developed by the Cochrane Collaborative. Eighteen articles from 16 studies were included, of which 9 were randomized controlled trials, 6 were observational, and 1 was a pre-posttest study. Only 2 specifically included a minority population (African American). Fourteen were conducted in the United States, primarily in the Wisconsin/Minnesota region (n = 8). Seven studies examined the RC model, whereas 9 examined derivative models. There was significant heterogeneity of outcomes examined. We found that there is a low level of evidence that RC and derivative models increase the incidence and prevalence of Advance Directive and Physician Orders for Life-Sustaining Treatment completion. There is a high level of evidence that RC and derivative models increase patient-surrogate congruence in Caucasian populations. The evidence is mixed, inconclusive, and too poor in quality to determine whether RC and derivative models change the consistency of treatment with wishes and overall health-care utilization in the end of life. We urge further studies be conducted, particularly with minority populations and focused on the outcomes of preference congruent treatment and health-care utilization. PMID- 29254358 TI - Validation of the ICD-9 Diagnostic Code for Palliative Care in Patients Hospitalized With Heart Failure Within the Veterans Health Administration. AB - BACKGROUND: Patients with heart failure (HF) are at increased risk of unmet palliative care needs. The International Classification of Diseases, Ninth Revision ( ICD-9) code, V66.7, can identify palliative care services. However, code validity for specialist palliative care in the Veterans Health Administration (VHA) has not been determined. OBJECTIVE: To validate the ICD-9 code for specialist palliative care and determine common reasons for specialist palliative care consultation among VHA patients hospitalized with HF. DESIGN: Electronic health record review of data from the Veterans Aging Cohort Study. SETTING/PARTICIPANTS: The sample included 100 patients hospitalized with HF from 2003 to 2012. MEASUREMENTS: Data from 50 patients with V66.7 were matched by age, race, site of care, hospital length of stay, intensive care unit admission, and fiscal year of study discharge to 50 patients with HF without V66.7 who had died within a year of hospitalization. We calculated positive and negative predictive values (PPV, NPV), sensitivity, and specificity. RESULTS: All patients included in the sample were male, 66% black ethnicity, and mean age = 65 years (standard deviations [SD] +/- 10.5 for cases; SD +/- 9.8 for matches). Specialist palliative care was documented for 49 of 50 patients with V66.7 (PPV = 98%, 95% confidence interval [CI]: 88-99) and 9 of 50 patients without the code (NPV = 82%, 95% CI: 68-91). Sensitivity was 84% (95% CI: 72-92), and specificity was 98% (95% CI: 86-99). Establishing goals of care was the most frequent reason for palliative care consultation (43% of the sample). CONCLUSION: The ICD-9 code V66.7 identifies specialist palliative care for hospitalized patients with HF in the VHA. Replication of findings in other data sources and populations is needed. PMID- 29254359 TI - Factors Associated With Frequency of Sugar-Sweetened Beverage Consumption Among US Adults With Diabetes or Prediabetes. AB - PURPOSE: This study assessed the associations between sociodemographic and behavioral characteristics and sugar-sweetened beverage (SSB) intake among US adults with diabetes or prediabetes. DESIGN: Quantitative, cross-sectional study. SETTING: The 2013 Behavioral Risk Factor Surveillance System. PARTICIPANTS: A total of 13 268 adults with diabetes and 9330 adults with prediabetes (median response rate: 46.8%). MEASURES: The outcome measure was SSB intake (0, >0 to <1, and >=1 time/day). The exposure measures were sociodemographic and behavioral characteristics. ANALYSIS: Both crude and age-adjusted prevalences were calculated. Multinomial logistic regressions were used to estimate the adjusted prevalence ratio (PR) for SSB intake by participants' characteristics. RESULTS: In 2013, 22.0% adults with diabetes and 38.2% adults with prediabetes consumed SSBs >=1 time/day. Among adults with diabetes, adjusted PR for consuming SSBs >=1 time/day was significantly greater for those who had shorter duration of diabetes (<=5 years: PR = 1.47; 6-10 years: PR = 1.33 vs >=11 years), less frequently self checking blood sugar (>=0 to <1 time/day: PR = 1.69; >=1 to <3 times/day: PR = 1.43 vs >=3 times/day), and no self-management of diabetes course taken (PR = 1.25 vs yes). Among adults with prediabetes, testing blood sugar <=3 years was not associated with consuming SSBs >=1 time/day. CONCLUSION: Daily SSB intake was associated with various characteristics among adults with diabetes or prediabetes. The findings can inform efforts to decrease SSB intake among high risk populations. PMID- 29254360 TI - Peer relationship and adolescent smartphone addiction: The mediating role of self esteem and the moderating role of the need to belong. AB - Background and aims Adolescent smartphone addiction has received increased attention in recent years, and peer relationship has been found to be a protective factor in adolescent smartphone. However, little is known about the mediating and moderating mechanisms underlying this relation. The aim of this study was to investigate (a) the mediating role of self-esteem in the association between student-student relationship and smartphone addiction, and (b) the moderating role of the need to belong in the indirect relationship between student-student relationship and adolescent smartphone addiction. Methods This model was examined with 768 Chinese adolescents (mean age = 16.81 years, SD = 0.73); the participants completed measurements regarding student-student relationship, self-esteem, the need to belong, and smartphone addiction. Results The correlation analyses indicated that student-student relationship was significantly negatively associated with adolescent smartphone addiction, and the need to belong was significantly positively associated with adolescent smartphone addiction. Mediation analyses revealed that self-esteem partially mediated the link between student-student relationship and adolescent smartphone addiction. Moderated mediation further indicated that the mediated path was weaker for adolescents with lower levels of the need to belong. Discussion and conclusion High self-esteem could be a protective factor against smartphone addiction for adolescents with a strong need to belong as these students appeared to be at elevated risk of developing smartphone addiction. PMID- 29254361 TI - Problem gambling and substance use in patients attending community mental health services. AB - Background and aims Relatively little is known about co-occurring gambling problems and their overlap with other addictive behaviors among individuals attending mental health services. We aimed to determine rates of gambling and substance use problems in patients accessing mental health services in Victoria, Australia. Methods A total of 837 adult patients were surveyed about their gambling and administered standardized screening tools for problem gambling and harmful tobacco, alcohol, and drug use. Prevalence of gambling problems was estimated and regression models used to determine predictors of problem gambling. Results The gambling participation rate was 41.6% [95% CI = 38.2-44.9]. The Problem Gambling Severity Index identified 19.7% [CI = 17.0-22.4] as "non-problem gamblers," 7.2% [CI = 5.4-8.9] as "low-risk" gamblers, 8.4% [CI = 6.5-10.2] as "moderate-risk" gamblers, and 6.3% [CI = 4.7-8.0] as "problem gamblers." One fifth (21.9%) of the sample and 52.6% of all gamblers were identified as either low-risk, moderate-risk, or problem gamblers (PGs). Patients classified as problem and moderate-risk gamblers had significantly elevated rates of nicotine and illicit drug dependence (p < .001) according to short screening tools. Current diagnosis of drug use (OR = 4.31 [CI = 1.98-9.37]), borderline personality (OR = 2.59 [CI = 1.13-5.94]), bipolar affective (OR = 2.01 [CI = 1.07 3.80]), and psychotic (OR = 1.83 [CI = 1.03-3.25]) disorders were significant predictors of problem gambling. Discussion and conclusions Patients were less likely to gamble, but eight times as likely to be classified as PG, relative to Victoria's adult general population. Elevated rates of harmful substance use among moderate-risk and PG suggest overlapping vulnerability to addictive behaviors. These findings suggest mental health services should embed routine screening into clinical practice, and train clinicians in the management of problem gambling. PMID- 29254362 TI - SMS messaging to improve ART adherence: perspectives of pregnant HIV-infected women in Kenya on HIV-related message content. AB - There is growing evidence that mobile health (mHealth) approaches including short messaging service (SMS) can improve antiretroviral therapy (ART) adherence, but consensus is lacking regarding communication of HIV-related information. Most interventions to date have delivered SMS that do not overtly refer to HIV or ART in order to avoid risk of status disclosure. In formative work for an ongoing randomized controlled trial (RCT) evaluating one-way and two-way educational SMS for prevention of mother-to-child-transmission (PMTCT) adherence in Kenya, we conducted 10 focus group discussions (FGDs) with 87 HIV-infected peripartum women to determine desirability and preferred terminology of HIV-related content. SMS for the RCT were developed based on FGD findings. Roughly half of FGD participants supported receiving SMS containing overtly HIV-related terms, such as "HIV" and "medication", citing desire for detailed educational messages about ART and PMTCT. Those opposed to overt content expressed concerns about confidentiality. Many participants argued that acceptability of HIV-related content depended on the recipient's disclosure status and others' access to her phone. Based on these findings, both covert and overt SMS were developed for the RCT and participants who owned their phone or had disclosed their HIV status to anyone with access to their phone were able to choose one of three options: (1) covert SMS only, (2) overt SMS only in response to HIV-related questions from the participant, (3) overt SMS routinely, initiated by the study. Of the 825 participants in the RCT, 94% were eligible to receive overt SMS. Of these, 66% opted to receive routine overt SMS and 10% to receive participant-initiated overt SMS. These findings show there may be interest in overt HIV-related information by SMS when risk of status disclosure is low, and support use of messaging strategies that allows participant choice in HIV-related content while protecting against undesired disclosure. PMID- 29254364 TI - Examining the Relationship Between Anxiogenic Parenting Practices and Cognitive Flexibility in Youth. AB - Cognitive flexibility (CF), a subdomain of executive functioning (EF), involves abilities such as set shifting and reversal learning. Some variability in CF is normative across youth due to the gradual refinement of broader EF along with the prefrontal cortex. Prior research has suggested that a supportive parenting environment contributes to strong EF, whereas harsh/controlling parenting is associated with deficits. The current investigation explores whether certain parenting practices (e.g., parental accommodation, over-involvement, modeling) are associated with such deficits. Anxiogenic parenting and CF were assessed in 112 youth aged 9 to 17 years, with results demonstrating that parenting practices were not predictive of CF in these youth. Age accounted for the majority of differences in set shifting performance, potentially emphasizing the influence of parenting at different stages of development. Accordingly, future research is necessary to determine the potential impact of anxiogenic parenting at specific points in the development of CF. PMID- 29254363 TI - Long term engagement in HIV care among postpartum women with perinatal HIV infection in the United States. AB - Despite growing literature on pregnancy in women with perinatally-acquired HIV infection (PHIV), little is known regarding HIV and reproductive health outcomes postpartum. We describe pregnancy, reproductive, and HIV care outcomes for 2 years postpartum among pregnant women with PHIV who delivered in a large urban health system in Atlanta, Georgia, USA from 2011-2016. We reviewed medical records of women with PHIV to estimate retention in HIV care (two HIV care visits or viral load measurements >90 days apart) and viral suppression (<200 copies/mL) at 12 and 24 months postpartum. Among 22 pregnant women with PHIV, 13 (59%) had a CD4 count of less than 300 cells/mm3 at the time of antenatal care entry; most (n = 13, 59%) women achieved viral suppression at time of delivery. Three quarters of women attended a postpartum HIV primary care visit, within an average of 193 (range 17-727) days. Only 4 (20%) women were retained and 3 (15%) virally suppressed at 12 postpartum, and 2 (12%) were retained and none virally suppressed at 24 months. Despite the unique challenges they face, multidisciplinary efforts are needed to engage women with PHIV during pregnancy and facilitate the transition to sustained HIV primary care in the postpartum period. PMID- 29254365 TI - Differences in knowledge, attitudes and behaviors of Israeli HIV-uninfected gay men in HIV-discordant vs. concordant steady relationships. AB - : HIV-discordant gay male couples may play an important role in HIV transmissions. This cross-sectional study compared the knowledge, attitudes and sexual behaviors of HIV-uninfected gay men, between those in HIV-discordant and those in HIV-concordant steady relationships. Anonymous questionnaires were distributed electronically in designated gay-related internet sites and in AIDS clinics in 2015. The dependent variable was defined as a steady relationship of an HIV-uninfected man with an HIV-infected partner. Risky sexual behavior was defined as unprotected anal intercourse (UAI) with a sex partner whose HIV-status was either positive or unknown. Of 2,319 responders, 460 (20%) were HIV uninfected gay men in steady relationships, of whom 72 were in HIV-discordant relationships and 388 were in HIV-concordant relationships. Those in HIV discordant relationships presented better established knowledge regarding HIV transmission, more lenient attitudes regarding UAI, and reported being involved in riskier sexual behavior, both within and outside their steady relationship compared to men in HIV-concordant relationships. UAI was performed by 48% of the HIV-discordant couples and was associated with the use of sero-positioning strategy and with achieving undetectable viral-load. These findings reflect the complexity of constant use of condoms during long-term sero-discordant relationships. Targeted interventions for HIV-prevention in HIV-discordant couples should be employed for balancing the partners' desire for intimacy and sexual pleasure in the relationship, while reducing the risk for acquiring HIV. ABBREVIATIONS: ART: Antiretroviral therapy; PEP: Post exposure prophylaxis; PrEP: Pre exposure prophylaxis; STI: Sexually transmitted infections; UAI: Unprotected anal intercourse. PMID- 29254366 TI - An Automated Baseline Correction Method Based on Iterative Morphological Operations. AB - Raman spectra usually suffer from baseline drift caused by fluorescence or other reasons. Therefore, baseline correction is a necessary and crucial step that must be performed before subsequent processing and analysis of Raman spectra. An automated baseline correction method based on iterative morphological operations is proposed in this work. The method can adaptively determine the structuring element first and then gradually remove the spectral peaks during iteration to get an estimated baseline. Experiments on simulated data and real-world Raman data show that the proposed method is accurate, fast, and flexible for handling different kinds of baselines in various practical situations. The comparison of the proposed method with some state-of-the-art baseline correction methods demonstrates its advantages over the existing methods in terms of accuracy, adaptability, and flexibility. Although only Raman spectra are investigated in this paper, the proposed method is hopefully to be used for the baseline correction of other analytical instrumental signals, such as IR spectra and chromatograms. PMID- 29254367 TI - A randomized controlled trial to enhance coping and posttraumatic growth and decrease posttraumatic stress disorder in HIV-Infected men who have sex with men in Beijing, China. AB - Although HIV-infected men who have sex with men (MSM) constitute a newly emerged high-risk group in China, little research outside Western countries is available on effective intervention programs to enhance their well-being. The purpose of this randomized controlled trial was to evaluate the efficacy of a group intervention program designed to improve the well-being and adaptive coping strategies of 60 HIV-infected MSM in Beijing, China, randomly assigned either to the intervention group for participation in four weekly sessions or to the control group for placement on a waiting list. They all completed measurements at pre- and postintervention. Compared with the control group, the intervention group reported significantly increased problem-focused coping strategies and levels of posttraumatic growth (PTG) as well as decreased symptoms of posttraumatic stress disorder (PTSD) at the completion of the intervention. In addition, mediation analysis showed that changes in problem-focused coping strategies mediated the intervention effect on increases in PTG; however, the mediating effect of coping strategies on the association of intervention and PTSD was not significant. This study provides empirical evidence for conducting psychological intervention to promote the well-being of HIV-infected MSM. The findings also elucidate the mechanism through which intervention improved PTG. PMID- 29254368 TI - Predictors of depression and life satisfaction in visually impaired people. AB - BACKGROUND: Visual impairment can lead loss of functional ability, necessity of accommodations and assistive technologies or having to rely on others for help. This can bring about feelings of sadness, dependency, inadequacy, and fear, which can put a person at risk for depression and affect one's satisfaction with life. PURPOSE: The aim of this study was to examine the effects of socio-demographic factors, disability-related factors, optimism, pessimism, self-esteem and social support on depression, and life satisfaction in visually impaired people. METHODS: A total of 94 visually impaired people completed the measures of socio demographic and disability-related characteristics, optimism and pessimism, self esteem, social support, depression and life satisfaction, administered by the authors. Correlational and hierarchical regression analysis was used to examine the relations and test the model for predicting depression and life satisfaction. RESULTS: The results have shown that depression was negatively related to the level of education, optimism, self-liking, self-competence, support from friends, family and coworkers, and positively related to comorbidity and pessimism. Life satisfaction was positively related to education, socio-economic status, optimism, self-liking, self-competence and support from friends, family and coworkers, and negatively to pessimism. Results have further shown that depression levels were predicted by education, comorbidity, optimism and self liking, and that self-liking mediated the relationship between optimism and depression. Life satisfaction was predicted by optimism, pessimism, self-liking, friends' support, and depression. Further analysis suggested that the path from optimism to life satisfaction goes through self-liking, friends' support, and depression. Pessimism showed indirect effects through self-liking but also had direct effects on life satisfaction. CONCLUSIONS: Focusing on optimism, pessimism, self-esteem, and social functioning of visually impaired is important in preventing depression and promoting life satisfaction, and should be a part of rehabilitation practices. Implications for Rehabilitation Screening for depression and mental health problems should be a part of rehabilitation process. Changes in the perception of future outcomes should be monitored and addressed throughout rehabilitation process in order to boost realistic optimism and prevent discouragement and hopelessness. Frequent feedback and positive reinforcement about a persons' progress and ability should be given throughout rehabilitation process in order to promote positive view of oneself and prevent self-esteem problems. Visually impaired people should be encouraged to socialise outside of their families and participate in social activities. This can be integrated in rehabilitation process as a part of everyday homework. PMID- 29254369 TI - Advancing the Study of Adolescent Substance Use Through the Use of Integrative Data Analysis. AB - A wealth of information is currently known about the epidemiology, etiology, and evaluation of drug and alcohol use across the life span. Despite this corpus of knowledge, much has yet to be learned. Many factors conspire to slow the pace of future advances in the field of substance use including the need for long-term longitudinal studies of often hard-to-reach subjects who are reporting rare and episodic behaviors. One promising option that might help move the field forward is integrative data analysis (IDA). IDA is a principled set of methodologies and statistical techniques that allow for the fitting of statistical models to data that have been pooled across multiple, independent samples. IDA offers a myriad of potential advantages including increased power, greater coverage of rare behaviors, more rigorous psychometric assessment of theoretical constructs, accelerated developmental time period under study, and enhanced reproducibility. However, IDA is not without limitations and may not be useful in a given application for a variety of reasons. The goal of this article is to describe the advantages and limitations of IDA in the study of individual development over time, particularly as it relates to trajectories of substance use. An empirical example of the measurement of polysubstance use is presented and this article concludes with recommendations for practice. PMID- 29254370 TI - Effect of cardiopulmonary bypass on cytochrome P450 enzyme activity: implications for pharmacotherapy. AB - For patients undergoing cardiopulmonary bypass (CPB) during cardiac surgery, there are well-documented changes in the pharmacokinetics (PK) of commonly administered drugs. Although multiple factors potentially underpin these changes, there has been scant research attention on the impact of CPB to alter the activities of cytochrome P450 (CYP) isoenzymes. PK changes during cardiac surgery with CPB have the potential to adversely affect the safety and efficacy of pharmacotherapy and increase the risk of drug-drug interactions. Clinically significant changes in drug PK during CPB are likely to be prominent for drugs where CYP metabolism is a major clearance (CL) mechanism. However, clinical data from patients undergoing CPB surgery in support of this hypothesis are lacking, leaving a significant knowledge gap. In this review, we address the effects of CPB on the release of pro-inflammatory cytokines, in surgeries with and without CPB, both pre and post initiation of surgery. We reviewed literature to explore the relationship between the release of pro-inflammatory cytokines, and the expression and activities of CYP enzymes. Through this approach, we provide new insight on the effects of CPB on the PK of drugs administered to patients in the clinical setting. Future research to address this knowledge gap will have considerable impact to assist clinicians with optimizing pharmacotherapy in this patient population. PMID- 29254371 TI - Effect modification of hypertension on the association of vitamin D deficiency with severity of coronary stenosis. AB - AIMS: There may exist an effect modification of hypertension on the relation of vitamin D deficiency with cardiovascular disease. The aim of this study was to investigate this interaction on coronary heart disease. METHODS: We investigated 348 consecutive patients (mean age 62.4 +/- 10.5 years; 56.3% male) who underwent coronary angiography because of chest discomfort at our heart center. Serum 25-OH vitamin D was also detected by ELISA method in these patients. Multivariable logistic regression models were used to estimate odd ratios (ORs) of CHD across vitamin D levels in hypertensives and normotensives, respectively. RESULTS: We found the multivariable-adjusted ORs of CHD in the bottom(<=8.5 ng/ml) and middle tertiles (8.5-13 ng/ml) of 25-OH vitamin D were 2.86 (95% confidence interval [CI]: 1.38, 5.92) and 1.63 (0.83, 3.20), respectively, compared with those in top tertiles (>13ng/ml) among hypertensives (Ptrend=0.005). In contrast, the corresponding ORs of the above two groups were 0.88 (0.28, 2.74) and 1.23 (0.42, 4.00), respectively, in the normotensives (Ptrend = 0.800; Peffect modification = 0.020). The multivariable-adjusted OR of CHD in patients with severe hypovitaminosis D (<10 ng/ml) versus those with higher vitamin D (?10 ng/ml) was also greater in hypertensives (2.76; 95% CI: 1.51, 5.04) than that in normotensives (0.92; 95% CI: 0.37, 2.33; Peffect modification=0.013). Similar results were observed when Gensini Score was treated as a dependent variable. CONCLUSION: Our finding suggests the presence of hypertension may modify the association of vitamin D deficiency with severity of coronary stenosis. PMID- 29254372 TI - Accessibility of online self-management support websites for people with osteoarthritis: A text content analysis. AB - Objectives This study assessed accessibility of online self-management support webpages for people with osteoarthritis by considering readability of text and inclusion of images and videos. Methods Eight key search terms developed and agreed with patient and public involvement representatives were entered into the Google search engine. Webpages from the first page of Google search results were identified. Readability of webpage text was assessed using two standardised readability indexes, and the number of images and videos included on each webpage was recorded. Results Forty-nine webpages met the inclusion criteria and were assessed. Only five of the webpages met the recommended reading level for health education literature. Almost half (44.9%) of webpages did not include any informative images to support written information. A minority of the webpages (6.12%) included relevant videos. Discussion Information provided on health webpages aiming to support patients to self-manage osteoarthritis may not be read, understood or used effectively by many people accessing it. Recommendations include using accessible language in health information, supplementing written information with visual resources and reviewing content and readability in collaboration with patient and public involvement representatives. PMID- 29254373 TI - The Effect of Music Listening on Pain, Heart Rate Variability, and Range of Motion in Older Adults After Total Knee Replacement. AB - The purpose of this study was to investigate the effects that listening and not listening to music had on pain relief, heart rate variability (HRV), and knee range of motion in total knee replacement (TKR) patients who underwent continuous passive motion (CPM) rehabilitation. We adopted a single-group quasi-experimental design. A sample of 49 TKR patients listened to music for 25 min during one session of CPM and no music during another session of CPM the same day for a total of 2 days. Results indicated that during CPM, patients exhibited a significant decrease in the pain level ( p < .05), an increase in the CPM knee flexion angle ( p < .05), a decrease in the low-frequency/high-frequency ratio (LF/HF) and normalized LF (nLF) of the HRV ( p < .01), and an increase in the normalized HF (nHF) and standard deviation of all normal-to-normal intervals (SDNN; p < .01) when listening to music compared with no music. This study demonstrated that listening to music can effectively decrease pain during CPM rehabilitation and improve the joint range of motion in patients who underwent TKR surgery. PMID- 29254374 TI - Temporal Patterns and Influential Factors of Blood Glucose Levels During the First 10-Day Critical Period After Brain Injury. AB - This study was conducted to document temporal patterns of blood glucose level changes during the first 10-day critical period and to identify factors that influence stress-induced hyperglycemia development in brain injury patients. The medical records of 190 brain injury patients were retrospectively reviewed. Blood glucose levels in the poor recovery group were significantly higher than in the good recovery group, particularly during the first 72 hr (158-172 mg/dl). The poor recovery group showed persistent, fluctuating hyperglycemia, whereas the good recovery group exhibited hyperglycemic peaks during the first 3 days that subsequently reduced linearly to normal. Gender, preexisting hypertension, disease severity at admission, total calorie intake, and steroid use were found to influence stress-induced hyperglycemia development significantly. In conclusion, close monitoring and adjustment are required to maintain safe blood glucose levels and the development of protocols for safe glycemic management is essential to improve critical care in brain injury patients. PMID- 29254375 TI - At the intersection of culture: Ethnically diverse dementia caregivers' service use. AB - This study used an ethnocultural approach to explore how cultural factors influenced ethnically diverse dementia caregivers' experiences and use of services. A modified thematic analysis of in-depth interviews with 15 caregivers, ranging in age from 50 to 75 years, including spouses, daughters, sons, cousins, and a friend, from three minority groups-African American, Hispanic, and South Korean caregivers-was conducted by a team of multi-lingual researchers. Caregiver stress was pervasive across all subgroups. Several themes emerged that were qualitatively different across groups, including knowledge about dementia, language barriers, religion and spirituality, and cultural differences in attitudes about caring and formal services. A two-pronged intervention model that includes a generic intervention to reduce caregiver stress along with a culturally targeted intervention tailored to a family's language, food preferences, religious practices, gender norms, and other values was recommended to more successfully reach and support these caregivers. PMID- 29254376 TI - Mirabegron improves quality-of-life, treatment satisfaction, and persistence in patients with overactive bladder: a multi-center, non-interventional, real-world, 12-month study. AB - OBJECTIVE: Observational studies can provide evidence about patient outcomes in routine clinical practice. This prospective, non-interventional study (BELIEVE) is the largest real-world European study to date to assess quality-of-life, treatment satisfaction, resource utilization, and persistence in patients with overactive bladder (OAB) who were prescribed mirabegron as part of routine clinical practice. METHODS: The primary objective was to evaluate change from baseline in quality-of-life based on overactive bladder questionnaire (OAB-q) sub scales. Secondary objectives included evaluation of treatment persistence, patient satisfaction, healthcare resource utilization and adverse events (AEs). Follow-up was for 12 months with visit windows at 2-4 and 10-12 months. Median change from baseline in total OAB-q and its sub-scales (Health-related quality-of life [HRQoL] and symptom bother scale) were assessed. RESULTS: Overall, 862 patients were enrolled from eight European countries. In the Full Analysis Set (FAS), 73.7% were female, mean age was 61.2 years; 47.7% >=65 years. At baseline, 41.3% had switched from other OAB treatments, 42.2% were treatment naive, 10.1% were lapsed, and 6.4% were on combination treatment. Symptom bother and HRQoL total scores improved from baseline to 2-4 and 10-12 months. There was a notable improvement in dry rate, increasing from 34.9% at baseline to 43.7% at 10-12 months in the FAS, and a reduction in pad use. Persistence was high, with 53.8% of FAS patients remaining on mirabegron at 10-12 months. Overall, no unexpected safety issues were observed and AEs were consistent with the known safety profile of mirabegron. CONCLUSION: Patients receiving mirabegron in a real-world setting reported meaningful improvements in QoL and health status, with a persistence rate of 53.8% at 12 months for the FAS. No unexpected safety issues were observed, and AEs were consistent with the known safety profile of mirabegron. PMID- 29254377 TI - Roxadustat in the treatment of anaemia in chronic kidney disease. AB - INTRODUCTION: Anaemia is one of the hallmarks of advanced chronic kidney disease (CKD); it correlates with a lower quality of life and increased cardiovascular risk. Currently its management is based on iron and erythropoiesis-stimulating agents (ESAs) therapy. Given safety issues on ESA therapy and excessive iron use, anaemia management is still suboptimal. Areas covered: The inhibitors of the prolyl-hydroxylases domain (PHD) are oral drugs which activate the hypoxia inducible factors (HIF) and stimulate the production of endogenous erythropoietin. Roxadustat (FG-4592) is a second-generation PHD inhibitor; it is undergoing now phase-III clinical development. Expert opinion: Phase-II clinical trials have shown that roxadustat is effective and save in the short term in either non-dialysis or dialysis CKD patients. Roxadustat is a chemical drug and thus has the potential of being cheaper than traditional ESAs. Given that the peaks of endogenous EPO are much lower than those observed with traditional ESA, it is possible to speculate the roxadustat (and more in general PHD inhibitors) will be safer than ESA on cardiovascular safety end-points. Considering that HIFs are involved in different pathways, with possible promotion of relevant side effects, their safety must be proven in long-term studies. PMID- 29254379 TI - Effect of salpingectomy on ovarian response to hyperstimulation during in vitro fertilization: does it really matter? PMID- 29254378 TI - Right ventricular remodeling in athletes and in arrhythmogenic cardiomyopathy. AB - OBJECTIVE: Changes in right ventricular (RV) structure and function following prolonged endurance training in athletes arise due to its unique anatomy and physiology. Arrhythmogenic cardiomyopathy (AC) should be differentiated from electrical, functional and structural adaptation of the heart in response to repetitive intense physical activity due to the negative contribution of exercise on AC progression and arrhythmic risk. DESIGN: For this review we performed a systematic search of the PubMed database up to October 2017 using terms and keywords pertaining to RV, athlete's heart (AH), AC, sudden cardiac death. RESULTS: This review summarizes currently available data on the impact of exercise on cardiac structure and function, discusses the debatable hypothesis of exercise-induced RV remodeling, compares the common features and search for distinctive characteristics between AH and AC. CONCLUSION: Exercise has a more profound impact on the structure and function of the RV than of the left ventricle. Differentiating physiologic RV remodeling following prolonged endurance exercise from subclinical cardiac pathology can be challenging. A multimodality approach is recommended to differentiate between exercise-induced physiological adaptations and cardiomyopathy. PMID- 29254380 TI - Multiple molecular modelling studies on some derivatives and analogues of glutamic acid as matrix metalloproteinase-2 inhibitors. AB - Matrix metalloproteinase-2 (MMP-2) is a potential target in anticancer drug discovery due to its association with angiogenesis, metastasis and tumour progression. In this study, 67 glutamic acid derivatives, synthesized and evaluated as MMP-2 inhibitors, were taken into account for multi-QSAR modelling study (regression-based 2D-QSAR, classification-based LDA-QSAR, Bayesian classification QSAR, HQSAR, 3D-QSAR CoMFA and CoMSIA as well as Open3DQSAR). All these QSAR studies were statistically validated individually. Regarding the 3D QSAR analysis, the Open3DQSAR results were better than CoMFA and CoMSIA, although all these 3D-QSAR models supported each other. The importance of biphenylsulphonyl moiety over phenylacetyl/naphthylacetyl moieties was established due to its association with favourable steric and hydrophobic characters. HQSAR, LDA-QSAR and Bayesian classification QSAR studies also suggested that the biphenylsulphonamido group was better than the phenylacetylcarboxamido function. Additionally, glutamines were proven to be far better inhibitors than isoglutamines. Observations obtained from the current study were revalidated and supported by the earlier reported molecular modelling studies. Depending on these observations, newer glutamic acid-based compounds may be designed further in future for potent MMP-2 inhibitory activity. PMID- 29254381 TI - Multipole models of sulphur for accurate anisotropic electrostatic interactions within force fields. AB - Nowadays, as computing has become much more available, a fresh momentum has been observed in the field of re-visioning and re-parameterizing the usual tools, as well as estimating for the incorporation of new qualitative capabilities, aimed at making more accurate and reliable predictions in drug discovery processes. Inspired by the success of modelling the electrostatic part of the halogen bonding (XB) by means of the distributed multipole expansion, a study is presented which attempts to extend this approach to a tougher case of sigma-hole interaction: sulphur-based chalcogen bonding. To that end, 11 anisotropic models have been derived and tested for their performance in the reproduction of reference ab initio molecular electrostatic potential. A careful examination resulted in three models which have been selected for further examination as a part of the molecular mechanics force field (GAFF). The combined force field was used to estimate inter- and intra-molecular interactions for the molecular systems, capable of differentiating the binding from the sigma-hole and other directions. The anisotropic models proposed were generally able to correct the wrong predictions of the sulphur models based only on isotropic charges and, thus, are a promising direction for further development of the refined electrostatics force fields. PMID- 29254382 TI - Psychometric properties of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy: a Rasch analysis. AB - PURPOSE: To explore the psychometric properties of the full 22-item English (UK and US) version of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy. MATERIALS AND METHODS: Caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States, recruited through the TREAT-NMD network, completed the Zarit Caregiver Burden Interview online. The psychometric properties of the Zarit Caregiver Burden Interview were examined using Rasch analysis. RESULTS: A total of 475 caregivers completed the Zarit Caregiver Burden Interview. Model misfit was identified for 9 of 22 items (mean item fit residual 0.061, SD: 2.736) and 13 of 22 items displayed disordered thresholds. The overall item-trait interaction chi-square value was 499 (198 degrees of freedom, p < 0.001). The mean person fit residual was estimated at -0.213 (SD: 1.235). The Person Separation Index and Cronbach's alpha were estimated at 0.902 and 0.914, respectively. Item dependency was low and we found no significant differential item functioning by country or sex. CONCLUSION: Our Rasch analysis shows that the Zarit Caregiver Burden Interview fails to fully operationalize a quantitative conceptualization of caregiver burden among caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States. Further research is needed to understand the psychometric properties of the Zarit Caregiver Burden Interview in other populations and settings. Implications for Rehabilitation Duchenne muscular dystrophy is a terminal disease characterized by progressive muscle degeneration resulting in substantial disability and a significant burden on family caregivers. The Zarit Caregiver Burden Interview is one of the most widely applied measures of caregiver burden. Our Rasch analysis suggests that the Zarit Caregiver Burden Interview is not fit for purpose to measure burden in UK and US caregivers to patients with Duchenne muscular dystrophy. Clinicians and decision makers should interpret Zarit Caregiver Burden Interview data from these populations with caution. PMID- 29254383 TI - Evaluation of the correlation between insulin like factor 3, polycystic ovary syndrome, and ovarian maldescent. AB - The aim of this study was to investigate a proposed correlation between the incidentally discovered undescended ovaries and their confirmed diagnosis as a polycystic ovary disease (PCOD) for all cases included, and to evaluate the role of estimated insulin like factor 3 (INSL3) circulating level in the pathogenesis of both abnormal findings. The study group (A) comprised 35 women whose ovaries had been incidentally found to be undescended during the routine laparoscopy for infertility causes, and all had been diagnosed as PCOD. The control category included two subgroups; subgroup (B) included 35 women group, diagnosed as PCOD but with normally allocated ovaries in the true pelvis, and subgroup (C) included 35 healthy women with regular menses and no signs of hyperandrogenism. Correlations between the level of INSL3 and other PCOD relevant biochemical tests: [e.g. BMI, waist-to-hip ratio (WHR), LH, FSH, androstendione (A), total and free testosterone (T & Ft), DHEA-S, and SHBG] had been also investigated. INSL3 levels were significantly higher in PCOD groups (A) and (B) compared to the healthy fertile control subgroup (C) (80.5 +/- 29.4, 65.11 +/- 15.6, and 41.11 +/ 10.2 pg/mL, respectively), and was highest in group (A). Moreover, we identified a strong correlation between INSL3 and androstenedione (r = 0.42, p = 0.0012), and free (r = 0.42, p = .0123) and total testosterone (r = 0.41, p = .004) in the PCOD (A) and (B) subgroup compared to the levels in subgroup (C). LH was significantly higher in all PCOD women in groups (A&B) (12. 3 +/- 3.4, and 11.2 +/- 1.4 mIU/L, respectively) compared to those in group (A) (5.7 +/- 2.5 mIU/L), with a fair correlation with INSL3. However, there was no statistically significant correlation between INSL3 and FSH, DHEA-S, glucose, basal insulin concentration or HOMA-IR in all PCOD women. The strong positive correlation between INSL3, and high ovarian androgens levels in all PCOD women, which appeared clearly in undescended polycystic ovaries could support the proposed syndrome hypothesis between those abnormal findings. PMID- 29254385 TI - Development of self-microemulsifying drug delivery system for oral delivery of poorly water-soluble nutraceuticals. AB - The objective of the study was to develop a self-microemulsifying drug delivery system (SMEDDS), also known as microemulsion preconcentrate, for oral delivery of five poorly water-soluble nutraceuticals or bioactive agents, namely, vitamin A, vitamin K2, coenzyme Q10, quercetin and trans-resveratrol. The SMEDDS contained a 1:1 mixture (w/w) of Capmul MCM NF (a medium chain monoglyceride) and Captex 355 EP/NF (a medium chain triglyceride) as the hydrophobic lipid and Tween 80 (polysorbate 80) as the hydrophilic surfactant. The lipid and surfactant were mixed at 50:50 w/w ratio. All three of the SMEDDS components have GRAS or safe food additive status. The solubility of nutraceuticals was determined in Capmul MCM, Captex 355, Tween 80, and the SMEDDS (microemulsion preconcentrate mixture). The solubility values of vitamin A palmitate, vitamin K2, coenzyme Q10, quercetin, and trans-resveratrol per g of SMEDDS were, respectively, 500, 12, 8, 56, and 87 mg. Appropriate formulations of nutraceuticals were prepared and filled into hard gelatin capsules. They were then subjected to in vitro dispersion testing using 250 mL of 0.01 N HCl in USP dissolution apparatus II. The dispersion test showed that all SMEDDS containing nutraceuticals dispersed spontaneously to form microemulsions after disintegration of capsule shells with globule size in the range of 25 to 200 nm. From all formulations, except that of vitamin K2, >80-90% nutraceuticals dispersed in 5-10 min and there was no precipitation of compounds during the test period of 120 min. Some variation in dispersion of vitamin K2 was observed due to the nature of the material used (vitamin K2 pre-adsorbed onto calcium phosphate). The present report provides a simple and organic cosolvent-free lipid-based SMEDDS for the oral delivery of poorly water-soluble nutraceuticals. Although a 50:50 w/w mixture of lipid to surfactant was used, the lipid content may be increased to 70:30 without compromising the formation of microemulsion. PMID- 29254384 TI - Upgrading of dissolution and anti-hypertensive effect of Carvedilol via two combined approaches: self-emulsification and liquisolid techniques. AB - OBJECTIVE: The aim of the study was to design a self-emulsifying drug delivery system (SEDDS) of the anti-hypertensive Carvedilol in liquid and liquisolid forms as a way to enhance its dissolution profile and anti-hypertensive effect. METHODS: Solubility studies of Carvedilol in various oils, surfactants and co surfactants were conducted, followed by the construction of pseudo-ternary phase diagrams and other in vitro assessments. The selected SEDDS formulation (S1) was adsorbed onto solid powder excipients and compressed into tablets. The resulting liquisolid tablets were evaluated under British Pharmacopoeia (B.P.) specifications. Pre- and post-compression studies were performed to determine the flow properties and evaluate the liquisolid systems, followed by in vivo studies in hypertensive rats. RESULTS: Attempts of self-emulsification, droplet size, and thermodynamic stability studies showed acceptable results for the S1 formulation containing Capryol 90, Tween 20, and Transcutol HP (10:53.3:26.2%), respectively. Pre-compression studies showed adequate flowability and compatibility of liquid and solid excipients with Carvedilol. The selected liquisolid tablet (LS7) demonstrated the best disintegration and water absorption ratio in addition to satisfactory friability and hardness. A significantly (p < .05) fast dissolution rate was observed for both SEDDS and liquisolid formulations when compared to pure drug and marketed Carvepress(r). The in vivo study of LS7 formulation revealed a rapid significant (p < .01) decrease in the mean arterial pressure (MAP) of the rats (112.72 mmHg) within the first 30 min followed by a further decline (107.22 mmHg) after 1 h when compared to Carvepress(r). CONCLUSION: Self emulsifying liquisolid tablets expressed rapid onset of action with enhanced anti hypertensive effect of Carvedilol. PMID- 29254386 TI - Association of tricuspid regurgitation within normal range on the development of left ventricular diastolic dysfunction in patients with uncomplicated hypertension. AB - AIM: Tricuspid regurgitation (TR) with the maximum velocity >2.8m/s has been newly integrated into the diagnostic criteria for left ventricular (LV) diastolic dysfunction. Although the maximum velocity of TR within the normal range (TR < 2.8m/s) is frequently detected in hypertensive patients and is associated with enlarged left atrial (LA) volumes, the influence of TR < 2.8m/s on LV diastolic dysfunction remains unknown in uncomplicated hypertension. METHODS: Echocardiography was performed to assess the mitral annular velocity (e'), E/e', LV mass, and LA phasic volumes and emptying fractions (total, passive, and active) in 100 patients with uncomplicated hypertension with TR within the normal range and in 77 of those without measurable TR. Patients were defined as having normal, inclusive, or dysfunction of LV diastolic function, according to how many parameters met the cut-off levels (maximum LA volume index >34ml/mm2, e'<7 cm/s, and E/e'>15). Pulmonary artery systolic pressure (PASP) was estimated by the formula; PASP =4 (maximum velocity of TR)2 + 5 mmHg. RESULTS: The maximum velocity of TR or PASP saw a positive correlation, and LA total or passive emptying fractions saw an inverse correlation with LV diastolic dysfunction in hypertensive patients with TR < 2.8. In contrast, pulse pressure and LV mass saw positive correlation in hypertensive patients without TR. A stepwise ordinal logistic regression analysis indicated that PASP and LA passive emptying fractions were associated with LV diastolic dysfunction in hypertensive patient with TR < 2.8m/s. CONCLUSION: The presence of TR may be related to the development of LV diastolic dysfunction in hypertensive patients with TR <2.8m/s. PMID- 29254388 TI - Fungal silver nanoparticles: synthesis, application and challenges. AB - PURPOSE: This paper aims to summarize recent developments regarding the synthesis, application and challenges of fungal AgNPs. Possible methods to overcome the challenge of synthesis and reduce the toxicity of AgNPs have been discussed. MATERIALS AND METHODS: This review consults and summary a large number of papers. RESULTS: Silver nanoparticles (AgNPs) have great potential in many areas, as they possess multiple novel characteristics. Conventional methods for AgNPs biosynthesis involve chemical agents, causing environmental toxicity and high energy consumption. Fungal bioconversion is a simple, low-cost and energy efficient biological method, which could successfully be used for AgNPs synthesis. Fungi can produce enzymes that act as both reducing and capping agents, to form stable and shape-controlled AgNPs. CONCLUSIONS: AgNPs have great potential in the medical and food industries, due to their antimicrobial, anticancer, anti-HIV, and catalytic activities. However, the observed in vitro and in vivo toxicity poses considerable challenges in the synthesis and application of AgNPs. PMID- 29254389 TI - Successes and failures of uterine leiomyoma drug discovery. AB - INTRODUCTION: To-date, the only cure for symptomatic uterine fibroids (UFs) is surgical intervention. However, surgery may eliminate the hope of future pregnancies; moreover, the intrinsic risks of surgery make it a less favorable to women with UFs. Because of this, conservative medical therapies have become an attractive and prior option for those women. Leuprolide acetate (LA), a gonadotropin-releasing hormone (GnRH) agonist, is the only pharmacological agent currently approved for the short-term and pre-operative management of symptomatic UFs in the USA. Areas covered: This systematic review covers the successes and failures of prominent drugs that have been researched for UFs in the past and agents that have shown promise in recent clinical trials. The most recent clinical trials and advances in drug therapy are presented in a comprehensive overview outlining the direction UF drug discovery is heading. Expert opinion: Experts in the field are already on the forefront leading the responsibility to uncover potential drugs as long term fertility friendly viable options for non invasive treatment/prevention of UFs. Indeed, a shift in the UF management is expected in the future. PMID- 29254390 TI - Long-acting reversible contraception (LARC) with the intrauterine system with levonorgestrel (6 mcg/d): observational study on the acceptability, quality of life, and sexuality in Italian women. AB - This observational study was conducted in healthy premenopausal women, who presented themselves for contraception with an intrauterine system (IUS) releasing LNG (6 mcg/d) (Jaydess(r), Bayer, Germany) at the outpatient Family Planning Clinics of the Departments of Obstetrics and Gynaecology of the Universities of Cagliari and Sassari (CA/SS), University-Hospitals of CA/SS (Italy). After a screening visit, 31 women without contraindications to Jaydess(r) were included in the study. No difficulty in Jaydess(r) insertion (Ji) was found in 87% of subjects, with pelvic pain (PP) (visual analogic scale, VAS:5.33 +/- 2.54) reported by 27/31 subjects at the Ji. Pelvic pain was reported by 17/31 subjects on the first day (VAS: 3.07 +/- 3.1), 16/31 subjects on the second day (VAS:2.37 +/- 2.71), and 11/31 subjects on the third day (VAS:1.18 +/- 2.02) from Ji, with a significant (p < .001) decrease in the intensity. The primary purposes of the study were to evaluate whether a 12-month-treatment (12-M T) with Jaydess(r) interferes on either the quality of life (QoL) or sexuality. Jaydess(r) did not modify either QoL or sexuality in the 25 subjects who completed the 12-M-T. Throughout the 12-M-T, PP, or pregnancies were not found; the menstrual blood loss was significantly (p < .0001) reduced, and the intensity VAS of dysmenorrhea (#14 subjects) significantly (p < .001) improved. PMID- 29254391 TI - Examining the Relationship Between Children's ADHD Symptomatology and Inadequate Parenting: The Role of Household Chaos. AB - OBJECTIVE: This study examines the interrelations of parenting practices, emotional climate, and household chaos in families with children with and without ADHD. In particular, indirect pathways from children's ADHD symptomatology to inadequate parenting and negative emotional climate via household chaos were investigated. METHOD: Parenting, emotional climate, and household chaos were assessed using questionnaires and a speech sample of parents of 31 children with and 53 without ADHD, aged 7 to 13 years. RESULTS: Group differences were found for certain parenting dimensions, the parent-child relationship, critical comments, and household chaos. While we found significant indirect effects between children's ADHD and certain parenting dimensions through household chaos, no effects were found for any aspect of emotional climate. CONCLUSION: Children's ADHD symptoms translate into inadequate parenting through household chaos, which underlines the need for interventions to improve household organization skills in parents of children with ADHD. PMID- 29254392 TI - Varicella epidemiology in Latin America and the Caribbean. AB - INTRODUCTION: The Latin American Society of Pediatric Infectious Diseases (SLIPE), with the support of the Americas Health Foundation (AHF), has developed a position paper on varicella prevention in Latin America and Caribbean countries (LAC). This article summarizes the most relevant aspects of varicella in LAC, and emphasizes the need to include the varicella vaccine in the national immunization programs in the Region and evaluate its impact disease burden. Areas covered: A systematic review was conducted of the medical evidence published and presented at various regional medical conferences on the disease burden in LAC, the advances made by prevention programs, the available vaccines in the Region, and their immunogenicity, efficacy, effectiveness, and safety. The different national varicella-prevention vaccination programs were reviewed, as was available information regarding the impact of these programs on the epidemiology of varicella in those countries implementing a varicella vaccine strategy. Following that initial publication, an update was conducted, including data from additional countries in the Region. Expert commentary: Varicella is a vaccine-preventable infectious disease, considered a 'benign disease' because of lower complication rates when compared with measles, pertussis. The incorporation of a two-dose varicella vaccine in national immunization schedules in all countries throughout LAC would be of great benefit to the health of the children. PMID- 29254393 TI - Reasons for attending support groups and organizational preferences: the European scleroderma support group members survey. AB - PURPOSE: The objectives were to identify reasons why patients attend scleroderma support groups and to ascertain preferences for how meetings are best organized. METHODS: The survey included 30-items on reasons for attending and nine items on organizational preferences. Patients were recruited through European patient organizations. Exploratory factor analysis was used to group reasons for attendance thematically. RESULTS: About 213 scleroderma patients (192 women) completed the survey. A three-factor model best described reasons for attending [chi2(348) = 586.1, p < 0.001; Comparative Fit Index = 0.98; Tucker Lewis Index = 0.97; Root Mean Square Error of Approximation = 0.06] with themes that included: (1) obtaining interpersonal and social support, (2) learning about treatment and symptom management strategies, and (3) discussing other aspects of scleroderma. Among organizational preferences, respondents emphasized that meetings should include educational aspects and the opportunity to share information and support. CONCLUSION: People with scleroderma attend support groups to give and obtain social support and for education about managing their disease and other aspects of living with scleroderma. Support groups should be structured to facilitate both educational and informational aspects and to provide opportunities for sharing and support between members. Implications for rehabilitation Local peer led support groups are an important support and informational resource for patients living with scleroderma. People with scleroderma attend support groups in order to: (1) obtain interpersonal and social support, (2) learn about disease treatment and symptom management strategies, and (3) discuss other aspects of living with scleroderma outside of symptom management. Most support group members prefer groups with a trained facilitator, that include family members or loved ones in the groups, that include between 11and 20 members, that last between 1 and 2 h, and that meet once every 1-3 months. Rehabilitation professionals can support the formation and management of local support groups or can refer patients to national scleroderma patient organizations for information on support groups that they may be able to access. PMID- 29254387 TI - The evolution into personalized therapies in pancreatic ductal adenocarcinoma: challenges and opportunities. AB - INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is projected to be the second leading cause of cancer related mortality in the United States in 2030, with a 5-year overall survival of less than 10% despite decades of extensive research. Pancreatic cancer is marked by the accumulation of complex molecular changes, complex tumor-stroma interaction, and an immunosuppressive tumor microenvironment. PDAC has proven to be resistant to many cytotoxic, targeted and immunologic treatment approaches. Areas covered: In this paper, we review the major areas of research in PDAC, with highlights on the challenges and areas of opportunity for personalized treatment approaches. Expert commentary: The focus of research in pancreatic cancer has moved away from developing conventional cytotoxic combinations. The marked advances in understanding the molecular biology of this disease especially in the areas of the microenvironment, metabolism, and DNA repair have opened new opportunities for developing novel treatment strategies. Improved understanding of molecular abnormalities allows the development of personalized treatment approaches. PMID- 29254394 TI - A Review and Reconsideration of Nonneoplastic Myometrial Pathology. AB - From 1861 to 1962, clinicopathologic research tried to explain the association of abnormal uterine bleeding with uterine enlargement. The etiology was theorized as metropathy, suggesting that myometrial dysfunction may predispose to abnormal uterine bleeding. Research reached a nadir in 1962, when a major review dismissed myometrial hypertrophy as a plausible explanation after prior rejections of the theories of chronic myometritis, fibrosis uteri, and subinvolution as causes of bleeding. Subsequent to this arose a crusade against unnecessary hysterectomies in the 1970s. Although myometrial hyperplasia was proposed in 1868, it is only in the past 25 years that tangible evidence has supported that idea. It now appears that clinically enlarged uteri are due to globoid outward bulging of the uterus, caused by increased intramural pressure-often unrelated to either uterine weight or myometrial thickness. Abnormal (dysfunctional) uterine bleeding may often be due to spontaneous rupture of thrombosed dilated endometrial vessels, due to the combined effects of obstructed venous drainage by increased intramural pressure, and Virchow's triad. Despite a century-old known association of parity with naturally occurring outer wall myometrial scars (fibrosis uteri with elastosis), it was not previously suggested that these may reflect healing reactions to muscle tears during labor and delivery. We now suggest that smaller, similar inner wall elastotic scars in the nerve-rich inner myometrium may explain many cases of pelvic pain. This review suggests that diverse pressure-related lesions may be present in clinically abnormal uteri that have been called "normal" since the crusade against unnecessary hysterectomy. PMID- 29254395 TI - Oxidative Stress as a Mechanism Involved in Kidney Damage After Subchronic Exposure to Vanadium Inhalation and Oral Sweetened Beverages in a Mouse Model. AB - Kidney diseases have notably increased in the last few years. This is partially explained by the increase in metabolic syndrome, diabetes, and systemic blood hypertension. However, there is a segment of the population that has neither of the previous risk factors, yet suffers kidney damage. Exposure to atmospheric pollutants has been suggested as a possible risk factor. Air-suspended particles carry on their surface a variety of fuel combustion-related residues such as metals, and vanadium is one of these. Vanadium might produce oxidative stress resulting in the damage of some organs such as the kidney. Additionally, in countries like Mexico, the ingestion of sweetened beverages is a major issue; whether these beverages alone are responsible for direct kidney damage or whether their ingestion promotes the progression of an existing renal damage generates controversy. In this study, we report the combined effect of vanadium inhalation and sweetened beverages ingestion in a mouse model. Forty CD-1 male mice were distributed in 4 groups: control, vanadium inhalation, 30% sucrose in drinking water, and vanadium inhalation plus sucrose 30% in drinking water. Our results support that vanadium inhalation and the ingestion of 30% sucrose induce functional and histological kidney damage and an increase in oxidative stress biomarkers, which were higher in the combined effect of vanadium plus 30% sucrose. The results also support that the ingestion of 30% sucrose alone without hyperglycemia also produces kidney damage. PMID- 29254397 TI - Latent Class Analysis of ADHD Symptoms in Korean Children and Adolescents. AB - OBJECTIVE: The objective of this study was to conduct latent class analysis (LCA) of ADHD symptoms to characterize the underlying structure of ADHD. METHOD: Participants were recruited from September 2012 to January 2015 from the Department of Psychiatry of Asan Medical Center, Seoul, Korea. Diagnoses of ADHD and comorbid psychiatric disorders were confirmed with the Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL). We performed LCA of ADHD symptoms in those who had ( n = 141, age = 8.1 +/- 2.3 years, 106 boys) and did not have ( n = 82, age = 9.1 +/- 2.5 years, 40 boys) ADHD. RESULTS: A three-class solution was found to be the best model, revealing classes of children with mostly combined and hyperactive/impulsive subtypes of ADHD (Class 1), non-ADHD (Class 2), and inattentive subtype of ADHD (Class 3). CONCLUSION: The three-class solution with LCA supports a two-factor two-class structure of ADHD symptoms. PMID- 29254396 TI - Treatment Responsivity of Aggressive Forensic Psychiatric Outpatients. AB - Aggression replacement training (ART) is widely used to reduce aggression. Results regarding its effectiveness, however, are inconclusive regarding adults and specific populations displaying severe aggression. The current open uncontrolled treatment study aimed at assessing the social skills and anger control modules of the ART to reduce aggression in forensic psychiatric outpatients (FPOs). Furthermore, characteristics associated with treatment outcome and dropout were examined. The results suggested that aggression changed during the ART. In addition, higher baseline levels of trait aggression were associated with greater reductions of aggression, whereas more cognitive distortions were associated with less reduction. Treatment dropouts were characterized by higher levels of psychopathic traits, proactive aggression, and more weekly substance use. As there was a considerable amount of dropout; it is important to assess risk of dropping out of treatment and, subsequently, improve treatment motivation. This might enhance treatment adherence which may lead to a more successful reduction of aggression. PMID- 29254398 TI - Impact of Latin Dance on Physical Activity, Cardiorespiratory Fitness, and Sedentary Behavior Among Latinos Attending an Adult Day Center. AB - OBJECTIVE: The aim of this study was to determine whether a Latin dance program with sedentary behavior information would have an impact on physical activity, cardiorespiratory fitness (CRF), and sedentary behavior among older Latinos attending an adult day center (ADC). METHOD: Participants ( N = 21, 75.4 +/- 6.3 years old, Mini-Mental State Examination [MMSE] score = 22.4 +/- 2.8) were randomized into a dance or wait-list control group. Participants wore an accelerometer and inclinometer and completed a sedentary behavior questionnaire, and a nonexercise equation was used to calculate CRF. RESULTS: Findings indicate small to medium effect sizes in the desired direction during midpoint of the intervention for physical activity, sedentary behavior-related outcomes, CRF, and self-reported sedentary behavior in the dance group; however; dance participants did not maintain that trajectory for the remaining 2 months of the intervention. DISCUSSION: Future studies may consider implementing behavioral strategies during midpoint of the intervention to encourage participants attending an ADC to maintain physical activity and sedentary behavior changes. PMID- 29254400 TI - Identification of new potential HIV-1 reverse transcriptase inhibitors by QSAR modeling and structure-based virtual screening. AB - Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity and low toxicity in antiretroviral combination therapies which are used to treat HIV. To design more specific HIV-1 inhibitors, 218 diverse non-nucleoside reverse transcriptase inhibitors with their EC50 values were collected. Then, different types of molecular descriptors were calculated. Also, genetic algorithm (GA) and enhanced replacement methods (ERM) were used as the variable selection approaches to choose more relevant features. Based on selected descriptors, a classification support vector machine (SVM) model was constructed to categorize compounds into two groups of active and inactive ones. The most active compound in the set was docked and was used as the input to the Pharmit server to screen the Molport and PubChem libraries by constructing a structure-based pharmacophore model. Shape filters for the protein and ligand as well as Lipinski's rule of five have been applied to filter out the output of virtual screening from pharmacophore search. Three hundred and thirty-four compounds were finally retrieved from the virtual screening and were fed to the previously constructed SVM model. Among them, the SVM model rendered seven active compounds and they were also analyzed by docking calculations and ADME/Tox parameters. PMID- 29254399 TI - Eighteen-year follow-up of the Goteborg Randomized Population-based Prostate Cancer Screening Trial: effect of sociodemographic variables on participation, prostate cancer incidence and mortality. AB - OBJECTIVE: This study examined whether previously reported results, indicating that prostate-specific antigen (PSA) screening can reduce prostate cancer (PC) mortality regardless of sociodemographic inequality, could be corroborated in an 18 year follow-up. MATERIALS AND METHODS: In 1994, 20,000 men aged 50-64 years were randomized from the Goteborg population register to PSA screening or control (1:1) (study ID: ISRCTN54449243). Men in the screening group (n = 9950) were invited for biennial PSA testing up to the median age of 69 years. Prostate biopsy was recommended for men with PSA >=2.5 ng/ml. Last follow-up was on 31 December 2012. RESULTS: In the screening group, 77% (7647/9950) attended at least once. After 18 years, 1396 men in the screening group and 962 controls had been diagnosed with PC [hazard ratio 1.51, 95% confidence interval (CI) 1.39-1.64]. Cumulative PC mortality was 0.98% (95% CI 0.78-1.22%) in the screening group versus 1.50% (95% CI 1.26-1.79%) in controls, an absolute reduction of 0.52% (95% CI 0.17-0.87%). The rate ratio (RR) for PC death was 0.65 (95% CI 0.49-0.87). To prevent one death from PC, the number needed to invite was 231 and the number needed to diagnose was 10. Systematic PSA screening demonstrated greater benefit in PC mortality for men who started screening at age 55-59 years (RR 0.47, 95% CI 0.29-0.78) and men with low education (RR 0.49, 95% CI 0.31-0.78). CONCLUSIONS: These data corroborate previous findings that systematic PSA screening reduces PC mortality and suggest that systematic screening may reduce sociodemographic inequality in PC mortality. PMID- 29254401 TI - Early Predictors of ADHD: Evidence from a Prospective Birth Cohort. AB - OBJECTIVE: To identify preschool predictors of registered ADHD diagnoses and compare two ADHD rating scales, Child Behavior Checklist (CBCL) and Conners' Parent Rating Scale (CPRS-R:S). METHOD: The Norwegian Mother and Child Cohort study (MoBa) is a prospective population-based cohort study. The sample were singletons whose mothers responded to MoBa questionnaires at child age 3 years ( n = 57,986) and 5 years ( n = 32,377). ADHD diagnoses were obtained from the Norwegian Patient Register. Predictors were child gender, development and symptoms, and maternal ADHD symptoms. We used Cox proportional hazard regression analyses. RESULTS: In all final models, ADHD symptoms at age 3 and 5 years predicted later ADHD: Age 3, CBCL: hazard ratio (HR) = 3.23 (CI [2.59, 4.02]); age 5, CBCL: HR = 10.30 (CI [7.44, 14.26]); and age 5 CPRS-R:S: HR = 5.92 (CI [4.95, 7.07]). CONCLUSION: The findings underline the importance of taking early parent-reported symptoms seriously. Both rating scales were useful for predicting ADHD. PMID- 29254402 TI - Caregiver Experiences Across Three Neurodegenerative Diseases: Alzheimer's, Parkinson's, and Parkinson's With Dementia. AB - OBJECTIVE: This article asks whether distinct caregiver experiences of Alzheimer's disease (AD), Parkinson's disease (PD), and Parkinson's disease with dementia (PDD) spouses are accounted for by disease diagnosis or by a unique combination of symptoms, demands, support, and quality of life (QOL) cross disease groups. METHOD: One hundred five live-in spouse caregivers (71.4 +/- 7 years) were surveyed for persons with AD (39%), PD (41%), and PDD (20%). A hierarchical cluster analysis organized caregivers across disease diagnosis into clusters with similar symptom presentation, care demands, support, and QoL. RESULTS: Four clusters cut across disease diagnosis. "Succeeding" cared for mild symptoms and had emotional support. "Coping" managed moderate stressors and utilized formal supports. "Getting by with support" and "Struggling" had the greatest stressors; available emotional support influenced whether burden/depression was moderate or severe. The results remain the same when diagnostic category is added to the cluster analysis. DISCUSSION: This study supports going beyond disease diagnosis when examining caregiver experiences. PMID- 29254403 TI - Glycogen-Rich Clear Cell Carcinoma: A Rare Variant of Breast Carcinoma of Uncertain Significance. PMID- 29254404 TI - Grandparent Caregiving, Race, and Cognitive Functioning in a Population-Based Sample of Older Adults. AB - OBJECTIVE: The aim of this study was to evaluate the association between noncustodial grandparent caregiving and cognition using the Health and Retirement Study (HRS), a population-based study of older adults. METHOD: Participants were White and African American grandparents aged >=65 years. Only noncustodial grandparents who reported not living with their grandchildren over the three waves were included in our analyses. Grandparent caregiving status and cognition were assessed in 2006, 2008, and 2010. Analyses controlled for demographics, baseline health, depressive symptoms, and baseline cognition. RESULTS: Both the number of waves of grandparent caregiving and the total number of grandparent caregiving hours across the three waves were associated with better cognitive functioning at 4-year follow-up in 2010. Associations were observed among Whites, but not among African Americans. DISCUSSION: This study uses longitudinal data to evaluate the association between grandparent caregiving and cognitive functioning. Findings suggest that providing care may be beneficial for some grandparents. PMID- 29254405 TI - Transitioning From Successful Aging: A Life Course Approach. AB - OBJECTIVE: The life course perspective and representative U.S. data are used to test Rowe and Kahn's Successful Aging (SA) conceptualization. Four sets of influences (childhood experiences, social structural factors, adult attainments, and later life behaviors) on SA transitions are examined to determine the relative role of structural factors and individual behaviors in SA. METHOD: Eight waves of Health and Retirement Study data for 12,108 respondents, 51 years and older, are used in logistic regression models predicting transitions out of SA status. RESULTS: Social structural factors and childhood experiences had a persistent influence on transitions from SA, even after accounting for adult attainments and later life behaviors-both of which also impact SA outcomes. DISCUSSION: The findings on sustained social structural influences call into question claims regarding the modifiability of SA outcomes originally made in presentation of the SA model. Implications for policy and the focus and timing of intervention are considered. PMID- 29254406 TI - Stressful Work Trajectories and Depressive Symptoms in Middle-Aged Couples: Moderating Effect of Marital Warmth. AB - OBJECTIVES: The present study investigated the decade-long actor and partner infleunces between husbands' and wives' trajectories of stressful work conditions (SWCs) and their depressive symptoms while also considering the moderation of these influences by spousal warmth. METHODS: Participants were 330 middle-aged dual-earner couples from the Iowa Midlife Transitions Project. Husbands and wives reported on own SWCs and reported on parenter's warmth in the years of 1991, 1992, and 1994. Depressive symptoms for husbands and wives were measured by the SCL-90-R in 1994 and 2001. Structural equation models, growth curves, and longitudinal data were used to perform our analyses. RESULTS: For husbands and wives, trajectories of SWCs over early middle years (1991-1994) contributed to depressive symptoms in 1994. Notably, for husbands and wives, the severity (level) of SWCs in 1991 had a persistent influence on depressive symptoms a decade later (2001). For husbands, under conditions of wives' low warmth, SWCs exerted a relatively strong influence on their depressive symptoms. However, under conditions of high warmth from wives, most of these influences were greatly diminished. DISCUSSION: Results from the current study indicate that contextual life experiences can have a persistent health influences over the life course. PMID- 29254407 TI - Life-Space Predicts Health Care Utilization in Community-Dwelling Older Adults. AB - OBJECTIVE: To determine whether decline in life-space mobility predicts increased health care utilization among community-dwelling older adults. METHOD: Health care utilization (number of emergency department [ED] visits and hospitalizations) was self-reported during monthly interviews among 419 community dwelling African American and non-Hispanic White adults aged 75 years and older in The University of Alabama at Birmingham (UAB) Study of Aging II. Life-space was measured using the UAB Life-Space Assessment. Generalized estimating equations were used to examine associations of life-space at the beginning of each interval with health care utilization over the 1-month interval. RESULTS: Overall, 400 participants were followed for 36 months. A 10-point decrease in life-space was associated with 14% increased odds of an ED visit and/or hospitalization over the next month, adjusting for demographics, transportation difficulty, comorbidity, and having a doctor visit in the last month. DISCUSSION: Life-space is a practical alternative in predicting future health care utilization to performance-based measures, which can be difficult to incorporate into clinical or public health practice. PMID- 29254409 TI - Correction to: Koroglu et al., Increased levels of the novel hepatokine fetuin B in patients with intrahepatic cholestasis of pregnancy. PMID- 29254408 TI - A Community-Based Collaborative Care Model to Improve Functional Health in Underserved Community-Dwelling Older Adults. AB - OBJECTIVE: Examine the effects of a 6-month health multidimensional intervention on physical function, bone density, and mood in a diverse sample of community dwelling older adults at risk for frailty and excess disability. METHOD: A quasi experimental, pre- post-program design was implemented. Adults aged 55 years and older ( n = 337, 60% African American) participated in the intervention and received assessments at baseline, 6 months, and 12 months. RESULTS: Physical function was maintained during the intervention for both African American and White elders but declined at 12 months for both groups ( p < .0001). Symptoms of depression improved during the intervention ( M = 0.65 +/- 0.07, M = 0.15 +/- 0.04, M = 0.68 +/- 0.07, p < .001, respectively) but worsened at 12 months ( M = 0.68 +/- 0.07, p < .001). Bone density scores remained stable from baseline (distal: -1.62 +/- 1.17, proximal: -2.73 +/- 1.85) to 12 months (distal: -1.72 +/ 1.21, proximal: -3.11 +/- 1.85, ps > .05) for both groups. DISCUSSION: Program findings may serve as a basis for the development of a randomized, controlled study to provide empirical evidence of intervention efficacy. Such findings may help inform the development of community-based programs to identify vulnerable older adults and provide vital preventative care to decrease frailty and excess disability. PMID- 29254410 TI - Childhood Disadvantage, Psychosocial Resiliency, and Later Life Functioning: Linking Early-Life Circumstances to Recovery From Mobility Limitation. AB - OBJECTIVE: There is limited knowledge about whether childhood disadvantage, defined as economic and health disadvantage, influences recovery from functional impairment. METHOD: Using data from the Health and Retirement Study (2008-2010), this research explores whether childhood disadvantage shapes recovery from mobility limitation. In addition, this research examines whether measures of psychosocial resiliency such as mastery, optimism, and religiosity moderate the relationship between childhood disadvantage and recovery. RESULTS: Childhood disadvantage appeared to shape recovery from mobility limitation in later life. Greater number of chronic childhood conditions and low maternal education decreased the odds of recovery. Mastery was a robust predictor of recovery and also a moderator of childhood disadvantage (i.e., moving for financial reasons) and recovery. DISCUSSION: Findings suggest that mastery may be able to diminish the negative effects of financial hardship in childhood on recovery outcomes in later life. PMID- 29254412 TI - Understanding violence when the perpetrator has an intellectual disability: The perceptions of professionals. AB - AIM: The research sought to enhance professional understanding of the violence perpetrated by some people with an intellectual disability. BACKGROUND: The violent behaviour exhibited by some people with intellectual disabilities remains poorly understood, particularly with regard to a clear and informative definition. DESIGN: A qualitative study investigated the views and perceptions of professionals working directly with people with an intellectual disability in different settings. METHODS: Twenty-two semi-structured interviews were undertaken with professionals from a variety of backgrounds, and four themes were generated through data analysis. FINDINGS: Themes produced comprised the degree of intellectual disability, impulsivity, intentionality and unpredictability. Findings indicated tension between understanding violence as purposeful and explaining it in relation to the intellectual disability and/or additional conditions. CONCLUSION: Intellectual disability is central to understanding the impact of the other three themes, though there is a professional reluctance to use such knowledge as evidence to inform practice. PMID- 29254411 TI - Reproductive toxicity of melamine against male mice and the related mechanism. AB - Melamine is a nitrogen-containing heterocyclic organic compound with a triazine skeleton, which has been widely applied in industrial and chemical fields. Previous toxicity studies of melamine mainly focused on renal toxicity and hepatic pathological changes, but its toxicity against the reproductive system has seldom been assessed. We investigated the effects of melamine on the reproductive system of male mice. Forty healthy male Kunming mice were randomly divided into a normal saline negative control group, a low-dose melamine group, a medium-dose melamine group and a high-dose melamine group (n = 10). The mice were administered for five consecutive days and killed on the 35th day after first administration. In melamine administration groups, seminiferous tubules had disordered, loose arrangement, and spermatogenic cells at all levels obviously decreased. The sperm count and motility decreased significantly, and the sperm deformity rate increased significantly. Melamine induced apoptosis of testicular spermatogenic cells. To further explore the mechanism, we detected metabolism related enzymes sorbitol dehydrogenase (SDH) and lactate dehydrogenase (LDH) as well as oxidative stress indices superoxide dismutase (SOD) and malondialdehyde (MDA). The activities of SDH, LDH and SOD in melamine treatment groups decreased significantly, and the MDA level increased obviously. The expressions of apoptosis-related proteins Bcl-2, Bax and caspase-3 were detected by immunohistochemistry. The expression of Bcl-2 significantly increased, but those of Bax and caspase-3 significantly reduced (p < 0.05). In conclusion, melamine damaged the reproductive system of mice via the oxidative stress pathway and by inducing cell apoptosis. PMID- 29254413 TI - The Relationship Between Emotional Support and Health-Related Self-Efficacy in Older Prisoners. AB - OBJECTIVE: To determine whether emotional support, and proportion of emotional support provided by specific sources (e.g., family, other prisoners, clinicians), is associated with health-related self-efficacy among older prisoners. METHOD: Cross-sectional study of 140 older prisoners age >=50 with chronic medical illness who completed face-to-face interviews. Logistic regression, controlling for demographic, incarceration, and clinical/behavioral factors evaluated the association between emotional support, operationalized as a score and as a proportion of total emotional support from specific sources, and health-related self-efficacy. RESULTS: Higher emotional support scores, and greater proportion of support from clinicians, were associated with lower likelihood of poor health related self-efficacy. Those with >50% of their emotional support coming from other prisoners had higher likelihood of poor self-efficacy. DISCUSSION: Among older prisoners with chronic illness, higher emotional support, particularly from clinicians, is associated with lower likelihood of poor self-efficacy; relying on other prisoners for emotional support is associated with poor health-related self efficacy. PMID- 29254414 TI - A Randomized Controlled Trial to Examine the Posttreatment Efficacy of Neurofeedback, Behavior Therapy, and Pharmacology on ADHD Measures. AB - OBJECTIVE: To examine the efficacy of neurofeedback (NF), behavior therapy (BT), and pharmacology (PH) on the improvement of ADHD-related symptoms. METHOD: Fifty nine children with ADHD ( M = 8.80 years, SD = 1.92 years) were randomly assigned to one of the three treatments in a pre/post assessment design. Mother- and teacher-rated ADHD scales and children were assessed using The Integrated Visual and Auditory Continuous Performance Test (IVA/CPT). RESULTS: The three treatments were effective on the IVA/CPT, but with different trends. BT and especially NF achieved improvement on response control and attention, and PH mainly in visual attention. On the rating scales, BT improved all measures, and NF and PH had a minor but interesting influence. CONCLUSION: From a global perspective, behavior therapy had the most extensive results, but PH had the greatest capacity to improve overall attention. NF was able to improve both control response and inattention. Clinical implications are discussed. PMID- 29254415 TI - Callous-unemotional traits and early life stress predict treatment effects on stress and sex hormone functioning in incarcerated male adolescents. AB - The stress response system is highly plastic, and hormone rhythms may "adaptively calibrate" in response to treatment. This investigation assessed whether stress and sex hormone diurnal rhythms changed over the course of behavioral treatment, and whether callous-unemotional (CU) traits and history of early adversity affected treatment results on diurnal hormone functioning in a sample of 28 incarcerated adolescent males. It was hypothesized that the treatment would have beneficial effects, such that healthier diurnal rhythms would emerge post treatment. Diurnal cortisol, testosterone, and dehydroepiandrosterone (DHEA) were sampled two weeks after admission to the correctional/treatment facility, and again approximately four months later. Positive treatment effects were detected for the whole sample, such that testosterone dampened across treatment. CU traits predicted a non-optimal hormone response to treatment, potentially indicating biological preparedness to respond to acts of social dominance and aggression. The interaction between CU traits and adversity predicted a promising and sensitized response to treatment including increased cortisol and a steeper testosterone drop across treatment. Results suggest that stress and sex hormones are highly receptive to treatment during this window of development. PMID- 29254416 TI - The Subventricular Zone: A Key Player in Human Neocortical Development. AB - One of the main characteristics of the developing brain is that all neurons and the majority of macroglia originate first in the ventricular zone (VZ), next to the lumen of the cerebral ventricles, and later on in a secondary germinal area above the VZ, the subventricular zone (SVZ). The SVZ is a transient compartment mitotically active in humans for several gestational months. It serves as a major source of cortical projection neurons as well as an additional source of glial cells and potentially some interneuron subpopulations. The SVZ is subdivided into the smaller inner (iSVZ) and the expanded outer SVZ (oSVZ). The enlargement of the SVZ and, in particular, the emergence of the oSVZ are evolutionary adaptations that were critical to the expansion and unique cellular composition of the primate cerebral cortex. In this review, we discuss the cell types and organization of the human SVZ during the first half of the 40 weeks of gestation that comprise intrauterine development. We focus on this period as it is when the bulk of neurogenesis in the human cerebral cortex takes place. We consider how the survival and fate of SVZ cells depend on environmental influences, by analyzing the results from in vitro experiments with human cortical progenitor cells. This in vitro model is a powerful tool to better understand human neocortex formation and the etiology of neurodevelopmental disorders, which in turn will facilitate the design of targeted preventive and/or therapeutic strategies. PMID- 29254417 TI - SDQ Dysregulation Profile and Its Relation to the Severity of Psychopathology and Psychosocial Functioning in a Sample of Children and Adolescents With ADHD. AB - OBJECTIVE: A substantial number of children and adolescents with ADHD show severe affective and behavioral dysregulation. A dysregulation profile (DP) distinguishes those participants at a higher risk of comorbidity, dysfunction, and a poorer response to treatment. It was identified as high scoring in certain subscales of the Strengths and Difficulties Questionnaire (SDQ-DP). We developed a cross-sectional study to assess the clinical utility of the SDQ-DP in ADHD. METHOD: Two hundred fifty clinic-referred children and adolescents with ADHD were assessed. Univariate and linear regression analyses were performed to compare those participants with high levels of SDQ-DP with those with low levels, as well as to examine the association between the SDQ-DP and clinical variables. RESULTS: In all, 28% of ADHD participants had high levels of SDQ-DP. These participants showed higher functional impairment and clinical severity. CONCLUSION: The use of the SDQ-DP will enable identification of those ADHD patients at greater risk. PMID- 29254418 TI - Radiation dosimetry in cell biology: comparison of calculated and measured absorbed dose for a range of culture vessels and clinical beam qualities. AB - PURPOSE: Cell culture studies are frequently used to evaluate the effects of cancer treatments such as radiotherapy, hormone therapy, chemotherapy, nanoparticle enhancement, and to determine any synergies between the treatments. To achieve valid results, the absorbed dose of each therapy needs to be well known and controlled. In this study, we aim to determine the uncertainty associated with radiation exposure in different experimental conditions. MATERIALS AND METHODS: We have performed an in-depth evaluation of the absorbed dose and dose distribution that would be delivered to a cell sample when cultivated in a number of the more popular designs of culture vessels. We focus on exposure to two beam types: a kilovoltage x-ray beam and a megavoltage photon beam, both of which are routinely used to treat cancer patients in the clinical environment. CONCLUSIONS: Our results identify large variations of up to 16% in the absorbed dose across multi-well culture plates, which if ignored in radiobiological experiments, have the potential to lead to erroneous conclusions. PMID- 29254419 TI - Accuracy of inter-hospital transfer information in Australian hospital administrative databases. AB - Inter-hospital transfers improve care delivery for which sending and receiving hospitals both accountable for patient outcomes. We aim to measure accuracy in recorded patient transfer information (indication of transfer and hospital identifier) over 2 years across 121 acute hospitals in New South Wales, Australia. Accuracy rate for 127,406 transfer-out separations was 87 per cent, with a low variability across hospitals (10% differences); it was 65 per cent for 151,978 transfer-in admissions with a greater inter-hospital variation (36% differences). Accuracy rate varied by departure and arrival pathways; at receiving hospitals, it was lower for transfer-in admission via emergency department (incidence rate ratio = 0.52, 95% confidence interval: 0.51-0.53) versus direct admission. Transfer-out data were more accurate for transfers to smaller hospitals (incidence rate ratio = 1.06, 95% confidence interval: 1.03 1.08) or re-transfers (incidence rate ratio > 1.08). Incorporation of transfer data from sending and receiving hospitals at patient level in administrative datasets and standardisation of documentation across hospitals would enhance accuracy and support improved attribution of hospital performance measures. PMID- 29254420 TI - Predicting Receipt of Social Security Administration Disability Benefits Using Biomarkers and Other Physiological Measures: Evidence From the Health and Retirement Study. AB - OBJECTIVES: The objective of this study was to assess how well physiological measures, including biomarkers and genetic indicators, predict receipt of Social Security Administration (SSA) disability benefits among U.S. adults aged 51 to 65 years. METHOD: We used data from the 2006 to 2012 waves of the Health and Retirement Study (HRS), linked to SSA administrative data. Using logistic regression, we predicted benefit receipt (either Social Security Disability Insurance or Supplemental Security Income) using 19 distinct physiological markers, adjusting for age, sex, race, and select medication use. We then calculated the propensity (i.e., predicted probability) that each HRS respondent received benefits and assessed how well propensity score-based classifications could identify beneficiaries and nonbeneficiaries. RESULTS: Thirteen percent of respondents received benefits. Using the propensity score cut point that maximized the sum of sensitivity and specificity, the model correctly predicted 75.9% of beneficiaries and 73.5% of nonbeneficiaries. DISCUSSION: Physiological measures have moderate power to predict SSA disability benefit receipt. PMID- 29254421 TI - Can Cognitive Speed of Processing Training Improve Everyday Functioning Among Older Adults With Psychometrically Defined Mild Cognitive Impairment? AB - OBJECTIVE: The aim of these secondary analyses was to examine cognitive speed of processing training (SPT) gains in cognitive and everyday functioning among older adults with psychometrically defined mild cognitive impairment (MCI). METHOD: A subgroup of participants from the Staying Keen in Later Life (SKILL) study with psychometrically defined MCI ( N = 49) were randomized to either the SPT intervention or an active control group of cognitive stimulation. Outcome measures included the Useful Field of View (UFOV), Road Sign Test, and Timed Instrumental Activities of Daily Living (IADL) Test. A 2 * 2 repeated-measures MANOVA revealed an overall effect of training, indicated by a significant group (SPT vs. control) by time (baseline vs. posttest) interaction. RESULTS: Effect sizes were large for improved UFOV, small for the Road Sign test, and medium for Timed IADL. DISCUSSION: Results indicate that further investigation of cognitive intervention strategies to improve everyday functioning in patients with MCI is warranted. PMID- 29254422 TI - Robust Respondents and Lost Limitations: The Implications of Nonrandom Missingness for the Estimation of Health Trajectories. AB - OBJECTIVE: We offer a strategy for quantifying the impact of mortality and attrition on inferences from later-life health trajectory models. METHOD: Using latent class growth analysis (LCGA), we identify functional limitation trajectory classes in the Health and Retirement Study. We compare results from complete case and full information maximum likelihood (FIML) analyses, and demonstrate a method for producing upper- and lower-bound estimates of the impact of attrition on results. RESULTS: LCGA inferences vary substantially depending on the handling of missing data. For older adults who die during the follow-up period, the widely used FIML approach may underestimate functional limitations by up to 20%. DISCUSSION: The most commonly used approaches to handling missing data likely underestimate the extent of poor health in aging populations. Although there is no single solution for nonrandom missingness, we show that bounding estimates can help analysts to better characterize patterns of health in later life. PMID- 29254424 TI - Do Individual Differences in Early Affective and Cognitive Self-Regulation Predict Developmental Change in ADHD Symptoms From Preschool to Adolescence? AB - OBJECTIVE: The role of heterogeneous self-regulation deficits in ADHD has long been emphasized. Yet, longitudinal studies examining distinct self-regulation processes as prospective predictors of developmental change in ADHD symptoms spanning wide developmental periods are scarce. The aim of the current study was to examine affective and cognitive self-regulation as predictors of developmental change in ADHD symptoms from preschool to adolescence in a sample with one third of the children being at risk for developing an ADHD and/or ODD diagnosis. METHOD: At 5 years laboratory measures for hot and cool executive function (EF) and parental and teacher ratings were used for regulation of positive and negative emotionality. Symptoms of ADHD and ODD were measured at 5 and 13 years using parental and teacher ratings based on the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV). RESULTS: Converging developmental paths in hyperactivity/impulsivity across time were found for those high versus low in early cognitive self-regulation, whereas the development of inattention symptoms diverged across time for those high versus low in early affective self regulation. CONCLUSION: These results support the idea that different aspects of self-regulation are important for developmental change in the two separate ADHD symptom domains from preschool to adolescence. PMID- 29254423 TI - Role of Late-Life Depression in the Association of Subclinical Cardiovascular Disease With All-Cause Mortality: Cardiovascular Health Study. AB - OBJECTIVES: To evaluate whether late-life depression mediates the association of subclinical cardiovascular disease (CVD) with all-cause mortality. METHOD: Using data from 3,473 Cardiovascular Health Study participants, the Cox proportional hazards model was used to examine the direct and indirect (via late-life depression) effects of the association between baseline subclinical CVD and all cause mortality with weights derived from multivariable logistic regression of late-life depression on subclinical CVD. RESULTS: Subclinical CVD led to a higher risk of all-cause mortality (hazard ratio [HR] = 1.51, 95% confidence interval, [CI] = [1.42, 1.94]). Total effect of subclinical CVD on all-cause mortality was decomposed into direct (HR = 1.41, 95% CI = [1.37, 1.58]) and indirect (HR = 1.07, 95% CI = [1.01, 1.23]) effects; 16.3% of the total effect of subclinical CVD on all-cause mortality was mediated by late-life depression. DISCUSSION: Late life depression accounts for little, if any, of the association between subclinical CVD, a risk factor of all-cause mortality, and all-cause mortality. PMID- 29254425 TI - Chronic Conditions May Be More Important Than Race or Ethnicity in Relation to Health Information Seeking and Use. AB - OBJECTIVE: This research examines health information (HI) seeking and use among middle-aged and older adults with chronic health conditions. METHOD: We used logistic regression models to analyze HI seeking ( N = 7,822) and use (N = 4,541 4,547) among participants (aged 45+ years) with chronic conditions from the nationally-representative Health Tracking Household Survey. RESULTS: Adults aged 45+ years with chronic conditions were significantly more likely to seek and use HI; however, these results varied based on the age and education. Compared with Whites, Latinos were less likely to seek HI but more likely to use HI to treat illness, and African Americans were more likely to use HI to maintain health. CONCLUSION: Middle-aged and older adults with chronic conditions are prominent HI seekers and users. Proficient HI seeking and use may have the potential to enhance control over one's own health, maintain independence in the community, and reduce the impact of negative health consequences on the health care system. PMID- 29254426 TI - Economic Adversity Transitions From Childhood to Older Adulthood Are Differentially Associated With Later-Life Physical Performance Measures in Men and Women in Middle and High-Income Sites. AB - OBJECTIVE: This study examines the relationship between economic adversity transitions from childhood to older adulthood and older adulthood physical performance among 1,998 community-dwelling older adults from five demographically diverse sites from middle and high-income countries. METHOD: The principal exposure variable was economic adversity transition. No adversity encompassed not experiencing poverty in both childhood and older adulthood, improved described having only experienced poverty in childhood, worsened captured having experienced poverty in older adulthood, and severe is having experienced poverty in both childhood and older adulthood. The short physical performance battery (SPPB) was used for outcome measures. Analyses of the continuous SPPB score used linear regression, while analysis of a binary outcome (SPPB < 8 vs. >=8) used Poisson regression models with robust error variance, both adjusting for sex, education, and site location. RESULT: In sex-stratified models, the SPPB < 8 prevalence rate ratio (PRR) was higher for the severe (PRR: 2.80, 95% confidence interval [CI] = [1.70, 4.61]), worsened (PRR: 2.40, 95% CI = [1.41, 4.09]), and improved (PRR: 1.82, 95% CI = [1.11, 3.01]) groups, compared with those with no adversity in childhood or as adults, but only for females. DISCUSSION: Findings from this study indicate that persistent economic adversity has a negative effect on older adult physical performance, especially among women. PMID- 29254427 TI - Clinical profiles and temporal patterns of psychiatric emergency room visitors in Sweden. AB - AIMS: To describe persons visiting the psychiatric emergency room (PER) in Sweden and to compare persons who frequently (PFV) and infrequently (PIFV) visit PERs in terms of group size, age, gender, PER location inside versus outside the home municipality, diagnosis (ICD 10), temporal patterns of visits and hospital admissions. METHODS: This register study included all visits to PERs in one Swedish county over 3 years, 2013-2015 (N = 67,031 visits). The study employed descriptive statistics as well as Chi-square tests combined with Bonferroni correction to compare PFV with PIFV. RESULTS: Of the total of 27,282 visitors, 2201 (8.1%) were identified as PFV (five or more visits within 12 months) and they accounted for 38.1% of the total visits. The study found differences between PFV and PIFV in gender, diagnostic profile, hospital admissions and temporal patterns. Differences were also detected with regard to distance between PERs and home municipalities. However, no age-related differences were found between the two groups. CONCLUSIONS: PFV and PIFV have different clinical profiles and temporal patterns. These results may be important when planning, developing and evaluating interventions targeting the needs of each group, which is in accordance with a person-centred approach. Such an approach might eventually result in fewer visits to PERs. PMID- 29254428 TI - Joint Trajectories of Spousal Social Support and Depressive Symptoms in Older Age. AB - OBJECTIVE: We describe changes in depressive symptoms and positive and negative social support from the spouse/partner in a representative sample of older people in England. METHOD: Men and women aged 50+ ( N = 7,171) from the English Longitudinal Study of Ageing reported social support and depressive symptoms (Center for Epidemiologic Studies Depression Scale) on up to five occasions between 2002-2003 and 2010-2011. Parallel process latent growth models estimated their bidirectional associations, adjusted for gender, wealth, education, and limiting illness. RESULTS: In age- and gender-adjusted models, positive spousal support decreased and negative support increased over time, especially among women. Greater increases over time in depressive symptoms were seen in those with lower positive support or higher negative support at baseline. More baseline depressive symptoms predicted greater declines in positive support and greater increases in negative support from the spouse. DISCUSSION: Improving older couple's relationship quality may help reduce depressive symptoms. PMID- 29254429 TI - Is Memory Decline Associated With Inflammatory Response? AB - OBJECTIVE: To examine whether changes in memory over a 10-year period could predict a change in C-reactive protein (CRP) levels. METHOD: A mixed model analysis was first conducted to obtain the estimates for change in memory over the 10-year period using data from the Health and Retirement Study. Then a multivariate regression to determine whether a change in episodic memory could predict subsequent CRP levels was conducted. Furthermore, a general linear model was conducted to determine differences in CRP levels among different rates of change in episodic memory. RESULTS: Greater declines in episodic memory were associated with higher levels of subsequent CRP (Estimate = -0.32, SE = 0.12, beta = -.03, p = .008). The general linear model revealed that those with greater memory declines were more likely to have higher levels of CRP, F = 26.50, p < .001. DISCUSSION: These results highlight the notion that memory decline and inflammation may be intertwined, and we discuss various avenues that warrant further investigation. PMID- 29254430 TI - Multimorbidity Profiles in German Centenarians: A Latent Class Analysis of Health Insurance Data. AB - OBJECTIVES: Multimorbidity in centenarians is common; although investigations of the prevalence of morbidity in centenarians are accumulating, research on profiles of co-occurrence of morbidities is still sparse. Our aim was to explore profiles of comorbidities in centenarians. METHOD: Health insurance data from 1,121 centenarians comprising inpatient and outpatient diagnoses from the past 5 years (2009-2013) were analyzed using latent class analysis with adjustments for sex, age, hospitalization, and long-term care. RESULTS: Four distinct comorbidity profiles emerged from the data: 36% of centenarians were categorized as "age associated"; 18% had a variety of comorbidities but were not diabetic were labeled "multimorbid without diabetes"; 9% were labeled "multimorbid with diabetes"; and 36% "low morbidity." CONCLUSION: Patterns of comorbidities describe the complexity of geriatric multimorbidity more appropriately than an approach focused on a single disease. The profiles described by this specific research may inform clinicians and health care planners for the oldest old. PMID- 29254432 TI - Racial Differences in Caregiving: Variation by Relationship Type and Dementia Care Status. AB - OBJECTIVE: To examine differences between White and African American caregivers in strain, health, and service use in a population-based sample of informal caregivers for older adults. We also assessed whether relationship type (parent, other family, friend) and dementia care status (yes or no) were moderators of any racial differences. METHOD: We examined 887 informal caregivers via covariate adjusted 3 * 2 * 2 factorial ANOVAs. RESULTS: After covariate adjustment, there were few significant racial differences in caregiving strain, health, and service use. Dementia caregivers reported greater strain, and there were three-way interactions among relationship type, dementia care status, and race for physical strain and emotional stress. DISCUSSION: Previous findings suggesting substantial racial differences in caregiver strain, which have primarily come from convenience samples that combined care relationship types, were not replicated. Racial and ethnic differences in caregiving may be context-specific. Historical changes in caregiving should be examined in future research. PMID- 29254431 TI - Protein kinase A governs growth and virulence in Candida tropicalis. AB - Candida tropicalis is one of the most important human fungal pathogens causing superficial infections in locations such as the oral mucosa and genital tract, as well as systemic infections with high mortality. In its sister species Candida albicans, the cyclic AMP/protein kinase A (cAMP/PKA) pathway regulates fungal adhesion and dimorphism, both of which correlate closely with virulence. CaTpk1 and CaTpk2, the catalytic subunits of PKA, not only share redundant functions in hyphal growth, adhesion, and biofilm formation, but also have distinct roles in stress responses and pathogenesis, respectively. However, studies on PKA in the emerging fungal pathogen C. tropicalis are limited. Our results suggest that Tpk1 is involved in cell wall integrity and drug tolerance. The tpk2/tpk2 mutants, which have no protein kinase A activity, have reduced hyphal growth and adhesion. In addition, the tpk1/tpk1 tpk2/tpk2 double deletion mutant demonstrated delayed growth and impaired hyphal formation. In a murine model of systemic infection, both TPK1 and TPK2 were required for full virulence. We further found that EFG1 and HWP1 expression is regulated by PKA, while BCR1, FLO8, GAL4, and RIM101 are upregulated in the tpk1/tpk1 tpk2/tpk2 mutant. This study demonstrates that Tpk1 is involved in drug tolerance and cell wall integrity, while Tpk2 serves as a key regulator in dimorphism and adhesion. Both Tpk1 and Tpk2 are required for growth and full virulence in C. tropicalis. PMID- 29254433 TI - Frozen-Thawed Embryo Transfer Cycles Have a Lower Incidence of Ectopic Pregnancy Compared With Fresh Embryo Transfer Cycles. AB - OBJECTIVE: To evaluate the risk of ectopic pregnancy of embryo transfer. DESIGN: A retrospective cohort study on the incidence of ectopic pregnancy in fresh and frozen-thawed embryo transfer cycles from January 1st, 2010, to January 1st, 2015. PATIENTS: Infertile women undergoing frozen-thawed transfer cycles or fresh transfer cycles. INTERVENTION: In-vitro fertilization, fresh embryo transfer, frozen-thawed embryo transfer, ectopic pregnancy. MAIN OUTCOME MEASURES: Ectopic pregnancy rate and clinical pregnancy rate. RESULT: A total of 69 756 in vitro fertilization-embryo transfer cycles from 2010 to 2015 were analyzed, including 45 960 (65.9%) fresh and 23 796 (34.1%) frozen-thawed embryo transfer cycles. The clinical pregnancy rate per embryo transfer was slightly lower in fresh embryo transfer cycles compared with frozen-thawed embryo transfer cycles (40.8% vs 43.1%, P < .001). Frozen-thawed embryo transfer is associated with a lower incidence of ectopic pregnancy per clinical pregnancy, compared with fresh embryo transfers (odds ratio = 0.31; 95% confidence interval = 0.24-0.39). Female age and body mass index have no influence on ectopic pregnancy. In the frozen-thawed embryo transfer cycles, blastocyst transfer shows a significantly lower incidence of ectopic pregnancy (0.8% vs 1.8%, P = .002) in comparison with day 3 cleavage embryo transfer. CONCLUSION: The risk of ectopic pregnancy is lower in frozen thawed embryo transfer cycles than fresh embryo transfer cycles, and blastocyst transfer could further decrease the ectopic pregnancy rate in frozen-thawed embryo transfer cycles. PMID- 29254434 TI - Fair data for next-generation management of multiple sclerosis. AB - Multiple sclerosis (MS) is a progressive demyelinating and degenerative disease of the central nervous system with symptoms depending on the disease type and the site of lesions and is featured by heterogeneity of clinical expressions and responses to treatment strategies. An individualized clinical follow-up and multidisciplinary treatment is required. Transforming the population-based management of today into an individualized, personalized and precision-level management is a major goal in research. Indeed, a complex and unique interplay between genetic background and environmental exposure in each case likely determines clinical heterogeneity. To reach insights at the individual level, extensive amount of data are required. Many databases have been developed over the last few decades, but access to them is limited, and data are acquired in different ways and differences in definitions and indexing and software platforms preclude direct integration. Most existing (inter)national registers and IT platforms are strictly observational or focus on disease epidemiology or access to new disease modifying drugs. Here, a method to revolutionize management of MS to a personalized, individualized and precision level is outlined. The key to achieve this next level is FAIR data. PMID- 29254435 TI - Predictors of Medication Nonadherence From Outpatient Pharmacy Data Within a Large, Academic Health System. AB - BACKGROUND: Medication nonadherence is a worldwide issue that can lead to poor clinical outcomes and increased health-care costs. OBJECTIVE: To determine the predictors of medication nonadherence. METHODS: A retrospective chart review was conducted for patients who received prescription medications from Cleveland Clinic outpatient pharmacies. Prediction variables consisted of demographics, socioeconomic status, number of medications, and number of daily administrations. These variables were analyzed using a logistic regression to determine independent predictors of medication adherence. RESULTS: Between January and September 2015, over 300 000 eligible prescriptions were filled, corresponding with over 70 000 unique patients. Of these, 29 134 patients were included. After multivariable regression, increasing age (odds ratio [OR]: 1.01), household income (OR: 1.03), and medication count (OR: 1.05) were found to be associated with adherence. Male gender (OR: 0.88), African American (OR: 0.45), Hispanic (OR: 0.62), or other race (OR: 0.87), being single (OR: 0.92), and increasing frequency of administrations per day (OR: 0.76) were associated with nonadherence. CONCLUSION: Medication nonadherence was associated with nonwhite race, single status, male gender, low socioeconomic status, and increasing frequency of medication administration. Based on these results, a risk prediction tool could be created to determine which patients are at the highest risk of medication nonadherence. PMID- 29254436 TI - Optimized adaptive enrichment designs. AB - Based on a Bayesian decision theoretic approach, we optimize frequentist single- and adaptive two-stage trial designs for the development of targeted therapies, where in addition to an overall population, a pre-defined subgroup is investigated. In such settings, the losses and gains of decisions can be quantified by utility functions that account for the preferences of different stakeholders. In particular, we optimize expected utilities from the perspectives both of a commercial sponsor, maximizing the net present value, and also of the society, maximizing cost-adjusted expected health benefits of a new treatment for a specific population. We consider single-stage and adaptive two-stage designs with partial enrichment, where the proportion of patients recruited from the subgroup is a design parameter. For the adaptive designs, we use a dynamic programming approach to derive optimal adaptation rules. The proposed designs are compared to trials which are non-enriched (i.e. the proportion of patients in the subgroup corresponds to the prevalence in the underlying population). We show that partial enrichment designs can substantially improve the expected utilities. Furthermore, adaptive partial enrichment designs are more robust than single stage designs and retain high expected utilities even if the expected utilities are evaluated under a different prior than the one used in the optimization. In addition, we find that trials optimized for the sponsor utility function have smaller sample sizes compared to trials optimized under the societal view and may include the overall population (with patients from the complement of the subgroup) even if there is substantial evidence that the therapy is only effective in the subgroup. PMID- 29254437 TI - Physical Function, Relocation, and Mortality Outcomes in Residential Care and Assisted Living Residents. AB - OBJECTIVE: This study aimed to identify predictors of 6-month physical function and 12-month relocation or death in 272 residents of 34 residential care/assisted communities. METHOD: Measures collected at baseline, 6, and 12 months included health and demographic characteristics; self-reported pain, fatigue, and depressive symptoms; exercise self-efficacy, barriers, and expectations; attitudes on aging; performance-based physical function and physical activity; and community demographics, programs, and policies. GLIMMIX procedures for regression analyses with community as a random effect were run. RESULTS: Better baseline physical function and grip strength, female sex, and residential care community predicted better 6-month physical function. At 12 months, 25.6% had relocated or died. The odds of 12-month relocation or death for 1-point increase in physical function score was 0.84 and for 1-point increase in depression score was 1.16. DISCUSSION: Targets to promote longer tenure in residential care/assisted living include programs to ameliorate functional decline and depression screening and treatment. PMID- 29254438 TI - The contribution of social cognition in predicting social participation following moderate and severe TBI in youth. AB - Youth with moderate or severe traumatic brain injury (TBI) are at risk for reduced social participation after the injury, and the contribution of social cognition to these changes in functioning has been little studied. This study aimed to examine social participation and to measure the contribution of social and non-social cognitive functions to social participation impairment in youth (ages 12-21) who sustained moderate or severe TBI. Youth with TBI (n = 23) were compared to typically developing (TD) controls on self- and parent-rated social participation questionnaires. Direct testing of social cognition (mentalising, social knowledge, emotion recognition) and higher order cognitive abilities (intellectual abilities, attention and executive functions) was also conducted. Significant differences were found between the TBI participants and TD controls on social participation measures. Mentalising and problem-solving abilities revealed to be significant correlates of social participation as reported by youth with brain-injury and their parents. Overall, these results corroborate previous findings by showing that social participation is significantly reduced after TBI, and further shows that mentalising, which is not always considered during rehabilitation, is an important contributing factor. In addition to executive function measures, social cognition should therefore be systematically included in assessment following youth TBI for intervention and prevention purposes. PMID- 29254439 TI - Strapped for Time or Stressed Out? Predictors of Work Interruption and Unmet Need for Workplace Support Among Informal Elder Caregivers. AB - OBJECTIVE: We evaluate whether strong associations between unmet need and work interruption observed among informal elder caregivers are explained by caregiver personal characteristics, caregiving situations, or diminished caregiver well being. METHOD: We analyze a proprietary survey of informal elder caregivers conducted by a single large U.S. employer ( N = 642 caregivers). RESULTS: Unmet need was about twice as common among those experiencing mild (29.79%) or severe interruption (35.00%) relative to those who did not interrupt work (16.87%). Although caregiver characteristics and aspects of caregiving situation show links to either unmet need or work interruption specifically, the association between unmet need and work interruption was not explained by these factors, or by caregiver well-being. DISCUSSION: Needs-related work interruptions may arise by other workplace processes, such as organizational culture, that should be measured and tested explicitly by future research. PMID- 29254440 TI - Trajectories of Maintenance and Resilience in Healthful Eating and Exercise Behaviors in Older Adults. AB - OBJECTIVE: Our objective was to describe behavioral change trajectories for healthful eating and exercise in a group of community-dwelling older adults. A secondary aim was to determine predictors of maintenance and resilience. METHOD: Subjects were participants in the Study of Exercise and Nutrition in Older Rhode Islanders (SENIOR) I study who had achieved postaction stage of change for at least one behavior by its end. They were recruited for SENIOR II, a 48-month study with annual assessments on demographic, anthropometric, cognitive, psychosocial, and behavioral variables. RESULTS: Maintainers generally had higher levels of healthy behaviors and better cognitive function. Resilient older adults were similar to maintainers but were older and had greater functional limitations. DISCUSSION: Findings suggest that both physical health and psychological capital provide important resources upon which to draw as older adults grow even older. The trajectory model can provide useful information for developing resilience interventions for older adults. PMID- 29254441 TI - The Level of Cognitive Impairment and Likelihood of Frequent Hospital Admissions. AB - OBJECTIVE: This study aims to examine the relationship between different levels of cognitive impairment (CI) and the frequency of hospital admission (HA). METHOD: Data from the National Health and Aging Trend Study, Round 1 (2011), with 8,245 respondents from Medicare beneficiaries were used. The data account for the number of hospital admissions for one year before the data collection. Clock Drawing Test and delayed word recall were employed to measure CI. RESULTS: The severity of CI is one of the factors significantly associated with HA. Controlling for the level of function, the likelihood of HA increased among respondents with moderate, mild-to-moderate, and mild CI. Counterintuitively, HA was reduced when CI is severe. DISCUSSION: People with CI are at more risk of frequent HA and the severity of impairment can increase this risk subsequently. Screening for CI at admission can open up the possibility of interventions, hence reducing complications during and after hospitalization. PMID- 29254442 TI - Estimating scaled treatment effects with multiple outcomes. AB - In classical study designs, the aim is often to learn about the effects of a treatment or intervention on a single outcome; in many modern studies, however, data on multiple outcomes are collected and it is of interest to explore effects on multiple outcomes simultaneously. Such designs can be particularly useful in patient-centered research, where different outcomes might be more or less important to different patients. In this paper, we propose scaled effect measures (via potential outcomes) that translate effects on multiple outcomes to a common scale, using mean-variance and median-interquartile range based standardizations. We present efficient, nonparametric, doubly robust methods for estimating these scaled effects (and weighted average summary measures), and for testing the null hypothesis that treatment affects all outcomes equally. We also discuss methods for exploring how treatment effects depend on covariates (i.e., effect modification). In addition to describing efficiency theory for our estimands and the asymptotic behavior of our estimators, we illustrate the methods in a simulation study and a data analysis. Importantly, and in contrast to much of the literature concerning effects on multiple outcomes, our methods are nonparametric and can be used not only in randomized trials to yield increased efficiency, but also in observational studies with high-dimensional covariates to reduce confounding bias. PMID- 29254443 TI - Decision making and uncertainty quantification for individualized treatments using Bayesian Additive Regression Trees. AB - Individualized treatment rules can improve health outcomes by recognizing that patients may respond differently to treatment and assigning therapy with the most desirable predicted outcome for each individual. Flexible and efficient prediction models are desired as a basis for such individualized treatment rules to handle potentially complex interactions between patient factors and treatment. Modern Bayesian semiparametric and nonparametric regression models provide an attractive avenue in this regard as these allow natural posterior uncertainty quantification of patient specific treatment decisions as well as the population wide value of the prediction-based individualized treatment rule. In addition, via the use of such models, inference is also available for the value of the optimal individualized treatment rules. We propose such an approach and implement it using Bayesian Additive Regression Trees as this model has been shown to perform well in fitting nonparametric regression functions to continuous and binary responses, even with many covariates. It is also computationally efficient for use in practice. With Bayesian Additive Regression Trees, we investigate a treatment strategy which utilizes individualized predictions of patient outcomes from Bayesian Additive Regression Trees models. Posterior distributions of patient outcomes under each treatment are used to assign the treatment that maximizes the expected posterior utility. We also describe how to approximate such a treatment policy with a clinically interpretable individualized treatment rule, and quantify its expected outcome. The proposed method performs very well in extensive simulation studies in comparison with several existing methods. We illustrate the usage of the proposed method to identify an individualized choice of conditioning regimen for patients undergoing hematopoietic cell transplantation and quantify the value of this method of choice in relation to the optimal individualized treatment rule as well as non-individualized treatment strategies. PMID- 29254444 TI - Exploring the Occupational Context of Independent Male Escorts Who Seek Male Clients: The Case of Job Success. AB - Male sex work (MSW) research has been generally limited to the examination of "social problems." Although there have been studies on occupational aspects, pointed examinations of the occupational environment, detailing the contemporary nature of the field, are rare. Research on nuances of the occupational context of MSW, providing insight on the rapidly changing face of the field, is wanting. Semistructured interviews were conducted with 20 escorts in Brisbane, Australia. This study explored job success, indicating that success in the field was well articulated, possibly highlighting that male independent escorting is becoming a professionalized occupation, with a shift away from current stigmatized understandings. PMID- 29254445 TI - Combined Popliteal Catheter With Single-Injection vs Continuous-Infusion Saphenous Nerve Block for Foot and Ankle Surgery. AB - BACKGROUND: The increasing scope and complexity of foot and ankle procedures performed in an outpatient setting require more intensive perioperative analgesia. Regional anesthesia (popliteal and saphenous nerve blocks) has been proven to provide satisfactory pain management, decreased postoperative opioid use, and earlier patient discharge. This can be further augmented with the placement of a continuous-flow catheter, typically inserted into the popliteal nerve region. This study investigated the use of a combined popliteal and saphenous continuous-flow catheter nerve block compared to a single popliteal catheter and single-injection saphenous nerve block in postoperative pain management after ambulatory foot and ankle surgery. METHODS: A prospective study was conducted using 60 patients who underwent foot and ankle surgery performed in an outpatient setting. Demographic data, degree of medial operative involvement, American Society of Anesthesiologists physical classification system, anesthesia time, and postanesthesia care unit time were recorded. Outcome measures included pain satisfaction, numeric pain scores (NPS) at rest and with activity, and opioid intake. Patients were also classified by degree of saphenous nerve involvement in the operative procedure, by the surgeon who was blinded to the anesthesia randomization. RESULTS: Patients in the dual-catheter group took significantly less opioid medication on the day of surgery and postoperative day 1 (POD 1) compared to the single-catheter group ( P = .02). The dual-catheter group reported significantly greater satisfaction with pain at POD 1 and POD 3 and a significantly lower NPS at POD 1, 2, and 3. This trend was observed in all 3 subgroups of medial operative involvement. CONCLUSION: Patients in the single catheter group reported more pain, less satisfaction with pain control, and increased opioid use on POD 1, suggesting dual-catheter use was superior to single-injection nerve blocks with regard to managing early postoperative pain in outpatient foot and ankle surgery. LEVEL OF EVIDENCE: Level II, prospective cohort study. PMID- 29254446 TI - Fatigue Bending Strength of Jones Fracture Specific Screw Fixation. AB - BACKGROUND: Intramedullary screw fixation is a common method of treating proximal metadiaphyseal fifth metatarsal (ie, Jones) fractures. Fatigue failure is a complication of this fixation. There are many screw designs available, including Jones fracture specific fixation, but the optimal choice of screw design is unknown. The purpose of this study was to compare the fatigue strength of Jones fracture specific screw designs as well as other commonly used screw designs. Our hypothesis was that there would be no difference in fatigue strength for Jones fracture specific screw designs at similar screw diameters. METHODS: A study was performed to determine the fatigue bending strength of 5 different screw designs including Jones fracture specific screw designs at 3 different screw diameters. Six screws of each size and design underwent cyclic fatigue testing, and a median fatigue limit (MFL) was determined for each screw design and size. RESULTS: The Stryker Asnis JFX solid 4.0-mm, 5.0-mm, and 6.0-mm screws had a higher MFL than all other screws with similar diameter tested (all P < .0001). Both Jones fracture specific screw designs (Stryker Asnis JFX solid screws and Charlotte Carolina Jones screws) had higher MFLs than the other screw designs tested. CONCLUSION: This study provides comparative fatigue strength data on larger screw diameters, which have not been previously reported. There was a statistically significant difference in screw fatigue properties at the screw diameters tested. CLINICAL RELEVANCE: The clinical significance of this study is that it provides surgeons with fatigue strength data to aid in screw selection for Jones fracture fixation. PMID- 29254447 TI - Correlation of Incisura Anatomy With Syndesmotic Malreduction. AB - BACKGROUND: The anatomy of the syndesmosis is variable, yet little is known on the correlation between differences in anatomy and syndesmosis reduction results. The aim of this study was to analyze the correlation between syndesmotic anatomy and the modes of syndesmotic malreduction. METHODS: Bilateral postreduction ankle computed tomography (CT) scans of 72 patients treated for fractures with syndesmotic disruption were analyzed. Incisura depth, fibular engagement into the incisura, and incisura rotation were correlated with degree of syndesmotic malreduction in coronal and sagittal planes as well as rotational malreduction. RESULTS: Clinically relevant malreduction in the coronal plane, sagittal plane, and rotation affected 8.3%, 27.8%, and 19.4% of syndesmoses, respectively. The syndesmoses with a deep incisura and the fibula not engaged into the tibial incisura were at risk of overcompression, anteverted incisuras at risk of anterior fibular translation, and retroverted incisuras at risk of posterior fibular translation. CONCLUSIONS: Certain morphologic configurations of the tibial incisura increased the risk of specific syndesmotic malreduction patterns. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 29254448 TI - Anatomic Evaluation of Percutaneous Achilles Tendon Lengthening. AB - BACKGROUND: The objective of the study was to evaluate the accuracy of percutaneous Achilles tendon lengthening (TAL) using a triple hemisection technique and the improvement in ankle dorsiflexion. METHODS: Ten fresh-frozen above-knee cadaveric specimens were used. A percutaneous triple hemisection of the Achilles tendon (proximal, intermediate, and distal) was performed. Maximum ankle dorsiflexion was evaluated pre- and postprocedure with a digital goniometer. After proper dissection, the relative width of the cuts was noted. Following forced ankle dorsiflexion, displacement in the tensile gaps was measured in all 3 cuts with a precision digital caliper. RESULTS: The overall relative width of the percutaneous cut was 51.3% +/- 16.3% of the Achilles tendon diameter, 44.3% +/- 13.6% for the proximal cut, 50.3% +/- 15.6% for the intermediate cut, and 59.3% +/- 18.4% for the distal cut. Tendon excursion averaged 13.0 +/- 3.8 mm for the proximal cuts, 12.5 +/- 4.7 mm for the intermediate cuts, and 8.2 +/- 3.7 mm for the distal cuts. One cadaver had a complete rupture of the Achilles tendon and was excluded from the excursion data analysis. The mean range of motion for ankle dorsiflexion was 8.1 +/- 3.9 degrees preprocedure and 27.6 +/- 5.3 degrees postprocedure. The dorsiflexion angle significantly increased ( P < .0001) at an average of 19.5 +/- 5.0 degrees following TAL. CONCLUSION: Our cadaveric study demonstrated that the percutaneous triple hemisection of the Achilles was an accurate technique that provided successful lengthening of the tendon and increased ankle dorsiflexion. Complete ruptures are possible complications. CLINICAL RELEVANCE: Our cadaveric study showed that in a clinical situation, triple hemisections of the Achilles tendon can be performed reliably, with significant improvement of the ankle dorsiflexion, mainly through increased tendon excursion at the proximal and intermediate cuts, and with low risk of complete ruptures. PMID- 29254449 TI - Factors Affecting Perceptions of Disability and Self-Rated Health Among Older Adult, Long-Term Cancer Survivors. AB - OBJECTIVE: This article examines the relative importance of cancer-related and noncancer illness factors as they predict the health quality of life among older adult, long-term cancer survivors. Specifically, it examines the effects that continuing cancer symptoms and comorbidities have on functional difficulties and how they in turn affect perceptions of disability and self-rated health. METHOD: Data from an National Cancer Institute (NCI)-funded, tumor registry-based 10-year study of 321 older adult (age 60+), long-term (5+years post diagnosis) survivors of breast colorectal and prostate cancer are examined using regression analyses. RESULTS: The analyses documented the independent effects of both cancer-related and age-related health factors as they contribute to explaining functional difficulties, perceptions of disability and self-rated health. Gender and racial differences in health quality of life were also identified. DISCUSSION: The findings suggest that geriatricians, geriatric nurses, and clinical gerontologists who work with cancer survivorsneed to be aware of the ways in which both cancer and noncancer illness factors work together in producing threats to health quality of life through the extent and nature of functional impairments. PMID- 29254450 TI - A Community-Based Evaluation of Screening, Brief Intervention, and Referral to Treatment (SBIRT) for the Black Community. AB - Limited research evaluates substance use prevention and intervention strategies for cultural sensitivity, appropriateness of content, patient/provider interactions, and implementation for racial and ethnic minority populations. This study uses the Consolidated Framework for Implementation Research (CFIR) to examine a community-based evaluation of Screening, Brief Intervention, and Referral to Treatment (SBIRT) for implementation among the Black community in a small, urban setting. Data were gathered through four separate focus groups, one for service providers ( n = 7), one for community youth leaders ( n = 8), and two for community members ( n = 10). Findings suggest that a range of multi-level service needs and underlying mechanisms of implementation should be considered when administering SBIRT within community health settings serving Black populations. This community-involved evaluation of SBIRT responds to the call for the examination of implementation in specific settings, and suggests a need for further examinations of strategies that support engagement through SBIRT and other innovations. PMID- 29254451 TI - Structural basis of flavonoids as dengue polymerase inhibitors: insights from QSAR and docking studies. AB - Dengue, one of the mosquito-borne viral infections, is a major public health concern across the world. The global incidence of dengue insists the need for a potent antiviral medication for its treatment. Flavonoids are one of the well known antiviral agents which are being studied with great interest on several viruses including dengue virus. In order to find the structural properties which favor antiviral activity in flavonoids in dengue polymerase, a quantitative structural activity relationship study is performed on a set of 33 flavonoids using multiple linear regression method. Our method showed that the descriptors such as hydrogen bond acceptors, branching index with respect to molecular size and electrotopology of carbon atom explain well the variance in the antiviral activity of flavonoids and the results are statistically significant. The differential interaction pattern observed in docking studies confirms the novelty of the model. The model is applied on a set of flavonoid derivatives, which predicted compounds, 5-hydroxy-3,3',4',6,7,8-hexamethylflavone, 4',5,6,7 tetramethylflavone, and 7"-methylamentoflavone as potent dengue polymerase inhibitors. PMID- 29254453 TI - Humanitarian response to reproductive and sexual health needs in a disaster: the Nepal Earthquake 2015 case study. AB - This case study describes the health response provided by the Ministry of Health of Nepal with support from UN agencies and several other organisations, to the 1.4 million women and adolescent girls affected by the major earthquake that struck Nepal in April 2015. After a post-disaster needs assessment, the response was provided to cater for the identified sexual and reproductive health (RH) needs, following the guidance of the Minimum Initial Service Package for RH developed by the global Inter-Agency Working Group. We describe the initiatives implemented to resume RH services: the distribution of medical camp kits, the deployment of nurses with birth attendance skills, the organisation of outreach RH camps, the provision of emergency RH kits and midwifery kits to health facilities and the psychosocial counselling support provided to maternity health workers. We also describe how shelter and transition homes were established for pregnant and post-partum mothers and their newborns, the distribution of dignity kits, of motivational kits for affected women and girls and female community health volunteers. We report on the establishment of female-friendly spaces near health facilities to offer a multisectoral response to gender-based violence, the setting up of adolescent-friendly service corners in outreach RH camps, the development of a menstrual health and hygiene management programme and the linkages established between adolescent-friendly information corners of schools and adolescent-friendly service centres in health facilities. Finally, we outline the gaps, challenges and lessons learned and suggest recommendations for preparedness and response interventions for future disasters. PMID- 29254452 TI - Successful Embolization of a Ruptured Ovarian Artery Aneurysm in a Postmenopausal Woman: Case Report and Literature Review of Gonadal Artery Aneurysms. AB - Gonadal artery aneurysms (GADs) are extremely rare; their prevalence and natural history are unknown and their pathogenesis remains poorly understood. Based on the limited literature reports, these might present with rupture (ovarian artery) or pain and acute thrombosis (testicular artery). The present article reports the case of an 80-year-old woman who came to the emergency department (ED) with acute onset of abdominal and left flank pain. A computed tomography angiography (CTA) revealed a large retroperitoneal hematoma associated with the presence of a left ovarian artery aneurysm. The patient was taken to the angiography suite for a selective vessel catheterization and embolization with N-butyl-2-cyanoacrylate (NBCA). Following the procedure, her serial hemoglobin remained stable, her symptoms subsided, and she was discharged home 2 days later. The GADs are unrecognized entities until an acute event such as rupture occurs, and vessel embolization is effective for hemorrhage control. Close communication and collaboration with gynecologists and urologists are crucial to better define the prevalence, natural history, and the appropriate behavior and timing for elective treatment. With this article, the authors additionally present a review of the literature. PMID- 29254454 TI - Clinical outreach refresher trainings in crisis settings (S-CORT): clinical management of sexual violence survivors and manual vacuum aspiration in Burkina Faso, Nepal, and South Sudan. AB - During the early humanitarian response to a crisis, there is limited time to train health providers in the life-saving clinical services of the Minimum Initial Services Package (MISP) for Reproductive Health. The Training Partnership Initiative of the Inter-agency Working Group on Reproductive Health in Crises developed the S-CORT model (Sexual and reproductive health Clinical Outreach Refresher Training) for service providers operating in acute humanitarian settings and needing to rapidly refresh their knowledge and skills. Through qualitative research, this study aimed to determine the operational enablers and barriers related to the implementation of two S-CORT modules: clinical management of sexual violence survivors (CMoSVS) and manual vacuum aspiration (MVA). Across three participating countries (Burkina Faso, Nepal, and South Sudan), 135 health staff attended the CMoSVS refresher training and 94 the MVA refresher training. Results from the focus group discussions and in-depth interviews suggest that the S-CORT approach is respectful of human rights and quality of care principles. Furthermore, it is potentially effective in enhancing the knowledge and skills of existing trained service providers, strengthening their capacity, and changing their attitudes towards abortion-related services, for example. The S-CORT is a promising model for implementation in the acute phase of an emergency upon stabilisation of the security situation. The model can also be integrated into broader post-crisis capacity development efforts. Future operational research should emphasise not only an assessment of new modules' contents, but whether implementing this refresher training model in remote outreach settings is feasible, effective, and efficient. PMID- 29254455 TI - Rhodococcus equi Infections in Goats: Characterization of Virulence Plasmids. AB - Rhodococcus equi is an uncommon cause of systemic pyogranulomatous infections in goats with macroscopic similarities to caseous lymphadenitis caused by Corynebacterium pseudotuberculosis. Caprine cases have previously been reported to be caused by avirulent R. equi strains. Six cases of R. equi infection in goats yielding 8 R. equi isolates were identified from 2000 to 2017. Lesions varied from bronchopneumonia, vertebral and humeral osteomyelitis, and subcutaneous abscesses, to disseminated infection involving the lungs, lymph nodes, and multiple visceral organs. Isolates of R. equi from infected goats were analyzed by polymerase chain reaction for R. equi virulence-associated plasmid ( vap) genes. Seven of 8 isolates carried the VapN plasmid, originally characterized in bovine isolates, while 1 isolate lacked virulence plasmids and was classified as avirulent. The VapN plasmid has not been described in isolates cultured from goats. PMID- 29254456 TI - Myxopapillary Ependymoma of Lumbar Soft Tissue: A Case Report With Gene Expression Evaluation. AB - Primary extraspinal myxopapillary ependymoma (MPE) is an exceptionally rare lesion that is mainly located in the subcutaneous sacrococcygeal region. We describe the first case of MPE that presented as an intramuscular tumor mass located in the lumbar area. Absence of the visible connection with the spinal cord and lack of any other tumors in the reported case argue for the primary ectopic origin of the MPE. The differential diagnosis of MPE is discussed. Additionally, we evaluated the expression level of molecular biomarkers that have a prognostic value in central nervous system tumors. PMID- 29254457 TI - Effect of ketogenic diets on leukocyte counts in patients with epilepsy. AB - OBJECTIVES: Ketogenic diets (KDs) have long been used to treat epilepsy and are being explored in a variety of diseases. Preclinical data suggest KDs affect inflammation and cytokine release. It is unknown whether KDs affect white blood cell (WBC) counts over time. This is particularly important in clinical populations who may be immune-suppressed at baseline, such as those with cancer or autoimmune disorders. METHODS: A retrospective review of 125 consecutive adults seen at the Adult Epilepsy Diet Center (AEDC) was conducted. Clinical data regarding compliance, laboratory data, weights, and diet records were collected. A control cohort consisted of patients evaluated at the AEDC who elected not to complete a prescribed KD. RESULTS: In 52 adults on KDs, there was a small but statistically significant decrease in WBC and absolute neutrophil counts at 6 and 12 months into KD therapy. There was no effect on lymphocyte counts. This pattern was also seen in a small population of patients with gliomas (n = 10) on KDs, most (n = 8) of whom had also received chemotherapy and radiation, putting them at risk for bone marrow suppression. Across both glioma and non-glioma groups, patients with pre-existing lymphopenia did not have further worsening of their counts on the KD. CONCLUSIONS: In this retrospective case-control study, a small but significant decrease in total WBC and neutrophil counts was observed in patients with epilepsy treated with the KDs. These patterns are similar in patients with and without gliomas suggesting baseline immunosuppression does not worsen with KD. These findings provide data for prospective confirmatory studies. PMID- 29254458 TI - Socioeconomic Position Across the Life Course and Cognitive Ability Later in Life: The Importance of Considering Early Cognitive Ability. AB - OBJECTIVE: Investigate direct and indirect associations between markers of socioeconomic position (SEP) across the life course and midlife cognitive ability while addressing methodological limitations in prior work. METHOD: Longitudinal data from the Danish Metropolit cohort of men born in 1953 ( N = 2,479) who completed ability tests at age 12, 18, and 56-58 linked to register-based information on paternal occupational class, educational attainment, and occupational level. Associations were assessed using structural equation models, and different models were estimated to examine the importance of accounting for childhood ability and measurement error. RESULTS: Associations between adult SEP measures and midlife ability decreased significantly when adjusting for childhood ability and measurement error. The association between childhood and midlife ability was by far the strongest. DISCUSSION: The impact of adult SEP on later life ability may be exaggerated when not accounting for the stability of individual differences in cognitive ability and measurement error in test scores. PMID- 29254459 TI - Editorial: Growth and Advances of OTJR. PMID- 29254462 TI - Pills for Prejudice: Implicit Bias and Technical Fix for Racism. PMID- 29254460 TI - Confessions of a New York rupture researcher: An insider's guide and critique. AB - OBJECTIVE: The study of alliance rupture has become quite prevalent since 1990 and especially in the past 10 years where we have seen a noticeable surge in empirical publications on the subject. This honorary paper attempts to provide a critical review of this literature from the perspective of someone who has contributed to it in his collaborative work on a research program designed to investigate ruptures and to develop intervention and training models to resolve them. METHOD: This paper is organized into three topics or sections: (1) alliance rupture, (2) rupture resolution, and (3) alliance training; and it addresses definitions, findings, questions, and lessons with regard to each topic. RESULTS/CONCLUSIONS: It suggests some clinical conceptualizations (concerning agency and communion as well as mutual recognition), training implications (regarding emotion regulation and deliberate practice), and methodological considerations (promoting pluralism and contextualism), along with future directions. Clinical or methodological significance of this article: The paper provides a critical review of research on a possible risk factor and potential change process in psychotherapy, including related training strategies, that has important implications for treatment outcome and professional development. PMID- 29254463 TI - Police Violence, Use of Force Policies, and Public Health. PMID- 29254461 TI - Impact of Lesion Morphology on Durability After Angioplasty of Failed Arteriovenous Fistulas in Hemodialysis Patients. AB - PURPOSE: To investigate if morphological patterns of arteriovenous fistula (AVF) venous lesions affect primary patency after percutaneous transluminal angioplasty (PTA). METHODS: From July 2014 to June 2015, 262 patients underwent PTA for failed AVFs. A total of 104 patients were excluded owing to (1) calcification or AVF occlusion precluding ultrasound examination, (2) central venous or arterial lesions, and (3) no follow-up, leaving 158 patients (mean age 71+/-12; 96 men) for analysis. More than half of the patients had one or more previous PTAs for the failed AVF. Prior to PTA the stenotic lesions were assessed using ultrasonography to determine stenotic patterns at the minimum lumen area site and to evaluate the flow volume in the brachial artery. Three stenotic patterns were identified: intimal hyperplasia (IH) stenosis (n=110), shrinking lumen stenosis (n=32), and venous valve-related stenosis (n=16). The main outcome measure was primary patency after PTA estimated using Kaplan-Meier analysis. Predictors for loss of primary patency were determined using a multivariate Cox proportional hazards model; the results are presented as the adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Median follow-up after PTA was 6.3 months (interquartile range 3.3, 10.5). The 6-month primary patency estimates were 56%+/ 5% in the IH group, 40+/-9% in the shrinking lumen group, and 100% in the valve stenosis group (IH vs shrinking, p=0.013; IH vs valve, p=0.003). In multivariate analysis, shrinking lumen morphology had a negative impact on primary patency (HR 2.05, 95% CI 1.25 to 3.36, p=0.005), while venous valve-related stenosis had a positive impact (HR 0.19, 95% CI 0.04 to 0.79, p=0.023). Flow volume (10-mL/min increments; HR 0.97, 95% CI 0.96 to 0.99, p=0.004) and history of PTA (HR 1.66, 95% CI 1.06 to 2.60, p=0.029) were also independently associated with primary patency after PTA. CONCLUSION: The patterns of AVF stenosis as determined by ultrasound can affect the outcome of treatment with balloon dilation. PMID- 29254464 TI - Theorizing Race and Racism: Preliminary Reflections on the Medical Curriculum. AB - The current political economic crisis in the United States places in sharp relief the tensions and contradictions of racial capitalism as it manifests materially in health care and in knowledge-producing practices. Despite nearly two decades of investment in research on racial inequality in disease, inequality persists. While the reasons for persistence of inequality are manifold, little attention has been directed to the role of medical education. Importantly, medical education has failed to foster critical theorizing on race and racism to illuminate the often-invisible ways in which race and racism shape biomedical knowledge and clinical practice. Medical students across the nation are advocating for more critical anti-racist education that centers the perspectives and knowledge of marginalized communities. This Article examines the contemporary resurgence in explicit forms of white supremacy in light of growing student activism and research that privileges notions of innate differences between races. It calls for a theoretical framework that draws on Critical Race Theory and the Black Radical Tradition to interrogate epistemological practices and advocacy initiatives in medical education. PMID- 29254465 TI - Intelligence, Disability, and Race: Intersections and Critical Questions. PMID- 29254466 TI - The Flexner Report: Standardizing Medical Students Through Region-, Gender-, and Race-Based Hierarchies. PMID- 29254467 TI - Cultura Obscura: Race, Power, and "Culture Talk" in the Health Sciences. AB - "The price of culture is a Lie." 1 This Article advances a critical race approach to the health sciences by examining "culture talk" as a discursive repertoire that attributes distinct beliefs, behaviors, and dispositions to ethno-racialized groups. Culture talk entails a twofold process of obfuscation - concealing the social reality of the people it describes and hiding the positionality of those who employ cultural generalizations. After tracing how culture talk circulates and reproduces racist narratives in and beyond the health sciences, I examine how cultural competency training in medical schools and diversity initiatives in stem cell research use the idiom of culture to manage and manufacture group differences. From culturing cells in the lab to enculturing people in the clinic, I apply the concept of coproduction to argue that culture talk is a precondition and product of scientific knowledge construction. PMID- 29254468 TI - Statistics, Adjusted Statistics, and Maladjusted Statistics. AB - Statistical adjustment is a ubiquitous practice in all quantitative fields that is meant to correct for improprieties or limitations in observed data, to remove the influence of nuisance variables or to turn observed correlations into causal inferences. These adjustments proceed by reporting not what was observed in the real world, but instead modeling what would have been observed in an imaginary world in which specific nuisances and improprieties are absent. These techniques are powerful and useful inferential tools, but their application can be hazardous or deleterious if consumers of the adjusted results mistake the imaginary world of models for the real world of data. Adjustments require decisions about which factors are of primary interest and which are imagined away, and yet many adjusted results are presented without any explanation or justification for these decisions. Adjustments can be harmful if poorly motivated, and are frequently misinterpreted in the media's reporting of scientific studies. Adjustment procedures have become so routinized that many scientists and readers lose the habit of relating the reported findings back to the real world in which we live. PMID- 29254470 TI - Race, the New Black: On Fashioning Genetic Brand. PMID- 29254469 TI - Introduction: Critical Race Theory and the Health Sciences. PMID- 29254471 TI - Pathology and Pathogenesis of Immune-Mediated Diseases of Animals. PMID- 29254472 TI - Horses With Pasture Asthma Have Airway Remodeling That Is Characteristic of Human Asthma. AB - Severe equine asthma, formerly recurrent airway obstruction (RAO), is the horse counterpart of human asthma, affecting horses maintained indoors in continental climates. Equine pasture asthma, formerly summer pasture RAO, is clinically similar but affects grazing horses during hot, humid conditions in the southeastern United States and United Kingdom. To advance translational relevance of equine pasture asthma to human asthma, histologic features of airway remodeling in human asthma were scored in lung lobes from 15 pasture asthma affected and 9 control horses of mixed breeds. All noncartilaginous airways were scored using a standardized grading rubric (0-3) in hematoxylin and eosin (HE) and Movat's pentachrome-stained sections; 15 airways were chosen randomly from each lobe for analysis. Logistic regression identified disease, age, and lobe effects on probability of histologic outcomes. Airway smooth muscle (odds ratio [OR] = 2.5, P < .001), goblet cell hyperplasia/metaplasia (OR = 37.6, P < .0001), peribronchiolar elastic system fibers (OR = 4.2, P < .001), peribronchiolar fibrosis (OR = 3.8, P = .01), airway occlusion by mucus/inflammation (OR = 4.2, P = .04), and airway adventitial inflammation (OR = 3.0, P = .01) were significantly greater in diseased airways. A novel complex tissue disorganization, designated terminal bronchiolar remodeling, was overrepresented in diseased airways (OR = 3.7, P < .0001). Distribution of terminal bronchiolar remodeling corresponded to putative sites of air trapping in human asthma, at secondary pulmonary lobules. Age (>15 years) was an independent risk factor for increased peribronchiolar fibrosis, elastic system fibers, and terminal bronchiolar remodeling. Remodeling differed significantly between lung lobes, congruent with nonhomogeneous remodeling in human asthma. Equine pasture asthma recapitulates airway remodeling in human asthma in a manner not achieved in induced animal asthma models, endorsing its translational relevance for human asthma investigation. PMID- 29254473 TI - Diagnostic Tools and Dilemmas With Equine Leukemias. PMID- 29254474 TI - Emerging Understanding of Tuberculosis and the Granuloma by Comparative Analysis in Humans, Cattle, Zebrafish, and Nonhuman Primates. PMID- 29254476 TI - IgA Antibodies Against Gliadin and Tissue Transglutaminase in Dogs With Chronic Enteritis and Intestinal T-Cell Lymphoma. AB - Molecular clonality analysis of T-cell receptor (TCR) genes for diagnosing T-cell lymphoma is widely used in veterinary medicine. However, differentiating chronic enteritis (CE) from intestinal lymphoma is challenging because of the incompatibility between histopathologic and clonality analysis results. On the basis of findings that canine intestinal T-cell lymphoma and celiac disease share some common features, we conducted serologic examinations in combination with histopathologic and T-cell receptor clonality analyses in 48 dogs diagnosed with either CE or intestinal lymphoma. Immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies against gliadin and tissue transglutaminase (tTG) were quantitatively measured using ELISA. The conditions were classified according to the histopathologic diagnosis, clonality analysis, and combined histopathologic/clonality analysis. Histopathologic analysis showed that dogs with intestinal lymphoma were likely to have high levels of serum IgA antibodies against gliadin and tTG, and serum IgG antibodies against tTG. No correlation between the diagnosed groups and control group was observed in the results of the clonality analysis and histopathologic/clonality analysis. It is interesting that dogs with intestinal lymphoma had a higher serum IgA titer against gliadin and tTG than did dogs with CE. These results suggest an association between repetitive inflammatory stimulation by gliadin peptides and subsequent intestinal lymphoma in dogs. PMID- 29254478 TI - Update of incidence and antimicrobial susceptibility trends of Escherichia coli and Klebsiella pneumoniae isolates from Chinese intra-abdominal infection patients. AB - BACKGROUND: To evaluate in vitro susceptibilities of aerobic and facultative Gram negative bacterial (GNB) isolates from intra-abdominal infections (IAIs) to 12 selected antimicrobials in Chinese hospitals from 2012 to 2014. METHODS: Hospital acquired (HA) and community acquired (CA) IAIs were collected from 21 centers in 16 Chinese cities. Extended spectrum beta-lactamase (ESBL) status and antimicrobial susceptibilities were determined at a central laboratory using CLSI broth microdilution and interpretive standards. RESULTS: From all isolated strains the Enterobacteriaceae (81.1%) Escherichia coli accounted for 45.4% and Klebsiella pneumoniae for 20.1%, followed by Enterobacter cloacae (5.2%), Proteus mirabilis (2.1%), Citrobacter freundii (1.8%), Enterobacter aerogenes (1.8%), Klebsiella oxytoca (1.4%), Morganella morganii (1.2%), Serratia marcescens (0.7%), Citrobacter koseri (0.3%), Proteus vulgaris (0.3%) and others (1.0%). Non Enterobacteriaceae (18.9%) included Pseudomonas aeruginosa (9.8%), Acinetobacter baumannii (6.7%), Stenotrophomonas maltophilia (0.9%), Aeromonas hydrophila (0.4%) and others (1.1%). ESBL-screen positive Escherichia coli isolates (ESBL+) showed a decreasing trend from 67.5% in 2012 to 58.9% in 2014 of all Escherichia coli isolates and the percentage of ESBL+ Klebsiella pneumoniae isolates also decreased from 2012 through 2014 (40.4% to 26.6%), which was due to reduced percentages of ESBL+ isolates in HA IAIs for both bacteria. The overall susceptibilities of all 5160 IAI isolates were 87.53% to amikacin (AMK), 78.12% to piperacillin-tazobactam (TZP) 81.41% to imipenem (IMP) and 73.12% to ertapenem (ETP). The susceptibility of ESBL-screen positive Escherichia coli strains was 96.77%-98.8% to IPM, 91.26%-93.16% to ETP, 89.48%-92.75% to AMK and 84.86%-89.34% to TZP, while ESBL-screen positive Klebsiella pneumoniae strains were 70.56% 80.15% susceptible to ETP, 80.0%-87.5% to IPM, 83.82%-87.06% to AMK and 63.53% 68.38% to TZP within the three year study. Susceptibilities to all cephalosporins and fluoroquinolones were less than 50% beside 66.5% and 56.07% to cefoxitin (FOX) for ESBL+ Escherichia coli and Klebsiella pneumoniae strains respectively. CONCLUSIONS: The total ESBL+ rates decreased in Escherichia coli and Klebsiella pneumoniae IAI isolates due to fewer prevalence in HA infections. IPM, ETP and AMK were the most effective antimicrobials against ESBL+ Escherichia coli and Klebsiella pneumoniae IAI isolates in 2012-2014 and a change of fluoroquinolone regimens for Chinese IAIs is recommended. PMID- 29254479 TI - Streptococcal toxic shock syndrome caused by the dissemination of an invasive emm3/ST15 strain of Streptococcus pyogenes. AB - BACKGROUND: Streptococcus pyogenes (group A Streptococcus [GAS]) is a major human pathogen that causes a wide spectrum of clinical manifestations. Although invasive GAS (iGAS) infections are relatively uncommon, emm3/ST15 GAS is a highly virulent, invasive, and pathogenic strain. Global molecular epidemiology analysis has suggested that the frequency of emm3 GAS has been recently increasing. CASE PRESENTATION: A 14-year-old patient was diagnosed with streptococcal toxic shock syndrome and severe pneumonia, impaired renal function, and rhabdomyolysis. GAS was isolated from a culture of endotracheal aspirates and designated as KS030. Comparative genome analysis suggested that KS030 is classified as emm3 (emm-type) and ST15 (multilocus sequencing typing [MLST]), which is similar to iGAS isolates identified in the UK (2013) and Switzerland (2015). CONCLUSIONS: We conclude that the global dissemination of emm3/ST15 GAS strain has the potential to cause invasive disease. PMID- 29254480 TI - Association between changes in body fat and disease progression after breast cancer surgery is moderated by menopausal status. AB - BACKGROUND: Obesity is linked to poor disease outcomes in breast cancer patients. However, this link was mostly based on body weight or BMI rather than body-fat. The purpose of this study was to evaluate the relationship between body-fat gain and disease progression in Taiwanese women after breast cancer surgery and how this relationship is influenced by menopausal status. METHODS: Body fat percentage was measured 1 day before and 6 months after surgery in 131 women with stages 0-III breast cancer. Disease outcomes (metastasis and death) were assessed by chart review and telephone contact 7 to 8 years after diagnosis. These data were analyzed by multivariate Cox proportional hazard model analysis. RESULTS: The percentage of women with over 5% gain in body-fat was 56% for premenopausal and 42% for postmenopausal. Rates of distant metastasis and all-cause mortality were 17.6 and 9.9%, respectively over the follow-up period. Distant metastases were predicted in postmenopausal but not premenopausal women with breast cancer by increased body fat percentage (HR = 1.3, p = 0.035), after controlling other potential covariates, including disease severity, estrogen receptor expression, progesterone receptors expression, age, and exercise habit before diagnosis. Survival was not significantly associated with body-fat percentage gains. CONCLUSIONS: Our results suggest that increased body fat percentage 6 months after breast surgery is an important predictor of distant metastasis in postmenopausal Taiwanese women with breast cancer. Clinicians may need to measure patients' body fat periodically. Our findings should be validated in studies with a longer follow-up time. PMID- 29254481 TI - Melanoma cells replicate through chemotherapy by reducing levels of key homologous recombination protein RAD51 and increasing expression of translesion synthesis DNA polymerase zeta. AB - BACKGROUND: The global incidence of melanoma has been increasing faster than any other form of cancer. New therapies offer exciting prospects for improved survival, but the development of resistance is a major problem and there remains a need for additional effective melanoma therapy. Platinum compounds, such as cisplatin, are the most effective chemotherapeutics for a number of major cancers, but are ineffective on metastatic melanoma. They cause monofunctional adducts and intrastrand crosslinks that are repaired by nucleotide excision repair, as well as the more toxic interstrand crosslinks that are repaired by a combination of nuclease activity and homologous recombination. METHODS: We investigated the mechanism of melanoma resistance to cisplatin using a panel of melanoma and control cell lines. Cisplatin-induced changes in levels of the key homologous recombination protein RAD51 and compensatory changes in translesion synthesis DNA polymerases were identified by western blotting and qRT-PCR. Flow cytometry, immunofluorescence and western blotting were used to compare the cell cycle and DNA damage response and the induction of apoptosis in cisplatin-treated melanoma and control cells. Ectopic expression of a tagged form of RAD51 and siRNA knockdown of translesion synthesis DNA polymerase zeta were used to investigate the mechanism that allowed cisplatin-treated melanoma cells to continue to replicate. RESULTS: We have identified and characterised a novel DNA damage response mechanism in melanoma. Instead of increasing levels of RAD51 on encountering cisplatin-induced interstrand crosslinks during replication, melanoma cells shut down RAD51 synthesis and instead boost levels of translesion synthesis DNA polymerase zeta to allow replication to proceed. This response also resulted in synthetic lethality to the PARP inhibitor olaparib. CONCLUSIONS: This unusual DNA damage response may be a more appropriate strategy for an aggressive and rapidly growing tumour like melanoma that enables it to better survive chemotherapy, but also results in increased sensitivity of cultured melanoma cells to the PARP inhibitor olaparib. PMID- 29254482 TI - Effects of caffeine on the detection of ischemia in patients undergoing adenosine stress cardiovascular magnetic resonance imaging. AB - BACKGROUND: Adenosine stress cardiovascular magnetic resonance (CMR) can detect significant coronary artery stenoses with high diagnostic accuracy. Caffeine is a nonselective competitive inhibitor of adenosine2A-receptors, which might hamper the vasodilator effect of adenosine stress, potentially yielding false-negative results. Much controversy exists about the influence of caffeine on adenosine myocardial perfusion imaging. Our study sought to investigate the effects of caffeine on ischemia detection in patients with suspected or known coronary artery disease (CAD) undergoing adenosine stress CMR. METHODS: Thirty patients with evidence of myocardial ischemia on caffeine-naive adenosine stress CMR were prospectively enrolled and underwent repeat adenosine stress CMR after intake of 200 mg caffeine. Both CMR exams were then compared for evaluation of ischemic burden. RESULTS: Despite intake of caffeine, no conversion of a positive to a negative stress study occurred on a per patient basis. Although we found significant lower ischemic burden in CMR exams with caffeine compared to caffeine naive CMR exams, absolute differences varied only slightly (1 segment based on a 16-segment model, 3 segments on a 60-segment model, and 1 ml in total ischemic myocardial volume, p < 0.001 each). Moreover, no relevant ischemia (>=2 segments in a 16-segment model) was missed by prior ingestion of caffeine. CONCLUSIONS: Although differences were small and no relevant myocardial ischemia had been missed, prior consumption of caffeine led to significant reduction of ischemic burden, and might lower the high diagnostic and prognostic value of adenosine stress CMR. Therefore, we suggest that patients should still refrain from caffeine prior adenosine stress CMR tests. PMID- 29254484 TI - Blood lipids and lipoproteins in relation to incidence and mortality risks for CVD and cancer in the prospective EPIC-Heidelberg cohort. AB - BACKGROUND: Circulating concentrations of lipid biomarkers are associated with risk of cardiovascular diseases (CVD). The evidence for a relationship with cancer risk, however, is not entirely consistent. This study aims to assess the relationships of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoprotein (a) (apo(a)), apoB-100, and lipoprotein(a) (Lp(a)) with risk of common cancer forms and total cancer mortality in comparison to incidence and mortality of CVD. METHODS: We selected a case-cohort sample out of the prospective EPIC-Heidelberg study, including a random subcohort (n = 2739), and cases of cancer (n = 1632), cancer mortality (n = 761), CVD (n = 1070), and CVD mortality (n = 381). Concentrations of lipid biomarkers were measured in pre-diagnostic blood samples. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Prentice-weighted Cox regression models. RESULTS: High levels of circulating apoB-100 and TG were inversely associated and high HDL-C levels were positively associated with breast cancer risk (highest vs. lowest quartile (Q4 vs. Q1), HRapoB 0.71, 95% CI 0.52 0.98; HRTG 0.65, 0.46-0.92; and HRHDL 1.39, 1.01-1.93). Higher levels of Lp(a) were associated with an increase in prostate cancer risk (Q4 vs. Q1, HRLp(a) 1.43, 1.02-2.03) and high levels of apo(a) were associated with a decrease in lung cancer risk (Q4 vs. Q1, HRapo(a) 0.52, 0.30-0.91). High TC, HDL-C, apo(a), and Lp(a) levels were associated with a reduction in total cancer mortality (Q4 vs. Q1, HRTC 0.71, 0.54-0.94; HRHDL 0.67, 0.50-0.91; HRapo(a) 0.71, 0.54-0.93; and HRLp(a) 0.74, 0.57-0.98). All lipid biomarkers were associated with risk of myocardial infarction, whereby TC, apoB-100, TG, and Lp(a) were positively and HLD-C and apo(a) inversely associated with risk. Only high levels of TG were associated with an increased risk of stroke. None of the lipids were associated with risk of colorectal cancer and with risk of CVD mortality after multivariable adjustments. CONCLUSIONS: This prospective study demonstrates inverse associations of lipid biomarkers with cancer incidence and mortality, with the exception of positive associations of HDL-C and Lp(a) with breast and prostate cancer risk, respectively. Thus, the observed cancer risk pattern clearly differs from the CVD risk pattern. PMID- 29254485 TI - Socially isolated individuals are more prone to have newly diagnosed and prevalent type 2 diabetes mellitus - the Maastricht study. AB - BACKGROUND: Social isolation is associated with type 2 diabetes (T2DM), but it is unclear which elements play a crucial role in this association. Therefore, we assessed the associations of a broad range of structural and functional social network characteristics with normal glucose metabolism, pre-diabetes, newly diagnosed T2DM and previously diagnosed T2DM. METHODS: Participants originated from The Maastricht Study, a population-based cohort study (n = 2861, mean age 60.0 +/- 8.2 years, 49% female, 28.8% T2DM (oversampled)). Social network characteristics were assessed through a name generator questionnaire. Diabetes status was determined by an oral glucose tolerance test. We used multinomial regression analyses to investigate the associations between social network characteristics and diabetes status, stratified by sex. RESULTS: More socially isolated individuals (smaller social network size) more frequently had newly diagnosed and previously diagnosed T2DM, while this association was not observed with pre-diabetes. In women, proximity and the type of relationship was associated with newly diagnosed and previously diagnosed T2DM. A lack of social participation was associated with pre-diabetes as well as with previously diagnosed T2DM in women, and with previously diagnosed T2DM in men. Living alone was associated with higher odds of previously diagnosed T2DM in men, but not in women. Less emotional support related to important decisions, less practical support related to jobs, and less practical support for sickness were associated with newly diagnosed and previously diagnosed T2DM in men and women, but not in pre-diabetes. CONCLUSION: This study shows that several aspects of structural and functional characteristics of the social network were associated with newly and previously diagnosed T2DM, partially different for men and women. These results may provide useful targets for T2DM prevention efforts. PMID- 29254483 TI - Gene expression, regulation of DEN and HBx induced HCC mice models and comparisons of tumor, para-tumor and normal tissues. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer mortality. Chemical and virus induction are two major risk factors, however, the potential molecular mechanisms of their differences remain elusive. In this study, to identify the similarities and differences between chemical and virus induced HCC models, we compared the gene expression profiles between DEN and HBx mice models, as well as the differences among tumor, para-tumor and normal tissues. METHODS: We sequenced both gene and microRNA (miRNA) expression for HCC tumor tissues, para-tumor and normal liver tissues from DEN model mice (30-week old) and downloaded the corresponding microarray expression data of HBx model from GEO database. Then differentially expressed genes (DEGs), miRNAs and transcription factors (TFs) were detected by R packages and performed functional enrichment analysis. To explore the gene regulatory network in HCC models, miRNA and TF regulatory networks were constructed by target prediction. RESULTS: For model comparison, although DEGs between tumor and normal tissues in DEN and HBx models only had a small part of overlapping, they shared common pathways including lipid metabolism, oxidation-reduction process and immune process. For tissue comparisons in each model, genes in oxidation-reduction process were down regulated in tumor tissues and genes in inflammatory response showed the highest expression level in para-tumor tissues. Genes highly expressed in both tumor and para-tumor tissues in two models mainly participated in immune and inflammatory response. Genes expressed in HBx model were also involved in cell proliferation and cell migration etc. Network analysis revealed that several miRNAs such as miR 381-3p, miR-142a-3p, miR-214-3p and TFs such as Egr1, Atf3 and Klf4 were the core regulators in HCC. CONCLUSIONS: Through the comparative analyses, we found that para-tumor tissue is a highly inflammatory tissue while the tumor tissue is specific with both inflammatory and cancer signaling pathways. The DEN and HBx mice models have different gene expression pattern but shared pathways. This work will help to elucidate the molecular mechanisms underlying different HCC models. PMID- 29254486 TI - Process evaluation of health fairs promoting cancer screenings. AB - BACKGROUND: Low income and uninsured individuals often have lower adherence to cancer screening for breast, cervical and colorectal cancer. Health fairs are a common community outreach strategy used to provide cancer-related health education and services. METHODS: This study was a process evaluation of seven health fairs focused on cancer screening across the U.S. We conducted key informant interviews with the fair coordinator and conducted baseline and follow up surveys with fair participants to describe characteristics of participants as well as their experiences. We collected baseline data with participants at the health fairs and telephone follow-up surveys 6 months following the fair. RESULTS: Attendance across the seven health fairs ranged from 41 to 212 participants. Most fairs provided group or individual education, print materials and cancer screening during the event. Overall, participants rated health fairs as very good and participants reported that the staff was knowledgeable and that they liked the materials distributed. After the fairs, about 60% of participants, who were reached at follow-up, had read the materials provided and had conversations with others about cancer screening, and 41% talked to their doctors about screening. Based on findings from evaluation including participant data and coordinator interviews, we describe 6 areas in planning for health fairs that may increase their effectiveness. These include: 1) use of a theoretical framework for health promotion to guide educational content and activities provided, 2) considering the community characteristics, 3) choosing a relevant setting, 4) promotion of the event, 5) considerations of the types of services to deliver, and 6) evaluation of the health fair. CONCLUSIONS: The events reported varied in reach and the participants represented diverse races and lower income populations overall. Most health fairs offered education, print materials and onsite cancer screening. Participants reported general satisfaction with these events and were motivated through their participation to read educational materials or discuss screening with providers. Public health professionals can benefit from this process evaluation and recommendations for designing and evaluating health fairs. PMID- 29254488 TI - Atrial volume and function during exercise in health and disease. AB - BACKGROUND: Although atrial function has prognostic significance in many cardiovascular conditions, changes during exercise have not previously been assessed. The aim of this study was to evaluate left atrial (LA) and right atrial (RA) volume and function during incremental exercise, both in normal individuals, healthy athletes, and in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Fifteen healthy non-athletes, 15 athletes and 15 CTEPH patients underwent multi-slice real-time cardiovascular magnetic resonance imaging at rest and during supine bicycle exercise with simultaneous invasive hemodynamic measurements. RESULTS: At rest, athletes had larger indexed maximal RA and LA volumes (iRAVmax, iLAVmax) than CTEPH patients and non-athletes, the latter two groups having similar values. CTEPH patients had lower RA and LA emptying functions (EmF) at rest. During exercise, RA volumes (maximum and minimum) increased in CTEPH patients, whilst decreasing in athletes and non athletes (P < 0.001). The exercise-induced change in iLAVmax was similar between groups, but iLAVmin did not decrease in CTEPH patients. Thus exercise-induced increases in RAEmF and LAEmF, as seen in normal physiology, were significantly impaired in CTEPH patients. At peak exercise, RA volumes (maximum and minimum) and EmF correlated strongly with RA pressure (R = 0.70; P = 0.005; R = 0.83; P < 0.001; R = -0.87; P < 0.001). On multivariate analysis, peak exercise RAEmF and iLAVmin were independent predictors of VO2peak in CTEPH patients and together explained 72% of the variance in VO2peak (beta =0.581 and beta = -0.515, respectively). CONCLUSIONS: In normal physiology, RAEmF and LAEmF increase with exercise, whereas CTEPH patients have impaired LAEmF and RAEmF, which becomes more apparent during exercise. Therefore, the changes in atrial volumes and function during exercise enable a far better distinction between physiological and pathological atrial remodeling than resting measures of volumes which are prone to confounding factors (e.g. endurance training). Peak exercise RAEmF is a good marker of poor functional state in CTEPH patients. PMID- 29254487 TI - Methodology of assessment and reporting of safety in anti-malarial treatment efficacy studies of uncomplicated falciparum malaria in pregnancy: a systematic literature review. AB - BACKGROUND: Considering the uncertainty of safety of anti-malarial drugs in pregnancy, efficacy studies are one of the few sources of clinical safety data. Complete safety evaluation is not usually incorporated in efficacy studies due to financial and human resource constraints. This review reports the methods used for the assessment of safety of artemisinin-based and quinine-based treatments in efficacy studies in pregnancy. METHODS: Methodology of assessment and reporting of safety in efficacy studies of artemisinin-based and quinine-based treatment in pregnancy was reviewed using seven databases and two clinical trial registries. The protocol was registered to PROSPERO (CRD42017054808). RESULTS: Of 48 eligible efficacy studies the method of estimation of gestational age was reported in only 32 studies (67%, 32/48) and ultrasound was used in 18 studies (38%, 18/48). Seventeen studies (35%, 17/48) reported parity, 9 (19%, 9/48) reported gravidity and 13 (27%, 13/48) reported both. Thirty-eight studies (79%, 38/48) followed participants through to pregnancy outcome. Fetal loss was assessed in 34 studies (89%, 34/38), but the definition of miscarriage and stillbirth were defined only in 11 (32%, 11/34) and 7 (21%, 7/34) studies, respectively. Preterm birth was assessed in 26 studies (68%, 26/38) but was defined in 16 studies (62%, 16/26). Newborn weight was assessed in 30 studies (79%, 30/38) and length in 10 studies (26%, 10/38). Assessment of birth weight took gestational age into account in four studies (13%, 4/30). Congenital abnormalities were reported in 32 studies (84%, 32/38). Other common risk factors for adverse pregnancy outcomes were not well-reported. CONCLUSION: Incomplete reporting and varied methodological assessment of pregnancy outcomes in anti-malarial drug efficacy studies limits comparison across studies. A standard list of minimal necessary parameters to assess and report the safety component of efficacy studies of anti-malarials in pregnancy is proposed. PMID- 29254490 TI - Aerospace medical association letter to the editor. PMID- 29254489 TI - High prevalence of diarrheagenic Escherichia coli carrying toxin-encoding genes isolated from children and adults in southeastern Brazil. AB - BACKGROUND: Diarrheagenic Escherichia coli (DEC) are important bacterial causes of childhood diarrhea in Brazil, but its impact in adults is unknown. This study aimed at investigating DEC among children and adults living in endemic areas. METHODS: A total of 327 stools specimens were collected from children (n = 141) and adults (n = 186) with diarrhea attending health centers. Diarrheagenic E. coli (DEC) were identified by their virulence genes (multiplex polymerase chain reaction) and HEp-2 cell adherence patterns. RESULTS: DEC were detected in 56 (40%) children and 74 (39%) adults; enteroaggregative E. coli (EAEC) (23%) was the most prevalent pathotype, followed by diffusely adherent E. coli (DAEC) (13%), and occurred at similar frequencies in both diarrheal groups. Atypical enteropathogenic E. coli (aEPEC) strains were recovered more frequently from children (6%) than from adults (1%). Twenty-six percent of the EAEC were classified as typical EAEC possessing aggR gene, and carried the aap gene. EAEC strains carrying aggR-aap-aatA genes were significantly more frequent among children than adults (p < 0.05). DAEC strains possessing Afa/Dr. genes were detected from children (10%) and adults (6%). EAEC and DAEC strains harboring genes for the EAST1 (astA), Pet, Pic, and Sat toxins were common in both diarrheal groups. The astA and the porcine AE/associated adhesin (paa) genes were found in most of aEPEC strains. High levels of resistance to antimicrobial drugs were found among DAEC and aEPEC isolates. CONCLUSION: The results show a high proportion of EAEC and DAEC carrying toxin-encoding genes among adults with diarrhea. PMID- 29254491 TI - Challenges in understanding common disease. AB - Peter M. Visscher discusses advances in our understanding of complex disease, the challenges in applying this knowledge to functional follow-up, and the potential implications for therapeutic interventions. PMID- 29254492 TI - Sporadic isolated congenital asplenia with fulminant pneumococcal meningitis: a case report and updated literature review. AB - BACKGROUND: Isolated congenital asplenia (ICA) is a rare and life-threatening condition that predisposes patients to severe bacterial infections. Most of the reported cases are familial and the mode of inheritance is usually autosomal dominant. Here, we report a case of sporadic isolated asplenia and review the literature while focusing on sporadic cases. CASE PRESENTATION: We report the case of an 11-month-old female infant who developed fulminant pneumococcal meningitis. The pneumococcal vaccine-unimmunized patient was hospitalized with fever, irritability, and purpura, and was diagnosed as having meningitis, septic shock, and disseminated intravascular coagulation. Streptococcus pneumoniae was isolated from both cerebrospinal fluid and blood. She was successfully treated with prompt antibiotic therapy. During hospitalization, abdominal ultrasonography and computed tomography findings, scintigraphy results, and Howell-Jolly body containing red blood cells indicated the presence of asplenia without any visceroarterial anomalies. Moreover, the findings of peripheral blood smears and spleen ultrasonographic examinations of her parents were normal. CONCLUSIONS: Majority of sporadic ICA cases were detected only after the onset of overwhelming infection and had a high mortality. In cases of severe invasive pneumococcal disease, a systematic search for Howell-Jolly bodies on blood smears and the presence of asplenia on abdominal imaging are essential for detecting ICA even in the absence of any family history. After the diagnosis of ICA, patient and parent education, vaccinations, antibiotic prophylaxis, and prompt empiric treatment of febrile episode should be provided. PMID- 29254493 TI - On the utility of a compartmental population kinetics model of intestinal epithelial stem cell proliferation and differentiation. AB - BACKGROUND: The small intestinal epithelium is a dynamic system with specialized cell types. The various cell populations of this tissue are continually renewed and replenished from stem cells that reside in the small intestinal crypt. The cell types and their locations in the crypt and villus are well known, but the details of the kinetics of stem cell division, and precursor cell proliferation and differentiation into mature enterocytes and secretory cells are still being studied. These proliferation and differentiation events have been extensively modeled with a variety of computational approaches in the past. METHODS: A compartmental population kinetics model, incorporating experimentally measured proliferation rates for various intestinal epithelial cell types, is implemented for a previously reported scheme for the intestinal cell dynamics. A sensitivity analysis is performed to determine the effect that varying the model parameters has upon the model outputs, the steady-state cell populations. RESULTS: The model is unable to reproduce the experimentally known timescale of renewal of the intestinal epithelium if literature values for the proliferation rates of stem cells and transit amplifying cells are employed. Unphysically large rates of proliferation result when these parameters are allowed to vary to reproduce this timescale and the steady-state populations of terminally differentiated intestinal epithelial cells. Sensitivity analysis reveals that the strongest contributor to the steady-state populations is the transit amplifying cell proliferation rate when literature values are used, but that the differentiation rate of transit amplifying cells to secretory progenitor cells dominates when all parameters are allowed to vary. CONCLUSIONS: A compartmental population kinetics model of proliferation and differentiation of cells of the intestinal epithelium can provide a simplifying means of understanding a complicated multistep process. However, when literature values for proliferation rates of the crypt based columnar and transit amplifying cell populations are employed in the model, it cannot reproduce the experimentally known timescale of intestinal epithelial renewal. Nevertheless, it remains a valuable conceptual tool, and its sensitivity analysis provides important clues for which events in the process are the most important in controlling the steady-state populations of specialized intestinal epithelial cells. PMID- 29254495 TI - Intraoperative oxygen concentration and neurocognition after cardiac surgery: study protocol for a randomized controlled trial. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication of cardiac surgery. Studies have identified potentially injurious roles for cardiopulmonary bypass (CPB) and subsequent reperfusion injury. Cognitive dysfunction has also been linked to the deleterious effects of hyperoxia following ischemia-reperfusion injuries in several disease states, but there has been surprisingly little study into the role of hyperoxia in reperfusion injury after CPB. The potential for tightly regulated intraoperative normoxia to ameliorate the neurocognitive decline following cardiac surgery has not been investigated in a prospective manner. We hypothesize that the use of a protocolized management strategy aimed towards maintenance of an intraoperative normoxic level of oxygen, as opposed to hyperoxia, will reduce the incidence of POCD in older patients undergoing cardiac surgery. METHODS/DESIGN: One hundred patients aged 65 years and older undergoing non-emergency coronary artery bypass grafting surgery on cardiopulmonary bypass will be enrolled in this prospective, randomized, controlled trial. Subjects will be randomized to receive a fraction of inspired oxygen of either 35% or 100% while under general anesthesia throughout the intraoperative period. The primary outcome measure will be the incidence of POCD in the acute postoperative phase and up to 6 months. The assessment of neurocognition will be undertaken by trained personnel, blinded to study group, with the telephone Montreal Cognitive Assessment (t-MoCA) tool. Secondary outcome measures will include assessment of delirium using the Confusion Assessment Method (CAM and CAM-ICU), as well as time to extubation, days of mechanical ventilation, length of ICU and hospital stay and mortality at 6 months. With the aim of later identifying mechanistic aspects of the effect of oxygen tension, blood, urine, and atrial tissue specimens will be taken at various time points during the perioperative period and later analyzed. DISCUSSION: This trial will be one of the first randomized controlled studies to prospectively assess the relationship between intraoperative oxygen levels and postoperative neurocognition in cardiac surgery. It addresses a promising biological avenue of intervention in this vulnerable aging population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02591589 , registered February 13, 2015. PMID- 29254496 TI - Brucellosis caused by the wood rat pathogen Brucella neotomae: two case reports. AB - BACKGROUND: Brucellosis is a chronic bacterial disease caused by members of the genus Brucella. Among the classical species stands Brucella neotomae, until now, a pathogen limited to wood rats. However, we have identified two brucellosis human cases caused by B. neotomae, demonstrating that this species has zoonotic potential. CASES PRESENTATION: Within almost 4 years of each other, a 64-year-old Costa Rican white Hispanic man and a 51-year-old Costa Rican white Hispanic man required medical care at public hospitals of Costa Rica. Their hematological and biochemical parameters were within normal limits. No adenopathies or visceral abnormalities were found. Both patients showed intermittent fever, disorientation, and general malaise and a positive Rose Bengal test compatible with Brucella infection. Blood and cerebrospinal fluid cultures rendered Gram negative coccobacilli identified by genomic analysis as B. neotomae. After antibiotic treatment, the patients recovered with normal mental activities. CONCLUSIONS: This is the first report describing in detail the clinical disease caused by B. neotomae in two unrelated patients. In spite of previous claims, this bacterium keeps zoonotic potential. Proposals to generate vaccines by using B. neotomae as an immunogen must be reexamined and countries housing the natural reservoir must consider the zoonotic risk. PMID- 29254494 TI - Mapping genetic variations to three-dimensional protein structures to enhance variant interpretation: a proposed framework. AB - The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods. PMID- 29254497 TI - Retrospective review of safety and efficacy of programmed cell death-1 inhibitors in refractory high grade gliomas. AB - BACKGROUND: Programmed cell death ligand-1 (PD-L1) expression has been reported in up to 61% of high grade gliomas (HGG). The purpose of this study was to describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs. METHODS: This Institutional Review Board approved single center retrospective study included adult patients with pathologically confirmed HGG who received a PD 1 inhibitor from 9/2014-10/2016 outside of a clinical trial at Memorial Sloan Kettering Cancer Center. RESULTS: Twenty five HGG patients received pembrolizumab as part of a compassionate use program. Median age was 50 years (range 30-72); 44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2 anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Median prior lines of treatments were 4 (range 1-9). Nineteen (76%) previously failed bevacizumab. Median KPS was 80 (range 50-100). Concurrent treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2 (8%) patients. Median number of doses administered was 3 (range 1-14). Outcomes were assessed in 24 patients. PD-1 inhibitor related adverse events included LFT elevations, hypothyroidism, diarrhea, myalgias/arthralgias, and rash. Best radiographic response was partial response (n = 2), stable disease (n = 5), and progressive disease (n = 17). Median progression free survival (PFS) was 1.4 months (range 0.2-9.4) and median overall survival (OS) was 4 months (range 0.5 13.8). Three-month PFS was 12% and 6-month OS was 28%. CONCLUSION: While response rates are low, a few patients had a prolonged PFS. Pembrolizumab was tolerated with few serious toxicities, even in patients receiving concomitant therapy. PMID- 29254498 TI - Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials. AB - BACKGROUND: Immunotherapies, specifically those based on immune checkpoint inhibitors, have shown promising activity in multiple tumor types. Other than mifamurtide (MEPACT(r)) for osteosarcoma approved by European Medicines Agency, there are no approved immunotherapies for sarcomas. METHODS: We analyzed medical records of patients with advanced sarcoma who were referred to Phase 1 clinic at MD Anderson and received an immunotherapy (checkpoint inhibitors, vaccines, or cytokine based therapies). Clinical parameters including demographics, clinical history, toxicity, and response were abstracted. RESULTS: Among 50 patients enrolled in immunotherapy trials (Bone 10; Soft-tissue 40) we found 14 different subtypes of sarcomas. Royal Marsden Hospital (RMH) prognostic score was <2 (86%). Performance status (PS) was 0-1 in 48 patients (96%); median number of prior therapies was 3 (0-12). Immunotherapy consisted of checkpoint inhibitors (82%: PD1 = 7, PD-L1 = 11, CTLA4 = 22, other = 1) of which 42% were combinations, as well as vaccines (14%), and cytokines (4%). Median overall survival (OS) was 13.4 months (11.2 months: not reached). Median progression free survival (PFS) was 2.4 months (95% CI = 1.9-3.2 months). Best response was partial response (PR) in 2 patients with alveolar soft part sarcoma (ASPS) and stable disease (SD) in 11 patients (3 GIST, 3 liposarcomas (2 DDLS, 1 WDLS), 2 ASPS, 2 leiomyo, 1 osteo). PFS was 34% (23%, at 50%) at 3 months, 16% (8%, 30%) at 6 months, and 6% (2%, 20%) at 1 year. Pseudo-progression followed by stable disease was observed in 2 patients (4%). Grade 3/4 adverse events included rash (10%), fever (6%), fatigue (6%), and nausea/vomiting (6%). CONCLUSION: Immunotherapies were well tolerated in advanced sarcoma patients enrolled in trials. All four ASPS patients had clinical benefit with checkpoint inhibitors and this was the only subtype experiencing partial response. Further evaluation of checkpoint inhibitors in ASPS is warranted. PMID- 29254499 TI - Low-dose strontium stimulates osteogenesis but high-dose doses cause apoptosis in human adipose-derived stem cells via regulation of the ERK1/2 signaling pathway. AB - BACKGROUND: Strontium is a widely used anti-osteoporotic agent due to its dual effects on inhibiting bone resorption and stimulating bone formation. Thus, we studied the dose response of strontium on osteo-inductive efficiency in human adipose-derived stem cells (hASCs). METHOD: Qualitative alkaline phosphatase (ALP) staining, quantitative ALP activity, Alizarin Red staining, real-time polymerase chain reaction and Western blot were used to investigate the in vitro effects of a range of strontium concentrations on hASC osteogenesis and associated signaling pathways. RESULTS: In vitro work revealed that strontium (25 500 MUM) promoted osteogenic differentiation of hASCs according to ALP activity, extracellular calcium deposition, and expression of osteogenic genes such as runt related transcription factor 2, ALP, collagen-1, and osteocalcin. However, osteogenic differentiation of hASCs was significantly inhibited with higher doses of strontium (1000-3000 MUM). These latter doses of strontium promoted apoptosis, and phosphorylation of ERK1/2 signaling was increased and accompanied by the downregulation of Bcl-2 and increased phosphorylation of BAX. The inhibition of ERK1/2 decreased apoptosis in hASCs. CONCLUSION: Lower concentrations of strontium facilitate osteogenic differentiation of hASCs up to a point; higher doses cause apoptosis of hASCs, with activation of the ERK1/2 signaling pathway contributing to this process. PMID- 29254500 TI - Developing adaptive interventions for adolescent substance use treatment settings: protocol of an observational, mixed-methods project. AB - BACKGROUND: Over 1.6 million adolescents in the United States meet criteria for substance use disorders (SUDs). While there are promising treatments for SUDs, adolescents respond to these treatments differentially in part based on the setting in which treatments are delivered. One way to address such individualized response to treatment is through the development of adaptive interventions (AIs): sequences of decision rules for altering treatment based on an individual's needs. This protocol describes a project with the overarching goal of beginning the development of AIs that provide recommendations for altering the setting of an adolescent's substance use treatment. This project has three discrete aims: (1) explore the views of various stakeholders (parents, providers, policymakers, and researchers) on deciding the setting of substance use treatment for an adolescent based on individualized need, (2) generate hypotheses concerning candidate AIs, and (3) compare the relative effectiveness among candidate AIs and non-adaptive interventions commonly used in everyday practice. METHODS: This project uses a mixed-methods approach. First, we will conduct an iterative stakeholder engagement process, using RAND's ExpertLens online system, to assess the importance of considering specific individual needs and clinical outcomes when deciding the setting for an adolescent's substance use treatment. Second, we will use results from the stakeholder engagement process to analyze an observational longitudinal data set of 15,656 adolescents in substance use treatment, supported by the Substance Abuse and Mental Health Services Administration, using the Global Appraisal of Individual Needs questionnaire. We will utilize methods based on Q-learning regression to generate hypotheses about candidate AIs. Third, we will use robust statistical methods that aim to appropriately handle casemix adjustment on a large number of covariates (marginal structural modeling and inverse probability of treatment weights) to compare the relative effectiveness among candidate AIs and non-adaptive decision rules that are commonly used in everyday practice. DISCUSSION: This project begins filling a major gap in clinical and research efforts for adolescents in substance use treatment. Findings could be used to inform the further development and revision of influential multi-dimensional assessment and treatment planning tools, or lay the foundation for subsequent experiments to further develop or test AIs for treatment planning. PMID- 29254501 TI - Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma. AB - BACKGROUND: There has been a significant improvement in survival of advanced malignancies with the advent of checkpoint inhibitors. These newer treatment modalities come with a wide spectrum of unique side effects, termed immune related adverse events (irAE), ranging from mild skin rash to severe colitis. Included in that spectrum is the rare side effect of autoimmune diabetes mellitus. Despite a few case reports illustrating the incidence of autoimmune diabetes associated with immunotherapy, there has not been much mentioned about exacerbation or acceleration of hyperglycemia in non-autoimmune settings leading to de novo diagnosis of type 2 diabetes mellitus. CASE PRESENTATION: We report the case of a 42 year old man with metastatic melanoma and no prior history of diabetes mellitus, who presented with diabetic ketoacidosis (DKA) after 3 cycles of combination checkpoint inhibitor therapy using nivolumab and ipilimumab. New onset diabetes mellitus was diagnosed on the basis of elevated hemoglobin A1c, in the absence of prior personal or family history. Autoimmune or type 1 diabetes mellitus was ruled out with normal levels of anti-glutamic acid decarboxylase 65 (GAD65) antibody, zinc transporter 8 (ZnT8) antibody, and islet antigen-2 (IA-2) antibody. CONCLUSIONS: This case report highlights the importance of recognizing rare but serious adverse events related to immunotherapy and incorporation of appropriate tools for early identification and management in national cancer treatment guidelines. PMID- 29254502 TI - Clinical implications and considerations for evaluation of in silico algorithms for use with ACMG/AMP clinical variant interpretation guidelines. AB - Clinical genetics laboratories have recently adopted guidelines for the interpretation of sequence variants set by the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP). The use of in silico algorithms to predict whether amino acid substitutions result in human disease is inconsistent across clinical laboratories. The clinical genetics community must carefully consider how in silico predictions can be incorporated into variant interpretation in clinical practice.Please see related Research article: https://doi.org/10.1186/s13059-017-1353-5. PMID- 29254503 TI - Estrogen exposure overrides the masculinizing effect of elevated temperature by a downregulation of the key genes implicated in sexual differentiation in a fish with mixed genetic and environmental sex determination. PMID- 29254505 TI - Anti-PD-1 Vasculitis of the central nervous system or radionecrosis? AB - Commentary on " Cerebral vasculitis mimicking intracranial metastatic progression of lung cancer during PD-1 blockade " by Laubli H et al., J Immunother Cancer. 2017;5:46.The authors diagnosed a cerebral tumor-like lymphocytic vasculitis associated with anti-endothelial cell auto-antibodies secondary to anti-PD-1 therapy, treated by surgical resection and corticosteroids. We thought that this diagnosis should be discussed for at least two reasons. First, etiological explorations were not sufficient. Second, the diagnostic of radionecrosis should also be discussed. PMID- 29254504 TI - Mathematical models used to inform study design or surveillance systems in infectious diseases: a systematic review. AB - BACKGROUND: Mathematical models offer the possibility to investigate the infectious disease dynamics over time and may help in informing design of studies. A systematic review was performed in order to determine to what extent mathematical models have been incorporated into the process of planning studies and hence inform study design for infectious diseases transmitted between humans and/or animals. METHODS: We searched Ovid Medline and two trial registry platforms (Cochrane, WHO) using search terms related to infection, mathematical model, and study design from the earliest dates to October 2016. Eligible publications and registered trials included mathematical models (compartmental, individual-based, or Markov) which were described and used to inform the design of infectious disease studies. We extracted information about the investigated infection, population, model characteristics, and study design. RESULTS: We identified 28 unique publications but no registered trials. Focusing on compartmental and individual-based models we found 12 observational/surveillance studies and 11 clinical trials. Infections studied were equally animal and human infectious diseases for the observational/surveillance studies, while all but one between humans for clinical trials. The mathematical models were used to inform, amongst other things, the required sample size (n = 16), the statistical power (n = 9), the frequency at which samples should be taken (n = 6), and from whom (n = 6). CONCLUSIONS: Despite the fact that mathematical models have been advocated to be used at the planning stage of studies or surveillance systems, they are used scarcely. With only one exception, the publications described theoretical studies, hence, not being utilised in real studies. PMID- 29254506 TI - Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIMSM registry. AB - BACKGROUND: Immune related adverse events (irAEs) are associated with immunotherapy for cancer and while results suggest improvement in tumor control and overall survival in those experiencing irAEs, the long-term impact is debated. We evaluated irAE reports related to high dose interleukin-2 therapy (IL 2) documented in the PROCLAIMSM registry data base from 2008 to 2016 (NCT01415167, August 9, 2011). METHODS: Reports on 1535 patients, including 623 with metastatic melanoma (mM) and 919 with metastatic renal cell cancer (mRCC) (7 patients had both diseases), were queried for irAEs. The timing of the event was categorized as occurring before, during or after IL-2 or related to any checkpoint inhibitor (CPI). mM patients and mRCC patients were analyzed separately. Tumor control [complete + partial response + stable disease (CR + PR + SD) was compared between those experiencing no irAE versus those with the development of irAEs. Survival was analyzed by tumor type related to timing of irAE and IL-2, and in those with or without exposure to CPI. RESULTS: Median follow-up was 3.5+ years (range 1-8+ years), 152 irAEs were reported in 130 patients (8.4% of all PROCLAIMSM patients): 99 (16%) in mM and 53 (5.8%) in mRCC patients. 31 irAEs occurred prior to IL-2, 24 during IL-2, and 97 after IL-2 therapy. 74 irAEs were attributed to IL-2 only (during/ after IL-2). Of the 97 post IL-2 irAEs, 24 were attributed to CPI, and 15 could not be distinguished as caused by IL-2 or CPI. Tumor control was 71% for those experiencing irAE, and 56% for those with no irAE (p = 0.0008). Overall survival was significantly greater for those experiencing irAEs during/ after IL-2 therapy, compared to those with no irAE or irAE before IL-2 therapy, in mM patients, median 48 months vs 18 months (p < 0.0001), and in mRCC patients, median 60 months vs 40 months (p = 0.0302), independent of CPI-related irAEs. IL-2-related irAEs were primarily vitiligo and thyroid dysfunction (70% of IL-2 related irAEs), with limited further impact. CONCLUSIONS: irAEs following IL-2 therapy are associated with improved tumor control and overall survival. IrAEs resulting from IL-2 and from CPIs are qualitatively different, and likely reflect different mechanisms of action of immune activation and response. PMID- 29254509 TI - Evaluating host-parasite co-adaptation relationships involving Angiostrongylus costaricensis. AB - Angiostrongylus costaricensis is a parasite that infects rodents, including the wild cotton rat Sigmodon hispidus and pygmy rice rats Oligoryzomys spp., among others. However, urban Rattus norvegicus and Mus musculus have not been identified as important hosts of A. costaricensis. In this study, Swiss mice (SW), Wistar R. norvegicus (RN), wild Oligoryzomys nigripes (ON) and a local strain of M. musculus (RGS) were experimentally infected with A. costaricensis. Survival, elimination of L1 (total sum per group, A0), and the number of adult worms recovered divided by the dose of each L3 inoculum (yield ratio, YR) were examined for each group after a 40-day post-infection period. The survival rates, A0 and YR values were: 27%, 207,589 and 0.42 for the SW group; 81%, 8691 and 0.01 for the RN group; and 63.6%, 26,560 and 0.16 for the RGS group, respectively, in each case. The survival rate for the ON group was 100% and the A0 value was 847,050. A YR was not calculated for the ON group since the ON group was maintained up to 565 days post-infection (pi) to examine long-term mortality. At 500 days pi (16 months), 50% of the ON group had died, while one animal (10%) survived 595 days pi (20 months). Taken together, these data indicate that A. costaricensis has undergone a greater degree of adaptation to the wild rodent, O. nigripes, than to R. norvegicus or a local M. musculus strain. In addition, titre curve (A0) modelling of adaptation status proved to be useful in evaluating A. costaricensis-rodent interactions. PMID- 29254507 TI - Radiotherapy enhances natural killer cell cytotoxicity and localization in pre clinical canine sarcomas and first-in-dog clinical trial. AB - BACKGROUND: We have previously shown that radiotherapy (RT) augments natural killer (NK) functions in pre-clinical models of human and mouse cancers, including sarcomas. Since dogs are an excellent outbred model for immunotherapy studies, we sought to assess RT plus local autologous NK transfer in canine sarcomas. METHODS: Dog NK cells (CD5dim, NKp46+) were isolated from PBMCs and expanded with irradiated K562-C9-mIL21 feeder cells and 100 IU/mL recombinant human IL-2. NK homing and cytotoxicity +/- RT were evaluated using canine osteosarcoma tumor lines and dog patient-derived xenografts (PDX). In a first-in dog clinical trial for spontaneous osteosarcoma, we evaluated RT and intra tumoral autologous NK transfer. RESULTS: After 14 days, mean NK expansion and yield were 19.0-fold (+/-8.6) and 258.9(+/-76.1) *106 cells, respectively. Post RT, NK cytotoxicity increased in a dose-dependent fashion in vitro reaching ~ 80% at effector:target ratios of >=10:1 (P < 0.001). In dog PDX models, allogeneic NK cells were cytotoxic in ex vivo killing assays and produced significant PDX tumor growth delay (P < 0.01) in vivo. After focal RT and intravenous NK transfer, we also observed significantly increased NK homing to tumors in vivo. Of 10 dogs with spontaneous osteosarcoma treated with focal RT and autologous NK transfer, 5 remain metastasis-free at the 6-month primary endpoint with resolution of suspicious pulmonary nodules in one patient. We also observed increased activation of circulating NK cells after treatment and persistence of labelled NK cells in vivo. CONCLUSIONS: NK cell homing and cytotoxicity are increased following RT in canine models of sarcoma. Results from a first-in-dog clinical trial are promising, including possible abscopal effects. PMID- 29254510 TI - Post-deployment family violence among UK military personnel. AB - BACKGROUND: Research into violence among military personnel has not differentiated between stranger- and family-directed violence. While military factors (combat exposure and post-deployment mental health problems) are risk factors for general violence, there has been limited research on their impact on violence within the family environment. This study aims to compare the prevalence of family-directed and stranger-directed violence among a deployed sample of UK military personnel and to explore risk factors associated with both family- and stranger-directed violence. METHOD: This study utilised data from a large cohort study which collected information by questionnaire from a representative sample of randomly selected deployed UK military personnel (n = 6711). RESULTS: The prevalence of family violence immediately following return from deployment was 3.6% and 7.8% for stranger violence. Family violence was significantly associated with having left service, while stranger violence was associated with younger age, male gender, being single, having a history of antisocial behaviour as well as having left service. Deployment in a combat role was significantly associated with both family and stranger violence after adjustment for confounders [adjusted odds ratio (aOR) = 1.92 (1.25-2.94), p = 0.003 and aOR = 1.77 (1.31-2.40), p < 0.001, respectively], as was the presence of symptoms of post-traumatic stress disorder, common mental disorders and aggression. CONCLUSIONS: Exposure to combat and post-deployment mental health problems are risk factors for violence both inside and outside the family environment and should be considered in violence reduction programmes for military personnel. Further research using a validated measurement tool for family violence would improve comparability with other research. PMID- 29254508 TI - Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. AB - BACKGROUND: Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. Here we use CB-1158, a potent and orally-bioavailable small molecule inhibitor of arginase, to investigate the role of Arg1 in regulating anti-tumor immunity. METHODS: CB-1158 was tested for the ability to block myeloid cell-mediated inhibition of T cell proliferation in vitro, and for tumor growth inhibition in syngeneic mouse models of cancer as a single agent and in combination with other therapies. Tumors from animals treated with CB-1158 were profiled for changes in immune cell subsets, expression of immune-related genes, and cytokines. Human tumor tissue microarrays were probed for Arg1 expression by immunohistochemistry and immunofluorescence. Cancer patient plasma samples were assessed for Arg1 protein and L-arginine by ELISA and mass spectrometry, respectively. RESULTS: CB-1158 blocked myeloid cell-mediated suppression of T cell proliferation in vitro and reduced tumor growth in multiple mouse models of cancer, as a single agent and in combination with checkpoint blockade, adoptive T cell therapy, adoptive NK cell therapy, and the chemotherapy agent gemcitabine. Profiling of the tumor microenvironment revealed that CB-1158 increased tumor infiltrating CD8+ T cells and NK cells, inflammatory cytokines, and expression of interferon-inducible genes. Patient tumor samples from multiple histologies expressed an abundance of tumor-infiltrating Arg1+ myeloid cells. Plasma samples from cancer patients exhibited elevated Arg1 and reduced L-arginine compared to healthy volunteers. CONCLUSIONS: These results demonstrate that Arg1 is a key mediator of immune suppression and that inhibiting Arg1 with CB-1158 shifts the immune landscape toward a pro-inflammatory environment, blunting myeloid cell mediated immune evasion and reducing tumor growth. Furthermore, our results suggest that arginase blockade by CB-1158 may be an effective therapy in multiple types of cancer and combining CB-1158 with standard-of-care chemotherapy or other immunotherapies may yield improved clinical responses. PMID- 29254511 TI - Burnout among psychosocial oncologists in Israel: The direct and indirect effects of job demands and job resources. AB - OBJECTIVE: Psychosocial oncologists may be particularly vulnerable to burnout. This study aimed to assess burnout among Israeli psychosocial oncologists in relation to the Job Demands-Resources model and the coping strategies model. METHOD: Participants included 85 of 128 listed psychosocial oncologists currently working with cancer patients. They completed a questionnaire assessing emotional exhaustion, depersonalization, job demands, job resources, work engagement, overcommitment, and perceived value of work. RESULTS: The mean level of burnout was low, whereas 16.3% experienced high levels of emotional exhaustion and only 2.4% experienced high levels of depersonalization. According to mediation analysis, overcommitment, partially mediated job demands-burnout associations, and work engagement mediated the perceived value-burnout association. Job resources and burnout were not related, either directly or indirectly. Significance of results The study extended the Job Demands-Resources model to include perceived value as an additional resource, and work-engagement and overcommitment as coping strategies. Two distinct patterns of associations were found between work characteristics and burnout: the positive-protective pattern (perceived value and work engagement) and the negative pattern (job demands and overcommitment). These two patterns should be considered for further research and for implementing preventive interventions to reduce burnout in the workplace setting. PMID- 29254512 TI - Effects of immunocastration and a beta-adrenergic agonist on retail cuts of feedlot finished Nellore cattle. AB - Immunocastration (ImC) has been proposed as an animal welfare-friendly alternative to reduce sexual and aggressive behavior and to increase carcass fat deposition with positive effects on meat quality. The beta-adrenergic agonists (beta-AA) are known as repartitioning agents that acts increasing lean tissue deposition. The combined use of these technologies can positively affect meat quality and increase retail cuts yield. Thus, this research was conducted to evaluate the combined effects of ImC and beta-AA (zilpaterol hydrochloride (ZH) and ractopamine hydrochloride (RH)) on retail cuts, bones, and fat trim of feedlot finished Bos indicus (Nellore) cattle. No interaction was observed between sexual condition and diet for any trait. The ImC decreased cold carcass, hindquarter (HQ), forequarter (FQ) and combined brisket, short ribs and flank (BSF) weights. The ImC also showed smaller weights of retail cuts and bones on the HQ and on the FQ than non-castrated (NoC). Fat trim weights did not differ from ImC and NoC. The most of subprimal cuts were heavier in NoC than in ImC. Feeding beta-AA did not affect cold carcass weight; however, animals fed ZH had higher weights of HQ and retail cuts in HQ when compared with RH and control (CO) group, with no differences between RH and CO for both traits. The weights of FQ, BSF, retail cuts in FQ, as well as bones and fat trimmings were not affected by beta-AA. In summary, ImC decreases carcass and retail cut weights, whereas ZH supplementation leads to an improvement in carcass lean tissue and retail cuts. PMID- 29254514 TI - 19th-century and early 20th-century jaundice outbreaks, the USA. AB - Historical enquiry into diseases with morbidity or mortality predilections for particular demographic groups can permit clarification of their emergence, endemicity, and epidemicity. During community-wide outbreaks of hepatitis A in the pre-vaccine era, clinical attack rates were higher among juveniles rather than adults. In community-wide hepatitis E outbreaks, past and present, mortality rates have been most pronounced among pregnant women. Examination for these characteristic predilections in reports of jaundice outbreaks in the USA traces the emergence of hepatitis A and also of hepatitis E to the closing three decades of the 19th century. Thereafter, outbreaks of hepatitis A burgeoned, whereas those of hepatitis E abated. There were, in addition, community-wide outbreaks that bore features of neither hepatitis A nor E; they occurred before the 1870s. The American Civil War antedated that period. If hepatitis A had yet to establish endemicity, then it would not underlie the jaundice epidemic that was widespread during the war. Such an assessment may be revised, however, with the discovery of more extant outbreak reports. PMID- 29254515 TI - Coordination of Infection Control Activities at the Healthcare System Level: Survey Results. PMID- 29254513 TI - The cross-national structure of mental disorders: results from the World Mental Health Surveys. AB - BACKGROUND: The patterns of comorbidity among mental disorders have led researchers to model the underlying structure of psychopathology. While studies have suggested a structure including internalizing and externalizing disorders, less is known with regard to the cross-national stability of this model. Moreover, little data are available on the placement of eating disorders, bipolar disorder and psychotic experiences (PEs) in this structure. METHODS: We evaluated the structure of mental disorders with data from the World Health Organization Composite International Diagnostic Interview, including 15 lifetime mental disorders and six PEs. Respondents (n = 5478-15 499) were included from 10 high-, middle- and lower middle-income countries across the world aged 18 years or older. Confirmatory factor analyses (CFAs) were used to evaluate and compare the fit of different factor structures to the lifetime disorder data. Measurement invariance was evaluated with multigroup CFA (MG-CFA). RESULTS: A second-order model with internalizing and externalizing factors and fear and distress subfactors best described the structure of common mental disorders. MG-CFA showed that this model was stable across countries. Of the uncommon disorders, bipolar disorder and eating disorder were best grouped with the internalizing factor, and PEs with a separate factor. CONCLUSIONS: These results indicate that cross national patterns of lifetime common mental-disorder comorbidity can be explained with a second-order underlying structure that is stable across countries and can be extended to also cover less common mental disorders. PMID- 29254516 TI - Comparative efficacy and acceptability of pharmacological treatments for post traumatic stress disorder in adults: a network meta-analysis. AB - BACKGROUND: Guidelines about post-traumatic stress disorder (PTSD) recommend broad categories of drugs, but uncertainty remains about what pharmacological treatment to select among all available compounds. METHODS: Cochrane Central Register of Controlled Trials register, MEDLINE, PsycINFO, National PTSD Center Pilots database, PubMed, trial registries, and databases of pharmaceutical companies were searched until February 2016 for double-blind randomised trials comparing any pharmacological intervention or placebo as oral therapy in adults with PTSD. Initially, we performed standard pairwise meta-analyses using a random effects model. We then carried out a network meta-analysis. The main outcome measures were mean change on a standardised scale and all-cause dropout rate. Acute treatment was defined as 8-week follow up. RESULTS: Desipramine, fluoxetine, paroxetine, phenelzine, risperidone, sertraline, and venlafaxine were more effective than placebo; phenelzine was better than many other active treatments and was the only drug, which was significantly better than placebo in terms of dropouts (odds ratio 7.50, 95% CI 1.72-32.80). Mirtazapine yielded a relatively high rank for efficacy, but the respective value for acceptability was not among the best treatments. Divalproex had overall the worst ranking. CONCLUSIONS: The efficacy and acceptability hierarchies generated by our study were robust against many sources of bias. The differences between drugs and placebo were small, with the only exception of phenelzine. Considering the small amount of available data, these results are probably not robust enough to suggest phenelzine as a drug of choice. However, findings from this review reinforce the idea that phenelzine should be prioritised in future trials in PTSD. PMID- 29254519 TI - Pushing the spatio-temporal limits of MRI and fMRI. PMID- 29254517 TI - The CDK-PLK1 axis targets the DNA damage checkpoint sensor protein RAD9 to promote cell proliferation and tolerance to genotoxic stress. AB - Genotoxic stress causes proliferating cells to activate the DNA damage checkpoint, to assist DNA damage recovery by slowing cell cycle progression. Thus, to drive proliferation, cells must tolerate DNA damage and suppress the checkpoint response. However, the mechanism underlying this negative regulation of checkpoint activation is still elusive. We show that human Cyclin-Dependent Kinases (CDKs) target the RAD9 subunit of the 9-1-1 checkpoint clamp on Thr292, to modulate DNA damage checkpoint activation. Thr292 phosphorylation on RAD9 creates a binding site for Polo-Like-Kinase1 (PLK1), which phosphorylates RAD9 on Thr313. These CDK-PLK1-dependent phosphorylations of RAD9 suppress checkpoint activation, therefore maintaining high DNA synthesis rates during DNA replication stress. Our results suggest that CDK locally initiates a PLK1-dependent signaling response that antagonizes the ability of the DNA damage checkpoint to detect DNA damage. These findings provide a mechanism for the suppression of DNA damage checkpoint signaling, to promote cell proliferation under genotoxic stress conditions. PMID- 29254518 TI - The diversity of floral temperature patterns, and their use by pollinators. AB - Pollinating insects utilise various sensory cues to identify and learn rewarding flower species. One such cue is floral temperature, created by captured sunlight or plant thermogenesis. Bumblebees, honeybees and stingless bees can distinguish flowers based on differences in overall temperature between flowers. We report here that floral temperature often differs between different parts of the flower creating a temperature structure or pattern. Temperature patterns are common, with 55% of 118 plant species thermographed, showing within-flower temperature differences greater than the 2 degrees C difference that bees are known to be able to detect. Using differential conditioning techniques, we show that bumblebees can distinguish artificial flowers differing in temperature patterns comparable to those seen in real flowers. Thus, bumblebees are able to perceive the shape of these within-flower temperature patterns. Floral temperature patterns may therefore represent a new floral cue that could assist pollinators in the recognition and learning of rewarding flowers. PMID- 29254520 TI - Advancing the Methods of the U.S. Preventive Services Task Force. PMID- 29254521 TI - Update on the Methods of the U.S. Preventive Services Task Force: Methods for Understanding Certainty and Net Benefit When Making Recommendations. AB - Since the 1980s, the U.S. Preventive Services Task Force (USPSTF) has developed and used rigorous methods to make evidence-based recommendations about preventive services to promote health and well-being for all Americans. Recommendations are based on the evidence of magnitude of net benefit (benefits minus harms). Expert opinion is not substituted when evidence is lacking. Evidence gaps are common. Few preventive services are supported by high-quality studies that directly and comprehensively determine the overall magnitude of benefits and harms in the same study. When assessing the body of evidence, studies may not have been conducted in primary care settings, studies may not have sufficiently included populations of interest, and long-term outcomes may not have been directly assessed. When direct evidence is not available, the USPSTF uses the methodologies of applicability to determine whether evidence can be generalized to an asymptomatic primary care population; coherence to link bodies of evidence and create an indirect evidence pathway; extrapolation to make inferences across the indirect evidence pathway, extend evidence to populations not specifically studied, consider service delivery intervals, and infer long-term outcomes; and conceptual bounding to set theoretical lower or upper limits for plausible benefits or harms. The USPSTF extends the evidence only so far as to maintain at least moderate certainty that its findings are preserved. This manuscript details with examples of how the USPSTF uses these methods to make recommendations that truly reflect the evidence. PMID- 29254522 TI - The Use of Rapid Review Methods for the U.S. Preventive Services Task Force. AB - Rapid review products are intended to synthesize available evidence in a timely fashion while still meeting the needs of healthcare decision makers. Various methods and products have been applied for rapid evidence syntheses, but no single approach has been uniformly adopted. Methods to gain efficiency and compress the review time period include focusing on a narrow clinical topic and key questions; limiting the literature search; performing single (versus dual) screening of abstracts and full-text articles for relevance; and limiting the analysis and synthesis. In order to maintain the scientific integrity, including transparency, of rapid evidence syntheses, it is imperative that procedures used to streamline standard systematic review methods are prespecified, based on sound review principles and empiric evidence when possible, and provide the end user with an accurate and comprehensive synthesis. The collection of clinical preventive service recommendations maintained by the U.S. Preventive Services Task Force, along with its commitment to rigorous methods development, provide a unique opportunity to refine, implement, and evaluate rapid evidence synthesis methods and add to an emerging evidence base on rapid review methods. This paper summarizes the U.S. Preventive Services Task Force's use of rapid review methodology, its criteria for selecting topics for rapid evidence syntheses, and proposed methods to streamline the review process. PMID- 29254523 TI - Framework for Using Risk Stratification to Improve Clinical Preventive Service Guidelines. AB - People should only receive a preventive service if the potential benefits of the service outweigh the potential harms. Both benefits and risks may vary for different populations. Thus, it is clinically important to understand when and how guidelines for preventive services should be stratified according to the underlying risk of the population. For example, preventive services may be risk stratified with specific clinical recommendations based on age, sex, race/ethnicity, family history, genotype, behavior risks, or comorbidities. This paper articulates the conceptual approach and practical tools that were developed for consideration by the U.S. Preventive Services Task Force to determine if and how risk stratification should be incorporated into clinical guidelines. This approach is described in an algorithm with six sequential questions: (1) Are there clinically relevant subpopulations? (2) Are there credible subgroup analyses for these subpopulations? (3) Do subgroup analyses show clinically important differences? (4) Do these differences result in variation of net benefit, or does the evidence only exist in persons with a narrow spectrum of risk? (5) Can the subpopulations be easily identified? and (6) Does a well validated multivariate risk tool improve identification of clinically relevant subpopulations compared with a simpler approach? This framework allows for a systematic approach to determine if and how to incorporate evidence for specific populations, a consistent application of critical thinking about this evidence, and transparent communication about the derivation of risk-stratified recommendations or evidence gaps. PMID- 29254524 TI - Evaluating Evidence on Intermediate Outcomes: Considerations for Groups Making Healthcare Recommendations. AB - INTRODUCTION: Groups making recommendations need evidence about whether preventive services improve health outcomes (HOs). When such evidence is not available, groups may choose to evaluate evidence about effects on intermediate outcomes (IOs) and the link between IOs and HOs. This paper aims to describe considerations for assessing the evidence linking changes in IOs to changes in HOs. METHODS: Working definitions of IOs, HOs, and other outcomes were developed. All current U.S. Preventive Services Task Force (USPSTF) recommendations through April 2016 were examined to identify how evidence of the IO-HO link was gathered and the criteria that appeared to be used to determine the adequacy of the evidence. Methods of other expert and recommendation-making groups were also examined. RESULTS: Forty-four USPSTF recommendations involved a relevant IO-HO link. The approaches used most commonly to gather evidence about the link were selected review (19 of 44, 43%) and systematic review (12 of 44, 27%). Some key considerations when assessing the adequacy of evidence about the IO-HO link include adjustment for confounding, proximity of the IO to the HO in the causal pathway, and independence of IO-HO relationship from specific treatments. CONCLUSIONS: Considerations were identified for recommendation-making groups to use when gathering and assessing the adequacy of evidence about the IO-HO link. Using a standard set of written principles could improve the transparency of assessments of the IO-HO link, especially if used together with judgment in a reasoned conjecture and refutation process. Ideally, the process would result in an estimate of the magnitude of change in HOs that is expected for specified changes in IOs. PMID- 29254525 TI - Update on the Methods of the U.S. Preventive Services Task Force: Linking Intermediate Outcomes and Health Outcomes in Prevention. AB - The U.S. Preventive Services Task Force (USPSTF) is an independent body of experts who make evidence-based recommendations about clinical preventive services using a transparent and objective process. Developing recommendations on a clinical preventive service requires evidence of its effect on health outcomes. Health outcomes are symptoms, functional levels, and conditions that affect a patient's quantity or quality of life and are measured by assessments of physical or psychologic well-being. Intermediate outcomes are pathologic, physiologic, psychologic, social, or behavioral measures related to a preventive service. Given the frequent lack of evidence on health outcomes, the USPSTF uses evidence on intermediate outcomes when appropriate. The ultimate goal is to determine precisely a consistent relationship between the direction and magnitude of change in an intermediate outcome with a predictable resultant direction and magnitude of change in the health outcomes. The USPSTF reviewed its historical use of intermediate outcomes, reviewed methods of other evidence-based guideline-making bodies, consulted with other experts, and reviewed scientific literature. Most important were the established criteria for causation, tenets of evidence-based medicine, and consistency with its current standards. Studies that follow participants over time following early treatment, stratify patients according to treatment response, and adjust for important confounders can provide useful information about the association between intermediate and health outcomes. However, such studies remain susceptible to residual confounding. The USPSTF will exercise great caution when making a recommendation that depends on the evidence linking intermediate and health outcomes because of inherent evidence limitations. PMID- 29254526 TI - Collaborative Modeling: Experience of the U.S. Preventive Services Task Force. AB - Models can be valuable tools to address uncertainty, trade-offs, and preferences when trying to understand the effects of interventions. Availability of results from two or more independently developed models that examine the same question (comparative modeling) allows systematic exploration of differences between models and the effect of these differences on model findings. Guideline groups sometimes commission comparative modeling to support their recommendation process. In this commissioned collaborative modeling, modelers work with the people who are developing a recommendation or policy not only to define the questions to be addressed but ideally, work side-by-side with each other and with systematic reviewers to standardize selected inputs and incorporate selected common assumptions. This paper describes the use of commissioned collaborative modeling by the U.S. Preventive Services Task Force (USPSTF), highlighting the general challenges and opportunities encountered and specific challenges for some topics. It delineates other approaches to use modeling to support evidence-based recommendations and the many strengths of collaborative modeling compared with other approaches. Unlike systematic reviews prepared for the USPSTF, the commissioned collaborative modeling reports used by the USPSTF in making recommendations about screening have not been required to follow a common format, sometimes making it challenging to understand key model features. This paper presents a checklist developed to critically appraise commissioned collaborative modeling reports about cancer screening topics prepared for the USPSTF. PMID- 29254527 TI - Challenges in Developing U.S. Preventive Services Task Force Child Health Recommendations. AB - The U.S. Preventive Services Task Force (USPSTF) uses an objective evidence-based approach to develop recommendations. As part of this process, the USPSTF also identifies important research gaps in scientific evidence. In March 2016, the USPSTF convened an expert panel to discuss its portfolio of child and adolescent recommendations and identify unique methodologic issues when evaluating evidence regarding children and adolescents. The panel identified key domains of challenges, including measuring patient-centered health outcomes; identifying intermediate outcomes predictive of important health outcomes; evaluating the long time horizon needed to assess the balance of benefits and harms; understanding trajectories of growth and development that result in unique windows of time when expected benefits or harms of a preventive service can vary; and considering the perspectives of other individuals who might be affected by the delivery of a preventive service to a child or adolescent. Although the expert panel expressed an interest in being able to make more recommendations for or against preventive services for children and adolescents, it also reinforced the importance of ensuring recommendations were based on sound and sufficient evidence to ensure greatest benefit and minimize unnecessary harms. Accordingly, the need to highlight areas with insufficient evidence is as important as making recommendations. Having identified these key challenges, the USPSTF and other organizations issuing guidelines have an opportunity to advance their methods of evidence synthesis and identified evidence gaps represent important opportunities for researchers and policy makers. PMID- 29254528 TI - Conflicts of Interest in Clinical Guidelines: Update of U.S. Preventive Services Task Force Policies and Procedures. AB - The U.S. Preventive Services Task Force (USPSTF) provides independent, objective, and scientifically rigorous recommendations for clinical preventive services. A primary concern is to avoid even the appearance of members having special interests that might influence their ability to judge evidence and formulate unbiased recommendations. The conflicts of interest policy for the USPSTF is described, as is the formal process by which best practices were incorporated to update the policy. The USPSTF performed a literature review, conducted key informant interviews, and reviewed conflicts of interest policies of ten similar organizations. Important findings included transparency and public accessibility; full disclosure of financial relationships; disclosure of non-financial relationships (that create the potential for bias and compromise a member's objective judgment); disclosure of family members' conflicts of interests; and establishment of appropriate reporting periods. Controversies in best practices include the threshold of financial disclosures, ease of access to conflicts of interest policies and declarations, vague definition of non-financial biases, and request for family members' conflicts of interests (particularly those that are non-financial in nature). The USPSTF conflicts of interest policy includes disclosures for immediate family members, a clear non-financial conflicts of interest definition, long look-back period and application of the policy to prospective members. Conflicts of interest is solicited from all members every 4 months, formally reviewed, adjudicated, and made publicly available. The USPSTF conflicts of interest policy is publicly available as part of the USPSTF Procedure Manual. A continuous improvement process can be applied to conflicts of interest policies to enhance public trust in members of panels, such as the USPSTF, that produce clinical guidelines and recommendations. PMID- 29254530 TI - Large Health Systems' Prevention Guideline Implementation: A Qualitative Study. AB - INTRODUCTION: Health systems now employ more than half of U.S. physicians. They have the potential to affect primary care through decision support and financial incentives around clinical prevention guidelines. The processes by which they respond to and implement clinical guidelines remain largely unexplored. METHODS: In 2015, the research team conducted and analyzed interviews with quality leaders from eight hospital-based systems and one physician organization which together employ >33,000 physicians and serve >15 million patients. Executives explained organizational processes to adapt, adopt, disseminate, and incentivize adherence to preventive services guidelines. RESULTS: Nearly all have a formal process for reviewing and refining guidelines, developing clinician support, and disseminating the approved guidelines. Internal and external factors like organizational structure, patient demographics, and payer contracts affect the review processes and resulting guideline adaptations. Challenges to guideline uptake include competing demands on clinician time and the absence of accurate and timely patient data in accessible and user-friendly formats. Interviewees reported that engaging clinicians in guideline review is critical to successful implementation. Electronic health record reminders represent the primary tool for guideline dissemination and reinforcement. Interviewees reported widespread use of performance monitoring and feedback to clinicians, with varying levels of success. Most organizations use financial incentives tied to performance for some of their clinicians, although details vary widely depending on network structures and contractual arrangements. CONCLUSIONS: Health systems play a critical intermediary role between guideline-developing organizations and practicing clinicians. Strengthening the adoption of guidelines requires attention to many factors beyond care delivery. PMID- 29254529 TI - U.S. Preventive Services Task Force Methods to Communicate and Disseminate Clinical Preventive Services Recommendations. AB - The U.S. Preventive Services Task Force (USPSTF) issues evidence-based screening and prevention recommendations, and key to this task is dissemination and implementation of these recommendations. The Task Force has recommendations for more than 84 topics; each USPSTF Recommendation Statement includes a letter grade, a topline summary to guide clinician interpretation in practice, and a summary of gaps in evidence to help catalyze clinically relevant research. The USPSTF aims to update existing topics regularly and considers new topics to add each year. Clearly communicating and disseminating each recommendation is a critical task to ensure maximum benefit from use of the recommendations. The primary USPSTF audience is primary care clinicians. Over time, other audiences have become interested in the USPSTF and these entities have broad and diverse needs, necessitating a range of communication platforms and approaches. This includes engagement with and input from topic experts, primary care and federal partners, and the public to help shape the development of the recommendations. It also includes engagement of partners to disseminate USPSTF recommendations to help ensure that the primary care workforce remains up-to-date on USPSTF recommendations. This paper outlines the approaches used by the USPSTF to both solicit input (e.g., public comment periods), as well as to facilitate dissemination of its recommendations to help improve the health of all Americans (e.g., web-based and mobile application tools, journal publications, and annual reports to Congress). PMID- 29254531 TI - U.S. Preventive Services Task Force Priorities for Prevention Research. AB - The U.S. Preventive Services Task Force (USPSTF) makes recommendations about clinical preventive services. The USPSTF examines chains of direct and indirect evidence to demonstrate the effectiveness of a clinical preventive service. Missing links across the chains of evidence reflect gaps in the research. Evidence gaps can occur for preventive services that receive a letter grade recommendation and those that receive an I statement (insufficient evidence). This article describes the types of evidence gaps that the USPSTF encounters across its various recommendations and how the USPSTF identifies and communicates these gaps to researchers and policymakers, who can help generate the needed evidence. Common types of evidence gaps include limited evidence in primary care settings and populations, a lack of appropriate health outcomes, limited evidence linking behavior change to health outcomes, and a lack of evidence for effective preventive services in diverse populations. The USPSTF annual report to Congress focuses on the evidence gaps of new recommendations from the past year and is sent to leading research funding agencies. The Office of Disease Prevention at NIH uses this report to help direct future funding opportunities that may address these evidence gaps. The USPSTF plays a critical role in highlighting the information needed to advance the science to optimize the use of clinical preventive services in primary care. PMID- 29254532 TI - Economic Impact of Emergency Visits due to Drug-Related Morbidity on a Brazilian Hospital. AB - OBJECTIVES: To estimate the cost of managing drug-related morbidity (DRM) that leads to visits to the emergency department of a Brazilian hospital. METHODS: This is a cost-of-illness study based on a retrospective cross-sectional analysis of patients' medical records. A questionnaire and analysis of medical records were used to identify patients who were being admitted to the emergency department because of DRM. The direct medical costs of patient management were estimated using a microcosting analysis, and a sensitivity analysis was conducted using the emergency department visit rates due to DRM reported in the literature. RESULTS: Of the total patients interviewed, 14.6% sought emergency care because of DRM and 58.9% were considered preventable. Mean treatment costs were US $900 +/- $1,569 (range US $18-$10,847). An extrapolation based on all emergency visits in the last year resulted in annual total treatment costs of US $7.5 million (US $1.1-$1.4 million). It was observed that 39.3% of the total cost of DRM was attributed to adverse drug reactions, 36.9% to nonadherence to treatment, and 16.9% to incorrect dosages. CONCLUSIONS: Adverse drug reactions and nonadherence to treatment are important causes of morbidity and cost to the health service. Much of this resource is spent to treat preventable cases of DRM, which represents a great waste of resources. PMID- 29254533 TI - A Cost-of-Illness Study of Patients with HIV/AIDS in Bogota, Colombia. AB - BACKGROUND: In 2014, 0.3% of the total population in Colombia was living with HIV/AIDS. The data currently available regarding the costs of these patients are very limited. OBJECTIVES: To estimate the societal costs of patients with HIV/AIDS in Bogota, Colombia. METHODS: This study is a quantitative, cross sectional cost-of-illness study. Costs were assessed with a prevalence-based, bottom-up approach. The data of 124 patients were collected from their medical records in a Bogota hospital and a questionnaire was developed to measure other health care costs, as well as patient and family costs. Subgroup analyses were performed according to sex, age, Centers for Disease Control and Prevention classification, and CD4 count (cluster of differentiation 4). RESULTS: The mean annual cost per patient with HIV/AIDS was estimated at $11,505 +/- 18,658 (2014 US dollars). The larger part was attributable to drug costs (a mean annual cost of $8,616, 75% of the total), whereas productivity costs represented a mean annual cost of $1,044 (10%). Total costs per patient were estimated for a CD4 count of 500 or more, 200 to 499, and less than 200 cells/ul at $13,116, $9,077, and $10,741, respectively (all values in 2014 US dollars). CONCLUSIONS: HIV/AIDS represents a high societal burden in Colombia. In comparison with the gross domestic product per capita of $7,904 in 2014, the mean annual cost per patient with HIV/AIDS was 40% higher, estimated at $11,505. The largest part of the HIV/AIDS costs was attributed to drugs, followed by productivity costs. Using extrapolation, the total cost of HIV/AIDS for the Colombian society would be $1.431 billion. PMID- 29254535 TI - Value in Health Regional Issues: PubMed Indexing and Our "Coming of Age". PMID- 29254534 TI - Cost-Effectiveness Analysis of Everolimus versus Mycophenolate in Kidney Transplant Recipients Receiving No Pharmacological Prophylaxis for Cytomegalovirus Infection: A Short-Term Pharmacoeconomic Evaluation (12 Months). AB - BACKGROUND: Modern immunosuppressive regimens, although associated with improved 1-year graft survival, are associated with adverse effects, including opportunistic infections, diabetes mellitus after transplantation, cardiovascular complications, and de novo malignancies. OBJECTIVES: To determine the short-term (12 months) cost-effectiveness of everolimus (EVR) versus mycophenolate sodium (MPS) in kidney transplant recipients receiving induction therapy, tacrolimus, prednisone, and no prophylaxis for cytomegalovirus infection. METHODS: A Markov state transition model was designed. Data from a single-center prospective trial were used along with data from the center's medical bills database. The target population comprised adults with low immunological risk submitted to first ABO compatible transplantation with kidneys recovered from living or deceased donors. The time horizon was 12 months. The interventions included tacrolimus and prednisone plus a single 3-mg/kg dose of rabbit antithymocyte globulin (ATG) and EVR or basiliximab (BAS) and EVR or BAS and MPS. The clinical outcomes considered for this analysis were cytomegalovirus infection/disease, acute rejection, graft dysfunction, surgical complications, graft loss, and life-years gained. RESULTS: ATG/EVR was cost-saving compared with BAS/MPS on all evaluated outcomes; BAS/EVR outperformed BAS/MPS on most of the evaluated outcomes. Results were confirmed by sensitivity analysis. CONCLUSIONS: Compared with MPS, EVR is an alternative immunosuppressive agent that is able to provide resource-saving to the health care provider with effectiveness gains for the patient. PMID- 29254536 TI - Presenteeism, Absenteeism, and Lost Work Productivity among Depressive Patients from Five Cities of Colombia. AB - OBJECTIVES: To estimate productivity losses due to absenteeism and presenteeism and their determinants in patients with depression from five Colombian cities. METHODS: We used data from a multicenter, mixed-methods study of adult patients diagnosed with major depressive disorder or double depression (major depressive disorder plus dysthymia) during 2010. The World Health Organization's Health and Work Performance Questionnaire was used to assess absenteeism and presenteeism. We explored the determinants of productivity losses using a two-part model. We also used a costing model to calculate the corresponding monetary losses. RESULTS: We analyzed data from 107 patients employed in the last 4 weeks. Absenteeism was reported by 70% of patients; presenteeism was reported by all but one. Half of the patients reported a level of performance at work at least 50% below usual. Average number of hours per month lost to absenteeism and presenteeism was 43 and 51, respectively. The probability of any absenteeism was 17 percentage points lower in patients rating their mental health favorably compared with those rating it poorly (standard error [SE] 0.09; P < 0.10) and 19 percentage points higher in patients with at least one comorbidity compared with patients with none (SE 0.10; P < 0.10). All other covariates showed no significant associations on hours lost to absenteeism. Patients with favorable mental health self-ratings had 16.4 fewer hours per month of presenteeism compared with those with poor self-ratings (SE 4.52; P < 0.01). The 2015 monetary value of productivity losses amounted to US $840 million. CONCLUSIONS: This study in a middle-income country confirms the high economic burden of depression. Health policies and workplace interventions ensuring adequate diagnosis and treatment of depression are recommended. PMID- 29254537 TI - HTA Implementation in Latin American Countries: Comparison of Current and Preferred Status. AB - OBJECTIVES: To provide an overview about the current status of health technology assessment (HTA) implementation in Latin American countries and to identify long term objectives considering regional commonalities. METHODS: We conducted a survey among participants of the 5th Latin American Future Trends Conference in October 2015. Thirty-seven respondents from eight Latin American countries provided insights about the current and preferred future status of HTA implementation related to human capacity building, HTA financing, process and organizational structure for HTA, scope of mandatory HTA, decision criteria, standardization of HTA methodology, mandating the use of local data, and international collaboration in HTA. RESULTS: Survey respondents reported insufficient human resources and public investment for HTA implementation. Organizational structure and legislation framework of HTA differ considerably across countries. According to survey respondents, in the future policymakers should rely more on the assessment of therapeutic value, cost-effectiveness, and budget impact criteria by applying explicit thresholds, potentially in a multicriteria decision analysis framework. HTA should not be restricted to policy decisions of new technologies but it should also be used for the revision of previous decisions. In addition, the quality and transparency of HTA have to be strengthened. CONCLUSIONS: HTA plays an increasingly important role in Latin American countries. Each country needs to record its current implementation status and identify components for improvement. Duplication of efforts can be reduced if international collaboration is integrated into national HTA implementation. PMID- 29254539 TI - Evaluacion de tecnologias sanitarias para la toma de decisiones y la rendicion de cuentas: una urgente reflexion para el sistema de salud chileno. PMID- 29254538 TI - Estudio de impacto presupuestal de Daclatasvir asociado a Asunaprevir desde la perspectiva del sistema de salud publico chileno. AB - OBJECTIVES: To assess the impact on the 2015 national health budget of incorporating Daclatasvir/Asunaprevir (DCV / ASV) for the treatment of Hepatitis C genotype 1b (HC1b) in Chile. METHODS: A Chilean HC1b patients cohort was modelled using local prevalence and incidence data. Two scenarios were built and compared, one were all patients receive Peginterferon/Ribavirin (PR) and another were all patients are treated with DCV/ASV. The analysis was conducted from the perspective of public health system of Chile assuming 100% reimbursement and a time horizon of 5 years. Costs associated with drug treatment, adverse events, other relevant resources and costs associated with disease complications were used. RESULTS: At a total DCV/ASV treatment price of USD $55,039, an additional of USD $65,6MM are required during the first year (prevalent cases) equivalent to 0.71% of the 2015 national health budget. From year 2 (incident cases), an additional of USD $12,3MM are needed (0.13% of the 2015 health budget). A price reduction of 33% (USD $36,693), requires an additional of USD $38,2MM the first year and USD $7,16MM from the second year (0.11% and 0.6% of the health budget). If the treatment price is reduced further (USD $18,347), an additional USD $10,9MM are required for the first year and USD $2,03MM from the second year (0.3% and 0.057% of the 2015 heath budget). CONCLUSION: The impact on the health budget ranges between 0.3% and 0.71% the first year and decreases to less than 0.15% from the second year considering the price assessed price range. PMID- 29254540 TI - Cost Effectiveness of Dulaglutide Compared with Liraglutide and Glargine in Type 2 Diabetes Mellitus Patients in Colombia. AB - BACKGROUND: Diabetes treatment includes very diverse drugs. It is essential to identify which drugs offer the best value for their costs. OBJECTIVES: To estimate comparative cost effectiveness for treating diabetes mellitus with dulaglutide, liraglutide, or glargine in Colombia. METHODS: A Markov model including diabetic microvascular and macrovascular complications was used to estimate cost-effectiveness. We used annual cycles, a 5-year time horizon, 5% discount rate, and third-party payer's perspective. Main outcomes were quality adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Transition probabilities were obtained from primary studies and costs from local databases and studies. We used a threshold of 3 times the Colombian per capita gross domestic product (US $17,270 for 2015; US $1 = 2,743 Columbian pesos) to assess cost effectiveness. RESULTS: Total costs related to dulaglutide, liraglutide, and glargine were US $8,633, US $10,756, and US $5,783, yielding 3.311 QALYs, 3.229 QALYs, and 3.156 QALYs, respectively. Dulaglutide dominated liraglutide given lower total costs and higher QALYs. The estimated ICER for dulaglutide compared with glargine was US $18,385, greater than the accepted threshold. Sensibility analysis shows that decreased dulaglutide cost, increased consumption of glargine, nondaily injection, and number and cost of glucometry could result in ICERs lower than the threshold. Probabilistic sensitivity analysis showed consistent results. CONCLUSIONS: This estimation indicates that dulaglutide dominates liraglutide. Its ICER is, however, greater than the accepted threshold for Colombia in base case compared with glargine. By increasing population weight or glargine consumption, dulaglutide becomes cost effective compared with glargine, which could identify a niche where dulaglutide is the best option. PMID- 29254542 TI - Editorial comment on Health Technology Assessment (HTA): Good Practices & Principles. FIFARMA's Position on HTA Processes in Latin America: The Devil Is in the Details. PMID- 29254541 TI - Burden of Culture-Confirmed Pediatric Pneumococcal Pneumonia in Latin America and the Caribbean: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Pneumococcal pneumonia (PP) causes almost one in five deaths in children younger than 5 years worldwide. In Latin America and the Caribbean (LAC), pneumonia causes 14% of all deaths. Although pneumococcal disease is a vaccine-preventable disease that accounts for a significant proportion of this burden, the decision-making process to introduce pneumococcal conjugate vaccines in official schedules is still complex in LAC. Confirmed PP cases and epidemiology are the basis for broader projections. OBJECTIVE: To gather all the information available in the LAC region to assist decision makers. METHODS: We performed a systematic review of studies of consolidating and culture-confirmed pediatric PP in LAC (2000-2016) using a generic academic Internet search and search engines without language restrictions. Pairs of reviewers independently selected and assessed the studies' methodological quality. We analyzed meta information on pneumococcal serotypes available from the SIREVA laboratory-based surveillance system. RESULTS: A total of 35 out of 750 initially identified studies were included. In the age group between 0 and 59 years, the incidence of culture-confirmed PP ranged from 10.2 to 43.0/100,000 children, with a pooled incidence of 20.4/100,000 children (95% confidence interval 0.0-123.2). Mortality ranged from 0.4 to 5.7/100,000 children, and the pooled mortality was 2.9/100,000 children (95% confidence interval 0.3-8.2). The pooled serotype distribution from surveillance data showed that serotypes 14, 1, and 6B were the most frequent serotypes in LAC, all included in licensed vaccines. CONCLUSIONS: Studies on confirmed pediatric PP were scarce in LAC in 2000 to 2016. Epidemiology indicators and health resource use are still poorly defined. PMID- 29254543 TI - Impacto del incremento del impuesto a los productos de tabaco sobre la recaudacion y los precios en Panama. PMID- 29254544 TI - Conducting and Disseminating Epidemiological Systematic Reviews in Latin America and the Caribbean: Pitfalls and Lessons Learned. AB - OBJECTIVES: To describe the experience, pitfalls, and lessons learned in conducting and disseminating epidemiological systematic reviews (SRs) in Latin America and the Caribbean between 2007 and 2016. METHODS: We used a mixed-methods approach, including a descriptive cross-sectional study and a qualitative study of pitfalls and lessons learned. The following end points were analyzed: number of primary research studies included, country of origin, study design, risk of bias, citations in social media, number of researchers and experts involved, and time devoted by them to conduct SRs. Data for the qualitative study were collected through sessions with multiprofessional focus groups of the reviewers' core team held from February to March 2016. We performed a thematic analysis of the following domains: sources of information, evidence quantity and quality, statistical analysis, and dissemination of findings in both academic and social media. RESULTS: A total of 19 SRs were produced, including 1016 primary research studies. Brazil (35%) and Argentina (19%) contributed the largest number of studies. The most frequent design was cross-sectional (35%). Only 27% of the studies included in the SRs were judged as having a low risk of bias. We identified key challenges at different stages of the process. We found substantial difficulties in all domains derived from the thematic analysis and proposed potential solutions for each of them. CONCLUSIONS: There are large gaps in epidemiological evidence from primary research, particularly from population based studies. Special approaches are needed to identify, assess, synthesize, interpret, and disseminate epidemiological evidence from Latin America and the Caribbean. PMID- 29254545 TI - Uso de recursos y costos de hospitalizaciones por insufi ciencia card i aca: un estudio retrospective multic e ntrico en Argentina. AB - OBJECTIVES: Heart failure has a great impact on health budget, mainly due to the cost of hospitalizations. Our aim was to describe health resource use and costs of heart failure admissions in three important institutions in Argentina. METHODS: Multi-center retrospective cohort study, with descriptive and analytical analysis by subgroups of ejection fraction, blood pressure and renal function at admission. Generalized linear models were used to assess the association of independent variables to main outcomes. RESULTS: We included 301 subjects; age 75.3+/-11.8 years; 37% women; 57% with depressed ejection fraction; 46% of coronary etiology. Blood pressure at admission was 129.8+/-29.7 mmHg; renal function 57.9+/-26.2 ml/min/1.73 m2. Overall mortality was 7%. Average length of stay was 7.82+/-7.06 days (median 5.69), and was significantly longer in patients with renal impairment (8.9 vs. 8.18; p=0.03) and shorter in those with high initial blood pressure (6.08+/-4.03; p=0.009). Mean cost per patient was AR$68,861+/-96,066 (US$=8,071; 1US$=AR$8.532); 71% attributable to hospital stay, 20% to interventional procedures and 6.7% to diagnostic studies. Variables independently associated with higher costs were depressed ejection fraction, presence of valvular disease, and impaired renal function. CONCLUSIONS: Resource use and costs associated to hospitalizations for heart failure is high, and the highest proportion is attributable to the costs related to hospital stay. PMID- 29254546 TI - Doctors Adjacent to Private Pharmacies: The New Ambulatory Care Provider for Mexican Health Care Seekers. AB - BACKGROUND: In 2010 Mexican health authorities enacted an antibiotic sale, prescription, and dispensation bill that increased the presence of a new kind of ambulatory care provider, the doctors adjacent to private pharmacies (DAPPs). OBJECTIVES: To analyze how DAPPs' presence in the Mexican ambulatory care market has modified health care seekers' behavior following a two-stage health care provider selection decision process. METHODS: The first stage focuses on individuals' propensity to captivity to the health care system structure before 2010. The second stage analyzes individuals' medical provider selection in a health system including DAPPs. This two-stage process analysis allowed us not only to show the determinants of each part in the decision process but also to understand the overall picture of DAPPs' impact in both the Mexican health care system and health care seekers, taking into account conditions such as the origins, evolution, and context of this new provider. We used data from individuals (N = 97,549) participating in the Mexican National Survey of Health and Nutrition in 2012. RESULTS: We found that DAPPs have become not only a widely accepted but also a preferred option among the Mexican ambulatory care providers that follow no specific income-level population user group (in spite of its original low-income population target). Our results showed DAPPs as an urban and rapidly expanded phenomenon, presumably keeping the growing pace of new communities and adapting to demographic changes. CONCLUSIONS: Individuals opt for DAPPs when they look for health care: in a nearby provider, for either the most recent or common ailments, and in an urban setting; regardless of most socioeconomic background. The relevance of location and accessibility variables in our study provides evidence of the role taken by this provider in the Mexican health care system. PMID- 29254547 TI - Single-Use Devices in Argentina: Cost Comparison Analysis of a "Re-Use" versus a "Single-Use" Policy for Trocars, Endocutters, Linear Cutters, and Harmonic Scalpels. AB - BACKGROUND: Re-use of medical devices labeled and marketed for single use only is a current practice around the world. OBJECTIVES: To estimate the average difference per surgery in device-related costs (DRCs) when performed with single use devices under a single-use policy (SUP) instead of a re-use policy (RP) from the perspective of the private health sector of Argentina. METHODS: An analytical model was developed in Microsoft Excel and populated with data from a literature review, a Delphi-like panel, and local cost estimations. Four single-use devices were selected for analysis: plastic trocars, endocutters, linear cutters, and harmonic scalpels. DRCs were expressed in 2012 US dollars and divided into four cost categories: devices, adverse events, device failure, and surgical time extension. Outputs were expressed as DRCs per surgery under a SUP, under a RP, the difference between them expressed in US dollars (Diff_$), and the difference between them expressed as a percentage of surgery costs (Diff_%S). Deterministic and probabilistic sensitivity analyses were performed to analyze the impact of uncertainty on results. RESULTS: Expected DRCs per surgery were as follows: for trocars: SUP, US $424.6; RP, US $244.2; Diff_$, US $-180.4; and Diff_%S, -3.8%; for endocutters: SUP, US $1667.4; RP, US $1102.3; Diff_$, US $-565.1; and Diff_%S, -11.1%; for linear cutters: SUP, US $1228.1; RP, US $1045.9; Diff_$, US $-182.2; and Diff_%S, -3.4%; and for harmonic scalpels: SUP, US $1040.9; RP, US $292.4; Diff_$, US $-748.5; and Diff_%S, -14.8%. Sensitivity analyses showed results to be robust. CONCLUSIONS: RP was shown to be less costly in all devices and scenarios considered. Nevertheless, the real frequency of adverse events and their cost implications are still uncertain. More research is needed to assess the effectiveness and safety of these off-label policies. PMID- 29254549 TI - Cost Effectiveness of Intracranial Pressure Monitoring in Pediatric Patients with Severe Traumatic Brain Injury: A Simulation Modeling Approach. AB - OBJECTIVES: To conduct an economic evaluation of intracranial pressure (ICP) monitoring on the basis of current evidence from pediatric patients with severe traumatic brain injury, through a statistical model. METHODS: The statistical model is a decision tree, whose branches take into account the severity of the lesion, the hospitalization costs, and the quality-adjusted life-year for the first 6 months post-trauma. The inputs consist of probability distributions calculated from a sample of 33 surviving children with severe traumatic brain injury, divided into two groups: with ICP monitoring (monitoring group) and without ICP monitoring (control group). The uncertainty of the parameters from the sample was quantified through a probabilistic sensitivity analysis using the Monte-Carlo simulation method. The model overcomes the drawbacks of small sample sizes, unequal groups, and the ethical difficulty in randomly assigning patients to a control group (without monitoring). RESULTS: The incremental cost in the monitoring group was Mex$3,934 (Mexican pesos), with an increase in quality adjusted life-year of 0.05. The incremental cost-effectiveness ratio was Mex$81,062. The cost-effectiveness acceptability curve had a maximum at 54% of the cost effective iterations. The incremental net health benefit for a willingness to pay equal to 1 time the per capita gross domestic product for Mexico was 0.03, and the incremental net monetary benefit was Mex$5,358. CONCLUSIONS: The results of the model suggest that ICP monitoring is cost effective because there was a monetary gain in terms of the incremental net monetary benefit. PMID- 29254548 TI - Costos medicos directos en pacientes con enfermedad pulmonar obstructiva Cronica en Mexico. AB - INTRODUCTION: chronic obstructive pulmonary disease (COPD) is a progressive, incurable and potentially mortal. COPD generates a high burden of illness and decreased quality of life in patients. The aim of this study was to determine the direct medical cost of COPD and the primary variables associated. METHODOLOGY: We conducted a multicenter clinical study, based in a retrospective cohort as base of a partial economic evaluation in patients diagnosed with moderate to severe COPD. It was considered an institutional point of view to determine medical costs, with an annual time horizon. For analysis of associations between explanatory and end point variables, a generalized lineal regression model was developed. RESULTS: We analyzed data from 283 patients, Fifty-nine percent were women, the average age was 72 years +/- 11, Sixty-five percent of patients had a history of smoking and 57.6 % were exposed to wood smoke. The annual direct medical costs (MXN 2016) was 20,754 and 41,887 for patients with moderate and severe COPD, respectively, this difference is mainly due to the use of oxygen as well as longer hospital stay (12.9 vs. 24.7 days) of patients with severe COPD. CONCLUSIONS: Although the severity level is associated with greater health care costs, the quality of life of the patients should be considered carefully because it is inversely associated with the cost of care for patients with COPD. PMID- 29254551 TI - Improving Health Screening Uptake in Men: A Systematic Review and Meta-analysis. AB - CONTEXT: Globally, uptake of health screening in men remains low and the effectiveness of interventions to promote screening uptake in men is not well established. This review aimed to determine the effectiveness of interventions in improving men's uptake of and intention to undergo screening, including interventions using information and communication technology and a male-sensitive approach. EVIDENCE ACQUISITION: Studies were sourced from five electronic databases (October 2015), experts, and references of included studies. This study included RCTs or cluster RCTs that recruited men and reported uptake of or intention to undergo screening. Two researchers independently performed study selection, appraisal, and data extraction. The interventions were grouped into those that increase uptake and those that promote informed decision making. They were further sub-analyzed according to types of intervention, male-sensitive, and web- and video-based interventions. The analysis was completed in December 2016. EVIDENCE SYNTHESIS: This review included 58 studies. Most studies were on prostate cancer (k=31) and HIV (k=11) screening. Most of the studies had low methodologic quality (79.3%) and after excluding them from the analysis, one study found that educational intervention (which was also male-sensitive) was effective in improving men's intention to screen (risk ratio=1.36, 95% CI=1.23, 1.50, k=1) and partner educational intervention increased men's screening uptake (risk ratio=1.77, 95% CI=1.48, 2.12, k=1). Video-based educational interventions reduced prostate cancer screening uptake (risk ratio=0.89, 95%CI=0.80, 0.99, k=1) but web-based interventions did not change men's screening intention or uptake. CONCLUSIONS: This review highlights the need to conduct more robust studies to provide conclusive evidence on the effectiveness of different interventions to improve men's screening behavior. PMID- 29254550 TI - Reducing Preventable Hospitalization and Disparity: Association With Local Health Department Mental Health Promotion Activities. AB - INTRODUCTION: Serving as the center of community-engaged health programs, local health departments can play a critical role in promoting community mental health. The objectives of this study were to explore the association between local health department activities and (1) preventable hospitalizations for individuals with mental disorders, and (2) associated racial disparities in preventable hospitalizations. METHOD: Employing the linked data sets of the 2012-2013 Healthcare Cost and Utilization Project state inpatient discharge file of the State of Maryland, the National Association of County and City Health Officials Profiles Survey, the Area Resource File, and U.S. Census data, the authors estimated the association between local health department activities (i.e., provision of mental health preventive care and community mental health promotion) and the reduction of the preventable hospitalizations for ambulatory care sensitive conditions and coexisting mental disorders. All the data analyses were conducted during September 2016-August 2017. RESULTS: Multilevel regression showed that local health departments' provision of mental health preventive care (OR=0.76, 95% CI=0.63, 0.92) and mental health promotion activities (OR=0.77, 95% CI=0.62, 0.94) were significantly associated with lower rates of preventable hospitalizations for individuals with ambulatory care-sensitive conditions and coexisting mental disorders. Decomposition results suggested that local health departments' direct provision of mental health preventive care could reduce 9% of the racial disparities. CONCLUSIONS: Improving care coordination and integration are essential to meeting the growing demands for healthcare access, while controlling costs and improving quality of service delivery. These results suggest that it will be effective to engage local health departments in the integrated behavioral health system. PMID- 29254552 TI - An Appreciation of the U.S. Preventive Services Task Force. PMID- 29254553 TI - Guideline Recommendations for Preventive Healthcare Services: Understanding and Managing Conflict of Interest When Population Health Meets Personalized Medicine. PMID- 29254554 TI - Fall Risk Factors in Mid-Age Women: The Australian Longitudinal Study on Women's Health. AB - INTRODUCTION: In contrast to older adults, little is known about risk factors for falls in adults aged 50-64 years, despite a high prevalence of falls in this age group. The aim was to identify risk factors for falls in mid-age women and explore how associations change with age. METHODS: Data were analyzed in 2016 from women aged 50-55 years in 2001 (born 1946-1951) in the Australian Longitudinal Study on Women's Health. The predictor variables were health-related factors (measured 2001, 2004, 2007, 2010) and the outcome was falls in the past 12 months (measured 2004, 2007, 2010, 2013). Prospective associations between predictor variables and falls measured 3 years later were analyzed using logistic regression with complete data for 4,629, 7,096, 5,911, and 5,774 participants. RESULTS: In surveys, 20.5% (2004), 30.7% (2007), 30.5% (2010), and 26.6% (2013) of women reported a fall in the previous 12 months. In the univariable models, most factors were associated with falls 3 years later. In the multivariable models, higher odds of falling were found for overweight and obese women compared with healthy weight women at all survey intervals (OR range, 1.15-1.43). Impaired vision (OR range, 1.25-1.35) and poor physical functioning (OR range, 1.24-1.66) were associated with falls at three survey intervals. Depression (OR range, 1.31 1.42), leaking urine (OR range, 1.25-1.49), stiff/painful joints (OR range, 1.26 1.62), severe tiredness (OR range, 1.29-1.49), osteoporosis (OR range, 1.25 1.52), and hormone replacement therapy (OR range, 0.69-0.79) were associated with falls at two survey intervals. There was no obvious age-related increase or decrease in the number of statistically significant associations. CONCLUSIONS: Identified fall risk factors varied over time, highlighting that falling involves a complex interplay of risk factors in mid-age women. PMID- 29254555 TI - Social Policy Expenditures and Life Expectancy in High-Income Countries. AB - INTRODUCTION: The U.S. spends more than any other country on health care, yet Americans have lower life expectancy than people in most industrialized countries. Recent studies suggest that lower expenditures on social policies in the U.S. may contribute to less-favorable trends in life expectancy. This study tests the hypothesis that greater social spending will be positively associated with life expectancy across the countries of the Organisation of Economic Co operation and Development and that the magnitude of these associations will outweigh those between government healthcare spending and life expectancy. METHODS: In 2016, longitudinal data on six domains of social expenditures for the U.S. and 19 other wealthy nations between 1980 and 2010 were used to estimate the associations between prior year expenditures on education, family, unemployment, incapacity, old age, and active labor market programs, and period life expectancy using fixed effects models. RESULTS: Controlling for a wide set of confounders and government healthcare expenditures, a 1% increase in prior year education expenditures was associated with 0.160 (95% CI=0.033, 0.286) of a year gain in life expectancy, whereas a 1% increase in prior year incapacity benefit expenditures was associated with 0.168 (95% CI=0.003, 0.333) of a year gain in life expectancy. Counterfactual models suggest that if the U.S. were to increase expenditures on education and incapacity to the levels of the country with the maximum expenditures, life expectancy would increase to 80.12 years. CONCLUSIONS: The U.S. life expectancy lag could be considerably smaller if U.S. expenditures on education and incapacity programs were comparable with those in other high income countries. PMID- 29254556 TI - Associations Between Neighborhood Environment, Health Behaviors, and Mortality. AB - INTRODUCTION: Considering the joint association of neighborhood socioeconomic environment and individual-level health behaviors with health outcomes may help officials design effective disease prevention strategies. This study evaluates the joint influences of neighborhood socioeconomic environment and individual health behaviors on mortality in a cohort primarily comprising people with low individual-level SES. METHODS: The prospective Southern Community Cohort Study includes 77,896 white and African American participants recruited in the years 2002-2009; 55% of participants had a household income <$15,000 at baseline interview. Mortality from cancer (n=2,471), cardiovascular diseases (n=3,005), and all-causes (n=10,099) was identified from the National Death Index through December 31, 2013 (median follow-up, 8 years). Data were analyzed in 2016 and 2017. Associations were assessed between mortality, a neighborhood deprivation index composed of 11 census tract-level variables, five health behaviors, and a composite healthy lifestyle score. RESULTS: Living in a neighborhood with the greatest socioeconomic disadvantage was associated with higher all-cause mortality in both men (hazard ratio=1.41, 95% CI=1.27, 1.57) and women (hazard ratio=1.77, 95% CI=1.57, 2.00). Associations were attenuated after adjustment for individual-level SES and major risk factors (hazard ratio for men=1.09, 95% CI=0.98, 1.22, and hazard ratio for women=1.26, 95% CI=1.12, 1.42). The dose response association between neighborhood disadvantage and mortality was less apparent among smokers. Nevertheless, individuals who lived in disadvantaged neighborhoods and had the unhealthiest lifestyle scores experienced the highest mortality. CONCLUSIONS: Disadvantaged neighborhood socioeconomic environments are associated with increased mortality in a cohort of individuals of low SES. Positive individual-level health behaviors may help negate the adverse effect of disadvantage on mortality. PMID- 29254557 TI - Vaccination Timeliness at Age 24 Months in Michigan Children Born 2006-2010. AB - INTRODUCTION: Delays in vaccination can stymie the development of herd immunity, and a large proportion of children in the U.S. are known not to receive vaccines on time. This study quantifies delays in vaccination, compares vaccination timeliness to the proportion of children vaccinated, and evaluates the impact of combination vaccine use and timely administration of hepatitis B vaccine birth dose on vaccine timeliness among Michigan children. METHODS: This retrospective cohort study used data from the Michigan Care Improvement Registry-the state immunization information system-for children born 2006-2010. Children aged 24 months as of December 31, 2012, were included. The proportion of children with timely administration of vaccine doses was calculated, and the mean days of vaccination delay with SD were reported. RESULTS: Among 620,592 Michigan children, 42.2% had received all vaccines, but only 13.2% were vaccinated on time by age 24 months. Children's vaccinations were delayed an average of 59.2 (SD=91.2) days by age 24 months for all recommended vaccine doses. Children who received a timely hepatitis B vaccine birth dose or who received a combination vaccine had less delay in vaccination. CONCLUSIONS: Michigan children have high vaccination coverage based on standard measures but few receive these vaccines on time. Promoting use of combination vaccines may improve parental compliance with timely vaccination of children. PMID- 29254558 TI - Post-traumatic Stress Disorder by Gender and Veteran Status. AB - INTRODUCTION: Population-based data on the prevalence, correlates, and treatment utilization of post-traumatic stress disorder by gender and veteran status are limited. With changes in post-traumatic stress disorder diagnostic criteria in 2013, current information from a uniform data source is needed. METHODS: This was a secondary analysis of the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III, which consisted of in-person interviews that were conducted with a representative sample of U.S. adults. The Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-5 Version was used to assess past-year and lifetime post-traumatic stress disorder among veterans (n=3,119) and civilians (n=32,982). Data were analyzed from January to March 2017. RESULTS: Adjusting for age and race/ethnicity, women veterans reported the highest rates of lifetime and past-year post-traumatic stress disorder (13.4%, 95% CI=8.8%, 17.9%, and 11.7%, 95% CI=7.1%, 16.4%) compared with women civilians (8.0%, 95% CI=7.4%, 8.6%, and 6.0%, 95% CI=5.5%, 6.6%); men veterans (7.7%, 95% CI=6.5%, 8.8%, and 6.7%, 95% CI=5.7%, 7.8%); and men civilians (3.4%, 95% CI=3.0%, 3.9%, and 2.6%, 95% CI=2.2%, 2.9%). Traumatic event exposure, correlates of lifetime post-traumatic stress disorder, and treatment seeking varied across subgroups. Men and women veterans were more likely than civilians to use a variety of treatment sources, with men civilians being least likely to seek treatment and men veterans exhibiting the longest delay in seeking treatment. CONCLUSIONS: Post traumatic stress disorder is a common mental health disorder that varies by gender and veteran status. Women veterans' high rates of post-traumatic stress disorder highlight a critical target for prevention and intervention, whereas understanding treatment barriers for men veterans and civilians is necessary. PMID- 29254559 TI - Potential of saliva steroid profiling for the detection of endogenous steroid abuse: Reference thresholds for oral fluid steroid concentrations and ratios. AB - Urine and blood samples are the primary matrices for the detection of exogenous substances in doping control and toxicology. Although these matrices are, in general, very suitable for a wide range of substances, they do show some issues in particular cases. Here, alternative matrices may provide an answer. In this work, a quantitative method for steroid profiling (5 endogenous steroids and their ratios) in oral fluid was developed and validated. In total, 826 saliva samples were analyzed, and inter-individual reference population thresholds for saliva steroid profile parameters were set up. Alterations of this steroid profile after administration of naturally occurring anabolic androgenic steroids (e.g. testosterone (T) or dehydroepiandrosterone (DHEA)) were investigated. In addition, intra-individual short and long-term natural fluctuations were investigated. For longitudinal monitoring in oral fluid, steroid profile ratios (e.g., T/DHEA) were superior to absolute concentrations due to lower susceptibility towards the diurnal pattern. For the detection of a transdermal application of T, the salivary parameter T/DHEA proved to have the highest sensitivity. In contrast with the current screening procedures in urine, there is no need for an additional expensive and time-consuming isotope ratio mass spectrometry confirmation procedure to unequivocally attribute the elevated parameter to an exogenous origin. PMID- 29254561 TI - A high sensitive and contaminant tolerant matrix for facile detection of membrane proteins by matrix-assisted laser desorption/ionization mass spectrometry. AB - Despite the significance of membrane proteins (MPs) in biological system is indisputable, their specific natures make them notoriously difficult to be analyzed. Particularly, the widely used Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) prefers analyses of hydrophilic cytosolic proteins and has a limited ionization efficiency towards hydrophobic MPs. Herein, a hydrophobic compound (E)-propyl alpha-Cyano-4-Hydroxyl Cinnamylate (CHCA-C3), a propyl-esterified derivative of alpha-cyano-4 hydroxycinnamic acid (CHCA), was applied as a contaminant tolerant matrix for high sensitivity MALDI-MS analyses of MPs. With CHCA-C3, the detection limits of hydrophobic peptides were 10- to 100-fold better than those using CHCA. Furthermore, high quality of spectra could be achieved in the presence of high concentration of chaotropes, salts and detergents, as well as human urinary and serum environment. Also, CHCA-C3 could generate uniform sample distribution even in the presence of contaminants. This high contaminant-resistance was revealed to be ascribed to the enhanced hydrophobicity of CHCA-C3 with a lower affinity towards hydrophilic contaminants. The application of CHCA-C3 is further demonstrated by the analysis of trypsin/CNBr digests of bacteriorhodopsin containing seven transmembrane domains (TMDs), which dramatically increased numbers of identified hydrophobic peptides in TMDs and sequence coverage (~100%). Besides, a combined method by using CHCA-C3 with fluoride solvent and a patterned paraffin plate was established for analysis of integral MPs. We achieved a low detection limit of 10 fmol for integral bacteriorhodopsin, which could not be detected using traditional matrices such as 3,5-dimethoxy-4-hydroxycinamic acid, 2,5-dihydroxyacetophenone even at sample concentration of 10 pmol. PMID- 29254560 TI - Development and validation of a LC/MS-based method for the measurement of intracellular superoxide anion. AB - Superoxide anion (O2.-), as the first generated reactive oxygen species (ROS), has been considered to be highly deleterious to cell functions. The measurement of intracellular O2.- level is of great importance to uncover its roles in a variety of oxidative damage diseases. Hydroethidium (HE) fluorescence-based method is dominating intracellular O2.- assay by monitoring the unique product 2 OH-E+ of HE/O2.- reaction. However, the avoid-less cross-interference of red fluorescence limited its ability to provide trustworthy information on intracellular O2.- formation. By the detection of 2-OH-E+, we herein developed and validated an improved LC/MS-based method for the measurement of intracellular O2.-. Firstly, we demonstrated the proportionality of HE/O2.- reaction. Secondly, ungerimine was used as internal standard to eliminate daily basis and matrix effect in the LC/MS-based detection of 2-OH-E+. Afterward, the total protein concentration was utilized for cell number normalization. Accordingly, an equation was further proposed to calculate the relative abundance (RA) of intracellular O2.-. Finally, the developed method has been successfully utilized to evaluate the inhibitory effects of natural compounds on O2.- generation, the result of which was validated by the HE-based fluorescent measurement. Compared with the fluorescent measurement, the LC/MS-based intracellular O2.- assay method is more sensitive, selective and accurate. PMID- 29254563 TI - Inner filter effect-based fluorescent sensing systems: A review. AB - Inner filter effect (IFE) was previously considered as an error in fluorescence measurement. In recent years, it has been developed as an important non irradiation energy conversion model of spectroscopic technique and found wide applications in the fields of chemical sensing and biosensing. In comparison with traditional techniques based on forster resonance energy transfer (FRET), the IFE based fluorescent approach is more flexible and straightforward without the link of absorber with fluorescer. The present review for the first time introduces the state of the art in the progress of the IFE-based fluorescent sensing systems, including sensing strategy, essential conditions, materials option, and their applications for the detection of various target analytes, e.g., ionic species, small molecules, and macromolecules. In addition, the benefits and limitations of the IFE-based fluorescent sensing systems are also critically discussed and highlighted. PMID- 29254562 TI - A simple and sensitive competitive bio-barcode immunoassay for triazophos based on multi-modified gold nanoparticles and fluorescent signal amplification. AB - A simple and highly sensitive immunoassay based on a competitive binding and bio barcode amplification was designed for detection of small molecules, triazophos. The gold nanoparticles (AuNPs) were modified with monoclonal antibodies and 6 carboxyfluorescein labeled single-stranded thiol-oligonucleotides (6-FAM-SH ssDNAs); the fluorescence of 6-FAM was quenched by AuNPs. Ovalbumin-linked haptens were coated on the bottom of microplate to compete with the triazophos in the sample for binding to the antibodies on the AuNP probes. The fluorescence intensity was inversely proportional to analyte concentration. Parameters of AuNP probes preparation and immune reaction were optimized. At the optimal conditions, the salting process was shortened to 1 h and 166 +/- 9 ssDNAs were loaded onto a single AuNP. The competitive fluorescence bio-barcode immunoassay was performed on water, rice, cucumber, cabbage and apple samples. The linear range of the method was 0.01-20 MUg L-1and the limit of detection (LOD) was 6 ng L-1. The recovery and relative standard deviations (RSDs) ranged from 85.0 to 110.3% and 9.4-17.4%, respectively. Good correlations were obtained between the results of the developed method and liquid chromatography-tandem mass spectrometry (LC MS/MS). In conclusion, it is suggested that the competitive fluorescent bio barcode immunoassay had the potential to be used as a sensitive method for detection of a variety of small molecules in various samples. PMID- 29254564 TI - Hydrogel-based suspension array for biomarker detection using horseradish peroxidase-mediated silver precipitation. AB - Advances in medical diagnostics and personalized therapy require robust, sensitive yet cost-effective diagnostic tools for rapid measurement of biomolecules including proteins in body fluids. State-of-the-art technologies are complex and rely on expensive or custom made detection system, and therefore, cannot be readily adapted for point-of-care (POC) analysis. The development of a novel detection platform, which leverages horseradish peroxidase (HRP)-mediated silver precipitation within antibody immobilized porosity tuned poly (ethylene) glycol diacrylate (PEGDA) hydrogel microparticles with the operational advantages of suspension arrays for sensitive quantification of biomarkers, is described. In this study, vascular endothelial growth factor (VEGF) has been used as a model protein. The silver deposition corresponded to the concentration of VEGF in solution. The detection limit of 5.2 +/- 1.0 pg/mL and assay time of 2 h highlights that this assay exceeds the conventional technologies in terms of sensitivity and speed. The practical applicability of the hydrogel microparticle based detection system has been established by demonstrating the ability of the system to quantify the production of VEGF by highly aggressive (MDA-MB-231) and non-aggressive (MCF-7) breast cancer cells. The reliance on simple instrument for quantification of clinically relevant markers bolsters the adaptability of the detection platform/method in POC settings. PMID- 29254565 TI - Enzyme-assisted polymer film degradation-enabled biomolecule sensing with poly (N isopropylacrylamide)-based optical devices. AB - A biosensor for mouse Immunoglobulin G (IgG) was generated from responsive polymer-based interference filters (etalons). To accomplish this, an excess amount of alkaline phosphatase-modified goat anti-mouse IgG (AP-GAM, F(ab')2 fragment specific to mouse IgG) was added to mouse IgG, and allowed to react for some time. After a given reaction time, the bound AP-GAM could be isolated from the unbound, excess AP-GAM by addition of goat anti-mouse IgG (Fc fragment specific)-modified magnetic microspheres (GAM-M) that bind the mouse IgG bound to AP-GAM. After application of a magnetic field, the free, unbound AP-GAM was isolated from the mixture and exposed to an etalon that has its upper Au surface modified with phosphate-containing polymer that can be degraded by AP-GAM. By the phosphate-containing polymer being degraded by the excess AP-GAM, the cleaved phosphate groups can diffuse into the interference filter's active polymer layer that yields a change in the optical properties that can be related to the amount of IgG in the sample. This concept is extremely straightforward to implement, and can be modified to detect a variety of other analytes of interest. PMID- 29254566 TI - Using magnetic beads and signal amplifiers to produce short and simple immunoassays: Application to MMP-9 detection in plasma samples. AB - Magnetic beads (MB) and signal amplifiers, such as horseradish peroxidase polymers (poly-HRP), have been used before for the production of highly sensitive immunoassays. However, most of the examples reported previously entailed long and tedious multi-step procedures, which were not necessarily shorter or simpler than classical paths such as Enzyme-Linked Immunosorbent Assay (ELISA). Here, instead of exploiting the combination of MB and poly-HRP to ameliorate sensitivity, we show that they conform a powerful tool that can be used to shorten the incubation times, which allows optimizing extremely simple, fast and efficient immunoassays with minimal technical requirements. In order to do so, here we used the highly sensitive and specific pair of antibodies of a commercial ELISA kit to optimize a magneto-ELISA for the detection of matrix metallopeptidase 9 (MMP-9). Three signal amplifiers were then tested and the best performing one was implemented in the magneto-assay to shorten the incubation times and improve assay performance. As we show, the shortened magneto-assay could be carried out in about 35 min, which included two 5-min incubations, washing, and incubation with enzyme substrate for 20 min before colorimetric detection. Moreover, the quantification of MMP-9 provided by the shortened assay in 12 plasma samples collected from patients was comparable to that generated by the 5-h ELISA, which was 8.5 times longer. PMID- 29254567 TI - Highly sensitive MicroRNA 146a detection using a gold nanoparticle-based CTG repeat probing system and isothermal amplification. AB - We have developed a gold nanoparticle (AuNP)-based CTG repeat probing system displaying high quenching capability and combined it with isothermal amplification for the detection of miRNA 146a. This method of using a AuNP-based CTG repeat probing system with isothermal amplification allowed the highly sensitive (14 aM) and selective detection of miRNA 146a. A AuNP-based CTG repeat probing system having a hairpin structure and a dTF fluorophore exhibited highly efficient quenching because the CTG repeat-based stable hairpin structure imposed a close distance between the AuNP and the dTF residue. A small amount of miRNA 146a induced multiple copies of the CAG repeat sequence during rolling circle amplification; the AuNP-based CTG repeat probing system then bound to the complementary multiple-copy CAG repeat sequence, thereby inducing a structural change from a hairpin to a linear structure with amplified fluorescence. This AuNP-based CTG probing system combined with isothermal amplification could also discriminate target miRNA 146a from one- and two-base-mismatched miRNAs (ORN 1 and ORN 2, respectively). This simple AuNP-based CTG probing system, combined with isothermal amplification to induce a highly sensitive change in fluorescence, allows the detection of miRNA 146a with high sensitivity (14 aM) and selectivity. PMID- 29254568 TI - Enhanced fluidity liquid chromatography of inulin fructans using ternary solvent strength and selectivity gradients. AB - The value of exploring selectivity and solvent strength ternary gradients in enhanced fluidity liquid chromatography (EFLC) is demonstrated for the separation of inulin-type fructans from chicory. Commercial binary pump systems for supercritical fluid chromatography only allow for the implementation of ternary solvent strength gradients which can be restrictive for the separation of polar polymeric analytes. In this work, a custom system was designed to extend the capability of EFLC to allow tuning of selectivity or solvent strength in ternary gradients. Gradient profiles were evaluated using the Berridge function (RF1), normalized resolution product (NRP), and gradient peak capacity (Pc). Selectivity gradients provided the separation of more analytes over time. The RF1 function showed favor to selectivity gradients with comparable Pc to that of solvent strength gradients. NRP did not strongly correlate with Pc or RF1 score. EFLC with the hydrophilic interaction chromatography, HILIC, separation mode was successfully employed to separate up to 47 fructan analytes in less than 25 min using a selectivity gradient. PMID- 29254569 TI - Homochiral porous organic cage used as stationary phase for open tubular capillary electrochromatography. AB - Porous organic molecular cages, as a new type of porous materials, have in recent years attracted a tremendous amount of attention for their potential applications. However, to the best of our knowledge, there has been no attempt to utilize porous organic molecular cages as stationary phases in capillary electrochromatography (CEC). We report herein the use of a homochiral porous organic cage (POC) (CC3-R) as a stationary phase in open tubular capillary electrochromatography (OT-CEC) for the separation of chiral compounds and positional isomers. The column was fabricated using CC3-R as the stationary phase by a static coating method. Separation of furoin, benzoin, and alprenlol were achieved on the CC3-R coated column, with the highest resolution value (Rs = 3.35) for the separation of benzoin. The influences of pH and buffer concentration on separation have been investigated. Besides, the CC3-R column also exhibited good selectivity for the separation of positional isomers, including those of nitrophenols, phenylenediamines, aminophenols, and ionones. The run-to-run (n = 5), day-to-day (n = 5), column-to-column (n = 3), and batch to-batch (n = 3) relative standard deviations (RSDs) for the analyte migration time were in the range of 0.5-1.5%, 0.2-1.8%, 1.2-2.1% and 1.5-2.8%, respectively. The RSDs for the migration time and enantioselectivity of the analyte were less than 5.9% and 2.2% (inter-day, n = 5) after a week of continuous use. This work also indicates that porous organic molecular materials are promising for enantioseparation in CEC and look set to become more attractive in separation science. PMID- 29254570 TI - Investigations on the selectivity of grafted high performance anion exchangers and the underlying graft mechanism. AB - Macroporous, monodisperse PS/DVB particles with diameters of 4.0-4.6 MUm were functionalized via free radical graft polymerization to create high performance anion exchangers. Varying the amount of monomer from 0 to 10 mmol per 2.0 g PS/DVB allows a control of the column capacity to create columns with capacities up to 350 MUeq/column for 100 mm columns. No further increase of the capacity is observed when using more than 6 mmol of the monomer due to a rivaling homopolymerization. With increasing capacity, the exchangers showed increasing selectivity factors of Br- and NO3- in reference to Cl- from 2.4 to 4.3 and 3.5 to 4.6, changing the elution order in the process. At the same time, contradicting the retention model, the selectivity of SO42- did not change with increasing capacity. Analyzing the amount of converted double bonds during functionalization allowed to identify a grafting-onto mechanism, as the amount of converted double bonds ranges from 0% to 52% depending on the amount of monomer used. This information also allowed the calculation of the average chain length, which ranges from 1 to 6 exchanger groups. The average chain length depends on the amount of monomer used, creating higher average chain lengths with higher amounts of monomer. However, it was not possible to link the observed selectivity differences to the average chain lengths of the columns or the influence of the column capacity on the ion exchange mechanism. PMID- 29254571 TI - Hydrophilic polymeric monoliths containing choline phosphate for separation science applications. AB - In this research, a hydrophilic polymeric monolith containing choline phosphate (CP) was fabricated through the thermally initiated free-radical polymerization of 2-{2-(methacryloyloxy) ethyldimethylammonium}ethyl n-butyl phosphate (MBP) with ethylene dimethacrylate (EDMA) using isopropanol and tetrahydrofuran as the porogenic system. Excellent mechanical strength, permeability, stability and reproducibility were obtained on the optimized poly(MBP-co-EDMA) monolith. Column efficiency as high as 107,500 plates/m was achieved for the analysis of thiourea at a flow velocity of 0.2 mm/s on the monolith. Both hydrophilic and electrostatic interactions were observed for the retention of charged analytes on the poly(MBP-co-EDMA) monolith. It is worth noting that the resulting monolith exhibits higher selectivity and efficiency than the classical 2 (methacryloyloxy)ethyl phosphorylcholine functionalized polymeric monolith for the chromatographic separation of polar analytes. Also, the novel monolithic column was successfully applied to enrich N-glycopeptides from tryptic digest of human IgG. In a word, the versatile MBP functionalized polymeric monolith not only opens up interesting possibilities for reverse zwitterionic CP derivative based polymeric materials in separation science, but also represents a promising hydrophilic interaction chromatography stationary phase. PMID- 29254572 TI - Continuous electromembrane extraction coupled with mass spectrometry - Perspectives and challenges. AB - This tutorial discusses continuous electromembrane extraction (c-EME) coupled directly to mass spectrometry (MS), and the applicability of such systems for on line and real-time monitoring of in-vitro drug metabolism. Parent drug substances and corresponding drug metabolites are extracted from the metabolic reaction mixture, through a supported liquid membrane (SLM), and into an acceptor solution on the other side. Extraction is accomplished using an external electrical field sustained over the SLM. The acceptor solution is continuously pumped into the mass spectrometer, and the decline of parent drug as well as the development of metabolites is followed directly with the mass spectrometer. The purpose of the extraction is to avoid proteins and salts from the reaction mixture from entering the mass spectrometer. This tutorial first discusses the principles and theory of operation. Second, technical development is highlighted with special focus on major challenges associated with c-EME-MS systems. Third, operational parameters and performance are discussed, and finally future perspectives and challenges are considered. PMID- 29254573 TI - Tutorial: Correction of shifts in single-stage LC-MS(/MS) data. AB - Label-free LC-MS(/MS) provides accurate quantitative profiling of proteins and metabolites in complex biological samples such as cell lines, tissues and body fluids. A label-free experiment consists of several LC-MS(/MS) chromatograms that might be acquired over several days, across multiple laboratories using different instruments. Single-stage part (MS1 map) of the LC-MS(/MS) contains quantitative information on all compounds that can be detected by LC-MS(/MS) and is the data of choice used by quantitative LC-MS(/MS) data pre-processing workflows. Differences in experimental conditions and fluctuation of analytical parameters influence the overall quality of the MS1 maps and are factors hampering comparative statistical analyses and data interpretation. The quality of the obtained MS1 maps can be assessed based on changes in the two separation dimensions (retention time, mass-to-charge ratio) and the readout (ion intensity) of MS1 maps. In this tutorial we discuss two types of changes, monotonic and non monotonic shifts, which may occur in the two separation dimensions and the readout of MS1 map. Monotonic shifts of MS1 maps can be corrected, while non monotonic ones can only be assessed but not corrected, since correction would require precise modelling of the underlying physicochemical effects, which would require additional parameters and analysis. We discuss reasons for monotonic and non-monotonic shifts in the two separation dimensions and readout of MS1 maps, as well as algorithms that can be used to correct monotonic or to assess the extent non-monotonic shifts. Relation of non-monotonic shift with peak elution order inversion and orthogonality as defined in analytical chemistry is discussed. We aim this tutorial for data generator and evaluators scientists who aim to known the condition and approaches to produce and pre-processed comparable MS1 maps. PMID- 29254574 TI - A highly sensitive gold nanoparticle-based electrochemical aptasensor for theophylline detection. AB - Theophylline is a common bronchodilator for the treatment of diseases like asthma, bronchitis and emphysema. However, it should be strictly used and monitored due to its toxicity when the concentration is above certain levels. In this work, an electrochemical biosensor for theophylline detection is proposed by recognition of RNA aptamer and gold nanoparticle (AuNP)-based amplification technique. First, RNA aptamer is splitted into two single-stranded RNA probes. One is hybridized with DNA tetrahedron and the resulted nanostructure is then immobilized onto a gold electrode; the other is modified on the surface of AuNPs which is also labeled with methylene blue (MB) as electrochemical species. The recognition process between the two RNA probes and theophylline causes the localization of AuNPs and the enrichment of MB on the electrode interface. A significant electrochemical response is thus generated which is related to the concentration of initial theophylline. This proposed aptasensor shows excellent sensitivity and selectivity which could also be applied in quantitatively detection of theophylline in serums samples. PMID- 29254575 TI - Carbon fiber brush electrode as a novel substrate for atmospheric solids analysis probe (ASAP) mass spectrometry: Electrochemical oxidation of brominated phenols. AB - A carbon fiber brush electrode (CFBE) was newly designed and used as a substrate for both controlled potential electrolysis and atmospheric solids analysis probe (ASAP) mass spectrometry. Electropolymerized and strongly adsorbed products of electrolysis were directly desorbed and ionized from the electrode surface. Electrochemical properties of the electrode investigated by cyclic voltammetry revealed large electroactive surface area (23 +/- 3 cm2) at 1.3 cm long array of carbon fibers with diameter 6-9 MUm. Some products of electrochemical oxidation of pentabromophenol and 2,4,6-tribromophenol formed a compact layer on the carbon fibers and were analyzed using ASAP. Eleven new oligomeric products were identified including quinones and biphenoquinones. These compounds were not observed previously in electrolyzed solutions by liquid or gas chromatography/mass spectrometry. The thickness around 58 nm and 45 nm of the oxidation products layers deposited on carbon fibers during electrolysis of pentabromophenol and 2,4,6-tribromophenol, respectively, was estimated from atomic force microscopy analysis and confirmed by scanning electron microscopy with energy-dispersive X-ray spectroscopy measurements. PMID- 29254576 TI - Rapid determination of immunosuppressive drug concentrations in whole blood by coated blade spray-tandem mass spectrometry (CBS-MS/MS). AB - Coated Blade Spray (CBS) is a technology that efficiently integrates sample preparation and direct coupling to mass spectrometry (MS) on a single device. In this article, we present CBS-tandem mass spectrometry (CBS-MS/MS) as a novel tool for the rapid and simultaneous determination of four commonly used immunosuppressive drugs (ISDs) in whole blood: tacrolimus (TAC) and cyclosporine A (CycA), which are calcineurin inhibitors; and sirolimus (SIR) and everolimus (EVR), which are both mTOR (mechanistic target of rapamycin) inhibitors. Given that CBS extracts via free concentration, analytes that are largely bound to plasma proteins or red blood cells provide considerably lower extraction recovery rates. Therefore, we defy the solventless philosophy of SPME-based techniques, like CBS, by performing the analyte-enrichment step via direct immersion in a solvent-modified matrix. The assay was linear within the evaluated range of concentrations (between 1 and 100 ng/mL for EVR/SIR/TAC and 10-1000 ng/mL for CycA), and the limits of quantification were determined to be 10 ng/mL for CycA and 1 ng/mL for EVR/SIR/TAC. Good accuracy (87-119%) and linearity (r2 >= 0.99) were attained over the evaluated range for all ISDs. Interassay imprecision (CV) determined from incurred sample reanalysis was <=10% for all ISDs. Our method was validated using LiquichekTM whole blood immunosuppressant quality control (QC) standards purchased from Bio-Rad. Concentrations determined by CBS-MS/MS were inside the range specified by Bio-Rad and within 15% of the expected mean value for all ISDs at all QC levels. Furthermore, the effect of different hematocrit levels (20, 45, and 70%) in the entire calibration range was carefully studied. No statistical differences (RSD <= 7%) in the calibration curve slopes of ISDs in blood were observed. CBS offers a simpler workflow than that of traditional methods; it eliminates the need for chromatographic separation and provides a clean extract that allows for long-term MS instrumental operation with minimal maintenance. Additionally, because CBS integrates all analytical steps into one device, it eliminates the risk of instrumental carry-over and can be used as a low-cost disposable device for sample preparation and analysis. Fully-automated sample preparation simplifies the method and allows for total analysis times as short as 3 min with turn-around times of less than 90 min. PMID- 29254577 TI - An integrated method for simultaneously determining 10 classes of per- and polyfluoroalkyl substances in one drop of human serum. AB - Per- and polyfluoroalkyl substances (PFASs) represent a group of synthetic chemicals, and they have quite different physicochemical properties, which result in difficulties of their simultaneous determination in a single injection. A sensitive, reliable, and fully automated method was developed for simultaneously detecting 10 classes of PFASs (total of 43) in human serum using online Turboflow SPE-UHPLC-MS/MS. This method provided high linearity of matrix-matched calibration standards (R > 0.99), excellent method limits of detection (MLODs) (0.013-0.089 ng mL-1), satisfactory matrix spiked recoveries (84.3-109%) and relative standard deviations (RSDs) (intra-day RSDs: 1.3-12.6%, inter-day RSDs: 1.7-13.8%, inter-week RSDs: 1.8-13.5%, inter-month RSDs: 3.1-12.4%), short analysis time (19 min per sample) and small sample amount requirement (25 MUL), which were suitable for large-scale epidemiologic studies. Moreover, the method provided the feasibility of real-time monitoring for the degradation kinetics of PFASs precursors both in vitro and in vivo. The quality of the present method was further verified by repetitive analysis of a standard reference material (SRM 1957), with the deviations of the targeted PFAS concentrations ranging from 1.9% to 14.2% (n = 5) between the detected and reference values. The present study also determined values for several PFASs in SRM 1957 other than those on the certificate, for the first time, such as N-EtFOSA, 6:2 Cl-PFESA, and PFBA. Finally, the established method was applied to detect PFASs in serum samples of 15 ordinary people and 15 occupational workers, and 6:2 FTSA was found as the dominant precursor. PMID- 29254578 TI - Development of a modified QuEChERS method for multi-class pesticide analysis in human hair by GC-MS and UPLC-MS/MS. AB - The present study assessed the suitability of using QuEChERS procedure for the simultaneous determination and quantification of 37 multi-class pesticides in human hair. Matrix co-eluted material had a large influence on instrumental response sensitivity. Purification was needed although dSPE cleanup sorbent selection critically influenced analyte recovery. Optimized protocol using Z-Sep+ sorbent successfully achieved recovery of 28 pesticides with high sensitivity, precision, and accuracy. Limits of detection ranged from 0.2 to 86.6 pg mg-1 and from 0.5 to 6.3 pg mg-1 for GC and UPLC amenable substances respectively. Pyrethroid pesticides were the most influenced by matrix effects which explained the higher limits of quantification retained for these substances. On the contrary, high sensitivity was achieved for UPLC amenable substances (LOD < 1 pg mg-1 for atrazine, deisopropylatrazine, desethylatrazine, and imidacloprid). Suitability for monitoring pesticide exposure was assessed by application of the proposed protocol to samples collected on the field. Hairs of the volunteers were found positive to 8 pesticides with every sample containing at least one residue. Among these pesticides, only 3 were reported as used in local vegetable production, which suggested other sources of exposure. The developed method offers a sensitive, robust, and accessible tool for biomonitoring of human exposure. PMID- 29254580 TI - Over time, differences in survival and favorable neurologic outcomes between conventional and compression-only cardiopulmonary resuscitation have been gradually reduced in pediatric out-of-hospital cardiac arrest. PMID- 29254579 TI - Rapid differentiation of Ganoderma species by direct ionization mass spectrometry. AB - In this study, direct ionization mass spectrometry (DI-MS) has been developed for rapid differentiation of Ganoderma (known as Lingzhi in Chinese), a very popular and valuable herbal medicine. Characteristic mass spectra can be generated by DI MS directly from the raw herbal medicines with the application of a high voltage and solvents. Rapid differentiation of the Ganoderma species that are officially stated in the Chinese pharmacopoeia from easily confused Ganoderma species could be achieved based on this method, as the acquired DI-MS spectra showed that ganoderic acids, the major active components of Ganoderma, could be found only in the official Ganoderma species but not in the confused Ganoderma species. In addition, classification of wild and cultivated Ganoderma and potential differentiation of Ganoderma from different geographical locations could be accomplished based on principal component analysis (PCA) or hierarchical clustering analysis (HCA). The method is rapid, simple and reproducible, and can be further extended to analysis of other herbal medicines. PMID- 29254582 TI - The impact of "Brexit" on nursing and health services: Editorial debate. PMID- 29254581 TI - Reply to: Point-of-care ultrasound during advanced cardiopulmonary resuscitation: Rule of art have to be respected! PMID- 29254583 TI - Empty promises. What will Brexit really mean for nurses and the British National Health Service? PMID- 29254584 TI - Brexit: Let democratic countries choose the health service they want. PMID- 29254585 TI - In vivo dose verification method in catheter based high dose rate brachytherapy. AB - In vivo dosimetry is a powerful tool for dose verification in radiotherapy. Its application in high dose rate (HDR) brachytherapy is usually limited to the estimation of gross errors, due to inability of the dosimetry system/ method to record non-uniform dose distribution in steep dose gradient fields close to the radioactive source. In vivo dose verification in interstitial catheter based HDR brachytherapy is crucial since the treatment is performed inserting radioactive source at the certain positions within the catheters that are pre-implanted into the tumour. We propose in vivo dose verification method for this type of brachytherapy treatment which is based on the comparison between experimentally measured and theoretical dose values calculated at well-defined locations corresponding dosemeter positions in the catheter. Dose measurements were performed using TLD 100-H rods (6 mm long, 1 mm diameter) inserted in a certain sequences into additionally pre-implanted dosimetry catheter. The adjustment of dosemeter positioning in the catheter was performed using reconstructed CT scans of patient with pre-implanted catheters. Doses to three Head&Neck and one Breast cancer patient have been measured during several randomly selected treatment fractions. It was found that the average experimental dose error varied from 4.02% to 12.93% during independent in vivo dosimetry control measurements for selected Head&Neck cancer patients and from 7.17% to 8.63% - for Breast cancer patient. Average experimental dose error was below the AAPM recommended margin of 20% and did not exceed the measurement uncertainty of 17.87% estimated for this type of dosemeters. Tendency of slightly increasing average dose error was observed in every following treatment fraction of the same patient. It was linked to the changes of theoretically estimated dosemeter positions due to the possible patient's organ movement between different treatment fractions, since catheter reconstruction was performed for the first treatment fraction only. These findings indicate potential for further average dose error reduction in catheter based brachytherapy by at least 2-3% in the case that catheter locations will be adjusted before each following treatment fraction, however it requires more detailed investigation. PMID- 29254586 TI - The robustness of dual isocenter VMAT radiation therapy for bilateral lymph node positive breast cancer. AB - PURPOSE: To investigate the use of dual isocenters for VMAT planning in patients with lymph node positive synchronous bilateral breast cancer (BBC) compared to a single isocenter option. METHODS: Treatment plans of 11 patients with lymph node positive BBC were retrospectively analyzed using two different VMAT planning techniques: dual-isocenter split-arc VMAT plans (Iso2) were compared with mono isocenter VMAT plans (Iso1). For Iso2 plans, PTV dose was investigated after introducing +/-2 and +/-5 mm couch shift errors between the two isocenters in the lateral, longitudinal and vertical direction. RESULTS: For both techniques the planning aims for PTV coverage and OARs were met. The mean dose for the bilateral lungs and heart was reduced from 11.3 Gy and 3.8 Gy to 10.9 Gy (p < .05) and 3.6 Gy (p < .05), respectively, for Iso2 plans when compared to Iso1 plans. Positive statistically significant correlation (rho = 0.76, p = .006) was found between PTV volume and D2ccPTV for Iso1 plans. No clinically significant change was seen in the D98CTV or D2ccPTV after the 2 and 5 mm errors were introduced between isocenters for Iso2 plans. CONCLUSIONS: The split arc method was shown to be a feasible treatment technique in the case of synchronous BBC for both mono and dual isocenter techniques. The dose parameters were slightly favoring dual isocenter option instead of mono-isocenter. The dual-isocenter method was shown to be a robust treatment option in the presence of <=5 mm errors in the shifts between the two isocenters. PMID- 29254587 TI - Dosimetric characterization of carbon fiber stabilization devices for post operative particle therapy. AB - PURPOSE: The aim of this study was to evaluate the dosimetric impact caused by recently introduced carbon fiber reinforced polyetheretherketone (CF/PEEK) stabilization devices, in comparison with conventional titanium (Ti) implants, for post-operative particle therapy (PT). METHODS: As a first step, protons and carbon ions Spread-Out Bragg Peaks (SOBPs) were delivered to CF/PEEK and Ti screws. Transversal dose profiles were acquired with EBT3 films to evaluate beam perturbation. Effects on image quality and reconstruction artifacts were then investigated. CT scans of CF/PEEK and Ti implants were acquired according to our clinical protocol and Hounsfield Unit (HU) mean values were evaluated in three regions of interest. Implants and artifacts were then contoured in the sample CT scans, together with a target volume to simulate a spine tumor. Dose calculation accuracy was assessed by comparing optimized dose distributions with Monte Carlo simulations. In the end, the treatment plans of nine real patients (seven with CF/PEEK and two with Ti stabilization devices) were retrospectively analyzed to evaluate the dosimetric impact potentially occurring if improper management of the spine implant was carried out. RESULTS: As expected, CF/PEEK screw caused a very slight beam perturbation in comparison with Ti ones, leading to a lower degree of dose degradation in case of contouring and/or set-up uncertainties. Furthermore, CF/PEEK devices did not determine appreciable HU artifacts on CT images thus improving image quality and, as a final result, dose calculation accuracy. CONCLUSIONS: CF/PEEK spinal fixation devices resulted dosimetrically more suitable than commonly-used Ti implants for post-operative PT. PMID- 29254588 TI - In vivo dosimetry with MOSFETs and GAFCHROMIC films during electron IORT for Accelerated Partial Breast Irradiation. AB - PURPOSE: The purpose of this study was to compare the delivered dose to the expected intraoperative radiation therapy (IORT) dose with in vivo dosimetry. For IORT using electrons in accelerated partial breast irradiation, this is especially relevant since a high dose is delivered in a single fraction. METHODS: For 47 of breast cancer patients, in vivo dosimetry was performed with MOSFETs and/or GAFCHROMIC EBT2 films. A total dose of 23.33 Gy at dmax was given directly after completing the lumpectomy procedure with electron beams generated with an IORT dedicated mobile accelerator. A protection disk was used to shield the thoracic wall. RESULTS: The results of in vivo MOSFET dosimetry for 27 patients and GAFROMIC film dosimetry for 20 patients were analysed. The entry dose for the breast tissue, measured with MOSFETs, (mean value 22.3 Gy, SD 3.4%) agreed within 1.7% with the expected dose (mean value 21.9 Gy). The dose in breast tissue, measured with GAFCHROMIC films (mean value 23.50 Gy) was on average within 0.7% (SD = 3.7%, range -5.5% to 5.6%) of the prescribed dose of 23.33 Gy. CONCLUSIONS: The dose measured with MOSFETs and GAFROMIC EBT2 films agreed well with the expected dose. For both methods, the dose to the thoracic wall, lungs and heart for left sided patents was lower than 2.5 Gy even when 12 MeV was applied. The positioning time of GAFCHROMIC films is negligible and based on our results we recommend its use as a standard tool for patient quality assurance during breast cancer IORT. PMID- 29254590 TI - Compass model-based quality assurance for stereotactic VMAT treatment plans. AB - PURPOSE: To use Compass as a model-based quality assurance (QA) tool for stereotactic body radiation therapy (SBRT) and stereotactic radiation therapy (SRT) volumetric modulated arc therapy (VMAT) treatment plans calculated with Eclipse treatment planning system (TPS). MATERIALS AND METHODS: Twenty clinical stereotactic VMAT SBRT and SRT treatment plans were blindly selected for evaluation. Those plans included four different treatment sites: prostate, brain, lung and body. The plans were evaluated against dose-volume histogram (DVH) parameters and 2D and 3D gamma analysis. The dose calculated with Eclipse treatment planning system (TPS) was compared to Compass calculated dose (CCD) and Compass reconstructed dose (CRD). RESULTS: The maximum differences in mean dose of planning target volume (PTV) were 2.7 +/- 1.0% between AAA and Acuros XB calculation algorithm TPS dose, -7.6 +/- 3.5% between Eclipse TPS dose and CCD dose and -5.9 +/- 3.7% between Eclipse TPS dose and CRD dose for both Eclipse calculation algorithms, respectively. 2D gamma analysis was not able to identify all the cases that 3D gamma analysis specified for further verification. CONCLUSIONS: Compass is suitable for QA of SBRT and SRT treatment plans. However, the QA process should include wide set of DVH-based dose parameters and 3D gamma analysis should be the preferred method when performing clinical patient QA. The results suggest that the Compass should not be used for smaller field sizes than 3 * 3 cm2 or the beam model should be adjusted separately for both small (FS <= 3 cm) and large (FS > 3 cm) field sizes. PMID- 29254589 TI - Implementation and application of a Monte Carlo model for an in vivo micro computed tomography system. AB - Micro computed tomography (uCT) scanners are used to create high-resolution images and to quantify properties of the scanned objects. While modern uCT scanners benefit from the cone beam geometry, they are compromised by scatter radiation. This work aims to develop a Monte Carlo (MC) model of a uCT scanner in order to characterize the scatter radiation in the detector plane. The EGS++ framework with the MC code EGSnrc was used to simulate the particle transport through the main components of the XtremeCT (SCANCO Medical AG, Switzerland). The developed MC model was based on specific information of the manufacturer and was validated against measurements. The primary and the scatter radiation were analyzed and by implementing a dedicated tracing method, the scatter radiation was subdivided into different scatter components. The comparisons of measured and simulated transmission values for different absorber and filter combinations result in a mean difference of 0.2% +/- 1.4%, with a maximal local difference of 3.4%. The reconstructed image of the phantom based on measurements agrees well with the image reconstructed using the MC model. The local contribution of scattered radiation is up to 10% of the total radiation in the detector plane and most of the scattered particles result from interactions in the scanned object. The MC simulations show that scatter radiation contains information about the structure of the object. In conclusion, a MC model for a uCT scanner was successfully validated and applied to analyze the characteristics of the scatter radiation for a uCT scanner. PMID- 29254591 TI - A review of the recommendations governing quality assurance of ultrasound systems used for guidance in prostate brachytherapy. AB - Ultrasound guided brachytherapy for the treatment of prostate cancer has become a routine treatment option, due to many benefits including patient recovery and dose localisation [1]; however it is not clear whether the standards which govern the image quality for these systems are adequate. Upon review of the recommended standards for ultrasound systems used in prostate brachytherapy procedures, the recommended tests do not appear to be specific to the clinical application of ultrasound guided prostate brachytherapy. Rather they are generic and similar to those recommended for other clinical applications such as general abdominal scanning [2]. Furthermore, there is growing evidence that these tests should be specific to the clinical application [3,4] in order to gain meaningful data about the performance of the system for the application, and also to detect clinically relevant changes in quality control results. An additional problem is that there are no clinically relevant test phantom recommended for the quality assurance of ultrasound systems used in prostate brachytherapy. The image quality for this application of ultrasound needs to be monitored to ensure consistent levels of confidence in the procedure. This paper reviews the currently recommended test guidelines and test phantoms for ultrasound systems used in prostate brachytherapy from the different standard bodies and professional organisations. A critical analysis of those tests which are most reflective of the imaging and guidance tasks undertaken in an ultrasound guided prostate brachytherapy procedure will also be presented to inform the design of a TRUS quality assurance protocol. PMID- 29254592 TI - Comparison of different treatment planning optimization methods for vaginal HDR brachytherapy with multichannel applicators: A reduction of the high doses to the vaginal mucosa is possible. AB - PURPOSE: A direct planning approach with multi-channel vaginal cylinders (MVCs) used for HDR brachytherapy of vaginal cancers is particularly challenging. Purpose of this study was to compare the dosimetric performances of different forward and inverse methods used for the optimization of MVC-based vaginal treatments for endometrial cancer, with a particular attention to the definition of strategies useful to limit the high doses to the vaginal mucosa. METHODS: Twelve postoperative vaginal HDR brachytherapy treatments performed with MVCs were considered. Plans were retrospectively optimized with three different methods: Dose Point Optimization followed by Graphical Optimization (DPO + GrO), Inverse Planning Simulated Annealing with two different class solutions as starting conditions (surflPSA and homogIPSA) and Hybrid Inverse Planning Optimization (HIPO). Several dosimetric parameters related to target coverage, hot spot extensions and sparing of organs at risk were analyzed to evaluate the quality of the achieved treatment plans. Dose homogeneity index (DHI), conformal index (COIN) and a further parameter quantifying the proportion of the central catheter loading with respect to the overall loading (i.e., the central catheter loading index: CCLI) were also quantified. RESULTS: The achieved PTV coverage parameters were highly correlated with each other but uncorrelated with the hot spot quantifiers. HomogIPSA and HIPO achieved higher DHIs and CCLIs and lower volumes of high doses than DPO + GrO and surflPSA. CONCLUSIONS: Within the investigated optimization methods, HIPO and homoglPSA showed the highest dose homogeneity to the target. In particular, homogIPSA resulted also the most effective in reducing hot spots to the vaginal mucosa. PMID- 29254593 TI - Determination of small field synthetic single-crystal diamond detector correction factors for CyberKnife, Leksell Gamma Knife Perfexion and linear accelerator. AB - PURPOSE: The aim of this study was to determine small field correction factors for a synthetic single-crystal diamond detector (PTW microDiamond) for routine use in clinical dosimetric measurements. MATERIALS AND METHODS: Correction factors following small field Alfonso formalism were calculated by comparison of PTW microDiamond measured ratio MQclinfclin/MQmsrfmsr with Monte Carlo (MC) based field output factors OmegaQclin,Qmsrfclin,fmsr determined using Dosimetry Diode E or with MC simulation itself. Diode measurements were used for the CyberKnife and Varian Clinac 2100C/D linear accelerator. PTW microDiamond correction factors for Leksell Gamma Knife (LGK) were derived using MC simulated reference values from the manufacturer. RESULTS: PTW microDiamond correction factors for CyberKnife field sizes 25-5 mm were mostly smaller than 1% (except for 2.9% for 5 mm Iris field and 1.4% for 7.5 mm fixed cone field). The correction of 0.1% and 2.0% for 8 mm and 4 mm collimators, respectively, needed to be applied to PTW microDiamond measurements for LGK Perfexion. Finally, PTW microDiamond MQclinfclin/MQmsrfmsr for the linear accelerator varied from MC corrected Dosimetry Diode data by less than 0.5% (except for 1 * 1 cm2 field size with 1.3% deviation). CONCLUSIONS: Regarding low resulting correction factor values, the PTW microDiamond detector may be considered an almost ideal tool for relative small field dosimetry in a large variety of stereotactic and radiosurgery treatment devices. PMID- 29254594 TI - A radiobiological Markov simulation tool for aiding decision making in proton therapy referral. AB - PURPOSE: Proton therapy can be a highly effective strategy for the treatment of tumours. However, compared with X-ray therapy it is more expensive and has limited availability. In addition, it is not always clear whether it will benefit an individual patient more than a course of traditional X-ray therapy. Basing a treatment decision on outcomes of clinical trials can be difficult due to a shortage of data. Predictive modelling studies are becoming an attractive alternative to supplement clinical decisions. The aim of the current work is to present a Markov framework that compares clinical outcomes for proton and X-ray therapy. METHODS: A Markov model has been developed which estimates the radiobiological effect of a given treatment plan. This radiobiological effect is estimated using the tumour control probability (TCP), normal tissue complication probability (NTCP) and second primary cancer induction probability (SPCIP). These metrics are used as transition probabilities in the Markov chain. The clinical outcome is quantified by the quality adjusted life expectancy. To demonstrate functionality, the model was applied to a 6-year-old patient presenting with skull base chordoma. RESULTS: The model was successfully developed to compare clinical outcomes for proton and X-ray treatment plans. For the example patient considered, it was predicted that proton therapy would offer a significant advantage compared with volumetric modulated arc therapy in terms of survival and mitigating injuries. CONCLUSIONS: The functionality of the model was demonstrated using the example patient. The proposed Markov method may be a useful tool for deciding on a treatment strategy for individual patients. PMID- 29254596 TI - Sclerodermatous Chronic Graft-versus-Host Disease Treated With Imatinib: A Dermatological Perspective. AB - INTRODUCTION: Chronic graft-versus-host disease (cGVHD) is the most important cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Sclerodermatous cGVHD is usually steroid refractory and remains a therapeutic challenge. Activating antibodies against the PDGFR have been reported in patients with sclerodermatous cGVHD. These antibodies induce PDGFR phosphorylation and lead to fibrosis. There is increasing evidence of successful treatment of sclerodermatous cGVHD with imatinib, a tyrosine kinase inhibitor. OBJECTIVE: To evaluate the response of cutaneous sclerodermatous cGVHD to imatinib. MATERIALS AND METHODS: Retrospective study of 18 patients with sclerodermatous cGVHD refractory to immunosuppressants treated with imatinib in a single center. Evaluation of treatment response was performed by clinicians' assessment and patients' subjective response at one, 3, 6, 9, 12 and 18 months after initiation of imatinib. Response was assessed as complete, partial, significant, no change or progression. Tapper off steroids was complete, partial or not possible. RESULTS: In our series, 4 (22%) patients achieved complete response, 9 (50%) patients partial response, 2 (11%) patients significant response, 2 (11%) patients had no change and one (6%) patient progressive disease at last follow-up. Mean time from initiation of imatinib to any degree of response was 2,75 months (range 1-9 months). CONCLUSIONS: This study provides further evidence of the role of imatinib for the treatment of steroid refractory sclerodermatous cGVHD. PMID- 29254597 TI - Hepatic safety of maraviroc in HIV-1-infected patients with hepatitis C and/or B co-infection. PMID- 29254598 TI - Quality and Readability of English-Language Internet Information for Voice Disorders. AB - PURPOSE: The purpose of this study is to evaluate the readability and quality of English-language Internet information related to vocal hygiene, vocal health, and prevention of voice disorders. This study extends recent work because it evaluates readability, content quality, and website origin across broader search criteria than previous studies evaluating online voice material. METHOD: Eighty five websites were aggregated using five different country-specific search engines. Websites were then analyzed using quality and readability assessments. The entire web page was evaluated; however, no information or links beyond the first page was reviewed. Statistical calculations were employed to examine website ratings, differences between website origin and quality and readability scores, and correlations between readability instruments. RESULT: Websites exhibited acceptable quality as measured by the DISCERN. However, only one website obtained the Health On the Net certification. Significant differences in quality were found among website origin, with government websites receiving higher quality ratings. Approximate educational levels required to comprehend information on the websites ranged from 8 to 9 years of education. Significant differences were found between website origin and readability measures with higher levels of education required to understand information on websites of nonprofit organizations. CONCLUSION: Current vocal hygiene, vocal health, and prevention of voice disorders websites were found to exhibit acceptable levels of quality and readability. However, highly rated Internet information related to voice care should be made more accessible to voice clients through Health On the Net certification. PMID- 29254595 TI - Polyclonal origin of parathyroid tumors is common and is associated with multiple gland disease in primary hyperparathyroidism. AB - BACKGROUND: Parathyroid tumors are mostly considered monoclonal neoplasms, the rationale for focused parathyroidectomy in primary hyperparathyroidism. We reported that flow sorting parathyroid tumor cells and methylation-sensitive polymerase chain reaction (me-PCR) of polymorphic human androgen receptor gene and phosphoglycerate kinase gene alleles in deoxyribonucleic acid reveals that <=35% of parathyroid tumors are polyclonal. We sought to confirm these findings and assess for clinical relevance. METHODS: Parathyroid tumors from 286 female primary hyperparathyroidism patients were analyzed for clonal status. Tumor clonal status was compared with clinical variables and operative findings. Statistical analysis was performed and significance was established at P < .05. RESULTS: In the study, 176 (62%) patients were informative for human androgen receptor gene and/or phosphoglycerate kinase gene. Assignment of clonal status was made in 119 (68%) tumors, of which 64 (54%) were monoclonal and 55 (46%) were polyclonal. Comparison of tumor clonal status to clinical variables in patients with complete operative data (N = 82) showed that while clinical features were the same between tumor types, patients with polyclonal tumors more often had multiple gland disease (risk ratio 4.066, confidence interval, 1.016-16.26; P = .039) potentially missed at unilateral neck exploration. CONCLUSION: This work confirms that primary hyperparathyroidism is often the result of polyclonal tumors and that parathyroid tumor clonal status may be associated with multiple gland disease. PMID- 29254599 TI - Minimal clinically important differences in Rowe and Western Ontario Shoulder Instability Index scores after arthroscopic repair of anterior shoulder instability. AB - BACKGROUND: The minimal clinically important difference (MCID) is the threshold value for a change that would be considered meaningful by the patient. The purpose of this study was to determine the MCIDs for the Rowe score and the Western Ontario Shoulder Instability Index (WOSI) score after arthroscopic repair of anterior shoulder instability. METHODS: The study enrolled 198 patients who underwent an arthroscopic stabilization procedure for anterior shoulder instability. Patients were assigned to no change and minimal change groups by a 15-item questionnaire at the 1-year postoperative visit. The Rowe and WOSI scores were assessed preoperatively and at a 1-year postoperative follow-up. The MCID was calculated using an anchor-based method and a distribution-based method. RESULTS: There were 9 patients in the no change group and 26 patients in the minimal change group. The MCID for the Rowe score was 9.7 according to the anchor based method. By the anchor-based method, the authors could not calculate MCID for the WOSI score because of insignificant difference of the mean score changes between the no change and minimal change groups. By the distribution-based method, MCIDs for the Rowe and the WOSI scores were 5.6 and 151.9 with the standard deviation-based estimate and 2.2 and 60.7 with the effect size-based estimate, respectively. CONCLUSIONS: To assess the effectiveness of an arthroscopic stabilization procedure for anterior shoulder instability using the Rowe score, a difference of at least 9.7 in the score is clinically relevant. To compare clinical outcomes between different modalities, we should consider not only statistically significant differences but also the MCID. PMID- 29254600 TI - Introduction. PMID- 29254601 TI - Bilateral Breast Cancer After Multimodality Treatment: A Report of Clinical Outcomes in an Asian Population. AB - BACKGROUND: Bilateral breast cancer (BBC) is an uncommon presentation. The characteristics and outcomes of synchronous and metachronous BBC were compared within an Indian cohort. PATIENTS AND METHODS: This was a retrospective audit of 193 BBC patients treated at a tertiary hospital in India over a period of 10 years from January 2004 to December 2014. The demographic, tumor and treatment characteristics were compared between synchronous (n = 131 patients) and metachronous tumors (n = 62 patients) using descriptive analysis. The survival outcomes were assessed using Kaplan-Meier survival curves and compared using the log rank test. Univariate and multivariate analysis was done using a Cox proportional hazards model to assess the effect of the prognostic factors on survival. RESULTS: The mean age of presentation in synchronous BBC (SBBC) and metachronous BBC (MBBC) was 55 years (SD, 12.5) and 51 years (SD, 9.5), respectively. The median time to contralateral presentation in MBBC was 3.8 years. Mean tumor size was larger in SBBC (P = .01). Breast Cancer gene mutation was positive in 13 of 38 evaluated patients (of whom 12 had MBBC). The concordance rates for the estrogen receptor (ER) and progesterone receptor negativity and triple-negative receptor status were higher in MBBC compared with SBBC (P < .001). Grade III tumor was more frequently seen in MBBC (P = .03). The median follow-up of the entire cohort was 42 months (range, 30-60 months): 45 months for SBBC and 35 months for MBBC. The 3-year rates of overall survival (OS), disease-free survival (DFS), and locoregional control (LRC) for SBBC and MBBC was 88% and 90%, 74% and 64% and 90% and 84%, respectively. There was no difference in overall OS, DFS, and LRC between SBBC and MBBC. CONCLUSION: BBC is an uncommon presentation. Synchronous presentation was more common. Metachronous tumors differ from synchronous with higher Grade of presentation and less expression of ER. There was no difference in outcome between patients with synchronous and metachronous tumors. PMID- 29254603 TI - Reduction in Total Radiation Exposure Using X-ray Image Guidance Illustrated in a Patient Receiving Pituitary Radiotherapy. PMID- 29254604 TI - Comments on "Novel fluorene-based supramolecular sensor for selective detection of amoxicillin in water and blood". PMID- 29254602 TI - The LepR-mediated leptin transport across brain barriers controls food reward. AB - OBJECTIVE: Leptin is a key hormone in the control of appetite and body weight. Predominantly produced by white adipose tissue, it acts on the brain to inhibit homeostatic feeding and food reward. Leptin has free access to circumventricular organs, such as the median eminence, but entry into other brain centers is restricted by the blood-brain and blood-CSF barriers. So far, it is unknown for which of its central effects leptin has to penetrate brain barriers. In addition, the mechanisms mediating the transport across barriers are unclear although high expression in brain barriers suggests an important role of the leptin receptor (LepR). METHODS: We selectively deleted LepR in brain endothelial and epithelial cells of mice (LepRbeKO). The expression of LepR in fenestrated vessels of the periphery and the median eminence as well as in tanycytes was not affected. RESULTS: Perfusion studies showed that leptin uptake by the brain depended on LepR in brain barriers. When being fed with a rewarding high-fat diet LepRbeKO mice gained more body weight than controls. The aggravated obesity of LepRbeKO mice was due to hyperphagia and a higher sensitivity to food reward. CONCLUSIONS: The LepR-mediated transport of leptin across brain barriers in endothelial cells lining microvessels and in epithelial cells of the choroid plexus controls food reward but is apparently not involved in homeostatic control of feeding. PMID- 29254605 TI - Direct Comparison of the Precision of the New Hologic Horizon Model With the Old Discovery Model. AB - Previous publications suggested that the precision of the new Hologic Horizon densitometer might be better than that of the previous Discovery model, but these observations were confounded by not using the same participants and technologists on both densitometers. We sought to study this issue methodically by measuring in vivo precision in both densitometers using the same patients and technologists. Precision studies for the Horizon and Discovery models were done by acquiring spine, hip, and forearm bone mineral density twice on 30 participants. The set of 4 scans on each participant (2 on the Discovery, 2 on the Horizon) was acquired by the same technologist using the same scanning mode. The pairs of data were used to calculate the least significant change according to the International Society for Clinical Densitometry guidelines. The significance of the difference between least significant changes was assessed using a Wilcoxon signed-rank test of the difference between the mean square error of the absolute value of the differences between paired measurements on the Discovery (Delta-Discovery) and the mean square error of the absolute value of the differences between paired measurements on the Horizon (Delta-Horizon). At virtually all anatomic sites, there was a nonsignificant trend for the precision to be better for the Horizon than for the Discovery. As more vertebrae were excluded from analysis, the precision deteriorated on both densitometers. The precision between densitometers was almost identical when reporting only 1 vertebral body. (1) There was a nonsignificant trend for greater precision on the new Hologic Horizon compared with the older Discovery model. (2) The difference in precision of the spine bone mineral density between the Horizon and the Discovery models decreases as fewer vertebrae are included. (3) These findings are substantially similar to previously published results which had not controlled as well for confounding from using different subjects and technologists. PMID- 29254607 TI - Commentary on: Restoration of motor function after operative reconstruction of the acutely transected spinal cord in the canine model. PMID- 29254606 TI - An academic career in global surgery: a position paper from the Society of University Surgeons Committee on Academic Global Surgery. AB - In recent years, as the high burden of surgical disease and poor access to surgical care in low- and middle-income countries have gained recognition as major public health problems, interest in global health has surged among surgical trainees and faculty. Traditionally, clinical volunteerism was at the forefront of the high-income country response to the significant burden of surgical disease in low- and middle-income countries. However, sustainable strategies for providing surgical care in low- and middle-income countries increasingly depend on bilateral clinical, research, and education collaborations to ensure effective resource allocation and contextual relevance. Academic global surgery creates avenues for interested surgeons to combine scholarship and education with their clinical global surgery passions through incorporation of basic/translational, education, clinical outcomes, or health services research with global surgery. Training in global health, either within residency or through advanced degrees, can provide the necessary skills to develop and sustain such initiatives. We further propose that creating cross-continental, bidirectional collaborations can maximize funding opportunities. Academic institutions are uniquely positioned to lead longitudinal and, importantly, sustainable global surgery efforts. However, for the individual global surgeon, the career path forward may be unclear. This paper reviews the development of academic global surgery, delineates the framework and factors critical to training global surgeons, and proposes models for establishing an academic career in this field. Overall, with determination, the academic global surgeon will not only carve out a niche of expertise but will define this critical field for future generations. PMID- 29254608 TI - Resource conservation approached with an appropriate collection and upgrade remanufacturing for used electronic products. AB - This comparative research represents an example for a better conservation of resources by reducing the amount of waste (kg) and providing it more value under the umbrella of remanufacturing. The three discussed cases will expose three issues already addressed separately in the literature. The generation of waste electrical and electronic equipment (WEEE) interacts with the environmental depletion. In this article, we gave the examples of addressed issues under the concept of remanufacturing. Online collection opportunity eliminating classical collection, a business to business (B2B) implementation for remanufactured servers and medical devices. The material reuse (recycling), component sustainability, reuse (part harvesting), product reuse (after repair/remanufacturing) indicates the recovery potential using remanufacturing tool for a better conservation of resources adding more value to the products. Our findings can provide an overview of new system organization for the general collection, market potential and the technological advantages using remanufacturing instead of recycling of WEEE or used electrical and electronic equipment. PMID- 29254609 TI - Bacteriuria is not associated with surgical site infection in patients undergoing cardiovascular surgery: Methodologic issues. PMID- 29254610 TI - Does nurse job satisfaction influence adherence to the central line insertion checklist and central line-associated bloodstream infections in the Veterans Health Administration? AB - Nurses satisfied with their jobs report less job stress, more effective nurse physician collaboration, and higher patient satisfaction scores. It is unknown if job satisfaction influences adherence to best practices or patient outcomes. This secondary data analysis investigated the relationship between job satisfaction, adherence to the central line insertion checklist, and central line-associated bloodstream infections (CLABSIs). Results showed a decreased risk of CLABSI with higher job satisfaction, on average. No relationship was observed with checklist adherence. PMID- 29254611 TI - Minimum alcohol pricing in Scotland. PMID- 29254612 TI - Microbiome analysis: ready for clinical use? PMID- 29254613 TI - Making optical biopsy a clinical reality in colonoscopy. PMID- 29254617 TI - Too much medicine: overdiagnosis and overtreatment of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is now the most common cause of liver disease. This remarkable rise in prevalence over the past 20 years is largely through the recognition of fatty liver in the absence of excessive alcohol consumption as a disease. The natural history of NAFLD is incompletely understood, and although a small proportion of individuals with NAFLD will develop complications of liver disease, most will not. This raises the prospect of widespread overdiagnosis of NAFLD. Clinical practice guidelines from the European specialist societies representing hepatology, endocrinology, and obesity endorse screening for NAFLD in at-risk groups, and this further increases the likelihood of overdiagnosis and consequent overtreatment through false-positive testing. Predictable outcomes of overdiagnosis include physical harms through investigation and treatment, and psychosocial harms through disease labelling. Prospective studies are required to better understand both the benefits and risks associated with an early diagnosis of NAFLD. PMID- 29254614 TI - What drives the hypoalgesic effect of neurostimulation? PMID- 29254618 TI - The painful reality of end-stage liver disease in NASH. PMID- 29254619 TI - Correction to Lancet Gastroenterol Hepatol 2017; 2: 877-89. PMID- 29254620 TI - Replay to "About European guidelines for heart failure 2016". PMID- 29254621 TI - Use of echo-contrast in the diagnosis of coronary fistula rupture. PMID- 29254622 TI - Paroxysmal sympathetic hyperactivity: An entity to keep in mind. AB - Paroxysmal sympathetic hyperactivity (PSH) is a potentially life-threatening neurological emergency secondary to multiple acute acquired brain injuries. It is clinically characterized by the cyclic and simultaneous appearance of signs and symptoms secondary to exacerbated sympathetic discharge. The diagnosis is based on the clinical findings, and high alert rates are required. No widely available and validated homogeneous diagnostic criteria have been established to date. There have been recent consensus attempts to shed light on this obscure phenomenon. Its physiopathology is complex and has not been fully clarified. However, the excitation-inhibition model is the theory that best explains the different aspects of this condition, including the response to treatment with the available drugs. The key therapeutic references are the early recognition of the disorder, avoiding secondary injuries and the triggering of paroxysms. Once sympathetic crises occur, they must peremptorily aborted and prevented. of the later the syndrome is recognized, the poorer the patient outcome. PMID- 29254623 TI - Posterolateral corner injuries: Epidemiology, anatomy, biomechanics and diagnosis. AB - Increased internal and external rotational laxity of the knee may result from a wide range of pathologies in or around the knee. However, the principal cause of increased external rotational laxity is damage to the posterolateral corner (PLC). The aim of the review is to discuss the epidemiology, anatomy, biomechanics and diagnosis of PLC injuries. PMID- 29254624 TI - Pedestrian traffic injury in Victoria, Australia. AB - INTRODUCTION: Road traffic injuries are the fifth leading cause of years of life lost, with pedestrians comprising 39% of all road deaths (Global Burden of Disease Mortality and Causes of Death Collaborators [1]). Programs that use injury surveillance data to identify high-risk targets for intervention are known to be effective for reducing injury. This study aims to identify trends in the population incidence of pedestrian traffic injury (PTI) in Victoria, Australia. METHOD: A retrospective review of data from the Victorian Emergency Minimum Dataset, the Victorian Admitted Episodes Dataset, the Victorian State Trauma Registry and the National Coronial Information System was conducted of patients with a PTI who present to a public hospital emergency department, were admitted to hospital, sustained major trauma or who died of their injuries from January 1st 2009 to December 31st 2013. The primary outcome measure was population incidence of pedestrian traffic-related emergency presentations, hospital admissions, major trauma and deaths. RESULTS: Over the study period, 1838 cases presented to a public hospital emergency department and were discharged without admission to hospital and an additional 3241 cases were admitted to hospital. Of these, 628 cases were classified as major trauma including 90 in-hospital deaths. From January 1st 2008 to December 31st 2011, a total of 216 deaths occurred. A decrease in the population incidence of emergency presentations for PTI was observed over the study period. No significant change was observed in the population incidence of hospital admissions, major trauma cases or deaths from PTI. The demographics of PTI were observed more commonly to be young, intoxicated males and pedestrians aged over 65 years. CONCLUSIONS: Although the population adjusted incidence of emergency presentations for PTI in Victoria has decreased from 2009 to 2013, no change was observed in the incidence of hospital admissions, major trauma or pedestrian fatalities. Novel programs designed to address high-risk groups should be considered to achieve further reductions in PTI and severity of injuries. PMID- 29254625 TI - Common Manual Therapy Practices in the Netherlands for Infants With Upper Cervical Dysfunction: A Prospective Cohort Study. AB - OBJECTIVE: The purpose of this study was to describe common clinical practices of manual therapists (MTs) in the Netherlands for infants with indications of upper cervical dysfunction (UCD). METHODS: A prospective observational cohort study was conducted to gain insight into characteristics, reasons for seeking care, and common clinical practice for infants (<27 weeks) with indications of UCD, referred to MTs. Pre- and posttreatment self-reported questionnaires were used to collect data from parents and MTs. Parents reported on infant characteristics and perceived effect of treatment. Manual therapists reported on diagnostics, therapeutic procedures, and outcomes. RESULTS: Between 2006 and 2007, data regarding 307 referred infants (mean age: 11.2 weeks) were collected by parents and 42 MTs. The most frequent reasons for seeking care were positional preference, restlessness, and/or abnormal head position. Manual therapists observed active, spontaneous, and provoked mobility and passive upper cervical mobility. Of the 307 infants, 295 were diagnosed with UCD based on positive outcomes on the flexion-rotation test and/or lateral flexion test. After treatment with mobilization techniques, positive outcomes on the flexion-rotation test decreased from 78.8% to 6.8%. For the lateral flexion test, the positive outcomes decreased from 91.5% to 6.2%. All parents perceived positive treatment effects. No serious adverse events were reported during this study. CONCLUSIONS: This is the first study to describe common clinical practice for infants referred for manual therapy. Infants with UCD were treated mainly with upper cervical mobilization techniques, and the greatest perceived effect was observed after approximately 2 treatment sessions. PMID- 29254626 TI - The Effectiveness of Hollowing and Bracing Strategies With Lumbar Stabilization Exercise in Older Adult Women With Nonspecific Low Back Pain: A Quasi Experimental Study on a Community-based Rehabilitation. AB - OBJECTIVE: The purpose of this study was to explore the therapeutic effectiveness of hollowing lumbar stabilization exercise (HLSE) and bracing lumbar stabilization exercise (BLSE) for older adult women with nonspecific low back pain (NSLBP) in community welfare centers. METHOD: A total of 38 older adult women with NSLBP were allocated to either the HLSE group (n = 17, 70.4 +/- 1.7 years) or the BLSE group (n = 21, 66.8 +/- 4.4 years). Both groups performed intervention for 12 consecutive weeks, 3 times per week. Each group performed 5 lumbar stabilization exercises, including side plank exercise, bridge exercise, 4 kneeling exercise, prone plank exercise, and prone back extension exercise with hollowing and bracing strategy, respectively. The baseline and post-test values of trunk strength, low back disability (Korean Oswestry Disability Index [K-ODI] and Korean Roland Morris Disability Questionnaire [K-RMDQ]), and static balance (1-leg standing test) were compared by using per-protocol analysis. RESULTS: In trunk strength, the trunk flexor had significant difference (F = 11.10, P = .001) between groups and within groups of BLSE (t = -5.56, P = .001) and HLSE (t = 2.50, P = .024). Trunk back extensor of HLSE (t = -6.00, P = .001) and BLSE (t = 9.19, P = .001) only had significant within-group difference. However, in trunk side flexor, HLSE and BLSE had only significant difference between groups. In low back disability, K-ODI for HLSE (t = 4.50, P = .001) and BLSE (t = 4.60, P = .001) had significant within-group difference but no significant difference between groups (F = 0.28, P = .202). In K-RMDQ, HLSE only had significant within group difference (t = 3.97, P = .001). In trunk muscle strength, the effect size of HLSE and BLSE groups for trunk flexor was HLSE -0.53 (medium) and BLSE -1.21 (large); trunk side flexor: HLSE 0.27 (small) and BLSE -0.24 (small); and trunk back extensor: HLSE 1.1 (large) and BLSE 2.00 (large), respectively. In low back disability, the effect size of both groups for K-ODI was HLSE 0.88 (large) and BLSE 1.05 (large), and K-RMDQ, HLSE 0.19 (small) and BLSE 0.40 (small), respectively. CONCLUSION: Our findings suggest that HLSE and BLSE could be recommended for community settings to improve trunk strength and low back disability in older adult women with NSLBP. Especially, HLSE and BLSE could be recommended for elderly women with NSLBP who have lower back disability and weak trunk muscle strength, respectively. PMID- 29254627 TI - Acute effects of physical exercises on the inflammatory markers of patients with fibromyalgia syndrome: A systematic review. AB - OBJECTIVE: In patients with fibromyalgia (FM), exercise is indicated for symptomatic treatment. However, little is known about the inflammatory response to acute exercise in these patients. This study examines the acute effects of exercise on the inflammatory response in patients with FM. METHODS: A systematic review was conducted using PubMed, PsycINFO, Web of Science, SportDiscus, Scopus, Virtual Health Library (VHL), and Cochrane Library databases. RESULTS: Six studies that met the inclusion criteria were included in the analysis; three of them evaluated the effects of resistive exercise, while three evaluated the effects of aerobic exercise. Several studies evaluated pro-inflammatory (interleukin [IL]-6, IL-8, IL-1beta, IL-18, tumor necrosis factor-alpha) and anti inflammatory cytokine levels (IL-10) and stress (Hsp72) protein levels before and after the intervention with exercise. Studies found a low-grade baseline chronic inflammatory state in patients with FM, demonstrated by the alteration of one or more of the studied markers. CONCLUSIONS: We suggest that patients with FM probably have low-grade chronic inflammation, because studies found higher concentrations of IL-8 and TNF-alpha and high expression of IL-10 in these patients; however, the effects of exercise on the inflammatory markers in these patients are unclear. Although more research is needed on the effect of exercise on inflammation, none of the studies reported worsening of symptoms with exercise recommended as treatment. PMID- 29254628 TI - Massive hematuria at pregnancy caused by ruptured angiomyolipoma: A case report. PMID- 29254629 TI - Prostate Cancer Death After Radiotherapy or Radical Prostatectomy: A Nationwide Population-based Observational Study. AB - BACKGROUND: There are no conclusive results from randomized trials on radiotherapy (RT) versus radical prostatectomy (RP) for prostate cancer. Numerous observational studies have suggested that RP is associated with a lower risk of prostate cancer death, but whether results have been biased due to limited adjustments for confounding factors is unknown. OBJECTIVE: To compare the risk of prostate cancer death after RT versus RP. DESIGN, SETTING, AND PARTICIPANTS: Nationwide population-based observational study of men in the Prostate Cancer data Base Sweden 3.0 who had undergone RT or RP between 1998 and 2012. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate cancer deaths were compared. Hazard ratios (HRs) were calculated in Cox regression models, including clinical T stage, M stage, Gleason grade group, serum levels of prostate-specific antigen, proportion of biopsy cores with cancer, mode of detection, comorbidity, age, educational level, and civil status. Period analysis with left truncation was performed. RESULTS AND LIMITATIONS: Primary treatment was RT or RP for 41 503 men. Treatment effect was associated with disease severity. In univariate analysis of RT versus RP, risk of prostate cancer death was higher after RT-low- and intermediate-risk cancer, HR 1.82 (95% confidence interval [CI]: 1.53-2.16), and high-risk cancer, HR 1.57 (95% CI: 1.33-1.85). After full adjustment in period analysis, this difference between the treatments was attenuated-low- and intermediate-risk cancer, HR 1.24 (95% CI: 0.97-1.58), and high-risk cancer, HR 1.03 (95% CI: 0.81-1.31). Confounding remained due to nonrandom allocation to treatment. CONCLUSIONS: In comparison with previous studies, the difference in prostate cancer mortality after RT and RP was much smaller. PATIENT SUMMARY: The difference in prostate cancer mortality after contemporary radiotherapy and radical prostatectomy was small in contrast to previous studies, indicating that potential side effects should be more emphasized when selecting treatment. PMID- 29254630 TI - Arbuscular mycorrhizal fungal communities in the rhizosphere of a continuous cropping soybean system at the seedling stage. AB - Arbuscular mycorrhizae (AM) fungi play a crucial role in the growth of soybean; however, the planting system employed is thought to have an effect on AM fungal communities in the rhizosphere. This study was performed to explore the influence of continuous soybean cropping on the diversity of Arbuscular mycorrhizal (AM) fungi, and to identify the dominant AM fungus during the seedling stage. Three soybean cultivars were planted under two and three years continuous cropping, respectively. The diversity of AM fungi in the rhizosphere soil at the seedling stage was subsequently analyzed using polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE). The results showed that an increase in cropping years improved the colonization rate of AM in all three soybean cultivars. Moreover, the dominant species were found to be Funneliformis mosseae and Glomus species. The results of cluster analysis further confirmed that the number of years of continuous cropping significantly affected the composition of rhizospheric AM fungal communities in different soybean cultivars. PMID- 29254631 TI - The improvement of bioactive secondary metabolites accumulation in Rumex gmelini Turcz through co-culture with endophytic fungi. AB - Aspergillus sp., Fusarium sp., and Ramularia sp. were endophytic fungi isolated from Rumex gmelini Turcz (RGT), all of these three strains could produce some similar bioactive secondary metabolites of their host. However the ability to produce active components degraded significantly after cultured these fungi alone for a long time, and were difficult to recover. In order to obtain more bioactive secondary metabolites, the co-culture of tissue culture seedlings of RGT and its endophytic fungi were established respectively, and RGT seedling was selected as producer. Among these fungi, Aspergillus sp. showed the most significant enhancement on bioactive components accumulation in RGT seedlings. When inoculated Aspergillus sp. spores into media of RGT seedlings that had taken root for 20d, and made spore concentration in co-culture medium was 1*104mL-1, after co-cultured for 12d, the yield of chrysophaein, resveratrol, chrysophanol, emodin and physcion were 3.52-, 3.70-, 3.60-, 4.25-, 3.85-fold of the control group. The extreme value of musizin yield was 0.289mg, which was not detected in the control groups. The results indicated that co-culture with endophytic fungi could significantly enhance bioactive secondary metabolites production of RGT seedlings. PMID- 29254633 TI - Effect on the mechanical properties of type I collagen of intra-molecular lysine arginine derived advanced glycation end-product cross-linking. AB - Non-enzymatic advanced glycation end product (AGE) cross-linking of collagen molecules has been hypothesised to result in significant changes to the mechanical properties of the connective tissues within the body, potentially resulting in a number of age related diseases. We have investigated the effect of two of these cross-links, glucosepane and DOGDIC, on the tensile and lateral moduli of the collagen molecule through the use of a steered molecular dynamics approach, using previously identified preferential formation sites for intra molecular cross-links. Our results show that the presence of intra-molecular AGE cross-links increases the tensile and lateral Young's moduli in the low strain domain by between 3.0-8.5% and 2.9-60.3% respectively, with little effect exhibited at higher strains. PMID- 29254634 TI - [How does salt intake influence blood pressure? Associated aetiopathogenic mechanisms]. AB - Abundant evidence from epidemiological and experimental studies has established a link between salt and blood pressure. However, there is heterogeneity in the blood pressure responses of humans to changes in sodium intake. Those individuals in whom a severe, abrupt change in salt intake causes the least change in arterial pressure and are termed salt-resistant, whereas in those in whom this leads to large changes in blood pressure, are called salt sensitive. Classically, Guyton's theory of the pressure-natriuresis phenomenon has been accepted to explain the pressor effect of salt, as well as the fundamental role played by the different protein sodium transporters of the renal tubules. In recent years, new theories have emerged pointing to the possible role of the immune system and the existence of a third sodium store in the body as aetiopathogenic factors. PMID- 29254632 TI - On/off dropped head syndrome: A severe adverse event after prolonged treatment with MEK inhibitor. PMID- 29254635 TI - Novel technique for stent removal in patient with bile leak after trans-gastric ERCP in the setting of Roux en gastric bypass: A stitch in time. PMID- 29254637 TI - Discussion. PMID- 29254636 TI - Lung adenocarcinoma with intraoperatively diagnosed pleural seeding: Is main tumor resection beneficial for prognosis? AB - OBJECTIVE: To evaluate whether main tumor resection improves survival compared with pleural biopsy alone in patients with lung adenocarcinoma with intraoperatively diagnosed pleural seeding. METHODS: Forty-three patients with lung adenocarcinoma with pleural seeding diagnosed unexpectedly during surgery performed between January 2006 and December 2014 were included in this retrospective study using a prospectively collected lung cancer database. Each surgeon decided whether to perform main tumor resection or pleural biopsy alone. RESULTS: Main tumor and visible pleural nodule resection was performed in 30 patients (tumor resection group). The remaining 13 patients underwent pleural nodule biopsy alone (open-close group). The clinical T stage was higher in the open-close group than in the tumor resection group (P = .02). The tumor resection group had longer operative times compared with the open-close group (mean, 141.8 vs 80.3 minutes). There were no other statistically significant differences in perioperative parameters. The surgical method was the sole statistically significant prognostic factor. Patients in the tumor resection group had better progression-free survival (3-year survival: 44.5% vs 0%; P = .009) and overall survival (3-year survival: 82.9% vs 38.5%; P = .013) than did the open-close group. There was no significant survival difference between sublobar resection and lobectomy for the main tumor resection. CONCLUSIONS: Our study demonstrated improved progression-free and overall survival after main tumor and visible pleural nodule resection in patients with lung adenocarcinoma with intraoperatively diagnosed pleural seeding. Further randomized trials are needed to define the role of main tumor resection in these patients. PMID- 29254638 TI - Relative incremental costs of complications of lobectomy for stage I non-small cell lung cancer. AB - OBJECTIVE: To evaluate the relative incremental cost of complications after lobectomy for stage I non-small cell lung cancer (NSCLC). METHODS: Patients treated with open or video-assisted thoracoscopic surgery (VATS) lobectomy for stage I NSCLC between 2008 and 2014 were selected. A patient registry was queried for all complications recorded during a 90-day postoperative interval. Hospital cost data for each patient was concatenated with clinical data. Linear regression was used to assess the impact on direct hospital costs of specific complications. RESULTS: Among the 488 patients included in this study, 34% experienced >=1 complication and 17% experienced >=1 major complication. In patients experiencing complications, atrial arrhythmia (13%), prolonged air leak (8.6%), atelectasis (6.4%), and transfusion requirement (4.5%) were most common. Minor complications increased the relative cost of lobectomy by 29% (95% confidence interval [CI], 23%-34%; P < .001) compared to the cost of an uncomplicated lobectomy. Major complications increased costs by 57% (95% CI, 53%-62%; P < .001). The greatest predictor of increased 90-day cost was major pulmonary complications, which increased cost by 111% (95% CI, 96%-126%; P < .001). Prolonged air leak increased relative mean cost by 22% (95% CI, 10%-33%; P < .001) and pneumonia by 96% (95% CI, 75%-117%; P < .001). CONCLUSIONS: Complications, both major and minor, contribute significantly to the total 90-day direct hospital cost of lobectomy for stage I NSCLC. Analysis of 90-day postoperative outcomes more accurately captures costs. Major pulmonary complications, atrial arrhythmia, pneumonia, and prolonged air leak represent 4 high-yield targets for cost reduction. Efforts to control health care spending while improving patient outcomes might optimally focus on reducing complications that incur the greatest relative incremental cost. PMID- 29254639 TI - What are the "costs" of cost-effectiveness? PMID- 29254640 TI - Is it time to mandate regional acute mechanical circulatory support/extracorporeal membrane oxygenation centers? PMID- 29254641 TI - Discovery of novel jaspine B analogues as autophagy inducer. AB - A series of 2-alkylaminomethyl jaspine B analogues were synthesized and evaluated for their cytotoxic effects on human lung adenocarcinoma, breast cancer, and prostate cancer cell lines and a mouse melanoma cell line. Most of the compounds exhibited moderate to good activity against the cancer cell lines. Compound 7f showed the best overall cytotoxicity on PC-3 cells (IC50 = 0.85 MUM). Further mechanistic studies revealed that compound 7f induced marked changes in PC-3 cell morphology, disrupted the mitochondrial membrane potential, and increased expression of the autophagy proteins beclin-1, LC3, and P62. PMID- 29254642 TI - Spiro-1-benzofuranpiperidinylalkanoic acids as a novel and selective sphingosine S1P5 receptor agonist chemotype. AB - The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6-34 as sphingosine S1P5 receptor agonists are described. The target compounds generally elicit high S1P5 receptor agonistic potencies and in general are selective against both S1P1 and S1P3 receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.8 after oral administration in rats. PMID- 29254643 TI - Discovery of potent and selective inhibitors of calmodulin-dependent kinase II (CaMKII). AB - We hereby disclose the discovery of inhibitors of CaMKII (7h and 7i) that are highly potent in rat ventricular myocytes, selective against hERG and other off target kinases, while possessing good CaMKII tissue isoform selectivity (cardiac gamma/delta vs. neuronal alpha/beta). In vitro and in vivo ADME/PK studies demonstrated the suitability of these CaMKII inhibitors for PO (7h rat F = 73%) and IV pharmacological studies. PMID- 29254644 TI - Chemical constituents from Taraxacum officinale and their alpha-glucosidase inhibitory activities. AB - Three novel butyrolactones (1-3) and butanoates (4-6), namely taraxiroside A-F, were isolated from Taraxacum officinale along with twenty-two known compounds (7 28). Their chemical structures were elucidated by interpretation of spectroscopic data and comparison with those of literatures. All isolates were evaluated for their alpha-glucosidase inhibitory activities. Novel compounds 1-6 (IC50 145.3 181.3 MUM) showed inhibitory activities similar to that of acarbose (IC50 179.9 MUM). Compound 7 and 12 were the most potent inhibitor with IC50 values of 61.2 and 39.8 MUM respectively. Compounds 2 and 12 showed as mixed-type inhibition, whereas compound 7 and acarbose showed competitive inhibition. PMID- 29254645 TI - Synthesis and biological evaluation of novel doxorubicin-containing ASGP-R targeted drug-conjugates. AB - Asialoglycoprotein receptor (ASGP-R) belongs to a wide family of C-type lectins and it is currently regarded as an attractive protein in the field of targeted drug delivery (TDD). It is abundantly expressed in hepatocytes and can be found predominantly on the sinusoidal surface especially of HepG2 cells. Therefore, ASGP-R can be used for the TDD of anticancer therapeutics against HCC and molecular diagnostic tools. To date, a variety of mono- and multivalent selective ASGP-R ligands have been discovered. Although many of these compounds have demonstrated a relatively high binding affinity towards the target, the reported synthetic schemes are not handled, complicated and include many non-trivial steps. In the current study, we describe a convenient and versatile synthetic approach to novel monovalent drug-conjugates containing N-acetyl-2-deoxy-2 aminogalactopyranose fragment as an ASGP-R-recognition "core-head" and well-known nonselective cytostatic - Doxorubicin (Dox). This is the first example of the direct conjugation of a drug molecule to the ASGP-targeted warhead by a really convenient manner via a simple linker sequence. The performed MTS-based biological evaluation in HepG2 cells revealed the novel conjugates as having anticancer activity. Confocal microscopy showed that the molecules readily penetrated HepG2 membrane and were mainly localized within the cytoplasm instead of the nucleus. Per contra, Dox under the same conditions demonstrated good anticancer activity and was predominantly concentrated in the nucleus. Therefore, we speculate that the amide "trigger" that we have used in this study for linker attachment is a sufficiently stable inside the cells to be enzymatically or spontaneously degraded. As a consequence, we did not observe the release of the drug. Ligands containing triggers that are more liable towards endogenous hydrolysis within the tissue of targeting are strongly required. PMID- 29254647 TI - Parents Who Allow Early Adolescents to Drink. AB - PURPOSE: Previous research on community samples reveals that a sizeable minority of parents allow their early adolescent children to drink alcohol. The present study documents in a national longitudinal study the prevalence of parents allowing 14-year-olds to drink and examines variation by sociodemographic background and parent alcohol use. METHODS: Children and parents (n = 10,210 families) participating in the ongoing Millennium Cohort Study provided self report data from when the child was an infant to age 14 years. RESULTS: About 17% of parents allowed their early adolescents to drink. Employed, more educated, and non-abstaining parents of white children were more likely to permit early adolescent drinking. Permitting alcohol use did not vary by child gender, teenage or single parenthood, or variation in parental drinking level. CONCLUSIONS: Socioeconomically advantaged, non-abstaining parents evidence a more permissive attitude about early drinking, which is a risk factor for early initiation, heavier use, and other problem behaviors. PMID- 29254646 TI - Dihydrobenzisoxazole-4-one compounds are novel selective inhibitors of aldosterone synthase (CYP11B2) with in vivo activity. AB - 6,7-Dihydro-5H-2,1-benzisoxazol-4-one analogs are potent inhibitors of aldosterone synthase (CYP11B2) with selectivity over the highly homologous enzyme cortisol synthase (CYP11B1). These compounds are unique among inhibitors of CYP11B2 in their lack of a strong-heme binding group such as a pyridine or imidazole. Poor metabolic stability in hepatocyte incubations was found to proceed via a reduction of the isoxazole ring. While the enzyme responsible for the reductive metabolism remains unknown, the rate of metabolism could be attenuated by the addition of polar functionality. The in vitro CYP11B2 potency and selectivity were confirmed in vivo in a cynomolgus monkey model by the inhibition of ACTH stimulated aldosterone production without impacting plasma cortisol concentrations. PMID- 29254648 TI - Does access to end-of-life homecare nursing differ by province and community size?: A population-based cohort study of cancer decedents across Canada. AB - BACKGROUND: Studies have demonstrated the strong association between increased end-of-life homecare nursing use and reduced acute care utilization. However, little research has described the utilization patterns of end-of-life homecare nursing and how this differs by region and community size. METHODS: A retrospective population-based cohort study of cancer decedents from Ontario, British Columbia, and Nova Scotia was conducted between 2004 and 2009. Provinces linked administrative databases which provide data about homecare nursing use for the last 6 months of life for each cancer decedent. Among weekly users of homecare nursing in their last six months of life, we describe the proportion of patients receiving end-of-life homecare nursing by province and community size. RESULTS: Our cohort included 83,746 cancer decedents across 3 provinces. Patients receiving end-of-life nursing among homecare nursing users increased from weeks 26 to -1 before death by: 78% to 93% in British Columbia, 40% to 81% in Ontario, and 52% to 91% in Nova Scotia. In all 3 provinces, the smallest community size had the lowest proportion of patients using end-of-life nursing compared to the second largest community size, which had the highest proportion. CONCLUSIONS: Differences in end-of-life homecare nursing use are much larger between provinces than between community sizes. PMID- 29254649 TI - Three- Versus Five-Fraction Regimens of Stereotactic Body Radiotherapy for Peripheral Early-Stage Non-Small-Cell Lung Cancer: A Two-Institution Propensity Score-Matched Analysis. AB - PURPOSE: To evaluate differences in outcomes of early-stage peripheral non-small cell lung cancer (NSCLC) treated with either 3- or 5-fraction stereotactic body radiotherapy (SBRT) at 2 institutions. PATIENTS AND METHODS: Patients diagnosed with peripherally located early-stage NSCLC who received either a median dose of 60 Gy (interquartile range [IQR], 60-60, biologically effective dose, 151-151) in 3 fractions or a median dose of 50 Gy (IQR, 50-50, biologically effective dose, 94-94) in 5 fractions were included in this study. All data were retrospectively collected and reviewed in an institutional review board-approved database. RESULTS: A total of 192 lesions in 192 patients were identified: 94 received 3 fraction SBRT and 98 received 5-fraction SBRT. Patients in the 5-fraction cohort had significantly smaller tumors (P = .0021). Larger tumor size was associated with worse overall survival (hazard ratio, 1.40, P = .0013) for all patients. A single grade 3 toxicity was reported in each cohort. A propensity score-matched cohort of 94 patients was constructed with a median follow-up of 29.3 months (IQR, 17.3-44.6) for the 3-fraction cohort and 31.0 months (IQR, 17.0-48.5) for the 5-fraction cohort (P = .84). There were no statistically significant differences between these 2 cohorts in overall survival (P = .33), progression free survival (P = .40), local failure (P = .86), and nodal or distant failure (P = .57) at 2 years. CONCLUSION: The 3- and 5-fraction SBRT regimens for early stage peripheral NSCLC had comparable clinical outcomes. Both regimens were well tolerated. A large tumor size was an adverse prognostic factor for worse survival. PMID- 29254650 TI - The Role of Three-Dimensional Printing in the Nuss Procedure: Three-Dimensional Printed Model-Assisted Nuss Procedure. AB - BACKGROUND: The Nuss procedure is a minimally invasive surgery for pectus excavatum. Success of the Nuss procedure is dependent on a previously bent pectus bar that is shaped to the desired curvature of the chest wall. Traditionally, the size and curvature of the metallic pectus bar are determined by trial and error. Herein, we introduce a novel design method for the metallic pectus bar to optimize the bar curvature and outcome after the Nuss procedure. METHODS: From August 2016 through March 2017, 10 consecutive patients with pectus excavatum underwent the three-dimensional (3D) printed model-assisted Nuss procedure. The computed tomography images were used to generate a 3D thorax model of pectus excavatum. The 3D models of personalized pectus bar curvature were completed by computer-aided design. Herein, we report the demographic data, treatment outcomes, and radiographic findings. RESULTS: All patients with pectus excavatum received one pectus bar insertion. The mean age was 19.80 +/- 4.73 years (range, 12 to 26). The mean preoperative Haller index was 3.48 +/- 0.35 (range, 3.06 to 3.95). We advantageously utilized preoperative planning; the mean interval change of the Haller index was 20.71% +/- 4.63%. With the benefit of 3D printed model simulation, the surgical duration was 59.8 +/- 23.2 minutes (range, 32 to 107). No patient had adverse events after operation. CONCLUSIONS: Our initial results revealed that the 3D printed model-assisted Nuss procedure reduces the surgical duration and facilitates an optimal morphological outcome. PMID- 29254652 TI - Nurses' Perceptions of Victims of Human Trafficking in an Urban Emergency Department: A Qualitative Study. AB - INTRODUCTION: Human trafficking is estimated to surpass the drug trade as the leading illegal industry in the world. According to a recent study, over 87.8% of trafficking survivors came into contact with a healthcare professional while they were enslaved and were not identified as a victim of human trafficking. The aims of this study are to understand the perceptions of emergency nurses about human trafficking, victims of violence, and prostitution. METHODS: A qualitative, descriptive study using a semi-structured interview approach was done with ten registered nurses in a large, urban Emergency Department in the northeastern U.S. Interviews were recorded and transcribed; thematic analysis was performed. RESULTS: Six themes emerged from the interviews including, "human trafficking exists in the patient population" yet no nurse has screened or treated a victim; human trafficking victims are perceived to be "young, female, and foreign born"; all of the emergency nurses reported having worked with or screened a victim of violence; victims of violence were viewed as patients who present as "sad and grieving"; prostitutes are seen as "hard and tough"; and emergency nurses did not have education on human trafficking victims' needs or resources. DISCUSSION: Emergency nurses should be more aware about victims of human trafficking. The media portrayal of human trafficking victims had influenced the nurses' perceptions of this population. Victims of violence are perceived to be very different from prostitutes, but there is a desire for education about violence as well as information about specific resources open to victims. PMID- 29254651 TI - Programmed Death-Ligand 1 Expression and EGFR Mutations in Multifocal Lung Cancer. AB - BACKGROUND: Little is known about the programmed death-ligand 1 (PD-L1) expression in multifocal lung cancer, such as the expression in multiple primary lung cancer and pulmonary metastasis. In this translational study, we investigated PD-L1 expression and its relationship with the epidermal growth factor receptor (EGFR) mutation status in resected multifocal lung cancer. METHODS: The PD-L1 expression in 152 samples of multifocal lung cancer from 59 patients was evaluated by an immunohistochemical analysis. RESULTS: Among the 152 lung cancer lesions of 59 patients, PD-L1 expression was observed in 29 lesions (19.1%) of 20 patients (33.9%). Among 43 patients with 112 multiple primary lung cancer lesions, 15 lesions (13.4%) of 13 patients (30.2%) were PD-L1 positive; and among 16 patients with 40 pulmonary metastatic lesions, 14 lesions (35.0%) of 7 patients (43.8%) were PD-L1-positive. Among 43 patients with multiple primary lung cancer, there was disagreement of PD-L1 expression in 12 patients (27.9%, kappa = 0.104). On the contrary, among 16 patients with pulmonary metastasis, disagreement of PD-L1 expression was observed only in 1 patient (6.3%, kappa = 0.871). In pulmonary metastatic lesions, the frequency of PD-L1 positivity among lesions with wild-type EGFR was significantly higher than among lesions with mutated EGFR (66.7% versus 0%: p < 0.001). CONCLUSIONS: This study provides important evidence of higher levels of agreement of PD-L1 expression in pulmonary metastasis compared with in multiple primary lung cancer, and high positivity of PD-L1 expression in pulmonary metastatic lesions with wild-type EGFR in an Asian population. PMID- 29254653 TI - Influenza virus infections from 0 to 2 years of age: A birth cohort study. AB - BACKGROUND/PURPOSE: Influenza vaccine has been recommended in Finland since 2007 for all children of 6-35 months of age and in 2009 for those >=6 months against pandemic influenza. We investigated the incidence of influenza and vaccine effectiveness in a birth cohort of children in 2008-2011. METHODS: We followed 923 children from birth to 2 years of age for respiratory tract infections. A nasal swab sample for PCR for influenza A and B viruses was taken at the onset of acute respiratory infections. Samples were collected either at the study clinic or at home by parents. Vaccination data was retrieved from the health registries. RESULTS: Vaccination coverage of children aged 6-23 months was 22-47% against seasonal influenza and 80% against the A(H1N1)pdm09 virus in the pandemic season 2009-2010. During 3 influenza seasons, 1607 nasal swab samples were collected. Influenza was confirmed in 56 (6.1%) of 923 children (16 A(H1N1), 14 A(H3N2), and 26 B viruses). The incidence of influenza was 5.1% in 2008-2009, 2.7% in 2009 2010, and 5.0% in 2010-2011. Effectiveness of the adjuvanted vaccine against the pandemic influenza A(H1N1)pdm09 was 97% (95% confidence interval, 76-100%). Three children with influenza were hospitalized. CONCLUSION: The yearly incidence of seasonal influenza was 5% in this cohort of very young children with variable influenza vaccine coverage. Adjuvanted vaccine against the pandemic influenza was highly effective. Both seasonal and pandemic influenza cases were mostly non severe. PMID- 29254654 TI - Organic matter modifies biochemical but not most behavioral responses of the clam Ruditapes philippinarum to nanosilver exposure. AB - Adsorption of dissolved organic matter (DOM) can alter the environmental fate, bioavailability and toxicity of silver nanoparticles (Ag NPs). However, a number of questions remain about DOM's ability to modify nanotoxicity. Here, we examine the impact of humic acid (HA, as a model DOM) on the toxicity of Ag NPs (10 MUg L 1) in the marine clam Ruditapes philippinarum. Results showed that DOM additions to Ag NP treatments reduce clam silver tissue burdens and the oxidative stress response. However, HA does not significantly affect the impact of Ag NPs on clam acetylcholinesterase activity and feeding behavior (measured as filtration rate). Overall, the integrated biological response index supports the conclusion that humic acid reduces the toxicity of Ag NPs, clearly indicating the importance of considering environmental factors when assessing potential risks posed by nanomaterials in natural settings. PMID- 29254655 TI - A four-tier classification system of pulmonary artery metrics on computed tomography for the diagnosis and prognosis of pulmonary hypertension. AB - BACKGROUND: We aimed to develop a severity classification system of the main pulmonary artery diameter (mPA) and its ratio to the ascending aorta diameter (ratio PA) for the diagnosis and prognosis of pulmonary hypertension (PH) on computed tomography (CT) scans. METHODS: In 228 patients (136 with PH) undergoing right heart catheterization (RHC) and CT for dyspnea, we measured mPA and ratio PA. In a derivation cohort (n = 114), we determined cutpoints for a four-tier severity grading system that would maximize sensitivity and specificity, and validated it in a separate cohort (n = 114). Cutpoints for mPA were defined with <=27 mm(F) and <=29 mm(M) as the normal reference range; mild as >27 to <31 mm(F) and >29 to <31 mm(M); moderate>=31-34 mm; and severe>34 mm. Cutpoints for ratio PA were defined as normal <=0.9; mild>0.9 to 1.0; moderate>1.0 to 1.1; and severe>1.1. RESULTS: Sensitivities for normal tier were 99% for mPA and 93% for ratio PA; while specificities for severe tier were 98% for mPA>34 mm and 100% for ratio PA>1.1. C-statistics for four-tier mPA and ratio PA were both 0.90 (derivation) and both 0.85 (validation). Severity of mPA and ratio PA corresponded to hemodynamics by RHC and echocardiography (both p < 0.001). Moderate-severe mPA values of >=31 mm and ratio PA>1.1 had worse survival than normal values (all p <= 0.01). CONCLUSION: A CT-based four-tier severity classification system of PA diameter and its ratio to the aortic diameter has high accuracy for PH diagnosis with increased mortality in patients with moderate severe severity grades. These results may support clinical utilization on chest and cardiac CT reports. PMID- 29254656 TI - Fifty years of sociological leadership at Social Science and Medicine. AB - In this review article, we examine some of the conceptual contributions of sociology of health and illness over the past fifty years. Specifically, we focus on research dealing with medicalization, the management of stigma, research on adherence and compliance, and patient-doctor interaction. We show how these themes that originated within sociology, diffused in other disciplines. Sociology in Social Science and Medicine started as an applied research tradition but morphed into a robust, stand-alone social science tradition. PMID- 29254657 TI - Cortical thickness, cortical surface area and subcortical volumes in schizophrenia and bipolar disorder patients with cannabis use. AB - Cannabis is associated with increased risk for severe mental illness and is commonly used among individuals with schizophrenia or bipolar disorder. In this study we investigated associations between cannabis use and brain structures among patients with schizophrenia or bipolar disorders. Magnetic resonance imaging scans were obtained for 77 schizophrenia and 55 bipolar patients with a history of cannabis use (defined as lifetime use >10 times during one month or abuse/dependence), and 97 schizophrenia, 85 bipolar disorder patients and 277 healthy controls without any previous cannabis use. Cortical thickness, cortical surface area and subcortical volumes were compared between groups. Both hypothesis-driven region-of-interest analyses from 11 preselected brain regions in each hemisphere and exploratory point-by-point analyses were performed. We tested for diagnostic interactions and controlled for potential confounders. After controlling for confounders such as tobacco use and alcohol use disorders we found reduced cortical thickness in the caudal middle frontal gyrus compared to non-user patients and healthy controls. The findings were not significant when patients with co-morbid alcohol and illicit drug use were excluded from the analyses, but onset of cannabis use before illness onset was associated with cortical thinning in the caudal middle frontal gyrus. To conclude, we found no structural brain changes associated with cannabis use among patients with severe mental illness, but the findings indicate excess cortical thinning among those who use cannabis before illness onset. The present findings support the understanding that cannabis use is associated with limited brain effects in schizophrenia as well as bipolar disorder. PMID- 29254659 TI - The polyunsaturated fatty acid balance in kidney health and disease: A review. AB - Epidemiological studies show that circulating polyunsaturated fatty acids contribute to preserve renal function. In renal disease states there is generally a lack of omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) as measured in biological samples, but despite intense research for more than 30 years, it is still unclear how and to what extent their supplementation would benefit kidney disorders. Studies evaluating the n-6 series and the kidney are less frequent. The last compilation of clinical trials with n-3 LCPUFA supplements focusing on renal function and damage dates back to 2012. We here discuss n-3 and n-6 fatty acids in relation to the kidney summarizing single- and double blind randomized controlled trials performed between 2012 and 2016. Nine were sub-studies/post-hoc analyses of previous parent trials. Twelve out of the twenty trials reported on fatty acid profile or fatty acid species. Factors that may explain inconsistent results obtained after supplementation with the n-3 LCPUFA EPA and DHA in kidney disease are discussed such as baseline levels determining response, drug interaction. The need of evaluating fatty acid status before and after intervention is emphasized, to match changes in outcome measure with changes of any fatty acid potentially involved. PMID- 29254660 TI - No clinically significant effect of new complete denture fabrication and simple dietary advice on nutrient intake and masticatory function of edentulous older people. PMID- 29254658 TI - The concept of violent suicide, its underlying trait and neurobiology: A critical perspective. AB - Suicide is one of the leading causes of death and represents a significant public health problem world-wide. Individuals who attempt or die by suicide represent a highly heterogeneous population. Recently, efforts have been made to identify sub populations and variables to categorize them. A popular dichotomy in suicide research of the past years is violent versus non-violent suicide - based on the method. This dichotomy is important given that there is an association between method of attempted suicide and risk of subsequent death by suicide. The differentiation concerning suicide methods is also critical regarding preventive efforts. In this review, we have tried to approach the concept of violent suicide from different perspectives, including a discussion about its definition and overlapping categories. In addition, we have critically discussed aggression as underlying trait, the question of intent to die, and sociodemographic, environmental, neuropsychological, and neurobiological factors potentially associated with violent suicide. PMID- 29254661 TI - Low reported taste function is associated with low preference for high protein products in advanced oesophagogastric cancer patients undergoing palliative chemotherapy. AB - BACKGROUND & AIMS: Cancer patients undergoing palliative chemotherapy can experience a variety of chemosensory and food preference changes which may impact their nutritional status and quality of life. However, evidence of these changes in oesophagogastric cancer (OGC) patients is currently mostly qualitative and not supported by quantitative data. The aim of this study was to assess how self reported and objective taste and smell function and food preferences change over time during chemotherapy in OGC patients. METHODS: This observational study included 15 advanced OGC patients planned for first line treatment with capecitabine and oxaliplatin. Participants completed two test sessions scheduled before start of cytotoxic treatment and after two cycles. Self-reported and objective taste and smell function and the macronutrient and taste preference ranking task were conducted at each test session. RESULTS: Self-reported taste and smell did not change upon chemotherapy. Objective taste function decreased during chemotherapy, although this was not statistically significant (p = 0.06), objective smell function did not change. Before and during chemotherapy, high protein foods were preferred over high carbohydrate and over low energy products, but food preferences did not change over time. A lower self-reported taste function correlated with a lower preference for high-protein products (rho = 0.526, p = 0.003). CONCLUSION: This study suggests that objective taste function decreases during chemotherapy in OGC patients, but not smell function. A low reported taste function was related to a lower preference for high-protein products. PMID- 29254662 TI - Blocking constitutive activity of GHSR1a in the lateral amygdala facilitates acquisition of conditioned taste aversion. AB - Ghrelin is a circulating peptide hormone promoting feeding and regulating energy metabolism in human and rodents. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), which are widely distributed throughout the brain including the amygdala, a brain region important for regulating valenced behavior, such as aversion. Interestingly, GHSR1a was once characterized by highly constitutive, ligand-independent activity. However, the physiological importance of such ligand-independent signaling on aversive memory processing has not been tested yet. Here, we applied [D-Arg1, D-Phe5, D Trp7,9, Leu11]-Substance P (D-SP), a full inverse agonist for GHSR1a, into the lateral amygdala (LA) and investigated the effect of blocking GHSR1a constitutive activity on conditioned taste aversion (CTA) in rats. We found that intra-LA infusion of a single low dose of D-SP (8ng/0.5MUl/side) facilitates CTA acquisition. Moreover, pre-administration of a high dose of D-SP into the LA abolishes the suppressive effect of exogenous ghrelin on CTA acquisition. In contrast, pre-administration of the same dose of D-SP does not affect the suppression of substance P, a potent neurokinin-1 (NK1) receptor ligand, on CTA. Therefore, our data indicated that the spontaneous or basal activity of GHSR1a signaling in the LA might interfere with CTA memory formation. D-SP decreases the constitutive activity of GHSR1a and thus facilitates CTA. Altogether, our present findings along with previous results support the idea that ghrelin/GHSR1a signaling in the LA circuit blocks conditioned taste aversion. PMID- 29254663 TI - Do selective serotonin reuptake inhibitors improve survival in multiple system atrophy? AB - INTRODUCTION: Loss of brainstem serotonergic neurons in MSA patients is implicated in respiratory dysfunction including stridor and may increase the risk of sudden death. Augmenting serotonergic transmission through selective serotonergic reuptake inhibitors (SSRIs) has been proposed to improve stridor and prolong survival in multiple system atrophy (MSA). We sought to determine whether MSA patients on an SSRI during their disease course have improved survival compared to those not on an SSRI. METHODS: Review of all MSA patients from 1998 to 2012 at Mayo Clinic, Rochester who completed autonomic function testing. Use of SSRI medications was obtained from patient-provided medication lists in the electronic medical record. Clinical symptoms were collected from patient histories; the presence of stridor was obtained from clinical histories and polysomnogram. Surviving patients were called to assess for stridor and SSRI use. RESULTS: Of 685 MSA patients, 132 (19%) were on an SSRI. Median time from symptom onset to death was 7.5 years with no difference based on SSRI use (p = .957). Rates of stridor were similar in SSRI users and non-users based on patient report and polysomnography (p = .494 and p = .181, respectively). SSRI use was associated with parkinsonism (p = .027) and falls (p = .002). Stridor was similar in SSRI users and those not on an SSRI. CONCLUSIONS: There was no difference in survival in MSA patients on an SSRI. However, SSRI use was associated with higher rates of parkinsonism and falls. PMID- 29254664 TI - Abnormal pain perception in patients with Multiple System Atrophy. AB - INTRODUCTION: Patients with Parkinson's disease or Multiple System Atrophy frequently experience painful sensations. The few studies investigating pain mechanisms in Multiple System Atrophy patients have reported contradictory results. In our study, we compared pain thresholds in Multiple System Atrophy and Parkinson's disease patients and healthy controls and evaluated the effect of l DOPA on pain thresholds. METHODS: We assessed subjective and objective pain thresholds (using a thermotest and RIII reflex), and pain tolerance in OFF and ON conditions, clinical pain, motor and psychological evaluation. RESULTS: Pain was reported in 78.6% of Multiple System Atrophy patients and in 37.5% of Parkinson's disease patients. In the OFF condition, subjective and objective pain thresholds were significantly lower in Multiple System Atrophy patients than in healthy controls (43.8 degrees C +/- 1.3 vs 45.7 degrees C +/- 0.8; p = 0.0005 and 7.4 mA +/- 3.8 vs 13.7 mA +/- 2.8; p = 0.002, respectively). They were also significantly reduced in Multiple System Atrophy compared to Parkinson's disease patients. No significant difference was found in pain tolerance for the 3 groups and in the effect of l-DOPA on pain thresholds in Multiple System Atrophy and Parkinson's disease patients. In the ON condition, pain tolerance tended to be reduced in Multiple System Atrophy versus Parkinson's disease patients (p = 0.05). CONCLUSION: Multiple System Atrophy patients had an increase in pain perception compared to Parkinson's disease patients and healthy controls. The l DOPA effect was similar for pain thresholds in Multiple System Atrophy and Parkinson's disease patients, but tended to worsen pain tolerance in Multiple System Atrophy. PMID- 29254665 TI - Pittsburgh Compound B and AV-1451 positron emission tomography assessment of molecular pathologies of Alzheimer's disease in progressive supranuclear palsy. AB - INTRODUCTION: Little is known about Alzheimer's disease molecular proteins, beta amyloid and paired helical filament (PHF) tau, in progressive supranuclear palsy (PSP). Recent techniques have been developed to allow for investigations of these proteins in PSP. We determined the frequency of beta-amyloid deposition in PSP, and whether beta-amyloid deposition in PSP is associated with PHF-tau deposition pattern, or clinical features. METHODS: Thirty probable PSP participants underwent MRI, [18F]AV-1451 PET and Pittsburgh compound B (PiB) PET. Apolipoprotein (APOE) genotyping was also performed. A global PiB standard-uptake value ratio (SUVR) was calculated. AV-1451 SUVRs were calculated for a set of Alzheimer's disease (AD)-related regions and a set of PSP-related regions. Voxel level analyses were conducted to assess for differences in AV-1451 uptake patterns and MRI atrophy between PiB(+) and PiB(-) cases compared to 60 normal PiB(-) controls. Statistical testing for correlations and associations between variables of interest were also performed. RESULTS: Twelve subjects (40%) showed beta-amyloid deposition. Higher PiB SUVR correlated with older age but not with AV-1451 SUVR in the AD- or PSP-related regions. Higher AV-1451 SUVR in AD-related regions was associated with higher AV-1451 SUVR in PSP-related regions. We found little evidence for beta-amyloid related differences in clinical metrics, proportion of APOE e4 carriers, pattern of AV-1451 uptake, or pattern of atrophy. CONCLUSION: Beta-amyloid deposition occurs in a relatively high proportion of PSP subjects. Unlike in Alzheimer's disease, however, there is little evidence that beta-amyloid, and PHF-tau, play a significant role in neurodegeneration in PSP. PMID- 29254666 TI - Do wave heights and water levels increase ocean lifeguard rescues? AB - OBJECTIVE: To investigate the association of wave height and tidal water level changes with the frequency of ocean lifeguard rescues. METHODS: All ocean lifeguard rescues recorded by Newport Beach Lifeguards in 2015 and 2016 were linked by time and location to weather and ocean variables contained in other historical databases. We performed separate multivariable analyses using mixed effects negative binomial regression to evaluate the total effects of wave height, mean water level (primarily set by tidal elevation), and rising vs. falling water level, on the frequency of ocean rescue in the study location, controlling for confounding variables. RESULTS: Newport Beach Lifeguards made 8046 rescues during the study period. In all areas of the beach, rescue frequency increased as waves got larger (IRR: 3.25; 95%CI: 2.91-3.79) but then decreased in large surf (IRR: 0.52; 95%CI: 0.37-0.73). In two sections of beach, lifeguards made more rescues during lower water levels, but in the third section of beach, made more rescues during higher water levels. Rescue frequency increased in two sections of beach with rising water levels, but did not in the other section. CONCLUSIONS: Wave height, water level, and water level direction were associated with rescue frequency, but the environmental factors included in the analysis did not fully account for most variation in rescue frequency. Other factors need to be evaluated to identify major determinants of rescue frequency. PMID- 29254667 TI - "Reply to letter, More questions than answers - advanced life support interventions for out of hospital cardiac arrest". PMID- 29254668 TI - Post-bariatric surgery starvation ketoacidosis and lipase elevation in the absence of DKA or pancreatitis. AB - We report a case of post bariatric surgery by laparoscopic sleeve gastrectomy who presented with post-surgical poor oral tolerance and high anion gap metabolic ketoacidosis, who was initially misdiagnosed with diabetic ketoacidosis and treated with volume supplementation without improvement. The metabolic derangements were found to be caused by starvation ketoacidosis, which was then treated with glucose supplementation, and the anion gap quickly closed. Moreover, this patient also presented with non-pancreatitis lipase elevation. This case highlights the recognition and management of post-bariatric surgery starvation ketoacidosis; additionally, clinicians should be vigilant about the interpretation and management of elevated lipase without clinical pancreatitis. PMID- 29254669 TI - Pain management of acute limb trauma patients with intravenous lidocaine in emergency department. AB - INTRODUCTION: This study was designed to assess the possible superiority of intravenous lidocaine to morphine for pain management. METHODS: This was a randomized double blind controlled superiority trial, carried on in the emergency department (ED). Traumatic patients older than 18-year-old with the complaint of acute pain greater than 4 on a numeric rating scale (NRS) from 0 to 10 on their extremities were eligible. One group received IV lidocaine (1.5 mg/kg), and the other received IV morphine (0.1mg/kg). Pain scores and adverse effects were assessed at 15, 30, 45 and 60 minutes and patients' satisfaction was evaluated two hours later. A minimum pain score reduction of 1.3 from baseline was considered clinically significant. RESULTS: Fifty patients with the mean age of 31.28+/-8.7 were enrolled (78% male). The demographic characteristics and pain scores of the two groups was similar. The on-arrival mean pain scores in two groups were, lidocaine: 7.9+/-1.4 and morphine: 8.0+/-1.4 (p=0.57) and after 1 hour were, lidocaine: 2.28+/-1.2 and morphine: 3.2+/-1.7. Although the pain score decreased significantly in both group (p=0.027), there were not any clinically and statistically significant difference between the two groups (p=0.77). Patients' satisfaction with pain management in both groups were almost similar (p=0.49). CONCLUSION: The reduction in pain score using IV lidocaine is not superior to IV morphine in adult ED patients with traumatic limb pain. PMID- 29254670 TI - Changes of heart rate variability predicting patients with acute exacerbation of chronic obstructive pulmonary disease requiring hospitalization after Emergency Department treatment. AB - BACKGROUND: Indexes of heart rate variability (HRV) appear to reflect severity and may have prognostic value in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We hypothesized that AECOPD without adequate treatment response would demonstrate impaired cardiac autonomic regulation and changes in HRV after emergency department (ED) treatment. METHODS: A prospective study of measuring HRV in admitted and discharged patients with AECOPD shortly after ED arrival and again 24 h after treatment. RESULTS: Total consecutive 33 patients (18 admitted and 15 discharged, age 77.1 +/- 1.6 years) were enrolled. Among admitted patients, high frequency in normalized unit (HF%) was significantly lower (P < 0.001) while Ratio of LF to HF (LF/HF ratio) was significantly higher (P < 0.001) than discharged. 24 h after treatment, admitted patients had a significantly larger increase in HF% (P < 0.002) and larger decrease in LF/HF ratio (P < 0.05) than discharged. ROC curve analysis show the relative potential of the DeltaHF% and DeltaLF/HF% in the discrimination of groups. The area under the ROC curve between the 2 groups was 0.807 (P < 0.01) and 0.722 (P < 0.05), respectively. The best cut-off value for the admission between groups was DeltaHF% >7.1 and DeltaLF/HF% ?-0.39. CONCLUSION: Patients with AECOPD requiring admission after ED treatment had a greater increase in HF% and greater decrease in LF/HF ratio compared to those discharged. Our study demonstrates patient with DeltaHF% was >7.1 or a DeltaLF/HF% ?-0.39 require admission despite 24 h of ED treatment. PMID- 29254671 TI - Optimizing androgen deprivation therapy with radiation therapy for aggressive localized and locally advanced prostate cancer. AB - Radiation therapy with androgen deprivation therapy (ADT) has historically been one of the mainstays of treatment for intermediate- and high-risk prostate cancer. The benefit of ADT likely derives from both enhancing local control and inhibiting micrometastatic disease. While level 1 evidence has demonstrated the benefits of 4-6 months of ADT for all men with intermediate-risk disease, further stratification of intermediate-risk prostate cancer into favorable and unfavorable subgroups indicates that ADT may not be necessary for favorable intermediate-risk disease but likely still provides a survival advantage for unfavorable intermediate-risk disease, even in the dose escalation era. Long course ADT, consisting of 2-3 years of treatment, is the standard of care for high-risk prostate cancer managed with RT based on phase III trials. However, emerging data from a randomized trial raises the possibility that 18 months of ADT could be sufficient for select high-risk patients. The desire to minimize exposure to ADT lies in its many adverse effects, including the potential for cardiovascular harm in certain patients with significant coexisting comorbidity, possibly increased risk for neurocognitive and psychiatric events, and the well documented metabolic changes. Providers need to carefully weigh these potential risks with the known survival benefits of ADT in aggressive localized and locally advanced prostate cancer. PMID- 29254672 TI - A comparison of overall survival and perioperative outcomes between partial and radical nephrectomy for cT1b and cT2 renal cell carcinoma-Analysis of a national cancer registry. AB - OBJECTIVES: Partial nephrectomy (PN) is the standard management of cT1a renal cell carcinoma (RCC), and there is a basis for expanding its indications to larger tumors (cT1b and cT2). We analyzed a large population-based cancer registry to compare the overall survival (OS) and perioperative outcomes in patients with cT1b and cT2 RCC undergoing PN with those undergoing radical nephrectomy (RN). MATERIALS AND METHODS: Patients with cT1bN0M0 and cT2N0M0 RCC were identified from the National Cancer Database (2004-2013). Patients were classified by the surgery performed and 1:1 propensity matched based on the likelihood of receiving PN. They were then compared for OS, 30-day readmission rates and 30- and 90-day mortality. RESULTS: A total of 6,072 patients underwent PN. PN was associated with better OS in cT1b tumors on multivariate analyses (OR = 0.8; 95% CI: 0.72-0.89; P<0.001). For cT2 tumors, PN was associated with better OS, however this was not statistically significant (OR = 0.8; 95% CI: 0.62-1.04; P = 0.092). Unplanned readmission at 30 days was significantly more common in patients undergoing PN (4.2%) vs. RN (2.9%) but there was no difference in 30- and 90-day mortality between the 2 groups. CONCLUSIONS: PN was associated with a significantly better OS than RN for cT1b but not cT2 RCC. PN had a higher 30-day readmission rate than RN in these tumors and appropriate patient selection is crucial. These results require further validation, ideally via randomized trials. PMID- 29254673 TI - Perioperative chemotherapy for bladder cancer in the general population: Are practice patterns finally changing? AB - BACKGROUND: Uptake of perioperative chemotherapy for muscle-invasive bladder cancer (MIBC) has been historically poor. We describe contemporary use of neoadjuvant (NACT) and adjuvant chemotherapy (ACT) as well as medical oncology (MO) referral patterns in routine practice. METHODS: Electronic treatment records were linked to the population-based Ontario Cancer Registry to identify all MIBC patients treated with cystectomy in Ontario 1994 to 2013. Physician billing records were used to identify consultation with MO. Practice patterns in the contemporary era (2009-2013) are compared with data from 1994 to 2008. RESULTS: A total of 5,582 patients had cystectomy for MIBC. Use of NACT increased from 4% in 1994 to 2008 to 19% in 2009 to 2013 (P<0.001); rates continued to rise in the most recent era from 12% in 2009 to 27% in 2013 (P<0.001). ACT was delivered to 20% of patients in 2009 to 2013 (19% in 1994-2008, P = 0.875). Use of any chemotherapy (NACT or ACT) in 2009 to 2013 was 35% compared to 23% in 1994 to 2008 (P<0.001). Preoperative referral rates during 2009 to 2013 to MO were greater than 1994 to 2008 (32% vs. 11%, P<0.001); referral rates continued to increase in recent years from 21% in 2009 to 44% in 2013 (P<0.001). The proportion of referred patients ultimately treated with NACT increased substantially; from 32% in 1994 to 1998 to 54% in 2009 to 2013 (P<0.001). CONCLUSIONS: After many years of practice lagging behind evidence, use of NACT in the general population has increased substantially. Our results suggest that increased uptake has been driven by greater preoperative referral to MO as well as greater propensity of MOs to treat referred patients. PMID- 29254674 TI - Arrhythmia care in a value-based environment: Past, present, and future: Developed and endorsed by the Heart Rhythm Society (HRS). PMID- 29254676 TI - Sport Concussion Assessment Tool: Interpreting day-of-injury scores in professional ice hockey players. AB - OBJECTIVES: To characterize the clinical utility of Sport Concussion Assessment Tool 3 (SCAT3) baseline and normative reference values for the assessment of acute concussion; and to identify the sensitivity of each SCAT3 subcomponent to the acute effects of concussion. DESIGN: Prospective cohort. METHODS: The day-of concussion SCAT3 results (n=27) of professional male ice hockey players (mean age=27, SD=4) were compared to athlete's individual baseline and to the league's normative reference values. Normative cutoffs corresponding to 10th percentile and natural distribution change cutoffs corresponding to 90th percentile cumulative frequency were considered uncommon. RESULTS: The percentages of the players with uncommon day-of-injury performance, when post-injury scores were compared to individual baseline versus (vs.) normative values, were as follows: symptoms: 96% vs. 100% (post-injury score: M=12, Md=12, SD=4; severity M=26, Md=23, SD=13); Standardized Assessment of Concussion (SAC): 33% vs. 27% (post injury M=25, Md=26, SD=3); modified-BESS (M-BESS): 46% vs. 46% (post-injury M=7, Md=5, SD=7); Tandem Gait: 18% vs. 31% (post-injury M=11, Md=12, SD=4); coordination: both 8%. The number and severity of post-injury symptoms were significantly greater, with extremely large effect sizes (Cohen's d=2.44-3.92), than normative values and individual baseline scores. The post-injury SAC score was significantly lower relative to both baseline (d=0.68) and normative values (d=0.88). The post-injury M-BESS performance was significantly worse when compared to both individual baseline (d=1.06) and league normative values (d=1.46). No significant day-of-injury Tandem Gait deficits were observed using either comparison method. CONCLUSIONS: SCAT3 league normative values were as sensitive as individual baseline scores during day-of-injury assessments. Symptoms were the most sensitive post-concussion component of the SCAT3. PMID- 29254675 TI - Late-Life Depressive Symptoms as Partial Mediators in the Associations between Subclinical Cardiovascular Disease with Onset of Mild Cognitive Impairment and Dementia. AB - OBJECTIVE: To study whether depression contributes to the association between subclinical cardiovascular disease (CVD) and dementia, and identify the contribution's magnitude. METHODS: Among participants from the Cardiovascular Health Study Cognition Study who did not have baseline CVD-related events (N = 2,450), causal mediation methodology was implemented to examine whether late-life depressive symptoms, defined as 10-item Center for Epidemiologic Studies Depression (mCES-D) Scale scores >=8 from 2 to 3 years after baseline, partially mediated the association of baseline subclinical CVD (CAC, carotid intimal medial thickness, stenosis, and ankle brachial index) with mild cognitive impairment (MCI)/dementia onset occurring between 5 and 10 years from baseline. The total effect was decomposed into direct and indirect effects (via late-life depressive symptoms), obtained from an accelerated failure time model with weights derived from multivariable logistic regression of late-life depressive symptoms on subclinical CVD. Analyses were adjusted by baseline covariates: age, race, sex, poverty status, marital status, body mass index, smoking status, ApoE4 status, and mCES-D. RESULTS: Participants contributed 20,994 person-years of follow-up with a median follow-up time of 9.4 years. Subclinical CVD was associated with 12% faster time to MCI/dementia (time ratio [TR]: 0.88; 95% CI: 0.83, 0.93). The total effect of subclinical CVD on MCI/dementia onset was decomposed into a direct effect (TR: 0.95, 95% CI: 0.92, 0.98) and indirect effect (TR: 0.92, 95% CI: 0.88, 0.97); 64.5% of the total effect was mediated by late-life depressive symptoms. CONCLUSIONS: These data suggest late-life depressive symptoms partially mediate the association of subclinical CVD with MCI/dementia onset. PMID- 29254677 TI - Trends in Length of Hospital Stay and the Impact on Prognosis of Early Discharge After a First Uncomplicated Acute Myocardial Infarction. AB - Few studies have examined recent trends in the length of stay (LOS) among patients hospitalized with a first uncomplicated acute myocardial infarction (AMI) and the impact of early hospital discharge on various short-term outcomes in these low-risk patients. We used data from 1,501 residents hospitalized with a first uncomplicated AMI from all central Massachusetts medical centers on a biennial basis between 2001 and 2011. The association between hospital LOS and subsequent hospital readmission or death was examined using logistic regression modeling. The average age of the study population was 63.7 years, 63.0% were men, and 91.4% were non-Hispanic whites. The average hospital LOS declined from 4.1 days in 2001 to 2.9 days in 2011. During the years under study, the average 30 day hospital readmission rate was 11.9%, whereas the 30- and 90-day death rates were 1.5% and 2.9%, respectively. The multivariable adjusted odds ratio of a 30 day hospital readmission (odds ratio [OR] = 0.81, 95% confidence interval [CI] = 0.52 to 1.41), or 30-day (OR = 0.93, 95% CI = 0.29 to 2.98) and 90-day (OR = 0.89, 95% CI = 0.36 to 2.20) death rates were not significantly different between patients who were discharged from central Massachusetts medical centers during the first 2 days as compared with those discharged thereafter. In conclusion, the average LOS in patients with a first uncomplicated AMI declined during the years under study, and early discharge from the hospital at day 2 or sooner of these low-risk patients does not appear to be associated with an increased risk of adverse events post discharge compared with those discharged at a later time. PMID- 29254678 TI - Usefulness of Inferior Vena Cava Filters in Unstable Patients With Acute Pulmonary Embolism and Patients Who Underwent Pulmonary Embolectomy. AB - Administrative data were analyzed from the Premier Healthcare Database, 2010 to 2014, to assess whether inferior vena cava (IVC) filters reduce mortality in unstable patients (in shock or on ventilator support) with acute pulmonary embolism and in stable patients who undergo surgical pulmonary embolectomy. Mortality was assumed to be due to pulmonary embolism in patients who had none of the co-morbid conditions listed in the Charlson Comorbidity Index. Data were determined on the basis of International Classification of Disease-9th Clinical Modification (ICD-9-CM) codes. All-cause mortality in unstable patients was lower with IVC filters in-hospital, 288 of 1,972 (23%) versus 1339 of 3002 (45%) (p <0.0001), and at 3 months, all-cause mortality was 316 of 1,272 (25%) versus 1,428 of 3,002 (48%) (p <0.0001). Pulmonary embolism mortality was lower with IVC filters in unstable patients in-hospital, 191 of 926 (21%) versus 913 of 2,138 (43%) (p <0.0001) and at 3 months, 215 of 926 (23%) versus 971 of 2,138 (45%) (p <0.0001). A lower in-hospital and 3-month all-cause mortality and pulmonary embolism mortality was also shown with IVC filters in stable patients who underwent pulmonary embolectomy. These data, in concert with previous retrospective data, suggest that unstable patients with pulmonary embolism and stable patients who undergo pulmonary embolectomy may benefit from an IVC filter. Further investigations would be useful. PMID- 29254679 TI - Relation Between Renin-Angiotensin System Blockers and Survival Following Isolated Aortic Valve Replacement for Aortic Stenosis. AB - Renin-angiotensin system blockers (RASb) improve cardiac remodeling, but their clinical utility after surgical aortic valve replacement (SAVR) for aortic stenosis (AS) is unclear. We aimed to assess the impact of RASb on short- and long-term survival following isolated SAVR for severe AS. From January 2005 to January 2014, 508 consecutive patients had isolated SAVR for severe AS. Patients with RASb (n = 286; 53%) were more often female (p = 0.039), hypertensive (p < 0.0001), and diabetic (p = 0.004), with higher body mass index (p < 0.0001) and EuroSCORE II (p = 0.025), and lower mean aortic pressure gradient (p = 0.011). The 30-day mortality was similar in both groups (RASb: 3% vs no RASb: 5.8%, p = 0.13), but lower under angiotensin receptor blockers (ARB) than angiotensin converting enzyme inhibitors (ACEi; 0.7% vs 5.6%, p = 0.017). Patients under RASb had a better 8-year survival than those without RASb (83 +/- 3% vs 52 +/- 5%, p < 0.0001), confirmed in a propensity score-matched pairs analysis (82 +/- 4% vs 50 +/- 7%, p < 0.0001). Regarding different types of RASb, patients under ARB had lower mortality than those under ACEi (87 +/- 3% vs 79 +/- 4%, p = 0.028). In multivariate analysis, the use of RASb was associated with improved survival (hazard ratio = 0.31, 95% confidence interval 0.20 to 0.47, p < 0.0001), with lower mortality under ARB than under ACEi (hazard ratio = 0.39, 95% confidence interval 0.18 to 0.85, p = 0.018). In this observational study, the use of RASb was associated with improved long-term outcome after isolated SAVR for severe AS. A randomized clinical trial is mandatory. PMID- 29254680 TI - Steady-State Clozapine and Norclozapine Pharmacokinetics in Maori and European Patients. AB - BACKGROUND: Clozapine is the most effective drug for treatment-resistant schizophrenia, but its use is limited by toxicity. Because ethnicity has been reported to affect clozapine metabolism, we compared its steady state pharmacokinetics in New Zealand Maori and European patients. METHODS: Clozapine and norclozapine steady state bioavailability was assessed over 24h under fasting and fed conditions in 12 Maori and 16 European patients treated for chronic psychotic illnesses with stable once-daily clozapine doses. Plasma clozapine and norclozapine concentrations were assessed using liquid chromatography with tandem mass spectrometry; pharmacokinetic parameters were calculated using standard non compartmental methods, and compared using unpaired t-tests. FINDINGS: Mean pharmacokinetic parameters (AUC, Cmax and Cmin) for clozapine and norclozapine were virtually identical in Maori and European subjects, under both fed and fasted conditions. DISCUSSION: Clozapine bioavailability does not vary between Maori and European patients, and thus does not need to be considered in prescribing decisions. Additional studies are needed to identify if there are differences between Maori and European populations for drugs metabolized by other enzyme pathways. PMID- 29254682 TI - SHOX deficiency in short Taiwanese children: A single-center experience. AB - BACKGROUND: SHOX deficiency is a common cause of idiopathic short stature. The aim of this study was to describe the clinical characteristics and molecular findings of patients with SHOX deficiency in Taiwan. METHODS: A phenotype scoring system was used to evaluate several anthropometric measures in patients with idiopathic short stature. Twenty-three patients with a phenotype score >7 were enrolled for SHOX gene analysis by MLPA and sequencing. Another patient with a deletion/insertion of the short arm of the X chromosome containing the SHOX gene was enrolled for the assessment. RESULTS: SHOX deficiency was detected in 26% of short children with a phenotype score >7. The arm-span-to-height ratio was significantly lower in SHOX-D patients than in non-SHOX-D patients. In patients with SHOX deficiency, an arm-span-to-height ratio <96.5% and short forearm were the most common characteristics. Three patients also exhibited typical radiological findings. A molecular analysis of the SHOX gene revealed five patients with intragenic deletions, one with a deletion in the regulatory region, and one with a missense mutation at exon 5. CONCLUSION: The phenotype scoring system is useful to select children with SHOX deficiency in Taiwan. Family history and radiological image of the radius are also of value for the diagnosis. This study may aid physicians in the early diagnosis of children with SHOX deficiency. PMID- 29254683 TI - 10-Point CT-ASPECTS-based reperfusion therapy for unknown onset stroke. AB - Under the time-based criteria, patients with unknown onset stroke (UOS) are ineligible for reperfusion therapies. However, previous studies suggest that some patients with UOS may benefit from reperfusion. Several imaging modalities have been suggested to select patients for intervention, but the optimal imaging criteria are still controversial. Herein we present a series of four cases using 10-point CT-ASPECTS to support our decision of reperfusion therapy. We decided based on history, symptoms, and the 10-point CT-ASPECTS alone. Each patient's history suggested that the stroke just took place. All four patients had apparent clinical symptoms, with 10-point CT-ASPECTS. All of them had a reduction in their NIHSS after the reperfusion therapy. 10-point CT-ASPECTS could be used to support the presumption that the stroke just happens in patients with UOS. Further study is warranted to elucidate the value of CT-ASPECTS for UOS patients. PMID- 29254684 TI - Risk factors for development of hepatocellular carcinoma in patients with chronic hepatitis C without sustained response to combination therapy. AB - BACKGROUND/PURPOSE: Although antiviral therapy reduces development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), HCC often develops in patients with non-sustained virologic response (non-SVR). We aimed to evaluate risk factors for HCC in HCV patients with non-SVR. METHODS: From March 2002 to December 2013, 800 patients with CHC who had received combined pegylated interferon (peg-IFN)/ribavirin (RBV) therapy without achieving SVR were enrolled. Main outcome measure was HCC development. Variables were cirrhosis, platelet count, alpha-fetoprotein (AFP) levels, aspartate aminotransferase (AST) to platelet ratio index (APRI), and IL28B polymorphism (CT + TT). RESULTS: One hundred of 800 non-SVR patients developed HCC within a median 53.5-months follow up. Cumulative incidence of HCC for all patients was 1.4%, 5.6% and 12.3%, respectively, at 1st, 3rd and 5th years of follow-up. In univariate analysis, patients who developed HCC tended to have LC (p< 0.001), lower platelet counts (<150 * 109/l, p < 0.001), higher AFP levels (>=20 ng/ml, p < 0.001), higher Fib 4 levels (p < 0.001), higher APRI levels (p < 0.001), IL 28B polymorphism (CT + TT) (p < 0.001) and higher incidence of diabetes mellitus (DM) (p = 0.019). Multivariate analysis in overall patients revealed that cirrhosis (HR: 2.94, 95% CI: 1.81-4.77, p < 0.001), IL28B rs12979860 (CT + TT) polymorphisms (HR: 3.22, 95% CI: 2.17-4.78, p < 0.001), and high APRI levels (>=2.57) (HR: 2.32, 95% CI: 1.47-3.67, p < 0.001) were independent risk factors for HCC. CONCLUSION: Liver cirrhosis, high APRI levels, and IL28B rs12979860 at baseline are independent risk factors for HCC development in patients without SVR after peg-IFN combination therapy. PMID- 29254681 TI - Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis. AB - Costello syndrome is a "RASopathy" that is characterized by growth retardation, dysmorphic facial appearance, hypertrophic cardiomyopathy and tumor predisposition. >80% of patients with Costello syndrome harbor a heterozygous germline G12S mutation in HRAS. Altered metabolic regulation has been suspected because patients with Costello syndrome exhibit hypoketotic hypoglycemia and increased resting energy expenditure, and their growth is severely retarded. To examine the mechanisms of energy reprogramming by HRAS activation in vivo, we generated knock-in mice expressing a heterozygous Hras G12S mutation (HrasG12S/+ mice) as a mouse model of Costello syndrome. On a high-fat diet, HrasG12S/+ mice developed a lean phenotype with microvesicular hepatic steatosis, resulting in early death compared with wild-type mice. Under starvation conditions, hypoketosis and elevated blood levels of long-chain fatty acylcarnitines were observed, suggesting impaired mitochondrial fatty acid oxidation. Our findings suggest that the oncogenic Hras mutation modulates energy homeostasis in vivo. PMID- 29254685 TI - Recent advances in tools and technologies for monitoring and controlling ovarian activity in marsupials. AB - Components of assisted reproduction technologies (ART), such as sperm cryopreservation, artificial insemination, superovulation and pouch young surrogacy, have been developed for a range of Australian and American marsupials. However, methods to effectively control ovarian function, arguably the key limiting factors in applying and integrating ART as a practical tool in conservation management, remain poorly developed. This is largely due to unique characteristics of the marsupial corpus luteum and its failure to respond to agents used to synchronize ovarian function in eutherian mammals. This paper presents an overview of relevant aspects of marsupial reproductive biology across marsupial taxonomic groups including information on the long-established technique of removal of suckling young to activate ovarian cycles. Ovarian monitoring tools for marsupials are reviewed and their usefulness for ART assessed (laparotomy, hormone cycling, vaginal cytology, laparoscopy and ultrasonography). We also discuss promising recent work examining the potential of manipulating hypothalamic-pituitary function using GnRH agonists and antagonists as the basis of ovarian control (female synchronization) strategies. PMID- 29254686 TI - Monitoring and controlling ovarian activities in wild ungulates. AB - Reproductive success in females relies primarily upon better understanding of fundamental ovarian processes to facilitate captive reproductive management and ultimately the development of assisted reproductive technologies as an alternative tool for conservation breeding of endangered wildlife species. Wild ungulates (cervids and non-domestic bovids) are an extraordinarily diverse group of mammals with remarkable diversity in reproductive biology (anatomy, behaviour, physiology and seasonality). This indicates a clear need, and indeed a big challenge, for acquiring such basic reproductive knowledge in severely threatened ungulates before attempting even a simpler technology such as artificial insemination. Despite a few sporadic successes of artificial insemination technology in ungulates, there is much to learn, including optimizing estrus synchronization protocols and an animal-friendly fixed-time insemination procedure that would maximize breeding success with minimal stress to the animal. Recent advances in non-invasive methodologies for monitoring endocrine profiles and assessment of ovarian function in wildlife species enable us to understand and characterize basic reproductive events in a species. This review discusses non-invasive approaches being used for monitoring endocrine and ovarian activity in wild ungulates. Further, it reviews the effectiveness of different methodologies for control of estrus and ovulation in non-domestic bovids and cervids. Additionally, the challenges regarding their application in different ungulates as a standard routine practice like in livestock are addressed. PMID- 29254687 TI - A pilot study of primary care physicians' attitude to weight loss surgery in England: are the young more prejudiced? AB - BACKGROUND: Primary care practitioners (PCP) are the "gate-keepers" for publicly funded weight loss surgery (WLS) in the United Kingdom, but their attitude toward WLS has not been studied to date. OBJECTIVE: This pilot study aimed to investigate opinions and experience of PCPs regarding WLS in the United Kingdom. SETTING: PCPs from 3 publicly funded primary care consortiums from distinct geographic areas within the United Kingdom were surveyed. METHODS: A cross sectional survey approach was used to assess PCP attitude to WLS surgery. A questionnaire was sent electronically to PCPs, designed to assess PCP demographic, experience, knowledge, and attitude regarding obesity and WLS. For the purposes of analysis, PCPs were divided into junior and senior based on duration of practice. RESULTS: Of PCPs, 35 completed and returned the questionnaire. Although PCPs stated that approximately 30% of their patients were obese, 17 (49%) had made not a single referral for WLS in the previous 12 months. PCPs overestimated early WLS mortality rate more than 10-fold and 23 (66%) did not feel confident providing care to patients post-WLS. Junior PCPs were significantly more likely to feel that WLS should not be publicly funded (P = .01). CONCLUSIONS: These findings suggest a prejudice against WLS amongst PCPs in England, particularly among junior doctors. PMID- 29254688 TI - Long-term durability of outcomes after bariatric surgery: thinking outside the box. PMID- 29254689 TI - Decreased visceral fat area correlates with improved total testosterone levels after Roux-en-Y gastric bypass in obese Chinese males with type 2 diabetes: a 12 month follow-up. AB - BACKGROUND: Obesity and type 2 diabetes (T2D) are recognized as risk factors for hypogonadism in males. Serum sex hormone profiles have not been assessed adequately in obese Chinese males with T2D who have undergone Roux-en-Y gastric bypass (RYGB). OBJECTIVE: This study was conducted to examine the changes in sex hormone profiles, anthropometric parameters, and metabolic indexes before and after RYGB. SETTING: University Hospital, China. METHODS: There were 45 obese males with T2D who had undergone RYGB enrolled in this retrospective study, focusing on anthropometric parameters, metabolic indexes, and sex hormone profiles before and after surgery. RESULTS: The baseline prevalence of hypogonadism (defined by total testosterone [TT] levels<8 nM) was 33.33%. After surgery, both the levels of TT and sex hormone-binding globulin increased, while the levels of estradiol decreased. However, the calculated free testosterone, follicle-stimulating hormone, and luteinizing hormone levels remained unchanged. Multiple linear regression analysis showed that the visceral fat area was the only significant and independent parameter associated with TT levels at baseline (beta = -.479, P = .001). After surgery, decreases in the visceral fat area continued to be negatively associated with increases in TT (r = -.411, P = .024). CONCLUSION: These preliminary results demonstrated that TT could be significantly increased in obese Chinese males with T2D after RYGB; this occurs in part via a reduction in adipose tissue, especially visceral fat. Therefore, RYGB might be a promising therapy to treat hypogonadism in obese men with T2D. PMID- 29254690 TI - Traffic risk behaviour: an observational study of drivers' behaviour in Braga (Portugal). PMID- 29254691 TI - PCSK9 inhibitors in clinical practice: Delivering on the promise? AB - BACKGROUND AND AIMS: In clinical trials, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors robustly lowered LDL-cholesterol (LDL-c) and had a favorable tolerability and safety profile. Based on these findings, PCSK9 inhibitors are incorporated in updates of clinical treatment guidelines. However, trial results do not necessarily predict the effectiveness under real-world conditions. The aim of the current study is to determine the efficacy and tolerability of PCSK9 inhibitors in routine outpatient care. METHODS: The cohort comprised all patients who were prescribed evolocumab or alirocumab at the outpatient clinic of a large university hospital in the Netherlands. Eligible patients required additional lipid-lowering despite maximally tolerated statin therapy and ezetimibe, or were statin intolerant. Data were systematically collected during routine outpatient visits. RESULTS: The study included 238 patients of whom 67.2% had familial hypercholesterolemia (FH) and 42.9% were statin intolerant. The mean LDL-c reduction was 55.0% from a baseline of 4.4 mmol/L. LDL-c goals were attained by 62.3% of patients. Side effects were reported by 15.5% of patients and 2.5% discontinued treatment. No meaningful differences in efficacy or tolerability were observed between patients with FH or statin intolerance, or across treatment regimens. CONCLUSIONS: The observed lipid reductions and side effects profile of PCSK9 inhibitors in a routine care setting were comparable to observations in clinical trials. PMID- 29254693 TI - Morphometric measurements of extracranial and intracranial atherosclerotic disease: A population-based autopsy study. AB - BACKGROUND AND AIMS: Intracranial (IAD) and extracranial atherosclerotic diseases (EAD) have been mostly investigated using imaging methods. Autopsy studies allow for a direct and complete evaluation of the atherosclerotic disease. We aimed to investigate the frequency of IAD and EAD, their association, and related risk profiles in a large cross-sectional autopsy study. METHODS: We measured the intima-media thickness and stenosis of the common (CCA) and internal carotid arteries (ICA), using morphometric measurements. The main outcome was stenosis (>=50%) in the artery with the largest obstruction among the 12 cerebral arteries. We used multivariable logistic regression models to investigate the association between EAD and IAD. RESULTS: In 661 participants (mean age = 71.3 +/ 11.7 y, 51% male), stenosis was more common in IAD than in EAD (59% vs. 51%). EAD was associated with Caucasian race, hypertension, and smoking, while IAD was associated with older age, less years of education, hypertension, diabetes, and a previous history of stroke. Stenosis in CCA and ICA was associated with more than two times the odds of having stenosis in the intracranial arteries (CCA: OR = 2.32, 95% CI = 1.64; 3.28; ICA: OR = 2.51, 95% CI = 1.76; 3.57). CONCLUSIONS: In this population-based autopsy study, IAD was common, even more common than EAD, but correlated with EAD. PMID- 29254694 TI - Persistent socioeconomic disparities in cardiovascular risk factors and health in the United States: Medical Expenditure Panel Survey 2002-2013. AB - BACKGROUND AND AIMS: Socioeconomic status (SES) has been linked to worse cardiovascular risk factor (CRF) profiles and higher rates of cardiovascular disease (CVD), with an especially high burden of disease for low-income groups. We aimed to describe the trends in prevalence of CRFs among US adults by SES from 2002 to 2013. METHODS: Data from the Medical Expenditure Panel Survey was analyzed. CRFs (obesity, diabetes, hypertension, physical inactivity, smoking and hypercholesterolemia), were ascertained by ICD-9-CM and/or self-report. RESULTS: The proportion of individuals with obesity, diabetes and hypertension increased overall, with low-income groups representing a higher prevalence for each CRF. Of note, physical inactivity had the highest prevalence increase, with the "lowest income" group observing a relative percent increase of 71.1%. CONCLUSIONS: Disparities in CRF burden continue to increase, across SES groups. Strategies to potentially eliminate the persistent health disparities gap may include a shift to greater coverage for prevention, and efforts to engage in healthy lifestyle behaviors. PMID- 29254695 TI - ACC/AATS/AHA/ASE/EACTS/HVS/SCA/SCAI/SCCT/SCMR/STS 2017 Appropriate Use Criteria for the Treatment of Patients With Severe Aortic Stenosis: A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Valve Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. AB - The American College of Cardiology collaborated with the American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Valve Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons to develop and evaluate Appropriate Use Criteria (AUC) for the treatment of patients with severe aortic stenosis (AS). This is the first AUC to address the topic of AS and its treatment options, including surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). A number of common patient scenarios experienced in daily practice were developed along with assumptions and definitions for those scenarios, which were all created using guidelines, clinical trial data, and expert opinion in the field of AS. The 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines(1) and its 2017 focused update paper (2) were used as the primary guiding references in developing these indications. The writing group identified 95 clinical scenarios based on patient symptoms and clinical presentation, and up to 6 potential treatment options for those patients. A separate, independent rating panel was asked to score each indication from 1 to 9, with 1-3 categorized as "Rarely Appropriate," 4-6 as "May Be Appropriate," and 7-9 as "Appropriate." After considering factors such as symptom status, left ventricular (LV) function, surgical risk, and the presence of concomitant coronary or other valve disease, the rating panel determined that either SAVR or TAVR is Appropriate in most patients with symptomatic AS at intermediate or high surgical risk; however, situations commonly arise in clinical practice in which the indications for SAVR or TAVR are less clear, including situations in which 1 form of valve replacement would appear reasonable when the other is less so, as do other circumstances in which neither intervention is the suitable treatment option. The purpose of this AUC is to provide guidance to clinicians in the care of patients with severe AS by identifying the reasonable treatment and intervention options available based on the myriad clinical scenarios with which patients present. This AUC document also serves as an educational and quality improvement tool to identify patterns of care and reduce the number of rarely appropriate interventions in clinical practice. PMID- 29254696 TI - What doesn't kill them doesn't make them stronger: Questioning our current notions of resilience. AB - This study expands on earlier analyses of the data generated by a cross-sectional study involving a random sample of 5149 middle-school students with a mean age of 14.5 years from four EU-countries (Austria, Germany, Slovenia, and Spain), in which every fourth respondent (23.0%) had been physically abused by his or her parents and almost every sixth respondent (17.3%) had witnessed physical spousal abuse. Contrary to expectations, some of these youths reported no engagement in peer violence and no symptoms of depression, which meant that they could be considered "resilient." Given their precarious conditions, we inquired into how these young people functioned on other protective and risk indicators when compared to non-violence exposed peers. Using Bonferroni post-hoc tests, we conducted an analysis of variance based comparison of levels of risk and protective factors on three groups of violence and depression-resilient youth (low, middle and high family violence experience) with those participants who reported no family violence or abuse, no depression and no use of violence. The violence and depression-resilient participants reported significantly higher levels of aggression supportive beliefs, alcohol consumption, drug use, verbal aggression towards and from teachers and use of indirect aggression, along with lower levels of social and personal protective characteristics such as self acceptance, emotional self-control, optimism about the future, and positive relations with parents and teachers, than students without family violence experiences. We therefore concluded that while some family violence exposed young people may not engage in violence or experience depression, this does not automatically imply an absence of other challenges and calls into question our current notions of resilience. PMID- 29254697 TI - Supporting resilience in war-affected children: How differential impact theory is useful in humanitarian practice. AB - This paper examines the utility of the Differential Impact Theory for child protection practitioners who work in humanitarian settings, with a focus on war affected children. A primary advantage of DIT is that it focuses efforts to strengthen children's resilience on improving children's social ecologies at different levels. This ecological focus is more likely to address the sources of children's suffering and resilience and also helps to avoid the problems associated with an individualized focus. It also shows how DIT provides a differentiated view of war-affected children and stimulates multiple interventions at different ecological levels, avoiding the common error of taking a one size fits all approach to intervention. In keeping with DIT, it suggests that child protection practice would benefit from addressing macro-level risks such as poverty and discrimination that are drivers of various harms to children and from more systematic linkages between macro- and micro-levels. It concludes that DIT serves as a critical lens for viewing current work on child protection in humanitarian settings and also for illuminating ways to develop more comprehensive supports for children's resilience. PMID- 29254699 TI - Pulmonary vasculitis: An update. PMID- 29254698 TI - Targeting the IDO1/TDO2-KYN-AhR Pathway for Cancer Immunotherapy - Challenges and Opportunities. AB - Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyze the commitment step of the kynurenine (KYN) metabolic pathway. Traditionally the immunosuppressive effect of IDO1 has been attributed mainly to reduced levels of tryptophan, which activates the kinase general control nonderepressible 2 (GCN2). Emerging data have shed light on an unexpected role of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) in transducing the tumor immune escape function imparted by IDO1 and TDO2. AhR activation by the IDO1/TDO2 product KYN leads to the generation of immune tolerant dendritic cells (DCs) and regulatory T cells, which collectively foster a tumor immunological microenvironment that is defective in recognizing and eradicating cancer cells. Multiple IDO1 inhibitors have been evaluated in clinical trials. There are novel modalities downstream of IDO1/TDO2 for pharmacological interventions. We review recent progress and future perspectives in targeting the IDO1/TDO2-KYN-AhR signaling pathway for the development of novel cancer immunotherapies. PMID- 29254700 TI - Morbidity of Pediatric Obstructive Sleep Apnea in Children: Myth, Reality, or Hidden Iceberg? PMID- 29254701 TI - Corrigendum to "Cardiac oxidative stress following maternal separation stress was mitigated following adolescent voluntary exercise in adult male rat "(Physiol. Behav., Volume 183, 1 January 2018, Pages 39-45). PMID- 29254702 TI - A novel technique for superior-based pharyngeal flaps: 10-year results with formal speech outcomes assessment. AB - PURPOSE: Describe a novel technique for superior-based pharyngeal flaps allowing restoration of bulk to the soft palate and intraoperative fine-tuning of lateral port size, while avoiding midline palate-splitting. Validated speech assessment tools are employed for quantitative analysis. METHODS: Retrospective review of all patients who underwent superior-based pharyngeal flap in a 10-year period by a single surgeon. Pittsburgh Weighted Values for Speech Symptoms Associated with VPI and the Goldman-Fristoe Test of Articulation were used for formal speech assessment. RESULTS: 78 patients met inclusion criteria with clinical data up to 10years postoperatively. 31 patients had congenital velopharyngeal insufficiency (VPI), and the remainder acquired VPI after cleft palate repair or adenoidectomy. 37 patients had a recognized syndrome. All patients noted subjective improvement in nasality, and evaluation with the validated speech assessment tools demonstrated statistically significant improvement in speech. Only one flap takedown was required in a patient with severe midface hypoplasia who developed sleep apnea several years postoperatively. CONCLUSIONS: This technique is successful in congenital and acquired VPI, and in patients with complex craniofacial syndromes. Customization of lateral ports based on preoperative nasopharyngoscopy, and avoidance of a midline palate splitting incision, make this an attractive option for superior-based flap surgery. PMID- 29254703 TI - Letter to the editor. PMID- 29254692 TI - Renal function is associated with 1-month and 1-year mortality in patients with ischemic stroke. AB - BACKGROUND AND AIMS: Renal dysfunction is a potent risk factor for cardiovascular diseases, including stroke. This study aimed to evaluate the impact of admission estimated glomerular filtration rate (eGFR) levels on short-term (1-month) and long-term (1-year) mortality in patients with acute ischemic stroke. METHODS: From the Taiwan Stroke Registry data, we classified ischemic stroke patients, identified from April 2006 to December 2015, into 5 groups by eGFR at admission: >= 90, 60-89, 30-59, 15-29, and <15 mL/min/1.73 m2 or on dialysis. Risks of 1 month mortality and 1-year mortality after ischemic stroke were investigated by the eGFR level. RESULTS: Among 52,732 ischemic stroke patients, 1480 died within one month. The 1-month mortality rate was over 5-fold greater in patients with eGFR <15 mL/min/1.73 m2 or dialysis than in patients with eGFR >=90 mL/min/1.73 m2 (2.88 versus 0.56 per 1000 person-days). The adjusted hazard ratio (HR) of 1 month mortality increased from 1.31 (95% CI = 1.08-1.59) for patients with eGFR 60-89 mL/min/1.73 m2 to 2.33 (95% CI = 1.80-3.02) for patients with eGFR < 15 mL/min/1.73 m2 or on dialysis. 3226 patients died within one year. The adjusted HR of mortality increased from 1.38 (95% CI = 1.21-1.59) for patients with eGFR 60-89 mL/min/1.73 m2 to 2.60 (95% CI 2.18-3.10) for patients with eGFR < 15 mL/min/1.73 m2 or on dialysis, compared to patients with eGFR >= 90 mL/min/1.73 m2. CONCLUSIONS: After acute ischemic stroke, patients with reduced eGFR are at elevated risks of short-term and long-term deaths in a graded relationship. PMID- 29254704 TI - Symptomatic unilateral vocal fold paralysis following cardiothoracic surgery. AB - PURPOSE: Unilateral vocal fold paralysis (UVFP) is a complication associated with cardiothoracic procedures that presents clinically as dysphonia and/or dysphagia with or without aspiration. The literature lacks both data on recovery of mobility and consensus on best management. Herein, our goals are to 1) Identify cardiothoracic procedures associated with symptomatic UVFP at our institution; 2) Review timing and nature of laryngology diagnosis and management; 3) Report spontaneous recovery rate of vocal fold mobility. MATERIALS AND METHODS: Retrospective case series at single tertiary referral center between 2002 and 2015. 141 patients were included who underwent laryngology interventions (micronized acellular dermis injection laryngoplasty and/or type 1 thyroplasty) to treat symptomatic UVFP diagnosed subsequent to cardiothoracic surgery. RESULTS: Pulmonary procedures were most often associated with UVFP (n=50/141; 35.5%). 87.2% had left-sided paralysis (n=123/141). Median time to diagnosis was 42days (x-=114+/-348). Over time, UVFP was diagnosed progressively earlier after cardiothoracic surgery. 63.4% of patients (n=95/141) underwent injection laryngoplasty as their initial intervention with median time from diagnosis to injection of 11days (x-=29.6+/-54). 41.1% (n=58/141) ultimately underwent type 1 thyroplasty at a median of 232.5days (x-=367+/-510.2) after cardiothoracic surgery. 10.2% (n=9/88) of those with adequate follow-up recovered full vocal fold mobility. CONCLUSIONS: Many cardiothoracic procedures are associated with symptomatic UVFP, predominantly left-sided. Our data showed poor recovery of vocal fold mobility relative to other studies. Early diagnosis and potential surgical medialization is important in the care of these patients. PMID- 29254705 TI - A 3-year surveillance on causes of death or reasons for euthanasia of domesticated dogs in Taiwan. AB - Over the last 2 decades, there has been growing interest in research on the mortality of domesticated pets. These studies relied on an effective data collecting system. During 2012-2014, a real-time reporting system was designed for mortality data in owned dogs and cats. The present retrospective study aimed to report on the causes of death (CODs) or reasons for euthanasia (RFEs) in domesticated dogs in Taiwan, and to investigate CODs/RFEs segregated by demographic variables. Data from 2306 domesticated dogs were acquired during the 3-year period in the present study. The median age at death of the study population was 10.2 years (median interquartile range 7.0-14.0; range 0.0-25.0). Crossbred, female, and neutered dogs showed greater ages at death than other groups. The most common COD/RFE was neoplasia, followed by multiple organ involvement (MOI) and cardiovascular diseases. Segregated by cut-off ages, the most common COD/RFE was infection among dogs younger than 3 years or 1year, and neoplasia among dogs at or older than 3 years or 1year of age; the most common COD/RFE was neoplasia among dogs younger than median age, and MOI among dogs at or older than median age. Segregated by geographic variables, the ranking and frequency of CODs/RFEs displayed different patterns between the capital city/non capital areas, and among areas stratified by human population densities. The study provides various insights into age at death and CODs/RFEs in owned-dog population in Taiwan, and provides new directions for future research. PMID- 29254706 TI - Economic impact of lumpy skin disease and cost effectiveness of vaccination for the control of outbreaks in Ethiopia. AB - Lumpy skin disease (LSD), an infectious viral disease of cattle, causes considerable financial losses in livestock industry of affected countries. A questionnaire survey with the objectives of determining direct economic losses of LSD (mortality loss, milk loss, draft loss) and treatment costs (medication and labour cost) per affected herd, and assessing the cost effectiveness of vaccination as a means for LSD control was carried out in the central and north western parts of Ethiopia. From a total of 4430 cattle (in 243 herds) surveyed, 941 animals (in 200 herds) were reported to be infected. The overall morbidity and mortality at animal level were 21.2% and 4.5%, and at herd level these were 82.3% and 24.3%. There was a significant difference in animal level morbidity and mortality between categories of animals. Over 94% of the herd owners ranked LSD as a big or very big problem for cattle production. A large proportion (92.2%) of the herd owners indicated that LSD affects cattle marketing. A median loss of USD 375 (USD 325 in local Zebu and USD 1250 in Holstein-Friesian local Zebu cross cattle) was estimated per dead animal. Median losses per affected lactating cow were USD 141 (USD 63 in local Zebu cows and USD 216 in Holstein-Friesian local Zebu cross cows) and, USD 36 per affected ox. Diagnosis and medication cost per affected animal were estimated at USD 5. The median total economic loss of an LSD outbreak at herd level was USD 1176 (USD 489 in subsistence farm and USD 2735 in commercial farm). At herd level, the largest component of the economic loss was due to mortality (USD 1000) followed by milk loss (USD 120). LSD control costs were the least contributor to herd level losses. The total herd level economic losses in the commercial farm type were significantly higher than in the subsistence farm type. The financial analysis showed a positive net profit of USD 136 (USD 56 for subsistence farm herds and USD 283 for commercial herds) per herd due to LSD vaccine investment. It should be noted that only the noticeable direct costs and treatment costs associated with the disease were considered in the study. Generally, vaccination is economically effective and should be encouraged. PMID- 29254707 TI - Assessing the impact of a novel strategy for delivering animal health interventions to smallholder farmers. AB - In many countries of the developing world village poultry play a vital role in the rural economy, providing a source of protein and valuable income with relatively small investments. In almost all areas in which village poultry are raised Newcastle disease (ND) is identified as one of the biggest causes of poultry loss, this is often coupled with a lack of knowledge of poultry management practices. Inexpensive and effective vaccines are available that are suitable for use in rural village environments, but in many areas service providers and reliable structures for delivery remain an obstacle to uptake of vaccines. To overcome this, GALVmed has implemented a network for vaccine distribution in which individuals in the villages are trained as vaccinators. The vaccinators purchase ND vaccines from local agro-veterinary stores and sell single doses at market determined prices. Implementation of these networks was preceded by a programme of smallholder sensitisation to increase awareness of diseases and flock management practices. Here we present analysis of the impacts of this scheme on village poultry production. We compare the results of a baseline survey carried out before implementation of the networks, with the results of a survey 16-24 months following implementation. We present results in terms of the uptake of ND vaccine, flock size, consumption of poultry meat, and poultry sales from Gairo district in Tanzania, Mayurbhanj district in India and Banke district in Nepal. In all areas, there was a significant increase in the numbers of flocks that were using ND vaccines, with over 75% uptake in all areas, reaching 98% in India. In all areas flock sizes doubled, the numbers of eggs that were set for hatching and that hatched increased by 25-50% and there was an increase in the frequency with which chicken meat was consumed and chickens were sold. Additionally, farmers reported fewer ND outbreaks, but this is prone to reporting bias and so improvements in production cannot be categorically ascribed to ND vaccination. These results have shown that establishing a market driven approach for the distribution of ND vaccines and community sensitisation on poultry husbandry practices results in a high rate of uptake of the vaccines. The results also suggest a reduction in the number of ND outbreaks and improvements to the livelihoods of rural smallholders. PMID- 29254708 TI - Characterization of Salmonella isolated from apparently healthy slaughtered cattle and retail beef in Hawassa, southern Ethiopia. AB - The present study was conducted to determine the occurrence, serotype distribution and antimicrobial resistance of Salmonella serotypes in slaughtered cattle, slaughterhouse environment and retail beef. Cecal content (CC), mesenteric lymph nodes (MLN), spleen and carcass swab (CS) samples (each, n=150) were collected from 150 cattle slaughtered at Hawassa municipality slaughterhouse. Floor swab specimens (SHFS) were collected on 11 occasions from the slaughterhouse, and 100 beef samples were collected from 100 butcher shops. The samples were cultured for Salmonella, following standard procedures. A total of 14 Salmonella isolates belonging to 3 serotypes namely Salmonella enterica serotype Muenchen (4 isolates), S. enterica serotype 1,4,5,12:i:- (5) and S. enterica serotype Korovi (5) were recovered. All of the 5 S. enterica serotype 1,4,5,12:i:- isolates belonged to phage type 120. Four (2.7%) of the slaughtered cattle carried Salmonella in their CC and/or MLN, while none of the spleen samples were positive for Salmonella. Salmonella was isolated from four (2.7%) CC and two (1.3%) MLN samples. Out of the total of 150 CS samples, two (1.3%) were found contaminated with Salmonella, while 4 (4%) of the 100 beef samples obtained from butcher shops yielded Salmonella. Two of the 11 (18%) SHFS were positive for Salmonella. All the four isolates from beef were S. enterica serotype Muenchen, while both of the isolates from MLN were S. enterica serotype1,4,5,12:i:-. Both S. enterica serotype1,4,5,12:i:- and S. enterica serotype Korovi were isolated from CC, CS and slaughterhouse environment. All the 14 isolates recovered during the study were tested and found pan-susceptible to a panel of 14 antimicrobials. The present study helped to update the information on the occurrence, serotype distribution and antibiogram of Salmonella in slaughter cattle and beef in Ethiopia. PMID- 29254709 TI - Association of farmers' socio-economics with bovine brucellosis epidemiology in the dry zone of Sri Lanka. AB - The aim of the study was to investigate the farmers' socio-economic factors and their association with Brucella prevalence in the dry zone of Sri Lanka. A cross sectional survey was planned and a total of 1,153 blood samples were collected from milking and dry animals of 155 farms from three selected veterinary ranges of Kalmunai, Navithanveli, and Mahaoya in the Ampara district, which is a multi ethnic area. The Rose Bengal Test (RBT) and competitive enzyme-linked immunosorbent assay (c-ELISA) were used for the Brucella screening and confirmation, respectively. Socio-economic attributes such as family income, poverty, education, main job, ethnicity, parent farmer, farming experience, and training in animal husbandry were determined as potential farmer-level risk factors. Meanwhile, herd size, grazing practice, breeding method, animal brought in to the farm, and abortions were considered as herd factors. The results revealed that the overall animal level sero-prevalence of brucellosis was 2.7% (35/1153; 95% confidence interval [CI]: 1.7, 3.7%) and the herd prevalence was 9.6% (15/155; 95% CI: 5.7, 15.7%) in the area of study. Brucellosis prevalence varies significantly (p<0.001) among the selected veterinary ranges with the highest herd prevalence in Kalmunai (20.0%) followed by Navithanveli (11.9%) and Mahaoya (2.7%). Disease prevalence showed variability (p<0.001) among ethnicities with the highest in Muslims (27.3%) followed by Tamils (8.1%) and Sinhalese (2.7%). Poverty was highly associated (OR=3.75; 95% CI: 1.43-10.00) with the disease. Free movement grazing practices (p<0.01) with OR=7.2 and animal brought in from outside (p<0.06) with OR=3.06 were positively related to brucellosis. It was revealed that farmers' socio-economics, such as ethnicity and poverty, and animal movement patterns, such as grazing practices are significantly associated with epidemiology of brucellosis in the dry zone of Sri Lanka. Therefore, the "farmer factor" should be carefully considered in veterinary epidemiological studies and animal disease control plans in the future. . PMID- 29254710 TI - Marginal structural Cox model to estimate the causal effect of clinical mastitis on Quebec dairy cow culling risk. AB - Health disorders, such as milk fever, displaced abomasum, or retained placenta, as well as poor reproductive performance, are known risk factors for culling in dairy cows. Clinical mastitis (CM) is one of the most influential culling risk factors. However the culling decision could be based either on the disease status or on the current milk yield, milk production being a significant confounder when modelling dairy cow culling risk. But milk yield (and somatic cell count) are time-varying confounders, which are also affected by prior CM and therefore lie on the causal pathway between the exposure of interest, CM, and the outcome, culling. Including these time-varying confounders could result in biased estimates. A marginal structural model (MSM) is a statistical technique allowing estimation of the causal effect of a time-varying exposure in the presence of time-varying covariates without conditioning on these covariates. The objective of this paper is to estimate the causal effect on culling of CM occurring between calving and 120 days in milk, using MSM to control for such time-varying confounders affected by previous exposure. A retrospective longitudinal study was conducted on data from dairy herds in the Province of Quebec, Canada, by extracting health information events from the dairy herd health management software used by most Quebec dairy producers and their veterinarians. The data were extracted for all lactations starting between January 1st and December 31st, 2010. A total of 3952 heifers and 8724 cows from 261 herds met the inclusion criteria and were used in the analysis. The estimated CM causal hazard ratios were 1.96 [1.57-2.44] and 1.47 [1.28-1.69] for heifers and cows, respectively, and as long as causal assumptions hold. Our findings confirm that CM was a risk factor for culling, but with a reduced effect compared to previous studies, which did not properly control for the presence of time-dependent confounders such as milk yield and somatic cell count. Cows experienced a lower risk for CM, with milk production having more influence on culling risk in cows than heifers. PMID- 29254711 TI - Culling from the herd's perspective-Exploring herd-level management factors and culling rates in Quebec dairy herds. AB - The relationship between cows' health, reproductive performance or disorders and their longevity is well demonstrated in the literature. However these associations at the cow level might not hold true at the herd level, and herd level variables can modify cow-level outcomes independently of the cows' characteristics. The interaction between cow-level and herd-level variables is a relevant issue for understanding the culling of dairy cows. However it requires the appropriate group-level variables to assess any contextual effect. Based on 10 years of health and production data, the objectives of this paper are:(a) to quantify the culling rates of dairy herds in Quebec; (b) to determine the profiles of the herds based on herd-level factors, such as demographics, reproduction, production and health indicators, and whether these profiles can be related to herd culling rates for use as potential contextual variables in multilevel modelling of culling risk. A retrospective longitudinal study was conducted on data from dairy herds in Quebec, Canada, by extracting health information events from the dairy herd health management software used by most Quebec producers and their veterinarians. Data were extracted for all lactations taking place between January 1st, 2001 and December 31st, 2010. A total of 432,733 lactations from 156,409 cows out of 763 herds were available for analysis. Thirty cow-level variables were aggregated for each herd and years of follow-up, and their relationship was investigated by Multiple Factor Analysis (MFA). The overall annual culling rate was 32%, with a 95% confidence interval (CI) of [31.6%,32.5%]. The dairy sale rate by 60 days in milk (DIM) was 3.2% [2.8%,3.6%]. The annual culling rate within 60 DIM was 8.2% [7.9%,8.4%]. The explained variance for each axis from the MFA was very low: 14.8% for the first axis and 13.1% for the second. From the MFA results, we conclude there is no relationship between the groups of herd-level indicators, demonstrating the heterogeneity among herds for their demographics, reproduction and production performance, and health status. However, based on Principal Component Analysis (PCA), the profiles of herds could be determined according to specific, single, herd-level indicators independently. The relationships between culling rates and specific herd-level variables within factors were limited to livestock sales, proportion of first lactation cows, herd size, proportion of calvings occurring in the fall, longer calving intervals and reduced 21-day pregnancy rates, increased days to first service, average age at first calving, and reduced milk fever incidence. The indicators found could be considered as contextual variables in multilevel model-building strategies to investigate cow culling risk. PMID- 29254712 TI - Farmers' knowledge and expectations of antimicrobial use and resistance are strongly related to usage in Dutch livestock sectors. AB - Comprehensive strategies to improve on-farm antimicrobial use (AMU) are needed to contain antimicrobial resistance (AMR). Little is known about farmers' motivating and enabling factors, and about their influence on AMU. In a cross-sectional online survey, Dutch dairy, veal and pig farmers (n=457) reported their on-farm AMU as "Defined Daily Dose Animal" per year (DDDAF) and completed a detailed questionnaire on their view, knowledge and behavior towards AMU and AMR. Exploratory factor analysis (EFA) on the questionnaire items identified four psychological factors labeled as 'referent beliefs', 'perceived risk', 'knowledge', and 'undesired attitude to regulations'. Linear regression was done to explore the relationship between the obtained factors and on-farm AMU across the three animal sectors. Dairy farmers showed the highest factor scores for 'knowledge' and the lowest for 'perceived risk'. 'Knowledge' scores were significantly and inversely related to AMU (P=0.0004). Borderline significant associations with AMU were found for 'perceived risk' and 'undesired attitude to regulations' (negative and positive relationships respectively). There were no apparent differences for these relationships between the three livestock sectors. Behavioral interventions in farmers such as educational campaigns or increased support by veterinarians could empower farmers with more prudent and rational practices, eventually reducing AMU in food animals. PMID- 29254714 TI - Estimating the true prevalence of bovine digital dermatitis in taranaki, New Zealand using a bayesian latent class model. AB - A Bayesian latent class model was developed to estimate the true prevalence of bovine digital dermatitis (BDD) in Taranaki, New Zealand. This model allowed farms to have zero prevalence as well as also accounting for between farm heterogeneity that was conditional on whether a farm was positive for bovine digital dermatitis. The estimated true farm level prevalence was 68.9% (95% credible interval [CrI]: 50.0%-85.7%), while on infected farms the overall cow level prevalence (number of infected cows/total number of cows on infected farms) was 2.9% (95%CrI: 2.1%-4.3%). The sensitivity analyses suggested that the prevalence estimates were reasonably robust when the variation of the priors fell within the biologically plausible range. These results indicated that visual inspection of standing animals during milking was sufficiently accurate to identify infected farms. However, for every 100 animals identified through visual inspection, 84 animals with lesions were missed. In other words, 46% (calculated as 84/184) of true positives at the animal level could be missed by visual inspection. The high and robust specificity (99.9%, 95%CrI: 99.8%-99.9%) suggested that lesions reported as BDD were very unlikely to be false positives. PMID- 29254715 TI - Implementing structural equation models to observational data from feedlot production systems. AB - The objective of this study was to illustrate the implementation of a mixed-model based structural equation modeling (SEM) approach to observational data in the context of feedlot production systems. Different from traditional multiple-trait models, SEMs allow assessment of potential causal interrelationships between outcomes and can effectively discriminate between direct and indirect effects. For illustration, we focused on feedlot performance and its relationship to health outcomes related to Bovine Respiratory Disease (BRD), which accounts for approximately 75% of morbidity and 50-80% of deaths in feedlots. Our data consisted of 1430 lots representing 178,983 cattle from 9 feedlot operations located across the US Great Plains. We explored functional links between arrival weight (AW; i = 1), BRD-related treatment costs (Trt$; as a proxy for health; i = 2) and average daily weight gain (ADG; as an indicator of productive performance i = 3), accounting for the fixed effect of sex and correlation patterns due to the clustering of lots within feedlots. We proposed competing plausible causal models based on expert knowledge. The best fitting model selected for inference supported direct effects of AW on ADG as well as indirect effects of AW on ADG mediated by Trt$. Direct effects from outcome i' to outcome i are quantified by the structural coefficient lambdaii', such that every unit increase in kg/head of AW had a direct effect of increasing ADG by approximately (estimate +/- standard error) lambda^31=0.002+/-0.0001 kg/head/day and also a direct effect of reducing Trt$ by an estimated lambda^21=$0.08+/-0.006 USD per head. In addition, every $1 USD spent on Trt$ directly decreased ADG by an estimated lambda^32=0.004+/-0.0006 kg/head/day. From these estimates, we show how to compute the indirect, Trt$ mediated, effect of AW on ADG, as well as the overall effect of AW on ADG, including both direct and indirect effects. We further compared estimates of SEM based effects with those obtained from standard linear regression mixed models and demonstrated the additional advantage of explicitly distinguishing direct and indirect components of an overall regression effect using SEMs. Understanding the direct and indirect mechanisms of interplay between health and performance outcomes may provide valuable insight into production systems. PMID- 29254713 TI - Bovine tuberculosis in Ethiopia: A systematic review and meta-analysis. AB - Bovine tuberculosis (bTB) is a known endemic disease of cattle in Ethiopia; however, there is lack of a comprehensive information on the status and distribution of the disease in the country. The objectives of this systematic review and meta-analysis were to provide a pooled prevalence estimate of bTB at a national level, assess the level of in-between variance among study reports and illustrate the spatial distribution pattern in the country. Articles published on bTB from January 2000 to December, 2016 in English language were included in the review. Pubmed, CAB direct, AJOL and Web of Science were the databases used in electronic search. A total of 127 articles were retrieved from online sources, of which 56 articles were selected for data extraction based on the specified inclusion criteria. From these selected published articles, 114 animal level data were extracted for quantitative analysis. A pooled prevalence estimate of bovine tuberculosis in Ethiopia was found to be 5.8% (95% CI: 4.5, 7.5). In a multivariable meta-regression analysis, breed and production system explained 40.9% of the explainable proportion of the in-between study variance computed. The prevalence of bovine tuberculosis in Holstein-Friesians, 21.6% (95% CI: 14.7 30.7), was higher than the prevalence in local zebus 4.1 (95% CI: 3.4-4.9). Cattle kept under intensive and semi-intensive production systems had higher prevalence, 16.6% (95% CI: 12.4-21.6), of bTB than those kept in extensive livestock production system, 4.6 (95% CI: 3.4-6.2). Bovine tuberculosis is widely distributed across major livestock producing regions of Ethiopia. However, no valid data could be retrieved from Benishanul-Gumuz, Harari and Dire Dawa. Data obtained on bTB from Somali and Gambella regional states are also few and further studies are suggested in these regions. In conclusion, this review showed that bTB in cattle in Ethiopia is widespread with high prevalence in intensive and semi-intensive management systsems that keep exotic breeds and their crosses in urban and peri-urban areas. Thus, it is suggested that the design and implementation of bTB control strategies in Ethiopia should prioritize these hotspots in order to reduce the impact of the disease on the growing dairy sector. PMID- 29254716 TI - Serological evidence of vaccination and perceptions concerning Foot-and-Mouth Disease control in cattle at the wildlife-livestock interface of the Kruger National Park, South Africa. AB - Communal livestock farming areas adjoining the Greater Kruger National Park Area within South Africa are part of the Foot-and-mouth disease (FMD) Protection Zone with Vaccination due to the proximity to wildlife reservoirs. FMD and its control affect the productivity of resource-poor farmers who often depend on livestock for their livelihoods. A cross-sectional study was performed with the objectives to evaluate the perceptions of farmers concerning FMD control, estimate the proportion of cattle with presumed protective antibody titres against FMD, as well as the proportion of herds with adequate herd immunity at the wildlife livestock interface within Mpumalanga Province. One hundred and four farmers were interviewed with 73% (76/104) being cattle owners and the remainder hired cattle herders. The majority of respondents (79%, 82/104) reported a high level of satisfaction with the current animal health programmes in general. The educational level of the respondents varied by satisfaction level: the median (interquartile range; IQR) education level was standard 9 (2-12) for non satisfied respondents, standard 3 (0-6) for little satisfied and standard 7 (2 11) for very satisfied respondents (P=0.036). Animals are not always treated at FMD inspections points, but satisfied respondents were more likely to seek veterinary assistance (P=0.001). The majority of respondents (92%, 96/104) identified the African buffalo (Syncerus caffer) as a risk factor for FMD outbreaks. Liquid-phase blocking ELISA antibody titres >=1.6log10 were used to indicate positive serology secondary to FMD vaccination. At the time of sampling and relative to this threshold, 23% (95% confidence interval (CI): 12%-34%) of the sampled cattle had positive serology to SAT-1, 41% (95%CI: 33%-48%) to SAT-2 and 29% (95%CI: 19%-39%) to SAT-3. The median (IQR) time between the previous vaccination and sampling was 189 (168-241) days. The sampled cattle had a longer inter-vaccination interval as scheduled by state veterinary services and antibody levels were low at the time of the study. The majority of respondents expressed high satisfaction with the currently applied FMD vaccination programme, which provides an opportunity for progressive adaption of animal health programmes within the study area. PMID- 29254717 TI - Evaluation of the efficacy of the Japanese rabies RC-HL strain vaccine in domestic dogs using past and present data: Prediction based on logistic regression and meta-analysis. AB - Japan is one of the few rabies-free countries or territories (under the OIE standard) which still implement the policy of mandatory vaccination of domestic dogs. Under the Rabies Prevention Law enacted since 1950, pet owners in Japan are obliged to vaccinate their dogs every year. However, the national vaccination rate is estimated to average 42% over the past decade. Given this low owner compliance, there is debate over whether or not the mandatory vaccination policy should be maintained and if it were to be maintained, whether the yearly booster requirement is necessary or not. Data on 144 companion dogs vaccinated with the Japanese rabies RC-HL strain vaccine were analysed using multiple logistic regression. An extensive literature review was conducted and five previous vaccination studies were selected for meta-analysis. Results of logistic regression indicate that the proportion of dogs having a satisfactory antibody level lasting for 12 months (P_protected12) with only one vaccination was 74.7% (95% prediction interval (PI): 51.4%-90.5%). By contrast, P_protected12 for dogs vaccinated 2-4 times and 5 times or more was estimated as 96.6% (95%PI: 83.1% 99.3%) and 98.7% (95%PI: 96.9%-99.6%), respectively. Moreover, P_protected for 36 months would drop to 33.4% (95%PI: 11.4%-71.6%) for dogs vaccinated only once, while it would be 83.0% (95% PI: 39.4%-97.1%) and 93.0% (95%PI: 59.7%-99.2%) for dogs vaccinated 2-4 times and 5 times or more, respectively. The pooled P_protected for at least 12 months from meta-analysis was estimated as 83.8% (95%CI: 66.1%-97.5%) for dogs vaccinated only once, while it was estimated as 94.7% (95%CI: 87.7%-99.1%) for dogs vaccinated at least twice. Therefore, the yearly booster requirement of the current mandatory vaccination policy in Japan is reasonable in terms of its frequency. However, there is potential for future policy amendment to one that requires less frequent boosters, i.e. a booster is required within one year after primary vaccination and then every two to three years. PMID- 29254718 TI - Echinococcus multilocularis management by fox culling: An inappropriate paradigm. AB - With the ongoing spread of Echinococcus multilocularis in Europe, sanitary authorities are looking for the most efficient ways of reducing the risk for human populations. Fox culling is one particular tool that has recently shifted from predation control to population health management. Our study aims to assess the effectiveness of this tool in limiting E. multilocularis prevalence in fox populations in France. During four years, a culling protocol by night shooting from cars was implemented around the city of Nancy (eastern France) representing ~1700h of night work and ~15,000km driven. The 776 foxes killed represented an overall increase of 35% of the pressure on the fox population over 693km2. Despite this consequent effort of culling, not only did night shooting of foxes fail to decrease the fox population, but it resulted in an increase in E. multilocularis prevalence from 40% to 55% while remaining stable in an adjacent control area (585km2). Though no significant change in age structure could be described, an increase in immigration and local recruitment is the best hypothesis for population resilience. The increase in prevalence is therefore considered to be linked to a higher rate of juvenile movement within the culled area shedding highly contaminated faeces. We therefore advocate managers to consider alternative methods such as anthelmintic baiting, which has been proven to be efficient elsewhere, to fight against alveolar echinococcosis. PMID- 29254719 TI - Associations between animal welfare indicators and Campylobacter spp. in broiler chickens under commercial settings: A case study. AB - Few studies have previously investigated how poor animal welfare might be associated with infection of zoonotic pathogens in humans. This paper assesses the predictive value of the presence of Campylobacter spp. in broiler chicken flocks when animal-based measures related to footpad dermatitis, hock burns, body lesions and arthritis are identified under commercial conditions (high density). The study population included 32 flocks analysed on farm and at slaughter, slaughtered between April and August 2008 in six different slaughter plants in Brittany, France. Welfare and health indicators are those indicated by the European legislation and sampling was carried out in the framework of the European baseline survey on the prevalence of Campylobacter in broiler chicken. Caecal contents, sampled both on farm and at slaughter, and carcass skin samples from the neck and breast at slaughter, were investigated for the presence of Campylobacter spp. Logistic models/classification trees were used to estimate the probability of the presence (or absence) of a specific foodborne pathogen in a flock based on specific animal-based measures (or combinations of measures) in order to study the potential relationship between welfare indicators and foodborne pathogen prevalence/incidence levels. On farm, flocks with more than 25% animals with severe lesions on between 25 and 50% of the footpad are predicted to be Campylobacter-positive whereas flocks where less than 13 individuals have arthritis are predicted to be Campylobacter-negative. The error rate on farm and at slaughter was 10 and 4% respectively indicating good predicting abilities. A poor welfare environment may result in stress, which reduces chicken immunocompetence making them more susceptible to Campylobacter spp. An infection with Campylobacter spp may lead to impaired defence and susceptibility to other pathogens which may result in greater intestinal excretion. Poor welfare and high growing rate lead to digestive troubles that lead to litter humidity. Litter humidity that, among other things, causes footpad dermatitis may also influence the horizontal transmission of the Campylobacter spp. infection due to the normal coprophagic behaviour of poultry. Reducing welfare problems by a better management of rearing conditions would not only improve broiler welfare, but it would also decrease the risks of Campylobacter contamination, of carcass condemnations and of economic loss for the poultry industry. PMID- 29254720 TI - Spatiotemporal pattern of peste des petits ruminants and its relationship with meteorological factors in China. AB - Peste des petits ruminants (PPR) is a severe infectious viral disease of domestic and wild small ruminants, and it threatens food security and livelihood of farmers across the world. In China, 292 PPR cases have been reported since it was first reported in 2007. Aiming to display the spatiotemporal patterns of PPR outbreaks and to understand its relationship with meteorological factors, we conducted a direction test, directional distribution analysis, and logistic regression analysis. The results showed that the spread of disease had a significant directional spread (P<0.05). Daily average temperature (DAT) [OR 0.063 (95% CI 0.047-0.076)], daily average relative humidity (DARH) [OR 0.871 (95% CI 0.804-0.944)], and daily hours of sunshine (DHS) [OR 0.411 (95% CI 0.389 0.582)] were inversely associated with the risk of PPR outbreak, while a positive association was observed for daily average air pressure (DAAP) [OR 1.211 (95% CI 1.036-1.417). Our findings indicate that meteorological factors may be important variables for affecting PPR transmission, and should be taken into account in the future monitoring programs for PPR. PMID- 29254721 TI - Factors affecting mortality risk during transportation of broiler chickens for slaughter in Atlantic Canada. AB - Mortality of broilers during transport and lairage before slaughter represents an economic loss to the poultry industry and a welfare issue that needs to be addressed. In Canada, broilers can be transported long distances and be exposed to environmental factors, such as cold temperatures, that can affect the percentage of dead-on-arrivals or DOAs. Slaughter plant records for loads transported over a 19-month period in 2009-2010 were examined to identify factors affecting mortality risk (% DOA) during transportation from the rearing barn to the slaughter plant. Information from 2007 loads was analysed using a multilevel linear model. Most of the variation in the mortality risk occurred at the load level rather than at the producer or barn level. There were significant effects of bird sex, age and weight, catching team, journey duration and holding barn duration on mortality risk. The following environmental risk factors increased mortality risk: cold temperatures during the journey and in the holding barn, low crate stocking density during journeys at cold temperature and increased trailer temperature when in the holding barn. The analyses identified risk factors that can be used to refine management practices to mitigate some of the mortality risk. Increased mortality in some loads was associated with environmental conditions that caused deaths from hypothermia, whereas in other circumstances, some deaths likely occurred from hyperthermia. The climatic conditions in Atlantic Canada were responsible for significant risk factors that affected the mortality risk. Although refinement of the management practices described in this study, such as reduced journey and lairage durations, and increased crate stocking density can mitigate some of the mortality risk, the extreme cold conditions experienced during some parts of the year exceeded the capacity of the systems of transportation used to provide environmental conditions that minimise mortality. PMID- 29254722 TI - Evidence of antimicrobial and disinfectant resistance in a remote, isolated wild pig population. AB - The spread of antimicrobial resistant E. coli within the environment is a global concern. Wildlife such as feral pigs have been identified as a possible reservoir of antimicrobial resistant bacteria. A cross-sectional survey of free-ranging, feral pigs within the Kimberley region of northwestern Australia was conducted to estimate the prevalence of antimicrobial and disinfectant resistant E. coli in this population. Of the 493 faecal samples collected, 115 E. coli isolates were randomly selected and their identity confirmed by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS). Isolates were screened for susceptibility to 14 veterinary antimicrobials (including antimicrobials not permitted for use in Australia) using MIC broth microdilution using SensititreTM (BOPO6F) and breakpoints according to CLSI and EUCAST guidelines. Isolates also underwent disinfectant susceptibility testing to six disinfectants at their recommended concentration for use as well as at a twofold dilution, based on methods adapted from the CLSI agar plate dilution method. A moderate prevalence of resistance was observed to sulfadimethoxine (50.4%; 58/115) and florfenicol (27.0%; 31/115). A low prevalence of resistance was estimated to chlortetracycline (5.2%; 6/115) and multi-drug resistance was only identified in 1.7% (2/115) of E.coli isolates tested. Isolates were susceptible to five of the six disinfectants screened. Feral pigs could potentially act as a reservoir of antimicrobial resistance in the environment with possible implications for domestic livestock. The role that feral pigs might play in transmission of antimicrobial resistance requires further investigation, and the occurrence of resistance in such isolated populations needs to be considered when attempting to infer source attribution of antimicrobial resistance in livestock and human populations. PMID- 29254723 TI - Canine Monocytic Ehrlichiosis among working dogs of organised kennels in India: A comprehensive analyses of clinico-pathology, serological and molecular epidemiological approach. AB - Canine Monocytic Ehrlichiosis (CME) is a serious tick-borne rickettsial disease affecting canine populations globally. Besides few reports from stray and pet dogs from localised geographical regions (cities/towns/small states), a comprehensive study on prevalence of Ehrlichia canis (E. canis) among working dogs from different geo-climatic zones of India was pertinently lacking. Study of CME among these dog populations was thus carried out, encompassing clinical aspects and different diagnostic methodologies viz., microscopy, serology and molecular biology. During the two-year study period, clinical specimens from 225 cases suspected of canine ehrlichiosis were examined for clinical pathology and presence of the haemoparasites. Overall prevalence of ehrlichiosis by microscopic examination, commercial dot-ELISA kit and nested PCR assay was estimated to be 1.3%, 19.1% and 5.8%, respectively, which were found to be statistically significant by McNemar Chi squared test (p<0.05). It was also observed that possibly due to widespread use of doxycycline therapy in field, CME presently does not remain a potential threat which it uses to pose earlier. However, concurrent infections of E. canis and Babesia gibsoni were found to be mostly fatal. Keeping in view of high number of apparently healthy dogs (24) out of total positive cases (46) observed during the study, it is recommended that prevalence studies on CME should also involve screening of apparently healthy dogs. Phylogenetic analysis carried on partial sequencing of 16S rRNA of E. canis strains revealed that all of the Indian strains clustered in a single clade with other E. canis species from India and rest of the world. Molecular divergence was observed among the sequences of Brazilian and American isolates which were also included in the present study. These findings have thus opened a new paradigm for planning of pragmatic control strategies against CME. PMID- 29254724 TI - Field study on the use of vaccination to control the occurrence of lumpy skin disease in Ethiopian cattle. AB - The current study was carried out in central and North-western parts of Ethiopia to assess the efficacy of Kenyan sheep pox virus strain vaccine (KS1 O-180) against natural lumpy skin disease (LSD) infection under field conditions by estimating its effect on the transmission and severity of the disease. For this study, an LSD outbreak was defined as the occurrence of at least one LSD case in a specified geographical area. An observational study was conducted on a total of 2053 (1304 vaccinated and 749 unvaccinated) cattle in 339 infected herds located in 10 sub-kebeles and a questionnaire survey was administered to 224 herd owners. Over 60% of the herd owners reported that the vaccine has a low to very low effect in protecting animals against clinical LSD; almost all of them indicated that the vaccine did not induce any adverse reactions. In the unvaccinated group of animals 31.1% were diagnosed with LSD while this was 22.5% in the vaccinated group (P<0.001). Severity of the disease was significantly reduced in vaccinated compared to unvaccinated animals (OR=0.68, 95% CI: 0.49; 0.96). Unvaccinated infected animals were more likely (predicted fraction=0.89) to develop moderate and severe disease than vaccinated infected animals (predicted fraction=0.84). LSD vaccine efficacy for susceptibility was estimated to be 0.46 (i.e. a susceptibility effect of 0.54) while the infectiousness effect of the vaccine was 1.83. In other words, the vaccine reduces the susceptibility by a factor of two and increases infectiousness by approximately the same amount. LSD transmission occurred in both vaccinated and unvaccinated animals, the estimated reproduction ratio (R) was 1.21 in unvaccinated animals compared to 1.19 in vaccinated ones, and not significantly different. In conclusion, KS1 O-180 vaccination, as applied currently in Ethiopia, has poor efficacy in protecting cattle populations against LSD, neither by direct clinical protection nor by reducing transmission, and this signifies the urgent need to either improve the quality of the vaccine or to develop potent alternative vaccines that will confer good protection against LSD. PMID- 29254725 TI - Comparison of antimicrobial resistance in E. coli isolated from rectal and floor samples in pens with diarrhoeic nursery pigs in Denmark. AB - INTRODUCTION: The prudent use of antibiotics in veterinary medicine necessitates the selection of antibiotic compounds with narrow-spectrums targeted against the specific pathogens involved. The same pathotype of enterotoxigenic E. coli (ETEC) was recently found both in diarrhoeic pigs and in samples from the pen floor where the pigs were housed. The first objective of this study was to compare resistance profiles from ETEC isolates and Non-ETEC isolates. The second objective was to evaluate the agreement between resistance profiles of ETEC isolated from pen floor samples and from individual rectal samples from pigs. Across three Danish pig herds, faecal samples were collected from the floors of 31 pens that had a within-pen diarrhoea prevalence of >25%, and from rectal samples of 93 diarrhoeic nursery pigs from the same pens. A total of 380 E. coli isolates were analysed by PCR and classified as ETEC when genes for adhesin factors and enterotoxins were detected. Minimum inhibitory concentrations of 13 antimicrobial agents were determined by the broth micro dilution method. Isolates were classified as resistant based on clinical breakpoints. RESULTS: Based on logistic regression models, the odds of Non-ETEC isolates (n=291) being pan susceptible were significantly higher compared to ETEC isolates (n=89), (P<0.001, OR=20.22, CI95%=6.35-64.35). The odds of ETEC isolates having multidrug resistance were significantly higher compared to Non-ETEC isolates (p<0.001, OR: 7.21, CI95%: 2.87-18.10). The odds of an isolate being resistant were significantly higher in ETEC isolates compared to Non-ETEC isolates for ampicillin (p<0.001), apramycin (p=0.003), sulphamethoxazole (p<0.001) and trimethoprim (p<0.001). No overlap of resistance patterns between the three study herds was observed in the sampled ETEC isolates. In addition, there was generally good or excellent agreement when comparing resistance profiles from isolates from the same pen (pen floor and pig samples), and perfect agreement (Kappa=1.000, SE=0.316) was observed for ampicillin, apramycin, gentamycin, sulphamethoxazole, tetracycline and trimethoprim. CONCLUSIONS: We found that ETEC isolates were more resistant than Non-ETEC isolates. Furthermore, this study indicates that resistance testing of ETEC isolates from pen floor samples can be used as a convenient sampling method for resistance testing and in the selection of clinically relevant antimicrobial agents in the treatment of diarrhoeic pigs. The herd-level variation of resistance in ETEC isolates emphasises the importance of performing antimicrobial susceptibility testing at farm level when selecting antimicrobial agents for the treatment of E. coli-related diarrhoea. PMID- 29254726 TI - The basic reproductive number estimated from a Mycoplasma conjunctivae outbreak in a dairy goat farm. AB - Clinicians can evaluate the relevance of an outbreak based on its basic reproductive number (R0). So far there has been no report on the R0 of Mycoplasma conjunctivae which is a major cause of goats' conjunctivitis in Taiwan. The present study sought to investigate an outbreak of infectious keratoconjunctivitis (IKC) by Mycoplasma conjunctivae (MC) in an indoor dairy goat barn. The epidemiological curve was recorded to build a susceptible-infected recovered model and to estimate the R0 by three methods In the investigated goat barn, 60% (31/55) goats showed degrees of IKC signs. The number of infected animals increased quickly after 15days, but slowed down after 41days. The sick goats began to recover after 30days. The epidemic fully stopped after 81days. The estimated R0 ranged from 1.35 to 4.46. In summary, this is the first MC report in Taiwan, and the first one to estimate the R0 of MC. PMID- 29254727 TI - Prevalence of antimicrobial resistance in fecal Escherichia coli and Salmonella enterica in Canadian commercial meat, companion, laboratory, and shelter rabbits (Oryctolagus cuniculus) and its association with routine antimicrobial use in commercial meat rabbits. AB - Antimicrobial resistance (AMR) in zoonotic (e.g. Salmonella spp.), pathogenic, and opportunistic (e.g. E. coli) bacteria in animals represents a potential reservoir of antimicrobial resistant bacteria and resistance genes to bacteria infecting humans and other animals. This study evaluated the prevalence of E. coli and Salmonella enterica, and the presence of associated AMR in commercial meat, companion, research, and shelter rabbits in Canada. Associations between antimicrobial usage and prevalence of AMR in bacterial isolates were also examined in commercial meat rabbits. Culture and susceptibility testing was conducted on pooled fecal samples from weanling and adult commercial meat rabbits taken during both summer and winter months (n=100, 27 farms), and from pooled laboratory (n=14, 8 laboratory facilities), companion (n=53), and shelter (n=15, 4 shelters) rabbit fecal samples. At the facility level, E. coli was identified in samples from each commercial rabbit farm, laboratory facility, and 3 of 4 shelters, and in 6 of 53 companion rabbit fecal samples. Seventy-nine of 314 (25.2%; CI: 20.7-30.2%) E. coli isolates demonstrated resistance to >1 antimicrobial agent. At least one E. coli isolate resistant to at least one antimicrobial agent was present in samples from 55.6% of commercial farms, and from 25% of each laboratory and shelter facilities, with resistance to tetracycline being most common; no resistance was identified in companion animal samples. Salmonella enterica subsp. was identified exclusively in pooled fecal samples from commercial rabbit farms; Salmonella enterica serovar London from one farm and Salmonella enterica serovar Kentucky from another. The S. Kentucky isolate was resistant to amoxicillin/clavulanic acid, ampicillin, cefoxitin, ceftiofur, ceftriaxone, streptomycin, and tetracycline, whereas the S. London isolate was pansusceptible. Routine use of antimicrobials on commercial meat rabbit farms was not significantly associated with the presence of antimicrobial resistant E. coli or S. enterica on farms; trends towards resistance were present when resistance to specific antimicrobial classes was examined. E. coli was widely prevalent in many Canadian domestic rabbit populations, while S. enterica was rare. The prevalence of AMR in isolated bacteria was variable and most common in isolates from commercial meat rabbits (96% of the AMR isolates were from commercial meat rabbit fecal samples). Our results highlight that domestic rabbits, and particularly meat rabbits, may be carriers of phenotypically antimicrobial-resistant bacteria and AMR genes, possibly contributing to transmission of these bacteria and their genes to bacteria in humans through food or direct contact, as well as to other co-housed animal species. PMID- 29254728 TI - Individual and pen-based oral fluid sampling: A welfare-friendly sampling method for group-housed gestating sows. AB - The aims of this study were to assess the feasibility of individual and pen-based oral fluid sampling (OFS) in 35 pig herds with group-housed sows, compare these methods to blood sampling, and assess the factors influencing the success of sampling. Individual samples were collected from at least 30 sows per herd. Pen based OFS was performed using devices placed in at least three pens for 45min. Information related to the farm, the sows, and their living conditions were collected. Factors significantly associated with the duration of sampling and the chewing behaviour of sows were identified by logistic regression. Individual OFS took 2min 42s on average; the type of floor, swab size, and operator were associated with a sampling time >2min. Pen-based OFS was obtained from 112 devices (62.2%). The type of floor, parity, pen-level activity, and type of feeding were associated with chewing behaviour. Pen activity was associated with the latency to interact with the device. The type of floor, gestation stage, parity, group size, and latency to interact with the device were associated with a chewing time >10min. After 15, 30 and 45min of pen-based OFS, 48%, 60% and 65% of the sows were lying down, respectively. The time spent after the beginning of sampling, genetic type, and time elapsed since the last meal were associated with 50% of the sows lying down at one time point. The mean time to blood sample the sows was 1min 16s and 2min 52s if the number of operators required was considered in the sampling time estimation. The genetic type, parity, and type of floor were significantly associated with a sampling time higher than 1min 30s. This study shows that individual OFS is easy to perform in group-housed sows by a single operator, even though straw-bedded animals take longer to sample than animals housed on slatted floors, and suggests some guidelines to optimise pen-based OFS success. PMID- 29254729 TI - Bayesian estimation of seroprevalence of small ruminant lentiviruses in sheep from Poland. AB - In Poland, no systematic survey of ruminant lentiviruses (SRLVs) infection was performed, neither at the national nor at the regional level and only limited knowledge exists on the prevalence of SRLVs among sheep. The aim of the present study was to establish the true prevalence of SRLVs infection in sheep from Poland at the animal and herd-levels. The blood samples used for this study were the fraction of samples collected by Veterinary Inspection during an official sampling for the national monitoring program for brucellosis. Under this program the animals and herds were randomly selected using the data available from ARMA (Agency for Restructuring and Modernisation of Agriculture). The sampling unit was the herd and the target population included at least 5% of sheep, over 6 months old, from each of 16 voievodships (provinces) of Poland. Two-stage cluster sampling design was performed in this study offering the possibility to determine the prevalence of SRLVs infection, when only a fraction of herds and a fraction of animals in the herds are tested. In total, 8233 sheep serum samples coming from 832 herds were tested by indirect ELISA. 1474 (17.9%) samples were positive and 261 (31.4%) herds with at least one seropositive animals were identified. The overall true prevalence estimated by the Bayesian framework was 9.3% (95% CI 6.8, 11.3) and 33.3% (95% CI 26.5, 38.2) on the animal and herd level, respectively. Large variation in the animal and herd prevalence between the voivodships was observed. True prevalence on the herd level varied from 0.0% (95% CI 0.0, 0.0) to 71.6% (95% CI 67.6, 75.9) whereas true prevalence on the animal level ranged from 0.0% (95% CI 0.0, 0.0) to 55.3% (95% CI 50.0, 61.2). The true prevalence of SRLVs infection at animal and herd level increased according to herd size as was proved by posterior probabilities (POPR). PMID- 29254730 TI - Climate change and cattle vector-borne diseases: Use of participatory epidemiology to investigate experiences in pastoral communities in Northern Tanzania. AB - Climate change is predicted to increase incidence of vector-borne diseases in humans, however, little is known about the impact of such diseases in livestock. In the absence of historical data with which to examine the inter-relation between climate and disease, participatory epidemiological (PE) methods were used with Maasai pastoralists of Monduli District, northern Tanzania to establish local observations on two major vector-borne diseases of cattle, namely East Coast fever (ECF) and African animal trypanosomiasis (AAT). Data collection involving gender segregated groups (10 men groups and 9 women groups) occurred in 10 randomly selected villages between November 2014 and March 2015. ECF and AAT were ranked amongst the top 5 most important cattle diseases with strong agreement across informant groups (Kendall's W=0.40 for men and 0.45 for women; p<0.01). Matrix scoring for both men and women groups confirmed that Masaai easily recognize these diseases. All groups associated ECF with the wet and cool dry seasons. AAT was more variable throughout the year, with more cases reported in the long dry season. Likewise, pastoralists reported differences in seasonal occurrence of disease vectors (Rhipicephalus appendiculatus and Glossina spp.) by village. Comparing 2014-1984, participant groups consistently reported declines in rainfall, vegetation cover and quality pasture, as well as increases in severe droughts. Experiences with ECF/AAT and vector abundance between these time periods was more variable across villages, and likely relates to changes in climate and animal management practices over the last 30 years. This baseline study is the first to document the inter-relation between climate and cattle vector-borne disease from the pastoralist perspective. Findings from this study reveal a complex interplay between human, animal and environmental factors, understanding of which is urgently required to devise approaches to mitigate effects of climate change in these vulnerable areas. PMID- 29254731 TI - The broiler meat system in Nairobi, Kenya: Using a value chain framework to understand animal and product flows, governance and sanitary risks. AB - Livestock food systems play key subsistence and income generation roles in low to middle income countries and are important networks for zoonotic disease transmission. The aim of this study was to use a value chain framework to characterize the broiler chicken meat system of Nairobi, its governance and sanitary risks. A total of 4 focus groups and 8 key informant interviews were used to collect cross-sectional data from: small-scale broiler farmers in selected Nairobi peri-urban and informal settlement areas; medium to large integrated broiler production companies; traders and meat inspectors in live chicken and chicken meat markets in Nairobi. Qualitative data were collected on types of people operating in the system, their interactions, sanitary measures in place, sourcing and selling of broiler chickens and products. Framework analysis was used to identify governance themes and risky sanitary practices present in the system. One large company was identified to supply 60% of Nairobi's day-old chicks to farmers, mainly through agrovet shops. Broiler meat products from integrated companies were sold in high-end retailers whereas their low value products were channelled through independent traders to consumers in informal settlements. Peri-urban small-scale farmers reported to slaughter the broilers on the farm and to sell carcasses to retailers (hotels and butcheries mainly) through brokers (80%), while farmers in the informal settlement reported to sell their broilers live to retailers (butcheries, hotels and hawkers mainly) directly. Broiler heads and legs were sold in informal settlements via roadside vendors. Sanitary risks identified were related to lack of biosecurity, cold chain and access to water, poor hygiene practices, lack of inspection at farm slaughter and limited health inspection in markets.? Large companies dominated the governance of the broiler system through the control of day-old chick production. Overall government control was described as relatively weak leading to minimal official regulatory enforcement. Large companies and brokers were identified as dominant groups in market information dissemination and price setting. Lack of farmer association was found to be system-wide and to limit market access. Other system barriers included lack of space and expertise, leading to poor infrastructure and limited ability to implement effective hygienic measures.? This study highlights significant structural differences between different broiler chains and inequalities in product quality and market access across the system. It provides a foundation for food safety assessments, disease control programmes and informs policy-making for the inclusive growth of this fast-evolving sector. PMID- 29254732 TI - LEM4/ANKLE-2 deficiency impairs post-mitotic re-localization of BAF, LAP2alpha and LaminA to the nucleus, causes nuclear envelope instability in telophase and leads to hyperploidy in HeLa cells. AB - The human LEM-domain protein family is involved in fundamental aspects of nuclear biology. The LEM-domain interacts with the barrier-to-autointegration factor (BAF), which itself binds DNA. LEM-domain proteins LAP2, emerin and MAN1 are proteins of the inner nuclear membrane; they have important functions: maintaining the integrity of the nuclear lamina and regulating gene expression at the nuclear periphery. LEM4/ANKLE-2 has been proposed to participate in nuclear envelope reassembly after mitosis and to mediate dephosphorylation of BAF through binding to phosphatase PP2A. Here, we used CRISPR/Cas9 to create several cell lines deficient in LEM4/ANKLE-2. By using time-lapse video microscopy, we show that absence of this protein severely compromises the post mitotic re-association of the nuclear proteins BAF, LAP2alpha and LaminA to chromosomes. These defects give rise to a strong mechanical instability of the nuclear envelope in telophase and to a chromosomal instability leading to increased number of hyperploid cells. Reintroducing LEM4/ANKLE-2 in the cells by transfection could efficiently restore the telophase association of BAF and LAP2alpha to the chromosomes. This rescue phenotype was abolished for N- or C-terminally truncated mutants that had lost the capacity to bind PP2A. We demonstrate also that, in addition to binding to PP2A, LEM4/ANKLE-2 binds BAF through its LEM-domain, providing further evidence for a generic function of this domain as a principal interactor of BAF. PMID- 29254733 TI - The hybrid assisted limb (HAL) for Care Support, a motion assisting robot providing exoskeletal lumbar support, can potentially reduce lumbar load in repetitive snow-shoveling movements. AB - An excessive lumbar load with snow-shoveling is a serious problem in snowfall areas. Various exoskeletal robots have been developed to reduce lumbar load in lifting work. However, few studies have reported the attempt of snow-shoveling work using exoskeletal robots. The purpose of the present study was to test the hypothesis that the HAL for Care Support robot would reduce lumbar load in repetitive snow-shoveling movements. Nine healthy male volunteers performed repetitive snow-shoveling movements outdoors in a snowfall area for as long as possible until they were fatigued. The snow-shoveling trial was performed under two conditions: with and without HAL for Care Support. Outcome measures were defined as the lumbar load assessed by the VAS of lumbar fatigue after the snow shoveling trial and the snow-shoveling performance, including the number of scoops, and snow shoveling time and distance. The mean of VAS of lumbar fatigue, the number of scoops, and snow-shoveling time and distance without HAL for Care Support were 75.4 mm, 50.3, 145 s, and 9.6 m, while with HAL for Care Support were 39.8 mm, 144, 366 s, and 35.4 m. The reduction of lumbar fatigue and improvement of snow-shoveling performance using HAL for Care Support were statistically significant. There was no adverse event during snow-shoveling with HAL for Care Support. In conclusion, the HAL for Care Support can reduce lumbar load in repetitive snow-shoveling movements. PMID- 29254734 TI - Eteplirsen for paediatric patients with Duchenne muscular dystrophy: A pooled analysis. AB - BACKGROUND: Duchenne Muscular Dystrophy is a paediatric disorder resulting from a defective dystrophin gene. It causes progressive loss of muscle fibres, muscle weakness, and eventually loss of ambulation during adolescence, with death due to respiratory or cardiovascular complications soon afterwards. The drug eteplirsen has received support from medical experts and parents of affected children, but the FDA has delayed their decision for approval of this drug. OBJECTIVE: This study analysed the results of previous studies to assess the safety and efficacy of the eteplirsen, and is the first pooled-analysis of its kind. METHODS: A literature search of electronic databases was performed. Only human studies using eteplirsen were eligible. RESULTS: A total of four relevant clinical studies were identified. A pooled-analysis was performed using data relating to percentage dystrophin-positive fibres obtained from muscle biopsy, and the six-minute walk test (6 MWT). The average increase in percentage dystrophin-positive fibres after treatment with eteplirsen was 24.23% (range -4 to 78; SD 24.44%). The average rate of decline in distance walked was 65metres (range -335 to 83; SD 100.08 m). CONCLUSIONS: Whether or not this increase in percentage dystrophin-positive fibres and distance walked is clinically significant is unclear, and there is therefore a need for more clinical trials. PMID- 29254735 TI - [Cerebral vasculopathy in children with sickle cell disease: Key issues and the latest data]. AB - Cerebral vasculopathy is a common and severe complication of sickle cell disease in children. The pathophysiology consists of progressive damage to the basal intracranial arteries and cerebral microcirculation, while chronic anemia worsens exposure to cerebral hypoxia. It results in stroke and subclinical or poorly symptomatic ischemic lesions. Many clinical, biological, and radiological risk factors have been identified. The prevention strategy through systematic transcranial Doppler screening of large-vessel vasculopathy has revolutionized the management of this disease and has greatly decreased the risk of developing stroke. MRI-MRA is a complementary diagnostic tool for anatomical analysis of parenchymal and vascular lesions, which is used for chronic disease monitoring or in the context of an acute neurological event. New exploration opportunities are offered by submandibular Doppler sonography and indirect evaluation methods of cerebral oxygenation and perfusion. If chronic blood transfusion therapy is used to prevent the occurrence and recurrence of cerebral complications of sickle cell disease, only allogeneic hematopoietic stem cell transplantation can safely and definitively stop the transfusion program. It should therefore be proposed early, before irreversible cerebral or vascular lesions occur. Hydroxycarbamide treatment has recently emerged as a potential substitute for chronic transfusions for the maintenance of transcranial Doppler velocities, but only after an initial treatment by transfusions and provided there is close follow-up. In the long run, cerebral vascular damage can cause progressive cognitive impairment and disability, even in children without radiologically identified lesions, indicating the importance of systematic and repeated neuropsychological testing. PMID- 29254736 TI - [Pediatrician's experience in announcing bad news]. AB - Few studies are available on pediatricians' experience with announcing bad news. Announcing bad news is an important component of medical practice and is even more complex in pediatrics because parents must be associated. We had 20 hospital pediatricians complete a questionnaire containing 30 questions about their own experience announcing bad news to a child or a teenager. In spite of their experience and the time they have spent practicing medicine, there are many limitations stemming from different factors concerning children, teenagers, their families, and themselves. The difficulties encountered by pediatricians are mainly related to the timing of the announcement, the location, the choice of the words used, and the poor understanding of children and families, due to intellectual, cultural, or psychological limitations. Pediatricians question their own capacity to make such an announcement, wondering if the information has actually been well understood. They indicate that they are themselves affected. Most of them develop and implement strategies to refute the emotional instability caused by the announcement of bad news. Yet many of them feel weak, even talking about a deep sense of loneliness and guilt. PMID- 29254737 TI - Augmenting Research, Education, and Outreach with Client-Side Web Programming. AB - The evolution of computing and web technologies over the past decade has enabled the development of fully fledged scientific applications that run directly on web browsers. Powered by JavaScript, the lingua franca of web programming, these 'web apps' are starting to revolutionize and democratize scientific research, education, and outreach. PMID- 29254738 TI - Comments on preoperative severe hypoalbuminemia is associated with an increased risk of postoperative delirium in elderly patients: Results of a secondary analysis. PMID- 29254739 TI - Response. PMID- 29254740 TI - Myocardial infarction and thrombophilia: Do not miss the right diagnosis! AB - Protein C deficiency is a coagulation cascade disorder often resulting in venous thromboembolic events but is also a possible contributor to arterial thrombosis. To date, approximately ten cases of myocardial infarction (MI) due to protein C deficiency have been reported in the literature. However, affirming this mechanism requires ruling out the most common causes of MI, i.e. the rupture or erosion of an atherosclerotic plaque. Intravascular imaging of coronary arteries can be of help to identify angiographically undetected atherosclerosis. We report a case of an ST-segment elevation myocardial infarction (STEMI) in a young man with apparent evidence of arterial thrombosis resulting from protein C deficiency and heterozygous factor Leiden mutation which was contradicted by intravascular imaging demonstrating atherosclerosis. PMID- 29254741 TI - Factors that affect the duration of antimicrobial therapy for cellulitis. AB - BACKGROUND: The recommended duration of antibiotic therapy for patients hospitalized with cellulitis is 5-14 days. However, factors that affect the duration of treatment have rarely been examined. METHODS: We conducted an observation study in a regional hospital in Japan to examine factors that affect the duration of antibiotic therapy for cellulitis. Our study included 102 patients with cellulitis of the lower extremities who were treated with intravenous cefazolin alone. Intravenous cefazolin was terminated when redness, swelling, and tenderness of the lower extremities disappeared, and subsequently the patients were discharged. The relationship between the duration (days) of treatment with intravenous cefazolin (DIVC) and clinical factors were analyzed. RESULTS: The median DIVC was 8 days (interquartile range, 7-10 days). On univariate analysis, DIVC correlated significantly with patient age (P = 0.0071) and with C-reactive protein levels before treatment (P = 0.0053). DIVC in patients with diabetes mellitus was significantly longer than that in patients without diabetes mellitus (P = 0.0033). DIVC in patients with blood stream infection was significantly longer than that in patients without blood stream infection (P = 0.029). On multivariate analysis, variables independently associated with longer DIVC included patient age (P = 0.044), C-reactive protein levels before treatment (P = 0.017), presence of diabetes mellitus (P = 0.0021), and presence of blood stream infection (P = 0.028). CONCLUSIONS: Duration of treatment with intravenous antibiotics for cellulitis is associated with patient age, C-reactive protein levels, coexisting diabetes mellitus, and coexisting blood stream infection. These findings should be considered when treatment plans for cellulitis are devised. PMID- 29254742 TI - Acute kidney injury and cholestasis associated with Kawasaki disease in a 9-year old: Case report. AB - Kawasaki disease (KD) is a systemic vasculitis frequent in children younger than 5 years of age. It involves coronary arteries and other medium-sized vessels. There also exists evidence of inflammatory and proliferative changes affecting the biliary tract and lymphocyte infiltration of the renal interstitial. We describe the case of a 9-year-old girl who developed high-grade fever, bilateral non-purulent conjunctivitis, "strawberry" tongue, desquamation of the fingers and toes, cholestatic syndrome, edema and elevated serum creatinine. KD is a diagnostic challenge for the pediatrician. In every patient with high-grade fever, cholestasis and acute kidney injury, KD should be included in the differential diagnosis, even though more research is necessary to evaluate this atypical association. PMID- 29254743 TI - RS3PE syndrome with positive rheumatoid factor. PMID- 29254744 TI - Anti C1q antibodies. A promising biomarker for cocaine-levamisole induced vasculitis. PMID- 29254746 TI - Effectiveness and safety of nivolumab in advanced non-small cell lung cancer: The real-life data. AB - OBJECTIVES: Nivolumab has recently received regulatory approval as a 2nd-line treatment of non-small cell lung cancer (NSCLC). The data regarding its effectiveness and safety in real life setting is lacking. MATERIALS AND METHODS: 260 consecutive patients with advanced NSCLC treated with nivolumab at five Israeli cancer centers between January 2015 and March 2016 were evaluated for overall survival (OS) and toxicity. OS was analyzed by the Cox proportional hazards regression model. Overall response rate (ORR) and progression-free survival (PFS) were assessed in 49 patients using RECIST, v.1.1. RESULTS: Median age was 67y (41-99); males 68%; smokers 76%; ECOG PS >=2 46%; non squamous/squamous/other/NR 70%/23%/6%/1%; brain metastases 21%; liver metastases 21%; treatment line: 1st/2nd/3rd+-line/NR 6%/64%/26%/4%. With median survival follow-up of 18.5 months (range, 12.0-26.9), 155 (60%) patients died; median OS comprised 5.9 months (95% CI 4.7-7.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS. Median OS of patients with ECOG PS 0/1 and ECOG PS >=2 comprised 9.5 months (95% CI, 6.7 NR) and 3.5 months (95% CI, 2.6-4.5), respectively. For 49 patients evaluable for response (median follow-up of 8.4 months (range, 2-16.8), ORR was 35%, median PFS was 2.8 months (95% CI, 1.8-7.7), incidence of pseudo-progression was 9%. The nivolumab safety profile was in accordance with the literature data, except for febrile neutropenia and pericarditis (observed in 1 case each). CONCLUSION: In real life setting, the effectiveness of nivolumab is reasonable yet less prominent than it has been demonstrated in clinical trials. ECOG PS >=2 is associated with poor prognosis. PMID- 29254745 TI - Multifaceted Fanconi Anemia Signaling. AB - In 1927 Guido Fanconi described a hereditary condition presenting panmyelopathy accompanied by short stature and hyperpigmentation, now better known as Fanconi anemia (FA). With this discovery the genetic and molecular basis underlying FA has emerged as a field of great interest. FA signaling is crucial in the DNA damage response (DDR) to mediate the repair of damaged DNA. This has attracted a diverse range of investigators, especially those interested in aging and cancer. However, recent evidence suggests FA signaling also regulates functions outside the DDR, with implications for many other frontiers of research. We discuss here the characteristics of FA functions and expand upon current perspectives regarding the genetics of FA, indicating that FA plays a role in a myriad of molecular and cellular processes. PMID- 29254747 TI - Collision of communicable and non-communicable disease epidemics-the case of HIV and COPD. PMID- 29254748 TI - Prevalence of chronic obstructive pulmonary disease in the global population with HIV: a systematic review and meta-analysis. AB - BACKGROUND: In recent years, the concept has been raised that people with HIV are at risk of developing chronic obstructive pulmonary disease (COPD) because of HIV infection. However, much remains to be understood about the relationship between COPD and HIV infection. We aimed to investigate this association by assessing studies that reported the prevalence of COPD in the global population with HIV. METHODS: In this systematic review and meta-analysis, we assessed observational studies of COPD in people with HIV. We searched PubMed, Embase, Web of Science, and Global Index Medicus, with no language restriction, to identify articles published until June 21, 2017, and we searched the reference lists of the retrieved articles. Eligible studies reported the prevalence of COPD or had enough data to compute these estimates. We excluded studies in subgroups of participants selected on the basis of the presence of COPD; studies that were limited to other specific groups or populations, such as people with other chronic respiratory diseases; and case series, letters, reviews, commentaries, editorials, and studies without primary data or an explicit description of methods. The main outcome assessed was prevalence of COPD. Each study was independently reviewed for methodological quality. We used a random-effects model to pool individual studies and assessed heterogeneity (I2) using the chi2 test on Cochrane's Q statistic. This study is registered with PROSPERO, number CRD42016052639. FINDINGS: Of 4036 studies identified, we included 30 studies (151 686 participants) from all WHO regions in the meta-analysis of COPD prevalence. 23 studies (77%) had low risk of bias, six (20%) had moderate risk of bias, and one (3%) had high risk of bias in their methodological quality. The overall prevalence of COPD was 10.5% (95% CI 6.2-15.7; I2=97.2%; six studies) according to the lower limit of normal definition of COPD, and 10.6% (6.9-15.0; 94.7%; 16 studies) according to the fixed-ratio definition. COPD prevalence was higher in Europe and among current and ever smokers, and increased with level of income and proportion of participants with detectable HIV viral load. Prevalence of COPD was significantly higher in patients with HIV than in HIV-negative controls (pooled odds ratio 1.14, 95% CI 1.05-1.25, I2=63.5%; 11 studies), even after adjustment for tobacco consumption (2.58, 1.05-6.35, 74.9%; four studies). INTERPRETATION: Our findings suggest a high prevalence of COPD in the global population with HIV, and an association with HIV. As such, COPD deserves more attention from HIV health-care providers, researchers, policy makers, and stakeholders for improved detection, overall proper management, and efficient control of COPD in people with HIV. Efforts to address this burden should focus on promoting the decrease of tobacco consumption and adherence to highly active antiretroviral therapy to reduce viral load. FUNDING: None. PMID- 29254749 TI - Effect of pre-donation fluid intake on fluid shift from interstitial to intravascular compartment in blood donors. AB - BACKGROUND: Fluid shifts from interstitial to intravascular space during blood donation helps in compensating the lost blood volume. We aimed to determine the volume of fluid shift following donation in donors with and without pre-donation fluid intake. METHODS: We studied the fluid shift in 325 blood donors prospectively. Donors were divided in groups- with no fluid intake (GI) and either water (GII) or oral rehydrating fluids (GIII) before donation. Fluid shift following donation was calculated based on the difference between the pre and post donation blood volume. The influence of oral fluid intake, age, gender and body mass index (BMI) on volume of fluid shift was analyzed. RESULTS: The fluid shift was significant between donors without fluids (GI: 127 +/- 81 ml) and donors with fluid intake (GII & III: 96 +/- 45 ml) (p < 0.05). The difference was not significant between donors with water intake (GII: 106 +/- 52 ml) and oral rehydrating fluid intake (GIII: 87 +/- 41 ml). The shifted fluid volume increased with increasing BMI and decreased with increasing age in females. The fluid shift increased in females than in males. CONCLUSION: The age, gender, BMI and VVR did not significantly contribute to the volume of fluid shift following donation. As per our observation, the oral fluids before donation might not contribute to increase in fluid shift in blood donors after donation. PMID- 29254751 TI - Constructing post-surgical discharge instructions through a Delphi consensus methodology. AB - OBJECTIVE: Patient education materials are a crucial part of physician-patient communication. We hypothesize that available discharge instructions are difficult to read and fail to address necessary topics. Our objective is to evaluate readability and content of surgical discharge instructions using thyroidectomy to develop standardized discharge materials. METHODS: Thyroidectomy discharge materials were analyzed for readability and assessed for content. Fifteen endocrine surgeons participated in a modified Delphi consensus panel to select necessary topics. Using readability best practices, we created standardized discharge instructions which included all selected topics. RESULTS: The panel evaluated 40 topics, selected 23, deemed 4 inappropriate, consolidated 5, and did not reach consensus on 8 topics after 4 rounds. The evaluated instructions' reading levels ranged from grade 6.5 to 13.2; none contained all consensus topics. CONCLUSION: Current post surgical thyroidectomy discharge instructions are more difficult to read than recommended by literacy standards and omit consensus warning signs of major complications. Our easy-to-read discharge instructions cover pertinent topics and may enhance patient education. Delphi methodology is useful for developing post-surgical instructions. PRACTICE IMPLICATIONS: Patient education materials need appropriate readability levels and content. We recommend the Delphi method to select content using consensus expert opinion whenever higher level data is lacking. PMID- 29254750 TI - Adult Female with Fever and Groin Pain. PMID- 29254752 TI - Antimicrobial resistance stewardship: it's up to us all. PMID- 29254753 TI - Assessment of the adult patient presenting with shoulder pain. PMID- 29254754 TI - A placenta clinic approach to the diagnosis and management of fetal growth restriction. AB - Effective detection and management of fetal growth restriction is relevant to all obstetric care providers. Models of best practice to care for these patients and their families continue to evolve. Since much of the disease burden in fetal growth restriction originates in the placenta, the concept of a multidisciplinary placenta clinic program, managed primarily within a maternal-fetal medicine division, has gained popularity. In this context, fetal growth restriction is merely one of many placenta-related disorders that can benefit from an interdisciplinary approach, incorporating expertise from specialist perinatal ultrasound and magnetic resonance imaging, reproductive genetics, neonatal pediatrics, internal medicine subspecialties, perinatal pathology, and nursing. The accurate diagnosis and prognosis for women with fetal growth restriction is established by comprehensive clinical review and detailed sonographic evaluation of the fetus, combined with uterine artery Doppler and morphologic assessment of the placenta. Diagnostic accuracy for placenta-mediated fetal growth restriction may be enhanced by quantification of maternal serum biomarkers including placenta growth factor alone or combined with soluble fms-like tyrosine kinase-1. Uterine artery Doppler is typically abnormal in most instances of early-onset fetal growth restriction and is associated with coexistent preeclampsia and underlying maternal vascular malperfusion pathology of the placenta. By contrast, rare but potentially more serious underlying placental diagnoses, such as massive perivillous fibrinoid deposition, chronic histiocytic intervillositis, or fetal thrombotic vasculopathy, may be associated with normal uterine artery Doppler waveforms. Despite minor variations in placental size, shape, and cord insertion, placental function remains, largely normal in the general population. Consequently, morphologic assessment of the placenta is not currently incorporated into current screening programs for placental complications. However, placental ultrasound can be diagnostic in the context of fetal growth restriction, for example in Breus' mole and triploidy, which in turn may enhance diagnosis and management. Several examples are illustrated in our figures and supplementary videos. Recent advances in the ability of multiparameter screening and intervention programs to reduce the risk of severe preeclampsia will likely increase efforts to deliver similar improvements for women at risk of fetal growth restriction. Placental pathology is important because the underlying pathologies associated with fetal growth restriction have a wide range of recurrence risks. Rare conditions such as massive perivillous fibrinoid deposition or chronic histolytic intervillositis may recur in >50% of subsequent pregnancies. Postpartum care in a placenta-focused program can provide effective counseling for modifiable maternal risk factors, and can assist in planning future pregnancy care based on the pathologic basis of fetal growth restriction. PMID- 29254757 TI - First Trimester Plasma Glucose Values in Women without Diabetes are Associated with Risk for Congenital Heart Disease in Offspring. AB - In a retrospective study of 19 171 mother-child dyads, elevated random plasma glucose values during early pregnancy were directly correlated with increased risk for congenital heart disease in offspring. Plasma glucose levels proximal to the period of cardiac development may represent a modifiable risk factor for congenital heart disease in expectant mothers without diabetes. PMID- 29254758 TI - Differentiating the Preterm Phenotype: Distinct Profiles of Cognitive and Behavioral Development Following Late and Moderately Preterm Birth. AB - OBJECTIVES: To explore patterns of comorbidity in cognitive and behavioral outcomes at 2 years' corrected age among children born late or moderately preterm (LMPT) and to identify predictors of different patterns of comorbidity. STUDY DESIGN: Geographical, prospective population-based cohort study of 1139 infants born LMPT (320/7 to 366/7 weeks' gestation) and 1255 infants born at term (370/7 to 426/7 weeks' gestation). Parent questionnaires were obtained to identify impaired cognitive and language development, behavioral problems, delayed social emotional competence, autistic features, and clinically significant eating difficulties at 24 months corrected age for 638 (57%) children born LMPT and 765 (62%) children born at term. RESULTS: Latent class analysis revealed 2 profiles of development among the term group: optimal (84%) and a profile of social, emotional, and behavioral impairments termed "nonoptimal" (16%). These 2 profiles were also identified among the LMPT group (optimal: 67%; nonoptimal: 26%). In the LMPT group, a third profile was identified (7%) that was similar to the phenotype previously identified in infants born very preterm. Nonwhite ethnicity, socioeconomic risk, and not receiving breast milk at hospital discharge were risk factors for nonoptimal outcomes in both groups. Male sex, greater gestational age, and pre-eclampsia were only associated with the preterm phenotype. CONCLUSIONS: Among children born LMPT with parent-reported cognitive or behavioral impairments, most had problems similar to the profile of difficulties observed in children born at term. A smaller proportion of children born LMPT had impairments consistent with the "very preterm phenotype" which are likely to have arisen through a preterm pathway. These results suggest that prematurity may affect development through several etiologic pathways in the late and moderately preterm population. PMID- 29254755 TI - Human genetics of infectious diseases: Unique insights into immunological redundancy. AB - For almost any given human-tropic virus, bacterium, fungus, or parasite, the clinical outcome of primary infection is enormously variable, ranging from asymptomatic to lethal infection. This variability has long been thought to be largely determined by the germline genetics of the human host, and this is increasingly being demonstrated to be the case. The number and diversity of known inborn errors of immunity is continually increasing, and we focus here on autosomal and X-linked recessive traits underlying complete deficiencies of the encoded protein. Schematically, four types of infectious phenotype have been observed in individuals with such deficiencies, each providing information about the redundancy of the corresponding human gene, in terms of host defense in natural conditions. The lack of a protein can confer vulnerability to a broad range of microbes in most, if not all patients, through the disruption of a key immunological component. In such cases, the gene concerned is of low redundancy. However, the lack of a protein may also confer vulnerability to a narrow range of microbes, sometimes a single pathogen, and not necessarily in all patients. In such cases, the gene concerned is highly redundant. Conversely, the deficiency may be apparently neutral, conferring no detectable predisposition to infection in any individual. In such cases, the gene concerned is completely redundant. Finally, the lack of a protein may, paradoxically, be advantageous to the host, conferring resistance to one or more infections. In such cases, the gene is considered to display beneficial redundancy. These findings reflect the current state of evolution of humans and microbes, and should not be considered predictive of redundancy, or of a lack of redundancy, in the distant future. Nevertheless, these observations are of potential interest to present-day biologists testing immunological hypotheses experimentally and physicians managing patients with immunological or infectious conditions. PMID- 29254759 TI - [Eosinophilic spongiosis]. PMID- 29254761 TI - STRIVE, San Diego! Methodology of a Community-Based Participatory Intervention to Enhance Healthy Dining at Asian and Pacific Islander Restaurants. AB - OBJECTIVE: Asian American, Native Hawaiian, and Pacific Islander (AANHPI) populations have elevated prevalence of dietary-related chronic conditions; however, culturally relevant dietary interventions are lacking. This article describes the methodology for a community-based participatory intervention. Strategies to Reach and Implement the Vision of Health Equity, San Diego! aims to increase access to healthy food in AANHPI restaurants, grocery stores, and farmers' markets. DESIGN: Time series quasi-experimental study design. Dietitians, health promotion specialists, and community partners collaborated with restaurant owners and chefs to develop culturally tailored approaches without compromising traditional flavors. SETTING: AANHPI restaurants in San Diego County, CA. PARTICIPANTS: Twenty restaurants and 600 diners are anticipated and will be sampled at 3 intervals for a total of 1,800 diners. INTERVENTION: We describe the community-based interventions within restaurants, including (1) analyzing and modifying selected recipes to create and promote healthier dishes; (2) providing nutrition labels on selected food items; (3) marketing healthy menu items through food tastings, signage, and social media promotion; and (4) offering low-sodium soy sauce and other condiments. MAIN OUTCOME MEASURES: Temporal changes in availability of healthful options, and the frequency of healthy dining choices. ANALYSIS: Program evaluation consists of assessment of the nutritional environment in 20 participating restaurants and surveys of customers' opinions and behaviors at baseline and at 3 and 12 months postintervention. Fifteen restaurants have been recruited to date. PMID- 29254762 TI - Levels of Community Change: A Game to Teach About Policy, System, and Environment Change. PMID- 29254760 TI - A Posterior Circulation Ischemia Risk Score System to Assist the Diagnosis of Dizziness. AB - BACKGROUND: We aimed to establish a risk score system without radio-image examination, which could help clinicians to differentiate patients with vertigo and posterior circulation ischemia (PCI) rapidly from the other dizzy patients. METHODS: We analyzed 304 patients with vertigo (50% PCI). The attributes with more significant contributions were selected as the risk factors for the PCI risk score system, and every one of them was assigned a value according to their respective odds ratio values. We also compared the respective receiver operating characteristic curves of the 3 diagnostic methods (PCI score system, ABCD2, and Essen score systems) to evaluate their prediction effectiveness. RESULTS: Nine risk factors were ultimately selected for PCI score system, including high blood pressure (1'), diabetes mellitus (1'), ischemic stroke (1'), rotating and rocking (-1'), difficulty in speech (5'), tinnitus (-5'), limb and sensory deficit (5'), gait ataxia (1'), and limb ataxia (5'). According to their respective PCI risk scores, the patients were divided into 3 subgroups: low risk (<=0', risk <37.4%), medium risk (1'-5'), and high risk (>=6', risk >95.0%). When 0' was selected as a cutoff point for differentiating the patients with PCI from patients without PCI, the sensitivity was 94.1%, with a specificity of 41.4%. The areas under the receiver operator curve value of PCI score system was .82 (P = .000), much higher than the areas under the receiver operator curve value of ABCD2 (.69, P = .000) and that of the Essen system (.67, P = .000) CONCLUSION: The PCI score system could help clinicians to differentiate patients with vertigo and PCI rapidly from the other dizzy patients. PMID- 29254756 TI - Neutrophils and PMN-MDSC: Their biological role and interaction with stromal cells. AB - Neutrophils and polymorphonucler myeloid-derived suppressor cells (PMN-MDSC) share origin and many morphological and phenotypic features. However, they have different biological role. Neutrophils are one of the major mechanisms of protection against invading pathogens, whereas PMN-MDSC have immune suppressive activity and restrict immune responses in cancer, chronic infectious disease, trauma, sepsis, and many other pathological conditions. Although in healthy adult individuals, PMN-MDSC are not or barely detectable, in patients with cancer and many other diseases they accumulate at various degree and co-exist with neutrophils. Recent advances allow for better distinction of these cells and better understanding of their biological role. Accumulating evidence indicates PMN-MDSC as pathologically activated neutrophils, with important role in regulation of immune responses. In this review, we provide an overview on the definition and characterization of PMN-MDSC and neutrophils, their pathological significance in a variety of diseases, and their interaction with other stromal components. PMID- 29254763 TI - Bone marrow-derived mesenchymal stem cells ameliorate parotid injury in ovariectomized rats. AB - BACKGROUND AIMS: Parotid hypofunction causes life-disrupting effects, and there are no effective medications for xerostomia. We hypothesized that mesenchymal stem cells (MSCs) have repairing effects on parotid glands of ovariectomized (OVX) rats. METHODS: Forty-five adult female rats were divided into three equal groups: group I (Control group), group II (OVX-group) and group III (OVX rats that received MSCs at 4 and 8 weeks post-ovariectomy). At 12 weeks post ovariectomy, histological (Masson's trichrome and periodic acid-Schiff with alcian blue stains), immunohistochemical (caspase-3 and CD44) and morphometric studies and salivary flow rate and saliva pH determination were carried out. RESULTS: Histologically, the OVX group displayed numerous irregular vacuolated acini, thickened septa with marked cellular infiltration and vascular congestion. Degenerated organelles and few or irregular secretory granules with a different density were observed. Caspase-3-positive cells were highly expressed. MSC treated glands exhibited a considerable degree of preservation of glandular architecture with numerous CD44-expressing and few caspase-3-expressing cells. Significant decrease of the salivary flow rate in the OVX group was detected, which reverted to normal levels in group III. CONCLUSIONS: MSCs ameliorated the damaging effects of ovariectomy on the parotid glands. PMID- 29254764 TI - Cell sheets in cell therapies. AB - This review aims to provide a broad introduction to the use of cell sheets and the role of materials in the delivery of cell sheets to patients within a clinical setting. Traditionally, cells sheets have been, and currently are, fabricated using established and accepted cell culture methods within standard formats (e.g., petri dishes) utilizing biological substrates. Synthetic surfaces provide a far more versatile system for culturing and delivering cell sheets. This has the potential to positively affect quality, and efficient, localized cell delivery has a significant impact on patient outcome and on the overall cost of goods. We highlight current applications of these advanced carriers and future applications of these surfaces and cell sheets with an emphasis both on clinical use and regulatory requirements. PMID- 29254765 TI - On the Fuzziness of Machine Learning, Neural Networks, and Artificial Intelligence in Radiation Oncology. PMID- 29254766 TI - The Touchy Topic of the Touch Cell: A Case of Merkel Cell Carcinoma. PMID- 29254767 TI - Radiation Therapy Rather Than Surgery for Merkel Cell Carcinoma: The Advantages of Radiation Therapy. PMID- 29254768 TI - Primary Radiation Therapy for Merkel Cell Carcinoma. PMID- 29254769 TI - Phase 2 Neoadjuvant Treatment Intensification Trials in Rectal Cancer: A Systematic Review. AB - PURPOSE: Multiple phase 2 trials of neoadjuvant treatment intensification in locally advanced rectal cancer have reported promising efficacy signals, but these have not translated into improved cancer outcomes in phase 3 trials. Improvements in phase 2 trial design are needed to reduce these false-positive signals. This systematic review evaluated the design of phase 2 trials of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification in locally advanced rectal cancer. METHODS AND MATERIALS: The PubMed, EMBASE, MEDLINE, and Cochrane Library databases were searched for published phase 2 trials of neoadjuvant treatment intensification from 2004 to 2016. Trial clinical design and outcomes were assessed, with statistical design and compliance rated using a previously published system. Multivariable meta regression analysis of pathologic complete response (pCR) was conducted. RESULTS: We identified 92 eligible trials. Patients with American Joint Committee on Cancer stage II and III equivalent disease were eligible in 87 trials (94.6%). In 43 trials (46.7%), local staging on magnetic resonance imaging was mandated. Only 12 trials (13.0%) were randomized, with 8 having a standard-treatment control arm. Just 51 trials (55.4%) described their statistical design, with 21 trials (22.8%) failing to report their sample size derivation. Most trials (n=84, 91.3%) defined a primary endpoint, but 15 different primary endpoints were used. All trials reported pCR rates. Only 38 trials (41.3%) adequately reported trial statistical design and compliance. Meta-analysis revealed a pooled pCR rate of 17.5% (95% confidence interval, 15.7%-19.4%) across treatment arms of neoadjuvant long-course radiation or chemoradiation therapy treatment intensification and substantial heterogeneity among the reported effect sizes (I2 = 55.3%, P<.001). Multivariable meta-regression analysis suggested increased pCR rates with higher radiation therapy doses (adjusted P=.025). CONCLUSIONS: Improvement in the design of future phase 2 rectal cancer trials is urgently required. A significant increase in randomized trials is essential to overcome selection bias and determine novel schedules suitable for phase 3 testing. This systematic review provides key recommendations to guide future treatment intensification trial design in rectal cancer. PMID- 29254770 TI - The Case for a Primary Surgical Approach. PMID- 29254771 TI - Consider Surgery, but Not in This Case. PMID- 29254772 TI - Intensity Modulated Radiation Therapy and Second Cancer Risk in Adults. PMID- 29254773 TI - Systematic Review of Synthetic Computed Tomography Generation Methodologies for Use in Magnetic Resonance Imaging-Only Radiation Therapy. AB - Magnetic resonance imaging (MRI) offers superior soft-tissue contrast as compared with computed tomography (CT), which is conventionally used for radiation therapy treatment planning (RTP) and patient positioning verification, resulting in improved target definition. The 2 modalities are co-registered for RTP; however, this introduces a systematic error. Implementing an MRI-only radiation therapy workflow would be advantageous because this error would be eliminated, the patient pathway simplified, and patient dose reduced. Unlike CT, in MRI there is no direct relationship between signal intensity and electron density; however, various methodologies for MRI-only RTP have been reported. A systematic review of these methods was undertaken. The PRISMA guidelines were followed. Embase and Medline databases were searched (1996 to March, 2017) for studies that generated synthetic CT scans (sCT)s for MRI-only radiation therapy. Sixty-one articles met the inclusion criteria. This review showed that MRI-only RTP techniques could be grouped into 3 categories: (1) bulk density override; (2) atlas-based; and (3) voxel-based techniques, which all produce an sCT scan from MR images. Bulk density override techniques either used a single homogeneous or multiple tissue override. The former produced large dosimetric errors (>2%) in some cases and the latter frequently required manual bone contouring. Atlas-based techniques used both single and multiple atlases and included methods incorporating pattern recognition techniques. Clinically acceptable sCTs were reported, but atypical anatomy led to erroneous results in some cases. Voxel-based techniques included methods using routine and specialized MRI sequences, namely ultra-short echo time imaging. High-quality sCTs were produced; however, use of multiple sequences led to long scanning times increasing the chances of patient movement. Using nonroutine sequences would currently be problematic in most radiation therapy centers. Atlas-based and voxel-based techniques were found to be the most clinically useful methods, with some studies reporting dosimetric differences of <1% between planning on the sCT and CT and <1-mm deviations when using sCTs for positional verification. PMID- 29254774 TI - Care for Patients, Not for Charts: A Future for Clinical Medical Physics. PMID- 29254775 TI - Efficient Interplay Effect Mitigation for Proton Pencil Beam Scanning by Spot Adapted Layered Repainting Evenly Spread out Over the Full Breathing Cycle. AB - PURPOSE: To develop and implement a practical repainting method for efficient interplay effect mitigation in proton pencil beam scanning (PBS). METHODS AND MATERIALS: A new flexible repainting scheme with spot-adapted numbers of repainting evenly spread out over the whole breathing cycle (assumed to be 4 seconds) was developed. Twelve fields from 5 thoracic and upper abdominal PBS plans were delivered 3 times using the new repainting scheme to an ion chamber array on a motion stage. One time was static and 2 used 4-second, 3-cm peak-to peak sinusoidal motion with delivery started at maximum inhalation and maximum exhalation. For comparison, all dose measurements were repeated with no repainting and with 8 repaintings. For each motion experiment, the 3%/3-mm gamma pass rate was calculated using the motion-convolved static dose as the reference. Simulations were first validated with the experiments and then used to extend the study to 0- to 5-cm motion magnitude, 2- to 6-second motion periods, patient measured liver tumor motion, and 1- to 6-fraction treatments. The effect of the proposed method was evaluated for the 5 clinical cases using 4-dimensional (4D) dose reconstruction in the planning 4D computed tomography scan. The target homogeneity index, HI = (D2 - D98)/Dmean, of a single-fraction delivery is reported, where D2 and D98 is the dose delivered to 2% and 98% of the target, respectively, and Dmean is the mean dose. RESULTS: The gamma pass rates were 59.6% +/- 9.7% with no repainting, 76.5% +/- 10.8% with 8 repaintings, and 92.4% +/- 3.8% with the new repainting scheme. Simulations reproduced the experimental gamma pass rates with a 1.3% root-mean-square error and demonstrated largely improved gamma pass rates with the new repainting scheme for all investigated motion scenarios. One- and two-fraction deliveries with the new repainting scheme had gamma pass rates similar to those of 3-4 and 6-fraction deliveries with 8 repaintings. The mean HI for the 5 clinical cases was 14.2% with no repainting, 13.7% with 8 repaintings, 12.0% with the new repainting scheme, and 11.6% for the 4D dose without interplay effects. CONCLUSIONS: A novel repainting strategy for efficient interplay effect mitigation was proposed, implemented, and shown to outperform conventional repainting in experiments, simulations, and dose reconstructions. This strategy could allow for safe and more optimal clinical delivery of thoracic and abdominal proton PBS and better facilitate hypofractionated and stereotactic treatments. PMID- 29254776 TI - Breast Cancer Biology: Clinical Implications for Breast Radiation Therapy. AB - Historically, prognosis and treatment decision making for breast cancer patients have been dictated by the anatomic extent of tumor spread. However, in recent years, "breast cancer" has proven to be a collection of unique phenotypes with distinct prognoses, patterns of failure, and treatment responses. Recent advances in biologically based assays and targeted therapies designed to exploit these unique phenotypes have profoundly altered systemic therapy practice patterns and treatment outcomes. Data associating locoregional outcomes with tumor biology are emerging. However, the likelihood of obtaining level I evidence for fundamental radiation therapy questions within each of the specific subtypes in the immediate future is low. As such, this review aims to summarize the existing data and provide practical context for the incorporation of breast tumor biology into clinical practice. PMID- 29254777 TI - In Regard to Chapman and Jagsi. PMID- 29254778 TI - In Reply to Thomas. PMID- 29254779 TI - Erratum to: Kanehira T, Matsuura T, Takao S, et al. Impact of Real-Time-Image Gating on Spot Scanning Proton Therapy for Lung Tumors: A Simulation Study. Int J Radiat Oncol Biol Phys 2016;97:173-181. PMID- 29254780 TI - Radiation Oncology in The Netherlands. PMID- 29254781 TI - Lack of Apparent Survival Benefit With Use of Androgen Deprivation Therapy in Patients With High-risk Prostate Cancer Receiving Combined External Beam Radiation Therapy and Brachytherapy. AB - PURPOSE: Although level 1 evidence has demonstrated a survival benefit from the addition of androgen deprivation therapy (ADT) to external beam radiation therapy (EBRT) for patients with high-risk prostate cancer, the benefits of ADT with combined EBRT and brachytherapy for high-risk patients are unclear. We examined the association between ADT and overall survival in a national cohort of high risk patients treated with EBRT with or without brachytherapy. METHODS AND MATERIALS: We identified 46,325 men in the National Cancer Database with a diagnosis of high-risk prostate cancer (Gleason score 8-10, clinical stage T3-T4, or prostate-specific antigen >20 ng/mL) who were treated with EBRT with or without brachytherapy and ADT from 2004 through 2011. Multivariable Cox regression analysis adjusting for sociodemographic and clinicopathologic factors was used to identify the association between ADT and overall survival. RESULTS: The median follow-up period was 48.6 and 59.2 months for patients treated with EBRT only and combined modality RT, respectively. ADT was associated with an improvement in overall survival for the 85.0% (39,361) of the study cohort who underwent EBRT alone (adjusted hazard ratio 0.91, P=.001) but not for patients treated with combined modality RT (adjusted hazard ratio 1.05, P=.496), with a significant interaction (Pinteraction=.036). CONCLUSIONS: In contrast to the known survival benefit when ADT is given with EBRT, our results suggest that ADT might not improve survival for high-risk patients who undergo combined EBRT and brachytherapy. Given the significant adverse effects of ADT, in particular, with long-term therapy, a randomized controlled trial of combined EBRT and brachytherapy with or without ADT for select high-risk patients using a noninferiority design should be undertaken. PMID- 29254783 TI - Time-Driven Activity-Based Costing in Oncology: A Step in the Right Direction. PMID- 29254782 TI - Prostate-Specific Antigen (PSA) Bounce After Dose-Escalated External Beam Radiation Therapy Is an Independent Predictor of PSA Recurrence, Metastasis, and Survival in Prostate Adenocarcinoma Patients. AB - PURPOSE: To evaluate the difference in prostate-specific antigen (PSA) recurrence free, distant metastasis-free, overall, and cancer-specific survival between PSA bounce (PSA-B) and non-bounce patients treated with dose-escalated external beam radiation therapy (DE-EBRT). METHODS AND MATERIALS: During 1990-2010, 1898 prostate adenocarcinoma patients were treated with DE-EBRT to >=75 Gy with >=5 years follow-up. Patients receiving neoadjuvant/concurrent androgen-deprivation therapy (n=1035) or with fewer than 4 PSA values obtained 6 months or more after post-EBRT completion (n=87) were excluded. The evaluable 776 patients were treated (median, 81.0 Gy). Prostate-specific antigen bounce was defined as a >=0.2-ng/mL increase above the interval PSA nadir, followed by a decrease to nadir or below. Prostate-specific antigen relapse was defined as post-radiation therapy PSA nadir + 2 ng/mL. Median follow-up was 9.2 years (interquartile range, 6.9-11.3 years). RESULTS: One hundred twenty-three patients (15.9%) experienced PSA-B after DE-EBRT at a median of 24.6 months (interquartile range, 16.1-38.5 months). On multivariate analysis, younger age (P=.001), lower Gleason score (P=.0003), and higher radiation therapy dose (P=.0002) independently predicted PSA-B. Prostate-specific antigen bounce was independently associated with decreased risk for PSA relapse (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.33-0.85; P=.008), distant metastatic disease (HR 0.34; 95% CI 0.12-0.94; P=.04), and all-cause mortality (HR 0.53; 95% CI 0.29-0.96; P=.04) on multivariate Cox analysis. Because all 50 prostate cancer-specific deaths in patients without PSA-B were in the non-bounce cohort, competing-risks analysis was not applicable. A nonparametric competing-risks test demonstrated that patients with PSA-B had superior cancer-specific survival compared with patients without PSA-B (P=.004). CONCLUSIONS: Patients treated with dose-escalated radiation therapy for prostate adenocarcinoma who experience posttreatment PSA-B have improved PSA recurrence-free survival, distant metastasis-free survival, overall survival, and cancer-specific survival outcomes. PMID- 29254784 TI - Prognostic impact of changes in base excision repair machinery in sporadic colorectal cancer. AB - OBJECTIVE: to evaluate the prognostic value of base excision repair proteins in sporadic colorectal cancer. METHODS: Pre-treatment tumor samples from 72 patients with sporadic colorectal adenocarcinoma were assessed for APC, MPG, Polbeta, XRCC1 and Fen1 expression by immunohistochemistry. The associations of molecular data were analyzed in relation to clinical features and TNM staging as a prognosis predictor and disease-free survival. RESULTS: Higher levels of MPG, Polbeta and XRCC1, but not Fen1, were associated with unfavorable pathological outcomes, such as poor cellular differentiation, advanced TNM stages, presence of lymphatic and perineural invasions and metastatic lymph nodes. MPG and Polbeta overexpression were associated with right-sided CRC. However, only MPG high expression is associated with shorter disease-free survival in CRC patients. CONCLUSIONS: Our results suggest that increased expression of MPG, Polbeta and XRCC1 are more likely to evolve to poor pathological outcomes, but only the elevated expression of MPG protein predicts recurrence. The BER proteins appear to be suitable candidates to refine the TNM current staging of colorectal cancer. PMID- 29254785 TI - Impact of DNA repair, folate and glutathione gene polymorphisms on risk of non small cell lung cancer. AB - Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC. No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC. PMID- 29254786 TI - Use of 2,3,5-triphenyltetrazolium chloride-stained brain tissues for immunofluorescence analyses after focal cerebral ischemia in rats. AB - The middle cerebral artery occlusion (MCAO) model in rodents has been widely used as model for studying brain ischemic stroke. TTC (2,3,5-triphenyltetrazolium chloride) staining in fresh tissues is used to evaluate the size of the infarct in MCAO model, and TTC-stained brain tissues are considered to be possible to bring a damage to the anatomical structure of neuronal cells and unsuitable for immunofluorescence analyses of cytology, and discarded after evaluation of infarct volume. Another group of models with in vivo fixation was required to the pathological or histological analyses of the infarct brains, which lead to double the numbers of animals in researches. However, some evidences indicate that if we properly optimized staining protocol, TTC-stained brain tissues might be suitable for cytological analyses. In this work, we have optimized the immunofluorescent staining methods of TTC-stained brain slices, and found that TTC-stained brain tissues are suitable for quantitative and qualitative analyses of microglia, astrocytes and neuroblasts, the morphology of theses cell were nearly identical to the in-vivo fixed models. Our optimized-protocol provide two advantages over traditional methods one of them is providing the precise the infarct region, which reduces the differences within groups, the other one is decreasing the total number of animals in research dramatically. PMID- 29254787 TI - Downregulation of miR-10B* is correlated with altered expression of mitotic kinases in osteosarcoma. AB - Dysregulated mitotic kinases have frequently been associated with cancer. Changes in their expression might result from diverse mechanisms including avoidance of the tight regulation exerted by miRNAs. Herein we show that miR-10b* is downregulated in osteosarcoma samples and demonstrate its correlation with PLK1, PLK4, BUB1, and BUBR1, which are strongly intercorrelated. The selection of miRNAs that coordinately target and regulate multiple members of cancer-related pathways are particularly advantageous to tumors. Thus, even though no associations with clinical parameters were found, our data place miR-10b* as a tumor suppressor that might contribute to guarantee genomic stability, deserving further functional confirmation. PMID- 29254788 TI - Cyclin D1 expression by histiocytes may mimic cyclin D1-positive proliferation centres of chronic lymphocytic leukaemia/small lymphocytic lymphoma. AB - AIMS: Cyclin D1, generally considered to be absent in chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), has been reported in the proliferation centres (PCs) of recent CLL/SLL cases. Cyclin D1 immunostaining in CLL/SLL may lead to diagnostic confusion. The objective of this study was to identify the types of stained cells and the impact on diagnosis. METHODS: Cyclin D1 expression was assessed by immunostaining samples from 46 cases of CLL/SLL. CD68 and double immunostaining with CD20/CyclinD1, CD68/CyclinD1, and CD163/CyclinD1 were then performed in cases of CLL/SLL positive for cyclinD1 in the PCs. RESULTS: Dim-positive cyclin D1 staining in randomly scattered cells in the CLL/SLLs were observed in 38/46 cases (82.6%). In five (10.9%) cases, more than 50 cyclin D1-positive cells per high-power field were detected within the PCs in CLL/SLL with weak to moderate intensity. Double immunochemical staining in these cases showed that cyclin D1 in these positive cells was mostly co-expressed with CD68 and CD163 and the cells were negative for CD20. CONCLUSIONS: The cyclin D1-positive CLL/SLL cells in this study were mostly histiocytes. The expression of cyclin D1 by histiocytes may mimic cyclin D1+ CLL/SLL; thus, the recognition of cyclin D1 expression by non-lymphoid cells in lymphoma is important. PMID- 29254789 TI - Bone marrow miR-10a overexpression is associated with genetic events but not affects clinical outcome in acute myeloid leukemia. AB - BACKGROUND: Accumulating studies have linked the disruptions of microRNA-10 (miR 10) to acute myeloid leukemia (AML) with NPM1 mutation. However, miR-10 expression and its clinical implication in AML remain poorly defined. Although a recent report showed high serum level of miR-10a was associated with adverse prognosis in AML, herein, we found bone marrow (BM) miR-10 overexpression was not a prognostic biomarker in AML. METHODS: BM miR-10 expression was examined by real time quantitative PCR in BM mononuclear cells in 115 de novo AML patients and 45 controls. RESULTS: BM miR-10 (miR-10a/b) expression was significantly up regulated in AML patients, and was positively correlated with each other. Overexpression of miR-10a was associated with lower percentage of BM blasts, whereas miR-10b overexpression tended to correlate with higher percentage of BM blasts. Importantly, miR-10a overexpression was significantly associated with FAB M3/t(15;17) subtypes and NPM1 mutation, meanwhile, overexpression of miR-10b was correlated with NPM1 and DNMT3A mutations. However, miR-10a/b overexpression was not associated with complete remission rate, and did not have an impact on both leukemia free survival and overall survival time in non-M3 AML patients without NPM1 mutation. CONCLUSIONS: BM miR-10 overexpression is associated with genetic events but not affects clinical outcome in AML. PMID- 29254790 TI - Study on expression of p16 and human papillomavirus 16 and 18 (E6) in OLP and its malignant transformation. AB - OBJECTIVE: The aim of this study is to investigate the expressions of p16 and HPV16/18(E6) in oral lichen planus (OLP) and malignant transformed OLP (MT-OLP). STUDY DESIGN: The expression of p16 and HPV16/18(E6) in 40 cases of OLP and 6 MT OLP was assessed by immunohistochemical staining. Twenty four cases of normal oral mucosa were used as controls. RESULTS: Compared to normal oral mucosa, the expression of p16 and HPV16/18(E6) protein increased in OLP and MT-OLP. And there was a correlation between p16 expression and HPV infection in OLP and OLP malignant lesions (p < 0.0001). CONCLUSIONS: The expression of p16 protein might predict HPV16/18 infection in OLP. And HPV16/18(E6) infection might contribute to OLP malignant transformation. PMID- 29254791 TI - Expression profiles of Annexin A1, formylated peptide receptors and cyclooxigenase-2 in gastroesophageal inflammations and neoplasias. AB - The anti-inflammatory protein Annexin-A1 (ANXA1) is associated to tumor invasion process and its actions can be mediated by formylated peptides receptors (FPRs). Therefore, we evaluated the expression and correlation of ANXA1, FPR and cyclooxygenase-2 (COX-2) enzyme in esophageal and stomach inflammations and neoplasias. The study of proteins was performed by immunohistochemistry in biopsies of esophagitis, Barrett's esophagus, squamous cell carcinoma and adenocarcinoma of the esophagus, as well as gastritis, stomach polypus and gastric adenocarcinoma. The intensity of the expressions was evaluated by densitometry. The immunohistochemical and densitometric analyzes showed specificity for the FPR1 receptor and modulation of the ANXA1, COX-2 and FPR1 expressions in the epithelial cells in the different studied conditions. Increased immunoreactivity of these proteins was observed in cases of inflammation and stomach polypus. Interestingly, moderate immunoreactivity for ANXA1 and FPR1 but increased immunolabeling for COX-2 were observed in Barretts esophagus and esophageal adenocarcinomas. Also, there was reduced expression of ANXA1 and FPR1 in esophageal carcinoma but COX-2 overexpression in this tumor. There was no expression of FPR2 but ANXA1 and FPR1 expressions were positively correlated in all clinical conditions studied. Positive correlation between ANXA1 and COX-2 were also observed in inflammation conditions while negative correlation between ANXA1 and COX-2 was observed in esophageal carcinoma. Our results demonstrate the unregulated expression of ANXA1 and COX-2 in precursor lesions of esophageal and stomach cancers, reinforcing their involvement in gastroesophageal carcinogenesis. In addition, the data show that the actions of ANXA1 in the inflammatory and neoplastic processes of the esophagus and stomach are specifically mediated by the FPR1 receptor. PMID- 29254792 TI - High expression of GRK3 is associated with favorable prognosis in pancreatic ductal adenocarcinoma. AB - BACKGROUND: It was found that G-protein-coupled receptor kinase 3 (GRK3) played key biological roles in some cancers. However, its associations with clinicopathologic features and prognosis in pancreatic ductal adenocarcinoma (PDAC) remain unknown. METHODS AND METHODS: Expression of GRK3 was detected, using tissue microarray-based immunohistochemistry, in paired formalin-fixed paraffin-embedded tumor and non-tumor samples from 165 patients with PDAC after curative resection, and was further correlated with clinicopathologic parameters and cancer-specific survival (CSS). RESULTS: It was shown that GRK3 expression was much lower in tumor than in non-tumor tissues. Moreover, expression of GRK3 in tumor tissues was significantly associated with gender and T stage. Univariately, high GRK3 expression was predictive for favorable CSS, along with some conventional clinicopathologic variables. In multivariate Cox regression test, GRK3 expression remained to be a significant prognostic marker for PDAC. Finally, combination of GRK3 with some clinicopathologic variables, especially N stage, obtained more precise prediction for CSS. CONCLUSIONS: Our data suggested that expression of GRK3 was down-regulated in PDAC and was an independent prognostic factor. PMID- 29254793 TI - Immunophenotypic profile of tumor buds in breast cancer. AB - BACKGROUND: Tumor buds are associated with lympho-vascular invasion and lymph node metastases leading to the assumption that they are involved in the early metastatic process. Hence, it would be important to know if tumor buds can be targeted with the most widely used targeted therapies in breast cancer (BC) and if changes in hormone and Her2 status occur. The aim of this study was to answer these questions by determining whether hormone receptor (HR) and Her2 status are expressed in the tumor buds of a large cohort of BCs. DESIGN: We constructed a tumor bud next-generation tissue microarray (ngTMA) consisting of n = 199 BCs of non-special type. Generally, two 1 mm punches were taken from the tumor bud areas in the periphery (PTB) and within the tumor center (ITB). HR and Her2 status was assessed using immunohistochemistry and fluorescence in situ hybridization, respectively. HR status was positive if >=1% of tumor bud cells were positive. Her2 status was considered positive if bud cells showed strong complete membranous Her2 over-expression or Her2 amplification. RESULTS: Most tumor buds were positive for estrogen (ER) (PTB: 86%; ITB: 88.3) and progesterone receptor (PgR) (PTB: 72%; ITB: 72.8%) and Her2 was positive in: PTB 11.5% and ITB 11%. A difference between the main tumor mass and tumor buds (PTB and ITB) was seen for PgR in 3.5% of cases (n = 7). No differences were seen for ER and Her2 between tumor buds and main tumor mass. CONCLUSION: Most tumor buds (96.5%) share the same HR and Her2 expression profile of the main tumor mass, implying that tumor buds relay on the same pathways as the main tumor mass and might be equally responsive to targeted therapies. PMID- 29254794 TI - Frequent methylation of DAB2, a Wnt pathway antagonist, in oral and oropharyngeal squamous cell carcinomas. AB - BACKGROUND: Aberrations in Wnt signaling pathway are related to the pathogenesis of head and neck carcinomas and their activation frequently results from epigenetic alterations. This study aimed to assess the frequency of the methylation of DAB2, which acts as a negative regulator of Wnt signaling, and correlate it with clinicopathological features in a group of oral cancer patients. MATERIAL AND METHODS: Forty nine patients with primary oral squamous cell carcinoma were enrolled in the study. DNA samples were isolated from surgical sections using phenol-chloroform extraction. Methylation-specific PCR was used to detect gene promoter methylation. RESULTS: The analysis of the occurrence of DAB2 promoter methylation in primary oral carcinomas indicated that the gene is methylated in 70% of cases. However, no correlation was found between its methylation and TNM staging or overall survival. CONCLUSIONS: Our findings corroborate that DAB2 is a frequent target of epigenetic silencing in oral carcinomas and may be potentially used for tumor detection. PMID- 29254796 TI - Accentuated p53 staining in usual type vulvar dysplasia-A potential diagnostic pitfall. AB - Evaluation of vulvar intraepithelial neoplasia (VIN) may be difficult due to overlapping histologic features seen in both usual (UVIN) and differentiated vulvar intraepithelial neoplasia (DVIN). DVIN represents a diagnostic challenge; poor inter-observer agreement is well documented. P53 has been described as a potentially helpful adjunct in some cases; however, intricacies in its interpretation remain. This study evaluated 41 consecutive cases which consisted of 23 keratinizing dysplasias that were morphologically suggestive of DVIN and 18 UVINs. All cases were stained with p16 and p53. Our results revealed that 22 of 41 (54%) VINs showed novel accentuated wild type (WT) staining with non-linear basal staining for p53, including 12 (52%) cases histologically suggestive of DVIN and 10 (56%) described as UVIN. P16 was positive in 100% of the accentuated wild type cases, consistent with a diagnosis of UVIN. Positive p53 and negative p16 staining was seen in 4 (17%) cases histologically suggestive of DVIN. Of these, 75% progressed to carcinoma, whereas only 1 of 35 (3%) patients with UVIN progressed to carcinoma. In conclusion, DVIN is difficult to diagnose due to potential histologic overlap with UVIN, especially the warty, or keratinizing, subtype. Accentuated WT p53 in absence of concurrent p16 staining may lead to misdiagnosis of DVIN, especially in small biopsy samples. P16/p53 staining should be performed in tandem with strict adherence to patterns considered positive, as patients with UVIN have significantly less risk of progression. PMID- 29254795 TI - Detection of H3F3A p.G35W and p.G35R in giant cell tumor of bone by Allele Specific Locked Nucleic Acid quantitative PCR (ASLNAqPCR). AB - Giant Cell Tumor (GCT) represents about 20% of benign bone tumors, is locally aggressive although malignant transformation is extremely rare, <1% of cases but 2-3% give pulmonary metastasis. Age at onset is between 20 and 40 years with a slight predominance for the female gender. GCT is characterized by specific mutations in H3F3A gene encoding the protein histone 3.3. The study of these mutations is important for the differential diagnosis with giant cell rich sarcomas, chondroblastoma and aneurysmal bone cyst. To identify the most frequent H3F3A mutations we developed a novel allele specific Real Time Polymerase Chain Reaction method, based on Allele Specific Locked Nucleic Acid (ASLNAqPCR) that is here described. Molecular analyses were performed on 20 GCT and 2 osteosarcoma arising on a previous GCT. All cases were verified by Sanger sequencing. We demonstrated that ASLNAqPCR is a quick, sensitive and reliable method to identify mutations of the H3F3A gene, in giant cell tumor of bone, to support diagnosis in morphologically ambiguous cases. PMID- 29254797 TI - Prognostic value of GRIM-19, NF-kappaB and IKK2 in patients with high-grade serous ovarian cancer. AB - AIMS: High grade serous carcinoma (HGSC) is an aggressive tumour, and most patients relapse after treatment, acquiring resistance to platinum-based chemotherapy. One of the resistance mechanisms proposed is apoptosis evasion triggered by drug-related cytotoxic effect in the cell. In this context, this study aims to evaluate the protein expression of GRIM-19, NF-kappaB and IKK2, their association with chemotherapy response and to determine their prognostic values in HGSC. METHODS: GRIM-19, NF-kappaB and IKK2 expression was evaluated by immunohistochemistry (IHC) in 71 patients with HGSC selected between 2003 and 2013, whose underwent primary debulking surgery with complete cytoreduction. Protein expression was analyzed in relation to platinum response groups, tumour progression, clinicopathological data and survival. RESULTS: Positive IKK2 expression was related to resistance (p = 0.011), shorter disease-free survival (p = 0.001) and overall survival (p = 0.026) and was also a risk factor for relapse (p = 0.002) and death (p = 0.032). The association between IKK2 and NF kappaB positivity predicted a subgroup with shorter overall survival (p = 0.004), disease-free survival (p = 0.003) and resistance to platinum-based chemotherapy (p = 0.036). NF-kappaB positivity was associated with worse overall survival (p = 0.005) and disease-free survival (p = 0.027) and was a positive predictor for relapse (p = 0.032) and death (p = 0.008). Higher expression of GRIM-19 was associated with higher disease-free survival (p = 0.039) and was a negative predictor for relapse (p = 0.046). CONCLUSIONS: GRIM-19 is a potential predictor of prognosis and disease recurrence in HGSC. IKK2 and NF-kappaB are related to poor prognosis and are potential predictors of response to platinum-based chemotherapy in HGSC. IHC analyses of GRIM19, IKK2 and NF-kappaB may be important in the attempt to provide prognostic values for relapse and response to treatment in patients with HGSC. PMID- 29254798 TI - An update on the molecular pathology of urinary bladder tumors. AB - Urothelial carcinoma is the fourth most common tumors after prostate cancer, lung, and colorectal carcinoma but the second most common urologic malignancy. Urothelial carcinoma composed more than 90% of bladder tumors while squamous cell carcinoma and adenocarcinomas composed 5% and 2% respectively. The intense research involving the different molecular aspects of bladder cancer has provided a great insight into identifying more about molecular profiling and pathways of bladder cancer. In this review, we will highlight the general concepts of the molecular features; profiling and classification as well as the molecular pathways for bladder carcinomas, especially urothelial carcinoma. Also, we will discuss the advances of molecular biomarkers for screening, early diagnosis, surveillance and potential prognosis of urothelial carcinoma of the bladder. Studies showed that accumulation of genetic alterations involving the clonal expansion of altered cells with growth advantages through sequential multi-step pathways results in progression of bladder tumors. The accumulated research data from literature has revealed that the genomic signatures of urothelial carcinoma are required to subclassify bladder cancer into genetically distinct subgroups. These findings could improve the understating of pathogenesis as well as will provide new therapeutic modules e.g. targeted therapy. PMID- 29254799 TI - Investigation of BRAF V600E detection approaches in papillary thyroid carcinoma. AB - OBJECTIVE: The detection of BRAF V600E mutation in papillary thyroid carcinoma (PTC) may be helpful to offer diagnostic confirmation. Additionally, such detection may provide a targeted therapeutic approach for the radioactive iodine resistant patients to predict adverse outcomes. To compare the results of immunohistochemistry (IHC) method using the anti-BRAF V600E (VE1) antibody with the Quantitative real-time polymerase chain reaction (qPCR) approach in examining BRAF V600E mutation in PTC, we investigated the sensitivity and specificity of BRAF V600E (clone VE1) mouse monoclonal antibody in detecting the BRAF V600E mutation and correlated BRAF V600E mutation with clinicopathologic features in PTC. METHODS: IHC and qPCR were performed in 40 cases of paraffin-embedded PTCs tissues. The association between BRAFV600E mutation and clinicopathologic features of PTC was assessed with the chi2 test. RESULTS: The concordance rate between IHC and qPCR analyses was 95% (38/40). The BRAF V600E (VE1) antibody has a sensitivity of 100% (34/34) and specificity of 66.67% (4/6) for detecting the mutation. Our study showed that there was no significant association of BRAF V600E mutation with the gender, age, tumor size and lymph node metastasis in PTCs. CONCLUSION: We may draw the conclusion that detection of BRAF V600E mutation by immunohistochemistry is highly sensitive and specific. Immunohistochemical detection of the mutated BRAF V600E protein in PTC may facilitate mutational analysis in the clinical setting. PMID- 29254800 TI - TL1A blocking ameliorates intestinal fibrosis in the T cell transfer model of chronic colitis in mice. AB - Tumor necrosis factor like cytokine 1A (TL1A) is a member of the TNF superfamily. Accumulating evidence demonstrated the importance of TL1A in the pathogenesis of inflammatory bowel disease (IBD) and suggested a potential role of TL1A blocking in IBD therapy. Here we aimed to explore whether the anti-TL1A antibody could ameliorate intestinal inflammation and fibrosis in IBD. A T cell transfer model of chronic colitis was induced by intraperitoneal injection of CD4+CD45RBhigh naive T cells isolated from either C57BL/6 wild type (WT) mice or LCK-CD2-Tl1a GFP transgenic (L-Tg) mice into recombinase activating gene-1-deficient (RAG-/-) mice. The colitis model mice were treated prophylactically or therapeutically with anti-Tl1a antibody or IgG isotype control. Haematoxylin and eosin staining (H&E staining), Masson's trichrome staining (MT staining) and sirius red staining were used to detect histopathological changes in colonic tissue; immunohistochemical staining was used to detect the expressions of collagen I, collagen III, TIMP1, vimentin, alpha-SMA and TGF-beta1/Smad3. Results showed that anti-Tl1a antibody could reduce intestinal inflammation and fibrosis by inhibiting the activation of intestinal fibroblasts and reducing the collagen synthesis in the T cell transfer model of chronic colitis. The mechanism may be related to the inhibition of TGF-1/Smad3 signaling pathway. PMID- 29254801 TI - The associations between CYP24A1 polymorphisms and cancer susceptibility: A meta analysis and trial sequential analysis. AB - PURPOSE: Published data have shown that vitamin D may have a protective effect on cancer development. CYP24A1, the main enzyme responsible for the degradation of active vitamin D, plays an important role in many cancer related cellular processes. Up to now, relationships between CYP24A1 polymorphisms and cancer susceptibility have been widely investigated, whereas the results are inconsistent. The aim of present meta-analysis was to explore the associations between CYP24A1 polymorphisms and cancer susceptibility. METHODS: We searched on EMBASE, Web of Science, PubMed and China National Knowledge Infrastructure (CNKI) electronic databases (up to July 1, 2017) for relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to make the evaluation clear. RESULTS: Twenty-nine studies published in eight publications involving 20,593 cases and 25,458 controls were included. Five CYP24A1 gene polymorphisms were evaluated: rs2181874, rs2585428, rs4809960, rs6022999, and rs6068816. Our analyses suggested that rs2585428 and rs4809960 polymorphisms were significantly associated with overall cancer risk. Stratification analyses of ethnicity indicated that rs2585428 and rs4809960 polymorphisms decreased the risk of cancer among Caucasians. When studies were stratified by cancer type, our results indicated that rs2585428 significantly decreased the risk of pancreas cancer, while rs4809960 significantly decreased the risk of breast cancer. There were no associations of rs2181874, rs6022999, or rs6068816 with overall cancer risks. CONCLUSION: Associations between CYP24A1 polymorphisms and cancer risks were examined, and additional multi-center studies with large samples are necessary to validate our results. PMID- 29254802 TI - Gallic acid modulates phenotypic behavior and gene expression in oral squamous cell carcinoma cells by interfering with leptin pathway. AB - Gallic acid is a polyphenolic compost appointed to interfere with neoplastic cells behavior. Evidence suggests an important role of leptin in carcinogenesis pathways, inducing a proliferative phenotype. We investigated the potential of gallic acid to modulate leptin-induced cell proliferation and migration of oral squamous cell carcinoma cell lines. The gallic acid effect on leptin secretion by oral squamous cell carcinoma cells, as well as the underlying molecular mechanisms, was also assessed. For this, we performed proliferation, migration, immunocytochemical and qPCR assays. The expression levels of cell migration related genes (MMP2, MMP9, Col1A1, and E-cadherin), angiogenesis (HIF-1alpha, mir210), leptin signaling (LepR, p44/42 MAPK), apoptosis (casp-3), and secreted leptin levels by oral squamous cell carcinoma cells were also measured. Gallic acid decreased proliferation and migration of leptin-treated oral squamous cell carcinoma cells, and reduced mRNA expression of MMP2, MMP9, Col1A1, mir210, but did not change HIF-1alpha. Gallic acid decreased levels of leptin secreted by oral squamous cell carcinoma cells, accordingly with downregulation of p44/42 MAPK expression. Thus, gallic acid appears to break down neoplastic phenotype of oral squamous cell carcinoma cells by interfering with leptin pathway. PMID- 29254803 TI - Clinical implementation of radiosurgery using the Helical TomoTherapy unit. AB - The American Society of Radiation Oncology has recently recommended the use of radiosurgery to manage brain metastases. For such a recommendation to be implemented in a widespread manner, radiosurgery must be accessible at community radiation therapy facilities. The work presented here describes our clinical experience in the implementation of radiosurgery using a Helical TomoTherapy unit. Helical TomoTherapy is a unique dose-delivery system designed to perform intensity-modulated radiation therapy (IMRT). The system built on the ring-based gantry has the tight machine tolerances required for radiosurgery. A frameless system consisting of a thermoplastic mask and a noninvasive "stereotactic radiosurgery (SRS)-stereotactic radiotherapy (SRT)" fixation device is used for patient immobilization. Treatment planning is performed using the TomoHD treatment planning system designed for IMRT. The image-guidance system on the Helical TomoTherapy is used for patient localization. Our clinical experience demonstrated that the radiosurgery procedure can be streamlined as we do for IMRT patients. The treatment time of about 10 minutes is comparable with that for IMRT patients. The same patient-specific quality assurance for IMRT is used for radiosurgery. As demonstrated, SRS using Helical TomoTherapy is not a whole-day event, unlike SRS using other dose-delivery systems or SRS performed in the past. PMID- 29254804 TI - In regard to the paper: Patient performance-based plan parameter optimization for prostate cancer in tomotherapy [Cao YJ, Lee S, Chang KH, Shim JB, Kim KH, Park YJ, Kim CY. Med Dosim. 2015;40(4):285-9. doi: 10.1016/j.meddos.2015.03.005. Epub 2015 Apr 11.]. PMID- 29254805 TI - Reply to comment by De Bernardo and Rosa on "Evaluation of Goldmann applanation tonometry, rebound tonometry and dynamic contour tonometry in keratoconus". PMID- 29254806 TI - Distribution of furanyl fentanyl and 4-ANPP in an accidental acute death: A case report. AB - Fatalities from emerging synthetic opioids have continued to reach new epidemic proportions throughout the world in recent years. Due to the sparsity of research in new opioid analogs, commonly observed lethal concentrations and their distribution following death have yet to be well documented. The prevalence of furanyl fentanyl in postmortem casework contributes to the opioid related deaths that are amongst half of drug-induced fatalities in the United States. In this case study, a 23-year-old man was found dead in San Francisco following the ingestion of blue pills imitating oxycodone. Initial toxicology screening did not detect oxycodone in blood. However, a positive fentanyl immunoassay result was obtained and analysis of the pills collected at the scene showed the presence of furanyl fentanyl. Analysis of postmortem samples revealed concentrations of furanyl fentanyl at 1.9ng/mL in peripheral blood, 2.8ng/mL in cardiac blood, and ~55,000ng in gastric contents. Metabolite 4-anilino-N-phenethyl-piperidine (4 ANPP) was also confirmed at 4.3ng/mL and 5.8ng/mL in peripheral blood and cardiac blood, respectively. Trace amounts of both analytes were detected in urine and the vitreous humor. Liver 4-ANPP concentrations of >40ng/g were also detected. This case study of acute furanyl fentanyl overdose in a young male thought to be using oxycodone highlights illicit drug users are often subject to unknown drug entities. The toxicological analysis provides preliminary information of the distribution of furanyl fentanyl and its metabolite in a range of postmortem specimens and collection sites. PMID- 29254807 TI - Consultation-Liaison Psychiatry vs Psychosomatic Medicine: What's in a name? AB - BACKGROUND: In November of 2017, The Academy of the Psychosomatic Medicine voted to change its name to the Academy of Consultation-Liaison Psychiatry. It followed a similar change in which the American Board of Medical Specialties voted to change the name of the field to Consultation-Liaison Psychiatry. OBJECTIVE: The authors, all instrumental in bringing about this change, discuss the history and rationale for this name change. PMID- 29254808 TI - Response to comments on natural history and predictors of survival in progressive supranuclear palsy. PMID- 29254809 TI - Comments on natural history and predictors of survival in progressive supranuclear palsy. PMID- 29254810 TI - Corrigendum to "A new PLA2G6 mutation in a family with infantile neuroaxonal dystrophy" [J. Neurol. Sci. 381C (2017) 209-212]. PMID- 29254811 TI - Analysis on clinical characteristics and drug resistance of Candida parapsilosis bloodstream infections in West China Hospital, China, from 2012 to 2015. AB - OBJECTIVE OF THE STUDY: Candida parapsilosis has emerged as an important cause of bloodstream infections (BSI) in the health care setting. We aimed to describe the clinical characteristics and drug resistance of C. parapsilosis BSI in West China Hospital of Sichuan University in China and provide the basis for prevention and treatment of this disease. PATIENTS: We retrospectively collected and analyzed patients presented in our hospital reported with C. parapsilosis BSI from January 2012 to January 2015. MATERIALS AND METHODS: Data regarding age, gender, the department distribution, the potential clinical risk factors and the result of clinical treatment and prognosis were retrospectively evaluated. As to the antifungal drugs susceptibility testing, we used Etest method for determining the minimum inhibitory concentrations (MICs) of amphotericin B, fluconazole, voriconazole, caspofungin and flucytosine for all the clinical isolates of C. parapsilosis. Standard quality strains were used as the controls. RESULTS: Most of the patients with C. parapsilosis BSI were over 60-year-old (37.5%) or within 10years old (28.13%). Among patients, 78.13% came from an intensive care unit or had undergone surgery in the past several months. The major risk factors associated with an increased risk of infection included the use of broad-spectrum antibacterial drugs and deep vein indwelling. The overall mortality of patients with C. parapsilosis BSI was 31.25%. The drug sensitivity tests revealed that all isolates were sensitive to amphotericin B and flucytosine. Two and 1 isolates were found susceptible to fluconazole and voriconazole in a dose-dependent manner, respectively. Only 1 isolate was resistant to fluconazole. 4 isolates (12.5%) were medium sensitive to caspofungin, but no one showed drug resistance. CONCLUSION: In summary, elders and newborns were more vulnerable to C. parapsilosis infections. C. parapsilosis was found frequently as pathogens leading to BSI in patients admitted to ICU and departments of surgery and often causing a high mortality rate. C. parapsilosis rarely showed drug resistance at present, so common antifungal drugs could be used for treatment. Recommendations for using of antifungal drugs focused on paying close attention to possible drug resistance trend. PMID- 29254812 TI - The impact on new-onset stress and PTSD in relatives of critically ill patients explored by diaries study (The "INSPIRED" study). AB - BACKGROUND: There is rising prevalence of post-traumatic-stress-disorder (PTSD) in patients and their relatives after ICU discharge. The impact of ICU diaries on PTSD in relatives of critically ill patients in Australia has not been fully evaluated. OBJECTIVES: To determine if relatives of an Australian critically ill population were interested in using ICU diaries. To determine the prevalence and impact of ICU diaries upon symptoms of PTSD, depression and anxiety in relatives of an Australian critically ill population. METHODS DESIGN: Prospective, observational, exploratory study. SETTING: Royal Adelaide Hospital (RAH), Adelaide, Australia. PARTICIPANTS: One hundred and eight consecutive patients, staying >48h in a level 3 ICU were identified. A survey using DASS-21, IES-R questionnaires was performed on admission followed by a repeat survey 90days post discharge from ICU. An IES-R score >33 was used to define severe PTSD symptoms. A comparison between subjects who did and did not complete their diaries was performed. RESULTS: Forty subjects refused to participate, eight were excluded, and sixty family members were included for analysis, thirty-six of whom completed diaries. There was no statistically significant difference between PTSD symptom scores at follow-up controlling for useful diary completion (complete - see methods) and PTSD at baseline. There was a statistically significant association between PTSD and unemployment, controlling for PTSD at baseline (P value=0.0045). Family members had significantly higher odds of PTSD at baseline compared to 3 month follow up (P value=0.0092, Odds Ratio=3.3, 95% CI: 1.3, 8.2). This was independent of the completeness of the diaries and adjusted for clustering on subject. Family members with incomplete diaries were less likely to report depressive symptoms at baseline (P value=0.0218, estimate=-4.6, 95% CI: -8.5, 0.7). Diary completion was not indicative of the likelihood of family members to report PTSD symptoms (P value=0.5468, estimate=-1.6, 95% CI: -6.8, 3.6). CONCLUSION: ICU diaries were often not completed and completion did not appear to be related to the incidence of stress, anxiety, depression and PTSD symptoms in the families of patients in the ICU. This may be because Australian families are generally not interested in maintaining a diary. PMID- 29254813 TI - Percentage of Gutta-percha-filled Areas in Canals Obturated by 3 Different Techniques with and without the Use of Endodontic Sealer. AB - INTRODUCTION: This study had 2 purposes: to compare the Microseal, continuous wave, and Thermafil techniques and to compare the same techniques with and without endodontic sealer. METHODS: Ninety extracted mandibular premolars were allocated into 6 groups obturated with Microseal (Analytic, Glendora, CA) and sealer (Mseal), Microseal without sealer (Mnoseal), System B (EIE Analytic Technology, Orange, CA) and sealer (SBseal), System B without sealer (SBnoseal), Thermafil (Dentsply, Tulsa Dental, Tulsa, OK) and sealer (Tseal), and (Tnoseal) Thermafil without sealer (Tnoseal). The teeth were sectioned at 1 and 3 mm from the apex. The total area of each canal segment was measured, and the areas were converted to the percentage of gutta-percha-filled areas, sealer-filled areas, and void areas. Data obtained were statistically elaborated using the t test (P <= .01). RESULTS: At 1 mm, SBseal produced a higher VA than Mseal and Tseal. At 3 mm, Tseal produced a lower VA than Mseal and SBseal, whereas Mseal produced a lower VA than SBseal (P > .01). At 1 mm, Tnoseal produced a significantly higher VA than Mnoseal and SBnoseal (P = .001). At 3 mm, Tnoseal produced a higher VA than Mnoseal and SBnoseal (P = .01). Tnoseal produced a significantly higher VA than Tseal both at 1 mm (P = .001) and 3 mm (P = .001). CONCLUSIONS: Endodontic space filling is traditionally provided by sealer and gutta-percha. In this study's conditions, gutta-percha alone showed better filling at both 3 mm and 1 mm in the Microseal and System B techniques. Considering the limits of our study, we can affirm that endodontic techniques using sealer could counteract thermoplasticized gutta-percha progression. PMID- 29254815 TI - Validation of Biofilm Assays to Assess Antibiofilm Efficacy in Instrumented Root Canals after Syringe Irrigation and Sonic Agitation. AB - INTRODUCTION: Different methods to characterize bacterial biofilms have been established, each presenting with distinct advantages and shortcomings. The aim of this study was to validate the ability of microbiological culture, the adenosine-5'-triphosphate (luminescence) assay, molecular, and microscopic methods to assess antibiofilm efficacy. METHODS: Thirty-nine extracted single rooted teeth were selected. Enterococcus faecalis biofilms were grown for 21 days and randomly distributed into 3 groups. All canals were instrumented (F3 ProTaper Universal; Dentsply Sirona, Johnson City, TN) and irrigated (ProRinse needles, Dentsply Sirona) as follows: group 1, sodium hypochlorite and EDTA irrigation; group 2, supplemented with sonic agitation of NaOCl, and group 3, sterile distilled water irrigation. Bacteriologic samples were collected before (S1) and after canal preparation (S2) and subjected to quantification by culture methods, quantitative reverse transcriptase real-time PCR (qRT-PCR), and luminescence assay. The biofilm structure and bacterial cell viability were evaluated under scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Data were subjected to statistical analysis to determine the statistical significance (P < .05). RESULTS: S1 samples showed approximately 8-log colony forming-units of bacteria using both culture and qRT-PCR. The reduction in bacterial population and relative luminescence was highly significant in the S2 samples from groups 1 and 2 (P < .001). SEM and CLSM showed well-matured root canal biofilms in the pretreatment samples that were reduced after treatment. Irrigation with NaOCl combined with sonic agitation significantly decreased the percentage of live cells (P < .05) but was not able to eliminate the biofilm structure. CONCLUSIONS: This study highlighted the maximum reduction of microbes after instrumentation-syringe irrigation. Although supplementary sonic agitation reduced the root canal biofilm further, it did not completely eliminate the biofilm from a single root canal model. The merits of combining microbiological and molecular quantification methods with CLSM for the comprehensive assessment of antibiofilm efficacy in root canals were emphasized. PMID- 29254814 TI - Long-term Evaluation of Treatment Planning Decisions for Nonhealing Endodontic Cases by Different Groups of Practitioners. AB - INTRODUCTION: The aim of this study was to investigate changes in treatment planning decisions among different practitioner groups over 7 years for teeth with apical periodontitis and a history of endodontic treatment. METHODS: A Web based survey was sent to dentists in Pennsylvania in 2009 consisting of 14 cases with nonhealing periapical lesions and intact restorations without evidence of recurrent caries. Participants selected among 5 treatment options: wait and observe, nonsurgical retreatment (NSRTX), surgical retreatment (SRTX), extraction and fixed partial denture, or extraction and implant (EXIMP). In 2016, the identical survey was resent to the original 2009 participants. RESULTS: In 2009, 262 dentists participated in the survey. Two hundred one participants were general practitioners (GPs: 76.7%), 26 endodontists (ENDOs: 9.9%), and 35 other specialists (prosthodontics, periodontics, and oral surgery [SPECs]: 13.4%) (n = 262). EXIMP, NSRTX, and SRTX were fairly equally selected but with great variation between practitioner groups (chi2 = 173.49, P < .05). A subset group of 104 participants (SUB) (39.7% of the original participants) retook the survey in 2016 (69 GPs [66.3%], 15 ENDOs [14.0%], and 20 SPECs [19.7%]). Comparisons among practitioner groups were significantly different in SUB (n = 104) for 2009 (chi2 = 95.536, P < .05) and 2016 (chi2 = 109.8889, P < .05). Intragroup reliability between 2009 and 2016 revealed no significant differences between the overall treatment planning choices for all practitioners (GPs, ENDOs, or SPECs). Intrapractitioner reliability showed many treatment planning decision changes on an individual level. Chances that individuals changed their original decision were 47.8% (95% confidence interval, 45.2%-50.4%) and were significantly different among the 3 practitioner groups (GPs > SPECs > ENDOs [chi2 = 11.2792, P < .05]). No significant changes were observed in the decision for tooth saving versus replacement treatment options (P = .520). CONCLUSIONS: No significant differences were noted between current and past treatment planning decisions in regard to tooth preservation by endodontic retreatment versus tooth extraction and replacement. However, individual practitioners lacked consistency in their decision making over time. PMID- 29254816 TI - Evaluation of Physicochemical Properties of a New Root Canal Sealer. AB - INTRODUCTION: The aim of this study was to evaluate some of the physicochemical properties of a new root canal sealer. METHODS: The sealers tested were Sealer Plus compared with AH Plus. For the radiopacity, flow, solubility, and fabrication of test specimens relative to setting times, the American National Standards Institute/American Dental Association No. 57 (2000) and International Organization for Standardization 6876 (2012) specifications were followed. To measure the initial and final setting times, the ASTM C266/2008 standard was used. pH was evaluated in the time intervals of 3, 24, 72, and 168 hours. Statistical tests were applied to the results obtained at a level of significance of 5%. RESULTS: The results demonstrated that the Sealer Plus sealer showed a lower radiopacity value than AH Plus sealer (P < .05); however, this was higher than the minimum value recommended by the specifications (ie, 3 mm Al). Relative to flow, the value for Sealer Plus was 19.19 mm and for AH Plus, 19.81 mm (P > .05). Sealer Plus presented initial and final setting times of 138 minutes and 210 minutes, respectively, whereas the values for AH Plus were 437 minutes and 849 minutes, respectively (P < .05). Relative to solubility, Sealer Plus presented 0.21% and AH Plus, 0.27% (P > .05). None of the sealers showed a significant increase in pH (P > .05). CONCLUSIONS: Sealer Plus sealer presented physicochemical properties in accordance with American National Standards Institute/American Dental Association (2000) No. 57 and International Organization for Standardization 6876 (2012) specifications. PMID- 29254817 TI - The Effect of Long-term Dressing with Calcium Hydroxide on the Fracture Susceptibility of Teeth. AB - INTRODUCTION: Calcium hydroxide has been widely used to treat immature teeth to achieve periodontal healing and to promote the formation of an apical barrier. However, retrospective clinical studies have shown a high incidence of cervical root fractures with long-term calcium hydroxide dressing. The alkalinity of calcium hydroxide has been suggested to weaken the root. In vitro studies using ovine teeth show conflicting results on fracture strength of dentine, although different commercial products may have influenced the results. The purpose of this study was to investigate the effects of 2 commercial products used in prior studies (Calasept Plus and UltraCal XS), as well as a new product (Calmix) that uses a nonaqueous vehicle that allows for a higher pH, on the fracture strength of dentine over time. METHODS: A total of 330 lamb incisor teeth were collected and the canals prepared so that 3 commercial calcium hydroxide products as well as a positive control of pure calcium hydroxide slurry that filled the root canal from the open apex and a negative control of saline was tested. The teeth were loaded until fracture with a universal testing machine at time points 0, 3, 6, and 9 months and the force to fracture was calculated. The data were analyzed with Friedman analysis of variance and Mann-Whitney t tests. RESULTS: No statistical differences were observed between the different calcium hydroxide products and the negative controls. CONCLUSIONS: Thin and fragile roots could be the cause of fracture rather than the calcium hydroxide dressing. PMID- 29254818 TI - Effect of Different Treatment Options on Biomechanics of Immature Teeth: A Finite Element Stress Analysis Study. AB - INTRODUCTION: Immature teeth (IT) can be managed by using several treatment options, depending on the vitality of the tooth. The aim of this finite element stress analysis study was to evaluate the effect of different treatment procedures on the stresses in three-dimensional IT models. METHODS: Three dimensional finite element stress analysis premolar tooth model was created as control (model 1), modified to simulate IT. Eleven models were created to simulate IT filled with (model 2) calcium hydroxide (CH), (model 3) mineral trioxide aggregate (MTA), (model 4) Biodentine (B), (models 5 and 6) MTA plug and B plug without root-filling, (models 7 and 8) MTA plug and B plug with root filling with composite restoration, and amputation by using (model 9) CH, (model 10) MTA, and (model 11) B. Materials and structures were assumed to be homogenous and isotropic. A 300 N load was applied to the models from the functional cusps and central fossa with a 135 degrees angle. Cosmosworks structural analysis program was used. The results were presented considering the von Mises criteria, and the scale range was limited to 0-10 + MPa. RESULTS: CH use in comparison with temporary filling increased the stresses within the root. MTA filling showed less stresses when compared with B filling. MTA and B plug increased the stresses at apical and root; however, when the roots were filled using gutta-percha and the crowns were restored with composite resin, the stresses at the coronal side of the roots were reduced. The stresses were distributed more favorably in the models simulating CH, MTA, or B amputation. Amputation by using MTA and B showed similar stresses with natural tooth model. CONCLUSIONS: CH is not a favorable dressing material for IT when compared with MTA and B. MTA or B plug increases the stresses at apical, whereas root-filling reduces the stresses within the root. Amputation by using CH, MTA, and B in combination with composite resin restoration may save both the coronal and root structure of IT. PMID- 29254819 TI - Removal of Root Canal Fillings in Curved Canals Using Either Mani GPR or HyFlex NT Followed by Passive Ultrasonic Irrigation. AB - This study compared the efficacy of HyFlex NT (HF; Coltene, New York, NY) and Mani GPR (MN; Mani Inc, Tokyo, Japan) systems followed by a supplementary approach with passive ultrasonic irrigation (PUI) in removing the filling material from curved root canals during retreatment. The mesial canals from 20 extracted mandibular molars with Vertucci type IV configuration were instrumented and obturated (N = 40). Each mesial canal was retreated using either HF or MN instruments, alternating the system used per canal from root to root. The final preparation size was 40/0.04 for both systems. The volume of canal filling material was assessed by means of micro-computed tomographic (micro-CT) imaging before and after retreatment, and the working time was recorded. Canals still showing remnants of filling material were subjected to a supplementary approach with PUI, and another micro-CT scan was taken. The percentage of filling material removed with MN instruments and HF was similar (95.5% and 92.7%, respectively) (P > .05). MN required significantly less time to remove the filling material (P < .05). The supplementary approach with PUI significantly enhanced the removal of filling material (P < .05). Both systems were equally effective in removing the root canal filling during retreatment. MN was faster than HF. The supplementary approach with PUI significantly improved filling material removal. PMID- 29254820 TI - Does Administration of Hypertonic Solutions Improve Mortality in Hemorrhagic Shock Compared With Isotonic Solutions? PMID- 29254821 TI - Is Adenosine or an Intravenous Calcium Channel Blocker More Effective for Treating Supraventricular Tachycardia? PMID- 29254822 TI - Colistin resistance in Pseudomonas aeruginosa and Achromobacter spp. cultured from Danish cystic fibrosis patients is not related to plasmid-mediated expression of mcr-1. PMID- 29254823 TI - Hypoglycaemia in cystic fibrosis: An analysis of a single centre adult cystic fibrosis clinic. AB - BACKGROUND: Hypoglycaemia in cystic fibrosis (CF) is known to occur during oral glucose tolerance tests (OGTT) and continuous glucose monitoring, however demographic, clinical and mechanistic data are limited. The aims of this study were to review patient electronic medical records (EMR) in order to 1) describe patient characteristics of a university teaching hospital CF clinic, 2) determine the prevalence of hypoglycaemia on OGTT and explore associations with demographic and clinical characteristics, and 3) explore patient reported symptoms suggestive of hypoglycaemia documented in the EMR. METHODS: Adults who attended the RPA CF clinic between January 2009 to April 2016 were included in the study. The prevalence of hypoglycaemia on OGTT was determined and clinical and demographic data were compared to age, sex and glucose tolerance matched controls. Reported symptoms suggestive of hypoglycaemia documented in EMR were qualitatively explored. RESULTS: Hypoglycaemia on OGTT was prevalent in 25 (3 fasting and 22 reactive) of 169 patients who had an OGTT. They were heavier, less likely to have pancreatic insufficiency and had a lower insulin response at 2-h. Another 14 patients reported symptoms suggestive of hypoglycaemia in their EMR. No patient appropriately suppressed insulin at 2-h on OGTT. CONCLUSIONS: This study identified two potentially different presentations of hypoglycaemia occur in different clinic sub-populations. Knowledge gaps in the aetiology and triggers of hypoglycaemia remain. PMID- 29254824 TI - Emerging themes in neuronal activity-dependent gene expression. AB - In this review, we attempt to discuss emerging themes in the regulation of neuronal activity-regulated genes, focusing primarily on an important subset of immediate-early genes. We first discuss earlier studies that have illuminated the role of cis-acting elements within the promoters of immediate-early genes, the corresponding transcription factors that bind these elements, and the roles of major activity-regulated signaling pathways. However, our emphasis is on new studies that have revealed an important role for epigenetic and topological mechanisms, including enhancer-promoter interactions, enhancer RNAs (eRNAs), and activity-induced DNA breaks, that have emerged as important factors that govern the temporal dynamics of activity-induced gene transcription. PMID- 29254825 TI - The histone demethylase Kdm6b regulates a mature gene expression program in differentiating cerebellar granule neurons. AB - The histone H3 lysine 27 (H3K27) demethylase Kdm6b (Jmjd3) can promote cellular differentiation, however its physiological functions in neurons remain to be fully determined. We studied the expression and function of Kdm6b in differentiating granule neurons of the developing postnatal mouse cerebellum. At postnatal day 7, Kdm6b is expressed throughout the layers of the developing cerebellar cortex, but its expression is upregulated in newborn cerebellar granule neurons (CGNs). Atoh1-Cre mediated conditional knockout of Kdm6b in CGN precursors either alone or in combination with Kdm6a did not disturb the gross morphological development of the cerebellum. Furthermore, RNAi-mediated knockdown of Kdm6b in cultured CGN precursors did not alter the induced expression of early neuronal marker genes upon cell cycle exit. By contrast, knockdown of Kdm6b significantly impaired the induction of a mature neuronal gene expression program, which includes gene products required for functional synapse maturation. Loss of Kdm6b also impaired the ability of Brain-Derived Neurotrophic Factor (BDNF) to induce expression of Grin2c and Tiam1 in maturing CGNs. Taken together, these data reveal a previously unknown role for Kdm6b in the postmitotic stages of CGN maturation and suggest that Kdm6b may work, at least in part, by a transcriptional mechanism that promotes gene sensitivity to regulation by BDNF. PMID- 29254828 TI - Understanding the Relationship Between 3-Month and 2-Year Pain and Function Scores After Total Knee Arthroplasty for Osteoarthritis. AB - BACKGROUND: Research to understand predictors of poor outcomes after total knee arthroplasty (TKA) has largely focused on presurgery factors. We examined whether pain and function 3-month postsurgery were predictive of longer-term outcomes ascertained 2 years after TKA. METHODS: Western Ontario McMaster University Osteoarthritis Index pain and physical function scores (scaled 0-20 and 0-68; higher = worse) were recorded pre-TKA and 3, 12, and 24 months post-TKA. A sequential series of regression models was used to examine the relative contribution of baseline score and baseline to 3-month and 3 to 12-month change score to explaining variability (R2) in 2-year pain and function scores, with consideration for presurgery covariates. RESULTS: Data from 560 patients were analyzed. Mean pain and function scores improved significantly presurgery to 2 years postsurgery; 10-4 and 33-16 (P < .001), respectively. Considerable variability in 2-year scores was observed. Overall, 80.3% and 79.9% of changes in pain and function scores over the 2 years occurred within the first 3 months. Change over these 3 months explained the greatest proportion of variability in 2 year scores, 16% and 23% for pain and function, respectively. The influences of these early changes were similar to those of baseline status. CONCLUSION: Changes in patient-reported pain and function occurring within the first 3 months post TKA strongly determine pain and function status at 2 years. Research to identify pre-/intra-/early postoperative factors associated with change in this early postoperative period that may be amenable to modification or used to better inform education and decision-making is warranted. PMID- 29254826 TI - Neuron-specific alternative splicing of transcriptional machineries: Implications for neurodevelopmental disorders. AB - The brain has long been known to display the most complex pattern of alternative splicing, thereby producing diverse protein isoforms compared to other tissues. Recent evidence indicates that many alternative exons are neuron-specific, evolutionarily conserved, and found in regulators of transcription including DNA binding protein and histone modifying enzymes. This raises a possibility that neurons adopt unique mechanisms of transcription. Given that transcriptional machineries are frequently mutated in neurodevelopmental disorders with cognitive dysfunction, it is important to understand how neuron-specific alternative splicing contributes to proper transcriptional regulation in the brain. In this review, we summarize current knowledge regarding how neuron-specific splicing events alter the function of transcriptional regulators and shape unique gene expression patterns in the brain and the implications of neuronal splicing to the pathophysiology of neurodevelopmental disorders. PMID- 29254829 TI - A severe female case of arthrogryposis multiplex congenita with brain atrophy, spastic quadriplegia and intellectual disability caused by ZC4H2 mutation. AB - Arthrogryposis multiplex congenita (AMC) is characterized by heterogeneous multiple congenital contractures appearing at birth. Mutations in X-linked zinc finger gene ZC4H2 were recently identified in some families and individuals with variable forms of AMC associated with dysmorphic signs, intellectual disability and spastic paresis. We present a non-consanguineous Japanese female presenting AMC with severe intellectual disability and spastic quadriplegia who also had progressive brain atrophy. Microarray-based comparative genomic hybridization identified 395 kb microdeletions at Xq11.2 which only included ZC4H2 gene. Previous reports showed that affected females have lesser symptoms and slight abnormality on brain MRI compared to male due to X-inactivation. Our case, however, showed severe manifestation than as ever reported as well as progressive diffuse brain atrophy, which implicated contribution of other genetic or environmental factors or extremely skewed X inactivation. PMID- 29254827 TI - Chromatin remodeling and epigenetic regulation of oligodendrocyte myelination and myelin repair. AB - Oligodendrocytes are essential for the development, function, and health of the vertebrate central nervous system. These cells maintain axon myelination to ensure saltatory propagation of action potentials. Oligodendrocyte develops from neural progenitor cells, in a step-wise process that involves oligodendrocyte precursor specification, proliferation, and differentiation. The lineage progression requires coordination of transcriptional and epigenetic circuits to mediate the stage-specific intricacies of oligodendrocyte development. Epigenetic mechanisms involve DNA methylation, histone modifications, ATP-dependent chromatin remodeling, and non-coding RNA modulation that regulate the chromatin state over regulatory genes, which must be expressed or repressed to establish oligodendrocyte identity and lineage progression. In this review, we will focus on epigenetic programming associated with histone modification enzymes, chromatin remodeling, and non-coding RNAs that regulate oligodendrocyte lineage progression, and discuss how these mechanisms might be harnessed to induce myelin repair for treatment of demyelinating diseases such as multiple sclerosis. PMID- 29254830 TI - Potential for waist-to-height ratio to detect overfat adolescents from a Pacific Island, even those within the normal BMI range. AB - INTRODUCTION: Waist-to-height ratio (WHtR) is a simple anthropometric proxy for central body fat; it is easy to use from a health education perspective. A WHtR value >0.5 has been proposed as a first level indicator of health risk. The first aim of this study was to compare WHtR with values based on body mass index (BMI) in their prediction of the percentage of body fat (%BF) in a multi-ethnic population of adolescents from New-Caledonia (age 11-16year). Secondly, to see whether WHtR >0.5 could be used to detect overfat subjects whose BMI was in the normal range. MATERIALS AND METHODS: Body fat percentage (%BF, based on skinfold measurements), BMI and WHtR were calculated for New Caledonian adolescents from different ethnic backgrounds. The relationship between %BF, BMI and WHtR was determined using quadratic models and from linear regression equations. The sensitivity and specificity of WHtR for detecting overfat adolescents (%BF >25% in boys and >30% in girls) were assessed and compared with those from the BMI based classification. RESULTS: WHtR showed better correlation with %BF than BMI based measurements. WHtR >0.5 was also more accurate than BMI in detecting overfat adolescents. Moreover, using this boundary value, 8% of adolescents in the normal BMI range were shown to be over-fat. CONCLUSIONS: WHtR is a good anthropometric proxy to detect overfat adolescents. Detecting overfat adolescents within the normal BMI range is particularly important for preventing non communicable diseases. We therefore recommend using WHtR for health education programs in the Pacific area and more generally. PMID- 29254831 TI - Idiopathic malignant premature ventricular contractions. AB - The presence of premature ventricular contractions (PVCs) in patients with structurally normal hearts was once considered a benign phenomenon. However, in susceptible patients, these "benign" or idiopathic PVCs may develop malignant potential and trigger ventricular fibrillation and result in sudden cardiac death. Alternatively, idiopathic PVCs can also induce cardiomyopathy. Clinical recognition of these entities can lead to effective targeted therapy. In the first instance, treatment consists of ablating the PVC source and implanting a defibrillator, whereas in the second scenario, ablating the PVC origin can normalize left ventricular function. PMID- 29254832 TI - Controversies in Brugada syndrome. AB - The Brugada syndrome is an inherited channelopathy associated with increased risk of ventricular arrhythmias and sudden death, often occurring during sleep or resting conditions. Although this entity has been described more than 20 years ago, it remains one of the most debated among channelopathies, with several open questions on its genetic substrate, arrhythmia mechanisms, and clinical management. Studies on the genetics and physiopathology bases of the Brugada syndrome have opened novel investigative pathways and concepts that are now entering the field of cardiovascular genetics and are applied to other inherited arrhythmias. In this perspective, Brugada syndrome can be seen as an example on how basic science discoveries have influenced clinical management and led to novel therapeutic approaches. PMID- 29254833 TI - Management of stage II and III rectal cancer in British Columbia: Is there a rural-urban difference? AB - BACKGROUND: This study assessed management of patients with locally advanced rectal cancer from rural, small and large local health authorities (LHA) in British Columbia (BC), Canada. METHODS: We analyzed patients from 2004-2009 using a prospective database. Patients were defined as living in rural, small or large LHA using Statistics Canada definitions. Differences in treatments and outcomes were analyzed using chi-squared and log-rank tests, respectively. RESULTS: Among 1964 patients, 13% lived in rural, 22% in small, and 66% in large LHAs. There were no differences in rates of abdominoperineal resections in rural (33%), small (39%) and large (35%) areas (p = 0.30). The proportion of patients who received radiotherapy (86-88%, p = 0.80) and adjuvant chemotherapy (56-57%, p = 0.89) were similar. There was no difference in 5-year disease-free survival (84-86%, p = 0.98) or overall survival (57-59%, p = 0.99). CONCLUSIONS: The management and outcome of locally advanced rectal cancer patients seems to be comparable for rural and non-rural BC. PMID- 29254834 TI - Electrophysiological technical procedures. AB - The reliability of the interpretation of SEEG data depends entirely on the technical quality of the acquisition recording. Digitalization of data and the development of computer technology, over the last 20 years have transformed electrophysiological procedures. Recording equipment must be able to record concomitantly clinical events and brain electrical activity. Recording is carried out during wakefulness and sleep and with use of various activation methods (hyperventilation, intermittent photic stimulation). Intracerebral electrical stimulations (with low and high frequency) and the acquisition of evoked potentials complete the SEEG exploration. This chapter will discuss the characteristics of video-EEG recording equipment, procedures for acquisition and creation of SEEG montages, technical recording and activations, procedures of intracerebral electrical stimulations and the acquisition of evoked potentials. PMID- 29254835 TI - Planning and management of SEEG. AB - Stereoelectroencephalography (SEEG) aims to define the epileptogenic zone (EZ), to study its relationship with functional areas and the causal lesion and to evaluate the possibility of surgical therapy. Planning of exploration is based on the validity of the hypotheses developed from electroclinical and imaging correlations. Further investigations can refine the implantation plan (e.g. fluorodeoxyglucose positron emission tomography [FDG-PET], single photon emission computerized tomography [SPECT], magnetoencephalography [MEG] and high resolution electroencephalography [EEG-HR]). The scheme is individualized according to the features of each clinical case, but a general approach can be systematized according to the regions involved (temporal versus extra-temporal), the existence of a lesion, its type and extent. It takes account of the hemispheric dominance for language if this can be determined. In "temporal plus" epilepsies, perisylvian and insular regions are among the key structures to investigate in addition to mesial and neocortical temporal areas. In frontal lobe epilepsies, determining the functional and anatomical organization of seizures (anterior versus posterior, mesial versus dorsolateral) allows better targeting of the implantation. Posterior epilepsies tend to have a complex organization leading to multilobar and often bilateral explorations. In lesional cases, it may be useful to implant one or several intralesional electrode(s), except in cases of vascular lesions or cyst. The strategy of implantation can be modified if thermocoagulations are considered. The management of SEEG implies continuous monitoring in a dedicated environment to determine the EZ with optimal safety conditions. This methodology includes spontaneous seizure recordings, low and high frequency stimulations and, if possible, sleep recording. SEEG is applicable in children, even the very young. Specific training of medical and paramedical teams is required. PMID- 29254836 TI - The influence of the site of conditioning sensory stimuli on prepulse modulation of the blink reflex. PMID- 29254837 TI - Evaluation of protection induced by immunisation of domestic pigs with deletion mutant African swine fever virus BeninDeltaMGF by different doses and routes. AB - A live attenuated African swine fever virus (ASFV) vaccine candidate, produced by deletion of several genes belonging to multi-gene families MGF360 and 505 from virulent Benin 97/1 strain (BeninDeltaMGF), induces protection in pigs against parental virulent strain. In order to better define the safety and efficacy of this attenuated vaccine candidate and to understand protective mechanisms, we extended previous studies by intramuscular immunisation of pigs with the deletion mutant BeninDeltaMFG at different doses (102, 103, 104 TCID50), together with intranasal immunisation at the 103 dose. Results demonstrated a strong correlation between both doses and routes of immunisation of BeninDeltaMFG and the percentage of protection achieved, the onset of clinical signs, the viremia levels reached and the onset of death in non-protected pigs. The results show that the intramuscular route using high doses (104 TCID50) is the best option for immunisation. Only transient increase in temperature associated with a peak of virus genome levels was observed in most pigs after immunisation. Then, virus genome levels progressively decreased throughout the experiment until reaching low or undetectable levels in those protected pigs that survived after challenge. The IgM antibody responses following immunisation were detected between day 7-10 post-immunisation and remained at elevated levels for 10-18 days in most pigs before dropping. IgG was detected from day 15 to 21 post-immunisation and maintained at increased levels for the remainder of the experiment in most pigs. Induction of IFNgamma and IL-10 was detected by ELISA in sera from some pigs immunised with 103 TCID50 by intramuscular or intranasal route at early times post-immunisation. IL-10 was also detected in serum from some non-protected pigs included in these groups after challenge. PMID- 29254838 TI - The impact of selection bias on vaccine effectiveness estimates from test negative studies. AB - INTRODUCTION: Estimates of vaccine effectiveness (VE) from test-negative studies may be subject to selection bias. In the context of influenza VE, we used simulations to identify situations in which meaningful selection bias can occur. We also analyzed observational study data for evidence of selection bias. METHODS: For the simulation study, we defined a hypothetical population whose members are at risk for acute respiratory illness (ARI) due to influenza and other pathogens. An unmeasured "healthcare seeking proclivity" affects both probability of vaccination and probability of seeking care for an ARI. We varied the direction and magnitude of these effects and identified situations where meaningful bias occurred. For the observational study, we reanalyzed data from the United States Influenza VE Network, an ongoing test-negative study. We compared "bias-naive" VE estimates to bias-adjusted estimates, which used data from the source populations to correct for sampling bias. RESULTS: In the simulation study, an unmeasured care-seeking proclivity could create selection bias if persons with influenza ARI were more (or less) likely to seek care than persons with non-influenza ARI. However, selection bias was only meaningful when rates of care seeking between influenza ARI and non-influenza ARI were very different. In the observational study, the bias-naive VE estimate of 55% (95% CI, 47--62%) was trivially different from the bias-adjusted VE estimate of 57% (95% CI, 49--63%). CONCLUSIONS: In combination, these studies suggest that while selection bias is possible in test-negative VE studies, this bias in unlikely to be meaningful under conditions likely to be encountered in practice. Researchers and public health officials can continue to rely on VE estimates from test negative studies. PMID- 29254839 TI - Bacillus Calmette-Guerin (BCG) vaccine: A global assessment of demand and supply balance. AB - Over the past decade, several countries across all regions, income groups and procurement methods have been unable to secure sufficient BCG vaccine supply. While the frequency of stock-outs has remained rather stable, duration increased in 2014-2015 due to manufacturing issues and attracted the attention of national, regional and global immunization stakeholders. This prompted an in-depth analysis of supply and demand dynamics aiming to characterize supply risks. This analysis is unique as it provides a global picture, where previous analyses have focused on a portion of the market procuring through UN entities. Through literature review, supplier interviews, appraisal of shortages, stock-outs and historical procurement data, and through demand forecasting, this analysis shows an important increase in global capacity in 2017: supply is sufficient to meet forecasted BCG vaccine demand and possibly buffer market shocks. Nevertheless, risks remain mainly due to supply concentration and limited investment in production process improvements, as well as inflexibility in demand. Identification of these market risks will allow implementation of risk-mitigating interventions in three areas: (1) enhancing information sharing between major global health actors, countries and suppliers, (2) identifying interests and incentives to expand product registration and investment in the BCG manufacturing process, and (3) working with countries for tighter vaccine management. PMID- 29254841 TI - The importance of distinguishing between cryptic species by morphological characters. PMID- 29254842 TI - Comment on "Epidermal growth factor receptor mutation predicts favorable outcomes in non-small cell lung cancer patients with brain metastases treated with stereotactic radiosurgery", by Yang WC et al. PMID- 29254843 TI - Presence of Stenotrophomonas maltophilia exhibiting high genetic similarity to clinical isolates in final effluents of pig farm wastewater treatment plants. AB - Although the prevalence of community-acquired Stenotrophomonas maltophilia infections is sharply increasing, the sources and likely transmission routes of this bacterium are poorly understood. We studied the significance of the presence of S. maltophilia in final effluents and receiving rivers of pig farm wastewater treatment plants (WWTPs). The loads and antibiotic resistance profiles of S. maltophilia in final effluents were assessed. Antibiotic resistance determinants and biofilm formation genes were detected by PCR, and genetic similarity to clinical isolates was investigated using multilocus sequence typing (MLST). S. maltophilia was recovered from final effluents at two of three farms and one corresponding receiving river. Tests of resistance to antibiotics recommended for S. maltophilia infection revealed that for each agent, at least one isolate was classified as resistant or intermediate, with the exception of minocycline. Furthermore, multidrug resistant S. maltophilia susceptible to antibiotics of only two categories was isolated and found to carry the sul2 gene, conferring trimethoprim/sulfamethoxazole resistance. All isolates carried spgM, encoding a major factor in biofilm formation. MLST revealed that isolates of the same sequence type (ST; ST189) were present in both effluent and receiving river samples, and phylogenetic analysis showed that all of the STs identified in this study clustered with clinical isolates. Moreover, one isolate (ST192) recovered in this investigation demonstrated 99.61% sequence identity with a clinical isolate (ST98) associated with a fatal infection in South Korea. Thus, the pathogenicity of the isolates reported here is likely similar to that of those from clinical environments, and WWTPs may play a role as a source of S. maltophilia from which this bacterium spreads to human communities. To the best of our knowledge, this represents the first report of S. maltophilia in pig farm WWTPs. Our results indicate that nationwide epidemiological investigations are needed to examine the possible link between WWTP-derived S. maltophilia and hospital- and community-acquired infections. PMID- 29254840 TI - Pre-vaccine plasma levels of soluble inflammatory indices negatively predict responses to HAV, HBV, and tetanus vaccines in HCV and HIV infection. AB - BACKGROUND: Chronic hepatitis C virus (HCV) and HIV infections are associated with impaired responses to neo-antigens contained in hepatitis A virus (HAV)/hepatitis B virus (HBV) vaccines, yet responsible mechanisms are unclear. METHODS: ACTG 5232 and CFAR0910 were clinical trials where pre-vaccine levels of plasma IP10, IL-6, sCD163 and sCD14 were measured in viremic HCV- (n = 15) or HIV infected participants (n = 24) and uninfected controls (n = 10). Accelerated dosing HAV/HBV vaccine and tetanus booster were administered and antibody response was measured at 0, 1, 3, 8, and 24 weeks. RESULTS: Pre-vaccine plasma IP10, IL-6, and sCD14 levels were elevated in both HCV and HIV-infected participants, while sCD163 was also elevated in HCV-infected participants. Pre immunization tetanus antibody levels were lower in HIV-infected than in uninfected participants, while vaccine induced antibody responses were intact in HCV and HIV-infected participants. After HAV/HBV vaccination, HCV and HIV infected participants had lower and less durable HAV and HBV antibody responses than uninfected controls. Among HCV-infected participants, pre-vaccine plasma IP10, IL-6, sCD14, and sCD163 levels inversely correlated with HAV, HBV and tetanus antibody responses after vaccine. Low HAV/HBV vaccine responses in HIV infected participants prohibited assessment of immune correlates. CONCLUSIONS: During HCV and HIV infection markers of systemic inflammation reflect immune dysfunction as demonstrated by poor response to HAV/HBV neo-antigen vaccine. PMID- 29254844 TI - Letter to the editor clarifying CLAY study group and published research findings. PMID- 29254845 TI - Molecular mechanisms underpinning T helper 17 cell heterogeneity and functions in rheumatoid arthritis. AB - T helper 17 (Th17) cells are important mediators of immune responses against extracellular bacteria and fungi, and as such play critical regulatory roles in maintaining mucosal homeostasis. Conversely, Th17 cells and their effector molecules interleukin 17A (IL-17A), IL-17F, interferon (IFN)gamma, tumor necrosis factor (TNF)alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) are implicated in the pathology of rheumatoid arthritis (RA). Interactions between Th17 cells and other immune cells or stromal cells that are present in the synovial tissue during the earliest phases of the disease, may eventually lead to chronic inflammation, irreversible cartilage degradation and bone erosions. Recent evidence points towards Th17 cell plasticity as an essential contributing process in RA pathology, since Th17 cells are able to adopt a pathogenic phenotype under the influence of environmental, inflammatory and genetic factors. A remarkable feature of this pathogenic Th17 cell phenotype is the high production of GM-CSF and TNFalpha and the co-appearance of Th1 cell characteristics, such as transcription factor T-box 21 (T-bet) and IFNgamma expression. Recently, much progress has been made in unravelling the mechanisms underlying Th17 cell plasticity and pathogenicity. Of interest, many of the environmental and inflammatory factors associated with RA pathology, such as pro inflammatory mediators and cytokines, microbiome dysbiosis, metabolism and diet, obesity, vitamins, steroids and hormones are linked to the development of pathogenic Th17 cells. Moreover proteins encoded by established genetic risk factors for RA including CCR6, CD226, CSF2, EOMES, ETS1, GATA3, IL2, IL6R, IL23R, IKZF3, IRAK1, IRF4, IRF8, PRKCQ, PRDM1, RBPJ, RUNX1 and TAGAP are directly involved in Th17 cell differentiation and/or function. This review provides a detailed overview of the molecular mechanisms involved in the heterogeneity and pathogenicity of Th17 cells in the context of autoimmune diseases, with a focus on RA. Understanding these mechanisms creates great potential to identify and select novel therapeutic targets which could improve current therapies or lead to development of new treatment strategies in RA. PMID- 29254846 TI - Laparoscopic adrenalectomy in children: A 25-case series and review of the literature. AB - BACKGROUND: Laparoscopic adrenalectomy (LA) is the gold standard and is widely performed in adults, but its use in children is relatively new. We aim to present our experience in twenty-five children with diverse adrenal pathologies and to discuss an extensive review of pediatric LA in English literature. METHODS: Medical records of children with adrenal tumors admitted to a tertiary center and treated with LA were reviewed. Characteristics and outcome of patients were compared with results of a systematic Pubmed/Medline literature review. RESULTS: Transperitoneal LAs were performed for 12 malignant and 14 benign adrenal masses (size range: 2-8cm) in 25 children (median age:63months). Fourteen lesions were on the right side, and there was one bilateral case. There were no conversion and no complication within 36months of follow-up. A literature review revealed 437 pediatric LAs with left side predomination (51.4%). The indication was a malignant lesion in 60.2% of the cases (sizes range: 1-10cm). The transperitoneal route was preferred in 94.2% of the procedures. Conversion and complication rates were 7.5% and 3.1%, respectively. CONCLUSION: LA should be preferred in selected children with adrenal pathologies. The transperitoneal route seems to be the standard approach for pediatric surgeons. Preoperative planning and surgical expertise are the keys to success. TYPE OF THE STUDY: Case series with systematic literature review. LEVEL OF EVIDENCE: IV. PMID- 29254848 TI - Towards Consensus: Training in Procedural Skills for Diagnostic Radiology Residents-Current Opinions of Residents and Faculty at a Large Academic Center. AB - RATIONALE AND OBJECTIVES: The Diagnostic Radiology Milestones Project provides a framework for measuring resident competence in radiologic procedures, but there are limited data available to assist in developing these guidelines. We performed a survey of current radiology residents and faculty at our institution as a first step toward obtaining data for this purpose. The survey addressed attitudes toward procedural standardization and procedures that trainees should be competent by the end of residency. MATERIALS AND METHODS: Current residents and faculty members were surveyed about whether or not there should be standardization of procedural training, in which procedures residents should achieve competency, and the number of times a procedure needs to be performed to achieve competency. RESULTS: Survey data were received from 60 study participants with an overall response rate of 32%. Sixty-five percent of respondents thought that procedural training should be standardized. Standardization of procedural training would include both the list of procedures that trainees should be competent in at the end of residency and the standard minimum number of procedures to achieve competency. Procedures that both residents and faculty agreed are important in which to achieve competency included central line/port procedures; CT-guided abdominal, thoracic, and musculoskeletal procedures; minor fluoroscopic-guided procedures; general fluoroscopy; peripheral line placements; and US-guided abdominal procedures. For most of these categories, most respondents believed that these procedures needed to be performed 6-20 times to achieve competency. CONCLUSION: Both resident and faculty respondents agreed that procedural training should be standardized during residency, and competence in specific procedures should be achieved at the completion of residency. Although this study is limited to a single institution, our data may provide assistance in developing future guidelines for standardizing image-guided procedure training. Future studies could be expanded to create a national consensus regarding the implementation of the Diagnostic Radiology Milestones Project. PMID- 29254847 TI - Changes in gait and posture as factors of dynamic stability during walking in pregnancy. AB - Changes in gait and postural control during pregnancy may lead to increased fall rates during walking relative to non-pregnant women. Due to lack of empirical evidence on balance and postural control in dynamic conditions, the primary aim of this study was investigate the changes in gait and postural control as factors of stability during walking. Gait and posture of thirty-five (35) pregnant women (27 +/- 6.1 years) were analysed at self-selected walking speed, and at different stage of pregnancy. The results indicate that although the gait kinematics did not differ between the trimesters, significant associations were noted between the step width, the lateral trunk lean, and the medio-lateral deviations in centre of gravity and centre of pressure. In contrast to the static conditions, anterior-posterior postural sway is not present during walking, whereas the lateral trunk lean is the primary factor women use in pregnancy to keep the centre of gravity closer to the base of support. Postural changes and those in gait kinematics were largely affected by the relative mass gain, rather than the absolute mass. Considering the importance of relative mass gain, more attention during healthy pregnancy should be given to monitoring the timing of onset of musculoskeletal changes, and design of antenatal exercise programs targeting core strength and pelvic stability. PMID- 29254849 TI - Factors Associated With Early Loss of Hallux Valgus Correction. AB - Recurrence is common after hallux valgus corrective surgery. Although many investigators have studied the risk factors associated with a suboptimal hallux position at the end of long-term follow-up, few have evaluated the factors associated with actual early loss of correction. We conducted a retrospective cohort study to identify the predictors of lateral deviation of the hallux during the postoperative period. We evaluated the demographic data, preoperative severity of the hallux valgus, other angular measurements characterizing underlying deformities, amount of hallux valgus correction, and postoperative alignment of the corrected hallux valgus for associations with recurrence. After adjusting for the covariates, the only factor associated with recurrence was the postoperative tibial sesamoid position. The recurrence rate was ~50% and ~60% when the postoperative tibial sesamoid position was >4 and >5 on the 7-point scale, respectively. PMID- 29254850 TI - Medial Double Arthrodesis: Technique Guide and Tips. AB - The triple arthrodesis procedure remains the historical standard to treat complex hindfoot pathology. However, in recent data, the medial double arthrodesis has been documented to provide similar benefit with decreased complication rates compared with the triple arthrodesis. Therefore, increased interest in this procedure for the treatment of complex hindfoot pathologies has ensued. We describe the technical components of the medial double arthrodesis. PMID- 29254851 TI - A Rare Presentation of a Giant Epidermoid Inclusion Cyst Mimicking Malignancy. AB - Epidermoid inclusion cysts, infundibular cysts, and retention cysts are dense, well-encapsulated benign soft tissue lesions that develop after a portion of the epidermis has become implanted in the dermis on a follicular surface such as the scalp, face, or trunk. However, on acral surfaces such as the palms and soles, these cysts present <10% of the time. Typically, these lesions will not progress to sizes >5 cm. However, a rare subtype of epidermal cysts known as giant epidermal cysts tends to be much larger. Unlike epidermal inclusion cysts, giant cysts lack a central punctum, present on areas of thick skin lacking hair follicles, and affect an older patient population. Because of their large size and unique characteristics, few cases of giant epidermal cysts localized to the foot have been reported. We present a case report of a 57-year-old male with a rapidly growing, large, ulcerated, atypical epidermal inclusion cyst that had developed on the medial aspect of his hallux with underlying osseous changes. In this particular case, the location, overlying skin changes, and rapid growth of the lesion raised suspicion for malignancy. In the present report, we discuss the unusual features of this particular cyst and the etiologies, treatment course, and short-term outcomes regarding this unique tumor. PMID- 29254852 TI - Herbal medicines use during pregnancy in Sierra Leone: An exploratory cross sectional study. AB - BACKGROUND: The influence of complementary therapies on maternal health has attracted the attention of policy makers, health professionals and researchers globally especially in developing countries. However, there is lack of evidence on whether Sierra Leonean women use herbal medicine during pregnancy which limit the chance of providing better maternity care. AIM: This study was conducted to determine the prevalence and pattern of herbal medicines use among pregnant women attending an antenatal clinic at a tertiary maternal hospital in Sierra Leone. METHODS: A cross-sectional study was conducted among pregnant women (n=134) who were at least 18 years of age and who have had at least one previous pregnancy, using face to face interview. Descriptive statistics, univariate and multivariate logistic regression analysis were used for data analysis. RESULTS: The response rate was 82.7%. Nearly two-thirds of pregnant women reported using herbal medicine (62.7%). Herbal medicine users were more likely to be Muslim than Christian. Luffa acutangula (L.) Roxb was the most cited herbal medicine used and was mostly indicated for urinary tract infection and pedal oedema. Perceived effectiveness and safety over conventional medicine (70.2%) was key driver for use, and majority did not disclose their use of herbs to their maternal health professional (95.2%). CONCLUSION: Herbal medicine use among pregnant women in this study was widespread. Maternal health providers should be aware of this relatively common practice and routinely discuss and educate pregnant women on the potential risks and benefits associated with the use of herbs. PMID- 29254853 TI - Self reported hearing difficulty, tinnitus, and normal audiometric thresholds, the National Health and Nutrition Examination Survey 1999-2002. AB - Perceived hearing difficulty (HD) and/or tinnitus in the presence of normal audiometric thresholds present a clinical challenge. Yet, there is limited data regarding prevalence and determinant factors contributing to HD. Here we present estimates generalized to the non-institutionalized population of the United States based on the cross-sectional population-based study, the National Health and Nutrition and Examination Survey (NHANES) in 2176 participants (20-69 years of age). Normal audiometric thresholds were defined by pure-tone average (PTA4) of 0.5, 1.0, 2.0, 4.0 kHz <= 25 dBHL in each ear. Hearing difficulty (HD) and tinnitus perception was self-reported. Of the 2176 participants with complete data, 2015 had normal audiometric thresholds based on PTA4; the prevalence of individuals with normal PTA4 that self-reported HD was 15%. The percentage of individuals with normal audiometric threshold and persistent tinnitus was 10.6%. Multivariate logistic regression adjusting for age, sex, and hearing thresholds identified the following variables related to increased odds of HD: tinnitus, balance issues, noise exposure, arthritis, vision difficulties, neuropathic symptoms, physical/mental/emotional issues; and for increased odds or reported persistent tinnitus: HD, diabetes, arthritis, vision difficulties, confusion/memory issues, balance issues, noise exposure, high alcohol consumption, neuropathic symptoms and analgesic use. Analyses using an alternative definition of normal hearing, pure-tone thresholds <=25 dBHL at 0.5, 1.0, 2.0, 4.0, 6.0, and 8.0 kHz in each ear, revealed lower prevalence of HD and tinnitus, but comparable multivariate relationships. The findings suggest that prevalence of HD is dependent on how normal hearing is defined and the factors that impact odds of reported HD include tinnitus, noise exposure, mental/cognitive status, and other sensory deficits. PMID- 29254854 TI - Workplace health promotion in health care settings in Finland, Latvia, and Lithuania. AB - BACKGROUND AND OBJECTIVE: Health care workers (HCWs) have a great background to promote their health - not only their professional knowledge on health but often also special equipment in their work environment. However, it is unclear if HCWs can use such infrastructure to promote their own health as well as what is their motivation to change their own lifestyles. Thus, the aim of the article was to describe workplace health promotion (WHP) situation in health care settings in Finland, Latvia, and Lithuania. MATERIALS AND METHODS: A questionnaire survey of 357 workers from health care sector in three European countries was conducted. Participants were asked to indicate various WHP activities/facilities/programs organized at their workplaces, WHP needs, opportunities to initiate changes related to the healthiness of their workplaces, and readiness to change their lifestyles. RESULTS: Participants from three European countries differed in their WHP needs and in their responses on various activities/facilities/programs implemented at the institutions. Workers from Finnish institutions had the greatest opportunities to make initiatives relevant to their workplaces' healthiness, while Lithuanian workers were least provided with such opportunities. Furthermore, the results showed that there were differences of readiness to change among the workers from the three countries. CONCLUSIONS: HCWs recognized various WHP activities, facilities and programs organized at their workplaces; however, their needs were notably higher than the situation reported. WHP situation differed among the three European countries. PMID- 29254855 TI - Relations between longitudinal trajectories of subjective financial wellbeing with self-rated health among elderly. AB - BACKGROUND AND OBJECTIVE: The relationship between income and health in late life is well established, but the link between subjective financial wellbeing (SFW) and self-rated health (SRH) has been relatively ignored, especially among elderly in Europe. Adopting a longitudinal person-oriented analytical approach this study investigates the relationship between SFW and SRH in late life in Italy. MATERIALS AND METHODS: Analysis of the European Statistics on Income and Living Conditions survey (EU-SILC) for the period 2010-2013 in Italy examined these relationships at ages 65-78 (N=1268). Latent class growth analysis and growth mixture modeling were used to identify latent trajectories of SFW. Post hoc analysis of variance examined how SFW latent groups differed in terms of SRH across time. RESULTS: A three-group latent trajectory model fitted the data best. The three SFW groups were named average-decreasing (n=238), low-stable (n=216), and high-stable (n=814). Repeated measures analysis of variance indicated a significant multivariate effect of SFW latent trajectory class on SRH, controlling for age, gender, and presence of chronic diseases. Post hoc analyses revealed that levels of SRH in the high-stable SFW group remained the highest compared to the other two groups and did not decrease over time, while the average-decreasing group showed a decrease in SRH levels. CONCLUSIONS: Results suggest that in late life longitudinal negative changes in perceptions of financial wellbeing may occur together with decreases levels of self-reported health. Future research on health inequalities in elderly should pay specific attention to the link between financial wellbeing and health from a self-reported perspective. PMID- 29254856 TI - Accelerated partial breast irradiation for suitable elderly women using a single fraction of multicatheter interstitial high-dose-rate brachytherapy: Early results of the Single-Fraction Elderly Breast Irradiation (SiFEBI) Phase I/II trial. AB - PURPOSE/OBJECTIVE: To evaluate feasibility and early clinical outcomes of a single fraction of multi-catheter interstitial high-dose rate brachytherapy for accelerated partial breast irradiation (APBI) in the elderly. MATERIAL/METHODS: From November 2012 to September 2014, 26 patients (>=70) with early breast cancer were enrolled in a prospective phase II trial (NCT01727011). After lumpectomy, intra-operative catheter implant was performed for post-operative APBI (single fraction 16 Gy). Surveillance was achieved at 1, 3 and 6 months after APBI, then twice a year. Acute toxicity was investigated. Early cosmetic outcome was analyzed (patient, radiation oncologist, 2 observers). Local and regional relapse free survival, cancer specific survival and overall survival were analyzed. RESULTS: Median age was 77 years [69-89]. Median CTV was 41 cc [22-95]. Acute toxicity was observed in 18 pts (70%) with a total of 44 events: G1: 75.7%; G2: 22.8%; G3: 4.5%. Breast fibrosis (31.8%), puncture site inflammation (13.6%) and skin hyperpigmentation (11.4%) were the most frequent side effects. Cosmetic evaluation at 6 months was excellent/good in 88%, 92%, 85% and 88% for patient, radiation oncologist, observer #1 and #2 respectively. With a median follow-up of 37.2 months [35.6-42.3], side effects were G1: 4 pts (15%) and G2: 1 pt (4%). Three-year Local and regional relapse-free survival, cancer specific survival and overall survival rates were 100%, 100%, 100% and 95.2% respectively. CONCLUSIONS: For elderly early breast cancer, a post-operative multi-catheter interstitial high-dose rate brachytherapy single dose (16 Gy) appears feasible. Acute toxicity is acceptable as well as early cosmetic outcome. Oncologic outcome seems encouraging and allows going forward with new clinical trials focusing on single fraction APBI. PMID- 29254857 TI - A two-step screening process reduces hip fractures. PMID- 29254859 TI - Shigellosis. AB - Shigellosis is a clinical syndrome caused by invasion of the epithelium lining the terminal ileum, colon, and rectum by Shigella species. Although infections occur globally, and in people of all ages, endemic infections among children aged 1-4 years living in low-income and middle-income settings constitute most of the disease burden. The versatile manifestations of these highly contagious organisms range from acute watery diarrhoea to fulminant dysentery characterised by frequent scant bloody stools with fever, prostration, and abdominal cramps. A broad array of uncommon, but often severe, intestinal and extraintestinal complications can occur. Despite marked reductions in mortality during the past three decades, there are roughly 164 000 annual deaths attributable to shigellosis. Intercontinental dissemination of multiresistant shigella strains, facilitated by travellers and men who have sex with men, has prompted new recommendations for antibiotic therapy. Awareness of disease burden and the emerging threats posed by shigella have accelerated interest in development of shigella vaccines, many of which are being tested in clinical trials. PMID- 29254858 TI - Screening in the community to reduce fractures in older women (SCOOP): a randomised controlled trial. AB - BACKGROUND: Despite effective assessment methods and medications targeting osteoporosis and related fractures, screening for fracture risk is not currently advocated in the UK. We tested whether a community-based screening intervention could reduce fractures in older women. METHODS: We did a two-arm randomised controlled trial in women aged 70-85 years to compare a screening programme using the Fracture Risk Assessment Tool (FRAX) with usual management. Women were recruited from 100 general practitioner (GP) practices in seven regions of the UK: Birmingham, Bristol, Manchester, Norwich, Sheffield, Southampton, and York. We excluded women who were currently on prescription anti-osteoporotic drugs and any individuals deemed to be unsuitable to enter a research study (eg, known dementia, terminally ill, or recently bereaved). The primary outcome was the proportion of individuals who had one or more osteoporosis-related fractures over a 5-year period. In the screening group, treatment was recommended in women identified to be at high risk of hip fracture, according to the FRAX 10-year hip fracture probability. Prespecified secondary outcomes were the proportions of participants who had at least one hip fracture, any clinical fracture, or mortality; and the effect of screening on anxiety and health-related quality of life. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN 55814835. FINDINGS: 12 483 eligible women were identified and participated in the trial, and 6233 women randomly assigned to the screening group between April 15, 2008, and July 2, 2009. Treatment was recommended in 898 (14%) of 6233 women. Use of osteoporosis medication was higher at the end of year 1 in the screening group compared with controls (15% vs 4%), with uptake particularly high (78% at 6 months) in the screening high-risk subgroup. Screening did not reduce the primary outcome of incidence of all osteoporosis-related fractures (hazard ratio [HR] 0.94, 95% CI 0.85-1.03, p=0.178), nor the overall incidence of all clinical fractures (0.94, 0.86-1.03, p=0.183), but screening reduced the incidence of hip fractures (0.72, 0.59-0.89, p=0.002). There was no evidence of differences in mortality, anxiety levels, or quality of life. INTERPRETATION: Systematic, community-based screening programme of fracture risk in older women in the UK is feasible, and could be effective in reducing hip fractures. FUNDING: Arthritis Research UK and Medical Research Council. PMID- 29254861 TI - Ceftazidime-avibactam versus meropenem for the treatment of nosocomial pneumonia. PMID- 29254860 TI - Somatosensory Evoked Potentials and Central Motor Conduction Times in children with dystonia and their correlation with outcomes from Deep Brain Stimulation of the Globus pallidus internus. AB - OBJECTIVES: To report Somatosensory Evoked Potentials (SEPs) and Central Motor Conduction Times (CMCT) in children with dystonia and to test the hypothesis that these parameters predict outcome from Deep Brain Stimulation (DBS). METHODS: 180 children with dystonia underwent assessment for Globus pallidus internus (GPi) DBS, mean age 10 years (range 2.5-19). CMCT to each limb was calculated using Transcranial Magnetic Stimulation. Median and posterior tibial nerve SEPs were recorded over contralateral and midline centro-parietal scalp. Structural abnormalities were assessed with cranial MRI. One-year outcome from DBS was assessed as percentage improvement in Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-m). RESULTS: Abnormal CMCTs and SEPs were found in 19% and 47% of children respectively and were observed more frequently in secondary than primary dystonia. Of children proceeding to DBS, better outcome was seen in those with normal (n = 78/89) versus abnormal CMCT (n = 11/89) (p = 0.002) and those with normal (n = 35/51) versus abnormal SEPs (n = 16/51) (p = 0.001). These relationships were independent of dystonia aetiology and cranial MRI findings. CONCLUSIONS: CMCTs and SEPs provide objective evidence of motor and sensory pathway dysfunction in children with dystonia and relate to DBS outcome. SIGNIFICANCE: CMCTs and SEPs can contribute to patient selection and counselling of families about potential benefit from neuromodulation for dystonia. PMID- 29254863 TI - Corrections. PMID- 29254862 TI - Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. AB - BACKGROUND: Nosocomial pneumonia is commonly associated with antimicrobial resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator associated pneumonia, compared with meropenem in a multinational, phase 3, double blind, non-inferiority trial (REPROVE). METHODS: Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7-14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21-25 days after randomisation). Non inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than -12.5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96). FINDINGS: Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68.8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73.0%) of 370 patients in the meropenem group (difference -4.2% [95% CI -10.8 to 2.5]). In the clinically evaluable population, 199 (77.4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78.1%) of 270 in the meropenem group (difference -0.7% [95% CI -7.9 to 6.4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related. INTERPRETATION: Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator associated pneumonia) caused by Gram-negative pathogens. FUNDING: AstraZeneca. PMID- 29254864 TI - IV Brazilian Consensus on Rhinitis - an update on allergic rhinitis. AB - INTRODUCTION: The guidelines on allergic rhinitis aim to update knowledge about the disease and care for affected patients. The initiative called "Allergic Rhinitis and its Impact on Asthma", initially published in 2001 and updated in 2008 and 2010, has been very successful in disseminating information and evidence, as well as providing a classification of severity and proposing a systemized treatment protocol. In order to include the participation of other medical professionals in the treatment of allergic rhinitis, it is important to develop algorithms that accurately indicate what should and can be done regionally. OBJECTIVE: To update the III Brazilian Consensus on Rhinitis - 2012, with the creation of an algorithm for allergic rhinitis management. METHODS: We invited 24 experts nominated by the Brazilian Association of Allergy and Immunology, Brazilian Association of Otorhinolaryngology and Head and Neck Surgery and Brazilian Society of Pediatrics to update the 2012 document. RESULTS: The update of the last Brazilian Consensus on Rhinitis incorporated and adapted the relevant information published in all "Allergic Rhinitis and its Impact on Asthma" Initiative documents to the Brazilian scenario, bringing new concepts such as local allergic rhinitis, new drugs and treatment evaluation methods. CONCLUSION: A flowchart for allergic rhinitis treatment has been proposed. PMID- 29254865 TI - On the relationship between radial structure heterogeneities and efficiency of chromatographic columns. AB - The general dispersion theory of Aris is applied to predict the virtual asymptotic dispersion behavior of packed columns. The derived model is also used to estimate the actual pre-asymptotic dispersion behavior of modern 2.1 mm * 50 mm columns packed with sub-2 MUm fully porous particles (FPPs) during the transient dispersion regime. The model accounts for the actual radial distribution of the flow velocity across the column diameter. From the wall to the center of the column, focused-ion-beam scanning electron microscopy (FIB-SEM) experiments were recently performed to reveal the existence of a thin (0.15dp wide, dp is the average particle diameter) hydrodynamic boundary layer (THBL), a thin (3dp wide) and loose orderly packed layer (TLOPL), a 60dp wide and dense randomly packed layer (WDRPL), and a large (?460dp) randomly packed bulk central region [1]. The theoretical calculations of the actual pre-asymptotic reduced van Deemter curves (2.1 mm * 50 mm column, sub-2 MUm BEH-C18 FPPs, n-hexanophenone analyte, acetonitrile/water eluent, 80/20, v/v, flow rate from 0.05 to 0.35 mL/min) confirm that the impact of the sole THBL on column dispersion can be neglected. In contrast, the contribution of the TLOPL to the reduced plate height (RPH) is about 0.2 h unit at optimum reduced velocity. Most remarkably, the negative impact of the TLOPL on column performance may be fully compensated by the presence of the adjacent WDRPL if the depth of the velocity well were to be 5% of the bulk velocity. In actual 2.1 mm * 50 mm columns packed with sub-2 MUm FPPs, this velocity depth is as large as 25% of the bulk velocity causing a significant RPH deviation of 0.7 h unit from the RPH of the bulk packing free from wall effects. Maximum column performance is expected for a reduction of WDRPL density. This suggests optimizing the packing process by finding the proper balance between the stress gradient across the WDRPL (responsible for the deep velocity well) and the friction forces between the packed particles (responsible for the rearrangement of the particles during bed consolidation). Past and recently reported RPH data support the theoretical insights: the stress gradient/particle friction balance in the WDRPL is better realized when packing superficially porous particles (SPPs) rather than FPPs in 2.1-4.6 mm i.d. columns (the RPH deviation is reduced to 0.4 h unit) or sub-2 MUm particles in 100 cm * 75 MUm i.d. capillaries combining high slurry concentrations and sonication (the RPH deviation is reduced to only 0.15 h unit). PMID- 29254866 TI - Graphical statistical approach to soil organic matter resilience using analytical pyrolysis data. AB - Pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS) of humic acids (HAs) from 30 agricultural soils from a volcanic island (Tenerife, Spain) was used to discern the molecular characteristics of soil organic matter (SOM) associated to resilience. For faster perceptual identification of the results, the yields of the pyrolysis products in the form of surface density plots were compared in an update of the Van Krevelen graphical statistical method. This approach, with respect to data reduction and visualization, was also used to collectively represent statistical indices that were obtained after simple and partial least squares (PLS) regression. The resulting plots illustrate different SOM structural domains (for example, carbohydrate- and lignin-derived and condensed lipid). The content of SOM and total mineralization coefficient (TMC) values can be well estimated from the relative abundance of 57 major pyrolysis compounds: SOM content and composition parallels the accumulation of lignin- and carbohydrate derived structures (lignocellulosic material) and the depletion of condensed polyalkyl structures. In other words, in the volcanic ash soils that were studied, we found that the higher the amount of SOM, the lower its quality in terms of resilience. Although no cause-and-effect is inferred from this fact, it is evident that the resistance to biodegradation of the SOM is related to its molecular composition. PMID- 29254867 TI - Dissociation after ketamine dosing: Is the CADSS fit for purpose? PMID- 29254868 TI - Oncological outcomes after hepatic resection and/or surgical microwave ablation for liver metastasis from gastric cancer. AB - BACKGROUND: Indications and efficacy of surgical treatment for liver metastases from gastric cancer (LMGCs) remain controversial. This retrospective study was designed to clarify the benefits of surgical treatment and identify prognostic factors. METHODS: Between December 1997 and December 2015, 34 consecutive patients underwent hepatic resection and surgical microwave ablation for synchronous or metachronous LMGCs at our institution. We analyzed their cumulative overall survival (OS) and recurrence-free survival (RFS) rates and clinical parameters to identify predictors of prognosis. RESULTS: Of the 34 patients, 14 underwent hepatic resection, 13 underwent surgical microwave ablation, and 7 underwent hepatic resection combined with surgical microwave ablation. Their OS rates were 1-year: 84.4%, 3-year: 38.6%, and 5-year: 34.7%; and their RFS rates were 1-year: 38.5%, 3-year: 28.0%, and 5-year: 28.0%. OS did not significantly vary among the surgical procedures. In multivariable analysis, positive of both CEA and CA19-9 were independent predictors of poor survival (hazard ratio [HR] 4.51; P = 0.049) and early recurrence (HR 5.70; P = 0.047). CONCLUSIONS: Both hepatic resection and surgical microwave ablation for LMGCs are effective and can improve survival in selected patients. PMID- 29254869 TI - Robot-assisted laparoscopic radical cystectomy is a safe and effective procedure for patients with bladder cancer compared to laparoscopic and open surgery: Perioperative outcomes of a single-center experience. AB - OBJECTIVE: We compared the perioperative outcomes of patients with bladder cancer according to three different procedures: robot-assisted laparoscopic radical cystectomy (RALC), laparoscopic radical cystectomy (LRC), and open radical cystectomy (ORC). METHODS: From April 2008 to March 2017, 36 consecutive patients underwent radical cystectomy and ileal conduit with RALC (n = 10), LRC (n = 10), or ORC (n = 16). All patients underwent RALC and LRC with extracorporeal urinary diversion. Perioperative data were patient demographics, perioperative laboratory data including hematocrit and creatinine, intraoperative crystalloids and colloids, estimated blood loss (EBL), allogeneic transfusion, respiratory parameters including maximum end-tidal carbon dioxide (EtCO2) and respiratory rate, arterial blood gas data including highest pH, partial pressure of CO2 (PaCO2), partial pressure of oxygen (PaO2), operative time, opiate consumption including intraoperative and postoperative anesthesia, time of hospital stay, time to oral intake and normal diet, and adverse events. RESULTS: EBL was less for RALC than for other procedures (p = 0.0004). No blood transfusions were performed for RALC, but ORC required significant blood transfusions (p = 0.003). Respiratory rate was highest and PaCO2 was lowest for RALC. Preoperative creatinine levels were significantly worse for the RALC group, but no significant differences were noted after surgery. There were no significant differences among the groups in regard to hematocrit levels. Operative time, laparoscopic time, intraoperative anesthesia, and postoperative anesthesia did not differ among the groups. High-grade adverse events were only seen for ORC. CONCLUSION: Although RALC required a steep Trendelenburg position, which might add elements of risk, RALC was safe even for this small cohort. PMID- 29254870 TI - Effect of infrahepatic inferior vena cava clamping on bleeding during hepatic resection: A meta-analysis. AB - This meta-analysis aimed to explore the effect of infrahepatic vena cava (IVC) clamping on bleeding during hepatic resection. PubMed and Embase databases were searched systematically to identify randomized controlled trials (RCTs) comparing infrahepatic IVC clamping to IVC nonclamping during hepatic resection. A random effects model was used to calculate weight and outcome measures. Five RCTs involving a total of 596 patients were identified for inclusion: 299 in infrahepatic IVC clamping group and 297 in nonclamping group. Infrahepatic IVC clamping was associated with a statistically significant reduction in total intraoperative blood loss (weighted mean difference [WMD] -181.72, 95% confidence interval [95% CI] -329.03 to -34.4; P = 0.02) and blood loss during parenchymal transaction (WMD -160.58, 95% CI, -261.9 to -59.27; P = 0.002). Postoperative morbidity, mortality, and hospital stay were comparable in both groups. Data from currently available literature suggest that infrahepatic IVC clamping is a safe procedure that facilitates intraoperative bleeding control during hepatic resection. PMID- 29254871 TI - Pediatric differentiated thyroid carcinoma: The clinicopathological features and the coexistence of Hashimoto's thyroiditis. AB - BACKGROUND/OBJECTIVE: The purpose of this study is to assess outcomes and the detailed clinicopathological features of differentiated thyroid carcinoma (DTC), including the relation of Hashimoto's thyroiditis and postoperative pathological features in child under 18 years old. METHODS: We reviewed patients with DTC under 18 years old (pediatric DTC patients) seen during recent 16 years. The clinicopathological features and outcomes of pediatric DTC were analyzed by comparison with patients of 19-20 years old or 21-44 years old. RESULTS: Sixty four children with DTC [median age 16 years (range, 5-18)] were studied. The ratio of female to male was 5:1, but no difference was found by comparison with adult of 21-44 years old. No difference was found in multifocality, but DTC in child showed lager tumor size (P < 0.001), higher rate of extrathyroidal extension (P = 0.017), more local or pulmonary metastasis (P < 0.001, P < 0.001 respectively) than adult thyroid carcinoma. High rate of Hashimoto's thyroiditis (19/43) without influence on pathological features was found in patients under 18 years old. No differences, except for distant metastasis, were found by comparison of clinicopathological features between patients under 18 years old and 19-20 years old. Pediatric patients possessed highest rates of persistent/recurrent disease, though only one child died. CONCLUSION: Pediatric DTC has more aggressive behavior characterized by a high rate of extrathyroidal extension, local and pulmonary metastasis. Pediatric DTC has low mortality, but active treatments are needed for the high risk of persistent or recurrent diseases. Hashimoto's thyroiditis may be associated with the pathogenesis or mechanism of pediatric DTC. PMID- 29254872 TI - In Vivo Assessment of the Potential for Renal Bio-Effects from the Vaporization of Perfluorocarbon Phase-Change Contrast Agents. AB - Low-boiling-point perfluorocarbon phase-change contrast agents (PCCAs) provide an alternative to microbubble contrast agents. Although parameter ranges related to in vivo bio-effects of microbubbles are fairly well characterized, few studies have been done to evaluate the potential of bio-effects related to PCCAs. To bridge this gap, we present an assessment of biological effects (e.g., hemorrhage) related to acoustically excited PCCAs in the rodent kidney. The presence or absence of bio-effects was observed after sonication with various perfluorocarbon core PCCAs (decafluorobutane, octafluoropropane or a 1:1 mixture) and as a function of activation pulse mechanical index (MI; minimum activation threshold, which was a moderate MI of 0.81-1.35 vs. a clinical maximum of 1.9). Bio-effects on renal tissue were assessed through hematology and histology including measurement of blood creatinine levels and the quantity of red blood cell (RBC) casts present in hematoxylin and eosin-stained kidney tissue sections after sonication. Short-term (24 h) and long-term (2 and 4 wk) analyses were performed after treatment. Results indicated that bio-effects from PCCA vaporization were not observed at lower mechanical indices. At higher mechanical indices, bio-effects were observed at 24 h, although these were not observable 2 wk after treatment. PMID- 29254873 TI - Epidemiology of basal cell carcinoma: a 10-year comparative study. AB - Basal cell carcinoma (BCC) is a slow-growing and locally aggressive skin cancer. Despite its high incidence, good quality epidemiological data are sparse. We therefore organised a retrospective study of two separate years' incidence of BCC in one county within the United Kingdom (Dorset) with an interval of 10 years between them. There were 2455 patients in 2006, and 3797 in 2016, who had a new diagnosis with corresponding crude incidences of 459.99 and 491.92/100,000 person years. The male:female ratio was 1:071 for both years. The head and neck was the most common site, with the cheek, nose, and forehead being the most common subsites. This is a substantial increase in the incidence of BCC, and is much higher than previous reported rates for the UK. More stringent local and national registries are required to monitor the increasing numbers of BCC and help health care systems to plan preventive strategies and provide the most effective treatment. PMID- 29254874 TI - Grafts of autogenous coronoid process to reconstruct the mandibular condyle in children with unilateral ankylosis of the temporomandibular joint: long-term effects on mandibular growth. AB - Injury to the mandibular condyle in children usually leads to malocclusion and disharmony of facial growth. Our aim was to study the facial growth after reconstruction of the mandibular condyle using autogenous coronoid process grafts in children with unilateral ankylosis of the temporomandibular joint (TMJ). We followed up 10 growing patients with unilateral bony ankylosis of the TMJ who had been admitted to the West China Hospital of Stomatology, Sichuan University (Chengdu, China) between 1 January 2008 and 31 December 2012. There were three boys and seven girls, age range 5-12 years at the time of operation. In each case, patients were treated by gap arthroplasty, reconstruction of the condyle with an ipsilateral coronoid process, and interposition of the pedicled temporalis fascial flap during one operation. The mean (range) postoperative follow up was 4.73 (3-6) years. Postoperative panoramic radiographs were taken, and the growth of the mandibular height and length on the affected side was measured and compared with the healthy side. All patients had an uneventful, normal recovery. The mean (range) maximal mouth opening at the end of follow up was 35.6 (32-41) mm. Both the height of the ramus and the length of the mandible continued to grow after successful treatment of the ankylosis (using autogenous coronoid process grafts for reconstruction of the condyle) but the deficit in growth was not completely made up. The final height of the ramus on the affected side (at the end of follow up) had increased by 25% (p=0.012) and the final length of the mandible on the affected side by 26% (p=0.010) compared with immediately after operation. For comparison of the rate of growth, the increased height of the ramus of the affected side was 47% lower (p=0.003), while the increased length of the mandible on the affected side was 27% shorter (p=0.008) compared with the healthy side. The mandible on the affected side continued to grow after successful treatment of the ankylosis, but the growth deficit was not made up completely. The rate of growth of the affected mandible seemed to be less than on the undisturbed side even after treatment of the ankylosis. PMID- 29254875 TI - Can dietary supplements improve a clinician's well-being and health? AB - Many people use dietary supplements to improve their physical and mental well being and their general health, but do not know if they really have any benefit. To our knowledge, little has been published on their use in the clinical environment, so we evaluated the evidence for their benefits in people whose work is physically and mentally challenging. Studies on nutrition and supplementation in athletes and military personnel have clearly shown that several compounds improve cognition, mental well-being, and physical performance. Based on this evidence, and with the many pressures faced by healthcare workers, as well as the need for concentration and endurance, some dietary supplements might be beneficial. Supplementation of a balanced diet with omega-3 fatty acids, vitamin B3, vitamin C and associated antioxidants, vitamin D, and protein, may improve a clinician's physical and mental health and their performance at work. Specific research is, however, needed to evaluate this more fully. PMID- 29254876 TI - A new paradigm shift in musculoskeletal rehabilitation: why we should exercise the brain? PMID- 29254877 TI - Aquatic weeds as the next generation feedstock for sustainable bioenergy production. AB - Increasing oil prices and depletion of existing fossil fuel reserves, combined with the continuous rise in greenhouse gas emissions, have fostered the need to explore and develop new renewable bioenergy feedstocks that do not require arable land and freshwater resources. In this regard, prolific biomass growth of invasive aquatic weeds in wastewater has gained much attention in recent years in utilizing them as a potential feedstock for bioenergy production. Aquatic weeds have an exceptionally higher reproduction rates and are rich in cellulose and hemicellulose with a very low lignin content that makes them an efficient next generation biofuel crop. Considering their potential as an effective phytoremediators, this review presents a model of integrated aquatic biomass production, phytoremediation and bioenergy generation to reduce the land, fresh water and fertilizer usage for sustainable and economical bioenergy. PMID- 29254879 TI - Diabetes-related distress is reduced in people with type 1, but not type 2 diabetes after participating in a diabetes treatment and teaching programme. PMID- 29254878 TI - The Early Psychosis Screener (EPS): Item development and qualitative validation. AB - A panel of experts assembled and analyzed a comprehensive item bank from which a highly sensitive and specific early psychosis screener could be developed. Twenty well-established assessments relating to the prodromal stage, early psychosis, and psychosis were identified. Using DSM-5 criteria, we identified the core concepts represented by each of the items in each of the assessments. These granular core concepts were converted into a uniform set of 490 self-report items using a Likert scale and a 'past 30days' time frame. Partial redundancy was allowed to assure adequate concept coverage. A panel of experts and TeleSage staff rated these items and eliminated 189 items, resulting in 301 items. The items were subjected to five rounds of cognitive interviewing with 16 individuals at clinically high risk for psychosis and 26 community mental health center patients. After each round, the expert panel iteratively reviewed, rated, revised, added, or deleted items to maximize clarity and centrality to the concept. As a result of the interviews, 36 items were revised, 52 items were added, and 205 items were deleted. By the last round of cognitive interviewing, all of the items were clearly understood by all participants. In future work, responses to the final set of 148 items and machine learning techniques will be used to quantitatively identify the subset of items that will best predict clinical high-risk status and conversion. PMID- 29254881 TI - Erratum to "Excessive atrial ectopic activity as an independent risk factor for ischemic stroke" [Int. J. Cardiol. (2017) 226-230]. PMID- 29254880 TI - Foreword by the Guest Editors of the new section of the IJC, "Migration and cardiovascular disease". PMID- 29254882 TI - The impact of delayed treatment on 6-minute walk distance test in patients with pulmonary arterial hypertension: A meta-analysis. AB - BACKGROUND: The impact of treatment delay in stable patients with pulmonary arterial hypertension (PAH) remains unaddressed. METHODS: This meta-analysis included six datasets of PAH therapies with randomized-controlled trials (RCT) and corresponding open-label extension (OLE) studies. We evaluated the change in 6MWD at 1year in the OLE studies by active treatment versus ex-placebo group. The ex-placebo group (i.e., the patients randomized to placebo in the RCT and ultimately treated with active therapy in the OLE) represented the "delay-in treatment" population. RESULTS: Patients with a treatment delay of 12-16weeks in PAH targeted therapy had an improvement in 6-minute walk distance (6MWD) test at 1year, but this improvement did not amount to the same degree of improvement as their initially treated counterparts. The difference in 6MWD was 15m to 20m at 1year. CONCLUSION: A short-term delay in PAH targeted therapy may adversely affect functional capacity in patients with PAH. This meta-analysis provides some insight as to whether earlier treatment would benefit stable patients with PAH. PMID- 29254883 TI - Quality of inclusion criteria in the registered clinical trials of heart failure with preserved ejection fraction: Is it time for a change? AB - BACKGROUND: No uniform diagnostic criteria have been developed for heart failure with preserved ejection fraction (HFpEF), resulting in huge discrepancies in the patient recruitments of HFpEF trials. This study aims to assess the quality of inclusion criteria in HFpEF trials. METHODS: We systematically searched the International Clinical Trials Registry Platform for HFpEF trials and extracted the basic characteristics and inclusion criteria. We then scored and compared the quality of inclusion criteria using an adapted 5-point scoring system of ejection fraction (EF), symptoms, signs, natriuretic peptides and other tests. RESULTS: A total of 121 trials and 19,494 patients were finally included for statistical analyses. More than half (67/121, 55.4%) of the trials employed 50% as the cut off value for diagnosing HFpEF. Symptoms (102/121, 84.3%) are mostly provided by trial registrars, followed by natriuretic peptides (46/121, 38.0%) and signs (32/121, 26.4%). Average total scores of inclusion criteria wavily increased from 2.00 in 2002 to 3.00 in 2016 (P=0.04). Interventional trials were not significantly different from observational trials (3.00+/-1.18 vs. 2.75+/-1.53, P=0.45), but ongoing trials were higher in total score than completed trials (3.28+/-1.24 vs. 2.72+/-1.17, P=0.01). Published trials were not significantly different from the unpublished trials at registration (2.76+/-1.13 vs. 2.69+/ 1.20, P=0.82), but their total scores significantly increased to 3.48+/-0.96 at publication (P<0.01). CONCLUSIONS: The qualities of inclusion criteria are heterogeneous and significantly improved with time in registered HFpEF clinical trials. EF, symptoms and signs should be specified at trial registration to make a more reliable diagnosis and to recruit a more homogenous population. PMID- 29254884 TI - Integrating marker-assisted background analysis with foreground selection for pyramiding bacterial blight resistance genes into Basmati rice. AB - Bacterial leaf blight (BB), caused by the bacterium Xanthomonas oryzae pv. Oryzae (Xoo), is the major constraint amongst rice diseases in India. CSR-30 is a very popular high-yielding, salt-tolerant Basmati variety widely grown in Haryana, India, but highly susceptible to BB. In the present study, we have successfully introgressed three BB resistance genes (Xa21, xa13 and xa5) from BB-resistant donor variety IRBB-60 into the BB-susceptible Basmati variety CSR-30 through marker-assisted selection (MAS) exercised with stringent phenotypic selection without compromising the Basmati traits. Background analysis using 131 polymorphic SSR markers revealed that recurrent parent genome (RPG) recovery ranged up to 97.1% among 15 BC3F1 three-gene-pyramided genotypes. Based on agronomic evaluation, BB reaction, aroma, percentage recovery of RPG, and grain quality evaluation, four genotypes, viz., IC-R28, IC-R68, IC-R32, and IC-R42, were found promising and advanced to BC3F2 generation. PMID- 29254885 TI - Merit-Based Incentive Payment System Participation: Radiologists Can Run but Cannot Hide. AB - PURPOSE: To optimize the flexibility and relevancy of its Merit-Based Incentive Payment System (MIPS), CMS exempts selected physicians and groups from participation and grants others relaxed reporting requirements. We assess the practical implications of such special status determinations. METHODS: For a random sample of 1,000 Medicare-participating radiologists, the CMS MIPS Participation Lookup Tool was manually searched. Individual radiologists' and associated groups' participation requirements and special statuses were assessed. RESULTS: Although only 55% of radiologists were required to participate in MIPS as individuals when considering only one associated taxpayer identification number (TIN), 83% were required to participate as individuals when considering all associated TINs. When using the group reporting option, 97% of radiology groups were required to participate. High participation requirements persisted across generalist and subspecialist radiologists, small and rural, and both academic and nonacademic practices. Non-patient-facing and hospital-based statuses were assigned to high fractions of individual radiologists (91% and 71%, respectively), but much lower fractions of group practices (72% and 25%). Rural and health professional shortage area statuses were assigned to higher percentages of groups (27% and 39%) than individuals (13% and 23%). Small practice status was assigned to 22% of individuals versus 16% of groups. CONCLUSION: Although not apparent if only considering individual radiologist-TIN combinations, the overwhelming majority of radiologists will be required to participate in MIPS, at the individual or group level. Radiology groups are strongly encouraged to review their physicians' MIPS participation requirements and special statuses to ensure optimal performance scores and payment bonuses. PMID- 29254886 TI - Chlorpyrifos degradation via photoreactive TiO2 nanoparticles: Assessing the impact of a multi-component degradation scenario. AB - High concentrations of pesticides enter surface waters following agricultural application, raising environmental and human health concerns. The use of photoreactive nanoparticles has shown promise for contaminant degradation and surface water remediation. However, it remains uncertain how the complexity of natural waters will impact the photodegradation process. Here, we investigate the photoreactivity of titanium dioxide nanoparticles, the capability to degrade the pesticide chlorpyrifos, and the effect of and impact on bacteria during the photodegradation process. Loss of chlorpyrifos in solution resulted solely from photocatalytic oxidation, with 80% degradation observed after 24 h in our reactor, either in the presence or absence of bacteria. Degradation of chlorpyrifos to chlorpyrifos oxon and 3,5,6-trichloro-2-pyridinol was observed via LC/MS-MS and effectively modeled for the given reactor conditions. Bacterial inactivation occurred over 60 min and was not impacted by the presence of chlorpyrifos. The relative affinity of bacteria and chlorpyrifos for the nanoparticle surface decreased the amount of Reactive Oxygen Species (ROS) detected in the bulk by up to 94%, suggesting that ROS measurements in simplified systems may overestimate the reactivity of photoreactive nanoparticles in complex environments. PMID- 29254888 TI - FOCUS4: a new trial design for evaluation of targeted drugs in colorectal cancer? PMID- 29254887 TI - Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D): a phase 2-3 randomised trial. AB - BACKGROUND: A substantial change in trial methodology for solid tumours has taken place, in response to increased understanding of cancer biology. FOCUS4 is a phase 2-3 trial programme testing targeted agents in patients with advanced colorectal cancer in molecularly stratified cohorts. Here, we aimed to test the hypothesis that combined inhibition of EGFR, HER2, and HER3 signalling with the tyrosine kinase inhibitor AZD8931 will control growth of all wild-type tumours. METHODS: In FOCUS4-D, we included patients from 18 hospitals in the UK with newly diagnosed advanced or metastatic colorectal cancer whose tumour was wild-type for BRAF, PIK3CA, KRAS, and NRAS. After 16 weeks of first-line therapy, patients with stable or responding tumours were randomised to oral AZD8931 (40 mg twice a day) or placebo. Randomisation was done by minimisation with a random element of 20%, minimisation by hospital site, site of primary tumour, WHO performance status, 16 week CT scan result, number of metastatic sites, and first-line chemotherapy regimen. The primary outcome was progression-free-survival. CT scans were assessed by local radiologists according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Preplanned interim analyses were assessed per protocol and were agreed using multiarm multistage (MAMS) trial design methodology triggered by occurrence of progression-free survival events in the placebo group. The final analysis was assessed by intention to treat. This trial is registered at controlled-trials.com, ISRCTN 90061546. FINDINGS: Between July 7, 2014, and March 7, 2016, 32 patients were randomised to study treatment, 16 to AZD8931 and 16 to placebo. At the first preplanned interim analysis (March, 2016), the independent data monitoring committee (IDMC) recommended closure of FOCUS4-D because of a lack of activity. At the final analysis (Aug 1, 2016), 31 patients had had a progression-free survival event (15 with AZD8931 and 16 with placebo). Median progression-free survival was 3.48 months (95% CI 1.51-5.09) in the placebo group and 2.96 months (1.94-5.62) in the AZD8931 group. No progression-free survival benefit of AZD8931 compared with placebo was noted (hazard ratio [HR] 1.10, 95% CI 0.47-3.57; p=0.95). The most common grade 3 adverse event in the AZD8931 group was skin rash (three [20%] of 15 patients with available data vs none of 16 patients in the placebo group), and in the placebo group it was diarrhoea (one [7%] vs one [6%]). No grade 4 adverse events were recorded and no treatment-related deaths were reported. INTERPRETATION: The MAMS trial design for FOCUS4 has shown efficiency and effectiveness in trial outcome delivery, informing the decision to proceed or stop clinical evaluation of a targeted treatment within a molecularly defined cohort of patients. The overarching FOCUS4 trial is now aiming to open a replacement arm in the cohort with all wild-type tumours. FUNDING: Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme, Cancer Research UK, NIHR Clinical Trials Research Network, Health and Care Research Wales, and AstraZeneca. PMID- 29254889 TI - High free triiodothyronine and free-triiodothyronine-to-free-thyroxine ratio levels are associated with metabolic syndrome in a euthyroid population. AB - AIMS: To determine the association between free triiodothyronine (FT3), free thyroxine (FT4) and free-triiodothyronine-to-free-thyroxine ratio (FT3/FT4) levels and Metabolic Syndrome (MetS). MATERIALS AND METHODS: We carried out an analytical cross-sectional study in euthyroid adults of both sexes, who attended the outpatient service of a private clinic in Lima-Peru during the 2014-2016 period. Participants were divided into tertiles (low, intermediate and high) according to their FT3, FT4, and FT3/FT4 ratio values. MetS was defined when three or more metabolic criteria were met by the participants. ROC curves were constructed, and Youden's Index were used to identify the optimal cut-points of each thyroid marker. We elaborated crude/adjusted Poisson regression models to evaluate the association between the thyroid markers and the presence of MetS. The reported association measure was the prevalence ratio (PR) with their respective 95% confidence intervals (95% CI). RESULTS: We analyzed 245 participants, the average age was 38.5 +/- 10.3 years, 29.8% were males, and the prevalence of MetS was 31%. In the adjusted Poisson regression models, the prevalence of MetS was higher among the high FT3 tertile compared to the low tertile (aPR = 2.01; 95% CI: 1.22-3.34). The prevalence of MetS was higher among the intermediate FT3/FT4 ratio tertile and the high FT3/FT4 ratio tertile compared to the low tertile, (aPR = 1.78; 95% CI: 1.02-3.10) and (aPR = 2.80; 95% CI: 1.67-4.72); respectively. The highest areas under the curve (AUC) were found for FT3 and FT3/FT4 ratio with areas of 0.654 (95% CI: 0.58-0.73) and 0.649 (95% CI: 0.57-0.72); respectively. CONCLUSION: Elevated levels of FT3 and FT3/FT4 ratio were associated with MetS in a euthyroid population. PMID- 29254890 TI - Paraoxonase-1 is a better indicator than HDL of Atherosclerosis - A pilot study in North Indian population. AB - OBJECTIVES: The present study aims to evaluate the levels of HDL and Paraoxonase 1 (PON1) and their correlation in atherosclerotic patients with and without diabetic mellitus (DM) as well as in control subjects in Northern Indian population. MATERIALS AND METHODS: We analyzed lipid profiles and Serum PON1 levels by automated analyzer and ELISA, respectively. Study subjects (N = 150) were divided in three groups; Group I: Atherosclerotic patients without DM (N = 50), Group II: Atherosclerotic patients with DM (N = 50); Group III: Controls (N = 50). RESULTS: We found a significantly (p < 0.0001) low levels of HDL-C in Group I (32.2 +/- 7.3) and Group II (36.9 +/- 11.5) as compared to Group III (41.0 +/- 7.1). PON-1 levels were also significantly lower in Group I (60.1 +/- 10.5) and Group II (50.0 +/- 13.9) when compared to Group III (95.0 +/- 12.0). We observed a significant correlation (r = 0.59, p < 0.001) between the levels of PON1 and HDL-C in study subjects. CONCLUSIONS: The reduced levels of HDL and PON 1 and their significant correlation in CAD patients may be associated with the pathogenesis of this disease. Considering HDL as a dependent variable, Paraoxonase-1 is the most important parameter contributing to the total variation in HDL in CAD. PMID- 29254891 TI - Elevated cardiac troponin I, creatine kinase and myoglobin and their relationship with cardiovascular risk factors in patients with type 2 diabetes. AB - BACKGROUND: Elevated cardiac troponin I, Creatine kinase (CK-MB) and Myoglobin levels are observed in the setting of acute myocardial damage. However sub clinical elevations occur in patients with diabetes mellitus. This study was carried out to determine the relationship between the presence of multiple cardiovascular risk factors and the metabolic syndrome and elevations in cardiac markers in patients with type2 diabetes mellitus. SUBJECTS AND METHODS: Consecutive stable out-patients with type2 diabetes mellitus at the University of Port Harcourt Teaching Hospital, Nigeria were recruited. Non-diabetic individuals such as hospital staff and the general public acted as controls. Baseline demographic data collection was done and waist circumference, weight, height and blood pressure were measured. Venous samples were assayed for CTnI, CK-MB and Myoglobin levels using ELISA. Data was analysed using SPSS v 20. RESULTS: There were 188 DM patients, who were older than the 200 control subjects (56.1 +/- 13.1 years and 42.7 +/- 5.7 years, p < 0.001). Mean duration of diabetes was 7.1(5.7) years. Hypertension was present in 59%, 84.6% had dyslipidaemia, while 76.1% had metabolic syndrome. All the cardiac markers were significantly higher in DM patients than controls. The presence of hypertension or dyslipidaemia was not significantly associated with the cardiac markers (p > 0.05 for all), however the DM patients with metabolic syndrome had higher levels of CK-MB and myoglobin but not CTnI than those without. CONCLUSION: Diabetes mellitus is associated with chronic sub-clinical elevation of cardiac markers and this is more in those with multiple cardiovascular risk factors and/or the metabolic syndrome. PMID- 29254893 TI - Development and optimization of a new synthetic process for lorcaserin. AB - A two-step process to synthesize racemic lorcaserin was developed from 2-(4 chlorophenyl)ethanol via formation of bromide or tosylate derivatives. These derivatives were reacted with allylamine in neat conditions to provide pure N-(4 chlorophenethyl)allylammonium chloride. This compound was cyclized in neat conditions using aluminum or zinc chloride to give racemic lorcaserin. After resolution of enantiomers, the wrong enantiomer was racemized and recycled to give new R-lorcaserin. PMID- 29254892 TI - Targeting protein-protein interaction between MLL1 and reciprocal proteins for leukemia therapy. AB - The mixed lineage leukemia protein-1 (MLL1), as a lysine methyltransferase, predominantly regulates the methylation of histone H3 lysine 4 (H3K4) and functions in hematopoietic stem cell (HSC) self-renewal. MLL1 gene fuses with partner genes that results in the generation of MLL1 fusion proteins (MLL1-FPs), which are frequently detected in acute leukemia. In the progress of leukemogenesis, a great deal of proteins cooperate with MLL1 to form multiprotein complexes serving for the dysregulation of H3K4 methylation, the overexpression of homeobox (HOX) cluster genes, and the consequent generation of leukemia. Hence, disrupting the interactions between MLL1 and the reciprocal proteins has been considered to be a new treatment strategy for leukemia. Here, we reviewed potential protein-protein interactions (PPIs) between MLL1 and its reciprocal proteins, and summarized the inhibitors to target MLL1 PPIs. The druggability of MLL1 PPIs for leukemia were also discussed. PMID- 29254894 TI - 2-Methyltetrahydro-3-benzazepin-1-ols - The missing link in SAR of GluN2B selective NMDA receptor antagonists. AB - The NMDA receptor containing GluN2B subunits represents a promising target for the development of drugs for the treatment of various neurological disorders including neurodegenerative diseases. In order to study the role of CH3 and OH moieties trisubstituted tetrahydro-3-benzazepines 4 were designed as missing link between tetra- and disubstituted 3-benzazepines 2 and 5. The synthesis of 4 comprises eight reaction steps starting from alanine. The intramolecular Friedel Crafts acylation to obtain the ketone 12 and the base-catalyzed elimination of trifluoromethanesulfinate (CF3SO2-) followed by NaBH4 reduction represent the key steps. The GluN2B affinity of the cis-configured 3-benzazepin-1-ol cis-4a with a 4-phenylbutyl side chain (Ki = 252 nM) is considerably lower than the GluN2B affinity of (R,R)-2 (Ki = 17 nM) indicating the importance of the phenolic OH moiety for the interaction with the receptor protein. Introduction of an additional CH3 moiety in 2-position led to a slight decrease of GluN2B affinity as can be seen by comparing the affinity data of cis-4a and 5. The homologous phenylpentyl derivative cis-4b shows the highest GluN2B affinity (Ki = 56 nM) of this series of compounds. According to docking studies cis-4a adopts the same binding mode as the cocrystallized ligand ifenprodil-keto 1A and 5 at the interface of the GluN2B and GluN1a subunits. The same crucial H-bonds are formed between the C(O)NH2 moiety of Gln110 within the GluN2B subunit and the protonated amino moiety and the OH moiety of (R,R)-cis-4a. PMID- 29254895 TI - Current knowledge on the nucleotide agonists for the P2Y2 receptor. AB - P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14). P2Y2 receptors are widely expressed and play important roles in multiple functionalities. Diquafosol tetrasodium, known as INS365, which was the first P2Y2 receptor agonists that had been approved in April 2010 and launched in Japan by Santen Pharmaceuticals. Besides, a series of similar agonists for the P2Y2 receptor are undergoing development to cure different diseases related to the P2Y2 receptor. This article illustrated the structure and functions of the P2Y2 receptor and focused on several kinds of agonists about their molecular structures, research progress and chemical synthesis methods. Last but not the least, we summarized the structures-activity relationship (SAR) of agonists for the P2Y2 receptor and expected more efficient agonists for the P2Y2 receptor. PMID- 29254896 TI - Cellular imaging using BODIPY-, pyrene- and phthalocyanine-based conjugates. AB - Fluorescent Probes aimed at absorbing in the blue/green region of the spectrum and emitting in the green/red have been synthesized (as the form of dyads pentads), studied by spectrofluorimetry, and used for cellular imaging. The synthesis of phthalocyanine-pyrene 1 was achieved by cyclotetramerization of pyrenyldicyanobenzene, whereas phthalocyanine-BODIPY 2c was synthesized by Sonogashira coupling between tetraiodophthalocyanine and meso-alkynylBODIPY. The standard four-steps BODIPY synthesis was applied to the BODIPY-pyrene dyad 3 starting from pyrenecarbaldehyde and dimethylpyrrole. 1H, 13C, 19F, 11BNMR, ICP, MS, and UV/Vis spectroscopic analyses demonstrated that 2c is a mixture of BODIPY Pc conjugates corresponding to an average ratio of 2.5 BODIPY per Pc unit, where its bis, tris, tetrakis components could not be separated. Fluorescence emission studies (MUM concentration in THF) showed that the design of the probes allowed excitation of their antenna (pyrene, BODIPY) in the blue/green region of the spectrum, and subsequent transfer to the acceptor platform (BODIPY, phthalocyanine) followed by its emission in the green/red (with up to 140-350 nm overall Stokes shifts). The fluorescent probes were used for cellular imaging of B16F10 melanoma cells upon solubilization in 1% DMSO containing RPMI or upon encapsulation in liposomes (injection method). Probes were used at 1-10 MUM concentrations, cells were fixed with methanol and imaged by biphoton and/or confocal microscopy, showing that probes could achieve the staining of cells membranes and not the nucleus. PMID- 29254897 TI - Characterization of tyrosinase inhibitory constituents from the aerial parts of Humulus japonicus using LC-MS/MS coupled online assay. AB - In the screening of natural products for the development as cosmetic ingredients, the EtOAc-soluble fraction of Humulus japonicus showed tyrosinase inhibitory activity. HPLC-MS/MS coupled online tyrosinase assay of EtOAc-soluble fraction of H. japonicus characterized the twenty-eight constituents including two unknown ones and their tyrosinase inhibitory activity. Fractionation of H. japonicus using various chromatographic techniques yielded thirty-eight compounds. The chemical structures of isolated compounds were identified by spectroscopic analysis. As characterized by HPLC-MS/MS analysis, we isolated twenty-four predicted compounds and further identified two unknown ones, named humulusides A (1) and B (2). Additional ten compounds were also identified by purification. Tyrosinase inhibitory activity of isolated compounds were evaluated, which was closely correlated with the results from HPLC-MS/MS coupled online tyrosinase assay. Consistent with predicted data, two major compounds, trans-N coumaroyltyramine (14) and cis-N-coumaroyltyramine (15) showed tyrosinase inhibition with IC50 values of 40.6 and 36.4 MUM. Taken together, H. japonicus is suggested as whitening ingredient in cosmetic products. In addition, HPLC-MS/MS coupled tyrosinase assay is powerful tool for predicting active compounds with short time and limited amounts, although identification of new compounds and verification of predicted data are also needs to be demonstrated by further experiment. PMID- 29254898 TI - A water-soluble near-infrared fluorescent probe for specific Pd2+ detection. AB - Palladium (Pd) is widely used in chemistry, biology, environmental science etc., and Pd2+ is the most plenitudinous oxidation state of the Pd that can exist under physiological conditions or in living cells, which could have adverse effects on both our health and environment. Thus, it is of great significance to monitor the changes of Pd2+. Hence, a novel near-infrared fluorescent probe M-PD has been developed for selective detection of Pd2+ based on naphthofluorescein in this work. The result demonstrated that M-PD exhibited favorable properties for sensing Pd2+ such as excellent water solubility, high selectivity and sensitivity. And the limit of detection was estimated as 10.8 nM, much lower than the threshold in drugs (5-10 ppm) specified by European Directorate for the Quality Control of Medicines. More importantly, detection and recovery experiments of Pd2+ in aspirin aqoeous solution and soil are satisfactory. In addition, M-PD has also been successfully used for near-infrared fluorescence imaging of Pd2+ in living cells, indicating that the probe has better feasibility and application potential in the determination of Pd2+. PMID- 29254899 TI - Are We Face Experts? AB - According to a widely used theoretical perspective, our everyday experiences lead us to become natural experts at perceiving and recognising human faces. However, there has been considerable debate about this view. We discuss criteria for expertise and show how the debate over face expertise has often missed key points concerning the role and nature of face familiarity. For identity recognition, most of us show only limited expertise with unfamiliar faces. Carefully evaluating the senses in which it is appropriate or inappropriate to assert that we are face experts leads to the conclusion that we are, in effect, familiar face experts. PMID- 29254900 TI - LECT2-associated renal amyloidosis (ALECT2): A case report. PMID- 29254901 TI - The Impact of Adolescent Dating Violence Training for Primary Care Providers. AB - OBJECTIVE: This study presents results from an educational training to increase adolescent dating violence (ADV) screening among primary care clinicians and provides adolescents' perceptions regarding discussing ADV with their clinicians. METHODS: A national dating violence advocacy group provided a training in ADV to 16 clinicians serving an urban health clinic. Knowledge, self-efficacy, and expectations were examined before training, after training, and at a 6-month follow-up. Forty-five adolescent patients of the clinicians were also surveyed. RESULTS: Analysis shows significant increases in clinician knowledge, self efficacy, outcome expectancies, and outcome expectations after training and at the 6-month follow-up. About half of adolescents reported that they would disclose if they were in an abusive relationship and believed that their providers could help them. DISCUSSION: This training successfully improved clinician self-efficacy, outcome expectancies, knowledge, and behavioral capability regarding ADV. Additional research is needed to determine whether the training leads to improved ADV screening and intervention. PMID- 29254902 TI - Qualitative Secondary Analysis: A Case Exemplar. AB - Qualitative secondary analysis (QSA) is the use of qualitative data that was collected by someone else or was collected to answer a different research question. Secondary analysis of qualitative data provides an opportunity to maximize data utility, particularly with difficult-to-reach patient populations. However, qualitative secondary analysis methods require careful consideration and explicit description to best understand, contextualize, and evaluate the research results. In this article, we describe methodologic considerations using a case exemplar to illustrate challenges specific to qualitative secondary analysis and strategies to overcome them. PMID- 29254903 TI - "You are always hiding. It's the worst way to live." Exploring Stigma in African Immigrants Living With HIV in a Large Northwest U.S. Metropolitan Area. AB - African immigrants living in the United States are disproportionately and uniquely affected by HIV. Evidence shows that stigma may contribute to this inequity. Applying a biopsychosocial model of health, our qualitative study explored HIV-related stigma and its impact on African immigrants living with HIV in a large northwestern U.S. metropolitan area. We conducted in-depth, semi structured interviews with 20 African immigrants living with HIV. In the biological health realm, HIV-related stigma contributed to adverse health care environments, disruptions in care, and poor physical health. In the psychological health realm, it was associated with emotional vulnerability, depressive symptoms, and negative coping. In the social health realm, stigma lead to disclosure challenges, isolation, and poor social support. HIV-related stigma was an extensive and pervasive burden for this population. The biopsychosocial model was a helpful lens through which to explore HIV-related stigma and identify opportunities for future research and intervention. PMID- 29254904 TI - Predictive Ability of Individual Items of the Cardiovascular Health Study (CHS) Scale Compared With the Summative Score. AB - OBJECTIVES: To examine the ability of each item of the Fried phenotype of frailty to predict physical limitation and physical performance measures after 4 years, walking speed and hospitalization after 7 years, and mortality after 12 years. DESIGN: Prospective cohort study. SETTING: Community-living older people in Hong Kong SAR, China. PARTICIPANTS: 4000 community-living Chinese men and women aged 65 and older were recruited using stratified sampling so that approximately 33% each would be aged 65-69, 70-74, and 75 and older. Those who were unable to walk independently, had had bilateral hip replacement, or were not competent to give informed consent were excluded. MEASUREMENTS: Information was collected from questionnaire to include sociodemographic and lifestyle data, medical history, cognition, mood, and ability to carry out daily functional tasks. Frailty was assessed using the 5-item Fried phenotype, or Cardiovascular Health Study (CHS) scale. Measurements include grip strength, 6-m walking speed, and chair stand. Length of hospital stay was obtained from the hospital records. Death was ascertained from the Death Registry. STATISTICAL ANALYSIS: Logistic regression was used to analyze the association between individual items and health outcomes, adjusting for age, education, chronic obstructive pulmonary disease, diabetes mellitus, hypertension, heart disease, current smoker, Mini-Mental State Examination score, and depression. The predictive ability of each item was examined using the area under the curve (AUC), and stepwise models were applied to assess the incremental predictive validity. RESULTS: In men, all items of the CHS scale predicted increased risk of physical limitation after 4 years with similar AUC values. The lowest quintile of walking speed and grip strength predicted increased risk of walking speed <0.8 m/s at 4 and 7 years. The other items had variable predictive ability for outcomes. For women, low walking speed and grip strength were the only 2 items that predicted all the adverse outcomes except mortality. When each item was entered into a stepwise model to predict adverse outcomes, low walking speed predicted nearly as well as the combined 5 item CHS. CONCLUSION: The 5-item Fried phenotype in frailty screening in clinical management may be replaced by a single physical performance measure such as walking speed or grip strength, but cut-off values derived from individual populations need to be applied. PMID- 29254905 TI - Mediastinitis as a complication of minimally invasive diagnostic and mediastinal staging techniques. PMID- 29254906 TI - A 6-Week Web-Based Osteoarthritis Treatment Program: Observational Quasi Experimental Study. AB - BACKGROUND: Osteoarthritis (OA) is one of the most common causes of disability, with a burden of disease estimated to increase over time. Joint Academy, a Web based treatment for individuals with clinically verified knee or hip OA, was developed to increase access to and facilitate implementation of evidence-based nonsurgical OA treatment in accordance with international guidelines. OBJECTIVE: The primary aim of this study was to evaluate joint pain, physical function, and health-related quality of life (HRQoL) over time of users of the Joint Academy program. METHODS: We enrolled 350 patients who were recruited online and completed the initial health journal in the 6-week program. We asked patients to complete an eHealth journal and e-questionnaires, including pain level assessed by a numerical rating scale, as well as a physical function evaluation using the 30-second chair-stand test. In addition, we assessed HRQoL using the 3-level version of the EQ-5D. We also asked participants whether they experienced difficulty walking and were afraid of physical activity due to their OA and their desire for surgery. We collected descriptive data and compared pre- versus postintervention data. As a reference group, we included results retrieved from the Swedish well-structured face-to-face self-supportive OA management program Better Management of Patients With Osteoarthritis (BOA). RESULTS: Of the study cohort (n=350 patients; 239 women, mean age 62 years, mean body mass index 27 kg/m2), 71.4% (n=250) completed the program and were included in the study. We used the questionnaires to secure a clinical diagnosis of OA and to establish baseline study values. After 6 weeks of treatment, the change in mean numerical rating scale was larger than the minimal clinical difference (5.4 vs 4.1; P<.001), while physical function increased (from 10.88 to 13.14; P<.001). The percentage of participants having walking difficulties decreased from 81.7% (196/240) to 62.1% (149/240; P<.001), those afraid of being physically active decreased from 22.1% (53/240) to 6.7% (16/240; P<.001), and 22.0% (55/250) reported that they had reduced the amount of OA-related medication. After 6 weeks, 24% (13/54) of those desiring surgery at the start of the program were no longer interested. In addition, the comparison between Joint Academy and the BOA program showed similar levels of pain at 3 months, but suggested greater reduction with the use of Joint Academy due to a higher level of pain at baseline. CONCLUSIONS: The reported data suggest that participation in Joint Academy is associated with a clinically relevant decrease in pain and an increase in physical function and HRQoL, as well as a decreasing fear of physical activity. This innovative Web-based OA treatment is scalable, is population specific, and can reach a large number of individuals with impaired joints who have Internet access. PMID- 29254907 TI - An E-Learning Module to Improve Nongenetic Health Professionals' Assessment of Colorectal Cancer Genetic Risk: Feasibility Study. AB - BACKGROUND: Nongenetic health providers may lack the relevant knowledge, experience, and communication skills to adequately detect familial colorectal cancer (CRC), despite a positive attitude toward the assessment of history of cancer in a family. Specific training may enable them to more optimally refer patients to genetic counseling. OBJECTIVE: The aim of this study was to develop an e-learning module for gastroenterologists and surgeons (in training) aimed at improving attitudes, knowledge, and comprehension of communication skills, and to assess the feasibility of the e-learning module for continued medical education of these specialists. METHODS: A focus group helped to inform the development of a training framework. The e-learning module was then developed, followed by a feasibility test among a group of surgeons-in-training (3rd- and 4th-year residents) and then among gastroenterologists, using pre- and posttest questionnaires. RESULTS: A total of 124 surgeons-in-training and 14 gastroenterologists participated. The e-learning was positively received (7.5 on a scale of 1 to 10). Between pre- and posttest, attitude increased significantly on 6 out of the 10 items. Mean test score showed that knowledge and comprehension of communication skills improved significantly from 49% to 72% correct at pretest to 67% to 87% correct at posttest. CONCLUSIONS: This study shows the feasibility of a problem-based e-learning module to help surgeons-in-training and gastroenterologists in recognizing a hereditary predisposition in patients with CRC. The e-learning led to improvements in attitude toward the assessment of cancer family history, knowledge on criteria for referral to genetic counseling for CRC, and comprehension of communication skills. PMID- 29254908 TI - Factors Influencing Engagement and Behavioral Determinants of Infant Feeding in an mHealth Program: Qualitative Evaluation of the Growing Healthy Program. AB - BACKGROUND: Infant feeding practices, including breastfeeding and optimal formula feeding practices, can play a role in the prevention of childhood obesity. The ubiquity of smartphone ownership among women of childbearing age provides important opportunities for the delivery of low-cost, broad reach parenting interventions delivered by mobile phone (mHealth or mobile health interventions). Little is known about how parents engage with mHealth programs targeting infant feeding and how such programs might influence infant feeding practices. OBJECTIVE: The objectives of this study were to explore participant views on (1) factors influencing engagement with the Growing healthy program, an mHealth program targeting healthy infant feeding practices from birth to 9 months of age, and (2) the ways in which the program influenced behavioral determinants of capability, opportunity, and motivation for breastfeeding and optimal formula feeding behaviors. METHODS: Semistructured, telephone interviews were conducted with a purposeful sample (n=24) of mothers participating in the Growing healthy program. Interviews explored participants' views about engagement with the program and its features, and the ways the program influenced determinants of infant feeding behaviors related to breastfeeding and optimal formula feeding. The interview schedule was informed by the Capability, Opportunity, Motivation, and Behavior (COM-B) model. RESULTS: Participants reported that engagement fluctuated depending on need and the degree to which the program was perceived to fit with existing parenting beliefs and values. Participants identified that the credibility of the program source, the user friendly interface, and tailoring of content and push notifications to baby's age and key transition points promoted engagement, whereas technical glitches were reported to reduce engagement. Participants discussed that the program increased confidence in feeding decisions. For breastfeeding mothers, this was achieved by helping them to overcome doubts about breast milk supply, whereas mothers using formula reported feeling more confident to feed to hunger and satiety cues rather than encouraging infants to finish the bottle. Participants discussed that the program provided around-the-clock, readily accessible, nonjudgmental information and support on infant feeding and helped to reinforce information received by health professionals or encouraged them to seek additional help if needed. Participants reflected that their plans for feeding were typically made before joining the program, limiting the potential for the program to influence this aspect of motivation. Rather, the program provided emotional reassurance to continue with current feeding plans. CONCLUSIONS: Our findings suggest that engagement with the program was influenced by an interplay between the program features and needs of the user. Participants reported that the program enhanced confidence in feeding decisions by providing a 24/7 accessible, expert, nonjudgmental support for infant feeding that complemented health professional advice. It is likely that interventions need to commence during pregnancy to maximize the impact on breastfeeding intentions and plans. PMID- 29254910 TI - An Intervention Delivered by App Instant Messaging to Increase Acceptability and Use of Effective Contraception Among Young Women in Bolivia: Protocol of a Randomized Controlled Trial. AB - BACKGROUND: Unintended pregnancy is associated with numerous poorer health outcomes for both women and their children. Fulfilling unmet need for contraception is essential in avoiding unintended pregnancies, yet millions of women in low- and middle-income countries continue to face obstacles in realizing their fertility desires. In Bolivia, family planning progress has improved in recent decades but lags behind other countries in the region. Unmet need for contraception among women aged 15 to 19 years is estimated to be 38%, with the adolescent fertility rate at 70 per 1000 women. Mobile phones are an established and popular mode in which to deliver health behavior support. The London School of Hygiene & Tropical Medicine and the Centro de Investigacion, Educacion y Servicios in Bolivia have partnered to develop and evaluate a contraceptive behavioral intervention for Bolivian young women delivered by mobile phone. The intervention was developed guided by behavioral science and consists of short instant messages sent through an app over 4 months. OBJECTIVE: The objective of this study is to evaluate the effect of the intervention on young women's use of and attitudes toward the most effective contraceptive methods. METHODS: We will allocate 1310 women aged 16 to 24 years with an unmet need for contraception in a 1:1 ratio to receive the intervention messages or the control messages about trial participation. The messages are sent through the Tu decides app, which contains standard family planning information. Coprimary outcomes are use and acceptability of at least one effective contraceptive method, both measured at 4 months. RESULTS: Recruitment commenced on March 1, 2017 and was completed on July 29, 2017. We estimate that the follow-up period will end in January 2018. CONCLUSIONS: This trial will evaluate the effect of the intervention on young women's use of and attitudes toward the (nonpermanent) effective contraception methods available in Bolivia. TRIAL REGISTRATION: ClinicalTrials.gov NCT02905526; https://clinicaltrials.gov/ct2/show/NCT02905526 (Archived by WebCite at http://www.webcitation.org/6vT0yIFfN). PMID- 29254909 TI - Direct to Public Peer Support and e-Therapy Program Versus Information to Aid Self-Management of Depression and Anxiety: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Regardless of geography or income, effective help for depression and anxiety only reaches a small proportion of those who might benefit from it. The scale of the problem suggests a role for effective, safe, anonymized public health-driven Web-based services such as Big White Wall (BWW), which offer immediate peer support at low cost. OBJECTIVE: Using Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) methodology, the aim of this study was to determine the population reach, effectiveness, cost-effectiveness, and barriers and drivers to implementation of BWW compared with Web-based information compiled by UK's National Health Service (NHS, NHS Choices Moodzone) in people with probable mild to moderate depression and anxiety disorder. METHODS: A pragmatic, parallel-group, single-blind randomized controlled trial (RCT) is being conducted using a fully automated trial website in which eligible participants are randomized to receive either 6 months access to BWW or signposted to the NHS Moodzone site. The recruitment of 2200 people to the study will be facilitated by a public health engagement campaign involving general marketing and social media, primary care clinical champions, health care staff, large employers, and third sector groups. People will refer themselves to the study and will be eligible if they are older than 16 years, have probable mild to moderate depression or anxiety disorders, and have access to the Internet. RESULTS: The primary outcome will be the Warwick-Edinburgh Mental Well-Being Scale at 6 weeks. We will also explore the reach, maintenance, cost effectiveness, and barriers and drivers to implementation and possible mechanisms of actions using a range of qualitative and quantitative methods. CONCLUSIONS: This will be the first fully digital trial of a direct to public online peer support program for common mental disorders. The potential advantages of adding this to current NHS mental health services and the challenges of designing a public health campaign and RCT of two digital interventions using a fully automated digital enrollment and data collection process are considered for people with depression and anxiety. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 12673428; http://www.controlled trials.com/ISRCTN12673428/12673428 (Archived by WebCite at http://www.webcitation.org/6uw6ZJk5a). PMID- 29254911 TI - Association Between a Wider Availability of Health Information and Health Care Utilization in Vietnam: Cross-Sectional Study. AB - BACKGROUND: The rapid and widespread development of mass media sources including the Internet is occurring worldwide. Users are being confronted with a flood of health information through a wide availability of sources. Studies on how the availability of health information has triggered users' interest in utilizing health care services remain limited within the Vietnamese population. OBJECTIVE: This study examined the associations between the wider availability of sources for health information and health care utilization in Vietnam after adjusting for potential confounding variables. METHODS: The data for this study were drawn from a cross-sectional study conducted over a 6-month period in Hue, a city in central Vietnam. The participants were 993 randomly selected adults aged between 18 and 60 years. Information was collected through face-to-face interviews on the types of information sources that were consulted, including traditional media (television), Internet, and health education courses, as well as the impact of such information on health care use (emergency department visits, hospitalizations, doctor visits). Multivariable logistic regression analyses were performed at a 95% confidence level. RESULTS: The prevalence of watching television, using the Internet, and attending health education courses to obtain health information were 50.9% (505/993), 32.9% (327/993), and 8.7% (86/993), respectively. After further adjustments for self-reported health status, the presence of health insurance, and monthly income, respondents who watched television and used the Internet to obtain health information were 1.7 times more likely to visit a doctor (television: adjusted odds ratio [AOR] 1.69, 95% CI 1.30 2.19; Internet: AOR 1.64, 95% CI 1.23-2.19), and also significantly associated with inpatient hospitalization (P=.003). CONCLUSIONS: The use of widely available mass media sources (eg, television and the Internet) to obtain health information was associated with higher health care utilization. How this interest in health related information can be used so that it will have a beneficial effect on care seeking behavior should be a topic of concern to further health promotion in developing countries. PMID- 29254912 TI - Mindfulness-Based Cognitive Therapy for Cancer Patients Delivered via Internet: Qualitative Study of Patient and Therapist Barriers and Facilitators. AB - BACKGROUND: The number of patients living with cancer is growing, and a substantial number of patients suffer from psychological distress. Mindfulness based interventions (MBIs) seem effective in alleviating psychological distress. Unfortunately, several cancer patients find it difficult, if not impossible, to attend a group-based course. Internet-based MBIs (eMBIs) such as Internet-based mindfulness-based cognitive therapy (eMBCT) may offer solutions. However, it is yet to be studied what facilitators and barriers cancer patients experience during eMBCT. OBJECTIVE: This study aimed to explore facilitators and barriers of individual asynchronous therapist-assisted eMBCT as experienced by both patients and therapists. METHODS: Patients with heterogeneous cancer diagnoses suffering from psychological distress were offered eMBCT. This 9-week intervention mirrored the group-based MBCT protocol and included weekly asynchronous written therapist feedback. Patients were granted access to a website that contained the eMBCT protocol and a secured inbox, and they were asked to practice and fill out diaries on which the therapist provided feedback. In total, 31 patients participated in an individual posttreatment interview on experienced facilitators and barriers during eMBCT. Moreover, eight therapists were interviewed. The data were analyzed with qualitative content analysis to identify barriers and facilitators in eMBCT. RESULTS: Both patients and therapists mentioned four overarching themes as facilitators and barriers: treatment setting (the individual and Internet-based nature of the treatment), treatment format (how the treatment and its guidance were organized and delivered), role of the therapist, and individual patient characteristics. CONCLUSIONS: The eMBCT provided flexibility in when, where, and how patients and therapists engage in MBCT. Future studies should assess how different eMBCT designs could further improve barriers that were found. PMID- 29254913 TI - Influence of Social Determinants, Lifestyle, Emotional Well-Being and the Use of Unconventional Therapies in Breast Cancer Progression in a Cohort of Women in Barcelona: Protocol for the DAMA Cohort. AB - BACKGROUND: Breast cancer continues to be the most commonly diagnosed cancer in women. Breast cancer survivors face numerous problems, especially after completing the first year of intense treatment. We present the protocol for an ongoing study to analyze the impact of a series of factors on breast cancer survival related to lifestyle, emotional well-being, and use of complementary and alternative medicine (CAM). OBJECTIVE: We aim to analyze the influence of social determinants, lifestyle changes, emotional well-being, and use of CAM in the progression of breast cancer in women diagnosed with breast cancer between 2003 and 2013 in Barcelona, Spain. METHODS: We will perform a mixed cohort study (prospective and retrospective) of women diagnosed with breast cancer, created using a convenience sample in which we study the evolution of the disease (relapse, death, or remaining disease-free). Once identified, we sent the women information about the study and an informed consent form that they are required to sign in order to participate; a total of 2235 women were recruited. We obtained the following information from all participants: sociodemographic profile via a phone interview, and a self-administered survey of information about the study's objectives (lifestyles, emotional well-being, health care services, and the use of CAM). Lastly, we examined clinical records to obtain data on the tumor at the time of diagnosis, the treatment received, the occurrence of relapses (if any), and the tumor typology. We present data on the women's social profile based on descriptive data obtained from the telephone interview (welcome survey). RESULTS: Based on the welcome survey, which was completed by 2712 women, 14.42% (391/2712) of respondents were <50 years of age, 45.50% (1234/2712) were between 50 and 65 years of age, and 40.08% (1087/2712) were >65 years of age. A total of 43.69% (1185/2712) belonged to the highest social classes (I and II), 31.27% (848/2712) to the middle class (III), and 23.49% (637/2712) to the working classes (IV and V). Approximately 22.71% (616/2712) lived alone, 38.31% (1039/2712) lived with one person, and 38.97% (1057/2712) lived with two or more people. CONCLUSIONS: We obtained information from a large cohort of women, but this study has limitations related to the convenience sampling strategy, one of which is reduced representativeness. Conversely, being a self-administered survey, the study introduces biases, especially from respondents that answered on paper. However, the information that the study provides will serve as the basis for designing future interventions aimed at improving the knowledge gaps indicated for women with breast cancer. PMID- 29254914 TI - Methods for Evaluating the Content, Usability, and Efficacy of Commercial Mobile Health Apps. AB - Commercial mobile apps for health behavior change are flourishing in the marketplace, but little evidence exists to support their use. This paper summarizes methods for evaluating the content, usability, and efficacy of commercially available health apps. Content analyses can be used to compare app features with clinical guidelines, evidence-based protocols, and behavior change techniques. Usability testing can establish how well an app functions and serves its intended purpose for a target population. Observational studies can explore the association between use and clinical and behavioral outcomes. Finally, efficacy testing can establish whether a commercial app impacts an outcome of interest via a variety of study designs, including randomized trials, multiphase optimization studies, and N-of-1 studies. Evidence in all these forms would increase adoption of commercial apps in clinical practice, inform the development of the next generation of apps, and ultimately increase the impact of commercial apps. PMID- 29254915 TI - Text Simplification Using Consumer Health Vocabulary to Generate Patient-Centered Radiology Reporting: Translation and Evaluation. AB - BACKGROUND: Radiology reporting is a clinically oriented form of documentation that reflects critical information for patients about their health care processes. Realizing its importance, many medical institutions have started providing radiology reports in patient portals. The gain, however, can be limited because of medical language barriers, which require a way for customizing these reports for patients. The open-access, collaborative consumer health vocabulary (CHV) is a terminology system created for such purposes and can be the basis of lexical simplification processes for clinical notes. OBJECTIVE: The aim of this study was to examine the comprehensibility and suitability of CHV in simplifying radiology reports for consumers. This was done by characterizing the content coverage and the lexical similarity between the terms in the reports and the CHV preferred terms. METHODS: The overall procedure was divided into the following two main stages: (1) translation and (2) evaluation. The translation process involved using MetaMap to link terms in the reports to CHV concepts. This is followed by replacing the terms with CHV-preferred terms using the concept names and sources table (MRCONSO) in the Unified Medical Language System (UMLS) Metathesaurus. In the second stage, medical terms in the reports and general terms that are used to describe medical phenomena were selected and evaluated by comparing the words in the original reports with the translated ones. The evaluation includes measuring the content coverage, investigating lexical similarity, and finding trends in missing concepts. RESULTS: Of the 792 terms selected from the radiology reports, 695 of them could be mapped directly to CHV concepts, indicating a content coverage of 88.5%. A total of 51 of the concepts (53%, 51/97) that could not be mapped are names of human anatomical structures and regions, followed by 28 anatomical descriptions and pathological variations (29%, 28/97). In addition, 12 radiology techniques and projections represented 12% of the unmapped concepts, whereas the remaining six concepts (6%, 12/97) were physiological descriptions. The rate of lexical similarity between the CHV preferred terms and the terms in the radiology reports was approximately 72.6%. CONCLUSIONS: The CHV covered a high percentage of concepts found in the radiology reports, but unmapped concepts are associated with areas that are commonly found in radiology reporting. CHV terms also showed a high percentage of lexical similarity with terms in the reports, which contain a myriad of medical jargon. This suggests that many CHV terms might not be suitable for lay consumers who would not be facile with radiology-specific vocabulary. Therefore, further patient-centered content changes are needed of the CHV to increase its usefulness and facilitate its integration into consumer-oriented applications. PMID- 29254916 TI - A Smartphone App (AfyaData) for Innovative One Health Disease Surveillance from Community to National Levels in Africa: Intervention in Disease Surveillance. AB - BACKGROUND: We describe the development and initial achievements of a participatory disease surveillance system that relies on mobile technology to promote Community Level One Health Security (CLOHS) in Africa. OBJECTIVE: The objective of this system, Enhancing Community-Based Disease Outbreak Detection and Response in East and Southern Africa (DODRES), is to empower community-based human and animal health reporters with training and information and communication technology (ICT)-based solutions to contribute to disease detection and response, thereby complementing strategies to improve the efficiency of infectious disease surveillance at national, regional, and global levels. In this study, we refer to techno-health as the application of ICT-based solutions to enhance early detection, timely reporting, and prompt response to health events in human and animal populations. METHODS: An EpiHack, involving human and animal health experts as well as ICT programmers, was held in Tanzania in 2014 to identify major challenges facing early detection, timely reporting, and prompt response to disease events. This was followed by a project inception workshop in 2015, which brought together key stakeholders, including policy makers and community representatives, to refine the objectives and implementation plan of the DODRES project. The digital ICT tools were developed and packaged together as the AfyaData app to support One Health disease surveillance. Community health reporters (CHRs) and officials from animal and human health sectors in Morogoro and Ngorongoro districts in Tanzania were trained to use the AfyaData app. The AfyaData supports near- to real-time data collection and submission at both community and health facility levels as well as the provision of feedback to reporters. The functionality of the One Health Knowledge Repository (OHKR) app has been integrated into the AfyaData app to provide health information on case definitions of diseases of humans and animals and to synthesize advice that can be transmitted to CHRs with next step response activities or interventions. Additionally, a WhatsApp social group was made to serve as a platform to sustain interactions between community members, local government officials, and DODRES team members. RESULTS: Within the first 5 months (August-December 2016) of AfyaData tool deployment, a total of 1915 clinical cases in livestock (1816) and humans (99) were reported in Morogoro (83) and Ngorongoro (1832) districts. CONCLUSIONS: These initial results suggest that the DODRES community-level model creates an opportunity for One Health engagement of people in their own communities in the detection of infectious human and animal disease threats. Participatory approaches supported by digital and mobile technologies should be promoted for early disease detection, timely reporting, and prompt response at the community, national, regional, and global levels. PMID- 29254917 TI - Research advances on the origin, evolution and genetic diversity of Chinese native sheep breeds. AB - China has a rich resource of native sheep breeds, some of which possess specific traits such as prolificacy, excellent lamb pelts, multiple horns, fat tails and strong stress resistance. All these have been the focus of research. However, there is still a controversy about the origin of sheep breeds and a lack of comprehensive and systematic studies on genetic diversity of Chinese native sheep. In this review, we summarize recent research advances on the origin, evolution and genetic diversity of Chinese native sheep breeds based on paternal, maternal, and autosomal markers. This review will provide useful information for the conservation and utilization of sheep genetic resources, breeding of new sheep breeds and the sustainable development of Chinese sheep industry. PMID- 29254918 TI - Progress in the molecular and genetic modification breeding of beef cattle in China. AB - The studies of beef cattle breeding in China have been greatly improved with the rapid development of the international beef cattle industrialization. The beef cattle breeding technologies have rapidly transformed from traditional breeding to molecular marker-assisted breeding, genomic selection and genetic modification breeding. Hundreds of candidate genes and molecular markers associated with growth, meat quality, reproduction performance and diseases resistance have been identified, and some of them have already been used in cattle breeding. Genes and molecular markers associated with growth and development are focused on the growth hormone, muscle regulatory factors, myostatin and insulin-like growth factors. Meat quality is mediated by fatty acid transport and deposition related signals, calpains and calpain system, muscle regulatory factors and muscle growth regulation pathways. Reproduction performance is regulated by GnRH-FSH-LH, growth differentiation factor 9, prolactin receptor and forkhead box protein O1. Disease resistance is modulated by the major histocompatibility complex gene family, toll like receptors, mannose-binding lectin and interferon gene signals. In this review, we summarize the most recent progress in beef cattle breeding in marker assisted selection, genome-wide selection and genetic modification breeding, aiming to provide a reference for further genetic breeding research of beef cattle in China. PMID- 29254919 TI - Progress in the physiological and genetic mechanisms underlying the high prolificacy of the Erhualian pig. AB - The Erhualian pig, originally distributed in the Taihu area, is well known for its universally high fertility. Previous studies have found that high ovulation numbers, low embryo mortality and high uterine volumes are important physiological characteristics underlying the high prolificacy of the Erhualian pig. Although candidate genes such as follicle-stimulating hormone beta (FSHbeta) and several quantitative trait loci (QTLs) on chromosome 2, 6, 7, 8, 12, 13 and 15 have been reported to affect the litter size in the Erhualian pig, the key genes related to high prolificacy remain poorly understood. In this review, we summarize the recent research progress in the physiological and genetic mechanisms underlying the high prolificacy of the Erhualian pig. First we review the role of high ovulation numbers, low embryo mortality rates and high uterine volumes in the formation of the high litter size in the Erhualian pig. Then we summarize candidate genes and QTLs for the high litter size detected by classical strategies, as well as by genomic strategies. Moreover, we describe the methods to investigate the causative genes of the high prolificacy through integrative analysis of multi-omics data including genomics, transcriptomics, proteomics and functional genomics. This review will provide insights to understand the molecular basis of the high prolificacy in the Erhualian pig. PMID- 29254920 TI - Genetic breeding of silkworms: from traditional hybridization to molecular design. AB - Sericulture is one of the great inventions of the Chinese people and has become an important cultural feature of China. As China is the long-lasting center of silk production, genetic breeding of silkworm was highly developed historically, and has formed a comprehensive system for breeding and preservation of new varieties. However, silkworm breeding reached a bottleneck recently, because most of the traditional genetic resources have been utilized and silkworm strains have become homogeneous. Meanwhile, sericulture in China meets huge challenges in the 21st century. In recent years, with the development and rapid application of molecular biology, genomics, transgene and genome editing, silkworm genetic breeding has entered a new era. In this review, we summarize the development of silkworm genetic breeding, especially the progress and perspective of transgene and genome editing in genetic engineering of silkworms. We also discuss the future development of silkworm genetic breeding. PMID- 29254921 TI - Application of genomic selection in farm animal breeding. AB - Genomic selection (GS) has become a widely accepted method in animal breeding to genetically improve economic traits. With the declining costs of high-density SNP chips and next-generation sequencing, GS has been applied in dairy cattle, swine, poultry and other animals and gained varying degrees of success. Currently, major challenges in GS studies include further reducing the cost of genome-wide SNP genotyping and improving the predictive accuracy of genomic estimated breeding value (GEBV). In this review, we summarize various methods for genome-wide SNP genotyping and GEBV prediction, and give a brief introduction of GS in livestock and poultry breeding. This review will provide a reference for further implementation of GS in farm animal breeding. PMID- 29254922 TI - Advances on microRNA in regulating mammalian skeletal muscle development. AB - MicroRNA (miRNA) is a class of short non-coding RNA, which is about 22 bp in length. In mammals, miRNA exerts its funtion through binding with the 3 degrees UTR region of target genes and inhibiting their translation. Skeletal muscle development is a complex event, including: proliferation, migration and differentiation of skeletal muscle stem cells; proliferation, differentiation and fusion of myocytes; as well as hypertrophy, energy metabolism and conversion of muscle fiber types. The miRNA plays important roles in all processes of skeletal muscle development through targeting the key factors of different stages. Herein we summarize the miRNA related to muscle development, providing a better understanding of the skeletal muscle development. PMID- 29254923 TI - Progress in long non-coding RNAs in animals. AB - Long non-coding RNAs (lncRNAs) are important transcripts that are more than 200 nucleotides in length, and distribute extensively in animal and plant genomes. Accumulated studies demonstrate that lncRNAs play critical roles in biological processes related to embryogenesis, muscle development, lipid deposition and immune responses. They assist protein complexes in translocating to appropriate locations and participate in regulating gene activation and inactivation. Recently, rapid progress of lncRNA research is emerging, largely due to molecular biological technologies and information developed in the human genome project and the Encyclopedia of DNA Elements (ENCODE) project. For example, a dwarf open reading frame (DWORF) encoded by an annotated lncRNA was reported to activate the SERCA pump. Moreover, small regulatory polypeptide of amino acid response (SPAR) encoded by lncRNA LINC00961 was found to regulate muscle regeneration. These new results have revealed a novel model that lncRNA regulates biological processes using its small peptide product. In this review, we summarize the characteristics, databases, biological functions and molecular regulatory models, as well as research interests of lncRNAs in the future. PMID- 29254924 TI - Genetic and epigenetic regulation of PPARgamma during adipogenesis. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) is the master regulator of adipogenesis and adipose tissue development. It also plays crucial roles in many other biological processes, including lipid and glucose metabolism and energy homeostasis. Recently, evidence has been accumulating that the PPARgamma gene is not only genetically regulated, but also epigenetically regulated by DNA methylation, histone modification, non-coding RNA and chromosome remodeling. In this review, we summarize the advances in the genetic and epigenetic regulation of the PPARgamma gene during adipogenesis, and discuss future research directions and trends for the study of its regulation. PMID- 29254925 TI - Genome editing technologies drive the development of pig genetic improvement. AB - Nuclease-mediated genome editing technologies contribute to the rapid advances in life sciences via the ability to edit the genomes within living cells, and present a new era for porcine genetic improvement. In this review, we introduce the development of various genomic editing technologies, particularly CRISPR/Cas9 strategies and characteristics of various naturally occurring and artificially engineered CRISPR enzymes. Also, we summarize progress in pig genetic improvement mediated by genome editing, especially those associated with meat quality traits and anti-virus resistance. We highlight the challenges in the implementation of pig genetic improvement and the prospects of pig genetic breeding based on genome editing technologies. PMID- 29254926 TI - Screening weight related genes of velvet antlers by whole genome re-sequencing. AB - The velvet antler is a special organ that has important biological significance for deer, and its growth is a complicated biological metabolism process. Growing evidence suggests that genetics factors play essential roles in the weight of velvet antlers. In this study, we investigated five sika deer (Cervus nippon) populations under the same feeding condition, and screened genetic variations in the 100 samples (including 50 heavy and 50 light velvet antler weight samples) by whole genome re-sequencing. The results showed that 94 genetic variations were related to the velvet antler weight, among which two single nucleotide polymorphism (SNP) sites were located on the exon regions of OAS2 and ALYREF/THOC4, respectively. Furthermore, ALYREF/THOC4 is highly expressed in the velvet antler. The biological functions of these genetic variations were highly related to the growth and development of deer velvet antlers. Collectively, we screened genes related to the velvet antler weight in sika deer populations by whole genome re-sequencing and identified 94 sites as candidate genetic variations related to the velvet antler weight. We hope that it will contribute to further mechanistic studies of velvet antler development and weight variations. PMID- 29254927 TI - Transcriptome sequencing identifies potential regulatory genes involved in chicken eggshell brownness. AB - Brown eggs are popular in many countries, and consumers regard eggshell brownness as an important indicator of egg quality. Brown eggshell color is controlled by polygene. However, the responsible genes and detailed molecular mechanisms regulating eggshell brownness have not been defined. In the present study, we applied the RNA-seq technology to analyze the transcriptome data of the shell gland epithelium of hens and investigated the candidate genes associated with eggshell brownness. The results indicated that 8461 genes were expressed in the shell gland epithelium, of which 34 genes were differentially expressed in hens laying dark vs. light brown eggs. Functional analysis revealed that two genes, ovotransferrin (TF) and heat-shock protein 70 (HSP70), as well as the oxidative phosphorylation pathway were involved in the synthesis and transport of protoporphyrin IX, which might influence the formation of eggshell brownness and result in different shades of brown. PMID- 29254928 TI - Childhood and Adolescent Adversity and Cardiometabolic Outcomes: A Scientific Statement From the American Heart Association. AB - Adverse experiences in childhood and adolescence, defined as subjectively perceived threats to the safety or security of the child's bodily integrity, family, or social structures, are known to be associated with cardiometabolic outcomes over the life course into adulthood. This American Heart Association scientific statement reviews the scientific literature on the influence of childhood adversity on cardiometabolic outcomes that constitute the greatest public health burden in the United States, including obesity, hypertension, type 2 diabetes mellitus, and cardiovascular disease. This statement also conceptually outlines pathways linking adversity to cardiometabolic health, identifies evidence gaps, and provides suggestions for future research to inform practice and policy. We note that, despite a lack of objective agreement on what subjectively qualifies as exposure to childhood adversity and a dearth of prospective studies, substantial evidence documents an association between childhood adversity and cardiometabolic outcomes across the life course. Future studies that focus on mechanisms, resiliency, and vulnerability factors would further strengthen the evidence and provide much-needed information on targets for effective interventions. Given that childhood adversities affect cardiometabolic health and multiple health domains across the life course, interventions that ameliorate these initial upstream exposures may be more appropriate than interventions remediating downstream cardiovascular disease risk factor effects later in life. PMID- 29254929 TI - Inhibition of JAK-STAT Signaling Suppresses Pathogenic Immune Responses in Medium and Large Vessel Vasculitis. AB - BACKGROUND: Giant cell arteritis, a chronic autoimmune disease of the aorta and its large branches, is complicated by aneurysm formation, dissection, and arterial occlusions. Arterial wall dendritic cells attract CD4+ T cells and macrophages to form prototypic granulomatous infiltrates. Vasculitic lesions contain a diverse array of effector T cells that persist despite corticosteroid therapy and sustain chronic, smoldering vasculitis. Transmural inflammation induces microvascular neoangiogenesis and results in lumen-occlusive intimal hyperplasia. We have examined whether persistent vessel wall inflammation is maintained by lesional T cells, including the newly identified tissue-resident memory T cells, and whether such T cells are sensitive to the cytokine-signaling inhibitor tofacitinib, a Janus kinase (JAK) inhibitor targeting JAK3 and JAK1. METHODS: Vascular inflammation was induced in human arteries engrafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with giant cell arteritis. Mice carrying inflamed human arteries were treated with tofacitinib or vehicle. Vasculitic arteries were examined for gene expression (reverse transcription polymerase chain reaction), protein expression (immunohistochemistry), and infiltrating cell populations (flow cytometry). RESULTS: Tofacitinib effectively suppressed innate and adaptive immunity in the vessel wall. Lesional T cells responded to tofacitinib with reduced proliferation rates (<10%) and minimal production of the effector molecules interferon-gamma, interleukin-17, and interleukin-21. Tofacitinib disrupted adventitial microvascular angiogenesis, reduced outgrowth of hyperplastic intima, and minimized CD4+CD103+ tissue-resident memory T cells. CONCLUSIONS: Cytokine signaling dependent on JAK3 and JAK1 is critically important in chronic inflammation of medium and large arteries. The JAK inhibitor tofacitinib effectively suppresses tissue-resident memory T cells and inhibits core vasculitogenic effector pathways. PMID- 29254930 TI - Genetic Predisposition to High Blood Pressure and Lifestyle Factors: Associations With Midlife Blood Pressure Levels and Cardiovascular Events. AB - BACKGROUND: High blood pressure (BP) is a major risk factor for cardiovascular diseases (CVDs), the leading cause of mortality worldwide. Both heritable and lifestyle risk factors contribute to elevated BP levels. We aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse BP genetic profile and its effect on CVD risk. METHODS: We constructed a genetic risk score for high BP by using 314 published BP loci in 277 005 individuals without previous CVD from the UK Biobank study, a prospective cohort of individuals aged 40 to 69 years, with a median of 6.11 years of follow-up. We scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. We examined the association between tertiles of genetic risk and tertiles of lifestyle score with BP levels and incident CVD by using linear regression and Cox regression models, respectively. RESULTS: Healthy lifestyle score was strongly associated with BP (P<10-320) for systolic and diastolic BP and CVD events regardless of the underlying BP genetic risk. Participants with a favorable in comparison with an unfavorable lifestyle (bottom versus top tertile lifestyle score) had 3.6, 3.5, and 3.6 mm Hg lower systolic BP in low, middle, and high genetic risk groups, respectively (P for interaction=0.0006). Similarly, favorable in comparison with unfavorable lifestyle showed 30%, 31%, and 33% lower risk of CVD among participants in low, middle, and high genetic risk groups, respectively (P for interaction=0.99). CONCLUSIONS: Our data further support population-wide efforts to lower BP in the population via lifestyle modification. The advantages and disadvantages of disclosing genetic predisposition to high BP for risk stratification needs careful evaluation. PMID- 29254932 TI - Nup62-mediated nuclear import of p63 in squamous cell carcinoma. PMID- 29254931 TI - Psychosocial development in survivors of childhood differentiated thyroid carcinoma: a cross-sectional study. AB - OBJECTIVE: The impact of childhood differentiated thyroid carcinoma (DTC) on psychosocial development has not yet been studied. The aim of this study was to evaluate the achievement of psychosocial developmental milestones in long-term survivors of childhood DTC. DESIGN AND METHODS: Survivors of childhood DTC diagnosed between 1970 and 2013 were included. Reasons for exclusion were age <18 or >35 years at follow-up, a follow-up period <5 years or diagnosis with DTC as a second malignant neoplasm. Survivors gathered peer controls of similar age and sex (n = 30). A comparison group non-affected with cancer (n = 508) and other childhood cancer survivors (CCS) were also used to compare psychosocial development. To assess the achievement of psychosocial milestones (social, autonomy and psychosexual development), the course of life questionnaire (CoLQ) was used. RESULTS: We included 39 survivors of childhood DTC (response rate 83.0%, mean age at diagnosis 15.6 years, and mean age at evaluation 26.1 years). CoLQ scores did not significantly differ between survivors of childhood DTC and the two non-affected groups. CoLQ scores of childhood DTC survivors were compared to scores of other CCS diagnosed at similar ages (n = 76). DTC survivors scored significantly higher on social development than other CCS, but scores were similar on autonomy and psychosexual developmental scales. CONCLUSIONS: Survivors of childhood DTC showed similar development on social, autonomy, and psychosexual domains compared to non-affected individuals. Social development was slightly more favorable in DTC survivors than in other CCS, but was similar on autonomy and psychosexual domains. PMID- 29254933 TI - No Association between Organochlorine Concentrations in Adipose Tissue and Survival after Non-Hodgkin Lymphoma. AB - Background: Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world. Involvement of organochlorines has been proposed in disease etiology. No study has investigated organochlorine exposure in relation to survival after a NHL diagnosis.Methods: In a survivor cohort consisting of 232 NHL cases from the Danish Diet, Cancer and Health cohort, we examined the association between adipose tissue organochlorine concentrations [polychlorinated biphenyls (PCBs) and pesticides] and subsequent survival, using Cox proportional hazards models.Results: We found no statistically significant association between organochlorine concentrations and subsequent survival. If anything, there was a nonsignificant tendency toward an inverse association with PCBs, but not pesticides.Conclusions: In conclusion, the current study does not support an increased risk of death among NHL patients with high tissue concentrations of organochlorines.Impact: This is the first study to investigate adipose organochlorine concentrations and survival after a NHL diagnosis. Cancer Epidemiol Biomarkers Prev; 27(2); 224-6. (c)2017 AACR. PMID- 29254934 TI - Research Strategies for Nutritional and Physical Activity Epidemiology and Cancer Prevention. AB - Very large international and ethnic differences in cancer rates exist, are minimally explained by genetic factors, and show the huge potential for cancer prevention. A substantial portion of the differences in cancer rates can be explained by modifiable factors, and many important relationships have been documented between diet, physical activity, and obesity, and incidence of important cancers. Other related factors, such as the microbiome and the metabolome, are emerging as important intermediary components in cancer prevention. It is possible with the incorporation of newer technologies and studies including long follow-up and evaluation of effects across the life cycle, additional convincing results will be produced. However, several challenges exist for cancer researchers; for example, measurement of diet and physical activity, and lack of standardization of samples for microbiome collection, and validation of metabolomic studies. The United States National Cancer Institute convened the Research Strategies for Nutritional and Physical Activity Epidemiology and Cancer Prevention Workshop on June 28-29, 2016, in Rockville, Maryland, during which the experts addressed the state of the science and areas of emphasis. This current paper reflects the state of the science and priorities for future research. Cancer Epidemiol Biomarkers Prev; 27(3); 233-44. (c)2017 AACR. PMID- 29254936 TI - Prediagnostic Antibodies to Serum p53 and Subsequent Colorectal Cancer. AB - Background: The presence of circulating antibodies to the p53 tumor suppressor protein is a potential early detection colorectal cancer biomarker. However, studies of prediagnostic measures of p53 seropositivity in relation to colorectal cancer risk are limited.Methods: We conducted a nested case-control study of serum p53 autoantibodies and risk of colorectal cancer within the Cancer Prevention Study-II Nutrition Cohort. Among cohort participants who were cancer free at the time of blood collection, 392 were subsequently diagnosed with colorectal cancer over 11 years of follow-up. Two controls were matched to each case on birth date, blood draw date, race, and sex. Autoantibodies to p53 were detected in 41 of the 392 cases (10.5%) and 49 of the 774 controls (6.3%).Results: Participants who were seropositive for p53 antibodies before diagnosis were more likely to be subsequently diagnosed with colorectal cancer [RR = 1.77; 95% confidence interval (CI), 1.12-2.78]. This association was strongest within 3 years of diagnosis (RR = 2.26; 95% CI, 1.06-4.83). An association was also suggested when colorectal cancer was diagnosed 4 to <6 years after p53 measurement (RR = 1.84; 95% CI, 0.89-3.79), but not 6 or more years later (RR = 1.15; 95% CI, 0.44-2.99).Conclusions: If these results are confirmed, serum p53 antibodies may be useful on a panel of early detection markers for colorectal cancer.Impact: Individuals who were seropositive for p53 antibodies were twice as likely to develop colorectal cancer within the next 3 years compared with those who were seronegative. This marker is a good candidate for inclusion on an early detection marker panel for colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(2); 219-23. (c)2017 AACR. PMID- 29254935 TI - "Future-Proofing" Blood Processing for Measurement of Circulating miRNAs in Samples from Biobanks and Prospective Clinical Trials. AB - Background: Quantifying circulating nucleic acids is an important new approach to cancer diagnosis/monitoring.Methods: We compared the suitability of serum versus plasma for measuring miRNAs using qRT-PCR and assessed how preanalytic variables that can affect circulating tumor DNA (ctDNA) quantification in plasma also influence miRNA levels.Results: Across 62 blood-derived specimens, plasma samples in EDTA, Streck-DNA, and Streck-RNA tubes showed significantly higher Ct values for multiple housekeeping miRNAs, compared with serum samples. For the EDTA plasma tubes, this difference was only seen when including the high-speed centrifugation protocol used to optimize ctDNA extraction. In plasma samples derived from blood stored at room temperature for up to 14 days (conditions that typically apply to samples processed for biobanking), levels of endogenous housekeeping miRNAs gradually increased, in parallel with the hemolysis marker hsa-miR-451a, consistent with release from blood cells/platelets. It was necessary to normalize levels of the housekeeping miRNAs to those of hsa-miR 451a, to obtain the stable values needed for referencing test miRNA levels.Conclusions: Our data indicate that plasma samples prepared for ctDNA extraction are suboptimal for miRNA quantification and require the incorporation of multiple data normalization steps. For prospective studies designed to measure both miRNAs and ctDNA, the most suitable approach would be to obtain both serum (for miRNAs) and plasma (for ctDNA). If only plasma can be collected, we recommend an initial low-speed centrifugation step, followed by aliquoting the supernatant into parallel samples, one for direct miRNA quantification, and the other for a further high-speed centrifugation step to optimize ctDNA retrieval.Impact: These recommendations will help "future-proof" clinical studies in which quantification of circulating miRNAs is a component. Cancer Epidemiol Biomarkers Prev; 27(2); 208-18. (c)2017 AACR. PMID- 29254937 TI - Bisphosphonate Use and Risk of Recurrence, Second Primary Breast Cancer, and Breast Cancer Mortality in a Population-Based Cohort of Breast Cancer Patients. AB - Background: Studies of bisphosphonate use and breast cancer recurrence have produced conflicting results. Analyses of large adjuvant trials suggest that bisphosphonates reduce recurrence risk only in postmenopausal women.Methods: We assessed the effect of noncancer treatment-related bisphosphonate use on breast cancer outcomes in a population-based prognostic cohort of women with early-stage invasive breast cancer (n = 1,813; median follow-up = 11.8 years). Using medical record, interview, and cancer registry data, information was assembled on risk factors, cancer treatment, medication use, and outcomes. Statistical analyses used Cox proportional hazards regression models.Results: Bisphosphonate use was associated with a significantly decreased risk of a breast cancer event [locoregional/distant recurrence or second primary breast cancer; HR ever use, 0.65; 95% confidence interval (CI), 0.47-0.90]. Reduced risks were observed in both pre/peri and postmenopausal women, in both ER-negative and ER-positive breast cancers, and for both earlier and later recurrences. Bisphosphonate use was also associated with a significantly decreased risk of breast cancer mortality (HR, 0.40; 95% CI, 0.23-0.69).Conclusions: Bisphosphonate use was associated with a reduction in risk of breast cancer events and improved breast cancer-specific survival in women with early-stage breast cancer. We hypothesize that the benefit of bisphosphonates on breast cancer outcomes may be present primarily in women with low bone density and regardless of menopausal status.Impact: Our findings suggest further consideration of bone density status as a modifier of bisphosphonate's potential beneficial benefits on breast cancer outcomes is warranted. Cancer Epidemiol Biomarkers Prev; 27(2); 165-73. (c)2017 AACR. PMID- 29254938 TI - Association of Pancreatic Cancer Susceptibility Variants with Risk of Breast Cancer in Women of European and African Ancestry. AB - Background: Pancreatic cancer mutation signatures closely resemble breast cancer, suggesting that both cancers may have common predisposition mechanisms that may include commonly inherited SNPs.Methods: We examined 23 genetic variants known to be associated with pancreatic cancer as breast cancer risk factors in the Root genome-wide association study (GWAS; 1,657 cases and 2,029 controls of African diaspora) and GAME-ON/DRIVE GWAS (16,003 cases and 41,335 controls of European ancestry).Results: None of the pancreatic cancer susceptibility variants were individually associated with breast cancer risk after adjustment for multiple testing (at alpha = 0.002) in the two populations. In Root GWAS, a change by one SD in the polygenic risk score (PRS) was not significantly associated with breast cancer. In addition, we did not observe a trend in the relationship between PRS percentiles and breast cancer risk.Conclusions: The association between reported pancreatic cancer genetic susceptibility variants and breast cancer development in women of African or European ancestry is likely weak, if it does exist.Impact: Known GWAS-derived susceptibility variants of pancreatic cancer do not explain its shared genetic etiology with breast cancer. Cancer Epidemiol Biomarkers Prev; 27(1); 116-8. (c)2017 AACR. PMID- 29254940 TI - Navigating individual and collective interests in medical ethics. PMID- 29254939 TI - Gunshot bullet embolisation in the middle cerebral artery. AB - Bullet embolism (BE) is a rare phenomenon following a gunshot wound. A middle cerebral artery BE was detected in a 36-year-old male patient following a perforating left thoracic gunshot wound without obvious cranial injury. This paper discusses a case of BE in the cranial circulation in conjunction with a review of the relevant literature. PMID- 29254941 TI - No country for old men: on mentoring in medicine, by David Loxterkamp. PMID- 29254943 TI - Transcription rate strongly affects splicing fidelity and cotranscriptionality in budding yeast. AB - The functional consequences of alternative splicing on altering the transcription rate have been the subject of intensive study in mammalian cells but less is known about effects of splicing on changing the transcription rate in yeast. We present several lines of evidence showing that slow RNA polymerase II elongation increases both cotranscriptional splicing and splicing efficiency and that faster elongation reduces cotranscriptional splicing and splicing efficiency in budding yeast, suggesting that splicing is more efficient when cotranscriptional. Moreover, we demonstrate that altering the RNA polymerase II elongation rate in either direction compromises splicing fidelity, and we reveal that splicing fidelity depends largely on intron length together with secondary structure and splice site score. These effects are notably stronger for the highly expressed ribosomal protein coding transcripts. We propose that transcription by RNA polymerase II is tuned to optimize the efficiency and accuracy of ribosomal protein gene expression, while allowing flexibility in splice site choice with the nonribosomal protein transcripts. PMID- 29254942 TI - Transcription factor activity rhythms and tissue-specific chromatin interactions explain circadian gene expression across organs. AB - Temporal control of physiology requires the interplay between gene networks involved in daily timekeeping and tissue function across different organs. How the circadian clock interweaves with tissue-specific transcriptional programs is poorly understood. Here, we dissected temporal and tissue-specific regulation at multiple gene regulatory layers by examining mouse tissues with an intact or disrupted clock over time. Integrated analysis uncovered two distinct regulatory modes underlying tissue-specific rhythms: tissue-specific oscillations in transcription factor (TF) activity, which were linked to feeding-fasting cycles in liver and sodium homeostasis in kidney; and colocalized binding of clock and tissue-specific transcription factors at distal enhancers. Chromosome conformation capture (4C-seq) in liver and kidney identified liver-specific chromatin loops that recruited clock-bound enhancers to promoters to regulate liver-specific transcriptional rhythms. Furthermore, this looping was remarkably promoter-specific on the scale of less than 10 kilobases (kb). Enhancers can contact a rhythmic promoter while looping out nearby nonrhythmic alternative promoters, confining rhythmic enhancer activity to specific promoters. These findings suggest that chromatin folding enables the clock to regulate rhythmic transcription of specific promoters to output temporal transcriptional programs tailored to different tissues. PMID- 29254944 TI - Conserved non-AUG uORFs revealed by a novel regression analysis of ribosome profiling data. AB - Upstream open reading frames (uORFs), located in transcript leaders (5' UTRs), are potent cis-acting regulators of translation and mRNA turnover. Recent genome wide ribosome profiling studies suggest that thousands of uORFs initiate with non AUG start codons. Although intriguing, these non-AUG uORF predictions have been made without statistical control or validation; thus, the importance of these elements remains to be demonstrated. To address this, we took a comparative genomics approach to study AUG and non-AUG uORFs. We mapped transcription leaders in multiple Saccharomyces yeast species and applied a novel machine learning algorithm (uORF-seqr) to ribosome profiling data to identify statistically significant uORFs. We found that AUG and non-AUG uORFs are both frequently found in Saccharomyces yeasts. Although most non-AUG uORFs are found in only one species, hundreds have either conserved sequence or position within Saccharomyces uORFs initiating with UUG are particularly common and are shared between species at rates similar to that of AUG uORFs. However, non-AUG uORFs are translated less efficiently than AUG-uORFs and are less subject to removal via alternative transcription initiation under normal growth conditions. These results suggest that a subset of non-AUG uORFs may play important roles in regulating gene expression. PMID- 29254946 TI - Ventricular Tachycardia Ablation in the Elderly: An International Ventricular Tachycardia Center Collaborative Group Analysis. AB - BACKGROUND: Successful ventricular tachycardia (VT) ablation is associated with improved survival in patients with heart failure. However, the safety and efficacy of VT ablation in the elderly, a population with higher competing nonsudden death risk and comorbidities, have not been well defined. METHODS AND RESULTS: The International Ventricular Tachycardia Center Collaborative Study Group registry of 2061 patients who underwent VT ablation at 12 international centers was analyzed. Kaplan-Meier analysis was used to estimate survival of patients >=70 years with and without VT recurrence. Of the 2049 patients who met inclusion criteria, 681 (33%) patients were >=70 years of age (mean age, 75+/-4 years). Among these, 92% were men, 71% had ischemic VT, and 42% had VT storm at presentation. Mean (+/-SD) left ventricular ejection fraction was 30+/-11%. Compared with patients <70 years, patients >=70 years had higher in-hospital (4.4% versus 2.3%; P=0.01) and 1-year mortality (15% versus 11%; P=0.002) but a similar incidence of VT recurrence at 1 year (26% versus 25%; P=0.74) and time to VT recurrence (280 versus 289 days; P=0.20). Absence of VT recurrence during follow-up was strongly associated with improved survival in patients >=70 years. CONCLUSION: VT ablation in the elderly is feasible and reasonably safe with a modestly higher in-hospital and 1-year mortality, with similar rates of VT recurrence at 1 year compared with younger patients. Successful VT ablation, that is, lack of VT recurrence, is strongly associated with improved survival even in this elderly subgroup. PMID- 29254947 TI - Ablation of Rotor Domains Effectively Modulates Dynamics of Human: Long-Standing Persistent Atrial Fibrillation. AB - BACKGROUND: In human long-standing persistent atrial fibrillation, rotors potentially explain atrial fibrillation maintenance, but their ablation remains controversial. We aimed to explore original phase/frequency mapping methods to locate rotors and track changes induced by their ablation. METHODS AND RESULTS: Thirteen patients with long-standing persistent atrial fibrillation (duration, 12 72 months) underwent phase/frequency mapping (Hilbert/Fourier transforms; CARTO Finder) of the left and right atria (PentaRay catheter). A rotor domain was defined as an area displaying at least 3 consecutive rotations. Ablation was performed by circumferential pulmonary vein isolation plus linear ablation of extrapulmonary rotor domains. We identified 19 rotor domains in 10 patients (1.8+/-1.1 per patient; 7 in the right atrium versus 12 in the left atrium; 15 extrapulmonary). Overall, rotor domains (9.2+/-2.2 rotations) displayed higher frequency of activation (6.41 Hz; 95% confidence interval, 6.24-6.57) than nonrotor domains (6.17 Hz; 95% confidence interval, 6.1-6.23; P=0.021), with interatrial frequency gradients established by the spatial location of the rotor domain (P=0.016). Fibrillatory conduction was suggested as a decrease in the frequency of the slower atria after ablation close to main interatrial conduction fascicles (P=0.035). Ablation of rotor domains (ablation line, 3.5+/-0.9 cm) effectively decreased the frequency of activation in both ipsilateral and contralateral atria (P<0.05 for both), whereas ablation of nonrotor domains did not. Acute conversion to sinus rhythm was observed in 2 patients after ablation of rotor domains. At 1-year follow-up, 70% remained in sinus rhythm (85% out-of antiarrhythmic drugs). CONCLUSIONS: Rotor domains appropriately explain long standing persistent atrial fibrillation physiology at its frequency content. Their ablation effectively modifies dynamics on restricted ablation. PMID- 29254948 TI - Ventricular Tachycardia Ablation: Are We in a New Age? PMID- 29254949 TI - Rotational Drivers in Atrial Fibrillation: Are Multiple Techniques Circling Similar Mechanisms? PMID- 29254945 TI - Age of First Arrhythmic Event in Brugada Syndrome: Data From the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 Patients. AB - BACKGROUND: Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE. METHODS AND RESULTS: A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter-defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (<16 years) and elderly patients (>70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9+/-14.8; range, 0.27-84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1+/-13.2 versus 39.4+/-15.0 years; P<0.001). In adult patients (>=16 years), women experienced AE 6.5 years later than men (P=0.003). Whites and Asians exhibited their AE at the same median age (43 years). CONCLUSIONS: SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE. PMID- 29254950 TI - Natural language processing: put your model where your mouth is. PMID- 29254952 TI - Toward an understanding of the protein interaction network of the human liver. PMID- 29254951 TI - Landscape of nuclear transport receptor cargo specificity. AB - Nuclear transport receptors (NTRs) recognize localization signals of cargos to facilitate their passage across the central channel of nuclear pore complexes (NPCs). About 30 different NTRs constitute different transport pathways in humans and bind to a multitude of different cargos. The exact cargo spectrum of the majority of NTRs, their specificity and even the extent to which active nucleocytoplasmic transport contributes to protein localization remains understudied because of the transient nature of these interactions and the wide dynamic range of cargo concentrations. To systematically map cargo-NTR relationships in situ, we used proximity ligation coupled to mass spectrometry (BioID). We systematically fused the engineered biotin ligase BirA* to 16 NTRs. We estimate that a considerable fraction of the human proteome is subject to active nuclear transport. We quantified the specificity and redundancy in NTR interactions and identified transport pathways for cargos. We extended the BioID method by the direct identification of biotinylation sites. This approach enabled us to identify interaction interfaces and to discriminate direct versus piggyback transport mechanisms. Data are available via ProteomeXchange with identifier PXD007976. PMID- 29254954 TI - History and contemporary significance of the Rhynie cherts-our earliest preserved terrestrial ecosystem. AB - The Rhynie cherts Unit is a 407 million-year old geological site in Scotland that preserves the most ancient known land plant ecosystem, including associated animals, fungi, algae and bacteria. The quality of preservation is astonishing, and the initial description of several plants 100 years ago had a huge impact on botany. Subsequent discoveries provided unparalleled insights into early life on land. These include the earliest records of plant life cycles and fungal symbioses, the nature of soil microorganisms and the diversity of arthropods. Today the Rhynie chert (here including the Rhynie and Windyfield cherts) takes on new relevance, especially in relation to advances in the fields of developmental genetics and Earth systems science. New methods and analytical techniques also contribute to a better understanding of the environment and its organisms. Key discoveries are reviewed, focusing on the geology of the site, the organisms and the palaeoenvironments. The plants and their symbionts are of particular relevance to understanding the early evolution of the plant life cycle and the origins of fundamental organs and tissue systems. The Rhynie chert provides remarkable insights into the structure and interactions of early terrestrial communities, and it has a significant role to play in developing our understanding of their broader impact on Earth systems.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254955 TI - A review of active hot-spring analogues of Rhynie: environments, habitats and ecosystems. AB - The Lower Devonian Rhynie chert formed as silica sinter entombed an early terrestrial ecosystem. Silica sinter precipitates only from water flowing from alkali-chloride hot springs and geysers, the surface expression of crustal-scale geothermal systems that form low-sulfidation mineral deposits in the shallow subsurface. Active alkali-chloride hot springs at Yellowstone National Park create a suite of geothermally influenced environments; vent pools, sinter aprons, run-off streams, supra-apron terrace pools and geothermal wetlands that are habitats for modern hot-spring ecosystems. The plant-rich chert, which makes Rhynie internationally famous, probably formed in low-temperature environments at the margins of a sinter apron where frequent flooding by geothermal water and less frequent flooding by river waters created ephemeral to permanent wetland conditions. Here, the plants and associated microbes and animals would be immersed in waters with elevated temperature, brackish salinity, high pH and a cocktail of phytotoxic elements which created stresses that the fossil ecosystem must have tolerated. The environment excluded coeval mesophytic plants, creating a low-diversity hot-spring flora. Comparison with Yellowstone suggests the Rhynie plants were preadapted to their environment by life in more common and widespread environments with elevated salinity and pH such as coastal marshes, salt lakes, estuaries and saline seeps.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254956 TI - Palaeoecology and palaeophytogeography of the Rhynie chert plants: further evidence from integrated analysis of in situ and dispersed spores. AB - The remarkably preserved Rhynie chert plants remain pivotal to our understanding of early land plants. The extraordinary anatomical detail they preserve is a consequence of exceptional preservation, by silicification, in the hot-springs environment they inhabited. However, this has prompted questions as to just how typical of early land plants the Rhynie chert plants really are. Some have suggested that they were highly adapted to the unusual hot-springs environment and are unrepresentative of 'normal' plants of the regional flora. New quantitative analysis of dispersed spore assemblages from the stratigraphical sequence of the Rhynie outlier, coupled with characterization of the in situ spores of the Rhynie chert plants, permits investigation of their palaeoecology and palaeophytogeography. It is shown that the Rhynie inland intermontane basin harboured a relatively diverse flora with only a small proportion of these plants actually inhabiting the hot-springs environment. However, the flora of the Rhynie basin differed from coeval lowland floodplain deposits on the same continent, as it was less diverse, lacked some important spore groups and contained some unique elements. At least some of the Rhynie plants (e.g. Horneophyton lignieri) existed outside the hot-springs environment, inhabiting the wider basin, and were indeed palaeogeographically widespread. They probably existed in the hot-springs environment because they were preadapted to this unstable and harsh setting.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254957 TI - Feeding strategies in arthropods from the Rhynie and Windyfield cherts: ecological diversification in an early non-marine biota. AB - The key to understanding fossil ecosystems is to understand the life habits of long extinct organisms. Yet, as direct observations are no longer possible, morphological details are usually the only available data source. One important aspect of lifestyle is feeding strategies, which can be inferred from morphological structures in comparison with those of extant relatives. The Lower Devonian Rhynie and Windyfield cherts preserve even minute structures to a high degree of detail, which allows investigation of the functional morphology of structures possibly involved in feeding. In this contribution, the feeding structures of different arthropods from the Rhynie and Windyfield cherts are described and the corresponding feeding strategies of the animals are discussed. This overview illustrates that in this early non-marine biota, a wide range of feeding strategies already existed.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254958 TI - Terrestrial invertebrates in the Rhynie chert ecosystem. AB - The Early Devonian Rhynie and Windyfield cherts remain a key locality for understanding early life and ecology on land. They host the oldest unequivocal nematode worm (Nematoda), which may also offer the earliest evidence for herbivory via plant parasitism. The trigonotarbids (Arachnida: Trigonotarbida) preserve the oldest book lungs and were probably predators that practiced liquid feeding. The oldest mites (Arachnida: Acariformes) are represented by taxa which include mycophages and predators on nematodes today. The earliest harvestman (Arachnida: Opiliones) includes the first preserved tracheae, and male and female genitalia. Myriapods are represented by a scutigeromorph centipede (Chilopoda: Scutigeromorpha), probably a cursorial predator on the substrate, and a putative millipede (Diplopoda). The oldest springtails (Hexapoda: Collembola) were probably mycophages, and another hexapod of uncertain affinities preserves a gut infill of phytodebris. The first true insects (Hexapoda: Insecta) are represented by a species known from chewing (non-carnivorous?) mandibles. Coprolites also provide insights into diet, and we challenge previous assumptions that several taxa were spore-feeders. Rhynie appears to preserve a largely intact community of terrestrial animals, although some expected groups are absent. The known fossils are (ecologically) consistent with at least part of the fauna found around modern Icelandic hot springs.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254959 TI - Antheridial development in the moss Physcomitrella patens: implications for understanding stem cells in mosses. AB - Stem cells self-renew and produce precursor cells that differentiate to become specialized cell types. Land plants generate several types of stem cells that give rise to most organs of the plant body and whose characters determine the body organization. The moss Physcomitrella patens forms eight types of stem cells throughout its life cycle. Under gametangium-inducing conditions, multiple antheridium apical stem cells are formed at the tip of the gametophore and each antheridium apical stem cell divides to form an antheridium. We found that the gametophore apical stem cell, which typically forms leaf and stem tissues, changes to become a new type of stem cell, which we term the antheridium initial stem cell. This antheridium initial stem cell produces multiple antheridium apical stem cells, resulting in a cluster of antheridia at the tip of gametophore. This is the first report of a land plant stem cell directly producing another type of stem cell during normal development. Notably, the antheridium apical stem cells are distally produced from the antheridium initial stem cell, similar to the root cap stem cells of vascular plants, suggesting the use of similar molecular mechanisms and a possible evolutionary relationship.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254960 TI - Organs and tissues of Rhynie chert plants. AB - The Early Devonian Rhynie chert and the nearby Windyfield chert contain the oldest in situ preserved terrestrial ecosystem. Two of the seven species of anatomically preserved land plants had naked axes, one an axis with a more or less regular pattern of short-longitudinal ribs, two species had spiny axes and one species had small leaf-like appendages. All plants mainly consist of parenchymatous tissues. In some species, conducting elements comprise uniformly thickened thick-walled cells resembling hydroids of larger bryophytes, whereas others have real tracheids with annular and/or spiral secondary wall thickenings. True phloem has never been demonstrated but in all species the thick-walled water conducting cells are encircled by a zone of thin-walled cells without intercellular spaces. The cortex is differentiated into two or three zones and forms the major part of the axes; in one species the cells of the middle cortex are sclerified. Some species have a hypodermis. In all species the epidermis is covered by a well-developed cuticle. Sporangia are known from all species. Sporangia are spindle-shaped, lobed or kidney-shaped and attached terminally or laterally with a short stalk. Gametophytes of four species have been described. Gametophytes are unisexual, isomorphic but much smaller than the sporophytes.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254961 TI - The origin and early evolution of vascular plant shoots and leaves. AB - The morphology of plant fossils from the Rhynie chert has generated longstanding questions about vascular plant shoot and leaf evolution, for instance, which morphologies were ancestral within land plants, when did vascular plants first arise and did leaves have multiple evolutionary origins? Recent advances combining insights from molecular phylogeny, palaeobotany and evo-devo research address these questions and suggest the sequence of morphological innovation during vascular plant shoot and leaf evolution. The evidence pinpoints testable developmental and genetic hypotheses relating to the origin of branching and indeterminate shoot architectures prior to the evolution of leaves, and demonstrates underestimation of polyphyly in the evolution of leaves from branching forms in 'telome theory' hypotheses of leaf evolution. This review discusses fossil, developmental and genetic evidence relating to the evolution of vascular plant shoots and leaves in a phylogenetic framework.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254962 TI - Evolution and palaeophysiology of the vascular system and other means of long distance transport. AB - Photolithotrophic growth on land using atmospheric CO2 inevitably involves H2O vapour loss. Embryophytes greater than or equal to 100 mm tall are homoiohydric and endohydric with mass flow of aqueous solution through the xylem in tracheophytes. Structural details in Rhynie sporophytes enable modelling of the hydraulics of H2O supply to the transpiring surface, and the potential for gas exchange with the Devonian atmosphere. Xylem carrying H2O under tension involves programmed cell death, rigid cell walls and embolism repair; fossils provide little evidence on these functions other than the presence of lignin. The phenylalanine ammonia lyase essential for lignin synthesis came from horizontal gene transfer. Rhynie plants lack endodermes, limiting regulation of the supply of soil nutrients to shoots. The transfer of organic solutes from photosynthetic sites to growing and storage tissues involves mass flow through phloem in extant tracheophytes. Rhynie plants show little evidence of phloem; possible alternatives for transport of organic solutes are discussed. Extant examples of the arbuscular mycorrhizas found in Rhynie plants exchange soil-derived nutrients (especially P) for plant-derived organic matter, involving bidirectional mass flow along the hyphae. The aquatic cyanobacteria and the charalean Palaeonitella at Rhynie also have long-distance (relative to the size of the organism) transport.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254963 TI - The evolution of the stomatal apparatus: intercellular spaces and sporophyte water relations in bryophytes-two ignored dimensions. AB - Cryo-scanning electron microscopy shows that nascent intercellular spaces (ICSs) in bryophytes are liquid-filled, whereas these are gas-filled from the outset in tracheophytes except in the gametophytes of Lycopodiales. ICSs are absent in moss gametophytes and remain liquid-filled in hornwort gametophytes and in both generations in liverworts. Liquid is replaced by gas following stomatal opening in hornworts and is ubiquitous in moss sporophytes even in astomate taxa. New data on moss water relations and sporophyte weights indicate that the latter are homiohydric while X-ray microanalysis reveals an absence of potassium pumps in the stomatal apparatus. The distribution of ICSs in bryophytes is strongly indicative of very ancient multiple origins. Inherent in this scenario is either the dual or triple evolution of stomata. The absence, in mosses, of any relationship between increases in sporophyte biomass and stomata numbers and absences, suggests that CO2 entry through the stomata, possible only after fluid replacement by gas in the ICSs, makes but a minor contribution to sporophyte nutrition. Save for a single claim of active regulation of aperture dimensions in mosses, all other functional and structural data point to the sporophyte desiccation, leading to spore discharge, as the primeval role of the stomatal apparatus.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254964 TI - Exploring the geochemical distribution of organic carbon in early land plants: a novel approach. AB - Terrestrialization depended on the evolution of biosynthetic pathways for biopolymers including lignin, cutin and suberin, which were concentrated in specific tissues, layers or organs such as the xylem, cuticle and roots on the submillimetre scale. However, it is often difficult, or even impossible especially for individual cells, to resolve the biomolecular composition of the different components of fossil plants on such a scale using the well-established coupled techniques of gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry. Here, we report the application of techniques for surface analysis to investigate the composition of Rhynia gwynne-vaughanii X ray photoelectron spectroscopy of two different spots (both 300 um * 600 um) confirmed the presence of carbon. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) revealed 'chemical maps' (imaging mode with 300 nm resolution) of aliphatic and aromatic carbon in the intact fossil that correlate with the vascular structures observed in high-resolution optical images. This study shows that imaging ToF-SIMS has value for determining the location of the molecular components of fossil embryophytes while retaining structural information that will help elucidate how terrestrialization shaped the early evolution of land plant cell wall biochemistry.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254965 TI - Fungi and fungal interactions in the Rhynie chert: a review of the evidence, with the description of Perexiflasca tayloriana gen. et sp. nov.?. AB - The Lower Devonian Rhynie chert is one of the most important rock deposits yielding comprehensive information on early continental plant, animal and microbial life. Fungi are especially abundant among the microbial remains, and include representatives of all major fungal lineages except Basidiomycota. This paper surveys the evidence assembled to date of fungal hyphae, mycelial cords and reproductive units (e.g. spores, sporangia, sporocarps), and presents examples of fungal associations and interactions with land plants, other fungi, algae, cyanobacteria and animals from the Rhynie chert. Moreover, a small, chytrid-like organism that occurs singly, in chain-like, linear arrangements, planar assemblages and three-dimensional aggregates of less than 10 to [Formula: see text] individuals in degrading land plant tissue in the Rhynie chert is formally described, and the name Perexiflasca tayloriana proposed for the organism. Perexiflasca tayloriana probably colonized senescent or atrophied plant parts and participated in the process of biological degradation. The fungal fossils described to date from the Rhynie chert constitute the largest body of structurally preserved evidence of fungi and fungal interactions from any rock deposit, and strongly suggest that fungi played important roles in the functioning of the Early Devonian Rhynie ecosystem.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254966 TI - New insights into the evolutionary history of Fungi from a 407 Ma Blastocladiomycota fossil showing a complex hyphal thallus. AB - Zoosporic fungi are key saprotrophs and parasites of plants, animals and other fungi, playing important roles in ecosystems. They comprise at least three phyla, of which two, Chytridiomycota and Blastocladiomycota, developed a range of thallus morphologies including branching hyphae. Here we describe Retesporangicus lyonii gen. et sp. nov., an exceptionally well preserved fossil, which is the earliest known to produce multiple sporangia on an expanded hyphal network. To better characterize the fungus we develop a new method to render surfaces from image stacks generated by confocal laser scanning microscopy. Here, the method helps to reveal thallus structure. Comparisons with cultures of living species and character state reconstructions analysed against recent molecular phylogenies of 24 modern zoosporic fungi indicate an affinity with Blastocladiomycota. We argue that in zoosporic fungi, kinds of filaments such as hyphae, rhizoids and rhizomycelium are developmentally similar structures adapted for varied functions including nutrient absorption and anchorage. The fossil is the earliest known type to develop hyphae which likely served as a saprotrophic adaptation to patchy resource availability. Evidence from the Rhynie chert provides our earliest insights into the biology of fungi and their roles in the environment. It demonstrates that zoosporic fungi were already diverse in 407 million-year-old terrestrial ecosystems.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254968 TI - Bilaterally symmetric axes with rhizoids composed the rooting structure of the common ancestor of vascular plants. AB - There are two general types of rooting systems in extant land plants: gametophyte rhizoids and sporophyte root axes. These structures carry out the rooting function in the free-living stage of almost all land plant gametophytes and sporophytes, respectively. Extant vascular plants develop a dominant, free-living sporophyte on which roots form, with the exception of a small number of taxa that have secondarily lost roots. However, fossil evidence indicates that early vascular plants did not develop sporophyte roots. We propose that the common ancestor of vascular plants developed a unique rooting system-rhizoidal sporophyte axes. Here we present a synthesis and reinterpretation of the rootless sporophytes of Horneophyton lignieri, Aglaophyton majus, Rhynia gwynne-vaughanii and Nothia aphylla preserved in the Rhynie chert. We show that the sporophyte rooting structures of all four plants comprised regions of plagiotropic (horizontal) axes that developed unicellular rhizoids on their underside. These regions of axes with rhizoids developed bilateral symmetry making them distinct from the other regions which were radially symmetrical. We hypothesize that rhizoidal sporophyte axes constituted the rooting structures in the common ancestor of vascular plants because the phylogenetic positions of these plants span the origin of the vascular lineage.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254967 TI - Nutrient acquisition by symbiotic fungi governs Palaeozoic climate transition. AB - Fossil evidence from the Rhynie chert indicates that early land plants, which evolved in a high-CO2 atmosphere during the Palaeozoic Era, hosted diverse fungal symbionts. It is hypothesized that the rise of early non-vascular land plants, and the later evolution of roots and vasculature, drove the long-term shift towards a high-oxygen, low CO2 climate that eventually permitted the evolution of mammals and, ultimately, humans. However, very little is known about the productivity of the early terrestrial biosphere, which depended on the acquisition of the limiting nutrient phosphorus via fungal symbiosis. Recent laboratory experiments have shown that plant-fungal symbiotic function is specific to fungal identity, with carbon-for-phosphorus exchange being either enhanced or suppressed under superambient CO2 By incorporating these experimental findings into a biogeochemical model, we show that the differences in these symbiotic nutrient acquisition strategies could greatly alter the plant-driven changes to climate, allowing drawdown of CO2 to glacial levels, and altering the nature of the rise of oxygen. We conclude that an accurate depiction of plant fungal symbiotic systems, informed by high-CO2 experiments, is key to resolving the question of how the first terrestrial ecosystems altered our planet.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254969 TI - Fertile Prototaxites taiti: a basal ascomycete with inoperculate, polysporous asci lacking croziers. AB - The affinities of Prototaxites have been debated ever since its fossils, some attaining tree-trunk proportions, were discovered in Canadian Lower Devonian rocks in 1859. Putative assignations include conifers, red and brown algae, liverworts and fungi (some lichenised). Detailed anatomical investigation led to the reconstruction of the type species, P. logani, as a giant sporophore (basidioma) of an agaricomycete (= holobasidiomycete), but evidence for its reproduction remained elusive. Tissues associated with P. taiti in the Rhynie chert plus charcoalified fragments from southern Britain are investigated here to describe the reproductive characters and hence affinities of Prototaxites Thin sections and peels (Pragian Rhynie chert, Aberdeenshire) were examined using light and confocal microscopy; Pridoli and Lochkovian charcoalified samples (Welsh Borderland) were liberated from the rock and examined with scanning electron microscopy. Prototaxites taiti possessed a superficial hymenium comprising an epihymenial layer, delicate septate paraphyses, inoperculate polysporic asci lacking croziers and a subhymenial layer composed predominantly of thin-walled hyphae and occasional larger hyphae. Prototaxites taiti combines features of extant Taphrinomycotina (Neolectomycetes lacking croziers) and Pezizomycotina (epihymenial layer secreted by paraphyses) but is not an ancestor of the latter. Brief consideration is given to its nutrition and potential position in the phylogeny of the Ascomycota.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254971 TI - Correction to 'Variation in recombination frequency and distribution across eukaryotes: patterns and processes'. PMID- 29254972 TI - Correction to 'Acquisition and metabolism of carbon in the Ochrophyta other than diatoms'. PMID- 29254970 TI - Changing expressions: a hypothesis for the origin of the vascular plant life cycle. AB - Plant life cycles underwent fundamental changes during the initial colonization of the land in the Early Palaeozoic, shaping the direction of evolution. Fossils reveal unanticipated diversity, including new variants of meiotic cell division and leafless gametophytes with mycorrhizal-like symbioses, rhizoids, vascular tissues and stomata. Exceptional fossils from the 407-Ma Rhynie chert (Scotland) play a key role in unlocking this diversity. These fossils are reviewed against progress in our understanding of the plant tree of life and recent advances in developmental genetics. Combining data from different sources sheds light on a switch in life cycle that gave rise to the vascular plants. One crucial step was the establishment of a free-living sporophyte from one that was an obligate matrotroph borne on the gametophyte. It is proposed that this difficult evolutionary transition was achieved through expansion of gene expression primarily from the gametophyte to the sporophyte, establishing a now extinct life cycle variant that was more isomorphic than heteromorphic. These changes also linked for the first time in one developmental system rhizoids, vascular tissues and stomata, putting in place the critical components that regulate transpiration and forming a physiological platform of primary importance to the diversification of vascular plants.This article is part of a discussion meeting issue 'The Rhynie cherts: our earliest terrestrial ecosystem revisited'. PMID- 29254973 TI - Dedication: Nigel Trewin (1944-2017). PMID- 29254974 TI - Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome? Targeting the Right Antigens in the Right Patients. AB - Recent advances in genomic sequencing and bioinformatics have empowered a revolution in immuno-oncology that has led to numerous unambiguous demonstrations of spontaneous and therapy-induced T-cell responses in patients against a subset of immunogenic tumor-specific somatic mutations known as neoantigens. These findings raise the exciting possibility that patients could be therapeutically treated with personalized vaccines against the mutations expressed by their own tumor. A central challenge for the broader clinical application of this approach will be to define the best antigens to target, to determine the subset of patients most likely to derive significant clinical benefit, and, finally, to discover both the best method of vaccine delivery and the optimal time in the disease course to do so. A growing number of translational immunologists believe that these challenges can be overcome and this perspective will discuss strategies to achieve this. PMID- 29254975 TI - Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Can Natural Killer and CD8 T Cells Switch Jobs? AB - Natural killer (NK) cells are components of innate immunity mediating defense at early times after viral infections. Their cytokine production and cell-mediated cytotoxicity functions overlap those of CD8 T cells elicited later during primary adaptive immune responses, but the populations are distinguished by their basal states and activating receptors as well as the kinetics of their responses. Demonstration of long-lived NK cells has led to speculation on the potential for inducing these to contribute to immunological memory. Conversely, activated CD8 T cells can acquire responses to innate cytokines and, as a result, have the potential to contribute to innate immunity. These observations beg the question: what is required to be a player in innate and adaptive immunity? PMID- 29254976 TI - Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Vaccination Strategies Based on NK Cell and ILC Memory. AB - Studies over the last decade have decisively shown that innate immune natural killer (NK) cells exhibit enhanced long-lasting functional responses following a single activation event. With the increased recognition of memory and memory-like properties of NK cells, questions have arisen with regard to their ability to effectively mediate vaccination responses in humans. Moreover, recently discovered innate lymphoid cells (ILCs) could also potentially exhibit memory like functions. Here, we review different forms of NK cell memory, and speculate about the ability of these cells and ILCs to meaningfully contribute to vaccination responses. PMID- 29254978 TI - Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? Natural Killer Cells in Vaccination. AB - Natural killer (NK) cells have historically been considered to be a part of the innate immune system, exerting a rapid response against pathogens and tumors in an antigen (Ag)-independent manner. However, over the past decade, evidence has accumulated suggesting that at least some NK cells display certain characteristics of adaptive immune cells. Indeed, NK cells can learn and remember encounters with a variety of Ags, including chemical haptens and viruses. Upon rechallenge, memory NK cells mount potent recall responses selectively to those Ags. This phenomenon, traditionally termed "immunological memory," has been reported in mice, nonhuman primates, and even humans and appears to be concentrated in discrete NK cell subsets. Because immunological memory protects against recurrent infections and is the central goal of active vaccination, it is crucial to define the mechanisms and consequences of NK cell memory. Here, we summarize the different kinds of memory responses that have been attributed to specific NK cell subsets and discuss the possibility to harness NK cell memory for vaccination purposes. PMID- 29254977 TI - Is a Human CD8 T-Cell Vaccine Possible, and if So, What Would It Take? Could a CD8+ T-Cell Vaccine Prevent Persistent HIV Infection? AB - Vaccines that stimulate CD8+ T cells could clear early virus infection or control ongoing infection and prevent disease. This could be valuable to combat human immunodeficiency virus type 1 (HIV-1) where it has not yet been possible to generate broadly reacting neutralizing antibodies with a vaccine. However, HIV-1 vaccines aimed at stimulating CD8+ T cells have had no success. In contrast, a cytomegalovirus vectored simian immunodeficiency virus (SIV) vaccine enabled clearance of early SIV infection. This may open the door to the design of an effective HIV vaccine. PMID- 29254980 TI - Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome? Neoantigens: Nothing New in Spite of the Name. AB - The term "neoantigen," as applied to molecules newly expressed on tumor cells, has a long history. The groundbreaking discovery of a cancer causing virus in chickens by Rous over 100 years ago, followed by discoveries of other tumor causing viruses in animals, suggested a viral etiology of human cancers. The search for other oncogenic viruses in the 1960s and 1970s resulted in the discoveries of Epstein-Barr virus (EBV), hepatitis B virus (HBV), and human papilloma virus (HPV), and continues until the present time. Contemporaneously, the budding field of immunology was posing the question can the immune system of animals or humans recognize a tumor that develops from one's own tissues and what types of antigens would distinguish the tumor from normal cells. Molecules encoded by oncogenic viruses provided the most logical candidates and evidence was quickly gathered for both humoral and cellular recognition of viral antigens, referred to as neoantigens. Often, however, serologic responses to virus-bearing tumors revealed neoantigens unrelated to viral proteins and expressed on multiple tumor types, foreshadowing later findings of multiple changes in other genes in tumor cells creating nonviral neoantigens. PMID- 29254979 TI - Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? NK Cell Memory and Immunization Strategies against Infectious Diseases and Cancer. AB - Immunological memory is an evolutionary adaptation of the vertebrate immune system that protects the host from repeated pathogen infection. T and B cells possess the specificity and longevity required to generate immune memory, whereas natural killer (NK) cells make up a component of the immune system that was not thought to possess these features. However, much evidence from the last decade has challenged this dogma. The investigators were asked to address the following questions: Is there NK cell memory? And can NK cell memory be harnessed for vaccination? Thus, this article explores the recent literature showing immune memory in NK cells. Along with highlighting these studies, we speculate how NK cell memory can be harnessed in immunization strategies against infectious diseases and cancer. PMID- 29254981 TI - Is It Possible to Develop Cancer Vaccines to Neoantigens, What Are the Major Challenges, and How Can These Be Overcome? Neoantigens as Vaccine Targets for Cancer. AB - Recent work by several groups has undoubtedly shown that we can produce cancer vaccines targeting neoantigens. However, each vaccine is essentially a single use, patient-specific product, making this approach resource-intensive. For this reason, it is important to ask whether this approach will be any more successful than what has been attempted during the last 30 years using vaccines targeting self-epitopes. Here, we discuss what might be expected from neoantigen vaccines based on our experience in chronic viral infections, and how this new approach may be applied to cancer immunotherapy. PMID- 29254982 TI - Is a Human CD8 T-Cell Vaccine Possible, and if So, What Would It Take? CD8 T-Cell Vaccines: To B or Not to B? AB - Although CD8 T-cell vaccines do not have the record of success of humoral mediated vaccines, they do not receive the same degree of effort. Many diseases, including malaria, tuberculosis, and acquired immune deficiency syndrome (AIDS) have not yielded to vaccines, and intrinsic barriers may impede approaches limited solely to generating antibodies. Moreover, population growth and modernization are driving an increased pace of new emerging global health threats (human immunodeficiency virus [HIV] is a recent example), which will create unpredictable challenges for vaccinologists. Vaccine-elicited CD8 T cells may contribute to protective modalities, although their development will require a more thorough understanding of CD8 T-cell biology, practices for manufacturing and delivering CD8 T-cell-eliciting vectors that have acceptable safety profiles, and, ultimately, the political will and faith of those that make vaccine research funding decisions. PMID- 29254983 TI - Is a Human CD8 T-Cell Vaccine Possible, and if So, What Would It Take? CD8 T-Cell Mediated Protective Immunity and Vaccination against Enteric Bacteria. AB - Although induction of CD8+ responses is widely accepted as critical in clearing viral infections and necessary for effective vaccines against viruses, much less is known regarding the role of these cells in bacterial and other infections, particularly those that enter the host via the gastrointestinal tract. In this commentary, I discuss the likelihood that CD8+ responses are also important in protection from intestinal Gram-negative bacteria, as well as the many factors that should be taken into consideration during the development of vaccines, based on eliciting long-term protection predominantly mediated by CD8+ responses against these organisms. PMID- 29254984 TI - Phytochrome, Carbon Sensing, Metabolism, and Plant Growth Plasticity. PMID- 29254985 TI - Retrograde Signals Navigate the Path to Chloroplast Development. PMID- 29254986 TI - TCP Transcription Factors Regulate Shade Avoidance via Directly Mediating the Expression of Both PHYTOCHROME INTERACTING FACTORs and Auxin Biosynthetic Genes. AB - Light quality surrounding a plant is largely determined by the density of its neighboring vegetation. Plants are able to sense shade light signals and initiate a series of adaptation responses, which is known as shade avoidance syndrome (SAS). PHYTOCHROME INTERACTING FACTORS (PIFs) are key factors in the SAS network by regulating the biosynthesis of multiple phytohormones and the expression of cell expansion genes. Although the protein levels of PIFs were found to be acumulated in shade, the transcriptional regulation of PIFs in response to such an environmental signal remains poorly understood. Here we show that TCP17 and its two closely related homologs, TCP5 and TCP13, play an important role in mediating shade-induced hypocotyl elongation by up-regulating auxin biosynthesis via a PIF-dependent and a PIF-independent pathway. In constitutive white light, a tcp5, 13, 17 triple mutant (3tcp) showed a subtle hypocotyl defective phenotype. In shade, however, 3tcp showed a significantly reduced hypocotyl elongation phenotype, indicating a positive role of TCPs in regulating SAS. Our in-depth biochemical and genetic analyses indicated that TCP17 can be significantly accumulated in shade. TCP17 binds to the promoters of PIFs and YUCCAs to indirectly or directly up-regulate auxin levels in shade. These data provide new insights into our better understanding of the regulatory mechanisms of SAS in plants. PMID- 29254987 TI - DPP-4 Inhibitors Improve Diabetic Wound Healing via Direct and Indirect Promotion of Epithelial-Mesenchymal Transition and Reduction of Scarring. AB - Patients with diabetes often experience multiple disease complications. Hypoglycemic agents can have both positive and negative effects on diabetic complications, which should be carefully assessed when personalized treatment strategies are developed. In this study we report that dipeptidyl peptidase 4 inhibitors (DPP-4is), a group of widely used antihyperglycemic agents, can improve diabetic wound healing, independent of their beneficial effects on glycemic control. In particular, DPP-4is promoted the migration and epithelial mesenchymal transition of keratinocytes, directly and indirectly, by inducing stromal cell-derived factor 1alpha production of fibroblasts in vitro and in diabetic mice. In addition, DPP-4is attenuated collagen synthesis and deposition, which may diminish scar formation. Furthermore, the results of a randomized clinical trial (NCT02742233) involving 67 patients with type 2 diabetes supported the role of DPP-4i treatment in diabetic wound healing. Our findings support the application of DPP-4i as a preferred option for treating ulcers in patients with diabetes. PMID- 29254988 TI - Natural and environmental oestrogens induce TGFB1 synthesis in oviduct cells. AB - Autocrine/paracrine factors generated in response to 17beta-oestradiol (E2), within the oviduct, facilitate early embryo development for implantation. Since transforming growth factor beta 1 (TGFB1) plays a key role in embryo implantation, regulation of its synthesis by E2 may be of biological/pathophysiological relevance. Here, we investigated whether oviduct cells synthesize TGFB1 and whether E2 and environmental oestrogens (EOEs; xenoestrogens and phytoestrogens) modulate its synthesis. Under basal conditions, bovine oviduct cells (OCs; oviduct epithelial cells and oviduct fibroblasts; 1:1 ratio) synthesized TGFB1. E2 concentration-dependent induced TGFB1 levels in OCs and these effects were mimicked by some, but not all EOEs (genistein, biochanin A and 4-hydroxy-2',4',6'-trichlorobiphenyl, 4-hydroxy-2',4',6'-dichlorobiphenyl); moreover, EOEs enhanced (P < 0.05) the stimulatory effects of E2 on TGFB1 synthesis. The OCs expressed oestrogen receptors alpha and beta and aryl hydrocarbon; moreover, co-treatment with ER antagonist ICI182780 blocked the stimulatory effects of E2 and EOEs on TGFB1 synthesis. Treatment with non permeable E2-BSA failed to induce TGFB1, thereby ruling out the involvement of membrane ERs. Cycloheximide (protein synthesis inhibitor) blocked E2-induced TGFB1 synthesis providing evidence for de novo synthesis. The stimulatory effects of E2 and EOEs, were inhibited (P < 0.05) by MAPK inhibitor (PD98059), whereas intracellular-Ca2+ chelator (BAPTA-AM) and adenylyl cyclase inhibitor (SQ22536) abrogated the effects of E2, but not EOEs, suggesting that post-ER effects of E2 and EOEs involve different pathways. Our results provide the first evidence that in OCs, E2 and EOEs stimulate TGFB1 synthesis via an ER-dependent pathway. Exposure of the oviduct to EOEs may result in continuous/sustained induction of TGFB1 levels in a non-cyclic fashion and may induce deleterious effects on reproduction. PMID- 29254989 TI - An interview with Claudio Stern. AB - Claudio Stern is the J. Z. Young Professor of Anatomy at University College London (UCL), UK. His lab studies the processes that regulate patterning and cell diversity in the early embryos of vertebrates, mostly in chick. Claudio, an elected fellow of the Royal Society, the UK Academy of Medical Sciences, and the Latin-American Academy of Medical Sciences, was awarded the 2006 Waddington Medal by the British Society of Developmental Biology, and he also served as President of the International Society for Developmental Biology (ISDB) from 2010-2013. At the 18th Congress of the ISDB (Singapore, June 2017), Claudio was awarded the ISDB's Ross Harrison Prize, which recognises an individual's outstanding contributions to developmental biology. We met with Claudio to ask him more about his career, his thoughts on the field, and his advice for early career researchers. PMID- 29254990 TI - The TGFbeta superfamily in Lisbon: navigating through development and disease. AB - The 10th FASEB meeting 'The TGFbeta Superfamily: Signaling in Development and Disease' took place in Lisbon, Portugal, in July 2017. As we review here, the findings presented at the meeting highlighted the important contributions of TGFbeta family signaling to normal development, adult homeostasis and disease, and also revealed novel mechanisms by which TGFbeta signals are transduced. PMID- 29254991 TI - The hallmarks of cell-cell fusion. AB - Cell-cell fusion is essential for fertilization and organ development. Dedicated proteins known as fusogens are responsible for mediating membrane fusion. However, until recently, these proteins either remained unidentified or were poorly understood at the mechanistic level. Here, we review how fusogens surmount multiple energy barriers to mediate cell-cell fusion. We describe how early preparatory steps bring membranes to a distance of ~10 nm, while fusogens act in the final approach between membranes. The mechanical force exerted by cell fusogens and the accompanying lipidic rearrangements constitute the hallmarks of cell-cell fusion. Finally, we discuss the relationship between viral and eukaryotic fusogens, highlight a classification scheme regrouping a superfamily of fusogens called Fusexins, and propose new questions and avenues of enquiry. PMID- 29254993 TI - Novel Targeting of Transcription and Metabolism in Glioblastoma. AB - Purpose: Glioblastoma (GBM) is highly resistant to treatment, largely due to disease heterogeneity and resistance mechanisms. We sought to investigate a promising drug that can inhibit multiple aspects of cancer cell survival mechanisms and become an effective therapeutic for GBM patients.Experimental Design: To investigate TG02, an agent with known penetration of the blood-brain barrier, we examined the effects as single agent and in combination with temozolomide, a commonly used chemotherapy in GBM. We used human GBM cells and a syngeneic mouse orthotopic GBM model, evaluating survival and the pharmacodynamics of TG02. Mechanistic studies included TG02-induced transcriptional regulation, apoptosis, and RNA sequencing in treated GBM cells as well as the investigation of mitochondrial and glycolytic function assays.Results: We demonstrated that TG02 inhibited cell proliferation, induced cell death, and synergized with temozolomide in GBM cells with different genetic background but not in astrocytes. TG02-induced cytotoxicity was blocked by the overexpression of phosphorylated CDK9, suggesting a CDK9-dependent cell killing. TG02 suppressed transcriptional progression of antiapoptotic proteins and induced apoptosis in GBM cells. We further demonstrated that TG02 caused mitochondrial dysfunction and glycolytic suppression and ultimately ATP depletion in GBM. A prolonged survival was observed in GBM mice receiving combined treatment of TG02 and temozolomide. The TG02-induced decrease of CDK9 phosphorylation was confirmed in the brain tumor tissue.Conclusions: TG02 inhibits multiple survival mechanisms and synergistically decreases energy production with temozolomide, representing a promising therapeutic strategy in GBM, currently under investigation in an ongoing clinical trial. Clin Cancer Res; 24(5); 1124-37. (c)2017 AACR. PMID- 29254996 TI - Nevada and Nebraska plan to use diazepam and fentanyl in upcoming executions. PMID- 29254994 TI - Detection of Epistasis for Flowering Time Using Bayesian Multilocus Estimation in a Barley MAGIC Population. AB - Gene-by-gene interactions, also known as epistasis, regulate many complex traits in different species. With the availability of low-cost genotyping it is now possible to study epistasis on a genome-wide scale. However, identifying genome wide epistasis is a high-dimensional multiple regression problem and needs the application of dimensionality reduction techniques. Flowering Time (FT) in crops is a complex trait that is known to be influenced by many interacting genes and pathways in various crops. In this study, we successfully apply Sure Independence Screening (SIS) for dimensionality reduction to identify two-way and three-way epistasis for the FT trait in a Multiparent Advanced Generation Inter-Cross (MAGIC) barley population using the Bayesian multilocus model. The MAGIC barley population was generated from intercrossing among eight parental lines and thus, offered greater genetic diversity to detect higher-order epistatic interactions. Our results suggest that SIS is an efficient dimensionality reduction approach to detect high-order interactions in a Bayesian multilocus model. We also observe that many of our findings (genomic regions with main or higher-order epistatic effects) overlap with known candidate genes that have been already reported in barley and closely related species for the FT trait. PMID- 29254997 TI - Pleiotropic Roles for ZEB1 in Cancer. AB - ZEB1 is a prime element of a network of transcription factors that controls epithelial-to-mesenchymal transition (EMT), a reversible embryonic transdifferentiation program that allows partial or complete transition from an epithelial to a mesenchymal state. Aberrant expression of ZEB1 has been reported in a variety of human cancers, where it is generally believed to foster migration, invasion, and metastasis. Over the past few years, in vitro and in vivo observations have highlighted unsuspected intrinsic oncogenic functions of ZEB1 that impact tumorigenesis from its earliest stages. Located downstream of regulatory processes that integrate microenvironmental signals and directly implicated in feedback loops controlled by miRNAs, ZEB1 appears to be a central switch that determines cell fate. Its expression fosters malignant transformation through the mitigation of critical oncosuppressive pathways and through the conferment of stemness properties. ZEB1 is also a key determinant of cell plasticity, endowing cells with the capacity to withstand an aberrant mitogenic activity, with a profound impact on the genetic history of tumorigenesis, and to adapt to the multiple constraints encountered over the course of tumor development. Cancer Res; 78(1); 30-35. (c)2017 AACR. PMID- 29254995 TI - Compensatory Internalization of Pma1 in V-ATPase Mutants in Saccharomyces cerevisiae Requires Calcium- and Glucose-Sensitive Phosphatases. AB - Loss of V-ATPase activity in organelles, whether through V-ATPase inhibition or V ATPase (vma) mutations, triggers a compensatory downregulation of the essential plasma membrane proton pump Pma1 in Saccharomyces cerevisiae We have previously determined that the alpha-arrestin Rim8 and ubiquitin ligase Rsp5 are essential for Pma1 ubiquination and endocytosis in response to loss of V-ATPase activity. Here, we show that Pma1 endocytosis in V-ATPase mutants does not require Rim101 pathway components upstream and downstream of Rim8, indicating that Rim8 is acting independently in Pma1 internalization. We find that two phosphatases, the calcium-responsive phosphatase calcineurin and the glucose-sensitive phosphatase Glc7 (PP1), and one of the Glc7 regulatory subunits Reg1, exhibit negative synthetic genetic interactions with vma mutants, and demonstrate that both phosphatases are essential for ubiquitination and endocytic downregulation of Pma1 in these mutants. Although both acute and chronic loss of V-ATPase activity trigger the internalization of ~50% of surface Pma1, a comparable reduction in Pma1 expression in a pma1-007 mutant neither compensates for loss of V-ATPase activity nor stops further Pma1 endocytosis. The results indicate that the cell surface level of Pma1 is not directly sensed and that internalized Pma1 may play a role in compensating for loss of V-ATPase-dependent acidification. Taken together, these results provide new insights into cross talk between two major proton pumps central to cellular pH control. PMID- 29254992 TI - Mechanisms of gene regulation in human embryos and pluripotent stem cells. AB - Pluripotent stem cells have broad utility in biomedical research and their molecular regulation has thus garnered substantial interest. While the principles that establish and regulate pluripotency have been well defined in the mouse, it has been difficult to extrapolate these insights to the human system due to species-specific differences and the distinct developmental identities of mouse versus human embryonic stem cells. In this Review, we examine genome-wide approaches to elucidate the regulatory principles of pluripotency in human embryos and stem cells, and highlight where differences exist in the regulation of pluripotency in mice and humans. We review recent insights into the nature of human pluripotent cells in vivo, obtained by the deep sequencing of pre implantation embryos. We also present an integrated overview of the principal layers of global gene regulation in human pluripotent stem cells. Finally, we discuss the transcriptional and epigenomic remodeling events associated with cell fate transitions into and out of human pluripotency. PMID- 29254999 TI - Urinary infections are complex and hard to treat. PMID- 29254998 TI - New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. AB - The human protein kinome comprises 535 proteins that, with the exception of approximately 50 pseudokinases, control intracellular signaling networks by catalyzing the phosphorylation of multiple protein substrates. While a major research focus of the last 30 years has been cancer-associated Tyr and Ser/Thr kinases, over 85% of the kinome has been identified to be dysregulated in at least one disease or developmental disorder. Despite this remarkable statistic, for the majority of protein kinases and pseudokinases, there are currently no inhibitors progressing toward the clinic, and in most cases, details of their physiologic and pathologic mechanisms remain at least partially obscure. By curating and annotating data from the literature and major public databases of phosphorylation sites, kinases, and disease associations, we generate an unbiased resource that highlights areas of unmet need within the kinome. We discuss strategies and challenges associated with characterizing catalytic and noncatalytic outputs in cells, and describe successes and new frontiers that will support more comprehensive cancer-targeting and therapeutic evaluation in the future. Cancer Res; 78(1); 15-29. (c)2017 AACR. PMID- 29255000 TI - Inhibition of Myeloperoxidase by N-Acetyl Lysyltyrosylcysteine Amide Reduces Oxidative Stress-Mediated Inflammation, Neuronal Damage, and Neural Stem Cell Injury in a Murine Model of Stroke. AB - Recent studies suggest that myeloperoxidase (MPO)-dependent oxidative stress plays a significant role in brain injury in stroke patients. We previously showed that N-acetyl lysyltyrosylcysteine amide (KYC), a novel MPO inhibitor, significantly decreased infarct size, blood-brain barrier leakage, infiltration of myeloid cells, loss of neurons, and apoptosis in the brains of middle cerebral artery occlusion (MCAO) mice. Inhibition of MPO also noticeably reduced neurologic severity scores of MCAO mice. Thus, our data support the idea that MPO dependent oxidative stress plays a detrimental role in tissue injury in ischemic stroke. However, the mechanisms of MPO-induced injury in stroke are still largely unknown. Here, we present new evidence showing that KYC treatment greatly reduced inflammation by decreasing the number of proinflammatory M1 microglial cells and N1 neutrophils in the brains of MCAO mice. KYC also markedly reduced the expression of high-mobility group box 1, receptor for advanced glycation end products, and nuclear factor-kappaB in the brains of MCAO mice. Both neurons and neural stem cells (NSCs) were oxidatively injured by MPO-dependent oxidative stress in MCAO mice. Inhibiting MPO-dependent oxidative stress with KYC significantly reduced oxidative injury and apoptosis in neurons and NSCs. KYC treatment also protected transplanted exogenous NSCs in the brains of MCAO mice. Thus, our studies suggest that MPO-dependent oxidative stress directly injures brain tissues by oxidizing neurons and NSCs and increasing inflammation during stroke. Inhibition of MPO activity with KYC preserves neuronal function and helps the brain recover from injury after stroke. PMID- 29255001 TI - IGF-binding proteins. AB - Insulin-like growth factor-binding proteins (IGFBPs) 1-6 bind IGFs but not insulin with high affinity. They were initially identified as serum carriers and passive inhibitors of IGF actions. However, subsequent studies showed that, although IGFBPs inhibit IGF actions in many circumstances, they may also potentiate these actions. IGFBPs are widely expressed in most tissues, and they are flexible endocrine and autocrine/paracrine regulators of IGF activity, which is essential for this important physiological system. More recently, individual IGFBPs have been shown to have IGF-independent actions. Mechanisms underlying these actions include (i) interaction with non-IGF proteins in compartments including the extracellular space and matrix, the cell surface and intracellular space, (ii) interaction with and modulation of other growth factor pathways including EGF, TGF-beta and VEGF, and (iii) direct or indirect transcriptional effects following nuclear entry of IGFBPs. Through these IGF-dependent and IGF independent actions, IGFBPs modulate essential cellular processes including proliferation, survival, migration, senescence, autophagy and angiogenesis. They have been implicated in a range of disorders including malignant, metabolic, neurological and immune diseases. A more complete understanding of their cellular roles may lead to the development of novel IGFBP-based therapeutic opportunities. PMID- 29255002 TI - DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage gated sodium channel 1.7 (Nav1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Nav1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Nav1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Nav1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Nav1.7 associated with spontaneous activity. Nav1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Nav1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain.SIGNIFICANCE STATEMENT This work demonstrates that the expression and function of the voltage gated sodium channel Nav1.7 are increased in a preclinical model of chemotherapy induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of function mutations in human Nav1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Nav1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class. PMID- 29255003 TI - Loss of Intercalated Cells (ITCs) in the Mouse Amygdala of Tshz1 Mutants Correlates with Fear, Depression, and Social Interaction Phenotypes. AB - The intercalated cells (ITCs) of the amygdala have been shown to be critical regulatory components of amygdalar circuits, which control appropriate fear responses. Despite this, the molecular processes guiding ITC development remain poorly understood. Here we establish the zinc finger transcription factor Tshz1 as a marker of ITCs during their migration from the dorsal lateral ganglionic eminence through maturity. Using germline and conditional knock-out (cKO) mouse models, we show that Tshz1 is required for the proper migration and differentiation of ITCs. In the absence of Tshz1, migrating ITC precursors fail to settle in their stereotypical locations encapsulating the lateral amygdala and BLA. Furthermore, they display reductions in the ITC marker Foxp2 and ectopic persistence of the dorsal lateral ganglionic eminence marker Sp8. Tshz1 mutant ITCs show increased cell death at postnatal time points, leading to a dramatic reduction by 3 weeks of age. In line with this, Foxp2-null mutants also show a loss of ITCs at postnatal time points, suggesting that Foxp2 may function downstream of Tshz1 in the maintenance of ITCs. Behavioral analysis of male Tshz1 cKOs revealed defects in fear extinction as well as an increase in floating during the forced swim test, indicative of a depression-like phenotype. Moreover, Tshz1 cKOs display significantly impaired social interaction (i.e., increased passivity) regardless of partner genetics. Together, these results suggest that Tshz1 plays a critical role in the development of ITCs and that fear, depression like and social behavioral deficits arise in their absence.SIGNIFICANCE STATEMENT We show here that the zinc finger transcription factor Tshz1 is expressed during development of the intercalated cells (ITCs) within the mouse amygdala. These neurons have previously been shown to play a crucial role in fear extinction. Tshz1 mouse mutants exhibit severely reduced numbers of ITCs as a result of abnormal migration, differentiation, and survival of these neurons. Furthermore, the loss of ITCs in mouse Tshz1 mutants correlates well with defects in fear extinction as well as the appearance of depression-like and abnormal social interaction behaviors reminiscent of depressive disorders observed in human patients with distal 18q deletions, including the Tshz1 locus. PMID- 29255005 TI - Attention Is Required for Knowledge-Based Sequential Grouping: Insights from the Integration of Syllables into Words. AB - How the brain groups sequential sensory events into chunks is a fundamental question in cognitive neuroscience. This study investigates whether top-down attention or specific tasks are required for the brain to apply lexical knowledge to group syllables into words. Neural responses tracking the syllabic and word rhythms of a rhythmic speech sequence were concurrently monitored using electroencephalography (EEG). The participants performed different tasks, attending to either the rhythmic speech sequence or a distractor, which was another speech stream or a nonlinguistic auditory/visual stimulus. Attention to speech, but not a lexical-meaning-related task, was required for reliable neural tracking of words, even when the distractor was a nonlinguistic stimulus presented cross-modally. Neural tracking of syllables, however, was reliably observed in all tested conditions. These results strongly suggest that neural encoding of individual auditory events (i.e., syllables) is automatic, while knowledge-based construction of temporal chunks (i.e., words) crucially relies on top-down attention.SIGNIFICANCE STATEMENT Why we cannot understand speech when not paying attention is an old question in psychology and cognitive neuroscience. Speech processing is a complex process that involves multiple stages, e.g., hearing and analyzing the speech sound, recognizing words, and combining words into phrases and sentences. The current study investigates which speech processing stage is blocked when we do not listen carefully. We show that the brain can reliably encode syllables, basic units of speech sounds, even when we do not pay attention. Nevertheless, when distracted, the brain cannot group syllables into multisyllabic words, which are basic units for speech meaning. Therefore, the process of converting speech sound into meaning crucially relies on attention. PMID- 29255006 TI - Cholinergic Overstimulation Attenuates Rule Selectivity in Macaque Prefrontal Cortex. AB - Acetylcholine is released in the prefrontal cortex (PFC) and is a key modulator of cognitive performance in primates. Cholinergic stimulation has been shown to have beneficial effects on performance of cognitive tasks, and cholinergic receptors are being actively explored as promising targets for ameliorating cognitive deficits in Alzheimer's disease. We hypothesized that cholinergic stimulation of PFC during performance of a cognitive task would augment neuronal activity and neuronal coding of task attributes. We iontophoretically applied the general cholinergic receptor agonist carbachol onto neurons in dorsolateral PFC (DLPFC) of male rhesus macaques performing rule-guided prosaccades and antisaccades, a well established oculomotor task for testing cognitive control. Carbachol application had heterogeneous effects on neuronal excitability, with both excitation and suppression observed in significant proportions. Contrary to our prediction, neurons with rule-selective activity exhibited a reduction in selectivity during carbachol application. Cholinergic stimulation disrupted rule selectivity regardless of whether it had suppressive or excitatory effects on these neurons. In addition, cholinergic stimulation excited putative pyramidal neurons, whereas the activity of putative interneurons remained unchanged. Moreover, cholinergic stimulation attenuated saccade direction selectivity in putative pyramidal neurons due to nonspecific increases in activity. Our results suggest excessive cholinergic stimulation has detrimental effects on DLPFC representations of task attributes. These findings delineate the complexity and heterogeneity of neuromodulation of cerebral cortex by cholinergic stimulation, an area of active exploration with respect to the development of cognitive enhancers.SIGNIFICANCE STATEMENT The neurotransmitter acetylcholine is known to be important for cognitive processes in the prefrontal cortex. Removal of acetylcholine from prefrontal cortex can disrupt short-term memory performance and is reminiscent of Alzheimer's disease, which is characterized by degeneration of acetylcholine-producing neurons. Stimulation of cholinergic receptors is being explored to create cognitive enhancers for the treatment of Alzheimer's disease and other psychiatric diseases. Here, we stimulated cholinergic receptors in prefrontal cortex and examined its effects on neurons that are engaged in cognitive behavior. Surprisingly, cholinergic stimulation decreased neurons' ability to discriminate between rules. This work suggests that overstimulation of acetylcholine receptors could disrupt neuronal processing during cognition and is relevant to the design of cognitive enhancers based on stimulating the cholinergic system. PMID- 29255004 TI - Prismatic Adaptation Modulates Oscillatory EEG Correlates of Motor Preparation but Not Visual Attention in Healthy Participants. AB - Prismatic adaption (PA) has been proposed as a tool to induce neural plasticity and is used to help neglect rehabilitation. It leads to a recalibration of visuomotor coordination during pointing as well as to aftereffects on a number of sensorimotor and attention tasks, but whether these effects originate at a motor or attentional level remains a matter of debate. Our aim was to further characterize PA aftereffects by using an approach that allows distinguishing between effects on attentional and motor processes. We recorded EEG in healthy human participants (9 females and 7 males) while performing a new double step, anticipatory attention/motor preparation paradigm before and after adaptation to rightward-shifting prisms, with neutral lenses as a control. We then examined PA aftereffects through changes in known oscillatory EEG signatures of spatial attention orienting and motor preparation in the alpha and beta frequency bands. Our results were twofold. First, we found PA to rightward-shifting prisms to selectively affect EEG signatures of motor but not attentional processes. More specifically, PA modulated preparatory motor EEG activity over central electrodes in the right hemisphere, contralateral to the PA-induced, compensatory leftward shift in pointing movements. No effects were found on EEG signatures of spatial attention orienting over occipitoparietal sites. Second, we found the PA effect on preparatory motor EEG activity to dominate in the beta frequency band. We conclude that changes to intentional visuomotor, rather than attentional visuospatial, processes underlie the PA aftereffect of rightward-deviating prisms in healthy participants.SIGNIFICANCE STATEMENT Prismatic adaptation (PA) has been proposed as a tool to induce neural plasticity in both healthy participants and patients, due to its aftereffect impacting on a number of visuospatial and visuomotor functions. However, the neural mechanisms underlying PA aftereffects are poorly understood as only little neuroimaging evidence is available. Here, we examined, for the first time, the origin of PA aftereffects studying oscillatory brain activity. Our results show a selective modulation of preparatory motor activity following PA in healthy participants but no effect on attention-related activity. This provides novel insight into the PA aftereffect in the healthy brain and may help to inform interventions in neglect patients. PMID- 29255007 TI - Early Procedural Pain Is Associated with Regionally-Specific Alterations in Thalamic Development in Preterm Neonates. AB - Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and N acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development.SIGNIFICANCE STATEMENT Early exposure to repetitive procedural pain in very preterm neonates may disrupt the development of regions involved in somatosensory processing, leading to poor functional outcomes. We demonstrate that early pain is associated with thalamic volume loss in the territory of the somatosensory thalamus and is accompanied by disruptions thalamic metabolic growth and thalamocortical pathway maturation, particularly in extremely preterm neonates. Thalamic growth was associated with cognitive and motor outcome at 3 years corrected age. Findings provide evidence for a developmentally sensitive period whereby subcortical structures in young neonates may be most vulnerable to procedural pain. Furthermore, results suggest that the thalamus may play a key role underlying the association between neonatal pain and poor neurodevelopmental outcomes in these high-risk neonates. PMID- 29255008 TI - A Computational Account of Optimizing Social Predictions Reveals That Adolescents Are Conservative Learners in Social Contexts. AB - As adolescents transition to the complex world of adults, optimizing predictions about others' preferences becomes vital for successful social interactions. Mounting evidence suggests that these social learning processes are affected by ongoing brain development across adolescence. A mechanistic understanding of how adolescents optimize social predictions and how these learning strategies are implemented in the brain is lacking. To fill this gap, we combined computational modeling with functional neuroimaging. In a novel social learning task, male and female human adolescents and adults predicted the preferences of peers and could update their predictions based on trial-by-trial feedback about the peers' actual preferences. Participants also rated their own preferences for the task items and similar additional items. To describe how participants optimize their inferences over time, we pitted simple reinforcement learning models against more specific "combination" models, which describe inferences based on a combination of reinforcement learning from past feedback and participants' own preferences. Formal model comparison revealed that, of the tested models, combination models best described how adults and adolescents update predictions of others. Parameter estimates of the best-fitting model differed between age groups, with adolescents showing more conservative updating. This developmental difference was accompanied by a shift in encoding predictions and the errors thereof within the medial prefrontal and fusiform cortices. In the adolescent group, encoding of own preferences and prediction errors scaled with parent-reported social traits, which provides additional external validity for our learning task and the winning computational model. Our findings thus help to specify adolescent-specific social learning processes.SIGNIFICANCE STATEMENT Adolescence is a unique developmental period of heightened awareness about other people. Here we probe the suitability of various computational models to describe how adolescents update their predictions of others' preferences. Within the tested model space, predictions of adults and adolescents are best described by the same learning model, but adolescents show more conservative updating. Compared with adults, brain activity of adolescents is modulated less by predictions themselves and more by prediction errors per se, and this relationship scales with adolescents' social traits. Our findings help specify social learning across adolescence and generate hypotheses about social dysfunctions in psychiatric populations. PMID- 29255009 TI - FK506-Binding Protein 12.6/1b, a Negative Regulator of [Ca2+], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats. AB - Hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of ryanodine receptor Ca2+ release, reverses aging-induced memory impairment and neuronal Ca2+ dysregulation. Here, we tested the hypothesis that FKBP1b also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of FKBP1b-expressing viral vector to male rats at either 13 months of age (long-term, LT) or 19 months of age (short-term, ST) and tested memory performance in the Morris water maze at 21 months of age. Aged rats treated ST or LT with FKBP1b substantially outperformed age-matched vector controls and performed similarly to each other and young controls (YCs). Transcriptional profiling in the same animals identified 2342 genes with hippocampal expression that was upregulated/downregulated in aged controls (ACs) compared with YCs (the aging effect). Of these aging-dependent genes, 876 (37%) also showed altered expression in aged FKBP1b-treated rats compared with ACs, with FKBP1b restoring expression of essentially all such genes (872/876, 99.5%) in the direction opposite the aging effect and closer to levels in YCs. This inverse relationship between the aging and FKBP1b effects suggests that the aging effects arise from FKBP1b deficiency. Functional category analysis revealed that genes downregulated with aging and restored by FKBP1b were associated predominantly with diverse brain structure categories, including cytoskeleton, membrane channels, and extracellular region. Conversely, genes upregulated with aging but not restored by FKBP1b associated primarily with glial neuroinflammatory, ribosomal, and lysosomal categories. Immunohistochemistry confirmed aging-induced rarefaction and FKBP1b-mediated restoration of neuronal microtubular structure. Therefore, a previously unrecognized genomic network modulating diverse brain structural processes is dysregulated by aging and restored by FKBP1b overexpression.SIGNIFICANCE STATEMENT Previously, we found that hippocampal overexpression of FK506-binding protein 12.6/1b (FKBP1b), a negative regulator of intracellular Ca2+ responses, reverses both aging-related Ca2+ dysregulation and cognitive impairment. Here, we tested whether hippocampal FKBP1b overexpression also counteracts aging changes in gene transcriptional networks. In addition to reducing memory deficits in aged rats, FKBP1b selectively counteracted aging-induced expression changes in 37% of aging dependent genes, with cytoskeletal and extracellular structure categories highly associated with the FKBP1b-rescued genes. Our results indicate that, in parallel with cognitive processes, a novel transcriptional network coordinating brain structural organization is dysregulated with aging and restored by FKBP1b. PMID- 29255011 TI - Standardised cigarette packaging may reduce the implied safety of Natural American Spirit cigarettes. AB - BACKGROUND: Over two-thirds of Natural American Spirit (NAS) smokers believe their cigarettes might be 'less harmful', but toxicological evidence does not support this belief. We assessed whether standardised packaging could reduce the possibility of erroneous inferences of 'safety' drawn from NAS cigarette packaging. METHODS: US adult smokers (n=909) were recruited to a between-subject survey experiment (3 brands*3 packaging/labelling styles) through Amazon Mechanical Turk and rated their perception of whether a randomly assigned cigarette package conveyed that the brand was 'safer' on a three-item scale (Cronbach's alpha=0.92). We assessed whether NAS packs were rated higher on the 'implied safety' scale than two other brands and estimated the effect that plain packaging (ie, all branding replaced with a drab dark brown colour) and Australian-like packaging (ie, all branding replaced with a drab dark brown colour and a graphic image and text on 75% of the pack surface) had on perceptions of the NAS cigarette package. RESULTS: Smokers' ratings of the standard NAS pack on the implied safety scale (mean=4.6; SD=2.9) were 1.9 times (P <0.001) higher than smokers' ratings of a Marlboro Red pack (mean=2.4; SD=2.3) and 1.7 times (P <0.001) higher than smokers' ratings of a Newport Menthol pack (mean=2.7; SD=2.4). These perceptions of implied safety were lower when plain packaging was used (Cohen's d=0.66; P <0.001) and much lower when Australian-like packaging was used (Cohen's d=1.56; P <0.001). CONCLUSION: The results suggest that NAS cigarette packaging conveys that its cigarettes are 'safer' and that such perceptions are lower with standardised packaging, both with and without warning images. PMID- 29255010 TI - Cryo-EM reconstruction of Type VI secretion system baseplate and sheath distal end. AB - The bacterial Type VI secretion system (T6SS) assembles from three major parts: a membrane complex that spans inner and outer membranes, a baseplate, and a sheath tube polymer. The baseplate assembles around a tip complex with associated effectors and connects to the membrane complex by TssK. The baseplate assembly initiates sheath-tube polymerization, which in some organisms requires TssA. Here, we analyzed both ends of isolated non-contractile Vibrio cholerae sheaths by cryo-electron microscopy. Our analysis suggests that the baseplate, solved to an average 8.0 A resolution, is composed of six subunits of TssE/F2/G and the baseplate periphery is decorated by six TssK trimers. The VgrG/PAAR tip complex in the center of the baseplate is surrounded by a cavity, which may accommodate up to ~450 kDa of effector proteins. The distal end of the sheath, resolved to an average 7.5 A resolution, shows sixfold symmetry; however, its protein composition is unclear. Our structures provide an important step toward an atomic model of the complete T6SS assembly. PMID- 29255012 TI - Darzi to lead new independent review of the NHS and social care. PMID- 29255013 TI - Evolutionary transition from blood feeding to obligate nonbiting in a mosquito. AB - The spread of blood-borne pathogens by mosquitoes relies on their taking a blood meal; if there is no bite, there is no disease transmission. Although many species of mosquitoes never take a blood meal, identifying genes that distinguish blood feeding from obligate nonbiting is hampered by the fact that these different lifestyles occur in separate, genetically incompatible species. There is, however, one unique extant species with populations that share a common genetic background but blood feed in one region and are obligate nonbiters in the rest of their range: Wyeomyia smithii Contemporary blood-feeding and obligate nonbiting populations represent end points of divergence between fully interfertile southern and northern populations. This divergence has undoubtedly resulted in genetic changes that are unrelated to blood feeding, and the challenge is to winnow out the unrelated genetic factors to identify those related specifically to the evolutionary transition from blood feeding to obligate nonbiting. Herein, we determine differential gene expression resulting from directional selection on blood feeding within a polymorphic population to isolate genetic differences between blood feeding and obligate nonbiting. We show that the evolution of nonbiting has resulted in a greatly reduced metabolic investment compared with biting populations, a greater reliance on opportunistic metabolic pathways, and greater reliance on visual rather than olfactory sensory input. W. smithii provides a unique starting point to determine if there are universal nonbiting genes in mosquitoes that could be manipulated as a means to control vector-borne disease. PMID- 29255015 TI - Structure of the chlorovirus PBCV-1 major capsid glycoprotein determined by combining crystallographic and carbohydrate molecular modeling approaches. AB - The glycans of the major capsid protein (Vp54) of Paramecium bursaria chlorella virus (PBCV-1) were recently described and found to be unusual. This prompted a reexamination of the previously reported Vp54 X-ray structure. A detailed description of the complete glycoprotein was achieved by combining crystallographic data with molecular modeling. The crystallographic data identified most of the monosaccharides located close to the protein backbone, but failed to detect those further from the glycosylation sites. Molecular modeling complemented this model by adding the missing monosaccharides and examined the conformational preference of the whole molecule, alone or within the crystallographic environment. Thus, combining X-ray crystallography with carbohydrate molecular modeling resulted in determining the complete glycosylated structure of a glycoprotein. In this case, it is the chlorovirus PBCV-1 major capsid protein. PMID- 29255014 TI - Organic matter processing by microbial communities throughout the Atlantic water column as revealed by metaproteomics. AB - The phylogenetic composition of the heterotrophic microbial community is depth stratified in the oceanic water column down to abyssopelagic layers. In the layers below the euphotic zone, it has been suggested that heterotrophic microbes rely largely on solubilized particulate organic matter as a carbon and energy source rather than on dissolved organic matter. To decipher whether changes in the phylogenetic composition with depth are reflected in changes in the bacterial and archaeal transporter proteins, we generated an extensive metaproteomic and metagenomic dataset of microbial communities collected from 100- to 5,000-m depth in the Atlantic Ocean. By identifying which compounds of the organic matter pool are absorbed, transported, and incorporated into microbial cells, intriguing insights into organic matter transformation in the deep ocean emerged. On average, solute transporters accounted for 23% of identified protein sequences in the lower euphotic and ~39% in the bathypelagic layer, indicating the central role of heterotrophy in the dark ocean. In the bathypelagic layer, substrate affinities of expressed transporters suggest that, in addition to amino acids, peptides and carbohydrates, carboxylic acids and compatible solutes may be essential substrates for the microbial community. Key players with highest expression of solute transporters were Alphaproteobacteria, Gammaproteobacteria, and Deltaproteobacteria, accounting for 40%, 11%, and 10%, respectively, of relative protein abundances. The in situ expression of solute transporters indicates that the heterotrophic prokaryotic community is geared toward the utilization of similar organic compounds throughout the water column, with yet higher abundances of transporters targeting aromatic compounds in the bathypelagic realm. PMID- 29255016 TI - Structure of sexual networks determines the operation of sexual selection. AB - Sexual selection is a fundamental evolutionary process but remains debated, particularly in the complexity of polyandrous populations where females mate with multiple males. This lack of resolution is partly because studies have largely ignored the structure of the sexual network, that is, the pattern of mate sharing. Here, we quantify what we call mating assortment with network analysis to specify explicitly the indirect as well as direct relationships between partners. We first review empirical studies, showing that mating assortment varies considerably in nature, due largely to basic properties of the sexual network (size and density) and partly to nonrandom patterns of mate sharing. We then use simulations to show how variation in mating assortment interacts with population-level polyandry to determine the strength of sexual selection on males. Controlling for average polyandry, positive mating assortment, arising when more polygynous males tend to mate with more polyandrous females, drastically decreases the intensity of precopulatory sexual selection on male mating success (Bateman gradient) and the covariance between male mating success and postcopulatory paternity share. Average polyandry independently weakened some measures of sexual selection and crucially also impacted sexual selection indirectly by constraining mating assortment through the saturation of the mating network. Mating assortment therefore represents a key-albeit overlooked-modulator of the strength of sexual selection. Our results show that jointly considering sexual network structure and average polyandry more precisely describes the strength of sexual selection. PMID- 29255017 TI - Lesion network localization of criminal behavior. AB - Following brain lesions, previously normal patients sometimes exhibit criminal behavior. Although rare, these cases can lend unique insight into the neurobiological substrate of criminality. Here we present a systematic mapping of lesions with known temporal association to criminal behavior, identifying 17 lesion cases. The lesion sites were spatially heterogeneous, including the medial prefrontal cortex, orbitofrontal cortex, and different locations within the bilateral temporal lobes. No single brain region was damaged in all cases. Because lesion-induced symptoms can come from sites connected to the lesion location and not just the lesion location itself, we also identified brain regions functionally connected to each lesion location. This technique, termed lesion network mapping, has recently identified regions involved in symptom generation across a variety of lesion-induced disorders. All lesions were functionally connected to the same network of brain regions. This criminality associated connectivity pattern was unique compared with lesions causing four other neuropsychiatric syndromes. This network includes regions involved in morality, value-based decision making, and theory of mind, but not regions involved in cognitive control or empathy. Finally, we replicated our results in a separate cohort of 23 cases in which a temporal relationship between brain lesions and criminal behavior was implied but not definitive. Our results suggest that lesions in criminals occur in different brain locations but localize to a unique resting state network, providing insight into the neurobiology of criminal behavior. PMID- 29255018 TI - Synergistic anti-HCV broadly neutralizing human monoclonal antibodies with independent mechanisms. AB - There is an urgent need for a vaccine to combat the hepatitis C virus (HCV) pandemic, and induction of broadly neutralizing monoclonal antibodies (bNAbs) against HCV is a major goal of vaccine development. Even within HCV genotype 1, no single bNAb effectively neutralizes all viral strains, so induction of multiple neutralizing monoclonal antibodies (NAbs) targeting distinct epitopes may be necessary for protective immunity. Therefore, identification of optimal NAb combinations and characterization of NAb interactions can guide vaccine development. We analyzed neutralization profiles of 12 human NAbs across diverse HCV strains, assigning the NAbs to two functionally distinct clusters. We then measured neutralizing breadth of 35 NAb combinations against genotype 1 isolates, with each combination including one NAb from each neutralization cluster. Many NAbs displayed complementary neutralizing breadth, forming combinations with greater neutralization across diverse strains than any individual bNAb. Remarkably, one of the most broadly neutralizing combinations of two NAbs, designated HEPC74/HEPC98, also displayed enhanced potency, with interactions matching the Bliss independence model, suggesting that these NAbs inhibit HCV infection through independent mechanisms. Subsequent experiments showed that HEPC74 primarily blocks HCV envelope protein binding to CD81, while HEPC98 primarily blocks binding to scavenger receptor B1 and heparan sulfate. Together, these data identify a critical vulnerability resulting from the reliance of HCV on multiple cell surface receptors, suggesting that vaccine induction of multiple NAbs with distinct neutralization profiles is likely to enhance the breadth and potency of the humoral immune response against HCV. PMID- 29255019 TI - Functions of maize genes encoding pyruvate phosphate dikinase in developing endosperm. AB - Maize opaque2 (o2) mutations are beneficial for endosperm nutritional quality but cause negative pleiotropic effects for reasons that are not fully understood. Direct targets of the bZIP transcriptional regulator encoded by o2 include pdk1 and pdk2 that specify pyruvate phosphate dikinase (PPDK). This enzyme reversibly converts AMP, pyrophosphate, and phosphoenolpyruvate to ATP, orthophosphate, and pyruvate and provides diverse functions in plants. This study addressed PPDK function in maize starchy endosperm where it is highly abundant during grain fill. pdk1 and pdk2 were inactivated individually by transposon insertions, and both genes were simultaneously targeted by endosperm-specific RNAi. pdk2 accounts for the large majority of endosperm PPDK, whereas pdk1 specifies the abundant mesophyll form. The pdk1- mutation is seedling-lethal, indicating that C4 photosynthesis is essential in maize. RNAi expression in transgenic endosperm eliminated detectable PPDK protein and enzyme activity. Transgenic kernels weighed the same on average as nontransgenic siblings, with normal endosperm starch and total N contents, indicating that PPDK is not required for net storage compound synthesis. An opaque phenotype resulted from complete PPDK knockout, including loss of vitreous endosperm character similar to the phenotype conditioned by o2-. Concentrations of multiple glycolytic intermediates were elevated in transgenic endosperm, energy charge was altered, and starch granules were more numerous but smaller on average than normal. The data indicate that PPDK modulates endosperm metabolism, potentially through reversible adjustments to energy charge, and reveal that o2- mutations can affect the opaque phenotype through regulation of PPDK in addition to their previously demonstrated effects on storage protein gene expression. PMID- 29255020 TI - Basal resistance enhances warming tolerance of alien over indigenous species across latitude. AB - Soil systems are being increasingly exposed to the interactive effects of biological invasions and climate change, with rising temperatures expected to benefit alien over indigenous species. We assessed this expectation for an important soil-dwelling group, the springtails, by determining whether alien species show broader thermal tolerance limits and greater tolerance to climate warming than their indigenous counterparts. We found that, from the tropics to the sub-Antarctic, alien species have the broadest thermal tolerances and greatest tolerance to environmental warming. Both groups of species show little phenotypic plasticity or potential for evolutionary change in tolerance to high temperature. These trait differences between alien and indigenous species suggest that biological invasions will exacerbate the impacts of climate change on soil systems, with profound implications for terrestrial ecosystem functioning. PMID- 29255021 TI - Weyl-Kondo semimetal in heavy-fermion systems. AB - Insulating states can be topologically nontrivial, a well-established notion that is exemplified by the quantum Hall effect and topological insulators. By contrast, topological metals have not been experimentally evidenced until recently. In systems with strong correlations, they have yet to be identified. Heavy-fermion semimetals are a prototype of strongly correlated systems and, given their strong spin-orbit coupling, present a natural setting to make progress. Here, we advance a Weyl-Kondo semimetal phase in a periodic Anderson model on a noncentrosymmetric lattice. The quasiparticles near the Weyl nodes develop out of the Kondo effect, as do the surface states that feature Fermi arcs. We determine the key signatures of this phase, which are realized in the heavy-fermion semimetal Ce3Bi4Pd3 Our findings provide the much-needed theoretical foundation for the experimental search of topological metals with strong correlations and open up an avenue for systematic studies of such quantum phases that naturally entangle multiple degrees of freedom. PMID- 29255024 TI - Nonequilibrium internal energy distributions during dissociation. AB - In this work, we propose a model for nonequilibrium vibrational and rotational energy distributions in nitrogen using surprisal analysis. The model is constructed by using data from direct molecular simulations (DMSs) of rapidly heated nitrogen gas using an ab initio potential energy surface (PES). The surprisal-based model is able to capture the overpopulation of high internal energy levels during the excitation phase and also the depletion of high internal energy levels during the quasi-steady-state (QSS) dissociation phase. Due to strong coupling between internal energy and dissociation chemistry, such non Boltzmann effects can influence the overall dissociation rate in the gas. Conditions representative of the flow behind strong shockwaves, relevant to hypersonic flight, are analyzed. The surprisal-based model captures important molecular-level nonequilibrium physics, yet the simple functional form leads to a continuum-level expression that now accounts for the underlying energy distributions and their coupling to dissociation. PMID- 29255023 TI - Dissecting the genetic and metabolic mechanisms of adaptation to the knockout of a major metabolic enzyme in Escherichia coli. AB - Unraveling the mechanisms of microbial adaptive evolution following genetic or environmental challenges is of fundamental interest in biological science and engineering. When the challenge is the loss of a metabolic enzyme, adaptive responses can also shed significant insight into metabolic robustness, regulation, and areas of kinetic limitation. In this study, whole-genome sequencing and high-resolution 13C-metabolic flux analysis were performed on 10 adaptively evolved pgi knockouts of Escherichia coliPgi catalyzes the first reaction in glycolysis, and its loss results in major physiological and carbon catabolism pathway changes, including an 80% reduction in growth rate. Following adaptive laboratory evolution (ALE), the knockouts increase their growth rate by up to 3.6-fold. Through combined genomic-fluxomic analysis, we characterized the mutations and resulting metabolic fluxes that enabled this fitness recovery. Large increases in pyridine cofactor transhydrogenase flux, correcting imbalanced production of NADPH and NADH, were enabled by direct mutations to the transhydrogenase genes sthA and pntAB The phosphotransferase system component crr was also found to be frequently mutated, which corresponded to elevated flux from pyruvate to phosphoenolpyruvate. The overall energy metabolism was found to be strikingly robust, and what have been previously described as latently activated Entner-Doudoroff and glyoxylate shunt pathways are shown here to represent no real increases in absolute flux relative to the wild type. These results indicate that the dominant mechanism of adaptation was to relieve the rate-limiting steps in cofactor metabolism and substrate uptake and to modulate global transcriptional regulation from stress response to catabolism. PMID- 29255022 TI - In vivo inhibition of tryptophan catabolism reorganizes the tuberculoma and augments immune-mediated control of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis continues to cause devastating levels of mortality due to tuberculosis (TB). The failure to control TB stems from an incomplete understanding of the highly specialized strategies that M. tuberculosis utilizes to modulate host immunity and thereby persist in host lungs. Here, we show that M. tuberculosis induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing, reduced checkpoint signaling, and the relocation of effector T cells to the center of the granulomata. The enhanced killing of M. tuberculosis in macrophages in vivo by CD4+ T cells was also replicated in vitro, in cocultures of macaque macrophages and CD4+ T cells. Collectively, these results suggest that there exists a potential for using IDO inhibition as an effective and clinically relevant host-directed therapy for TB. PMID- 29255025 TI - Abiotic synthesis of purine and pyrimidine ribonucleosides in aqueous microdroplets. AB - Aqueous microdroplets (<1.3 um in diameter on average) containing 15 mM d-ribose, 15 mM phosphoric acid, and 5 mM of a nucleobase (uracil, adenine, cytosine, or hypoxanthine) are electrosprayed from a capillary at +5 kV into a mass spectrometer at room temperature and 1 atm pressure with 3 mM divalent magnesium ion (Mg2+) as a catalyst. Mass spectra show the formation of ribonucleosides that comprise a four-letter alphabet of RNA with a yield of 2.5% of uridine (U), 2.5% of adenosine (A), 0.7% of cytidine (C), and 1.7% of inosine (I) during the flight time of ~50 us. In the case of uridine, no catalyst is required. An aqueous solution containing guanine cannot be generated under the same conditions given the extreme insolubility of guanine in water. However, inosine can base pair with cytidine and thus substitute for guanosine. Thus, a full set of ribonucleosides to generate the purine-pyrimidine base pairs A-U and I-C are spontaneously generated in aqueous microdroplets under similar mild conditions. PMID- 29255026 TI - Behavioral state modulates the ON visual motion pathway of Drosophila. AB - The behavioral state of an animal can dynamically modulate visual processing. In flies, the behavioral state is known to alter the temporal tuning of neurons that carry visual motion information into the central brain. However, where this modulation occurs and how it tunes the properties of this neural circuit are not well understood. Here, we show that the behavioral state alters the baseline activity levels and the temporal tuning of the first directionally selective neuron in the ON motion pathway (T4) as well as its primary input neurons (Mi1, Tm3, Mi4, Mi9). These effects are especially prominent in the inhibitory neuron Mi4, and we show that central octopaminergic neurons provide input to Mi4 and increase its excitability. We further show that octopamine neurons are required for sustained behavioral responses to fast-moving, but not slow-moving, visual stimuli in walking flies. These results indicate that behavioral-state modulation acts directly on the inputs to the directionally selective neurons and supports efficient neural coding of motion stimuli. PMID- 29255027 TI - Differential regulation of striatal motor behavior and related cellular responses by dopamine D2L and D2S isoforms. AB - The dopamine D2 receptor (D2R) is a major component of the dopamine system. D2R mediated signaling in dopamine neurons is involved in the presynaptic regulation of dopamine levels. Postsynaptically, i.e., in striatal neurons, D2R signaling controls complex functions such as motor activity through regulation of cell firing and heterologous neurotransmitter release. The presence of two isoforms, D2L and D2S, which are generated by a mechanism of alternative splicing of the Drd2 gene, raises the question of whether both isoforms may equally control presynaptic and postsynaptic events. Here, we addressed this question by comparing behavioral and cellular responses of mice with the selective ablation of either D2L or D2S isoform. We establish that the presence of either D2L or D2S can support postsynaptic functions related to the control of motor activity in basal conditions. On the contrary, absence of D2S but not D2L prevents the inhibition of tyrosine hydroxylase phosphorylation and, thereby, of dopamine synthesis, supporting a major presynaptic role for D2S. Interestingly, boosting dopamine signaling in the striatum by acute cocaine administration reveals that absence of D2L, but not of D2S, strongly impairs the motor and cellular response to the drug, in a manner similar to the ablation of both isoforms. These results suggest that when the dopamine system is challenged, D2L signaling is required for the control of striatal circuits regulating motor activity. Thus, our findings show that D2L and D2S share similar functions in basal conditions but not in response to stimulation of the dopamine system. PMID- 29255028 TI - Dynamic and heterogeneous effects of sibling death on children's outcomes. AB - This paper explores the effects of experiencing the death of a sibling on children's developmental outcomes. Recent work has shown that experiencing a sibling death is common and long-term effects are large. We extend understanding of these effects by estimating dynamic effects on surviving siblings' cognitive and socioemotional outcomes, as well as emotional and cognitive support by parents. Using the Children of the National Longitudinal Survey of Youth 1979 (CNLSY79), we find large initial effects on cognitive and noncognitive outcomes that decline over time. We also provide evidence that the effects are larger if the surviving child is older and less prominent if the deceased child was either disabled or an infant, suggesting sensitive periods of exposure. Auxiliary results show that parental investments in the emotional support of surviving children decline following the death of their child. PMID- 29255030 TI - Retraction for Ottmann et al., Long-term aggregation of larval fish siblings during dispersal along an open coast. PMID- 29255029 TI - Enhancer adoption caused by genomic insertion elicits interdigital Shh expression and syndactyly in mouse. AB - Acquisition of new cis-regulatory elements (CREs) can cause alteration of developmental gene regulation and may introduce morphological novelty in evolution. Although structural variation in the genome generated by chromosomal rearrangement is one possible source of new CREs, only a few examples are known, except for cases of retrotransposition. In this study, we show the acquisition of novel regulatory sequences as a result of large genomic insertion in the spontaneous mouse mutation Hammer toe (Hm). Hm mice exhibit syndactyly with webbing, due to suppression of interdigital cell death in limb development. We reveal that, in the Hm genome, a 150-kb noncoding DNA fragment from chromosome 14 is inserted into the region upstream of the Sonic hedgehog (Shh) promoter in chromosome 5. Phenotyping of mouse embryos with a series of CRISPR/Cas9-aided partial deletion of the 150-kb insert clearly indicated that two different regions are necessary for the syndactyly phenotype of Hm We found that each of the two regions contains at least one enhancer for interdigital regulation. These results show that a set of enhancers brought by the large genomic insertion elicits the interdigital Shh expression and the Hm phenotype. Transcriptome analysis indicates that ectopic expression of Shh up-regulates Chordin (Chrd) that antagonizes bone morphogenetic protein signaling in the interdigital region. Indeed, Chrd-overexpressing transgenic mice recapitulated syndactyly with webbing. Thus, the Hm mutation provides an insight into enhancer acquisition as a source of creation of novel gene regulation. PMID- 29255031 TI - Vocal similarity predicts the relative attraction of musical chords. AB - Musical chords are combinations of two or more tones played together. While many different chords are used in music, some are heard as more attractive (consonant) than others. We have previously suggested that, for reasons of biological advantage, human tonal preferences can be understood in terms of the spectral similarity of tone combinations to harmonic human vocalizations. Using the chromatic scale, we tested this theory further by assessing the perceived consonance of all possible dyads, triads, and tetrads within a single octave. Our results show that the consonance of chords is predicted by their relative similarity to voiced speech sounds. These observations support the hypothesis that the relative attraction of musical tone combinations is due, at least in part, to the biological advantages that accrue from recognizing and responding to conspecific vocal stimuli. PMID- 29255032 TI - State-space multitaper time-frequency analysis. AB - Time series are an important data class that includes recordings ranging from radio emissions, seismic activity, global positioning data, and stock prices to EEG measurements, vital signs, and voice recordings. Rapid growth in sensor and recording technologies is increasing the production of time series data and the importance of rapid, accurate analyses. Time series data are commonly analyzed using time-varying spectral methods to characterize their nonstationary and often oscillatory structure. Current methods provide local estimates of data features. However, they do not offer a statistical inference framework that applies to the entire time series. The important advances that we report are state-space multitaper (SS-MT) methods, which provide a statistical inference framework for time-varying spectral analysis of nonstationary time series. We model nonstationary time series as a sequence of second-order stationary Gaussian processes defined on nonoverlapping intervals. We use a frequency-domain random walk model to relate the spectral representations of the Gaussian processes across intervals. The SS-MT algorithm efficiently computes spectral updates using parallel 1D complex Kalman filters. An expectation-maximization algorithm computes static and dynamic model parameter estimates. We test the framework in time-varying spectral analyses of simulated time series and EEG recordings from patients receiving general anesthesia. Relative to standard multitaper (MT), SS MT gave enhanced spectral resolution and noise reduction ([Formula: see text]10 dB) and allowed statistical comparisons of spectral properties among arbitrary time series segments. SS-MT also extracts time-domain estimates of signal components. The SS-MT paradigm is a broadly applicable, empirical Bayes' framework for statistical inference that can help ensure accurate, reproducible findings from nonstationary time series analyses. PMID- 29255033 TI - Remote electrochemical modulation of pKa in a rotaxane by co-conformational allostery. AB - Allosteric control, one of Nature's most effective ways to regulate functions in biomolecular machinery, involves the transfer of information between distant sites. The mechanistic details of such a transfer are still an object of intensive investigation and debate, and the idea that intramolecular communication could be enabled by dynamic processes is gaining attention as a complement to traditional explanations. Mechanically interlocked molecules, owing to the particular kind of connection between their components and the resulting dynamic behavior, are attractive systems to investigate allosteric mechanisms and exploit them to develop functionalities with artificial species. We show that the pKa of an ammonium site located on the axle component of a [2]rotaxane can be reversibly modulated by changing the affinity of a remote recognition site for the interlocked crown ether ring through electrochemical stimulation. The use of a reversible ternary redox switch enables us to set the pKa to three different values, encompassing more than seven units. Our results demonstrate that in the axle the two sites do not communicate, and that in the rotaxane the transfer of information between them is made possible by the shuttling of the ring, that is, by a dynamic intramolecular process. The investigated coupling of electron- and proton-transfer reactions is reminiscent of the operation of the protein complex I of the respiratory chain. PMID- 29255034 TI - Artificial antibody created by conformational reconstruction of the complementary determining region on gold nanoparticles. AB - To impart biomedical functions to nanoparticles (NPs), the common approach is to conjugate functional groups onto NPs by dint of the functions of those groups per se. It is still beyond current reach to create protein-like specific interactions and functions on NPs by conformational engineering of nonfunctional groups on NPs. Here, we develop a conformational engineering method to create an NP-based artificial antibody, denoted "Goldbody," through conformational reconstruction of the complementary-determining regions (CDRs) of natural antibodies on gold NPs (AuNPs). The seemingly insurmountable task of controlling the conformation of the CDR loops, which are flexible and nonfunctional in the free form, was accomplished unexpectedly in a simple way. Upon anchoring both terminals of the free CDR loops on AuNPs, we managed to reconstruct the "active" conformation of the CDR loops by tuning the span between the two terminals and, as a result, the original specificity was successfully reconstructed on the AuNPs. Two Goldbodies have been created by this strategy to specifically bind with hen egg white lysozyme and epidermal growth factor receptor, with apparent affinities several orders of magnitude stronger than that of the original natural antibodies. Our work demonstrates that it is possible to create protein-like functions on NPs in a protein-like way, namely by tuning flexible surface groups to the correct conformation. Given the apparent merits, including good stability, of Goldbodies, we anticipate that a category of Goldbodies could be created to target different antigens and thus used as substitutes for natural antibodies in various applications. PMID- 29255035 TI - C-terminal modification of the insulin B:11-23 peptide creates superagonists in mouse and human type 1 diabetes. AB - A polymorphism at beta57 in some major histocompatibility complex class II (MHCII) alleles of rodents and humans is associated with a high risk for developing type 1 diabetes (T1D). However, a highly diabetogenic insulin B chain epitope within the B:9-23 peptide is presented poorly by these alleles to a variety of mouse and human CD4 T cells isolated from either nonobese diabetic (NOD) mice or humans with T1D. We have shown for both species that mutations at the C-terminal end of this epitope dramatically improve presentation to these T cells. Here we present the crystal structures of these mutated peptides bound to mouse IAg7 and human HLA-DQ8 that show how the mutations function to improve T cell activation. In both peptide binding grooves, the mutation of B:22R to E in the peptide changes a highly unfavorable side chain for the p9 pocket to an optimal one that is dependent on the beta57 polymorphism, accounting for why these peptides bind much better to these MHCIIs. Furthermore, a second mutation of the adjacent B:21 (E to G) removes a side chain from the surface of the complex that is highly unfavorable for a subset of NOD mouse CD4 cells, thereby greatly enhancing their response to the complex. These results point out the similarities between the mouse and human responses to this B chain epitope in T1D and suggest there may be common posttranslational modifications at the C terminus of the peptide in vivo to create the pathogenic epitopes in both species. PMID- 29255036 TI - MicroRNA-351 promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor. AB - Aberrant expression of microRNAs (miRNAs) underlies a spectrum of human diseases including organ fibrosis, and hepatic stellate cells (HSCs) are the main effectors of hepatic fibrosis. Here, we showed that the expression of host miR 351 in HSCs was markedly reduced during the early stage of Schistosoma infection. However, this expression was significantly increased during the later stage of infection (after 52 d of infection). The elevated levels of miR-351 promoted hepatic fibrosis by targeting the vitamin D receptor (VDR), which is an antagonist of SMAD signaling. Importantly, efficient and sustained inhibition of miR-351 in liver tissues using the highly hepatotropic recombinant adeno associated virus serotype 8 (rAAV8), alleviated the hepatic fibrosis, partially protecting the host from lethal schistosomiasis. In addition, we found that miR 351 is negatively regulated by IFN-gamma in HSCs during infection. At the early stage of infection, the elevated levels of IFN-gamma inhibited the expression of miR-351 in HSCs through activation of signal transducer and activator of transcription 1 and induction of IFN regulatory factor 2, which binds the promotor of pre-miR-351 Our study provides insights into the mechanisms by which miR-351 regulates schistosomiasis hepatic fibrosis and highlights the potential of rAAV8-mediated miR-351 inhibition as a therapeutic intervention for fibrotic diseases. PMID- 29255037 TI - Controlled molecular self-assembly of complex three-dimensional structures in soft materials. AB - Many applications in tissue engineering, flexible electronics, and soft robotics call for approaches that are capable of producing complex 3D architectures in soft materials. Here we present a method using molecular self-assembly to generate hydrogel-based 3D architectures that resembles the appealing features of the bottom-up process in morphogenesis of living tissues. Our strategy effectively utilizes the three essential components dictating living tissue morphogenesis to produce complex 3D architectures: modulation of local chemistry, material transport, and mechanics, which can be engineered by controlling the local distribution of polymerization inhibitor (i.e., oxygen), diffusion of monomers/cross-linkers through the porous structures of cross-linked polymer network, and mechanical constraints, respectively. We show that oxygen plays a role in hydrogel polymerization which is mechanistically similar to the role of growth factors in tissue growth, and the continued growth of hydrogel enabled by diffusion of monomers/cross-linkers into the porous hydrogel similar to the mechanisms of tissue growth enabled by material transport. The capability and versatility of our strategy are demonstrated through biomimetics of tissue morphogenesis for both plants and animals, and its application to generate other complex 3D architectures. Our technique opens avenues to studying many growth phenomena found in nature and generating complex 3D structures to benefit diverse applications. PMID- 29255039 TI - Initial elevation bias in subjective reports. AB - People's reports of their thoughts, feelings, and behaviors are used in many fields of biomedical and social science. When these states have been studied over time, researchers have often observed an unpredicted and puzzling decrease with repeated assessment. When noted, this pattern has been called an "attenuation effect," suggesting that the effect is due to bias in later reports. However, the pattern could also be consistent with an initial elevation bias. We present systematic, experimental investigations of this effect in four field studies (study 1: n = 870; study 2: n = 246; study 3: n = 870; study 4: n = 141). Findings show clear support for an initial elevation bias rather than a later decline. This bias is larger for reports of internal states than for behaviors and for negative mental states and physical symptoms than for positive states. We encourage increased awareness and investigation of this initial elevation bias in all research using subjective reports. PMID- 29255038 TI - Epigenetic control of pheromone MAPK signaling determines sexual fecundity in Candida albicans. AB - Several pathogenic Candida species are capable of heritable and reversible switching between two epigenetic states, "white" and "opaque." In Candida albicans, white cells are essentially sterile, whereas opaque cells are mating proficient. Here, we interrogate the mechanism by which the white-opaque switch regulates sexual fecundity and identify four genes in the pheromone MAPK pathway that are expressed at significantly higher levels in opaque cells than in white cells. These genes encode the beta subunit of the G-protein complex (STE4), the pheromone MAPK scaffold (CST5), and the two terminal MAP kinases (CEK1/CEK2). To define the contribution of each factor to mating, C. albicans white cells were reverse-engineered to express elevated, opaque-like levels of these factors, either singly or in combination. We show that white cells co-overexpressing STE4, CST5, and CEK2 undergo mating four orders of magnitude more efficiently than control white cells and at a frequency approaching that of opaque cells. Moreover, engineered white cells recapitulate the transcriptional and morphological responses of opaque cells to pheromone. These results therefore reveal multiple bottlenecks in pheromone MAPK signaling in white cells and that alleviation of these bottlenecks enables efficient mating by these "sterile" cell types. Taken together, our findings establish that differential expression of several MAPK factors underlies the epigenetic control of mating in C. albicans We also discuss how fitness advantages could have driven the evolution of a toggle switch to regulate sexual reproduction in pathogenic Candida species. PMID- 29255041 TI - Conserved epitope on influenza-virus hemagglutinin head defined by a vaccine induced antibody. AB - Circulating influenza viruses evade neutralization in their human hosts by acquiring escape mutations at epitopes of prevalent antibodies. A goal for next generation influenza vaccines is to reduce escape likelihood by selectively eliciting antibodies recognizing conserved surfaces on the viral hemagglutinin (HA). The receptor-binding site (RBS) on the HA "head" and a region near the fusion peptide on the HA "stem" are two such sites. We describe here a human antibody clonal lineage, designated CL6649, members of which bind a third conserved site ("lateral patch") on the side of the H1-subtype, HA head. A crystal structure of HA with bound Fab6649 shows the conserved antibody footprint. The site was invariant in isolates from 1977 (seasonal) to 2012 (pdm2009); antibodies in CL6649 recognize HAs from the entire period. In 2013, human H1 viruses acquired mutations in this epitope that were retained in subsequent seasons, prompting modification of the H1 vaccine component in 2017. The mutations inhibit Fab6649 binding. We infer from the rapid spread of these mutations in circulating H1 influenza viruses that the previously subdominant, conserved lateral patch had become immunodominant for individuals with B-cell memory imprinted by earlier H1 exposure. We suggest that introduction of the pdm2009 H1 virus, to which most of the broadly prevalent, neutralizing antibodies did not bind, conferred a selective advantage in the immune systems of infected hosts to recall of memory B cells that recognized the lateral patch, the principal exposed epitope that did not change when pdm2009 displaced previous seasonal H1 viruses. PMID- 29255040 TI - College completion predicts lower depression but higher metabolic syndrome among disadvantaged minorities in young adulthood. AB - Individuals with higher educational attainment live healthier and longer lives. However, not everyone benefits equally from higher education. In particular, the black-white gap in life expectancy is greater at higher levels of educational attainment. Furthermore, recent research suggests that disadvantaged African Americans in the rural Southeast who attend college have worse physical health than their similarly disadvantaged peers who do not attend college. The extent to which this pattern generalizes to a nationally representative, mixed-race sample is unknown. Using data from the National Longitudinal Study of Adolescent to Adult Health, we test whether the health benefits associated with college completion vary by level of childhood disadvantage for depression and metabolic syndrome in young adulthood, across race/ethnicity. We find uniform lower depression associated with college completion regardless of childhood disadvantage, and across non-Hispanic white, non-Hispanic black, and Hispanic young adults. College completion is associated with lower metabolic syndrome for whites across all levels of childhood disadvantage. In contrast, college completion is associated with higher metabolic syndrome among black and Hispanic young adults from disadvantaged childhood environments. Our findings suggest that, for minorities from disadvantaged backgrounds, finishing college pays substantial dividends for mental health but simultaneously exacts costs with regard to physical health. This pattern contrasts starkly with whites and minorities from more privileged backgrounds, for whom college completion is associated with benefits to both mental and physical health. These results suggest that racial disparities in health may persist in part because the health of upwardly mobile minorities is compromised in young adulthood. PMID- 29255042 TI - Atmospheric autoxidation is increasingly important in urban and suburban North America. AB - Gas-phase autoxidation-regenerative peroxy radical formation following intramolecular hydrogen shifts-is known to be important in the combustion of organic materials. The relevance of this chemistry in the oxidation of organics in the atmosphere has received less attention due, in part, to the lack of kinetic data at relevant temperatures. Here, we combine computational and experimental approaches to investigate the rate of autoxidation for organic peroxy radicals (RO2) produced in the oxidation of a prototypical atmospheric pollutant, n-hexane. We find that the reaction rate depends critically on the molecular configuration of the RO2 radical undergoing hydrogen transfer (H shift). RO2 H-shift rate coefficients via transition states involving six- and seven-membered rings (1,5 and 1,6 H-shifts, respectively) of alpha-OH hydrogens (HOC-H) formed in this system are of order 0.1 s-1 at 296 K, while the 1,4 H shift is calculated to be orders of magnitude slower. Consistent with H-shift reactions over a substantial energetic barrier, we find that the rate coefficients of these reactions increase rapidly with temperature and exhibit a large, primary, kinetic isotope effect. The observed H-shift rate coefficients are sufficiently fast that, as a result of ongoing NO x emission reductions, autoxidation is now competing with bimolecular chemistry even in the most polluted North American cities, particularly during summer afternoons when NO levels are low and temperatures are elevated. PMID- 29255043 TI - Closing the loop on impulsivity via nucleus accumbens delta-band activity in mice and man. AB - Reward hypersensitization is a common feature of neuropsychiatric disorders, manifesting as impulsivity for anticipated incentives. Temporally specific changes in activity within the nucleus accumbens (NAc), which occur during anticipatory periods preceding consummatory behavior, represent a critical opportunity for intervention. However, no available therapy is capable of automatically sensing and therapeutically responding to this vulnerable moment in time when anticipation-related neural signals may be present. To identify translatable biomarkers for an off-the-shelf responsive neurostimulation system, we record local field potentials from the NAc of mice and a human anticipating conventional rewards. We find increased power in 1- to 4-Hz oscillations predominate during reward anticipation, which can effectively trigger neurostimulation that reduces consummatory behavior in mice sensitized to highly palatable food. Similar oscillations are present in human NAc during reward anticipation, highlighting the translational potential of our findings in the development of a treatment for a major unmet need. PMID- 29255045 TI - Correction for Larsen and Noack, Identifying the landscape drivers of agricultural insecticide use leveraging evidence from 100,000 fields. PMID- 29255044 TI - Evidence of directional and stabilizing selection in contemporary humans. AB - Modern molecular genetic datasets, primarily collected to study the biology of human health and disease, can be used to directly measure the action of natural selection and reveal important features of contemporary human evolution. Here we leverage the UK Biobank data to test for the presence of linear and nonlinear natural selection in a contemporary population of the United Kingdom. We obtain phenotypic and genetic evidence consistent with the action of linear/directional selection. Phenotypic evidence suggests that stabilizing selection, which acts to reduce variance in the population without necessarily modifying the population mean, is widespread and relatively weak in comparison with estimates from other species. PMID- 29255046 TI - Accurate quantification of brown adipose tissue mass by xenon-enhanced computed tomography. AB - Detection and quantification of brown adipose tissue (BAT) mass remains a major challenge, as current tomographic imaging techniques are either nonspecific or lack the necessary resolution to quantify BAT mass, especially in obese phenotypes, in which this tissue may be present but inactive. Here, we report quantification of BAT mass by xenon-enhanced computed tomography. We show that, during stimulation of BAT thermogenesis, the lipophilic gas xenon preferentially accumulates in BAT, leading to a radiodensity enhancement comparable to that seen in the lungs. This enhancement is mediated by a selective reduction in BAT vascular resistance, which greatly increases vascular perfusion of BAT. This enhancement enables precise identification and quantification of BAT mass not only in lean, but also in obese, mouse phenotypes, in which this tissue is invisible to conventional tomographic imaging techniques. The method is developed and validated in rodents and then applied in macaques to assess its feasibility in larger species. PMID- 29255048 TI - Form finding in elastic gridshells. AB - Elastic gridshells comprise an initially planar network of elastic rods that are actuated into a shell-like structure by loading their extremities. The resulting actuated form derives from the elastic buckling of the rods subjected to inextensibility. We study elastic gridshells with a focus on the rational design of the final shapes. Our precision desktop experiments exhibit complex geometries, even from seemingly simple initial configurations and actuation processes. The numerical simulations capture this nonintuitive behavior with excellent quantitative agreement, allowing for an exploration of parameter space that reveals multistable states. We then turn to the theory of smooth Chebyshev nets to address the inverse design of hemispherical elastic gridshells. The results suggest that rod inextensibility, not elastic response, dictates the zeroth-order shape of an actuated elastic gridshell. As it turns out, this is the shape of a common household strainer. Therefore, the geometry of Chebyshev nets can be further used to understand elastic gridshells. In particular, we introduce a way to quantify the intrinsic shape of the empty, but enclosed regions, which we then use to rationalize the nonlocal deformation of elastic gridshells to point loading. This justifies the observed difficulty in form finding. Nevertheless, we close with an exploration of concatenating multiple elastic gridshell building blocks. PMID- 29255047 TI - Enzyme leaps fuel antichemotaxis. AB - There is mounting evidence that enzyme diffusivity is enhanced when the enzyme is catalytically active. Here, using superresolution microscopy [stimulated emission depletion fluorescence correlation spectroscopy (STED-FCS)], we show that active enzymes migrate spontaneously in the direction of lower substrate concentration ("antichemotaxis") by a process analogous to the run-and-tumble foraging strategy of swimming microorganisms and our theory quantifies the mechanism. The two enzymes studied, urease and acetylcholinesterase, display two families of transit times through subdiffraction-sized focus spots, a diffusive mode and a ballistic mode, and the latter transit time is close to the inverse rate of catalytic turnover. This biochemical information-processing algorithm may be useful to design synthetic self-propelled swimmers and nanoparticles relevant to active materials. Executed by molecules lacking the decision-making circuitry of microorganisms, antichemotaxis by this run-and-tumble process offers the biological function to homogenize product concentration, which could be significant in situations when the reactant concentration varies from spot to spot. PMID- 29255049 TI - Dietary species richness as a measure of food biodiversity and nutritional quality of diets. AB - Biodiversity is key for human and environmental health. Available dietary and ecological indicators are not designed to assess the intricate relationship between food biodiversity and diet quality. We applied biodiversity indicators to dietary intake data from and assessed associations with diet quality of women and young children. Data from 24-hour diet recalls (55% in the wet season) of n = 6,226 participants (34% women) in rural areas from seven low- and middle-income countries were analyzed. Mean adequacies of vitamin A, vitamin C, folate, calcium, iron, and zinc and diet diversity score (DDS) were used to assess diet quality. Associations of biodiversity indicators with nutrient adequacy were quantified using multilevel models, receiver operating characteristic curves, and test sensitivity and specificity. A total of 234 different species were consumed, of which <30% were consumed in more than one country. Nine species were consumed in all countries and provided, on average, 61% of total energy intake and a significant contribution of micronutrients in the wet season. Compared with Simpson's index of diversity and functional diversity, species richness (SR) showed stronger associations and better diagnostic properties with micronutrient adequacy. For every additional species consumed, dietary nutrient adequacy increased by 0.03 (P < 0.001). Diets with higher nutrient adequacy were mostly obtained when both SR and DDS were maximal. Adding SR to the minimum cutoff for minimum diet diversity improved the ability to detect diets with higher micronutrient adequacy in women but not in children. Dietary SR is recommended as the most appropriate measure of food biodiversity in diets. PMID- 29255050 TI - Gender disparities in colloquium speakers at top universities. AB - Colloquium talks at prestigious universities both create and reflect academic researchers' reputations. Gender disparities in colloquium talks can arise through a variety of mechanisms. The current study examines gender differences in colloquium speakers at 50 prestigious US colleges and universities in 2013-2014. Using archival data, we analyzed 3,652 talks in six academic disciplines. Men were more likely than women to be colloquium speakers even after controlling for the gender and rank of the available speakers. Eliminating alternative explanations (e.g., women declining invitations more often than men), our follow up data revealed that female and male faculty at top universities reported no differences in the extent to which they (i) valued and (ii) turned down speaking engagements. Additional data revealed that the presence of women as colloquium chairs (and potentially on colloquium committees) increased the likelihood of women appearing as colloquium speakers. Our data suggest that those who invite and schedule speakers serve as gender gatekeepers with the power to create or reduce gender differences in academic reputations. PMID- 29255051 TI - Correction for Waldrop, News Feature: The genuine problem of fake news. PMID- 29255052 TI - Observational evidence of European summer weather patterns predictable from spring. AB - Forecasts of summer weather patterns months in advance would be of great value for a wide range of applications. However, seasonal dynamical model forecasts for European summers have very little skill, particularly for rainfall. It has not been clear whether this low skill reflects inherent unpredictability of summer weather or, alternatively, is a consequence of weaknesses in current forecast systems. Here we analyze atmosphere and ocean observations and identify evidence that a specific pattern of summertime atmospheric circulation--the summer East Atlantic (SEA) pattern--is predictable from the previous spring. An index of North Atlantic sea-surface temperatures in March-April can predict the SEA pattern in July-August with a cross-validated correlation skill above 0.6. Our analyses show that the sea-surface temperatures influence atmospheric circulation and the position of the jet stream over the North Atlantic. The SEA pattern has a particularly strong influence on rainfall in the British Isles, which we find can also be predicted months ahead with a significant skill of 0.56. Our results have immediate application to empirical forecasts of summer rainfall for the United Kingdom, Ireland, and northern France and also suggest that current dynamical model forecast systems have large potential for improvement. PMID- 29255053 TI - SIMS analyses of the oldest known assemblage of microfossils document their taxon correlated carbon isotope compositions. AB - Analyses by secondary ion mass spectroscopy (SIMS) of 11 specimens of five taxa of prokaryotic filamentous kerogenous cellular microfossils permineralized in a petrographic thin section of the ~3,465 Ma Apex chert of northwestern Western Australia, prepared from the same rock sample from which this earliest known assemblage of cellular fossils was described more than two decades ago, show their delta13C compositions to vary systematically taxon to taxon from -310/00 to -390/00. These morphospecies-correlated carbon isotope compositions confirm the biogenicity of the Apex fossils and validate their morphology-based taxonomic assignments. Perhaps most significantly, the delta13C values of each of the five taxa are lower than those of bulk samples of Apex kerogen (-270/00), those of SIMS-measured fossil-associated dispersed particulate kerogen (-27.60/00), and those typical of modern prokaryotic phototrophs (-25 +/- 100/00). The SIMS data for the two highest delta13C Apex taxa are consistent with those of extant phototrophic bacteria; those for a somewhat lower delta13C taxon, with nonbacterial methane-producing Archaea; and those for the two lowest delta13C taxa, with methane-metabolizing gamma-proteobacteria. Although the existence of both methanogens and methanotrophs has been inferred from bulk analyses of the carbon isotopic compositions of pre-2,500 Ma kerogens, these in situ SIMS analyses of individual microfossils present data interpretable as evidencing the cellular preservation of such microorganisms and are consistent with the near basal position of the Archaea in rRNA phylogenies. PMID- 29255054 TI - Direct electrical stimulation of the amygdala enhances declarative memory in humans. AB - Emotional events are often remembered better than neutral events, a benefit that many studies have hypothesized to depend on the amygdala's interactions with memory systems. These studies have indicated that the amygdala can modulate memory-consolidation processes in other brain regions such as the hippocampus and perirhinal cortex. Indeed, rodent studies have demonstrated that direct activation of the amygdala can enhance memory consolidation even during nonemotional events. However, the premise that the amygdala causally enhances declarative memory has not been directly tested in humans. Here we tested whether brief electrical stimulation to the amygdala could enhance declarative memory for specific images of neutral objects without eliciting a subjective emotional response. Fourteen epilepsy patients undergoing monitoring of seizures via intracranial depth electrodes viewed a series of neutral object images, half of which were immediately followed by brief, low-amplitude electrical stimulation to the amygdala. Amygdala stimulation elicited no subjective emotional response but led to reliably improved memory compared with control images when patients were given a recognition-memory test the next day. Neuronal oscillations in the amygdala, hippocampus, and perirhinal cortex during this next-day memory test indicated that a neural correlate of the memory enhancement was increased theta and gamma oscillatory interactions between these regions, consistent with the idea that the amygdala prioritizes consolidation by engaging other memory regions. These results show that the amygdala can initiate endogenous memory prioritization processes in the absence of emotional input, addressing a fundamental question and opening a path to future therapies. PMID- 29255055 TI - Antagonistic actions of juvenile hormone and 20-hydroxyecdysone within the ring gland determine developmental transitions in Drosophila. AB - In both vertebrates and insects, developmental transition from the juvenile stage to adulthood is regulated by steroid hormones. In insects, the steroid hormone, 20-hydroxyecdysone (20E), elicits metamorphosis, thus promoting this transition, while the sesquiterpenoid juvenile hormone (JH) antagonizes 20E signaling to prevent precocious metamorphosis during the larval stages. However, not much is known about the mechanisms involved in cross-talk between these two hormones. In this study, we discovered that in the ring gland (RG) of Drosophila larvae, JH and 20E control each other's biosynthesis. JH induces expression of a Kruppel like transcription factor gene Kr-h1 in the prothoracic gland (PG), a portion of the RG that produces the 20E precursor ecdysone. By reducing both steroidogenesis autoregulation and PG size, high levels of Kr-h1 in the PG inhibit ecdysteriod biosynthesis, thus maintaining juvenile status. JH biosynthesis is prevented by 20E in the corpus allatum, the other portion of the RG that produces JH, to ensure the occurrence of metamorphosis. Hence, antagonistic actions of JH and 20E within the RG determine developmental transitions in Drosophila Our study proposes a mechanism of cross-talk between the two major hormones in the regulation of insect metamorphosis. PMID- 29255056 TI - Three-dimensional forces exerted by leukocytes and vascular endothelial cells dynamically facilitate diapedesis. AB - Leukocyte transmigration across vessel walls is a critical step in the innate immune response. Upon their activation and firm adhesion to vascular endothelial cells (VECs), leukocytes preferentially extravasate across junctional gaps in the endothelial monolayer (paracellular diapedesis). It has been hypothesized that VECs facilitate paracellular diapedesis by opening their cell-cell junctions in response to the presence of an adhering leukocyte. However, it is unclear how leukocytes interact mechanically with VECs to open the VEC junctions and migrate across the endothelium. In this study, we measured the spatial and temporal evolution of the 3D traction stresses generated by the leukocytes and VECs to elucidate the sequence of mechanical events involved in paracellular diapedesis. Our measurements suggest that the contractile stresses exerted by the leukocytes and the VECs can separately perturb the junctional tensions of VECs to result in the opening of gaps before the initiation of leukocyte transmigration. Decoupling the stresses exerted by the transmigrating leukocytes and the VECs reveals that the leukocytes actively contract the VECs to open a junctional gap and then push themselves across the gap by generating strong stresses that push into the matrix. In addition, we found that diapedesis is facilitated when the tension fluctuations in the VEC monolayer were increased by proinflammatory thrombin treatment. Our findings demonstrate that diapedesis can be mechanically regulated by the transmigrating leukocytes and by proinflammatory signals that increase VEC contractility. PMID- 29255057 TI - Bifidobacterium can mitigate intestinal immunopathology in the context of CTLA-4 blockade. AB - Antibodies that attenuate immune tolerance have been used to effectively treat cancer, but they can also trigger severe autoimmunity. To investigate this, we combined anti-CTLA-4 treatment with a standard colitis model to give mice a more severe form of the disease. Pretreatment with an antibiotic, vancomycin, provoked an even more severe, largely fatal form, suggesting that a Gram-positive component of the microbiota had a mitigating effect. We then found that a commonly used probiotic, Bifidobacterium, could largely rescue the mice from immunopathology without an apparent effect on antitumor immunity, and this effect may be dependent on regulatory T cells. PMID- 29255058 TI - Dynamic Prognostic Score to Predict Kidney Allograft Survival in Patients with Antibody-Mediated Rejection. AB - No tool is available for the early assessment of response to antibody-mediated rejection (ABMR) therapies in kidney allograft recipients. This study was designed to define a dynamic composite prognostic ABMR score to predict kidney allograft survival, integrating the disease characteristics at diagnosis and the response to treatment. Among 1978 kidney recipients who underwent transplant between 2008 and 2014, we included 278 patients diagnosed with active ABMR and receiving standard treatment, including plasma exchange, intravenous Ig, and rituximab. Patients were prospectively assessed at diagnosis and after treatment for clinical data, histologic characteristics (allograft biopsy specimen), and donor-specific anti-HLA antibodies (DSA). The dynamic ABMR prediction model included GFR (P<0.001) and presence of interstitial fibrosis/tubular atrophy (P=0.003) at diagnosis and changes in GFR (P<0.001), peritubular capillaritis Banff score (P=0.002), and DSA mean fluorescence intensity (P<0.001) after treatment. Overall, this model showed good calibration and discrimination (C statistic=0.84). The ABMR prognostic score derived from the prediction model identified three risk strata with 6-year kidney allograft survival rates of 6.0% (high-risk group, n=40), 44.9% (intermediate-risk group, n=36), and 84.4% (low risk group, n=202), and it provided greater net clinical benefit to patients than did considering them all to have the same level of risk of allograft loss. The performance of the ABMR prognostic score was validated in an independent cohort of 202 kidney recipients with ABMR (C-statistic=0.79). The ABMR prognostic score could be used to inform therapeutic decisions in clinical practice and for the design of clinical trials. PMID- 29255059 TI - Pharmacologic and clinical assessment of kratom. AB - PURPOSE: This article reviews the pharmacology, clinical utility, adverse effects, and abuse potential of kratom. SUMMARY: The leaves of Mitragyna speciosa contain the biologically active alkaloids of kratom. Kratom exerts opioid and alpha-2 receptor agonistic effects as well as antiinflammatory and parasympathetic-impeding effects. There are no published human pharmacologic, pharmacokinetic, or drug interaction studies on kratom or mitragynine, making it virtually impossible to fully understand kratom's therapeutic potential and risks and the populations most likely to benefit or experience harm from its use. Kratom has been used to ameliorate opioid withdrawal symptoms but also induces withdrawal. Human pharmacologic, pharmacokinetic, and clinical data are of low quality, precluding any firm conclusions regarding safety and efficacy. Respiratory depression has not been commonly reported, but kratom does cause a host of adverse effects without clear guidance for how they should be treated. There are numerous assessments where people have been unable to stop using kratom therapy, and withdrawal signs and symptoms are problematic. Kratom does not appear in normal drug screens and, when taken with other substances of abuse, may not be recognized. Thirty-six deaths have been attributed to kratom, and the Food and Drug Administration issued a public health warning about the substance in November 2017. CONCLUSION: Kratom exerts opioid and alpha-2 receptor agonistic effects as well as antiinflammatory and parasympathetic-impeding effects. Human pharmacologic, pharmacokinetic, and clinical data are of low quality, precluding any firm conclusions regarding safety and efficacy. PMID- 29255060 TI - The Bidirectional Association Between Depression and Severe Hypoglycemic and Hyperglycemic Events in Type 1 Diabetes. AB - OBJECTIVE: Severe hyperglycemia and hypoglycemia ("severe dysglycemia") are serious complications of type 1 diabetes (T1D). Depression has been associated with severe dysglycemia in type 2 diabetes but has not been thoroughly examined specifically in T1D. We evaluated bidirectional associations between depression and severe dysglycemia among older people with T1D. RESEARCH DESIGN AND METHODS: We abstracted depression and severe dysglycemia requiring emergency room visit or hospitalization from medical health records in 3,742 patients with T1D during the study period (1996-2015). Cox proportional hazards models estimated the associations between depression and severe dysglycemia in both directions, adjusting for demographics, micro- and macrovascular complications, and HbA1c. RESULTS: During the study period, 41% had depression and 376 (11%) and 641 (20%) had hyperglycemia and hypoglycemia, respectively. Depression was strongly associated with a 2.5-fold increased risk of severe hyperglycemic events (hazard ratio [HR] 2.47 [95% CI 2.00, 3.05]) and 89% increased risk of severe hypoglycemic events (HR 1.89 [95% CI 1.61, 2.22]). The association was strongest within the first 6 months (HRhyperglycemia 7.14 [95% CI 5.29, 9.63]; HRhypoglycemia 5.58 [95% CI 4.46, 6.99]) to 1 year (HRhyperglycemia 5.16 [95% CI 3.88, 6.88]; HRhypoglycemia 4.05 [95% CI 3.26, 5.04]) after depression diagnosis. In models specifying severe dysglycemia as the exposure, hyperglycemic and hypoglycemic events were associated with 143% (HR 2.43 [95% CI 2.03, 2.91]) and 74% (HR 1.75 [95% CI 1.49, 2.05]) increased risk of depression, respectively. CONCLUSIONS: Depression and severe dysglycemia are associated bidirectionally among patients with T1D. Depression greatly increases the risk of severe hypoglycemic and hyperglycemic events, particularly in the first 6 months to 1 year after diagnosis, and depression risk increases after severe dysglycemia episodes. PMID- 29255061 TI - Effect of Changing Work Stressors and Coping Resources on the Risk of Type 2 Diabetes: The OHSPIW Cohort Study. AB - OBJECTIVE: Little is known about the relationship between changing psychosocial work conditions and type 2 diabetes. We determined whether changing work stressors and coping resources affect the risk of type 2 diabetes. RESEARCH DESIGN AND METHODS: In this prospective cohort (2003-2014) of 3,740 workers without diabetes (OHSPIW [Occupational Health Study of Petroleum Industry Workers]), participants completed an evaluation of work-related stress and coping resources and type 2 diabetes diagnosis at baseline and 12 years follow-up (two waves). The changes in work stressors and coping resources were measured with the Occupation Stress Inventory-Revised and the Instrument for Stress-Related Job Analysis (Version 6.0). Type 2 diabetes was diagnosed on the basis of an oral glucose tolerance test supplemented by physician report. RESULTS: Increased task stressors (relative risk [RR] 1.57 [95% CI 1.03-2.63]) and decreased coping resources (RR 1.68 [95% CI 1.02-2.83]) were associated with risk of type 2 diabetes. The main risk factors were increased role overload, increased role insufficiency, increased physical environment stressors, decreased self-care, and decreased rational coping. Increased coping resources also had a buffering effect on increased task stressors and type 2 diabetes. CONCLUSIONS: Changes in work stressors and coping resources have an influence on the risk for type 2 diabetes, highlighting the importance of preventive measures against adverse psychosocial work conditions and reduced coping resources for diabetes prevention in the workplace. PMID- 29255065 TI - The Dialysis Facility Compare Five-Star Rating System at 2 Years. PMID- 29255064 TI - A View of the Bundle from a Home Dialysis Perspective: Present at the Creation. PMID- 29255063 TI - Drosophila Bag-of-marbles directly interacts with the CAF40 subunit of the CCR4 NOT complex to elicit repression of mRNA targets. AB - Drosophila melanogaster Bag-of-marbles (Bam) promotes germline stem cell (GSC) differentiation by repressing the expression of mRNAs encoding stem cell maintenance factors. Bam interacts with Benign gonial cell neoplasm (Bgcn) and the CCR4 deadenylase, a catalytic subunit of the CCR4-NOT complex. Bam has been proposed to bind CCR4 and displace it from the CCR4-NOT complex. Here, we investigated the interaction of Bam with the CCR4-NOT complex by using purified recombinant proteins. Unexpectedly, we found that Bam does not interact with CCR4 directly but instead binds to the CAF40 subunit of the complex in a manner mediated by a conserved N-terminal CAF40-binding motif (CBM). The crystal structure of the Bam CBM bound to CAF40 reveals that the CBM peptide adopts an alpha-helical conformation after binding to the concave surface of the crescent shaped CAF40 protein. We further show that Bam-mediated mRNA decay and translational repression depend entirely on Bam's interaction with CAF40. Thus, Bam regulates the expression of its mRNA targets by recruiting the CCR4-NOT complex through interaction with CAF40. PMID- 29255066 TI - A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL. AB - Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naive patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD- rates between arms, the log of the PFS hazard ratio decreased by 0.188 (95% confidence interval, -0.321 to -0.055; P = .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action. PMID- 29255062 TI - Mutations in the U11/U12-65K protein associated with isolated growth hormone deficiency lead to structural destabilization and impaired binding of U12 snRNA. AB - Mutations in the components of the minor spliceosome underlie several human diseases. A subset of patients with isolated growth hormone deficiency (IGHD) harbors mutations in the RNPC3 gene, which encodes the minor spliceosome-specific U11/U12-65K protein. Although a previous study showed that IGHD patient cells have defects in U12-type intron recognition, the biochemical effects of these mutations on the 65K protein have not been characterized. Here, we show that a proline-to-threonine missense mutation (P474T) and a nonsense mutation (R502X) in the C-terminal RNA recognition motif (C-RRM) of the 65K protein impair the binding of 65K to U12 and U6atac snRNAs. We further show that the nonsense allele is targeted to the nonsense-mediated decay (NMD) pathway, but in an isoform specific manner, with the nuclear-retained 65K long-3'UTR isoform escaping the NMD pathway. In contrast, the missense P474T mutation leads, in addition to the RNA-binding defect, to a partial defect in the folding of the C-RRM and reduced stability of the full-length protein, thus reducing the formation of U11/U12 di snRNP complexes. We propose that both the C-RRM folding defect and NMD-mediated decrease in the levels of the U11/U12-65K protein reduce formation of the U12 type intron recognition complex and missplicing of a subset of minor introns leading to pituitary hypoplasia and a subsequent defect in growth hormone secretion. PMID- 29255067 TI - How I treat CLL patients with ibrutinib. AB - Ibrutinib is a transformative therapy for high-risk and relapsed refractory chronic lymphocytic leukemia (CLL) patients. In clinical trials in relatively healthy younger patients, ibrutinib has been well tolerated. As its use has become more widespread in the community, however, its full adverse event profile has emerged and proven more challenging than was initially anticipated. Reports of community-based use have estimated discontinuation rates as high as 40% in the first year of therapy. This article therefore reviews my approach to the evaluation and management of a CLL patient starting on ibrutinib, with the goal of minimizing and managing toxicity to maintain patients on ibrutinib. Key topics discussed include bleeding risk; cardiac complications, particularly atrial fibrillation; drug interactions; and infections. PMID- 29255069 TI - Loss of NRF2 function exacerbates the pathophysiology of sickle cell disease in a transgenic mouse model. AB - The basic leucine zipper transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays a critical role in the cellular antioxidant response under oxidative stress conditions. In this study, we investigated the role of NRF2 in fetal hemoglobin expression and the pathophysiology of sickle cell disease (SCD) in a NRF2 knockout (SCD/NRF2-/-) transgenic mouse model. NRF2 loss impaired survival of SCD pups during gestation and in the first 2 months of life. Furthermore, fetal hemoglobin expression was inhibited during erythropoiesis in embryonic day 13.5 and embryonic day 18.5 fetal liver and adult spleen and bone marrow cells, respectively. Examination of peripheral red blood cells revealed an increase of reactive oxygen species (ROS) and sickling under hypoxic conditions. Loss of NRF2 function in SCD/NRF2-/- mice produced greater splenomegaly with red pulp expansion and obscured architecture. In addition, NRF2 knockout reduced the expression of its target antioxidant proteins, leading to increased levels of ROS, proinflammatory cytokines, and adhesion molecules in SCD mice. Genetic knockout of NRF2 demonstrates its role in developmentally regulated gamma-globin gene expression and the ability to control oxidative stress and the phenotypic severity of SCD. PMID- 29255068 TI - Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia. AB - Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO2). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO2, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA (P < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels. PMID- 29255070 TI - How I treat disseminated intravascular coagulation. AB - Disseminated intravascular coagulation (DIC) is a condition characterized by systemic activation of coagulation, potentially leading to thrombotic obstruction of small and midsize vessels, thereby contributing to organ dysfunction. At the same time, ongoing consumption of platelets and coagulation proteins results in thrombocytopenia and low concentrations of clotting factors, which may cause profuse hemorrhagic complications. DIC is always secondary to an underlying condition, such as severe infections, solid or hematologic malignancies, trauma, or obstetric calamities. A reliable diagnosis of DIC can be made through simple scoring algorithms based on readily available routine hemostatic parameters. The cornerstone of supportive treatment of this coagulopathy is management of the underlying condition. Additionally, administration of heparin may be useful, and restoration of physiological anticoagulants has been suggested, but has not been proven successful in improving clinically relevant outcomes so far. In patients with major bleeding or at risk for hemorrhagic complications, administration of platelet concentrates, plasma, or coagulation factor concentrates should be considered. PMID- 29255071 TI - Geographical Variations in Blood Pressure Level and Seasonality in Hemodialysis Patients. AB - Seasons and climate influence the regulation of blood pressure (BP) in the general population and in hemodialysis patients. It is unknown whether this phenomenon varies across the world. Our objective was to estimate BP seasonality in hemodialysis patients from different geographical locations. Patients from 7 European countries (Spain, Italy, France, Belgium, Germany, United Kingdom, and Sweden) participating in the DOPPS (Dialysis Outcomes and Practice Patterns Study) on years 2005 to 2011 were studied. Factors influencing pre- and postdialysis systolic BP and diastolic BP levels were analyzed by mixed models. There were 9655 patients (median age, 68; 59% male) from 263 facilities, seen every 4 months during a median duration of 1.3 years. Pre- and postdialysis systolic BP increased by a mean estimate of 5.1 mm Hg (95% confidence interval [CI], 3.7-6.4 mm Hg) and 4.4 mm Hg (95% CI, 2.9-5.9 mm Hg) for each 10 degrees increase in latitude (1111 km to the North). In the longitudinal analysis, predialysis systolic BP was lower in summer and higher in winter (difference, 1.7 mm Hg; 95% CI, 1.3-2.2 mm Hg), with greater differences in southern locations (Pinteraction=0.04). Predialysis systolic BP was inversely associated with outdoor temperature (-0.8 mm Hg/7.2 degrees C; 95% CI, -1.0 to -0.5 mm Hg/7.2 degrees C), with steeper slopes in southern locations (Pinteraction=0.005). Results were similar for predialysis diastolic BP. In conclusion, there is a geographical and seasonal gradient of BP in European hemodialysis patients. There is a need to consider these effects when evaluating and treating BP in this population and potentially in others. PMID- 29255072 TI - Peak Blood Pressure Responses During Maximum Cardiopulmonary Exercise Testing: Reference Standards From FRIEND (Fitness Registry and the Importance of Exercise: A National Database). AB - The objective of this study is to expand on previous efforts in establishing normative standards of exercising blood pressure (BP) at maximal physical exertion derived from treadmill cardiopulmonary exercise testing in the United States. Four experienced laboratories in the United States with established quality control procedures contributed data from September 1, 1986, to February 1, 2015. A total of 2917 maximal (peak respiratory exchange ratio >=1.00) treadmill cardiopulmonary exercise testing responses from apparently healthy men and women (aged 20-79 years) without cardiovascular disease were submitted to FRIEND (Fitness Registry and the Importance of Exercise: A National Database). Percentiles of maximal systolic and diastolic BP were determined for each decade. Our results show a continued increase in peak systolic BP with age in both men and women to the sixth decade, followed by a plateau between the sixth and seventh decades. However, the trajectory of peak diastolic BP with age is different between men and women. Men showed an increase in peak systolic BP until the fifth decade, which plateaued by the seventh decade. In contrast, women showed a continued increase in peak diastolic BP across each decade. Existing reference data for exercising BP have not been updated for >20 years. Normative peak exercising BP values from FRIEND can be used to provide a more current representation of maximal BP during exercise testing in the US population. PMID- 29255074 TI - Attended Versus Unattended Blood Pressure Measurement in a Real Life Setting. AB - The debate on the generalizability of the SPRINT (Systolic Blood Pressure Intervention Trial) findings raised considerable interest in the technique of unattended office blood pressure (BP) measurement. It remains elusive, however, whether unattended BP measurement yields lower values than conventional measurements in a real world setting with subjects consulting their personal general practitioner in a familiar office. We performed a cross-sectional study in 158 patients in 4 general practitioners' offices and compared conventional auscultatory office BP to unattended automated office BP in 107 subjects (group 1) and unattended to attended automated office BP in another 51 subjects (group 2). Unattended BP was calculated as the mean of 3 automated measurements performed in a separate room after 5 minutes of rest. Additionally, patients documented home BP for 7 days after the consultation. Mean auscultatory office, unattended office and home BP were 144.6/81.0, 144.1/79.9, and 135.5/78.3 mm Hg in group 1; unattended and attended automated office BP were 134.2/80.6 and 135.7/80.6 mm Hg in group 2. Systolic attended and unattended office BP values were significantly higher than home BP (P<0.001, P<0.01, respectively). Attended and unattended office BP, however, did neither show a significant difference in group 1 nor in group 2 (P>0.05 each). Bland-Altman analysis revealed a bias of 0.5 mm Hg systolic and 1.1 mm Hg diastolic in group 1 and -1.5 mm Hg systolic and 0 mm Hg diastolic in group 2. In conclusion, the present findings show that unattended and attended office BP measurements achieve comparable results, if measurements take place at a familiar general practitioner's office. PMID- 29255073 TI - MicroRNA-221/222 Family Counteracts Myocardial Fibrosis in Pressure Overload Induced Heart Failure. AB - Pressure overload causes cardiac fibroblast activation and transdifferentiation, leading to increased interstitial fibrosis formation and subsequently myocardial stiffness, diastolic and systolic dysfunction, and eventually heart failure. A better understanding of the molecular mechanisms underlying pressure overload induced cardiac remodeling and fibrosis will have implications for heart failure treatment strategies. The microRNA (miRNA)-221/222 family, consisting of miR-221 3p and miR-222-3p, is differentially regulated in mouse and human cardiac pathology and inversely associated with kidney and liver fibrosis. We investigated the role of this miRNA family during pressure overload-induced cardiac remodeling. In myocardial biopsies of patients with severe fibrosis and dilated cardiomyopathy or aortic stenosis, we found significantly lower miRNA 221/222 levels as compared to matched patients with nonsevere fibrosis. In addition, miRNA-221/222 levels in aortic stenosis patients correlated negatively with the extent of myocardial fibrosis and with left ventricular stiffness. Inhibition of both miRNAs during AngII (angiotensin II)-mediated pressure overload in mice led to increased fibrosis and aggravated left ventricular dilation and dysfunction. In rat cardiac fibroblasts, inhibition of miRNA-221/222 derepressed TGF-beta (transforming growth factor-beta)-mediated profibrotic SMAD2 (mothers against decapentaplegic homolog 2) signaling and downstream gene expression, whereas overexpression of both miRNAs blunted TGF-beta-induced profibrotic signaling. We found that the miRNA-221/222 family may target several genes involved in TGF-beta signaling, including JNK1 (c-Jun N-terminal kinase 1), TGF-beta receptor 1 and TGF-beta receptor 2, and ETS-1 (ETS proto-oncogene 1). Our findings show that heart failure-associated downregulation of the miRNA 221/222 family enables profibrotic signaling in the pressure-overloaded heart. PMID- 29255075 TI - Cutting Edge: Allograft Rejection Is Associated with Weak T Cell Responses to Many Different Graft Leukocyte-Derived Peptides. AB - Organ transplants are rapidly rejected because T cells in the recipient attack the foreign MHC molecules on the graft. The robustness of the T cell response to histoincompatible tissue is not understood. We found that mice have many small T cell populations with Ag receptors specific for a foreign MHC class II molecule type loaded with peptides from leukocytes from the graft. These T cells proliferated modestly after skin transplantation and underwent relatively weak functional differentiation compared with T cells stimulated by a vaccine. Thus, the potency of the T cell response to histoincompatible tissue is likely due to many small T cell populations responding weakly to hundreds of MHC-bound peptides from graft-derived leukocytes. PMID- 29255076 TI - Intestinal Inflammation-Mediated Clearance of Amebic Parasites Is Dependent on IFN-gamma. AB - Intestinal amebiasis is a major cause of diarrhea. However, research on host amebae interactions has been hampered owing to a lack of appropriate animal models. Recently, a mouse model of intestinal amebiasis was established, and using it, we reported that Entamoeba moshkovskii colonized the intestine in a manner similar to that of the pathogenic Entamoeba histolytica In this study, we evaluated the protective mechanisms present against amebae using this model. CBA/J mice infected with E. histolytica had a persistent infection without apparent symptoms. In contrast, E. moshkovskii-infected mice rapidly expelled the ameba, which was associated with weight loss, diarrhea, and intestinal damage characterized by apoptosis of intestinal epithelial cells (IECs). Expression of NKG2D on intestinal intraepithelial lymphocytes (IELs) and IFN-gamma-producing cells in Peyer's patches were significantly induced after infection with E. moshkovskii but not with E. histolytica IFN-gamma-deficient mice infected with E. moshkovskii showed no obvious symptoms. Notably, none of these mice expelled E. moshkovskii, indicating that IFN-gamma is responsible not only for intestinal symptoms but also for the expulsion of amebae. Furthermore, apoptosis of IECs and expression of NKG2D on IELs observed in E. moshkovskii-infected mice did not occur in the absence of IFN-gamma. In vivo blocking of NKG2D in mice infected with E. moshkovskii enabled ameba to survive longer and remarkably reduced apoptotic IECs. Our results clearly demonstrate a novel protective mechanism exerted by IFN-gamma against intestinal amebae, including induction of cytotoxicity of IELs toward IECs. PMID- 29255077 TI - Deficiency of the AIM2-ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-gamma Immunity in Mycobacterial Infection. AB - The nucleic acids of Mycobacterium tuberculosis can be detected by intracellular DNA sensors, such as cyclic GMP-AMP synthase and absent in melanoma 2 (AIM2), which results in the release of type I IFN and the proinflammatory cytokine IL 1beta. However, whether cross-talk occurs between AIM2-IL-1beta and cyclic GMP AMP synthase-type I IFN signaling upon M. tuberculosis infection in vivo is unclear. In this article, we demonstrate that mycobacterial infection of AIM2-/- mice reciprocally induces overreactive IFN-beta and depressive IFN-gamma responses, leading to higher infection burdens and more severe pathology. We also describe the underlying mechanism whereby activated apoptosis-associated speck like protein interacts with a key adaptor, known as stimulator of IFN genes (STING), and inhibits the interaction between STING and downstream TANK-binding kinase 1 in bone marrow-derived macrophages and bone marrow-derived dendritic cells, consequently reducing the induction of type I IFN. Of note, apoptosis associated speck-like protein expression is inversely correlated with IFN-beta levels in PBMCs from tuberculosis patients. These data demonstrate that the AIM2 IL-1beta signaling pathway negatively regulates the STING-type I IFN signaling pathway by impeding the association between STING and TANK-binding kinase 1, which protects the host from M. tuberculosis infection. This finding has potential clinical significance. PMID- 29255078 TI - ATP Evokes Ca2+ Responses and CXCL5 Secretion via P2X4 Receptor Activation in Human Monocyte-Derived Macrophages. AB - Leukocytes sense extracellular ATP, a danger-associated molecular pattern, released during cellular stress and death, via activation of cell surface P2X and P2Y receptors. Here, we investigate P2 receptor expression in primary human monocyte-derived macrophages and receptors that mediate ATP-evoked intracellular [Ca2+]i signals and cytokine production in response to ATP concentrations that exclude P2X7 receptor activation. Expression of P2X1, P2X4, P2X5, P2X7, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, and P2Y13 was confirmed by quantitative RT-PCR and immunocytochemistry. ATP elicited intracellular Ca2+ responses in a concentration dependent fashion (EC50 = 11.4 +/- 2.9 MUM, n = 3). P2Y11 and P2Y13 activations mediated the amplitude of [Ca2+]i response, whereas P2X4 activation, but not P2X1 or P2X7, determined the duration of Ca2+ response during a sustained phase. ATP mediated gene induction of CXCL5, a proinflammatory chemokine. P2X4 antagonism (PSB-12062 or BX430) inhibited ATP-mediated induction of CXCL5 gene expression and secretion of CXCL5 by primary macrophage. Inhibition of CXCL5 secretion by P2X4 antagonists was lost in the absence of extracellular Ca2+ Reciprocally, positive allosteric modulation of P2X4 (ivermectin) augmented ATP-mediated CXCL5 secretion. P2X7, P2Y11, or P2Y13 receptor did not contribute to CXCL5 secretion. Together, the data reveals a role for P2X4 in determining the duration of ATP evoked Ca2+ responses and CXCL5 secretion in human primary macrophage. PMID- 29255079 TI - Death, injury and disability from kinetic impact projectiles in crowd-control settings: a systematic review. AB - OBJECTIVE: We conducted a systematic review of the available literature on deaths, injuries and permanent disability from rubber and plastic bullets, as well as from bean bag rounds, shot pellets and other projectiles used in arrests, protests and other contexts from 1 January 1990 until 1 June 2017. DATA SOURCES: PubMed, Scopus, JSTOR and grey literature. DATA SYNTHESIS: We report on descriptive statistics as well as data on injury severity, permanent disability and death. We analysed potential risk factors for injury severity, including the site of impact, firing distance and access to medical care. RESULTS: Of 3228 identified articles, 26 articles met inclusion criteria. These articles included injury data on 1984 people, 53 of whom died as a result of their injuries. 300 people suffered permanent disability. Deaths and permanent disability often resulted from strikes to the head and neck (49.1% of deaths and 82.6% of permanent disabilities). Of the 2135 injuries in those who survived their injuries, 71% were severe, injuries to the skin and to the extremities were most frequent. Anatomical site of impact, firing distance and timely access to medical care were correlated with injury severity and risk of disability. CONCLUSIONS: Kinetic impact projectiles (KIPs), often called rubber or plastic bullets, are used commonly in crowd-control settings. We find that these projectiles have caused significant morbidity and mortality during the past 27 years, much of it from penetrative injuries and head, neck and torso trauma. Given their inherent inaccuracy, potential for misuse and associated health consequences of severe injury, disability and death, KIPs do not appear to be appropriate weapons for use in crowd-control settings. There is an urgent need to establish international guidelines on the use of crowd-control weapons to prevent unnecessary injuries and deaths. PMID- 29255080 TI - Exemptions From Mandatory Immunization After Legally Mandated Parental Counseling. AB - BACKGROUND: The success of health care provider counseling-based interventions to address vaccine hesitancy is not clear. In 2011, Washington State implemented Senate Bill 5005 (SB5005), requiring counseling and a signed form from a licensed health care provider to obtain an exemption. Evaluating the impact of a counseling intervention can provide important insight into population-level interventions that focus on interpersonal communication by a health care provider. METHODS: We used segmented regression and interaction and aggregation indices to assess the impact of SB5005 on immunization coverage and exemption rates in Washington State from school years 1997-1998 through 2013-2014. RESULTS: After SB5005 was implemented, there was a significant relative decrease of 40.2% (95% confidence interval: -43.6% to -36.6%) in exemption rates. This translates to a significant absolute reduction of 2.9 percentage points (95% confidence interval: -4.2% to -1.7%) in exemption rates. There were increases in vaccine coverage for all vaccines required for school entrance, with the exception of the hepatitis B vaccine. The probability that kindergarteners without exemptions would encounter kindergarteners with exemptions (interaction index) decreased, and the probability that kindergarteners with exemptions would encounter other such kindergarteners (aggregation index) also decreased after SB5005. Moreover, SB5005 was associated with a decline in geographic clustering of vaccine exemptors. CONCLUSIONS: States in the United States and jurisdictions in other countries should consider adding parental counseling by health care provider as a requirement for obtaining exemptions to vaccination requirements. PMID- 29255081 TI - ADHD and Early Experience: Revisiting the Case of Low Birth Weight. PMID- 29255082 TI - Restoring Community Immunity in America. PMID- 29255083 TI - Attention-Deficit/Hyperactivity Disorder and Very Preterm/Very Low Birth Weight: A Meta-analysis. AB - CONTEXT: Although very preterm (VP), extremely preterm (EP), very low birth weight (VLBW), and extremely low birth weight (ELBW) newborns seem to have a higher risk of later attention-deficit/hyperactivity disorder (ADHD), the magnitude of the risk is not well-defined. OBJECTIVE: To systematically review and meta-analyze the risk of VP/VLBW and EP/ELBW individuals to develop a ADHD categorical diagnosis or dimensional symptomatology compared with controls with normal weight and/or birth age. DATA SOURCES: We used PsycINFO, Medline, Embase, and Cochrane databases. STUDY SELECTION: We selected cross-sectional, prospective, or retrospective studies with no time or language restriction. DATA EXTRACTION: Independent reviewers screened and extracted data using predefined standard procedures. RESULTS: In 12 studies (N = 1787), researchers relying on a categorical diagnosis showed that both VP/VLBW and EP/ELBW subjects have a higher ADHD risk (odds ratio [OR] = 3.04 higher than controls; 95% confidence interval [CI] 2.19 to 4.21). In subgroup analyses, we demonstrated that the more extreme the cases, the higher the ORs (VP/VLBW: OR = 2.25 [95% CI 1.56 to 3.26]; EP/ELBW: OR = 4.05 [95% CI 2.38 to 6.87]). We drew data from 29 studies (N = 3504) on ADHD symptomatology and found significant associations with inattention (standardized mean difference [SMD] = 1.31, 95% CI 0.66 to 1.96), hyperactivity and impulsivity (SMD = 0.74, 95% CI 0.35 to 1.13), and combined symptoms (SMD = 0.55, 95% CI 0.42 to 0.68) when compared with controls. LIMITATIONS: Heterogeneity was significantly high for all analyses involving the 3 ADHD dimensions. CONCLUSIONS: With our results, we provide evidence that VP/VLBW subjects have an increased risk of ADHD diagnosis and symptomatology compared with controls, and these findings are even stronger in the EP/ELBW group. Future researchers should address which risk factors related to prematurity or low birth weight lead to ADHD. PMID- 29255084 TI - Roles of activating functions 1 and 2 of estrogen receptor alpha in lymphopoiesis. AB - Apart from the role of sex steroids in reproduction, sex steroids are also important regulators of the immune system. 17beta-estradiol (E2) represses T and B cell development, but augments B cell function, possibly explaining the different nature of immune responses in men and women. Both E2 and selective estrogen receptors modulators (SERM) act via estrogen receptors (ER). Activating functions (AF)-1 and 2 of the ER bind to coregulators and thus influence target gene transcription and subsequent cellular response to ER activation. The importance of ERalphaAF-1 and AF-2 in the immunomodulatory effects of E2/SERM has previously not been reported. Thus, detailed studies of T and B lymphopoiesis were performed in ovariectomized E2-, lasofoxifene- or raloxifene-treated mice lacking either AF-1 or AF-2 domains of ERalpha, and their wild-type littermate controls. Immune cell phenotypes were analyzed with flow cytometry. All E2 and SERM-mediated inhibitory effects on thymus cellularity and thymic T cell development were clearly dependent on both ERalphaAFs. Interestingly, divergent roles of ERalphaAF-1 and ERalphaAF-2 in E2 and SERM-mediated modulation of bone marrow B lymphopoiesis were found. In contrast to E2, effects of lasofoxifene on early B cells did not require functional ERalphaAF-2, while ERalphaAF-1 was indispensable. Raloxifene reduced early B cells partly independent of both ERalphaAF-1 and ERalphaAF-2. Results from this study increase the understanding of the impact of ER modulation on the immune system, which can be useful in the clarification of the molecular actions of SERMs and in the development of new SERM. PMID- 29255086 TI - The Reign of Antibodies: A Celebration of and Tribute to Michael Potter and His Homogeneous Immunoglobulin Workshops. PMID- 29255085 TI - A Beginner's Guide to Analyzing and Visualizing Mass Cytometry Data. AB - Mass cytometry has revolutionized the study of cellular and phenotypic diversity, significantly expanding the number of phenotypic and functional characteristics that can be measured at the single-cell level. This high-dimensional analysis platform has necessitated the development of new data analysis approaches. Many of these algorithms circumvent traditional approaches used in flow cytometric analysis, fundamentally changing the way these data are analyzed and interpreted. For the beginner, however, the large number of algorithms that have been developed, as well as the lack of consensus on best practices for analyzing these data, raise multiple questions: Which algorithm is the best for analyzing a dataset? How do different algorithms compare? How can one move beyond data visualization to gain new biological insights? In this article, we describe our experiences as recent adopters of mass cytometry. By analyzing a single dataset using five cytometry by time-of-flight analysis platforms (viSNE, SPADE, X-shift, PhenoGraph, and Citrus), we identify important considerations and challenges that users should be aware of when using these different methods and common and unique insights that can be revealed by these different methods. By providing annotated workflow and figures, these analyses present a practical guide for investigators analyzing high-dimensional datasets. In total, these analyses emphasize the benefits of integrating multiple cytometry by time-of-flight analysis algorithms to gain complementary insights into these high-dimensional datasets. PMID- 29255087 TI - Pillars Article: Evidence for Amino Acid Sequence Differences among Proteins Resembling the L-chain Subunits of Immunoglobulins. J. Mol. Biol. 1965. 12: 81 87. PMID- 29255088 TI - Salmonella Vaccines: Conduits for Protective Antigens. AB - Vaccines afford a better and more cost-effective approach to combatting infectious diseases than continued reliance on antibiotics or antiviral or antiparasite drugs in the current era of increasing incidences of diseases caused by drug-resistant pathogens. Recombinant attenuated Salmonella vaccines (RASVs) have been significantly improved to exhibit the same or better attributes than wild-type parental strains to colonize internal lymphoid tissues and persist there to serve as factories to continuously synthesize and deliver rAgs. Encoded by codon-optimized pathogen genes, Ags are selected to induce protective immunity to infection by that pathogen. After immunization through a mucosal surface, the RASV attributes maximize their abilities to elicit mucosal and systemic Ab responses and cell-mediated immune responses. This article summarizes many of the numerous innovative technologies and discoveries that have resulted in RASV platforms that will enable development of safe efficacious RASVs to protect animals and humans against a diversity of infectious disease agents. PMID- 29255089 TI - G4941K substitution in the pore-lining S6 helix of the skeletal muscle ryanodine receptor increases RyR1 sensitivity to cytosolic and luminal Ca2. AB - The ryanodine receptor ion channel RyR1 is present in skeletal muscle and has a large cytoplasmic N-terminal domain and smaller C-terminal pore-forming domain comprising six transmembrane helices, a pore helix, and a selectivity filter. The RyR1 S6 pore-lining helix has two conserved glycines, Gly-4934 and Gly-4941, that facilitate RyR1 channel gating by providing S6 flexibility and minimizing amino acid clashes. Here, we report that substitution of Gly-4941 with Asp or Lys results in functional channels as indicated by caffeine-induced Ca2+ release response in HEK293 cells, whereas a low response of the corresponding Gly-4934 variants suggested loss of function. Following purification, the RyR1 mutants G4934D, G4934K, and G4941D did not noticeably conduct Ca2+ in single-channel measurements. Gly-4941 replacement with Lys resulted in channels having reduced K+ conductance and reduced selectivity for Ca2+ compared with wildtype. RyR1 G4941K did not fully close at nanomolar cytosolic Ca2+ concentrations and nearly fully opened at 2 MUm cytosolic or sarcoplasmic reticulum luminal Ca2+, and Ca2+- and voltage-dependent regulation of RyR1-G4941K mutant channels was demonstrated. Computational methods and single-channel recordings indicated that the open G4941K variant results in the formation of a salt bridge to Asp-4938. In contrast, wildtype RyR1 was closed and not activated by luminal Ca2+ at low cytosolic Ca2+ levels. A model suggested that luminal Ca2+ activates RyR1 by accessing a recently identified cytosolic Ca2+-binding site in the open channel as the Ca2+ ions pass through the pore. PMID- 29255090 TI - Kelch-like ECH-associated protein 1 (KEAP1) differentially regulates nuclear factor erythroid-2-related factors 1 and 2 (NRF1 and NRF2). AB - Nuclear factor erythroid-2-related factor 1 (NRF1) and NRF2 are essential for maintaining redox homeostasis and coordinating cellular stress responses. They are highly homologous transcription factors that regulate the expression of genes bearing antioxidant-response elements (AREs). Genetic ablation of NRF1 or NRF2 results in vastly different phenotypic outcomes, implying that they play different roles and may be differentially regulated. Kelch-like ECH-associated protein 1 (KEAP1) is the main negative regulator of NRF2 and mediates ubiquitylation and degradation of NRF2 through its NRF2-ECH homology-like domain 2 (Neh2). Here, we report that KEAP1 binds to the Neh2-like (Neh2L) domain of NRF1 and stabilizes it. Consistently, NRF1 is more stable in KEAP1+/+ than in KEAP1-/- isogenic cell lines, whereas NRF2 is dramatically stabilized in KEAP1-/- cells. Replacing NRF1's Neh2L domain with NRF2's Neh2 domain renders NRF1 sensitive to KEAP1-mediated degradation, indicating that the amino acids between the DLG and ETGE motifs, not just the motifs themselves, are essential for KEAP1 mediated degradation. Systematic site-directed mutagenesis identified the core amino acid residues required for KEAP1-mediated degradation and further indicated that the DLG and ETGE motifs with correct spacing are insufficient as a KEAP1 degron. Our results offer critical insights into our understanding of the differential regulation of NRF1 and NRF2 by KEAP1 and their different physiological roles. PMID- 29255091 TI - Mechanisms of bacterial membrane permeabilization by crotalicidin (Ctn) and its fragment Ctn(15-34), antimicrobial peptides from rattlesnake venom. AB - Crotalicidin (Ctn), a cathelicidin-related peptide from the venom of a South American rattlesnake, possesses potent antimicrobial, antitumor, and antifungal properties. Previously, we have shown that its C-terminal fragment, Ctn(15-34), retains the antimicrobial and antitumor activities but is less toxic to healthy cells and has improved serum stability. Here, we investigated the mechanisms of action of Ctn and Ctn(15-34) against Gram-negative bacteria. Both peptides were bactericidal, killing ~90% of Escherichia coli and Pseudomonas aeruginosa cells within 90-120 and 5-30 min, respectively. Studies of zeta potential at the bacterial cell membrane suggested that both peptides accumulate at and neutralize negative charges on the bacterial surface. Flow cytometry experiments confirmed that both peptides permeabilize the bacterial cell membrane but suggested slightly different mechanisms of action. Ctn(15-34) permeabilized the membrane immediately upon addition to the cells, whereas Ctn had a lag phase before inducing membrane damage and exhibited more complex cell-killing activity, probably because of two different modes of membrane permeabilization. Using surface plasmon resonance and leakage assays with model vesicles, we confirmed that Ctn(15-34) binds to and disrupts lipid membranes and also observed that Ctn(15-34) has a preference for vesicles that mimic bacterial or tumor cell membranes. Atomic force microscopy visualized the effect of these peptides on bacterial cells, and confocal microscopy confirmed their localization on the bacterial surface. Our studies shed light onto the antimicrobial mechanisms of Ctn and Ctn(15-34), suggesting Ctn(15-34) as a promising lead for development as an antibacterial/antitumor agent. PMID- 29255092 TI - Ligand-activated epidermal growth factor receptor (EGFR) signaling governs endocytic trafficking of unliganded receptor monomers by non-canonical phosphorylation. AB - The canonical description of transmembrane receptor function is initial binding of ligand, followed by initiation of intracellular signaling and then internalization en route to degradation or recycling to the cell surface. It is known that low concentrations of extracellular ligand lead to a higher proportion of receptor that is recycled and that non-canonical mechanisms of receptor activation, including phosphorylation by the kinase p38, can induce internalization and recycling. However, no connections have been made between these pathways; i.e. it has yet to be established what happens to unbound receptors following stimulation with ligand. Here we demonstrate that a minimal level of activation of epidermal growth factor receptor (EGFR) tyrosine kinase by low levels of ligand is sufficient to fully activate downstream mitogen-activated protein kinase (MAPK) pathways, with most of the remaining unbound EGFR molecules being efficiently phosphorylated at intracellular serine/threonine residues by activated mitogen-activated protein kinase. This non-canonical, p38-mediated phosphorylation of the C-tail of EGFR, near Ser-1015, induces the clathrin mediated endocytosis of the unliganded EGFR monomers, which occurs slightly later than the canonical endocytosis of ligand-bound EGFR dimers via tyrosine autophosphorylation. EGFR endocytosed via the non-canonical pathway is largely recycled back to the plasma membrane as functional receptors, whereas p38 independent populations are mainly sorted for lysosomal degradation. Moreover, ligand concentrations balance these endocytic trafficking pathways. These results demonstrate that ligand-activated EGFR signaling controls unliganded receptors through feedback phosphorylation, identifying a dual-mode regulation of the endocytic trafficking dynamics of EGFR. PMID- 29255093 TI - X-linked inhibitor of apoptosis protein (XIAP) is a client of heat shock protein 70 (Hsp70) and a biomarker of its inhibition. AB - Heat shock protein 70 (Hsp70) and Hsp90 are molecular chaperones that play essential roles in tumor growth by stabilizing pro-survival client proteins. However, although the development of Hsp90 inhibitors has benefited from the identification of clients, such as Raf-1 proto-oncogene, Ser/Thr kinase (RAF1), that are particularly dependent on this chaperone, no equivalent clients for Hsp70 have been reported. Using chemical probes and MDA-MB-231 breast cancer cells, we found here that the inhibitors of apoptosis proteins, including c-IAP1 and X-linked inhibitor of apoptosis protein (XIAP), are obligate Hsp70 clients that are rapidly (within ~3-12 h) lost after inhibition of Hsp70 but not of Hsp90. Mutagenesis and pulldown experiments revealed multiple Hsp70-binding sites on XIAP, suggesting that it is a direct, physical Hsp70 client. Interestingly, this interaction was unusually tight (~260 nm) for an Hsp70-client interaction and involved non-canonical regions of the chaperone. Finally, we also found that Hsp70 inhibitor treatments caused loss of c-IAP1 and XIAP in multiple cancer cell lines and in tumor xenografts, but not in healthy cells. These results are expected to significantly accelerate Hsp70 drug discovery by providing XIAP as a pharmacodynamic biomarker. More broadly, our findings further suggest that Hsp70 and Hsp90 have partially non-overlapping sets of obligate protein clients in cancer cells. PMID- 29255094 TI - Genetic testing for indeterminate thyroid cytology: review and meta-analysis. AB - Thyroid cancer is the most frequent endocrine malignancy, and its incidence is increasing. A current limitation of cytological evaluation of thyroid nodules is that 20-25% are reported as indeterminate. Therefore, an important challenge for clinicians is to determine whether an indeterminate nodule is malignant, and should undergo surgery, or benign, and should be recommended to follow-up. The emergence of precision medicine has offered a valuable solution for this problem, with four tests currently available for the molecular diagnosis of indeterminate cytologies. However, efforts to critically analyze the quality of the accumulated evidence are scarce. This systematic review and meta-analysis is aimed to contribute to a better knowledge about the four available molecular tests, their technical characteristics, clinical performance, and ultimately to help clinicians to make better decisions to provide the best care options possible. For this purpose, we address three critical topics: (i) the proper theoretical accuracy, considering the intended clinical use of the test (rule-in vs rule-out) and the impact on clinical decisions; (ii) the quality of the evidence reported for each test (iii) and how accurate and effective have the tests proved to be after their clinical use. Together with the upcoming evidence, this work provides significant and useful information for healthcare system decision-makers to consider the use of molecular testing as a public health need, avoiding unnecessary surgical risks and costs. PMID- 29255095 TI - Mesenteric fibrosis and palliative surgery in small intestinal neuroendocrine tumours. AB - Mesenteric fibrosis (MF) surrounding a mesenteric mass is a hallmark feature of small intestinal neuroendocrine tumours (SI-NETs). Since this can induce intestinal obstruction, oedema and ischaemia, prophylactic resection of the primary tumour and mesenteric mass is often recommended. This study assessed the predictors for mesenteric metastasis and fibrosis and the effect of MF and palliative surgery on survival. A retrospective analysis of 559 patients with pathologically proven SI-NET and available CT-imaging data was performed. Clinical characteristics, presence of mesenteric mass and fibrosis on CT imaging and the effect of palliative abdominal surgery on overall survival were assessed. We found that MF was present in 41.4%. Older age, 5-HIAA excretion >=67 MUmol/24 h, serum CgA >=121.5 MUg/L and a mesenteric mass >=27.5 mm were independent predictors of MF. In patients <=52 years, mesenteric mass was less often found in women than in men (39% vs 64%, P = 0.002). Corrected for age, tumour grade, CgA and liver metastasis, MF was not a prognostic factor for overall survival. In patients undergoing palliative surgery, metastasectomy of mesenteric mass or prophylactic surgery did not result in survival benefit. In conclusion, we confirmed known predictors of MF and mesenteric mass and suggest a role for sex hormones as women <=52 years have less often a mesenteric mass. Furthermore, the presence of MF has no effect on survival in a multivariate analysis, and we found no benefit of metastasectomy of mesenteric mass or prophylactic surgery on overall survival. PMID- 29255097 TI - We need to mandate drug cost transparency on electronic medical records. PMID- 29255096 TI - Tetrac downregulates beta-catenin and HMGA2 to promote the effect of resveratrol in colon cancer. AB - The molecular pathogenesis of colorectal cancer encompasses the activation of several oncogenic signaling pathways that include the Wnt/beta-catenin pathway and the overexpression of high mobility group protein A2 (HMGA2). Resveratrol - the polyphenolic phytoalexin - binds to integrin alphavbeta3 to induce apoptosis in cancer cells via cyclooxygenase 2 (COX-2) nuclear accumulation and p53 dependent apoptosis. Tetraiodothyroacetic acid (tetrac) is a de-aminated derivative of l-thyroxine (T4), which - in contrast to the parental hormone - impairs cancer cell proliferation. In the current study, we found that tetrac promoted resveratrol-induced anti-proliferation in colon cancer cell lines, in primary cultures of colon cancer cells, and in vivo The mechanisms implicated in this action involved the downregulation of nuclear beta-catenin and HMGA2, which are capable of compromising resveratrol-induced COX-2 nuclear translocation. Silencing of either beta-catenin or HMGA2 promoted resveratrol-induced anti proliferation and COX-2 nuclear accumulation which is essential for integrin alphavbeta3-mediated-resveratrol-induced apoptosis in cancer cells. Concurrently, tetrac enhanced nuclear abundance of chibby family member 1, the nuclear beta catenin antagonist, which may further compromise the nuclear beta-catenin dependent gene expression and proliferation. Taken together, these results suggest that tetrac targets beta-catenin and HMGA2 to promote resveratrol-induced anti-proliferation in colon cancers, highlighting its potential in anti-cancer combination therapy. PMID- 29255099 TI - Newborn screening for severe combined immunodeficiency: a primer for clinicians. PMID- 29255100 TI - Risks of novel therapeutics: gonococcemia in an immune-suppressed patient receiving eculizumab. PMID- 29255101 TI - Calcific tendinitis of the gluteus maximus of a 53-year-old woman. PMID- 29255098 TI - Probiotic capsules and xylitol chewing gum to manage symptoms of pharyngitis: a randomized controlled factorial trial. AB - BACKGROUND: Reducing the use of antibiotics for upper respiratory tract infections is needed to limit the global threat of antibiotic resistance. We estimated the effectiveness of probiotics and xylitol for the management of pharyngitis. METHODS: In this parallel-group factorial randomized controlled trial, participants in primary care (aged 3 years or older) with pharyngitis underwent randomization by nurses who provided sequential intervention packs. Pack contents for 3 kinds of material and advice were previously determined by computer-generated random numbers: no chewing gum, xylitol-based chewing gum (15% xylitol; 5 pieces daily) and sorbitol gum (5 pieces daily). Half of each group were also randomly assigned to receive either probiotic capsules (containing 24 * 109 colony-forming units of lactobacilli and bifidobacteria) or placebo. The primary outcome was mean self-reported severity of sore throat and difficulty swallowing (scale 0-6) in the first 3 days. We used multiple imputation to avoid the assumption that data were missing completely at random. RESULTS: A total of 1009 individuals consented, 934 completed the baseline assessment, and 689 provided complete data for the primary outcome. Probiotics were not effective in reducing the severity of symptoms: mean severity scores 2.75 with no probiotic and 2.78 with probiotic (adjusted difference -0.001, 95% confidence interval [CI] -0.24 to 0.24). Chewing gum was also ineffective: mean severity scores 2.73 without gum, 2.72 with sorbitol gum (adjusted difference 0.07, 95% CI -0.23 to 0.37) and 2.73 with xylitol gum (adjusted difference 0.01, 95% CI -0.29 to 0.30). None of the secondary outcomes differed significantly between groups, and no harms were reported. INTERPRETATION: Neither probiotics nor advice to chew xylitol-based chewing gum was effective for managing pharyngitis. Trial registration: ISRCTN, no. ISRCTN51472596. PMID- 29255102 TI - The Canadian Medical Association should support a medical access stream for cannabis. PMID- 29255103 TI - Updating our language around substance use disorders. PMID- 29255104 TI - Viral misinformation threatens public health. PMID- 29255105 TI - An outpatient "evolution" in orthopedic surgery. PMID- 29255107 TI - Beyond health care: the other determinants of health. PMID- 29255106 TI - Medical schools addressing student anxiety, burnout and depression. PMID- 29255108 TI - Associations between diagnostic activity and measures of patient experience in primary care: a cross-sectional ecological study of English general practices. AB - BACKGROUND: Lower use of endoscopies and urgent referrals for suspected cancer has been linked to poorer outcomes for patients with cancer; it is important to examine potential predictors of variable use. AIM: To examine the associations between general practice measures of patient experience and practice use of endoscopies or urgent referrals for suspected cancer. DESIGN AND SETTING: Cross sectional ecological analysis in English general practices. METHOD: Data were taken from the GP Patient Survey and the Cancer Services Public Health Profiles. After adjustment for practice population characteristics, practice-level associations were examined between the use of endoscopy and urgent referrals for suspected cancer, and the ability to book an appointment (used as proxy for ease of access), the ability to see a preferred doctor (used as proxy for relational continuity), and doctor/nurse communication skills. RESULTS: Taking into account practice scores for the ability to book an appointment, practices rated higher for the proxy measure of relational continuity used urgent referrals and endoscopies less often (for example, 30% lower urgent referral and 15% lower gastroscopy rates between practices in the 90th/10th centiles, respectively). In contrast, practices rated higher for doctor communication skills used urgent referrals and endoscopies more often (for example, 26% higher urgent referral and 17% higher gastroscopy rates between practices in the 90th/10th centiles, respectively). Patients with cancer in practices that were rated higher for doctor communication skills were less likely to be diagnosed as emergencies (1.7% lower between practices in the 90th than in the 10th centile). CONCLUSION: Practices where patients rated doctor communication highly were more likely to investigate and refer patients urgently but, in contrast, practices where patients could see their preferred doctor more readily were less likely to do so. This article discusses the possible implications of these findings for clinical practice. PMID- 29255110 TI - GPs' perceptions of advance care planning with frail and older people: a qualitative study. AB - BACKGROUND: Frail and older people are estimated to account for 40% of deaths. Despite conversations about end-of-life care being an important component of the national End of Life Care Strategy, there is a marked disparity between the majority who would like to discuss advance care plans, and the minority who currently have this opportunity. AIM: To investigate the attitudes of GPs to advance care planning (ACP) discussions with frail and older individuals. DESIGN AND SETTING: Focus group study with GPs in Cambridgeshire between September 2015 and January 2016. METHOD: Five focus groups with 21 GPs were purposively sampled to maximise diversity. Framework analysis was used to analyse transcripts and develop themes. RESULTS: Although some GPs were concerned it might cause distress, the majority felt that raising ACP was important, especially as preparation for future emergencies. Knowing the individuals, introducing the idea as part of ongoing discussions, and public awareness campaigns were all facilitators identified. Several considered that service limitations made it difficult to fulfil patients' wishes and risked raising unrealistic patient expectations. Other barriers identified included uncertainty over prognosis and difficulties ensuring that individuals' wishes were respected. CONCLUSION: Most GPs viewed ACP as important. However, their enthusiasm was tempered by experience. This study highlights the difficulties for GPs of encouraging dialogue and respecting individuals' wishes within the constraints of the existing health and social care system. National publicity campaigns and encouraging patients to prioritise healthcare outcomes could help GPs raise care preferences without causing a detrimental impact on patients or raising unrealistic expectations. Once patients agree their care preferences, they need to be documented, accessible, and reviewed by all relevant health and social care providers to ensure that their wishes are respected, and plans amended as their circumstances change. PMID- 29255109 TI - PsyScan e-tool to support diagnosis and management of psychological problems in general practice: a randomised controlled trial. AB - BACKGROUND: GPs are crucial in adequately diagnosing and initiating appropriate management for patients with psychological problems, but face many challenges and require support. AIM: To determine the effects of the e-tool PsyScan. DESIGN AND SETTING: A randomised controlled trial with a 1-year follow-up, comparing care using PsyScan with usual care for psychological problems, was undertaken in 10 multidisciplinary primary healthcare centres in Eindhoven, the Netherlands. METHOD: Between consultations with their GP, participants in the intervention group could complete PsyScan. The e-tool consists of a distress screener and Four Dimensional Symptom Questionnaire to differentiate between stress, depression, anxiety, and somatisation symptoms, and to explore symptom severity. PsyScan generated diagnostic and therapeutic advice for GPs and participants that was automatically transferred to each patient's electronic medical record. The primary outcome was the proportion of participants that achieved a successful treatment result; namely, a decrease of >=50% on the Symptom Checklist-90 Revised, after 1 year. RESULTS: There were 176 participants in the intervention group and 160 in the control group. After multiple imputation, the participants in the intervention group had higher chances of achieving a successful treatment result compared with those in the control group (odds ratio [OR] 2.7, 95% confidence interval [CI] = 1.5 to 4.8, P = 0.002). Quality of life was higher in the intervention group at 12 months (mean difference in EuroQol 5 Dimensions 5 Levels index values was 0.076, 95% CI = 0.015 to 0.136, P = 0.01). The mean 1 year costs per participant were similar (?13 622 in intervention group, ?12 487 in control group [beta = -0.03, P = 0.71, R2 = 0.05]). CONCLUSION: PsyScan generated clinically relevant and statistically significant effects, and could be useful in offering effective individualised care to patients. PMID- 29255111 TI - Diagnosing cancer in primary care: results from the National Cancer Diagnosis Audit. AB - BACKGROUND: Continual improvements in diagnostic processes are needed to minimise the proportion of patients with cancer who experience diagnostic delays. Clinical audit is a means of achieving this. AIM: To characterise key aspects of the diagnostic process for cancer and to generate baseline measures for future re audit. DESIGN AND SETTING: Clinical audit of cancer diagnosis in general practices in England. METHOD: Information on patient and tumour characteristics held in the English National Cancer Registry was supplemented by information from GPs in participating practices. Data items included diagnostic timepoints, patient characteristics, and clinical management. RESULTS: Data were collected on 17 042 patients with a new diagnosis of cancer during 2014 from 439 practices. Participating practices were similar to non-participating ones, particularly regarding population age, urban/rural location, and practice-based patient experience measures. The median diagnostic interval for all patients was 40 days (interquartile range [IQR] 15-86 days). Most patients were referred promptly (median primary care interval 5 days [IQR 0-27 days]). Where GPs deemed diagnostic delays to have occurred (22% of cases), patient, clinician, or system factors were responsible in 26%, 28%, and 34% of instances, respectively. Safety netting was recorded for 44% of patients. At least one primary care-led investigation was carried out for 45% of patients. Most patients (76%) had at least one existing comorbid condition; 21% had three or more. CONCLUSION: The findings identify avenues for quality improvement activity and provide a baseline for future audit of the impact of 2015 National Institute for Health and Care Excellence guidance on management and referral of suspected cancer. PMID- 29255113 TI - RETRACTION. PMID- 29255112 TI - MLK1 and MLK2 Coordinate RGA and CCA1 Activity to Regulate Hypocotyl Elongation in Arabidopsis thaliana. AB - Gibberellins (GAs) modulate diverse developmental processes throughout the plant life cycle. However, the interaction between GAs and the circadian rhythm remains unclear. Here, we report that MUT9p-LIKE KINASE1 (MLK1) and MLK2 mediate the interaction between GAs and the circadian clock to regulate hypocotyl elongation in Arabidopsis thaliana DELLA proteins function as master growth repressors that integrate phytohormone signaling and environmental pathways in plant development. MLK1 and MLK2 interact with the DELLA protein REPRESSOR OF ga1-3 (RGA). Loss of MLK1 and MLK2 function results in plants with short hypocotyls and hyposensitivity to GAs. MLK1/2 and RGA directly interact with CIRCADIAN CLOCK ASSOCIATED1 (CCA1), which targets the promoter of DWARF4 (DWF4) to regulate its roles in cell expansion. MLK1/2 antagonize the ability of RGA to bind CCA1, and these factors coordinately regulate the expression of DWF4 RGA suppressed the ability of CCA1 to activate expression from the DWF4 promoter, but MLK1/2 reversed this suppression. Genetically, MLK1/2 act in the same pathway as RGA and CCA1 in hypocotyl elongation. Together, our results provide insight into the mechanism by which MLK1 and MLK2 antagonize the function of RGA in hypocotyl elongation and suggest that MLK1/2 coordinately mediate the regulation of plant development by GAs and the circadian rhythm in Arabidopsis. PMID- 29255114 TI - N-Glycan-dependent protein folding and endoplasmic reticulum retention regulate GPI-anchor processing. AB - Glycosylphosphatidylinositol (GPI) anchoring of proteins is a conserved posttranslational modification in the endoplasmic reticulum (ER). Soon after GPI is attached, an acyl chain on the GPI inositol is removed by post-GPI attachment to proteins 1 (PGAP1), a GPI-inositol deacylase. This is crucial for switching GPI-anchored proteins (GPI-APs) from protein folding to transport states. We performed haploid genetic screens to identify factors regulating GPI-inositol deacylation, identifying seven genes. In particular, calnexin cycle impairment caused inefficient GPI-inositol deacylation. Calnexin was specifically associated with GPI-APs, dependent on N-glycan and GPI moieties, and assisted efficient GPI inositol deacylation by PGAP1. Under chronic ER stress caused by misfolded GPI APs, inositol-acylated GPI-APs were exposed on the cell surface. These results indicated that N-glycans participate in quality control and temporal ER retention of GPI-APs, ensuring their correct folding and GPI processing before exiting from the ER. Once the system is disrupted by ER stress, unprocessed GPI-APs become exposed on the cell surface. PMID- 29255115 TI - Joint Analysis of Strain and Parent-of-Origin Effects for Recombinant Inbred Intercrosses Generated from Multiparent Populations with the Collaborative Cross as an Example. AB - Multiparent populations (MPP) have become popular resources for complex trait mapping because of their wider allelic diversity and larger population size compared with traditional two-way recombinant inbred (RI) strains. In mice, the collaborative cross (CC) is one of the most popular MPP and is derived from eight genetically diverse inbred founder strains. The strategy of generating RI intercrosses (RIX) from MPP in general and from the CC in particular can produce a large number of completely reproducible heterozygote genomes that better represent the (outbred) human population. Since both maternal and paternal haplotypes of each RIX are readily available, RIX is a powerful resource for studying both standing genetic and epigenetic variations of complex traits, in particular, the parent-of-origin (PoO) effects, which are important contributors to many complex traits. Furthermore, most complex traits are affected by >1 genes, where multiple quantitative trait locus mapping could be more advantageous. In this paper, for MPP-RIX data but taking CC-RIX as a working example, we propose a general Bayesian variable selection procedure to simultaneously search for multiple genes with founder allelic effects and PoO effects. The proposed model respects the complex relationship among RIX samples, and the performance of the proposed method is examined by extensive simulations. PMID- 29255116 TI - Selection Mapping Identifies Loci Underpinning Autumn Dormancy in Alfalfa (Medicago sativa). AB - Autumn dormancy in alfalfa (Medicago sativa) is associated with agronomically important traits including regrowth rate, maturity, and winter survival. Historical recurrent selection experiments have been able to manipulate the dormancy response. We hypothesized that artificial selection for dormancy phenotypes in these experiments had altered allele frequencies of dormancy related genes. Here, we follow this hypothesis and analyze allele frequency changes using genome-wide polymorphisms in the pre- and postselection populations from one historical selection experiment. We screened the nondormant cultivar CUF 101 and populations developed by three cycles of recurrent phenotypic selection for taller and shorter plants in autumn with markers derived from genotyping-by sequencing (GBS). We validated the robustness of our GBS-derived allele frequency estimates using an empirical approach. Our results suggest that selection mapping is a powerful means of identifying genomic regions associated with traits, and that it can be exploited to provide regions on which to focus further mapping and cloning projects. PMID- 29255119 TI - Recognized Outstanding Reviewers for Circulation in 2017. PMID- 29255117 TI - Genomic Prediction Accuracy for Resistance Against Piscirickettsia salmonis in Farmed Rainbow Trout. AB - Salmonid rickettsial syndrome (SRS), caused by the intracellular bacterium Piscirickettsia salmonis, is one of the main diseases affecting rainbow trout (Oncorhynchus mykiss) farming. To accelerate genetic progress, genomic selection methods can be used as an effective approach to control the disease. The aims of this study were: (i) to compare the accuracy of estimated breeding values using pedigree-based best linear unbiased prediction (PBLUP) with genomic BLUP (GBLUP), single-step GBLUP (ssGBLUP), Bayes C, and Bayesian Lasso (LASSO); and (ii) to test the accuracy of genomic prediction and PBLUP using different marker densities (0.5, 3, 10, 20, and 27 K) for resistance against P. salmonis in rainbow trout. Phenotypes were recorded as number of days to death (DD) and binary survival (BS) from 2416 fish challenged with P. salmonis A total of 1934 fish were genotyped using a 57 K single-nucleotide polymorphism (SNP) array. All genomic prediction methods achieved higher accuracies than PBLUP. The relative increase in accuracy for different genomic models ranged from 28 to 41% for both DD and BS at 27 K SNP. Between different genomic models, the highest relative increase in accuracy was obtained with Bayes C (~40%), where 3 K SNP was enough to achieve a similar accuracy to that of the 27 K SNP for both traits. For resistance against P. salmonis in rainbow trout, we showed that genomic predictions using GBLUP, ssGBLUP, Bayes C, and LASSO can increase accuracy compared with PBLUP. Moreover, it is possible to use relatively low-density SNP panels for genomic prediction without compromising accuracy predictions for resistance against P. salmonis in rainbow trout. PMID- 29255120 TI - Absence of an Ideal Observer II: The Agonizing Search for Experts Without a Conflict of Interest. PMID- 29255118 TI - Genomic Prediction and Association Mapping of Curd-Related Traits in Gene Bank Accessions of Cauliflower. AB - Genetic resources are an important source of genetic variation for plant breeding. Genome-wide association studies (GWAS) and genomic prediction greatly facilitate the analysis and utilization of useful genetic diversity for improving complex phenotypic traits in crop plants. We explored the potential of GWAS and genomic prediction for improving curd-related traits in cauliflower (Brassica oleracea var. botrytis) by combining 174 randomly selected cauliflower gene bank accessions from two different gene banks. The collection was genotyped with genotyping-by-sequencing (GBS) and phenotyped for six curd-related traits at two locations and three growing seasons. A GWAS analysis based on 120,693 single nucleotide polymorphisms identified a total of 24 significant associations for curd-related traits. The potential for genomic prediction was assessed with a genomic best linear unbiased prediction model and BayesB. Prediction abilities ranged from 0.10 to 0.66 for different traits and did not differ between prediction methods. Imputation of missing genotypes only slightly improved prediction ability. Our results demonstrate that GWAS and genomic prediction in combination with GBS and phenotyping of highly heritable traits can be used to identify useful quantitative trait loci and genotypes among genetically diverse gene bank material for subsequent utilization as genetic resources in cauliflower breeding. PMID- 29255121 TI - Embolic Stroke. PMID- 29255122 TI - Health Risks of Ionizing Radiation: Dr Roentgen Today. PMID- 29255123 TI - Atrial Fibrillation in Hypertrophic Cardiomyopathy: New Light on an Old Problem. PMID- 29255124 TI - Pyruvate Kinase and Warburg Metabolism in Pulmonary Arterial Hypertension: Uncoupled Glycolysis and the Cancer-Like Phenotype of Pulmonary Arterial Hypertension. PMID- 29255126 TI - Efforts Aim to Promote Safer Anticoagulant Prescribing. PMID- 29255127 TI - Highlights From the Circulation Family of Journals. PMID- 29255125 TI - Cardiac Imaging in Patients With Ventricular Tachycardia. AB - Ventricular tachycardia (VT) is a major cause of sudden cardiac death. The majority of malignant VTs occur in patients with structural heart disease. Multimodality imaging techniques play an integral role in determining the underlying etiology and prognostic significance of VT. In recent years, advances in imaging technology have enabled characterization of the structural arrhythmogenic substrate in patients with VT with increasing precision. In parallel with these advances, the role of cardiac imaging has expanded from a largely diagnostic tool to an adjunctive tool to guide interventional approaches for treatment of VT. Invasive and noninvasive imaging techniques, often used in combination, have made it possible to integrate structural and electrophysiological information during VT ablation procedures. An important area of current development is the use of noninvasive imaging techniques based on body surface electrocardiographic mapping to elucidate the mechanisms of VT. In the future, these techniques may provide a priori information on mechanisms of VT in patients undergoing interventional procedures. This review provides an overview of the role of cardiac imaging in patients with VT. PMID- 29255129 TI - Letter by Farina Regarding Article, "A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative". PMID- 29255128 TI - Left Ventricular Hypertrophy Revisited: Cell and Matrix Expansion Have Disease Specific Relationships. PMID- 29255130 TI - Response by Hess and Hiatt to Letter Regarding Article, "A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative". PMID- 29255131 TI - Letter by Jin-Shan and Xue-Bin Regarding Article, "Out-of-Hospital Cardiac Arrest: An Underlying Reversible Cause". PMID- 29255132 TI - Response by Derkenne et al Regarding Article, "Out-of-Hospital Cardiac Arrest: An Underlying Reversible Cause". PMID- 29255134 TI - Correction to: Direct Comparison of Cardiac Myosin-Binding Protein C With Cardiac Troponins for the Early Diagnosis of Acute Myocardial Infarction. PMID- 29255133 TI - Correction to: 2017 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations Summary. PMID- 29255135 TI - Notice of Retraction: Patient Education After CABG: Are We Teaching the Wrong Information? (Conference Abstract). PMID- 29255136 TI - Specificity of Phosphorylation Responses to Mitogen Activated Protein (MAP) Kinase Pathway Inhibitors in Melanoma Cells. AB - The BRAF-MKK1/2-ERK1/2 pathway is constitutively activated in response to oncogenic mutations of BRAF in many cancer types, including melanoma. Although small molecules that inhibit oncogenic BRAF and MAP kinase kinase (MKK)1/2 have been successful in clinical settings, resistance invariably develops. High affinity inhibitors of ERK1/2 have been shown in preclinical studies to bypass the resistance of melanoma and colon cancer cells to BRAF and MKK1/2 inhibitors, and are thus promising additions to current treatment protocols. But still unknown is how molecular responses to ERK1/2 inhibitors compare with inhibitors currently in clinical use. Here, we employ quantitative phosphoproteomics to evaluate changes in phosphorylation in response to the ERK inhibitors, SCH772984 and GDC0994, and compare these to the clinically used MKK1/2 inhibitor, trametinib. Combined with previous studies measuring phosphoproteomic responses to the MKK1/2 inhibitor, selumetinib, and the BRAF inhibitor, vemurafenib, the outcomes reveal key insights into pathway organization, phosphorylation specificity and off-target effects of these inhibitors. The results demonstrate linearity in signaling from BRAF to MKK1/2 and from MKK1/2 to ERK1/2. They identify likely targets of direct phosphorylation by ERK1/2, as well as inhibitor off-targets, including an off-target regulation of the p38alpha mitogen activated protein kinase (MAPK) pathway by the MKK1/2 inhibitor, trametinib, at concentrations used in the literature but higher than in vivo drug concentrations. In addition, several known phosphorylation targets of ERK1/2 are insensitive to MKK or ERK inhibitors, revealing variability in canonical pathway responses between different cell systems. By comparing multiple inhibitors targeted to multiple tiers of protein kinases in the MAPK pathway, we gain insight into regulation and new targets of the oncogenic BRAF driver pathway in cancer cells, and a useful approach for evaluating the specificity of drugs and drug candidates. PMID- 29255137 TI - Optimal Vitamin D Status in a Middle-Aged and Elderly Population Residing in Shanghai, China. AB - BACKGROUND The aim of this study was to investigate the optimal vitamin D status in the middle-aged and elderly population residing in Shanghai, China. MATERIAL AND METHODS A total of 1,829 males and postmenopausal females older than 45 years of age in the Changfeng community of Shanghai were included in this study. The optimal vitamin D level was determined according to the suppression of parathyroid hormone (PTH) and the highest bone mineral density (BMD). Locally weighted scatter plot smoothing (LOWESS) was performed to study the correlations of 25(OH)D with PTH and BMD in the lumbar spine and total hip, adjusting for gender, age, weight, use of calcium and vitamin D supplements, eGFR, smoking status, and alcohol consumption. RESULTS The mean serum 25(OH)D concentration was 48.0+/-19.2 nmol/L for the whole study population. The circulating PTH was maximally suppressed by the serum 25(OH)D of 55 nmol/L in the total population (60 nmol/L for males and 50 nmol/L for females). The 25(OH)D concentrations corresponding to the highest BMD at lumbar spine (L1-L4) and total hip were 53 nmol/L and 75 nmol/L, respectively, for the whole population. These values were also higher in males than females. CONCLUSIONS The optimal 25(OH)D concentration of 55 nmol/L is sufficient to maintain the bone health and metabolic status in middle-aged and elderly individuals living in Shanghai. Males probably need higher vitamin D concentration than females. There are differences between vitamin D status based on lumbar spine BMD and total hip BMD. PMID- 29255138 TI - Transfer of Everolimus into Colostrum of a Kidney Transplant Mother. AB - BACKGROUND Transplanted women are increasingly expressing their desire to breast feed. Due to the unknown effects that might occur in newborns of everolimus treated mothers, it is now recommended to inhibit lactation. This report discusses the assessment of everolimus levels in maternal, umbilical, and neonatal blood, and colostrum of a kidney transplant mother. CASE REPORT A 28 year-old white primipara after second kidney transplant, treated with everolimus, conceived unintentionally. Due to the high risk of recurrence of primary disease, the immunosuppressive treatment remained unchanged. At 37 weeks of gestation, due to mild preeclampsia, the woman was qualified for induction of labor and vaginally delivered a healthy infant. The highest concentration of everolimus in the colostrum was observed 4 h after drug administration and was 0.066 ng/ml. The estimated maximal dose of everolimus in colostrum was 0.38% of the mother's dose. CONCLUSIONS Breast-feeding in transplanted women treated with everolimus seems possible, particularly in mothers who are willing to breast-feed, especially in the first days after labor, when levels of immunoglobulins in colostrum are high and the concentrations of everolimus are low. PMID- 29255139 TI - Telluriding monolayer MoS2 and WS2 via alkali metal scooter. AB - The conversion of chalcogen atoms to other types in transition metal dichalcogenides has significant advantages for tuning bandgaps and constructing in-plane heterojunctions; however, difficulty arises from the conversion of sulfur or selenium to tellurium atoms owing to the low decomposition temperature of tellurides. Here, we propose the use of sodium for converting monolayer molybdenum disulfide (MoS2) to molybdenum ditelluride (MoTe2) under Te-rich vapors. Sodium easily anchors tellurium and reduces the exchange barrier energy by scooting the tellurium to replace sulfur. The conversion was initiated at the edges and grain boundaries of MoS2, followed by complete conversion in the entire region. By controlling sodium concentration and reaction temperature of monolayer MoS2, we tailored various phases such as semiconducting 2H-MoTe2, metallic 1T' MoTe2, and 2H-MoS2-x Te x alloys. This concept was further extended to WS2. A high valley polarization of ~37% in circularly polarized photoluminescence was obtained in the monolayer WS2-x Te x alloy at room temperature. PMID- 29255141 TI - High Density Arrayed Ni/NiO Core-shell Nanospheres Evenly Distributed on Graphene for Ultrahigh Performance Supercapacitor. AB - A novel NiO/Ni/RGO three-dimensional core-shell architecture consisting of Ni nanoparticles as core, NiO as shell and reduced graphene oxide (RGO) as conductivity layer, has been constructed by redox reactions with hydrothermal method and heat treatment. High density arrayed nickel nanoparticles (20 nm diameter) semi-coated by a 3 nm thick layer of NiO are evenly distributed on the surface of graphene. This elaborate design not only uses abundant NiO surfaces to provide a wealth of active sites, but also bridges electrochemical active NiO shell and graphene by Ni core to construct an interconnected 3D conductive network. Since both electrochemical activity and excellent conductivity are reserved in this Ni/NiO core-shell/graphene layer 3D structure, the as-prepared electrode material exhibits an extremely high specific capacitance (2048.3 F g-1 at current density of 1 A g-1) and excellent cycle stability (77.8% capacitance retention after 10000 cycles at current density of 50 A g-1). The novel method presented here is easy and effective and would provide reference for the preparation of other high performance supercapacitor electrodes. PMID- 29255140 TI - Frustration-driven C 4 symmetric order in a naturally-heterostructured superconductor Sr2VO3FeAs. AB - A subtle balance between competing interactions in iron-based superconductors (FeSCs) can be tipped by additional interfacial interactions in a heterostructure, often inducing exotic phases with unprecedented properties. Particularly when the proximity-coupled layer is magnetically active, rich phase diagrams are expected in FeSCs, but this has not been explored yet. Here, using high-accuracy 75As and 51V nuclear magnetic resonance measurements, we investigate an electronic phase that emerges in the FeAs layer below T 0 ~ 155 K of Sr2VO3FeAs, a naturally assembled heterostructure of an FeSC and a Mott insulating vanadium oxide. We find that frustration of the otherwise dominant Fe stripe and V Neel fluctuations via interfacial coupling induces a charge/orbital order in the FeAs layers, without either static magnetism or broken C 4 symmetry, while suppressing the Neel antiferromagnetism in the SrVO3 layers. These findings demonstrate that the magnetic proximity coupling stabilizes a hidden order in FeSCs, which may also apply to other strongly correlated heterostructures. PMID- 29255142 TI - A flexible ontology for inference of emergent whole cell function from relationships between subcellular processes. AB - Whole cell responses arise from coordinated interactions between diverse human gene products functioning within various pathways underlying sub-cellular processes (SCP). Lower level SCPs interact to form higher level SCPs, often in a context specific manner to give rise to whole cell function. We sought to determine if capturing such relationships enables us to describe the emergence of whole cell functions from interacting SCPs. We developed the Molecular Biology of the Cell Ontology based on standard cell biology and biochemistry textbooks and review articles. Currently, our ontology contains 5,384 genes, 753 SCPs and 19,180 expertly curated gene-SCP associations. Our algorithm to populate the SCPs with genes enables extension of the ontology on demand and the adaption of the ontology to the continuously growing cell biological knowledge. Since whole cell responses most often arise from the coordinated activity of multiple SCPs, we developed a dynamic enrichment algorithm that flexibly predicts SCP-SCP relationships beyond the current taxonomy. This algorithm enables us to identify interactions between SCPs as a basis for higher order function in a context dependent manner, allowing us to provide a detailed description of how SCPs together can give rise to whole cell functions. We conclude that this ontology can, from omics data sets, enable the development of detailed SCP networks for predictive modeling of emergent whole cell functions. PMID- 29255143 TI - Molecular characterization of a Rhodococcus jostii RHA1 gamma-butyrolactone( like) signalling molecule and its main biosynthesis gene gblA. AB - Rhodococcus genome sequence analysis has revealed a surprisingly large (and unexplored) potential for the production of secondary metabolites. Also, putative gamma-butyrolactone gene clusters have been identified in some Rhodococci. These signalling molecules are known to regulate secondary metabolism in Streptomyces. This work provides evidence for synthesis of a gamma-butyrolactone(-like) molecule by Rhodococci (RJB), the first report in the Rhodococcus genus. The Rhodococcus jostii RHA1 RJB molecule was detected by a reporter system based on the gamma-butyrolactone receptor protein (ScbR) of Streptomyces coelicolor. This RJB is structurally identical to 6-dehydro SCB2, the predicted precursor of the S. coelicolor gamma-butyrolactone SCB2. The R. jostii RHA1 key RJB biosynthesis gene was identified (gblA): Deletion of gblA resulted in complete loss of RJB synthesis whereas higher RJB levels were detected when gblA was overexpressed. Interaction of the RJB molecule with ScbR indicates that communication may occur between these two Actinomycete genera in their natural habitat. Furthermore, RJB may provide a highly relevant tool for awakening cryptic secondary metabolic gene clusters in Rhodococci. This study provides preliminary evidence that R. jostii RHA1 indeed synthesizes diffusible molecules with antimicrobial activity, but a possible role for RJB in this remains to be established. PMID- 29255144 TI - Characterization of a major QTL for manganese accumulation in rice grain. AB - Some diets lack sufficient manganese (Mn), an essential mineral. Increasing Mn in grain by biofortification could prevent Mn deficiency, but may increase levels of the toxic element cadmium (Cd). Here, we investigated Mn in rice (Oryza sativa) grains in recombinant inbred lines (RILs) from the cross of 93-11 (low grain Mn) with PA64s (high grain Mn). Quantitative trait locus (QTL) analysis to identify loci controlling grain Mn identified a major QTL, qGMN7.1, on the short arm of chromosome 7; qGMN7.1 explained 15.6% and 22.8% of the phenotypic variation in the RIL populations grown in two distinct environments. We validated the QTL with a chromosome segment substitution line (CSSL), CSSL-qGMN7.1, in the 93-11 background harboring qGMN7.1 from PA64s. Compared to 93-11, CSSL-qGMN7.1 grain had increased Mn and decreased Cd concentrations; CSSL-qGMN7.1 roots also showed enhanced Mn uptake. Fine mapping delimited qGMN7.1 to a 49.3-kb region containing OsNRAMP5, a gene responsible for Mn and Cd uptake. Sequence variations in the OsNRAMP5 promoter caused changes in its transcript level, and in grain Mn levels. Our study thus cloned a major QTL for grain Mn concentration in rice, and identified materials for breeding rice for high Mn and low Cd concentrations in the grain. PMID- 29255146 TI - Misato underlies visceral myopathy in Drosophila. AB - Genetic mechanisms for the pathogenesis of visceral myopathy (VM) have been rarely demonstrated. Here we report the visceral role of misato (mst) in Drosophila and its implications for the pathogenesis of VM. Depletion of mst using three independent RNAi lines expressed by a pan-muscular driver elicited characteristic symptoms of VM, such as abnormal dilation of intestinal tracts, reduced gut motility, feeding defects, and decreased life span. By contrast, exaggerated expression of mst reduced intestine diameters, but increased intestinal motilities along with thickened muscle fibers, demonstrating a critical role of mst in the visceral muscle. Mst expression was detected in the adult intestine with its prominent localization to actin filaments and was required for maintenance of intestinal tubulin and actomyosin structures. Consistent with the subcellular localization of Mst, the intestinal defects induced by mst depletion were dramatically rescued by exogenous expression of an actin member. Upon ageing the intestinal defects were deteriorative with marked increase of apoptotic responses in the visceral muscle. Taken together, we propose the impairment of actomyosin structures induced by mst depletion in the visceral muscle as a pathogenic mechanism for VM. PMID- 29255145 TI - Photoluminescence Study of the Photoinduced Phase Separation in Mixed-Halide Hybrid Perovskite CH3NH3Pb(BrxI1-x)3 Crystals Synthesized via a Solvothermal Method. AB - We systematically synthesized mixed-halide hybrid perovskite CH3NH3Pb(BrxI1-x)3 (0 <= x <= 1) crystals in the full composition range by a solvothermal method. The as-synthesized crystals retained cuboid shapes, and the crystalline structure transitioned from the tetragonal phase to the cubic phase with an increasing Br ion content. The photoluminescence (PL) of CH3NH3Pb(BrxI1-x)3 crystals exhibited a continuous variation from red (768 nm) to green (549 nm) with increasing the volume ratio of HBr (VHBr%), corresponding to a variation in the bandgap from 1.61 eV to 2.26 eV. Moreover, the bandgap of the crystals changed nonlinearly as a quadratic function of x with a bowing parameter of 0.53 eV. Notably, the CH3NH3Pb(BrxI1-x)3 (0.4 <= x <= 0.6) crystals exhibited obvious phase separation by prolonged illumination. The cause for the phase separation was attributed to the formation of small clusters enriched in lower-band-gap, iodide-rich and higher-band-gap, bromide-rich domains, which induced localized strain to promote halide phase separation. We also clarified the relationship between the PL features and the band structures of the crystals. PMID- 29255147 TI - Clinical outcomes of late decompression surgery following cervical spinal cord injury with pre-existing cord compression. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVES: The purpose of the current study was to examine the effectiveness of late decompression surgery for traumatic cervical spinal cord injury (CSCI) with pre-existing cord compression. SETTING: Murayama Medical Center, National Hospital Organization, Tokyo, Japan. METHODS: In total 78 patients with traumatic CSCI without bone injury hospitalized in 2012-2015 in our institute for rehabilitation after initial emergency care were divided into four groups according to the compression rate (CR) of the injured level and whether or not decompression surgery was performed. Neurological status was evaluated by American Spinal Injury Association impairment scale (AIS), Barthel index, and Spinal Cord Independence Measure (SCIM). RESULTS: In the severe compression group (CR >= 40%), >2 grade improvement in the AIS was observed in 30% of patients with surgical treatment, although it was not observed in any patient without surgery. The SCIM improvement rate at discharge was 60% in the surgical treatment group and 20% in the non surgical treatment group. In the minor compression group (CR < 40%), >2 grade improvement in the AIS was observed in 18% of patients with surgical treatment and in 11% without surgery. The SCIM improvement rate at discharge was 52% in the surgical treatment group and 43% in the non-surgical treatment group. CONCLUSIONS: These results indicate that surgical treatment has an advantage for patients following traumatic CSCI with severe cord compression. In contrast, surgical efficacy is not proved for CSCI patients without severe cord compression. PMID- 29255148 TI - Tyrosine phosphatase SHP2 negatively regulates NLRP3 inflammasome activation via ANT1-dependent mitochondrial homeostasis. AB - Aberrant activation of NLRP3 inflammasome has an important function in the pathogenesis of various inflammatory diseases. Although many components and mediators of inflammasome activation have been identified, how NLRP3 inflammasome is regulated to prevent excessive inflammation is unclear. Here we show NLRP3 inflammasome stimulators trigger Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) translocation to the mitochondria, to interact with and dephosphorylate adenine nucleotide translocase 1 (ANT1), a central molecule controlling mitochondrial permeability transition. This mechanism prevents collapse of mitochondrial membrane potential and the subsequent release of mitochondrial DNA and reactive oxygen species, thus preventing hyperactivation of NLRP3 inflammasome. Ablation or inhibition of SHP2 in macrophages causes intensified NLRP3 activation, overproduction of proinflammatory cytokines IL 1beta and IL-18, and increased sensitivity to peritonitis. Collectively, our data highlight that, by inhibiting ANT1 and mitochondrial dysfunction, SHP2 orchestrates an intrinsic regulatory loop to limit excessive NLRP3 inflammasome activation. PMID- 29255149 TI - BCAT1 is a New MR Imaging-related Biomarker for Prognosis Prediction in IDH1 wildtype Glioblastoma Patients. AB - Isocitrate dehydrogenase 1 (IDH1)-wildtype glioblastoma (GBM) has found to be accompanied with increased expression of branched-chain amino acid trasaminase1 (BCAT1), which is associated with tumor growth and disease progression. In this retrospective study, quantitative RT-PCR, immunohistochemistry, and western blot were performed with GBM patient tissues to evaluate the BCAT1 level. Quantitative MR imaging parameters were evaluated from DSC perfusion imaging, DWI, contrast enhanced T1WI and FLAIR imaging using a 3T MR scanner. The level of BCAT1 was significantly higher in IDH1-wildtype patients than in IDH1-mutant patients obtained in immunohistochemistry and western blot. The BCAT1 level was significantly correlated with the mean and 95th percentile-normalized CBV as well as the mean ADC based on FLAIR images. In addition, the 95th percentile normalized CBV from CE T1WI also had a significant correlation with the BCAT1 level. Moreover, the median PFS in patients with BCAT1 expression <100 was longer than in those with BCAT1 expression >=100. Taken together, we found that a high BCAT1 level is correlated with high CBV and a low ADC value as well as the poor prognosis of BCAT1 expression is related to the aggressive nature of GBM. PMID- 29255151 TI - Downregulation of Deiodinase 3 is the earliest event in photoperiodic and photorefractory activation of the gonadotropic axis in seasonal hamsters. AB - In seasonal rodents, reproduction is activated by a long photoperiod. Furthermore, maintaining an inhibitory short photoperiod for over 20 weeks triggers a spontaneous reactivation of the gonadotropic axis called photorefractoriness. Photoactivation is proposed to involve melatonin, hypothalamic thyroid hormones (TH) and (Arg) (Phe)-amide peptides. The mechanisms involved in photorefractoriness are so far unknown. We analyzed the dynamic changes in long photoperiod- and photorefractory-induced activation of reproduction in both Syrian and Djungarian hamsters to validate the current model of photoactivation and to uncover the mechanisms involved in photorefractoriness. We detected a conserved early inhibition of expression of the TH catabolizing enzyme deiodinase 3 (Dio3) in tanycytes, associated with a late decrease of the TH transporter MCT8. This suggests that an early peak of hypothalamic TH may be involved in both photoinduced and photorefractory reactivation. In photoactivation, Dio3 downregulation is followed by an upregulation of Dio2, which is not observed in photorefraction. The upregulation of (Arg) (Phe)-amides occurs several weeks after the initial Dio3 inhibition. In conclusion, we uncovered a so far unreported early inhibition of Dio3. This early downregulation of Dio3 is reinforced by an upregulation of Dio2 in photoactivated hamsters. In photorefractoriness, the Dio3 downregulation might be sufficient to reactivate the gonadotropic axis. PMID- 29255150 TI - RNA degradation by the plant RNA exosome involves both phosphorolytic and hydrolytic activities. AB - The RNA exosome provides eukaryotic cells with an essential 3'-5' exoribonucleolytic activity, which processes or eliminates many classes of RNAs. Its nine-subunit core (Exo9) is structurally related to prokaryotic phosphorolytic exoribonucleases. Yet, yeast and animal Exo9s have lost the primordial phosphorolytic capacity and rely instead on associated hydrolytic ribonucleases for catalytic activity. Here, we demonstrate that Arabidopsis Exo9 has retained a distributive phosphorolytic activity, which contributes to rRNA maturation processes, the hallmark of exosome function. High-density mapping of 3' extremities of rRNA maturation intermediates reveals the intricate interplay between three exoribonucleolytic activities coordinated by the plant exosome. Interestingly, the analysis of RRP41 protein diversity across eukaryotes suggests that Exo9's intrinsic activity operates throughout the green lineage, and possibly in some earlier-branching non-plant eukaryotes. Our results reveal a remarkable evolutionary variation of this essential RNA degradation machine in eukaryotes. PMID- 29255152 TI - Comprehensive Expression Analysis of microRNAs and mRNAs in Synovial Tissue from a Mouse Model of Early Post-Traumatic Osteoarthritis. AB - To better understand the molecular processes involved in driving osteoarthritis disease progression we characterized expression profiles of microRNAs (miRNA) and mRNAs in synovial tissue from a post-traumatic OA mouse model. OA was induced in 10-12 week old male C57BL6 mice by bilateral surgical destabilization of the medial meniscus (DMM). RNA isolated from the anterior synovium of mice at 1 and 6 weeks post-surgery was subject to expression profiling using Agilent microarrays and qPCR. OA severity was determined histologically. Anterior and posterior synovitis decreased with post-operative time after sham and DMM. No differences in synovitis parameters were evident between sham and DMM in the anterior synovium at either time. While expression profiling revealed 394 miRNAs were dysregulated between 1 and 6 week time-points in the anterior synovium, there were no significant changes in miRNA or mRNA expression between DMM and sham mice at both time-points. Bioinformatic analysis of the miRNAs and mRNAs differentially expressed in tandem with the resolution of anterior synovial inflammation revealed similar biological processes and functions, including organismal injury, connective tissue disorder and inflammatory responses. Our data demonstrates that early OA-specific patterns of synovial miRNAs or mRNAs dysregulation could not be identified in this model of post-traumatic OA. PMID- 29255154 TI - Bee pollination increases yield quantity and quality of cash crops in Burkina Faso, West Africa. AB - Mutualistic biotic interactions as among flowering plants and their animal pollinators are a key component of biodiversity. Pollination, especially by insects, is a key element in ecosystem functioning, and hence constitutes an ecosystem service of global importance. Not only sexual reproduction of plants is ensured, but also yields are stabilized and genetic variability of crops is maintained, counteracting inbreeding depression and facilitating system resilience. While experiencing rapid environmental change, there is an increased demand for food and income security, especially in sub-Saharan communities, which are highly dependent on small scale agriculture. By combining exclusion experiments, pollinator surveys and field manipulations, this study for the first time quantifies the contribution of bee pollinators to smallholders' production of the major cash crops, cotton and sesame, in Burkina Faso. Pollination by honeybees and wild bees significantly increased yield quantity and quality on average up to 62%, while exclusion of pollinators caused an average yield gap of 37% in cotton and 59% in sesame. Self-pollination revealed inbreeding depression effects on fruit set and low germination rates in the F1-generation. Our results highlight potential negative consequences of any pollinator decline, provoking risks to agriculture and compromising crop yields in sub-Saharan West Africa. PMID- 29255153 TI - Survey of solution dynamics in Src kinase reveals allosteric cross talk between the ligand binding and regulatory sites. AB - The catalytic domain of protein tyrosine kinases can interconvert between active and inactive conformations in response to regulatory inputs. We recently demonstrated that Src kinase features an allosteric network that couples substrate-binding sites. However, the extent of conformational and dynamic changes that are propagated throughout the kinase domain remains poorly understood. Here, we monitor by NMR the effect of conformationally selective inhibitors on kinase backbone dynamics. We find that inhibitor binding and activation loop autophosphorylation induces dynamic changes across the entire kinase. We identify a highly conserved amino acid, Gly449, that is necessary for Src activation. Finally, we show for the first time how the SH3-SH2 domains perturb the dynamics of the kinase domain in the context of the full length protein. We provide experimental support for long-range communication in Src kinase that leads to the relative stabilization of active or inactive conformations and modulation of substrate affinity. PMID- 29255155 TI - Electrical stimulation of macaque lateral prefrontal cortex modulates oculomotor behavior indicative of a disruption of top-down attention. AB - The lateral prefrontal cortex (lPFC) of primates is hypothesized to be heavily involved in decision-making and selective visual attention. Recent neurophysiological evidence suggests that information necessary for an orchestration of those high-level cognitive factors are indeed represented in the lPFC. However, we know little about the specific contribution of sub-networks within lPFC to the deployment of top-down influences that can be measured in extrastriate visual cortex. Here, we systematically applied electrical stimulations to areas 8Av and 45 of two macaque monkeys performing a concurrent goal-directed saccade task. Despite using currents well above saccadic thresholds of the directly adjacent Frontal Eye Fields (FEF), saccades were only rarely evoked by the stimulation. Instead, two types of behavioral effects were observed: Stimulations of caudal sites in 8Av (close to FEF) shortened or prolonged saccadic reaction times, depending on the task-instructed saccade, while rostral stimulations of 8Av/45 seem to affect the relative attentional weighting of saccade targets as well as saccadic reaction times. These results illuminate important differences in the causal involvement of different sub networks within the lPFC and are most compatible with a stimulation-induced biasing of stimulus processing that accelerates the detection of saccade targets presented ipsilateral to stimulation through a disruption of contralaterally deployed top-down attention. PMID- 29255156 TI - A novel mode of cytokinesis without cell-substratum adhesion. AB - Cytokinesis is a final step in cell division. Dictyostelium cells, a model organism for the study of cytokinesis, have multiple modes, denoted cytokinesis A, B, C, and D. All these modes have been mainly investigated using cells adhering to the substratum although they can grow in shaking suspension culture. Here, we observed how cells divide without adhering to the substratum using a new non-adhesive material. These detached cells formed the cleavage furrow but eventually failed in the final abscission. Thus, the cells cannot divide without adhesion, suggesting that they cannot divide only through the conventional cytokinesis A. However, in a long-term culture, the detached cells adhered each other to form multicellular aggregates and divided properly in these aggregates. Myosin II-null cells also formed such aggregates but could not divide in the aggregates. Several lines of experiments using mutant cells showed that the process of cytokinesis in multicellular aggregates is a novel mode utilizing a confined space in the aggregate in a myosin II-dependent manner. These results shed light on a poorly characterized mechanism of cytokinesis in multicellular spheroids or tissues. We propose to redefine and classify multiple modes of cytokinesis. PMID- 29255157 TI - Quantifying Nearshore Sea Turtle Densities: Applications of Unmanned Aerial Systems for Population Assessments. AB - Although sea turtles face significant pressure from human activities, some populations are recovering due to conservation programs, bans on the trade of turtle products, and reductions in bycatch. While these trends are encouraging, the status of many populations remains unknown and scientific monitoring is needed to inform conservation and management decisions. To address these gaps, this study presents methods for using unmanned aerial systems (UAS) to conduct population assessments. Using a fixed-wing UAS and a modified strip-transect method, we conducted aerial surveys along a three-kilometer track line at Ostional, Costa Rica during a mass-nesting event of olive ridley turtles (Lepidochelys olivacea). We visually assessed images collected during six transects for sea turtle presence, resulting in 682 certain detections. A cumulative total of 1091 certain and probable turtles were detected in the collected imagery. Using these data, we calculate estimates of sea turtle density (km-2) in nearshore waters. After adjusting for both availability and perception biases, we developed a low-end estimate of 1299 +/- 458 and a high-end estimate of 2086 +/- 803 turtles per km-2. This pilot study illustrates how UAS can be used to conduct robust, safe, and cost-effective population assessments of sea turtle populations in coastal marine ecosystems. PMID- 29255158 TI - A gut pathobiont synergizes with the microbiota to instigate inflammatory disease marked by immunoreactivity against other symbionts but not itself. AB - Inflammatory bowel diseases (IBD) are likely driven by aberrant immune responses directed against the resident microbiota. Although IBD is commonly associated with a dysbiotic microbiota enriched in putative pathobionts, the etiological agents of IBD remain unknown. Using a pathobiont-induced intestinal inflammation model and a defined bacterial community, we provide new insights into the immune microbiota interactions during disease. In this model system, the pathobiont Helicobacter bilis instigates disease following sub-pathological dextran sulfate sodium treatment. We show that H. bilis causes mild inflammation in mono associated mice, but severe disease in the presence of a microbiota, demonstrating synergy between the pathobiont and microbiota in exacerbating pathology. Remarkably, inflammation depends on the presence of H. bilis, but is marked by a predominant Th17 response against specific members of the microbiota and not the pathobiont, even upon the removal of the most immune-dominant taxa. Neither increases in pathobiont burden nor unique changes in immune-targeted microbiota member abundances are observed during disease. Collectively, our findings demonstrate that a pathobiont instigates inflammation without being the primary target of a Th17 response or by altering the microbiota community structure. Moreover, our findings point toward monitoring pathobiont-induced changes in microbiota immune targeting as a new concept in IBD diagnotics. PMID- 29255159 TI - Trypsin-Ligand binding affinities calculated using an effective interaction entropy method under polarized force field. AB - Molecular dynamics (MD) simulation in the explicit water is performed to study the interaction mechanism of trypsin-ligand binding under the AMBER force field and polarized protein-specific charge (PPC) force field combined the new developed highly efficient interaction entropy (IE) method for calculation of entropy change. And the detailed analysis and comparison of the results of MD simulation for two trypsin-ligand systems show that the root-mean-square deviation (RMSD) of backbone atoms, B-factor, intra-protein and protein-ligand hydrogen bonds are more stable under PPC force field than AMBER force field. Our results demonstrate that the IE method is superior than the traditional normal mode (Nmode) method in the calculation of entropy change and the calculated binding free energy under the PPC force field combined with the IE method is more close to the experimental value than other three combinations (AMBER-Nmode, AMBER IE and PPC-Nmode). And three critical hydrogen bonds between trypsin and ligand are broken under AMBER force field. However, they are well preserved under PPC force field. Detailed binding interactions of ligands with trypsin are further analyzed. The present work demonstrates that the polarized force field combined the highly efficient IE method is critical in MD simulation and free energy calculation. PMID- 29255161 TI - Functional characterization of the circadian clock in the Antarctic krill, Euphausia superba. AB - Antarctic krill (Euphausia superba) is a key species in Southern Ocean ecosystem where it plays a central role in the Antarctic food web. Available information supports the existence of an endogenous timing system in krill enabling it to synchronize metabolism and behavior with an environment characterized by extreme seasonal changes in terms of day length, food availability, and surface ice extent. A screening of our transcriptome database "KrillDB" allowed us to identify the putative orthologues of 20 circadian clock components. Mapping of conserved domains and phylogenetic analyses strongly supported annotations of the identified sequences. Luciferase assays and co-immunoprecipitation experiments allowed us to define the role of the main clock components. Our findings provide an overall picture of the molecular mechanisms underlying the functioning of the endogenous circadian clock in the Antarctic krill and shed light on their evolution throughout crustaceans speciation. Interestingly, the core clock machinery shows both mammalian and insect features that presumably contribute to an evolutionary strategy to cope with polar environment's challenges. Moreover, despite the extreme variability characterizing the Antarctic seasonal day length, the conserved light mediated degradation of the photoreceptor EsCRY1 suggests a persisting pivotal role of light as a Zeitgeber. PMID- 29255162 TI - An Adaptive Cultural Algorithm with Improved Quantum-behaved Particle Swarm Optimization for Sonar Image Detection. AB - This paper proposes an adaptive cultural algorithm with improved quantum-behaved particle swarm optimization (ACA-IQPSO) to detect the underwater sonar image. In the population space, to improve searching ability of particles, iterative times and the fitness value of particles are regarded as factors to adaptively adjust the contraction-expansion coefficient of the quantum-behaved particle swarm optimization algorithm (QPSO). The improved quantum-behaved particle swarm optimization algorithm (IQPSO) can make particles adjust their behaviours according to their quality. In the belief space, a new update strategy is adopted to update cultural individuals according to the idea of the update strategy in shuffled frog leaping algorithm (SFLA). Moreover, to enhance the utilization of information in the population space and belief space, accept function and influence function are redesigned in the new communication protocol. The experimental results show that ACA-IQPSO can obtain good clustering centres according to the grey distribution information of underwater sonar images, and accurately complete underwater objects detection. Compared with other algorithms, the proposed ACA-IQPSO has good effectiveness, excellent adaptability, a powerful searching ability and high convergence efficiency. Meanwhile, the experimental results of the benchmark functions can further demonstrate that the proposed ACA IQPSO has better searching ability, convergence efficiency and stability. PMID- 29255160 TI - Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer. AB - Advanced-stage epithelial ovarian cancers are amongst the most difficult to treat tumors and have proven to be refractory to most cytotoxic, molecularly targeted, or immunotherapeutic approaches. Here, we report that nanoparticle-drug conjugates (NDCs) of monomethyl auristatin E (MMAE) significantly increase loading on a per-vehicle basis as compared to antibody-drug conjugates (ADCs). Their intraperitoneal administration enabled triggered release of the active MMAE toxin to inhibit tumor growth and to extend animal survival to >90 days in a cell line xenograft model of disseminated ovarian cancer. In a patient-derived xenograft model of advanced-stage and platinum-resistant ovarian cancer, an MMAE based NDC doubled the duration of tumor growth inhibition as compared to cisplatin. NDCs of highly potent toxins thus introduce a translatable platform that may be exploited to maximize the safety and efficacy of cytotoxic chemotherapies, combining the best features of ADCs with those of nanoparticle based therapeutics. PMID- 29255163 TI - Computational and biological profile of boronic acids for the detection of bacterial serine- and metallo-beta-lactamases. AB - beta-Lactamases (BLs) able to hydrolyze beta-lactam antibiotics and more importantly the last resort carbapenems, represent a major mechanism of resistance in Gram-negative bacteria showing multi-drug or extensively drug resistant phenotypes. The early detection of BLs responsible of resistant infections is challenging: approaches aiming at the identification of new BLs inhibitors (BLI) can thus serve as the basis for the development of highly needed diagnostic tools. Starting from benzo-[b]-thiophene-2-boronic acid (BZB), a nanomolar inhibitor of AmpC beta-lactamase (K i = 27 nM), we have identified and characterized a set of BZB analogues able to inhibit clinically-relevant beta lactamases, including AmpC, Extended-Spectrum BLs (ESBL), KPC- and OXA-type carbapenemases and metallo-beta-lactamases (MBL). A multiligand set of boronic acid (BA) beta-lactamase inhibitors was obtained using covalent molecular modeling, synthetic chemistry, enzyme kinetics and antibacterial susceptibility testing. Data confirmed the possibility to discriminate between clinically relevant beta-lactamases on the basis of their inhibition profile. Interestingly, this work also allowed the identification of potent KPC-2 and NDM-1 inhibitors able to potentiate the activity of cefotaxime (CTX) and ceftazidime (CAZ) against resistant clinical isolates (MIC reduction, 32-fold). Our results open the way to the potential use of our set of compounds as a diagnostic tool for the sensitive detection of clinically-relevant beta-lactamases. PMID- 29255164 TI - VEGFR2 alteration in Alzheimer's disease. AB - Alzheimer's disease (AD) is a common disorder of progressive cognitive decline among elderly subjects. Angiogenesis-related factors including vascular endothelial growth factor (VEGF) might be involved in the pathogenesis of AD. Soluble form of the VEGF receptor is likely to be an intrinsic negative counterpart of VEGF. We measured the plasma levels of VEGF and its two soluble receptors (sVEGFR1 and sVEGFR2) in 120 control subjects, 75 patients with mild cognitive impairment, and 76 patients with AD using ELISA. Plasma levels of VEGF in patients with AD were higher than those in healthy control subjects. However, plasma levels of sVEGFR1 and sVEGFR2 were lower in patients with AD than in healthy control subjects. Levels of VEGFR2 mRNA were significantly decreased in human umbilical vein endothelial cells after amyloid-beta treatment. Further, protein levels of VEGFR2 were also decreased in the brains of AD model mice. In addition, we show that the expression of sVEGFR2 and VEGFR2 was also decreased by the transfection with the Notch intracellular domain. These results indicate that the alterations of VEGF and its two receptors levels might be associated with those at risk for Alzheimer's disease. PMID- 29255165 TI - 3-D Modelling and Experimental Comparison of Reactive Flow in Carbonates under Radial Flow Conditions. AB - We use a two-scale continuum model to simulate reactive flow and wormhole formation in carbonate rocks under 3-D radial flow conditions. More specifically, we present a new structure-property relationship based on the fractal geometry theory, to describe the evolution of local permeability, pore radius, and specific area with porosity variation. In the numerical calculation, to improve the convergence rate, the heterogeneous medium in question is extended by adding a thin layer of homogeneous porous medium to its inlet. We compare the simulation results with the available experimental observations and find that they are qualitatively consistent with each other. Additionally, sensitivity analysis of the dissolution process with respect to acid injection rate and rock heterogeneity, including heterogeneity magnitude and correlation length, is presented. PMID- 29255166 TI - Publisher Correction: An interactive framework for whole-brain maps at cellular resolution. AB - In the version of this article initially published online, Daniel Furth was not listed as a corresponding author. The error has been corrected in the print, PDF and HTML versions of this article. PMID- 29255167 TI - Excellent Rectifying Properties of the n-3C-SiC/p-Si Heterojunction Subjected to High Temperature Annealing for Electronics, MEMS, and LED Applications. AB - This work examines the stability of epitaxial 3C-SiC/Si heterojunctions subjected to heat treatments between 1000 degrees C and 1300 degrees C. Because of the potential for silicon carbide in high temperature and harsh environment applications, and the economic advantages of growing the 3C-SiC polytype on large diameter silicon wafers, its stability after high temperature processing is an important consideration. Yet recently, this has been thrown into question by claims that the heterojunction suffers catastrophic degradation at temperatures above 1000 degrees C. Here we present results showing that the heterojunction maintains excellent diode characteristics following heat treatment up to 1100 degrees C and while some changes were observed between 1100 degrees C and 1300 degrees C, diodes maintained their rectifying characteristics, enabling compatibility with a large range of device fabrication. The parameters of as grown diodes were J0 = 1 * 10-11 A/mm2, n = 1.02, and +/-2V rectification ratio of 9 * 106. Capacitance and thermal current-voltage analysis was used to characterize the excess current leakage mechanism. The change in diode characteristics depends on diode area, with larger areas (1 mm2) having reduced rectification ratio while smaller areas (0.04 mm2) maintained excellent characteristics of J0 = 2 * 10-10 A/mm2, n = 1.28, and +/-2V ratio of 3 * 106. This points to localized defect regions degrading after heat treatment rather than a fundamental issue of the heterojunction. PMID- 29255168 TI - Plerixafor in poor mobilizers with non-Hodgkin's lymphoma: a multi-center time motion analysis. AB - High-dose chemotherapy alongside peripheral blood stem cell (PBSC) infusion has become the standard of care in different hematologic malignancies. The goal of PBSC mobilization is to allow collection of sufficient CD34+ cells to proceed to transplantation. The current mobilization regimen with granulocyte colony stimulating factor (G-CSF), alone or in combination with chemotherapy, still fails in 10-25% of patients. Plerixafor is able to rescue most of these patients from mobilization failure. In this study, we investigated the impact of plerixafor on the cost and time spent on apheresis in patients who were considered poor mobilizers, with <20 * 106/ul peripheral CD34+ cells after mobilization but prior to apheresis. Patient hospital records from ten centers in three European countries were reviewed and compared during two time periods, namely prior and after plerixafor introduction to the market. During the plerixafor period, patients spent less time on apheresis (350 vs. 461 min). Poor mobilizers given plerixafor collected more CD34+ cells during the first apheresis session, leading to a decrease in the average number of apheresis sessions needed. The total apheresis yield was unaffected. This analysis shows that the use of plerixafor lessens the time-effort associated with the management of poor mobilizers and reduces apheresis costs. PMID- 29255169 TI - Outcomes of haploidentical stem cell transplantation for chronic lymphocytic leukemia: a retrospective study on behalf of the chronic malignancies working party of the EBMT. AB - Allogeneic hematopoietic stem cell transplantation (HCT) may result in long-term disease control in high-risk chronic lymphocytic leukemia (CLL). Recently, haploidentical HCT is gaining interest because of better outcomes with post transplantation cyclophosphamide (PTCY). We analyzed patients with CLL who received an allogeneic HCT with a haploidentical donor and whose data were available in the EBMT registry. In total 117 patients (74% males) were included; 38% received PTCY as GVHD prophylaxis. For the whole study cohort OS at 2 and 5 yrs was 48 and 38%, respectively. PFS at 2 and 5 yrs was 38 and 31%, respectively. Cumulative incidence (CI) of NRM in the whole group at 2 and 5 years were 40 and 44%, respectively. CI of relapse at 2 and 5 yrs were 22 and 26%, respectively. All outcomes were not statistically different in patients who received PTCY compared to other types of GVHD prophylaxis. In conclusion, results of haploidentical HCT in CLL seem almost identical to those with HLA-matched donors. Thereby, haploidentical HCT is an appropriate alternative in high risk CLL patients with a transplant indication but no available HLA-matched donor. Despite the use of PTCY, the CI of relapse seems not higher than observed after HLA-matched HCT. PMID- 29255170 TI - Unresolved recombination intermediates lead to ultra-fine anaphase bridges, chromosome breaks and aberrations. AB - The resolution of joint molecules that link recombining sister chromatids is essential for chromosome segregation. Here, we determine the fate of unresolved recombination intermediates arising in cells lacking two nucleases required for resolution (GEN1 -/- knockout cells depleted of MUS81). We find that intermediates persist until mitosis and form a distinct class of anaphase bridges, which we term homologous recombination ultra-fine bridges (HR-UFBs). HR UFBs are distinct from replication stress-associated UFBs, which arise at common fragile sites, and from centromeric UFBs. HR-UFBs are processed by BLM helicase to generate single-stranded RPA-coated bridges that are broken during mitosis. In the next cell cycle, DNA breaks activate the DNA damage checkpoint response, and chromosome fusions arise by non-homologous end joining. Consequently, the cells undergo cell cycle delay and massive cell death. These results lead us to present a model detailing how unresolved recombination intermediates can promote DNA damage and chromosomal instability. PMID- 29255173 TI - The autophagy receptor ALLO-1 and the IKKE-1 kinase control clearance of paternal mitochondria in Caenorhabditis elegans. AB - In Caenorhabditis elegans embryos, paternally provided organelles, including mitochondria, are eliminated by a process of selective autophagy called allophagy, the mechanism by which mitochondrial DNA is inherited maternally. However, it remains unclear how paternal organelles are recognized and targeted for autophagy. Here, we identified an autophagy receptor for allophagy, ALLO-1. ALLO-1 is essential for autophagosome formation around paternal organelles and directly binds to the worm LC3 homologue LGG-1 through its LC3-interacting region (LIR) motif. After fertilization, ALLO-1 accumulates on the paternal organelles before autophagosome formation, and this localization depends on the ubiquitin modification of the paternal organelles. We also identified IKKE-1, a worm homologue of the TBK1 and IKKepsilon family kinase, as another critical regulator of allophagy. IKKE-1 interacts with ALLO-1, and the IKKE-1-dependent phosphorylation of ALLO-1 is important for paternal organelle clearance. Thus, we propose that ALLO-1 is the allophagy receptor whose function is regulated by IKKE 1-dependent phosphorylation. PMID- 29255172 TI - Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis. AB - Tumour-associated p53 missense mutants act as driver oncogenes affecting cancer progression, metastatic potential and drug resistance (gain-of-function) 1 . Mutant p53 protein stabilization is a prerequisite for gain-of-function manifestation; however, it does not represent an intrinsic property of p53 mutants, but rather requires secondary events 2 . Moreover, mutant p53 protein levels are often heterogeneous even within the same tumour, raising questions on the mechanisms that control local mutant p53 accumulation in some tumour cells but not in their neighbours 2,3 . By investigating the cellular pathways that induce protection of mutant p53 from ubiquitin-mediated proteolysis, we found that HDAC6/Hsp90-dependent mutant p53 accumulation is sustained by RhoA geranylgeranylation downstream of the mevalonate pathway, as well as by RhoA- and actin-dependent transduction of mechanical inputs, such as the stiffness of the extracellular environment. Our results provide evidence for an unpredicted layer of mutant p53 regulation that relies on metabolic and mechanical cues. PMID- 29255171 TI - ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs. AB - Human pluripotent stem cells (hPSCs) can be directed to differentiate into skeletal muscle progenitor cells (SMPCs). However, the myogenicity of hPSC-SMPCs relative to human fetal or adult satellite cells remains unclear. We observed that hPSC-SMPCs derived by directed differentiation are less functional in vitro and in vivo compared to human satellite cells. Using RNA sequencing, we found that the cell surface receptors ERBB3 and NGFR demarcate myogenic populations, including PAX7 progenitors in human fetal development and hPSC-SMPCs. We demonstrated that hPSC skeletal muscle is immature, but inhibition of transforming growth factor-beta signalling during differentiation improved fusion efficiency, ultrastructural organization and the expression of adult myosins. This enrichment and maturation strategy restored dystrophin in hundreds of dystrophin-deficient myofibres after engraftment of CRISPR-Cas9-corrected Duchenne muscular dystrophy human induced pluripotent stem cell-SMPCs. The work provides an in-depth characterization of human myogenesis, and identifies candidates that improve the in vivo myogenic potential of hPSC-SMPCs to levels that are equal to directly isolated human fetal muscle cells. PMID- 29255174 TI - A Drosophila ex vivo model of olfactory appetitive learning. AB - During olfactory appetitive learning, animals associate an odor, or conditioned stimulus (CS), with an unconditioned stimulus (US), often a sugar reward. This association induces feeding behavior, a conditioned response (CR), upon subsequent exposure to the CS. In this study, we developed a model of this behavior in isolated Drosophila brains. Artificial activation of neurons expressing the Gr5a sugar-responsive gustatory receptor (Gr5a GRNs) induces feeding behavior in starved flies. Consistent with this, we find that in dissected brains, activation of Gr5a GRNs induces Ca2+ transients in motor neurons, MN11 + 12, required for ingestion. Significantly, activation of Gr5a GRNs can substitute for presentation of sugar rewards during olfactory appetitive learning. Similarly, in dissected brains, coincident stimulation of Gr5a GRNs and the antennal lobe (AL), which processes olfactory information, results in increased Ca2+ influx into MN11 + 12 cells upon subsequent AL stimulation. Importantly, olfactory appetitive associations are not formed in satiated flies. Likewise, AL-evoked Ca2+ transients in MN11 + 12 are not produced in ex vivo brains from satiated flies. Our results suggest that a starved/satiated state is maintained in dissected brains, and that this ex vivo system will be useful for identification of neural networks involved in olfactory appetitive learning. PMID- 29255175 TI - Effects of meal timing on changes in circulating epinephrine, norepinephrine, and acylated ghrelin concentrations: a pilot study. AB - BACKGROUND: Timing of food intake impacts on metabolic diseases. Few data are available about post-meal changes in epinephrine (E), norepinephrine (NE), and acylated ghrelin (AG) at different times of the day. SUBJECTS AND METHODS: This randomized cross-over trial investigated E/NE/AG concentrations after identical meals consumed at 0800 or 2000 hours in 20 healthy volunteers, by standardizing diet, exercise, duration of fast, and resting. Participants randomly received the test meal at 0800 or 2000 hours, and vice versa after 1 week. Blood samples were collected before and up to 180-min post-meal, every 30 min, with participants supine, motionless, but awake. RESULTS: Median E levels increased at 30-60 min, then declined and rose again at 150 min; values at 60 min (19.0 vs. 15.0 ng/l, p = 0.03) and 180 min (25.0 vs. 11.0 ng/l, p < 0.001) were higher after the morning meals. NE rose at 30-60 min and then progressively declined; median values at 60 min (235.3 vs. 206.3 ng/l, p = 0.02) and 120 min (208.8 vs. 142.0 ng/l, p = 0.04) increased more after morning meals. AG progressively declined to increase again at 90 min after meal; median AG area-under-the-curve (AUC) values were lower at morning (7206.8 vs. 8828.3 pg/mL*h). AG-AUC was inversely associated with diet induced thermogenesis (beta = -121.6; 95% CI -201.0 to 42.2; p = 0.009 for each unit increase), while log NE-AUC was inversely associated with log-triglyceride AUC (beta = -0.57; 95% CI -0.98 to 0.16; p = 0.015) in a multiple regression model, after multiple adjustments. CONCLUSIONS: In conclusion, E/NE concentrations were higher after the morning meal, while AG showed an opposite behavior. These data, although requiring confirmation in larger samples, suggest an adjunctive possible mechanism explaining the unfavorable effects of evening eating on metabolic risk. PMID- 29255176 TI - Repeat genetic testing with targeted capture sequencing in primary arrhythmia syndrome and cardiomyopathy. AB - In inherited primary arrhythmia syndromes (PAS) and cardiomyopathies (CMP), the yield of genetic testing varies between 20 and 75% in different diseases according to studies performed in the pre next-generation sequencing (NGS) era. It is unknown whether retesting historical negative samples with NGS techniques is worthwhile. Therefore, we assessed the value of NGS-based panel testing in previously genotype negative-phenotype positive probands. We selected 107 patients (47 PAS and 60 CMP) with a clear phenotype who remained genotype negative after genetic analysis of the main genes implicated in their specific phenotype. Targeted sequencing of the coding regions of 71 PAS- and CMP-related genes was performed. Variant interpretation and classification was done according to a cardiology-specific scoring algorithm ('Amsterdam criteria') and the ACMG AMP criteria. Co-segregation analysis was performed when DNA and clinical data of family members were available. Finally, a genetic diagnosis could be established in 21 patients (20%), 5 PAS (11%) and 16 CMP (27%) patients, respectively. The increased detection rate was due to sequencing of novel genes in 52% of the cases and due to technical failures with the historical analysis in 48%. A total of 118 individuals were informed about their carrier state and either reassured or scheduled for proper follow-up. To conclude, genetic retesting in clinically overt PAS and CMP cases, who were genotype negative with older techniques, resulted in an additional genetic diagnosis in up to 20% of the cases. This clearly supports a policy for genetic retesting with NGS-based panels. PMID- 29255177 TI - Immunoglobulin therapy ameliorates the phenotype and increases lifespan in the severely affected dystrophin-utrophin double knockout mice. AB - Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, caused by mutations in the dystrophin gene, affecting 1:3500-5000 boys worldwide. The lack of dystrophin induces degeneration of muscle cells and elicits an immune response characterized by an intensive secretion of pro-inflammatory cytokines. Immunoglobulins modulate the inflammatory response through several mechanisms and have been widely used as an adjuvant therapy for autoimmune diseases. Here we evaluated the effect of immunoglobulin G (IG) injected intraperitoneally in a severely affected double knockout (dko) mouse model for Duchenne muscular dystrophy. The IG dko treated mice were compared regarding activity rates, survival and histopathology with a control untreated group. Additionally, dendritic cells and naive lymphocytes from these two groups and WT mice were obtained to study in vitro the role of the immune system associated to DMD pathophysiology. We show that IG therapy significantly enhances activity rate and lifespan of dko mice. It diminishes muscle tissue inflammation by decreasing the expression of costimulatory molecules MHC, CD86 and CD40 and reducing Th1-related cytokines IFN-gamma, IL-1beta and TNF-alpha release. IG therapy dampens the effector immune responses supporting the hypothesis according to which the immune response accelerates DMD progression. As IG therapy is already approved by FDA for treating autoimmune disorders, with less side-effects than currently used glucocorticoids, our results may open a new therapeutic option aiming to improve life quality and lifespan of DMD patients. PMID- 29255179 TI - WISExome: a within-sample comparison approach to detect copy number variations in whole exome sequencing data. AB - In clinical genetics, detection of single nucleotide polymorphisms (SNVs) as well as copy number variations (CNVs) is essential for patient genotyping. Obtaining both CNV and SNV information from WES data would significantly simplify clinical workflow. Unfortunately, the sequence reads obtained with WES vary between samples, complicating accurate CNV detection with WES. To avoid being dependent on other samples, we developed a within-sample comparison approach (WISExome). For every (WES) target region on the genome, we identified a set of reference target regions elsewhere on the genome with similar read frequency behavior. For a new sample, aberrations are detected by comparing the read frequency of a target region with the distribution of read frequencies in the reference set. WISExome correctly identifies known pathogenic CNVs (range 4 Kb-5.2 Mb). Moreover, WISExome prioritizes pathogenic CNVs by sorting them on quality and annotations of overlapping genes in OMIM. When comparing WISExome to four existing CNV detection tools, we found that CoNIFER detects much fewer CNVs and XHMM breaks calls made by other tools into smaller calls (fragmentation). CODEX and CLAMMS seem to perform more similar to WISExome. CODEX finds all known pathogenic CNVs, but detects much more calls than all other methods. CLAMMS and WISExome agree the most. CLAMMS does, however, miss one of the known CNVs and shows slightly more fragmentation. Taken together, WISExome is a promising tool for genome diagnostics laboratories as the workflow can be solely based on WES data. PMID- 29255178 TI - Patients with a Kabuki syndrome phenotype demonstrate DNA methylation abnormalities. AB - Kabuki syndrome is a monogenic disorder caused by loss of function variants in either of two genes encoding histone-modifying enzymes. We performed targeted sequencing in a cohort of 27 probands with a clinical diagnosis of Kabuki syndrome. Of these, 12 had causative variants in the two known Kabuki syndrome genes. In 2, we identified presumptive loss of function de novo variants in KMT2A (missense and splice site variants), a gene that encodes another histone modifying enzyme previously exclusively associated with Wiedermann-Steiner syndrome. Although Kabuki syndrome is a disorder of histone modification, we also find alterations in DNA methylation among individuals with a Kabuki syndrome diagnosis relative to matched normal controls, regardless of whether they carry a variant in KMT2A or KMT2D or not. Furthermore, we observed characteristic global abnormalities of DNA methylation that distinguished patients with a loss of function variant in KMT2D or missense or splice site variants in either KMT2D or KMT2A from normal controls. Our results provide new insights into the relationship of genotype to epigenotype and phenotype and indicate cross-talk between histone and DNA methylation machineries exposed by inborn errors of the epigenetic apparatus. PMID- 29255180 TI - Contribution of germline deleterious variants in the RAD51 paralogs to breast and ovarian cancers. AB - RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) have recently been involved in breast and ovarian cancer predisposition: RAD51B, RAD51C, and RAD51D in ovarian cancer, RAD51B and XRCC2 in breast cancer. The aim of this study was to estimate the contribution of deleterious variants in the five RAD51 paralogs to breast and ovarian cancers. The five RAD51 paralog genes were analyzed by next generation sequencing technologies in germline DNA from 2649 consecutive patients diagnosed with breast and/or ovarian cancer. Twenty-one different deleterious variants were identified in the RAD51 paralogs in 30 patients: RAD51B (n = 4), RAD51C (n = 12), RAD51D (n = 7), XRCC2 (n = 2), and XRCC3 (n = 5). The overall deleterious variant rate was 1.13% (95% confidence interval (CI): 0.72-1.55%) (30/2649), including 15 variants in breast cancer only cases (15/2063; 0.73% (95% CI: 0.34-1.11%)) and 15 variants in cases with at least one ovarian cancer (15/570; 2.63% (95% CI: 1.24-4.02%)). This study is the first evaluation of the five RAD51 paralogs in breast and ovarian cancer predisposition and it demonstrates that deleterious variants can be present in breast cancer only cases. Moreover, this is the first time that XRCC3 deleterious variants have been identified in breast and ovarian cancer cases. PMID- 29255181 TI - Next-generation sequencing of patients with congenital anosmia. AB - We performed whole exome or genome sequencing in eight multiply affected families with ostensibly isolated congenital anosmia. Hypothesis-free analyses based on the assumption of fully penetrant recessive/dominant/X-linked models obtained no strong single candidate variant in any of these families. In total, these eight families showed 548 rare segregating variants that were predicted to be damaging, in 510 genes. Three Kallmann syndrome genes (FGFR1, SEMA3A, and CHD7) were identified. We performed permutation-based analysis to test for overall enrichment of these 510 genes carrying these 548 variants with genes mutated in Kallmann syndrome and with a control set of genes mutated in hypogonadotrophic hypogonadism without anosmia. The variants were found to be enriched for Kallmann syndrome genes (3 observed vs. 0.398 expected, p = 0.007), but not for the second set of genes. Among these three variants, two have been already reported in genes related to syndromic anosmia (FGFR1 (p.(R250W)), CHD7 (p.(L2806V))) and one was novel (SEMA3A (p.(T717I))). To replicate these findings, we performed targeted sequencing of 16 genes involved in Kallmann syndrome and hypogonadotrophic hypogonadism in 29 additional families, mostly singletons. This yielded an additional 6 variants in 5 Kallmann syndrome genes (PROKR2, SEMA3A, CHD7, PROK2, ANOS1), two of them already reported to cause Kallmann syndrome. In all, our study suggests involvement of 6 syndromic Kallmann genes in isolated anosmia. Further, we report a yet unreported appearance of di-genic inheritance in a family with congenital isolated anosmia. These results are consistent with a complex molecular basis of congenital anosmia. PMID- 29255183 TI - No controversial role of alcohol consumption in the development of inflammatory bowel diseases. PMID- 29255182 TI - A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity. AB - ARL13B encodes for the ADP-ribosylation factor-like 13B GTPase, which is required for normal cilia structure and Sonic hedgehog (Shh) signaling. Disruptions in cilia structure or function lead to a class of human disorders called ciliopathies. Joubert syndrome is characterized by a wide spectrum of symptoms, including a variable degree of intellectual disability, ataxia, and ocular abnormalities. Here we report a novel homozygous missense variant c.[223G>A] (p.(Gly75Arg) in the ARL13B gene, which was identified by whole-exome sequencing of a trio from a consanguineous family with multiple-affected individuals suffering from intellectual disability, ataxia, ocular defects, and epilepsy. The same variant was also identified in a second family. We saw a striking difference in the severity of ataxia between affected male and female individuals in both families. Both ARL13B and ARL13B-c.[223G>A] (p.(Gly75Arg) expression rescued the cilia length and Shh defects displayed by Arl13b hennin (null) cells, indicating that the variant did not disrupt either ARL13B function. In contrast, ARL13B c.[223G>A] (p.(Gly75Arg) displayed a marked loss of ARL3 guanine nucleotide exchange factor activity, with retention of its GTPase activities, highlighting the correlation between its loss of function as an ARL3 guanine nucleotide exchange factor and Joubert syndrome. PMID- 29255184 TI - Controversial role of alcohol consumption in the development of inflammatory bowel diseases. PMID- 29255185 TI - Standardized feeding and probiotic supplementation for reducing necrotizing enterocolitis in preterm infants in a resource limited set up. AB - BACKGROUND/OBJECTIVES: Necrotizing enterocolitis (NEC >= Stage II) is associated with high mortality and morbidity in preterm infants. To assess if introduction of standardized feeding regimen (SFR) and routine probiotic supplementation (RPS) was associated with reduced incidence of NEC in preterm infants in our nursery in a resource limited set up. SUBJECTS/METHODS: This was a retrospective cohort study assessing the incidence of NEC >= Stage II before (Epoch 1: N = 144) vs. after (Epoch 2, N = 144) implementation of SFR and RPS in preterm infants < 35 weeks. RESULTS: The median (IQR) gestation and birth weight in epoch 1 and epoch 2 was [32 (30, 33.5) vs. 31.5 (30, 34) weeks, p = 0.829], and [1350 (1100, 1700) vs. 1370 (1110, 1550) g, p = 0.363] respectively. Both groups had predominantly outborn infants (Epoch 1: 79.2% vs. Epoch 2: 78.2%; p = 1.00). Multivariate analysis after adjusting for potential confounders found a significantly lower incidence of NEC >= Stage II after implementing SFR and RPS (Epoch 1: 17.4% vs. Epoch 2:9.0%, adjusted odds ratio aOR: 0.19; 95% CI: 0.05, 0.71, p = 0.013). The incidence of the composite outcome of 'NEC or Mortality' was also significantly lower after the intervention (Epoch 1: 21.5% vs. Epoch 2: 14.6%; aOR 0.24, 95% CI: 0.07, 0.85, p = 0.027). CONCLUSIONS: Introduction of SFR and RPS was associated with significant reduction in NEC >= Stage II and the composite outcome of NEC >= Stage II /mortality in preterm infants. PMID- 29255186 TI - Is nutritional quality of food-at-home purchases improving? 1969-2010: 40 years of household consumption surveys in France. AB - BACKGROUND/OBJECTIVES: The rise of nutrition-related diseases in developed countries prompts investigation into the role played by changing food patterns. Our aim was to observe changes in food-at-home purchases by French households and their impacts on nutritional quality over the past 40 years (1969-2010). SUBJECTS/METHODS: Time-series of food-at-home purchases from representative samples of French households were built based on two sources of data: the INSEE National Food Survey (1969-1991) and the Kantar Food Consumption Panel (1989 2010). Food-at-home purchases were converted into energy and nutrients using the French CIQUAL food composition table. The nutritional quality of food-at-home purchases was estimated using the mean adequacy ratio (MAR) for 15 key nutrients. MAR was expressed per 2000 kcal to assess the nutrient density of food-at-home purchases. RESULTS: Between 1969 and 2010, food-at-home purchases showed dramatic changes in many food groups, with increasing processed vs raw products. The purchase of calories increased (+6.7%) and nutrient density improved (MAR per 2000 kcal + 12.9 points). However, this overall trend harbors heterogeneous patterns: food-at-home calories decreased and nutrient density improved up to 2002, but then calories increased while nutrient density stabilized. CONCLUSIONS: The nutritional quality of French households' food-at-home purchases improved over the last 40 years, as shown by increasing nutrient density. However, during the last decade, nutrient density ceased to increase and the purchase of calories increased, advocating a need for public action to promote healthier food purchasing patterns. PMID- 29255187 TI - Fresnel diffractograms from pure-phase wave fields under perfect spatio-temporal coherence: Non-linear/non-local aspects and far-field behavior. AB - Recently, the diffractogram, that is, the Fourier transform of the intensity contrast induced by Fresnel free-space propagation of a given (exit) wave field, was investigated non-perturbatively in the phase-scaling factor S (controlling the strength of phase variation) for the special case of a Gaussian phase of width [Formula: see text]. Surprisingly, an additional low-frequency zero sigma* = sigma*(S, F) >0 emerges critically at small Fresnel number F (sigma proportional to square of 2D spatial frequency). Here, we study the S-scaling behavior of the entire diffractogram. We identify a valley of maximum S-scaling linearity in the F - sigma plane corresponding to a nearly universal physical frequency ximl = (0:143 +/- 0.001)w -1/2. Large values of F (near field) are shown to imply S-scaling linearity for low sigma but nowhere else (overdamped non oscillatory). In contrast, small F values (far field) entail distinct, sizable s bands of good S-scaling linearity (damped oscillatory). These bands also occur in simulated diffractograms induced by a complex phase map (Lena). The transition from damped oscillatory to overdamped non-oscillatory diffractograms is shown to be a critical phenomenon for the Gaussian case. We also give evidence for the occurrence of this transition in an X-ray imaging experiment. Finally, we show that the extreme far-field limit generates a sigma-universal diffractogram under certain requirements on the phase map: information on phase shape then is solely encoded in S-scaling behavior. PMID- 29255188 TI - Entropy and Polarity Control the Partition and Transportation of Drug-like Molecules in Biological Membrane. AB - Partition and transportation of drug in the plasma membrane of a mammalian cell are the prerequisite for its function on target protein. Therefore, comprehensive understanding of the physicochemical properties and mechanism behind these complex phenomena is crucial in pharmaceutical research. By using the state-of art molecular simulations with polarization effect implicitly or explicitly included, we studied the permeation behavior of 2-aminoethoxydiphenyl borate (2 APB), a broad-spectrum modulator for a number of membrane proteins. We showed that the protonation state and therefore the polarity of the drug is critical for its partition, and that the drug is likely to switch between different protonation states along its permeation pathway. By changing the degrees of freedom, protonation further affects the thermodynamic of the permeation pathway of 2-APB, leading to different entropic contributions. A survey on 54 analog structures with similar backbone to 2-APB showed that delicate balance between entropy and polarity plays an important role in drugs' potency. PMID- 29255189 TI - The combination of penile revascularization surgery with penile corrective techniques as an alternative to prosthesis implantation in patients with peyronie's disease accompanied by erectile dysfunction: Long-term results. AB - This study aimed to investigate the long-term outcomes of the surgical combination of revascularization and penile corrective techniques after having obtained promising preliminary results from a previous study. Between 2008 and 2015, the combined treatment was undertaken for 60 patients with Peyronie's disease and erectile dysfunction. A preoperative urological evaluation was performed with penile color Doppler ultrasonography, electromyography of the corpus cavernosum and cavernosometry. All the patients completed 15-item and 5 item IIEFs preoperatively and at postoperative follow-up. The mean age of the patients was 53.78 +/- 6.48 years ranging from 47 to 63. The mean follow-up period was 48 (14-68) months. The degree of penile angulation was >40 in all the patients. Urethra dissection was required in five patients. Penile disassembly was performed on one patient due to distal complex corporeal deformity. None of the patients reported complications after surgery. The mean total IIEF score was reported to be 25.4 +/- 2.8 before the operation and 52.23 +/- 1.2 at the end of the follow-up (p < 0.05). The mean IIEF-5 score was 7.3 +/- 1.3 preoperatively and 20.9 +/- 1.9 at the end of follow-up (p < 0.05). The results of IIEF-15 for erectile function demonstrated that 32 patients had a cutoff value of >26, indicating no ED. Although all patients had complete penile straightening, 7 (11.66%) reported shortening of the penis but was not dissatisfied with the treatment. The number of patients satisfied with the outcomes of the operation was 53. The statistically significant improvement and satisfactory results achieved with the IIEF questionnaires suggest that the proposed combined treatment could be an alternative to penile prosthesis in highly selected patients with Peyronie's disease, particularly those with erectile dysfunction; however, more studies are needed to confirm these results. PMID- 29255190 TI - Effect and safety of timing of cord clamping on neonatal hematocrit values and clinical outcomes in term infants: A randomized controlled trial. AB - OBJECTIVE: To evaluate the effect and safety of different umbilical cord clamping (UCC) timing. STUDY DESIGN: This was a randomized trial of 720 term mothers/infants from the Tianjin Central Hospital of Obstetrics and Gynecology delivered from December 2014 to May 2015 and randomized to immediate cord clamping (ICC) within 15 s, delayed cord clamping (DCC) by 30, 60, 90, 120, 150, or 180 s, or when the umbilical cord pulsation ceased. RESULTS: 24 h after delivery, the mean infant hematocrit levels were 56.5, 57.3, 58.8, 59.7, 59.5, 59.7, 60.3, and 61.0% in the ICC, 30, 60, 90, 120, 150, and 180-second DCC, and no pulsation groups, respectively (P = 0.021, 0.001, 0.003, 0.001, <0.001, and <0.001, respectively; standard deviations ranging 5.4-8.7%). There was no significant difference between the 30-second DCC and ICC groups. No significant differences were found in other neonatal and maternal outcomes among these groups. CONCLUSION: For term infants, DCC increases the hematocrit values, without apparent harmful effects on the infants and their mothers. PMID- 29255191 TI - The use of clinical examination and cranial ultrasound in the diagnosis and management of post-hemorrhagic ventricular dilation in extremely premature infants. AB - OBJECTIVES: The objective of this study is to describe clinical and ultrasound changes in a cohort of premature newborns with post-hemorrhagic ventricular dilation (PHVD), and to correlate these changes with outcome. STUDY DESIGN: Premature newborns <29 weeks gestational age (GA) and <= 1,500 g birth weight with intraventricular hemorrhage were retrospectively reviewed. Clinical signs and cranial ultrasound (CUS) findings between time after birth and time before first cerebrospinal fluid temporizing intervention were compared with GA equivalent newborns without interventions. White matter injury was assessed on brain magnetic resonance imaging. RESULTS: Between 2011 and 2014, 64 newborns met inclusion criteria; 23% had PHVD. The growth rates of the ventricles on CUS and the head circumference (HC) were higher in newborns with PHVD (p < 0.01 and p = 0.04, respectively) and correlated inversely with white matter injury (p = 0.006 and p < 0.001, respectively). CONCLUSION: Progression of PHVD in premature newborns as demonstrated by CUS and the HC correlated with outcome. Consistent measurement of these simple parameters will allow for much needed treatment comparisons, to define optimal protocols that decrease the risk of cerebral palsy in extremely preterm populations. PMID- 29255192 TI - Spatial and environmental correlates of organism colonization and infection in the neonatal intensive care unit. AB - OBJECTIVE: To examine organism colonization and infection in the neonatal intensive care unit as a result of environmental and spatial factors. STUDY DESIGN: A retrospective cohort of infants admitted between 2006 and 2015 (n = 11 428), to assess the relationship between location and four outcomes: methicillin resistant Staphylococcus aureus (MRSA) colonization; culture-confirmed late-onset sepsis; and, if intubated, endotracheal tube colonization with Pseudomonas aeruginosa or Klebsiella pneumonia. Independent risk factors were identified with mixed-effects logistic regression models and Moran's I for spatial autocorrelation. RESULT: All four outcomes statistically clustered by location; neighboring colonization also influenced risk of MRSA (p < 0.05). For P. aeruginosa, being in a location with space for more medical equipment was associated with 2.61 times the odds of colonization (95% CrI: 1.19, 5.78). CONCLUSION: Extrinsic factors partially explained risk for neonatal colonization and infection. For P. aeruginosa, infection prevention efforts at locations with space for more equipment may lower future colonization. PMID- 29255193 TI - Surfactant proteins gene variants in premature newborn infants with severe respiratory distress syndrome. AB - OBJECTIVE: Genetic surfactant dysfunction causes respiratory failure in term and near-term newborn infants, but little is known of such condition in prematures. We evaluated genetic surfactant dysfunction in premature newborn infants with severe RDS. PATIENTS AND METHODS: A total of 68 preterm newborn infants with gestational age <=32 weeks affected by unusually severe RDS were analysed for mutations in SFTPB, SFTPC and ABCA3. Therapies included oxygen supplementation, nasal CPAP, different modalities of ventilatory support, administration of exogenous surfactant, inhaled nitric oxide and steroids. Molecular analyses were performed on genomic DNA extracted from peripheral blood and Sanger sequencing of whole gene coding regions and intron junctions. In one case histology and electron microscopy on lung tissue was performed. RESULTS: Heterozygous previously described rare or novel variants in surfactant proteins genes ABCA3, SFTPB and SFTPC were identified in 24 newborn infants. In total, 11 infants died at age of 2 to 6 months. Ultrastructural analysis of lung tissue of one infant showed features suggesting ABCA3 dysfunction. DISCUSSION: Rare or novel genetic variants in genes encoding surfactant proteins were identified in a large proportion (35%) of premature newborn infants with particularly severe RDS. We speculate that interaction of developmental immaturity of surfactant production in association with abnormalities of surfactant metabolism of genetic origin may have a synergic worsening phenotypic effect. PMID- 29255194 TI - Designing flows to resolve human and environmental water needs in a dam-regulated river. AB - Navigating trade-offs between meeting societal water needs and supporting functioning ecosystems is integral to river management policy. Emerging frameworks provide the opportunity to consider multiple river uses explicitly, but balancing multiple priorities remains challenging. Here we quantify relationships between hydrologic regimes and the abundance of multiple native and nonnative fish species over 18 years in a large, dryland river basin in southwestern United States. These models were incorporated into a multi-objective optimization framework to design dam operation releases that balance human water needs with the dual conservation targets of benefiting native fishes while disadvantaging nonnative fishes. Predicted designer flow prescriptions indicate significant opportunities to favor native over nonnative fishes while rarely, if ever, encroaching on human water needs. The predicted benefits surpass those generated by natural flow mimicry, and were retained across periods of heightened drought. We provide a quantitative illustration of theoretical predictions that designer flows can offer multiple ecological and societal benefits in human altered rivers. PMID- 29255195 TI - Single-molecule imaging reveals multiple pathways for the recruitment of translesion polymerases after DNA damage. AB - Unrepaired DNA lesions are a potent block to replication, leading to replication fork collapse, double-strand DNA breaks, and cell death. Error-prone polymerases overcome this blockade by synthesizing past DNA lesions in a process called translesion synthesis (TLS), but how TLS polymerases gain access to the DNA template remains poorly understood. In this study, we use particle-tracking PALM to image live Escherichia coli cells containing a functional fusion of the endogenous copy of Pol IV to the photoactivatable fluorescent protein PAmCherry. We find that Pol IV is strongly enriched near sites of replication only upon DNA damage. Surprisingly, we find that the mechanism of Pol IV recruitment is dependent on the type of DNA lesion, and that interactions with proteins other than the processivity factor beta play a role under certain conditions. Collectively, these results suggest that multiple interactions, influenced by lesion identity, recruit Pol IV to sites of DNA damage. PMID- 29255196 TI - Evolution of sequence-specific anti-silencing systems in Arabidopsis. AB - The arms race between parasitic sequences and their hosts is a major driving force for evolution of gene control systems. Since transposable elements (TEs) are potentially deleterious, eukaryotes silence them by epigenetic mechanisms such as DNA methylation. Little is known about how TEs counteract silencing to propagate during evolution. Here, we report behavior of sequence-specific anti silencing proteins used by Arabidopsis TEs and evolution of those proteins and their target sequences. We show that VANC, a TE-encoded anti-silencing protein, induces extensive DNA methylation loss throughout TEs. Related VANC proteins have evolved to hypomethylate TEs of completely different spectra. Targets for VANC proteins often form tandem repeats, which vary considerably between related TEs. We propose that evolution of VANC proteins and their targets allow propagation of TEs while causing minimal host damage. Our findings provide insight into the evolutionary dynamics of these apparently "selfish" sequences. They also provide potential tools to edit epigenomes in a sequence-specific manner. PMID- 29255197 TI - Central European Woolly Mammoth Population Dynamics: Insights from Late Pleistocene Mitochondrial Genomes. AB - The population dynamics of the Pleistocene woolly mammoth (Mammuthus primigenius) has been the subject of intensive palaeogenetic research. Although a large number of mitochondrial genomes across Eurasia have been reconstructed, the available data remains geographically sparse and mostly focused on eastern Eurasia. Thus, population dynamics in other regions have not been extensively investigated. Here, we use a multi-method approach utilising proteomic, stable isotope and genetic techniques to identify and generate twenty woolly mammoth mitochondrial genomes, and associated dietary stable isotopic data, from highly fragmentary Late Pleistocene material from central Europe. We begin to address region specific questions regarding central European woolly mammoth populations, highlighting parallels with a previous replacement event in eastern Eurasia ten thousand years earlier. A high number of shared derived mutations between woolly mammoth mitochondrial clades are identified, questioning previous phylogenetic analysis and thus emphasizing the need for nuclear DNA studies to explicate the increasingly complex genetic history of the woolly mammoth. PMID- 29255198 TI - sEMG-assisted inverse modelling of 3D lip movement: a feasibility study towards person-specific modelling. AB - We propose a surface-electromyographic (sEMG) assisted inverse-modelling (IM) approach for a biomechanical model of the face to obtain realistic person specific muscle activations (MA) by tracking movements as well as innervation trajectories. We obtained sEMG data of facial muscles and 3D positions of lip markers in six volunteers and, using a generic finite element (FE) face model in ArtiSynth, performed inverse static optimisation with and without sEMG tracking on both simulation data and experimental data. IM with simulated data and experimental data without sEMG data showed good correlations of tracked positions (0.93 and 0.67) and poor correlations of MA (0.27 and 0.20). When utilising the sEMG-assisted IM approach, MA correlations increased drastically (0.83 and 0.59) without sacrificing performance in position correlations (0.92 and 0.70). RMS errors show similar trends with an error of 0.15 in MA and of 1.10 mm in position. Therefore, we conclude that we were able to demonstrate the feasibility of an sEMG-assisted inverse modelling algorithm for the perioral region. This approach may help to solve the ambiguity problem in inverse modelling and may be useful, for instance, in future applications for preoperatively predicting treatment-related function loss. PMID- 29255199 TI - Mechanically stable solvent-free lipid bilayers in nano- and micro-tapered apertures for reconstitution of cell-free synthesized hERG channels. AB - The self-assembled bilayer lipid membrane (BLM) is the basic component of the cell membrane. The reconstitution of ion channel proteins in artificially formed BLMs represents a well-defined system for the functional analysis of ion channels and screening the effects of drugs that act on them. However, because BLMs are unstable, this limits the experimental throughput of BLM reconstitution systems. Here we report on the formation of mechanically stable solvent-free BLMs in microfabricated apertures with defined nano- and micro-tapered edge structures. The role of such nano- and micro-tapered structures on the stability of the BLMs was also investigated. Finally, this BLM system was combined with a cell-free synthesized human ether-a-go-go-related gene channel, a cardiac potassium channel whose relation to arrhythmic side effects following drug treatment is well recognized. Such stable BLMs as these, when combined with a cell-free system, represent a potential platform for screening the effects of drugs that act on various ion-channel genotypes. PMID- 29255200 TI - Deformation and dynamic response of abdominal aortic aneurysm sealing. AB - Endovascular sealing is a new technique for the repair of abdominal aortic aneurysms. Commercially available in Europe since 2013, it takes a revolutionary approach to aneurysm repair through minimally invasive techniques. Although aneurysm sealing may be thought as more stable than conventional endovascular stent graft repairs, post-implantation movement of the endoprosthesis has been described, potentially leading to late complications. The paper presents for the first time a model, which explains the nature of forces, in static and dynamic regimes, acting on sealed abdominal aortic aneurysms, with references to real case studies. It is shown that elastic deformation of the aorta and of the endoprosthesis induced by static forces and vibrations during daily activities can potentially promote undesired movements of the endovascular sealing structure. PMID- 29255201 TI - Piezo type mechanosensitive ion channel component 1 functions as a regulator of the cell fate determination of mesenchymal stem cells. AB - The extracellular environment regulates the dynamic behaviors of cells. However, the effects of hydrostatic pressure (HP) on cell fate determination of mesenchymal stem cells (MSCs) are not clearly understood. Here, we established a cell culture chamber to control HP. Using this system, we found that the promotion of osteogenic differentiation by HP is depend on bone morphogenetic protein 2 (BMP2) expression regulated by Piezo type mechanosensitive ion channel component 1 (PIEZO1) in MSCs. The PIEZO1 was expressed and induced after HP loading in primary MSCs and MSC lines, UE7T-13 and SDP11. HP and Yoda1, an activator of PIEZO1, promoted BMP2 expression and osteoblast differentiation, whereas inhibits adipocyte differentiation. Conversely, PIEZO1 inhibition reduced osteoblast differentiation and BMP2 expression. Furthermore, Blocking of BMP2 function by noggin inhibits HP induced osteogenic maker genes expression. In addition, in an in vivo model of medaka with HP loading, HP promoted caudal fin ray development whereas inhibition of piezo1 using GsMTx4 suppressed its development. Thus, our results suggested that PIEZO1 is responsible for HP and could functions as a factor for cell fate determination of MSCs by regulating BMP2 expression. PMID- 29255202 TI - Effects of maternal and fetal LEP common variants on maternal glycemic traits in pregnancy. AB - Previous studies suggest that leptin (LEP) has an important role in glucose metabolism in the nonpregnant state. During pregnancy, circulating maternal concentrations of leptin rise significantly, mainly due to increased secretion of leptin from maternal adipose tissue and placenta. This study aimed to analyze the impact of maternal and fetal common LEP variants on glucose homeostasis in the pregnant state. Several glycemic traits, including fasting plasma glucose, fasting plasma insulin (FPI), and plasma glucose 1 hour after a 50-g oral glucose load, were measured in 1,112 unrelated Chinese Han pregnant women at 24-28 weeks gestation. Homeostatic model assessment (HOMA) was used to assess beta cell function (HOMA1-beta and HOMA2-beta) and insulin resistance (HOMA1-IR and HOMA2 IR).The relationships between glycemic traits and 12 LEP variants were determined. After applying the Bonferroni correction, we detected that (1) maternal rs10954173 and fetal rs10244329 were associated with maternal FPI although the effect of fetal rs10244329 may be not independent of maternal rs10244329, and (2) maternal rs12537573 was associated with maternal FPI and HOMA2-IR. This study provides genetic evidence that both maternal and fetal LEP polymorphisms may affect maternal glucose metabolism in pregnancy. PMID- 29255203 TI - Growth Associated Protein 43 (GAP-43) as a Novel Target for the Diagnosis, Treatment and Prevention of Epileptogenesis. AB - We previously showed increased growth associated protein 43 (GAP-43) expression in brain samples resected from patients with cortical dysplasia (CD), which was correlated with duration of epilepsy. Here, we used a rat model of CD to examine the regulation of GAP-43 in the brain and serum over the course of epileptogenesis. Baseline GAP-43 expression was higher in CD animals compared to control non-CD rats. An acute seizure increased GAP-43 expression in both CD and control rats. However, GAP-43 expression decreased by day 15 post-seizure in control rats, which did not develop spontaneous seizures. In contrast, GAP-43 remained up-regulated in CD rats, and over 50% developed chronic epilepsy with increased GAP-43 levels in their serum. GAP-43 protein was primarily located in excitatory neurons, suggesting its functional significance in epileptogenesis. Inhibition of GAP-43 expression by shRNA significantly reduced seizure duration and severity in CD rats after acute seizures with subsequent reduction in interictal spiking. Serum GAP-43 levels were significantly higher in CD rats that developed spontaneous seizures. Together, these results suggest GAP-43 as a key factor promoting epileptogenesis, a possible therapeutic target for treatment of progressive epilepsy and a potential biomarker for epilepsy progression in CD. PMID- 29255204 TI - Impact of systematic urinary catheterization protocol in delivery room on covert postpartum urinary retention: a before-after study. AB - We investigated whether implementation of a routine catheterization procedure in labor improves covert postpartum urinary retention (cPUR) rates. We conducted a prospective before-after study. 121 women admitted to delivery room in the observational group, and 82 in the intervention group, in a tertiary university hospital in Southern France were included. All patients in the intervention group were systematically catheterized 2 hours after delivery. cPUR was screened for in both groups. The primary end-point was cPUR (post-void residual bladder volume >150 ml when voided volume is >150 mL). The rate of cPUR decreased from 50% (60 out of 121 patients) in the observational group to 17% (14/82) in the intervention group (OR = 0.21; 95% Confidence Interval [0.13;0.58]; p < 0.001). Similarly, in the subgroup of patients who underwent instrumental delivery, the rate of cPUR was lower in the intervention group (18%, 2/11) than in the observational group (65%, 15/23) (p = 0.02). Systematic intermittent bladder catheterization immediately postpartum could decrease cPUR. Further studies are necessary to assess the long-term outcomes and improve understanding of postpartum voiding dysfunction. PMID- 29255206 TI - Hormonal Contraceptives Differentially Suppress TFV and TAF Inhibition of HIV Infection and TFV-DP in Blood and Genital Tract CD4+ T cells. AB - HIV prevention research is focused on combining antiretrovirals (ARV) and progestin contraceptives to prevent HIV infection and pregnancy. The possibility that progestins compromise ARV anti-HIV activity prompted us to evaluate the effects of progestins on tenofovir (TFV) and TFV-alafenamide (TAF) on HIV infection and intracellular TFV-diphosphate (TFV-DP) concentrations in blood and genital CD4+ T cells. Following incubation of blood CD4+ T cells with TFV or TAF, Medroxyprogesterone acetate (MPA), but not Levonorgestrel, Norethisterone or progesterone, suppressed the anti-HIV effect of TFV by reducing intracellular TFV DP, but had no effect on TAF inhibition of infection or TFV-DP. In contrast, with genital CD4+ T cells, MPA suppressed TAF inhibition of HIV infection and lowered of TFV-DP concentrations without affecting TFV protection. These findings demonstrate that MPA selectively compromises TFV and TAF protection in blood and genital CD4+ T cells and suggests that MPA may decrease ARV protection in individuals who use ARV intermittently for prevention. PMID- 29255207 TI - A new and general approach to signal denoising and eye movement classification based on segmented linear regression. AB - We introduce a conceptually novel method for eye-movement signal analysis. The method is general in that it does not place severe restrictions on sampling frequency, measurement noise or subject behavior. Event identification is based on segmentation that simultaneously denoises the signal and determines event boundaries. The full gaze position time-series is segmented into an approximately optimal piecewise linear function in O(n) time. Gaze feature parameters for classification into fixations, saccades, smooth pursuits and post-saccadic oscillations are derived from human labeling in a data-driven manner. The range of oculomotor events identified and the powerful denoising performance make the method useable for both low-noise controlled laboratory settings and high-noise complex field experiments. This is desirable for harmonizing the gaze behavior (in the wild) and oculomotor event identification (in the laboratory) approaches to eye movement behavior. Denoising and classification performance are assessed using multiple datasets. Full open source implementation is included. PMID- 29255205 TI - Associations between self-rated health, sickness behaviour and inflammatory markers in primary care patients with allergic asthma: a longitudinal study. AB - Allergic asthma is a chronic inflammatory disorder associated with elevated levels of immunoglobulin E (IgE), serum eosinophilic cationic protein (S-ECP), plasma eosinophil-derived neurotoxin (P-EDN) and fraction of exhaled nitric oxide (FENO). Poor self-rated health and sickness behaviour has repeatedly been associated with inflammatory markers, but the nature of this relationship in chronic inflammatory disease is not known. Likewise, such findings largely rely on cross-sectional investigations. Self-rated health (How would you rate your general state of health?), sickness behaviour (mean rating of satisfaction with energy, sleep, fitness, appetite and memory), IgE, S-ECP, P-EDN, and FENO were assessed in 181 non-smoking primary care patients with asthma in a 1-year longitudinal study. Associations between repeated measurements were calculated using mixed regression models and Spearman's correlations for change scores. Poor self-rated health was associated with high levels of seasonal IgE (p = 0.05) and food IgE (p = 0.04), but not total IgE or inflammatory markers. An increase over 1 year in perennial IgE was associated with a worsening of self-rated health (rho = 0.16, p = 0.04). Poor self-rated health was associated with more pronounced sickness behaviour (p < 0.001), and a worsening in sickness behaviour was associated with a worsening of self-rated health over time (rho = 0.21, p = 0.007). The study corroborates the importance of sickness behaviour as a determinant of self-rated health by showing that these factors co-vary over a 1 year period in a group of patients with allergic asthma. The importance of specific IgE for perceived health in primary care patients with mild to moderate asthma needs further investigation. PMID- 29255208 TI - High-resolution adaptive optical imaging within thick scattering media using closed-loop accumulation of single scattering. AB - Thick biological tissues give rise to not only the multiple scattering of incoming light waves, but also the aberrations of remaining signal waves. The challenge for existing optical microscopy methods to overcome both problems simultaneously has limited sub-micron spatial resolution imaging to shallow depths. Here we present an optical coherence imaging method that can identify aberrations of waves incident to and reflected from the samples separately, and eliminate such aberrations even in the presence of multiple light scattering. The proposed method records the time-gated complex-field maps of backscattered waves over various illumination channels, and performs a closed-loop optimization of signal waves for both forward and phase-conjugation processes. We demonstrated the enhancement of the Strehl ratio by more than 500 times, an order of magnitude or more improvement over conventional adaptive optics, and achieved a spatial resolution of 600 nm up to an imaging depth of seven scattering mean free paths. PMID- 29255209 TI - Enzymatic production of all fourteen partially acetylated chitosan tetramers using different chitin deacetylases acting in forward or reverse mode. AB - Some of the most abundant biomolecules on earth are the polysaccharides chitin and chitosan of which especially the oligomeric fractions have been extensively studied regarding their biological activities. However, most of these studies have not been able to assess the activity of a single, defined, partially acetylated chitosan oligosaccharide (paCOS). Instead, they have typically analyzed chemically produced, rather poorly characterized mixtures, at best with a single, defined degree of polymerization (DP) and a known average degree of acetylation (DA), as no pure and well-defined paCOS are currently available. We here present data on the enzymatic production of all 14 possible partially acetylated chitosan tetramers, out of which four were purified (>95%) regarding DP, DA, and pattern of acetylation (PA). We used bacterial, fungal, and viral chitin deacetylases (CDAs), either to partially deacetylate the chitin tetramer; or to partially re-N-acetylate the glucosamine tetramer. Both reactions proceeded with surprisingly strong and enzyme-specific regio-specificity. These pure and fully defined chitosans will allow to investigate the particular influence of DP, DA, and PA on the biological activities of chitosans, improving our basic understanding of their modes of action, e.g. their molecular perception by patter recognition receptors, but also increasing their usefulness in industrial applications. PMID- 29255210 TI - Spondyloarthropathies: Tofacitinib shows promise in PsA trials. PMID- 29255212 TI - Epidemiology: Arthritis more common than expected. PMID- 29255214 TI - Corrigendum: Synovial tissue research: a state-of-the-art review. AB - This corrects the article DOI: 10.1038/nrrheum.2017.115. PMID- 29255211 TI - Autoimmunity and primary immunodeficiency: two sides of the same coin? AB - Autoimmunity and immunodeficiency were previously considered to be mutually exclusive conditions; however, increased understanding of the complex immune regulatory and signalling mechanisms involved, coupled with the application of genetic analysis, is revealing the complex relationships between primary immunodeficiency syndromes and autoimmune diseases. Single-gene defects can cause rare diseases that predominantly present with autoimmune symptoms. Such genetic defects also predispose individuals to recurrent infections (a hallmark of immunodeficiency) and can cause primary immunodeficiencies, which can also lead to immune dysregulation and autoimmunity. Moreover, risk factors for polygenic rheumatic diseases often exist in the same genes as the mutations that give rise to primary immunodeficiency syndromes. In this Review, various primary immunodeficiency syndromes are presented, along with their pathogenetic mechanisms and relationship to autoimmune diseases, in an effort to increase awareness of immunodeficiencies that occur concurrently with autoimmune diseases and to highlight the need to initiate appropriate genetic tests. The growing knowledge of various genetically determined pathologic mechanisms in patients with immunodeficiencies who have autoimmune symptoms opens up new avenues for personalized molecular therapies that could potentially treat immunodeficiency and autoimmunity at the same time, and that could be further explored in the context of autoimmune rheumatic diseases. PMID- 29255215 TI - Potential usefulness of Brevibacillus for bacterial cancer therapy: intratumoral provision of tumor necrosis factor-alpha and anticancer effects. AB - Bacterial cancer therapy, wherein bacteria are used as a gene expression system for the exogenous protein of interest in the body, has started becoming a focus area of research; therefore, studying potential bacterial species for use is extremely important. Here, we investigated the use of Brevibacillus choshinensis as an effective and safe provider of anticancer proteins in the body, using a transformant expressing murine tumor necrosis factor-alpha (mTNF-alpha). The transformant sustainably provided mTNF-alpha in tumors in mice for a few hours post-injection. The growth of TNF-alpha-sensitive tumors was inhibited even by the control transformant, which did not provide mTNF-alpha; intratumoral mTNF alpha provision by Brevibacillus choshinensis had additive effects on tumor growth inhibition. In contrast, intratumorally injected recombinant mTNF-alpha did not inhibit tumor growth because of rapid elimination from the tumor. Blood biochemical and histochemical analyses showed that intravenous injection of the transformant that did not provide mTNF-alpha did not lead to tissue injury and dysfunction or infiltration of inflammatory cells over 1 week. Considering the findings, this approach is expected to have a high degree of usability as a delivery system for protein pharmaceuticals, especially from the viewpoints of loading capacity and cost effectiveness. PMID- 29255213 TI - Joint diseases: from connexins to gap junctions. AB - Connexons form the basis of hemichannels and gap junctions. They are composed of six tetraspan proteins called connexins. Connexons can function as individual hemichannels, releasing cytosolic factors (such as ATP) into the pericellular environment. Alternatively, two hemichannel connexons from neighbouring cells can come together to form gap junctions, membrane-spanning channels that facilitate cell-cell communication by enabling signalling molecules of approximately 1 kDa to pass from one cell to an adjacent cell. Connexins are expressed in joint tissues including bone, cartilage, skeletal muscle and the synovium. Indicative of their importance as gap junction components, connexins are also known as gap junction proteins, but individual connexin proteins are gaining recognition for their channel-independent roles, which include scaffolding and signalling functions. Considerable evidence indicates that connexons contribute to the function of bone and muscle, but less is known about the function of connexons in other joint tissues. However, the implication that connexins and gap junctional channels might be involved in joint disease, including age-related bone loss, osteoarthritis and rheumatoid arthritis, emphasizes the need for further research into these areas and highlights the therapeutic potential of connexins. PMID- 29255216 TI - Radiation-enhanced delivery of plasmid DNA to tumors utilizing a novel PEI polyplex. AB - The excitement surrounding the potential of gene therapy has been tempered due to the challenges that have thus far limited its successful implementation in the clinic such as issues regarding stability, transfection efficiency, and toxicity. In this study, low molecular weight linear polyethyleneimine (2.5 kDa) was modified by conjugation to a lipid, lithocholic acid, and complexed with a natural polysaccharide, dermatan sulfate (DS), to mask extra cationic charges of the modified polymer. In vitro examination revealed that these modifications improved complex stability with plasmid DNA (pDNA) and transfection efficiency. This novel ternary polyplex (pDNA/3E/DS) was used to investigate if tumor targeted radiotherapy led to enhanced accumulation and retention of gene therapy vectors in vivo in tumor-bearing mice. Imaging of biodistribution revealed that tumor irradiation led to increased accumulation and retention as well as decreased off-target tissue buildup of pDNA in not only pDNA/3E/DS, but also in associated PEI-based polyplexes and commercial DNA delivery vehicles. The DS containing complexes developed in this study displayed the greatest increase in tumor-specific pDNA delivery. These findings demonstrate a step forward in nucleic acid vehicle design as well as a promising approach to overall cancer gene therapy through utilization of radiotherapy as a tool for enhanced delivery. PMID- 29255217 TI - Congenital adrenal hyperplasia causing hypertension: an illustrative review. AB - Congenital adrenal hyperplasia (CAH) is often considered a pediatric endocrinology condition, but we present two cases of young adults who presented with hypertension. An 18-year-old woman was found to have hypertension and hypokalemia when she presented for gonadectomy for 46, XY gonadal dysgenesis. She was subsequently found to have low cortisol, elevated progesterone, and elevated aldosterone. Genetic testing confirmed 17-alpha hydroxylase deficiency (17OHD). Her case was unique in that 17OHD usually presents with hypoaldosteronism. We also present the case of a 15-year-old man (46, XX) with resistant hypertension due to 11-beta hydroxylase deficiency (11OHD) who underwent bilateral adrenalectomy for control of hypertension. The relevant literature is reviewed including the pathophysiology, clinical presentation, and treatment of the hypertensive variants of congenital adrenal hyperplasia. We also review the unique areas of hyperaldosteronism in 17OHD and the use of bilateral adrenalectomy for control of hypertension in CAH. PMID- 29255218 TI - Investigating the association of vitamin D with blood pressure and the renin angiotensin-aldosterone system in hypertensive subjects: a cross-sectional prospective study. AB - The hypothesis that vitamin D (25(OH)D) insufficiency plays a role in occurring of various disease has led to a rise in requests of dosages and to an increase of health-care costs. 25(OH)D insufficiency is associated with increased risk of cardiovascular disease and hypertension in many studies. Animal studies demonstrated that 25(OH)D insufficiency activates renin angiotensin system but corresponding humans data are limited. The aim of the study was to document relationship between 25(OH)D, blood pressure, and renin angiotensin system in hypertensive subjects. In all, 248 hypertensive individuals, 46.8 years (+/-14), were hospitalized for an etiological assessment of hypertension in this cross sectional study over two calendar years. 25(OH)D, plasma renin activity, and aldosterone were determined in stringent conditions and blood pressure was measure. Statistical analyses were carried out to analyze the association between 25(OH)D, blood pressure, and renin angiotensin system using linear and logistic regressions with adjustments on relevant variables. In all, 80% of the studied population had a 25(OH)D insufficiency. There were no significant association between 25(OH)D and levels of systolic or diastolic blood pressure, plasma renin activity, and aldosterone whatever the statiscal method used after adjustment. 25(OH)D is not associated with blood pressure and renin angiontensin component in hypertensive subjects. These results corroborate the interventional studies which are for a large majority negatives. A new definition of the 25(OH)D insufficiency in general population is necessary. PMID- 29255219 TI - Scattering of Ultra-relativistic Electrons in the Van Allen Radiation Belts Accounting for Hot Plasma Effects. AB - Electron flux in the Earth's outer radiation belt is highly variable due to a delicate balance between competing acceleration and loss processes. It has been long recognized that Electromagnetic Ion Cyclotron (EMIC) waves may play a crucial role in the loss of radiation belt electrons. Previous theoretical studies proposed that EMIC waves may account for the loss of the relativistic electron population. However, recent observations showed that while EMIC waves are responsible for the significant loss of ultra-relativistic electrons, the relativistic electron population is almost unaffected. In this study, we provide a theoretical explanation for this discrepancy between previous theoretical studies and recent observations. We demonstrate that EMIC waves mainly contribute to the loss of ultra-relativistic electrons. This study significantly improves the current understanding of the electron dynamics in the Earth's radiation belt and also can help us understand the radiation environments of the exoplanets and outer planets. PMID- 29255220 TI - The kinematics of handwriting movements as expression of cognitive and sensorimotor impairments in people with multiple sclerosis. AB - Handwriting is an important activity of daily living, which requires sensorimotor and cognitive skills that could deteriorate in presence of neurological diseases. Handwriting impairments are common in people with multiple sclerosis (PwMS). Aims of the present study were to characterize handwriting movement features of PwMS in comparison with those of healthy adults, and to evaluate the relationship between kinematic parameters of handwriting movements and the results of the assessment of cognitive and motor domains. A new handwriting evaluation methodology was applied to quantify handwriting features of 19 PwMS and 22 age matched healthy controls who were required to write a sentence on a digitizing tablet. Kinematic parameters of the sentence and of the strokes were used to evaluate handwriting performance. PwMS showed an altered handwriting kinematics with respect to healthy controls: higher movement duration, fragmented velocity profile and higher jerk. Furthermore, motor abilities and cognitive status of PwMS were related to handwriting parameters in accordance with the evidence that MS is a multifactorial disease affecting different domains. These results suggested that the proposed methodology might be a valuable tool to quantitatively assess handwriting impairments and the efficacy of handwriting treatments in PwMS. PMID- 29255222 TI - Colloids: Chiral interactions in liquid crystals. PMID- 29255223 TI - Corrigendum: Robust resistive memory devices using solution-processable metal coordinated azo aromatics. AB - This corrects the article DOI: 10.1038/nmat5009. PMID- 29255221 TI - Curcumin activates DNA repair pathway in bone marrow to improve carboplatin induced myelosuppression. AB - Carboplatin, a second-generation platinum agent, has been used as a cancer therapy for decades and exhibits strong anti-tumor activity. However, the wide application of carboplatin is largely limited due to its side effects, especially myelosuppression. Here, we combined carboplatin with curcumin, a natural product that improves tumor-induced anemia, for the treatment of fibrosarcoma to improve the side effects of carboplatin. We first examined the synergistic and attenuated effects of the two agents in a T241-bearing mouse model. The combination therapy caused no obvious synergistic effect, but curcumin significantly improved the survival rate of carboplatin-treated mice. Histologic analysis of the kidney and bone marrow revealed that curcumin improved carboplatin-induced myelosuppression but did not affect the kidney. To determine the mechanism involved, we introduced a probe derived from curcumin to identify its targets in bone marrow cells and the results provided us a clue that curcumin might affect the DNA repair pathway. Western blot analysis revealed that curcumin up-regulated BRCA1, BRCA2 and ERCC1 expression in bone marrow. In conclusion, curcumin attenuates carboplatin-induced myelosuppression by activating the DNA repair pathway in bone marrow cells. PMID- 29255224 TI - Metallurgy: Printing steels. PMID- 29255225 TI - Critical assessment of charge mobility extraction in FETs. PMID- 29255226 TI - Colloidal nanocrystals: Virtues of defects. PMID- 29255227 TI - A cure for mobility problems. PMID- 29255228 TI - Corrigendum: Fibronectin-bound alpha5beta1 integrins sense load and signal to reinforce adhesion in less than a second. AB - This corrects the article DOI: 10.1038/nmat5023. PMID- 29255229 TI - Correction. AB - This corrects the article DOI: 10.1038/nmat5009. PMID- 29255230 TI - Material witness: How does it feel? PMID- 29255231 TI - Atomic segregation: Activity at the surface. PMID- 29255232 TI - Isolation and pathogenicity of Xylella fastidiosa associated to the olive quick decline syndrome in southern Italy. AB - In autumn 2013, the presence of Xylella fastidiosa, a xylem-limited Gram-negative bacterium, was detected in olive stands of an area of the Ionian coast of the Salento peninsula (Apulia, southern Italy), that were severely affected by a disease denoted olive quick decline syndrome (OQDS). Studies were carried out for determining the involvement of this bacterium in the genesis of OQDS and of the leaf scorching shown by a number of naturally infected plants other than olive. Isolation in axenic culture was attempted and assays were carried out for determining its pathogenicity to olive, oleander and myrtle-leaf milkwort. The bacterium was readily detected by quantitative polymerase chain reaction (qPCR) in all diseased olive trees sampled in different and geographically separated infection foci, and culturing of 51 isolates, each from a distinct OQDS focus, was accomplished. Needle-inoculation experiments under different environmental conditions proved that the Salentinian isolate De Donno belonging to the subspecies pauca is able to multiply and systemically invade artificially inoculated hosts, reproducing symptoms observed in the field. Bacterial colonization occurred in prick-inoculated olives of all tested cultivars. However, the severity of and timing of symptoms appearance differed with the cultivar, confirming their differential reaction. PMID- 29255234 TI - Feed gas effect on plasma inactivation mechanism of Salmonella Typhimurium in onion and quality assessment of the treated sample. AB - A submerged dielectric barrier discharge (DBD) plasma reactor was used to inactivate artificially inoculated reference strains of Salmonella Typhimurium ATCC 14028 on sliced onion (3 cm * 3 cm). Salmonella Typhimurium reductions obtained after 10 min of treatment were 3.96 log CFU/slice and 1.64 log CFU/slice for clean dry air and N2 feed gas, respectively. Variations observed in Optical Emission Spectra (OES) for different feed gases are responsible for the inactivation level variations of Salmonella Typhimurium. The physiochemical properties of the onion slices, such as quercetin content, ascorbic acid content and color parameters, were monitored before and after treatment and the changes that occurred were measured to be in the acceptable range. Quercetin content was reduced only 3.74-5.07% for 10 min treatment, higher reduction was obtained for the use of clean dry air than that of N2 feed gas. Ascorbic acid loss was measured to be 11.82% and 7.98% for a 10 min treatment with clean dry air and N2 feed gas, respectively. The color parameters did not show significant changes upon treatment (p > 0.05) of the same duration for the uses of different feed gases. PMID- 29255233 TI - Longitudinal intravital imaging of the femoral bone marrow reveals plasticity within marrow vasculature. AB - The bone marrow is a central organ of the immune system, which hosts complex interactions of bone and immune compartments critical for hematopoiesis, immunological memory, and bone regeneration. Although these processes take place over months, most existing imaging techniques allow us to follow snapshots of only a few hours, at subcellular resolution. Here, we develop a microendoscopic multi-photon imaging approach called LIMB (longitudinal intravital imaging of the bone marrow) to analyze cellular dynamics within the deep marrow. The approach consists of a biocompatible plate surgically fixated to the mouse femur containing a gradient refractive index lens. This microendoscope allows highly resolved imaging, repeatedly at the same regions within marrow tissue, over months. LIMB reveals extensive vascular plasticity during bone healing and steady state homeostasis. To our knowledge, this vascular plasticity is unique among mammalian tissues, and we expect this insight will decisively change our understanding of essential phenomena occurring within the bone marrow. PMID- 29255235 TI - Immunotherapy: dMMR presents opportunities to enhance immunotherapy. PMID- 29255236 TI - Lung cancer: OSNA enables more accurate detection of micrometastases. PMID- 29255237 TI - Palliative care: Anamorelin provides benefit to patients with cachexia. PMID- 29255238 TI - Acute lymphoblastic leukaemia in 2017: Immunotherapy for ALL takes the world by storm. PMID- 29255240 TI - Bladder cancer: Multi-omic profiling refines the molecular view. PMID- 29255239 TI - The evidence framework for precision cancer medicine. AB - Precision cancer medicine (PCM) is a concept in which oncologists increasingly strive to tailor the use of targeted therapies in order to match the complexity of the cancer genome. This approach contradicts the historical framework used to support oncology practice that requires evidence from randomized controlled trials in order to change standards of care. This contrast demonstrates the irony of PCM: the therapies themselves are more precise than standard cytotoxic agents, although the clinical evidence supporting the benefits of these therapies is often considerably less precise. Nevertheless, the implementation of PCM should still be based on a framework of evidence-based development that supports clinical decision-making; this approach should not be simple off-label prescription of drugs following sequencing of a tumour biopsy sample. The clinical validation of increasingly complex diagnostic tests, the development of novel methods of evaluating efficacy, and the re-assessment of the standards of evidence sufficient to demonstrate the benefit of precision cancer therapies are all needed before PCM becomes the standard of care for patients with tumours harbouring genomic abnormalities of uncertain clinical significance. PMID- 29255241 TI - Prostate cancer: Genomic information improves risk prediction. PMID- 29255242 TI - Fluorine-19 nuclear magnetic resonance of chimeric antigen receptor T cell biodistribution in murine cancer model. AB - Discovery of effective cell therapies against cancer can be accelerated by the adaptation of tools to rapidly quantitate cell biodistribution and survival after delivery. Here, we describe the use of nuclear magnetic resonance (NMR) 'cytometry' to quantify the biodistribution of immunotherapeutic T cells in intact tissue samples. In this study, chimeric antigen receptor (CAR) T cells expressing EGFRvIII targeting transgene were labeled with a perfluorocarbon (PFC) emulsion ex vivo and infused into immunocompromised mice bearing subcutaneous human U87 glioblastomas expressing EGFRvIII and luciferase. Intact organs were harvested at day 2, 7 and 14 for whole-sample fluorine-19 (19F) NMR to quantitatively measure the presence of PFC-labeled CAR T cells, followed by histological validation. NMR measurements showed greater CAR T cell homing and persistence in the tumors and spleen compared to untransduced T cells. Tumor growth was monitored with bioluminescence imaging, showing that CAR T cell treatment resulted in significant tumor regression compared to untransduced T cells. Overall, 19F NMR cytometry is a rapid and quantitative method to evaluate cell biodistribution, tumor homing, and fate in preclinical studies. PMID- 29255243 TI - Heritability of the melatonin synthesis variability in autism spectrum disorders. AB - Autism Spectrum Disorders (ASD) are heterogeneous neurodevelopmental disorders with a complex genetic architecture. They are characterized by impaired social communication, stereotyped behaviors and restricted interests and are frequently associated with comorbidities such as intellectual disability, epilepsy and severe sleep disorders. Hyperserotonemia and low melatonin levels are among the most replicated endophenotypes reported in ASD, but their genetic causes remain largely unknown. Based on the biochemical profile of 717 individuals including 213 children with ASD, 128 unaffected siblings and 376 parents and other relatives, we estimated the heritability of whole-blood serotonin, platelet N acetylserotonin (NAS) and plasma melatonin levels, as well as the two enzymes arylalkylamine N-acetyltransferase (AANAT) and acetylserotonin O methyltransferase (ASMT) activities measured in platelets. Overall, heritability was higher for NAS (0.72 +/- 0.091) and ASMT (0.59 +/- 0.097) compared with serotonin (0.31 +/- 0.078), AANAT (0.34 +/- 0.077) and melatonin (0.22 +/- 0.071). Bivariate analyses showed high phenotypic and genetic correlations between traits of the second step of the metabolic pathway (NAS, ASMT and melatonin) indicating the contribution of shared genetic factors. A better knowledge of the heritability of the melatonin synthesis variability constitutes an important step to identify the factors that perturb this pathway in individuals with ASD. PMID- 29255244 TI - ANGPTL8 negatively regulates NF-kappaB activation by facilitating selective autophagic degradation of IKKgamma. AB - Excessive nuclear factor-kappaB (NF-kappaB) activation mediated by tumor necrosis factor alpha (TNFalpha) plays a critical role in inflammation. Here we demonstrate that angiopoietin-like 8 (ANGPTL8) functions as a negative feedback regulator in TNFalpha-triggered NF-kappaB activation intracellularly. Inflammatory stimuli induce ANGPTL8 expression, and knockdown or knockout of ANGPTL8 potentiates TNFalpha-induced NF-kappaB activation in vitro. Mechanistically, upon TNFalpha stimulation, ANGPTL8 facilitates the interaction of IKKgamma with p62 via forming a complex, thus promoting the selective autophagic degradation of IKKgamma. Furthermore, the N-terminal domain mediated self-oligomerization of ANGPTL8 is essential for IKKgamma degradation and NF kappaB activation. In vivo, circulating ANGPTL8 level is high in patients diagnosed with infectious diseases, and the ANGPTL8/p62-IKKgamma axis is responsive to inflammatory stimuli in the liver of LPS-injected mice. Altogether, our study suggests the ANGPTL8/p62-IKKgamma axis as a negative feedback loop that regulates NF-kappaB activation, and extends the role of selective autophagy in fine-tuned inflammatory responses. PMID- 29255245 TI - Blueprint for Large-Scale Silicon Optical Phased Array Using Electro-Optical Micro-Ring Pixels. AB - We propose a modularized architecture of a large-scale optical phased array (OPA) on a silicon on insulator (SOI) platform, using electro-optical (EO) pixels. Each pixel contains a directional coupler, a micro-ring phase shifter, and a grating optical antenna, on a compact configuration of area 50 MUm * 50 MUm, with optical and electrical interconnections. Moreover, we present an exemplary blueprint of an OPA consisting of 32 * 32 EO pixels, which sets the width of the main lobe as 0.04 degrees * 0.04 degrees and the field of view as 1.78 degrees . By applying an over-coupled condition, the modulation efficiency and the accompanying intensity modulation are balanced, thus, the OPA performance is not severely degraded. The discussion on the fabrication tolerance shows that the proposed architecture is robust and feasible regarding the state-of-the-art fabrication process, and the performance of the main lobe width and field of view can be further optimized by a larger system size and smaller pixel size. Furthermore, the complexity of interconnections linearly depends on the number of rows and columns, making it highly scalable. PMID- 29255246 TI - A 1-phytase type III effector interferes with plant hormone signaling. AB - Most Gram-negative phytopathogenic bacteria inject type III effector (T3E) proteins into plant cells to manipulate signaling pathways to the pathogen's benefit. In resistant plants, specialized immune receptors recognize single T3Es or their biochemical activities, thus halting pathogen ingress. However, molecular function and mode of recognition for most T3Es remains elusive. Here, we show that the Xanthomonas T3E XopH possesses phytase activity, i.e., dephosphorylates phytate (myo-inositol-hexakisphosphate, InsP6), the major phosphate storage compound in plants, which is also involved in pathogen defense. A combination of biochemical approaches, including a new NMR-based method to discriminate inositol polyphosphate enantiomers, identifies XopH as a naturally occurring 1-phytase that dephosphorylates InsP6 at C1. Infection of Nicotiana benthamiana and pepper by Xanthomonas results in a XopH-dependent conversion of InsP6 to InsP5. 1-phytase activity is required for XopH-mediated immunity of plants carrying the Bs7 resistance gene, and for induction of jasmonate- and ethylene-responsive genes in N. benthamiana. PMID- 29255247 TI - GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers. AB - Treatment failure in solid tumors occurs due to the survival of specific subpopulations of cells that possess tumor-initiating (TIC) phenotypes. Studies have implicated G protein-coupled-receptors (GPCRs) in cancer progression and the acquisition of TIC phenotypes. Many of the implicated GPCRs signal through the G protein GNA13. In this study, we demonstrate that GNA13 is upregulated in many solid tumors and impacts survival and metastases in patients. GNA13 levels modulate drug resistance and TIC-like phenotypes in patient-derived head and neck squamous cell carcinoma (HNSCC) cells in vitro and in vivo. Blockade of GNA13 expression, or of select downstream pathways, using small-molecule inhibitors abrogates GNA13-induced TIC phenotypes, rendering cells vulnerable to standard-of care cytotoxic therapies. Taken together, these data indicate that GNA13 expression is a potential prognostic biomarker for tumor progression, and that interfering with GNA13-induced signaling provides a novel strategy to block TICs and drug resistance in HNSCCs. PMID- 29255249 TI - N-Acetylcysteine Attenuates the Development of Renal Fibrosis in Transgenic Mice with Dilated Cardiomyopathy. AB - Mechanisms underlying the renal pathology in cardiorenal syndrome (CRS) type 2 remain elusive. We hypothesised that renal glutathione deficiency is central to the development of CRS type 2. Glutathione precursor, N-acetylcysteine (NAC;40 mg/kg/day; 8 weeks) or saline were administered to transgenic mice with dilated cardiomyopathy (DCM) and wild-type (WT) controls. Cardiac structure, function and glutathione levels were assessed at the end of this protocol. Renal fibrosis, glutathione content, expression of inflammatory and fibrotic markers, and function were also evaluated. In both genotypes, NAC had minimal effect on cardiac glutathione, structure and function (P >= 0.20). In NAC treated DCM mice, loss of glomerular filtration rate (GFR), tubulointerstitial and glomerular fibrosis and renal oxidised glutathione levels were attenuated by 38%, 99%, 70% and 52% respectively, compared to saline treated DCM mice (P <= 0.01). Renal expression of PAI-1 was greater in saline treated DCM mice than in WT mice (P < 0.05). Renal PAI-1 expression was less in NAC treated DCM mice than in vehicle treated DCM mice (P = 0.03). Renal IL-10 expression was greater in the former cohort compared to the latter (P < 0.01). These data indicate that normalisation of renal oxidized glutathione levels attenuates PAI-1 expression and renal inflammation preventing loss of GFR in experimental DCM. PMID- 29255250 TI - Structure and piezo-ferroelectricity relationship study of (K0.5Na0.5)0.985La0.005NbO3 epitaxial films deposited on SrTiO3 by sputtering. AB - This work demonstrates that the rf-sputtering technique, combined with appropriate heat treatments, is potentially effective to develop new materials and devices based on oxide-interface and strain engineering. We report a study of the structural-physical properties relationship of high crystalline quality, highly oriented and epitaxial thin films of the lead-free (K0.5Na0.5)0.985La0.005NbO3 (KNNLa) compound which were successfully deposited on Nb-doped SrTiO3 substrates, with orientations [100] (NSTO100) and [110] (NSTO110). The crystalline growth and the local ferroelectric and piezoelectric properties were evaluated by piezoresponse force microscopy combined with transmission electron microscopy and texture analysis by X-ray diffraction. Conditioned by the STO surface parameters, in the KNNLa films on NSTO100 coexist a commensurate [001]-tetragonal phase and two incommensurate [010]-monoclinic phases; while on NSTO110 the KNNLa films grew only in an incommensurate [101] monoclinic phase. Both samples show excellent out-of-plane polarization switching patterns consistent with 180 degrees domains walls; while for KNNLa/NSTO100 ferroelectric domains grow with the polarization pointing down, for KNNLa/NSTO110 they prefer to grow with the polarization pointing up. Comparing with previous reports on epitaxial KNN films, we find our samples to be of very high quality regarding their crystalline growth with highly ordered ferroelectric domains arrangements and, consequently, great potential for domain engineering. PMID- 29255248 TI - Dual role of autophagy in hallmarks of cancer. AB - Evolutionarily conserved across eukaryotic cells, macroautophagy (herein autophagy) is an intracellular catabolic degradative process targeting damaged and superfluous cellular proteins, organelles, and other cytoplasmic components. Mechanistically, it involves formation of double-membrane vesicles called autophagosomes that capture cytosolic cargo and deliver it to lysosomes, wherein the breakdown products are eventually recycled back to the cytoplasm. Dysregulation of autophagy often results in various disease manifestations, including neurodegeneration, microbial infections, and cancer. In the case of cancer, extensive attention has been devoted to understanding the paradoxical roles of autophagy in tumor suppression and tumor promotion. In this review, while we summarize how this self-eating process is implicated at various stages of tumorigenesis, most importantly, we address the link between autophagy and hallmarks of cancer. This would eventually provide a better understanding of tumor dependence on autophagy. We also discuss how therapeutics targeting autophagy can counter various transformations involved in tumorigenesis. Finally, this review will provide a novel insight into the mutational landscapes of autophagy-related genes in several human cancers, using genetic information collected from an array of cancers. PMID- 29255251 TI - Dual direction CRISPR transcriptional regulation screening uncovers gene networks driving drug resistance. AB - Pooled CRISPR-Cas9 knock out screens provide a valuable addition to the methods available for novel drug target identification and validation. However, where gene editing is targeted to amplified loci, the resulting multiple DNA cleavage events can be a cause of false positive hit identification. The generation of nuclease deficient versions of Cas9 has enabled the development of two additional techniques - CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) - that enable the repression or overexpression, respectively, of target genes. Here we report the first direct combination of all three approaches (CRISPRko, CRISPRi and CRISPRa) in the context of genome-wide screens to identify components that influence resistance and sensitivity to the BRAF inhibitor, vemurafenib. The pairing of both loss- and gain-of-function datasets reveals complex gene networks which control drug response and illustrates how such data can add substantial confidence to target identification and validation analyses. PMID- 29255252 TI - Aerobic exercise improves endothelial function and serum adropin levels in obese adolescents independent of body weight loss. AB - Adropin is a secreted protein that regulates endothelial function. However, adropin levels in obese adolescent patients are currently uncertain. Therefore, we evaluated the association between plasma adropin levels and vascular endothelial function and investigated the effect of aerobic exercise in obese adolescents. A total of 45 obese adolescents and 20 controls (age 16-19 years) were included in our study. The obese adolescents received 12 weeks of aerobic exercise training. Serum adropin was detected using enzyme-linked immunosorbent assay. Vascular reactive hyperemia indexes (RHIs) were obtained using Endo PAT2000. Adropin levels and RHI were significantly lower in obese adolescents than in normal-weight adolescents. Adropin levels and RHI increased significantly independently of changes in body weight after an exercise intervention (P < 0.01). Pearson correlation analysis revealed that adropin levels positively correlated with HDL-C levels (r = 0.389, P < 0.01) and RHI (r = 0.32, P < 0.01). Multiple linear stepwise regression analysis showed that the insulin resistance index (t = -3.301, P < 0.01) and HDL-C level (t = 2.620, P = 0.011) were independent risk factors of adropin levels. In addition, Deltaadropin (t = 3.261, P < 0.01) was an independent influencing factor of DeltaRHI. Our findings suggest that adropin plays an important role in vascular endothelial function in obese adolescents. PMID- 29255253 TI - Oxidative rearrangement of (+)-sesamin by CYP92B14 co-generates twin dietary lignans in sesame. AB - (+)-Sesamin, (+)-sesamolin, and (+)-sesaminol glucosides are phenylpropanoid derived specialized metabolites called lignans, and are rich in sesame (Sesamum indicum) seed. Despite their renowned anti-oxidative and health-promoting properties, the biosynthesis of (+)-sesamolin and (+)-sesaminol remained largely elusive. Here we show that (+)-sesamolin deficiency in sesame is genetically associated with the deletion of four C-terminal amino acids (Del4C) in a P450 enzyme CYP92B14 that constitutes a novel clade separate from sesamin synthase CYP81Q1. Recombinant CYP92B14 converts (+)-sesamin to (+)-sesamolin and, unexpectedly, (+)-sesaminol through an oxygenation scheme designated as oxidative rearrangement of alpha-oxy-substituted aryl groups (ORA). Intriguingly, CYP92B14 also generates (+)-sesaminol through direct oxygenation of the aromatic ring. The activity of CYP92B14 is enhanced when co-expressed with CYP81Q1, implying functional coordination of CYP81Q1 with CYP92B14. The discovery of CYP92B14 not only uncovers the last steps in sesame lignan biosynthesis but highlights the remarkable catalytic plasticity of P450s that contributes to metabolic diversity in nature. PMID- 29255254 TI - Dietary pectic glycans are degraded by coordinated enzyme pathways in human colonic Bacteroides. AB - The major nutrients available to human colonic Bacteroides species are glycans, exemplified by pectins, a network of covalently linked plant cell wall polysaccharides containing galacturonic acid (GalA). Metabolism of complex carbohydrates by the Bacteroides genus is orchestrated by polysaccharide utilization loci (PULs). In Bacteroides thetaiotaomicron, a human colonic bacterium, the PULs activated by different pectin domains have been identified; however, the mechanism by which these loci contribute to the degradation of these GalA-containing polysaccharides is poorly understood. Here we show that each PUL orchestrates the metabolism of specific pectin molecules, recruiting enzymes from two previously unknown glycoside hydrolase families. The apparatus that depolymerizes the backbone of rhamnogalacturonan-I is particularly complex. This system contains several glycoside hydrolases that trim the remnants of other pectin domains attached to rhamnogalacturonan-I, and nine enzymes that contribute to the degradation of the backbone that makes up a rhamnose-GalA repeating unit. The catalytic properties of the pectin-degrading enzymes are optimized to protect the glycan cues that activate the specific PULs ensuring a continuous supply of inducing molecules throughout growth. The contribution of Bacteroides spp. to metabolism of the pectic network is illustrated by cross-feeding between organisms. PMID- 29255255 TI - Archaeal cells share common size control with bacteria despite noisier growth and division. AB - In nature, microorganisms exhibit different volumes spanning six orders of magnitude 1 . Despite their capability to create different sizes, a clonal population in a given environment maintains a uniform size across individual cells. Recent studies in eukaryotic and bacterial organisms showed that this homogeneity in cell size can be accomplished by growing a constant size between two cell cycle events (that is, the adder model 2-6 ). Demonstration of the adder model led to the hypothesis that this phenomenon is a consequence of convergent evolution. Given that archaeal cells share characteristics with both bacteria and eukaryotes, we investigated whether and how archaeal cells exhibit control over cell size. To this end, we developed a soft-lithography method of growing the archaeal cells to enable quantitative time-lapse imaging and single-cell analysis, which would be useful for other microorganisms. Using this method, we demonstrated that Halobacterium salinarum, a hypersaline-adapted archaeal organism, grows exponentially at the single-cell level and maintains a narrow size distribution by adding a constant length between cell division events. Interestingly, the archaeal cells exhibited greater variability in cell division placement and exponential growth rate across individual cells in a population relative to those observed in Escherichia coli 6-9 . Here, we present a theoretical framework that explains how these larger fluctuations in archaeal cell cycle events contribute to cell size variability and control. PMID- 29255256 TI - Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using In Silico Structure-Based-Drug-Design. AB - Therapeutics are currently unavailable for Venezuelan equine encephalitis virus (VEEV), which elicits flu-like symptoms and encephalitis in humans, with an estimated 14% of cases resulting in neurological disease. Here we identify anti VEEV agents using in silico structure-based-drug-design (SBDD) for the first time, characterising inhibitors that block recognition of VEEV capsid protein (C) by the host importin (IMP) alpha/beta1 nuclear transport proteins. From an initial screen of 1.5 million compounds, followed by in silico refinement and screening for biological activity in vitro, we identified 21 hit compounds which inhibited IMPalpha/beta1:C binding with IC50s as low as 5 uM. Four compounds were found to inhibit nuclear import of C in transfected cells, with one able to reduce VEEV replication at uM concentration, concomitant with reduced C nuclear accumulation in infected cells. Further, this compound was inactive against a mutant VEEV that lacks high affinity IMPalpha/beta1:C interaction, supporting the mode of its antiviral action to be through inhibiting C nuclear localization. This successful application of SBDD paves the way for lead optimization for VEEV antivirals, and is an exciting prospect to identify inhibitors for the many other viral pathogens of significance that require IMPalpha/beta1 in their infectious cycle. PMID- 29255257 TI - Sexual-lineage-specific DNA methylation regulates meiosis in Arabidopsis. AB - DNA methylation regulates eukaryotic gene expression and is extensively reprogrammed during animal development. However, whether developmental methylation reprogramming during the sporophytic life cycle of flowering plants regulates genes is presently unknown. Here we report a distinctive gene-targeted RNA-directed DNA methylation (RdDM) activity in the Arabidopsis thaliana male sexual lineage that regulates gene expression in meiocytes. Loss of sexual lineage-specific RdDM causes mis-splicing of the MPS1 gene (also known as PRD2), thereby disrupting meiosis. Our results establish a regulatory paradigm in which de novo methylation creates a cell-lineage-specific epigenetic signature that controls gene expression and contributes to cellular function in flowering plants. PMID- 29255258 TI - Single-cell DNA methylome sequencing of human preimplantation embryos. AB - DNA methylation is a crucial layer of epigenetic regulation during mammalian embryonic development 1-3 . Although the DNA methylome of early human embryos has been analyzed 4-6 , some of the key features have not been addressed thus far. Here we performed single-cell DNA methylome sequencing for human preimplantation embryos and found that tens of thousands of genomic loci exhibited de novo DNA methylation. This finding indicates that genome-wide DNA methylation reprogramming during preimplantation development is a dynamic balance between strong global demethylation and drastic focused remethylation. Furthermore, demethylation of the paternal genome is much faster and thorough than that of the maternal genome. From the two-cell to the postimplantation stage, methylation of the paternal genome is consistently lower than that of the maternal genome. We also show that the genetic lineage of early blastomeres can be traced by DNA methylation analysis. Our work paves the way for deciphering the secrets of DNA methylation reprogramming in early human embryos. PMID- 29255259 TI - Hidden genetic variation shapes the structure of functional elements in Drosophila. AB - Mutations that add, subtract, rearrange, or otherwise refashion genome structure often affect phenotypes, although the fragmented nature of most contemporary assemblies obscures them. To discover such mutations, we assembled the first new reference-quality genome of Drosophila melanogaster since its initial sequencing. By comparing this new genome to the existing D. melanogaster assembly, we created a structural variant map of unprecedented resolution and identified extensive genetic variation that has remained hidden until now. Many of these variants constitute candidates underlying phenotypic variation, including tandem duplications and a transposable element insertion that amplifies the expression of detoxification-related genes associated with nicotine resistance. The abundance of important genetic variation that still evades discovery highlights how crucial high-quality reference genomes are to deciphering phenotypes. PMID- 29255260 TI - Genomic features of bacterial adaptation to plants. AB - Plants intimately associate with diverse bacteria. Plant-associated bacteria have ostensibly evolved genes that enable them to adapt to plant environments. However, the identities of such genes are mostly unknown, and their functions are poorly characterized. We sequenced 484 genomes of bacterial isolates from roots of Brassicaceae, poplar, and maize. We then compared 3,837 bacterial genomes to identify thousands of plant-associated gene clusters. Genomes of plant-associated bacteria encode more carbohydrate metabolism functions and fewer mobile elements than related non-plant-associated genomes do. We experimentally validated candidates from two sets of plant-associated genes: one involved in plant colonization, and the other serving in microbe-microbe competition between plant associated bacteria. We also identified 64 plant-associated protein domains that potentially mimic plant domains; some are shared with plant-associated fungi and oomycetes. This work expands the genome-based understanding of plant-microbe interactions and provides potential leads for efficient and sustainable agriculture through microbiome engineering. PMID- 29255261 TI - Association analysis in over 329,000 individuals identifies 116 independent variants influencing neuroticism. AB - Neuroticism is a relatively stable personality trait characterized by negative emotionality (for example, worry and guilt) 1 ; heritability estimated from twin studies ranges from 30 to 50% 2 , and SNP-based heritability ranges from 6 to 15% 3-6 . Increased neuroticism is associated with poorer mental and physical health 7,8 , translating to high economic burden 9 . Genome-wide association studies (GWAS) of neuroticism have identified up to 11 associated genetic loci 3,4 . Here we report 116 significant independent loci from a GWAS of neuroticism in 329,821 UK Biobank participants; 15 of these loci replicated at P < 0.00045 in an unrelated cohort (N = 122,867). Genetic signals were enriched in neuronal genesis and differentiation pathways, and substantial genetic correlations were found between neuroticism and depressive symptoms (r g = 0.82, standard error (s.e.) = 0.03), major depressive disorder (MDD; r g = 0.69, s.e. = 0.07) and subjective well-being (r g = -0.68, s.e. = 0.03) alongside other mental health traits. These discoveries significantly advance understanding of neuroticism and its association with MDD. PMID- 29255262 TI - Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis. AB - Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to H2O2, formaldehyde, and H2S, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a malodor syndrome. PMID- 29255263 TI - A molecular roadmap for the emergence of early-embryonic-like cells in culture. AB - Unlike pluripotent cells, which generate only embryonic tissues, totipotent cells can generate a full organism, including extra-embryonic tissues. A rare population of cells resembling 2-cell-stage embryos arises in pluripotent embryonic stem (ES) cell cultures. These 2-cell-like cells display molecular features of totipotency and broader developmental plasticity. However, their specific nature and the process through which they arise remain outstanding questions. Here we identified intermediate cellular states and molecular determinants during the emergence of 2-cell-like cells. By deploying a quantitative single-cell expression approach, we identified an intermediate population characterized by expression of the transcription factor ZSCAN4 as a precursor of 2-cell-like cells. By using a small interfering RNA (siRNA) screen, we identified epigenetic regulators of 2-cell-like cell emergence, including the non-canonical PRC1 complex PRC1.6 and the EP400-TIP60 complex. Our data shed light on the mechanisms that underlie exit from the ES cell state toward the formation of early-embryonic-like cells in culture and identify key epigenetic pathways that promote this transition. PMID- 29255265 TI - Author Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells. AB - In the version of this article initially published, in the Methods, the Gene Expression Omnibus accession code for H3K36me3 ChIP-seq data was incorrectly given as GSM1003585 instead of GSM733725. The error has been corrected in the HTML, PDF and print versions of the article. PMID- 29255264 TI - Identification of H3K4me1-associated proteins at mammalian enhancers. AB - Enhancers act to regulate cell-type-specific gene expression by facilitating the transcription of target genes. In mammalian cells, active or primed enhancers are commonly marked by monomethylation of histone H3 at lysine 4 (H3K4me1) in a cell type-specific manner. Whether and how this histone modification regulates enhancer-dependent transcription programs in mammals is unclear. In this study, we conducted SILAC mass spectrometry experiments with mononucleosomes and identified multiple H3K4me1-associated proteins, including many involved in chromatin remodeling. We demonstrate that H3K4me1 augments association of the chromatin-remodeling complex BAF to enhancers in vivo and that, in vitro, H3K4me1 marked nucleosomes are more efficiently remodeled by the BAF complex. Crystal structures of the BAF component BAF45C indicate that monomethylation, but not trimethylation, is accommodated by BAF45C's H3K4-binding site. Our results suggest that H3K4me1 has an active role at enhancers by facilitating binding of the BAF complex and possibly other chromatin regulators. PMID- 29255266 TI - Publisher Correction: TET proteins safeguard bivalent promoters from de novo methylation in human embryonic stem cells. AB - The version of the Supplementary Text and Figures file initially posted was missing Supplementary Tables 1-6 and the Supplementary Note and used incorrect versions of the supplementary figures. PMID- 29255267 TI - Detection of Cystic Fibrosis Serological Biomarkers Using a T7 Phage Display Library. AB - Cystic fibrosis (CF) is an autosomal recessive disorder affecting the cystic fibrosis transmembrane conductance regulator (CFTR). CF is characterized by repeated lung infections leading to respiratory failure. Using a high-throughput method, we developed a T7 phage display cDNA library derived from mRNA isolated from bronchoalveolar lavage (BAL) cells and leukocytes of sarcoidosis patients. This library was biopanned to obtain 1070 potential antigens. A microarray platform was constructed and immunoscreened with sera from healthy (n = 49), lung cancer (LC) (n = 31) and CF (n = 31) subjects. We built 1,000 naive Bayes models on the training sets. We selected the top 20 frequently significant clones ranked with student t-test discriminating CF antigens from healthy controls and LC at a False Discovery Rate (FDR) < 0.01. The performances of the models were validated on an independent validation set. The mean of the area under the receiver operating characteristic (ROC) curve for the classifiers was 0.973 with a sensitivity of 0.999 and specificity of 0.959. Finally, we identified CF specific clones that correlate highly with sweat chloride test, BMI, and FEV1% predicted values. For the first time, we show that CF specific serological biomarkers can be identified through immunocreenings of a T7 phage display library with high accuracy, which may have utility in development of molecular therapy. PMID- 29255268 TI - Progress and challenges for understanding the function of cortical microcircuits in auditory processing. AB - An important outstanding question in auditory neuroscience is to identify the mechanisms by which specific motifs within inter-connected neural circuits affect auditory processing and, ultimately, behavior. In the auditory cortex, a combination of large-scale electrophysiological recordings and concurrent optogenetic manipulations are improving our understanding of the role of inhibitory-excitatory interactions. At the same time, computational approaches have grown to incorporate diverse neuronal types and connectivity patterns. However, we are still far from understanding how cortical microcircuits encode and transmit information about complex acoustic scenes. In this review, we focus on recent results identifying the special function of different cortical neurons in the auditory cortex and discuss a computational framework for future work that incorporates ideas from network science and network dynamics toward the coding of complex auditory scenes. PMID- 29255269 TI - Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway. AB - Reactive oxygen species (ROS) are generated by virus-infected cells; however, the physiological importance of ROS generated under these conditions is unclear. Here we found that the inflammation and cell death induced by exposure of mice or cells to sources of ROS were not altered in the absence of canonical ROS-sensing pathways or known cell-death pathways. ROS-induced cell-death signaling involved interactions among the cellular ROS sensor and antioxidant factor KEAP1, the phosphatase PGAM5 and the proapoptotic factor AIFM1. Pgam5 -/- mice showed exacerbated lung inflammation and proinflammatory cytokines in an ozone-exposure model. Similarly, challenge with influenza A virus led to increased infiltration of the virus, lymphocytic bronchiolitis and reduced survival of Pgam5 -/- mice. This pathway, which we have called 'oxeiptosis', was a ROS-sensitive, caspase independent, non-inflammatory cell-death pathway and was important for protection against inflammation induced by ROS or ROS-generating agents such as viral pathogens. PMID- 29255270 TI - Genome-Wide Identification of Mitogen-activated Protein Kinase Cascade Genes and Transcriptional Profiling Analysis during Organ Development in Eucommia ulmoides. AB - The mitogen-activated protein kinase (MAPK) cascades, which play crucial roles in plant development processes, are universal modules of signal transduction in eukaryotes and consist of a core module of three sequentially phosphorylated kinases: MAPK, MAPK kinase (MAPKK), and MAPKK kinase (MAPKKK). This is the first report on the identification and analysis of MAPK cascades in Eucommia ulmoides. We conducted a genome-wide screening and identified 13 EuMAPKs, five EuMAPKKs, and 57 EuMAPKKKs. The construction of phylogenetic trees revealed that EuMAPKs and EuMAPKKs were divided into four groups (A, B, C, and D), and EuMAPKKKs were divided into three subfamilies (MEKK, RAF, and ZIK). These subfamilies were further confirmed by conserved domain/motif analysis and gene structure analysis. Based on the expression profiles of all identified EuMAPK cascades in various organs at different developmental stages, three genes (EuRAF22-2, EuRAF34-1, and EuRAF33-2) with stable expression patterns at all stages of fruit or leaf development, three genes (EuRAF2-3, EuMPK11, and EuMEKK21) with differential expression patterns, and two highly expressed genes (EuZIK1 and EuMKK2) were screened and validated by qRT-PCR. Overall, our results could be used for further research on the precise role of MAPK cascades during organ development in E. ulmoides. PMID- 29255271 TI - Bouncing of an ellipsoidal drop on a superhydrophobic surface. AB - Drop impact on superhydrophobic surfaces has received significant attention because of the advantages of self-cleaning and anti-icing attained by minimum contact time with the surface. Drop hydrodynamics is generally assumed to be axisymmetric, and the contact time is still bounded below by a theoretical Rayleigh limit. In this study, we report an ellipsoidal drop impact on a superhydrophobic surface to demonstrate an efficient way to reduce the contact time and suppress the bounce magnitude by breaking the symmetry. The outcome of the bounce is characterized in terms of a geometric aspect ratio (AR) and Weber number of the drop by comparing the dynamics with a spherical drop. The experimental result shows that the bouncing of the ellipsoidal drop can reduce the contact time and maximum bounce height below the spherical one by at least 30% and 60%, respectively. The exceptional rim dynamics at high AR produces a liquid alignment along the principal direction, leading to the symmetry breaking in the mass and momentum distribution and the subsequent fast drop detachment, which is quantitatively rationalized by the numerical study. The distinct features of the ellipsoidal drop impact will provide an insight into shape dependent dynamics and open up new opportunities for self-cleaning and anti-icing strategies. PMID- 29255272 TI - Safety and Efficacy of Losartan 50 mg in Reducing Blood Pressure among Patients with Post-Dialysis Euvolemic Hypertension: A Randomized Control Trial. AB - The aim of current study was to assess the effectiveness of losartan 50 mg in reducing blood pressure among post-dialysis euvolemic hypertensive patients, observing their survival trends and adverse events during the course of study. A multicentre, prospective, randomised, single-blind trial was conducted to assess the effect of losartan 50 mg every other day (EOD), once a morning (OM) among post-dialysis euvolemic hypertensive patients. Post-dialysis euvolemic assessment was done by a body composition monitor (BCM). Covariate Adaptive Randomization was used for allocation of participants to the standard or intervention arm. Of the total 229 patients, 96 (41.9%) were identified as post-dialysis euvolemic hypertensive. Final samples of 88 (40.1%) patients were randomized into standard and intervention arms. After follow-up of 12 months' pre-dialysis systolic (p < 0.001) and diastolic (p 0.01), intradialysis diastolic (p 0.02), post-dialysis systolic (p < 0.001) and diastolic (p < 0.001) blood pressure was reduced from the baseline among intervention-arm patients Compared to only pre-dialysis systolic blood pressure (p 0.003) among standard arm patients after 12 months of follow. Total of six deaths were reported among standard-arm patients compared to 2 deaths among the intervention arm. Losartan 50 mg achieve an overall significant decline in blood pressure among post-dialysis euvolemic hypertensive patients. PMID- 29255273 TI - Diversity of antigenic mutants of influenza A(H1N1)pdm09 virus escaped from human monoclonal antibodies. AB - Since the 2017 Southern Hemisphere influenza season, the A(H1N1)pdm09-like virus recommended for use in the vaccine was changed because human, but not ferret, sera distinguish A(H1N1)pdm09 viruses isolated after 2013 from the previously circulating strains. An amino acid substitution, lysine to glutamine, at position 166 (H3 numbering) in the major antigenic site of HA was reported to be responsible for the antigenic drift. Here, we obtained two anti-A(H1N1)pdm09 HA monoclonal antibodies that failed to neutralize viruses isolated after 2013 from a vaccinated volunteer. Escape mutations were identified at position 129, 165, or 166 in the major antigenic site of HA. Competitive growth of the escape mutant viruses with the wild-type virus revealed that some escape mutants possessing an amino acid substitution other than K166Q showed superior growth to that of the wild-type virus. These results suggest that in addition to the K166Q mutation that occurred in epidemic strains, other HA mutations can confer resistance to antibodies that recognize the K166 area, leading to emergence of epidemic strains with such mutations. PMID- 29255274 TI - Electric-field control of ferromagnetism through oxygen ion gating. AB - Electric-field-driven oxygen ion evolution in the metal/oxide heterostructures emerges as an effective approach to achieve the electric-field control of ferromagnetism. However, the involved redox reaction of the metal layer typically requires extended operation time and elevated temperature condition, which greatly hinders its practical applications. Here, we achieve reversible sub millisecond and room-temperature electric-field control of ferromagnetism in the Co layer of a Co/SrCoO2.5 system accompanied by bipolar resistance switching. In contrast to the previously reported redox reaction scenario, the oxygen ion evolution occurs only within the SrCoO2.5 layer, which serves as an oxygen ion gating layer, leading to modulation of the interfacial oxygen stoichiometry and magnetic state. This work identifies a simple and effective pathway to realize the electric-field control of ferromagnetism at room temperature, and may lead to applications that take advantage of both the resistance switching and magnetoelectric coupling. PMID- 29255276 TI - CHARGE syndrome: a recurrent hotspot of mutations in CHD7 IVS25 analyzed by bioinformatic tools and minigene assays. AB - CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3' splice site, of which the existence was confirmed using pSpliceExpress, an easy to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis. PMID- 29255277 TI - Satellite Observations of Imprint of Oceanic Current on Wind Stress by Air-Sea Coupling. AB - Mesoscale eddies are present everywhere in the ocean and partly determine the mean state of the circulation and ecosystem. The current feedback on the surface wind stress modulates the air-sea transfer of momentum by providing a sink of mesoscale eddy energy as an atmospheric source. Using nine years of satellite measurements of surface stress and geostrophic currents over the global ocean, we confirm that the current-induced surface stress curl is linearly related to the current vorticity. The resulting coupling coefficient between current and surface stress (stau [N s m-3]) is heterogeneous and can be roughly expressed as a linear function of the mean surface wind. stau expresses the sink of eddy energy induced by the current feedback. This has important implications for air-sea interaction and implies that oceanic mean and mesoscale circulations and their effects on surface-layer ventilation and carbon uptake are better represented in oceanic models that include this feedback. PMID- 29255278 TI - A basal ursine bear (Protarctos abstrusus) from the Pliocene High Arctic reveals Eurasian affinities and a diet rich in fermentable sugars. AB - The skeletal remains of a small bear (Protarctos abstrusus) were collected at the Beaver Pond fossil site in the High Arctic (Ellesmere I., Nunavut). This mid Pliocene deposit has also yielded 12 other mammals and the remains of a boreal forest community. Phylogenetic analysis reveals this bear to be basal to modern bears. It appears to represent an immigration event from Asia, leaving no living North American descendants. The dentition shows only modest specialization for herbivory, consistent with its basal position within Ursinae. However, the appearance of dental caries suggest a diet high in fermentable-carbohydrates. Fossil plants remains, including diverse berries, suggests that, like modern northern black bears, P. abstrusus may have exploited a high-sugar diet in the fall to promote fat accumulation and facilitate hibernation. A tendency toward a sugar-rich diet appears to have arisen early in Ursinae, and may have played a role in allowing ursine lineages to occupy cold habitats. PMID- 29255275 TI - Evidence for causal top-down frontal contributions to predictive processes in speech perception. AB - Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception. PMID- 29255280 TI - Peer review is not broken. PMID- 29255281 TI - Phaged and confused by biofilm matrix. PMID- 29255279 TI - Urinary miR-21 as a potential biomarker of hypertensive kidney injury and fibrosis. AB - Kidney biopsy is considered the golden criterion for diagnosing the etiology of kidney disease but accompanied by non-negligible complications. We explored the possibility of using urinary microRNA (miRNA) as a non-invasive biomarker for hypertensive kidney injury. We assessed differential miRNA expressions in the kidneys and urine of hypertensive mice with kidney injury induced by deoxycorticosterone acetate (DOCA)-salt compared to the controls. DOCA-salt treatment significantly increased renal tubular lesions from day 2 and mRNA expression of fibrosis-related genes from day 4 compared to the controls, respectively. Urinary albumin and N-acetyl-beta-D-glucosaminidase was significantly increased on day 8 compared to the controls. Array results showed that 20 out of 585 miRNAs were highly expressed in the kidneys and significantly increased on day 8 compared to the controls, including miR-21, miR-146b, miR-155 and miR-132, which were confirmed by real-time polymerase chain reaction and were significantly higher from day 4. The miR-21/creatinine in the urine from day 4 was significantly higher than that of the controls and was detected earlier than urinary albumin. In conclusion, we have identified urinary miR-21 that correlates with histopathological lesions and functional markers of kidney damage to facilitate a potential noninvasive detection for hypertensive kidney injury. PMID- 29255282 TI - Sensing fungi at the oral epithelium. PMID- 29255283 TI - Assigning function to symbionts. PMID- 29255286 TI - Peltier cooling at molecular scale. PMID- 29255285 TI - iDTI-ESBoost: Identification of Drug Target Interaction Using Evolutionary and Structural Features with Boosting. AB - Prediction of new drug-target interactions is critically important as it can lead the researchers to find new uses for old drugs and to disclose their therapeutic profiles or side effects. However, experimental prediction of drug-target interactions is expensive and time-consuming. As a result, computational methods for predictioning new drug-target interactions have gained a tremendous interest in recent times. Here we present iDTI-ESBoost, a prediction model for identification of drug-target interactions using evolutionary and structural features. Our proposed method uses a novel data balancing and boosting technique to predict drug-target interaction. On four benchmark datasets taken from a gold standard data, iDTI-ESBoost outperforms the state-of-the-art methods in terms of area under receiver operating characteristic (auROC) curve. iDTI-ESBoost also outperforms the latest and the best-performing method found in the literature in terms of area under precision recall (auPR) curve. This is significant as auPR curves are argued as suitable metric for comparison for imbalanced datasets similar to the one studied here. Our reported results show the effectiveness of the classifier, balancing methods and the novel features incorporated in iDTI ESBoost. iDTI-ESBoost is a novel prediction method that has for the first time exploited the structural features along with the evolutionary features to predict drug-protein interactions. We believe the excellent performance of iDTI-ESBoost both in terms of auROC and auPR would motivate the researchers and practitioners to use it to predict drug-target interactions. To facilitate that, iDTI-ESBoost is implemented and made publicly available at: http://farshidrayhan.pythonanywhere.com/iDTI-ESBoost/ . PMID- 29255287 TI - Steep-slope hysteresis-free negative capacitance MoS2 transistors. AB - The so-called Boltzmann tyranny defines the fundamental thermionic limit of the subthreshold slope of a metal-oxide-semiconductor field-effect transistor (MOSFET) at 60 mV dec-1 at room temperature and therefore precludes lowering of the supply voltage and overall power consumption 1,2 . Adding a ferroelectric negative capacitor to the gate stack of a MOSFET may offer a promising solution to bypassing this fundamental barrier 3 . Meanwhile, two-dimensional semiconductors such as atomically thin transition-metal dichalcogenides, due to their low dielectric constant and ease of integration into a junctionless transistor topology, offer enhanced electrostatic control of the channel 4-12 . Here, we combine these two advantages and demonstrate a molybdenum disulfide (MoS2) two-dimensional steep-slope transistor with a ferroelectric hafnium zirconium oxide layer in the gate dielectric stack. This device exhibits excellent performance in both on and off states, with a maximum drain current of 510 MUA MUm-1 and a sub-thermionic subthreshold slope, and is essentially hysteresis-free. Negative differential resistance was observed at room temperature in the MoS2 negative-capacitance FETs as the result of negative capacitance due to the negative drain-induced barrier lowering. A high on-current induced self-heating effect was also observed and studied. PMID- 29255288 TI - A few-layer molecular film on polymer substrates to enhance the performance of organic devices. AB - In organic electronics the functionalization of dielectric substrates with self assembled monolayers is regarded as an effective surface modification strategy that may significantly improve the resulting device performance. However, this technique is not suitable for polymer substrates typically used in flexible electronics. Here, we report organic modifiers based on a paraffinic tripodal triptycene, which self-assembles into a completely oriented two-dimensional hexagonal triptycene array and one-dimensional layer stacking structure on polymer surfaces. Such few-layer films are analogous to conventional self assembled monolayers on inorganic substrates in that they neutralize the polymer surface. Furthermore, the triptycene films significantly improve the crystallinity of an organic semiconductor and the overall performance of organic thin-film transistors, therefore enabling the fabrication of high-performance organic complementary circuits on polymer substrates with high oscillation speeds and low operation voltage. PMID- 29255289 TI - Excitonic pathway to photoinduced magnetism in colloidal nanocrystals with nonmagnetic dopants. AB - Electronic doping of colloidal semiconductor nanostructures holds promise for future device concepts in optoelectronic and spin-based technologies. Ag+ is an emerging electronic dopant in III-V and II-VI nanostructures, introducing intragap electronic states optically coupled to the host conduction band. With its full 4d shell Ag+ is nonmagnetic, and the dopant-related luminescence is ascribed to decay of the conduction-band electron following transfer of the photoexcited hole to Ag+. This optical activation process and the associated modification of the electronic configuration of Ag+ remain unclear. Here, we trace a comprehensive picture of the excitonic process in Ag-doped CdSe nanocrystals and demonstrate that, in contrast to expectations, capture of the photohole leads to conversion of Ag+ to paramagnetic Ag2+. The process of exciton recombination is thus inextricably tied to photoinduced magnetism. Accordingly, we observe strong optically activated magnetism and diluted magnetic semiconductor behaviour, demonstrating that optically switchable magnetic nanomaterials can be obtained by exploiting excitonic processes involving nonmagnetic impurities. PMID- 29255290 TI - Ultrahard carbon film from epitaxial two-layer graphene. AB - Atomically thin graphene exhibits fascinating mechanical properties, although its hardness and transverse stiffness are inferior to those of diamond. So far, there has been no practical demonstration of the transformation of multilayer graphene into diamond-like ultrahard structures. Here we show that at room temperature and after nano-indentation, two-layer graphene on SiC(0001) exhibits a transverse stiffness and hardness comparable to diamond, is resistant to perforation with a diamond indenter and shows a reversible drop in electrical conductivity upon indentation. Density functional theory calculations suggest that, upon compression, the two-layer graphene film transforms into a diamond-like film, producing both elastic deformations and sp 2 to sp 3 chemical changes. Experiments and calculations show that this reversible phase change is not observed for a single buffer layer on SiC or graphene films thicker than three to five layers. Indeed, calculations show that whereas in two-layer graphene layer stacking configuration controls the conformation of the diamond-like film, in a multilayer film it hinders the phase transformation. PMID- 29255284 TI - Enterotypes in the landscape of gut microbial community composition. AB - Population stratification is a useful approach for a better understanding of complex biological problems in human health and wellbeing. The proposal that such stratification applies to the human gut microbiome, in the form of distinct community composition types termed enterotypes, has been met with both excitement and controversy. In view of accumulated data and re-analyses since the original work, we revisit the concept of enterotypes, discuss different methods of dividing up the landscape of possible microbiome configurations, and put these concepts into functional, ecological and medical contexts. As enterotypes are of use in describing the gut microbial community landscape and may become relevant in clinical practice, we aim to reconcile differing views and encourage a balanced application of the concept. PMID- 29255291 TI - Peltier cooling in molecular junctions. AB - The study of thermoelectricity in molecular junctions is of fundamental interest for the development of various technologies including cooling (refrigeration) and heat-to-electricity conversion 1-4 . Recent experimental progress in probing the thermopower (Seebeck effect) of molecular junctions 5-9 has enabled studies of the relationship between thermoelectricity and molecular structure 10,11 . However, observations of Peltier cooling in molecular junctions-a critical step for establishing molecular-based refrigeration-have remained inaccessible. Here, we report direct experimental observations of Peltier cooling in molecular junctions. By integrating conducting-probe atomic force microscopy 12,13 with custom-fabricated picowatt-resolution calorimetric microdevices, we created an experimental platform that enables the unified characterization of electrical, thermoelectric and energy dissipation characteristics of molecular junctions. Using this platform, we studied gold junctions with prototypical molecules (Au biphenyl-4,4'-dithiol-Au, Au-terphenyl-4,4''-dithiol-Au and Au-4,4'-bipyridine Au) and revealed the relationship between heating or cooling and charge transmission characteristics. Our experimental conclusions are supported by self energy-corrected density functional theory calculations. We expect these advances to stimulate studies of both thermal and thermoelectric transport in molecular junctions where the possibility of extraordinarily efficient energy conversion has been theoretically predicted 2-4,14 . PMID- 29255293 TI - Negative capacitance gives a positive boost. PMID- 29255292 TI - A quantum-dot spin qubit with coherence limited by charge noise and fidelity higher than 99.9. AB - The isolation of qubits from noise sources, such as surrounding nuclear spins and spin-electric susceptibility 1-4 , has enabled extensions of quantum coherence times in recent pivotal advances towards the concrete implementation of spin based quantum computation. In fact, the possibility of achieving enhanced quantum coherence has been substantially doubted for nanostructures due to the characteristic high degree of background charge fluctuations 5-7 . Still, a sizeable spin-electric coupling will be needed in realistic multiple-qubit systems to address single-spin and spin-spin manipulations 8-10 . Here, we realize a single-electron spin qubit with an isotopically enriched phase coherence time (20 MUs) 11,12 and fast electrical control speed (up to 30 MHz) mediated by extrinsic spin-electric coupling. Using rapid spin rotations, we reveal that the free-evolution dephasing is caused by charge noise-rather than conventional magnetic noise-as highlighted by a 1/f spectrum extended over seven decades of frequency. The qubit exhibits superior performance with single-qubit gate fidelities exceeding 99.9% on average, offering a promising route to large scale spin-qubit systems with fault-tolerant controllability. PMID- 29255295 TI - Estimating the occurrence of primary ubiquinone deficiency by analysis of large scale sequencing data. AB - Primary ubiquinone (UQ) deficiency is an important subset of mitochondrial disease that is caused by mutations in UQ biosynthesis genes. To guide therapeutic efforts we sought to estimate the number of individuals who are born with pathogenic variants likely to cause this disorder. We used the NCBI ClinVar database and literature reviews to identify pathogenic genetic variants that have been shown to cause primary UQ deficiency, and used the gnomAD database of full genome or exome sequences to estimate the frequency of both homozygous and compound heterozygotes within seven genetically-defined populations. We used known population sizes to estimate the number of afflicted individuals in these populations and in the mixed population of the USA. We then performed the same analysis on predicted pathogenic loss-of-function and missense variants that we identified in gnomAD. When including only known pathogenic variants, our analysis predicts 1,665 affected individuals worldwide and 192 in the USA. Adding predicted pathogenic variants, our estimate grows to 123,789 worldwide and 1,462 in the USA. This analysis predicts that there are many undiagnosed cases of primary UQ deficiency, and that a large proportion of these will be in developing regions of the world. PMID- 29255294 TI - PAX7 target genes are globally repressed in facioscapulohumeral muscular dystrophy skeletal muscle. AB - Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to hypomethylation of D4Z4 repeats on chromosome 4q causing expression of the DUX4 transcription factor. However, DUX4 is difficult to detect in FSHD muscle biopsies and it is debatable how robust changes in DUX4 target gene expression are as an FSHD biomarker. PAX7 is a master regulator of myogenesis that rescues DUX4-mediated apoptosis. Here, we show that suppression of PAX7 target genes is a hallmark of FSHD, and that it is as major a signature of FSHD muscle as DUX4 target gene expression. This is shown using meta-analysis of over six FSHD muscle biopsy gene expression studies, and validated by RNA-sequencing on FSHD patient-derived myoblasts. DUX4 also inhibits PAX7 from activating its transcriptional target genes and vice versa. Furthermore, PAX7 target gene repression can explain oxidative stress sensitivity and epigenetic changes in FSHD. Thus, PAX7 target gene repression is a hallmark of FSHD that should be considered in the investigation of FSHD pathology and therapy. PMID- 29255296 TI - Evidence for hippocampal dependence of value-based decisions. AB - Consistent decisions are intuitively desirable and theoretically important for utility maximization. Neuroeconomics has established the neurobiological substrate of value representation, but brain regions that provide input to this network is less explored. The constructed-preference tradition within behavioral decision research gives a critical role to associative cognitive processes, suggesting a hippocampal role in making consistent decisions. We compared the performance of 31 patients with mediotemporal lobe (MTL) epilepsy and hippocampal lesions, 30 patients with extratemporal lobe epilepsy, and 30 healthy controls on two tasks: binary choices between candy bars based on their preferences and a number-comparison control task where the larger number is chosen. MTL patients made more inconsistent choices than the other two groups for the value-based choice but not the number-comparison task. These inconsistencies correlated with the volume of compromised hippocampal tissue. These results add to increasing evidence on a critical involvement of the MTL in preference construction and value-based choices. PMID- 29255297 TI - Quantitative species-level ecology of reef fish larvae via metabarcoding. AB - The larval pool of coral reef fish has a crucial role in the dynamics of adult fish populations. However, large-scale species-level monitoring of species-rich larval pools has been technically impractical. Here, we use high-throughput metabarcoding to study larval ecology in the Gulf of Aqaba, a region that is inhabited by >500 reef fish species. We analysed 9,933 larvae from 383 samples that were stratified over sites, depth and time. Metagenomic DNA extracted from pooled larvae was matched to a mitochondrial cytochrome c oxidase subunit I barcode database compiled for 77% of known fish species within this region. This yielded species-level reconstruction of the larval community, allowing robust estimation of larval spatio-temporal distributions. We found significant correlations between species abundance in the larval pool and in local adult assemblages, suggesting a major role for larval supply in determining local adult densities. We documented larval flux of species whose adults were never documented in the region, suggesting environmental filtering as the reason for the absence of these species. Larvae of several deep-sea fishes were found in shallow waters, supporting their dispersal over shallow bathymetries, potentially allowing Lessepsian migration into the Mediterranean Sea. Our method is applicable to any larval community and could assist coral reef conservation and fishery management efforts. PMID- 29255298 TI - An interplay between plasticity and parental phenotype determines impacts of ocean acidification on a reef fish. AB - The impacts of ocean acidification will depend on the ability of marine organisms to tolerate, acclimate and eventually adapt to changes in ocean chemistry. Here, we use a unique transgenerational experiment to determine the molecular response of a coral reef fish to short-term, developmental and transgenerational exposure to elevated CO2, and to test how these responses are influenced by variations in tolerance to elevated CO2 exhibited by the parents. Within-generation responses in gene expression to end-of-century predicted CO2 levels indicate that a self amplifying cycle in GABAergic neurotransmission is triggered, explaining previously reported neurological and behavioural impairments. Furthermore, epigenetic regulator genes exhibited a within-generation specific response, but with some divergence due to parental phenotype. Importantly, we find that altered gene expression for the majority of within-generation responses returns to baseline levels following parental exposure to elevated CO2 conditions. Our results show that both parental variation in tolerance and cross-generation exposure to elevated CO2 are crucial factors in determining the response of reef fish to changing ocean chemistry. PMID- 29255299 TI - Consistent effects of biodiversity loss on multifunctionality across contrasting ecosystems. AB - Understanding how loss of biodiversity affects ecosystem functioning, and thus the delivery of ecosystem goods and services, has become increasingly necessary in a changing world. Considerable recent attention has focused on predicting how biodiversity loss simultaneously impacts multiple ecosystem functions (that is, ecosystem multifunctionality), but the ways in which these effects vary across ecosystems remain unclear. Here, we report the results of two 19-year plant diversity manipulation experiments, each established across a strong environmental gradient. Although the effects of plant and associated fungal diversity loss on individual functions frequently differed among ecosystems, the consequences of biodiversity loss for multifunctionality were relatively invariant. However, the context-dependency of biodiversity effects also worked in opposing directions for different individual functions, meaning that similar multifunctionality values across contrasting ecosystems could potentially mask important differences in the effects of biodiversity on functioning among ecosystems. Our findings highlight that an understanding of the relative contribution of species or functional groups to individual ecosystem functions among contrasting ecosystems and their interactions (that is, complementarity versus competition) is critical for guiding management efforts aimed at maintaining ecosystem multifunctionality and the delivery of multiple ecosystem services. PMID- 29255301 TI - Functional diversity and community assembly of river invertebrates show globally consistent responses to decreasing glacier cover. AB - Global change threatens invertebrate biodiversity and its central role in numerous ecosystem functions and services. Functional trait analyses have been advocated to uncover global mechanisms behind biodiversity responses to environmental change, but the application of this approach for invertebrates is underdeveloped relative to other organism groups. From an evaluation of 363 records comprising >1.23 million invertebrates collected from rivers across nine biogeographic regions on three continents, consistent responses of community trait composition and diversity to replicated gradients of reduced glacier cover are demonstrated. After accounting for a systematic regional effect of latitude, the processes shaping river invertebrate functional diversity are globally consistent. Analyses nested within individual regions identified an increase in functional diversity as glacier cover decreases. Community assembly models demonstrated that dispersal limitation was the dominant process underlying these patterns, although environmental filtering was also evident in highly glacierized basins. These findings indicate that predictable mechanisms govern river invertebrate community responses to decreasing glacier cover globally. PMID- 29255300 TI - The genetic basis and evolution of red blood cell sickling in deer. AB - Crescent-shaped red blood cells, the hallmark of sickle-cell disease, present a striking departure from the biconcave disc shape normally found in mammals. Characterized by increased mechanical fragility, sickled cells promote haemolytic anaemia and vaso-occlusions and contribute directly to disease in humans. Remarkably, a similar sickle-shaped morphology has been observed in erythrocytes from several deer species, without obvious pathological consequences. The genetic basis of erythrocyte sickling in deer, however, remains unknown. Here, we determine the sequences of human beta-globin orthologues in 15 deer species and use protein structural modelling to identify a sickling mechanism distinct from the human disease, coordinated by a derived valine (E22V) that is unique to sickling deer. Evidence for long-term maintenance of a trans-species sickling/non sickling polymorphism suggests that sickling in deer is adaptive. Our results have implications for understanding the ecological regimes and molecular architectures that have promoted convergent evolution of sickling erythrocytes across vertebrates. PMID- 29255302 TI - Social transmission of avoidance among predators facilitates the spread of novel prey. AB - Warning signals are an effective defence strategy for aposematic prey, but only if they are recognized by potential predators. If predators must eat prey to associate novel warning signals with unpalatability, how can aposematic prey ever evolve? Using experiments with great tits (Parus major) as predators, we show that social transmission enhances the acquisition of avoidance by a predator population. Observing another predator's disgust towards tasting one novel conspicuous prey item led to fewer aposematic than cryptic prey being eaten for the predator population to learn. Despite reduced personal encounters with unpalatable prey, avoidance persisted and increased over subsequent trials. Next we use a mathematical model to show that social transmission can shift the evolutionary trajectory of prey populations from fixation of crypsis to fixation of aposematism more easily than was previously thought. Therefore, social information use by predators has the potential to have evolutionary consequences across ecological communities. PMID- 29255303 TI - Genomic basis and evolutionary potential for extreme drought adaptation in Arabidopsis thaliana. AB - As Earth is currently experiencing dramatic climate change, it is of critical interest to understand how species will respond to it. The chance of a species withstanding climate change is likely to depend on the diversity within the species and, particularly, whether there are sub-populations that are already adapted to extreme environments. However, most predictive studies ignore that species comprise genetically diverse individuals. We have identified genetic variants in Arabidopsis thaliana that are associated with survival of an extreme drought event-a major consequence of global warming. Subsequently, we determined how these variants are distributed across the native range of the species. Genetic alleles conferring higher drought survival showed signatures of polygenic adaptation and were more frequently found in Mediterranean and Scandinavian regions. Using geo-environmental models, we predicted that Central European, but not Mediterranean, populations might lag behind in adaptation by the end of the twenty-first century. Further analyses showed that a population decline could nevertheless be compensated by natural selection acting efficiently over standing variation or by migration of adapted individuals from populations at the margins of the species' distribution. These findings highlight the importance of within species genetic heterogeneity in facilitating an evolutionary response to a changing climate. PMID- 29255304 TI - Adaptation of Plasmodium falciparum to its transmission environment. AB - Success in eliminating malaria will depend on whether parasite evolution outpaces control efforts. Here, we show that Plasmodium falciparum parasites (the deadliest of the species causing human malaria) found in low-transmission intensity areas have evolved to invest more in transmission to new hosts (reproduction) and less in within-host replication (growth) than parasites found in high-transmission areas. At the cellular level, this adaptation manifests as increased production of reproductive forms (gametocytes) early in the infection at the expense of processes associated with multiplication inside red blood cells, especially membrane transport and protein trafficking. At the molecular level, this manifests as changes in the expression levels of genes encoding epigenetic and translational machinery. Specifically, expression levels of the gene encoding AP2-G-the transcription factor that initiates reproduction-increase as transmission intensity decreases. This is accompanied by downregulation and upregulation of genes encoding HDAC1 and HDA1-two histone deacetylases that epigenetically regulate the parasite's replicative and reproductive life-stage programmes, respectively. Parasites in reproductive mode show increased reliance on the prokaryotic translation machinery found inside the plastid-derived organelles. Thus, our dissection of the parasite's adaptive regulatory architecture has identified new potential molecular targets for malaria control. PMID- 29255305 TI - Evolutionary action and structural basis of the allosteric switch controlling beta2AR functional selectivity. AB - Functional selectivity of G-protein-coupled receptors is believed to originate from ligand-specific conformations that activate only subsets of signaling effectors. In this study, to identify molecular motifs playing important roles in transducing ligand binding into distinct signaling responses, we combined in silico evolutionary lineage analysis and structure-guided site-directed mutagenesis with large-scale functional signaling characterization and non negative matrix factorization clustering of signaling profiles. Clustering based on the signaling profiles of 28 variants of the beta2-adrenergic receptor reveals three clearly distinct phenotypical clusters, showing selective impairments of either the Gi or betaarrestin/endocytosis pathways with no effect on Gs activation. Robustness of the results is confirmed using simulation-based error propagation. The structural changes resulting from functionally biasing mutations centered around the DRY, NPxxY, and PIF motifs, selectively linking these micro switches to unique signaling profiles. Our data identify different receptor regions that are important for the stabilization of distinct conformations underlying functional selectivity. PMID- 29255306 TI - No evolutionary change in the mating system of Solanum rostratum (Solanaceae) during its invasion in China. AB - The mating system of flowering plants plays a key role during the process of invasion. Evolution from outcrossing to selfing can allow rapid regeneration of a population after long-distance dispersal by providing reproductive assurance. Solanum rostratum is a self-compatible annual herb that exhibits a high level of outcrossing in its native populations. However, the mating system of invasive populations of S. rostratum has never been assessed. Here, we investigated the mating system based on 11 microsatellite loci and explored ecological factors that may influence the outcrossing rate among 10 invasive populations of S. rostratum in China. We found that the mean outcrossing rate was 0.69 +/- 0.12 (range 0.49 to 0.83) with multiple paternity within progeny arrays (average effective number of sires = 7.86), which suggests a mixed mating system dominated by outcrossing. Combined with the uniformly high outcrossing rate (0.70 +/- 0.03) previously reported in its native range, these results indicate that there has been no evolutionary shift in mating system during the invasion in China by S. rostratum. There were no relationships between outcrossing and population size, population density, altitude, latitude or longitude. Furthermore, high outcrossing of S. rostratum in China may be facilitated by enantiostyly and heteranthery. PMID- 29255307 TI - Chemical Adsorption and Physical Confinement of Polysulfides with the Janus-faced Interlayer for High-performance Lithium-Sulfur Batteries. AB - We design the Janus-like interlayer with two different functional faces for suppressing the shuttle of soluble lithium polysulfides (LPSs) in lithium-sulfur batteries (LSBs). At the front face, the conductive functionalized carbon fiber paper (f-CFP) having oxygen-containing groups i.e., -OH and -COOH on its surface was placed face to face with the sulfur cathode serving as the first barrier accommodating the volume expansion during cycling process and the oxygen containing groups can also adsorb the soluble LPSs via lithium bonds. At the back face, a crystalline coordination network of [Zn(H2PO4)2(TzH)2]n (ZnPTz) was coated on the back side of f-CFP serving as the second barrier retarding the left LPSs passing through the front face via both physical confinement and chemical adsorption (i.e. Li bonding). The LSB using the Janus-like interlayer exhibits a high reversible discharge capacity of 1,416 mAh g-1 at 0.1C with a low capacity fading of 0.05% per cycle, 92% capacity retention after 200 cycles and ca. 100% coulombic efficiency. The fully charged LSB cell can practically supply electricity to a spinning motor with a nominal voltage of 3.0 V for 28 min demonstrating many potential applications. PMID- 29255308 TI - Prevalence of Alcohol Consumption and Knowledge About Alcohol at Bhimtar, Sindhupalchowk. AB - INTRODUCTION: Alcohol causes several health problems, economic and social consequences across the world. Nepal is a multicultural and multi-ethnic country with an ambivalent regarding alcohol use according to social, religious and cultural values. Alcohol use is very common and easily available everywhere in Nepal. Objective of study is to find the prevalence of alcohol consumption and knowledge of alcohol among people at Bhimtar. METHODS: A cross sectional study was conducted on a total of 369 households, age above 20 years of Bhimtar, Sindhupalchowk district on November 2016. Total 41 households were selected using cluster sampling from all nine wards of Bhimtar village development committee. RESULTS: The prevalence of alcohol consumption was 232 (62.9%) in which 144 (77.4%) of males and 88 (48.1%) of females. There was 3.3 times more chance of consuming alcohol in male than female. Majority 137 (37%) consumed Raksi followed by Jaand/Chhyang 115 (31.3% ) and mix 97 (26.4%). On knowledge of alcohol consumption, 280 (75.9 %) and 288 (78.0%) of current drinker opined that it would effects own health and on the family respectively. After drinking alcohol 118 (31.9%) felt it relieved tiredness followed by felt better 103 (28%) and reduced stress 70 (18.9%). It affects heart and damage liver said by 72 (19.4%) and 59 (16%) respectively. There were family conflict after drinking alcohol replied by 132 (35.8%). They have good knowledge about the affect of alcohol on pregnant women. Only 50 (13.5%) of respondent expressed that it can be given to pregnant women. CONCLUSIONS: The prevalence of alcohol consumption was very high. There is markedly differed in alcohol consumption by sex. It is affecting their health and family. Consumption of alcohol is financial burden and makes conflict in the family, which will also make psychological affect on their children. There is significant difference in knowledge of harm on alcohol consumption by education status. It is essential to plan and develop a specific health education program among these at-risk populations for prevention of alcohol consumption. PMID- 29255309 TI - Non-Invasive Predictors of Gastro-Oesophageal Varices. AB - INTRODUCTION: The worldwide accepted tool for screening and monitoring gastro oesophageal varices in patients with liver cirrhosis is upper gastrointestinal endoscopy. Endoscopy needs clinical expertise and has got its own procedure related complications. Repeated endoscopies may be expensive and patients tend to develop poor compliance. This study was undertaken to establish the role of noninvasive parameters in predicting gastro-esophageal varices. METHODS: Two hundred patients with clinical features, laboratory and sonological findings suggestive of cirrhosis of liver and endoscopic evidence of portal hypertension were included in the study. Blood parameters like serum albumin, international normalized ratio (INR), platelets count and ultrasonography assessments of portal vein diameter and spleen size were compared with presence of gastro-oesophageal varices. RESULTS: At cutoff point of 2.55g/dl, serum albumin had high specificity of 99% whereas platelets count <1,44,000/mm3 had 87.9% sensitivity for presence of oesophageal varices. Sensitivities of 92.72% and 94.5% while specificities of 90% and 75% were detected for presence of oesophageal varices when the cutoff values for portal vein diameter and spleen size were 12.25 mm and 13.9 cm respectively. CONCLUSIONS: Measurements of serum albumin, platelets count, portal vein diameter and spleen size by ultrasonography can be recommended as a non invasive predictor for gastro-oesophageal varices in cirrhosis of liver. All these non-invasive parameters could be useful to patients with liver cirrhosis with portal hypertension in predicting presence of varices as well as in long term clinical monitoring and management. PMID- 29255310 TI - Incidence and Outcome of Ventilator Associated Pneumonia in ICU of a Tertiary Care Hospital in Nepal. AB - INTRODUCTION: Ventilator associated pneumonia is an important intensive care unit acquired infection in mechanically ventilated patients. Early and correct diagnosis of Ventilator associated pneumonia is difficult but is an urgent challenge for an optimal antibiotic treatment. METHODS: A prospective observational study was conducted in Intensive Care Unit of a tertiary care hospital in Nepal. Consecutive patients were considered during the study period, who met the criteria were included for the study. Clinical Pulmonary Infection Score was used to diagnose Ventilator associated pneumonia. RESULTS: Among 60 patients ventilated for more than 48 hours, 25 (41.6%) developed ventilator associated pneumonia. The incidence was 25 VAPs per 100 ventilated patients or 26 VAPs per 1000 ventilator days during the period of study. Days on ventilator and duration in ICU were higher in the VAP group. There was a trend towards increasing mortality in the VAP group (P value=0.06). CONCLUSIONS: There exists a high rate of VAP in our Intensive Care Unit. Targeted strategies aimed at reducing Ventilator associated pneumonia should be implemented to improve patient outcome and reduce length of Intensive Care Unit stay and costs. PMID- 29255311 TI - Gestational Weight Gain and its Relation with Birth Weight of the Newborn. AB - INTRODUCTION: Gestational weight gain is an important predictor of the health of the newborn. It is affected by body mass index of the women. This study was conducted to find out gestational weight gain according to Institute of Medicine 2009 recommendation and relationship of newborn birth weight to body mass index and gestational weight gain of the women. METHODS: It was cross sectional, hospital based study. The women, who attended at term pregnancy for delivery and having recorded first trimester body weight, were included in the study. Their body mass index was calculated and they were stratified into 4 groups according to body mass index. The gestational weight gain was calculated by subtracting first trimester body weight from body weight at the time of admission for delivery. All the women were followed till delivery. The newborn birth weight was taken immediately after delivery. RESULTS: A total of 227 women were enrolled in the study. More than half of the women had normal body mass index. There were 84 (37%) overweight and obese women. Mean gestational weight gain was 10.21 kg, and mean weight of the newborn was 3.05 kg. There were equal number of women who had adequate weight gain and less weight gain according to recommendation. Excess weight gain was seen in 34 (15%) women. Women of higher body mass index and women who had gain more weight during pregnancy had larger newborns. CONCLUSIONS: Body mass index and gestational weight gain of the women were important predictors of birth weight of the newborn. There is a positive correlation between gestational weight gain of the women and birth weight of the newborn. PMID- 29255312 TI - Prediction of Difficult Airway Among Patients Requiring Endotracheal Intubation in a Tertiary Care Hospital in Eastern Nepal. AB - INTRODUCTION: Various screening tests are done for predicting difficult laryngoscopy with variable diagnostic accuracy. Difficult laryngoscopy is being considered a surrogate indicator of difficult intubation, though it is not the exact measure of intubation difficulty. Our objectives were to find out the better predictor of difficult laryngoscopy amongst the routinely used tests and also to find the ability of difficult laryngoscopy to predict difficult intubation. METHODS: This prospective, observational study involved 314, ASA I/II adult patients requiring endotracheal intubation. Measurement of sternomental, thyromental and inter-incisor distances and gradings of mandibular protrusion and modified Mallampati were done. Statistical values including sensitivity and specificity of these tests were calculated to find the better predictor of difficult laryngoscopy. Cormack and Lehane laryngoscopy grade III/IV was defined as difficult laryngoscopy. Requirement of >3 attempts for endotracheal intubation was defined as difficult intubation. RESULTS: The sensitivity of the Modified Mallampatti Test for predicting difficult laryngoscopy was highest, 83% compared to other tests. Total 12 (3.8%) patients had difficult laryngoscopy. Intubation was difficult in 7 (2.2%) patients, of which four had difficult laryngoscopy (P<0.001). CONCLUSIONS: Modified Mallampati test was better for predicting difficult laryngoscopy compared to other bedside screening tests. Difficult laryngoscop could significantly predict difficult intubation in our patients. PMID- 29255313 TI - Clinicohematological Study of Pancytopenia in a Tertiary Care Hospital of Western Region of Nepal. AB - INTRODUCTION: Pancytopenia is a relatively common hematological entity and is a manifestation of many illnesses which can be life threatening at times. The severity of pancytopenia and the underlying pathology determine the management and prognosis. This study was conducted to evaluate hematological and bone marrow findings in patients presenting with pancytopenia. METHODS: A prospective observational study was conducted in Department of Pathology, Manipal College of Medical Sciences, Pokhara from January 2011 to December 2016. Clinical and hematological parameters including bone marrow aspiration and biopsy were evaluated in all patients who presented with pancytopenia. RESULTS: Among 138 cases studied, patients' age ranged from 2 to 82 years with a mean age of 43.95 years, and there was male predominance. Most of the patients presented with generalized weakness, pallor, dypnoea and fever. Hypoplastic marrow was seen in 38 (27.5%) cases, followed by 26 (18.8%) cases of megaloblastic anemia and 19 (13.76%) cases of acute leukemia. Other findings included one case each of hemophagocyosis, leishmaniasis, plasmodium vivex malaria and metastatic carcinoma. CONCLUSIONS: This study highlights that pancytopenia is a common hematological problem and that the study of detailed primary hematological investigations along with bone marrow study in patients with pancytopenia will help to identify the cause for further planning and management. PMID- 29255314 TI - Gestational Age Specific Postnatal Growth Curves for Singleton Babies in A Tertiary Hospital of Western Nepal. AB - INTRODUCTION: Measurement of birth weight, crown-heel length, head circumference and chest circumference used to assess the intrauterine growth of a baby vary with altitude, race, gender, socioeconomic status, maternal size, and maternal diseases. The study aimed to construct centile charts for birth weight, crown heel length and head circumference for new born at different gestational ages in Western Nepal. METHODS: This was a descriptive cross-sectional study done over a period of 15 months in a tertiary care hospital of Western Nepal. Birth weight, length, head circumference and chest circumference were measured within 12-24 hours of birth. Gestational age was estimated from the first day of last menstrual period and New Ballard's scoring system. Microsoft 2007 Excel and SPSS 16 was used for data analysis. Cole's Lambda Mu Sigma method was used for constructing centile curves. RESULTS: Out of 2000 babies analysed, 1910 samples were used to construct smoothed intrauterine growth curve of birth weight, crown heel length, and head circumference from 33-42 weeks of gestation. Among all, 1147 (57.35%) were male and 853 (42.65%) were female, mean gestational age was 38.13+/-2.44 weeks. The means of birth weight, crown-heel length, head and chest circumference were 2744.78 gm, 47.80 cm, 33.18 cm, and 30.20 cm with standard deviations of 528.29, 3.124, 1.78, and 2.35 respectively. CONCLUSIONS: This necessitates the update in the existing growth charts and development in different geographical regions of a country. PMID- 29255315 TI - Patterns of Injury and Mortality in Pediatric Patients Attending Emergency Department in a Tertiary Care Center in Eastern Nepal. AB - INTRODUCTION: Trauma is a major and increasing global health concern in the recent world. It is now the leading cause of death among people less than 18 years old. The aim of this study is to analyze all injuries from trauma-related causes among children and adolescents under 18 years old of age. METHODS: This is a retrospective cross sectional study done in Emergency Department of B.P. Koirala Institute of Health Sciences. Patients aged less than 16 years were included with history of trauma from January 1st 2013 to 31st December 2013.The details of patient were taken from computerized medical records of the hospital. The demographic data, pattern of injury, mode of injury, diagnosis and outcomes were tabulated in Microsoft Excel. RESULTS: Total 3958 pediatrics patient were enrolled in this study with Male: Female=3.6:1 and Mean age 9.6+/-3.2 years. The common modes of injury were fall injury 2596 (65.6%) and RTAs 1176 (29.7%). Whereas the commonest patters were Fractures 1385 (35%) and Soft Tissue Injuries 784 (19.8%). CONCLUSIONS: Fall Injury and Road Traffic Accidents are major and serious problem for children in Low Income countries like Nepal. PMID- 29255316 TI - Clinical Profile of Atrial Fibrillation in a Tertiary Hospital in Central Nepal. AB - INTRODUCTION: Atrial fibrillation is a common cardiac arrhythmia in elderly causing morbidity and mortality. METHODS: A cross-sectional descriptive study was conducted in College of Medical Sciences Teaching Hospital from August 2013 to July 2016. All in-patients diagnosed with atrial fibrillation were included. RESULTS: Total 205 patients were studied. There were 154 (75.1%) nonvalvular and 51 (24.9%) valvular causes for atrial fibrillation. Common presentations were shortness of breath 84 (41%), palpitations 57 (27.8%) and stroke 38 (24.6 %). For valvular causes, common lesion was of mitral valve (90%). Warfarin was used in 32 (62.7%) with mean INR of 2.038 +/- 0.6. Seventeen (53.1%) had INR below 2. In nonvalvular cases, types were paroxysmal (55.2%), persistent (34.4%) and permanent (10.4%). Common risk factors were heart failure 87 (56.5%), old age (>75 years) 66 (42.8%), hypertension 47 (30.5%), dilated cardiomyopathy 23 (14.9%), degenerative multivalvular heart disease 23 (14.9%) and ischemic heart disease (13.6%). CHADS(2) calculated 2 or more were in 98 (63.6%) patients. Warfarin was used in 39 (25.3%) and aspirin was used in 103 (66.9%) patients in CHADS(2) score 2 or more. Mean INR in nonvalvular AF was 1.5 +/-0.4. CONCLUSIONS: Atrial fibrillation occurred as a result of valvular or nonvalvular origin. Common presentations were shortness of breath, palpitations and stroke. Common risk factors in nonvalvular atrial fibrillation were old age, hypertension and heart failure. Warfarin was underused in nonvalvular cases in our setting. PMID- 29255317 TI - Evaluation of Dental Caries Among Preschool Children in Kathmandu- Using Significant Caries Index. AB - INTRODUCTION: Dental caries among preschool children is common but there is scarcity of updated data about its prevalence among Nepalese preschool children. This study was conducted to evaluate prevalence, Significant Caries Index, Caries pattern, Restorative care index and Disparity ratio among preschool children of Kathmandu aged 3-6 years. METHODS: A cross sectional study was conducted on 17 preschools of Kathmandu following WHO criteria. Data were analysed using SPSS 20 and descriptive statistics was applied. RESULTS: Prevalence of dental caries was 803 (55.6%) with a mean deft of 3.28+/-3.581 and Significant Caries Index score was 7.439. Caries pattern showed the most commonly decayed teeth were mandibular second molars followed by maxillary central incisors. The least affected teeth were mandibular lateral incisors. The restorative care index was 106 (7.32%) in the total sample size and 14 (2.86%) in the SiC and disparity ratio was 2.26. CONCLUSIONS: The SiC Index indicated high dental caries prevalence; severity rates and restorative care index indicated little experience of restorative treatment in preschool children of Kathmandu identifying the need for more targeted efforts to reach preschool children early to effectively address unmet oral health needs. PMID- 29255318 TI - Knowledge and Practice of Hemodialysis Amongst Dialysis Nurses. AB - INTRODUCTION: Dialysis nurses should have a good knowledge regarding hemodialysis treatment. The status of Nepalese dialysis nurses on this aspect is unknown. This study was done to assess the knowledge and practice on different aspects of the hemodialysis treatment. METHODS: We distributed validated questionnaires to the participants in a biannual conference in Kathmandu on 24th September as most of the dialysis nurses attend the event. We calculated mean and standard deviation for continuous variables and frequencies and percentage for the responses and compared counseling with different parameters. RESULTS: Total 94 out of 116 participants who were giving care to dialysis patients were in the study. Total 39 (42%) received formal nursing training in hemodialysis and 71 (78%) respondents always counseled patients regarding fluid intake. A total of 37 (96%) trained nurses always counseled the importance of regular dialysis. Seventy-six (81.7%) respondents did counseling on vaccination against Hepatitis B. Counseling on vaccination against influenza and pneumococcus was 47 (50%). When comparing educational status, respondents below bachelor level did more frequent counseling than level above (P=0.03). All the respondents knew the importance of hand washing and BP monitoring during hemodialysis. Ninety-one (96.7%) respondents knew how to deal with BP changes during hemodialysis. Seventy-three (77.6%) respondents were very confident on managing complications. Only 31 (33%) respondents knew how to deal with patients on continuous ambulatory peritoneal dialysis. CONCLUSIONS: Dialysis nurses have knowledge on basic procedures of hemodialysis but there is a space for improvement in dealing with complications to provide quality service to hemodialysis patients. PMID- 29255319 TI - Pattern of Body Mass Index and Common Health Problems in Women of Reproductive Age Group in a Private Clinic in Kathmandu. AB - INTRODUCTION: High Body Mass Index is one of the risk factors for many chronic diseases and adverse health outcomes. It is associated with an increased risk of coronary heart disease, ischemic stroke, high blood pressure and type 2 diabetes mellitus. It also have many adverse effect on reproductive health of the women like sub fertility, polycystic ovarian disease, menstrual abnormality etc. The purpose of this study is to find Basal Metabolic Rate and the diseases pattern of reproductive age woman in Nepal. METHODS: This is a descriptive study of women of reproductive age (15 to 49 years) attending a private gynaecology clinic in Kathmandu Valley from October 2016 to June 2017. Six hundred and eight women of current reproductive age group participated in this study. Women's particulars and complaints were noted down. Detailed history was taken. Height, weight and blood pressure were recorded and general examination was done. BMI was calculated as BMI is weight in kilogram divided by height in meter square, and it was interpreted as per WHO guidelines. RESULTS: Out of the total 608 participants, 243 (40%) were overweight, 96 (15.8%) were obese. Regarding the common health problems, 154 (25.3%) have sub fertility and 199 (32%) had genitourinary infection. Similarly, 90 (14.8%) had menstrual problems. CONCLUSIONS: Prevalence of overweight and obesity has risen significantly comparing to the study done decade ago in same setting. Similarly, sub fertility rate has also risen whereas the prevalence of genitourinary infections has decreased. PMID- 29255320 TI - Outcome of Needle Fenestration, Subacromial Steroid and Diclofenac Phonophoresis in Acute Calcific Tendinitis of Shoulder. AB - INTRODUCTION: Acute calcific tendinitis of shoulder is very painful and disturbing condition. There are many modalities with variable outcome to address the condition. We studied needling technique with multiple fenestration, subacromial steroid and diclofenac phonophoresis and evaluated the outcome in term of pain relief and improvement of shoulder function at a simple outpatient clinical set up without image or ultrasound guidance. METHODS: We studied cases of acute calcific tendinitis presenting within one week from onset of symptoms and X-ray showing calcific deposit. All underwent needle fenestration at maximum tender site with lignocaine loaded syringe, subsequent injection of 40 mg subacromial methylprednisolone and diclofenac phonophoresis done by qualified physiotherapist for five days. Visual Analogue Scale was used to measure pain, Simple shoulder Test applied to evaluate shoulder function and size of calcific deposit was measured at maximum length. RESULTS: Pain subsided dramatically and there was substantial improvement of shoulder function within a week. CONCLUSIONS: Needle fenestration and subacromial methylprednisolone along with diclofenac phonophoresis without image guidance gives excellent pain reduction and improves shoulder function which can be done at simple outpatient clinic. PMID- 29255321 TI - Prevalence of Oral Mucosal Lesions in a Tertiary Care Dental Hospital of Kathmandu. AB - INTRODUCTION: Oral mucosa can be affected by a variety of soft tissue lesions and conditions. Benign as well as malignant lesions of oral cavity are common. Squamous cell carcinoma is one of the commonest malignancies. The present retrospective study was undertaken to study the prevalence of various oral mucosal lesions in a tertiary care dental hospital of Kathmandu. METHODS: This retrospective study was carried out in the Department of Oral and Maxillofacial Pathology at Kantipur Dental College and Teaching hospital from January 2015 to January 2017. The study included biopsy specimen from the oral cavity. The parameters included in the study were age, gender, site of the lesion and histopathological diagnosis. The data collected was statistically analyzed. RESULTS: A total of 111 biopsy cases were included in the present study. Out of which, there were 16 (14.4%) cases of non-neoplastic and 16 (14.4%) cases of benign pathology. The oral cavity lesions were commonly seen in age range between 6-74 years where males 59 (53.2%) were mostly affected. The most common site for oral lesion was buccal mucosa 23 (20.7%) and anterior gingiva 23 (20.7%). Total 15 (13.5%) cases of oral squamous cell carcinoma were seen as the predominant malignancy affecting in the vestibular region 8 (7.2%). CONCLUSIONS: The present study shows benign as well as the non-neoplastic lesions were more prevalent in oral mucosa with the buccal mucosa and anterior gingiva as the commonest site of occurrence. PMID- 29255322 TI - Mastoid Osteoma - Is "Trauma" A Possible Etiologic Factor. AB - A 19 year old female presented with painful postaural swelling of three years duration with preceding history of trauma. Clinically and radilogically the diagnosis of mastoid osteoma was made. As patient was symptomatic the osteoma was removed and cortical mastoidectomy was done. We emphasise that symptomatic mastoid osteomas must be treated early even if they are small in size to prevent the development of giant osteomas. The case is reported for its rarity with relevant review of literature. To the best of our knowledge this is the first case report in which there is a definitive history of trauma preceding the development of osteoma suggesting its possible role as an inciting factor. PMID- 29255323 TI - Incisional Hernia Repair: Current Perspectives. PMID- 29255324 TI - Cholera Outbreak in Gaidataar: A Lesson for Further Strengthening the Task Force for Epidemic Management in Nepal. AB - Cholera is an acute enteric infection caused by the ingestion of bacterium Vibrio cholerae1. Cholera is transmitted through contaminated food and water. Prevention and preparedness of cholera require a coordinated multi-disciplinary approach. The extremely short incubation period enhances the potentially explosive pattern of outbreaks. Cholera can lead to severe dehydration and death if left untreated. The laboratory testing is required for antimicrobial sensitivity testing and for confirming the end of an outbreak. Provision of safe drinking water, proper sanitation, and food safety are critical for preventing occurrence of cholera. Health education aims at communities adopting preventive behavior for averting contamination. Specific training for all the staffs about proper case management including avoidance of noso-comial infection (like face masks, gloves, antiseptic solution, hand scrubs). Sufficient pre-positioned medical supplies for case management (diarrhoeal disease kits, iv fluids, antibiotics, safety measures). Improved access to water, effective sanitation, proper waste management and vector control. Improved communication and public information. Oral Rehydration Salts can treat 80% of cholera1. Appropriate antibiotics can reduce the duration of purging. With a well and properly managed team of health experts with all essential medicines and a good rapid response team, any outbreak can be prevented, controlled and managed. PMID- 29255325 TI - [Efficacy and safety of beclomethasone dipropionate HFA.] PMID- 29255326 TI - The Emergence and Collapse of Knowledge Boundaries. AB - The dynamics of knowledge transfer is an important topic for engineering managers. In this paper, we study knowledge boundaries - barriers to knowledge transfer - in groups of experts, using topic modeling, a natural language processing technique, applied to transcript data from the U.S. Food and Drug Administration's Circulatory Systems Advisory Panel. As predicted by prior theory, we find that knowledge boundaries emerge as the group faces increasingly challenging problems. Beyond this theory, we find that knowledge boundaries cease to structure communications between communities of practice when the group's expert ability is insufficient to solve its task, such as in the presence of high novelty. We conjecture that the amount of expert knowledge that the group can collectively bring to bear is a determining factor in boundary formation. This implies that some of the factors underlying knowledge boundary formation may aid rather than hinder - knowledge aggregation. We briefly explore this conjecture using qualitative exploration of several relevant meetings. Finally, we discuss implications of these results for organizations attempting to leverage their expertise given the state of their collective knowledge. PMID- 29255328 TI - Women's health: Ideology or science? AB - Countless resources have been spent advocating for women's health. Yet many of the proposals appear to be ideologically driven rather than based on hard science and an integral understanding of the human person. To advance the health of women, ideologies need to be set aside. PMID- 29255327 TI - Utilizing Mechanistic Cross-Linking Technology to Study Protein-Protein Interactions: An Experiment Designed for an Undergraduate Biochemistry Lab. AB - Over the past decade, mechanistic crosslinking probes have been used to study protein-protein interactions in natural product biosynthetic pathways. This approach is highly interdisciplinary, combining elements of protein biochemistry, organic chemistry, and computational docking. The development of an experiment to engage undergraduate students in multidisciplinary research is described that leverages mechanistic crosslinking probes to study protein conformations and protein-protein interactions. This experiment provides students with a platform to learn chemoenzymatic synthesis, polyacrylamide gel electrophoresis, biochemical assays, and computational docking all while exploring a contemporary biochemical topic. PMID- 29255330 TI - Catholic social teaching and America's suboptimal breastfeeding rate: Where faith and policy should meet to combat injustice. AB - : Despite the numerous health benefits of breastfeeding, few American women breastfeed for the optimal duration of time. Reasons given for not following national and global institutional breastfeeding recommendations are various and multi-faceted. However, for many American women who would like to breastfeed, unjust historical, social, economic, cultural, and environmental factors negatively impact their ability to breastfeed. Catholic social teaching seeks to protect the poor and the vulnerable by working for social and economic justice, encourages stewardship of the environment, and uplifts the family as the most important unit in society. As such, Catholic social teaching has clear implications for individuals and institutions seeking to make breastfeeding a more widespread, accepted practice. In response to the crisis in American rates of breastfeeding, American Catholic healthcare institutions should work to promote the just economic and social conditions necessary for American women to breastfeed their children, starting by implementing breastfeeding-friendly policies for patients and employees in their own institutions. Summary: For many American women who would like to breastfeed, unjust historical, social, economic, cultural, and environmental factors negatively impact their ability to breastfeed. Catholic social teaching has clear implications for individuals and institutions seeking to make breastfeeding a more widespread, accepted practice. Therefore, American Catholic healthcare institutions should work particularly hard to promote the just economic and social conditions necessary for American women to breastfeed their children, starting by implementing breastfeeding friendly policies for patients and employees in their own institutions. PMID- 29255329 TI - Ovulation, a sign of health. AB - : The concept of the ovarian continuum can be understood as a process that occurs during a woman's lifetime and begins during intrauterine life with fertilization. Women start their reproductive years with approximately five hundred thousand follicles containing oocytes, of which only around five hundred will be released during ovulation. Ovulation has been recognized as an event linked with reproduction; however, recent evidence supports the role of ovulation as a sign of health. The use of biomarkers that help women recognize ovulation enables them to identify their health status. This knowledge helps medical healthcare providers in the prevention, diagnosis, and treatment of different pathologies related with endocrine disorders, gynecological abnormalities, autoimmune, genetic, and neoplastic diseases, as well as pregnancy-related issues. The knowledge of the ovarian continuum and the use of biomarkers to recognize ovulation should be considered a powerful tool for women and medical professionals. Summary: The ovarian continuum is a process that occurs during a woman's lifetime. It begins during intrauterine life with fertilization and ends with menopause. This process can be greatly affected by different conditions such as changes in hormonal levels and illnesses. Therefore, understanding and promoting the knowledge and use of biomarkers of ovulation in women is a key aspect to consider when evaluating their health status. The knowledge and education about the ovarian continuum should be taken into account as a powerful tool for women and medical professionals. PMID- 29255331 TI - Devastating consequences of sex trafficking on women's health. AB - : Sex trafficking has devastating consequences on the physical and mental well being of millions of women around the world. These trafficking victims often come in contact with medical personnel, and these encounters with suitably prepared staff can be a step toward healing of the victims. The Catholic Church, especially through Pope Francis, is making strenuous efforts to curb the spread of sex trafficking. Same-sex feelings and behavior may arise post-trafficking in individuals, although this does not appear to be mentioned thus far in the literature. Here, we are most likely dealing with a type of "pseudo-lesbianism" post-trauma. The trafficking survivor can be helped to understand some of the likely roots of her feelings such as anti-male sentiments following abuse. She needs to be patiently, and expertly, accompanied to process the trauma she has experienced, and learn how to meet her genuine needs for female affection and affirmation in healthy, chaste, and non-erotic ways. Summary: Around the world, millions of female victims of human trafficking are forced into sex "work," often resulting in serious physical and mental-health problems. Healthcare staff should be alert to spot victims of sex trafficking and be ready to assist them. The Catholic Church, especially through Pope Francis, has been vocal in denouncing this form of modern slavery. Some female victims of sex trafficking may experience same-sex feelings afterward. Healing for such young women involves helping them to process their traumatic experiences, as well as patiently accompanying them as they seek to develop healthy, chaste friendships with other females and males. PMID- 29255332 TI - Spiritual care of the woman physician: Insights from Edith Stein and the Catholic tradition. AB - In the face of physician stress, burn-out, divorce, and suicide, the spiritual care of the Catholic woman physician must be addressed. Employing the insights of Edith Stein and the Catholic tradition, this article presents both theoretical propositions and practical applications regarding the three primary spheres of the woman physician's life: the spiritual, the familial, and the professional. Since woman's ultimate vocation is union with God through self-gift, prayer must occupy a central place in her life. Because she is wife and mother, family relationships must be given priority over the professional activity that is also her inestimable gift to humanity. PMID- 29255333 TI - The woman physician as antidote to the ills of modern medicine. AB - This article, drawing on the work of Edith Stein, reflects on the feminine aspects of the medical profession, specifically attention to the whole person and personal accompaniment. It presents these feminine aspects, in light of the mechanistic, highly specialized, and often impersonal ethos of modern medicine, as a needed corrective to such an ethos. Finally, this thesis is illustrated with an example from physician Victoria Sweet. PMID- 29255335 TI - Special Issue in Commemoration of the Fiftieth Anniversary of Humanae Vitae. PMID- 29255334 TI - Building a culture of life by embracing the feminine genius: A message to Catholic women in health care. AB - This article is written to encourage women working in various healthcare fields to understand their call and responsibility to help build a culture of life. By using their natural "feminine genius," women are uniquely gifted to uphold the sacredness of sex and the dignity of human life in every clinical encounter. PMID- 29255337 TI - A Continuous Threshold Expectile Model. AB - Expectile regression is a useful tool for exploring the relation between the response and the explanatory variables beyond the conditional mean. A continuous threshold expectile regression is developed for modeling data in which the effect of a covariate on the response variable is linear but varies below and above an unknown threshold in a continuous way. The estimators for the threshold and the regression coefficients are obtained using a grid search approach. The asymptotic properties for all the estimators are derived, and the estimator for the threshold is shown to achieve root-n consistency. A weighted CUSUM type test statistic is proposed for the existence of a threshold at a given expectile, and its asymptotic properties are derived under both the null and the local alternative models. This test only requires fitting the model under the null hypothesis in the absence of a threshold, thus it is computationally more efficient than the likelihood-ratio type tests. Simulation studies show that the proposed estimators and test have desirable finite sample performance in both homoscedastic and heteroscedastic cases. The application of the proposed method on a Dutch growth data and a baseball pitcher salary data reveals interesting insights. The proposed method is implemented in the R package cthreshER. PMID- 29255338 TI - Alcoholics Anonymous-Related Benefit for Urban Native Americans: Does Urban Native American Gender Moderate AA Engagement and Outcomes? AB - Alcoholics Anonymous (AA) is one of the most commonly accessed resources for individuals seeking to reduce their drinking. How urban Native Americans fare in AA is only beginning to be investigated in spite of circumstantial evidence suggesting that a majority of treatment-seeking urban Native Americans will receive 12-step treatment. Even less is known about Native American gender differences with regard to AA-related benefit. The current study addressed this gap by investigating urban Native American gender differences in AA attendance rates and outcomes. To this end, as part of two larger NIH-funded studies we recruited 63 Native American men and women and followed them for 9 months in this naturalistic study (n= 35 males, n = 28 females). Urban Native Americans significantly reduced their drinking over the study period, and AA attendance explained, in part, increased abstinence of study participants. No significant differences in AA attendance and drinking outcomes were observed between Native American men and women; however, descriptively men reported greater reductions in hazardous drinking relative to women. Clinical implications and future directions are discussed. PMID- 29255336 TI - Coelomycetous Dothideomycetes with emphasis on the families Cucurbitariaceae and Didymellaceae. AB - The taxonomy of the coelomycetes has undergone dramatic changes in recent years, but remains controversial due to the high number of taxa involved, their poor morphological differentiation, the rare occurrence of the sexual morphs, and rapid loss of fertility in vitro. In the present study, we revisited the families Cucurbitariaceae and Didymellaceae (Pleosporales, Dothideomycetes), which include numerous plant pathogens, endophytic species associated with a wide host range, and saprobes. The taxonomy of two of the most relevant genera, i.e. Phoma and Pyrenochaeta, remains ambiguous after several phylogenetic studies, and needs further revision. We have studied a total of 143 strains of coelomycetes from clinical or environmental origin, by combining the LSU, ITS, tub2 and rpb2 sequences for a multi-locus analysis and a detailed morphological comparison. The resulting phylogenetic tree revealed that some fungi previously considered as members of Cucurbitariaceae represented five different families, and four of them, Neopyrenochaetaceae, Parapyrenochaetaceae, Pseudopyrenochaetaceae and Pyrenochaetopsidaceae, are proposed here as new. Furthermore, 13 new genera, 28 new species, and 20 new combinations are proposed within the Pleosporineae. Moreover, four new typifications are introduced to stabilise the taxonomy of these fungi. PMID- 29255339 TI - Comprehension in Proficient Readers: The Nature of Individual Variation. AB - Individual-difference research on reading comprehension is challenging because reader characteristics are as correlated with each other as they are with comprehension. This study was conducted to determine which abilities are central to explaining comprehension and which are secondary to other abilities. A battery of psycholinguistic and cognitive tests was administered to community college and university students. Seven constructs were identified: word decoding, working memory capacity (WMC), general reasoning, verbal fluency, perceptual speed, inhibition, and language experience. Only general reasoning and language experience had direct effects; these two variables accounted for as much variance in comprehension as did the complete set. Direct effects of WMC and decoding were found only when general reasoning and language experience were deleted from the models. The authors question the need to include WMC in our theories of variability in adult reading comprehension and highlight the need to understand precisely how vocabulary facilitates comprehension. PMID- 29255340 TI - Towards Replacing Resistance Thermometry with Photonic Thermometry. AB - Resistance thermometry provides a time-tested method for taking temperature measurements that has been painstakingly developed over the last century. However, fundamental limits to resistance-based approaches along with a desire to reduce the cost of sensor ownership and increase sensor stability has produced considerable interest in developing photonic temperature sensors. Here we demonstrate that silicon photonic crystal cavity-based thermometers can measure temperature with uncertainities of 175 mK (k = 1), where uncertainties are dominated by ageing effects originating from the hysteresis in the device packaging materials. Our results, a ~ 4-fold improvement over recent developments, clearly demonstate the rapid progress of silicon photonic sensors in replacing legacy devices. PMID- 29255341 TI - Miniaturized Planar Room Temperature Ionic Liquid Electrochemical Gas Sensor for Rapid Multiple Gas Pollutants Monitoring. AB - The growing impact of airborne pollutants and explosive gases on human health and occupational safety has escalated the demand of sensors to monitor hazardous gases. This paper presents a new miniaturized planar electrochemical gas sensor for rapid measurement of multiple gaseous hazards. The gas sensor features a porous polytetrafluoroethylene substrate that enables fast gas diffusion and room temperature ionic liquid as the electrolyte. Metal sputtering was utilized for platinum electrodes fabrication to enhance adhesion between the electrodes and the substrate. Together with carefully selected electrochemical methods, the miniaturized gas sensor is capable of measuring multiple gases including oxygen, methane, ozone and sulfur dioxide that are important to human health and safety. Compared to its manually-assembled Clark-cell predecessor, this sensor provides better sensitivity, linearity and repeatability, as validated for oxygen monitoring. With solid performance, fast response and miniaturized size, this sensor is promising for deployment in wearable devices for real-time point-of exposure gas pollutant monitoring. PMID- 29255342 TI - A SEMI-LAGRANGIAN TWO-LEVEL PRECONDITIONED NEWTON-KRYLOV SOLVER FOR CONSTRAINED DIFFEOMORPHIC IMAGE REGISTRATION. AB - We propose an efficient numerical algorithm for the solution of diffeomorphic image registration problems. We use a variational formulation constrained by a partial differential equation (PDE), where the constraints are a scalar transport equation. We use a pseudospectral discretization in space and second-order accurate semi-Lagrangian time stepping scheme for the transport equations. We solve for a stationary velocity field using a preconditioned, globalized, matrix free Newton-Krylov scheme. We propose and test a two-level Hessian preconditioner. We consider two strategies for inverting the preconditioner on the coarse grid: a nested preconditioned conjugate gradient method (exact solve) and a nested Chebyshev iterative method (inexact solve) with a fixed number of iterations. We test the performance of our solver in different synthetic and real world two-dimensional application scenarios. We study grid convergence and computational efficiency of our new scheme. We compare the performance of our solver against our initial implementation that uses the same spatial discretization but a standard, explicit, second-order Runge-Kutta scheme for the numerical time integration of the transport equations and a single-level preconditioner. Our improved scheme delivers significant speedups over our original implementation. As a highlight, we observe a 20* speedup for a two dimensional, real world multi-subject medical image registration problem. PMID- 29255343 TI - Iterative Jacobian-Based Inverse Kinematics and Open-Loop Control of an MRI Guided Magnetically Actuated Steerable Catheter System. AB - This paper presents an iterative Jacobian-based inverse kinematics method for an MRI-guided magnetically-actuated steerable intravascular catheter system. The catheter is directly actuated by magnetic torques generated on a set of current carrying micro-coils embedded on the catheter tip, by the magnetic field of the magnetic resonance imaging (MRI) scanner. The Jacobian matrix relating changes of the currents through the coils to changes of the tip position is derived using a three dimensional kinematic model of the catheter deflection. The inverse kinematics is numerically computed by iteratively applying the inverse of the Jacobian matrix. The damped least square method is implemented to avoid numerical instability issues that exist during the computation of the inverse of the Jacobian matrix. The performance of the proposed inverse kinematics approach is validated using a prototype of the robotic catheter by comparing the actual trajectories of the catheter tip obtained via open-loop control with the desired trajectories. The results of reproducibility and accuracy evaluations demonstrate that the proposed Jacobian-based inverse kinematics method can be used to actuate the catheter in open-loop to successfully perform complex ablation trajectories required in atrial fibrillation ablation procedures. This study paves the way for effective and accurate closed-loop control of the robotic catheter with real-time feedback from MRI guidance in subsequent research. PMID- 29255344 TI - Influences on rebubble rate in Descemet's membrane endothelial keratoplasty. AB - Purpose: Descemet's membrane endothelial keratoplasty (DMEK) is a minimally invasive partial corneal transplant procedure used in patients with failing endothelial membranes. This study aims to identify those factors which influence the need for a rebubble of the corneal graft. Methods: A total of 94 eyes that received DMEK between March 2014 and January 2016 at Vance Thompson Vision were used in the study. Demographic and graft data were collected from the patients and donors, and perioperative statistics of the procedures. A logistical regression was used to compare eyes that did and did not require a rebubble. Results: Among those characteristics that were included (patient age/sex, donor age/sex, death to processing time, donation to surgery time, death to procurement time, specular cell count density, burping procedure, postoperative day 1 intraocular pressure [IOP], and postoperative week 1 IOP, concurrent phacoemulsification, and how well the Descemet graft was centered), only a lower specular cell count density of the corneal graft, and a graft that was not well centered correlated with needing a rebubble due to partial graft detachment (p=0.021) and (p=0.023), respectively. Conclusion: An increased specular cell count density may allow for better placement of the corneal graft by allowing for better unfolding in DMEK procedures. A well-centered graft may decrease postoperative complications by increasing adherence. Additionally, postoperative management of IOP may not affect the rebubble rate, and therefore should be left to the discretion of the provider to determine whether it is necessary. PMID- 29255345 TI - Octreotide long-acting repeatable in the treatment of neuroendocrine tumors: patient selection and perspectives. AB - Over the past three decades, the incidence and prevalence of neuroendocrine tumors have gradually increased. Due to the slow-growing nature of these tumors, most cases are diagnosed at advanced stages. Prognosis and survival are associated with location of primary lesion, biochemical functional status, differentiation, initial staging, and response to therapy. Octreotide, the first synthetic somatostatin analog, was initially used for the management of gastrointestinal symptoms associated with functional carcinoid tumors. Its commercial development over time led to long-acting repeatable octreotide acetate, a long-acting version that provided greater administration convenience. Recent research demonstrates that octreotide's efficacy has evolved beyond symptomatic management to targeted therapy with antitumoral effects. This review examines the history and development of octreotide, provides a synopsis on the classification, grading, and staging of neuroendocrine tumors, and reviews the evidence of long-acting repeatable octreotide acetate as monotherapy and in combination with other treatment modalities in the management of non-pituitary neuroendocrine tumors with special attention to recent high-quality Phase III trials. PMID- 29255346 TI - Hepatoprotective effect of calculus bovis sativus on nonalcoholic fatty liver disease in mice by inhibiting oxidative stress and apoptosis of hepatocytes. AB - Calculus bovis (CB, niu-huang) is a high-class therapeutic drug that is often used in traditional Chinese medicine. CB helps to eliminate heat and toxic components, and prevents the accumulation of phlegm and blood stasis in the liver. In Asian countries, CB Sativus (CBS), an ideal substitute for natural CB, is presently extensively used for long-term treatment of chronic liver diseases. The present study aimed to evaluate the effects and potential mechanism(s) of action of CBS on mice with fructose-induced nonalcoholic fatty liver disease (NAFLD). The NAFLD model was established in C57BL/6 mice by exclusively feeding fluids containing 30% fructose for 8 consecutive weeks. After these 8 weeks, mice were given CBS (50 mg/kg/day or 100 mg/kg/day) for 2 consecutive weeks. Treatment with CBS reversed the fructose-induced impaired glucose tolerance. Compared with the model group, in which mice received 8 weeks of high-fructose diet and 2 weeks of 0.5% sodium carboxymethyl cellulose, CBS treatment significantly decreased the levels of fasting serum glucose, fasting insulin, triglyceride, and total cholesterol, and increased levels of high-density lipoprotein-cholesterol. CBS treatment also significantly decreased the levels of triglyceride, total cholesterol, and free fatty acid in the liver. The activity of superoxide dismutase in the liver was increased after treatment with CBS, however, levels of malondialdehyde and reactive oxygen species decreased. Histopathological examination showed that liver steatosis and injury were significantly reduced in CBS-treated mice. The expression of fatty acid synthase, nuclear factor kappa light-chain-enhancer of activated B cells, Cysteinyl aspartate-specific proteinase-3, and synonyms B-cell leukemia/lymphoma-2 gene-associated X protein were downregulated after treatment with CBS, whereas the expression of nuclear factor erythroid-2-related factor 2 was upregulated. In conclusion, CBS treatment exerted therapeutic effects in the liver of mice with NAFLD, which may be associated with amelioration of metabolic disorders, enhanced antioxidant effects, and alleviation of apoptosis. PMID- 29255347 TI - Pharmacokinetic and pharmacodynamic interaction between ezetimibe and rosuvastatin in healthy male subjects. AB - Background and objective: Rosuvastatin and ezetimibe are commonly applied in lipid-lowering pharmacotherapy. However, the pharmacokinetic (PK) interaction was not clear by the coadministration of rosuvastatin and ezetimibe. This study investigated the pharmacodynamic (PD) and PK interactions between rosuvastatin and ezetimibe through a crossover clinical trial. Subjects and methods: A randomized, open-label, multiple-dose, two-treatment, two-period, two-sequence crossover study with two treatment parts was conducted in healthy male subjects. Study part A involved rosuvastatin, and study part B involved ezetimibe. A total of 25 subjects in both parts completed the PK and PD evaluations. Rosuvastatin (20 mg) or ezetimibe (10 mg) was administered once daily for 7 days as monotherapy or co-therapy. The plasma concentrations of rosuvastatin, total ezetimibe and free ezetimibe were measured for 72 h after day 7. Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) were investigated for the PD assessments on day 1 (pretreatment) and day 8. Results: Rosuvastatin and ezetimibe presented multiple peaks. The 90% confidence intervals (CIs) of the geometric mean ratios for the peak plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve during the dosing interval at steady state (AUCtau,ss) of rosuvastatin and total ezetimibe were within the range 0.8-1.25. However, the coadministration increased the systemic exposure of free ezetimibe. In the PD assessments, rosuvastatin and ezetimibe monotherapy reduced the LDL-C and TC levels effectively. In addition, the lipid-lowering effects of the coadministration corresponded to an approximate summation of the effects of rosuvastatin and ezetimibe monotherapy. However, no significant changes in HDL-C were observed with rosuvastatin or ezetimibe treatment. No significant safety issue was noted. Conclusion: The coadministration of rosuvastatin and ezetimibe revealed a bioequivalent PK interaction. Additional lipid-lowering effects, including decreased LDL-C and TC, were observed as expected in combination therapy without significant safety concern. PMID- 29255348 TI - Variability in the therapeutic management of advanced ovarian cancer patients: a five-country survey of oncologists. AB - Background: Advanced ovarian cancer patients have a poor prognosis, mainly because the disease is diagnosed at a late stage. A number of therapeutic approaches, such as neoadjuvant and maintenance therapies, have been developed to try to improve treatment outcome. In parallel, the targeted therapies bevacizumab and olaparib have recently been approved for ovarian cancer treatment. The goal of our survey was to provide a comprehensive, global depiction of advanced ovarian cancer treatments across different regions. Patients and methods: Oncologists from France, Italy, Germany, the UK, and the USA were invited to participate in an online survey. Participants were eligible if they personally managed at least 15 ovarian cancer patients. Quantitative questions addressed the proportion of patients in neoadjuvant, treatment, and maintenance settings; proportion of BRCA-positive patients; and the type of treatment prescribed per setting and per line of therapy, depending on the patient's BRCA status. Results: A total of 138 respondents completed our survey in Europe and 132 in the USA. The proportions of patients in treatment, maintenance, and remission were identical across each country and line of treatment at 60%, 20%, and 20%, respectively. The proportion of BRCA-tested patients ranged from 45% in Italy to 73% in the USA, with 10% (UK)-21% (Italy) of tested patients having a positive status. Levels of bevacizumab and olaparib prescriptions differed based on the country, line of treatment, and setting, with a significant share of patients receiving both drugs outside of their approved indications for ovarian cancer treatment. Conclusion: This survey provides real-world data on how advanced ovarian cancer patients are currently treated: 1) BRCA testing was not performed systematically, which raises concerns regarding access to treatment and 2) absence of consensus regarding which chemotherapeutic regimens or targeted therapy to use in different stages of the disease. PMID- 29255349 TI - Preparation and evaluation of RGD and TAT co-modified docetaxel-loaded liposome. AB - The aim of this study is to develop a novel RGD and TAT co-modified docetaxel (DTX)-loaded liposome (LP) by the emulsification-solvent evaporation method. The prepared LPs were found to be in the size of 100 nm-110 nm. The transmission electron microscope photomicrographs were smooth, sub-spherical in shape, and aggregated to form small clusters. The DTX cumulative release from TAT and RGD co modified LPs was significantly higher than that from other LPs due to decreased diffusion distance. Results of cell uptake showed that surface modification could indicate when cell internalization was changed and more drugs entered the cells successfully. Surprisingly, TAT and RGD co-modified DTX-LPs demonstrated a superior antiproliferative effect on A549 cells with a possible mechanism that suppressed the multidrug resistance phenomenon and exhibited a clear synergistic effect. In antitumor study, our results indicated that the form of TAT and RGD co modified LPs had a better antitumor effect in vivo than the other formulations. PMID- 29255350 TI - Involvement of poly(ADP-ribose) polymerase-1 in development of spinal cord injury in Chinese individuals: a Chinese clinical study. AB - Objective: We aimed to evaluate whether the polymorphism of poly(ADP-ribose) polymerase-1 (PARP-1) is involved as potential risk factor in the development of spinal cord injury (SCI) among Chinese individuals. Patients and methods: Patients with a confirmed diagnosis of SCI (other than traumatic injury) and healthy individuals with no clinical symptoms of SCI were enrolled at Spinal Cord Injury Care Center, The Third People's Hospital of Dalian, China. Genetic polymorphisms were studied in plasma samples by polymerase chain reaction restriction fragment length polymorphism assay. Results: A total of 130 Chinese patients with SCI and 130 healthy Chinese individuals were included. We found that patients with the GG genotype (odds ratio [OR]: 4.09, 95% confidence interval [CI] 2.42-6.90, P<0.001) and carriers of the G allele (OR 3.96, 95% CI 2.33-6.74, P<0.0001) were at high risk of developing SCI. A del/ins polymorphism of the NF-kappaB1 gene (OR 3.32, 95% CI 1.96-5.61, P<0.001) was also found to be associated with SCI. Conclusion: Our study suggests that PARP-1 polymorphisms are involved in the development of SCI in Chinese individuals. Thus, PARP-1 polymorphisms can be considered as one of the potential risk factors for developing SCI. PMID- 29255351 TI - Heart-type fatty acid binding protein levels in elderly diabetics without known cardiovascular disease. AB - Background: Cardiovascular disease (CVD) is reported to be higher in elderly diabetics. Serum heart-type fatty acid binding protein (H-FABP) is a serum marker of myocardial ischemia. We aimed to investigate the association between serum H FABP level and conventional cardiovascular risk factors, inflammatory markers and subclinical atherosclerosis in elderly diabetics without overt CVD. Patients and methods: A total of 50 elderly diabetic patients without overt CVD and 30 age-, sex- and body mass index (BMI)-matched healthy controls were enrolled. Anthropometric and biochemical parameters, serum H-FABP, high-sensitivity C reactive protein (hs-CRP), fibrinogen and carotid intima-media thickness (CIMT) were measured. Logistic regression analyses (adjustments for age, sex, hypertension, smoking, diabetes, BMI, blood pressure, lipid, blood glucose, hemoglobin A1c, hs-CRP and fibrinogen) were performed to evaluate the association between H-FABP and cardiovascular risk factors and atherosclerosis indices. Results: Serum fibrinogen (421.50+/-85.52 mg/dL vs 319.17+/-30.77 mg/dL, p=0.023), CIMT (0.70+/-0.12 mm vs 0.59+/-0.06 mm, p<0.001) and hs-CRP (5.72+/ 4.50 mg/dL vs 1.60+/-0.72 mg/dL, p<0.001) were significantly higher in diabetic patients than controls. The mean serum H-FABP level did not differ between groups (1571.79+/-604.60 ng/mL vs 1500.25+/-463.35 ng/mL, p=0.905). H-FABP was positively correlated with fibrinogen (r2=0.473, p<0.001), hs-CRP (r2=0.323, p=0.003) and CIMT (r2=0.467, p<0.001). After full adjustments, the serum H-FABP level was independently associated with an increase in the fibrinogen level (odds ratio [OR] =4.21, 95% confidence level [CI] =1.49-11.90). Conclusion: Serum H FABP was similar in the elderly diabetic patients without known CVD when compared with the nondiabetic control group. H-FABP does not possess a high diagnostic value as a cardiovascular marker when used alone; however, it may add supplementary information in patients with a high fibrinogen level. PMID- 29255352 TI - Role of adipose tissue in facial aging. AB - Age-dependent modification of the facial subcutaneous white adipose tissue (sWAT) connected with reduction of its volume, modification of collagen content and adhesion between dermal and adipose layers can significantly influence mechanical stability of the skin and cause the development of aging symptoms such as wrinkles. Typical aging appearance in facial skin is at least partly connected with special phenotypical features of facial preadipocytes and mature adipocytes. In this paper, we have discussed the possible roles of local inflammation, compartmental structure of facial sWAT and trans-differentiation processes such as beiging of white adipocytes and adipocyte-myofibroblast transition in facial skin aging. PMID- 29255353 TI - Pneumococcal vaccination and chronic respiratory diseases. AB - Patients with COPD and other chronic respiratory diseases are especially vulnerable to viral and bacterial pulmonary infections, which are major causes of exacerbations, hospitalization, disease progression, and mortality in COPD patients. Effective vaccines could reduce the burden of respiratory infections and acute exacerbations in COPD patients, but what is the evidence for this? This article reviews and discusses the existing evidence for pneumococcal vaccination efficacy and its changing role in patients with chronic respiratory diseases, especially COPD. Specifically, the recent Community-Acquired Pneumonia Immunization Trial in Adults (CAPITA) showed the efficacy of pneumococcal conjugate vaccine in older adults, many of whom had additional risk factors for pneumococcal disease, including chronic lung diseases. Taken together, the evidence suggests that pneumococcal and influenza vaccinations can prevent community-acquired pneumonia and acute exacerbations in COPD patients, while pneumococcal vaccination early in the course of COPD could help maintain stable health status. Despite the need to prevent pulmonary infections in patients with chronic respiratory diseases and evidence for the efficacy of pneumococcal conjugate vaccine, pneumococcal vaccine coverage and awareness are low and need to be improved. Respiratory physicians need to communicate the benefits of vaccination more effectively to their patients who suffer from chronic respiratory diseases. PMID- 29255355 TI - Doxofylline is not just another theophylline! AB - Doxofylline, which differs from theophylline in containing the dioxalane group at position 7, has comparable efficacy to theophylline in the treatment of respiratory diseases, but with an improved tolerability profile and a favorable risk-to-benefit ratio. Furthermore, it does not have significant drug-drug interactions as exhibited with theophylline, which make using theophylline more challenging, especially in elderly patients with co-morbidities receiving multiple classes of drug. It is now clear that doxofylline also possesses a distinct pharmacological profile from theophylline (no significant effect on any of the known phosphodiesterase isoforms, no significant adenosine receptor antagonism, no direct effect on histone deacetylases, interaction with beta2 adrenoceptors) and therefore, should not be considered as just a modified theophylline. Randomized clinical trials of doxofylline to investigate the use of this drug to reduce exacerbations and hospitalizations due to asthma or COPD as an alternative to expensive biologics, and certainly as an alternative to theophylline are to be encouraged. PMID- 29255354 TI - The impact of dual bronchodilation on cardiovascular serious adverse events and mortality in COPD: a quantitative synthesis. AB - Objective: Long-acting beta2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are burdened by the potential risk of inducing cardiovascular serious adverse events (SAEs) in COPD patients. Since the risk of combining a LABA with a LAMA could be greater, we have carried out a quantitative synthesis to investigate the cardiovascular safety profile of LABA/LAMA fixed-dose combinations (FDCs). Methods: A pair-wise and network meta-analysis was performed by using the data of the repository database ClinicalTrials.gov concerning the impact of approved LABA/LAMA FDCs versus monocomponents and/or placebo on cardiovascular SAEs in COPD. Results: Overall, LABA/LAMA FDCs did not significantly (P>0.05) modulate the risk of cardiovascular SAEs versus monocomponents. However, the network meta-analysis indicated that aclidinium/formoterol 400/12 ug and tiotropium/olodaterol 5/5 ug were the safest FDCs, followed by umeclidinium/vilanterol 62.5/25 ug which was as safe as placebo, whereas glycopyrronium/formoterol 14.9/9.6, glycopyrronium/indacaterol 15.6/27.5 ug, and glycopyrronium/indacaterol 50/110 ug were the least safe FDCs. No impact on mortality was detected for each specific FDC. Conclusion: This meta analysis indicates that LABA/LAMA FDC therapy is characterized by an excellent cardiovascular safety profile in COPD patients. However, the findings of this quantitative synthesis have been obtained from populations that participated in randomized clinical trials, and were devoid of major cardiovascular diseases. Thus, post-marketing surveillance and observational studies may help to better define the real impact of specific FDCs with regard to the cardiovascular risk. PMID- 29255356 TI - Predictive value of ADAMTS-13 on concealed chronic renal failure in COPD patients. AB - Background: Impaired renal function is often neglected in COPD patients. Considering that COPD patients usually have an ongoing prothrombotic state and systemic inflammation status, we investigated the association among them and explored the predictive value of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), on concealed chronic renal failure (CRF) in COPD patients. Methods: COPD patients were recruited from the First Affiliated Hospital of Sun Yat-Sen University between January 2015 and December 2016. Control was selected from contemporaneous hospitalized patients without COPD and matched by age and gender at a ratio of 1:1. Estimated glomerular filtration rate (eGFR) was calculated by using the Chronic Kidney Disease Epidemiology Collaboration formula, and all subjects were categorized as having normal renal function (eGFR >=60 mL min-1 1.73 m-2) and having concealed CRF (normal serum creatinine while eGFR <60 mL min-1 1.73 m-2). Independent correlates of concealed CRF were investigated by logistic regression analysis, and receiver operating characteristic (ROC) curves were used to determine the predictive value of ADAMTS-13. Results: In total, 106 COPD and 106 non-COPD patients were finally recruited, and the incidences of concealed CRF were 19.81% and 7.55%, respectively. ADAMTS-13 (odds ratio [OR] =0.858, 95% CI =0.795-0.926), D-dimer (OR =1.095, 95% CI =1.027-1.169), and C-reactive protein (OR =1.252, 95% CI =1.058-1.480) were significantly associated with concealed CRF. Sensitivity and specificity at an ADAMTS-13 cutoff of 318.72 ng/mL were 100% and 81.2%, respectively. The area under the ROC curve was 0.959. Conclusion: Prothrombotic state and systemic inflammation status might contribute to explaining the high incidence of concealed CRF in COPD, and plasma ADAMTS-13 levels may serve as a strong predictor. PMID- 29255357 TI - Zinc deficiency as a codeterminant for airway epithelial barrier dysfunction in an ex vivo model of COPD. AB - There is now convincing evidence that the airway epithelium drives the pathogenesis of COPD. A major aspect of this is the disease-related reduction in barrier function that is potentiated by dysregulation of tight junction (TJ) protein complexes. However, a significant number of studies using in vitro smoke exposure models have not observed alterations in barrier permeability. We have previously shown that zinc (Zn) is an influential cytoprotective factor for the airway epithelium, and its depletion by cigarette smoke produces disease-related modifications consistent with inflammatory changes in COPD. We hypothesized that Zn deficiency is a significant co-stimulus with cigarette smoke extract (CSE) for potentiating the leaky barrier phenotype exhibited in COPD. We employed an ex vivo model of differentiated human airway epithelium exposed to Zn depletion and CSE to determine the contribution of Zn in maintaining normal epithelial permeability. Western blot analysis demonstrated a significant downregulation of the TJ proteins such as ZO-1 (-1.93-fold, P<0.05) and Claudin-1 (-3.37-fold, P<0.01) with the combination exposure. Assessment of barrier function via paracellular ionic conductance and tracer permeability also showed that Zn depletion was an important factor, which potentiated an increase in epithelial permeability (P<0.001 for both) compared to Zn depletion or CSE exposures in isolation. Visual inspection of the epithelium using transmission electron microscopy revealed a marked reduction in junction complexes between the adjacent airway epithelial cells treated with a combination of Zn depletion and CSE. These observations identify Zn deficiency as a significant codeterminant with CSE as a factor leading to an increase in airway epithelial permeability. Hence, as Zn dyshomeostasis has been reported in the airway epithelium exposed to chronic cigarette smoke and inflammation, targeting these phenomena may represent a promising strategy to ameliorate the leaky barrier phenotype that is synonymous with COPD. PMID- 29255358 TI - Metabolic changes of different high-resolution computed tomography phenotypes of COPD after budesonide-formoterol treatment. AB - Background: Metabolomics is the global unbiased analysis of all the small molecule metabolites within a biological system. Metabolic profiling of different high-resolution computed tomography (HRCT) phenotypes of COPD patients before and after treatment may identify discriminatory metabolites that can serve as biomarkers and therapeutic agents. Patients and methods: 1H nuclear magnetic resonance spectroscopy (1H-NMR)-based metabolomics was performed on a discovery set of plasma samples from 50 patients with stable COPD. Patients were assigned into two groups on the basis of HRCT findings including phenotype E (n=22) and phenotype M (n=28). After budesonide-formoterol treatment (160/4.5 ug *2 inhalations twice daily for 3 months), clinical characteristics and metabolites were then compared between phenotype E pretreatment and posttreatment, phenotype M pretreatment and posttreatment, phenotype E pretreatment and phenotype M pretreatment, and phenotype E posttreatment and phenotype M posttreatment. Results: Inhaled budesonide-formoterol therapy for both phenotype E (emphysema without bronchial wall thickening) and phenotype M (emphysema with bronchial wall thickening) was effective. However, phenotype E and phenotype M were different in response to therapy. Patients with phenotype M in response to therapeutic effects were significantly greater compared with phenotype E. Certain metabolites were identified, which were closely related to the treatment and phenotype. Metabolic changes in phenotype E or phenotype M after treatment may be involved with adenosine diphosphate (ADP), guanosine, choline, malonate, tyrosine, glycine, proline, l-alanine, l-valine, l-threonine leucine, uridine, pyruvic acid, acetone and metabolism disturbance. Metabolic differences between phenotype E and phenotype M in pretreatment and posttreatment covered glycine, d-glucose, pyruvic acid, succinate, lactate, proline, l-valine and leucine. Conclusion: Bronchial wall thickening in COPD may be an indicator for predicting the better response to the treatment with bronchodilator and corticosteroid. The identification of metabolic alterations provides new insights into different HRCT phenotypes and therapeutic assessment of COPD. PMID- 29255359 TI - Pullulan-coated phospholipid and Pluronic F68 complex nanoparticles for carrying IR780 and paclitaxel to treat hepatocellular carcinoma by combining photothermal therapy/photodynamic therapy and chemotherapy. AB - IR780, a near-infrared dye, can also be used as a photosensitizer both for photothermal therapy (PTT) and photodynamic therapy (PDT). In this study, we designed a simple but effective nanoparticle system for carrying IR780 and paclitaxel, thus hoping to combine PTT/PDT and chemotherapy to treat hepatocellular carcinoma (HCC). This nanosystem, named PDF nanoparticles, consisted of phospholipid/Pluronic F68 complex nanocores and pullulan shells. IR780 and paclitaxel were loaded separately into PDF nanoparticles to form PDFI and PDFP nanoparticles, which had regular sphere shapes and relatively small sizes. Upon near-infrared laser irradiation at 808 nm, PDFI nanoparticles showed strong PTT/PDT efficacy both in vitro and in vivo. In MHCC-97H cells, the combined treatment of PDFI nanoparticles/laser irradiation and PDFP nanoparticles exhibited significant synergistic effects on inhibiting cell proliferation and inducing cell apoptosis and cell cycle arrest at G2/M phase. In MHCC-97H tumor bearing mice, PDFI nanoparticles exhibited excellent HCC-targeting and accumulating capability after intravenous injection. Furthermore, the combined treatment of PDFI nanoparticles/laser irradiation and PDFP nanoparticles also effectively inhibited the tumor growth and the tumor angiogenesis in MHCC-97H tumor-bearing mice. In summary, we put forward a therapeutic strategy for HCC treatment by combining PTT/PDT and chemotherapy. PMID- 29255362 TI - Mortality risk factors during readmission at the Department of Medicine. AB - Background: Readmission is an indicator of quality of inpatient care. A study from Hong Kong found readmission mortality rate to be 5.1%. There are limited reports on risk factors for mortality other than co-morbid diseases in readmission patients. This study, thus, aims to evaluate risk factors for mortality during readmission. Methods: This study was conducted at a university hospital in Thailand. The inclusion criteria were patients aged >=15 years and readmission to internal medicine wards within 28 days after discharge. The outcome of the study was death during readmission. Risk factors for readmission mortality were analyzed using multivariate logistic regression analysis. Results: There were 10,389 admissions to the Department of Medicine, Khon Kaen University, of which 407 required readmission (3.90%). Of those patients, 75 (18.43%) died during readmission. There were 6 independent factors associated with death in patients who were readmitted, including advanced age (>60 years), presence of more than 2 co-morbid diseases, admission duration of >14 days, fever at previous discharge, low hemoglobin (<12 g/dL), and having undergone over 5 procedures. Conclusion: Older age, co-morbid diseases, readmission duration, presence of low hemoglobin at previous discharge, and numbers of procedures at readmission were significantly associated with increased mortality risk for readmission patients. PMID- 29255361 TI - Potential link between genetic polymorphisms of catechol-O-methyltransferase and dopamine receptors and treatment efficacy of risperidone on schizophrenia. AB - Objective: The current study aimed to explore the association of single nucleotide polymorphisms (SNPs) within catechol-O-methyltransferase (COMT) and dopamine receptors with schizophrenia and genetic association with risperidone treatment response. Methods: A total of 690 schizophrenic patients (case group) were selected and 430 healthy people were included as the controls. All patients received risperidone treatment continuously for 8 weeks. Next, peripheral venous blood samples were collected and were subjected to polymerase chain reaction restriction fragment length polymorphism to amplify and genotype the SNPs within COMT and dopamine receptors. Then, correlation analysis was conducted between Positive and Negative Syndrome Scale improvement rates and SNPs within COMT and the dopamine receptor gene. Results: The allele of DRD1 rs11749676 (A) emerged as a key element in reducing schizophrenia risk with statistical significance (P<0.001). Remarkably, alleles of COMT rs165774 (G), DRD2 rs6277 (T), and DRD3 rs6280 (C) were associated with raised predisposition to schizophrenia (all P<0.001). Regarding DRD1 rs11746641, DRD1 rs11749676, DRD2 rs6277, and DRD3 rs6280, the case group exhibited a lesser frequency of heterozygotes in comparison with wild homozygotes genotype (all P<0.001). SNPs (COMT rs4680, DRD2 rs6275, DRD2 rs1801028, and DRD2 rs6277) were remarkably associated with improvement rates of PANSS total scores (P<0.05). SNPs (COMT rs165599 and DRD2 rs1801028) were significantly associated with risperidone efficacy on negative symptoms (P<0.05). Conclusion: COMT SNPs and dopamine receptor SNPs were correlated with prevalence of schizophrenia and risperidone treatment efficacy of schizophrenia. PMID- 29255360 TI - Screening for mild cognitive impairment in patients with cardiovascular risk factors. AB - Aim: Cardiovascular risk factors are also risk factors for cognitive impairment. They have cumulative effect in target organ damage. The precise correlation between cardiovascular risk factors and cognitive impairment, as well as assessing the extent to which they may affect cognitive functioning, is difficult to ascertain in everyday clinical practice. Quick, specific, and sensitive neuropsychological tests may be useful in screening for, and the prophylaxis of, target organ damage in hypertensive patients. Methods: We gathered full anamnesis, performed physical examination, laboratory screening and echocardiography. These variables were observed at office and home for all patients, For half of the patients, 24-hour ambulatory blood pressure monitoring and neuropsychological testing using Montreal Cognitive Assessment (MoCA), Mini Mental State Examination (MMSE), Geriatric Depression Scale, and the 4 instrumental activities of daily living scale were undertaken. Results: For a period of 2 years, 931 patients were included after applying the inclusion and exclusion criteria. The mean age was 65.90+/-10.00 years. Two hundred and sixty three patients (85 [32.32%] males and 178 [67.68%] females) were reevaluated after a mean follow-up period of 12 months (6-20 months). The mean results of MoCA and MMSE were significantly lower (p<0.05) in the group of patients with poorly controlled blood pressure and cardiovascular risk factors. There was mild to intermediate negative correlation between Systematic Coronary Risk Evaluation (SCORE) and the neuropsychological tests' results. Conclusion: Cardiovascular risk factors play an important role for the development of cognitive impairment in the eastern European population because of their high frequency and interaction. The use of easily applicable neuropsychological tests in everyday clinical practice of specialties other than neurology may help in stratifying the risk for development and progression of mild cognitive impairment in this high risk group. PMID- 29255363 TI - A qualitative study examining methods of accessing and identifying research relevant to clinical practice among rehabilitation clinicians. AB - Purpose: Research examining the utilization of evidence-based practice (EBP) specifically among rehabilitation clinicians is limited. The objective of this study was to examine how various rehabilitative clinicians including physical therapists, occupational therapists, rehabilitation counselors, and physiatrists are gaining access to literature and whether they are able to implement the available research into practice. Methods: A total of 21 total clinicians were interviewed via telephone. Using NVivo, a qualitative analysis of the responses was performed. Results: There were similarities found with respect to the information-seeking behaviors and translation of research across the different clinician types. Lack of time was reported to be a barrier for both access to literature and implementation of research across all clinician types. The majority of clinicians who reported having difficulty with utilizing the published literature indicated that the literature was not applicable to their practice, the research was not specific enough to be put into practice, or the research found was too outdated to be relevant. In addition, having a supportive work environment aided in the search and utilization of research through providing resources central to assisting clinicians in gaining access to health information. Conclusion: Our study identified several barriers that affect EBP for rehabilitation clinicians. The findings suggest the need for researchers to ensure that their work is applicable and specific to clinical practice for implementation to occur. PMID- 29255364 TI - The burden of family caregiving in the United States: work productivity, health care resource utilization, and mental health among employed adults. AB - Background: Family caregiving is an increasingly important component of care for patients and the elderly. Objective: The aim of this study is to characterize the burden of family caregiving among employed adults. Methods: Employed adults (>=18 years) from the 2013 US National Health and Wellness Survey (NHWS) were classified as family caregivers if they reported currently caring for at least one adult relative. Chi-square tests and one-way analyses of variance assessed whether employed caregivers, weighted to the US population, differed from employed non-caregivers on behavioral characteristics, workplace productivity, and health care resource utilization. Results: Eight million workers were family caregivers in the United States, more often female than male (51% vs. 49%, P < 0.05), and 53% were between 40 and 64 years of age. Eighteen percent of caregivers were Hispanic compared with 15% of non-caregivers (P < 0.05). Similar behavioral characteristics between caregivers and non-caregivers included daily alcohol consumption (6% vs. 5%) and lack of vigorous exercise (25% vs. 29%), but caregivers had a higher prevalence of smoking (26% vs. 19%, P < 0.05). Caregivers reported a higher mean percentage of work time missed (8% vs. 4%, P < 0.05) and greater productivity impairment (24% vs. 14%, P < 0.05). Some form of depression was reported by 53% of caregivers compared with 32% of non-caregivers (P < 0.05), and more caregivers had self-reported insomnia than non-caregivers (46% vs. 37%, P < 0.05). The number of self-reported diagnosed comorbidities was higher among caregivers compared with that of non-caregivers (5.0 vs. 3.1, P < 0.05), as was the mean number of outpatient visits in the previous 6 months (4.1 vs. 2.7, P < 0.05). Conclusion: Family caregiving is associated with a multidimensional burden that impacts caregivers and has implications for employers and the health care system. Clinicians and employers need to recognize and understand this burden. Characterization of caregivers as reported in this study can inform development of targeted programs to help mitigate the burden. PMID- 29255365 TI - Impact of aristolochic acid exposure on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. AB - Objective: To investigate the effect of aristolochic acids (AA) exposure, including exposure duration and years since last exposure, on oncologic outcomes of patients with upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). Methods: We retrospectively collected clinicopathologic and AA exposure variables for 942 UTUC patients treated with RNU between 1999 and 2014 in a high-volume center of China. AA exposure duration was categorized as (>3 vs <=3 years) and time since last AA exposure to surgery as (>5 vs <=5 years). Results: A total of 856 patients (90.9%) had none or possible AA exposure and 86 patients (9.1%) had credible AA exposure history. Among the 86 patients, 57 (66.3%) had AA exposure for <=3 years and 29 (33.7%) had exposure for >3 years. The median follow-up duration was 60 months. By multivariate analysis, AA exposure history was significantly associated with cancer specific survival (hazard ratio [HR]: 0.43, p=0.02), intravesical recurrence (IVR) (HR: 2.25, p<0.001) and contralateral UTUC recurrence (HR: 2.71, p=0.001). After adjusted for the effects of standard clinicopathologic characteristics, exposure duration was independent risk factor for subsequent IVR (exposure duration <=3 years vs none/possible AA, HR: 1.87, p=0.009; exposure duration >3 years vs none/possible AA, HR: 3.07, p<0.001), but not for cancer-specific survival (p=0.06). Also, of those patients who had AA exposure, those having exposure within 5 years prior to RNU did not differ from patients having last exposure >5 years ago regarding cancer specific mortality (p=0.67) and IVR (p=0.54). Conclusion: AA exposure was associated with worse cancer-specific survival, higher rate of IVR and contralateral UTUC recurrence of UTUC treated with RNU. The association between AA exposure and IVR seems to be time-dependent. Exposure cessation >5 years prior to RNU cannot mitigate the impact of AA on the UTUC prognosis. PMID- 29255366 TI - CircRNA_100782 regulates pancreatic carcinoma proliferation through the IL6-STAT3 pathway. AB - Circular RNAs (circRNAs) are a novel class of noncoding RNAs that play an important role in cancer. However, the mechanisms by which circRNAs regulate gene expression in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study seeks to elucidate the role that circRNAs play in the proliferation of PDAC cells. On the basis of previous studies of circRNA expression profiles in PDAC, we found that the circRNA_100782 was markedly upregulated in PDAC tissue. Functional experiments revealed that circRNA_100782 down-regulation inhibited BxPC3 cell proliferation and colony formation. Loss-of-function studies showed that knockdown of circRNA_100782 inhibited cell proliferation by downregulating the microRNA-124 (miR-124) target genes interleukin-6 receptor (IL6R) and signal transducer and activator of transcription 3 (STAT3). Overexpression of miR-124 also inhibited BxPC3 cell proliferation by reducing the expression of IL6R and STAT3, which was consistent with the result of silencing circRNA_100782. In addition, luciferase assay revealed that miR-124 was a direct target of circRNA_100782. Silencing STAT3 inhibited BxPC3 cell proliferation and colony formation. Cell viability was reduced in BxPC3 cells treated with si circRNA_100782 and miR-124 mimic, and this effect could be attenuated by activating STAT3. In vivo study validated that circRNA_100782 knockdown suppressed BxPC3 xenografts in nude mice. Taken together, these results suggest that circRNA_100782 regulates BxPC3 cell proliferation by acting as miR-124 sponge through the IL6-STAT3 pathway. PMID- 29255367 TI - "De-escalation" strategy using micafungin for the treatment of systemic Candida infections: budget impact in France and Germany. AB - Background: The incidence of azole-resistant Candida infections is increasing. Consequently, guidelines for treating systemic Candida infection (SCI) recommend a "de-escalation" strategy: initial broad-spectrum antifungal agents (e.g., echinocandins), followed by switching to fluconazole if isolates are fluconazole sensitive, rather than "escalation" with initial fluconazole treatment and then switching to echinocandins if isolates are fluconazole resistant. However, fluconazole may continue to be used as first-line treatment in view of its low acquisition costs. The aim of this study was, therefore, to evaluate the budget impact of the de-escalation strategy using micafungin compared with the escalation strategy in France and Germany. Methods: A budget impact model was used to compare de-escalation to escalation strategies. As well as survival, clinical success (resolution/reduction of symptoms and radiographic abnormalities associated with fungal infection), was considered, as was mycological success (eradication of Candida from the bloodstream). Health economic outcomes included cost per health state according to clinical success and mycological success, and budget impact. A 42-day time horizon was used. Results: For all patients with SCI, the budget impact of using de-escalation rather than escalation was greater, but improved rates of survival, clinical success and mycological success were apparent with de-escalation. In patients with fluconazole-resistant isolates, clinical success rates and survival were improved by ~72% with de-escalation versus escalation, producing cost savings of ?6,374 and ?356 per patient in France and Germany, respectively; improvements of ~72% in mycological success rates with de-escalation versus escalation did not translate into cost savings. Conclusion: Modeling provides evidence that when treating SCI in individuals at risk of azole-resistant infections, de-escalation from micafungin has potential cost savings associated with improved clinical success rates. PMID- 29255368 TI - Effect of different doses of statins on the development of type 2 diabetes mellitus in patients with myocardial infarction. AB - Background: Cardiovascular diseases and type 2 diabetes mellitus (T2DM) may have common developmental mechanisms associated with lipid metabolism disorders. Dyslipidemia and progression of atherosclerosis in people with T2DM are accompanied by an increase in cardiovascular mortality. This study examined the dose-dependent action of atorvastatin on carbohydrate metabolism and adipokine status in patients within 12 months after myocardial infarction (MI). Methods: A total of 156 male MI patients who had received atorvastatin 20 mg/day (78 patients) or 40 mg/day (78 patients) starting from day 1 of onset were enrolled. Glucose, insulin, C-peptide, resistin, adiponectin, and ghrelin levels were measured at baseline, day 12, and months 3 and 12. Patients were monitored for new incidences of T2DM for 12 months after MI. Results: For acute phase MI, patients had moderate insulin resistance, hyperglycemia, and hyper-insulinemia, high leptin and resistin levels, and low ghrelin and adiponectin levels. Atorvastatin 20 mg/day was more effective at correcting the imbalances. Patients taking atorvastatin 40 mg/day (group 2) following MI showed increases in levels of glucose, insulin, and C-peptide and insulin resistance progression after 12 months of therapy, as evidenced by increased quantitative insulin sensitivity check index scores and detection of new T2DM cases. Conclusion: Atorvastatin improved adipokine profiles and ghrelin levels, with low doses showing more significant effects. Atorvastatin dose prescribed for MI patients should take into account the degree of insulin resistance and adipokine status. PMID- 29255369 TI - Transition from pre-diabetes to diabetes and predictors of risk in Mexican Americans. AB - Background: No studies have examined risk factors for the transition from pre diabetes to diabetes in populations with widespread obesity and diabetes. We determined proximal changes and factors affecting the transition among Mexican Americans with pre-diabetes. Methods: Participants with pre-diabetes (n=285) were recruited from our randomly sampled population-based Cameron County Hispanic Cohort. These participants were followed for an average of 27 months with repeat examination every 3 to 4 months. Metabolic health was defined as having less than 2 metabolic abnormalities (e.g., hypertension, elevated low-density lipoprotein, etc). Diabetes was identified as fasting blood glucose >=126 mg/dL, glycated hemoglobin >=6.5% and/or on hypoglycemic medication. Results: Ninety-six of 285 (33.7%) participants transitioned to overt diabetes. The increased risk of diabetes in the metabolically unhealthy varying with follow-up time was 81% (adjusted odds ratio [OR]: 1.81; 95% CI: 1.09-3.02). The risk of diabetes increased 8% for each kg/m2 of increase in body mass index (BMI, OR: 1.08; 95% CI: 1.05-1.11) independent of covariates. Transition to diabetes was accompanied by a mean increase in BMI of 0.28 kg/m2, and deterioration in metabolic health of 9% (OR: 1.09; 95% CI: 1.003-1.18) compared with those who did not transition. Conclusions: Deteriorating metabolic health and/or increasing BMI significantly raises the risk of transitioning from pre-diabetes to diabetes. Transition itself was accompanied by further increase in BMI and deterioration in metabolic health. These data underline the importance of improving metabolic health and avoiding weight gain in pre-diabetes as simple but clear diabetes prevention targets, and emphasize the importance of lifestyle management. PMID- 29255371 TI - Ethiopian health care professionals' knowledge, attitude, and interests toward pharmacogenomics. AB - Background: Pharmacogenomics is a field of science which studies the impact of inheritance on individual variation in medication therapy response. Aim: We assessed healthcare professionals' knowledge, attitude, and interest toward pharmacogenomics. Methods: A cross-sectional survey was conducted using a 32-item questionnaire among physicians, nurses, and pharmacists who were working at the University of Gondar Referral and Teaching Hospital in northwest Ethiopia. Descriptive statistics was applied, and the categorical variables were summarized as frequency and percentages. An analysis of variance (ANOVA) test was performed to compare mean scores among health professionals. A p-value of <0.05 was considered as statistically significant. Results: Of 292 health professionals who responded, the majority were male (60%) and the mean age of study participants was 27.00 (+/-4.85 SD) years. The mean knowledge scores of all participants, pharmacists, physicians, and nurses were 2.343+/-1.109, 2.671+/-1.059, 2.375+/ 1.093, and 2.173+/-1.110, respectively. Based on the ANOVA test, a statistically significant difference was noted in mean knowledge score between pharmacists and nurses (p=0.002). More than two-thirds (67.33%) of nurses, 42.86% of pharmacists, and 40.27% of physicians who participated did not know that genetic variations can account for as much as 95% of the variability in drug disposition and effects. The ability to accurately apply their knowledge to drug therapy selection, dosing, or monitoring parameter was reported by 35.3% of the participants. More than two-thirds (69.2%) of participants thought that pharmacogenomic testing will allow the identification of the right drug with less side effects. Most of the participants (83.2%) also requested to have training on pharmacogenomics. Conclusion: Participants showed limited knowledge, but they had positive attitude toward pharmacogenomics. Educational programs focusing on pharmacogenomic testing and its clinical application need to be emphasized. PMID- 29255370 TI - The association between stress and acne among female medical students in Jeddah, Saudi Arabia. AB - Introduction: Although there is widespread acceptance of a relationship between stress and acne, not many studies have been performed to assess this relationship. The objective of this study was to determine the relationship between stress and acne severity. Methods: A cross-sectional study was conducted among 144 6th year female medical students 22 to 24 years in age attending the medical faculty at King Abdulaziz University. This study used the global acne grading system (GAGS) to assess acne severity in relation to stress using the Perceived Stress Scale (PSS). The questionnaire also included some confounding factors involved in acne severity. Results: The results indicated an increase in stress severity strongly correlated with an increase in acne severity, which was statistically significant (p<0.01). Subjects with higher stress scores, determined using the PSS, had higher acne severity when examined and graded using the GAGS. Conclusion: On the basis of this study, it is concluded that stress positively correlates with acne severity. PMID- 29255373 TI - Sites of metastasis and overall survival in esophageal cancer: a population-based study. AB - Background: There are few population-based studies of the sites of distant metastasis (DM) and survival from esophageal cancer (EC). The aim of this study was to assess the patterns and survival outcomes for site-specific DM from EC using a population-based approach. Methods: Patients diagnosed with de novo stage IV EC between 2010 and 2014 were identified from the Surveillance, Epidemiology, and End Results program database. Overall survival (OS) was compared according to the site of DM. Results: We included 3218 patients in this study; the most common site of DM was the liver, followed by distant lymph nodes, lung, bone and brain. Median OS for patients with liver, distant lymph node, lung, bone, and brain metastases was 5, 10, 6, 4, and 6 months, respectively (p<0.001). Site and number of distant metastases were independent prognostic factors for OS. In patients with a single site of DM, using liver metastases as reference, OS was lower for bone metastases (p=0.026) and higher for distant lymph node metastases (p=0.008), while brain (p=0.653) or lung (p=0.081) metastases had similar OS compared with liver metastases. Similar site-specific survival differences were observed in the subgroup with esophageal adenocarcinoma. However, distant lymph node metastases was associated with better survival (p=0.002) compared to liver, bone, or lung metastases in esophageal squamous cell carcinoma. Conclusion: Site of metastasis affects survival in metastatic EC; OS was worst for bone metastases and greatest for distant lymph node metastases. PMID- 29255372 TI - Spatial-temporal signature of resting-state BOLD signals in classic trigeminal neuralgia. AB - Resting-state functional magnetic resonance imaging (R-fMRI) signals are spatiotemporally organized. R-fMRI studies in patients with classic trigeminal neuralgia (CTN) have suggested alterations in functional connectivity. However, far less attention has been given to investigations of the local oscillations and their frequency-specific changes in these patients. The objective of this study was to address this issue in patients with CTN. R-fMRI data from 17 patients with CTN and 19 age- and gender-matched healthy controls (HCs) were analyzed using amplitude of low-frequency fluctuation (ALFF). The ALFF was computed across different frequencies (slow-4: 0.027-0.073 Hz; slow-5: 0.01-0.027 Hz; and typical band: 0.01-0.08 Hz) in patients with CTN compared to HCs. In the typical band, patients with CTN showed increases of ALFF in bilateral temporal, occipital, and left middle frontal regions and in the left middle cingulate gyrus, as well as decreases of ALFF in the right inferior temporal region and in regions (medial prefrontal regions) of default mode network. These significant group differences were identified in different sub-bands, with greater brainstem findings in higher frequencies (slow-4) and extensive default mode network and right postparietal results in lower frequencies (slow-5). Furthermore, significant relationships were found between subjective pain ratings and both amplitudes of higher frequency (slow-4) blood oxygen level-dependent (BOLD) signals in pain localization brain regions and lower frequencies (slow-5) in pain signaling/modulating brain regions in the patients, and decreased ALFF within the prefrontal regions was significantly correlated with pain duration in the patients. This result supports our hypothesis that trigeminal pain has a characteristic spatiotemporal distribution of low-frequency BOLD signals. These findings might contribute to a better understanding of the impact of CTN on the brain's intrinsic architecture. Future studies should take the frequencies into account when measuring brain resting BOLD signals of patients with CTN. PMID- 29255374 TI - Impact of patient demographics, tumor characteristics, and treatment type on treatment delay throughout breast cancer care at a diverse academic medical center. AB - Purpose and objective: The aim of this study was to examine the impact of patient demographics, tumor characteristics, and treatment type on time to treatment (TTT) in patients with breast cancer treated at a safety net medical center with a diverse patient population. Patients and methods: A total of 1,130 patients were diagnosed and treated for breast cancer between 2004 and 2014 at our institution. We retrospectively collected data on patient age at diagnosis, race/ethnicity, primary language spoken, marital status, insurance coverage, American Joint Committee on Cancer (AJCC) stage, hormone receptor status, and treatment dates. TTT was determined from the date of breast cancer biopsy to treatment start date. Nonparametric Mann-Whitney U-test (or Kruskal-Wallis test when appropriate) and multivariable quantile regression models were employed to assess for significant differences in TTT associated with each factor. Results: Longer median TTT was noted for Black (P=0.002) and single (P=0.002) patients. AJCC stage IV patients had shorter TTT (27.5 days) compared to earlier AJCC patients (36, 35, 37, 37 days for stage 0, I, II, III, respectively), P=0.028. Age, primary language spoken, insurance coverage, and hormone receptor status had no significant impact on TTT. On multivariate analysis, race/ethnicity remained the only significant factor with Black reporting longer TTT, P=0.025. However, race was not a significant factor for time from first to second treatment. More Black patients were noted to be single (P<0.0001) and received chemotherapy as first treatment (P=0.008) compared to White, Hispanic, or other race/ethnicity patients. Conclusion: In this retrospective analysis, Black patients had longer TTT, were more likely to receive chemotherapy as first treatment, and have a single marital status. These patient factors will help identify vulnerable patients and guide further research to understand the barriers to care and the impact of treatment delays on outcomes. PMID- 29255375 TI - Acute alcohol effects on facial expressions of emotions in social drinkers: a systematic review. AB - Background: As known from everyday experience and experimental research, alcohol modulates emotions. Particularly regarding social interaction, the effects of alcohol on the facial expression of emotion might be of relevance. However, these effects have not been systematically studied. We performed a systematic review on acute alcohol effects on social drinkers' facial expressions of induced positive and negative emotions. Materials and methods: With a predefined algorithm, we searched three electronic databases (PubMed, PsycInfo, and Web of Science) for studies conducted on social drinkers that used acute alcohol administration, emotion induction, and standardized methods to record facial expressions. We excluded those studies that failed common quality standards, and finally selected 13 investigations for this review. Results: Overall, alcohol exerted effects on facial expressions of emotions in social drinkers. These effects were not generally disinhibiting, but varied depending on the valence of emotion and on social interaction. Being consumed within social groups, alcohol mostly influenced facial expressions of emotions in a socially desirable way, thus underscoring the view of alcohol as social lubricant. However, methodical differences regarding alcohol administration between the studies complicated comparability. Conclusion: Our review highlighted the relevance of emotional valence and social-context factors for acute alcohol effects on social drinkers' facial expressions of emotions. Future research should investigate how these alcohol effects influence the development of problematic drinking behavior in social drinkers. PMID- 29255376 TI - Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature. AB - Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is a universal event and limits clinical efficacy. The third generation EGFR inhibitor osimertinib is active in EGFR-mutant/T790M positive non small-cell lung cancer. Mechanisms of acquired resistance are emerging, and here we describe a cis-oriented solvent-front EGFR G796S mutation as the resistance mechanism observed in a progression biopsy and circulating tumor DNA (ctDNA) from a patient with initial response followed by progression on osimertinib. This is one of the earliest reports of a sole solvent-front tertiary EGFR mutation as a resistance mechanism to osimertinib. Our case suggests a monoclonal resistance mechanism. We review the importance of the solvent-front residues across TKIs and describe known osimertinib resistance mechanisms. We observe that nearly all clinical osimertinib-resistant tertiary EGFR mutations are oriented in cis with EGFR T790M. This case highlights the importance of mutations affecting EGFR kinase domains and supports the feasibility of broad panel ctDNA assays for detection of novel acquired resistance and tumor heterogeneity in routine clinical care. PMID- 29255377 TI - Breast tuberculosis: a report of five cases. AB - Background: Breast tuberculosis is a rare form of extrapulmonary tuberculosis with clinical and radiological misleading presentations. We report herein a retrospective study of clinicopathological features of five cases of breast tuberculosis collected at Hassan II University Hospital of Fes, Morocco, a country where tuberculosis is endemic. Case presentation: The mean age was 40.6 years (range of 21-59 years). Two patients presented with abscessed lesions, and three cases presented with breast lumps with a suspicion of malignancy on imaging techniques. The diagnosis has been made on histological specimens (3 biopsy specimens, 1 excisional biopsy, and 1 lumpectomy). All patients have been successfully treated after the completion of the standard antibiotherapy. Conclusions: Our current study shows that the breast is rarely affected by tuberculosis even in endemic area. The clinical presentation is often misleading, and the histopathological analysis constitutes a valuable diagnostic tool. The prognosis of breast tuberculosis is good after treatment by a standard antibiotherapy. PMID- 29255378 TI - The human, F-actin-based cytoskeleton as a mutagen sensor. AB - Background: Forty years ago the actin cytoskeleton was determined to be disrupted in fibroblasts from persons with DNA repair-defective, hereditary colon cancer, with no clear connection between the cytoskeleton and DNA repair defects at that time. Recently, the large number of sequenced genomes has indicated that mammalian mutagenesis has a large stochastic component. As a result, large coding regions are large mutagen targets. Cytoskeletal protein-related coding regions (CPCRs), including extra-cellular matrix proteins, are among the largest coding regions in the genome and are indeed very commonly mutated in cancer. Methods: To determine whether mutagen sensitivity of the actin cytoskeleton could be assessed experimentally, we treated tissue culture cells with 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone and quantified overall cytoskeleton integrity with rhodamine phalloidin stains for F-actin. Results: The above approach indicated cytoskeletal degradation with increasing mutagen exposure, consistent with increased mutagenesis of CPCRs in TCGA, smoker samples, where overall mutation rates correlate with CPCR mutation rates (R2 = 0.8694; p < 0.00001). In addition, mutagen exposure correlated with a decreasing cell perimeter to area ratio, raising questions about potential decreasing, intracellular diffusion and concentrations of chemotherapy drugs, with increasing mutagenesis and decreasing cytoskeleton integrity. Conclusion: Determination of cytoskeletal integrity may provide the opportunity to assess mutation burdens in nonclonal cell populations, such as in intact tissues, where DNA sequencing for heterogeneous mutation burdens can be challenging. PMID- 29255379 TI - Maintaining RNA Integrity for Transcriptomic Profiling of Ex Vivo Cultured Limbal Epithelial Stem Cells after Fluorescence-Activated Cell Sorting (FACS). AB - Background: Transcriptomic profiling of ex vivo cultured human limbal epithelial stem cells (hLESCs) will foster better understanding of corneal physiology and novel treatment paradigms to limbal stem cell deficiency (LSCD). However, currently such profiling studies are hampered due to difficulties with producing sufficient amounts of intact mRNA for deep RNA sequencing (RNA-seq) from subpopulations sorted on the basis of co-expression of membrane and intracellular antigens by fluorescence-activated cell sorting (FACS). Methods: To address this problem, we systematically analyzed the critical steps, and found that ethanol fixation together with optimized downstream procedures provided a pipeline that yielded high quality total RNA in amounts to readily support the RNA-seq procedure, while still preserving good discrimination between the individual hLESC immunophenotypes. Results: The average RNA integrity number (RIN) was 7.7 +/- 0.4, and the average yield was 4.6 +/- 1.7 pg of RNA per cell. The sequencing analysis of the isolated RNA produced high quality data with more than 70% of read pairs mapping uniformly to the reference genome and 80% of bases with a Phred score of at least 30. Conclusion: In this study, we developed a reliable FACS-based procedure using ethanol as a fixative that would support accurate isolation of limbal epithelial progenitor subpopulations along with RNA yield and quality sufficient to enable deep transcriptomic profiling. PMID- 29255380 TI - Hybrid identification and genetic variation of Elymus sibiricus hybrid populations using EST-SSR markers. AB - Background: Elymus sibiricus is an important native grass in Qinghai-Tibetan Plateau. Seed shattering is a serious problem for E. sibiricus, especially at harvest time. Cross breeding is an effective way to create new varieties with beneficial characteristic or improved traits, and to broaden genetic base. Results: In this study, we created five hybrid populations by crossing seven E. sibiricus genotypes that have seed shattering variation. Then, nine EST-SSR primers were used for hybrid identification based on DNA fingerprinting, and genetic diversity analysis of hybrid populations and their respective parents. A total of 15 hybrids were identified. An analysis of amplified polymorphic bands among genuine hybrids and their respective parents revealed mainly two types of markers: 1) hybrids shared bands exclusively amplified in both parents; 2)hybrids shared bands exclusively amplified in male parents. For each hybrid population, the total number of amplified bands ranged from 37 to 57, the percentage of polymorphism varied from 65.12% to 75.68%, with an average of 70.51%. Novel bands found in each hybrid population varied from 0 to 9 bands, suggesting an occurrence of rearrangements in the hybrid population. The structure analysis revealed that all hybrid populations and parents were assigned to eight groups. The principal coordinate analysis (PCoA) showed similar results. Conclusions: In general, this study proved EST-SSR markers are efficient for hybrid identification, and suggested more genetic variation could be captured in hybrid populations by crossing breeding. PMID- 29255382 TI - New bioactive triterpenoids and antimalarial activity of Diospyros rubra Lec. AB - The first investigation of the chemical constituents and bioactivities of Diospyros rubra Lec. is reported. D. rubra extracts were screened for antimicrobial, antimalarial and cytotoxic activities. They were only shown to be active antimalarials. The extracts with good antimalarial activity were isolated and extensively purified to give lupeol (1), lupenone (2), betulin (3), lupeol acetate (4), 28-O-acetylbetulin (5), beta-sitosteryl-3-O-beta-D-glucopyranoside (6) and a mixture of beta-sitosterol and stigmasterol. Some of the isolates were tested for antimicrobial and cytotoxic actions. Betulin (3) displayed antimicrobial activity against Streptococcus pyogenes with a minimum inhibitory concentration (MIC) of 85 MUg/mL. Interestingly, bioactive fractions all selectively exerted some antimicrobial activity against Corynebacterium diphtheriae NCTC 10356 with the MIC range of 64-256 MUg/mL. The study provides data to support the medicinal importance of the D. rubra. PMID- 29255384 TI - Identification of protein types in Bambara nut seeds: Perspectives for dietary protein supply in developing countries. AB - This study aims to identify the types of proteins in malted and dry Bambara groundnut seeds and through a comparative analysis, identify similarities and their known uses. Dry viable bambara seed was stored for five days to malt. The proteins in the dry and malted seed were subsequently extracted in potassium phosphate buffer pH 7.0 and precipitated with saturated ammonium sulphate. MudPit (multidimensional protein identification technology) and LC-MALDI TOF-TOF (liquid chromatography - matrix-assisted laser desorption ionization tandem time-of flight) mass spectrometry were thereafter used to identify the different types of proteins. A total of ten and twelve different types of proteins present in other legume species were identified in the malted and dry seeds respectively from the 214 peptides isolated after searching 586 proteins of the genus Vigna. Seed storage protein B and vicilin were observed to be the major proteins common to both malted and dry seeds and are similar to Vigna luteola. Some of the other proteins observed showed amino acid sequence homology with Vigna radiata and Vigna unguiculata species. The following proteins BV1, Heat shock and Bowman-Birk Inhibitor (a protease), were observed only in the malted state. This information may enhance the appreciation of the nutritional and health benefits of the seed. PMID- 29255383 TI - N-methyl-D-aspartate receptor NR1 subunit gene (GRIN1) G1001C polymorphism and susceptibility to schizophrenia: A meta-analysis. AB - A comprehensive literature search was conducted to identify all case-control studies investigating the association between GRIN1 G1001C polymorphism and schizophrenia susceptibility (MIM: 138249; dbSNP: rs 11146020). A total of 6 eligible studies (including 1639 schizophrenia cases and 1489 controls) were identified for the meta-analysis. Including all studies, there was significant heterogeneity between studies. In overall the GC (OR=1.00, 95 % CI: 0.0.85-1.19) and CC (OR=1.09, 95 % CI: 0.67-1.79) genotypes were not associated with schizophrenia risk compared with the GG genotype. In one study patients were diagnosed using DSM-IIIR criteria and in another study the genotypic frequencies of control subjects showed significant deviation from the expected frequencies according to the Hardy-Weinberg equilibrium. After excluding these studies from the meta-analysis, the heterogeneity between studies dramatically decreased. Statistical analysis showed that the GC genotype compared with the GG genotype significantly increased the risk of schizophrenia (OR=1.85, 95 % CI: 1.43-2.42, P<0.0001). The CC versus GG genotype significantly increased the schizophrenia risk (OR=2.46, 95% CI: 1.17-6.84, P=0.017). There was significant linear trend for presence of 0, 1, and 2 of the C allele and risk of schizophrenia (chi2=25.45, P<0.0001). In conclusion, the C variant allele may be associated with an increased risk for developing schizophrenia. PMID- 29255385 TI - Prediction of relative solvent accessibility by support vector regression and best-first method. AB - Since, it is believed that the native structure of most proteins is defined by their sequences, utilizing data mining methods to extract hidden knowledge from protein sequences, are unavoidable. A major difficulty in mining bioinformatics data is due to the size of the datasets which contain frequently large numbers of variables. In this study, a two-step procedure for prediction of relative solvent accessibility of proteins is presented. In a first "feature selection" step, a small subset of evolutionary information is identified on the basis of selected physicochemical properties. In the second step, support vector regression is used to real value prediction of protein solvent accessibility with these custom selected features of evolutionary information. The experiment results show that the proposed method is an improvement in average prediction accuracy and training time. PMID- 29255381 TI - Endocrine disrupting compounds exposure and testis development in mammals. AB - In the last few decades, there is substantial evidence that male reproductive function is deteriorating in humans and wildlife and this is associated with unintentional exposure to widely used synthetic chemicals. Subsequently, much has been done to show that certain chemicals in the environment adversely interfere with the developing fetal gonads of the laboratory animals. Some in vitro studies have demonstrated treatment-induced reproductive problems in offspring exposed to endocrine disrupting compounds (EDC) which are similar to those observed in wildlife and human population. Few EDC studies have demonstrated that there are certain periods of gestation when the developing fetus is highly sensitive and at risk of small endocrine changes. Similar observations have been made in the sewage sludge model, however, while animal studies have been insightful in providing valuable information about the range of effects that can be attributed to in utero exposure to EDCs, varying levels of maternal doses administered in different studies exaggerated extrapolation of these results to human. Thus the EDC concentration representative of fetal exposure levels is uncertain because of the complexities of its nature. So far, the level of fetal exposure can only be roughly estimated. There is substantial evidence from animal data to prove that EDCs can adversely affect reproductive development and function in male and more has accumulated on the mechanisms by which they exert their effects. This paper therefore, reviews previous studies to highlight the extent to which testis development can be disrupted during fetal life. PMID- 29255386 TI - Changes in haematological indices and protein concentrations in Trypanosoma brucei infected rats treated with homidium chloride and diminazene aceturate. AB - Anaemia and immunosuppresion have been shown to be a cardinal feature in African trypanosomosis. In this study, we have evaluated and compared the capacity of two registered veterinary trypanocides Novidium(r) (homidium chloride) and Berenil(r) (diminazene aceturate) to reduce haematological and biochemical lesions in rats experimentally infected with T. brucei. Packed cell volume (PCV), lymphocyte and eosinophil values in infected negative control group were significantly different and lower compared to positive control group as well as infected animals treated with homidium chloride and diminazene aceturate (P<0.05). Also the white blood cell (WBC) and neutrophil counts in the negative control group were lower and significantly different from the other groups indicating evidence of infection induced immunosuppresion. Haematological indices in infected rats treated with homidium chloride and diminazene aceturate were higher (P<0.05) than obtained in infected negative control group and significantly different from positive control (P<0.05). Total protein and albumin concentrations in infected negative control group were higher and significantly different from control and treated animals (P<0.05). In contrast, significantly lower values were obtained for albumin concentrations in treated animals compared to both negative and positive control groups (P<0.05). Results suggest that drugs administered have capacity to improved blood components as well as reverse immunosuppressive action of infecting trypanosomes. PMID- 29255387 TI - Effect of spironolactone on pain responses in mice. AB - The effects of spironolactone, a non-selective aldosterone antagonist, were examined on thermally-induced pain using the hot-plate and tail-flick tests, on chemogenic pain induced by intraplantar capsaicin, on electrically-induced pain, on visceral nociception induced by intraperitoneal acetic acid injection and on haloperidol-induced catalepsy in mice. Spironolactone significantly shortened response latency in the mouse tail-flick test but produced modest decreases in response latencies in the mouse hot plate test. The drug reduced the antinociceptive effect of tramadol in the hot plate test. Spironolactone in addition decreased nociceptive thresholds of electrically-induced pain in mice. In contrast, spironolactone elicited significant antinociceptive actions in the mouse acetic-acid-induced writhing assay and at doses of 20-160 mg/kg decreased capsaicin-induced chemogenic pain. Spironolactone at doses of 40 or 80 mg/kg reduced spontaneous activity and produced a significant impairment on the rotarod test in mice. The drug (10-80 mg/kg) increased the duration of catalepsy induced by haloperidol by 56.3-188.5 %. In conclusion, spironolactone increased pain behavior in a dose-dependent manner in models of thermal and electrical pain, but decreased inflammatory visceral pain due to intraperitoneal acetic acid and chemogenic pain due to intraplantar capsaicin. The effect of spironolactone on various types of pain needs further evaluation. PMID- 29255388 TI - Evaluation of CD4+ T cells in HIV patients presenting with malaria at the University of Ilorin Teaching Hospital Nigeria. AB - CD4 count is an important immunological marker of disease progression in HIV seropositive patients. This study was carried out to determine the effect of malaria or fever of unknown origin on the population of CD4+ T lymphocytes of HIV seropositive patients attending the highly active antiretroviral therapy (HAART) clinic of the University of Ilorin Teaching Hospital, Ilorin, Nigeria. 36 subjects were selected for this study. Ongoing history of fever was used as a case definition for malaria and malaria was confirmed from microscopic examination of thick and thin film of blood sample obtained from the patients during presentation with fever. The CD4 count was evaluated during presentation of fever and post-fever using flow cytometry. There was significant decrease in CD4 count of the patients. However, upon classifying the patients into 2 groups - those that returned to the clinic after a week and those that returned after a month; a significant increase in CD4 count was noticed in the group that returned after a week, while a significant decrease was noticed in the group that returned after a month (at p value of 95 %). Further classification of the patients based on presence of malaria parasite, and body temperature resulted in varying effects on CD4 count post-fever (in the general group, 27 were positive for malaria parasites). Of these 27, there was an increase in CD4 count in 9 (33.3 %). However in the group that returned after a week, all 6 (100 %) that were positive for malaria parasites showed increase in CD4 count. Five (26.3 %) of the 19 patients that had body temperature within the range of 35.5-37.4 degrees C showed an increase in CD4 count, while 7 (41.2 %) of the 17 patients that had body temperature of 37.5 degrees C and above showed an increase in CD4 count. The results led to the conclusion that while some components of the immune response to malaria could strengthen the immune system of HIV seropositive patients by increasing their CD4 count, other components will suppress their immunity by decreasing their CD4 count, accelerating the progression to AIDS. PMID- 29255389 TI - G-CSF mobilized PBMCs contribute to the liver function of cirrhotic rats. AB - On the basis of the recently recognized potential of bone marrow stem cells to give rise to hepatocytes, we here investigated the role of G-CSF priming PBMCs played in the liver of cirrhotic rats. The animal model of liver cirrhosis was induced by injecting CCl4 in SD rats, and G-CSF was administered in hematopoietic stem cell mobilization doses. After the liver cirrhosis model was established, the female cirrhotic rats were divided into two groups. Group I only received G CSF mobilization, group II received G-CSF mobilized PBMCs transplanted from the male cirrhotic rats. PKH26 staining and sex-determining region for the Y chromosome gene were used to trace the transplanted cells. Liver function related factors were assayed under the animal automatic biochemistry analyzer, and the liver pathological changes were evaluated by HE staining. The comparative liver functions of the two groups were investigated by analysis of two sample t-tests. A P value of <0.05 was considered as significant in all analyses. Our results showed that the transplanted PBMCs could locate in the livers of the female rats. In addition, compared with the group I, rats in group II displayed significant liver improvement in serum ALB, ALT, AST and TBIL (p<0.05). However, the semi quantitative classification of the liver pathological changes in both groups did not indicate a significant difference (p>0.05). The results indicated that mobilized PBMC transplant could contribute to liver function in cirrhotic livers, which might be an alternative therapy for liver cirrhosis. PMID- 29255390 TI - Offspring sex ratio at birth and maternal breast cancer risk: A case-control study and meta-analysis of literature. AB - To investigate whether offspring sex ratio at birth (SRB) was associated with maternal breast cancer risk, the present case-control study and a meta-analysis of literature were done. A total of 389 female breast cancer patients who had at least one offspring participated in the study. From general population 356 healthy female were selected as a control group. Control subjects were frequency matched with patients according to age and number of offspring. Among control group, 1324 offspring (666 males, 658 females) and within families of the breast cancer patients 1326 offspring (648 males, 678 females) were identified. There was no difference for SRB between breast cancer patients and control subjects (P>0.05). Meta-analysis was performed using 7 eligible studies. There was significant heterogeneity between studies (P<0.05). In overall the SRB was negatively associated with the maternal breast cancer risk (OR=0.95; 95 % CI: 0.92-0.99, P=0.02). Menopausal status of the patients was not associated with offspring SRB (P=0.07). Further researches are needed to determine the possible association between gender of offspring and maternal breast cancer risk. PMID- 29255391 TI - Data mining of magnetocardiograms for prediction of ischemic heart disease. AB - Ischemic Heart Disease (IHD) is a major cause of death. Early and accurate detection of IHD along with rapid diagnosis are important for reducing the mortality rate. Magnetocardiogram (MCG) is a tool for detecting electro physiological activity of the myocardium. MCG is a fully non-contact method, which avoids the problems of skin-electrode contact in the Electrocardiogram (ECG) method. However, the interpretation of MCG recordings is time-consuming and requires analysis by an expert. Therefore, we propose the use of machine learning for identification of IHD patients. Back-propagation neural network (BPNN), the Bayesian neural network (BNN), the probabilistic neural network (PNN) and the support vector machine (SVM) were applied to develop classification models for identifying IHD patients. MCG data was acquired by sequential measurement, above the torso, of the magnetic field emitted by the myocardium using a J-T interval of 125 cases. The training and validation data of 74 cases employed 10-fold cross validation methods to optimize support vector machine and neural network parameters. The predictive performance was assessed on the testing data of 51 cases using the following metrics: accuracy, sensitivity, and specificity and area under the receiver operating characteristic (ROC) curve. The results demonstrated that both BPNN and BNN displayed the highest and the same level of accuracy at 78.43 %. Furthermore, the decision threshold and the area under the ROC curve was -0.2774 and 0.9059, respectively, for BPNN and 0.0470 and 0.8495, respectively, for BNN. This indicated that BPNN was the best classification model, BNN was the best performing model with sensitivity of 96.65 %, and SVM employing the radial basis function kernel displayed the highest specificity of 86.36 %. PMID- 29255392 TI - Impact of various lecture delivery methods in pharmacology. AB - The aim of the study was to assess the impact of three common lecture delivery methods viz. the lectures using chalkboard, the lectures using PowerPoint presentations and the lectures utilizing transparencies with an overhead projector. By filling in a questionnaire, the second year MBBS students were asked to assess the impact of three pharmacology lectures given by three different methods of lecture delivery. Also after each lecture an objective test was given to compare the impact of the lecture delivered by different methods. The results of the study show that as per the subjective assessment of the lectures, students preferred PowerPoint teaching the most. As far as the students' performance is concerned the impact of traditional Chalkboard and PowerPoint teaching was much more than the lectures using transparency and overhead projector (OHP). PMID- 29255393 TI - A new sulfoxide analog of 1,2,3,6-tetrahydrophenylpyridine and antimicrobial activity. AB - Bioactivities of thiotetrahydropyridines were previously described. Herein, a novel bioactive sulfoxide analog; N-acetyl-2-(1-adamantylsulfoxo)-3-acetoxy-4 phenyl-6-hydroxy-1,2,3,6-tetrahydropyridine (3) from the deoxydative substitution of 4-phenylpyridine 1-oxide is reported. Its structure was elucidated using spectral data including 2D-NMR, MS, IR and UV. The sulfoxide 3 exhibited antibacterial activity against Moraxella catarrhalis and Streptococcus pyogenes with minimum inhibitory concentration of 128 and 256 ug/mL, respectively. PMID- 29255394 TI - Proteomic alterations of Escherichia coli by paraquat. AB - Paraquat (PQ; a widely used herbicide) exerts its harmful effect to human, mammals and microorganisms upon intracellular conversion to superoxide radical. Cellular responses against toxic paraquat remain not fully understood, especially on the adaptive metabolic changes as a consequence of oxidative burden. In this study, alterations of metabolic processes of Escherichia coli (E. coli) by paraquat were systematically investigated by two-dimensional gel electrophoresis (2-DE) in conjunction with peptide mass fingerprinting (PMF). In host cells, the first line mechanism was scrutinized by a remarkable induction of endogenous superoxide dismutase (E. coli SOD). The second line involved in the metabolic adaptation and compensation for energy production by up- or down-regulation of the enzymes implicated in glycolysis and tricarboxylic acid cycle. Notably, down regulation of aconitase enzyme and changes of enzyme isoform from the acidic (pI~5.29) to the higher basidic form (pI~5.59) were detected. Meanwhile, up regulation of fumarase approximately 4-5 folds were observed. Importantly, overexpression of human manganese superoxide dismutase (human Mn-SOD) in E. coli cells could in turn down-regulate the expression of fumarase enzyme. This observation was not found when the cells expressing human catalase were tested. Other mechanisms such as changes of purine nucleoside phosphorylase and protein transporters (D-ribose-binding protein and oligopeptide binding protein) were also accounted. However, among all the differentially expressed proteins, the fumarase enzyme is evidenced to be a major target responsible for superoxide generating paraquat, which may further be applied as a potential biomarker for paraquat toxicity in the future. PMID- 29255396 TI - Fast protein classification by using the most significant pairs. AB - This study introduces a new approach to speed up the protein classification process. The basic idea is rewriting the sequences of each family by using the most significant pairs, where the total number of the pairs that can be appeared in the protein sequences is 400 different pairs. The sequence length could be reduced to 0.86, 0.91 and 0.95 by using the most 100, 200 and 300 significant pairs, respectively. The average time reduction is 0.53 %, 0.33 % and 0.22 % for 100, 200, and 300 pairs, respectively. In the three cases the suggested procedure can be adopted to speed up the testing time. However to get identical classification rate to the previous profile HMM, 300 pairs at least must be used. PMID- 29255395 TI - Melatonin protects against alterations in hippocampal cholinergic system, trace metals and oxidative stress induced by gestational and lactational exposure to cadmium. AB - Dietary exposure to cadmium, even at lower doses, can lead to free radical induced neurotoxicity, neurobehavioral changes and alteration in neurotransmitters. Such changes are likely to be more pronounced in the developing brain due to incompleteness of blood brain barrier (BBB). Hippocampus being the seat of intelligence has a role in learning and cognitive behavior and any damage to hippocampus during developmental stage is likely to result in neurodegenerative changes in later life. To this end, fetal and neonatal exposure to cadmium was induced by exposing pregnant dams of Swiss albino strain throughout the period of gestation and following parturition up till 5th day post partum (pp) through drinking water (3ppm/animal/day). The neonates were sacrificed on day 6 pp and indices of oxidative stress, levels of trace elements and changes in cholinergic system were evaluated in the hippocampus. Increased lipid peroxidation, surge in reactive oxygen species (ROS), depressed antioxidant defense, increased accumulation of cadmium, differential alterations in trace elements and decreased activity of AChE were the features of cadmium toxicity. Simultaneous administration of melatonin to cadmium challenged animals offset these detrimental changes. The results suggest that melatonin co-administration can effectively protect against the adverse effects of cadmium on endogenous antioxidant status, changes in trace metal concentrations and compromised hippocampal cholinergic system. PMID- 29255398 TI - Isolation of 3-(4-hydroxyphenyl) methylpropenoate and bioactivity evaluation of Gomphrena celosioides extracts. AB - The efficacy of Gomphrenacelosioides extracts in traditional medicine in the treatment of infectious diseases was evaluated by biological assays. The bioactivities of the extracts of this plant were tested against organisms. The ethyl acetate and methanol extracts of the plant displayed inhibition activities on Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Escherichia coli and Salmonella typhi. Methanol extract was active against Candida albicans, Aspergillus niger and Trichophyton species with diameter zones of inhibition between 14 and 20 mm. Fractionation of the methanol extract produced 3-(4 hydroxyphenyl) methylpropenoate with mild antimicrobial activity against the test microorganisms. The anthelmintic assay showed ethyl acetate and methanol extracts to be active against Fasciola gigantica,Taenia solium and Pheretimapasthuma. Ethyl acetate was the most toxic of the extracts causing paralysis of Taenia solium within 15 minutes and the death of Fasciola gigantica within 20 minutes of application. The brine shrimp assay gave an LC50 of 52.15 and 77.98 ug/ml on hexane and methanol extracts respectively. The result of this work corroborated the folkloric use of Gomphrenacelosioides in the treatment of infectious diseases. PMID- 29255397 TI - Human paraoxonase 2. AB - Human paraoxonase 2 (PON2), which is a member of the paraoxonase family, possesses unique properties that distinguish it from PON1 and PON3. PON2 is ubiquitously expressed in many different tissue types and is highly expressed in the vital organs, such as the heart and lungs. Early research revealed that PON2 is exclusively intracellularly found, wherein it functions as an anti-oxidative protein by reducing intracellular and local oxidative stress. Studies in the last five years have demonstrated that PON2 protects against atherosclerosis by preventing low-density lipoprotein (LDL) oxidation, reversing the oxidation of mildly oxidised LDL, inhibiting monocyte chemotaxis, and increasing cholesterol efflux. Recently, emerging evidence has proposed that PON2 is an anti atherosclerotic and may be associated with cardiovascular disease (CVD). The number of investigations concerning the relationship between two common PON2 polymorphisms and CVD among different ethnic groups and regions is rapidly growing. Here, we briefly review the developments in PON2 research by focusing on past and recent findings. PMID- 29255399 TI - Hepatoprotective effects of methanolic extract and fractions of African mistletoe Tapinanthus bangwensis (Engl. & K. Krause) from Nigeria. AB - Methanolic extract and fractions, ethylacetate (EtF) and butanol (BuF) of leaves of African mistletoe (Tapinanthus bangwensis, Engl. & K. Krause) were evaluated for their hepatoprotective potential using CCl4-induced hepatotoxicity in Wistar albino rats. The activities of the marker enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and bilirubin were highest in rats treated with CCl4 alone. Oral administration at a fixed dose of 400 mg/kg body weight (BW) of the extract and fractions of T. bangwensis for seven days significantly (p <= 0.05) decreased the activity of marker enzymes and bilirubin. Total protein concentration increased significantly (p <= 0.05). These extracts also decreased the concentration of thiobarbituric acid reactive substances (TBARS) which indicated a reduction in lipid peroxidation. Histopathological examination of hepatocytes of rats administered methanolic extract (MeE) and fractions (EtF and BuF) showed normal architecture whereas rats treated with CCl4 alone was characterized by necrosis of the liver. Generally, among the three extracts, the BuF and EtF showed more hepatoprotective effect. The crude methanolic extract did not show any mortality up to a dose of 2000 g/kg BW. These findings suggest that T. bangwensis possesses strong antioxidant properties and hepatoprotective potentials against CCl4-induced hepatotoxicity in rats. PMID- 29255400 TI - Differential vascular cell adhesion molecule-1 expression and superoxide production in simulated microgravity rat vasculature. AB - Exposure to microgravity leads to orthostatic intolerance in astronauts and differential vascular structural and functional adaptations have been implicated in its occurrence. The present study tended to clarify the characteristics of vascular inflammation and oxidative stress in hindlimb unweighting (HU) rat vasculature. Male Sprague-Dawley rats were randomly divided into control (CON) and hindlimb unweighting (HU) groups. Three weeks later, immunohistochemistry was used to localize the expression of vascular cell adhesion molecule-1 (VCAM-1) and laser scanning confocal microscope were used to detect superoxide production. Immunohistochemical results revealed positive staining of VCAM-1 on endothelial cells in HU rat basilar and carotid arteries compared with CON, but not in abdominal aorta and femoral arteries. Meanwhile, HU increased O2.- levels in all the layers of basilar and carotid arteries from HU rat but not in abdominal aorta and femoral arteries from HU rat. These data suggested that differential expression of VCAM-1 and O2.- production were concomitant with the vascular adaptations to simulated microgravity and whether they participate in vascular structure and function remodeling merits further investigation. PMID- 29255401 TI - Matrix-producing metaplastic breast carcinoma - a rare tumor with heterologous elements. AB - Metaplastic breast carcinomas are ductal carcinomas that undergo metaplasia into non-glandular growth patterns. They are very rare and account for less than 1% of all invasive breast carcinomas. Matrix-producing carcinoma is an extremely rare and aggressive subtype of metaplastic breast carcinoma that is characterized by a ductal carcinomatous component with direct transition to areas with cartilaginous/osseous differentiation without an intervening spindle cell element. It has a better prognosis than metaplastic carcinoma. Even though these tumors are composed of a mixture of infiltrating ductal carcinomas and areas of heterologous stroma, each of which behaves aggressively individually, these composite tumors have a better 5-year survival rate with rare nodal metastasis. Immunohistochemically, they are positive for keratin, epithelial membrane antigen and S100. The tumor, which is matrix-producing, is S100-reactive and nonreactive for cytokeratin. They are usually hormone receptor-negative. The average age of these patients is approximately 58 years. Since these tumors are usually triple negative, chemotherapy after surgery is the mainstay of therapy, using either mastectomy or local excision. Our report highlights this rare entity in a 55-year old female patient with matrix-producing metaplastic breast carcinoma. Its distinctive histological features and peculiar clinical behavior warrants clear knowledge about this unique entity. PMID- 29255402 TI - Effect of Different References on Auditory-Evoked Potentials in Children with Cochlear Implants. AB - Background: Nose reference (NR), mastoid reference (MR), and montage average reference (MAR) are usually used in auditory event-related potential (AEP) studies with a recently developed reference electrode standardization technique (REST), which may reduce the reference effect. For children with cochlear implants (CIs), auditory deprivation may hinder normal development of the auditory cortex, and the reference effect may be different between CIs and a normal developing group. Methods: Thirteen right-side-CI children were recruited, comprising 7 males and 6 females, ages 2-5 years, with CI usage of ~1 year. Eleven sex- and age-matched healthy children were recruited for normal controls; 1,000 Hz pure tone evoked AEPs were recorded, and the data were re-referenced to NR, left mastoid reference (LMR, which is the opposite side of the implanted cochlear), MAR, and REST. CI artifact and P1-N1 complex (latency, amplitudes) at Fz were analyzed. Results: Confirmed P1-N1 complex could be found in Fz using NR, LMR, MAR, and REST with a 128-electrode scalp. P1 amplitude was larger using LMR than MAR and NR, while no statistically significant difference was found between NR and MAR in the CI group; REST had no significant difference with the three other references. In the control group, no statistically significant difference was found with different references. Group difference of P1 amplitude could be found when using MR, MAR, and REST. For P1 latency, no significant difference among the four references was shown, whether in the CI or control group. Group difference in P1 latency could be found in MR and MAR. N1 amplitude in LMR was significantly lower than NR and MAR in the control group. LMR, MAR, and REST could distinguish the difference in the N1 amplitude between the CI and control group. Contralateral MR or MAR was found to be better in differentiating CI children versus controls. No group difference was found for the artifact component. Conclusions: Different references for AEP studies do not affect the CI artifact. In addition, contralateral MR is preferable for P1-N1 component studies involving CI children, as well as methodology-like studies. PMID- 29255403 TI - Classifying the Perceptual Interpretations of a Bistable Image Using EEG and Artificial Neural Networks. AB - In order to classify different human brain states related to visual perception of ambiguous images, we use an artificial neural network (ANN) to analyze multichannel EEG. The classifier built on the basis of a multilayer perceptron achieves up to 95% accuracy in classifying EEG patterns corresponding to two different interpretations of the Necker cube. The important feature of our classifier is that trained on one subject it can be used for the classification of EEG traces of other subjects. This result suggests the existence of common features in the EEG structure associated with distinct interpretations of bistable objects. We firmly believe that the significance of our results is not limited to visual perception of the Necker cube images; the proposed experimental approach and developed computational technique based on ANN can also be applied to study and classify different brain states using neurophysiological data recordings. This may give new directions for future research in the field of cognitive and pathological brain activity, and for the development of brain computer interfaces. PMID- 29255404 TI - Loss of CIB2 Causes Profound Hearing Loss and Abolishes Mechanoelectrical Transduction in Mice. AB - Calcium and integrin-binding protein 2 (CIB2) belongs to a protein family with four known members, CIB1 through CIB4, which are characterized by multiple calcium-binding EF-hand domains. Among the family members, the Cib1 and Cib2 genes are expressed in mouse cochlear hair cells, and mutations in the human CIB2 gene have been associated with nonsyndromic deafness DFNB48 and syndromic deafness USH1J. To further explore the function of CIB1 and CIB2 in hearing, we established Cib1 and Cib2 knockout mice using the clustered regularly interspaced short palindromic repeat (CRISPR)-associated Cas9 nuclease (CRISPR/Cas9) genome editing technique. We found that loss of CIB1 protein does not affect auditory function, whereas loss of CIB2 protein causes profound hearing loss in mice. Further investigation revealed that hair cell stereocilia development is affected in Cib2 knockout mice. Noticeably, loss of CIB2 abolishes mechanoelectrical transduction (MET) currents in auditory hair cells. In conclusion, we show here that although both CIB1 and CIB2 are readily detected in the cochlea, only loss of CIB2 results in profound hearing loss, and that CIB2 is essential for auditory hair cell MET. PMID- 29255405 TI - Corrigendum: On the Basis of Synaptic Integration Constancy during Growth of a Neuronal Circuit. AB - [This corrects the article on p. 198 in vol. 10, PMID: 27587998.]. PMID- 29255406 TI - Using the Optical Fractionator to Estimate Total Cell Numbers in the Normal and Abnormal Developing Human Forebrain. AB - Human fetal brain development is a complex process which is vulnerable to disruption at many stages. Although histogenesis is well-documented, only a few studies have quantified cell numbers across normal human fetal brain growth. Due to the present lack of normative data it is difficult to gauge abnormal development. Furthermore, many studies of brain cell numbers have employed biased counting methods, whereas innovations in stereology during the past 20-30 years enable reliable and efficient estimates of cell numbers. However, estimates of cell volumes and densities in fetal brain samples are unreliable due to unpredictable shrinking artifacts, and the fragility of the fetal brain requires particular care in handling and processing. The optical fractionator design offers a direct and robust estimate of total cell numbers in the fetal brain with a minimum of handling of the tissue. Bearing this in mind, we have used the optical fractionator to quantify the growth of total cell numbers as a function of fetal age. We discovered a two-phased development in total cell numbers in the human fetal forebrain consisting of an initial steep rise in total cell numbers between 13 and 20 weeks of gestation, followed by a slower linear phase extending from mid-gestation to 40 weeks of gestation. Furthermore, we have demonstrated a reduced total cell number in the forebrain in fetuses with Down syndome at midgestation and in intrauterine growth-restricted fetuses during the third trimester. PMID- 29255408 TI - Gamma and Beta Oscillations in Human MEG Encode the Contents of Vibrotactile Working Memory. AB - Ample evidence suggests that oscillations in the beta band represent quantitative information about somatosensory features during stimulus retention. Visual and auditory working memory (WM) research, on the other hand, has indicated a predominant role of gamma oscillations for active WM processing. Here we reconciled these findings by recording whole-head magnetoencephalography during a vibrotactile frequency comparison task. A Braille stimulator presented healthy subjects with a vibration to the left fingertip that was retained in WM for comparison with a second stimulus presented after a short delay. During this retention interval spectral power in the beta band from the right intraparietal sulcus and inferior frontal gyrus (IFG) monotonically increased with the to-be remembered vibrotactile frequency. In contrast, induced gamma power showed the inverse of this pattern and decreased with higher stimulus frequency in the right IFG. Together, these results expand the previously established role of beta oscillations for somatosensory WM to the gamma band and give further evidence that quantitative information may be processed in a fronto-parietal network. PMID- 29255409 TI - Frontal Alpha Asymmetry, a Potential Biomarker for the Effect of Neuromodulation on Brain's Affective Circuitry-Preliminary Evidence from a Deep Brain Stimulation Study. AB - Neuromodulation techniques targeting limbic circuits can be used to treat refractory psychiatric or neurological disorders. However, objective measure for the impact of neuromodulation on affective brain circuits is lacking. Deep brain stimulation at a key node of the limbic circuit, the anterior thalamic nuclei (ANT-DBS), is used to treat refractory epilepsy. While effective in reducing seizures, patients have reported subjective depressive symptoms as a side effect. In line with potential vulnerability to depression, we have previously shown ANT DBS to increase attention allocation to threat evidenced by behavior and brain physiology. Rightward frontal alpha asymmetry with greater right hemispheric activation is thought to reflect brain physiology linked with depression and anxiety. To that end, we investigated whether high-frequency electric stimulation at ANT influences frontal alpha asymmetry. Furthermore, we explored the impact of DBS on emotional modulation of frontal alpha asymmetry and whether it is linked with emotional modulation of response speed. Electrical stimulation at ANT led to an increased rightward frontal alpha asymmetry compared to situations where stimulation was off (F(1,12) = 14.09, p = 0.003) or the thalamic control location was stimulated (F(1,12) = 10.19, p = 0.008), along with prolonged reaction times in the context of emotional distractors (F(1,7) = 16.66, p = 0.005). The change was specifically driven by increased activity in the right hemisphere. Furthermore, we found a correlation between the emotional modulation of frontal alpha asymmetry and emotional interference of response speed due to ANT stimulation (r = 0.78, p = 0.02). In conclusion, DBS at ANT increased relative right hemispheric activity and this was linked with emotional modulation of behavior. Previous studies have linked frontal alpha asymmetry with emotion related symptoms and furthermore, Vagus Nerve Stimulation (VNS) has been shown to modulate alpha asymmetry. Thus, in the light of the previous literature and the current findings, we suggest that frontal alpha asymmetry along with emotional interference of response speed might be a feasible biomarker for the effects of neuromodulation on brain's affective circuitry in general. PMID- 29255410 TI - Intra-Subject Consistency during Locomotion: Similarity in Shared and Subject Specific Muscle Synergies. AB - Human locomotion is a complex motor task. Previous research hypothesized that muscle synergies reflect the modular control of muscle groups operated by the Central Nervous System (CNS). Despite the high stride-to-stride variability characterizing human gait, most studies analyze only a few strides. This may be limiting, because the intra-subject variability of motor output is neglected. This gap could be filled by recording and analyzing many gait cycles during a single walking task. In this way, it can be investigated if CNS recruits the same muscle synergies consistently or if different strategies are adopted during the locomotion task. The aim of this work is to investigate the intra-subject consistency of muscle synergies during overground walking. Twelve young healthy volunteers were instructed to walk for 5 min at their natural pace. On the average, 181 +/- 10 gait cycles were analyzed for each subject. Surface electromyography was recorded from 12 muscles of the dominant lower limb and the trunk. Gait cycles were grouped into subgroups containing 10 gait cycles each. The consistency of the muscle synergies extracted during the gait trial was assessed by measuring cosine similarity (CS) of muscle weights vectors, and zero lag cross-correlation (CC) of activation signals. The average intra-subject CS and CC were 0.94 +/- 0.10 and 0.96 +/- 0.06, respectively. We found five synergies shared by all the subjects: high consistency values were found for these synergies (CS = 0.96 +/- 0.05, CC = 0.97 +/- 0.03). In addition, we found 10 subject-specific synergies. These synergies were less consistent (CS = 0.80 +/ 0.20, CC = 0.89 +/- 0.14). In conclusion, our results demonstrated that shared muscle synergies were highly consistent during walking. Subject-specific muscle synergies were also consistent, although to a lesser extent. PMID- 29255411 TI - Prefrontal-Amygdala Connectivity and State Anxiety during Fear Extinction Recall in Adolescents. AB - While deficits in fear extinction recall have been suggested to underlie vulnerability to anxiety disorders in adolescents, the neurobiology of these deficits remain underexplored. Here we investigate the functional connectivity (FC) of the ventromedial prefrontal cortex (vmPFC) and dorsolateral PFC (dlPFC) underlying extinction recall in healthy adolescents, and assess associations between FC and state/trait anxiety. Adolescents (17) and adults (14, for comparison) completed a fear-learning paradigm involving extinction and extinction recall during a functional magnetic resonance imaging session, in which skin conductance response (SCR) was recorded. Psychophysiological interaction analyses revealed that during extinction recall there was significant negative connectivity between the vmPFC and amygdala in adults, but not adolescents. vmPFC-amygdala connectivity was positively correlated with SCR. Adolescents showed significant negative FC between the dlPFC and the left and right hippocampus, and the amygdala, which was positively correlated with state anxiety. Recall was also associated with negative connectivity between the dlPFC and thalamus, posterior cingulate cortex, fusiform gyrus, and pallidum in adolescents. These results demonstrate that fear extinction recall in healthy adolescents is associated with FC between prefrontal and limbic brain regions, and suggest that alterations in connectivity may be associated with vulnerability to anxiety in adolescence. PMID- 29255412 TI - Hierarchical Compliance Control of a Soft Ankle Rehabilitation Robot Actuated by Pneumatic Muscles. AB - Traditional compliance control of a rehabilitation robot is implemented in task space by using impedance or admittance control algorithms. The soft robot actuated by pneumatic muscle actuators (PMAs) is becoming prominent for patients as it enables the compliance being adjusted in each active link, which, however, has not been reported in the literature. This paper proposes a new compliance control method of a soft ankle rehabilitation robot that is driven by four PMAs configured in parallel to enable three degrees of freedom movement of the ankle joint. A new hierarchical compliance control structure, including a low-level compliance adjustment controller in joint space and a high-level admittance controller in task space, is designed. An adaptive compliance control paradigm is further developed by taking into account patient's active contribution and movement ability during a previous period of time, in order to provide robot assistance only when it is necessarily required. Experiments on healthy and impaired human subjects were conducted to verify the adaptive hierarchical compliance control scheme. The results show that the robot hierarchical compliance can be online adjusted according to the participant's assessment. The robot reduces its assistance output when participants contribute more and vice versa, thus providing a potentially feasible solution to the patient-in-loop cooperative training strategy. PMID- 29255407 TI - PACAP/Receptor System in Urinary Bladder Dysfunction and Pelvic Pain Following Urinary Bladder Inflammation or Stress. AB - Complex organization of CNS and PNS pathways is necessary for the coordinated and reciprocal functions of the urinary bladder, urethra and urethral sphincters. Injury, inflammation, psychogenic stress or diseases that affect these nerve pathways and target organs can produce lower urinary tract (LUT) dysfunction. Numerous neuropeptide/receptor systems are expressed in the neural pathways of the LUT and non-neural components of the LUT (e.g., urothelium) also express peptides. One such neuropeptide receptor system, pituitary adenylate cyclase activating polypeptide (PACAP; Adcyap1) and its cognate receptor, PAC1 (Adcyap1r1), have tissue-specific distributions in the LUT. Mice with a genetic deletion of PACAP exhibit bladder dysfunction and altered somatic sensation. PACAP and associated receptors are expressed in the LUT and exhibit neuroplastic changes with neural injury, inflammation, and diseases of the LUT as well as psychogenic stress. Blockade of the PACAP/PAC1 receptor system reduces voiding frequency in preclinical animal models and transgenic mouse models that mirror some clinical symptoms of bladder dysfunction. A change in the balance of the expression and resulting function of the PACAP/receptor system in CNS and PNS bladder reflex pathways may underlie LUT dysfunction including symptoms of urinary urgency, increased voiding frequency, and visceral pain. The PACAP/receptor system in micturition pathways may represent a potential target for therapeutic intervention to reduce LUT dysfunction. PMID- 29255413 TI - A Paleolithic Diet with and without Combined Aerobic and Resistance Exercise Increases Functional Brain Responses and Hippocampal Volume in Subjects with Type 2 Diabetes. AB - Type 2 diabetes is associated with impaired episodic memory functions and increased risk of different dementing disorders. Diet and exercise may potentially reverse these impairments. In this study, sedentary individuals with type 2 diabetes treated by lifestyle +/- metformin were randomized to a Paleolithic diet (PD, n = 12) with and without high intensity exercise (PDEX, n = 12) for 12 weeks. Episodic memory function, associated functional brain responses and hippocampal gray matter volume was measured by magnetic resonance imaging. A matched, but not randomized, non-interventional group was included as a reference (n = 6). The PD included a high intake of unsaturated fatty acids and protein, and excluded the intake of dairy products, grains, refined sugar and salt. The exercise intervention consisted of 180 min of supervised aerobic and resistance exercise per week. Both interventions induced a significant weight loss, improved insulin sensitivity and increased peak oxygen uptake without any significant group differences. Furthermore, both interventions were associated with increased functional brain responses within the right anterior hippocampus, right inferior occipital gyrus and increased volume of the right posterior hippocampus. There were no changes in memory performance. We conclude that life-style modification may improve neuronal plasticity in brain areas linked to cognitive function in type 2 diabetes. Putative long-term effects on cognitive functions including decreased risk of dementing disorders await further studies. Clinical trials registration number: Clinicaltrials. gov NCT01513798. PMID- 29255416 TI - (+)-Catechin in a 1:2 Complex with Lysine Inhibits Cancer Cell Migration and Metastatic Take in Mice. AB - Metastasis is of dismal prognosis for cancer patients, but recent evidence in mouse models of cancer shows that metastasis prevention is a reachable clinical objective. These experiments indicate that altered mitochondrial activities are associated with the metastatic phenotype. Mitochondrial transfer from metastatic to non-metastatic cells can indeed transfer the metastatic phenotype, and metastatic progenitor cells differ from other cancer cells by a higher sublethal production of mitochondrial reactive oxygen species (ROS). Moreover, mitochondria targeted antioxidants can prevent metastatic dissemination in mouse models of cancer. Comparatively, general antioxidants have unpredictable effects on cancer metastasis, most probably because they affect several cell types, several subcellular ROS production sites and, often, several endogenous oxidant species. Thus, targeting antioxidants to mitochondria could improve their antimetastatic activities, as previously exemplified with mitochondria-targeted mitoTEMPO and mitoQ that can prevent metastatic dissemination in cancer-bearing mice. Our objective in this study was to identify whether catechins, which are known to be potent antioxidants, can inhibit cancer cell migration in vitro and metastatic take in vivo. Comparative analysis of the response to epigallocatechin-3-gallate, (+)-catechin and (+)-catechin:lysine complexes revealed that, whereas all compounds had similar general antioxidant properties, (+)-catechin:lysine 1:2, but not epigallocatechin-3-gallate, can prevent metastatic take of melanoma cells to the lungs of mice. (+)-Catechin:lysine 1:2 possesses two net positive charges provided by lysines at physiological pH, which could provide high affinity for the negatively charged mitochondrial matrix. While this study reveals that (+) catechin:lysine 1:2 has interesting antimetastatic effects, future experiments are needed to formally demonstrate the stability of the complex, its effective tropism for mitochondria and whether or not its activity can be globally attributed to its antioxidant activity at this precise subcellular location. PMID- 29255414 TI - Biological and Clinical Implications of Comorbidities in Parkinson's Disease. AB - A wide spectrum of comorbidities has been associated with Parkinson's disease (PD), a progressive neurodegenerative disease that affects more than seven million people worldwide. Emerging evidence indicates that chronic diseases including diabetes, depression, anemia and cancer may be implicated in the pathogenesis and progression of PD. Recent epidemiological studies suggest that some of these comorbidities may increase the risk of PD and precede the onset of motor symptoms. Further, drugs to treat diabetes and cancer have elicited neuroprotective effects in PD models. Nonetheless, the mechanisms underlying the occurrence of these comorbidities remain elusive. Herein, we discuss the biological and clinical implications of comorbidities in the pathogenesis, progression, and clinical management, with an emphasis on personalized medicine applications for PD. PMID- 29255417 TI - Rolipram, a Selective Phosphodiesterase 4 Inhibitor, Ameliorates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain through Inhibition of Inflammatory Cytokines in the Dorsal Root Ganglion. AB - Chemotherapy-induced neuropathic pain is a significant side effect of chemotherapeutic agents and is the most common reason for stopping chemotherapy. The aim of the present study was to find the major site and mechanisms of action by which rolipram, a selective phosphodiesterase-4 inhibitor, alleviates paclitaxel-induced neuropathic pain. Chemotherapy-induced neuropathic pain was induced in adult male Sprague-Dawley rats by intraperitoneal injection of paclitaxel on four alternate days. Rolipram was administered systemically or locally into the lumbar spinal cord, L5 dorsal root ganglion, sciatic nerve, or skin nerve terminal. The mechanical threshold, the protein level of several inflammatory cytokines, and the cellular locations of phosphodiesterase-4 and interleukin-1beta in the dorsal root ganglion were measured by using behavioral testing, Western blotting, and immunohistochemistry, respectively. The local administration (0.03-mg) of rolipram in the L5 dorsal root ganglion ameliorated paclitaxel-induced pain behavior more effectively than did local administration in the other sites. Paclitaxel significantly increased the expression of inflammatory cytokines including tumor necrosis factor-alpha (2.2 times) and interleukin-1beta (2.7 times) in the lumbar dorsal root ganglion, and rolipram significantly decreased it. In addition, phosphodiesterase-4 and interleukin 1beta were expressed in the dorsal root ganglion neurons and satellite cells and paclitaxel significantly increased the intensity of interleukin-1beta (2 times) and rolipram significantly decreased it. These results suggest that the major site of action of rolipram on paclitaxel-induced neuropathic pain in rats was the dorsal root ganglion. Rolipram decreased the expression of inflammatory cytokines in the dorsal root ganglion. Thus, phosphodiesterase-4 inhibitors may ameliorate chemotherapy-induced neuropathic pain by decreasing expression of inflammatory cytokines in the dorsal root ganglion. PMID- 29255418 TI - vNN Web Server for ADMET Predictions. AB - In drug development, early assessments of pharmacokinetic and toxic properties are important stepping stones to avoid costly and unnecessary failures. Considerable progress has recently been made in the development of computer-based (in silico) models to estimate such properties. Nonetheless, such models can be further improved in terms of their ability to make predictions more rapidly, easily, and with greater reliability. To address this issue, we have used our vNN method to develop 15 absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction models. These models quickly assess some of the most important properties of potential drug candidates, including their cytotoxicity, mutagenicity, cardiotoxicity, drug-drug interactions, microsomal stability, and likelihood of causing drug-induced liver injury. Here we summarize the ability of each of these models to predict such properties and discuss their overall performance. All of these ADMET models are publically available on our website (https://vnnadmet.bhsai.org/), which also offers the capability of using the vNN method to customize and build new models. PMID- 29255419 TI - Skeletal Muscle Fibre-Specific Knockout of p53 Does Not Reduce Mitochondrial Content or Enzyme Activity. AB - Tumour protein 53 (p53) has been implicated in the regulation of mitochondrial biogenesis in skeletal muscle, with whole-body p53 knockout mice displaying impairments in basal mitochondrial content, respiratory capacity, and enzyme activity. This study aimed to determine the effect of skeletal muscle-specific loss of p53 on mitochondrial content and enzyme activity. Mitochondrial protein content, enzyme activity and mRNA profiles were assessed in skeletal muscle of 8 week-old male muscle fibre-specific p53 knockout mice (p53 mKO) and floxed littermate controls (WT) under basal conditions. p53 mKO and WT mice displayed similar content of electron transport chain proteins I-V and citrate synthase enzyme activity in skeletal muscle. In addition, the content of proteins regulating mitochondrial morphology (MFN2, mitofillin, OPA1, DRP1, FIS1), fatty acid metabolism (beta-HAD, ACADM, ACADL, ACADVL), carbohydrate metabolism (HKII, PDH), energy sensing (AMPKalpha2, AMPKbeta2), and gene transcription (NRF1, PGC 1alpha, and TFAM) were comparable in p53 mKO and WT mice (p > 0.05). Furthermore, p53 mKO mice exhibited normal mRNA profiles of targeted mitochondrial, metabolic and transcriptional proteins (p > 0.05). Thus, it appears that p53 expression in skeletal muscle fibres is not required to develop or maintain mitochondrial protein content or enzyme function in skeletal muscle under basal conditions. PMID- 29255420 TI - Length-Dependent Prolongation of Force Relaxation Is Unaltered by Delay of Intracellular Calcium Decline in Early-Stage Rabbit Right Ventricular Hypertrophy. AB - Chronic pressure overload can result in ventricular hypertrophy and eventually diastolic dysfunction. In normal myocardium, the time from peak tension to 50% relaxation of isolated cardiac myocardium is not directly determined by the time for calcium decline. This study aims to determine whether the time for calcium decline is altered with a change in preload in early-stage hypertrophied myocardium, and whether this change in time for calcium decline alters the rate of relaxation of the myocardium. Young New Zealand white rabbits underwent a pulmonary artery banding procedure and were euthanized 10 weeks later. Twitch contractions and calibrated bis-fura-2 calcium transients were measured in isolated thin right ventricular trabeculae at optimal length and with the muscle taut. Systolic calcium, calcium transient amplitude, and time from peak tension to 50% relaxation all increased with an increase in preload for both hypertrophied and sham groups. Time for intracellular calcium decline increased both with an increase in preload and an increase in extracellular calcium concentration in hypertrophied myocardium but not in sham, while time from peak tension to 50% relaxation did not significantly change between groups under either condition. Also, time for intracellular calcium decline generally decreased with an increase in extracellular calcium for both hypertrophied and sham groups, while time from peak tension to 50% relaxation generally did not significantly change in either group. Combined, these results indicate that the mild hypertrophy significantly changes calcium handling, but does not impact on the rate of force relaxation. This implies that the rate-limiting step in force relaxation is not directly related to calcium transient decline. PMID- 29255415 TI - Adenosine Receptors As Drug Targets for Treatment of Pulmonary Arterial Hypertension. AB - Pulmonary arterial hypertension (PAH) is a clinical condition characterized by pulmonary arterial remodeling and vasoconstriction, which promote chronic vessel obstruction and elevation of pulmonary vascular resistance. Long-term right ventricular (RV) overload leads to RV dysfunction and failure, which are the main determinants of life expectancy in PAH subjects. Therapeutic options for PAH remain limited, despite the introduction of prostacyclin analogs, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylyl cyclase stimulators within the last 15 years. Through addressing the pulmonary endothelial and smooth muscle cell dysfunctions associated with PAH, these interventions delay disease progression but do not offer a cure. Emerging approaches to improve treatment efficacy have focused on beneficial actions to both the pulmonary vasculature and myocardium, and several new targets have been investigated and validated in experimental PAH models. Herein, we review the effects of adenosine and adenosine receptors (A1, A2A, A2B, and A3) on the cardiovascular system, focusing on the A2A receptor as a pharmacological target. This receptor induces pulmonary vascular and heart protection in experimental models, specifically models of PAH. Targeting the A2A receptor could potentially serve as a novel and efficient approach for treating PAH and concomitant RV failure. A2A receptor activation induces pulmonary endothelial nitric oxide synthesis, smooth muscle cell hyperpolarization, and vasodilation, with important antiproliferative activities through the inhibition of collagen deposition and vessel wall remodeling in the pulmonary arterioles. The pleiotropic potential of A2A receptor activation is highlighted by its additional expression in the heart tissue, where it participates in the regulation of intracellular calcium handling and maintenance of heart chamber structure and function. In this way, the activation of A2A receptor could prevent the production of a hypertrophic and dysfunctional phenotype in animal models of cardiovascular diseases. PMID- 29255422 TI - Accuracy and Artistry in Anatomical Illustration of Perivascular Adipose Tissue. PMID- 29255421 TI - Comparative Analysis of Muscle Hypertrophy Models Reveals Divergent Gene Transcription Profiles and Points to Translational Regulation of Muscle Growth through Increased mTOR Signaling. AB - Skeletal muscle mass is a result of the balance between protein breakdown and protein synthesis. It has been shown that multiple conditions of muscle atrophy are characterized by the common regulation of a specific set of genes, termed atrogenes. It is not known whether various models of muscle hypertrophy are similarly regulated by a common transcriptional program. Here, we characterized gene expression changes in three different conditions of muscle growth, examining each condition during acute and chronic phases. Specifically, we compared the transcriptome of Extensor Digitorum Longus (EDL) muscles collected (1) during the rapid phase of postnatal growth at 2 and 4 weeks of age, (2) 24 h or 3 weeks after constitutive activation of AKT, and (3) 24 h or 3 weeks after overload hypertrophy caused by tenotomy of the Tibialis Anterior muscle. We observed an important overlap between significantly regulated genes when comparing each single condition at the two different timepoints. Furthermore, examining the transcriptional changes occurring 24 h after a hypertrophic stimulus, we identify an important role for genes linked to a stress response, despite the absence of muscle damage in the AKT model. However, when we compared all different growth conditions, we did not find a common transcriptional fingerprint. On the other hand, all conditions showed a marked increase in mTORC1 signaling and increased ribosome biogenesis, suggesting that muscle growth is characterized more by translational, than transcriptional regulation. PMID- 29255423 TI - Calcium Sensing Receptors Mediate Local Inhibitory Reflexes Evoked by L Phenylalanine in Guinea Pig Jejunum. AB - Amino acids applied to the mucosa evoke inhibitory reflexes in guinea-pig jejunum, but the receptors involved in sensory transduction are still unclear. One promising candidate is the extracellular calcium sensing receptor (CaSR), which is expressed by mucosal enteroendocrine cells and is preferentially activated by aromatic L-amino acids. We tested this by applying various amino acids to the mucosa and recording the resulting inhibitory junction potentials (IJPs) in nearby circular smooth muscle via intracellular recording. The CaSR is stereospecific and L-Phenylalanine evoked a significantly larger response than D Phenylalanine when both were applied to the same site. The same pattern was seen with L- and D-Tryptophan, another aromatic amino acid. The CaSR is preferentially activated by aromatic amino acids and responses to L-Leucine and L-Lysine were significantly lower than those to L-Phenylalanine applied to the same site. Responses to L-Phenylalanine were dose-dependently suppressed by blockade of the CaSR with NPS2143, a CaSR antagonist, and mimicked by mucosal application of cinacalcet, a CaSR agonist. Responses to cinacalcet had similar pharmacology to that of responses to L-Phenylalanine, in that each requires both P2 purinoreceptors and 5-HT receptors. L-Glutamate evoked IJPs similar to those produced by L-Phenylalanine and these were depressed by blockade of P2 receptors and 5-HT3 plus 5-HT4 receptors, but NPS2143 was ineffective. The AMPA receptor antagonists DNQX (10 MUM) and CNQX (10 MUM) reduced IJPs evoked by L-Glutamate by 88 and 79% respectively, but neither BAY367260 (mGluR5 antagonist) nor 2APV (NMDA antagonist) affected IJPs evoked by L-Glutamate. We conclude that local inhibitory reflexes evoked by aromatic L-amino acids in guinea pig jejunum involve activation of CaSRs which triggers release of ATP and 5-HT from the mucosa. L-Glutamate also evokes inhibitory reflexes, via a pathway that does not involve CaSRs. It is likely there are multiple receptors acting as sensory transducers for different luminal amino acids. PMID- 29255424 TI - Phenylephrine Affects Peripapillary Retinal Vasculature-an Optic Coherence Tomography Angiography Study. AB - Purpose: To evaluate and compare the effect of topical mydriatic eye drops (0.5% tropicamide alone, and a 0.5% tropicamide/0.5% phenylephrine mixture) on the retinal perfusion using optic coherence tomography angiography (OCTA). Methods: The perfused vessel density in the macular and peripapillary areas of both eyes was measured in eight healthy subjects using OCTA and a split-spectrum amplitude decorrelation angiography algorithm (SSADA). Various parameters, including retinal vessel density, were obtained at baseline and again 30 min after the instillation of either the tropicamide or the tropicamide/phenylephrine mixture eye drops in the right eye. Results: Following instillation of the tropicamide/phenylephrine mixture eye drops, there was a significant reduction of vessel density in the peripapillary area (from 89.63 +/- 4.53% to 85.00 +/- 4.14%, P = 0.034), but not in the macular areas. The mean effect size in the peripapillary area was -4.63%, and was not correlated with age, sex, or baseline vessel density. There was no reduction in vessel density in the macular or peripapillary areas after instillation of 0.5% tropicamide alone, and no reduction in vessel density in the contralateral (control) eyes. Conclusion: Topical phenylephrine reduced the retinal vessel density within the peripapillary area, but not within the macular area. Therefore, studies using OCTA, especially those focusing on the peripapillary area, should take into account this effect of phenylephrine on vessel density. PMID- 29255425 TI - Editorial: The Pathogenetic Mechanisms at the Basis of Aortopathy Associated with Bicuspid Aortic Valve: Insights from "Omics", Models of Disease and Emergent Technologies. PMID- 29255426 TI - The Action of Red Cell Calcium Ions on Human Erythrophagocytosis in Vitro. AB - In the present work we have studied in vitro the effect of increasing red cell Ca2+ ions on human erythrophagocytosis by peripheral monocyte-derived autologous macrophages. In addition, the relative contribution to phagocytosis of phosphatidylserine exposure, autologous IgG binding, complement deposition and Gardos channel activity was also investigated. Monocytes were obtained after ficoll-hypaque fractionation and induced to transform by adherence to glass coverslips, for 24 h at 37 degrees C in a RPMI medium, containing 10% fetal calf serum. Red blood cells (RBC) were loaded with Ca2+ using 10 MUM A23187 and 1 mM Ca-EGTA buffers, in the absence of Mg2+. Ca2+-loaded cells were transferred to above coverslips and incubated for 2 h at 37 degrees C under various experimental conditions, after which phagocytosis was assessed by light microscopy. Confirming earlier findings, phagocytosis depended on internal Ca2+. Accordingly; it was linearly raised from about 2-15% by increasing the free Ca2+ content of the loading solution from 0.5 to 20 MUM, respectively. Such a linear increase was virtually doubled by the presence of 40% autologous serum. At 7 MUM Ca2+, the phagocytosis degree attained with serum was practically equal to that obtained with either 2 mg/ml affinity-purified IgG or 40% IgG-depleted serum. However, phagocytosis was reduced to levels found with Ca2+ alone when IgG-depleted serum was inactivated by heat, implying an involvement of complement. On the other hand, phagocytosis in the absence of serum was markedly reduced by preincubating macrophages with phosphatidylserine-containing liposomes. In contrast, a similar incubation in the presence of serum affected it partially whereas employing liposomes made only of phosphatidylcholine essentially had no effect. Significantly, the Gardos channel inhibitors clotrimazole (2 MUM) and TRAM-34 (100 nM) fully blocked serum-dependent phagocytosis. These findings show that a raised internal Ca2+ promotes erythrophagocytosis by independently triggering phosphatidylserine externalization, complement deposition and IgG binding. Serum appeared to stimulate phagocytosis in a way dependent on Gardos activity. It seems likely that Ca2+ promoted IgG-binding to erythrocytes via Gardos channel activation. This can be an important signal for clearance of senescent human erythrocytes under physiological conditions. PMID- 29255428 TI - Editorial: High-Intensity Exercise in Hypoxia: Beneficial Aspects and Potential Drawbacks. PMID- 29255427 TI - Weighted Gene Co-expression Network Analysis Identifies FKBP11 as a Key Regulator in Acute Aortic Dissection through a NF-kB Dependent Pathway. AB - Acute aortic dissection (AAD) is a life-threatening disease. Despite the higher risk of mortality, currently there are no effective therapies that can ameliorate AAD development or progression. Identification of meaningful clusters of co expressed genes or representative biomarkers for AAD may help to identify new pathomechanisms and foster development of new therapies. To this end, we performed a weighted gene co-expression network analysis (WGCNA) and calculated module-trait correlations based on a public microarray dataset (GSE 52093) and discovered 9 modules were found to be related to AAD. The module which has the strongest positive correlation with AAD was further analyzed and the top 10 hub genes SLC20A1, GINS2, CNN1, FAM198B, MAD2L2, UBE2T, FKBP11, SLMAP, CCDC34, and GALK1 were identified. Furthermore, we validated the data by qRT-PCR in an independent sample set originated from our study center. Overall, the qRT-PCR results were consistent with the results of the microarray analysis. Intriguingly, the highest change was found for FKBP11, a protein belongs to the FKBP family of peptidyl-prolyl cis/trans isomerases, which catalyze the folding of proline-containing polypeptides. In congruent with the gene expression analysis, FKBP11 expression was induced in cultured endothelial cells by angiotensin II treatment and endothelium of the dissected aorta. More importantly we show that FKBP11 provokes inflammation in endothelial cells by interacting with NF-kB p65 subunit, resulting in pro-inflammatory cytokines production. Accordingly, siRNA mediated knockdown of FKBP11 in cultured endothelial cells suppressed angiotensin II induced monocyte transmigration through the endothelial monolayer. Based on these data, we hypothesize that pro-inflammatory cytokines elicited by FKBP11 overexpression in the endothelium under AAD condition could facilitate transendothelial migration of the circulating monocytes into the aorta, where they differentiate into active macrophages and secrete MMPs and other extracellular matrix (ECM) degrading proteins, contributing to sustained inflammation and AAD. Taken together, our data identify important role of FKBP11 which can serve as biomarker and/or therapeutic target for AAD. PMID- 29255429 TI - Moderating Effects of Alexithymia on Associations between the Therapeutic Alliance and the Outcome of Brief Psychodynamic-Interpersonal Psychotherapy for Multisomatoform Disorder. AB - This secondary analysis of a trial on brief psychodynamic-interpersonal therapy (PIT) for patients with multisomatoform disorder investigated whether alexithymia moderates the associations between the therapeutic alliance and the outcome of PIT and whether moderating effects of alexithymia remain significant when controlling for depression. Eighty-three patients with multisomatoform disorder receiving PIT were statistically analyzed. Moderation analyses were performed with the SPSS macro PROCESS. The primary outcome (Y), self-reported physical quality of life at 9-month after the end of PIT, was measured with the physical component summary (PCS) of the SF-36 Health Survey. The potential moderator (M) alexithymia was operationalized with the Toronto Alexithymia Scale (TAS-20) at pre-treatment and the predictor (X) the therapeutic alliance was rated by both patients and therapists via the Helping Alliance Questionnaire (HAQ) at the end of PIT. Moreover, the PCS at pre-treatment functioned as covariate in all moderation models. When the patients' alliance ratings were analyzed, alexithymia did not moderate associations between the alliance and the outcome. When the therapists' alliance ratings were evaluated, alexithymia moderated the relationship between the alliance and the outcome (p < 0.05): a stronger alliance in the therapists' perspective was beneficial for the outcome only for patients scoring above 61 on the TAS-20. This moderating effect of alexithymia was, however, not statistically significant anymore when adding the pre-treatment depression scores (PHQ-9) as a covariate to the moderation model. The results underline the importance of a good therapists' view of the alliance when treating alexithymic patients and highlight the complex interaction between alexithymia and depression. Future studies are needed to extend the scope of research regarding which psychotherapeutic mechanisms of change are beneficial for which patients. PMID- 29255430 TI - Levels of Social Sharing and Clinical Implications for Severe Social Withdrawal in Patients with Personality Disorders. AB - Social sharing capacities have attracted attention from a number of fields of social cognition and have been variously defined and analyzed in numerous studies. Social sharing consists in the subjective awareness that aspects of the self's experience are held in common with other individuals. The definition of social sharing must take a variety of elements into consideration: the motivational element, the contents of the social sharing experience, the emotional responses it evokes, the behavioral outcomes, and finally, the circumstances and the skills which enable social sharing. The primary objective of this study is to explore some of the diverse forms of human social sharing and to classify them according to levels of complexity. We identify four different types of social sharing, categorized according to the nature of the content being shared and the complexity of the mindreading skills required. The second objective of this study is to consider possible applications of this graded model of social sharing experience in clinical settings. Specifically, this model may support the development of graded, focused clinical interventions for patients with personality disorders characterized by severe social withdrawal. PMID- 29255431 TI - Arterial Hypertension and Health-Related Quality of Life. AB - Purpose: To investigate the effect of awareness of arterial hypertension on quality of life in hypertensive patients in Greece. Materials and methods: This was a prospective observational study that included 189 aware hypertensive patients on treatment with antihypertensive therapy. Patients were ambulatory men or women >=18 years old, with diagnosed essential hypertension. The administration and fulfillment of the questionnaires was given at the outpatient hypertensive clinic starting with the SF-36 and continuing with the BDI-I test. Results: The mean BDI score was 9.9 +/- 6.9, and 58, 25, 8.9, and 7.3% were identified as without, with minimal, moderate, and 0.8% with severe depression, respectively. The mean score for physical component summary (PCS-36) was 48.9 +/- 7.6, and the mean score for mental component summary (MCS-36) was 46.0 +/- 10.6. The stage of hypertension was not an independent predictor for any of the SF-36 dimensions. Dippers had not different levels of health-related quality of life (HRQOL) as compared with non-dippers. LV hypertrophy was associated with lower scores on bodily pain (p < 0.05) and kidney failure was associated with lower scores on general health perception (p < 0.05). Female gender, increased age, and the presence of COPD were independently associated with lower physical and mental health scores (p < 0.05). Score on BDI independently correlated with all dimensions of SF-36, indicating that greater depression levels are associated with lower levels of HRQOL. Conclusion: The stage as well as awareness of arterial hypertension does not affect physical and mental health. The fact that arterial hypertension per se is not a symptomatic disease may explain these results at least in patients with uncomplicated hypertension. PMID- 29255434 TI - Emotional Responses to Music: Shifts in Frontal Brain Asymmetry Mark Periods of Musical Change. AB - Recent studies have demonstrated increased activity in brain regions associated with emotion and reward when listening to pleasurable music. Unexpected change in musical features intensity and tempo - and thereby enhanced tension and anticipation - is proposed to be one of the primary mechanisms by which music induces a strong emotional response in listeners. Whether such musical features coincide with central measures of emotional response has not, however, been extensively examined. In this study, subjective and physiological measures of experienced emotion were obtained continuously from 18 participants (12 females, 6 males; 18-38 years) who listened to four stimuli-pleasant music, unpleasant music (dissonant manipulations of their own music), neutral music, and no music, in a counter-balanced order. Each stimulus was presented twice: electroencephalograph (EEG) data were collected during the first, while participants continuously subjectively rated the stimuli during the second presentation. Frontal asymmetry (FA) indices from frontal and temporal sites were calculated, and peak periods of bias toward the left (indicating a shift toward positive affect) were identified across the sample. The music pieces were also examined to define the temporal onset of key musical features. Subjective reports of emotional experience averaged across the condition confirmed participants rated their music selection as very positive, the scrambled music as negative, and the neutral music and silence as neither positive nor negative. Significant effects in FA were observed in the frontal electrode pair FC3-FC4, and the greatest increase in left bias from baseline was observed in response to pleasurable music. These results are consistent with findings from previous research. Peak FA responses at this site were also found to co-occur with key musical events relating to change, for instance, the introduction of a new motif, or an instrument change, or a change in low level acoustic factors such as pitch, dynamics or texture. These findings provide empirical support for the proposal that change in basic musical features is a fundamental trigger of emotional responses in listeners. PMID- 29255433 TI - Cognitive Remediation Interventions for Gambling Disorder: A Systematic Review. AB - Various therapeutic approaches are available for the treatment of gambling disorder (GD), especially cognitive behavioral therapy (CBT; the most widely used treatment). However, CBT has high dropout and relapse rates as well as non compliance issues, which may be partly due to resistance to changing core characteristics, such as executive functioning, attention, and emotional regulation abnormalities. Finding new therapeutic approaches to treat GD is thus a key challenge. Cognitive remediation (CR) interventions represent a promising approach to GD management, which has recently been demonstrated to have efficacy for treating other addictive disorders. The objective of this review is to describe the possible benefits of CR interventions for GD management. Two systematic searches in MEDLINE and ScienceDirect databases were conducted up until January 2017. Potential neurocognitive targets of CR interventions for GD were reviewed, as is the use and efficacy of such interventions for GD. While there is evidence of several neurocognitive deficits in individuals with GD in terms of impulsive, reflective, and interoceptive processes, the literature on CR interventions is virtually absent. No clinical studies were found in the literature, apart from a trial of a very specific program using Playmancer, a serious videogame, which was tested in cases of bulimia nervosa and GD. However, neurocognitive impairments in individuals with addictive disorders are highly significant, not only affecting quality of life, but also making abstinence and recovery more difficult. Given that CR interventions represent a relatively novel therapeutic approach to addiction and that there is currently a scarcity of studies on clinical populations suffering from GD, further research is needed to examine the potential targets of such interventions and the effectiveness of different training approaches. So far, no consensus has been reached on the optimal parameters of CR interventions (duration, intensity, frequency, group vs. individual, pencil-and-paper vs. computerized delivery, etc.). Although no firm conclusions can be drawn, CR interventions represent a promising adjunct treatment for GD. Such a novel therapy could be associated with common interventions, such as CBT and educational and motivational interventions, in order to make therapies more effective and longer-lasting and to decrease the risk of relapse. PMID- 29255435 TI - Cross-modal Association between Auditory and Visuospatial Information in Mandarin Tone Perception in Noise by Native and Non-native Perceivers. AB - Speech perception involves multiple input modalities. Research has indicated that perceivers establish cross-modal associations between auditory and visuospatial events to aid perception. Such intermodal relations can be particularly beneficial for speech development and learning, where infants and non-native perceivers need additional resources to acquire and process new sounds. This study examines how facial articulatory cues and co-speech hand gestures mimicking pitch contours in space affect non-native Mandarin tone perception. Native English as well as Mandarin perceivers identified tones embedded in noise with either congruent or incongruent Auditory-Facial (AF) and Auditory-FacialGestural (AFG) inputs. Native Mandarin results showed the expected ceiling-level performance in the congruent AF and AFG conditions. In the incongruent conditions, while AF identification was primarily auditory-based, AFG identification was partially based on gestures, demonstrating the use of gestures as valid cues in tone identification. The English perceivers' performance was poor in the congruent AF condition, but improved significantly in AFG. While the incongruent AF identification showed some reliance on facial information, incongruent AFG identification relied more on gestural than auditory-facial information. These results indicate positive effects of facial and especially gestural input on non-native tone perception, suggesting that cross-modal (visuospatial) resources can be recruited to aid auditory perception when phonetic demands are high. The current findings may inform patterns of tone acquisition and development, suggesting how multi-modal speech enhancement principles may be applied to facilitate speech learning. PMID- 29255436 TI - Choice-Supportive Misremembering: A New Taxonomy and Review. AB - Although the literature on the influence of memory on decisions is well developed, research on the effects of decision making on memory is rather sparse and scattered. Choice-supportive misremembering (i.e., misremembering choice related information that boosts the chosen option and/or demotes the foregone options) has been observed in several studies and has the potential to affect future choices. Nonetheless, no attempt has been made to review the relevant literature, categorize the different types of choice-supportive misremembering observed, and critically appraise the existing evidence and proposed explanations. Thus, starting from a new theoretically motivated and empirically grounded taxonomy, we review the current research. Our taxonomy classifies choice supportive misremembering into four conceptually distinct types: misattribution is when information is attributed to the wrong source, fact distortion when the facts are remembered in a distorted manner, false memory when items that were not part of the original decision scenarios are remembered as presented and, finally, selective forgetting is when information is selectively forgotten. After assessing the impact of various potentially moderating factors, we evaluate the evidence for each type of misremembering and conclude that the support for the phenomenon is solid in relation to misattribution when recognition memory is assessed, but significantly weaker for the other three types, and when other memory tests are used to assess memory. Finally, we review the cognitive and emotional explanations proposed for choice-supportive misremembering in the light of the available evidence and identify the main gaps in the current knowledge and the more promising avenues for future research. PMID- 29255437 TI - A Binocular Information Source for Size Perception. AB - For too long, size perception research has been guided by the size distance invariance hypothesis. Although research to validate this hypothesis has been largely inconclusive, the hypothesis has endured, perhaps in part because alternative information sources for size perception were lacking. Here, I propose a binocular information source for size perception. The model, drawing on the binocular geometry of viewing a physical extent, is expressed solely in terms of four angular measures and interocular distance, with the explicit exclusion of egocentric distance information. Thus, the proposed information source, if utilized by the binocular system, should be able to augment the few existing sources of information for size perception (e.g., familiar size, texture gradient, and horizon ratio). PMID- 29255432 TI - Emerging Directions in Emotional Episodic Memory. AB - Building upon the existing literature on emotional memory, the present review examines emerging evidence from brain imaging investigations regarding four research directions: (1) Social Emotional Memory, (2) The Role of Emotion Regulation in the Impact of Emotion on Memory, (3) The Impact of Emotion on Associative or Relational Memory, and (4) The Role of Individual Differences in Emotional Memory. Across these four domains, available evidence demonstrates that emotion- and memory-related medial temporal lobe brain regions (amygdala and hippocampus, respectively), together with prefrontal cortical regions, play a pivotal role during both encoding and retrieval of emotional episodic memories. This evidence sheds light on the neural mechanisms of emotional memories in healthy functioning, and has important implications for understanding clinical conditions that are associated with negative affective biases in encoding and retrieving emotional memories. PMID- 29255438 TI - Self-Control of Haptic Assistance for Motor Learning: Influences of Frequency and Opinion of Utility. AB - Studies of self-controlled practice have shown benefits when learners controlled feedback schedule, use of assistive devices and task difficulty, with benefits attributed to information processing and motivational advantages of self-control. Although haptic assistance serves as feedback, aids task performance and modifies task difficulty, researchers have yet to explore whether self-control over haptic assistance could be beneficial for learning. We explored whether self-control of haptic assistance would be beneficial for learning a tracing task. Self controlled participants selected practice blocks on which they would receive haptic assistance, while participants in a yoked group received haptic assistance on blocks determined by a matched self-controlled participant. We inferred learning from performance on retention tests without haptic assistance. From qualitative analysis of open-ended questions related to rationales for/experiences of the haptic assistance that was chosen/provided, themes emerged regarding participants' views of the utility of haptic assistance for performance and learning. Results showed that learning was directly impacted by the frequency of haptic assistance for self-controlled participants only and view of haptic assistance. Furthermore, self-controlled participants' views were significantly associated with their requested haptic assistance frequency. We discuss these findings as further support for the beneficial role of self-controlled practice for motor learning. PMID- 29255439 TI - Motivated Forgetting in Early Mathematics: A Proof-of-Concept Study. AB - Educators assume that students are motivated to retain what they are taught. Yet, students commonly report that they forget most of what they learn, especially in mathematics. In the current study I ask whether students may be motivated to forget mathematics because of academic experiences threaten the self-perceptions they are committed to maintaining. Using a large dataset of 1st and 2nd grade children (N = 812), I hypothesize that math anxiety creates negative experiences in the classroom that threaten children's positive math self-perceptions, which in turn spurs a motivation to forget mathematics. I argue that this motivation to forget is activated during the winter break, which in turn reduces the extent to which children grow in achievement across the school year. Children were assessed for math self-perceptions, math anxiety and math achievement in the fall before going into winter break. During the spring, children's math achievement was measured once again. A math achievement growth score was devised from a regression model of fall math achievement predicting spring achievement. Results show that children with higher math self-perceptions showed reduced growth in math achievement across the school year as a function of math anxiety. Children with lower math interest self-perceptions did not show this relationship. Results serve as a proof-of-concept for a scientific account of motivated forgetting within the context of education. PMID- 29255440 TI - The Influence of Concreteness of Concepts on the Integration of Novel Words into the Semantic Network. AB - On the basis of previous studies revealing a processing advantage of concrete words over abstract words, the current study aimed to further explore the influence of concreteness on the integration of novel words into semantic memory with the event related potential (ERP) technique. In the experiment during the learning phase participants read two-sentence contexts and inferred the meaning of novel words. The novel words were two-character non-words in Chinese language. Their meaning was either a concrete or abstract known concept which could be inferred from the contexts. During the testing phase participants performed a lexical decision task in which the learned novel words served as primes for either their corresponding concepts, semantically related or unrelated targets. For the concrete novel words, the semantically related words belonged to the same semantic categories with their corresponding concepts. For the abstract novel words, the semantically related words were synonyms of their corresponding concepts. The unrelated targets were real words which were concrete or abstract for the concrete or abstract novel words respectively. The ERP results showed that the corresponding concepts and the semantically related words elicited smaller N400s than the unrelated words. The N400 effect was not modulated by the concreteness of the concepts. In addition, the concrete corresponding concepts elicited a smaller late positive component (LPC) than the concrete unrelated words. This LPC effect was absent for the abstract words. The results indicate that although both concrete and abstract novel words can be acquired and linked to their related words in the semantic network after a short learning phase, the concrete novel words are learned better. Our findings support the (extended) dual coding theory and broaden our understanding of adult word learning and changes in concept organization. PMID- 29255442 TI - Sliding Mode Tracking Control of a Wire-Driven Upper-Limb Rehabilitation Robot with Nonlinear Disturbance Observer. AB - Robot-aided rehabilitation has become an important technology to restore and reinforce motor functions of patients with extremity impairment, whereas it can be extremely challenging to achieve satisfactory tracking performance due to uncertainties and disturbances during rehabilitation training. In this paper, a wire-driven rehabilitation robot that can work over a three-dimensional space is designed for upper-limb rehabilitation, and sliding mode control with nonlinear disturbance observer is designed for the robot to deal with the problem of unpredictable disturbances during robot-assisted training. Then, simulation and experiments of trajectory tracking are carried out to evaluate the performance of the system, the position errors, and the output forces of the designed control scheme are compared with those of the traditional sliding mode control (SMC) scheme. The results show that the designed control scheme can effectively reduce the tracking errors and chattering of the output forces as compared with the traditional SMC scheme, which indicates that the nonlinear disturbance observer can reduce the effect of unpredictable disturbances. The designed control scheme for the wire-driven rehabilitation robot has potential to assist patients with stroke in performing repetitive rehabilitation training. PMID- 29255441 TI - Morphological and Functional Inner and Outer Retinal Layer Abnormalities in Eyes with Permanent Temporal Hemianopia from Chiasmal Compression. AB - Purpose: The aims of this study are to compare optical coherence tomography (OCT) measured macular retinal layers in eyes with permanent temporal hemianopia from chiasmal compression and control eyes; to compare regular and slow-flash multifocal electroretinography (mfERG) in patients and controls; and to assess the correlation between OCT, mfERG, and central visual field (SAP) data. Methods: Forty-three eyes of 30 patients with permanent temporal hemianopia due to pituitary tumors who were previously submitted to chiasm decompression and 37 healthy eyes of 19 controls were submitted to macular spectral domain OCT, mfERG, and 10-2 SAP testing. After segmentation, the thickness of the macular retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer, and photoreceptor layer (PRL) was measured. Amplitudes and oscillatory potentials (OPs) were measured on regular and slow-flash mfERG, respectively, and expressed as the mean values per quadrant and hemifield. Results: RNFL, GCL, and IPL thickness measurements were significantly reduced in all quadrants, whereas INL, OPL, and PRL thicknesses were significantly increased in the nasal quadrants in patients compared to those in controls. Significant correlations between OCT and 10-2 SAP measurements were positive for the RNFL, GCL, and IPL and negative for the INL, OPL, and PRL. OPs and mfERG N1 amplitudes were significantly reduced in the nasal hemiretina of patients. Significant correlations were found between OP and mfERG amplitudes for inner and outer nasal hemiretina OCT measurements, respectively. Conclusion: Patients with permanent temporal hemianopia from previously treated chiasmal compression demonstrated significant thinning of the RNFL, GCL, IPL, and thickening of the INL, OPL, and PRL associated with reduced OP and mfERG N1 amplitudes, suggesting that axonal injury to the inner retina leads to secondary damage to the outer retina in this condition. PMID- 29255443 TI - A Systematic Review of the Usefulness of Glial Fibrillary Acidic Protein for Predicting Acute Intracranial Lesions following Head Trauma. AB - Background: The extensive use of computed tomography (CT) after acute head injury is costly and carries potential iatrogenic risk. This systematic review examined the usefulness of blood-based glial fibrillary acidic protein (GFAP) for predicting acute trauma-related CT-positive intracranial lesions following head trauma. The main objective was to summarize the current evidence on blood-based GFAP as a potential screening test for acute CT-positive intracranial lesions following head trauma. Methods: We screened MEDLINE, EMBASE, PsychInfo, CINAHL, Web of Science, the Cochrane Database, Scopus, Clinical Trials, OpenGrey, ResearchGate, and the reference lists of eligible publications for original contributions published between January 1980 and January 2017. Eligibility criteria included: (i) population: human head and brain injuries of all severities and ages; (ii) intervention: blood-based GFAP measurement <=24 h post injury; and (iii) outcome: acute traumatic lesion on non-contrast head CT <=24 h post-injury. Three authors completed the publication screening, data extraction, and quality assessment of eligible articles. Results: The initial search identified 4,706 articles, with 51 eligible for subsequent full-text assessment. Twenty-seven articles were ultimately included. Twenty-four (89%) studies reported a positive association between GFAP level and acute trauma-related intracranial lesions on head CT. The area under the receiver operating characteristic curve for GFAP prediction of intracranial pathology ranged from 0.74 to 0.98 indicating good to excellent discrimination. GFAP seemed to discriminate mass lesions and diffuse injury, with mass lesions having significantly higher GFAP levels. There was considerable variability between the measured GFAP averages between studies and assays. No well-designed diagnostic studies with specific GFAP cutoff values predictive of acute traumatic intracranial lesions have been published. Conclusion: Intracranial CT-positive trauma lesions were associated with elevated GFAP levels in the majority of studies. Methodological heterogeneity in GFAP assessments and the lack of well designed diagnostic studies with commercially validated GFAP platforms hinder the level of evidence, and variability in levels of GFAP with no clearly established cutoff for abnormality limit the clinical usefulness of the biomarker. However, blood-based GFAP holds promise as a means of screening for acute traumatic CT positive lesion following head trauma. PMID- 29255444 TI - Stopping Onabotulinum Treatment after the First Two Cycles Might Not Be Justified: Results of a Real-life Monocentric Prospective Study in Chronic Migraine. AB - Introduction: Onabotulinum toxin A (OnabotA) cyclic treatment is approved for the prophylactic treatment of chronic migraine (CM), a highly disabling disorder. Although treatment response varies among patients, current guidelines suggest to stop treatment after cycle 2 if no response is achieved. This prospective study aimed to define, in real-life setting, the evolution of the response to OnabotA over five cycles of treatment among patients non-responding to cycle 1. The results of this study might help in decision-making, in particular whether prosecuting OnabotA further or not, when facing a patient not responding to cycle 1. Methods: Patients failing to respond at cycle 1 were recruited to complete five cycles. Key outcomes were: (i) a >=50% reduction in headache days, (ii) a >=50% reduction in total cumulative hours of headache on headache days and (iii) a >=5-point improvement in Headache Impact Test-6 (HIT-6) scores. Results: Overall, 56 patients were included. Mean age was 45.7 years (female 83.9%). Severe (>=60) HIT-6 score was reported at baseline by 95.8% of patients. Responders (headache days reduction of more than 50%) progressively increased cycle after cycle, doubling from cycle 2 to cycle 5 (from 27 to 48%). In addition, patients regressed from CM to episodic migraine moving on with each cycle, with 78% of them reaching less than nine migraine days/month after cycle 5. The headache days per month decreased significantly from cycle 1 to cycle 5 (overall from 23.3 +/- 5.7 to 9.2 +/- 3.6; p < 0.001). During 12 months (5 cycles), migraine days per month progressively abated (from 18.5 to 8.7; p < 0.001), days with symptomatic medications intake/month consistently decreased (from 17.4 to 8.1; p < 0.001), and mean HIT-6 score lowered (from 72.4 +/- 5.7 to 50.2 +/- 4.3; p < 0.001). Conclusion: The positive effect of OnabotA treatment spreads over the course of the treatment and might also manifest late in treatment course among patients with no benefit after the first two cycles. Thus, the results of this real-life study suggest to extend OnabotA treatment further, beyond cycle 2, to avoid premature withdrawal in patients who would have become responders at cycle 3, 4, or 5. PMID- 29255445 TI - The Stem Cell Connection of Pituitary Tumors. AB - Tumors in the pituitary gland are typically benign but cause serious morbidity due to compression of neighboring structures and hormonal disruptions. Overall, therapy efficiency remains suboptimal with negative impact on health and comfort of life, including considerable risk of therapy resistance and tumor recurrence. To date, little is known on the pathogenesis of pituitary tumors. Stem cells may represent important forces in this process. The pituitary tumors may contain a driving tumor stem cell population while the resident tissue stem cells may be directly or indirectly linked to tumor development and growth. Here, we will briefly summarize recent studies that afforded a glance behind the scenes of this stem cell connection. A better knowledge of the mechanisms underlying pituitary tumorigenesis is essential to identify more efficacious treatment modalities and improve clinical management. PMID- 29255446 TI - Early and Late Postnatal Accelerated Growth Have Distinct Effects on Metabolic Health in Normal Birth Weight Infants. AB - Accelerated growth in postnatal life in low birth weight infants has been associated with insulin resistance and metabolic syndrome-related disorders in later life. Postnatal accelerated growth in also common in normal birth weight infants, but little is known about the impact on metabolic health. In a prospective cohort study of 203 term normal birth weight infants, we evaluated the impacts of accelerated (Deltaweight Z score > 0.5) or decelerated (Deltaweight DeltaZ < -0.5) growth during early (0-3 months) and late (3-12 months) postnatal life on metabolic health indicators at age 1-year. The primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR), beta cell function [homeostasis model assessment of beta-cell function (HOMA-beta)], and fasting plasma lipids. Adjusting for maternal, paternal, and infant characteristics, accelerated growth during the first 3 months of life was associated with a 41.6% (95% confidence interval 8.9-84.2%) increase in HOMA beta, and a 8.3% (0.7-15.4%) decrease in fasting plasma total cholesterols, and was not associated with HOMA-IR in infants at age 1-year. Accelerated growth during 3-12 months was associated with a 30.9% (3.3-66.0%) increase in HOMA-IR and was not associated with HOMA-beta. Neither accelerated nor decelerated growth was associated with fasting plasma triglycerides, high-density lipoprotein or low density lipoprotein cholesterol concentrations in infants at age 1-year. Accelerated growth during early postnatal life may be beneficial for beta-cell function, but during late postnatal life harmful for insulin sensitivity in normal birth weight infants. PMID- 29255447 TI - Clinical and Preclinical Advances in Gastroenteropancreatic Neuroendocrine Tumor Therapy. AB - The molecular events leading to gastroenteropancreatic neuroendocrine tumor (GEP NET) formation are largely unknown. Over the past decades, systemic chemotherapies have been replaced by therapies directed at particular molecular targets such as the somatostatin receptors, mTOR complexes or proangiogenic molecules. These approaches have demonstrated some success in subtypes of this heterogeneous tumor group, but responses are still widely varied. This review highlights the clinical trials ongoing for neuroendocrine tumors (NETs) and includes emerging immunotherapy, which holds great promise for NETs based on successes in other tumor types. Current avenues of preclinical research, including Notch and PI3K/AKT, will lead to additional targeted therapies based on genome-wide studies that have cast a wide net in the search for driver mutations. Future preclinical and clinical investigations are required to identify those mutations predictive of therapeutic response or disease progression. Results of current clinical trials outlined here will better inform patient management with respect to agent selection, timing, duration and combination therapy in the treatment of NETs. PMID- 29255448 TI - Prevalence and Antibiotic Resistance against Tetracycline in Campylobacter jejuni and C. coli in Cattle and Beef Meat from Selangor, Malaysia. AB - Campylobacter is a major foodborne pathogen frequently associated with human bacterial gastroenteritis in the world. This study was conducted to determine the prevalence and antibiotic resistance of Campylobacter spp. in the beef food system in Malaysia. A total of 340 samples consisting of cattle feces (n = 100), beef (n = 120) from wet markets and beef (n = 120) from hypermarkets were analyzed for Campylobacter spp. The overall prevalence of Campylobacter was 17.4%, consisting of 33% in cattle fecal samples, 14.2% in raw beef from wet market and 7.5% in raw beef from the hypermarket. The multiplex-polymerase chain reaction (PCR) identified 55% of the strains as C. jejuni, 26% as C. coli, and 19% as other Campylobacter spp. A high percentage of Campylobacter spp. were resistant to tetracycline (76.9%) and ampicillin (69.2%), whilst low resistance was exhibited to chloramphenicol (7.6%). The MAR Index of Campylobacter isolates from this study ranged from 0.09 to 0.73. The present study indicates the potential public health risk associated with the beef food system, hence stringent surveillance, regulatory measures, and appropriate interventions are required to minimize Campylobacter contamination and prudent antibiotic usage that can ensure consumer safety. PMID- 29255449 TI - Conjugation Inhibitors and Their Potential Use to Prevent Dissemination of Antibiotic Resistance Genes in Bacteria. AB - Antibiotic resistance has become one of the most challenging problems in health care. Bacteria conjugation is one of the main mechanisms whereby bacteria become resistant to antibiotics. Therefore, the search for specific conjugation inhibitors (COINs) is of interest in the fight against the spread of antibiotic resistances in a variety of laboratory and natural environments. Several compounds, discovered as COINs, are promising candidates in the fight against plasmid dissemination. In this review, we survey the effectiveness and toxicity of the most relevant compounds. Particular emphasis has been placed on unsaturated fatty acid derivatives, as they have been shown to be efficient in preventing plasmid invasiveness in bacterial populations. Biochemical and structural studies have provided insights concerning their potential molecular targets and inhibitory mechanisms. These findings open a new avenue in the search of new and more effective synthetic inhibitors. In this pursuit, the use of structure-based drug design methods will be of great importance for the screening of ligands and binding sites of putative targets. PMID- 29255451 TI - Effective Antimicrobial Activity of Plectasin-Derived Antimicrobial Peptides against Staphylococcus aureus Infection in Mammary Glands. AB - Staphylococcus aureus (S. aureus) is the causative agent for a wide variety of illnesses ranging from minor skin infections to life-threatening diseases. Development of antibiotic resistance by the bacteria has rendered many antibiotics ineffective. It has been known that plectasin-derived antimicrobial peptides (AMPs; NZ2114 and MP1102) are promising alternatives to antibiotics. However, their activities against S. aureus in mammary glands were unknown. Our objective was to assess the antimicrobial activities of NZ2114 and MP1102 against S. aureus in milk, in cultured mammary epithelial cells, and in a mouse model in order to evaluate their potentials as anti-mastitis agents. NZ2114 and MP1102 showed in vitro bactericidal effects against S. aureus in both the culture medium and the milk. NZ2114 and MP1102 at the concentration of 100 MUg/mL reduced the number of S. aureus by almost 100% within 4 h in processed bovine milk. Similarly, both NZ2114 and MP1102 were efficient to reduce the number of internalized S. aureus in cultured mammary epithelial cells. Finally, both AMPs significantly reduced the S. aureus load and concentrations of TNF-alpha and IL-6 in mammary glands, compared to a buffer control in the mouse model. Our results suggest that NZ2114 and MP1102 may be used to treat S. aureus-induced mastitis. PMID- 29255450 TI - Bifidobacteria and Their Molecular Communication with the Immune System. AB - Bifidobacterium represents a genus within the phylum Actinobacteria which is one of the major phyla in the healthy intestinal tract of humans. Bifidobacterium is one of the most abundant genera in adults, but its predominance is even more pronounced in infants, especially during lactation, when they can constitute the majority of the total bacterial population. They are one of the pioneering colonizers of the early gut microbiota, and they are known to play important roles in the metabolism of dietary components, otherwise indigestible in the upper parts of the intestine, and in the maturation of the immune system. Bifidobacteria have been shown to interact with human immune cells and to modulate specific pathways, involving innate and adaptive immune processes. In this mini-review, we provide an overview of the current knowledge on the immunomodulatory properties of bifidobacteria and the mechanisms and molecular players underlying these processes, focusing on the corresponding implications for human health. We deal with in vitro models suitable for studying strain specific immunomodulatory activities. These include peripheral blood mononuclear cells and T cell-mediated immune responses, both effector and regulatory cell responses, as well as the modulation of the phenotype of dendritic cells, among others. Furthermore, preclinical studies, mainly germ-free, gnotobiotic, and conventional murine models, and human clinical trials, are also discussed. Finally, we highlight evidence supporting the immunomodulatory effects of bifidobacterial molecules (proteins and peptides, exopolysaccharides, metabolites, and DNA), as well as the role of bifidobacterial metabolism in maintaining immune homeostasis through cross-feeding mechanisms. PMID- 29255452 TI - Temporal Dynamics of the Microbial Community Composition with a Focus on Toxic Cyanobacteria and Toxin Presence during Harmful Algal Blooms in Two South German Lakes. AB - Bacterioplankton plays an essential role in aquatic ecosystems, and cyanobacteria are an influential part of the microbiome in many water bodies. In freshwaters used for recreational activities or drinking water, toxic cyanobacteria cause concerns due to the risk of intoxication with cyanotoxins, such as microcystins. In this study, we aimed to unmask relationships between toxicity, cyanobacterial community composition, and environmental factors. At the same time, we assessed the correlation of a genetic marker with microcystin concentration and aimed to identify the main microcystin producer. We used Illumina MiSeq sequencing to study the bacterioplankton in two recreational lakes in South Germany. We quantified a microcystin biosynthesis gene (mcyB) using qPCR and linked this information with microcystin concentration to assess toxicity. Microcystin biosynthesis gene (mcyE)-clone libraries were used to determine the origin of microcystin biosynthesis genes. Bloom toxicity did not alter the bacterial community composition, which was highly dynamic at the lowest taxonomic level for some phyla such as Cyanobacteria. At the OTU level, we found distinctly different degrees of temporal variation between major bacteria phyla. Cyanobacteria and Bacteroidetes showed drastic temporal changes in their community compositions, while the composition of Actinobacteria remained rather stable in both lakes. The bacterial community composition of Alpha- and Beta-proteobacteria remained stable over time in Lake Klostersee, but it showed temporal variations in Lake Bergknappweiher. The presence of potential microcystin degraders and potential algicidal bacteria amongst prevalent Bacteroidetes and Alphaproteobacteria implied a role of those co-occurring heterotrophic bacteria in cyanobacterial bloom dynamics. Comparison of both lakes studied revealed a large shared microbiome, which was shaped toward the lake specific community composition by environmental factors. Microcystin variants detected were microcystin-LR, -RR, and -YR. The maximum microcystin concentrations measured was 6.7 MUg/L, a value still acceptable for recreational waters but not drinking water. Microcystin concentration correlated positively with total phosphorus and mcyB copy number. We identified low abundant Microcystis sp. as the only microcystin producer in both lakes. Therefore, risk assessment efforts need to take into account the fact that non-dominant species may cause toxicity of the blooms observed. PMID- 29255454 TI - Bacterial Diversity and Biogeochemistry of Two Marine Shallow-Water Hydrothermal Systems off Dominica (Lesser Antilles). AB - Shallow-water hydrothermal systems represent extreme environments with unique biogeochemistry and high biological productivity, at which autotrophic microorganisms use both light and chemical energy for the production of biomass. Microbial communities of these ecosystems are metabolically diverse and possess the capacity to transform a large range of chemical compounds. Yet, little is known about their diversity or factors shaping their structure or how they compare to coastal sediments not impacted by hydrothermalism. To this end, we have used automated ribosomal intergenic spacer analysis (ARISA) and high throughput Illumina sequencing combined with porewater geochemical analysis to investigate microbial communities along geochemical gradients in two shallow water hydrothermal systems off the island of Dominica (Lesser Antilles). At both sites, venting of hydrothermal fluids substantially altered the porewater geochemistry by enriching it with silica, iron and dissolved inorganic carbon, resulting in island-like habitats with distinct biogeochemistry. The magnitude of fluid flow and difference in sediment grain size, which impedes mixing of the fluids with seawater, were correlated with the observed differences in the porewater geochemistry between the two sites. Concomitantly, individual sites harbored microbial communities with a significantly different community structure. These differences could be statistically linked to variations in the porewater geochemistry and the hydrothermal fluids. The two shallow-water hydrothermal systems of Dominica harbored bacterial communities with high taxonomical and metabolic diversity, predominated by heterotrophic microorganisms associated with the Gammaproteobacterial genera Pseudomonas and Pseudoalteromonas, indicating the importance of heterotrophic processes. Overall, this study shows that shallow-water hydrothermal systems contribute substantially to the biogeochemical heterogeneity and bacterial diversity of coastal sediments. PMID- 29255455 TI - Sperm-Mediated Transgenerational Inheritance. AB - Spermatozoa of virtually all species can spontaneously take up exogenous DNA or RNA molecules and internalize them into nuclei. In this article I review evidence for a key role of a reverse transcriptase (RT) activity, encoded by LINE-1 retrotransposons, in the fate of the internalized nucleic acid molecules and their implication in transgenerational inheritance. LINE-1-derived RT, present in sperm heads, can reverse-transcribe the internalized molecules in cDNA copies: exogenous RNA is reverse-transcribed in a one-step reaction, whereas DNA is first transcribed into RNA and subsequently reverse-transcribed. Both RNA and cDNA molecules can be delivered from sperm cells to oocytes at fertilization, further propagated throughout embryogenesis and inherited in a non-Mendelian fashion in tissues of adult animals. The reverse-transcribed sequences are extrachromosomal, low-abundance, and mosaic distributed in tissues of adult individuals, where they are variably expressed. These "retrogenes" are transcriptionally competent and induce novel phenotypic traits in animals. Growing evidence indicate that cancer tissues produce DNA- and RNA-containing exosomes. We recently found that these exosomes are released in the bloodstream and eventually taken up into epididymal spermatozoa, consistent with the emerging view that a transgenerational flow of extrachromosomal RNA connects soma to germline and, further, to next generation embryos. Spermatozoa play a crucial bridging role in this process: they act as collectors of somatic information and as delivering vectors to the next generation. On the whole, this phenomenon is compatible with a Lamarckian-type view and closely resembles Darwinian pangenesis. PMID- 29255456 TI - Screening and Identification of the Host Proteins Interacting with Toxoplasma gondii Rhoptry Protein ROP16. AB - Toxoplasma gondii, as a zoonotic protozoan parasite, develops sophisticated strategies to manipulate hosts for efficient intracellular survival. After successful invasion, T. gondii injects many effector proteins into host cells for various purposes. TgROP16 (T. gondii rhoptry protein 16), which is secreted from rhoptries into host cells, can activate the host STAT (signal transducer and activator of transcription) signaling pathway through phosphorylation of STAT3 and STAT6. However, whether there are other host proteins modulated by TgROP16 is currently unknown. In this study, yeast two-hybrid (Y2H) screen was used to look for additional host proteins interacting with TgROP16. Yeast cells expressing a mouse cDNA library cloned into the prey vector were used to mate with yeasts expressing ROP16 without signal peptide. Two mouse proteins, Dnaja1 (DnaJ heat shock protein family member A1) and Gabra4 (gamma-aminobutyric acid A receptor, subunit alpha 4) were identified to interact with ROP16 from this screen. Further analysis suggested that the Predomain of ROP16 played key roles in mediating interactions with these host proteins, whereas the contribution from the Kinase domain was minor. The interactions between Dnaja1 and different parts of ROP16 were also estimated in vivo by co-immunoprecipitation. The results showed that the Predomain of ROP16 was the major region to interact with Dnaja1, which is consistent with the Y2H results. Based on the gene ontology analysis, Dnaja1 is predicted to participate in stress response while Gabra4 is involved in the system development process. The discovery of new host proteins that interact with ROP16 of T. gondii will help us to further investigate the functions of this effector proteins during T. gondii infection. PMID- 29255453 TI - Zoonotic Hepatitis E Virus: An Ignored Risk for Public Health. AB - Hepatitis E virus (HEV) is a quasi-enveloped, single-stranded positive-sense RNA virus. HEV belongs to the family Hepeviridae, a family comprised of highly diverse viruses originating from various species. Since confirmation of HEV's zoonosis, HEV-induced hepatitis has been a public health concern both for developing and developed countries. Meanwhile, the demonstration of a broad host range for zoonotic HEV suggests the existence of a variety of transmission routes that could lead to human infection. Moreover, anti-HEV antibody serosurveillance worldwide demonstrates a higher than expected HEV prevalence rate that conflicts with the rarity and sporadic nature of reported acute hepatitis E cases. In recent years, chronic HEV infection, HEV-related acute hepatic failure, and extrahepatic manifestations caused by HEV infection have been frequently reported. These observations suggest a significant underestimation of the number and complexity of transmission routes previously predicted to cause HEV-related disease, with special emphasis on zoonotic HEV as a public health concern. Significant research has revealed details regarding the virology and infectivity of zoonotic HEV in both humans and animals. In this review, the discovery of HEV zoonosis, recent progress in our understanding of the zoonotic HEV host range, and classification of diverse HEV or HEV-like isolates from various hosts are reviewed in a historic context. Ultimately, this review focuses on current understanding of viral pathogenesis and cross-species transmission of zoonotic HEV. Moreover, host factors and viral determinants influencing HEV host tropism are discussed to provide new insights into HEV transmission and prevalence mechanisms. PMID- 29255457 TI - Corrigendum: Application of Nanotechnology in Food Science: Perception and Overview. AB - [This corrects the article on p. 1501 in vol. 8, PMID: 28824605.]. PMID- 29255459 TI - Suppression of Gingival NK Cells in Precancerous and Cancerous Stages of Pancreatic Cancer in KC and BLT-Humanized Mice. AB - The aim of our studies is to determine the dynamics of natural killer (NK) cell modulation in gingivae in precancerous and cancerous stages of pancreatic and oral cancers in P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation and BLT-humanized mice. Wild type and KC mice fed with control diet (CD) or high-fat calorie diet (HFCD), and the pancreatic and oral tumor-bearing humanized BLT (hu-BLT) mice were used to determine precancerous and cancer induced changes in numbers and function of gingival NK cells. Increased numbers of PanIN lesions and the greatest score of inflammation in pancreas of KC mice fed with CD and HFCD co-related with significant decline in percentages of circulating and gingival NK cells, lack of DX5+ NK expansion and increased secretion of IFN-gamma and IL-6 after culture. At the malignant stage of pancreatic cancer, hu-BLT tumor-bearing mice had the lowest secretion of IFN gamma from cells dissociated from the gingival tissues as compared to those from non-tumor-bearing mice. Injection of NK cells into tumor-bearing mice increased IFN-gamma secretion, and the secretion was similar or higher than those obtained by gingival cells from non-tumor-bearing hu-BLT control mice. The highest increase in IFN-gamma secretion was observed when tumor-bearing mice were fed with AJ2 probiotic bacteria and injected with the NK cells. Along with an increase in secretion of IFN-gamma, injection of NK cells in the presence and absence of feeding with AJ2 in pancreatic tumor-bearing mice increased percentages of CD45+ and CD3+ T cells in oral gingival cells. Similar results were observed with oral tumors. In conclusion, these results indicated that oral cavity may mirror systemic disease and provide a rationale for why cancer patients may be prone to suffer from diverse oral pathologies. PMID- 29255460 TI - O-Serotype Conversion in Salmonella Typhimurium Induces Protective Immune Responses against Invasive Non-Typhoidal Salmonella Infections. AB - Salmonella infections remain a big problem worldwide, causing enteric fever by Salmonella Typhi (or Paratyphi) or self-limiting gastroenteritis by non-typhoidal Salmonella (NTS) in healthy individuals. NTS may become invasive and cause septicemia in elderly or immuno-compromised individuals, leading to high mortality and morbidity. No vaccines are currently available for preventing NTS infection in human. As these invasive NTS are restricted to several O-antigen serogroups including B1, D1, C1, and C2, O-antigen polysaccharide is believed to be a good target for vaccine development. In this study, a strategy of O-serotype conversion was investigated to develop live attenuated S. Typhimurium vaccines against the major serovars of NTS infections. The immunodominant O4 serotype of S. Typhimurium was converted into O9, O7, and O8 serotypes through unmarked chromosomal deletion-insertion mutations. O-serotype conversion was confirmed by LPS silver staining and western blotting. All O-serotype conversion mutations were successfully introduced into the live attenuated S. Typhimurium vaccine S738 (Deltacrp Deltacya) to evaluate their immunogenicity in mice model. The vaccine candidates induced high amounts of heterologous O-polysaccharide-specific functional IgG responses. Vaccinated mice survived a challenge of 100 times the 50% lethality dose (LD50) of wild-type S. Typhimurium. Protective efficacy against heterologous virulent Salmonella challenges was highly O-serotype related. Furthermore, broad-spectrum protection against S. Typhimurium, S. Enteritidis, and S. Choleraesuis was observed by co-vaccination of O9 and O7 O serotype-converted vaccine candidates. This study highlights the strategy of expressing heterologous O-polysaccharides via genetic engineering in developing live attenuated S. Typhimurium vaccines against NTS infections. PMID- 29255461 TI - Type I IFNs Are Required to Promote Central Nervous System Immune Surveillance through the Recruitment of Inflammatory Monocytes upon Systemic Inflammation. AB - Brain-resident microglia and peripheral migratory leukocytes play essential roles in shaping the immune response in the central nervous system. These cells activate and migrate in response to chemokines produced during active immune responses and may contribute to the progression of neuroinflammation. Herein, we addressed the participation of type I-II interferons in the response displayed by microglia and inflammatory monocytes to comprehend the contribution of these cytokines in the establishment and development of a neuroinflammatory process. Following systemic lipopolysaccharide (LPS) challenge, we found glial reactivity and an active recruitment of CD45hi leukocytes close to CD31+ vascular endothelial cells in circumventricular organs. Isolated CD11b+ CD45hi Ly6Chi Ly6G -primed inflammatory monocytes were able to induce T cell proliferation, unlike CD11b+ CD45lo microglia. Moreover, ex vivo re-stimulation with LPS exhibited an enhancement of T cell proliferative response promoted by inflammatory monocytes. These myeloid cells also proved to be recruited in a type I interferon-dependent fashion as opposed to neutrophils, unveiling a role of these cytokines in their trafficking. Together, our results compares the phenotypic and functional features between tissue-resident vs peripheral recruited cells in an inflamed microenvironment, identifying inflammatory monocytes as key sentinels in a LPS induced murine model of neuroinflammation. PMID- 29255458 TI - PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response? AB - PD-1-PD-L1 interaction is known to drive T cell dysfunction, which can be blocked by anti-PD-1/PD-L1 antibodies. However, studies have also shown that the function of the PD-1-PD-L1 axis is affected by the complex immunologic regulation network, and some CD8+ T cells can enter an irreversible dysfunctional state that cannot be rescued by PD-1/PD-L1 blockade. In most advanced cancers, except Hodgkin lymphoma (which has high PD-L1/L2 expression) and melanoma (which has high tumor mutational burden), the objective response rate with anti-PD-1/PD-L1 monotherapy is only ~20%, and immune-related toxicities and hyperprogression can occur in a small subset of patients during PD-1/PD-L1 blockade therapy. The lack of efficacy in up to 80% of patients was not necessarily associated with negative PD-1 and PD L1 expression, suggesting that the roles of PD-1/PD-L1 in immune suppression and the mechanisms of action of antibodies remain to be better defined. In addition, important immune regulatory mechanisms within or outside of the PD-1/PD-L1 network need to be discovered and targeted to increase the response rate and to reduce the toxicities of immune checkpoint blockade therapies. This paper reviews the major functional and clinical studies of PD-1/PD-L1, including those with discrepancies in the pathologic and biomarker role of PD-1 and PD-L1 and the effectiveness of PD-1/PD-L1 blockade. The goal is to improve understanding of the efficacy of PD-1/PD-L1 blockade immunotherapy, as well as enhance the development of therapeutic strategies to overcome the resistance mechanisms and unleash the antitumor immune response to combat cancer. PMID- 29255463 TI - Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings. AB - Germline mutations in the RING finger protein gene RNF168 have been identified in a combined immunodeficiency disorder called RIDDLE syndrome. Since only two patients have been described with somewhat different phenotypes, there is need to identify further patients. Here, we report on two Polish siblings with RNF168 deficiency due to homozygosity for a novel frameshift mutation, c.295delG, that was identified through exome sequencing. Both patients presented with immunoglobulin deficiency, telangiectasia, cellular radiosensitivity, and increased alpha-fetoprotein (AFP) levels. The younger sibling had a more pronounced neurological and morphological phenotype, and she also carried an ATM gene mutation in the heterozygous state. Immunoblot analyses showed absence of RNF168 protein, whereas ATM levels and function were proficient in lymphoblastoid cells from both patients. Consistent with the absence of RNF168 protein, 53BP1 recruitment to DNA double-strand breaks (DSBs) after irradiation was undetectable in lymphoblasts or primary fibroblasts from either of the two patients. gammaH2AX foci accumulated normally but they disappeared with significant delay, indicating a severe defect in DSB repair. A comparison with the two previously identified patients indicates immunoglobulin deficiency, cellular radiosensitivity, and increased AFP levels as hallmarks of RNF168 deficiency. The variability in its clinical expression despite similar cellular phenotypes suggests that some manifestations of RNF168 deficiency may be modified by additional genetic or epidemiological factors. PMID- 29255462 TI - Inflammatory Processes Associated with Canine Intervertebral Disc Herniation. AB - Intervertebral disc herniation (IVDH) is an important pathology in humans and also in dogs. While the molecular disease mechanisms are well investigated in humans, little is known about the inflammatory mediators in naturally occurring canine IVDH. The objective of this study was to investigate whether the involved proinflammatory cytokines in human IVDH are also key cytokines in canine IVDH and thus to elucidate the suitability of the dog as a model for human trials. 59 samples from 25 dogs with surgically confirmed thoracolumbar IVDH were collected and classified in three subgroups: herniated (H), affected non-herniated (NH) disc, and adjacent non-affected (NA) disc. Discs from 11 healthy dogs acted as controls (C). Samples were analyzed for IL-1, IL-6, IL-8, and TNF-alpha expression (qPCR/ELISA) as well as cell infiltration and activation of the MAP kinase pathways (immunohistochemistry). Gene and protein expression of all key cytokines could be detected in IVDH affected dogs. Canine IVDH was significantly associated with a higher gene expression of IL-6 (H > C, NH > C) and TNF-alpha (H > C, NH > C, NA > C) and a significant down-regulation of IL-1beta (H < C). Dogs with spontaneous pain had significantly higher IL-6 mRNA compared to those with pain arising only upon palpation. An inter-donor comparison (H and HN relative to NA) revealed a significant increase of IL-6 gene expression (H > NA, NH > NA). IL 8 (H > C, NA > C) and TNF-alpha (NH > C) protein levels were significantly increased in diseased dogs while inversely, IL-6 protein levels were significantly higher in patients with better clinical outcome. Aside from resident IVD cells, mostly monocytes and macrophages were found in extruded material, with concomitant activation of extracellular signal-regulated kinase p38 in the majority of samples. Dogs with spontaneous IVDH might provide a useful model for human disc diseases. Although the expression of key cytokines found in human IVDH was also demonstrated in canine tissue, the inflammatory mechanisms accompanying canine IVDH diverges partially from humans, which will require further investigations in the future. In dogs, IL-6 seems to play an important pathological role and may represent a new potential therapeutic target for canine patients. PMID- 29255464 TI - Antifungal Activity of Plasmacytoid Dendritic Cells and the Impact of Chronic HIV Infection. AB - Due to the effectiveness of combined antiretroviral therapy, people living with HIV can control viral replication and live longer lifespans than ever. However, HIV-positive individuals still face challenges to their health and well-being, including dysregulation of the immune system resulting from years of chronic immune activation, as well as opportunistic infections from pathogenic fungi. This review focuses on one of the key players in HIV immunology, the plasmacytoid dendritic cell (pDC), which links the innate and adaptive immune response and is notable for being the body's most potent producer of type-I interferons (IFNs). During chronic HIV infection, the pDC compartment is greatly dysregulated, experiencing a substantial depletion in number and compromise in function. This immune dysregulation may leave patients further susceptible to opportunistic infections. This is especially important when considering a new role for pDCs currently emerging in the literature: in addition to their role in antiviral immunity, recent studies suggest that pDCs also play an important role in antifungal immunity. Supporting this new role, pDCs express C-type lectin receptors including dectin-1, dectin-2, dectin-3, and mannose receptor, and toll like receptors-4 and -9 that are involved in recognition, signaling, and response to a wide variety of fungal pathogens, including Aspergillus fumigatus, Cryptococcus neoformans, Candida albicans, and Pneumocystis jirovecii. Accordingly, pDCs have been demonstrated to recognize and respond to certain pathogenic fungi, measured via activation, cytokine production, and fungistatic activity in vitro, while in vivo mouse models indicated a strikingly vital role for pDCs in survival against pulmonary Aspergillus challenge. Here, we discuss the role of the pDC compartment and the dysregulation it undergoes during chronic HIV infection, as well as what is known so far about the role and mechanisms of pDC antifungal activity. PMID- 29255465 TI - The "Phagocytic Synapse" and Clearance of Apoptotic Cells. AB - Apoptosis and subsequent phagocytic clearance of apoptotic cells is important for embryonic development, maintenance of tissues that require regular cellular renewal and innate immunity. The timely removal of apoptotic cells prevents progression to secondary necrosis and release of cellular contents, preventing cellular stress and inflammation. In addition, altered phagocyte behavior following apoptotic cell contact and phagocytosis engages an anti-inflammatory phenotype, which impacts upon development and progression of inflammatory and immune responses. Defective apoptotic cell clearance underlies the development of various inflammatory and autoimmune diseases. There is considerable functional redundancy in the receptors that mediate apoptotic cell clearance, highlighting the importance of this process in diverse physiological processes. A single phagocyte may utilize multiple receptor pathways for the efficient capture of apoptotic cells by phagocytes (tethering) and the subsequent initiation of signaling events necessary for internalization. In this review, we will consider the surface alterations and molecular opsonization events associated with apoptosis that may represent a tunable signal that confers distinct intracellular signaling events and hence specific phagocyte responses in a context-dependent manner. Efficient molecular communication between phagocytes and apoptotic targets may require cooperative receptor utilization and the establishment of efferocytic synapse, which acts to stabilize adhesive interactions and facilitate the organization of signaling platforms that are necessary for controlling phagocyte responses. PMID- 29255467 TI - Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D2 Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species. AB - Prostaglandin D2 (PGD2) is a potent lipid mediator that controls inflammation, and its dysregulation has been implicated in diverse inflammatory disorders. Despite significant progress made in understanding the role of PGD2 as a key regulator of immune responses, the molecular mechanism underlying PGD2 production remains unclear, particularly upon challenge with different and multiple inflammatory stimuli. Interferons (IFNs) potentiate macrophage activation and act in concert with exogenous inflammatory mediators such as toll-like receptor (TLR) ligands to amplify inflammatory responses. A recent study found that IFN-gamma enhanced lipopolysaccharide-induced PGD2 production, indicating a role of IFNs in PGD2 regulation. Here, we demonstrate that TLR-induced PGD2 production by macrophages was significantly potentiated by signaling common to IFN-beta and IFN gamma in a signal transducer and activators of transcription (STAT)1-dependent mechanism. Such potentiation by IFNs was also observed for PGE2 production, despite the differential regulation of PGD synthase and PGE synthase isoforms mediating PGD2 and PGE2 production under inflammatory conditions. Mechanistic analysis revealed that the generation of intracellular reactive oxygen species (ROS) was remarkably potentiated by IFNs and required for PGD2 production, but was nullified by STAT1 deficiency. Conversely, the regulation of STAT1 level and activity by IFNs was largely dependent on ROS levels. Using a model of zymosan induced peritonitis, the relevance of this finding in vivo was supported by marked inhibition of PGD2 and ROS produced in peritoneal exudate cells by STAT1 deficiency. Collectively, our findings suggest that IFNs, although not activating on their own, are potent amplifiers of TLR-induced PGD2 production via positive feedback regulation between STAT1 and ROS. PMID- 29255466 TI - CD215+ Myeloid Cells Respond to Interleukin 15 Stimulation and Promote Tumor Progression. AB - Interleukin 15 (IL-15) regulates the development, survival, and functions of multiple innate and adaptive immune cells and plays a dual role in promoting both tumor cell growth and antitumor immunity. Here, we demonstrated that the in vivo injection of recombinant human IL-15 (200 ug/kg) or murine IL-15 (3 ug/kg) to tumor-bearing NOD-SCID-IL2Rg-/- (NSI) mice resulted in increased tumor progression and CD45+ CD11b+ Gr-1+ CD215+ cell expansion in the tumors and spleen. In B16F10-bearing C57BL/6 mice model, we found that murine IL-15 has antitumoral effect since the activation and expansion of CD8+ T cells with murine IL-15 treatment. But no enhanced or reduced tumor growth was observed in mice when human IL-15 was used. However, both murine and human IL-15 promote CD45+ CD11b+ Gr-1+ CD215+ cells expansion. In xenograft tumor models, CD215+ myeloid cells, but not CD215- cells, responded to human IL-15 stimulation and promoted tumor growth. Furthermore, we found that human IL-15 mediated insulin-like growth factor-1 production in CD215+ myeloid cells and blocking IGF-1 reduced the tumor promoting effect of IL-15. Finally, we observed that higher IGF-1 expression is an indicator of poor prognosis among lung adenocarcinoma patients. These findings provide evidence that IL-15 may promote tumor cell progression via CD215+ myeloid cells, and IGF-1 may be an important candidate that IL-15 facilitates tumor growth. PMID- 29255469 TI - Shared IgG Infection Signatures vs. Hemorrhage-Restricted IgA Clusters in Human Dengue: A Phenotype of Differential Class-Switch via TGFbeta1. AB - Phenotypic manifestations of infectious diseases are closely related to individual immune responses. Methods to extract information from patients' own immune reactions would be of great use for both diagnosis and treatment. Dengue fever is one of the diseases that clinical aggravations could occur paradoxically after humoral immunity appears. This property makes dengue fever an excellent disease model to explore. A principal component analyses (PCAs)-based framework derived from a prior vaccination study was developed. The framework was verified by successful demonstrations of known IgG signatures from a Mexico Dengue data set. Afterward the pipeline was tested upon de novo IgG and IgA libraries of Dengue patients from southern Taiwan. We discovered four infection signatures within IgG repertoires, two of which were identical to previous reports. However, it was IgA but not IgG that could differentiate hemorrhagic from non-hemorrhagic patients. IgA repertoires were found more diversified among bleeders, from whom seven signature clusters were characterized. The expressions of transforming growth factor beta 1 (TGFbeta1) and accordingly mediated class-switch activity of IgA were distinct only among the PCA-segregated bleeding group. In sum, intercontinental sharing of IgG signatures in dengue fever was demonstrated via a unified working flow. Differential regulation of IgA class-switch with associated diversity expansion plus existences of hemorrhage-restricted clusters were shown. The ability of the framework to find common IgG signatures would implicate applications to infections even from unknown pathogens. The clusters within IgA repertoires could offer perspectives to other IgA-related bleeding disorders such as Henoch-Schonlein purpura or IgA nephropathy. Substantiated grounds for IgA specific effector function via TGFbeta1-mediated class-switch would be a new factor to consider for infectious diseases. PMID- 29255468 TI - The Role of Estrogen Membrane Receptor (G Protein-Coupled Estrogen Receptor 1) in Skin Inflammation Induced by Systemic Lupus Erythematosus Serum IgG. AB - Skin injury is the second most common clinical manifestation in patients with systemic lupus erythematosus (SLE). Estrogen may affect the onset and development of SLE through its receptor. In this study, we investigated the role of estrogen membrane receptor G protein-coupled estrogen receptor 1 (GPER1) in skin injury of SLE. We found that skin injury induced by SLE serum was more severe in female mice and required monocytes. Estrogen promoted activation of monocytes induced by lupus IgG through the membrane receptor GPER1 which was located in lipid rafts. Blockade of GPER1 and lipid rafts reduced skin inflammation induced by SLE serum. The results we obtained suggest that GPER1 plays an important role in the pathogenesis of skin inflammation induced by lupus IgG and might be a therapeutic target in skin lesions of patients with SLE. PMID- 29255471 TI - Editorial: Cytotoxic CD4+ T Cells in Viral Infections. PMID- 29255470 TI - CpG Oligodeoxinucleotides and Flagellin Modulate the Immune Response to Antigens Targeted to CD8alpha+ and CD8alpha- Conventional Dendritic Cell Subsets. AB - Dendritic cells (DCs) are antigen-presenting cells essential for the induction of adaptive immune responses. Their unprecedented ability to present antigens to T cells has made them excellent targets for vaccine development. In the last years, a new technology based on antigen delivery directly to different DC subsets through the use of hybrid monoclonal antibodies (mAbs) to DC surface receptors fused to antigens of interest opened new perspectives for the induction of robust immune responses. Normally, the hybrid mAbs are administered with adjuvants that induce DC maturation. In this work, we targeted an antigen to the CD8alpha+ or the CD8alpha- DC subsets in the presence of CpG oligodeoxinucleotides (ODN) or bacterial flagellin, using hybrid alphaDEC205 or alphaDCIR2 mAbs, respectively. We also accessed the role of toll-like receptors (TLRs) 5 and 9 signaling in the induction of specific humoral and cellular immune responses. Wild-type and TLR5 or TLR9 knockout mice were immunized with two doses of the hybrid alphaDEC205 or alphaDCIR2 mAbs, as well as with an isotype control, together with CpG ODN 1826 or flagellin. A chimeric antigen containing the Plasmodium vivax 19 kDa portion of the merozoite surface protein (MSP119) linked to the Pan-allelic DR epitope was fused to each mAb. Specific CD4+ T cell proliferation, cytokine, and antibody production were analyzed. We found that CpG ODN 1826 or flagellin were able to induce CD4+ T cell proliferation, CD4+ T cells producing pro-inflammatory cytokines, and specific antibodies when the antigen was targeted to the CD8alpha+ DC subset. On the other hand, antigen targeting to CD8alpha- DC subset promoted specific antibody responses and proliferation, but no detectable pro-inflammatory CD4+ T cell responses. Also, specific antibody responses after antigen targeting to CD8alpha+ or CD8alpha- DCs were reduced in the absence of TLR9 or TLR5 signaling, while CD4+ T cell proliferation was mainly affected after antigen targeting to CD8alpha+ DCs and in the absence of TLR9 signaling. These results extend our understanding of the modulation of specific immune responses induced by antigen targeting to DCs in the presence of different adjuvants. Such knowledge may be useful for the optimization of DC-based vaccines. PMID- 29255472 TI - Immunity to alpha-Gal: The Opportunity for Malaria and Tuberculosis Control. PMID- 29255473 TI - When a Plant Resistance Inducer Leaves the Lab for the Field: Integrating ASM into Routine Apple Protection Practices. AB - Plant resistance inducers, also called elicitors, could be useful to reduce the use of pesticides. However, their performance in controlling diseases in the field remains unsatisfactory due to lack of specific knowledge of how they can integrate crop protection practices. In this work, we focused on apple crop and acibenzolar-S-methyl (ASM), a well-known SAR (systemic acquired resistance) inducer of numerous plant species. We provide a protocol for orchard-effective control of apple scab due to the ascomycete fungus Venturia inaequalis, by applying ASM in combination with a light integrated pest management program. Besides we pave the way for future optimization levers by demonstrating in controlled conditions (i) the high influence of apple genotypes, (ii) the ability of ASM to prime defenses in newly formed leaves, (iii) the positive effect of repeated elicitor applications, (iv) the additive effect of a thinning fruit agent. PMID- 29255474 TI - Corrigendum: Involvement of Polyamine Oxidase-Produced Hydrogen Peroxide during Coleorhiza-Limited Germination of Rice Seeds. AB - [This corrects the article on p. 1219 in vol. 7, PMID: 27570530.]. PMID- 29255475 TI - Benznidazole affects expression of Th1, Th17 and Treg cytokines during acute experimental Trypanosoma cruzi infection. AB - Background: The present study evaluated the effect of treatment with benznidazole on mRNA expression of IFN-gamma, IL-17, IL-10, TGF-beta and FoxP3 in spleen and heart tissue of BALB/c mice in the acute phase of an experimental infection with Trypanosoma cruzi, strains JLP or Y. Methods: The mRNA expression of cytokines and parasite load were assessed by q-PCR. Dependent groups were compared using Student's paired t-test and independent groups were compared using Student's unpaired t-test. Results: Infection with the JLP or Y strains increased expression of IFN-gamma in the heart and of IL-10 and IL-17 in the spleen and heart compared to uninfected animals. Treatment increased the expression of IFN gamma and decreased the expression of IL-17, IL-10, TGF- beta and Foxp3 in spleen and heart tissue compared to untreated infected animals. Conclusion: Benznidazole can induce Th1 profile in the initial of the acute phase. The treatment decreased the parasite load in both organs, although the number of parasites in Y-strain infected mice remained high. The data suggest that benznidazole may modulate cytokine expression in infection and can be dependent of the strain. However, treatment was not fully effective in the infection provoked by Y strain, probably due to the characteristics of the strain itself. PMID- 29255476 TI - MPO-ANCA associated vasculitis with mononeuritis multiplex following influenza vaccination. AB - Background: Although influenza vaccines are generally safe and effective, a variety of autoimmune phenomena have been reported after vaccination over the past years, such as Guillain-Barre syndrome, rheumatoid arthritis, pemphigus vulgaris, psoriasis, giant cell arteritis and anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). Case report: We describe the case of a 67-year old man who presented with a myeloperoxidase-ANCA associated vasculitis with renal involvement and mononeuritis multiplex after seasonal influenza vaccination. He was initially treated with intravenous cyclophosphamide and high dose prednisolone followed by maintenance treatment consisting of azathioprine and prednisolone. Conclusion: We hypothesize that seasonal influenza vaccination triggered a systemic immune response in a susceptible patient to develop AAV with renal involvement and vasculitic neuropathy. In general, seasonal influenza vaccinations are considered to be safe, however, clinicians should be aware of this rare phenomenon. PMID- 29255477 TI - Unraveling climate influences on the distribution of the parapatric newts Lissotriton vulgaris meridionalis and L. italicus. AB - Background: Climate is often considered as a key ecological factor limiting the capability of expansion of most species and the extent of suitable habitats. In this contribution, we implement Species Distribution Models (SDMs) to study two parapatric amphibians, Lissotriton vulgaris meridionalis and L. italicus, investigating if and how climate has influenced their present and past (Last Glacial Maximum and Holocene) distributions. A database of 901 GPS presence records was generated for the two newts. SDMs were built through Boosted Regression Trees and Maxent, using the Worldclim bioclimatic variables as predictors. Results: Precipitation-linked variables and the temperature annual range strongly influence the current occurrence patterns of the two Lissotriton species analyzed. The two newts show opposite responses to the most contributing variables, such as BIO7 (temperature annual range), BIO12 (annual precipitation), BIO17 (precipitation of the driest quarter) and BIO19 (precipitation of the coldest quarter). The hypothesis of climate influencing the distributions of these species is also supported by the fact that the co-occurrences within the sympatric area fall in localities characterized by intermediate values of these predictors. Projections to the Last Glacial Maximum and Holocene scenarios provided a coherent representation of climate influences on the past distributions of the target species. Computation of pairwise variables interactions and the discriminant analysis allowed a deeper interpretation of SDMs' outputs. Further, we propose a multivariate environmental dissimilarity index (MEDI), derived through a transformation of the multivariate environmental similarity surface (MESS), to deal with extrapolation-linked uncertainties in model projections to past climate. Finally, the niche equivalency and niche similarity tests confirmed the link between SDMs outputs and actual differences in the ecological niches of the two species. Conclusions: The different responses of the two species to climatic factors have significantly contributed to shape their current distribution, through contractions, expansions and shifts over time, allowing to maintain two wide allopatric areas with an area of sympatry in Central Italy. Moreover, our SDMs hindcasting shows many concordances with previous phylogeographic studies carried out on the same species, thus corroborating the scenarios of potential distribution during the Last Glacial Maximum and the Holocene emerging from the models obtained. PMID- 29255478 TI - Comparison of mitochondrial gene expression and polysome loading in different tobacco tissues. AB - Background: To investigate translational regulation of gene expression in plant mitochondria, a mitochondrial polysome isolation protocol was established for tobacco to investigate polysomal mRNA loading as a proxy for translational activity. Furthermore, we developed an oligonucleotide based microarray platform to determine the level of Nicotiana tabacum and Arabidopsis thaliana mitochondrial mRNA. Results: Microarray analysis of free and polysomal mRNAs was used to characterize differences in the levels of free transcripts and ribosome bound mRNAs in various organs of tobacco plants. We have observed higher mitochondrial transcript levels in young leaves, flowers and floral buds as compared to fully expanded leaves and roots. A similar pattern of abundance was observed for ribosome-bound mitochondrial mRNAs in these tissues. However, the accumulation of the mitochondrial protein COX2 was found to be inversely related to that of its ribosome-bound mRNA. Conclusions: Our results indicate that the association of mitochondrial mRNAs to ribosomes is largely determined by the total transcript level of a gene. However, at least for Cox2, we demonstrated that the level of ribosome-bound mRNA is not reflected by the amount of COX2 protein. PMID- 29255479 TI - Insights into the mechanism of a novel shockwave-assisted needle-free drug delivery device driven by in situ-generated oxyhydrogen mixture which provides efficient protection against mycobacterial infections. AB - Background: Needle-free, painless and localized drug delivery has been a coveted technology in the area of biomedical research. We present an innovative way of trans-dermal vaccine delivery using a miniature detonation-driven shock tube device. This device utilizes~2.5 bar of in situ generated oxyhydrogen mixture to produce a strong shockwave that accelerates liquid jets to velocities of about 94 m/s. Method: Oxyhydrogen driven shock tube was optimized for efficiently delivering vaccines in the intradermal region in vivo. Efficiency of vaccination was evaluated by pathogen challenge and host immune response. Expression levels of molecular markers were checked by qRT-PCR. Results: High efficiency vaccination was achieved using the device. Post pathogen challenge with Mycobacterium tuberculosis, 100% survival was observed in vaccinated animals. Immune response to vaccination was significantly higher in the animals vaccinated using the device as compared to conventional route of vaccination. Conclusion: A novel device was developed and optimized for intra dermal vaccine delivery in murine model. Conventional as well in-house developed vaccine strains were used to test the system. It was found that the vaccine delivery and immune response was at par with the conventional routes of vaccination. Thus, the device reported can be used for delivering live attenuated vaccines in the future. PMID- 29255481 TI - Re-using biological devices: a model-aided analysis of interconnected transcriptional cascades designed from the bottom-up. AB - Background: The study of simplified, ad-hoc constructed model systems can help to elucidate if quantitatively characterized biological parts can be effectively re used in composite circuits to yield predictable functions. Synthetic systems designed from the bottom-up can enable the building of complex interconnected devices via rational approach, supported by mathematical modelling. However, such process is affected by different, usually non-modelled, unpredictability sources, like cell burden. Methods: Here, we analyzed a set of synthetic transcriptional cascades in Escherichia coli. We aimed to test the predictive power of a simple Hill function activation/repression model (no-burden model, NBM) and of a recently proposed model, including Hill functions and the modulation of proteins expression by cell load (burden model, BM). To test the bottom-up approach, the circuit collection was divided into training and test sets, used to learn individual component functions and test the predicted output of interconnected circuits, respectively. Results: Among the constructed configurations, two test set circuits showed unexpected logic behaviour. Both NBM and BM were able to predict the quantitative output of interconnected devices with expected behaviour, but only the BM was also able to predict the output of one circuit with unexpected behaviour. Moreover, considering training and test set data together, the BM captures circuits output with higher accuracy than the NBM, which is unable to capture the experimental output exhibited by some of the circuits even qualitatively. Finally, resource usage parameters, estimated via BM, guided the successful construction of new corrected variants of the two circuits showing unexpected behaviour. Conclusions: Superior descriptive and predictive capabilities were achieved considering resource limitation modelling, but further efforts are needed to improve the accuracy of models for biological engineering. PMID- 29255483 TI - Detection and imaging of lipids of Scenedesmus obliquus based on confocal Raman microspectroscopy. AB - In this study, confocal Raman microspectroscopy was used to detect lipids in microalgae rapidly and non-destructively. Microalgae cells were cultured under nitrogen deficiency. The accumulation of lipids in Scenedesmus obliquus was observed by Nile red staining, and the total amount of lipids accumulated in the cells was measured by gravimetric method. The signals from different microalgae cells were collected by confocal Raman microspectroscopy to establish a prediction model of intracellular lipid content, and surface scanning signals for drawing pseudo color images of lipids distribution. The images can show the location of pyrenoid and lipid accumulation in cells. Analyze Raman spectrum data and build PCA-LDA model using four different bands (full bands, pigments, lipids, and mixed features). Models of full bands or pigment characteristic bands were capable of identifying S. obliquus cells under different nitrogen stress culture time. The prediction accuracy of model of lipid characteristic bands is relatively low. The correlation between the fatty acid content measured by the gravimetric method and the integral Raman intensity of the oil characteristic peak (1445 cm-1) measured by Raman spectroscopy was analyzed. There was significant correlation (R2 = 0.83), which means that Raman spectroscopy is applicable to semi-quantitative detection of microalgal lipid content. PMID- 29255482 TI - Production of C2-C4 diols from renewable bioresources: new metabolic pathways and metabolic engineering strategies. AB - C2-C4 diols classically derived from fossil resource are very important bulk chemicals which have been used in a wide range of areas, including solvents, fuels, polymers, cosmetics, and pharmaceuticals. Production of C2-C4 diols from renewable resources has received significant interest in consideration of the reducing fossil resource and the increasing environmental issues. While bioproduction of certain diols like 1,3-propanediol has been commercialized in recent years, biosynthesis of many other important C2-C4 diol isomers is highly challenging due to the lack of natural synthesis pathways. Recent advances in synthetic biology have enabled the de novo design of completely new pathways to non-natural molecules from renewable feedstocks. In this study, we review recent advances in bioproduction of C2-C4 diols, focusing on new metabolic pathways and metabolic engineering strategies being developed. We also discuss the challenges and future trends toward the development of economically competitive processes for bio-based diol production. PMID- 29255480 TI - Immunological challenges associated with artificial skin grafts: available solutions and stem cells in future design of synthetic skin. AB - The repair or replacement of damaged skins is still an important, challenging public health problem. Immune acceptance and long-term survival of skin grafts represent the major problem to overcome in grafting given that in most situations autografts cannot be used. The emergence of artificial skin substitutes provides alternative treatment with the capacity to reduce the dependency on the increasing demand of cadaver skin grafts. Over the years, considerable research efforts have focused on strategies for skin repair or permanent skin graft transplantations. Available skin substitutes include pre- or post-transplantation treatments of donor cells, stem cell-based therapies, and skin equivalents composed of bio-engineered acellular or cellular skin substitutes. However, skin substitutes are still prone to immunological rejection, and as such, there is currently no skin substitute available to overcome this phenomenon. This review focuses on the mechanisms of skin rejection and tolerance induction and outlines in detail current available strategies and alternatives that may allow achieving full-thickness skin replacement and repair. PMID- 29255484 TI - Lipopeptide produced from Bacillus sp. W112 improves the hydrolysis of lignocellulose by specifically reducing non-productive binding of cellulases with and without CBMs. AB - Background: Surfactants have attracted increasing interest for their capability to improve the enzymatic hydrolysis of lignocellulosic biomass. Compared to chemical surfactants, biosurfactants have a broader prospect for industrial applications because they are more environmentally friendly and more effective in some researches. Commercial cellulase preparations are mainly composed of endoglucanases (EGs) and cellobiohydrolases (CBHs) that possess carbohydrate binding modules (CBMs). However, the effects of lipopeptide-type biosurfactants on enzymatic saccharification of lignocellulose and adsorption behaviors of cellulases with CBMs remain unclear. Results: In this study, we found that Bacillus sp. W112 could produce a lipopeptide-type biosurfactant from untreated biomass, such as wheat bran and Jerusalem artichoke tuber. The lipopeptide could enhance the enzymatic hydrolysis of dilute acid pretreated Giant Juncao grass (DA GJG) by fungal and bacterial enzymes. The enhancement increased over a range of temperatures from 30 to 50 degrees C. Lipopeptide was shown to be more effective in promoting DA-GJG saccharification than chemical surfactants at low dosages, with a best stimulatory degree of 20.8% at 2% loading of the substrates (w/w). Lipopeptide increased the thermostability of EG and CBH in commercial cellulase cocktails. Moreover, the dual effects of lipopeptide on the adsorption behaviors of cellulases were found. It specifically lowered the non-productive binding of cellulases to lignin and increased the binding of cellulases to cellulose. In addition, we investigated the influence of lipopeptide on the adsorption behaviors of CBHs with CBMs for the first time. Our results showed that lipopeptide reduced the adsorption of CBM-deleted CBH to DA-GJG to a greater extent than that of intact CBH while the non-productive binding of intact CBH to lignin was reduced more, indicating that lipopeptide decreased the binding of CBMs onto lignin but not their combination with cellulose. Conclusions: In this study, we found that lipopeptide from Bacillus sp. W112 promoted the enzymatic hydrolysis of DA-GJG at relative low loadings. The stimulatory effect could be attributed to increasing the cellulase thermostability, reducing non-productive adsorption of cellulases with CBMs caused by lignin and enhancing the binding of cellulases to cellulose. PMID- 29255485 TI - The effect of temperature and retention time on methane production and microbial community composition in staged anaerobic digesters fed with food waste. AB - Background: Food waste is a large bio-resource that may be converted to biogas that can be used for heat and power production, or as transport fuel. We studied the anaerobic digestion of food waste in a staged digestion system consisting of separate acidogenic and methanogenic reactor vessels. Two anaerobic digestion parameters were investigated. First, we tested the effect of 55 vs. 65 degrees C acidogenic reactor temperature, and second, we examined the effect of reducing the hydraulic retention time (HRT) from 17 to 10 days in the methanogenic reactor. Process parameters including biogas production were monitored, and the microbial community composition was characterized by 16S amplicon sequencing. Results: Neither organic matter removal nor methane production were significantly different for the 55 and 65 degrees C systems, despite the higher acetate and butyrate concentrations observed in the 65 degrees C acidogenic reactor. Ammonium levels in the methanogenic reactors were about 950 mg/L NH4+ when HRT was 17 days but were reduced to 550 mg/L NH4+ at 10 days HRT. Methane production increased from ~ 3600 mL/day to ~ 7800 when the HRT was decreased. Each reactor had unique environmental parameters and a correspondingly unique microbial community. In fact, the distinct values in each reactor for just two parameters, pH and ammonium concentration, recapitulate the separation seen in microbial community composition. The thermophilic and mesophilic digesters were particularly distinct from one another. The 55 degrees C acidogenic reactor was mainly dominated by Thermoanaerobacterium and Ruminococcus, whereas the 65 degrees C acidogenic reactor was initially dominated by Thermoanaerobacterium but later was overtaken by Coprothermobacter. The acidogenic reactors were lower in diversity (34-101 observed OTU0.97, 1.3-2.5 Shannon) compared to the methanogenic reactors (472-513 observed OTU0.97, 5.1-5.6 Shannon). The microbial communities in the acidogenic reactors were > 90% Firmicutes, and the Euryarchaeota were higher in relative abundance in the methanogenic reactors. Conclusions: The digestion systems had similar biogas production and COD removal rates, and hence differences in temperature, NH4+ concentration, and pH in the reactors resulted in distinct but similarly functioning microbial communities over this range of operating parameters. Consequently, one could reduce operational costs by lowering both the hydrolysis temperature from 65 to 55 degrees C and the HRT from 17 to 10 days. PMID- 29255486 TI - Enhancing methane production from food waste fermentate using biochar: the added value of electrochemical testing in pre-selecting the most effective type of biochar. AB - Background: Recent studies have suggested that addition of electrically conductive biochar particles is an effective strategy to improve the methanogenic conversion of waste organic substrates, by promoting syntrophic associations between acetogenic and methanogenic organisms based on interspecies electron transfer processes. However, the underlying fundamentals of the process are still largely speculative and, therefore, a priori identification, screening, and even design of suitable biochar materials for a given biotechnological process are not yet possible. Results: Here, three charcoal-like products (i.e., biochars) obtained from the pyrolysis of different lignocellulosic materials, (i.e., wheat bran pellets, coppiced woodlands, and orchard pruning) were tested for their capacity to enhance methane production from a food waste fermentate. In all biochar-supplemented (25 g/L) batch experiments, the complete methanogenic conversion of fermentate volatile fatty acids proceeded at a rate that was up to 5 times higher than that observed in the unamended (or sand-supplemented) controls. Fluorescent in situ hybridization analysis coupled with confocal laser scanning microscopy revealed an intimate association between archaea and bacteria around the biochar particles and provided a clear indication that biochar also shaped the composition of the microbial consortium. Based on the application of a suite of physico-chemical and electrochemical characterization techniques, we demonstrated that the positive effect of biochar is directly related to the electron-donating capacity (EDC) of the material, but is independent of its bulk electrical conductivity and specific surface area. The latter properties were all previously hypothesized to play a major role in the biochar-mediated interspecies electron transfer process in methanogenic consortia. Conclusions: Collectively, these results of this study suggest that for biochar addition in anaerobic digester operation, the screening and identification of the most suitable biochar material should be based on EDC determination, via simple electrochemical tests. PMID- 29255487 TI - Insect biorefinery: a green approach for conversion of crop residues into biodiesel and protein. AB - Background: As a major lignocellulosic biomass, which represented more than half of the world's agricultural phytomass, crop residues have been considered as feedstock for biofuel production. However, large-scale application of this conventional biofuel process has been facing obstacles from cost efficiency, pretreatment procedure, and secondary pollution. To meet the growing demands for food, feed, and energy as the global population continues to grow, certain kinds of insects, many of which are voracious feeders of organic wastes that may help address environmental, economic, and health issues, have been highlighted as a source of protein and fat. Results: The biorefinery studied includes initial corn stover degradation by yellow mealworm (Tenebrio molitor L.), followed by a second stage that employs black soldier fly (Hermetia illucens L.), to utilize the residues produced during the first stage. These two insect-based biorefinery yielded 8.50 g of insect biomass with a waste dry mass reduction rate of 51.32%, which resulted in 1.95 g crude grease from larval biomass that produced 1.76 g biodiesel, 6.55 g protein, and 111.59 g biofertilizer. The conversion rate of free fatty acids of crude grease into biodiesel reached 90%. The components of cellulose, hemicellulose, and lignin contained in corn stover hydrolyzed harmoniously, resulting in declines of 45.69, 51.85, and 58.35%, respectively. Moreover, fluctuations in lipid, protein, and reducing sugar were also analyzed. Conclusion: The investigation findings demonstrated that successive co-conversion of corn stover by insects possessing different feeding habits could be an attractive option for efficient utilization of lignocellulosic resources, and represents a potentially valuable solution to crop residues management, rise of global liquid energy, and animal feed demand. PMID- 29255488 TI - Modulation of the main porcine enteric neuropeptides by a single low-dose of lipopolysaccharide (LPS) Salmonella Enteritidis. AB - Background: The present research was conducted to investigate the influence of a low, single dose of LPS, which does not result in any clinical symptoms of intoxication on the expression of selected neuropeptides within the intestines of the domestic pig. Methods: This experiment was conducted on immature female pigs of the Pitrain * Duroc breed (n = five per group). Seven days after the intravenous injection of 10 mL saline solution for control animals and 5 MUg/kg b.w. (in 10 mL saline solution) LPS Salmonella Enteritidis for the experimental group, the excised segments of duodenum, jejunum, ileum, ileocecal valve, caecum, descending colon, transverse colon, ascending colon and rectum were prepared to extract the main enteric neuropeptides, including GAL, NPY, SOM, SP, VIP. Results: The results of this research indicate that single low-dose LPS S. Enteritidis produced changes in the content of the selected neuropeptides of the porcine intestine. The most visible changes were observed in the transverse colon, where LPS induced the increase of GAL expression from 19.41 +/- 7.121 to 92.92 +/- 11.447 ng/g tissue. Conclusion: The exact functions of the substances studied and mechanisms of responses to LPS action depend on the sections of the intestines. The mechanisms of observed changes are not fully understood, but fluctuations in neuronal active substance levels may be connected with neurodegenerative and/or pro-inflammatory activity of LPS. PMID- 29255489 TI - Recovery of Salmonella isolated from eggs and the commercial layer farms. AB - Background: Salmonella is recognized as a common bacterial cause of foodborne diarrheal illness worldwide, and animal or its food products have been the most common vehicles of the Salmonella infections. This study aimed to investigate the distribution of Salmonella in two commercial layer farms and to determine the genetic relatedness between these strains. The Salmonella isolates were serotyped by slide agglutination using commercial antisera and analyzed for genetic relatedness using pulsed-field gel electrophoresis (PFGE). Results: The internal environment had the highest prevalence of Salmonella (14/15, 93.3%), followed by external environment (60/96, 62.5%) and egg samples (23/84, 27.3%). The prevalence of Salmonella in the environment was significantly higher than that in egg samples (p < 0.05). The occurrence of Salmonella in the internal environment (93.3%) was relatively higher than in the external environment (55.6-77.2%). The 111 isolates were distributed among 15 PFGE types, and the PFGE results suggested that there existed cross-contamination between these strains not only from eggs, but also from the environments. Conclusions: The findings indicated ongoing Salmonella cross-contamination inside or outside of the layer farms, and that Salmonella could also spread along the egg production line. PMID- 29255490 TI - Exposure to environmental microbiota explains persistent abdominal pain and irritable bowel syndrome after a major flood. AB - Background: After an environmental disaster, the affected community is at increased risk for persistent abdominal pain but mechanisms are unclear. Therefore, our study aimed to determine association between abdominal pain and poor water, sanitation and hygiene (WaSH) practices, and if small intestinal bacterial overgrowth (SIBO) and/or gut dysbiosis explain IBS, impaired quality of life (QOL), anxiety and/or depression after a major flood. Results: New onset abdominal pain, IBS based on the Rome III criteria, WaSH practices, QOL, anxiety and/or depression, SIBO (hydrogen breath testing) and stools for metagenomic sequencing were assessed in flood victims. Of 211 participants, 37.9% (n = 80) had abdominal pain and 17% (n = 36) with IBS subtyped diarrhea and/or mixed type (n = 27 or 12.8%) being the most common. Poor WaSH practices and impaired quality of life during flood were significantly associated with IBS. Using linear discriminant analysis effect size method, gut dysbiosis was observed in those with anxiety (Bacteroidetes and Proteobacteria, effect size 4.8), abdominal pain (Fusobacteria, Staphylococcus, Megamonas and Plesiomonas, effect size 4.0) and IBS (Plesiomonas and Trabulsiella, effect size 3.0). Conclusion: Disturbed gut microbiota because of environmentally-derived organisms may explain persistent abdominal pain and IBS after a major environmental disaster in the presence of poor WaSH practices. PMID- 29255491 TI - Favourable metabolic profile sustains mitophagy and prevents metabolic abnormalities in metabolically healthy obese individuals. AB - Background: Obesity-mediated oxidative stress results in mitochondrial dysfunction, which has been implicated in the pathogenesis of metabolic syndrome and T2DM. Recently, mitophagy, a cell-reparative process has emerged as a key facet in maintaining the mitochondrial health, which may contribute to contain the metabolic abnormalities in obese individuals. However, the status of mitophagy in metabolically healthy obese (MHO) and metabolically abnormal diabetic obese (MADO) subjects remains to be elucidated. Hence, the present study aims to unravel the alterations in mitochondrial oxidative stress (MOS) and mitophagy in these subjects. Methods: 60 subjects including MHNO (metabolically healthy non-obese), MHO and MADO were enrolled as per the Asian criteria for obesity (n = 20 each). Biochemical parameters, MOS indices, transcriptional and translational expression of mitophagy markers (PINK1, PARKIN, MFN2, NIX, LC3-II, and LAMP-2), and transmission electron microscopic (TEM) studies were performed in peripheral blood mononuclear cells. Results: The MHO subjects displayed a favorable metabolic profile, despite accompanied by an increased adiposity as compared to the MHNO group; while MADO group exhibited several metabolic abnormalities, inspite of similar body composition as MHO subjects. A progressive rise in the MOS was observed in MHO and MADO subjects as compared to the MHNO group, and it showed a positive and significant correlation with the body composition in these groups. Further, mitophagy remained unaltered in the MHO group, while it was significantly downregulated in the MADO group. In addition, TEM studies revealed a significant increase in the percentage of damaged mitochondria in MADO patients as compared to other groups, while MHO and MHNO groups did not show any significant alterations for the same. Conclusion: A favorable metabolic profile and moderate levels of MOS in the MHO group may play a crucial role in the sustenance of mitophagy, which may further limit the aggravation of MOS, inflammation, and emergence of metabolic aberrations in contrast to MADO subjects, who exhibited multiple metabolic abnormalities and attenuated mitophagy. Therefore, these MHO subjects are likely to be at a lower risk of developing metabolic syndrome and T2DM. PMID- 29255492 TI - Locus-specific hypomethylation of the mouse IAP retrotransposon is associated with transcription factor-binding sites. AB - Background: Intracisternal A particle (IAP) is one of the most transpositionally active retrotransposons in the mouse genome, but its expression varies between cell types. This variation is believed to arise from differences in the epigenetic state (e.g., DNA methylation) of the 5' long terminal repeat (LTR), where transcription starts. However, owing to the high copy number and high sequence similarity between copies, it is difficult to analyze the epigenetic states of individual IAP LTRs in a comprehensive manner. Results: We have developed a method called Target Enrichment after Post-Bisulfite Adaptor Tagging (TEPBAT) to analyze the DNA methylation states of a large number of individual retrotransposon copies at once. Using this method, we determined the DNA methylation levels of >8500 copies of genomic IAP LTRs (almost all copies that we aimed to target by the PCR primers) in the sperm and tail. This revealed that the vast majority of the LTRs were heavily methylated in both sperm and tail; however, hypomethylated copies were more frequently found in the sperm than in the tail. Interestingly, most of these hypomethylated LTRs were solo-type, belonged to specific IAP subfamilies, and carried binding sites for transcription factors (TFs) that are active in male germ cells. Conclusions: The current study revealed subfamily- and locus-specific hypomethylation of IAP LTRs, and suggests that binding of TFs is involved in the protection from DNA methylation, whereas the IAP internal sequence enhances methylation. Furthermore, the study demonstrated that TEPBAT offers a cost-effective method for a variety of DNA methylome studies that focus on retrotransposon sequences. PMID- 29255493 TI - De-novo emergence of SINE retroposons during the early evolution of passerine birds. AB - Background: Passeriformes ("perching birds" or passerines) make up more than half of all extant bird species. The genome of the zebra finch, a passerine model organism for vocal learning, was noted previously to contain thousands of short interspersed elements (SINEs), a group of retroposons that is abundant in mammalian genomes but considered largely inactive in avian genomes. Results: Here we resolve the deep phylogenetic relationships of passerines using presence/absence patterns of SINEs. The resultant retroposon-based phylogeny provides a powerful and independent corroboration of previous sequence-based analyses. Notably, SINE activity began in the common ancestor of Eupasseres (passerines excluding the New Zealand wrens Acanthisittidae) and ceased before the rapid diversification of oscine passerines (suborder Passeri - songbirds). Furthermore, we find evidence for very recent SINE activity within suboscine passerines (suborder Tyranni), following the emergence of a SINE via acquisition of a different tRNA head as we suggest through template switching. Conclusions: We propose that the early evolution of passerines was unusual among birds in that it was accompanied by de-novo emergence and activity of SINEs. Their genomic and transcriptomic impact warrants further study in the light of the massive diversification of passerines. PMID- 29255494 TI - Fast Quantitation of Pyrazole Fungicides in Wine by Ambient Ionization Mass Spectrometry. AB - Fungicides are widely used for growing the grapes that are used for making wines. Chromatography coupled with tandem mass spectrometry is usually time and labor consuming for quantitation of fungicides in wines. In this work, a simple ambient mass spectrometry method using paper capillary spray was developed for the fast quantitation of four pyrazole fungicides in wines. Direct analysis of the wine samples was achieved without any sample preparation, obtaining limits of quantitation as low as 2 ng/mL for all four pyrazole fungicides. Quality control experiments also showed adequate accuracy and precision for the analysis of pyrazole fungicides in wine products. PMID- 29255495 TI - A scheme for a flexible classification of dietary and health biomarkers. AB - Biomarkers are an efficient means to examine intakes or exposures and their biological effects and to assess system susceptibility. Aided by novel profiling technologies, the biomarker research field is undergoing rapid development and new putative biomarkers are continuously emerging in the scientific literature. However, the existing concepts for classification of biomarkers in the dietary and health area may be ambiguous, leading to uncertainty about their application. In order to better understand the potential of biomarkers and to communicate their use and application, it is imperative to have a solid scheme for biomarker classification that will provide a well-defined ontology for the field. In this manuscript, we provide an improved scheme for biomarker classification based on their intended use rather than the technology or outcomes (six subclasses are suggested: food compound intake biomarkers (FCIBs), food or food component intake biomarkers (FIBs), dietary pattern biomarkers (DPBs), food compound status biomarkers (FCSBs), effect biomarkers, physiological or health state biomarkers). The application of this scheme is described in detail for the dietary and health area and is compared with previous biomarker classification for this field of research. PMID- 29255496 TI - Serum microRNA array analysis identifies miR-140-3p, miR-33b-3p and miR-671-3p as potential osteoarthritis biomarkers involved in metabolic processes. AB - Background: MicroRNAs (miRNAs) in circulation have emerged as promising biomarkers. In this study, we aimed to identify a circulating miRNA signature for osteoarthritis (OA) patients and in combination with bioinformatics analysis to evaluate the utility of selected differentially expressed miRNAs in the serum as potential OA biomarkers. Methods: Serum samples were collected from 12 primary OA patients, and 12 healthy individuals were screened using the Agilent Human miRNA Microarray platform interrogating 2549 miRNAs. Receiver Operating Characteristic (ROC) curves were constructed to evaluate the diagnostic performance of the deregulated miRNAs. Expression levels of selected miRNAs were validated by quantitative real-time PCR (qRT-PCR) in all serum and in articular cartilage samples from OA patients (n = 12) and healthy individuals (n = 7). Bioinformatics analysis was used to investigate the involved pathways and target genes for the above miRNAs. Results: We identified 279 differentially expressed miRNAs in the serum of OA patients compared to controls. Two hundred and five miRNAs (73.5%) were upregulated and 74 (26.5%) downregulated. ROC analysis revealed that 77 miRNAs had area under the curve (AUC) > 0.8 and p < 0.05. Bioinformatics analysis in the 77 miRNAs revealed that their target genes were involved in multiple signaling pathways associated with OA, among which FoxO, mTOR, Wnt, pI3K/akt, TGF beta signaling pathways, ECM-receptor interaction, and fatty acid biosynthesis. qRT-PCR validation in seven selected out of the 77 miRNAs revealed 3 significantly downregulated miRNAs (hsa-miR-33b-3p, hsa-miR-671-3p, and hsa-miR 140-3p) in the serum of OA patients, which were in silico predicted to be enriched in pathways involved in metabolic processes. Target-gene analysis of hsa miR-140-3p, hsa-miR-33b-3p, and hsa-miR-671-3p revealed that InsR and IGFR1 were common targets of all three miRNAs, highlighting their involvement in regulation of metabolic processes that contribute to OA pathology. Hsa-miR-140-3p and hsa miR-671-3p expression levels were consistently downregulated in articular cartilage of OA patients compared to healthy individuals. Conclusions: A serum miRNA signature was established for the first time using high density resolution miR-arrays in OA patients. We identified a three-miRNA signature, hsa-miR-140-3p, hsa-miR-671-3p, and hsa-miR-33b-3p, in the serum of OA patients, predicted to regulate metabolic processes, which could serve as a potential biomarker for the evaluation of OA risk and progression. PMID- 29255497 TI - Association between long interspersed nuclear element-1 methylation levels and relapse in Wilms tumors. AB - Background: Wilms tumor (WT) is a curable pediatric renal malignancy, but there is a need for new molecular biomarkers to improve relapse risk-directed therapy. Somatic alterations occur at relatively low frequencies whereas epigenetic changes at 11p15 are the most common aberration. We analyzed long interspersed element-1 (LINE-1) methylation levels in the blastemal component of WT and normal kidney samples to explore their prognostic significance. Results: WT samples presented a hypomethylated pattern at all five CpG sites compared to matched normal kidney samples; therefore, the averaged methylation levels of the five CpG sites were used for further analyses. WT presented a hypomethylation profile (median 65.0%, 47.4-73.2%) compared to normal kidney samples (median 71.8%, 51.5 77.5%; p < 0.0001). No significant associations were found between LINE-1 methylation levels and clinical-pathological characteristics. We observed that LINE-1 methylation levels were lower in tumor samples from patients with relapse (median methylation 60.5%) compared to patients without relapse (median methylation 66.5%; p = 0.0005), and a receiving operating characteristic curve analysis was applied to verify the ability of LINE-1 methylation levels to discriminate WT samples from these patients. Using a cut-off value of 62.71% for LINE-1 methylation levels, the area under the curve was 0.808, with a sensitivity of 76.5% and a specificity of 83.3%. Having identified differences in LINE-1 methylation between WT samples from patients with and without relapse in this cohort, we evaluated other prognostic factors using a logistic regression model. This analysis showed that in risk stratification, LINE-1 methylation level was an independent variable for relapse risk: the lower the methylation levels, the higher the risk of relapse. The logistic regression model indicated a relapse risk increase of 30% per decreased unit of methylation (odds ratio 1.30; 95% confidence interval 1.07-1.57). Conclusion: Our results reinforce previous data showing a global hypomethylation profile in WT. LINE-1 methylation levels can be suggested as a marker of relapse after chemotherapy treatment in addition to risk classification, helping to guide new treatment approaches. PMID- 29255498 TI - Syncope and the risk of sudden cardiac death: Evaluation, management, and prevention. AB - Syncope is a clinical syndrome defined as a relatively brief self-limited transient loss of consciousness (TLOC) caused by a period of inadequate cerebral nutrient flow. Most often the trigger is an abrupt drop of systemic blood pressure. True syncope must be distinguished from other common non-syncope conditions in which real or apparent TLOC may occur such as seizures, concussions, or accidental falls. The causes of syncope are diverse, but in most instances, are relatively benign (e.g., reflex and orthostatic faints) with the main risks being accidents and/or injury. However, in some instances, syncope may be due to more worrisome conditions (particularly those associated with cardiac structural disease or channelopathies); in such circumstances, syncope may be an indicator of increased morbidity and mortality risk, including sudden cardiac death (SCD). Establishing an accurate basis for the etiology of syncope is crucial in order to initiate effective therapy. In this review, we focus primarily on the causes of syncope that are associated with increased SCD risk (i.e., sudden arrhythmic cardiac death), and the management of these patients. In addition, we discuss the limitations of our understanding of SCD in relation to syncope, and propose future studies that may ultimately address how to improve outcomes of syncope patients and reduce SCD risk. PMID- 29255499 TI - Reflex syncope: Diagnosis and treatment. AB - For the diagnosis of reflex syncope, diligent history-building with the patient and a witness is required. In the Emergency Department (ED), the assessment of syncope is a challenge which may be addressed by an ED Observation Unit or by a referral to a Syncope Unit. Hospital admission is necessary for those with life threatening cardiac conditions although risk stratification remains an unsolved problem. Other patients may be investigated with less urgency by carotid sinus massage (>40 years), tilt testing, and electrocardiogram loop recorder insertion resulting in a clear cause for syncope. Management includes, in general terms, patient education, avoidance of circumstances in which syncope is likely, increase in fluid and salt consumption, and physical counter-pressure maneuvers. In older patients, those that will benefit from cardiac pacing are now well defined. In all patients, the benefit of drug therapy is often disappointing and there remains no ideal drug. A role for catheter ablation may emerge for the highly symptomatic reflex syncope patient. PMID- 29255500 TI - Life-threatening arrhythmias leading to syncope in patients with vasospastic angina. AB - The coronary artery diseases (CAD) that can lead to the occurrence of a syncopal attack include acute coronary syndrome, vasospastic angina, effort angina, and prior myocardial infarction. The possible mechanisms considered to lead to syncope in patients with CAD are pump failure, tachyarrhythmia, bradycardia, and vagal stimulation. Coronary artery spasm, in particular, is occasionally observed in patients with unexplained syncope in Japan. Life-threatening arrhythmias are among the most serious complications of an ischemic attack caused by coronary spasm, and are associated with an increased risk of syncope and/or sudden cardiac death (SCD). Therefore, during the initial evaluation of unexplained syncope, the diagnosis of vasospastic angina (VSA) needs to be made promptly, to avert the risk of SCD as a consequence of syncope triggered by the lethal arrhythmia. The inducibility of polymorphic ventricular tachycardia or ventricular fibrillation, increased QT dispersion, T-wave alternans, and early repolarization during the asymptomatic period are considered risk markers for ventricular arrhythmias during coronary spasm. In view of the conclusions from several studies, implantable cardioverter/defibrillator therapy should be considered in patients who are at high risk for recurrence of syncope due to a fatal ventricular arrhythmia triggered by coronary spasm, despite appropriate medical therapy. PMID- 29255502 TI - Role of head-up tilt table testing in patients with syncope or transient loss of consciousness. AB - The tilt table test (TTT) is a useful method for the management of reflex syncope. However, the TTT is incomplete and has several problems. The indications for this test are established using guidelines. The TTT is not suitable for all syncopal patients. It is currently unclear (1) When should the TTT be used, (2) for which types of patients TTT should be performed, and (3) does the TTT provide useful information to guide indication for pacing therapy for reflex syncope. The answers to these questions appear in recent reports from two guidelines published by the European Society of Cardiology and the Japan Circulation Society. The indications for TTT do not apply to all syncopal patients, but selected patients. For patients with low risks and rare syncopal events, the TTT is not necessary, even when diagnoses are unconfirmed. The TTT is used not only for diagnosis of reflex syncope, but also for many clinical management of several conditions (i.e., exclusion of cardiac syncope). Positive TTT results cannot predict the effects of pacing therapy for reflex syncope. The decision to use pacing therapy should be based on documented electrocardiograms and other findings, including TTT results. PMID- 29255501 TI - Syncope and paroxysmal atrioventricular block. AB - Current literature reveals three types of paroxysmal atrioventricular block (AVB) that can cause syncope: Intrinsic paroxysmal atrioventricular block is due to an intrinsic disease of the AV conduction system; this type of "cardiac syncope" is also called Stokes-Adams attack; Extrinsic vagal paroxysmal atrioventricular block is linked to the effect of the parasympathetic nervous system on cardiac conduction and is one of the mechanisms involved in "reflex syncope." Extrinsic idiopathic paroxysmal atrioventricular block is associated with low levels of endogenous adenosine and is supposed to be one of the mechanisms involved in "low adenosine syncope." These three types of paroxysmal AVB present different clinical and electrocardiographic features. Additionally, the efficacy of cardiac pacing and theophylline therapy to prevent syncopal recurrences is also different for these three types of AVB. PMID- 29255503 TI - Syncope in patients with inherited arrhythmias. AB - Syncope, a common symptom of cerebral ischemia often shows a multifactorial etiopathogenesis. Although inherited arrhythmias causing syncope is uncommon, such an occurrence could be a warning sign preceding cardiac arrest. Long QT syndrome (LQTS) is a typical inherited arrhythmia causing syncope in children. Early diagnosis and treatment of LQTS using beta-blockers prevents recurrent syncope in LQTS. Brugada syndrome, another typical inherited arrhythmia causes syncope or sudden cardiac arrest in young individuals. Syncope as a symptom is useful for risk stratification of fatal arrhythmias and in selection of appropriate therapy. Catecholaminergic polymorphic ventricular tachycardia, another rare inherited arrhythmia causing recurrent syncope is associated with poor outcomes without medication. Early detection and therapeutic intervention improve prognosis; thus, correct diagnosis of syncope is imperative in cases of these inherited arrhythmias. We describe syncope associated with three typical inherited arrhythmias and discuss various diagnostic modalities. PMID- 29255504 TI - Use of implantable and external loop recorders in syncope with unknown causes. AB - The gold standard for diagnosing syncope is to elucidate the symptom electrocardiogram (ECG) correlation. The ECG recordings during syncope allow physicians to either confirm or exclude an arrhythmia as the mechanism of syncope. Many studies have investigated the use of internal loop recorder (ILR), while few studies have used external loop recorder (ELR) for patients with unexplained syncope. The aim of this review is to clarify the clinical usefulness of ILR and ELR in the diagnosis and management of patients with unexplained syncope. Many observational and four randomized control studies have shown that ILR for patients with unknown syncope is a useful tool for early diagnosis and improving diagnosis rate. ILR also provides important information on the mechanism of syncope and treatment strategy. However, there is no evidence of total mortality or quality of life improvements with ILR. The diagnostic yield of ELR in patients with syncope was similar to that with ILR within the same timeframe. Therefore, ELR could be considered for long-term ECG monitoring before a patient switches to using ILR. A systematic approach and selection of ECG monitoring tools reduces health care costs and improves the selection of patients for optimal treatment possibilities. PMID- 29255505 TI - Ambulatory electrocardiogram monitoring devices for evaluating transient loss of consciousness or other related symptoms. AB - Capturing electrocardiograms (ECGs) during spontaneous events is the most powerful available tool to identify or exclude an arrhythmic cause of symptoms, and often can elucidate the definite diagnosis for different conditions, such as transient loss of consciousness (T-LOC), lightheadedness, or palpitations. Current ambulatory ECG monitoring technologies include 24-hour Holter, wearable event recorder, external loop recorder (ELR), and insertable cardiac monitoring (ICM). Of them, Holter ECG is most frequently used in daily practice in Japan, while ELR and ICM are less frequently used. However, the appropriate monitor choice should be based on the expected frequency of symptoms. Frequent events may be adequately detected by Holter ECG, but less frequent symptoms are more effectively assessed by longer-term monitoring (i.e., ELR or ICM). In this report, based on our clinical experience, we review the usefulness of ambulatory ECG monitoring devices, especially of ELR, for evaluating T-LOC and other potentially arrhythmia-related symptoms. Specifically, we focus on the use of ELR and ICM for evaluating Japanese patients with T-LOC. PMID- 29255506 TI - Driving restrictions for patients with reflex syncope. AB - Reflex syncope is the most common form of syncope that occurs while driving. The 2014 revision of Japanese Road Traffic Laws placed stricter driving restrictions, along with some associated legal penalties, on individuals with recurrent syncope. "Recurrent syncope" is defined as the occurrence of more than two episodes of syncope over a period of 5 years. No restrictions are recommended for private drivers unless they experience syncope without a reliable prodrome while driving or sitting. For commercial drivers, a driving restriction is recommended unless the efficacy of treatment can be confirmed. The "risk of harm" (RH) to other road users appears to be particularly high when commercial driving is involved. The RH formula is calculated using the time of driving, the type of vehicle driven, the risk of sudden cardiac incapacitation, and the probability of a fatal or injury-producing accident. Reducing the driving time or driving a lighter vehicle can reduce the RH. Physicians should talk to their patients about driving and advise their high-risk patients to refrain from driving. PMID- 29255507 TI - Driving restrictions in patients with implantable cardioverter defibrillators and pacemakers. AB - Implantable cardioverter-defibrillators (ICDs) improve the survival in patients at risk of sudden cardiac death. However, these patients have an ongoing risk of sudden incapacitation that may cause harm to individuals and others when driving. Considerable disagreement exists about whether and when these patients should be allowed to resume driving after ICD therapies. This information is critical for the management decisions to avoid future potentially lethal incidents and unnecessary restrictions for ICD patients. The cardiac implantable device committee of the Japanese Heart Rhythm Society reassessed the risk of driving for ICD patients based on the literature and domestic data. We reviewed the driving restrictions of ICD patients in various regions and here present updated Japanese driving restrictions. PMID- 29255508 TI - Value of adenosine test to reveal dormant conduction or adenosine-induced atrial fibrillation after pulmonary vein isolation. AB - Background: Recent studies investigating the implications of additional ablation guided by dormant pulmonary vein (PV) conduction testing using adenosine showed conflicting results, and the data about atrial fibrillation (AF) recurrence after trigger site elimination in adenosine-induced AF are still lacking. Methods: Of 846 patients with paroxysmal AF (PAF) who underwent PV isolation (PVI), adenosine test after PVI was performed in 148 patients. Results: PVI was successfully achieved in 846 patients. We excluded 58 patients due to loss to the follow-up. A higher rate of AF recurrence was found in the group without adenosine test (136/644, 21%) compared to the group with adenosine test (20/144, 13%, log-rank P=0.047). In multivariate analysis model for AF freedom during the follow-up period, the only significant clinical predictor of AF freedom was adenosine test (hazard ratio [HR] 1.97; 95% confidence interval [CI]: 1.2-3.23; P=0.007).Among 148 patients with adenosine test, 114 (77%) patients showed neither dormant conductions nor AF-induced, 22 (15%) showed positive dormant conductions only, and 12 (8%) revealed adenosine-induced AF (6 of them also showed dormant conduction). After additional ablation in positive dormant conduction group and adenosine-induced AF group, AF recurrence was noted in 4/21 (19%) patients in positive dormant conduction group and 2/11 (18%) patients in adenosine-induced AF group, which was not different from that of patients in negative dormant conduction/ no AF-induced group (14/112, 12%, log-rank P=0.67). Conclusions: Adenosine test after PVI to confirm the absence of dormant conduction and triggers initiating AF is beneficial to improve the outcomes after catheter ablation of PAF. PMID- 29255509 TI - Clinical implications of serum adiponectin on progression of atrial fibrillation. AB - Background: The association between circulating adiponectin levels and atrial fibrillation (AF) is uncertain. We, therefore, investigated whether an increased serum adiponectin level is implicated in the long-term recurrence of AF after ablation therapy. Methods: Our study included 100 consecutive patients (88 men; median age, 57.9+/-10.9 years) who underwent catheter ablation for AF at our hospital between 2011 and 2013. The adiponectin and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured before ablation and compared between those in whom AF recurred and those in whom AF did not recur. Results: Elevation in adiponectin levels was significantly associated with female sex, non paroxysmal AF, heart failure, higher NT-proBNP and matrix metallo-proteinase-2 levels, and lower body mass index. After a stepwise adjustment for any potential confounding variables, the adiponectin levels remained significantly associated with female sex (beta=0.2601, P=0.0041), non-paroxysmal AF (beta=0.2708, P=0.0080), and higher NT-proBNP levels (beta=0.2536, P= 0.0138). During the median follow-up period of 26.2 months, AF recurred in 48 of the 100 patients. Stepwise multivariate adjustment showed that an increased log-transformed NT proBNP (Hazard ratio [HR], 2.18; 95% confidence interval [CI] 1.25-4.00; P=0.0055), longer duration of AF (HR, 1.87; 95%CI 1.01-3.76; P=0.0465), and decreased left ventricular ejection fraction (HR, 0.96; 95%CI 0.93-0.99; P=0.0391) were independent predictors of recurrent AF after catheter ablation, but adiponectin was not. Conclusions: Our data indicated that adiponectin was partially responsible for progression of AF, but the correlation between adiponectin levels and AF recurrence was not significant. PMID- 29255510 TI - Transesophageal echocardiographic thromboembolic risk is associated with smoking status in patients with atrial fibrillation. AB - Background: Smoking is a risk factor for cardiovascular diseases, but it is unclear whether smoking status, including environmental tobacco smoke, increases stroke risk in patients with atrial fibrillation (AF). Abnormalities of the left atrium (LA) and aortic atherosclerosis, as detected by transesophageal echocardiography (TEE), are risk factors for stroke and thromboembolism in AF patients. We investigated the impact of smoking status on thromboembolic risk by TEE in patients with nonvalvular AF. Methods: In 122 patients with AF (mean age, 63 years; chronic AF 50%) who underwent TEE before catheter ablation of AF or for detection of the potential cardioembolic source, urinary concentrations of cotinine and clinical variables including smoking status and the CHA2DS2-VASc score were determined. Results: Severe aortic atherosclerosis and increased aortic wall thickness were more frequently detected by TEE in current smokers than in non-smokers (p<0.05), though these findings did not significantly differ between non-smokers and environmental smokers. Patients in AF rhythm during TEE, who were environmental smokers and at relatively low risk, as stratified by their CHA2DS2-VASc score (<= 2), showed lower LA appendage flow velocity than those without environmental smoking (47+/-22 vs. 34+/-13 cm/sec, p<0.05). Conclusions: TEE findings indicated that smoking status could be associated with thromboembolic risk in patients with AF. PMID- 29255511 TI - Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non-valvular atrial fibrillation. AB - Background: Dabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co-administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug-drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated. Methods: Changes in blood dabigatran concentration (DC) were investigated using the dilute thrombin time test in a randomized, open label, two-period crossover study including 34 Japanese patients with NVAF receiving dabigatran therapy with or without PPI. Results: The average trough DC was significantly higher without PPI than with PPI (83 +/- 42.3 vs. 55.5 +/- 24.6 ng/mL, respectively; P < 0.001). Similarly, the average peak DC was significantly higher without PPI than with PPI (184.1 +/- 107.7 vs. 124 +/- 59.2 ng/mL, respectively; P = 0.0029). The average ratio of DC change at the trough and peak levels did not differ significantly among the three PPI types. Conclusions: PPI administration significantly decreased the trough and peak DCs in patients with NVAF. Therefore, when prescribing PPIs for patients with NVAF in a clinical setting, the possibility that the bioavailability of dabigatran may decrease should be considered. PMID- 29255513 TI - Radiofrequency ablation of ventricular premature contraction originating from a native coronary cusp after transcatheter aortic valve replacement. AB - We describe a case of radiofrequency ablation of ventricular premature contraction (VPC) originating from the left ventricular outflow tract after transcatheter aortic valve replacement. The VPC origin was the native aortic valve annulus between the left and right coronary cusps. Radiofrequency ablation was successfully performed by manipulating the ablation catheter from the gap between the sinotubular junction and implanted valve. PMID- 29255512 TI - Ten-year experience in atenolol use and exercise evaluation in children with genetically proven long QT syndrome. AB - Background: Due to its availability, atenolol is the primary beta-blocker used in Australia for children with long QT syndrome. There is limited data on long-term follow-up of its use. Methods: A single-tertiary-center, retrospective, observational study investigating all children and adolescents who had genetically proven long QT syndrome type 1 (LQT1) and type 2 (LQT2) was conducted. Their pretreatment exercise tests were evaluated for QTc intervals into the recovery phase of exercise. Results: Eighty six patients were identified (LQT1, 67, and LQT2, 19) from 2004 to 2014. The majority (86%) of patients were initially referred for family screening. Atenolol was administered at a mean dose of 1.58 +/- 0.51 mg/kg/day. During the median follow-up period of 4.29 years, only one proband developed ventricular arrhythmia whilst taking atenolol, No patient had cardiac arrest or aborted cardiac arrest. With respect to side effects of atenolol, only two patients had intolerable side effects necessitating changes of medication. Evaluation of exercise tests (pretreatment) demonstrated that corrected QT (QTc) intervals at 2-3 min into the recovery phase of exercise were significantly prolonged for LQT1 patients. LQT1 patients with transmembrane mutation had longer QTc intervals than their C-terminus mutation counterparts, reaching statistical significance at 3 min into the recovery phase of exercise. Conclusions: Atenolol is an effective treatment for genetically proven LQT1 and LQT2 children and adolescents, with good tolerability. In LQT1 patients, QTc intervals at 2-3 min into the recovery phase of exercise were significantly prolonged, particularly in patients with transmembrane mutations. PMID- 29255514 TI - Marshall bundle reentrant atrial tachycardia after the Cox-Maze IV procedure: The last barrier of the conduction pathway between the coronary sinus and left atrium. AB - A 74-year-old woman who developed atrial tachycardia following the Cox-Maze IV procedure underwent catheter ablation. The reentrant circuit included the coronary sinus (CS), Marshall bundle (MB), distal MB-left atrial (LA) connection, and anterolateral mitral annulus. The distal MB-LA connection was the last barrier in the conduction pathway between the CS and the left atrium. PMID- 29255515 TI - Pacing failure caused by automatic pacing threshold adjustment system. AB - Ventricular capture management is an automatic pacing threshold adjustment algorithm that automatically measures pacing threshold through detection of the evoked response after a pacing stimulus. Although it is principally designed to save device battery under the maintenance of the patient's safety, we experienced a rare case with serious pacing failure due to a weakness of this algorithm. This pacing failure might be explained by a large variation in the ventricular pacing threshold depending on the atrioventricular interval and daily variation of pacing threshold and concomitant steroid use in this patient. PMID- 29255516 TI - The details of an unusual "ghost" after transvenous lead extraction: Three dimensional computed tomography analysis. AB - Transvenous lead extraction (TLE) is performed to prevent deaths in patients with device infections. Intracardiac masses detected by echocardiography, i.e., "ghosts," are reported in 8% of patients after a TLE in retrospective studies and in 14% in prospective studies. We herein describe a case with unusual ghosts after a TLE. Three-dimensional computed tomography (3DCT) is useful for revealing all the details of unusual ghosts. In this case, the residual silicone insulation and "cast," including the fibrous sheath and severe calcifications could be visualized and differentiated by 3DCT. PMID- 29255517 TI - Complex regional pain syndrome induced by pacemaker implantation for sick sinus syndrome. AB - A 53-year-old woman reported burning pain, muscle weakness, and dysesthesia of the left arm 2 months after permanent pacemaker insertion in the ipsilateral side for the treatment of sick sinus syndrome. Complex regional pain syndrome (CRPS) induced by pacemaker implantation was diagnosed. In 2017, her pulse generator became exhausted and was exchanged carefully to avoid exacerbation of CRPS, under the application of local anesthesia and premedication. Six months later, the patient's grip strength in her left hand remained lower relative to that in her right hand. Although rare, the presence of CRPS following device implantation should be remembered. PMID- 29255518 TI - Extracardiac compression of the inferolateral branch of the coronary vein by the descending aorta in a patient with dilated cardiomyopathy. AB - Extracardiac structures can cause distortion of cardiac anatomy particularly in patients presenting with a significantly dilated heart, and/or thoracic deformities. We present the case of a 69-year-old woman with dilated cardiomyopathy who underwent cardiac resynchronization therapy. Preoperative electrocardiography-gated contrast-enhanced computed tomography revealed the inferolateral wall of her significantly dilated and leftward-rotated heart was close to the descending aorta, and the descending aorta compressed the sandwiched inferolateral branch of the coronary vein. Retrograde coronary venography performed at the time of device implantation confirmed focal stenosis of the inferolateral branch of the coronary vein. PMID- 29255519 TI - Cardiac resynchronization therapy via transvenous approach in a 2-year-old boy with a complete atrioventricular block after a tetralogy of Fallot repair. AB - Cardiac resychronization therapy (CRT) was performed via transvenous approach in a 2-year-old boy with a tetralogy of Fallot and postoperative severe heart failure, and complete atrioventricular block treated with a dual-chamber pacemaker. Epicardial leads were unavailable because of mediastinitis and the presence of severe bilateral pleural effusions requiring continuous drainage. There were no procedural complications. Biventricular pacing was significantly effective and both mediastinitis and pleural effusions recurred. The transvenous CRT was exchanged for an epicardial CRT after 4 months because of the possibility of a venous obstruction. PMID- 29255520 TI - Loss of cardiac resynchronization therapy in a patient with a biventricular implantable cardioverter-defibrillator. AB - Here, we discuss the case of a man with a history of ischemic cardiomyopathy and cardiac resynchronization therapy defibrillator implantation, who presented to emergency department with decompensated heart failure due to the loss of resynchronization therapy. The reason for the malfunction was left ventricle upper rate interval lock-in due to inappropriate programming of the device. PMID- 29255521 TI - Uninterrupted dabigatran is safer than warfarin in patients undergoing ablation for atrial fibrillation. PMID- 29255522 TI - Factors affecting ambulatory ability in patients aged 90 years and older following proximal femoral fractures. AB - Objectives: To investigate the details of patients' status on admission and at discharge at our hospital, to compare the ambulatory group and non-ambulatory group at discharge, and to assess the factors associated with ambulatory ability at discharge in patients aged >= 90 years with proximal femoral fractures (PFFs). Patients/Materials and Methods: Twenty patients admitted to our hospital for rehabilitation after surgery for a PFF were evaluated retrospectively. The rate of regaining ambulatory ability, presence of dementia, body mass index, serum albumin level, hemoglobin level, lymphocyte count, and functional independence measure (FIM) were assessed on admission and at discharge. Relationships between patients' ambulatory ability and ambulatory parameters were compared between the ambulatory and non-ambulatory groups. Results: The rate of regaining ambulatory ability was 55% at discharge. The serum albumin level at discharge was significantly higher in the ambulatory group than that in the non-ambulatory group. More patients had dementia on admission in the non-ambulatory group than in the ambulatory group. On admission, scores for the cognitive items of the FIM ("expression" and "memory") were significantly higher in the ambulatory group than those in the non-ambulatory group. Conclusions: The rate of ambulatory ability at discharge was 55% in those with a PFF, who were aged >= 90 years. The presence of dementia on admission and serum albumin level at discharge were factors related to ambulatory ability. It is very important to use a general rehabilitation protocol that takes cognitive function and nourishment into account, in addition to the physical aspect. PMID- 29255523 TI - A retrospective cohort study on the risk assessment of newly certificated long term care need of elderly individuals in a community: Basic checklist and specific health checkup. AB - Objective: This study aimed to examine the factors influencing the requirement of a certificate of long-term care using a basic checklist and items listed in the Special Health Checkup. Method: This study included 7,820 individuals living in Uji city, who were selected from among 8,000 elderly individuals who, in 2008, underwent a specific health checkup (hereafter referred to as the 'specific health checkup for the old-old elderly individuals') for those aged 75 years and above. They answered questions from basic checklists at the time, and 180 individuals were excluded as they had already qualified for requiring the certificate of long-term care at the time of the checkup. The follow-up period extended from the day of the specific health checkup for the old-old elderly individuals to March 31, 2013. The data were analyzed using the certificate of needing long-term care as the response variable. The explanatory variables were the basic attributes, items listed in the specific health checkup for the old-old elderly individuals, interview sheets, and basic checklists. Cox proportional hazards regression analysis was conducted. Results: In total, 1,280 elderly individuals qualified for requiring the certificate of needing long-term care. The risk factors for the young-old elderly individuals aged 65 to 74 years were as follows: hepatic dysfunction (hazard ratio {HR}=1.69), the presence of subjective symptoms (HR=1.41), an above-normal abdominal circumference (HR=1.36), old age (HR=1.13), a reduced frequency of going out since the previous year (HR=1.87), the use of support for standing up after being seated on a chair (HR=1.86), no deposit or withdrawals made (HR=1.84), the anxiety of falling down (HR=1.50), an inability to climb stairs without holding a railing or wall (HR=1.49), as well as an increased difficulty in eating tough food items compared with 6 months prior (HR=1.44). The risk factors for the old-old elderly individuals were as follows: a positive reaction on proteinuria (HR=1.27), anemia (HR=1.18), old age (HR=1.10), inability to travel on a bus or train by themselves (HR=1.53), the inability to climb stairs without holding a railing or wall (HR=1.48), weight loss (HR=1.36), a reduced sense of appreciation of the activities they had previously participated in, over a span of 2 weeks (HR=1.30), the use of support for standing up after being seated on a chair (HR=1.23), and the anxiety of falling down (HR=1.20). Conclusion: The items listed in the specific medical checkup as well as the basic checklists were found to be risk factors for both the young-old elderly individuals and the old-old elderly individuals, indicating the need to utilize these lists for the prevention of nursing even in the late stages of life. Moreover, these results suggest the importance of screening elderly individuals suffering from hyperkinesis using the basic checklist and conducting preventive interventions in order to maintain and improve their physical functions. PMID- 29255524 TI - Investigation of amputees with prosthetic limbs at our hospital. AB - Objectives: This study was performed to elucidate the characteristics of amputees in our hospital. We also evaluated whether the causes and characteristics of the amputations influenced the patients' prosthetic walking ability. Materials and Methods: We retrospectively examined 47 amputees in our hospital from December 1996 to April 2016 with respect to the causes and levels of amputation. Of 28 lower limb amputees from April 2008 to April 2016, 22 received prostheses and were divided into 2 groups according to the cause of the amputation, as follows: the internal cause group (e.g., vascular deficiency and infection) and the external cause group (e.g., trauma, burn injury, and crush syndrome). The characteristics and process of achieving prosthetic ambulation were compared between these groups. Results: Trauma was the most common cause of both upper (70.0%) and lower limb amputations (40.5%). Unilateral amputation was performed in 93.2% of patients (upper limb amputation, 100.0%; lower limb amputation, 91.9%). Patients were older in the internal than in the external cause group (P = 0.026). The serum albumin (P = 0.003) and total cholesterol concentrations (P = 0.046) on admission were significantly lower in the internal than in the external cause group. All patients in the internal cause group had comorbidities. The proportions of patients with diabetes mellitus (P = 0.011) and cerebrovascular disease (P=0.036) were significantly higher in the internal than in the external cause group. No significant difference in walking ability was found between the internal and external cause groups at the time of discharge. Conclusion: Most amputees in our hospital underwent unilateral lower limb amputation due to trauma. Although the patients with internal causes of amputation were older, more frequently had malnutrition, and had more comorbidities than those with external causes, they achieved prosthetic walking with statistically insignificant difference at the end of hospitalization, excluding six patients who had no prosthetic prescription. PMID- 29255525 TI - Effects of practicing in remote Japanese islands on physicians' control of negative emotions: A qualitative study. AB - Objective: To explore how rural physicians practicing in the remote islands of Okinawa, Japan experience and manage their negative emotions. Materials and Methods: We conducted semi-structured interviews with doctors who had worked in a clinic on a remote island in Okinawa prefecture for 2 years. The interviews were conducted using an Internet video conferencing system, and were recorded and transcribed. The transcribed data were then analyzed using the Steps Coding and Theorization method as a framework. Results: All four participants were male. The mean interview time was 61 minutes. In the category of induction of negative emotions, we extracted five themes: differences in recognition between rural physicians and patients, invasion of professionalism, suppression by one's role as a rural physician, discordance with multiple occupations, and relationships with unfamiliar hospital physicians. In the category of controlling negative emotions, we also extracted five themes: time flow, reflection, acceptance of islanders' characteristics, and growth through their role. Conclusion: Rural physicians in the remote islands of Okinawa experienced negative emotions in relation to patients, other islanders, and medical staff. They deepened their understanding of the islanders, including the cultural background, over time and through discussion and reflection with other medical professionals. In this way, they realized their potential for growth and how to control negative emotions. Thus, rural physicians may be able to effectively control their negative emotions through recognizing temporal changes in human relations and their own adaptation to the remote island life. PMID- 29255526 TI - Evaluation of the knowledge of women and registered nurses in Japan regarding the benefits and risks of breast cancer screening. AB - Objective: Routine, population-based mammographic screening for breast cancer has been implemented nationally in Japan for the past decade. The objective of this study was to evaluate the knowledge of the general public and of nurses concerning breast screening practices in Japan, especially with regards to the benefits and risks of breast cancer screening. Methods: In 2014, a questionnaire regarding the benefits and risks of breast cancer screening was administered to women who underwent breast cancer screening and to registered nurses. The questionnaire was distributed to 1,649 women and 1,905 registered nurses. Results: Completed questionnaires were returned by 1,552 (94.1%) of the screened participants and 1,710 (89.8%) nurses. The majority of the screened participants and registered nurses believed that screening prevented or reduced the risk of developing breast cancer (86% and 62%, respectively); that screening reduced the mortality risk of breast cancer by more than 50% (69% and 60%, respectively); and that 10 years of regular screening for 50-year-old women could prevent >= 10 breast cancer deaths per 1,000 women (62% and 61%, respectively). Conclusions: Women in the target population and registered nurses were aware that earlier diagnosis led to better prognosis, but demonstrated misconceptions regarding other aspects of the benefits and risks of breast cancer screening. In Japan, all women should be educated on both the benefits and risks of breast cancer screening to enable them to make an informed decision on whether to participate in the mammographic breast cancer screening program. PMID- 29255527 TI - A pilot study of gemcitabine and paclitaxel as third-line chemotherapy in metastatic urothelial carcinoma. AB - Background: We evaluated the effectiveness of gemcitabine and paclitaxel therapy in patients with metastatic urothelial carcinoma for whom two lines of sequential chemotherapy had been unsuccessful. Methods: A total number of 105 patients who had previously received first-line chemotherapy consisting of gemcitabine and cisplatin or carboplatin, were treated with second-line gemcitabine and docetaxel therapy between June 2006 and May 2015. Of these patients, 15 with an Eastern Cooperative Oncology Group Performance Status of 0 or 1 were administered gemcitabine and paclitaxel as third-line treatment from 2013 after failure of the second-line therapy. For each 21-day cycle, gemcitabine (1000 mg/m2) was administered on days 1, 8, and 15, and paclitaxel (200 mg/m2) on day 1. Patients were assessed for each cycle and any adverse events were noted. Furthermore, a Short Form Health Survey questionnaire was used to assess each patient's quality of life. Results: Third-line gemcitabine and paclitaxel treatment cycles were undertaken for a median of four times (range 2-9). The disease control rate was 80.0%. After second-line gemcitabine and docetaxel therapy was completed, median progression-free survival and median overall survival were determined as 9.8 and 13.0 months, respectively. The only prognostic factor for overall survival, as determined by univariate and multivariate analyses, was third-line gemcitabine and paclitaxel therapy. Neutropenia (66.7%) and thrombocytopenia (53.3%) were noted as the grade 3 treatment-related toxicities. After two cycles of third-line gemcitabine and paclitaxel therapy, the pre- and post-treatment quality of life scores did not differ significantly. Conclusions: Results demonstrate that third line combination therapy using gemcitabine and paclitaxel is a feasible option for metastatic urothelial carcinoma patients. PMID- 29255528 TI - Feasibility of metronomic chemotherapy with tegafur-uracil, cisplatin, and dexamethasone for docetaxel-refractory prostate cancer. AB - Objectives: To evaluate the efficacy of tegafur-uracil (UFT), a prodrug of 5 fluorouracil, plus cisplatin and dexamethasone in patients with docetaxel refractory prostate cancers. Methods: Twenty-five patients with docetaxel refractory prostate cancer were administered oral UFT plus intravenous cisplatin (UFT-P therapy) and dexamethasone. Treatment responses were assessed monthly via prostate-specific antigen (PSA) level measurements. Treatment-related adverse events and overall survival were also assessed. Results: UFT-P therapy resulted in decreased PSA levels in 14 (56%) patients and increased PSA levels in 11 (44%). In patients with increased PSA levels, 7 (64%) of the 11 patients displayed decreased PSA doubling times. The UFT-P therapy response rate was 84% (21/25 patients). Imaging studies revealed that tumor shrinkage during UFT-P therapy occurred in 1 patient in whom bilateral hydronephrosis caused by lymph node metastasis improved. The median survival time from docetaxel initiation was 36 months. In UFT-P-treated patients, the median PSA progression and overall survival times were 6 and 14 months, respectively. UFT-P treatment-related adverse events were mild diarrhea, general fatigue, and anorexia. Treatment was not discontinued for any of the patients. UFT-P therapy did not cause serious hepatic or renal dysfunction or pancytopenia. Conclusions: UFT-P therapy is a safe and effective treatment for patients with docetaxel-refractory prostate cancer, although large-scale, multicenter, prospective studies are needed to validate these findings. PMID- 29255529 TI - Soft-tissue release for hip subluxation and dislocation in cerebral palsy. AB - Objective: This study aimed to evaluate the effectiveness of soft-tissue release on hip subluxation and dislocation in cerebral palsy as well as activities of daily living after surgery. Patients and Methods: Soft-tissue release was performed in 13 patients (19 hips) with cerebral palsy. Of them, 10 had spastic quadriplegia and three had spastic diplegia. Mean ages were 8.6 years at surgery and 13.8 years at the last investigation. The mean follow-up period was 5.2 years. Hip subluxation and dislocation severities were analyzed before and after surgery and at the final investigation as migration percentage on radiographs. Postoperative activities of daily living were also evaluated in 12 patients. Results: Seven hips classified as mild and moderate preoperatively were classified as good, mild, and moderate at the last investigation. Nine of 12 hips classified as severe preoperatively continued to be severe at the last investigation. However, three of 12 hips classified as severe preoperatively improved at the last investigation. There was a positive correlation between preoperative migration percentage and that at the last investigation. Daily activities improved postoperatively in 12 patients. Conclusions: Early treatment is necessary to prevent hip dislocation and improve hip subluxation. However, several patients with severe subluxation might experience improvement with soft tissue release alone. Soft-tissue release is effective for treating hip dislocation and subluxation in cerebral palsy and improving daily activities. PMID- 29255530 TI - A case of neuromyelitis optica diagnosed with a chronic subdural hematoma. AB - Background: Chronic subdural hematoma (CSDH) is often found in the elderly owing to slight head trauma and is associated with several neurological disorders. Neurological deficits are cured by a simple surgical removal of the hematoma; however, these deficits persist if there is insufficient hematoma removal. It is rare for patients to continue having neurological disorders once the hematoma is removed. Case report: A 61-year-old woman presented with gait disturbance. She was diagnosed with a subdural hematoma through head computed tomography. After hematoma irrigation, her gait disturbance exacerbated, and she developed urinary tract dysfunction. Ubiquitous neurodegeneration in the midbrain and spinal cord was suspected owing to a hyperintense signal on fluid-attenuated inversion recovery of magnetic resonance imaging. The anti-aquaporin 4 antibody was detected in the patient's serum, and she was diagnosed with neuromyelitis optica (NMO). Conclusions: Progressive NMO caused gait dysfunction and triggered head trauma, followed by CSDH. Although NMO rarely causes CSDH, it should be considered in uncommon cases of CSDH. PMID- 29255531 TI - A case of wild-type transthyretin amyloidosis associated with organizing pneumonia. AB - An 81-year-old man was referred to our hospital with bilateral multiple patchy opacities on chest radiography. His chief complaints were a few months' history of intermittent mild cough and slightly yellow sputum. Chest computed tomography (CT) showed non-segmental air-space consolidations with ground-glass opacities. Amyloid deposition with organizing pneumonia (OP) was seen in transbronchial lung biopsy (TBLB) specimens from the left S8. Three months later, the infiltration originally seen in the left lower lobe was remarkably diminished, and new infiltrations in the lingual and right lower lobes were detected on chest CT. Amyloid deposition with OP was seen in TBLB specimens from the left S4. Transthyretin was detected following immunohistochemical examination. The presence of wild-type transthyretin (ATTRwt) was proven using genetic analysis. The present report describes a rare case of ATTRwt amyloidosis associated with OP. PMID- 29255532 TI - Parsonage-Turner syndrome in a patient with bilateral shoulder pain: A case report. AB - Objective: Parsonage-Turner syndrome is a peripheral neuropathy characterized by acute onset shoulder pain, myalgia, and sensory disturbances. The present report discusses a rare case of Parsonage-Turner syndrome and highlights the importance of accurate history recording and thorough physical examination for the diagnosis of the disease in rural areas. Patient: A 28-year-old woman presented to our clinic with acute bilateral shoulder pain and difficulty moving her right arm. A diagnosis of Parsonage-Turner syndrome was suspected based on the progression of symptoms, severity of pain, and lack of musculoskeletal inflammation. The diagnosis was confirmed by neurological specialists, and the patient was treated with methylprednisolone, after which her symptoms gradually improved. Discussion: The differential diagnosis of shoulder pain is complicated due to the wide variety of conditions sharing similar symptoms. Accurate history recording and thorough physical examination are required to differentiate among conditions involving the central nerves, peripheral nerves, and nerve plexuses. Conclusion: Although the symptoms of Parsonage-Turner syndrome vary based on disease progression and the location of impairment, proper diagnosis of acute shoulder pain without central neurological symptoms can be achieved in rural areas via thorough examination. PMID- 29255533 TI - Infective endocarditis in a patient with lupus nephritis who was undergoing immunosuppressive therapy: A case of survival. AB - Systemic lupus erythematosus is an autoimmune disease associated with mild valvular regurgitation. However, there have been no detailed reports of infective endocarditis in patients with systemic lupus erythematosus. Here, we describe a case of a 55-year-old woman without any cardiac abnormalities who was diagnosed with lupus nephritis by renal biopsy; she contracted infective endocarditis while receiving immunosuppressive therapy. Our case emphasizes that special consideration of the occurrence of infective endocarditis, and its early diagnosis and treatment are mandatory for patient survival. We propose that echocardiography should be performed before treating patients with systemic lupus erythematosus who have an uncertain cardiac status. PMID- 29255534 TI - Pneumonia as a trigger for atrial fibrillation. AB - In a rural mountainous region on a Friday, a 78-year-old man was seen in his physician's office for leg edema and diagnosed with new onset atrial fibrillation. He was discharged home to start medications for atrial fibrillation and heart failure. He was hospitalized the next day with septic shock due to pneumococcal pneumonia. The new onset of atrial fibrillation requires a trigger acting on a vulnerable substrate. These triggers include acute conditions such as alcohol intoxication, myocardial infarction and pulmonary embolism. Pneumonia may act as a trigger causing the new onset of atrial fibrillation. PMID- 29255535 TI - Ambulant treatment for a very elderly patient with acute deep vein thrombosis in a rural area: A case report. AB - Acute symptomatic deep vein thrombosis (DVT) is usually managed by intravenous heparin and oral warfarin. Recently, direct oral anticoagulants (DOAC) have been introduced for the treatment of acute DVT. DOAC may be useful for very elderly patients who live in rural areas, where medical resources are limited. An 83-year old woman presented to our clinic with left leg edema. Contrast enhanced computed tomography showed massive deep vein thrombosis in her left internal iliac vein. We diagnosed her with acute deep vein thrombosis. Since she refused to be hospitalized, we treated her with rivaroxaban as an outpatient. She had a good clinical course without hospitalization or an adverse event. DOAC may be useful for very elderly patients in rural areas. PMID- 29255536 TI - Unplanned Readmission in Outpatient Hand Surgery: An Analysis of 23,613 Patients in the NSQIP Data Set. AB - Objective: In an era of controlling cost and improving care, 30-day readmission rates have become an important quality measure. The purpose of this study was to identify the rates of 30-day unplanned readmission and the associated risk factors in patients undergoing outpatient hand surgery. Methods: The 2011-2014 National Surgical Quality Improvement Project data were queried for patients who met 368 hand-specific Current Procedural Terminology codes. Univariable and multivariable analyses were performed to identify patient- and surgery-specific risk factors associated with unplanned readmission within 30 days. Results: Of the 368 Current Procedural Terminology codes queried, 208 were represented in the data, for a total of 23,613 patients. The overall unplanned readmission rate was 0.88% (207/23,613). On both univariable and multivariable analyses, operative year (2012), increasing age, obesity, smoking status, chronic obstructive pulmonary disease, preoperative steroid use, preoperative anemia, increasing American Society of Anesthesiologists classification, increasing operative time, and a procedure performed by a surgeon other than a plastic or orthopedic surgeon were associated with increased readmission rates. Diabetes, hypertension, low albumin levels, elevated international normalized ratio, and dirty/infected wound classification were only significant in univariable analysis. Current Procedural Terminology codes associated with the highest readmission rates were related to amputations. The most common readmission diagnoses were wound complications, followed by uncontrolled postoperative pain. Conclusions: The incidence of unplanned readmission is low in patients undergoing outpatient hand surgery. Specific patient comorbidities are associated with increased unplanned readmission rates. This information may be useful in identifying patients at higher risk for unplanned readmission and in counseling of high-risk patients preparing for surgery. PMID- 29255537 TI - Assessing the ownership, usage and knowledge of Insecticide Treated Nets (ITNs) in Malaria Prevention in the Hohoe Municipality, Ghana. AB - Introduction: Malaria remains one of the top five killer diseases in sub-Saharan Africa (SSA) and its burden is skewed towards pregnant women and children under five. Insecticide Treated Bed-Net (ITN) usage is considered one of the most cost effective, preventive interventions against malaria. This study sought to assess ownership, usage, effectiveness, knowledge, access and availability of ITNs among mothers with children under five in the Hohoe municipality. Methods: In August 2010 a cross-sectional survey was carried out in 30 communities, selected using the WHO 30 cluster sampling technique. In the selected communities, mothers/caregivers with children under five years were selected using the snowball method. Data were collected through questionnaires and direct observation of ITN. Descriptive statistics was used to analyse the data collected. Results: A total of 450 mothers/caregivers were interviewed and their mean age was 30 +/- 7 years. ITN ownership was 81.3%, and usage was 66.4%. The majority (97.8%) of the mothers/caregivers said ITNs were effective for malaria prevention. Awareness about ITNs was high (98.7%) and the majority (52.9%) had heard about ITNs from Reproductive and Child Health (RCH) Clinic and antenatal care ANC clinic (33.6%). Over 60% of the ITNs were acquired through free distribution at RCH clinics, clinic and home distribution during mass immunization sessions. The majority of the mothers/caregivers (78.6%) knew the signs and symptoms of malaria, what causes malaria (82.2%) and who is most at risk (90%). Conclusion: Behaviour change communication strategies on ITN use may need to be further targeted to ensure full use of available ITNs. PMID- 29255538 TI - Prevalence of bovine brucellosis in slaughtered cattle and barriers to better protection of abattoir workers in Ibadan, South-Western Nigeria. AB - Introduction: Brucellosis is a neglected zoonosis of public health importance. This study was conducted to determine the prevalence and risk factors of brucellosis among slaughtered cattle as well as challenges to the protection of abattoir workers in Nigeria. Methods: A slaughterhouse study was conducted in a major abattoir in Ibadan from March to August, 2013. To diagnose brucellosis, serum samples from 1,241 slaughtered cattle were tested using Rose-Bengal test (RBT) and competitive enzyme-linked immunosorbent assay (cELISA); again, 57 milk samples were tested with milk ring test (MRT) and indirect ELISA (iELISA). Furthermore, a survey on the usage of personal protective equipment (PPE) and challenges to its use by abattoir workers was done. Data were analysed using Stata 12. Results: Seroprevalence by RBT was 7.8%; 77.3% (75/97) of these were corroborated by cELISA. Prevalence in milk samples by MRT and indirect ELISA were 33.3% and 3.5%, respectively. Sex (OR: 2.5; 95%CI:1.3-4.5) was the factor significantly associated with Brucella seropositivity. None of the abattoir workers used standard protective overalls; while, 99.6% of the meat handlers and 84.1% of the butchers worked barefoot. Most of the workers (75.7%) wore no protective gloves. The respondents agreed that provision of free PPE and sanctions against non-users would encourage its use. Conclusion: Our findings indicate moderate prevalence (7.8%) of bovine brucellosis with sex of cattle being a risk factor. A notable barrier to better protection of abattoir workers against brucellosis is perceived inconvenience arising from use of gloves. Therefore, preventive and control measures against brucellosis must include education and use of PPE among abattoir workers. PMID- 29255539 TI - A rare presentation of hepatocellular carcinoma in non-cirrhotic liver. AB - Hepatocellular carcinoma is the most frequent type of liver malignancy. Most cases of hepatocellular carcinoma are secondary to either viral hepatitis (hepatitis B, C) or alcoholic cirrhosis. Liver cirrhosis due to any other causes is considered as a risk factor for development of hepatocellular carcinoma; however, hepatocellular carcinoma in non cirrhotic livers remains a rare condition. The present case report describes a 59-year-old woman patient admitted to explore right hypochondriac and epigastric pain, with no evidence of pre existing liver disease and with a good general condition. The computed tomography was very suggestive of a gastro-intestinal stromal tumor. But, at laparotomy, a huge hepatic tumor was discovered. Histopathological study confirmed the presence of primary hepatocellular carcinoma. Hepatocellular carcinoma occurs more frequently on a cirrhotic liver. However, it can occur on a non cirrhotic liver and remains and extremely rare case. PMID- 29255540 TI - Right congenital diaphragmatic hernia associated with abnormality of the liver in adult. AB - A Bochdalek hernia (BH) occurs when abdominal contents herniate through the postero-lateral segment of the diaphragm. The right side is affected considerably less commonly than the left. Most BHs present are diagnosed early in life, with some element of cardio-respiratory distress. Rarely, hernias that remain clinically silent until adulthood when they present as life-threatening surgical emergencies. We report a case 35 year old female who emergency exploratory laparotomy for a complete mechanical bowel obstruction. At surgery the redundant transverse colon was twisted and incarcerated within the right hemithorax, creating a closed loop obstruction. The right colon, appendix, terminal ilium, and three accessories right liver lobes were also dragged into the right thoracic cavity. After reducing the hernia, the diaphragmatic defect was primarily repaired with non-absorbable suture. The redundant transvers colon which had been compromised was resected and primary end-to- end anastomosis was carried out. Incidental appendectomy was done. The patient was sent into ICU for post operative monitoring. She made an uneventful recovery and remains asymptomatic at nine month follow-up. I discuss what i believe to be the first case report of complicated right diaphragmatic hernia in Botswana, associated with another congenital mal-formation (accessories hepatic lobes, partial mal-rotation, and redundant transvers colon) in adult. PMID- 29255542 TI - [Unusual location of giant seborrhoeic keratoses]. AB - Seborrhoeic keratoses (SK) are benign tumors that mainly occur in the head and in the trunk. Their size generally varies from a few millimeters up to a few centimeters. Giant lesions are very rare but pose a problem in terms both of treatment and transformation. Their occurrence in the genital area is even more rare, posing a problem in differential diagnosis of genital warts. Differentiation is only based on histopathology. We report the case of a 80-year old man, with no particular past medical history, who presented with asymptomatic abdominal and genital lesions evolving over the last twenty years. Clinical examination showed four hyperpigmented, humped, well-defined tumors, with warty surface measuring 2-10 cm along its longer axis (A). Dermoscopic examination showed cerebriform convolutions appearance suggesting seborrhoeic keratoses (B). Histology confirmed the diagnosis, without signs of viral infection or malignant transformation. The patient underwent surgical resection resulting in permanent scar. PMID- 29255541 TI - [Differentiated thyroid cancer in children and adolescents: about 22 cases]. AB - This study aimed to highlight the features of thyroid cancer in children and adolescents and to evaluate our results compared to the international literature on the basis of the most representative case series in Morocco: 22 cases. We conducted a retrosective study of patients with differentiated thyroid cancer hospitalized in the otorhinolaryngology and cervicofacial surgery department at the Hopital 20 Aout, Casablanca, Morocco over the period January 1995-March 2015. We collected data on 22 cases that met our inclusion criteria. The average age of our patients was 14 years, with a sex-ratio of 3.4; most of our patients presented with thyroid nodule, associated with cervical lymphadenopathy in 22.7% of cases and with signs of compression in 9.1% of cases. All patients underwent total thyroidectomy, followed by lymph node dissection in 31.82% of cases. The diagnosis of thyroid cancer was based on the anatomo-pathological examination of the surgical specimen, that showed papillary carcinoma in 95.4% of cases and vesicular carcinoma in 4.5% of cases. Radioactive iodine-131 treatment was performed in 100% of cases. Subsequently all patients underwent thyroid hormone therapy. Close and regular monitoring allowed the detection of nodal metastases in 3 patients and of distant metastases in 4 patients. Differentiated thyroid cancer in children and adolescents is rare but aggressive. Treatment is based on surgery associated with iratherapy, with excellent prognosis. PMID- 29255543 TI - [Glomus tumor of the thigh: a new case report and literature review]. AB - Glomus tumors are rare and benign. They originate from the neuromyoarterial glomus body. Digital glomus tumors are a well-known condition in hand surgery. On the contrary, there is a lack of knowledge with regard to extradigital glomus tumor resulting in diagnostic and therapeutic errors. We here report a new case of glomus tumor of the thigh. Our literature review aims to focus attention on these uncommon locations. PMID- 29255544 TI - [Risk factors for retinal detachment in Togo]. AB - Introduction: Retinal detachment poses management problems in developing countries due to the shortage of technical equipment. Prevention passes through knowledge and elimination of risk factors. This study aimed to identify the risk factors for retinal detachment in people living in Togo. Methods: We conducted a retrospective and descriptive study in the Department of Ophthalmology at the Chu Campus and in an ophthalmology office in Lome from 2 January 2011 to 31 December 2015. The medical records of patients with retinal detachment were included in the study. The diagnosis of retinal detachment was confirmed based on funduscopic exam or ocular ultrasound. Results: in total, 116 eyes of 100 patients had retinal detachment of whom 40 in the RE, 44 in the LE and 16 bilaterally. The average age of patients was 46.65 +/- 16.46 years [07 years; 87 years], with a male predominance and with a sex-ratio = 0.32 (W/M). Diabetic patients accounted for 17% and patients with sickle cell disease accounted for 16%. Myopic patients accounted for 5%, pseudophakic patients accounted for 17.2% and aphakic patients accounted for 3.4%. Four patients had retinal tear (14.28% of rhegmatogenous detachment) including 2 superotemporal tears, 1 inferior nasal tear and 1 inferior temporala tear. 35 eyes (52.2%) had total retinal detachment while 24 eyes (35.8%) had partial retinal detachment. Twenty eyes had vitreoretinal proliferations, 5 eyes had itreous hemorrhage and 6 eyes had hyalite. Diabetes and sickle cell disease were the risk factors for tractional RD (p=0.006 and p=0.0003) while cataract surgery was the risk factor for rhegmatogenous RD (p=0.0097). Conclusion: Diabetes, sickle cell anemia and eye surgery were the major risk factors for RD. A better management of these pathologies and ophthalmologist's mastery of cataract surgery may prevent retinal detachment. PMID- 29255545 TI - HIV screening among TB patients and level of antiretroviral therapy and co trimoxazole preventive therapy for TB/HIV patients in Hawassa University Referral Hospital: a five year retrospective study. AB - Introduction: Initiation of antiretroviral therapy (ART) and co-trimoxazole preventive therapy (CPT) is recommended for tuberculosis (TB)/human immunodeficiency virus (HIV) co-infected patients to prevent opportunistic infection. The aim of this study was to assess the prevalence of HIV among TB patients and initiation of ART and provision of CPT for TB/HIV co-infected patients in Hawassa university referral hospital. Methods: A five year document review was done on 1961 TB patients who are registered at TB clinic of Hawassa university referral hospital from September 2009 to august 2014. Data were collected using checklist. Data analysis was done by using SPSS version 20 software. Bivariate and multivariate logistic regression analysis was used to determine the predictors of TB/HIV co-infection. Results: Among 1961 TB patients diagnosed in the hospital, 95% (1765) were screened for HIV. Of these, 13.9% (246) were HIV positive. Out of 246 TB/HIV co-infected patients 31.7% (78/246) and 37.4% (92/246) were enrolled to start ART and CPT respectively. Roughly the trends of TB/HIV co-infection decreased with increased linkage to CPT, while linkage to ART was not regular across the year. The rate of TB/HIV co-infection was significantly associated with type of TB. Conclusion: Although, trend of HIV among TB patients has decreased across the year, only a minority of co-infected patients was linked to start ART and CPT. Therefore, screening of all TB patients for HIV and linkage of co-infected patients to HIV care to start ART and CPT should be strengthened in-line with the national guidelines. PMID- 29255546 TI - [Frequency and characteristics of strokes involving the perforating arteries in the Department of Neurology at the Befelatanana General Hospital, Antananarivo]. AB - Introduction: Strokes of the perforating arteries are mainly arteriolopathies. They result in dementia and stroke recurrence. This study aimed to evaluate the frequency and characteristics of these strokes to better prevent these complications. Methods: We conducted a descriptive, retrospective study in the department of neurology at the Befelatanana general hospital, Antananarivo over the period 01 March-25 September 2015. All patients with abrupt neurological deficit and deep brain involvement on brain scanner were included in the study. The features of strokes involving the perforating arteries were collected. Data were processed with SPSS 20 software. Results: Out of 172 patients with a stroke, 83(48.25%) had stroke involving the perforating arteries. Stroke involving the perforating arteries affected young people (65.06%) aged less than 65 years and preferentially the male population (61.44%). Haemorrhagic forms accounted for 67.46%. Thirty-one patients (37.34%) had stroke recurrences and, among them, almost a quarter had 2 recurrences (38.70%) in less than a year. All patients with recurrence had dysexecutive disorder (p < 0.0001) and poor antihypertensive medication adherence. Mortality accounted for only 6.02% in patients with onset of these strokes during hospitalization. Conclusion: Specific neurologic follow up is necessary after a first stroke involving perforating arteries in order to make an early diagnosis of dementia and to prevent recurrences. PMID- 29255547 TI - [Childbirth among primiparous women in Lubumbashi: maternal and perinatal prognosis]. AB - Introduction: Childbirth in primiparous women is associated with many complications and, therefore, primiparous women are considered high risk due to maternal and fetal concerns. This study aims to determine birth rate in primiparous women in our environment, to identify factors associated with delivery by cesarean section and to assess maternal and perinatal morbi-mortality from childbirth in primiparous women living in Lubumbashi. Methods: We conducted a cross-sectional, analytical study of singleton births in 10 referral maternity hospitals in Lubumbashi over the period December 2013-May 2014. Primiparous births were compared to multiparous births. Maternal sociodemographic parameters as well as maternal and perinatal morbi-mortality were analyzed. The odds ratio and its confidence interval were calculated. Threshold significance level was set at p < 0.05. Results: Primiparity rate was 19.9%. Compared to multiparous births, primiparous births were mainly observed in adolescents (OR=11. 27, (7.98-15.91)), in students (OR = 5.61 (3.33-9.45)) and in women living alone (OR=7.62 (4.36 13.30)). Risk factors associated with delivery by cesarean section in primiparous women included obstetric evacuation (OR = 9.69 (4.75-19.74)), the lack of prenatal monitoring (OR=2.57, (1.32-5.01)), size <= 150 cm (OR = 2.42 (1.04 5.65)), uterine height > 34 cm (OR = 2.33 (1.32-4.10)) and malpresentation (OR = 6.37 (2.92-13.87)). With regard to maternal prognosis, we observed that high blood pressure (OR = 1.91 (1.32-2.74)), malpresentation (OR = 1.95 (1.16-3.17)), oxytocin use (OR = 2.03 (1.64-2.52)), cesarean section (OR = 2.04 (1.47-2.83)), episiotomy (OR=11.89 (8.61-16.43)) and eclampsia (OR = 4.21 (1.55-11.44)) were significantly associated with primiparity. The rates of low 5th minute Apgar score (OR = 1.55 (1.03-2.32)) and of deaths occurred during early neonatal period (OR=1.80 (1.08-2.98)) were significantly higher in primiparous women than in multiparous women. Conclusion: This study shows that primiparous birth is a problem in Lubumbashi. Hence improvement in mother-child care during primiparous childbirth includes the development of protocols for adequate management of childbirths. PMID- 29255549 TI - Left ventricular hypertrophy among chronic kidney disease patients in Ghana. AB - Introduction: The presence of left ventricular hypertrophy (LVH) in patients with Chronic Kidney Disease (CKD) is associated with worsening cardiovascular outcomes. There is a dearth of data on LVH in Ghanaian CKD patients. Methods: This was a cross sectional study carried out at the Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana. A questionnaire was used to obtain information on clinical features of CKD. The MDRD-4 equation was used to calculate eGFR. Information on the prevalence and factors associated with electrocardiographic left ventricular hypertrophy were obtained during the initial assessment. Results: About 64.5% of the 203 participants were male and the mean age was 43.9 +/- 17.8 years. Most subjects (79.8%) had stage 5 disease. The mean systolic and diastolic blood pressures were 167.86 +/- 39.87 and 101.8 +/- 24.4 respectively. Approximately 43% of respondents had LVH. eGFR correlated negatively with LVH. High systolic pressure (OR 4.9, CI 2.4 - 10.4; p < 0.05), high diastolic pressure (OR 8.1, CI 4.0 - 16.1; p < 0.05) increased pulse pressure (OR 3.4 CI 2.6-9.3, p < 0.05), increased body mass index (OR 3.6 CI 1.7-11.2, p < 0.001) as well as male gender (OR 4.7, 95% CI 2.4 - 9.1; p <0.05) were associated with the presence of LVH. Conclusion: LVH is common in our cohort. High pulse pressure, high DBP, increased BMI and male gender are significant associated factors. Adequate treatment of high blood pressure as well as early detection of LVH and interventions aimed at prevention and/or regression of LVH are to be encouraged. PMID- 29255548 TI - [First experience with outpatient laparoscopic cholecystectomy in Tunisia]. AB - Introduction: Laparoscopic cholecystectomy is the gold standard treatment for symptomatic gallstones. There is some debate as to whether it should be performed in outpatient surgery or in one-day surgery to improve patient safety. This study aimed to evaluate the impact of laparoscopic cholecystectomy performed in outpatient surgery versus one-day surgery on standards such as mortality, serious adverse events and quality of life. Methods: We conducted a cross-sectional descriptive study in the Department of General Surgery at the Habib Thameur Hospital over the period May 2009-February 2010. We here report 67 cases of symptomatic vesical lithiasis treated with outpatient laparoscopic cholecystectomy (OLC). ASA III and IV patients, diabetic patients treated with sulfonamides or insulin, severely obese patients, patients over 65 years of age and under 18 years of age, patients with a history of major abdominal surgery, patients with suspected lithiasis of the common bile duct, acute cholecystitis or pancreatitis were excluded from the study. Patients had to reside within 50 km of the hospital and be accompanied by an adult to undergo OLC. Results: Seventeen patients were included and then excluded from our study because of the perioperative detection of signs of acute cholecystitis or difficulties in dissection leading to subhepatic drainage using Redon catheter at the end of the intervention. Finally, our study included 50 patients, 7 men and 43 women; the average age was 48 years. Surgery was based on the most common procedures. After leaving the recovery room, patients were conducted in the outpatient sector where they received a liquid diet. The patients were examined before 7 o'clock in the evening and discharge was established on the basis of the possibility of establishing an oral analgesic treatment, patients tolerance to liquid diet, the lack of urinary disorder, patients acceptance for discharge and analgesic and anti-inflammatory treatment if needed. Thirty-nine patients (78%) were discharged from hospital and 11 were kept in hospital. Patients > 45 years of age, anesthesia duration > 70 minutes and post operative fatigue were identified as risk factors for unsuccessful discharge. No readmission was observed. Discharged patients were satisfied with the therapeutic protocol, resulting in excellent and good outcome in the majority of cases (94%). Conclusion: Outpatient laparoscopic cholecystectomy seems to be as safe as day surgery laparoscopic cholecystectomy having low rate of complications and of hospital readmissions in some selected patients and lower surgery costs. PMID- 29255550 TI - [Drug-induced acute pancreatitis: about 10 cases]. AB - Drug-induced acute pancreatitis (AP) accounts for approximately 2% of acute pancreatitis. Its incidence is increasing, with more than 260 incriminated drugs. However, very few cases have been described in the literature due to accountability problem. We report our experience with 10 cases whose data were collected over a period of 7 years. Clinical presentation of AP was often equivocal. Ranson's score ranged from 0 to 5. We recorded 5 cases of edematous pancreatitis and 5 cases of necro-bleeding pancreatitis. These pancreatitis were often successfully treated without recurrence after discontinuation of the incriminated drug. PMID- 29255551 TI - [Implication of early extubation after cardiac surgery for postoperative rehabilitation]. AB - Introduction: Postoperative rehabilitation after cardiac surgery is based on medical-surgical management in order to reduce the lenght of stay in hospital and the costs of this high risk surgery. Early tracheal extubation (within the first 6 hours) is the cornerstone of fast-track surgery. Our study aimed to evaluate fast-track practice and early tracheal extubation in scheduled cardiac surgery for adult patients in our Institution. Methods: We conducted a descriptive study including all patients aged over 18 years who consecutively had undergone scheduled cardiac surgery and postoperative treatment in the post-operative intensive care unit in the Department of Thoracic and Cardiovascular Surgery at the Habib Bourguiba University Hospital, Sfax. Inclusion criteria were: patients aged 18 years and older who had undergone scheduled cardiac surgery and postoperative treatment in the post-operative intensive care unit in the Department of Thoracic and Cardiovascular Surgery. Standardized anaesthetic protocol was used in all cases: propofol, remifentanil, cisatracrium. We recorded the mean postoperative extubation time and the factors affecting extubation time. Results: We collected data from 200 patients who consecutively had undergone scheduled cardiac surgery. Among these patients, 115 underwent coronary artery bypass surgery, 79 valvular surgery and 6 combined surgery or another surgical procedure. Patients' demographic characteristics were comparable. 152 patients (76%) underwent postoperative extubation within the first 6 hours. 48 patients couldn't be extubated within the FIrst 6 hours. The main causes of early extubation failure were: catecholamines in high doses, bleeding, arrhythmia and neurological disorders. Conclusion: Our study demonstrates that postoperative rehabilitation can be performed in our Institution and that all patients undergoing scheduled cardiac surgery should be candidates for early extubation. PMID- 29255553 TI - [Bacteremia due to Kingella denitrificans in a child followed-up for bone marrow failure syndrome]. AB - Kingella denitrificans is a non-pathogenic micro-organism present in oropharyngeal flora. This germ has been recently recognized as responsible for opportunistic invasive infections mainly affecting immunosuppressed patients. We here report the case of a child aged 3 years and 7 months followed-up since the age of one year for bone marrow failure syndrome associated with pancytopenia of undetermined origin who had bacteremia due to Kingella denitrificans, a group of difficult to culture gram-negative bacteria rarely described in the literature. Clinicians and microbiologists should suspect the presence of this germ especially in immunosuppressed patients. The use of blood culture bottle contributes in a significant way to the detection of this germ. PMID- 29255552 TI - [Seroprevalence and factors associated with Voluntary Counselling and Testing (VCT) for HIV among children in Lubumbashi, Democratic Republic of the Congo]. AB - Introduction: Despite proposals for screening infants or preschool children for HIV infection, the proportion of children who grow or die with unknown HIV status is high in the Democratic Republic of the Congo (DRC). This study aimed to determine the seroprevalence during a voluntary screening and to identify factors associated with Voluntary Counselling and Testing (VCT) for HIV in the paediatric population of non-HIV infected or non-HIV exposed infants and children in Lubumbashi, DRC. Methods: We conducted a cross-sectional prospective analytical study in 4 community VCT centers divided into 4 health zones in the city of Lubumbashi, DRC (Lubumbashi, Ruashi, Kampemba and Kenya) over the period 1 August 2006 - 31 September 2007. The study aimed to evaluate voluntary testing for HIV among children less than 15 years. The sociodemographic characteristics and the parameters related to Voluntary Counselling and Testing (VCT) for HIV were analyzed. Usual descriptive statistical analyses and logistic regression were perfomed. Results: Out of 463 children screened for HIV, 41 (8.9%; 95% CI: 6.5% 11.9%) were HIV positive. Voluntary Counselling and Testing (VCT) for HIV in the paediatric population of non-HIV infected or non-HIV exposed infants or children was significantly higher in children over 2 years of age (adjusted odds ratio (AOR)=3.6 [95% CI: 1,1-12,2]) when both of their parents had negative or uknown HIV status (AOR = 27.4 [95% CI: 9,4-80,0]), when either or both of their biological parents were alive (AOR = 24.9 [95% CI: 2,4-250,8]) and when screening programs were not only carried out by health professionals (AOR = 2.9 [95% CI: 1,0-7,9]). Conclusion: Our study shows a high HIV prevalence among children supporting the need for VCT highly accepted by parents and tutors in the city of Lubumbashi. PMID- 29255554 TI - [Role of splenectomy in the treatment of non-cirrhotic portal hypertension: about 3 cases]. AB - Non-cirrhotic portal hypertension was first described by Guido BANTI in 1898 as a condition characterized by the association of portal hypertension with splenomegaly, anemia and healthy liver. The diagnosis was based on abdominal ultrasound, splenoportography and liver biopsy. Our study aimed to evaluate the role of splenectomy in non-cirrhotic portal hypertension. We conducted a retrospective study of 3 patients (2 women and 1 man) treated by our staff over the period January 2010 -September 2016. The diagnosis of idiopathic portal hypertension was based on the following criteria: portal hypertension, the presence of oesophageal varices associated with splenomegaly, the absence of cirrhosis or of other liver disorders responsible of portal hypertension. All patients underwent splenectomy. Outcome after splenectomy was marked by the standardization of clinical, radiological and biological signs of this disease associated with the absence of oesophageal varices recurrence. Splenectomy associated with ligation of oesophageal varices may be sufficient to treat this syndrome and especially its consequences without using splenorenal bypass. PMID- 29255555 TI - [Spontaneous hemothorax: a rare complication of neurofibromatosis type 1]. AB - Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen's disease is an autosomal dominant genetic disorder. It is the most common of phacomatoses. Pulmonary complications have been rarely described in the literature. Vascular complications have been reported in 3.6% of patients. We here report the case of a 38-year old female patient, followed-up for neurofibromatosis type 1, admitted to the Emergency Department with hemorrhagic shock. Clinical examination showed several coffee-with-milk colored spots, many plexiform neurofibromas, left-sided pleural effusion syndrome. Pleural puncture objectified coagulable haemorrhagic fluid. The patient received transfusion and emergency chest drainage. Patient's assessment was completed by angioscanner which showed no pulmonary embolism or other associated lesions. Spontaneous hemothorax is a rare and severe complication of neurofibromatosis. It is probably due to vascular injury caused by this disease. PMID- 29255556 TI - [Villonodular synovitis of the knee: about 20 cases]. AB - Pigmented villonodular synovitis (PVNS) is a rare benign proliferation of synovial joints, serous bursa, tendinous sheaths of unknown etiopathogeny. We here report 20 cases of PVNS of the knee recorded at the Avicenne Military Hospital, Marrakech over a period of 9 years, from January 2000 to December 2009. This study aimed to identify the specific features of this lesion and to examine its anatomoclinic and prognostic aspects. Annual incidence was 2.2 cases per year: 15 men and 5 women. The average age was 32.5 years. It occurred in the right-hand in 55%, 18 patients had monoarticular presentation of the disease while 1 patient had biarticular presentation of the disease. 80% of cases had pain and swelling, palpable mass was detected in 1 case, meniscal syndrome in 1 case, monoseptic arthritis in 3 cases while popliteal cyst in 2 cases. 14 cases (70%) had diffuse involvement, 6 cases had localized involvement. MRI was evocative in 3 patients out of 5; 2 patients underwent diagnostic arthroscopy. Diagnosis was based on anatomo-pathological examination. Treatment was based on subtotal synovectomy in 15 cases and on tumor excision in patients with localized involvement. 2 cases with osteocartilaginous destruction underwent arthroplasty. Patients' evolution was marked by 2 diffuse recurrences after a mean follow-up of 3-7 years. 3 patients had stiffness associated with quadriceps atrophy, therefore arthrolysis was performed. One case of histologically confirmed PVNS had proved to be a monophasic synovial sarcoma invading the bone 5 months after total synovectomy. Hence, the indication for amputation. PMID- 29255558 TI - Primary idiopathic osteoarthropathy. PMID- 29255557 TI - Detection and sequencing of rotavirus among sudanese children. AB - Introduction: Diarrheal diseases are a big public health problem worldwide, particularly among developing countries. The current study was conducted to detect and characterize group A rotavirus among admitted children with gastroenteritis to the pediatric hospitals, Sudan. Methods: A total of 755 stool samples were collected from Sudanese children with less than 5 years of age presenting with acute gastroenteritis during the period from April to September 2010. Enzyme-linked immunosorbent assay (ELISA) was used to Detection of Rotavirus antigens. Ribonucleic acid (RNAs) were extracted from rotavirus positive stool samples using (QIAamp(r) Viral RNA Mini Kit). (Omniscript(r) Reverse Transcription kit) was used to convert RNA to complementary Deoxyribonucleic acid (cDNA). The cDNAs were used as template for detection of VP4-P (P for Protease-sensitive) and VP7-G (G for Glycoprotein) genotyping of Rotavirus using nested PCR and sequencing. Results: Out of the 755 stool samples from children with acute gastroenteritis, 121 were positive for rotavirus A. Among 24 samples that were sequenced; the VP7 predominant G type was G1 (83.3%), followed by G9 (16.7%). Out of these samples, only one VP4 P[8] genotype was detected. Conclusion: As a conclusion the VP7 predominant G type was G1, followed by G9 whereas only one VP4 genotype was detected and showed similarity to P[8] GenBank strain. It appears that the recently approved rotavirus vaccines in Sudan are well matched to the rotavirus genotypes identified in this study, though more studies are needed. PMID- 29255559 TI - Impact of heart rate in atrial fibrillation versus sinus rhythm on mortality in octogenarian patients with acute coronary syndrome. AB - Introduction: Association of heart rate (HR) with mortality in patients with acute coronary syndrome (ACS) and aged >= 80 years are underrepresented in clinical trials. We therefore aimed to investigate the association of HR in atrial fibrillation (AF) versus sinus rhythm (SR) with all-cause mortality in octogenarian patients with ACS. Methods: A total of 336 patients with ACS patients and aged >= 80 years were enrolled into the current study. The end point of interest was death from any cause. Association of HR in AF versus SR with mortality was analyzed by Kaplan-Meier curve following log-rank test and multivariable Cox regression analysis. Results: In total, 63 (87.5%) of patients with AF were dead and 147 (59.8%) of patients with SR were dead during the follow up period. The best cut-off was 80 bpm, with a sensitivity of 62% and specificity of 66%. HR <= 80 bpm in SR but not in AF was associated with better outcome as compared with HR > 80 bpm (Chi-Square = 26.55, Log rank P < 0.001). In SR subgroup, the hazard ratios of HR <= 80 bpm were 0.51(95% CI 0.37-0.70, P < 0.001) adjusted for age, 0.46 (95%CI 0.33-0.63, P < 0.001) adjusted for gender, 0.62 (95%CI 0.42- 0.93, P = 0.020) adjusted for multivariables respectively. In AF subgroup, the hazard ratios of HR <= 80 bpm were 0.83(95% CI 0.49-1.38, P = 0.464) adjusted for age, 0.96 (95%CI 0.59-1.58, P = 0.882) adjusted for gender, 0.72(95% CI 0.41-1.26, P = 0.249) adjusted for multivariables respectively. Conclusion: The current study demonstrates that heart rate is an independent prognostic predictor for all-cause mortality, and HR <= 80 bpm is associated with improved outcome in SR but not in AF in octogenarian patients with ACS. PMID- 29255560 TI - Pattern and outcome of acute kidney injury among Sudanese adults admitted to a tertiary level hospital: a retrospective cohort study. AB - Introduction: Little is known about the pattern and outcome of Acute Kidney injury (AKI) in Sudan. This study aimed to determine the etiology and outcome of AKI among Sudanese adults. Methods: A retrospective cohort study was conducted in a tertiary level hospital, Soba University Hospital, Sudan. The medical records of all adults admitted to hospital from the 1st of January to 31st of December 2014 were reviewed. The diagnosis and severity of AKI was defined as per the Kidney Disease Improving Global Outcomes (KDIGO) recommendations. Results: The medical records of 6769 patients were reviewed. AKI was diagnosed in 384 patients (5.7%); being community acquired in 82.6% of cases. Sepsis, volume depletion, obstructive uropathy, heart failure, acute glomerulonephritis and severe malaria were the commonest causes of AKI diagnosed in 44%, 38.5%, 8.9%, 5.7%, 4.7% and 3.1% of patients, respectively. Following treatment complete renal recovery was seen in 35.7% of patients; whereas 31.2% of patients died. Predictors of increased risk of death were old age [OR 1.03, 95% CI (1.01-1.057); P=0.003], presence of chronic liver disease [OR 2.877, 95% CI (1.5-5.5); P=0.001], sepsis [OR 2.51, 95% CI (1.912-4.493);P=0.002] and the severity of AKI [OR 3.873, 95% CI(1.498-10.013);P=0.005]. Conclusion: AKI was diagnosed in 5.7% of adults admitted to hospital. Most patients were having community acquired AKI. Old age, the presence of chronic liver disease, sepsis, and the severity of AKI as per KDIQO staging were significant predictors of mortality. PMID- 29255562 TI - Unusual location of fibrous plaque in Indonesian child with tuberosclerosis complex. PMID- 29255561 TI - Awareness of breast cancer and breast self-examination among female undergraduate students in a higher teachers training college in Cameroon. AB - Introduction: The incidence of breast cancer (BCa) in Cameroon is on the rise and accounts for a leading cause of mortality. An understanding of the knowledge and practices on breast cancer and breast self-examination (BSE) among teachers are important first steps which will guide the designing of interventions aimed at raising awareness across the general population. Methods: We conducted a cross sectional study in April 2016 involving 345 consenting female undergraduate students in the Higher Teachers Training College, Bambili, Cameroon. Data was collected using a pretested self-administered questionnaire and analysed using descriptive methods. Results: The mean age of the respondents was 22.5+/-3.2years and a vast majority (n = 304, 88.1%) had heard about BCa primarily from the television/radio (n=196, 64.5%). Overall, less than a quarter (n=65, 21.4%) of respondents who had heard about BCa had sufficient knowledge on its risk factors and signs/symptoms. A plurality (53.3%) thought BCa can be prevented via vaccination while over a third (38.7%) opined that BCa can be treated spiritually. Less than half (47%) of respondents who had heard about BCa had heard about BSE amongst which only 55 (38.5%) had ever practiced it. Conclusion: Though most students are aware of the existence of breast cancer, their overall knowledge on its risk factors and clinical presentation is insufficient with a concomitant low practice of BSE. These highlighted gaps warrants intensification of sensitization campaigns and educational programmes in order to raise knowledge levels and enhance prevention strategies that would aid in reducing the burden of breast cancer in Cameroon. PMID- 29255563 TI - Irritable bowel syndrome in adolescents in Lagos. AB - Introduction: irritable bowel syndrome (IBS) is one of the functional gastrointestinal disorders (FGIDs) which has been well described in western populations especially as the commonest cause of recurrent abdominal pain The aim of this study was to document the prevalence of Irritable bowel syndrome (IBS) amongst children in western Nigeria and increase the aware ness of IBS amongst physicians who manage children with abdominal pain. Methods: This was a cross sectional study conducted amongst children aged 10-18 years in 8 schools located in two local government areas of Lagos state. A multistage stratified random sampling survey was conducted using the validated Rome III criteria to assess for IBS and associated risk factors. The subtypes of IBS and associated extra intestinal symptoms were also documented. Results: The prevalence of IBS was 16.0% in the study participants and the prevalence decreased with increasing age (p=0.05). Sixty two (62.5%) of the students with recurrent abdominal pain had IBS. IBS was more prevalent in the females compared to the males (p=0.000). The significant risk factors for IBS identified were gender (p=0.000), socioeconomic status (p=0.001) and past history of gastroenteritis (p=0.011). The commonest subtype of IBS seen was the alternating subtype. Conclusion: IBS is prevalent in African children. Physicians who attend to children need to have a high index of suspicion for IBS in children who present with abdominal pain when there are no alarm symptoms. The need for further longitudinal studies in African children cannot be overemphasized. PMID- 29255564 TI - Functional extra-adrenal paraganglioma of the retroperitoneum giving thoracolumbar spine metastases after a five-year disease-free follow-up: a rare malignant condition with challenging management. AB - Paragangliomas are benign neoplasms that arise from the autonomic nervous system and the associated paraganglia. Although benign, they have been shown to possess metastatic potential. Extra-adrenal retroperitoneal paraganglioma with vertebral metastasis is considered very uncommon. Here, we present a case of a functional extra-adrenal paraganglioma of the retroperitoneum giving metastasis to T4 vertebra after five years of follow-up in a 48-year-old man who had been initially treated with complete resection of the primary tumor. The condition of the patient improved significantly after radiosurgery and somatostatin analogs treatment, until lumbar spine lesions appeared six months later. Our case demonstrates that retroperitoneal paraganglioma is a rare condition which should be considered in the differential diagnosis of a retroperitoneal mass combined with vertebral lesions. Additionally, increased physician awareness and long-term follow-up is mandatory for all patients with history of retroperitoneal paraganglioma since metastases may occur after long latent intervals from the initial diagnosis. PMID- 29255565 TI - Bone metastasis as the first sign of gastric cancer. AB - The skeleton is a common metastatic site for visceral carcinomas. However, the presentation of gastric cancer as bony metastases without preceding gastrointestinal symptoms is rare which has been infrequently reported in the literature. We report an infrequent case of a 60-year-old patient diagnosed having a gastric carcinoma with bone metastasis as the first evidence. She has consulted with worsening backache which started two months priorly. PMID- 29255567 TI - Knowledge of postnatal mothers on essential newborn care practices at the Kenyatta National Hospital: a cross sectional study. AB - Introduction: Of the 130 million babies born yearly, nearly 4 million die in the neonatal period. Kenya Demographic Health Survey (KDHS) 2014 places neonatal mortality rate at 22 deaths per 1,000 live births, well above the Sustainable Development Goal (SDG) 3 that aims to reduce these mortalities to at least 12 deaths per 1000 live births by 2030. The aim of the study was to assess maternal knowledge on selected components of essential newborn care: breastfeeding, cord care, immunisation, eye care and thermoregulation. Methods: A hospital based cross-sectional study was conducted on 380 postnatal mothers in Kenyatta National Hospital. Interviews were conducted using structured pretested questionnaires. A score of one was given for correct response and zero for incorrect. Data were analysed using SPSS version 18. Results: Modes of thermoregulation identified included kangaroo care (7%), warm room (4%) and warm clothing (93%). Almost all mothers knew of breastfeeding on demand, exclusive breastfeeding and colostrum use. Only 17.8% of mothers identified Bacillus Calmette-Guerin (BCG) and Oral Polio Vaccine (OPV) were birth vaccines. Only 4 mothers knew no substances should be applied to the cord. In logistic regression, factors significantly associated with poor knowledge included lack of education on newborn care during pregnancy, incomplete (less than 3) or no antenatal visits with an odds ratio (OR) of 3.3 (95% confidence interval (CI), 1.5 to 7.4 ), 2.5(1.5 to 4.2), 5.1(1.3 to 19.3) and p values of 0.003, 0.001 and 0.018 respectively. Conclusion: Knowledge gaps existed regarding cord care, eye care, and immunization. Mothers had good knowledge on breastfeeding practices. Those who fail to fully attend antenatal clinics should be targeted for newborn care education. PMID- 29255566 TI - [Feasibility and relevance of safety checklist in the central operating block at the Regional Medical Center, Saint Louis, Senegal]. AB - Introduction: Safety checklist (CL) in the operating block is a quality tool which allows to reduce perioperative morbidity and mortality. That is one of the French National Health Authority requirements for the certification procedure of healthcare institutions. This study aimed to conduct a quantitative and qualitative evaluation of the use of this tool in the central operating block at the Regional Medical Center in Saint Louis. Methods: A prospective evaluation of the indicators for monitoring the practical use of the checklist and the contribution to the improvement of surgical practices in the operating block at the Regional Medical Center in Saint Louis was initiated since the launch of this study in March 2016. Results: CL utilization rate was 75%, compliance rate was 60%; information rate was 99% for the pre-induction items, 93% for the pre incision items and 88% for the postoperative items. Only 73% of analyzed CL were filled with an effective oral communication according to the three items. CL helped to detect hardware failures and/or adverse events in 15% of cases. No patient's identification or operated side error were objectified in our study. Conclusion: CL contributes in the development of the culture of patient's safety in the operating block and has led to the establishment of a risk mapping in the operating block. Nevertheless, while important, it shouldn't be considered a magic tool to avoid errors but integrated into the improvement in health care quality with other programs such as the reporting of adverse events and the the review of morbidity and mortality. PMID- 29255568 TI - [Perineal verrucous lesions]. AB - Verrucous lichen planus (VLP), is a chronic inflammatory dermatosis mainly involving the lower limbs. It rarely affects the perineal area, where it occurs in association with other mucocutaneous lichen lesions. We here report the case of a 51-year old patient with isolated perineal verrucous lichen planus. The patient, who had no significant medical history, presented with painless, verrucous, slightly itchy lesions in the perineal area that had gradually increased in volume over the past 8 years. Clinical examination revealed the presence of multiple firm grayish budding lesions with a rough surface, measuring 1-4 cm in diameter, in the perianal and scrotal area (A). The remainder of the somatic examination was normal. Histology showed verrucous acanthotic epidermis associated with mainly lymphocytic inflammatory infiltrate penetrating the basement membrane and pigmentary incontinence with the formation of apoptotic bodies in the basal layer of epidermis, without signs of viral infection or malignant transformation (B). The diagnosis of verrucous lichen planus was retained. Hepatitis C serology, lipid assessment as well as abdominal ultrasound were normal. A very strong local corticosteroid therapy was prescribed. The patient had a favorable outcome without recidivism at 18-months' follow-up. PMID- 29255569 TI - Chromosomal abnormalities in 163 Tunisian couples with recurrent miscarriages. AB - Recurrent miscarriage (RM) is defined as three or more consecutive pregnancy losses before 24 weeks of gestation. Parental chromosomal abnormalities represent an important etiology of RM. The aim of the present study was to identify the distribution of chromosome abnormalities among Tunisian couples with RM referred to the Department of Cytogenetic at the Pasteur Institute of Tunis (Tunisia) during the last five years. Standard cytogenetic analysis was carried out in a total of 163 couples presenting with two or more spontaneous abortions. Karyotypes were analyzed by R-banding. We identified 14 chromosomal abnormalities including autosomal reciprocal translocation, Robertsonian translocation, inversion, mosaic aneuploidy and heteromorphysm. The overall prevalence of chromosomal abnormalities was 8.5% in our cohort. This finding underlies the importance of cytogenetic investigations in the routine management of RM. PMID- 29255571 TI - High-quality draft genome sequence of Effusibacillus lacus strain skLN1T, facultative anaerobic spore-former isolated from freshwater lake sediment. AB - 10.1601/nm.25721 strain skLN1T is the type strain of the type species in the genus 10.1601/nm.25720 which is the one of the genera in the family 10.1601/nm.5070 within the phylum 10.1601/nm.3874. 10.1601/nm.25721 strain skLN1T is a Gram-positive, spore-forming thermophilic neutrophile isolated from freshwater lake sediment. Here, we present the draft genome sequence of strain skLN1T, which consists of 3,902,380 bp with a G + C content of 50.38%. PMID- 29255570 TI - The complete genome sequence of Ensifer meliloti strain CCMM B554 (FSM-MA), a highly effective nitrogen-fixing microsymbiont of Medicago truncatula Gaertn. AB - Strain CCMM B554, also known as FSM-MA, is a soil dwelling and nodule forming, nitrogen-fixing bacterium isolated from the nodules of the legume Medicago arborea L. in the Maamora Forest, Morocco. The strain forms effective nitrogen fixing nodules on species of the Medicago, Melilotus and Trigonella genera and is exceptional because it is a highly effective symbiotic partner of the two most widely used accessions, A17 and R108, of the model legume Medicago truncatula Gaertn. Based on 16S rRNA gene sequence, multilocus sequence and average nucleotide identity analyses, FSM-MA is identified as a new Ensifer meliloti strain. The genome is 6,70 Mbp and is comprised of the chromosome (3,64 Mbp) harboring 3574 predicted genes and two megaplasmids, pSymA (1,42 Mbp) and pSymB (1,64 Mbp) with respectively 1481 and 1595 predicted genes. The average GC content of the genome is 61.93%. The FSM-MA genome structure is highly similar and co-linear to other E. meliloti strains in the chromosome and the pSymB megaplasmid while, in contrast, it shows high variability in the pSymA plasmid. The large number of strain-specific sequences in pSymA as well as strain-specific genes on pSymB involved in the biosynthesis of the lipopolysaccharide and capsular polysaccharide surface polysaccharides may encode novel symbiotic functions explaining the high symbiotic performance of FSM-MA. PMID- 29255572 TI - Draft genome sequence of the type strain of the sulfur-oxidizing acidophile, Acidithiobacillus albertensis (DSM 14366). AB - Acidithiobacillus albertensis is an extremely acidophilic, mesophilic, obligatory autotrophic sulfur-oxidizer, with potential importance in the bioleaching of sulfidic metal ores, first described in the 1980s. Here we present the draft genome sequence of Acidithiobacillus albertensis DSM 14366T, thereby both filling a long-standing gap in the genomics of the acidithiobacilli, and providing further insight into the understanding of the biology of the non iron-oxidizing members of the Acidithiobacillus genus. The assembled genome is 3,1 Mb, and contains 47 tRNAs, tmRNA gene and 2 rRNA operons, along with 3149 protein-coding predicted genes. The Whole Genome Shotgun project was deposited in DDBJ/EMBL/GenBank under the accession MOAD00000000. PMID- 29255573 TI - Draft genome sequence of Pseudomonas extremaustralis strain USBA-GBX 515 isolated from Superparamo soil samples in Colombian Andes. AB - Here we present the physiological features of Pseudomonas extremaustralis strain USBA-GBX-515 (CMPUJU 515), isolated from soils in Superparamo ecosystems, > 4000 m.a.s.l, in the northern Andes of South America, as well as the thorough analysis of the draft genome. Strain USBA-GBX-515 is a Gram-negative rod shaped bacterium of 1.0-3.0 MUm * 0.5-1 MUm, motile and unable to form spores, it grows aerobically and cells show one single flagellum. Several genetic indices, the phylogenetic analysis of the 16S rRNA gene sequence and the phenotypic characterization confirmed that USBA-GBX-515 is a member of Pseudomonas genus and, the similarity of the 16S rDNA sequence was 100% with P. extremaustralis strain CT14-3T. The draft genome of P. extremaustralis strain USBA-GBX-515 consisted of 6,143,638 Mb with a G + C content of 60.9 mol%. A total of 5665 genes were predicted and of those, 5544 were protein coding genes and 121 were RNA genes. The distribution of genes into COG functional categories showed that most genes were classified in the category of amino acid transport and metabolism (10.5%) followed by transcription (8.4%) and signal transduction mechanisms (7.3%). We performed experimental analyses of the lipolytic activity and results showed activity mainly on short chain fatty acids. The genome analysis demonstrated the existence of two genes, lip515A and est515A, related to a triacylglycerol lipase and carboxylesterase, respectively. Ammonification genes were also observed, mainly nitrate reductase genes. Genes related with synthesis of poly-hydroxyalkanoates (PHAs), especially poly-hydroxybutyrates (PHBs), were detected. The phaABC and phbABC operons also appeared complete in the genome. P. extremaustralis strain USBA-GBX-515 conserves the same gene organization of the type strain CT14-3T. We also thoroughly analyzed the potential for production of secondary metabolites finding close to 400 genes in 32 biosynthetic gene clusters involved in their production. PMID- 29255575 TI - WHY ADULT VIEWS MATTER: SCHOOL PERSONNEL PERSPECTIVES ABOUT CHILD SCHOOL PARTICIPATION. AB - Community-Based Participatory Research promotes the inclusion of diverse voices in the research process and in decision-making processes. However, there are very few research studies that collaborate with children, especially within the context of schools. Promoting child participation has benefits both for children as well as for schools. Nonetheless, this may depend on how adults react to such participation. The present study is part of a broader study on school violence prevention. Our objective is to explore school personnel's concept of childhood and how it relates to their opinions about child school participation. We conducted a discussion group with nineteen (19) faculty and non-faculty members of a public school to ask them questions about the topic. We categorized participants' answers and analyzed relationships among them. Results suggest that participants' concept of childhood is linked to socio-cultural and historical factors and that it impacts their opinions about child participation. Also, school personnel recognize that child participation has benefits for children, the school and the wider society. This contrasts with deficiencies on how to articulate this participation beyond traditional classroom strategies. We discuss the implications of these results for pedagogical practice and for participatory research as promoters of children voices in context. PMID- 29255574 TI - Draft genome of Paraburkholderia caballeronis TNe-841T, a free-living, nitrogen fixing, tomato plant-associated bacterium. AB - 10.1601/nm.26956 caballeronis is a plant-associated bacterium. Strain TNe-841T was isolated from the rhizosphere of tomato (Solanum lycopersicum L. var. lycopersicum) growing in Nepantla Mexico State. Initially this bacterium was found to effectively nodulate Phaseolus vulgaris L. However, from an analysis of the genome of strain TNe-841T and from repeat inoculation experiments, we found that this strain did not nodulate bean and also lacked nodulation genes, suggesting that the genes were lost. The genome consists of 7,115,141 bp with a G + C content of 67.01%. The sequence includes 6251 protein-coding genes and 87 RNA genes. PMID- 29255577 TI - Anatomical Variations of the Biliary Tree Found with Endoscopic Retrograde Cholagiopancreatography in a Referral Center in Southern Iran. AB - BACKGROUND Anatomical variations in the biliary system have been proven to be of clinical importance. Awareness of the pattern of these variations in a specific population may help to prevent and manage biliary injuries during surgical and endoscopic procedures. Knowledge of the biliary anatomy will be also of great help in planning the drainage of adequate percentage of liver parenchyma in endoscopic or radiological procedures. METHODS All consecutive patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) from April 2013 to April 2015 at Nemazee Hospital, a referral center in the south of Iran, were included in this cross-sectional study. The patients with previous hepatic or biliary surgery, liver injury or destructive biliary disease were excluded from the study. All ERCPs were reviewed by two expert gastroenterologists in this field. The disagreed images by the two gastroenterologists were excluded. Huang classification was used for categorizing the different structural variants of the biliary tree, and the frequency of each variant was recorded. RESULTS Totally, 362 patients (181 men and 181 women) were included in the study. 163 patients (45%) had type A1 Huang classification (right dominant), which was the most prevalent type among our patients. 55% of them had non-right dominant anatomy. The result of the Chi-square test revealed that there was no statistically significant difference between the men and women regarding the anatomical variations (p = 0.413). CONCLUSION The anatomical variation in the biliary system among Iranian patients is comparable to other regions of the world. Significant proportions of our patients are non-right dominant and may need bilateral biliary drainage. PMID- 29255576 TI - Improving Quality of Care in Patients with Liver Cirrhosis. AB - Liver cirrhosis is a major chronic disease in the field of digestive diseases. It causes more than one million deaths per year. Despite established evidence based guidelines, the adherence to standard of care or quality indicators are variable. Complete adherence to the recommendations of guidelines is less than 50%. To improve the quality of care in patients with cirrhosis, we need a more holistic view. Because of high rate of death due to cardiovascular disease and neoplasms, the care of comorbid conditions and risk factors such as smoking, hypertension, high blood sugar or cholesterol, would be important in addition to the management of primary liver disease. Despite a holistic multidisciplinary approach for this goal, the management of such patients should be patient centered and individualized. The diagnosis of underlying etiology and its appropriate treatment is the most important step. Definition and customizing the quality indicators for quality measure in patients are needed. Because most suggested quality indicators are designed for measuring the quality of care in decompensated liver cirrhosis, we need special quality indicators for compensated and milder forms of chronic liver disease as well. Training the patients for participation in their own management, design of special clinics with dedicated health professionals in a form of chronic disease model, is suggested for improvement of quality of care in this group of patients. Special day care centers by a dedicated gastroenterologist and a trained nurse may be a practical model for better management of such patients. PMID- 29255578 TI - Impact of Propranolol on Preventing Renal Dysfunction in Patients with Cirrhosis. AB - BACKGROUND One of the earliest diagnostic signs of hepatorenal syndrome in patients suffering from liver cirrhosis is an increase in the renal vascular resistive index (RI). In this study, the impact of propranolol on decreasing this index and to postpone the probability of hepatorenal syndrome has been investigated. METHODS In the current research, 30 patients with liver cirrhosis with different age and sexes have been enrolled. Demographic data and complete medical history have been collected using a specific questionnaire. At first, renal artery Doppler ultrasonography was performed to determine the RI. The patients were then treated with propranolol, and under supervision, the dose of the drug was increased gradually every 3 to 5 days to reach the target of 25% decrease in resting heart rate. One month after reaching the target dose of the medicine, Doppler ultrasonography was repeated for the patients and the second RI was compared with the pretreatment ones. RESULTS According to our results after treatment with propranolol, a significant decrease of RI was observed (p < 0.01). However, there was no significant difference in the glomerular filtration rate (GFR) before and after treatment with propranolol (p = 0.290). In our study, we found that administering propranolol was associated with significant changes in RI and GFR between the patients with compensated and decompensated cirrhosis (mean change: -0.005 +/- 0.017 vs. -0.058 +/- 0.045; p < 0.01 for RI and -4.226 +/- 17.440 vs. 13.486 +/- 12.047; p < 0.01 for GFR in patients with compensated and decompensated cirrhosis, respectively). CONCLUSION Propranolol reduces renal vascular RI in patients with cirrhosis. The response rates in the patients with decompensating cirrhosis were significantly higher than the patients with compensating cirrhosis. PMID- 29255579 TI - Bowel Preparation for a Better Colonoscopy Using Polyethylene Glycol or C-lax: A Double Blind Randomized Clinical Trial. AB - BACKGROUND Ideal bowel preparation regimen for a suitable colonoscopy should be safe, and well tolerated, and should rapidly clear gastrointestinal tract. Soluble polyethylene glycol (PEG) is the most common cleansing drug and Senna or C-Lax (Cassia angustifolia Vahl) is an alternative herbal one. This study was designed to compare the efficacy of PEG and C-lax in bowel preparation. METHODS In this randomized double blind trial (registry number in IRCT.ir: IRCT201601161264N7), 320 patients were randomly assigned in PEG or C-lax groups. PEG solution was prepared from 5*70 gr sachets in 20*250cc water (250 ml every 15 minutes), prescribed 24h before the colonoscopy. In the other group 3*60 ml C-lax syrup glasses (each containing 90 mg senozid B) was given in two divided doses (1.5 glasses of 250cc every 12 hours), 24h before the colonoscopy. Ottawa score was used to evaluate the quality of bowel preparation. Chi-square test, Student t test, MannWhitney test and multivariate analysis were used to analyze the data. RESULTS Of these patients with the mean (SD) age of 50 (15.16) years, 162 (50.8%) were men. Mean (SD) Ottawa score was 2.57 (0.2) and 3.15 (0.31) in the PEG and C lax group, respectively (p value = 0.81). Multivariate analysis showed that less opium consumption (p < 0.001) and higher educational level (p =0.005) were associated with better bowel preparation. CONCLUSION C-Lax is non-inferior to PEG solution in cleansing colon. The quality of bowel preparation was lower in opium consumers and better in those with higher educational level. PMID- 29255580 TI - Comparison of Intermittent and Bolus Enteral Feeding Methods on Enteral Feeding Intolerance of Patients with Sepsis: A Triple-blind Controlled Trial in Intensive Care Units. AB - BACKGROUND Recent trials have shown controversial results on which enteral feeding methods has a lower risk of enteral feeding intolerance. Therefore, we aimed to compare two methods of bolus and intermittent feeding on enteral feeding intolerance of patients with sepsis. METHODS This triple-blind randomized controlled trial was conducted on 60 patients with sepsis, who were fed through tubes for at least 3 days. The patients were randomly assigned into bolus feeding, intermittent feeding, and control groups. Enteral feeding intolerance of all patients was recorded in 3 consecutive days by a researcher-made checklist including the data on gastric residual volume, vomiting, diarrhea, constipation, and abdominal distension. RESULTS There were no significant differences between the three studied groups in none of the intervention days pertaining to constipation, diarrhea, vomiting, abdominal distention, and gastric residual volume (p > 0.05). Also, no statistically significant difference was found between all variables in the three studied groups during the 3 days (p > 0.05). CONCLUSION As enteral feeding intolerance of patients with sepsis was similar in both bolus and intermittent feeding methods, it can be concluded that bolus method can still be used as a standard method to decrease the risk of enteral feeding intolerance if it is used properly. PMID- 29255581 TI - The Association between Modulating Inflammatory Cytokines and Constipation of Geriatrics in Iran. AB - BACKGROUND The effect of changes in intestinal microbiota on constipation is contraversial. Constipation is more prevalent in elderly. Therefore, the current study was designed to assess the role of modulating inflammatory cytokines in old age patients with constipation by evaluating the serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1 (IL-l), and interleukin 6 (IL-6). METHODS This case-control study was done on 100 participants, aged 65 years or higher, with and without functional constipation according to ROME III criteria (50 participants in each group). Baseline demographic, clinical characteristics, and serum levels of TNF-alpha, IL-1, and IL-6 were compared between the case and control groups. Independent t test and Chi-square test were used for analysis of data. RESULTS Mean levels of TNF-alpha, IL-1, and IL-6 were (666.80 +/- 101.40 pg/mL vs. 489.20 +/- 53.68 pg/mL, p < 0.001), (435.96 +/- 52.31 pg/mL vs. 296.44 +/- 45.50 pg/mL, p < 0.001) and (438.18 +/- 59.57 pg/mL vs. 290.14 +/- 36.39 pg/mL, p < 0.001) in the case and control groups, respectively. A reverse correlation was found between the aging process and TNF-alpha (r = -0.26; p = 0.04), as well as IL-1 level (r = -0.41; p = 0.003) in the control group. A direct correlation was observed between the aging process and TNF-alpha (r = 0.40; p = 0.004) and IL-6 (r = 0.44; p = 0.002) levels in the case group. CONCLUSION This study showed a significant association between the serum level of modulating inflammatory cytokines and age-related constipation in Iranian subjects. It seems that the serum level of modulating inflammatory cytokines can be affected by diversity and abundance in the gut microbiota. The role of diversity in microbial population and their abundance in gut must be evaluated in further studies. PMID- 29255582 TI - Ulcerative Colitis Following Orthotopic Cardiac Transplantation. AB - Inflammatory bowel disease following a solid organ transplantation while the patient is receiving immunosuppressive therapy is a rare phenomenon. Here we present a 48-year-old man who underwent cardiac transplantation 9 years earlier and was receiving cyclosporine as immunosuppressive therapy since then, presenting with complaints of rectorrhagia and diarrhea. In follow-up, he was diagnosed as having ulcerative colitis. We also reviewed the literature for similar cases, which yielded very few similar ones. PMID- 29255583 TI - Pancreatic Tuberculosis in an Immunocompetent Patient: A Case Report and Review of the Literature. AB - Pancreatic tuberculosis is extremely rare and its clinical and radiological findings are similar to those of pancreatic malignancy. The diagnosis of pancreatic tuberculosis is not usually made prior to surgery. Here, we report a case of pancreatic tuberculosis, presented with abdominal pain and weight loss. Abdominal computed tomography (CT) showed a 62 mm * 32 mm septate solid-cystic mass in the pancreatic head area with extension into the hilum of the liver. There was no evidence of inflammation or pancreatitis. Endoscopic ultrasound-fine needle aspiration (EUSFNA) could not yield the diagnosis. Exploratory laparotomy and further pathological evaluation suggested pancreatic tuberculosis. Response to antituberculosis treatment confirmed the diagnosis. Finally, previous case reports and case studies of pancreatic tuberculosis in the literature are fully investigated. PMID- 29255584 TI - Non-parasitic Splenic Cyst. PMID- 29255585 TI - Chest Pain and Alternate Dysphagia. PMID- 29255586 TI - Vaccination of Hepatitis A; To Do or Not to Do? PMID- 29255587 TI - Effects of model-mimic frequency on insect visitation and plant reproduction in a self-mimicry pollination system. AB - The proportion of mimics and models is a key parameter in mimetic systems. In monoecious plants with self-mimicry pollination systems, the mimic-model ratio is determined by the floral sex ratio. While an equal sex ratio (1:1) could provide the perfect balance between pollen donors and stigma surfaces able to receive the pollen, an unequal ratio could increase pollination by production of a greater number of rewarding, model flowers. The aim of the present study is to test the differences in visitation frequency and reproductive rates of different mimic and model flower arrays in order to assess the efficacy of the mimetic system in a Begonia cucullata population. The frequencies of visitors to groups of flowers with three distinctive sex ratio arrays (male-biased, female-biased and equal ratio) were compared using a Bayesian approach. The reproductive outcomes were compared in order to detect advantages of particular sex ratios. Low visitation frequency was recorded in all arrays. Pollinators showed similar behaviour regardless of sex ratio; they tended to avoid female, rewardless flowers. Pollination quality was highest in the equal sex ratio array. The current study shows that sex ratio plays a critical role in the pollination of B. cucullata and that the efficacy of the self-mimicry system appears to be doubtful. Visitation frequency may be associated with visual or chemical cues that allow pollinators to recognize models and mimics, regardless of their frequency in the population. PMID- 29255588 TI - Preventing Suicide in Montana: A Community-Based Theatre Intervention. AB - Purpose: This study examined whether a community-based suicide prevention project could increase willingness to seek professional help for suicidal ideation among eastern Montana youth. Design: Online surveys were administered at baseline (N = 224) and six months post-test (N = 217) consisting of the Risk Behavior Diagnosis Scale (RBD), self-report questions on suicidality, willingness to engage with suicide prevention resources, and willingness to communicate with peers, family members, teachers or counselors about suicide. Findings: A comparison of means within groups from pre- to post-test showed increases in self-efficacy for communicating about suicidal concerns with a teacher, school counselor or social worker; increases in self-efficacy for helping others; and increases in response efficacy of interpersonal communication about suicide with a teacher, school counselor or social worker. Practical Implications: Young adults need to be willing and able to intervene in life-threatening situations affecting their peers. In step with narrative empowerment education, personal experiences can be used to communicatively reduce peer resistance to behavior change. Originality: Health communicators tend to rely on overly didactic education and awareness raising when addressing suicide prevention. This research shows the importance of direct and personal forms of influence advocated by social marketing professionals. PMID- 29255589 TI - Metachronous solitary metacarpal bone metastasis from rectal cancer. AB - Metachronous solitary metacarpal bone metastasis from rectal cancer has not been reported previously. Here, we describe a 54-year-old woman who underwent abdominoperineal resection for rectal cancer following neoadjuvant chemoradiotherapy. The resected specimen contained adenocarcinoma with no lymph node metastases (Stage II, T3N0M0); no adjuvant chemotherapy was administered. Fifteen months after surgery, the patient presented with pain and swelling of the right thumb. Radiography revealed metacarpal bone destruction, and fluorine-18 fluorodeoxyglucose positron emission tomography showed uptake only in the metacarpal bone. Open biopsy revealed an adenocarcinoma, and a right thumb resection was performed. Histological examination indicated features of adenocarcinoma similar to the findings of a rectal lesion, leading to a diagnosis of metachronous solitary metacarpal bone metastasis from rectal cancer. The patient remains free of disease after 6 years of follow-up. Our findings suggest that surgical resection may lead to favorable outcomes in patients with resectable solitary bone metastases. PMID- 29255590 TI - Extra peritoneal giant pelvic hibernoma: a case report. AB - Abdominal hibernoma is a rare slow-growing tumor originating from brown adipose tissue. Due to its rarity, only a few case reports have been published so far. Pelvic localization is anedoctal and preoperative differential diagnosis with other malignancies may be challenging. We present the case of a woman who, due to a lower abdominal pain, underwent an abdominal ultrasonography with diagnosis of a 15 cm hyperechogenous pelvic mass. A subsequent MRI showed a 16 * 5.8 * 7.8 cm3 lesion anterior to the left iliacus muscle, with an intra- and extrapelvic component longitudinally extending from the left anterior superior iliac spine until the lesser trochanter. Surgical resection was performed and final histopathology was consistent with hibernoma. This report emphasizes the necessity to include hibernoma among differential diagnosis when a retroperitoneal abdominal mass is diagnosed and the difficulty to perform preoperatively this diagnosis due to the extreme rarity of these neoplasms. PMID- 29255591 TI - The lncRNA MEG3 downregulation leads to osteoarthritis progression via miR 16/SMAD7 axis. AB - Background: Osteoarthritis (OA) is a chronic joint disease and there is no a definitive cure at present. Long non-coding RNAs (lncRNAs) have been confirmed to play important roles in the development of OA. However, the underlying mechanism of lncRNA maternally expressed gene 3 (MEG3) in OA has not been well elucidated. Methods: The rat OA model and interleukin-1beta (IL-1beta)-induced rat chondrocytes were constructed. The expression pattern of lncRNA MEG3 and miR-16 was detected by RT-qPCR assay in cartilage tissues of rat OA model. The effect of MEG3 and miR-16 on IL-1beta-induced chondrocytes was evaluated on the basis of cell viability and apoptosis. Then, the interaction among MEG3, miR-16 SMAD7 was explored by dual-luciferase reporter assay and RIP assay. Results: It is found that lncRNA MEG3 was down-regulated and miR-16 was up-regulated in rat OA cartilage tissues. MEG3 knockdown promoted proliferation and inhibited apoptosis, while miR-16 knockdown suppressed proliferation and promoted apoptosis in IL 1beta-induced rat chondrocytes. Moreover, MEG3 was involved in miR-16 pathway and MEG3 suppressed miR-16 expression. Additionally, SMAD7 was a target gene of miR 16 and miR-16 suppressed SMAD7 expression in IL-1beta-induced chondrocytes. Moreover, the expression of SMAD7 induced by MEG3 or si-MEG3 was markedly reversed by the introduction of miR-16 or anti-miR-16. Furthermore, MEG3 exerted its anti-proliferation and pro-apoptosis by regulating miR-16 and SMAD7. Conclusion: MEG3 was down-regulated and miR-16 was up-regulated in cartilage tissues of rat OA model. MEG3 knockdown might lead to the progression of OA through miR-16/SMAD7 axis. PMID- 29255592 TI - Heart regeneration in adult Xenopus tropicalis after apical resection. AB - Background: Myocardium regeneration in adult mammals is very limited, but has enormous therapeutic potentials. However, we are far from complete understanding the cellular and molecular mechanisms by which heart tissue can regenerate. The full functional ability of amphibians to regenerate makes them powerful animal models for elucidating how damaged mature organs are naturally reconstituted in an adult organism. Like other amphibians, such as newts and axolotls, adult Xenopus displays high regenerative capacity such as retina. So far, whether the adult frog heart processes regenerative capacity after injury has not been well delineated. Results: We examined the regeneration of adult cardiac tissues of Xenopus tropicalis after resection of heart apex. We showed, for the first time, that the adult X. tropicalis heart can regenerate perfectly in a nearly scar-free manner approximately 30 days after injury via apical resection. We observed that the injured heart was sealed through coagulation immediately after resection, which was followed by transient fibrous tissue production. Finally, the amputated area was regenerated by cardiomyocytes. During the regeneration process, the cardiomyocytes in the border area of the myocardium adjacent to the wound exhibited high proliferation after injury, thus contribute the newly formed heart tissue. Conclusions: Establishing a cardiac regeneration model in adult X. tropicalis provides a powerful tool for recapitulating a perfect regeneration phenomenon and elucidating the underlying molecular mechanisms of cardiac regeneration in an adult heart, and findings from this model may be applicable in mammals. PMID- 29255593 TI - Research priorities of the Canadian chiropractic profession: a consensus study using a modified Delphi technique. AB - Background: Research funds are limited and a healthcare profession that supports research activity should establish research priority areas. The study objective was to identify research priority areas for the Canadian chiropractic profession, and for stakeholders in the chiropractic profession to rank these in order of importance. Methods: We conducted a modified Delphi consensus study between August 2015 and May 2017 to determine the views of Canadian chiropractic organisations (e.g. Canadian Chiropractic Association; provincial associations) and stakeholder groups (e.g. chiropractic educational institutions; researchers). Participants completed three online Delphi survey rounds. In Round 1, participants suggested research areas within four broad research themes: 1) Basic science; 2) Clinical; 3) Health services; and 4) Population health. In Round 2, researchers created sub-themes by categorising the areas suggested in Round 1, and participants judged the importance of the research sub-themes. We defined consensus as at least 70% of participants agreeing that a research area was "essential" or "very important". In Round 3, results from Round 2 were presented to the participants to re-evaluate the importance of sub-themes. Finally, participants completed an online pairwise ranking activity to determine the rank order of the list of important research sub-themes. Results: Fifty-seven participants, of 85 people invited, completed Round 1 (response rate 67%). Fifty six participants completed Round 2, 55 completed Round 3, and 53 completed the ranking activity. After three Delphi rounds and the pairwise ranking activity was completed, the ranked list of research sub-themes considered important were: 1) Integration of chiropractic care into multidisciplinary settings; 2) Costs and cost-effectiveness of chiropractic care; 3) Effect of chiropractic care on reducing medical services; 4) Effects of chiropractic care; 5) Safety/side effects of chiropractic care; 6) Chiropractic care for older adults; 7) Neurophysiological mechanisms and effects of spinal manipulative therapy; 8) General mechanisms and effects of spinal manipulative therapy. Conclusions: This project identified research priority areas for the Canadian chiropractic profession. The top three priority areas were all in the area of health services research: 1) Integration of chiropractic care into multidisciplinary settings; 2) Costs and cost-effectiveness of chiropractic care; 3) Effect of chiropractic care on reducing medical services. PMID- 29167732 TI - Blockchain protocols in clinical trials: Transparency and traceability of consent. AB - Clinical trial consent for protocols and their revisions should be transparent for patients and traceable for stakeholders. Our goal is to implement a process allowing for collection of patients' informed consent, which is bound to protocol revisions, storing and tracking the consent in a secure, unfalsifiable and publicly verifiable way, and enabling the sharing of this information in real time. For that, we build a consent workflow using a trending technology called Blockchain. This is a distributed technology that brings a built-in layer of transparency and traceability. From a more general and prospective point of view, we believe Blockchain technology brings a paradigmatical shift to the entire clinical research field. We designed a Proof-of-Concept protocol consisting of time-stamping each step of the patient's consent collection using Blockchain, thus archiving and historicising the consent through cryptographic validation in a securely unfalsifiable and transparent way. For each protocol revision, consent was sought again. We obtained a single document, in an open format, that accounted for the whole consent collection process: a time-stamped consent status regarding each version of the protocol. This document cannot be corrupted and can be checked on any dedicated public website. It should be considered a robust proof of data. However, in a live clinical trial, the authentication system should be strengthened to remove the need for third parties, here trial stakeholders, and give participative control to the peer users. In the future, the complex data flow of a clinical trial could be tracked by using Blockchain, which core functionality, named Smart Contract, could help prevent clinical trial events not occurring in the correct chronological order, for example including patients before they consented or analysing case report form data before freezing the database. Globally, Blockchain could help with reliability, security, transparency and could be a consistent step toward reproducibility. PMID- 29188014 TI - Assessment of injection safety in Ha Dong General Hospital, Hanoi, in 2012. AB - Background: Injection is one of the most frequently used medical methods to introduce drugs or other substances into the body for purposes of treatment or prevention. Unsafe injection can cause adverse outcomes, such as abscess and anaphylactic shock, and increases the risk of blood-borne transmission of viruses to patients and health care workers, as well as the community. Recognizing the importance of injection safety, in 2000 the Vietnamese Ministry of Health (MOH) collaborated with the Vietnam Nurses Association to launch the "Safe injection" program throughout the country, including Hanoi. Methods: This cross-sectional study, combining quantitative and qualitative analysis, was conducted from February to August 2012 in Ha Dong General Hospital using a structured questionnaire and observation checklist. The target population of the study was 109 nurses working in clinical departments and 436 injections were observed. Results: The percentage of nurses who are familiar with injection safety standards was found to be 82.6%. The proportion of practical injections that met the 23 standards of injection safety set by the MOH amounted to 22.2%. The factors related to safe injection practice of nurses who were younger age group (OR=3.1; p<0.05) and fewer number of years working as a nurse (OR=2.8; p<0.05). Conclusions: While nurses have high level of knowledge about safe injections but a small proportion actually practiced. Experience may not always guarantee safe practices. Injection safety training should be regularly imparted upon all categories of nurses. PMID- 29123644 TI - RNAi targeting Caenorhabditis elegans alpha-arrestins has little effect on lifespan. AB - Background: alpha-arrestins are a family of proteins that are implicated in multiple biological processes, including metabolism and receptor desensitization. Methods: Here, we sought to examine the roles of alpha-arrestins in the longevity of Caenorhabditis elegans through an RNA interference screen. Results: We found that feeding worms with bacteria expressing double-stranded RNA against each of 24 out of total 29 C. elegans alpha-arrestins had little effect on lifespan. Thus, individual C. elegans alpha-arrestins may have minor effects on longevity. Conclusions: This study will provide useful information for future research on the functional role of alpha-arrestins in aging and longevity. PMID- 29225777 TI - Evaluation of electrochemiluminescence immunoassays for immunosuppressive drugs on the Roche cobas e411 analyzer. AB - Background: Therapeutic drug monitoring of immunosuppressant drugs are used to monitor drug efficacy and toxicity and to prevent organ transplant rejection. This study evaluates the analytical performance of semi-automated electrochemiluminescence immunoassays (ECLIA) for cyclosporine (CSA), tacrolimus (TAC) and sirolimus (SRL) on the Roche cobas e 411 analyzer at a major transplant hospital to assess method suitability and limitations. Methods: Residual whole blood samples from patients undergoing immunosuppressant therapy were used for evaluation. Imprecision, linearity, functional sensitivity, method comparisons and lot-to-lot comparisons were assessed. Results: Total imprecision ranged from 3.3 to 7.1% for CSA, 3.9 to 9.4% for TAC, and 4.6 to 8.2% for SRL. Linearity was verified from 30.0 to 960.9 MUg/L for CSA, from 1.1 to 27.1 MUg/L for TAC, and from 0.5 to 32.3 ug/L for SRL. The functional sensitivity met the manufacturer's claims and was determined to be <6.5 MUg/L for CSA, 1.1 MUg/L for TAC, and <0.1 ug/L for SRL (CV<=20%). Deming regression analysis of method comparisons with the ARCHITECT immunoassay yielded slopes of 0.917 (95%CI: 0.885-0.949) and r of 0.985 for CSA, 0.938 (95%CI: 0.895-0.981) and r of 0.974 for TAC, and 0.842 (0.810 1.110) and r of 0.982 for SRL. Deming regression analysis of comparisons with the LC-MS/MS method yielded slopes of 1.331 (95%CI: 1.167-1.496) and r of 0.969 for CSA, 0.924 (95%CI: 0.843-1.005) and r of 0.984 for TAC, and 0.971 (95%CI: 0.913 1.030) and r of 0.993 for SRL. Conclusions: The cobas e 411 ECLIA for CSA, TAC, and SRL have acceptable precision, linearity, and functional sensitivity. The method comparisons correlated well with the ARCHITECT immunoassay and LC-MS/MS and is fit for therapeutic drug monitoring. PMID- 29225780 TI - The decision to delivery interval in emergency caesarean sections: Impact of anaesthetic technique and work shift. AB - Background: One important task of the emergency anaesthesia service is to provide rapid, safe and effective anaesthesia for emergency caesarean sections (ECS). A Decision to Delivery Interval (DDI) <30 minutes for ECS is a quality indicator for this service. The aim of this study was to assess the DDI and the impact of chosen anaesthetic technique (general anaesthesia (GA), spinal anaesthesia (SPA) with opioid supplementation, or "top-up" of labour epidural analgesia (tEDA) with local anaesthesia and fentanyl mixture) and work shift for ECS at Danderyds Hospital, Sweden. Methods: A retrospective chart review of ECS at Danderyds Hospital was performed between January and October 2016. Time between decision for CS, start of anaesthesia, time for incision and delivery, type of anaesthetic technique, and time of day, working hours or on call and day of week, Monday - Friday, and weekend was compiled and analysed. Time events are presented as mean +/- standard deviation. Non-parametric tests were used. Results: In total, 135 ECS were analysed: 92% of the cases were delivered within 30 minutes and mean DDI for all cases was 17.3+/-8.1 minutes. GA shortened the DDI by 10 and 13 minutes compared to SPA and tEDA (p<0.0005). DDI for SPA and tEDA did not differ. There was no difference in DDI regarding time of day or weekday. Apgar <7 at 5' was more commonly seen in ECS having GA (11 out of 64) compared to SPA (2/30) and tEDA (1/41) (p<0.05). Conclusion: GA shortens the DDI for ECS, but the use of SPA as well as tEDA with opioid supplementation maintains a short DDI and should be considered when time allows. Top-up epidural did not prolong the DDI compared to SPA. The day of week or time of ECS had no influence on the anaesthesia service as measured by the DDI. PMID- 29255599 TI - The effect of imputing missing clinical attribute values on training lung cancer survival prediction model performance. AB - According to the estimations of the World Health Organization and the International Agency for Research in Cancer, lung cancer is the most common cause of death from cancer worldwide. The last few years have witnessed a rise in the attention given to the use of clinical decision support systems in medicine generally and in cancer in particular. These can predict patients' likelihood of survival based on analysis of and learning from previously treated patients. The datasets that are mined for developing clinical decision support functionality are often incomplete, which adversely impacts the quality of the models developed and the decision support offered. Imputing missing data using a statistical analysis approach is a common method to addressing the missing data problem. This work investigates the effect of imputation methods for missing data in preparing a training dataset for a Non-Small Cell Lung Cancer survival prediction model using several machine learning algorithms. The investigation includes an assessment of the effect of imputation algorithm error on performance prediction and also a comparison between using a smaller complete real dataset or a larger dataset with imputed data. Our results show that even when the proportion of records with some missing data is very high (> 80%) imputation can lead to prediction models with an AUC (0.68-0.72) comparable to those trained with complete data records. PMID- 29255602 TI - Streamlined manuscript submission guidelines: Beyond overdue. PMID- 29255600 TI - No apparent transmission of livestock-associated methicillin-resistant Staphylococcus aureus CC398 in a survey of staff at a regional Danish hospital. AB - Background: In recent years, livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) multi locus sequence type CC398 has spread widely in the livestock production in Europe. The rates of LA-MRSA in hospitals have been found to be largely determined by contact to and density of livestock in the area. Methods: This is a cross sectional study of the prevalence of LA-MRSA among hospital staff in a Danish hospital situated in a livestock production region. We analysed nasal swabs, air and dust samples for the presence of MRSA using PCR and mass spectrometry. Results: Of 1745 employees, 545 (31%) contributed nasal swabs. MRSA was not detected in any participant, nor was it detected in air or dust at the hospital or in houses of employees living on farms. Four percent of the participants had contact to pigs either directly or through household members. LA MRSA was detected in two of 26 samples from animal sheds, both of them from pig farms. The participation rate was relatively low, but participants were representative for the source population with regards to animal contact and job titles. Conclusions: The study suggests a low point prevalence of LA-MRSA carriage in Danish hospital staff even in regions where livestock production is dense. Should more studies confirm our findings we see no need for additional hospital precautions towards LA-MRSA in Denmark at the moment. We think that our data might reduce potential stigmatization of hospital workers with contact to LA MRSA positive farms at their work places and in their communities. PMID- 29255601 TI - Identification of Ser465 as a novel PINK1 autophosphorylation site. AB - Background: PINK1 (PTEN-induced putative kinase 1) gene is the causal gene for recessive familial type 6 of Parkinson's disease (PARK6), which is an early-onset autosomal recessive inherited neurodegenerative disease. PINK1 has been reported to exert both autophosphorylation and phosphorylation activity, affecting cell damage under stress and other physiological responses. However, there has been no report on the identification of PINK1 autophosphorylation sites and their physiological functions. Methods: (1) We adopted mass spectrometry assay to identify the autophosphorylation site of PINK1, and autoradiography assay was further conducted to confirm this result. (2) Kinase activity assay was used to compare the kinase activity of both Ser465 mutant PINK1 and disease-causing mutant PINK1. (3) We use Pulse-chase analysis to measure whether Ser465 may affect PINK1 degradation. (4) Immunocytochemistry staining was used to study the PINK1 subcellular localization and Parkin transition in subcellular level. Result: In our study, we identified the 465th serine residue (Ser465) as one of the autophosphorylation sites in PINK1 protein. The inactivation of Ser465 can decrease the kinase activity of PINK1. Either dissipated or excessive Ser465 site phosphorylation of PINK1 can slow down its degradation. PINK1 autophosphorylation contributes to the transit of Parkin to mitochondria, and has no effect on its subcellular localization. PARK6 causal mutations, T313 M and R492X, display the same characteristics as Ser465A mutation PINK1 protein, such as decreasing PINK1 kinase activity and affecting its interaction with Parkin. Conclusion: Ser465 was identified as one of the autophosphorylation sites of PINK1, which affected PINK1 kinase activity. In addition, Ser465 is involved in the degradation of PINK1 and the transit of Parkin to mitochondria. T313 M and R492X, two novel PARK6 mutations on Thr313 and Arg492, were similar to Ser465 mutation, including decreasing PINK1 phosphorylation activity and Parkin subcellular localization. PMID- 29255603 TI - Violence against doctors, a serious concern for healthcare organizations to ponder about. AB - Background: Aggression and Violence against primary care physicians is reportedly common in Pakistan but there is no any documented study to-date on this burning issue. Methods: A formed written questionnaire was distributed among 769 primary care physicians aged 31 +/- 7.68 years. Apart from the demographic data, the questionnaire included questions regarding the level of safety that primary care physicians felt during their work setups and on-call duties, along with the experience of aggression against them by the perpetrators & the support provided by the hospital management in such cases. Result: Response rate was 68% i.e. 524 physicians agreed to participate in the study. It was found that majority (85%) of the physicians has faced mild events, 62% have faced moderate events and roughly 38% were subjected to severe violence. Some physicians revealed more than one form of aggression being faced by them in 12 months preceding months which makes the collective percentage greater than 100%. Verbal abuse is the most frequent type of mistreatment faced by the doctors from the patients or their attendants. Conclusion: A considerable number of physicians participated have faced mild violence in which verbal abuse was commonest; followed by moderate and severe events. PMID- 29255604 TI - Adoption and sustained use of cleaner cooking fuels in rural India: a case control study protocol to understand household, network, and organizational drivers. AB - Background: Implementing efficient stoves and clean fuels in low and middle income countries are critical for improving health of poor women and children and improve the environment. Cleaner biomass stoves, however, perform poorly against the World Health Organization's indoor air quality guidelines. This has shifted the focus to systematic dissemination and implementation of cleaner cooking systems such as liquefied petroleum gas (LPG) among poor communities. Even when there is some uptake of LPG by poor communities, its sustained use has been low. Concurrent use of LPG with traditional biomass cookstoves compromises reductions in household air pollution and limits health and environmental dividends. Therefore understanding key drivers of adoption and sustained implementation of clean fuels among the poor is critical. There is a significant gap, however, in the research to understand determinants and sustained exclusive use of clean fuels in rural poor communities. Methods/design: Using a case control study design, this study will explore the impact of affordability, accessibility, and awareness on adoption and sustained use of LPG among rural poor communities of India. The study uses a multistage random sampling to collect primary data from 510 households. Case group or LPG adopters constitute 255 households while control group or non-LPG adopters constitute the remaining 255 households. The study will deploy sophisticated stove use monitoring sensors in each of the stoves in 100 case group households to monitor stove use and stacking behavior (using clean and traditional systems of cooking) of participants for 12 months. Moreover, this will be the first study to explore the impact of personal social networks striated by gender on LPG adoption. This study is guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) implementation science evaluation framework. Discussion: Lessons from this study will feed into a larger discussion on developing a pro-poor strategy to foster uptake and sustained use of cleaner cooking systems such as LPG. Understanding the determinants of adoption and sustained use of cleaner cooking systems through the RE-AIM framework will expand our insights on implementation of cleaner cooking systems among poor communities and will advance implementation science in the clean cooking sector. A thorough study of such implementation strategies is crucial to realize multiple UN Sustainable Development Goals on global health, climate change, and energy security. PMID- 29255605 TI - How does family functioning effect the outcome of family based treatment for adolescents with severe anorexia nervosa? AB - Background: The aim of this research was to investigate the relationship between family functioning, adolescent-parent attachment and remission, as well as changes in these variables over time for adolescents with severe anorexia nervosa treated with family based treatment (FBT). Understanding how families respond to treatment is important because the family will be the ongoing context for psychosocial development in the longer term. The relationship between family functioning and outcome is also an important variable because it is potentially modifiable during treatment and this may improve outcome. Methods: Fifty-seven female adolescents treated with FBT in a randomised controlled trial were assessed at baseline, FBT session 20 and 12-months post FBT session 20. Data on family functioning and adolescent-parent attachment was collected from patients and their parents at each time point. A series of regression analyses were used to determine the relationship between family functioning and comorbidity at baseline, and the relationship with remission status over time. Repeat measure mixed-effects models were used to assess changes in family functioning and attachment quality over time. Results: Greater adolescent perceived family functioning impairment was positively related to psychiatric comorbidity at the start of treatment. Conversely, better family functioning predicted higher self esteem and stronger attachment quality. Adolescent's reporting better general family functioning, communication and problem solving were more likely to be remitted at session 20, but not at 12-month follow-up. There was no overall improvement in family functioning for any respondent either during treatment or at follow-up, and no significant relationship between change and remission at either session 20 or follow-up. Conclusions: The adolescent's perspective on family functioning at the start of treatment impacts on a positive outcome. Addressing family issues earlier in FBT may be important for some patients. Further research is needed in this area to determine how these findings could be integrated into the current FBT model. Trial registration: Australian Clinical Trials Register number: ACTRN012607000009415 (www.anzctr.org.au). PMID- 29255606 TI - Enhanced cell uptake of fluorescent drug-loaded nanoparticles via an implantable photothermal fibrous patch for more effective cancer cell killing. AB - Great efforts have been devoted to effective delivery of therapeutics into cells for cancer therapy. The exploration of nanoparticle based drug delivery systems (DDSs) faces daunting challenges in low efficacy of intracellular delivery. Herein, a localized drug delivery device consisting of photoluminescent mesoporous silica nanoparticles (PLMSNs) and photothermal fibrous matrix was investigated. Specifically, PLMSNs modified with a pH-sensitive polydopamine (PDA) 'gatekeeper' served as a doxorubicin (DOX) carrier and could release DOX once the PLMSNs were up-taken by the cancer cells. The PLMSNs were electrostatically assembled on the surface of electrospun biodegradable poly(epsilon-caprolactone)/gelatin fibrous mesh incorporated with photothermal carbon nanoparticles (CNPs), leading to an implantable patch used as localized delivery platform. Comparing to free particulate DDSs, this implantable composite patch device was found to significantly enable superior cell up-taking effect and consequently enhance in-vitro therapeutic efficacy against tumor cells. Namely, under near infrared irradiation, the photothermal effect of CNPs in the implantable patch weakens the electrostatic interaction between the PLMSNs and poly(epsilon-caprolactone)/gelatin/CNP fibrous mesh, resulting in the controlled release of the PLMSNs and subsequent internalization into the tumor cells for more effective cancer cell killing. This implantable therapeutic device may therefore inspire another way of developing localized cancer therapy. PMID- 29255608 TI - Thermoregulatory performance and habitat selection of the eastern box turtle (Terrapene carolina carolina). AB - Environmental conditions may affect individual physiological processes that influence short-term performance and ultimately growth, survival and reproduction. As such, habitats selected by animals must provide suitable and adequate resources. Ectothermic species are highly dependent on climatic conditions and ambient temperatures that dictate body temperature regulation and in turn physiological processes. We investigated the thermoregulatory performance, habitat selection, and movements of an ectothermic vertebrate, the Eastern box turtle (Terrapene carolina carolina) to assess the importance of thermoregulatory physiology in habitat selection. We evaluated the relationship between habitat selection and thermoregulatory performance in Southwest Ohio over two active seasons from May until October. We found that T. carolina selected shaded habitats, including evergreen and deciduous forests, as well as herbaceous grasslands, conformed to the ambient temperatures throughout the active season, although these habitats had temperatures below those expected based on thermal optima of box turtles. Further, we found that movement was not correlated with internal body temperature. Our study shows that thermal conditions are not paramount in habitat selection of box turtles, but that cooler temperatures do not have an effect on the extent of their locomotion. PMID- 29255607 TI - Interleukin-10 and soluble tumor necrosis factor receptor II are potential biomarkers of Plasmodium falciparum infections in pregnant women: a case-control study from Nanoro, Burkina Faso. AB - Background: Diagnosis of malaria in pregnancy is problematic due to the low sensitivity of conventional diagnostic tests (rapid diagnostic test and microscopy), which is exacerbated due to low peripheral parasite densities, and lack of clinical symptoms. In this study, six potential biomarkers to support malaria diagnosis in pregnancy were evaluated. Methods: Blood samples were collected from pregnant women at antenatal clinic visits and at delivery. Microscopy and real-time PCR were performed for malaria diagnosis and biomarker analyses were performed by ELISA (interleukin 10, IL-10; tumor necrosis factor alpha, TNF-alpha; soluble tumor necrosis factor receptor II, sTNF-RII; soluble fms-like tyrosine kinase 1, sFlt-1; leptin and apolipoprotein B, Apo-B). A placental biopsy was collected at delivery to determine placental malaria. Results: IL-10 and sTNF-RII were significantly higher at all time-points in malaria-infected women (p < 0.001). Both markers were also positively associated with parasite density (p < 0.001 and p = 0.003 for IL-10 and sTNF-RII respectively). IL-10 levels at delivery, but not during pregnancy, were negatively associated with birth weight. A prediction model was created using IL 10 and sTNF-RII cut-off points. For primigravidae the model had a sensitivity of 88.9% (95%CI 45.7-98.7%) and specificity of 83.3% (95% CI 57.1-94.9%) for diagnosing malaria during pregnancy. For secundi- and multigravidae the sensitivity (81.8% and 56.5% respectively) was lower, while specificity (100.0% and 94.3% respectively) was relatively high. Sub-microscopic infections were detected in 2 out of 3 secundi- and 5 out of 12 multigravidae. Conclusions: The combination of biomarkers IL-10 and sTNF-RII have the potential to support malaria diagnosis in pregnancy. Additional markers may be needed to increase sensitivity and specificity, this is of particular importance in populations with sub-microscopic infections or in whom other inflammatory diseases are prevalent. PMID- 29255609 TI - Endocarditis due to Rhodotorula mucilaginosa in a kidney transplanted patient: case report and review of medical literature. AB - Introduction. Endocarditis caused by yeasts is currently an emerging cause of infective endocarditis and, when accompanied byfever of unknown origin, is more severe since interferes with proper diagnosis and endocarditis treatment. Case presentation. The Rio de Janeiro Infective Endocarditis Study Group reports a case of infectious endocarditis (IE) with negative blood cultures in a 45-year old white female resident in Rio de Janeiro, Brazil, previously submitted to kidney transplantation. After diagnosis and intervention, the valve culture revealed Rhodotorula mucilaginosa. The clinical aspects and overview of endocarditis caused by Rhodotorula spp. demonstrated that R. muscilaginosa have been isolated from the last IE cases from kidney transplanted patients. Conclusion. Though most of the patients (in literature) recovered well from endocarditis caused by Rhodotorula spp., physicians must be aware for diagnosis of fungemia and fungal treatment in kidney transplanted patients suffering of fever of unknown origin in the modern immunosuppressive treatment. PMID- 29255610 TI - Helicobacter canis bacteraemia and cellulitis in a patient with end-stage renal disease. AB - Introduction. Invasive infections by Helicobacter canis are uncommon and occur primarily in immunocompromised patients. Here, we describe a case of H. canis bacteraemia and cellulitis in a patient with end-stage renal disease (ESRD). Case presentation. A 49-year-old male with ESRD on haemodialysis presented to an emergency department with cellulitis overlying his left upper extremity arteriovenous fistula for 3 days without constitutional symptoms. Mild leucocytosis and thrombocytopenia was noted on initial laboratory work up. The patient received a dose of vancomycin initially, and then transitioned to oral doxycycline prior to discharge 3 days later. Blood cultures drawn on admission were positive with curved Gram-negative rods at day 5. Routine sub-cultures initially failed to isolate the organism; however, small, tan colonies were observed on sheep blood agar incubated under microaerobic conditions. H. canis was identified by 16S rRNA sequencing. Antimicrobial-susceptibility testing was not performed due to poor growth and lack of interpretive guidelines. The patient was ultimately treated successfully with amoxicillin/clavulanic acid. Conclusion. This case illustrates the importance of recognizing H. canis infections in immunocompromised patients, especially in those with recent pet exposure. In addition, this case highlights the need for improved laboratory diagnostics for H. canis as isolation and identification of this fastidious organism is challenging. PMID- 29255611 TI - Vertical transmission of Salmonella enterica serotype Paratyphi A leading to abortion. AB - Introduction. Enteric fever, caused by Salmonella enterica serotype Typhi (typhoid fever) or S. enterica serotype Paratyphi A, B or C (paratyphoid fever), is a major health problem in developing countries. Vertical transmission of Salmonella can cause miscarriage, still birth, preterm labour and neonatal sepsis. In the literature, many cases of vertical transmission of S. enterica Typhi from mother to foetus have been reported, but there are very limited studies showing vertical transmission of S. enterica Paratyphi. Case presentation. Here, we report a rare case of S. enterica serotype Paratyphi A infection in a pregnant woman resulting in a spontaneous miscarriage. S. enterica serotype Paratyphi A was isolated from placental membrane in culture. Conclusion. A high index of suspicion, along with timely cultures of relevant samples, like blood and stool, and timely initiation of antibiotic therapy in pregnancy could possibly save the lives of such foetuses. PMID- 29255612 TI - Aeromonas wound infection in a healthy boy. PMID- 29255613 TI - Nocardia cyriacigeorgica threatening an immunocompetent host; a rare case of paramediastinal abscess. AB - We describe a rare case of anterior paramediastnial abscess due to Nocardia cyriacigeorgica in an immunocompetent patient without pre-existing lung disease. High suspicious should be taken in those patients that failed to improve after first course of antibiotic therapy. Similarly, when suspected, isolation is crucial because of the variation in antibiotic susceptibilities among Nocardia spp. in order to provide adequate therapy to reduce associated comorbidities and mortality rate. PMID- 29255614 TI - Aggressive and fatal statin-induced dermatomyositis: a case report. AB - Statins are widely used and are currently the state-of-the-art treatment for primary and secondary prevention of cardiovascular disease. Although statins are generally well tolerated and present an excellent safety profile, adverse effects from muscle toxicity may occur in some patients. Statin-induced dermatomyositis (DM) is a rare adverse event associated with its use and very few fatal cases have been reported. We present the case of a 69-year-old man with early onset DM precipitated by a small dose of simvastatin. Despite immediate cessation of the agent and the use of systemic corticosteroids, the case took a very aggressive and fatal course. Such progression is extremely unusual for statin-induced DM. Despite the safety of statins, we highlight the importance of identifying potential side effects associated with this class of medications. We also emphasize the importance of correct diagnosis and close follow-up of patients with statin side effects. PMID- 29255615 TI - Adductor focal laryngeal Dystonia: correlation between clinicians' ratings and subjects' perception of Dysphonia. AB - Background: Although considerable research has focused on the etiology and symptomology of adductor focal laryngeal dystonia (AD-FLD), little is known about the correlation between clinicians' ratings and patients' perception of this voice disturbance. This study has five objectives: first, to determine if there is a relationship between subjects' symptom-severity and its impact on their quality of life; to compare clinicians' ratings with subjects' perception of the individual characteristics and severity of AD-FLD; to document the subjects' perception of changes in dysphonia since diagnosis; to record the frequency of voice arrest during connected speech; and, finally, to calculate inter-clinician reliability based on results from the Unified Spasmodic Dysphonia Rating Scale (USDRS) (Stewart et al, J Voice 1195-10, 1997). Methods: Sixty subjects with AD FLD who were receiving ongoing injections of BoNT participated in this study. Subjects' mean age was 60.78 years and their mean duration of symptoms was 16.1 years. Subjects completed the Disease Symptom Questionnaire (DSQ) (specifically designed for this study) and the Voice Handicap Index-10 (VHI-10) (Jacobson et al, Am J Speech Lang Pathol 6:66-70, 1997) to measure the symptoms of their dysphonia and the impact of the disease on their quality of life.Two speech language pathologists and two laryngologists used the Voice Arrest Measure (VAM) (specifically designed for this study) and the USDRS to independently rate voice recordings of 56/60 subjects. Results: The mean VHI-10 score was 21.3 which is clinically significant. The results of the DSQ and the USDRS were highly correlated. The most severe symptoms identified by both subjects and clinicians were roughness, strain-strangled voice quality, and increased expiratory effort. Voice arrest, aphonia, and tremor were uncommon. Subjects rated their current voice quality at the time of reinjection (i.e., at the time of the study) as significantly better than at the time of their initial AD-FLD diagnosis (p < 0.0001). Inter-clinician reliability on the USDRS was significant at the 0.001 level. Conclusions: The findings from the VHI-10 suggest that AD-FLD has a profound impact on quality of life. The results of the DSQ and the USDRS suggest that there is a strong correlation between subjects' perception and clinicians' assessment of the individual symptoms and the severity of the dysphonia. The findings from the VAM suggest that voice arrests are infrequent in subjects with AD-FLD who are receiving ongoing BoNT injections. The strong inter-clinician reliability on the USDRS suggests that it is an appropriate measure for identifying symptoms and severity of AD-FLD. PMID- 29255616 TI - Why do pregnant women present late for their first antenatal care consultation in Cameroon? AB - Background: Early initiation of antenatal care visits is an essential component of services to improving maternal and new born health. The Cameroonian Demographic and Health Survey conducted in 2011 indicated that only 34% of pregnant women start antenatal care in the first trimester. However, detailed study to identify factors associated with late initiation of care has not been conducted in Cameroon. The aim of this study was to assess the prevalence of late booking first ANC visit amongst attendance of first ANC and the determinants of late first ANC in Douala general hospital. Methods: It was a cross sectional analytic study over the period of 5 months in Douala general hospital. The study subjects were pregnant women visiting the facilities for the first time during the index pregnancy. Data were collected using pre-tested questionnaire. Logistic regression analysis was done to identify factors associated with late first ANC with the level of significance set at 0.05. Results: A total of 293 women participated in the study; 129 (44.0%) of them came for their first ANC visit late, after 12 weeks of gestation. Most common reasons for coming late for first ANC were financial constraints (34.5%, 45) and long distance to the hospital (34.5%, 45). Factors associated with late start of first ANC after logistic regression were: family size greater than 4 (OR = 2, 95% CI = 1.25-3.19, p value = 0.004), long distance to the hospital (OR = 1.84, 95% CI = 1.1-3.07, p value = 0.02) and low monthly income level less than 200US dollars (OR = 3.2, 95% CI = 1.33-3.54, p value = 0.002). Conclusion: About half of pregnant women do not start ANC early in the first trimester largely due to large family size, low monthly income and long distance to the hospital. PMID- 29255618 TI - Chitosan immunomodulatory properties: perspectives on the impact of structural properties and dosage. PMID- 29255617 TI - A sodium binding system alleviates acute salt stress during seawater acclimation in eels. AB - Background: Teleosts transiting from freshwater (FW) to seawater (SW) environments face an immediate osmotic stress from ion influxes and water loss, but some euryhaline species such as eels can maintain a stable plasma osmolality during early SW exposure. The time course changes in the gene expression, protein abundance, and localization of key ion transporters suggested that the reversal of the ion transport systems was gradual, and we investigate how eels utilize a Na-binding strategy to slow down the ion invasion and complement the transporter mediated osmoregulation. Results: Using an electron probe micro-analyzer, we localized bound Na in various eel tissues in response to SW transfer, suggesting that the Na-binding molecules were produced to sequester excess ionic Na+ to negate its osmotic potential, thus preventing acute cellular dehydration. Mucus cells were acutely activated in digestive tract, gill, and skin after SW transfer, producing Na-binding molecule-containing mucus layers that fence off high osmolality of SW. Using gel filtration HPLC, some molecules at 18 kDa were found to bind Na in the luminal secretion of esophagus and intestine, and higher binding was associated with SW transfer. Transcriptome and protein interaction results indicated that downregulation of Notch and beta-catenin pathways, and dynamic changes in TGFbeta pathways in intestine were involved during early SW transition, supporting the observed histological changes on epithelial desquamation and increased mucus production. Conclusions: The timing for the activation of the Na-binding mechanism to alleviate the adverse osmotic gradient was temporally complementary to the subsequent remodeling of branchial ionocytes and transporting epithelia of the digestive tract. The strategy to manipulate the osmotic potential of Na+ by specific binding molecules is similar to the osmotically inactive Na described in human skin and muscle. The Na-binding molecules provide a buffer to tolerate the salinity changes, which is advantageous to the estuary and migrating fishes. Our data pave the way to identify this unknown class of molecules and open a new area of vertebrate osmoregulation research. PMID- 29255619 TI - Advances in nanomedicine drug delivery applications for HIV therapy. PMID- 29255620 TI - Patient outcomes from lung cancer and diabetes mellitus: a matched case-control study. AB - Aim: This case-control study examined the impact of diabetes mellitus (DM) on survival in lung cancer patients and lung cancer on glycemic control in DM. Materials & methods: Patients with a new lung cancer diagnosis and DM (n = 124) were matched to 124 lung cancer patients without DM. Laboratory results and DM and cancer therapies were obtained from electronic records. Results: Five-year overall survival for lung cancer patients with and without DM was 20 versus 29% (p = .12). Glycemic control among DM patients did not change significantly with time. Conclusion: DM does not cause adverse impact on lung cancer survival. Lung cancer does not affect glycemic control. PMID- 29255621 TI - Novel biomarker SYT12 may contribute to predicting papillary thyroid cancer outcomes. AB - Aim: To investigate biomarkers for predicting papillary thyroid cancer outcomes. Materials & methods: The expression of biomarkers (ITGA2, SYT12 and CDH3) was studied in a prospective cohort of patients with papillary thyroid cancer. Three outcomes of initial metastases, baseline status and longitudinal status were analyzed and correlated with the biomarkers. Results: SYT12 provided the best prediction of initial metastasis (sensitivity: 72%; specificity: 54%). SYT12 had the highest accuracy for predicting longitudinal status (sensitivity: 100%; specificity: 47%). The best performance for longitudinal status resulted from combining SYT12 with American Thyroid Association risk stratification, with sensitivity and specificity of 88 and 73%, respectively. Conclusion: SYT12 has some prognostic significance in papillary thyroid cancer. Further validation studies in larger populations are warranted. PMID- 29255622 TI - Liver fibrosis: a compilation on the biomarkers status and their significance during disease progression. AB - Liver fibrosis occurs in response to different etiologies of chronic liver injury. Diagnosing degree of liver fibrosis is a crucial step in evaluation of severity of the disease. An invasive liver biopsy is the gold standard method associated with pain and complications. Biomarkers to detect liver fibrosis include direct markers of extracellular matrix turnover and indirect markers as a reflection of liver dysfunction. Although a single marker may not be useful for successful management, a mathematical equation combining tests might be effective. The main purpose of this review is to understand the diagnostic accuracy of biomarkers and scoring systems for liver fibrosis. Advances in -omics approach have generated clinically significant biomarker candidates for liver fibrosis that need further evaluation. PMID- 29255623 TI - The role of biomarkers in the diagnosis and risk stratification of acute coronary syndrome. AB - Coronary artery disease is a growing concern. Although traditional biomarkers, such as troponins and creatine kinase, play a central role in the diagnosis, risk stratification and management of coronary artery disease, they are unable to detect myocardial ischemia in the absence of necrosis. Therefore, early detection of ischemia in patients presenting with acute coronary syndrome still remains a burning question. High-sensitivity troponin is evolving as a reliable biomarker in this regard and has been absorbed into clinical practice. Biomarkers are currently the focus of immense interest as it not only helps with diagnosis and management but also helps to understand the pathophysiology of the disease process. In addition, analysis using a multimarker strategy has also proven to be a very useful tool in risk stratification. This review will focus on the biomarkers and its application in the diagnosis and risk stratification of acute coronary syndrome. PMID- 29255625 TI - Duration of suppression of bone turnover following treatment with zoledronic acid in men with metastatic castration-resistant prostate cancer. AB - Aim: Zoledronate is approved for use every 3 weeks in men with bone metastases from castrate-resistant prostate cancer (CRPC) but the basis for such frequency is unclear. Methods: In men with bone metastasis from CRPC we measured the markers of bone turnover - urine and serum telopeptides before the first injection of zoledronate and at four 3-weekly intervals thereafter. Men received further zoledronate treatment after 12 weeks, or earlier if the telopeptides did not meet predefined adequate suppression. The primary end point was the proportion of evaluable subjects with suppressed telopeptides at 12 weeks. Exploratory analyses evaluated predictors of bone turnover suppression and quality-of-life. Results: 31 patients were enrolled. Median age was 70 (range: 53 86) years. 65%, (95% CI: 46-81%) had suppressed telopeptides at 12 weeks. Prior skeletal-related events, chemotherapy, bone surgery and higher baseline levels of telopeptides were associated with shorter duration of telopeptides. Conclusion: 12-weekly zoledronate suppresses bone turnover in the majority of men with bone metastasis from CRPC. PMID- 29255624 TI - Dual inhibitors of hepatitis C virus and hepatocellular carcinoma: design, synthesis and docking studies. AB - Aim: Simultaneous inhibition of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may enhance anti-HCV effects and reduce resistance and side effects. Results/methodology: Novel hybrid derivatives were designed and synthesized to exhibit dual activity against HCV and its associated major complication, HCC. The synthesized compounds were screened for their potential activity against HCV and HCC. Compounds 5f, 5j, 5l, 5p, 5q, 5r, 6c and 6d exhibited potential in vitro anticancer activity against HCC cell line HepG2, while compounds 5a, 5l, 5p and 5v showed in vitro anti-HCV activity. Docking studies suggested that the newly synthesized compounds could suppress HCC through VEGFR2 tyrosine kinase inhibition. Conclusion: Compounds 5l and 5p exhibited dual activity against HCV and HCC in vitro. PMID- 29255626 TI - Partial weight bearing in hip fracture rehabilitation. PMID- 29255627 TI - Plasma lipidomics of tuberculosis patients: altered phosphatidylcholine remodeling. AB - Aim: Decreased circulating levels of lysophosphatidylcholines have been monitored in the serum of tuberculosis (TB) patients. However, the etiology of these findings has not been explored and other critical lung surfactant lipids have not been examined. Materials & methods: We undertook a lipidomics analysis of 30 controls and 30 TB patients, utilizing a high-resolution mass spectrometric analytical platform that assays over 1800 lipids. Findings: As previously reported, we found decrements in the plasma levels of lysophosphatidylcholines in TB patients. In addition, we report for the first time that there are increases in the plasma levels of phosphatidylcholines and phosphatidylglycerols in TB patients. Conclusion: These data suggest that TB results in altered glycerophosphocholine remodeling involving deacylation-reacylation reactions at sn-2 of the glycerol backbone. Such alterations in lipid remodeling have the potential to exert negative effects on the function of lung surfactant, on signal transduction mechanisms and membrane structural lipid architecture in TB patients. PMID- 29255629 TI - Welcome to volume 4 of Future Science OA. PMID- 29255628 TI - Basal-bolus insulin therapy in postoperative inpatients with diabetes mellitus: directions for future quality-improvement initiatives. AB - Aim: To determine variables associated with hyperglycemia and insulin therapy in postoperative inpatients with diabetes mellitus following a quality-improvement initiative. Materials & methods: Patients with diabetes mellitus following an elective surgical procedure (n = 782; 877 surgical procedures) were selected. Results: Age, hemoglobin A1c corticosteroids, insulin therapy and year of surgery were associated (p < 0.01) with hyperglycemia. Hemoglobin A1c, hyperglycemia, case mix index and corticosteroids were associated (p <= 0.03) with insulin therapy. Hyperglycemia and use of insulin varied by surgical specialty. Conclusion: Data could be used to modify current treatment algorithms. Variations in hyperglycemia and insulin use by surgical specialty require further investigation. PMID- 29255630 TI - Analysis of quasispecies variation in single and mixed viral infection. AB - Population diversity was examined in individual and natural mixed infections of Cowpea chlorotic mottle virus (CCMV) and Cucumber mosaic virus (CMV) isolates in two systemic hosts, cowpea and Nicotiana benthamiana. Isolates of CCMV and CMV obtained from a cowpea field in Arkansas were separated biologically in cowpea and tobacco plants, respectively. After separation, individual and mixed cultures of both viruses were serially passaged ten times by mechanical inoculation in cowpea and N. benthamiana. High-fidelity reverse transcriptase-polymerase chain reaction (HiFi RT-PCR) of RNA 3, followed by cDNA cloning and sequence analysis was used to assess the quasispecies cloud size of CCMV and CMV populations in passages zero and ten of each host species. The levels of population variation were generally higher in individual infections of CCMV-Car1 and-Car2 isolates, and the CMV-Car2 isolate compared with mixed infections, in both host species, although the significance of the differences varied depending on how mutations were counted. There were no significant differences in the levels of population variation in individual and mixed infections of the CMV-Car1 isolate. Partially fixed mutations were observed in both individual and mixed infections of the CCMV Car2 isolate in N. benthamiana and CMV-Car1 and-Car2 isolates in both cowpea and N. benthamiana. PMID- 29255632 TI - Preface from ERS President 2018 Mina Gaga and ERS Early-Career Member Committee Chair Lieuwe Bos. PMID- 29255633 TI - ERS International Congress 2017: a peek of outstanding abstracts from the clinical assembly. AB - This review highlights a selection of abstracts from the 2017 ERS International Congress in Milan presented by the clinical assembly's groups of interventional pulmonology, general practice and primary care and rehabilitation and chronic care. Attention is brought to the increasing burden of disease of COPD and end stage emphysema patients in China. The considerable efforts of Chinese pulmonary centers to conduct multicenter, randomized and controlled trials, investigating the possibilities of bronchoscopic lung volume reduction is underlined in the review. Furthermore, the key objectives of asthma management are stressed. We point out presentations emphasizing on achieving good control of daily symptoms and reducing the risk of asthma exacerbations. The findings of a randomized clinical trial evaluating the role of oxygen supplementation in rehabilitation therapy of COPD patients are analyzed. Additionally, another randomized clinical trial researching the influence of whole body vibration training (WBVT) in long term (>1 year) lung transplant patients are discussed. PMID- 29255634 TI - Clinical physiology and sleep: insights from the European Respiratory Society Congress 2017. PMID- 29255635 TI - Abstracts from the European Respiratory Society Annual Conference 2017 on respiratory critical care. PMID- 29255631 TI - Genetic analysis of a rabies virus host shift event reveals within-host viral dynamics in a new host. AB - Host shift events play an important role in epizootics as adaptation to new hosts can profoundly affect the spread of the disease and the measures needed to control it. During the late 1990s, an epizootic in Turkey resulted in a sustained maintenance of rabies virus (RABV) within the fox population. We used Bayesian inferences to investigate whole genome sequences from fox and dog brain tissues from Turkey to demonstrate that the epizootic occurred in 1997 (+/-1 year). Furthermore, these data indicated that the epizootic was most likely due to a host shift from locally infected domestic dogs, rather than an incursion of a novel fox or dog RABV. No evidence was observed for genetic adaptation to foxes at consensus sequence level and dN/dS analysis suggested purifying selection. Therefore, the deep sequence data were analysed to investigate the sub-viral population during a host shift event. Viral heterogeneity was measured in all RABV samples; viruses from the early period after the host shift exhibited greater sequence variation in comparison to those from the later stage, and to those not involved in the host shift event, possibly indicating a role in establishing transmission within a new host. The transient increase in variation observed in the new host species may represent virus replication within a new environment, perhaps due to increased replication within the CNS, resulting in a larger population of viruses, or due to the lack of host constraints present in the new host reservoir. PMID- 29255636 TI - Best of Milan 2017-ERS Lung Science Conference session "Lung tissue repair and remodeling in chronic lung diseases: mechanisms and therapeutic approaches". PMID- 29255637 TI - Best of Milan 2017-repair of the emphysematous lung: mesenchymal stromal cell and matrix. PMID- 29255638 TI - European Respiratory Society International Congress programme highlights on occupation and epidemiology. PMID- 29255639 TI - Airways diseases: insights from the European Respiratory Society Annual Congress 2017. PMID- 29255640 TI - Highlights from the European Respiratory Society 2017 annual congress: epidemiology and environment (assembly 6). PMID- 29255641 TI - European respiratory society international congress 2017: insights from the paediatric assembly. PMID- 29255642 TI - Respiratory infection: insights from Assembly 10 of the European Respiratory Society 2017 Annual Congress. PMID- 29255643 TI - Best of lung cancer session presented during ERS 2017 Chinese language day: lung cancer screening. PMID- 29255644 TI - Severe ketorolac-induced asthma diagnosed by chest computed tomography. AB - Aspirin-exacerbated respiratory disease (AERD) affects 15% of severe asthmatics and drug reactions cause 200,000 annual deaths in Europe. A 65-year-old lady presented to emergency for progressive abdominal pain. Her medical history included gallstones, asthma, rhinosinusitis and hypertension. She was regularly medicated with inhaled fluticasone, vilanterol and tiotropium, nasal budesonide, pantoprazole, oxazepam and perindopril. She reported partial asthma control and an exacerbation requiring admission to a respiratory ward 6 weeks before. On examination, there was right upper quadrant tenderness and no other changes. Blood tests were normal, and an ultrasound showed gallbladder stones with normal wall. Intravenous ketorolac led to prompt pain resolution. After 30 minutes she became severely dyspnoeic, with an O2 saturation of 85% on high flow O2. She had no breath sounds on the left lung, and there was no wheezing or prolonged expiration. A chest X-ray showed no pneumothorax and a computed tomography (CT) angiography was performed showing bilateral mucoid impaction and sub-segmental atelectasis. Continuous bronchodilation and systemic steroids led to gradual improving in the following 6 hours. After 9 days of admission on a respiratory ward she was discharged home with no symptoms and normal oxygenation. Importantly, she denied previous allergies to nonsteroidal anti-inflammatory drugs (NSAIDs) and had actually taken diclofenac and nimesulid before with no reactions. This report illustrates both an intravenous NSAID causing severe AERD, and how a chest CT may be instrumental for the diagnosis of life-threatening asthma. PMID- 29255645 TI - Advances in Spinal Functional Magnetic Resonance Imaging in the Healthy and Injured Spinal Cords. AB - Purpose of Review: This review provides an overview of the current spinal functional magnetic resonance imaging (fMRI) studies that investigate the healthy and injured spinal cords. Recent Findings: Spinal fMRI-derived outcome measures have previously been suggested to be sensitive to changes in neurological function in the spinal cord. A body of recent task-activated fMRI studies seems to confirm that detecting neural activity in the spinal cord using spinal fMRI may be feasible as well as reliable. Furthermore, a growing number of studies has shown that resting state fMRI in the spinal cord is also feasible, demonstrating that the investigation of changes in neural activity can also be performed in the absence of explicit tasks. Summary: Current task-activated and resting state fMRI studies suggest that spinal fMRI has a strong potential to provide novel imaging biomarkers that can be used to investigate plastic changes in the injured spinal cord. PMID- 29255646 TI - Characterization of a de novo assembled transcriptome of the Common Blackbird (Turdus merula). AB - Background: In recent years, next generation high throughput sequencing technologies have proven to be useful tools for investigations concerning the genomics or transcriptomics also of non-model species. Consequently, ornithologists have adopted these technologies and the respective bioinformatics tools to survey the genomes and transcriptomes of a few avian non-model species. The Common Blackbird is one of the most common bird species living in European cities, which has successfully colonized urban areas and for which no reference genome or transcriptome is publicly available. However, to target questions like genome wide gene expression analysis, a reference genome or transcriptome is needed. Methods: Therefore, in this study two Common Blackbirds were sacrificed, their mRNA was isolated and analyzed by RNA-Seq to de novo assemble a transcriptome and characterize it. Illumina reads (125 bp paired-end) and a Velvet/Oases pipeline led to 162,158 transcripts. For the annotation (using Blast+), an unfiltered protein database was used. SNPs were identified using SAMtools and BCFtools. Furthermore, mRNA from three single tissues (brain, heart and liver) of the same two Common Blackbirds were sequenced by Illumina (75 bp single-end reads). The draft transcriptome and the three single tissues were compared by their BLAST hits with the package VennDiagram in R. Results: Following the annotation against protein databases, we found evidence for 15,580 genes in the transcriptome (all well characterized hits after annotation). On 18% of the assembled transcripts, 144,742 SNPs were identified which are, consequently, 0.09% of all nucleotides in the assembled transcriptome. In the transcriptome and in the single tissues (brain, heart and liver), 10,182 shared genes were found. Discussion: Using a next-generation technology and bioinformatics tools, we made a first step towards the genomic investigation of the Common Blackbird. The de novo assembled transcriptome is usable for downstream analyses such as differential gene expression analysis and SNP identification. This study shows the importance of the approach to sequence single tissues to understand functions of tissues, proteins and the phenotype. PMID- 29255647 TI - Shift of symbiont communities in Acropora tenuis juveniles under heat stress. AB - Ocean warming is a major threat to coral reefs, leading to an increasing frequency and amplitude of coral bleaching events, where the coral and its algal symbiont associations breakdown. Long-term change and resilience of a symbiont community in coral juveniles is thought to be one of the most important aspects for determining thermal tolerance of the coral holobionts; however, despite its importance, they are not well documented in both under elevated temperature and even under natural condition. Here we investigated changes in symbiont communities in juveniles of the coral Acropora tenuis under controlled heat stress conditions (30 degrees C, 31/32 degrees C) and natural variations in seawater temperatures (19-30 degrees C) for up to four months. Compared with the ambient temperature conditions, coral survival rates were higher when exposed to 30 degrees C, but survival rates decreased when exposed to 31/32 degrees C. Symbiodinium types A3, C1, and D1-4 were detected in the juveniles under all thermal conditions; however, in higher water temperatures (31/32 degrees C), both the prevalence of D1-4 Symbiodinium and the number of juveniles harboring only this type of symbiont increased after two to four months later. In contrast, colonies at lower temperatures (30 degrees C and ambient) harbored multiple clades of symbionts over the same experimental period. These results highlight the flexibility of the coral-Symbiodinium symbiosis for juvenile A. tenuis under variable thermal conditions. In particular, the benefit of the preferential association with type D1-4 can be considered as a response when under heat-stress conditions, and that could help corals to cope with ocean warming. PMID- 29255648 TI - Evaluating the role of wild songbirds or rodents in spreading avian influenza virus across an agricultural landscape. AB - Background: Avian influenza virus (AIV) infections occur naturally in wild bird populations and can cross the wildlife-domestic animal interface, often with devastating impacts on commercial poultry. Migratory waterfowl and shorebirds are natural AIV reservoirs and can carry the virus along migratory pathways, often without exhibiting clinical signs. However, these species rarely inhabit poultry farms, so transmission into domestic birds likely occurs through other means. In many cases, human activities are thought to spread the virus into domestic populations. Consequently, biosecurity measures have been implemented to limit human-facilitated outbreaks. The 2015 avian influenza outbreak in the United States, which occurred among poultry operations with strict biosecurity controls, suggests that alternative routes of virus infiltration may exist, including bridge hosts: wild animals that transfer virus from areas of high waterfowl and shorebird densities. Methods: Here, we examined small, wild birds (songbirds, woodpeckers, etc.) and mammals in Iowa, one of the regions hit hardest by the 2015 avian influenza epizootic, to determine whether these animals carry AIV. To assess whether influenza A virus was present in other species in Iowa during our sampling period, we also present results from surveillance of waterfowl by the Iowa Department of Natural Resources and Unites Stated Department of Agriculture. Results: Capturing animals at wetlands and near poultry facilities, we swabbed 449 individuals, internally and externally, for the presence of influenza A virus and no samples tested positive by qPCR. Similarly, serology from 402 animals showed no antibodies against influenza A. Although several species were captured at both wetland and poultry sites, the overall community structure of wild species differed significantly between these types of sites. In contrast, 83 out of 527 sampled waterfowl tested positive for influenza A via qPCR. Discussion: These results suggest that even though influenza A viruses were present on the Iowa landscape at the time of our sampling, small, wild birds and rodents were unlikely to be frequent bridge hosts. PMID- 29255649 TI - Motor performance in Prader-Willi syndrome patients and its potential influence on caregiver's quality of life. AB - Background: Prader-Willi syndrome (PWS) is a complex, multisystem genetic disorder characterized by a variety of physical, cognitive, and behavioral impairments. PWS is a unique sarcopenia model characterized by an abnormal increase in body fat mass and a decrease in muscle mass that predisposes patients to reduced physical activity, functional limitations, and disability. These manifestations may require both symptomatic and supportive management, thus negatively influencing their lifelong family caregiver's quality of life. The aim of this study was to examine the functional motor performance of adults with PWS in Taiwan and to measure the quality of life of their primary family caregivers. Methods: The functional motor tests consisted of the following: (1) 30-s sit-to stand test, (2) timed up-and-go test, (3) hand grip and lateral pinch strength tests, and (4) Berg Balance Scale. The World Health Organization Quality of Life short form (WHOQOL-BREF) and the Short-Form 36 Health Survey Questionnaire (SF 36) were used to evaluate health-related quality of life, and the parenting stress index was used to assess the magnitude of stress within the parent-child system. Results: The participants included seven adults (two females and five males) with genetically confirmed PWS and their respective main caregivers. The mean age of the adults with PWS was 25.28 years; range 18-31 years, SD 5.10; the mean BMI was 29.2 kg/m2, SD 6.43. All adults with PWS showed lower hand grip and lateral pinch strengths, fewer sit-to-stand cycles during the 30-s chair stand test, and greater average time during the timed up-and-go test when compared to the normative data on healthy adults. Balance was negatively correlated with the caregiver's health concepts of social functioning (rs -0.879, P = 0.009) and with role limitations due to physical problems (rs -0.899, P = 0.006) and emotional problems (rs -0.794, P = 0.033); hand grip strength was negatively correlated with bodily pain (rs -0.800, P = 0.031), as assessed using the SF-36 questionnaire. The timed up-and-go test was positively correlated with the social relationship domain (rs 0.831, P = 0.021), as assessed using the WHOQOL-BREF questionnaire. The parenting stress index showed no association with the PWS patient's physical activities. Conclusions: All adults with PWS showed decreased upper and lower limb strength and functional mobility when compared to healthy adults. Some of their motor performance might have negative effects on their primary family members in terms of social participation and physical and emotional role limitations. Future research should explore the relationship between physical performances, psychological difficulties of PWS and caregiver's QOL. PMID- 29255652 TI - Combining occurrence and abundance distribution models for the conservation of the Great Bustard. AB - Species distribution models (SDMs) have become important and essential tools in conservation and management. However, SDMs built with count data, referred to as species abundance models (SAMs), are still less commonly used to date, but increasingly receiving attention. Species occurrence and abundance do not frequently display similar patterns, and often they are not even well correlated. Therefore, only using information based on SDMs or SAMs leads to an insufficient or misleading conservation efforts. How to combine information from SDMs and SAMs and how to apply the combined information to achieve unified conservation remains a challenge. In this study, we introduce and propose a priority protection index (PI). The PI combines the prediction results of the occurrence and abundance models. As a case study, we used the best-available presence and count records for an endangered farmland species, the Great Bustard (Otis tarda dybowskii), in Bohai Bay, China. We then applied the Random Forest algorithm (Salford Systems Ltd. Implementation) with eleven predictor variables to forecast the spatial occurrence as well as the abundance distribution. The results show that the occurrence model had a decent performance (ROC: 0.77) and the abundance model had a RMSE of 26.54. It is noteworthy that environmental variables influenced bustard occurrence and abundance differently. The area of farmland, and the distance to residential areas were the top important variables influencing bustard occurrence. While the distance to national roads and to expressways were the most important influencing abundance. In addition, the occurrence and abundance models displayed different spatial distribution patterns. The regions with a high index of occurrence were concentrated in the south-central part of the study area; and the abundance distribution showed high populations occurrence in the central and northwestern parts of the study area. However, combining occurrence and abundance indices to produce a priority protection index (PI) to be used for conservation could guide the protection of the areas with high occurrence and high abundance (e.g., in Strategic Conservation Planning). Due to the widespread use of SDMs and the easy subsequent employment of SAMs, these findings have a wide relevance and applicability than just those only based on SDMs or SAMs. We promote and strongly encourage researchers to further test, apply and update the priority protection index (PI) elsewhere to explore the generality of these findings and methods that are now readily available. PMID- 29255650 TI - Formoterol attenuates increased oxidative stress and myosin protein loss in respiratory and limb muscles of cancer cachectic rats. AB - Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Therapeutic options are still scarce. We hypothesized that cachexia-induced muscle oxidative stress may be attenuated in response to treatment with beta2-adrenoceptor-selective agonist formoterol in rats. In diaphragm and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with formoterol (0.3 mg/kg body weight/day for seven days, daily subcutaneous injection), redox balance (protein oxidation and nitration and antioxidants) and muscle proteins (1-dimensional immunoblots), carbonylated proteins (2-dimensional immunoblots), inflammatory cells (immunohistochemistry), and mitochondrial respiratory chain (MRC) complex activities were explored. In the gastrocnemius, but not the diaphragm, of cancer cachectic rats compared to the controls, protein oxidation and nitration levels were increased, several functional and structural proteins were carbonylated, and in both study muscles, myosin content was reduced, inflammatory cell counts were greater, while no significant differences were seen in MRC complex activities (I, II, and IV). Treatment of cachectic rats with formoterol attenuated all the events in both respiratory and limb muscles. In this in vivo model of cancer-cachectic rats, the diaphragm is more resistant to oxidative stress. Formoterol treatment attenuated the rise in oxidative stress in the limb muscles, inflammatory cell infiltration, and the loss of myosin content seen in both study muscles, whereas no effects were observed in the MRC complex activities. These findings have therapeutic implications as they demonstrate beneficial effects of the beta2 agonist through decreased protein oxidation and inflammation in cachectic muscles, especially the gastrocnemius. PMID- 29255651 TI - In silico identification of off-target pesticidal dsRNA binding in honey bees (Apis mellifera). AB - Background: Pesticidal RNAs that silence critical gene function have great potential in pest management, but the benefits of this technology must be weighed against non-target organism risks. Methods: Published studies that developed pesticidal double stranded RNAs (dsRNAs) were collated into a database. The target gene sequences for these pesticidal RNAs were determined, and the degree of similarity with sequences in the honey bee genome were evaluated statistically. Results: We identified 101 insecticidal RNAs sharing high sequence similarity with genomic regions in honey bees. The likelihood that off-target sequences were similar increased with the number of nucleotides in the dsRNA molecule. The similarities of non-target genes to the pesticidal RNA was unaffected by taxonomic relatedness of the target insect to honey bees, contrary to previous assertions. Gene groups active during honey bee development had disproportionately high sequence similarity with pesticidal RNAs relative to other areas of the genome. Discussion: Although sequence similarity does not itself guarantee a significant phenotypic effect in honey bees by the primary dsRNA, in silico screening may help to identify appropriate experimental endpoints within a risk assessment framework for pesticidal RNAi. PMID- 29255653 TI - Spectro-Temporal Electrocardiogram Analysis for Noise-Robust Heart Rate and Heart Rate Variability Measurement. AB - The last few years has seen a proliferation of wearable electrocardiogram (ECG) devices in the market with applications in fitness tracking, patient monitoring, athletic performance assessment, stress and fatigue detection, and biometrics, to name a few. The majority of these applications rely on the computation of the heart rate (HR) and the so-called heart rate variability (HRV) index via time-, frequency-, or non-linear-domain approaches. Wearable/portable devices, however, are highly susceptible to artifacts, particularly those resultant from movement. These artifacts can hamper HR/HRV measurement, thus pose a serious threat to cardiac monitoring applications. While current solutions rely on ECG enhancement as a pre-processing step prior to HR/HRV calculation, existing artifact removal algorithms still perform poorly under extremely noisy scenarios. To overcome this limitation, we take an alternate approach and propose the use of a spectro temporal ECG signal representation that we show separates cardiac components from artifacts. More specifically, by quantifying the rate-of-change of ECG spectral components over time, we show that heart rate estimates can be reliably obtained even in extremely noisy signals, thus bypassing the need for ECG enhancement. With such HR measurements in hands, we then propose a new noise-robust HRV index termed MD-HRV (modulation-domain HRV) computed as the standard deviation of the obtained HR values. Experiments with synthetic ECG signals corrupted at various different signal-to-noise levels, as well as recorded noisy signals show the proposed measure outperforming several HRV benchmark parameters computed post wavelet-based enhancement. These findings suggest that the proposed HR measures and derived MD-HRV metric are well-suited for ambulant cardiac monitoring applications, particularly those involving intense movement (e.g., elite athletic training). PMID- 29255654 TI - Evaluation of Computer-Based Target Achievement Tests for Myoelectric Control. AB - Real-time evaluation of novel prosthetic control schemes is critical for translational research on artificial limbs. Recently, two computer-based, real time evaluation tools, the target achievement control (TAC) test and the Fitts' law test (FLT), have been proposed to assess real-time controllability. Whereas TAC tests provides an anthropomorphic visual representation of the limb at the cost of confusing visual feedback, FLT clarifies the current and target locations by simplified non-anthropomorphic representations. Here, we investigated these two approaches and quantified differences in common performance metrics that can result from the chosen method of visual feedback. Ten able-bodied and one amputee subject performed target achievement tasks corresponding to the FLT and TAC test with equivalent indices of difficulty. Able-bodied subjects exhibited significantly (p <0.05) better completion rate, path efficiency, and overshoot when performing the FLT, although no significant difference was seen in throughput performance. The amputee subject showed significantly better performance in overshoot at the FLT, but showed no significant difference in completion rate, path efficiency, and throughput. Results from the FLT showed a strong linear relationship between the movement time and the index of difficulty (R2 = 0.96), whereas TAC test results showed no apparent linear relationship (R2 = 0.19). These results suggest that in relatively similar conditions, the confusing location of virtual limb representation used in the TAC test contributed to poorer performance. Establishing an understanding of the biases of various evaluation protocols is critical to the translation of research into clinical practice. PMID- 29255655 TI - Progression of Vertebral Compression Fractures After Previous Vertebral Augmentation: Technical Reasons for Recurrent Fractures in a Previously Treated Vertebra. AB - It is well recognized that patients can develop additional vertebral compression fractures (VCF) in an adjacent vertebra or at another vertebral level after successful vertebral augmentation. Factors such as the patient's bone mineral density, post procedure activity, and chronic corticosteroid use contribute to an increased risk of re-fracture or development of new fractures in the first three months after the initial procedure. However, there is a very small subgroup of patients that have unchanged or worse pain after the vertebral augmentation that may indicate continued progression of the treated compression fracture or a recurrent fracture at the previously treated level. This review examines the clinical findings, radiologic signs, and intraprocedural technical failures that may occur during the initial vertebral augmentation that can lead to a progressive fracture in a previously treated vertebra. Causes of failure of the initial vertebral augmentation procedure include inadequate or incomplete filling of the fracture site, the cement missing the actual fracture allowing continued osteoporotic compression, and persistent or worsened intravertebral fluid-filled clefts. The existence of an unfilled intravertebral fluid cleft on preoperative diagnostic studies is the most important indicator of risk for progression as is the later development of fluid at the bone cement interface. PMID- 29255656 TI - Therapeutic Stroke - an Interesting Case of Ischemic Stroke in Bilateral Thalamic and Subthalamic Regions Resulting in Reduction of Essential Tremor. AB - Essential tremor (ET) is the commonest adult-onset movement disorder, and its prevalence increases with age. About 10% of the patients with ET can be severely handicapped by it. Medical management is the first line of treatment for ET. In the past, refractory cases of ET underwent thalamotomy, a neurosurgical procedure that caused selective thalamic lesions. We describe a case of an elderly woman with ET that showed a dramatic improvement of her tremor after sustaining an acute stroke in bilateral thalamic and subthalamic regions. This ischemic insult essentially served the purpose of thalamotomy resulting in an improvement in her tremor. PMID- 29255657 TI - Common Disconnections in Glioma Surgery: An Anatomic Description. AB - Within the surgical treatment of glioma, extended survival is predicated upon extent of resection which is limited by proximity and/or invasion of eloquent structures. Diffusion tensor imaging (DTI) tractography is a very useful tool for guiding supramaximal surgical resection while preserving eloquence. Although gliomas can vary significantly in size, shape, and invasion of functionally significant brain tissue, typical surgical disconnection patterns emerge. In this study, our typical surgical paradigm is outlined. We describe our surgical philosophy for resecting gliomas supramaximally summarized as define, divide, and destroy with the adjuvant utilization of neuronavigation and DTI. We describe the most common disconnections involved in glioma surgery at our institution; specifically, delineating tumor disconnections involving the medial posterior frontal, lateral posterior frontal, posterior temporal, anterior occipital, medial parietal, and insular regions. Although gliomas are highly variable, common patterns emerge in relation to the necessary disconnections required to preserve eloquent brain while maximizing the extent of resection. PMID- 29255658 TI - Incidental Chronic Neutropenia in an Asymptomatic Adult. AB - Chronic neutropenia is a rare hematologic abnormality encountered in primary care. It can be caused by a wide range of acquired and congenital factors. Very rarely, it can occur as isolated chronic neutropenia where other hematologic cell lines are completely intact. The case discussed here dealt with a similar situation where a 29-year-old female patient presented with severe neutropenia and otherwise intact cell lines in an asymptomatic fashion. Laboratory testing conducted at multiple intervals showed a consistently and severely depressed absolute neutrophil count (ANC) for a prolonged time. In addition, the patient had some abnormalities in serum immunoglobulin levels that pointed towards an underlying autoimmune or malignant pathology but these were insufficient to arrive at a clear diagnosis. The unique presentation in this patient presents an opportunity to study the pathological causation for neutropenia and, more specifically, isolated neutropenia. PMID- 29255659 TI - Edema Bullae Mimicking Disseminated Herpes Zoster. AB - Edema bullae typically forms at the site of skin swelling during acute states of volume overload, most commonly during renal or cardiac failure. Herpes zoster is a reactivation of latent varicella zoster virus that typically presents as painful vesicles in a dermatomal distribution. In immunocompromised individuals, disseminated herpes zoster skin manifestations may occur with several lesions in multiple dermatomes or widespread individual lesions or both, even visceral organs can be involved. Additionally, many conditions are known to mimic the lesions and distribution of herpes zoster. A 53-year-old immunosuppressed male with a history of renal transplant presented with dermatomal and non-dermatomal, disseminated herpes zoster that was confirmed by polymerase chain reaction testing. After one week of intravenous antiviral therapy during which his virus infection-associated lesions were resolved, new blisters developed near the insertion site of a peripheral venous line located on a previously uninvolved yet swollen upper extremity. The varicella zoster virus disease was initially suspected, but lab studies and skin biopsy of a blister excluded progressive or persistent viral infection and established a diagnosis of acute edema bullae. The blisters resolved following removal of the peripheral catheter. Acute edema bullae should be added to the list of mimickers of disseminated varicella zoster virus infection. PMID- 29255661 TI - Rocking pneumonia. AB - Ever since Chuck Berry coined the term "rocking pneumonia" in his 1956 song "Roll over Beethoven", pneumonia has been mentioned frequently in modern blues and rock songs. We analyzed the lyrics of these songs to examine how various elements of pneumonia have been represented in popular music, specifically the cause of pneumonia, the risk groups, comorbidity (such as the boogie woogie flu), the clinical symptoms, and treatment and outcome. Up to this day, songwriters suggest that pneumonia is caused mainly by the cold and rain and that treatment is hardly possible, aside from a shot of rhythm and blues. PMID- 29255660 TI - Clinical Anatomy and Significance of the Retromolar Foramina and Their Canals: A Literature Review. AB - The retromolar foramina (RMF) and the retromolar canal (RMC) are anatomic variants in the mandible located distally to the last molar. The retromolar nerve, which runs through the RMC, is a type 1 bifidity of the mandibular canal. The investigations of the RMF and RMC have been performed by dry mandible studies, the panoramic radiograph (PAN), computed tomography (CT), and the cone beam computed tomography (CBCT) studies. The CBCT has been shown to be the superior method for visualizing the RMF and RMC. There is wide variation in the frequency, location, diameter, and distance of the canal in different individuals. Overall, there is no significant difference in the frequency of the canal in the mandible between sexes or sides of the mandible. The peak incidence of the RMF may occur in adolescence. The RMC is significant due to the neurovascular bundle which runs through it. Injury to this neurovascular bundle during surgical procedures, such as third molar extraction, implant placement, or split sagittal osteotomy, may lead to paresthesia, excessive bleeding, or traumatic neuroma. The presence of RMC may also lead to insufficient anesthesia in the mandible which may be overcome with alternative anesthetic techniques. PMID- 29255662 TI - Why just exercise if you can play? Interest in a modified sports program to enhance physical activity among primary care patients. AB - Fewer adults meet guidelines for aerobic physical activity, and many report a lack of enjoyment as a barrier. This survey was designed to determine the interest of primary care patients in participating in program designed to maximize enjoyment. Primary care patients (n = 540) in Central Pennsylvania reported their interest in participating in a "a regular fitness program where people your own age played games, such as softball, floor hockey and soccer, that were made to be easier to play and less competitive." Mean age was 58.4 years (SD = 16.5, range = 18-98). More than one-third (37.0%), including 59.6% of those under age 50, were interested in the modified sports fitness program. After adjusting for confounders, patients under age 40 were 5.9 (95% CI: 2.6-13.9) times as interested (v. age > 70) and non-white patients were 3.4 (95% CI: 1.3 8.5) times interested. Female patients and those with hypertension, high cholesterol or obesity were equally interested. A fitness program that consists of modified sports may be of interest to most primary care patients under age 50. Patients' initial interest appears high enough to warrant further development and testing. PMID- 29255663 TI - Children's adherence to health behavior recommendations associated with reducing risk of non-communicable disease. AB - The aim of this study is to report the proportions of Australian children age 5 16 years meeting six health behavior recommendations associated with reducing risk of non-communicable disease. Data comes from a representative cross sectional population survey conducted in 2015. Parents completed a health behavior questionnaire for children age < 10 years and adolescents age > 10 years self-reported. Adherence rates were calculated separately for children and adolescents on meeting recommendations for fruit (2-serves/day), vegetables (5 serves/day), physical activity (>= 60 min/day), screen-time (< 2 h/day), oral health (brush-teeth twice daily) and sleep (children 9-11 h/night; adolescents: 8 10 h/night). Participants were 3884 children and 3671 adolescents. Adherence to recommendations was low, with children adhering to an average of 2.5 and adolescents to 2.3 of six recommendations. Overall, recommendation adherence rates were 7% for vegetables, 18% for screen-time, 20% for physical activity, 56% for sleep, 67% for dental (teeth brushing) 79% for fruit; 3.3% reported zero adherence with recommendations and < 0.5% adhered to all six recommendations. There was evidence of social disparity in adherence rates; children and adolescents from low socioeconomic neighborhoods met fewer recommendations and were less likely to meet screen-time and dental recommendations, compared with high socioeconomic peers. Children and adolescents from rural areas met more recommendations, compared with urban peers. Children's and adolescents' adherence to health behavior recommendations is sub-optimal, exposing them to risk of developing non-communicable diseases during adulthood. Better communication and health promotion strategies are required to improve parents' and children's awareness of and adherence to health behavior recommendations. PMID- 29255664 TI - Optimism predicts sustained vigorous physical activity in postmenopausal women. AB - Optimism and cynical hostility are associated with health behaviors and health outcomes, including morbidity and mortality. This analysis assesses their association with longitudinal vigorous physical activity (PA) in postmenopausal women of the Women's Health Initiative (WHI). Subjects include 73,485 women nationwide without history of cancer or cardiovascular disease (CVD), and no missing baseline optimism, cynical hostility, or PA data. The Life Orientation Test-Revised Scale measured optimism. A Cook Medley questionnaire subscale measured cynical hostility. Scale scores were divided into quartiles. Vigorous PA three times or more per week was assessed via self-report at study baseline (1994 1998) and through follow-up year 6. Descriptive analysis mapped lifetime trajectories of vigorous PA (recalled at ages 18, 25, 50; prospectively assessed at baseline, and 3 and 6 years later). Hierarchical generalized linear mixed models examined the prospective association between optimism, cynical hostility, and vigorous PA over 6 years. Models adjusted for baseline sociodemographic variables, psychosocial characteristics, and health conditions and behaviors. Vigorous PA rates were highest for most optimistic women, but fell for all women by approximately 60% between age 50 and study baseline. In adjusted models from baseline through year 6, most vs. least optimistic women were 15% more likely to exercise vigorously (p < 0.001). Cynical hostility was not associated with lower odds of longitudinal vigorous PA after adjustment. Results did not differ by race/ethnicity or socioeconomic status. Higher optimism is associated with maintaining vigorous PA over time in post-menopausal women, and may protect women's health over the lifespan. PMID- 29255665 TI - Neighbourhood disadvantage and behavioural problems during childhood and the risk of cardiovascular disease risk factors and events from a prospective cohort. AB - Both low socioeconomic status (SES) and behavioural problems in childhood are associated with cardiovascular disease (CVD) in adulthood, but their combined effects on CVD are unknown. Study objectives were to investigate the effect of neighbourhood level SES and behavioural problems during childhood on the development of CVD risk factors and events during adulthood. Participants were from a longitudinal cohort (n = 3792, baseline: 6-13 years of age) of Montreal children, followed from 1976 to 2010. SES was a composite measure of neighbourhood income, employment, education, and single-parent households separately assessed from census micro data sets in 1976, 2001, and 2006. Behavioural problems were assessed based on sex-specific peer assessments. CVD events were from medical records. Sex-stratified multivariable Cox regression models adjusted for age, frequency of medical visits, and parental history of CVD. Males from disadvantaged neighbourhoods during childhood were 2.06 (95% CI: 1.09-3.90, p = 0.03) and 2.51 (95% CI: 1.49-4.22, p = 0.0005) times more likely to develop a CVD risk factor or an event, respectively, than males not from disadvantaged neighbourhoods. Aggressive males were also 50% more likely to develop a CVD risk factor or event. Females from disadvantaged neighbourhoods during childhood were 1.85 (95% CI: 1.33-2.59, p = 0.0003) times more likely to develop a CVD risk factor. Future studies should aim to disentangle the interpersonal from the socioeconomic effects on CVD incidence. PMID- 29255666 TI - Socio-demographic and cardiovascular disease risk factors associated with dementia: Results of a cross-sectional study from Lebanon. AB - Little evidence from the Arab region is available on dementia and its associated risk factors. This study is the first in Lebanon to examine the association between community older adults' socio-demographics and cardiovascular disease risk factors (CVDRF) and dementia in the aim of closing the knowledge gap. A cross-sectional household survey was conducted in 2013 in Beirut and two districts of Mount Lebanon with 502 older adults (65 years and above) and their informants. Data was collected on CVDRF and socio-demographics using structured questionnaires and dementia was assessed using the 10/66 Dementia Research Group validated tools. Multivariable analysis was done using a generalized estimating equation to account for cluster effect. Being older and perceiving personal income as insufficient significantly increased the odds of dementia [OR75-84 years = 4.00 (95%CI = 1.46, 10.95); OR85 + years = 7.07 (1.84, 27.03); ORinsufficient income = 3.90 (1.58, 9.60)]. Having uncontrolled hypertension (versus no hypertension) was the only significant CVDRF that increased the odds of dementia [OR = 6.35 (1.60, 25.10)]. Interventions targeting uncontrolled hypertension that aim to increase awareness about proper management of this chronic condition would contribute to the needed preventive efforts against CVDRFs in response to dementia risk. Further research on the association between income sufficiency - one indicator of low socio-economic status - and dementia is warranted. PMID- 29255668 TI - Smoke-free homes among single-parent families: Differences associated with parental race/ethnicity and smoking behaviors. AB - We assessed differences in the rates of smoke-free homes among single-parent households with regard to parental race/ethnicity and smoking status. We identified two cohorts representative of the U.S. single-parent households with underage children (children under the age of 18) based on the Tobacco Use Supplement to the Current Population Survey: 2010-11 (n = 6474) and 2014-15 (n = 6114). The interviews were conducted by phone and in-person. Statistical analysis was performed in 2017. The overall rate of smoke-free homes was 82% in 2010-11 and 86% in 2014-15. The rate of a smoke-free home was highest for Non-Hispanic (NH) Asian (94%) and Hispanic (92%) parents and lowest for NH Multiracial (77% in 2010-11 and 82% in 2014-15) in both survey periods. However, 2014-15 model-based comparisons relative to NH Whites indicated only one significant difference: the rate was lower for NH Blacks (OR = 0.46, 99% CI = 0.32:0.66). The smoke-free homes were least prevalent among daily smokers, followed by occasional smokers, followed by former smokers, and most prevalent among never smokers in each survey period. The 2010-11 and 2014-15 rates were 45% and 54% for daily, 64% and 72% for occasional, 89% and 91% for former, and 93% and 94% for never smokers. The gap in the rates of smoke-free homes for diverse parental racial/ethnic groups observed in 2010-11 decreased by 2014-15. While smoke-free homes became more prevalent in 2014-15, the rates remain drastically different among families with different parental smoking behaviors. Exposure to secondhand smoke at home remains common among single-parent households where the parent smokes. PMID- 29255667 TI - Correlates of objectively measured sedentary time in adults with intellectual disabilities. AB - Sedentary behaviour is an independent risk factor for adverse health conditions. Adults with intellectual disabilities spend a high proportion of their day engaged in sedentary behaviour, however, there is limited evidence on potential correlates of objectively measured sedentary behaviour in this population group. In Glasgow, UK from July to September 2017, a secondary analysis of pooled baseline accelerometer data from two randomised controlled trials of lifestyle behaviour change programmes was conducted. Backwards linear regression was used to investigate the associations between demographic, biological, and environmental correlates and objective measure of sedentary behaviour (percentage of time spent sedentary). One-hundred and forty-three participants provided valid accelerometer data. Mean percentage time spent sedentary (adjusted for wear time) was 72.9% [Standard Deviation (SD) = 8.7] per day. In the final model, physical and mental health problems were significantly (p < 0.05) associated with increased percentage time spent sedentary. This is the first study to provide evidence on multi-level, demographic, biological, and environmental correlates of objectively measured sedentary behaviour in adults with intellectual disabilities. To inform the development of interventions to modify sedentary behaviours in adults with intellectual disabilities, further research is required including a wide range of socio-ecological correlates. PMID- 29255669 TI - Retrospective investigation of "paint brush borders" sign in association with local recurrence of giant cell tumor of bone after intralesional curettage. PMID- 29255670 TI - Pulmonary venous thrombosis secondary to radiofrequency ablation of the pulmonary veins. AB - Background: Pulmonary Vein Thrombosis (PVT) is a rare and underdiagnosed entity produced by local mechanical nature mechanisms, vascular torsion or direct injury to the vein. PVT has been described in clinical cases or small multicenter series mainly in relation to pulmonary vein stenosis, metastatic carcinoma, fibrosing mediastinitis, as an early surgical complication of lung transplantation lobectomy and radiofrequency ablation performed in patients with atrial fibrillation, although in some cases the cause is not known. Case: We report the case of a 57 years old male with history of atrial fibrillation treated by radiofrequency ablation who was admitted in our center because of a two-week history of consistent pleuritic pain in the left hemithorax and low-grade hemoptysis and a lung consolidation treated as a pneumonia with antibiotic but not responding to medical therapy. In view of the poor evolution of the patient, computed tomography angiography was performed with findings of PVT and secondary venous infarction and anticoagulation therapy was optimized. At the end, pulmonary resection was performed due to hemorrhagic recurrence. Conclusion: PVT remains a rare complication of radiofrequency ablation and other procedures involving pulmonary veins. Clinical suspicion and early diagnosis is crucial because is a potentially life-threatening entity. PMID- 29255672 TI - Genome-scale model guided design of Propionibacterium for enhanced propionic acid production. AB - Production of propionic acid by fermentation of propionibacteria has gained increasing attention in the past few years. However, biomanufacturing of propionic acid cannot compete with the current oxo-petrochemical synthesis process due to its well-established infrastructure, low oil prices and the high downstream purification costs of microbial production. Strain improvement to increase propionic acid yield is the best alternative to reduce downstream purification costs. The recent generation of genome-scale models for a number of Propionibacterium species facilitates the rational design of metabolic engineering strategies and provides a new opportunity to explore the metabolic potential of the Wood-Werkman cycle. Previous strategies for strain improvement have individually targeted acid tolerance, rate of propionate production or minimisation of by-products. Here we used the P. freudenreichii subsp. shermanii and the pan-Propionibacterium genome-scale metabolic models (GEMs) to simultaneously target these combined issues. This was achieved by focussing on strategies which yield higher energies and directly suppress acetate formation. Using P. freudenreichii subsp. shermanii, two strategies were assessed. The first tested the ability to manipulate the redox balance to favour propionate production by over-expressing the first two enzymes of the pentose-phosphate pathway (PPP), Zwf (glucose-6-phosphate 1-dehydrogenase) and Pgl (6 phosphogluconolactonase). Results showed a 4-fold increase in propionate to acetate ratio during the exponential growth phase. Secondly, the ability to enhance the energy yield from propionate production by over-expressing an ATP dependent phosphoenolpyruvate carboxykinase (PEPCK) and sodium-pumping methylmalonyl-CoA decarboxylase (MMD) was tested, which extended the exponential growth phase. Together, these strategies demonstrate that in silico design strategies are predictive and can be used to reduce by-product formation in Propionibacterium. We also describe the benefit of carbon dioxide to propionibacteria growth, substrate conversion and propionate yield. PMID- 29255671 TI - Molecular and functional PET-fMRI measures of placebo analgesia in episodic migraine: Preliminary findings. AB - Pain interventions with no active ingredient, placebo, are sometimes effective in treating chronic pain conditions. Prior studies on the neurobiological underpinnings of placebo analgesia indicate endogenous opioid release and changes in brain responses and functional connectivity during pain anticipation and pain experience in healthy subjects. Here, we investigated placebo analgesia in healthy subjects and in interictal migraine patients (n = 9) and matched healthy controls (n = 9) using 11C-diprenoprhine Positron Emission Tomography (PET) and simultaneous functional Magnetic Resonance Imaging (fMRI). Intravenous saline injections (the placebo) led to lower pain ratings, but we did not find evidence for an altered placebo response in interictal migraine subjects as compared to healthy subjects. PMID- 29255673 TI - A recurrent hydatid cyst of the thigh diagnosed 13 years after initial presentation. AB - This case presents a hydatid cyst of the thigh in a 57-year-old patient born and raised in rural Montenegro. He presented with a painful erythematous mass on the lateral aspect of the right thigh at the site of a previous cystic mass resection 13 years earlier. Complete surgical resection was conducted, histopathology revealed laminated membranes and polymerase chain reaction was positive for Echinococcus granulosus. Primary musculoskeletal hydatidosis is a rare entity and diagnosis is challenging. Any cystic lesion in a patient from an endemic area should raise the possibility of echinococcosis, regardless of anatomic location. The key aspects of diagnosis, albendazole treatment and surgical management are discussed. PMID- 29255674 TI - Visceral leishmaniasis with cutaneous involvement caused by Leishmania infantum chagasi. AB - We report the case of a 66 year-old woman who presented nodular skin lesions on her back and upper extremities. Biopsy revealed amastigotes that were identified as Leishmania infantum-chagasi by PCR. Evaluation also showed hepatomegaly and pulmonary nodules. Treatment with amphotericin B led to complete resolution of skin lesions. PMID- 29255675 TI - Infective endocarditis following urinary tract infection caused by Globicatella sanguinis. AB - We report the first case of infective endocarditis following urinary tract infection (UTI) caused by Globicatella sanguinis in an 87-year-old Japanese woman with recurrent episodes of UTI. We identified the pathogen using the Rapid ID32 Strep system. Accurate identification of this infection is important and essential for the effective antimicrobial coverage to this pathogen. PMID- 29255676 TI - Two cases of listeria rhombencephalitis. AB - Listeria rhombencephalitis (LRE) is a rare encephalitis of the hindbrain that can present with a variety of neurological symptoms. It is a diagnostic challenge, but prompt antimicrobial therapy is important to prevent high rates of mortality and morbidity. We report two cases of LRE, with several contrasting clinical features and different disease courses. Despite being rare, it is important to consider listeria in patients with possible meningoencephalitis, even if cultures are negative. Empirical treatment of meningoencephalitis should provide coverage for listeria, especially if the patient is at risk of listeriosis or there is a potential history of listeria exposure. PMID- 29255677 TI - Case report: Extragonadal mixed germ cell tumor in the thigh. PMID- 29255678 TI - Excisional biopsy of an extravesicular hemangioma. PMID- 29255679 TI - Ipsilateral synchronous clear and papillary renal cell carcinoma: A case report and review of the literature. AB - Clear cell renal cell carcinoma and papillary renal cell carcinoma are the most common types of renal tumors. However, coexistence of both tumors in the same kidney is a rare condition. We report a 56-year old male who was found to have ipsilateral synchronous clear cell and papillary renal cell carcinoma in the left kidney. Review of related literature is provided to estimate the prevalence of similar cases. PMID- 29255680 TI - Low power HOLEP after failed urolift: A case report using 50 Watt laser. PMID- 29255681 TI - Lower ureteric obstruction by crossing vessel - Is it possible? PMID- 29255682 TI - Sporadic breast metastasis derived from renal cell carcinoma: A case report. PMID- 29255683 TI - Progression from tubulovillous adenoma to high-grade adenocarcinoma in Indiana pouch urinary diversion. PMID- 29255684 TI - Next-generation sequencing applications in clinical bacteriology. AB - With the rapid advances in next generation sequencing (NGS) technologies, clinical and public health microbiology laboratories are increasingly adopting NGS technology in their workflows into their existing diagnostic cycles. In this bacteriology focused review, we review aspects and considerations for applying NGS in the clinical microbiology settings, and highlight the impact of such implementation on the analytical and post-analytical stages of diagnosis. PMID- 29255685 TI - Amplification of nonspecific products in quantitative polymerase chain reactions (qPCR). AB - Quantitative PCR allows the precise measurement of DNA concentrations and is generally considered to be straightforward and trouble free. However, a survey with 93 validated assays for genes in the Wnt-pathway showed that the amplification of nonspecific products occurs frequently and is unrelated to Cq or PCR efficiency values. Titration experiments showed that the occurrence of low and high melting temperature artifacts was shown to be determined by annealing temperature, primer concentration and cDNA input. To explore the range of input variations that occur in the normal use of the Cre assay these conditions were mimicked in a complete two-way design of template -plasmid DNA- and non-template mouse cDNA- concentrations. These experiments showed that the frequency of the amplification of the correct product and the artifact, as well as the valid quantification of the correct product, depended on the concentration of the non template cDNA. This finding questions the interpretation of dilution series in which template as well as non-template concentrations are simultaneously decreasing. Repetition of this cDNA concentration experiment with other templates revealed that exact reproduction qPCR experiments was affected by the time it takes to complete the pipetting of a qPCR plate. Long bench times were observed to lead to significantly more artifacts. However, the measurement of artifact associated fluorescence can be avoided by inclusion of a small heating step after the elongation phase in the amplification protocol. Taken together, this trouble shooting journey showed that reliability and reproducibility of qPCR experiments not only depends on standardization and reporting of the biochemistry and technical aspects but also on hitherto neglected factors as sample dilution and waiting times in the laboratory work flow. PMID- 29255686 TI - Advances in cardiac CT. PMID- 29255687 TI - Coronary CT angiography-future directions. AB - Clinical applications of coronary CT angiography (CTA) will typically be based on the method's very high sensitivity to identify coronary stenosis if image quality is good and if the pre-test likelihood of the patients is in the lower range. Guidelines of national and international cardiac societies are starting to incorporate coronary CTA into their recommendations for the management of patients with stable and acute chest pain. Initial data show that in the future, the use of coronary CTA may not only be able to replace other forms of diagnostic testing, but, in fact, may improve patient outcome. In this article, a perspective is provided on the future directions of coronary CTA. PMID- 29255688 TI - Advances in cardiac CT contrast injection and acquisition protocols. AB - Cardiac computed tomography (CT) imaging has become an important part of modern cardiovascular care. Coronary CT angiography (CTA) is the first choice imaging modality for non-invasive visualization of coronary artery stenosis. In addition, cardiac CT does not only provide anatomical evaluation, but also functional and valvular assessment, and myocardial perfusion evaluation. In this article we outline the factors which influence contrast enhancement, give an overview of current contrast injection and acquisition protocols, with focus on current emerging topics such as pre-transcatheter aortic valve replacement (TAVR) planning, cardiac CT for congenital heart disease (CHD) patients, and myocardial CT perfusion (CTP). Further, we point out areas where we see potential for future improvements in cardiac CT imaging based on a closer interaction between CT scanner settings and contrast injection protocols to tailor injections to patient and exam-specific factors. PMID- 29255689 TI - Myocardial computed tomography perfusion. AB - Despite having excellent diagnostic accuracy to detect anatomical coronary stenosis, coronary CT angiography (CTA) has a limited specificity to detect myocardial ischemia. CT perfusion (CTP) can identify myocardial perfusion defects during vasodilator stress, and when added to coronary CTA, improves the specificity of detecting hemodynamically significant stenosis. A CTP protocol typically involves the acquisition of two separate data sets: (I) a rest scan that can be used as both a coronary CTA and for evaluating rest myocardial perfusion, and (II) a stress CTP scan acquired during vasodilator stress testing. This review summarizes some the techniques, strengths, and limitations of CTP, and provides an overview of the recent evidence supporting the potential use of CTP in clinical practice. PMID- 29255690 TI - Fractional flow reserve computed tomography in the evaluation of coronary artery disease. AB - Amongst patients with suspected obstructive coronary artery disease (CAD), less than a third of patients have obstructive disease on invasive coronary angiography (ICA) and fewer still have flow-limiting obstructive disease as determined by invasive fractional flow reserve (FFR). FFR is a powerful tool in guiding revascularization of flow-limiting lesions which in turn improves clinical outcome in those with haemodynamically significant obstructive disease. However FFR is infrequently performed due to the cost, time and patient discomfort the procedure entails. Further advances in non-invasive imaging has allowed FFR to be derived non-invasively by applying computational fluid dynamic (CFD) modeling to the coronary computed tomography angiography (CCTA) dataset without the need to induce hyperemia or modify the standard CCTA acquisition protocol. FFR derived from CCTA has been shown to have excellent correlation with invasive FFR and remains diagnostically robust in presence of reduced signal-to noise ratio (SNR), coronary calcification and motion artifact. More recently, new data have emerged evaluating the clinical impact of fractional flow reserve computed tomography (FFRCT) on the assessment and management of patients with stable chest pain. One such study is the Prospective LongitudinAl trial of FFRCT: Outcome and Resource IMpacts (PLATFORM) study which showed an improved patient selection for ICA using CCTA-FFRCT approach by increasing the likelihood of identifying obstructive CAD at ICA amongst those intended for invasive testing. CCTA-FFRCT may therefore serve as efficacious gatekeeper to ICA that enriches the ICA population. The utility of FFRCT has also helped deepened our understanding of CAD. Through CFD modeling, it is now recognized that there are mechanistic forces of wall shear stress (WSS) and axial plaque force acting on coronary plaques. This has created further interest in exploring the possible interplay between these mechanistic forces on the development of coronary plaque and vulnerability of these plaques to rupture. PMID- 29255691 TI - Myocardial ischemia testing with computed tomography: emerging strategies. AB - Although cardiac computed tomography (CT) has high negative predictive value to exclude obstructive coronary artery disease (CAD), particularly in the low to intermediate risk population, it has low specificity in the diagnosis of ischemia inducing lesions. This inability to predict hemodynamically significant stenosis hampers the ability of CT to be an effective gatekeeper for invasive angiography and to guide appropriate revascularization. Recent advances in CT technology have resulted in the development of multiple techniques to provide hemodynamic information and detect lesion-specific ischemia, namely CT perfusion (CTP), CT derived fractional flow reserve (CT-FFR) and coronary transluminal attenuation gradient (TAG). In this article, we provide a perspective on these emerging CT techniques in the evaluation of myocardial ischemia. PMID- 29255693 TI - 3D printing from cardiovascular CT: a practical guide and review. AB - Current cardiovascular imaging techniques allow anatomical relationships and pathological conditions to be captured in three dimensions. Three-dimensional (3D) printing, or rapid prototyping, has also become readily available and made it possible to transform virtual reconstructions into physical 3D models. This technology has been utilised to demonstrate cardiovascular anatomy and disease in clinical, research and educational settings. In particular, 3D models have been generated from cardiovascular computed tomography (CT) imaging data for purposes such as surgical planning and teaching. This review summarises applications, limitations and practical steps required to create a 3D printed model from cardiovascular CT. PMID- 29255692 TI - Plaque imaging with CT-a comprehensive review on coronary CT angiography based risk assessment. AB - CT based technologies have evolved considerably in recent years. Coronary CT angiography (CTA) provides robust assessment of coronary artery disease (CAD). Early coronary CTA imaging-as a gate-keeper of invasive angiography-has focused on the presence of obstructive stenosis. Coronary CTA is currently the only non invasive imaging modality for the evaluation of non-obstructive CAD, which has been shown to contribute to adverse cardiac events. Importantly, improved spatial resolution of CT scanners and novel image reconstruction algorithms enable the quantification and characterization of atherosclerotic plaques. State-of-the-art CT imaging can therefore reliably assess the extent of CAD and differentiate between various plaque features. Recent studies have demonstrated the incremental prognostic value of adverse plaque features over luminal stenosis. Comprehensive coronary plaque assessment holds potential to significantly improve individual risk assessment incorporating adverse plaque characteristics, the extent and severity of atherosclerotic plaque burden. As a result, several coronary CTA based composite risk scores have been proposed recently to determine patients at high risk for adverse events. Coronary CTA became a promising modality for the evaluation of functional significance of coronary lesions using CT derived fractional flow reserve (FFR-CT) and/or rest/dynamic myocardial CT perfusion. This could lead to substantial reduction in unnecessary invasive catheterization procedures and provide information on ischemic burden of CAD. Discordance between the degree of stenosis and ischemia has been recognized in clinical landmark trials using invasive FFR. Both lesion stenosis and composition are possibly related to myocardial ischemia. The evaluation of lesion-specific ischemia using combined functional and morphological plaque information could ultimately improve the diagnostic performance of CTA and thus patient care. In this review we aimed to summarize current evidence on comprehensive coronary artery plaque assessment using coronary CTA. PMID- 29255696 TI - Communicating complex scientific research ideas for curing lung cancer using North East Indian folklore and visual art. PMID- 29255694 TI - The role of advanced reconstruction algorithms in cardiac CT. AB - Non-linear iterative reconstruction (IR) algorithms have been increasingly incorporated into clinical cardiac CT protocols at institutions around the world. Multiple IR algorithms are available commercially from various vendors. IR algorithms decrease image noise and are primarily used to enable lower radiation dose protocols. IR can also be used to improve image quality for imaging of obese patients, coronary atherosclerotic plaques, coronary stents, and myocardial perfusion. In this article, we will review the various applications of IR algorithms in cardiac imaging and evaluate how they have changed practice. PMID- 29255695 TI - Computed tomography of cardiomyopathies. AB - Cardiac computed tomography (CT) is increasingly used in the evaluation of cardiomyopathies, particularly in patients who are not able to undergo other non invasive imaging tests such as magnetic resonance imaging (MRI) due to the presence of MRI-incompatible pacemakers/defibrillators or other contraindications or due to extensive artifacts from indwelling metallic devices. Advances in scanner technology enable acquisition of CT images with high spatial resolution, good temporal resolution, wide field of view and multi-planar reconstruction capabilities. CT is useful in cardiomyopathies in several ways, particularly in the evaluation of coronary arteries, characterization of cardiomyopathy phenotype, quantification of cardiac volumes and function, treatment-planning, and post-treatment evaluation. In this article, we review the imaging techniques and specific applications of CT in the evaluation of cardiomyopathies. PMID- 29255697 TI - Neoadjuvant Chemoradiotherapy for Stage III Non-Small Cell Lung Cancer. AB - The local management of stage III non-small cell lung cancer is controversial. Although definitive chemoradiotherapy (CRT) is considered a standard-of-care in the curative management of the disease, inadequate local control outcomes have led to various treatment strategies that incorporate surgical resection. Surgery alone has long been recognized as insufficient for this stage, and thus neoadjuvant strategies have been developed to treat micrometastatic disease and increase the probability of a complete resection. The optimal induction strategy has not yet been defined, however, with arguments favoring either preoperative chemotherapy or CRT. In this article, the data supporting the use of neoadjuvant CRT and the randomized literature comparing the two approaches will be reviewed. The article will conclude with summary comparisons of these induction paradigms. PMID- 29255698 TI - Modeling Myeloid Malignancies Using Zebrafish. AB - Human myeloid malignancies represent a substantial disease burden to individuals, with significant morbidity and death. The genetic underpinnings of disease formation and progression remain incompletely understood. Large-scale human population studies have identified a high frequency of potential driver mutations in spliceosomal and epigenetic regulators that contribute to malignancies, such as myelodysplastic syndromes (MDS) and leukemias. The high conservation of cell types and genes between humans and model organisms permits the investigation of the underlying mechanisms of leukemic development and potential therapeutic testing in genetically pliable pre-clinical systems. Due to the many technical advantages, such as large-scale screening, lineage-tracing studies, tumor transplantation, and high-throughput drug screening approaches, zebrafish is emerging as a model system for myeloid malignancies. In this review, we discuss recent advances in MDS and leukemia using the zebrafish model. PMID- 29255700 TI - New Methods for Imaging Evaluation of Chest Wall Deformities. AB - Aim: The purpose of this study is to describe the development of an external 3 dimensional (3D) scanner as a noninvasive method for imaging chest wall deformities. It allows objective assessment, reconstruction of the area of interest, and evaluation of the severity of the deformity by using external indexes. External 3D scanning system: The OrtenBodyOne scanner (Orten, Lyon, France) uses depth sensors to scan the entire 3D external body surface of a patient. The depth sensors combine structured light with two classic computer vision techniques: depth from focus and depth from stereo. The data acquired are processed and analyzed using the Orten-Clinic software. Materials and methods: To investigate the performance of the device, a preliminary prospective study (January 2015-March 2016) was carried out in patients attending our hospital chest wall deformities unit. In total, 100 patients (children and young adults) with pectus excavatum or pectus carinatum, treated by surgery or non-operative methods were included. In patients undergoing non-operative treatment, external 3D scanning was performed monthly until complete correction was achieved. In surgically treated patients, scanning was done before and after surgical correction. In 42 patients, computed tomography (CT) was additionally performed and correlations between the Haller index calculated by CT and the external Haller index using external scanning were investigated using a Student's test (r = 0.83). Conclusion: External scanning is an effective, objective, radiation-free means to diagnose and follow-up patients with chest wall deformities. Externally measured indexes can be used to evaluate the severity of these conditions and the treatment outcomes. PMID- 29255699 TI - The current status of immunobased therapies for metastatic renal-cell carcinoma. AB - The management of metastatic renal-cell carcinoma (mRCC) represents an important clinical challenge. Since being approved in the early 1990s, aspecific immunotherapy has been a mainstay of treatment for mRCC and the only therapy that has demonstrated long-term cures for mRCC. However, in recent times there have been landmark advances made in the field of specific immunotherapy for a number of malignancies, including kidney cancer. This review outlines the range of immunobased agents currently available for the treatment of mRCC. PMID- 29255701 TI - Integration of Next-Generation Sequencing to Treat Acute Lymphoblastic Leukemia with Targetable Lesions: The St. Jude Children's Research Hospital Approach. AB - Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children. In recent Total Therapy studies conducted at St. Jude Children's Research Hospital, children with ALL had a 5-year overall survival of around 94%. This is the result of a combination of risk stratification based on the biological features of the leukemic cells and the response to treatment (as assessed by the detection of minimal residual disease), treatment modification based on pharmacodynamic and pharmacogenomic data, and improved supportive care. However, innovative approaches are required to further improve survival to as close to 100% as possible and to reduce the adverse effects of treatment. Next-generation sequencing of leukemic cell DNA and RNA, as well as of germline DNA, can identify submicroscopic genetic structural changes and sequence alterations that contribute to leukemogenesis. Next-generation sequencing data can be used to define new ALL subtypes, to help improve treatment response and reduce adverse effects, and to identify novel prognostic markers and therapeutic targets to facilitate personalized precision medicine. In this article, we describe our approach to detecting targetable lesions in patients with ALL by next-generation sequencing and explain how we integrate the sequencing data into the treatment of these patients. PMID- 29255702 TI - Bronchopulmonary Sequestration with Morbid Neonatal Pleural Effusion despite Successful Antenatal Treatment. AB - Introduction: Bronchopulmonary sequestration (BPS) may cause prenatal pleural effusion (PE) or even hydrops. This case describes a fetus presenting with severe PE, which prenatally waned completely under steroid treatment, yet surprisingly reappeared rapidly after birth, requiring early surgical intervention. Case description: A male fetus was diagnosed with left BPS and severe PE. After three courses of prenatal steroid therapy for each recurrence of PE from 27 weeks of gestation, we observed a complete regression of PE prenatally. Yet, PE recurred 18 h after birth and persisted after repeated drainages and steroid therapy. Early total resection of the extralobar BPS was performed and led to complete recovery without recurrence of PE. Conclusion: This report underlines that in cases of BPS presenting with prenatal PE needing fetal intervention, even if full regression of PE is observed before birth, there might be a need for surgical excision during the neonatal period. PMID- 29255703 TI - Corrigendum: Assessment of Sensory Processing Characteristics in Children between 3 and 11 Years Old: A Systematic Review. AB - [This corrects the article on p. 57 in vol. 5, PMID: 28424762.]. PMID- 29255704 TI - Editorial: Mobile Genetic Elements in Cellular Differentiation, Genome Stability, and Cancer. PMID- 29255705 TI - Redox-Responsive Manganese Dioxide Nanoparticles for Enhanced MR Imaging and Radiotherapy of Lung Cancer. AB - In this study, we synthesized manganese dioxide nanoparticles (MnO2 NPs) stabilized with biocompatible polymers (polyvinylpyrrolidone and polyacrylic acid) and analyzed their effect on non-small cell lung cancer (NSCLC) cells with or without gefitinib resistance in vitro. MnO2 NPs showed glutathione (GSH) responsive dissolution and subsequent enhancement in magnetic resonance (MR) imaging. Of note, treatment with MnO2 NPs induced significant cytotoxic effects on NSCLC cells, and additional dose-dependent therapeutic effects were obtained upon X-ray irradiation. Normal cells treated with MnO2 NPs were viable at the tested concentrations. In addition, increased therapeutic efficacy could be achieved when the cells were treated with MnO2 NPs in hypoxic conditions. Therefore, we conclude that the use of MnO2 NPs in MR imaging and combination radiotherapy may be an efficient strategy for the imaging and therapy of NSCLC. PMID- 29255706 TI - Diversifying Natural Products with Promiscuous Glycosyltransferase Enzymes via a Sustainable Microbial Fermentation Approach. PMID- 29255707 TI - Interfacing Neural Network Components and Nucleic Acids. AB - Translating neural activity into nucleic acid modifications in a controlled manner harbors unique advantages for basic neurobiology and bioengineering. It would allow for a new generation of biological computers that store output in ultra-compact and long-lived DNA and enable the investigation of animal nervous systems at unprecedented scales. Furthermore, by exploiting the ability of DNA to precisely influence neuronal activity and structure, it could be possible to more effectively create cellular therapy approaches for psychiatric diseases that are currently difficult to treat. PMID- 29255708 TI - New Insights into Drug Reaction with Eosinophilia and Systemic Symptoms Pathophysiology. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug induced hypersensitivity syndrome, is a severe type of cutaneous drug-induced eruption. DRESS may be a difficult disease to diagnose since the symptoms mimic those of cutaneous and systemic infectious pathologies and can appear up to 3 months after the initial culprit drug exposure. The symptoms of DRESS syndrome include rash development after a minimum of 3 weeks after the onset of a new medication, associated with facial edema, lymphadenopathy, and fever. Biological findings include liver abnormalities, leukocytosis, eosinophilia, atypical lymphocytosis, and reactivation of certain human herpes viruses. In DRESS, liver, kidneys, and lungs are frequently involved in disease evolution. Patients with serious systemic involvement are treated with oral corticosteroids, and full recovery is achieved in the majority of cases. DRESS is a rare disease, and little is known about factors that predict its occurrence. The key features of this reaction are eosinophil involvement, the role of the culprit drug, and virus reactivation that trigger an inappropriate systemic immune response in DRESS patients. Interestingly, it was evidenced that at-risk individuals within a genetically restricted population shared a particular HLA loci. In this respect, a limited number of well-known drugs were able to induce DRESS. This review describes the up-to-date advances in our understanding of the pathogenesis of DRESS. PMID- 29255709 TI - Disease Severity, Activity, Impact, and Control and How to Assess Them in Patients with Hereditary Angioedema. AB - Hereditary angioedema (HAE) is a group of rare, potentially life-threatening, and frequently debilitating diseases characterized by recurrent, and often with an unpredictable onset, of swelling attacks. HAE is heterogeneous, with considerable differences between its subtypes, patients, and even within the same patient over time. During the past few years, several new on demand and prophylactic therapies have become available for HAE, allowing for individualized treatment. Therefore, to optimize HAE management, it is important to determine in all patients, the severity of their attacks, their disease activity, its therapeutic control, and its impact on their quality of life. In this manuscript, we review the existing tools to assess these aspects of HAE management, many of which are patient reported outcome instruments. Also, we outline the current gaps of knowledge and what tools are still missing to allow for a comprehensive assessment of all patients with HAE including children. PMID- 29255710 TI - Pathogen Inactivation of Cellular Blood Products-An Additional Safety Layer in Transfusion Medicine. AB - In line with current microbial risk reduction efforts, pathogen inactivation (PI) technologies for blood components promise to reduce the residual risk of known and emerging infectious agents. The implementation of PI of labile blood components is slowly but steadily increasing. This review discusses the relevance of PI for the field of transfusion medicine and describes the available and emerging PI technologies that can be used to treat cellular blood products such as platelet and red blood cell units. In collaboration with the French medical device manufacturer Macopharma, the German Red Cross Blood Services developed a new UVC light-based PI method for platelet units, which is currently being investigated in clinical trials. PMID- 29255711 TI - Starch Hydrolysis, Polyphenol Contents, and In Vitro Alpha Amylase Inhibitory Properties of Some Nigerian Foods As Affected by Cooking. AB - The effect of cooking on starch hydrolysis, polyphenol contents, and in vitro alpha-amylase inhibitory properties of mushrooms (two varieties Russula virescens and Auricularia auricula-judae), sweet potato (Ipomea batatas), and potato (Solanum tuberosum) was investigated. The total, resistant, and digestible starch contents of the raw and cooked food samples (FS) ranged from 6.4 to 64.9; 0 to 10.1; and 6.4 to 62.7 g/100 g, respectively, while their percentages of starch digestibility (DS values expressed as percentages of total starch hydrolyzed) ranged from 45.99 to 100. Raw and boiled unpeeled potato, raw and boiled peeled potato, raw A. auricula-judae, and sweet potato showed mild to high alpha-amylase inhibition (over a range of concentration of 10-50 mg/mL), which was lower than that of acarbose (that had 69% inhibition of alpha-amylase over a range of concentration of 2-10 mg/mL), unlike raw R. virescens, boiled A. auricula-judae, and boiled sweet potatoes that activated alpha-amylase and boiled R. virescens that gave 0% inhibition. The FS contained flavonoids and phenols in addition. The significant negative correlation (r = -0.55; P = 0.05) between the alpha-amylase inhibitory properties of the raw and cooked FS versus their SD indicates that the alpha-amylase inhibitors in these FS also influenced the digestibility of their starches. In addition, the significant positive correlation between the alpha amylase inhibitory properties of the raw and cooked FS versus their resistant starch (RS) (r = 0.59; P = 0.01) contents indicates that the RS constituents of these FS contributed to their alpha-amylase inhibitory properties. The study showed the usefulness of boiled unpeeled potato, boiled potato peeled, and raw sweet potato as functional foods for people with type 2 diabetes. PMID- 29255712 TI - Perioperative Management of Subarachnoid Hemorrhage in a Patient with Alagille Syndrome and Unrepaired Tetralogy of Fallot: Case Report. AB - Alagille syndrome (ALGS) is a genetic disorder associated with multisystem dysfunction involving the hepatic, cardiovascular, and neurologic systems. Tetralogy of Fallot (TOF), a congenital cardiac anomaly, is commonly found in these patients. Patients with ALGS may also have an increased risk of cerebrovascular abnormalities and bleeding. Ruptured cerebral aneurysm and subarachnoid hemorrhage (SAH) may be developed, increasing the incidence of morbidity and mortality. Advances in neuroimaging and neurosurgery have allowed early identification and treatment of such vascular abnormalities, improving patients' outcomes and reducing life-threatening complications such as intracranial bleeding. Authors describe the perioperative management of a patient with ALGS and TOF who was admitted to the emergency department due a ruptured intracranial aneurysm with concomitant SAH. Surgical treatment included diagnostic cerebral arteriography with coil embolization of a left posterior communicating artery aneurysm, and placement of right external ventricular drain (EVD). The combination of neuroprotective anesthetic techniques, fast emergence from anesthesia, and maintenance of intraoperative hemodynamic stability led to a successful perioperative management. A multidisciplinary approach in specialized centers is essential for the treatment of patients with SAH, especially in patients with ALGS and complex congenital heart disease such as TOF. PMID- 29255713 TI - Wilhelm von Waldeyer-Hartz-A Great Forefather: His Contributions to Anatomy with Particular Attention to "His" Fascia. AB - Wilhelm Waldeyer was, at his time, one of the most well-known authors in the field of Anatomy, Pathology, and Embryology. He held various distinguished academic positions. He was Professor of (Pathological) Anatomy in Breslau, Strasbourg, and Berlin. He remained in Berlin for the unusually long period of 33.5 years, as Full Professor for Anatomy and Director of the Anatomical Institute. His great talent as a teacher ensured that his lectures were always filled to the brim. Between 1862 and 1920, he published 270 works, including classics such as "Das Becken" (The Pelvis). The portrayal of this most important area is counted as one of the most complete which has ever been accomplished in the field of topographic anatomy, it includes the description of the fascia of Waldeyer. He also coined the phrases "chromosome" and "neuron" with their anatomical-morphological concepts. Already during his lifetime, his teaching ability significantly preceded the research capacity. It would, however, be false to overshadow Waldeyer's merits as a researcher. His main scientific merit is in his excellent summarizing interpretations of current questions of anatomy and evolution, which particularly shows his simultaneous gift as a researcher and a teacher. PMID- 29255714 TI - Mouse d-Amino-Acid Oxidase: Distribution and Physiological Substrates. AB - d-Amino-acid oxidase (DAO) catalyzes the oxidative deamination of d-amino acids. DAO is present in a wide variety of organisms and has important roles. Here, we review the distribution and physiological substrates of mouse DAO. Mouse DAO is present in the kidney, brain, and spinal cord, like DAOs in other mammals. However, in contrast to other animals, it is not present in the mouse liver. Recently, DAO has been detected in the neutrophils, retina, and small intestine in mice. To determine the physiological substrates of mouse DAO, mutant mice lacking DAO activity are helpful. As DAO has wide substrate specificity and degrades various d-amino acids, many d-amino acids accumulate in the tissues and body fluids of the mutant mice. These amino acids are d-methionine, d-alanine, d serine, d-leucine, d-proline, d-phenylalanine, d-tyrosine, and d-citrulline. Even in wild-type mice, administration of DAO inhibitors elevates D-serine levels in the plasma and brain. Among the above d-amino acids, the main physiological substrates of mouse DAO are d-alanine and d-serine. These two d-amino acids are most abundant in the tissues and body fluids of mice. d-Alanine derives from bacteria and produces bactericidal reactive oxygen species by the action of DAO. d-Serine is synthesized by serine racemase and is present especially in the central nervous system, where it serves as a neuromodulator. DAO is responsible for the metabolism of d-serine. Since DAO has been implicated in the etiology of neuropsychiatric diseases, mouse DAO has been used as a representative model. Recent reports, however, suggest that mouse DAO is different from human DAO with respect to important properties. PMID- 29255715 TI - Breed-Specific Magnetic Resonance Imaging Characteristics of Necrotizing Encephalitis in Dogs. AB - Diagnosing necrotizing encephalitis, with its subcategories of necrotizing leukoencephalitis and necrotizing meningoencephalitis, based on magnetic resonance imaging alone can be challenging. However, there are breed-specific imaging characteristics in both subcategories that allow establishing a clinical diagnosis with a relatively high degree of certainty. Typical breed specific imaging features, such as lesion distribution, signal intensity, contrast enhancement, and gross changes of brain structure (midline shift, ventriculomegaly, and brain herniation) are summarized here, using current literature, for the most commonly affected canine breeds: Yorkshire Terrier, French Bulldog, Pug, and Chihuahua. PMID- 29255716 TI - Antimicrobial Susceptibility of Bacteria That Cause Bovine Respiratory Disease Complex in Alberta, Canada. AB - Bovine respiratory disease (BRD) is the most important illness of feedlot cattle. Disease management targets the associated bacterial pathogens, Mannheimia haemolytica, Mycoplasma bovis, Pasteurella multocida, Histophilus somni, and Trueperella pyogenes. We conducted a cross-sectional study to measure the frequencies of antimicrobial-resistant BRD pathogens using a collaborative network of veterinarians, industry, government, and a diagnostic laboratory. Seven private veterinary practices in southern Alberta collected samples from both living and dead BRD-affected animals at commercial feedlots. Susceptibility testing of 745 isolates showed that 100% of the M. haemolytica, M. bovis, P. multocida, and T. pyogenes isolates and 66.7% of the H. somni isolates were resistant to at least one antimicrobial class. Resistance to macrolide antimicrobials (90.2% of all isolates) was notable for their importance to beef production and human medicine. Multidrug resistance (MDR) was high in all target pathogens with 47.2% of the isolates resistant to four or five antimicrobial classes and 24.0% resistance to six to nine classes. We compared the MDR profiles of isolates from two feedlots serviced by different veterinary practices. Differences in the average number of resistant classes were found for M. haemolytica (p < 0.001) and P. multocida (p = 0.002). Compared to previous studies, this study suggests an increasing trend of resistance in BRD pathogens against the antimicrobials used to manage the disease in Alberta. For the veterinary clinician, the results emphasize the importance of ongoing susceptibility testing of BRD pathogens to inform treatment protocols. Surveillance studies that collect additional epidemiological information and manage sampling bias will be necessary to develop strategies to limit the spread of resistance. PMID- 29255717 TI - HIV-associated disruption of lung cytokine networks is incompletely restored in asymptomatic HIV-infected Malawian adults on antiretroviral therapy. AB - Disruption of lung cytokine networks during chronic HIV infection is incompletely restored in individuals on antiretroviral therapy. PMID- 29255719 TI - Inhaled beclomethasone/formoterol in idiopathic pulmonary fibrosis: a randomised controlled exploratory study. AB - IPF biomarker improved by ICS/LABA http://ow.ly/CHub30gzHry. PMID- 29255718 TI - Natural history of COPD: gaps and opportunities. AB - Understanding the natural history of a disease is as important as knowing its cause(s) for effective disease prevention and treatment. Yet, our current understanding of the natural history of chronic obstructive pulmonary disease (COPD) is incomplete and often controversial. This article discusses the current gaps, and hence opportunities for research, in this field. In particular, it discusses the following six specific questions. 1) Is COPD a "single" disease? 2) Is COPD "only" a lung disease? 3) When does COPD begin or what is "early" COPD? 4) How does COPD "progress"? 5) How do we assess disease "severity"? 6) Can COPD be prevented (beyond smoking cessation) or its course be modified once detected? PMID- 29255720 TI - mMRC dyspnoea scale indicates impaired quality of life and increased pain in patients with idiopathic pulmonary fibrosis. AB - This study was undertaken to investigate idiopathic pulmonary fibrosis (IPF) patients' health-related quality of life (HRQoL) and symptoms in a real-life cross-sectional study. Our secondary aim was to create a simple identification method for patients with increased need for palliative care by studying the relationship between modified Medical Research Council (mMRC) dyspnoea scale, HRQoL and symptoms. We sent a self-rating HRQoL questionnaire (RAND-36) and modified Edmonton Symptom Assessment Scale (ESAS) to 300 IPF patients; 84% of the patients responded to these questionnaires. The most prevalent (>80%) symptoms were tiredness, breathlessness, cough and pain in movement. An increasing mMRC score showed a linear relationship (p<0.001) to impaired HRQoL in all dimensions of RAND-36 and the severity of all symptoms in ESAS. Dimensions of RAND-36 fell below general population reference values in patients with mMRC score >=2. The intensity of pain in movement (p<0.001) and at rest (p=0.041), and the prevalence of chest pain (p<0.001) had a positive linear relationship to increased mMRC score. An increasing mMRC score reflects impaired HRQoL and a high symptom burden. In clinical practice, the mMRC scale could be used for screening and identification of IPF patients with increased need for palliative care. PMID- 29255721 TI - Looking under the bonnet of patient-ventilator asynchrony during noninvasive ventilation: does it add value? AB - During noninvasive ventilation it is reasonable to try to abolish clinically apparent patient-ventilator asynchronies but the use of more invasive tests to detect subtle asynchronies cannot be justified http://ow.ly/rXoA30gCm8O. PMID- 29255722 TI - Idiopathic Colonic Varices: A Rare Cause of Recurrent Lower Gastrointestinal Bleeding. PMID- 29255723 TI - Intrapancreatic Enteric Duplication Cyst Masquerading as Groove Pancreatitis. AB - Intrapancreatic enteric duplication cysts are exceedingly rare, and the clinical presentation varies. We present a 48-year-old man with significant alcohol and tobacco abuse and a diagnosis of groove pancreatitis complicated by a pancreatic duct stricture, pseudocyst, and recurrent biliary obstruction. Due to failure of endoscopic therapy and concerning findings on endoscopic ultrasound with negative pathology, he underwent a pancreaticoduodenectomy. Pathology revealed an intrapancreatic enteric duplication cyst, minimal chronic pancreatitis changes associated with pancreaticobiliary strictures, and no evidence of malignancy. This rare diagnosis should be considered in the differential for patients with idiopathic recurrent pancreaticobiliary duct strictures and pancreatic pseudomasses. PMID- 29255724 TI - Vitamin D Supplementation Does Not Affect Metabolic Changes Seen With ART Initiation. AB - Background: Insulin resistance and lipid changes are common after antiretroviral therapy (ART) initiation. Observational studies suggest that vitamin D supplementation reduces the risk of developing diabetes and improves lipid profiles. Methods: This 48-week prospective, randomized, double-blind, placebo controlled study evaluated high-dose vitamin D3 (4000 IU daily) plus calcium supplementation (1000 mg calcium carbonate daily) in HIV-infected participants initiating ART with efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Changes in insulin resistance (as estimated by homeostatic model assessment), fasting lipid profile, and components of the metabolic syndrome were assessed at baseline, 24 weeks, and 48 weeks. Stratified Wilcoxon rank sum tests and stratified normal score tests were used to evaluate differences between treatment arms, stratified by screening 25-OH vitamin D stratum (<=/>20 ng/mL). Results: A total of 165 participants enrolled: 79 in the vitamin D/calcium (Vit D/Cal) arm and 86 in the placebo arm. Only the placebo arm experienced a modest increase in insulin resistance at week 24 (P < .001). While increases in total and high-density lipoprotein cholesterol were significant in both arms at weeks 24 and 48, increases in low-density lipoprotein cholesterol at week 24 were only identified in the placebo arm (P = .011). Body mass index remained stable, whereas modest increases in waist circumference were observed in the placebo arm. Metabolic syndrome was present in 19 participants (12%) at baseline and 20 participants (14%) at week 48, without differences between arms. Conclusions: Vit D/Cal supplementation over 48 weeks did not alter the lipid profile or glucose metabolism experienced with initiation of EFV/FTC/TDF in ART-naive persons. Vitamin D supplementation is unlikely to be an effective strategy to attenuate metabolic dysregulations with ART initiation. PMID- 29255725 TI - Outpatient Macrolide Antibiotic Prescribing in the United States, 2008-2011. AB - National Ambulatory Medical Care Survey data were used to assess outpatient macrolide prescribing and selection. Conditions for which macrolides are firstline therapy represented 5% of macrolide prescribing. Family practitioners selected macrolides for children more frequently than pediatricians. Macrolides are an important antibiotic stewardship target. PMID- 29255726 TI - The Impact of Human Pegivirus on CD4 Cell Count in HIV-Positive Persons in Botswana. AB - Background: Human pegiviruses (HPgV)-formerly known as hepatitis G virus or GB virus C (GBV-C)-are common single-stranded RNA viruses that may have a beneficial impact on slowing HIV disease progression. The data on HPgV in resource-limited regions such as Sub-Saharan Africa are scarce. Thus, we conducted the first study of HPgV in Botswana as part of a natural history study of HIV subtype C disease progression. Methods: Plasma samples from 133 HIV-positive adults were evaluated for HPgV RNA, and the 5'UTR was sequenced to determine the HPgV genotype. Results: HPgV RNA was detected in 41 (30.8%) individuals. While the presence of HPgV RNA had no impact on baseline HIV viral load, a significant difference in baseline CD4 cell count was observed. HPgV genotypes were determined for 27 individuals and included 5 individuals (18.5%) with genotype 1 and 22 (81.5%) with genotype 5. Baseline CD4 cell counts were significantly higher for persons infected with HPgV genotype 5 compared with genotype 1. Conclusions: These data suggest that HPgV infection is common among HIV-positive individuals in Botswana and has a significant impact on CD4 cell count. This difference in CD4 cell count based on HPgV genotype suggests that HPgV genotype should be evaluated as a possible predictor of HIV disease progression and highlights the need for additional studies of this virus in resource-limited settings. PMID- 29255727 TI - Early Antimicrobial De-escalation and Stewardship in Adult Hematopoietic Stem Cell Transplantation Recipients: Retrospective Review. AB - Background: Antimicrobial stewardship in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients remains underutilized in North America. European guidelines advise de-escalation of broad-spectrum therapy after 72 hours in select patients with neutropenic fever of unknown origin. This is not commonplace in the United States, as current guidelines recommend broad-spectrum therapy until neutrophil engraftment. If de-escalating after at least 5 days of broad-spectrum therapy and defervescence in neutropenic allo-HSCT recipients does not predispose them to recurrent fever or infection, the practice could afford several benefits. Methods: The primary end point was rate of recurrent fever. Secondary outcomes included Clostridium difficile-associated infections, length of stay, intensive care unit (ICU) admission incidence, in-hospital mortality rate, need for re-escalation of therapy, rate of positive blood cultures for patients who had recurrent fevers, overall antimicrobial utilization from neutropenic fever onset, and pharmacoeconomic impact. Results: A total of 120 patients were assessed in 2 groups as cohort 1 (n = 46), which received early de escalation, and cohort 2 (n = 74), which did not. The primary end point met criteria for noninferiority, as 7 patients (15%) in cohort 1 had recurrent fever within the specified time frame compared with 14 (19%) in cohort 2 (90% CI, 0.0878 to 0.1629, P = .026). Patients in cohort 1 received significantly less gram-positive broad-spectrum antimicrobials, with trends toward lower use of broad-spectrum gram-negative agents and lower associated costs and no differences in length of stay, ICU admission incidence, need for re-escalation of therapy, rate of culture-positive bacteremia after de-escalation or discontinuation of broad-spectrum therapy, or in-hospital mortality rate. Conclusions: De-escalating after at least 5 days of broad-spectrum therapy and defervescence did not appear to affect the rate of recurrent fever. This allowed for significant reductions in gram-positive broad-spectrum antimicrobial utilization, with trends toward lower use of broad-spectrum gram-negative agents and associated costs and no difference in clinical outcomes compared with those continuing such therapy until neutrophil engraftment. PMID- 29255728 TI - Fatal Puumala Hantavirus Disease: Involvement of Complement Activation and Vascular Leakage in the Pathobiology. AB - The case-fatality rate of hantavirus disease depends strongly on the causative hantavirus, ranging from 0.1% to 40%. However, the pathogenesis is not fully understood, and at present no licensed therapies exist. We describe fatal cases caused by Puumala hantavirus indicating involvement of complement activation and vascular leakage. PMID- 29255729 TI - Emergence of Resistance Mutations in Salmonella enterica Serovar Typhi Against Fluoroquinolones. AB - Background: Little is known about the evolutionary process and emergence time of resistance mutations to fluoroquinolone in Salmonella enterica serovar Typhi. Methods: We analyzed S. Typhi isolates collected from returned travelers between 2001 and 2016. Based on ciprofloxacin susceptibility, isolates were categorized as highly resistant (minimum inhibitory concentration [MIC] >= 4 MUg/mL [CIPHR]), resistant (MIC = 1-2 MUg/mL [CIPR]), intermediate susceptible (MIC = 0.12-0.5 MUg/mL [CIPI]), and susceptible (MIC <= 0.06 MUg/mL [CIPS]). Results: A total of 107 isolates (33 CIPHR, 14 CIPR, 30 CIPI, and 30 CIPS) were analyzed by whole genome sequencing; 2461 single nucleotide polymorphisms (SNPs) were identified. CIPS had no mutations in the gyrA or parC genes, while each CIPI had 1 of 3 single mutations in gyrA (encoding Ser83Phe [63.3%], Ser83Tyr [33.3%], or Asp87Asn [3.3%]). CIPHR had the same 3 mutations: 2 SNPs in gyrA (encoding Ser83Phe and Asp87Asn) and a third in parC (encoding Ser80Ile). CIPHR shared a common ancestor with CIPR and CIPI isolates harboring a single mutation in gyrA encoding Ser83Phe, suggesting that CIPHR emerged 16 to 23 years ago. Conclusions: Three SNPs-2 in gyrA and 1 in parC-are present in S. Typhi strains highly resistant to fluoroquinolone, which were found to have evolved in 1993-2000, approximately 10 years after the beginning of the ciprofloxacin era. Highly resistant strains with survival advantages arose from strains harboring a single mutation in gyrA encoding Ser83Phe. Judicious use of fluoroquinolones is warranted to prevent acceleration of such resistance mechanisms in the future. PMID- 29255730 TI - Sulfamethoxazole-Trimethoprim (Cotrimoxazole) for Skin and Soft Tissue Infections Including Impetigo, Cellulitis, and Abscess. AB - Skin and soft tissue infections (SSTI) affect millions of people globally, which represents a significant burden on ambulatory care and hospital settings. The role of sulfamethoxazole-trimethoprim (SXT) in SSTI treatment, particularly when group A Streptococcus (GAS) is involved, is controversial. We conducted a systematic review of clinical trials and observational studies that address the utility of SXT for SSTI treatment, caused by either GAS or Staphylococcus aureus, including methicillin-resistant (MRSA). We identified 196 studies, and 15 underwent full text review by 2 reviewers. Observational studies, which mainly focused on SSTI due to S aureus, supported the use of SXT when compared with clindamycin or beta-lactams. Of 10 randomized controlled trials, 8 demonstrated the efficacy of SXT for SSTI treatment including conditions involving GAS. These findings support SXT use for treatment of impetigo and purulent cellulitis (without an additional beta-lactam agent) and abscess and wound infection. For nonpurulent cellulitis, beta-lactams remain the treatment of choice. PMID- 29255732 TI - A Propensity-Matched Analysis Between Standard Versus Tapered Oral Vancomycin Courses for the Management of Recurrent Clostridium difficile Infection. AB - Background: This study was conducted to compare clinical outcomes of oral vancomycin courses without taper versus oral vancomycin courses with taper for treatment of recurrent Clostridium difficile infection (CDI). Methods: This investigation was a multicenter, retrospective, propensity score-matched analysis study using a Veterans Health Administration national clinical administrative database. Adult patients who were treated for recurrent CDI from any Veterans Affairs Medical Center between June 1, 2011 and October 31, 2016 were included if they were treated with oral vancomycin with or without a tapering regimen. The 2 groups were matched by next-nearest approach from a propensity score formula derived from independent variables associated with the selection of a taper regimen. Results: Propensity score matching resulted in 2 well-matched groups consisting of 226 episodes of patients treated with a vancomycin taper regimen and 678 episodes treated by vancomycin regimen without taper. No difference was found for the primary outcome of 180-day recurrence (59 of 226 [26.1%] for taper regimens versus 161 of 678 [23.8%], P = .48). A secondary outcome of 90-day all cause mortality met statistical significance, favoring a taper regimen (5.31% vs 9.29%, P = .049); however, secondary outcomes of 90-day recurrence and 180-day all-cause mortality were not different. Conclusions: Vancomycin taper regimens did not provide benefit over vancomycin regimens without taper in preventing additional CDI recurrence in patients with first or second recurrent episodes in this propensity score-matched analysis. PMID- 29255733 TI - Human Brucellosis in Rural Uganda: Clinical Manifestations, Diagnosis, and Comorbidities at Kabale Regional Referral Hospital, Kabale, Uganda. AB - Background: Brucellosis is a zoonotic infection transmitted to humans through direct contact with infected animals, their products, or excreta such as urine or dung. Brucellosis is associated with significant morbidity in Southwestern Uganda, where cattle and goat rearing are a major economic industry. As in many settings in sub-Saharan Africa, diagnosis and management of brucellosis remain a challenge due to the presence of comorbidities and limitations in resources for diagnostic testing and therapy. Methods: A chart review was conducted to characterize the clinical manifestations, diagnosis, comorbidities, and management of 101 patients treated for brucellosis at the Kabale Regional Referral Hospital from September 2002 to May 2010. Results: Patients presented with substantial comorbidities. The most common manifestation of illness was osteoarticular, but disease manifestations were quite varied. A high rate of focal illness in this cohort (77%) was observed. Conclusions: Clinicians in this setting should be cognizant of the varied presentations, comorbidities, and treatment options for this disease. PMID- 29255731 TI - Implication of First-Line Antiretroviral Therapy Choice on Second-Line Options. AB - Background: Although there are a number of studies comparing the currently recommended preferred and alternative first-line (1L) antiretroviral therapy (ART) regimens on clinical outcomes, there are limited data examining the impact of 1L regimen choice and duration of virologic failure (VF) on accumulation of drug resistance mutations (DRM). The patterns of DRM from patients failing zidovudine (AZT)-containing versus tenofovir (TDF)-containing ART were assessed to evaluate the predicted susceptibility to second-line (2L) nucleoside reverse transcriptase inhibitor (NRTI) backbone options in the context of an ongoing programmatic setting that uses viral load (VL) monitoring. Methods: Paired samples from Nigerian ART patients who experienced VF and switched to 2L ART were retrospectively identified. For each sample, the human immunodeficiency virus (HIV)-1 polymerase gene was sequenced at 2 time points, and DRM was analyzed using Stanford University's HIVdb program. Results: Sequences were generated for 191 patients. At time of 2L switch, 28.2% of patients on AZT-containing regimens developed resistance to TDF, whereas only 6.8% of patients on TDF-containing 1L had mutations compromising susceptibility to AZT. In a stratified evaluation, patients with 0-6 months between tested VL samples had no difference in proportion compromised to 2L, whereas those with >6 months between samples had a statistically significant difference in proportion with compromised 2L NRTI. In multivariate analyses, patients on 1L AZT had 9.90 times higher odds of having a compromised 2L NRTI option than patients on 1L TDF. Conclusions: In the context of constrained resources, where VL monitoring is limited, we present further evidence to support use of TDF as the preferred 1L NRTI because it allows for preservation of the recommended 2L NRTI option. PMID- 29255734 TI - Rapid Influenza Testing in an Austere Setting, Mongolia. AB - In 2015-2017, we helped rural Mongolian clinicians with poor infrastructure adopt rapid influenza diagnostic tests (RIDTs). In their hands, the Quidel Sofia Influenza A Test was both sensitive (75%) and specific (100%). If made widely available, such RIDTs would have the potential to markedly reduce influenza morbidity and mortality in Mongolia. PMID- 29255736 TI - Gram-Positive Rods on a Cerebrospinal Fluid Gram Stain. AB - Cerebrospinal fluid (CSF) access device placement in the pediatric population presents challenges due to the development of infections following placement, access or revision, and/or shunt malfunctions. Here we report an unusual pediatric case of L. monocytogenes ventriculitis/VP shunt (VPS) infection and associated pseudocyst with an emphasis on the importance of VPS removal in clearing the infection due to biofilm formation. PMID- 29255735 TI - Weight Gain: A Possible Side Effect of All Antiretrovirals. AB - Weight gain and body mass index (BMI) increase are central issues in patients living with HIV who need to minimize the risk of metabolic disease. Information collected through the SCOLTA cohort revealed significant 1-year BMI increase in patients treated with dolutegravir (P = .004), raltegravir (P = .0004), elvitegravir (P = .004), darunavir (P = .0006), and rilpivirine (P = .029). BMI gain correlated with low baseline BMI (P = .002) and older age (P = .0007) in Centers for Disease Control and Prevention stages A/B, with lower BMI (P = .005) and CD4+ T-cell count (P = .007) at enrollment in stage C. PMID- 29255737 TI - Diagnostic Importance of Hyphae on Heart Valve Tissue in Histoplasma Endocarditis and Treatment With Isavuconazole. AB - A patient who never resided in an endemic area for dimorphic fungi was diagnosed with Histoplasma capsulatum endocarditis. His diagnosis was suggested by yeast and hyphae on cardiac valve tissue pathology. Isavuconazole was an optimal therapeutic option due to renal dysfunction and anticoagulation with warfarin for mechanical valve replacement. PMID- 29255738 TI - Pitfalls Associated With the Use of Molecular Diagnostic Panels in the Diagnosis of Cryptococcal Meningitis. AB - We report the case of a kidney transplantation patient on chronic immunosuppressive therapy presenting with subacute meningitis. The final diagnosis of cryptococcal meningitis was delayed due to 2 false-negative cryptococcal results on a molecular diagnostic panel. Caution with such platforms in suspected cryptococcal meningitis is needed. PMID- 29255739 TI - Extended Screening Costs Associated With Selecting Donors for Fecal Microbiota Transplantation for Treatment of Metabolic Syndrome-Associated Diseases. AB - Background: Knowledge of the impact of the gut microbiome on conditions other than Clostridium difficile infection has been rapidly increasing, and the potential usefulness of fecal microbiota transplantation (FMT) in these indications is being explored. The need to exclude donors with an increased risk of these diseases has left uncertainties regarding the cost and feasibility of donor screening. The aim of this study was to compare our experience to other donor-screening programs and report the costs associated with establishing a donor-screening program, for the treatment of metabolic syndrome-related conditions. Methods: Forty-six potential donors (PDs) had their medical histories and physical examinations undertaken by a physician. Blood, stool, and urine were screened for 31 viral, bacterial, fungal, and protozoan agents in addition to biochemical characteristics. The price of advertising, doctor's visits and diagnostic tests were calculated to determine the cost of finding a donor. Results: Of the PDs screened, 5 of 46 passed the history, examination, blood, stool, and urine tests. The most common reasons for exclusion included a body mass index >25 or the detection of Blastocystis hominis, Dientamoeba fragilis, or Helicobacter pylori. Four of five eligible donors had subsequent travel or illness that contraindicated donation, so only 1 of 46 PDs was suitable. The total cost for finding a single suitable donor was $15190 US dollars. This screening was performed in Canada, and costs in the United States would be substantially higher. Conclusions: New potential therapeutic uses for FMT have created a demand for stricter exclusion criteria for donors. This study illustrates that screening many individuals to find a donor and the subsequent associated costs may make central processing and shipment a more reasonable alternative. PMID- 29255740 TI - A Robust System for Production of Superabundant VP1 Recombinant AAV Vectors. AB - Recombinant adeno-associated viral (rAAV) vectors have been widely used in human gene therapy. One major impediment to its broad application is the inability to produce high-quality vectors in mass quantity. Here, an efficient and scalable suspension cell culture system for the production of rAAV vectors is described. In this system, the AAV trans factors, Rep78, Rep52, VP1, VP2, and VP3, were stably integrated into a single vaccinia virus carrier by maximizing the use of alternative codons between genes with identical amino acids, and the cis rAAV genome was carried by an E1/E3 gene-deleted adenovirus. Infection of improved, E1 integrated, suspension-cultured cells with these two viral vectors resulted in the robust production of rAAV vectors. The newly enhanced system can consistently produce ~1 * 1015 genome containing rAAV vectors per liter of suspension cells. Moreover, the capsid composition of rAAV vectors produced by this system is markedly different from those produced using the traditional system in that the VP1 protein is more abundant than the VP2 protein (19:1 versus 1:1). The unique VP1 superabundant rAAV vectors produced in this new system exhibited improved transduction in vivo after intravitreal injection. PMID- 29255742 TI - Engineering PTEN-L for Cell-Mediated Delivery. AB - The tumor suppressor PTEN is frequently inactivated in glioblastoma. PTEN-L is a long form of PTEN produced by translation from an alternate upstream start codon. Unlike PTEN, PTEN-L has a signal sequence and a tract of six arginine residues that allow PTEN-L to be secreted from cells and be taken up by neighboring cells. This suggests that PTEN-L could be used as a therapeutic to restore PTEN activity. However, effective delivery of therapeutic proteins to treat CNS cancers such as glioblastoma is challenging. One method under evaluation is cell mediated therapy, where cells with tumor-homing abilities such as neural stem cells are genetically modified to express a therapeutic protein. Here, we have developed a version of PTEN-L that is engineered for enhanced cell-mediated delivery. This was accomplished by replacement of the native leader sequence of PTEN-L with a leader sequence from human light-chain immunoglobulin G (IgG). This version of PTEN-L showed increased secretion and an increased ability to transfer to neighboring cells. Neural stem cells derived from human fibroblasts could be modified to express this version of PTEN-L and were able to deliver catalytically active light-chain leader PTEN-L (lclPTEN-L) to neighboring glioblastoma cells. PMID- 29255741 TI - A Combined In Vivo HSC Transduction/Selection Approach Results in Efficient and Stable Gene Expression in Peripheral Blood Cells in Mice. AB - We recently reported on an in vivo hematopoietic stem cell (HSC) gene therapy approach. It involves the subcutaneous injections of G-CSF/AMD3100 to mobilize HSCs from the bone marrow into the peripheral blood stream and the intravenous injection of an integrating helper-dependent adenovirus vector system. HSCs transduced in the periphery homed back to the bone marrow, where they persisted long-term. However, high transgene marking rates found in primitive bone marrow HSCs were not reflected in peripheral blood cells. Here, we tested small-molecule drugs to achieve selective mobilization and transduction of HSCs. We found more efficient GFP marking in bone marrow HSCs but no increased marking in the peripheral blood cells. We then used an in vivo HSC chemo-selection based on a mutant of the O6-methylguanine-DNA methyltransferase (mgmtP140K) gene that confers resistance to O6-BG/BCNU and should give stably transduced HSCs a proliferation stimulus and allow for the selective survival and expansion of progeny cells. Short-term exposure of G-CSF/AMD3100-mobilized, in vivo-transduced mice to relatively low selection drug doses resulted in stable GFP expression in up to 80% of peripheral blood cells. Overall, the further improvement of our in vivo HSC transduction approach creates the basis for a simpler HSC gene therapy. PMID- 29255743 TI - Infliximab-Induced Lupus: A Case Report. AB - We report the case of a 48-year-old, leukodermic female diagnosed with ulcerative proctitis for 4 years and latent tuberculosis. She was allergic to salicylates and had a minor allergic reaction to infliximab (rash, vertigo, and headache). Thereafter, she started azathioprine (2.5 mg/kg/day). She maintained intravenous infliximab, together with prophylaxis with clemastine and hydrocortisone, due to the steroid-dependent proctitis. The therapy was continued every 8 weeks with anti-tumor necrosis factor for about 3 years. The analytical evaluation when she was diagnosed with ulcerative proctitis (February 2011) showed negative antinuclear antibodies (ANA), double-stranded-DNA antibodies (anti-dsDNA), antineutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibodies, and a positive outer membrane protein antibody. About 2 years and 6 months after starting infliximab (November 2013), the patient complained of inflammatory symmetrical polyarthralgia (knee, shoulder, elbow, and wrist) without synovitis, which started every week before the administration of infliximab. Resolution of symptoms was observed after each infliximab infusion. In July 2014, the autoantibody re-evaluation showed positive ANA with a homogeneous pattern with a titer of 1:640, weak positive anti-dsDNA (30.2), and positive anti-histone with C3 decreased (80.3). She was then diagnosed with lupus induced by infliximab and initiated hydroxychloroquine 400 mg. Infliximab was suspended. On re-evaluation, the erythrocyte sedimentation rate was 25 mm/h (1st hour), C-reactive protein 0.5 mg/dL (previously erythrocyte sedimentation rate 15 mm/h and C-reactive protein 1.2 mg/dL), and endoscopically, the mucosa was scarred, with some atrophy and scarce mucus in the lower rectum. About 10 months after discontinuation of infliximab, repeated autoantibodies proved all negative, keeping only low C3 (87). The patient also reported complete resolution of the arthralgia. PMID- 29255744 TI - Controlled Attenuation Parameter as a Noninvasive Method to Detect and Quantify Hepatic Steatosis in Chronic Liver Disease: What Is the Clinical Relevance? PMID- 29255746 TI - Treatment of Postoperative Leaks of the Upper Gastrointestinal Tract with Colonic Self-Expandable Metal Stents. AB - Introduction: The use of self-expandable metal stents (SEMS) for the treatment of postoperative leaks of the upper gastrointestinal tract is already established. However, there are discrepancies between the relatively small caliber of the esophageal stents available and the postsurgical luminal size, which may determine an inadequate juxtaposition. As colonic stents have a bigger diameter, they might be more adequate. Additionally, stents with a larger diameter might have a lower risk of migration. Materials and Methods: The aim of this study was to evaluate the efficacy and complications associated with the use of colonic fully covered SEMS (FSEMS) in the treatment of postoperative leaks in critical patients. All patients with postoperative leaks of the upper gastrointestinal tract treated with colonic stents (Hanarostent(r) CCI) between 2010 and 2013 were retrospectively included. Results: Four patients with postoperative leaks were treated with colonic SEMS. The underlying surgeries were a gastric bypass, an esophagogastrectomy for Boerhaave syndrome, a primary repair of esophagopleural fistula due to Boerhaave syndrome, and an esophagectomy due to esophageal cancer. The leaks were detected on average 17 days after the initial surgery. All patients needed admission to a critical care unit after index surgery. Stent placement was technically feasible in all patients. The median residence time of the stents was 7 weeks, and no complications were verified when they were removed. There were no cases of stent migration. The treatment was successful in all patients, with complete healing of the leaks. Discussion and Conclusions: The placement of colonic FSEMS seems to be successful and safe in the treatment of postoperative leaks of the upper gastrointestinal tract. PMID- 29255745 TI - Diagnostic Accuracy of Controlled Attenuation Parameter for Detecting Hepatic Steatosis in Patients with Chronic Liver Disease. AB - Introduction: Controlled attenuation parameter (CAP), measured by transient elastography, has been suggested as a noninvasive method for the detection and quantification of steatosis. We aimed to assess the accuracy of CAP to detect steatosis in patients with chronic liver disease (CLD) compared with liver histology and to evaluate factors that correlate with the CAP value. Methods: Patients with CLD who underwent liver biopsy and simultaneous CAP determination were consecutively enrolled. CAP was measured using the M probe of FibroScan(r) (Echosens, Paris, France). Histologically, steatosis was categorized as absent (S0: <5%), mild (S1: 5-33%), moderate (S2: 34-66%) and severe (S3: >66% of all hepatocytes). Results: We analyzed 159 patients with CLD (61% men, mean age 47.9 +/- 12.9 years). We found a positive correlation between CAP and steatosis in histology (rs = 0.869, p < 0.001), arterial hypertension (rs = 0.222, p = 0.005), type 2 diabetes mellitus (rs = 0.279, p < 0.001), body mass index (BMI; rs = 0.533, p < 0.001), total cholesterol (rs = 0.442, p < 0.001), triglycerides (rs = 0.272, p = 0.001), and non-alcoholic fatty liver disease (NAFLD; rs = 0.588, p < 0.001). In the multivariate analysis, BMI >25 (odds ratio [OR] 48.4, 95% confidence interval [CI] 23.78-72.95, p < 0.001), serum total cholesterol (OR 3.803, 95% CI 2.203-13.889, p = 0.008), and NAFLD etiology (OR 40.8, 95% CI 15.01 66.66, p = 0.002) were independently associated with higher CAP values. We did not find any significant correlation between CAP and the grade of necroinflammatory activity (rs = 0.063, p = 0.808) or fibrosis (rs = 0.071, p = 0.713) in histology and with alanine aminotransferase (rs = 0.190, p = 0.356) or aspartate aminotransferase (rs = 0.117, p = 0.142). Optimal CAP cutoff values for detecting steatosis >=S1, >=S2, and >=S3 were 206.5, 232.5, and 282.5 dB/m, respectively. CAP performance was 0.822, 0.956, and 0.976 for diagnosing steatosis >=S1, >=S2, and >=S3, respectively. Conclusions: CAP had an excellent diagnostic accuracy for the detection of steatosis in diverse CLD patients. A CAP value cutoff of <282.5 dB/m excludes severe steatosis >=S3 with an accuracy of 98%. PMID- 29255747 TI - Endoscopic Treatment for Gastric Antral Vascular Ectasia: Current Options. AB - Gastric antral vascular ectasia (GAVE) is a capillary-type vascular malformation located primarily in the gastric antrum. Patients can present with iron deficiency anemia, overt gastrointestinal bleeding, or both. Diagnosis and characterization is made at endoscopic examination, and the preferred management of patients with GAVE is endoscopic therapy. Herein, we present a review of the evidence about the efficacy, complications, and outcomes of the most frequently used endoscopic therapies for GAVE. PMID- 29255748 TI - Intestinal Obstruction by Giant Meckel's Diverticulum. AB - Background: Meckel's diverticulum is the most common congenital anomaly of the small bowel and is caused by the incomplete obliteration of the omphalomesenteric duct during the eighth week of gestation. Methods: We report the case of a 51 year-old male who presented to the emergency department with epigastric pain, vomiting, and abdominal distension. Clinically, he had a high intestinal obstruction without any mechanical cause on computed tomography scan. A median laparotomy was proposed. Results: An internal ileum hernia was identified twisted around a giant Meckel's diverticulum with a mesodiverticular artery, coursing from the base of the mesentery to the diverticulum. A small bowel segmental resection was performed, containing the diverticulum. Histology revealed a 15-cm long Meckel's diverticulum with no heterotopic mucosa. Conclusion: Small bowel obstruction due to an internal ileum hernia twisted around a giant Meckel's diverticulum with a mesodiverticular artery is very rare, and its diagnosis is challenging, requires a high level of suspicion, and it is only performed by exploratory surgery. PMID- 29255749 TI - Splenic Rupture as a Complication of Colonoscopy. AB - Splenic rupture is a rare but serious complication after colonoscopy, with high global mortality (5%). Diagnosis requires a high index of suspicion because presentation can be subtle, nonspecific, and delayed from hours to days and then not easily attributed to a recent endoscopy. Urgent splenectomy is the most common treatment option. A 73-year-old woman was admitted to the emergency department 8 h following a diagnostic colonoscopy. She presented abdominal pain and syncope. The diagnosis of splenic rupture was made and a splenectomy was urgently performed. The patient's postoperative recovery was uneventful. Splenic rupture is a rare complication of colonoscopy which cannot be underestimated in the differential diagnosis of abdominal pain after this procedure. Splenic injuries may occur in apparently uncomplicated, easy colonoscopies performed by experienced endoscopists, with no risk factors identified, as in this case. PMID- 29255750 TI - Mediastinal Mass in a Patient with Colorectal Cancer: A Diagnostic Challenge. AB - The differential diagnosis of mediastinal masses involves many benign and malignant conditions, such as lymphadenopathies and cystic lesions. Metastatic mediastinal adenopathies are usually due to lung, esophagus, and stomach cancer and, rarely, due to colorectal cancer. Gastrointestinal duplication cysts are uncommon inherited lesions usually diagnosed during childhood and may involve the esophagus in 20% of cases. In adults, they are usually asymptomatic and diagnosed incidentally. We report the case of a 54-year-old male who recently underwent sigmoidectomy due to an obstructive colon adenocarcinoma. Staging computed tomography scan showed a hypodense lesion in the posterior mediastinum suggestive of metastatic adenopathy. Endoscopic ultrasound revealed a homogeneous and hypoechogenic lesion with intramural location in the upper esophagus, suggestive of a duplication esophageal cyst. Given the oncologic background and to exclude metastatic disease, endoscopic ultrasound-guided fine needle aspiration was performed, and a mucinous fluid was aspirated. The cytologic examination supported the ultrasonographic diagnostic hypothesis. This case highlights the role of endoscopic ultrasound in the differential diagnosis of mediastinal masses, particularly in oncologic patients, in order to rule out more ominous lesions. PMID- 29255751 TI - Gastric Adenomyoma: The Unexpected Mimicker. AB - Gastric adenomyoma is a rare benign tumor composed of epithelial structures and smooth muscle stroma. Here, we report an unusual case of gastric adenomyoma mostly composed of smooth muscle that was incidentally found during a laparoscopic intervention. On radiology, it mimicked an acquired hypertrophic pyloric stenosis in an adult patient, and pathologically it resembled a pure smooth muscle hamartoma. Complete submission of the lesion for histology was necessary to find the epithelial component and make the right diagnosis. As a mimicker of benign and malignant entities, gastric adenomyoma is usually an unexpected finding after surgery. The aim of this report is to analyze this adenomyoma variant in the setting of an unexplained thickening of the gastric wall, with explanations concerning histogenesis and biological potential. PMID- 29255752 TI - Jejunal Stent-in-Stent for Recurrent Malignant Occlusion Using Single-Balloon Enteroscopy. PMID- 29255753 TI - Eosinophilic Ascites: Uncommon Presentation of Eosinophilic Gastroenteritis in a Young Adult Male. PMID- 29255754 TI - Quality in Endoscopy: It's Time for an Audit! PMID- 29255755 TI - Quality in Colonoscopy: Beyond the Adenoma Detection Rate Fever. AB - Background: Colonoscopy quality is a hot topic in gastroenterological communities, with several actual guidelines focusing on this aspect. Although the adenoma detection rate (ADR) is the single most important indicator, several other metrics are described and need reporting. Electronic medical reports are essential for the audit of quality indicators; nevertheless, they have proved not to be faultless. Aim: The aim of this study was to analyse and audit quality indicators (apart from ADR) using only our internal electronic endoscopy records as a starting point for improvement. Methods: An analysis of electronically recorded information of 8,851 total colonoscopies from a single tertiary centre from 2010 to 2015 was performed. Results: The mean patient age was 63.4 +/- 8.5 years; 45.5% of them were female, and in 14.6% sedation was used. Photographic documentation was done in 98.4% with 10.7 photographs on average, and 37.4% reports had <8 pictures per exam. Bowel preparation was rated as adequate in 67%, fair in 27% and inadequate in 4.9% of cases. The adjusted caecal intubation rate (CIR) was 92%, while negative predictors were inadequate preparation (OR 119, 95% CI 84-170), no sedation (OR 2.39, 95% CI 1.81-3.15), female gender (OR 1.61, 95% CI 1.38-1.88) and age >=65 years (OR 1.56, 95% CI 1.34-1.82). In 28% of patients, a snare polypectomy was performed, correlating with adequate preparation (OR 5.75, 95% CI 3.90-8.48), male gender (OR 1.82, 95% CI 1.64-2.01) and age >=65 years (OR 1.25, 95% CI 1.13-1.37; p < 0.01) as positive predictors. An annual evolution was observed with improvements in photographic documentation (10.7 vs. 12.9; p < 0.001), CIR (91 vs. 94%; p = 0.002) and "adequate" bowel preparation (p = 0.004). Conclusions: There is much more to report than the ADR to ensure quality in colonoscopy practice. Better registry systematization and integrated software should be goals to achieve in the short term. PMID- 29255756 TI - Clinical and Endoscopic Features of Gastrointestinal Kaposi Sarcoma: A Single Center Portuguese Experience over the Last Decade. AB - Background: Kaposi sarcoma (KS) is an angioproliferative tumor caused by human herpesvirus 8 (HHV-8). Gastrointestinal (GI) involvement by KS is a rare endoscopic finding, scarcely characterized in the literature. Objective: To characterize clinical and endoscopic features of patients with GI KS. Methods: This is a single-center retrospective study of GI KS cases confirmed by immunohistochemistry in the last decade (2006-2015). The following variables were analyzed: demographic data; clinical data (extraintestinal involvement, symptoms, presence and stage of HIV infection, immunosuppressive therapy); endoscopic data; stage-stratified therapeutic approach; and mortality (at 3 and 6 months). Results: Thirteen patients with GI KS were identified: 77% were men, the mean age was 55 years, and 62% of them were Native Africans. In most cases (n = 10, 77%), KS was associated with HIV. A total of 90% of the HIV patients had a CD4+ count of <200/MUL (C3, CDC classification), and 80% of them had KS as the initial manifestation of HIV infection. Thirty percent of the cases had other AIDS defining illnesses, and only 20% received antiretroviral therapy. In the remaining 3 patients (23%), KS was associated with immunosuppressive therapy. Most patients (85%) had cutaneous lesions and 15% lung involvement. In most cases (85%), the lesions were diagnosed in the upper digestive tract in asymptomatic patients (7 stomach; 2 stomach and duodenum; 2 esophagus). Colonic involvement occurred in 2 patients presenting with hematochezia. Nearly half of the patients had more than 3 endoscopic lesions and the most frequent morphologic type was polypoid/nodular (62%). Treatment was based on antiretroviral therapy or reduction of immunosuppression and in 39% of the patients on administration of doxorubicin. Survival at 3 and 6 months was 46 and 39%, respectively. Conclusion: GI KS is mostly found in nontreated, stage 3, HIV patients, and particularly in men from areas where HHV-8 is endemic. Involvement of the upper digestive tract is often asymptomatic. The endoscopic appearance is variable and these patients have a poor prognosis. PMID- 29255757 TI - A Case Series of Anal Carcinoma Misdiagnosed as Idiopathic Chronic Anal Fissure. AB - Chronic anal fissure is a linear ulcer in the anal canal that has not cicatrized for more than 8-12 weeks of treatment. Most anal fissures are idiopathic and are located in the posterior midline. Squamous cell carcinoma of the anus commonly presents as bleeding and anal pain. It may also present as a mass, nonhealing ulcer, itching, discharge, fecal incontinence and fistulae. Not uncommonly, small and early cancers are misdiagnosed as benign anorectal disorders like anal fissures or hemorrhoids. The clinical suspicion of squamous cell carcinoma of the anus is of paramount importance in patients with nonhealing anal fissures, fissures in atypical positions or with indurated or ulcerated anal tags and in patients with risk factors for the development of anal squamous intraepithelial lesions that are precursors of invasive anal squamous cell carcinoma. The authors present 3 cases of squamous cell carcinoma of the anus initially misdiagnosed as benign chronic anal fissure. PMID- 29255758 TI - Endoscopic Management of Colonic Perforation due to Ventriculoperitoneal Shunt: Case Report and Literature Review. AB - The authors report the case of a 41-year-old woman with a colonic perforation due to a ventriculoperitoneal shunt (VPS) catheter. Left-sided colonic perforation was diagnosed by abdominal computed tomography 28 years after shunt placement, following acute meningitis caused by Escherichia coli. The proximal end of the VPS was exteriorized and it was decided to remove the distal end by colonoscopy. After pulling out the catheter with a polypectomy snare, it broke at the site where it was entering the colon, leaving a small perforation in the colonic wall which was closed with 2 endoclips. The endoluminal fragment of the catheter, being 20 cm in length, was removed through the rectum. The patient is asymptomatic at the 12-month follow-up. A review of the literature regarding 9 endoscopically managed cases of digestive tract perforation caused by VPS is presented. PMID- 29255759 TI - Uncommon Solid Pancreatic Neoplasm: The Role of New Modalities of Ultrasound Endoscopy. AB - Undifferentiated carcinoma with osteoclast-like cells is a rare pancreatic neoplasm with unique ultrasound endoscopic features. A 59-year-old female presented with a 3-month history of weight loss. Abdominal computed tomography and endoscopic ultrasound showed a large pancreatic tumor with a heterogeneous echotexture and liver metastasis. Endoscopic ultrasound fine needle aspiration was used to establish the diagnosis. In this case report, we review the endoscopic, clinical, and pathological features of this type of tumor and describe for the first time the endoscopic features of real-time elastography and contrast enhancement. Real-time elastography revealed a heterogeneous predominantly blue pattern suggestive of pancreatic malignancy, and the contrast enhanced endosonography showed a hypervascular mass and distinctive vascular (solid) and avascular (liquid/necrotic) components of the lesion, guiding the fine needle aspiration. PMID- 29255760 TI - Uncertainties in the Management of a Lynch Syndrome Patient: A Case Report. AB - Introduction: Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome, is characterized by mutations in mismatch repair (MMR) genes leading to an increased cancer risk, namely colorectal cancer. Case: In the context of surveillance colonoscopy, a 40-mm flat lesion (0-IIa+b, Paris classification) was identified and submitted to piecemeal mucosal endoscopic resection in a 64-year old LS patient with an MLH1 germline mutation (262delATC) and two previous segmental resections due to metachronous colorectal cancer. Pathology raised the suspicion of superficial submucosal invasive carcinoma with poor differentiation. Immunochemistry showed heterogeneous MLH1 expression and PMS2 loss. In a short term follow-up colonoscopy, another 30-mm advanced carcinoma was identified. The patient was referred to surgery. Conclusion: This case raises several issues: (1) the potentially fast tumorigenesis and progression to carcinoma in LS and implications for endoscopic screening and surveillance; (2) pitfalls in the interpretation of MMR proteins immunochemistry; (3) the role of endoscopic resection in LS. PMID- 29255761 TI - A Rare Cause of Dysphagia. PMID- 29255762 TI - Spontaneous Recurrent Pneumoperitoneum in Systemic Sclerosis. PMID- 29255763 TI - Elastography and Contrast-Enhanced Endoscopic Ultrasound Findings in a Pseudo Solid Variant of a Pancreatic Serous Cystadenoma. PMID- 29255764 TI - Underwater Endoscopic Mucosal Resection of a Large Flat Adenoma with Pseudoinvasion in the Rectum. PMID- 29255765 TI - Cytomegalovirus Disease of the Upper Gastrointestinal Tract: An Emerging Infection in Immunocompetent Hosts. PMID- 29255766 TI - Cytomegalovirus Disease of the Upper Gastrointestinal Tract: A 10-Year Retrospective Study. AB - Background and Aims: Cytomegalovirus (CMV) disease of the gastrointestinal (GI) tract is a major cause of morbidity and mortality in immunocompromised patients. The colon is the most commonly affected site, and the literature is scarce regarding CMV disease of the upper GI tract. Therefore, our study aimed to evaluate the clinical and endoscopic features of upper GI CMV disease. Methods: This 10-year retrospective study included all patients with a histopathological diagnosis of upper GI CMV infection. Patients' clinical, endoscopic, therapy, and follow-up data were collected from medical records. Results: Twelve patients with histopathologically proven upper GI CMV disease were identified (age 61 +/- 18 years, 50% men). Most of the patients were immunocompromised (75%) due to acquired immunodeficiency syndrome (AIDS), malignancy, and/or immunosuppressive therapy. In the remainder (25%), the disease occurred in the absence of immunodeficiency and immunosuppression. Three patients (all with AIDS) presented with disseminated CMV infection. In the majority of the cases (83%), upper GI CMV disease was symptomatic, and the most common clinical presentations were odynophagia/dysphagia (25%) and nausea/vomiting (25%). Endoscopically, there were 5 cases of esophagitis (42%) and 7 cases of gastritis (58%). The lower esophagus (33%) and the gastric antrum (42%) were the most frequently affected GI sites. Regardless of the location, mucosal ulceration was the most common endoscopic finding (75%) and was associated with very deep ulceration resembling cavitation in 2 cases. Other endoscopic features were mucosal edema, hyperemia, and nodularity (25%). Eleven patients (92%) received antiviral treatment (duration 26 +/- 12 days). The 1-month and 1-year mortality rates were 16.7 and 25%, respectively. Conclusions: Upper GI CMV disease can occur in the absence of immunodeficiency and immunosuppression. It is usually symptomatic, and mucosal ulceration is often evident at endoscopy. It is associated with significant mortality; therefore, early diagnosis and adequate antiviral treatment are essential. PMID- 29255767 TI - Image Documentation in Gastrointestinal Endoscopy: Review of Recommendations. AB - In recent years, endoscopic image documentation has gained an important role in gastrointestinal (GI) endoscopic reporting and has become an integral aspect of quality control. Since 2001, several important guidelines and statements, some from major endoscopic societies, have been published to standardize endoscopic image documentation. Therefore, and according to the most recent recommendations of the European Society of Gastrointestinal Endoscopy, we propose a set of images to be routinely captured in upper and lower GI endoscopy. Systematic acquisition of 10 and 9 photographs of specific landmarks is recommended in upper-GI endoscopy and colonoscopy, respectively. In addition to photo documentation of the normal endoscopic features, imaging of pathologic findings is also advocated. Considering accurate and adequate image documentation as an essential part of endoscopic reporting, it should be systematically performed in upper and lower GI endoscopy. PMID- 29255768 TI - Celiac Disease: What Do We Know in 2017? AB - Celiac disease is one of the most prevalent digestive conditions. Diagnosis requires that strict criteria are used so that a life-long gluten-free diet may be correctly prescribed. Although genetic susceptibility has been known for a long time, there have been elusive environmental factors that lead to the occurrence of clinical disease. Many studies have addressed the identification of environmental modifiers, and different lines of research have been tried with variable success and even contradictory results. Infections and age of gluten introduction into the diet in the first few months of life have been evaluated, but a firm relationship could not be established. A recent paper addresses a fascinating hypothesis that could explain how some infectious agents might modulate the immune system and modify response to dietary antigens. Subsequently, animal models with genetic susceptibility were tested, and, indeed, there was abnormal response to gluten. These observations still do not provide final answers about the pathophysiology of celiac disease but certainly lead to progress in the knowledge of gluten sensitization and the role of some environmental factors. PMID- 29255769 TI - Hodgkin's Lymphoma in Crohn's Disease Treated with Infliximab. AB - Introduction: Lymphoproliferative disorders, particularly non-Hodgkin's and Hodgkin's lymphomas, are rare in patients with inflammatory bowel diseases. The use of thiopurines and infection by Epstein-Barr virus are well-known cofactors that can raise its prevalence. Other risk factors such as disease activity and biological treatment are the subject of discussion, without enough data in the literature to confirm a potential association. Methods: We report a case of Hodgkin's lymphoma in a patient who had been treated with azathioprine and was on long-term monotherapy with infliximab. Conclusions: We stress the importance of recognizing the possible occurrence of a lymphoproliferative disorder in association with anti-tumor necrosis factor-alpha therapy. PMID- 29255770 TI - Perforated Gastric Ulcer Associated with Anti-Angiogenic Therapy. AB - Anti-angiogenic therapy with bevacizumab, an inhibitor of vascular endothelial growth factor, is commonly used in metastatic colorectal cancer and is rarely associated with gastrointestinal perforation, perforation being more frequent in the primary tumor site or at the anastomotic level. We present the case of a 64 year-old male with stage IV rectal adenocarcinoma who was on palliative chemotherapy with FOLFOX and bevacizumab. After the 4th chemotherapy cycle, our patient started fever and epigastric pain. He was hemodynamically stable, and signs of peritoneal irritation were absent. There were no alterations in the abdominal X-ray, and C-reactive protein was markedly elevated. A CT scan revealed a de novo thickness in the gastric antrum. Upper digestive endoscopy showed an ulcerated 40-mm lesion in the angulus, with a 20-mm orifice communicating with an exsudative cavity revested by the omentum. A conservative approach was decided including fasting, broad-spectrum intravenous antibiotics, and proton-pump inhibitors. Subsequent gastroduodenal series showed no contrast extravasation, allowing the resumption of oral nutrition. Esophagogastroduodenoscopy after 8 weeks showed perforation closure. Biopsies did not show neoplastic cells or Heliobacter pylori infection. Although the success in the conservative management of perforation allowing the maintenance of palliative chemotherapy (without bevacizumab), the patient died after 4 months due to liver failure. The reported case shows an uncommon endoscopic finding due to a rare complication of anti angiogenic therapy. Additionally, it reminds clinicians that a history of gastroduodenal ulcers should be actively sought before starting anti-angiogenic treatment and that suspicion for perforation should be high in these cases. PMID- 29255771 TI - Endoscopic Mucosectomy in a Child Presenting with Gastric Heterotopia of the Rectum. AB - Gastric mucosal heterotopia has been described in all levels of the gastrointestinal tract. Its occurrence in the rectum is uncommon. We report the case of a 4-year-old boy referred to Pediatric Gastroenterology for intermittent rectal bleeding for the past 2 years. Total ileocolonoscopy revealed a flat, well circumscribed lesion of 4 cm, with elevated margins, localized at 10 cm from the anal verge. Histologic examination showed typical gastric mucosa of the oxyntic type. Treatment with proton pump inhibitors was started without resolution of the symptoms and, therefore, an endoscopic mucosal resection was performed. Heterotopic gastric mucosa represents a rare cause of rectal bleeding in children and endoscopic evaluation is fundamental for diagnosis. Although not usually performed in pediatric ages, endoscopic mucosectomy allows complete resolution of the problem avoiding surgery. PMID- 29255772 TI - Adult Celiac Disease: The Importance of Extraintestinal Manifestations. AB - Celiac disease (CD) is a chronic immune-mediated enteropathy driven by gluten and affecting individuals of all ages. The diagnosis of CD in adulthood is emerging and patients often present with nonclassical extraintestinal manifestations. We report the case of a 53-year-old man presenting with neuromuscular symptoms, skin rash, inconspicuous chronic diarrhea, marked weight loss, and biochemical markers of malabsorption. A strong clinical suspicion led to the diagnosis of CD with clinical recovery after the initiation of a gluten-free diet. Clinical presentation with atypical symptoms in adult CD patients is the rule and not the exception. Most of the extraintestinal manifestations depend on background autoimmune phenomena and micronutrient malabsorption. A gluten-free diet re establishes homeostasis and prevents long-term complications. PMID- 29255774 TI - Hematidrosis, Hemolacria, and Gastrointestinal Bleeding. PMID- 29255773 TI - Type 2 Autoimmune Pancreatitis: A Challenge in the Differential Diagnosis of a Pancreatic Mass. AB - Introduction: Autoimmune pancreatitis is a rare entity of unknown etiology that can mimic pancreatic cancer and whose diagnosis involves clinical, serological, imagiological, and histological findings. There are two types of autoimmune pancreatitis: type 1, in which the pancreas is involved as one part of a systemic immunoglobulin G4-related disease, and type 2, generally without immunoglobulin G4-positive cells and without systemic involvement. Case: We report the case of a 45-year-old female, who underwent an abdominal magnetic resonance imaging for etiological study of a solid liver lesion, which revealed a tail pancreatic mass. Laboratory analyses showed normal levels of immunoglobulin G4 and negative antinuclear antibodies. Endoscopic ultrasound revealed a homogeneous and hypoechogenic lesion in the pancreatic tail with a "sausage-like" appearance. Endoscopic ultrasound-guided fine needle aspiration was inconclusive and the patient underwent a laparoscopic distal pancreatectomy. Histopathology examination confirmed the diagnosis of type 2 autoimmune pancreatitis. Conclusion: This case highlights the challenge in the diagnostic approach of a pancreatic mass, particularly in distinguishing benign from malignant disease. PMID- 29255775 TI - Percutaneous Transhepatic Cholangiography Rendez-Vous Procedure to Reach the Duodenum for Enteroscopy-Assisted Endoscopic Retrograde Cholangiopancreatography in Surgically Altered Anatomy. PMID- 29255776 TI - An Unusual Diagnosis in a Patient with Suspected Colorectal Cancer. PMID- 29255777 TI - Spatial Responses, Immediate Experience, and Memory in the Monkey Hippocampus. AB - Debate about the function of the hippocampus often pits theories advocating for spatial mapping against those that argue for a central role in memory. This review addresses whether research in the monkey supports the view that processing spatial information is fundamental to the function of the hippocampus. In support of spatial processing theories, neurons in the monkey hippocampal formation have striking spatial tuning, and an intact hippocampus is necessary to effectively utilize allocentric spatial relationships. However, the hippocampus also supports non-spatial processes, as its neurons acutely respond to distinct task events and hippocampal damage disrupts both expedient task acquisition and the monitoring of ongoing events in non-spatial paradigms. The features that are shared between spatial and non-spatial hippocampal-dependent tasks point toward a common mechanism underlying hippocampal function that is independent of processing spatial information. We suggest that spatial information is only one facet of immediate experience represented by the hippocampus. The current data support the idea that the hippocampus tracks many aspects of ongoing experience and the primary role of the hippocampus may be in linking experienced events into unitary episodes. PMID- 29255779 TI - Transcriptome data of Epinephelus fuscoguttatus infected by Vibrio vulnificus. AB - Vibriosis disease by Vibrio spp. greatly reduced productivity of aquaculture, such as brown-marbled grouper (Epinephelus fuscoguttatus), which is an economically important fish species in Malaysia. Preventive measures and immediate treatment are critical to reduce the mortality of E. fuscoguttatus from vibriosis. To investigate the molecular mechanisms associated with immune response and host-bacteria interaction, a transcriptomic analysis was performed to compare between healthy and Vibrio-infected groupers. This permits the discovery of immune-related genes, specifically the resistance genes upon infection. Herein, we provide the raw transcriptome data from Illumina HiSeq. 4000 that have been deposited into NCBI SRA database with the BioProject accession number PRJNA396437. A total of 493,403,076 raw sequences of 74.5 Gb were obtained. Trimming of the raw data produced 437,186,232 clean reads of ~58 Gb. These datasets will be useful to elucidate the defence mechanisms of E. fuscoguttatus against Vibrio vulnificus infection for future development of effective prevention and treatment of vibriosis. PMID- 29255780 TI - Dataset of surface refractivity in Southeast, Nigeria. AB - In this data article, analysis of surface refractivity and water vapour density in Southeast, Nigeria were reported. The meteorological data were collected for the period of 39 years between 1973 and 2012 from National Oceanic and Atmospheric Administration (NOAA) Climatology Centre. Five locations considered in the study area includes: Enugu, Onitsha, Abakaliki, Aba and Ihiala. Descriptive statistics were used to show an increase in monthly variation of refractivity of about 299.8 N units at Enugu in January to peak value of about 385.81 N units at Abakaliki in May. Hence, the seasonal variation for South East indicate maximum value within the months of March to May in the rainy season and a minimum value around December to February which is the dry season. The results from this data will help engineers in proper design and planning of radiowave propagation and satellite communication systems in southeastern, Nigeria. PMID- 29255778 TI - Differential impact of Met receptor gene interaction with early-life stress on neuronal morphology and behavior in mice. AB - Early adversity in childhood increases the risk of anxiety, mood, and post traumatic stress disorders in adulthood, and specific gene-by-environment interactions may increase risk further. A common functional variant in the promoter region of the gene encoding the human MET receptor tyrosine kinase (rs1858830 'C' allele) reduces expression of MET and is associated with altered cortical circuit function and structural connectivity. Mice with reduced Met expression exhibit changes in anxiety-like and conditioned fear behavior, precocious synaptic maturation in the hippocampus, and reduced neuronal arbor complexity and synaptogenesis. These phenotypes also can be produced independently by early adversity in wild-type mice. The present study addresses the outcome of combining early-life stress and genetic influences that alter timing of maturation on enduring functional and structural phenotypes. Using a model of reduced Met expression (Met+/- ) and early-life stress from postnatal day 2-9, social, anxiety-like, and contextual fear behaviors in later life were measured. Mice that experienced early-life stress exhibited impairments in social interaction, whereas alterations in anxiety-like behavior and fear learning were driven by Met haploinsufficiency, independent of rearing condition. Early-life stress or reduced Met expression decreased arbor complexity of ventral hippocampal CA1 pyramidal neurons projecting to basolateral amygdala. Paradoxically, arbor complexity in Met+/- mice was increased following early-life stress, and thus not different from arbors in wild-type mice raised in control conditions. The changes in dendritic morphology are consistent with the hypothesis that the physiological state of maturation of CA1 neurons in Met+/- mice influences their responsiveness to early-life stress. The dissociation of behavioral and structural changes suggests that there may be phenotype-specific sensitivities to early-life stress. PMID- 29255781 TI - Infection after open heart surgery in Golestan teaching hospital of Ahvaz, Iran. AB - The present study surveyed demographic and infection data which were obtained after open heart surgery (OHS) through patient's admission in Golestan teaching hospital, Ahvaz metropolitan city of Iran, taking into account the confirmed location of the infection, microorganism and antibiotic susceptibility. The occurrence of infection among patients during 48 to 72 h after surgery and hospital admission is the definition of Nosocomial infections (NIs) (Salmanzadeh et al., 2015) [1]. All of them after OHS were chosen for this study. In this paper, type of catheter, fever, type of microorganism, antibiotic susceptibility, location of the infection and outcome (live or death) were studied (Juhl et al., 2017; Salsano et al., 2017) [2], [3]. After the completion of the observations and recording patients' medical records, the coded data were fed into EXCELL. Data analysis was performed using SPSS 16. PMID- 29255782 TI - Chemical properties and colors of fermenting materials in salmon fish sauce production. AB - This data article reports the chemical properties (moisture, pH, salinity, and soluble solid content) and colors of fermenting materials in salmon fish sauce products. The fish sauce was produced by mixing salt with differing proportions of raw salmon materials and fermenting for three months; the salmon materials comprised flesh, viscera, an inedible portion, and soft roe. Chemical properties and colors of the unrefined fish sauce (moromi), and the refined fish sauce, were analyzed at one, two, and three months following the start of fermentation. Data determined for all products are provided in table format. PMID- 29255783 TI - Dataset on the activation of Muller cells through macrophages upon hypoxia in the retina. AB - The dataset presented in this article complements the article entitled "Myeloid cells contribute indirectly to VEGF expression upon hypoxia via activation of Muller cells" (C. Nurnberg, N. Kociok, C. Brockmann, T. Lischke, S. Crespo Garcia, N. Reichhart, S. Wolf, R. Baumgrass, S.A. Eming, S. Beer-Hammer, and A.M. Joussen). This complementary dataset provides further insight into the experimental validation of the VEGFfl/fl LysMCre (here named VEGFmcko) knockout model used in the main article through genomic and quantitative Real-Time PCR in various murine tissues as well as additional flow cytometry data and immunohistochemical stainings. By providing these data, we aim to enable researcher to reproduce and critically analyze our data. PMID- 29255784 TI - Dermatomyositis - key to diagnosing ovarian cancer, monitoring treatment and detecting recurrent disease: Case report. AB - *Young women with dermatomyositis are at high risk for underlying ovarian cancer.*Dermatomyositis symptoms can be used to assess treatment and recurrence of disease.*Immunosuppression can complicate postoperative recovery in ovarian cancer patients.*Ovarian cancer patients with dermatomyositis should have genetic testing. PMID- 29255785 TI - Advanced small cell carcinoma of the cervix - Successful treatment with concurrent etoposide and cisplatin chemotherapy and extended field radiation: A case report and discussion. AB - The purpose of this article is to present a case of successful treatment of a patient with stage IVB small cell carcinoma of the cervix (SCCC) who was treated with concurrent chemoradiotherapy (CCRT) consisting of etoposide/cisplatin (EP) chemotherapy, external beam radiation therapy (EBRT), and brachytherapy. The patient has since remained without evidence of disease for nearly six years. This report reviews and summarizes the existing case literature on SCCC. PMID- 29255786 TI - Antimicrobial resistance, trade, food safety and security. PMID- 29255787 TI - Continuous measurement of object location memory is sensitive to effects of age and mild cognitive impairment and related to medial temporal lobe volume. AB - Introduction: We present findings of a novel and ecologically relevant associative memory test, the Object Location Touchscreen Test (OLTT), which was posited as sensitive to early medial temporal lobe compromise associated with mild cognitive impairment (MCI). Methods: A total of 114 participants, including healthy young and older controls and patients with MCI, completed the OLTT and standard neuropsychological testing. The OLTT required participants to recall the location of objects under free and cued recall conditions, with accuracy evaluated using distance measures (i.e., a continuous error score), and a standard recognition format. Correlations between performance and volumetric data were evaluated from a subset of 77 participants. Results: Significant age effects were dwarfed by MCI effects across all test conditions. OLTT Cued Recall was strongly and specifically related to the volume of disease-relevant medial temporal lobe regions, generally more than traditional memory tests. Discussion: The OLTT may be sensitive to early structural compromise in regions affected by Alzheimer's disease. PMID- 29255788 TI - Changes in place of death among people with dementia in Finland between 1998 and 2013: A register study. AB - Introduction: The place of death is suggested as a quality indicator for end-of life care. We investigated how the place of death changed between 1998 and 2013 among people with dementia. Methods: Data from the Finnish national health and social care registers were extracted for all people with dementia, who had died at 70 years old during these years (N = 140,034). Descriptive analysis and logistic regression analysis were conducted. Results: In 2013, the most common place of death was the primary care hospital (39.8%), followed by nursing home and sheltered housing with 24-hour assistance (20.5%). Dying at home was rare (8.1%). During the study years, dying in the hospital decreased while dying in sheltered housing with 24-hour assistance increased. Discussion: The place of death for people with dementia has changed from institutions to noninstitutional care facilities. Further research on noninstitutional care facilities' ability to provide high-quality care at the end of life is needed. PMID- 29255789 TI - Type 2 diabetes mellitus and cerebrospinal fluid Alzheimer's disease biomarker amyloid beta1-42 in Alzheimer's Disease Neuroimaging Initiative participants. AB - Introduction: Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease. Cerebrospinal fluid (CSF) amyloid beta (Abeta) 1-42 is an important Alzheimer's disease biomarker. However, it is inconclusive on how T2DM is related to CSF Abeta1-42. Methods: Participants with T2DM were selected from the Alzheimer's Disease Neuroimaging Initiative by searching keywords from the medical history database. A two-way analysis of covariance model was used to analyze how T2DM associates with CSF Abeta1-42 or cerebral cortical Abeta. Results: CSF Abeta1-42 was higher in the T2DM group than the nondiabetic group. The inverse relation between CSF Abeta1-42 and cerebral cortical Abeta was independent of T2DM status. Participants with T2DM had a lower cerebral cortical Abeta in anterior cingulate, precuneus, and temporal lobe than controls. Discussion: T2DM is positively associated with CSF Abeta1-42 but negatively with cerebral cortical Abeta. The decreased cerebral cortical Abeta associated with T2DM is preferentially located in certain brain regions. PMID- 29255791 TI - Drug discovery and development: Role of basic biological research. AB - This article provides a brief overview of the processes of drug discovery and development. Our aim is to help scientists whose research may be relevant to drug discovery and/or development to frame their research report in a way that appropriately places their findings within the drug discovery and development process and thereby support effective translation of preclinical research to humans. One overall theme of our article is that the process is sufficiently long, complex, and expensive so that many biological targets must be considered for every new medicine eventually approved for clinical use and new research tools may be needed to investigate each new target. Studies that contribute to solving any of the many scientific and operational issues involved in the development process can improve the efficiency of the process. An awareness of these issues allows the early implementation of measures to increase the opportunity for success. As editors of the journal, we encourage submission of research reports that provide data relevant to the issues presented. PMID- 29255790 TI - Letter. PMID- 29255792 TI - Tangled tau: Active pathology or footprint of disease? PMID- 29255793 TI - Integrating sex and gender into neurodegeneration research: A six-component strategy. AB - Introduction: Despite important sex differences, there remains a paucity of studies examining sex and gender differences in neurodegeneration. The Canadian Consortium on Neurodegeneration in Aging (CCNA), a national network of researchers, provides an ideal platform to incorporate sex and gender. Methods: CCNA's Women, Gender, Sex and Dementia program developed and implemented a six component strategy involving executive oversight, training, research collaboration, progress report assessment, results dissemination, and ongoing manuscript review. The inclusion of sex and gender in current and planned CCNA projects was examined in two progress reporting periods in 2016. Results: Sex and gender research productivity increased substantially for both preclinical (36% 45%) and human (56%-60%) cohorts. The main barrier was lack of funding. Discussion: The Women, Gender, Sex and Dementia strategy resulted in a major increase of sex and gender into research on neurodegenerative disorders. This best practice model could be utilized by a wide variety of large multidisciplinary groups. PMID- 29255794 TI - Prestimulus EEG Power Predicts Conscious Awareness But Not Objective Visual Performance. AB - Prestimulus oscillatory neural activity has been linked to perceptual outcomes during performance of psychophysical detection and discrimination tasks. Specifically, the power and phase of low frequency oscillations have been found to predict whether an upcoming weak visual target will be detected or not. However, the mechanisms by which baseline oscillatory activity influences perception remain unclear. Recent studies suggest that the frequently reported negative relationship between alpha power and stimulus detection may be explained by changes in detection criterion (i.e., increased target present responses regardless of whether the target was present/absent) driven by the state of neural excitability, rather than changes in visual sensitivity (i.e., more veridical percepts). Here, we recorded EEG while human participants performed a luminance discrimination task on perithreshold stimuli in combination with single trial ratings of perceptual awareness. Our aim was to investigate whether the power and/or phase of prestimulus oscillatory activity predict discrimination accuracy and/or perceptual awareness on a trial-by-trial basis. Prestimulus power (3-28 Hz) was inversely related to perceptual awareness ratings (i.e., higher ratings in states of low prestimulus power/high excitability) but did not predict discrimination accuracy. In contrast, prestimulus oscillatory phase did not predict awareness ratings or accuracy in any frequency band. These results provide evidence that prestimulus alpha power influences the level of subjective awareness of threshold visual stimuli but does not influence visual sensitivity when a decision has to be made regarding stimulus features. Hence, we find a clear dissociation between the influence of ongoing neural activity on conscious awareness and objective performance. PMID- 29255795 TI - The Maintenance of Synaptic Homeostasis at the Drosophila Neuromuscular Junction Is Reversible and Sensitive to High Temperature. AB - Homeostasis is a vital mode of biological self-regulation. The hallmarks of homeostasis for any biological system are a baseline set point of physiological activity, detection of unacceptable deviations from the set point, and effective corrective measures to counteract deviations. Homeostatic synaptic plasticity (HSP) is a form of neuroplasticity in which neurons and circuits resist environmental perturbations and stabilize levels of activity. One assumption is that if a perturbation triggers homeostatic corrective changes in neuronal properties, those corrective measures should be reversed upon removal of the perturbation. We test the reversibility and limits of HSP at the well-studied Drosophila melanogaster neuromuscular junction (NMJ). At the Drosophila NMJ, impairment of glutamate receptors causes a decrease in quantal size, which is offset by a corrective, homeostatic increase in the number of vesicles released per evoked presynaptic stimulus, or quantal content. This process has been termed presynaptic homeostatic potentiation (PHP). Taking advantage of the GAL4/GAL80TS/UAS expression system, we triggered PHP by expressing a dominant negative glutamate receptor subunit at the NMJ. We then reversed PHP by halting expression of the dominant-negative receptor. Our data show that PHP is fully reversible over a time course of 48-72 h after the dominant-negative glutamate receptor stops being genetically expressed. As an extension of these experiments, we find that when glutamate receptors are impaired, neither PHP nor NMJ growth is reliably sustained at high culturing temperatures (30-32 degrees C). These data suggest that a limitation of homeostatic signaling at high temperatures could stem from the synapse facing a combination of challenges simultaneously. PMID- 29255798 TI - Shear-wave anisotropy reveals pore fluid pressure-induced seismicity in the U.S. midcontinent. AB - Seismicity in the U.S. midcontinent has increased by orders of magnitude over the past decade. Spatiotemporal correlations of seismicity to wastewater injection operations have suggested that injection-related pore fluid pressure increases are inducing the earthquakes. We present direct evidence linking earthquake occurrence to pore pressure increase in the U.S. midcontinent through time-lapse shear-wave (S-wave) anisotropy analysis. Since the onset of the observation period in 2010, the orientation of the fast S-wave polarization has flipped from inline with the maximum horizontal stress to inline with the minimum horizontal stress, a change known to be associated with critical pore pressure buildup. The time delay between fast and slow S-wave arrivals exhibits increased variance through time, which is common in critical pore fluid settings. Near-basement borehole fluid pressure measurements indicate pore pressure increase in the region over the earthquake monitoring period. PMID- 29255796 TI - The RNA-Binding Protein hnRNP K Mediates the Effect of BDNF on Dendritic mRNA Metabolism and Regulates Synaptic NMDA Receptors in Hippocampal Neurons. AB - Brain-derived neurotrophic factor (BDNF) is an important mediator of long-term synaptic potentiation (LTP) in the hippocampus. The local effects of BDNF depend on the activation of translation activity, which requires the delivery of transcripts to the synapse. In this work, we found that neuronal activity regulates the dendritic localization of the RNA-binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP K) in cultured rat hippocampal neurons by stimulating BDNF-Trk signaling. Microarray experiments identified a large number of transcripts that are coimmunoprecipitated with hnRNP K, and about 60% of these transcripts are dissociated from the protein upon stimulation of rat hippocampal neurons with BDNF. In vivo studies also showed a role for TrkB signaling in the dissociation of transcripts from hnRNP K upon high-frequency stimulation (HFS) of medial perforant path-granule cell synapses of male rat dentate gyrus (DG). Furthermore, treatment of rat hippocampal synaptoneurosomes with BDNF decreased the coimmunoprecipitation of hnRNP K with mRNAs coding for glutamate receptor subunits, Ca2+- and calmodulin-dependent protein kinase IIbeta (CaMKIIbeta) and BDNF. Downregulation of hnRNP K impaired the BDNF-induced enhancement of NMDA receptor (NMDAR)-mediated mEPSC, and similar results were obtained upon inhibition of protein synthesis with cycloheximide. The results demonstrate that BDNF regulates specific populations of hnRNP-associated mRNAs in neuronal dendrites and suggests an important role of hnRNP K in BDNF-dependent forms of synaptic plasticity. PMID- 29255799 TI - The Indian monsoon variability and civilization changes in the Indian subcontinent. AB - The vast Indo-Gangetic Plain in South Asia has been home to some of the world's oldest civilizations, whose fortunes ebbed and flowed with time-plausibly driven in part by shifts in the spatiotemporal patterns of the Indian summer monsoon rainfall. We use speleothem oxygen isotope records from North India to reconstruct the monsoon's variability on socially relevant time scales, allowing us to examine the history of civilization changes in the context of varying hydroclimatic conditions over the past 5700 years. Our data suggest that significant shifts in monsoon rainfall have occurred in concert with changes in the Northern Hemisphere temperatures and the discharges of the Himalayan rivers. The close temporal relationship between these large-scale hydroclimatic changes and the intervals marking the significant sociopolitical developments of the Indus Valley and Vedic civilizations suggests a plausible role of climate change in shaping the important chapters of the history of human civilization in the Indian subcontinent. PMID- 29255800 TI - Elastic properties of silicate melts: Implications for low velocity zones at the lithosphere-asthenosphere boundary. AB - Low seismic velocity regions in the mantle and crust are commonly attributed to the presence of silicate melts. Determining melt volume and geometric distribution is fundamental to understanding planetary dynamics. We present a new model for seismic velocity reductions that accounts for the anomalous compressibility of silicate melt, rendering compressional wave velocities more sensitive to melt fraction and distribution than previous estimates. Forward modeling predicts comparable velocity reductions for compressional and shear waves for partially molten mantle, and for low velocity regions associated with the lithosphere-asthenosphere boundary (LAB), melt present at <5% distributed in near-textural equilibrium. These findings reconcile seismic observations for the LAB regionally and locally and favor models of strong coupling across the LAB rather than melt channeling due to shear deformation. PMID- 29255797 TI - Sensory Coding and Sensitivity to Local Estrogens Shift during Critical Period Milestones in the Auditory Cortex of Male Songbirds. AB - Vocal learning occurs during an experience-dependent, age-limited critical period early in development. In songbirds, vocal learning begins when presinging birds acquire an auditory memory of their tutor's song (sensory phase) followed by the onset of vocal production and refinement (sensorimotor phase). Hearing is necessary throughout the vocal learning critical period. One key brain area for songbird auditory processing is the caudomedial nidopallium (NCM), a telencephalic region analogous to mammalian auditory cortex. Despite NCM's established role in auditory processing, it is unclear how the response properties of NCM neurons may shift across development. Moreover, communication processing in NCM is rapidly enhanced by local 17beta-estradiol (E2) administration in adult songbirds; however, the function of dynamically fluctuating E2 in NCM during development is unknown. We collected bilateral extracellular recordings in NCM coupled with reverse microdialysis delivery in juvenile male zebra finches (Taeniopygia guttata) across the vocal learning critical period. We found that auditory-evoked activity and coding accuracy were substantially higher in the NCM of sensory-aged animals compared to sensorimotor aged animals. Further, we observed both age-dependent and lateralized effects of local E2 administration on sensory processing. In sensory-aged subjects, E2 decreased auditory responsiveness across both hemispheres; however, a similar trend was observed in age-matched control subjects. In sensorimotor-aged subjects, E2 dampened auditory responsiveness in left NCM but enhanced auditory responsiveness in right NCM. Our results reveal an age-dependent physiological shift in auditory processing and lateralized E2 sensitivity that each precisely track a key neural "switch point" from purely sensory (pre-singing) to sensorimotor (singing) in developing songbirds. PMID- 29255801 TI - A mixed-kinetic model describes unloaded velocities of smooth, skeletal, and cardiac muscle myosin filaments in vitro. AB - In vitro motility assays, where purified myosin and actin move relative to one another, are used to better understand the mechanochemistry of the actomyosin adenosine triphosphatase (ATPase) cycle. We examined the relationship between the relative velocity (V) of actin and myosin and the number of available myosin heads (N) or [ATP] for smooth (SMM), skeletal (SKM), and cardiac (CMM) muscle myosin filaments moving over actin as well as V from actin filaments moving over a bed of monomeric SKM. These data do not fit well to a widely accepted model that predicts that V is limited by myosin detachment from actin (d/ton), where d equals step size and ton equals time a myosin head remains attached to actin. To account for these data, we have developed a mixed-kinetic model where V is influenced by both attachment and detachment kinetics. The relative contributions at a given V vary with the probability that a head will remain attached to actin long enough to reach the end of its flexible S2 tether. Detachment kinetics are affected by L/ton, where L is related to the tether length. We show that L is relatively long for SMM, SKM, and CMM filaments (59 +/- 3 nm, 22 +/- 9 nm, and 22 +/- 2 nm, respectively). In contrast, L is shorter (8 +/- 3 nm) when myosin monomers are attached to a surface. This suggests that the behavior of the S2 domain may be an important mechanical feature of myosin filaments that influences unloaded shortening velocities of muscle. PMID- 29255802 TI - Elastic and electronic tuning of magnetoresistance in MoTe2. AB - Quasi-two-dimensional transition metal dichalcogenides exhibit dramatic properties that may transform electronic and photonic devices. We report on how the anomalously large magnetoresistance (MR) observed under high magnetic field in MoTe2, a type II Weyl semimetal, can be reversibly controlled under tensile strain. The MR is enhanced by as much as ~30% at low temperatures and high magnetic fields when uniaxial strain is applied along the a crystallographic direction and reduced by about the same amount when strain is applied along the b direction. We show that the large in-plane electric anisotropy is coupled with the structural transition from the 1T' monoclinic to the Td orthorhombic Weyl phase. A shift of the Td-1T' phase boundary is achieved by minimal tensile strain. The sensitivity of the MR to tensile strain suggests the possibility of a nontrivial spin-orbital texture of the electron and hole pockets in the vicinity of Weyl points. Our ab initio calculations show a significant orbital mixing on the Fermi surface, which is modified by the tensile strains. PMID- 29255803 TI - Ultrafast all-climate aluminum-graphene battery with quarter-million cycle life. AB - Rechargeable aluminum-ion batteries are promising in high-power density but still face critical challenges of limited lifetime, rate capability, and cathodic capacity. We design a "trihigh tricontinuous" (3H3C) graphene film cathode with features of high quality, orientation, and channeling for local structures (3H) and continuous electron-conducting matrix, ion-diffusion highway, and electroactive mass for the whole electrode (3C). Such a cathode retains high specific capacity of around 120 mAh g-1 at ultrahigh current density of 400 A g-1 (charged in 1.1 s) with 91.7% retention after 250,000 cycles, surpassing all the previous batteries in terms of rate capability and cycle life. The assembled aluminum-graphene battery works well within a wide temperature range of -40 to 120 degrees C with remarkable flexibility bearing 10,000 times of folding, promising for all-climate wearable energy devices. This design opens an avenue for a future super-batteries. PMID- 29255804 TI - Optimization principles and the figure of merit for triboelectric generators. AB - Energy harvesting with triboelectric nanogenerators is a burgeoning field, with a growing portfolio of creative application schemes attracting much interest. Although power generation capabilities and its optimization are one of the most important subjects, a satisfactory elemental model that illustrates the basic principles and sets the optimization guideline remains elusive. We use a simple model to clarify how the energy generation mechanism is electrostatic induction but with a time-varying character that makes the optimal matching for power generation more restrictive. By combining multiple parameters into dimensionless variables, we pinpoint the optimum condition with only two independent parameters, leading to predictions of the maximum limit of power density, which allows us to derive the triboelectric material and device figure of merit. We reveal the importance of optimizing device capacitance, not only load resistance, and minimizing the impact of parasitic capacitance. Optimized capacitances can lead to an overall increase in power density of more than 10 times. PMID- 29255805 TI - Hepatitis C is now curable, but what happens with cirrhosis and portal hypertension afterwards? AB - Results from the interferon era have demonstrated reversibility of cirrhosis following viral eradication, but only for patients in the initial stage of cirrhosis. Although direct-acting antivirals (DAA) represent revolutionary treatment of hepatitis C, there are currently no studies showing histological effects of therapy on a large number of cirrhotic patients. However, studies involving transient elastography demonstrated a rapid decrease in liver stiffness after successful DAA therapy, probably due to resolution of inflammation, rather than fibrosis regression, as the latter requires a longer period of time. Reversal of fibrosis and cirrhosis upon viral eradication is a prerequisite for the reduction of portal pressure, but this effect has only been observed for the subclinical stage of portal hypertension (PH). On the other hand, the majority of patients with clinically significant PH remain at risk of decompensation and death, despite hepatitis C virus cure, as PH remains high in this setting. This calls for novel therapeutic approaches. PMID- 29255806 TI - Non-invasive evaluation of the liver disease severity in children with chronic viral hepatitis using FibroTest and ActiTest - comparison with histopathological assessment. AB - Aim of the study: Was to evaluate liver disease severity in children with chronic viral hepatitis using the FibroTest and ActiTest (FT/AT), and compare the results with the liver biopsy. Material and methods: The study included 11 treatment naive children [mean age, 9.0 +/- 3.0 years, 10 infected with hepatitis C virus (HCV), and 1 with hepatitis B virus (HBV)] who underwent an FT/AT. Ten of the children underwent a liver biopsy. The histopathological evaluation was based on the METAVIR scoring system. The FT/AT and METAVIR scores were considered concordant if the necroinflammatory activity or the fibrosis did not differ by more than one grade or stage. To analyze the agreement between the FT/AT and the histopathological evaluation, the inter-rater agreement (kappa) was used. Results: In the histopathological evaluation, most children presented with mild necroinflammatory activity (METAVIR A1) and with minimal to mild fibrosis (METAVIR F1-2). Both the AT and FT values did not show any linear increases with advancing METAVIR scores A and F, respectively. A discordance between the FT and METAVIR scores was observed in 3/10 (30%) cases; concordance between the AT and METAVIR scores was found in 9/10 cases. The inter-rater agreement test showed poor agreement between the FT/AT and the histopathological evaluation (kappa for AT: 0.0667, and kappa for FT: 0.176). Conclusions: The FT and AT values poorly correlate with histopathological evaluation. Further studies on non-invasive methods to evaluate liver disease severity in children with chronic viral hepatitis are needed. PMID- 29255807 TI - Accelerated hepatocellular carcinoma recurrence rate after postoperative direct acting antivirals treatment - preliminary report. AB - Aim of the study: New interferon-free direct-acting antiviral (DAA) therapy has led to major progress in hepatitis C virus (HCV) treatment. Current outcomes are promising, especially in compensated cirrhosis. However, there are reports of accelerated hepatocellular carcinoma (HCC) recurrence after surgery in patients treated with DAAs. The influence of DAA therapy on the timing and frequency of recurrence after surgical treatment needs further observation. Material and methods: Fifty-one HCV infected patients with advanced liver cirrhosis and history of surgical treatment for HCC in 2012-2016 were analyzed in a case control study. Nineteen patients received DAA therapy (DAA group) after tumor remission achieved by surgery and 32 patients were not treated with DAA (NDAA group). Follow-up included multiphase computed tomography scan or magnetic resonance imaging of the liver and alpha-fetoprotein level in 3-6-month intervals. Results: An sustained virological response was achieved in 18 (95%) DAA treated patients. Hepatocellular carcinoma recurrence was observed in 8 (42.1%) patients from the DAA group and in 21 (65.6%) from the NDAA group (p = 0.058). Relapse occurred within 265 days after surgery in the DAA group vs. 532 days in the NDAA group (p = 0.033). The one-year recurrence-free survival (RFS) rate was 47.3% vs. 75% in the DAA and NDAA group respectively (p = 0.45). Conclusions: Use of DAA therapy in patients with a history of HCC may result in significantly accelerated relapse of the disease. The number of analyzed patients in this study is too small to state unquestionable conclusions. Further observation with a longer follow-up and larger patient group is needed. The study confirms that contemporary HCV treatment is highly effective. PMID- 29255808 TI - Clinical usefulness of new noninvasive serum biomarkers for the assessment of liver fibrosis and steatosis in children with chronic hepatitis C. AB - Aim of the study: Recently, novel serum markers modified by the body mass index z score (BMI z-score) were proposed as a reliable noninvasive alternative for the detection of significant fibrosis and steatosis in children with chronic hepatitis C (CHC). The aim of this study was to evaluate the clinical usefulness of these biomarkers. Material and methods: Thirty children aged 9.4 +/- 3.7 years (14 males, 16 females) with CHC were included in this study. In all patients, histopathological evaluation of the liver fibrosis was performed using a 5-point METAVIR scoring system (>= 2 points = significant fibrosis). Significant steatosis was diagnosed with > 33% of hepatocytes affected. The following noninvasive markers of liver disease were calculated: the modified aspartate transaminase (AST)-to-platelet ratio index (M-APRI: BMI z-score * APRI), the modified Fibrosis-4 index (M-FIB-4: BMI z-score * FIB-4), and a novel marker, B AST (BMI z-score * AST). The clinically useful cut-offs for each marker were selected as simple round numbers, indicating significant fibrosis and steatosis. Results: Significant fibrosis was detected in 7/30 (23%) cases, and significant steatosis was observed in 4 (13%) patients. Comparison with the histopathological evaluation revealed that B-AST < 0 excluded significant fibrosis, and < 100 excluded all patients with significant steatosis. For the M-APRI, < 0 excluded significant fibrosis, and < 0.5 excluded significant steatosis. For the M-FIB-4, < 0 excluded significant fibrosis and < 0.2 excluded significant steatosis. Conclusions: Negative values of all three markers that included the BMI z-score excluded all patients with both significant fibrosis and significant steatosis. PMID- 29255809 TI - Autoimmune hepatitis and pregnancy: report of two cases with different maternal outcomes. AB - Women of childbearing age with autoimmune hepatitis (AIH) are now able to get pregnant. The progress of the disease during pregnancy is not well clarified yet. The first pregnant woman had cirrhosis secondary to AIH, and she delivered by cesarean section. The patient had severe thrombocytopenia at the time of hospitalization. Unfortunately, she died due to massive thromboembolism at the 24th hour after delivery. The other patient had three recurrent abortions with a diagnosis of AIH. Low-dose low molecular weight heparin and low-dose acetylsalicylic acid along with low-dose prednisolone were administered during the course of the following pregnancies. The following pregnancies ended up with a living child. There is a high morbidity and mortality risk for both fetus and mother. Hepatic performance of the patients, thrombotic events, inflammatory disorders and autoimmune system activation must be the main concerns together with necessary precautions. PMID- 29255810 TI - A rare cause of gastrointestinal bleeding in the post-transplant setting. AB - Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication noted after solid organ transplantation and is frequently related to Epstein-Barr virus infection. The present case highlights an unusual presentation of PTLD - gastrointestinal bleeding - in the absence of systemic symptoms. PMID- 29255811 TI - Immediate and 6-month Bond Strengths of Different Adhesives in the Oral Environment. AB - PURPOSE: To evaluate the microtensile bond strength (MUTBS) of three adhesives to dentin after 1 week and 6 months in an oral environment. MATERIALS AND METHODS: Class I cavities were prepared in the third molars of 30 patients and randomized into 3 groups according to the following adhesives: Scotchbond Multi-Purpose (SM), Clearfil Protect Bond (CF), and Scotchbond Universal (UN). These molars were then subdivided into two groups according to the exposure time in the oral environment: one week (1W) and 6 months (6M). After the exposure time, the teeth were extracted, cut into beams, and submitted to the MUTBS test. The data were analyzed using the Shapiro-Wilk test and two-way ANOVA followed by Tukey's post hoc test with a significance level of 5%, and fracture modes were analyzed. RESULTS: The bond strengths in MPa (mean +/- SD) were SM-1W: 39.5 +/- 7.9; SM-6M: 29.7 +/- 1.8; CF-1W: 30.5 +/- 1.4; CF-6M: 28.6 +/- 4.1; UN-1W: 30.6 +/- 3.2; and UN-6M: 26.7 +/- 2.0. The SM-1W group exhibited significantly increased MUTBS compared with the other groups. After 6 months in the oral environment, a significant reduction of MUTBS was only observed for the SM group, whereas similar bond strengths were observed for the other groups. SM-1W exhibited a predominance of mixed fractures, whereas the other groups showed a predominance of adhesive fractures. CONCLUSIONS: The adhesives which were applied in the self etching mode maintained bond strength after six months in the oral environment. A reduction of MUTBS was only observed for the three-step etch-and-rinse adhesive. PMID- 29255812 TI - Effect of Veneering Techniques on Shear and Microtensile Bond Strengths of Zirconia-Based All-Ceramic Systems. AB - PURPOSE: To evaluate shear (SBS) and microtensile (MUTBS) bond strengths of zirconia cores veneered using different fabrication techniques. MATERIALS AND METHODS: Seventy-five IPS e.max ZirCAD plates were fabricated and divided into three groups according to the following veneering techniques: layering, pressing, and CAD-on. The specimens of the layering group were veneered with IPS e.max Ceram, and the specimens of the pressing group were veneered with IPS e.max Zir- Press. Veneering ceramics in the CAD-on group were milled from IPS e.max CAD, fused with the core by using a glass-fusion ceramic, and then crystallized. Bond strength tests were performed using a universal testing machine at a crosshead speed of 0.5 mm/min for the SBS test and 1 mm/min for the MUTBS test. Mean SBS and MUTBS (MPa) were analyzed with one-way ANOVA and Tukey's HSD test (p < 0.05). RESULTS: Significant differences in SBS were observed between the groups (p < 0.05). The mean SBS for the CAD-on group was significantly higher (31.89 +/- 5.83 MPa) than those of the layering (14.27 +/- 4.45 MPa) and pressing (12.23 +/- 3.04 MPa) groups. However, the mean MUTBS of the CAD-on (30.41 +/- 8.64 MPa), layering (21.71 +/- 3.40 MPa) and pressing (20.74 +/- 6.36 MPa) groups were not statistically significant (p > 0.05). CONCLUSION: The CAD-on technique showed the highest shear bond strengths of the tested groups, and most of the specimens failed cohesively instead of failing at the adhesive interface. PMID- 29255813 TI - Cerium oxide as an efficient electron extraction layer for p-i-n structured perovskite solar cells. AB - Cerium oxide, solution processed at a low temperature (~100 degrees C), was successfully employed as an electron extraction layer on top of a perovskite. The CeOx layer shows good charge selectivity and increases light reflection from an Ag electrode. Besides this, the CeOx layer not only protects the perovskite from water, but also acts as a dense diffusion barrier to prevent the corrosion of the metal electrode. PMID- 29255814 TI - Flash nanoprecipitation permits versatile assembly and loading of polymeric bicontinuous cubic nanospheres. AB - Polymeric bicontinuous nanospheres (BCNs) that are analogous to lipid cubosomes possess high internal surface area and porosity that can accommodate the loading of a wide range of hydrophobic and hydrophilic molecules for diverse applications. Self-assembly of BCNs has been reported using complex amphiphilic polymeric structures, with co-solvent dispersion being the only documented method of formation. Here, we report a simple amphiphilic diblock copolymer, poly(ethylene glycol)17-block-poly(propylene sulfide)75 (PEG17-bl-PPS75), to form BCNs using the rapid and scalable technique of flash nanoprecipitation (FNP). Dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryoTEM) verified low polydispersity and the formation of bicontinuous structures with internal aqueous channels, respectively. Small-angle X-ray scattering (SAXS) confirmed a primitive cubic (Im3m) internal organization for BCNs assembled by FNP. Both hydrophobic and hydrophilic molecules were effectively loaded into BCNs via FNP, and encapsulated payloads were found to release in controlled manner in aqueous solutions. Due to the oxidation sensitivity of PPS, biologically relevant concentrations of reactive oxygen species could trigger payload release on demand. BCNs were found to be non-toxic and endocytosed by phagocytic cells. Furthermore, an in vitro functional assay showed BCNs co-loaded with antigen ovalbumin and adjuvant monophosphoryl lipid A (MPL) to promote peptide/MHCI surface presentation by dendritic cells, a critical step for vaccine formulations during immunization. In conclusion, FNP supports the facile and scalable assembly and loading of PEG-bl-PPS BCNs, making them an attractive nanoscale delivery vehicle for both hydrophilic and hydrophobic molecules. PMID- 29255815 TI - Defect chemistry and electrical properties of garnet-type Li7La3Zr2O12. AB - Garnet-type cubic Li7La3Zr2O12 exhibits one of the highest lithium-ion conductivity values amongst oxides (up to ~2 mS cm-1 at room temperature). This compound has also emerged as a promising candidate for solid electrolytes in all solid-state lithium batteries, due to its high ionic conductivity, good chemical stability against lithium metal, and wide electrochemical stability window. Defect chemistry of this class of materials, although less studied, is critical to the understanding of the nature of ionic conductivity and predicting the properties of grain boundaries and heterogeneous solid interfaces. In this study, the electrical properties of nominally undoped cubic Li7La3Zr2O12 are characterized as a function of temperature and pO2 using a suite of AC impedance and DC polarization techniques. The formation of ionic defects and defect pairs as well as their impact on the transport properties are discussed, and a Brouwer type diagram is constructed. PMID- 29255816 TI - Commensurability between protein nanotubes in contractile ejection nanomachines. AB - Contractile ejection nanomachines being sheath-tube assemblies create an opening in the cell membrane to translocate molecules or ions across it. Here, on the most structurally investigated examples of the bacteriophage T4 tail and pyocin R2, we show that the rearrangement of the sheath structure resulting in its contraction and twist occurs in such a way that the contracted sheath becomes commensurate with the inner tube. This fact dictates the previously unknown simple geometrical relationship between the nanotube symmetries. Using the Frank and van der Merwe classical theory of commensurability, we study an interaction between two protein nanotubes forming such nanomachines and obtain an expression for the corresponding energy, which depends on the tube structures and their mutual arrangement. The appearance of commensurability between the contracted sheath and the inner tube decreases both the interaction energy and the total energy of the system. It improves the nanomachine efficiency, since the energy gain obtained increases the torque of the inner tube piercing the cell membrane. PMID- 29255817 TI - Genetically-encoded fragment-based discovery (GE-FBD) of glycopeptide ligands with differential selectivity for antibodies related to mycobacterial infections. AB - Accurate identification of tuberculosis (TB), caused by Mycobacterium tuberculosis, is important for global disease management. Point-of-care serological tests may improve TB diagnosis; however, specificities of available serodiagnostics are sub-optimal. We employed genetically encoded fragment-based discovery (GE-FBD) to select ligands for antibodies directed against the mycobacterial cell wall component lipoarabinomannan (LAM), a potent antigen. GE FBD employed a phage displayed library of 108 heptapeptides, chemically modified with an arabinofuranosyl hexasaccharide fragment of LAM (Ara6), and the anti-LAM antibody CS-35 as a bait. The selection gave rise to glycopeptides with an enhanced affinity and selectivity for CS-35 but not for 906.4321 antibody, both of which bind to Ara6 with a comparable affinity. Multivalent assays incorporating the discovered ligands Ara6-ANSSFAP, Ara6-DAHATLR and Ara6-TTYVVNP exhibited up to 19-fold discrimination between CS-35 and 906.4321. The use of the Ara6 antigen alone failed to distinguish these antibodies. Thus, GE-FBD gives rise to ligands that differentiate monoclonal antibodies with enhanced specificity. This technology could facilitate the development of effective point of-care serological tests for mycobacterial and other infections. PMID- 29255818 TI - Insight into the ADOR zeolite-to-zeolite transformation: the UOV case. AB - IPC-12 zeolite is the first member of the ADOR family produced by the structural transformation of UOV. The details of the UOV rearrangement were studied to determine the influence of the properties of the parent zeolite and treatment conditions on the outcome of IPC-12 formation. It was established that incomplete disassembly of UOV can be caused by insufficient lability of interlayer connectivity in the parent material possessing Si-enriched D4Rs or by inhibition of hydrolysis by diluted acid at high temperature. The impacts of specific interactions of the framework with anions on controllable breaking of interlayer connectivity and the conditions of the treatment at low pH (<-1) on the characteristics of the produced IPC-12 were found to be negligible. The concentration of the acid significantly influences the extent and even the direction of UOV transformation. Layer disassembly is inhibited in 1-4 M acid solutions, and complete hydrolysis to a layered precursor can be achieved in 0.1 M solution, while application of 12 M solution led to direct formation of IPC-12. Layer reassembly followed using in situ XRD measurement with a synchrotron source was found to be a gradual process starting at 40 degrees C and completing at 200 220 degrees C. PMID- 29255819 TI - Photoluminescence nonuniformity from self-seeding nuclei in CVD-grown monolayer MoSe2. AB - We present optical spectroscopy (photoluminescence and Raman spectrum) studies of monolayer transition metal dichalcogenide MoSe2, with spatial location, temperature and excitation power dependence. The investigated spectra show location-dependent behavior with an increase in photoluminescence and Raman intensity and a blue-shift in photoluminescence peak position in the inner region. The observed behaviors of a large shift in the photoluminescence peak position at the edge and biexciton emissions in the inner region confirm that the monolayer MoSe2 crystals grow from nucleation centers during the CVD process. Temperature activated energy and dependence of the peak position are attributed to residual oxygen during the growth. Investigating this information provides a basis for precisely controlling the synthesis of TMDCs and their application in advanced optoelectronics. PMID- 29255820 TI - A photochemical approach for evaluating the reactivity of substituted lappaconitines. AB - Lappaconitine (LC) is a natural diterpenoid alkaloid (DTA), acting as a human heart sodium channel blocker and possessing a wide range of biological activities, the cellular and molecular mechanisms of which are widely studied. This interest is due to the fact that various representatives of this DTA class show opposite biological activities. The possible reasons for this difference seem to be related to the peculiarities of the substituent effect on the drug receptor binding process. In this work, the influence of substituents on the reactivity of LC and its derivatives has been studied by using elementary processes of photodecomposition. The given approach includes the joint analysis of the photophysical properties of the studied systems and their photodecomposition quantum yields. It allows us to trace the influence of substituents, located in the diterpenoid skeleton and anthranilic fragment, on processes in both moieties of LC. Summarizing the data obtained, an inverse dependence of fluorescence and photodegradation quantum yields has been observed. This correlation established for LCs, in particular, allows one to propose a way to evaluate the photostability of potential drugs based on fluorescence analysis. This would be appropriate for compounds in which the reactivity depends on intersystem crossing, i.e. in the cases where the initial and reacting excited states differ in multiplicity. PMID- 29255821 TI - Synthesis, characterization and cytotoxicity of arene-ruthenium(ii) complexes with acylpyrazolones functionalized with aromatic groups in the acyl moiety. AB - A series of neutral ruthenium(ii)-arene complexes, [(arene)Ru(QR)Cl] (arene = p cymene or hexamethylbenzene), containing 4-acyl-5-pyrazolonate (QR) ligands with aromatic substituents in the acyl moiety (a phenyl in QPh and a 1-naphthyl in Qnaph) and related ionic complexes [(arene)Ru(QR)(PTA)][PF6] (PTA = 1,3,5-triaza 7-phosphaadamantane) have been synthesized and characterized by IR, 1H, 13C and 31P NMR spectroscopy, elemental analysis and ESI mass spectrometry. The structures of five of these compounds were also determined by X-ray crystallography. DFT studies have been performed on all complexes and, in the case of two cationic [(arene)Ru(Qnaph)(PTA)][PF6], the existence of two conformers with a different relative orientation of the naphthyl group in the Qnaph ligand has been assessed, showing that they possess similar energies, in agreement with the experimentally observed NMR spectra in solution. The cytotoxicity of the 4-acyl-5-pyrazolonate proligands (HQR) and complexes was evaluated in vitro against human ovarian carcinoma cells (A2780 and A2780cisR) and non-tumorous human embryonic kidney (HEK293) cells. In general, each complex is about equally cytotoxic to all three cell lines and the PTA derivatives with the naphthyl-modified QR ligands are the most active of the series. PMID- 29255822 TI - Influence of chalcogen composition on the structural transition and on the electronic and optical properties of the monolayer titanium trichalcogenide ordered alloys. AB - Based on first-principles spin-polarized density functional theory, we investigate the effects of chalcogen composition on the structural, electronic, and optical properties of monolayer (where X and X' = S, Se, Te) ordered alloys with values of x of 0, 0.167, 0.333, 0.500, 0.667, 0.833, and 1. We determine the optimized geometry for all possible substitutional adsorptions of chalcogen atoms for each x composition, and identify the energetically most stable allotropes as a function of composition. Our extensive analysis reveals that the structural and electronic properties depend on the chemical composition of the monolayers, and the band gap of TiX3 nanosheets can be tuned by adjusting the ratio of chalcogen compositions. While substitutional doping of tellurium atoms into TiS3 or TiSe3 monolayers results in a semiconductor-metal transition, the alloys remain a semiconductor under the transition from TiS3 to TiSe3 with band gaps which are very suitable for optical devices and infrared detectors. We also find that each TiS3(1-x)Se3x structure has an anisotropic dielectric function. Because of the anisotropy of the dielectric function, they can be useful materials for application in the transition metal trichalcogenide-based nanoelectronics industry in the future. PMID- 29255823 TI - A novel cell-scale bio-nanogenerator based on electron-ion interaction for fast light power conversion. AB - Natural energy haversting devices serve as an alternative candidate for power supply in many micro-/nano-systems. However, traditional nanogenerators based on piezoelectricity or triboelectric power generation face challenges in terms of biocompatibility and stability in various biological systems. The bacteriorhodopsin (bR) protein in Halobacterium halobium is an ideal biocompatible material for photoelectric conversion. Conventional bR systems based on ion transport or enhanced light absorption layers have a limited light power conversion speed. On the other hand, bR-based biohybrid devices have a great potential for sensitive light power conversion as compared to conventional nanogenerators. Herein, we present a biohybrid nanogenerator made of bR and horizontally aligned-long carbon nanotubes (CNTs) with electron-ion interaction for the first time for sensitive light power conversion. The bR layer serves as the proton pump, whereas CNTs are utilized to enhance the photocurrent; thus, the photocurrent frequency response improves significantly because of the effect of the electron-ion interaction. The photocurrent shows a linear relationship with the intensity of light and can still obtain a stable signal at a light intensity of 0.03 mW cm-2. With regard to the influence of the light on-off period, the photocurrent initially increases and then decreases with an increase in flickering frequency up to 360 Hz; this can be ascribed to the combinational influence of light switch speed and photocycle decay time. The photocurrent shows highest value (99 nA cm-2) at a frequency of about 50 Hz at a light intensity of 0.43 mW cm-2, which matches well with the frequency standard of the electrical power supply system. Moreover, we found that a higher density of CNTs contributed to improve performance of the nanogenerators. Furthermore, a H+ ion releasing model was proposed to interpret the operating mechanism of the biohybrid nanogenerator. The biohybrid nanogenerator shows great potential for applications as a power source for bio-nanosystems. PMID- 29255824 TI - The half Heusler system Ti1+xFe1.33-xSb-TiCoSb with Sb/Sn substitution: phase relations, crystal structures and thermoelectric properties. AB - Investigations of phase relations in the ternary system Ti-Fe-Sb show that the single-phase region of the Heusler phase is significantly shifted from stoichiometric TiFeSb (reported previously in the literature) to the Fe-rich composition TiFe1.33Sb. This compound also exhibits Fe/Ti substitution according to Ti1+xFe1.33-xSb (-0.17 <= x <= 0.25 at 800 degrees C). Its stability, crystal symmetry and site preference were established by using X-ray powder techniques and were backed by DFT calculations. The ab initio modeling revealed TiFe1.375Sb to be the most stable composition and established the mechanisms behind Fe/Ti substitution for the region Ti1+xFe1.33-xSb, and of the Fe/Co substitution within the isopleth TiFe1.33Sb-TiCoSb. The calculated residual resistivity of Ti1+xFe1.33-xSb, as well as of the isopleths TiFe1.33Sb-TiCoSb, TiFe0.665Co0.5Sb TiCoSb0.75Sn0.25 and TiFe0.33Co0.75Sb-TiCoSb0.75Sn0.25, are in a good correlation with the experimental data. From magnetic measurements and 57Fe Mossbauer spectrometry, a paramagnetic behavior down to 4.2 K was observed for TiFe1.33Sb, with a paramagnetic Curie-Weiss temperature of -8 K and an effective moment of 1.11MUB per Fe. Thermoelectric (TE) properties were obtained for the four isopleths Ti1+xFe1.33-xSb, TiFe1.33Sb-TiCoSb, TiFe0.665Co0.5Sb-TiCoSb0.75Sn0.25 and TiFe0.29Co0.78Sb-TiCoSb0.75Sn0.25 by measurements of electrical resistivity (rho), Seebeck coefficient (S) and thermal conductivity (lambda) at temperatures from 300 K to 823 K allowing the calculation of the dimensionless figure of merit (ZT). Although p-type Ti1+xFe1.33-xSb indicates a semi-conducting behavior for the Fe rich composition (x = -0.133), the conductivity changes to a metallic type with increasing Ti content. The highest ZT = 0.3 at 800 K was found for the composition TiFe1.33Sb. The TE performance also increases with Fe/Co substitution and reaches ZT = 0.42 for TiCo0.5Fe0.665Sb. No further increase of the TE performance was observed for the Sb/Sn substituted compounds within the sections TiFe0.665Co0.5Sb-TiCoSb0.75Sn0.25 and TiFe0.33Co0.75Sb-TiCoSb0.75Sn0.25. However, ZT-values could be enhanced by about 12% via the optimization of the preparation route (ball-mill conditions and heat treatments). PMID- 29255825 TI - Slow relaxation of magnetization in a bis-mer-tridentate octahedral Co(ii) complex. AB - Reaction of a rigid tridentate ligand o-[(1H-imidazol-2 yl)methylideneamino]phenol (2-H2imap) with Co(ClO4)2 in the presence of NaN3, or Co(NO3)2 without a base yields [CoII(2-Himap)2] 1 and [CoIII(2-Himap)2]NO3.MeOH 2, respectively. Both complexes exhibit a mer-octahedral geometry with the cobalt centre being distorted along an octahedral-trigonal prismatic pathway. The packing in 1 and 2 is dominated by H-bonding forming 2D sheets and 1D chains, respectively. Detailed dc and ac magnetic studies indicate that 1 is a field induced single-ion magnet (SIM) with D = 36.7 cm-1 and E = 2.0 cm-1. Extensive ab initio calculations support these conclusions and suggest that relaxation of the magnetization occurs principally through direct quantum tunnelling in the ground state, with the Raman process dominant in an applied field. This contrasts with the recently reported series of mer-[Co(L)2] (L = monoanionic NNO donor ligand; Inorg. Chem., 2017, 56, 6056-6066) complexes where D is negative, as these compounds have a more ambiguous geometry, and highlights the importance of supramolecular interactions in subtly altering the coordination sphere thereby impacting the magnetic behaviour. PMID- 29255826 TI - A mechanistic study of silica-etching by hot water. AB - The etching of colloidal silica by hot water provides a green chemistry method for the preparation of mesoporous silica. Nevertheless, the reaction mechanism of this etching process has not been elucidated and its reproducibility is often questionable, which has hindered its widespread application in the preparation of mesoporous silica materials. Herein, we present a systematic study on the hot water etching of sol-gel derived silica shells coated on alpha-Fe2O3 particles. Transmission electron microscopy and infrared spectroscopy studies provide substantial evidence that colloidal silica with low hydrolysis and condensation degrees (or aging degrees) is preferentially etched by hot water. More importantly, we show that the aging degree of silica shells, which determines the etching rate, can be precisely tuned by controlling the sol-gel preparation time and the storage time in room-temperature water prior to hot-water etching. These results provide novel insights into the physicochemical properties of sol-gel derived colloidal silica and the mechanistic understanding of the reaction kinetics of silica etching by hot water. PMID- 29255827 TI - The renascence of continuous-flow peptide synthesis - an abridged account of solid and solution-based approaches. AB - Within a decade of Merrifield's seminal description of solid-phase peptide synthesis, the synergies between solid-phase approaches and flow synthesis were noted by a number of groups. However, despite the various advantages flow brings to peptide synthesis, throughout the 1990s and 2000s, interest in the technique was overshadowed by microwave assisted approaches. However, the current expansion of flow technologies has reinvigorated interest in both solid-phase and solution phase continuous-flow approaches for assembling peptides. This perspective traces the introduction and evolution of continuous-flow solid-phase synthesis from a practical aspect with a particular focus on solid supports, acylation protocols, and racemisation suppression. Practical aspects of solution-phase continuous-flow peptide synthesis are also considered with an evaluation of microreactor systems, coupling protocols, and fragment-based approaches for assembly of extended peptide units. PMID- 29255828 TI - Anomalies in the low frequency vibrational density of states for a polymer with intrinsic microporosity - the Boson peak of PIM-1. AB - Polymers with intrinsic microporosity are promising candidates for the active separation layer in gas separation membranes. Here, the vibrational density of states (VDOS) for PIM-1, the prototypical polymer with intrinsic microporosity, is investigated by means of inelastic neutron scattering. The results are compared to data measured for a more conventional high-performance polyimide used in gas separation membranes (Matrimid). The measured data show the characteristic low frequency excess contribution to VDOS above the Debye sound wave level, generally known as the Boson peak in glass-forming materials. In comparison to the Boson peak of Matrimid, that of PIM-1 is shifted to lower frequencies. This shift is discussed considering the microporous, sponge-like structure of PIM-1 as providing a higher compressibility at the molecular scale than for conventional polymers. For an annealed PIM-1 sample, the Boson peak shifts to higher frequencies in comparison to the un-annealed sample. These changes in the VDOS of the annealed PIM-1 sample are related to changes in the microporous structure as confirmed by X-ray scattering. PMID- 29255829 TI - Total synthesis of (+)-brasilenyne via concise construction of an oxonane framework containing a 1,3-cis,cis-diene. AB - The enantioselective total synthesis of (+)-brasilenyne has been accomplished. The key features of the synthesis include the convergent preparation of a highly functionalized endocyclization precursor via selective epoxide opening, the construction of an oxonene skeleton through perfect regioselective Pd(0) catalyzed endocyclization, and the installation of a 1,3-cis,cis-diene unit via a decarboxylative photophenylselenylation and site-selective selenoxide elimination sequence. PMID- 29255830 TI - Dementia Prevention Strategies - Beyond the Randomized Controlled Trial? PMID- 29255831 TI - E.U./U.S. CTAD Task Force on Alzheimer's Trial Populations for Study. PMID- 29255833 TI - Alzheimer's Disease Drug Development: Trial-Ready Cohorts Should Help. PMID- 29255832 TI - A New Era: Disease Modifying Alzheimer Disease Prevention Trials. PMID- 29255834 TI - Clinical Trials for Alzheimer's Disease Turned a Corner in 2013'. PMID- 29255835 TI - Curcumin Micelles Improve Mitochondrial Function in a Mouse Model of Alzheimer's Disease. AB - Preventive strategies for late-onset Alzheimer's disease (AD) should start early at a prodromal stage. Mitochondrial dysfunction has been found to play an important role in the initiation of both aging and the pathogenesis of Alzheimer's disease. Curcumin, a widely used spice and food-coloring agent, is a polyphenol derived from the rhizome of Curcuma longa. It is known to have anti oxidant, anti-inflammatory, and anti-protein-aggregate activities which are usually considered beneficial for mitochondrial function. We assessed brain mitochondrial function and concentrations of soluble Abeta40 in a mouse model of AD (Thy1-APP751SL transgenic mice) after 3-week administration of curcumin micelles. Curcumin micelles are a newly developed formulation that account for increased curcumin bioavailability. Curcumin treatment had positive effects on mitochondrial membrane potential and respiratory control ratio. Additionally, it decreased levels of soluble Abeta40 in brains of Thy1-APPSL transgenic mice. Hence, curcumin micelles are a promising neutraceutical for the prevention of AD. PMID- 29255836 TI - Neuroprotective Effects of a Variety of Pomegranate Juice Extracts (PJE) Against the Excitotoxin Quinolinic Acid in Human Primary Neurons. AB - BACKGROUND: Quinolinic acid (QUIN) excitotoxicity is mediated by elevated intracellular Ca2+ levels, and nitric oxide (NO*) mediated oxidative stress leading to DNA damage, and cell death due to energy restriction. METHODS: We evaluated the effect of a series of pomegranate juice extracts (PJE), Helow, Malasi, Qusum, and Hamedh, with antioxidant properties on QUIN induced excitotoxicity on primary cultures of human neurons. RESULTS: We showed that Helow and Malasi can attenuate QUIN-induced excitotoxicity to a greater extent than Qusum and Hamedh from Oman. Similarly, both Helow and Malasi were able to attenuate QUIN-induced Ca2+ influx and nNOS activity to a greater extent compared to Qusum, and Hamedh. All extracts reduced the oxidative effects of increased NO* production, and hence preventing NAD+ depletion and cell death. CONCLUSION: In addition to the well-known antioxidant properties of these natural phytochemicals, the inhibitory effect of some of these compounds on specific excitotoxic processes such as calcium influx provides additional evidence for the beneficial health effects of PJE in excitable tissue, particularly within the CNS. PMID- 29255837 TI - EU./U.S. CTAD Task Force on Alzheimer's Trial Populations. AB - Successful therapeutic trials require well-targeted populations to demonstrate the effectiveness of a drug candidate. Most trials in the field of Alzheimer's disease (AD) have been conducted in patients with mild to moderate dementia. However, the advent of amyloid PET imaging has demonstrated that a significant proportion of individuals enrolled in such studies do not have evidence of brain amyloidosis and may in fact not have Alzheimer's disease. Further, dementia represents an advanced stage of neurodegeneration, perhaps too late for significant benefits of disease-modifying interventions. The successful development of effective disease-slowing therapies requires a study population selected in accordance with the mechanism of the specific intervention. An international task force of investigators from academia, industry, non-profit foundations, and regulatory agencies met in San Diego, California, USA, on November 13, 2013, to address issues related to screening and identification of clinical trial participants, and the ramifications of decisions made in this regard for drug development in AD and other dementias. PMID- 29255838 TI - Hippocampal Astrocytes and Alzheimer's Disease. AB - Considerable progress has been made in elucidating the molecules involved in the pathology of Alzheimer's disease (AD). However, it is still uncertain why the hippocampus is the focus of this pathology, since these molecules (amyloid precursor protein, beta secretase, apolipoprotein E) are not more abundant within the hippocampus than in other, undamaged brain areas. Several unique features of the hippocampus may make it more vulnerable to this age-related pathology. These include 1) a specialized metabolism that enhances damaging effects of oxidative stress, 2) a capacity for neurogenesis, and 3) specializations in mitochondrial and metal homeostasis. The thesis of this paper is that an unusual subset of hippocampal astrocytes makes a fundamental contribution to all three of these hippocampal features and allows different and seemingly conflicting risk factors for AD to be viewed in a unified manner. These astrocytes participate in neurogenesis, produce fatty acid binding protein 7, unlike most astrocytes in the mature brain, and undergo an age-related mitochondrial degeneration. Degeneration of astrocyte mitochondria appears due to oxidative stress arising from fatty acid metabolism. This mitochondrial degeneration produces intracellular deposits of iron and copper, metals that have been shown to harmfully interact with cleavage products of amyloid precursor protein. Pharmacological and dietary manipulations that protect these astrocytes from age-related oxidative stress may prove to be useful strategies in combatting the progression of AD. PMID- 29255839 TI - Physical Activity Interventions in Preventing Cognitive Decline and Alzheimer Type Dementia: A Systematic Review. AB - Background: The prevalence of cognitive impairment and dementia is expected to increase dramatically as the population ages, creating burdens on families and health care systems. Purpose: To assess the effectiveness of physical activity interventions in slowing cognitive decline and delaying the onset of cognitive impairment and dementia in adults without diagnosed cognitive impairments. Data Sources: Several electronic databases from January 2009 to July 2017 and bibliographies of systematic reviews. Study Selection: Trials published in English that lasted 6 months or longer, enrolled adults without clinically diagnosed cognitive impairments, and compared cognitive and dementia outcomes between physical activity interventions and inactive controls. Data Extraction: Extraction by 1 reviewer and confirmed by a second; dual-reviewer assessment of risk of bias; consensus determination of strength of evidence. Data Synthesis: Of 32 eligible trials, 16 with low to moderate risk of bias compared a physical activity intervention with an inactive control. Most trials had 6-month follow up; a few had 1- or 2-year follow-up. Evidence was insufficient to draw conclusions about the effectiveness of aerobic training, resistance training, or tai chi for improving cognition. Low-strength evidence showed that multicomponent physical activity interventions had no effect on cognitive function. Low-strength evidence showed that a multidomain intervention comprising physical activity, diet, and cognitive training improved several cognitive outcomes. Evidence regarding effects on dementia prevention was insufficient for all physical activity interventions. Limitation: Heterogeneous interventions and cognitive test measures, small and underpowered studies, and inability to assess the clinical significance of cognitive test outcomes. Conclusion: Evidence that short term, single-component physical activity interventions promote cognitive function and prevent cognitive decline or dementia in older adults is largely insufficient. A multidomain intervention showed a delay in cognitive decline (low strength evidence). Primary Funding Source: Agency for Healthcare Research and Quality. PMID- 29255841 TI - Looking at the Moon. PMID- 29255840 TI - Deep Brain Stimulation for Parkinson Disease Dementia: A New Frontier? PMID- 29255842 TI - Does Cognitive Training Prevent Cognitive Decline?: A Systematic Review. AB - Background: Structured activities to stimulate brain function-that is, cognitive training exercises-are promoted to slow or prevent cognitive decline, including dementia, but their effectiveness is highly debated. Purpose: To summarize evidence on the effects of cognitive training on cognitive performance and incident dementia outcomes for adults with normal cognition or mild cognitive impairment (MCI). Data Sources: Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and PsycINFO through July 2017, supplemented by hand-searches. Study Selection: Trials (published in English) lasting at least 6 months that compared cognitive training with usual care, waitlist, information, or attention controls in adults without dementia. Data Extraction: Single reviewer extraction of study characteristics confirmed by a second reviewer; dual reviewer risk-of-bias assessment; consensus determination of strength of evidence. Only studies with low or medium risk of bias were analyzed. Data Synthesis: Of 11 trials with low or medium risk of bias, 6 enrolled healthy adults with normal cognition and 5 enrolled adults with MCI. Trainings for healthy older adults were mostly computer based; those for adults with MCI were mostly held in group sessions. The MCI trials used attention controls more often than trials with healthy populations. For healthy older adults, training improved cognitive performance in the domain trained but not in other domains (moderate strength evidence). Results for populations with MCI suggested no effect of training on performance (low-strength and insufficient evidence). Evidence for prevention of cognitive decline or dementia was insufficient. Adverse events were not reported. Limitation: Heterogeneous interventions and outcome measures; outcomes that mostly assessed test performance rather than global function or dementia diagnosis; potential publication bias. Conclusion: In older adults with normal cognition, training improves cognitive performance in the domain trained. Evidence regarding prevention or delay of cognitive decline or dementia is insufficient. Primary Funding Source: Agency for Healthcare Research and Quality. PMID- 29255843 TI - Is Single Payer the Answer for the US Health Care System? PMID- 29255844 TI - Why Medicaid Accountable Care Organizations Fail and How They Can Succeed. PMID- 29255846 TI - Do Infants Born Very Premature and Who Have Very Low Birth Weight Catch Up With Their Full Term Peers in Their Language Abilities by Early School Age? AB - Purpose: This study examined the extent to which children born preterm (< 37 weeks) and/or who have low birth weight (< 2,500 g) catch up with their full term peers in terms of their language abilities at early school age (>= 5 to < 9 years). Method: A systematic literature search identified empirical studies that fit the inclusion criteria. Data from the tests/questionnaires used for meta analysis spanned the following language categories: total language score, expressive language, receptive language, pragmatics, phonological awareness, and grammar. The means (standard deviations) were extracted from the studies and were converted to mean difference and 95% confidence intervals to test for overall effect. Results: Sixteen studies met the inclusionary criteria, for a total of 2,739 participants, of which 1,224 were born full term and 1,515 were born preterm. It is important to note that the preterm cohort represented very preterm infants who have a very low birth weight. The meta-analysis found that preterm infants scored significantly worse on total language (p < .001), receptive language (p < .001), expressive language (p < .001), phonological awareness (p < .001), and grammar (p = .03) than their full term peers. However, preterm infants did not score significantly worse than their peers on their pragmatics (p = .19). Conclusions: Children born VPT and who have VLBW perform worse than their peers on their total language, receptive language, expressive language, phonological awareness, and grammar abilities by early school age. This information is important for speech-language pathologists to consider as children born prematurely reach school age. PMID- 29255845 TI - Use of the Kidney Failure Risk Equation to Determine the Risk of Progression to End-stage Renal Disease in Children With Chronic Kidney Disease. AB - Importance: The kidney failure risk equation (KFRE) has been shown to accurately estimate progression to kidney failure in adults with chronic kidney disease (CKD). Use of the KFRE in children with CKD, if accurate, would help to optimize planning for end-stage renal disease (ESRD) care. Objective: To determine whether the KFRE adequately discriminates the risk of ESRD in children with CKD. Design, Setting, and Participants: This retrospective cohort study included 603 children with an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2 in the Chronic Kidney Disease in Children study, a national multicenter observational study. Data were collected from January 1, 2005, through July 31, 2013, and analyzed from September 30, 2016, through September 8, 2017. Exposures: The primary predictive factors were the 4-variable (age, sex, bedside Schwartz estimated glomerular filtration rate, and ratio of albumin to creatinine levels) and 8-variable (4 variables plus serum calcium, phosphate, bicarbonate, and albumin levels) KFREs, which provide 1-, 2-, and 5-year estimates of the risk of progression to ESRD. Main Outcomes and Measures: Time to ESRD. The Cox proportional hazards model was used to examine the association between the KFRE score and time to ESRD. C statistics were used to discriminate ESRD risk by the KFRE, with a value of greater than 0.80 indicating strong discrimination. Results: Of the 603 children included in the study, 378 were boys (62.7%) and 225 were girls (37.3%); median age at study entry was 12 years (interquartile range, 8-15 years). Median estimated glomerular filtration rate was 44 mL/min/1.73 m2. Four hundred fifty-seven participants (75.8%) had a nonglomerular cause of CKD. Median observation time was 3.8 years (interquartile range, 1.7-6.2 years); 144 (23.9%) developed ESRD within 5 years of enrollment. The 4-variable KFRE scores discriminated risk of ESRD, with C statistics of 0.90, 0.86, and 0.81 for the 1-, 2-, and 5-year risk scores, respectively. Results were similar using the 8 variable equation. Conclusions and Relevance: The KFRE is a simple tool that provides excellent discrimination of the risk of ESRD. Results suggest that the KFRE could be incorporated into the clinical care of children with CKD to aid in anticipatory guidance, timing of referral for transplant evaluation, and planning for dialysis access. PMID- 29255847 TI - Pharmacologic Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review. AB - Background: Optimal treatment to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia is uncertain. Purpose: To summarize current evidence on the efficacy and harms of pharmacologic interventions to prevent or delay cognitive decline, MCI, or dementia in adults with normal cognition or MCI. Data Sources: Several electronic databases from January 2009 to July 2017, bibliographies, and expert recommendations. Study Selection: English language trials of at least 6 months' duration enrolling adults without dementia and comparing pharmacologic interventions with placebo, usual care, or active control on cognitive outcomes. Data Extraction: Two reviewers independently rated risk of bias and strength of evidence; 1 extracted data, and a second checked accuracy. Data Synthesis: Fifty-one unique trials were rated as having low to moderate risk of bias (including 3 that studied dementia medications, 16 antihypertensives, 4 diabetes medications, 2 nonsteroidal anti-inflammatory drugs [NSAIDs] or aspirin, 17 hormones, and 7 lipid-lowering agents). In persons with normal cognition, estrogen and estrogen-progestin increased risk for dementia or a combined outcome of MCI or dementia (1 trial, low strength of evidence); high dose raloxifene decreased risk for MCI but not for dementia (1 trial, low strength of evidence); and antihypertensives (4 trials), NSAIDs (1 trial), and statins (1 trial) did not alter dementia risk (low to insufficient strength of evidence). In persons with MCI, cholinesterase inhibitors did not reduce dementia risk (1 trial, low strength of evidence). In persons with normal cognition and those with MCI, these pharmacologic treatments neither improved nor slowed decline in cognitive test performance (low to insufficient strength of evidence). Adverse events were inconsistently reported but were increased for estrogen (stroke), estrogen-progestin (stroke, coronary heart disease, invasive breast cancer, and pulmonary embolism), and raloxifene (venous thromboembolism). Limitation: High attrition, short follow-up, inconsistent cognitive outcomes, and possible selective reporting and publication. Conclusion: Evidence does not support use of the studied pharmacologic treatments for cognitive protection in persons with normal cognition or MCI. Primary Funding Source: Agency for Healthcare Research and Quality. PMID- 29255848 TI - Machine Learning and the Prediction of Hydrocephalus: Can Quantitative Image Analysis Assist the Clinician? PMID- 29255849 TI - Visualizing the Consistency of Thickened Liquids With Simple Tools: Implications for Clinical Practice. AB - Purpose: Accurate texture modifications to thin liquids are a critical aspect of patients' nutritional health and well-being. This study explored the use of 3 tools (2 distance- and 1 time-measuring devices) to characterize texture-modified liquids. The objectives were to use the tools to measure modified liquids, to determine if measurements differentiated nectar and honey levels of modification, and to compare measurements with other published reports. Method: We measured the flow distance of 33 prethickened water samples in centimeters (cm) using a line spread apparatus and a Bostwick Consistometer (Christison Particle Technologies). We selected a Zahn viscosity cup to measure the stream time of each prethickened liquid in seconds. Results: The 2 distance-measuring devices (line spread and Bostwick Consistometer) showed that thinner (nectar-thick) modifications spread or flowed a farther distance in comparison to thicker (honey-like) modifications. Testing with the line spread indicated that an average spread distance of 4.5 cm differentiated nectar-thick and honey-like consistencies. A flow distance of greater than 15 cm differentiated nectar from honey consistency measured with a Bostwick Consistometer. We were not successful in using the Zahn viscosity cup to determine the stream time of modified liquids. Conclusions: Two of the tools provided objective information about levels of liquid modification, which has implications for day-to-day preparation. Measurement tools that are accurate and easy to use have the potential to provide quick and dependable feedback to verify a prescribed level of liquid modification. Further efforts are needed to standardize the application of simple measurement tools in the management of patients who consume thickened liquids. PMID- 29255850 TI - The Relationship Between Motor Delays and Language Development in Very Low Birthweight Premature Children at 18 Months Corrected Age. AB - Purpose: The aim of this study is to determine if there is a specific association between motor delays and receptive and expressive language function, respectively, in prematurely born children. Method: Retrospective data review: 126 premature children <= 1,250-g birthweight from English-speaking families were evaluated on motor development (normal, mild delay, and moderate-severe delay) and the cognitive and language scales of the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley, 2006) at 18 months corrected age. Cognitive scores were categorized as normal, suspect, and abnormal. Gender, demographic, and perinatal variables were recorded and analyzed with respect to motor category. Results: Lower birthweight, chronic need for oxygen, severe intraventricular hemorrhage, and intestinal infection/inflammation were related to poorer motor development. On receptive language, the normal motor group attained significantly higher scores than the moderate-severe motor group but did not differ significantly from the mild delay motor group. On expressive language, the normal motor group had significantly higher scores than both the mild and moderate-severe groups. Girls performed better than boys on receptive and expressive language, but there was no significant interaction between gender and motor category on any of the Bayley scores. Cognitive, but not motor, category significantly contributed to variance of receptive language scores; cognitive and motor category each independently contributed to the variance in expressive language. Conclusion: Findings suggest that motor control areas of the brain may be implicated in expressive language development of premature children. Further research is needed to determine the underlying factors for the association between motor and expressive language function. PMID- 29255851 TI - A Baby-Led Approach to Complementary Feeding-Reply. PMID- 29255852 TI - Review: Weak evidence of benefits of cannabis for chronic neuropathic pain; moderate to weak evidence of adverse effects. PMID- 29255854 TI - Review: In patients with a first VTE, extended testing for undiagnosed cancer does not reduce mortality. PMID- 29255853 TI - Tocilizumab increased sustained glucocorticoid-free remission from giant cell arteritis. PMID- 29255855 TI - Colonoscopy outreach increased CRC screening more than FIT outreach; both were better than usual care. PMID- 29255856 TI - Liraglutide reduced a composite renal outcome at a median 4 y in patients with type 2 diabetes and high CV risk. PMID- 29255857 TI - Exenatide did not reduce major cardiovascular outcomes in type 2 diabetes. PMID- 29255858 TI - Review: In HF with preserved EF, beta-blockers reduced mortality; drug treatment overall did not. PMID- 29255859 TI - Guided early deescalation of antiplatelet treatment was noninferior to usual prasugrel care in PCI-treated ACS. PMID- 29255860 TI - After PCI in AF, dual antithrombotic therapy with dabigatran reduced bleeding compared with triple therapy. PMID- 29255861 TI - In adults, benzodiazepines were not linked to increased risk for mortality at 6 mo but were linked at 12 and 48 mo. PMID- 29255862 TI - Correction: Functional Status and Quality of Life After Transcatheter Aortic Valve Replacement. PMID- 29255863 TI - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women. PMID- 29255864 TI - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women. PMID- 29255865 TI - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women. PMID- 29255866 TI - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women. PMID- 29255867 TI - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women. PMID- 29255868 TI - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women. PMID- 29255869 TI - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women. PMID- 29255870 TI - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women. PMID- 29255872 TI - A Time to Talk. PMID- 29255871 TI - Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women. PMID- 29255873 TI - Web Exclusives. Annals for Hospitalists Inpatient Notes - Trends in Rates of Catheter-Associated Bloodstream Infection-Zeroing In on Zero or Just Fake News? PMID- 29255875 TI - Web Exclusives. Annals Story Slam - There's No Place Like Home. PMID- 29255876 TI - Web Exclusives. Annals Story Slam - Unlisted. PMID- 29255878 TI - Web Exclusives. Annals Story Slam - Getting Home. PMID- 29255877 TI - Web Exclusives. Annals Story Slam - Just One More Question. PMID- 29255879 TI - Web Exclusives. Annals Story Slam - A Son of Health Disparity. PMID- 29255880 TI - Web Exclusives. Annals Story Slam - A Long Stay. PMID- 29255882 TI - Annals for Educators - 19 December 2017. PMID- 29255881 TI - Web Exclusives. Annals Story Slam - I Don't Think It's a Good Fit. PMID- 29255883 TI - Annals for Hospitalists - 19 December 2017. PMID- 29255884 TI - Prevention of Late-Life Dementia: No Magic Bullet. PMID- 29255886 TI - Prolonged Asystole After a Loading Dose of Ticagrelor. PMID- 29255885 TI - Bilateral Deep Brain Stimulation of the Nucleus Basalis of Meynert for Parkinson Disease Dementia: A Randomized Clinical Trial. AB - Importance: Deep brain stimulation of the nucleus basalis of Meynert (NBM DBS) has been proposed as a treatment option for Parkinson disease dementia. Objective: To evaluate the safety and potential symptomatic effects of NBM DBS in patients with Parkinson disease dementia. Design, Setting, and Participants: A randomized, double-blind, crossover clinical trial evaluated the results of 6 patients with Parkinson disease dementia who were treated with NBM DBS at a neurosurgical referral center in the United Kingdom from October 26, 2012, to July 31, 2015. Eligible patients met the diagnostic criteria for Parkinson disease dementia, had motor fluctuations, were appropriate surgical candidates aside from the coexistence of dementia, were age 35 to 80 years, were able to give informed consent, had a Mini-Mental State Examination score of 21 to 26, had minimal atrophy seen on results of brain magnetic resonance imaging, and lived at home with a caregiver-informant. Interventions: After surgery, patients were assigned to receive either active stimulation (bilateral, low-frequency [20 Hz] NBM DBS) or sham stimulation for 6 weeks, followed by the opposite condition for 6 weeks. Main Outcomes and Measures: The primary outcome was the difference in scores on each item of an abbreviated cognitive battery (California Verbal Learning Test-II, Wechsler Adult Intelligence Scale-III digit span, verbal fluency, Posner covert attention test, and simple and choice reaction times) between the 2 conditions. Secondary outcomes were exploratory and included differences in scores on standardized measurements of cognitive, psychiatric, and motor symptoms and resting state functional magnetic resonance imaging. Results: Surgery and stimulation were well tolerated by all 6 patients (all men; mean [SD] age, 65.2 [10.7] years), with no serious adverse events during the trial. No consistent improvements were observed in the primary cognitive outcomes or in results of resting state functional magnetic resonance imaging. An improvement in scores on the Neuropsychiatric Inventory was observed with NBM DBS (8.5 points [range, 4-26 points]) compared with sham stimulation (12 points [range, 8-38 points]; median difference, 5 points; 95% CI, 2.5-8.5 points; P = .03) and the preoperative baseline (13 points [range, 5-25 points]; median difference, 2 points; 95% CI, -8 to 5.5 points; P = .69). Conclusions and Relevance: Low frequency NBM DBS was safely conducted in patients with Parkinson disease dementia; however, no improvements were observed in the primary cognitive outcomes. Further studies may be warranted to explore its potential to improve troublesome neuropsychiatric symptoms. Trial Registration: clinicaltrials.gov Identifier: NCT01701544. PMID- 29255887 TI - A Baby-Led Approach to Complementary Feeding. PMID- 29255888 TI - New Criteria Needed for Antisynthetase Syndrome. PMID- 29255889 TI - Tocilizumab for Giant Cell Arteritis-A New Giant Step in an Old Disease. PMID- 29255891 TI - New Criteria Needed for Antisynthetase Syndrome-Reply. PMID- 29255893 TI - Canada as Single-Payer Exemplar for Universal Health Care in the United States: A Borderline Option. PMID- 29255894 TI - The Renal Challenge With Left Ventricular Assist Device Therapy-When Enough Is Enough. PMID- 29255892 TI - Use of Fetal Magnetic Resonance Image Analysis and Machine Learning to Predict the Need for Postnatal Cerebrospinal Fluid Diversion in Fetal Ventriculomegaly. AB - Importance: Which children with fetal ventriculomegaly, or enlargement of the cerebral ventricles in utero, will develop hydrocephalus requiring treatment after birth is unclear. Objective: To determine whether extraction of multiple imaging features from fetal magnetic resonance imaging (MRI) and integration using machine learning techniques can predict which patients require postnatal cerebrospinal fluid (CSF) diversion after birth. Design, Setting, and Patients: This retrospective case-control study used an institutional database of 253 patients with fetal ventriculomegaly from January 1, 2008, through December 31, 2014, to generate a predictive model. Data were analyzed from January 1, 2008, through December 31, 2015. All 25 patients who required postnatal CSF diversion were selected and matched by gestational age with 25 patients with fetal ventriculomegaly who did not require CSF diversion (discovery cohort). The model was applied to a sample of 24 consecutive patients with fetal ventriculomegaly who underwent evaluation at a separate institution (replication cohort) from January 1, 1998, through December 31, 2007. Data were analyzed from January 1, 1998, through December 31, 2009. Exposures: To generate the model, linear measurements, area, volume, and morphologic features were extracted from the fetal MRI, and a machine learning algorithm analyzed multiple features simultaneously to find the combination that was most predictive of the need for postnatal CSF diversion. Main Outcomes and Measures: Accuracy, sensitivity, and specificity of the model in correctly classifying patients requiring postnatal CSF diversion. Results: A total of 74 patients (41 girls [55%] and 33 boys [45%]; mean [SD] gestational age, 27.0 [5.6] months) were included from both cohorts. In the discovery cohort, median time to CSF diversion was 6 days (interquartile range [IQR], 2-51 days), and patients with fetal ventriculomegaly who did not develop symptoms were followed up for a median of 29 months (IQR, 9-46 months). The model correctly classified patients who required CSF diversion with 82% accuracy, 80% sensitivity, and 84% specificity. In the replication cohort, the model achieved 91% accuracy, 75% sensitivity, and 95% specificity. Conclusion and Relevance: Image analysis and machine learning can be applied to fetal MRI findings to predict the need for postnatal CSF diversion. The model provides prognostic information that may guide clinical management and select candidates for potential fetal surgical intervention. PMID- 29255895 TI - The Horses of San Marco. PMID- 29255897 TI - The Red Parasol. PMID- 29255896 TI - Outcomes Associated With Left Ventricular Assist Devices Among Recipients With and Without End-stage Renal Disease. AB - Importance: Left ventricular assist devices (LVADs) are widely used both as a bridge to heart transplant and as destination therapy in advanced heart failure. Although heart failure is common in patients with end-stage renal disease (ESRD), little is known about outcomes after LVAD implantation in this population. Objective: To determine the utilization of and outcomes associated with LVADs in nationally representative cohorts of patients with and without ESRD. Design, Setting and Participants: We described LVAD utilization and outcomes among Medicare beneficiaries after ESRD onset (defined as having received maintenance dialysis or a kidney transplant) from 2003 to 2013 based on Medicare claims linked to data from the United States Renal Data System (USRDS), a national registry for ESRD. We compared Medicare beneficiaries with ESRD to a 5% sample of Medicare beneficiaries without ESRD. Exposures: ESRD (vs no ESRD) among patients who underwent LVAD placement. Main Outcomes and Measures: The primary outcome was survival after LVAD placement. Results: Among the patients with ESRD, the mean age was 58.4 (12.1) years and 62.0% (96) were male. Among those without ESRD, the mean age was 62.2 (12.6) years and 75.1% (196) were male. From 2003 to 2013, 155 Medicare beneficiaries with ESRD (median and interquartile range [IQR] days from ESRD onset to LVAD placement were 1655 days [453-3050 days]) and 261 beneficiaries without ESRD in the Medicare 5% sample received an LVAD. During a median follow-up of 762 days (IQR, 92-3850 days), 127 patients (81.9%) with and 95 (36.4%) without ESRD died. more than half of patients with ESRD (80 [51.6%]) compared with 11 (4%) of those without ESRD died during the index hospitalization. The median time to death was 16 days (IQR 2-447 days) for patients with ESRD compared with 2125 days (IQR, 565-3850 days) for those without ESRD. With adjustment for demographics, comorbidity and time period, patients with ESRD had a markedly increased adjusted risk of death (hazard ratio, 36.3; 95% CI, 15.6-84.5), especially in the first 60 days after LVAD placement. Conclusions and Relevance: Patients with ESRD at the time of LVAD placement had an extremely poor prognosis, with most surviving for less than 3 weeks. This information may be crucial in supporting shared decision-making around treatments for advanced heart failure for patients with ESRD. PMID- 29255899 TI - Competing for Spring Beauties. PMID- 29255898 TI - Association of Emergency-Only vs Standard Hemodialysis With Mortality and Health Care Use Among Undocumented Immigrants With End-stage Renal Disease. AB - Importance: Undocumented immigrants with end-stage renal disease have variable access to hemodialysis in the United States despite evidence-based standards for frequency of dialysis care. Objective: To determine whether mortality and health care use differs among undocumented immigrants who receive emergency-only hemodialysis vs standard hemodialysis (3 times weekly at a health care center). Design, Setting, and Participants: A retrospective cohort study was conducted of undocumented immigrants with incident end-stage renal disease who initiated emergency-only hemodialysis (Denver Health, Denver, Colorado, and Harris Health, Houston, Texas) or standard (Zuckerberg San Francisco General Hospital, San Francisco, California) hemodialysis between January 1, 2007, and July 15, 2014. Exposures: Access to emergency-only hemodialysis vs standard hemodialysis. Main Outcomes and Measures: The primary outcome was mortality. Secondary outcomes were health care use (acute care days and ambulatory care visits) and rates of bacteremia. Outcomes were adjusted for propensity to undergo emergency hemodialysis vs standard hemodialysis. Results: A total of 211 undocumented patients (86 women and 125 men; mean [SD] age, 46.5 [14.6] years; 42 from the standard hemodialysis group and 169 from the emergency-only hemodialysis group) initiated hemodialysis during the study period. Patients receiving standard hemodialysis were more likely to initiate hemodialysis with an arteriovenous fistula or graft and had higher albumin and hemoglobin levels than patients receiving emergency-only hemodialysis. Adjusting for propensity score, the mean 3 year relative hazard of mortality among patients who received emergency-only hemodialysis was nearly 5-fold (hazard ratio, 4.96; 95% CI, 0.93-26.45; P = .06) greater compared with patients who received standard hemodialysis. Mean 5-year relative hazard of mortality for patients who received emergency-only hemodialysis was more than 14-fold (hazard ratio, 14.13; 95% CI, 1.24-161.00; P = .03) higher than for those who received standard hemodialysis after adjustment for propensity score. The number of acute care days for patients who received emergency-only hemodialysis was 9.81 times (95% CI, 6.27-15.35; P < .001) the expected number of days for patients who had standard hemodialysis after adjustment for propensity score. Ambulatory care visits for patients who received emergency-only hemodialysis were 0.31 (95% CI, 0.21-0.46; P < .001) times less than the expected number of days for patients who received standard hemodialysis. Conclusions and Relevance: Undocumented immigrants with end-stage renal disease treated with emergency-only hemodialysis have higher mortality and spend more days in the hospital than those receiving standard hemodialysis. States and cities should consider offering standard hemodialysis to undocumented immigrants. PMID- 29255900 TI - Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine Prevention: A Randomized Clinical Trial. AB - Importance: Galcanezumab (LY2951742), a monoclonal antibody against calcitonin gene-related peptide (CGRP), is one of a novel class of new medicines for migraine prevention. Objective: To assess whether at least 1 dose of galcanezumab was superior to placebo for episodic migraine prevention. Design, Setting, and Participants: A randomized clinical trial was conducted in the United States (July 7, 2014, to August 19, 2015) in clinics of 37 licensed physicians with a specialty including, but not limited to, psychiatry, neurology, internal medicine, and primary care. Subcutaneous injections of galcanezumab, 5, 50, 120, or 300 mg, or placebo were given monthly during the 3-month treatment period. A total of 936 patients were assessed; 526 did not meet study entry or baseline criteria and 410 patients were randomly assigned to receive placebo or galcanezumab. Analyses were conducted on an intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study drug. Interventions: Short-term migraine treatments were allowed as needed except for opioids or barbiturates. Main Outcomes and Measures: To determine if at least 1 of the 4 doses of galcanezumab tested was superior to placebo for migraine prevention measured by the mean change from baseline in the number of migraine headache days 9 weeks to 12 weeks after randomization. Results: Of the 936 patients assessed, 410 met entry criteria (aged 18-65 years with 4-14 migraine headache days per month and migraine onset prior to age 50 years) and were randomized to receive placebo or galcanezumab. For the primary end point, galcanezumab, 120 mg, significantly reduced migraine headache days compared with placebo (99.6% posterior probability -4.8 days; 90% BCI, -5.4 to -4.2 days vs 95% superiority threshold [Bayesian analysis] -3.7 days; 90% BCI, -4.1 to -3.2 days). Adverse events reported by 5% or more of patients in at least 1 galcanezumab dose group and more frequently than placebo included injection-site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea, and nausea. Conclusions and Relevance: Monthly subcutaneous injections of galcanezumab, both 120 mg and 300 mg, demonstrated efficacy (repeated-measures analysis) for the preventive treatment of migraine and support further development in larger phase 3 studies. All dosages were safe and well tolerated for the preventive treatment of episodic migraine. Trial Registration: clinicaltrials.gov Identifier: NCT02163993. PMID- 29255901 TI - Longitudinal Study of Language and Speech of Twins at 4 and 6 Years: Twinning Effects Decrease, Zygosity Effects Disappear, and Heritability Increases. AB - Purpose: This study investigates the heritability of language, speech, and nonverbal cognitive development of twins at 4 and 6 years of age. Possible confounding effects of twinning and zygosity, evident at 2 years, were investigated among other possible predictors of outcomes. Method: The population based twin sample included 627 twin pairs and 1 twin without a co-twin (197 monozygotic and 431 dizygotic), 610 boys and 645 girls, 1,255 children in total. Nine phenotypes from the same comprehensive direct behavioral assessment protocol were investigated at 4 and 6 years of age. Twinning effects were estimated for each phenotype at each age using general linear mixed models using maximum likelihood. Results: Twinning effects decreased from 4 to 6 years; zygosity effects disappeared by 6 years. Heritability increased from 4 to 6 years across all 9 phenotypes, and the heritability estimates were higher than reported previously, in the range of .44-.92 at 6 years. The highest estimate, .92, was for the clinical grammar marker. Conclusions: Across multiple dimensions of speech, language, and nonverbal cognition, heritability estimates are robust. A finiteness marker of grammar shows the highest inherited influences in this early period of children's language acquisition. PMID- 29255902 TI - An Examination of Deintensification Recommendations in Clinical Practice Guidelines: Stepping Up or Scaling Back? PMID- 29255903 TI - Time to Implement the Kidney Failure Risk Equation Into Pediatric Practice. PMID- 29255904 TI - Starting Out After Rail. PMID- 29255905 TI - Types and Distributions of Biomedical Industry Payments to Men and Women Physicians by Specialty, 2015. PMID- 29255906 TI - The Pier at Rocky Neck, Gloucester. PMID- 29255908 TI - Forest of Coubron. PMID- 29255907 TI - Modifiable Risk Factors and Prevention of Dementia: What Is the Latest Evidence? PMID- 29255909 TI - Over-the-Counter Supplement Interventions to Prevent Cognitive Decline, Mild Cognitive Impairment, and Clinical Alzheimer-Type Dementia: A Systematic Review. AB - Background: Optimal interventions to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia are uncertain. Purpose: To summarize the evidence on efficacy and harms of over-the-counter (OTC) supplements to prevent or delay cognitive decline, MCI, or clinical Alzheimer-type dementia in adults with normal cognition or MCI but no dementia diagnosis. Data Sources: Multiple electronic databases from 2009 to July 2017 and bibliographies of systematic reviews. Study Selection: English-language trials of at least 6 months' duration that enrolled adults without dementia and compared cognitive outcomes with an OTC supplement versus placebo or active controls. Data Extraction: Extraction performed by a single reviewer and confirmed by a second reviewer; dual-reviewer assessment of risk of bias; consensus determination of strength of evidence. Data Synthesis: Thirty-eight trials with low to medium risk of bias compared omega-3 fatty acids, soy, ginkgo biloba, B vitamins, vitamin D plus calcium, vitamin C or beta-carotene, multi-ingredient supplements, or other OTC interventions with placebo or other supplements. Few studies examined effects on clinical Alzheimer type dementia or MCI, and those that did suggested no benefit. Daily folic acid plus vitamin B12 was associated with improvements in performance on some objectively measured memory tests that were statistically significant but of questionable clinical significance. Moderate-strength evidence showed that vitamin E had no benefit on cognition. Evidence about effects of omega-3 fatty acids, soy, ginkgo biloba, folic acid alone or with other B vitamins, beta carotene, vitamin C, vitamin D plus calcium, and multivitamins or multi ingredient supplements was either insufficient or low-strength, suggesting that these supplements did not reduce risk for cognitive decline. Adverse events were rarely reported. Limitation: Studies had high attrition and short follow-up and used a highly variable set of cognitive outcome measures. Conclusion: Evidence is insufficient to recommend any OTC supplement for cognitive protection in adults with normal cognition or MCI. Primary Funding Source: Agency for Healthcare Research and Quality. PMID- 29255910 TI - Renal denervation for mild-moderate treatment-resistant hypertension : A timely intervention? AB - BACKGROUND: Renal denervation (RDN) has been proposed as a novel antihypertensive intervention for treating resistant hypertension. It remains to be investigated which patient groups can potentially benefit from RDN. The present study aimed to evaluate the efficacy and safety of RDN in patients with mild-moderate resistant hypertension, i. e., systolic office blood pressure (BP) of 140-160 mm Hg despite treatment with three antihypertensive drugs including one diuretic, or mean systolic BP by ambulatory BP monitoring (ABPM) of 135-150 mm Hg. METHODS: We evaluated data from four relevant clinical studies, all conducted in Europe, comprising 185 eligible patients. The patients' age was 62.1 +/- 10.3 years and 73% were male (RDN group n = 149, control group n = 36). RESULTS: A self-control comparison showed that RDN led to significantly reduced ABPM at the 6-month follow-up (systolic ABPM: 147.3 +/- 13.4 mm Hg vs. 136.9 +/- 15.5 mm Hg; diastolic ABPM: 81.1 +/- 9.6 mm Hg vs. 76.2 +/- 9.7 mm Hg; p < 0.001). RDN was associated with a greater improvement in ABPM as compared with that in the control group (?systolic-ABPM: -10.4 +/- 9.4 vs. -3.5 +/- 9.6 mm Hg, p < 0.001; ?diastolic-ABPM: -5 +/- 5.8 vs. -2.1 +/- 5.5 mm Hg; p = 0.005, respectively). The decrease of office BP in the RDN group was also statistically significant. RDN led to a reduced number of antihypertensive medications. No severe adverse events were found during follow-up. Regression analysis showed that the available baseline characteristics did not correlate with the ABPM improvement after RDN. CONCLUSION: RDN appears to be a safe and effective intervention for patients with mild-moderate resistant hypertension; however, randomized studies are warranted. PMID- 29255912 TI - [Dysphagia and tonsillitis in a 25-year-old male patient : The nearly forgotten severe complication of a common ailment]. AB - We report the case of a patient with a severe dysphagia accompanying progressive tonsillitis. The clinical examination supported the possibility of a severe septic soft tissue infection. The blood cultures revealed a largely anaerobic sepsis with Fusobacterium necrophorum. This unusual pathogen is the most common cause of Lemierre's syndrome. A duplex sonogram and magnetic resonance imaging (MRI) of the neck region and vessels suggested a thrombophlebitis of the left internal jugular vein with partial occlusion, so that Lemierre's syndrome could be diagnosed. The patient was treated with appropriate antibiotics according to the resistogram and also with rivaroxaban. PMID- 29255911 TI - Colonization with multidrug-resistant bacteria increases the risk of complications and a fatal outcome after allogeneic hematopoietic cell transplantation. AB - Composition of the gut microbiota seems to influence early complications of allogeneic hematopoietic cell transplantation (HCT) such as bacterial infections and acute graft-versus-host disease (GVHD). In this study, we assessed the impact of colonization with multidrug-resistant bacteria (MDRB) prior to HCT and the use of antibiotics against anaerobic bacteria on the outcomes of HCT. We retrospectively analyzed the data of 120 patients who underwent HCT for hematologic disorders between 2012 and 2014. Fifty-one (42.5%) patients were colonized with MDRB and 39 (32.5%) had infections caused by MDRB. Prior colonization was significantly correlated with MDRB infections (P < 0.001), especially bacteremia (P = 0.038). A higher incidence of MDRB infections was observed in patients with acute (P = 0.014) or chronic (P = 0.002) GVHD and in patients aged > 40 years (P = 0.002). Colonization had a negative impact on overall survival (OS) after HCT (64 vs. 47% at 24 months; P = 0.034) and infection-associated mortality (P < 0.001). Use of metronidazole was correlated with an increased incidence of acute GVHD (P < 0.001) and lower OS (P = 0.002). Patients colonized with MDRB are more susceptible to life-threatening infections. Colonization with virulent flora is the most probable source of neutropenic infection; therefore, information about prior positive colonization should be crucial for the selection of empiric antibiotic therapy. The use of metronidazole, affecting the biodiversity of the intestinal microbiome, seems to have a significant impact on OS and acute GVHD. PMID- 29255913 TI - [Meatal and glandular urethral strictures]. AB - Distal urethral strictures comprise meatal or glandular stenoses and occur due to trauma, iatrogenic instrumentalization, infection, skin diseases such as lichen sclerosus or idiopathically. Given that 18% of anterior strictures (bulbar, penile, or glandular) are located in the very distal part, meatal/glandular stricture disease represents a non-negligible subgroup among all urethral strictures. The prevalence within Western industrialized countries is estimated to be approximately 0.6-0.9%, which translates into a total of 250,000 men being affected in Germany. Without any therapy, there is a severe risk of functional damage to the kidneys and the remaining urinary tract as well as significant reduction of quality of life. The therapeutic success of regaining sufficient micturition and a satisfying cosmetic result can only be obtained by means of surgical intervention. Besides dilatation and urethrotomy, preferably a single or multiple staged open urethroplasty with transplantation of autogenous genital or non-genital tissue can be performed. The choice of the appropriate surgical concept depends on stricture etiology, comorbidity status, and the patient's compliance. In case of histologically diagnosed lichen sclerosus, the use of genital skin should be avoided. To date, there are no universally accepted recommendations regarding the optimal use of substitution techniques. However, the use of oral mucosal tissue grafts seem to be the most promising, given low recurrence rates, and thus can be considered as the current gold standard. PMID- 29255914 TI - Outcomes of Right Ventricular Outflow Tract Reconstruction for Children with Persistent Truncus Arteriosus: A 10-Year Single-Center Experience. AB - The purpose of this report is to assess the mid- and long-term outcomes of right ventricular outflow tract (RVOT) reconstruction for children with persistent truncus arteriosus. Between September 2006 and 2016, 105 patients with persistent truncus arteriosus (PTA) received surgical treatment at Shanghai Children's Medical Center. Direct right ventricle-pulmonary artery anastomosis (pulmonary artery pull-down) was performed in 51 patients; a left auricle or pericardial conduit was inserted between the RVOT and pulmonary artery as a connection in 17 patients; heterograft (bovine jugular vein or Gore-tex) conduits and homograft conduits were used in 30 and 7 cases, respectively, to connect the distal pulmonary and right ventricle outflow tract; and pulmonary valve reconstruction was performed in 38 patients using a Gore-tex monocusp. There were six in hospital deaths and one delayed death 5 months after operation. After a mean follow-up of 55.8 +/- 16.5 months (6-113 months), 19 patients underwent reoperation (3 with pulmonary patch enlargement, 14 with conduit replacement and 2 with aortic valve replacement) 10-89 months after the first operation, with 1 hospital death. The actuarial survival rates were 94.2, 93.3 and 93.3% at 1, 5 and 10 years, respectively. Freedom from reoperation was 98.0, 87.8 and 82.7% at 1, 5 and 10 years, respectively. The follow-up variables included echocardiography, chest radiography, cardiac CT and cardiac function. At the last examination, most of the patients exhibited an improvement of New York Heart Association functional class from III or IV preoperatively to I or II at follow up. Surgical treatment for PTA has an acceptable survival rate and satisfactory outcomes. Most patients exhibited an improvement in cardiac function during follow-up. Aortic arch deformity, truncal valvular regurgitation and long cardiopulmonary bypass time were regarded as risk factors for hospital mortality. Autologous tissue has a lower reoperation rate and better growth potential than extracardiac conduits. A monocusp valve effectively reduces pulmonary regurgitation in the early postoperative stage. PMID- 29255915 TI - Correction to: Alignment in the transverse plane, but not sagittal or coronal plane, affects the risk of recurrent patella dislocation. AB - The author would like to correct the errors in the publication of the original article. The corrected detail is given below for your reading. PMID- 29255916 TI - Correction to: Dissociating the capture of attention from saccade activation by subliminal abrupt onsets. AB - Attentional capture and effects on saccade metrics by subliminal abrupt onset cues have been studied with peripheral cues at one out of several (two to four) display locations, swiftly followed by additional onsets at the other display locations. The lead time of the cue was too short to be seen. Here, we were interested in whether such subliminal onset cues influenced saccades primarily by way of attention or by way of direct saccade activation. In separate blocks, participants made speeded pro-saccades towards a black target or anti-saccades away from the target. Prior to the targets, an abrupt onset cue was presented either at the same side as the target (valid condition) or at the opposite side (invalid condition). If cues influenced performance by way of attentional capture, we expected facilitation of target processing in valid compared to invalid conditions (cueing effect) in the pro- as well as in the anti-saccade task. If the cues activated saccades in their direction, we expected the cueing effect to drop in the anti-saccade task compared to the pro-saccade task because in the anti-saccade task the invalid cue would activate the finally required response, whereas the valid cue would activate the alternative response, leading to interference. Results were in line with the former of these possibilities suggesting that subliminal abrupt onsets influenced saccades by way of attention with no or little direct activation of saccades. PMID- 29255917 TI - The effect of proprioceptive acuity variability on motor adaptation in older adults. AB - Motor adaptation requires efficient integration of sensory information with predicted sensory consequences of one's own action. However, the effect of reduced sensory acuity on motor adaptation in humans remains to be further investigated. Here, we examined the variability of proprioceptive acuity during an arm-position matching task and the pattern of visuomotor adaptation in older and young adults, and determined the relationship between the two variables. The older adults, a known example of impaired proprioceptive acuity, exhibited greater trial-to-trial variability during the arm-position matching task as compared with the young adults. Furthermore, the older adults showed a slower rate of adaptation to a 30 degrees visuomotor rotation during targeted reaching movements, as well as larger movement errors in the later phase of adaptation, than the young adults. Our correlation analyses indicated a negative association between the variability in proprioceptive acuity and the rate of visuomotor adaptation in the older adults; and no association was observed in the young adults. These findings point to a possibility that an increase in the variability of proprioceptive acuity due to aging may weaken the integration of predicted and actual sensory feedback, which in turn may result in poor visuomotor adaptation in older adults. PMID- 29255918 TI - Anisotropy of lateral peripersonal space is linked to handedness. AB - The space immediately surrounding our bodies, i.e., peripersonal space (PPS), is a critical area for the interaction with the external world, be it to deal with imminent threat or to attain objects of interest. In the brain, a dedicated system codes PPS in motor terms for the purpose of action. Yet, humans have asymmetric motor abilities: the dominant hand has an advantage in term of movements' precision and reaction time. Furthermore, spatial attention is asymmetric and seems to be linked to a right hemispheric dominance for spatial processing. Here, we tested whether handedness and attentional asymmetries impact the detection of a tactile stimulus when an irrelevant auditory stimulus is looming towards the individual from the right or left hemispace. We examined the distance at which sound started speeding up tactile detection to estimate the morphometry of peri-trunk PPS. Our results show that right-handers' PPS is larger in the left than in the right hemispace, whereas left-handers' PPS is symmetric. The expansion of right-handers' PPS on the side of the non-dominant hand is coherent with a protective function of PPS. Left-handers' symmetric PPS can be related to the symmetric request of their motor abilities induced by living in a right-handers' world. These findings reveal that PPS is not uniform and suggest that general mechanisms of spatial processing as well as motor skills could play a role in the representation of peri-trunk PPS. PMID- 29255919 TI - Metabolic topography of autoimmune non-paraneoplastic encephalitis. AB - PURPOSE: F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is emerging to be a useful tool in supporting the diagnosis of AIE. In this study, we describe the metabolic patterns on F-18 FDG PET imaging in AIE. METHODS: Twenty-four antibody-positive patients (anti-NMDA-15, anti-VGKC/LGI1-6, and anti GAD-3), 14 females and 10 males, with an age range of 2-83 years were included in this study. Each PET study was evaluated visually for the presence of hypometabolism or hypermetabolism and semiquantitatively using Cortex ID (GE) and Scenium (Siemens) by measuring regional Z-scores. These patterns were correlated with corresponding antibody positivity once available. RESULTS: Visually, a pattern of hypometabolism, hypermetabolism, or both in various spatial distributions was appreciated in all 24 patients. On quantitative analysis using scenium parietal and occipital lobes showed significant hypometabolism with median Z-score of -3.8 (R) and -3.7 (L) and -2.2 (R) and -2.5 (L) respectively. Two-thirds (16/24) showed significant hypermetabolism involving the basal ganglia with median Z-score of 2.4 (R) and 3.0 (L). Similarly on Cortex ID, the median Z score for hypometabolism in parietal and occipital lobes was -2.2 (R) and -2.4 (L) and -2.6 (R) and -2.4 (L) respectively, while subcortical regions were not evaluated. MRI showed signal alterations in only 11 of these patients. CONCLUSION: There is heterogeneity in metabolic topography of AIE which is characterized by hypometabolism most commonly involving the parietal and occipital cortices and hypermetabolism most commonly involving the basal ganglia. Scenium analysis using regional Z-scores can complement visual evaluation for demonstration of these metabolic patterns on FDG PET. PMID- 29255921 TI - Abandoning dislodged shunt catheters-unraveling Pandora's box. PMID- 29255920 TI - Early vagal nerve stimulator implantation in children: personal experience and review of the literature. AB - AIM: Data concerning the benefit of vagal nerve stimulation (VNS) in children under the age of 12 years is sparse. It was shown that reduction of seizure frequency and duration at an early age could lead to better psychomotor development. We therefore compare the outcome between early (<= 5 years of age) and late (> 5 years of age) implantation of VNS in children. METHODS: This study is a prospective review of patients analyzing primarily the reduction of seizure frequency and secondarily epilepsy outcome assessed by the McHugh and Engel classification, reduction of antiepileptic drugs (AED), psychomotor development measured by the Vineland Adaptive Behavior Scale (VABS), and quality of life using the caregiver impression (CGI) scale. Mean follow-up time was 36 and 31 months in the early and late group, respectively. RESULTS: Out of 12 consecutive VNS implantations for therapy refractory epilepsy, 5 were early implantations and 7 late implantations. Reduction of seizure frequency, McHugh and Engel classification, quality of life, psychomotor development and reduction of AED were comparable in both groups. One patient in the late group suffered from a postoperative infection resulting in explanation of the VNS device and re implantation on the opposite side, while mortality rate was 0%. CONCLUSIONS: VNS seems to be a safe and feasible therapy in children even under the age of 5 years. Responder rate, quality of life, and psychomotor development do not seem to be influenced by the child's age at implantation; however, larger studies analyzing the outcome of early VNS implantation are warranted. PMID- 29255922 TI - Long-term follow-up for keystone design perforator island flap for closure of myelomeningocele. AB - PURPOSE: We have previously reported a small series on the closure of large myelomeningocele (MMC) defects with a keystone design perforator island flap (KDPIF) in a paediatric neurosurgical centre in Australia. We are now presenting an updated longer term follow-up of an expanded series demonstrating longer term durability of this vascularized flap for large myelomeningocele defects. METHODS: The prospective data from the Monash Neurosurgical Database were used to select all cases of MMC between December 2008 and September 2016. Retrospective analysis of the neurosurgical database revealed an additional three patients who underwent KDPIF closure at the Monash Medical Centre for MMC repair at birth. RESULTS: Wound healing was satisfactory in all six cases. With delayed follow-up, there was no associated skin flap separation, skin flap dehiscence, skin flap necrosis, cerebro-spinal fluid leak, however two infections were encountered, both resolved with conservative management including antibiotics and simple washout. CONCLUSION: In this expanded case series with increased longevity of follow-up, the keystone design perforator island flap remains a robust alternative for closure of large myelomeningocele defects. PMID- 29255923 TI - Real-time beam monitoring for error detection in IMRT plans and impact on dose volume histograms : A multi-center study. AB - PURPOSE: This study aimed to test the sensitivity of a transmission detector for online dose monitoring of intensity-modulated radiation therapy (IMRT) for detecting small delivery errors. Furthermore, the correlation of changes in detector output induced by small delivery errors with other metrics commonly employed to quantify the deviations between calculated and delivered dose distributions was investigated. METHODS: Transmission detector measurements were performed at three institutions. Seven types of errors were induced in nine clinical step-and-shoot (S&S) IMRT plans by modifying the number of monitor units (MU) and introducing small deviations in leaf positions. Signal reproducibility was investigated for short- and long-term stability. Calculated dose distributions were compared in terms of gamma passing rates and dose-volume histogram (DVH) metrics (e.g., Dmean, Dx%, Vx%). The correlation between detector signal variations, gamma passing rates, and DVH parameters was investigated. RESULTS: Both short- and long-term reproducibility was within 1%. Dose variations down to 1 MU (?signal 1.1 +/- 0.4%) as well as changes in field size and positions down to 1 mm (?signal 2.6 +/- 1.0%) were detected, thus indicating high error-detection sensitivity. A moderate correlation of detector signal was observed with gamma passing rates (R2 = 0.57-0.70), while a good correlation was observed with DVH metrics (R2 = 0.75-0.98). CONCLUSION: The detector is capable of detecting small delivery errors in MU and leaf positions, and is thus a highly sensitive dose monitoring device for S&S IMRT for clinical practice. The results of this study indicate a good correlation of detector signal with DVH metrics; therefore, clinical action levels can be defined based on the presented data. PMID- 29255924 TI - Salvage radiotherapy in prostate cancer patients with biochemical relapse after radical prostatectomy : Prolongation of prostate-specific antigen doubling time in patients with subsequent biochemical progression. AB - BACKGROUND: In patients with prostate cancer (PCa) and biochemical progression (BP) after radical prostatectomy (RP), salvage radiotherapy (sRT) improves prostate cancer-specific survival (PCSS), but this evidence is based only on retrospective data. PATIENTS AND METHODS: In addition to our previous study of 151 patients with PCa and BP after RP, we performed univariate analyses of prostate-specific antigen (PSA) kinetics during sRT. In 11 patients with BP or initiation of hormonal treatment (HT) within 180 days after sRT, risk factors were assessed using Mann-Whitney U tests. PSA doubling times (PSADT) before and after sRT in 82 patients with BP after sRT were compared by a Wilcoxon test. RESULTS: After a median follow-up of 82 months, analysis of PSA kinetics during sRT did not show a statistically significant impact on a subsequent BP, PCSS, or overall survival at an administered dose of 30 or 45 Gy. The subgroup analysis of patients with early BP or early HT revealed higher Gleason scores (p = 0.008) and preoperative PSA values (p = 0.005), shorter PSADT prior to sRT (p < 0.0005), and longer time intervals from RP until the start of sRT (p = 0.005) compared to all other patients. In patients with subsequent BP, PSADTs were significantly prolonged after sRT (median PSADT 4.5 months before and 9.9 months after sRT, p < 0.0005). CONCLUSION: PSA monitoring during sRT did not predict the therapeutic success. Subgroup analysis suggests a lower probability of benefit for patients with the abovenamed risk factors . However, the prolonged PSADT after sRT reflects a benefit of sRT for the vast majority of patients. PMID- 29255925 TI - Increased senescent CD8+ T cells in the peripheral blood mononuclear cells of Behcet's disease patients. AB - Behcet's disease (BD) is a chronic inflammatory disease characterized by recurrent mucocutaneous, ocular, and skin lesions. Immunosenescence is associated with increased susceptibility to infection and chronic low grade inflammation. This study aimed to investigate the differences in the frequencies of immunosenescent cells in the peripheral blood mononuclear cells (PBMCs) of patients with BD. PBMCs were isolated from age-matched patients with active BD (n = 19), inactive BD (n = 20), disease controls (DCs, n = 15) and healthy controls (HCs, n = 15). The frequencies of senescent CD4+ T cells (CD3+ CD4+ CD27- CD28- cells), CD8+ T cells (CD3+ CD8+ CD27- CD28- cells) and B cells (CD19+ CD27- IgD- cells) were analyzed using flow cytometry. Senescence-associated beta galactosidase activity was also measured in CD8+ T cells using flow cytometry with 5-dodecanoylaminofluorescein di-beta-D-galactopyranoside. Frequencies of senescent CD4+ and CD19+ cells were not significantly different between the groups. The frequency of senescent CD8+ T cells was significantly higher in active BD than in DCs and HCs. C-reactive protein and erythrocyte sedimentation rate levels, which indicate disease activity, did not correlate with increased frequencies of immunosenescent cells. Steroid treatment, specific organ involvement, and HLA-B51 status did not have a significant influence on the frequencies of immunosenescent cells. Frequencies of senescence-associated beta galactosidase+ CD8+ T cells were significantly higher in active BD and inactive BD compared to DCs and HCs. There was an increased frequency of senescent CD8+ T cells in the PBMCs of patients with BD. PMID- 29255926 TI - Optically stimulated luminescence (OSL) dosimetry in irradiated alumina substrates from mobile phone resistors. AB - In this study the dosimetric properties of alumina (Al2O3) substrates found in resistors retrieved from mobile phones were investigated. Measurements of the decline of optically stimulated luminescence (OSL) generated following exposure of these substrates to ionising radiation showed that 16% of the signal could still be detected after 2 years (735 days). Further, the magnitude of the regenerative dose (calibration dose; D i) had no impact on the accuracy of dose estimates. Therefore, it is recommended that the D i be set as low as is practicable, so as to accelerate data retrieval. The critical dose, D CL, and dose limit of detection, D DL, taking into account the uncertainty in the dose response relation as well as the uncertainty in the background signal, was estimated to be 7 and 13 mGy, respectively, 1 h after exposure. It is concluded that given the significant long-term component of fading, an absorbed dose of 0.5 Gy might still be detectable up to 6 years after the exposure. Thus, OSL from alumina substrates can be used for dosimetry for time periods far in excess of those previously thought. PMID- 29255927 TI - Trochlear pain: clinical characteristics and treatment outcomes. AB - Trochlear pain is frequently overlooked as published data regarding the clinical characteristic and current treatment are limited. The aim of this study is to evaluate this information from our experiences with trochlear pain. Medical records of 43 patients with trochlear pain from HRH Princess Maha Chakri Sirindhorn Medical Center between November 2010 and April 2017 were reviewed. Most patients were female (88%), with a median age of 51 years. Common characteristic symptoms of trochlear pain were acute, episodic, dull or pressure like, periorbital pain, often radiating to the forehead, and aggravated by eye movements, especially reading. The causes of trochlear pain were idiopathic or primary trochlear headache (n = 33, 77%) and trochleitis (n = 10, 23%). Treatments included oral NSAIDs or dexamethasone injection into the trochlear region. At a median follow-up of 11 months (range 0-64), 67% of the patients reported complete remission using oral medication. Local steroid injection is useful in non-responding patients to oral therapy with an overall remission of 86%. Successful treatment outcome was achieved in most patients. PMID- 29255928 TI - The effect of case-based discussion of topics with experts on learners' opinions: implications for spinal education and training. AB - PURPOSE: This investigation aimed to examine the extent to which case-based discussion with experts could influence the audience's opinions on the treatment of patients during a continuing medical education event for spine surgeons. METHODS: We conducted a prospective controlled crossover study of 90 surgeons. During a continuing medical education activity using case-based discussion, quiz questions were used which asked participants (attendants and faculty group) their opinions on the best choices about diagnosis and treatment in a number of cases. No answer was considered correct, but we evaluated the number of participants choosing each specific answer among a number of valid options. Quiz questions were collected with an automated response system at the entry and at the end of each case discussion. Change in participant's opinions was estimated from the change in the preferred answers between the entry and exit quizzes. Chi-square analysis was performed to determine significance. RESULTS: Sixty-two attendants out of eighty three (75%) and six faculties out of twelve (50%) responded to the survey. After the case discussion, 68.2% (p < 0.04, Chi-square test) of the attendants changed their opinion on the appropriate treatment. The faculty answers, however, showed no significant change in opinions regarding the identification of the appropriate treatment. CONCLUSIONS: On the basis of our results, case-based discussion driven by experts, as a form of teaching, has a measurable effect in terms of changes in the learners' opinions. PMID- 29255929 TI - Reactivity of silagermenylidene toward nitrous oxide: a preliminary DFT study. AB - The possible reaction mechanism of silagermenylidene and its NHC (N-heterocyclic carbene) coordinated form with N2O were investigated by DFT methods. Mainly, the potential energy surfaces of the five pathways I-IV were explored. Pathways I, II, III, and III' deal with the oxidation of silagermenylidene, whereas that of NHC coordinated form is associated with pathways I, III, III', and IV. Pathway I is initiated by the interaction between terminal N atom of N2O and Si atom of silagermenylidene in a stepwise manner. Pathway II details concerted direct oxidation of silagermenylidene. Pathways III and III' are related to the concerted 1,3-dipolar cycloaddition steps. Pathway IV is about the interaction of terminal atoms of N2O with carbenic Ge atom of silagermenylidene. All the proposed pathways I-IV portray the isomerization of silagermenylidenes to silagermoxiranylidenes. The subsequent N2O addition to the silagermoxiranylidenes was also investigated in the present study. Somehow with a trend similar to silagermenylidenes, the proposed pathways I-IV exist for the second molecule N2O activation by silagermoxiranylidenes. A comparison of the free energy profiles of the proposed pathways gave the important result that pathways III and III' remain the most facile mechanisms to activate N2O in all cases. We strongly believe that the proposed mechanisms will be effective to better understand the chemistry of heavier vinylidenes and provide further impetus to this field. Graphical Abstract The possible oxidation reaction mechanism of silagermenylidene with nitrous oxide was investigatedthrough density functional calculations. The concerted 1,3 dipolar cycloadditions are determined to beenergetically most facile pathways. PMID- 29255930 TI - Effects of folic acid supplementation on cognitive function and Abeta-related biomarkers in mild cognitive impairment: a randomized controlled trial. AB - PURPOSE: Observational studies have frequently reported that low blood folate concentrations are associated with poor cognitive performance. Our previous studies have shown the potential beneficial effect on the metabolite levels of methionine cycle and peripheral blood inflammatory cytokines from 6- and 12-month folic acid supplementation on cognitive function in mild cognitive impairment (MCI). This study aims to continue exploring the effect of 24-month folic acid supplementation on cognitive function and pathological mechanism in MCI. METHODS: 180 individuals with MCI were identified and randomly divided into intervention (folic acid 400 ug/day, n = 90) and convention (n = 90) groups. Cognitive function (WAIS-RC) and blood Abeta-related biomarkers were measured at baseline and at 6, 12, 18, and 24 months. Data were analyzed using generalized estimating equation. This trial has been registered with Trial Number: ChiCTR-TRC-13003227. RESULTS: During the follow-up, scores of full scale IQ, verbal IQ, and subdomains of Information and Digit Span were significantly higher in the intervention group than those in the convention group (P < 0.05). In the intervention group, blood homocysteine, S-adenosylhomocysteine (SAH), Abeta-42, and the expression of APP mRNA were decreased (P < 0.05), while S-adenosylmethionine (SAM), SAM/SAH ratio, and the expression of DNA methyltransferase mRNA were increased (P < 0.05). CONCLUSION: Folic acid supplementation appears to improve cognitive function and reduce blood levels of Abeta-related biomarkers in MCI. Larger-scale double-blind placebo-controlled randomized trials of longer duration are needed. PMID- 29255931 TI - Dietary guanidinoacetic acid does not accumulate in the brain of healthy men. AB - We conducted a secondary analysis of a previously completed trial to determine the effects of 8-week guanidinoacetic acid (GAA) loading on brain GAA levels in five healthy men. Brain magnetic resonance spectroscopy (1H-MRS) was taken at baseline and post-administration, with spectra additionally analyzed for brain GAA and glutamate concentrations using TARQUIN 4.3.10 software. Brain GAA levels remained essentially unchanged at follow-up (an increase of 7.7% from baseline levels; 95% confidence interval, - 24.1% to 39.5%; P = 0.88) when averaged across 12 white and grey matter voxel locations. No significant changes were found for brain glutamate levels during the study (P = 0.64). Supplemental GAA appears to be safe intervention concerning brain GAA deposition, at least with GAA dosages used. PMID- 29255932 TI - Correction to: Determination of trace metal concentration in compost, DAP, and TSP fertilizers by neutron activation analysis (NAA) and insights from density functional theory calculations. AB - The original version of this article unfortunately contained an error in the body text and in Tables 4 and 6. The corrected version of the sentences and Tables are given below. PMID- 29255933 TI - RE: Comment on Asghari et al. 2017: On the mechanisms of melatonin in protection of aluminum phosphide cardiotoxicity. PMID- 29255934 TI - Cardiovascular effects of Hodgkin's lymphoma: a review of literature. AB - Hodgkin's lymphoma (HL) constitutes 0.6% of all the cancers diagnosed worldwide and 10% of all lymphomas. Ten-year survival rate for HL is estimated to be 80% and cardiovascular death is the prevalent cause for a non-malignant death among these HL survivors. We are reviewing the cardiovascular morbidities associated with Hodgkin's lymphoma from the available literature. We performed a systematic review of all articles published from January 1, 1960 to October 1, 2016 on the MEDLINE database using PubMed search engine. Key factors in the diagnosis and management of these conditions are discussed in individual sections. PMID- 29255936 TI - Bacterioplankton Responses to Increased Organic Carbon and Nutrient Loading in a Boreal Estuary-Separate and Interactive Effects on Growth and Respiration. AB - Increases in the terrestrial export of dissolved organic carbon (C) to rivers may be associated with additional loading of organic nitrogen (N) and phosphorus (P) to the coastal zone. However, little is known about how these resources interact in the regulation of heterotrophic bacterioplankton metabolism in boreal coastal ecosystems. Here, we measured changes in bacterioplankton production (BP) and respiration (BR) in response to full-factorial (C, N, and P) enrichment experiments at two sites within the Ore estuary, northern Sweden. The BR was stimulated by single C additions and further enhanced by combined additions of C and other nutrients. Single addition of N or P had no effect on BR rates. In contrast, BP was primarily limited by P at the site close to the river mouth and did not respond to C or N additions. However, at the site further away from the near the river mouth, BP was slightly stimulated by single additions of C. Possibly, the natural inflow of riverine bioavailable dissolved organic carbon induced local P limitation of BP near the river mouth, which was then exhausted and resulted in C-limited BP further away from the river mouth. We observed positive interactions between all elements on all responses except for BP at the site close to the river mouth, where P showed an independent effect. In light of predicted increases in terrestrial P and C deliveries, we expect future increases in BP and increases of BR of terrestrially delivered C substrates at the Ore estuary and similar areas. PMID- 29255935 TI - Cloning, purification and characterization of novel Cu-containing nitrite reductase from the Bacillus firmus GY-49. AB - Nitrite is generated from the nitrogen cycle and its accumulation is harmful to environment and it can be reduced to nitric oxid by nitrite reductase. A novel gene from Bacillus firmus GY-49 is identified as a nirK gene encoding Cu containing nitrite reductase by genome sequence. The full-length protein included a putative signal peptide of 26 amino acids and shown 72.73% similarity with other Cu-containing nitrite reductase whose function was verified. The 993-bp fragment encoding the mature peptide of NirK was cloned into pET-28a (+) vector and overexpressed as an active protein of 36.41 kDa in the E.coli system. The purified enzyme was green in the oxidized state and displayed double gentle peaks at 456 and 608 nm. The specific activity of purified enzyme was 98.4 U/mg toward sodium nitrite around pH 6.5 and 35 degrees C. The K m and K cat of NirK on sodium nitrite were 0.27 mM and 0.36 * 103 s-1, respectively. Finally, homology model analysis of NirK indicated that the enzyme was a homotrimer structure and well conserved in Cu-binding sites for enzymatic functions. This is a first report for nitrite reductase from Bacillus firmus, which augment the acquaintance of nitrite reductase. PMID- 29255937 TI - Quantitative Analysis of Uncertainty in Medical Reporting: Part 3: Customizable Education, Decision Support, and Automated Alerts. AB - In order to better elucidate and understand the causative factors and clinical implications of uncertainty in medical reporting, one must first create a referenceable database which records a number of standardized metrics related to uncertainty language, clinical context, technology, and provider and patient data. The resulting analytics can in turn be used to create context and user specific reporting guidelines, real-time decision support, educational resources, and quality assurance measures. If this technology can be directly integrated into reporting technology and workflow, the goal is to proactively improve clinical outcomes at the point of care. PMID- 29255938 TI - Immunotherapy in triple-negative breast cancer. AB - Breast cancer can be classified based on the expression or lack of expression of protein receptors including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (Her2). The basal molecular subtype is mostly made up of breast cancers that do not express ER/PR or Her2, triple negative breast cancers (TNBC) (Bertucci et al. in Int J Cancer 123(1):236, 2008). TNBC tends to be more aggressive as there are no approved targeted treatments and the only treatment option currently is cytotoxic chemotherapy. Recent data show that some chemotherapies, specifically anthracyclines, not only have cytotoxic effects but also use the immune system by activating CD8+ T cell responses to kill cancer cells (Stagg et al. in Ther Adv Med Oncol 5(3):169-181, 2013), and thus, tumor-infiltrating lymphocytes respond well to chemotherapy. Currently, systemic immunotherapy which utilizes the patient's own immune system directly to eradicate and target neoplastic cells is being explored as treatment for TNBC as this type of breast cancer has been shown to be immunogenic (Yu et al. in Int J Environ Res Public Health 14:68, 2017). According to the Cancer Genome Atlas, TNBC has higher PD-L1 mRNA expression (Mittendorf et al. Cancer Immunol Res 2(4):361-370, 2014). Higher rates of CD8+ T cell infiltration were also found in TNBC according to a study by Liu et al. (Breast Cancer Res 14:R48, 2012). In TNBC patients, Pembrolizumab, a monoclonal antibody that targets programmed cell death protein 1 (PD-1), and Atezolizumab, a monoclonal antibody that targets its ligand, have been investigated to assess dose tolerability and side effects. Further studies involving vaccines, immunotherapy that targets cytotoxic T lymphocyte-associated protein-4 and PD-L1, are currently being investigated for treatment of TNBC. This review outlines the systemic immunotherapies that are currently being investigated for patients with TNBC. PMID- 29255939 TI - Development of a Novel Technique to Record 3D Intersegmental Angular Kinematics During Dynamic Spine Movements. AB - A novel method of recording intersegmental spine kinematics was developed. The method was required to: (1) have similar accuracy and precision as current methods that record gross spine kinematics; (2) be reasonably insensitive to errors associated with marker detection or misplacement; and (3) be reasonably insensitive to skin movement artefacts. Four healthy participants performed trunk flexion, lateral bending, and axial twist movements; data were collected using the intersegmental method as well as electromagnetic sensors. Comparing methods, gross angular kinematic differences were within 1 SD during flexion and lateral bend, while axial twist resulted in the largest differences. To test sensitivity to marker error, random error was added to marker positions. The most proximal and distal intersegmental units were the most sensitive to marker error. Adding additional markers at the ends or interpolating padded markers reduced this sensitivity. The influence of skin movement artefact was investigated by digitizing locations of the skin with respect to the spinous processes in both neutral and fully flexed postures. In the lumbar region, large skin artefacts had minimal effect on intersegmental angles. The greatest strength of this method is the ability to dynamically record intersegmental spine kinematics. PMID- 29255940 TI - Mechanism and regioselectivity of electrophilic aromatic nitration in solution: the validity of the transition state approach. AB - The potential energy surfaces in gas phase and in aqueous solution for the nitration of benzene, chlorobenzene, and phenol have been elucidated with density functional theory at the M06-2X/6-311G(d,p) level combined with the polarizable continuum solvent model (PCM). Three reaction intermediates have been identified along both surfaces: the unoriented pi-complex (I), the oriented reaction complex (II), and the sigma-complex (III). In order to obtain quantitatively reliable results for positional selectivity and for modeling the expulsion of the proton, it is crucial to take solvent effects into consideration. The results are in agreement with Olah's conclusion from over 40 years ago that the transition state leading to (II) is the rate-determining step in activated cases, while it is the one leading to (III) for deactivated cases. The simplified reactivity approach of using the free energy for the formation of (III) as a model of the rate determining transition state has previously been shown to be very successful for halogenations, but problematic for nitrations. These observations are rationalized with the geometric and energetic resemblance, and lack of resemblance respectively, between (III) and the corresponding rate determining transition state. At this level of theory, neither the sigma-complex (III) nor the reaction complex (II) can be used to accurately model the rate-determining transition state for nitrations. PMID- 29255941 TI - Pupillometry as an indicator of L-DOPA dosages in Parkinson's disease patients. AB - Dopamine was shown to induce mydriasis by excitation of alpha-adrenergic receptors at the dilator pupillae muscle. Pupilla diameter may thus serve as an indirect measure of peripheral pharmacokinetics of L-DOPA and dopamine. The aim of this study is to evaluate the effect of L-DOPA dosage on pupillometric parameters in Parkinson's disease (PD) patients. Sixteen PD patients and 14 healthy control subjects (CS) were studied. The statistical analysis revealed significant differences between CS and PD patients for the mean maximum and minimum pupil diameters (p = 0.017, p = 0.028, respectively), with higher values found in PD. Moreover, a significant dose-response relationship was found between the maximum pupil diameter and both the morning L-DOPA dose (R 2 = 0.78) and the total daily L-DOPA dose (R 2 = 0.93). A sigmoid-shaped curve best describes the dose-response relationship, with a ceiling effect at about 400 mg L-DOPA daily dose. In conclusion, measuring pupillometric parameters represents a sensitive tool for non-invasive evaluation of the peripheral effect of L-DOPA, especially with daily doses below 400 mg L-DOPA. PMID- 29255942 TI - Effects of long-term feed deprivation on body weight loss, muscle composition, plasma metabolites, and intermediate metabolism of meagre (Argyrosomus regius) under different water temperatures. AB - The effect of feed deprivation at four water temperatures (17, 20, 23, 26 degrees C) was investigated in meagre (Argyrosomus regius) of initial mean weight +/- SD, 116.16 +/- 4.74 g, in triplicate groups. Fish were deprived of feed for a period of 60 days and sampled on days 0, 14, 41, and 60, during which body weight, specific growth rate, somatic indices, muscle proximate composition, plasma metabolite levels (total lipids, proteins, cholesterol, triglycerides, glucose), and liver and muscle enzymatic activities [L-lactate dehydrogenase (L LDH), citrate synthase (CS), malate dehydrogenase (MDH)] were evaluated. Long term feed deprivation resulted in a significant decrease in body weight, condition factor (CF), hepatosomatic index (HSI), muscle lipids, and plasma metabolites (all except proteins) and increase in muscle moisture. Plasma glucose concentration decreased with time and became significantly lower at 41 and 60 days. Glucose concentration and weight loss expressed a different response in the short term (14 days) than in the long term (14 and 60 days) of feed deprivation, suggesting a change in glucose metabolic profile. After 60 days of feed deprivation, there was an increase in the L-LDH activity in the liver at all temperature levels, which reflects a rising glycolytic potential by activating the carbohydrate metabolism and an ATP-dependent demand. MDH activity increased in the liver and muscle, except at 17 degrees C in the muscle, which indicates aerobic glycolysis and lipolysis. CS activity in the liver increased after the 60 days, whereas that in the muscle decreased, indicating the muscle is less dependent on aerobic oxidation for energy reserves. PMID- 29255943 TI - Discovering the role of the apolipoprotein gene and the genes in the putative pullulan biosynthesis pathway on the synthesis of pullulan, heavy oil and melanin in Aureobasidium pullulans. AB - Pullulan produced by Aureobasidium pullulans presents various applications in food manufacturing and pharmaceutical industry. However, the pullulan biosynthesis mechanism remains unclear. This work proposed a pathway suggesting that heavy oil and melanin may correlate with pullulan production. The effects of overexpression or deletion of genes encoding apolipoprotein, UDPG pyrophosphorylase, glucosyltransferase, and alpha-phosphoglucose mutase on the production of pullulan, heavy oil, and melanin were examined. Pullulan production increased by 16.93 and 8.52% with the overexpression of UDPG-pyrophosphorylase and apolipoprotein genes, respectively. Nevertheless, the overexpression or deletion of other genes exerted little effect on pullulan biosynthesis. Heavy oil production increased by 146.30, 64.81, and 33.33% with the overexpression of UDPG pyrophosphorylase, alpha-phosphoglucose mutase, and apolipoprotein genes, respectively. Furthermore, the syntheses of pullulan, heavy oil, and melanin can compete with one another. This work may provide new guidance to improve the production of pullulan, heavy oil, and melanin through genetic approach. PMID- 29255944 TI - Natural plant hormones cytokinins increase stress resistance and longevity of Caenorhabditis elegans. AB - Cytokinins are phytohormones that are involved in many processes in plants, including growth, differentiation and leaf senescence. However, they also have various activities in animals. For example, kinetin and trans-zeatin can reduce levels of several aging markers in human fibroblasts. Kinetin can also protect mice against oxidative and glyoxidative stress, and prolong fruit flies' lifespan. Additionally, several cytokinins are currently used in cosmetics. To extend knowledge of the breadth of cytokinins' activities, we examined effects of natural cytokinin bases on the model nematode Caenorhabditis elegans. We found that kinetin, para-topolin and meta-topolin prolonged the lifespan of C. elegans. Kinetin also protected the organism against oxidative and heat stress. Furthermore, our results suggest that presence of reactive oxygen species, but not DAF-16 (the main effector of the insulin/insulin-like growth factor signaling pathway), is required for the beneficial effects of kinetin. Ultra-high performance liquid chromatography-tandem mass spectrometric analysis showed that kinetin is unlikely to occur naturally in C. elegans, but the worm efficiently absorbs and metabolizes it into kinetin riboside and kinetin riboside-5' monophosphate. PMID- 29255945 TI - Food for thought: association between dietary tyrosine and cognitive performance in younger and older adults. AB - The fact that tyrosine increases dopamine availability that, in turn, may enhance cognitive performance has led to numerous studies on healthy young participants taking tyrosine as a food supplement. As a result of this dietary intervention, participants show performance increases in working memory and executive functions. However, the potential association between habitual dietary tyrosine intake and cognitive performance has not been investigated to date. The present study aims at clarifying the association of episodic memory (EM), working memory (WM) and fluid intelligence (Gf), and tyrosine intake in younger and older adults. To this end, we acquired habitual tyrosine intake (food frequency questionnaire) from 1724 participants of the Berlin Aging Study II (1383 older adults, 341 younger adults) and modelled its relations to cognitive performance assessed in a broad battery of cognitive tasks using structural equation modeling. We observed a significant association between tyrosine intake and the latent factor capturing WM, Gf, and EM in the younger and the older sample. Due to partial strong factorial invariance between age groups for a confirmatory factor analysis on cognitive performance, we were able to compare the relationship between tyrosine and cognition between age groups and found no difference. Above and beyond previous studies on tyrosine food supplementation the present result extend this to a cross-sectional association between habitual tyrosine intake levels in daily nutrition and cognitive performance (WM, Gf, and EM). This corroborates nutritional recommendations that are thus far derived from single-dose administration studies. PMID- 29255946 TI - Bayesian evolutionary analysis for emerging infectious disease: an exemplified application for H7N9 avian influenza viruses. PMID- 29255947 TI - Pre-aggregation kinetics and intermediates of alpha-synuclein monitored by the ESIPT probe 7MFE. AB - The defining feature of the extensive family of amyloid diseases is the formation of networks of entangled elongated protein fibrils and amorphous aggregates exhibiting crossed beta-sheet secondary structure. The time course of amyloid conversion has been studied extensively in vitro with the proteins involved in the neurodegenerative pathology of Parkinson's disease (alpha-synuclein), Alzheimer's disease (Tau) and Huntington's disease (Huntingtin). Although much is known about the thermodynamics and kinetics of the transition from a soluble, intrinsically disordered monomer to the fibrillar end state, the putative oligomeric intermediates, currently considered to be the major initiators of cellular toxicity, are as yet poorly defined. We have detected and characterized amyloid precursors by monitoring AS aggregation with ESIPT (excited state intramolecular protein transfer) probes, one of which, 7MFE [7-(3-maleimido-N propanamide)-2-(4-diethyaminophenyl)-3-hydroxychromone], is introduced here and compared with a related compound, 6MFC, used previously. A series of 140 spectra for sparsely labeled AS was acquired during the course of aggregation, and resolved into the relative contributions (spectra, intensities) of discrete molecular species including the monomeric, fibrillar, and ensemble of intermediate forms. Based on these findings, a kinetic scheme was devised to simulate progress curves as a function of key parameters. An essential feature of the model, one not previously invoked in schemes of amyloid aggregation, is the catalysis of molecular fuzziness by discrete colloidal nanoparticles arising spontaneously via monomer condensation upon exposure of AS to >= 37 degrees C. PMID- 29255948 TI - Thromboelastometry for diagnosis of neonatal sepsis-associated coagulopathy: an observational study. AB - : Our aim was to evaluate the potential role of standard extrinsically activated thromboelastometry (EXTEM) assay in the early detection of neonatal sepsis. We studied 91 hospitalized neonates categorized in two groups: group A included 35 neonates with confirmed sepsis, while group B included 56 neonates with suspected sepsis; 274 healthy neonates served as controls. Whenever sepsis was suspected, EXTEM assay was performed, Score for Neonatal Acute Physiology Perinatal Extension (SNAPPE) and Tomicronllner score were calculated, and clinical findings and laboratory results were recorded. Septic neonates had significantly prolonged clotting time (CT) and clot formation time (CFT), and reduced maximum clot firmness (MCF), compared to neonates with suspected sepsis (p values 0.001, 0.001, and 0.009, respectively) or healthy neonates (p values 0.001, 0.001, and 0.021, respectively). EXTEM parameters (CT, CFT, MCF) demonstrated a more intense hypocoagulable profile in septic neonates with hemorrhagic diathesis than those without (p values 0.021, 0.007, and 0.033, respectively). In septic neonates, CFT was correlated with platelet count, SNAPPE, Tollner score, and day of full enteral feeding (p values 0.01, 0.02, 0.05, and 0.03, respectively). CONCLUSIONS: A ROTEM hypocoagulable profile at admission seems promising for the early detection of sepsis in neonates while the degree of hypocoagulation may be associated with sepsis severity. What is Known: * The early phase of septicemia might be difficult to be recognized in neonates. In adult septic patients, the diagnostic and prognostic role of thromboelastometry (ROTEM) have been extensively investigated. * Limited data are available on the role of ROTEM as an indicator of early neonatal sepsis. What is New: * ROTEM measurements indicate an early appearance of hypocoagulability in neonatal sepsis, while the degree of hypocoagulation might be associated with severity of sepsis. * ROTEM could be a useful tool in the early detection of sepsis in neonates. PMID- 29255949 TI - Measured parental height in Turner syndrome-a valuable but underused diagnostic tool. AB - : Early diagnosis of Turner syndrome (TS) is necessary to facilitate appropriate management, including growth promotion. Not all girls with TS have overt short stature, and comparison with parental height (Ht) is needed for appropriate evaluation. We examined both the prevalence and diagnostic sensitivity of measured parental Ht in a dedicated TS clinic between 1989 and 2013. Lower end of parental target range (LTR) was calculated as mid-parental Ht (correction factor 12.5 cm minus 8.5 cm) and converted to standard deviation scores (SDS) using UK 1990 data, then compared with patient Ht SDS at first accurate measurement aged > 1 year. Information was available in 172 girls of whom 142 (82.6%) were short at first measurement. However, both parents had been measured in only 94 girls (54.6%). In 92 of these girls age at measurement was 6.93 +/- 3.9 years, Ht SDS vs LTR SDS - 2.63 +/- 0.94 vs - 1.77 +/- 0.81 (p < 0.001), Ht SDS < LTR in 78/92 (85%). Eleven of the remaining 14 girls were < 5 years, while karyotype was 45,X/46,XX in 2 and 45,X/47,XXX in 3. CONCLUSION: This study confirms the sensitivity of evaluating height status against parental height but shows that the latter is not being consistently measured. What is Known: * Girls with Turner syndrome are short in relation to parental heights, with untreated final height approximately 20 cm below female population mean. * Measured parental height is more accurate than reported height. What is New: * In a dedicated Turner clinic, there was 85% sensitivity when comparing patient height standard deviation score at first accurate measurement beyond 1 year of age with the lower end of the parental target range standard deviation. * However, measured height in both parents had been recorded in only 54.6% of the Turner girls attending the clinic. This indicates the need to improve the quality of growth assessment in tertiary care. PMID- 29255950 TI - Clinical and genetic characterisation of a series of patients with triple A syndrome. AB - : Triple A syndrome (TAS) or Allgrove syndrome (OMIM #231550) is a rare autosomal recessive disorder characterised by adrenocorticotropic hormone-resistant adrenal insufficiency, alacrima, achalasia, and neurological and dermatological abnormalities. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Between 2006 and 2017, we evaluated six patients with a clinical diagnosis of TAS, based on the presence of at least two symptoms, usually adrenal insufficiency and alacrima. In all cases, genetic analysis revealed homozygous mutations in the AAAS gene. One novel mutation was detected: a homozygous 10-bp deletion (c.1264_1273del, p.Q422NfsX126) in exon 14 of the AAAS gene that caused a frameshift that introduced an aberrant stop codon after 126 amino acids. This genetic variant is likely to be pathogenic because it caused a significant change in protein structure. A precise genotype-phenotype correlation was impossible to establish. CONCLUSIONS: Based on our experience, we recommend that molecular analysis should be performed in the presence of alacrima and at least one more symptom of TAS. Our cases share many clinical features of TAS and underline the variability in this syndrome, as well as the need for thorough investigation following a multidisciplinary approach. What is known: * Triple A syndrome is characterised by achalasia, alacrima, adrenal insufficiency, neurological impairment, and dermatological abnormalities. * A precise genotype-phenotype correlation has proved impossible to establish. What is new: * These cases add to a large number of similar case reports with limited novel information. * The newly identified AAAS gene mutation was reported. PMID- 29255951 TI - Impact of war on child health in northern Syria: the experience of Medecins Sans Frontieres. AB - : Few data are available to evaluate the impact of Syrian war on civilian population; to describe this impact on child health, this article uses data from Medecins Sans Frontieres-Operational Centre Amsterdam's activities in Tal-Abyad and Kobane cities, northern Syria (2013-2016). Data were obtained from routine medical datasets and narrative reports, for out-patient clinics, immunisation, nutritional monitoring and assessments, and in-patient care, and were analysed quantitatively and qualitatively. Infections were the largest contributor to morbidity. The proportion of < 5 year out-patient consultations of infectious diseases that are listed for outbreak monitoring in emergencies was 15% in 2013, 51% in 2014, 75% in 2015 and 70% in 2016. Thalassemia was recorded in 0.5% of 2014 < 5 year out-patient consultations and 3.4% of 2013-2014 < 18-year in patient admissions. Measles immunisation activities and routine Extended Programme for Immunisation were re-activated across northern Syria; however, immunisation coverage could not be calculated. Results from our routine data must be compared cautiously, due to differences in settings and disease categories. CONCLUSION: With such scattered interventions, routine data are limited in providing a quantified evidence of emergency's health impact; however, they help in drawing a picture of children's health status and highlighting difficulties in providing curative and preventive services, in order to reflect part of population's plight. What is Known * Few data exist to evaluate the impact of the Syrian war on the health of children; * Medecins Sans Frontieres (MSF-OCA) has worked in northern Syria during different times since 2013. What is New * Quantitative and qualitative analysis of MSF's routine medical data and situtation reports show that one fifth of all consultations in children < 5 years in MSF health facilities in northern Syria 2013-2016 were due to communicable diseases; * The analysis also highlights the burden of chronic conditions that were prevalent in Syria before the war, e.g. thalassemia. PMID- 29255952 TI - Employee-Organization Pro-environmental Values Fit and Pro-environmental Behavior: The Role of Supervisors' Personal Values. AB - This study examines the relationship among the employees-organization pro environmental values fit (E-O PEVs fit), supervisors' PEVs and employees' pro environmental behaviors (PEB). Informed by the PEB, organizational values and employee-organization fit literature, we propose and test hypotheses that under egoistic, altruistic and biosphere-value orientations, E-O PEVs fit versus non fit have significant effects on employees' private-sphere PEB and public-sphere PEB, identifying supervisors' PEVs as a moderator. An empirical investigation indicates that the effect of E-O PEVs fit on employees' private-sphere PEB and public-sphere PEB varies as the value orientation differs. More specifically, under the context of altruistic and biosphere-value orientations, if the organizational PEVs do not match the employees' PEVs, especially when the former exceeds the latter, employees' PEB will rise as the organizational PEVs increase. As for egoistic value orientation, when organizational PEVs exceed employees' PEVs, not only will public-sphere PEB stop decreasing and tend to stabilize, but also private-sphere PEB will rise to a slight degree. Furthermore, compared with altruistic and biospheric values dimensions, supervisors who promote egoistic PEVs will have a more significant effect on the relationship between global E-O PEVs fit and employees' PEB. Finally, we suggest that the goals of an organization and its supervisors need to be combined within the actual situation of Chinese corporations to truly implement corporate green practices by balancing the profit goal and the environmental goal. PMID- 29255953 TI - Synthetic Biology and the Translational Imperative. AB - Advances at the interface between the biological sciences and engineering are giving rise to emerging research fields such as synthetic biology. Harnessing the potential of synthetic biology requires timely and adequate translation into clinical practice. However, the translational research enterprise is currently facing fundamental obstacles that slow down the transition of scientific discoveries from the laboratory to the patient bedside. These obstacles including scarce financial resources and deficiency of organizational and logistic settings are widely discussed as primary impediments to translational research. In addition, a number of socio-ethical considerations inherent in translational research need to be addressed. As the translational capacity of synthetic biology is tightly linked to its social acceptance and ethical approval, ethical limitations may-together with financial and organizational problems-be co determinants of suboptimal translation. Therefore, an early assessment of such limitations will contribute to proactively favor successful translation and prevent the promising potential of synthetic biology from remaining under expressed. Through the discussion of two case-specific inventions in synthetic biology and their associated ethical implications, we illustrate the socio ethical challenges ahead in the process of implementing synthetic biology into clinical practice. Since reducing the translational lag is essential for delivering the benefits of basic biomedical research to society at large and promoting global health, we advocate a moral obligation to accelerating translational research: the "translational imperative." PMID- 29255955 TI - Splenic Artery Pseudoaneurysm. AB - Splenic artery pseudoaneurysm is an extremely rare entity, although it is the most frequent location of visceral pseudoaneurysms. Trauma or previous pancreatitis (where the proteolytic pancreatic enzymes lead to the formation of pseudoaneurysm, as a result of enzymatic injury to the splenic artery wall) (Amico and Alves in Pancreatology 14: 144-145, 2014) is the most frequent causes. A high degree of suspicion is required for the accurate diagnosis. The authors present a case of splenic artery pseudoaneurysm in a middle-aged man who came to the emergency department with several days of abdominal pain. PMID- 29255954 TI - Amine transaminases in chiral amines synthesis: recent advances and challenges. AB - Transaminases, which catalyze the stereoselective transfer of an amino group between an amino donor and a prochiral ketone substrate, are interesting biocatalytic tools for the generation of optically pure chiral amines. In particular, amine transaminases (ATAs) are of industrial interest because they are capable of performing reductive amination reactions using a broad range of amine donors and acceptors. The most remarkable example of ATAs industrial application is in the production process of the anti-hyperglycaemic drug sitagliptin (Januvia(r)/Janumet(r)), which generated around 6 billion U.S. dollars of revenue to Merck in 2016. In this review, an update about the availability of microbial ATAs, discovered by both screening and database-mining approaches, or obtained by protein engineering of wild-type enzymes, will be provided. Current challenges in ATAs application and possible solutions will be also discussed. In particular, innovative biocatalytic process strategies aimed at the improvement of ATAs performances in chiral amines synthesis, e.g., using in situ product removal process strategies or flow reactors, will be presented. The progress in the industrial exploitation of these enzymes will be highlighted by selected examples of large-scale ATA-catalyzed processes. PMID- 29255956 TI - A Large Intussuscepting Gastric Lipoma. AB - Lipomas of the lower foregut are exceptionally rare. Presenting symptoms often include bleeding, weight loss, and obstructive symptoms. Surgical resection remains the standard treatment. We report a case of a large intussuscepting gastric lipoma. PMID- 29255957 TI - Pelvic Solitary Fibrous Tumor. PMID- 29255958 TI - [Relevance and therapy of intracranial arachnoidal cysts]. AB - Intracranial arachnoidal cysts (AC) are relevant due to their space-demanding character. The pathophysiological sequelae are dependent on the size and location of the cyst and the patient's age. Direct pressure on surrounding tissue causes headaches (meninges) or rarely seizures (brain tissue). Cerebrospinal fluid (CSF) circulation disturbances resulting from brain mass displacement with occlusion of, for example, the foramen monroi or the aqueduct cause occlusive hydrocephalus, which can lead to an increase in intracranial pressure. Depending on age, the typical primary clinical symptoms or findings differ. In adults and older children, headaches are usually the first clinical symptom. Children, in whom skull growth is not yet complete, present with a head circumference above the 97th percentile. An abnormal one-sided deflection of the calotte in the region of the underlying AC may also be present. Cranial magnetic resonance imaging (cMRI), the first-line diagnostic tool of choice to demonstrate size and location of the cysts and the surrounding intracranial structures, is of utmost importance for therapy planning. In addition, further malformations can be detected. Moreover, cMRI may also be useful for a rough assessment of increased intracranial pressure (ICP). In most symptomatic AC, surgical treatment is unavoidable. The primarily goal is to establish communication between the CSF and the cysts' content in order to effect pressure equalization. If the CSF reabsorption capacity is insufficient, it may also be necessary to implant a CSF shunt. Asymptomatic arachnoidal cysts should be strictly followed clinically and by cMRI over time. The reasonable frequency for follow-up depends on the size and location of the cyst. PMID- 29255960 TI - Brief Report: Improving Social Outcomes for Students with Autism at Recess Through Peer-Mediated Pivotal Response Training. AB - Many students with Autism Spectrum Disorder (ASD) struggle to appropriately interact and play with their peers at recess. In this pilot feasibility study, we tested the efficacy of practitioner-implemented, peer-mediated Pivotal Response Training (PRT) with 11 elementary and middle school students with ASD. Participants were randomly assigned to a treatment or control group. We measured outcomes at multiple time points, and analyzed data using multi-level modeling with time nested within student. We demonstrated large and statistically significant increases in peer interaction (d = 1.13). Appropriate play with peers also increased substantially (d = 0.89). Practitioners and students provided positive feedback. These findings suggest school staff can feasibly facilitate peer-implemented PRT that improves social outcomes for students with ASD at recess. PMID- 29255959 TI - Composition and functional property of photosynthetic pigments under circadian rhythm in the cyanobacterium Spirulina platensis. AB - Circadian rhythm is an important endogenous biological signal for sustainable growth and development of cyanobacteria in natural ecosystems. Circadian effects of photosynthetically active radiation (PAR), ultraviolet-A (UV-A) and ultraviolet-B (UV-B) radiations on pigment composition have been studied in the cyanobacterium Spirulina platensis under light (L)/dark (D) oscillation with a combination of 4/20, 8/16, 12/12, 16/8, 20/4 and 24/24 h time duration. Circadian exposure of PAR + UV-A (PA) and PAR + UV-A + UV-B (PAB) showed more than twofold decline in Chl a, total protein and phycocyanin (PC) in light phase and significant recovery was achieved in dark phase. The fluorescence emission wavelength of PC was shifted towards lower wavelengths in the light phase of PAB in comparison to P and PA whereas the same wavelength was retrieved in the dark phase. The production of free radicals was accelerated twofold in the light phase (24 h L) whereas the same was retrieved to the level of control during the dark phase. Oxidatively induced damage was alleviated by antioxidative enzymes such as catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and ascorbate peroxidase (APX) in the light phase (0-24-h L) whereas the dark phase showed significant inhibition of the same enzymes. Similar characteristic inhibition of free radicals and recovery of PC was observed inside cellular filament after circadian rhythm of 24/24 h (L/D). Circadian exposure of P, PA and PAB significantly altered the synthesis and recovery of pigments that could be crucial for optimization and sustainable production of photosynthetic products for human welfare. PMID- 29255961 TI - Laparoscopic cholecystectomy with two mini cosmetic incisions. AB - Minimally invasive surgery gained popularity between general surgeons especially laparoscopic four-port cholecystectomy. By introducing different methods such as NOTES and SILS, the costs elevated with its cosmetics. We aim to study a new technique of laparoscopic cholecystectomy by two incisions with best cosmetics, and same quality and lower cost as conventional four-port laparoscopic cholecystectomy and make a comparison between them. In a double-blind clinical trial from December 2012 to September 2014, patients with cholelithiasis who presented to general surgery clinic and candidate for laparoscopic cholecystectomy were studied. Half of patients underwent double-incision laparoscopic cholecystectomy and other half underwent conventional four-port laparoscopic cholecystectomy. The mean age and BMI were higher in double-incision and four-port group, respectively, but not statistically different. Also male to female ratio was 6:1 in double-incision group and 9:1 in four-port group, and they were not statistically different. The mean operation time was about 2 min more in double-incision group, but it is trivial to consider a significant difference at level of 5%. The mean pain score (0-10) was significantly lower in double incision group in comparison with four-port group (p < 0.0001). Patients in double incision group reported higher satisfaction and were sooner in return to work than in four-port group (p < 0.0001). It seems that DILS for uncomplicated cholelithiasis is safe. By reducing port number, we succeed in reducing the pain and need for analgesics, reducing hospital staying and sooner return to work. By taking into account using conventional CLS instrument and lowering the hospital charges, it could be a good alternative to SILS. PMID- 29255962 TI - Can we correlate pelvic floor dysfunction severity on MR defecography with patient-reported symptom severity? AB - MR defecography (MRD) is an alternative to conventional defecography (CD) which allows for dynamic visualisation of the pelvic floor. The aim of this study was to assess whether MRI features indicative of pelvic floor dysfunction correlated with patient-reported symptom severity. MR proctograms were matched to a prospectively-maintained functional database. Univariate and multivariate analyses were performed using pre-treatment questionnaire responses to the Birmingham Bowel, Bladder and Urinary Symptom Questionnaire (BBUSQ), Wexner Incontinence Score (WIS), and modified Obstructed Defecation Symptom (ODS) Score. 302 MRI proctograms were performed between January 2012 and April 2015. 170 patients were included. Patients with a rectocele > 2 cm (p = 0.003; OR 5.756) or MRD features suggestive of puborectalis syndrome (p = 0.025; OR 8.602) were more likely to report a higher ODS score on multivariate analysis. Lack of rectal evacuation was negatively associated with an abnormal WIS (p = 0.007; OR 0.228). Age > 50 (p = 0.027, OR 2.204) and a history of pelvic floor surgery (p = 0.042, OR 0.359) were correlated with an abnormal BBUSQ incontinence score. Lack of rectal evacuation (p = 0.027, OR 3.602) was associated with an abnormal BBUSQ constipation score. Age > 50 (p = 0.07, OR 0.156) and the presence of rectoanal intussusception (p = 0.010, OR 0.138) were associated with an abnormal BBUSQ evacuation score. Whilst MRD is a useful tool in aiding multidisciplinary decision making, overall, it is poorly correlated with patient-reported symptom severity, and treatment decisions should not rest solely on results. PMID- 29255963 TI - When aphasia is due to aphasic status epilepticus: a diagnostic challenge. AB - Aphasic status epilepticus is an uncommon entity that should be included in the differential diagnosis of persistent and sudden language disorders. In our study, we describe seven patients admitted with clinical and electroencephalographic diagnosis of aphasic status, who were studied with both neuroimaging and electroencephalogram. The mean age was 65.9 years (range of 39-89). Three of the patients had previously been diagnosed of epilepsy. The aphasia was global in six patients. In one case, we found foci of the left hemorrhagic contusions. The initial electroencephalogram (EEG) was not conclusive of status in two patients. In one patient, neuroimaging showed left hemispheric hypoperfusion, compatible with postictal changes. Six out of seven patients required at least two antiepileptic drugs. Three patients died of systemic complications (infectious causes), whereas the other four cases had a complete recovery. Our study highlights that a second EEG study might be necessary to confirm epileptiform activity, when clinical features and other tests suggest an epileptic origin. An early and specific treatment, avoiding or diminishing comorbidities, might significantly improve the prognosis of these patients. PMID- 29255964 TI - Prevalence, intensity and population dynamics of hard ticks (Acari: Ixodidae) on sheep in the humid tropics of Mexico. AB - Hard ticks are a perennial problem in livestock systems throughout Mexico. No data are currently available on tick prevalence, infestation intensity and population dynamics for sheep in the humid tropics of Mexico. Blackbelly sheep (n = 30) in Tabasco state, Mexico, were examined every 3 weeks for 1 year, and all Ixodidae ticks were counted and removed for analysis. Tick species were identified, infestation prevalence and intensity calculated per animal, and infestation per body zone determined. Overall infestation on the studied animals was 51.9%. Four tick species were identified (Amblyomma mixtum, A. imitator, Rhipicephalus microplus and R. annulatus), the most abundant being A. mixtum (94.9%). Prevalence was highest during the northwinds season (61.9%), followed by the dry (48.5%) and rainy (47.3%) seasons; however, the intensity (2.01-2.07 ticks/sheep) did not differ between seasons. Infestation was most frequent in certain zones including the axilla, crotch, udder, abdomen, thorax and rib area. Sheep in the humid tropics of Tabasco, Mexico, are parasitized by four hard tick species and prevalence is highest in the northwinds season. The present data constitute an important baseline for developing sustainable tick control programs for sheep in the humid tropics of Mexico. PMID- 29255965 TI - External morphology of the mouthparts and observations on behavior of Tuckerella japonica on Camellia sinensis in the continental USA. AB - Tuckerella japonica Ehara (Acari: Tetranychoidea: Tuckerellidae) was found on stems of seedling plants of Camellia sinensis (L.) O. Kuntze (Theaceae) in the continental USA. This mite is able to pierce exposed green periderm tissue with its paired stylets on 1- to 3- or 4-year-old stems where the outer bark had split longitudinally. The mite was not found on branches older than 3 or 4 years, where splitting diminished and, eventually, a uniform covering of bark was formed. The mouthparts of T. japonica were examined under scanning electron microscopy and their external morphology was compared with known Tetranychoidea. There were usually one or two feeding holes in an area where the female subsequently deposited one or more eggs. Females were observed defending the areas where their eggs and/or young occurred. This behavior along with potentially limited access to exposed periderm or availability of shoots in the rows of plants may restrict higher populations of T. japonica from becoming established. The potential of T. japonica as an economic pest remains unknown at this time. PMID- 29255966 TI - Thrombin inhibitor from the salivary gland of the camel tick Hyalomma dromedarii. AB - Blood-sucking arthropods have different types of anticoagulants to allow the ingestion of a blood meal from their hosts. In this study, five anticoagulants prolonging the activated partial thromboplastin time were resolved from the salivary gland crude extract of the camel tick Hyalomma dromedarii by chromatography on diethylaminoethyl (DEAE)-cellulose column. They were designated P1, P2, P3, P4 and P5 according to their elution order. P5 was found to be a potent thrombin inhibitor and purified by ultrafiltration through two centrifugal concentrators of 50 and 30 kDa molecular weight cut-off (MWCO), respectively. The camel tick salivary gland thrombin inhibitor was purified 60.6 folds with a specific activity of 564 units/mg protein. It turned out to be homogenous on native-PAGE with molecular weight of 36 kDa as detected on 12% SDS-PAGE. It inhibits bovine thrombin competitively with K i value of 0.55 MUM. A task for the future will be the elucidation of this thrombin inhibitor structure to allow its application in thrombosis treatment. PMID- 29255967 TI - VATS segmentectomy: past, present, and future. AB - Video-assisted thoracoscopic surgery (VATS) has gradually been implemented in thoracic surgery, and the VATS approach has now been extended to technically challenging procedures, such as segmentectomy. The definition of VATS segmentectomy is changing over time, and the repertoire of segmentectomy is getting wider with increasing reports on atypical segmentectomy. VATS segmentectomy bears surgical, oncological, and technical advantages; however, there are still areas of controversy, particularly regarding oncological outcomes. The indication of VATS segmentectomy is diverse and is used for treating lung cancer, metastatic lung tumors, or a variety of nonmalignant diseases. It is particularly valuable for the lung-sparing resection of deeply located small nodules or repeated surgery for multiple lung lesions. VATS segmentectomy requires a thorough analysis of segmental anatomy and a tailored preoperative planning with the assessment of surgical margins. Technical challenges include intraoperative navigation, methods to identify and dissect the intersegmental plane, and the prevention of air leakage. This review will discuss the present state of VATS segmentectomy, with a focus on past studies, current indications and techniques, and future view. PMID- 29255968 TI - A surgical case of methotrexate-associated lymphomatoid granuloma. AB - We reported a surgical case of methotrexate-associated lymphomatoid granuloma. A 69-year-old female had been treated with methotrexate for rheumatoid arthritis for 35 months. The patient underwent partial resection of the right upper pulmonary lobe for lung cancer when she was 67 years old. A nodule was detected in the left lung field on a chest radiograph performed during the postoperative follow-up period. Computed tomography revealed a 28-mm nodule in the lower left pulmonary lobe. A transbronchial biopsy examination did not lead to a diagnosis. The pulmonary nodule subsequently increased in size. We suspected a malignant tumor and performed lower left lobectomy. A pathological examination revealed lymphomatoid granuloma. Finally, the patient was diagnosed with methotrexate associated lymphomatoid granuloma based on her history of oral methotrexate treatment. PMID- 29255969 TI - Recombinant entomopathogenic agents: a review of biotechnological approaches to pest insect control. AB - Although the use of chemical pesticides has decreased in recent years, it is still a common method of pest control. However, chemical use leads to challenging problems. The harm caused by these chemicals and the length of time that they will remain in the environment is of great concern to the future and safety of humans. Therefore, developing new pest control agents that are safer and environmentally compatible, as well as assuring their widespread use is important. Entomopathogenic agents are microorganisms that play an important role in the biological control of pest insects and are eco-friendly alternatives to chemical control. They consist of viruses (non-cellular organisms), bacteria (prokaryotic organisms), fungi and protists (eukaryotic organisms), and nematodes (multicellular organisms). Genetic modification (recombinant technology) provides potential new methods for developing entomopathogens to manage pests. In this review, we focus on the important roles of recombinant entomopathogens in terms of pest insect control, placing them into perspective with other views to discuss, examine and evaluate the use of entomopathogenic agents in biological control. PMID- 29255970 TI - Timing of tracheostomy in patients with prolonged endotracheal intubation: a systematic review. AB - The objective of this article is to evaluate the appropriate timing of tracheostomy in patients with prolonged intubationregarding the incidence of hospital-acquired pneumonia, mortality, length of stay in intensive care unit (ICU) and duration of artificial ventilation. The study included published articles yielded by a search concerning timing of tracheostomy in adult and pediatric patients with prolonged intubation. The search was limited to articles published in English language in the last 30 years (between 1987 and 2017). For the 690 relevant articles, we applied our inclusion and exclusion criteria and only 43 articles were included. 41 studies in the adult age group including 222,501 patients and 2 studies in pediatric age group including 140 patients met our criteria. Studies in adult age group were divided into three groups according to the methodology of determining the cut off timing for early tracheostomy, they were divided into studies that considered early tracheostomy within the first 7, 14 or 21 days of endotracheal intubation, while in pediatric age group the cut off timing for early tracheostomy was within the first 7 days of endotracheal intubation. There was a significant difference in favor of early tracheostomy in adults' three groups and pediatric age group as early tracheostomy was superior regarding reduced duration of mechanical ventilation, with less mortality rates and less duration of stay in ICU. Regarding hospital-acquired pneumonia, it was significantly less in adult groups but with no significant difference in pediatric age group (3 patients out of 72 pediatric patient with early tracheostomy had pneumonia compared to 11 patients out of 68 with late tracheostomy). Studies defining early tracheostomy as that done within 7 days of intubation had better results than those defining early tracheostomy as that done within 14 or 21 days of intubation. In conclusion, early tracheostomy within 7 days of intubation should be done for both adults and pediatric patients with prolonged intubation. PMID- 29255971 TI - Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects. AB - BACKGROUND: A fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1. OBJECTIVE: The objective of this study was to assess the combination's drug-drug interaction potential in vivo using a validated cocktail of eight cytochrome P450 (CYP) and transporter probes. METHODS: We conducted an open-label single-sequence study in healthy adults (n = 20) given single-dose caffeine (CYP1A2 substrate), metoprolol (CYP2D6), flurbiprofen (CYP2C9), montelukast (CYP2C8), omeprazole (CYP2C19), midazolam (CYP3A4), digoxin (P glycoprotein), and pravastatin (organic anion-transporting polypeptide), alone or with steady-state twice-daily DCV/ASV/BCV 30/200/75 mg (with or without additional BCV 75 mg to adjust for higher exposure in hepatitis C virus infection). RESULTS: Daclatasvir/asunaprevir/beclabuvir did not affect CYP1A2, CYP2C8, or CYP2C9; the probe maximum observed concentration and area under the concentration-time curve extrapolated to infinite time geometric mean ratios and 90% confidence intervals were all within the 0.8-1.25 bioequivalence range. Beclabuvir showed moderate dose-dependent CYP2C19 induction; omeprazole maximum observed concentration and area under the concentration-time curve from 0 to the last quantifiable concentration were lower with additional BCV [geometric mean ratio 0.36 (90% confidence interval 0.23-0.55) and 0.34 (0.25-0.46), respectively] than without [0.57 (0.42-0.78), 0.48 (0.39-0.59)]. Weak-to-moderate CYP3A4 induction was observed, plus weak CYP2D6, P-glycoprotein, and organic anion-transporting polypeptide inhibition [maximum observed concentration and area under the concentration-time curve extrapolated to infinite time without additional BCV: midazolam 0.57 (0.50-0.65), 0.53 (0.47-0.60); metoprolol 1.40 (1.20-1.64), 1.71 (1.49-1.97); digoxin 1.23 (1.12-1.35), 1.23 (1.17-1.29); pravastatin 2.01 (1.63-2.47), 1.68 (1.43-1.97)]. CONCLUSIONS: No dose adjustments with DCV/ASV/BCV are indicated for CYP1A2, CYP2C8, CYP2C9, or P-glycoprotein substrates. CYP3A4, CYP2D6, and OATP substrates should be co-administered with caution. Co-administration with agents solely metabolized by CYP2C19 is not recommended. PMID- 29255973 TI - Reconsidering the Clapeyron equation in the freezing of colloidal suspensions: From macroscale to the microscale. AB - A long controversy of ice lensing exists in the research of frost heave. By elucidating the mechanical and thermodynamic equilibria at the interface, the thermodynamics of the water/ice interface is revealed from macroscale to microscale for the freezing of colloidal suspensions. The application of the Clapeyron equation is confirmed both at macroscale to microscale via curvature effect. The origin of ice lensing/banding can be initialized from the growth of pore ice in the interpretation of thermodynamics at the interface, even without the traditional mechanical analyses. It is also proposed that the packing status of the porous structure in the particle layer ahead of the water/ice interface determines the ice lensing behaviors. The results presented here show different scenarios compared with previous theoretical investigations of frost heave, and may shed light on the researches of this area. PMID- 29255972 TI - Decreased miR-17-92 cluster expression level in serum and granulocytes preceding onset of antithyroid drug-induced agranulocytosis. AB - PURPOSE: We aimed to determine changes in miR-17-92 cluster expression in serum and granulocytes from patients with antithyroid drug (ATD)-induced agranulocytosis. METHODS: In this study, real-time polymerase chain reaction (PCR) was used to detect serum miR-17-92 expression levels in 20 ATD-induced agranulocytosis and 16 control patients. Importantly, dynamic changes in neutrophil counts from granulocytopenia to agranulocytosis were observed in 6 of the 20 patients. miR-17-92 expression levels in granulocytes of those six patients under the granulocytopenia condition were measured and compared with corresponding granulocyte samples after recovery. Additionally, the expression levels of these miRNAs in patients with type I or type II bone marrow characteristics were analyzed, and the correlation between miR-17-92 and serum free thyroxine level was analyzed. RESULTS: We found that levels of miR-17-92 expression decreased in both serum and pre-agranulocytosis granulocytes from patients with ATD-induced agranulocytosis compared with those in serum and granulocytes from both recovered patients and control patients. However, no difference among patients with either type of bone marrow characteristics was observed, and no correlation between serum miR-17-92 and free thyroxine levels was found. CONCLUSION: In ATD-induced agranulocytosis, expression of the miR-17 92 cluster is reduced in both serum and granulocytes, though this alteration does not correlate with bone marrow characteristics or thyroid function. PMID- 29255975 TI - Family Trajectories Across Time and Space: Increasing Complexity in Family Life Courses in Europe? AB - Family life courses are thought to have become more complex in Europe. This study uses SHARELIFE data from 14 European countries to analyze the family life courses of individuals born in 1924-1956 from ages 15 to 50. A new methodological approach, combining complexity metrics developed in sequence analysis with cross classified multilevel modeling, is used to simultaneously quantify the proportions of variance attributable to birth cohort and country differences. This approach allows the direct comparison of changing levels of family trajectory differentiation across birth cohorts with cross-national variation, which provides a benchmark against which temporal change may be evaluated. The results demonstrate that family trajectories have indeed become more differentiated but that change over time is minor compared with substantial cross national variation. Further, cross-national differences in family trajectory differentiation correspond with differences in dominant family life course patterns. With regard to debates surrounding the second demographic transition thesis and the comparative life course literature, the results indicate that the degree of change over time tends to be overstated relative to large cross national differences. PMID- 29255974 TI - Comparing Observed and Unobserved Components of Childhood: Evidence From Finnish Register Data on Midlife Mortality From Siblings and Their Parents. AB - In this study, we argue that the long arm of childhood that determines adult mortality should be thought of as comprising an observed part and its unobserved counterpart, reflecting the observed socioeconomic position of individuals and their parents and unobserved factors shared within a family. Our estimates of the observed and unobserved parts of the long arm of childhood are based on family level variance in a survival analytic regression model, using siblings nested within families as the units of analysis. The study uses a sample of Finnish siblings born between 1936 and 1950 obtained from Finnish census data. Individuals are followed from ages 35 to 72. To explain familial influence on mortality, we use demographic background factors, the socioeconomic position of the parents, and the individuals' own socioeconomic position at age 35 as predictors of all-cause and cause-specific mortality. The observed part demographic and socioeconomic factors, including region; number of siblings; native language; parents' education and occupation; and individuals' income, occupation, tenancy status, and education-accounts for between 10 % and 25 % of the total familial influence on mortality. The larger part of the influence of the family on mortality is not explained by observed individual and parental socioeconomic position or demographic background and thus remains an unobserved component of the arm of childhood. This component highlights the need to investigate the influence of childhood circumstances on adult mortality in a comprehensive framework, including demographic, social, behavioral, and genetic information from the family of origin. PMID- 29255976 TI - Transport of Escherichia coli phage through saturated porous media considering managed aquifer recharge. AB - Virus is one of the most potentially harmful microorganisms in groundwater. In this paper, the effects of hydrodynamic and hydrogeochemical conditions on the transportation of the colloidal virus considering managed aquifer recharge were systematically investigated. Escherichia coli phage, vB_EcoM-ep3, has a broad host range and was able to lyse pathogenic Escherichia coli. Bacteriophage with low risk to infect human has been found extensively in the groundwater environment, so it is considered as a representative model of groundwater viruses. Laboratory studies were carried out to analyze the transport of the Escherichia coli phage under varying conditions of pH, ionic strength, cation valence, flow rate, porous media, and phosphate buffer concentration. The results indicated that decreasing the pH will increase the adsorption of Escherichia coli phage. Increasing the ionic strength, either Na+ or Ca2+, will form negative condition for the migration of Escherichia coli phage. A comparison of different cation valence tests indicated that changes in transport and deposition were more pronounced with divalent Ca2+ than monovalent Na+. As the flow rate increases, the release of Escherichia coli phage increases and the retention of Escherichia coli phage in the aquifer medium reduces. Changes in porous media had a significant effect on Escherichia coli phage migration. With increase of phosphate buffer concentration, the suspension stability and migration ability of Escherichia coli phage are both increased. Based on laboratory-scale column experiments, a one-dimensional transport model was established to quantitatively describe the virus transport in saturated porous medium. PMID- 29255978 TI - Siting and sizing of distributed generators based on improved simulated annealing particle swarm optimization. AB - Distributed power grids generally contain multiple diverse types of distributed generators (DGs). Traditional particle swarm optimization (PSO) and simulated annealing PSO (SA-PSO) algorithms have some deficiencies in site selection and capacity determination of DGs, such as slow convergence speed and easily falling into local trap. In this paper, an improved SA-PSO (ISA-PSO) algorithm is proposed by introducing crossover and mutation operators of genetic algorithm (GA) into SA-PSO, so that the capabilities of the algorithm are well embodied in global searching and local exploration. In addition, diverse types of DGs are made equivalent to four types of nodes in flow calculation by the backward or forward sweep method, and reactive power sharing principles and allocation theory are applied to determine initial reactive power value and execute subsequent correction, thus providing the algorithm a better start to speed up the convergence. Finally, a mathematical model of the minimum economic cost is established for the siting and sizing of DGs under the location and capacity uncertainties of each single DG. Its objective function considers investment and operation cost of DGs, grid loss cost, annual purchase electricity cost, and environmental pollution cost, and the constraints include power flow, bus voltage, conductor current, and DG capacity. Through applications in an IEEE33 node distributed system, it is found that the proposed method can achieve desirable economic efficiency and safer voltage level relative to traditional PSO and SA-PSO algorithms, and is a more effective planning method for the siting and sizing of DGs in distributed power grids. PMID- 29255977 TI - A systematic assessment of watershed-scale nonpoint source pollution during rainfall-runoff events in the Miyun Reservoir watershed. AB - The assessment of peak flow rate, total runoff volume, and pollutant loads during rainfall process are very important for the watershed management and the ecological restoration of aquatic environment. Real-time measurements of rainfall runoff and pollutant loads are always the most reliable approach but are difficult to carry out at all desired location in the watersheds considering the large consumption of material and financial resources. An integrated environmental modeling approach for the estimation of flash streamflow that combines the various hydrological and quality processes during rainstorms within the agricultural watersheds is essential to develop targeted management strategies for the endangered drinking water. This study applied the Hydrological Simulation Program-Fortran (HSPF) to simulate the spatial and temporal variation in hydrological processes and pollutant transport processes during rainstorm events in the Miyun Reservoir watershed, a drinking water resource area in Beijing. The model performance indicators ensured the acceptable applicability of the HSPF model to simulate flow and pollutant loads in the studied watershed and to establish a relationship between land use and the parameter values. The proportion of soil and land use was then identified as the influencing factors of the pollution intensities. The results indicated that the flush concentrations were much higher than those observed during normal flow periods and considerably exceeded the limits of Class III Environmental Quality Standards for Surface Water (GB3838-2002) for the secondary protection zones of the drinking water resource in China. Agricultural land and leached cinnamon soils were identified as the key sources of sediment, nutrients, and fecal coliforms. Precipitation volume was identified as a driving factor that determined the amount of runoff and pollutant loads during rainfall processes. These results are useful to improve the streamflow predictions, provide useful information for the identification of highly polluted areas, and aid the development of integrated watershed management system in the drinking water resource area. PMID- 29255979 TI - Single-phase cerium oxide nanospheres: An efficient photocatalyst for the abatement of rhodamine B dye. AB - Single-phase mesoporous CeO2 nanospheres were synthesized by template-free hydrothermal approach by the synthesis of CeCO3OH precursor combined with the calcination at 350 degrees C for 3.0 h. Precursor and calcined products were characterized by XRD, TGA, FESEM, EDX, TEM, N2 adsorption-desorption and pore size distribution analysis, UV-vis diffuse reflectance (UV-vis DRS), and photoluminescence (PL) analysis. The morphologies of CeO2 nanospheres were controlled via the optimization of urea concentration during the synthesis. Calcined CeO2 exhibited excellent photocatalytic activity of rhodamine B (RhB) dye degradation under UV-visible irradiation and mild acidic condition. Scavenger test analysis was used to confirm that the hydroxyl radicals, superoxide radicals, and photogenerated holes are the active photoinduced species of RhB degradation. A comparative study of PL intensity, dye adsorption, and zeta potential measurement revealed the efficient dye adsorption over different CeO2 photocatalysts. The RhB degradation rate constant has been found to raise linearly with increase of the surface properties. Repeatability test analysis proved the higher catalytic stability of CeO2 nanospheres without any noticeable loss of activity. Mass spectroscopy and ion chromatography analyses were used to detect the intermediate by-product formation. Finally, based on the results of intermediate detection, possible degradation pathways were also proposed including radical reactions, ring opening, and de-nitrification. PMID- 29255980 TI - Persistent plasticizers and bisphenol in the cheese of Tunisian markets induced biochemical and histopathological alterations in male BALB/c mice. AB - Clinical evidences, experimental models, and epidemiology of many studies suggest that phthalate-based plasticizers, aliphatic ester, and bisphenol A (BPA) have major risks for humans by targeting different organs and body systems. The current study has been designed firstly to analyze three categories of cheese with and without their exposure to the sun and packed in packages with an inner surface plastic-covered film in order to identify the dibutyl phthalate (DBP); benzyl butyl phthalate (BBP); bis(2-ethylhexyl) phthalate (DEHP); diisodecyl phthalate (DiDP); diisononyl phthalate (DiNP); and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) by GC-MS/MS, except for the bisphenol A, which is by UPLC-MS/MS, and secondly to assess the toxicity of the identified chemical molecules and cheese samples on the liver and kidney of mice. Our results showed that the cheese contains high quantities of DBP and DEHP with the concentrations up to 0.46 and 2.339 mg/kg, respectively. Other types of cheese, such as rolled and triangular cheeses, contain little quantities of the all substances at concentrations below the standard limits. In vivo, the obtained data clearly demonstrated that the acute administration of DBP, DEHP, and the tested cheese significantly induced liver and kidney injuries in mice manifested by a rise in plasma alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, lactate dehydrogenase, urea, creatinine, and uric acid when compared with control animals. In addition, the histopathological study confirmed the perturbation of biochemical parameters and showed that the hepatic and renal structures were altered. Indeed, the hepatotoxic and nephrotoxic effects are more pronounced when cheese was exposed to the sun. PMID- 29255981 TI - The effects of dissolved organic matter and feeding on bioconcentration and oxidative stress of ethylhexyl dimethyl p-aminobenzoate (OD-PABA) to crucian carp (Carassius auratus). AB - Bioconcentration of UV filters in organisms is an important indicator for the assessment of environmental hazards. However, bioconcentration testing rarely accounts for the influence of natural aquatic environmental factors. In order to better assess the ecological risk of organic UV filters (OUV-Fs) in an actual water environment, this study determined the influences of dissolved organic matter (DOM) (0, 1, 10, and 20 mg/L) and feeding (0, 0.5, 1, and 2% body weight/d) on bioconcentration of ethylhexyl dimethyl p-aminobenzoate (OD-PABA) in various tissues of crucian carp (Carassius auratus). Moreover, oxidative stress in the fish liver caused by the OD-PABA was also investigated by measuring activities of superoxide dismutase (SOD), catalase (CAT) and glutathione S transferase (GST), and levels of glutathione (GSH) and malondialdehyde (MDA). The bioconcentration of OD-PABA in the fish tissues was significantly decreased with the presence of DOM indicating a reduction of OD-PABA bioavailability caused by DOM. The bioconcentration factors (BCFs) decreased by 28.00~50.93% in the muscle, 72.67~96.74% in the gill, 37.84~87.72% in the liver, and 10.32~79.38% in the kidney at different DOM concentrations compared to those of the non-DOM treatments. Significant changes in SOD, CAT, GST, GSH, and MDA levels were found in the DOM- and OD-PABA-alone treatments. However, there were no significant differences in the SOD, CAT, GST, and MDA levels found when co-exposure to OD PABA and DOM. Feeding led to lower OD-PABA concentrations in the fish tissues, and the concentrations were decreased with increasing feeding ratios. BCFs in various tissues reduced by 39.75~72.52% in the muscle, 56.86~79.73% in the gill, 66.41~87.50% in the liver, and 75.88~89.10% in the kidney, respectively. In the unfed treatments, the levels of SOD and MDA were significantly higher than those of the fed ones while GST and GSH levels were remarkably inhibited indicating the enhanced effect of starvation to oxidative stress. There was no markedly alternation of the biomarker levels observed between different fed treatments. In conclusion, our study indicated that both DOM and feeding reduced bioconcentration of OD-PABA and alleviated oxidative stress to some extent in the crucian carp. PMID- 29255982 TI - Diversification and microscopic structure of tissues in endemic and endangered species of Dawkinsia tambraparniei from the river Tamiraparani, Tamil Nadu, India. AB - We investigated the study on the endemic and endangered species of Dawkinsia tambraparniei were confined only the areas of the river Tamiraparani. These species are under threats due to the menace of anthropogenic stress. To recognize the crisis behind the particular species, it was analyzed histologically and molecularly from the five pollutant levels of river Tamiraparani. Histologically, the microscopic examinations were also carried out from the crucial organs such as the brain, gill, heart, kidney, and liver, which confirm the spiky survivability of the endemic fish. Assessment of fish organ damages was observed highly in Kokkirakulam and Vannarapettai. Probably with conserved molecular sequences, the species can be identified out from the encountered surveillance of the particular taxa leading to the evolutionary circumstances. The phylogenetic analysis of Dawkinsia tambraparniei populations showed that Cheranmadevi and Vallandau sites populations were closely distributed. Even though the species have similarity sequences of each population were shown that the closely related with same genus but other sub-species. The observed results emphasize the conventional measures to conserve the endemic species and more effectual planning to the proximity of endurances in inhabited zone. PMID- 29255983 TI - Low temperature effects on nitrification and nitrifier community structure in V ASP for decentralized wastewater treatment and its improvement by bio augmentation. AB - The vegetation-activated sludge process (V-ASP) has been proved to be an environment-friendly decentralized wastewater treatment system with extra esthetic function and less footprint. However, the effects of low temperature on the treatment performance of V-ASP and related improvement methods are rarely investigated, up to now. In this work, the effect of low temperature on nitrification in V-ASP was comprehensively investigated from overall nitrification performance, substrate utilization kinetics, functional enzymatic activities, and microbial community structure shift by comparison with conventional ASP. Bio-augmentation methods in terms of single-time nitrifier enriched biomass dosage were employed to improve nitrification efficiency in bench- and full-scale systems. The experiment results demonstrated that the NH4+ N removal efficiency in V-ASP system decreased when the operational temperature decreased from 30 to 15 degrees C, and the decreasing extent was rather smaller compared to ASP, as well as ammonium and nitrite oxidation rates and enzymatic activities, which indicated the V-ASP system possesses high resistance to low temperature. With direct dosage of 1.6 mg nitrifier/gSS sludge, the nitrification efficiency in V-ASP was enhanced dramatically from below 50% to above 90%, implying that bio-augmentation was effective for V-ASP whose enzymatic activities and microbial communities were both also improved. The feasibility and effectiveness of bio-augmentation was further confirmed in a full-scale V-ASP system after a long-term experiment which is instructive for the practical application. PMID- 29255984 TI - Experimental research on the electromagnetic radiation (EMR) characteristics of cracked rock. AB - Coal rock would emit the electromagnetic radiation (EMR) while deformation and fracture, and there exists structural body in the coal rock because of mining and geological structure. In this paper, we conducted an experimental test the EMR characteristics of cracked rock under loading. Results show that crack appears firstly in the prefabricated crack tip then grows stably parallel to the maximum principal stress, and the coal rock buckling failure is caused by the wing crack tension. Besides, the compressive strength significantly decreases because of the precrack, and the compressive strength increases with the crack angle. Intact rock EMR increases with the loading, and the cracked rock EMR shows stage and fluctuant characteristics. The bigger the angle, the more obvious the stage and fluctuant characteristics, that is EMR becomes richer. While the cracked angle is little, EMR is mainly caused by the electric charge rapid separates because of friction sliding. While the cracked angle is big, there is another significant contribution to EMR, which is caused by the electric dipole transient of crack expansion. Through this, we can know more clear about the crack extends route and the corresponding influence on the EMR characteristic and mechanism, which has important theoretical and practical significance to monitor the coal rock dynamical disasters. PMID- 29255985 TI - Analogies and differences among bacterial and viral disinfection by the photo Fenton process at neutral pH: a mini review. AB - Over the last years, the photo-Fenton process has been established as an effective, green alternative to chemical disinfection of waters and wastewaters. Microorganisms' inactivation is the latest success story in the application of this process at near-neutral pH, albeit without clearly elucidated inactivation mechanisms. In this review, the main pathways of the combined photo-Fenton process against the most frequent pathogen models (Escherichia coli for bacteria and MS2 bacteriophage for viruses) are analyzed. Firstly, the action of solar light is described and the specific inactivation mechanisms in bacteria (internal photo-Fenton) and viruses (genome damage) are presented. The contribution of the external pathways due to the potential presence of organic matter in generating reactive oxygen species (ROS) and their effects on microorganism inactivation are discussed. Afterwards, the effects of the gradual addition of Fe and H2O2 are assessed and the differences among bacterial and viral inactivation are highlighted. As a final step, the simultaneous addition of both reagents induces the photo-Fenton in the bulk, focusing on the differences induced by the homogeneous or heterogeneous fraction of the process and the variation among the two respective targets. This work exploits the accumulated evidence on the mechanisms of bacterial inactivation and the scarce ones towards viral targets, aiming to bridge this knowledge gap and make possible the further application of the photo-Fenton process in the field of water/wastewater treatment. PMID- 29255987 TI - Impacts of global changes on the biogeochemistry and environmental effects of dissolved organic matter at the land-ocean interface: a review. AB - Dissolved organic matter (DOM) is an important component in the biogeochemistry and ecosystem function of aquatic environments at the highly populated land-ocean interface. The mobilization and transformation of DOM at this critical interface are increasingly affected by a series of notable global changes such as the increasing storm events, intense human activities, and accelerating glacier loss. This review provides an overview of the changes in the quantity and quality of DOM under the influences of multiple global changes. The profound implications of changing DOM for aquatic ecosystem and human society are further discussed, and future research needs are suggested for filling current knowledge gaps. The fluvial export of DOM is strongly intensified during storm events, which is accompanied with notable changes in the chemical composition and reactivity of DOM. Land use not only changes the mobilization of natural DOM source pools within watersheds but also adds DOM of distinct chemical composition and reactivity from anthropogenic sources. Glacier loss brings highly biolabile DOM to downstream water bodies. The changing DOM leads to significant changes in heterotrophic activity, CO2 out gassing, nutrient and pollutant biogeochemistry, and disinfection by-product formation. Further studies on the source, transformations, and downstream effects of storm DOM, temporal variations of DOM and its interactions with other pollutants in human-modified watersheds, photo degradability of glacier DOM, and potential priming effects, are essential for better understanding the responses and feedbacks of DOM at the land-ocean interface under the impacts of global changes. PMID- 29255986 TI - The effect of electron competition on chromate reduction using methane as electron donor. AB - We studied the effect of electron competition on chromate (Cr(VI)) reduction in a methane (CH4)-based membrane biofilm reactor (MBfR), since the reduction rate was usually limited by electron supply. A low surface loading of SO42- promoted Cr(VI) reduction. The Cr(VI) removal percentage increased from 60 to 70% when the SO42- loading increased from 0 to 4.7 mg SO42-/m2-d. After the SO42- loading decreased back to zero, the Cr(VI) removal further increased to 90%, suggesting that some sulfate-reducing bacteria (SRB) stayed in the reactor to reduce Cr(VI). However, a high surface loading of SO42- (26.6 mg SO42-/m2-d) significantly slowed down the Cr(VI) reduction to 40% removal, which was probably due to competition between Cr(VI) and SO42- reduction. Similarly, when 0.5 mg/L of Se(VI) was introduced into the MBfR, Cr(VI) removal percentage slightly decreased to 60% and then increased to 80% when input Se(VI) was removed again. The microbial community strongly depended on the loadings of Cr(VI) and SO42-. In the sulfate effect experiment, three genera were dominant. Based on the correlation between the abundances of the three genera and the loadings of Cr(VI) and SO42-, we conclude that Methylocystis, a type II methanotroph, reduced both Cr(VI) and sulfate, Meiothermus only reduced Cr(VI), and Ferruginibacter only reduced SO42-. PMID- 29255988 TI - Genetic screening of regulatory regions of pituitary transcription factors in patients with idiopathic pituitary hormone deficiencies. AB - PURPOSE: Mutation frequencies of PROP1, POU1F1 and HESX1 in patients with combined pituitary hormone deficiencies (CPHD) vary substantially between populations. They are low in sporadic CPHD patients in Western Europe. However, most clinicians still routinely send DNA of their CPHD patients for genetic screening of these pituitary transcription factors. Before we can recommend against screening of PROP1, POU1F1 and HESX1 as part of routine work-up for Western-European sporadic CPHD patients, it is crucial to rule out possible defects in regulatory regions of these genes, which could also disturb the complex process of pituitary organogenesis. METHODS: The regulatory regions of PROP1, POU1F1 and HESX1 are not covered by Whole Exome Sequencing as they are largely located outside the coding regions. Therefore, we manually sequenced the regulatory regions, previously defined in the literature, of PROP1, POU1F1 and HESX1 among 88 Dutch patients with CPHD. We studied promoter SNPs in relation to phenotypic data. RESULTS: We found six known SNPs in the PROP1 promoter. In the POU1F1 promoter, we found one new variant and two known SNPs. We did not find any variant in the HESX1 promoter. CONCLUSION: Although the new POU1F1 variant might explain the phenotype of one patient, the general conclusion of this study is that variants in regulatory regions of PROP1, POU1F1 and HESX1 are rare in patients with sporadic CPHD in the Netherlands. We recommend that genetic screening of these pituitary transcription factors should no longer be part of routine work-up for Western-European, and especially Dutch, sporadic CPHD patients. PMID- 29255989 TI - Identification and manipulation of a novel locus to improve cell tolerance to short-chain alcohols in Escherichia coli. AB - Escherichia coli KO11 is a popular ethanologenic strain, but is more sensitive to ethanol than other producers. Here, an ethanol-tolerant mutant EM was isolated from ultraviolet mutagenesis library of KO11. Comparative genomic analysis added by piecewise knockout strategy and complementation assay revealed EKO11_3023 (espA) within the 36.6-kb deletion from KO11 was the only locus responsible for ethanol sensitivity. Interestingly, when espA was deleted in strain W (the parent strain of KO11), ethanol tolerance was dramatically elevated to the level of espA free hosts [e.g., MG1655 and BL21(DE3)]. And overexpression of espA in strains MG1655 and BL21(DE3) led to significantly enhanced ethanol sensitivity. In addition to ethanol, deletion of espA also improved cell tolerance to other short chain (C2-C4) alcohols, including methanol, isopropanol, n-butanol, isobutanol and 2-butanol. Therefore, espA was responsible for short-chain alcohol sensitivity of W-strains compared to other cells, which provides a potential engineering target for alcohols production. PMID- 29255990 TI - Discovery of a new diol-containing polyketide by heterologous expression of a silent biosynthetic gene cluster from Streptomyces lavendulae FRI-5. AB - The genome of streptomycetes has the ability to produce many novel and potentially useful bioactive compounds, but most of which are not produced under standard laboratory cultivation conditions and are referred to as silent/cryptic secondary metabolites. Streptomyces lavendulae FRI-5 produces several types of bioactive compounds. However, this strain may also have the potential to biosynthesize more useful secondary metabolites. Here, we activated a silent biosynthetic gene cluster of an uncharacterized compound from S. lavendulae FRI-5 using heterologous expression. The engineered strain carrying the silent gene cluster produced compound 5, which was undetectable in the culture broth of S. lavendulae FRI-5. Using various spectroscopic analyses, we elucidated the chemical structure of compound 5 (named lavendiol) as a new diol-containing polyketide. The proposed assembly line of lavendiol shows a unique biosynthetic mechanism for polyketide compounds. The results of this study suggest the possibility of discovering more silent useful compounds from streptomycetes by genome mining and heterologous expression. PMID- 29255991 TI - Output ordering and prioritisation system (OOPS): ranking biosynthetic gene clusters to enhance bioactive metabolite discovery. AB - The rapid increase of publicly available microbial genome sequences has highlighted the presence of hundreds of thousands of biosynthetic gene clusters (BGCs) encoding valuable secondary metabolites. The experimental characterization of new BGCs is extremely laborious and struggles to keep pace with the in silico identification of potential BGCs. Therefore, the prioritisation of promising candidates among computationally predicted BGCs represents a pressing need. Here, we propose an output ordering and prioritisation system (OOPS) which helps sorting identified BGCs by a wide variety of custom-weighted biological and biochemical criteria in a flexible and user-friendly interface. OOPS facilitates a judicious prioritisation of BGCs using G+C content, coding sequence length, gene number, cluster self-similarity and codon bias parameters, as well as enabling the user to rank BGCs based upon BGC type, novelty, and taxonomic distribution. Effective prioritisation of BGCs will help to reduce experimental attrition rates and improve the breadth of bioactive metabolites characterized. PMID- 29255992 TI - Adverse drug reaction reporting: how can drug consumption information add to analyses using spontaneous reports? AB - PURPOSE: Spontaneous reporting of adverse drug reactions (ADRs) is a cornerstone in pharmacovigilance. However, information about the underlying consumption of drugs is rarely used when analysing spontaneous reports. The purpose of this study was to combine ADR reports with drug consumption data to demonstrate the additional information this gives in various scenarios, comparing different drugs, gender-stratified sub-populations and changes in reporting over time. METHODS: We combined all Norwegian ADR reports in 2004-2013 from the EudraVigilance database (n = 14.028) with dispensing data from the Norwegian Prescription Database (more than 800 million dispensed prescriptions during 2004 2013). This was done in order to calculate drug-specific consumption-adjusted adverse drug reaction reporting rates (CADRRs) by dividing the number of reports for each drug with the number of users of the drug during the same time period. RESULTS: Among the ten drugs with the highest number of ADR reports and the ten drugs with the highest CADRR, only four drugs were in both categories. This indicates that drugs with a high number of reports often also have a high number of users and that CADRR captures drugs with potentially relevant safety issues but a smaller number of users. Comparing reported ADRs in females and males using methylphenidate, we found that the two groups report different ADRs. Finally, we showed that changes in ADR reporting for simvastatin and atorvastatin during 2004 2013 were due to changes in consumption and that atorvastatin had a higher CADRR but fewer reports than simvastatin. CONCLUSIONS: CADRR provides additional information compared with number of reports alone in studies using spontaneous reports. It is important for researchers to adjust for consumption whenever possible in pharmacovigilance studies. PMID- 29255993 TI - Prevalence and nature of statin drug-drug interactions in a university hospital by electronic health record mining. AB - AIM: Our aim was to describe prevalence, nature, and level of severity of potential statin drug-drug interactions in a university hospital. METHODS: In a cross-sectional study, statin drug-drug interactions were screened from medical record of 10,506 in-patients treated stored in the clinical data warehouse "eHOP." We screened drug-drug interactions using Theriaque and Micromedex drug databases. RESULTS: A total of 22.5% of patients were exposed to at least one statin drug-drug interaction. Given their lipophilicity and CYP3A4 metabolic pathway, atorvastatin and simvastatin presented a higher prevalence of drug-drug interactions while fluvastatin presented the lowest prevalence. Up to 1% of the patients was exposed to a contraindicated drug-drug interaction, the most frequent drug-drug interaction involving influx-transporter (i.e., OATP1B1) interactions between simvastatin or rosuvastatin with cyclosporin. The second most frequent contraindicated drug-drug interaction involved CYP3A4 interaction between atorvastatin or simvastatin with either posaconazole or erythromycin. Furthermore, our analysis showed some discrepancies between Theriaque and Micromedex in the prevalence and the nature of drug-drug interactions. CONCLUSIONS: Different drug-drug interaction profiles were observed between statins with a higher prevalence of CYP3A4-based interactions for lipophilic statins. Analyzing the three most frequent DDIs, the more significant DDIs (level 1: contraindication) were reported for transporter-based DDI involving OATP1B1 influx transporter. These points are of concern to improve prescriptions of statins. PMID- 29255994 TI - Esophageal Stents for Acute Variceal Bleeding: Expanding the Possibilities. PMID- 29255995 TI - Effectiveness of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Physical Injuries: A Systematic Review and Meta-Analysis of Observational Studies. AB - BACKGROUND: Patients with attention-deficit/hyperactivity disorder (ADHD) are more prone to physical injuries, including motor vehicle accidents, fractures and brain injuries. Several observational studies have been published investigating the association between the use of pharmacological treatment for ADHD and the incidence of physical injuries among patients with ADHD; however, the findings are not concordant. OBJECTIVE: This study is a systematic review and meta analysis of the existing literature and estimates the overall association between the use of ADHD medications and physical injury. Injury is defined as medically attended physical injuries in the form of hospitalisations, emergency department visits or general practitioners visits. METHODS: The PubMed, EMBASE, PsycINFO, CINAHL and Cochrane Review databases were searched for relevant studies published up to May 2017 relating to ADHD medication and risk of injuries. Observational studies with any study design, all age groups (children and adults) and all ADHD medications (stimulant and non-stimulants) were included. Studies relevant to the association between ADHD medication exposure and risk of injuries in ADHD patients were extracted and compiled for meta-analysis. Both within-individual and between-individual analyses were conducted. RESULTS: Overall, 2001 citations were identified and 10 observational studies were included. Three self-controlled case series and two self-controlled cohorts were eligible for meta-analysis of within-individual studies. Five cohort studies were included in the meta-analysis of between-individual studies. The adjusted rate ratio of the within-individual methods was 0.76 (95% confidence interval [CI] 0.61-0.93) and 0.88 (95% CI 0.85 0.92) for between-individual studies. CONCLUSION: The findings of this meta analysis support a reduced risk of injuries among ADHD patients who were treated with ADHD medications. PMID- 29255996 TI - A Severe Anaphylactic Reaction Associated with IgM-Class Anti-Human IgG Antibodies in a Hyper-IgM Syndrome Type 2 Patient. AB - PURPOSE: A 42-year-old man with hyper-IgM syndrome type 2 caused by activation induced cytidine deaminase (AID) deficiency developed a severe anaphylactic reaction to intravenous immunoglobulin. The purpose of this study was to clarify the cause of the anaphylactic reaction of the patient. METHODS: We measured IgM class anti-human IgG and anti-human IgA antibodies in his serum by sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The sandwich ELISA assay revealed that serum from the patient, but not the controls, reacted to three different IgG products and purified human IgA. This indicated that the patient had IgM-class anti-human IgG and IgA antibodies in his serum, which associated with the anaphylactic reactions after the administration of IgG products. The anti-IgG antibody was likely to be the main cause of the reactions because an IgA depleted IgG product also induced a severe reaction in this case and showed high absorbance in the ELISA system, similar to other IgG products containing more IgA. CONCLUSIONS: This is the first report of IgM-class anti-human IgG associated with an anaphylactic reaction to an IgG infusion. The anaphylactic reactions were very severe in this case, probably because IgM-class antibodies are potent activators of the complement pathway. PMID- 29255997 TI - Mirabegron Toxicosis in Dogs: a Retrospective Study. AB - Mirabegron is a selective beta (B)3 adrenoreceptor agonist marketed for human treatment of an overactive bladder (OAB). It has a wide margin of safety in humans, but in dogs, severe adverse effects have occurred. We sought to determine the effects and outcome of mirabegron toxicosis in dogs. A retrospective review of all calls within the Pet Poison Helpline (PPH), an international animal poison control center, database was performed for mirabegron exposures between 2013 and 2015. Potential ingested doses ranging from 1.31 to 8.3 mg/kg. Many dogs remained asymptomatic and no fatalities occurred in any dogs. The most commonly reported signs were tachycardia and erythema. While mirabegron was found to have a very narrow margin of safety and high toxicity risk to dogs during preclinical trials, effects appear to differ greatly in the nonclinical field environment and further study is needed. PMID- 29255998 TI - Comparison between the STENTYS self-apposing bare metal and paclitaxel-eluting coronary stents for the treatment of saphenous vein grafts (ADEPT trial). AB - AIMS: To describe the safety and performance of STENTYS self-expandable bare metal stents (BMS) versus paclitaxel-eluting stents (PES) in saphenous vein grafts (SVGs). METHODS AND RESULTS: A randomised controlled trial was performed in four hospitals in three European countries between December 2011 and December 2013. Patients with de novo lesions (>50% stenosis) in an SVG with a diameter between 2.5-6 mm were included. Primary endpoint was late lumen loss at 6 months. Secondary endpoints included procedural success and the occurrence of major adverse cardiac events (MACE) at 12 months. A total of 57 patients were randomised to STENTYS self-apposing BMS (n = 27) or PES (n = 30). Procedural success was obtained in 89.5%. No significant differences in late lumen loss were found between BMS and PES at 6 months (0.53 mm vs 0.47; p = 0.86). MACE rates at 12 months were comparable in both groups (BMS 22.2% vs. PES 26.7%; p = 0.70). CONCLUSIONS: Treatment of SVGs with STENTYS self-expandable stents is safe and effective. No significant differences were found in late lumen loss and MACE between BMS and PES. PMID- 29255999 TI - Tepidimonas sediminis sp. nov. and Tepidimonas alkaliphilus sp. nov., two novel moderately thermophilic species isolated from a hot spring. AB - The taxonomic positions of two moderately thermophilic bacteria, strains YIM 72259T and YIM 72238T, isolated from a hot spring sediment sample were determined using polyphasic taxonomic approaches. Pairwise comparison of the 16S rRNA gene sequences showed that strains YIM 72259T and YIM 72238T are closely related to Tepidimonas ignava SPS-1037T (97.0 and 97.5%, respectively), Tepidimonas taiwanensis I1-1T (96.5 and 97.3%), while sharing 98.0% sequence similarity with each other. The DNA-DNA relatedness values of strains YIM 72238T with T. ignava SPS-1037T and T. taiwanensis I1-1T were determined to be 25.2 +/- 1.2 and 24.6 +/ 3.1%, respectively, while the two strains (YIM 72259T and YIM 72238T) had a relatedness value of 38.3 +/- 4.4% between themselves. The two strains were aerobic, Gram-stain negative, motile by means of a polar flagellum and formed non pigmented colonies. The DNA G+C contents of strains YIM 72259T and YIM 72238T were determined to be 71.6 and 68.9 mol%, respectively. The major fatty acids in both strains were identified as (> 10%) C16:0, C17:0 and summed feature 8, while the strain YIM 72238T contained a moderately high amount of summed feature 3 as well. The polar lipid profiles for strains YIM 72259T and YIM 72238T consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, an unidentified aminolipid and several unidentified phospholipids. Besides the morphological and chemotaxonomic characteristics, phylogenetic analyses of the 16S rRNA gene sequences and the biochemical characteristics indicated that the two strains represented two novel members of the genus Tepidimonas, for which the name Tepidimonas sediminis sp. nov. [type strain YIM 72259T (= NBRC 112410T = CGMCC 1.15971T) and Tepidimonas alkaliphilus sp. nov. [type strain YIM 72238T (= KCTC 52717T = CCTCC AB 2017168T)] are proposed. PMID- 29256000 TI - A re-evaluation of Tubakia, including three new species on Quercus and six new combinations. AB - Morphological comparisons and phylogenetic analyses of Tubakia species from leaves of Quercus spp. in Iowa and other areas of eastern USA revealed three novel species: Tubakia hallii, Tubakia macnabbii, and Tubakia tiffanyae. These species, as well as Tubakia dryina and Tubakia iowensis, are common leaf endophytes and pathogens on Quercus and Castanea in eastern USA, as is Tubakia americana comb. nov, originally described from Quercus in New Jersey as Actinopelte americana. New combinations of species on leaves of other hosts in the eastern USA include Tubakia gloeosporioides, Tubakia liquidambaris, and Tubakia nyssae. Asian species of Tubakia are phylogenetically compared, and the new combination Tubakia supraseptata is made to accommodate a Japanese endophyte known only by its sexual state. The earlier description of Dicarpella dryina as the sexual state of T. dryina is questioned. The new combination Tubakia stellata is made to accommodate an unusual species from Brazil. PMID- 29256003 TI - Amigas Latinas Motivando el Alma (ALMA): an Evaluation of a Mindfulness Intervention to Promote Mental Health among Latina Immigrant Mothers. AB - Latina immigrants are at increased risk for poor mental health. Amigas Latinas Motivando el Alma (ALMA) is a group-based intervention to reduce symptoms of depression, anxiety, and stress among Latina immigrants. Based on participants' feedback and growing evidence supporting mindfulness as a way to reduce stress and improve mental health, additional sessions of the ALMA intervention were developed and pilot tested to provide more training on mindfulness as a coping strategy. The feasibility and potential efficacy were evaluated in a community sample using a pre- and post-test study design. Findings suggested that women were satisfied with the sessions and used mindfulness strategies they learned in their daily lives. The program also reduced symptoms of depression and anxiety (19% reduction in mean depression scores and 26% reduction in mean anxiety scores). Further evaluation is needed to test the efficacy of the intervention. PMID- 29256001 TI - The impact of childbirth on pelvic floor morphology in primiparous Black South African women: a prospective longitudinal observational study. AB - INTRODUCTION AND HYPOTHESIS: There is a lack of prospective studies evaluating the impact of childbirth on the pelvic floor in non-white populations. We intended to study delivery-related changes in pelvic floor morphology in Black South African primiparae. We also intended to determine the impact of anatomical changes on symptoms in the postpartum period. METHODS: A total of 153 nulliparous women between 35 and 39 weeks gestation were recruited from a district antenatal clinic. All women had a standardized interview, completed the International Consultation on Incontinence Vaginal Symptoms questionnaire followed by three/four dimensional transperineal ultrasonography. This was repeated at 3-6 months postpartum. RESULTS: Of the 153 women, 84 (54.9%) returned at a mean of 4.8 months postpartum. Of these women, 60 (71.4%) had a vaginal delivery and the remainder a caesarean section (20 emergency and 4 elective). Overall, there were statistically significant increases in bladder neck descent (P = 0.003), pelvic organ descent and levator hiatal distensibility (all P < 0001) at the postpartum assessment. Levator avulsion was diagnosed in nine (15%) of those delivered vaginally. Postpartum vaginal laxity was the commonest bothersome vaginal symptom, reported by 51 women (60.7%). CONCLUSIONS: There is significant alteration in pelvic organ support and levator hiatal distensibility postpartum, with more marked effects in women after vaginal delivery. Of Black primiparous women, 15% sustained levator trauma after their first vaginal delivery. PMID- 29256004 TI - Double suicidal gunshot wounds to the heart. AB - A case of double gunshot wounds to the heart is reported, where police investigations determined the manner of death to be suicide. In addition, the autopsy findings supported this conclusion. The localization, appearance, and mutual relations of the inflicted wounds, as well as the direction of the bullet trajectories, helped to determine the most probable sequence of events. The victim had been able to act after the first shot and inflict the second shot as the conduction system of the heart was at least partially preserved. Even when the circumstances indicate the most probable manner of death, multiple gunshot wounds represent a challenge for forensic pathologists; a victim's ability to act after the first shot must be determined with respect to the degree of initial incapacitation. PMID- 29256005 TI - The NcZrg-17 gene of Neurospora crassa encodes a cation diffusion facilitator transporter required for vegetative development, tolerance to endoplasmic reticulum stress and cellulose degradation under low zinc conditions. AB - The Neurospora crassa gene NcZrg-17 encodes a membrane protein with homology to the cation diffusion facilitator (CDF) family of transporters. We analyzed the phenotypic and functional characteristics of DeltaNcZrg-17 and the implications of these characteristics in vivo. The DeltaNcZrg-17 mutant showed several phenotypes that are zinc suppressible such as reduced growth rate, short aerial hyphae, increased hyphal branching, early and enhanced conidiation and delayed conidial germination. Furthermore, the NcZrg-17 gene was found to be crucial for survival in the presence of endoplasmic reticulum (ER) stress inducing chemical agents. In addition, we found that DeltaNcZrg-17 mutant is defective in protein secretion on cellulose media under low zinc conditions, pointing towards a physiological role for NcZrg-17 in N. crassa. A gradual and delayed transcriptional upregulation (~ threefold) of NcZrg-17 on exposure to low zinc suggests its role in adaptation to low zinc rather than zinc homeostasis. Together our findings support a function of NcZrg-17 in normal vegetative growth, tolerance to ER stress and degradation of cellulose under low zinc conditions in N. crassa. PMID- 29256006 TI - Gene selection for microarray data classification via subspace learning and manifold regularization. AB - With the rapid development of DNA microarray technology, large amount of genomic data has been generated. Classification of these microarray data is a challenge task since gene expression data are often with thousands of genes but a small number of samples. In this paper, an effective gene selection method is proposed to select the best subset of genes for microarray data with the irrelevant and redundant genes removed. Compared with original data, the selected gene subset can benefit the classification task. We formulate the gene selection task as a manifold regularized subspace learning problem. In detail, a projection matrix is used to project the original high dimensional microarray data into a lower dimensional subspace, with the constraint that the original genes can be well represented by the selected genes. Meanwhile, the local manifold structure of original data is preserved by a Laplacian graph regularization term on the low dimensional data space. The projection matrix can serve as an importance indicator of different genes. An iterative update algorithm is developed for solving the problem. Experimental results on six publicly available microarray datasets and one clinical dataset demonstrate that the proposed method performs better when compared with other state-of-the-art methods in terms of microarray data classification. Graphical Abstract The graphical abstract of this work. PMID- 29256007 TI - Methylation of cytokines gene promoters in IL-1beta-treated human intestinal epithelial cells. AB - OBJECTIVE AND DESIGN: Epigenetic regulation is important in the activation of inflammatory cells. In the present study, we evaluated if DNA-methylation variations are involved in Interleukin-1beta (IL-1beta)-induced intestinal epithelial cells activation. MATERIALS AND METHODS: Differentiated Caco-2 cells were exposed to IL-1beta or to 5-azadeoxycytidine (5-azadC) for 24 or 48 h. Genome-wide methylation status was evaluated, while DNA methylation status at the promoter region of the gene encoding interleukin-6, 8 and 10 (IL-6, 8 and 10) was estimated. The levels of the corresponding gene products as well as DNA methyltransferases (DNMTs) quantity were assessed. RESULTS: IL-1beta decreased genomic methylation of human intestinal epithelial cells and induced demethylation at cg-specific sites at the promoter of pro-inflammatory genes IL6 and IL8; conversely it did not change the methylation of the IL10 promoter. IL 1beta also increased the release of IL-6 and IL-8 but did not change the IL-10 expression. Finally, cell exposure to IL-1beta decreased the DNMT3b expression, increased DNMT3a and was not able to change DNMT1 expression. CONCLUSIONS: Our results suggest a potential role of IL-1beta as modulator of DNA methylation in activated differentiated Caco-2 cell line. PMID- 29256009 TI - Dr. Yang Zhong: An explorer on the road forever. PMID- 29256008 TI - Development and Optimization of a High-Throughput Screening Assay for Rapid Evaluation of Lipstatin Production by Streptomyces Strains. AB - Pancreatic lipase inhibitors, such as tetrahydrolipstatin (orlistat), are used in anti-obesity treatments. Orlistat is the only anti-obesity drug approved by the European Medicines Agency (EMA). The drug is synthesized by saturation of lipstatin, a beta-lactone compound, isolated from Streptomyces toxytricini and S. virginiae. To identify producers of novel pancreatic lipase inhibitors or microbial strains with improved lipstatin production and higher chemical purity remains still a priority. In this study, a high-throughput screening method to identify Streptomyces strains producing potent pancreatic lipase inhibitors was established. The assay was optimized and validated using S. toxytricini NRRL 15443 and its mutants. Strains grew in 24-well titer plates. Lipstatin levels were assessed directly in culture medium at the end of cultivation by monitoring lipolytic activity in the presence of a chromogenic substrate, 1,2-Di-O-lauryl rac-glycero-3-glutaric acid 6-methylresorufin ester (DGGR). The lipase activity decreased in response to lipstatin production, and this was demonstrated by accumulation of red-purple methylresorufin, a product of DGGR digestion. The sensitivity of the assay was achieved by adding a lipase of high lipolytic activity and sensitivity to lipstatin to the reaction mixture. In the assay, the fungal lipase from Mucor javanicus was used as an alternative to the human pancreatic lipase. Many fungal lipases preserve high lipolytic activity in extreme conditions and are not colipase dependent. The assay proved to be reliable in differentiation of strains with high and low lipstatin productivity. PMID- 29256010 TI - Mechanism of actions of Oncocin, a proline-rich antimicrobial peptide, in early elongation revealed by single-molecule FRET. PMID- 29256011 TI - Improvement of the quality of maize grain silage by a synergistic action of selected lactobacilli strains. AB - As silage is one of the most important feed sources for dairy cattle it is recommended for farmers to preserve silage by fermentation. Interaction of the five strains of Lactobacillus genera [Lactobacillus buchneri A KKP 2047 p (LB), L. reuteri M KKP 2048 p (LR), L. plantarum K KKP 593 p (LPk), L. plantarum S KKP 2021 p (LPs), L. fermentum N KKP 2020 p (LF)] has been shown aiming to increase the safety of corn grain silage fodder. Experiments were conducted in polyethylene microsilos for 48 days and on production scale in an experimental farm for 3 years. Synergistic activity of the studied bacterial strains in terms of reducing aflatoxin B1 and ochratoxin A levels was clear in these experimental variants wherein to the inoculants of the LB + LR strains subsequent bacterial strains LPk, LPs and LF were sequentially added. Silages inoculated with five bacterial strains were free from pathogens and showed the lowest yeast and mold count values among all experimental variants. As a result of employing the preparation starter culture for ensiling corn grain there were obtained silages characterized by high stability, microbiological and chemical purity, thus safe in feeding livestock. PMID- 29256012 TI - Computational study of the structure and properties of bicyclo[3.1.1]heptane derivatives for new high-energy density compounds with low impact sensitivity. AB - To design new high-energy density compounds (HEDCs), a series of new bicyclo[2.2.1]heptane derivatives containing an aza nitrogen atom and nitro substituent were designed and studied theoretically. The density, heat of sublimation and impact sensitivity were estimated by electrostatic potential analysis of the molecular surface. Based on the designed isodesmic reaction, and the reliable heat of formation (HOF) of the reference compounds, HOFs were calculated and compared at B3LYP/6-311G(d,p) and B3P86/6-311G(d,p), respectively. The detonation performances, bond dissociation energies (BDE) and impact sensitivity were calculated to evaluate the designed compounds. The calculated results show that the number of aza nitrogen atoms and NO2 groups are two important factors for improving HOF, density and detonation properties. Thermal stability generally decreases with increasing nitro groups. And the N-NO2 bond is the trigger bond for all designed compounds except B8, whose trigger bond is C NO2. Importantly, the BDE values are between 86.95 and 179.71 kJ mol-1 and meet the requirement for HEDCs. Detonation velocity and detonation pressure were found to be 5.77-9.65 km s-1 and 12.30-43.64 GPa, respectively. After comprehensive consideration of thermal stability, impact sensitivity and detonation properties, A7, A8, B8, C8, D7, E7, F7 and G6 may be considered as potential HEDCs. Especially, A8, B8, C8, and D7 have better detonation properties than the famous caged nitramine CL-20 (D = 9.40 km/s, P = 42.00GPa). Besides, all the designed potential HEDCs have reasonable impact sensitivity. Graphical abstract New high energy density compounds (HEDCs) with low impact sensitivity (A8, B8, C8 and D7 have better detonation properties than CL-20). PMID- 29256013 TI - Enrichment of high-grade tumors in breast cancer gene expression studies. AB - PURPOSE: Gene expression (GE) profiling for breast cancer classification and prognostication has become increasingly used in clinical diagnostics. GE profiling requires a reasonable tumor cell percentage and high-quality RNA. As a consequence, a certain amount of samples drop out. If tumor characteristics are different between samples included and excluded from GE profiling, this can lead to bias. Therefore, we assessed whether patient and tumor characteristics differ between tumors suitable or unsuitable for generating GE profiles in breast cancer. METHODS: In a consecutive cohort of 738 breast cancer patients who received neoadjuvant chemotherapy at the Netherlands Cancer Institute, GE profiling was performed. We compared tumor characteristics and treatment outcome between patients included and excluded from GE profiling. Results were validated in an independent cohort of 812 patients treated with primary surgery. RESULTS: GE analysis could be performed in 53% of the samples. Patients with tumor GE profiles more often had high-grade tumors [odds ratio 2.57 (95%CI 1.77-3.72), p < 0.001] and were more often lymph node positive [odds ratio 1.50 (95%CI 1.03 2.19), p = 0.035] compared to the group for which GE profiling was not possible. In the validation cohort, tumors suitable for gene expression analysis were more often high grade. CONCLUSIONS: In our gene expression studies, tumors suitable for GE profiling had more often an unfavorable prognostic profile. Due to selection of samples with a high tumor percentage, we automatically select for tumors with specific features, i.e., tumors with a higher grade and lymph node involvement. It is important to be aware of this phenomenon when performing gene expression analysis in a research or clinical context. PMID- 29256015 TI - To Improve is to Change. PMID- 29256014 TI - Genetic variation in TNFalpha, PPARgamma, and IRS-1 genes, and their association with breast-cancer survival in the HEAL cohort. AB - PURPOSE: Tumor necrosis factor-alpha (TNF-alpha), peroxisome proliferator activated receptor-gamma (PPARgamma), and insulin receptor substrate-1 (IRS-1) are associated with obesity, insulin resistance, and inflammation. Few data exist on associations between polymorphisms in these genes and mortality in breast cancer survivors. METHODS: We investigated associations between TNF-alpha -308G > A (rs1800629); PPARgamma Pro12Ala (rs1801282); and IRS-1 Gly972Arg (rs1801278) polymorphisms and anthropometric variables, circulating levels of previously measured biomarkers, and tumor characteristics in 553 women enrolled in the Health, Eating, Activity, and Lifestyle Study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer between 1995 and 1999 (median follow-up 14.7 years). Using Cox proportional hazards models adjusted for possible confounders, we evaluated associations between these polymorphisms and mortality. RESULTS: Carriers of the PPARgamma variant allele had statistically significantly lower rates of type 2 diabetes (P = 0.04), lower BMI (P = 0.01), and HOMA scores [P = 0.004; non-Hispanic White (NHWs) only]; carriers of the TNF-alpha variant A allele had higher serum glucose (P = 0.004, NHW only); and the IRS-1 variant was associated with higher leptin levels (P = 0.003, Hispanics only). There were no associations between any of the polymorphisms and tumor characteristics. Among 141 deaths, 62 were due to breast cancer. Carriers of the TNF-alpha-variant A allele had a decreased risk of breast-cancer-specific mortality [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.10-0.83] and all-cause mortality (HR 0.51; 95% CI 0.28-0.91). CONCLUSIONS: Neither the PPARgamma nor the IRS-1 polymorphism was associated with mortality outcome. The TNF-alpha -308 G > A polymorphism was associated with reduced breast-cancer specific and all-cause mortality. PMID- 29256016 TI - On the Reproducibility of Label-Free Quantitative Cross-Linking/Mass Spectrometry. AB - Quantitative cross-linking/mass spectrometry (QCLMS) is an emerging approach to study conformational changes of proteins and multi-subunit complexes. Distinguishing protein conformations requires reproducibly identifying and quantifying cross-linked peptides. Here we analyzed the variation between multiple cross-linking reactions using bis[sulfosuccinimidyl] suberate (BS3) cross-linked human serum albumin (HSA) and evaluated how reproducible cross linked peptides can be identified and quantified by LC-MS analysis. To make QCLMS accessible to a broader research community, we developed a workflow that integrates the established software tools MaxQuant for spectra preprocessing, Xi for cross-linked peptide identification, and finally Skyline for quantification (MS1 filtering). Out of the 221 unique residue pairs identified in our sample, 124 were subsequently quantified across 10 analyses with coefficient of variation (CV) values of 14% (injection replica) and 32% (reaction replica). Thus our results demonstrate that the reproducibility of QCLMS is in line with the reproducibility of general quantitative proteomics and we establish a robust workflow for MS1-based quantitation of cross-linked peptides. Graphical Abstract ?. PMID- 29256017 TI - Tips and tricks for robotic urology using ICG. PMID- 29256018 TI - Letter to the Editor: A prospective, randomized trial comparing thulium vapoenucleation with holmium laser enucleation of the prostate for the treatment of symptomatic benign prostatic obstruction: perioperative safety and efficacy. PMID- 29256019 TI - Fuhrman grading is inappropriate for papillary renal cell carcinoma. PMID- 29256021 TI - Development of the "rare-earth" hypothesis to explain the reasons of geophagy in Teletskoye Lake are kudurs (Gorny Altai, Russia). AB - The mineral and chemical composition of the liquid and lithogenous substances, consumed by the wild ungulate animals, at the kudurs of the Teletskoye Lake, Gorny Altai, Russia, was studied. It was investigated that all examined kudurits are argillous-aleurolitic and get in the interval from 1 to 100 MUm with the predominance of the fraction 10 MUm. By the mineral composition, the lithogenous kudurits present the quartz-feldspathic-hydromicaceous-chloritic mineral formations with the large content of the quartz particles (20-43%) and sodium containing plagioclases (albite, 15-32 wt%). The lithogenous kudurits are the products of the reconstitution of the metamorphic cleaving stones as a result of the glacier abrasive effect, subsequent its aqueous deposits and then eolation in the subaerial conditions. The fontinal waters consumed at the kudurs are subsaline chloride-hydrocarbonate-sodium and sulphated-hydrocarbonate-calcium types. It essentially differs by the increased content of rare-earth elements in reference to the lake water. The acid (HCl, pH-1) extracts from the kudurits more actively extract calcium (10-35% of the gross contents; sodium extracts at the level of 1-3%). The most fluent in the microelements composition are Cu, Be, Sr, Co, Cd, Pb, Sc, Y and rare-earth elements. The transit of all these elements into the dissoluted form fluctuates about 10% from the gross contents. The reason of geophagy is related to tendency of herbivores to absorb mineralized subsoils enriched by the biologically accessible forms of rare-earth elements, arisen as a result of vital activity of specific microflora. PMID- 29256022 TI - A Critical View of "On TB Vaccines, Patients' Demands, and Modern Printed Media in Times of Biomedical Uncertainties: Buenos Aires, 1920-1950". AB - The putative Pueyo's vaccine was a commercial venture that obtained marketing authorization in 1946, a turbulent period of Argentine history. After a few months, health authorities withdrew financial support from the state to buy the vaccine and required patients to sign a written consent to receive that product. An independent investigation did not find any evidence of benefit in non-clinical and clinical evaluation of the putative vaccine. PMID- 29256020 TI - Prognostic effect of cytoreductive nephrectomy in synchronous metastatic renal cell carcinoma: a comparative study using inverse probability of treatment weighting. AB - PURPOSE: To test the hypothesis that cytoreductive nephrectomy (CN) improves overall survival (OS) of patients with synchronous metastatic renal cell carcinoma (mRCC), who subsequently receive targeted therapies (TT). METHODS: We identified 261 patients who received TT for synchronous mRCC with or without prior CN. To achieve balance in baseline characteristics between groups, we used the inverse probability of treatment weighting (IPTW) method. We conducted OS analyses, including IPTW-adjusted Kaplan-Meier curves, Cox regression models, interaction term, and landmark and sensitivity analyses. RESULTS: Of the 261 patients, 97 (37.2%) received CN and 164 (62.8%) did not. IPTW-adjusted analyses showed a statistically significant OS benefit for patients treated with CN (HR 0.63, 95% CI 0.46-0.83, P = 0.0015). While there was no statistically significant difference in OS at 3 months (P = 0.97), 6 months (P = 0.67), and 12 months (P = 0.11) from diagnosis, a benefit for the CN group was noted at 18 months (P = 0.005) and 24 months (P = 0.004). On interaction term analyses, the beneficial effect of CN increased with better performance status (P = 0.06), in women (P = 0.03), and in patients with thrombocytosis (P = 0.01). CONCLUSIONS: IPTW-adjusted analysis of our patient cohort suggests that CN improves OS of patients with synchronous mRCC treated with TT. On the whole, the survival difference appears after 12 months. Specific subgroups may particularly benefit from CN, and these subgroups warrant further investigation in prospective trials. PMID- 29256023 TI - Effect of everolimus treatment for renal angiomyolipoma associated with tuberous sclerosis complex: an evaluation based on tumor density. AB - BACKGROUND: The aim of this study was to evaluate the influence of components of angiomyolipoma (AML) on the efficacy of everolimus. METHODS: We investigated a total of 40 patients with tuberous sclerosis complex (TSC) who had AML >=4 cm in diameter. The components of the AML were determined using abdominal computed tomography (CT) images. The AML density was measured as the mean Hounsfield unit (HU) values of the whole area of the AML on axial CT images. We classified them into two groups, i.e., a lipid group with a predominant lipid component (HU <= 50) and a solid group with predominant vascular and muscle components (HU >=30). For each patient, we measured the AML reduction rate and transition of the mean HU value. RESULTS: The mean reduction rate of AML in the lipid group was 24%, whereas it was 68% in the solid group (P < 0.001). The mean tumor density after 6 months was decreased in both groups. In particular, the density significantly decreased compared to the baseline in the solid group (P < 0.001). The tumor density did not change after 6 months in either group. CONCLUSION: The effect of everolimus on TSC-AML is mainly a reduction of the solid components consisting of angioma and leiomyoma. The tumor density at the start of treatment might be a predictive marker for the response to everolimus in TSC-AML. PMID- 29256024 TI - Are beryllium-containing biphenyl derivatives efficient anion sponges? AB - The structures and stabilities of 2,2'-diBeX-1,1'-biphenyl (X = H, F, Cl, CN) derivatives and their affinities for F-, Cl-, and CN- were theoretically investigated using a B3LYP/6-311 + G(3df,2p)//B3LYP/6-31 + G(d,p) model. The results obtained show that the 2,2'-diBeX-1,1'-biphenyl derivatives (X = H, F, Cl, CN) exhibit very high F-, Cl-, and CN- affinities, albeit lower than those reported before for their 1,8-diBeX-naphthalene analogs, in spite of the fact that the biphenyl derivatives are more flexible than their naphthalene counterparts. Nevertheless, some of the biphenyl derivatives investigated are predicted to have anion affinities larger than those measured for SbF5, which is considered one of the strongest anion capturers. Therefore, although weaker than their naphthalene analogs, the 2,2'-diBeX-1,1'-biphenyl derivatives can still be considered powerful anion sponges. This study supports the idea that compounds containing -BeX groups in chelating positions behave as anion sponges due to the electron-deficient nature and consequently high intrinsic Lewis acidity of these groups. Graphical Abstract Compounds containing -BeX groups in chelating positions, such as 2,2'-diBeX-1,1'-biphenyl (X = H, F, Cl, CN) derivatives, behave as anion sponges due to the electron-deficient nature of these groups. PMID- 29256025 TI - Anxiety and Depression During Childhood and Adolescence: Testing Theoretical Models of Continuity and Discontinuity. AB - The present study sought to clarify the trajectory (i.e., continuous vs. discontinuous) and expression (i.e., homotypic vs. heterotypic) of anxiety and depressive symptoms across childhood and adolescence. We utilized a state-of-the science analytic approach to simultaneously test theoretical models that describe the development of internalizing symptoms in youth. In a sample of 636 children (53% female; M age = 7.04; SD age = 0.35) self-report measures of anxiety and depression were completed annually by youth through their freshman year of high school. For both anxiety and depression, a piecewise growth curve model provided the best fit for the data, with symptoms decreasing until age 12 (the "developmental knot") and then increasing into early adolescence. The trajectory of anxiety symptoms was best described by a discontinuous homotypic pattern in which childhood anxiety predicted adolescent anxiety. For depression, two distinct pathways were discovered: A discontinuous homotypic pathway in which childhood depression predicted adolescent depression and a discontinuous heterotypic pathway in which childhood anxiety predicted adolescent depression. Analytical, methodological, and clinical implications of these findings are discussed. PMID- 29256026 TI - Trajectories of Social Anxiety in Children: Influence of Child Cortisol Reactivity and Parental Social Anxiety. AB - Few studies have examined the interactive effect of intra- and extra-individual vulnerability factors on the trajectory of social anxiety in children. In this study, we examined the joint influence of familial vulnerability (i.e., parental social anxiety) and child biological stress vulnerability (i.e., cortisol reactivity) on trajectories of social anxiety. Children (N = 112 (57 males), M age = 8.14 years, S.D. = 2.25) were followed over three visits spanning approximately three years. Parental social anxiety was assessed using the Social Phobia and Anxiety Inventory, children's behavior and salivary cortisol reactivity were measured in response to a speech task, and children's social anxiety was assessed at all three visits using the Screen for Child Related Emotional Disorders (SCARED; Parent-report). A growth curve analysis was used to examine trajectories of child social anxiety as predicted by children's cortisol reactivity and parental social anxiety, adjusting for covariates. We found a significant interaction between parental social anxiety and child cortisol reactivity in predicting child social anxiety across time. Having a socially anxious parent coupled with heightened cortisol reactivity predicted the highest levels of child social anxiety, with scores that remained above clinically significant levels for social anxiety across all visits. Children with familial risk for social anxiety and who also exhibit high stress-reactivity appear to be at risk for persistent, clinically significant social anxiety. This highlights the importance of considering the interaction between both biological and contextual factors when considering the development, maintenance, and treatment of social anxiety in children across time. PMID- 29256027 TI - Impact of Low Social Preference on the Development of Depressive and Aggressive Symptoms: Buffering by Children's Prosocial Behavior. AB - Holding a low social position among peers has been widely demonstrated to be associated with the development of depressive and aggressive symptoms in children. However, little is known about potential protective factors in this association. The present study examined whether increases in children's prosocial behavior can buffer the association between their low social preference among peers and the development of depressive and aggressive symptoms in the first few school years. We followed 324 children over 1.5 years with three assessments across kindergarten and first grade elementary school. Children rated the (dis)likability of each of their classroom peers and teachers rated each child's prosocial behavior, depressive and aggressive symptoms. Results showed that low social preference at the start of kindergarten predicted persistent low social preference at the start of first grade in elementary school, which in turn predicted increases in both depressive and aggressive symptoms at the end of first grade. However, the indirect pathways were moderated by change in prosocial behavior. Specifically, for children whose prosocial behavior increased during kindergarten, low social preference in first grade elementary school no longer predicted increases in depressive and aggressive symptoms. In contrast, for children whose prosocial behavior did not increase, their low social preference in first grade elementary school continued to predict increases in both depressive and aggressive symptoms. These results suggest that improving prosocial behavior in children with low social preference as early as kindergarten may reduce subsequent risk of developing depressive and aggressive symptom. PMID- 29256028 TI - ADHD Symptoms in Middle Adolescence Predict Exposure to Person-Related Life Stressors in Late Adolescence in 5-HTTLPR S-allele Homozygotes. AB - Literature suggests that life stressors predict attention-deficit/hyperactivity disorder (ADHD) symptoms and that this relationship is moderated by the serotonin transporter polymorphism (5-HTTLPR). It is less clear whether, on reverse, ADHD symptoms may influence the risk of exposure to life stressors. Furthermore, the role of life stressors may vary across development depending on the type of life stressor. We used threewave longitudinal data of 1,306 adolescents from the general population and clinicreferred cohort of the TRacking Adolescents' Individual Lives Survey. The 5-HTTLPR genotype (SS, LS, LL), parent-reported ADHD symptoms at three time points (T1: Mage = 11.2; T2: Mage = 13.5; T3: Mage = 16.2 years), and the number of personrelated ('dependent') and environment-related ('independent') life stressors occurring between measurements (T1-T2, T2-T3) were assessed. Using path analyses, we examined bidirectional relations between exposure to these life stressors and ADHD symptoms between the separate waves moderated by 5-HTTLPR status. Exposure to life stressors did not predict ADHD symptoms. Rather, we found that in 5-HTTLPR Sallele homozygotes, ADHD symptoms in middle adolescence (T2) predicted exposure to the number of person-related life stressors later in adolescence (T2-T3, p = 0.001). There was no relation with environment-related life stressors. Our study suggests that S-allele homozygotes with higher levels of ADHD symptoms in middle adolescence are more vulnerable to becoming exposed to person-related ('dependent') life stressors in late adolescence. Findings emphasize the need to be aware of social-emotional adversities that may occur in genetically vulnerable adolescents with ADHD symptoms in the transition into adulthood. PMID- 29256029 TI - Like Father, like Child: Early Life Family Adversity and Children's Bullying Behaviors in Elementary School. AB - Family adversity has been associated with children's bullying behaviors. The evidence is, however, dominated by mothers' perceptions of the family environment and a focus on mothers' behaviors. This prospective population-based study examined whether children's bullying behaviors were associated with mother- and father-reported family adversity, assessed before and after child birth. Peer nominations were used to assess bullying behaviors of 1298 children in elementary school (mean age 7.5 years). The following paternal risk factors were prospectively associated with children's bullying behaviors: (1) father-reported prenatal family distress, (2) fathers' hostility at preschool age, and (3) fathers' harsh disciplinary practices at preschool age, but effect sizes were relatively small. The effect of maternal risk factors was less consistent, only mother-reported family distress in childhood was associated with children's bullying behaviors. The associations were independent of background family risk factors (i.e., life stress, contextual factors, and other background factors such as parental education and risk taking record) and early childhood externalizing problems. Moreover, our results indicated that father-reported family adversity predicted children's bullying behaviors over and above the background family risk factors, early childhood externalizing problems and mother-reported family adversity. We also demonstrated that the association of fathers' prenatal hostility and family distress with subsequent bullying behavior of their child at school was partly mediated by fathers' harsh disciplinary practices at preschool age. Our findings highlight the importance of fathers' behaviors in the development of children's bullying behaviors. PMID- 29256030 TI - Polar Cycles. PMID- 29256031 TI - Residents Teaching Residents: Results of an Interdisciplinary Educational Endeavor. AB - OBJECTIVES: Resident physicians across disciplines are engaged in teaching at multiple levels. Available literature focuses on medical student education and intra-disciplinary teaching. The national shortage of psychiatrists coupled with an increasing mental illness burden necessitates development of creative interdisciplinary collaboration. The authors report on an interdisciplinary, resident-to-resident didactic series assessing whether such a model could improve internal medicine resident comfort with managing psychiatric illness on inpatient medical wards. METHODS: Internal medicine residents were assessed regarding their comfort level with managing certain common inpatient psychiatric presentations before and after the delivery of a teaching curriculum designed and delivered by psychiatry residents. RESULTS: Internal medicine residents' overall confidence with identifying and managing common psychiatric problems on inpatient medical wards improved. Comfort level with managing depression and demoralization and determining decisional capacity both improved to a statistically significant degree. CONCLUSIONS: Collaborative, interdisciplinary care is complex and its benefits can be difficult to assess. Data from this study showed that interdisciplinary teaching at the resident level has the potential to be an effective means for building collaboration and can lead to a subjective improvement in comfort managing common inpatient psychiatric presentations on medical wards. Additionally, qualitative observations suggest that such an intervention can improve interdisciplinary collaboration. PMID- 29256032 TI - From Information to Simulation: Improving Competency in ECT Training Using High Fidelity Simulation. AB - OBJECTIVE: This study was intended to develop a new educational model that supplements ECT didactics with simulation-based procedural training and to evaluate the learning gains conferred by such a curriculum. METHODS: Two types of curricula were evaluated for educational efficacy in this prospective randomized controlled trial. Psychiatry residents (n = 35) completed surveys to ascertain their baseline experience, knowledge, and proficiency with the ECT procedure. They were then block-randomized to receive either a didactic ECT curriculum (non SIM) or one augmented by simulation training (SIM). Three months post-completion of the two types of instruction, all residents were re-administered the surveys and a procedural post-assessment. RESULTS: The median number of ECTs performed prior to the study was similar between the two groups (SIM group = 3, non-SIM group = 4.) The SIM group showed significant improvement on pre- and post- survey theoretical knowledge scores: 51% (95% CI = 41 to 61%) and 69% (95% CI = 64 to 74%), respectively, p = .02; this difference was not significant in the non-SIM group, p = .2. Improvement between pre- and post- proficiency scores were seen in the SIM group: 22% (95% CI = 13 to 32%) and 51% (95% CI = 53 to 59%), p < .001 while the effect was less pronounced in the non-SIM group. Inter-rater agreement for the proficiency assessment was excellent: k, = .9. CONCLUSIONS: Residents showed significant improvement in knowledge, comfort, and skills following ECT simulation training. With the proposed curriculum, residents would receive comprehensive education not only in the theory behind ECT but also in procedural skills. This curriculum can be modeled in other programs that do not have extensive ECT facilities. PMID- 29256034 TI - To Feel or Not to Feel: Empathy and Physician Burnout. PMID- 29256033 TI - Web-Based Tools and Mobile Applications To Mitigate Burnout, Depression, and Suicidality Among Healthcare Students and Professionals: a Systematic Review. AB - OBJECTIVE: Being a healthcare professional can be a uniquely rewarding calling. However, the demands of training and practice can lead to chronic distress and serious psychological, interpersonal, and personal health burdens. Although higher burnout, depression, and suicide rates have been reported in healthcare professionals, only a minority receive treatment. Concerns regarding confidentiality, stigma, potential career implications, and cost and time constraints are cited as key barriers. Web-based and mobile applications have been shown to mitigate stress, burnout, depression, and suicidal ideation among several populations and may circumvent these barriers. Here, we reviewed published data on such resources and selected a small sample that readily can be used by healthcare providers. METHODS: We searched PubMed for articles evaluating stress, burnout, depression, and suicide prevention or intervention for healthcare students or providers and identified five categories of programs with significant effectiveness: Cognitive Behavioral Therapy (online), meditation, mindfulness, breathing, and relaxation techniques. Using these categories, we searched for Web-based (through Google and beacon.anu.edu.au -a wellness resource website) and mobile applications (Apple and mobile. va.gov/appstore ) for stress, burnout, depression, and suicide prevention and identified 36 resources to further evaluate based on relevance, applicability to healthcare providers (confidentiality, convenience, and cost), and the strength of findings supporting their effectiveness. RESULTS: We selected seven resources under five general categories designed to foster wellness and reduce burnout, depression, and suicide risk among healthcare workers: breathing (Breath2Relax), meditation (Headspace, guided meditation audios), Web-based Cognitive Behavioral Therapy (MoodGYM, Stress Gym), and suicide prevention apps (Stay Alive, Virtual Hope Box). CONCLUSIONS: This list serves as a starting point to enhance coping with stressors as a healthcare student or professional in order to help mitigate burnout, depression, and suicidality. The next steps include adapting digital health strategies to specifically fit the needs of healthcare providers, with the ultimate goal of facilitating in-person care when warranted. PMID- 29256035 TI - The Cost of Depression-Related Presenteeism in Resident Physicians. PMID- 29256036 TI - How Medical Students View the Influence of a Student-Run Free Clinic on Empathy Development: a Pilot Study. PMID- 29256037 TI - Prevalence of pulmonary hypertension in systemic lupus erythematosus: a meta analysis. AB - BACKGROUND AND AIMS: Pulmonary hypertension (PH) has been suggested to be associated with systemic lupus erythematosus (SLE). However, the results of prevalence studies on PH in SLE vary substantially. To derive a more precise estimation on the prevalence of PH in SLE, a meta-analysis was performed. METHODS: Relevant literatures were searched in PubMed and EMBASE until November 2017. A total of 1366 articles were obtained after searching databases, and 23 studies were finally included in the meta-analysis. Heterogeneity test was performed, and publication bias was evaluated. RESULTS: The result of analysis in random effect model showed that the pooled prevalence was 8% (95%CI 5-12%). There was no evidence of publication bias (p = 0.51). To evaluate the stability of our results, sensitivity analyses were performed, and the results showed no significant change when any one study was excluded. Subgroup analyses demonstrated that there were significant differences in PH prevalence in SLE patients of different gender, age, regions, year of publication, and diagnostic methods. CONCLUSIONS: PH is prevalent in SLE patients, but it was significantly different between different gender, age, regions, year of publication, and diagnostic methods. PMID- 29256038 TI - International Review of Precipitants to Patient Assaults on Staff, 2013-2017. AB - In studying psychiatric patient assaults, assessing the person x event x environment interaction is important in enhancing safety and ensuring quality care. Precipitants to patient assaults have traditionally received less attention than the patient characteristics of such assaults. Reviews of inpatient precipitants from 1960 to 2012 noted acute psychosis, denial of services, and substance abuse as commonly occurring precipitants. The present study reviewed the literature on precipitants from 2013 to 2017. A variety of precipitants, including acute psychosis, substance abuse, and denial of services were observed. The literature in this review broke new ground in subjects, methodologies, and precipitants. These new findings and a detailed methodological inquiry are presented. PMID- 29256039 TI - When do models of NeuroAIDS faithfully imitate "the real thing"? AB - HIV-infected patients treated with antiretroviral medicines (ART) still face neurological challenges. HIV-associated neurocognitive disturbances (HAND) can occur, and latent viral DNA persisting in the central nervous system (CNS) prevents eradication of HIV. This communication focuses on how to develop experimental models of HAND and CNS HIV latency that best imitate the CNS pathophysiology in diseased humans, which we take to be "the real thing." Models of HIV encephalitis (HIVE) with active CNS viral replication were developed in the early years of the AIDS pandemic. The clinical relevancy of such models is in sharp decline because HIVE seldom occurs in virally suppressed patients, while HAND remains common. The search for improved models of HAND should incorporate the neurochemical, neuroimmunological and neuropathological features of virally suppressed patients. Common anomalies in these patients as established in autopsy brain specimens include brain endothelial cell activation and neurochemical imbalances of synaptic transmission; classical neurodegeneration may not be as crucial. With regard to latent HIV with viral suppression, human brain specimens show that the pool of latent proviral HIV DNA in the CNS is relatively small relative to the total body pool and does not change substantially over years. The CNS pool of latent virus probably differs from lymphoid tissues, because the mononuclear phagocyte system sustains productive infection (versus lymphocytes). These and yet-to-be discovered aspects of the human CNS of virally suppressed patients need to be better defined and addressed in experimental models. To maintain clinical relevancy, models of HAND and viral latency should faithfully emulate "the real thing." PMID- 29256040 TI - Relationship between brain large artery characteristics and their downstream arterioles. AB - We aimed to test the hypothesis that brain large artery diameters relate to distal downstream arteriolar diameters. In a sample of 110 autopsied individuals (69% men, 76% HIV+, mean age 51), we used multilevel models to relate large artery lumen and lumen-to-wall ratio to left frontal lobe arteriolar lumen and lumen-to-wall ratio adjusting for demographics and vascular risk factors. Comparing the large artery characteristics of the whole brain did not disclose significant associations with frontal lobe arteriolar characteristics. However, restricting the comparison to large arteries upstream of the studied arterioles demonstrated an independent association between left-sided frontal lobe arteriolar luminal diameter with large artery luminal diameters (B = 1.82 +/- 0.77, P = 0.01) and with large artery lumen-to-wall ratio (B = 0.58 +/- 0.29, P = 0.05). In stratified models, the point estimates in the HIV+ subsample were larger than in the HIV- subsample. These finding suggest coupling between higher proximal blood flow represented by large artery diameter and lower distal resistance represented by arteriolar dilatation. The relationship between arteriolar dilatation and brain parenchyma homeostasis should be further studied. PMID- 29256042 TI - Clinical usability of aspartate aminotransferase to evaluate the prognosis of periodontal regeneration therapies: prospective, longitudinal study. AB - To evaluate the degree of periodontal tissue destruction, aspartate aminotransferase (AST) levels in the gingival crevicular fluid (GCF) are utilized as a predictor of periodontal therapy. We have previously shown that the usefulness of AST activities [periodontal tissue monitor (PTM) values] using a PTM-kit to evaluate the effects of initial periodontal therapy and periodontal regeneration therapy by enamel matrix derivative (EMD). This prospective, longitudinal study was conducted using 38 healthy and 80 periodontitis sites with probing depth (PD) of 5-10 mm for guided tissue regeneration (GTR) and EMD from 36 patients. GCF samples were used to evaluate PTM values at base line (BL) and after 6 months of surgeries (re-evaluation: RE), and periodontal examinations were performed concurrently. PTM values at BL were statistically improved at RE, accompanied by the improvement of periodontal parameters in both groups. PTM values and PD, and the clinical attachment level (CAL) showed high correlations. PD, CAL and bleeding on probing (BOP) were highly correlated with PTM values in both groups, whereas only PD showed a significant correlation with PTM values at RE in the GTR group. Change in the amounts of PD, CAL and BOP between BL and RE in both groups showed no correlation with PTM values. In the negative PTM value sites at BL in EMD group, the mean PD was significantly reduced at RE compared with positive PTM sites at BL. PTM values are able to be utilized as the biochemical predictor of prognosis after periodontal regeneration therapy. PMID- 29256041 TI - HIV-1 infection of microglial cells in a reconstituted humanized mouse model and identification of compounds that selectively reverse HIV latency. AB - Most studies of HIV latency focus on the peripheral population of resting memory T cells, but the brain also contains a distinct reservoir of HIV-infected cells in microglia, perivascular macrophages, and astrocytes. Studying HIV in the brain has been challenging, since live cells are difficult to recover from autopsy samples and primate models of SIV infection utilize viruses that are more myeloid tropic than HIV due to the expression of Vpx. Development of a realistic small animal model would greatly advance studies of this important reservoir and permit definitive studies of HIV latency. When radiation or busulfan-conditioned, immune deficient NSG mice are transplanted with human hematopoietic stem cells, human cells from the bone marrow enter the brain and differentiate to express microglia specific markers. After infection with replication competent HIV, virus was detected in these bone marrow-derived human microglia. Studies of HIV latency in this model would be greatly enhanced by the development of compounds that can selectively reverse HIV latency in microglial cells. Our studies have identified members of the CoREST repression complex as key regulators of HIV latency in microglia in both rat and human microglial cell lines. The monoamine oxidase (MAO) and potential CoREST inhibitor, phenelzine, which is brain penetrant, was able to stimulate HIV production in human microglial cell lines and human glial cells recovered from the brains of HIV-infected humanized mice. The humanized mice we have developed therefore show great promise as a model system for the development of strategies aimed at defining and reducing the CNS reservoir. PMID- 29256043 TI - Correlation between plasma brain natriuretic peptide levels and left atrial appendage flow velocity in patients with non-valvular atrial fibrillation and normal left ventricular systolic function. AB - BACKGROUND: The left atrial appendage (LAA) flow velocity is an important factor for thrombus formation in patients with non-valvular atrial fibrillation (NV-AF). Recently, the relation of plasma brain natriuretic peptide (BNP) levels and thromboembolism has been reported in patients with NV-AF. The aim of this study was to determine whether the plasma BNP is predictive of lower LAA flow velocity in patients with NV-AF and normal left ventricular (LV) systolic function. METHODS AND RESULTS: A total of 184 patients with NV-AF (132 men; 65 +/- 12 years, LV ejection fraction; 65 +/- 10%) underwent transthoracic echocardiography, transesophageal echocardiography (TEE), and measurement of plasma BNP. The LAA flow velocity was obtained by pulsed Doppler TEE. Multivariate logistic regression analysis demonstrated that plasma BNP levels, left atrial volume index (LAVI), LV mass index (LVMI), and the CHADS2 score were independent predictors of lower LAA flow velocity (< 20 cm/s). Plasma BNP levels (r = - 0.58, p < 0.001) were correlated with LAA flow velocity. The area under the curve (AUC) for BNP (AUC 0.803) was larger than that for the CHADS2 score (AUC 0.712), LAVI (AUC 0.664) and LVMI (AUC 0.608) with an optimal BNP cut-off value of 164 pg/ml (sensitivity 75.7%, specificity 71.1%). CONCLUSIONS: This study showed that a higher plasma BNP was associated with a lower LAA flow velocity in patients with NV-AF and normal LV systolic function. The plasma BNP may complement the role of the CHADS2 score in predicting lower LAA flow velocity. PMID- 29256045 TI - Metformin Promotes 2-Deoxy-2-[18F]Fluoro-D-Glucose Uptake in Hepatocellular Carcinoma Cells Through FoxO1-Mediated Downregulation of Glucose-6-Phosphatase. AB - PURPOSE: The early diagnosis of primary hepatocellular carcinoma (HCC) has the potential to lead to significant improvements for the treatment and survival rates of cancer patients. 2-Deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is often used as a tracer for positive emission tomography (PET) and X-ray computed tomography (CT) imaging of cancer cells; however, [18F]FDG PET/CT cannot currently be used as an early diagnostic technique for HCC. This is because these cancer cells express high levels of glucose-6-phosphatase (G6Pase) that is responsible for poor cellular retention of [18F]FDG. Here, we sought to investigate the feasibility of metformin treatment to promote [18F]FDG uptake in HCC and the mechanism involved. PROCEDURES: Human SMMC-7721 HCC cells were treated with metformin (up to 10 mM) or FoxO1 siRNA. The transcriptional and expression levels of FoxO1 and G6Pase were determined by quantitative RT-PCR and Western blotting, respectively. The feasibility of using metformin to promote [18F]FDG uptake was investigated by both in vitro cell uptake analysis and in vivo microPET/CT imaging. Stable doxycycline-inducible cell lines with FoxO1 overexpression (FoxO1-OE) and FoxO1-knockdown (FoxO1-KD) were constructed to evaluate the impact of FoxO1 on G6Pase expression in vitro and [18F]FDG uptake in vivo. RESULTS: Treatment of HCC cells with metformin (Met) leads to a dose dependent reduction in the expression levels of FoxO1 at the protein level, but not at the mRNA level. Met-induced phosphorylation of FoxO1 initiates a reduction in the expression levels of G6Pase mRNA, which results in an overall increase in the uptake of [18F]FDG into HCC cells and tumors. CONCLUSIONS: We propose that treatment of HCC cells with Met may be a useful strategy for improving the efficacy of [18F]FDG as a tracer for PET/CT imaging of HCC tumors in patients. PMID- 29256044 TI - Treatment of Older Patients with Acute Lymphoblastic Leukaemia. AB - The outcome of adult acute lymphoblastic leukaemia (ALL) has improved significantly during the past decade, mainly due to intensive paediatric-based chemotherapy. Less improvement has been observed in older patients. A significantly lower rate of complete remissions, higher early mortality, higher relapse rate and poorer survival is observed in older compared with younger ALL patients. Most importantly, intensive chemotherapy with or without stem-cell transplantation is less well tolerated in older patients. In addition, there is an increasing incidence of poor prognostic factors with increasing age. Progress has been made with the development of age-adapted, moderately intensive chemotherapy protocols for Ph/BCR-ABL-negative ALL and combinations of tyrosine kinase inhibitors with chemotherapy in Ph/BCR-ABL-positive ALL. Future progress can be expected from new targeted therapies, particularly novel immunotherapies, moderately intensified consolidation strategies and reduced intensity stem-cell transplantation. For this purpose, prospective clinical trials for older patients are urgently needed. PMID- 29256046 TI - Prostate Cancer Theranostics Targeting Gastrin-Releasing Peptide Receptors. AB - Gastrin-releasing peptide receptors (GRPRs), part of the bombesin (BBN) family, are aberrantly overexpressed in many cancers, including those of the breast, prostate, pancreas, and lung, and therefore present an attractive target for cancer diagnosis and therapy. Different bombesin analogs have been radiolabeled and used for imaging diagnosis, staging, evaluation of biochemical recurrence, and assessment of metastatic disease in patients with prostate cancer. Recently, interest has shifted from BBN-like receptor agonists to antagonists, because the latter does not induce adverse effects and demonstrate superior in vivo pharmacokinetics. We review the preclinical and clinical literatures on the use of GRPRs as targets for imaging and therapy of prostate cancer, with a focus on the newer developments and theranostic potential of GRPR peptides. PMID- 29256047 TI - A mathematical model of the effects of resistance exercise-induced muscle hypertrophy on body composition. AB - PURPOSE: Current diet and exercise methods used to maintain or improve body composition often have poor long-term outcomes. We hypothesize that resistance exercise (RE) should aid in the maintenance of a healthy body composition by preserving lean mass (LM) and metabolic rate. METHOD: We extended a previously developed energy balance model of human metabolism to include muscle hypertrophy in response to RE. We first fit model parameters to a hypothetical individual to simulate an RE program and then compared the effects of a hypocaloric diet only to the diet with either cardiovascular exercise (CE) or RE. We then simulated a cohort of individuals with different responses to RE by varying the parameters controlling it using Latin Hypercube Sampling (LHS). Finally, we fit the model to mean data from an elderly population on an RE program. CONCLUSION: The model is able to reproduce the time course of change in LM in response to RE and can be used to generate a simulated cohort for in silico clinical studies. Simulations suggest that the additional LM generated by RE may shift the body composition to a healthier state. PMID- 29256048 TI - Traditional and new candidate cardiac biomarkers assessed before, early, and late after half marathon in trained subjects. AB - PURPOSE: Cardiac Troponins (cTnI, cTnT), NT-proBNP, and galectin-3 (GAL-3) mirror cardiomyocyte injury, stretch, and fibrosis. However, although these biomarkers has been thoroughly studied in marathon or ultramarathon, the effects occurring running shorter distances, as half-marathon, are less known and data are generally limited to immediately post-race evaluation. Moreover, significant variation of alpha-1 antitrypsin (AAT), an anti-protease factor with anti inflammatory properties, has been recently observed in heart failure, but not investigated in paraphysiological settings. The aim of the study was to evaluate these biomarkers concentration and trends in trained runners before half-marathon run and during a 48-h recovery period. METHODS: In 18 half-marathon runners (15 males, 46 +/- 6 years), cTnI, GAL-3 (Architect, Abbott), cTnT, NT-proBNP (Cobas e411, Roche), and AAT (Abcam, Cambridge, UK) were evaluated at rest, immediately post-run, and at 24 and 48-h recovery period. RESULTS: cTnT, NT-proBNP, and GAL-3 transiently increased after post-race, but normalized at 24 h (GAL-3 p < 0.01, cTnT < 0.001) or 48 h (NT-proBNP < 0.001), while cTnI and AAT did not significantly change. The frequency of values exceeding the diagnostic threshold, as evaluated at baseline and after the race, did not differ for cTnI ([Formula: see text] = 1.1, p = ns), and NT-proBNP ([Formula: see text] = 6, p = ns), but significantly increased for cTnT ([Formula: see text] = 23, p < 0.001) and GAL-3 ([Formula: see text] = 6.3, p < 0.05). None of the subjects showed AAT values exceeding the reference range at baseline and at any of the time points after the race. CONCLUSION: The transient cTnT, NT-proBNP, and GAL-3 increase may suggest a temporary stress on the myocyte. However, being the increase of all biomarkers moderate and reversible, it may represent a physiological response to acute exercise. PMID- 29256049 TI - A Pilot Study of the Normative Range of Overnight Urinary Free Cortisol Corrected for Creatinine in Children. AB - BACKGROUND: For more than a decade, urinary free cortisol corrected for creatinine (OUFCC) has been used to assess the systemic bioactivity of inhaled corticosteroids in children with asthma. Paediatric normative ranges, however, have not been established. The aim of the present study was to define a preliminary range for OUFCC in Tanner stage 1 children. METHODS: A post hoc analysis was performed of 26 Tanner stage one children (aged 5-11 years) with mild asthma only requiring prn (pro re nata) treatment with short-acting beta2 agonists, who participated in a 3-way cross-over knemometry study. The study comprised a run-in, two washout periods and three treatment periods (2 weeks each). Urine was collected at the end of each period. A normative range was derived using the 95% prediction interval for the geometric mean OUFCC, calculated from run-in and washout periods. RESULTS: Twenty-six children contributed 41 OUFCC values. The geometric mean OUFCC was 9.0 nmol/mmol (95% PI: 3.6, 22.7 nmol/mmol). CONCLUSIONS: The OUFCC preliminary normative range was 3.6 to 22.7 nmol/mmol in Tanner stage one children. A larger study in healthy children is warranted to confirm these findings and to assess potential differences in OUFCC across developmental stages and age groups, and by gender and race. EUDRACT NUMBER: 2013-004719-32, CLINICALTRIALS. GOV IDENTIFIER: NCT02063139. PMID- 29256051 TI - Neuroanatomical Correlates of Transcranial Magnetic Stimulation in Presymptomatic Granulin Mutation Carriers. AB - Frontotemporal dementia (FTD) is characterized by behavioural and language impairment, accompanied by atrophic changes in fronto-temporo-insular cortices. In the presymptomatic phases of genetic FTD, subtle or no volumetric changes have been reported. Transcranial magnetic stimulation (TMS) represents an approach to explore cortical connectivity, and some TMS measures have been demonstrated to be impaired in Granulin (GRN) mutation carriers. We aimed at exploring cross sectional changes in cortical thickness (CT) and surface area (SA) in the presymptomatic phases of GRN-related FTD, and their relationship with TMS parameters. Nineteen presymptomatic GRN mutation carriers and seventeen age and sex-matched non-carriers underwent 3T MRI scanning and a paired-pulse TMS protocol. The surface-based pipeline of FreeSurfer was applied in order to obtain cortical volumes (CVs), CT and SA measures. Then, between groups differences and correlation with TMS parameters were assessed. GRN carriers showed increased CT and decreased SA of the right parietal lobe, without significant volume changes. TMS parameters of intracortical inhibition and facilitation, which were significantly impaired in presymptomatic GRN mutation carriers, correlated with reduced SA and CV of the right insula. Our results suggest that splitting CV into its two main components could improve the sensitivity when exploring structural brain changes in presymptomatic or early phases of neurodegenerative conditions. TMS parameters might reflect damage within cortical regions reported to be affected early in the conversion to the symptomatic phase of the disease. PMID- 29256050 TI - Impact of plant-associated bacteria biosensors on plant growth in the presence of hexavalent chromium. AB - Cr(VI) is a highly toxic metal produced by anthropogenic activity which may impact the environment, affecting plants and animals. In plants, chromium both as Cr(III) or Cr(VI) can be absorbed by roots, is poorly translocated and affects negatively plant growth. Plants used in phytoremediation need to cope with chromium toxicity. This work aimed to evaluate strains of Ochrobactrum tritici and Nitrospirillum amazonense, resistant and modified in order to become chromate whole-cell biosensors, as plant-protectors enabling plants to withstand contaminated soils. In vitro tests were performed in three rice varieties and one maize variety. Initial evaluations of Cr(VI) toxicity to plants showed that plants had different sensitivities and BRS 6 CHUI rice variety was the most resistant. The metal affected plant growth and development, essentially in roots which were totally inhibited in rice varieties at 500 MUM. This effect was plant dependent. Modified N. amazonense proved to protect maize plants independently of the inoculation dose but O. tritici showed plant specificity and some toxicity when inoculated at high numbers, inhibiting rice development but not maize. Inoculants were directly responsible for growth improvements of specific plant varieties at 1.25 ppm Cr(VI), a concentration which corresponds to a weak soil contamination. Improvements were observed relatively to the Cr(VI)-treated controls, but also relative to the untreated controls, i.e., the benefits went beyond a simple neutralization of inhibition brought by Cr(VI) toxicity. PMID- 29256052 TI - CONTeMPLATE-a mnemonic to help medical educators infuse reflection into their residency curriculum. AB - Reflection, where clinical experiences are analyzed to gain greater understanding and meaning, is an important step in workplace learning. Residency programs must teach their residents the skills needed for deep reflection. Medical educators may find it difficult to construct a curriculum which includes the key elements needed to enable learners to attain these skills. When we first implemented reflection into our residency curriculum, we soon realized that our curriculum only taught residents how to engage in superficial reflection. Our curriculum lacked some key elements. To help guide the transformation of our curriculum, we combed the literature for best practices. The CONTeMPLATE mnemonic was born out of this process. It is a tool to help medical educators consider and implement key elements required to enable deep reflection. The purpose of this article is to show medical educators how they can use the CONTeMPLATE mnemonic to incorporate reflective practice into their own curriculum. PMID- 29256053 TI - Effects of medical school selection on student motivation: a PhD thesis report. AB - INTRODUCTION: High stakes are involved in student selection, for both medical schools and applicants. This thesis investigated the effects of selection on the medical student population and applicant pool in the Dutch setting. METHODS: This thesis consists of six papers: two quantitative studies, one qualitative study, two mixed methods studies and one perspective paper based on a review of the literature. RESULTS: (1) Compared with a lottery, selection does not result in a student population with better motivation, engagement and performance, both in the clinical and pre-clinical phases of the study. (2) Selection seems to have a temporary stimulating effect on student motivation through enhancing perceived autonomy, competence and relatedness. (3) Applicants adopt a strategic approach, based on the selection procedure, in their choice of medical school. (4) The description of an applicant's motivation is not a reliable and valid tool to assess motivation during selection. (5) Gaining healthcare experience is crucial for applicants' motivation, but inequalities in access to such experiences can demotivate certain student groups from applying to medical school. (6) The gains yielded from selection compared with a lottery seem to be small. Unintentionally induced self-selection among certain groups of students and biased selection procedures may compromise student diversity. DISCUSSION: The added value of selection procedures compared with a weighted lottery for admitting students to medical school is questionable. Students are generally motivated and perform well, irrespective of how they enrolled in medical school. Selection yields only small gains, while student diversity may be hampered. PMID- 29256054 TI - Bad faith, medical education, and post-truth. PMID- 29256055 TI - Using parent feedback: A qualitative study of residents' and physician-educators' perspectives. AB - INTRODUCTION: Patients and family members can contribute to resident assessment in competency-based medical education. However, few studies have examined the use of patient/family member feedback generated from questionnaire-based assessments. To implement appropriate assessment strategies and optimize feedback use, we need to understand how residents and physician-educators would use feedback from these stakeholders. This study aimed to understand how paediatric residents and physician-educators would use parent feedback generated from questionnaire-based assessments. METHODS: This study was conducted at a paediatric academic health science centre. We held dyadic interviews with six residents and six physician educators. A three-step approach was used to analyze the data: data reduction, data display, and conclusions/verifications. We developed an initial coding scheme, conducted an in-depth review of the data and coded it, finalized our coding scheme, and identified categories. RESULTS: Participants described that they would use parent feedback to: (a) provide additional direct observations of residents' performances, (b) teach and coach residents, (c) assess residents' overall performance and progression, and (d) encourage resident self-assessment and behaviour change. DISCUSSION: Parents directly observe residents as they interact with them and their children and, therefore, can provide feedback on residents' performances. Residency programs should include parent feedback and promote and facilitate its use by residents and physician-educators. CONCLUSION: This study provides an initial understanding of how paediatric residents and physician-educators would use parent feedback if they were to receive it. This information, combined with future research, can inform the development and implementation of parent feedback strategies in competency-based medical education. PMID- 29256056 TI - Negatives and Positives: Contaminants and Other Stressors in Aquatic Ecosystems. AB - Published research is reviewed to provide examples of both positive and negative interactions of contaminants and: climate change; habitat change; invasive and introduced species; and, eutrophication including harmful algal blooms. None of these stressor interactions results solely in negative effects. Research must shift from examining contaminants or other stressors in isolation to considering potential positive and negative effects of interactions, with the ultimate goal of providing the necessary information for the effective management of ecosystem services. PMID- 29256058 TI - Long-pulsed 1064-nm Nd: YAG laser ameliorates LL-37-induced rosacea-like skin lesions through promoting collagen remodeling in BALB/c mice. AB - Long-pulsed 1064-nm neodymium: yttrium-aluminum-garnet laser (LPND) effectively treats rosacea, although the underlying mechanism is unclear, to evaluate the histological effects and molecular mechanism of LPND on LL-37-induced rosacea like skin lesions in mice. Intradermal injection of LL-37 was performed into the dorsal skin of BALB/c mice (n = 30) twice a day for 2 days. Fifteen mice were treated with LPND. After 48 h, the excised skin sample was stained for histology and type I collagen; transforming growth factor (TGF)-beta, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase (TIMP)-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1alpha mRNA levels were determined by real-time RT-PCR. Intradermal injection of LL-37 induced rosacea like clinical features. LPND treatment significantly reduced erythema and increased dermal collagen production. Levels of Type I collagen, TGF-beta, and MMP-1 mRNA were significantly higher in LPND-treated mice than in untreated mice. LPND may improve rosacea by ameliorating dermal connective tissue disorganization and elastosis through MMP-mediated dermal collagen remodeling. PMID- 29256057 TI - The Clinical Significance of GP73 in Immunologically Mediated Chronic Liver Diseases: Experimental Data and Literature Review. AB - There is significant void in establishing validated non-invasive surrogate biomarkers of liver fibrosis/cirrhosis in chronic liver diseases (CLD). Golgi protein 73 (GP73) has been suggested as a potential serum marker for the diagnosis of hepatocellular carcinoma (HCC). However, significant background of cirrhosis could have accounted for the elevation of serum GP73 in HCC. In this study, we have taken advantage of a well-defined extensive cohort of 3044 patients with either compensated cirrhosis (n = 1247), decompensated cirrhosis (n = 841) or pre-cirrhotic CLD (n = 956) and our ability to quantify serum GP73 to define the potential of serum GP73 as a biomarker of liver cirrhosis/fibrosis in CLD. The diagnostic value of GP73 was compared with aspartate aminotransferase-to platelet ratio index (APRI), fibrosis index based on four factors (FIB-4) and liver stiffness measurement (LSM). Immunohistochemical analysis was performed to measure hepatic GP73 expression. Receiver operating characteristic curve analysis demonstrated that serum GP73 had a good diagnostic potential for compensated cirrhosis regardless of etiology. The diagnostic performance of GP73 is better than APRI, FIB-4 and similar with LSM, especially in patients with severe inflammation, steatosis and cholestasis. Notably, in patients of autoimmune liver diseases, non-alcoholic fatty liver disease and viral hepatitis, serum GP73 also exhibited diagnostic value for advanced fibrosis as well as cirrhosis. Furthermore, there is also a gradual increase in GP73 expression with disease progression from mild fibrosis to cirrhosis. In conclusion, GP73 is an effective and reliable serological marker for the diagnosis of advanced fibrosis and prediction of appearance of cirrhosis. PMID- 29256059 TI - X inactivation in a mammal species with three sex chromosomes. AB - X inactivation is a fundamental mechanism in eutherian mammals to restore a balance of X-linked gene products between XY males and XX females. However, it has never been extensively studied in a eutherian species with a sex determination system that deviates from the ubiquitous XX/XY. In this study, we explore the X inactivation process in the African pygmy mouse Mus minutoides, that harbours a polygenic sex determination with three sex chromosomes: Y, X, and a feminizing mutant X, named X*; females can thus be XX, XX*, or X*Y, and all males are XY. Using immunofluorescence, we investigated histone modification patterns between the two X chromosome types. We found that the X and X* chromosomes are randomly inactivated in XX* females, while no histone modifications were detected in X*Y females. Furthermore, in M. minutoides, X and X* chromosomes are fused to different autosomes, and we were able to show that the X inactivation never spreads into the autosomal segments. Evaluation of X inactivation by immunofluorescence is an excellent quantitative procedure, but it is only applicable when there is a structural difference between the two chromosomes that allows them to be distinguished. PMID- 29256061 TI - The physiologic basis for goal-directed hemodynamic and fluid therapy: the pivotal role of the venous circulation. AB - PURPOSE: Understanding cardiovascular physiology should help clinicians to understand the purpose of fluid and drug management during the perioperative period. The purpose of this narrative review is to describe the pivotal role of the venous circulation in goal-directed hemodynamic and fluid therapy. SOURCE: We selected relevant literature that examines the appropriateness of fluid therapy and pharmacologic interventions during the perioperative period. PRINCIPAL FINDINGS: The interaction between the stressed and unstressed intravascular volume (Vs and Vu, respectively) regulates the venous return, which is the main determinant of cardiac output. The lack of hemodynamic response to an intravascular fluid challenge likely results from an unpredictable distribution of infused fluid between the Vs and Vu. Other factors affecting hemodynamic responses include the pharmacodynamics of common vasoactive drugs, which further highlight the complexity of the regulation of venous return during infusion of exogenous catecholamines. The response to even a highly selective agent can result in different hemodynamic effects. Low doses of alpha-adrenergic agonists constrict veins and may often shift blood from the Vu to the Vs, subsequently increasing the venous return and cardiac output, whereas higher drug doses constrict arteries and usually decrease cardiac output. CONCLUSIONS: The physiologic basis of goal-directed hemodynamic therapy is complex and not necessarily reflected in the information received from hemodynamic monitors. Understanding the physiologic basis of such therapy is a logical step towards its optimal use. PMID- 29256062 TI - Correction to: Neuraxial anesthesia and bladder dysfunction in the perioperative period: a systematic review. AB - The following row on page 691 of Table 3, as highlighted in bold under Incidence of Retention (%) should read "0" instead of "N/A". PMID- 29256063 TI - Benzodiazepine administration during adult cardiac surgery: a survey of current practice among Canadian anesthesiologists working in academic centres. AB - BACKGROUND: Benzodiazepines are commonly administered during cardiac surgery because of their limited effect on hemodynamics and presumed role in preventing intraoperative awareness. Recent concerns about an increased risk of delirium with benzodiazepines have resulted in decreased usage in the intensive care unit and in geriatric perioperative practice. Little is known, however, about current benzodiazepine usage in the setting of adult cardiac surgery. METHODS: We contacted all academic anesthesia departments in Canada to identify practicing attending cardiac anesthesiologists; this group constituted our sampling frame. Information regarding participant demographics, benzodiazepine usage, type, dose, and other administration details were obtained by electronic survey. Responses were analyzed descriptively. RESULTS: The survey was completed by 243/346 (70%) of cardiac anesthesiologists. Eleven percent of respondents do not administer benzodiazepines. Midazolam was the most commonly used benzodiazepine, with a mean (standard deviation) dose of 4.9 (3.8) mg given to an average patient. When respondents were asked the proportion of patients that they gave benzodiazepines, the response was bimodal. The most common considerations that influenced benzodiazepine use were patient age (73%), patient anxiety (63%), history of alcohol/drug/benzodiazepine use (60%), and the presence of risk factors for intraoperative awareness (44%). CONCLUSIONS: Benzodiazepine use is common among academic cardiac anesthesiologists in Canada. Nonetheless, heterogeneity exists between individual practices, suggesting clinical equipoise between restrictive and liberal administration of benzodiazepines for cardiac anesthesia. L'administration de benzodiazepines pendant la chirurgie cardiaque chez l'adulte: evaluation de la pratique actuelle des anesthesiologistes canadiens exercant en milieu universitaire. PMID- 29256064 TI - The utility and safety of flexible bronchoscopy in critically ill acute leukemia patients: a retrospective cohort study. AB - PURPOSE: Flexible bronchoscopy with bronchoalveolar lavage (BAL) is commonly performed in immunocompromised patients. Nevertheless, it remains unclear whether bronchoscopy with BAL leads to changes in medical management or is associated with procedural complications among critically ill acute leukemia (AL) patients. METHODS: We evaluated 71 AL patients who underwent diagnostic bronchoscopy with BAL in the intensive care unit (ICU) between 1 January 2007 and 31 December 2012. We recorded baseline characteristics, vital signs (before, during, and after the procedure), changes in medical management following the procedure, and procedural complications. Using a multivariable logistic regression model, we explored the relationship between patient characteristics and whether bronchoscopy changed management or caused complications. Patient characteristics included as predictors in the regression model were age, sex, immunosuppression status (those undergoing active chemotherapy), and the Acute Physiology And Chronic Health Evaluation II score. RESULTS: The most common indication for ICU admission was respiratory failure (51 patients, 72%), followed by sepsis (14 patients, 20%). Overall, the results obtained from bronchoscopy with BAL were associated with a change in management in 32 patients (45%), most commonly a change in antimicrobial therapy as a result of an infectious pathogen being identified (17 patients, 24%). Complications were documented in nine patients (13%) and included post-procedural hypoxia (six patients, 8%), the need for intubation (one patient, 9% of non-intubated patients), and tracheal perforation (one patient, 1%). No clinically significant changes in patient vital signs were observed during or immediately following the procedure. Patient characteristics did not predict whether bronchoscopy was associated with changes in medical management or procedural complications in multivariable analyses. CONCLUSIONS: Flexible bronchoscopy with BAL is relatively safe and helps to guide medical management among patients with AL admitted to the ICU. PMID- 29256065 TI - Age at death as a useful indicator of healthy aging at population level: a 50 year follow-up of the Italian Rural Areas of the Seven Countries Study. AB - OBJECTIVES: To explore age at death (AD), overall and for different causes of death, in a cohort followed up to quasi-extinction. MATERIALS AND METHODS: In 1960, in the Italian Rural Areas of the Seven Countries Study, 1712 men aged 40 59 years were enrolled, examined and then followed up for 50 years. AD was computed for all fatal events and compared across 12 groups of causes of death. Multiple linear regression model was used to estimate AD and Cox model to predict each of the 12 causes of death, as a function of 28 selected baseline risk factors. RESULTS: After 50 years, 97.5% of men had died. Mean AD was 75.0 years (median 76), while large variation was found across the 12 causes of death, with the highest levels for Heart Disease of Uncertain Etiology (HDUE) and Senility plus Causes Unknown (SNUNK), having means of 79.2 and 84.5 (median of 80 and 86) years, respectively. Many risk factors were directly associated with overall AD, the most significant being subscapular skinfold, arm circumference, Mediterranean diet, age at baseline examination, never smokers and vigorous physical activity. Systolic blood pressure (SBP) was inversely related. The relevant modifiable risk factors predicting single causes of death were SBP and the lifestyle behaviors of dietary, motion and smoking habits. CONCLUSIONS: AD proved to be a useful indicator of previous health and aging of populations. HDUE and SNUNK seem the most "physiological" causes of death. SBP and lifestyle risk factors are the most relevant characteristics associated with AD. PMID- 29256066 TI - Middle-aged female with palpable swelling over the abdominal wall. Dermatofibrosarcoma protuberans. PMID- 29256067 TI - Unmanned aerial vehicle (UAV)-based monitoring of a landslide: Gallenzerkogel landslide (Ybbs-Lower Austria) case study. AB - In the present study, UAV-based monitoring of the Gallenzerkogel landslide (Ybbs, Lower Austria) was carried out by three flight missions. High-resolution digital elevation models (DEMs), orthophotos, and density point clouds were generated from UAV-based aerial photos via structure-from-motion (SfM). According to ground control points (GCPs), an average of 4 cm root mean square error (RMSE) was found for all models. In addition, light detection and ranging (LIDAR) data from 2009, representing the prefailure topography, was utilized as a digital terrain model (DTM) and digital surface model (DSM). First, the DEM of difference (DoD) between the first UAV flight data and the LIDAR-DTM was determined and according to the generated DoD deformation map, an elevation difference of between - 6.6 and 2 m was found. Over the landslide area, a total of 4380.1 m3 of slope material had been eroded, while 297.4 m3 of the material had accumulated within the most active part of the slope. In addition, 688.3 m3 of the total eroded material had belonged to the road destroyed by the landslide. Because of the vegetation surrounding the landslide area, the Multiscale Model-to-Model Cloud Comparison (M3C2) algorithm was then applied to compare the first and second UAV flight data. After eliminating both the distance uncertainty values of higher than 15 cm and the nonsignificant changes, the M3C2 distance obtained was between - 2.5 and 2.5 m. Moreover, the high-resolution orthophoto generated by the third flight allowed visual monitoring of the ongoing control/stabilization work in the area. PMID- 29256069 TI - Psychological consequences of pelvic floor trauma following vaginal birth: a qualitative study from two Australian tertiary maternity units. AB - Vaginal birth may result in damage to the levator ani muscle (LAM) with subsequent pelvic floor dysfunction and there may be accompanying psychological problems. This study examines associations between these somatic injuries and psychological symptoms. A qualitative study using semi-structured interviews to examine the experiences of primiparous women (n = 40) with known LAM trauma was undertaken. Participants were identified from a population of 504 women retrospectively assessed by a perinatal imaging study at two obstetric units in Sydney, Australia. LAM avulsion was diagnosed by 3D/4D translabial ultrasound 3-6 months postpartum. The template consisted of open-ended questions. Main outcome measures were quality of information provided antenatally; intrapartum events; postpartum symptoms; and coping mechanisms. Thematic analysis of maternal experiences was employed to evaluate prevalence of themes. Ten statement categories were identified: (1) limited antenatal education (29/40); (2) no information provided on potential morbidities (36/40); (3) conflicting advice (35/40); (4) traumatized partners (21/40); (5) long-term sexual dysfunction/relationship issues (27/40); (6) no postnatal assessment of injuries (36/40); (7) multiple symptoms of pelvic floor dysfunction (35/40); (8) "putting up" with injuries (36/40); (9) symptoms of post-traumatic stress disorder (PTSD) (27/40); (10) dismissive staff responses (26/40). Women who sustain LAM damage after vaginal birth have reduced quality of life due to psychological and somatic morbidities. PTSD symptoms are common. Clinicians may be unaware of the severity of this damage. Women report they feel traumatized and abandoned because such morbidities were not discussed prior to birth or postpartum. PMID- 29256068 TI - Health-related quality of life and coping strategies among people living with HIV: the moderating role of gender. AB - The aim of the study was to explore gender differences in the level of health related quality of life (HRQoL) and coping strategies among people living with the human immunodeficiency virus (HIV) (PLWH). In particular, the moderating role of participants' gender on the relationship between coping strategies and HRQoL was explored, while controlling for socio-medical data. A total of 444 HIV infected men and 86 HIV-infected women were recruited to participate in the study. This was a cross-sectional study with the HRQoL assessed by the World Health Organization (WHO) Quality of Life-BREF (WHOQOL-BREF) and the coping strategies measured by the Brief COPE inventory. Although the HIV-infected men and HIV-infected women differed in terms of some HRQoL domains, these differences disappeared in the regression analysis after controlling for socio-demographic data (employment and higher education). In addition, several statistically significant interactions between participants' gender and coping strategies in relation to HRQoL domains were observed. Future research on gender differences in HRQoL among PLWH should take into account unique differences between HIV-infected men and HIV-infected women across, not only in respect to socio-medical factors but also regarding psychosocial variables. PMID- 29256070 TI - Caspase cleavage of Mcl-1 impairs its anti-apoptotic activity and proteasomal degradation in non-small lung cancer cells. AB - Global cleavage of cellular proteins by activated caspases is a hallmark of apoptosis, which causes biochemical collapse of the cell. Recent studies suggest that, rather than completely destroying a protein, caspase cleavage can confer novel characteristics or functions. In this respect, the post-caspase role of Bcl 2 family proteins remains uncharacterized. Here, we showed that Mcl-1, a pro survival member of the Bcl-2 family, was cleaved by caspase-3 in non-small cell lung cancer (NSCLC) cells undergoing chemotherapeutic agent-triggered apoptosis. Caspase cleavage partially impaired the anti-apoptotic activity of Mcl-1 by reducing its mitochondrial localization and impeding its association with the permeability transition pore-forming protein Bak. However, the stability of cleaved Mcl-1 was markedly enhanced because it was more refractory to ubiquitination-dependent proteasomal degradation, thereby improving cell viability to a greater extent than full-length Mcl-1 when transiently expressed in NSCLC cells. These findings shed new light on the role of Mcl-1 in apoptosis and suggest potential novel targets for optimizing the tumoricidal capacity of chemotherapy. PMID- 29256071 TI - Modern Techniques of Lymphangiography and Interventions: Current Status and Future Development. AB - One of the crucial functions of the lymphatic system is maintenance of fluid balance. Nonetheless, due to lack of clinical imaging and interventional techniques, the lymphatic system has been under the radar of the medical community. The recently developed intranodal lymphangiography and dynamic contrast-enhanced MR lymphangiography provide new insight into lymphatic pathology. Thoracic duct embolization has become the method of choice for the treatment of patients with chylous leaks. Interstitial lymphatic embolization further expanded the lymphatic embolization approaches. Liver lymphatic lymphangiography and embolization allow treatment of postsurgical liver lymphorrhea and protein-losing enteropathy. The potential for further growth of lymphatic interventions is vast and includes liver lymphatic procedures and advanced thoracic duct interventions, such as thoracic duct externalization and stenting. These current and future advances will open up a realm of new treatments and diagnostic opportunities. PMID- 29256072 TI - Comprehensive survey of radionuclides in contemporary smokeless tobacco products. AB - There is considerable interest in the chemical composition of smokeless tobacco products (STPs), owing to health concerns associated with their use. Previous studies have documented levels of 210Po, 210Pb and uranium in STP samples. Here, the levels of 13 alpha-particle and 15 beta-radiation emitting radionuclides have been measured in a broad and representative range of contemporary STPs commercially available in the United States and Sweden. For each radionuclide, the level of radioactivity and calculated mass per gram of STP are reported. The results indicate that, among 34 Swedish snus and 44 US STPs, a more complex radionuclide content exists than previously reported for these products. Of the 28 radionuclides examined, 13 were detected and quantified in one or more STPs. The most frequently identified radionuclides in these STPs were 40K, 14C, 210Po and 226Ra. Over half the STPs also contained 228Th, and an additional 8 radionuclides were identified in a small number of STPs. The presence of 14C, 3H and 230Th are reported in tobacco for the first time. The activity of beta emitters was much greater than those of alpha-emitters, and the beta-emitter 40K was present in the STPs with both the greatest radioactivity and mass concentrations. Since the three radionuclides included in the FDA's HPHC list were either not detected (235U), identified in only three of 78 samples (238U), and/or had activity levels over fifty times lower than that of 40K (210Po, 238U), there may be a rationale for reconsidering the radionuclides currently included in the FDA HPHC list, particularly with respect to 40K. Using a model of the physical and biological compartments which must be considered to estimate the exposure of STP users to radionuclides, we conclude that exposure from alpha emitters may be minimal to STP users, but 40K in particular may expose the oral cavities of STP users to beta-radiation. Although a more comprehensive picture of the radioisotope content of STPs has emerged from this study, epidemiological evidence suggests that the levels of radionuclides measured in this study appear unlikely to present significant risks to STP users. PMID- 29256073 TI - Quantification of hydroxycinnamic derivatives in wines by UHPLC-MRM-MS. AB - A UHPLC-MS/MS method was developed for the quantification of the main compounds involved in oxidation reactions occurring in white musts and wines such as hydroxycinnamic acids, their glutathione and cysteinylglycine adducts (GRP, GRP2, 5-(S-glutathionyl)-trans-caftaric acid, 2-(S-cysteinylglycyl)-trans-caftaric acid, and 2-(S-glutathionyl)-trans-caffeic acid), and reduced and oxidized glutathione (GSH, GSSG) in wine. Since oxidation is the main concern in white wine-making, directly affecting its quality, the developed method was then applied in a series of white wines made with different pre-fermentation treatments to limit oxidation at must stage. The glucose esters and/or glucosides of hydroxycinnamic acids were quantified as glucogallin equivalent. The developed method led to an overall improvement in the limits of detection (LODs) and quantification (LOQs) for all the compounds studied in comparison to other methods such as high-performance liquid chromatography with fluorescence detection (HPLC-FLD) or diode array UV detection (HPLC-DAD). LOD values ranged from 0.0002 to 0.0140 mg/L and LOQs from 0.0005 to 0.0470 mg/L. The recoveries ranged between 80 and 110% in wines, and the relative standard deviation (RSD) for precision intra- and inter-day was below 15%. The accuracy and intra- and inter-day precision met the acceptance criteria of the AOAC international norms. As far as we know, this study is the first report of quantification of GRP, 2-(S cysteinylglycyl)-trans-caftaric acid, and 2-(S-glutathionyl)-trans-caffeic acid using these non-commercially available compounds as external standards. Those compounds represent a significant proportion of hydroxycinnamic acid derivatives in wines. The methodology described is suitable for the analysis of hydroxycinnamic derivatives in wines. PMID- 29256074 TI - Identification of bacteriocins secreted by the probiotic Lactococcus lactis following microwave-assisted acid hydrolysis (MAAH), amino acid content analysis, and bioinformatics. AB - A novel, generally applicable method of identifying peptides using HPLC, microwave-assisted acid hydrolysis (MAAH), and bioinformatics is described. Method validation was performed on bacteriocins-antibacterial peptides produced by probiotic bacteria-using nine different bacteriocin isolates secreted by the probiotic Lactococcus lactis. Calibration curves were constructed for 23 amino acid PTH derivatives, and analysis was performed using norleucine as the internal standard. Validation of amino acid analysis performed in the range 2.5-100 nmol/mL indicated excellent method linearity, while the LODs ranged from 0.17 to 2.88 nmol/mL and the LOQs from 0.51 to 8.75 nmol/mL. The MAAH method was developed by irradiating nisaplin for various durations at 700 W, with 7 min providing the best results. The amino acid content of each sample was estimated following the application of MAAH to ten different samples. The bacteriocins in our samples were identified using the UniProt database. Eight of nine peptides were identified as UniProt entries: nisin A (P13068), nisin Z (P29559), I4DSZ9, OB7236, P36499, OB7237, A0A0M7BH60, and T2C9F0. The phylogenetic tree was constructed for nisin A and nisin Z using the multiple sequence aligning tool Clustal Omega. The identified nisin types presented excellent correlation with their ModBase-predicted structures. The present method gives true, precise, and rapid results, and requires only standard technical equipment. Our results suggest that the present approach can facilitate the discovery of novel bacteriocins and provide useful information on not only the amino acid contents of peptides but also the evolution of protein biology. Graphical abstract Identification of eight bacteriocins secreted by the probiotic L. lactis, following microwave assisted acid hydrolysis (MAAH), amino acid content analysis of each sample with HPLC-DAD and bioinformatics analysis using Uniprot, Clustal Omega and ModBase. PMID- 29256075 TI - Two complementary reversed-phase separations for comprehensive coverage of the semipolar and nonpolar metabolome. AB - Although it is common in untargeted metabolomics to apply reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC) methods that have been systematically optimized for lipids and central carbon metabolites, here we show that these established protocols provide poor coverage of semipolar metabolites because of inadequate retention. Our objective was to develop an RPLC approach that improved detection of these metabolites without sacrificing lipid coverage. We initially evaluated columns recently released by Waters under the CORTECS line by analyzing 47 small-molecule standards that evenly span the nonpolar and semipolar ranges. An RPLC method commonly used in untargeted metabolomics was considered a benchmarking reference. We found that highly nonpolar and semipolar metabolites cannot be reliably profiled with any single method because of retention and solubility limitations of the injection solvent. Instead, we optimized a multiplexed approach using the CORTECS T3 column to analyze semipolar compounds and the CORTECS C8 column to analyze lipids. Strikingly, we determined that combining these methods allowed detection of 41 of the total 47 standards, whereas our reference RPLC method detected only 10 of the 47 standards. We then applied credentialing to compare method performance at the comprehensive scale. The tandem method showed more than a fivefold increase in credentialing coverage relative to our RPLC benchmark. Our results demonstrate that comprehensive coverage of metabolites amenable to reversed-phase separation necessitates two reconstitution solvents and chromatographic methods. Thus, we suggest complementing HILIC methods with a dual T3 and C8 RPLC approach to increase coverage of semipolar metabolites and lipids for untargeted metabolomics. Graphical abstract Analysis of semipolar and nonpolar metabolites necessitates two reversed-phase chromatography (RPLC) methods, which extend metabolome coverage more than fivefold for untargeted profiling. HILIC hydrophilic interaction liquid chromatography. PMID- 29256077 TI - VS2 quantum dot label-free fluorescent probe for sensitive and selective detection of ALP. AB - As an essential enzyme highly associated with various human diseases, alkaline phosphatase (ALP) plays an important role in human tissues. Developing new materials and strategies for monitoring ALP is thus important. We have developed a novel label-free fluorescent sensing system for ALP activity that is based on the "turn-on" fluorescence of VS2 quantum dots. The fluorescence of VS2 quantum dots quenched by Fe3+ can be restored by ascorbic acid, which is generated by hydrolysis of L-ascorbic acid 2-phosphate catalyzed by ALP. Rapid, convenient, and sensitive detection of ALP is achieved in the range from 3 to 1000 U/L (R 2 =0.9985), with a detection limit of 0.27 U/L. The proposed sensor exhibits excellent selectivity for ALP compared with other enzymes and proteins, such as glucose oxidase, lysozyme, trypsin, human serum albumin, and bovine serum albumin. The reliability for ALP determination in human serum plasma has been demonstrated with satisfactory recovery, revealing promising application in clinical diagnosis and biomedical research. Graphical abstract Hydrothermally synthesized VS2 quantum dots serving as a novel turn-on fluorescent probe for detection of alkaline phosphatase (ALP) activity. AA L-ascorbic acid, AAP L ascorbic acid 2-phosphate, NAC N-acetyl-L-cysteine. PMID- 29256078 TI - Imaging and size measurement of nanoparticles in aqueous medium by use of atomic force microscopy. AB - Size control of nanoparticles in nanotechnology-based drug products is crucial for their successful development, since the in vivo pharmacokinetics of nanoparticles are size-dependent. In this study, we evaluated the use of atomic force microscopy (AFM) for imaging and size measurement of nanoparticles in aqueous medium. The height sizes of rigid polystyrene nanoparticles and soft liposomes were measured by AFM and were compared with the hydrodynamic sizes measured by dynamic light scattering (DLS). The lipid compositions of the studied liposomes were similar to those of commercial products. AFM proved to be a viable method for obtaining images of both polystyrene nanoparticles and liposomes in aqueous medium. For the polystyrene nanoparticles, the average height size observed by AFM was similar to the average number-weighted diameter obtained by DLS, indicating the usefulness of AFM for measuring the sizes of nanoparticles in aqueous medium. For the liposomes, the height sizes obtained by AFM differed depending upon the procedures of immobilizing the liposomes onto a solid substrate. In addition, the resultant average height sizes of the liposomes were smaller than those obtained by DLS. This knowledge will help the correct use of AFM as a powerful tool for imaging and size measurement of nanotechnology-based drug products for clinical use. PMID- 29256076 TI - Recent mass spectrometry-based techniques and considerations for disulfide bond characterization in proteins. AB - Disulfide bonds are important structural moieties of proteins: they ensure proper folding, provide stability, and ensure proper function. With the increasing use of proteins for biotherapeutics, particularly monoclonal antibodies, which are highly disulfide bonded, it is now important to confirm the correct disulfide bond connectivity and to verify the presence, or absence, of disulfide bond variants in the protein therapeutics. These studies help to ensure safety and efficacy. Hence, disulfide bonds are among the critical quality attributes of proteins that have to be monitored closely during the development of biotherapeutics. However, disulfide bond analysis is challenging because of the complexity of the biomolecules. Mass spectrometry (MS) has been the go-to analytical tool for the characterization of such complex biomolecules, and several methods have been reported to meet the challenging task of mapping disulfide bonds in proteins. In this review, we describe the relevant, recent MS based techniques and provide important considerations needed for efficient disulfide bond analysis in proteins. The review focuses on methods for proper sample preparation, fragmentation techniques for disulfide bond analysis, recent disulfide bond mapping methods based on the fragmentation techniques, and automated algorithms designed for rapid analysis of disulfide bonds from liquid chromatography-MS/MS data. Researchers involved in method development for protein characterization can use the information herein to facilitate development of new MS-based methods for protein disulfide bond analysis. In addition, individuals characterizing biotherapeutics, especially by disulfide bond mapping in antibodies, can use this review to choose the best strategies for disulfide bond assignment of their biologic products. Graphical Abstract This review, describing characterization methods for disulfide bonds in proteins, focuses on three critical components: sample preparation, mass spectrometry data, and software tools. PMID- 29256079 TI - Characterization of an easy-to-use method for the routine analysis of the central metabolism using an affordable low-resolution GC-MS system: application to Arthrospira platensis. AB - We developed an easy-to-use method for the routine analysis of the central metabolism using an affordable low-resolution GC-MS system run in SIM mode. The profiling approach was optimized for the derivatization protocol of some 60 targeted metabolites. The performance of two silylation reagents (MSTFA and BSTFA) that allowed the comprehensive derivatization of 42 key intermediary metabolites of the 60 initially targeted (organic acids, phosphate derivatives, monosaccharides and amino acids) was measured. The experimental results unequivocally showed that the MSTFA reagent met mandatory criteria including ease of handling (a very simple one-step protocol was developed), comprehensiveness of derivatization (the 42 compounds covered the extended metabolic pathways of the central carbon metabolism, with a coverage percentage ranging from 17% for the worst to 90% for the best result), optimized response coefficient of the whole derivatives (median value greater than the others by one order of magnitude) and repeatability of the protocol (RSD value below 25% for the whole procedure). When tested in real conditions (cyanobacteria polar extract), the experimental results showed that the profiling methodology was adequately repeatable (RSD = 35%) to ensure quantification results comparable with much more sensitive analytical techniques (capillary electrophoresis/mass spectrometry and liquid chromatography/triple quadrupole mass spectrometry system), while needing only about twice the quantity of biomass. Graphical abstract Schematic overview of an easy-to-use profiling method for the routine analysis of the central metabolism using a low-resolution GC-MS system. PMID- 29256080 TI - Rapid screening and characterization of glutathione-trapped reactive metabolites using a polarity switch-based approach on a high-resolution quadrupole orbitrap mass spectrometer. AB - Formation of reactive metabolites that are capable to react with macromolecules could contribute to drug-induced toxicity. As part of early drug screening strategy to support small molecule structure-activity relationship analysis, glutathione (GSH) trapping is commonly used for the detection of reactive metabolites. When trapped, the GSH conjugates can be characterized using mass spectrometry (MS)-based methods. In the present study, an efficient method was developed for rapid identification and characterization of GSH-trapped metabolites with a single run using a quadrupole orbitrap high-resolution mass spectrometer. The selective ion monitoring of m/z 272.0888, a characteristic product ion corresponding to deprotonated gamma-glutamic-dehydroalanyl-glycine in the negative ionization mode, was applied as a survey scan leveraging all ion fragmentation mode using in-source collision-induced dissociation. Detection of the extracted product ions within 5.0 Deltappm mass accuracy indicated the presence of putative GSH conjugates. Incorporation of fast polarity switching option and multiple data-dependent acquisition scans in a single cycle allowed the determination of accurate mass and multiple MS/MS spectra of GSH conjugates in both negative and positive ionization modes, which featured rich fragments for structural characterization. The effectiveness of this method was evaluated with four model compounds including acetaminophen, clozapine, diclofenac, and nefazodone in both liver microsome and cryopreserved hepatocyte incubations. Successful characterization of multiple GSH conjugates in each case validated this method. Overall, this approach provided a sensitive tool for rapid detection and characterization of GSH conjugates in vitro. Notably, this method could be suitable for high-throughput screening of reactive metabolites in the early drug discovery process. Graphical abstract Sensitive detection and characterization of glutatione conjugates using a high-resolution quadrupole orbitrap mass spectrometer. PMID- 29256081 TI - Microbial biosensing of ciprofloxacin residues in food by a portable lens-free CCD-based analyzer. AB - We present a rapid and simple approach for sensitive detection of antibiotic residues in food samples based on luminescence induction by live bacterial sensor strains integrated into a CCD-based lens-free optical analyzer (LumiSense). Using ciprofloxacin as a model antibiotic, we demonstrate response times of between 20 and 80 min, and detection thresholds of 8 ng/mL for milk, egg white, and chicken essence, and 64 ng/mL for egg yolk. These values are below the minimal allowed values as defined by European Union regulations. Although not intended to replace traditional analytical equipment and regulation-approved methods, LumiSense and similar systems, sample preparation for which involves only simple mixing, dilution, and homogenization, may nevertheless provide a simple means for high throughput food sample screening. Graphical abstract Detection of bioluminescence from genetically modified bacteria offers a simple and effective way for monitoring an antibiotic, ciprofloxacin, in milk without prior sample preparation. PMID- 29256082 TI - Fast, sensitive and reliable multi-residue method for routine determination of 34 pesticides from various chemical groups in water samples by using dispersive liquid-liquid microextraction coupled with gas chromatography-mass spectrometry. AB - A simple and efficient dispersive liquid-liquid microextraction technique (DLLME) was developed by using a mixture of two solvents: 40 MUL of tetrachlorethylene (extraction solvent) and 1.0 mL of methanol (disperser solvent), which was rapidly injected with a syringe into 10 mL of water sample. Some important parameters affecting the extraction efficiency, such as type and volume of solvents, water sample volume, extraction time, temperature, pH adjustment and salt addition effect were investigated. Simultaneous determination of 34 commonly used pesticides was performed by using gas chromatography coupled with mass spectrometry (GC-MS). The procedure has been validated in order to obtain the highest efficiency at the lowest concentration levels of analytes to fulfill the requirements of regulations on maximum residue limits. Under the optimum conditions, the linearity range was within 0.0096-100 MUg L-1. The limits of detection (LODs) of the developed DLLME-GC-MS methodology for all investigated pesticides were in the range of 0.0032 (endrin)-0.0174 (diazinon) MUg L-1 and limits of quantification (LOQs) from 0.0096 to 0.052 MUg L-1. At lower concentration of 1 MUg L-1 for each pesticide, recoveries ranged between 84% (tebufenpyrad) and 108% (deltamethrin) with relative standard deviations (RSDs) (n = 7) from 1.1% (metconazole) to 11% (parathion-mehtyl). This methodology was successfully applied to check contamination of environmental samples. The procedure has proved to be selective, sensitive and precise for the simultaneous determination of various pesticides. The optimized analytical method is very simple and rapid (less than 5 min). Graphical abstract Analytical procedure for testing water samples consists of dispersive liquid-liquid microextraction (DLLME) and gas chromatography coupled with mass spectrometry (GC-MS). PMID- 29256083 TI - Safety and effectiveness of transcatheter embolization in the treatment of internal mammary artery injuries. AB - PURPOSE: Demonstrate the role of endovascular management in the treatment of internal mammary artery (IMA) injuries using transcatheter embolization reviewing our 7-year experience. MATERIALS AND METHODS: Our retrospective analysis of cases consists of a total of 12 patients (8 M and 4 F; mean age 52 years) who underwent angiographic studies and transcatheter embolization for IMA injuries. Causes of vascular injury were divided in high-energy trauma (n = 6), iatrogenic (n = 3) and penetrating injuries (n = 3). Type of trauma, associated injury, imaging findings, treatments and complications were assessed. Imaging findings included active haemorrhage, pseudoaneurysm and focal dissection. RESULTS: Embolization was performed with microcoils in all patients; complete thrombosis was obtained in four patients by additional injection of Spongostan pledgets and in two patients with 300-500 MUm particles. The technical success rate was 100%. No patient died as a direct result of vascular injury; one died of myocardial contusion and one for severe multiorgan failure related to high-energy trauma. No major and minor complications were registered. No patient required emergency surgery or subsequent surgical treatment. CONCLUSION: Transcatheter embolization offers an effective, efficient and safe alternative to conventional surgical management of IMA injuries. PMID- 29256084 TI - Fusion with the cold-active esterase facilitates autotransporter-based surface display of the 10th human fibronectin domain in Escherichia coli. AB - Cell surface display is a popular approach for the construction of whole-cell biocatalysts, live vaccines, and screening of combinatorial libraries. To develop a novel surface display system for the popular scaffold protein 10th human fibronectin type III domain (10Fn3) in Escherichia coli cells, we have used an alpha-helical linker and a C-terminal translocator domain from previously characterized autotransporter from Psychrobacter cryohalolentis K5T. The level of 10Fn3 passenger exposure at the cell surface provided by the hybrid autotransporter Fn877 and its C-terminal variants was low. To improve it, the fusion proteins containing 10Fn3 and the native autotransporter passenger Est877 or the cold-active esterase EstPc in different orientations were constructed and expressed as passenger domains. Using the whole-cell ELISA and activity assays, we have demonstrated that N-terminal position of EstPc in the passenger significantly improves the efficiency of the surface display of 10Fn3 in E. coli cells. PMID- 29256086 TI - Awareness of Diagnostic Error among Japanese Residents: a Nationwide Study. AB - BACKGROUND: Residents' understanding of diagnostic error may differ between countries. We sought to explore the relationship between diagnostic error knowledge and self-study, clinical knowledge, and experience. METHODS: Our nationwide study involved postgraduate year 1 and 2 (PGY-1 and -2) Japanese residents. The Diagnostic Error Knowledge Assessment Test (D-KAT) and General Medicine In-Training Examination (GM-ITE) were administered at the end of the 2014 academic year. D-KAT scores were compared with the benchmark scores of US residents. Associations between D-KAT score and gender, PGY, emergency department (ED) rotations per month, mean number of inpatients handled at any given time, and mean daily minutes of self-study were also analyzed, both with and without adjusting for GM-ITE scores. Student's t test was used for comparisons with linear mixed models and structural equation models (SEM) to explore associations with D-KAT or GM-ITE scores. RESULTS: The mean D-KAT score among Japanese PGY-2 residents was significantly lower than that of their US PGY-2 counterparts (6.2 vs. 8.3, p < 0.001). GM-ITE scores correlated with ED rotations (>=6 rotations: 2.14; 0.16-4.13; p = 0.03), inpatient caseloads (5-9 patients: 1.79; 0.82-2.76; p < 0.001), and average daily minutes of self-study (>=91 min: 2.05; 0.56-3.53; p = 0.01). SEM revealed that D-KAT scores were directly associated with GM-ITE scores (beta = 0.37, 95% CI: 0.34-0.41) and indirectly associated with ED rotations (beta = 0.06, 95% CI: 0.02-0.10), inpatient caseload (beta = 0.04, 95% CI: 0.003 0.08), and average daily minutes of study (beta = 0.13, 95% CI: 0.09-0.17). CONCLUSIONS: Knowledge regarding diagnostic error among Japanese residents was poor compared with that among US residents. D-KAT scores correlated strongly with GM-ITE scores, and the latter scores were positively associated with a greater number of ED rotations, larger caseload (though only up to 15 patients), and more time spent studying. PMID- 29256087 TI - Capsule Commentary on Zickmund et al., Racial, Ethnic, and Gender Equity in Veteran Satisfaction with Health Care in the Veterans Affairs Health Care System. PMID- 29256085 TI - Collaborative Care for Depression among Patients with Limited English Proficiency: a Systematic Review. AB - BACKGROUND: Patients with limited English proficiency (LEP) have high rates of depression, yet face challenges accessing effective care in outpatient settings. We undertook a systematic review to investigate the effectiveness of the collaborative care model for depression for LEP patients in primary care. METHODS: We queried online PubMed, PsycINFO, CINAHL and EMBASE databases (January 1, 2000, to June 10, 2017) for quantitative studies comparing collaborative care to usual care to treat depression in adults with LEP in primary care. We evaluated the impact of collaborative care on depressive symptoms or on depression treatment. Two reviewers independently extracted key data from the studies and assessed risk of bias using the Cochrane bias and quality assessment tool (RCTs) and the Newcastle-Ottawa Quality Assessment Scale (non-RCTs). RESULTS: Of 86 titles identified, 15 were included (representing 9 studies: 5 RCTs, 3 cohort studies, and 1 case-control study). Studies included 4859 participants; 2679 (55%) reported LEP. The majority spoke Spanish (93%). The wide variability in study design and outcome definitions precluded performing a meta analysis. Follow-up ranged from 3 months to 2 years. Three of four high-quality RCTs reported that 13-25% more patients had improved depressive symptoms when treated with culturally tailored collaborative care compared to usual care; the last had high treatment in the control arm and found equal improvement. Two non RCT studies suggest that Spanish-speaking patients may benefit as much as, if not more than, English-speaking patients treated with collaborative care. The remaining studies reported increased receipt of preferred depression treatment (therapy vs. antidepressants) in the intervention groups. Eight of nine studies used bilingual providers to deliver the intervention. DISCUSSION: While limited by the number and variability of studies, the available research suggests that collaborative care for depression delivered by bilingual providers may be more effective than usual care among patients with LEP. Implementation studies of collaborative care, particularly among Asian and non-Spanish-speakers, are needed. PMID- 29256088 TI - Ethical Issues in the Design and Implementation of Population Health Programs. AB - Spurred on by recent health care reforms and the Triple Aim's goals of improving population health outcomes, reducing health care costs, and improving the patient experience of care, emphasis on population health is increasing throughout medicine. Population health has the potential to improve patient care and health outcomes for individual patients. However, specific population health activities may not be in every patient's best interest in every circumstance, which can create ethical tensions for individual physicians and other health care professionals. Because individual medical professionals remain committed primarily to the best interests of individual patients, physicians have a unique role to play in ensuring population health supports this ethical obligation. Using widely recognized principles of medical ethics-nonmaleficence/beneficence, respect for persons, and justice-this article describes the ethical issues that may arise in contemporary population health programs and how to manage them. Attending to these principles will improve the design and implementation of population health programs and help maintain trust in the medical profession. PMID- 29256090 TI - The Adrenal Incidentaloma: An Opportunity to Improve Patient Care. PMID- 29256089 TI - Diabetes Mellitus Management Among Patients with Limited English Proficiency: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Patients with limited English proficiency (LEP) and type 2 diabetes mellitus (T2DM) have several health disparities, including suboptimal patient provider interactions, poorer glycemic control, and T2DM complications. Understanding existing interventions for improving T2DM outcomes in this population is critical for reducing disparities. METHODS: We performed a systematic review of randomized controlled trials (RCTs) and observational studies examining the effectiveness of interventions in improving T2DM outcomes among patients with LEP in North America. Quality was assessed using the Cochrane risk of bias tool for RCTs and the Newcastle-Ottawa Scale for non-RCT studies. Meta-analysis was conducted using the random-effects model. RESULTS: Fifty-four studies, 39 of which reported sufficient data for meta-analysis of glycemic control, were included. The interventions were associated with a statistically significant reduction in hemoglobin A1c (HbA1c) (weighted difference in means, 0.84% [95% CI, -0.97 to -0.71]) that was, however, very heterogeneous across studies (I2 = 95.9%). Heterogeneity was explained by study design (lower efficacy in RCTs than non-RCTs) and by intervention length and delivery mode (greater reduction in interventions lasting <6 months or delivered face-to-face); P < 0.05 for all three covariates. The interventions were also associated in most studies with improvement in knowledge, self-efficacy in diabetes management, quality of life, blood pressure, and low-density lipoprotein cholesterol. DISCUSSION: Multiple types of interventions are available for T2DM management in patients with LEP. Multicomponent interventions delivered face-to-face seem most effective for glycemic control. More research is needed to better understand other aspects of multicomponent interventions that are critical for improving important outcomes among patients with T2DM and LEP. PMID- 29256091 TI - Mindfulness-Based Stress Reduction for Residents: A Randomized Controlled Trial. AB - BACKGROUND: Burnout is highly prevalent in residents. No randomized controlled trials have been conducted measuring the effects of Mindfulness-Based Stress Reduction (MBSR) on burnout in residents. OBJECTIVE: To determine the effectiveness of MBSR in reducing burnout in residents. DESIGN: A randomized controlled trial comparing MBSR with a waitlist control group. PARTICIPANTS: Residents from all medical, surgical and primary care disciplines were eligible to participate. Participants were self-referred. INTERVENTION: The MBSR consisted of eight weekly 2.5-h sessions and one 6-h silent day. MAIN MEASURES: The primary outcome was the emotional exhaustion subscale of the Dutch version of the Maslach Burnout Inventory-Human Service Survey. Secondary outcomes included the depersonalization and reduced personal accomplishment subscales of burnout, worry, work-home interference, mindfulness skills, self-compassion, positive mental health, empathy and medical errors. Assessment took place at baseline and post-intervention approximately 3 months later. KEY RESULTS: Of the 148 residents participating, 138 (93%) completed the post-intervention assessment. No significant difference in emotional exhaustion was found between the two groups. However, the MBSR group reported significantly greater improvements than the control group in personal accomplishment (p = 0.028, d = 0.24), worry (p = 0.036, d = 0.23), mindfulness skills (p = 0.010, d = 0.33), self-compassion (p = 0.010, d = 0.35) and perspective-taking (empathy) (p = 0.025, d = 0.33). No effects were found for the other measures. Exploratory moderation analysis showed that the intervention outcome was moderated by baseline severity of emotional exhaustion; those with greater emotional exhaustion did seem to benefit. CONCLUSIONS: The results of our primary outcome analysis did not support the effectiveness of MBSR for reducing emotional exhaustion in residents. However, residents with high baseline levels of emotional exhaustion did appear to benefit from MBSR. Furthermore, they demonstrated modest improvements in personal accomplishment, worry, mindfulness skills, self-compassion and perspective-taking. More research is needed to confirm these results. PMID- 29256092 TI - Allergen-Specific T Cells in IgE-Mediated Food Allergy. AB - Food allergy is the major reason for severe anaphylaxis in childhood and adolescence. Currently, effective and safe treatments for food allergy are unavailable. Allergen-specific CD4+ T cells have a pivotal role in causing and maintaining the allergic response to food allergens. The purpose of this review is to provide an overview on the role of allergen-specific T cells in food allergy during allergic sensitization, natural tolerance development and allergen immunotherapy. Allergen-specific T cells in the context of food allergy are predominantly of a Th2 type with slightly different surface marker expression patterns in different food allergies. During the process of reverting food allergy to a status of tolerance or sustained unresponsiveness there is a loss of this Th2 committed compartment with an asymptotic approximation to a regulatory and Th0/Th1 dominated compartment seen in non-allergic individuals. This process is accompanied by a significant reduction of absolute frequencies of allergen specific T cells. Particularly, regulatory T cells may provide significant help to achieve sustained control of the effector cell populations via suppression of effector cell function and possibly induction of blocking antibodies. PMID- 29256093 TI - Variation of Regulatory T Lymphocytes in the Peripheral Blood of Children with Allergic Rhinitis. AB - The studies of T-regulatory (Treg) cells in the pediatric allergic disorders, especially allergic rhinitis (AR), are very few and still far from being elucidated. The aim of this study is to assess the frequencies of CD4+CD25+Foxp3+ (CD4+Tregs) and CD8+CD25+highFoxp3+ (CD8+Tregs) regulatory T lymphocytes in the peripheral blood of children with AR. In fresh whole blood of 60 children with AR and 40 healthy controls, the frequencies of CD4+Tregs and CD8+Tregs were examined by flow cytometry. The total IgE concentration in the serum was measured. In AR children, the frequencies of CD4+Tregs and CD8+Tregs were significantly reduced when compared to control group (p = 0.041, p = 0.011, respectively). Moreover, the expressions of Foxp3+ in CD4+CD25+high and CD8+CD25+high cells were significantly lower in patient group than controls. We found a significant negative correlation between the frequencies of CD4+Tregs and the total IgE concentration (p < 0.01). In conclusion, the present study demonstrated that the percentages of CD8+Tregs and CD4+Tregs T cells were significantly decreased in children with AR. This suggests that decreased Treg cells might represent a defect in the compartment of T-cell population in children with AR. Further studies are warranted to fully appreciate the clinical relevance of Tregs in children with AR. PMID- 29256095 TI - Human Saliva for Oral Precancer Detection: a Comparison of Fluorescence & Stokes Shift Spectroscopy. AB - We report here a study on human saliva tested as a diagnostic medium for oral cancer detection on three groups: oral squamous cell carcinoma (OSCC), oral sub mucous fibrosis (OSMF; precancer), and healthy controls (normal). Measurements have been conducted using fluorescence spectroscopy with 350 nm excitation and Stokes shift (SS) spectroscopy (SSS) with 120 nm shift from a total of 99 saliva samples. For classification, principal component analysis (PCA) and linear discriminant analysis (LDA) have been applied on the data sets. Linear discriminant (LD) scores of fluorescence spectra are able to differentiate OSCC to normal, OSMF to normal and OSCC to OSMF with sensitivities 91%, 92%, 91% and specificities 97%, 100%, 94% respectively, while LD scores of SS spectra differentiate respective groups with sensitivities 100%, 94%, 94% and specificities 97%, 100%, 94%. Cross-validation on the datasets of PC scores during LDA illustrates that sensitivity and specificity of SSS data are less affected than those of fluorescence data. Saliva is thus seen as a potential non invasive and simple diagnostic medium, with SS spectroscopy as a better diagnostic tool for oral precancer. PMID- 29256096 TI - Modulation of the Photophysical Properties of beta-substituted BODIPY Dyes. AB - Photophysical properties of BODIPY dyes containing acetyl acetone and benzoyl acetone BF2 unit as an electron accepting substituent at beta position linked via double bond have been investigated using a wide range of solvents of different polarities. The substitution effect at beta position of the BODIPY dyes on their absorption, emission and quantum yield of fluorescence have been the aim of present study. For the synthesized BODIPY dyes fluorescence quantum yields and lifetimes show very sharp decrease with an increase in the solvent polarity, suggesting the involvement of highly polar ICT state de-excitation mechanism along with the local excitation process. The polarity dependent changes in average fluorescence life time and quantum yield values rationalize the formation of ICT states. PMID- 29256097 TI - Practice reduces set-specific capture costs only superficially. AB - Contingent attentional capture costs are doubled or tripled under certain conditions when multiple attentional sets guide visual search (e.g., "search for green letters" and "search for orange letters"). Such "set-specific" capture occurs when a potential target that matches one attentional set (e.g., a green stimulus) impairs the ability to identify a temporally proximal target that matches another attentional set (e.g., an orange stimulus). In the present study, we examined whether these severe set-specific capture effects could be attenuated through training. In Experiment 1, half of participants experienced training consisting of mostly trials involving a set switch from distractor to target, while the other half experienced training consisting of mostly trials in which a set switch was not required. Upon test, participants trained on set switches produced greatly reduced set-specific capture effects compared to their own pretraining levels and compared to participants trained on trials without a set switch. However, in Experiments 2 and 3, we found that these training effects did not transfer to a new color context or even a single new target color, indicating that they were specific and involved low-level associative learning. We concluded that set-specific capture is pervasive and largely immutable, even with practice. PMID- 29256094 TI - Blocking of opioid receptors in experimental formaline-inactivated respiratory syncytial virus (FI-RSV) immunopathogenesis: from beneficial to harmful impacts. AB - Opioid system plays a significant role in pathophysiological processes, such as immune response and impacts on disease severity. Here, we investigated the effect of opioid system on the immunopathogenesis of respiratory syncytial virus (RSV) vaccine (FI-RSV)-mediated illness in a widely used mouse model. Female Balb/c mice were immunized at days 0 and 21 with FI-RSV (2 * 106 pfu, i.m.) and challenged with RSV-A2 (3 * 106 pfu, i.n.) at day 42. Nalmefene as a universal opioid receptors blocker administered at a dose of 1 mg/kg in combination with FI RSV (FI-RSV + NL), and daily after live virus challenge (RSV + NL). Mice were sacrificed at day 5 after challenge and bronchoalveolar lavage (BAL) fluid and lungs were harvested to measure airway immune cells influx, T lymphocyte subtypes, cytokines/chemokines secretion, lung histopathology, and viral load. Administration of nalmefene in combination with FI-RSV (FI-RSV + NL-RSV) resulted in the reduction of the immune cells infiltration to the BAL fluid, the ratio of CD4/CD8 T lymphocyte, the level of IL-5, IL-10, MIP-1alpha, lung pathology, and restored weight loss after RSV infection. Blocking of opioid receptors during RSV infection in vaccinated mice (FI-RSV-RSV + NL) had no significant effects on RSV immunopathogenesis. Moreover, administration of nalmefene in combination with FI RSV and blocking opioid receptors during RSV infection (FI-RSV + NL-RSV + NL) resulted in an increased influx of the immune cells to the BAL fluid, increases the level of IFN-gamma, lung pathology, and weight loss in compared to control condition. Although nalmefene administration within FI-RSV vaccine decreases vaccine-enhanced infection during subsequent exposure to the virus, opioid receptor blocking during RSV infection aggravates the host inflammatory response to RSV infection. Thus, caution is required due to beneficial/harmful functions of opioid systems while targeting as potentially therapies. PMID- 29256098 TI - Bayesian active probabilistic classification for psychometric field estimation. AB - Psychometric functions are typically estimated by fitting a parametric model to categorical subject responses. Procedures to estimate unidimensional psychometric functions (i.e., psychometric curves) have been subjected to the most research, with modern adaptive methods capable of quickly obtaining accurate estimates. These capabilities have been extended to some multidimensional psychometric functions (i.e., psychometric fields) that are easily parameterizable, but flexible procedures for general psychometric field estimation are lacking. This study introduces a nonparametric Bayesian psychometric field estimator operating on subject queries sequentially selected to improve the estimate in some targeted way. This estimator implements probabilistic classification using Gaussian processes trained by active learning. The accuracy and efficiency of two different actively sampled estimators were compared to two non-actively sampled estimators for simulations of one of the simplest psychometric fields in common use: the pure-tone audiogram. The actively sampled methods achieved estimate accuracy equivalent to the non-actively sampled methods with fewer observations. This trend held for a variety of audiogram phenotypes representative of the range of human auditory perception. Gaussian process classification is a general estimation procedure capable of extending to multiple input variables and response classes. Its success with a two-dimensional psychometric field informed by binary subject responses holds great promise for extension to complex perceptual models currently inaccessible to practical estimation. PMID- 29256099 TI - Dispersion and Persistence of Trichogrammatoidea bactrae (Nagaraja) over Tuta absoluta (Meyrick), in Tomato Greenhouses. AB - Inundative biological control depends on the ability of natural enemies to disperse and persist in the environment. The objective was to evaluate the dispersion and persistence of Trichogrammatoidea bactrae (Nagaraja) on Tuta absoluta (Meyrick) eggs. Inundative releases of this parasitoid were performed in experimental tomato greenhouses. For vertical dispersion, leaves of the upper and middle third of plants were artificially infested with T. absoluta eggs; for horizontal dispersion, plants at increasing distances from a release point were infested. These eggs were renewed at days 2 and 4 to evaluate persistence. The amount of parasitized patches was registered. Logistic regression analysis was used. The position of the eggs in the plant did not affect the DE (discovery efficiency: proportion of parasitized patches). Time since release negatively affected the DE, while distance affected it only when plants were higher. These results could be used to adjust the release methodology of T. bactrae. PMID- 29256100 TI - The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: a systematic review of human prospective studies. AB - Rheumatoid arthritis is a progressive autoimmune disease characterised by severely swollen and painful joints. To compliment pharmacotherapy, people living with rheumatoid arthritis often turn to dietary interventions such as the Mediterranean diet. The aim of the present systematic review is to discuss the effects of the Mediterranean diet on the management and prevention of rheumatoid arthritis in human prospective studies. Four studies met the inclusion criteria, including two intervention studies reporting improvement in the pain visual analogue scale (p < 0.05) and a decrease in the health assessment questionnaire for rheumatoid arthritis score (p < 0.05) in the Mediterranean diet groups. Only one study reported a reduction in the 28 joint count disease activity score for rheumatoid arthritis for the Mediterranean diet group (p < 0.05). This review has identified beneficial effects of the Mediterranean diet in reducing pain and increasing physical function in people living with rheumatoid arthritis. However, there is currently insufficient evidence to support widespread recommendation of the Mediterranean diet for prevention of rheumatoid arthritis. PMID- 29256101 TI - Scale invariance and longitudinal stability of the Physical Functioning Western Ontario and MacMaster Universities Osteoarthritis Index using the Rasch model. AB - The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) measures the quality of life of patients with osteoarthritis (OA), and there is a specific scale for the physical functioning dimension, the short version with seven items WOMAC-pf. This study describes the application of the Rasch model to explore scale invariance and response stability of the WOMAC-pf short version across affected joint and over time. A sample of 884 patients with OA, from 15 hospitals in Spain, completed the WOMAC-pf before surgery (baseline) and at 3, 6 and 12 months post-surgery of hip or knee. The invariance by joint was explored through the differential item functioning (DIF) analysis of the Rasch model using baseline data, and time stability (DIF by time) were evaluated in stack data (each participant is represented four times, one by time point). Mean age of the patients was of 69.13 years (SD 10.01), 59.3% of them were women (n = 524), 59.2% had knee OA (n = 523) and 40.8% hip OA (n = 361). Item "putting on socks" showed DIF by joint and time. Fit to the Rasch model using stack data improved when this item was removed. Good reliability for individual use, local independency and unidimensionality of the models were confirmed. WOMAC-pf 7-item short version was invariant over time and joint when item "putting on socks" was removed. Researchers should carefully evaluate this item as it presents problems in scale invariance and stability, which could affect results when comparing data by joint or when computing change scores. PMID- 29256102 TI - Picroside II Exerts a Neuroprotective Effect by Inhibiting mPTP Permeability and EndoG Release after Cerebral Ischemia/Reperfusion Injury in Rats. AB - Mitochondrial membrane permeability is closely related to cerebral ischemia/reperfusion (I/R) injury. This paper explored the neuroprotective effect of picroside II (Picr), which inhibits the permeability of mitochondrial permeability transition pore (mPTP) and endonuclease G (EndoG) release from mitochondria into cytoplasm after cerebral I/R in rats. After 2 h of cerebral ischemia and 24 h of reperfusion in rats with different intervention measures, the neurobehavioral function, infarction volume, and reactive oxygen species (ROS) content in brain tissues were observed by modified neurological severity scale (mNSS), triphenyl tetrazolium chloride (TTC) staining, and enzyme-linked immunosorbent assay, respectively. The permeability of mPTP was assayed using spectrophotometry. The morphology and apoptotic cells of brain tissues were observed by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay, respectively. The expressions of EndoG and voltage dependent anion channel 1 (VDAC1) were determined by immunohistochemical assay and western blot. The Picr group exhibited clear decreases in mNSS scores, ROS content, number of apoptotic cells, mPTP permeability and expression of VDAC1, and EndoG in cytoplasm and nuclei, and the morphology of brain tissue was improved as compared with the model group (P < 0.05). Picr could attenuate cerebral I/R injury by downregulating the expression of VDAC1 and decreasing the permeability of mPTP, thereby inhibiting EndoG release from mitochondria into cytoplasm. PMID- 29256103 TI - Characterization of Streptomyces spp. isolated from the rhizosphere of oil palm and evaluation of their ability to suppress basal stem rot disease in oil palm seedlings when applied as powder formulations in a glasshouse trial. AB - Ganoderma boninense, the main causal agent of oil palm (Elaeis guineensis) basal stem rot (BSR), severely reduces oil palm yields around the world. To reduce reliance on fungicide applications to control BSR, we are investigating the efficacy of alternative control methods, such as the application of biological control agents. In this study, we used four Streptomyces-like actinomycetes (isolates AGA43, AGA48, AGA347 and AGA506) that had been isolated from the oil palm rhizosphere and screened for antagonism towards G. boninense in a previous study. The aim of this study was to characterize these four isolates and then to assess their ability to suppress BSR in oil palm seedlings when applied individually to the soil in a vermiculite powder formulation. Analysis of partial 16S rRNA gene sequences (512 bp) revealed that the isolates exhibited a very high level of sequence similarity (> 98%) with GenBank reference sequences. Isolates AGA347 and AGA506 showed 99% similarity with Streptomyces hygroscopicus subsp. hygroscopicus and Streptomyces ahygroscopicus, respectively. Isolates AGA43 and AGA48 also belonged to the Streptomyces genus. The most effective formulation, AGA347, reduced BSR in seedlings by 73.1%. Formulations using the known antifungal producer Streptomyces noursei, AGA043, AGA048 or AGA506 reduced BSR by 47.4, 30.1, 54.8 and 44.1%, respectively. This glasshouse trial indicates that these Streptomyces spp. show promise as potential biological control agents against Ganoderma in oil palm. Further investigations are needed to determine the mechanism of antagonism and to increase the shelf life of Streptomyces formulations. PMID- 29256105 TI - Mental Health Needs and Psychoactive Drug Use in a User Population of the Family Health Strategy (FHS) in Ribeirao Preto, Sao Paulo, Brazil. AB - This cross-sectional study was conducted in Family Health Care's field of Ribeirao Preto city, Sao Paulo, Brazil to identify the prevalence of substance related disorders and mental distress among patients with mental disorders. We also aimed to identify sociodemographic and social support risk factors. The data collection was done using medical records, the Social Support Questionnaire (SSQ 6), Self Report Questionnaire (SRQ-20) and home visits. Of the 272 families studied, 211 contained individuals with mental disorders, and 61 included individuals who had substance-related disorders, or both. The mental disorders recorded in these families were most frequently mood disorders, followed by neurotic disorders, stress-related disorders and somatoform disorders. Women received twice as many psychotropic prescriptions associated with non-psychiatric medication. A significant relationship was established between education and mental distress as measured using the SRQ-20 (p = 0.024). The SSQ-6 revealed a family presence of social support in all of the conditions established by the six questions. PMID- 29256104 TI - Population Genomics Reveals Genetic Divergence and Adaptive Differentiation of Chinese Sea Bass (Lateolabrax maculatus). AB - The marine species usually show high dispersal capabilities accompanied by high levels of gene flow. On the other hand, many physical barriers distribute along the continental marginal seas and may prevent dispersals and increase population divergence. These complexities along the continental margin generate serious challenges to population genetic studies of marine species. Chinese sea bass Lateolabrax maculatus distributes broad latitudinal gradient spanning from the tropical to the mid-temperate zones in the continental margin seas of the Northwest Pacific Ocean. Using the double digest restriction-site-associated DNA tag sequencing (ddRAD) approach, we genotyped 10,297 SNPs for 219 Chinese seabass individuals of 12 populations along the Chinese coast in the Northwest Pacific region. Genetic divergence among these populations was evaluated, and population structure was established. The results suggested that geographically distant populations in the Bohai Gulf and the Beibu Gulf retain significant genetic divergence, which are connected by a series of intermediate populations in between. The results also suggested that Leizhou Peninsula, Hainan Island, and Shandong Peninsula are major physical barriers and substantially block gene flow and genetic admixture of L. maculatus. We also investigated the potential genetic basis of local adaptation correlating with population differentiation of L. maculatus. The sea surface temperature is a significantly differentiated environmental factor for the distribution of L. maculatus. The correlation of water temperature and genetic variations in extensively distributed populations was investigated with Bayesian-based approaches. The candidate genes underlying the local selection in geographically divergent populations were identified and annotated, providing clues to understand the potential mechanisms of adaptive evolution. Overall, our genome scale population genetic analysis provided insight into population divergence and local adaptation of Chinese sea bass in the continental marginal seas along Chinese coast. PMID- 29256106 TI - Is Bariatric Surgery a Prophylaxis for Pelvic Floor Disorders? AB - INTRODUCTION: Obesity is one of the well-documented risk factors of pelvic floor disorders (PFDs). The PFDs include urinary and fecal incontinence (UI, FI) and pelvic organ prolapse (POP). Surgery-induced weight loss improves different kinds of incontinence as well as POP symptoms. However, there is a lack of evidence how bariatric surgery influences pelvic floor anatomy and function in women without previous PFDs and whether it may be concerned as PFD prophylaxis tool. MATERIALS AND METHODS: The present analysis is a prospective, non-randomized case-control study from January 2014 to September 2017. Participants underwent pelvic floor ultrasound examination with bladder neck position estimation at rest, during levator ani tension, and at Valsalva maneuver before surgery and 12-18 months after. Pelvic organ prolapse quantification (POPQ) > 2 stage and PFD complaints were the exclusion criteria. RESULTS: Fifty-nine patients underwent bariatric surgery (57 sleeve gastrectomy and 2 gastric bypass). Mean BMI decreased from 43.8 +/- 5.9 to 29 +/- 4.6 kg/m2 after surgery (p < 0.001). Statistically significant higher position of the bladder neck at rest, during tension, and at Valsalva maneuver (p < 0.05) was shown after surgery. We did not demonstrate differences in bladder neck mobility and bladder neck elevation at tension after weight loss. CONCLUSIONS: Bariatric surgery is associated with a betterment of bladder neck position at rest, tension, and Valsalva maneuver in women without PFDs. We postulate that bariatric surgery may be a tool for PFD prevention. It does not improve levator ani function and does not limit bladder neck mobility, which implicates that it has no influence on preexisting pelvic dysfunction. PMID- 29256107 TI - Randomized Controlled Trials or Observational Studies? It Depends on the Research Question. PMID- 29256108 TI - Correction to: Arctic Micromonas uses protein pools and non-photochemical quenching to cope with temperature restrictions on Photosystem II protein turnover. AB - In Table 2 of the original publication, all instances of krec in the Parameter and Equation columns should read krecinact. PMID- 29256109 TI - Long-Term Health Effects of PCBs and Related Compounds: A Comparative Analysis of Patients Suffering from Yusho and the General Population. AB - Yusho, which refers to a mass poisoning caused by the ingestion of rice bran oil contaminated with polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans, was first reported in October 1968 in Japan. Yusho patients suffer from various symptoms; however, after 40 years, some emerging symptoms have been attributed to aging. The prevalence of symptoms and diseases among Yusho patients and the general population was compared in this study. The data obtained from the survey among Yusho patients (1131 patients) by the Ministry of Health, Labour, and Welfare of Japan in 2008 were compared with the data from a survey conducted among the general population. When selecting the comparison group, the age and residential area (prefecture) were taken into account to match the baseline characteristics of Yusho patients. A logistic regression analysis was performed to identify the association between Yusho and the prevalence of symptoms and was adjusted for various potential confounding factors (age, sex, body mass index, cigarette smoking, frequency of drinking, and walking time). Skin pigmentation and acneiform eruption were found to be characteristic symptoms of Yusho and were more prevalent in these patients. Other symptoms and diseases associated with Yusho included orthostatic hypotension, hypohidrosis, dysgeusia, Basedow's disease, hoarseness, cardiac insufficiency, tachycardia, eczema, and hair loss. Symptoms related to aging, such as general fatigue, arthralgia, and numbness in the extremities, were significantly higher in Yusho patients after adjusting for age and lifestyle. This study demonstrated that, 40 years after the outbreak of Yusho, the prevalence of various symptoms and diseases in Yusho patients, including age-related diseases, was higher than that in the general population. PMID- 29256110 TI - Serum substance P: an indicator of disease activity and subclinical inflammation in rheumatoid arthritis. AB - The aim of the is study is to examine the role of serum substance P (SP) levels as a simple biomarker for rheumatoid arthritis (RA) disease activity, its correlation with other markers of disease activity, and with selected clinical parameters. The study comprised 90 RA patients and 24 healthy controls. RA activity was assessed by means of the disease activity 28-C-reactive protein (DAS28-CRP) index and ultrasound power Doppler (USPD) by the German ultrasound score based on seven joints. SP serum values were obtained by means of an ELISA commercial kit. Statistics were achieved by the Student's t test and Spearman correlation analysis with Bonferroni correction. As a group, RA patients had significantly increased levels of SP compared with healthy controls (p < 0.0001). SP levels correlated with DAS28-CRP (r = 0.5050, p < 0.0001), number of tender joints (NTJ, r = 0.4668, p < 0.0001), number of swollen joints (NSJ, r = 0.4439, p < 0.0001), visual analogue scale (VAS, r = 0.5131, p < 0.0001). However, SP did not correlate with CRP levels (r = 0.0468, p = 0.6613), nor with the USPD (r = 0.1740, p = 0.1009). Elevated serum SP is a common feature of RA patients, which also appears to correlate with clinical measurements of disease activity and with subjective clinical data (NTJ and VAS). Thus, although SP is higher in RA patients with high disease activity, it also detects subtle RA disease activity even in patients in apparent remission, which suggests its usefulness for therapeutic decisions. PMID- 29256111 TI - Safety profile of autologous hematopoietic stem cell mobilization and transplantation in patients with systemic sclerosis. AB - Autologous hematopoietic stem cell transplantation (AHSCT) is thought to be effective therapeutic approach in patients with poor prognosis systemic sclerosis; however, the toxicity remains a challenge. Between years 2003 and 2016, we enrolled 18 patients with systemic sclerosis at median age at transplant of 52 years (range 24-68). The median duration of disease before AHSCT was 14 months (range 2-85). Peripheral blood stem cells were mobilized with cyclophosphamide (CY) and granulocyte colony-stimulating factor. Conditioning regimen included CY (200 mg/kg) and alemtuzumab (median dose, 60 mg) [n = 11], melphalan (MEL; 140 mg/m2) and alemtuzumab [n = 2], CY and rabbit anti-thymocyte globulin (rATG; 7.5 mg/kg) [n = 4], and CY alone (n = 1). Four deaths occurred early after transplant. There were three males and one female at median age at death of 51 years (range 24-68). The AHSCT-related deaths have been observed on days + 1, + 4, + 9, and + 15 after procedure. The causes of death included bilateral pneumonia followed by multi-organ failure in three patients and myocardial infarction in one. Three patients expired late during post-transplant follow-up, after 5, 21, and 42 months. The causes of death were disease progression in two patients and sudden heart attack in one. Eleven patients are alive after median follow-up after AHSCT of 42.0 months (range 0-95). Before proceeding to AHSCT in systemic sclerosis, there is a strong need to optimize patient selection to reduce toxicity. The administration of alemtuzumab should be avoided due to high risk of life-threatening infectious complications. PMID- 29256112 TI - Sensitivity analyses of four systemic lupus erythematosus disease activity indices in predicting the treatment changes in consecutive visits: a longitudinal study. AB - This study was conducted to assess the ability of the British Isles Lupus Assessment Group-2004 (BILAG-2004), the SLE Disease Activity Index-2K (SLEDAI 2K), the European Consensus Lupus Activity Measurement (ECLAM), and the Revised Systemic Lupus Activity Measure (SLAM-R) to detect the need to treatment change in daily clinical practice. One hundred and two patients with SLE were enrolled and followed up for 2 to 8 months and visited at least 3 times. Physician Global Assessment, BILAG-2004, SLEDAI-2K, SLAM-R, and ECLAM, were calculated in every visit. Treatment change, dependent variable, was categorized as decrease/no change vs. increase. The aforementioned indices, independent variables, were compared to learn their ability in predicting the treatment change. The probability of treatment change was measured by generalized linear-mixed effect model (GLMM) and generalized estimating equations (GEE). Adjusted odds ratios were calculated. Predictive power of indices was compared by area under the curve (AUC) in plots of sensitivity vs. 1-specificity and application of receiver operating characteristic curves (ROC). BILAG-2004 and SLEDAI-2K had substantial correlation with treatment change. Among different GLMM models, BILAG-2004 followed by SLEDAI-2K showed the highest associations with treatment change. Among various GEE models, similar findings were observed. Also, these 2 indices had the highest sensitivity (the largest AUC) towards treatment change; BILAG 2004 (AUC = 0.779, 95% CI = 0.710-0.848, p = 0.001) and SLEDAI-2K (AUC = 0.771, 95% CI = 0.698-0.843, p = 0.001). BILAG-2004 followed by SLEDAI-2K had the highest predictability of treatment change. PMID- 29256113 TI - Dermatologic Reactions to Immune Checkpoint Inhibitors : Skin Toxicities and Immunotherapy. AB - The development of immune checkpoint inhibitors [monoclonal antibodies targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1)] represents a major breakthrough in cancer therapy. Although they present a favorable risk/benefit ratio, immune checkpoint blockade therapies have a very specific safety profile. Due to their unique mechanism of action, they entail a new spectrum of adverse events that are mostly immune related [immune-related adverse events (irAEs)], notably mediated by the triggering of cytotoxic CD4+/CD8+ T cell activation. Cutaneous toxicities appear to be one of the most prevalent irAEs, both with anti PD-1 and anti-CTLA-4 agents or with the newly developed anti-PD-L1 agents, which corresponds to a class effect. They are observed in more than one-third of the treated patients, mainly in the form of a maculopapular rash (eczema-like spongiotic dermatitis) and pruritus. A wide range of other dermatologic manifestations can also occur, including lichenoid reactions, psoriasis, acneiform rashes, vitiligo-like lesions, autoimmune skin diseases (e.g., bullous pemphigoid, dermatomyositis, alopecia areata), sarcoidosis or nail and oral mucosal changes. In addition, the use of anti-CTLA-4 and anti-PD-1 therapies in combination is associated with the development of more frequent, more severe and earlier cutaneous irAEs compared to single agents. In most cases, these dysimmune dermatologic adverse events remain self-limiting and readily manageable. Early recognition and adequate management, however, are critical to prevent exacerbation of the lesions, to limit treatment interruption and to minimize quality of life impairment. This review describes the variable clinical and histopathologic aspects of dermatologic irAEs induced by immune checkpoint inhibitors. Appropriate treatment and counseling are also proposed, with a step by-step approach for optimized management by both practicing oncologists and dermatologists. PMID- 29256114 TI - Vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase signaling facilitates granulation tissue formation with recruitment of VEGFR1+ cells from bone marrow. AB - Vascular endothelial growth factor (VEGF)-A facilitates wound healing. VEGF-A binds to VEGF receptor 1 (VEGFR1) and VEGFR2 and induces wound healing through the receptor's tyrosine kinase (TK) domain. During blood flow recovery and lung regeneration, expression of VEGFR1 is elevated. However, the precise mechanism of wound healing, especially granulation formation on VEGFR1, is not well understood. We hypothesized that VEGFR1-TK signaling induces wound healing by promoting granulation tissue formation. A surgical sponge implantation model was made by implanting a sponge disk into dorsal subcutaneous tissue of mice. Granulation formation was estimated from the weight of the sponge and the granulation area from the immunohistochemical analysis of collagen I. The expression of fibroblast markers was estimated from the expression of transforming growth factor-beta (TGF-beta) and cellular fibroblast growth factor 2 (FGF-2) using real-time PCR (polymerase chain reaction) and from the immunohistochemical analysis of S100A4. VEGFR1 TK knockout (TK-/-) mice exhibited suppressed granulation tissue formation compared to that in wild-type (WT) mice. Expression of FGF-2, TGF-beta, and VEGF-A was significantly suppressed in VEGFR1 TK-/- mice, and the accumulation of VEGFR1+ cells in granulation tissue was reduced in VEGFR1 TK-/- mice compared to that in WT mice. The numbers of VEGFR1+ cells and S100A4+ cells derived from bone marrow (BM) were higher in WT mice transplanted with green fluorescent protein (GFP) transgenic WT BM than in VEGFR1 TK-/- mice transplanted with GFP transgenic VEGFR1 TK-/- BM. These results indicated that VEGFR1-TK signaling induced the accumulation of BM-derived VEGFR1+ cells expressing F4/80 and S100A4 and contributed to granulation formation around the surgically implanted sponge area in a mouse model. PMID- 29256115 TI - Apocynin prevents isoproterenol-induced cardiac hypertrophy in rat. AB - Oxidative stress is implicated in the pathogenesis of a plethora of cardiovascular diseases including interstitial fibrosis, contractile dysfunction, ischemia-reperfusion injury, and cardiac remodeling. However, antioxidant therapies targeting oxidative stress in the progression of those diseases have largely been unsuccessful. The current study evaluated the effects of a NADPH oxidase inhibitor, apocynin (Apo), on the production of reactive oxygen species and the development of pathological cardiac hypertrophy under sustained beta adrenergic stimulation in male Wistar rats. As evident from the HW/BW ratio, HW/TL ratio, echocardiography, and histopathology, hypertrophic responses induced by isoproterenol (Iso; 5 mg/Kg body weight, subcutaneous) were blocked by Apo (10 mg/Kg body weight, intraperitoneal). Iso treatment increased the transcript levels of cybb and p22-phox, the two subunits of Nox. Iso treatment also caused a decrease in reduced glutathione level that was restored by Apo. Increase in mRNA levels of a number of markers of hypertrophy, viz., ANP, BNP, beta-MHC, and ACTA 1 by Iso was either partially or completely prevented by Apo. Activation of key signaling kinases such as PKA, Erk, and Akt by Iso was also prevented by Apo treatment. Our study thus provided hemodynamic, biochemical, and molecular evidences supporting the therapeutic value of Apo in ameliorating adrenergic stress-induced cardiac hypertrophy. PMID- 29256116 TI - Prognostic accuracy of age-adapted SOFA, SIRS, PELOD-2, and qSOFA for in-hospital mortality among children with suspected infection admitted to the intensive care unit. AB - PURPOSE: The Sepsis-3 consensus task force defined sepsis as life-threatening organ dysfunction caused by dysregulated host response to infection. However, the clinical criteria for this definition were neither designed for nor validated in children. We validated the performance of SIRS, age-adapted SOFA, quick SOFA and PELOD-2 scores as predictors of outcome in children. METHODS: We performed a multicentre binational cohort study of patients < 18 years admitted with infection to ICUs in Australia and New Zealand. The primary outcome was ICU mortality. SIRS, age-adapted SOFA, quick SOFA and PELOD-2 scores were compared using crude and adjusted area under the receiver operating characteristic curve (AUROC) analysis. RESULTS: Of 2594 paediatric ICU admissions due to infection, 151 (5.8%) children died, and 949/2594 (36.6%) patients died or experienced an ICU length of stay >= 3 days. A >= 2-point increase in the individual score was associated with a crude mortality increase from 3.1 to 6.8% for SIRS, from 1.9 to 7.6% for age-adapted SOFA, from 1.7 to 7.3% for PELOD-2, and from 3.9 to 8.1% for qSOFA (p < 0.001). The discrimination of outcomes was significantly higher for SOFA (adjusted AUROC 0.829; 0.791-0.868) and PELOD-2 (0.816; 0.777-0.854) than for qSOFA (0.739; 0.695-0.784) and SIRS (0.710; 0.664-0.756). CONCLUSIONS: SIRS criteria lack specificity to identify children with infection at substantially higher risk of mortality. We demonstrate that adapting Sepsis-3 to age-specific criteria performs better than Sepsis-2-based criteria. Our findings support the translation of Sepsis-3 into paediatric-specific sepsis definitions and highlight the importance of robust paediatric organ dysfunction characterization. PMID- 29256117 TI - Heat denaturation of the antibody, a multi-domain protein. AB - The antibody is one of the most well-studied multi-domain proteins because of its abundance and physiological importance. In this article, we describe the effect of the complex, multi-domain structure of the antibody on its denaturation by heat. Natural antibodies are composed of 6 to 70 immunoglobulin fold domains, and are irreversibly denatured at high temperatures. Although the separated single immunoglobulin fold domain can be refolded after heat denaturation, denaturation of pairs of such domains is irreversible. Each antibody subclass exhibits a distinct heat tolerance, and IgE is especially known to be heat-labile. IgE starts unfolding at a lower temperature compared to other antibodies, because of the low stability of its CH3 domain. Each immunoglobulin domain starts unfolding at different temperatures. For instance, the CH3 domain of IgG unfolds at a higher temperature than its CH2 domain. Thus, the antibody has a mixture of folded and unfolded structures at a certain temperature. Co-existence of these folded and unfolded domains in a single polypeptide chain may increase the tendency to aggregate which causes the inactivation of the antibody. PMID- 29256118 TI - Lipid environment of membrane proteins in cryo-EM based structural analysis. AB - Cryoelectron microscopy (cryo-EM) in association with a single particle analysis method (SPA) is now a promising tool to determine the structures of proteins and their macromolecular complexes. The development of direct electron detection cameras and image processing technologies has allowed the structures of many important proteins to be solved at near-atomic resolution or, in some cases, at atomic resolution, by overcoming difficulties in crystallization or low yield of protein production. In the case of membrane-integrated proteins, the proteins were traditionally solubilized and stabilized with various kind of detergents. However, the density of detergent micelles diminished the contrast of membrane proteins in cryo-EM studies and made it difficult to obtain high-resolution structures. To improve the resolution of membrane protein structures in cryo-EM studies, major improvements have been made both in sample preparation techniques and in hardware and software developments. The focus of our review is on improvements which have been made in the various techniques for sample preparation for cryo-EM studies, with a specific interest placed on techniques for mimicking the lipid environment of membrane proteins. PMID- 29256119 TI - High-speed atomic force microscopy and its future prospects. AB - Various techniques have been developed and used to investigate how proteins produce complex biological architectures and phenomena. Among these techniques, high-speed atomic force microscopy (HS-AFM) holds a unique position. It is only HS-AFM that allows the simultaneous assessment of structure and dynamics of single protein molecules in action. This new microscopy tool has been successfully applied to a variety of proteins, from motor proteins to membrane proteins, antibodies, enzymes, and even to intrinsically disordered proteins. And yet there still remain many biomolecular phenomena that cannot be addressed by HS AFM in its current form. Here, I present a brief history of HS-AFM development, describe the current state of HS-AFM, and then discuss which new biological scanning probe microscopy techniques will be coming up next. PMID- 29256121 TI - Introduction to Medication Effects on Male Reproduction. AB - The over-arching goal of this volume is to help infertility practitioners evaluate and manage their patients with poor semen quality. Medications can negatively impact on male reproduction and these effects are of increasing concern. People world-wide are using more medications than in the past, including men of childbearing age. In addition, men are fathering children later in life than previously, which is associated with greater medication use in the reproductive population. Finally, people are experiencing more chronic disease at earlier ages, particularly in developed countries. Taken together, these factors have increased the number of prescribed and over-the-counter (OTC) drugs being taken by men attempting fatherhood. There is some evidence in the literature that medications, even some common OTC medications, can negatively impact male reproduction, and yet, medication use is inadequately addressed in the evaluation of male infertility and fertility plans are rarely considered by providers before prescribing medications. In this volume, we systematically consider medications being used world-wide, focusing on those that might cause poor semen quality in men with otherwise idiopathic infertility. Extensive tables are provided in this volume that summarize the research for each specific medication, and it is our hope that these tables will be useful in day-to-day counseling of infertility patients and of men desiring fertility. Although some specialist practitioners are aware that there are pharmacological negative effects on male fertility, most practitioners are not, and the published evidence is surprisingly sparse. We hope that this volume will encourage our readers to conduct robust, well-designed studies to inform clinical practice. PMID- 29256120 TI - Salt-induced formations of partially folded intermediates and amyloid fibrils suggests a common underlying mechanism. AB - Amyloid fibrils are misfolded forms of proteins and are involved in various diseases. They have been studied extensively with the aim to obtain a comprehensive understanding of protein folding and misfolding and to use this knowledge to develop therapeutic strategies against the associated diseases. Salt conditions are important factors determining the formation and stability of amyloid fibrils. In the 1990s, salt effects were studied extensively to understand the conformational stability of acid-denatured proteins, and the results of these studies revealed the role of electrostatic repulsion in forming the compact intermediate states. In this review, we compare the effects of salts on the compact intermediate states with those on the formation of amyloid fibrils under acidic conditions. The results argue that both protein folding and misfolding are driven by the same forces, although the resultant conformations are distinct because they are monomeric and multimeric reactions, respectively. PMID- 29256122 TI - Challenges of Obtaining Evidence-Based Information Regarding Medications and Male Fertility. AB - In the clinic, the existing literature is insufficient to counsel our infertile men on medication use. Most studies have flaws that limit their application to evidence-based practice. In this chapter, we discuss the limitations of the current literature and the challenges to designing more useful studies. Among the most important weaknesses of existing studies is lack of power; that is, too few men are included to draw conclusions about the existence and size of medication effects. Adequate power is particularly important when confirming an absence of medication effect. Bias is also a problem in most studies. Early studies were rarely randomized, placebo-controlled, or blinded; a common example is patients receiving different medication regimes based on the severity of their symptoms making it impossible to attribute differences between treated and untreated men to the medications. Additional bias is introduced by failing to include other factors that influence the outcome in the experimental design. A uniform population amenable to randomization and placebo-control are experimental species, and useful information has been gained from these models. However, application to humans is limited by differences from other species in route of drug administration, absorption of the drug, concentration in the male genital tract tissues, and genital tract physiology. To a lesser degree, there is variation among individual men in their response to drugs. In addition, drugs in the same class may have different effects, limiting the applicability of data across drugs of a single class. Complicating matters further, a toxic medication may seem to improve fertility endpoints by improving a disease condition that diminishes fertility. Finally, drug interactions have not been studied, and actual fertility data (pregnancy/fecundity) in humans are rare. A healthy dose of skepticism is warranted when evaluating studies of medications and male reproductive health. PMID- 29256123 TI - Male Reproductive Functions Disrupted by Pharmacological Agents. AB - In this chapter, we review the male reproductive functions disrupted by medications. Medications can affect the hypothalamic-pituitary-gonad axis, acting as endocrine disrupting chemicals (EDCs). Disturbances may be directly at androgen receptors, modifying the activity of endogenous androgens at the target tissue, or may disrupt feedback loops at the hypothalamus or pituitary resulting in modification of gonadotropin release. Impaired testosterone production and/or spermatogenesis result. Other EDC activities can be indirect via effects on levels of prolactin (PRL), estrogen, cortisol, thyroid hormone, or sex hormone binding globulin (SHBG). Appropriate regulation of these hormones and SHBG are essential for normal reproductive function. An increase in circulating PRL levels is a common adverse medication effect. The consequence is lower gonadotropin and testosterone secretion. Drugs can also have direct toxicity on the seminiferous tubule epithelium, including effects on Leydig cells, Sertoli cells, or germ cells. In some cases, spermatogenesis is severely impaired. After leaving the testis, sperm spend a week or more in the epididymis. It is clear from the timing of some drug effects that sperm are damaged during epididymal transit. There can also be impairment of the ejaculatory reflex, resulting in alterations of emission or expulsion of semen. Even after ejaculation, exposure to seminal plasma can alter sperm function, and some drugs may affect sperm at this stage. The most critical effects on male reproduction are decreased fertility and/or health effects on offspring. These endpoints have received little research attention. Another consideration is the metabolism of drugs. Medications may become more toxic if metabolic systems are suboptimal due to comorbid conditions. PMID- 29256124 TI - Exogenous Androgens and Male Reproduction. AB - Due in part to aggressive marketing, the prevalence of exogenous androgen use has increased to disturbing levels. Prescribing practitioners are often unaware of the severity of the anti-fertility effects. Exogenous androgens should only be prescribed if hypogonadism has been established by appropriate investigation, and preferably the patient does not intend to father a child. There are alternative medications, or combinations of medications, that can be used if hypogonadism is present and fertility is desired.It is somewhat counterintuitive that testosterone treatment will decrease or abolish fertility. Exogenous testosterone inhibits spermatogenesis by removing the feedback response to low testosterone at the hypothalamus and pituitary. This results in reduced synthesis and secretion of gonadotropins required to stimulate endogenous testosterone production and to support spermatogenesis. It is important to realize that the normal testicular levels of testosterone are approximately 100 times the concentration in circulation. These high levels are required locally to support spermatogenesis. So even with circulating androgen levels within the normal range, spermatogenesis fails due to insufficient gonadotropin and local testosterone support. Androgenic herbal supplements and illicit use of anabolic steroids have contributed to this serious challenge in the treatment of infertile men. Most men will recover normal spermatogenesis after cessation of exogenous testosterone treatment, but this requires 6 months or more in most men. In rare cases fertility is permanently impaired. PMID- 29256125 TI - Phosphodiesterase Inhibitors (PDE Inhibitors) and Male Reproduction. AB - The nonspecific PDE inhibitors, particularly the methylxanthines: caffeine, pentoxifylline (PTX), and theophylline, are known to stimulate sperm motility in vitro and have been used to treat sperm prior to insemination. The in vivo effects are less dramatic. A beneficial effect of caffeine, which is a constituent of some medications, remains controversial. Very high doses of caffeine do have negative effects on fertility endpoints in men and experimental species. The specific PDE5 inhibitors, particularly sildenafil and tadalafil, are prescribed for erectile dysfunction, as well as pulmonary hypertension, lower urinary tract symptoms, and premature ejaculation. PDE5 is expressed throughout the contractile tissues of the male reproductive tract, generally increasing contractility. Some PDE5 inhibitors tend to increase circulating testosterone levels somewhat. For short-term exposure consistent with use prior to intercourse, there appears to be minimal effects on semen quality. Several large, randomized controlled trials (RCTs) in healthy men have not found adverse effects of long-term use of these drugs on semen quality. RCTs in infertile men have demonstrated a modest increase in semen quality. Animal studies at human equivalent doses (HED) have produced similar results in young males, but a study in aging male rats found progressive decreases in epididymal sperm quality accompanied by consistent degeneration of the seminal tubules suggesting that studies in older men might be warranted. A concerning study in mice found lower fertilization rates in males treated with HED of sildenafil and mated the next day to untreated females than for control males. Fertility studies in humans are needed. PMID- 29256126 TI - Pain Medications and Male Reproduction. AB - The increasing use of opioid medications has become a crisis in developed countries. The profound negative effects of opioids on male reproduction are well known, but this topic is absent from the current conversations about these medications. In the fertility clinic, a significant proportion of our patients are using opioids for pain management, and the options for these men are unclear. Opioids exert their negative effects by a variety of mechanisms. At high doses, testosterone levels fall significantly and hypogonadism is seen. In part, this results from increased prolactin and inhibition of gonadotropin production/secretion by the pituitary. However, negative effects on the testis are seen even in the absence of decreased androgen levels. As we review in this chapter, Leydig and germ cells produce endogenous opioids, and receptors for these substances are present throughout the testis. For example, endogenous opioids produced by Leydig and germ cells provide paracrine inhibition at Sertoli cell receptors, decreasing the production of androgen binding protein, which is required for intra-testis transport of androgens. Morphine also increases the expression of aromatase in the brain and testis and acts directly on the testis and germ cells to decrease testicular function. Exogenous opioids in men reduce semen quality, including increased DNA fragmentation. All opioids have these effects, but less damage is caused by lower doses, shorter-acting opioids, and by some drugs with mixed receptor activity, such as tramadol and tapentadol. The non steroid anti-inflammatory drugs (NSAIDS) have much less effect on the male reproductive system, although there is a paucity of human studies. Paracetamol has been shown to cause sperm abnormalities, including DNA fragmentation, and to increase time to pregnancy and may prove to be of greater concern. In rodents, paracetamol has negative impacts on seminiferous tubule histology and fertility. Robust, well-designed studies in humans are needed. PMID- 29256127 TI - 5alpha-Reductase Inhibitors (5ARIs) and Male Reproduction. AB - The 5ARIs, finasteride and dutasteride, are used to treat benign prostate hyperplasia and lower urinary tract symptoms. At much lower doses, 5ARI treatment reduces male hair loss. These drugs inhibit the conversion of testosterone to the more active dihydrotestosterone (DHT). In men taking these medications, DHT levels are reduced by some 90% while testosterone levels remain relatively stable. Well known for their negative effects on libido and erectile function, 5ARIs also cause ejaculatory dysfunction in some men, having the potential to decrease semen quality. In fact, some studies of men treated with these drugs have reported lower total sperm count, along with lower sperm motility, although the changes are probably insufficient to reduce fertility in men with normal semen before treatment. There is a population of men with more severely decreased sperm numbers; as low as 10% of pretreatment values. Fewer studies have looked at the lower doses used for male alopecia, indicating little affect in men with normal semen quality, but a negative effect on sperm numbers in men with oligozoospermia. There have been no studies looking at fertility endpoints for these medications. PMID- 29256128 TI - Psychotropics and Male Reproduction. AB - Psychotropic drugs, including antidepressants, antipsychotics, and anticonvulsants, all have negative effects on sexual function and semen quality. These adverse events vary among men and are less pronounced for some medications, allowing their effects to be managed to some extent. Use of specific serotonin reuptake inhibitors (SSRIs) is prevalent in men of reproductive age; and application to treat premature ejaculation increases the number of young men on SSRI therapy. Oxidative damage to sperm can result from prolonged residence in the male reproductive tract. The increase in ejaculatory latency seen with SSRIs likely underlies some of their negative effects on semen quality, including higher sperm DNA fragmentation, seen in all SSRIs evaluated thus far. These medications increase prolactin (PRL) levels in some men, and this is often credited with inhibitory effects on male reproduction; however, testosterone levels are generally normal, reducing the likelihood of direct HPG axis inhibition by PRL. The tricyclic antidepressants have also been shown to increase PRL levels in some studies but not in others. The exception is the tricyclic antidepressant clomipramine, which profoundly increases PRL levels and may depress semen quality. Other antidepressants modulating synaptic levels of serotonin, norepinephrine, and/or dopamine may have toxicity similar to SSRIs, but most have not been evaluated. In limited studies, norepinephrine-dopamine reuptake inhibitors (NDRIs) and serotonin agonist/reuptake inhibitors (SARIs) have had minimal effects on PRL levels and on sexual side effects. Antipsychotic medications increase PRL, decrease testosterone, and increase sexual side effects, including ejaculatory dysfunction. The greatest evidence is for chlorpromazine, haloperidol, reserpine, risperidone, and thioridazine, with less effects seen with aripiprazole and clozapine. Remarkably few studies have looked at antipsychotic effects on semen quality, and this is an important knowledge gap in reproductive pharmacology. Lithium increases PRL and LH levels and decreases testosterone although this is informed by few studies. The anticonvulsants, many used for other indications, generally decrease free or bioavailable testosterone with variable effects on the other reproductive hormones. Valproate, carbamazepine, oxcarbazepine, and levetiracetam decrease semen quality; other anticonvulsants have not been investigated for this adverse reaction. Studies are required evaluating endpoints of pregnancy and offspring health for psychotropic medications. PMID- 29256129 TI - Cardiovascular/Pulmonary Medications and Male Reproduction. AB - Cardiovascular and respiratory medications are used by men of reproductive age although use of the former is most prevalent in advanced age. Many of these drugs have been associated with sexual dysfunction, including erectile and ejaculatory dysfunction, but for most there is insufficient evidence to link their use with testicular dysfunction, reduced semen quality or infertility. Some exceptions are the irreversible alpha1-adrenergic antagonist phenoxybenzamine, which carries a high risk of retrograde ejaculation; the specific alpha1A-adrenergic antagonists silodosin and tamsulosin, used primarily to treat BPH/lower urinary tract symptoms, which can cause retrograde ejaculation; and the peripheral beta1 adrenergic antagonist atenolol, used to treat hypertension, which may decrease testosterone/free-testosterone levels. In this chapter, we review the evidence available regarding adverse reactions on male reproduction of adrenergic receptor agonists/antagonists, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics, digoxin, and hydralazine. For some of these medications, there is some evidence for male reproductive effects, along with some solid work in experimental and companion animal species suggesting negative effects. In contrast, and of special note, are calcium channel blockers, which have long been included on lists of medications with the potential to cause male infertility. This turns out to be a good example of a substance with profound effects on sperm function in vitro, but with limited evidence for in vivo effects on semen quality or fertility, even in experimental species. We hope that the evidence provided in this chapter will stimulate additional studies for these important classes of medications. PMID- 29256130 TI - Antimicrobials and Male Reproduction. AB - Antibiotics have long been suspected of contributing to male infertility; however, there are remarkably limited data to support this premise. A major challenge for evaluating antibiotic effects is that the diseases they treat often have negative impacts on male reproduction, so treatment with the antimicrobial can improve reproductive endpoints. This is particularly true for diseases of the male reproductive tract. As a class, anti-parasitic drugs are toxic to eukaryotic cells and have significant potential for reproductive toxicity. A variety of these medications are also used in companion and food animal species; in this chapter we review the literature on anti-parasitic drugs on male reproduction in these species. In humans, only niridazole has been shown to cause reversible spermatogenic arrest in 20 men with schistosomiasis. Of the antifungal medications, ketoconazole has been shown in some studies to transiently decrease testosterone levels in men, but work is lacking for semen quality or fertility. We review studies of antibacterial medications in the chapter, with some minimal human data available for decreased semen quality in men taking nitrofurantoin, ciprofloxacin, ofloxacin, or sulfamethoxazole. These and some other antibacterials have been studied in other species with results suggestive of negative impacts on male fertility endpoints. In light of the common assumption of reproductive toxicity for antimicrobial medications, and the decided lack of supporting evidence, there is a substantial need for well-designed clinical trials in this area. PMID- 29256131 TI - Antivirals and Male Reproduction. AB - The use of antiviral medications has increased with the recognition and treatment of HIV infections, and these drugs are the main focus of this chapter. HIV has become a chronic disease, and many men with HIV desire children. The disease itself has profound negative effects on semen quality, as does infection with hepatitis C virus (HCV), so treatment with antivirals generally improves semen quality in men with longer duration of infection and/or greater symptoms. Several changes in medical practice have allowed studies of pharmacopathology of antiviral medications and brought focus on medication effects in asymptomatic men: (1) the successful practice of specialized sperm washing of asymptomatic men with HIV infection for insemination of their HIV-negative partner; (2) the recommendation that men begin anti-retroviral treatment before HIV symptoms appear; and (3) the recommendation that men without HIV infection who have HIV seropositive partners take HIV prophylaxis. Early cases of HIV infection were generally treated by monotherapy with the nucleoside analog reverse transcriptase inhibitor (NRTI) zidovudine (AZT). Currently, men with HIV infections take combination anti-retroviral therapy (cART), involving three or more medications, making it difficult to assess the toxicity of individual medications. In general, zidovudine alone or cART have minimal negative effects on semen quality; the most common being decreased rapid swimming of motile sperm. We review studies with other outcomes and animal studies in this chapter. Peginterferon-alpha, which is utilized together with ribavirin to treat HCV, does appear to decrease testosterone levels and semen quality although studies showing these effects have been small. Antiviral medications used to treat viral infections other than HIV and HCV have received little experimental attention for male reproductive effects, even in experimental species. PMID- 29256132 TI - Immunosuppressants and Male Reproduction. AB - Prolonged use of immunosuppressant medications is occasionally seen in infertile men with chronic inflammatory conditions; autoimmune disorders; or an organ or hematopoietic stem cell transplant. Chronic inflammation impacts negatively on male reproductive endpoints, so immunosuppressant therapy can produce improvements. Corticosteroids have been used to treat antisperm antibodies and even as an empirical treatment for male infertility in general. Trials of these methods have provided mixed results on semen quality and fertility, with improvement, no change and negative effects reported by different investigators. In a substantial number of observational studies, patients on long-term therapy with prednisone for chronic inflammatory disease, testosterone levels were lower compared to untreated controls, though randomized controlled trials have not been conducted. Similarly decreases in testosterone have been reported in men receiving corticosteroids to minimize transplant rejection; however, most were treated with multiple immunosuppressive medications that may have contributed to this effect. A large number of trials of healthy men treated with corticosteroids have shown some disruption in reproductive hormone levels, but other studies reported no effect. Studies in monkeys, rats (at human equivalent dose), cattle, sheep, and horses have shown endocrine disruption, including low testosterone with dexamethasone treatment. Of the cytostatic immunosuppressives, which have high potential for cellular damage, cyclophosphamide has received the most attention, sometimes lowering sperm counts significantly. Methotrexate may decrease sperm numbers in humans and has significant negative impacts in rodents. Other chemotherapeutic drugs used as immunosuppressants are likely to impact negatively on male fertility endpoints, but few data have been collected. The TNF alpha Inhibitors have also received little experimental attention. There is some evidence that the immunophilin modulators: cyclosporine, sirolimus, and everolimus cause endocrine disruption and semen quality impairment. As we review in this chapter, results in experimental species are concerning, and well designed studies are lacking for the effects of these medications on reproductive endpoints in men. PMID- 29256133 TI - Miscellaneous Drugs and Male Reproduction. AB - In addition to main categories of medications believed to have negative impacts on male reproduction, there are a number of miscellaneous drugs with some evidence for such adverse reactions. Because of its widespread use and over-the counter availability, the H2 receptor antagonist cimetidine is most concerning. As a competitive antagonist at androgen receptors, it can impact the HPG axis and semen quality. In this chapter, we review the studies of this drug and other histamine H2 receptor antagonists in men and experimental species. Several other medications are concerning and the evidence for negative effects on reproduction are covered: colchicine, domperidone, hydroxyurea, metformin, metoclopramide, mifepristone, retinoids, and statins. PMID- 29256135 TI - Cell and Gene Therapy for HIV Cure. AB - As the HIV pandemic rapidly spread worldwide in the 1980s and 1990s, a new approach to treat cancer, genetic diseases, and infectious diseases was also emerging. Cell and gene therapy strategies are connected with human pathologies at a fundamental level, by delivering DNA and RNA molecules that could correct and/or ameliorate the underlying genetic factors of any illness. The history of HIV gene therapy is especially intriguing, in that the virus that was targeted was soon co-opted to become part of the targeting strategy. Today, HIV-based lentiviral vectors, along with many other gene delivery strategies, have been used to evaluate HIV cure approaches in cell culture, small and large animal models, and in patients. Here, we trace HIV cell and gene therapy from the earliest clinical trials, using genetically unmodified cell products from the patient or from matched donors, through current state-of-the-art strategies. These include engineering HIV-specific immunity in T-cells, gene editing approaches to render all blood cells in the body HIV-resistant, and most importantly, combination therapies that draw from both of these respective "offensive" and "defensive" approaches. It is widely agreed upon that combinatorial approaches are the most promising route to functional cure/remission of HIV infection. This chapter outlines cell and gene therapy strategies that are poised to play an essential role in eradicating HIV-infected cells in vivo. PMID- 29256134 TI - Theoretical insights on the oxygen-reduction reaction mechanism of LaN4-embedded graphene. AB - We studied the structural stability, adsorption behavior of the key intermediates in the oxygen-reduction reaction (ORR) process, and ORR mechanism on LaN4 embedded graphene (LaN4-Gra) theoretically in an acid environment. The geometry optimization and energy calculations in this study were performed using the generalized gradient approximation (GGA) within the Perdew-Burke-Ernzerhof (PBE) functional. The thermodynamic stability of LaN4-Gra is confirmed by its negative formation energy. The sequential hydrogenation of O2 to generate H2O molecules is the most favorable pathway and it is a four-electron process. The last hydrogenation of OH species to form H2O molecules is the rate-determining step in the whole ORR process. Compared with the energy barrier of pure Pt electrocatalyst (0.8 eV), the close energy barrier value for LaN4-Gra (0.89 eV) is quite favorable. This implies that LaN4-embedded graphene could be a potential ORR catalyst. Finally, the ORR free energy of LaN4-Gra electrocatalyst was also analyzed. PMID- 29256136 TI - The diagnostic value of 18F-FDG-PET/CT and MRI in suspected vertebral osteomyelitis - a prospective study. AB - PURPOSE: The aim of this study was to determine the diagnostic value of 18F fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) and magnetic resonance imaging (MRI) in diagnosing vertebral osteomyelitis. METHODS: From November 2015 until December 2016, 32 patients with suspected vertebral osteomyelitis were prospectively included. All patients underwent both 18F-FDG-PET/CT and MRI within 48 h. All images were independently reevaluated by two radiologists and two nuclear medicine physicians who were blinded to each others' image interpretation. 18F-FDG-PET/CT and MRI were compared to the clinical diagnosis according to international guidelines. RESULTS: For 18F-FDG-PET/CT, sensitivity, specificity, PPV, and NPV in diagnosing vertebral osteomyelitis were 100%, 83.3%, 90.9%, and 100%, respectively. For MRI, sensitivity, specificity, PPV, and NPV were 100%, 91.7%, 95.2%, and 100%, respectively. MRI detected more epidural/spinal abscesses. An important advantage of 18F-FDG-PET/CT is the detection of metastatic infection (16 patients, 50.0%). CONCLUSION: 18F-FDG-PET/CT and MRI are both necessary techniques in diagnosing vertebral osteomyelitis. An important advantage of 18F-FDG-PET/CT is the visualization of metastatic infection, especially in patients with bacteremia. MRI is more sensitive in detection of small epidural abscesses. PMID- 29256137 TI - Estimating the postmortem interval of human skeletal remains by analyzing their fluorescence at 365 and 490 nm. AB - The study presented here is regarded as a continuation of the experiments of Sterzik et al., who developed a new practical method to distinguish between historical and recent human skeletal remains. Bone cross-sections were illuminated using light with wavelengths of 365 and 490 nm, causing fluorescence. The fluorescence was documented by photography and further analyzed to examine the areal extent of a certain fluorescent color. Contrary to the previous experiments of Sterzik et al., the present study focused on bones with postmortem intervals (PMIs) >= 50 years. Therefore, this study fills the gap created by the former study, pointing towards a correlation between the PMI and the areal extent of the fluorescent surface in both tests. The presence of blue and red fluorescent surfaces < 1% indicated a PMI >= 50 years. Furthermore, the presence of blue and red fluorescent surfaces > 1% can be regarded as a marker to exclude a PMI >= 50 years; in fact, these bones are likely to have a PMI < 30 years. PMID- 29256138 TI - Virtual reality simulation for surgery: from video games to transanal total mesorectal excision. PMID- 29256140 TI - Double peritoneal fat flap in the treatment of an enterovesical fistula. PMID- 29256139 TI - Early outcomes of fluorescence angiography in the setting of endorectal mucosa advancement flaps. AB - BACKGROUND: Fistula-in-ano has a reported incidence of 31-34%. Besides fistulotomy, options for fistula repair are seton placement, endorectal advancement flap (ERAF), fibrin sealant, anal fistula plug and ligation of the intersphincteric fistula tract. Despite having a reported success rate as high as 75-98%, ERAF is not without complications, including flap breakdown, recurrence and fecal incontinence. Traditionally, maintaining a broad base to preserve blood supply has been advocated to reduce flap failure. And the aim of the present study was to evaluate outcomes of adult patients who underwent ERAF for complex fistula-in-ano with the use of intraoperative fluorescence angiography (FA) at our institution between July 2014 and July 2016. METHODS: We retrospectively reviewed consecutive cases of complex fistula-in-ano repair with ERAF and FA from a prospectively maintained dataset of adult patients with complex fistula-in-ano. Demographics, intraoperative data and 60-day outcomes were recorded and reviewed. RESULTS: Six patients [five males and one female with a mean age of 40 years (range 25-46 years)], with a total of seven fistulas, were identified. Six (85.7%) of these patients had undergone prior surgery for fistula-in-ano. No recurrences or complications of any type were noted at 2-week and 8-week follow up. The majority of patients (71.4%) required flap revision based on intraoperative FA prior to flap fixation. CONCLUSIONS: FA is safe and offers real time assessment of flap perfusion prior to and after fixation in anal fistula repair. The rate of flap ischemia may be underestimated, and therefore, to improve outcomes in ERAF, intraoperative FA should be included in the surgical armamentarium. PMID- 29256141 TI - Inferior pancreatic approach for laparoscopic splenic flexure mobilization. PMID- 29256142 TI - Pet dogs synchronize their walking pace with that of their owners in open outdoor areas. AB - Affiliation between interacting partners is associated with a high level of behavioural synchronization in many species. Pet dogs are known to share strong affiliative bonds with their owners and to synchronize their behaviour with them when moving freely indoors. Surprisingly, outdoor dog-human interspecific synchronization has seldom been investigated. We therefore explored whether, when allowed to move freely in a familiar outdoor space, dogs synchronize their behaviour with their owners' movements. We found that dogs visibly synchronized both their location (staying in close proximity) and their activity (moving when their owner moved, and at the same pace, and standing still when their owner stood still) with those of their owners. By demonstrating that owners act as attractors for their dogs in an outdoor space, the present study contributes new data to the understanding of interspecific behavioural synchronization. PMID- 29256143 TI - Crucial information for efficient face searching by humans and Japanese macaques. AB - Humans can efficiently detect a face among non-face objects, but few studies of this ability have been conducted in animals. Here, in Japanese macaques and humans, we examined visual searching for a face and explored what factors contribute to efficient facial information processing. Subjects were asked to search for an odd target among the different numbers of distracters. Faces of the subjects' own species, the backs of the head of the subjects' own species, faces of the subjects' closely related species or race, and faces of species that are clearly different from the subjects' own species were used as the target. Both the macaques and humans detected a face of their own species more efficiently than a face from a clearly different species. Similar efficient detections were confirmed for the faces of the subjects' closely related species or race. These results suggest that conspecific faces and faces that share morphological similarity with conspecific faces can be detected efficiently among non-face objects by both humans and Japanese macaques. In another experiment, facial recognition efficiency was observed when the subjects searched for own-species faces that had lower-spatial-frequency components compared to faces with higher spatial-frequency components. It seems reasonable that the ability to search efficiently for faces by using holistic face processing is derived from fundamental social cognition abilities that are broadly shared among species. PMID- 29256144 TI - Towards an e-Health Cloud Solution for Remote Regions at Bahia-Brazil. AB - This paper presents CloudMedic, an e-Health Cloud solution that manages health care services in remote regions of Bahia-Brazil. For that, six main modules: Clinic, Hospital, Supply, Administrative, Billing and Health Business Intelligence, were developed to control the health flow among health actors at health institutions. They provided database model and procedures for health business rules, a standard gateway for data maintenance between web views and database layer, and a multi-front-end framework based on web views and web commands configurations. These resources were used by 2042 health actors in 261 health posts covering health demands from 118 municipalities at Bahia state. They also managed approximately 2.4 million health service 'orders and approximately 13.5 million health exams for more than 1.3 million registered patients. As a result, a collection of health functionalities available in a cloud infrastructure was successfully developed, deployed and validated in more than 28% of Bahia municipalities. A viable e-Health Cloud solution that, despite municipality limitations in remote regions, decentralized and improved the access to health care services at Bahia state. PMID- 29256145 TI - Development of a new surgical sheet containing both silk fibroin and thermoplastic polyurethane for cardiovascular surgery. AB - PURPOSE: The surgical sheets that are currently used for congenital cardiovascular surgery have several drawbacks, including material deterioration, calcification, and pseudo-intimal proliferation resulting in hemodynamic disturbance. The aim of this study was to evaluate a newly developed sheet made from a combination of silk fibroin (SF) and a synthetic polymer, thermoplastic polyurethane (TPU), for surgical use. METHODS: The hybrid SF/TPU sheet was a non woven fabric with nanofibers that was made using the electrospinning method. The mechanical properties of the SF/TPU sheet were characterized. To determine its biocompatibility, part of the wall of the canine descending aorta was replaced with a SF/TPU sheet as a patch. The patches were removed after 3 months and a histological examination was performed. RESULTS: The flexibility, water permeability, and suture retention strength of the SF/TPU sheet were excellent and equivalent to those of existing sheets. The SF/TPU sheet had excellent handling properties and fit well into the vascular wall without needle hole bleeding. The histological examination revealed that the intimal tissue was restored well over the intraluminal surface of the explanted SF/TPU sheet, the absence of calcium deposition, and minimal inflammatory reaction, without signs of degradation. CONCLUSION: The SF/TPU sheet had excellent mechanical properties and tissue biocompatibility. These favorable features and possible biodegradability of the SF portion warrant a long-term follow-up study. PMID- 29256146 TI - Nectin-1 expression in cancer-associated fibroblasts is a predictor of poor prognosis for pancreatic ductal adenocarcinoma. AB - PURPOSE: Nectin-1 is a cell adhesion molecule that regulates the formation of adherens junctions and tight junctions. We measured the expression of nectin-1 in cancer-associated fibroblasts (CAFs) in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Nectin-1 expression was measured via immunohistochemistry using tissue microarray blocks constructed from resected PDAC tissue from 258 patients. We screened for associations between nectin-1 expression and clinicopathological parameters. According to the percentage of CAFs stained, expression was classified as negative at <= 30% and positive at > 30%. RESULTS: Nectin-1 expression was confirmed in CAFs from 64 patients (24.8%), and was associated with lymph node metastasis (p = 0.016), advanced Union for International Cancer Control stage (p = 0.016), perineural invasion (p = 0.022), pancreatic head tumors (p = 0.023), and shorter overall survival (p = 0.003). Multivariate analysis revealed that nectin-1 expression in CAFs was an independent prognostic factor (p = 0.038). CONCLUSIONS: Diffuse nectin-1 expression in the CAFs of PDAC patients is associated with invasion, metastasis, and shorter survival. PMID- 29256147 TI - Robust vascular invasion concurrent with intense EGFR immunostaining can predict recurrence in patients with stage IB node-negative gastric cancer. AB - PURPOSE: The prognosis of most patients with stage IB node-negative gastric cancer is good without postoperative chemotherapy; however, about 10% suffer recurrence and inevitably die. We conducted this study to establish the optimal indications for postoperative adjuvant chemotherapy in patients at risk of recurrence. METHODS: The subjects of this retrospective study were 124 patients with stage IB node-negative gastric cancer, who underwent gastrectomy at the Kitasato University East Hospital, between 2001 and 2010. We reviewed EGFR immunohistochemistry (IHC) as well as clinicopathological factors. RESULTS: Of the 124 patients, 47 (38%) showed intense EGFR IHC (2+ or 3+), with significantly less frequency than in stage II/III advanced gastric cancer (p < 0.001). According to univariate analysis, intense EGFR IHC was significantly associated with relapse-free survival (RFS) (p = 0.023) and associated with overall survival (OS) (p = 0.045) as well as vascular invasion (p = 0.031). On the multivariate Cox proportional hazards model, intense EGFR IHC(p = 0.016) was an independent prognostic predictor for RFS, and both vascular invasion (p = 0.033) and intense EGFR IHC (p = 0.031) were independent prognostic predictors for OS. The combination of both factors increased the risk of recurrence (p = 0.001). CONCLUSIONS: In stage IB node-negative gastric cancer, vascular invasion and intense EGFR IHC increase the likelihood of recurrence. We recommend adjuvant chemotherapy for such patients because of the high risk of metachronous recurrence. PMID- 29256149 TI - Cardiovascular profile improvement during Natalizumab treatment. AB - Cardiovascular comorbidities are associated with the risk of MS progression. Thus, we aim to measure variations of cardiovascular risk factors during Natalizumab treatment and their possible clinical associations. Seventy-one relapsing-remitting MS patients treated with Natalizumab were followed-up during a 12.9 +/- 6.2 months. Cardiovascular risk factors were recorded on first and last study visits: systolic blood pressure, uric acid, total cholesterol, LDL, HDL, and triglycerides. EDSS progression and relapse occurrence were recorded. At multilevel mixed-effects linear regression models, the population presented with a significant reduction of total cholesterol (Coeff = -7.340; 95%CI = -13.152- 1.527; p = 0.013), and of HDL cholesterol (Coeff = -3.473; 95%CI = -6.333--0.613; p = 0.017), and a non-significant reduction of LDL cholesterol (Coeff = -1.872; 95%CI = -8.481-0.736; p = 0.053), and of triglycerides (Coeff = -8.815; 95%CI = 34.011-5.380; p = 0.094). Uric acid levels increased during the study period (Coeff = 0.159; 95%CI = 0.212-0.340; p = 0.038). No significant associations were found with clinical outcomes. Serum lipids decreased and anti-oxidant uric acid increased during Natalizumab treatment. These biomarkers need to be further explored in relation to clinical outcomes on larger cohorts with longer follow ups. PMID- 29256150 TI - Response to Commentaries: Meta-Analysis of Probability Samples and Other New Evidence. PMID- 29256148 TI - Hormone secreting gastro-entero-pancreatic neuroendocrine neoplasias (GEP-NEN): When to consider, how to diagnose? AB - Neuroendocrine neoplasms of the digestive system (GEP-NEN) represent a heterogeneous group of malignancies with various clinical presentation and prognosis. GEP-NENs can potentially affect all organs of the gastrointestinal tract; characteristically they share the biological property to produce and secrete peptides and neuroamines. About 30% of GEP-NENs are hormonally active and can cause specific clinical syndromes. The clinical presentation mainly depends on the primary site of the tumor and its functionality. Because of the wide spectrum of clinical symptoms and their misperceived rarity, diagnosis of GEP NENs is often delayed for years and tumors are detected first in an advanced stage. Early identification of a specific hormonal syndrome can significantly impact tumor diagnosis and treatment, moreover the preoperative management of NEN hormonal release avoids potential life threatening hormonal crisis. However, GEP NEN diagnostic work-up is challenging, it requires a multidisciplinary team and needs particular experience; standardized protocols and clinical experience are essential for a proper endocrine diagnostic work-up. In addition to the biochemical diagnostic, further radiologic and endoscopic imaging modalities are required moreover, somatostatin-receptor based functional imaging, using either Octreotide-scintigraphy or novel PET-based techniques with specific isotopes like Ga68-DOTA-octreotate, plays an important role for the detection of the primary tumor as well as for the evaluation of the tumor extent. PMID- 29256151 TI - Evaluation of Probiotic Lactobacillus fermentum CCM 7421 Administration with Alginite in Dogs. AB - There are growing efforts to find applications for various naturally occurring organo-mineral rocks. They have so far been preferentially used in agriculture and forestry; however, medicine and nutrition may also be interesting areas for their application. This study investigates the effects of dietary supplementation with canine-derived probiotic strain Lactobacillus fermentum CCM 7421 in combination with alginite in dogs. Alginite is a loam-like material of volcanic origin composed of clay minerals and fossilised unicellular algae. The effects of these additives on faecal microbiota, faecal characteristics, short-chain fatty acid profile, haematology, serum biochemistry and cellular immunity parameters were monitored. Forty dogs were randomly divided into four treatment groups: control group (C), alginite-supplemented group (A; 1% diet), probiotic group (LF; L. fermentum CCM 7421 at a dose of 109 cfu/day/dog) and combined group (A + LF group); 10 dogs in each group. The experiment lasted for 35 days with a 14-day treatment period (sample collection at days 0, 7, 14 and 35). The results of this straightforward experiment showed beneficial effects in the combined A + LF group. In detail, a decrease in faecal coliforms and clostridia and an increase in lactic acid bacteria, haemoglobin and serum magnesium levels compared to baseline were observed in the A + LF group (P < 0.05). In contrast, sole application of alginite (A group) led to several unexpected effects such as an increase in clostridial population and serum alanine aminotrasferase and a decrease in haemoglobin concentration (P < 0.05). The addition of alginite prevented a decrease in faecal pH and serum mineral content observed in the LF group. This indicates the possibility of applying alginite also in the nutrition of dogs as a combinative additive with probiotic bacteria for restoring optimal acid-alkali balance without affecting positive probiotic effects. PMID- 29256152 TI - Photodegradation of Moxifloxacin Hydrochloride Solutions under Visible Light Irradiation: Identification of Products and the Effect of pH on their Formation. AB - The photodegradation study is essential for the phototoxicity assessment of fluoroquinolones. Various LC-MS techniques and ultraviolet (UV) lamp irradiation conditions have been used for the identification of their photodegradation products. In this study, visible light (400-760 nm) lamp irradiation was selected for the photodegradation of moxifloxacin (MOXI) hydrochloride solutions. Two photodegradation products were identified by LC-MS/MS at first, but one product could not be speculated from the mass spectrum and any known degradation mechanisms. To obtain an adequate amount for the structure elucidation, this unknown product was isolated by recrystallization and semi-preparative HPLC. Then, its structure was further identified by 1H-NMR, 13C-NMR, and 2D-NMR. Based on spectral data, this new photodegradation product was unambiguously named as 7 [3-(3-aminopropyl)-1H-pyrrol-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4 dihydroquinoline-3-carboxylic acid, which was formed through the open of hexahydroxy N-containing heterocycle and the formation of two alkene bonds in pyrrole ring. The effects of solution pH value on the formation of photodegradation products were compared. Their production was minimum at pH 5.0 and maximum at pH 7.0. Because MOXI hydrochloride has been used extensively in clinical practice and visible light is the most possible light source that pharmaceutical products are exposed to, our study is important for the quality control of MOXI liquid preparations. PMID- 29256154 TI - SEOM-SERAM-SEMNIM guidelines on the use of functional and molecular imaging techniques in advanced non-small-cell lung cancer. AB - Imaging in oncology is an essential tool for patient management but its potential is being profoundly underutilized. Each of the techniques used in the diagnostic process also conveys functional information that can be relevant in treatment decision-making. New imaging algorithms and techniques enhance our knowledge about the phenotype of the tumor and its potential response to different therapies. Functional imaging can be defined as the one that provides information beyond the purely morphological data, and include all the techniques that make it possible to measure specific physiological functions of the tumor, whereas molecular imaging would include techniques that allow us to measure metabolic changes. Functional and molecular techniques included in this document are based on multi-detector computed tomography (CT), 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), magnetic resonance imaging (MRI), and hybrid equipments, integrating PET with CT (PET/CT) or MRI (PET-MRI). Lung cancer is one of the most frequent and deadly tumors although survival is increasing thanks to advances in diagnostic methods and new treatments. This increased survival poises challenges in terms of proper follow-up and definitions of response and progression, as exemplified by immune therapy-related pseudoprogression. In this consensus document, the use of functional and molecular imaging techniques will be addressed to exploit their current potential and explore future applications in the diagnosis, evaluation of response and detection of recurrence of advanced NSCLC. PMID- 29256155 TI - Adjuvant concurrent chemoradiation therapy in patients with microscopic residual tumor after curative resection for extrahepatic cholangiocarcinoma. AB - PURPOSE: We investigated the role of adjuvant concurrent chemoradiation therapy (CCRT) in patients with a microscopically positive resection margin (R1) after curative resection for extrahepatic cholangiocarcinoma (EHCC). METHODS/PATIENTS: A total of 84 patients treated with curative resection for EHCC were included. Fifty-two patients with negative resection margins did not receive any adjuvant treatments (R0 + S group). The remaining 32 patients with microscopically positive resection margins received either adjuvant CCRT (R1 + CCRT group, n = 19) or adjuvant radiation therapy (RT) alone (R1 + RT group, n = 13). RESULTS: During the median follow-up period of 26 months, the 2-year locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival rates (OS) were: 81.8, 62.6, and 61.5% for R0 + S group; 71.8, 57.8, and 57.9% for R1 + CCRT group; and 16.8, 9.6, and 15.4% for R1 + RT group, respectively. Multivariate analysis revealed that the R1 + CCRT group did not show any significant difference in survival rates compared with the R0 + S group. The R1 + RT group had lower LRRFS [hazard ratio (HR) 3.008; p = 0.044], DFS (HR 2.364; p = 0.022), and OS (HR 2.417; p = 0.011) when compared with the R0 + S and R1 + CCRT group. CONCLUSIONS: A lack of significant survival difference between R0 + S group and R1 + CCRT group suggests that adjuvant CCRT ameliorates the negative effect of microscopic positive resection margin. In contrast, adjuvant RT alone is appeared to be inadequate for controlling microscopically residual tumor. PMID- 29256156 TI - IL-6 and IL-10 are associated with good prognosis in early stage invasive breast cancer patients. AB - Macrophage-associated cytokines play an important role in cancer metastasis; however, the functions of interleukins (IL) 6 and 10 in breast cancer (BC) progression and metastasis are not clear. In this study the roles of IL-6/IL-10 in regulating vascular invasion and their prognostic significance in BC are investigated. MDA-MB-231 and MCF-7 migration (+/- IL-6 or IL-10) was assessed by scratch wound assay. Cancer cell adhesion to IL-6/IL-10 stimulated blood and lymphatic endothelial cells (EC) was investigated. Expression of IL-6 /IL-10 was assessed using immunohistochemistry in an annotated cohort of early stage BC (n = 1380) and associations with clinicopathological variables and clinical outcome evaluated. IL-6 did not alter BC cell migration however a dose-dependent inhibition in MDA-MB-231 migration with IL-10 treatment was observed (P = 0.03). BC cells were more adhesive to blood vs lymphatic EC, however, IL-6/IL-10 had no effect on adhesion patterns. High expression of IL-6/IL-10 was associated with clinicopathological criteria (e.g. hormone receptor status, all P < 0.05), improved disease-free survival (DFS; P < 0.05) and improved BC-specific survival (BCSS; only IL-6, P = 0.017). However, neither IL-6 nor IL-10 expression were independent prognostic factors from multivariate analysis. In BC subgroups, IL-6 and IL-10 were good prognosticators in terms of DFS in non-basal, non-triple negative (non-TN), ER-positive, PgR-positive (only IL-10), and Her-2-negative (only IL-6) BC (all P < 0.05). IL-6 was associated with improved BCSS in non basal, ER-positive and non-TN BC (all P < 0.05). PMID- 29256157 TI - Therapeutic effect of andiroba oil (Carapa guianensis Aubl.) against oral mucositis: an experimental study in golden Syrian hamsters. AB - OBJECTIVES: The aim of this study was to investigate the healing activity of andiroba (Carapa guianensis Aubl.) against oral mucositis (OM) induced by 5 fluorouracil in golden Syrian hamsters. MATERIALS AND METHODS: A total of 122 animals were randomized and divided into six groups: andiroba oil 100%, andiroba oil 10%, andiroba oil 10% refined, no treatment group, all n = 28; and negative control (NC) and cyclophosphamide (CPA) groups, both n = 5. OM was induced by intraperitoneal administration of 60 mg/kg 5-FU on days 0, 5 and 10 followed by mechanical trauma on the oral mucosa on days 1 and 2. From day 1 to day 15, the animals of the andiroba group were treated three times a day. On days 4, 8, 12 and 15, the mucosa was photographed and removed for clinical and histopathological analysis. The bone marrow of the femur was removed and the micronucleus test was performed to evaluate the cytotoxicity and genotoxicity. The data were subjected to analysis of variance, followed by the Tukey and Bonferroni test. RESULTS: Treatment with 100% andiroba oil reduced the degree of OM compared to that reported in the other groups (p < 0.05). Andiroba oil at both concentrations was not cytotoxic, but treatment with 100% andiroba oil showed a genotoxic potential (p < 0.001). CONCLUSIONS: Frequent administration of andiroba oil accelerated the healing process in an experimental model of 5-fluorouracil induced OM. However, the genotoxicity of andiroba in other cell systems and under other conditions are being tested. CLINICAL RELEVANCE: The use of andiroba in topical form may be associated with reduced intensity of OM. Seek therapeutic alternatives to minimize the pain and suffering that these side effects cause cancer patients is an important scientific step. PMID- 29256158 TI - Psychological functioning in adolescents referred to specialist gender identity clinics across Europe: a clinical comparison study between four clinics. AB - Adolescents seeking professional help with their gender identity development often present with psychological difficulties. Existing literature on psychological functioning of gender diverse young people is limited and mostly bound to national chart reviews. This study examined the prevalence of psychological functioning and peer relationship problems in adolescents across four European specialist gender services (The Netherlands, Belgium, the UK, and Switzerland), using the Child Behavioural Checklist (CBCL) and the Youth Self Report (YSR). Differences in psychological functioning and peer relationships were found in gender diverse adolescents across Europe. Overall, emotional and behavioural problems and peer relationship problems were most prevalent in adolescents from the UK, followed by Switzerland and Belgium. The least behavioural and emotional problems and peer relationship problems were reported by adolescents from The Netherlands. Across the four clinics, a similar pattern of gender differences was found. Birth-assigned girls showed more behavioural problems and externalising problems in the clinical range, as reported by their parents. According to self-report, internalising problems in the clinical range were more prevalent in adolescent birth-assigned boys. More research is needed to gain a better understanding of the difference in clinical presentations in gender diverse adolescents and to investigate what contextual factors that may contribute to this. PMID- 29256159 TI - Design, synthesis and biological evaluation of antimalarial activity of new derivatives of 2,4,6-s-triazine. AB - Dihydrofolate reductase (DHFR) is an important enzyme for de novo synthesis of nucleotides in Plasmodium falciparum and it is essential for cell proliferation. DHFR is a well known antimalarial target for drugs like cycloguanil and pyrimethamine which target its inhibition for their pharmacological actions. However, the clinical efficacies of these antimalarial drugs have been compromising due to multiple mutations occurring in DHFR that lead to drug resistance. In this background, we have designed 22 s -triazine compounds using the best five parameters based 3D-QSAR model built by using genetic function approximation. In-silico designed compounds were further filtered to 6 compounds based upon their ADME properties, docking studies and predicted minimum inhibitory concentrations (MIC). Out of 6 compounds, 3 compounds were synthesized in good yield over 95% and characterized using IR, 1HNMR, 13CNMR and mass spectroscopic techniques. Parasitemia inhibition assay was used to evaluate the antimalarial activity of s -triazine compounds against 3D7 strain of P. falciparum. All the three compounds (7, 13 and 18) showed 30 times higher potency than cycloguanil (standard drug). It was observed that compound 18 was the most active while the compound 13 was the least active. On the closer inspection of physicochemical properties and SAR, it was observed that the presence of electron donating groups, number of hydrogen bond formation, lipophilicity of ligands and coulson charge of nitrogen atom present in the triazine ring enhances the DHFR inhibition significantly. This study will contribute to further endeavours of more potent DHFR inhibitors. PMID- 29256160 TI - Firearm ownership among American veterans: findings from the 2015 National Firearm Survey. AB - BACKGROUND: While the majority of veteran suicides involve firearms, no contemporary data describing firearm ownership among US veterans are available. This study uses survey data to describe the prevalence of firearm ownership among a nationally representative sample of veterans, as well as veterans' reasons for firearm ownership. METHODS: A cross-sectional, nationally representative web based survey conducted in 2015. RESULTS: Nearly half of all veterans own one or more firearms (44.9%, 95% CI 41.3-48.6%), with male veterans more commonly owning firearms than do female veterans (47.2%, 95% CI 43.4-51.0% versus 24.4%, 95%CI 15.6-36.1%). Most veteran firearm owners own both handguns and long guns (56.5%, 95% CI 51.1-61.8%); a majority cite protection as a primary reason for firearm ownership (63.1%, 95% CI 58.2-67.8%). CONCLUSIONS: The current study is the first to provide detailed, nationally representative information about firearm ownership among U.S. veterans. Better understanding firearm ownership among veterans can usefully inform ongoing suicide prevention efforts aiming to facilitate lethal means safety among vulnerable veterans during at-risk periods. PMID- 29256161 TI - Purification and Characterization of Vitellin from the Egg of the Suminoe Oyster Crassostrea ariakensis and Cross-Reactivity of Anti-vitellin Antibody with Other Marine Invertebrate Egg Proteins. AB - A polyclonal antibody specific to an egg protein of Suminoe oyster Crassostrea ariakensis was previously developed in our laboratory to assess the reproductive life cycle of the oyster. The present study was undertaken to investigate vitellin of C. ariakensis (CAVt). Vitellin is an essential component of egg proteins in marine invertebrates as it provides energy and nutrients to the embryo and larvae. CAVt was purified from eggs of the oyster using ammonium sulfate precipitation followed by affinity chromatography with Concanavalin A agarose. Native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate PAGE showed that CAVt is a high molecular weight [532 kiloDaltons (kDa)] protein, with multiple subunits. Similar to other vitellin proteins, it is a phospholipoglycoprotein composed of phospholipids (12.06%), carbohydrates (mannose, 10.08% or glucose, 9.84%), and alkali-labile phosphates (4.16%). Affinity chromatography, enzyme-linked immunosorbent aasay (ELISA) and western blot analysis revealed that CAVt is only present in the ovary, and two subunits of CAVt (72 and 35 kDa) are believed to be incorporated from the hemolymph into the oocyte. The antibody specific to CAVt (anti-CAVt), raised in rabbit, strongly cross reacted with the egg proteins of oyster species and scallops, suggesting that the antigenic epitopes are highly conserved among species. Our results suggest that the anti-CAVt antibody can be used to develop a tool similar to ELISA or western blotting for investigation of the effect of microorganisms on reproduction as well as the effect of chemicals on the endocrine system in C. ariakensis. PMID- 29256162 TI - Comparing the Effect of Thinking Maps Training Package Developed by the Thinking Maps Method on the Reading Performance of Dyslexic Students. AB - The present study aimed to develop the thinking maps training package and compare its training effect with the thinking maps method on the reading performance of second and fifth grade of elementary school male dyslexic students. For this mixed method exploratory study, from among the above mentioned grades' students in Isfahan, 90 students who met the inclusion criteria were selected by multistage sampling and randomly assigned into six experimental and control groups. The data were collected by reading and dyslexia test and Wechsler Intelligence Scale for Children-fourth edition. The results of covariance analysis indicated a significant difference between the reading performance of the experimental (thinking maps training package and thinking maps method groups) and control groups ([Formula: see text]). Moreover, there were significant differences between the thinking maps training package group and thinking maps method group in some of the subtests ([Formula: see text]). It can be concluded that thinking maps training package and the thinking maps method exert a positive influence on the reading performance of dyslexic students; therefore, thinking maps can be used as an effective training and treatment method. PMID- 29256164 TI - Retinal vasculitis associated with cutaneous leukocytoclastic vasculitis. AB - INTRODUCTION: To report a case of retinal vasculitis associated with cutaneous leukocytoclastic vasculitis. METHODS: Retrospective chart review. RESULTS: A 28 year-old man, who initially presented with occlusive retinal vasculitis and vitreous hemorrhage in right eye that resolved with sectoral photocoagulation. Laboratory investigations for tuberculosis, sarcoidosis, syphilis and sickle cell disease were negative. Past history included recent diagnosis of Enterobacter epididymo-orchitis and multiple red nodules on skin of forearm. Fourteen months later, he developed active retinal vasculitis in right eye and recurrent nodules on forearm. Skin biopsy revealed neutrophilic infiltrates in and around dermal vessels with destruction of vessel walls leading to scattered neutrophils, lymphocytes and histiocytes between collagen bundles, suggestive of leukocytoclastic vasculitis. Both skin and ocular lesions resolved with oral corticosteroid and methotrexate therapy and did not recur over a six-year period. CONCLUSION: We have reported the first case of clinically manifest retinal vasculitis, associated with a common form of cutaneous vasculitis. PMID- 29256165 TI - Central corneal epithelial thickness changes after half-moon supracapsular nucleofractis phacoemulsification technique. AB - PURPOSE: To find out the effect of half-moon supracapsular nucleofractis technique on central corneal epithelial thickness (CET) measured by spectral domain anterior segment optical coherence tomography (AS-OCT). MATERIALS AND METHODS: Patients who underwent uneventful cataract surgery by the same surgeon with the same technique were recruited in this study. The effective phaco time (EPT) was recorded in each surgery. Central CET was measured by AS-OCT 1 day before and 1, 3, 7 days after surgery. CET was measured without precorneal tear film layer, and non-epithelial central corneal thickness was also calculated manually. Preoperative and postoperative values were compared by statistical analysis. RESULTS: Thirty-one eyes of 31 patients were included in this study. The mean age of patients was 65.03 +/- 11.47 years. On the first day of surgery, increase in mean CET was statistically significant, but on the 3rd and 7th day after surgery, this increase was declined (p = 0.001, p = 0.367, p = 1, respectively). A statistically significant positive correlation was found between mean EPT and mean CET on the first postoperative day (p = 0.013, r = 0.470). On the 3rd and 7th day, this correlation was not statistically significant (p = 0.055, p = 0.454, respectively). CONCLUSION: Mean central CET was statistically thicker and positive correlated with EPT on the first postoperative day. But on the 7th day, it declined to preoperative values. PMID- 29256163 TI - Plant-Mediated Synthesis and Applications of Iron Nanoparticles. AB - Nanoscale iron particles have attracted substantial interest due to their unique physical and chemical properties. Over the years, various physical and chemical methods have been developed to synthesize these nanostructures which are usually expensive and potentially harmful to human health and the environment. Synthesis of iron nanoparticles (INPs) by using plant extract is now of great interest in order to develop a novel and sustainable approach toward green chemistry. In this method the chemical compounds and organic solvents are replaced with phytochemicals and aqueous matrixes, respectively. Similar to any chemical and biochemical reaction, factors such as reaction temperature, concentration of iron precursor, concentration of leaf extract, and reaction time have critical effects on the reaction yield. This review focuses on the novel approaches used for green synthesis of INPs by using plant resources. The currently available statistics including the factors affecting the synthesis process and potential applications of the fabricated nanoparticles are discussed. Recommendations are also given for areas of future research in order to improve the production process. PMID- 29256166 TI - Choroidal hypoperfusion: an indicator of low tension neovascular glaucoma. AB - PURPOSE: To report a case of low tension neovascular glaucoma in ocular ischemic syndrome. METHODS: An elderly man presenting with vision loss after an episode of hemiparesis was investigated to look for the cause of vision loss and treated. RESULTS: Fluorescein angiography demonstrated poor uveal perfusion and treatment with panretinal photocoagulation led to rapid closure of the angle. CONCLUSION: This case highlights the typical ophthalmic features of ocular ischemic syndrome and emphasizes the necessity of patient education and prognostication. PMID- 29256167 TI - Effectiveness of photodynamic therapy with verteporfin combined with intrastromal bevacizumab for corneal neovascularization in Stevens-Johnson syndrome. AB - PURPOSE: To investigate the effectiveness of combined photodynamic therapy with verteporfin and intrastromal injection of bevacizumab for the treatment of corneal neovascularization in patients with Stevens-Johnson syndrome (SJS). METHODS: Eight eyes of eight patients with SJS having corneal neovascularization who were refractory to 1% prednisolone instillation received photodynamic therapy with verteporfin (6 mg/m2) combined with intrastromal bevacizumab injection (2.5 mg/0.1 mL). Best-corrected visual acuity and intraocular pressure were assessed, and slit-lamp biomicroscopic examination was performed before treatment and at 1 week and every month. A chronic ocular manifestation score was assigned based on the involvement area or the severity before treatment. The cumulative length of corneal blood vessels and area of corneal neovascularization were measured by anterior segment photographs before and after treatment. RESULTS: At 3 and 6 months after treatment, all eyes showed regression of corneal neovascularization. Complete regression was achieved in five eyes (62.5%) and partial regression in three eyes (37.5%). Among five patients who were followed up for more than 1 year, two eyes maintained complete regression and one eye maintained partial regression at 1 year. However, two eyes with severe chronic ocular manifestation showed revascularization. CONCLUSIONS: Combined photodynamic therapy with intrastromal bevacizumab injection can effectively inhibit corneal neovascularization in patients with SJS. However, patients with severe chronic ocular manifestation may exhibit revascularization. PMID- 29256168 TI - Primary vitrectomy with short-term silicone oil tamponade for uncomplicated rhegmatogenous retinal detachment. AB - PURPOSE: To compare the outcomes of phakic and pseudophakic uncomplicated rhegmatogenous retinal detachment (RRD) treated with primary pars plana vitrectomy (PPV) and short-term silicone oil (SO) tamponade. METHODS: A retrospective chart review of 201 eyes (185 patients) with uncomplicated RRD treated with primary 23-gauge PPV and short-term SO tamponade. Anatomical success was defined as a reattached retina for at least 6 months after SO removal. RESULTS: The analysis consisted of 111 phakic eyes and 90 pseudophakic eyes. The mean duration of SO tamponade in phakic eyes was 8.5 +/- 1.9 and in pseudophakic eyes was 8.3 +/- 1.9 months (P = 0.39). The primary reattachment rate was 93% in the phakic group and 98% in the pseudophakic group (P = 0.19). The mean Snellen VA equivalent at the final visit was 20/30 in both groups. Final VA >= 20/40 was achieved in 81% of phakic and 86% of pseudophakic eyes (P = 0.69). Postoperative complications included cataract in the phakic group (100%), transient elevation of intraocular pressure (IOP) (29%), epiretinal membrane (8%), proliferative vitreoretinopathy (7%), cystoid macular edema (3%), secondary macular hole (2%), persistent elevation of IOP (1.5%), and persistent hypotony (1%). CONCLUSIONS: The success rates and functional outcomes of primary 23-gauge PPV with short-term SO tamponade did not differ significantly between the two groups, suggesting that lens status is not the single most important factor influencing the final results. The use of short-term SO was not associated with keratopathy, visual loss without any apparent reason and high rates of chronic elevation of IOP or redetachment following SO removal. PMID- 29256169 TI - Comparison of corneal endothelial cell analysis in patients with uveitis and healthy subjects. AB - PURPOSE: The aim of this study is to investigate the effect of uveitis in corneal endothelial cell number and morphology by non-contact specular microscopy. METHODS: Our cross-sectional study was performed on 56 eyes of uveitis patients and 53 eyes of healthy subjects. Non-contact specular microscopy was performed to all subjects. The cell density (CD), coefficient of variation, cell minimum area (Min) and cell maximum area (Max), the average of cell size (AVG), percent of hexagonality (HEX%), central corneal thickness (CCT), intraocular pressure (IOP) during uveitis and during remission were measured and compared between two groups. RESULTS: The mean endothelial cell analysis of the patients was 2540 +/- 619 cells/mm2, and the mean endothelial cell analysis of the control group was 2834 +/- 413 cells/mm2. The difference was statistically significant between the groups (p = 0.01). There was a statistically significant difference between two groups in terms of Max, Min, AVG, and HEX values. However, there was no difference in terms of CCT between two groups. There was a significant negative correlation between CD and IOP during uveitis attack. There was a significant negative correlation between the anterior chamber cell value and CD. CONCLUSION: Our results suggested that uveitis affected endothelial cell density, cell size and shape but not the corneal thickness without being influenced by the duration and number of attacks. Increased IOP during uveitis and anterior chamber cell value had an important role on CD in patients with uveitis. PMID- 29256170 TI - Vision-threatening bilateral panuveitis and TRAPS in a child: an uncommon association. AB - PURPOSE: To report a childhood case of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) carrying the R92Q variant with a vision-threatening bilateral panuveitis. METHODS: Case report and review of the literature. RESULTS: A 7-year-old boy presented with an active bilateral panuveitis and a macular rash associated with fever. Fundus examination showed two choroidal lesions on the posterior pole of the right eye, and fluorescein angiography revealed early hypofluorescence and late hyperfluorescence of the lesions, which were hyper autofluorescent. Extensive clinical laboratory analyses ruled out autoimmune diseases and systemic infection. The only remarkable finding was a positive IgG for herpes simplex 1. He underwent two successive diagnostic pars plana vitrectomies as well as cataract and glaucoma surgeries. Genetic analysis revealed a mutation in the TNFRSF1A gene, and the patient was diagnosed with TRAPS-associated bilateral panuveitis. He was treated with adalimumab and has been free of active inflammation since then. CONCLUSIONS: We present here the first case reported of panuveitis in a patient with TRAPS. This finding stresses the increasing importance of genetic analysis in search of autoinflammatory diseases to establish an adequate diagnosis and treatment in cases of uveitis of unknown etiology. PMID- 29256172 TI - Multiple Reaction Monitoring Using Double Isotopologue Peptide Standards for Protein Quantification. AB - Multiple reaction monitoring (MRM) is a technique used in tandem mass spectrometry where the first mass analyzer preselects parent ions for fragmentation and the second mass analyzer transmits selected product ions to the detector. This targeted technique has found widespread application in bottom-up proteomics for monitoring target peptides in a complex enzymatic digest. Quantitative MRM can be performed on enzymatically digested samples using spiked in synthetic peptide standards, providing unsurpassed quantitative accuracy and a dynamic range of four orders of magnitude, often eliminating the need for prior depletion of high-abundance proteins. The development of MRM assays requires technical rigor, and this chapter details a methodology for sample preparation, data acquisition, and analyses to successfully perform quantitative MRM assays using two distinct isotopologue peptide standards to quantify proteins in mouse plasma and heart tissue. PMID- 29256171 TI - Multiple enhancer regions govern the transcription of CCN2 during embryonic development. AB - CCN2 is a critical matricellular protein that is expressed in several cells with major implications in physiology and different pathologies. However, the transcriptional regulation of this gene remains obscure. We used the Encyclopaedia of DNA Elements browser (ENCODE) to visualise the region spanning from 300 kb upstream to the CCN2 start site in silico in order to identify enhancer regions that regulate transcription of this gene. Selection was based on three criteria associated with enhancer regions: 1) H3K4me1 and H3K27ac histone modifications, 2) DNase I hypersensitivity of chromatin and 3) inter-species conservation. Reporter constructs were created with sequences spanning each of the regions of interest placed upstream of an Hsp68 silent proximal promoter sequence in order to drive the expression of beta-galactosidase transgene. Each of these constructs was subsequently used to create transgenic mice in which reporter gene production was assessed at the E15.5 developmental stage. Four functional enhancers were identified, with each driving distinct, tissue-specific patterns of transgene expression. An enhancer located -100 kb from the CCN2 transcription start site facilitated expression within vascular tissue. An enhancer -135 kb upstream of CCN2 drove expression within the articular chondrocytes of synovial joints. The other two enhancers, located at -198 kb and 229 kb, mediated transgene expression within dermal fibroblasts, however the most prevalent activity was found within hypertrophic chondrocytes and periosteal tissue, respectively. These findings suggest that the global expression of CCN2 during development results from the activity of several tissue-specific enhancer regions in addition to proximal regulatory elements that have previously been demonstrated to drive transcription of the gene during development. PMID- 29256173 TI - Gene Network Analysis of Interstitial Macrophages After Treatment with Induced Pluripotent Stem Cells Secretome (iPSC-cm) in the Bleomycin Injured Rat Lung. AB - Idiopathic pulmonary fibrosis (IPF) is a complex disease involving various cell types. Macrophages are essential in maintenance of physiological homeostasis, wound repair and fibrosis in the lung. Macrophages play a crucial role in repair and remodeling by altering their phenotype and secretory pattern in response to injury. The secretome of induced pluripotent stem cells (iPSC-cm) attenuates injury and fibrosis in bleomycin injured rat lungs. In the current study, we evaluate the effect of iPSC-cm on gene expression and phenotype of interstitial macrophage in bleomycin injured rat lungs in vivo. iPSC-cm was intratracheally instilled 7 days after bleomycin induced lung injury and assessed 7 days later and single cell isolation was performed. Macrophages were FACS sorted and microarray analysis was performed. We characterized changes in the rat lung interstitial macrophages using transcriptional profiling. iPSC-cm reduced the total collagen content of the lung and reduced different macrophage populations. Gene set enrichment analysis revealed involvement of three essential pathways (a) immune modulation, (b) branching morphogenesis and (c) canonical Wnt signaling. This study demonstrates that iPSC-cm reduces fibrosis in bleomycin injured rat lung by partially altering the macrophages and regulating their gene expression. PMID- 29256175 TI - Erratum to: High Content Screening. PMID- 29256174 TI - Analysis of Portuguese language blogs about bariatric surgery: key doubts of internauts regarding the postoperative period. AB - BACKGROUND: The Internet, particularly blogs have become an important tool for patients to disseminate and exchange information on a variety of health topics, including bariatric surgery. By virtue of its interactivity being free of judgement from health care providers, blogs expose gaps in patients' knowledge and understanding. PURPOSE: This study analyzes the main doubts expressed in blogs by patients in the postoperative period of bariatric surgery. METHOD: This is a qualitative exploratory study of 11 blogs of patients, who underwent bariatric surgery, that were available on the Internet between October 2013 and May 2017. The data were collected through a structured instrument and analyzed according to Bardin's suggestions. The sampling method used was intentional. RESULTS: Evolution of diet, weight loss, plateau effect, weight regain, physical exercises, physiological changes, complications, use of contraceptive and pregnancy were the main areas of concern. CONCLUSION: More needs to be done to educate and prepare bariatric patients for the postoperative period. The content found in blogs serves towards building better links with patients, helps them make better decisions, and provides them an opportunity to be active participants in their own treatment. PMID- 29256176 TI - Susceptibility to mycobacterial disease due to mutations in IL-12Rbeta1 in three Iranian patients. AB - In the last decade, autosomal recessive interleukin-12 receptor beta1 (IL 12Rbeta1) deficiency, the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), has been diagnosed in a few children and adults with severe tuberculosis in Iran. Here, we report three cases referred to the Immunology, Asthma and Allergy ward at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) at Masih Daneshvari Hospital from 2012 to 2017 with Mycobacterium tuberculosis and non-tuberculous mycobacteria infections due to defects in IL-12Rbeta1 but with different clinical manifestations. All three were homozygous for either an IL-12Rbeta1 missense or nonsense mutation that caused the IL-12Rbeta1 protein not to be expressed on the cell membrane and completely abolished the cellular response to recombinant IL-12. Our findings suggest that the presence of IL-12Rbeta1 deficiency should be determined in children with mycobacterial infections at least in countries with a high prevalence of parental consanguinity and in areas endemic for TB like Iran. PMID- 29256178 TI - Taurine supplementation reduces neuroinflammation and protects against white matter injury after intracerebral hemorrhage in rats. AB - Intracerebral hemorrhage (ICH) initiates a neuroinflammatory cascade that contributes to substantial neuronal damage and neurological deterioration. Taurine, an abundant amino acid in the nervous system, is reported to reduce inflammatory injury in various central nervous system diseases, but its role and the possible underlying mechanisms in the pathology following ICH remains unclear. This study was designed to evaluate the effect of taurine supplementation on neurological deficits, acute inflammatory responses and white matter injury in a model of ICH in rats. Adult male Sprague-Dawley (SD) rats subjected to collagenase-induced ICH injury were injected intravenously with different concentrations of taurine or vehicle 10 min after ICH and subsequently daily for 3 days. Behavioral studies, brain water content, and assessments of hemorrhagic lesion volume were quantified at day 1 and day 3 post-ICH. Neuronal damage, peri-hematomal inflammatory responses, and white matter injury were determined at 24 h, meanwhile, the content of hydrogen sulfide (H2S) along with the expression of cystathionine-beta-synthase (CBS) and P2X7 receptor (P2X7R) in peri-hematomal tissues was analyzed to investigate the possible anti-inflammatory mechanism of taurine. Treatment with a high dosage of taurine (50 mg/kg) significantly attenuated functional deficits and reduced brain edema and hemorrhagic lesion volume after ICH. Taurine administration also resulted in significant amelioration of neuronal damage and white matter injury. These changes were associated with marked reductions in neutrophil infiltration, glial activation, and expression levels of inflammatory mediators. Moreover, the anti inflammatory effect of taurine was accompanied by increased H2S content, enhanced CBS expression, and less expression of P2X7R. Our study demonstrated that the high dosage of taurine supplementation effectively mitigated the severity of pathological inflammation and white matter injury after ICH, and the mechanism may be related to upregulation of H2S content and reduced P2X7R expression. PMID- 29256179 TI - Lattice Boltzmann study of chemically-driven self-propelled droplets. AB - We numerically study the behavior of self-propelled liquid droplets whose motion is triggered by a Marangoni-like flow. This latter is generated by variations of surfactant concentration which affect the droplet surface tension promoting its motion. In the present paper a model for droplets with a third amphiphilic component is adopted. The dynamics is described by Navier-Stokes and convection diffusion equations, solved by the lattice Boltzmann method coupled with finite difference schemes. We focus on two cases. First, the study of self-propulsion of an isolated droplet is carried on and, then, the interaction of two self propelled droplets is investigated. In both cases, when the surfactant migrates towards the interface, a quadrupolar vortex of the velocity field forms inside the droplet and causes the motion. A weaker dipolar field emerges instead when the surfactant is mainly diluted in the bulk. The dynamics of two interacting droplets is more complex and strongly depends on their reciprocal distance. If, in a head-on collision, droplets are close enough, the velocity field initially attracts them until a motionless steady state is achieved. If the droplets are vertically shifted, the hydrodynamic field leads to an initial reciprocal attraction followed by a scattering along opposite directions. This hydrodynamic interaction acts on a separation of some droplet radii otherwise it becomes negligible and droplets motion is only driven by the Marangoni effect. Finally, if one of the droplets is passive, this latter is generally advected by the fluid flow generated by the active one. PMID- 29256180 TI - IL-2 mediates NK cell proliferation but not hyperactivity. AB - Natural killer cells play a major role in innate immunity against tumor and virus infected cells. NK cells express activating and inhibitory receptors to regulate their function. It has been established that modulation in the NK cell receptor profile results in altered function of NK cell against target cells. Here, we study the effect of IL-2 stimulation on NK cell inhibitory receptors Ly49A, Ly49C, and activating receptor Ly49D in C57BL/6 mice. It was observed that there was significant increase in expression of Ly49A but no change in expression of Ly49C and Ly49D on IL-2 stimulation. We further noticed that although IL-2 stimulation increased the NK cell population and expression of activation marker NK1.1 but IL-2 stimulation does not cause hyper-responsiveness in NK cells, as there was no increase in MIP-1alpha and IFN-gamma production in IL-2 stimulated NK cells as compared to unstimulated controls. These findings provide a framework to understand the effect of IL-2 stimulation on cognate and non-cognate receptor ligand interactions and suggest stratagies for immunotherapies in conjunction with IL-2 combinatorial therapies. PMID- 29256177 TI - Inferring the evolution of the major histocompatibility complex of wild pigs and peccaries using hybridisation DNA capture-based sequencing. AB - The major histocompatibility complex (MHC) is a key genomic model region for understanding the evolution of gene families and the co-evolution between host and pathogen. To date, MHC studies have mostly focused on species from major vertebrate lineages. The evolution of MHC classical (Ia) and non-classical (Ib) genes in pigs has attracted interest because of their antigen presentation roles as part of the adaptive immune system. The pig family Suidae comprises over 18 extant species (mostly wild), but only the domestic pig has been extensively sequenced and annotated. To address this, we used a DNA-capture approach, with probes designed from the domestic pig genome, to generate MHC data for 11 wild species of pigs and their closest living family, Tayassuidae. The approach showed good efficiency for wild pigs (~80% reads mapped, ~87* coverage), compared to tayassuids (~12% reads mapped, ~4* coverage). We retrieved 145 MHC loci across both families. Phylogenetic analyses show that the class Ia and Ib genes underwent multiple duplications and diversifications before suids and tayassuids diverged from their common ancestor. The histocompatibility genes mostly form orthologous groups and there is genetic differentiation for most of these genes between Eurasian and sub-Saharan African wild pigs. Tests of selection showed that the peptide-binding region of class Ib genes was under positive selection. These findings contribute to better understanding of the evolutionary history of the MHC, specifically, the class I genes, and provide useful data for investigating the immune response of wild populations against pathogens. PMID- 29256182 TI - [Model study programs in medicine : Innovations in medical education in Hamburg and Berlin]. AB - Medical science is constantly evolving. Teaching and training must keep pace with these innovations and react in a flexible fashion to new requirements. Model medical education programs, which are governed by the provisions of Sect. 41 of the Regulations for the Licensing of Medical Practitioners (AAppO), permit the piloting of innovative teaching programs, which support the continuous development of medical training through incorporation into the standard curricula. This paper reports on the model study programs at the University Medical Centre Hamburg-Eppendorf (iMED) and Charite - University Medicine Berlin (MSM). It describes the reform objectives, the curricula and selected projects accompanying both models and concludes by exploring the significance of various training concepts for the development of medical education. PMID- 29256181 TI - Antioxidant effects of beta-carotene, but not of retinol and vitamin E, in orbital fibroblasts from patients with Graves' orbitopathy (GO). AB - BACKGROUND: Oxidative stress is involved in the pathogenesis of Graves' orbitopathy (GO) and several antioxidant agents, namely, selenium, quercetin, enalapril, vitamin C, N-acetyl-L-cysteine, and melatonin, have been shown to reduce oxidative stress and its consequences in primary culture of orbital fibroblasts. In addition, selenium is effective for the treatment of mild GO. Here, we investigated the action of three additional antioxidants in orbital fibroblasts, namely, retinol, beta-carotene, and vitamin E. METHODS: Primary cultures of orbital fibroblasts were established from GO patients and control subjects. To induce oxidative stress, cells were treated with H2O2, after which glutathione disulfide (GSSG) (a parameter of oxidative stress), cell proliferation, hyaluronic acid, TNFalpha, IFNgamma, and IL1beta were measured. RESULTS: H2O2-dependent oxidative stress (augmented GSSG) was associated with increased cell proliferation and cytokine release. All the three antioxidant substances reduced GSSG in both GO and control fibroblasts. beta-carotene reduced proliferation in GO, but not in control fibroblasts. IL1beta was reduced by all three substances. Retinol reduced IFNgamma in GO and control fibroblasts. CONCLUSIONS: Our study supports an antioxidant role of retinol, beta-carotene, and vitamin E in orbital fibroblasts from patients with GO and provides a basis for a possible clinical use these substances. PMID- 29256183 TI - The relationship between the degree of displacement of the atlas to axis and the clinical data in atlanto-axial subluxation due to rheumatoid arthritis. AB - INTRODUCTION: The most common type of anatomical cervical spine involvement is atlanto-axial subluxation (AAS) in rheumatoid arthritis (RA). The purpose of this study was to clarify the relationship between the displacement of the atlas to axis and the clinical data obtained in patients with AAS due to RA. METHODS: Fifty patients with AAS due to RA that were treated by surgery are herein reviewed. Based on the findings of preoperative lateral cervical radiographs in the neutral position, the patients were classified into two groups as follows: a 10 + group with an atlanto-dental interval (ADI) of ? 10 mm, and a 10 - group with an ADI < 10 mm. RESULTS: Preoperative lateral cervical radiographs demonstrated 15 cases to belong to the 10 + group, while 35 cases belonged to the 10 - group. In the preoperative MR imaging, an intramedullary high signal intensity was observed in seven cases that belonged to the 10 + group and in four cases belonging to the 10 - group. Regarding the neurological severity, the 10 + group included significantly more cases showing severe neurological deficits before surgery; however, there was no significant difference between the two groups regarding the presence of severe deficits even after surgery. CONCLUSIONS: The severe displacement group included significantly more cases showing an intramedullary high signal intensity in the preoperative MR images. Our results also suggest that a severe displacement before surgery affected the presence of neurological deficits before surgery; however, it did not affect the neurological recovery from such severe neurological deficits. PMID- 29256184 TI - The nail-shaft-axis of the of proximal femoral nail antirotation (PFNA) is an important prognostic factor in the operative treatment of intertrochanteric fractures. AB - INTRODUCTION: Due to the world's aging population, intertrochanteric fractures are frequent. Considering age and comorbidities of most of these patients, it is indispensable to enable early postoperative mobilization of these patients. Intramedullary osteosynthesis with PFN-A is widely used and, in general, considered safe and reliable for the operative treatment of intertrochanteric fractures. However, implant -related complications are reported in 6-21% of all cases. In this study, we are analyzing complication rates and risk factors for implant-related complications. MATERIALS AND METHODS: All intertrochanteric fractures admitted to our hospital and treated with PFN-A between January 2012 and January 2016 were analysed retrospectively. Radiological analyses of the CCD and the lateral offset on the uninjured side was compared to the CCD initially postoperatively and during follow-up on the operated side. Furthermore, we analysed the tip-apex distance (TAD), blade position in the femoral head and introduced the nail-shaft axis as a new parameter. RESULTS: Within 101 intertrochanteric fractures included, 16 implant-related complications were encountered (15.84%). Analyses of risk factors for secondary varus displacement of greater than 10 degrees within the follow-up and thus risk for cut-out in the osteosynthesis revealed that etasblished risk factors such as a TAD > 25 mm, reduction in varus and an improper position of the blade were also significant risk factors in our cohort for failure of the osteosynthesis. Moreover, we introduced the nail-shaft axis a new potential risk factor and could show that a too medial or too lateral nail-shaft axis is also significantly associated with secondary varus displacement. CONCLUSION: When treating introchanteric fractures with PFNA reduction in neutral or even slight valgus, aiming for a TAD < 25 mm and a correct position of the blade within the femoral head reduced the risk for secondary varus displacement significantly. Furthermore, we suggest to aim for a central nail-shaft axis. PMID- 29256185 TI - Lab-on-a-chip device made by autohesion-bonded polymers. AB - Polymers have the obvious advantages of flexibility in design and cost effectiveness to fabricate a lab-on-a-chip (LOC) device. Polyether ether ketone (PEEK) in particular is very attractive choice as it adds biocompatibility in addition to the possibility of hematic sealing in a 3D design. Hereby, we extend our previous successful technology of autohesive hermetic bonding of medical implants into lab-on-a-chip devices. We explore a conceptual 3D micro channels design with hermetic potential using PEEK and PS sheets. A hermetic and mechanically strong (through tensile test) 3D multilayer device was obtained using plasma treatment with oxygen and methane as precursors followed by pressing at temperature near of Tg + 20 of the polymer with the lowest Tg (PS). This nanotexturing technique is also used to facilitate thermal and mechanical stability of the microchannels for microfluidic applications. X-ray tomography measurements showed that 3D polymer made chips, at certain plasma and press bonding conditions, have structural integrity and no deformation were detected in channels shape post thermal pressing process. The dimension stability of channels and reservoirs and the rigid interfacial region at PEEK-PS make this chip design attractive and feasible for advanced lab-on-a-chip applications. PMID- 29256186 TI - Bladder cancer in an inguinal vesical hernia. AB - A 60-year-old male patient presented with intermittent right-sided scrotal swelling for the last 4 months. On ultrasonography, a fluid-filled cavity extending through the right inguinal canal into the scrotum was noted with inferior displacement of the right testis. Multiple papillary hyperechoic lesions with internal vascularity on Doppler ultrasound were protruding into the fluid filled cavity. Computed tomography showed herniation of the bladder through the right inguinal canal into the scrotum with mural components in the herniated segment. Hernioplasty followed by transurethral tumor resection showed urothelial carcinoma with invasion into the muscular layer. Vesical herniation through the inguinal canal is uncommon. Additionally, the presence of bladder carcinoma within a herniated portion of the bladder is exceedingly rare. PMID- 29256188 TI - Effect of Polygonum Aviculare L. on Nephrolithiasis Induced by Ethylene Glycol and Ammonium Chloride in Rats. AB - PURPOSE: Nephrolithiasis is a common urinary tract disease, in addition to the pain and treatment costs, there may be significant complications resulting from the stones. This study intended to investigate the effects of Polygonum Aviculare L. aqueous extract (PAE) on urolithiasis induced by ethylene glycol (EG) and ammonium chloride (AC) in rats. MATERIALS AND METHODS: Sixty-four male Wistar rats were randomly divided into eight groups (n = 8). Rats in the normal control group (I) received no treatment. The sham groups (III and IV) were given PAE. at 100 and400 mg/kg by gavage for 28 days. The disease control group (II), the prevention groups ( V and VI), and the therapeutic groups (VII and VIII), received 1% EG and .25 AC in their drinking water for 28 days. The prevention groups (from the start of EG administration), and the therapeutic groups (from the 14th day of EG administration),received PAE at 100 and 400 mg/kg by gavage. At the end of the experiment, kidneys were examined for CaOx deposits and tubulointerstitial changes. RESULTS: The number of CaOx crystals and tubulointerstitial changes increased significantly in group II rats compared to groups I, III, and IV (P < .001). The number of CaOx crystals (P < .001) and tubulointerstitial changes (P < .001) in the prevention groups, and the number of CaOx crystals (P < .05) and interstitial changes (P < .05) inthe therapeutic groups declined significantly compared to group II. CONCLUSION: Results show aqueous extract of Polygonum Aviculare L. is effective in the prevention and treatment of kidney stones. PMID- 29256189 TI - Female Genital Mutilation as a Concern for Special Operations and Tactical Emergency Medical Support Medics. AB - Female genital mutilation (FGM), frequently called female genital cutting or female circumcision, is the intentional disfigurement of the external genitalia in young girls and women for the purpose of reducing libido and ensuring premarital virginity. This traditional, nontherapeutic procedure to suppress libido and prevent sexual intercourse before marriage has been pervasive in Northern Africa, the Middle East, and the Arabian peninsula for over 2,500 years. FGM permanently destroys the genital anatomy while frequently causing multiple and serious complications. The International Federation of Gynecology and Obstetrics proposed a classification system of FGM according to the specific genital anatomy removed and the extensiveness of genital disfigurement. Although it has been ruled illegal in most countries, FGM continues to be performed worldwide. With African, Asian, and Middle Eastern immigration to the United States and Europe, western countries are experiencing FGM in regions where these immigrants have concentrated. As deployments of Special Operations Forces (SOF) increase to regions in which FGM is pervasive, and as African, Asian, and Middle Eastern immigration to the United States increases, SOF and Tactical Emergency Medical Support (TEMS) medics will necessarily be called upon to evaluate and treat complications resulting from FGM. The purpose of this article is to educate SOF/TEMS medical personnel about the history, geographic regions, classification of procedures, complications, and medical treatment of patients with FGM. PMID- 29256187 TI - Vascular ultrasound in pediatrics: utility and application of location and measurement of jugular and femoral vessels. AB - OBJECTIVE: To measure the depth (D p) and diameter (D m) of the internal jugular vein (IJV), femoral vein (FV), and femoral artery (FA) in pediatric patients to evaluate the clinical implications. METHODS: This study included 125 pediatric patients. All of them underwent bilateral ultrasound study of vessels and were classified into three groups based on anthropometric and demographic parameters. RESULTS: Measured mean D p values were: 0.72 (0.34) cm for the FA, 0.79 (0.35) cm for the FV, and 0.77 (0.24) cm for the IJV. Mean antero-posterior D m values were: 0.37 (0.17) cm for the FA, 0.42 (0.22) cm for the FV, and 0.59 (0.23) cm for the IJV. D p and D m increased with age (A), weight (W), height (H), and body surface area (BSA). In the lower ranges of these variables, D p was similar for all three studied vessels (0.6-0.7 cm). In the higher ranges, femoral vessel D p values (1.1-1.2 cm) were larger than jugular ones (0.9 cm). Additionally, in these low ranges, IJV D m values were larger than femoral ones (0.45-0.50 vs. 0.25 cm). In the higher ranges, diameter values were similar (0.6-0.7 cm). CONCLUSIONS: In pediatric patients, major vessels can be located and their depth and diameter measured by vascular ultrasound. In younger patients, jugular and femoral vessels had similar depth values; in older ones, they had similar diameters. Ultrasound measurements in pediatric patients could facilitate the choice of the vessel to be cannulated, the catheter diameter, and the length of the needle to be used. Vascular canalization of IJV may be recommended as the first choice because of its low depth and large diameter. PMID- 29256190 TI - Extraglottic Airways in Tactical Combat Casualty Care: TCCC Guidelines Change 17 01 28 August 2017. AB - Extraglottic airway (EGA) devices have been used by both physicians and prehospital providers for several decades. The original TCCC Guidelines published in 1996 included a recommendation to use the laryngeal mask airway (LMA) as an option to assist in securing the airway in Tactical Evacuation (TACEVAC) phase of care. Since then, a variety of EGAs have been used in both combat casualty care and civilian trauma care. In 2012, the Committee on TCCC (CoTCCC) and the Defense Health Board (DHB) reaffirmed support for the use of supraglottic airway (SGA) devices in the TACEVAC phase of TCCC, but did not recommend a specific SGA based on the evidence available at that point in time. This paper will use the more inclusive term "extraglottic airway" instead of the term "supragottic airway" used in the DHB memo. Current evidence suggests that the i-gel(r) (Intersurgical Complete Respiratory Systems; http://www.intersurgical.com/info/igel) EGA performs as well or better than the other EGAs available and has other advantages in ease of training, size and weight, cost, safety, and simplicity of use. The gel-filled cuff in the i-gel both eliminates the need for cuff pressure monitoring during flight and reduces the risk of pressure-induced neuropraxia to cranial nerves in the oropharynx and hypopharynx as a complication of EGA use. The i-gel thus makes the medic's tasks simpler and frees him or her from the requirement to carry a cuff manometer as part of the medical kit. This latest change to the TCCC Guidelines as described below does the following things: (1) adds extraglottic airways (EGAs) as an option for airway management in Tactical Field Care; (2) recommends the i-gel as the preferred EGA in TCCC because its gel filled cuff makes it simpler to use than EGAs with air-filled cuffs and also eliminates the need for monitoring of cuff pressure; (3) notes that should an EGA with an air-filled cuff be used, the pressure in the cuff must be monitored, especially during and after changes in altitude during casualty transport; (4) emphasizes COL Bob Mabry's often-made point that extraglottic airways will not be tolerated by a casualty unless he or she is deeply unconscious and notes that an NPA is a better option if there is doubt about whether or not the casualty will tolerate an EGA; (5) adds the use of suction as an adjunct to airway management when available and appropriate (i.e., when needed to remove blood and vomitus); (6) clarifies the wording regarding cervical spine stabilization to emphasize that it is not needed for casualties who have sustained only penetrating trauma (without blunt force trauma); (7) reinforces that surgical cricothyroidotomies should not be performed simply because a casualty is unconscious; (8) provides a reminder that, for casualties with facial trauma or facial burns with suspected inhalation injury, neither NPAs nor EGAs may be adequate for airway management, and a surgical cricothyroidotomy may be required; (9) adds that pulse oximetry monitoring is a useful adjunct to assess airway patency and that capnography should also be used in the TACEVAC phase of care; and (10) reinforces that a casualty's airway status may change over time and that he or she should be frequently reassessed. PMID- 29256191 TI - Assessment of User, Glove, and Device Effects on Performance of Tourniquet Use in Simulated First Aid. AB - BACKGROUND: The effects of users, glove types, and tourniquet devices on the performance of limb tourniquet use in simulated first aid were measured. MATERIALS AND METHODS: Four users conducted 180 tests of tourniquet performance in eight glove groups compared with bare hands as a control. RESULTS: Among tests, 99% (n = 179) had favorable results for each of the following: effectiveness (i.e., bleeding control), distal pulse stoppage, and tourniquet placement at the correct site. However, only 90% of tests ended with a satisfactory result, which is a composite outcome of aggregated metrics if all (patient status is stable, tourniquet placement is good, and pressure is good) are satisfactory. Of 18 unsatisfactory results, 17 (94%) were due to pressure problems. Most of the variance of the majority of continuous metrics (time to determination of bleeding control, trial time, overall time, pressure, and blood loss) could be attributed to the users (62%, 55%, 61%, 8%, and 68%, respectively). Glove effects impaired and slowed performance; three groups (cold gloves layered under mittens, mittens, and cold gloves) consistently had significant effects and five groups (examination gloves, flight gloves, leather gloves, glove liners, and glove liners layered under leather gloves) did not. For time to bleeding control and blood loss, performance using these same three glove groups had worse results compared with bare hands by 26, 18, and 17 seconds and by 188, 116, and 124mL, respectively. Device effects occurred only with continuous metrics and were often dominated by user effects. CONCLUSION: In simulated first aid with tourniquets used to control bleeding, users had major effects on most performance metrics. Glove effects were significant for three of eight glove types. Tourniquet device effects occurred only with continuous metrics and were often dominated by user effects. PMID- 29256192 TI - Effects of Distance Between Paired Tourniquets. AB - BACKGROUND: In practice, the distance between paired tourniquets varies with unknown effects. METHODS: Ratcheting Medical Tourniquets were applied to both thighs of 15 subjects distally (fixed location) and proximally (0, 2, 4, 8, 12cm gap widths, randomized block). Applications were pair, single distal, single appropriate proximal. Tightening ended one-ratchet tooth advance past Doppler indicated occlusion. Pairs had alternating tightening starting distal. RESULTS: Occlusion pressures were higher for: each single than respective individual pair tourniquet, each pair distal than respective pair proximal, and each single distal than respective single proximal (all p < .0001). Despite thigh circumference increasing proximally, occlusion pressures were lower with proximal tourniquet involvement (pair or single, p < .0001). Occlusion losses before 120 seconds occurred most frequently with pairs (0cm 4, 2cm 4, 4cm 6, 8cm 7, 12cm 5 for 26 of 150), in increasing frequency with increasingly proximal singles (0cm 0, 2cm 1, 4cm 1, 8cm 2, 12cm 6 for 10 of 150, p < .0001 for trend), and least with single distal (2 of 150, p < .0001). Paired tourniquets required fewer ratchet advances per tourniquet (pair distal 5 +/- 1, pair proximal 4 +/- 1, single distal 6 +/- 1, single proximal 6 +/- 1). Final ratchet tooth advancement pressure increases (mmHg) were greatest for singles (distal 61 +/- 10, proximal 0cm 53 +/- 7, 2cm 51 +/- 9, 4cm 50 +/- 7, 8cm 45 +/- 7, 12cm 36 +/- 7) and least in pairs (distal 41 +/- 8, proximal 32 +/- 7) with progressively less pair interaction as distance increased (pressure change for the pair tourniquet not directly advanced: 0cm 13 +/- 4, 2cm 10 +/- 4, 4cm 6 +/- 3, 8cm 1 +/- 2, 12cm -1 +/- 2). CONCLUSIONS: Occlusion pressures are lower for paired than single tourniquets despite variable intertourniquet distances. Very proximal placement has a pressure advantage; however, pairs and very proximal locations may be less likely to maintain occlusion. Increasingly proximal placements also increase tissue at risk; therefore, distal placements and minimal intertourniquet distances should still be recommended. PMID- 29256193 TI - Use of Physical Therapists to Identify and Treat Musculoskeletal Injuries at "The Tip of the Trident". AB - Musculoskeletal injuries continue to be the most common cause of decreased readiness and loss of productivity in all military environments. In commands with smaller footprints, such as Naval Special Warfare (NSW), every asset is critical for mission success. Studies have shown that early intervention by a medical provider can enhance healing and maintain unit readiness by preventing medical evacuations. Reports are limited with regard to Special Forces commands, especially during deployment. This article describes the injury characteristics and treatment of injuries seen by a physical therapist while deployed at forward operation commands embedded with NSW Group 2 Team 4. Over 4 months, 282 patients were evaluated and treated in southeast Afghanistan. In descending order, the three most common injured body regions were the lumbar/sacral spine (n = 82), shoulder (n = 59), and knee (n = 28). Therapy exercises (n = 461) were the most frequently performed treatment modality, followed by mobilization/manipulation (n = 394) and dry needling (n = 176). No patient evaluated was medically evacuated from the area or sent to an advanced medical site. Our data are similar to other published data reported on deployed units in terms of mechanisms and locations of injuries; thus, Special Forces commands do not appear to have unique injury patterns. These results support continued use of physical therapists in forward operations because of their ability to evaluate injuries and provide treatment modalities that help maintain the integrity of small commands at the site of injury. PMID- 29256194 TI - Staff Attitudes Regarding the Impact of a Therapy Dog Program on Military Behavioral Health Patients. AB - BACKGROUND: Human-animal interactions in the form of animal-assisted therapy (AAT) have become common in both civilian and military health care facilities. Evidence supports AAT as a beneficial therapeutic alternative for patients with physical disabilities and psychological disorders. Few studies have been conducted in the civilian health care setting to evaluate staff attitudes regarding the impact of an AAT program on behavioral health (BH) patients. To our knowledge, no research has examined staff attitudes on the impact and effectiveness of AAT on active-duty Servicemembers in a BH program at a military facility. METHODS: At the completion of a year-long AAT dog program and after institutional review board exemption, an anonymous, six-question survey was used to examine staff attitudes (n = 29) regarding the impact and continuation of the program with military BH patients. RESULTS: Most staff members (86%) believed the AAT dog program had a positive impact on the BH patients, including improved patient mood, greater patient relaxation, improved patient attitude toward therapy, and increased social interactions among patients. All the staff reported a desire to continue the program at the military facility. CONCLUSION: Most BH staff thought the year-long AAT dog program had a positive impact on patients. All staff supported continuation of the program. PMID- 29256195 TI - The SOF Truths for Army Special Operations Forces Surgical Teams. AB - The US Army Special Operations Command and Army Medical Command are at a critical junction in Army medical training. Army Special Operations Forces (ARSOF) will receive Forward Resuscitative Surgical Teams (FRSTs) in the near future and must establish a training model to enable successful support for ARSOF operations. The military has been directed by Congress through the 2017 National Defense Authorization Act to embed trauma combat casualty care teams in civilian trauma centers. ARSOF FRSTs should be embedded in the nation's leading civilian trauma centers to build and sustain true expertise in delivering trauma care on the battlefield. The SOF Truths provide valuable insights into the required conditions for success of this new training paradigm. PMID- 29256196 TI - Humanitarian Surgical Missions: Guidelines for Successful Anesthesia Support. AB - Many anesthesiologists and CRNAs are provided little training in preparing for a humanitarian surgical mission. Furthermore, there is very little published literature that outlines how to plan and prepare for anesthesia support of a humanitarian surgical mission. This article attempts to serve as an in-depth planning guide for anesthesia support of humanitarian surgical missions. Recommendations are provided on planning requirements that most anesthesiologists and CRNAs do not have to consider on routinely, such as key questions to be answered before agreeing to support a mission, ordering and shipping supplies and medications, travel and lodging arrangements, and coordinating translators in a host nation. Detailed considerations are included for all the phases of mission planning: advanced, mission-specific, final, mission-execution, and postmission follow-up planning, as well as a timeline in which to complete each phase. With the proper planning and execution, the anesthetic support of humanitarian surgical missions is a very manageable task that can result in an extremely satisfying sense of accomplishment and a rewarding experience. The authors suggest this article should be used as a reference document by any anesthesia professional tasked with planning and supporting a humanitarian surgical mission. PMID- 29256197 TI - Advise and Assist: A Basic Medical Skills Course for Partner Forces. AB - BACKGROUND: Training partner forces in battlefield first-responder medical skills is an important component of US military advise-and-assist operations. We designed and executed a training curriculum focused on high-yield-based medical skills to prevent death on the battlefield for non-English speaking members of the Turkish, Azerbaijani, and Albanian militaries deployed to Afghanistan. METHODS: We designed a 2-hour training curriculum focusing on four basic medical skills: (1) assessment of scene safety; (2) limb tourniquet application; (3) wound bandaging; and (4) patient transportation via litter. Our combat medics delivered standardized training using both didactic and practicum components. Instructors made beforeand- after assessments of the proficiency of each participant for each skill in accordance with the Dreyfus model of skill acquisition. We also administered before-and-after, Likertscale- based surveys for training participants to report their self-assessed comfort level with each of the four skills. RESULTS: We delivered training to 187 participants over five classes. All 28 participants in the final teaching class completed the study. Instructors categorized each participant's skill level as novice before training for all four skills. After the training curriculum, all participants achieved a skill level consistent with advanced beginner for all four skills. Participants reported significant improvements in self-reported comfort levels for all taught procedures (rho < .001 by Wilcoxon signed-rank test for all four skills). The largest reported increase in median comfort level was for tourniquet application: median pretraining comfort level, 4 (interquartile range [IQR], 0-6.25) versus 9.5 (IQR, 9-10) posttraining. CONCLUSION: Our curriculum resulted in significant improvements in instructor-assessed proficiency and self-reported comfort level for all four basic medical skills. Although our outcome measures have important limitations, this curriculum may be useful framework for future medics and physicians designing battlefield first-responder training curricula for members of foreign militaries. PMID- 29256198 TI - Experience With Prehospital Damage Control Capability in Modern Conflict: Results From Surgical Resuscitation Team Use. AB - BACKGROUND: Early resuscitation and damage control surgery (DCS) are critical components of modern combat casualty care. Early and effective DCS capabilities can be delivered in a variety of settings through the use of a mobile surgical resuscitation team (SRT). METHODS: Twelve years of after-action reports from SRTs were reviewed. Demographics, interventions, and outcomes were analyzed. RESULTS: Data from 190 casualties (185 human, five canine) were reviewed. Among human casualties, 12 had no signs of life at intercept and did not survive. Of the remaining 173 human casualties, 96.0% were male and 90.8% sustained penetrating injuries. Interventions by the SRT included intravascular access (50.9%) and advanced airway establishment (29.5%). Resuscitation included whole blood (3.5%), packed red blood cells (20.8%), and thawed plasma (11.0%). Surgery was provided for 63 of the 173 human casualties (36.4%), including damage control laparotomy (23.8%) and arterial injury shunting or repair (19.0%). SRTs were effectively used to augment an existing medical treatment facility (70.5%), to facilitate casualty transport (13.3%), as an independent surgical entity at a forward ground structure (9.2%), and in mobile response directly to the point of injury (6.9%). Overall survival was 97.1%. CONCLUSION: An SRT provides a unique DCS capability that can be successfully used in a variety of flexible roles. PMID- 29256199 TI - Diagnostic Accuracy of Emergency Bedside Ultrasonography to Detect Cutaneous Wooden Foreign Bodies: Does Size Matter? AB - BACKGROUND: Soft-tissue occult foreign bodies are a concerning cause of morbidity in the emergency department. The identification of wooden foreign bodies is a unique challenge because they are often not detectable by plain radiography. The purpose of this study was to determine the diagnostic accuracy of emergency physician-performed ultrasonography to detect wooden foreign bodies of varying sizes. We hypothesized that sonographic sensitivity would improve with increasing foreign body size. METHODS: We conducted a blinded, prospective evaluation using a previously validated, chicken, soft-tissue model to simulate human tissue. We inserted wooden toothpicks of varying lengths (1mm, 2.5mm, 5mm, 7.5mm, 10mm) to a depth of 1cm in five tissue models. Five additional models were left without a foreign body to serve as controls. Fifty emergency physicians with prior ultrasonography training performed sonographic examinations of all 10 models and reported on the presence or absence of wooden foreign bodies. RESULTS: Subjects performed 10 ultrasonography examinations each for a total of 500 examinations. For the detection of wooden foreign bodies, overall test characteristics for sonography included sensitivity 48.4% (95% confidence interval [CI], 42.1%-54.8%) and specificity 67.6% (95% CI, 61.3%- 73.2%). Sensitivity did not change as object size increased (rho = s.709). CONCLUSION: Emergency physician bedside ultrasonography demonstrated poor diagnostic accuracy for the detection of wooden foreign bodies. Accuracy did not improve with increasing object size up to 10mm. Providers should consider alternative diagnostic modalities if there is persistent clinical concern for a retained, radiolucent, soft-tissue foreign body. PMID- 29256200 TI - Expeditionary Resuscitation Surgical Team: The US Army's Initiative to Provide Damage Control Resuscitation and Surgery to Forces in Austere Settings. AB - Improvements in surgical care on the battlefield have contributed to reduced morbidity and mortality in wounded Servicemembers. 1 Point-of-injury care and early surgical intervention, along with improved personal protective equipment, have produced the lowest casualty statistics in modern warfare, resulting in improved force strength, morale, and social acceptance of conflict. It is undeniable that point-of-care injury, followed by early resuscitation and damage control surgery, saves lives on the battlefield. The US Army's Expeditionary Resuscitation Surgical Team (ERST) is a highly mobile, interprofessional medical team that can perform damage control resuscitation and surgery in austere locations. Its configuration and capabilities vary; however, in general, a typical surgical element can perform one major surgery and one minor surgery without resupply. The critical care element can provide prolonged holding in garrison, but this diminishes in the austere setting with complex and acutely injured patients. PMID- 29256201 TI - Efficacy of the Mnemonic Device "MARCH PAWS" as a Checklist for Pararescuemen During Tactical Field Care and Tactical Evacuation. AB - BACKGROUND: The application of Tactical Combat Casualty Care (TCCC) represents evidence-based medicine to improve survival in combat. Over the past several years, US Air Force Pararescuemen (PJs) have expanded the mnemonic device "MARCH" to "MARCH PAWS" for use during tactical field care and tactical evacuation (TACEVAC). The mnemonic stands for massive bleeding, airway, respiration, circulation, head and hypothermia, pain, antibiotics, wounds, and splinting. We undertook this performance improvement project to determine the efficacy of this device as a treatment checklist. METHODS: The mission reports of a 16-PJ combat rescue deployment to Operation Enduring Freedom (OEF) from January through June 2012 were reviewed. The triage category, mechanism of injury, injury, and treatments were noted. The treatments were then categorized to determine if they were included in MARCH PAWS. RESULTS: The recorded data for missions involving 465 patients show that 45%, 48%, and 7%, were in category A, B, and C, respectively (urgent, priority, routine); 55% were battle injuries (BIs) and 45% were nonbattle injuries (NBIs). All treatments for BI were accounted for in MARCH PAWS. Only 9 patients' treatments with NBI were not in MARCH PAWS. CONCLUSION: This simple mnemonic device is a reliable checklist for PJs, corpsmen, and medics to perform TACEVAC during combat Operations, as well as care for noncombat trauma patients. PMID- 29256202 TI - Clinical Update: The Risk of Opioid Toxicity and Naloxone Use in Operational K9s. AB - The increasing use of opioids (e.g., fentanyl, carfentanil) for illicit drug manufacturing poses a potential life-threatening hazard to law enforcement officers and first responders (e.g., EMS, fire and rescue) who may unknowingly come into contact with these drugs during the course of their daily activities. Similarly, Operational canines (OpK9s) of all disciplines-detection (drug, explosive, accelerant), patrol, tracking, search and rescue, and others-are at risk for accidental illicit opioid exposure. The most serious adverse effect of opioid exposure is respiratory depression leading to slow, shallow breathing or complete cessation of voluntary breathing (respiratory arrest). Naloxone, an opioid antagonist, is the antidote for reversing the effects of an opioid overdose in both humans and OpK9s. This clinical update describes the potential risks associated with opioid exposure as well as the use of naloxone as it pertains to the OpK9. PMID- 29256203 TI - Hand Injuries. PMID- 29256204 TI - Optimizing Musculoskeletal Performance Through Injury Prevention. AB - Musculoskeletal injuries (MSK-Is) are ubiquitous throughout the Special Operations Forces (SOF) because of the physical demands of executing missions and carrying heavy loads. Preventing MSK-I has been a priority among SOF but is especially challenging because most MSK-Is are chronic or recurring. For many SOF, musculoskeletal issues and MSK pain are just part of doing their job. Ways to focus, target, and integrate injury prevention efforts across the continuum of training, active duty and SOF status are critical because MSK-Is are a significant barrier to human performance optimization. In this article, we describe how to incorporate these efforts at all levels of training. The need for improving valid, objective, fit-for-full-duty metrics after injury and sharing such information continuously with SOF is discussed. Last, strategies for engaging all levels to begin a culture shift away from the acceptance of MSK-I and pain as a way of life toward embracing MSK-I prevention as a regular part of everyday training are presented. PMID- 29256205 TI - Shigellosis. PMID- 29256206 TI - Tools to Assess and Reduce Injury Risk (Part 2). AB - Research has shown that many injuries are preventable if the operational environment is understood. Useful tools are available to assist in assessing injury risks and in developing methods to reduce risks. This is part 2 of a two part article that discusses these tools, which include the Haddon Matrix, the 10 Countermeasure Strategies, the Injury Prevention Process, and the US Army Risk Management Process. Part 1 covered the Haddon Matrix and the 10 Countermeasure Strategies; part 2 outlines and provides examples of the Injury Prevention Process and the US Army Risk Management Process. The Injury Prevention Process is largely oriented to systematic research and involves (1) surveillance and survey to document the size of the injury problem, (2) identification of the causes of and risk factors for injuries, (3) intervention to identify what works to prevent injuries, (4) program implementation based on documented research, and (5) program evaluation to see how well the program works in the operational environment. The US Army Risk Management Process involves (1) identifying hazards, (2) assessing hazards, (3) developing controls for reducing hazards, (4) implementing controls, and (5) supervising and evaluating controls. There is overlap among the four approaches, but each has unique aspects that can be useful for thinking about and implementing injury prevention and control measures. PMID- 29256207 TI - Energy Balance and Diet Quality During the US Marine Corps Forces Special Operations Command Individual Training Course. AB - METHODS: This study characterized the total daily energy expenditure (TDEE), energy intake (EI), body weight, and diet quality (using the Healthy Eating Index 2010 [HEI]) of 20 male US Marines participating in the 9-month US Marine Corps Forces Special Operations Command Individual Training Course (ITC). RESULTS: TDEE was highest (rho < .05) during Raider Spirit (RS; 6,376 +/- 712kcal/d) compared with Survival, Evasion, Resistance, and Escape (SERE; 4,011 +/- 475kcal/d) School, Close-Quarters Battle (CQB; 4,189 +/- 476kcal/d), and Derna Bridge (DB; 3,754 +/- 314kcal/d). Body mass was lost (rho < .05) during SERE, RS, and DB because EI was less than TDEE (SERE, -3,665kcal/d +/- 475kcal/d; RS, -3,966 +/- 776kcal/d; and DB, -1,027 +/- 740kcal/d; p < .05). However, body mass was restored before the start of each subsequent phase and was not different between the start (86.4 +/- 9.8kg) and end of ITC (86.7 +/- 9.0kg). HEI score declined during ITC (before, 65.6 +/- 11.2 versus after, 60.9 +/- 9.7; p < .05) because less greens or beans and more empty calories were consumed (rho < .05). Dietary protein intake was lowest during RS (0.9 +/- 0.4g/kg) compared with all other phases, and carbohydrate intake during RS (3.6 +/- 1g/kg), CQB (3.6 +/- 1.0g/kg), and DB (3.7 +/- 1.0g/kg) was lower than during the academic phase of SERE (5.1 +/ 1.0g/kg; p < .05). CONCLUSION: These data suggest that ITC students, on average, adequately restore body mass between intermittent periods of negative energy balance. Education regarding the importance of maintaining healthy eating patterns while in garrison, consuming more carbohydrate and protein, and better matching EI with TDEE during strenuous training exercises may be warranted. PMID- 29256208 TI - Prolonged Field Care for the Winter 2017 Edition. PMID- 29256209 TI - Evaluation and Treatment of Ocular Injuries and Vision-Threatening Conditions in Prolonged Field Care. PMID- 29256210 TI - Pleuritic Chest Pain: This Can't Be Happening! PMID- 29256211 TI - Mastering the Basics Makes the Best Medics in the World: An Interview With Shawn Kane, SWMG (A) Commander and Dean of the JSOMTC. PMID- 29256212 TI - Use of a Tuning Fork for Fracture Evaluation: An Introduction for Education and Exposure. AB - Radiographs, bones scans, and even ultrasound may be rare in the austere or acute environment for the evaluation of suspected musculoskeletal fractures. Having an easy, simple, and confident means of objective evaluation used in conjunction with the patient presentation, history, and physical findings may provide a more efficient and economical means of treatment. This introduction and review of selected literature are meant to provide a fuller understanding and consideration for the methods of using a tuning fork in fracture assessment. PMID- 29256214 TI - TCCC Updates. PMID- 29256213 TI - "Evita Una Muerte, Esta en Tus Manos" Program: Bystander First Aid Training for Terrorist Attacks. AB - BACKGROUND: The latest terrorist attacks in Europe and in the rest of the world, and the military experience in the most recent conflicts leave us with several lessons learned. The most important is that the fate of the wounded rests in the hands of the one who applies the first dressing, because the victims usually die within the first 10 minutes, before professional care providers or police personnel arrive at the scene. A second lesson is that the primary cause of preventable death in these types of incidents involving explosives and firearms is massive hemorraghe. OBJECTIVE: There is a need to develop a training oriented to citizens so they can identify and use available resources to avoid preventable deaths that occur in this kind of incidents, especially massive hemorrhage. METHODS: A 7-hour training intervention program was developed and conducted between January and May 2017. Data were collected from participants' answers on a multiple-choice test before and after undertaking the training. Improved mean score for at least 75% of a group's members on the posttraining test was considered reflective of adequate knowledge. RESULTS: A total of 173 participants (n = 74 men [42.8%]; n = 99 women [57.2%]) attended the training. They were classified into three groups: a group of citizens/ first responders with no prior health training, a group of health professionals, and a group of nursing students. Significant differences (rho < .05) between mean pre- and post-training test scores occurred in each of the three groups. CONCLUSION: There was a clear improvement in the knowledge of the students after the training when pre- and post-training test scores were compared within the three groups. The greatest improvement was seen in the citizens/first responders group. PMID- 29256215 TI - Peripheral Eosinophilia and Clinico-radiological Characteristics among Health Screening Program Recipients. AB - BACKGROUND: Eosinophilia is well recognized in specific conditions. The objective of the present study was to determine clinico-radiologic characteristics of eosinophilia and changes in prevalence over 10 years in recipients of private health screening program at a tertiary hospital in Korea. METHODS: Data of private health screening program recipients at the health promotion center of Chung-Ang University Hospital from 2004 to 2013 were collected. Health-related questionnaires and laboratory findings of private health screening program with possible relation with eosinophilia were reviewed. Results of enzyme-linked immunosorbent assay (ELISA) for parasite, chest computed tomography, and pulmonary function test were also reviewed. RESULTS: The cumulative prevalence of eosinophilia was 4.0% (1,963 of 48,928). Prevalence of eosinophilia showed a decreased trend from 2004 to 2013. Most cases (96.6%) had mild degree of eosinophilia. Eosinophilic subjects were older and male-predominant. They showed lower levels of forced expiratory volume in 1 second (FEV1%), forced vital capacity (FVC%), and FEV1/FVC than those without eosinophilia. Eosinophilic subjects showed higher positive rate for common parasite in ELISA than those without eosinophilia. On radiologic findings, consolidation and ground glass opacities were positively associated with the degree of eosinophilia. When eosinophil was classified based on severity, statistically significant correlation between the severity of eosinophil and radiologic abnormalities was found. CONCLUSION: Eosinophilia is uncommon in healthy population. It usually occurs at a mild degree. Eosinophilic patients have more radiologic abnormalities compared to those without eosinophilia. Such radiologic abnormalities are associated with the severity of eosinophilia. PMID- 29256216 TI - Osteoporosis in Patients with Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome. AB - BACKGROUND: Osteoporosis is a common disease that occurs comorbidly in patients with chronic inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap syndrome (ACOS). However, the prevalence of osteoporosis in patients with ACOS has not widely been evaluated. Therefore, we investigated the prevalence of osteoporosis and its relationship with the clinical parameters of patients with asthma, COPD, and ACOS. METHODS: This was a retrospective, cross-sectional study. Bone mineral density (BMD), lung function tests, and disease status evaluations were conducted. RESULTS: A total of 321 patients were enrolled: 138 with asthma, 46 with ACOS, and 137 with COPD. One hundred and ninety-three patients (60.1%) were diagnosed with osteoporosis (53.6% of asthma, 65.2% of ACOS, and 65.0% of COPD). Patients with ACOS showed a significantly lower BMD and T-score than did those with asthma. In addition to age, sex, and body mass index (BMI), which were previously reported to be associated with BMD, BMD also had a negative correlation with the diagnosis of ACOS, as compared to a diagnosis of asthma, after adjusting for age, sex, BMI, smoking, and inhaled corticosteroid use (p=0.001). Among those patients with COPD and ACOS, BMD was negatively associated with the COPD Assessment Test (CAT) after adjustment (p<0.001). Inhaled corticosteroid was not associated with the prevalence of osteoporosis and BMD. CONCLUSION: Patients with ACOS, particularly aged and lean women, should be more carefully monitored for osteoporosis as compared to patients with asthma. PMID- 29256217 TI - Is Osteoporosis a Common Comorbidity in Different Chronic Airway Diseases? PMID- 29256218 TI - Comparison of Interferon-gamma Release Assays and the Tuberculin Skin Test for Diagnosis of Tuberculosis in Human Immunodeficiency Virus: A Systematic Review. AB - BACKGROUND: It remains uncertain if interferon-gamma release assays (IGRAs) are superior to the tuberculin skin test (TST) for the diagnosis of active tuberculosis (TB) or latent tuberculosis infection (LTBI) in immunosuppressed populations including people with human immunodeficiency virus (HIV) infection. The purpose of this study was to systematically review the performance of IGRAs and the TST in people with HIV with active TB or LTBI in low and high prevalence TB countries. METHODS: We searched the MEDLINE database from 1966 through to January 2017 for studies that compared results of the TST with either the commercial QuantiFERON-TB Gold in Tube (QFTGT) assay or previous assay versions, the T-SPOT.TB assay or in-house IGRAs. Data were summarized by TB prevalence. Tests for concordance and differences in proportions were undertaken as appropriate. The variation in study methodology was appraised. RESULTS: Thirty two studies including 4,856 HIV subjects met the search criteria. Fourteen studies compared the tests in subjects with LTBI in low TB prevalence settings. The QFTGT had a similar rate of reactivity to the TST, although the first generation version of that assay was reactive more commonly. IGRAs were more frequently positive than the TST in HIV infected subjects with active TB. There was considerable study methodology and population heterogeneity, and generally low concordance between tests. Both the TST and IGRAs were affected by CD4 T-cell immunodeficiency. CONCLUSION: Our review of comparative data does not provide robust evidence to support the assertion that the IGRAs are superior to the TST when used in HIV infected subjects to diagnose either active TB or LTBI. PMID- 29256219 TI - Detection of Deep Vein Thrombosis by Follow-up Indirect Computed Tomography Venography after Pulmonary Embolism. AB - BACKGROUND: Information regarding the incidence and risk factors for deep vein thrombosis (DVT) detected by follow-up computed tomographic (CT) venography after pulmonary embolism (PE) is sparse. The aim of the present study was to identify the predictors of DVT in follow-up CT images, and to elucidate their clinical significance. METHODS: Patients with PE were classified into the following three cohorts based on the time of indirect CT venography follow-up: within 1 month, 1 to 3 months, and 3 to 9 months after the initial CT scan. Each cohort was subdivided into patients with or without DVT detected by follow-up CT. Clinical variables were compared between the two groups. RESULTS: Follow-up CT revealed DVT in 61% of patients with PE within 1 month, in 15% of patients with PE at 1 to 3 months, and in 9% of patients with PE at 3 to 9 months after the initial CT scan. Right ventricular (RV) dilation on the initial CT (odds ratio [OR], 8.30; 95% confidence interval [CI], 1.89-36.40; p=0.005) and proximal DVT at the initial presentation (OR, 6.93; 95% CI, 1.90-25.20; p=0.003) were found to independently predict DVT in follow-up CT images within 1 month, proximal DVT at the initial presentation was found to independently predict DVT in follow-up CT images at 1 to 3 months (OR, 6.69; 95% CI, 1.53-29.23; p=0.012), and central PE was found to independently predict DVT in follow-up CT images at 3 to 9 months (OR, 4.25; 95% CI, 1.22-4.83; p=0.023) after the initial CT scan. Furthermore, the detection of DVT by follow-up CT independently predicted the recurrence of venous thromboembolism (VTE) (OR, 4.67; 95% CI, 2.24-9.74; p<0.001). CONCLUSION: Three months after PE, DVT was not detected by follow-up CT in most patients with PE. RV dilation on the initial CT, central PE, and proximal DVT at the initial presentation were found to predict DVT on follow-up CT, which might predict VTE recurrence. PMID- 29256220 TI - Add-on Therapy for Symptomatic Asthma despite Long-Acting Beta-Agonists/Inhaled Corticosteroid. AB - Asthma, remains symptomatic despite ongoing treatment with high doses of inhaled corticosteroids (ICS) in conjunction with long-acting beta-agonists (LABA), is classified as "severe" asthma. In the course of caring for those patients diagnosed with severe asthma, stepping up from ICS/LABA to more aggressive therapeutic measures would be justified, though several aspects have to be checked in advance (including inhaler technique, adherence to therapy, and possible associated comorbidities). That accomplished, it would be advisable to step up care in accordance with the Global Initiative for Asthma (GINA) recommendations. Possible strategies include the addition of a leukotriene receptor antagonist or tiotropium (to the treatment regimen). The latter has been shown to be effective in the management of several subgroups of asthma. Oral corticosteroids have commonly been used for the treatment of patients with severe asthma in the past; however, the use of oral corticosteroids is commonly associated with corticosteroid-related adverse events and comorbidities. Therefore, according to GINA 2017 these patients should be referred to experts who specialize in the treatment of severe asthma to check further therapeutic options including biologics before starting treatment with oral corticosteroids. PMID- 29256221 TI - [Effects of siRNAs targeting CD97 immune epitopes on biological behavior in breast cancer cell line MDA-MB231]. AB - OBJECTIVE: To investigate the effects of siRNAs targeting CD97 immune epitopes on proliferation, infiltration, apoptosis and cell cycle of breast cancer cells. METHODS: siRNA sequences targeting CD97EGF and CD97Stalk immune epitopes were designed according to Gene Bank NM_001025160.2 with smart siCatchTM siRNA design software. CD97siRNAs were transfected into MDA-MB231 cells in which CD97 was highly expressed. Highest sensitive CD97EGF and CD97Stalk siRNA were screened by Western blotting. Inverted microscope was used to observe the growth of CD97siRNAs-transfected MDA-MB231 cells; the proliferation activity of MDA-MB231 cells was detected by MTT method; the wound healing assay and Transwell migration test were performed to examine the migration and infiltration ability of CD97EGF and CD97Stalk siRNA-transfected MDA-MB231 cells; the effects of CD97EGF siRNA and CD97Stalk siRNA on cell apoptosis and cell cycle of MDA-MB231 cells were detected by TUNEL and flow cytometry. RESULTS: The growth and proliferation activity of CD97siRNAs-transfected MDA-MB231 cells were significantly lower than those in the control groups, and such differences were more significant in CD97Stalk siRNA transfected group (all P<0.05); scratch test showed that the wound healing rate was lower in CD97siRNAs-transfected groups, especially in CD97Stalk siRNA transfected group (all P<0.05); Transwell migration showed that the number of MDA MB231 cells crossing through chambers were less in CD97siRNAs-transfected groups, especially in CD97Stalk siRNA-transfected group (all P<0.05); no significant difference in cell apoptosis was observed between CD97siRNAs-transfected groups and control groups; cell cycle detection showed that CD97siRNAs-transfected groups had less cells in G0/G1 phase and more cells in S phase compared with the control groups, and such effect on cell cycle was more marked in CD97Stalk siRNA transfected group (all P<0.05). CONCLUSIONS: CD97 plays an important role in the cell growth, proliferation, migration and invasion of breast cancer MDA-MB231 cells, and compared with CD97EGF, CD97Stalk may have more effective inhibitory effects on cellular malignant behaviors. PMID- 29256222 TI - [Effect of microRNA-29b on proliferation and migration of breast cancer cells and its molecular mechanism]. AB - OBJECTIVE: To investigate the effects of microRNA(miRNA)-29b on the proliferation and migration of breast cancer cells and its molecular mechanism. METHODS: The recombinant lentiviral expression vector (lenti-miRNA-29b) was constructed and transfected into 293T cells to obtain lentivirus particles that were used to infect breast cancer MCF-7 cells. Transfection efficiency of lenti-miRNA-29b in MCF-7 cells was identified by the expression of green fluorescent protein (GFP). The expression of miRNA-29b was detected by real-time PCR. The cell proliferation and migration were detected by CCK8 assay and Transwell assay, respectively. The bioinformatics softwares were used to predict and screen the downstream target genes regulated by miRNA-29b, which were verified by double luciferase reporter gene assay, RT-PCR and Western blot. The effects of screened target gene RTKN on the growth and migration of MCF-7 cells were verified by RTKN siRNA. RESULTS: Recombinant lentiviral expression vector of miRNA-29b were successfully constructed. About 90% and 60% of the breast cancer cells showed green fluorescence in lenti-miRNA-29b and lenti-miRNA-NC groups, respectively. The expression of miRNA-29b in lenti-miRNA-29b group increased significantly compared with the lenti-miRNA-NC group and blank control group (all P<0.05); the proliferation and migration ability of MCF-7 cells significantly reduced compared with the control group (all P<0.05). The screening with bioinformatics softwares found that the 3'UTR coding region RTKN had the binding site to miRNA-29b; the dual luciferase reporter gene assay showed that the luciferase activity decreased significantly after the MCF-7 cells were co-transfected with wild type RTKN-WT 3'UTR and miRNA-29b mimics report gene vector (P<0.05). The RTKN proteins in MCF 7 cells were significantly decreased after transfection with siRNA-RTKN, and the proliferation and migration ability of MCF-7 cells were significantly reduced (all P<0.05). CONCLUSIONS: MiRNA-29b can inhibit the proliferation, invasion and metastasis of breast cancer cells by inhibiting the expression of RTKN. PMID- 29256223 TI - [CXC chemokine receptor 4 regulates breast cancer cell cycle through S phase kinase associated protein 2]. AB - OBJECTIVE: To investigate the effect of CXC chemokine receptor 4 (CXCR4) on cell cycle of breast cancer and its molecular mechanisms. METHODS: The expression of CXCR4 and S phase kinase associated protein 2 (Skp2) was detected by real-time fluorescence quantitative PCR (fqRT-PCR) and Western blot in breast cancer cells. The expression of signal proteins and the downstream genes of Skp2 was detected by Western blot. The effect of CXCR4, PI3K/Akt pathway inhibitor LY294002 and ERK pathway inhibitor U0126 on cell cycle of breast cancer was detected by propidium iodide staining. RESULTS: Skp2 was significantly down-regulated in CXCR4 downregulated cells and up-regulated in CXCR4-upregulated cells. CXCR4 also regulated the expression of Skp2 and other downstream genes by signaling protein. The proportion of cells in G0/G1 phase increased and that in S phase declined in CXCR4-downregulated cell, and the effect was more significant when combined with the use of LY294002 or U0126. CONCLUSIONS: CXCR4 can affect cell cycle and inhibit the proliferation of breast cancer cells by regulating Skp2 gene expression through PI3K/Akt and ERK signaling pathway. PMID- 29256224 TI - [Effects of lncRNA RP11-770J1.3 and TMEM25 expression on paclitaxel resistance in human breast cancer cells]. AB - OBJECTIVE: To investigate the effects of long non-coding RNA(lncRNA) RP11-770J1.3 and transmembrane protein 25 (TMEM25) on paclitaxel resistance in human breast cancer MCF-7/PR cell line. METHODS: The expression of lncRNA RP11-770J1.3 and TMEM25 in human breast cancer MCF-7(paclitaxel sensitive) and MCF-7/PR(paclitaxel resistant) cells were detected by quantitative RT-PCR. The synthetic interfering fragments of lncRNA RP11-770J1.3 and TMEM25 were transfected into MCF-7/PR cells. Sulforhodamine B assay was used to detect the sensitivity of MCF-7/PR cells to paclitaxel after interference of lncRNA RP11-770J1.3 and TMEM25. The expression of multidrug-resistance genes and proteins were detected by qRT-PCR and Western blot, respectively. RESULTS: lncRNA RP11-770J1.3 and TMEM25 were highly expressed in MCF-7/PR cells, and were significantly down-regulated after transfection of synthetic interfering fragments. Down-regulation of lncRNA RP11-770J1.3 and TMEM25 enhanced the sensitivity of MCF-7/PR cells to paclitaxel, and inhibited the expression of MRP, BCRP and MDR1/P-gp (all P<0.05). Such effects were more significant when lncRNA RP11-770J1.3 and TMEM25 were both down-regulated (all P<0.05). CONCLUSIONS: lncRNA RP11-770J1.3 and TMEM25 are highly expressed in MCF 7/PR cells, and the down-regulation of lncRNA RP11-770J1.3 and TMEM25 can enhance paclitaxel sensitivity in MCF-7/PR cells. PMID- 29256225 TI - [Relationship between dynamic CT angiography-based collateral flow evaluation and outcome of patients with stroke induced by acute basilar artery occlusion]. AB - OBJECTIVE: To evaluate the collateral flow in patients with ischemic stroke due to acute basilar artery occlusion by dynamic CT angiography and to predict the outcome after reperfusion therapy. METHODS: Forty-five patients with stroke due to acute basilar artery occlusion undergoing reperfusion treatment in the Second Affiliated Hospital of Zhejiang University School of Medicine during January 2012 and August 2016 were retrospectively reviewed. Univariate and binary logistic regression model were used to identify the independent predictors of patient's outcome, and the receiver operating characteristic (ROC) curve was used to determine the optimal threshold of the posterior circulation collateral score (PC CS) in predicting the prognosis of the patients. RESULTS: Binary logistic regression analysis indicated that the baseline National Institutes of Health Stroke Scale (NIHSS) score (OR=0.886, 95% CI:0.802-0.979, P<0.05) and PC-CS (OR=1.962, 95%CI:1.026-3.752, P<0.05) were independent predictors of patient's outcome, and PC-CS 4.5 was the optimal threshold (AUC:0.837, sensitivity of 68.2%, specificity of 87.0%). CONCLUSIONS: Dynamic CT angiography based on CT perfusion imaging can be used to evaluate collaterals in posterior circulation, and to predict clinical outcome after reperfusion therapy in patients with acute basilar artery occlusion. PMID- 29256226 TI - [Collateral score based on CT perfusion can predict the prognosis of patients with anterior circulation ischemic stroke after thrombectomy]. AB - OBJECTIVE: To evaluate the value of collateral score based on CT perfusion (CTP CS) in predicting the clinical outcome of patients with anterior circulation ischemic stroke after thrombectomy. METHODS: Clinical data of acute ischemic stroke patients with anterior artery occlusion undergoing endovascular treatment in the Second Affiliated Hospital, Zhejiang University School of Medicine during October 2013 and October 2016 were retrospectively reviewed. Collateral scores were assessed based on CTP and digital subtraction angiography (DSA) images, respectively. And DSA-CS or CTP-CS 3-4 was defined as good collateral vessels. Good clinical outcome was defined as a modified Rankin Scale (mRS) <= 2 at 3 months after stroke. The binary logistic regression model was used to analyze the correlation between the collateral score and clinical outcome, and the receiver operating characteristic (ROC) curve was used to analyze the value of DSA-CS and CTP-CS in predicting the clinical outcome. RESULTS: Among 40 patients, 33 (82.5%) acquired recanalization and 16 (40.0%) got good outcome. Compared with poor outcome group, the collateral score (all P<0.05) and the rate of good collateral vessels were higher in good outcome group (all P<0.01). After adjust baseline National Institute of Health Stroke Scale (NIHSS) and onset to recanalization time (ORT), good collateral vessels were independent factor of good outcome (CTP CS:OR=48.404, 95% CI:1.373-1706.585, P<0.05; DSA-CS:OR=34.651, 95% CI:1.147 1047.018, P<0.05). Collateral scores based on CTP and DSA had good consistency (kappa=0.697, P<0.01), and ROC curve showed that the predictive value of CTP-CS and DSA-CS were comparable (both AUC=0.726, 95%CI:0.559-0.893, P<0.05). CONCLUSIONS: CTP-CS can predict the clinical outcome of patients with anterior circulation ischemic stroke after thrombectomy. PMID- 29256227 TI - [Maximal infarct volume to benefit from intravenous thrombolysis and its relation with onset to treatment time]. AB - OBJECTIVE: To investigate the relationship between maximal infarct volume to benefit from intravenous thrombolysis (IVT) and onset to needle time (ONT). METHODS: The clinical and image data of acute ischemic stroke patients who received IVT in the second Affiliated Hospital, Zhejiang University School of Medicine during May 2009 to June 2016 were retrospectively reviewed. Patients were classified into within-time-window group (ONT <= 4.5 h) and beyond-time window group (ONT>4.5 h). Good and poor outcome were defined as modified Rankin scale (mRS) <= 2 or >2 at 3 months, respectively. The maximal infarct volume was analyzed by receiver operating characteristic (ROC) curve. RESULTS: Among 587 patients (465 cases were within-time-window, 122 cases were beyond-time-window), baseline core volume was 15(2-46)mL,and 324 (55.2%) patients achieved good outcome. Compared with the good-outcome group, the baseline core volume was larger in the poor-outcome group (32 mL vs 5 mL,Z=-9.766,P<0.01). After adjusting age, ONT, baseline National Institutes of Health Stroke Scale (NIHSS) and atrial fibrillation, baseline infarct core volume independently predicted poor outcome (OR=1.014, 95% CI:1.008-1.020, P<0.01). The ROC curve analysis showed that the maximal infarct core volume for achieving good outcome in the within-time-window group and beyond-time-window group were 152 mL and 71mL, respectively. The maximal infarct volume to benefit from IVT diminished with the increasing delayed ONT of every 30 min (rho=-0.691, P<0.05). CONCLUSIONS: The maximal infarct volume to benefit from thrombolysis is larger in patients treated within time window than those beyond the time window, and that volume diminishes with ONT delay. PMID- 29256228 TI - [Association of serum folate level with severity of white matter hyperintensity and presence of cerebral microbleeds]. AB - OBJECTIVE: To investigate the association of serum folate level with the severity of white matter hyperintensity (WMH) and presence of cerebral microbleeds (CMB). METHODS: Clinical data of WMH patients from the second affiliated Hospital, Zhejiang University school of Medicine during July 2011 and February 2016 were retrospectively reviewed. According to Fazekas score based on T2-Flair images, patients were classified into mild WMH (0-3) and severe WMH (4-6). The presence of CMB was assessed on susceptibility weighted imaging (SWI). Binary logistic analysis was conducted to identify the independent predictors for severe WMH and the presence of CMB. RESULTS: Two hundred and twenty eight patients with WMH were included, among whom 149(65.35%)had severe WMH. In patients with high folate (>= 15.68 nmol/L), low folate (6.8-15.67 nmol/L) and folate deficiency (<6.8 nmol/L), the proportions of severe WMH were 52.88%, 73.33% and 89.47%, respectively. Binary logistic regression analysis revealed that compared with high folate group, severe WMH was more common in groups with low folate (OR=2.109, 95% CI:1.112-4.001,P<0.05) and folate deficiency (OR=6.383, 95% CI:1.168-34.866, P<0.05). Eighty-eight(48.09%) of 183 patients receiving SWI scan presented with CMB. Although the subjects with CMB had lower serum folate level than those without CMB(13.42 vs 16.51 nmol/L, P<0.01), binary logistic regression analysis did not reveal the independent association between serum folate level and the presence of CMB after adjusting for hyperhomocysteinemia (P>0.05). CONCLUSIONS: Lower serum folate level is independently associated with severe WMH, but not with the CMB concurrence. PMID- 29256229 TI - [Safety of tirofiban in patients with acute cerebral infarct receiving endovascular therapy]. AB - OBJECTIVE: To investigate the effect of tirofiban on hemorrhagic transformation and neurological outcome in patients with acute cerebral infarct treated with endovascular therapy. METHODS: One hundred and fifteen patients with acute cerebral infarct who received endovascular stent mechanical thrombectomy in the Second Affiliated Hospital, Zhejiang University School of Medicine during October 2013 and April 2017 were included in the study. Among 115 patients, 30 received tirofiban treatment. Hemorrhagic transformation and neurological outcomes were assessed using the ECASS II criteria and modified Rankin scale (mRS), respectively. Unfavorable outcome was defined as mRS>2. Binary logistic regression model was used to analyze the independent predictors of hemorrhagic transformation and neurological outcome. RESULTS: Binary logistic regression analysis showed that tirofiban treatment did not increase the risk of hemorrhagic transformation (OR=0.437, 95% CI:0.168-1.132, P>0.05); baseline NIHSS (OR=1.136, 95% CI:1.014-1.273, P<0.05), recanalization (OR=0.060, 95% CI:0.010-0.365, P<0.01), hypertension (OR=4.233, 95% CI:1.320-13.570, P<0.05) and onset to treatment time(OR=1.006, 95% CI:1.001-1.011, P<0.05) were independently associated with unfavorable outcome, while such association was not observed in tirofiban treatment (OR=1.923, 95% CI:0.536-6.568, P>0.05). CONCLUSIONS: Tirofiban appears to be safe for patients with acute cerebral infarct receiving endovascular therapy. PMID- 29256230 TI - [Inhibiting mammalian target of rapamycin signaling pathway improves cognitive function in mice with chronic cerebral ischemia]. AB - OBJECTIVE: To investigate the effect of mammalian target of rapamycin(mTOR) inhibitor-rapamycin on cognitive function after chronic cerebral ischemia in mice and its molecular mechanism. METHODS: The chronic cerebral ischemia model was induced by ligation of right common carotid artery (rUCCAO) in 6-week-old ICR mice. The expressions of mTOR, S6K, S6 and corresponding phosphorylated proteins were detected by Western blotting at different time interval (1 h, 3 h, 6 h, 24 h, 3 d, 7 d, 2 w, 4 w, 6 w) after rUCCAO to determine the changes of mTOR signaling pathway. Rapamycin was administrated i.p. at the dose of 3.0 mg/kg 24 h after rUCCAO. Fluoro Jade B staining was used to detect the apoptotic cells. The expressions of Beclin and LC3-II were detected by Western blotting to determine the status of autophagy. Morris water maze test and Y maze test were performed to evaluate cognitive functions. RESULTS: The mTOR signaling pathway was abnormally activated from 6 h to 6 w after rUCCAO in mouse cortex. The activation of mTOR signaling pathway induced by rUCCAO was reversed by administration of rapamycin, and the apoptotic cell number was significantly decreased (146.1+/-16.3 vs 84.5+/ 9.6, P<0.05). Meanwhile, the elevation of Beclin and LC3-II protein induced by rUCCAO was reversed by rapamycin administration. Furthermore, compared with vehicle-treated mice, the latent period[(11.1+/-2.3) s vs (8.1+/-1.8) s, P<0.05] and swimming distance[(672.8+/-128.5) cm vs (558.2+/-124.9) cm, P<0.05] were significantly decreased and the number of crossing the platform quadrant in Morris water maze increased(2.8+/-0.9 vs 5.2+/-0.8, P<0.05) in rapamycin-treated mice. Correct response rate in the Y maze was also increased significantly in rapamycin-treated mice[(38.5+/-9.2)% vs (64.9+/-7.9)%, P<0.05]. CONCLUSIONS: Inhibiting mTOR pathway by rapamycin reverses the rUCCAO-induced cognitive impairment partly through the suppression of apoptosis and autophagy. PMID- 29256231 TI - [Drug resistance and protoporphyrin ferrochelatase of Ralstonia mannitolilytica]. AB - OBJECTIVE: To investigate the drug resistance, beta-lactamase-encoding genes and protoporphyrin ferrochelatase-encoding genes of Ralstonia mannitolilytica, and to explore its structure and pathogenic function. METHODS: The strain was isolated by plate streaking method and identified by automatic bacteria detection system and 16S RNA gene PCR. Microdilution method was applied for drug susceptibility test. beta-lactamases, extended spectrum beta-lactamases (ESBL) and carbapenemases were detected using nitrocefin-disk, Kirby-Bauer disk, and Hodge test, respectively. Five beta-lactamase-encoding genes and protoporphyrin ferrochelatase-encoding gene of the isolate were amplified by PCR for sequencing. Bioinformatic softwares were used to analyze the structure and function of the product of protoporphyrin ferrochelatase-encoding gene. RESULTS: A strain belonging to Ralstonia mannitolilytica was isolated. This isolate was sensitive to cefepime, ciprofloxacin, ofloxacin and tigecycline, but resistant to five penicillins, four cephalosporins and two carbapenems antibiotics. The isolate produced beta-lactamases but did not produce ESBL and carbapenemases. The isolate had five distinct beta-lactamase-encoding genes and protoporphyrin ferrochelatase encoding gene. The product of protoporphyrin ferrochelatase-encoding gene contained two functional domains of protoporphyrin ferrochelatase belonging to type II chelatase superfamily that presented the most closely genetic relationship with the protoporphyrin ferrochelatase of Neisseria meningidis. CONCLUSIONS: The isolate of Ralstonia mannitolilytica has a higher resistance to beta-lactam antibiotics and its beta-lactamase-encoding genes are different with the common bacterial beta-lactamase-encoding genes. Protoporphyrin ferrochelatase may act as an important virulence factor of Ralstonia mannitolilytica. PMID- 29256232 TI - [Efficacy and safety of humanized interleukin-6 receptor antibody in treatment of systemic juvenile idiopathic arthritis]. AB - OBJECTIVE: To evaluate the efficacy and safety of humanized anti-IL-6 receptor monoclonal antibody (tocilizumab) in treatment of systemic juvenile idiopathic arthritis (sJIA). METHODS: Thirteen sJIA patients admitted between December 2015 and November 2016 and received tocilizumab treatment were enrolled in the study. The complete blood count (CBC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), interleukin-6 (IL-6) and ferritin levels were measured; American College of Rheumatology Pediatric(ACR Pedi)30/50/70/90 scores were assessed; and the use of glucocorticosteroid and adverse events were documented. RESULTS: Compared with the baseline levels, the CRP and ESR at d3 were decreased (all P<0.05); hemoglobin was increased and platelet was decreased at week 2 (all P<0.05), ferritin decreased at week 4, white blood cell (WBC) decreased at week 8 after treatment with tocilizumab (all P<0.05). The level of IL-6 was rising at d3 and week 2 and descending at week 4, but no significant difference was observed compared with the baseline level (all P>0.05). All 13 patients achieved ACR Pedi 30 remission at week 4, 61.5% achieved ACR Pedi 90 remission and glucocorticosteroids were withdrawn at week 20. Twenty two adverse events occurred, and infection accounted for 54.5% (12/22); no severe adverse reactions were observed during 20-week follow-up. CONCLUSIONS: Tocilizumab is safe and effective in treatment of sJIA, with decreasing inflammation, improving disease activity and reducing glucocorticosteroid use. PMID- 29256233 TI - [Construction of all-in-one CRISPR/Cas9 vector system targeting miR-101a gene in mouse hepatic cell line AML12]. AB - OBJECTIVE: To develop an all-in-one CRISPR/Cas9 vector system that can efficiently knockdown miR-101a expression in mice. METHODS: Three sgRNAs targeting mouse miR-101a gene and a small guide (sgRNA) targeting green fluorescent protein gene were designed and constructed into an all-in-one vector system (pENTRY-U6-sgRNA-WT Cas9). Moreover, sgRNA1 and sgRNA3 were selected and constructed into a double-nicking Cas9 vector (pENTRY-U6-sgRNA-U6-sgRNA-Cas9 D10A). The constructed plasmids were transfected into mouse liver AML12 cells for validation by T7 EndoI(T7EI) 72 h after transfection. The pAD vectors were cloned via the Gateway system, and the recombinant adenovirus vectors were packaged in 293A cells. The virus particles were used to infect AML12 cells and the expression levels of mature miR-101a were analyzed to monitor the knockout efficiency after 72 h. RESULTS: The constructed pENTRY all-in-one vectors were validated by gene sequencing and T7EI assay, which showed CRISPR/Cas9-mediated mismatches at target sites of miR-101a gene. The adenovirus vectors were constructed successfully. The CRISPR/Cas9 containing adenovirus was introduced to AML12 cells and the quantitative real-time PCR assays indicated that the expression level of mature miR-101a was significantly decreased compared with that of the control (all P<0.01). CONCLUSIONS: We have successfully constructed two "all-in-one" CRISPR/Cas9 vector systems targeting miR-101a gene in mouse liver AML12 cells with high efficiency. It provides experimental basis for research of microRNA, and a reference method for knockout of other miRNAs. PMID- 29256234 TI - [Effects of low salt diet on gene expression in dog's heart]. AB - OBJECTIVE: To investigate the effect of low-salt diet on gene expression of canine cardiac tissue. METHODS: Microarray data (GSE17149) of heart tissue from dogs fed with low-salt diet was obtained from the Gene Expression Omnibus (GEO). The data were analyzed by Qlucore Omics Explorer 3.1, STRING 10.0, Genclip 2.0 and GCBI. The protein-protein interactions (PPI) of the differentially expressed genes in low-salt and control groups were conducted to screen the key node genes between the two groups. RESULTS: Compared with the control group, the gene expression profile of the dog heart tissue was changed in the low-salt diet group, and 1343 (3.12%) differentially expressed genes were found in 43 035 genes. The differentially expressed gene protein interaction analysis revealed a most obvious protein (NFKBIA) as the core, which might be related to inhibiting the differentiation of macrophage-derived foam cell and promoting cholesterol discharge and decomposition. CONCLUSIONS: Gene expression of heart tissue in dogs fed with low-salt diet is significantly changed and low-salt diet may reduce the risk of cardiovascular disease by up-regulating the expression of NFKBIA. PMID- 29256235 TI - [Volume of 4% neutral buffered formaldehyde affects the results of HER2 gene detected by fluorescence in situ hybridization in primary invasive breast cancer]. AB - OBJECTIVE: To investigate the effects of the volume of 4% neutral phosphate buffered formalin fixative solution on the detection of human epidermal growth factor receptor 2 (HER2) gene by fluorescence in situ hybridization (FISH) in primary invasive breast cancer. METHODS: Tissue samples were collected from 109 patients with primary invasive breast cancer admitted in Zhongshan Boai Hospital from June 2014 to October 2016. The ratios of 4% phosphate buffered formalin fixative solution to sample volume samples were 3:1, 6:1, 9:1, 10:1, 15:1, 20:1 or 25:1 (groups A, B, C, D, E, F and G), respectively. Paraffin sections were made after 15 h of fixation. The amplification of HER2 gene was detected by FISH. The gene amplification results of HER2 were observed and compared in different groups. RESULTS: Fluorescence microscope showed that the tissue contour in groups A, B and C was vague, cell debris appeared, and the probe was positioned poorly; while the tissue contour was clear and complete in groups D, E, F and G and the probe was positioned accurately. The positive rate of HER2 was gradually increased from group A to D(chi2=8.601, P<0.01), and that remained stable at 24.77% in groups D to G. The positive rate of gene amplification in groups D, E, F and G was significantly higher than that in groups A, B and C (all P<0.05). CONCLUSIONS: When using FISH to detect HER2 gene in samples of primary breast invasive carcinoma, the volume of fixative solution should be at least 10 times of the sample volume to obtain accurate and stable results. PMID- 29256236 TI - [Hypoglossal canal dural arteriovenous fistulas treated with transvenous embolization:report of two cases and literature review]. AB - Two cases of hypoglossal canal dural arteriovenous fistulas (HCDAVF) were reported. The clinical manifestation, radiological features, treatment and prognosis were reviewed. Both cases presented chemosis and pulsatile tinnitus. 3D time-of-flight (TOF) magnetic resonance angiography (MRA) demonstrated abnormal high signal in hypoglossal canal. Cerebral digital subtraction angiography (DSA) showed that these HCDAVFs were supplied by multiple intracranial and extracranial arteries, and fistulas were located in hypoglossal canal. Fistulas were blocked by coils and Onyx-18 through transvenous approach, and the angiography after the embolism showed complete occlusion of fistula. No adverse events after treatment and no recurrence during the follow up were observed. PMID- 29256237 TI - [Progress on the study of NLRP3 inflammasome in autoinflammatory diseases of children]. AB - Autoinflammatory diseases (AID) in childhood is one of refractory diseases, whose pathogenesis is not completely clear. In recent years, a large number of studies have shown that NLRP3 inflammasome plays an important role in the development of AIDs in children. Inflammasome is a cytosolic multiprotein complex that can activate cysteinyl aspartate-specific protease-1 (caspase-1), to further promote the maturation and secretion of proinflammatory cytokines IL-1beta and IL-18 as well as pyroptosis and regulate innate immune response. IL-1 receptor antagonist (Anakinra) and IL-1beta monoclonal antibody (Canakinumab) have good therapeutic effects in children with AIDs. This article reviews the research progress of NLRP3 inflammasome in the pathogenesis of autoinflammatory diseases. PMID- 29256238 TI - Ametropia, retinal anatomy, and OCT abnormality patterns in glaucoma. 2. Impacts of optic nerve head parameters. AB - Clinicians use retinal nerve fiber layer thickness (RNFLT) measured by optical coherence tomography (OCT) as an adjunct to glaucoma diagnosis. Ametropia is accompanied by changes to the optic nerve head (ONH), which may affect how OCT machines mark RNFLT measurements as abnormal. These changes in abnormality patterns may bias glaucoma diagnosis. Here, we investigate the relationship between OCT abnormality patterns and the following ONH-related and ametropia associated parameters on 421 eyes of glaucoma patients: optic disc tilt and torsion, central retinal vessel trunk location (CRVTL), and nasal and temporal retinal curvature adjacent to ONH, quantified as nasal/temporal slopes of the inner limiting membrane. We applied multivariate logistic regression with abnormality marks as regressands to 40,401 locations of the peripapillary region and generated spatial maps of locations of false positive/negative abnormality marks independent of glaucoma severity. Effects of torsion and temporal slope were negligible. The effect of tilt could be explained by covariation with ametropia. For CRVTL/nasal slope, abnormality pattern shifts at 7.2%/23.5% of the peripapillary region were detected, respectively, independent of glaucoma severity and ametropia. Therefore, CRVTL and nasal curvature should be included in OCT RNFLT norms. Our spatial location maps may aid clinicians to improve diagnostic accuracy. PMID- 29256239 TI - Special Section Guest Editorial: Commemorating 25 Years of Optical Coherence Tomography: a Perspective on Biomedical Applications. AB - This guest editorial introduces the Special Section on 25 Years of OCT. PMID- 29256240 TI - Tungsten Oxide Photonic Crystals as Optical Transducer for Gas Sensing. AB - Some metal oxide semiconductors, such as tungsten trioxide or tin dioxide, are well-known as resistive transducers for gas sensing and offer high sensitivities down to the part per billion level. Electrical signal read-out, however, limits the information obtained on the electronic properties of metal oxides to a certain frequency range and its application because of the required electrical contacts. Therefore, a novel approach for building an optical transducer for gas reactions utilizing metal oxide photonic crystals is presented here. By the rational design of the structure and composition it is possible to synthesize a functional material which allows one to obtain insight into its electronic properties in the optical frequency range with simple experimental measures. The concept is demonstrated by tungsten trioxide inverse opal structure as optical transducer material for hydrogen sensing. The sensing behavior is analyzed in a temperature range from room temperature to 500 degrees C and in a wide hydrogen concentration range (3000 ppm to 10%). The sensing mechanism is mainly the refractive index change resulting from hydrogen intercalation in tungsten trioxide, but the back reaction has also impact on the optical properties of this system. Detailed chemical reaction studies provide suggestions for specific sensing conditions. PMID- 29256241 TI - Molecular Simulation Insights on Xe/Kr Separation in a Set of Nanoporous Crystalline Membranes. AB - Separation of xenon and krypton is highly relevant to several applications such as spent nuclear fuel processing. Molecular simulation has been extensively used to understand the Kr/Xe separation performance of nanoporous materials for adsorption-based technologies but less frequently for membrane-based technologies. Motivated by recent experimental reports on krypton-selective membranes, herein, we present grand canonical Monte Carlo and biased molecular dynamics simulations (using adaptive biasing force) to elucidate the nature of adsorption- and diffusion-based Kr/Xe separation mechanisms in a set of nanoporous materials: SAPO-34, ZIF-8, UiO-66, and IRMOF-1. Xenon is found to preferentially adsorb on all materials, but diffusion selectivity for krypton is found to dominate the overall membrane separation selectivity. To increase adsorption selectivity for krypton, large pore cages are found to be desirable. To increase diffusion selectivity for krypton, stiff pore windows with a diameter smaller than xenon (but larger than krypton) are found to be desirable. No perfect molecular sieving was found, but the relatively rigid SAPO-34 was more effective at excluding xenon than the more flexible ZIF-8. Indeed, during xenon "window crossing," the SAPO-34 window opened to only 3.8 A, while the ZIF-8 window opened to 4.1 A, resulting in a lower free energy "diffusion" barrier for xenon in ZIF-8. Therefore, an ideal membrane material for Kr/Xe separation should be rigid and have large pore cages and small pore windows. Temperature was found to have opposite effects on adsorption and diffusion selectivity, but because of the dominance of diffusion selectivity, our simulations indicate that it is preferable to operate membranes for Kr/Xe separation at lower temperatures than at higher ones. PMID- 29256242 TI - Iron and Copper Active Sites in Zeolites and Their Correlation to Metalloenzymes. AB - Metal-exchanged zeolites are a class of heterogeneous catalysts that perform important functions ranging from selective hydrocarbon oxidation to remediation of NO x pollutants. Among these, copper and iron zeolites are remarkably reactive, hydroxylating methane and benzene selectively at low temperature to form methanol and phenol, respectively. In these systems, reactivity occurs at well-defined molecular transition metal active sites, and in this review we discuss recent advances in the spectroscopic characterization of these active sites and their reactive intermediates. Site-selective spectroscopy continues to play a key role, making it possible to focus on active sites that exist within a distribution of inactive spectator metal centers. The definition of the geometric and electronic structures of metallozeolites has advanced to the level of bioinorganic chemistry, enabling direct comparison of metallozeolite active sites to functionally analogous Fe and Cu sites in biology. We identify significant parallels and differences in the strategies used by each to achieve high reactivity, highlighting potentially interesting mechanisms to tune the performance of synthetic catalysts. PMID- 29256244 TI - Study of Oscillating Electroosmotic Flows with High Temporal and Spatial Resolution. AB - Near-wall velocity of oscillating electroosmotic flow (OEOF) driven by an AC electric field has been investigated using a laser-induced fluorescence photobleaching anemometer (LIFPA). For the first time, an up to 3 kHz velocity response of OEOF has been successfully measured experimentally, even though the oscillating velocity is as low as 600 nm/s. It is found that the oscillating velocity decays with the forcing frequency ff as ff-0.66. In the investigated range of electric field intensity (EA), below 1 kHz, the linear relation between oscillating velocity and EA is also observed. Because the oscillating velocity at high frequency is very small, the contribution of noise to velocity measurement is significant, and it is discussed in this manuscript. The investigation reveals the instantaneous response of OEOF to the temporal change of electric fields, which exists in almost all AC electrokinetic flows. Furthermore, the experimental observations are important for designing OEOF-based micro/nanofluidics systems. PMID- 29256243 TI - Single-Cell RT-PCR in Microfluidic Droplets with Integrated Chemical Lysis. AB - Droplet microfluidics can identify and sort cells using digital reverse transcription polymerase chain reaction (RT-PCR) signals from individual cells. However, current methods require multiple microfabricated devices for enzymatic cell lysis and PCR reagent addition, making the process complex and prone to failure. Here, we describe a new approach that integrates all components into a single device. The method enables controlled exposure of isolated single cells to a high pH buffer, which lyses cells and inactivates reaction inhibitors but can be instantly neutralized with RT-PCR buffer. Using our chemical lysis approach, we distinguish individual cells' gene expression with data quality equivalent to more complex two-step workflows. Our system accepts cells and produces droplets ready for amplification, making single-cell droplet RT-PCR faster and more reliable. PMID- 29256245 TI - Optical Field Enhancement in Au Nanoparticle-Decorated Nanorod Arrays Prepared by Femtosecond Laser and Their Tunable Surface-Enhanced Raman Scattering Applications. AB - Various Au nanostructures have been demonstrated to have an enhanced local electric field around them because of surface plasmons. Herein, we propose a novel method for fabricating Au nanoparticle-decorated nanorod (NPDN) arrays through femtosecond laser irradiation combined with Au coating and annealing. The nanorod cavities strongly confined light and produced an enhanced optical field in response to Au nanoparticles (NPs) introduction. The nanogap and diameter of the fabricated Au NPs significantly affected the surface-enhanced Raman scattering (SERS) performance and could be simultaneously tuned with thickness controllable Au films and substrate morphologies. The resulting Au NPDN substrate was observed to have efficient "hot spots" for tunable SERS applications. We experimentally determined that the enhancement factor of the Au NPDN substrate reached up to 8.3 * 107 at optimal parameters. Moreover, the Au NPDN substrate showed superior chemical stability, with the greatest intensity deviation of 3.2% on exposure to air for 2 months. This work provides a promising method to fabricate tunable plasmonic surfaces for highly sensitive, reproducible, and chemically stable SERS applications. PMID- 29256247 TI - Improved Separation of Pa from Th and U in Marine Sediments with TK400 Resin. AB - Protactinium-231 is a radionuclide of broad interest in paleoceanography and paleoclimatology. This study describes an improved method for the purification and separation of Pa from marine sediment samples using the new TK400 resin by TrisKem International. The focus lies on the improvement of the separation of the abundant 232Th from the Pa fraction of the sample, which would reduce the peak tailing from 232Th on masses 231 and 233 during ICP-MS measurement. Furthermore, the reusability of TK400 has been tested. For this purpose, the conventional method using Dowex AG1X8 for the separation and purification of Pa has been compared to methods using the TK400 resin. A combination of a Dowex AG1X8 prior to a TK400 column has shown most convincing results. Based on our results we suggest a new efficient procedural method of analyzing 231Pa from marine sediment samples using TK400. Chemical Pa yields for a Dowex-TK400 combination are highest compared to the Dowex only method. Furthermore, the 232Th/231Pa ratio of the Pa fractions has been reduced by 1 order of magnitude compared to conventional methods with Dowex AG1X8. Additionally, the reusability of TK400 resin up to nine times has been proven. The usage of TK400 is only limited in the presence of samples with a high matrix load (e.g., Fe). Therefore, matrix from sediment samples needs to be removed (here using Dowex resin) before samples are loaded onto TK400. We also report a series of concentration measurements from standard reference materials (UREM-11, NIST 2702), which have been used for 233Pa calibration. PMID- 29256246 TI - Identification of Aging-Associated Food Quality Changes in Citrus Products Using Untargeted Chemical Profiling. AB - Chemometric techniques have seen wide application in biological and medical sciences, but they are still developing in the food sciences. This study illustrated the use of untargeted LC/MS chemometric methods to identify features (retention time_m/z) associated with food quality changes as products age (freshness). Extracts of three citrus fruit varietals aged over four time points that corresponded to noted changes in sensory attributes were chemically profiled and modeled by two discriminatory multivariate statistical techniques, projection partial least-squares discrimant analysis (PLS-DA) and machine learning random forest (RF). Age-associated compounds across the citrus platform were identified. Varietal was treated as a nuisance variable to emphasize aging chemistry, and further variable selection using age-related piecewise model generation and meta filtering to emphasize features associated with general aging chemistry common to all the citrus extracts. The identified features were further replicated in a validation study to illustrate the validity and persistence of these markers for applications in citrus food platforms. PMID- 29256248 TI - Regioselective Halogenation of Arenes and Heterocycles in Hexafluoroisopropanol. AB - Regioselective halogenation of arenes and heterocycles with N-halosuccinimides in fluorinated alcohols is disclosed. Under mild condition reactions, a wide diversity of halogenated arenes are obtained in good yields with high regioselectivity. Additionally, the versatility of the method is demonstrated by the development of one-pot sequential halogenation and halogenation-Suzuki cross coupling reactions. PMID- 29256250 TI - Polarization-Dependent Optoelectronic Performances in Hybrid Halide Perovskite MAPbX3 (X = Br, Cl) Single-Crystal Photodetectors. AB - Hybrid organic-inorganic lead halide perovskites (HOIPs) have received significant attention because of their impressive performances in the fields of solar cells and photoelectric detection. In the past five years, great efforts have been made to improve the crystallinity, reduce grain boundaries, and enhance the stabilities of perovskite films. Compared with films, HOIP single crystals possess fewer grain boundaries and stronger optoelectronic properties and can be applied in optoelectronic devices. As the most popular HOIP member, single crystals of MAPbX3 (X = Br, Cl) are deemed as important candidates for ultraviolet-visible photodetectors, in which the crystal structure anisotropy largely affects the detection performance. In this study, high-quality cubic single crystals of MAPbBr3 and MAPbCl3 were successfully grown from solutions. Taking advantages of their smooth (100) facets, planar metal-semiconductor-metal photodetectors were fabricated using Au interdigitated electrodes. The optoelectronic performances under nonpolarized and linearly polarized lights were explored. The optoelectronic performances were dependent on linearly polarized lights. Interestingly, both responsivity and external quantum efficiency were greatly enhanced under the excitation with linearly polarized lights. Moreover, the polarization-related optical absorptions and the electron densities within the (100) plane could be used to interpret different optoelectronic performances of single crystals of MAPbX3 (X = Br, Cl) under various linearly polarized lights. PMID- 29256249 TI - Biomimetic Chemical Sensing by Fluorescence Signals Using a Virus-like Particle Based Platform. AB - The chemical receptors present in living organisms are promising tools for developing biomimetic chemical sensors. However, these receptors require lipid membranes for functioning under physiological conditions, which prevents their utilization in the production of cell-free in vitro chemical sensing systems. Here, we report the development of a cell-free biomimetic sensing platform using virus-like particles (VLPs) with intact ligand-gated Ca2+ channels and genetically encoded Ca2+ indicator (GECI). We observed that targeting GECI to the plasma membrane was essential for efficient loading GECI in the VLPs. Although the physiological Ca2+ concentration [Ca2+] maintained in the cells was low (~10 nM), the concentration in the VLPs was high. This prevented the detection of the increase in [Ca2+] caused by binding of the ligand to the receptor. To address this problem, we employed Lyn-R-CEPIA1, which had low affinity for Ca2+, and a membrane targeting sequence. Thus, we succeeded in monitoring the activation of cyclic nucleotide-gated channels (CNG) on the VLPs by measuring the increase in fluorescence of Lyn-R-CEPIA1. Our VLP-based sensing system can act as a fundamental platform for all kinds of ligand-gated channels. PMID- 29256251 TI - Assembly of Diverse Spirocyclic Pyrrolidines via Transient Directing Group Enabled Ortho-C(sp2)-H Alkylation of Benzaldehydes. AB - A diversity-oriented synthesis of useful spirocyclic pyrrolidines was successfully accomplished via late-stage cascade reactions of o-succinimide substituted benzaldehydes. A catalytic amount of aniline as a transient directing group was efficient for the ruthenium-catalyzed ortho-C(sp2)-H alkylation of benzaldehyde with maleimide. The in situ formed imine overrided a series of other traditional directing groups with excellent site selectivities. More importantly, only 0.5 mol % of ruthenium catalyst was sufficient for a 100 mmol scale-up reaction without column chromatography purification. PMID- 29256252 TI - Electroconvulsive therapy in the continuation and maintenance treatment of depression: Systematic review and meta-analyses. AB - OBJECTIVE: Acute course of electroconvulsive therapy is effective in inducing remission from depression, but recurrence rate is unacceptably high following termination of electroconvulsive therapy despite continued pharmacotherapy. Continuation electroconvulsive therapy and maintenance electroconvulsive therapy have been studied for their efficacy in preventing relapse and recurrence of depression. The purpose of this meta-analysis was to examine the efficacy of continuation electroconvulsive therapy and maintenance electroconvulsive therapy in preventing relapse and recurrence of depression in comparison to antidepressant pharmacotherapy alone. METHODS: We searched MEDLINE, Embase, PsycINFO, clinicaltrials.gov and Cochrane register of controlled trials from the database inception to December 2016 without restriction on language or publication status for randomized trials of continuation electroconvulsive therapy and maintenance electroconvulsive therapy. Two independent Cochrane reviewers extracted the data in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for systematic reviews and meta analyses. The risk of bias was assessed using four domains of the Cochrane Collaboration Risk of Bias Tool. Outcomes were pooled using random effect model. The primary outcome was relapse or recurrence of depression. RESULTS: Five studies involving 436 patients were included in the meta-analysis. Analysis of the pooled data showed that continuation electroconvulsive therapy and maintenance electroconvulsive therapy, both with pharmacotherapy, were associated with significantly fewer relapses and recurrences than pharmacotherapy alone at 6 months and 1 year after a successful acute course of electroconvulsive therapy (risk ratio = 0.64, 95% confidence interval = [0.41, 0.98], p = 0.04, risk ratio = 0.46, 95% confidence interval = [0.21, 0.98], p = 0.05, respectively). There was insufficient data to perform a meta-analysis of stand-alone continuation electroconvulsive therapy or maintenance electroconvulsive therapy beyond 1 year. CONCLUSION: There are only a few randomized trials of continuation electroconvulsive therapy and maintenance electroconvulsive therapy. The preliminary and limited evidence suggests the modest efficacy of continuation electroconvulsive therapy and maintenance electroconvulsive therapy with concomitant pharmacotherapy in preventing relapse and recurrence of depressive episodes for 1 year after the remission of index episode with the acute course of electroconvulsive therapy. PMID- 29256253 TI - Headache in the pediatric emergency department: A 5-year retrospective study. AB - Aim To determine the red flags for serious organic causes of headache in children, to analyze if the management of headache in the Pediatric Emergency Department is appropriate, and whether the follow-up may limit repeated visits to the Emergency Department. Methods All the patients <= 18 years referred to our pediatric Emergency Department for non-traumatic headache over 5 years were retrospectively reviewed. The patients followed up by the Pediatric Headache Centre were also screened. Statistical analysis was undertaken using the Chi squared test or Fisher's exact test and multivariate analysis; significance at p < 0.05. Results 1833 patients (54.6% males) accessed our Emergency Department 2086 times; 62.1% had primary headache, 30.0% had secondary headache, 7.8% received inconsistent diagnosis. Among those with secondary headache, 24 (1.1% of total visits) were diagnosed with serious disorders. The clinical red flags for "serious headache" were: Cranial nerves palsy, strabismus, and drowsiness. One hundred and eighty four patients (8.8 %) underwent neuroimaging (rate of pathological findings: 7.1 %); 37.2 % of the patients received analgesic therapy. One hundred and fifteen patients (6.2 %) returned within three months; 24 of these were referred to the Headache Centre, with only one accessing the Emergency Department again. Conclusions The vast majority of headaches referred to the Pediatric Emergency Department are benign, and primary forms prevail. "Serious headache" is rare and shows typical clinical features and abnormal neurologic evaluation; specific clinical red flags, along with suggestive personal history, should lead the pediatrician to prescribe only appropriate neuroimaging. Pain relief is still insufficient in the Pediatric Emergency Department despite appropriate guidelines. Last, the collaboration with the Headache Centre is crucial to limit repeated visits. PMID- 29256254 TI - A Clear-Cut Case of Diabetes? PMID- 29256255 TI - The Danish Headache Center: From origin to full development. PMID- 29256257 TI - Academic dissertations from the Danish Headache Center 1980-2016. PMID- 29256258 TI - Academic dissertations from the Danish Headache Center 1980-2016. PMID- 29256261 TI - Computerized Self-Administered Substance Use Screening in a General Adolescent Clinic. PMID- 29256260 TI - Prognostic value of the maximum standardized uptake value of pre-treatment primary lesions in small-cell lung cancer on 18F-FDG PET/CT: a meta-analysis. AB - Background 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) has been widely used in clinical practice. However, the prognostic value of the pre-treatment standardized uptake value (SUV) for patients with small-cell lung cancer (SCLC) remains controversial. Purpose To investigate the prognostic role of pre-treatment 18F-FDG PET on SCLC patients by meta-analysis. Material and Methods Extensive literature searches of the PubMed, EMBASE, Web of Science, and Cochrane Library databases were conducted to identify literature published until 5 May 2017. Comparative analyses of the pooled hazard ratios (HRs) for event-free survival (EFS) and overall survival (OS) were performed to assess their correlations with the pre-treatment maximum SUV (SUVmax). Either the fixed- or the random-effects model was adopted, depending on the heterogeneity observed across the studies. Subgroup analyses were performed to assess the robustness of the results. Results Twelve studies with 1062 patients were included. The pooled HR for OS of 11 studies was 1.13 (95% confidence interval [CI] = 1.05-1.22; P = 0.001; I2 = 0%) and the pooled HR for EFS of nine studies was 1.09 (95% CI = 1.02-1.17; P = 0.014; I2 = 0%), indicating that patients with high SUVs may have poorer prognoses. Begg's test detected no significant publication bias. The prognostic role of the SUVmax remained similar in the subgroup analyses. Conclusion Our meta-analysis indicated that the pre treatment SUVmax of primary lesions can be an important prognostic factor for OS and EFS in patients with SCLC. A high SUVmax may indicate poorer prognosis. PMID- 29256262 TI - Polymorphisms and expression of genes encoding Argonautes 1 and 2 in autoimmune thyroid diseases. AB - The microRNA (miRNA) biogenesis pathway is regulated by specific proteins and enzymes, including Dicer, Drosha, DGCR8, Exportin 5 and the Argonaute (AGO) family. In this study, we investigated the AGO family, which is the primary component of RISC (RNA-induced silencing complex) and directly binds to microRNA. We examined the association of polymorphisms in AGO family genes with AGO expression and with the development and prognosis of autoimmune thyroid diseases. We genotyped AGO1 rs636832A/G, AGO2 rs7005286C/T, AGO2 rs11166985A/G and AGO2 rs2292779C/G polymorphisms in 184 Graves' disease (GD) patients, 195 Hashimoto's disease (HD) patients and 122 healthy volunteers using the polymerase chain reaction-restriction fragment length polymorphism method. We also examined the expression of AGO1 and AGO2 mRNAs in peripheral blood mononuclear cells (PBMC) obtained from 52 GD patients, 41 HD patients, and 25 healthy volunteers using quantitative RT-PCR methods. The G allele of AGO1 rs636832 and the A allele of AGO2 rs11166985 polymorphisms were significantly more frequent in GD patients than in healthy controls. The A allele of AGO2 rs11166985 was also significantly more frequent in intractable GD patients than in controls. The C carrier (CC + CG genotypes) and C allele of AGO2 rs2292779 polymorphism were significantly more frequent in intractable GD patients than in patients with GD in remission. Expression of AGO1 mRNA in PBMC was significantly higher in AITD patient than in controls, and that of AGO2 mRNA in PBMC was significantly higher in intractable GD patients than in patients with GD in remission. Furthermore, the expression levels of both the AGO1 and AGO2 genes were significantly correlated with the proportions of Th17 cells in PBMC. In conclusion, the polymorphisms of the AGO1 and AGO2 genes, the expression levels of which correlated with the proportion of Th17 cells, were associated with the development and prognosis of GD. The AGO2 rs2292779 C carrier and C allele were associated with the intractability of GD. PMID- 29256263 TI - IL-17 and related cytokines involved in systemic sclerosis: Perspectives. AB - Systemic sclerosis (SSc) is a multisystemic, complex, and rare disease of connective tissue, with high morbidity and mortality, and without specific treatment. The disease is characterized by three main principles: vascular disease, autoantibody production and inflammation, and fibrosis. Since it is well defined that SSc is characterized by elevated production of TGF-beta, IL-6, and IL-1, all of them cytokines related to Th17 differentiation, the hypothesis is that this disease may be strongly related to a polarization of the immune response towards the Th17 pathway. Considering the importance of a better understanding of the pathophysiology of Th17 pathway in SSc, this article aims to propose an update for a better understanding of current knowledge on main cytokines secreted by the Th17 cells (IL-17 A, IL-21, and IL-22) and the future prospects in the current disease. PMID- 29256264 TI - Investigating consistent patterns of variation in short-notice cancellations of elective operations: The potential for learning and improvement through multi site evaluations. AB - As part of efforts to increase productivity in healthcare, there is considerable interest in the extent and causes of variation in the performance of provider organisations. In this study, we use publically available data from the English NHS to examine the characteristics of variation in the rates of short-notice cancellations of elective operations due to hospital reasons (e.g. lack of the required resources such as operating theatres and beds). We find that the variation between hospital trusts is very non-random. There is a fourfold difference in the cancellation rates between the top and bottom deciles of performance. Little is known about the causes of this. There is a large and striking consistency in the relative performance of hospital trusts on cancellation rates over the last five years. Thus, the best and worst performers are consistently relatively very good or very poor, so a multi-site comparison of practices, and accounting for confounds like patient demographics, could be very valuable to inform both this knowledge gap and practice in healthcare. Of particular interest is that the cancellation rates could be a symptom of deeper issues with the efficiency of patient flows within hospitals. PMID- 29256259 TI - Evolution of the magic bullet: Single chain antibody fragments for the targeted delivery of immunomodulatory proteins. AB - Immunocytokines are fusion proteins that combine the specific antigen binding capacities of an antibody or derivative thereof and the potent bioactivity of a cytokine partner. These novel biopharmaceuticals have been directed to various targets of oncological as well as non-oncological origin and a handful of promising constructs are currently advancing in the clinical trial pipeline. Several factors such as the choice of a disease specific antigen, the antibody format and the modulatory nature of the payload are crucial, not only for therapeutic efficacy and safety but also for the commercial success of such a product. In this review, we provide an overview of the basic principles and obstacles in immunocytokine design with a specific focus on single chain antibody fragment-based constructs that employ interleukins as the immunoactive component. Impact statement Selective activation of the immune system in a variety of malignancies represents an attractive approach when existing strategies have failed to provide adequate treatment options. Immunocytokines as a novel class of bifunctional protein therapeutics have emerged recently and generated promising results in preclinical and clinical studies. In order to harness their full potential, multiple different aspects have to be taken into consideration. Several key points of these fusion constructs are discussed here and should provide an outline for the development of novel products based on an overview of selected formats. PMID- 29256265 TI - Temporal augmentation with poly methyl methacrylate at the time of autologous cranioplasty. AB - Patients undergoing decompressive hemicraniectomy often have temporal wasting. We present a technique to manage temporalis wasting at the time of cranioplasty. Using poly methyl methacrylate, a small temporal implant is placed during cranioplasty. This is both a simple and cost effective technique for temporal augmentation at the time of cranioplasty. PMID- 29256266 TI - Correction to Levi-Belz et al., 2017 (https://doi.org/10.1027/0227-5910/a000482). PMID- 29256267 TI - The Feasibility and Clinical Utility of Conducting a Confidential Inquiry Into Suicide in Southwestern Ontario. AB - BACKGROUND AND AIMS: Given the effectiveness of the National Confidential Inquiry into Suicide and Homicide by People with Mental Illness (NCI) in the UK, the present study evaluated this approach in Southwestern Ontario. A systematic confidential examination of suicides in Ontario was developed to guide quality improvement of services and suicide prevention. METHOD: A 3-year case series of consecutive suicides in Southwestern Ontario identified by the Office of the Chief Coroner was compiled. Clinicians who provided care to suicide decedents completed an online confidential suicide questionnaire offered through a secured portal. RESULTS: A total of 476 suicide cases were analyzed. In all, 270 invitations to clinicians were sent, 237 (87.8%) responded to the invitation and 187 (69.3%) completed the online questionnaire. The majority of the suicide decedents (54.6%, n = 260), were between the ages of 40 and 64 (x = 47.2, SD = 17.1), White (91.4%, n = 416), single (34.2%, n = 439), and male (74.4%, n = 476). Of the 86 cases of self-poisoning, prescription medications were used in 66.3%. Almost two thirds of decedents visited the clinician in the month prior to their death. LIMITATIONS: The results of the survey were drawn from suicides in Southwestern Ontario and generalizing these findings should be done with caution. CONCLUSION: This study highlights (a) the value of the clinicians' survey to identify gaps in clinical services and (b) the necessity of improvements in suicide risk assessment/management and restriction of prescription medications. PMID- 29256268 TI - Suicidal Behavior and Non-Suicidal Self-Injury in Emergency Departments Underestimated by Administrative Claims Data. AB - BACKGROUND: External causes of injury codes (E-codes) are used in administrative and claims databases for billing and often employed to estimate the number of self-injury visits to emergency departments (EDs). AIMS: This study assessed the accuracy of E-codes using standardized, independently administered research assessments at the time of ED visits. METHOD: We recruited 254 patients at three psychiatric emergency departments in the United States between 2007 and 2011, who completed research assessments after presenting for suicide-related concerns and were classified as suicide attempters (50.4%, n = 128), nonsuicidal self-injurers (11.8%, n = 30), psychiatric controls (29.9%, n = 76), or interrupted suicide attempters (7.8%, n = 20). These classifications were compared with their E-code classifications. RESULTS: Of the participants, 21.7% (55/254) received an E-code. In all, 36.7% of research-classified suicide attempters and 26.7% of research classified nonsuicidal self-injurers received self-inflicted injury E-codes. Those who did not receive an E-code but should have based on the research assessments had more severe psychopathology, more Axis I diagnoses, more suicide attempts, and greater suicidal ideation. LIMITATIONS: The sample came from three large academic medical centers and these findings may not be generalizable to all EDs. CONCLUSION: The frequency of ED visits for self-inflicted injury is much greater than current figures indicate and should be increased threefold. PMID- 29256269 TI - A Systematic Mapping of Suicide Bereavement and Postvention Research and a Proposed Strategic Research Agenda. AB - BACKGROUND: Suicide may have disruptive and/or devastating effects on family, friends, and the broader community. Of late, increased interest from suicide researchers has given rise to an upsurge in research productivity addressing suicide bereavement and postvention. At this critical juncture, the establishment of an agenda will help guide the direction of future scholarly research in this field. AIMS: To conduct an exhaustive systematic mapping review and bibliometric analysis of peer-reviewed suicide bereavement and postvention research published over the past 50 years. METHOD: A comprehensive and strategic search of electronic databases and web-based search engines for original research studies was conducted resulting in the identification of 443 articles. RESULTS: Since 1965, the global research activities in the field of suicide bereavement and postvention is approximately 8.86 papers per year. There remains a lack of evaluation studies on the effects of interventions/programs with the majority of papers being explanatory in nature. Several areas of study within this field remain neglected. LIMITATIONS: While the search strategy was rigorous, potential limitations exist due to nonstandardized nomenclature and English language only inclusion, which inherently favors research from high-income countries. CONCLUSION: Suggested topics for a research agenda are proposed from the current limitations in the field. PMID- 29256270 TI - Hearing the Suicidal Patient's Emotional Pain. AB - BACKGROUND: Escaping from emotional pain is a recognized driver in suicidal patients' desire to die. Formal scales of emotional pain are rarely used during routine contact between patients and their care team. No study has explored facilitators and inhibitors of emotional pain communication between staff and suicidal patients during regular care. AIMS: To identify factors impeding or facilitating emotional pain communication between patients at risk of suicide and mental health professionals. METHOD: Nine patients with a history of a medically serious suicide attempt and 26 mental health (NHS) staff participated in individualized and focus group interviews, respectively. RESULTS: A typological model was created, describing how patients either speak out or inhibit communication, and professionals may hear the communication or fail to do so. Four permutations are possible: unspoken/unheard, spoken/unheard, spoken/heard, and unspoken/heard. We found 14 subthemes of impediments and facilitators, which include misaligned, alienated and, co-bearing. LIMITATIONS: No male patients participated. CONCLUSION: Numerous factors influence whether emotional pain communication is responded to, missed, or ignored. Patients may try more than one way to communicate. Some patients fear that being able to speak out results in their emotional pain being taken less seriously. Knowledge of this model should improve the care of suicidal patients. PMID- 29256271 TI - A new multipartite plate system for anterior cervical spine surgery; finite element analysis. AB - BACKGROUND: There are numerous available plates, almost all of which are compact one-piece plates. During the placement of relatively long plates in the treatment of multi-level cervical pathologies, instrument related complications might appear. In order to overcome this potential problem, a novel 'articulated plate system' is designed. We aimed to delineate finite element analysis and mechanical evaluations. MATERIAL AND METHODS: A new plate system consisting of multi partite structure for anterior cervical stabilization was designed. Segmental plates were designed for application onto the ventral surface of the vertebral body. Plates differed from 9 to13 mm in length. There are rods at one end and hooks at the other end. Terminal points consisted of either hooks or rods at one end but the other ends are blind. Finite element and mechanical tests of the construct were performed applying bending, axial loading, and distraction forces. RESULTS: Finite element and mechanical testing results yielded the cut off values for functional failure and breakage of the system. CONCLUSIONS: The articulated system proved to be mechanically safe and it lets extension of the system on either side as needed. Ease of application needs further verification via a cadaveric study. PMID- 29256272 TI - Enacting localist health policy in the English NHS: the 'governing assemblage' of Clinical Commissioning Groups. AB - Objectives The Health and Social Care Act 2012 introduced Clinical Commissioning Groups to take responsibility for commissioning (i.e. planning and purchasing) the majority of services for local populations in the English NHS. Constituted as 'membership organizations', with membership compulsory for all GP practices, Clinical Commissioning Groups are overseen by, and are accountable to, a new arm's-length body, NHS England. This paper critically engages with the content and policy narrative of the 2012 Act and explores this in relation to the reality of local policy enactment. Methods Set against a careful review of the 2012 Act, a case study of a nascent Clinical Commissioning Groups was conducted. The research included observations of Clinical Commissioning Group meetings and events (87 h), and in-depth interviews (16) with clinical commissioners, GPs, and managers. Results The 2012 Act was presented as part of a broader government agenda of decentralization and localism. Clinical Commissioning Group membership organizations were framed as a means of better meeting the needs and preferences of local patients and realizing a desirable increase in localism. The policy delineated the 'governing body' and 'the membership', with the former elected from/by the latter to oversee the organization. 'The membership' was duty bound to be 'good', engaged members and to represent their patients' interests. Fieldwork with Notchcroft Clinical Commissioning Group revealed that Clinical Commissioning Groups' statutory duty to NHS England to 'ensure the continuous improvement' of GP practice members involved performance scrutiny of GP practices. These governance processes were carried out by a varied cast of individuals, many of whom did not fit into the binary categorization of membership and governing body constructed in the policy. A concept, the governing assemblage, was developed to describe the dynamic cast of people involved in shaping the work and direction of the Clinical Commissioning Group, many of whom were unelected and of uncertain status. This was of particular significance in Notchcroft Clinical Commissioning Group because the organization explicitly pursued a governance system based on developing positions of consensus. The governing assemblage concept is valuable in articulating the actual practices of Clinical Commissioning Group governance, how these relate to the normative content of the 2012 Act, and the tensions that emerge. Conclusions The governing assemblage concept provided clarity in discussion of the dynamics of organizational governance in Notchcroft Clinical Commissioning Group, which did not follow the simple template articulated in the 2012 Act. The concept merits application in the study of other Clinical Commissioning Groups and may prove valuable in illuminating governance processes within a range of other health care organizations in different contexts. The governing assemblage holds promise for the analysis of ongoing changes to NHS organization, as well as international health care organizations such as accountable care organizations in the US. PMID- 29256273 TI - Integration - reflections from Northern Ireland. PMID- 29256274 TI - Mother tongue as a universal human right. AB - Article 19 of the Universal Declaration of Human Rights enshrines the right to freedom of opinion and expression. UN Resolution A/RES/61/266 called upon Member States "to promote the preservation and protection of all languages used by peoples of the world". This resolution has particular relevance for minority language groups where mother tongue - so vital to self-expression - is primarily a spoken medium, often ascribed low status. With few fluent readers and writers, and a consequent dearth of written resources, a vicious circle develops and linguistic and cultural heritage erodes. Not all governments are vigilant with appropriate policies and funding. Even in a community like Shetland, where there is no class connotation associated with speaking Shetlandic, the proportion of fluent dialect speakers is now relatively small. It therefore falls to the writer to create resources for children, to help stem the tide. Engaging in translation can also help raise the status of dialect and pinpoint the somewhat arbitrary distinction between dialect and language. There are many problems in publishing in minority tongues; for example, uneconomic print runs, language authenticity versus contemporaneity, standardisation of orthography and the trend to "exotic ise" dialect in mainstream literature. PMID- 29256275 TI - Phenelzine reduces the oxidative damage induced by peroxynitrite in plasma lipids and proteins. AB - Peroxynitrite is a reactive nitrogen species produced in the intravascular compartment from superoxide anion and nitric oxide. Peroxynitrite destroys blood plasma proteins and membranes of red blood cells and of platelets. This explains why excessive production of peroxynitrite contributes to diseases and to ageing. Therapeutics that antagonize peroxynitrite may delay ageing and the progression of disease. We developed an in vitro assay that allows the investigation of the oxidative damage caused by peroxynitrite in the intravascular compartment. This assay correlates the damage with the rate of formation of protein carbonyl groups, 3-nitrotyrosine (3-NT) and thiobarbituric acid reactive substances. Using this assay, we evaluated the ability of phenelzine, a scavenger of reactive aldehydes, to antagonize the effects of peroxynitrite. Herein, we showed that phenelzine significantly decreased the lipid peroxidative damage caused by peroxynitirite in blood plasma and platelets. Moreover, it inhibited carbonyl group and 3-NT formation in blood plasma and platelet proteins. PMID- 29256277 TI - Introductory paragraph. PMID- 29256278 TI - Seroprevalence and risk factors of Besnoitia besnoiti infection in Korean cattle short communication. AB - Besnoitia besnoiti is an obligate intracellular parasite that is transmitted by direct contact or via mechanical transmission by flies as vectors. Besnoitiosis causes economic losses in the cattle industry and is regarded as a re-emerging disease in Europe. This study evaluated the seroprevalence of B. besnoiti in Korean cattle using a commercial ELISA kit. Among 558 serum samples, 19 (3.4%) tested seropositive for B. besnoiti. The statistically significant risk factors included age (>= 2 years), sex (castrated males), and region (lower latitudes) (P < 0.05). The overall seroprevalence suggested a wide distribution of B. besnoiti infection in cattle reared in Korea. Thus, the practice of intensive cattle husbandry and the regionally different seroprevalence of B. besnoiti infection in cattle in Korea warrant routine monitoring and vector control to reduce economical losses due to bovine besnoitiosis in the country. PMID- 29256279 TI - The effect of dietary immunostimulants on the susceptibility of common carp (Cyprinus carpio) to the white spot parasite, Ichthyophthirius multifiliis. AB - One of the main obstacles in freshwater aquaculture is the parasitic ciliate Ichthyophthirius multifiliis (Ich), the causative agent of white spot disease. The use of immunostimulants as feed additives may be a promising approach to control Ich infection. In the present study, we tested the prophylactic effect of orally administered beta-1,3/1,6-glucan and propolis extract E50 against Ich infection in common carp. In total, 122 fish were separated into three experimental groups fed with a control, 3% beta-glucan and 1% propolis diet for 40 consecutive days, respectively. On day 40, 16 fish per group were individually exposed to Ich theronts and the number of trophonts was counted 5 days post exposure. Relative gene expression of interleukin 1-beta (IL-1-beta) in common carp liver was examined by qPCR. Compared to control, the mean infection intensity was lower in the beta-glucan- and propolis-fed groups; however, the difference was not statistically significant. The relative expression of IL-1 beta significantly decreased in the propolis-fed group at day 10. In the beta glucan-fed group, a significant IL-1-beta decrease was detected at day 15 compared to control. Although the Ich infection intensity was slightly decreased in both treated groups, and IL-1-beta was moderately down-regulated in the liver of common carp, our results suggest that the applied feeding regime is insufficient to prevent Ich outbreaks in common carp. PMID- 29256280 TI - DNA of free-living bodonids (Euglenozoa: Kinetoplastea) in bat ectoparasites: potential relevance to the evolution of parasitic trypanosomatids. AB - Kinetoplastids are flagellated protozoa, including principally free-living bodonids and exclusively parasitic trypanosomatids. In the most species-rich genus, Trypanosoma, more than thirty species were found to infect bats worldwide. Bat trypanosomes are also known to have played a significant role in the evolution of T. cruzi, a species with high veterinary medical significance. Although preliminary data attested the occurrence of bat trypanosomes in Hungary, these were never sought for with molecular methods. Therefore, amplification of an approx. 900-bp fragment of the 18S rRNA gene of kinetoplastids was attempted from 307 ixodid and 299 argasid ticks collected from bats, and from 207 cimicid bugs collected from or near bats in Hungary and Romania. Three samples, one per each bat ectoparasite group, were PCR positive. Sequencing revealed the presence of DNA from free-living bodonids (Bodo saltans and neobodonids), but no trypanosomes were detected. The most likely source of bodonid DNA detected here in engorged bat ectoparasites is the blood of their bat hosts. However, how bodonids were acquired by bats, can only be speculated. Bats are known to drink from freshwater bodies, i.e. the natural habitats of B. saltans and related species, allowing bats to ingest bodonids. Consequently, these results suggest that at least the DNA of bodonids might pass through the alimentary mucosa of bats into their circulation. The above findings highlight the importance of studying bats and other mammals for the occurrence of bodonids in their blood and excreta, with potential relevance to the evolution of free-living kinetoplastids towards parasitism. PMID- 29256281 TI - Detection of a putative novel adenovirus by PCR amplification, sequencing and phylogenetic characterisation of two gene fragments from formalin-fixed paraffin embedded tissues of a cat diagnosed with disseminated adenovirus disease. AB - Adenoviral nucleic acid was detected by polymerase chain reaction (PCR) in formalin-fixed paraffin-embedded tissue samples of a cat that had suffered from disseminated adenovirus infection. The identity of the amplified products from the hexon and DNA-dependent DNA polymerase genes was confirmed by DNA sequencing. The sequences were clearly distinguishable from corresponding hexon and polymerase sequences of other mastadenoviruses, including human adenoviruses. These results suggest the possible existence of a distinct feline adenovirus. PMID- 29256282 TI - Assessment of adrenocortical reserve capacity and inflammatory parameters in critically ill dogs. AB - Inflammatory markers and adrenocorticotropic hormone (ACTH) stimulation test results may help us recognise critically ill dogs with poor disease outcome. Systemic inflammatory response syndrome (SIRS) criteria, the fast version of the Acute Patient Physiologic and Laboratory Evaluation Score (APPLEfast), complete blood count, albumin and C-reactive protein (CRP) levels, baseline and stimulated cortisol levels and Deltacortisol value were recorded in 50 client-owned dogs admitted to the Small Animal Hospital of the University of Veterinary Medicine Budapest with various inflammatory or neoplastic conditions. Increasing APPLEfast score was associated with a decreasing chance of survival (P = 0.0420). The Deltacortisol value was significantly higher in SIRS dogs than in non-SIRS dogs (mean +/- SD DeltacortisolSIRS: 342.5 +/- 273.96; mean +/- SD Deltacortisolnon SIRS: 175.3 +/- 150.35; P = 0.0443). Elevated baseline or stimulated cortisol levels were associated with a higher chance of non-survival (P = 0.0135 and P = 0.0311, respectively). These data indicate that pathologically higher baseline and stimulated cortisol levels represent an exaggerated stress response in critically ill dogs, which is negatively associated with survival. PMID- 29256283 TI - Review of gastric torsion in eight guinea pigs (Cavia porcellus). AB - The authors present eight cases of gastric dilatation and volvulus (GDV) in guinea pigs from the Department and Clinic of Exotic Animal and Wildlife Medicine, University of Veterinary Medicine, Budapest, Hungary between 2012 and 2016. Seven animals were operated on and two survived. Gastric torsion has been noted in many mammalian species. Gastric volvulus has a high morbidity and high mortality rate with a guarded to poor prognosis in all of these species. How GDV develops is still not widely understood. Postmortem examinations, in both our cases and previously reported cases, have failed to reveal the exact causes of the gastric torsions. The aetiology of gastric torsion in guinea pigs is probably multifactorial. Feeding fewer meals per day, eating rapidly, decreased food particle size, exercise, stress after a meal, competition, age, and an aggressive or fearful temperament, are all likely and potential risk factors for GDV development in a similar fashion to dogs. Sex, breeding, dental diseases, anatomical abnormalities, pain and pregnancy may also be contributing factors. PMID- 29256284 TI - X- and Y-chromosome-specific variants of the amelogenin gene allow non-invasive sex diagnosis for the detection of pseudohermaphrodite goats. AB - The Polled Intersex Syndrome (PIS) is responsible for the absence of horns in homozygous and heterozygous goats causing a female-to-male sex reversal in the homozygous polled genotypic female (XX) goats. A simple and efficient non invasive method was elaborated to detect the genotypic sex from hair and faecal samples using a pair of primers to amplify the X- and Y-linked alleles of the amelogenin gene. The PCR products were easily distinguishable using agarose gel electrophoresis: we detected an X-specific single band in samples originating from healthy phenotypic females and double (X- and Y-) bands in samples from males. The new PCR method is applicable for diagnosing the sex of PIS-affected animals already as newborn kids, in contrast with the phenotypic findings appearing only after puberty, and thus it may replace the cumbersome chromosome investigations. PMID- 29256285 TI - Prevalence of Trypanosoma cruzi and organ alterations in Virginia opossums (Didelphis virginiana) from western Mexico - short communication. AB - Small populations of Virginia opossum (Didelphis virginiana) in western Mexico are endangered by hunting and natural predators as well as by different kinds of diseases. After two serological analyses using Serodia(r) latex particle agglutination and indirect haemagglutination (IHA) tests, 35 (53.03%) of 66 collected opossums in two small towns in western Mexico were positive for the presence of Trypanosoma cruzi. Twenty-eight of the 35 seropositive opossums had pathological lesions: 11 had changes in only one organ, 13 in two organs, and four had pathological changes in three organs. Splenomegaly was the most common finding in the examined opossums, followed by hepatomegaly. These potentially fatal pathological changes could contribute to the scarcity of the opossum population, even leading to the extinction of this species in western Mexico. PMID- 29256286 TI - Effect of temperament on cortisol response to a single exercise bout in Thoroughbred racehorses - short communication. AB - Temperament has not been taken into account in previous studies evaluating the stress response to exercise in horses. The aim of the present study was to investigate the cortisol response in Thoroughbred racehorses to a single exercise bout, and to analyse the results based on the basic personality of the horse examined. Twenty healthy Thoroughbred horses were selected for the study based on a 25-item rating questionnaire survey used for characterising equine temperament. Eight temperamental and twelve calm horses took part in the experiment. The horses trotted as a warm-up activity, and then galloped on a rounded sand track. Blood sampling was conducted four times for each horse. Horses with a more excitable temperament showed a higher cortisol response to the test (P = 0.036). In conclusion, cortisol levels in response to a mild intensive exercise can be affected by temperament in horses. Serum cortisol may be a relevant marker to quantify individual temperamental differences in racehorses. PMID- 29256287 TI - Effect of storage tube material and resveratrol during liquid storage of matured bovine oocytes on subsequent development. AB - This study determined the optimum storage vessel and the effects of resveratrol for the storage of in vitro matured (IVM) bovine oocytes. After IVM, the oocytes were kept in a Hepes-buffered medium at 25 degrees C for 20 h in different containers including Eppendorf tubes (ET) made of polypropylene (PP) and polystyrene (PS), and tissue culture tubes (TCT) made of PP, PS, and glass. Then oocytes were subjected to IVF and subsequent in vitro embryo development was compared among the groups and to that of a control group without storage. The percentage of blastocyst development in the control group was significantly higher than in the stored groups (P < 0.05). Among oocytes stored in TCT, the percentage of blastocyst development of oocytes stored in glass TCT was significantly higher than that of oocytes stored in PP and PS TCT (P < 0.05); however, it did not differ from that of oocytes stored in ET. The quality of blastocysts did not differ among the control and stored groups. Embryo development was not affected when 0.1, 1 or 10 MUM resveratrol was added to the medium during oocyte storage. In conclusion, glass tubes were optimal for oocyte storage and resveratrol did not improve the development of stored oocytes. PMID- 29256288 TI - Transurethral urinary bladder eversion and prolapse in a castrated male pet rabbit. AB - A 7-year-old castrated male rabbit was presented with a red oedematous mass at the prepuce. The tissue was identified as the urinary bladder, and the condition was diagnosed as complete transurethral urinary bladder eversion. Exploratory laparotomy was performed, the prolapse was successfully reduced and the bladder was secured to the body wall with cystopexy. The surgery was successful and the bladder remained in place without complications until the time of this report (three years after surgery). Transurethral bladder prolapse is a very rare condition previously reported only in women, mares, cows, bitches, queens, and rabbit does. The case herein is the first reported case of transurethral bladder prolapse in a male of any species. PMID- 29256289 TI - The silent spread of Porcine Bocavirus in Croatian pigs: should we be concerned? AB - A survey was conducted to evaluate the presence and prevalence of Porcine Bocavirus (PBoV) in Croatian domestic pigs by means of PCR targeting the NS1 gene fragment of PBoV. This study included testing of faecal samples collected from 10 small commercial farms and 11 small backyard holdings in Croatia. The presence of PBoV was confirmed by PCR in 24 out of 57 composite faecal samples from small commercial farms and in 12 out of 43 composite faecal samples from small backyard holdings. The PCR products of 18 positive samples were sequenced for genotyping. PBoV sequences grouped into the PBoV-a, PBoV-b and PBoV-c groups with 90.81% to 99.25% nucleotide identity. All Croatian PBoV sequences showed a high nucleotide and amino acid identity with PBoV sequences from China and Hong Kong, the United States, Sweden, and Slovenia. These results clearly show that PBoV is circulating among the domestic pig population in Croatia. PMID- 29256290 TI - Pathogenicity determinants and antibiotic resistance profiles of enterococci from foods of animal origin in Turkey. AB - In this study, the presence of genes responsible for the pathogenicity and antibiotic resistance profile of enterococci isolated from various foodstuffs of animal origin was investigated. The percentage prevalence of enterococci was 54.1% (203/375) and the average count was found to be 3.81 log cfu/ml-g. Species specific primers revealed Enterococcus faecalis as the predominant species carrying one or more virulence-associated traits of efa, gelE, ace, esp and agg genetic markers. Only one E. faecium isolate (from milk) was positive for the esp gene. Regarding antibiotic resistance, the highest frequency of resistance was observed for tetracycline (21.7%), followed by quinupristin/dalfopristin (13.3%), ciprofloxacin (2.0%), penicillin (2.0%), linezolid (1.0%), ampicillin (1.0%), streptomycin (1.0%), and gentamicin (0.5%). Enterococcus faecalis showed a higher prevalence of antibiotic resistance than other enterococci. The percentage of multidrug resistance among the isolates was 3.4%. Twenty-nine E. faecalis isolates (26.6%) carrying one of the virulence-associated traits were at the same time resistant to at least one antibiotic. Our results show that foods of animal origin, including ready-to-eat products, may be reservoirs of antibiotic resistant and potentially virulent enterococci. PMID- 29256291 TI - Patent foramen ovale and cryptogenic stroke: contemporary evidence and treatment. AB - INTRODUCTION: Patent foramen ovale (PFO) is a common anatomical variant in the adult circulation. It is a channel allowing communication between the left and right atria and is a remnant of the foetal circulation. In approximately 25% of the population, this channel persists into adulthood. PFO has been proposed as a potential pathophysiological mechanism for cryptogenic stroke. Areas covered: This review will examine the contemporary evidence for both the association between cryptogenic stroke and PFO and the management of this condition. The authors hope to provide a comprehensive overview of the current evidence and best practice in relation to PFO closure. In addition, the authors will propose some potential avenues for future research in this controversial area and try to predict how PFOs in cryptogenic stroke will be managed in the near future. Expert commentary: In carefully selected patients with cryptogenic stroke, PFO closure represents an evidence based treatment option for the prevention of further ischemic neurological events. A multidisciplinary approach is necessary to ensure appropriate patient selection for the procedure. This should include a vascular neurologist/stroke physician and an interventional cardiologist with an interest in PFO closure. PMID- 29256292 TI - Pramlintide regulation of extracellular matrix (ECM) and apoptosis through mitochondrial-dependent pathways in human nucleus pulposus cells. AB - Pramlintide, an approved analog of amylin, is responsible for regulating the physiology of energy homeostasis. The goals of this study were to investigate the roles of pramlintide in the regulation of cell survival and matrix metabolism, and further explore their underlying mechanisms, in human nucleus pulposus (NP) cells. NP cells were treated with different concentrations of pramlintide in normoxic or hypoxic conditions. Cell viability, LAC concentration, calcium concentration, mitochondrial membrane potential (DeltaPsim), MMPs proteins, and apoptotic related proteins were detected. The results indicate that pramlintide could improve NP cell proliferation, glycolytic activity, and the ECM synthesis under hypoxia, which is evident from the increased precipitation of proteoglycans; increased expression of AGG, Col2, and SOX9 proteins; and decreased expression of MMP3, MMP9, and MMP13 proteins, which are Ca2+-dependent enzymes. And, pramlintide could facilitate the survival of NP cells through mitochondrial-mediated, Bcl-2/caspase-3-dependent apoptosis. In addition, activation of AKT-AMPK/mTOR signaling pathway is also observed by the treatment. These findings demonstrate that pramlintide may play a pivotal role in reversing intervertebral disk degeneration and may relieve the impairment of ECM metabolism and NP cells survival through mitochondrial-dependent apoptotic signaling pathway, thus offering a novel potential pharmacological treatment strategy. PMID- 29256294 TI - The Q-tip test of the vulva as a diagnostic aid for vulvodynia: sensitivity, specificity and predictive values. PMID- 29256295 TI - How long is the ovary relevant for synthesis of steroids after menopause? AB - This study aimed to determine whether the ovaries synthesize estradiol (E2), testosterone (T), and androstenedione (A) after menopause. The first group (30 patients) underwent surgical menopause (SM) - their ovaries were removed due to a benign condition around the time of menopause. The second group (30 patients) consisted of patients with natural menopause (NM). The E2 median level was 10.0 pg/ml (CI +/- 2.18) and 9.5 pg/ml (CI +/- 1.63) in the NM and SM groups (p = .69), respectively. The median level of total T was 0.12 ng/ml (CI +/- 0.01) and 0.11 ng/ml (CI +/- 0.03) in NM and SM, respectively (p = .96). The median level of A was 783.85 pg/ml (CI +/- 154.39) and 883.48 pg/dl (CI +/- 201.03) in NM and SM, respectively (p = .57). The FAI (free androgen index) was 1.06 (CI +/- 0.24) and 1.35 (CI +/- 0.68) for NM and SM, respectively (p = .98). We concluded that 5 10 years after menopause the ovaries are no longer relevant for sex steroid synthesis. PMID- 29256296 TI - letters. PMID- 29256293 TI - Sifting through the surfeit of neuroinflammation tracers. AB - The first phase of molecular brain imaging of microglial activation in neuroinflammatory conditions began some 20 years ago with the introduction of [11C]-( R)-PK11195, the prototype isoquinoline ligand for translocator protein (18 kDa) (TSPO). Investigations by positron emission tomography (PET) revealed microgliosis in numerous brain diseases, despite the rather low specific binding signal imparted by [11C]-( R)-PK11195. There has since been enormous expansion of the repertoire of TSPO tracers, many with higher specific binding, albeit complicated by allelic dependence of the affinity. However, the specificity of TSPO PET for revealing microglial activation not been fully established, and it has been difficult to judge the relative merits of the competing tracers and analysis methods with respect to their sensitivity for detecting microglial activation. We therefore present a systematic comparison of 13 TSPO PET and single photon computed tomography (SPECT) tracers belonging to five structural classes, each of which has been investigated by compartmental analysis in healthy human brain relative to a metabolite-corrected arterial input. We emphasize the need to establish the non-displaceable binding component for each ligand and conclude with five recommendations for a standard approach to define the cellular distribution of TSPO signals, and to characterize the properties of candidate TSPO tracers. PMID- 29256299 TI - scanning sports. PMID- 29256298 TI - brief reports. PMID- 29256300 TI - a need to know. PMID- 29256301 TI - Running a la Mode. PMID- 29256303 TI - Exercise and Menstrual Function. AB - Physicians need more information about the causes and the long-term consequences of amenorrhea due to exercise and weight loss before they can give proper advice to women who exercise strenuously. PMID- 29256304 TI - Employee Fitness Programs. AB - The results of industry fitness programs haven't been measured objectively. But as one panelist points out, business people can act on trends instead of waiting until all the evidence is in. PMID- 29256302 TI - Standards for Sportsmedicine Clinics. PMID- 29256305 TI - A Study of Players With Pain. AB - The results of this study suggest that the harmful effects of tennis are cumulative and that many variables may interact before elbow pain occurs. PMID- 29256306 TI - Bicycling Injuries. AB - The increase in the use of bicycles has been paralleled by an increase in bicycle accidents. Safety education programs, especially for young people, might reduce the number of injuries. PMID- 29256307 TI - A Mimic of the Sick Sinus Syndrome in a Middle-Aged Athlete. AB - Highly trained athletes may have physiological alterations in cardiac pacemaker and conduction function. This article helps clinicians recognize arrhythmias related to exercise conditioning. PMID- 29256308 TI - The Health Supervision Loop in Sport. AB - The health supervision loop is a model that will help community sports programs care for their athletes as safely as possible within the limits of their resources. PMID- 29256309 TI - Kenneth Cooper: Preaching the Gospel of Fitness. AB - In the ten years since he opened the Aerobics Center in Dallas, Kenneth H. Cooper, MD, has made many friends and a few foes. But even his detractors acknowledge his tremendous contribution to the fitness boom. PMID- 29256310 TI - Team USA's Road to Glory. AB - The physician for the US Hockey Team kept a diary while the players scrambled through 52 injuries between the start of training camp and their gold medal in Lake Placid. PMID- 29256312 TI - Testing Anterior Cruciate Ligaments. PMID- 29256311 TI - OHP: Bureaucratizing Sportsmedicine. AB - Federal grant authorizations for sportsmedicine research haven't been funded yet, and there's nothing HEW's Office of Health Promotion can do but wait. PMID- 29256313 TI - Thirty More Pains of Sportsmedicine. PMID- 29256314 TI - Hepatitis B virus reactivation in patients with rheumatoid arthritis: A single center study. AB - OBJECTIVES: This study aimed to investigate the frequency of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) and to verify the guidelines relating to HBV reactivation in Japan. METHODS: We retrospectively investigated 1351 RA patients who were treated with antirheumatic drugs at our hospital. RESULTS: Fifty patients (3.7%; 50/1351) were determined to be HBV carriers and 360 patients (26.7%; 360/1351) had resolved infections. HBV reactivation occurred in six cases (1.7%: 6/360) with resolved infections, of whom, two cases (0.6%; 2/360) developed de novo HBV infections. Eleven of the patients who were HBV carriers received a nucleoside analogue (NA) prophylactically. In all of the cases, the HBV-DNA levels became undetectable and the patients' liver function normalized. Sixteen patients, who had lower titers of the HBV surface antigen and undetectable HBV-DNA levels, did not show HBV reactivation in the absence of NA therapy. CONCLUSIONS: The results from this study suggest that HBV reactivation might not be so frequent among RA patients, and that reliable indicators for prescribing a NA should be clarified for RA patients. PMID- 29256315 TI - Provider Practices of Phenobarbital Discontinuation in Neonatal Seizures. AB - Neonatal seizures are treated with phenobarbital and prolonged treatment does not prevent postneonatal epilepsy. The authors documented factors influencing phenobarbital use and determined whether published data changed practice. A total of 83 neonates with symptomatic seizures, clinical or electrographic, were evaluated for treatment, incidence of postneonatal epilepsy, and associated factors. Median phenobarbital treatment was 81 days. Nineteen children (23%) developed postneonatal epilepsy. Longer duration of seizures and an infectious etiology were associated with postneonatal epilepsy suggesting no impact on duration of phenobarbital treatment. Treatment duration was associated with duration of seizures and use of a second antiseizure medication. This study supports early discontinuation of phenobarbital and suggests providers utilize factors such as use of a second antiseizure medication and time to seizure control to determine phenobarbital duration, despite prior studies suggesting no impact of treatment length. PMID- 29256317 TI - The impact of major physical diseases and its outcomes on depressive symptoms among Chinese population. AB - BACKGROUND: Depression was common among people with physical diseases. Evidence was lacked on the impact of outcomes of physical diseases on mental health. AIM: Using a national representative data of the China Health and Retirement Longitudinal Study, we aimed to explore the impact of major physical diseases and its outcomes on mental health among Chinese population. METHODS: Using a multi stage cluster sampling design, the CHARLS survey collected information of 19 549 subjects in the 2013/2014 follow-up survey. Depressive symptoms were measured by the 10-item version of the Center for Epidemiological Studies Depression (CES-D). RESULTS: The prevalence rate of depressive symptoms in the study population was 21.2%. Major physical diseases were significantly associated with depressive symptoms. Compared to people who did not experience major physical diseases, participants who fully recovered after hospitalization were at similar level of developing depressive symptoms (OR = 1.16), participants who experienced major physical diseases but were not admitted to hospitals were more likely to develop depressive symptoms (OR = 2.14), and those who discharged from hospitals without recovery were also more likely to have depressive symptoms (OR = 2.24). CONCLUSIONS: Screening for depression among hospitalized population and training among general practitioners were necessary. During hospitalization, collaborative care for both physical and mental health could be beneficial. PMID- 29256316 TI - Geraniol as a novel antivirulence agent against bacillary dysentery-causing Shigella sonnei. AB - Antimicrobial resistance has emerged as a major challenge to modern medicine and it has become urgent to seek alternative approaches to treat infections caused by fast-evolving multi-resistant clones of bacillary dysentery-causing Shigella sonnei. Here, we show that geraniol, a natural substance present in the essential oils of plants such as rose and lemongrass, can reduce S. sonnei proliferation inside host cells and protect Galleria mellonella larvae from killing by S. sonnei infection. We present evidence that geraniol competitively inhibits the catalytic activity of the master virulence regulator, DsbA, a periplasmic disulphide bond oxidoreductase required for Shigella survival in the host cell cytosol. Our observations suggest that geraniol holds a great therapeutic potential that should be further exploited. PMID- 29256318 TI - Predicting the intention to use herbal medicines for anxiety symptoms: a model of health behaviour. AB - BACKGROUND: Anxiety is a prevalent mental health condition in the Western world. Adults experiencing anxiety have been found to use a range of herbal medicines to manage anxiety symptoms. AIM: This study aimed to test a theoretical model based on the theory of planned behaviour that predicted the intention to use herbal medicines for anxiety symptoms, and to identify individual predictors of intention. METHODS: An online survey was conducted with Australian adults who experienced anxiety and used herbal medicines (N = 400). A two-step approach to structural equation modelling was used to test a path model predicting the intention to use herbal medicines. RESULTS: The model was found to be well fitting. Attitude, subjective norms, control beliefs and severity of anxiety symptoms each significantly positively predicted intention to use herbal medicines for anxiety symptoms explaining 56% of the variance. CONCLUSIONS: The results suggest that mental health practitioners and policy makers need to ensure people experiencing anxiety have access to accurate and reliable information about herbal medicines to ensure they can effectively manage anxiety symptoms and safely engage in self-care. PMID- 29256319 TI - Antibody response to feline panleukopenia virus vaccination in healthy adult cats. AB - OBJECTIVES: According to prior studies, between 25.0% and 92.8% of adult cats have antibodies against feline panleukopenia virus (FPV) and thus are likely protected against FPV infection. It is, however, unknown how healthy adult cats with different antibody titres react to FPV vaccination in the field. Therefore, the aim of the study was to measure antibody titres in healthy adult cats within a period of 28 days after vaccination against FPV and to evaluate factors that are associated with a lack of adequate response to vaccination. METHODS: One hundred and twelve healthy adult cats were vaccinated with a vaccine against FPV, feline herpesvirus and feline calicivirus. Antibodies against FPV were determined before vaccination (day 0), on day 7 and day 28 after vaccination by haemagglutination inhibition (HI). A HI titre ?1:40 was defined as protective. An adequate response to vaccination was defined as a four-fold titre increase. Uni- and multivariate statistical analysis was used to determine factors associated with an adequate response. RESULTS: Pre-vaccination antibody titres of ?1:40 were present in 64.3% (72/112; 95% confidence interval [CI] 55.1-72.6). Only 47.3% (53/112; 95% CI 37.8-57.0) of cats had an adequate response to vaccination. Factors associated with an adequate response to vaccination were lack of previous vaccination (odds ratio [OR] 15.58; 95% CI 1.4-179.1; P = 0.035), lack of antibodies (?1:40) prior to vaccination (OR 23.10; 95% CI 5.4-98.8; P <0.001) and breed (domestic shorthair cats; OR 7.40; 95% CI 1.4-38.4; P = 0.017). CONCLUSIONS AND RELEVANCE: As none of the cats with high pre-vaccination antibody titres (?1:160) had an at least four-fold increase in FPV antibody titres, measurement of antibodies rather than regular revaccinations should be performed. Thus, evaluation of FPV antibody titre in cats with previous vaccinations against FPV are recommended prior to revaccination. PMID- 29256320 TI - Differential effects of public and private funding in the medical device industry. AB - INTRODUCTION: Funding for scientific advancement comes from two dominant sources: public funds used to generate knowledge, and private sector funds in the pursuit of commercial products. It is unclear how to compare the outputs of these two financial mechanisms because both sectors are motivated by common goods but are also governed by divergent forces. Employment within a geographic region may be a metric of mutual value that can be applied equally to assess the societal impacts of two financing sources. Areas covered: The authors focused on the medical device industry, which is a robust sector of growth for the U.S. economy. The U.S. NIH and venture capital community are representatives of public and private capital, respectively. Using a longitudinal employment dataset of 247 distinct locations, the authors found that NIH funding tends to create more jobs directly compared to venture capital funding. Moreover, the indirect effect of governmental funding is initially smaller than that of venture capital funding for the first two years, but eventually surpasses that of venture capital funding. Expert commentary: These findings imply that policy decisions regarding financial allocations in the medical device industry should consider the appropriate typology of financial capital and its consequences. PMID- 29256321 TI - Evaluation of three herbal compounds used for the management of lower urinary tract disease in healthy cats: a pilot study. AB - OBJECTIVES: Lower urinary tract disease (LUTD) occurs commonly in cats, and idiopathic cystitis (FIC) and urolithiasis account for >80% of cases in cats <10 years of age. Although several strategies have been recommended, a common recommendation is to induce dilute urine resulting in more frequent urination and to dilute calculogenic constituents. In addition to conventional therapy using modified diets, traditional Chinese and Western herbs have been recommended, although only one - choreito - has published data available. We evaluated three commonly used herbal treatments recommended for use in cats with LUTD: San Ren Tang, Wei Ling Tang and Alisma. We hypothesized that these three Chinese herbal preparations would induce increased urine volume, decreased urine saturation for calcium oxalate and struvite, and differences in mineral and electrolyte excretions in healthy cats. METHODS: Six healthy spayed female adult cats were evaluated in a placebo-controlled, randomized, crossover design study. Cats were randomized to one of four treatments, including placebo, San Ren Tang, Wei Ling Tang or Alisma. Treatment was for 2 weeks each with a 1 week washout period between treatments. At the end of each treatment period, a 24 h urine sample was collected using modified litter boxes. RESULTS: Body weights were not different between treatments. No differences were found in 24 h urinary analyte excretions, urine volume, urine pH or urinary saturation for calcium oxalate or struvite between treatments. CONCLUSIONS AND RELEVANCE: The results of this study do not support the hypothesis; however, evaluation of longer-term and different dosage studies in cats with LUTD is warranted. PMID- 29256322 TI - Hydrophilic surface modification of coronary stent using an atmospheric pressure plasma jet for endothelialization. AB - The first two authors contributed equally to this study. Bioactivity and cell adhesion properties are major factors for fabricating medical devices such as coronary stents. The aim of this study was to evaluate the advantages of atmospheric-pressure plasma jet in enhancing the biocompatibility and endothelial cell-favorites. The experimental objects were divided into before and after atmospheric-pressure plasma jet treatment with the ratio of nitrogen:argon = 3:1, which is similar to air. The treated surfaces were basically characterized by means of a contact angle analyzer for the activation property on their surfaces. The effect of atmospheric-pressure plasma jet on cellular response was examined by endothelial cell adhesion and XTT analysis. It was difficult to detect any changeable morphology after atmospheric-pressure plasma jet treatment on the surface. The roughness was increased after atmospheric-pressure plasma jet treatment compared to nonatmospheric-pressure plasma jet treatment (86.781 and 7.964 nm, respectively). The X-ray photoelectron spectroscopy results showed that the surface concentration of the C-O groups increased slightly from 6% to 8% after plasma activation. The contact angle dramatically decreased in the atmospheric-pressure plasma jet treated group (22.6 +/- 15.26 degrees ) compared to the nonatmospheric-pressure plasma jet treated group (72.4 +/- 15.26 degrees ) ( n = 10, p < 0.05). The effect of the increment in hydrophilicity due to the atmospheric-pressure plasma jet on endothelial cell migration and proliferation was 85.2% +/- 12.01% and 34.2% +/- 2.68%, respectively, at 7 days, compared to the nonatmospheric-pressure plasma jet treated group (58.2% +/- 11.44% in migration, n = 10, p < 0.05). Taken together, the stent surface could easily obtain a hydrophilic property by the atmospheric-pressure plasma jet method. Moreover, the atmospheric-pressure plasma jet might affect re-endothelialization after stenting. PMID- 29256323 TI - "It's often liberating": consumers discuss causal beliefs in the treatment process. AB - BACKGROUND: Causal beliefs are thought to influence consumers' perceptions of their mental illness and self-stigma, and may impact treatment and recovery. Understanding consumers' perspective on causes being addressed in treatment is vital to help guide future research and improve services. AIM: This study aimed to explore consumers' views on causes of mental illness being addressed in treatment, along with their subjective experiences of how causes were focused on in their treatment. METHODS: Using a qualitative approach, semi-structured interviews were conducted with 23 consumers who self-identified as having a mental illness. A thematic analytic framework was used to identify and analyse themes that emerged within the data. RESULTS: Consumers believed that causes were important and should be addressed in treatment, and identified several associated benefits including increased insight/personal understanding of their illness, symptom management and relapse prevention and reduced self-blame. Negative consequences and considerations were also identified. CONCLUSION: Causes help consumers make sense of their illness, and consumers would like causes to be addressed in treatment. More research is needed on how mental health professionals can address causes effectively as consumers are currently dissatisfied with how causes were discussed in their treatment. PMID- 29256325 TI - Endoscopic Anatomy of the Tensor Fold and Anterior Attic. AB - Objectives The objectives of the study were to (1) study the anatomical variations of the tensor fold and its anatomic relation with transverse crest, supratubal recess, and anterior epitympanic space and (2) explore the most appropriate endoscopic surgical approach to each type of the tensor fold variants. Study Design Cadaver dissection study. Setting Temporal bone dissection laboratory. Subjects and Methods Twenty-eight human temporal bones (26 preserved and 2 fresh) were dissected through an endoscopic transcanal approach between September 2016 and June 2017. The anatomical variations of the tensor fold, transverse crest, supratubal recess, and anterior epitympanic space were studied before and after removing ossicles. Results Three different tensor fold orientations were observed: vertical (type A, 11/28, 39.3%) with attachment to the transverse crest, oblique (type B, 13/28, 46.4%) with attachment to the anterior tegmen tympani, and horizontal (type C, 4/28, 14.3%) with attachment to the tensor tympani canal. The tensor fold was a complete membrane in 20 of 28 (71.4%) specimens, preventing direct ventilation between the supratubal recess and anterior epitympanic space. We identified 3 surgical endoscopic approaches, which allowed visualization of the tensor fold without removing the ossicles. Conclusions The orientation of the tensor fold is the determining structure that dictates the conformation and limits of the epitympanic space. We propose a classification of the tensor fold based on 3 anatomical variants. We also describe 3 different minimally invasive endoscopic approaches to identify the orientation of the tensor fold while maintaining ossicular chain continuity. PMID- 29256324 TI - The effect of phosphodiesterase-5 inhibitors on cerebral blood flow in humans: A systematic review. AB - Agents that augment cerebral blood flow (CBF) could be potential treatments for vascular cognitive impairment. Phosphodiesterase-5 inhibitors are vasodilating drugs established in the treatment of erectile dysfunction (ED) and pulmonary hypertension. We reviewed published data on the effects of phosphodiesterase-5 inhibitors on CBF in adult humans. A systematic review according to PRISMA guidelines was performed. Embase, Medline and Cochrane Library Trials databases were searched. Sixteen studies with 353 participants in total were retrieved. Studies included healthy volunteers and patients with migraine, ED, type 2 diabetes, stroke, pulmonary hypertension, Becker muscular dystrophy and subarachnoid haemorrhage. Most studies used middle cerebral artery flow velocity to estimate CBF. Few studies employed direct measurements of tissue perfusion. Resting CBF velocity was unaffected by phosphodiesterase-5 inhibitors, but cerebrovascular regulation was improved in ED, pulmonary hypertension, diabetes, Becker's and a group of healthy volunteers. This evidence suggests that phosphodiesterase-5 inhibitors improve responsiveness of the cerebral vasculature, particularly in disease states associated with an impaired endothelial dilatory response. This supports the potential therapeutic use of phosphodiesterase-5 inhibitors in vascular cognitive impairment where CBF is reduced. Further studies with better resolution of deep CBF are warranted. The review is registered on the PROSPERO database (registration number CRD42016029668). PMID- 29256326 TI - Primary Surgery vs Radiotherapy for Early Stage Oral Cavity Cancer. AB - Objective The goal of this study is to determine the effect of primary surgery vs radiotherapy (RT) on overall survival (OS) in patients with early stage oral cavity squamous cell carcinoma (OCSCC). In addition, this study attempts to identify factors associated with receiving primary RT. Study Design Retrospective cohort study. Setting National Cancer Database (NCDB, 2004-2013). Subjects and Methods Reviewing the NCDB from 2004 to 2013, patients with early stage I to II OCSCC were identified. Kaplan-Meier estimates of survival, Cox regression analysis, and propensity score matching were used to examine differences in OS between primary surgery and primary RT. Multivariable logistic regression analysis was performed to identify factors associated with primary RT. Results Of the 20,779 patients included in the study, 95.4% (19,823 patients) underwent primary surgery and 4.6% (956 patients) underwent primary RT. After adjusting for covariates, primary RT was associated with an increased risk of mortality (adjusted hazard ratio [aHR], 1.97; 99% confidence interval [CI], 1.74-2.22). On multivariable analysis, factors associated with primary RT included age >=70 years, black race, Medicaid or Medicare insurance, no insurance, oral cavity subsite other than tongue, clinical stage II disease, low-volume treatment facilities, and earlier treatment year. Conclusion Primary RT for early stage OCSCC is associated with increased mortality. Approximately 5% of patients receive primary RT; however, this percentage is decreasing. Patients at highest risk for receiving primary RT include those who are elderly, black, with public insurance, and treated at low-volume facilities. PMID- 29256328 TI - Association of Socioeconomic Status, Race and Insurance Status with Chronic Rhinosinusitis Patient-Reported Outcome Measures. AB - Objective Disparities in health and health care access are widely prevalent. However, disparities among patients with chronic rhinosinusitis (CRS) are poorly understood. We investigated if CRS severity at presentation according to socioeconomic factors. Study Design Cross-sectional study. Setting Tertiary rhinology center. Subjects and Methods Three hundred prospectively recruited patients presenting with CRS were included. Outcome variables included CRS symptomatology, as reflected by the 22-item Sinonasal Outcome Test (SNOT-22); general health status, as reflected by the EuroQol 5-dimensional visual analog scale (EQ-5D VAS); and CRS-related antibiotic and systemic corticosteroid use. Race/ethnicity, zip code income bracket, education level, and insurance status were used as predictor variables. Regression, controlling for clinical and demographic characteristics, was used to determine associations between predictor and outcome variables. Results Mean SNOT-22 score was 33.8 (SD, 23.2), and mean EQ-5D VAS score was 74.2 (SD, 18.9). On multivariable analysis, presenting SNOT 22 and EQ-5D VAS scores were not associated with nonwhite patient race/ethnicity ( P = .634 and P = .866), education ( P = .106 and P = .586), or the percentage of households in zip code with incomes <$50,000 per year ( P = .917 and P = .979, respectively). SNOT-22 scores did not differ by insurance type, but patients receiving Medicare reported worse general health status. Use of oral antibiotics or oral steroids for CRS was not associated with predictor variables. Conclusion Patients with CRS presented to a tertiary rhinology center with similar metrics for CRS severity and pre-presentation medical management regardless of race/ethnicity, education status, or zip code income level. Patients with Medicare had worse general health status. Further research should investigate potential disparities in diagnosis of CRS, specialist referral, and treatment outcomes. PMID- 29256327 TI - Probabilistic population projections for countries with generalized HIV/AIDS epidemics. AB - In 2015, the United Nations (UN) issued probabilistic population projections for all countries up to 2100, by simulating future levels of total fertility and life expectancy and combining the results using a standard cohort component projection method. For the 40 countries with generalized HIV/AIDS epidemics, the mortality projections used the Spectrum/Estimation and Projection Package (EPP) model, a complex, multistate model designed for short-term projections of policy-relevant quantities for the epidemic. We propose a simpler approach that is more compatible with existing UN projection methods for other countries. Changes in life expectancy are projected probabilistically using a simple time series regression and then converted to age- and sex-specific mortality rates using model life tables designed for countries with HIV/AIDS epidemics. These are then input to the cohort component method, as for other countries. The method performed well in an out-of-sample cross-validation experiment. It gives similar short-run projections to Spectrum/EPP, while being simpler and avoiding multistate modelling. PMID- 29256329 TI - Utilization and Survival of Postoperative Radiation or Chemoradiation for pT1 2N1M0 Head and Neck Cancer. AB - Objective To analyze the patterns of care and survival for pT1-2N1M0 head and neck cancer based on receipt of surgery alone, surgery + postoperative radiotherapy (S + RT), or surgery + postoperative chemoradiotherapy (S + CRT). Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods We queried the database for patients with stage pT1-2N1M0 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx between 2004 and 2012 who were treated with surgery with negative margins and no extracapsular extension. Logistic regression was used to assess predictors of receipt of postoperative treatment. Overall survival was assessed by the Kaplan Meier method, and Cox regression analysis identified covariates that affected it. Results There were 1598 patients included in this study: 566 (35.4%) received surgery alone; 726 (45.4%), S + RT; and 306 (19.1%), S + CRT. The 5-year overall survival was 68.8%, 74.0%, and 87.8%, respectively ( P = .009 comparing S + RT and surgery alone, P < .001 for all other comparisons). On multivariable logistic regression, academic centers were associated with a decreased likelihood of S + RT (odds ratio = 0.71) and S + CRT (odds ratio = 0.66). Multivariable Cox regression demonstrated no difference in survival for S + RT over surgery alone (hazard ratio = 0.88, 95% CI = 0.70-1.09, P = .24); however, there was a survival benefit associated with S + CRT (hazard ratio = 0.57, 95% CI = 0.39-0.81, P = .002). Conclusion Nearly 65% of patients with pT1-2N1 head and neck cancer with negative margins and no extracapsular extension received S + RT or S + CRT. Improvement in survival was noted only for patients who received S + CRT. PMID- 29256330 TI - Balancing relapses versus cognitive impairment in primary central nervous system lymphoma: a single-center experience. AB - OBJECTIVES: The outcomes of primary central nervous system lymphoma (PCNSL) are much improved with multi-modality regimens. Unfortunately, in limited-resource countries, chemo-radiotherapy is the only option of curative-intent treatment. This study aimed to evaluate the effects of low-dose whole brain radiotherapy (WBRT) as a consolidation on disease control and long-term neurocognitive functions. METHODS: We conducted a retrospective single-center study enrolling PCNSL patients from 2011 to May 2016 to evaluate the real-life treatment outcome and neurotoxicity from treatment especially radiotherapy. RESULTS: Thirty-seven newly diagnosed immunocompetent PCNSL patients were treated with a high-dose methotrexate-based regimen with or without WBRT. The median age was 56 (range 16 78) years old. After chemotherapy, the overall response and complete response (CR) rates were 59.5% and 43.2%, respectively. All 6 partial response (PR) patients and 6 of 16 CR patients underwent radiotherapy. In 22 patients who achieved CR, the progression-free survival (PFS) of patients without WBRT was significantly inferior to the WBRT group with the hazard ratio of 4.7 (95% confidence interval 1.14-19.82, p = 0.03). The 3-year PFS were 35% and 78.75%, respectively, but there was no difference in overall survival. The serial Montreal Cognitive Assessment evaluations (20-72 months post chemotherapy) of 10 long-term CR patients revealed one dementia among three patients without WBRT and five mild cognitive impairments in seven patients with WBRT. Except for the dementia case, all the other patients can perform daily activities without assistance. CONCLUSION: The low-dose WBRT consolidation is associated with lower PCNSL relapses with only mild neurocognitive toxicity. PMID- 29256331 TI - Observations on self-incineration characteristics in 24 years (1993-2016) of autopsies in the city of Milan. AB - Self-incineration is one of the most dramatic and lethal suicide methods. It is rarely reported in Western countries and is more frequent in developing regions. We illustrate the forensic cases of self-immolation occurring over 24 years in the city of Milan, Italy, highlighting the main issues of such a complex and rare suicide. We selected 33 cases of self-incineration among 23,417 autopsies (4022 suicides) performed at the Department of Legal Medicine of the University of Milan over a period of 24 years (1993-2016). Several parameters were included and analysed: gender and age of the victims, pathological history, previous suicide intentions/attempts, duration of burning, place of death or discovery of the corpse, circumstantial data of fatal events and autopsy findings, with particular attention to thermal injuries. Self-incineration was found in 0.8% of total suicides and 0.14% of total autopsies. One of these cases involved a complex modality (association with plastic-bag suffocation). The typical characteristics of the victim were an Italian man with psychiatric illness, frequently moved by passion, existential discomfort and economic problems. During the 24-year period, the number of cases of self-incineration progressively reduced. This study provides a general overview in one of the biggest metropolitan Italian areas and is one of the few works performed on this topic. It may be helpful in understanding and studying such an unusual manner of suicide. PMID- 29256332 TI - Influence of occupational factors on regional differences in sick leave: A prospective population study. AB - AIMS: Number of sick leave days vary by county, but little is known about the extent to which this gradient may be explained by differences pertaining to occupational composition and occupational exposure. METHODS: A randomly drawn cohort from the general population in Norway, aged 18-69 years, was interviewed by telephone in the second half of 2009 ( n=12,255; response at baseline=60.9%) and followed up in national registries to the end of 2010. Eligible respondents were registered with an active employee relationship in 2009 and 2010 ( n=8275). Information on counties ( n=19) was based on the administrative register. The outcome of interest was the number of physician-certified sick-leave days divided by scheduled man-days during 2010 (i.e. sick-leave percentage (SLP)). RESULTS: The average SLP during 2010 was 5.2%. The between-county variation in SLP ranged from 4.0% to 7.2%. Compared to the age- and gender-adjusted model, adjustment for occupation, economic sector and self-reported occupational exposure reduced the median difference in SLP between the county with the lowest SLP (reference county) and the SLP in the other counties by 1.08 percentage points (i.e. a 58% reduction). The impact of occupational composition and occupational exposure on the total between-county variance in SLP was a 16% reduction. CONCLUSIONS: Occupational composition and self-reported occupational exposure help to explain a significant part of the difference in SLP between counties, and appear to be more important explanatory factors than demographic variables, self-reported health and smoking. PMID- 29256333 TI - Lonoctocog alfa (rVIII-SingleChain) for the treatment of haemophilia A. AB - INTRODUCTION: The administration of factor VIII (FVIII) concentrates on-demand or on long-term prophylaxis is the effective and safe standard of care of patients with hemophilia A (HA). Development of neutralizing antibodies against exogenous FVIII and the short half-life of the current available products remain major challenges. There is currently a great interest towards newer FVIII products with the goal of reducing the inhibitor risk and increasing the half-life. Area covered: In this review, the authors describe the efficacy and safety of rVIII SingleChain (Lonoctocog alfa), the first and only single chain recombinant FVIII (rFVIII) molecule developed for the prevention and treatment of bleeding episodes in HA patients. The pre-clinical and clinical studies of rVIII-SingleChain as well as the results of the AFFINITY trial program in previously treated patients both adults and pediatric are presented and discussed. Expert opinion: The results from PTP studies document the efficacy and safety profile of the rVIII SingleChain. However, even if rFVIII-SingleChain presents advantageous pharmacokinetic features compared to conventional rFVIII, it should not be considered as an EHL-FVIII while its immunogenicity is currently being studied in PUPs. The slightly better PK profile of rFVIII-SingleChain could however allow a small number of selected patients to be treated with a less intensive regimen. PMID- 29256334 TI - Utility of various WAIS-IV Digit Span indices for identifying noncredible performance validity among cognitively impaired and unimpaired examinees. AB - OBJECTIVE: Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) Reliable Digit Span (RDS), RDS-revised (RDS-R), and age-corrected scaled score (ACSS) are validated and commonly used embedded performance validity tests (PVTs), though existing validation studies have largely examined younger (approximate ages 19 35) patients with mild traumatic brain injury or those without cognitive impairment. This study compared the classification accuracy of RDS, RDS-R, and ACSS in a mixed clinical sample of relatively older (M age = 54.61) veterans with and without neurocognitive impairment. METHOD: During a comprehensive neuropsychological evaluation, 113 clinically-referred veterans completed the WAIS-IV Digit Span subtest and the following criterion PVTs: Dot Counting Test, Word Choice Test, and Test of Memory Malingering. Those with <=1 criterion PVT failure were classified as valid (n = 87), whereas those with >=2 failures were classified as noncredible (n = 26). Among valid participants, 49% were cognitively impaired. RESULTS: RDS, RDS-R, and ACSS all significantly predicted validity group membership with respective areas under the curve (AUCs) of .79, .81, and .85, and optimal cut scores of RDS <= 5, RDS-R <= 9, and ACSS <= 5. Lower accuracy and AUCs were observed for the valid-cognitively impaired subsample across indices, but to a greater degree for traditional RDS. ACSS evidenced maximal sensitivity/specificity for the total sample (<=5; .62/.87), cognitively unimpaired subsample (<=5; .62/.95), and cognitively impaired subsample (<=4; .39/.86). CONCLUSIONS: ACSS yielded better classification accuracy and sensitivity/specificity than RDS and RDS-R. While all three indices have utility as embedded PVTs, ACSS <= 5 may be most robust to cognitive impairment while identifying noncredible performance. PMID- 29256335 TI - Characterisation and management of concrete grinding residuals. AB - Concrete grinding residue is the waste product resulting from the grinding, cutting, and resurfacing of concrete pavement. Potential beneficial applications for concrete grinding residue include use as a soil amendment and as a construction material, including as an additive to Portland cement concrete. Concrete grinding residue exhibits a high pH, and though not hazardous, it is sufficiently elevated that precautions need to be taken around aquatic ecosystems. Best management practices and state regulations focus on reducing the impact on such aquatic environment. Heavy metals are present in concrete grinding residue, but concentrations are of the same magnitude as typically recycled concrete residuals. The chemical composition of concrete grinding residue makes it a useful product for some soil amendment purposes at appropriate land application rates. The presence of unreacted concrete in concrete grinding residue was examined for potential use as partial replacement of cement in new concrete. Testing of Florida concrete grinding residue revealed no dramatic reactivity or improvement in mortar strength. PMID- 29256336 TI - A new look at the schema therapy model: organization and role of early maladaptive schemas. AB - This study reexamined the organization of Young's 18 early maladaptive schemas and their hypothesized associations with experiences of need-thwarting parental experiences in childhood and the "vulnerable child" mode of emotional distress in adulthood. A large Danish sample (N = 1054) of 658 clinical- and 391 nonclinical adults completed measures of early maladaptive schemas, parenting styles, and the vulnerable child mode. We identified four higher-order schema domains as most appropriate in terms of interpretability and empirical indices ("Disconnection & Rejection", "Impaired Autonomy & Performance", "Excessive Responsibility & Standards", and "Impaired Limits"). All four schema domains were differentially associated with conceptually relevant need-thwarting parental experiences. Apart from "Impaired Limits", the schema domains meaningfully accounted for the association between need-thwarting parental experiences in childhood and emotional states of feeling like a "vulnerable child" in adulthood. We conclude that four domains of early maladaptive schemas are empirically and conceptually consistent with Young's schema therapy model of personality pathology and longstanding emotional disorders. Findings warrant replication using different populations and if possible a prospective multi-method design. A scoring key for computing the four schema domains is provided. PMID- 29256337 TI - Effectiveness of a Self-Management Intervention to Promote an Active Lifestyle in Persons With Long-Term Spinal Cord Injury: The HABITS Randomized Clinical Trial. AB - BACKGROUND: Most people with long-term spinal cord injury (SCI) have a very inactive lifestyle. Higher activity levels have been associated with health benefits and enhanced quality of life. Consequently, encouraging an active lifestyle is important and behavioral interventions are needed to establish durable lifestyle changes. OBJECTIVE: The Healthy Active Behavioral Intervention in SCI (HABITS) study was aimed to evaluate the effectiveness of a structured self-management intervention to promote an active lifestyle in inactive persons with long-term SCI. METHODS: This assessor-blinded randomized controlled trial was conducted at 4 specialized SCI units in the Netherlands. Sixty-four individuals with long-term SCI (>10 years), wheelchair-user and physically inactive, were included. Participants were randomized to either a 16-week self management intervention consisting of group meetings and individual counseling and a book, or to a control group that only received information about active lifestyle by one group meeting and a book. Measurements were performed at baseline, 16 weeks, and 42 weeks. Primary outcome measures were self-reported physical activity and minutes per day spent in wheelchair driving. Secondary outcomes included perceived behavioral control (exercise self-efficacy, proactive coping), stages of change concerning exercise, and attitude toward exercise. RESULTS: Mixed models analyses adjusted for age, sex, level of SCI, time since injury, baseline body mass index, and location did not show significant differences between the intervention and control groups on the primary and secondary outcomes ( P >= .05). CONCLUSIONS: A structured 16-week self-management intervention was not effective to change behavior toward a more active lifestyle and to improve perceived behavioral control, stages of change, and attitude. PMID- 29256338 TI - Building capacity for community waste management in low- and middle-income countries. PMID- 29256339 TI - Implementation of treat-to-target principles in the management of systemic lupus erythematosus. PMID- 29256340 TI - A North American perspective of content and quality of websites in the English language on childhood-onset lupus erythematosus. AB - Objective The objective of this article is to examine the quality, content, and readability of information and resources in the English language and accessible on the internet by pediatric patients with systemic lupus erythematosus (SLE) and their families in North America. Methods Keywords relevant to SLE were generated by an undergraduate student, a first-year medical student, and a third-year pediatric resident, and a search was conducted across five commonly used search engines. Quality of information found was evaluated independently by an undergraduate student, a graduate student, a first-year medical student, and a third-year pediatric resident using the DISCERN tool. Two pediatric rheumatologists assessed website accuracy and completeness. Readability of websites was determined using the Flesch-Kincaid grade level and Reading Ease score. Results Out of 2000 websites generated in the search, only 34 unique websites met inclusion criteria. Only 16 of these websites had DISCERN scores above 50% (fair quality). Overall quality of website information was fair with mean +/-standard deviation (SD) DISCERN quality score of 44 +/- 7 (range: 30-56). Only nine websites of 34 had DISCERN scores above 50 (>66%, indicating greater quality) and were further assessed for completeness. Flesch-Kincaid grade level was 11 +/- 1 (mean+/-SD) and reading ease score was 39 +/- 10 (mean+/-SD, range of 11-61). Conclusion Our study highlights the need for more complete, readable information regarding the unique needs of pediatric patients with childhood-onset SLE and their families. PMID- 29256341 TI - Gold Nanoparticles Conjugated with Glycopeptides for Lectin Detection and Imaging on Cell Surface. AB - BACKGROUND: Lectins are carbohydrate binding proteins and related to various biological events and diseases including virus infection and cancer metastasis. In particular, galactose-binding lectins have attracted attention as targets for drug delivery and cancer markers. We, previously, demonstrated that sugar modified peptides (glycopeptides) were useful ligands for the detection and characterization of lectins compared to the sugar unit alone. Gold nanoparticles (GNPs) conjugated with mannose-modified glycopeptides were useful in detection of concanavalin A, a mannose binding lectin. OBJECTIVES: The main objective of this study was to expand our glycopeptide-GNP conjugates for detection and imaging of galactose-binding lectins. METHODS: Four galactose-modified peptides (glycopeptides) were synthesized by Fmoc-based solid peptide synthesis method. Synthesized glycopeptides were conjugated with PEG-coated GNPs using thiol maleimide chemistry. The interaction between glycopeptide-GNPs (GP/GNPs) (0.5 nM) and RCA120, a galactose binding lectin, (0.5-1000 nM) was evaluated by mesuring absorption spectra of GNPs. The inhibition experiment in the interaction between GP/GNPs (0.5 nM) and RCA120 (100 nM) was performed in the presence of 60 mM alpha methyl mannose or 60 mM lactose. HepG2 and MCF7 cells were placed on 22*22 mm cover slip in 6 well cell culture plates (2*105 cells / well) and cultured overnight at 37 degrees C under 5% CO2 condition. 1 mL of GP/GNPs (0.2 nM) were added in each well and incubated for 18 h at 37 degrees C under 5% CO2 condition. After incubation, cells were washed twice with PBS and fixed with 4% paraformaldehyde solution. The cover slips were coated with 90% glycerol and sealed to slide glass. Dark-field images based on elastic light scattering were taken using a Nikon microscope (TieU) with an immersion dark field condenser. RESULTS: In the titration experiment of RCA120, GP/GNPs showed a decrease of absorbance according to the addition of RCA120, suggesting that the aggregation of GP/GNPs is induced through the binding to RCA120. The EC50 values of AA(Gal)/GNP, WF(Gal)/GNP, TS(Gal)/GNP and ED(Gal)/ GNP were estimated as 66.2 nM, 43.2 nM, 38.6 nM and 104.4 nM, respectively. TS(Gal)/GNP showed the lowest EC50 value among GP/GNPs. RCA120 has several binding sites for the galactose, and there are hydrophilic amino acids (Thr24, Glu26, Gln35, Asn42 and Asp44) around one of galactose binding sites. This result indicates that the hydrogen bonds between these amino acids and Thr/Ser residues of TS(Gal) contribute to the efficient aggregation of TS(Gal)/GNP. Next, inhibition experiments in the aggregation of WF(Gal)/GNP with RCA120 revealed that lactose inhibits the WF(Gal)/GNP binding with RCA120, but alpha-methyl mannose does not, and that WF(Gal)/GNP selectively interacts with RCA120 and forms the aggregate. Finally, a galactose binding protein on the surface of HepG2 cells was successfully visualized by using GP/GNPs as optical probes. CONCLUSION: Our results demonstrated that GP/GNPs could detect RCA120 by the selective binding and the aggregation formation. Furthermore, a galactose binding protein on the surface of HepG2 cells is successfully visualized using WF(Gal)/GNP as an optical probe. Thus, GNPs conjugated with glycopeptides will be useful probes for the selective detection and imaging of lectins. PMID- 29256342 TI - Cyclodextrins as Drug Carriers in Pharmaceutical Technology: The State of the Art. AB - BACKGROUND: Cyclodextrins (CDs) are versatile excipients with an essential role in drug delivery, as they can form non-covalently bonded inclusion complexes (host-guest complexes) with several drugs either in solution or in the solid state. METHODS: The main purpose of this publication was to carry out a state of the art of CDs as complexing agents in drug carrier systems. In this way, the history, properties and pharmaceutical applications of the CDs were highlighted with typical examples. The methods to enhance the Complexation Efficiency (CE) and the CDs applications in solid dosage forms were emphasized in more detail. RESULTS: The main advantages of using these cyclic oligosaccharides are as follows: (1) to enhance solubility/ dissolution/ bioavailability of poorly soluble drugs; (2) to enhance drug stability; (3) to modify the drug release site and/or time profile; and (4) to reduce drug side effects (for example, gastric or ocular irritation). These compounds present favorable toxicological profile for human use and therefore there are various medicines containing CDs approved by regulatory authorities worldwide. On the other hand, the major drawback of CDs is the increase in formulation bulk, once the CE is, in general, very low. This aspect is particularly relevant in solid dosage forms and limits the use of CDs to potent drugs. CONCLUSION: CDs have great potential as drug carriers in Pharmaceutical Technology and can be used by the formulator in order to improve the drug properties such as solubility, bioavailability and stability. Additionally, recent studies have shown that these compounds can be applied as active pharmaceutical ingredients. PMID- 29256343 TI - Computational method for distinguishing lysine acetylation, sumoylation, and ubiquitination using the random forest algorithm with a feature selection procedure. AB - BACKGROUND: The post-translational modifications (PTMs) on the side chains of conserved lysine (Lys) residues play important roles in myriad cellular processes, such as histone modification, protein degradation, and regulation of DNA damage responses. To date, several computational methods have been developed to identify different PTMs on Lys residues. However, most of these methods focused on identifying one particular PTM regardless of other types of PTMs. OBJECTIVE: In this study, we first conducted a computational investigation of three types of PTMs (acetylation, sumoylation, and ubiquitination) at the same time by analyzing the protein structure and sequence factors surrounding the substrate Lys residues in these types of PTMs. METHOD: To extract fully the structural and sequence information around the Lys residues, six types of features were used to encode the peptide segments containing the substrates. Next, through a feature selection method, i.e., maximum relevance minimum redundancy (mRMR), two feature lists, i.e., MaxRel feature list and mRMR feature list, were obtained. For the mRMR feature list, it was applied to extract optimal features of the random forest algorithm for distinguishing three types of PTMs. RESULTS: An optimal classification model with overall accuracy of 0.989 was built. For the MaxRel feature list, we investigated the top-ranked features to uncover the site-preference and residue-preference of Lys residues. CONCLUSION: The results suggested that the disorder structure and the preference of flanking residues were the most important attributes to distinguish the three types of PTMs, which was consistent with the results reported in previous studies. PMID- 29256344 TI - Prediction of Drug-Plasma Protein Binding Using Artificial Intelligence Based Algorithms. AB - AIM AND OBJECTIVE: Plasma protein binding (PPB) has vital importance in the characterization of drug distribution in the systemic circulation. Unfavorable PPB can pose a negative effect on clinical development of promising drug candidates. The drug distribution properties should be considered at the initial phases of the drug design and development. Therefore, PPB prediction models are receiving an increased attention. MATERIALS AND METHODS: In the current study, we present a systematic approach using Support vector machine, Artificial neural network, k- nearest neighbor, Probabilistic neural network, Partial least square and Linear discriminant analysis to relate various in vitro and in silico molecular descriptors to a diverse dataset of 736 drugs/drug-like compounds. RESULTS: The overall accuracy of Support vector machine with Radial basis function kernel came out to be comparatively better than the rest of the applied algorithms. The training set accuracy, validation set accuracy, precision, sensitivity, specificity and F1 score for the Suprort vector machine was found to be 89.73%, 89.97%, 92.56%, 87.26%, 91.97% and 0.898, respectively. CONCLUSION: This model can potentially be useful in screening of relevant drug candidates at the preliminary stages of drug design and development. PMID- 29256345 TI - Epigallocatechin-3-gallate(EGCG) : mechanisms and the combined applications. AB - EGCG is the most important pharmacological component in tea. Researches have confirmed its effects, including anti-tumor, anti-inflammation, anti-aging, anti obesity, anti-diabetic, cardiovascular disease prevention and protection, immunoregulation and neuroprotection. Paradoxically, the clinical application of EGCG is very rare. One of the most important reasons is its poor stability and low bioavailability. Excepting for altering the dosage form or synthesizing the analogues to overcome the loss during absorption, an increasing number of studies indicate that EGCG can exert certain auxiliary effect and enhance chemosensitivity in combined medication. The pharmacological action, the pharmacology network including mutation of signaling receptor and modulation of intracellular signaling pathway, and the combination treatment strategy of EGCG are clarified and sorted out, both the possible targets and combinatorial applications based on the characteristics of EGCG are systematically summarized. PMID- 29256346 TI - Analysis of key GO terms and KEGG pathways associated with carcinogenic chemicals. AB - Cancer is one of the serious disease that causes several human deaths every year. Up to now, we have spent lots of time and money to investigate this disease, thereby designing effective treatments. Previous studies mainly focus on studying genetic background of different subtypes of cancer and neglect another important factor, environmental factor. Carcinogenic chemical is one of the type of environmental factor, exposure of such chemical may definitely initiate and promote the tumorigenesis. In this study, we tried to partly describe the differences between carcinogenic and non-carcinogenic chemicals using gene ontology (GO) terms and KEGG pathways. The carcinogenic and non-carcinogenic chemicals that were retrieved from Carcinogenic Potency Database (CPDB) were encoded into numeric vectors using the enrichment theories of GO terms and KEGG pathways. Then, the minimal redundancy maximal relevance (mRMR) method was adopted to analyze all features, resulting in some important GO terms and KEGG pathways. The extensive analysis of the identified GO terms and KEGG pathways indicate that they all play roles during the tumorigenesis, inducing that they can be key indicator for identification of carcinogenic chemicals. PMID- 29256347 TI - Aerosol Drug Delivery Through High Flow Nasal Cannula. AB - BACKGROUND: High flow nasal cannula (HFNC) is widely utilized to support critically ill adults, pediatrics and neonates. Through the continuous delivery of oxygen at high flow rates that meet or exceed patients' inspiratory flow, HFNC improves oxygenation, respiratory rates, patient comfort, and tolerance during therapy. As HFNC becomes more widely employed, clinicians have started to consider aerosol drug delivery through HFNC. CONCLUSION: Using HFNC along with nebulizers as a potential therapy in aerosol medicine is a new and innovative approach for aerosol drug delivery to patients with pulmonary diseases. The purpose of this paper is to review current in vitro and in vivo studies on aerosol drug delivery through HFNC in adults and children. PMID- 29256348 TI - The Importance of Some Plant Extracts as Skin Anti-aging Resources: A Review. AB - BACKGROUND: Skin is the largest and most visible organ of the body. Many of its functions include temperature regulation, immunity from microorganisms, maintaining electrolyte balance, and protection from physical injuries, chemical agents and ultraviolet (UV) radiation. Aging occurs in every layer of the skin, primarily due to the degradation of its components. Induction of degradative enzymes and the abundant production of reactive oxygen species lead to skin aging. Understanding the complexity of skin structure and factors contributing to the skin aging will help us impede the aging process. Applications of anti-aging products are a common method to prevent or repair damages that lead to aging. CONCLUSION: This review will provide information on the causes and indicators of skin aging as well as examine studies that have used plants to produce anti-aging products. PMID- 29256349 TI - CXCR1/2 Chemokine Network Regulates Melanoma Resistance to Chemotherapies Mediated by NF-kappaB. AB - BACKGROUND: Cancer-related inflammation is recognized as a driver for tumor progression and chemokines are important players in both inflammation and the progression of many cancer types. CXC chemokines, especially CXCL8, have been implicated in melanoma growth and metastasis, while less is known for their roles in drug resistance. METHODS: We generated drug-resistant cells by continuous exposure to chemotherapeutic drugs and analyzed the mechanism(s) of therapy resistance in malignant melanoma. RESULTS: We report chemotherapies induced upregulation of a variety of chemokines in the CXCR1/CXCR2 network by an NF kappaB-dependent mechanism. Notably, analysis of the drug-resistant melanoma cell line selected after prolonged exposure to chemotherapeutic drug dacarbazine revealed higher levels of CXCL8 and CXCR2 compared with parent cells as a signature of drug resistance. CXCR2 neutralization markedly improved sensitivity to dacarbazine in melanoma cells. CONCLUSION: These data provide insights into what drives melanoma cells to survive after chemotherapy treatment, thus pointing to strategies for developing combined drug therapies for combating the problem of chemotherapy resistance in melanoma. PMID- 29256350 TI - Epigenetic Changes Induced by Green Tea Catechins a re Associated with Prostate Cancer. AB - Prostate cancer is one of the most difficult cancers to treat especially when it becomes hormone resistant such as castrate resistant prostate cancer (CRPC) and subsequent metastatic CRPC. Apart from the genetic alterations in prostate cancer, epigenetic modifications also play an important role in the development and neoplastic progression of this disease. These include DNA methylation, histone modifications, and non-coding microRNAs. miRNAs are a novel class of small endogenous single-stranded non-coding RNAs of 19-25 nucleotides in length that typically silence gene expression. Considering the reversibility of epigenetic alterations in early carcinogenesis process, reversion (correction) of these modifications by green tea catechins could be a promising strategy for cancer chemoprevention and therapy. Recent evidence suggests that green tea catechins such as epigallocatechin gallate (EGCG) not only act as epigenetic modulators but can also modify miRNA expression and their target mRNAs, consistently contributing to the inhibition of prostate carcinogenesis. Various studies also indicate that several green tea polyphenols (GTPs) exert synergistic effects with other cancer chemotherapeutic agents. Therefore, the use of appropriate combinations of green tea catechins with the existing chemotherapeutics will lead to a reduction in side effects without decreasing the chemotherapeutic effects. This review will summarize the key results from recent studies detailing the effects of green tea catechins such as EGCG on epigenetic alterations and miRNA expression in prostate cancer. PMID- 29256351 TI - The Emerging Role of Helicobacter Pylori-Induced Metabolic Gastrointestinal Dysmotility and Neurodegeneration. AB - Helicobacter pylori infection (Hp-I) is a prevalent disorder identified in the majority of the population in many countries around the world and is responsible for substantial gastrointestinal morbidity. Likewise, neurodegenerative diseases such as Alzheimer's disease, Parkinson's diseases, multiple sclerosis or glaucoma defined as ocular Alzheimer's disease, are associated with a large public health burden and are among the leading causes of disability. Emerging evidences suggest that Hp-I may be associated with neurodegenerative conditions. Moreover, Hp-I could be a predictor of metabolic syndrome (MetS). Hp-I and its related MetS may induce gastrointestinal tract dys-motility disorders with systemic complications possibly including central nervous system neurodegenerative pathologies. We hereby explore the emerging role of Hprelated metabolic gastrointestinal dys motilities on the molecular pathophysiology of Hprelated neurodegenerative and gastrointestinal disorders. Improving understanding of such Hp-I pathophysiology in brain pathologies may offer benefits by application of new relative therapeutic strategies including novel opportunities toward enhancing Hp eradication. PMID- 29256352 TI - Puerarin Stimulates Osteogenic Differentiation and Bone Formation Through the ERK1/2 and p38-MAPK Signaling Pathways. AB - BACKGROUND: Osteoporosis is a world-wide health problem, which leads to decreased bone strength and increased susceptibility to fractures. Puerarin, a phytoestrogen extracted from Pueraria lobata (Willd.) Ohwi, has been identified as a promising intervention for preventing bone loss and promoting bone regeneration. However, the underlying mechanisms for its anabolic action are still not clear. In the present study, we aimed to investigate the effect of puerarin on the osteogenic differentiation of bone marrow stromal cells (BMSCs) and the possible molecular mechanism mediating its action. METHODS: Bone marrow stromal cells (BMSCs) and intragastric administration on ovariectomized(OVX) rats were used to study the anti-osteoporotic function of puerarin. The involvement of mitogen-activated protein kinase (MAPK) signaling pathways was determined. RESULTS: Our results demonstrated that at optimal concentration, puerarin could promote osteogenic differentiation of BMSCs in vitro. This induction was mediated by MAPK signaling pathway. Further detailed study revealed that ERK1/2-Runx2 signaling pathway had more prominent effect than p38 signaling pathway in puerarin-induced differentiation of BMSCs toward the osteogenic phenotype. We also found that puerarin protected against reduction in bone mineral density and improved femur trabecular bone structure in ovariectomized rats. CONCLUSION: Our findings revealed the functional mechanism of puerarin in promoting osteogenic differentiation which involved ERK1/2 and p38-MAPK pathway and provided experimental evidence for the potential application of puerarin for estrogen replacement therapy of osteoporosis. PMID- 29256353 TI - Putative mechanisms of action and clinical use of lithium in children and adolescents: a critical review. AB - BACKGROUND: Lithium is a first-line treatment for bipolar disorder in adults, but its mechanism of action is still far from clear. Furthermore, evidences of its use in pediatric populations are sparse, not only for bipolar disorders, but also for other possible indications. OBJECTIVES: To provide a synthesis of published data on the possible mechanisms of action of lithium, as well as on its use in pediatric samples, including pharmacokinetics, efficacy, and safety data. METHODS: Clinical trials in pediatric samples with at least one standardized measure of efficacy/effectiveness were included in this review. We considered: i) randomized and open label trials, ii) combination studies iii) augmentation studies iv) case series including at least 5 patients. RESULTS: Different and non alternative mechanisms of action can explain the clinical efficacy of lithium. Clinical studies in pediatric samples suggest that lithium is effective in managing manic symptoms/episodes of bipolar disorder, both in the acute phase and as maintenance strategy. Efficacy on depressive symptoms/phases of bipolar disorder is much less clear, while studies do not support its use in unipolar depression and severe mood dysregulation. Conversely, it may be effective on aggression in the context of conduct disorder. Other possible indications, with limited published evidence, are the acute attacks in Kleine-Levin syndrome, behavioral symptoms of X-fragile syndrome, and the management of clozapine- or chemotherapy- induced neutropenia. Generally, lithium resulted relatively safe. CONCLUSIONS: Lithium seems an effective and well-tolerated medication on pediatric bipolar disorder and aggression, while further evidences are needed for other clinical indications. PMID- 29256354 TI - Knowledge, Practice and Attitudes Toward Pharmacovigilance and Adverse Drug Reactions Reporting Process Among Health Care Providers in Dammam, Saudi Arabia. AB - BACKGROUND: Pharmacovigilance is the science that plays an essential role in the reduction of ADRs which helps in predicting unwanted effects of drugs in community. Studying adverse drug reaction is an important arm of patient care. It aims at making the safe use of medicines for the treatment or prevention of disease. OBJECTIVES: To assess knowledge, Practice and attitudes toward pharmacovigilance and adverse drug reactions reporting process among Health Care Providers in Dammam, KSA. METHODS: This was a cross-sectional and questionnaire based study involving health care providers working in different hospitals. 160 questionnaires were distributed to the respondents (25 doctors, 65 nurses, 50 pharmacists and 25 other health care provides). Participants were selected randomly and those not willing to participate were excluded from the study. Chi square test was used for the calculation of P-Value. RESULTS: 135 participants responded to the questionnaire, while 160 participants were recruited for the study. The majority (n= 99, 73.33%, p=0.007) had no idea about national pharmacovigilance centers of KSA. The standard SFDA adverse drug reaction form was only known to 38.51 %, p=0.028 and only 38.51 %, p=0.002 were aware about electronic reporting of ADR. Only 34 %, p =0.002 of the respondents had ever reported an adverse drug reactions, 76.29 %, p=0.041 have not attended any training on ADR reporting and 86.66%, p=0.045 participants have no idea about impact of ADR reporting. CONCLUSION: The knowledge and attitude to ADR reporting was inadequate, our study has shown that the actual practice of ADR reporting is unsatisfactory. This indicates that there is a need to create an awareness of the importance of ADR reporting through CME/training of ADR reporting among healthcare providers. PMID- 29256355 TI - Anticancer Activity of Resorcinarene-PAMAM-Dendrimer Conjugates of Flutamide. AB - The synthesis of conjugates of flutamide with resorcinarene-PAMAM-dendrimers as well as alkyl and ethyl phenyl chains in the lower part of the macrocycle as a nucleus and diethylenetriamines in the dendritic branches gives the opportunity to obtain conjugates in one step of synthesis with 16 and 64 flutamide moieties in the structure. The in vitro anticancer studies showed that the conjugates of flutamide are more active than the free flutamide and the flutamide derivatives, thus diminishing the amount of flutamide used. The resorcinarene-dendrimer flutamide conjugates with a high drug payload improve the activity of the drug. This is important in delivering a sufficient amount of flutamide and suggests that the dendrimer facilitates more of the drug being introduced into cells. It was also observed that the new conjugates are less toxic than the anti-androgens. PMID- 29256356 TI - Cell Cycle Arrest and Apoptosis Induction of Phloroacetophenone Glycosides and Caffeoylquinic Acid Derivatives in Gastric Adenocarcinoma (AGS) Cells. AB - INTRODUCTION: In the present study, we analyzed anti-proliferative and apoptosis induction activity of five phenolic compounds: echisoside, pleoside, chlorogenic acid, 4,5-Di-O-caffeoylquinic acid, and cynarin on AGS (adenocarcinoma gastric) cell line. METHOD: These phenolic compounds were isolated from methanol extract of Dorema glabrum root. An MTT assay was conducted to evaluate the inhibitory effect on cancer cells. EB/AO staining was done to assess the mode of cell death and morphological changes of the cells' nuclei. Cell cycle distribution of the cells was analyzed by flow cytometry, and for further confirmation of the pathway, mRNA levels of apoptosis cascade players were quantified by qRT-PCR. RESULT: We found that echisoside, pleoside, chlorogenic acid, 4,5-Di-O caffeoylquinic acid, and cynarin inhibited the proliferation of AGS cancer cells in vitro. Our data revealed that these compounds triggered morphological changes characteristic of apoptotic cell death. These compounds up-regulated bax and caspase3 expression and down-regulated cyclin D1, bcl2, VEGFA, c-myc and survivin. Moreover, cell population increased at the G1 phase, and a number of cells at the G2/M phase of the cell cycle decreased after treatment. CONCLUSION: All these data suggest that phenolic compounds have a cytotoxic effect on gastric cancer cells and could trigger apoptosis. Besides cytotoxic activity, they could potentially arrest the cell cycle at the G1 phase. PMID- 29256357 TI - Emodin enhances the chemosensitivity of endometrial cancer by inhibiting ROS mediated Cisplatin-resistance. AB - Background Endometrial cancer is a common cause of death in gynecological malignancies. Cisplatin is a clinically chemotherapeutic agent. However, drug resistance is the primary cause of treatment failure. Objective Emodin is commonly used clinically to increase the sensitivity of chemotherapeutic agents, yet whether Emodin promotes the role of Cisplatin in the treatment of endometrial cancer has not been studied. Method CCK-8 kit was utilized to determine the growth of two endometrial cancer cell lines, Ishikawa and HEC-IB. The apoptosis level of Ishikawa and HEC-IB cells was detected by Annexin V / propidium iodide double-staining assay. ROS level was detected by DCFH-DA and NADPH oxidase expression. Expressions of drug-resistant genes were examined by real-time PCR and Western blotting. Results Emodin combined with Cisplatin reduced cell growth and increased the apoptosis of endometrial cancer cells. Co-treatment of Emodin and Cisplatin increased chemosensitivity by inhibiting the expression of drug resistant genes through reducing the ROS levels in endometrial cancer cells. In an endometrial cancer xenograft murine model, the tumor size was reduced and animal survival time was increased by co-treatment of Emodin and Cisplatin. Conclusion This study demonstrates that Emodin enhances the chemosensitivity of Cisplatin on endometrial cancer by inhibiting ROS-mediated expression of drug resistance genes. PMID- 29256358 TI - Synthesis, Spectral Characterization, Antibacterial and Anticancer Activity of some Titanium Complexes. AB - BACKGROUND: After the discovery of cisplatin, first non platinum anticancer drugs having excellent efficacy were budotitane and TiCl2(cp)2 but action mechanism is not clear. Therefore, we hereby reporting synthesis and biological activities novel titanium complexes to explore their mode of action. OBJECTIVES: Synthesis, spectral characterization, antibacterial and anticancer activity of some titanium complexes. Antibacterial studies on various bacterial strains and anticancer studies on HeLa, C6, CHO cancerous cell lines have been performed. Further, the cell death mechanistic study was done on CHO cell lines. METHOD: Titanium complexes with and without labile groups have been synthesized by reacting of TiCl4 with nitrogen containing ligands viz. 1,2-diaminocyclohexane, 1,10 Phenanthroline, adamantylamine, 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine in predetermined molar ratios. Antibacterial and anticancer studies were performed by agar well diffusion method and MTT assay respectively. Cell cycle analysis is done by using flow cytometry. RESULTS: Complex 2 i.e TiCl2(Phen)2 showed better activity than other complexes as an antibacterial as well as anticancer agent. Phase contrast imaging indicates that observed morphological changes of cells was dose dependent. Cell death mechanistic study have shown the increase in sub G0 phase population as well as formation of blebbing and fragmentation of chromatin material which is an indicative measure of apoptosis. CONCLUSION: Complex 2 proved to be more effective bactericide and cytotoxic agent. Cell cycle analysis showed cell arrest in G0 phase. Apoptosis percentage was found to increase in a dose dependent manner. So, prepared titanium complexes can be put to use as an important chemotherapeutic agents. PMID- 29256359 TI - Translational Research in Cutaneous Melanoma: New Therapeutic Perspectives. AB - Melanoma is an aggressive form of skin cancer characterized by poor prognosis and high mortality. The development of targeted agents based on the discovery of driver mutations as well as the implementation of checkpoint inhibitor-based immunotherapy represents a major breakthrough in the treatment of metastatic melanoma. However, in both cases the development of drug resistance and immune escape mechanisms as well as the lack of predictive biomarkers limits their extraordinary clinical efficacy. In this article, we summarize the available therapeutic options for patients with metastatic melanoma, outline the mechanisms implicated in the resistance to both targeted agents and immunotherapy, discuss potential predictive biomarkers and outline future therapeutic approaches under investigation. PMID- 29256360 TI - Roles of Glutamate and Glutamine Transport in Ammonia Neurotoxicity: State of the Art and Question Marks. AB - BACKGROUND: Excessive accumulation of ammonia in the brain is a causative factor of an array of neurological manifestations of hyperammonemic encephalopathies ("hyperammonemias", HA) among which hepatic encephalopathy (HE) is a major epidemiologic and therapeutic challenge. While ammonia neurotoxicity is symptomatically and mechanistically very complex, there is a consensus with regard to the leading role in its pathogenesis of: i) astrocytes being the primary cellular target of ammonia toxicity; ii) alterations of glutamate (Glu) dependent neurotransmission (over-excitation followed by inhibition of glutamatergic tone) being the cornerstone of its neurophysiological manifestations; and iii) brain edema, an often lethal consequence of astrocytic swelling, being among other factors caused by the retention of glutamine (Gln) in these cells. OBJECTIVE: This article critically evaluates the present literature attempting to relate manifestations of HA to changes in astrocytic Glu and Gln transport as observed in different in vivo and in vitro HA and/or HE models. Emphasis is put on two disproportions in the state of the art: i) the paucity of available data regarding ammonia-dependent changes in Glu transport activity vs the relative abundance of information on the expression of astrocytic Glu transporters (GLT-1/EAAT2 and GLAST/EAAT1); ii) the just emerging still not very conclusive knowledge on the response of astrocytic Gln transporters SN1 and SN2. CONCLUSION: The review on the above issues is complemented by own recent data which fill some of the many gaps in the knowledge. A brief account is included on the roles of heteromeric cell membrane Glu/arginine (Arg) exchanger y+LAT2 and on the mitochondrial Gln transport. PMID- 29256361 TI - Hidden hunger in South Asia: a review of recent trends and persistent challenges. AB - 'Hidden hunger' is a term used to describe human deficiencies of key vitamins and minerals, also known as micronutrients. While global in scale, the prevalence of micronutrient deficiencies is particularly high in South Asia despite recent successes in economic growth, agricultural output and health care. The present paper reviews the most recent evidence on patterns and trends of hidden hunger across the region, with a focus on the most significant deficiencies - iodine, Fe, vitamin A and Zn - and interprets these in terms of health and economic consequences. The challenge for South Asian policy makers is to invest in actions that can cost-effectively resolve chronic nutrient gaps facing millions of households. Appropriate solutions are available today, so governments should build on evidence-based successes that combine targeted health system delivery of quality services with carefully designed multisector actions that help promote healthier diets, reduce poverty and ensure social protection simultaneously. PMID- 29256362 TI - Expression of Concern: Loop structures in the 5' untranslated region and antisense RNA mediate pilE gene expression in Neisseria gonorrhoeae. PMID- 29256363 TI - AALAS Publications: Write for All Readers. PMID- 29256364 TI - Comparison of Submental Blood Collection with the Retroorbital and Submandibular Methods in Mice (Mus musculus). PMID- 29256365 TI - Effects of an Extended Cage-change Interval on Ammonia Levels and Reproduction in Mongolian Gerbils (Meriones unguiculatus). AB - Prompted by the cage cleanliness of Mongolian gerbils (Meriones unguiculatus), we evaluated a prolonged cage-change interval. We compared the effects of a 2-wk and 6-wk cage-change schedule on ammonia levels, temperature, humidity, and reproductive performance in breeding pairs housed in IVC. We hypothesized that ammonia levels would remain below our threshold for cage changing and that reproductive performance would not be affected. Although ammonia levels increased over time, they remained low (less than 5 ppm) over the 6-wk period. In addition, the 6-wk cage-change interval did not significantly influence reproductive parameters, such as average pup weaning weight, number of litters, and number of pups per litter. We conclude that an extended cage-change interval (6-wk) can be used for gerbils without significant increases in intracage ammonia levels or effects on reproduction. PMID- 29256366 TI - Physiologic Correlates of Interactions between Adult Male and Immature Long tailed Macaques (Macaca fascicularis). AB - Interactions between adult males and immature members of the same species are rare in most mammals; in contrast, an estimated 40% of primate species are characterized by an involvement of males in the social life of infants and juveniles. The proximate mechanisms of male-infant interactions are largely unstudied, and very few direct benefits for males have been proposed, especially in uniparental species in which the identity of the male parent is uncertain. In this study, we aimed to assess the relationship among behavioral and physiologic stress, health, and various affiliative behaviors initiated by adult males toward infants and juveniles in long-tailed macaques. We hypothesized that males that spent more time with infants and juveniles would have lower physiologic and social stress and better health than males with less interaction. We observed 2 troops of macaques with established social hierarchies (n = 18 in troop 1 and n = 8 in troop 2), each occupying a stable area within the enclosure, for more than 200 h. Fecal samples were used to assess cortisol levels as a measure of physiologic stress, and blood samples were collected to measure oxytocin levels as an index of social responsiveness. Our results indicated that male affiliative behavior directed toward immature animals was significantly higher in the troop characterized by more social conflicts; midranking males interacted more with infants than high- and low-ranking males in both troops. Furthermore, the DHEA:cortisol ratio, a physiologic index of resilience and coping, was positively correlated with males' affiliative responses, suggesting a neuroprotective role of male-infant interactions. In summary, our data support a proximate mechanism of alloparenting or paternal behavior in uniparental species. Interacting with infants and juveniles could provide an immediate neurobiologic benefit to adult males by facilitating adaptive coping responses to social tensions. PMID- 29256367 TI - Two Methods of Social Separation for Paired Adolescent Male Rhesus Macaques (Macaca mulatta). AB - Literature-based recommendations regarding how to separate pairs of laboratory housed NHP when required for research, veterinary, or management needs are unavailable. This study assessed 2 separation techniques-rapid and stepwise-to determine whether a period of limited social access mitigates the behavioral stress response after complete separation. Researchers observed 12 pairs of mother-reared, adolescent male rhesus macaques before and after separation with a solid divider; 6 of the pairs experienced a transitional week of limited social access through a perforated panel. Observers collected 30-min focal animal scans during study phase, totaling 144 h of behavioral data. Target behaviors included those classified as protest, agitation, tension, and withdrawn or self-directed. Social separation resulted in a significant change in behavior. Separated monkeys displayed more withdrawn or self-directed behaviors (for example, huddling, self directed stereotypies) than when pair-housed. Stepwise separation resulted in increased agitation behaviors in the limited contact phase and did not mitigate separation effects. Adverse behavioral changes during the limited contact phase support continuous pair housing until required individual housing. PMID- 29256368 TI - Relationship between Environmental Enrichment and the Response to Novelty in Laboratory-housed Pigs. AB - Environmental enrichment is the enhancement of the physical or social environment in which an animal lives with the goal to improve its quality of life. Our objective was to investigate the effect of providing environmental enrichment in the home pen on responsiveness to novelty in laboratory-housed pigs. Pigs were housed (4 pigs per pen) in enriched (n = 32) or barren (control; n = 32) pens for 3 wk total and tested in 2 anxiety behavioral tests, the novel object (NOT) and human interaction (HIT) tests. Pigs were placed in a novel arena for a 5-min familiarization period, after which either a novel object (NOT) or an unfamiliar human (HIT) was introduced for a 5-min interaction period. Behavior in the home pen and during NOT and HIT was monitored through direct observations and videorecording. In the home pen, enriched pigs spent more time active and interacting with the environment, whereas control pigs spent more time inactive and in social interactions. In addition, enriched pigs crossed more squares during the familiarization period, tended to freeze more, and interacted less with the novel object or person than control pigs. In conclusion, enrichment may improve welfare by stimulating activity and decreasing aggressive behaviors in the home pen. However, enriched pigs may experience increased anxiety when exposed to novelty, whereas pigs housed without environmental enrichment-due to lack of stimulation in the home pen-may be more motivated to interact with sources of novelty or enrichment during testing than their enriched counterparts. PMID- 29256369 TI - Staphylococcus xylosus PCR-validated Decontamination of Murine Individually Ventilated Cage Racks and Air Handling Units by Using 'Active-Closed' Exposure to Vaporized Hydrogen Peroxide. AB - Vaporized hydrogen peroxide (VHP) is used to decontaminate clinical, biocontainment, and research animal rooms and equipment. To assist with its implementation in a murine facility, we developed a safe and effective method of VHP sterilization of IVC racks and air handling units (AHU). Safety of VHP decontamination was assessed by ensuring VHP levels dissipated to less than 1 ppm in the room prior to personnel reentry and inside the primary enclosure prior to the return of mice; this condition occurred at least 18 h after the VHP cycle. Efficacy of VHP sterilization was assessed by using chemical indicators, biologic indicators, and PCR testing for Staphylococcus xylosus, a commensal organism of murine skin and an opportunistic pathogen, which was present in 160 of 172 (93%) of specimens from occupied IVC racks and the interior surfaces of in-use AHU. Neither mechanized washing nor hand-sanitizing eradicated S. xylosus from equipment airway interiors, with 17% to 24% of specimens remaining PCR-positive for S. xylosus. 'Static-open' VHP exposure of sanitized equipment did not ensure its sterilization. In contrast, 'active-closed' VHP exposure, in which IVC racks were assembled, sealed, and connected to AHU set to the VHP cycle, increased the proportion of chemical indicators that detected sterilizing levels of VHP inside the assembled equipment, and significantly decreased PCR-detectable S. xylosus inside the equipment. Supplementing bulk steam sterilization of the primary enclosure with VHP sterilization of the secondary housing equipment during room change-outs may help to mitigate opportunistic agents that jeopardize studies involving immunodeficient strains. PMID- 29256370 TI - PCR Testing of IVC Filter Tops as a Method for Detecting Murine Pinworms and Fur Mites. AB - We evaluated PCR testing of filter tops from cages maintained on an IVC system through which exhaust air is filtered at the cage level as a method for detecting parasite-infected and -infested cages. Cages containing 4 naive Swiss Webster mice received 360 mL of uncontaminated aspen chip or alpha-cellulose bedding (n = 18 cages each) and 60 mL of the same type of bedding weekly from each of the following 4 groups of cages housing mice infected or infested with Syphacia obvelata (SO), Aspiculuris tetraptera (AT), Myocoptes musculinus (MC), or Myobia musculi (MB) and Radfordia affinis (RA; 240 mL bedding total). Detection rates were compared at 30, 60, and 90 d after initiating bedding exposure, by using PCR analysis of filter tops (media extract and swabs) and testing of mouse samples (fur swab [direct] PCR testing, fecal flotation, anal tape test, direct examination of intestinal contents, and skin scrape). PCR testing of filter media extract detected 100% of all parasites at 30 d (both bedding types) except for AT (alpha-cellulose bedding, 67% detection rate); identified more cages with fur mites (MB and MC) than direct PCR when cellulose bedding was used; and was better at detecting parasites than all nonmolecular methods evaluated. PCR analysis of filter media extract was superior to swab and direct PCR for all parasites cumulatively for each bedding type. Direct PCR more effectively detected MC and all parasites combined for aspen chip compared with cellulose bedding. PCR analysis of filter media extract for IVC systems in which exhaust air is filtered at the cage level was shown to be a highly effective environmental testing method. PMID- 29256372 TI - Pharmacokinetics and Adverse Effects of 3 Sustained-release Buprenorphine Dosages in Healthy Guinea Pigs (Cavia porcellus). AB - In guinea pigs, studies addressing the efficacy, safety, and pharmacokinetic profiles of different sustained-release buprenorphine (SRB) formulations are still in their infancy. Here we assessed the pharmacokinetic profiles of 3 SRB dosages (SR-LAB, ZooPharm; SRBLow, 0.15 mg/kg; SRBMedium, 0.3 mg/kg; and SRBHigh, 0.6 mg/kg) for 72 h after a single subcutaneous administration to 8 (4 male and 4 female) healthy guinea pigs. Body weight, fecal output, and cortisol levels were also monitored and the results compared with those of the sham group. Within the first h after administration, the maximal plasma concentration (Cmax) of the drug was 64.3 +/- 9.2 ng/mL (males) and 71.3 +/- 3.7 ng/mL (females) in the SRBHigh group; 11.5 +/- 3.2 ng/mL (males) and 6.9 +/- 0.9 ng/mL (females) in the SRBMedium group; and 2.3 +/- 0.8 ng/mL (males) and 2.0 +/- 0.5 ng/mL (females) in the SRBLow group. After 72 h, therapeutic levels of the drug (>1 ng/mL) were observed only in guinea pigs treated with SRBHigh (both sexes) and males treated with SRBMediu cm. Fecal output (quantity and distribution) and body weight were significantly lower in the SRB groups as compared with the sham group, and with the SRBHigh group showing larger reductions. Baseline levels of serum cortisol in healthy females (1440 +/- 106 ng/mL) were significantly greater than in males (550 +/- 66 ng/mL). But, independent of the sex, SRB administration significantly reduced those levels. In conclusion, the data indicate that all 3 SRB dosages can be safely used in guinea pigs. However, therapeutic levels of the drug were observed for at least 48 h only guinea pigs treated with SRBHigh and SRBMedium. Further investigation is needed to determine if these dosages can alleviate pain in guinea pigs. PMID- 29256371 TI - Plasma Concentration of Meloxicam in Pediatric Rats. AB - In this study, we compared the plasma concentrations of meloxicam in pediatric rat pups (ages: 7, 14, 21, and 28 d) with those of young adult rats. Adult rats received 1.34 mg/kg SC meloxicam to determine the target peak plasma concentration (Cmax) for comparison with the pediatric animals. Pediatric rats received 1.34 mg/kg SC meloxicam, and in all age groups, Cmax met or exceeded that in adults (11.5 +/-2.7 MUg/mL). Plasma concentrations were similar between male and female pups within age groups, and peak plasma concentration was achieved more rapidly in rat pups than adults. The analgesic efficacy of this dose was not evaluated in this study. PMID- 29256373 TI - Effects of Repeated Intraperitoneal Injection of Pharmaceutical-grade and Nonpharmaceutical-grade Corn Oil in Female C57BL/6J Mice. AB - Due to potential adverse effects on animal wellbeing, the use of nonpharmaceutical-grade substances in animal research must be scientifically justified in cases where a pharmaceutical-grade version of the substance exists. This requirement applies to all substances, including vehicles used to solubilize experimental drugs. To date, no studies have evaluated the direct effect of the pharmaceutical classification of a compound on animal wellbeing. In this study, we evaluated intraperitoneal administration of pharmaceutical-grade corn oil, nonpharmaceutical-grade corn oil, and saline in female C57BL/6J mice. Compounds were administered every 48 h for a total of 4 injections. Mice were evaluated clinically by using body weight, body condition score, visual assessment score, CBC, and serum chemistries. Animals were euthanized at 24 h and 14 d after the final injection. Inflammation of the peritoneal wall and mesenteric fat was assessed microscopically by using a semiquantitative scoring system. Saline-dosed groups had lower pathology scores at both time points. At day 21, pharmaceutical grade corn oil had a significantly higher pathology score compared with nonpharmaceutical-grade corn oil. No other significant differences between the corn oil groups were observed. The use of nonpharmaceutical grade corn oil did not result in adverse clinical consequences and is presumed safe to use for intraperitoneal injection in mice. Differences in inflammation between the 2 groups suggest that the use of either pharmaceutical-grade or nonpharmaceutical grade corn oil should be consistent within a study. PMID- 29256374 TI - Heating Pad Performance and Efficacy of 2 Durations of Warming after Isoflurane Anesthesia of Sprague-Dawley Rats (Rattus norvegicus). AB - Anesthetic agents depress thermoregulatory mechanisms, causing hypothermia within minutes of induction of general anesthesia. The consequences of hypothermia include delayed recovery and increased experimental variability. Even when normothermia is maintained during anesthesia, hypothermia may occur during recovery. The primary aim of this study was to identify an effective warming period for maintaining normothermia during recovery. Adult male (n = 8) and female (n = 9) Sprague-Dawley rats were randomized to 30 min (post30) or 60 min (post60) of warming after recovery from anesthesia. During a 40-min anesthetic period, normothermia (target, 37.5 +/- 1.1 degrees C) was maintained by manual adjustment of an electric heating pad in response to measured rectal temperatures (corrected to estimate core body temperature). Warming was continued in a recovery cage according to treatment group. Rectal temperature was measured for a total of 120 min after anesthesia. Heating pad performance was assessed by measuring temperatures at various sites over its surface. One female rat in the post30 group was excluded from analysis. Normothermia was effectively maintained during and after anesthesia without significant differences between groups. In the post60 group, core temperature was slightly but significantly increased at 90 and 100 min compared with baseline. One rat in each treatment group became hyperthermic (>38.6 degrees C) during recovery. During recovery, the cage floor temperature required approximately 30 min to stabilize. The heating pad produced heat unevenly over its surface, and measured temperatures frequently exceeded the programmed temperature. Providing 30 min of warming immediately after anesthesia effectively prevented hypothermia in rats. Shorter warming periods may be useful when recovery cages are preheated. PMID- 29256377 TI - ACLAM Position Statement on Adoption of Research Animals. PMID- 29256375 TI - Using Telemetry Data to Refine Endpoints for New Zealand White Rabbits Challenged with Bacillus anthracis. AB - We used a continuous-monitoring digital telemetry system to investigate temperature response in New Zealand White rabbits after inhalation or subcutaneous challenge with Bacillus anthracis. Two spore preparations of B. anthracis Ames A2084 were evaluated by using a nose-only inhalation model, and 2 strains, B. anthracis Ames A2084 and B. anthracis UT500, were evaluated in a subcutaneous model. Animal body temperature greater than 3 SD above the mean baseline temperature was considered a significant increase in body temperature (SIBT). All rabbits that exhibited SIBT after challenge by either route of infection or bacterial strain eventually died or were euthanized due to infection, and all rabbits that died or were euthanized due to infection exhibited SIBT during the course of disease. The time at onset of SIBT preceded clinical signs of disease in 94% of the rabbits tested by as long as 2 days. In addition, continuous temperature monitoring facilitated discrimination between the 2 B. anthracis strains with regard to the time interval between SIBT and death. These data suggest that for the New Zealand White rabbit anthrax model, SIBT is a reliable indicator of infection, is predictive of experimental outcome in the absence of treatment, and is measurable prior to the appearance of more severe signs of disease. The use of digital telemetry to monitor infectious disease course in animal models of anthrax can potentially be used in conjunction with other clinical score metrics to refine endpoint euthanasia criteria. PMID- 29256376 TI - Evaluation of Best Practices for the Euthanasia of Zebra Finches (Taeniopygia guttata). AB - Although zebra finches (Taeniopygia guttata) have been used in biomedical research for many years, no published reports are available about euthanizing these small birds. In this study, we compared 5 methods for zebra finch euthanasia: sodium pentobarbital (NaP) given intracoelomically with physical restraint but no anesthesia; isoflurane anesthesia followed by intracoelomic injection of NaP; and CO2 asphyxiation at 20%, 40%, and 80% chamber displacement rates (percentage of chamber volume per minute). Birds undergoing euthanasia were videorecorded and scored by 2 observers for behaviors potentially related to discomfort or distress. Time to recumbency and time until respiratory arrest (RA) were also assessed. RA was achieved faster by using NaP in a conscious bird compared to using isoflurane anesthesia followed by NaP; however, neither method caused behaviors that might affect animal welfare, such as open-mouth breathing, to any appreciable extent. Among the CO2 treatment groups, there was an inverse correlation between the chamber displacement rate used and the duration of open mouth breathing, onset of head retroflexion, and time to RA. The results demonstrate that the intracoelomic administration of NaP in an awake, restrained zebra finch is a rapid and effective method of euthanasia. If CO2 is used to euthanize these birds, a high displacement rate (for example, 80%) will minimize the duration of the procedure and associated behaviors. PMID- 29256378 TI - Editorial. PMID- 29256379 TI - Post-event reviews: Using a quantitative approach for analysing incident response to demonstrate the value of business continuity programmes and increase planning efficiency. AB - Business continuity management is often thought of as a proactive planning process for minimising impact from large-scale incidents and disasters. While this is true, and it is critical to plan for the worst, consistently validating plan effectiveness against smaller disruptions can enable an organisation to gain key insights about its business continuity readiness, drive programme improvements, reduce costs and provide an opportunity to quantitatively demonstrate the value of the programme to management. This paper describes a post mortem framework which is used as a continuous improvement mechanism for tracking, reviewing and learning from real-world events at Microsoft Customer Service & Support. This approach was developed and adopted because conducting regular business continuity exercises proved difficult and expensive in a complex and distributed operations environment with high availability requirements. Using a quantitative approach to measure response to incidents, and categorising outcomes based on such responses, enables business continuity teams to provide data-driven insights to leadership, change perceptions of incident root cause, and instil a higher level of confidence towards disaster response readiness and incident management. The scope of the framework discussed here is specific to reviewing and driving improvements from operational incidents. However, the concept can be extended to learning and evolving readiness plans for other types of incidents. PMID- 29256380 TI - How Belfius Bank's response to the terrorist attacks in Brussels helped embed business continuity in the company culture. AB - Until 2015, major terrorist incidents in Belgium were considered a 'black swan'. However, the suicide attacks in Paris on 13th November, 2015 provided a wake-up call. Investigations revealed that the raid was prepared in Belgium by jihadists who grew up in Brussels and was coordinated by Belgian ISIS fighters in Syria. In an instant, it became clear that terror had been embedded in Belgian society and could erupt at any moment. At Belfius Bank Belgium, the subsequent months were a rollercoaster ride of terrorist-related events. Business activities were strongly affected, as the company's head office is located in the centre of Brussels. This paper focuses on the way Belfius responded to the events and how the lessons learned have helped to improve its business continuity and crisis management capability. PMID- 29256381 TI - The Fort McMurray, Alberta wildfires: Emergency and recovery management of healthcare services. AB - One of the largest wildfires in Canadian history raged through northern Alberta in May to July 2016, and prompted the largest emergency air evacuation in Canadian history. Central to the challenges were the evacuation of a regional hospital, and the emergency and recovery management associated with healthcare services. This paper describes multiple phases of emergency and recovery management, which employed and adapted the Incident Command System to healthcare services. There were no injuries reported throughout the medical evacuation and recovery of medical services. The leadership and management of healthcare services achieved the goals of evacuating patients and staff effectively, supporting emergency first responders and the re-entry of the population to Fort McMurray. PMID- 29256382 TI - Best practice vendor risk management in today's interconnected world. AB - This paper explains why vendor/third-party risk is so important to all organisations, as well as the principal risks that organisations must consider. It describes the responsibility of management to manage these risks with support from risk experts at the selection phase and through the ongoing relationship. Different sources of information about the management of the key risks and alternative ways of collecting the data are evaluated. The paper concludes by discussing how both customer and supplier organisations benefit from a balanced approach to risk management. The approach described in the paper applies to organisations of all types and sizes and can be applied to varied supply chains. The data and insights are based on research conducted by CEB. PMID- 29256383 TI - Enhancing infrastructure resilience through business continuity planning. AB - Critical infrastructure is crucial to the functionality and wellbeing of the world around us. It is a complex network that works together to create an efficient society. The core components of critical infrastructure are dependent on one another to function at their full potential. Organisations face unprecedented environmental risks such as increased reliance on information technology and telecommunications, increased infrastructure interdependencies and globalisation. Successful organisations should integrate the components of cyber physical and infrastructure interdependencies into a holistic risk framework. Physical security plans, cyber security plans and business continuity plans can help mitigate environmental risks. Cyber security plans are becoming the most crucial to have, yet are the least commonly found in organisations. As the reliance on cyber continues to grow, it is imperative that organisations update their business continuity and emergency preparedness activities to include this. PMID- 29256384 TI - Coordinating management disciplines to build operational resilience in response to a major crisis situation. AB - Using case studies of the Ebola outbreak in Western Africa in 2014, and the terrorist attacks in Paris and Brussels in 2015 and 2016 respectively, this paper demonstrates how various resilience-related corporate functions contributed to effective crisis response. This paper describes the logical order of actions taken in each of the cases, and how the organisation prioritised its assets and coordinated activities to ensure the response was adequate, efficient and timely. The article demonstrates how business continuity, physical security, threat management, security intelligence and incident management worked together to support the organisation's crisis management structures in complex crisis situations. PMID- 29256385 TI - Developing a research-specific emergency management programme for municipal resilience following the 2013 flood in southern Alberta. AB - Calgary was significantly impacted by the southern Alberta floods in 2013. Prior to the 2016 Fort McMurray wildfires (also in Alberta), these floods were the costliest disaster in Canadian history. In the aftermath, the Conference Board of Canada's independent review of the overall performance of Calgary's Recovery Operations Centre (ROC) recommended the need to: (1) include community actors and external stakeholders; and (2) develop pre-event situational awareness for those citizens who lack the ability to request assistance through regular channels. In response to these findings and a seemingly consistent experience of emergencies and disasters, the Calgary Emergency Management Agency (CEMA) sought to develop a comprehensive all-hazards emergency management programme for community leaders and citizens to further enhance municipal resilience when faced with inevitable future challenges. Using a case study approach, this paper presents the background, methodology and realisation of this programme, offers recommendations for challenges and limitations, and considers the key impetus for its development - the prevalent yet complex concept of resilience in disaster and emergency management. PMID- 29256386 TI - Editor's Comment and Announcement. AB - It is hard to believe but Clinical and Investigative Medicine (CIM), the official journal of Canadian Society for Clinical Investigation (CSCI), will soon celebrate its 40th birthday! Over these past four decades, CIM has been the premier journal for Canadian clinician scientists; publishing over 1,000 articles on breakthroughs and major advances from Canada and around the world. We are listed on Medline, PubMed and the Library of Science. We have been, and will continue to be, an independent journal. To celebrate this auspicious occasion, we have plans to become an even bigger showpiece for national and international clinical advances. We want to connect more closely with Canadian clinician scientists and trainees and we particularly want to encourage more Canadian publications. Changes will soon be coming to CIM with several new features: Newsletter with announcements and news on activities of interest to clinician scientists and trainees; Focused Reviews on specific areas of research; Reflections on work and life experiences of trainees and senior clinician scientists; Methods Papers describing novel methods anticipated to be useful for others; and Guidelines or Recommendations on clinical care that are endorsed by a Canadian Medical or Surgical Society. Starting in 2018, we will be publishing on a quarterly basis. This will help to ensure we will focus on important breakthroughs and commentaries. However, we are also planning a special edition in the autumn to commemorate the 40th birthday. Stay tuned! Of course CIM will continue to publish original papers on discoveries in pathophysiology, prevention, management, treatment and outcome of clinical problems confronting clinicians in Canada and around the world. Please join us as we embark on these changes and a new era for CIM, Robert Bortolussi Clinical and Investigative Medicine (CIM) Editor in Chief. PMID- 29256387 TI - Association among tenascin-C and NT-proBNP levels and arrhythmia prevalence in heart failure. AB - PURPOSE: Tenascin-C (TN-C) and amino-terminal fragment of the B-type natriuretic peptide (NT-proBNP) are the important predictors in prognosis of heart failure (HF). The aim of this study was to analyze the relationship of TN-C and NT-proBNP levels with the frequency and severity of ventricular arrhythmia. MATERIALS AND METHODS: Our study included 107 HF patients with EF < 45%. According to Holter analysis, the patients were divided into two groups as malignant arrhythmia group (n=29) with Lown Class 4a and 4b arrhythmia and benign arrhythmia group(n=78) with Lown Class 0-3b arrhythmia. The groups were compared with respect to levels of TN-C and NT-proBNP. The relationship of TN-C and NT-proBNP levels with frequency of ventricular premature beat (VPB) was also analyzed. FINDINGS: NT proBNP (5042.1+/-1626 versus 1417.1+/-1711.6 pg/ml) and TN-C (1089+/-348.6 versus 758.5+/-423.9 ng/ml) levels were significantly higher in the malignant arrhythmia group than that of the benign arrhythmia group (p. PMID- 29256388 TI - Plaque distribution in common femoral artery bifurcations, based on multi-slice computed tomography assessment. AB - PURPOSE: The aim of this study was to observe the exact plaque distribution at the common femoral artery bifurcation by multi-slice computed tomography angiography and to examine the relationship between plaque distribution and carina location. METHODS: Symptomatic outpatients who underwent multi-slice computed tomography angiography between May 2013 and February 2015 were enrolled in this study. The presence and distribution of atherosclerotic plaques were assessed in cross section views of vessel lumen. Each vessel lumen cross section was divided into four equal quadrants for the common femoral, superficial femoral and profunda femoral arteries. The quadrant of the superficial femoral artery in which the carina was located was also recorded. RESULTS: In total, 184 common femoral artery bifurcations in 92 patients were analyzed. Normal arteries were more common in profunda femoral arteries than in common femoral arteries and superficial femoral arteries (both P< 0.001). Plaques were found more medial and posterior quadrants in common femoral arteries. In superficial femoral arteries, plaques were found most frequently in anterior quadrants (78.3%, n=144) and least frequently in posterior quadrants (49.5%, n=91). The carina was located in the posterior quadrant in 160 bifurcations (87.0%) of superficial femoral arteries. Quadrants opposite the carina contained plaque most proportionally (77.2%) and quadrants of carina were affected least proportionally (52.7%) in superficial femoral arteries (P. PMID- 29256389 TI - Adolescent obesity and the role of the fat mass and obesity-associated gene polymorphism. AB - PURPOSE: The association between fat mass and obesity-associated (FTO) gene and obesity is unclear in both adults and adolescents. The aim of this study was to examine the role of the FTO gene variant rs9939609 as a candidate gene for obesity and the relationship between insulin resistance (IR), metabolic syndrome (MetS), estimated glomerular filtration rate (eGFR) and neutrophil-to-lymphocyte ratio (NLR). METHODS: Obese adolescents (n=100) and healthy controls (n=100) were included. Rs9939609 polymorphism in the FTO gene was genotyped by PCR-SNaPshot. RESULTS: The prevalence of insulin resistance (IR), metabolic syndrome (MetS) and hyperfiltration were 47%, 60% and 27%, respectively. There were no significant differences in genotype and allele frequencies between obese adolescents and controls; however, prevalence of MetS in female patients with A allele carriers was more frequent and prevalence of hyperfiltration was less frequent with T allele carriers (P. PMID- 29256390 TI - Predicting Acute Kidney Injury following Transcatheter Aortic Valve Replacement. AB - PURPOSE: Acute kidney injury occurs in up to a quarter of patients following transcatheter aortic valve replacement (TAVR) and has been associated with increased short and long-term mortality rates. A variety of patient characteristics predictive of post-TAVR acute kidney injury (AKI) have been identified, however discrepancies among studies exist almost uniformly. We investigated the hypothesis that the change in glomerular filtration rate (DeltaGFR) in response to contrast administered during pre-TAVR coronary angiography is predictive of DeltaGFR post-TAVR. METHODS: The study comprised 195 patients who underwent TAVR at a single center between August 2008 and June 2015 and were prospectively included in the CAPITAL TAVR registry. Multiple linear regression analysis was conducted to estimate the effect of independent variables on the change in renal function post-TAVR. RESULTS: There was no relationship identified between the DeltaGFR post-angiogram and the DeltaGFR post-TAVR (r=0.043, P=0.582). Multiple linear regression analysis revealed that a significant amount of the change in renal function post-TAVR can be explained by the patient's baseline creatinine (beta coefficient, -0.310, P. PMID- 29256391 TI - Pattern reversal visual evoked potentials in adults: variability with age. AB - PURPOSE: Pattern reversal visual evoked potential (PRVEP) is an electrophysiological test for evaluating the visual pathway. This study measured the changes in the latencies and amplitudes of the PRVEP with age and gender in normal subjects. METHODS: Healthy participants (n=81; 162 total eyes), between the ages of 20 and 92 years were recruited for the study. Stimulation was performed monocularly with a high-contrast (>50%) black-white checkerboard pattern with a check size of 30 degrees at a reversal rate of 2 Hz, a band-pass of 1-100 Hz, a sweep of 250 msec and an average of 150 stimulations in a dark room. Mean and standard deviations for three latencies (N75, P100 and N145) and the amplitude (N75-P100) for each decade were measured. RESULTS: There was a linear trend by age for all three latencies, indicating that the higher age groups had longer latencies. The latencies decreased in the 5th decade before increasing in the higher age groups. The amplitude of N75-P100 decreased with age. The P100 latencies were longer in males than females in all age groups and the difference increased with increasing age. PMID- 29256392 TI - Inhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia. AB - Tumor tissues are chronically exposed to hypoxia owing to aberrant vascularity. Lipid droplet (LD) accumulation is a hallmark of hypoxic cancer cells, yet how LDs form and function during hypoxia remains poorly understood. Herein, we report that in various cancer cells upon oxygen deprivation, HIF-1 activation down modulates LD catabolism mediated by adipose triglyceride lipase (ATGL), the key enzyme for intracellular lipolysis. Proteomics and functional analyses identified hypoxia-inducible gene 2 (HIG2), a HIF-1 target, as a new inhibitor of ATGL. Knockout of HIG2 enhanced LD breakdown and fatty acid (FA) oxidation, leading to increased ROS production and apoptosis in hypoxic cancer cells as well as impaired growth of tumor xenografts. All of these effects were reversed by co ablation of ATGL. Thus, by inhibiting ATGL, HIG2 acts downstream of HIF-1 to sequester FAs in LDs away from the mitochondrial pathways for oxidation and ROS generation, thereby sustaining cancer cell survival in hypoxia. PMID- 29256395 TI - Achieving sustainable solidarity development goals. PMID- 29256393 TI - Neural activity in cortico-basal ganglia circuits of juvenile songbirds encodes performance during goal-directed learning. AB - Cortico-basal ganglia circuits are thought to mediate goal-directed learning by a process of outcome evaluation to gradually select appropriate motor actions. We investigated spiking activity in core and shell subregions of the cortical nucleus LMAN during development as juvenile zebra finches are actively engaged in evaluating feedback of self-generated behavior in relation to their memorized tutor song (the goal). Spiking patterns of single neurons in both core and shell subregions during singing correlated with acoustic similarity to tutor syllables, suggesting a process of outcome evaluation. Both core and shell neurons encoded tutor similarity via either increases or decreases in firing rate, although only shell neurons showed a significant association at the population level. Tutor similarity predicted firing rates most strongly during early stages of learning, and shell but not core neurons showed decreases in response variability across development, suggesting that the activity of shell neurons reflects the progression of learning. PMID- 29256396 TI - The balancing act of orphan drug pricing. PMID- 29256397 TI - Dementia burden coming into focus. PMID- 29256394 TI - Sculpting ion channel functional expression with engineered ubiquitin ligases. AB - The functional repertoire of surface ion channels is sustained by dynamic processes of trafficking, sorting, and degradation. Dysregulation of these processes underlies diverse ion channelopathies including cardiac arrhythmias and cystic fibrosis. Ubiquitination powerfully regulates multiple steps in the channel lifecycle, yet basic mechanistic understanding is confounded by promiscuity among E3 ligase/substrate interactions and ubiquitin code complexity. Here we targeted the catalytic domain of E3 ligase, CHIP, to YFP-tagged KCNQ1 +/- KCNE1 subunits with a GFP-nanobody to selectively manipulate this channel complex in heterologous cells and adult rat cardiomyocytes. Engineered CHIP enhanced KCNQ1 ubiquitination, eliminated KCNQ1 surface-density, and abolished reconstituted K+ currents without affecting protein expression. A chemo-genetic variation enabling chemical control of ubiquitination revealed KCNQ1 surface density declined with a ~ 3.5 hr t1/2 by impaired forward trafficking. The results illustrate utility of engineered E3 ligases to elucidate mechanisms underlying ubiquitin regulation of membrane proteins, and to achieve effective post-translational functional knockdown of ion channels. PMID- 29256398 TI - Offline: The unspoken dangers facing UK medical science. PMID- 29256399 TI - The cost of mass-casualty attacks. PMID- 29256400 TI - Time for WHO to renew its commitment to health research. PMID- 29256401 TI - A call to reinstate Pakistan's death penalty moratorium. PMID- 29256402 TI - Targeted-release budesonide therapy for IgA nephropathy - Authors' reply. PMID- 29256403 TI - Targeted-release budesonide therapy for IgA nephropathy. PMID- 29256404 TI - Timely sensory stimulation and early childhood development. PMID- 29256405 TI - Public availability of trial protocols. PMID- 29256406 TI - Magnesium supplementation affects gene expression related to insulin and lipid in patients with gestational diabetes. AB - Magnesium is known to exert several beneficial effects, including antiglycemic and antilipidemic properties. The aim of this study was to evaluate the effects of magnesium supplementation on gene expression related to insulin and lipid metabolism in women with gestational diabetes (GDM) who were not on oral hypoglycemic agents. This randomized double-blind, placebo-controlled trial was conducted among 40 patients diagnosed with GDM, aged 18-40 years. Participants were randomly allocated into two groups to take either 250 mg/day of magnesium supplements in the form of magnesium oxide (n = 20) or placebo (n = 20) for 6 weeks. Gene expression related to insulin and lipid metabolism was assessed in peripheral blood mononuclear cells (PBMCs) of women with GDM using RT-PCR method. Compared with the placebo, magnesium supplementation to women with GDM resulted in a significant decrease in levels of fasting plasma glucose (FPG) (-9.7 +/- 5.6 vs. -0.1 +/- 8.5 mg/dL, P<0.001). Quantitative results of RT-PCR demonstrated that compared with the placebo, magnesium supplementation upregulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-gamma) (P = 0.003) and glucose transporter 1 (GLUT-1) (P = 0.004) and downregulated gene expression of oxidized low-density lipoprotein receptor (LDLR) (P = 0.001) in PBMCs of women with GDM. In addition, a trend toward a greater decrease in gene expression of lipoprotein (a) [LP(a)] was observed in the patients belonging to magnesium group compared to placebo group (P = 0.08). Overall, magnesium supplementation for 6 weeks in women with GDM significantly improved FPG levels, and gene expression of PPAR-gamma, GLUT-1, and LDLR. PMID- 29256407 TI - Effect of oral magnesium supplementation on the transcription of TRPM6, TRPM7, and SLC41A1 in individuals newly diagnosed of pre-hypertension. A randomized, double-blind, placebo-controlled trial. AB - A stringent regulation of influx and efflux of magnesium by cation transporters seems to play an important role in the regulation of blood pressure (BP). With this regard, we evaluate the effect of oral magnesium supplementation on the transcription of TRPM6, TRPM7, and SLC41A1, in individuals with incident pre hypertension (preHTN). For such purpose, we conducted a randomized, double-blind, placebo-controlled trial that compared 18 individuals who received oral magnesium lactate (360 mg elemental magnesium) versus 18 individuals who received placebo, during 4 months. Diagnosis of hypertension or normal BP, diabetes, alcohol intake, chronic diarrhea, use of diuretics, intake of magnesium supplementation, and reduced renal function were exclusion criteria. Regarding the transcription analysis of TRPM6, TRPM7, and SLC41A1 using RT-qPCR, leukocyte-rich plasma was obtained and total RNA was isolated with the kit Direct-zolTM RNA MiniPrep (Zymo). The leukocyte TRPM6 mRNA relative expression showed a significant increase (2.1 +/- 1.37 and 0.8 +/- 0.4, P<0.05), whereas the mRNA relative expression of both leukocyte TRPM7 (0.8 +/- 1.1 and 0.9 +/- 0.6, pNS) and SLC41A1 (0.9 +/- 1.0 and 0.7 +/- 0.6, pNS) showed no significant differences, between the magnesium and placebo groups, respectively. Oral magnesium supplementation increases the leukocyte TRPM6 mRNA relative expression, in subjects with new diagnosis of preHTN. PMID- 29256408 TI - Magnesium enhances the beneficial effects of NK1 antagonist administration on blood-brain barrier permeability and motor outcome after traumatic brain injury. AB - The current study investigated whether adding magnesium to an NK1 tachykinin receptor antagonist after traumatic brain injury would enhance efficacy to further reduce blood-brain barrier permeability and improve functional recovery compared to either treatment alone. Sprague-Dawley rats were injured using the impact acceleration model of diffuse brain injury, and received either no treatment, MgSO4 (30 mg/kg IV), the NK1 antagonist n-acetyl L tryptophan (2.5 mg/kg IP), or both agents combined. Animals were then killed at either 1, 5, or 24 h postinjury for determination of blood-brain barrier permeability using previously administered Evans blue dye or assessed for functional outcome over a 1-week period using the rotarod motor test. As expected, both MgSO4 and n-acetyl L tryptophan significantly reduced blood-brain barrier permeability and improved functional outcome. However, combined n-acetyl L tryptophan and MgSO4 was more effective at reducing blood-brain barrier permeability (P < 0.05) and improving functional outcome (P < 0.001) compared to the individual compounds. Our results demonstrate that combination therapy with magnesium and an NK1 antagonist may be a more effective therapy for TBI than either compound administered alone. PMID- 29256409 TI - Magnesium deficiency affects HNF1beta expression in rat liver in vivo and in vitro. AB - Hepatocyte nuclear factor 1beta (HNF1beta) is a transcription factor that is involved in embryonic development and tissue-specific gene expression in several organs, including the kidney and the liver. HNF1beta mutations are associated with hypomagnesemia and renal magnesium wasting; however, to date, the exact molecular mechanism involved in this regulation is unclear. Furthermore, it is not known whether the Mg concentration could per se participate to this regulation by modifying HNF1beta expression. We have studied in rats the effects of a 6-week diet with deficient or supplemented Mg concentrations compared to a diet with a standard Mg concentration on HNF1beta protein expression. HNF1beta expression was increased in the Mg-deficient group as compared to the other groups in the liver but not in the kidney. No changes in tissue Mg level were obtained in both organs. By contrast, a significant correlation between plasma Mg concentration and HNF1beta level in the rat liver was evidenced. In rat hepatocyte cultures exposed for 72h to various extracellular Mg concentrations, HNF1beta expression was modified after 72h of treatment of the hepatocytes with the lowest Mg concentrations as compared to the other Mg conditions. Moreover, these changes were correlated with extracellular but not intracellular Mg concentrations. In conclusion, HNF1beta expression is modified by the extracellular Mg concentration in the liver, both in vivo and in vitro, suggesting regulations with membrane events in hepatocytes. PMID- 29256410 TI - Patterns of anti-TNF use and associated treatment outcomes in inflammatory bowel disease patients: results from an analysis of Dutch health insurance claims data. AB - INTRODUCTION: Real-life patterns of anti-tumour necrosis factor (anti-TNF) use remain largely unknown. We aimed to investigate survival rates, clinical outcomes and costs of anti-TNF agents in a large population of patients with inflammatory bowel disease (IBD). METHODS: Health insurance data from 22,082 IBD patients were provided by Achmea Healthcare. Time to anti-TNF discontinuation, treatment intensification, corticosteroid initiation and hospitalisation were analysed in patients starting on anti-TNF treatment from January 2008 until December 2014. Treatment regimens were analysed at different time points. RESULTS: In this cohort, 855 and 1199 subjects started infliximab and adalimumab treatment, respectively. The median time to anti-TNF discontinuation was 600 days (IQR 156 1693). The proportion of subjects receiving intensified treatment increased over time (infliximab at 3 vs. 24 months: 22.2% vs. 33.6%, p = 0.01; adalimumab at 3 vs. 24 months: 10.5% vs. 19.3%, p < 0.001). Cessation of anti-TNF treatment was less common in Crohn's disease patients (HR 0.79, p = 0.001) and in patients receiving intensified treatment (HR 0.62, p = 0.001). Immunomodulator use was associated with a longer time to corticosteroid initiation (HR 0.80, p = 0.048), but not with longer drug survival (HR 0.99, p = 0.617). Hospitalisation was more common in Crohn's patients (HR 1.49, p = 0.011). Corticosteroid initiation was lower in Crohn's patients (HR 0.57, p < 0.001) and in patients using infliximab (HR 0.55, p < 0.001). CONCLUSIONS: Discontinuation of anti-TNF therapy occurred earlier than previously reported and was associated with a diagnosis of ulcerative colitis and non-intensified anti-TNF treatment. Immunomodulator use at the start of anti-TNF treatment was associated with a longer time to corticosteroid initiation, but not with longer drug survival. PMID- 29256411 TI - The added value of clinical geriatric assessment prior to geriatric rehabilitation. AB - BACKGROUND: Community dwelling elderly who are temporarily unable to live independently due to functional decline can be referred for geriatric rehabilitation care at a nursing home. This referral is always preceded by a comprehensive geriatric assessment (CGA) by a geriatrician in hospital to rule out an indication for clinical admission and to evaluate geriatric multimorbidity. Because there is little evidence of the effectiveness of this procedure, we aimed to evaluate the results of this assessment and to elaborate on its relevance. METHODS: All patients who were referred by their general practitioner for a CGA in our hospital prior to geriatric rehabilitation care between March and December 2016 were included prospectively. Data were analysed retrospectively. Our primary aim was to describe the percentage of patients with an indication for hospital admission. Other outcomes included new diagnostic findings from the geriatric assessment and recommendations given to the elderly care physician in the geriatric rehabilitation facility. RESULTS: Of the 32 assessed patients, 25% required admission to hospital, either due to somatic illness, mainly infections or suspected neurological disorders, needing clinical treatment, or for further diagnostics. New findings by geriatric assessment mostly concerned vitamin deficiency and infection, for which treatment recommendations were given to the elderly care physician. CONCLUSION: Geriatric assessment prior to geriatric rehabilitation referral is essential as it identifies patients needing hospital care, which cannot be provided at a nursing home. Furthermore, the assessment results in important recommendations to the elderly care physician in the geriatric rehabilitation facility. PMID- 29256412 TI - Nephrotic syndrome under treatment with dasatinib: be aware of a possible adverse drug reaction. AB - The protein kinase inhibitor dasatinib, targeting BCR-ABL and Src family kinases, is used in chronic myeloid leukaemia and Philadelphia-chromosome positive acute lymphoblastic leukaemia. The Netherlands Pharmacovigilance Centre Lareb has received one report of nephrotic syndrome associated with the use of dasatinib. With some other protein kinase inhibitors, targeting vascular endothelial growth factor, nephrotic syndrome is a well-known adverse drug reaction. The Dutch and European pharmacovigilance databases and scientific literature contain several cases indicating a causal relationship between dasatinib and nephrotic syndrome. Nephrotic syndrome was recently added to the list of adverse drug reactions in the Dutch summary of product characteristics for dasatinib. It is important to recognise the possibility of this adverse drug reaction when a patient develops nephrotic syndrome under treatment with dasatinib. PMID- 29256413 TI - Why a case report is more than just an unexpected observation. PMID- 29256414 TI - 'Khatatonia' - cathinone-induced hypertensive encephalopathy. AB - Khat consumption is an under-recognised cause of hypertensive encephalopathy and intraparenchymal brain haemorrhage. We report the radiological findings of extensive periventricular, subcortical and brain stem white matter pathology of a patient who had consumed excessive amounts of Khat. The Khat plant contains cathinone, an amphetamine-like alkaloid which has been associated with chronic hypertensive end-organ damage, but is seldom considered a cause of cerebrovascular events in northern Europe. PMID- 29256415 TI - Successful treatment of leptomeningeally metastasised pituitary carcinoma with temozolomide. AB - A 69-year-old man presented with leptomeningeally metastasised pituitary carcinoma, rapidly progressing despite previous treatment with resection, radiotherapy and cabergoline. The patient received temozolomide chemotherapy, resulting in a complete clinical, radiological and biochemical response after 14 cycles, which has been maintained since then. This case lends further support to the role of temozolomide in refractory pituitary tumours. PMID- 29256416 TI - Solitary mediastinal angiomatosis: report of two cases and review of the literature. AB - Angiomatosis is a rare benign vascular lesion, usually seen in females in the first two decades of life. It commonly involves the lower extremities. Angiomatosis of mediastinum is very rare and we report two such cases with a review of the literature on solitary mediastinal angiomatosis. Both of our patients were female, aged 34 and 57 years. One patient presented with left-sided subcutaneous supraclavicular swelling. Magnetic resonance imaging showed a mass extending from the left upper mediastinum to the left supraclavicular area. The other patient presented with pleural effusion. Computed tomography of the chest disclosed an infiltrative mass in the mediastinum. Both patients were treated by excision of the lesions, histologically confirmed to be angiomatosis. Despite the rarity of mediastinal angiomatosis, this clinicopathological entity must be taken into consideration when the treatment of mediastinal tumours is planned. PMID- 29256417 TI - Fatal sudden paralysis of the lower extremities. PMID- 29256418 TI - Answer to Photo Quiz: Fatal sudden paralysis of the lower extremities. PMID- 29256419 TI - Air is everywhere. PMID- 29256420 TI - Answer to Photo Quiz: Air is everywhere. PMID- 29256421 TI - A more restrictive use of quinolones in patients with community acquired pneumonia is urgently needed. PMID- 29256422 TI - Partial 18S rRNA sequences of apicomplexan parasite 'X' (APX), associated with flat oysters Ostrea chilensis in New Zealand. AB - Apicomplexa is a large phylum of parasitic protists renowned for significant negative health impacts on humans and livestock worldwide. Despite the prevalence and negative impacts of apicomplexans across many animal groups, relatively little attention has been given to apicomplexan parasites of invertebrates, especially marine invertebrates. Previous work has reported an apicomplexan parasite 'X' (APX), a parasite that has been histologically and ultrastructurally identified from the commercially important flat oyster Ostrea chilensis in New Zealand. This apicomplexan may exacerbate host vulnerability to the infectious disease bonamiosis. In this study, we report 18S rRNA sequences amplified from APX-infected O. chilensis tissues. Phylogenetic analyses clearly established that the 18S sequences were of apicomplexan origin; however, their detailed relationship to known apicomplexan groups is less resolved. Two specific probes, designed from the putative APX 18S rRNA sequence, co-localised with APX cells in in situ hybridisations, further supporting our hypothesis that the 18S sequences were from APX. These sequences will facilitate the future development of inexpensive and sensitive molecular diagnostic tests for APX, thereby assisting research focussed on the biology and ecology of this organism and its role in morbidity and mortality of O. chilensis. PMID- 29256423 TI - Viral haemorrhagic septicaemia virus (VHSV) remains viable for several days but at low levels in the water flea Moina macrocopa. AB - Viral haemorrhagic septicaemia virus (VHSV) Genotype IVb has been isolated from amphipods belonging to the genus Diporeia, but it has yet to be established whether crustacean zooplankton act as vectors of this virus for fish species. Therefore, we evaluated the viability of infectious VHSV in the water flea Moina macrocopa. VHSV was re-isolated from replicate groups of M. macrocopa that had been immersed with 108.0, 107.0, and 105.0 TCID50 ml-1 of VHSV (DK-3592B, Genotype Ia). Furthermore, 40 M. macrocopa that had been immersed with 108.0 TCID50 ml-1 of VHSV for 72 h had VHSV titers of 102.7-104.3 TCID50. Thus, VHSV was clearly taken up by M. macrocopa and remained viable in this crustacean for several days. However, no mortality was observed over a 28 d period in rainbow trout Oncorhynchus mykiss that were fed VHSV-contaminated M. macrocopa for 14 d, and we found that the virus titer significantly decreased after a 4 h incubation with pyloric caecal extracts from rainbow trout, indicating that passage through the gut is likely to result in a significant decrease in viral titer. This may explain why consumption of prey containing low levels of VHSV did not result in clinical VHS. PMID- 29256424 TI - Molecular investigations of outbreaks of Perch perhabdovirus infections in pike perch. AB - In 2016, a total of 5 massive mortality episodes each affecting hundreds of thousands of pike-perch Sander lucioperca larvae occurred at 2 sites in 2 Western European countries. For each episode, perhabdoviruses related to the perch rhabdovirus (PRV) were detected in samples, using either PCR or cell culture combined with PCR. The sequences of the glycoprotein (g), phosphoprotein (p) and nucleoprotein (n) genes of these samples demonstrated that 2 different genotypes were present at 1 site, each associated with 1 of the 3 episodes. At the other site, a single genotype was associated with the 2 outbreaks. Furthermore, this genotype was strictly identical to 1 genotype involved in the outbreaks of the first site, strongly suggesting a common origin for these 2 viruses. The common origin was confirmed a posteriori because some larvae introduced to both sites had exactly the same geographic origin in Eastern Europe. Taken together, the molecular and epidemiological data suggest that both horizontal and vertical transmission of 2 distinct strains of perhabdoviruses were involved in the various outbreaks affecting pike-perch. PMID- 29256425 TI - Infection dynamics of Kudoa inornata (Cnidaria: Myxosporea) in spotted seatrout Cynoscion nebulosus (Teleostei: Sciaenidae). AB - Kudoa inornata is a myxosporean parasite that develops in the somatic muscle of spotted seatrout Cynoscion nebulosus, an economically and ecologically important fish in estuaries and harbors in southeastern North America. In South Carolina (SC), USA, over 90% of wild adult spotted seatrout are infected. To inform potential mitigation strategies, we conducted 3 experiments using naive sentinel seatrout and infectious stages of K. inornata naturally present in raw water from Charleston Harbor, SC, to determine (1) if K. inornata infection follows a seasonal pattern, and (2) how long it takes for myxospores to develop in fish muscle. Infection by K. inornata was determined by visual detection of myxospores in fish muscle squashes, and any visually negative samples were then assayed for K. inornata ribosomal DNA using novel parasite-specific PCR primers. We observed that K. inornata infection in seatrout followed a seasonal pattern, with high prevalence when water temperature was highest (27-31 degrees C; July-September) and infections that were either covert (at ~13-15 degrees C) or not detected (<13 degrees C) at the lowest water temperatures in January-February. Myxospore development occurred within 476 degree-days, i.e. 2 wk in a typical SC summer. Infection was dependent on fish density, which limited presumptive actinospore dose. Our findings suggest that the life cycle of the parasite may be disrupted by preventing spore-rich seatrout carcasses (e.g. at angler cleaning stations) being thrown back into harbors and estuaries throughout the year. PMID- 29256426 TI - Fatal fibrino-hemorrhagic bronchopneumonia associated with Morganella morganii in a bottlenose dolphin: a case report. AB - A 5 yr old, 184 kg, and 262 cm total length female bottlenose dolphin Tursiops truncatus was found dead in a display after bloody discharge from the blowhole was observed 3 h prior to death. Pathological examination revealed fibrinous bronchopneumonia with prominent areas of necrosis (sequestra) and numerous Gram negative bacilli within alveoli and in blood vessels of the lungs and liver and between muscle fibers. The cause of death was attributed to septicemia. Often, cases of fibrinous bronchopneumonia are characterized by bacteremia in the latter stages of infection, resulting in the death of the animal. Septicemia likely accounts for the ecchymoses and petechiae noted on the spleen, pancreas, forestomach, lungs, visceral peritoneum, and small intestine. Additional lesions included hemothorax, stable red frothy fluid in the trachea, and lymphoid depletion in the spleen and lymph nodes. Pure growth of Morganella morganii was isolated from the lungs, blood, liver, and blowhole mucosa. Sequencing of 16s rRNA of the isolated bacteria showed more than 99.6% identity with M. morganii strain FDAARGOS_172. To our knowledge, this is the first report of fatal fibrinonecrotizing bronchopneumonia associated with M. morganii infection in a cetacean. PMID- 29256427 TI - Quantifying parasite presence in relation to biological parameters of harbour porpoises Phocoena phocoena stranded on the Dutch coast. AB - Harbour porpoises are often found to be infected by endoparasites in several organs including the lungs and stomach as well as the heart, liver and ears. Nevertheless there is still little knowledge about the impact, ecology, transmission, and virulence of these parasitic infections. Here, we profile the presence of parasites in 4 frequently infected organs (lungs, stomach, liver and ears) in relation to biological parameters of harbour porpoises stranded along the Dutch coastline between December 2008 and December 2013. We found that parasites were common, with prevalence of 68% in lungs, 74.4% in ears, 26% in stomach and 23.5% in liver. We used generalised linear models to further quantify parasite presence in relation to biological data gathered during necropsy (sex, body length and nutritive condition). Body length (used as a proxy for age) was significant in explaining parasite presence for all organs with increasing probability of having the parasite with increasing body length. For the parasitic infections in the ears and stomach the nutritive condition was an additional significant factor, with a higher probability of parasite presence in porpoises in a poorer nutritive condition. The results of this study can be used as a baseline for assessing parasite presence in harbour porpoises and are a first step towards linking parasite infections to basic biological data gathered during necropsy. PMID- 29256428 TI - Parasites in the inner ear of harbour porpoise: cases from the North and Baltic Seas. AB - Peribullar sinuses of harbour porpoises Phocoena phocoena are parasitized with high prevalence by the nematode Stenurus minor. The effect of S. minor on the hearing ability of this species is still undetermined. Here, we review the occurrence of S. minor in the inner ear of harbour porpoises recovered from strandings in the North and Baltic Seas. In particular, we present the results from ears collected in German and Danish waters from 2002 to 2016 and from Dutch waters from 2010 to 2016. While the prevalence of S. minor in pterygoid and peribullar sinuses and tympanic cavity was high in harbour porpoises (66.67% in our cases), its prevalence in the cochlea was rare. Only 1 case out of 129 analysed by either histology, electron microscopy or immunofluorescence showed the presence of a nematode parasite morphologically consistent with S. minor at the most basal portion of the right cochlea. This individual also had severe haemorrhage along the right cochlear spiral, which was likely caused by ectopic S. minor migration. Although this animal might have had impaired hearing in the right ear, it was otherwise in good body condition with evidence of recent feeding. These findings highlight the need to study the effect of parasites on hearing, and other pathological changes that might impair appropriate processing of acoustic information. PMID- 29256429 TI - Investigating seagrass in Toxoplasma gondii transmission in Florida (Trichechus manatus latirostris) and Antillean (T. m. manatus) manatees. AB - Toxoplasma gondii is a feline protozoan reported to cause morbidity and mortality in manatees and other marine mammals. Given the herbivorous nature of manatees, ingestion of oocysts from contaminated water or seagrass is presumed to be their primary mode of infection. The objectives of this study were to investigate oocyst contamination of seagrass beds in Puerto Rico and determine the seroprevalence of T. gondii in Antillean (Trichechus manatus manatus) and Florida (T. m. latirostris) manatees. Sera or plasma from Antillean (n = 5) and Florida (n = 351) manatees were tested for T. gondii antibodies using the modified agglutination test. No T. gondii DNA was detected via PCR in seagrass samples (n = 33) collected from Puerto Rico. Seroprevalence was 0%, suggesting a lower prevalence of T. gondii in these manatee populations than previously reported. This was the first study to investigate the potential oocyst contamination of the manatee diet, and similar studies are important for understanding the epidemiology of T. gondii in herbivorous marine mammals. PMID- 29256430 TI - Hepatic lipomas and myelolipomas in subsistence-harvested bowhead whales Balaena mysticetus, Alaska (USA): a case review 1980-2016. AB - We describe a case series of benign hepatic fatty tumors in 10 subsistence harvested bowhead whales. Microscopic features included lipomatous and myelolipomatous masses. Extensive atrophy and/or destruction of hepatic parenchyma was not observed. No other significant disease was present except in an animal with unrelated chronic pleuritis. Based on our longitudinal case series (1980-2016) which identified 1-2 hepatic lipomas and myelolipomas in landed whales annually at Barrow, Alaska (USA), since 2012, hepatic lipomas and myelolipomas are occasionally seen in hunter-harvested bowhead whales. A conservative estimate for the percentage of bowhead whales with hepatic fatty tumors in landed whales in Barrow from 2012 to 2016 was 6% (7/111). The pathogenesis and exact cell origin of these benign fatty tumors in bowhead whales is undetermined. Assessment of further cases is warranted to better define the tissue distribution and pathogenesis of these tumors in bowhead whale liver. PMID- 29256431 TI - Using environmental DNA for early detection of amphibian chytrid fungus Batrachochytrium dendrobatidis prior to a ranid die-off. AB - Amphibian chytridiomycosis caused by the fungus Batrachochytrium dendrobatidis (Bd) is an emerging infectious disease that has been associated with mass mortality and extinctions of amphibians worldwide. Environmental DNA (eDNA) techniques have been used to detect the presence of Bd in the environment, but not to detect Bd prior to an amphibian die-off. We collected eDNA using filtered water samples from 13 lakes across Sequoia Kings Canyon National Park. Seven of those sites had populations of mountain yellow-legged frogs, an amphibian highly susceptible to chytridiomycosis, and 3 of those populations experienced a Bd related die-off 1 mo post-eDNA sampling. We detected Bd in eDNA samples that were collected 1 mo prior to the observed Bd-caused die-off at all 3 sites affected by Bd, and we did not detect Bd at the other sites where no die-off was observed. Our study indicates the potential to use eDNA techniques for early detection of Bd in the environment. PMID- 29256432 TI - Mechanical characterization of diesel soot nanoparticles: in situ compression in a transmission electron microscope and simulations. AB - Incomplete fuel burning inside an internal combustion engine results in the creation of soot in the form of nanoparticles. Some of these soot nanoparticles (SNP) become adsorbed into the lubricating oil film present on the cylinder walls, which adversely affects the tribological performance of the lubricant. In order to better understand the mechanisms underlying the wear caused by SNPs, it is important to understand the behavior of SNPs and to characterize potential changes in their mechanical properties (e.g. hardness) caused by (or during) mechanical stress. In this study, the behavior of individual SNPs originating from diesel engines was studied under compression. The experiments were performed in a transmission electron microscope using a nanoindentation device. The nanoparticles exhibited elasto-plastic behavior in response to consecutive compression cycles. From the experimental data, the Young's modulus and hardness of the SNPs were calculated. The Young's modulus and hardness of the nanoparticles increased with the number of compression cycles. Using an electron energy loss spectroscopy technique, it was shown that the sp2/sp3 ratio within the compressed nanoparticle decreases, which is suggested to be the cause of the increase in elasticity and hardness. In order to corroborate the experimental findings, molecular dynamics simulations of a model SNP were performed. The SNP model was constructed using carbon and hydrogen atoms with morphology and composition comparable to those observed in the experiment. The model SNP was subjected to repeated compressions between two virtual rigid walls. During the simulation, the nanoparticle exhibited elasto-plastic behavior like that in the experiments. The results of the simulations confirm that the increase in the elastic modulus and hardness is associated with a decrease in the sp2/sp3 ratio. PMID- 29256433 TI - Boundary states in the chiral symmetric systems with a spatial symmetry. AB - We study topological systems with both a chiral and a spatial symmetry which result in an additional spatial chiral symmetry. We distinguish the topologically nontrivial states according to the chiral symmetries protecting them and study several models in 1D and 3D systems. The perturbations breaking the spatial symmetry can break only one of the two chiral symmetries while the perturbations preserving the spatial symmetry always break or preserve both of them. In 3D systems, besides the 3D symmetries, the topologically nontrivial boundary modes may also be protected by the hidden lower dimensional symmetries. We then figure out the corresponding topological invariants and connect them with the 3D invariants. PMID- 29256434 TI - Myocardial blood flow estimates from dynamic contrast-enhanced magnetic resonance imaging: three quantitative methods. AB - Dynamic contrast-enhanced cardiovascular magnetic resonance imaging can be used to quantitatively assess the myocardial blood flow (MBF), recovering the tissue impulse response function for the transit of a gadolinium bolus through the myocardium. Several deconvolution techniques are available, using various models for the impulse response. The method of choice may influence the results, producing differences that have not been deeply investigated yet. Three methods for quantifying myocardial perfusion have been compared: Fermi function modelling (FFM), the Tofts model (TM) and the gamma function model (GF), with the latter traditionally used in brain perfusion MRI. Thirty human subjects were studied at rest as well as under cold pressor test stress (submerging hands in ice-cold water), and a single bolus of gadolinium weighing 0.1 +/- 0.05 mmol kg-1 was injected. Perfusion estimate differences between the methods were analysed by paired comparisons with Student's t-test, linear regression analysis, and Bland Altman plots, as well as also using the two-way ANOVA, considering the MBF values of all patients grouped according to two categories: calculation method and rest/stress conditions. Perfusion estimates obtained by various methods in both rest and stress conditions were not significantly different, and were in good agreement with the literature. The results obtained during the first-pass transit time (20 s) yielded p-values in the range 0.20-0.28 for Student's t-test, linear regression analysis slopes between 0.98-1.03, and R values between 0.92-1.01. From the Bland-Altman plots, the paired comparisons yielded a bias (and a 95% CI) expressed as ml/min/g-for FFM versus TM, -0.01 (-0.20, 0.17) or 0.02 (-0.49, 0.52) at rest or under stress respectively, for FFM versus GF, -0.05 (-0.29, 0.20) or -0.07 (-0.55, 0.41) at rest or under stress, and for TM versus GF, 0.03 (-0.30, 0.24) or -0.09 (-0.43, 0.26) at rest or under stress. With the two way ANOVA, the results were p = 0.20 for the method effect (not significant), p < 0.0001 for the rest/stress condition effect (highly significant, as expected), whereas no interaction resulted between the rest/stress condition and method (p = 0.70, not significant). Considering a wider time-frame (60 s), the estimates for both rest and stress conditions were 25%-30% higher (p in the range 0.016-0.025) than those obtained in the 20 s time-frame. MBF estimates obtained by various methods under rest/stress conditions were not significantly different in the first-pass transit time, encouraging quantitative perfusion estimates in DCE-CMRI with the used methods. PMID- 29256435 TI - A direct optic flow-based strategy for inverse flight altitude estimation with monocular vision and IMU measurements. AB - With tiny and limited nervous systems, insects demonstrate a remarkable ability to fly through complex environments. Optic flow has been identified to play a crucial role in regulating flight conditions and navigation in flies and bees. In robotics, optic flow has been widely studied thanks to the low computational requirements. However, with only monocular visual information, optic flow is inherently devoid of a scale factor required for estimating the absolute distance. In this paper, we propose a strategy for estimating the flight altitude of a flying robot with a ventral camera by combining the optic flow with measurements from an inertial measurement unit. Instead of using the prevalent feature-based approach for calculation of optic flow, we implement a direct method that evaluates the flow information via image gradients. We show that the direct approach notably simplifies the computation steps compared to the feature based method. When combined with an extended Kalman filter for fusion of inertial measurement units measurements, the flight altitude can be estimated in real time. We carried out extensive flight tests in different settings. Among 31 hovering and vertical flights near the altitude of 40 cm, we achieved the RMS errors in the altitude estimate of 2.51 cm. Further analysis of factors that affect the quality of the flow and the distance estimate is also provided. PMID- 29256436 TI - L-arginine modified magnetic nanoparticles: green synthesis and characterization. AB - In recent years, there has been considerable interest in Arg which is a unique, nontoxic, and biocompatible biomolecule since it can be utilized as an agent for the functionalization and subsequent stabilization of MNPs against oxidation and aggregation, during or after a synthesis procedure. Our studies demonstrate that Arg has great impacts on MNPs with the decreasing size of the particle. Also, saturation magnetization and electrostatic interactions of RMNPs have a direct impact on biological molecules such as proteins and nucleic acids. By controlling the concentration of Arg, it is possible to accurately control the above mentioned characteristics, which are useful tools for applications such as connecting to antibodies, catalysis, drug loading, and modification of MNP stability. In the current study, three RMNPs with different Arg densities, i.e. 0.42, 1.62, and 2.29 MUg per mg were successfully synthesized through a simple co precipitation method (named p 0.5, p 1, and p 1.5, respectively) and verified by colorimetric determination. Also, the as-synthesized RMNP powders were characterized by XRD, SEM/EDAX, FTIR, VSM, and zeta potential analysis. The presence of a magnetic core was proved by XRD, FTIR, and EDAX. Colorimetric analysis showed the existence of Arg in the synthesized samples. According to the zeta potential and VSM results, increasing the cap of Arg on the MNP surface leads to an increase in the surface charge and decrease in the magnetization of the RMNPs, respectively. PMID- 29256437 TI - Pressure-induced metallization in layered ReSe2. AB - The evolution of the crystal structure and electrical transport properties of distorted layered transition metal dichalcogenide ReSe2 was studied under high pressure up to ~90 GPa by Raman spectroscopy and electrical resistivity measurements accompanied by ab initio electronic band structure calculations. Raman spectroscopy studies indicate an isostructural phase transition due to layer sliding at ~7 GPa, to the distorted 1T-phase which remains stable up to the highest pressures employed in these experiments. From a direct band gap semiconductor at ambient pressure, ReSe2 undergoes pressure-induced metallization at pressures ~35 GPa, in agreement with the ab initio calculations. Resistivity measurements performed with different loading conditions reveal the possible emergence of superconductivity, which is most likely not an intrinsic property of ReSe2, but is rather conditioned by internal stresses upon compression. PMID- 29256438 TI - Sr-doped nanowire modification of Ca-Si-based coatings for improved osteogenic activities and reduced inflammatory reactions. AB - Biomedical coatings for orthopedic implants should facilitate osseointegration and mitigate implant-induced inflammatory reactions. In our study, Ca-Si coatings with Sr-containing nanowire-like structures (NW-Sr-CS) were achieved via hydrothermal treatment. In order to identify the effect of nanowire-like topography and Sr dopant on the biological properties of Ca-Si-based coatings, the original Ca-Si coating, Ca-Si coatings modified with nanoplate (NP-CS) and similar nanowire-like structure (NW-CS) were fabricated as the control. Surface morphology, phase composition, surface area, zeta potential and ion release of these coatings were characterized. The in vitro osteogenic activities and immunomodulatory properties were evaluated with bone marrow stromal cells (BMSCs) and RAW 264.7 cells, a mouse macrophage cell line. Compared with the CS and NP-CS coatings, the NW-CS coating possessed a larger surface area and pore volume, beneficial protein adsorption, up-regulated the expression levels of integrin beta1, Vinculin and focal adhesion kinase and promoted cell spreading. Furthermore, the NW-CS coating significantly enhanced the osteogenic differentiation and mineralization as indicated by the up-regulation of ALP activity, mineralized nodule formation and osteoblastogenesis-related gene expression. With the introduction of Sr, the NW-Sr-CS coatings exerted a greater effect on the BMSC proliferation rate, calcium sensitive receptor gene expression as well as PKC and ERK1/2 phosphorylation. In addition, the Sr-doped coatings significantly up-regulated the ratio of OPG/RANKL in the BMSCs. The NW-Sr-CS coatings could modulate the polarization of macrophages towards the wound-healing M2 phenotype, reduce the mRNA expression levels of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) and enhance anti-inflammatory cytokines (IL-1ra, IL 10). The Sr-doped nanowire modification may be a valuable approach to enhance osteogenic activities and reduce inflammatory reactions. PMID- 29256439 TI - Adsorption of H2, O2, H2O, OH and H on monolayer MoS2. AB - Hydrogen and hydrogen-containing gases are commonly used as reductants in chemical vapor deposition growth of MoS2. Here, we consider the defects resulting from the presence of hydrogen during growth and the resulting electronically active defects. In particular, we find that the interstitial hydrogen defect is a negative-U center with amphoteric donor and acceptor properties. Additionally, we consider the effects of interaction with water and oxygen. The defects are analysed using density functional theory calculations. PMID- 29256440 TI - In vitro magnetic hyperthermia using polyphenol-coated Fe3O4@gammaFe2O3 nanoparticles from Cinnamomun verum and Vanilla planifolia: the concert of green synthesis and therapeutic possibilities. PMID- 29256441 TI - A comprehensive study of lateral fall-off (penumbra) optimisation for pencil beam scanning (PBS) proton therapy. AB - The lateral fall-off is crucial for sparing organs at risk in proton therapy. It is therefore of high importance to minimize the penumbra for PBS. Three optimisation approaches are investigated: Edge-collimated uniformly weighted spots (collimation), pencil beam optimisation of uncollimated pencil beams (edge enhancement) and the optimisation of edge collimated pencil beams (collimated edge-enhancement). To deliver energies below 70MeV, these strategies are evaluated in combination with the following pre-absorber methods: field specific fixed thickness pre-absorption (fixed), range specific, fixed thickness pre absorption (automatic) and range specific, variable thickness pre-absorption (variable). All techniques are evaluated by Monte Carlo simulating square fields in a water tank. For a typical air gap of 10cm, without pre-absorber collimation reduces the penumbra only for water equivalent ranges (WER) between 4cm to 11cm by up to 2.2mm. The sharpest lateral fall-off is achieved through collimated edge enhancement, which lowers the penumbra down to 2.8mm. When using a pre-absorber, the sharpest fall-offs are obtained when combining collimated edge-enhancement with a variable pre-absorber. For edge-enhancement and large air gaps, it is crucial to minimize the amount of material in the beam. For small air gaps however, the superior phase space of higher energetic beams can be employed when more material is used. In conclusion, collimated edge-enhancement combined with the variable pre-absorber is the recommended setting to minimize the lateral penumbra for PBS. Without collimator, it would be favourable to use a variable pre-absorber for large air gaps and an automatic pre-absorber for small air gaps. PMID- 29256442 TI - Construction and evaluation of BSA-CaP nanomaterials with enhanced transgene performance via biocorona-inspired caveolae-mediated endocytosis. AB - Non-viral nanovectors have attracted much attention owing to their ability to condense genetic materials and their ease of modification. However, their poor stability, low biocompatibility and gene degradation in endosomes or lysosomes has significantly hampered their application in vivo and in the clinic. In an attempt to overcome these difficulties a series of bovine serum albumin (BSA) calcium phosphate (CaP) nanoparticles were constructed. The CaP condenses with DNA to form nanocomplexes coated with a biomimetic corona of BSA. Such complexes may retain the inherent endocytosis profile of BSA, with improved biocompatibility. In particular the transgene performance may be enhanced by stimulating the cellular uptake pathway via caveolae-mediated endocytosis. Two methods were employed to construct and optimize the formulation of BSA-CaP nanomaterials. The optimized BSA-CaP-50-M2 nanoparticles prepared by our second method exhibited good stability, negligible cytotoxicity and enhanced transgene performance with long-term expression for 72 h in vivo even with a single dose. Determination of the cellular uptake pathway and Western blot revealed that cellular uptake of the designed BSA-CaP-50-M2 nanoparticles was mainly via caveolae-mediated endocytosis in a non-degradative pathway in which the biomimetic uptake profile of BSA was retained. PMID- 29256443 TI - Self-powered gustation electronic skin for mimicking taste buds based on piezoelectric-enzymatic reaction coupling process. AB - A new self-powered wearable gustation electronic skin for mimicking taste buds has been realized based on enzyme-modified/ZnO nanowire arrays on patterned electrode flexible substrate. The e-skin can actively taste beverages or fruits without any external electric power. Through the piezoelectric-enzymatic reaction coupling effect, the nanowires can harvest the mechanical energy of body movement and output piezoelectric signal. The piezoelectric output is significantly dependent on the concentration of target analyte. The response for detecting 2 * 10-2 M ascorbic acid (ascorbate acid oxidase@ZnO) is up to 171.747, and the selectivity is high. The response for detecting 50% alcohol (alcohol oxidase@ZnO) is up to 45.867. Our results provide a new research direction for the development of multifunctional e-skin and expand the study scope for self-powered bionic systems. PMID- 29256444 TI - Evidence of beta-antimonene at the Sb/Bi2Se3 interface. AB - We report a study of the interface between antimony and the prototypical topological insulator Sb/Bi2Se3. Scanning tunnelling microscopy measurements show the presence of ordered domains displaying a perfect lattice match with bismuth selenide. Density functional theory calculations of the most stable atomic configurations demonstrate that the ordered domains can be attributed to stacks of beta-antimonene. PMID- 29256445 TI - Compressive yield stress of depletion gels from stationary centrifugation profiles. AB - We have investigated the stationary sedimentation profiles of colloidal gels obtained by an arrested phase-separation process driven by depletion forces, which have been compressed either by natural gravity or by a centrifugal acceleration ranging between 6g and 2300g. Our measurements show that the gel rheological properties display a drastic change when the gel particle volume fraction exceeds a value [Formula: see text], which barely depends on the strength of the interparticle attractive forces that consolidate the network. In particular, the gel compressive yield stress [Formula: see text], which increases as [Formula: see text] for [Formula: see text], displays a diverging behaviour for [Formula: see text], with an asymptotic value that is close to the random close packing value for hard spheres. The evidence we obtained suggests that [Formula: see text] basically coincides with the liquid (colloid-rich) branch of the metastable coexistence curve, rather than with the lower (and phi-dependent) values expected for an attractive glass line penetrating inside the coexistence region. PMID- 29256446 TI - Theoretical study of nitride short period superlattices. AB - Discussion of band gap behavior based on first principles calculations of electronic band structures for various short period nitride superlattices is presented. Binary superlattices, as InN/GaN and GaN/AlN as well as superlattices containing alloys, as InGaN/GaN, GaN/AlGaN, and GaN/InAlN are considered. Taking into account different crystallographic directions of growth (polar, semipolar and nonpolar) and different strain conditions (free-standing and pseudomorphic) all the factors influencing the band gap engineering are analyzed. Dependence on internal strain and lattice geometry is considered, but the main attention is devoted to the influence of the internal electric field and the hybridization of well and barrier wave functions. The contributions of these two important factors to band gap behavior are illustrated and estimated quantitatively. It appears that there are two interesting ranges of layer thicknesses; in one (few atomic monolayers in barriers and wells) the influence of the wave function hybridization is dominant, whereas in the other (layers thicker than roughly five to six monolayers) dependence of electric field on the band gaps is more important. The band gap behavior in superlattices is compared with the band gap dependence on composition in the corresponding ternary and quaternary alloys. It is shown that for superlattices it is possible to exceed by far the range of band gap values, which can be realized in ternary alloys. The calculated values of the band gaps are compared with the photoluminescence emission energies, when the corresponding data are available. Finally, similarities and differences between nitride and oxide polar superlattices are pointed out by comparison of wurtzite GaN/AlN and ZnO/MgO. PMID- 29256447 TI - Editorial: Introduction about fluorescence in China. PMID- 29256448 TI - Antidot patterned single and bilayer thin films based on ferrimagnetic Tb-Co alloy with perpendicular magnetic anisotropy. AB - Hysteresis properties and magnetization reversal in TbCo(30 nm) and FeNi(10 nm)/TbCo(30 nm) films with nanoscale antidot lattices are investigated to test the effect of nanoholes on the perpendicular anisotropy in the TbCo layer and the induced exchange bias in the FeNi layer. The antidots are introduced by depositing the films on top of hexagonally ordered porous anodic alumina substrates with pore diameter and interpore distance fixed to 75 nm and 105 nm, respectively. The analysis of combined vibrating sample magnetometry, Kerr microscopy and magnetic force microscopy imaging measurements has allowed us to link macroscopic and local magnetization reversal processes. For magnetically hard TbCo films, we demonstrate the tunability of magnetic anisotropy and coercive field (i.e., it increases from 0.2 T for the continuous film to 0.5 T for the antidot film). For the antidot FeNi/TbCo film, magnetization of FeNi is confirmed to be in plane. Although an exchange bias has been locally detected in the FeNi layer, the integrated hysteresis loop has increased coercivity and zero shift along the field axis due to the significantly decreased magnetic anisotropy of TbCo layer. PMID- 29256449 TI - A novel upwind stabilized discontinuous finite element angular framework for deterministic dose calculations in magnetic fields. AB - Angular discretization impacts nearly every aspect of a deterministic solution to the linear Boltzmann transport equation, especially in the presence of magnetic fields, as modeled by a streaming operator in angle. In this work a novel stabilization treatment of the magnetic field term is developed for an angular finite element discretization on the unit sphere, specifically involving piecewise partitioning of path integrals along curved element edges into uninterrupted segments of incoming and outgoing flux, with outgoing components updated iteratively. Correct order-of-accuracy for this angular framework is verified using the method of manufactured solutions for linear, quadratic, and cubic basis functions in angle. Higher order basis functions were found to reduce the error especially in strong magnetic fields and low density media. We combine an angular finite element mesh respecting octant boundaries on the unit sphere to spatial Cartesian voxel elements to guarantee an unambiguous transport sweep ordering in space. Accuracy for a dosimetrically challenging scenario involving bone and air in the presence of a 1.5 T parallel magnetic field is validated against the Monte Carlo package GEANT4. Accuracy and relative computational efficiency were investigated for various angular discretization parameters. 32 angular elements with quadratic basis functions yielded a reasonable compromise, with gamma passing rates of 99.96% (96.22%) for a 2%/2 mm (1%/1 mm) criterion. A rotational transformation of the spatial calculation geometry is performed to orient an arbitrary magnetic field vector to be along the z-axis, a requirement for a constant azimuthal angular sweep ordering. Working on the unit sphere, we apply the same rotational transformation to the angular domain to align its octants with the rotated Cartesian mesh. Simulating an oblique 1.5 T magnetic field against GEANT4 yielded gamma passing rates of 99.42% (95.45%) for a 2%/2 mm (1%/1 mm) criterion. PMID- 29256450 TI - Independent Monte-Carlo dose calculation for MLC based CyberKnife radiotherapy. AB - This work aims to develop, implement and validate a Monte Carlo (MC)-based independent dose calculation (IDC) framework to perform patient-specific quality assurance (QA) for multi-leaf collimator (MLC)-based CyberKnife(r) (Accuray Inc., Sunnyvale, CA) treatment plans. The IDC framework uses an XML-format treatment plan as exported from the treatment planning system (TPS) and DICOM format patient CT data, an MC beam model using phase spaces, CyberKnife MLC beam modifier transport using the EGS++ class library, a beam sampling and coordinate transformation engine and dose scoring using DOSXYZnrc. The framework is validated against dose profiles and depth dose curves of single beams with varying field sizes in a water tank in units of cGy/Monitor Unit and against a 2D dose distribution of a full prostate treatment plan measured with Gafchromic EBT3 (Ashland Advanced Materials, Bridgewater, NJ) film in a homogeneous water equivalent slab phantom. The film measurement is compared to IDC results by gamma analysis using 2% (global)/2 mm criteria. Further, the dose distribution of the clinical treatment plan in the patient CT is compared to TPS calculation by gamma analysis using the same criteria. Dose profiles from IDC calculation in a homogeneous water phantom agree within 2.3% of the global max dose or 1 mm distance to agreement to measurements for all except the smallest field size. Comparing the film measurement to calculated dose, 99.9% of all voxels pass gamma analysis, comparing dose calculated by the IDC framework to TPS calculated dose for the clinical prostate plan shows 99.0% passing rate. IDC calculated dose is found to be up to 5.6% lower than dose calculated by the TPS in this case near metal fiducial markers. An MC-based modular IDC framework was successfully developed, implemented and validated against measurements and is now available to perform patient-specific QA by IDC. PMID- 29256451 TI - CPU time optimization and precise adjustment of the Geant4 physics parameters for a VARIAN 2100 C/D gamma radiotherapy linear accelerator simulation using GAMOS. AB - We have verified the GAMOS/Geant4 simulation model of a 6 MV VARIAN Clinac 2100 C/D linear accelerator by the procedure of adjusting the initial beam parameters to fit the percentage depth dose and cross-profile dose experimental data at different depths in a water phantom. Thanks to the use of a wide range of field sizes, from 2 * 2 cm2 to 40 * 40 cm2, a small phantom voxel size and high statistics, fine precision in the determination of the beam parameters has been achieved. This precision has allowed us to make a thorough study of the different physics models and parameters that Geant4 offers. The three Geant4 electromagnetic physics sets of models, i.e. Standard, Livermore and Penelope, have been compared to the experiment, testing the four different models of angular bremsstrahlung distributions as well as the three available multiple scattering models, and optimizing the most relevant Geant4 electromagnetic physics parameters. Before the fitting, a comprehensive CPU time optimization has been done, using several of the Geant4 efficiency improvement techniques plus a few more developed in GAMOS. PMID- 29256453 TI - Need for more research on burden of oral diseases in India. PMID- 29256452 TI - Quality management - Dental office applications. PMID- 29256454 TI - Evaluation of knowledge, awareness, and attitude toward emergency dental trauma management among the school teachers of Kolkata. AB - INTRODUCTION: Traumatic dental injuries (TDIs) are very common in childhood. Majority of TDI occur at home followed by schools. The prognosis of TDIs to a great extent is dependent on prompt emergency measures taken at the site of accident. Hence, it is of paramount importance to assess the knowledge of people present at the site of accident that generally includes parents, teachers, and sports coaches. AIM OF STUDY: The aim of the study was to assess the knowledge, attitude, and awareness of school teachers of Kolkata regarding management of TDIs. MATERIALS AND METHODS: A cross-sectional survey was conducted on 400 school teachers of Kolkata over a period of 2 months using a pretested close-ended questionnaire. The questionnaire had three parts: Part 1 contained questions on personal information, Part 2 contained questions based on two imaginary cases of trauma, and Part 3 related to their attitude toward dental trauma education. Chi square test was done to describe the strength of the associations. RESULTS: The overall knowledge of school teachers regarding management of TDIs was not found to be satisfactory. It was observed that most of the teachers were in favor of taking immediate professional consultation for the emergency management, but most of them were unaware of the steps to be taken on their part to minimize complications and improve prognosis. CONCLUSION: Despite the lack of knowledge and awareness regarding management of dental trauma, school teachers of Kolkata had a good attitude toward management of dental trauma and its education. PMID- 29256455 TI - Are dentists happy? A study among dental practitioners in coastal Andhra Pradesh using subjective happiness scale. AB - INTRODUCTION: The role of dental professionals in the society is vital. This profession allows the flexibility to balance a professional and personal life. Practice of dentistry at times is quite stressful, and stress impedes happiness and subjective well-being. Several studies have reported about stress among dental professionals and their various effects; however, studies evaluating the level of happiness (happiness index) among dentists are few and lack in this geographic region. OBJECTIVES: The present study was conducted to assess the subjective happiness level among dental professionals. MATERIALS AND METHODS: A cross-sectional study was conducted among 194 dentists in Andhra Pradesh, India. A questionnaire measuring dimensions of professional satisfaction by Subjective Happiness Scale was used to assess the happiness level. The results were expressed in percentages, means, and mean rank. Independent samples nonparametric tests (Mann-Whitney U-test and Kruskal-Wallis test) and multivariable analyses were used to assess the determinants of happiness. RESULTS: The mean happiness index of the respondents was 21.71 (0.26 standard error). Overall 67% of the respondents had an above average happiness score. Higher happiness score was found to be significantly associated with age, postgraduate degree, male gender, type of professional attachment, duration of practice, urban location of practice, and spouse employment status in univariate analysis. However, multivariable analysis showed association with type of professional attachment only. CONCLUSION: Although dentistry has been recognized as a stressful profession, majority of the dentists under study had a happiness score above the mean, and the level of satisfaction was influenced by various sociodemographic factors. PMID- 29256456 TI - Human permanent teeth are divided into two parts at the cemento-enamel junction in the divine golden ratio. AB - AIM: The aim of this study is to find out whether tooth length (crown length + root length) follows the rule of most divine and mysterious phi (phi) or the golden ratio. METHODS: A total of 140 teeth were included in the study. The crown root ratio was manually calculated using vernier caliper and its approximation to golden ratio or the divine number phi (phi) was examined. RESULTS: The average root-crown ratio (R/C) for maxillary central incisor was 1.627 +/- 0.04, and of its antagonist, mandibular central incisor was 1.628 +/- 0.02. The tooth-root ratio (T/R) for the same was 1.609 +/- 0.016 and 1.61 +/- 0.008, respectively. Similar values were appreciated for lateral incisors where the R/C ratio in the maxillary and mandibular teeth was 1.632 +/- 0.015 and 1.641 +/- 0.012 and the T/R ratio was 1.606 +/- 0.005 and 1.605 +/- 0.005, respectively. CONCLUSION: On measuring the tooth length in linear fashion from the cusp tip to the root apex, we found that the tooth was divided into two parts at the cemento-enamel junction in the golden ratio. This information can be exploited in restorative and implant dentistry in future. PMID- 29256457 TI - Re-evaluation of interarch space determination in fully dentate adults with different facial forms: A clinical study. AB - AIM: The aim is to determine the average inter-arch space of fully dentate subjects at rest and at occlusion with different facial forms. MATERIALS AND METHODS: Fifty subjects each of three groups of facial form, square, taper, and oval facial with a complete set of maxillary and mandibular arch teeth with average age from 25 to 40 years were included in this study. An equal number of male and females were included in all the groups. Vertical height at rest and at occlusion was recorded in every subject of the all the three groups using a prescribed procedure, and freeway space (FWS) was measured. RESULTS: The collected data were statistically evaluated, and it showed the mean and median for each facial form subjects, square facial form (3, 2.32), taper facial form (2.62, 2), and ovoid facial form (2.68, 2), respectively. No significant difference between any of the readings (P < 0.05). However, 9% of the individuals showed the FWS range of 5-6 mm. The lowest and highest FWS measurements were 1 and 7 mm, respectively. One more significant factor is that majority (56%) of the square facial form subjects showed FWS range of 3-4 mm. CONCLUSION: The conclusions were drawn, to understand the average inter-arch space in various facial forms, which was more than 3-4 mm. PMID- 29256458 TI - Topographic assessment of human enamel surface treated with different topical sodium fluoride agents: Scanning electron microscope consideration. AB - INTRODUCTION: Continuous balanced demineralization and remineralization are natural dynamic processes in enamel. If the balance is interrupted and demineralization process dominates, it may eventually lead to the development of carious lesions in enamel and dentine. Fluoride helps control decay by enhancing remineralization and altering the structure of the tooth, making the surface less soluble. METHODOLOGY: One hundred and twenty sound human permanent incisors randomly and equally distributed into six groups as follows: Group I - Control, II - Sodium fluoride solution, III - Sodium fluoride gel, IV - Sodium fluoride varnish, V - Clinpro Tooth Creme (3M ESPE), and VI-GC Tooth Mousse Plus or MI Paste Plus. The samples were kept in artificial saliva for 12 months, and the topical fluoride agents were applied to the respective sample groups as per the manufacturer instructions. Scanning electron microscope (SEM) evaluation of all the samples after 6 and 12 months was made. RESULTS: Morphological changes on the enamel surface after application of fluoride in SEM revealed the presence of globular precipitate in all treated samples. Amorphous, globular, and crystalline structures were seen on the enamel surface of the treated samples. Clear differences were observed between the treated and untreated samples. CONCLUSION: Globular structures consisting of amorphous CaF2precipitates, which acted as a fluoride reservoir, were observed on the enamel surface after action of different sodium fluoride agents. CPP-ACPF (Tooth Mousse) and Tricalcium phosphate with fluoride (Clinpro tooth creme) are excellent delivery vehicles available in a slow release amorphous form to localize fluoride at the tooth surface. PMID- 29256459 TI - Velar morphological variants in oral submucous fibrosis: A comparative digital cephalometric study. AB - CONTEXT: Soft palate (velar) plays a significant role in various important functions in the head and neck region. Its diverse morphology is implicated in a variety of diseases. Knowledge about the varied morphological pattern of soft palate in oral submucous fibrosis (OSMF) patients can give us a clear understanding about disease progress in the oropharyngeal region for a proper diagnosis and also help the maxillofacial surgeon in successful structural and functional corrections associated with this disorder. AIM: (1) To evaluate the morphological variations of soft palate in OSMF patients using digital lateral cephalogram. (2) To assess the morphological variations of soft palate with respect to the different clinical stages of OSMF patients. SUBJECTS AND METHODS: A total number of 300 patients were included in the study (150 participants each in study and control group), evaluated clinically, and subjected for digital lateral cephalogram for evaluating velar morphological variants. STATISTICAL ANALYSIS: The data were statistically evaluated using SPSS 11.5 software with Student's t-test, Chi-square test, and ANOVA. RESULTS: Among Group I, 34 participants had Stage I OSMF, 90 participants had Stage II OSMF, and 26 participants had Stage III OSMF. Type I velar was commonly seen in Stage I OSMF, Type VI velar in Stage II OSMF, and Type III velar in Stage III OSMF. There was statistically highly significant decrease in anterior-posterior (AP) length and increase in width of superior-inferior (SI) measurement, as compared to the Group II. CONCLUSION: There was diminution in AP length and increase in SI measurement as the OSMF disease progressed. PMID- 29256460 TI - Knowledge, attitude and practices of institution-based dentists toward nicotine replacement therapy. AB - BACKGROUND: Dental institutions provide very good platform to educate budding dentists to inculcate the habit of tobacco cessation counseling, including nicotine replacement therapy (NRT). AIMS: The aim of this study is to assess and compare the knowledge, attitude, and practice of institutionally attached postgraduate students and faculty members of the dental profession toward NRT. METHODS: For a cross-sectional survey among 201 participants from four dental colleges in Odisha, India, a 28-item questionnaire was developed, subdivided into four categories: demographic details, assessment of NRT knowledge (21-item), assessment of attitude (5-item), practice (1-item with 4 subgroup questions), and 1-item assessing barriers. STATISTICAL ANALYSIS USED: Data were analyzed using descriptive statistics, Chi-square test, and multiple logistic regression. RESULTS: Only one-third of participants were aware of the dosage, mechanism of action, pharmacology, duration of the prescription, brand name, side effects, contraindications, and availability. Around two-third of participants who claimed to practice NRT, agreed to follow up the patients whom they prescribed NRT. Half of the study participants reported that they do not keep a record of these patients. Around 10% of respondents practicing NRT were confident enough to practice it without facing any problem. Major barriers for practicing NRT was found to be a lack of awareness (54.22%) followed by availability and bitter taste. The total knowledge score was found to be the strongest predictor of practicing NRT in multiple logistic regression. CONCLUSION: Lack of detailed knowledge regarding NRT reduces the chance of practicing inspite of having a positive attitude among institutionally attached dentists. PMID- 29256461 TI - Dermatoglyphics in periodontics: An assessment of the relationship between fingerprints and periodontal status - A cross-sectional observation study. AB - CONTEXT: Widespread interest in epidermal ridges developed only in the last several decades; however, it is still at infancy in the world of dentistry. The word "dermatoglyphics" comes from two Greek words (derma: Skin and glyphe: Carve) and refers to the epidermal skin ridge formations which appear on the fingers, palms of the hands, and soles of the feet. AIMS: This study aims to assess the relationship between finger prints and chronic periodontitis. MATERIALS AND METHODS: Two hundred patients were equally divided into chronic periodontitis and periodontally healthy group. The fingerprint patterns of the participants were recorded with a rolling impression technique using duplicating ink on executive bond paper. STATISTICAL ANALYSIS USED: The descriptive analysis of the data was presented as percentage frequency. The percentage frequencies of each pattern on each individual finger were calculated, and statistical tests were applied. Unpaired t-test was used for intergroup comparisons (P < 0.05). RESULTS: There were statistically more whorls and less arches in both right and left hands in patients with chronic periodontitis. CONCLUSIONS: Dermatoglyphics can lead to early diagnosis, treatment, and better prevention of many genetic disorders of the oral cavity and other diseases whose etiology may be influenced directly or indirectly by genetic inheritance. PMID- 29256462 TI - Association of level of education and utilization of restorative dental care among rural women in India: Cross-sectional study. AB - BACKGROUND: The utilization of restorative dental care is very scarce in rural India. Association between level of education and health of a person has been well-documented in many countries and time periods with a range of potential factors shaping the connection between both. OBJECTIVES: This cross-sectional survey was conducted to evaluate an association between the level of education (educational qualification) and utilization of restorative dental care among rural women associated with self-help groups. MATERIALS AND METHODS: A semi structured questionnaire was administrated to 660 rural women associated with self-help group by trained research assistants. The 604 completed questionnaires were received and reviewed. The education levels were divided into three groups: Group 1 - illiterates (17.2%), Group 2 - school educated (69.4%), and Group 3 - college educated (13.4%). Chi-square test was applied to evaluate the utilization of dental services by rural women, and logistic regression was applied to evaluate the influence of their educational qualifications on utilization. RESULTS: A total of 604 properly filled questionnaires out of 660 (91.51% response rate) were included in the analysis. Only 56.9% of the sampled rural women indicated that they have visited dentists earlier. The maximum number of individuals who have never visited the dentist belonged to illiterate group (55.7%), and the association was statistically significant (0.004) when compared with educated individuals. CONCLUSION: The results of this study concluded that the level of education has a significant influence on the utilization of dental care. PMID- 29256463 TI - Perceptions about toothbrush contamination and disinfection among dental students in Bengaluru City: A cross-sectional study. AB - INTRODUCTION: Toothbrushes are vital to remove dental biofilm and to prevent dental caries and periodontal disease. Repeated use of toothbrushes leads to contamination; hence, disinfection is essential in the maintenance of a brush. Current understanding and perception among dental students about toothbrush contamination and disinfection are essential. AIM: The aim of this study was to assess the perceptions about toothbrush contamination and disinfection among postgraduates and interns in Bengaluru city. MATERIALS AND METHODS: A cross sectional study was conducted using self-administered questionnaire among 400 postgraduates and interns from five dental colleges in Bengaluru. The statistics were computed with the Statistical Package of Social Sciences (SPSS) version 22 software and Chi-square test was used. A P < 0.05 was considered statistically significant. RESULTS: There was a statistically significant difference regarding the source of information on tooth brush contamination (P = 0.008) and common mode of transmission of contamination (P = 0.01) between the two groups. The difference was found to be statistically significant (P = 0.01) regarding sharing of toothpaste. Only less than half of the participants, in both the groups practiced disinfection. CONCLUSION: There was a statistically significant difference in the perceptions about tooth brush contamination and disinfection among postgraduates and interns that might be attributed to their higher academic knowledge and clinical experience. PMID- 29256465 TI - Influence of arthrocentesis irrigation volume at temporomandibular disorder treatment. AB - INTRODUCTION: Temporomandibular disorder (TMD) treatment varies from conservative therapy to invasive procedures such as arthrocentesis. The procedure is simple and has speed, low cost, low morbidity and good patient acceptance. Literature variations, however, have been found about the type and volume of the solution used for the irrigation of temporomandibular joint (TMJ). SUBJECTS AND METHODS: The aim of this study was to compare the results provided by two different volumes of 0.9% saline solution (100 ml and 250 ml) used in arthrocentesis technique for TMD treatment. It included patients unresponsive to conservative treatment. Preoperative (T0) and postoperative evaluations were performed at T1 (30th day), T2 (60th day), and T3 (90th day), in which maximal mouth opening (MMO), pain, and the presence or absence of joint sounds were recorded. Patients were randomized into two groups: 1 - submitted to arthrocentesis using 100 ml of 0.9% saline solution in TMJ and 2 - arthrocentesis performed using 250 ml of 0.9% saline solution in each TMJ. Data were submitted to descriptive and comparative analyses for each parameter per group and between groups. The effect size was calculated according to Cohen test. Minimum detectable change (MDC) was obtained and the sensibility was calculated. A statistical significance of 5% was established. Group 1 obtained increase in MMO and decrease in pain (statistically significant); in Group 2, pain decreased significantly. In Group 1, clicking decreased significantly. No statistical differences were found between groups (P = 0.333). MMO and pain results exceeded MDC, and sensibility was good. CONCLUSION: In conclusion, arthrocentesis is effective in TMD symptoms' relief, without statistical difference between the volumes used. PMID- 29256464 TI - Gingival and periodontal changes in patients undergoing in vitro fertilization treatment: A clinical study. AB - AIMS: The aim of this study was to investigate the effect of in vitro fertilization (IVF) treatment on different parameters of periodontal status. SETTINGS AND DESIGN: This was a clinical observational study. MATERIALS AND METHODS: One hundred and seventy-nine patients who underwent IVF treatment according to the standard IVF protocols were examined using the simplified oral hygiene, gingival index (GI), sulcus bleeding index (SBI), and determining the clinical attachment loss (CAL). A full-mouth examination except for the third molars was performed at 4 sites per tooth (mesiobuccal, distobuccal, mesiolingual, and distolingual). Periodontal evaluation was performed before infertility treatment, at the end of infertility treatment, and 14 days after embryo transfer. STATISTICAL ANALYSIS: The Kruskal-Wallis or Fisher's tests were used to compare the median or mean values as appropriate. RESULTS: The oral hygiene index simplified was 0.49, 0.32, and 0.37 at pretreatment, on the day of human chorionic gonadotropin (HCG) trigger, and on the day of the pregnancy test, respectively. The GI showed significant differences before and after treatment. The mean GI was 0.13 at pretreatment compared to 0.51 and 0.53 on the days of HCG trigger and of the pregnancy test, respectively. The same trend was seen for SBI. There were no differences in CAL among the three examinations. There was no difference between the two groups except for GI (0.71 vs. 0.48 for a positive pregnancy test vs. nonpregnancy, respectively). CONCLUSIONS: IVF medications and a superphysiological condition affect oral health, particularly gingival and periodontal statuses, and likely complicate the relationship between infertility, sex hormones, and infertility management. Larg-scale studies are needed to confirm the effect of such treatment on oral health. PMID- 29256466 TI - Angular cheilitis: A clinical and microbial study. AB - AIMS: The aim of the present study was to examine clinical types and microbiological flora isolated from angular chelitis. MATERIALS AND METHODS: An eroded and/or erythematous, with or without fissure formation, nonvesicular lesion radiating from the angle of the mouth was considered to be angular chelitis. A sample of the present study comprised of 40 patients having unilateral or bilateral angular chelitis and 20 healthy individuals without any lip lesions. Clinical examination was done. In both test and control groups, the sample for microbial analysis was obtained from angle of the mouth. RESULTS: Clinically, four types of angular cheilitis lesions were found, Type I, II, III, and IV. The most common type of lesion found was Type I lesion. Microorganisms isolated from the lesion were Staphylococcus aureus, Candida or Streptococci in 33 (82.5%) cases either in pure culture or mixed culture. Among these 33 patients, S. aureus was found in 25 (75.5%) cases, Candida in 16 (48.4%) cases, and Streptococci in 5 (13.5%) cases, respectively. Out of 16 cases positive for Candida, in 13 cases further isolation of Candida was possible. Candida albicans was found in 6 cases and Candida stellastodia in 7 cases. In majority of the dentulous and edentulous patients, S. aureus showed profuse growth. CONCLUSIONS: There are microorganisms associated with angular cheilitis. PMID- 29256467 TI - A study for determination of various positioning errors in digital panoramic radiography for evaluation of diagnostic image quality. AB - : Faulty radiographs have poor diagnostic quality, and repetition of such poor quality radiographs leads to increased patient exposure to radiation. Since digital panoramic radiography has replaced manual radiography, the only hindrance in producing good-quality radiographs is the positioning errors. OBJECTIVES: Our study aims to determine the various positioning errors and their relative frequency and to identify those errors directly responsible for diagnostically inadequate images. MATERIALS AND METHODS: Five hundred panoramic radiographs taken serially (from the year 2007) were retrospectively assessed for the positioning errors by three oral and maxillofacial radiology specialists using a performa enlisting the errors. The three specialists had different duration of clinical experience and they evaluated the orthopantograms as diagnostically acceptable or unacceptable. They also observed the relative frequency of all the positioning errors. STATISTICAL ANALYSIS: The kappa value for intraobserver agreement was calculated, which suggested that the agreement among the observers was fair. RESULTS: Of the 500 panoramic radiographs viewed by the three observers, 25 (5%) had no errors, while 475 (95%) showed one or more positioning errors. The most common error in our study was found to be head turned to one side (33.8%) and the least common error was patient movement during exposure (1.8%). CONCLUSION: Positioning errors are very common in digital panoramic radiography, and they lead to production of poor-quality radiographs. The operator should take this fact into consideration and spend more time in patient positioning, thereby reducing the repetition of radiographs and unwanted patient exposure. PMID- 29256468 TI - Repercussion of noni mouthwash on surface characterization of Nickel-Titanium archwire. AB - OBJECTIVE: Maintaining oral hygiene is very important during orthodontic therapy mouthwashes are prescribed as an adjunct to improve patient's oral hygiene. Commercially available mouthwashes e.g. Chlorhexidine, Listerine, fluoride containing mouthwashes have shown to alter the surface characteristics of orthodontic wires. Hence the purpose of the study was to evaluate the effect of Noni mouthwash on surface quality and compositional changes of Nickel Titanium orthodontic wires. MATERIALS AND METHODS: In this in vitro study pre-formed 0.014 inch NiTi arch wire was used. The study comprised of two samples, one control and one test sample which were 25mm in length. Control sample was stored at room temperature without any manipulation while test sample was immersed in Noni mouthwash solution for 1.5 hours, after which the test specimen was removed from the mouthwash solution and rinsed with distilled water. Both control and test samples were sent for scanning electron microscopy analysis, to qualitatively characterize the topography of the wire surface. Electron dispersion spectrum analysis was done to evaluate the various components of both the wires. RESULTS: No significant difference in the average surface roughness for both wire samples was observed. There was no significant difference seen in the composition of wire after immersion in Noni mouthwash. CONCLUSION: Noni mouthwash did not have significant influence on the surface roughness or altered the composition of the Ni-Ti wire. Hence Noni mouthwash may be prescribed as a natural, non-destructive prophylactic agent for orthodontic patients. PMID- 29256469 TI - Comparative evaluation of different periods of enamel microabrasion on the microleakage of class V resin-modified glass ionomer and compomer restorations: An In vitro study. AB - CONTEXT: The design of the class V cavity presents a clinical challenge in the field of adhesive dentistry as the margin placement is partially in enamel and partly in dentin, and the trouble associated with this design is the microleakage at the dentinal margin. When these restorations undergo microabrasion due to cosmetic reasons, this trouble aggravates to the significant levels. AIMS: The aim of this study was the measurement of microleakage of class V glass ionomer restorations over two different periods of enamel microabrasion. SETTINGS AND DESIGN: This in vitro experimental study was conducted on 120 class V cavities which had been prepared on the buccal and lingual surfaces of 60 sound human premolars. One-half of the cavities were restored with the resin-modified glass ionomer cement (GIC) (60 cavities) and another half with the compomer (60 cavities). Finishing and polishing were performed. SUBJECTS AND METHODS: Then, the teeth were classified into six groups (n = 20). Microabrasion treatment was performed with Opaluster (Ultradent Product Inc., South Jordan, UT, USA) for 0 (control no treatment), 60 and 120 s. Then, teeth were thermocycled between 5 degrees C and 55 degrees C, immersed in rhodamine B solution (24 h), and sectioned longitudinally in buccolingual direction. Dye penetration was examined with stereomicroscope (*10). Microleakage scores were statistically analyzed. The mean occlusal margin scores and gingival margin scores were compared between all the groups using the Kruskal-Wallis test, Mann-Whitney U-test, Wilcoxon signed rank test, and post hoc comparison. There was a significant difference between Group 1a, Group 2a, Group 1b, Group 2b, Group 1c, and Group 2c. STATISTICAL ANALYSIS USED: Statistical analysis used in this study was Kruskal-Wallis test, Mann-Whitney U-test, Wilcoxon signed-rank test, and post hoc comparison. RESULTS: The least microleakage scores were observed in occlusal margins of control groups (without microabrasion). Moreover, in both restorations, the microleakage scores in occlusal margins were higher than gingival margins, and compoglass had less microleakage in occlusal and occlusal plus axial walls of class V cavities compared with resin-modified GIC. Whereas, the light-cured glass ionomer had less microleakage in the gingival and gingival plus axial walls of class V cavities when compared with compoglass. CONCLUSIONS: The least microleakage scores were observed in occlusal margins of control groups (without microabrasion). Moreover, in both restorations, the microleakage scores in occlusal margins were higher than gingival margins. PMID- 29256470 TI - Effect of smear layer thickness and pH of self-adhesive resin cements on the shear bond strength to dentin. AB - CONTEXT: There are concerns in relation to the bonding efficacy of self-adhesive resin cements to dentin covered with the smear layer. AIMS: This study aims to evaluate the effect of smear layer thickness and different pH values of self adhesive resin cements on the shear bond strength to dentin. MATERIALS AND METHODS: The dentin on the buccal and lingual surfaces of 48 sound human premolars were abraded with 60- and 600-grit silicon carbide papers to achieve thick and thin smear layers, respectively. The samples were divided into three groups (n = 16) based on the cement pH: Rely-X Unicem (RXU) (pH < 2); Clearfil SA Luting (CSL) (pH = 3); and Speed CEM (SPC) (pH = 4.5). In each group, composite resin blocks were bonded to the buccal and lingual surfaces. After 24 h, the shear bond strength values were measured in MPa, and the failure modes were evaluated under a stereomicroscope. STATISTICAL ANALYSIS: Data were analyzed with two-way ANOVA and post hoc least significant difference tests (P < 0.05). RESULTS: Cement pH had a significant effect on the shear bond strength (P = 0.02); however, the smear layer thickness had no significant effect on the shear bond strength (P > 0.05). The cumulative effect of these variables was not significant, either (P = 0.11). CONCLUSION: The shear bond strengths of SPC and CSL self-adhesive resin cements were similar and significantly lower than that of RXU. The smear layer thickness was not a determining factor for the shear bond strength value of self-adhesive resin cements. PMID- 29256471 TI - Epidermal growth factor receptor: Role in human cancer. AB - Cells are constantly exposed to various external stimuli which regulate the growth and survival of the cells. The signal transduction from the external environment to the interior of the cell is carried out by cell surface or transmembrane receptors. Epidermal growth factor receptor (EGFR) is a type I receptor tyrosine kinase and along with its ligands, EGFR is involved in the regulation of multiple cellular pathways. EGFR and its signaling pathway have been studied extensively for the biological and pathophysiological role in health and disease. There is enough evidence to suggest that EGFR is involved in the pathogenesis and progression of various cancers. This review discusses the structural anatomy and physiology of EGFR and its ligands, the role of EGFR in cancer and EGFR-targeted therapy. PMID- 29256472 TI - Surgical management of recurrent neurofibroma of infratemporal region: A case report with 20-year follow-up. AB - Head-and-neck region is one of the common locations for neurogenic tumors such as neurofibroma. Neurofibromas are usually found in individuals with neurofibromatosis, which is an autosomal dominant disease. Although mostly associated with neurofibromatosis, solitary forms have also been reported. Solitary neurofibromas are rare tumors and widely described in the literature as benign. Mostly, these solitary tumors tend to occur in the gastrointestinal system. Neurofibromas of the head and neck are not uncommon, but rarely been reported to occur in the infratemporal region. We report a very rare case of recurrent solitary neurofibroma originating from the infratemporal region. Complete excision of the primary tumor was done before 20 years. Tumor arising in this anatomical location requires a conservative surgical approach for cosmetic reason. PMID- 29256473 TI - An uncommon case of fibrolipoma. AB - Lipoma is a common benign soft-tissue neoplasm derived from mature adipose tissue neoplasm, but its presence in the oral and pharyngeal region is relatively uncommon. Oral lipoma was first described by Roux in 1848 as "yellow epulis." It has an incidence rate of about 1%-4% of all benign oral lesions, with a prevalence rate of about 0.0002%. Fibrolipoma is an extremely rare subtype of lipoma which accounts for 1.6% of all facial lipomas. Specific anatomic locations of occurrence within the oral and maxillofacial region include the parotid region, buccal mucosa, lips, submandibular region, tongue, floor of mouth, and palate. Here, we present fibrolipoma, a very rare subtype of lipoma involving the left retromolar region in a 50-year-old female patient. PMID- 29256474 TI - Rare molariform supernumerary teeth: Why are they bilateral? AB - Anterior supernumerary teeth in the permanent dentition may be supplemental or rudimentary. Rudimentary types are further classified as conical, tuberculate, and molariform. The molariform type has been only rarely reported. We report a rare variety of anterior supernumerary teeth - the molariform type, occurring bilaterally and in association with a midline supernumerary tooth. We also suggest a hypothesis for the bilateral occurrence of supernumerary teeth. PMID- 29256475 TI - Tobacco use, oral cancer screening, and oral disease burden in Indian women. AB - INTRODUCTION: India lacks data on national level adaptation of oral cancer screening measures and burden of oral diseases. We intend to address the issue through a secondary data analysis of existing data and reports. MATERIALS AND METHODS: Data were acquired from the National Family Health Survey-4 (2015-2016). Of the 699,686 responses, representing 99% of India's women population living in all of India, the following data from the age group of 15-49 years were mined - any tobacco use, desire to quit tobacco use, and oral cavity screening for cancers. Data from Central Health Intelligence Bureau 2016 was used to identify population served by dentists in each state. The state-level data of the District Level Household and Facility Survey-4 (2012-2013) were mined for household population having symptoms of chronic illness including mouth/dental illness persisting for more than 1 month and had sought treatment. STATISTICAL ANALYSIS USED: SPSS version 20; Descriptive statistics for values in proportions; Pearson's correlation test assessed between the various factors. RESULTS: Tobacco use in any form was highly prevalent among the North Eastern states, and there was also a lack of willingness to quit the habit. There was unequal distribution of dentists in different states. No significant statistical correlation was found between the proportions. CONCLUSION: There is disparity existing in treating seeking behavior of the general population as well as the need for dental treatment. The skewedness in dentists' distribution among the nation as compared with oral burden of diseases needs to be correlated before oral health policies are planned. PMID- 29256476 TI - Stem cells in dentistry: A study regarding awareness of stem cells among dental professionals. AB - BACKGROUND: Dental stem cell, a type of adult stem cell, exhibits multipotent differentiation capacity and is drawing worldwide attention because of its numerous applications. The advances in applications of dental stem cells seem to be unsurpassed in the near future, for which specialized skills and knowledge in this arena are of prime significance. Hence, there is a need to acquire more knowledge about dental stem cells to obtain maximum benefits from it in the coming years. Dental stem cells in India are still at the budding stage, and there seems to be limited awareness regarding dental stem cells. AIM: This study aimed to assess the awareness of stem cells among the dental professionals. METHODOLOGY: The present study was a questionnaire-based study of dental professionals (MDS, BDS, postgraduates, and interns) of three different institutions. RESULTS: Results showed that 95.2% of dental professionals are aware of the terminology dental stem cells and 53.9% of them are aware of various applications of dental stem cells. Chi-square test showed a significant correlation between the sources of information, source of dental stem cells, and clinical applications in relation to the academic qualification of the dental professionals. CONCLUSION: This study revealed a good level of awareness among the dental professionals, and it also showed the need to spread more knowledge about the advances in applications, storage, banking, and guidelines related to dental stem cells. PMID- 29256477 TI - [Alcohol-associated mortality in Russia (based on the materials for the period from 2011 till 2016)]. AB - The objective of the present study was to evaluate the frequency of alcoholic drunkenness documented during forensic medical expertises (investigations) of the corpses carried out in this country throughout the period from 2011 till 2016. The investigations were conducted with the use of medical statistics methods by calculating the fractional difference, dynamics, and rates of detection of the cases of alcoholic intoxication depending on the cause of death. The study has demonstrated the high frequency of the cases of alcoholic drunkenness revealed during forensic medical expertises (investigations) of the corpses that amounted to 30.5% [15, 16]. The total number of the corpses examined in 2016 was 8.6% higher than in 2011. The frequency of the documented cases of alcoholic drunkenness during the same period decreased by 19.7%. The frequency of the documented cases of alcoholic drunkenness in the cases of violent death was 2.8 times that in the cases of death from various diseases (52.8 and 19.0% respectively). The enhanced frequency of alcoholic drunkenness in relation to the number of the conducted forensic medical expertises was documented in the cases of death by drowning and from hypothermia whereas the lowest frequency of alcoholic intoxication was recorded for the corpses of the people who had died from malignant tumours and diseases of the nervous system. Various regions of Russia differed in terms of the frequency of alcoholic drunkenness recorded among the recently deceased people. PMID- 29256478 TI - [The forensic medical evaluation of the changes in the cerebral tissue in the case of sudden death from alcoholic cardiomyopathy]. AB - This article presents the results of the retrospective analysis of the protocols of forensic medical autopsies and histological studies of the cerebral tissues together with the data obtained by their statistical treatment. The objective of present work was to study and evaluate the structural changes in the cerebral tissues associated with sudden cardiac death from alcoholic cardiomyopathy. It was shown that the morphological changes in the endothelial lining of the microcirculatory bed of the cerebral tissue can be a consequence of both the direct cytotoxic action of ethanol or its metabolites and the influence of cellular modulators liberation of which results in enhanced vascular permeability associated with trophic disturbances in the tissue. These changes provide a substrate for the development of the dystrophic and necrobiotic processes in the main structural components of the organ in question. The clustering of glial cells around atrophic neutrons or instead of the dead ones in the brain as well as around the microcysts of the cerebral tissue as a compensatory response to the lesion can be in its turn considered as a pathognomonic sign of chronic alcoholic intoxication. The severe dystrophic and destructive processes proceeding in the main components of the histohematological barrier revealed in the cerebral tissue as a result of the present analysis are believed to reflect the toxic action of ethanol and/or its metabolites that play an important role in the development of dyscirculatory disorders responsibly for cerebral tissue hypoxia. PMID- 29256479 TI - [Child-pedestrian injuries inflicted in the road traffic accidents as a forensic medical problem]. AB - The road traffic accidents are known to make the greatest contribution to the overall structure of pediatric traumatism with the fatal outcome. The problem of pediatric traumatism remains on top of its relevancy despite numerous administrative, legal, technical, and financial measures taken at the government level in an attempt to reduce the mortality rate associated with the child pedestrian injuries inflicted in the road traffic accidents. The objective of the present study was to summarize and interpret the results published in the scientific literature concerning child-pedestrian injuries inflicted in the road traffic accidents with special reference to the age of the victims and the type of the injury. The analysis of the publications of the domestic and foreign authors has demonstrated that the available data of interest remain to be systematized and that the forensic medical aspects of the problem in question are poorly represented in these materials. It was shown that forensic medical expertises of child-pedestrian injuries inflicted in the road traffic accidents are frequently carried out without taking into consideration the peculiar anatomical and physiological features of the child's organism. The available data concerning the mechanisms and evaluation of severe injuries inflicted to the children in the road traffic accidents are insufficient for the development of the algorithms for the relevant adequate forensic medical expertise. In the light of these findings, the problem of the child-pedestrian injuries inflicted in the road traffic accidents takes on new significance when considered in the context of pediatric traumatism. There is evidently the growing necessity to formulate the universal database containing systematized objective information for the development of new methods of forensic medical expertise for the elucidation of the mechanisms of road traffic injuries inflicted to the children of different age groups depending on the type of the injury and the circumstances of the accident. The embodiment of this idea into an action program would allow to address the problem of child-pedestrian injuries inflicted in the road traffic accidents in the framework of the separate division of forensic medical expertise traumatism. PMID- 29256480 TI - [The possibility of three-dimensional modeling of the mechanisms of damage formation in the framework of situational expertise]. AB - This article was designed to share the experience gained with the three dimensional modeling for the purpose of situational expertise intended to reconstruct the occurrence circumstances and check up the alternative investigative leads concerning formation of potential injuries to a concrete person. Simulation was performed with the use of the dimensionally scaled model of the place of occurrence as well as the models of the human head and body totally consistent with the anthropometric characteristics of the victim. The results of this work made it possible to reject several potential opportunities for the formation of injuries to the victim and identify the most probable version. PMID- 29256481 TI - [The efficient method for the forensic medical investigation of the thoracic wound channels for the reconstruction of the victim's body position at the moment of injury]. AB - The objective of the present study was the development of the expert action algorithm for the purpose of forensic medical expertise of a corpse with punctured, stab and slash, and gunshot wounds with the purpose of reconstruction of the victim's body position at the moment of injury. The following methods were proposed based on the results of the study: the method for the access to the internal organs of the corpse allowing to preserve the configuration of the thoracic wound channels during the full-scale autopsy for its subsequent evaluation and the method for the reconstruction of the initial shape of the wound channels in the body and the extremities and thereby to facilitate the forensic medical expertise examination of the corpse. In addition, the real-world examples are presented to demonstrate the effectiveness of the proposed approach to the planning, organization, and performance of the expert actions for the purpose of the reconstruction of the victim's body position at the moment of injury. PMID- 29256483 TI - [The possibilities for the expert diagnostics of the influence of the glance of a bullet on the character of the injuries inflicted by shooting a hunting weapon]. AB - The objective of the present work was to study and analyze the available data concerning the influence of the glance of a bullet on the character of the injuries inflicted by shooting certain types of hunting weapons. This review gives evidence of the possibility of the objective diagnostics of the injuries inflicted by gunshots using the rifle-bore weapons. However, we have failed to find information about the diagnostic criteria for the evaluation of the wounds inflicted by the bullets shot from smooth-bore hunting rifles after their glance from various surfaces in the available special literature publications. Such situation creates the prerequisites for the erroneous conclusions from the results of forensic medical expertise of the after-penetration blunt wounds. PMID- 29256482 TI - [The modern view of the problem of the identification of the dominant hand]. AB - There are currently the increasing requirements for the development of new scientifically substantiated approaches to and methods of forensic medical expertise for the purpose of personality identification. The necessity of such work arises from the constantly growing number of the unidentified persons and the current living conditions characterized by the heightened dangers posed by the risk of terrorism, local military conflicts, railway and flight accidents. This article contains the analytical review giving evidence that the identification of the dominant hand based on the characteristics of the hard dental tissues provides a promising additional tool for personality identification for the purpose of forensic medical expertise. PMID- 29256484 TI - [The program for the clinical residency and internship in the speciality 31.08.10 'forensic medical expertise' as a component of the integral educational space]. AB - The objective of the present study was the development and implementation of the educational program for the training of the highly qualified specialists within the framework the clinical residency and internship in the speciality 31.08.10 'forensic medical expertise' aimed at the adherence to and the maintenance of the systemic approach to the training in compliance with the upgraded regulatory documents at the medical institutions of the Russian Federation authorized to carry out post-graduate educational activities. The residency program for the training of the highly qualified specialists in the speciality 31.08.10 'forensic medical expertise' has been developed and implemented based at the Russian Federal Centre of Forensic Medical Expertise with the extension of the elective part of the working residency program in order to provide the delivery of the lectures and holding seminars on the selected issues of forensic medicine and criminalistics. The ongoing modernization of the healthcare system in this country taking into consideration the public needs and the challenges for practical medicine, the necessity of formation of the integral educational medium, the development of the unique systemic approach to the effective training of the highly qualified specialists in forensic medical expertise, and further optimization of the educational process are intended to propel forensic medical education and the training of the forensic medical experts to the qualitatively new level. PMID- 29256485 TI - [Professional competence of the graduates of the clinical residency and internship in the speciality 31.08.10 'forensic medical expertise']. AB - The objective of the present study was the definition of the basic professional competences of the graduates of the clinical residency and internship in the speciality 31.08.10 'forensic medical expertise'. The program for the acquirement of the basic knowledge, skills, and professional competences needed to be trained in the speciality 31.08.10 'forensic medical expertise' has been elaborated in the framework of the more extensive program for the clinical residency and internship intended for the training of the highly qualified specialists in this discipline. The preliminary list of basic professional competences of a graduate from the clinical residency and internship has been formulated in accordance with the program for the training of a competitive and highly qualified forensic medical experts. The practical professional activities are considered to be an indispensable component of the training and educational process for a future forensic medical expert. It is believed that the strengthening of this training component will greatly contribute to the improvement of the quality of training of such specialists. PMID- 29256486 TI - [The work of professor V.M. Bekhterev in the field of forensic medicine (on the occasion of his 160 birthday anniversary)]. PMID- 29256487 TI - [R.S. Belkin - on the occasion of the 95 birthday anniversary of the outstanding Soviet and Russian specialist in criminal law]. PMID- 29256488 TI - [V All-Russian scientific and practical conference with international participation 'The topical problems of forensic medical expertise. The opinions of the young scientists', Perm, 21 April 2017]. PMID- 29256489 TI - [The Inter-regional scientific and practical conference 'The topical problems of infectious pathology in the context of forensic medical expertise'. Syktyvkar, 1 2 June, 2017]. PMID- 29256490 TI - Testicular cancer in 2017: Sequencing advances understanding. PMID- 29256491 TI - Prostate cancer: Singled out: single-cell genomics for diagnosis. PMID- 29256492 TI - Prostate cancer: Genomic information improves risk prediction. PMID- 29256493 TI - BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance. AB - Poly(ADP-ribose) polymerase inhibition (PARPi) is a promising new therapeutic approach for the treatment of cancers that show homologous recombination deficiency (HRD). Despite the success of PARPi in targeting HRD in tumors that lack the tumor suppressor function of BRCA1 or BRCA2, drug resistance poses a major obstacle. We developed three-dimensional cancer organoids derived from genetically engineered mouse models (GEMMs) for BRCA1- and BRCA2-deficient cancers. Unlike conventional cell lines or mammospheres, organoid cultures can be efficiently derived and rapidly expanded in vitro. Orthotopically transplanted organoids give rise to mammary tumors that recapitulate the epithelial morphology and preserve the drug response of the original tumor. Notably, GEMM-tumor-derived organoids can be easily genetically modified, making them a powerful tool for genetic studies of tumor biology and drug resistance. PMID- 29256494 TI - Biotinylation by antibody recognition-a method for proximity labeling. AB - The high-throughput detection of organelle composition and proteomic mapping of protein environment directly from primary tissue as well as the identification of interactors of insoluble proteins that form higher-order structures have remained challenges in biological research. We report a proximity-based labeling approach that uses an antibody to a target antigen to guide biotin deposition onto adjacent proteins in fixed cells and primary tissues, which allows proteins in close proximity to the target antigen to be captured and identified by mass spectrometry. We demonstrated the specificity and sensitivity of our method by examining the well-studied mitochondrial matrix. We then used the method to profile the dynamic interactome of lamin A/C in multiple cell and tissue types under various treatment conditions. The ability to detect proximal proteins and putative interactors in intact tissues, and to quantify changes caused by different conditions or in the presence of disease mutations, can provide a window into cell biology and disease pathogenesis. PMID- 29256495 TI - Mapping the 3D orientation of piconewton integrin traction forces. AB - Mechanical forces are integral to many biological processes; however, current techniques cannot map the magnitude and direction of piconewton molecular forces. Here, we describe molecular force microscopy, leveraging molecular tension probes and fluorescence polarization microscopy to measure the magnitude and 3D orientation of cellular forces. We mapped the orientation of integrin-based traction forces in mouse fibroblasts and human platelets, revealing alignment between the organization of force-bearing structures and their force orientations. PMID- 29256496 TI - Resolving systematic errors in widely used enhancer activity assays in human cells. AB - The identification of transcriptional enhancers in the human genome is a prime goal in biology. Enhancers are typically predicted via chromatin marks, yet their function is primarily assessed with plasmid-based reporter assays. Here, we show that such assays are rendered unreliable by two previously reported phenomena relating to plasmid transfection into human cells: (i) the bacterial plasmid origin of replication (ORI) functions as a conflicting core promoter and (ii) a type I interferon (IFN-I) response is activated. These cause confounding false positives and negatives in luciferase assays and STARR-seq screens. We overcome both problems by employing the ORI as core promoter and by inhibiting two IFN-I inducing kinases, enabling genome-wide STARR-seq screens in human cells. In HeLa S3 cells, we uncover strong enhancers, IFN-I-induced enhancers, and enhancers endogenously silenced at the chromatin level. Our findings apply to all episomal enhancer activity assays in mammalian cells and are key to the characterization of human enhancers. PMID- 29256498 TI - Self-assembly of polyhedral metal-organic framework particles into three dimensional ordered superstructures. AB - Self-assembly of particles into long-range, three-dimensional, ordered superstructures is crucial for the design of a variety of materials, including plasmonic sensing materials, energy or gas storage systems, catalysts and photonic crystals. Here, we have combined experimental and simulation data to show that truncated rhombic dodecahedral particles of the metal-organic framework (MOF) ZIF-8 can self-assemble into millimetre-sized superstructures with an underlying three-dimensional rhombohedral lattice that behave as photonic crystals. Those superstructures feature a photonic bandgap that can be tuned by controlling the size of the ZIF-8 particles and is also responsive to the adsorption of guest substances in the micropores of the ZIF-8 particles. In addition, superstructures with different lattices can also be assembled by tuning the truncation of ZIF-8 particles, or by using octahedral UiO-66 MOF particles instead. These well-ordered, sub-micrometre-sized superstructures might ultimately facilitate the design of three-dimensional photonic materials for applications in sensing. PMID- 29256497 TI - Polyoxometalate electrocatalysts based on earth-abundant metals for efficient water oxidation in acidic media. AB - Water splitting is a promising approach to the efficient and cost-effective production of renewable fuels, but water oxidation remains a bottleneck in its technological development because it largely relies on noble-metal catalysts. Although inexpensive transition-metal oxides are competitive water oxidation catalysts in alkaline media, they cannot compete with noble metals in acidic media, in which hydrogen production is easier and faster. Here, we report a water oxidation catalyst based on earth-abundant metals that performs well in acidic conditions. Specifically, we report the enhanced catalytic activity of insoluble salts of polyoxometalates with caesium or barium counter-cations for oxygen evolution. In particular, the barium salt of a cobalt-phosphotungstate polyanion outperforms the state-of-the-art IrO2 catalyst even at pH < 1, with an overpotential of 189 mV at 1 mA cm-2. In addition, we find that a carbon-paste conducting support with a hydrocarbon binder can improve the stability of metal oxide catalysts in acidic media by providing a hydrophobic environment. PMID- 29256499 TI - Predicting DNA hybridization kinetics from sequence. AB - Hybridization is a key molecular process in biology and biotechnology, but so far there is no predictive model for accurately determining hybridization rate constants based on sequence information. Here, we report a weighted neighbour voting (WNV) prediction algorithm, in which the hybridization rate constant of an unknown sequence is predicted based on similarity reactions with known rate constants. To construct this algorithm we first performed 210 fluorescence kinetics experiments to observe the hybridization kinetics of 100 different DNA target and probe pairs (36 nt sub-sequences of the CYCS and VEGF genes) at temperatures ranging from 28 to 55 degrees C. Automated feature selection and weighting optimization resulted in a final six-feature WNV model, which can predict hybridization rate constants of new sequences to within a factor of 3 with ~91% accuracy, based on leave-one-out cross-validation. Accurate prediction of hybridization kinetics allows the design of efficient probe sequences for genomics research. PMID- 29256500 TI - Water splitting: Passing the acid test. PMID- 29256501 TI - Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions. AB - The selective (and controllable) modification of complex molecules with disparate functional groups (for example, natural products) is a long-standing challenge that has been addressed using catalysts tuned to perform singular transformations (for example, C-H hydroxylation). A method whereby reactions with diverse functional groups within a single natural product are feasible depending on which catalyst or reagent is chosen would widen the possible structures one could obtain. Fluoroarylborane catalysts can heterolytically split Si-H bonds to yield an oxophilic silylium (R3Si+) equivalent along with a reducing (H-) equivalent. Together, these reactive intermediates enable the reduction of multiple functional groups. Exogenous phosphine Lewis bases further modify the catalyst speciation and attenuate aggressive silylium ions for the selective modification of complex natural products. Manipulation of the catalyst, silane reagent and the reaction conditions provides experimental control over which site is modified (and how). Applying this catalytic method to complex bioactive compounds (natural products or drugs) provides a powerful tool for studying structure-activity relationships. PMID- 29256502 TI - Erratum: Glucose-responsive insulin by molecular and physical design. AB - This corrects the article DOI: 10.1038/nchem.2857. PMID- 29256503 TI - Synthetic nat- or ent-steroids in as few as five chemical steps from epichlorohydrin. AB - Today, more than 100 Food and Drug Administration-approved steroidal agents are prescribed daily for indications including heart failure, inflammation, pain and cancer. While triumphs in organic chemistry have enabled the establishment and sustained growth of the steroid pharmaceutical industry, the production of highly functionalized synthetic steroids of varying substitution and stereochemistry remains challenging, despite the numerous reports of elegant strategies for their de novo synthesis. Here, we describe an advance in chemical synthesis that has established an enantiospecific means to access novel steroids with unprecedented facility and flexibility through the sequential use of two powerful ring-forming reactions: a modern metallacycle-mediated annulative cross-coupling and a new acid-catalysed vinylcyclopropane rearrangement cascade. In addition to accessing synthetic steroids of either enantiomeric series, these steroidal products have been selectively functionalized within each of the four carbocyclic rings, a synthetic ent-steroid has been prepared on a multigram scale, the enantiomer of a selective oestrogen has been synthesized, and a novel ent-steroid with growth inhibitory properties in three cancer cell lines has been discovered. PMID- 29256505 TI - Multi-electron transfer photochemistry: Caught in the act. PMID- 29256504 TI - Organocatalytic asymmetric arylation of indoles enabled by azo groups. AB - Arylation is a fundamental reaction that can be mostly fulfilled by electrophilic aromatic substitution and transition-metal-catalysed aryl functionalization. Although the azo group has been used as a directing group for many transformations via transition-metal-catalysed aryl carbon-hydrogen (C-H) bond activation, there remain significant unmet challenges in organocatalytic arylation. Here, we show that the azo group can effectively act as both a directing and activating group for organocatalytic asymmetric arylation of indoles via formal nucleophilic aromatic substitution of azobenzene derivatives. Thus, a wide range of axially chiral arylindoles have been achieved in good yields with excellent enantioselectivities by utilizing chiral phosphoric acid as catalyst. Furthermore, highly enantioenriched pyrroloindoles bearing two contiguous quaternary chiral centres have also been obtained via a cascade enantioselective formal nucleophilic aromatic substitution-cyclization process. This strategy should be useful in other related research fields and will open new avenues for organocatalytic asymmetric aryl functionalization. PMID- 29256507 TI - Flexible molecular materials: Stressed out crystals. PMID- 29256506 TI - Mechanism-based enhancement of scope and enantioselectivity for reactions involving a copper-substituted stereogenic carbon centre. AB - A rapidly emerging set of catalytic reactions involves intermediates that contain a copper-substituted stereogenic carbon centre. Here, we demonstrate that an intimate understanding of this distinction provides ways for addressing limitations in reaction scope and explaining why unexpected variations in enantioselectivity often occur. By using catalytic enantioselective Cu-boryl addition to alkenes as the model process, we elucidate several key mechanistic principles. We show that higher electrophile concentration can lead to elevated enantioselectivity. This is because diastereoselective Cu-H elimination may be avoided and/or achiral Cu-boryl intermediates can be converted to allyl-B(pin) rather than add to an alkene. We illustrate that lower alkene amounts and/or higher chiral ligand concentration can minimize the deleterious influence of achiral Cu-alkyl species, resulting in improved enantiomeric ratios. Moreover, and surprisingly, we find that enantioselectivities are higher with the less reactive allylphenyl carbonates as chemoselective copper-hydride elimination is faster with an achiral Cu-alkyl species. PMID- 29256508 TI - Designing cooperatively folded abiotic uni- and multimolecular helix bundles. AB - Abiotic foldamers, that is foldamers that have backbones chemically remote from peptidic and nucleotidic skeletons, may give access to shapes and functions different to those of peptides and nucleotides. However, design methodologies towards abiotic tertiary and quaternary structures are yet to be developed. Here we report rationally designed interactional patterns to guide the folding and assembly of abiotic helix bundles. Computational design facilitated the introduction of hydrogen-bonding functionalities at defined locations on the aromatic amide backbones that promote cooperative folding into helix-turn-helix motifs in organic solvents. The hydrogen-bond-directed aggregation of helices not linked by a turn unit produced several thermodynamically and kinetically stable homochiral dimeric and trimeric bundles with structures that are distinct from the designed helix-turn-helix. Relative helix orientation within the bundles may be changed from parallel to tilted on subtle solvent variations. Altogether, these results prefigure the richness and uniqueness of abiotic tertiary structure behaviour. PMID- 29256509 TI - Dynamic covalent chemistry enables formation of antimicrobial peptide quaternary assemblies in a completely abiotic manner. AB - Naturally occurring peptides and proteins often use dynamic disulfide bonds to impart defined tertiary/quaternary structures for the formation of binding pockets with uniform size and function. Although peptide synthesis and modification are well established, controlling quaternary structure formation remains a significant challenge. Here, we report the facile incorporation of aryl aldehyde and acyl hydrazide functionalities into peptide oligomers via solid phase copper-catalysed azide-alkyne cycloaddition (SP-CuAAC) click reactions. When mixed, these complementary functional groups rapidly react in aqueous media at neutral pH to form peptide-peptide intermolecular macrocycles with highly tunable ring sizes. Moreover, sequence-specific figure-of-eight, dumbbell-shaped, zipper-like and multi-loop quaternary structures were formed selectively. Controlling the proportions of reacting peptides with mismatched numbers of complementary reactive groups results in the formation of higher-molecular-weight sequence-defined ladder polymers. This also amplified antimicrobial effectiveness in select cases. This strategy represents a general approach to the creation of complex abiotic peptide quaternary structures. PMID- 29256510 TI - Direct observation of sequential oxidations of a titania-bound molecular proxy catalyst generated through illumination of molecular sensitizers. AB - Natural photosynthesis uses the energy in sunlight to oxidize or reduce reaction centres multiple times, therefore preparing each reaction centre for a multiple electron-transfer reaction that will ultimately generate stable reaction products. This process relies on multiple chromophores per reaction centre to quickly generate the active state of the reaction centre and to outcompete deleterious charge recombination. Using a similar design principle, we report spectroscopic evidence for the generation of a twice-oxidized TiO2-bound molecular proxy catalyst after low-intensity visible-light excitation of co anchored molecular Ru(II)-polypyridyl dyes. Electron transfer from an excited dye to TiO2 generated a Ru(III) state that subsequently and repeatedly reacted with neighbouring Ru(II) dyes via self-exchange electron transfer to ultimately oxidize a distant co-anchored proxy catalyst before charge recombination. The largest yield for twice-oxidized proxy catalysts occurred when they were present at low coverage, suggesting that large dye/electrocatalyst ratios are also desired in dye-sensitized photoelectrochemical cells. PMID- 29256512 TI - Atomic resolution of structural changes in elastic crystals of copper(II) acetylacetonate. AB - Single crystals are typically brittle, inelastic materials. Such mechanical responses limit their use in practical applications, particularly in flexible electronics and optical devices. Here we describe single crystals of a well-known coordination compound-copper(II) acetylacetonate-that are flexible enough to be reversibly tied into a knot. Mechanical measurements indicate that the crystals exhibit an elasticity similar to that of soft materials such as nylon, and thus display properties normally associated with both hard and soft matter. Using microfocused synchrotron radiation, we mapped the changes in crystal structure that occur on bending, and determined the mechanism that allows this flexibility with atomic precision. We show that, under strain, the molecules in the crystal reversibly rotate, and thus reorganize to allow the mechanical compression and expansion required for elasticity and still maintain the integrity of the crystal structure. PMID- 29256513 TI - Correction. AB - This corrects the article DOI: 10.1038/nchem.2895. PMID- 29256511 TI - Chromophore twisting in the excited state of a photoswitchable fluorescent protein captured by time-resolved serial femtosecond crystallography. AB - Chromophores absorb light in photosensitive proteins and thereby initiate fundamental biological processes such as photosynthesis, vision and biofluorescence. An important goal in their understanding is the provision of detailed structural descriptions of the ultrafast photochemical events that they undergo, in particular of the excited states that connect chemistry to biological function. Here we report on the structures of two excited states in the reversibly photoswitchable fluorescent protein rsEGFP2. We populated the states through femtosecond illumination of rsEGFP2 in its non-fluorescent off state and observed their build-up (within less than one picosecond) and decay (on the several picosecond timescale). Using an X-ray free-electron laser, we performed picosecond time-resolved crystallography and show that the hydroxybenzylidene imidazolinone chromophore in one of the excited states assumes a near-canonical twisted configuration halfway between the trans and cis isomers. This is in line with excited-state quantum mechanics/molecular mechanics and classical molecular dynamics simulations. Our new understanding of the structure around the twisted chromophore enabled the design of a mutant that displays a twofold increase in its off-to-on photoswitching quantum yield. PMID- 29256516 TI - Making molecular monsters. PMID- 29256514 TI - Collaborative routes to clarifying the murky waters of aqueous supramolecular chemistry. AB - On planet Earth, water is everywhere: the majority of the surface is covered with it; it is a key component of all life; its vapour and droplets fill the lower atmosphere; and even rocks contain it and undergo geomorphological changes because of it. A community of physical scientists largely drives studies of the chemistry of water and aqueous solutions, with expertise in biochemistry, spectroscopy and computer modelling. More recently, however, supramolecular chemists - with their expertise in macrocyclic synthesis and measuring supramolecular interactions - have renewed their interest in water-mediated non covalent interactions. These two groups offer complementary expertise that, if harnessed, offer to accelerate our understanding of aqueous supramolecular chemistry and water writ large. This Review summarizes the state-of-the-art of the two fields, and highlights where there is latent chemical space for collaborative exploration by the two groups. PMID- 29256517 TI - Terbium glows green. PMID- 29256518 TI - Involving culinary science as part of the diabetes care team. PMID- 29256515 TI - Bioinspired chemical synthesis of monomeric and dimeric stephacidin A congeners. AB - Stephacidin A and its congeners are a collection of secondary metabolites that possess intriguing structural motifs. They stem from unusual biosynthetic sequences that lead to the incorporation of a prenyl or reverse-prenyl group into a bicyclo[2.2.2]diazaoctane framework, a chromene unit or the vestige thereof. To complement biosynthetic studies, which normally play a significant role in unveiling the biosynthetic pathways of natural products, here we demonstrate that chemical synthesis can provide important insights into biosynthesis. We identify a short total synthesis of congeners in the reverse-prenylated indole alkaloid family related to stephacidin A by taking advantage of a direct indole C6 halogenation of the related ketopremalbrancheamide. This novel strategic approach has now made possible the syntheses of several natural products, including malbrancheamides B and C, notoamides F, I and R, aspergamide B, and waikialoid A, which is a heterodimer of avrainvillamide and aspergamide B. Our approach to the preparation of these prenylated and reverse-prenylated indole alkaloids is bioinspired, and may also inform the as-yet undetermined biosynthesis of several congeners. PMID- 29256519 TI - Seasonal and spatial quantitative changes in Aedes aegypti under distinctly different ecological areas of Lahore, Pakistan. AB - OBJECTIVE: To find out the variations in larval and adult density of Aedes aegypti in different seasons under different ecological conditions. METHODS: This study was undertaken in all the nine towns and the cantonment board of Lahore, Pakistan, during four seasons in 2011, 2012 and 2013. Ovitraps were placed in houses in residential areas and were visited weekly in rainy and post-rainy seasons each year to determine the presence of immature and mature forms of Ae.aegypti. Densities of these were measured by ovitrap index and per man hour density, respectively. Correlation coefficient and coefficient of determination between ovitrap index, per man hour density and climatic variables were established. SPSS 19 was used for data analysis. RESULTS: Ovitrap index and per man hour density values were lower in early rainy season compared to late rainy and early post-rainy seasons. These became lowest in late post rainy season. Strong correlation coefficient and its determination between ovitrap, per man hour density and climatic variables were observed.? CONCLUSIONS: Density of immature and mature forms of Ae.aegypti was influenced by environmental degradation. PMID- 29256520 TI - Association of stress with anxiety and depression during pregnancy. AB - OBJECTIVE: To find out the association of stress with anxiety and depression during pregnancy and to identify common stressors in women. METHODS: This cross sectional study was conducted at Divisional Headquarters Teaching Hospital, Kohat, Pakistan, from February 2011 to October 2012, and comprised pregnant women. Convenient sampling technique was used. The participants were administered Urdu-translated version of A-Z perceived stress scale and Aga Khan University anxiety and depression scale. Women with a score of >19 on the Aga Khan University scale were labelled as anxious and depressed. Data was collected on a pre-designed proforma. SPSS 17 was used for data analysis. RESULTS: There were 500 participants with an overall mean age of 28.3+/-6.3 years. The overall mean stress score on A-Z perceived stress scale was 12.93+/-5.19 and mean Aga Khan University anxiety and depression scale score was 28.58+/-13.82. Mean A-Z score was 14.18+/-4.881 in women with anxiety-depression and 9.75+/-4.58 in non depressed women (p<0.001). Mean Aga Khan score in women with >10 stressors was significantly higher (32.18+/-13.79) compared to women with <10 stressors (19.87+/-9.30) (p<0.01). A-Z stressors score had significant positive correlation with the Aga Khan scale (p<0.001]. The most common stressors were concern about husband's worries and concern about feeling unwell during pregnancy, present in 433(86.6%) patients each, followed by concern about increase in the prices of everyday goods which was present in 364(72.8%) patients. CONCLUSIONS: The magnitude of stress was significantly associated with high anxiety and depression during pregnancy. PMID- 29256521 TI - Knowledge of female doctors about smoking risks and their attitude toward cessation in antenatal clinics - perspective from tertiary care hospitals in Karachi. AB - OBJECTIVE: To assess the knowledge and attitude of doctors with regard to smoking risks and cessation, and to identify factors associated with self- reported assessment of smoking. METHODS: This cross-sectional survey was performed in 5 hospitals of Karachi from February to April 2014, and comprised doctors providing antenatal care. Data was collected using a questionnaire. SPSS 21 was used for data analysis. RESULTS: Of the 164 respondents,150(91.5%) considered the assessment of smoking an integral part of their medical responsibilities, but only 53(32.4%) reported that they asked regarding smoking habit in 100% of patients and 77(47.3%) inquired about passive smoking. The mean knowledge score for risks and cessation was 2.57+/-0.278 and 2.12+/-0.457, respectively. A few misconceptions were also found, such as 94(57.3%) doctors were against the use of nicotine replacement therapy in pregnant females and 114(69.4%) falsely believed that smoking was associated with pre-eclampsia. Factors independently associated with good baseline knowledge were: formal training (p=0.01) and hospital's smoke free policy (p=0.004). Doctors with formal training more frequently assessed smoking habit of their patients and were more confident while counselling patients for smoking cessation (p=0.05). CONCLUSIONS: Basic misconceptions showed inadequate knowledge among doctors working in antenatal clinics. PMID- 29256522 TI - Remaining dentine thickness of root canals prepared with K-3 and ProTaper rotary systems. AB - OBJECTIVE: To compare the remaining dentine thickness of root canals prepared with K-3 and ProTaper files.. METHODS: This in-vitro experimental study was conducted from 1st April-30th September 2015 at the dental clinics of Aga Khan University Hospital, Karachi, and comprised human teeth. Extracted human premolars and molars were included in the study using non-probability consecutive sampling. Canals were randomly allocated into two groups i.e. K-3 and ProTaper. Changes in inner and outer walls of canals were measured using Vixwin software at 1mm, 4mm, 7mm and 10mm from the apex. SPSS 20 was used for data analysis. RESULTS: Of the 214 canals, 107(50%) were assigned to each group. No statistically significant difference was found in the remaining dentine thickness at 1mm, 4mm, 7mm and 10mm from the apex of the teeth prepared with in K-3 versus ProTapers system (p>0.05). CONCLUSIONS: The remaining dentine thickness of the root canals prepared with K-3 files was similar to that of canals prepared with ProTaper files. PMID- 29256523 TI - Prevalence of diabetic foot syndrome amongst population with type 2 diabetes in Pakistan in primary care settings. AB - OBJECTIVE: To determine the prevalence of diabetic foot syndrome in type 2 diabetes mellitus patients. METHODS: This cross-sectional study was conducted at 25 centres across eight cities in Pakistan from August 2010 to March 2011, and comprised adult type 2 diabetics. The subjects underwent ankle brachial pressure index evaluation for diabetic foot, and neurological assessment using 10g monofilament for sensation and 128Hz tuning fork to elicit vibration. RESULTS: Of the 230 subjects, 94(40.86%) were males and 136(59.13%) females. The overall mean age was 53.82+/-9.96 years and mean glycated haemoglobin was 8.81+/-2.04%. The prevalence of diabetic foot syndrome was 32(13.9%). Based on established diabetic foot risk classification, 37(16.08%) patients were in category-1, 6(2.60%) in category-2, 32(13.91%) in category-3 and 148(64.34%) in category-0. On ankle brachial pressure index assessment, 94(40.86%) patients had impaired values (p<0.9). Sensation was impaired in 50(21.73%) patients, vibrations could not be detected in 37(16.08%), ankle reflexes could not be elicited in 35(15.21%), and foot pulses could not palpated in 28(12.17%) patients. CONCLUSIONS: A high prevalence of diabetic foot syndrome was observed. PMID- 29256524 TI - Screening of cardiometabolic risks clustering in young Pakistani adults classified by anthropometric traits. AB - OBJECTIVE: To estimate frequencies of metabolic risk phenotypes and their associations in body mass index and waist circumference-based obesity categories. METHODS: The cross-sectional study was conducted at Pir Mehr Ali Shah Arid Agriculture University, Rawalpindi, Pakistan, from August 2014 to March 2016. Anthropometric and clinical data of young adults was collected. All subjects were categorised into body mass index, waist circumference-based obesity categories and common metabolic risk phenotypes (hypertension, hyperglycaemia, dyslipidaemia) frequencies and their associations were estimated in age and gender adjusted models. Data was analysed using SPSS 21. RESULTS: Of the 2,000 participants, 800(40%) were females and 1,200(60%) were males. There were 500(25%) participants in each group, i.e. underweight, normal weight, overweight and obese. The overall mean age was 23.68+/-4.33 years (range: 16-30 years). All clinical parameters were significantly raised in general and abdominally obese class (p<0.05). Based on body mass index and waist circumference, the frequency of general obesity was 324(16.2%) and abdominal obesity was 994(49.7%). Co-morbid metabolic risk phenotypes were as follows: hypertension 1,098(54.9%) and 924(46.2%); hyperglycaemia 1,116(55.8%) and 550(27.5%); dyslipidaemia 300(15%) and 194(9.7%), respectively. The strongest associations of body mass index and waist circumference alone catergorised obesity were found with hyperglycaemia, (Odds ratio: 7.23, 6.49) followed by dyslipidemia (Odds ratio: 5.60, 5.67) and hypertension (Odds ratio: 3.28, 3.02). . CONCLUSIONS: Body mass index and waist circumference were found to be powerful, discriminating predictors of co morbidities linked with general and abdominal obesity. PMID- 29256525 TI - Foeto-maternal outcome in instrumental vaginal delivery attending a secondary hospital in Hyderabad (Aga Khan Maternal and Child Care Centre). AB - OBJECTIVE: To evaluate the foeto-maternal outcome in instrumental delivery. METHODS: This retrospective record review was conducted at Aga Khan Maternal and Child Care Centre, Hyderabad, Pakistan, and comprised medical records from January 2014 to January 2016. Data related to all women with singleton pregnancy at term gestation and having undergone vacuum or forceps delivery was included. Data of women who had multiple pregnancies, caesarean section, and presentation other than cephalic, placenta previa were excluded. SPSS 19 was used for data analysis. RESULTS: Of the 400 participants, 255(63.75%) were aged between 22-28 years and 145(36.25%) between 29-35 years. Moreover, 268(67%) women were primigravida. Of them, 225(56.25%) presented at more than 40 weeks of the gestation. The foetal complication such as cephalohaematoma was observed in 3(0.75%) cases. CONCLUSIONS: Instrumental vaginal delivery was found to be safe and is the best substitute of the caesarean sections. PMID- 29256526 TI - Clinical presentation of acute myeloid leukaemia - A decade-long institutional follow-up. AB - OBJECTIVE: To analyse a decade-long pattern of clinical presentation of acute myeloid leukaemia patients and compare it with contemporary data. METHODS: The retrospective cohort study was conducted at the National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, and comprised of medical record of acute myeloid leukaemia patients from March 2006 to October 2016. Data noted age at presentation, gender, medical history, physical examination, blood and bone marrow investigations such as, haemoglobin levels, blood cell count myeloperoxidase activity, periodic acid-Schiff and reticulin staining as well as final diagnosis. Comparison, where possible, was done with contemporary literature. SPSS 19 was used for data analysis. RESULTS: Of the 626 subjects, 248(39.6%) were females and 378(60.4%) males. The overall mean age was 35.3+/ 17.1 years. The most common age group was 15-40 years with 354(56.5%) patients. The most common subtype was acute myeloid leukaemia with maturation 183(33.6%). Myeloperoxidase activity was positive for the majority of the acute myeloid leukaemia patients. Periodic acid-Schiff test, done on only selected patients, was mostly negative. Reticulin staining was positive for 113(65.3%) patients. The most common presenting complaints were fever 266(71.9%) and weakness 168(45.4%). Mean haemoglobin and red blood cell count were 8.3 +/- 2.4 g/dL and 2.9 +/- 1.2 1012/L, respectively. CONCLUSIONS: Acute myeloid leukaemia was found to be a highly variable disease that presented with non-specific signs and symptoms. PMID- 29256527 TI - Association of dyslipidaemia in patients with varying degrees of Vitamin D deficiency in the Asian population. AB - OBJECTIVE: To investigate the associations of dyslipidaemia with varying levels of 25 hydroxy vitamin D3 deficiency. METHODS: This cross-sectional study was conducted at the Pakistan Institute of Medical Sciences, Islamabad, Pakistan, from July 2016 to January 2017, and comprised patients having varying levels of 25 hydroxy vitamin D3 deficiency. Patients were stratified according to the severity of deficiency and had their serum fasting lipid profiles measured. SPSS 20 was used for data analysis. RESULTS: Of the 175 participants, 124(70.9%) were female and 51(29.1%) were male. The overall mean age of the patients was 47.7+/ 12.2 years (range: 18-65 years). A very strong inverse correlation was found between vitamin D levels and low-density lipoprotein cholesterol (p<0.001) and a similar trend was obtained for vitamin D and total cholesterol (p<0.001). With regards to triglycerides, a modest inverse correlation was found (p=0.05). No significant association was documented between 25 hydroxy vitamin D3 levels and high-density lipoprotein cholesterol (p=0.3). CONCLUSIONS: An inversely proportional relationship was found between total cholesterol, low-density lipoprotein cholesterol and triglycerides against varying levels of vitamin D deficiency. PMID- 29256528 TI - Comparison of metformin and pioglitazone in achieving sustained virological response in chronic hepatitis C patients with insulin resistance: A quasi experimental study. AB - OBJECTIVE: To compare metformin and pioglitazone with standard interferon and ribavirin in achieving sustained virological response in chronic hepatitis C patients. METHODS: This quasi-experimental, comparative, interventional study was conducted at Mayo Hospital, Lahore, Pakistan, from January 2015 to March 2016, and comprised chronic hepatitis C patients who had insulin resistance. The patients were divided evenly in three groups. Group A had patients treated with interferon 3 million units, three times in a week and ribavirin 400mg three times in a day. In addition to interferon and ribavirin, group B was treated with metformin, and group C received pioglitazone. Polymerase chain reaction was done at the completion of 24 and 48 weeks to assess the end treatment and sustained virological response, respectively. SPSS 20 was used for data analysis. RESULTS: Of the 138 patients, there were 46(33.3%) in each group. The mean age of the patients in group A was 36.83+/-9.65 years, in group B was 37.72+/-10.00 years and in group C it was 38.07+/-8.85 years. Overall, there were 70(50.72%) males and 68(49.28%) females. At the end of 24 weeks, polymerase chain reaction exhibited that in group A, the score was <100 in 28(60.9%) and >100 in 18(39.1%) patients. In group-B, it was <100 in 39(84.8%) and >100 in 7(15.2%) patients. In group-C, it was <100 in 31(67.4%) and >100 in 15(32.6%) patients. The sustained virological response was considerably higher in group B (p=0.003). CONCLUSIONS: Sustained virological response with standard therapy with metformin gave high-end response as compared to other groups. PMID- 29256529 TI - Visual outcome and its prognostic factors in patients presenting with ocular war injuries at an army hospital in Pakistan. AB - OBJECTIVE: To determine the visual outcome and its prognostic factors in patients presenting with ocular war injuries. METHODS: This descriptive, observational study was conducted at the Combined Military Hospital, Peshawar, Pakistan, from June 2012 to March 2016, and comprised soldiers with ocular war injuries. Informed consent was obtained from all participants. A predesigned proforma was used to record patient's demographic details along with the cause, side, type and severity of injury. Injuries were classified as open globe or closed globe injuries. Ocular trauma score grade was used to describe the severity of injury. RESULTS: There were 210 participants with an overall mean age of 29.34+/-5.35 years (range: 20-43 years). All of them were male. Left side was more frequently involved, i.e. in 126(60%) cases. The most frequent underlying cause was improvised explosive device blast injury 114(54.3%), followed by blunt trauma 42(20%) and road traffic accidents 24(11.4%). Closed globe injuries were more frequent and were recorded in 120(57.1%) patients. The visual outcome was good in 62(29.5%) patients, followed by fair in 51(24.3%) patients while 51(24.3%) patients had worst visual outcome. When stratified, there was no significant difference of worst visual outcome with patient's age (p=0.279). However, improvised explosive device blast (p=0.002), open globe injury (p=0.000), ocular trauma score grade 1; open globe (p=0.049), closed globe (p=0.003) were associated with significantly higher frequency of worst visual outcome. Zone-III injury was also prognostic of worst visual outcome, but the difference was significant only in case of open globe injury (p=0.003). CONCLUSIONS: Improvised explosive device blast, open globe injury and ocular trauma score grade 1 were poor prognostic features and resulted in significantly higher frequency of poor visual outcome. PMID- 29256530 TI - Endothelial dysfunction and developmental outcomes of very low birth weight newborns with hypoxic encephalopathy. AB - OBJECTIVE: To investigate the levels of endothelial constricting and dilating mediators in preterm infants with hypoxic-ischaemic encephalopathy and prospectively evaluate the association between levels measured during the perinatal period and the diagnosis of neurodevelopmental disorders at 3 years of age. METHODS: This regional observational cohort study was conducted at the Azerbaijan Medical University, Baku, Azerbaijan, from November 2011 to January 2013, and comprised very-low-birth-weight infants admitted to the intensive care unit during the perinatal period. Blood concentrations of nitric oxide, endothelin-1 and endothelial nitric oxide synthase were measured on days 1-3 and 5-7 of the neonatal period. Concentrations of neuron-specific enolase and antibodies against N-methyl-D-aspartate glutamate receptors were measured in peripheral blood samples for detection of brain damage in the early neonatal period of life. The infants were divided in 3 different groups: those diagnosed with moderate-to-severe neurodevelopmental disorders or cerebral palsy were included in the first group; those with mild neurologic changes were in the second group; and children without evidence of neurological impairment were in the third group. The fourth group comprised controls. SPSS 20 was used for data analysis. RESULTS: Of the 62 participants, there were 8(12.9%) in the first group, 20(32.3%) in second, 14(22.6%) in third and 20(32.3%) in the control group. The activity of endothelial nitric oxide synthase was reduced and nitric oxide concentrations were increased in the first group compared to those in the third group (p<0.05). Deep endothelial nitric oxide synthase depression and insufficient endothelin-1 synthesis were associated with diagnosis in the first group (p<0.05). No differences in concentrations of neuron-specific enolase and NR2 antibodies were identified among infants with and without a subsequent diagnosis of neurodevelopmental disorders (p>0.05). CONCLUSIONS: The association between depressed endothelial nitric oxide synthase activation and insufficient endothelin-1 synthesis in the early days of life of very-low-birth-weight infants might be one of the causes of more serious and irreversible injury of brain tissue. PMID- 29256531 TI - Perception of educational environment in the operating theatre by surgical residents, a single-centre prospective study. AB - OBJECTIVE: To evaluate the perception of operation theatre educational environment using surgical theatre educational environmental measure. METHODS: This cross-sectional study was conducted at Liaquat National Hospital, Karachi, from August 2015 to February 2016, and comprised surgical and allied trainees. The reliability of the surgical theatre educational environmental measure questionnaire was assessed by Cronbach's alpha. The minimum score on the questionnaire was 40 and possible maximum score was 200. A score of at least 120 out of 200 was considered favourable. SPSS 22 was used for data analysis. RESULTS: Of the 103 participants who completed the questionnaire, 52(50.4%) were males and 51(49.5%) females. The results showed favourable operating theatre educational environment with the total score of 129. The overall reliability was calculated to be 0.97. Male residents perceived the educational environment more adequate than females (p<0.05). CONCLUSIONS: The questionnaire was found to be an easy, reliable and practical tool for measuring the perception of operating theatre educational environment. PMID- 29256532 TI - Evaluation of students' experience with Problem-based Learning (PBL) applied at the College of Medicine, Al-Jouf University, Saudi Arabia. AB - OBJECTIVE: To evaluate the students' experience with problem-based learning. METHODS: This cross-sectional, qualitative study was conducted at the College of Medicine, Al Jouf University, Sakakah, Saudi Arabia, in October 2015, and comprised medical students of the 1st to 5th levels. Interviews were conducted using Students' Course Experience Questionnaire. The questionnaire contained 37 questions covering six evaluative categories: appropriate assessment, appropriate workload, clear goals and standards, generic skills, good teaching, and overall satisfaction. The questionnaire follows the Likert's scale model. Mean values were interpreted as: >2.5= at least disagree, 2.5->3= neither/nor (uncertain), and 3 or more= at least agree. RESULTS: Of the 170 respondents, 72(42.7%) agreed that there was an appropriate assessment accompanied with the problem-based learning. Also, 107(63.13%) students agreed that there was a heavy workload on them. The goal and standards of the course were clear for 71(42.35%) students, 104(61.3%) agreed that problem-based learning improved their generic skills, 65(38.07%) agreed the teaching was good and 82(48.08%) students showed overall satisfaction. CONCLUSIONS: The students were satisfied with their experience with the problem-based learning. PMID- 29256533 TI - Needle stick injuries among nurses of two tertiary care hospitals of Lahore: A KAP study. AB - OBJECTIVE: To estimate the prevalence of needle-stick injuries in female nurses of a public and private hospital and compare the findings. METHODS: This cross sectional study was conducted at one public and one private tertiary care hospital in Lahore, Pakistan, from March to June 2015, and comprised female nurses who were selected using non-probability purposive sampling. A structured questionnaire was used to interview the subjects. Data analysis was done using SPSS 17. RESULTS: Of the 386 participants, there were 193(50%) from each of the two hospitals. The prevalence of needle-stick injuries was found to be 85(44%) in public and 51(26.4%) in the private hospital. The highest proportion of injuries in both hospitals occurred while disposing or recapping needles, 36(42.4%) and 32(62.7 %) in public and private hospitals, respectively, especially in the morning shift, i.e. 42(49.4%) in public and 32(62.7%) in private hospital. Syringe needles were mostly involved, 51(60%) in public and 45(88.2%) in private hospital. CONCLUSIONS: The prevalence of needle-stick injuries was higher in public hospital. PMID- 29256534 TI - Study on awareness of osteoporosis and its associated risk factors among housewives and working women in Karachi. AB - OBJECTIVE: To compare awareness of osteoporosis and its associated risks among working women and housewives. METHODS: This cross-sectional study was conducted at Karachi University and Dow University of Health Sciences, Karachi, from January to April 2015, and comprised working women and housewives who were enrolled using convenience sampling. Data was collected on awareness, dairy, fruit, vegetable, poultry/fish consumption as well as exercise, diagnosis and treatment taken for deficiency of vitamin D. Weight, height and body mass index were noted. Analysis was done using SPSS 17. RESULTS: Of the 600 participants, 300(50%) were housewives and 300(50%) were working women. Significant differences were observed in marriage years, number of children and income (p <0.05). Body mass index of groups demonstrated that more working women were within normal range weight than housewives (p<0.05). Fewer housewives had awareness about osteoporosis and the majority of them had a sedentary lifestyle (p<0.001). More housewives were diagnosed with vitamin D deficiency and were prescribed for treatment (p<0.001). Dairy and vegetable consumption was found comparable while fruits and poultry/ fish intake was better in working women (p<0.05). Since the subjects in both groups had no regular exercise programme, therefore the overall results were insignificant (p>0.05). CONCLUSIONS: Greater number of working women had awareness of osteoporosis. PMID- 29256535 TI - Pioglitazone attenuates cardiometabolic risk factors in non-diabetic patients with dyslipidemia. AB - OBJECTIVE: To determine the effect of pioglitazone on cardiometabolic risk factors in non-diabetic patients with dyslipidaemia. METHODS: This prospective, randomised clinical trial was conducted at Sheikh Zayed Medical College and Hospital, Rahim Yar Khan, Pakistan, from August to October 2016, and comprised non-diabetic patients with dyslipidaemia. They were randomly divided into three groups. First and second groups were given a daily dose of tab pioglitazone 30mg and gemfibrozil 600mg, respectively, while the third group served as the healthy control. Body weight, body mass index and serum lipid profile were analysed pre- and post-treatment. SPSS 16 was used for data analysis. RESULTS: Of the 135 participants, there were 45(33.3%) in each group. After 12 weeks' treatment, the pioglitazone group showed a highly significant reduction in body weight (83+/ 10.5 to 76+/-13.5kg) and body mass index (27.7+/-4.4 to 25.5+/-6.4kg/m2) (p<0.01) compared to the gemfibrozil group. The pioglitazone group showed a significant improvement in serum lipid profile after 12 weeks (p<0.05) while the gemfibrozil group showed a highly significant improvement in serum lipid profile (p<0.01). CONCLUSIONS: Pioglitazone independently improved cardiometabolic risk factors, even in non-diabetics. PMID- 29256537 TI - Graft and mesh use in vaginal surgery. AB - Pelvic organ prolapse and urinary incontinence are among the most common chronic disorders in women. These are common problems whose pathogenesis remains unclear. As life expectancy increases, significantly greater number of women now present with pelvic organ prolapse and urinary incontinence requiring surgical intervention. Currently, the lifetime risk of undergoing prolapse or continence surgery is one in 11, and up to 30% of patients will require repeat reconstructive surgery and repeat surgery for incontinence in 10%. In an attempt to improve surgical outcomes and to preserve vaginal capacity and coital function, a number of synthetic and biological prostheses have been developed. This review aims to look at the role of graft and mesh in vaginal surgery. We conducted a search for English-language articles published during 1997 to 2016, using MEDLINE, PubMed and United States' National Library of Medicine databases. We reviewed around 50 papers but referenced only 30 for this article. The literature review provided us a new insight regarding safety of mesh. Polypropylene mesh is safe for vaginal surgery if used by experienced surgeons. The safety of mesh becomes compromised in the hands of commercial surgical kit providers. All the new mesh tailored kits should undergo evidence-based trials and then can be safely used worldwide. PMID- 29256536 TI - A historical glance: Challenges for male nurses. AB - Nurses are primary care providers and are responsible for caring of patients. Since centuries, the nursing profession has been known as a profession only for females. Therefore, the history of nurses in early ages only states the role of the female, although males at that time also took part in patient-care along with females. The aim of this paper is to provide detailed review of national and international literature available related to male nursing students, and their experiences in the nursing profession. PMID- 29256538 TI - Health literacy in Pakistan: Exploring new ways of addressing an old challenge. AB - Pakistan continues to struggle with low health literacy that often results in late presentation of disease, poor adherence to treatment and meagre understanding of wellness and disease prevention. In a country burdened by diseases of the developing and the developed world, with poor healthcare infrastructure and low literacy levels improving healthcare literacy could have major influence on health and wellness of our masses. Utilising our rapidly expanding mobile technology and media for dissemination of health information is a viable solution. Public service announcements for media and health information apps for mobile technology can be developed by the government, health sector and media partnership. A systematic, multi-level targeted approach to health literacy would allow health seekers the opportunity to understand and comprehend disease prevention, symptomatology and treatment. PMID- 29256539 TI - Multiple mini interviews as a measure of non-cognitive skills for admissions into undergraduate medical education programme in Pakistan: A validity study. AB - Student selection for Undergraduate Medical Education Programmes (UGME) is a highly selective process globally. Health care practice requires many attributes like communication skills, professionalism, critical thinking and problem solving in addition to cognitive abilities. This study reports the development and administration of Multiple Mini Interviews (MMI), the descriptive and psychometric properties of the MMI station scores and assesses the validity of MMI stations to ascertain if the stations measured the intended attributes. Nine attributes considered most essential for a successful health care professional were selected. A 5 point rating scale was used to rate each item on the station. The scores were then converted into percentage scores. The mean scores on each MMI station ranged from 27.4% to 80.0%. The reliability of stations using Cronbach's alpha ranged from 0.64 to 0.98. MMI can be used to make reliable and valid decisions to select students with desired non cognitive attributes. PMID- 29256540 TI - Respiratory and physical ailments correlated with occupational exposure among welders in Pakistan. AB - Disruption of normal respiratory function is associated with occupational disorders. Exposure to welding fumes on long term basis affects the lung function of the workers and prompts allergic responses. Therefore, the aim of the study was to manifest the association of exposure to welding fumes and respiratory complications with reference to the undermining of normal lung function and respiratory symptoms. A cross sectional study was conducted in different areas of Lahore in 2016. A comparison was made among welders on the basis of lung function and other physical ailments. Questionnaire survey was performed along with the computation of lung function by using spirometer. Data was statistically analyzed by using analysis of variance (ANOVA). The study confirmed a statistically highly significant decline in FVC, FEV1, FEF 25-75%, PEFR and FEV1/FVC ratio among different types of welders. The current study expressed that occupational exposure to welding fumes can considerably distress the lung function. The application of preventive measures is required to solve the health related questions for welders. PMID- 29256541 TI - Self-esteem in severely burned adults. AB - A cross-sectional study was conducted to investigate the level of and gender difference in self-esteem among adult victims of severe burn injuries. Severely burned adults aged 20 to 40 years participated in this investigation from March 2015 to April 2016 in five hospitals of Faisalabad and Lahore. Purposive sampling technique was used and a self-esteem scale was used to assess different dimensions of self-esteem. Out of 40 patients, there were 25 men (62.5%) and 15 women (37.5%) with mean age of 28.28+/-4.60 years (range: 20-40 years). A significant positive relationship between subscales of self-esteem scale were found: self-acceptance and self-competence r=0.55, p<0.01; self-acceptance and academic self-competence r=0.47, p<0.01; self-acceptance and social and physical acceptance r=0.57, p<0.01; self-competence and academic self-competence r=0.48, p<0.01; self-competence and social and physical acceptance r=0.50, p<0.01; academic self-competence and social and physical acceptance r=0.45, p<0.01). Independent sample t-test indicated a significant difference between self competence among severely burned men and women (t=2.18; p<0.05). A significant gender difference indicated higher affected levels specifically in the self competency component of self-esteem among women victims. PMID- 29256542 TI - Incidence of acute endophthalmitis after office based intravitreal bevacizumab injection. AB - The burden of intravitreal injections has increased tremendously over the past few years. Since traditionally the operation theatre setup is currently used for this procedure, it is increasingly becoming difficult to manage such a patient load in the theatres. To overcome this challenge, office-based setup for intravitreal injection was started. This study was planned to determine the incidence of endophthalmitis after office-based intravitreal bevacizumab injection and to compare it with previously reported incidence of endophthalmitis after operation theatre-based intravitreal injections. The study was conducted at Al-Ehsan Eye Hospital, Lahore, Pakistan, from July 2015 to June 2016, and comprised patients who received intravitreal injections of bevacizumab (Avastin) for different ocular indications. A total of 1,047 intravitreal injections were given in an office-based set-up. Of them, 2(0.19%) cases of clinically suspected endophthalmitis were identified. Office-based set-up for intravitreal bevacizumab injection was found to have comparable safety profile with traditional operation theatre-based set-up. PMID- 29256543 TI - Correlates of myopia in students of Bahauddin Zakariya University, Multan. AB - The present study was conducted to determine the prevalence of myopia in young students of Bahaudin Zakariya University, Multan. A total sample of 620 students of both gender (male=295; female=325) was collected during 2014. The data was divided in two breeding pattern groups, five groups on account of age at myopia onset and different family size. Out of 620 subjects, 150 had myopia (male=85; female=65). The overall prevalence of myopia was 24.19%. The myopia prevalence was apparently higher in males 28.8% as compared to females 20%. It was observed that myopia was more in age group 21 (37.33%) and less in age group 18 (2.67%). Myopia was found to be higher in inbreeding group (cousin marriage) 56.67% when compared with out-breeding group 43.33% and was found significantly (P< 0.05) more 69.33% in family size of 6-9 as compared 5 (5.33%) respectively. PMID- 29256544 TI - Follicular dendritic cell sarcoma presenting as colonic intussusception. AB - Follicular dendritic cell sarcoma (FDCS) is a rare intermediate grade sarcoma involving a variety of nodal and extra nodal sites. It has two histological subtypes, conventional and inflammatory pseudotumour like variant. We report this interesting case of FDCS presenting colonic intussusception at Shifa International Hospital, Islamabad, Pakistan. Conventional FDCS presenting as a colocolic intussusception is an unusual presentation, and to our knowledge, has never been reported previously. It has wide morphological spectrum on light microscopy and has characteristic immune-reactivity for dendritic cell markers (CD21, CD23, and CD35). Surgical excision is required in all cases while role of adjuvant chemotherapy and radiotherapy is not clearly demonstrated in literature. PMID- 29256545 TI - Caught in the act - Migration of a large right atrial thrombus to pulmonary artery during transthoracic echocardiography - A case report. AB - In cases of pulmonary embolism, the visualization of a free-floating right heart thrombus on conventional transthoracic echocardiography is extremely rare. Even rarer is an echocardiographic recording of migration of a free-floating clot from the right heart into the pulmonary vasculature leading to pulmonary embolism. We present a unique case of an elderly man who presented with dyspnoea, in whom a routine 2-D bed side transthoracic echo recorded the live transit of a free floating thrombus from the right heart into the pulmonary artery resulting in pulmonary embolism. The patient remained haemodynamically stable and was managed with anticoagulation. Our case objectively highlights the rare occurrence of free floating right heart thrombi and their association with pulmonary embolism and also focuses on the options of management of such thrombi. PMID- 29256546 TI - Hypermucoviscous Klebsiella syndrome it's in the community! AB - Hypermucoviscous Klebsiella syndrome is a unique syndrome caused by a new variant of Klebsiella pneumoniae (KP), characterized by abscess formation at distant body sites. This emerging KP strain is different from the usual classic strains in having the rmp gene which increases capsule formation making this strain resistant to phagocytosis and helping in its dissemination to distant organs. A 50 years old diabetic man presented with facial swelling after dental procedure which progressively increased despite being on antibiotics. On examination he was febrile, had neck swelling with signs of inflammation and tender hepatomegaly. Ultrasonography showed submental and liver abscesses which were subsequently drained and both cultures isolated KP with hypermucoid colonies on agar plate and a positive string test indicating the presence of this new hypervirulent strain of KP. Therefore, a diagnosis of Hypermucoviscous Klebsiella syndrome should be considered in all patients who present with KP infection with multiple organ abscesses.. PMID- 29256547 TI - Anaesthetic management for pheochromocytoma resection in a 5-year-old boy with cerebral haemorrhage and intestinal obstruction. AB - Pheochromocytoma is rarely seen under the age of 8 years and the anaesthesia for pheochromocytoma surgery is challenging. We present the perioperative management of a 5-year-old boy with intestinal obstruction and two episodes of cerebral haemorrhage who presented for pheochromocytoma resection and enterolysis. Important issues in the management of this patient included choice of vasoactive agents and anaesthetics, control of blood pressure and intracranial pressure, preioperative fluid management, and monitoring technique. Imbalance of fluid and electrolyte disturbance as well as a potentially inevitable drop in blood pressures after complete excision of tumour further complicate patient care. Knowledge of different medical issues involved in this case and their potential impact on anaesthetic management is paramount for safe perioperative patient care. PMID- 29256548 TI - Phosphine induced acute cardiotoxicity in children: A need for health awareness. AB - Aluminum Phosphate (AP) is a cheap and highly effective pesticide. Phosphine is the active pesticidal component which is highly toxic. Mortality is high and ranges between 40-70%. There is a desperate need for creating awareness. We report a case series with a mortality of 40% and emphasize the need for public awareness. PMID- 29256549 TI - Transcranial approach to craniopharyngiomas; review of management and outcomes. AB - Craniopharyngiomas are rare tumours of the central nervous system. Their successful treatment is marred by a high rate of recurrence and postoperative complications. Their occurrence is sufficiently rare to merit treatment at specialized high volume centers. We have described our experience with these tumours because we feel that published literature is rare from our region.We treated 7 patients during this period. Their complete history was taken and full neurological examination was performed. Scans included a plain head CT and an MRI scan with contrast. Follow up was done at 2 weeks, 1 month, 3 months, 6 months, 1 year and 2 year following surgery. The outcome in all patients was classified as according to the Karnofsky outcome scale for brain tumours. Craniopharyngiomas are a rare and challenging form of tumour to treat due to its close proximity to vital structures. Treatment is usually multi-disciplinary at reducing recurrence and maintaining quality of life. PMID- 29256551 TI - Communication in diabetes care. PMID- 29256550 TI - Central venoplasty in AV (Arteriovenous) fistula dysfunction a palliative endovascular approach. AB - The ultimate treatment of chronic kidney disease is renal transplant. Patients with CKD who need temporary haemodialysis have to have indwelling catheters. The catheters used are either temporary or permacath (A permacath is a piece of plastic tubing very similar to jugular catheter used for haemodialysis). The issues with these catheters are stenosis of central vein especially subclavian. Central venous stenosis leads to impairment in optimal dialysis. We report two cases of central venous stenosis in which patients presented with pain and oedema of the arm. Venogram showed totally occluded right subclavain vein and left innominate vein. Venoplasty was done which on followup showed a normalization of arm and resumption of dialysis through AV fistula. . PMID- 29256552 TI - The Berlin Declaration: Inspiration for primary care. AB - This paper describes the seminal Berlin Declaration, released in December 2016, and draws inspiration from it to ensure early prevention, early detection, and early control of diabetes, and provide early access to the right interventions for diabetes care. Discussion focuses on actions which primary care physicians can take in their individual practices to help achieve the goals laid down in Berlin Declaration. Collective efforts, involving simple, achievable and measurable interventions, will facilitate fulfillment of the Berlin Declaration's aims and objectives. PMID- 29256553 TI - Survival benefit of surgery in recurrent glioblastoma multiforme. AB - There is an ongoing debate regarding role of surgery for recurrent glioblastoma multiforme (GBM). Older literature hinted at only modest survival benefits with surgery and a high rate of morbidity. However, more recent literature suggests better survival that may be attributed to better surgical techniques and better options in adjuvant treatment. Herein the authors review recent literature with regards to the possible role of surgery in recurrent GBM and also look into the key factors impacting second surgery. . PMID- 29256555 TI - Use of Nile Tilapia (Oreochromisniloticus) skin in the management of skin burns. PMID- 29256554 TI - Role of Ajwa in the treatment and prevention of ischaemic heart disease. PMID- 29256556 TI - Pathological bone fractures in a patient with parathyroid carcinoma - A Case Report. AB - Parathyroid carcinoma is a rare malignant neoplasm of the parathyroid glands which results in enlargement and excessive production of parathyroid hormone (PTH) responsible for pathologically raising calcium levels in the blood resulting in bone pain/fractures, renal stones and other signs of hypercalcaemia. A 37 year old woman presented with sudden, spontaneous bone pain and fracture of the right femoral shaft. This unusual presentation was explained by extremely high PTH levels and hypercalcaemia in the blood and a hard, solitary mass palpable in the neck. During surgical excision of this mass, finding of several adhesions, possible capsular invasion and lymph node enlargement led to a diagnosis of parathyroid carcinoma. The neoplasm proliferates via adenoma carcinoma sequence so early diagnosis and prompt surgical excision with post operative care may provide palliation and keep recurrences in check. Pancreas and pituitary evaluation is also necessary as this presentation may be a part of Wermer (MEN-1) syndrome. . PMID- 29256558 TI - Chickungunya: Is it more common than we thought? PMID- 29256557 TI - Chikungunya virus: Underestimating its burden. PMID- 29256559 TI - Prophylactic platelet transfusion in dengue: A dilemma. PMID- 29256560 TI - Interaction of cells with patterned reactors. AB - Surface coatings that allow externally controlled interaction with cells are of interested for diverse biomedical applications. We fabricated particle patterns and assessed the interaction of these substrates with endothelial cells and hepatocytes. The particles were turned into subcompartmentalized reactors by immobilizing glucose oxidase loaded liposomes sandwiched between polymer layers. The reactor activities depending on the number of liposome deposition steps were confirmed in solution and on patterned surfaces. Finally, reduced viability of hepatocytes adhering to the reactor patterned surfaces in the presence of glucose was observed due to the local production of hydrogen peroxide. This first report on patterned reactors in combination with cells opens up vast opportunities to assemble interactive nanobiointerfaces. PMID- 29256561 TI - Palladium-catalyzed synthesis of fluoreones from bis(2-bromophenyl)methanols. AB - A palladium-catalyzed synthesis method of fluorenones has been developed. A variety of bis(2-bromophenyl)methanols could undergo the reaction smoothly in the presence of Pd(OAc)2, affording a series of fluorenones in moderate to good yields (two steps). Mechanistic studies reveal that the reaction might be triggered by oxidation of alcohol followed by intramolecular reductive coupling. PMID- 29256562 TI - A fluorescent activatable probe for imaging intracellular Mg2+ . AB - An activatable BODIPY probe for in vitro detection and fluorescence cell imaging of free Mg2+ without interference from Ca2+ is described. Fluorescence amplification of the probe is observed upon detection of physiological concentrations of Mg2+ due to reduced rotation of the fluorophore and effective chelation by a quinolizine-based core. PMID- 29256563 TI - Enhanced thermoelectric performance of Cu3SbS4 flower-like hierarchical architectures composed of Cl doped nanoflakes via an in situ generated CuS template. AB - In this work, Cu3SbS4 hierarchical flower-like microspheres composed of chlorine (Cl-)-doped Cu3SbS4 nanoflakes are realized via a one pot solvothermal ion exchange reaction. The kinetic factors including the duration time, the ratio of source materials, and the KOH concentration, are systematically investigated. Using a suite of analytical techniques, including SEM, XRD and FTIR, the mechanism of the two stage in situ chemical transformation of CuS flower-like microspheres consisting of nanoflake intermediates to the target product Cu3SbS4 is elucidated. The difference in solubility between reactants and products (Ksp(CuS) > Ksp(CuSbSx)) determines that the ion-exchange reaction from transition binary to ternary metal chalcogenides is favorable under the impetus of a thermodynamic driving force. In addition, the optical and enhanced thermoelectric transport properties are investigated. The results revealed that Cl-doped Cu3SbS4 exhibited an improved power factor, which was 8 times higher than that of undoped Cu3SbS4 at 500 K. The current study not only provides a facile and economical way to synthesize high-quality Cl-doped Cu-Sb-S three dimensional (3D) hierarchical nanostructures, but also opens up a new route for preparation of other I-V-VI multicomponent chalcogenide NCs, such as Cu-Bi-S and Cu-Pb-S systems, which would be difficult to obtain otherwise. PMID- 29256564 TI - Correction: Synthesis of kinase inhibitors containing a pentafluorosulfanyl moiety. AB - Correction for 'Synthesis of kinase inhibitors containing a pentafluorosulfanyl moiety' by Supojjanee Sansook et al., Org. Biomol. Chem., 2017, 15, 8655-8660. PMID- 29256565 TI - Enrichment of rare earth metal ions by the highly selective adsorption of phytate intercalated layered double hydroxide. AB - Phytate intercalated MgAl layered double hydroxide (MgAl-LDH) was prepared by an anion exchange method with the precursor NO3- containing MgAl-LDH. The final as synthesized product [Mg0.69Al0.31(OH)2] (phytateNa6)0.05 (NO3)0.01.mH2O (phytate LDH) has highly selective adsorption ability for some metal ions and can be used to enrich rare earth metal ions in mixed solution, such as Pr3+ and Ce3+ from a mixed solution of them with Pb2+ and Co2+. At first, phytate-LDH has good adsorption performance for these ions in single metal ion solutions. At low concentration (below 10 mg L-1), all the capture rates of the four metal ions were more than 97%, for highly toxic Pb2+ it was even up to nearly 100%, and a high capture rate (99.87%) was maintained for Pb2+ at a high concentration (100 mg L-1). When all the four metal ions are co-existing in aqueous solution, the selectivity order is Pb2+ ? Pr3+ ~ Ce3+ > Co2+. In a solution containing mixtures of the three metal ions of Pr3+, Ce3+, and Co2+, the selectivity order is Pr3+ ~ Ce3+ ? Co2+, and in a solution containing mixtures of Pr3+ with Co2+ and Ce3+ with Co2+, the selectivity orders are Pr3+ ? Co2+ and Ce3+ ? Co2+, respectively. The high selectivity and adsorption capacities for Pb2+, Co2+, Pr3+, and Ce3+ result in the efficient removal of Pb2+ and enrichment of the rare earth metal ions Pr3+ and Ce3+ by phytate-LDH. Based on the elemental analysis, it is found that the difference of the adsorption capacities is mainly due to the different coordination number of them with phytate-LDH. With molecular simulation, we believe that the adsorption selectivity is due to the difference of the binding energy between the metal ion and phytate-LDH. Therefore, the phytate-LDH is promising for the enrichment and/or purification of the rare earth metal ions and removal of toxic metal ions from waste water. PMID- 29256566 TI - Selective and reversible adsorption of cationic dyes by mixed ligand Zn(ii) coordination polymers synthesized by reactant ratio modulation. AB - Dye capture and separation through coordination polymers (CPs) has been a promising research field in recent times due to the toxic and nondegradable nature of organic dyes released into the environment from various industries as well as the reusability of CPs for the said purpose. Here, we report the synthesis and characterization of two mixed ligand CPs {[Zn2(HBTC)2(L)(H2O)2](C2H5OH)3}n (CP1) and {[Zn5(BTC)2(L)3(OH)4(H2O)2](H2O)4(CH3OH)11}n (CP2) (where H3BTC = 1,3,5-benzene tricarboxylic acid and L = 1,4-bis(4-pyridyl)-2,3-diaza-1,3-butadiene) by the stoichiometric variation of the precursors. The crystal structure analysis revealed that CP1 is a 2D network composed of a [Zn2(HBTC)2(H2O)2]n motif linked via terminal nitrogen atoms of L and CP2 is a 3D framework in which symmetrically disposed two-dimensional {[Zn5(BTC)2(L)3(OH)4(H2O)2]}n sheets composed of pentanuclear [Zn5(RCO2)6(MU3-OH)2(MU2-OH)2(H2O)2] SBUs are pillared by L ligands. Adsorption and separation of cationic dyes by CP1 and the solid-state fluorescence properties of both CPs have been investigated. Cationic dyes (RhB, MB, and MV) can be effectively adsorbed by CP1 from their aqueous solution (61%, 90%, and 97%, respectively) while the anionic dye methyl orange (MO) remains uncaptured. Dye desorption studies and CP1 as a column chromatographic filler for the separation of cationic dyes in water have also been demonstrated. PMID- 29256567 TI - A typical diffusion monitored by flow cytometry: slow diffusion of small molecules in polyelectrolyte multilayers. AB - An innovative approach has been developed to measure small molecule diffusion in polyelectrolyte multilayers (PEMs) assembled on colloidal particles by means of flow cytometry (FACS). FACS allows changes in fluorescence emission as a function of time to be recorded per particle in a colloidal dispersion. Dithionite, S2O42 , diffusion in PEMs composed of polyallylamine hydrochloride (PAH) and poly styrene sulfonate (PSS) assembled on silica particles has been studied by recording the quenching of (7-nitrobenz-2-oxa-1,3-diazol-4yl)amino (NBD) labelled PAH layers by FACS. NBD is reduced when it encounters dithionite, and is therefore no longer fluorescent. The decay in fluorescence will be used to follow the kinetics of dithionite diffusion. The fluorescence decay curves show slow diffusion that does not follow classical Fickean law. However, by assuming that the diffusion coefficient is time dependent and follows an inverse power law in an atypical diffusion case, it was possible to obtain an excellent fit for the decay curves. PMID- 29256568 TI - Upconverting nanocomposites with combined photothermal and photodynamic effects. AB - Lanthanide-doped upconverting nanoparticles (UCNPs) have been studied for diverse biomedical applications due to their inherent ability to convert near-infrared (NIR) excitation light to higher energies (spanning the ultraviolet, visible, and NIR regions). To explore additional functionalities, rational combination with other optically active nanostructures may lead to the development of new multimodal nanoplatforms with theranostic (therapy and diagnostic) capabilities. Here, we develop a nanocomposite consisting of NaGdF4:Er3+, Yb3+ UCNPs, mesoporous silica (SiO2), gold nanorods (GNRs) and a photosensitizer, with integrated functionalities including luminescence imaging, photothermal generation, nanothermometry and photodynamic effects. Under 980 nm irradiation, GNRs and UCNPs are simultaneously excited due to the overlap between the surface plasmon resonance of the GNRs and the absorption of the UCNPs leading to plasmonic enhancement of the upconverted luminescence, while concomitantly creating a temperature gradient. The temperature increase can be determined from the intensity ratio of the upconverted green emission of the UCNPs. Finally, a photosensitizer, zinc phthalocyanine, was loaded into the mesoporous SiO2. Upon laser irradiation, the upconverted visible light subsequently activates the photosensitizer to release reactive oxygen species. The multifunctional GNR@SiO2@UCNPs nanocomposites showed strong luminescence signal when incubated in HeLa cervical cancer cells, making them ideal bioprobes for future theranostic applications. PMID- 29256570 TI - Pd/Cu dual catalysis: highly enantioselective access to alpha-substituted alpha amino acids and alpha-amino amides. AB - The asymmetric allylation of glycine iminoesters has been accomplished through a synergistic Pd/Cu catalyst system, affording a range of alpha-substituted alpha amino acids in high yields and with excellent enantioselectivities (88 -> 99% ee). The introduction of a Cu-P,N-metallocenyl complex-activated glycine iminoester to the chiral palladium-catalyzed allylic allylation process is crucial owing to its high reactivity and excellent enantioselectivities. Importantly, this Pd/Cu dual catalysis strategy can be used for the asymmetric allylic alkylation of prochiral glycine amide derivatives, which could be further utilized to synthesize biologically important vicinal diamines. PMID- 29256571 TI - A novel ferrocenyl-naphthalimide as a multichannel probe for the detection of Cu(ii) and Hg(ii) in aqueous media and living cells. AB - A novel ferrocenyl-naphthalimide multichannel probe 1 was designed and synthesized using a facile method. The color of the solution containing probe 1 changed from yellow to colorless upon the addition of Cu2+ or Hg2+. Interestingly, probe 1 exhibited highly selective fluorescent turn-on for Cu2+ and turn-off for Hg2+ in aqueous solution. Probe 1 was an electrochemical Cu2+ and Hg2+ ion sensor, in which the Fc/Fc+ redox couple was significantly shifted (DeltaE1/2 = 178 mV and DeltaE1/2 = 53 mV, respectively) upon complexation. Therefore, probe 1 can act as a naked-eye chemosensor, as well as an electrochemical and a fluorescent probe for Cu2+ and Hg2+. Furthermore, this is the first reported probe that can be used for the bifunctional fluorescent detection of intracellular Cu2+ and Hg2+ by fluorescent imaging studies. These characteristics give this probe considerable potential in the study and analysis of Cu2+ and Hg2+ in complex biosystems. PMID- 29256569 TI - Dietary compound proanthocyanidins from Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves attenuate chemotherapy-resistant ovarian cancer stem cell traits via targeting the Wnt/beta-catenin signaling pathway and inducing G1 cell cycle arrest. AB - Cancer stem cells (CSCs) represent a small population of cancer cells characterized by self-renewal ability, tumorigenesis and drug resistance. Ovarian cancer is one of the leading causes of death related to the female reproductive system in Western countries and has been evaluated as a type of CSC-related cancer in recent years. Natural products have attracted great attention in cancer treatment in recent years due to drug resistance and a high relapse rate of ovarian cancer. Chinese bayberry leaf proanthocyanidins (BLPs) contain epigallocatechin-3-O-gallate as their terminal and major extension units, which is quite unusual in the plant kingdom. BLPs showed strong antioxidant and antiproliferative abilities in previous studies. In the present study, chemotherapy-resistant OVCAR-3 spheroid (SP) cells were obtained by sphere culturing and exhibited CSC-like properties by showing a higher ALDH+ population and higher expression of stemness-related proteins. BLPs exhibited inhibitory effects on the growth and CSC characteristics of OVCAR-3 SP cells by showing decreased cell viability, sphere and colony formation ability, ALDH+ population and expression of stemness-related proteins. BLPs also targeted the Wnt/beta catenin pathway by reducing the expression of beta-catenin, cyclin D1 and c-Myc and thus inhibited the self-renewal ability of OVCAR-3 SP cells. Furthermore, BLPs also induced G1 cell cycle arrest in OVCAR-3 SP cells. Taken together, these findings suggested that BLPs may be an important agent in the development of therapeutics for ovarian cancer patients. PMID- 29256572 TI - Adsorbed carbon nanomaterials for surface and interface-engineered stable rubidium multi-cation perovskite solar cells. AB - The current work reports the simultaneous enhancement in efficiency and stability of low-temperature, solution-processed triple cation based MA0.57FA0.38Rb0.05PbI3 (MA: methyl ammonium, FA: formamidinium, Rb: rubidium) perovskite solar cells (PSCs) by means of adsorbed carbon nanomaterials at the perovskite/electron transporting layer interface. The quantity and quality of the adsorbents are precisely controlled to electronically modify the ETL surface and lower the energy barrier across the interface. Carbon derivatives namely fullerene (C60) and PC71BM ([6,6]-phenyl C71 butyric acid methyl ester) are employed as adsorbents in conjunction with ZnO and together serve as a bilayer electron transporting layer (ETL). The adsorbed fullerene (C60-ZnO, abbreviated as C-ZnO) passivates the interstitial trap-sites of ZnO with interstitial intercalation of oxygen atoms in the ZnO lattice structure. C-ZnO ETL based PSCs demonstrate about a 19% higher average PCE compared to conventional ZnO ETL based devices and a nearly 9% higher average PCE than PC71BM adsorbed-ZnO (P-ZnO) ETL based PSCs. In addition, the interstitial trap-state passivation with a C-ZnO film upshifts the Fermi-level position of the C-ZnO ETL by 130 meV, with reference to the ZnO ETL, which contributes to an enhanced n-type conductivity. The photocurrent hysteresis phenomenon in C-ZnO PSCs is also substantially reduced due to mitigated charge trapping phenomena and concomitant reduction in an electrode polarization process. Another major highlight of this work is that, C-ZnO PSCs demonstrate a superior device stability retaining about 94% of its initial PCE in the course of a month-long, systematic degradation study conducted in our work. The enhanced device stability with C-ZnO PSCs is attributed to their high resistance to aging induced recombination phenomena and a water-induced perovskite degradation process, due to a lower content of oxygen-related chemisorbed species on the C ZnO ETL. The intricate mechanisms behind the efficiency and stability enhancement are investigated in detail and explained in the context of enhanced surface and interfacial electronic properties. PMID- 29256573 TI - Bilateral versus unilateral hearing aids for bilateral hearing impairment in adults. AB - BACKGROUND: Acquired hearing loss is common and its incidence increases markedly with age. In most people, 'age-related' hearing loss is sensorineural (due to the loss of cochlear hair cells) and bilateral, affecting both ears to the same degree. Hearing loss categorised as mild, moderate or severe is primarily managed with hearing aids. People with bilateral hearing loss may be offered one aid, fitted to one specific ear, or two aids fitted to both ears. There is uncertainty about the relative benefits to people with hearing loss of these different strategies. OBJECTIVES: To assess the effects of bilateral versus unilateral hearing aids in adults with a bilateral hearing impairment. SEARCH METHODS: The Cochrane ENT Information Specialist searched the ENT Trials Register; Cochrane Register of Studies Online; PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 8 June 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the fitting of two versus one ear-level acoustic hearing aids in adults (over 18 years) with a bilateral hearing impairment, both ears being eligible for hearing aids. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were patient preference for bilateral or unilateral aids, hearing-specific health-related quality of life and adverse effects (pain or discomfort in the ear, initiation or exacerbation of middle or outer ear infection). Secondary outcomes included: usage of hearing aids (as measured by, for example, data logging or battery consumption), generic health-related quality of life, listening ability and audiometric benefit measured as binaural loudness summation. We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics. MAIN RESULTS: We included four cross-over RCTs with a total of 209 participants, ranging in age from 23 to 85 and with a preponderance of men. All the studies allowed the use of hearing aids for a total period of at least eight weeks before questions on preference were asked. All studies recruited patients with bilateral hearing loss but there was considerable variation in the types and degree of sensorineural hearing loss that the participants were experiencing.Three of the studies were published before the mid 1990s whereas the fourth study was published in 2011. Therefore, only the most recent study used hearing aids incorporating technology comparable to that currently readily available in high-income settings. Of the four studies, two were conducted in the UK in National Health Service (NHS - public sector) patients: one recruited patients from primary care with hearing loss detected by a screening programme whereas the other recruited patients who had been referred by their primary care practitioner to an otolaryngology department for hearing aids. The other two studies were conducted in the United States: one study recruited only military personnel or veterans with noise-induced hearing loss whereas about half of the participants in the other study were veterans.Only one primary outcome (patient preference) was reported in all studies. The percentage of patients who preferred bilateral hearing aids varied between studies: this was 54% (51 out of 94 participants), 39% (22 out of 56), 55% (16 out of 29) and 77% (23 out of 30), respectively. We have not combined the data from these four studies. The evidence for this outcome is of very low quality.The other outcomes of interest were not reported in the included studies. AUTHORS' CONCLUSIONS: This review identified only four studies comparing the use of one hearing aid with two. The studies were small and included participants of widely varying ages. There was also considerable variation in the types and degree of sensorineural hearing loss that the participants were experiencing.For the most part, the types of hearing aid evaluated would now be regarded, in high-income settings, as 'old technology', with only one study looking at 'modern' digital aids. However, the relevance of this is uncertain, as this review did not evaluate the differences in outcomes between the different types of technology.We were unable to pool data from the four studies and the very low quality of the evidence leads us to conclude that we do not know if people with hearing loss have a preference for one aid or two. Similarly, we do not know if hearing-specific health-related quality of life, or any of our other outcomes, are better with bilateral or unilateral aids. PMID- 29256574 TI - Medical Devices; Obstetrical and Gynecological Devices; Classification of the Fetal Head Elevator. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the fetal head elevator into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the fetal head elevator's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 29256575 TI - Medical Devices; Ophthalmic Devices; Classification of the Tear Electrostimulation Device. Final order. AB - The Food and Drug Administration (FDA or we) is classifying the tear electrostimulation device into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the tear electrostimulation device's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens. PMID- 29256576 TI - Editorial. PMID- 29256577 TI - SKIN INTEGRITY PORTFOLIO HOLDERS ARE GOLDEN. AB - I have been the Skin Integrity Clinical Nurse Consultant (SICNC) at Peninsula Health for about eight years. In my role, I oversee wound care and pressure prevention measures. PMID- 29256578 TI - ANMF PARTICIPATES IN INTERNATIONAL NURSING SYMPOSIUM ON SHIFT WORK. AB - Nurses and other health workers have long understood the often deleterious impacts that shift work can have on sleep, wellbeing and performance at work. PMID- 29256579 TI - SAFETY AND SECURITY IS EVERYONE'S BUSINESS. AB - Workplace safety and security should be a given but as we all know this is not always the case. PMID- 29256581 TI - siRNA Delivery Using a Cationic-Lipid-Based Highly Selective Human DNA Ligase I Inhibitor. AB - The present article illustrates the serendipitous discovery of a cationic-lipid based human DNA ligase (hLig) I inhibitor and the development of siRNA delivering, a hLigI-targeted cationic-lipid-based nonviral vector. We have tested a small in-house library of structurally similar cationic lipo-anisamides for antiligase activity, and amongst tested, N-dodecyl-N-(2-(4 methoxybenzamido)ethyl)-N-methyldodecan-1-ammonium iodide (C12M) selectively and efficiently inhibited the enzyme activity of hLigI, compared to other human ligases (hLigIIIbeta and hLigIV/XRCC4) and bacterial T4 DNA ligase. Furthermore, upon hydration with equimolar cholesterol, C12M produced antiligase cationic liposomes, which transfected survivin siRNA and showed significant inhibition of tumor growth. PMID- 29256582 TI - Temperature Gradient-Induced Instability of Perovskite via Ion Transport. AB - Perovskite has been known as a promising novel material for photovoltaics and other fields because of its excellent opto-electric properties and convenient fabrication. However, its stability has been a widely known haunting factor that has severely deteriorated its application in reality. In this work, it has been discovered for the first time that perovskite can become significantly chemically unstable with the existence of a temperature gradient in the system, even at temperature far below its thermal decomposition condition. A study of the detailed mechanism has revealed that the existence of a temperature gradient could induce a mass transport process of extrinsic ionic species into the perovskite layer, which enhances its decomposition process. Moreover, this instability could be effectively suppressed with a reduced temperature gradient by simple structural modification of the device. Further experiments have proved the existence of this phenomenon in different perovskites with various mainstream substrates, indicating the universality of this phenomenon in many previous studies and future research. Hopefully, this work may bring deeper understanding of its formation mechanisms and facilitate the general development of perovskite toward its real application. PMID- 29256580 TI - Multifunctional Copper-Containing Carboxymethyl Chitosan/Alginate Scaffolds for Eradicating Clinical Bacterial Infection and Promoting Bone Formation. AB - Repairing infected bone defects relies on a scaffold that can not only fill the defects to promote bone formation but also kill clinically present bacterial pathogens such as Staphylococcus aureus (S. aureus). To meet this demand, here, we develop a new copper (Cu) containing natural polymeric scaffold with a full potential for repairing infected bone defects. Instead of directly adding antibacterial Cu2+ ions to the polymer mixtures, which caused uncontrolled polymer cross-linking, we added Cu nanoparticles to the mixture of anionic carboxymethyl chitosan (CMC) and alginate (Alg). Then, the Cu2+ ions released from the Cu nanoparticles gradually cross-linked the polymer mixtures, which was further turned into a scaffold (CMC/Alg/Cu) with an interconnected porous structure by freeze-drying. We found that the CMC/Alg/Cu scaffolds showed significantly improved capabilities of osteogenesis and killing clinical bacteria compared to CMC/Alg scaffolds fabricated by the same procedure but without adding Cu nanoparticles. Specifically, in vitro studies showed that the CMC/Alg/Cu scaffolds with excellent biocompatibility could enhance preosteoblastic cell adhesion by upregulating the expression level of adhesion-related genes (focal adhesion kinase (FAK), paxillin (PXN), and vinculin (VCL)), promoting osteogenic differentiation and mineralization by upregulating the osteogenesis-related gene expression and extracellular calcium deposition. In vivo studies further demonstrated that CMC/Alg/Cu scaffolds could induce the formation of vascularized new bone tissue in 4 weeks while avoiding clinical bacterial infection even when the implantation sites were challenged with the clinically collected S. aureus bacteria. This work represents a facile and innovative approach to the fabrication of Cu containing polymer scaffolds that can potentially be used to repair infected bone defects. PMID- 29256583 TI - Healability Demonstrates Enhanced Shape-Recovery of Graphene-Oxide-Reinforced Shape-Memory Polymeric Films. AB - The fabrication of shape-memory polymers or films that can simultaneously heal the mechanical damage and the fatigued shape-memory function remains challenging. In this study, mechanically robust healable shape-memory polymeric films that can heal the mechanical damage and the fatigued shape-memory function in the presence of water are fabricated by layer-by-layer assembly of branched poly(ethylenimine) (bPEI)-graphene oxide (GO) complexes with poly(acrylic acid) (PAA), followed by the release of the (PAA/bPEI-GO)*n films from the underlying substrates. The free standing (PAA/bPEI-GO0.02)*35 films made of bPEI-GO complexes with a mass ratio of 0.02 between GO nanosheets and bPEI are mechanically robust with a Young's modulus of 19.8 +/- 2.1 GPa and a hardness of 0.92 +/- 0.15 GPa and exhibit excellent humidity-induced healing and shape-memory functions. Benefiting from the highly efficient healing function, the (PAA/bPEI-GO0.02)*35 films can heal cuts penetrating thorough the entire film and achieve an ~100% shape-recovery ratio for a long-term shape-memory application. Meanwhile, the shape-memory function of the mechanically damaged (PAA/bPEI-GO0.02)*35 films can be finely restored after being healed in water. The shape-memory functions of the (PAA/bPEI GO0.02)*35 films and their healing capacity originate from the reversibility of electrostatic and hydrogen-bonding interactions induced by water between PAA and bPEI-GO complexes. PMID- 29256584 TI - Boronic Acid Moiety as Functional Defect in UiO-66 and Its Effect on Hydrogen Uptake Capacity and Selective CO2 Adsorption: A Comparative Study. AB - Herein, we use linker fragmentation approach to introduce boronic acid moieties as functional defects into Zr-based metal-organic frameworks (MOFs, UiO-66). Our findings show that the amount of permanently incorporated boronic acid containing ligand is directly dependent on the synthesis method. The accessible boronic acid moieties in the pore surfaces significantly improve the hydrogen uptake values, which are 3.10 and 3.44 wt % at 21 bar, 77 K for dimethylformamide (DMF)/H2O and DMF/HCI synthesis methods, respectively. Also, CO2 selectivity of the resulting MOFs over N2 and CH4 significantly increases due to the quadrupolar interaction between active surfaces and CO2 molecules. To the best of our knowledge, both hydrogen storage and selectivity of CO2 for UiO-66 are the highest reported values in the literature to date. Furthermore, another striking result that emerged from the high-pressure hydrogen uptake isotherms is the direct correlation between the defects and hysteric adsorption behavior, which may result in the shift from rigidity to flexibility of the framework due to the uncoordinated sites. PMID- 29256585 TI - Retraction of "The L3MBTL3 Methyl-Lysine Reader Domain Functions As a Dimer". PMID- 29256586 TI - Magnetic and Electric Resonances in Particle-to-Film-Coupled Functional Nanostructures. AB - We investigate the plasmonic coupling of metallic nanoparticles with continuous metal films by studying the effect of the particle-to-film distance, cavity geometry, and particle size. To efficiently screen these parameters, we fabricated a particle-to-film-coupled functional nanostructure for which the particle size and distance vary. We use gold-core/poly(N-isopropylacrylamide) shell nanoparticles to self-assemble a monolayer of well-separated plasmonic particles, introduce a gradient in the nanoparticle size by an overgrowth process, and finally add a coupling metal film by evaporation. These assemblies are characterized using surface probing and optical methods to show localized magnetic and electric field enhancement. The results are in agreement with finite difference time-domain modeling methods and calculations of the effective permeability and permittivity. Finally, we provide a proof of concept for dynamic tuning of the cavity size by swelling of the hydrogel layer. Thus, the tunability of the coupled resonance and the macroscopic self-assembly technique provides access to a cost-efficient library for magnetic and electric resonances. PMID- 29256587 TI - Cellulose Fiber-Based Hierarchical Porous Bismuth Telluride for High-Performance Flexible and Tailorable Thermoelectrics. AB - Porous modification is a general approach to endowing the rigid inorganic thermoelectric (TE) materials with considerable flexibility, however, by which the TE performances are severely sacrificed. Thus, there remains an ongoing struggle against the trade-off between TE properties and flexibility. Herein, we develop a novel strategy to combine Bi2Te3 thick film with ubiquitous cellulose fibers (CFs) via an unbalanced magnetron sputtering technique. Owing to the nano micro hierarchical porous structures and the excellent resistance to crack propagation of the Bi2Te3/CF architectures, the obtained sample with a nominal Bi2Te3 deposition thickness of tens of micrometers exhibits excellent mechanically reliable flexibility, of which the bending deformation radius could be as small as a few millimeters. Furthermore, the Bi2Te3/CF with rational internal resistance and tailorable shapes and dimensions are successfully fabricated for practical use in TE devices. Enhanced Seebeck coefficients are observed in the Bi2Te3/CF as compared to the dense Bi2Te3 films, and the lattice thermal conductivity is remarkably reduced due to the strong phonon scattering effect. As a result, the TE figure of merit, ZT, is achieved as high as ~0.38 at 473 K, which competes with the best flexible TEs and can be further improved by optimizing the carrier concentrations. We believe this developed technique not only opens up a new window to engineer flexible TE materials for practical applications but also promotes the robust development of the fields, such as paper-based flexible electronics and thin-film electronics. PMID- 29256588 TI - Unconventional Clathrates with Transition Metal-Phosphorus Frameworks. AB - In this Account, we focused on a unique class of inclusion compounds, intermetallic clathrates, which exist in a variety of structures and exhibit diverse physical properties. These compounds combine covalent tetrahedral frameworks with rattling guest atoms situated inside their framework cages. Tetrels, the group 14 elements, are the basis for conventional clathrates because they fulfill the bonding requirement of four electrons per framework atom. In analogy to the replacement of Ge with GaAs in semiconductors, we focused on unconventional tetrel-free clathrates with frameworks composed of phosphorus and late transition metals. Compared to tetrels, these elements exhibit greater flexibility in their local coordinations and bonding. Tetrel elements cannot tolerate high deviations from regular tetrahedral coordinations. Thus, they exile a number of theoretically predicted framework topologies that are composed of a single type of polyhedral cage with square faces, such as the truncated octahedron. Unconventional clathrates are capable of stabilizing both envisaged and unique, unforeseen topologies. Clathrate structures with guest atoms held inside their cages by weak electrostatic interactions are predicted to be efficient thermoelectrics due to their low thermal conductivities. Unconventional clathrates may exhibit ultralow thermal conductivities, below 1 W m-1 K-1, without a need for heavy elements in their frameworks. The different chemical natures of transition metals and phosphorus led to their segregation over different framework positions, fulfilling the elements' specific local coordination and bonding requirements. This resulted in the formation of short- and long-range ordered superstructures with complex phonon dispersions and ultralow thermal conductivities. Aliovalent substitutions are commonly used to tune charge carrier concentrations in materials science. They are often performed under the "doping" assumption that substitutions with neighboring elements in the periodic system should not affect the parent structure but only adjust the charge carrier concentrations. This is not the case for unconventional clathrates. We investigated the tunability of the prototype Ba8Cu16P30 clathrate by the aliovalent substitution of Cu with either Zn or Ge. These substitutions resulted in significant alterations of the local chemical bonding and led to the rearrangement of the whole crystal structure. Remarkable thermoelectric properties were achieved for the substituted unconventional clathrates, exhibiting an overall order of magnitude increase in the thermoelectric performance. Aliovalent substitution allowed us to vary the charge carrier concentration in one structure type within the limits of the structure's stability. Exceeding these limits in the Ba-Cu-Zn-P system resulted in a transition from the covalent 2c-2e bonding found in conventional clathrates to the multicenter bonding common for metal-rich intermetallic compounds. This caused the complete rearrangement of the crystal structure into a new unique clathrate where a majority of the framework atoms are five- and six-coordinated, and all metal atoms are joined in Cu-Zn dumbbells. Our work shows that unconventional clathrates exhibit diverse crystal structures and unique chemical bonding, which result in tunable transport properties. While they are similar to their tetrel counterparts in some ways, they are very different in others. Specifically, the high thermal and chemical stabilities and low thermal conductivities of unconventional clathrates make them promising bases for further development of thermoelectric materials. PMID- 29256589 TI - Effect of Alkali Carbonates (Single, Binary, and Ternary) on Doped Ceria: A Composite Electrolyte for Low-Temperature Solid Oxide Fuel Cells. AB - Samarium-doped ceria (SDC) carbonate has become an attractive electrolyte for fuel cells because of its remarkable ion conductivity and high performance. Different doped ceria-carbonate (single-carbonate SDC, binary-carbonate SDC, and ternary-carbonate SDC) electrolytes were synthesized by the coprecipitation/oxalate method, to optimize the electrochemical performance. The structure; morphology; and thermal, optical, and surface properties have been studied using a variety of techniques. The X-ray diffraction results confirmed the successful incorporation of samarium into ceria as a crystalline structure and inclusion of carbonate, which is amorphous in nature. To analyze the conduction mechanism, direct current conductivity was measured in a H2/O2 atmosphere. Doped ceria-binary carbonate ((Li/Na)CO3-SDC) showed the best conductivity of 0.31 S cm-1 and power density of 617 mW cm-2, at 600 degrees C. The enhancement in the ionic conductivity and performance of the composites is due to the contribution of hybrid ions (O2-, H+). The crystallite size of the composites was in the range 21-41 nm. For the calculation of band gaps, optical absorption spectra of the synthesized powders were analyzed, and they showed a red shift with the band gap energy in the range 2.6-3.01 eV, when compared to that of pure ceria (3.20 eV). PMID- 29256590 TI - Bioinspired Catecholic Primers for Rigid and Ductile Dental Resin Composites. AB - In the construction of dental restorative polymer composite materials, surface priming on mineral fillers is essential to improve the mechanical performance of the composites. Here we present bioinspired catechol-functionalized primers for a tougher dental resin composite containing glass fillers. The catecholic primers with different polymerizable end groups were designed and then coated on glass surfaces using a simple drop-casting or dip-coating process. The surface binding ability and possible cross-linking (coupling or chemical bridging between the glass substrate and the dental resin) of the catecholic bifunctional primers were evaluated using atomic force microscopy, contact angle measurements, and the knife shear bonding test and compared to a state-of-the-art silane-based coupling agent. Various mechanical tests including shrinkage and compression tests of the dental resin composites were also conducted. Compression tests of the composites containing the catecholic primed fillers exhibited enhanced mechanical properties, owing to the bidentate hydrogen bonding of catechol moieties to the oxide mineral surface. Furthermore, the superior biocompatibility of the primed surface was confirmed via cell attachment assay, thus providing applicability of catecholic primers for practical dental and biomedical applications. PMID- 29256591 TI - Highly Flexible Resistive Switching Memory Based on the Electronic Switching Mechanism in the Al/TiO2/Al/Polyimide Structure. AB - A highly flexible resistive switching (RS) memory was fabricated in the Al/TiO2/Al/polyimide structure using a simple and cost-effective method. An electronic-resistive-switching-based flexible memory with high performance that can withstand a bending strain of up to 3.6% was obtained. The RS properties showed no obvious degradation even after the bending tests that were conducted up to 10 000 times, and over 4000 writing/erasing cycles were confirmed at the maximally bent state. The superior electrical properties against the mechanical stress of the device can be ascribed to the electronic RS mechanism related to electron trapping/detrapping, which can prevent the inevitable degradation in the case of the RS related with the ionic defects. PMID- 29256592 TI - Transient Mass and Thermal Transport during Methane Adsorption into the Metal Organic Framework HKUST-1. AB - Methane adsorption into the metal-organic framework (MOF) HKUST-1 and the resulting heat generation and dissipation are investigated using molecular dynamics simulations. Transient simulations reveal that thermal transport in the MOF occurs two orders of magnitude faster than gas diffusion. A large thermal resistance at the MOF-gas interface (equivalent to 127 nm of bulk HKUST-1), however, prevents fast release of the generated heat. The mass transport resistance at the MOF-gas interface is equivalent to 1 nm of bulk HKUST-1 and does not present a bottleneck in the adsorption process. These results provide important insights into the application of MOFs for gas storage applications. PMID- 29256593 TI - Dual-Gate Black Phosphorus Field-Effect Transistors with Hexagonal Boron Nitride as Dielectric and Passivation Layers. AB - Two-dimensional black phosphorus (BP) has attracted much attention recently because of its applicability in high-performance electronic and optoelectronic devices. BP field-effect transistors (FETs) with a tunable band gap (0.3-1.5 eV) have demonstrated a high on-off current ratio and a high hole mobility with an ambipolar behavior in global-gated devices. However, local-gated BP FETs for integrated circuits have been reported with only p-type behaviors and a low on current compared with global-gated BP FETs. Furthermore, BP, which is not stable in air, forms sharp spikes on its surface when exposed to humid air. This phenomenon plays a role in accelerating the degradation of the electrical properties of BP devices, which can occur even within a day. In this paper, we first demonstrate the origin of transport limitations of local-gated BP FETs by comparing the transport properties of hexagonal boron nitride (h-BN)-based device architectures with those of a bottom-gated BP FET on a Si/SiO2 substrate. By using h-BN as passivation and dielectric layers, BP FETs with a low gate operating voltage were fabricated with two different transistor geometries: top gated and bottom-gated FETs. The highest mobility extracted from the global-gated BP FETs was 249 cm2 V-1 s-1 with a subthreshold swing of 848 mV dec-1. PMID- 29256594 TI - Performance Improvement of V-Fe-Cr-Ti Solid State Hydrogen Storage Materials in Impure Hydrogen Gas. AB - Two approaches of engineering surface structures of V-Ti-based solid solution hydrogen storage alloys are presented, which enable improved tolerance toward gaseous oxygen (O2) impurities in hydrogen (H2) gas. Surface modification is achieved through engineering lanthanum (La)- or nickel (Ni)-rich surface layers with enhanced cyclic stability in an H2/O2 mixture. The formation of a Ni-rich surface layer does not improve the cycling stability in H2/O2 mixtures. Mischmetal (Mm, a mixture of La and Ce) agglomerates are observed within the bulk and surface of the alloy when small amounts of this material are added during arc melting synthesis. These agglomerates provide hydrogen-transparent diffusion pathways into the bulk of the V-Ti-Cr-Fe hydrogen storage alloy when the remaining oxidized surface is already nontransparent for hydrogen. Thus, the cycling stability of the alloy is improved in an O2-containing hydrogen environment as compared to the same alloy without addition of Mm. The obtained surface-engineered storage material still absorbs hydrogen after 20 cycles in a hydrogen-oxygen mixture, while the original material is already deactivated after 4 cycles. PMID- 29256595 TI - Reticular V2O5.0.6H2O Xerogel as Cathode for Rechargeable Potassium Ion Batteries. AB - Potassium ion batteries (KIBs), because of their low price, may exhibit advantages over lithium ion batteries as potential candidates for large-scale energy storage systems. However, owing to the large ionic radii of K-ions, it is challenging to find a suitable intercalation host for KIBs and thus the rechargeable KIB electrode materials are still largely unexplored. In this work, a reticular V2O5.0.6H2O xerogel was synthesized via a hydrothermal process as a cathode material for rechargeable KIBs. Compared with the orthorhombic crystalline V2O5, the hydrated vanadium pentoxide (V2O5.0.6H2O) exhibits the ability of accommodating larger alkali metal ions of K+ because of the enlarged layer space by hosting structural H2O molecules in the interlayer. By intercalation of H2O into the V2O5 layers, its potassium electrochemical activity is significantly improved. It exhibits an initial discharge capacity of ~224.4 mA h g-1 and a discharge capacity of ~103.5 mA h g-1 even after 500 discharge/charge cycles at a current density of 50 mA g-1, which is much higher than that of the V2O5 electrode without structural water. Meanwhile, X-ray diffraction and X-ray photoelectron spectroscopy combined with energy dispersive spectroscopy techniques are carried out to investigate the potassiation/depotassiation process of the V2O5.0.6H2O electrodes, which confirmed the potassium intercalation storage mechanisms of this hydrated material. The results demonstrate that the interlayer-spacing-enlarged V2O5.0.6H2O is a promising cathode candidate for KIBs. PMID- 29256596 TI - Porphyrin Antenna-Enriched BODIPY-Thiophene Copolymer for Efficient Solar Cells. AB - Low bandgap A-pi-D copolymer, P(BdP-DEHT), consisting of alternating BOronDIPYrromethene (BODIPY) and thiophene units bridged by ethynyl linkers, and its porphyrin-enriched analogue, P(BdP/Por-DEHT), were prepared, and their optical and electrochemical properties were studied. P(BdP-DEHT) exhibits strong absorption in the 500-800 nm range with an optical bandgap of 1.74 eV. On the basis of cyclic voltammetry, the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels are evaluated to be 5.40 and -3.66 eV, respectively. After the anchoring of zinc(II) porphyrin on the BODIPY unit, P(BdP/Por-DEHT) displays broadened absorption, thanks to porphyrins, and the optical bandgap decreases to 1.59 eV because of extension of BODIPY conjugation. The resulting estimated HOMO and LUMO energy levels, respectively, move to -5.32 and -3.73 eV. After optimization of the P(BdP-DEHT) or P(BdP/Por DEHT) to PC71BM weight ratio to 1:2 in dichlorobenzene solution, the bulk heterojunction polymer solar cells show overall power conversion efficiencies (PCEs) of 3.03 and 3.86%, respectively. After solvent vapor annealing (SVA) treatment in CH2Cl2 for 40 s, the PCEs increased to 7.40% [Voc of 0.95 V, Jsc of 12.77 mA/cm2, and fill factor (FF) of 0.61 with energy loss of 0.79 eV] and 8.79% (Voc of 0.92 V, Jsc of 14.48 mA/cm2, and FF of 0.66 with energy loss of 0.67 eV). The increase in the PCE for P(BdP/Por-DEHT)-based devices is mainly attributed to the enhancement in Jsc and FF, which may be related to the broader absorption spectra, lower band gap, and better charge transport of P(BdP/Por-DEHT) compared to P(BdP-DEHT). This could also be related to the optimized nanoscale morphology of the active layer for both efficient exciton dissociation and charge transport toward the electrodes and a balanced charge transport in the device, induced by the SVA treatment of the active layer. PMID- 29256597 TI - High-Pressure Formation of Cobalt Polyhydrides: A First-Principle Study. AB - The high-pressure phase diagram, crystal structures, and electronic properties of cobalt hydrides are systematically investigated in the pressure range of 1 atm to 300 GPa by first-principle calculations. Except for the experimentally found CoH, two new cobalt polyhydrides CoH2 and CoH3 are discovered at 10 and 30 GPa, respectively. The crystal structure of CoH2 is determined to have cubic symmetry with the space group Fm3m and then transforms into the I4/mmm phase above 42 GPa. In addition, CoH3 with Pm3m is stable between 30 and 300 GPa, which can be used as a potential hydrogen storage material with a high volumetric hydrogen density of 425 g H2/L. All the cobalt polyhydrides exhibit metallic and ionic characteristics at high pressure. Furthermore, application of the Allen-Dynes modified McMillan equation estimated no superconductivity for cobalt polyhydrides. PMID- 29256598 TI - Mind Your Ears: A New Antidote to Aminoglycoside Toxicity? AB - Aminoglycoside antibiotics are known toxins to cochlear hair cells, causing permanent hearing loss. Using the zebrafish lateral line system as a platform for drug screen and subsequent validation in the rat cochlea in vivo, Chowdhury et al. characterized a novel otoprotectant working against aminoglycoside-induced hearing loss. PMID- 29256599 TI - 7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of alpha-Amino-3-hydroxy-5-methyl-4 isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency. AB - We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4 benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4 cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1 dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine dioxide AMPApam to reach the nanomolar range. PMID- 29256601 TI - Alkylated Piperazines and Piperazine-Azole Hybrids as Antifungal Agents. AB - The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells. Many of these molecules exhibited broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against non-albicans Candida and Aspergillus strains. The most promising compounds were found to be less hemolytic than the FDA-approved antifungal agent voriconazole (VOR). Finally, we demonstrate that the synthetic alkylated piperazine-azole hybrids do not function by fungal membrane disruption, but instead by disruption of the ergosterol biosynthetic pathway via inhibition of the 14alpha-demethylase enzyme present in fungal cells. PMID- 29256600 TI - Slow Dynamics of Tryptophan-Water Networks in Proteins. AB - Water has a profound effect on the dynamics of biomolecules and governs many biological processes, leading to the concept that function is slaved to solvent dynamics within and surrounding the biomolecule. Protein conformational changes on MUs-ms time scales are frequently associated with protein function, but little is known about the behavior of protein-bound water on these time scales. Here we have used NMR relaxation dispersion measurements to probe the tryptophan indoles in the enzyme dihydrofolate reductase (DHFR). We find that during structural changes on the MUs-ms time scale, large chemical shift changes are often observed for the NH proton on the indole ring, while relatively smaller chemical shift changes are observed for the ring nitrogen atom. Comparison with experimental chemical shifts and density functional theory-based chemical shift predictions show that during the structural change the tryptophan indole NHs remain bound to water, but the geometry of the protein-bound water networks changes. These results establish that relaxation dispersion measurements can indirectly probe water dynamics and indicate that water can influence, or be influenced by, protein conformational changes on the MUs-ms time scale. Our data show that structurally conserved bound water molecules can play a critical role in transmitting information between functionally important regions of the protein and provide evidence that internal protein motions can be coupled through the mediation of hydrogen-bonded water bound in the protein structure. PMID- 29256604 TI - Nanostructuring of Strontium Hexaboride via Lithiation. AB - We describe the top-down nanostructuring of a metal boride using SrB6 as an example. To accomplish this transformation, we demonstrate (1) the direct lithiation of a metal boride using n-butyllithium and then (2) the reactive disassembly of Li-SrB6 into nanoparticles using water. The identity of the Li SrB6 intermediate, a mixture of Li2B6, LixSr1-2xB6, and SrB6 phases, was established by powder X-ray diffraction (PXRD), solid-state 11B and 7Li NMR, transmission electron microscopy, selected-area electron diffraction, and scanning electron microscopy. The necessary 2Li+/Sr2+ substitution is enabled by cation mobility within the hexaboride lattice. The subsequent reaction with water results in Li2B6 decomposition and the release of <100 nm SrB6 nanoparticles, which were characterized by PXRD, solid-state 11B and 7Li NMR, and high resolution TEM. This chemistry opens new solution-based modification and processing options for metal borides. PMID- 29256602 TI - Enhanced Targeted Gene Transduction: AAV2 Vectors Conjugated to Multiple Aptamers via Reducible Disulfide Linkages. AB - Enhanced targeted gene transduction by AAV2 vectors is achieved by linking the vector to multiple sgc8 aptamers, which are selective for cell membrane protein PTK7. Aptamer molecules are conjugated to multiple sites on a DNA dendrimer (G sgc8), which is then linked to AAV2 via a dithiobis(succinimidyl propionate) cross-linker containing a disulfide group, which can facilitate the release of AAV2 vectors by reaction with the reduced form of intracellular glutathione. The G-sgc8-AAV2 vectors showed a 21-fold enhancement in binding affinity and an enhanced ability to protect sgc8 aptamers against nuclease degradation to cells expressing PTK7 compared to single aptamer-AAV2 conjugates. The transduction efficiency was tested by loading AAV2 with the gene for green fluorescent protein. Therefore, this modified recombinant vector is an attractive and promising tool for targeted biomedical applications. PMID- 29256603 TI - Ribocomputing: Cellular Logic Computation Using RNA Devices. PMID- 29256605 TI - Synthesis, Crystal Structures, and EPR Studies of First MnIIILnIII Hetero binuclear Complexes. AB - A new family of binuclear complexes [MnIIILnIII(dpm)4(MeO)2(MeOH)2] is reported (where Ln = LaIII (1), PrIII (2), and EuIII(3)). These compounds were obtained from a one-pot reaction between 2,2,6,6-tetramethyl-3,5-heptanodione (Hdpm), MnII, and the respective LnIII salt in the presence of sodium methoxide. The derivative containing the diamagnetic ion LaIII has been synthesized in order to characterize the local anisotropy of the MnIII ion. High-field electron paramagnetic resonance (HFEPR) spectroscopy shows that the MnIII ion, with an elongated octahedral geometry in all compounds, has a significant axial zero field splitting and a small rhombic anisotropy. Additionally, the HFEPR measurements indicate that there is almost no exchange between the spin carriers in these compounds, all of which exhibit field-induced slow relaxation of the magnetization. PMID- 29256607 TI - Catalytic Defluoroalkylation of Trifluoromethylaromatics with Unactivated Alkenes. AB - We describe a new catalytic approach to selective functionalization of the strong C-F bonds in trifluoromethylaromatic (Ar-CF3) systems. In this approach, single electron reduction of Ar-CF3 substrates (using a photoredox catalyst) results in difluorobenzylic radical formation through a C-F cleavage mechanism. These radicals undergo efficient intermolecular coupling with simple alkenes in a defluoroalkylation process where radical termination is accomplished by a polarity reversal catalyst. This mild catalytic protocol engages a wide range of substrates to give medicinally relevant fluorinated substructures with complete regiocontrol. PMID- 29256608 TI - Reactive Intermediates Involved in Cobalt Corrole Catalyzed Water Oxidation (and Oxygen Reduction). AB - A detailed investigation of the cobalt corrole Co(tpfc) as molecular catalyst for electrochemical water oxidation uncovered many important mechanism-of-action details that are crucial for the design of optimally performing systems. This includes the identification of the redox states that do and do not participate in catalysis and very significant axial ligand effects on the activity of the doubly oxidized complex. Specifics deduced for the electrocatalysis under homogeneous conditions include the following: the one-electron oxidation of the cobalt(III) corrole is completely unaffected by reaction conditions; catalysis coincides with the second oxidation event; two catalytic waves develop in the presence of OH-, and the one at lower overpotential is dominant under more basic conditions. Comparative spectroelectrochemical measurements performed for Co(tpfc) and Al(tpfc), the analogous corrole chelated by the nonredox active aluminum, revealed that the second oxidation process of Co(tpfc) is much more significantly metal-centered than the first one. EPR studies revealed that shift from fully corrole-centered to partially metal-centered in the singly oxidized complex [Co(tpfc)]+ is achievable with fluoride as axial ligand. The analogous experiment, but with hydroxide instead of fluoride, could not be performed because of a surprising phenomenon: formation of a cobalt-superoxide complex that is actually relevant to oxygen reduction rather than to water oxidation. Nevertheless, fluoride and hydroxide induce very similar effects in terms of the appearance of two catalytic waves, lowering of onset potentials, and increasing the catalytic activity. The main conclusions from the accumulated data are that the apparent pH effect is actually due to hydroxide binding to the cobalt center and that pi-donating axial ligands play pivotal and beneficial roles regarding the main factors that are important for facilitating the oxidation of water. PMID- 29256606 TI - Phase Transitioning the Centrosome into a Microtubule Nucleator. AB - Centrosomes are self-assembling, micron-scale, nonmembrane bound organelles that nucleate microtubules (MTs) and organize the microtubule cytoskeleton of the cell. They orchestrate critical cellular processes such as ciliary-based motility, vesicle trafficking, and cell division. Much is known about the role of the centrosome in these contexts, but we have a less comprehensive understanding of how the centrosome assembles and generates microtubules. Studies over the past 10 years have fundamentally shifted our view of these processes. Subdiffraction imaging has probed the amorphous haze of material surrounding the core of the centrosome revealing a complex, hierarchically organized structure whose composition and size changes profoundly during the transition from interphase to mitosis. New biophysical insights into protein phase transitions, where a diffuse protein spontaneously separates into a locally concentrated, nonmembrane bounded compartment, have provided a fresh perspective into how the centrosome might rapidly condense from diffuse cytoplasmic components. In this Perspective, we focus on recent findings that identify several centrosomal proteins that undergo phase transitions. We discuss how to reconcile these results with the current model of the underlying organization of proteins in the centrosome. Furthermore, we reflect on how these findings impact our understanding of how the centrosome undergoes self-assembly and promotes MT nucleation. PMID- 29256609 TI - Structural Origin of Shear Viscosity of Liquid Water. AB - The relation between the microscopic structure and shear viscosity of liquid water was analyzed by calculating the cross-correlation between the shear stress and the two-body density using the molecular dynamics simulation. The slow viscoelastic relaxation that dominates the steady-state shear viscosity was ascribed to the destruction of the hydrogen-bonding network structure along the compression axis of the shear distortion, which resembles the structural change under isotropic hydrostatic compression. It means that the shear viscosity of liquid water reflects the anisotropic destruction-formation dynamics of the hydrogen-bonding network. PMID- 29256610 TI - Origin of Plasmon Lineshape and Enhanced Hot Electron Generation in Metal Nanoparticles. AB - Plasmon-generated hot carriers are currently being studied intensively for their role in enhancing the efficiency of photovoltaic and photocatalytic processes. Theoretical studies of the hot electrons subsystem have generated insight, but we show that a unified quantum-mechanical treatment of the plasmon and hot electrons reveals new physical phenomena. Instead of a unidirectional energy transfer process in Landau damping, back energy transfer is predicted in small metal nanoparticles (MNPs) within a model-Hamiltonian approach. As a result, the single Lorentzian plasmonic line shape is modulated by a multipeak structure, whose individual line width provides a direct way to probe the electronic dephasing. More importantly, the hot electron generation can be enhanced greatly by matching the incident energy to the peaks of the modulated line shape. PMID- 29256611 TI - Nitrogen-Iodine Exchange of Diaryliodonium Salts: Access to Acridine and Carbazole. AB - A nitrogen-iodine exchange protocol of diaryliodonium salts with sodium azide salt is developed for general construction of significant functional acridines and carbazoles, in which introduction of nitrogen at a late stage was successfully established avoiding heteroatom incompatibility. Inorganic sodium azide served as the sole nitrogen atom source in this transformation. The diversiform functional acridines and carbazoles were comprehensively achieved through annulated diaryliodonium salts, respectively. Notably, Acridine orange (a fluorescent indicator for cell lysosomal dye) and Carprofen (a nonsteroidal anti inflammatory drug) were efficiently established through this protocol. PMID- 29256612 TI - Intersubband Quantum Disc-in-Nanowire Photodetectors with Normal-Incidence Response in the Long-Wavelength Infrared. AB - Semiconductor nanowires have great potential for realizing broadband photodetectors monolithically integrated with silicon. However, the spectral range of such detectors has so far been limited to selected regions in the ultraviolet, visible, and near-infrared regions. Here, we report on the first intersubband nanowire heterostructure array photodetectors exhibiting a spectrally resolved photoresponse from the visible to long-wavelength infrared. In particular, the infrared response from 3 to 20 MUm is enabled by intersubband transitions in low-bandgap InAsP quantum discs synthesized axially within InP nanowires. The intriguing optical characteristics, including unexpected sensitivity to normal incident radiation, are explained by excitation of the longitudinal component of optical modes in the photonic crystal formed by the nanostructured portion of the detectors. Our results provide a generalizable insight into how broadband nanowire photodetectors may be designed and how engineered nanowire heterostructures open up new, fascinating opportunities for optoelectronics. PMID- 29256613 TI - Weakly Coordinating, Ketone-Directed Cp*Co(III)-Catalyzed C-H Allylation on Arenes and Indoles. AB - Weakly coordinating, ketone-directed, regioselective monoallylation of arenes and indoles is reported using a stable and cost-effective high-valent cobalt(III) catalyst to access several important molecular building blocks. The allylation proceeds smoothly with a variety of substrates in the presence of various electron-rich and -deficient substituents. The method was applied to the formal synthesis of an ancisheynine alkaloid, a highly conjugated azatetracene, and isochroman. The mechanistic study reveals that the allylation reaction follows a base-assisted intermolecular electrophilic substitution pathway. PMID- 29256614 TI - Reaction Mechanism of Organocatalytic Michael Addition of Nitromethane to Cinnamaldehyde: A Case Study on Catalyst Regeneration and Solvent Effects. AB - The Michael addition of nitromethane to cinnamaldehyde has been computationally studied in the absence of a catalyst and the presence of a biotinylated secondary amine by a combined computational and experimental approach. The calculations were performed at the density functional theory (DFT) level with the M06-2X hybrid functional, and a polarizable continuum model has been employed to mimic the effect of two different solvents: dichloromethane (DCM) and water. Contrary to common assumption, the product-derived iminium intermediate was absent in both of the solvents tested. Instead, hydrating the C1-C2 double bond in the enamine intermediate directly yields the tetrahedral intermediate, which is key for forming the product and regenerating the catalyst. Enamine hydration is concerted and found to be rate-limiting in DCM but segregated into two non-rate-limiting steps when the solvent is replaced with water. However, further analysis revealed that the use of water as solvent also raises the energy barriers for other chemical steps, particularly the critical step of C-C bond formation between the iminium intermediate and nucleophile; this consequently lowers both the reaction yield and enantioselectivity of this LUMO-lowering reaction, as experimentally detected. These findings provide a logical explanation to why water often enhances organocatalysis when used as an additive but hampers the reaction progress when employed as a solvent. PMID- 29256615 TI - Development of a One-Pot Four C-C Bond-Forming Sequence Based on Palladium/Ruthenium Tandem Catalysis. AB - A one-pot four C-C bond-forming sequence has been developed using two distinct transition metal complexes. The sequence entails a double Pd-catalyzed allylic alkylation followed by a Ru-catalyzed ring-closing metathesis and a Pd-catalyzed Heck coupling. The use of various active methylene nucleophiles was examined with yields up to 76% (93% per C-C bond). PMID- 29256616 TI - Photoswitchable Heparinase III for Enzymatic Preparation of Low Molecular Weight Heparin. AB - A photocontrollable biocatalyst was rationally designed by site-specifically linking a photoswitchable azobenzene derivative to the only cysteine residue in heparinase III mutant (K130C). Upon photoswitch, the enzymatic degradation of heparin could be artificially controlled to produce low molecular weight heparin with more uniform molecular weight and an increase in anticoagulant activity. PMID- 29256617 TI - Integrated Experimental and Modeling Study of Enzymatic Degradation Using Novel Autofluorescent BSA Microspheres. AB - Autofluorescent bovine serum albumin (BSA) hydrogel microspheres were prepared through the spray-drying of glutaraldehyde cross-linked BSA nanoparticles and then used for a proteinase K based degradation study in an aqueous solution. Experimental results and empirical models are presented to characterize the kinetics of BSA hydrogel microsphere degradation, as well as the accompanying release of synthesized fluorophore. The BSA gel degradation dynamics is primarily controlled by the concentration of proteinase K within the Tris buffer. The coupling of swelling dynamics and the transient distributions of fluorophore are traced by confocal microscopy. Models are developed based on the linear theory of elastic deformation coupled to enzyme and fluorophore transport. This study represents a fundamental investigation of the degradation and release kinetics of protein-based materials, which can potentially be applied for the dynamic and photostable tracking of relevant in vivo systems. PMID- 29256618 TI - Designing Efficient Solar-Thermal Fuels with [n.n](9,10)Anthracene Cyclophanes: A Theoretical Perspective. AB - Molecular solar thermal storage (MOST) systems have been largely limited to three classes of molecular motifs: azo-benzene, norbornadiene, and transition metal based fulvalene-tetracarbonyl systems. Photodimerization of anthracene has been known for a century; however, this photoprocess has not been successfully exploited for MOST purposes due to its poor energy storage. Using well-calibrated theoretical methods on a series of [n.n](9,10)bis-anthracene cyclophanes, we have exposed that they can store solar energy into chemical bonds and can release in the form of heat energy on demand under mild conditions. The storage is mainly attributed to the strain in the rings formed by the alkyl linkers upon photoexcitation. Our results demonstrate that the gravimetric energy storage density for longer alkyl-chain linkers (n > 3) are comparable to those for the best-known candidates; however, it lacks some of the deleterious attributes of known systems, thus making the proposed molecules desirable targets for MOST applications. PMID- 29256619 TI - Biexciton Auger Recombination Differs in Hybrid and Inorganic Halide Perovskite Quantum Dots. AB - We use time-resolved photoluminescence measurements to determine the biexciton Auger recombination rate in both hybrid organic-inorganic and fully inorganic halide perovskite nanocrystals as a function of nanocrystal volume. We find that the volume scaling of the biexciton Auger rate in the hybrid perovskites, containing a polar organic A-site cation, is significantly shallower than in the fully inorganic Cs-based nanocrystals. As the nanocrystals become smaller, the Auger rate in the hybrid nanocrystals increases even less than expected, compared to the fully inorganic nanocrystals, which already show a shallower volume dependence than other material systems such as chalcogenide quantum dots. This finding suggests there may be differences in the strength of Coulombic interactions between the fully inorganic and hybrid perovskites, which may prove to be crucial in selecting materials to obtain the highest performing devices in the future, and hints that there could be something "special" about the hybrid materials. PMID- 29256620 TI - Direct Measurement of the Differential Capacitance of Solvent-Free and Dilute Ionic Liquids. AB - Differential capacitance is a key quantity in the understanding of electrical double-layer charging of electrolytes. However, experimental observations of ionic liquid systems are controversial, inconsistent, and often unable of confirming or refuting existing theories as well as highlighting discrepancies between the measurement techniques. We study the differential capacitance in both pure and dilute ionic liquids at room temperature. Using chronoamperometry to measure the differential capacitance of the liquids at a polycrystalline platinum electrode, we find good agreement between the measured capacitance curves and the extended mean-field model of Goodwin-Kornyshev [Goodwin, Z. A.; et al. Electrochim. Acta. 2017, 225, 190-197]. A crossover is found from the pure to the dilute regime, as shown by a transition from a camel-shape capacitance curve to a U-like one, together with a nonmonotonic dependence of capacitance with electrolyte concentration. PMID- 29256621 TI - Rapid Syntheses of Heteroaryl-Substituted Imidazo[1,5-a]indole and Pyrrolo[1,2 c]imidazole via Aerobic C2-H Functionalizations. AB - Here we report an aerobic Pd(0) catalyzed C2-H functionalization of indoles and pyrroles with tethered N-methoxylamide as the directing group. A Pd(0)-initiated mechanism overcomes the directing or poisoning effect from a wide range of heterocycles including pyridine, pyrimidine, and thiazole. The imidazo[1,5 a]indole products are transformed to bioactive analogs after one-step manipulations, demonstrating the potential utility of this reaction in drug discovery. PMID- 29256622 TI - Total Synthesis of Tunicamycin V. AB - The total synthesis of tunicamycin V is described. This strategy is based on the initial construction of tunicaminyluracil, which is regarded to play an important role in the observed biological activities. The key to the synthesis was a Mukaiyama aldol reaction followed by a furan-oxidation to construct the undecose skeleton, a [3,3] sigmatropic rearrangement of a cyanate, and a highly selective trehalose-type glycosylation. PMID- 29256623 TI - Identification of Drug Candidates to Suppress Cigarette Smoke-induced Inflammation via Connectivity Map Analyses. AB - Cigarette smoking is the main risk factor for chronic obstructive pulmonary disease, and to date, existing pharmacologic interventions have been ineffective at controlling inflammatory processes associated with the disease. To address this issue, we used the Connectivity Map (cMap) database to identify drug candidates with the potential to attenuate cigarette smoke-induced inflammation. We queried cMap using three independent in-house cohorts of healthy nonsmokers and smokers. Potential drug candidates were validated against four publicly available human datasets, as well as six independent datasets from cigarette smoke-exposed mice. Overall, these analyses yielded two potential drug candidates: kaempferol and bethanechol. Subsequently, the efficacy of each drug was validated in vivo in a model of cigarette smoke-induced inflammation. BALB/c mice were exposed to room air or cigarette smoke and treated with each of the two candidate drugs either prophylactically or therapeutically. We found that kaempferol, but not bethanechol, was able to reduce cigarette smoke-induced neutrophilia, both when administered prophylactically and when administered therapeutically. Mechanistically, kaempferol decreased expression of IL-1alpha and CXCL5 concentrations in the lung. Our data suggest that cMap analyses may serve as a useful tool to identify novel drug candidates against cigarette smoke induced inflammation. PMID- 29256625 TI - The Low-Risk Profile in Pulmonary Arterial Hypertension. Time for a Paradigm Shift to Goal-oriented Clinical Trial Endpoints? PMID- 29256624 TI - Ivacaftor-treated Patients with Cystic Fibrosis Derive Long-Term Benefit Despite No Short-Term Clinical Improvement. PMID- 29256626 TI - Effects of Tai Chi-based cardiac rehabilitation on aerobic endurance, psychosocial well-being, and cardiovascular risk reduction among patients with coronary heart disease: A systematic review and meta-analysis. AB - INTRODUCTION: Tai Chi is an attractive exercise to improve cardiovascular health. This review aimed to synthesize articles written both in Chinese and in English to evaluate the effects of Tai Chi-based cardiac rehabilitation on aerobic endurance, psychosocial well-being and cardiovascular diseases risk reduction for coronary heart diseases patients. METHODS: PRISMA guidelines were used to search major health databases to identify randomized controlled trials or non-randomized controlled clinical trials that evaluated Tai Chi intervention compared with active or non-active control groups in coronary heart disease patients. When suitable, data were pooled using a random-effects meta-analysis model. RESULTS: Thirteen studies met the inclusion criteria. Tai Chi groups showed a large and significant improvement in aerobic endurance compared with both active and non active control interventions (standard mean difference (SMD) 1.12; 95% confidence interval (CI): 0.58-1.66; p <0.001). Tai Chi groups also showed a significantly lower level of anxiety (SMD=9.28; CI: 17.46-1.10; p=0.03) and depression (SMD=9.42; CI: 13.59-5.26; p <0.001), and significantly better quality of life (SMD=0.73; 95% CI: 0.39-1.08; p <0.001) compared with non-active control groups. CONCLUSION: Significant effects of Tai Chi have been found in improving aerobic endurance and psychosocial well-being among coronary heart disease patients. Tai Chi could be a cost-effective and safe exercise option in cardiac rehabilitation. However, the effect of Tai Chi on cardiovascular disease risk reduction has not been amply investigated among coronary heart disease patients. Caution is also warranted in view of a small number of studies for this meta-analysis and potential heterogeneity in differences in the varied designs of Tai Chi intervention. PMID- 29256627 TI - The Bolton Treo endograft for treatment of abdominal aortic aneurysms: just another trimodular platform? AB - INTRODUCTION: The Treo abdominal aortic stent graft system (Bolton Medical, Barcelona, Spain) is a trimodular endovascular endoprosthesis recently introduced for the endovascular repair of abdominal aortic aneurysms (AAA). It presents some unique structural characteristics such as the combination of suprarenal and infrarenal fixation, variability of the main-body length, lock-stent mechanism in the iliac limbs to enhance their stability. Areas covered: This article discusses the technical features and clinical performance of Treo as well as the interesting hemodynamic consequences of its design. Expert commentary: The Treo aortic stent-graft provides accurate deployment, secure proximal seal and fixation as well as efficient conformability in angulated necks. Early results drawn from single-center studies are promising with acceptable technical and clinical success. Moreover, the custom-made solution provided with the Treo platform is one of the most intriguing challenges in current endovascular era and is expected to broaden significantly the armamentarium of endovascular specialists. PMID- 29256628 TI - Physical activity and CVD in older adults: an expert's perspective. AB - INTRODUCTION: The benefits of physical activity have long been recognized as powerful preventive opportunities for both prevention of cardiovascular disease and aging-related morbidity. However, physical activity remains under-prescribed and under-utilized. Areas covered: In this narrative review, the authors focus on physical activity as a modifiable lifestyle factor that can modify aging processes as well as cardiovascular pathophysiology that is often exacerbated by aging. Specific recommendations are provided for physical activity over the range of typical older individuals, spanning from those who are sedentary and frail to those who are active and robust. Expert commentary: Physical activity is a critically underused preventive strategy that can prevent cardiovascular disease and mitigate some of the physiological changes that occur with aging. Identifying activities that are accessible and enjoyable, while considering issues of safety, are key to developing an individualized exercise prescription for all older adults. PMID- 29256629 TI - Worldwide Use of Antiretropulsive Techniques: Observations from the Clinical Research Office of the Endourological Society Ureteroscopy Global Study. AB - INTRODUCTION: Retropulsion, defined as unintended migration of a stone under the influence of the fragmentation device in ureteroscopy (URS) procedures, occurs in 2% to 60% of the cases. Antiretropulsive devices (ARDs) have been studied in experimental and small clinical studies. The current study aims at describing the worldwide usage of ARD and the outcomes related to their usage. METHODS: The Clinical Research Office of the Endourological Society URS Global Study enrolled 11,885 patients who underwent URS and stone fragmentation for ureteral and/or renal stones. Of the 11,885 treated patients, 9877 were treated for ureteral stones, and data were available on stone migration and ARD use. RESULTS: Of all procedures, 14.5% were performed with the use of an ARD. Less stone migration ( 2.0%; p = 0.050), higher stone-free rates (SFRs) (2.8%; p < 0.001), and shorter length of stay (-4.7%; p = 0.001) were observed in the antiretropulsive group. CONCLUSIONS: When an ARD is used during URS, less migration, higher SFRs, and shorter length of hospital stay are observed. This effect is independent from baseline differences and corrected for other treatment characteristics. PMID- 29256630 TI - Pharmacological repositioning of Achyranthes aspera as an antidepressant using pharmacoinformatic tools PASS and PharmaExpert: a case study with wet lab validation. AB - Traditional knowledge guides the use of plants for restricted therapeutic indications, but their pharmacological actions may be found beyond their ethnic therapeutic indications employing emerging computational tools. In this context, the present study was envisaged to explore the novel pharmacological effect of Achyranthes aspera (A. aspera) using PASS and PharmaExpert software tools. Based on the predicted mechanisms of the antidepressant effect for all analysed phytoconstituents of A. aspera, one may suggest its significant antidepressant action. The possible mechanism of this novel pharmacological effect is the enhancement of serotonin release, in particular caused by hexatriacontane. Therefore, pharmacological validation of the methanolic extract, hexatriacontane rich (HRF) and hexatriacontane lacking fraction (HLF) of A. aspera was carried out using the Forced Swimming Test and Tail suspension test in mice. The cortical and hippocampal monoamine and their metabolite levels were measured using high performance liquid chromatography (HPLC). A. aspera methanolic extract, HRF treatments showed a significant antidepressant effect comparable to imipramine. Further, the corresponding surge in cortical and hippocampal monoamine and their metabolite levels was also observed with these treatments. In conclusion, A. aspera has shown a significant antidepressant effect, possibly due to hexatriacontane, by raising monoamine levels. PMID- 29256631 TI - "I've Had Bad Experiences With Team Sport": Sport Participation, Peer Need Thwarting, and Need-Supporting Behaviors Among Youth Identifying With Physical Disability. AB - This study was guided by self-determination theory to explore the sport experiences of youth with a physical disability and the role of peers within this context. Interviews were conducted with eight youths using a relational mapping technique and analyzed using a deductive thematic approach. Sport peers were broadly defined by the youth as individuals from a large age range and of all abilities. Youth perceived their sport peers to have dynamic roles throughout their participation in sport. The perceived roles of these sport peers included supporting and thwarting basic psychological needs, and influencing the youths' processing of sport internalization. Findings focus on the complexity of peer need-thwarting and need-supporting interactions in sport for youth with physical disabilities. Overall, peers have a multifaceted role in the sport experiences of youth identifying with a physical disability and may, in some cases, thwart youths' basic psychological needs. PMID- 29256632 TI - Comparative Study of Video Endoscopic Inguinal Lymphadenectomy Through a Hypogastric vs Leg Subcutaneous Approach for Penile Cancer. AB - OBJECTIVE: To compare the efficacy and safety of video endoscopic inguinal lymphadenectomy through a hypogastric subcutaneous approach (VEIL-H) with a leg subcutaneous approach (VEIL-L) in the surgical management of penile cancer. MATERIALS AND METHODS: Between October 2012 and October 2016, 72 penile cancer patients who underwent VEIL-H (n = 37) or VEIL-L (n = 35) by one experienced surgeon in our hospital were retrospectively included. Data associated with demographic characteristics and perioperative outcomes were evaluated and compared between two groups. RESULTS: No intraoperative complications occurred and no deaths were recorded. No difference was noted with respect to demographic and clinicopathological data, operative time, estimated blood loss, spare of the great saphenous vein, dissected inguinal lymph nodes, patients with inguinal lymph node metastasis, positive inguinal lymph nodes, duration of drain, postoperative hospital days, and postoperative complications between two groups (p > 0.05). Two patients of each group received a bilateral laparoscopic pelvic lymphadenectomy in one session. The pathological results of all dissected pelvic lymph nodes were negative. Median follow-up was 16.2 months, during which time three patients in VEIL-L group and two patients in VEIL-H group developed regional or distant metastases. CONCLUSIONS: Hypogastric approach is as effective and safe as VEIL-L for penile cancer. Moreover, VEIL-H can avoid the operation on both the limb and abdomen if laparoscopic pelvic lymphadenectomy is required. PMID- 29256633 TI - The development of stimuli-responsive polymeric micelles for effective delivery of chemotherapeutic agents. AB - Stimuli-responsive polymeric micelles, a novel category of polymeric micelles with response to endogenous or exogenous environments, show variable physicochemical properties as the variation of endogenous or exogenous circumstances. Because of differences between tumour tissues and normal tissues in physicochemical properties and sensitivity to variation of endogenous or exogenous environments, the application of chemotherapeutic agents loaded stimuli responsive polymeric micelles are regarded as promising strategies for tumour treatment. In this article, the recent developments of chemotherapeutic agents loaded stimuli-responsive polymeric micelles, for example the preparation of novel stimuli-responsive polymeric micelles and the research progresses of action mechanisms of chemotherapeutic agents loaded micelles, were reviewed and discussed in detail. The advantages of stimuli-responsive chemotherapeutic agents loaded polymeric micelles in practical tumour treatment were also illustrated with the assistance of examples of stimuli-responsive polymeric micelles for antitumor agents delivery. PMID- 29256634 TI - Neuromuscular Responses and Physiological Changes During Small-Sided Games in Wheelchair Basketball. AB - The aim was to analyze the changes of physical performance and physiological responses during a high-intensity training task in wheelchair basketball (WB) players. Thirteen Spanish first division WB male players participated in this study. A test battery (change of direction ability, sprints, and sled towing) was performed to study neuromuscular responses before (pre) and after (post) the small-sided games (SSG). Furthermore, tympanic temperature and blood lactate concentration were measured before and immediately after players finished the SSG. The SSG tasks consisted in four players against four, 4 bouts of 4 min with 2 min of recovery periods. There was a 1.10% decline in performance in both 5- and 20-m sprints (p < .01; effect size [ES] <= 0.14), 1.82% decline in 5-m sled towing (p < .05; ES = 0.18), and 2.68% decline in 20-m sled towing (p < .01; ES = 0.27) between pre- and post-SSG. As in physical performance results, significant differences were observed between pre and post in physiological markers, with increasing tympanic temperature (36.21 +/- 0.60 degrees C to 36.97 +/- 0.59 degrees C; p < .001; ES = 1.27) and blood lactate concentrations (1.95 +/- 1.30 mmol/L to 5.84 +/- 2.04 mmol/L; p < .001; ES = 2.99) after SSG. The SSG produced a decrease in sprint and sled towing performance after 16 min of intense exercise. Moreover, the decrease in physical performance was accompanied with an increase in physiological responses. These neuromuscular responses could be similar in the real game; thus, coaching staff could benefit from this information when changing bench players. PMID- 29256635 TI - Trends in clinical outcomes and survival following prehospital thrombolytic therapy given by ambulance clinicians for ST-elevation myocardial infarction in rural sub-arctic Norway. AB - BACKGROUND: Prehospital thrombolytic therapy given by ambulance emergency medical services to patients with acute ST-segment elevation myocardial infarction (STEMI) may produce earlier reperfusion than percutaneous coronary intervention. Clinical results from prehospital thrombolytic therapy in rural areas are scarce. METHODS: We studied outcomes during 11 years of a prehospital thrombolytic therapy system in rural sub-arctic Norway. Ambulance personnel gave protocol basic treatment and transmitted electrocardiograms to hospital physicians who made the decision for prehospital thrombolytic therapy. The study was divided into three time periods; 2000-2003, 2004-2007 and 2008-2011. RESULTS: A total of 385 STEMI patients received prehospital thrombolytic therapy, median patient age was 61.2 years, and 77% were men. Time saved by prehospital reperfusion therapy was 131 minutes. The proportion who got prehospital thrombolytic therapy within 2 hours of symptom onset increased from 21% in 2000-2003 to 39% in 2008-2011 ( P=0.003). The proportion who underwent coronary angiography or percutaneous coronary intervention within 24 hours of first medical contact increased from 56.4% to 95.4% ( P<0.001). Post-STEMI systolic heart failure decreased from 19.4% to 8.1% ( P=0.02), while 1-year mortality fell, non-significantly, by 50% over time to reach 5.6%. Thirteen patients suffered acute out-of-hospital cardiac arrest; all were successfully defibrillated. Ten patients had major bleeding events (2.6%). CONCLUSION: A decentralised prehospital thrombolytic therapy system based on ambulance personnel, telemetry and centralised 7/24 invasive diagnosis and treatment service, combined with system maturation over time, was associated with earlier reperfusion, improved clinical outcomes and better survival. Prehospital thrombolytic therapy is a feasible and safe intervention used in rural settings with long evacuation lines to percutaneous coronary intervention facilities. PMID- 29256637 TI - Characterization of Campylobacter jejuni and Campylobacter coli Broiler Isolates by Whole-Genome Sequencing. AB - Campylobacter has been the most commonly reported cause of bacterial diarrheal disease in humans in the European Union since 2005. Most broiler batches at slaughter are colonized with Campylobacter, and the major source of infection is contaminated poultry meat. The aim of this study was to characterize a selection of Campylobacter jejuni and Campylobacter coli isolates from broilers through whole-genome sequencing (WGS). A total of 16 isolates (C. jejuni = 12 and C. coli = 4) from five broiler farms from Catalonia (northeastern Spain) were analyzed. A phylogenetic analysis based on 8420 single-nucleotide polymorphisms showed two main cluster grouping strains by species. Phenotypic resistances to quinolones (100%), tetracycline (81%), streptomycin (75%), erythromycin (56%), and gentamicin (13%) were found. All the isolates carried the C257T point mutation in the subunit A of the DNA gyrase gene (Thr86Ile) conferring resistance to quinolones, while all the isolates showing resistance to tetracycline carried the tet(O) gene. The genes aph(3')-III and aadE conferring resistance to aminoglycosides were identified in the two isolates (one C. jejuni and one C. coli) resistant to streptomycin and gentamicin. The point mutation A2075G on the 23S rDNA conferring high resistance to macrolides was detected in three C. coli isolates. The CmeABC multidrug efflux pump was also detected, both in C. jejuni and C. coli isolates. All C. jejuni and C. coli isolates were positive for most of the 34 virulence-associated genes studied related to motility, chemotaxis, adhesion, and invasion. Interestingly, the wlaN gene involved in the Guillain Barre syndrome was found in two isolates. The results underline the power of WGS for investigation of virulence, clonality, and antimicrobial resistance in Campylobacter. PMID- 29256638 TI - Mitochondria, the NLRP3 Inflammasome, and Sirtuins in Type 2 Diabetes: New Therapeutic Targets. AB - SIGNIFICANCE: Type 2 diabetes mellitus and hyperglycemia can lead to the development of comorbidities such as atherosclerosis and microvascular/macrovascular complications. Both type 2 diabetes and its complications are related to mitochondrial dysfunction and oxidative stress. Type 2 diabetes is also a chronic inflammatory condition that leads to inflammasome activation and the release of proinflammatory mediators, including interleukins (ILs) IL-1beta and IL-18. Moreover, sirtuins are energetic sensors that respond to metabolic load, which highlights their relevance in metabolic diseases, such as type 2 diabetes. Recent Advances: Over the past decade, great progress has been made in clarifying the signaling events regulated by mitochondria, inflammasomes, and sirtuins. Nod-like receptor family pyrin domain containing 3 (NLRP3) is the best characterized inflammasome, and the generation of oxidant species seems to be critical for its activation. NLRP3 inflammasome activation and altered sirtuin levels have been observed in type 2 diabetes. Critical Issue: Despite increasing evidence of the relationship between the NLRP3 inflammasome, mitochondrial dysfunction, and oxidative stress and of their participation in type 2 diabetes physiopathology, therapeutic strategies to combat type 2 diabetes that target NLRP3 inflammasome and sirtuins are yet to be consolidated. FUTURE DIRECTIONS: In this review article, we attempt to provide an overview of the existing literature concerning the crosstalk between mitochondrial impairment and the inflammasome, with particular attention to cellular and mitochondrial redox metabolism and the potential role of the NLRP3 inflammasome and sirtuins in the pathogenesis of type 2 diabetes. In addition, we discuss potential targets for therapeutic intervention based on these molecular interactions. Antioxid. Redox Signal. 29, 749-791. PMID- 29256636 TI - Pluripotency transcription factors and Metabolic reprogramming of mitochondria in tumor-initiating stem-like cells. AB - SIGNIFICANCE: Neoplasms contain tumor-initiating stem-like cells (TICs) that drive malignant progression and tumor growth with drug resistance. TICs proliferate through self-renewal process in which the two daughter cells differ in their proliferative potential, with one retaining self-renewing phenotype and another displaying the differentiated phenotype. Recent advances: Cancer traits (hepatocellular carcinoma: HCC) are triggered by alcoholism, obesity and hepatitis B or C virus (HBV and HCV), including genetic changes, angiogenesis, defective tumor immunity, immortalization, metabolic reprogramming, excessive & prolonged inflammation, migration/invasion/metastasis, evasion of cell cycle arrest, anti-cell death and compensatory regeneration/proliferation. CRITICAL ISSUES: This review describes how metabolic reprogramming in mitochondria promotes self-renewal and oncogenicity of TICs. Pluripotency transcription factors NANOG, OCT4, MYC and SOX2 contribute to cancer progression by mitochondrial reprogramming leading to the genesis of TICs and cancer. For example, oxidative phosphorylation (OXPHOS) and fatty acid metabolism are identified as major pathways contributing to pluripotency transcription factor mediated oncogenesis. FUTURE DIRECTIONS: Identification of novel metabolic pathways provides potential drug targets for neutralizing the activity of highly malignant TICs found in cancer patients. PMID- 29256639 TI - MRI Displays the Prostatic Cancer Anatomy and Improves the Bundles Management Before Robot-Assisted Radical Prostatectomy. AB - OBJECTIVES: To evaluate the impact of multiparametric magnetic0 resonance imaging (mpMRI) to guide the nerve-sparing (NS) surgical plan in prostate cancer (PCa) patients referred to robot-assisted radical prostatectomy (RARP). METHODS: One hundred thirty-seven consecutive PCa patients were submitted to RARP between September 2016 and February 2017 at two high-volume European centers. Before RARP, each patient was referred to 1.5T or 3T mpMRI. NS was recorded as Grade 1, Grade 2, Grade 3, and Grade 4 according to Tewari and colleagues classification. A preliminary surgical plan to determinate the extent of NS approach was recorded based on clinical data. The final surgical plan was reassessed after mpMRI revision. The appropriateness of surgical plan change was considered based on the presence of extracapsular extension or positive surgical margins (PSMs) at level of neurovascular bundles area at final pathology. Furthermore, we analyzed a control group during the same period of 166 PCa patients referred to RARP in both institutions without preoperative mpMRI to assess the impact of the use of mpMRI on the surgical margins. RESULTS: Considering 137 patients with preoperative mpMRI, the mpMRI revision induced the main surgeon to change the NS surgical plan in 46.7% of cases on patient-based and 56.2% on side-based analysis. The surgical plan change results equally assigned between the direction of more radical and less radical approach both on patient-based (54.7% vs 54.3%) and on side-based levels (50% vs 50%), resulting an overall appropriateness of 75%. Moreover, patients staged with mpMRI revealed significant lower overall PSMs compared with control group with no mpMRI (12.4% vs 24.1%; p <= 0.01). CONCLUSIONS: mpMRI induces robotic surgeons to change the surgical plan in almost half of individuals, thus tailoring the NS approach, without compromising the oncologic outcomes. Compared to patients treated without mpMRI, the use of preoperative mpMRI can significantly reduce the overall PSMs. PMID- 29256640 TI - Satisfaction and perceptions of long-term manual wheelchair users with a spinal cord injury upon completion of a locomotor training program with an overground robotic exoskeleton. AB - AIM: The main objectives of this study were to quantify clients' satisfaction and perception upon completion of a locomotor training program with an overground robotic exoskeleton. METHODS: A group of 14 wheelchair users with a spinal cord injury, who finished a 6-8-week locomotor training program with the robotic exoskeleton (18 training sessions), were invited to complete a web-based electronic questionnaire. This questionnaire encompassed 41 statements organized around seven key domains: overall satisfaction related to the training program, satisfaction related to the overground robotic exoskeleton, satisfaction related to the program attributes, perceived learnability, perceived health benefits and risks and perceived motivation to engage in physical activity. Each statement was rated using a visual analogue scale ranging from "0 = totally disagree" to "100 = completely agree". RESULTS: Overall, respondents unanimously considered themselves satisfied with the locomotor training program with the robotic exoskeleton (95.7 +/- 0.7%) and provided positive feedback about the robotic exoskeleton itself (82.3 +/- 6.9%), the attributes of the locomotor training program (84.5 +/- 6.9%) and their ability to learn to perform sit-stand transfers and walk with the robotic exoskeleton (79.6 +/- 17%). Respondents perceived some health benefits (67.9 +/- 16.7%) and have reported no fear of developing secondary complications or of potential risk for themselves linked to the use of the robotic exoskeleton (16.7 +/- 8.2%). At the end of the program, respondents felt motivated to engage in a regular physical activity program (91.3 +/- 0.1%). CONCLUSION: This study provides new insights on satisfaction and perceptions of wheelchair users while also confirming the relevance to continue to improve such technologies, and informing the development of future clinical trials. Implications for Rehabilitation All long-term manual wheelchair users with a spinal cord injury who participated in the study are unanimously satisfied upon completion of a 6-8-week locomotor training program with the robotic exoskeleton and would recommend the program to their peers. All long-term manual wheelchair users with a spinal cord injury who participated in the study offered positive feedback about the robotic exoskeleton itself and feel it is easy to learn to perform sit-stand transfers and walk with the robotic exoskeleton. All long-term manual wheelchair users with a spinal cord injury who participated in the study predominantly perceived improvements in their overall health status, upper limb strength and endurance as well as in their sleep and psychological well-being upon completion of a 6-8-week locomotor training program with the robotic exoskeleton. All long-term manual wheelchair users with a spinal cord injury who participated in the study unanimously felt motivated to engage in a regular physical activity program adapted to their condition and most of them do plan to continue to participate in moderate-to-strenuous physical exercise. Additional research on clients' perspectives, especially satisfaction with the overground exoskeleton and locomotor training program attributes, is needed. PMID- 29256641 TI - Timothy Ray Brown's Continuing Activism Toward Curing HIV. PMID- 29256642 TI - Acoustic reflexes are common but not pervasive: evidence using a diagnostic middle ear analyser. AB - OBJECTIVE: The objective of this study is to determine whether acoustic reflexes are pervasive (i.e. known with 95% confidence to be observed in at least 95% of people) by examining the frequency of occurrence using a friction-fit diagnostic middle ear analyser. DESIGN: Adult participants with very good hearing sensitivity underwent audiometric and middle ear testing. Acoustic reflexes were tested ipsilaterally and contralaterally in both ears across a range of elicitor frequencies. Reflex elicitors were 700 ms tones presented at maximum level of 100 dB HL. Two automated methods were used to detect the presence of an acoustic reflex. STUDY SAMPLE: A group of 285 adult volunteers with normal hearing. RESULTS: There were no conditions in which the proportion of participants exhibiting acoustic reflexes was high enough to be deemed pervasive. Ipsilateral reflexes were more likely to be observed than contralateral reflexes and reflexes were more common at 0.5 and 1 kHz elicitor frequencies as compared with 2 and 4 kHz elicitor frequencies. CONCLUSIONS: Acoustic reflexes are common among individuals with good hearing. However, acoustic reflexes are not pervasive and should not be included in damage risk criteria and health hazard assessments for impulsive noise. PMID- 29256643 TI - The effects of single and combined application of ramipril and losartan on renal structure and function in hypertensive rats. AB - The objective of the present study was to investigate the effects of single and combined administration of ramipril and losartan on renal structure and function in spontaneously hypertensive rats (SHRs). Thirty-two 9-week-old SHRs and eight Wistar-Kyoto (WKY) rats were randomly divided into five groups: the WKY control group, the SHR control group, the SHR-ramipril group, the SHR-losartan group, and the SHR-combined mediation group. The rat body weight, SBP, heart rate, and urinary albumin excretion rate (UAER) were measured. (1) The SBP was reduced to the normal level in all groups of rats except for the SHR control group. Combined administration of ramipril and losartan can be reduced to the normal level earlier than single (P < 0.01). (2) The SHR-ramipril group and the SHR-losartan group still experienced a higher UAER than that in the WKY control group (P < 0.01). (3) The renal mass/BW ratio was decreased in the SHR-ramipril group, SHR losartan group, and SHR-combined medication group compared to that in the SHR control group (P < 0.01). (4) Compared with the SHR control group, the SHR ramipril group, the SHR-losartan group, and the SHR-combined medication group had a lower percentage of the IOD of glomerular collagen relative to the glomerular area (P < 0.01). (5) The reduction in tubulointerstitial injury score was more significant in the SHR-combined medication group than in the SHR-ramipril group and the SHR-losartan group (P < 0.01). The combination of ramipril and losartan is superior to either single drug in reducing the UAER, resisting glomerular collagen deposition, and protecting renal tubular structure. PMID- 29256644 TI - Improving mental health through social support: building positive and empowering relationships. PMID- 29256645 TI - Sports Sciences Research: Olympic Opportunity. AB - Today's sports scientists must accept the responsibilities to athletes and coaches that come with new research opportunities. Communication and cooperation should be as important as results. PMID- 29256647 TI - action arena. PMID- 29256649 TI - Compression Splint For Temporary Knee Immobilization. PMID- 29256648 TI - scanning sports. PMID- 29256651 TI - The Freak Injury. PMID- 29256652 TI - Alcohol and Athletes-A Round Table for CME Credit. AB - Society's acceptance of alcohol complicates the problems of athletes and coaches. The panel discusses the social as well as the physiological implications of alcohol use and abuse. PMID- 29256650 TI - Ever the Pothunter. PMID- 29256653 TI - Protective Equipment for Baseball. AB - Little League experience shows that injuries can be reduced by eliminating steel spikes and the on-deck circle, screening dugouts, using face protectors for batters, and using breakaway bases if sliding is permitted. PMID- 29256654 TI - Hand, Wrist, and Forearm Injuries in Baseball. AB - Almost all phases of baseball can injure the hands-throwing, catching, sliding into the bases, running into another player or the outfield fence. Hand injuries must have expert treatment to avoid long-term disability. PMID- 29256655 TI - Physiological Profiles of Elite Rowers. AB - Unlike distance runners, who set an aerobic pace, elite rowers quickly achieve extremely high energy expenditures, and therefore high lactate levels, which they must tolerate throughout the race. PMID- 29256656 TI - Science and Sport. PMID- 29256657 TI - Circadian Rhythms and Athletic Performance. AB - Travel across time zones can have an adverse effect on athletes' performances. It helps to know how to resynchronize the 'body clock.' PMID- 29256658 TI - letters. PMID- 29256659 TI - New Fitness for Police and Fire Fighters. AB - Police and firemen have dangerous jobs, but now department chiefs are finding that fitness programs reduce injuries and sick time, improve performance in emergencies, and fight the hidden killer-coronary heart disease. PMID- 29256660 TI - brief reports. PMID- 29256661 TI - Femoral Stress Fracture. PMID- 29256662 TI - a need to know. PMID- 29256664 TI - A Needless Risk for Mr. Carter. PMID- 29256663 TI - Heart Disease in Marathon Runners. AB - Most physicians agree that endurance exercise benefits the heart, but they vigorously debate the particulars: Does marathon running immunize people to heart disease? Or is it just one of many risk factors? PMID- 29256665 TI - Orthopedic Problems in Middle-Aged Athletes. AB - Middle-aged athletes are just like other athletes-they don't want to stop participating when they are injured. This article describes some special problems and solutions for this group. PMID- 29256666 TI - An Industry Health Management Program. AB - An employee fitness program helped reduce some coronary risk factors, but this is only one measure of success. The author says that long-term changes in diet and exercise habits are the real challenge. PMID- 29256667 TI - The Insulin-Dependent Diabetic Runner. AB - Dr. Berg explains how the insulin-dependent diabetic runner can monitor blood sugar levels, insulin dosage, diet, and activity-and complete long-distance races. PMID- 29256668 TI - Intercollegiate Wrestling Injuries. AB - Time loss from participation is often used to define injury, but one physician uses different criteria in evaluating wrestlers. PMID- 29256669 TI - Fit to Work. PMID- 29256671 TI - letters. PMID- 29256670 TI - Physical Profile of the Wrestlers at the 1977 NCAA Championships. AB - Differences in physical characteristics affect athletic performance, but the author says there are other more far-reaching implications. PMID- 29256672 TI - Flexibility: Day of the Static Stretch. AB - Even with all the attention now given to stretching exercises, many experts say our athletes are too tight. Physicians can help by telling their patients both the why and how of flexibility exercises. PMID- 29256673 TI - brief reports. PMID- 29256676 TI - Thomas K. Cureton, Jr: Sportsmedicine Pioneer. AB - Thomas Kirk Cureton gave physical fitness a new meaning for everyone, and his career paralleled the growth of sportsmedicine and preventive medicine for 30 formative years. PMID- 29256677 TI - scanning sports. PMID- 29256679 TI - In Touch With Class. PMID- 29256678 TI - Ankle Rehabilitation with Cryotherapy. PMID- 29256680 TI - Racquetball Injuries. AB - It doesn't take a lot of skill to play racquetball and benefit from the excellent exercise it provides. Most of the injuries can be prevented if safety precautions are observed. PMID- 29256681 TI - Physical Fitness Profiles and Reproductive Physiology of the Female Distance Runner. AB - Stress, percentage of body fat, and circulating hormones all may influence menstrual dysfunction in female endurance athletes, but the mechanisms are not fully understood. PMID- 29256682 TI - Knee Injuries Due to Blocking: A Continuing Problem. AB - Legislation making hazardous football techniques illegal reduces certain injuries, but rule changesmust be evaluated after implementation to make sure that new techniques don't cause different injuries. PMID- 29256683 TI - letters. PMID- 29256684 TI - Mitral Valve Prolapse in a Professional Basketball Player. AB - The sequence of events in this case suggests that mitral valve prolapse may be an underlying cause of 'athlete's heart syndrome,' especially when it's accompanied by symptomatic arrhythmias. PMID- 29256685 TI - brief reports. PMID- 29256686 TI - Serum Lipid Levels in Male Runners. AB - It isn't necessary to run marathon distances to reduce serum lipids. According to this study, high- mileage runners and those who run 3 miles, three times per week reap the same benefits. PMID- 29256688 TI - Emergency on the Karakoram Massif. AB - Sept 15, 1978. Urdukas Camp, Baltoro Glacier, K2. Jim is dying-each night he gets worse-more painful coughing (pleurisy) and increasing hemoptysis, so that I am afraid to anticoagulate him-respirations rising alarmingly and he can travel only a few paces uphill without going into paroxysms of bloody coughing. PMID- 29256689 TI - Racquetball and the Calf Muscles. PMID- 29256690 TI - Annapurna: Women at the World's Top. AB - Preclimb conditioning programs made this year's all-woman assault on the world's tenth highest mountain, Annapurna, a sportsmedicine triumph, though marred by the tragedy of death. PMID- 29256691 TI - scanning sports. PMID- 29256692 TI - Women's Pro Basketball: Guts Without Glory. AB - Big money, glamour, and TV endorsements, that's what pro sports are made of except in the new Women's Basketball League, where the team physicians, trainers, and players are all in their first year. PMID- 29256693 TI - Pseudoanemia: Sign of Fitness, Not Fatigue. PMID- 29256695 TI - Mitral Valve Prolapse. PMID- 29256694 TI - action arena. PMID- 29256696 TI - Muscle Fuel for Competition. AB - An athlete who suddenly feels fatigued is probably experiencing glycogen depletion, which can be avoided through diet and training. Endurance athletes long-distance runners, swimmers, cross-country skiers-are most vulnerable. PMID- 29256698 TI - Erratum. PMID- 29256697 TI - The changing nature of work, leisure and involvement in society: some possible ideas from an old philosopher. PMID- 29256700 TI - Beware of Unbalanced Shoes. PMID- 29256701 TI - a need to know. PMID- 29256702 TI - brief reports. PMID- 29256703 TI - Beitostolen: Shangri-la for the Handicapped. AB - One of the first of its kind in the world, this Scandinavian health sports center puts the emphasis on what the clients can do. The goal is self-confidence, self respect, and a better adjustment to the world outside. PMID- 29256705 TI - FIMS: Time to Get Involved. PMID- 29256704 TI - letters. PMID- 29256706 TI - Endurance Training of Recreationally Active Men. AB - Tennis, golf, surfing, and skin diving don't build high cardiovascular fitness because the bursts of activity are too short. Regular participants in these activities adapted to a jogging program as though they were untrained. PMID- 29256707 TI - Olympic Weight-Lifting Injuries. AB - Because most Olympic weightlifting injuries are caused by inflexibility and improper technique, the well-trained lifter concentrates on improving these abilities. PMID- 29256708 TI - An Assessment of Compressive Neck Loads Under Injury-Producing Conditions. AB - Injury reference curves for axial compressive forces on the neck were derived from impact tests of a spring-loaded tackling block on football helmets. Results suggest that helmets, especially those with resilient liners, reduce these forces. PMID- 29256709 TI - Management of Hematoma of the Wrestler's Ear. AB - Hematoma of the auricle may produce ear deformity. The hallmarks of the surgical treatment are thorough evacuation with incisions through the skin and perichondrium, and subsequent compression of the auricle. PMID- 29256711 TI - Viral Infections of Athletes' Skin. PMID- 29256710 TI - Injuries in Preadolescent Wrestlers. AB - Is wrestling safe for children? Injury of an unfused epiphysis may worry some physicians, but muscle strains, ocular contusions, and laryngitic contusions are more common. PMID- 29256712 TI - Water: Runners' Magic Fluid. PMID- 29256714 TI - Wilderness Medicine-A Matter of Survival. AB - As Americans continue to take to the woods and hills for their leisure, books and courses from Foxfire to Outward Bound prepare them for the very real medical emergencies that can occur in the wild. PMID- 29256715 TI - Digital age and the Public eHealth perspective: Prevailing health app use among Austrian Internet users. AB - New technological developments affect almost every sector of our daily lives including the healthcare sector. Successful adoption and sustainable integration of eHealth and telemedicine in Public Health strategies (also known as Public eHealth) depend on knowledge and constant evaluation of consumers' needs, proficiencies, and preferences. We therefore assessed how the general Austrian population perceived innovative Public eHealth solutions. The online survey on 562 Austrian adults (58.9% females) collected self-reported data on current and expected use of smartphone-based health applications (apps) of digital natives (35 years and younger) and digital immigrants (aged 35+). In total, 26.7% (95% CI 23.0-30.4) of participants already used health apps, especially lifestyle associated apps for monitoring exercise habits and nutritional habits. We found substantial digital age group differences; compared to digital immigrants digital natives were more likely to use mobile devices and health apps. Health apps have the potential to improve community health and prevent lifestyle diseases cost effectively and efficiently, and thus build an important pillar of Public eHealth. With regard to aging societies, healthcare providers could take advantage of consumer-oriented health apps by assessing individual needs of specific target groups such as elderly people. PMID- 29256716 TI - PMab-48 Recognizes Dog Podoplanin of Lymphatic Endothelial Cells. AB - Podoplanin, a type I transmembrane glycoprotein, is a specific marker of lymphatic endothelial cells (LECs). Recently, we developed PMab-38, an anti-dog podoplanin monoclonal antibody that did not stain canine LECs. In this study, we newly developed PMab-48 against dog podoplanin. Immunohistochemical analysis revealed that PMab-48 reacts not only with canine squamous cell carcinoma cells but also with LECs of the normal colon. Therefore, PMab-48 may be useful in investigating the function of dog podoplanin in LECs. PMID- 29256717 TI - Endophthalmitis Progressing to Panophthalmitis: Clinical Features, Demographic Profile, and Factors Predicting Outcome. AB - PURPOSE: To describe clinical features, demographic profile and factors predicting outcome of endophthalmitis under care progressing to panophthalmitis at a tertiary eye institute. SETTING: Retrospective consecutive case series. METHODS: All cases diagnosed as endophthalmitis of any etiology and undergoing treatment which progressed to panophthalmitis from January 2005 to December 2015 were included. Case records of all patients coded as endophthalmitis and then panophthalmitis were included. Data were collected regarding the clinical features, demographic profile, and treatment outcomes of those cases. RESULTS: This study included 33 eyes of 33 patients. The mean age at presentation was 42.33 +/- 21.66 years (median 40, range 5-75). The commonest etiology of endophthalmitis progressing to panophthalmitis was noted following open globe injury endophthalmitis, seen in 13/33 (39.4%) of eyes followed by endophthalmitis associated with microbial keratitis seen in 8/33 (27.3%) eyes. The time interval in days between the diagnosis of endophthalmitis and progression to panophthalmitis was 4.5 +/- 3.88 days (median 3 days, range 1-14 days). Fifteen eyes denied perception of light (PL) at the time of diagnosing panophthalmitis. Culture was positive in 16 cases (48.4%), Streptococcus pneumoniae was the commonest species (4 cases) followed by Pseudomonas aeruginosa (3 cases) and Staphylococcus epidermidis (2 cases). Nine cases (27.27%) were additionally given systemic steroids along with the systemic antibiotics. The odds ratio of a favorable outcome was significantly higher when systemic steroids with antibiotics were administered (OR = 80.5, 95% C.I. 6.311026, p = 0.007), when the patient was of a younger age group (< 40 years) (OR 1.53, 95% C.I. 0.37.87, p = 0.6), when the presenting vision at diagnosis was at least light perception (OR 9.8, 95% C.I. 1.03692.7, p = 0.04), when the smear showed Gram-positive cocci (OR 6.66, 95% C.I. 1.0940.43, p = 0.03), if there was culture positivity (OR 10.5, 95% C.I. 1.1198.9, p = 0.03) and when intravenous antibiotics were administered (OR 21.43, 95% C.I. 1.11411.7, p = 0.04). CONCLUSIONS: Risk of progression of endophthalmitis to panophthalmitis is there even under care. Close observation and keen clinical examination for cases that do not respond well is essential. Intravenous antibiotics and systemic steroids should be considered in all cases of endophthalmitis that progress to panophthalmitis. PMID- 29256719 TI - Case Report: Depressed Skull Fracture in an Ice Hockey Player Wearing a Helmet. PMID- 29256720 TI - brief reports. PMID- 29256718 TI - Applications of Drug Anesthesia in Control Chronic Pain. AB - Surgery is one of the major causes of chronic pain in patients that have undergone any kind of surgeries. These complain are not only associated with major surgeries; even common minor surgeries like hernia repair have a significant risk of chronic pain. The development of chronic postsurgical pain (CPSP) depends on the type of surgical technique used. Furthermore, changes in the central nervous system have been associated with the development of persistent and chronic pain after surgical trauma and nerve injury. Anesthesia agents that block the mechanisms stimulating the process of central sensitization may be efficient in reducing the incidence of CPSP and finally psychosocial factors have been reported to be an important factor in the progression of chronic pain and as such should be addressed as part of perioperative care. The purpose of this mini-review is to give a comprehensive summary of the application of anesthesia drugs to reduce or control chronic pain during or after surgery. PMID- 29256721 TI - Nutritional Practices of Coaches in the Big Ten. AB - Many coaches in Big Ten schools still burden their athletes with a protein-rich precompetition meal. This survey indicates that coaches need-and want-more and better information about nutrition. PMID- 29256722 TI - a need to know. PMID- 29256724 TI - scanning sports. PMID- 29256723 TI - Figure Skating: In Search of the Winning Edge. AB - Figure skating's basic conservatism in training programs is changing to meet the challenge of Eastern European Olympic dominance with new off-ice conditioning and weight-lifting regimens. PMID- 29256725 TI - Rugby Medicine: No More Magic Sponge. AB - The English gave the world rugby, but an American physician is showing the English-and the rest of the rugby world-sportsmedicine designed for this game of ardent amateurs. PMID- 29256727 TI - On Stress, Mental Health, and Religion. PMID- 29256728 TI - Mouth Protection in Sports. PMID- 29256729 TI - Snow Sports: Down the Tube. AB - Schuss, slam, snap! Snow tubing is a youngster's delight and an orthopedic surgeon's nightmare-no helmets, no padding, and no control. PMID- 29256730 TI - Meat and Potatoes. PMID- 29256732 TI - Trends in Ice Hockey Injuries: 1965 to 1977. AB - More effective ice hockey equipment could reduce lower body injuries caused by collisions; better coaching and refereeing could reduce upper body injuries, usually caused when players break the rules. PMID- 29256731 TI - Negative Addiction in Runners. AB - A hard-core exercise addict 'can't live' without daily running, manifests withdrawal symptoms if deprived of exercise, and runs even when his physician says he shouldn't. PMID- 29256733 TI - Incidence of Facial Trauma in Intercollegiate and Junior Hockey. AB - Protective facial masks reduced facial injuries in hockey players who were required to wear them. This author recommends that they be mandatory at all levels of play. PMID- 29256734 TI - The Ice Hockey Helmet: How Effective Is It? AB - Thicker liners, fewer openings, and more protection over the temporal area in newer models of ice hockey helmets have made them more effective in reducing the potential for serious head injury. PMID- 29256735 TI - letters. PMID- 29256736 TI - Navigating the system: Physiotherapy student perceptions of performance-based assessment. AB - BACKGROUND: Performance-based assessment (PBA) is an integral component of health professional education as it determines students' readiness for independent practice. Stakeholder input can provide valuable insight regarding its challenges, facilitators, and impact on student learning, which may further its evolution. Currently, evidence of stakeholder opinion is limited. Thus, we aimed to explore physiotherapy students' perceptions of performance-based assessment in their capacity as its central stakeholders. METHODS: A qualitative interpretive constructivist approach was employed using focus group interviews for data collection. Six focus groups were completed (n = 33). Inductive thematic analysis was used to explore the data. RESULTS: Two themes were identified. The first outlined perceived inconsistencies within the process, and how these impacted on student learning. The second described how students used their experiential knowledge to identify strategies to manage these challenges thus identifying key areas for improvement. CONCLUSION: Inconsistencies outlined within the current physiotherapy performance-based assessment process encourage an emphasis on grades rather than on learning. It is timely that the physiotherapy academic and clinical communities consider these findings alongside evidence from other health professions to improve assessment procedures and assure public confidence and patient safety. PMID- 29256737 TI - Mitochondrial DNA deletions in tissues of mice after ionizing radiation exposure. AB - PURPOSE: The objective of the study was to estimate the presence of large mtDNA deletions in brain and spleen tissues of mice four months after exposure to 2 and 5 Gy. MATERIALS AND METHODS: The male BALB/c mice underwent X-ray total-body acute radiation. Four months after irradiation, the mice were decapitated, and the samples of spleen and brain tissues were examined. A long-distance PCR was used to detect mtDNA deletions and their levels in samples of brain and spleen tissues. RESULTS: Four months after irradiation the levels of mtDNA deletions in the brain and spleen tissues were higher in animals exposed to 5 Gy than in animals at an irradiation dose of 2 Gy and in control mice. The levels of deletions in the mice brain tissues were higher 4 months than 1 month after X-ray exposure to both doses (2 and 5 Gy). In spleen tissues, a higher level of deletions was observed only at an irradiation dose of 5 Gy. CONCLUSIONS: Our data have shown that ionizing radiation induces an increase of mtDNA copies with deletions in tissues of mice four months after the post-irradiation period. The level of deletions depends on the animal age, type of tissue, irradiation dose and length of the post-irradiation period. PMID- 29256739 TI - Erratum. PMID- 29256738 TI - Retinal Layers Measurements following Silicone Oil Tamponade for Retinal Detachment Surgery. AB - This study aimed to investigate the influence of silicone oil on the retinal nerve fiber layer (RNFL) thickness in patients with primary rhegmatogenous retinal detachment who underwent vitreoretinal surgery. The study included 47 patients (eyes), who underwent a pars plana vitrectomy with the silicone oil tamponade. The control group included unoperated eye of all participants. Spectral-domain optical coherence tomography (SD-OCT) was used for the measurements of peripapilar and macular RNFL thickness. The average peripapillary RNFL thickness was significantly higher in the silicone oil filled eyes during endotamponade and after its removal. The eyes with elevated IOP had less thickening of the RNFL in comparison to the eyes with normal IOP. Central macular thickness and macular volume were decreased in the silicone oil filled eyes in comparison to the control eyes. In conclusion, silicone oil caused peripapilar RNFL thickening in the vitrectomized eyes during endotamponade and after silicone oil removal. PMID- 29256741 TI - Functional Characterization of TvCyt2, a Member of the p450 Monooxygenases From Trichoderma virens Relevant During the Association With Plants and Mycoparasitism. AB - Secondary metabolites are crucial for the establishment of interactions between plants and microbes, as in the case of Trichoderma-plant interactions. In the biosynthetic pathway of secondary metabolites, specific enzymes participate in the formation of hydroxyl and epoxy groups, belonging to the p450 monooxygenases family. Here, we show that the product of the gene TvCyt2 from Trichoderma virens encodes a new protein homologous to the cytochrome p450, which is down-regulated at the beginning of Trichoderma-Arabidopsis interaction. To investigate its role in the interactions established by Trichoderma spp., we analyzed the metabolic profile obtained from the overexpressing (OETvCyt2) and null mutant (Deltatvcyt2) strains, observing that the OETvCyt2 strains produce a higher concentration of some metabolites than the wild-type (WT) strain. Deltatvcyt2 strains showed a decreased antagonistic activity against Rhizoctonia solani in antibiosis assays. Arabidopsis plants cocultivated with the OETvCyt2 strains showed stronger induction of systemic acquired resistance than plants cocultivated with the WT strain, as well as increases in biomass and fitness. Our data suggest that the product of the TvCyt2 gene is involved in secondary metabolite biosynthesis, which can increase antagonistic activity with phytopathogenic fungi and the capacity to promote plant growth. PMID- 29256742 TI - Erratum. PMID- 29256743 TI - Candidate prognostic indicators in cats with histoplasmosis treated with antifungal therapy. AB - Objectives The aim of this study was to retrospectively identify candidate prognostic indicators in cats with histoplasmosis treated with antifungal therapy. Methods Medical records of cats diagnosed with histoplasmosis were reviewed. Candidate prognostic indicators were assessed for an association with survival to hospital discharge and survival to 1 and 6 months after diagnosis. Potential indicators included easily obtained data at the time of the initial hospital visit derived from cat signalment, historical information, physical examination, laboratory data, form of disease and initial treatment. Results Approximately 88% of cats survived to discharge, with 77% and 67% surviving to 1 and 6 months, respectively. Clinical variables significantly associated with death at more than one outcome time point included the presence of dyspnea, adventitial lung sounds, fungemia, neurologic disease, neutropenia, lymphopenia, multiple cytopenias (anemia, neutropenia, thrombocytopenia), hyperbilirubinemia and increased creatinine kinase activity. Cats that did not survive were more likely to have received corticosteroids, oxygen supplementation and required hospitalization. In addition, cats that did not survive required significantly longer hospitalization. There was no significant difference between initial antifungal drug and survival. Conclusions and relevance Potential prognostic indicators were associated with more severe respiratory, hepatic, hematologic or neurologic disease. Prospective investigation concerning clinical indicators of disease severity of these body systems is indicated. PMID- 29256744 TI - A New Perspective on Coronary Heart Disease. AB - A former world-class athlete found that exercise did not protect him from coronary artery disease, and he speculates about the reasons. PMID- 29256745 TI - Cardiovascular Response to the Karate Kata. AB - The karate kata develops speed, agility, and strength. The authors studied heart rates during training to see if it develops cardiovascular fitness as well. PMID- 29256746 TI - Principles and Problems of Underwater Diving. AB - When things go wrong under water, minor problems can quickly become major ones. This review of the physics and physiology of diving will help physicians treat their patients who dive. PMID- 29256747 TI - Women on Annapurna. AB - Physiological tests and individualized r training programs helped prepare these women to become the first US team to climb Annapurna, 26,545 ft. PMID- 29256748 TI - Index Metacarpal Fractures in Karate. AB - Improperly executed karate thrusts result in an unusually high incidence of this uncommon injury. PMID- 29256749 TI - A Call to Action. PMID- 29256750 TI - Injuries in Interscholastic Wrestling. AB - Many of the offensive and defensive leg maneuvers which are taught as an integral part of the interscholastic wrestling style lead to a unique situation for injury to the lower extremities. PMID- 29256751 TI - letters. PMID- 29256753 TI - scanning sports. PMID- 29256752 TI - Insect Allergy and the Sportsman. AB - Many outdoor athletes are allergic to insect stings. Dr. Frazier gives practical tips on how to minimize the odds of being stung and what to do if stung. PMID- 29256754 TI - Men's and Women's Injuries in Comparable Sports. AB - The author studied men's and women's sports injury patterns in basketball, baseball/softball, and gymnastics. She found more similarities than differences. PMID- 29256755 TI - a need to know. PMID- 29256757 TI - Responses of Recreational Runners to Their Injuries. AB - Running injuries differ in nature and etiology from other athletic injuries. Most occur from overuse, not trauma, and runners often continue running while injured. PMID- 29256760 TI - Preparing for the Perfect Life. PMID- 29256759 TI - The New Physical Education: Cooperation on the Move. AB - Alternative approaches to physical education that emphasize self-image and decision-making are showing that winning isn't everything. PMID- 29256762 TI - editorial. PMID- 29256761 TI - Anabolic Steroids and Athletes. PMID- 29256763 TI - The Use of the Anchor System Reduces Postural Sway During Upright Standing Irrespective of Plantar Flexors Muscle Fatigue in Young and Older Adults. AB - Our purpose was to verify the effects of the use of the anchors on postural control after the fatigue of the plantar flexor muscles in young and older adults. They stood barefoot, with their eyes closed in four conditions combining the use of the anchors and the fatigue. When using the anchors, participants held one cable in each hand and kept the cable taut without removing the loads (125 g) from the ground. The fatigue protocol consisted of performing a single series of bilateral plantar flexion movements. The fatigue protocol increased postural sway in both groups. Both groups reduced postural sway with the anchors, but this effect was independent of fatigue. We conclude that the anchors contributed to the reduction of postural sway in young and older adults, but they were unable to compensate for the disturbing effect in postural control created by fatigue of the plantar flexor muscles. PMID- 29256764 TI - Normalizing fibromyalgia as a chronic illness. AB - Fibromyalgia (FM) is a complex chronic disease that affects 3-10% of the general adult population and is principally characterized by widespread pain, and is often associated with disrupted sleep, fatigue, and comorbidities, among other symptoms. There are many gaps in our knowledge of FM, such that, compared with other chronic illnesses including diabetes, rheumatoid arthritis, and asthma, it is far behind in terms of provider understanding and therapeutic approaches. The experience that healthcare professionals (HCPs) historically gained in developing approaches to manage and treat patients with these chronic illnesses may help show how they can address similar problems in patients with FM. In this review, we examine some of the issues around the management and treatment of FM, and discuss how HCPs can implement appropriate strategies for the benefit of patients with FM. These issues include understanding that FM is a legitimate condition, the benefits of prompt diagnosis, use of non-drug and pharmacotherapies, patient and HCP education, watchful waiting, and assessing patients by FM domain so as not to focus exclusively on one symptom to the detriment of others. Developing successful approaches is of particular importance for HCPs in the primary care setting who are in the ideal position to provide long-term care for patients with FM. In this way, FM may be normalized as a chronic illness to the benefit of both patients and HCPs. PMID- 29256765 TI - Design, characterisation and evaluation of a soft robotic sock device on healthy subjects for assisted ankle rehabilitation. AB - Motor impairment is one of the common neurological conditions suffered by stroke patients, where this chronic immobility together with the absence of early limb mobilisation can lead to conditions such as joint contracture with spastic limbs. In this study, a soft robotic sock device was developed, which can provide compliant actuation to the ankle joint in the early stage of stroke recovery. The device is fitted with soft extension actuators and when the actuators are inflated, they extend and guide the foot into plantarflexion; upon deflation, the actuators will resume their initial conformations. Each actuator is linked to a pneumatic pump-valve control system that injects pressurised air into or release air from the system. In this study, the design and characterisation of the soft actuators will be presented, where the theoretical and experimental forces generated by the actuators were compared. The performance of the device was also evaluated on healthy subjects and the results had shown that the device was able to move the subjects' ankles into cycles of dorsiflexion-plantarflexion, in the absence of voluntary muscle effort. The findings suggested that the soft wearable robotic device was capable of assisting the subjects in performing repeated cycles of ankle flexion. PMID- 29256766 TI - Impact of Different Visual Field Instruction Strategies on Reliability Indices. AB - PURPOSE: To investigate and compare the visual field performance following three different types of visual field instruction strategies. METHOD: Ninety consecutive visual field-naive glaucoma patients who can perform the test and understand instructions were imparted three forms of instructions prior to the visual field test. Patients with visual acuity <20/200, central corneal opacities, or anterior segment pathology and patients unable to understand general instructions/uncooperative were excluded. All forms of instructions were given by a trained optometrist in the patients' own language as an instruction leaflet read out in 5 min for a verbal group (group1) and by a 5 min video created in house (group 2). Group 3 patients were shown the video first, followed by verbal instructions. We evaluated the reliability parameters in each group after visual field testing by an independent optometrist blinded to the form of instruction given. RESULTS: Among the three groups, group 3 patients had the least number of repeat tests. Eyes with MD<-12Db had better reliability than that of the other groups. Mixed-model linear regression analysis shows that the duration of the test was significantly influenced by the severity of glaucoma in group 1, which is further predisposed by false negatives (FN; beta = 0.06, p < 0.0001, R2 61.7%). CONCLUSION: The video with verbal instruction can minimize the number of repeated tests compared with only verbal or only video instruction medium. The video as well as the combined video/verbal instructions have a practical influence of obtaining more reliable fields compared with only verbal instruction. PMID- 29256767 TI - Lumbar Spine Injuries in Military Parachute Jumpers. AB - Jumpers with lumbar spine injuries caused by bad landings had a high incidence of chip or slice fractures, but degenerative disk disease was unrelated to jumping injuries. PMID- 29256768 TI - Roller Skating: Flying on Wheels. AB - The new roller skates, jazzed up with urethane wheels, are flipping the disco 'rexers' and weekend thrill seekers into the emergency room-but it's too much fun to stop. PMID- 29256769 TI - scanning sports. PMID- 29256770 TI - Anatomy of a Meeting. AB - Sportsmedicine meetings have proliferated in recent years, paralleling public interest in the field. But whether the right information reaches the right audiences remains debatable. PMID- 29256773 TI - If I Only Knew the Date. PMID- 29256774 TI - A Hit in the Head. PMID- 29256775 TI - Exercise and the Cardiovascular System. AB - Whether regular endurance exercise will increase life span has not been conclusively proved, but as one panelist says, 'If you want to take a gamble, it's a good one.' PMID- 29256776 TI - Dietary Iron Supplementation In Women Athletes. AB - Although iron is one of the most commonly used nutritional supplements, this study concluded that iron supplementation did not alter the iron status of the women athletes studied. PMID- 29256777 TI - letters. PMID- 29256779 TI - New Faces and a New Department. PMID- 29256778 TI - Children's Sports Injuries: Are They Avoidable? AB - In this study of 51 children's sports injuries, 21 injuries occurred in a nonorganized setting and 32 were deemed avoidable. Preventive measures are discussed. PMID- 29256780 TI - Injuries in Youth League Football. AB - Although younger football players have less risk of injury, the injury rate is higher in youth leagues than previously reported, and emergency medical care is often nonexistent. PMID- 29256781 TI - brief reports. PMID- 29256782 TI - Case Report: Rotary Subluxation of the First Cervical Vertebra. AB - Because a rotary subluxation of C-1 is rare in football, the injured player's modified cervical collar was held suspect until studies showed that it did not cause the injury. PMID- 29256783 TI - a need to know. PMID- 29256784 TI - Return to Sports Participation. AB - Although a quick return to participation a is desirable, the physician must recognize potentially serious injuries. And even when athletes are ready for competition, their rehabilitation must be monitored. PMID- 29256785 TI - Fitness, Aerobic Points, and Coronary Risk. AB - The aerobic point system is a convenient way to prescribe endurance exercise, but is not valid in predicting a person's level of fitness. The authors prefer direct peak oxygen uptake analysis. PMID- 29256786 TI - The Generalist as Team Physician. AB - A college team physician treats problems ranging from tendon ruptures to influenza. With proper backup from specialists, a generalist is well qualified for the job. PMID- 29256787 TI - Aerobic Dance: A Step to Fitness. AB - If jogging and biking don't appeal to your patients, recommend 45 minutes of the Suzy Q, the hoedown jump, or the sunshine jog to boost their VO2 max. PMID- 29256788 TI - scanning sports. PMID- 29256789 TI - letters. PMID- 29256790 TI - Total Injury Rehabilitation. PMID- 29256791 TI - brief reports. PMID- 29256792 TI - a need to know. PMID- 29256793 TI - The Game Never Ends. PMID- 29256794 TI - Whither the Sports Physical Examination? PMID- 29256795 TI - Chondromalacia Patellae. AB - Chondromalacia patellae can occur when structure or activity disrupts the delicate balance between the quadriceps and the patella. Dr. Levine discusses etiology, diagnosis, and treatment. PMID- 29256796 TI - Rehabilitation of Injured Soccer Players. AB - Treatment of soccer injuries revolves around preventing pain, edema, and reinjury, and rehabilitation is aimed at restoring the players' high levels of physical fitness. PMID- 29256798 TI - Injuries in a Women's Varsity Athletic Program. AB - Injury rates are rising as more and more women participate in sports. Better conditioning programs offer a means of prevention. PMID- 29256797 TI - Erratum. PMID- 29256799 TI - letters. PMID- 29256800 TI - Cardiac Evaluation for Participation in Sports. AB - A cardiac abnormality does not always restrict a young athlete's participation in sports. Comprehensive evaluations of heart murmurs, blood pressure, and arrhythmias are necessary. PMID- 29256801 TI - editor's notes. PMID- 29256802 TI - Sudden Death and Jogging. AB - Meticulous necropsy studies might help unravel the puzzle of deaths in seemingly healthy individuals; exercise stress testing is a useful screening device. PMID- 29256803 TI - Anabolic Steroids: The Myth Dies Hard. PMID- 29256804 TI - The 'Variant Normal' Electrocardiogram of the Professional Football Player. AB - The ECGs of highly trained athletes reveal variants that may incorrectly be called abnormal. PMID- 29256805 TI - Ice Skating Therapy. AB - Ice skating is a simple, effective means of providing therapy for a wide range of physical and mental disabilities. PMID- 29256806 TI - Sport and Recreation for the Handicapped. PMID- 29256807 TI - Get Out of the Hammock and Relax. PMID- 29256808 TI - Anabolic-Androgenic Steroids in Sports. PMID- 29256809 TI - scanning sports. PMID- 29256810 TI - Olympic Games, Beggars, and a Boy Named Brad. PMID- 29256811 TI - a need to know. PMID- 29256812 TI - Nonvenereal Sexually Transmitted Disease in Athletes. AB - Nonvenereal diseases can be transmitted by sexual contact, close living conditions, exchange of clothing, or just plain horseplay, and they can sideline an athlete just as effectively as an injury. PMID- 29256813 TI - brief reports. PMID- 29256815 TI - action arena. PMID- 29256816 TI - Corporate Health: A Result of Employee Fitness. AB - Employees and management alike reap the benefits of industry fitness programs: increased productivity, reduced medical costs-and better health. PMID- 29256817 TI - Assessing the effectiveness of integrating ergonomics and sustainability: a case study of a Mexican maquiladora. AB - In 2015, the United Nations defined sustainable industrialization as one of 17 sustainable development goals. In this article, an analysis is performed to assess the opportunities for ergonomics to contribute toward sustainability in the manufacturing industry. To that effect, a case study was carried out in a maquiladora of electronic components in the northwestern region of Mexico. The investigation was developed in four stages: (a) diagnosis; (b) planning; (c) implementations; (d) verification of results. Barriers found during each stage are presented. Finally, a discussion of the obtained results is provided, and areas of opportunity for programs or actions to prevent health risks are identified. PMID- 29256818 TI - Motor Function in Former Professional Football Players with History of Multiple Concussions. AB - The objective of this study was to assess the incidence of motor impairment in former professional Canadian Football League (ex-CFL) players with multiple concussions. We investigated motor symptoms and signs in 45 ex-CFL players with multiple concussions and 25 age- and education-matched healthy controls with no history of concussion. Neurological assessment included items from the SCAT3 (Sport Concussion Assessment Tool 3) and the Unified Parkinson's Disease Rating Scale part III (UPDRS-Part III). A performance-based measurement of manual motor function was undertaken using the Grooved Pegboard test. Cognition was measured with patient-reported outcomes for memory, executive and behavioral symptoms as well as performance-based measures of memory and executive function. Symptoms of anxiety and depression were measured using the Personality Assessment Inventory. There was no significant difference between the ex-CFL players and controls on the UPDRS-Part III scores, and neither group reported clinically significant motor complaints. Ex-CFL players did not perform differently from control subjects on the Grooved Pegboard test. In contrast, with regard to cognitive and mood testing, players were more symptomatic: The ex-CFL players reported significantly more memory (77.8% vs. 16%, respectively, p < 0.001), executive (53.3% vs. 8%, respectively, p < 0.001), and behavioral symptoms (66.7% vs. 20%, respectively, p < 0.001). No significant differences were found when comparing ex CFL players and controls in performance on memory and executive tests. In summary, in a group of retired CFL players who self-reported declines in memory, executive and behavioral symptoms, no motor symptoms were reported and no motor signs were detected. PMID- 29256820 TI - Validation of a Novel Clinical Score: The Rostock Functional and Cosmetic Cranioplasty Score. AB - With a rising number of cranioplasty (CP) procedures and an increasing percentage of patients with a good clinical outcome and prolonged survival after CP, looking at the functional and aesthetic outcome of these patients becomes more and more important. The aim of our study was to evaluate a novel score, combining functional and cosmetics aspects after CP, created at our institution: the Rostock Functional and Cosmetic Cranioplasty (RFCC-) Score. A total of 27 patients were enrolled, representing all indications for a secondary CP after decompressive craniectomy or extended temporal trephination with a complete separation of the temporalis muscle. Besides the clinical evaluation, five different already established clinical rating systems were tested and compared with our score. For reasons of objectivity, the score was also tested against the patient's own rating. Our findings showed that the RFCC-Score, derived from a health professional, is superior to other scoring systems, which only display a facet of the functional state of the patient. Our score is objective and independent of a disposition for a depression of the patient. It can be obtained without the need of a verbal communication, making it applicable for nearly all patients after CP. The score is time-saving, clearly arranged, and reliable, which are inevitable requirements for the comparing and evaluation of different surgical techniques and associated complications of CP. PMID- 29256822 TI - The frequency of kissing as part of sexual activity differs depending on how men meet their male casual sexual partners. AB - Previous studies have shown that men who have sex with men (MSM) who use smartphone dating applications (apps) are at higher risk of gonorrhoea, but not HIV. We have hypothesised that kissing may be a risk factor for oropharyngeal gonorrhoea. We measured differences in kissing practices among MSM who use different methods to find male casual sexual partners (CSPs). If MSM who use apps kiss more CSPs, then this may help to explain why these men are at increased risk of gonorrhoea but not HIV. This was a cross-sectional questionnaire-based study of MSM attending Melbourne Sexual Health Centre, Australia, between March and September 2015. We measured differences in kissing practices among MSM who use different methods to find male casual sexual partners (CSPs). The questionnaire included questions about numbers of CSPs, numbers of CSPs kissed, and how men found CSPs. We surveyed 753 MSM with a median age of 29 years (interquartile range 25-36). Six hundred and one men (79.8%) reported using apps to find CSPs in the last three months. Users of apps had a higher number of CSPs than non-users (5.0 vs. 3.2; p < 0.001). Users of apps kissed a higher number (4.6 vs. 2.2; p < 0.001), and a higher proportion (90.4% vs. 71.0%; p < 0.001) of CSPs compared to non-users. We are currently investigating whether kissing is a significant mode of transmission of gonorrhoea, and if this proves correct then this study suggests that users of apps would particularly benefit from health promotion that addresses this mode of transmission. PMID- 29256819 TI - Lung Vascular Remodeling, Cardiac Hypertrophy, and Inflammatory Cytokines in SHIVnef-Infected Macaques. AB - Fatal pulmonary arterial hypertension (PAH) affects HIV-infected individuals at significantly higher frequencies. We previously showed plexiform-like lesions characterized by recanalized lumenal obliteration, intimal disruption, medial hypertrophy, and thrombosis consistent with PAH in rhesus macaques infected with chimeric SHIVnef but not with the parental SIVmac239, suggesting that Nef is implicated in the pathophysiology of HIV-PAH. However, the current literature on non-human primates as animal models for SIV(HIV)-associated pulmonary disease reports the ultimate pathogenic pulmonary outcomes of the research efforts; however, the variability and features in the actual disease progression remain poorly described, particularly when using different viral sources for infection. We analyzed lung histopathology, performed immunophenotyping of cells in plexogenic lesions pathognomonic of PAH, and measured cardiac hypertrophy biomarkers and cytokine expression in plasma and lung of juvenile SHIVnef infected macaques. Here, we report significant hematopathologies, changes in cardiac biomarkers consistent with ventricular hypertrophy, significantly increased levels of interleukin-12 and GM-CSF and significantly decreased sCD40 L, CCL-2, and CXCL-1 in plasma of the SHIVnef group. Pathway analysis of inflammatory gene expression predicted activation of NF-kappaB transcription factor RelB and inhibition of bone morphogenetic protein type-2 in the setting of SHIVnef infection. Our findings highlight the utility of SHIVnef-infected macaques as suitable models of HIV-associated pulmonary vascular remodeling as pathogenetic changes are concordant with features of idiopathic, familial, scleroderma, and HIV-PAH. PMID- 29256823 TI - A fast-growing cold skin abscess revealing disseminated Mycobacterium intracellulare infection in an HIV-infected patient. AB - A 66-year-old woman with HIV-1 infection recently commenced on antiretroviral therapy (CD4+ 25 cells/mm3 was referred to the Dermatology Clinic the following month due to a well-demarcated nodule in the extensor surface of the left arm with evident fluctuation but only slight pain on palpation, with no increase in temperature. Surgical drainage was performed with aspiration of yellowish-green exudate, with no characteristic smell. In culture of cutaneous exudate, Mycobacterium intracellulare was isolated. Upon careful review of the laboratory tests that were in progress at discharge, the same agent was isolated in one of the bronchoalveolar lavage cultures. The diagnosis of cutaneous abscess caused by M. intracellulare from hematogenous dissemination of lung infection was made. The patient was treated with clarithromycin, ethambutol and rifabutin for 24 months. M. intracellulare species and Mycobacterium avium constitute the Mycobacterium avium-intracellulare complex (MAC), responsible for the majority of human infections by atypical mycobacteria. They are ubiquitous bacteria and MAC infection mainly affect immunocompromised patients, with M. intracellulare being isolated in <5% of HIV patients with MAC infection. Cutaneous infection is rare and may present clinically with erythematous plaques, chronic ulcers or abscesses. When present, skin involvement is usually secondary to pulmonary infection. PMID- 29256826 TI - Evaluation of otoscopy simulation as a training tool for real-time remote otoscopy. AB - OBJECTIVE: Teleotoscopy requires the assistance of telehealth facilitators; but their training requirements remain to be determined. We evaluated the use of an otoscopy simulator to train facilitators to remote otoscopies sent via the Internet using a teleaudiology platform. DESIGN: Neurotologists experts were asked to identify images using the otoscopy simulator and to perform an identification task of significant anatomical landmarks. The experts were asked to repeat those tasks remotely, with the help of facilitators who either received basic training, or no training prior to the experiment. STUDY SAMPLE: Three experts, three trained facilitators and three untrained facilitators participated in this study. RESULTS: The use of an otoscopy simulator in addition to remote otoscopy yielded a good inter- and intrarater agreement (kappa between 0.81-1, and 0.80-0.87, respectively). The accuracy of diagnosis was high on-site (11.7% error) and remotely (0% error). The time required for landmark identification task was not increased when performed remotely with a trained facilitator versus on-site otoscopy (9.3 versus 9.2 s/landmark). Conversely, the lack of training of facilitators increased significantly this time (15.6 s/landmark, p < 0.001). CONCLUSION: An otoscopic simulator coupled to teleaudiology software can be used to efficiently train both experts and facilitators to perform remote otoscopy. PMID- 29256827 TI - Reassessment of Differentiated Thyroid Cancer Patients Using the Eighth TNM/AJCC Classification System: A Comparative Study. AB - BACKGROUND: Facing the prevailing concept that increased diagnosis with no change in mortality drives the increased incidence of differentiated thyroid cancer (DTC), considerable modifications have been introduced in the new edition of the tumor node metastasis (TNM)/American Joint Committee on Cancer (AJCC) staging system. The aim of this study was to compare a group of DTC patients before and after restaging, by mortality, disease severity, and disease outcomes. METHODS: DTC patients (N = 433) were restaged according to the eighth TNM/AJCC edition, and the results were compared to the seventh edition for clinicopathologic data, treatment modalities, and disease outcomes. RESULTS: When switched to the eighth edition, 97.5% of patients fell into stage I-II compared to 76.4% before, and only 11/102 patients remained in stages III-IV. Disease-specific mortality was recorded in 11/433 patients, six of whom were in stages I-II upon restaging, compared to none before (p > 0.05). In addition, more recurrences were seen in stages II (p = 0.05) and III (p = 0.03) using the eighth edition compared to the seventh edition. Stage II was affected the most, with recurrence risk increasing from 29% to 76% (p = 0.001) and persistence at last visit from 19% to 43% when switching to the eighth edition (p = 0.01). Considering stages I and II together, the recurrence risk increased from 16.7% to 28.2% (p = 0.01), lymph node metastases from 1.9% to 26.5% (p = 0.01), and persistence at last visit from 10% to 15% (p > 0.05). Of the 129 patients in the 45- to 54-year-old age group, 53 shifted to stage I (20 from stage II, 29 from stage III, and 4 from stage IV) and five shifted to stage II (all from stage IV). When comparing this age group in stage II only, the eighth edition showed more lymph node metastases (p = 0.001), more distant metastases (p = 0.003), higher recurrence risk (p = 0.002), and more persistence at the last visit (p > 0.05). CONCLUSION: The eighth TNM/AJCC edition provides a more accurate system to discriminate mortality and persistence in DTC patients. Yet, the severity of disease, especially in the 45- to 55-year-old age group and in stage II patients, should not be underestimated following the downstaging of these patients. PMID- 29256825 TI - Salvianolic Acid B Enhances Hepatic Differentiation of Human Embryonic Stem Cells Through Upregulation of WNT Pathway and Inhibition of Notch Pathway. AB - Hepatocytes differentiated from human embryonic stem cells (ESCs) could provide a powerful tool for enabling cell-based therapies, studying the mechanisms underlying human liver development and disease, and testing the efficacy and safety of pharmaceuticals. However, currently most in vitro protocols yield hepatocytes with low levels of liver function. In this study, we investigated the potential of Salvianolic acid B (Sal B), an active pharmaceutical compound present in Salvia miltiorrhiza, which has been shown to have an antifibrotic effect in previous studies, to enhance hepatocyte differentiation from human ESCs. After treatment with Sal B, albumin expression and secretion were consistently increased, indicating that Sal B could promote hepatocyte differentiation process. Expression of a large number of important phase 1 and 2 metabolizing enzymes and phase 3 transporters was also increased in treated cells, indicating an enhanced biotransformation function. Our investigations further revealed the activation of Wnt pathway in treated cells, as determined by upregulation of Wnts, which increased amounts of nuclear beta-catenin. This increased nuclear beta-catenin led in turn to the enhanced expression of T cell factor (TCF) 3 and lymphoid enhancer-binding factor (LEF) 1 which upregulated their downstream targets, cyclin D1 and c-Myc. Notch receptors (Notch1, Notch3), Notch ligand (Jagged2), and Notch receptor targets [hairy and enhancer of split (Hes) 1, 5] were downregulated in treated cells, suggesting that Notch pathway was inhibited. Consistent with the inhibition of Notch pathway, expression of cholangiocyte marker, CK7, was significantly reduced by treatment with Sal B. Numb, a direct transcriptional target of Wnt pathway and a negative regulator of Notch pathway, was upregulated, consistent with activation of Wnt signaling and suppression of Notch signaling. In conclusion, our study demonstrated that Sal B enhanced hepatocyte differentiation from human ESCs through activation of Wnt pathway and inhibition of Notch pathway. Therefore, this study suggests that Sal B can be used as a potential agent to generate more mature hepatocytes for cell based therapeutics and pharmaceutical studies. PMID- 29256828 TI - Succession of Fungal and Oomycete Communities in Glyphosate-Killed Wheat Roots. AB - The successional dynamics of root-colonizing microbes are hypothesized to be critical to displacing fungal pathogens that can proliferate after the use of some herbicides. Applications of glyphosate in particular, which compromises the plant defense system by interfering with the production of aromatic amino acids, are thought to promote a buildup of root pathogens and can result in a "greenbridge" between weeds or volunteers and crop hosts. By planting 2 to 3 weeks after spraying, growers can avoid most negative impacts of the greenbridge by allowing pathogen populations to decline, but with the added cost of delayed planting dates. However, the specific changes in microbial communities during this period of root death and the microbial taxa likely to be involved in displacing pathogens are poorly characterized. Using high-throughput sequencing, we characterized fungal and oomycete communities in roots after applications of herbicides with different modes of action (glyphosate or clethodim) and tracked their dynamics over 3 weeks in both naturally infested soil and soil inoculated with Rhizoctonia solani AG-8. We found that many unexpected taxa were present at high relative abundance (e.g., Pythium volutum and Myrmecridium species) in live and dying wheat roots and may play an under-recognized role in greenbridge dynamics. Moreover, communities were highly dynamic over time and had herbicide specific successional patterns, but became relatively stable by 2 weeks after herbicide application. Network analysis of communities over time revealed patterns of interactions among taxa that were both common and unique to each herbicide treatment and identified two primary groups of taxa with many positive associations within-groups but negative associations between-groups, suggesting that these groups are antagonistic to one another in dying roots and may play a role in displacing pathogen populations during greenbridge dynamics. PMID- 29256829 TI - Insights Into the Roles of Two Genes of the Histidine Biosynthesis Operon in Pathogenicity of Xanthomonas oryzae pv. oryzicola. AB - Xanthomonas oryzae pv. oryzicola is an X. oryzae pathovar that causes bacterial leaf streak in rice. In this study, we performed functional characterization of a nine-gene his operon in X. oryzae pv. oryzicola. Sequence analysis indicates that this operon is highly conserved in Xanthomonas spp. Auxotrophic assays confirmed that the his operon was involved in histidine biosynthesis. We found that two genes within this operon, trpR and hisB, were required for virulence and bacterial growth in planta. Further research revealed that trpR and hisB play different roles in X. oryzae pv. oryzicola. The trpR acts as a transcriptional repressor and could negatively regulate the expression of hisG, -D, -C, -B, -H, A, and -F. hisB, which encodes a bifunctional enzyme implicated in histidine biosynthesis, was shown to be required for xanthomonadin production in X. oryzae pv. oryzicola. The disruption of hisB reduced the transcriptional expression of five known shikimate pathway-related genes xanB2, aroE, aroA, aroC, and aroK. We found that the his operon in X. oryzae pv. oryzicola is not involved in hypersensitive response in nonhost tobacco plants. Collectively, our results revealed that two genes in histidine biosynthesis operon play an important role in the pathogenicity of X. oryzae pv. oryzicola Rs105. PMID- 29256831 TI - Wheat Resistances to Fusarium Root Rot and Head Blight Are Both Associated with Deoxynivalenol- and Jasmonate-Related Gene Expression. AB - Fusarium graminearum is a major pathogen of wheat causing Fusarium head blight (FHB). Its ability to colonize wheat via seedling root infection has been reported recently. Our previous study on Fusarium root rot (FRR) has disclosed histological characteristics of pathogenesis and pathogen defense that mirror processes of spike infection. Therefore, it would be interesting to understand whether genes relevant for FHB resistance are induced in roots. The concept of similar-acting defense mechanisms provides a basis for research at broad Fusarium resistance in crop plants. However, molecular defense responses involved in FRR as well as their relation to spike resistance are unknown. To test the hypothesis of a conserved defense response, a candidate gene expression study was conducted to test the activity of selected prominent FHB defense-related genes in seedling roots, adult plant roots, spikes, and shoots. FRR was examined at seedling and adult plant stages to assess age-related pattern of disease and pathogen resistance. This study offers first evidence for a significant genetic overlap in root and spike defense responses, both in local and distant tissues. The results point to plant development-specific rather than organ-specific determinants of resistance, and suggest roots as an interesting model for studies on wheat Fusarium interactions. PMID- 29256830 TI - Phytocercomonas venanatans, a New Species of Cercozoa Associated with Chlorotic Streak of Sugarcane. AB - Chlorotic streak is a global disease of commercial sugarcane (Saccharum spp. hybrids). The disease is transmitted by wet soil, water, as well as in diseased planting material. Although first recognized almost 90 years ago and despite significant research effort, the identity of the causal agent has been elusive. Metagenomic high throughput sequencing (HTS) facilitated the discovery of novel protistan ribosomal and nuclear genes in chlorotic streak-infected sugarcane. These sequences suggest a possible causal agent belonging to the order Cercomonadida (Rhizaria, phylum Cercozoa). An organism with morphological features similar to cercomonads (=Cercomonadida) was isolated into pure axenic culture from internal stalk tissues of infected sugarcane. The isolated organism contained DNA sequences identical to those identified in infected plants by HTS. The DNA sequences and the morphology of the organism did not match any known species. Here we present a new genus and species, Phytocercomonas venanatans, which is associated with chlorotic streak of sugarcane. Amplicon sequencing also supports that P. venanatans is associated with this disease. This is the first reported member from Cercomonadida showing a probable pathogenic association with higher plants. PMID- 29256824 TI - Measles Vaccine. AB - Measles remains an important cause of child morbidity and mortality worldwide despite the availability of a safe and efficacious vaccine. The current measles virus (MeV) vaccine was developed empirically by attenuation of wild-type (WT) MeV by in vitro passage in human and chicken cells and licensed in 1963. Additional passages led to further attenuation and the successful vaccine strains in widespread use today. Attenuation is associated with decreased replication in lymphoid tissue, but the molecular basis for this restriction has not been identified. The immune response is age dependent, inhibited by maternal antibody (Ab) and involves induction of both Ab and T cell responses that resemble the responses to WT MeV infection, but are lower in magnitude. Protective immunity is correlated with levels of neutralizing Ab, but the actual immunologic determinants of protection are not known. Because measles is highly transmissible, control requires high levels of population immunity. Delivery of the two doses of vaccine needed to achieve >90% immunity is accomplished by routine immunization of infants at 9-15 months of age followed by a second dose delivered before school entry or by periodic mass vaccination campaigns. Because delivery by injection creates hurdles to sustained high coverage, there are efforts to deliver MeV vaccine by inhalation. In addition, the safety record for the vaccine combined with advances in reverse genetics for negative strand viruses has expanded proposed uses for recombinant versions of measles vaccine as vectors for immunization against other infections and as oncolytic agents for a variety of tumors. PMID- 29256832 TI - Temporal Trends in Functional Outcomes after Severe Traumatic Brain Injury: 2006 2015. AB - Severe traumatic brain injury (TBI) is associated with poor outcomes; however, little is known about whether these outcomes are improving over time. This study examined temporal trends in functional outcomes of severe TBI at six months post injury. We conducted a retrospective cohort study (January 1, 2006 to December 31, 2015) of hospitalized adult (>=16 years) patients with severe TBI using data from the population-based Victorian State Trauma Registry. The primary outcome was the Glasgow Outcome Scale-Extended (GOS-E) at six months post-injury, dichotomized as upper severe disability or worse (GOS-E <=4, termed "unfavorable outcome") and lower moderate disability or better (GOS-E >=5; termed "favorable outcome"). Multivariable logistic regression was used to investigate temporal trends in functional outcomes at six months post-injury. Of the 1966 patients with severe TBI who were followed up at six months post-injury (median age, 42 years (interquartile range [IQR]: 25-68); male, 73%), a majority of patients had an unfavorable outcome (GOS-E <=4; n = 1372, 70%). After adjusting for confounders, there was no change in functional outcomes over time (adjusted odds ratio [AOR] = 1.02, 95% confidence interval [CI]: 0.98,1.06; p = 0.35). Similarly, there was no change in the adjusted odds of death (GOS-E = 1) at six months post-injury (AOR = 1.04, 95% CI: 1.00,1.08; p = 0.08). Using a population wide, high quality, comprehensive registry, we demonstrated no change in death or functional outcomes after severe TBI between 2006 and 2015 in a mature trauma system. There is a clear need to identify targeted improvements in the treatment of these patients with the aim of reducing in-hospital death and improving long term outcomes. PMID- 29256833 TI - Message from the Technical Editor-in-Chief: JA&WMA dedicates this issue to its exceptional reviewers and editors. PMID- 29256835 TI - Implication of Formulation Strategies on the Bioavailability of Selected Plant Derived Hepatoprotectants. AB - Plant-derived active ingredients with hepatoprotective activity have been used extensively in the treatment of various liver diseases. These compounds are used either in their natural form or the chemical constituents present therein serve as templates for the development of synthetic-based therapeutic entities. Current research interests are focused on formulation development and pharmacokinetic studies of herbal medicines. This article provides a comprehensive review on formulation influences on the preclinical/clinical pharmacokinetics of selected hepatoprotectants such as silymarin, curcumin, glycyrrhizin, andrographolide, phyllanthin, hypophyllanthin, and picroside I and II. Both the formulation and pharmacokinetic factors could affect the target-site concentrations of the active herbal components and, thus, the therapeutic responses. This review contributes to the establishment of a comprehensive understanding of the influence of formulation/dosage form on the pharmacokinetic profile of the hepatoprotective compounds. PMID- 29256836 TI - Clinical Success versus Attrition of Investigational Pharmaceuticals: A Vignette. AB - The clinical success of investigational pharmaceuticals remains doubtful due to an unacceptable level of attrition during clinical drug development and declining clinical approval rates. Countless molecules are being withdrawn during drug discovery and clinical trial phases due to poor pharmacokinetics (ADME), lack of safety and efficacy, commercial interests, market competition, and patent protection expiry. Consequently, the novel drug pipelines are running dry. Because huge capital is involved in different clinical trial phases, the task of bringing a new drug or drug formulation to the market is a very costly venture. Running a clinical trial is a complex, expensive, and time-intensive project. It is often tedious and troublesome to change a study design after its inception; thus, it is necessary to design the study for easy and comprehensive data analysis and interpretation. Cohort, cross-sectional, and case-control studies, collectively touted as observational studies, provide an option for solving clinical problems when a randomized controlled trial (RCT) is not feasible due to time, money, or ethical restraints. This review article presents three prime observational research methodologies using relevant examples, common causes of spurious results, and ways to trivialize their impacts, including the most popular indices for measuring clinical relevance of the treatment effects. The article also explores attrition issues and issues related to the improvement of clinical approval success, with an emphasis on possible applications of drug delivery technologies to salvage drug molecules. PMID- 29256837 TI - Expanding the domain of drug delivery for HIV prevention: exploration of the transdermal route. AB - Constant efforts for HIV prevention using antiretroviral drugs, pre- and postexposure prophylactic agents, and microbicides are being made by researchers. Drug-delivery systems such as oral tablets and coitally dependent vaginal gels are short acting, require daily application, and are associated with user adherence issues, whereas the coitally independent systems such as injectables and biodegradable implants are long acting, lasting several months, during which time the termination of prophylaxis is impractical in case of adverse effects. An effective drug-delivery system to be used for an intermediate duration, if available, would be an attractive alternative option for users in terms of adherence. Transdermal delivery systems, overcoming most of the limitations of the other routes of administration and aiming to provide sustained delivery of drugs through skin, may be explored for HIV prevention. Passive and physical enhancement techniques may be designed strategically to improve the transdermal delivery of HIV preventive agents. PMID- 29256838 TI - Emerging Trends in Therapeutic Algorithm of Chronic Wound Healers: Recent Advances in Drug Delivery Systems, Concepts-to-Clinical Application and Future Prospects. AB - Chronic wounds which include diabetic foot ulcer (DFU), pressure ulcer, and arterial or venous ulcers compel a significant burden to the patients, healthcare providers, and the healthcare system. Chronic wounds are characterized by an excessive persistent inflammatory phase, prolonged infection, and the failure of defense cells to respond to environmental stimuli. Unlike acute wounds, chronic nonhealing wounds pose a substantial challenge to conventional wound dressings, and the development of novel and advanced wound healing modalities is needed. Toward this end, numerous conventional wound-healing modalities have been evaluated in the management of nonhealing wounds, but a multifaceted approach is lacking. Therefore, this review aims to compile and explore the wide therapeutic algorithm of current and advanced wound healing approaches to the treatment of chronic wounds. The algorithm of chronic wound healing techniques includes conventional wound dressings; approaches based on autografts, allografts, and cultured epithelial autografts; and recent modalities based on natural, modified or synthetic polymers and biomaterials, processed mutually in the form of hydrogels, films, hydrocolloids, and foams. Moreover, this review also explores the promising potential of advanced drug delivery systems for the sustained delivery of growth factors, curcumin, aloe vera, hyaluronic acid, and other bioactive substances as well as stem cell therapy. The current review summarizes the convincing evidence for the clinical dominance of polymer-based chronic wound healing modalities as well as the latest and innovative therapeutic strategies for the treatment of chronic wounds. PMID- 29256839 TI - A Review on Potential of Proteins as an Excipient for Developing a Nano-Carrier Delivery System. AB - In neo-age research, nano-materials have emerged as potential tools for the revolution of diagnostic and therapeutic field because of their nano-scale effects, increased surface area-volume ratio, and other beneficial properties. For the last few decades, protein has been regarded as the most attractive and versatile natural bio-macromolecule among all of the available biopolymers. Protein is largely exploited as a nano-carrier system in the pharmaceutical industry due to its low cytotoxocity, biocompatibility, biodegradability, abundant renewable sources, significant attaching ability, clinically useful targeting, and site-specific efficient uptake. This review mainly emphasizes on the latest development and progress achieved in the utilization of protein as a nano-vehicle for a large number of therapeutics such as drugs, genes, hormones, enzymse, nutraceuticals, antibodies, peptides, etc. We also discuss the sources of protein materials, fabrication aspects, advantages, constraints, in vivo and in vitro studies and provide a comparative analysis between the different types of proteins as nano-carriers. The variation of the release pattern and molecular mechanism of the encapsulated molecule with respect to different protein types and various nano-structures are also highlighted here to explore the enormous promises of this novel approach. PMID- 29256840 TI - Functional Properties of Partially Characterized Polysaccharide from the Medicinal Mushroom Ganoderma neo-japonicum (Agaricomycetes). AB - This study was conducted to evaluate the mycochemical composition and antiglycemic and antioxidant activities of Ganoderma neo-japonicum hot aqueous extracts, prepared at different boiling durations, and polysaccharides isolated from them. Ground basidiocarps of G. neo-japonicum were double-boiled at 100 degrees C for 0.5, 3, or 4 hours, and the antiglycemic activity was assessed by alpha-amylase and alpha-glucosidase enzyme inhibition assays. The antioxidant capacity of the crude hot aqueous extracts (AE-1, AE-2, AE-3) was assessed by DPPH and ABTS radical scavenging and ferric-reducing antioxidant power assays. The total phenolics, protein, and sugar in the crude extracts were also determined. The hot aqueous extract (AE-3) containing a significant amount of total sugar and having enhanced antiglycemic and antioxidant activities was selected for polysaccharide isolation. The isolated crude polysaccharide was separated and purified using diethylaminoethyl-cellulose-52 and Sepharose 6B column chromatography. Fourier transform infrared spectroscopy studies of the purified polysaccharide fraction (PF) showed the presence of typical bands corresponding to polysaccharides. The estimated beta-glucan concentration in the PF was 39.26%. In general, the PF exhibited significantly lower antioxidant activity than AE-3. Nevertheless, its potency in inhibiting carbohydratehydrolyzing enzymes may have potential in the management of diabetes mellitus. PMID- 29256841 TI - The Efficacy and Toxicity of Using the Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), and Its Products in Chemotherapy (Review). AB - Around the world, cancer patients often combine conventional anticancer treatment with complementary alternative medicines derived from natural sources such as fungi and mushrooms, including the popular lingzhi or reishi medicinal mushroom Ganoderma lucidum. Many studies to date have described the anticancer properties of G. lucidum, which are attributed to its major pharmacologically bioactive compounds, such as terpenoids and polysaccharides. Moreover, several scientific observations have suggested a potential beneficial therapeutic strategy using G. lucidum in combination with chemotherapeutic agents to improve therapeutic outcome. However, to my knowledge, no systematic review has been conducted in this area. Therefore, this review summarizes the current knowledge on G. lucidum or its individual components in relation to chemotherapeutic efficacy, ability to reverse multidrug resistance, and chemotherapeutic toxicity. PMID- 29256842 TI - Water-Soluble Polysaccharide Extracts from the Oyster Culinary-Medicinal Mushroom Pleurotus ostreatus (Agaricomycetes) with HMGCR Inhibitory Activity. AB - Water extracts from Pleurotus ostreatus containing no statins showed 3-hydroxy-3 methyl-glutaryl CoA reductase (HMGCR) inhibitory activity (in vitro) that might be due to specific water-soluble polysaccharides (WSPs); when isolated and deproteinized, increasing concentrations of the WSP extract induced higher inhibition. The WSP extract contained mainly beta-glucans, mannogalactans, and glycogen (e.g., alpha-glucans), although derivatives or fragments with lower molecular weights (between 14 and 3.5 kDa) were present and were able to induce the inhibitory activity. The extract contained more beta-(1->3)-glucans than beta (11->3),(11->6)-glucans, and they partially survived digestion and managed to pass through Caco2 cell monolayers to the lower compartment after in vitro digestion and transport experiments. The WSP might also modulate Caco2 membrane integrity. PMID- 29256843 TI - Anti-Inflammatory and Wound-Healing Potential of Golden Chanterelle Mushroom, Cantharellus cibarius (Agaricomycetes). AB - The golden chanterelle mushroom, Cantharellus cibarius, is an edible mushroom with medicinal value. Given that this species has good radical scavenging activity and strong antioxidant potential and bactericidal effects, this study was designed to investigate the anti-inflammatory and wound-healing activity of C. cibarius extract in rats. For this experimental study, circular excision and linear incision wound models were used in 4 groups of male Wistar rats: nontreated, vehicle-treated, treated with C. cibarius extract ointment (2% w/w), and treated with the reference drug (Madecassol). All the animals were treated topically once a day. The circular and linear wounds were treated for 9 and 17 days, respectively. At the end of the study, samples from healing wounds were taken for histopathological assessment to determine the in vivo anti-inflammatory activity and investigate immunohistochemistry by cyclooxygenase-2 (COX-2). Significant wound-healing activity in each wound model was observed in the C. cibarius extract-treated and Madecassol-treated groups compared with the nontreated and vehicle-treated groups (P < 0.05). Histological assessment showed complete repair of the epidermal layer, increased collagen production, and a remarkable degree of neovascularization and epithelization in the extract group, which were significantly different from those in the other groups (P < 0.05). In addition, a significantly lower rate of COX-2 expression was detected in the extract group than in the nontreated and vehicle-treated groups (P < 0.0001). Therefore, the experimental data reveal that C. cibarius extract showed significant wound-healing and anti-inflammatory effects, which could be the scientific rationale for the medicinal use of the golden chanterelle mushroom in treating wounds. PMID- 29256844 TI - A Primary Study of the Antioxidant, Hypoglycemic, Hypolipidemic, and Antitumor Activities of Ethanol Extract of Brown Slimecap Mushroom, Chroogomphus rutilus (Agaricomycetes). AB - In vivo and in vitro treatments were carried out to investigate the effects of a 95% ethanol extract of Chroogomphus rutilus (CRE) on antioxidant, hypoglycemic, hypolipidemic, and antitumor properties. CRE showed potent radical scavenging activity against DPPH in vitro. It could increase antioxidant enzymatic activities (superoxide dismutase and glutathione peroxidase) and could reduce malondialdehyde content in vivo in mice in which aging was induced by D galactose. CRE had hypoglycemic activity and could significantly inhibit alpha glucosidase activity in vitro and decrease blood glucose concentration in vivo. CRE could decrease the serum total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels and increase the high-density lipoprotein cholesterol level in diabetic mice. The MTT assay showed that CRE also had a certain inhibitory effect on the tumor cells. These results suggest that CRE may be beneficial for human health and could be useful for applications in medicine, the food industry, and agriculture. PMID- 29256845 TI - Anti-Inflammatory Activity and Bioactive Constituents of Cultivated Fruiting Bodies of Xylaria nigripes (Ascomycetes), a Chinese Medicinal Fungus. AB - Xylaria nigripes, also known as Wu Ling Shen, is popular for treating insomnia and trauma in traditional Chinese medicine. This study aimed to examine the anti inflammatory activity and bioactive constituents of cultivated X. nigripes fruiting bodies in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. Results showed that among the different extracts, the hexane fraction exhibited the best protection against cell toxicity induced by 1 MUg/mL LPS and the strongest inhibitory effect on nitric oxide (NO) production. This fraction led to the isolation of 2 bioactive compounds (namely, XN-CP1 and XN-CP2), which were confirmed to be ergostarien-3beta-ol and ergosterol peroxide, respectively. Although both XN-CP1 and XN-CP2 showed good inhibitory effects on NO, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and prostaglandin E2 production in LPS-stimulated macrophages, XN-CP2 was shown to have a stronger anti-inflammatory activity; this was further supported by its strong suppressive effects on inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression and nuclear factor (NF)-kappaB activation. These results conclude that ergosterol peroxide (XN-CP2) could be the main bioactive compound contributing to the potent anti-inflammatory activity of X. nigripes, and its mechanism of action is mediated through inhibition of iNOS and COX-2 expression via the NF-kappaB signaling pathway. PMID- 29256846 TI - Culinary-Medicinal Mushroom Products as a Potential Source of Vitamin D. AB - The incidence of vitamin D deficiency has increased in recent years, mainly in Europe. The consumption of processed mushrooms may play an important role in preventing diseases associated with vitamin D deficiency. We determined the effects of 2 kinds of freezing (blast, cryogenic), canning (mild and strong brine), and drying (air-drying, freeze-drying) on the retention of vitamin D2 and ergosterol in Agaricus bisporus. Fresh and processed A. bisporus mushrooms can be a good dietary source of vitamin D2. After 12 months of storage, canned mushrooms retained the largest amount of vitamin D2 and ergosterol, whereas the smallest amount was retained in dried mushrooms. Cryogenic freezing resulted in higher levels of vitamin D2, whereas ergosterol levels were higher using air-blast freezing. The drying method had a significant effect only on ergosterol levels, which were higher in the case of freeze-drying. Room temperature gave the best results for storing dried mushrooms. In canned mushrooms, the type of brine had an effect only on levels of vitamin D2; retention was higher using the strong brine. Retention of vitamin D2 was higher at cool temperatures, whereas room temperature resulted in higher retention of ergosterol in the canned products. PMID- 29256847 TI - Evaluation of Fatty Acid Composition and Antioxidant Activity of Wild-Growing Mushrooms from Southwest China. AB - To better understand the medicinal and nutritional value of mushrooms, we studied the fatty acid (FA) compositions and DPPH scavenging abilities of 11 mushrooms from Southwest China. The crude fat (CF) contents were examined initially, then 3 methods of FA methyl esterification were compared to identify which acid treatment was the most appropriate method. Then methyl esterification methods for 12 CFs were performed with acid treatment and the FA compositions were analyzed with gas chromatography-mass spectrometry. The results showed that tetradecanoic acid (14:0), hexadecenoic acid (16:1), hexadecanoic acid (16:0), heptadecanoic acid (17:0), octadecadienoic acid (18:2), octadecenoic acid (18:1), octadecanoic acid (18:0), docosanoic acid (22:0), and tetracosanoic acid (24:0) were detected in all the samples, with large amounts of hexadecanoic acid (16:0), octadecadienoic acid (18:2), octadecenoic acid (18:1), and octadecanoic acid (18:0). Daldinia eschscholtzii and Sarcodon imbricatus had the highest ratio value of unsaturated FAs to saturated FAs (4.33 and 3.03, respectively). The DPPH scavenging ability of 12 CFs was also tested. The free radical scavenging rates of the CFs were almost < 10% at a concentration of 0.10 mg/mL, except that of S. imbricatus, which reached 81.25%, with a half-maximal inhibitory concentration of 0.054 mg/mL. This strong DPPH free radical scavenging ability of S. imbricatus may be related to alpha-hydroxy FA. PMID- 29256848 TI - Ethnomycological and Nutritional Analyses of Some Wild Edible Mushrooms from Western Himalayas, Azad Jammu and Kashmir (Pakistan). AB - Mushrooms have had a long association with humankind and have great biological and economic effects. This study aimed to record ethnomycological and nutritional analysis of some edible mushrooms from the Western Himalayas (Neelum Valley), Azad Jammu and Kashmir, Pakistan. Mushrooms from different taxonomical and ecological groups were collected and properly identified with the help of the available literature: Morchella esculenta, M. crassipes, M. elata, M. conica, Pleurotus ostreatus, Lycoperdon gemmatum, Helvella crispa, Tricholoma megnivelare, Gyrometra esculenta, Agaricus campestris, Hydnum imbricatum, and Sparassis crispa. The local communities are familiar with the morphological features, habitats, and qualities of these mushrooms. Ethnomycological data were collected through the use of a questionnaire; we found that these species have great medicinal value against different ailments. Four species (A. campestris, H. imbricatum, P. ostreatus, and S. crispa) were selected for nutritional analysis (proteins, fats, fiber, and moisture) on the basis of their frequent use in the study area. The largest amounts of protein (1.627 and 1.493 mg/mL) were found in H. imbricatum and S. crispa, respectively. The largest amount of fiber was found in P. ostreatus (14%); S. crispa contains the largest amount of fat (12.7%). PMID- 29256849 TI - TOWARD INTEGRATION IN THE CONTEXT OF HEALTH TECHNOLOGY ASSESSMENT: THE NEED FOR EVALUATIVE FRAMEWORKS. AB - OBJECTIVES: A comprehensive health technology assessment (HTA) enables a patient centered assessment of the effectiveness, economic, ethical, socio-cultural, and legal issues of health technologies that takes context and implementation into account. A question is whether these various pieces of evidence need to be integrated, and if so, how that might be achieved. The objective of our study is to discuss the meaning of integration in the context of HTA and suggest how it may be achieved in a more structured way. METHODS: An analysis of the concept of integration in the context of HTA and a review of approaches that were adopted in the INTEGRATE-HTA project that may support integration. RESULTS: Current approaches to integration in HTA are mainly methods of commensuration, which are not optimally geared to support public deliberation. In contrast, articulating evaluative frameworks could be an important means of integration which allows for exploring how facts and values can be brought to bear on each other. CONCLUSIONS: Integration is not something that only needs to be addressed at the end, but rather throughout an HTA, right from the start. Integration can be conceived as a matter of accounting for the relevance of empirical evidence in view of a commitment to a set of potentially conflicting values. Various elements of the INTEGRATE-HTA project, such as scoping and the development of logic models, can help to achieve integration in HTA. PMID- 29256850 TI - The experimental transmission of reticuloendotheliosis virus by cock semen. AB - Following artificial insemination, the egg-laying rate of a large-scale breeder chicken flock declined by10-15 %. Real-time quantitative polymerase chain reaction (qPCR) analysis detected the presence of reticuloendotheliosis virus (REV) in semen from the breeder cocks used. Six REV strains were successfully isolated from semen randomly extracted from those cocks. Additionally, the whole sequence of SDAUR-S1 was sequenced and analysed. Cock models with continuous production of REV-positive semen were established by intravenous injection with SDAUR-S1. Eggs were then collected from hens after artificial insemination with REV-positive semen, for virus detection. The positive REV antibody rate for egg albumen was 58.3 % and the REV-positive rate for hatched embryos was 8.3 %, which suggested not only that REV can infect cock semen, but can also infect the offspring. In conclusion, the present study is the first to report on the isolation, genome analysis and transmission of REV in cock semen. PMID- 29256852 TI - Chryseobacterium salipaludis sp. nov., isolated at a wild ass sanctuary. AB - A Gram-stain-negative, rod-shaped, non-motile, aerobic bacterium was isolated from a sediment sample obtained from a wild ass sanctuary in Gujarat, India. The strain designated JC490T was oxidase- and catalase-positive. The 16S rRNA gene sequence analysis and sequence comparison data indicated that strain JC490T was a member of the genus Chryseobacterium and was closely related to Chryseobacterium jeonii AT1047T (96.4 %) and with other members of the genus Chryseobacterium (<96.3 %). The DNA G+C content of strain JC490T was 34 mol%. Strain JC490T had phosphatidylethanolamine, two unidentified aminolipids, two unidentified phospholipids and five unidentified polar lipids. Menaquinone-6 was the only respiratory quinone found. Iso-C15 : 0, anteiso-C15 : 0 and iso-C17 : 0 3-OH were the major fatty acids of strain JC490T. On the basis of physiological, genotypic, phylogenetic and chemotaxonomic analyses, it is concluded that strain JC490T constitutes a novel species of the genus Chryseobacterium, for which the name Chryseobacterium salipaludis sp. nov. is proposed. The type strain is JC490T (=KCTC 52835T=LMG 30048T). PMID- 29256853 TI - OpaR and RpoS are positive regulators of a virulence factor PrtA in Vibrio parahaemolyticus. AB - PrtA is an extracellular serine protease of Vibrio parahaemolyticus and has haemolytic and cytotoxic activities. Many extracellular proteases have been shown to be required for nutrient intake and the infection mechanism of vibrios. In this study, we report that OpaR, a quorum sensing regulator, and RpoS, a general stress response regulator, play important roles in the PrtA regulation pathway. Extracellular protease activity was highest during the late-log growth of Vibrio parahaemolyticus no.93 (VP93). The absence of PrtA distinctly decreased the extracellular protease activity. Deletion of opaR or rpoS alone reduced PrtA specific activity of VP93. Quantitative reverse-transcriptase PCR and Western blot analysis suggested that OpaR and RpoS promote PrtA expression at the transcriptional level and affect the amount of extracellular PrtA. A luciferase assay revealed that OpaR regulates prtA on the prtA promoter region. Electrophoretic mobility shift assays indicated that the purified His-OpaR was able to bind specifically to two sequences (PrtA-1 and PrtA-2) of the prtA promoter region. Footprinting analysis showed that OpaR regulates prtA by binding to the promoter region of prtA at positions -269 to -246 and -88 to -68 from the prtA translational start site. Together, the results suggest that PrtA was upregulated by two global regulators, OpaR and RpoS. PMID- 29256854 TI - How to Crack the Sugar Code. AB - The known ubiquitous presence of glycans fulfils an essential prerequisite for fundamental roles in cell sociology. Since carbohydrates are chemically predestined to form biochemical messages of a maximum of structural diversity in a minimum of space, coding of biological information by sugars is the reason for the broad occurrence of cellular glycoconjugates. Their glycans originate from sophisticated enzymatic assembly and dynamically adaptable remodelling. These signals are read and translated into effects by receptors (lectins). The functional pairing between lectins and their counterreceptor(s) is highly specific, often orchestrated by intimate co-regulation of the receptor, the cognate glycan and the bioactive scaffold (e.g., an integrin). Bottom-up approaches, teaming up synthetic and supramolecular chemistry to prepare fully programmable nanoparticles as binding partners with systematic network analysis of lectins and rational design of variants, enable us to delineate the rules of the sugar code. PMID- 29256851 TI - Galactooligosaccharide supplementation provides protection against Citrobacter rodentium-induced colitis without limiting pathogen burden. AB - Many enteric pathogens, including Salmonella and enteropathogenic and enterohemorrhagic Escherichia coli, express adhesins that recognize and bind to carbohydrate moieties expressed on epithelial cells. An attractive strategy for inhibiting bacterial adherence employs molecules that mimic these epithelial binding sites. Prebiotic oligosaccharides are non-digestible, fermentable fibres capable of modulating the gut microbiota. Moreover, they may act as molecular decoys that competitively inhibit adherence of pathogens to host cells. In particular, galactooligosaccharides (GOS) and other prebiotic fibres have been shown to inhibit pathogen adherence to epithelial cells in vitro. In the present study, we determined the ability of prophylactic GOS administration to reduce enteric pathogen adherence both in vitro and in vivo as well as protect against intestinal inflammation. GOS supplementation significantly reduced the adherence of the epithelial-adherent murine bacterial pathogen Citrobacter rodentium in a dose-dependent manner to the surface of epithelial cells in vitro. A 1- to 2-log reduction in bacterial adherence was observed at the lowest and highest doses tested, respectively. However, mouse studies revealed that treatment with GOS neither reduced the adherence of C. rodentium to the distal colon nor decreased its dissemination to systemic organs. Despite the absence of adherence inhibition, colonic disease scores for GOS-treated, C. rodentium-infected mice were significantly lower than those of untreated C. rodentium-infected animals (P=0.028). Together, these data suggest that GOS has a direct protective effect in ameliorating disease severity following C. rodentium infection through an anti adherence-independent mechanism. PMID- 29256855 TI - The Differentiation Potential of Human Natal Dental Pulp Stem Cells into Insulin Producing Cells. AB - Mesenchymal stem cells have the ability to differentiate into insulin-producing cells, raising the hope for diabetes mellitus treatment. The aim of this research was to study the ability of stem cells from discarded natal teeth to differentiate into insulinproducing cells. Two vital human natal teeth were obtained from a healthy 2-day-old female. Stem cells from the dental pulp were isolated, cultured under xenogenic-free conditions, propagated and characterized. Proliferative activity, population doubling time and viability were measured, and the multipotent differentiation ability was investigated. A twostep protocol was used to induce the human natal dental pulp stem cells to differentiate into insulinproducing cells. Phenotypic analysis was done using flow cytometry. Immunohistochemistry was performed to detect insulin and C-peptide. PDX1, HES1 and Glut2 gene expression analysis was performed by quantitative reverse transcription-polymerase chain reaction. Human natal dental pulp stem cells were able to undergo osteogenic, chondrogenic and adipogenic differentiation upon exposure to the specific differentiation media for each lineage. Their differentiation into insulin-producing cells was confirmed by expression of C peptide and insulin, as well as by 975.4 % higher expression of PDX-1 and 469.5 % higher expression of HES1 in comparison to the cells cultivated in standard cultivation media. Glut2 transporter mRNA was absent in the non-differentiated cells, and differentiation of the stem cells into insulin-producing cells induced appearance of the mRNA of this transporter. We were the first to demonstrate that stem cells obtained from the pulp of natal teeth could be differentiated into insulinproducing cells, which might prove useful in the stem cell therapy for type 1 diabetes. PMID- 29256856 TI - Highly Conserved Keratin-Associated Protein 7-1 Gene in Yak, Taurine and Zebu Cattle. AB - Keratin-associated proteins (KRTAPs) play a critical role in cross-linking the keratin intermediate filaments to build a hair shaft. The genetic polymorphisms of the bovine KRTAP7-1 gene were investigated for the first time in this study. The complete coding sequence of the KRTAP7-1 gene in 108 domestic yak, taurine and zebu cattle from China and Indonesia were successfully amplified using polymerase chain reaction and then directly sequenced. Only two single-nucleotide polymorphisms (one nonsynonymous at c.7C/G and another synonymous at c.21C/T) and three haplotypes (BOVIN-KRTAP7-1*A, B and C) were identified in the complete coding sequence of the bovine KRTAP7-1 gene among all animals. There was no polymorphism across three Chinese indigenous yak breeds and one Indonesian zebu cattle population, all sharing the BOVINKRTAP71*A haplotype. The four taurine cattle populations also had BOVIN-KRTAP7-1*A as the most common haplotype with a frequency of 0.80. The frequency of novel haplotype BOVIN-KRTAP7-1*B was only 0.07 present in one heterozygous animal in each of the four taurine cattle populations, while BOVINKRTAP7- 1*C was only found in a Simmental and a local Chinese Yellow cattle population with frequencies of 0.17 and 0.36, respectively. The monomorphic yak KRTAP7-1 gene in particular, and highly conserved bovine, sheep and goat KRTAP7-1 genes in general, demonstrated its unique intrinsic structural property (e.g., > 21% high glycine content) and primary functional importance in supporting the mechanical strength and shape of hair. PMID- 29256857 TI - Expression of c-MET Protein in Various Subtypes of Hepatocellular Adenoma Compared to Hepatocellular Carcinoma and Non-Neoplastic Liver in Human Tissue. AB - Hepatocellular adenoma (HA) is a benign neoplasm of the liver, whose aetiopathogenesis is little known. Newest research allowed dividing all cases into three types based on molecular characteristics: inflammatory HA, HA with HNF1A mutation, beta-catenin-mutated HA. The clinical significance of HA is chiefly due to the possibility of malignant transformation into hepatocellular carcinoma (HCC). The aim of the present study was to immunohistochemically assess the expression pattern and level of c-MET protein in hepatocellular adenoma (taking into account its status of Wnt/beta-catenin pathway functioning) and intertwining the results into a wider pattern of expression in non-neoplastic liver and hepatocellular carcinoma of various histological grades. It was found that expression of c-MET in poorly-differentiated HCC was significantly higher than in non-neoplastic liver and well- to moderately-differentiated HCC. The expression in HA was variable and differed between molecular subtypes of this neoplasm: inflammatory and HNF1A mutation-associated type are characterized by overexpression of c-MET to an extent comparable with poorly-differentiated HCC, whereas Wnt/beta-catenin dysfunction-associated type lacks overexpression, and the amount of c-MET protein accumulated in its cells is similar to the levels in non-neoplastic tissue and well- to moderately-differentiated HCC. These findings suggest that c-MET overexpression in HA is not an early event in hepatocarcinogenesis, but constitutes a divergent molecular pathway leading to neoplastic change compared to overexpression observed in the late stages of tumour progression. PMID- 29256858 TI - Oridonin Induces Apoptosis in Human Nasopharyngeal Carcinoma Cells Involving ROS Generation. AB - Oridonin, an ent-kaurene diterpenoid isolated from the traditional Chinese herb Rabdosia rubescens, has been reported to be a potent cytotoxic agent against a wide array of cancer cells. However, its effect on human nasopharyngeal carcinoma (NPC) cells has not been well investigated. The present study aimed to explore the anti-tumour effect of oridonin in NPC cells and its underlying mechanisms. Cell viability was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and colony formation assay. Apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and expression of apoptosis-related proteins were analysed by flow cytometry with propidium iodide staining, JC-1 staining, DCFH-DA staining, and Western blot analysis, respectively. The results showed that oridonin concentration-dependently inhibited the cell viability, decreased the colony formation, and enhanced the apoptotic rate in NPC cells. Further, oridonin-induced apoptosis was mediated by the mitochondrial pathway in NPC cells, which was confirmed by the loss of MMP, downregulation of anti-apoptotic Bcl-2 family protein Mcl-1 and Bcl-2, upregulation of pro-apoptotic Bcl-2 family member Bax, and activation of caspase 3 and PARP. Notably, the augmented ROS generation played an essential role in oridonin-induced apoptosis in NPC cells, as the apoptosis-inducing effect was attenuated by ROS scavenger N-acetyl-L-cysteine. These results indicate that oridonin triggers apoptosis through the ROSmediated mitochondrial pathway in NPC cells. This study supports oridonin to be an interesting candidate drug for the treatment of human NPC. PMID- 29256860 TI - The zinc-finger transcription factor Hindsight regulates ovulation competency of Drosophila follicles. AB - Follicle rupture, the final step in ovulation, utilizes conserved molecular mechanisms including matrix metalloproteinases (Mmps), steroid signaling, and adrenergic signaling. It is still unknown how follicles become competent for follicle rupture/ovulation. Here, we identify a zinc-finger transcription factor Hindsight (Hnt) as the first transcription factor regulating follicle's competency for ovulation in Drosophila. Hnt is not expressed in immature stage-13 follicle cells but is upregulated in mature stage-14 follicle cells, which is essential for follicle rupture/ovulation. Hnt upregulates Mmp2 expression in posterior follicle cells (essential for the breakdown of the follicle wall) and Oamb expression in all follicle cells (the receptor for receiving adrenergic signaling and inducing Mmp2 activation). Hnt's role in regulating Mmp2 and Oamb can be replaced by its human homolog Ras-responsive element-binding protein 1 (RREB-1). Our data suggest that Hnt/RREB-1 plays conserved role in regulating follicle maturation and competency for ovulation. PMID- 29256859 TI - Severe infections emerge from commensal bacteria by adaptive evolution. AB - Bacteria responsible for the greatest global mortality colonize the human microbiota far more frequently than they cause severe infections. Whether mutation and selection among commensal bacteria are associated with infection is unknown. We investigated de novo mutation in 1163 Staphylococcus aureus genomes from 105 infected patients with nose colonization. We report that 72% of infections emerged from the nose, with infecting and nose-colonizing bacteria showing parallel adaptive differences. We found 2.8-to-3.6-fold adaptive enrichments of protein-altering variants in genes responding to rsp, which regulates surface antigens and toxin production; agr, which regulates quorum sensing, toxin production and abscess formation; and host-derived antimicrobial peptides. Adaptive mutations in pathogenesis-associated genes were 3.1-fold enriched in infecting but not nose-colonizing bacteria. None of these signatures were observed in healthy carriers nor at the species-level, suggesting infection associated, short-term, within-host selection pressures. Our results show that signatures of spontaneous adaptive evolution are specifically associated with infection, raising new possibilities for diagnosis and treatment. PMID- 29256861 TI - Inhibition of PIP4Kgamma ameliorates the pathological effects of mutant huntingtin protein. AB - The discovery of the causative gene for Huntington's disease (HD) has promoted numerous efforts to uncover cellular pathways that lower levels of mutant huntingtin protein (mHtt) and potentially forestall the appearance of HD-related neurological defects. Using a cell-based model of pathogenic huntingtin expression, we identified a class of compounds that protect cells through selective inhibition of a lipid kinase, PIP4Kgamma. Pharmacological inhibition or knock-down of PIP4Kgamma modulates the equilibrium between phosphatidylinositide (PI) species within the cell and increases basal autophagy, reducing the total amount of mHtt protein in human patient fibroblasts and aggregates in neurons. In two Drosophila models of Huntington's disease, genetic knockdown of PIP4K ameliorated neuronal dysfunction and degeneration as assessed using motor performance and retinal degeneration assays respectively. Together, these results suggest that PIP4Kgamma is a druggable target whose inhibition enhances productive autophagy and mHtt proteolysis, revealing a useful pharmacological point of intervention for the treatment of Huntington's disease, and potentially for other neurodegenerative disorders. PMID- 29256862 TI - Distinct SoxB1 networks are required for naive and primed pluripotency. AB - Deletion of Sox2 from mouse embryonic stem cells (ESCs) causes trophectodermal differentiation. While this can be prevented by enforced expression of the related SOXB1 proteins, SOX1 or SOX3, the roles of SOXB1 proteins in epiblast stem cell (EpiSC) pluripotency are unknown. Here, we show that Sox2 can be deleted from EpiSCs with impunity. This is due to a shift in the balance of SoxB1 expression in EpiSCs, which have decreased Sox2 and increased Sox3 compared to ESCs. Consistent with functional redundancy, Sox3 can also be deleted from EpiSCs without eliminating self-renewal. However, deletion of both Sox2 and Sox3 prevents self-renewal. The overall SOXB1 levels in ESCs affect differentiation choices: neural differentiation of Sox2 heterozygous ESCs is compromised, while increased SOXB1 levels divert the ESC to EpiSC transition towards neural differentiation. Therefore, optimal SOXB1 levels are critical for each pluripotent state and for cell fate decisions during exit from naive pluripotency. PMID- 29256863 TI - Paradoxical response reversal of top-down modulation in cortical circuits with three interneuron types. AB - Pyramidal cells and interneurons expressing parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) show cell-type-specific connectivity patterns leading to a canonical microcircuit across cortex. Experiments recording from this circuit often report counterintuitive and seemingly contradictory findings. For example, the response of SST cells in mouse V1 to top-down behavioral modulation can change its sign when the visual input changes, a phenomenon that we call response reversal. We developed a theoretical framework to explain these seemingly contradictory effects as emerging phenomena in circuits with two key features: interactions between multiple neural populations and a nonlinear neuronal input-output relationship. Furthermore, we built a cortical circuit model which reproduces counterintuitive dynamics observed in mouse V1. Our analytical calculations pinpoint connection properties critical to response reversal, and predict additional novel types of complex dynamics that could be tested in future experiments. PMID- 29256864 TI - Mechanistic insights into the active site and allosteric communication pathways in human nonmuscle myosin-2C. AB - Despite a generic, highly conserved motor domain, ATP turnover kinetics and their activation by F-actin vary greatly between myosin-2 isoforms. Here, we present a 2.25 A pre-powerstroke state (ADP?VO4) crystal structure of the human nonmuscle myosin-2C motor domain, one of the slowest myosins characterized. In combination with integrated mutagenesis, ensemble-solution kinetics, and molecular dynamics simulation approaches, the structure reveals an allosteric communication pathway that connects the distal end of the motor domain with the active site. Disruption of this pathway by mutation of hub residue R788, which forms the center of a cluster of interactions connecting the converter, the SH1-SH2 helix, the relay helix, and the lever, abolishes nonmuscle myosin-2 specific kinetic signatures. Our results provide insights into structural changes in the myosin motor domain that are triggered upon F-actin binding and contribute critically to the mechanochemical behavior of stress fibers, actin arcs, and cortical actin-based structures. PMID- 29256867 TI - Collapsed adhesion of carbon nanotubes on silicon substrates: continuum mechanics and atomistic simulations. AB - Carbon nanotubes (CNTs) can undergo collapse from the ordinary cylindrical configurations to bilayer ribbons when adhered on substrates. In this study, the collapsed adhesion of CNTs on the silicon substrates is investigated using both classical molecular dynamics (MD) simulations and continuum analysis. The governing equations and transversality conditions are derived based on the minimum potential energy principle and the energy-variational method, considering both the van der Waals interactions between CNTs and substrates and those inside CNTs. Closed-form solutions for the collapsed configuration are obtained which show good agreement with the results of MD simulations. The stability of adhesive configurations is investigated by analyzing the energy states. It is found that the adhesive states of single-walled CNTs (SWCNTs) (n, n) on the silicon substrates can be categorized by two critical radii, 0.716 and 0.892 nm. For SWCNTs with radius larger than 0.892 nm, they would fully collapse on the silicon substrates. For SWCNTs with radius less than 0.716 nm, the initial cylindrical configuration is energetically favorable. For SWCNTs with radius between two critical radii, the radially deformed state is metastable. The non-contact ends of all collapsed SWCNTs are identical with the same arc length of 2.38 nm. Finally, the role of number of walls on the adhesive configuration is investigated quantitatively. For multi-walled CNTs with the number of walls exceeding a certain value, the cylindrical configuration is stable due to the increasing bending stiffness. The present study can be useful for the design of CNT-based nanodevices. PMID- 29256866 TI - Percutaneous nephrolithotripsy: C-arm CT with 3D virtual navigation in non dilated renal collecting systems. AB - PURPOSE: We aimed to evaluate the clinical superiority of using C-arm computed tomography (CT) to establish percutaneous nephrolithotripsy (PCNL) access for patients with non-dilated renal collecting systems. METHODS: From May 2014 to May 2015, 33 patients underwent C-arm CT-guided puncture to establish PCNL access after failed attempts of ultrasonography-guided nephrostomy. Technical success, procedure details, radiation exposure, complications, and stone-free rate were recorded. RESULTS: The technical success rate was 97% (32/33) with a mean puncture score of 4.5/5. Mean puncture, dilation, and fragmentation times were 17.9+/-6.0, 12.6+/-3.9, and 33.1+/-8.8 minutes, respectively. Mean radiation exposure was 4.8+/-2.1 mSv without serious complications. Stone-free rate was 93.8%. CONCLUSION: C-arm CT is a useful tool to establish PCNL access, particularly in cases of upper pole access or complicated anatomy. PMID- 29256868 TI - Microstructure and optical response optimization of Ge/Si quantum dots transformed from the sputtering-grown Ge thin film by manipulating the thermal annealing. AB - A series of zero-dimensional Ge/Si quantum dots (QDs) samples are fabricated by inducing the transformation from the two-dimensional Ge thin film, which is grown by the traditional direct current (DC) magnetron sputtering, via regulating the annealing process. The QD density increases sharply after the post rapid thermal annealing (PRTA). The observations of atomic force microscopy (AFM) and Raman spectroscopy suggest that the good morphology of Ge QDs results from an appropriate thermodynamics and kinetics surrounding shaped by the cooperative interaction of the Ge-Si lattice mismatch, the film's surface temperature, and the difference in thermal expansion coefficients between Ge and Si. The photoluminescence (PL) peaks of Ge QDs are detected in monolayer Ge QDs with ultrahigh density at 17 K. The Metal-Ge/Si QDs-Metal (MGM) photodetector fabricated from the ultrahigh-density QDs sample exhibits a relatively high current gain, absolute photoelectric responsivity, and internal quantum efficiency (IQE). Our results demonstrate that the high-quality Ge QDs with strong light absorption and quantum confinement effect can be realized by modulating DC magnetron sputtering and the PRTA process. This paves the way for realizing silicon-based optoelectronic devices with high performance by the traditional, relatively low-cost, and large-scale production nanomaterial fabricating method. PMID- 29256865 TI - HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. AB - Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naive mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors. PMID- 29256869 TI - Nanotribological behavior of a single silver nanowire on graphite. AB - The nanotribological characteristics of silver nanowires (Ag NWs) are of great importance for the reliability of their applications in flexible nanodevices involving mechanical interactions. The frictional behaviors of Ag NWs on graphite substrate were directly investigated by atomic force microscopy (AFM) nanomanipulation. The relatively short NWs demonstrate three forms of motion rotation, translation and a combination of the two-whose frictional behaviors behave like rigid rods. The relatively long Ag NW shows characteristics of a flexible beam, whose friction increases with an increase in the bending angle of the NW. The friction between the NW and substrate increases linearly with an increase in the length of the NW. The long Ag NW displays extraordinary flexibility that can be folded to different shapes, and the friction of the folded NW becomes smaller due to the decreased bending deformation. The critical aspect ratio of the Ag NW on graphite substrate for two different frictional behaviors between the relatively long and short NWs is found to be 12-15. These findings can deepen the understanding of the frictional characteristics of Ag NWs and contribute to their quantitative interface design. PMID- 29256870 TI - Contrasting properties of hydrogenated and protonated single-layer h-BN from first-principles. AB - Hydrogenation is an efficient approach to tune the electronic, magnetic and chemical properties of single-layer hexagon boron nitride (h-BN). The relative stabilities and electronic properties of hydrogenated and protonated h-BN sheets are studied by means of density functional theory calculations. H and [Formula: see text] show very contrasting behaviors in chemisorption and clustering on h BN, in which a single H atom prefers to adsorb on the top site of the boron (B) atom, and more H atoms tend to cluster on both sides of the h-BN layers in an alternating manner; while single [Formula: see text] prefers to stay on the nitrogen (N) atom, and protons are more likely to separate from each other on h BN. The collective [Formula: see text] bonding feature of H-decorated h-BN lattice plays a key role in stabilizing the H clusters on the h-BN sheet. The non magnetic H clusters with an even number of H atoms ([Formula: see text]) are energetically favored, compared with those with odd [Formula: see text]. Both the binding energy and band gap width vary in an oscillatory way as a function of [Formula: see text]. PMID- 29256871 TI - Interface-engineered Li4Ti5O12-TiO2 dual-phase nanoparticles and CNT additive for supercapacitor-like high-power Li-ion battery applications. AB - The single-pot synthesis of dual-phase spinel-Li4Ti5O12 and anatase-TiO2 (LTO TiO2) nanoparticles over all the phase fractions ranging from pure LTO to pure TiO2 is conducted. Carrying out the process over the complete range enabled the identification of a unique weight ratio of 85:15 (LTO:TiO2), providing the best combination of capacity, rate capability and cycling stability. We show that for this composition dual-phase nanoparticles have a predominant interfacial orientation of (111)LTO??(004)TiO2 , while it is (111)LTO??(101)TiO2 for other compositions. This study therefore shows that the dual-phase interface with these specific orientations gives the best performance. The synergistic combination of dual-phase nanoparticles with multi-wall carbon nanotubes improves the performance further. This results in an electrode with supercapacitor-like rate capability delivering high discharge capacities of 174, 127, 119, 110, 101 and 91 mAh g-1 at specific currents of 2000, 6000, 12 000, 18 000, 24 000 and 30 000 mA g-1, respectively. A discharge capacity of 174 mAh g-1 at a specific current of 2000 mA g-1 with only 0.005% capacity loss per cycle over 3000 cycles is demonstrated. At current densities of 6000, 12 000 and 24 000 mA g-1, stable cycling is obtained for 1500 cycles. The present work enables nano-engineered interfaces in LTO-TiO2 dual-phase nanoparticles with an electrochemical performance that is better than its individual components, opening up the potential for high-power Li-ion battery applications. PMID- 29256872 TI - Tuning electronic and optical properties of arsenene/C3N van der Waals heterostructure by vertical strain and external electric field. AB - Searching for new van der Waals (vdW) heterostructure with novel electronic and optical properties is of great interest and importance for the next generation of devices. By using first-principles calculations, we show that the electronic and optical properties of the arsenene/C3N vdW heterostructure can be effectively modulated by applying vertical strain and external electric field. Our results suggest that this heterostructure has an intrinsic type-II band alignment with an indirect bandgap of 0.16 eV, facilitating the separation of photogenerated electron-hole pairs. The bandgap in the heterostructure can be tuned from 0-0.35 eV via the strain, experiencing an indirect-to-direct bandgap transition. Moreover, the bandgap of the heterostructure varies linearly with respect to a moderate external electric field, and the semiconductor-to-metal transition can be realized in the presence of a strong electric field. The calculated band alignment and the optical absorption reveal that the arsenene/C3N heterostructure could present excellent light-harvesting performance. Our designed vdW heterostructure is expected to have great potential applications in nanoelectronic devices and photovoltaics. PMID- 29256873 TI - Impact of early (3 months) dual antiplatelet treatment interruption prior to renal transplantation in patients with second-generation DES on perioperative stent thrombosis and MACEs. AB - OBJECTIVE: Early cessation of dual antiplatelet therapy (DAPT) is related to stent thrombosis (ST). The use of second-generation everolimus- and zotarolimus eluting stents is associated with low restenosis rates and short duration of clopidogrel usage. Non-cardiac surgery in recently stent-implanted patients is associated with major adverse cardiac events (MACEs). Chronic renal failure patients awaiting renal transplantation may also undergo coronary stent implantation prior to surgery. Here we aimed to investigate the safety of early (3 months) DAPT interruption in second-generation drug-eluting stent (DES) implanted renal transplant recipients. METHODS: In total, 106 previously stent implanted chronic renal failure patients who underwent renal transplantation were retrospectively enrolled. Three groups were formed according to stent type and the duration of DAPT: early-interruption (3 months from DES implantation), lateinterruption (3-12 months from DES implantation), and bare-metal stent (BMS; at least 1 month from BMS implantation) groups. RESULTS: Comparison among BMS, DES-early and DES-late groups indicated no difference in ST, myocardial infarction, death, and MACEs. In addition, no difference was observed in ST (p=0.998), myocardial infarction (p=0.998), death (p=0.999), and MACEs (p=0.998) between DES-early and DES-late groups. CONCLUSION: Early (3 months) interruption of antiplatelet treatment with second-generation stents before renal transplantation seems to be safe and does not lead to increase in the occurrence of ST and MACEs. PMID- 29256874 TI - Evaluation of ventricular repolarization features with novel electrocardiographic parameters (Tp-e, Tp-e/QT) in patients with psoriasis. AB - OBJECTIVE: Psoriasis is a chronic inflammatory disorder, which affects around 1% 3% of the human population worldwide. Cardiovascular events are the leading cause of morbidity and mortality in patients with psoriasis. Some studies have reported that psoriasis is related to increased arrhythmias. The Tp-e interval and Tp-e/QT ratio have been accepted as new markers for the assessment of myocardial repolarization and ventricular arrhythmogenesis. The aim of this study was to assess ventricular repolarization in patients with psoriasis using Tp-e interval and Tp-e/QT ratio. METHODS: The study population consisted of 74 patients with psoriasis and 74 healthy volunteers. The diagnosis of psoriasis was based on a clinical or histopathological examination of all patients. QT interval, corrected QT (QTc), QT dispersion (QTd), Tp-e interval, corrected Tp-e, and Tp-e/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared between groups. RESULTS: According to the electrocardiographic parameters, QT and QTc intervals and QTd were significantly higher in patients with psoriasis than in control subjects (p<0.001; p<0.001; p=0.014; respectively). The Tp-e interval, corrected Tp-e, and Tp-e/QT ratio were significantly higher in patients with psoriasis than in control subjects [93+/-13 milliseconds (ms) vs. 98+/-14 ms, p=0.040; 104+/-17 ms vs. 111+/-17 ms, p=0.008; 0.23+/-0.03 vs. 0.25+/-0.03, p<0.001; respectively]. Additionally, the CRP value was an independent predictor of an increased Tp-e/QT ratio (beta=0.537, p< 0.001). CONCLUSION: Our study revealed that ventricular repolarization features were impaired in patients with psoriasis. Therefore, these patients should be more closely screened for ventricular arrhythmias. PMID- 29256875 TI - Relationship of activin A levels with clinical presentation, extent, and severity of coronary artery disease. AB - OBJECTIVE: We aimed to evaluate the relationship of serum activin A levels with risk factors, clinical presentation, biochemical marker levels, extent, and severity of atherosclerotic coronary artery disease (CAD). METHODS: In total, 310 CAD patients [92 with ST-segment elevation myocardial infarction (STEMI), 111 with non-STEMI (NSTEMI), and 107 with unstable angina (UA)] and 207 healthy subjects (controls) were enrolled. Activin A levels in all participants were measured using ELISA. Angiographic measurements were performed in patients and not in the healthy subjects. RESULTS: Activin A levels were higher in all patient groups than in controls (patients vs. controls, p=0.041; NSTEMI vs. UA, p=0.744; STEMI vs. UA, p=0.172; NSTEMI vs. STEMI, p=0.104). According to the cut-off value of activin A level, patients with high and low activin A levels had a similar distribution of clinical and biochemical variables but the prevalence of severe stenosis was observed in groups with high activin A levels. Our results revealed that activin A levels did not decrease as thrombolysis in myocardial infarction (risk score increased (p=0.590). The area under the ROC curve for activin A levels in patients was 0.590+/-0.047 (95% CI: 0.439-0.591, p=0.193). In multiple analysis of the overall population, male gender (beta=-0.260; 95% CI: -617.39 to 110.04; p=0.005) was an independent predictor of activin A levels. CONCLUSION: This study indicated that activin A can not be a predictive marker in CAD and is not associated with extensive and severe CAD. In contrast, the increase in activin A levels in patients, especially in patients with different clinical groups of acute coronary syndromes, suggested its involvement in atherosclerosis. PMID- 29256877 TI - Turkey's top publications in cardiovascular medicine in the past 25 years: evaluation of its impact. AB - OBJECTIVE: To identify "genuine" publications from Turkey's institutions since 1992 that have cumulatively contributed the most to global cardiovascular medicine. METHODS: Based on data from the Web of Science, 146 publications from Turkey were identified having received >=50 citations as of late July, 2017. Papers with more than a minor share by international authors were excluded. RESULTS: Hundred and ten primary authors generated 147 medical papers which received >=50 (interquartile range, 54; 86) citations. These articles corresponded in quality to the top 12% global papers. Half of the articles were published from 2002 to late 2007, with a median exposure period of 12 years. Peak performance was reached in 2004-'07, with a mean of 15-20 papers annually, which then regressed to five papers in 2008-'13, representing an estimated 50% decline. Cardiology generated 105 articles (20 in collaboration with other branches), cardiovascular surgery generated 27 articles, and pediatric cardiology generated 5 articles. Publications arose from 26 medical faculties, Gulhane Military Academy, and 9 hospitals not which were not academically affiliated. The performance of many related Turkish institutions was disappointing. CONCLUSION: Turkey's contribution to cardiovascular medicine has further declined slightly in the current assessment, particularly since 2007. To prevent a further gap in Turkey's contribution to the field, an undelayed return is needed by building an environment that allows focusing on research with a potential to contribute to medicine. PMID- 29256876 TI - Impact of long-term glycemic variability on development of atrial fibrillation in type 2 diabetic patients. AB - OBJECTIVE: It is well known that patients with type 2 diabetes mellitus (T2DM) have a high risk of atrial fibrillation (AF). The current study was designed to determine the relationship between long-term glycemic variability and incidence of new-onset AF in T2DM patients. METHODS: Between January 2008 and December 2009, we conducted a retrospective cohort study in patients with T2DM referred to our hospital. In 505 consecutive patients without any medical history of AF at baseline, the relationship between hemoglobin A1c (HbA1c) variability and future AF incidence was evaluated, with adjustments for other possible confounding factors. HbA1c variability was determined by standard deviation (SD) and coefficient of variation (CV). RESULTS: Over a median of 6.9-year follow-up period, 48 patients (9.5%) developed incident AF. Multiple cox regression revealed that higher HbA1c-SD (HR: 1.726, 95% CI: 1.104-1.830, p=0.001) or HbA1c CV (HR: 1.241, 95% CI: 1.029-1.497, p=0.024) remained the remarkable predictor of new-onset AF after adjusting for age, body mass index, left ventricular mass index, and left atrium diameter. Receiver operating curve analysis identified thresholds for HbA1c-SD (0.665%, sensitivity 71.4%, specificity 54.9%) and HbA1c CV (8.970%, sensitivity 73.8%, specificity 47.1%) to detect new-onset AF development. CONCLUSION: In patients with T2DM, higher HbA1c variability is significantly associated with future AF development. PMID- 29256878 TI - Cardiac catheterization procedures in pediatric patients undergoing extracorporeal membrane oxygenation cardiac catheterization, ECMO. AB - OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) is a lifesaving intervention for pediatric patients with respiratory and/or cardiovascular failure. In this study, we evaluated the cardiac catheterization results of pediatric patients on ECMO support. METHODS: Between January 2012 and October 2016, 98 patients (5.2% of all surgery patients) needed ECMO support during perioperative cardiac surgery. We retrospectively reviewed the clinical data of 16 patients who underwent cardiac catheterization under ECMO support. RESULTS: The median age at catheterization was 6.5 months (range, 3.3-60 months), and the median weight was 6.0 kg (range, 3.7-16 kg ). Eight of the catheterizations were diagnostic, and the remaining eight were interventional. Five out of these eight patients underwent surgical palliation after diagnostic catheterization. Right pulmonary artery (RPA) stenting, right ventricular outflow tract (RVOT) stenting, combined left pulmonary artery (LPA) and RVOT stenting, combined LPA and modified Blalock-Taussig shunt stenting, bilateral pulmonary artery balloon angioplasty, and bilateral pulmonary artery stenting were each performed once, whereas LPA stenting was performed in two different patients. In one patient undergoing RVOT stenting, a complete atrioventricular block developed, resulting in hypotension; however, this was overcome with an ECMO flow increase. In another patient, the ECMO tubing disconnected from the arterial line. Minor vascular complications were seen in three patients. Twelve patients (75%) were successfully weaned from ECMO after the procedure and ten (63%) were discharged. CONCLUSION: Diagnostic and interventional cardiac catheterization can be safely and effectively performed in patients on ECMO. If the patient cannot be weaned from ECMO support, clinicians should consider performing an early angiogram either to treat or clarify the underlying problem. PMID- 29256879 TI - ECMO in children post cardiac surgery-opportunity for redress. PMID- 29256880 TI - Successful treatment of abdominal aorto-right atrial fistula by vascular plug: A previously unreported cardiac malformation. PMID- 29256881 TI - A novel mutation in the desmoplakin gene in two female siblings with a rare form of dilated cardiomyopathy: Carvajal syndrome. PMID- 29256882 TI - A Mexican Standoff: Mitral stenosis, mitral balloon valvuloplasty, Tp-e interval, Tp-e/QT and Tp-e/QTc ratios and sympathetic activity. PMID- 29256883 TI - Author's Reply. PMID- 29256884 TI - Atrioventricular block after reperfusion: A reflection on early beta-blocker therapy for acute myocardial infarction. PMID- 29256885 TI - Stenotrophomonas maltophilia pericarditis. PMID- 29256886 TI - Assessment of hemodynamic changes in preterm infants with respiratory distress syndrome. PMID- 29256887 TI - In memory of Prof. Dr. Altan Onat. PMID- 29256888 TI - A rare radiodiagnostic finding: Porcelain atrium. PMID- 29256889 TI - A rare cause of pericardial tamponade: Chylopericardium. PMID- 29256890 TI - Effusive constrictive pericarditis diagnosed with PET/CT and treated medically. PMID- 29256891 TI - Featured in this issue. PMID- 29256892 TI - Protective effect of celastrol on myocardial ischemia-reperfusion injury. AB - OBJECTIVE: Celastrol, a major active constituent of Tripterygium wilfordii, has antioxidant, anti-inflammatory, and anticancer effects. However, whether celastrol can exert protective effect on myocardial ischemia-reperfusion injury (MIRI) is unknown. The aim of this study was to test the protective effect of celastrol on MIRI and elucidate its underlying mechanism. METHODS: Cardiomyocytes (H9c2 cells) were subjected to hypoxia for 8 h followed by reoxygenation for 4 h to create hypoxia/reoxygenation (H/R) model, an in vitro MIRI model. Celastrol was added to the medium 60 min before the H/R process . Cell viability was detected using MTT assay. Myocardial injury was evaluated by measuring lactate dehydrogenase (LDH) and creatine kinase MB isoenzyme (CK-MB) activity. Changes in mRNA and protein expression of TNF-alpha, IL-1beta, and nuclear factor-K B (NF-K B) were measured with RT-qPCR assay and western blot analysis. RESULTS: Results showed that low-dose celastrol (20 and 50 nM) treatment significantly increased cell viability and decreased LDH and CK-MB activity in the condition of H/R, but high-dose celastrol (200 and 400 nM) resulted in extra injury to cardiomyocytes. Moreover, treatment with 50 nM celastrol significantly downregulated mRNA and protein expression of TNF-alpha and IL-1beta. Meanwhile, NF-K B mRNA and protein in the nucleus were also correspondingly reduced. CONCLUSION: Our study demonstrated that low-dose celastrol could prevent MIRI in cardiomyocytes by inhibiting the activation of NF-K B, and celastrol may be a potential therapeutic agent for preventing MIRI. PMID- 29256893 TI - Enhanced antinociception with repeated microinjections of apomorphine into the periaqueductal gray of male and female rats. AB - Dopamine neurons in the ventrolateral periaqueductal gray (PAG) have been reported to contribute to antinociception. The objective of this study was to determine how this dopamine-mediated antinociception differs from what is known about morphine-induced antinociception. Microinjection of the dopamine receptor agonist apomorphine into the PAG produced a dose-dependent increase in hot plate latency and a decrease in open field activity that was greater in male than in female rats. The peak antinociceptive effect occurred 5 min after apomorphine administration. Surprisingly, the antinociceptive potency of apomorphine was enhanced following systemic administration of the opioid receptor antagonist naloxone in male, but not in female rats. The antinociceptive potency of microinjecting apomorphine into the ventrolateral PAG in male and female rats was also enhanced following twice-daily injections for 2 days. The characteristics of apomorphine-induced antinociception differ from previous reports of morphine antinociception following PAG microinjections in that morphine antinociception peaks at 15 min, is blocked by naloxone, and is susceptible to tolerance with repeated administration. These results indicate that apomorphine-induced antinociception is distinct from opioid-induced antinociception, and that dopamine receptor agonists may provide a novel approach to pain modulation. PMID- 29256895 TI - Recent developments in visual field testing for glaucoma. AB - PURPOSE OF REVIEW: Visual field testing remains one of the most important tools for characterizing and monitoring vision loss in glaucoma. Despite its current mainstream use, new developments continue to emerge on its current use and potentially better methods for its testing and analysis. This review summarizes new developments in visual field testing and, in particular, standard automated perimetry. RECENT FINDINGS: Evidence-based guidance has recently been provided on the impact of testing frequency on the ability to detect visual field progression. An increasing body of evidence also highlights numerous factors that can impact the interpretation of visual field results currently considered reliable (e.g. the reliability indices themselves, fixation tracking parameters, and cognitive decline). More targeted visual field testing paradigms for central and peripheral visual fields have been explored, although further work is needed to understand their role in clinical care. Exploiting retinal imaging during visual field testing with fundus-tracked perimetry shows promise for improving precision. Thresholding algorithms that account for spatial and structural information and novel analytical techniques for longitudinal data could also improve the ability to detect and monitor visual field loss. New promising methods for objective and portable assessment of visual function have also emerged. SUMMARY: New developments in visual field testing shows promise for improving this challenging, yet fundamental, clinical test for glaucoma management. PMID- 29256894 TI - Critical Care Organizations: Building and Integrating Academic Programs. AB - OBJECTIVE: Academic medical centers in North America are expanding their missions from the traditional triad of patient care, research, and education to include the broader issue of healthcare delivery improvement. In recent years, integrated Critical Care Organizations have developed within academic centers to better meet the challenges of this broadening mission. The goal of this article was to provide interested administrators and intensivists with the proper resources, lines of communication, and organizational approach to accomplish integration and Critical Care Organization formation effectively. DESIGN: The Academic Critical Care Organization Building section workgroup of the taskforce established regular monthly conference calls to reach consensus on the development of a toolkit utilizing methods proven to advance the development of their own academic Critical Care Organizations. Relevant medical literature was reviewed by literature search. Materials from federal agencies and other national organizations were accessed through the Internet. SETTING: The Society of Critical Care Medicine convened a taskforce entitled "Academic Leaders in Critical Care Medicine" on February 22, 2016 at the 45th Critical Care Congress using the expertise of successful leaders of advanced governance Critical Care Organizations in North America to develop a toolkit for advancing Critical Care Organizations. MEASUREMENTS AND MAIN RESULTS: Key elements of an academic Critical Care Organization are outlined. The vital missions of multidisciplinary patient care, safety, and quality are linked to the research, education, and professional development missions that enhance the value of such organizations. Core features, benefits, barriers, and recommendations for integration of academic programs within Critical Care Organizations are described. Selected readings and resources to successfully implement the recommendations are provided. Communication with medical school and hospital leadership is discussed. CONCLUSIONS: We present the rationale for critical care programs to transition to integrated Critical Care Organizations within academic medical centers and provide recommendations and resources to facilitate this transition and foster Critical Care Organization effectiveness and future success. PMID- 29256896 TI - Anticlotting agents and the surgical management of glaucoma. AB - PURPOSE OF REVIEW: A large subset of patients with glaucoma uses anticlotting agents. No standardized guidelines currently exist for managing these agents in the specific perioperative setting of glaucoma surgery. The present review focuses on currently available anticlotting agents, their influence on hemorrhagic complications following glaucoma surgery, and management strategies for their use in the perioperative period RECENT FINDINGS: Anticlotting agents increase the risk of perioperative hemorrhagic complications following glaucoma surgery. Other factors that increase that risk have been identified as well, including the type of glaucoma surgery, preoperative intraocular pressure, postoperative hypotony, previous ocular surgeries, and race. Although general guidelines in the perioperative management of blood thinning agents exist, the best way to apply these guidelines specifically to glaucoma surgery remains unclear. SUMMARY: Blood thinners are widely used and can increase the risk of hemorrhagic complications in patients undergoing glaucoma surgery. Managing these agents in the perioperative setting is challenging and should be done in collaboration with the patient's primary care provider, hematologist, or cardiologist. Management strategies should be tailored to each individual's risk of hemorrhage versus thromboembolism. Additionally, surgical plans can be modified to help minimize hemorrhagic outcomes, especially in patients who are deemed to be at high risk for perioperative bleeding. PMID- 29256897 TI - Complications of micro-invasive glaucoma surgery. AB - PURPOSE OF REVIEW: Micro-invasive glaucoma surgery (MIGS) is gaining favor with both comprehensive ophthalmologists and glaucoma specialists due in part to its improved safety profile when compared to traditional incisional glaucoma surgery. Despite a micro-invasive approach and minimal induced tissue trauma, each MIGS procedure is associated with unique complications. The present article summarizes evidence from the 2016 to 2017 review period regarding the safety profiles of Schlemm's canal-based, suprachoroidal, and subconjunctival microstents. RECENT FINDINGS: Ab-interno microstents are subject to intraoperative malpositioning, which can result in luminal obstruction and decreased efficacy. Acutely elevated intraocular pressure (IOP) has been observed with the iStent (Glaukos Corp., Laguna Hills, CA, USA; 2-4.3%), Hydrus Microstent (Ivantis Inc., Irvine, CA, USA; 6%), Cypass Microstent (Alcon, Fort Worth, TX, USA; 3-10.8%), and Xen Gel Stent (Allergan Plc, Dublin, Ireland; 21.5%). Meanwhile, most cases of hypotony (IOP < 6 mmHg) occurred within the first postoperative month, resolved with conservative treatment and without further surgical intervention, and were not associated with vision-threatening sequelae. SUMMARY: Interest in MIGS continues to grow as these procedures allow surgeons to intervene earlier in the disease course for patients with milder stages of glaucoma. Complications associated with MIGS, albeit infrequent and mostly transient, do occur despite a less invasive approach than trabeculectomy and tube shunt surgery. PMID- 29256899 TI - SUMOylation regulates TGF-beta1/Smad4 signalling in-resistant glioma cells. AB - The aim of this study was to explore the role of TGF-beta1/Smad4 signalling in the DNA damage-induced ionization radiation (IR) resistance of glioma cells. T98G cells were assigned to the IR group (treated with IR) or the Blank group (with no treatment). The IR-treated cells were also treated/transfected with the TGF-beta receptor inhibitor SB431542, SUMO1-overexpressing plasmids (SUMO1 group), SUMO1 interfering plasmids (si-SUMO1 group) or negative control plasmids group. The wound-healing capacity, cell proliferation and cell apoptosis were evaluated by the scratch assay, flow cytometry and the CCK-8 assay, respectively, and protein interactions were investigated by coimmunoprecipitation and colocalization assays. IR-treated T98G cells had DNA damage, but the wound-healing capacity and cell apoptosis were not significantly suppressed. DNA damage also induced TGF beta1, Smad4, SUMO1, SUMO2/3 and Ubc9 expression. In IR-treated cells cultured with SB431542, the wound-healing capacity and proliferation were promoted. SUMO1 and Smad4 colocalized in the nucleus of T98G cells, and the IR-treated cells had a significantly higher expression of the SUMO1-Smad4 protein complex. Smad4 expression in the nucleus was significantly reduced in the si-SUMO1 group, but was markedly increased in the SUMO1 group; the SUMO1 group had significantly elevated apoptotic activity, whereas the si-SUMO1 group showed significantly suppressed apoptotic activity and the si-SUMO1+SB41542 group had the lowest levels of cell apoptosis. DNA damage may activate Smad4 SUMOylation and the SUMOylation of Smad4 participates in the activation of TGF-beta/Smad4 signalling; therefore, enhanced Smad4 SUMOylation is critical for the damage-induced activation of IR resistance. PMID- 29256900 TI - Anticancer properties of thiophene derivatives in breast cancer MCF-7 cells. AB - Substitutions in thiophene structure give rise to new derivatives with different biological and pharmacological activities. The present study investigated the cytotoxicity activity of some thiophene derivatives in breast cancer cells maintained in two-dimensional (2D) or in three-dimensional (3D) culture and evaluated the anticancer mechanism of these compounds. Cytotoxicity assays were performed against untransformed cells and against breast cancer cell MCF-7. Apoptosis analysis and in-vitro migration assay were also performed to evaluate the mechanism of induction of cell death. All thiophene derivatives reduced the cell viability in breast cancer cells, showing cytotoxic activity (IC50<30 umol/l), and SB-200 compound showed the best selectivity index in MCF-7 cells compared with doxorubicin in 2D culture. All thiophene derivatives significantly induced G0/G1 phase cell cycle arrest. However, only SB-83 treatment was effective against motility of MCF-7 cells in 2D culture (P=0.0059). The SB-200 derivative treatment induced an increased proportion of acridine orange/Hoechst double-stained cells (35.35 vs. 3.14%, P=0.0002) compared with nontreated cells, with apoptosis morphological alterations independent of caspase 7 activation (P>0.05). MCF-7 cells became less responsive to SB-200 and to doxorubicin in 3D culture compared with cells in 2D culture (higher IC50 values); however, SB-200 showed a better cytotoxic effect compared with doxorubicin in 3D culture. Therefore, the current study provides an insight into anticancer potential of thiophene derivatives, and further studies should be conducted to understand the mechanism by which thiophene derivatives act on cancer cells. PMID- 29256898 TI - Mechanisms of vascular comorbidity in autoimmune diseases. AB - PURPOSE OF REVIEW: Persuasive statistics support the clinical observation that because of cardiovascular comorbidities patients with inflammatory joint disease die significantly earlier despite anti-inflammatory therapy. RECENT FINDINGS: The reason for this earlier death is multifactorial and involves a combination of a complex genetic background, environmental influences, classical cardiovascular risk factors and the impact of anti-inflammatory therapy. We will describe the importance of several new mechanisms, especially the diverse intercellular communication routes including extracellular vesicles and microRNAs that support the development of cardiovascular comorbidities. SUMMARY: The aim of this review is to give an updated overview about the known risk factors in the development of cardiovascular comorbidities with the latest insights about their mechanism of action. Furthermore, the impact of newly identified risk factors and significance will be discussed. PMID- 29256901 TI - Treatment of ALK-positive nonsmall cell lung cancer: recent advances. AB - PURPOSE OF REVIEW: The review will highlight recent advances in development of ALK-TKIs and management of patients with ALK-positive nonsmall cell lung cancer. RECENT FINDINGS: There has been rapid progress in the use of targeted therapies for ALK-positive NSCLC. Since the discovery, development and approval of crizotinib in 2011, three second-generation ALK-TKIs, ceritinib, alectinib and brigatinib have been approved by the FDA. A range of newer generation ALK inhibitors with improved potency against ALK and against mutations that confer resistance to crizotinib are in clinical development. SUMMARY: Our review will discuss the recent phase III data with ceritinib and alectinib as well as clinical trials with other ALK inhibitors. We will also address two important issues in the management of ALK-positive NSCLC, prevention and treatment of brain metastases and management of emergent ALK-TKI resistance mechanisms. PMID- 29256902 TI - Update on adjuvant melanoma therapy. AB - PURPOSE OF REVIEW: We review the results from relevant clinical trials and discuss current strategies in the melanoma adjuvant setting. RECENT FINDINGS: The favorable therapeutic efficacy and the significant less toxicity of nivolumab compared with ipilimumab, fully substitutes today's approval of ipilimumab, regardless mutation status, whereas in BRAF-mutated patients, dabrafenib and trametinib seem to confirm their high efficacy also in adjuvant setting. The use of interferon is restricted to patients with ulcerated melanoma and countries with no access to the new drugs. SUMMARY: Systemic adjuvant treatment after complete disease resection in high-risk melanoma patients aims to increase relapse-free survival (RFS) and overall survival (OS). According to the eighth edition of melanoma classification of American Joint Committee on Cancer (AJCC), the prognosis in stage III patients is heterogeneous and depends not only on N (nodal) but also on T (tumor thickness) category criteria. Recent data from randomized, phase-3 clinical trials analyzing the use of adjuvant anti-programmed death-1 and targeted therapies ultimately affect the standard of care and change the landscape of the adjuvant treatment. PMID- 29256903 TI - Improving the Diagnosis of Allergic Contact Dermatitis Using Patch Test With Gloves. PMID- 29256905 TI - Contemporary techniques and outcomes of robotic cystectomy and intracorporeal urinary diversions. AB - PURPOSE OF REVIEW: Robot-assisted radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) is being increasingly performed worldwide. This review summarizes recent technical developments and outcome data for RARC with ICUD. RECENT FINDINGS: With the recent description of intracorporeal continent cutaneous diversion, all classes of urinary diversion can presently be performed totally intracorporeally. The summary of our seven cases of intracorporeal continent cutaneous diversion in this article brings the number of reported cases in the literature to 17. Additional recent advancements in ICUD focus on novel technical descriptions and outcome data. Several intracorporeal orthotopic ileal neobladder techniques have been described with intermediate perioperative outcomes. There is some rationale for reduced overall, wound, gastrointestinal and genitourinary complications with ICUD. SUMMARY: RARC with intracorporeal diversion is a feasible option for patients with bladder cancer. Prospective and randomized outcome data are needed to better characterize the benefit of ICUD in patients following radical cystectomy. PMID- 29256904 TI - Contact Dermatitis Associated With Skin Cleansers: Retrospective Analysis of North American Contact Dermatitis Group Data 2000-2014. AB - BACKGROUND: There is limited information regarding contact dermatitis (CD) associated with skin cleansers (SCs). OBJECTIVE: The aim of the study was to evaluate the prevalence of allergic patch test (APT) reactions and irritant CD (ICD) associated with SCs. METHODS: A retrospective cross-sectional analysis was performed using North American Contact Dermatitis Group data, 2000-2014. RESULTS: Of 32,945 tested patients, 1069 (3.24%) had either APT reaction or ICD associated with SCs. Of these, 692 (64.7%) had APT reaction only, 350 (32.7%) had ICD only, and 27 (2.5%) had both. Individuals with APT reaction and/or ICD were more likely to have occupationally related skin disease (relative risk [RR] = 3.8 [95% confidence interval {CI} = 3.3-4.5] for APT reaction and 10.0 [95% CI = 8.2-12.2] for ICD, respectively, P < 0.0001). As compared with those without APT reaction to SC, individuals with APT reaction had significantly higher frequencies of hand (RR = 2.4 [95% CI = 2.1-2.7]) and arm dermatitis (RR = 1.3 [95% CI = 1.1-1.6], P <= 0.001). Irritant CD was strongly associated with hand dermatitis (RR = 6.2 [95% CI = 5.2-7.3], P < 0.0001). More than 50 allergens were associated with SCs including quaternium-15 (11.2%), cocamidopropyl betaine (9.5%), methylchloroisothiazolinone/methylisothiazolinone (8.4%), coconut diethanolamide (7.9%), fragrance mix I (7.7%), Myroxylon pereirae (5.9%), 4-chloro-3,5-xylenol (5.8%), amidoamine (5.5%), and formaldehyde (4.4%). CONCLUSIONS: Many allergens, especially preservatives and surfactants, were associated with SCs. Most cases involved the hands and were occupationally related. PMID- 29256906 TI - Out of proportion pulmonary hypertension in obstructive lung diseases. AB - PURPOSE OF REVIEW: Pulmonary hypertension is common (25-90%) in chronic obstructive pulmonary diseases (COPDs). Severe pulmonary hypertension, however, is quite rare (1-3%). The term 'out of proportion' pulmonary hypertension is still widely used. New guidelines instead propose to use the term 'Severe pulmonary hypertension' if mean pulmonary arterial pressure at least 35 mmHg or cardiac index (CI) is less than 2.0 l/min/m on right heart catheterization (RHC). Why only a minority of COPD patients develop severe pulmonary hypertension is unclear. RECENT FINDINGS: When present, severe pulmonary hypertension in COPD is associated with increased dyspnea and decreased survival and often does not closely correlate with degree of obstructive abnormality on pulmonary function testing. COPD patients with severe pulmonary hypertension experience circulatory limitation at maximum exercise, and not ventilatory limitation, which is typical for moderate-to-severe COPD patients with no or moderate pulmonary hypertension. SUMMARY: There is no conclusive evidence to support or completely reject the possibility of the use of specific pulmonary arterial hypertension (PAH) therapies in pulmonary hypertension associated with COPD. In mild-to-moderate COPD patients who have severe and progressive symptoms, and have evidence of severe pulmonary hypertension on RHC, specific PAH therapies may be used similar to WHO group-I PAH guidelines. PMID- 29256907 TI - Prevalence and drug treatment practices of inflammatory bowel diseases in Poland in the years 2012-2014: an analysis of nationwide databases. AB - BACKGROUND: Inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) are chronic autoimmune disorders that constitute a major societal and economic burden for individual patients, their families and the society. The aim of this study was to assess the current prevalence and treatment patterns of IBD in Poland. PATIENTS AND METHODS: We carried out a retrospective analysis of the nationwide databases of the National Health Fund for the years from 2012 to 2014 to obtain data on the prevalence and treatment patterns of IBD. Patients with IBD were identified according to the ICD-10 codes indicated in medical records and the type of medical resource utilized during the study. Pharmacotherapy for IBD by age group, sex and IBD types was presented. RESULTS: The prevalence of IBDs was 157/100 000 individuals, including 35 patients with CD per 100 000 individuals. The use of drugs differed by age and diagnosis (P<0.001). Biologics, steroids and immunosuppressants were used more often by patients with CD than those with UC (13.2 vs. 0.3%, 54.5 vs. 37.5%, and 44.8 vs. 15.1%, respectively). Aminosalicylates were used more often by patients with UC than those with CD. Biologics were used most often by the youngest patients (<=18 years) and seldom by patients aged 65 years or older (7.7 and 0.1%, respectively). CONCLUSION: Our study showed a moderate prevalence of IBD in Poland. Treatment patterns depended on the patient's age and IBD type. The use of biologics was higher among young patients with CD than among older patients with other IBDs. Although not recommended, aminosalicylates were still commonly used in patients with CD, even during biologic and/or immunosuppressive treatment. PMID- 29256909 TI - Comparison of Two Versions of the Hospital Anxiety and Depression Scale in Assessing Depression in a Neurologic Setting. AB - BACKGROUND: The Hospital Anxiety and Depression Scale-Depression Subscale (HADS D) is widely used to assess depression in people with multiple sclerosis (MS). Developed specifically for use in a medical setting, the scale has one item, "I feel as if I am slowed down," that might represent a significant somatic confounder, possibly biasing the assessment. OBJECTIVE: We sought to determine whether inclusion or exclusion of the "slowed down" item in the HADS-D affects the detection of depression and the scale's associations with impaired cognition, fatigue, and employment status. METHODS: A sample of 193 people with confirmed MS completed the HADS. To identify depressed participants, we used previously established cutoff scores for the HADS-D with (>=8) and without (>=6) the "slowed down" item. Linear and logistic regression models were used to determine predictors of cognition and employment status. RESULTS: The HADS-D with and without the "slowed down" item detected similar rates of depression: 30.6% and 31.6%, respectively. Both versions of the HADS-D predicted processing speed and executive functioning, but not memory. Neither version predicted employment status. CONCLUSIONS: The HADS-D is an easy-to-use and clinically relevant self report psychometric scale for detecting depression in MS. Removing the "slowed down" item from the HADS-D does not influence its internal consistency, and both versions have similar associations with clinical outcomes. PMID- 29256908 TI - Functional Reorganization of Right Prefrontal Cortex Underlies Sustained Naming Improvements in Chronic Aphasia via Repetitive Transcranial Magnetic Stimulation. AB - BACKGROUND AND OBJECTIVE: While noninvasive brain stimulation techniques show promise for language recovery after stroke, the underlying mechanisms remain unclear. We applied inhibitory repetitive transcranial magnetic stimulation (rTMS) to regions of interest in the right inferior frontal gyrus of patients with chronic poststroke aphasia and examined changes in picture naming performance and cortical activation. METHODS: Nine patients received 10 days of 1 Hz rTMS (Monday through Friday for 2 weeks). We assessed naming performance before and immediately after stimulation on the first and last days of rTMS therapy, and then again at 2 and 6 months post-rTMS. A subset of six of these patients underwent functional magnetic resonance imaging pre-rTMS (baseline) and at 2 and 6 months post-rTMS. RESULTS: Naming accuracy increased from pre- to post rTMS on both the first and last days of treatment. We also found naming improvements long after rTMS, with the greatest improvements at 6 months post rTMS. Long-lasting effects were associated with a posterior shift in the recruitment of the right inferior frontal gyrus: from the more anterior Brodmann area 45 to the more posterior Brodmann areas 6, 44, and 46. The number of left hemispheric regions recruited for naming also increased. CONCLUSIONS: This study found that rTMS to the right hemisphere Broca area homologue confers long-lasting improvements in picture naming performance. The mechanism involves dynamic bilateral neural network changes in language processing, which take place within the right prefrontal cortex and the left hemisphere more generally. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (Identifier NCT00608582). PMID- 29256910 TI - CERAD Neuropsychological Battery-Arabic Version: Regression-Based and Stratified Normative Data and Effects of Demographic Variables on Cognitive Performance in Older Omanis. AB - BACKGROUND AND OBJECTIVES: Normative data on cognitive performance for the Omani population are scarce. In this study, we tested a sample of older (>=50 years) community-dwelling Omanis on the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery-Arabic version (CERAD-ArNB). We analyzed the participants' cognitive performance and how it was affected by their sex, age, and level of education. METHODS: We enrolled 150 older Arabic-speaking Omanis from March 2014 to June 2015. Most of the participants were visitors to patients admitted to a tertiary referral center in the Sultanate of Oman. All participants underwent screening to ensure normal cognitive function before taking the CERAD-ArNB. We used multiple regression analysis and stratification according to demographic variables to illustrate the normative data. RESULTS: A total of 125 participants, 65 men (52%) and 60 women (48%), met the inclusion criteria and completed the testing. Multiple regression and univariate analyses showed that although sex and age significantly affected cognitive performance on some CERAD-ArNB subtests, education level had by far the greatest effect. CONCLUSIONS: Lower education level was associated with poorer CERAD-ArNB performance in a sample of cognitively normal Omanis aged 50 years and older. The normative data obtained from this study will help clinicians correctly interpret cognitive performance in the Omani elderly population, and probably in other, culturally similar Arabic-speaking communities. PMID- 29256911 TI - Semantic Feature Disturbance in Alzheimer Disease: Evidence from an Object Decision Task. AB - BACKGROUND AND OBJECTIVE: It is widely held that semantic disturbance in Alzheimer disease (AD) involves the loss of distinctive features but the relative sparing of nondistinctive features. Many previous studies of semantic feature disturbance have used cognitively challenging tasks with verbal stimuli that allow for potential cognitive confounds. Our objective was to use a task with lower memory demands to investigate distinctive feature disturbance in AD. METHODS: We used an object decision task to compare the processing of distinctive and nondistinctive semantic features in people with AD and age-matched controls. The task included six conditions based on the relationship between each prime and target object. We tested the processing of distinctive and nondistinctive features by selectively altering distinctive and nondistinctive semantic features between prime and target pairs. RESULTS: Performance accuracy was significantly lower for participants with AD than for age-matched controls when distinctive features were manipulated, but no difference was found when nondistinctive features were manipulated. CONCLUSIONS: Our results provide evidence of semantic content disturbance in AD in the context of a task with low cognitive demands. PMID- 29256912 TI - Apathy and Cognitive Deficits in Patients with Transient Global Ischemia After Cardiac Arrest. AB - BACKGROUND AND OBJECTIVE: Despite the extensive literature on cognitive deficits in the course of transient global ischemia after cardiac arrest with delayed resuscitation, apathy has been studied less frequently and systematically. We aimed to evaluate the frequency of apathy, defined as changes in drive or lack of motivation, and its relation to cognition as well as depression in people with transient global ischemia after cardiac arrest. METHODS: In a retrospective study using the clinical data of 38 cardiac arrest survivors, we analyzed the frequency and severity of deficits in four cognitive domains (attention, memory spans, long term memory, and executive functions) as well as apathy. RESULTS: As in previous studies, long-term memory problems were predominant, but occurred rarely in isolation. Problems in drive were frequent and correlated with the severity of deficits in all cognitive domains except memory spans (and executive functions only as a trend). Influences of apathy were independent of the presence of a depressive syndrome. CONCLUSIONS: Transient global ischemia after cardiac arrest generally leads to a broad pattern of cognitive decline with predominating memory deficits. Apathy is a frequent sequela and is associated with cognitive deficits, independent of depression. Studies investigating the cognitive profile after cardiac arrest should account for modulating influences of apathy. PMID- 29256913 TI - Leftward Bias of Visual Attention in Patients with End-Stage Renal Disease Receiving Dialysis: A Neglected Phenomenon. AB - BACKGROUND AND OBJECTIVE: Patients with end-stage renal disease (ESRD) who are receiving dialysis often have cognitive and behavioral changes, including impairments in sustained attention. Impairments in sustained attention appear to be the consequence of right hemisphere dysfunction. Right hemisphere brain networks are also important for the allocation of spatial attention. Therefore, the objective of this study was to learn whether patients with ESRD receiving dialysis might also have a spatial attentional bias. PARTICIPANTS AND METHODS: Eighteen nondemented patients with ESRD receiving dialysis but without any neurologic diseases (age range: 20 to 60 years) and 18 demographically matched healthy controls participated in this study. Participants performed a standard line bisection task using 24 horizontal lines (24 cm long and 2 mm thick) that were sequentially placed at eye level on a white board. RESULTS: Patients receiving dialysis had a significantly greater leftward bias than healthy controls. CONCLUSIONS: Patients with ESRD receiving dialysis appear to have an impaired ability to correctly allocate their spatial attention (spatial neglect). Although the reason for the patients' leftward bias needs to be elucidated, ESRD and/or dialysis may have induced right frontal-subcortical dysfunction that disinhibited the right parietal lobe, producing a left-sided attentional bias. Further studies are needed to test this hypothesis. PMID- 29256914 TI - Indications of cholecystectomy in gallstone disease. AB - PURPOSE OF REVIEW: Recent studies showed new insights in the indication and timing of cholecystectomy in gallstone disease. This review will provide an overview. RECENT FINDINGS: Considerable variations in indication for gallbladder surgery have been noticed leading to a significant number of unnecessary cholecystectomies. As a consequence, up to 33% of patients with uncomplicated symptomatic gallstone disease have persistent abdominal pain after cholecystectomy. On the other hand, studies showed that certain patients with acute cholecystitis, common bile duct stones and biliary pancreatitis benefit from same admission instead of delayed cholecystectomy. SUMMARY: A critical view on indications for cholecystectomy in patients with uncomplicated symptomatic gallstone disease prevents unnecessary cholecystectomies. In patients with mild to-moderate complicated symptomatic gallstone disease, same-admission cholecystectomy reduces the risk of recurrent complications. PMID- 29256915 TI - Incidence of gallstone disease and complications. AB - PURPOSE OF REVIEW: The purpose of this review was to describe the epidemiology of gallstone disease in the era of ultrasound screening and laparoscopic cholecystectomy. RECENT FINDINGS: Recent general population cohorts, including ultrasound screenings, have contributed to our understanding of formation and clinical course of gallstone disease. Cohorts of symptomatic gallstone disease have been informative about symptom recurrence and need of treatment. Preventive targets for gallstone formation may include obesity and the associated metabolic changes. The presence of gallstone disease is best described as a continuum from asymptomatic to symptomatic disease, with the latter including both pain attacks and complicated disease. Symptomatic disease causes a persistent high risk of symptom recurrence and need of cholecystectomy. The majority of gallstone carriers will remain asymptomatic and about one in five will develop symptoms. Determinants of disease progression from asymptomatic to symptomatic disease include sex, age, body mass index, and gallstone ultrasound characteristics. SUMMARY: Because of the absence of effective gallstone formation prevention, targets against the metabolic changes in obesity should be further explored in randomized controlled trials. To optimize patient selection for cholecystectomy, treatment algorithms including identified determinants of symptomatic disease in gallstone carriers should be explored in prospective clinical trials. PMID- 29256916 TI - Are diets the answers to colon ills? Food, irritable bowel syndrome and the microbiome. PMID- 29256918 TI - Kaposi sarcoma presenting shortly after primary infection by HIV and human herpesvirus-8. PMID- 29256919 TI - Improving management of sexually transmitted infections in those who use pre exposure prophylaxis for human immunodeficiency virus infection. PMID- 29256920 TI - Visual Acuity and Cognition in Older Adults With and Without Hearing Loss: Evidence For Late-Life Sensory Compensation? AB - OBJECTIVES: Relationships between cognitive and sensory functioning become stronger with advancing age, and the debate on underlying mechanisms continues. Interestingly, the potential mechanism of compensation by the unaffected sensory modality has so far been investigated in younger age groups with congenital sensory impairment but not in older adults with late-life sensory loss. We compared associations between visual acuity and cognitive functioning in hearing impaired older adults (HI), and sensory-unimpaired controls (UI). We expected stronger associations in the HI group as compared with the UI group. DESIGN: Our study sample was drawn from the pools of outpatients from regional university clinics and city registries and consisted of n = 266 older adults (mean age = 82.45 years, SD = 4.76 years; HI: n = 116; UI: n = 150). For the assessment of cognitive performance, multiple established tests (e.g., subtests of the revised Wechsler Adult Intelligence Scale) were used. Moreover, objective visual acuity (distance vision) was assessed. RESULTS: As expected, bivariate correlations between vision and cognitive abilities were stronger in the HI group compared with the UI group. In regression models controlling for age, sex, education, subjective health and number of chronic diseases, distance visual acuity was a significant predictor of general cognitive ability in the HI group only. CONCLUSIONS: Our findings suggest that visual acuity may play an important compensatory role for maintaining cognitive ability when hearing impairment sets in, which may reflect an adaptive process of late-life sensory compensation. PMID- 29256921 TI - Accuracy of oscillometric blood pressure measurement in atrial fibrillation. AB - OBJECTIVE: The primary aim of this study was to assess the accuracy of automated oscillometry (AO) in outpatients with atrial fibrillation (AF). The secondary aim was to explore whether AO accuracy is influenced by beat-to-beat blood pressure (BP) variability or heart frequency (HF). METHODS: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by AO and beat-to-beat BP using a validated Volume Clamp Method (VCM) technique. AO accuracy was analyzed separately in tertiles of beat-to-beat BP variability and HF. RESULTS: The main study included 58 AF and 38 sinus rhythm (SR) patients in whom the Welch Allyn Spot Vital Signs (WASVS) was used. An auxiliary study in 23 AF patients used the Philips M3002A IntelliVue *2. For AF and SR patients, respectively, SBP by WASVS deviated by +0.1 (+/-14.8) mmHg and -7.9 (+/-15.7) mmHg from VCM. WASVS-DBP was higher than VCM in AF and SR by 6.3 (+/-9.2) mmHg and 5.0 (+/-7.7) mmHg, respectively. High beat-to-beat BP variability and high HF decreased WASVS accuracy for both SBP and DBP. SBP and DBP measurements by Philips M3002A IntelliVue *2 deviated by -6.8 (+/-13.2) mmHg and 9.4 (+/-8.1) mmHg, respectively. CONCLUSION: Overall, AO accuracy in AF is limited; in individual patients, AO inaccuracy may be considerable. AO accuracy is especially reduced in patients showing large beat-to-beat BP variability or high HF. PMID- 29256922 TI - Sleep disturbance in mild cognitive impairment: a systematic review of recent findings. AB - PURPOSE OF REVIEW: Research interest in sleep as a risk factor for dementia has grown, warranting an update in advances over the last 18 months, particularly in the mild cognitive impairment (MCI) stage in which interventions may be best targeted. RECENT FINDINGS: The current systematic review includes empiric research articles published since 2016 that have investigated sleep (excluding obstructive sleep apnea) in MCI. Published articles include case-control studies, those examining clinical correlates of sleep problems, sleep microarchitecture, neuroimaging studies and novel cerebrospinal and blood-based markers. SUMMARY: Evidence accumulated since 2016 continues to demonstrate that people with MCI manifest sleep disturbance on self-report measures. Neurophysiologically, sleep disturbance in MCI appears to be associated with diminished sleep spindles, key processes involved in overnight memory consolidation. Those with both MCI and sleep disturbance appear to have more pronounced functional connectivity alterations in temporoparietal brain regions and higher levels of the wake promoting neurotransmitter orexin in cerebrospinal fluid than those with MCI alone. Novel findings also suggest that sleep may mediate homocysteine and oxidative stress mechanisms, warranting further exploration. Further studies focusing on novel interventions for sleep and circadian disturbance in MCI are warranted, particularly those targeting sleep spindles, orexin/hypocretin and the oxidative stress system. PMID- 29256923 TI - Cannabinoids for the treatment of neuropsychiatric symptoms, pain and weight loss in dementia. AB - PURPOSE OF REVIEW: Efficacious treatment for neuropsychiatric symptoms (NPS), pain and weight loss for dementia patients is desperately needed. This review presents an up-to-date look at the literature investigating the use of cannabinoid for these symptoms in dementia. RECENT FINDINGS: We searched electronically for publications regarding cannabinoid use in dementia, with a focus on Alzheimer's disease. Seven studies and one case report have been conducted to examine the use of cannabinoids for the treatment of NPS of dementia, and three of these trials reported on the effect of cannabinoids on weight. Five studies reported decreased agitation or improvements in sleep with cannabinoid use. One crossover trial found that cannabinoids positively impacted weight, whereas a chart review study found no impact on weight with cannabinoids, but an increase in food intake. There were no trials examining the use of cannabinoids for pain in dementia. SUMMARY: Findings from trials with small sample sizes and various clinical populations suggest that cannabinoid use may be well tolerated and effective for treatment of NPS such as agitation as well as weight and pain management in patients with dementia. Additional studies are necessary to further elucidate the relative risks and benefits of this treatment. PMID- 29256924 TI - Electroconvulsive therapy for self-injurious behaviour in autism spectrum disorders: recognizing catatonia is key. AB - PURPOSE OF REVIEW: Self-injurious behaviour (SIB) is a devastating condition frequently encountered in autism spectrum disorders (ASDs) that can lead to dangerous tissue injury and profound psychosocial difficulty. An increasing number of reports over the past decade have demonstrated the swift and well tolerated resolution of intractable SIB with electroconvulsive therapy (ECT) when psychopharmacological and behavioural interventions are ineffective. The current article provides a review of the salient literature, including the conceptualization of repetitive self-injury along the catatonia spectrum, and further clarifies the critical distinction between ECT and contingent electric shock. RECENT FINDINGS: We searched electronically for literature regarding ECT for self-injurious behaviour from 1982 to present, as the first known report was published in 1982. Eleven reports were identified that presented ECT in the resolution of self-injury in autistic or intellectually disabled patients, and another five reports discussed such in typically developing individuals. These reports and related literature present such self-injury along the spectrum of agitated catatonia, with subsequent implications for ECT. SUMMARY: Intractable self-injury remains a significant challenge in ASDs, especially when patients do not respond adequately to behavioural and psychopharmacological interventions. ECT is well tolerated and efficacious treatment for catatonia, and can confer marked reduction in SIB along the agitated catatonia spectrum. PMID- 29256925 TI - Dispelling myths about intravenous fish oil-based lipid emulsions: a clinical perspective. AB - PURPOSE OF REVIEW: Intravenous lipid emulsions (IVLEs) are an essential component of parenteral nutrition. With the recent incorporation of new lipid emulsions into the Canadian and American market, the clinician responsible for prescribing these lipids should be educated regarding the different fatty acid (FA) profiles of these lipids, as well as their metabolic and functional effects. RECENT FINDINGS: New IVLEs contain a mix of soybean oil and olive oil, or a mix of soybean oil, coconut oil, olive oil and fish oil. These new lipid emulsions provide less essential fatty acids (FAs) (linoleic and alpha linolenic acids) than in pure soybean oil, yet incorporation of fish oil into an IVLE may decrease the amount of essential FAs required. Fish oil is a treatment for hypertriglyceridemia, and therefore, IVLEs that include fish oil may decrease serum triglycerides. Historical perspective is that fish oil can be associated with increased bleeding time. Evidence suggests that there is no association between fish oil and increased bleeding in patients, even those who are using anticoagulants. New IVLEs provide less vitamin K than soybean oil alone. Patients, or the parenteral nutrition solutions that include these new IVLEs should be supplemented with vitamin K. SUMMARY: Canadian and American Guidelines for IVLEs were based on soybean oil. Current practice should be tailored to which IVLE is being prescribed. PMID- 29256926 TI - Driver mutations in primary myelofibrosis and their implications. AB - PURPOSE OF REVIEW: Primary myelofibrosis (PMF) is one of the classic BCR-ABL1 negative myeloproliferative neoplasms (MPN). Oncogenic driver mutations in PMF include Janus kinase 2, calreticulin (CALR), and myeloproliferative leukemia virus oncogene. These mutations are not only pathogenetically relevant but might also influence disease outcome. Our objective for the current communication is to comprehensively review the distinct phenotypic, therapeutic, and prognostic implications of driver mutations in PMF. RECENT FINDINGS: The discovery of driver mutations has revolutionized our understanding of pathogenic mechanisms and clinical heterogeneity in MPN, including PMF. Recently, there have been further advances in our knowledge of the molecular pathogenesis of MPN, particularly pertaining to CALR and its mutation. Moreover, the type and number of additional mutations, their order of acquisition, and their myriad combinatorial interactions with driver mutations may have dynamic pathogenic and clinical consequences. There are also additional data supporting the role of these genetic lesions and their associated allele burdens in modulating clinical features, including outcomes following treatment. SUMMARY: Literature exists to support both phenotypic and prognostic correlates of conventional driver mutations in PMF. As the genetic landscape becomes increasingly complex, establishing the functional impact of these mutations and defining their interactions with other molecular, cytogenetic, and extrinsic factors will further our insight and potentially alter our clinical approach. PMID- 29256927 TI - Changes in the World Health Organization 2016 classification of myeloid neoplasms everyone should know. AB - PURPOSE OF REVIEW: This review highlights the main changes in the revised 2016 WHO classification of myeloid neoplasms (published in 2017) that impact diagnosis and ultimately impact management of patients with these diseases. RECENT FINDINGS: The revision was based on data accumulated since the 2008 WHO classification, much of which relate to new molecular genetic information about these neoplasms. This massive recent influx of data concerning the significance of pathogenic mutations has affected all myeloid neoplasm categories. The new information has been incorporated as part of the diagnostic criteria of many diseases and has led to the creation of new provisional entities defined by genetic features. Germline mutations that predispose to myeloid neoplasms are also emerging as important findings that impact disease classification. SUMMARY: The growing body of genetic data have not only altered the classification of myeloid neoplasms, but are also impacting patient management. Genetically-defined disease categories have characteristic prognoses and predicted clinical behavior. Some mutations are associated with responsiveness to certain therapies, including those that target relevant oncogenes. The disease categories in the new classification facilitate the application of risk-adapted therapy based on the most recently available data. PMID- 29256928 TI - Defining the Process of a Cardiovascular Risk Assessment Program: Lessons Learnt From Cardiac Assessment of Elite Soccer Players in the United Kingdom. AB - OBJECTIVE: Retrospectively analyze the cardiac assessment process for elite soccer players, and provide team physicians with a systematic guide to managing longitudinal cardiac risk. DESIGN: Descriptive Epidemiology Study. SETTING: Cardiac assessments incorporating clinical examination, 12-lead ECG, echocardiography, and health questionnaire. PARTICIPANTS: Soccer players at 5 professional clubs in England, the United Kingdom. INTERVENTION: Data was retrospectively collected, inspected, and analyzed to determine their clinical management and subsequent follow-up. RESULTS: Over 2 years, 265 soccer players, aged 13 to 37 years with 66% of white European ethnicity, were included in the cohort. Eleven percent had "not-normal" assessments, of these assessments, 83% were considered gray screens, falling into three broad categories: structural cardiac features (including valvular abnormalities), functional cardiac features, and electrocardiogram changes. After cardiology consultation, all assessments were grouped into low, enhanced and high-risk categories for ongoing longitudinal risk management. Overall clear-cut pathology was identified in 2%. CONCLUSIONS: Cardiovascular assessment is a vital tool in identifying athletes at risk of sudden cardiac death to mitigate their risk through surveillance, intervention, or participation restriction. The decision whether a player is fit to play or not requires a robust risk assessment followed by input from a multidisciplinary team that includes both the team physician and cardiologist. This educational article proposes a clinical management pathway to aid clinicians with this process. CLINICAL RELEVANCE: Sudden cardiac death is the important medical cause of death during exercise. The team physician should assume responsibility for the management of the longitudinal risk of their players' cardiac assessments in conjunction with sports cardiologist. PMID- 29256929 TI - Influence of Sex and Previous Concussion History on Postconcussive Recovery in Young Athletes. AB - OBJECTIVE: To determine whether concussed female athletes with a previous history of concussion have longer postconcussive recovery than that of male counterparts. DESIGN: Retrospective cohort study. SETTING: Outpatient sports medicine clinic in an academic practice. PARTICIPANTS: Male and female youth, high school, and collegiate athletes (n = 431; ages = 10-21 years) who sustained a sport-related concussion (SRC). INTERVENTIONS: The clinical courses of young athletes treated for concussion by 1 provider at an outpatient sports medicine clinic were retrospectively reviewed. MAIN OUTCOME MEASURES: Recovery time was compared after an SRC with relationship to sex and previous concussion history. RESULTS: When comparing male and female athletes with a previous history of concussion, there were no differences found (P = 0.820) in SRC recovery time. Regardless of previous concussion history, males recovered faster from an SRC compared with their female counterparts (P = 0.0002). Without regard to sex, those with no previous history of concussion recovered faster than those with a previous concussion history, although the difference was not statistically significant (P = 0.668). Athletes with a previous history of concussion were more likely to require neuropsychology referral than those with no previous concussion history (P = 0.021), and females, without regard to concussion history, were more likely to require neuropsychology referral than males (P = 0.001). CONCLUSIONS: A previous concussion history does not appear to significantly influence postconcussive recovery time in young athletes, although it does increase the probability of neuropsychological referral. Without regard to a previous concussion history, young female athletes recover slower than males from concussion and are also more likely to require neuropsychological referral. PMID- 29256930 TI - Systematic review and meta-analysis in cardiac surgery: a primer. AB - PURPOSE OF REVIEW: The purpose of this article is to review the strengths and weaknesses of systematic reviews and meta-analyses to inform our current understanding of cardiac surgery. RECENT FINDINGS: A systematic review and meta analysis of a focused topic can provide a quantitative estimate for the effect of a treatment intervention or exposure. In cardiac surgery, observational studies and small, single-center prospective trials provide most of the clinical outcomes that form the evidence base for patient management and guideline recommendations. As such, meta-analyses can be particularly valuable in synthesizing the literature for a particular focused surgical question. Since the year 2000, there are over 800 meta-analysis-related publications in our field. There are some limitations to this technique, including clinical, methodological and statistical heterogeneity, among other challenges. Despite these caveats, results of meta analyses have been useful in forming treatment recommendations or in providing guidance in the design of future clinical trials. SUMMARY: There is a growing number of meta-analyses in the field of cardiac surgery. Knowledge translation via meta-analyses will continue to guide and inform cardiac surgical practice and our practice guidelines. PMID- 29256931 TI - The first seizure as an indicator of epilepsy. AB - PURPOSE OF REVIEW: Optimal treatment of a possible first seizure depends on the determination if the paroxysmal event was an epileptic seizure and was on an accurate assessment of the recurrence risk. This review summarizes evidence from the last 5 years addressing the following questions: Is it an epileptic seizure? Is it a first seizure? When does a first seizure indicate epilepsy? RECENT FINDINGS: The acts of taking and interpreting the history from patients and witnesses continue to be the most important tools in the diagnosis of first seizures. Assessment tools based on factual questions and the observation of patients' conversational behaviour can contribute to the differentiation of patients with epileptic seizures from those who have experienced other types of transient loss of consciousness (TLOC). At present, only about 40% of patients are seen after their very first seizure. Tests have a limited role in the initial diagnosis of a seizure but help to determine the recurrence risk based on the cause. A remote symptomatic cause and detection of epileptiform discharges are associated with a recurrence risk of at least 60% and allow a diagnosis of epilepsy after a first seizure. The risk of recurrence after an acute symptomatic first seizure is well below 60%. SUMMARY: Expert history-taking continues to be the most important tool in the diagnosis of a first seizure. Cause is the most important determinant of the recurrence risk. Unfortunately, there is currently no formula enabling a precise calculation of an individualized recurrence risk. PMID- 29256932 TI - Modifiable and Nonmodifiable Factors Associated With Perioperative Failure of Extraglottic Airway Devices. AB - BACKGROUND: Extraglottic airway device (EGA) failure can be associated with severe complications and adverse patient outcomes. Prior research has identified patient- and procedure-related predictors of EGA failure. In this retrospective study, we assessed the incidence of perioperative EGA failure at our institution and identified modifiable factors associated with this complication that may be the target of preventative or mitigating interventions. METHODS: We performed a 5 year retrospective analysis of adult general anesthesia cases managed with EGAs in a single academic center. Univariable and multivariable logistic regressions were used to identify clinically modifiable and nonmodifiable factors significantly associated with 3 different types of perioperative EGA failure: (1) "EGA placement failure," (2) "EGA failure before procedure start," and (3) "EGA failure after procedure start." RESULTS: A total of 19,693 cases involving an EGA were included in the analysis dataset. EGA failure occurred in 383 (1.9%) of the cases. EGA placement failure occurred in 222 (1.13%) of the cases. EGA failure before procedure start occurred in 76 (0.39%) of the cases. EGA failure after procedure start occurred in 85 (0.43%) of the cases. Factors significantly associated with each type of failure and controllable by the anesthesia team were as follows: (1) EGA placement failure: use of desflurane (odds ratio [OR], 1.67; 95% confidence interval [CI], 1.23-2.25) and EGA size 4 or 5 vs 2 or 3 (OR, 0.07; 95% CI, 0.05-0.10); (2) EGA failure before procedure start: use of desflurane (OR, 2.05; 95% CI, 1.23-3.40) and 3 or more placement attempts (OR, 4.69; 95% CI, 2.57-8.56); and (3) EGA failure after procedure start: 3 or more placement attempts (OR, 2.06; 95% CI, 1.02-4.16) and increasing anesthesia time (OR, 1.35; 95% CI, 1.17-1.55). CONCLUSIONS: The overall incidence of EGA failure was 1.9%, and EGA placement failure was the most common type of failure. We also found that use of desflurane and use of smaller EGA sizes in adult patients were factors under the direct control of anesthesia clinicians associated with EGA failure. An increasing number of attempts at EGA placement was associated with later device failures. Our findings also confirm the association of EGA failure with previously identified patient- and procedure-related factors such as increased body mass index, male sex, and position other than supine. PMID- 29256933 TI - Preoperative Blood Tests Conducted Before Low-Risk Surgery in Japan: A Retrospective Observational Study Using a Nationwide Insurance Claims Database. AB - BACKGROUND: Routine preoperative testing is discouraged before low-risk surgery because testing does not provide any beneficial effect in terms of patient outcome. However, few studies have assessed the utilization of hospital health care resources in terms of preoperative tests in a real-world setting. Here, we aimed to assess the prevalence and factors associated with preoperative blood tests before low-risk surgery in Japan. METHODS: In this retrospective observational study, we used the nationwide insurance claims data of Japan. Patients who underwent low-risk surgeries between April 1, 2012 and March 31, 2016, were included. Our primary outcome was the receipt of any preoperative tests within 60 days before an index procedure: complete blood count, basic metabolic panel, coagulation tests, and liver function tests. We performed a descriptive analysis to estimate the proportions of preoperative blood tests, and examined the associations between patient-level and institutional-level factors and preoperative blood tests, using multilevel logistic regression analysis. Interinstitutional variation in the utilization of preoperative tests was summarized using the median odds ratio (OR). RESULTS: The study sample included 59,818 patients (mean [standard deviation] age, 44.0 [11.3] years; 33,574 [56.1%] women) from 9746 institutions. The overall proportion of each test was: complete blood count, 58.7%; metabolic panel, 47.8%; coagulation tests, 36.6%; and liver function tests, 48.5%. The proportion receiving any preoperative tests in the overall sample was 59.5%. Multilevel logistic regression analysis indicated that preoperative blood tests were associated with the Charlson comorbidity index score (score >=3: adjusted OR, 4.21; 95% confidence interval [CI], 3.69-4.80), anticoagulant use (adjusted OR, 4.12; 95% CI, 2.35-7.22), type of anesthesia (general anesthesia: adjusted OR, 5.69; 95% CI, 4.85-6.68; regional anesthesia: adjusted OR, 3.76; 95% CI, 3.28-4.30), surgical setting (inpatient procedure: adjusted OR, 3.64; 95% CI, 3.30-4.00), and number of beds (>=100 beds: adjusted OR, 3.61; 95% CI, 3.19-4.08). The median institutional-specific proportion of preoperative tests was 40.0% (interquartile range, 0%-100%). The median OR for interinstitutional variation in ordering preoperative tests was 4.34. These findings were consistent across a sensitivity analysis. CONCLUSIONS: Preoperative blood tests were performed before 59.5% of low-risk surgeries. Preoperative tests were associated with the type of anesthesia, patient characteristics, and medical facility status. There was a substantial interinstitutional variation in the utilization of preoperative tests. PMID- 29256935 TI - Differential Effects of Anesthetics and Opioid Receptor Activation on Cardioprotection Elicited by Reactive Oxygen Species-Mediated Postconditioning in Sprague-Dawley Rat Hearts. AB - BACKGROUND: Despite an array of cardioprotective interventions identified in preclinical models of ischemia-reperfusion (IR) injury, successful clinical translation has not been achieved. This study investigated whether drugs routinely used in clinical anesthesia influence cardioprotective effectiveness by reducing effects of reactive oxygen species (ROS), upstream triggers of cardioprotective signaling. Effects of propofol, sevoflurane, or remifentanil were compared on postischemic functional recovery induced by ROS-mediated postconditioning with Intralipid. METHODS: Recovery of left ventricular (LV) work, an index of IR injury, was measured in isolated Sprague-Dawley rat hearts subjected to global ischemia (20 minutes) and reperfusion (30 minutes). Hearts were either untreated or were treated with postconditioning with Intralipid (1%, throughout reperfusion). Propofol (10 MUM), sevoflurane (2 vol%), remifentanil (3 nM), or combinations thereof were administered peri-ischemically (before and during IR). The effects of anesthetics on ROS production were measured in LV cardiac fibers by Amplex Red assay under phosphorylating and nonphosphorylating conditions. RESULTS: Recovery of LV work (expressed as percentage of the preischemic value +/- standard deviation) in untreated hearts was poor (20% +/- 7%) and was improved by Intralipid postconditioning (58% +/- 8%, P = .001). In the absence of Intralipid postconditioning, recovery of LV work was enhanced by propofol (28% +/- 9%, P = .049), sevoflurane (49% +/- 5%, P < .001), and remifentanil (51% +/- 6%, P < .001). The benefit of Intralipid postconditioning was abolished by propofol (33% +/- 10%, P < .001), but enhanced by sevoflurane (80% +/- 7%, P < .001) or remifentanil (80% +/- 9%, P < .001). ROS signaling in LV fibers was abolished by propofol, but unaffected by sevoflurane or remifentanil. We conclude that propofol abolishes ROS-mediated Intralipid postconditioning by acting as a ROS scavenger. Sevoflurane and remifentanil are protective per se and provide additive cardioprotection to ROS-mediated cardioprotection. CONCLUSIONS: These divergent effects of routinely used drugs in clinical anesthesia may influence the translatability of cardioprotective therapies such as Intralipid postconditioning. PMID- 29256937 TI - Macintosh Blade Videolaryngoscopy Combined With Rigid Bonfils Intubation Endoscope Offers a Suitable Alternative for Patients With Difficult Airways. AB - BACKGROUND: In the armamentarium of an anesthesiologist, videolaryngoscopy is a valuable addition to secure the airway. However, when the videolaryngoscope (VLS) offers no solution, few options remain. Earlier, we presented an intubation technique combining Macintosh blade VLS and Bonfils intubation endoscope (BIE) for a patient with a history of very difficult intubation. In the present study, we evaluated this technique to establish whether it is a valuable alternative. METHODS: In this single-blinded nonrandomized study, 38 patients with a history of difficult intubation or 1 or more predictors of difficult intubation, scoring a Cormack & Lehane (C&L) grade III or IV using Macintosh blade VLS, were included. Patients were intubated combining the VLS with the BIE. The C&L grade was scored 3 times during (1) direct laryngoscopy; (2) indirect videolaryngoscopy; and (3) using the combined technique (VLS + BIE). Afterward, 2 blinded anesthesiologists assessed the C&L grade using the pictures taken during the procedure. RESULTS: Data of 38 patients were analyzed. An improvement of the C&L grade with the combined technique occurred in 33 of 38 patients (86.8%; 95% confidence interval, 71.9%-95.6%). Reviewer 1 reported an improvement of the C&L grade with the combined technique in 37 of 38 patients. Reviewer 2 reported improvement in 33 and deterioration in 2 of the patients. No complications occurred. CONCLUSIONS: The combined use of a VLS with Macintosh blade and BIE gives the anesthesiologist a valuable alternative intubation option in patients with extremely difficult airways. PMID- 29256938 TI - Impact of Inhalational Anesthetics on Liver Regeneration After Living Donor Hepatectomy: A Propensity Score-Matched Analysis. AB - BACKGROUND: Although desflurane and sevoflurane, the most commonly used inhalational anesthetics, have been linked to postoperative liver injury, their impact on liver regeneration remains unclear. We compared the influence of these anesthetics on the postoperative liver regeneration index (LRI) after living donor hepatectomy (LDH). METHODS: We conducted a retrospective chart review of 1629 living donors who underwent right hepatectomy for LDH between January 2008 and August 2016. The patients were divided into sevoflurane (n = 1206) and desflurane (n = 423) groups. Factors associated with LRI were investigated using multivariable logistic regression analysis. Propensity score matching analysis compared early (1 postoperative week) and late (within 1-2 months) LRIs and delayed recovery of hepatic function between the 2 groups. RESULTS: The mean early and late LRIs in the 1629 patients were 63.3% +/- 41.5% and 93.7% +/- 48.1%, respectively. After propensity score matching (n = 403 pairs), there were no significant differences in early and late LRIs between the sevoflurane and desflurane groups (early LRI: 61.2% +/- 41.5% vs 58.9% +/- 42.4%, P = .438; late LRI: 88.3% +/- 44.3% vs 94.6% +/- 52.4%, P = .168). Male sex (regression coefficient [beta], 4.6; confidence interval, 1.6-7.6; P = .003) and remnant liver volume (beta, -4.92; confidence interval, -5.2 to -4.7; P < .001) were associated with LRI. The incidence of delayed recovery of hepatic function was 3.6% (n = 29) with no significant difference between the 2 groups (3.0% vs 4.2%, P = .375) after LDH. CONCLUSIONS: Both sevoflurane and desflurane can be safely used without affecting liver regeneration and delaying liver function recovery after LDH. PMID- 29256939 TI - Sources of Variation in Anesthetic Drug Costs. AB - BACKGROUND: Increasing attention has been focused on health care expenditures, which include anesthetic-related drug costs. Using data from 2 large academic medical centers, we sought to identify significant contributors to anesthetic drug cost variation. METHODS: Using anesthesia information management systems, we calculated volatile and intravenous drug costs for 8 types of inpatient surgical procedures performed from July 1, 2009, to December 31, 2011. For each case, we determined patient age, American Society of Anesthesiologists (ASA) physical status, gender, institution, case duration, in-room provider, and attending anesthesiologist. These variables were then entered into 2 fixed-effects linear regression models, both with logarithmically transformed case cost as the outcome variable. The first model included duration, attending anesthesiologist, patient age, ASA physical status, and patient gender as independent variables. The second model included case type, institution, patient age, ASA physical status, and patient gender as independent variables. When all variables were entered into 1 model, redundancy analyses showed that case type was highly correlated (R = 0.92) with the other variables in the model. More specifically, a model that included case type was no better at predicting cost than a model without the variable, as long as that model contained the combination of attending anesthesiologist and case duration. Therefore, because we were interested in determining the effect both variables had on cost, 2 models were created instead of 1. The average change in cost resulting from each variable compared to the average cost of the reference category was calculated by first exponentiating the beta coefficient and subtracting 1 to get the percent difference in cost. We then multiplied that value by the mean cost of the associated reference group. RESULTS: A total of 5504 records were identified, of which 4856 were analyzed. The median anesthetic drug cost was $38.45 (25th percentile = $23.23, 75th percentile = $63.82). The majority of the variation was not described by our models-35.2% was explained in the model containing case duration, and 32.3% was explained in the model containing case type. However, the largest sources of variation our models identified were attending anesthesiologist, case type, and procedure duration. With all else held constant, the average change in cost between attending anesthesiologists ranged from a cost decrease of $41.25 to a cost increase of $95.67 (10th percentile = -$19.96, 90th percentile = +$20.20) when compared to the provider with the median value for mean cost per case. The average change in cost between institutions was significant but minor ($5.73). CONCLUSIONS: The majority of the variation was not described by the models, possibly indicating high per-case random variation. The largest sources of variation identified by our models included attending anesthesiologist, procedure type, and case duration. The difference in cost between institutions was statistically significant but was minor. While many prior studies have found significant savings resulting from cost-reducing interventions, our findings suggest that because the overall cost of anesthetic drugs was small, the savings resulting from interventions focused on the clinical practice of attending anesthesiologists may be negligible, especially in institutions where access to more expensive drugs is already limited. Thus, cost-saving efforts may be better focused elsewhere. PMID- 29256940 TI - Promoting a Restrictive Intraoperative Transfusion Strategy: The Influence of a Transfusion Guideline and a Novel Software Tool. AB - BACKGROUND: The effect of neither transfusion guidelines nor decision support tools on intraoperative transfusion has been previously evaluated. The University of Michigan introduced a transfusion guideline in 2009, and in 2011, the Department of Anesthesiology developed a transfusion decision support tool. The primary aim of this study was to assess the associations of the transfusion guideline and the optional use of the software transfusion tool with intraoperative behaviors; pretransfusion hematocrit assessment (whether or not a hematocrit was checked before each red cell unit) and restrictive red cell use (withholding transfusion unless the hematocrit was <=21%). METHODS: This was a before-after retrospective study without a concurrent control group of patients transfused 1-3 units of red cells intraoperatively. Three phases were studied to provide data both before and after the implementation of the transfusion guideline and the intraoperative software tool. Within each phase, trends of checking hematocrits before transfusion and restrictive transfusion were charted against time. F tests were used to measure differences of slopes. The difference between means of each phase was measured using Mann-Whitney U tests. Independent associations were measured using mixed-effects multivariable logistic regression. A secondary outcome analysis was conducted for 30-day mortality, myocardial infarction, renal injury, and their combination. RESULTS: The transfusion guideline was associated with increased pretransfusion hematocrit evaluation (67.4%, standard deviation [SD] 3.9 vs 76.5%, SD 2.7; P < .001) and restrictive transfusion practice (14.0%, SD 7.4 vs 33.3%, SD 4.4; P = .001). After adjustment for confounders, the guideline phase was independently associated with increased hematocrit checking (odds ratio, 1.72; 95% confidence interval, 1.46-2.03; P < .001) and restrictive red cell transfusion (odds ratio, 2.95; 95% confidence interval, 2.46-3.54; P < .001). The software tool was not associated with either transfusion behavior. There was no significant change in the rate of renal injury (16.06%), myocardial injury (4.93%), 30-day mortality (5.47%), or a composite (21.90%). CONCLUSIONS: The introduction of a transfusion guideline was independently associated with increased intraoperative pretransfusion hematocrit assessment and restrictive transfusion. The use of a software tool did not further influence either behavior. PMID- 29256941 TI - Novel Technique for Reconstruction of the Severely Resorbed Posterior Maxillae: Tuberosity-Flip Approach. AB - PURPOSE: This report describes a novel technique that allows for 3-dimensional augmentation of localized bone defects of the posterior maxilla and simultaneous implant placement by means of using the maxillary tuberosity as a block graft. MATERIALS AND METHODS: The residual bone in maxillary tuberosity is harvested as a whole. The recipient site and the bone graft are prepared with compatible implant drills. The bone graft is flipped to fit the defect and fixated in place using the dental implant, which anchors both the graft and the subantral bone. RESULTS: The defect of the posterior maxilla is reconstructed with autogenous bone harvested from maxillary tuberosity, and simultaneous implant placement is achieved. CONCLUSION: The proposed technique enables the clinician to reconstruct alveolar defects of the posterior maxilla without the need for an additional donor site and simultaneously place dental implants. PMID- 29256942 TI - Evaluation of Failed Implants by Metallographic and Energy Dispersive X-ray Analysis. AB - OBJECTIVE: To evaluate the microscopic structure and chemical composition of titanium dental implants removed from patients with implant failure. MATERIALS AND METHODS: Thirty-eight dental implants removed from 29 patients between January 2012 and September 2014 were studied by metallographic analysis, and 7 of these implants were also studied by energy-dispersive x-ray (EDX) analysis. Medical records of these patients were examined. RESULTS: Dental implants were removed in a median of 54.6 +/- 88.1 weeks after insertion. The lack of osseointegration without symptomatology or signs of infection was the main reason for implant failure (55.17%). Seventeen patients presented implant failure in the maxilla and 12 patients in the mandible. Metallographic analysis revealed that all the dental implants were manufactured from commercially pure titanium, presenting microscopic uniform appearance, with no "alpha case". The implants studied by EDX analysis presented between 99.85% and 99.87% of titanium and 0.13% and 0.15% of iron by mass. All the implants evaluated were within the ASTM specifications in both analyses. CONCLUSION: There was no relationship between dental implant failure and the microscopic structure and chemical composition of these devices. PMID- 29256943 TI - Intersecting Evidence-Based Practice With a Lean Improvement Model. AB - In our journey from Magnet designation to a Lean hospital, a team of advanced practice nurses, a nurse scientist, and Lean specialists developed a crosswalk of evidence-based practice (EBP) with Lean to explicitly embed the use of evidence in our organization's 4-step problem-solving method. Once finalized, the blended Lean-EBP model now guides improvement work as highlighted in the example of updating our practice for frequency of changing peripheral intravenous catheters. PMID- 29256944 TI - Decisional Involvement: Differences Related to Nurse Characteristics, Role, and Shared Leadership Participation. AB - A sample of 1933 registered nurses working in 24 hospitals with shared leadership was surveyed to examine perceptions of nurse decisional involvement. Council participation was associated with higher decisional involvement scores (P = .03), and nurse experience was a statistically significant predictor of decisional involvement (P < .01). Nurse manager and staff registered nurse scores were significantly different (P < .01). Shared leadership may promote staff nurse perceptions of involvement in decision-making. PMID- 29256946 TI - Humerus. PMID- 29256945 TI - Introduction: Fracture and Dislocation Classification Compendium-2018: International Comprehensive Classification of Fractures and Dislocations Committee. PMID- 29256948 TI - Femur. PMID- 29256947 TI - Radius and Ulna. PMID- 29256949 TI - Patella. PMID- 29256951 TI - Fibula. PMID- 29256950 TI - Tibia. PMID- 29256953 TI - Pelvic Ring. PMID- 29256952 TI - Malleolar Segment. PMID- 29256954 TI - Acetabulum. PMID- 29256955 TI - Hand and carpus. PMID- 29256956 TI - Foot. PMID- 29256957 TI - Scapula. PMID- 29256958 TI - Clavicle. PMID- 29256960 TI - Dislocations. PMID- 29256959 TI - OTA Open Fracture Classification (OTA-OFC). PMID- 29256962 TI - Unified Classification System for Periprosthetic Fractures (UCPF). PMID- 29256961 TI - AO Pediatric Comprehensive Classification of Long Bone Fractures (PCCF). PMID- 29256964 TI - Thorax. PMID- 29256963 TI - Spine. PMID- 29256965 TI - Appendix. PMID- 29256966 TI - Influence of donor liver CYP3A4*20 loss-of-function genotype on tacrolimus pharmacokinetics in transplanted patients. AB - OBJECTIVE: Cytochrome P450 3A4 (CYP3A4) metabolizes about half of all drugs on the market; however, the impact of CYP3A4 loss-of-function variants on drug exposures remains poorly characterized. Here, we report the effect of the CYP3A4*20 frameshift allele in two Spanish liver transplant patients treated with tacrolimus. PATIENTS AND METHODS: A series of 90 transplanted patients (with DNA available for 89 of the recipients and 76 of the liver donors) treated with tacrolimus were included in the study. The genotypes of liver donors and of the recipients for CYP3A4*20 (rs67666821), CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) were compared with weight-adjusted tacrolimus dose (D), tacrolimus trough concentration (C0), and dose-adjusted tacrolimus trough concentrations (C0/D) using the Mann-Whitney U-nonparametric test. RESULTS: The CYP3A4*20 allele was detected in two of the liver donors. This genotype yielded at all times higher C0/D (2.6-fold, average) than intermediate CYP3A metabolizers (CYP3A4*1/*1 and CYP3A5*3/*3) (P=0.045, 90 days after transplantation). CYP3A4*22 carriers showed a 1.9-fold average increase in C0/D (P=0.047, 0.025, and 0.053; at days 7, 14, and 30 after transplantation, respectively) compared with intermediate metabolizers. In terms of recipients' genotype, CYP3A5*1 had reduced (P=0.025) and CYP3A4*22 increased C0/D (P=0.056) 7 days after transplantation. The incidence of biopsy-proven acute rejection was 0, 12, and 20% for livers with poor, intermediate, and extensive CYP3A-metabolizing capacity, respectively (P=0.0995). CONCLUSION: This first description of CYP3A4*20 null genotype in liver-transplanted patients, supports the relevance of CYP3A genotyping in tacrolimus therapy. PMID- 29256967 TI - Investigation of differential HDAC4 methylation patterns in eating disorders. AB - The objective of this study was to investigate the relationship between methylation patterns of the histone deacetylase 4 gene and eating disorders in a site previously associated with anorexia nervosa (AN). Women with AN (N=28) or bulimia nervosa (BN) (N=19) were age-matched and sex-matched to controls (N=45). We obtained saliva-derived DNA and use bisulfite pyrosequencing to examine region specific methylation differences between cases and controls. The region assayed includes 15 CpGs. We found no significant association between the previously implicated CpG and either AN or BN. We found that three CpGs were nominally associated with AN (P=0.02-0.03); the largest difference was a 9% hypermethylation in AN. One CpG was nominally associated with BN (P=0.04), with 4% hypomethylation. None of these results remained significant after correction for multiple testing. We did not replicate previous findings, though through expanded coverage, we identified additional CpGs that were nominally associated with eating disorders. PMID- 29256968 TI - Lack of association between triggering receptor expressed on myeloid cells 2 polymorphism rs75932628 and late-onset Alzheimer's disease in a Chinese Han population. AB - Recently, several studies have investigated the association between the rare mutation of triggering receptor expressed on myeloid cells 2 (TREM2) gene (rs75932628-T) and the risk of late-onset Alzheimer's disease (LOAD), but they did not draw the same conclusion. Our aim was to investigate the link between the TREM2 polymorphism and LOAD in the Chinese Han population. We examined 786 patients and 803 controls in this study. The rs75932628 polymorphism was evaluated using high-resolution melting analysis and direct sequencing. rs75932628-T (predicted to cause an R47H substitution) was absent in our cohort. We did not find an association between the rs75932628 single nucleotide polymorphism of TREM2 and LOAD in this study. Thus, rs75932628 is unlikely to be related to LOAD in the Chinese Han population. PMID- 29256969 TI - Fast and Straightforward Method for the Quantification of Pazopanib in Human Plasma Using LC-MS/MS. AB - BACKGROUND: Pazopanib is an angiogenesis inhibitor approved for renal cell carcinoma and soft-tissue sarcoma. Studies indicate that treatment with pazopanib could be optimized by adapting the dose based on measured pazopanib plasma concentrations. METHODS: We describe the validation and clinical application of a fast and straightforward method for the quantification of pazopanib in human plasma for the purpose of therapeutic drug monitoring and bioanalytical support of clinical trials. Stable isotopically labeled C,H3-pazopanib was used as internal standard. Plasma samples were prepared for analysis by protein precipitation using methanol and diluted with 10 mmol/L ammonium hydroxide buffer. Chromatographic separation was performed on a C18 column using isocratic elution with ammonium hydroxide in water and methanol. For detection, a tandem mass spectrometer, equipped with a turbo ion spray interface was used in positive ion mode at m/z 438 -> m/z 357 for pazopanib and m/z 442 -> m/z 361 for the internal standard. RESULTS: Final runtime was 2.5 minutes. All validated parameters were within pre-established limits and fulfilled the FDA and EMA requirements for bioanalytical method validation. After completion of the validation, the routine application of the method was tested by analyzing clinical study samples that were collected for the purpose of therapeutic drug monitoring. CONCLUSIONS: In conclusion, the described method was successfully validated and was found to be robust for routine application to analyze samples from cancer patients treated with pazopanib. PMID- 29256971 TI - Cardioprotective Mechanisms of Exenatide in Isoprenaline-induced Myocardial Infarction: Novel Effects on Myocardial alpha-Estrogen Receptor Expression and IGF-1/IGF-2 System. AB - Myocardial infarction (MI) is one of the main causes of morbidity and mortality in diabetic patients. The antidiabetic glucagon-like polypeptide-1 receptor (GLP 1R) agonists, such as exenatide, proved to confer cardioprotection; however, their exact mechanisms are not fully elucidated. Although the cardioprotective effect of alpha-estrogen receptor (ERalpha) activation is well established, its involvement in exenatide-induced cardioprotection has never been investigated. Moreover, modulation of insulin-like growth factor-1/2 (IGF-1/IGF-2) system by exenatide, and the consequent effect on cardiomyocyte apoptosis, is yet to be established. Current study aimed to investigate the cardioprotective potential of exenatide versus the standard cardioprotective agent, 17beta-estradiol, against isoprenaline (ISO)-induced MI in rats. MI-insulted group showed electrocardiographic abnormalities, elevated serum cardiac markers, higher serum IGF-2 level along with histopathological abnormalities. Treatment with exenatide and/or 17beta-estradiol, commenced 8 weeks before ISO insult, ameliorated these anomalies with maximum cardioprotection achieved with combined treatment. This was associated with upregulation of both ERalpha and IGF-1R, and downregulation of IGF-2R in left ventricles. Inhibition of ERs in Langendorff preparations confirmed their involvement in mediating exenatide-induced cardioprotective effect. Current study showed that the GLP-1R agonist exenatide exerted cardioprotection associated with upregulation of ERalpha and modulation of IGF 1/IGF-2 signaling in favor of antiapoptosis. PMID- 29256972 TI - Factors Influencing Various Aspects of Patients' Knowledge of Oral Anticoagulation. AB - OBJECTIVES: To identify and examine individual characteristics and socioeconomic factors that contribute to the knowledge of patients who receive warfarin anticoagulation. METHODS: All patients treated using warfarin for anticoagulation were enrolled during a 6-month period at a university-affiliated cardiac clinic. All relevant demographic and clinical information were collected and the Anticoagulation Knowledge Assessment (AKA) questionnaire consisting of 29 questions was administered. After completion, the questionnaires were scored and the percent correct answers were analyzed for overall scores, as well as the following categories: drug/food interactions, pharmacological knowledge, recognition of complications, and patient compliance. Multiple linear regression analysis was used to identify the contributing factors to the knowledge level of the patients in each category. RESULTS: One hundred fifty patients (79 men and 71 women) with a median age of 61.5 years completed the AKA questionnaire. The average overall score was 29.3%. Living alone (P = 0.008), higher levels of education (P = 0.001), and durations of >=3 years of warfarin therapy (P = 0.018) positively impacted overall AKA scores. CONCLUSIONS: Socioeconomic factors and level of general education remain the most important elements determining the patient awareness of therapeutic goals, possible drug/food interaction, recognition of adverse effects, and compliance of warfarin treatment. PMID- 29256973 TI - Screening, Brief Intervention, and Referral to Treatment in the Emergency Department: An Examination of Health Care Utilization and Costs. AB - BACKGROUND: There is increasing interest in deploying screening, brief intervention, and referral to treatment (SBIRT) practices in emergency departments (ED) to intervene with patients at risk for substance use disorders. However, the current literature is inconclusive on whether SBIRT practices are effective in reducing costs and utilization. OBJECTIVE: This study sought to evaluate the health care costs and health care utilization associated with SBIRT services in the ED. RESEARCH DESIGN: This study analyzed downstream health care utilization and costs for patients who were exposed to SBIRT services within an Allegheny County, Pennsylvania, ED through a program titled Safe Landing compared with 3 control groups of ED patients (intervention hospital preintervention, and preintervention and postintervention time period at a comparable, nonintervention hospital). SUBJECTS: The subjects were patients who received ED SBIRT services from January 1 to December 31 in 2012 as part of the Safe Landing program. One control group received ED services at the same hospital during a previous year. Two other control groups were patients who received ED services at another comparable hospital. MEASURES: Measures include total health care costs, 30-day ED visits, 1-year ED visits, inpatient claims, and behavioral health claims. RESULTS: Results found that patients who received SBIRT services experienced a 21% reduction in health care costs and a significant reduction in 1-year ED visits (decrease of 3.3 percentage points). CONCLUSIONS: This study provides further support that SBIRT programs are cost-effective and cost-beneficial approaches to substance use disorders management, important factors as policy advocates continue to disseminate SBIRT practices throughout the health care system. PMID- 29256974 TI - Commentary: Copyright Restrictions Versus Open Access to Survey Instruments. PMID- 29256976 TI - Management of Moderate to Severe Hip Displacement in Nonambulatory Children with Cerebral Palsy. PMID- 29256975 TI - Gene Expression Profiling of Bronchoalveolar Lavage Cells During Aspergillus Colonization of the Lung Allograft. AB - BACKGROUND: Aspergillus colonization after lung transplant is associated with an increased risk of chronic lung allograft dysfunction (CLAD). We hypothesized that gene expression during Aspergillus colonization could provide clues to CLAD pathogenesis. METHODS: We examined transcriptional profiles in 3- or 6-month surveillance bronchoalveolar lavage fluid cell pellets from recipients with Aspergillus fumigatus colonization (n = 12) and without colonization (n = 10). Among the Aspergillus colonized, we also explored profiles in those who developed CLAD (n = 6) or remained CLAD-free (n = 6). Transcription profiles were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression was based on an absolute fold difference of 2.0 or greater and unadjusted P value less than 0.05. We used NIH Database for Annotation, Visualization and Integrated Discovery for functional analyses, with false discovery rates less than 5% considered significant. RESULTS: Aspergillus colonization was associated with differential expression of 489 probe sets, representing 404 unique genes. "Defense response" genes and genes in the "cytokine-cytokine receptor" Kyoto Encyclopedia of Genes and Genomes pathway were notably enriched in this list. Among Aspergillus colonized patients, CLAD development was associated with differential expression of 69 probe sets, representing 64 unique genes. This list was enriched for genes involved in "immune response" and "response to wounding", among others. Notably, both chitinase 3-like-1 and chitotriosidase were associated with progression to CLAD. CONCLUSIONS: Aspergillus colonization is associated with gene expression profiles related to defense responses including cytokine signaling. Epithelial wounding, as well as the innate immune response to chitin that is present in the fungal cell wall, may be key in the link between Aspergillus colonization and CLAD. PMID- 29256977 TI - Pretreatment with minocycline improves neurogenesis and behavior performance after midazolam exposure in neonatal rats. AB - Laboratory studies suggested that general anesthetics induce neuroapoptosis and inhibit neurogenesis in developing brains of animals. Minocycline exerts neuroprotection against a wide range of toxic insults in neurodegenerative diseases models. Here, we investigate whether minocycline can alleviate neurogenetic damage and improve cognition following midazolam exposure in neonatal rats. Postnatal 7 days rats were divided randomly into three groups: control group (C), midazolam group (M), and minocycline pretreatment group (MP). After exposure to midazolam, the cell proliferation in the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampus in pups was analyzed by bromodeoxyuridine immunochemistry at 7 days after the administration of anesthesia. Cognitive function was assessed using the Morris water-maze test at 35 days after midazolam exposure. Compared with the control, midazolam reduced cell proliferation both in the SVZ and in the SGZ of the hippocampus of neonatal rats, and decreased spatial learning and memory ability of rats in adulthood significantly. Pretreatment with minocycline increased cell proliferation both in the SVZ and in the SGZ of the hippocampus and improved spatial learning and memory ability compared with midazolam, but it did not mitigate the changes to the normal levels compared with the controls. Our results indicated that pretreatment with minocycline can alleviate midazolam-induced damage in neural stem cell proliferation of neonatal rats and improve spatial learning and memory ability of rats in adulthood. PMID- 29256978 TI - Electrophysiological evidence of language switching for bidialectals: an event related potential study. AB - Language switching is an important issue in the study of bilinguals. However, how the nontarget language affects the production of the target language under the language switch condition is still unclear, especially for bilinguals who speak two dialects (bidialectals). In the present study, we investigate this issue by a picture-naming task and using an event-related potential (ERP) technique. Two groups of proficient bidialectals, Mandarin (L1)-Cantonese (L2) and Cantonese (L1)-Mandarin (L2), participated in the study. They were required to name pictures with Mandarin or Cantonese under language switching conditions and language nonswitching conditions. The results showed that participants of both groups showed significant longer reaction time, larger P200, and smaller N400 under language switching conditions than that under language nonswitching conditions, which reflects the language switching costs. Moreover, participants of the two groups showed different P200 and N400 between Mandarin-Cantonese (MC) switching conditions and Cantonese-Mandarin (CM) switching conditions. Specifically, MC bidialectals showed larger P200 under the CM condition than that under the MC condition, whereas CM bidialectals showed an opposite P200 pattern (CM conditionCM condition). These findings supported the language-unspecific selection theory. Overall, our study is the first to provide electrophysiological evidence of language switching between two dialects. PMID- 29256979 TI - Self-Reported Cognitive Biases Are Equally Present in Patients Diagnosed With Psychotic Versus Nonpsychotic Disorders. AB - We investigated the relation between subjective cognitive biases measured with the Dutch Davos Assessment of Cognitive Biases (DACOBS-NL) and (1) the presence of a psychotic versus nonpsychotic psychiatric disorder, (2) the current dose of antipsychotic medication and current psychotic symptoms, and (3) the Personality Inventory for the DSM-5 (PID-5) Psychoticism personality trait. Results showed that DACOBS-NL subjective cognitive biases (1) were equally present in patients diagnosed with nonpsychotic disorders compared with patients with a psychotic disorder, (2) could not be explained by the current dose of antipsychotic medication, nor by current psychotic symptoms, and (3) significantly correlated with all PID-5 Personality domains. Moreover, in predicting membership of the psychotic versus nonpsychotic psychiatric disorder group, the addition of the PID 5 domains in step 2 rendered the contribution of the DACOBS-NL subjective cognitive biases in step 1 nonsignificant. Further research is needed to clarify the interplay between cognitive biases and aberrant salience in the prediction of psychotic disorders. PMID- 29256980 TI - Loneliness Among Persons With Severe Mental Illness. AB - Although studies show that loneliness increases risk of illness and hastens death, it is poorly understood among persons with severe mental illness (SMI). Using data on 150 people with SMI, we used logistic regression to predict (1) loneliness from sociodemographic and clinical characteristics, and (2) psychiatric hospitalization from presence of loneliness. We also examined mediating effects. Study participants who were most willing to ask for help were 70% less likely (odds ratio [OR], 0.30; confidence interval [CI], 0.09-0.99; p < 0.05) to be lonely than those who were least willing, and participants with high levels of internalized stigma were 9.25 times as likely (CI, 9.25; OR, 2.29 37.32; p < 0.01) as other participants to be lonely. Participants who were most lonely were 2.69 times (CI, 1.03-7.04, p < 0.05) as likely to be placed in psychiatric hospitals as those who were less lonely. Loneliness mediates the association between internalized stigma and psychiatric hospitalization (OR, 1.30; CI, 1.04-1.73). Findings can be used to help prevent inpatient stay. PMID- 29256981 TI - Reconsidering Sequential Double Running Suture Removal After Penetrating Keratoplasty: A Prospective Randomized Study Comparing Excimer Laser and Motor Trephination. AB - PURPOSE: We assessed the impact of sequential double running suture removal on corneal curvature after penetrating keratoplasty (PK), comparing mechanical and nonmechanical excimer laser trephination. METHODS: PK was performed in 134 patients (mean age 51 +/- 18 yrs) using either the excimer laser [excimer, n = 60 (37 keratoconus and 23 Fuchs dystrophy)] or motor trephination [control, n = 74 (44 keratoconus and 30 Fuchs dystrophy)] and a double running cross-stitch suture. Refractometry, Zeiss keratometry, and Tomey corneal topography were performed before removal of the first suture (15.2 +/- 4.2 mo) and immediately before and at least 6 weeks after removal of the second suture (21.4 +/- 5.6 mo). RESULTS: Keratometry before removal of the first (-1.7 +/- 2.3 D vs. -3.1 +/- 2.8 D) and second (-2.3 +/- 2.6 D vs. -3.8 +/- 2.8 D) sutures showed that the change in the corneal base curve was significantly smaller in the excimer group than the control group (P < 0.004). After complete suture removal, astigmatism decreased in 52% and 11%, remained stable (+/-0.5 D) in 27% and 9%, and increased in 21% and 80% of eyes in the excimer and control groups, respectively, resulting in significantly lower astigmatism in the excimer (3.1 +/- 2.1 D) group compared with the control group (6.2 +/- 2.9 D) with "all-sutures-out" (P < 0.0001). The change in vector-corrected astigmatism (Jaffe) was significantly smaller in the excimer group (4.3 +/- 3.5 D) than in the control group (6.9 +/- 4.5 D; P < 0.001). CONCLUSIONS: In conclusion, less change in astigmatism and the base curve after sequential removal of a double running suture indicates better alignment of the graft in the recipient bed after excimer laser trephination. After double running suture removal, astigmatism decreases or remains unchanged in 79% of patients after excimer laser keratoplasty and increases in 80% of patients after conventional motor trephination. PMID- 29256982 TI - Persistence of the Cone on the Posterior Corneal Surface Affecting Corneal Aberration Changes After Intracorneal Ring Segment Implantation in Patients With Keratoconus. AB - PURPOSE: To analyze the changes in anterior and posterior corneal surfaces and aberrations in patients who underwent intracorneal ring segment (ICRS) implantation for the treatment of keratoconus. METHODS: Eighty-nine eyes of 59 patients with keratoconus who underwent ICRS implantation were analyzed. All eyes were evaluated using a tomography system combining a Placido disc and Scheimpflug photography before and at least 6 months after surgery. Total, anterior, and posterior corneal aberrations, anterior and posterior sagittal and tangential anterior and posterior curve analysis, keratometry (K), minimum corneal thickness, and anterior chamber depth were analyzed before and after surgery. RESULTS: Flattening with a decrease in the cone shape on the anterior corneal surface and steepening in the paracentral area with persistence of cone appearance on the posterior corneal surface were noted in all cases after ICRS implantation. The total corneal higher-order aberrations (HOAs) significantly decreased from 1.09 +/- 0.43 to 0.71 +/- 0.32 MUm, and anterior corneal HOAs significantly decreased from 0.98 +/- 0.46 to 0.81 +/- 0.37 MUm, whereas the posterior corneal HOAs increased from 0.53 +/- 0.29 to 0.66 +/- 0.25 MUm after ICRS implantation (P < 0.05). There was a significant decrease in anterior maximum keratometry, but there was a significant increase in posterior maximum keratometry after ICRS implantation (P < 0.05). CONCLUSIONS: The cone shape persists on the posterior corneal surface despite its correction on the anterior corneal surface, leading to a decrease in anterior corneal aberrations and an increase in posterior corneal aberrations after ICRS implantation in eyes with keratoconus. PMID- 29256983 TI - Comparison of In Vivo Confocal Microscopy, PCR and Culture of Corneal Scrapes in the Diagnosis of Acanthamoeba Keratitis. AB - PURPOSE: Acanthamoeba keratitis (AK) is an uncommon but serious corneal infection, in which delayed diagnosis carries a poor prognosis. Conventional culture requires a long incubation period and has low sensitivity. Polymerase chain reaction (PCR) and in vivo confocal microscopy (IVCM) are available alternative diagnostic modalities that have increasing clinical utility. This study compares confocal microscopy, PCR, and corneal scrape culture in the early diagnosis of AK. METHODS: We reviewed the case notes of patients with a differential diagnosis of AK between June 2016 and February 2017 at the Bristol Eye Hospital, United Kingdom. Clinical features at presentation, and results of IVCM, PCR, and corneal scrape cultures were analyzed. RESULTS: A total of 25 case records were reviewed. AK was diagnosed in 14 patients (15 eyes). Based on the definition of "definite AK," the diagnostic sensitivities of IVCM, PCR, and corneal scrape cultures were 100% [95% confidence interval (CI), 63.1%-100%], 71.4% (95% CI, 41.9%-91.6%) and 33.3% (95% CI, 9.9%-65.1%), respectively. The 3 methods showed a specificity of 100% and a positive predictive value of 100%. Using a reference standard of only positive corneal cultures, IVCM, and PCR had a sensitivity of 100% (95% CI, 29.2%-100%) and 75% (95% CI, 19.4%-99.4%), respectively. CONCLUSIONS: All 3 diagnostic tests are highly specific, and a positive test result is highly predictive of disease presence. IVCM is both highly sensitive and specific when performed by an experienced operator. PCR is a useful adjunct in the diagnosis of AK because of its wider availability compared with IVCM, and it may be used in combination with IVCM for microbiologic confirmation. PMID- 29256984 TI - Unilateral Posterior Interstitial Keratitis as a Clinical Presentation of Herpes Simplex Virus Disease. AB - PURPOSE: To describe a case series of patients with unilateral, posterior interstitial keratitis presumed to be caused by herpes simplex virus. METHODS: Retrospective case series. RESULTS: Five patients were found to have unilateral, posterior interstitial keratitis. Three of the involved eyes had decreased corneal sensation, and 2 eyes had corneal stromal neovascularization. All patients were treated with topical steroids and an oral antiviral, and among those with long-term follow-up, clinical improvement required treatment over an extended duration. A review of the literature revealed 1 reported case with a similar clinical appearance, although that case was attributed to Lyme disease. CONCLUSIONS: The clinical presentation of unilateral, posterior interstitial keratitis may be a rare manifestation of herpes simplex virus keratitis. PMID- 29256987 TI - APPLICATION OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY TO ASSESS ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY IN MYOPIC CHOROIDAL NEOVASCULARIZATION. AB - PURPOSE: Using optical coherence tomography (OCT) angiography to assess the therapeutic effect of intravitreal anti-vascular endothelial growth factor on myopic choroidal neovascularization (CNV) by detecting the changes of shape, size, and flow area. METHODS: Our prospective case series recruited consecutive patients with myopic CNV from January 2016 to August 2016. Intravitreal injections of ranibizumab were conducted on all patients. Patients received OCT angiography on 3 different follow-ups, including before treatment, 1 week after treatment, and 1 month after treatment. At each visit, we measured the best corrected visual acuity, central macular thickness , greatest linear dimension of CNV, selected CNV area and flow area using OCT angiography. RESULTS: This study involved 13 eyes of 12 patients, in which 9 eyes were of 9 women and 4 eyes were of 3 men, with mean age of 49.92 +/- 14.79 years. Best-corrected visual acuity was significantly improved with decreased central macular thickness, greatest linear dimension, intraretinal fluid, or subretinal fluid 7 days or 30 days after treatment (All P < 0.05). Myopic CNV was presented as irregular or nearly round closed mass at the level of the outer retinal layer in all eyes at the initial visit. Thirty days after treatment, the size of selected CNV area and flow area were further decreased (t = 4.012, P = 0.003). CONCLUSION: Combined with OCT B scan, OCT angiography, a new technique, could provide sensitive and intuitive images and quantitative analysis for monitoring and evaluating the therapeutic effect of intravitreal anti-vascular endothelial growth factor for myopic CNV. PMID- 29256985 TI - Novel Image-Based Analysis for Reduction of Clinician-Dependent Variability in Measurement of the Corneal Ulcer Size. AB - PURPOSE: To assess variability in corneal ulcer measurements between ophthalmologists and reduce clinician-dependent variability using semiautomated segmentation of the ulcer from photographs. METHODS: Three ophthalmologists measured 50 patients' eyes for epithelial defects (EDs) and the stromal infiltrate (SI) size using slit-lamp (SL) calipers. SL photographs were obtained. An algorithm was developed for semiautomatic segmenting of the ED and SI in the photographs. Semiautomatic segmentation was repeated 3 times by different users (2 ophthalmologists and 1 trainee). Clinically significant variability was assessed with intraclass correlation coefficients (ICCs) and the percentage of pairwise measurements differing by >=0.5 mm. Semiautomatic segmentation measurements were compared with manual delineation of the image by a corneal specialist (gold standard) using Dice similarity coefficients. RESULTS: Ophthalmologists' reliability in measurements by SL calipers had an ICC from 0.84 to 0.88 between examiners. Measurements by semiautomatic segmentation had an ICC from 0.96 to 0.98. SL measures of ulcers by clinical versus semiautomatic segmentation measures differed by >=0.5 mm in 24% to 38% versus 8% to 28% (ED height); 30% to 52% versus 12% to 34% (ED width); 26% to 38% versus 10% to 32% (SI height); and 38% to 58% versus 14% to 34% (SI width), respectively. Average Dice similarity coefficients between manual and repeated semiautomatic segmentation ranged from 0.83 to 0.86 for the ED and 0.78 to 0.83 for the SI. CONCLUSIONS: Variability exists when measuring corneal ulcers, even among ophthalmologists. Photography and computerized methods for quantifying the ulcer size could reduce variability while remaining accurate and impact quantitative measurement endpoints. PMID- 29256988 TI - THE INTEGRATIVE SURGICAL THEATER: Combining Intraoperative Optical Coherence Tomography and 3D Digital Visualization for Vitreoretinal Surgery in the DISCOVER Study. AB - PURPOSE: To evaluate the feasibility of integrating intraoperative optical coherence tomography (OCT) with a digital visualization platform for vitreoretinal surgery. METHODS: The DISCOVER study is a prospective study examining microscope-integrated intraoperative OCT across multiple prototypes and platforms. For this assessment, a microscope-integrated OCT platform was combined with a three-dimensional (3D) surgical visualization system to allow for digital display of the OCT data stream on the large immersive display. Intraoperative OCT scans were obtained at various surgical milestones that were directly overlaid to the surgical view in a 55-inch passive 3D 4K high-definition display. Surgeon feedback was obtained related to system performance and integration into the surgical procedures through a prespecified surgeon questionnaire. RESULTS: Seven eyes of seven subjects were identified. Clinical diagnosis included epiretinal membrane (n = 3), macular hole (2), symptomatic vitreous opacity (1), and proliferative vitreoretinopathy (1). Optical coherence tomography images were successfully obtained and displayed on the 4K screen in all cases. Intraoperative OCT images facilitated identification of subtle retinal alterations. Surgeons reported that the 4K screen seemed to provide improved visualization of the OCT data stream compared with the semitransparent ocular view. Surgeons were able to examine the OCT data on the 4K screen without reverting to the external display system of the microscope. The system provided a uniform surgical visualization experience for both the surgeon and the assistant. In addition, the digital platform allowed all surgical personnel to simultaneously view both the OCT and the surgical field. All eyes underwent uneventful vitrectomy without reverting to the conventional microscope. No intraoperative adverse events occurred. CONCLUSION: Integration of OCT into the digital visualization system may enable unique opportunities for surgeon feedback of intraoperative diagnostics. The overlay of the OCT data onto the 4K monitor seemed to provide excellent visualization of OCT details. Further research is needed to compare the conventional microscope-based approach to the digital 3D screen approach in regards to intraoperative OCT. PMID- 29256990 TI - Emergency Department Burden of Gastroparesis in the United States, 2006 to 2013. AB - BACKGROUND AND AIMS: Gastroparesis, a chronic gastrointestinal disorder defined by delayed stomach emptying in the absence of obstruction, is often associated with frequent and costly visits to the emergency department (ED). The aim of this study was to analyze trends in gastroparesis-related ED visits from 2006 to 2013. MATERIALS AND METHODS: Patients with a primary diagnosis of gastroparesis were identified from the Nationwide Emergency Department Sample (NEDS), the largest publicly available ED all-payer representative database in the United States. ED visits, admission rates, duration of hospitalizations, and charges were compiled. Patients with a secondary diagnosis of diabetes mellitus were analyzed as a subgroup. RESULTS: The number of ED visits for gastroparesis as a primary diagnosis in the United States increased from 15,459 in 2006 to 36,820 in 2013, an increase from 12.9 to 27.3 per 100,000 ED visits. The total charges associated with these ED visits and subsequent admissions increased from $286 million to $592 million. In contrast, admission rates through the ED decreased by 22%, procedure rates decreased by 6.2%, and the mean length of stay was shortened by 0.6 days. ED visits for patients with diabetic gastroparesis increased from 5696 to 14,114, an increase from 4.7 to 10.5 per 100,000 ED visits, with an increase in total associated charges for ED visits and subsequent admissions from $84 million to $182 million. CONCLUSIONS: The number of ED visits and associated charges for a primary diagnosis of gastroparesis with or without a secondary diagnosis of diabetes mellitus rose significantly from 2006 to 2013. PMID- 29256991 TI - Fecal Matrix Metalloproteinase-9 Measurement for Optimizing Detection of Disease Activity in Inflammatory Bowel Disease. PMID- 29256989 TI - Diagnostic Yield of 2 Strategies for Adult Celiac Disease Identification in Primary Care. AB - GOALS: To compare the diagnostic yield and cost-consequences of 2 strategies, screening regardless of symptoms versus case finding (CF), using a point-of-care test (POCT), for the detection of celiac disease (CD) in primary care, to bridge the diagnostic gap of CD in adults. MATERIALS AND METHODS: All subjects under 75 years of age who consecutively went to their general practitioners' offices were offered POCT for anti-transglutaminase immunoglobulin A antibodies. The POCT was performed on all subjects who agreed, and then a systematic search for symptoms or conditions associated with higher risk for CD was performed, immediately after the test but before knowing the test results. The 2 resulting groups were: (a) POCT positive and (b) symptomatic subject at CF. Subjects were defined as symptomatic at CF in the presence of 1 or more symptoms. All POCT-positive or symptomatic subjects at CF were referred to the CD Centers for confirmation of CD. Data on resource consumption were gathered from patients' charts. Cost of examinations, and diagnostic and laboratory tests were estimated with regional outpatient tariffs (Sicily), and a price of &OV0556;2.5 was used for each POCT. RESULTS: Of a total of 2197 subjects who agreed to participate in the study, 36 (1.6%) and 671 (30.5%) were POCT positive and symptomatic at CF, respectively. The yield from the screening and CF was 5 new celiac patients. The total cost and mean cost for each new CD case were &OV0556;7497.35 and &OV0556;1499.47 for the POCT screening strategy, and &OV0556;9855.14 and &OV0556;1971.03 for the CF strategy, respectively. Assuming consecutive use of both strategies, performing POCT only in symptomatic subjects at CF, the calculated yield would be 4 new diagnoses with a total cost of &OV0556;2345.84 and a mean cost of &OV0556;586.46 for each newly diagnosed patient. Only 1 patient was celiac despite a negative POCT. CONCLUSIONS: Testing symptomatic subjects at CF only by POCT seems the most cost-effective strategy to bridge the diagnostic gap of adult CD in primary care. PMID- 29256992 TI - An Update on Current Management Strategies for Achalasia and Future Perspectives. AB - The last decade has seen growing insight into the pathophysiology of achalasia, and current treatments decreasing the resting pressure in the lower esophageal sphincter by endoscopic (botulinum toxin injection, pneumatic dilation, peroral endoscopic myotomy) or surgical means (Heller myotomy). Manometry is considered the gold standard to confirm the diagnosis of achalasia. Pneumatic dilation and laparoscopic Heller myotomy have similar effectiveness and are both more successful in patients with type II achalasia. Laparoscopic myotomy when combined with partial fundoplication is an effective surgical technique and has been considered the operative procedure of choice until recently. Peroral endoscopic myotomy is an emerging therapy with promising results since it offers a minimally invasive and efficacious option especially in type III achalasia. However, it remains to be determined if peroral endoscopic myotomy offers long-term efficacy. PMID- 29256993 TI - The Multiple-Patient Simulation Toolkit: Purpose, Process, and Pilot. AB - Educating nursing students to safely care for multiple patients has become an important but challenging focus for nurse educators. New graduate nurses are expected to manage care for multiple patients in a complex and multifaceted health care system. With patient safety as a priority, multiple-patient assignments are necessary in order for nursing students to learn how to effectively prioritize and delegate care. The purpose of this project was the construction of an adaptable and flexible template for the development of multiple-patient simulations. Through utilization, the template moved to a toolkit adding an operational guide, sample-populated template, and bibliography. PMID- 29256994 TI - Exploring Truth, Justice, Compassion, Community, and Partnership While Learning to Care for Veterans Through Study, Reflection, and Action. AB - This article describes an innovative elective nursing course developed and implemented in a private, liberal arts school of nursing grounded in Dominican values of study, reflection, and action. Course development, course content, and highlights and lowlights of the first cohort experience and implications for the community are discussed, along with background about veteran-centered care. PMID- 29256995 TI - Interprofessional Education and Team-Based Learning in a Research Methods Course. AB - This article describes team-based pedagogical strategies for a hybrid, four credit research methods course with students from nursing, exercise, and nutrition science. The research problem of concussion in football, a socially relevant and controversial topic, was used to explore interprofessional perspectives and develop shared problem solving. The course was designed using permanent teams, readiness assurance, application exercises, and peer evaluation to facilitate student achievement of competencies related to interprofessional collaboration and research application. Feedback from students, faculty, and the Readiness for Interprofessional Learning Scale was used to evaluate the learning innovation. PMID- 29256997 TI - Preoperative Alveolar Segment Position as a Predictor of Successful Gingivoperiosteoplasty in Patients with Unilateral Cleft Lip and Palate. AB - BACKGROUND: Gingivoperiosteoplasty can avoid secondary alveolar bone grafting in up to 60 percent of patients with a cleft. However, preoperative predictors of success have not been characterized. This study reports on the preoperative alveolar segment position most favorable for successful gingivoperiosteoplasty. METHODS: The authors performed a single-institution, retrospective review of patients with a unilateral cleft who underwent nasoalveolar molding. Alveolar segment morphology was directly measured from maxillary dental models created before and after nasoalveolar molding. Statistical analysis was performed to identify parameters associated with the decision to perform gingivoperiosteoplasty and its success, defined as the absence of an eventual need for alveolar bone grafting. RESULTS: Fifty patients with a unilateral cleft who received nasoalveolar molding therapy were included in this study (40 underwent gingivoperiosteoplasty and 10 did not). Eighteen alveolar morphology and position characteristics were tested, including cleft gap width, horizontal and vertical positions of the alveolar segments, alveolar stepoff, and degree of alveolar segment apposition. Post-nasoalveolar molding vertical rotation of the greater segment and the percentage of segment alignment in the correct anatomical zone were statistically significant predictors of the decision to perform gingivoperiosteoplasty (86 percent predictive power). Cleft gap, greater/lesser segment overlap, alveolar segment alignment, greater segment horizontal rotation, and alveolar segment width following nasoalveolar molding were significant predictors of gingivoperiosteoplasty success (86.5 percent predictive power). CONCLUSIONS: Greater segment vertical rotation and proper alveolar segment anatomical alignment are positive predictors of the decision to perform gingivoperiosteoplasty. Post-nasoalveolar molding evidence of proper alignment and direct contact between the alveolar segments were significant predictors of successful gingivoperiosteoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 29256998 TI - Is There a Limit? A Risk Assessment Model of Liposuction and Lipoaspirate Volume on Complications in Abdominoplasty. AB - BACKGROUND: Combining liposuction and abdominoplasty is controversial because of concerns for increased complications and potential for vascular compromise of the abdominoplasty flap. Also, the lipoaspirate volume in abdominoplasty is regulated in some areas to as little as 500 ml when performed with abdominoplasty. This study measures abdominoplasty complication rates when performed with and without trunk liposuction, and evaluates the effect of lipoaspirate volume on complications. METHODS: Abdominoplasty and liposuction of the trunk procedures were identified in the Tracking Operations and Outcomes for Plastic Surgeons database. Multivariate regression models determined the effect of liposuction with abdominoplasty on complications compared with abdominoplasty alone and determined the effect of liposuction volume on complications. RESULTS: Eleven thousand one hundred ninety-one patients were identified: 9638 (86.1 percent) having abdominoplasty with truncal liposuction and 1553 (13.9 percent) having abdominoplasty alone. Overall complication rates were 10.5 percent and 13.0 percent, respectively. Combined liposuction and abdominoplasty was independently associated with a reduced risk of both overall complications (p = 0.046) and seroma (p = 0.030). Given existing laws limiting liposuction volume to 500 or 1000 ml in combination with abdominoplasty, each of these thresholds was evaluated, with no effect on complications. Surprisingly, increasing liposuction volume was not independently associated with an increased risk of any complication. CONCLUSIONS: When done by board-certified plastic surgeons, abdominoplasty with truncal liposuction is safe, with fewer complications than abdominoplasty alone. Regulations governing liposuction volumes in abdominoplasty are arbitrary and do not reflect valid thresholds for increased complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29256999 TI - Tamoxifen-Prefabricated Beige Adipose Tissue Improves Fat Graft Survival in Mice. AB - BACKGROUND: Fat grafting has become an important tool for breast reconstruction in breast cancer patients. Tamoxifen, the hormone therapy agent most frequently used for breast cancer, can affect adipose metabolism and cause browning of adipose tissue. This study hypothesized that tamoxifen could increase fat graft survival by altering adipose metabolism. METHODS: C57/BL6 mice were divided into three groups receiving different treatments before and after fat grafting. The tamoxifen/grafting/tamoxifen group was pretreated with daily tamoxifen for 8 weeks, received fat grafting, and was treated with daily tamoxifen. The graft/tamoxifen group was pretreated with daily phosphate-buffered saline for 8 weeks, received fat grafting, and was treated with daily tamoxifen. The control group was pretreated with daily phosphate-buffered saline for 8 weeks, received fat grafting, and was treated with daily phosphate-buffered saline. The inguinal fat used for transplantation and the transferred fat at weeks 4 and 12 after transplantation were harvested and analyzed. RESULTS: Tamoxifen-pretreated inguinal fat showed beige fat features, with smaller adipocyte size, up-regulated uncoupling protein 1 expression, and improved vascularization. The retention rate of transferred fat was significantly higher in the tamoxifen/grafting/tamoxifen group than in the control group (69 +/- 12 percent versus 36 +/- 13 percent; p < 0.05), but fat grafts in the graft/tamoxifen group had a retention rate similar to that in the control group (31 +/- 12 percent versus 36 +/- 13 percent; p > 0.05). Improved angiogenesis and increased vascular endothelial growth factor expression were found in the tamoxifen/grafting/tamoxifen group but not in the graft/tamoxifen group. CONCLUSIONS: Tamoxifen treatment before fat grafting resulted in prefabricated vascularized beige fat with small adipocytes, which greatly improve fat graft survival. However, tamoxifen after fat grafting did not affect fat graft evolution. PMID- 29257000 TI - External Volume Expansion Up-Regulates CXCL12 Expression and Enhances Mesenchymal Stromal Cell Recruitment toward Expanded Prefabricated Adipose Tissue in Rats. AB - BACKGROUND: External volume expansion devices are effective for adipose tissue regeneration. However, the detailed mechanisms by which external volume expansion devices induce adipose tissue regeneration remain unclear. METHODS: An external volume expansion device was used to construct expanded prefabricated adipose tissue in a rat model. CXCL12 levels in local exudate and serum were measured by enzyme-linked immunosorbent assay, and CXCL12 expression in adipose tissue was assessed immunohistochemically. Fluorescent dye (CM-DiI)-labeled bone marrow derived mesenchymal stromal cells and labeled mesenchymal stromal cells pretreated with the CXCR4 antagonist AMD3100 were transplanted into rats and tracked in vivo by fluorescence imaging. RESULTS: CXCL12 levels in local exudate and serum peaked 2 and 7 days, respectively, after external volume expansion device application. CXCL12 cell counts were significantly higher in the external volume expansion than in the control group. These CXCL12 cells were mainly columnar or cuboidal and began to express peroxisome proliferator-activated receptor gamma on day 9. CM-DiI-labeled mesenchymal stromal cells were successfully recruited to the expanded prefabricated adipose tissue, a process partly inhibited by the CXCR4 antagonist AMD3100. These recruited CM-DiI-labeled mesenchymal stromal cells were found among the CXCL12 columnar cells. CONCLUSIONS: External volume expansion devices enhance CXCL12 expression levels, especially in columnar and cuboidal cells. The CXCL12/CXCR4 pathway is involved in recruiting circulating mesenchymal stromal cells to participate in adipose regeneration. These findings may reveal the mechanism underlying external volume expansion and provide insights into the refinement of these devices. PMID- 29257001 TI - Objective Assessment of the Unilateral Cleft Lip Nasal Deformity Using Three Dimensional Stereophotogrammetry: Severity and Outcome. AB - BACKGROUND: Optimization of care to correct the unilateral cleft lip nasal deformity is hampered by lack of objective measures to quantify preoperative severity and outcome. The purpose of this study was to develop a consensus standard of nasal appearance using three-dimensional stereophotogrammetry; determine whether anthropometric measurements could be used to quantify severity and outcome; and determine whether preoperative severity predicts postoperative outcome. METHODS: The authors collected facial three-dimensional images of 100 subjects in three groups: 45 infants before cleft lip repair; the same 45 infants after cleft lip repair; and 45 children aged 8 to 10 years with previous repairs. Five additional age-matched unaffected control subjects were included in each group. Seven expert surgeons ranked images in each group according to nasal appearance. The rank sum score was used as consensus standard. Anthropometric analysis was performed on each image and compared to the rank sum score. Preoperative rank and anthropometric measurements were compared to postoperative rank. RESULTS: Interrater and intrarater reliability was excellent (intraclass correlation coefficient, >0.76; Pearson correlation, >0.75) on each of the three image sets. Columellar angle, nostril width ratio, and lateral lip height ratio were highly correlated with preoperative severity and moderately correlated with postoperative nasal appearance. Postoperative outcome was associated with preoperative severity (rank and anthropometric measurement). CONCLUSIONS: Consensus ranking of preoperative severity and postoperative outcome can be achieved on three-dimensional images. Preoperative severity predicts postoperative outcomes. Columellar angle, nostril width ratio, and lateral lip height ratio are objective measures that correlate with consensus ratings by surgeons at multiple ages. PMID- 29257002 TI - Capsular Biofilm Formation at the Interface of Textured Expanders and Human Acellular Dermal Matrix: A Comparative Scanning Electron Microscopy Study. AB - BACKGROUND: Despite benefits in reducing capsular contractures, textured implants have been associated with significant pitfalls, such a propensity for biofilm formation. Few studies have investigated whether the use of acellular dermal matrix on textured implants produces similar findings. This study aims to characterize biofilm formation at the capsular-acellular dermal matrix interface with scanning electron microscopy. METHODS: The authors performed a prospective observational pilot study in patients undergoing two-stage expander-to-permanent implant exchange. Patients were inflated with Biocell or Siltex expanders, and specimens from the capsular-pectoralis interface and capsular-acellular dermal matrix interface were obtained and examined under scanning electron microscopy for capsular ingrowth and biofilm formation using the Van Herdeen Biofilm Grading System and the Biofilm Thickness Grading Scale. RESULTS: Nine patients including 14 breasts (28 capsular samples in total) were examined. Thick biofilm formation was observed in all specimens from the capsular-acellular dermal matrix interface with Biocell and 25 percent of capsule-pectoralis interface, whereas no biofilm formation was found in Siltex implants. For Biocell implants, a significant difference in biofilm coverage between the upper and lower poles was observed using the Van Herdeen Biofilm Grading System (p = 0.0028) and the Biofilm Thickness Grading Scale (p = 0.0161). CONCLUSIONS: Biocell implants produce a significant rate of biofilm formation over acellular dermal matrix-covered capsules, which is not present in the muscular region or in Siltex implants. Further randomized controlled trials will further elucidate the clinical impact of using acellular dermal matrices with macrotextured implants. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29257003 TI - Critical Differences between Microscopic (MIFE) and Macroscopic (MAFE) Fat Embolism during Liposuction and Gluteal Lipoinjection. AB - BACKGROUND: Liposuction and gluteal lipoinjection are two of the most frequent surgical procedures in body contouring surgery, and two of the most important complications are microscopic (MIFE) and macroscopic (MAFE) fat embolism. Despite a high index of morbidity and mortality, few reports exist about these complications, and although they have the same causal agent, their etiopathogenesis, clinical evolution, treatment, prognosis, and prevention are totally different. Therefore, the authors performed a comprehensive review of the literature to exhaustively analyze both pathologic conditions and present the differences between them. METHODS: A detailed search was carried out in PubMed of studies on humans from 1946 to March of 2017 in any language and including the keywords microscopic fat embolism and macroscopic fat embolism with either liposuction or gluteal lipoinjection. The articles found were selected according to the search criteria and were analyzed to provide the final data and recommendations. RESULTS: Of the 1245 and 26 articles that were found on complications related to liposuction and gluteal lipoinjection, respectively, only 41 on liposuction and microscopic fat embolism and seven on gluteal lipoinjection and microscopic fat embolism met the specific criteria for inclusion in the analysis. Only two articles on liposuction and two on gluteal lipoinjection referred to macroscopic fat embolism as a complication. CONCLUSION: Although microscopic fat embolism and macroscopic fat embolism are pathologic conditions with high morbidity and mortality rates in association with liposuction and gluteal lipoinjection, few reports about them exist; therefore, the authors made recommendations based on this study for their diagnosis, prevention, and treatment. PMID- 29257005 TI - Airway Volume Simulation in Virtual Mandibular Distraction: A Cohort Study. AB - BACKGROUND: The authors investigated the accuracy of virtual surgical planning in predicting airway volume changes after mandibular distraction in patients with Pierre Robin sequence and associated tongue-based airway obstruction. METHODS: The authors completed a single-institution retrospective review of patients for whom virtual surgical planning was used during mandibular distraction osteogenesis for treatment of tongue-based airway obstruction. Preoperative airway volume, virtual surgical planning-predicted airway volume, and postoperative airway volume were calculated from three-dimensional computed tomographic scans using industry software. A blinded institutional radiologist also calculated pre- and post-operative airway volumes. Pre- and post-operative polysomnography was used to titrate the endpoint of mandibular lengthening. RESULTS: Eleven patients were included in the study. Mean apnea-hypopnea index (5.42 +/- 4.53 versus 44.96 +/- 20.57; p < 0.001) and mean nadir oxygen saturation (70.3 +/- 9.72 percent versus 82.9 +/- 9.62 percent; p = 0.003) improved with mandibular distraction. There was moderate correlation between predicted and actual mandibular distraction lengths (R = 0.65; p = 0.003). There was a strong correlation between predicted and industry-calculated actual post distraction airway volume (R = 0.99; p < 0.001). There was no significant correlation between actual mandibular distraction length and industry-calculated actual post-distraction airway volume for the entire cohort (R = 0.05; p = 0.49), but correlation approached significance by institutional calculations. No significant correlation existed between industry and institutional-calculated percentage change in post-distraction airway volume (R = 0.06; p = 0.57). CONCLUSIONS: Predictive airway volume calculation may be an effective adjunct to determine anatomic endpoint of mandibular distraction but small sample size, operator and software variability, and patient airway morphology may confound firm conclusions. Further studies are warranted. PMID- 29257004 TI - Use and Associated Spending for Anesthesiologist-Administered Services in Minor Hand Surgery. AB - BACKGROUND: Evidence is lacking to support the use of specialized anesthesia providers in minor surgical operations for patients without medical necessity. The authors sought to estimate the extent of potentially discretionary service use (anesthesiologist-administered anesthesia services among low-risk patients). METHODS: The authors performed a retrospective claims analysis using the Truven MarketScan Database to estimate the prevalence and cost of anesthesiologist administered anesthesia services provided to patients undergoing minor hand surgery (i.e., carpal tunnel release, trigger finger release, or de Quervain release) from 2010 to 2015. A predictive probability model was created to estimate patient risk status. The authors examined the relationship between patient risk status and anesthesia use using multivariable regression models. RESULTS: Of 441,579 eligible procedures, 352,779 (80 percent) involved anesthesiologist-administered anesthesia services. The total proportion of estimated anesthesiologist-administered anesthesia use in low-risk patients who did not need anesthesiologist support declined over the study period (from 69.7 percent in 2010 to 65.8 percent in 2015). Although total payments for these services remained steady between 2010 and 2014, the average payment per procedure increased regardless of procedure type (from $376.8 in 2010 to $427.9 in 2015 for a carpal tunnel release operation). Approximately 83.7 percent of payments ($133 million) to anesthesia providers is credited to services in low-risk patients. CONCLUSIONS: Anesthesiologist-administered anesthesia services are commonly rendered to low-risk surgical patients. Existing health care reform efforts do not adequately address discretionary services that can be a targeted area for cost saving. It is important to consider the implications of potentially discretionary use of specialized anesthesia providers, particularly with the advancement of bundled payment models. PMID- 29257006 TI - 68Ga-PSMA-HBED-CC PET/CT imaging in Black versus White South African patients with prostate carcinoma presenting with a low volume, androgen-dependent biochemical recurrence: a prospective study. AB - OBJECTIVE: To compare the diagnostic accuracy of Ga-prostate-specific membrane antigen (PSMA)-HBED-CC PET/computed tomography (CT) imaging for the detection of androgen-dependent recurrent prostate carcinoma (ADPC) in Black South Africans (BSAs) versus White South Africans (WSAs) with increasing serum prostate-specific antigen (PSA) values below or equal to 10 ng/ml. PATIENTS AND METHODS: A total of 61 patients with ADPC were prospectively included in the study (mean age: 66.7 years): 38 WSAs and 23 BSAs. Ga-PSMA-HBED-CC PET/CT imaging results obtained were related to serum PSA levels and to ethnicity. RESULTS: A total of 41 (67%) patients had a positive Ga-PSMA-HBED-CC scan result. Ga-PSMA-HBED-CC PET/CT positivity was significantly higher in patients with PSA values more than 2 ng/ml [32/38 (84%) patients] when compared with patients with PSA values less than 0.5 ng/ml [6/11 (55%) patients] or PSA values of 0.5-2 ng/ml [3/12 (25%) patients] (P=0.0001). Mean PSA values proved not significantly different in patients presenting with extrapelvic involvement when compared with those with intrapelvic involvement or between patients who presented with bone involvement versus those who did not on Ga-PSMA-HBED-CC PET/CT) (P>=0.147). Age, Gleason-scores, median PSA values, the frequency of a positive scan result, the frequency of bone involvement, and extrapelvic involvement proved similar in WSAs and BSAs (P>=0.417). CONCLUSION: Ga-PSMA-HBED-CC PET/CT imaging identified a recurrence in 67% of the patients under study. Higher PSA levels were associated with Ga-PSMA HBED-CC PET/CT positivity and the detection rate. Imaging results obtained proved similar in BSAs and WSAs, suggesting that the tumor burden and growth rate of ADPC are similar in both races. PMID- 29257007 TI - Apoptosis and cell proliferation in short-term and long-term effects of radioiodine-131-induced kidney damage: an experimental and immunohistochemical study. AB - OBJECTIVE: Radioiodine-131 is a radionuclide that is used for therapeutic purposes in hyperthyroidism and thyroid cancer. The aim of this study was to evaluate apoptotosis and proliferative changes in radioiodine-related kidney damage. MATERIALS AND METHODS: Three groups (n=10/group) of rats were used as follows: the rats were in group 1 untreated, and the rats in groups 2 and 3 were treated once with oral radioiodine (111 MBq). The animals in group 2 were killed at the end of the seventh day and the rats in group 3 were killed at the end of the 10th week. The kidneys were removed and evaluated immunohistochemically. The presence of radioiodine in the kidneys was shown by the Na+/I-symporter antibody and proliferating cell nuclear antigen, Ki-67, caspase-3, caspase-8, caspase-9, and terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling assay were used to detect cell proliferation and apoptosis. RESULTS: Na+/I-symporter protein accumulation in the kidneys was observed to be significantly greater in group 2 than in group 3 (P<0.05). All the immunohistochemical analyses showed that cell proliferation and apoptosis began on the seventh day and peaked in the 10th week. The proliferating cell nuclear antigen, Ki-67, and caspase expressions and terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling values were all found to be statistically significantly increased in group 3 compared with the other groups (P<0.05). CONCLUSION: Radioiodine caused cell proliferation and apoptosis as shown by immunohistochemistry. PMID- 29257008 TI - Which is the optimal threshold for defining functional lung in single-photon emission computed tomography lung perfusion imaging of lung cancer patients? AB - PURPOSE: The aim of this study was to investigate the optimal threshold for the functional lung (FL) definition of single-photon emission computed tomography (SPECT) lung perfusion imaging. PATIENTS AND METHODS: Forty consecutive stage III non-small-cell lung cancer patients underwent SPECT lung perfusion scans and PET/CT scans for treatment planning, and the images were coregistered. Total lung and perfusion lung volumes corresponding to 10, 20, ..., 60% of the maximum SPECT count were segmented automatically. The SPECT-weighted mean lung dose (SWMDx%) and the percentage of FL volume receiving more than 20 Gy (Fx%V20) of different thresholds were investigated using SPECT-weighted dose-volume histograms. Receiver-operator characteristic curves were used to identify SWMD and FV20 of different thresholds in predicting the incidence of radiation pneumonitis (RP). RESULTS: Eleven (27.5%) patients developed RP (grades 1, 2, 3, and 4 were 10.0, 7.5, 7.5, and 2.5%, respectively) after treatment. The largest area under the receiver-operator characteristic curve was 0.881 for the ability of SWMD to predict RP with 20% as the threshold and 0.928 for the ability of FV20 with 20% as the threshold. CONCLUSION: The SWMD20% and FV20 of FL using 20% of the maximum SPECT count as the threshold may be better predictors for the risk of RP. PMID- 29257009 TI - The Effectiveness of Progressive Aerobic Interval Training in Cardiac Rehabilitation. AB - INTRODUCTION: Aerobic interval training (AIT) has recently emerged as a more effective strategy than moderate-intensity continuous exercise (MICE) for improving peak oxygen consumption (VO2peak) in coronary artery disease (CAD) patients. The primary purpose of this retrospective study was to describe the change in VO2peak, and cardiovascular (CV) risk profile characteristics (secondary outcomes) after progressive AIT practiced in the largest, outpatient cardiac rehabilitation (CR) program in North America compared with usual care CR involving MICE. METHODS: Electronic database records were retrieved from consecutively enrolled patients with CAD who attended the Toronto Rehabilitation Institute, between January 1, 2005, and December 31, 2015. Patients were then separated into two, age and sex propensity score-matched groups: 772 patients were prescribed 26 wk of MICE (60%-80% of VO2peak, five times per week) as per usual care CR (56.0 +/- 9.2 yr; 12% female/88% male; VO2peak: 20.8 +/- 5.9 mL.kg.min), and 772 patients were prescribed 26 wk of progressive walk/jog intervals (15 min.mile walking pace, 12 min.mile jogging pace, five times per week) (55.9 +/- 9.3 yr; 12% female/88% male; VO2peak: 24.8 +/- 5.7 mL.kg .min). Treatment effect analysis of AIT on VO2peak and CV risk profile characteristics was performed using multiple regression with baseline values as covariates. RESULTS: Treatment effect analysis revealed a 3.84-mL.kg.min superior improvement in VO2peak in the AIT group compared to usual care MICE group (P < 0.001). Furthermore, AIT significantly improved BMI, triglycerides, hip and abdominal girth, and depression score compared with MICE (P < 0.023 for all). CONCLUSIONS: Progressive AIT performed in a standard, outpatient CR program appears to be superior to usual care MICE for improving VO2peak, CV risk profile characteristics, and depression score in stable CAD patients. These findings may have important implications for exercise training guidelines in the rehabilitation setting, and in future studies. PMID- 29257010 TI - Intravenous and Topical Tranexamic Acid Alone Are Superior to Tourniquet Use for Primary Total Knee Arthroplasty: A Prospective, Randomized Controlled Trial. AB - BACKGROUND: Tourniquet use during primary total knee arthroplasty is thought to reduce intraoperative blood loss and improve visibility. Our goal was to investigate whether tourniquet use is necessary for controlling intraoperative blood loss when alternatives such as tranexamic acid (TXA) are available. METHODS: One hundred and fifty patients were equally randomized to 3 groups. Group A was treated with a tourniquet as well as multiple doses of intravenous TXA (20 mg/kg 5 to 10 minutes before the skin incision and 10 mg/kg 3, 6, 12, and 24 hours later) along with 1 g of topical TXA, Group B was treated the same as Group A but without the tourniquet, and Group C was treated with the tourniquet only. RESULTS: The amount of intraoperative blood loss was similar for the 3 groups. Group B had significantly less hidden blood loss than Group A (p = 0.018) and Group C (p < 0.001). No significant differences (p > 0.05) were observed between Group A and Group B with regard to total blood loss, drainage volume, intraoperative blood loss, transfusion rate, or maximum change in the hemoglobin (Hb) level. We also found significantly more benefits for Group B compared with Groups A and C with regard to postoperative swelling ratio, levels of inflammatory biomarkers, visual analog scale (VAS) pain scores, range of motion at discharge, Hospital for Special Surgery (HSS) score, and patient satisfaction. There were no significant differences (p > 0.05) in the deep venous thrombosis or pulmonary embolus rates among the 3 groups. More wound secretion was observed in the groups in which a tourniquet was used. CONCLUSIONS: Patients treated with multiple doses of intravenous and topical TXA without a tourniquet had less hidden blood loss, a lower ratio of postoperative knee swelling, less postoperative knee pain, lower levels of inflammatory biomarkers, better early knee function, and even better early satisfaction than those treated with a tourniquet. Long-term follow-up should be performed to evaluate the effects on prosthetic fixation and long-term survival of total knee arthroplasty performed without a tourniquet. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257011 TI - A Historical Analysis of Randomized Controlled Trials in Anterior Cruciate Ligament Surgery. AB - BACKGROUND: The purpose of this systematic review was to comprehensively assess the quality of reporting of randomized controlled trials (RCTs) relating to anterior cruciate ligament (ACL) reconstruction. Specifically, this review explored factors related to the quality of the RCTs and trends in the quality of reporting over time. METHODS: The online databases PubMed, Ovid (MEDLINE), and Embase were used to search for all RCTs on the topic of ACL reconstruction from database inception until April 14, 2016. The quality of reporting was evaluated using the Detsky quality index and the Consolidated Standards of Reporting Trials (CONSORT) checklist for reporting trials of nonpharmacologic treatments. A multivariate regression analysis was used to assess predictors of quality reporting. RESULTS: The online search yielded 2,933 articles, 412 of which met the inclusion criteria and were assessed for quality of reporting. There was a significant (p < 0.0001) increase in the number of RCTs published over time. The mean Detsky score (and standard deviation) across all included RCTs was 68.9% +/- 13.2%. The strongest predictors of quality reporting were the inclusion of a CONSORT flow diagram (beta-coefficient, 10.0; 95% confidence interval [CI]: 8.45 to 11.61; p < 0.0001) and being published in the year 2009 or later (beta coefficient, 5.2; 95% CI: 3.87 to 6.45; p < 0.0001). The factors demonstrating the greatest improvement over time were the inclusion of a full description of the randomization procedure (p = 0.001) and prospective calculation of the sample size (p = 0.002). CONCLUSIONS: There has been a significant increase in both the quantity and quality of RCTs relating to ACL reconstruction over time. Specifically, the reporting of a methodologically sound randomization process and prospective calculation of sample size have significantly improved in recent years. However, since the year 2009, the number of trials and reporting in these trials has remained relatively consistent. The use of a CONSORT flow diagram is a strong predictor of high-quality reporting. PMID- 29257012 TI - Allograft-Prosthetic Composite Reconstruction for Massive Proximal Humeral Bone Loss in Reverse Shoulder Arthroplasty. AB - BACKGROUND: Reverse total shoulder arthroplasty (RTSA) performed in the setting of massive proximal humeral bone loss often requires special reconstructive techniques. Restoration of the proximal part of the humerus with an allograft provides a number of theoretical benefits, including implant support, restoration of humeral length, deltoid tensioning, and an opportunity to repair the posterior aspect of the cuff to improve strength in external rotation and repair of the subscapularis to improve stability. However, reverse allograft-prosthesis composites (APCs) are costly, are technically demanding to use, and can be compromised by progressive allograft resorption. METHODS: Between 2005 and 2012, the lead author used an APC reconstruction in 8 primary and 18 revision RTSAs (26 patients; mean age, 62 years; mean body mass index, 27.9 kg/m). The indications for the primary RTSAs included severe proximal humeral bone loss after trauma (n = 5) and tumor resection (n = 3). The indications in the revision setting were failed hemiarthroplasty (n = 11), anatomic total shoulder arthroplasty (n = 4), and reverse arthroplasty (n = 3). The most common reason for revision was instability (n = 10). A compression plate was used for graft-to-host fixation in all shoulders. Shoulders were assessed for pain, motion, American Shoulder and Elbow Surgeons (ASES) score, Simple Shoulder Test (SST) score, Neer score, revision or reoperation, radiographic evidence of graft union or resorption, and implant fixation. The mean duration of follow-up was 4 years (range, 2 to 10 years). RESULTS: RTSA using an APC construct resulted in substantial improvements in pain scores (p < 0.0001), elevation (p < 0.0001), and external rotation (p = 0.004). With the numbers available, there were no significant differences in clinical outcomes between primary and revision cases. No patients required revision surgery for nonunion at the host-allograft junction. The mean time to union was 7 months, with 1 patient requiring bone-grafting for delayed union. Other complications included dislocation, deep infection, graft fracture, and periprosthetic fracture distal to the previous APC construct in 1 patient each. The 2 and 5-year revision-free survival rate was 96%. CONCLUSIONS: Reconstruction of proximal humeral bone loss with an APC at the time of primary or revision RTSA is safe and effective, with acceptable functional outcomes and complication rates. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257013 TI - Synovial Fluid Biomarkers for the Diagnosis of Periprosthetic Joint Infection: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The search for a single standard reference test for determining periprosthetic joint infection (PJI) through analysis of synovial fluid has yielded numerous biomarkers as potential candidates. The purpose of the present systematic review and meta-analysis was to evaluate the diagnostic accuracy of synovial fluid biomarkers and to determine which test has the highest diagnostic odds ratio (DOR) for the diagnosis of PJI. METHODS: An online literature search of the MEDLINE, Embase, and Cochrane databases identified 33 articles reporting a total of 13 major parameters for diagnosing PJI through analysis of synovial fluid. Each of the included articles was independently analyzed for risk of bias and for concerns regarding applicability utilizing the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool. The mada (meta-analysis of diagnostic accuracy) tool was used to generate forest plots for sensitivity, specificity, and the log of the DOR, as well as summary statistics. RESULTS: In this analysis, 13 index tests (leukocyte count; measurement of the percentage of polymorphonucleocytes [PMN%] and the levels of C-reactive protein [CRP], alpha defensin, leukocyte esterase [LE], interleukin [IL]-6, IL-8, IL-10, IL-1beta, vascular endothelial growth factor [VEGF], and granulocyte-colony stimulating factor [G-CSF]; culture; and polymerase chain reaction [PCR] analysis) were evaluated on the basis of >=2 articles. Of these tests, 8 (leukocyte count, PMN%, CRP, alpha-defensin, LE, IL-6, IL-8, and culture) were appropriate for pooled analysis. The overall sensitivity of these 8 markers was 0.85, and all but culture showed a sensitivity of >=0.8. All markers showed a specificity of >=0.9. Of the 8 tests, measurement of the alpha-defensin level showed the highest log DOR. CONCLUSIONS: Synovial fluid leukocyte count, PMN%, CRP, alpha-defensin, LE, IL-6, and IL-8 all demonstrated high sensitivity for diagnosing PJI, with alpha defensin being the best synovial marker based on the highest log DOR. However, other synovial fluid tests that demonstrate good diagnostic performance can also be used in combination for the diagnosis of PJI. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257014 TI - Postoperative Stiffness Requiring Manipulation Under Anesthesia Is Significantly Reduced After Simultaneous Versus Staged Bilateral Total Knee Arthroplasty. AB - BACKGROUND: For patients with symptomatic bilateral knee arthritis, it is unknown whether the risk of developing stiffness requiring manipulation under anesthesia postoperatively is higher or lower for those undergoing simultaneous bilateral total knee arthroplasty (TKA) compared with those having staged bilateral TKA. Therefore, we undertook this study to evaluate the risk of requiring manipulation under anesthesia in staged versus simultaneous bilateral TKA as well as patients undergoing unilateral TKA. METHODS: We utilized the California Patient Discharge Database, which is linked with the California Emergency Department, Ambulatory Surgery, and master death file databases. Using a literature-based estimate of the number of patients who failed to undergo the second stage of a staged bilateral TKA, replacement cases were randomly selected from patients who had unilateral TKA and were matched on 8 clinical characteristics of the patients who had staged bilateral TKA. Hierarchical multivariate logistic regression was performed to determine the risk-adjusted odds of manipulation in patients undergoing unilateral TKA, staged bilateral TKA, and simultaneous bilateral TKA using yearly hospital TKA volume as a random effect. Adjustment was made to allow fair comparison of the outcome at 90 and 180 days of follow-up after staged compared with simultaneous bilateral TKA. RESULTS: During the time period from 2005 through 2013, the cumulative incidence of manipulation within 90 days was 2.14% for unilateral TKA (4,398 events per 205,744 patients), 2.11% for staged bilateral TKA (724 events per 34,352 patients), and 1.62% for simultaneous bilateral TKA (195 events per 12,013 patients). At 180 days of complete follow up, the cumulative incidence of manipulation was 3.07% after unilateral TKA (6,313 events per 205,649 patients), 2.89% after staged bilateral TKAs (957 events per 33,169 patients), and 2.29% after simultaneous bilateral TKA (267 events per 11,653 patients). With multivariate analyses used to adjust for relevant risk factors, the 90-day odds ratio (OR) of undergoing manipulation after simultaneous bilateral TKA was significantly lower than that for unilateral TKA (OR = 0.70; 95% confidence interval [CI], 0.57 to 0.86) and staged bilateral TKA (OR = 0.71; 95% CI, 0.57 to 0.90). Similarly, at 180 days, the odds of undergoing manipulation were significantly lower after simultaneous bilateral TKA than after both unilateral TKA (OR = 0.71; 95% CI, 0.59 to 0.84) and staged bilateral TKA (OR = 0.76; 95% CI, 0.63 to 0.93). The frequency of manipulation was significantly associated with younger age, fewer comorbidities, black race, and the absence of obesity. CONCLUSIONS: Although the ORs were small (close to 1), simultaneous bilateral TKA had a significantly decreased rate of stiffness requiring manipulation under anesthesia at 90 days and 180 days after knee replacement compared with that after staged bilateral TKA and unilateral TKA. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257015 TI - Quantitative Assessment of Femoral Head Perfusion Following Arthroscopic Femoral Osteochondroplasty: A Cadaveric Study. AB - BACKGROUND: Disruption of the arterial supply to the femoral head, and subsequent development of femoral head osteonecrosis, is of serious concern with intracapsular hip procedures. However, the effect of arthroscopic femoral osteochondroplasty on femoral head perfusion is unknown. We aimed to quantify the effects of both standard and posterosuperior extension of arthroscopic femoral osteochondroplasty on femoral head vascularity. We hypothesized that extension of the superior resection zone posteriorly would negatively affect femoral head perfusion. METHODS: In 12 cadaveric pelvic specimens, we cannulated the medial femoral circumflex artery (MFCA). One hip per pelvis was randomly selected to be in 1 of 2 experimental groups based on the superior extent of the osteochondroplasty: standard resection (resection anterior to the 12 o'clock [0 degrees of 360 degrees ] position) or extended resection (resection extended posterior to the 12 o'clock position). Computed tomography (CT) scans were obtained prior to and following arthroscopic resection to delineate the resection margins. Gadolinium enhancement on magnetic resonance imaging (MRI) was quantified in the femoral head by volumetric analysis using custom software. A polyurethane compound was injected and gross dissection of the vasculature was performed. RESULTS: Extension of the osteochondroplasty posteriorly (the extended resection group), to a mean of 41.3 degrees (range, 34 degrees to 47 degrees ) posterior to the 12 o'clock position, decreased femoral head perfusion by a mean of 28% (range, 18% to 38%). The standard-resection group demonstrated a mean decrease in femoral head perfusion of 7% (range, 4% to 11%). Correlation analysis demonstrated a significant negative correlation (correlation coefficient, -0.877; p < 0.001; R = 0.747). For every 1 degrees that the superior resection margin extended posteriorly, a corresponding 0.88% decrease in femoral head perfusion was found. CONCLUSIONS: Femoral head perfusion is almost fully maintained with arthroscopic osteochondroplasty when the superior resection margin is anterior to the 12 o'clock position. Perfusion is also well maintained if the superior resection margin is extended no more than 10 degrees posterior to 12 o'clock. Further posterior extension correlated with greater decreases in femoral head perfusion. CLINICAL RELEVANCE: Our study provides previously unreported quantitative MRI data on femoral head perfusion following arthroscopic femoral osteochondroplasty for the treatment of cam-type femoroacetabular impingement. PMID- 29257016 TI - Who Is Performing Hip Arthroscopy?: An Analysis of the American Board of Orthopaedic Surgery Part-II Database. AB - BACKGROUND: Hip arthroscopy utilization has increased dramatically over the last decade. However, the lack of a formal training curriculum raises concern that inconsistent technical performance may be an issue for early-career hip arthroscopists. The purpose of the present study was to investigate hip arthroscopy utilization by early-career orthopaedic surgeons while focusing on fellowship training status to better guide future development of a hip arthroscopy training curriculum. METHODS: The American Board of Orthopaedic Surgery (ABOS) Part-II database was used to identify candidates who had performed >=1 hip arthroscopy procedures between 2006 and 2015. Procedures were categorized using Common Procedural Terminology (CPT) codes, and candidates were categorized by fellowship training experience. Trends in hip arthroscopy utilization were evaluated using univariate and regression analyses while stratifying by fellowship training experience. RESULTS: Overall, 9.2% (643) of 6,987 ABOS candidates had performed >=1 hip arthroscopy procedures. Over the study period, both the proportion of candidates performing hip arthroscopy and the proportion of hip arthroscopy procedures performed (relative to all procedures performed, of any type) increased (p < 0.001). Candidates performing hip arthroscopy most frequently reported sports medicine fellowship training (74.5%; 479 of 643). Also, among the candidates who performed hip arthroscopy, the proportion who had sports medicine fellowship training increased over the study period (p = 0.001). The majority of candidates performing hip arthroscopy (67.2%; 432 of 643) performed <=5 hip arthroscopy procedures, while a small number of high-volume hip arthroscopists (6.5%; 42 of 643) performed 34.6% (1,403 of 4,054) of all hip arthroscopy procedures. CONCLUSIONS: The increase in hip arthroscopy utilization in this cohort appears to have been driven primarily by the increased number of candidates performing hip arthroscopy and less by an increasing number of hip arthroscopy procedures being performed by individual candidates. The majority of candidates performing hip arthroscopy were sports-medicine-fellowship trained. This information is valuable for both trainees and educators interested in improving education and defining a curriculum for future hip arthroscopy training. PMID- 29257017 TI - Serum Albumin Predicts Survival and Postoperative Course Following Surgery for Geriatric Hip Fracture. AB - BACKGROUND: Serum albumin level is the most well-established serum marker of malnutrition, with a serum albumin concentration <3.5 g/dL considered to be suggestive of malnutrition. The purpose of this study was to test if serum albumin level is associated with death, specific postoperative complications (e.g., pneumonia), length of hospital stay, and readmission following a surgical procedure for geriatric hip fracture. METHODS: A retrospective cohort study of geriatric patients (>=65 years of age) undergoing a hip fracture surgical procedure as part of the American College of Surgeons National Surgical Quality Improvement Program was conducted. Outcomes were compared between patients with and without hypoalbuminemia. All comparisons were adjusted for baseline and procedural differences between populations, and patients with missing serum albumin concentration were included in analyses using a missing data indicator. RESULTS: There were 29,377 geriatric patients undergoing a hip fracture surgical procedure who met inclusion criteria; of these patients, 17,651 (60.1%) had serum albumin available for analysis. The prevalence of hypoalbuminemia was 45.9%. Following adjustment for baseline and procedural characteristics, the risk of death was inversely associated with serum albumin concentration as a continuous variable (adjusted relative risk, 0.59 [95% confidence interval (CI), 0.53 to 0.65]; p < 0.001). In comparison with patients with normal albumin concentration, patients with hypoalbuminemia had higher rates of death (9.94% compared with 5.53% [adjusted relative risk, 1.52 (95% CI, 1.37 to 1.70); p < 0.001]), sepsis (1.19% compared with 0.53% [adjusted relative risk, 1.92 (95% CI, 1.36 to 2.72); p < 0.001]), and unplanned intubation (2.64% compared with 1.47% [adjusted relative risk, 1.51 (95% CI, 1.21 to 1.88); p < 0.001]). The mean length of stay (and standard deviation) was longer among patients with hypoalbuminemia at 5.67 +/- 4.68 days compared with those without hypoalbuminemia at 4.99 +/- 3.95 days; the adjusted difference was 0.50 day (95% CI, 0.38 to 0.63 day; p < 0.001). However, the rate of readmission did not differ (p = 0.054) between patients with hypoalbuminemia (10.91%) and those without hypoalbuminemia (9.03%); the adjusted relative risk was 1.10 (95% CI, 1.00 to 1.21). CONCLUSIONS: Hypoalbuminemia is a powerful independent risk factor for mortality following a surgical procedure for geriatric hip fracture. These data suggest that further investigation into postoperative nutritional supplementation is warranted to decrease the risk of complications. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257018 TI - Attenuation of Robust Glial Scar Formation Facilitates Functional Recovery in Animal Models of Chronic Nerve Compression Injury. AB - BACKGROUND: Late surgery for chronic nerve compression injuries usually improves sensation but rarely reverses motor atrophy. We hypothesized that a persistent glial scar after chronic nerve compression injury might account for poor motor recovery and that degradation of the glial scar as an adjunct to surgical decompression would improve functional recovery. METHODS: A previously described model of chronic nerve compression injury was created in C57BL/6 mice and Sprague Dawley rats, and the nerves were harvested early or late after electrophysiological confirmation of the injury. Western blot, polymerase chain reaction, and quantitative immunohistochemical analyses were performed to determine levels of chondroitin sulfate proteoglycans and extracellular matrix molecules. Subsets of mice were treated either with surgical decompression alone or with decompression coupled with intraepineurial injection of a low dose (0.1 MUgMUL) or a high dose (0.2 MUg/MUL) of chondroitinase ABC at 6 weeks after injury. RESULTS: Aggrecan showed the greatest change in mRNA and protein levels at the early and late time points following creation of the chronic nerve compression injury. Quantitative immunohistochemical analysis revealed early aggrecan upregulation localized primarily to the endoneurium and late upregulation localized to the perineurium and epineurium (p < 0.0105). Quantitative immunohistochemical analysis for collagen IV, laminin-alpha2, and fibronectin also showed early upregulation with perineurial scarring. Quantitative immunohistochemical analysis and Western blot analysis for aggrecan demonstrated a marked increase in the endoneurium at the early time points and upregulation of expression in the epineurium and perineurium at the late time points. Decompression along with intraepineurial injection of high-dose chondroitinase ABC at 6 weeks after creation of the compression injury resulted in marked attenuation of decorin and aggrecan expression with functional improvement in nerve conduction velocity. CONCLUSIONS: Significant upregulation of chondroitin sulfate proteoglycans and other extracellular matrix components contributes to the pathogenesis of compression neuropathies in murine models. The administration of chondroitinase ABC degrades these chondroitin sulfate proteoglycans and improves functional recovery after chronic nerve compression injury; thus, it can be considered as a possible therapeutic adjunct. PMID- 29257020 TI - What's New in Musculoskeletal Tumor Surgery. PMID- 29257019 TI - Correction of "Wrist" Deformity in Radial Dysplasia: A Systematic Review and Meta Analysis. AB - BACKGROUND: Radial dysplasia affects 1 in 6,000 to 8,000 births, classically presenting with a shortened, bowed ulna and radially deviated hand. The optimal treatment remains unclear, with several opposing approaches advocated. This review aims to clarify the long-term outcomes of nonsurgical and surgical treatment of the "wrist" deformity. METHODS: The Embase, MEDLINE, PubMed, Cochrane Central, ClinicalTrials.gov, and World Health Organization International Clinical Trials Registry Platform (ICTRP) databases were searched for published and unpublished studies reporting long-term outcomes of surgical or nonsurgical treatment of children with radial dysplasia. Results were not restricted by date or language. Primary outcomes were hand-forearm angle, ulnar length, and "wrist" active range of motion (ROM). Studies were assessed using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) criteria. Data for the change in hand-forearm angle were pooled using random-effects meta-analysis, and mean differences and 95% confidence intervals were obtained. Primary outcome data at last follow-up were pooled, and means and standard deviations were obtained. The PROSPERO registration of this study was CRD42016036665. RESULTS: Of 104 studies identified, 12 were included in this review. Five were retrospective cohort studies and 7 were case series. No randomized studies were found. Study quality was low or very low according to the GRADE criteria. The hand-forearm angle of nonsurgically treated patients worsened during childhood, from 66 degrees to 84 degrees , whereas "wrist" active ROM, at 61 degrees , was better than that for most surgically treated patients. Ulnar length with nonsurgical treatment was predicted to be 64% of normal, but was not directly reported. Isolated soft-tissue release provided a modest reduction in hand-forearm angle compared with nonsurgical treatment. Soft-tissue distraction with centralization or radialization achieved the best hand-forearm angle correction (16 degrees radial deviation). Radialization maintained better "wrist" active ROM (46 degrees ) and ulnar length than centralization. Microvascular second metatarsophalangeal joint transfer yielded better reported "wrist" active ROM (83 degrees ) and good ulnar length compared with other surgical techniques, but a slightly worse hand forearm angle (28 degrees ). CONCLUSIONS: There was low-quality evidence that soft-tissue distraction plus centralization or radialization achieved the best correction of the hand-forearm angle for children with radial dysplasia. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257022 TI - Orthopaedic Care in Underserved Areas-What Are We Going to Do? Symposium Presented at the AOA Annual Meeting, June 23, 2016: AOA Critical Issues. PMID- 29257021 TI - Advanced Imaging Adds Little Value in the Diagnosis of Femoroacetabular Impingement Syndrome. AB - BACKGROUND: Femoroacetabular impingement (FAI) syndrome is an increasingly recognized source of hip pain and disability in young active adults. In order to confirm the diagnosis, providers often supplement physical examination maneuvers and radiographs with intra-articular hip injection, magnetic resonance imaging (MRI), or magnetic resonance arthrography (MRA). Since diagnostic imaging represents the fastest rising cost segment in U.S. health care, there is a need for value-driven diagnostic algorithms. The purpose of this study was to identify cost-effective diagnostic strategies for symptomatic FAI, comparing history and physical examination (H&P) alone (utilizing only radiographic imaging) with supplementation with injection, MRI, or MRA. METHODS: A simple-chain decision model run as a cost-utility analysis was constructed to assess the diagnostic value of the MRI, MRA, and injection that are added to the H&P and radiographs in diagnosing symptomatic FAI. Strategies were compared using the incremental cost utility ratio (ICUR) with a willingness to pay (WTP) of $100,000/QALY (quality adjusted life year). Direct costs were measured using the Humana database (PearlDiver). Diagnostic test accuracy, treatment outcome probabilities, and utilities were extracted from the literature. RESULTS: H&P with and without supplemental diagnostic injection was the most cost-effective. Adjunct injection was preferred in situations with a WTP of >$60,000/QALY, low examination sensitivity, and high FAI prevalence. With low disease prevalence and low examination sensitivity, as may occur in a general practitioner's office, H&P with injection was the most cost-effective strategy, whereas in the reciprocal scenario, H&P with injection was only favored at exceptionally high WTP (~$990,000). CONCLUSIONS: H&P and radiographs with supplemental diagnostic injection are preferred over advanced imaging, even with reasonable deviations from published values of disease prevalence, test sensitivity, and test specificity. Providers with low examination sensitivity in situations with low disease prevalence may benefit most from including injection in their diagnostic strategy. Providers with high examination sensitivity in situations with high disease prevalence may not benefit from including injection in their diagnostic strategy. Providers should not routinely rely on advanced imaging to diagnose FAI syndrome, although advanced imaging may have a role in challenging clinical scenarios. LEVEL OF EVIDENCE: Economic and Decision Analysis Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257024 TI - Benefits of Tranexamic Acid Not Debatable but Leave Tourniquet Use to Surgeon's Discretion: Commentary on an article by ZeYu Huang, MD, PhD, et al.: "Intravenous and Topical Tranexamic Acid Alone Are Superior to Tourniquet Use for Primary Total Knee Arthroplasty. A Prospective, Randomized Controlled Trial". PMID- 29257026 TI - Should We Be Concerned About Who Is Performing Hip Arthroscopy?: Commentary on an article by Kyle R. Duchman, MD, et al.: "Who Is Performing Hip Arthroscopy? An Analysis of the American Board of Orthopaedic Surgery Part-II Database". PMID- 29257025 TI - Blood Is Thicker Than Water: Commentary on an article by Lionel E. Lazaro, MD, et al.: "Quantitative Assessment of Femoral Head Perfusion Following Arthroscopic Femoral Osteochondroplasty. A Cadaveric Study". PMID- 29257027 TI - Intra-Articular Hip Injection Is a Valuable and Cost-Effective Diagnostic Tool but Replacing Advanced Diagnostic Methods Is Not Currently the Way to Go: Commentary on an article by Daniel J. Cunningham, MD, MHS, et al.: "Advanced Imaging Adds Little Value in the Diagnosis of Femoroacetabular Impingement Syndrome". PMID- 29257028 TI - Condoliase for the Treatment of Lumbar Disc Herniation: A Randomized Controlled Trial. AB - STUDY DESIGN: A randomized, double-blind, placebo-controlled, multicenter phase III clinical trial. OBJECTIVE: To evaluate the efficacy and safety of chemonucleolysis with condoliase in patients with lumbar disc herniation (LDH). SUMMARY OF BACKGROUND DATA: Condoliase is a pure mucopolysaccharidase derived from a bacterium, Proteus vulgaris that has high substrate specificity for chondroitin sulfate and hyaluronic acid in the nucleus pulposus of the intervertebral disc. METHODS: In this study, patients aged 20 to 70 years with unilateral leg pain, positive straight leg raise test, and a contained LDH were recruited in Japan. Patients were treated with a single injection of condoliase (1.25 U) or placebo and were followed for 1 year after administration. The primary endpoint was change in worst leg pain from baseline to week 13. The secondary endpoints included responder rate, and the changes from baseline up to week 52 in the worst leg pain, worst back pain, Oswestry Disability Index, 36 Item Short-Form Health Survey, neurologic examinations, and imaging parameters. RESULTS: A total of 82 and 81 patients received an injection of condoliase and placebo, respectively. The average changes in worst leg pain from baseline to week 13 (primary endpoint) were -49.5 mm in the condoliase group and -34.3 mm in the placebo group, and the difference of -15.2 mm was significant (95% confidence interval, -24.2 to -6.2; P = 0.001). Significant improvements were observed in the condoliase groups, compared with the placebo group, in most secondary endpoints at 1 year after administration. In the condoliase group, back pain, Modic type 1 change, and decrease in disc height were frequently reported, without any clinically relevant consequences. CONCLUSION: Condoliase significantly improved symptoms in patients with LDH and was well tolerated. Condoliase is a novel and potent chemonucleolytic drug for the treatment of LDH. LEVEL OF EVIDENCE: 1. PMID- 29257029 TI - Outpatient Spine Clinic Utilization is Associated With Reduced Emergency Department Visits Following Spine Surgery. AB - STUDY DESIGN: Review of TRICARE claims (2006-2014) data to assess Emergency Department (ED) utilization following spine surgery. OBJECTIVE: The aim of this study was to determine utilization rates and predictors of ED utilization following spine surgical interventions. SUMMARY OF BACKGROUND DATA: Visits to the ED following surgical intervention represent an additional stress to the healthcare system. While factors associated with readmission following spine surgery have been studied, drivers of postsurgical ED visits, including appropriate and inappropriate use, remain underinvestigated. METHODS: TRICARE claims were queried to identify patients who had undergone one of three common spine procedures (lumbar arthrodesis, discectomy, decompression). ED utilization at 30- and 90 days was assessed as the primary outcome. Outpatient spine surgical clinic utilization was considered the primary predictor variable. Multivariable logistic regression was used to adjust for confounders. RESULTS: Between 2006 and 2014, 48,868 patients met inclusion criteria. Fifteen percent (n = 7183) presented to the ED within 30 days postdischarge. By 90 days, 29% of patients (n = 14,388) presented to an ED. The 30- and 90-day complication rates were 6% (n = 2802) and 8% (n = 4034), respectively, and readmission rates were 5% (n = 2344) and 8% (n = 3842), respectively. Use of outpatient spine clinic services significantly reduced the likelihood of ED utilization at 30 [odds ratio (OR) 0.48; 95% confidence interval (95% CI) 0.46-0.53] and 90 days (OR 0.55; 95% CI 0.52-0.57). CONCLUSION: Within 90 days following spine surgery, 29% of patients sought care in the ED. However, only one-third of these patients had a complication recorded, and even fewer were readmitted. This suggests a high rate of unnecessary ED utilization. Outpatient utilization of spine clinics was the only factor independently associated with a reduced likelihood of ED utilization. LEVEL OF EVIDENCE: 3. PMID- 29257030 TI - Complications of Intravenous Substance Use Disorders (SUDs): A Multimodality Pictorial Essay for Cardiothoracic Radiologists. AB - With the growing substance use disorders epidemic in the United States, a wide range of complications may be seen in both the acute and chronic clinical setting. This article will use a multimodality approach to review complications of intravenous substance use that cardiothoracic radiologists are likely to encounter. Radiologists should be aware of these multisystem complications that can affect the cardiovascular, respiratory, and musculoskeletal systems in order to make an accurate and timely diagnosis, which can drastically alter the management of these patients. PMID- 29257031 TI - Association between the age-related decline in renal function and lumbar spine bone mineral density in healthy Chinese postmenopausal women. AB - OBJECTIVES: The relationship between the decline of renal function and bone mineral density (BMD) in healthy populations is not well-researched. The aim of this study was to investigate the association between the age-related decline in renal function and lumbar spine BMD (LBMD) in a community-based cross-sectional study of 390 healthy postmenopausal women (mean age 62.97 +/- 8.79 years) from Shenyang, China. METHODS: Dual-energy x-ray absorptiometry was used to measure LBMD. Estimated glomerular filtration rate (eGFR) was calculated using a modified Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for Asians and the CKD-EPI serum creatinine-cystatin c equation. Pearson's correlation analysis and binary logistic regression were used to evaluate associations. RESULTS: The eGFR-ASIA and eGFR-Scys were positively correlated with LBMD (r = 0.120 and r = 0.108, respectively). After adjustments for numerous potential confounders, the odds ratio for participants with LBMD decline in eGFR-ASIA quartile 3 group and 4 group were 2.45 (95% confidence interval [CI] 1.12-5.38, P < 0.05) and 3.89 (95% CI 1.55-9.76, P < 0.01), respectively, with P = 0.003 for the trend in eGFR-ASIA compared with the lowest quartile 1 group of eGFR-ASIA, where the odds ratio of eGFR-Scys for the quartile of 3 and 4 groups were 2.47 (95% CI 1.09-5.62, P < 0.05) and 2.63 (95% CI 1.10-6.29, P < 0.05), respectively, with P = 0.016 for the trend in eGFR-Scys compared with the lowest quartile 1 group of eGFR-Scys. CONCLUSIONS: The renal function decline was independently associated with decreased LBMD, and it was possible that the age-related decline in kidney function was an independent risk factor for decreased LBMD in healthy Chinese postmenopausal women. PMID- 29257032 TI - GP registrar consultations addressing menopause-related symptoms: a cross sectional analysis. AB - OBJECTIVE: To investigate the prevalence and associations of general practitioner registrars' (trainees') management of women with menopause-related symptoms. METHODS: A cross-sectional analysis from the Registrar Clinical Encounters in Training (ReCEnT) cohort study. In ReCEnT registrars collected data of 60 consecutive consultations on three occasions during training. The outcome factor was menopause-related problems/diagnoses (compared with other problems/diagnoses). Associations of registrar, patient, practice, and consultation-independent variables were assessed by univariate and multivariable logistic regression. RESULTS: In all, 1,333 registrars conducted 189,774 consultations involving 295,017 problems/diagnoses. Of these, there were 1,291 problems/diagnoses (0.44% of all problems/diagnoses) relating to menopause. Significant multivariable independent associations of a problem being menopause related were registrar female sex (odds ratio [OR] 2.74, 95% confidence interval [CI] 2.30-3.26) and registrars working part-time (OR 0.84, 95% CI 0.72-0.98 for full-time work). Consultation-related associations included an increased number of problems addressed in the consultation (OR 1.29, 95% CI 1.21-1.37), and menopause-related problems/diagnoses not being new (OR 0.75, 95% CI 0.66-0.86). Significant educational associations were increased odds of recourse to in consultation sources of information or assistance (OR 2.09, 95% CI 1.80-2.44) and of generating learning goals (OR 3.15, 95% CI 2.66-3.72). CONCLUSIONS: Registrars seek more assistance and further knowledge about menopause compared with other problems. Thus, they may find the area particularly challenging and could benefit from further education regarding managing menopause. Our findings may help inform the design of measures aimed at improving the delivery of menopause training for general practice registrars. PMID- 29257034 TI - Screening mammography for average-risk women. AB - This Practice Pearl describes an approach to screening mammography for average risk women that encourages the use of shared decision-making that addresses benefits (early diagnosis and decreased mortality) and potential harms (false positives and overdiagnosis/overtreatment) in determining screening mammography initiation, frequency, and duration for women at average risk of breast cancer. PMID- 29257035 TI - Chasing the Mission for 30 Years: Bridging the Gap. PMID- 29257033 TI - Left ventricular remodeling and arterial afterload in older women with uncontrolled and controlled hypertension. AB - OBJECTIVE: The prevalence of hypertension increases with advancing age in women. Blood pressure control is more difficult to achieve in older women, and despite well-controlled blood pressure, the cardiovascular mortality remains high. However, the underlying mechanisms are not understood. METHODS: Nineteen women with uncontrolled hypertension on drug treatment (70 +/- 2 [SE] years, ambulatory awake blood pressure; 152 +/- 2/84 +/- 2 mm Hg), 19 with controlled hypertension (68 +/- 1 years, 128 +/- 2/71 +/- 2 mm Hg), and 31 healthy normotensive women (68 +/- 1 years, 127 +/- 1/73 +/- 1 mm Hg) were recruited. Participants were weaned from antihypertensive drugs and underwent 3 weeks of run-in before cardiac vascular assessments. Left ventricular morphology was evaluated with cardiac magnetic resonance imaging. Arterial load and vascular stiffness were measured via ultrasound and applanation tonometry. RESULTS: Left ventricular mass normalized by body surface area was not different between hypertension groups (uncontrolled vs controlled: 50.0 +/- 1.7 vs 51.8 +/- 2.3 g/m), but it was lower in the normotensive group (41.7 +/- 0.9 g/m; one-way analysis of variance [ANOVA] P = 0.004). Likewise, central pulse wave velocity was not different between hypertension groups (11.5 +/- 0.6 vs 11.1 +/- 0.5 m/s) and lower in the normotensive group (9.1 +/- 0.3 m/s; 1-way ANOVA P = 0.0001). Total peripheral resistance was greater in uncontrolled hypertension (HTN) compared with normotensive group (2051 +/- 323 vs 1719 +/- 380 dyns/cm), whereas controlled HTN group (1925 +/- 527 dyns/cm) was not different to either groups. CONCLUSION: Regardless of current blood pressure control, hypertensive older women exhibited increased cardiac mass and arterial stiffness compared with normotensives. Future large-scale longitudinal studies are warranted to directly investigate the mechanisms for the high cardiovascular mortality among older hypertensive women with well-controlled blood pressure. PMID- 29257036 TI - How to Approach Fellowship Match: Tips for the Applicant and Fellowship Programs. PMID- 29257037 TI - Human Papillomavirus (HPV)-associated Lymphoepithelioma-like Carcinoma of the Vagina and Anal Canal: A Rare Variant of Squamous Cell Carcinoma. AB - Lymphoepithelioma-like carcinoma (LELC) is an uncommon variant of squamous cell carcinoma, which is histologically identical to lymphoepithelial carcinoma of the nasopharynx. LELCs have been reported at a variety of sites, including the stomach, salivary gland, thymus, cervix, endometrium, breast, skin, bladder, and lung. We report 2 LELCs of the vagina and 1 of the anal canal, the first report of LELC at the latter site. All 3 neoplasms were diffusely positive with p16 (block-type immunoreactivity) and the anal canal lesion contained high-risk human papillomavirus type 16; the 2 vaginal neoplasms underwent human papillomavirus testing but were unsuitable for analysis. All cases were Epstein-Barr virus negative. In reporting these cases, we highlight the potential for misdiagnosis and suggest an association with human papillomavirus infection similar to LELCs in the uterine cervix. PMID- 29257038 TI - The Spectrum of Morphologic Alterations Associated With Infarction in Endometrial Polyps: A Report of 41 Cases. AB - The authors describe the clinicopathologic features of a group of endometrial polyps that exhibited large areas of infarction, to highlight the spectrum of morphologic alterations that may occur in this setting, including moderate cytologic atypia in a subset. Forty-one infarcted endometrial polyps, classified as such based on the presence therein of confluent zones of stromal necrosis and/or sharply demarcated zones of paucicellular to acellular stromal hyalinization, were assembled from multiple institutions. All were diagnosed in biopsies, polypectomies, or curettages. The morphologic profile of the epithelium associated with the infarcted zones was compared with those of a control group of 40 consecutive noninfarcted polyps. The patients with infarcted polyps ranged in age from 23 to 94 yr and were significantly older than the control group patients (mean ages, 60.8 vs. 49 yr respectively; P=0.02). The most common architectural alteration in infarcted polyps was a distinctive cellular tufting or pseudopapillary change, possibly representing an exuberant iteration of papillary syncytial change, which was seen in 39% of cases. Among the features that were significantly more prevalent in infarcted polyps than the control group were grade 2 pleomorphism (i.e., a 2-3-fold variation in nuclear size and/or shape) (37% vs. 2.5%, respectively; P=0.00029), cellular syncytia (44% vs. 15%; P=0.069), vesicular chromatin greater than background glands (56% vs. 7.5%; P <0.0001), hobnail cells (27% vs. 0%; P=0.0004), clear cells (12% vs. 0%; P=0.055), and eosinophilic cells (56% vs. 15%; P=0.000115). The 2 groups were not significantly different regarding mitotic index and a variety of other morphologic variables. Irrespective of morphology, epithelia within the infarcted zones at least focally showed a core immunophenotype (p53-wild type, p16 diffusely positive; low proliferative index) that was essentially identical to the phenotype displayed by foci of papillary syncytial metaplasia unassociated with polyps in a 10-case comparison group. None of the 34 patients with follow-up information has subsequently been diagnosed with a uterine neoplasm. In summary, infarcted endometrial polyps frequently display a spectrum of cytoarchitecturally atypical epithelial changes. These pseudoneoplastic alterations are most likely degenerative and/or metaplastic in nature. PMID- 29257039 TI - Incidental Gynecologic Tract Neoplasms in Women Undergoing Anterior Pelvic Exenteration for Urothelial Carcinoma. AB - Urothelial carcinoma (UC) invasive into the muscularis propria or tumors unresponsive to treatment are indications for cystectomy. In females, with the goal of achieving complete cancer eradication and for concerns of UC extension into the adjacent pelvic organs, this may also warrant resection of the gynecologic organs. This study is aimed to assess the prevalence of unanticipated gynecologic neoplasms in anterior pelvic exenteration specimens. A retrospective review of pathology reports to identify women undergoing anterior pelvic exenteration for UC was performed (N=221), and incidentally discovered gynecologic tract neoplasms were recorded. Concomitant malignant or premalignant lesions of the gynecologic tract were identified in 8 patients (3.6%). These included endometrial adenocarcinoma [endometrioid type, International Federation of Gynecology and Obstetrics grade 1 (n=2, 0.9%)], cervical high-grade squamous intraepithelial lesion (n=2, 0.9%), Sertoli-Leydig cell tumor of intermediate differentiation (n=1, 0.5%), endometrioid adenocarcinoma of the ovary (n=1, 0.5%), and high-grade serous carcinoma of the ovary (n=1, 0.5%) and fallopian tube (n=1, 0.5%). Benign uterine neoplasms included leiomyomas (n=81, 37%), adenomyoma (n=3, 1.4%), and adenomatoid tumors (n=2, 0.9%). Benign ovarian neoplasms included serous cystadenoma (n=7, 3%), serous cystadenofibroma (n=4, 2%), benign Brenner tumor (n=5, 2.3%), mature teratoma (n=4, 2%), stromal luteoma (n=2, 0.9%), mucinous cystadenoma (n=1, 0.5%), thecoma (n=1, 0.5%), and endometrioid cystadenoma (n=1, 0.5%). Involvement of the gynecologic tract by UC was identified in 11 patients (5%). Spread of UC to the reproductive organs is rare in anterior pelvic exenteration specimens. Coexisting neoplasms of the gynecologic tract are occasionally identified, therefore careful evaluation of these organs is necessary. PMID- 29257040 TI - Complete Histologic Regression of Endometrioid Adenocarcinoma on Endometrial Biopsy After Progestin Treatment Does Not Guarantee the Regression of an Invasive Carcinoma Within the Myometrium. AB - Currently, the indications for progestin therapy are limited to endometrioid adenocarcinoma that are International Federation of Gynecology and Obstetrics (FIGO) grade 1, FIGO stage IA, and confined to the endometrium. However, there have been attempts to broaden the indications of progestin therapy to patients with higher FIGO grades and/or with superficial myometrial invasion. We experienced a case with myoinvasive endometrioid adenocarcinoma treated with oral progestin, whose follow-up endometrial curettage specimen showed an apparent complete histologic regression; however, the final hysterectomy specimen disclosed myoinvasive endometrioid adenocarcinoma within the superficial myometrium, with absence of residual tumor in the endometrium. We describe this case to inform that complete histologic regression of the endometrial lesion in a follow-up curettage specimen after progestin treatment does not guarantee histologic regression of the carcinoma within the myometrium. Our case indicates that current indications for progestin treatment should not be broadened to patients with superficial myometrial invasion. PMID- 29257041 TI - A Rare Case of a Vaginal Solitary Fibrous Tumor, Presenting as a Cystic Mass, Showing NAB2ex4-STAT6ex2 Fusion and STAT6 Immunostaining. AB - Solitary fibrous tumor (SFT) has been rarely documented in the female genital tract. Until now, only 5 such cases have been reported in the vagina. A 40-yr-old referred to us with a history of antitubercular treatment and intra-abdominal adhesions; for which she previously underwent laparoscopic. Subsequently, she developed a vaginal mass, which appeared as a complex cyst on ultrasonogram. Histopathologic examination of the excised mass revealed a cellular spindle cell tumor with collagenous deposition in the stroma. The tumor cells were composed of oval to spindle shaped nuclei and were arranged in a diffuse, as well as in a focally, hemangiopercytomatous pattern. There were no significant mitotic figures or tumor necrosis. By immunohistochemistry, the tumor cells showed patchy positivity for CD34 and diffuse intranuclear positivity for STAT6, along with cytoplasmic positivity for MIC2 and BCL2. Few cells were estrogen receptor positive. MIB1/Ki67 highlighted 2% to 3% tumor nuclei (low). Diagnosis of a SFT was rendered. Subsequently, the tumor was subjected to molecular analysis, by reverse transcriptase-polymerase chain reaction and sequencing, which revealed presence of NAB2ex4-STAT6ex2 fusion transcript. This case constitutes the first case of a vaginal SFT confirmed by STAT6 immunostaining and NAB2-STAT6 fusion. It exemplifies the role of specific immunohistochemical markers, such as STAT6 in differentiating a SFT from various other spindle cell tumors occurring in this location. Literature review of similar reported cases and treatment implications in such cases are discussed. PMID- 29257043 TI - A Quantum Hybrid PSO Combined with Fuzzy k-NN Approach to Feature Selection and Cell Classification in Cervical Cancer Detection. AB - A quantum hybrid (QH) intelligent approach that blends the adaptive search capability of the quantum-behaved particle swarm optimisation (QPSO) method with the intuitionistic rationality of traditional fuzzy k-nearest neighbours (Fuzzy k NN) algorithm (known simply as the Q-Fuzzy approach) is proposed for efficient feature selection and classification of cells in cervical smeared (CS) images. From an initial multitude of 17 features describing the geometry, colour, and texture of the CS images, the QPSO stage of our proposed technique is used to select the best subset features (i.e., global best particles) that represent a pruned down collection of seven features. Using a dataset of almost 1000 images, performance evaluation of our proposed Q-Fuzzy approach assesses the impact of our feature selection on classification accuracy by way of three experimental scenarios that are compared alongside two other approaches: the All-features (i.e., classification without prior feature selection) and another hybrid technique combining the standard PSO algorithm with the Fuzzy k-NN technique (P Fuzzy approach). In the first and second scenarios, we further divided the assessment criteria in terms of classification accuracy based on the choice of best features and those in terms of the different categories of the cervical cells. In the third scenario, we introduced new QH hybrid techniques, i.e., QPSO combined with other supervised learning methods, and compared the classification accuracy alongside our proposed Q-Fuzzy approach. Furthermore, we employed statistical approaches to establish qualitative agreement with regards to the feature selection in the experimental scenarios 1 and 3. The synergy between the QPSO and Fuzzy k-NN in the proposed Q-Fuzzy approach improves classification accuracy as manifest in the reduction in number cell features, which is crucial for effective cervical cancer detection and diagnosis. PMID- 29257044 TI - An Indoor Location-Based Control System Using Bluetooth Beacons for IoT Systems. AB - The indoor location-based control system estimates the indoor position of a user to provide the service he/she requires. The major elements involved in the system are the localization server, service-provision client, user application positioning technology. The localization server controls access of terminal devices (e.g., Smart Phones and other wireless devices) to determine their locations within a specified space first and then the service-provision client initiates required services such as indoor navigation and monitoring/surveillance. The user application provides necessary data to let the server to localize the devices or allow the user to receive various services from the client. The major technological elements involved in this system are indoor space partition method, Bluetooth 4.0, RSSI (Received Signal Strength Indication) and trilateration. The system also employs the BLE communication technology when determining the position of the user in an indoor space. The position information obtained is then used to control a specific device(s). These technologies are fundamental in achieving a "Smart Living". An indoor location-based control system that provides services by estimating user's indoor locations has been implemented in this study (First scenario). The algorithm introduced in this study (Second scenario) is effective in extracting valid samples from the RSSI dataset but has it has some drawbacks as well. Although we used a range-average algorithm that measures the shortest distance, there are some limitations because the measurement results depend on the sample size and the sample efficiency depends on sampling speeds and environmental changes. However, the Bluetooth system can be implemented at a relatively low cost so that once the problem of precision is solved, it can be applied to various fields. PMID- 29257042 TI - Aqueous Extract of Pomegranate Alone or in Combination with Citalopram Produces Antidepressant-Like Effects in an Animal Model of Menopause: Participation of Estrogen Receptors. AB - It has been reported that the aqueous extract of pomegranate (AE-PG) has polyphenols with estrogenic-like activities. The present work determines if AE-PG alone or in combination with the selective serotonin reuptake inhibitor, citalopram, has antidepressant-like effects. It was also analyzed the participation of estrogen receptors (ER). AE-PG (0.1, 1.0, 10, or 100 mg/kg) was evaluated in ovariectomized female Wistar rats subjected to the forced swimming test. The effects induced by AE-PG were compared with those of citalopram (2.5, 5.0, 10, and 20.0 mg/kg) and 17beta-estradiol (E2; 2.5 5.0, and 10 MUg/rat). Likewise, the combination of suboptimal doses of AE-PG (0.1 mg/kg) plus citalopram (2.5 mg/kg) was evaluated. To determine if ER participates in the antidepressant-like action of pomegranate, the estrogen antagonist tamoxifen (15 mg/kg) was administered with AE-PG (1 mg/kg). AE-PG produced antidepressant-like actions with a similar behavioral profile induced by citalopram and E2. Suboptimal doses of citalopram plus AE-PG produced antidepressant-like effects. Tamoxifen was able to block AE-PG's antidepressant-like actions. These results confirm the participation of ER in AE-PG's antidepressant-like effects. Furthermore, the additive effects observed with the combined treatment of AE-PG plus citalopram could be advantageous in the treatment of depressive disorders, such as menopause. PMID- 29257045 TI - Sensitivity Analysis of Different Shapes of a Plastic Optical Fiber-Based Immunosensor for Escherichia coli: Simulation and Experimental Results. AB - Conventional pathogen detection methods require trained personnel, specialized laboratories and can take days to provide a result. Thus, portable biosensors with rapid detection response are vital for the current needs for in-loco quality assays. In this work the authors analyze the characteristics of an immunosensor based on the evanescent field in plastic optical fibers with macro curvature by comparing experimental with simulated results. The work studies different shapes of evanescent-wave based fiber optic sensors, adopting a computational modeling to evaluate the probes with the best sensitivity. The simulation showed that for a U-Shaped sensor, the best results can be achieved with a sensor of 980 um diameter by 5.0 mm in curvature for refractive index sensing, whereas the meander shaped sensor with 250 MUm in diameter with radius of curvature of 1.5 mm, showed better sensitivity for either bacteria and refractive index (RI) sensing. Then, an immunosensor was developed, firstly to measure refractive index and after that, functionalized to detect Escherichia coli. Based on the results with the simulation, we conducted studies with a real sensor for RI measurements and for Escherichia coli detection aiming to establish the best diameter and curvature radius in order to obtain an optimized sensor. On comparing the experimental results with predictions made from the modelling, good agreements were obtained. The simulations performed allowed the evaluation of new geometric configurations of biosensors that can be easily constructed and that promise improved sensitivity. PMID- 29257046 TI - New Cytotoxic Terpenoids from Soft Corals Nephthea chabroli and Paralemnalia thyrsoides. AB - A novel cytotoxic diterpenoid, chabrolin A (1) (possessing an unprecedented terpenoid skeleton), as well as three new cytotoxic sesquiterpenoids, parathyrsoidins E-G (2-4), were isolated by cytotoxicity-guided fractionation from soft corals Nephtheachabroli and Paralemnalia thyrsoides. The structures of the new compounds were determined by extensive analysis of spectroscopic data. PMID- 29257047 TI - High Conservation of Tetanus and Botulinum Neurotoxins Cleavage Sites on Human SNARE Proteins Suggests That These Pathogens Exerted Little or No Evolutionary Pressure on Humans. AB - The Genome Aggregation Database presently contains >120,000 human genomes. We searched in this database for the presence of mutations at the sites of tetanus (TeNT) and botulinum neurotoxins (BoNTs) cleavages of the three SNARE proteins: VAMP, SNAP-25 and Syntaxin. These mutations could account for some of the BoNT/A resistant patients. At the same time, this approach was aimed at testing the possibility that TeNT and BoNT may have acted as selective agents in the development of resistance to tetanus or botulism. We found that mutations of the SNARE proteins are very rare and concentrated outside the SNARE motif required for the formation of the SNARE complex involved in neuroexocytosis. No changes were found at the BoNT cleavage sites of VAMP and syntaxins and only one very rare mutation was found in the essential C-terminus region of SNAP-25, where Arg198 was replaced with a Cys residue. This is the P1' cleavage site for BoNT/A and the P1 cleavage site for BoNT/C. We found that the Arg198Cys mutation renders SNAP-25 resistant to BoNT/A. Nonetheless, its low frequency (1.8 * 10-5) indicates that mutations of SNAP-25 at the BoNT/A cleavage site are unlikely to account for the existence of BoNT/A resistant patients. More in general, the present findings indicate that tetanus and botulinum neurotoxins have not acted as selective agents during human evolution as it appears to have been the case for tetanus in rats and chicken. PMID- 29257049 TI - How Nutrition Sensitive Are the Nutrition Policies of New Zealand Food Manufacturers? A Benchmarking Study. AB - : Nutrition sensitive policy addresses the underlying determinants of nutrition related disease and is a powerful tool in reducing the incidence of non communicable disease. Some members of the food industry have long standing commitments to health-oriented nutrition policies. The aim of this study was to develop and apply a balanced scorecard of nutrition sensitive indicators to the policies of influential New Zealand food and beverage manufacturers and explore factors affecting policy processes. RESULTS: The average nutrition sensitivity score of the twenty influential manufacturers policies was 42 against a benchmark of 75. Some manufacturers performed well whilst others had substantial scope for improvement, the largest variation was in policy development and implementation, whereas nutrition quality was relatively consistent. Manufacturers with written policy (n = 11) scored on average three times higher than their counterparts with verbal policy. The value a manufacturer placed on nutrition influenced whether formal nutrition policies were developed. The reputational risk of failing to deliver on publicly declared nutrition commitments acted as an informal accountability mechanism. We conclude the balanced scorecard offers a useful tool for assessing the nutrition sensitivity of influential food and beverage manufacturers' policies. Our results provide a baseline for repeat assessments of the nutrition sensitivity of food manufacturers' policies. PMID- 29257048 TI - Vanadium Compounds as PTP Inhibitors. AB - Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential. PMID- 29257051 TI - Identification of Tequila with an Array of ZnO Thin Films: A Simple and Cost Effective Method. AB - An array of ZnO thin film sensors was obtained by thermal oxidation of physical vapor deposited thin Zn films. Different conditions of the thermal treatment (duration and temperature) were applied in view of obtaining ZnO sensors with different gas sensing properties. Films having undergone a long thermal treatment exhibited high responses to low ethanol concentrations, while short thermal treatments generally led to sensors with high ethanol sensitivity. The sensor array was used to distinguish among Tequilas and Agave liquor. Linear discriminant analysis and the multilayer perceptron neural network reached 100% and 86.3% success rates in the discrimination between real Tequila and Agave liquor and in the identification of Tequila brands, respectively. These results are promising for the development of an inexpensive tool offering low complexity and cost of analysis for detecting fraud in spirits. PMID- 29257050 TI - Mutations in HPV18 E1^E4 Impact Virus Capsid Assembly, Infectivity Competence, and Maturation. AB - The most highly expressed protein during the productive phase of the human papillomavirus (HPV) life cycle is E1^E4. Its full role during infection remains to be established. HPV E1^E4 is expressed during both the early and late stages of the virus life cycle and contributes to viral genome amplification. In an attempt to further outline the functions of E1^E4, and determine whether it plays a role in viral capsid assembly and viral infectivity, we examined wild-type E1^E4 as well as four E1^E4 truncation mutants. Our study revealed that HPV18 genomes containing the shortest truncated form of E1^E4, the 17/18 mutant, produced viral titers that were similar to wild-type virus and significantly higher compared to virions containing the three longer E1^E4 mutants. Additionally, the infectivity of virus containing the shortest E1^E4 mutation was equivalent to wild-type and significantly higher than the other three mutants. In contrast, infectivity was completely abrogated for virus containing the longer E1^E4 mutants, regardless of virion maturity. Taken together, our results indicate for the first time that HPV18 E1^E4 impacts capsid assembly and viral infectivity as well as virus maturation. PMID- 29257053 TI - How Do the First Days Count? A Case Study of Qatar Experience in Emergency Risk Communication during the MERS-CoV Outbreak. AB - : This case study is the first to be developed in the Middle East region to document what happened during the response to the 2013 MERS outbreak in Qatar. It provides a description of key epidemiologic events and news released from a prime daily newspaper and main Emergency Risk Communication (ERC) actions that were undertaken by public health authorities. Using the Crisis and Emergency Risk Communication (CERC) theoretical framework, the study analyzes how the performed ERC strategies during the first days of the outbreak might have contributed to the outbreak management. METHODS: MERS-CoV related events were chronologically tracked, together with the relevant stories that were published in a major newspaper over the course of three distinct phases of the epidemic. The collected media stories were then assessed against the practiced emergency risk communication (ERC) activities during the same time frame. RESULTS: The Crisis & Emergency Risk Communication (CERC) framework was partially followed during the early days of the MERS-CoV epidemic, which were characterized by overwhelming uncertainty. The SCH's commitment to a proactive and open risk communication strategy since day one, contributed to creating the SCH's image as a credible source of information and allowed for the quick initiation of the overall response efforts. Yet, conflicting messages and over reassurance were among the observed pitfalls of the implemented ERC strategy. CONCLUSION: The adoption of CERC principles can help restore and maintain the credibility of responding agencies. Further work is needed to develop more rigorous and comprehensive research strategies that address sharing of information by mainstream as well as social media for a more accurate assessment of the impact of the ERC strategy. PMID- 29257054 TI - Having a Child Diagnosed with Cancer: Raising the Challenges Encountered by the Caregivers at the Pediatric Oncology Ward in Egypt. AB - Having a child diagnosed with a life-threatening illness, and undergoing a severe treatment regimen, is a massive challenge for many caregivers, not the least of who are those with low socioeconomic status and living in a society where deeply rooted cultural and societal misconceptions are immensely noticeable. The aim of the study is to raise the great concerns experienced by the caregivers at the pediatric oncology ward in Egypt. The study is comprised of 24 caregivers of children with cancer undergoing treatment at the inpatient ward. Semi-structured interviews and participant observations were used as a means of data collection. Numerous concerns are addressed in this study which are all related to fear of the illness and guilty feelings of having caused the child this illness. The fears and concerns addressed in this paper seem to obstruct the caregivers' overall psychosocial wellbeing, which is known to have multiple effects on the child's overall wellbeing. Thus, it is very important to take into consideration caregivers in the child's cancer treatment. PMID- 29257052 TI - The Role of Nicotinamide Adenine Dinucleotide Phosphate Oxidases in Lung Architecture Remodeling. AB - Chronic lung disorders, such as pulmonary artery hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma and neonatal bronchopulmonary dysplasia (BPD), are characterized by airway and/or vascular remodeling. Despite differences in the pathology, reactive oxygen species (ROS) have been highlighted as a critical contributor to the initiation and development of airway and vascular remodeling. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) appear to play a pivotal role in lung signaling, leading to marked changes in pulmonary airway and vascular cell phenotypes, including proliferation, hypertrophy and apoptosis. In this review, we summarized the current literature regarding the role of Nox in the airway and vascular remodeling. PMID- 29257055 TI - Domain IV of Annexin A5 Is Critical for Binding Calcium and Guarantees Its Maximum Binding to the Phosphatidylserine Membrane. AB - Background: Although domain IV of annexin A5 (anxA5) may be less effective in binding phosphatidylserine (PS), the four domains together may guarantee the maximum binding of anxA5 to the PS membrane. Additionally, previous research has shown that annexin mutants lacking one or more domain(s) have different biological activities compared to the wild-type. The present research mainly aims to study the role of domain IV in the crucial PS-binding function of anxA5. Methods: The domain IV-truncated anxA5 protein was constructed and purified. Isothermal titration calorimetry, flow cytometry and activated partial thromboplastin time were adopted to examine the function of domain IV in anxA5-PS binding directly or indirectly. Results: The domain IV-truncated form of anxA5 is impaired in binding PS liposome and apoptotic cells, and anticoagulation activity. The mutant cannot bind calcium, but binds PS only in the presence of calcium. Conclusions: Truncation of domain IV of anxA5 destroys its calcium binding ability and impairs its PS-binding activity. Truncation of domain IV may induce conformation change of anxA5 or reduce the hydrophobic interactions between protein and membrane, which may explain the decrease of PS-binding affinity of the mutant. PMID- 29257056 TI - Vaccination with Combination DNA and Virus-Like Particles Enhances Humoral and Cellular Immune Responses upon Boost with Recombinant Modified Vaccinia Virus Ankara Expressing Human Immunodeficiency Virus Envelope Proteins. AB - Heterologous prime boost with DNA and recombinant modified vaccinia virus Ankara (rMVA) vaccines is considered as a promising vaccination approach against human immunodeficiency virus (HIV-1). To further enhance the efficacy of DNA-rMVA vaccination, we investigated humoral and cellular immune responses in mice after three sequential immunizations with DNA, a combination of DNA and virus-like particles (VLP), and rMVA expressing HIV-1 89.6 gp120 envelope proteins (Env). DNA prime and boost with a combination of VLP and DNA vaccines followed by an rMVA boost induced over a 100-fold increase in Env-specific IgG antibody titers compared to three sequential immunizations with DNA and rMVA. Cellular immune responses were induced by VLP-DNA and rMVA vaccinations at high levels in CD8 T cells, CD4 T cells, and peripheral blood mononuclear cells secreting interferon (IFN)-gamma, and spleen cells producing interleukin (IL)-2, 4, 5 cytokines. This study suggests that a DNA and VLP combination vaccine with MVA is a promising strategy in enhancing the efficacy of DNA-rMVA vaccination against HIV-1. PMID- 29257057 TI - The Influence of E1A C-Terminus on Adenovirus Replicative Cycle. AB - Adenovirus Early 1A proteins (E1A) are crucial for initiation of the viral life cycle after infection. The E1A gene is encoded at the left end of the viral genome and consists of two exons, the first encoding 185 amino acids in the 289 residues adenovirus 5 E1A, while the second exon encodes 104 residues. The second exon-encoded region of E1A is conserved across all E1A isoforms except for the 55 residues protein, which has a unique C-terminus due to a frame shift following splicing into the second exon. This region of E1A contributes to a variety of processes including the regulation of viral and cellular gene expression, immortalization and transformation. Here we evaluated the contributions that different regions of the second exon of E1A make to the viral life cycle using deletion mutants. The region of E1A encoded by the second exon was found to be important for overall virus growth, induction of viral and cellular gene expression, viral genome replication and deregulation of the cell cycle. Efficient viral replication was found to require exon 2 and the nuclear localization signal, as loss of either resulted in severe growth deficiency. Induction of cellular DNA synthesis was also deficient with any deletion of E1A within the C-terminus even if these deletions were outside of conserved region 4. Overall, our study provides the first comprehensive insight into the contributions of the C-terminus of E1A to the replicative fitness of human adenovirus 5 in arrested lung fibroblasts. PMID- 29257058 TI - Diarylheptanoid Glycosides of Morella salicifolia Bark. AB - A methanolic extract of Morella salicifolia bark was fractionated by various chromatographic techniques yielding six previously unknown cyclic diarylheptanoids, namely, 7-hydroxymyricanol 5-O-beta-d-glucopyranoside (1), juglanin B 3-O-beta-d-glucopyranoside (2), 16-hydroxyjuglanin B 17-O-beta-d glucopyranoside (3), myricanone 5-O-beta-d-gluco-pranosyl-(1->6)-beta-d glucopyranoside (4), neomyricanone 5-O-beta-d-glucopranosyl-(1->6)-beta-d glucopyranoside (5), and myricanone 17-O-alpha-l-arabino-furanosyl-(1->6)-beta-d glucopyranoside (6), respectively, together with 10 known cyclic diarylheptanoids. The structural diversity of the diarylheptanoid pattern in M. salicifolia resulted from varying glycosidation at C-3, C-5, and C-17 as well as from substitution at C-11 with hydroxy, carbonyl or sulfate groups, respectively. Structure elucidation of the isolated compounds was achieved on the basis of one- and two-dimensional nuclear magnetic resonance (NMR) as well as high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS) analyses. The absolute configuration of the glycosides was confirmed after hydrolysis and synthesis of O (S)-methyl butyrated (SMB) sugar derivatives by comparison of their 1H-NMR data with those of reference sugars. Additionally, absolute configuration of diarylheptanoid aglycones at C-11 was determined by electronic circular dichroism (ECD) spectra simulation and comparison with experimental CD spectra after hydrolysis. PMID- 29257059 TI - Proliferation Cycle Causes Age Dependent Mitochondrial Deficiencies and Contributes to the Aging of Stem Cells. AB - In addition to chronological aging, stem cells are also subject to proliferative aging during the adult life span. However, the consequences of proliferative cycle and their contributions to stem cells aging have not been well investigated. Using Drosophila female germ line stem cells as a model, we found that the replication cycle leads to the age dependent decline of female fecundity, and is a major factor causing developmental abnormalities in the progeny of old females. The proliferative aging does not cause telomere shortening, but causes an accumulation of mitochondrial DNA (mtDNA) mutations or rearrangements at the control region. We propose that damaging mutations on mtDNA caused by accumulation of proliferation cycles in aged stem cells may disrupt mitochondrial respiration chain and impair mtDNA replication and represent a conserved mechanism underlying stem cell aging. PMID- 29257061 TI - Biopersistence of NiO and TiO2 Nanoparticles Following Intratracheal Instillation and Inhalation. AB - The hazards of various types of nanoparticles with high functionality have not been fully assessed. We investigated the usefulness of biopersistence as a hazard indicator of nanoparticles by performing inhalation and intratracheal instillation studies and comparing the biopersistence of two nanoparticles with different toxicities: NiO and TiO2 nanoparticles with high and low toxicity among nanoparticles, respectively. In the 4-week inhalation studies, the average exposure concentrations were 0.32 and 1.65 mg/m3 for NiO, and 0.50 and 1.84 mg/m3 for TiO2. In the instillation studies, 0.2 and 1.0 mg of NiO nanoparticles and 0.2, 0.36, and 1.0 mg of TiO2 were dispersed in 0.4 mL water and instilled to rats. After the exposure, the lung burden in each of five rats was determined by Inductively Coupled Plasma-Atomic Emission Spectrometer (ICP-AES) from 3 days to 3 months for inhalation studies and to 6 months for instillation studies. In both the inhalation and instillation studies, NiO nanoparticles persisted for longer in the lung compared with TiO2 nanoparticles, and the calculated biological half times (BHTs) of the NiO nanoparticles was longer than that of the TiO2 nanoparticles. Biopersistence also correlated with histopathological changes, inflammatory response, and other biomarkers in bronchoalveolar lavage fluid (BALF) after the exposure to nanoparticles. These results suggested that the biopersistence is a good indicator of the hazards of nanoparticles. PMID- 29257062 TI - Flavonoids of Kudzu Root Fermented by Eurtotium cristatum Protected Rat Pheochromocytoma Line 12 (PC12) Cells against H2O2-Induced Apoptosis. AB - Novel bioactive components have greatly attracted attention as they demonstrate health benefits. Reversed-phase high performance liquid chromatography (RP-HPLC) showed that isoflavonoid compounds of kudzu root (Pueraria lobata) fermented by Eurtotium cristatum and extracted using de-ionized water were higher active compared with non-fermented. A model of H2O2-inducd cell damage was built using rat pheochromocytoma line 12 (PC12) cell to observe the protective effect of non fermented kudzu root (Pueraria lobata) (NFK) and fermented kudzu root (Pueraria lobata) (FK). Cell viability and apoptosis were analyzed through inverted microscopy and flow cytometry. The level of lactate dehydrogenase, catalase activity, superoxide dismutase, glutathione, and reactive oxygen species (ROS) were evaluated. Results showed that NFK and FK could significantly protect PC12 cell against damage caused by H2O2-induced oxidative stress. The intracellular antioxidant system was increased, protected the cell membrane inhibit H2O2 induced apoptosis by scavenging of ROS. Moreover, NFK and FK regulated the cell cycle to prevent cell apoptosis. Isoflavonoid from the kudzu root especially fermented kudzu root with E. cristatum are potentially therapeutic drugs against diseases induced by oxidative damage. PMID- 29257063 TI - 3D-Printed Detector Band for Magnetic Off-Plane Flux Measurements in Laminated Machine Cores. AB - Laminated soft magnetic cores of transformers, rotating machines etc. may exhibit complex 3D flux distributions with pronounced normal fluxes (off-plane fluxes), perpendicular to the plane of magnetization. As recent research activities have shown, detections of off-plane fluxes tend to be essential for the optimization of core performances aiming at a reduction of core losses and of audible noise. Conventional sensors for off-plane flux measurements tend to be either of high thickness, influencing the measured fluxes significantly, or require laborious preparations. In the current work, thin novel detector bands for effective and simple off-plane flux detections in laminated machine cores were manufactured. They are printed in an automatic way by an in-house developed 3D/2D assembler. The latter enables a unique combination of conductive and non-conductive materials. The detector bands were effectively tested in the interior of a two package, three-phase model transformer core. They proved to be mechanically resilient, even for strong clamping of the core. PMID- 29257060 TI - How Human Papillomavirus Replication and Immune Evasion Strategies Take Advantage of the Host DNA Damage Repair Machinery. AB - The DNA damage response (DDR) is a complex signalling network activated when DNA is altered by intrinsic or extrinsic agents. DDR plays important roles in genome stability and cell cycle regulation, as well as in tumour transformation. Viruses have evolved successful life cycle strategies in order to ensure a chronic persistence in the host, virtually avoiding systemic sequelae and death. This process promotes the periodic shedding of large amounts of infectious particles to maintain a virus reservoir in individual hosts, while allowing virus spreading within the community. To achieve such a successful lifestyle, the human papilloma virus (HPV) needs to escape the host defence systems. The key to understanding how this is achieved is in the virus replication process that provides by itself an evasion mechanism by inhibiting and delaying the host immune response against the viral infection. Numerous studies have demonstrated that HPV exploits both the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and rad3 related (ATR) DDR pathways to replicate its genome and maintain a persistent infection by downregulating the innate and cell-mediated immunity. This review outlines how HPV interacts with the ATM- and ATR-dependent DDR machinery during the viral life cycle to create an environment favourable to viral replication, and how the interaction with the signal transducers and activators of transcription (STAT) protein family and the deregulation of the Janus kinase (JAK)-STAT pathways may impact the expression of interferon-inducible genes and the innate immune responses. PMID- 29257064 TI - A Proposed Mechanism for Development of CTE Following Concussive Events: Head Impact, Water Hammer Injury, Neurofilament Release, and Autoimmune Processes. AB - During the past decade, there has been an increasing interest in early diagnosis and treatment of traumatic brain injuries (TBI) that lead to chronic traumatic encephalopathy (CTE). The subjects involved range from soldiers exposed to concussive injuries from improvised explosive devices (IEDs) to a significant number of athletes involved in repetitive high force impacts. Although the forces from IEDs are much greater by a magnitude than those from contact sports, the higher frequency associated with contact sports allows for more controlled assessment of the mechanism of action. In our study, we report findings in university-level women soccer athletes followed over a period of four and a half years from accession to graduation. Parameters investigated included T1-, T2-, and susceptibility-weighted magnetic resonance images (SWI), IMPACT (Immediate Post-Concussion Assessment and Cognitive Testing), and C3 Logix behavioral and physiological assessment measures. The MRI Studies show several significant findings: first, a marked increase in the width of sulci in the frontal to occipital cortices; second, an appearance of subtle hemorrhagic changes at the base of the sulci; third was a sustained reduction in total brain volume in several soccer players at a developmental time when brain growth is generally seen. Although all of the athletes successfully completed their college degree and none exhibited long term clinical deficits at the time of graduation, the changes documented by MRI represent a clue to the pathological mechanism following an injury paradigm. The authors propose that our findings and those of prior publications support a mechanism of injury in CTE caused by an autoimmune process associated with the release of neural proteins from nerve cells at the base of the sulcus from a water hammer injury effect. As evidence accumulates to support this hypothesis, there are pharmacological treatment strategies that may be able to mitigate the development of long-term disability from TBI. PMID- 29257065 TI - Effects of Continuously Feeding Diets Containing Cereal Ergot Alkaloids on Nutrient Digestibility, Alkaloid Recovery in Feces, and Performance Traits of Ram Lambs. AB - Allowable limits for cereal ergot alkaloids in livestock feeds are being re examined, and the objective of this study was to compare nutrient digestibility, growth performance and carcass characteristics of ram lambs fed a range of alkaloid concentrations, including the maximum currently allowed in Canada (2 to 3 ppm). Four pelleted diets were fed: control, with no added alkaloids; 930; 1402; and 2447 ppb alkaloids based on total R and S epimers. Eight ram lambs (30.0 +/- 3.1 kg) were used to examine the impacts of dietary treatments on nutrient digestibility and alkaloid recovery from feces. Concentrations of dietary alkaloids evaluated did not affect nutrient digestibility or N metabolism. Excepting ergocornine and ergocryptine, recovery of alkaloids in feces varied among periods, suggesting that individual lambs may differ in their ability to metabolize ergocristine, ergometrine, ergosine, ergotamine and their S epimers. In a second experiment, ram lambs (n = 47, 30 +/- 8 kg) were randomly assigned to a diet and weighed weekly until they achieved a slaughter weight of >= 45 kg (average 9 weeks; range 6 to 13 weeks). Intake of DM did not differ (p = 0.91) among diets, although lambs fed 2447 ppb alkaloids had a lower (p < 0.01) ADG than did lambs receiving other treatments. The concentration of serum prolactin linearly declined (p < 0.01) with increasing alkaloids. Feeding 2447 ppb total alkaloids negatively impacted growth, while feeding 1402 ppb did not harm growth performance, but reduced carcass dressing percentage. Due to different concentrations of alkaloids affecting growth and carcass characteristics in the present study, determining allowable limits for total dietary alkaloids will require a better understanding of impacts of alkaloid profiles and interactions among individual alkaloids. PMID- 29257066 TI - An Enhanced Three-Factor User Authentication Scheme Using Elliptic Curve Cryptosystem for Wireless Sensor Networks. AB - As an essential part of Internet of Things (IoT), wireless sensor networks (WSNs) have touched every aspect of our lives, such as health monitoring, environmental monitoring and traffic monitoring. However, due to its openness, wireless sensor networks are vulnerable to various security threats. User authentication, as the first fundamental step to protect systems from various attacks, has attracted much attention. Numerous user authentication protocols armed with formal proof are springing up. Recently, two biometric-based schemes were proposed with confidence to be resistant to the known attacks including offline dictionary attack, impersonation attack and so on. However, after a scrutinization of these two schemes, we found them not secure enough as claimed, and then demonstrated that these schemes suffer from various attacks, such as offline dictionary attack, impersonation attack, no user anonymity, no forward secrecy, etc. Furthermore, we proposed an enhanced scheme to overcome the identified weaknesses, and proved its security via Burrows-Abadi-Needham (BAN) logic and the heuristic analysis. Finally, we compared our scheme with other related schemes, and the results showed the superiority of our scheme. PMID- 29257067 TI - Quinoline-Based Hybrid Compounds with Antimalarial Activity. AB - The application of quinoline-based compounds for the treatment of malaria infections is hampered by drug resistance. Drug resistance has led to the combination of quinolines with other classes of antimalarials resulting in enhanced therapeutic outcomes. However, the combination of antimalarials is limited by drug-drug interactions. In order to overcome the aforementioned factors, several researchers have reported hybrid compounds prepared by reacting quinoline-based compounds with other compounds via selected functionalities. This review will focus on the currently reported quinoline-based hybrid compounds and their preclinical studies. PMID- 29257068 TI - The Effect of Environmental Regulation on Employment in Resource-Based Areas of China-An Empirical Research Based on the Mediating Effect Model. AB - While environmental pollution is becoming more and more serious, many countries are adopting policies to control pollution. At the same time, the environmental regulation will inevitably affect economic and social development, especially employment growth. The environmental regulation will not only affect the scale of employment directly, but it will also have indirect effects by stimulating upgrades in the industrial structure and in technological innovation. This paper examines the impact of environmental regulation on employment, using a mediating model based on the data from five typical resource-based provinces in China from 2000 to 2015. The estimation is performed based on the system GMM (Generalized Method of Moments) estimator. The results show that the implementation of environmental regulation in resource-based areas has both a direct effect and a mediating effect on employment. These findings provide policy implications for these resource-based areas to promote the coordinating development between the environment and employment. PMID- 29257069 TI - Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance. AB - Focus on the Warburg effect, initially descriptive of increased glycolysis in cancer cells, has served to illuminate mitochondrial function in many other pathologies. This review explores our current understanding of the Warburg effect's role in cancer, diabetes and ageing. We highlight how it can be regulated through a chain of oncogenic events, as a chosen response to impaired glucose metabolism or by chance acquisition of genetic changes associated with ageing. Such chain, choice or chance perspectives can be extended to help understand neurodegeneration, such as Alzheimer's disease, providing clues with scope for therapeutic intervention. It is anticipated that exploration of Warburg effect pathways in extreme conditions, such as deep space, will provide further insights crucial for comprehending complex metabolic diseases, a frontier for medicine that remains equally significant for humanity in space and on earth. PMID- 29257070 TI - Recent Advances in Cancer Therapy Based on Dual Mode Gold Nanoparticles. AB - Many tumor-targeted strategies have been used worldwide to limit the side effects and improve the effectiveness of therapies, such as chemotherapy, radiotherapy (RT), etc. Biophotonic therapy modalities comprise very promising alternative techniques for cancer treatment with minimal invasiveness and side-effects. These modalities use light e.g., laser irradiation in an extracorporeal or intravenous mode to activate photosensitizer agents with selectivity in the target tissue. Photothermal therapy (PTT) is a minimally invasive technique for cancer treatment which uses laser-activated photoabsorbers to convert photon energy into heat sufficient to induce cells destruction via apoptosis, necroptosis and/or necrosis. During the last decade, PTT has attracted an increased interest since the therapy can be combined with customized functionalized nanoparticles (NPs). Recent advances in nanotechnology have given rise to generation of various types of NPs, like gold NPs (AuNPs), designed to act both as radiosensitizers and photothermal sensitizing agents due to their unique optical and electrical properties i.e., functioning in dual mode. Functionalized AuNPS can be employed in combination with non-ionizing and ionizing radiation to significantly improve the efficacy of cancer treatment while at the same time sparing normal tissues. Here, we first provide an overview of the use of NPs for cancer therapy. Then we review many recent advances on the use of gold NPs in PTT, RT and PTT/RT based on different types of AuNPs, irradiation conditions and protocols. We refer to the interaction mechanisms of AuNPs with cancer cells via the effects of non-ionizing and ionizing radiations and we provide recent existing experimental data as a baseline for the design of optimized protocols in PTT, RT and PTT/RT combined treatment. PMID- 29257071 TI - Control of Nucleotide Metabolism Enables Mutant p53's Oncogenic Gain-of-Function Activity. AB - Since its discovery as an oncoprotein in 1979, investigation into p53's many identities has completed a full circle and today it is inarguably the most extensively studied tumor suppressor (wild-type p53 form or WTp53) and oncogene (mutant p53 form or mtp53) in cancer research. After the p53 protein was declared "Molecule of the Year" by Science in 1993, the p53 field exploded and a plethora of excellent reviews is now available on every aspect of p53 genetics and functional repertoire in a cell. Nevertheless, new functions of p53 continue to emerge. Here, we discuss a novel mechanism that contributes to mtp53's Gain of Functions GOF (gain-of-function) activities and involves the upregulation of both nucleotide de novo synthesis and nucleoside salvage pathways. PMID- 29257074 TI - Report from the Scientific Poster Session at the 12th Annual Cardiometabolic Health Congress in Boston, USA, 4-7 October 2017. PMID- 29257073 TI - The Room-Temperature Chemiresistive Properties of Potassium Titanate Whiskers versus Organic Vapors. AB - The development of portable gas-sensing units implies a special care of their power efficiency, which is often approached by operation at room temperature. This issue primarily appeals to a choice of suitable materials whose functional properties are sensitive toward gas vapors at these conditions. While the gas sensitivity is nowadays advanced by employing the materials at nano-dimensional domain, the room temperature operation might be targeted via the application of layered solid-state electrolytes, like titanates. Here, we report gas-sensitive properties of potassium titanate whiskers, which are placed over a multielectrode chip by drop casting from suspension to yield a matrix mono-layer of varied density. The material synthesis conditions are straightforward both to get stable single-crystalline quasi-one-dimensional whiskers with a great extent of potassium replacement and to favor the increase of specific surface area of the structures. The whisker layer is found to be sensitive towards volatile organic compounds (ethanol, isopropanol, acetone) in the mixture with air at room temperature. The vapor identification is obtained via processing the vector signal generated by sensor array of the multielectrode chip with the help of pattern recognition algorithms. PMID- 29257075 TI - Acidic Mesoporous Zeolite ZSM-5 Supported Cu Catalyst with Good Catalytic Performance in the Hydroxysulfurization of Styrenes with Disulfides. AB - Development of highly active heterogeneous catalysts is an effective strategy for modern organic synthesis chemistry. In this work, acidic mesoporous zeolite ZSM-5 (HZSM-5-M), acidic-free mesoporous zeolite TS-1 (TS-1-M), and basic ETS-10 zeolite supported metal Cu catalysts were prepared to investigate their catalytic performances in the hydroxysulfurization of styrenes with diaryl disulfides. The effect of pore size and acidities of the supports, as well as the Cu species electronic properties of the catalysts on reaction activity were investigated. The results show that Cu+ and Cu2+ binded on HZSM-5-M show the highest activity and product selectivity for the desired beta-hydroxysulfides compounds. PMID- 29257076 TI - Porous TiO2-Based Gas Sensors for Cyber Chemical Systems to Provide Security and Medical Diagnosis. AB - Gas sensors play an important role in our life, providing control and security of technical processes, environment, transportation and healthcare. Consequently, the development of high performance gas sensor devices is the subject of intense research. TiO2, with its excellent physical and chemical properties, is a very attractive material for the fabrication of chemical sensors. Meanwhile, the emerging technologies are focused on the fabrication of more flexible and smart systems for precise monitoring and diagnosis in real-time. The proposed cyber chemical systems in this paper are based on the integration of cyber elements with the chemical sensor devices. These systems may have a crucial effect on the environmental and industrial safety, control of carriage of dangerous goods and medicine. This review highlights the recent developments on fabrication of porous TiO2-based chemical gas sensors for their application in cyber chemical system showing the convenience and feasibility of such a model to provide the security and to perform the diagnostics. The most of reports have demonstrated that the fabrication of doped, mixed and composite structures based on porous TiO2 may drastically improve its sensing performance. In addition, each component has its unique effect on the sensing properties of material. PMID- 29257072 TI - The Mitochondrial Basis of Aging and Age-Related Disorders. AB - Aging is a natural phenomenon characterized by progressive decline in tissue and organ function leading to increased risk of disease and mortality. Among diverse factors that contribute to human aging, the mitochondrial dysfunction has emerged as one of the key hallmarks of aging process and is linked to the development of numerous age-related pathologies including metabolic syndrome, neurodegenerative disorders, cardiovascular diseases and cancer. Mitochondria are central in the regulation of energy and metabolic homeostasis, and harbor a complex quality control system that limits mitochondrial damage to ensure mitochondrial integrity and function. The intricate regulatory network that balances the generation of new and removal of damaged mitochondria forms the basis of aging and longevity. Here, I will review our current understanding on how mitochondrial functional decline contributes to aging, including the role of somatic mitochondrial DNA (mtDNA) mutations, reactive oxygen species (ROS), mitochondrial dynamics and quality control pathways. I will further discuss the emerging evidence on how dysregulated mitochondrial dynamics, mitochondrial biogenesis and turnover mechanisms contribute to the pathogenesis of age-related disorders. Strategies aimed to enhance mitochondrial function by targeting mitochondrial dynamics, quality control, and mitohormesis pathways might promote healthy aging, protect against age-related diseases, and mediate longevity. PMID- 29257077 TI - Genome-Wide Transcriptional Changes and Lipid Profile Modifications Induced by Medicago truncatula N5 Overexpression at an Early Stage of the Symbiotic Interaction with Sinorhizobium meliloti. AB - Plant lipid-transfer proteins (LTPs) are small basic secreted proteins, which are characterized by lipid-binding capacity and are putatively involved in lipid trafficking. LTPs play a role in several biological processes, including the root nodule symbiosis. In this regard, the Medicago truncatula nodulin 5 (MtN5) LTP has been proved to positively regulate the nodulation capacity, controlling rhizobial infection and nodule primordia invasion. To better define the lipid transfer protein MtN5 function during the symbiosis, we produced MtN5 downregulated and -overexpressing plants, and we analysed the transcriptomic changes occurring in the roots at an early stage of Sinorhizobium meliloti infection. We also carried out the lipid profile analysis of wild type (WT) and MtN5-overexpressing roots after rhizobia infection. The downregulation of MtN5 increased the root hair curling, an early event of rhizobia infection, and concomitantly induced changes in the expression of defence-related genes. On the other hand, MtN5 overexpression favoured the invasion of the nodules by rhizobia and determined in the roots the modulation of genes that are involved in lipid transport and metabolism as well as an increased content of lipids, especially galactolipids that characterize the symbiosome membranes. Our findings suggest the potential participation of LTPs in the synthesis and rearrangement of membranes occurring during the formation of the infection threads and the symbiosome membrane. PMID- 29257078 TI - Pre-Scheduled and Self Organized Sleep-Scheduling Algorithms for Efficient K Coverage in Wireless Sensor Networks. AB - The K-coverage configuration that guarantees coverage of each location by at least K sensors is highly popular and is extensively used to monitor diversified applications in wireless sensor networks. Long network lifetime and high detection quality are the essentials of such K-covered sleep-scheduling algorithms. However, the existing sleep-scheduling algorithms either cause high cost or cannot preserve the detection quality effectively. In this paper, the Pre Scheduling-based K-coverage Group Scheduling (PSKGS) and Self-Organized K coverage Scheduling (SKS) algorithms are proposed to settle the problems in the existing sleep-scheduling algorithms. Simulation results show that our pre scheduled-based KGS approach enhances the detection quality and network lifetime, whereas the self-organized-based SKS algorithm minimizes the computation and communication cost of the nodes and thereby is energy efficient. Besides, SKS outperforms PSKGS in terms of network lifetime and detection quality as it is self-organized. PMID- 29257079 TI - Sulfuretin Attenuates MPP+-Induced Neurotoxicity through Akt/GSK3beta and ERK Signaling Pathways. AB - Parkinson's disease (PD) is the second most common neurodegenerative disease. It is caused by the death of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress and mitochondrial dysfunction contribute to the loss of dopaminergic neurons in PD. Sulfuretin is a potent antioxidant that is reported to be beneficial in the treatment of neurodegenerative diseases. In this study, we examined the protective effect of sulfuretin against 1-methyl-4-phenyl pyridinium (MPP+)-induced cell model of PD in SH-SY5Y cells and the underlying molecular mechanisms. Sulfuretin significantly decreased MPP+-induced apoptotic cell death, accompanied by a reduction in caspase 3 activity and polyADP-ribose polymerase (PARP) cleavage. Furthermore, it attenuated MPP+-induced production of intracellular reactive oxygen species (ROS) and disruption of mitochondrial membrane potential (MMP). Consistently, sulfuretin decreased p53 expression and the Bax/Bcl-2 ratio. Moreover, sulfuretin significantly increased the phosphorylation of Akt, GSK3beta, and ERK. Pharmacological inhibitors of PI3K/Akt and ERK abolished the cytoprotective effects of sulfuretin against MPP+. An inhibitor of GSK3beta mimicked sulfuretin-induced protection against MPP+. Taken together, these results suggest that sulfuretin significantly attenuates MPP+ induced neurotoxicity through Akt/GSK3beta and ERK signaling pathways in SH-SY5Y cells. Our findings suggest that sulfuretin might be one of the potential candidates for the treatment of PD. PMID- 29257081 TI - Blind Compensation of I/Q Impairments in Wireless Transceivers. AB - The majority of techniques that deal with the mitigation of in-phase and quadrature-phase (I/Q) imbalance at the transmitter (pre-compensation) require long training sequences, reducing the throughput of the system. These techniques also require a feedback path, which adds more complexity and cost to the transmitter architecture. Blind estimation techniques are attractive for avoiding the use of long training sequences. In this paper, we propose a blind frequency independent I/Q imbalance compensation method based on the maximum likelihood (ML) estimation of the imbalance parameters of a transceiver. A closed-form joint probability density function (PDF) for the imbalanced I and Q signals is derived and validated. ML estimation is then used to estimate the imbalance parameters using the derived joint PDF of the output I and Q signals. Various figures of merit have been used to evaluate the efficacy of the proposed approach using extensive computer simulations and measurements. Additionally, the bit error rate curves show the effectiveness of the proposed method in the presence of the wireless channel and Additive White Gaussian Noise. Real-world experimental results show an image rejection of greater than 30 dB as compared to the uncompensated system. This method has also been found to be robust in the presence of practical system impairments, such as time and phase delay mismatches. PMID- 29257080 TI - Study of mcr-1 Gene-Mediated Colistin Resistance in Enterobacteriaceae Isolated from Humans and Animals in Different Countries. AB - In this study, we aim to characterize the genetic environment of the plasmid mediated colistin resistance gene mcr-1 in 25 Escherichia coli and seven Klebsiella pneumoniae strains from different countries and continents. Multilocus sequence typing, conjugation experiments, plasmid typing, and the presence and location of the insertion sequence ISApl1 were investigated. Whole genome sequencing of four E. coli was performed to analyse the genetic environment of the mcr-1 gene. Colistin minimum inhibitory concentration of mcr-1 strains varied from 3 to 32 ug/mL. Six E. coli sequence types were detected: ST 4015, ST 3997, ST 10, ST 93, ST 48, and ST 648. IncHI2, IncI2, and IncP plasmid types were predominant and were unrelated to a specific country of origin. ISApl1 was found in 69% of analysed plasmids that were mainly around the mcr-1 gene. Analysis of four closed mcr-1 plasmids revealed the integration of mcr-1 into hotspots. We found that the spread of mcr-1 gene was due to the diffusion of a composite transposon and not to the diffusion of a specific plasmid or a specific bacterial clone. The ease with which the mcr-1 gene integrates into various regions facilitates its dissemination among bacteria and explains its large diffusion all over the world, both in animals and in humans. PMID- 29257082 TI - Galectin-7 in Epithelial Homeostasis and Carcinomas. AB - Galectins are small unglycosylated soluble lectins distributed both inside and outside the cells. They share a conserved domain for the recognition of carbohydrates (CRD). Although galectins have a common affinity for beta galatosides, they exhibit different binding preferences for complex glycans. First described twenty years ago, galectin-7 is a prototypic galectin, with a single CRD, able to form divalent homodimers. This lectin, which is mainly expressed in stratified epithelia, has been described in epithelial tissues as being involved in apoptotic responses, in proliferation and differentiation but also in cell adhesion and migration. Most members of the galectins family have been associated with cancer biology. One of the main functions of galectins in cancer is their immunomodulating potential and anti-angiogenic activity. Indeed, galectin-1 and -3, are already targeted in clinical trials. Another relevant function of galectins in tumour progression is their ability to regulate cell migration and cell adhesion. Among these galectins, galectin-7 is abnormally expressed in various cancers, most prominently in carcinomas, and is involved in cancer progression and metastasis but its precise functions in tumour biology remain poorly understood. In this issue, we will focus on the physiological functions of galectin-7 in epithelia and present the alterations of galectin-7 expression in carcinomas with the aim to describe its possible functions in tumour progression. PMID- 29257083 TI - Dynamics of Monoterpene Formation in Spike Lavender Plants. AB - The metabolic cross-talk between the mevalonate (MVA) and the methylerythritol phosphate (MEP) pathways was analyzed in spike lavender (Lavandula latifolia Med) on the basis of 13CO2-labelling experiments using wildtype and transgenic plants overexpressing the 3-hydroxy-3-methylglutaryl CoA reductase (HMGR), the first and key enzyme of the MVA pathway. The plants were labelled in the presence of 13CO2 in a gas chamber for controlled pulse and chase periods of time. GC/MS and NMR analysis of 1,8-cineole and camphor, the major monoterpenes present in their essential oil, indicated that the C5-precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) of both monoterpenes are predominantly biosynthesized via the MEP pathway. Surprisingly, overexpression of HMGR did not have significant impact upon the crosstalk between the MVA and MEP pathways indicating that the MEP route is the preferred pathway for the synthesis of C5 monoterpene precursors in spike lavender. PMID- 29257084 TI - Studies on the Anti-Oxidative Function of trans-Cinnamaldehyde-Included beta Cyclodextrin Complex. AB - trans-Cinnamaldehyde (tCIN), an active compound found in cinnamon, is well known for its antioxidant, anticancer, and anti-inflammatory activities. The beta cyclodextrin (beta-CD) oligomer has been used for a variety of applications in nanotechnology, including pharmaceutical and cosmetic applications. Here, we aimed to evaluate the anti-inflammatory and antioxidant effects of tCIN self included in beta-CD complexes (CIs) in lipopolysaccharide (LPS)-treated murine RAW 264.7 macrophages. RAW 264.7 macrophages were treated with increasing concentrations of beta-CD, tCIN, or CIs for different times. beta-CD alone did not affect the production of nitric oxide (NO) or reactive oxygen species (ROS). However, both tCIN and CI significantly reduced NO and ROS production. Thus, CIs may have strong anti-inflammatory and antioxidant effects, similar to those of tCIN when used alone. PMID- 29257085 TI - Sulfophenyl-Functionalized Reduced Graphene Oxide Networks on Electrospun 3D Scaffold for Ultrasensitive NO2 Gas Sensor. AB - Ultrasensitive room temperature real-time NO2 sensors are highly desirable due to potential threats on environmental security and personal respiratory. Traditional NO2 gas sensors with highly operated temperatures (200-600 degrees C) and limited reversibility are mainly constructed from semiconducting oxide-deposited ceramic tubes or inter-finger probes. Herein, we report the functionalized graphene network film sensors assembled on an electrospun three-dimensional (3D) nanonetwork skeleton for ultrasensitive NO2 sensing. The functional 3D scaffold was prepared by electrospinning interconnected polyacrylonitrile (PAN) nanofibers onto a nylon window screen to provide a 3D nanonetwork skeleton. Then, the sulfophenyl-functionalized reduced graphene oxide (SFRGO) was assembled on the electrospun 3D nanonetwork skeleton to form SFRGO network films. The assembled functionalized graphene network film sensors exhibit excellent NO2 sensing performance (10 ppb to 20 ppm) at room temperature, reliable reversibility, good selectivity, and better sensing cycle stability. These improvements can be ascribed to the functionalization of graphene with electron-withdrawing sulfophenyl groups, the high surface-to-volume ratio, and the effective sensing channels from SFRGO wrapping onto the interconnected 3D scaffold. The SFRGO network-sensing film has the advantages of simple preparation, low cost, good processability, and ultrasensitive NO2 sensing, all advantages that can be utilized for potential integration into smart windows and wearable electronic devices for real-time household gas sensors. PMID- 29257086 TI - Investigating Methodological Differences in the Assessment of Dendritic Morphology of Basolateral Amygdala Principal Neurons-A Comparison of Golgi-Cox and Neurobiotin Electroporation Techniques. AB - Quantitative assessments of neuronal subtypes in numerous brain regions show large variations in dendritic arbor size. A critical experimental factor is the method used to visualize neurons. We chose to investigate quantitative differences in basolateral amygdala (BLA) principal neuron morphology using two of the most common visualization methods: Golgi-Cox staining and neurobiotin (NB) filling. We show in 8-week-old Wistar rats that NB-filling reveals significantly larger dendritic arbors and different spine densities, compared to Golgi-Cox stained BLA neurons. Our results demonstrate important differences and provide methodological insights into quantitative disparities of BLA principal neuron morphology reported in the literature. PMID- 29257087 TI - Microsomal Prostaglandin E Synthase-1 Facilitates an Intercellular Interaction between CD4+ T Cells through IL-1beta Autocrine Function in Experimental Autoimmune Encephalomyelitis. AB - Microsomal prostaglandin synthetase-1 (mPGES-1) is an inducible terminal enzyme that produces prostaglandin E2 (PGE2). In our previous study, we investigated the role of mPGES-1 in the inflammation and demyelination observed in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, using mPGES-1-deficient (mPGES-1-/-) and wild-type (wt) mice. We found that mPGES-1 facilitated inflammation, demyelination, and paralysis and was induced in vascular endothelial cells and macrophages and microglia around inflammatory foci. Here, we investigated the role of interleukin-1beta (IL-1beta) in the intercellular mechanism stimulated by mPGES-1 in EAE spinal cords in the presence of inflammation. We found that the area invaded by CD4-positive (CD4+) T cells was extensive, and that PGE2 receptors EP1-4 were more induced in activated CD4+ T cells of wt mice than in those of mPGES-1-/- mice. Moreover, IL-1beta and IL-1 receptor 1 (IL-1r1) were produced by 65% and 48% of CD4+ T cells in wt mice and by 44% and 27% of CD4+ T cells in mPGES-1-/- mice. Furthermore, interleukin-17 (IL-17) was released from the activated CD4+ T cells. Therefore, mPGES-1 stimulates an intercellular interaction between CD4+ T cells by upregulating the autocrine function of IL-1beta in activated CD4+ T cells, which release IL-17 to facilitate axonal and myelin damage in EAE mice. PMID- 29257088 TI - Quantity and Quality of Carbohydrate Intake during Pregnancy, Newborn Body Fatness and Cardiac Autonomic Control: Conferred Cardiovascular Risk? AB - The fetal environment has an important influence on health and disease over the life course. Maternal nutritional status during pregnancy is potentially a powerful contributor to the intrauterine environment, and may alter offspring physiology and later life cardio-metabolic risk. Putative early life markers of cardio-metabolic risk include newborn body fatness and cardiac autonomic control. We sought to determine whether maternal dietary carbohydrate quantity and/or quality during pregnancy are associated with newborn body composition and cardiac autonomic function. Maternal diet during pregnancy was assessed in 142 mother infant pairs using a validated food frequency questionnaire. Infant adiposity and body composition were assessed at birth using air-displacement plethysmography. Cardiac autonomic function was assessed as heart rate variability. The quantity of carbohydrates consumed during pregnancy, as a percentage of total energy intake, was not associated with meaningful differences in offspring birth weight, adiposity or heart rate variability (p > 0.05). There was some evidence that maternal carbohydrate quality, specifically higher fibre and lower glycemic index, is associated with higher heart rate variability in the newborn offspring (p = 0.06). This suggests that poor maternal carbohydrate quality may be an important population-level inter-generational risk factor for later cardiac and hemodynamic risk of their offspring. PMID- 29257090 TI - Dead Pericarps of Dry Fruits Function as Long-Term Storage for Active Hydrolytic Enzymes and Other Substances That Affect Germination and Microbial Growth. AB - It is commonly assumed that dead pericarps of dry indehiscent fruits have evolved to provide an additional physical layer for embryo protection and as a means for long distance dispersal. The pericarps of dry fruits undergo programmed cell death (PCD) during maturation whereby most macromolecules such DNA, RNA, and proteins are thought to be degraded and their constituents remobilized to filial tissues such as embryo and endosperm. We wanted to test the hypothesis that the dead pericarp represents an elaborated layer that is capable of storing active proteins and other substances for increasing survival rate of germinating seeds. Using in gel assays we found that dead pericarps of both dehiscent and indehiscent dry fruits of various plant species including Arabidopsis thaliana and Sinapis alba release upon hydration multiple active hydrolytic enzymes that can persist in an active form for decades, including nucleases, proteases, and chitinases. Proteomic analysis of indehiscent pericarp of S. alba revealed multiple proteins released upon hydration, among them proteases and chitinases, as well as proteins involved in reactive oxygen species (ROS) detoxification and cell wall modification. Pericarps appear to function also as a nutritional element-rich storage for nitrate, potassium, phosphorus, sulfur, and others. Sinapis alba dehiscent and indehiscent pericarps possess germination inhibitory substances as well as substances that promote microbial growth. Collectively, our study explored previously unknown features of the dead pericarp acting also as a reservoir of biological active proteins, and other substances capable of "engineering" the microenvironment for the benefit of the embryo. PMID- 29257089 TI - The Native Hawaiian Insect Microbiome Initiative: A Critical Perspective for Hawaiian Insect Evolution. AB - Insects associate with a diversity of microbes that can shape host ecology and diversity by providing essential biological and adaptive services. For most insect groups, the evolutionary implications of host-microbe interactions remain poorly understood. Geographically discrete areas with high biodiversity offer powerful, simplified model systems to better understand insect-microbe interactions. Hawaii boasts a diverse endemic insect fauna (~6000 species) characterized by spectacular adaptive radiations. Despite this, little is known about the role of bacteria in shaping this diversity. To address this knowledge gap, we inaugurate the Native Hawaiian Insect Microbiome Initiative (NHIMI). The NHIMI is an effort intended to develop a framework for informing evolutionary and biological studies in Hawaii. To initiate this effort, we have sequenced the bacterial microbiomes of thirteen species representing iconic, endemic Hawaiian insect groups. Our results show that native Hawaiian insects associate with a diversity of bacteria that exhibit a wide phylogenetic breadth. Several groups show predictable associations with obligate microbes that permit diet specialization. Others exhibit unique ecological transitions that are correlated with shifts in their microbiomes (e.g., transition to carrion feeding from plant feeding in Nysius wekiuicola). Finally, some groups, such as the Hawaiian Drosophila, have relatively diverse microbiomes with a conserved core of bacterial taxa across multiple species and islands. PMID- 29257091 TI - Comparative Transcriptome Analysis of Male and Female Conelets and Development of Microsatellite Markers in Pinus bungeana, an Endemic Conifer in China. AB - The sex determination in gymnosperms is still poorly characterized due to the lack of genomic/transcriptome resources and useful molecular genetic markers. To enhance our understanding of the molecular mechanisms of the determination of sexual recognition of reproductive structures in conifers, the transcriptome of male and female conelets were characterized in a Chinese endemic conifer species, Pinus bungeana Zucc. ex Endl. The 39.62 Gb high-throughput sequencing reads were obtained from two kinds of sexual conelets. After de novo assembly of the obtained reads, 85,305 unigenes were identified, 53,944 (63.23%) of which were annotated with public databases. A total of 12,073 differentially expressed genes were detected between the two types of sexes in P. bungeana, and 5766 (47.76%) of them were up-regulated in females. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enriched analysis suggested that some of the genes were significantly associated with the sex determination process of P. bungeana, such as those involved in tryptophan metabolism, zeatin biosynthesis, and cysteine and methionine metabolism, and the phenylpropanoid biosynthesis pathways. Meanwhile, some important plant hormone pathways (e.g., the gibberellin (GA) pathway, carotenoid biosynthesis, and brassinosteroid biosynthesis (BR) pathway) that affected sexual determination were also induced in P. bungeana. In addition, 8791 expressed sequence tag-simple sequence repeats (EST-SSRs) from 7859 unigenes were detected in P. bungeana. The most abundant repeat types were dinucleotides (1926), followed by trinucleotides (1711). The dominant classes of the sequence repeat were A/T (4942) in mononucleotides and AT/AT (1283) in dinucleotides. Among these EST-SSRs, 84 pairs of primers were randomly selected for the characterization of potential molecular genetic markers. Finally, 19 polymorphic EST-SSR primers were characterized. We found low to moderate levels of genetic diversity (NA = 1.754; HO = 0.206; HE = 0.205) across natural populations of P. bungeana. The cluster analysis revealed two distinct genetic groups for the six populations that were sampled in this endemic species, which might be caused by the fragmentation of habitats and long-term geographic isolation among different populations. Taken together, this work provides important insights into the molecular mechanisms of sexual identity in the reproductive organs of P. bungeana. The molecular genetic resources that were identified in this study will also facilitate further studies in functional genomics and population genetics in the Pinus species. PMID- 29257094 TI - Integrity Testing of Pile Cover Using Distributed Fibre Optic Sensing. AB - The integrity of cast-in-place foundation piles is a major concern in geotechnical engineering. In this study, distributed fibre optic sensing (DFOS) cables, embedded in a pile during concreting, are used to measure the changes in concrete curing temperature profile to infer concrete cover thickness through modelling of heat transfer processes within the concrete and adjacent ground. A field trial was conducted at a high-rise building construction site in London during the construction of a 51 m long test pile. DFOS cables were attached to the reinforcement cage of the pile at four different axial directions to obtain distributed temperature change data along the pile. The monitoring data shows a clear development of concrete hydration temperature with time and the pattern of the change varies due to small changes in concrete cover. A one-dimensional axisymmetric heat transfer finite element (FE) model is used to estimate the pile geometry with depth by back analysing the DFOS data. The results show that the estimated pile diameter varies with depth in the range between 1.40 and 1.56 m for this instrumented pile. This average pile diameter profile compares well to that obtained with the standard Thermal Integrity Profiling (TIP) method. A parametric study is conducted to examine the sensitivity of concrete and soil thermal properties on estimating the pile geometry. PMID- 29257092 TI - Environmental Factors Correlated with Culturable Enterococci Concentrations in Tropical Recreational Waters: A Case Study in Escambron Beach, San Juan, Puerto Rico. AB - Enterococci concentration variability at Escambron Beach, San Juan, Puerto Rico, was examined in the context of environmental conditions observed during 2005 2015. Satellite-derived sea surface temperature (SST), turbidity, direct normal irradiance, and dew point were combined with local precipitation, winds, and mean sea level (MSL) observations in a stepwise multiple regression analyses (Akaike Information Criteria model selection). Precipitation, MSL, irradiance, SST, and turbidity explained 20% of the variation in observed enterococci concentrations based upon these analyses. Changes in these parameters preceded increases in enterococci concentrations by 24 h up to 11 days, particularly during positive anomalies of turbidity, SST, and 480-960 mm of accumulated (4 days) precipitation, which relates to bacterial ecology. Weaker, yet still significant, increases in enterococci concentrations were also observed during positive dew point anomalies. Enterococci concentrations decreased with elevated irradiance and MSL anomalies. Unsafe enterococci concentrations per US EPA recreational water quality guidelines occurred when 4-day cumulative precipitation ranged 481 960 mm; irradiance < 667 W.m-2; daily average turbidity anomaly >0.005 sr-1; SST anomaly >0.8 degrees C; and 3-day average MSL anomaly <-18.8 cm. This case study shows that satellite-derived environmental data can be used to inform future water quality studies and protect human health. PMID- 29257093 TI - Adjunctive Therapy Approaches for Ischemic Stroke: Innovations to Expand Time Window of Treatment. AB - Tissue plasminogen activator (tPA) thrombolysis remains the gold standard treatment for ischemic stroke. A time-constrained therapeutic window, with the drug to be given within 4.5 h after stroke onset, and lethal side effects associated with delayed treatment, most notably hemorrhagic transformation (HT), limit the clinical use of tPA. Co-administering tPA with other agents, including drug or non-drug interventions, has been proposed as a practical strategy to address the limitations of tPA. Here, we discuss the pharmacological and non-drug approaches that were examined to mitigate the complications-especially HT associated with delayed tPA treatment. The pharmacological treatments include those that preserve the blood-brain barrier (e.g., atovarstatin, batimastat, candesartan, cilostazol, fasudil, minocycline, etc.), enhance vascularization and protect the cerebrovasculature (e.g., coumarin derivate IMM-H004 and granulocyte colony stimulating factor (G-CSF)), and exert their effects through other modes of action (e.g., oxygen transporters, ascorbic acid, etc.). The non-drug approaches include stem cell treatments and gas therapy with multi-pronged biological effects. Co-administering tPA with the abovementioned therapies showed promise in attenuating delayed tPA-induced side effects and stroke-induced neurological and behavioral deficits. Thus, adjunctive treatment approach is an innovative therapeutic modality that can address the limitations of tPA treatment and potentially expand the time window for ischemic stroke therapy. PMID- 29257095 TI - Outcomes in the Utilization of Single Percutaneous Cholecystostomy in a Low Income Population. AB - Numerous studies have investigated the applicable populations for percutaneous cholecystostomy (PC) procedures, but the outcomes of PC in low-income populations (LIPs) have been insufficiently studied. Data for 11,184 patients who underwent PC were collected from the National Health Insurance Research Database of Taiwan during 2003 and 2012. The overall crude rate of single PC for the LIP was 64% higher than that for the general population (GP). After propensity score matching for the LIP and GP at a ratio of 1:5, the outcome analysis of patients who underwent PC showed that in-hospital mortality was significantly higher in the LIP group than in the GP group, but one-year recurrence was lower. The rates of 30-day mortality and in-hospital complications were higher for the LIP patients than for the GP patients, and the rate of routine discharge was lower, but the differences were not significant. In conclusion, LIP patients undergoing PC exhibit poor prognoses relative to GP patients, indicating that a low socioeconomic status has an adverse impact on the outcome of PC. We suggest that surgeons fully consider the patient's financial situation during the operation and further consider the possible poor post-surgical outcomes for LIP patients. PMID- 29257096 TI - Comparative Analysis of Four Calypogeia Species Revealed Unexpected Change in Evolutionarily-Stable Liverwort Mitogenomes. AB - Liverwort mitogenomes are considered to be evolutionarily stable. A comparative analysis of four Calypogeia species revealed differences compared to previously sequenced liverwort mitogenomes. Such differences involve unexpected structural changes in the two genes, cox1 and atp1, which have lost three and two introns, respectively. The group I introns in the cox1 gene are proposed to have been lost by two-step localized retroprocessing, whereas one-step retroprocessing could be responsible for the disappearance of the group II introns in the atp1 gene. These cases represent the first identified losses of introns in mitogenomes of leafy liverworts (Jungermanniopsida) contrasting the stability of mitochondrial gene order with certain changes in the gene content and intron set in liverworts. PMID- 29257097 TI - Overexpression and Down-Regulation of Barley Lipoxygenase LOX2.2 Affects Jasmonate-Regulated Genes and Aphid Fecundity. AB - Aphids are pests on many crops and depend on plant phloem sap as their food source. In an attempt to find factors improving plant resistance against aphids, we studied the effects of overexpression and down-regulation of the lipoxygenase gene LOX2.2 in barley (Hordeum vulgare L.) on the performance of two aphid species. A specialist, bird cherry-oat aphid (Rhopalosiphum padi L.) and a generalist, green peach aphid (Myzus persicae Sulzer) were studied. LOX2.2 overexpressing lines showed up-regulation of some other jasmonic acid (JA) regulated genes, and antisense lines showed down-regulation of such genes. Overexpression or suppression of LOX2.2 did not affect aphid settling or the life span on the plants, but in short term fecundity tests, overexpressing plants supported lower aphid numbers and antisense plants higher aphid numbers. The amounts and composition of released volatile organic compounds did not differ between control and LOX2.2 overexpressing lines. Up-regulation of genes was similar for both aphid species. The results suggest that LOX2.2 plays a role in the activation of JA-mediated responses and indicates the involvement of LOX2.2 in basic defense responses. PMID- 29257098 TI - High-Performance and Self-Powered Deep UV Photodetectors Based on High Quality 2D Boron Nitride Nanosheets. AB - High-quality two-dimensional (2D) crystalline boron nitride nanosheets (BNNSs) were grown on silicon wafers by using pulsed plasma beam deposition techniques. Self-powered deep ultraviolet (DUV) photodetectors (PDs) based on BNNSs with Schottky contact structures are designed and fabricated. By connecting the fabricated DUV photodetector to an ammeter, the response strength, response time and recovery time to different DUV wavelengths at different intensities have been characterized using the output short circuit photocurrent without a power supply. Furthermore, effects of temperature and plasma treatment on the induced photocurrent response of detectors have also been investigated. The experimental data clearly indicate that plasma treatment would significantly improve both induced photocurrent and response time. The BNNS-based DUV photodetector is demonstrated to possess excellent performance at a temperature up to 400 degrees C, including high sensitivity, high signal-to-noise ratio, high spectral selectivity, high speed, and high stability, which is better than almost all reported semiconducting nanomaterial-based self-powered photodetectors. PMID- 29257099 TI - Performance Comparison of Systemic Inflammatory Response Syndrome with Logistic Regression Models to Predict Sepsis in Neonates. AB - In 2005, an international pediatric sepsis consensus conference defined systemic inflammatory response syndrome (SIRS) for children <18 years of age, but excluded premature infants. In 2012, Hofer et al. investigated the predictive power of SIRS for term neonates. In this paper, we examined the accuracy of SIRS in predicting sepsis in neonates, irrespective of their gestational age (i.e., pre term, term, and post-term). We also created two prediction models, named Model A and Model B, using binary logistic regression. Both models performed better than SIRS. We also developed an android application so that physicians can easily use Model A and Model B in real-world scenarios. The sensitivity, specificity, positive likelihood ratio (PLR) and negative likelihood ratio (NLR) in cases of SIRS were 16.15%, 95.53%, 3.61, and 0.88, respectively, whereas they were 29.17%, 97.82%, 13.36, and 0.72, respectively, in the case of Model A, and 31.25%, 97.30%, 11.56, and 0.71, respectively, in the case of Model B. All models were significant with p < 0.001. PMID- 29257100 TI - An Evidence-Based Review of Impacts, Strategies and Tools to Mitigate Urban Heat Islands. AB - The impacts of climate changes on cities, which are home to over half of the world's population, are already being felt. In many cases, the intensive speed with which urban centres have been growing means that little attention has been paid to the role played by climatic factors in maintaining quality of life. Among the negative consequences of rapid city growth is the expansion of the problems posed by urban heat islands (UHIs), defined as areas in a city that are much warmer than other sites, especially in comparison with rural areas. This paper analyses the consistency of the UHI-related literature in three stages: first it outlines its characteristics and impacts in a wide variety of cities around the world, which poses pressures to public health in many different countries. Then it introduces strategies which may be employed in order to reduce its effects, and finally it analyses available tools to systematize the initial high level assessment of the phenomenon for multidisciplinary teams involved in the urban planning process. The analysis of literature on the characteristics, impacts, strategies and digital tools to assess on the UHI, reveals the wide variety of parameters, methods, tools and strategies analysed and suggested in the different studies, which does not always allow to compare or standardize the diagnosis or solutions. PMID- 29257101 TI - Effect of an Extract from Aronia melanocarpa L. Berries on the Body Status of Zinc and Copper under Chronic Exposure to Cadmium: An In Vivo Experimental Study. AB - In an experimental model of low-level and moderate environmental human exposure to cadmium (Cd), it was investigated whether the consumption of a polyphenol-rich Aronia melanocarpa L. berries (chokeberries) extract (AE) may influence the body status of zinc (Zn) and copper (Cu). The bioelements' apparent absorption, body retention, serum and tissue concentrations, total pool in internal organs, excretion, and the degree of binding to metallothionein were evaluated in female rats administered 0.1% aqueous AE or/and Cd in their diet (1 and 5 mg/kg) for 3 24 months. The consumption of AE alone had no influence on the body status of Zn and Cu. The extract administration at both levels of Cd treatment significantly (completely or partially) protected against most of the changes in the metabolism of Zn and Cu caused by this xenobiotic; however, it increased or decreased some of the Cd-unchanged indices of their body status. Based on the findings, it seems that rational amounts of chokeberry products may be included in the daily diet without the risk of destroying Zn and Cu metabolisms; however, their potential prophylactic use under exposure to Cd needs further study to exclude any unfavourable impact of these essential elements on the metabolism. PMID- 29257102 TI - Achievements and Prospects in Electrochemical-Based Biosensing Platforms for Aflatoxin M1 Detection in Milk and Dairy Products. AB - Aflatoxins, which are mainly produced by Aspergillus flavus and parasiticus growing on plants and products stored under inappropriate conditions, represent the most studied group of mycotoxins. Contamination of human and animal milk with aflatoxin M1, the hydroxylated metabolite of aflatoxin B1, is an important health risk factor due to its carcinogenicity and mutagenicity. Due to the low concentration of this aflatoxin in milk and milk products, the analytical methods used for its quantification have to be highly sensitive, specific and simple. This paper presents an overview of the analytical methods, especially of the electrochemical immunosensors and aptasensors, used for determination of aflatoxin M1. PMID- 29257104 TI - Micro-Arc Oxidation Enhances the Blood Compatibility of Ultrafine-Grained Pure Titanium. AB - Ultrafine-grained pure titanium prepared by equal-channel angular pressing has favorable mechanical performance and does not contain alloy elements that are toxic to the human body. It has potential clinical value in applications such as cardiac valve prostheses, vascular stents, and hip prostheses. To overcome the material's inherent thrombogenicity, surface-coating modification is a crucial pathway to enhancing blood compatibility. An electrolyte solution of sodium silicate + sodium polyphosphate + calcium acetate and the micro-arc oxidation (MAO) technique were employed for in situ oxidation of an ultrafine-grained pure titanium surface. A porous coating with anatase- and rutile-phase TiO2 was generated and wettability and blood compatibility were examined. The results showed that, in comparison with ultrafine-grained pure titanium substrate, the MAO coating had a rougher surface, smaller contact angles for distilled water and higher surface energy. MAO modification effectively reduced the hemolysis rate; extended the dynamic coagulation time, prothrombin time (PT), and activated partial thromboplastin time (APTT); reduced the amount of platelet adhesion and the degree of deformation; and enhanced blood compatibility. In particular, the sample with an oxidation time of 9 min possessed the highest surface energy, largest PT and APTT values, smallest hemolysis rate, less platelet adhesion, a lesser degree of deformation, and more favorable blood compatibility. The MAO method can significantly enhance the blood compatibility of ultrafine-grained pure titanium, increasing its potential for practical applications. PMID- 29257103 TI - Characterization of HIV-1 Near Full-Length Proviral Genome Quasispecies from Patients with Undetectable Viral Load Undergoing First-Line HAART Therapy. AB - Increased access to highly active antiretroviral therapy (HAART) by human immunodeficiency virus postive (HIV+) individuals has become a reality worldwide. In Brazil, HAART currently reaches over half of HIV-infected subjects. In the context of a remarkable HIV-1 genetic variability, highly related variants, called quasispecies, are generated. HIV quasispecies generated during infection can influence virus persistence and pathogenicity, representing a challenge to treatment. However, the clinical relevance of minority quasispecies is still uncertain. In this study, we have determined the archived proviral sequences, viral subtype and drug resistance mutations from a cohort of HIV+ patients with undetectable viral load undergoing HAART as first-line therapy using next generation sequencing for near full-length virus genome (NFLG) assembly. HIV-1 consensus sequences representing NFLG were obtained for eleven patients, while for another twelve varying genome coverage rates were obtained. Phylogenetic analysis showed the predominance of subtype B (83%; 19/23). Considering the minority variants, 18 patients carried archived virus harboring at least one mutation conferring antiretroviral resistance; for six patients, the mutations correlated with the current ARVs used. These data highlight the importance of monitoring HIV minority drug resistant variants and their clinical impact, to guide future regimen switches and improve HIV treatment success. PMID- 29257107 TI - Visible Light Photoinitiator for 3D-Printing of Tough Methacrylate Resins. AB - Lithography-based additive manufacturing was introduced in the 1980s, and is still the method of choice for printing accurate plastic parts with high surface quality. Recent progress in this field has made tough photopolymer resins and cheap LED light engines available. This study presents the influence of photoinitiator selection and post-processing on the thermomechanical properties of various tough photopolymers. The influence of three photoinitiators (Ivocerin, BAPO, and TPO-L) on the double-bond conversion and mechanical properties was investigated by mid infrared spectroscopy, dynamic mechanical analysis and tensile tests. It was found that 1.18 wt % TPO-L would provide the best overall results in terms of double-bond conversion and mechanical properties. A correlation between double-bond conversion, yield strength, and glass transition temperature was found. Elongation at break remained high after post-curing at about 80-100%, and was not influenced by higher photoinitiator concentration. Finally, functional parts with 41 MPa tensile strength, 82% elongation at break, and 112 degrees C glass transition temperature were printed on a 405 nm DLP (digital light processing) printer. PMID- 29257105 TI - Potent Inhibition of miR-34b on Migration and Invasion in Metastatic Prostate Cancer Cells by Regulating the TGF-beta Pathway. AB - The importance of miRNAs in the progression of prostate cancer (PCa) has further been supported by the finding that miRNAs have been identified as potential oncogenes or tumor suppressors in PCa. Indeed, in eukaryotes, miRNAs have been found to regulate and control gene expression by degrading mRNA at the post transcriptional level. In this study, we investigated the expression of miR-34 family members, miR-34b and miR-34c, in different PCa cell lines, and discussed the molecular mechanism of miR-34b in the invasion and migration of PCa cells in vitro. The difference analyses of the transcriptome between the DU145 and PC3 cell lines demonstrated that both miR-34b and -34c target critical pathways that are involved in metabolism, such as proliferation, and migration, and invasion. The molecular expression of miR-34b/c were lower in PC3 cells. Moreover, over expression of miR-34b/c in PC3 cells caused profound phenotypic changes, including decreased cell proliferation, migration and invasion. Moreover, the players that regulate expression levels of transforming growth factor-beta (TGF beta), TGF-beta receptor 1 (TGF-betaR1), and p53 or phosphorylation levels of mothers against decapentaplegic 3 (SMAD3) in the TGF-beta/Smad3 signaling pathway have yet to be elucidated, and will provide novel tools for diagnosis and treatment of metastatic PCa. PMID- 29257108 TI - Anti-Runaway Prevention System with Wireless Sensors for Intelligent Track Skates at Railway Stations. AB - Anti-runaway prevention of rolling stocks at a railway station is essential in railway safety management. The traditional track skates for anti-runaway prevention of rolling stocks have some disadvantages since they are operated and monitored completely manually. This paper describes an anti-runaway prevention system (ARPS) based on intelligent track skates equipped with sensors and real time monitoring and management system. This system, which has been updated from the traditional track skates, comprises four parts: intelligent track skates, a signal reader, a database station, and a monitoring system. This system can monitor the real-time situation of track skates without changing their workflow for anti-runaway prevention, and thus realize the integration of anti-runaway prevention information management. This system was successfully tested and practiced at Sunjia station in Harbin Railway Bureau in 2014, and the results confirmed that the system showed 100% accuracy in reflecting the usage status of the track skates. The system could meet practical demands, as it is highly reliable and supports long-distance communication. PMID- 29257106 TI - A Genome-Wide Association Study and Complex Network Identify Four Core Hub Genes in Bipolar Disorder. AB - Bipolar disorder is a common and severe mental illness with unsolved pathophysiology. A genome-wide association study (GWAS) has been used to find a number of risk genes, but it is difficult for a GWAS to find genes indirectly associated with a disease. To find core hub genes, we introduce a network analysis after the GWAS was conducted. Six thousand four hundred fifty eight single nucleotide polymorphisms (SNPs) with p < 0.01 were sifted out from Wellcome Trust Case Control Consortium (WTCCC) dataset and mapped to 2045 genes, which are then compared with the protein-protein network. One hundred twelve genes with a degree >17 were chosen as hub genes from which five significant modules and four core hub genes (FBXL13, WDFY2, bFGF, and MTHFD1L) were found. These core hub genes have not been reported to be directly associated with BD but may function by interacting with genes directly related to BD. Our method engenders new thoughts on finding genes indirectly associated with, but important for, complex diseases. PMID- 29257110 TI - Prebiotic Oligosaccharides Potentiate Host Protective Responses against L. Monocytogenes Infection. AB - Prebiotic oligosaccharides are used to modulate enteric pathogens and reduce pathogen shedding. The interactions with prebiotics that alter Listeria monocytogenes infection are not yet clearly delineated. L. monocytogenes cellular invasion requires a concerted manipulation of host epithelial cell membrane receptors to initiate internalization and infection often via receptor glycosylation. Bacterial interactions with host glycans are intimately involved in modulating cellular responses through signaling cascades at the membrane and in intracellular compartments. Characterizing the mechanisms underpinning these modulations is essential for predictive use of dietary prebiotics to diminish pathogen association. We demonstrated that human milk oligosaccharide (HMO) pretreatment of colonic epithelial cells (Caco-2) led to a 50% decrease in Listeria association, while Biomos pretreatment increased host association by 150%. L. monocytogenes-induced gene expression changes due to oligosaccharide pretreatment revealed global alterations in host signaling pathways that resulted in differential subcellular localization of L. monocytogenes during early infection. Ultimately, HMO pretreatment led to bacterial clearance in Caco-2 cells via induction of the unfolded protein response and eIF2 signaling, while Biomos pretreatment resulted in the induction of host autophagy and L. monocytogenes vacuolar escape earlier in the infection progression. This study demonstrates the capacity of prebiotic oligosaccharides to minimize infection through induction of host-intrinsic protective responses. PMID- 29257111 TI - Experimental Cowpox Virus (CPXV) Infections of Bank Voles: Exceptional Clinical Resistance and Variable Reservoir Competence. AB - Cowpox virus (CPXV) is a zoonotic virus and endemic in wild rodent populations in Eurasia. Serological surveys in Europe have reported high prevalence in different vole and mouse species. Here, we report on experimental CPXV infections of bank voles (Myodes glareolus) from different evolutionary lineages with a spectrum of CPXV strains. All bank voles, independently of lineage, sex and age, were resistant to clinical signs following CPXV inoculation, and no virus shedding was detected in nasal or buccal swabs. In-contact control animals became only rarely infected. However, depending on the CPXV strain used, inoculated animals seroconverted and viral DNA could be detected preferentially in the upper respiratory tract. The highest antibody titers and virus DNA loads in the lungs were detected after inoculation with two strains from Britain and Finland. We conclude from our experiments that the role of bank voles as an efficient and exclusive CPXV reservoir seems questionable, and that CPXV may be maintained in most regions by other hosts, including other vole species. Further investigations are needed to identify factors that allow and modulate CPXV maintenance in bank voles and other potential reservoirs, which may also influence spill-over infections to accidental hosts. PMID- 29257109 TI - Vitamin D and Its Analogues Decrease Amyloid-beta (Abeta) Formation and Increase Abeta-Degradation. AB - Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-beta (Abeta), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Abeta-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D2 and D3 analogues decreased Abeta production and increased Abeta-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Abeta-producing enzymes BACE1 and gamma-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the gamma-secretase. Vitamin D and analogues decreased beta secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention. PMID- 29257112 TI - Comparative Analysis of Fruit Ripening-Related miRNAs and Their Targets in Blueberry Using Small RNA and Degradome Sequencing. AB - MicroRNAs (miRNAs) play vital roles in the regulation of fruit development and ripening. Blueberry is an important small berry fruit crop with economical and nutritional value. However, nothing is known about the miRNAs and their targets involved in blueberry fruit ripening. In this study, using high-throughput sequencing of small RNAs, 84 known miRNAs belonging to 28 families and 16 novel miRNAs were identified in white fruit (WF) and blue fruit (BF) libraries, which represent fruit ripening onset and in progress, respectively. Among them, 41 miRNAs were shown to be differentially expressed during fruit maturation, and 16 miRNAs representing 16 families were further chosen to validate the sRNA sequencing data by stem-loop qRT-PCR. Meanwhile, 178 targets were identified for 41 known and 7 novel miRNAs in WF and BF libraries using degradome sequencing, and targets of miR160 were validated using RLM-RACE (RNA Ligase-Mediated (RLM) Rapid Amplification of cDNA Ends) approach. Moreover, the expression patterns of 6 miRNAs and their targets were examined during fruit development and ripening. Finally, integrative analysis of miRNAs and their targets revealed a complex miRNA-mRNA regulatory network involving a wide variety of biological processes. The findings will facilitate future investigations of the miRNA-mediated mechanisms that regulate fruit development and ripening in blueberry. PMID- 29257113 TI - Sensors and Biosensors for C-Reactive Protein, Temperature and pH, and Their Applications for Monitoring Wound Healing: A Review. AB - Wound assessment is usually performed in hospitals or specialized labs. However, since patients spend most of their time at home, a remote real time wound monitoring would help providing a better care and improving the healing rate. This review describes the advances in sensors and biosensors for monitoring the concentration of C-reactive protein (CRP), temperature and pH in wounds. These three parameters can be used as qualitative biomarkers to assess the wound status and the effectiveness of therapy. CRP biosensors can be classified in: (a) field effect transistors, (b) optical immunosensors based on surface plasmon resonance, total internal reflection, fluorescence and chemiluminescence, (c) electrochemical sensors based on potentiometry, amperometry, and electrochemical impedance, and (d) piezoresistive sensors, such as quartz crystal microbalances and microcantilevers. The last section reports the most recent developments for wearable non-invasive temperature and pH sensors suitable for wound monitoring. PMID- 29257116 TI - Preparation and Characterization of Nanoparticles Made from Co-Incubation of SOD and Glucose. AB - The attractive potential of natural superoxide dismutase (SOD) in the fields of medicine and functional food is limited by its short half-life in circulation and poor permeability across the cell membrane. The nanoparticle form of SOD might overcome these limitations. However, most preparative methods have disadvantages, such as complicated operation, a variety of reagents-some of them even highly toxic-and low encapsulation efficiency or low release rate. The aim of this study is to present a simple and green approach for the preparation of SOD nanoparticles (NPs) by means of co-incubation of Cu/Zn SOD with glucose. This method was designed to prepare nanoscale aggregates based on the possible inhibitory effect of Maillard reaction on heating-induced aggregation during the co-incubation. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) results indicated that the Maillard reaction occurred during the co incubation process. It was found that enzymatically active NPs of Cu/Zn SOD were simultaneously generated during the reaction, with an average particle size of 175.86 +/- 0.71 nm, and a Zeta potential of -17.27 +/- 0.59 mV, as established by the measurement of enzymatic activity, observations using field emission scanning electron microscope, and analysis of dynamic light scattering, respectively. The preparative conditions for the SOD NPs were optimized by response surface design to increase SOD activity 20.43 fold. These SOD NPs showed storage stability for 25 days and better cell uptake efficacy than natural SOD. Therefore, these NPs of SOD are expected to be a potential drug candidate or functional food factor. To our knowledge, this is the first report on the preparation of nanoparticles possessing the bioactivity of the graft component protein, using the simple and green approach of co-incubation with glucose, which occurs frequently in the food industry during thermal processing. PMID- 29257117 TI - Comprehensive Performance Evaluation for Hydrological and Nutrients Simulation Using the Hydrological Simulation Program-Fortran in a Mesoscale Monsoon Watershed, China. AB - The Hydrological Simulation Program-Fortran (HSPF) is a hydrological and water quality computer model that was developed by the United States Environmental Protection Agency. Comprehensive performance evaluations were carried out for hydrological and nutrient simulation using the HSPF model in the Xitiaoxi watershed in China. Streamflow simulation was calibrated from 1 January 2002 to 31 December 2007 and then validated from 1 January 2008 to 31 December 2010 using daily observed data, and nutrient simulation was calibrated and validated using monthly observed data during the period from July 2009 to July 2010. These results of model performance evaluation showed that the streamflows were well simulated over the study period. The determination coefficient (R2) was 0.87, 0.77 and 0.63, and the Nash-Sutcliffe coefficient of efficiency (Ens) was 0.82, 0.76 and 0.65 for the streamflow simulation in annual, monthly and daily time steps, respectively. Although limited to monthly observed data, satisfactory performance was still achieved during the quantitative evaluation for nutrients. The R2 was 0.73, 0.82 and 0.92, and the Ens was 0.67, 0.74 and 0.86 for nitrate, ammonium and orthophosphate simulation, respectively. Some issues may affect the application of HSPF were also discussed, such as input data quality, parameter values, etc. Overall, the HSPF model can be successfully used to describe streamflow and nutrients transport in the mesoscale watershed located in the East Asian monsoon climate area. This study is expected to serve as a comprehensive and systematic documentation of understanding the HSPF model for wide application and avoiding possible misuses. PMID- 29257118 TI - Dual-Color Fluorescence Imaging of EpCAM and EGFR in Breast Cancer Cells with a Bull's Eye-Type Plasmonic Chip. AB - Surface plasmon field-enhanced fluorescence microscopic observation of a live breast cancer cell was performed with a plasmonic chip. Two cell lines, MDA-MB 231 and Michigan Cancer Foundation-7 (MCF-7), were selected as breast cancer cells, with two kinds of membrane protein, epithelial cell adhesion molecule (EpCAM) and epidermal growth factor receptor (EGFR), observed in both cells. The membrane proteins are surface markers used to differentiate and classify breast cancer cells. EGFR and EpCAM were detected with Alexa Fluor(r) 488-labeled anti EGFR antibody (488-EGFR) and allophycocyanin (APC)-labeled anti-EpCAM antibody (APC-EpCAM), respectively. In MDA-MB231 cells, three-fold plus or minus one and seven-fold plus or minus two brighter fluorescence of 488-EGFR were observed on the 480-nm pitch and the 400-nm pitch compared with that on a glass slide. Results show the 400-nm pitch is useful. Dual-color fluorescence of 488-EGFR and APC-EpCAM in MDA-MB231 was clearly observed with seven-fold plus or minus two and nine-fold plus or minus three, respectively, on the 400-nm pitch pattern of a plasmonic chip. Therefore, the 400-nm pitch contributed to the dual-color fluorescence enhancement for these wavelengths. An optimal grating pitch of a plasmonic chip improved a fluorescence image of membrane proteins with the help of the surface plasmon-enhanced field. PMID- 29257114 TI - Amikacin: Uses, Resistance, and Prospects for Inhibition. AB - Aminoglycosides are a group of antibiotics used since the 1940s to primarily treat a broad spectrum of bacterial infections. The primary resistance mechanism against these antibiotics is enzymatic modification by aminoglycoside-modifying enzymes that are divided into acetyl-transferases, phosphotransferases, and nucleotidyltransferases. To overcome this problem, new semisynthetic aminoglycosides were developed in the 70s. The most widely used semisynthetic aminoglycoside is amikacin, which is refractory to most aminoglycoside modifying enzymes. Amikacin was synthesized by acylation with the l-(-)-gamma-amino-alpha hydroxybutyryl side chain at the C-1 amino group of the deoxystreptamine moiety of kanamycin A. The main amikacin resistance mechanism found in the clinics is acetylation by the aminoglycoside 6'-N-acetyltransferase type Ib [AAC(6')-Ib], an enzyme coded for by a gene found in integrons, transposons, plasmids, and chromosomes of Gram-negative bacteria. Numerous efforts are focused on finding strategies to neutralize the action of AAC(6')-Ib and extend the useful life of amikacin. Small molecules as well as complexes ionophore-Zn+2 or Cu+2 were found to inhibit the acetylation reaction and induced phenotypic conversion to susceptibility in bacteria harboring the aac(6')-Ib gene. A new semisynthetic aminoglycoside, plazomicin, is in advance stage of development and will contribute to renewed interest in this kind of antibiotics. PMID- 29257120 TI - A Fast and Validated Reversed-Phase HPLC Method for Simultaneous Determination of Simvastatin, Atorvastatin, Telmisartan and Irbesartan in Bulk Drugs and Tablet Formulations. AB - The aim of this study was to develop and validate a fast and simple reversed phase HPLC method for simultaneous determination of four cardiovascular agents atorvastatin, simvastatin, telmisartan and irbesartan in bulk drugs and tablet oral dosage forms. The chromatographic separation was accomplished by using Symmetry C18 column (75 mm * 4.6 mm; 3.5 MU) with a mobile phase consisting of ammonium acetate buffer (10 mM; pH 4.0) and acetonitrile in a ratio 40:60 v/v. Flow rate was maintained at 1 mL/min up to 3.5 min, and then suddenly changed to 2 mL/min till the end of the run (7.5 min). The data was acquired using ultraviolet detector monitored at 220 nm. The method was validated for linearity, precision, accuracy and specificity. The developed method has shown excellent linearity (R2 > 0.999) over the concentration range of 1-16 ug/mL. The limits of detection (LODs) and limits of quantification (LOQs) were in the range of 0.189 0.190 and 0.603-0.630 ug/mL, respectively. Inter-day and intra-day accuracy and precision data were recorded in the acceptable limits. The new method has successfully been applied for quantification of all four drugs in their tablet dosage forms with percent recovery within 100 +/- 2%. PMID- 29257119 TI - Effects and Mechanisms of Total Flavonoids from Blumea balsamifera (L.) DC. on Skin Wound in Rats. AB - Chinese herbal medicine (CHM) evolved through thousands of years of practice and was popular not only among the Chinese population, but also most countries in the world. Blumea balsamifera (L.) DC. as a traditional treatment for wound healing in Li Nationality Medicine has a long history of nearly 2000 years. This study was to evaluate the effects of total flavonoids from Blumea balsamifera (L.) DC. on skin excisional wound on the back of Sprague-Dawley rats, reveal its chemical constitution, and postulate its action mechanism. The rats were divided into five groups and the model groups were treated with 30% glycerol, the positive control groups with Jing Wan Hong (JWH) ointment, and three treatment groups with high dose (2.52 g.kg-1), medium dose (1.26 g.kg-1), and low dose (0.63 g.kg-1) of total flavonoids from B. balsamifera. During 10 consecutive days of treatment, the therapeutic effects of rates were evaluated. On day 1, day 3, day 5, day 7, and day 10 after treatment, skin samples were taken from all the rats for further study. Significant increases of granulation tissue, fibroblast, and capillary vessel proliferation were observed at day 7 in the high dose and positive control groups, compared with the model group, with the method of 4% paraformaldehyde for histopathological examination and immunofluorescence staining. To reveal the action mechanisms of total flavonoids on wound healing, the levels of CD68, vascular endothelial growth factor (VEGF), transforming growth factor-beta1 (TGF beta1), and hydroxyproline were measured at different days. Results showed that total flavonoids had significant effects on rat skin excisional wound healing compared with controls, especially high dose ones (p < 0.05). Furthermore, the total flavonoid extract was investigated phytochemically, and twenty-seven compounds were identified from the total flavonoid sample by ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry/diode array detector (UPLC-Q-TOF-MS/DAD), including 16 flavonoid aglucons, five flavonoid glycosides (main peaks in chromatogram), five chlorogenic acid analogs, and 1 coumarin. Reports show that flavonoid glycoside possesses therapeutic effects of curing wounds by inducing neovascularization, and chlorogenic acid also has anti-inflammatory and wound healing activities; we postulated that all the ingredients in total flavonoids sample maybe exert a synergetic effect on wound curing. Accompanied with detection of four growth factors, the upregulation of these key growth factors may be the mechanism of therapeutic activities of total flavonoids. The present study confirmed undoubtedly that flavonoids were the main active constituents that contribute to excisional wound healing, and suggested its action mechanism of improving expression levels of growth factors at different healing phases. PMID- 29257115 TI - Functional Analysis of Human Hub Proteins and Their Interactors Involved in the Intrinsic Disorder-Enriched Interactions. AB - Some of the intrinsically disordered proteins and protein regions are promiscuous interactors that are involved in one-to-many and many-to-one binding. Several studies have analyzed enrichment of intrinsic disorder among the promiscuous hub proteins. We extended these works by providing a detailed functional characterization of the disorder-enriched hub protein-protein interactions (PPIs), including both hubs and their interactors, and by analyzing their enrichment among disease-associated proteins. We focused on the human interactome, given its high degree of completeness and relevance to the analysis of the disease-linked proteins. We quantified and investigated numerous functional and structural characteristics of the disorder-enriched hub PPIs, including protein binding, structural stability, evolutionary conservation, several categories of functional sites, and presence of over twenty types of posttranslational modifications (PTMs). We showed that the disorder-enriched hub PPIs have a significantly enlarged number of disordered protein binding regions and long intrinsically disordered regions. They also include high numbers of targeting, catalytic, and many types of PTM sites. We empirically demonstrated that these hub PPIs are significantly enriched among 11 out of 18 considered classes of human diseases that are associated with at least 100 human proteins. Finally, we also illustrated how over a dozen specific human hubs utilize intrinsic disorder for their promiscuous PPIs. PMID- 29257121 TI - Supporting Active Mobility and Green Jobs through the Promotion of Cycling. AB - This article is a summary of the main findings of the study "Riding towards the green economy: cycling and green jobs", which was developed in the context of the Transport, Health and Environment pan-European Programme (THE PEP). It builds on previous work under THE PEP, which demonstrated the job creation potential of cycling and of green and healthy transport more generally. The report summarized in this article collected data on jobs associated with cycling directly from city authorities and analysed these to re-assess previous estimates of the job creation potential of cycling. It concluded that the number of cycling-related jobs in the pan-European Region could increase by 435,000 in selected major cities if they increased their cycling share to that of the Danish capital Copenhagen. The implications and potential role of municipal and sub-national authorities in facilitating cycling while supporting economic development are then discussed. These findings indicate that investment in policies that promote cycling could deliver not only important benefits for health, the environment and the quality of urban life, but could also contribute to a sizable creation of job opportunities. Authorities need to be proactive in promoting cycling in order to deliver these benefits. PMID- 29257122 TI - Coinfection with Epstein-Barr Virus (EBV), Human Papilloma Virus (HPV) and Polyoma BK Virus (BKPyV) in Laryngeal, Oropharyngeal and Oral Cavity Cancer. AB - Most research providing evidence for the role of oncogenic viruses in head and neck squamous cell carcinoma (SCC) development is focused on one type of virus without analyzing possible interactions between two or more types of viruses. The aim of this study was to analyse the prevalence of co-infection with human papillomavirus (HPV), Epstein-Barr virus (EBV) and polyoma BK virus (BKPyV) in oral, oropharyngeal and laryngeal squamous cell carcinomas in Polish patients. The correlations between viral infection, SCC, demographic parameters, evidence of metastases and grading were also investigated. Fresh-frozen tumour tissue samples were collected from 146 patients with laryngeal, oropharyngeal and oral cancer. After DNA extraction, the DNA of the studied viruses was detected using polymerase chain rection (PCR) assay. Males (87.7%) with a history of smoking (70.6%) and alcohol abuse (59.6%) prevailed in the studied group. Histological type G2 was recognized in 64.4% cases. The patients were most frequently diagnosed with T2 stage (36.3%) and with N1 stage (45.8%). Infection with at least two viruses was detected in 56.2% of patients. In this group, co-infection with HPV/EBV was identified in 34.1% of cases, EBV/BKV in 23.2%, HPV/BKV in 22.0%, and HPV/EBV/BKV in 20.7%. No difference of multiple infection in different locations of cancer was observed. The prevalence of poorly differentiated tumours (G3) was more frequent in co-infection with all three viruses than EBV or BKV alone. A significant correlation was observed between tumour dimensions (T) and lymph-node involvement (N) in co-infected patients compared to single infection. Further studies are necessary to clarify whether co-infection plays an important role in the initiation and/or progression of oncogenic transformation of oral, oropharyngeal and laryngeal epithelial cells. PMID- 29257123 TI - A Chemical Genetics Strategy that Identifies Small Molecules which Induce the Triple Response in Arabidopsis. AB - To explore small molecules with ethylene-like biological activity, we conducted a triple response-based assay system for chemical library screening. Among 9600 compounds, we found N-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]-N-methyl-2 naphthalenesulfonamide (EH-1) displayed promising biological activity on inducing a triple response in Arabidopsis seedlings. Chemical synthesis and structure activity relationship (SAR) analysis of EH-1 analogues with different substitution patterns on the phenyl ring structure of the sulfonamide group indicated that 3,4-dichloro-N-methyl-N-(1,3,5-trimethyl-1H-pyrazol-4-yl-methyl) benzenesulfonamide (8) exhibits the most potent biological activity. To determine the mechanism of action, we conducted RNA sequencing (RNA-Seq) analysis of the effect of EH-1 and 1-aminocyclopropane-1-carboxylate (ACC), the precursor of ethylene biosynthesis, following the quantitative real-time polymerase chain reaction (RT-PCR) confirmation. Data obtained from RNA-Seq analysis indicated that EH-1 and ACC significantly induced the expression of 39 and 48 genes, respectively (above 20 fold of control), among which five genes are up-regulated by EH-1 as well as by ACC. We also found 67 and 32 genes that are significantly down-regulated, respectively, among which seven genes are in common. For quantitative RT-PCR analysis. 12 up-regulated genes were selected from the data obtained from RNA-Seq analysis. We found a good correlation of quantitative RT PCR analysis and RNA-Seq analysis. Based on these results, we conclude that the action mechanism of EH-1 on inducing triple response in Arabidopsis is different from that of ACC. PMID- 29257125 TI - Automatized image processing of bovine blastocysts produced in vitro for quantitative variable determination. AB - There is currently no objective, real-time and non-invasive method for evaluating the quality of mammalian embryos. In this study, we processed images of in vitro produced bovine blastocysts to obtain a deeper comprehension of the embryonic morphological aspects that are related to the standard evaluation of blastocysts. Information was extracted from 482 digital images of blastocysts. The resulting imaging data were individually evaluated by three experienced embryologists who graded their quality. To avoid evaluation bias, each image was related to the modal value of the evaluations. Automated image processing produced 36 quantitative variables for each image. The images, the modal and individual quality grades, and the variables extracted could potentially be used in the development of artificial intelligence techniques (e.g., evolutionary algorithms and artificial neural networks), multivariate modelling and the study of defined structures of the whole blastocyst. PMID- 29257124 TI - Genome Editing Tools in Plants. AB - Genome editing tools have the potential to change the genomic architecture of a genome at precise locations, with desired accuracy. These tools have been efficiently used for trait discovery and for the generation of plants with high crop yields and resistance to biotic and abiotic stresses. Due to complex genomic architecture, it is challenging to edit all of the genes/genomes using a particular genome editing tool. Therefore, to overcome this challenging task, several genome editing tools have been developed to facilitate efficient genome editing. Some of the major genome editing tools used to edit plant genomes are: Homologous recombination (HR), zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), pentatricopeptide repeat proteins (PPRs), the CRISPR/Cas9 system, RNA interference (RNAi), cisgenesis, and intragenesis. In addition, site-directed sequence editing and oligonucleotide directed mutagenesis have the potential to edit the genome at the single nucleotide level. Recently, adenine base editors (ABEs) have been developed to mutate A-T base pairs to G-C base pairs. ABEs use deoxyadeninedeaminase (TadA) with catalytically impaired Cas9 nickase to mutate A-T base pairs to G-C base pairs. PMID- 29257127 TI - ANI-1, A data set of 20 million calculated off-equilibrium conformations for organic molecules. AB - One of the grand challenges in modern theoretical chemistry is designing and implementing approximations that expedite ab initio methods without loss of accuracy. Machine learning (ML) methods are emerging as a powerful approach to constructing various forms of transferable atomistic potentials. They have been successfully applied in a variety of applications in chemistry, biology, catalysis, and solid-state physics. However, these models are heavily dependent on the quality and quantity of data used in their fitting. Fitting highly flexible ML potentials, such as neural networks, comes at a cost: a vast amount of reference data is required to properly train these models. We address this need by providing access to a large computational DFT database, which consists of more than 20 M off equilibrium conformations for 57,462 small organic molecules. We believe it will become a new standard benchmark for comparison of current and future methods in the ML potential community. PMID- 29257128 TI - A dataset for preparing pristine graphene-palladium nanocomposites using swollen liquid crystal templates. AB - Pristine graphene (G) has not received much attention as a catalyst support, presumably due to its relative inertness as compared to reduced graphene oxide (RGO). In the present work, we used swollen liquid crystals (SLCs) as nano reactors for graphene-palladium nanocomposites synthesis. The 'soft' confinement of SLCs directs the growth of palladium (Pd) nanoparticles over the G sheets. In this dataset we include all the parameters and details of different techniques used for the characterization of G, SLCs and synthesized G-Pd nanocomposites. The synthesized G-palladium nanocomposites (Pd-G) exhibited improved catalytic activity compared with Pd-RGO and Pd nanoparticles, in the hydrogenation of nitrophenols and C-C coupling reactions. PMID- 29257126 TI - An open resource for transdiagnostic research in pediatric mental health and learning disorders. AB - Technological and methodological innovations are equipping researchers with unprecedented capabilities for detecting and characterizing pathologic processes in the developing human brain. As a result, ambitions to achieve clinically useful tools to assist in the diagnosis and management of mental health and learning disorders are gaining momentum. To this end, it is critical to accrue large-scale multimodal datasets that capture a broad range of commonly encountered clinical psychopathology. The Child Mind Institute has launched the Healthy Brain Network (HBN), an ongoing initiative focused on creating and sharing a biobank of data from 10,000 New York area participants (ages 5-21). The HBN Biobank houses data about psychiatric, behavioral, cognitive, and lifestyle phenotypes, as well as multimodal brain imaging (resting and naturalistic viewing fMRI, diffusion MRI, morphometric MRI), electroencephalography, eye-tracking, voice and video recordings, genetics and actigraphy. Here, we present the rationale, design and implementation of HBN protocols. We describe the first data release (n=664) and the potential of the biobank to advance related areas (e.g., biophysical modeling, voice analysis). PMID- 29257129 TI - Verification of Arabidopsis stock collections using SNPmatch, a tool for genotyping high-plexed samples. AB - Large-scale studies such as the Arabidopsis thaliana '1,001 Genomes' Project require routine genotyping of stocks to avoid sample contamination. To genotype samples efficiently and economically, sequencing must be inexpensive and data processing simple. Here we present SNPmatch, a tool that identifies strains (or inbred lines, or accessions) by matching them to a SNP database. We tested the tool by performing low-coverage resequencing of over 2,000 strains from our lab seed stock collection. SNPmatch correctly genotyped samples from 1-fold coverage sequencing data, and could also identify the parents of F1 or F2 individuals. SNPmatch can be run either on the command line or through AraGeno (https://arageno.gmi.oeaw.ac.at), a web interface that permits sample genotyping from a user-uploaded VCF or BED file. PMID- 29257130 TI - Neural progenitor fate decision defects, cortical hypoplasia and behavioral impairment in Celsr1-deficient mice. AB - The development of the cerebral cortex is a tightly regulated process that relies on exquisitely coordinated actions of intrinsic and extrinsic cues. Here, we show that the communication between forebrain meninges and apical neural progenitor cells (aNPC) is essential to cortical development, and that the basal compartment of aNPC is key to this communication process. We found that Celsr1, a cadherin of the adhesion G protein coupled receptor family, controls branching of aNPC basal processes abutting the meninges and thereby regulates retinoic acid (RA) dependent neurogenesis. Loss-of-function of Celsr1 results in a decreased number of endfeet, modifies RA-dependent transcriptional activity and biases aNPC commitment toward self-renewal at the expense of basal progenitor and neuron production. The mutant cortex has a reduced number of neurons, and Celsr1 mutant mice exhibit microcephaly and behavioral abnormalities. Our results uncover an important role for Celsr1 protein and for the basal compartment of neural progenitor cells in fate decision during the development of the cerebral cortex. PMID- 29257131 TI - Differential effects of chronic stress in young-adult and old female mice: cognitive-behavioral manifestations and neurobiological correlates. AB - Stress-related psychopathology is highly prevalent among elderly individuals and is associated with detrimental effects on mood, appetite and cognition. Conversely, under certain circumstances repeated mild-to-moderate stressors have been shown to enhance cognitive performance in rodents and exert stress inoculating effects in humans. As most stress-related favorable outcomes have been reported in adolescence and young-adulthood, this apparent disparity could result from fundamental differences in how aging organisms respond to stress. Furthermore, given prominent age-related alterations in sex hormones, the effect of chronic stress in aging females remains a highly relevant yet little studied issue. In the present study, female C57BL/6 mice aged 3 (young-adult) and 20-23 (old) months were subjected to 8 weeks of chronic unpredictable stress (CUS). Behavioral outcomes were measured during the last 3 weeks of the CUS protocol, followed by brain dissection for histological and molecular end points. We found that in young-adult female mice, CUS resulted in decreased anxiety-like behavior and enhanced cognitive performance, whereas in old female mice it led to weight loss, dysregulated locomotion and memory impairment. These phenotypes were paralleled by differential changes in the expression of hypothalamic insulin and melanocortin-4 receptors and were consistent with an age-dependent reduction in the dynamic range of stress-related changes in the hippocampal transcriptome. Supported by an integrated microRNA (miRNA)-mRNA expression analysis, the present study proposes that, when confronted with ongoing stress, neuroprotective mechanisms involving the upregulation of neurogenesis, Wnt signaling and miR-375 can be harnessed more effectively during young-adulthood. Conversely, we suggest that aging alters the pattern of immune activation elicited by stress. Ultimately, interventions that modulate these processes could reduce the burden of stress-related psychopathology in late life. PMID- 29257132 TI - A curated mammography data set for use in computer-aided detection and diagnosis research. AB - Published research results are difficult to replicate due to the lack of a standard evaluation data set in the area of decision support systems in mammography; most computer-aided diagnosis (CADx) and detection (CADe) algorithms for breast cancer in mammography are evaluated on private data sets or on unspecified subsets of public databases. This causes an inability to directly compare the performance of methods or to replicate prior results. We seek to resolve this substantial challenge by releasing an updated and standardized version of the Digital Database for Screening Mammography (DDSM) for evaluation of future CADx and CADe systems (sometimes referred to generally as CAD) research in mammography. Our data set, the CBIS-DDSM (Curated Breast Imaging Subset of DDSM), includes decompressed images, data selection and curation by trained mammographers, updated mass segmentation and bounding boxes, and pathologic diagnosis for training data, formatted similarly to modern computer vision data sets. The data set contains 753 calcification cases and 891 mass cases, providing a data-set size capable of analyzing decision support systems in mammography. PMID- 29257134 TI - Long-read sequencing of the human cytomegalovirus transcriptome with the Pacific Biosciences RSII platform. AB - Long-read RNA sequencing allows for the precise characterization of full-length transcripts, which makes it an indispensable tool in transcriptomics. The human cytomegalovirus (HCMV) genome has been first sequenced in 1989 and although short read sequencing studies have uncovered much of the complexity of its transcriptome, only few of its transcripts have been fully annotated. We hereby present a long-read RNA sequencing dataset of HCMV infected human lung fibroblast cells sequenced by the Pacific Biosciences RSII platform. Seven SMRT cells were sequenced using oligo(dT) primers to reverse transcribe poly(A)-selected RNA molecules and one library was prepared using random primers for the reverse transcription of the rRNA-depleted sample. Our dataset contains 122,636 human and 33,086 viral (HMCV strain Towne) reads. The described data include raw and processed sequencing files, and combined with other datasets, they can be used to validate transcriptome analysis tools, to compare library preparation methods, to test base calling algorithms or to identify genetic variants. PMID- 29257135 TI - Take-off engine particle emission indices for in-service aircraft at Los Angeles International Airport. AB - We present ground-based, advected aircraft engine emissions from flights taking off at Los Angeles International Airport. 275 discrete engine take-off plumes were observed on 18 and 25 May 2014 at a distance of 400 m downwind of the runway. CO2 measurements are used to convert the aerosol data into plume-average emissions indices that are suitable for modelling aircraft emissions. Total and non-volatile particle number EIs are of order 1016-1017 kg-1 and 1014-1016 kg-1, respectively. Black-carbon-equivalent particle mass EIs vary between 175-941 mg kg-1 (except for the GE GEnx engines at 46 mg kg-1). Aircraft tail numbers recorded for each take-off event are used to incorporate aircraft- and engine specific parameters into the data set. Data acquisition and processing follow standard methods for quality assurance. A unique aspect of the data set is the mapping of aerosol concentration time series to integrated plume EIs, aircraft and engine specifications, and manufacturer-reported engine emissions certifications. The integrated data enable future studies seeking to understand and model aircraft emissions and their impact on air quality. PMID- 29257136 TI - Assembly of an early-matured japonica (Geng) rice genome, Suijing18, based on PacBio and Illumina sequencing. AB - The early-matured japonica (Geng) rice variety, Suijing18 (SJ18), carries multiple elite traits including durable blast resistance, good grain quality, and high yield. Using PacBio SMRT technology, we produced over 25 Gb of long-read sequencing raw data from SJ18 with a coverage of 62*. Using Illumina paired-end whole-genome shotgun sequencing technology, we generated 59 Gb of short-read sequencing data from SJ18 (23.6 Gb from a 200 bp library with a coverage of 59* and 35.4 Gb from an 800 bp library with a coverage of 88*). With these data, we assembled a single SJ18 genome and then generated a set of annotation data. These data sets can be used to test new programs for variation deep mining, and will provide new insights into the genome structure, function, and evolution of SJ18, and will provide essential support for biological research in general. PMID- 29257138 TI - Proteomic analysis of JAK2V617F-induced changes identifies potential new combinatorial therapeutic approaches. AB - This corrects the article DOI: 10.1038/leu.2017.143. PMID- 29257137 TI - Ash leaf metabolomes reveal differences between trees tolerant and susceptible to ash dieback disease. AB - European common ash, Fraxinus excelsior, is currently threatened by Ash dieback (ADB) caused by the fungus, Hymenoscyphus fraxineus. To detect and identify metabolites that may be products of pathways important in contributing to resistance against H. fraxineus, we performed untargeted metabolomic profiling on leaves from five high-susceptibility and five low-susceptibility F. excelsior individuals identified during Danish field trials. We describe in this study, two datasets. The first is untargeted LC-MS metabolomics raw data from ash leaves with high-susceptibility and low-susceptibility to ADB in positive and negative mode. These data allow the application of peak picking, alignment, gap-filling and retention-time correlation analyses to be performed in alternative ways. The second, a processed dataset containing abundances of aligned features across all samples enables further mining of the data. Here we illustrate the utility of this dataset which has previously been used to identify putative iridoid glycosides, well known anti-herbivory terpenoid derivatives, and show differential abundance in tolerant and susceptible ash samples. PMID- 29257139 TI - Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond. AB - Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed. PMID- 29257140 TI - Effects of Antidepressants on Gastric Function in Patients with Functional Dyspepsia. AB - BACKGROUND: Functional dyspepsia (FD) is a highly prevalent functional bowel disorder. The effects of antidepressant therapy (ADTx) on gastric sensorimotor function in FD patients are poorly understood. AIMS: Determine whether FD and subtypes with abnormalities in gastric function respond differently to ADTx compared to those with normal physiology. METHODS: This multicenter, prospective trial randomized FD patients to 12 weeks of amitriptyline (AMI; 50 mg), escitalopram (ESC; 10 mg), or matching placebo. Demographics, symptoms, psychological distress, gastric emptying, and satiation were measured. Gastric accommodation (GA) using single-photon emission computed tomography imaging was performed in a subset of patients. An intent to treat analysis included all randomized subjects. The effect of treatment on gastric emptying was assessed using ANCOVA. A post hoc appraisal of the data was performed categorizing patients according to the Rome III subgrouping (PDS and EPS). RESULTS: In total, 292 subjects were randomized; mean age=44 yrs. 21% had delayed gastric emptying. Neither antidepressant altered gastric emptying, even in those with baseline delayed gastric emptying. GA increased with ADTx (P=0.02). Neither antidepressant affected the maximal-tolerated volume (MTV) of the nutrient drink test although aggregate symptom scores improved compared to placebo (P=0.04). Patients with the combined EPS-PDS subtype (48%) had a lower MTV on the nutrient drink test compared to the EPS group at baseline (P=0.02). Postprandial bloating improved with both AMI (P=0.03) and ESC (P=0.02). CONCLUSIONS: Amitriptyline (50 mg) improves FD symptoms but does not delay gastric emptying, even in patients with baseline delayed gastric emptying. GA improved with low-dose ADTx; the precise mechanism of action is unknown warranting further study. PMID- 29257142 TI - Using the Rome IV Criteria to Help Manage the Complex IBS Patient. PMID- 29257141 TI - Prediction of Fungal Infection Development and Their Impact on Survival Using the NACSELD Cohort. AB - OBJECTIVES: Bacterial infections are associated with negative outcomes in cirrhosis but fungal infections are being increasingly recognized. The objective of this study is to define risk factors for fungal infection development and impact on 30-day survival. METHODS: In a large, multi-center cirrhotic inpatient cohort, demographics, cirrhosis details, intensive care unit (ICU), organ failures/acute-on-chronic liver failure (ACLF), and 30-day survival were compared between patients without infections and with bacterial infections alone, with those with fungal infections. Variables associated with fungal infection development were determined using multi-variable regression. Ordinal variables (0=no infection, 1=community-acquired bacterial infection, 2=nosocomial bacterial, and 3=fungal infection) were input into a 30-day survival model. RESULTS: A total of 2,743 patients (1,691 no infection, 918 bacterial, and 134 fungal infections) were included. Patients with fungal infection, all of which were nosocomial, were more likely to be admitted with bacterial infections, on spontaneous bacterial peritonitis prophylaxis, and have diabetes and advanced cirrhosis. Bacterial infection types did not predict risk for fungal infections. Multi-variable analysis showed male gender to be protective, whereas diabetes, longer stay, ICU admission, acute kidney injury (AKI), and admission bacterial infection were associated with fungal infection development (area under the curve (AUC)=0.82). Fungal infections were associated with significantly higher ACLF, inpatient stay, ICU admission, and worse 30-day survival. The case fatality rate was 30% with most fungal infections but >50% for fungemia and fungal peritonitis. On a multi-variable analysis, age, AKI, model for end-stage liver disease, ICU admission, and ordinal infection variables impaired survival (P<0.0001, AUC=0.83). CONCLUSIONS: Fungal infections are associated with a poor 30-day survival in hospitalized cirrhotic patients compared with uninfected patients, and those with bacterial infections. Patients with diabetes, AKI, and those with an admission bacterial infection form a high-risk subgroup. PMID- 29257144 TI - Corrigendum: Research to the N-Power: The Strengths of Networked Clinical Collaboration in Spain. AB - This corrects the article DOI: 10.1038/ajg.2017.416. PMID- 29257143 TI - Effects of Interferential Electrical Stimulation Plus Pelvic Floor Muscles Exercises on Functional Constipation in Children: A Randomized Clinical Trial. AB - OBJECTIVES: Functional constipation is a common condition in children. We assessed the effectiveness of combined interferential (IF) electrical stimulation and pelvic floor muscle (PFM) exercises on functional constipation in children. METHODS: We conducted a single-center, double-blind randomized clinical trial study during 2014-2017 in Tehran, Iran. Ninety children, aged 5-13 years, who fulfilled Rome III criteria were enrolled and randomly assigned into two treatment groups. Case group (n=45) underwent IF electrical stimulation and PFM exercises, whereas the control group (n=45) received PFM exercises plus sham stimulation. A complete bowel habit diary (with concerning data on the frequency of defecation per week, stool form, and the number of fecal soiling episodes), a constipation score questionnaire, and a visual pain score were recorded before, after the treatment and 6 months later for all participants. In addition, children in both groups were assessed with a constipation-related quality-of-life questionnaire before, after the end of treatment sessions, and 6 months after the treatment. RESULTS: Treatment success was achieved for 88.4% of children in the case group compared with 43.2% of children in the control group after the treatment (P<0.003). The median constipation score was reduced in both groups, with the cases having significantly lower scores after the treatment (4 vs. 8, P<0.000). Stool form normalized in 75.6% of the cases and 45.5% of the controls after the treatment (P<0.01). CONCLUSIONS: Our results showed that using IF electrical stimulation as an adjuvant therapy to the medical and rehabilitation programs significantly boosts the effects of treatment among these patients. PMID- 29257145 TI - Timed Barium Swallow: Diagnostic Role and Predictive Value in Untreated Achalasia, Esophagogastric Junction Outflow Obstruction, and Non-Achalasia Dysphagia. AB - OBJECTIVES: Timed barium swallow (TBS) assesses esophageal emptying in patients with achalasia and is considered the standard workup for patients with dysphagia. Our aim was to determine the usefulness of TBS in differentiating patients with achalasia (type 1-3), esophagogastric junction outflow obstruction (EGJOO), and non-achalasia dysphagia. METHODS: We performed a retrospective cohort study including consecutive patients who underwent TBS evaluation between May 2013 and September 2015. Patients were separated into untreated achalasia (n=117), EGJOO (n=46), and non-achalasia (n=146) groups. Diagnosis of achalasia/EGJOO was based on high-resolution manometry using Chicago Classification. Receiver operating characteristic (ROC) curve analysis was performed to determine the accuracy of TBS (barium height at 1 and 5 min and tablet retention) in identifying achalasia vs. EGJOO and non-achalasia. RESULTS: Barium column height of 5 cm at 1 min showed a sensitivity of 94% and specificity of 71% and barium column height of 2 cm at 5 min showed a sensitivity of 85% and specificity of 86% in differentiating untreated achalasia from EGJOO and non-achalasia. Combined liquid barium and tablet increases diagnostic yield from 79.5 to 100% in untreated achalasia patients and from 48.9 to 60% in EGJOO patients. CONCLUSIONS: TBS is a simple and useful test in differentiating untreated achalasia, EGJOO, and non-achalasia dysphagia. We propose that barium height >2 cm at 5 min be used as cutoff point for identifying achalasia. Combination of liquid barium and tablet increased the diagnostic yield of TBS in achalasia and EGJOO. Retention of barium tablet alone suggests functional/anatomic obstruction at the esophagogastric junction. PMID- 29257146 TI - Platelet Count Does Not Predict Bleeding in Cirrhotic Patients: Results from the PRO-LIVER Study. AB - OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ~4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64+/-37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count <=50 * 103/MUl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients. PMID- 29257147 TI - Utility of Magnetic Resonance Enterography For Small Bowel Endoscopic Healing in Patients With Crohn's Disease. AB - OBJECTIVES: Small bowel (SB) endoscopic healing has not been well studied in patients with Crohn's disease (CD). This study aims to evaluate the utility of magnetic resonance (MR) enterography (MRE) for SB lesions in comparison with balloon-assisted enteroscopy (BAE) findings. METHODS: In total, 139 patients with CD in clinical-serological remission were prospectively followed after BAE and MRE procedures. We applied a modified version of the Simple Endoscopic Score for CD (SES-CD) for an endoscopic evaluation of the SB, called the Simple Endoscopic Active Score for CD (SES-CDa). We also used the MR index of activity (MaRIA) for MR evaluations. The primary end points were time to clinical relapse (CD activity index of >150 with an increase of >70 points) and serological relapse (abnormal elevation of C-reactive protein). RESULTS: Clinical and serological relapses occurred in 30 (21.6%) and 62 (44.6%) patients, respectively. SB endoscopic healing (SES-CDa<5) was observed in 76 (54.7%) patients. A multiple regression analysis showed that the lack of SB endoscopic healing was an independent risk factor for clinical relapses (hazard ratio (HR): 5.34; 95% confidence interval (CI): 2.06-13.81) and serological relapses (HR: 3.02; 95% CI: 1.65-5.51), respectively. MR ulcer healing (MaRIA score <11) demonstrated a high diagnostic accuracy (90.9%; 95% CI: 87.9-93.2%) for endoscopic healing. The kappa coefficient between BAE and MRE for longitudinal responsiveness was 0.754 (95% CI: 0.658-0.850) for clinical relapse and 0.783 (95% CI: 0.701-0.865) for serological relapse. CONCLUSIONS: SB inflammation was associated with a poor prognosis in patients with clinical-serological remission. MRE is a valid and reliable examination for SB inflammatory activity both for cross-sectional evaluations and prognostic prediction. PMID- 29257148 TI - Corrigendum: Surgical Rates for Crohn's Disease Are Decreasing: A Population Based Time Trend Analysis and Validation Study. AB - This corrects the article DOI: 10.1038/ajg.2017.394. PMID- 29257149 TI - Corrigendum: Accuracy and Safety of the Cytosponge for Assessing Histologic Activity in Eosinophilic Esophagitis: A Two-Center Study. AB - This corrects the article DOI: 10.1038/ajg.2017.244. PMID- 29257150 TI - [Prognostic importance of cross-linked fibrin degradation products (D-dimer) in oncology]. AB - Cross-linked fibrin degradation products (D-dimer) are formed in two ways: on the one hand through coagulation cascade and on the other hand through fibrinolytic cascade. In the former case, plasmin cleaves the soluble cross-linked fibrin, and in the latter it cleaves the non-soluble cross-linked fibrin. In patients with malignant diseases, several factors influence the clinical evaluation of the result of D-dimer assay. First, D-dimer level can be elevated in cancer patients without thrombosis, which can be explained by procoagulant factors produced by malignant cells. Second, none of the algorithms used for diagnosing venous thromboembolism have been validated on patients with malignant diseases. Furthermore, the negative predictive value of D-dimer on thrombosis or thromboembolism is lower in cancer patients comparing to those who are not suffering from malignant disease. In patients with malignant disease, where venous thrombosis has not been proven, higher D-dimer level correlates with shorter survival. Based on the available data of the literature, the authors summarize some important studies which revealed the relationship between baseline D-dimer level and prognosis in cancer patients. PMID- 29257151 TI - [Pathogenic alterations within the neurofibromin gene in various cancers]. AB - The product of the neurofibromin gene (NF1) belongs to the family of tumor suppressor proteins. Neurofibromin plays important roles in the negative regulation of signaling pathways where the Ras oncogen is involved. The protein and gene names were derived from the disease, neurofibromatosis type 1 that is caused by germline mutations in NF1 and inherited by an autosomal dominant manner. Besides germline mutations, acquired, somatic mutations are also observed in NF1 in several malignant and benign tumors. NF1 mutations have been identified in a great number of solid tumors, leukemias and malignant skin lesions (e.g. melanoma). Such mutations define certain subsets of gliomas. More specifically, a molecular subset of glioblastomas, termed the mesenchymal subtype, is most frequently associated with somatic NF1 deletions and mutations. The aim of this survey is to provide an overview of the most frequent alterations in the NF1 gene with their effects on the function of the protein and the biology of the cell, as well as of the resultant diseases. Simultaneously, we give some insight into ongoing research studies investigating abnormalities of NF1. PMID- 29257152 TI - [Laparoscopic resection of giant hepatocellular carcinoma and the Barcelona staging]. AB - Liver resection is the most effective treatment for hepatocellular carcinoma, however, decision for surgery remained confusing. In Europe the most accepted Barcelona staging system sets minimal value on surgical interventions. Long lasting diagnostic steps and uncertainty for indication of resection are possible consequences of this approach. The reported case is an example for the fact that exceptionally large tumor having been grown during time-consuming diagnostic attempts might be removed by laparoscopic surgery. The case hopefully could lead to widespread acceptance of up-to-date surgical treatment of hepatocellular carcinoma. PMID- 29257133 TI - Sequence data and association statistics from 12,940 type 2 diabetes cases and controls. AB - To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D. PMID- 29257153 TI - [Health-related quality of life from a new perspective - The role of illness representations in patients with breast cancer]. AB - In the modern oncology care the subject of quality of life has an emphasized importance. In our research we assessed aspects which may predict the quality of life. We hypothesized that after controlling the demographical and some medical factors, psychological distress and illness representations would have significant roles as predictors. The research has been carried out in Budapest at the Radiology Diagnostic Department of the National Institute of Oncology; participants were women (N=221) treated for malignant breast tumour (C50). The research tools included the Shortened Beck Depression Inventory, Quality of Life Questionnaire (EORTC QLQ-C30, QLQBR23), Spielberger's State-Trait Anxiety Inventory (STAI-T), and the Revised Illness Perception Questionnaire (IPQ-R). In terms of functional (beta=-0.705, p=0.000; beta=0.493, p=0.003), and symptom quality of life (beta=0.517, p=0.000) negative affectivity has an outstanding role as predictor. Among the illness representations, the functional quality of life is influenced by cognitions concerning the illness consequences (beta=0.243, p=0.008) and by emotional representations (beta=0.220, p=0.034). Cognitive representations influencing the symptom quality of life are serious consequences (beta=0.240, p=0.016) and illness perception (beta=0.212, p=0.011). In the improvement of quality of life, treating negative affectivity has determining and the modification of dysfunctional illness cognitions play important roles. PMID- 29257154 TI - [The post-treatment cognitive impairment ("chemobrain") in breast cancer patients. Short review.] AB - With the continually growing number of cancer survivors in the past decades there is an increased interest in understanding and treating the adverse events of cancer therapy, which damage the survivor's quality of life. Post-treatment cognitive impairment (chemobrain) is well known in women with breast cancer and other patients with malignancy. The goal of the current short review is to arouse the caregivers' attention to the not severe, but real problem. PMID- 29257155 TI - [Experience with cabazitaxel therapy for patients with metastatic castrate resistant prostate cancer in Hungary]. AB - Our aim was to assess the efficacy and adverse effects of cabazitaxel (CBZ), a chemotherapeutic agent that can be administered to patients with metastatic castrate resistant prostate cancer (mCRPC) after docetaxel (DOC) therapy. We retrospectively analyzed data of CBZ received by mCRPC patients in 12 Hungarian oncological centers between 01/2016 and 06/2017. CBZ (25 or 20 mg/m2 q3w) was administered after DOC. Physical and laboratory examinations were performed in every cycle, tumor response was evaluated in every third cycle based on PCWG2 criteria. Adverse effects were evaluated based on CTCAE 4.0. Data of 60 patients were analyzed. CBZ was administered in 2nd and 3rd lines in 31.6% and 46.6%, while in 4th and 5th lines in 15% and 6.6% patients, respectively. Its starting dose was 25 mg/m2 and 20 mg/m2 in 65% and 35% of cases, respectively. The median number of cycles was 5. Progression-free survival and overall survival were 5.52 and 15.77 months, respectively. Survival results were similar in case of DOC-CBZ ART/alfaradin and DOC-ART/alfaradin-CBZ sequences. Adverse effects were detected in 63,3% of patients. The most common adverse effects were neutropenia, anemia, and diarrhea. Our observations suggest that CBZ, with the appropriate support and chemotherapeutic experience, is well-tolerated and effective therapy of mCRPC after DOC. PMID- 29257156 TI - [Quality and performance indicators of the pilot program for cervical cancer screening by health visitors]. AB - The aim of our analysis was the assessment of the qualitative and performance indicators of a pilot program for health visitors' cervical cancer screening. The analysis involved the data from the Communication module of the Office of the National Chief Medical Officer. In the examined period (October, 2013 - September, 2015) the participation indicators of women aged 25-65, the prevalence rates of human papillomavirus and the cervical intraepithelial neoplasia were determined. In the screening period, the call-in rate was 32.45% nationally, with the compliance of 8.26%. The occurrence of a positive result was 1.85% nationally, with the highest rate in Hajdu-Bihar county (7.24%). HPV infection was detected in 113 cases (0.45%) nationally, HPV prevalence was 37.44/100,000 persons. The willingness for participation among women was low concerning the indicators. Their raising should be an emphasized task for public health in favor of reducing mortality from morbidities. PMID- 29257157 TI - [Epidemiology of soft tissue sarcomas in a university center in Hungary]. AB - Our aim was to investigate the rare malignant soft tissue sarcomas responsible for 1.5% of all malignant tumors, to compare our epidemiological data from the patient population of the Department of Orthopaedics, Semmelweis University, to data described in the international literature for soft tissue tumors. We reviewed 595 cases of primary soft tissue sarcomas treated between 1994 and 2014 and compared results to international data from the literature. Our results were similar to those found in the international literature: mean age, mild male predominance, the most common sarcoma subgroups, the superficial and deep sarcoma ratio, low and high grade sarcoma ratio, the ratio of patients with a primary lung metastasis. Compared to other European data we found significantly longer patient referral to centers (3.6 months in case of superficial sarcomas, 8 months in case of deep localization) which surprisingly had no substantial effect on average tumor size (superficial: 5 cm, deep: 10.5 cm). This corresponds with data from the literature. The long delay period in patients' request of medical service draws attention to difficulties in differential diagnosis in this rare type of tumor, delays in referring patients to a center, and the lack of consultation. We recommend that the required investigations be performed in a musculoskeletal oncology center where this type of cancer is treated. PMID- 29257158 TI - [Anticancer drug research in Hungary, 1950-2000]. AB - The present review about the history of anticancer drug research in Hungary intends to call attention to the importance of studies on their mode of action. Several lines of evidence suggest that clinically usable oncopharmacological properties could be revealed by this way. Among the numerous compounds certain alkylating sugar alcohols and 2'-deoxyuridine derivatives were submitted to detailed investigations concerning their mode of action. Myelobromol with selective action on the myeloid elements of bone marrow has been justified for its application in chronic myeloid leukemia therapy and also in bone marrow ablation before transplantation. Mitolactol is able to cross bloodbrain barrier, consequently could control certain brain tumors. 5-etil-2'-deoxyuridine by reducing dihydropyrimidine dehydrogenase activity is able to increase 5 fluorouracil concentration in the blood, resulting in improved antitumor effect. In contrast, 5-hexil-2'-deoxyuridine, as an inhibitor of glycoconjugate pathway by reducing heparan sulfate production, has the ability to prevent metastasis. Noteworthy, the remarkable effects of vinca alkaloids, antiestrogens, and GNRH analogues were also presented in this review. PMID- 29257159 TI - [Stereotactic ablative body radiotherapy (SABRT) for locally advanced pancreatic cancer. Case report and review of literature]. AB - Pancreatic cancer has one of the worst outcomes among malignant tumors. At the time of diagnosis only 20% of the cases are resectable and 30-50% are locally advanced, when curative intervention cannot be performed. After resection local relapse occurs in 20-60%, and in 30% it is the reason of death. This latter highlights the importance of local control. However, there have been no convincing results with conformal radiation therapy and radiochemotherapy yet. Adjuvant radiochemotherapy has been settled into the routine in the US, but not in Europe and Asia and only sporadic data are available about neoadjuvant radiotherapy. Based on the result of recent studies, conformal radiation therapy does not seem to become part of the standard treatment of locally advanced disease. Radiation resistance, long treatment time and incompatibility with the most advanced chemotherapy regimens may make conformal radiotherapy ineffective. Stereotactic ablative body radiotherapy (SABRT) when a limited target volume is irradiated in few fractions, with high precision and high biological effective dose, is ablative for the tumor and could be a possible solution for this issue. In our report, we describe to our knowledge the first SABRT for locally advanced pancreatic cancer in Hungary and give a short literature review. PMID- 29257160 TI - Nanoparticles of metal-organic cages designed to encapsulate platinum-based anticancer agents. AB - We present a novel design to use metal-organic cages (MOCs) to encapsulate Pt based anticancer agents for delivery. A fluorescein-conjugated Pt(iv) prodrug of cisplatin is developed for its encapsulation in a cationic MOC via host-guest interactions, which then forms drug-loaded nanoparticles with an anionic polymer. PMID- 29257161 TI - Induced chirality of cage metal complexes switched by their supramolecular and covalent binding. AB - An ability of the ribbed-functionalized iron(ii) clathrochelates to induce a CD output in interactions with a protein, covalent bonding or supramolecular interactions with a low-molecular-weight chiral inductor, was discovered. The interactions of CD inactive, carboxyl-terminated iron(ii) clathrochelates with serum albumin induced their molecular asymmetry, causing an appearance of strong CD signals in the range of 350-600 nm, whereas methyl ester and amide clathrochelate derivatives remained almost CD inactive. The CD spectra of carboxyl-terminated clathrochelates on supramolecular interactions or covalent bonding with (R)-(+)-1-phenylethylamine gave a substantially lower CD output than with albumin, affected by both the solvent polarity and the isomerism of clathrochelate's ribbed substituents. In supramolecular assemblies, the bands were most intensive for ortho-substituted carboxyl-terminated clathrochelates. The ortho- and meta-phenylethylamide cage complexes in tetrachloromethane inverted the signs of their CD bands compared with those in acetonitrile. It was suggested that the tris-dioximate metal clathrochelates possess a Russian doll like molecular system. Because of the distorted TP-TAP geometry, their coordination polyhedron had no inversion centre and possessed an inherent chirality together with the equiprobability of its left(Lambda)- and right(Delta) handle twists. The selective fixation of one of these C3-distorted conformations resulted in the appearance of the CD signal in the range of their visible metal to-ligand charge transfer bands. Calculations by DFT methods were used to illustrate the possible conformations of the macrobicyclic molecules, as well as the intramolecular interactions between the cage framework and optically active distal substituents responsible for the chirality induction of the metal-centred coordination polyhedra. PMID- 29257162 TI - Is secondary organic aerosol yield governed by kinetic factors rather than equilibrium partitioning? AB - The numerical description of the formation of secondary organic aerosol (SOA) in the atmosphere relies on the use of particle yields, which are often determined in chamber experiments. What is sometimes not appreciated is that such yields (i) can be defined in different ways and (ii) depend on atmospheric conditions. Here we show with the help of hypothetical scenario simulations that the differential SOA yield upon addition of oxidation products to an atmosphere already containing such products and SOA is more relevant in the ambient atmosphere than the commonly used integrative yield from chamber studies. Furthermore, we suggest that the SOA formation scenarios that have been studied so far comprise merely a subset of possible atmospheric situations. In particular, while in the standard scenarios factors such as volatility and aerosol loading are important, scenarios can be envisaged where these factors become less important while the differential yield approaches unity for all oxidation products. Finally, we suggest aerosol growth in the atmosphere should be seen as being determined by a dynamic situation arising from many simultaneously occurring kinetic processes rather than a thermodynamic equilibrium process. PMID- 29257163 TI - Enhancement of visible-light-driven CO2 reduction performance using an amine functionalized zirconium metal-organic framework. AB - By employing a conjugated amine-functionalized dicarboxylic ligand (H2L = 2,2' diamino-4,4'-stilbenedicarboxylic acid, H2SDCA-NH2), we have successfully synthesized and characterized a porous and visible light responsive zirconium metal-organic framework ([Zr6O4(OH)4(L)6].8DMF, denoted as Zr-SDCA-NH2). This Zr MOF showed good chemical stability and broad visible light absorption with an absorption edge at about 600 nm. When used as a photocatalyst, Zr-SDCA-NH2 exhibits visible-light activity for CO2 reduction with a formate formation rate of 96.2 MUmol h-1 mmolMOF-1, which is higher than the series of reported amine functionalized Zr-MOFs. Mott-Schottky measurements, photoluminescence study and photocatalytic experiments demonstrated that the Zr6 oxo cluster through the LMCT process and the organic ligand both contributed to the CO2 photoreduction. This study indicates that the combination of amino groups and highly conjugated molecules is a feasible and simple strategy to extend light absorption of the organic ligand, which is beneficial for designing a visible light responsive MOF photocatalyst. PMID- 29257181 TI - Critical Assessment of an Ocular Photoscreener. AB - PURPOSE: To determine the accuracy of the PlusoptiX A12 photoscreener (PlusoptiX, Inc., Atlanta, GA) in detecting amblyopia or ambylogenic risk factors in pediatric patients in Nebraska. METHODS: Using the PlusoptiX A12 photoscreener, data were collected from pediatric patients seen at a single pediatric ophthalmology practice. Each patient was screened using the device and also received a comprehensive ophthalmic examination. The results of the PlusoptiX A12 photoscreener were compared to the gold standard, comprehensive ophthalmic examination findings. The assessment of amblyopia or amblyogenic risk factors in the patients was based on the updated American Association for Pediatric Ophthalmology and Strabismus (AAPOS) referral criteria guidelines. RESULTS: Data were collected from 219 consecutive pediatric patients (438 eyes) during the 3 month study period. Among the patients, 87 (40%) children were determined to have amblyopia or ambylogenic risk factors after the comprehensive pediatric ophthalmology examination based on the AAPOS guidelines. The PlusoptiX A12 photoscreener was found to have a sensitivity of 93.02%, specificity of 84.96%, false-positive rate of 9.13%, false-negative rate of 2.74%, positive predictive value of 80.00%, and negative predictive value of 94.96%. CONCLUSIONS: The PlusoptiX A12 photoscreener is viable and comparable to various commercially available devices in the detection of refractive amblyogenic risk factors based on the Nebraska pediatric patient population. Future studies may show increased sensitivity by combining the use of the PlusoptiX A12 photoscreener with an alternate cover test. [J Pediatr Ophthalmol Strabismus. 2018;55(3):194-199.]. PMID- 29257182 TI - Rigid Gas Permeable Contact Lens as a Vision-Sparing Tool in Children After Traumatic Corneal Laceration. AB - PURPOSE: To evaluate the clinical value of rigid gas permeable contact lenses in children after traumatic corneal scarring. METHODS: This comparative study included 15 children (age range: 5.7 to 14 years; mean +/- standard deviation = 9.4 +/- 2.9 years) with corneal scars and best corrected visual acuity (BCVA) of worse than 20/20, history of penetrating ocular trauma, and/or cataract extraction. All children were advised to wear spherical rigid gas permeable contact lenses for 6 months with a special regimen. Visual acuity was compared before and after fitting. The total and anterior surface aberrations of all children were measured using a corneal topographer before and after treatment. RESULTS: There was a significant improvement in the BCVA after wearing rigid gas permeable contact lenses compared to spectacle visual acuity (P = .001). There was also significant improvement of the keratometric astigmatism (P = .001) and corneal aberrations such as higher order aberrations (P = .008), lower order aberrations, root mean square, and point spread function (P = .001). CONCLUSIONS: The optical performance of rigid gas permeable contact lenses has been demonstrated to be effective in the visual rehabilitation of children with traumatic corneal lacerations. Corneal topography was an objective tool for detecting optical disorders. [J Pediatr Ophthalmol Strabismus. 2018;55(3):178 181.]. PMID- 29257183 TI - Retinoblastoma in the United States: A 40-Year Incidence and Survival Analysis. AB - PURPOSE: To determine the incidence of retinoblastoma in the United States from 1973 to 2012 (40 years) and characterize the 5-year overall survival rate of the included patients. METHODS: Cases of retinoblastoma were derived from the Surveillance, Epidemiology, and End Results (SEER) Program (National Cancer Institute, Rockville, MD). Incidence rates were calculated using U.S. Census Bureau data as the standard population, and trends over time were determined using the chi-square test. Hazard ratios with a 95% confidence interval (CI) were estimated for variables associated with mortality using Cox regression models. Survival rates were calculated using the Kaplan-Meier method and compared among different clinical and demographic categories. RESULTS: A total of 879 cases of retinoblastoma were derived from the SEER databases. The annual incidence rates of retinoblastoma for a period of 40 years were 12.14 (95% CI: 11.32 to 12.96) cases per 1 million children 4 years or younger and 0.49 (95% CI: 0.36 to 0.65) cases per 1 million children between the ages of 5 and 9 years. There was no significant trend for children 4 years or younger (P = .6324) or between the ages of 5 and 9 years (P = .7695). The 5-year overall survival rates were 97.6%, 92.7%, 91.1%, and 96.4% for children diagnosed at the first, second, third, and after the third year of life, respectively (P = .0136). The 5-year overall survival rates were 92.5% for bilateral and 96.3% for unilateral cases (P = .0116). The 5-year overall survival rates were 90.8%, 92.5%, 97.6%, 97.3% for increasing time intervals (1973 to 1979, 1980 to 1989, 1990 to 1999, and 2000 to 2012, respectively; P = .0017). CONCLUSIONS: The incidence rate of retinoblastoma in the United States has remained stable for the past 40 years. Survival rate analysis indicates a significant effect of laterality of tumor, age at diagnosis, and decade of diagnosis. [J Pediatr Ophthalmol Strabismus. 2018;55(3):182-188.]. PMID- 29257184 TI - Assessment of an Advanced Vision Screener in the Detection of Amblyopia in the Nebraska Pediatric Population. AB - PURPOSE: To determine the validity of the OPTEC 5500 vision screener (Stereo Optical Co., Inc., Chicago, IL) in assessing visual acuity and amblyopia in pediatric patients between the ages of 3 and 17 years by comparing it statistically to gold standard comprehensive ophthalmic examinations. METHODS: A cross-sectional study was conducted of 64 patients between the ages of 3 and 17 years who underwent a vision screening test at a pediatric ophthalmology office using the OPTEC 5500 vision screener, followed by traditional visual acuity testing via the Snellen or Lea optotypes. After data were collected, the results of the OPTEC 5500 vision screener were compared to the Snellen and Lea visual acuity tests and statistical analysis was subsequently performed for the right and left eyes separately. Patients were considered to have risk factors for amblyopia based on the American Association for Pediatric Ophthalmology and Strabismus referral criteria guidelines. RESULTS: The results of the OPTEC 5500 vision screener for the right eye of participants of all ages were a sensitivity of 77.4%, specificity of 100.0%, positive predictive value of 100.0%, negative predictive value of 50.0%, and accuracy of 81.5%. Results for the left eye were a sensitivity of 81.0%, specificity of 87.0%, positive predictive value of 91.9%, negative predictive value of 71.4%, and accuracy of 83.1%. CONCLUSIONS: Although the specificity and positive predictive value were acceptable, the sensitivity and negative predictive value of the OPTEC 5500 vision screener were below average when compared to other available devices, exhibiting some of the weaknesses of the device. Additional studies of the OPTEC 5500 vision screener with a larger population are necessary to assess the device in the general pediatric population, such as in general pediatric clinics and public schools. Additionally, other options for pediatric vision screening devices should be explored. [J Pediatr Ophthalmol Strabismus. 2018;55(3):189-193.]. PMID- 29257185 TI - Horizontal Deviations in Congenital Brown Syndrome. AB - PURPOSE: To report the incidence of horizontal deviations requiring surgical correction in patients with congenital Brown syndrome. METHODS: In a retrospective study, the medical records of all children who underwent a surgical correction of congenital Brown syndrome at Schneider Children's Medical Center of Israel from 1998 to 2016 were reviewed, analyzing the presence of preoperative primary position horizontal misalignment. RESULTS: Overall, 19 eyes (8 right and 11 left eyes) of 16 patients (7 males, 9 females; mean age: 4.2 +/- 2.6 years) were included in this study. Fourteen patients (88%) had surgery for correction of a compensatory head position, including 8 patients (50%) with a head tilt and 6 patients (38%) with a chin-up position, and 2 patients had surgery for primary position hypotropia. All of them underwent a weakening procedure of the superior oblique tendon, by either Z-tenectomy (81%, n = 13) or suture elongation of the superior oblique tendon (19%, n = 3). Fifty-six percent of patients (n = 9) had primary position horizontal deviation before surgery, including 50% (n = 8) exodeviations, ranging from exophoria of 4 prism diopters (PD) to exotropia of 30 PD, and one esotropia of 14 PD. Fifty percent of patients (n = 8) had surgery to correct the horizontal deviation by a recession of either one (31%, n = 5) or two (19%, n = 3) muscles. Mean preoperative horizontal deviation (9.3 +/- 3.4 PD) decreased significantly following surgery (1.7 +/- 1 PD, P = .001) (paired t test). CONCLUSIONS: Significant horizontal misalignment is often present in patients with congenital Brown syndrome and its correction should be considered at the time of surgery. [J Pediatr Ophthalmol Strabismus. 2018;55(2):113-116.]. PMID- 29257187 TI - Diagnosis and Treatment Options for Achromatopsia: A Review of the Literature. AB - Achromatopsia is a complex inherited retinal disease that affects the cone cell function. It is usually an autosomal-recessive disease and is characterized by pendular nystagmus, poor visual acuity, lack of color vision, and marked photophobia. CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6 gene mutations have been identified as associated with this disease. New diagnostic and therapeutic tools are being studied. Optical coherence tomography and fundus autofluorescence are important imaging techniques that provide significant information about the progression of the disease. The genetic approach for these patients is a current important issue and gene therapy is an ongoing therapeutic option already being studied in clinical trials. The purpose of this review was to survey the current knowledge on diagnosis and treatment options in achromatopsia. [J Pediatr Ophthalmol Strabismus. 2018;55(2):85-92.]. PMID- 29257186 TI - Double Rhomboid Suture Technique for Congenital Ptosis. AB - PURPOSE: Congenital ptosis is a troubling eye condition for pediatric ophthalmologists. There are many considerations to contemplate when deciding when to operate and which technique to use. METHODS: A retrospective chart review of 69 pediatric patients treated for congenital ptosis using a double rhomboid frontalis sling with a nylon suture at a single tertiary care center. RESULTS: For patients with more than 6 months of follow-up, there were 38 patients with 46 primary surgeries (22 [58%] males and 16 [42%] females). The average age at the first surgery was 39.34 +/- 33.18 months. There was a mean follow-up time of 51.87 +/- 53.79 months. There were 7 children who needed one revision and 1 child who needed a second revision, equaling a 23.9% rate of revision. Patients who had surgery before the age of 3 years had a statistically significant likelihood of needing a second surgery (chi-square test = 7.246, P = .007, 95% confidence interval = 0.027 to 0.687). It was also statistically significant (P < .05) that, throughout childhood, older patients were less likely to need a revision. CONCLUSIONS: A double rhomboid frontalis sling using a nylon suture is an effective technique to treat congenital ptosis. This technique is easy to master and has a low cost compared to techniques involving autografts and allografts. It is also important to advise the family of the likelihood of a second surgery if there is a need to operate at a young age. [J Pediatr Ophthalmol Strabismus. 2018;55(2):117-121.]. PMID- 29257188 TI - Monitoring of Callus Maturation and Measurement of Resistance Rates Using Bioelectrical Impedance for Patients Treated With an External Fixator. AB - Evaluation of callus maturation and the decision to remove an external fixator depend on radiographic and clinical findings, which are subjective. Callus fracture or recurrent deformity may occur after premature removal of a fixator. The authors applied a technique to measure bioelectrical impedance to assess callus maturation. This study included 27 limbs that underwent deformity correction or callus distraction using a fixator. Mean patient age at the time of surgery was 17.2 years. Overall impedance during callus maturation was measured from after completion of correction or distraction to removal of the fixator. Temporal changes in impedance values were measured, and maximum and final values were compared with initial values. The resistance rates were compared by age (<15 or >=15 years), correction site (femur or tibia), and treatment method (noncontact or contact). Mean overall impedance increased gradually. Compared with initial values, maximum and final impedance values were 1.21 times and 1.15 times higher, respectively. Resistance rates by age, correction site, and treatment method were significantly higher in patients 15 years and older, in the tibia, and in the contact group, respectively. Overall impedance tended to increase during callus maturation but varied among patients. Therefore, resistance rates were calculated to classify differences for individual patients. Age and treatment method were important predictors of resistance rates. These data by age, correction site, and treatment method, which assume overall impedance from after completion of correction or distraction, can serve as a useful index to determine when a fixator should be removed. [Orthopedics. 2018; 41(1):54-58.]. PMID- 29257189 TI - Risk Factors for Dysphagia After Anterior Cervical Spine Surgery. AB - This study evaluated the risk factors for dysphagia after anterior cervical spine surgery by multidimensional analysis and investigated the predictive values of these risk factors for dysphagia. The patients underwent anterior cervical spine surgery and were followed for at least 6 months. Sex, age, tracheal mobility, smoking history, implant type, C3 anterior vertebral soft tissue swelling, narrowest esophageal distance before internal fixation, cervical curvature, operative time, occurrence of fusion, number of operative segments, and highest vertebral segment were recorded. Chi-square test and logistic regression were performed to analyze the predictive value of each dimension for dysphagia. A total of 158 patients were included in this study. The mean C3 anterior vertebral soft tissue swelling was 8.8+/-4.5 mm, the mean narrowest esophageal distance before internal fixation was 6.9+/-4.4 mm, and the mean operative time was 78.5+/ 39.2 minutes. Chi-square test results showed that age 60 years and older, female sex, internal fixation with titanium plate/titanium mesh, narrowest esophageal distance before internal fixation of less than 5 mm, and 3 operative segments indicated a relatively high incidence of dysphagia. Logistic regression analyses showed that age, sex, implant type, narrowest esophageal distance before internal fixation, and number of operative segments were all risk factors predictive of postoperative dysphagia. The area under the receiver operating characteristic curve was 0.872. Age 60 years and older, female sex, internal fixation with titanium plate/titanium mesh, narrowest esophageal distance before internal fixation of less than 5 mm, and 3 operative segments were risk factors for dysphagia after anterior cervical surgery. The regression equation may be used to predict the occurrence of dysphagia. [Orthopedics. 2018; 41(1):e110-e116.]. PMID- 29257190 TI - Hypertrophy Associated With Vascular Malformations: Analysis of Growth and Results of Epiphysiodesis. AB - Limb-length inequality is a clinical problem in children with hypertrophy associated with vascular malformations. The purpose of this study was to determine a pattern of growth, predict discrepancy at maturity, and evaluate the timing and results of epiphysiodesis. Hypertrophy with vascular malformation, follow-up from childhood until maturity, annual physical examination, and annual orthoroentgenograms and anteroposterior left hand-wrist radiographs were the inclusion criteria. The developmental pattern of the growth discrepancy was established. Limb-length discrepancy and remaining growth were calculated. All 3 patients underwent distal femur or proximal tibia and fibula percutaneous epiphysiodesis. All cases showed the constant upward slope of the developmental pattern of discrepancy until the time of epiphysiodesis. The length of the uninvolved limb at maturity corresponded to the length predicted by the methods that used skeletal age, allowing calculation of the proper timing for epiphysiodesis. The multiplier and the rule of thumb methods failed, with skeletal age not corresponding to chronological age. In these 3 cases, limb length discrepancy was successfully treated with percutaneous epiphysiodesis, and there were no complications. [Orthopedics. 2018; 41(4):e574-e579.]. PMID- 29257191 TI - Adverse Local Tissue Reaction After a Metal-on-Metal Total Hip Prosthesis Without Elevated Serum Metal Ion Levels. AB - In the 1990s, metal-on-metal (MoM) bearings were reintroduced in total hip arthroplasty (THA), having the proposed advantages of decreased wear and improved stability. However, catastrophic adverse local tissue reaction (ALTR) secondary to metal debris from both the bearing surface and the head-neck junction is a well-recognized complication. The measurement of metal ion levels in the serum is often a first-line test to identify failure of a MoM bearing. The authors describe a 70-year-old man who presented with a multiply revised MoM THA and a large periprosthetic fluid collection incidentally seen during computed tomography for renal nephrolithiasis. The patient reported painless, progressive swelling over the lateral aspect of the hip. An infectious workup including serum erythrocyte sedimentation rate, C-reactive protein, and intraarticular hip aspiration yielded negative results. Metal ion levels in the serum, including a minimally elevated cobalt level, were unremarkable, and metal-lymphocyte transformation testing yielded negative results. Radiographic imaging revealed progressive osteolysis around the proximal femur, and magnetic resonance imaging showed large fluid collections with irregular wall thickening surrounding the gluteal and iliopsoas musculature. At revision surgery, a large fluid collection and corrosion at the head-neck junction were present. Pathology specimens confirmed the presence of an ALTR. This report presents a previously undescribed case of an ALTR secondary to MoM THA in the absence of elevated serum metal ion levels. This indicates the necessity of considering all aspects of a patient's clinical presentation, imaging modalities, and laboratory testing in the evaluation and diagnosis of a symptomatic MoM THA. [Orthopedics. 2018; 41(3):e438 e441.]. PMID- 29257192 TI - Schwannoma of the Palmar Cutaneous Branch of the Median Nerve. AB - Peripheral schwannomas are benign tumors originating from the Schwann cells of the peripheral nerve sheath. They make up a small percentage of the overall incidence of tumors of the hand, most commonly involving the ulnar nerve. The authors report a case of a 59-year-old patient with a slowly enlarging mass over his right wrist and no other symptoms. During surgery, a schwannoma involving the palmar cutaneous branch of the median nerve was found and successfully removed. This is a rare clinical entity, with few cases reported in the literature. In the current case, the lesion did not cause significant symptoms, and the authors demonstrated successful surgical enucleation of the lesion without complication. [Orthopedics. 2018; 41(4):e572-e573.]. PMID- 29257193 TI - Left-Biased Clavicle Length Asymmetry in Children and Young Adults 12 to 25 Years Old. AB - Management of clavicle fractures depends in part on the magnitude of shortening compared with the contralateral, intact clavicle. However, estimating prefracture length may be complicated by side-to-side asymmetry. The authors retrospectively reviewed chest radiographs using a ruler tool to measure clavicle length in 696 patients 12 to 25 years old. Absolute and relative least significant change values that represented statistically significant true biological differences were 3.54 mm and 2.44%, respectively. Length differences in which the left was greater than the right or the right was greater than the left exceeding the absolute least significant change were found in 35.2% of males and 39.8% of females. Length differences exceeding 5 mm and 10 mm were 19% and 2.6% in males and 22.6% and 0.9% in females, respectively. There was a statistically significant left bias in length difference, with a 2.1-fold and a 1.6-fold greater chance of the left being longer than the right (although usually <5 mm in actual length) in males and females, respectively. The authors concluded that small but significant left-biased length asymmetry prevailed in both sexes. Differences exceeding 10 mm were rare. Contralateral clavicles can be used to estimate prefracture length of presenting fractures with the understanding that small left-right length discrepancy is common. [Orthopedics. 2018; 41(1):e104 e109.]. PMID- 29257194 TI - Compromise of Radiology Studies From Nonstandardized Viewing Platforms. AB - There is no standardization of proprietary radiology viewing software platform functions allowing recorded digital radiographic imaging studies on compact discs (CDs) to be viewed in a standardized manner at subsequent institutions. Primary concerns include the following: (1) a large number of image viewing software platforms with a wide variety of features making familiarity with use difficult, (2) an inordinate amount of time required to load imaging data, (3) imaging data may not upload or be viewed with the care center's picture archiving and communication system, (4) navigation through imaging studies is inconsistent and tedious, and (5) image viewing requires additional software downloads. Additionally, images generated from "outside CDs" are frequently of low quality and resolution, eliminating the ability to render a reliable diagnosis. The authors sought to determine the frequency and extent of these functional problems by analyzing a sample of 50 consecutive radiology CDs containing imaging studies referred to a university orthopedic oncology practice. Eighteen different viewing software platforms were encountered. Only 24 (48%) of the CDs met all optimal system criteria. Mean time required to load the studies was 3.4 seconds using the picture archiving and communication system and 37.9 seconds using the proprietary viewing software (P<.001). Fifteen (30%) of the CDs did not upload to the institution's picture archiving and communication system, and 18 (36%) required additional downloads and/or license agreements. Four CDs did not contain Digital Imaging and Communications in Medicine images. Physicians using radiology studies on CDs encounter numerous difficulties in evaluating patients' imaging data because of the plethora of viewing software platforms. These difficulties add time and cost and compromise patient care. [Orthopedics. 2018; 41(1):e136-e141.]. PMID- 29257195 TI - Effects of telehealth by allied health professionals and nurses in rural and remote areas: A systematic review and meta-analysis. AB - OBJECTIVE: To describe telehealth interventions delivered by allied health professionals and nurses in rural and remote areas, and to compare the effects of telehealth interventions with standard face-to-face interventions. DATA SOURCES: CINAHL, Embase, PsycINFO and PubMed databases were searched. The content of relevant journals and published articles were also searched. STUDY SELECTION: Studies examining the effectiveness of allied health and nursing telehealth interventions for rural and remote populations were included in descriptive analyses. Studies comparing telehealth intervention with standard face-to-face interventions grouped by type of intervention approach were used to examine between-groups effect sizes. DATA EXTRACTION: Methodological quality of studies was rated using the QualSyst critical appraisal tool and the National Health and Medical Research Council (NHMRC) Evidence Hierarchy levels. DATA SYNTHESIS: After quality ratings, 43 studies were included. A majority of studies had strong methodological quality. The disciplines of psychology and nursing were represented most frequently, as were studies using a cognitive intervention approach. Meta-analysis results slightly favoured telehealth interventions compared with face-to-face interventions, but did not show significant differences. Interventions using a combined physical and cognitive approach appeared to be more effective. CONCLUSION: Telehealth services may be as effective as face-to-face interventions, which is encouraging given the potential benefits of telehealth in rural and remote areas with regards to healthcare access and time and cost savings. PMID- 29257196 TI - Effect of cigarette smoke extract and nicotine on the expression of thrombomodulin and endothelial protein C receptor in cultured human umbilical vein endothelial cells. AB - The present study investigated the influence of cigarette smoke extract (CSE) and nicotine on the expression of thrombomodulin (TM) and endothelial protein C receptor (EPCR) in human umbilical vein endothelial cells (HUVECs). Smoking is associated with intravascular thrombosis. As a vital anticoagulation cofactor, TM is located on the endothelial cell surface and regulates intravascular coagulation by binding to thrombin, hence activating protein C. Activated protein C is a natural anticoagulant that interacts with EPCR to enhance the function of anticoagulation system. The effects of CSE (0.5-5%) and nicotine (10-3-10-9 mol/l) on the expression of TM and EPCR in HUVECs were observed. Reverse transcription-quantitative polymerase chain reaction and flow cytometric analysis techniques were used for detecting TM and EPCR mRNA and protein expression levels, respectively. After 6-h exposure, TM protein and mRNA expression levels decreased in a dose-dependent manner. Stimulation with 5% CSE for 0, 6, 10, 12 and 24 h led to a decrease in the levels of TM mRNA and protein over time, which reached a peak at 12 h. The levels were significantly reduced compared with the control group (P<0.001). However, CSE had no effect on EPCR. Furthermore, nicotine had no influence on TM and EPCR. In conclusion, the present study supports a novel molecular mechanism of cigarette smoking-associated thrombosis by the decreased expression of TM. Further studies are required to identify specific components in CSE responsible for decreasing TM expression and its associated consequences. PMID- 29257198 TI - P2Y1 receptor antagonists mitigate oxygen and glucose deprivation-induced astrocyte injury. AB - The aim of the present study was to elucidate the effects of blocking the calcium signaling pathway of astrocytes (ASs) on oxygen and glucose deprivation (OGD) induced AS injury. The association between the changes in the concentrations of AS-derived transmitter ATP and glutamic acid, and the changes in calcium signaling under the challenge of OGD were investigated. The cortical ASs of Sprague Dawley rats were cultured to establish the OGD models of ASs. The extracellular concentrations of ATP and glutamic acid in the normal group and the OGD group were detected, and the intracellular concentration of calcium ions (Ca2+) was detected. The effects of 2'-deoxy-N6-methyl adenosine 3', 5' diphosphate diammonium salt (MRS2179), a P2Y1 receptor antagonist, on the release of calcium and glutamic acid of ASs under the condition of OGD were observed. The OGD challenge induced the release of glutamic acid and ATP by ASs in a time dependent manner, whereas elevation in the concentration of glutamic acid lagged behind that of the ATP and Ca2+. The concentration of Ca2+ inside ASs peaked 16 h after OGD, following which the concentration of Ca2+ was decreased. The effects of elevated release of glutamic acid by ASs when challenged by OGD may be blocked by MRS2179, a P2Y1 receptor antagonist. Furthermore, MRS2179 may significantly mitigate OGD-induced AS injury and increase cell survival. The ASs of rats cultured in vitro expressed P2Y1 receptors, which may inhibit excessive elevation in the concentration of intracellular Ca2+. Avoidance of intracellular calcium overload and the excessive release of glutamic acid may be an important reason why MRS2179 mitigates OGD-induced AS injury. PMID- 29257197 TI - H89 dihydrochloride hydrate and calphostin C lower the body temperature through TRPV1. AB - The transient receptor potential vanilloid (TRPV1) serves as a negative regulator of body temperature, and during fever conditions its expression can lead to a decrease in temperature. TRPV1 is regulated by a variety of enzymes; however, it is currently unclear whether the regulation of TRPV1 phosphorylation may serve a role in the increase in TRPV1 expression during fever. In the present study, using an in vivo experimental method, rat brain ventricles were injected with the protein kinase A (PKA) antagonist, H89, and the protein kinase C (PKC) antagonist, calphostin C, and fever was induced using lipopolysaccharide (LPS) in order to detect the expression of TRPV1 and phosphorylated (p-)TRPV1, the intracellular Ca2+ concentration [(Ca2+)i] of hypothalami and rat body temperature. The results demonstrated that following the generation of fever using LPS, the expressions of TRPV1 and p-TRPV1, and hypothalamic [Ca2+]i markedly increased. In addition, following an injection with the PKA or PKC antagonist, the temperature increased further due to the inhibition of p-TRPV1. Thus, it was hypothesized that PKA and PKC may be involved in TRPV1 phosphorylation, resulting in a temperature reduction during LPS-induced fever conditions. PMID- 29257201 TI - The regulatory role of Fos related antigen-1 in inflammatory bowel disease. AB - The etiology of inflammatory bowel disease (IBD) remains unclear. The ratio of Fos related antigen-1 (Fra-1)-positive intestinal mucosa epithelial cells is significantly increased in active IBD. This study intends to explore the regulatory role of Fra-1 in IBD. The Fra-1 eukaryotic expression vector was constructed and stably transfected to establish the Fra-1 overexpression HCT-116 (116-Fra-1) intestinal epithelial cell line. The impact of Fra-1 overexpression on intestinal mucosal epithelial cell damage repair function was tested using a scratch assay. The role of Fra-1 overexpression on intestinal mucosal epithelial cell proliferation was evaluated using a Cell Counting Kit-8 assay. Apoptosis related proteins, B-cell lymphoma 2 (Bcl-2), c-Myc, Survivin and Bcl-extra large (Bcl-xL), expression levels were detected by western blotting. Fra-1 suppressed intestinal mucosal epithelial cell damage repair and proliferation. Fra-1 inhibited the protein levels of Bcl-2, c-Myc, Survivin, and Bcl-xL. Fra-1 overexpression in intestinal mucosal epithelial cells may restrain damage repair after intestinal mucosal injury in IBD remittent period through weakening the protective effect of intestinal mucosa, thus increasing the risk of recurrence. Therefore, suppressing Fra-1 expression in intestinal mucosal epithelial cells may contribute to IBD remittent maintenance and recurrence delay. PMID- 29257200 TI - Protective effects of atorvastatin on cerebral vessel autoregulation in an experimental rabbit model of subarachnoid hemorrhage. AB - The aim of the present study was to assess the therapeutic effects of atorvastatin on cerebral vessel autoregulation and to explore the underlying mechanisms in a rabbit model of subarachnoid hemorrhage (SAH). A total of 48 healthy male New Zealand rabbits (weight, 2-2.5 kg) were randomly allocated into SAH, Sham or SAH + atorvastatin groups (n=16/group). The Sham group received 20 mg/kg/d saline solution, whereas 20 mg/kg/d atorvastatin was administered to rabbits in the SAH + atorvastatin group following SAH induction. Changes in diameter, perimeter and basilar artery (BA) area were assessed and expression levels of the vasoactive molecules endothelin-1 (ET-1), von Willebrand factor (vWF) and thrombomodulin (TM) were measured. Neuronal apoptosis was analyzed 72 h following SAH by terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL) staining. The mortality rate in the SAH group was 18.75, 25% in the SAH + atorvastatin treated group and 0% in the Sham group (n=16/group). The neurological score in the SAH + atorvastatin group was 1.75+/-0.68, which was significantly higher compared with the Sham group (0.38+/-0.49; P<0.05). The BA area in the SAH + atorvastatin group (89.6+/-9.11) was significantly lower compared with the SAH group (115.4+/-11.0; P<0.01). The present study demonstrated that SAH induction resulted in a significant increase in the diameter, perimeter and cross-sectional area of the BA in the SAH + atorvastatin group. Administration of atorvastatin may significantly downregulate the expression levels of ET-1, vWF and TM (all P<0.01) vs. sham and SAH groups. TUNEL staining demonstrated that neuronal apoptosis was remarkably reduced in the hippocampus of SAH rabbits following treatment with atorvastatin (P<0.05). Atorvastatin treatment may alleviate cerebral vasospasm and mediate structural and functional remodeling of vascular endothelial cells, in addition to promoting anti-apoptotic signaling. These results provided supporting evidence for the use of atorvastatin as an effective and well-tolerated treatment for SAH in various clinical settings and may protect the autoregulation of cerebral vessels. PMID- 29257199 TI - Human induced pluripotent stem cell-derived mesenchymal stem cells alleviate atherosclerosis by modulating inflammatory responses. AB - The transplantation of mesenchymal stem cells (MSCs) has been a reported method for alleviating atherosclerosis (AS). Because the availability of bone marrow derived MSCs (BM-MSCs) is limited, the authors used this study to explore the use of a new type of MSC, human induced pluripotent stem cell-derived MSCs (iPSC MSCs), to evaluate whether these cells could alleviate AS. iPSC-MSCs were intravenously administered to ApoE knock out mice fed on a high-fat diet (HFD) for 12 weeks. It was reported that systematically administering iPSC-MSCs clearly reduced the size of plaques. In addition, the numbers of macrophages and lipids in plaques were lower in the HFD + iPSC-MSCs group than in the HFD group. Furthermore, iPSC-MSCs attenuated AS-associated inflammation by decreasing the levels of inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, in serum. In addition, the expression of Notch1 was higher in the HFD group, and injecting iPSC-MSCs reversed this effect. In conclusion, the current study provides the first evidence indicating that iPSC-MSCs may be a new optional MSC-based strategy for treating AS. PMID- 29257202 TI - Overexpression of microRNA-146 protects against oxygen-glucose deprivation/recovery-induced cardiomyocyte apoptosis by inhibiting the NF kappaB/TNF-alpha signaling pathway. AB - MicroRNA (miR) has been reported to be associated with ischemia and reperfusion (I/R) and cell apoptosis. Suppression of cell apoptosis may reduce the irreversible damage induced by reperfusion. The aims of the current study were to explore the cytoprotective effects of miR-146 against oxygen-glucose deprivation/recovery (OGD/R)-induced injury in H9c2 rat myocardial cells, as well as the underlying mechanisms. Following stimulation with OGD/R, the cells were transfected with miR-146 mimics or negative controls. The levels of miR-146 were analyzed by reverse transcription-quantitative polymerase chain reaction. Thereafter, cell viability and cell apoptosis were analyzed by MTT assay and terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assay, respectively. In addition, the levels of tumor necrosis factor (TNF)-alpha were determined by ELISA and the levels of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), Bcl-2 and phosphorylated (p)-nuclear factor (NF)-kappaB were measured by western blotting. The results demonstrated that overexpression of miR 146 significantly increased cell viability and decreased apoptosis (P<0.05). It was observed that overexpression of miR-146 statistically reduced the levels of Bax, TNF-alpha and p-NF-kappaB but markedly upregulated the levels of Bcl-2 (P<0.05). These results indicate that overexpression of miR-146 may protect against OGD/R-induced cardiomyocyte apoptosis. Overexpression of miR-146 may alleviate the irreversible injury associated with reperfusion and the effects may be achieved by inhibiting the NF-kappaB/TNF-alpha signaling pathway. PMID- 29257203 TI - Long noncoding RNA-ATB promotes cell proliferation, migration and invasion in gastric cancer. AB - Long noncoding RNA (lncRNA)-activated by transforming growth factor (TGF)-beta (lncRNA-ATB) was recognized as an unfavorable prognostic factor in various cancers; however, its regulatory role in gastric cancer (GC) remains elusive. The present study aimed to measure lncRNA-ATB expression in GC and to explore its involvement in GC progression. lncRNA-ATB expression levels were measured in 40 pairs of GC tissues and their normal adjacent tissues, as well as in 5 GC cell lines and a normal gastric mucosal cell line by reverse transcription quantitative polymerase chain reaction. Knockdown experiments were performed to explore the effect of lncRNA-ATB on the cell proliferation, invasion and migration. The results demonstrated that lncRNA-ATB expression levels in GC tissues and GC cell lines were significantly higher than in the adjacent normal tissues and normal gastric mucosal cells. Further analysis of the correlation between the clinicopathological features and lncRNA-ATB expression indicated that higher expression of lncRNA-ATB was correlated with increased invasion depth, more distant metastasis and advanced tumor-node-metastasis stage. In addition, downregulated lncRNA-ATB expression suppressed cellular proliferation, invasion and migration of GC cells. In conclusion, these data suggested that lncRNA-ATB may serve as a clinical outcome predictor and potential therapeutic target in GC. PMID- 29257204 TI - SK channels participate in the formation of after burst hyperpolarization and partly inhibit the burst strength of epileptic ictal discharges. AB - Epilepsy is a common disease of the central nervous system. Tetanic spasms and convulsions are the key symptoms exhibited during epileptic seizures. However, the majority of patients have a significant post-seizure silence following a serious seizure; the underlying molecular neural mechanisms in this burst interval are unclear. The aim of the present study was to reveal the effect and role of calcium-activated potassium channels during this seizure interval silence period. Cyclothiazide (CTZ) was used to establish the seizure model in rat hippocampal cultured neurons, then the after-burst hyperpolarization (ABH) activities were recorded using the patch clamp technique. By comparing the amplitude and duration of hyperpolarizations, the present study analyzed the association between epileptiform bursts and ABHs when treated with different concentrations of CTZ. In addition, apamin and iberiotoxin were used for pharmacological tests. An intracranial electroencephalogram (EEG) recording was also performed when the CTZ experiments were repeated on animals. The experimental results revealed that treatment with high levels of CTZ induced larger ABHs and was associated with stronger burst activities, which suggested a positive correlation between ABH and epileptiform burst. Apamin, an antagonist of small conductance calcium-activated potassium (SK) channels, decreased the amplitude of ABH; however, reduced ABH was associated with enhanced burst activity, in burst probability and burst strength. These results revealed an important role of SK channels in the formation of ABH and in the inhibition of burst activity. Iberiotoxin, an antagonist of big conductance calcium-activated potassium (BK) channels, had no significant effect on ABH and burst activity. In addition, a positive correlation was identified between burst duration and ABH parameters. An intracellular calcium chelator impaired the amplitude of ABH; however, it did not affect the burst parameters. The rat cortical EEG recordings also exhibited a similar positive correlation between the duration of epileptic burst and after burst depression. Collectively, the results indicate that ABH may serve in the physiological feedback system to reduce the strength of epileptic hyperexcitation, a process in which SK channels are important. PMID- 29257205 TI - Effects of Tianxiangdan Granule treatment on atherosclerosis via NF-kappaB and p38 MAPK signaling pathways. AB - The present study aimed to determine the effects of Tianxiangdan Granule on nuclear factor (NF)-kappaB p65 and p38 mitogen-activated protein kinase (MAPK) inflammatory signaling pathways, and explored the possible mechanism underlying the effects of Tianxiangdan Granule on prevention and treatment of atherosclerosis. A total of 48 apolipoprotein E-/- mice (age, 8 weeks) were selected and divided into two groups: The normal control group (n=12) and the modeling group (n=36). In the modeling group, mice were fed a high-fat diet and were maintained in an artificial climate box, in order to stimulate the climate and eating habit characteristics of Xinjiang. Every morning, ApoE-/- mice in the modeling group were placed in the artificial climate box at 10:00 am and were taken out at 09:00 pm and placed back in the room temperature environment. The temperature of the artificial climate box was set at 6+/-2C, relative humidity was controlled at 25-32.8% and the light-dark cycle was 12 h/day. The purpose of this method was to establish the Huizhuo Tanzu type atherosclerosis model. Following successful generation of the model, mice in the modeling group were randomly divided into three groups: Model group (n=10), Tianxiangdan group (n=10) and atorvastatin group (n=10). After 12 weeks, mice were sacrificed and the serum levels of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in each group were detected. Furthermore, the expression levels of NF-kappaB p65 and p38 MAPK in aortic tissue were detected. The results indicated that the concentrations of IL-1beta and TNF-alpha were significantly higher in mice in the model group compared with in the normal control group (P<0.01), whereas the concentrations of IL-1beta and TNF-alpha were lower in the Tianxiangdan and atorvastatin groups compared with in the model group (P<0.01). Furthermore, the protein expression levels of phosphorylated (p)-NF-kappaB p65 and p-p38 MAPK protein were higher in aortic tissues from the model group compared with in the normal control group (P<0.01), p-NF-kappaB p65 and p-p38 MAPK protein expression was reduced in the atorvastatin and Tianxiangdan groups compared with in the model group. The present study indicated that the mechanism underlying the effects of Tianxiangdan Granule on the prevention and treatment of atherosclerosis may be as follows: Tianxiangdan Granule may decrease the expression of the inflammatory cytokines IL-1beta and TNF-alpha, and suppress activation of the NF-kappaB p65 and p38 MAPK signaling pathways. PMID- 29257206 TI - Application of next-generation sequencing to identify mitochondrial mutations: Study on m.7511T>C in patients with hearing loss. AB - Interruptions in the activity of mitochondria induced by mutations in the mitochondrial genome (mtDNA) can be the source of numerous diseases including hearing loss (HL). One of the mitochondrial variants responsible for HL is the m.7511T>C mutation located in the mitochondrially encoded tRNA serine 1 (UCN) gene. Next-generation sequencing was used to search for the HL mutations in the whole mtDNA of 2 patients with maternal inheritance and real time-polymerase chain reaction was applied for population screening of the m.7511T>C mutation in a group of 1,644 patients with HL. Sequencing of the whole mtDNA in 2 probands revealed a homoplasmic m.7511T>C mutation. Inheritance of the m.7511T>C mutation has been confirmed in examined matrilineal relatives in both families. The mean age of HL onset was 14.1 years old with the mean degree of HL equaling 74.8 dB. A large-scale search for the m.7511T>C mutation among the patients with HL established the frequency of the m.7511T>C mutation at 0.12% among Polish patients with HL. In conclusion, this first report on central European patients harboring the m.7511T>C mutation reveals that the m.7511T>C may be important when diagnosing patients with maternally inherited HL. PMID- 29257207 TI - microRNA-625 targets Yes-associated protein 1 to suppress cell proliferation and invasion of osteosarcoma. AB - Osteosarcoma (OS) is the leading cause of cancer-associated mortality in adolescents and children. MicroRNAs (miRNAs) have critical roles in cancer, particularly in the initiation and progression of OS. Therefore, OS-associated miRNAs should be identified for use as therapeutic targets for treatment of OS. This study aimed to investigate the expression pattern, potential roles and underlying mechanism of microRNA-625 (miR-625) in OS. miR-625 was markedly downregulated in OS tissues and cell lines compared with that in associated adjacent non-tumor tissues and human normal osteoblasts, respectively. The enforced expression of miR-625 using miRNA mimics significantly reduced the proliferation and invasion of OS cells. Bioinformatics analysis and luciferase reporter assays indicated that miR-625 targeted the 3'-untranslated region of Yes associated protein 1 (YAP-1). Furthermore, upregulation of miR-625 reduced endogenous YAP1 expression at the mRNA and protein levels. The upregulated expression of YAP1 in OS tissues was inversely correlated with miR-625 expression. YAP1 restoration using a recombinant plasmid rescued the miR-625 mediated tumor-suppressive effects in OS cells. In conclusion, miR-625 attenuated the cell proliferation and invasion of OS by suppressing YAP1. Thus, miR-625 may be a potential target for OS therapy. PMID- 29257208 TI - Local honokiol application inhibits intimal thickening in rabbits following carotid artery balloon injury. AB - Honokiol is a natural bioactive product with anti-tumor, anti-inflammatory, anti oxidative, anti-angiogenic and neuroprotective properties. The present study aimed to investigate the effects of honokiol treatment on intimal thickening following vascular balloon injury. The current study determined that perivascular honokiol application reduced intimal thickening in rabbits 14 days after carotid artery injury, it may inhibit vascular smooth muscle cell (VSMCs) proliferation and reduce collagen deposition in local arteries. The findings of the presents study also suggested that honikiol may increase the mRNA expression levels of matrix metalloproteinase-1 (MMP-1), MMP-2 and MMP-9 and decrease tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression in the rabbit arteries. Additionally, perivascular honokiol application inhibited intimal thickening, possibly via inhibition of the phosphorylation of SMAD family member 2/3. PMID- 29257210 TI - Neuroprotective effect of tanshinone IIA weakens spastic cerebral palsy through inflammation, p38MAPK and VEGF in neonatal rats. AB - As one of main active ingredients of salvia miltiorrhizae, which is a traditional Chinese medicine, tanshinone IIA is the basis of its pharmacological activities. In the present study, the effect of tanshinone IIA on weakening spastic cerebral palsy (SCP) in neonatal rats was investigated. Radial arm water maze and holding tests were used to measure the alterations of spastic cerebral palsy, inflammation was measured using an ELISA kit, and western blot analysis was used to analyze the protein expression of p-p38 mitogen-activated protein kinase (MAPK) and vascular endothelial growth factor (VEGF). The central mechanisms involved in the mediation or modulation of inflammation, p-p38 MAPK and VEGF were also investigated. Treatment with tanshinone IIA effectively inhibited spastic cerebral palsy, and the activities of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, monocyte chemoattractant protein 1, cyclooxygenase-2 and prostaglandin E2 in a neonatal rat model of SCP. Tanshinone IIA effectively suppressed the protein expression of inducible nitric oxide synthase (NOS), phosphorylated (p-) nuclear factor (NF)-kappaB, p-p38MAPK and VEGF, and activated the phosphorylation of inhibitor of NF-kappaB and the protein expression of neuronal NOS in the SCP rat model. These results suggested that the neuroprotective effect of tanshinone IIA weakened SCP through inflammation, p38MAPK and VEGF in the neonatal rats. PMID- 29257209 TI - Paeoniflorin blocks the proliferation of vascular smooth muscle cells induced by platelet-derived growth factor-BB through ROS mediated ERK1/2 and p38 signaling pathways. AB - The proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of vascular remodeling. In the present study, the effect of paeoniflorin (PAE) on the platelet derived growth factor-BB (PDGF-BB)-induced proliferation of primary cultured rat VSMCs and its molecular mechanism was investigated. The toxicity was determined by the try pan blue exclusion test. Cell proliferation was determined using a CCK-8 assay, DNA synthesis was assessed by measuring the incorporation of BrdU. Cell cycle progression was determined using PI staining and fluorescence-activated cell sorting. The level of intracellular reactive oxygen species (ROS) generation was assessed using dichlorodihydro fluorescein diacetate. mRNA expression was determined by reverse transcription quantitative polymerase chain reaction. Changes of p38, JNK, ERK1/2 signaling pathways were determined by western blot analysis. Cell migration was detected by scratch assay. PAE was demonstrated to significantly inhibit VSMC proliferation induced by PDGF-BB in a dose-and time-dependent manner without cell cytotoxicity. Thus, PAE blocked progression through the G0/G1 to Sphase of the cell cycle. Furthermore, inhibition of the cell cycle was associated with the inhibition of them RNA expression of cyclin D1, cyclin E, cyclin dependent kinase (CDK) 4 and CDK2 as well as with increased cyclin dependent kinase inhibitor 1A mRNA expression in PDGF-BB-stimulated VSMCs. Further studies showed that the beneficial effect of PAE on blocking VSMCs proliferation was related to the suppression of the ROS-mediated extra cellular signal-regulated kinase (ERK)1/2 and p38 signaling pathways, although PAE had no significant effect on the c-Jun N terminal kinase signalling pathway. These results demonstrated that PAE suppressed PDGF-BB-induced VSMC proliferation through the ROS-mediated ERK1/2 and p38 signaling pathways, suggesting that it may be a feasible therapy for vascular remodelling diseases. PMID- 29257211 TI - The long noncoding RNA cancer susceptibility candidate 2 inhibits tumor progression in osteosarcoma. AB - Long noncoding RNA (lncRNA) has been identified to serve a critical role in the development of various types of cancer. Cancer susceptibility candidate 2 (CASC2) is a cancer-associated lncRNA. However, whether CASC2 regulates osteosarcoma progression remains unclear. Reverse transcription-quantitative polymerase chain reaction, western blot, invasion and migration assays were used to evaluate the role of CASC2 in osteosarcoma. The present study reported that CASC2 may inhibit osteosarcoma development. Osteosarcoma tissues demonstrated reduced CASC2 expression compared with normal adjacent tissues. In addition, CASC2 transduction may decrease proliferation, migration and invasion of osteosarcoma cell lines whereas knockdown of CASC2 displayed opposing effects. Patients with low CASC2 levels were predicted to have a poor survival. In vivo implantation studies using pcDNA-CASC2 or short interfering-CASC2 exhibited decreased or increased tumor weight, respectively. These results suggested that CASC2 may serve as a potential tumor suppressor lncRNA in osteosarcoma and may provide potential insight into targeted intervention. PMID- 29257212 TI - MicroRNA-376a inhibits cell proliferation and invasion in glioblastoma multiforme by directly targeting specificity protein 1. AB - Glioblastoma multiforme (GBM), a World Health Organization grade IV glioma, is the most common and aggressive primary brain tumor in humans. microRNAs (miRNAs) are aberrantly expressed in numerous cancer types, including GBM. Abnormally expressed miRNAs are commonly associated with malignant characteristics of GBM, including malignant growth, proliferation, apoptosis, invasion, metastasis and resistance to chemotherapy. miRNA (miR)-376a is abnormally expressed in multiple human cancers; however, the expression pattern and role of miR-376a in GBM, and the underlying molecular mechanisms by which miR-376a exerts its functions remain to be elucidated. Therefore, the aim of this study was to measure miR-376a expression and determine its biological roles in GBM as well as its associated molecular mechanism. In the present study, miR-376a expression was markedly downregulated in GBM tissues and cell lines. Overexpression of miR-376a markedly decreased the proliferation and invasion of GBM cells in vitro. In the present study, specificity protein 1 (SP1) was demonstrated to be a direct target of miR 376a. In addition, a negative association between SP1 mRNA and miR-376a expression was observed in GBM tissues. SP1 upregulation reduced the effects of miR-376a overexpression on GBM cell proliferation and invasion. miR-376a may be a therapeutic target for the treatment of patients with GBM. PMID- 29257213 TI - Nanoparticles for death-induced gene therapy in cancer (Review). AB - Due to the high toxicity and side effects of the use of traditional chemotherapy in cancer, scientists are working on the development of alternative therapeutic technologies. An example of this is the use of death-induced gene therapy. This therapy consists of the killing of tumor cells via transfection with plasmid DNA (pDNA) that contains a gene which produces a protein that results in the apoptosis of cancerous cells. The cell death is caused by the direct activation of apoptosis (apoptosis-induced gene therapy) or by the protein toxic effects (toxin-induced gene therapy). The introduction of pDNA into the tumor cells has been a challenge for the development of this therapy. The most recent implementation of gene vectors is the use of polymeric or inorganic nanoparticles, which have biological and physicochemical properties (shape, size, surface charge, water interaction and biodegradation rate) that allow them to carry the pDNA into the tumor cell. Furthermore, nanoparticles may be functionalized with specific molecules for the recognition of molecular markers on the surface of tumor cells. The binding between the nanoparticle and the tumor cell induces specific endocytosis, avoiding toxicity in healthy cells. Currently, there are no clinical protocols approved for the use of nanoparticles in death induced gene therapy. There are still various challenges in the design of the perfect transfection vector, however nanoparticles have been demonstrated to be a suitable candidate. This review describes the role of nanoparticles used for pDNA transfection and key aspects for their use in death-induced gene therapy. PMID- 29257214 TI - Icariin ameliorates dexamethasone-induced bone deterioration in an experimental mouse model via activation of microRNA-186 inhibition of cathepsin K. AB - The present study aimed to investigate bone deterioration in glucocorticoid induced osteoporosis (GIOP) mice, and the anti-osteoporosis effect and underlying molecular mechanism of icariin. Dexamethasone (DSM) treatment was demonstrated to facilitate the induction of hypercalciuria in GIOP mice. Icariin treatment reversed the dexamethasone (DXM)-induced disequilibrium of calcium homeostasis and bone resorption, and increased serum alkaline phosphatase, tartrate resistant acid phosphatase, osteocalcin and deoxypyridinoline. Haematoxylin and eosin staining revealed an increase in disconnections and separation in the trabecular bone network of the tibial proximal metaphysis, in the GIOP group. Icariin treatment reversed the DXM-induced trabecular deleterious effects, and stimulated bone remodeling in GIOP mice. Furthermore, the results demonstrated that the mRNA and protein expression of cathepsin K were significantly increased in GIOP mice, compared with the control group. Icariin treatment may suppress the expression of cathepsin K in the tibia of GIOP mice. The levels of microRNA (miR)-186 were markedly reduced in the tibia of GIOP mice compared with control group; however, this was inhibited by icariin treatment. Bioinformatics analysis demonstrated that miR-186 regulates cathepsin K via binding to the upstream 3'-untranslated region. Furthermore, transfection with miR-186 mimics resulted in inhibition of cathepsin K expression, whereas miR-186 inhibitors facilitated cathepsin K expression in osteoclasts. In conclusion, the present study demonstrated the protective effects of icariin against bone deteriorations in the experimental GIOP mice, and the underlying mechanism was mediated, at least partially, via activation of miR-186-mediated suppression of cathepsin K. These results provide evidence to support the use of icariin as a therapeutic approach in the management of glucocorticoid-induced bone loss, and the disequilibrium of calcium homeostasis. PMID- 29257215 TI - Cellular properties of the fermented microalgae Pavlova lutheri and its isolated active peptide in osteoblastic differentiation of MG-63 cells. AB - Fermented microalgae Pavlova lutheri (P. lutheri), the product of Hansenula polymorpha fermentation, exhibited an increase in alkaline phosphatase (ALP) activity in MG-63 osteoblastic cells when compared to that of non-fermented P. lutheri. Fractionation of the fermented P. lutheri resulted in identification of the active peptide [peptide of P. lutheri fermentation (PPLF)] with the sequence of EPQWFL. PPLF significantly increased ALP release from MG-63 cells and mineralization in a dose-dependent manner. In addition, the intracellular levels of ALP and osteocalcin (OCN) proteins were augmented by PPLF treatment. To identify the molecular mechanism underlying the effect of PPLF on osteoblastic differentiation, the phosphorylation levels of the mitogen-activated protein kinases, p38, extracellular signal-regulated kinases 1/2 and Jun, and nuclear factor (NF)-kappaB were determined following PPLF treatment and the differences in expression were analyzed using p38 and NF-kappaB selective inhibitors. These results concluded that PPLF from fermented P. lutheri induced osteoblastic differentiation by increasing ALP and OCN release in MG-63 cells via the p38/p65 signaling pathway, indicating that PPLF supplement may be effective for therapeutic application in the field of bone health. PMID- 29257216 TI - Molecular mechanisms of Ellis-van Creveld gene variations in ventricular septal defect. AB - The Ellis-van Creveld (EVC) gene is associated with various congenital heart diseases. However, studies on EVC gene variations in ventricular septal defect (VSD) and the underlying molecular mechanisms are sparse. The present study detected 11 single-nucleotide polymorphisms (SNPs) in 65 patients with VSD and 210 control patients from the Chinese Han population. Of the identified SNPs only the c.1727G>A SNP site was positively associated with the development of VSD (P<0.007). A known mutation, c.343C>G, was also identified, which causes a leucine to valine substitution at amino acid 115 of the EVC protein (p.L115V). The results of functional prediction indicated that c.343C>G may be a pathogenic mutation. In addition, in NIH3T3 mouse embryonic fibroblast cells, the EVC c.343C>G mutation significantly decreased cell proliferation and increased apoptosis. Further investigation demonstrated that in NIH3T3 cells, overexpression of EVC c.343C>G mutation reduced the binding between EVC and smoothened, which further downregulated the activity of the hedgehog (Hh) signaling pathway and the expression of downstream cyclin D1 and B-cell lymphoma 2 proteins with SAG. The c.1727G>A SNP of the EVC gene increased VSD susceptibility in patients from the Chinese Han population. The molecular mechanism underlying the development of VSD induced by the EVC c.343C>G mutation may be due to a reduction in the anti-apoptotic and proliferative abilities of cardiomyocytes via downregulation of Hh pathway activity. The results of the present study may provide novel targets for the diagnosis and treatment of patients with VSD. PMID- 29257217 TI - TWEAK/Fn14 promotes oxidative stress through AMPK/PGC-1alpha/MnSOD signaling pathway in endothelial cells. AB - Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) contributes to dysfunction of endothelial cells via its receptor, Fn14. However, its role in the production of reactive oxygen species (ROS), particularly mitochondrial ROS (mtROS) and the subsequent decrease in nitric oxide (NO) in endothelial cells remains unclear. In this study, the effect of TWEAK/Fn14 on generation of ROS, mtROS and NO in endothelial cells and its potential mechanism was investigated. Human umbilical vein endothelial cells (HUVECs) were treated with TWEAK with Fn14 small interfering (si)RNA or negative control RNA. It was demonstrated that TWEAK induced the production of ROS and mtROS in HUVECs, which were detected by fluorescent microscope, and flow cytometry. In addition, TWEAK decreased the generation of NO as indicated using the Nitric Oxide Assay kit. Furthermore, TWEAK aggravated mtDNA damage as measured by quantitative polymerase chain reaction analysis. Inhibition of Fn14 by Fn14 siRNA decreased TWEAK-induced ROS and mtROS production, as well as mtDNA damage, while it increased the production of NO in endothelial cells. In addition, TWEAK inhibited the expression of active AMP-activated protein kinase (AMPK) and its downstream protein peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and manganese superoxide dismutase (MnSOD). Notably, Fn14 siRNA enhanced the expression of the aforementioned proteins. Taken together, TWEAK/Fn14 contributes to endothelial dysfunction through modulation of ROS and mtROS. In addition, the underlying mechanism is implicated in the AMPK/PGC-1alpha/MnSOD signaling pathway. PMID- 29257218 TI - Mechanism of Astragalus polysaccharides in attenuating insulin resistance in Rats with type 2 diabetes mellitus via the regulation of liver microRNA-203a-3p. AB - Insulin resistance (IR) is a common feature of type 2 diabetes mellitus (T2DM). Astragalus polysaccharides (APS) is a natural medicine that is used to treat T2DM. However, the mechanism by which APS regulates micro (mi)RNA in the treatment of IR has not been investigated. The purpose of the present study was to investigate differential miRNA expression between normal, T2DM model and APS treatment rats, as well as changes in miRNA and its downstream gene expression levels after APS treatment in T2DM Goto Kakizaki (GK) rats. Results suggested that miRNA (miR)-203a-3p expression level was significantly decreased in the liver of T2DM GK rats. Furthermore, it was identified that glucose-regulated protein (GRP)78 was the target gene of miR-203a-3p. GRP78 mRNA and protein expression levels of GRP78, CAAT-enhancer-binding protein homologous protein (CHOP), phosphorylated-c-Jun N-terminal kinase (pJNK)1, and caspase-12 were significantly increased in the liver of T2DM GK rats. Furthermore, miR-203a-3p was upregulated following APS treatment, and the protein expression levels of GRP78, CHOP, pJNK1 and caspase-12 were significantly decreased. In addition, miR 203a-3p overexpression in IR cells decreased the protein expression levels of these factors and anti-miR-203a-3p produced the opposite result. These findings provided evidence that miR-203a-3p may have a functional role in endoplasmic reticulum stress (ERS) signaling in the liver of T2DM GK rats. In addition, APS attenuated IR in T2DM, likely through upregulating or maintaining the miR-203a-3p expression levels, decreasing GRP78 mRNA and protein expression levels and regulating the protein expression of the ERS signaling pathway. PMID- 29257220 TI - Curcumin improves diabetes mellitus-associated cerebral infarction by increasing the expression of GLUT1 and GLUT3. AB - Curcumin is characterized by anti-inflammatory, anti-oxidative, antiviral, antifibrotic, anticoagulation and glucose regulatory functions. However, whether it is protective in diabetes mellitus-associated cerebral infarction remains to be fully elucidated. In the present study, it was demonstrated for the first time, to the best of our knowledge, that curcumin markedly improved neurological deficits, cerebral infarct volume and brain edema rate following middle cerebral artery occlusion (MCAO) surgery. It was also shown that the expression levels of glucose transporter (GLUT)1 and GLUT3 were reduced in the MCAO group. However, following curcumin treatment, the levels of GLUT1 and GLUT3 were markedly increased. In addition, curcumin markedly decreased cell apoptosis, indicating an anti-apoptotic role of curcumin in the brain. To further evaluate whether curcumin prevented cell apoptosis by modulating the expression of GLUT1 and GLUT3, small interfering RNAs targeting GLUT1 and GLUT3 were selected. It was found that the knockdown of GLUT1 and GLUT3 inhibited the abundance of GLUT1, GLUT3 and B-cell lymphoma 2, even following incubation with curcumin. These data showed that curcumin protected brain cells from apoptosis and cerebral infarction, predominantly by upregulating GLUT1 and GLUT3. PMID- 29257219 TI - Effect of prehypertensive losartan therapy on AT1R and ATRAP methylation of adipose tissue in the later life of high-fat-fed spontaneously hypertensive rats. AB - Hypertension is frequently associated with metabolic disorders. The present study was designed to investigate the long-term effect of prehypertensive losartan therapy on metabolic disorders in high-fat-fed spontaneously hypertensive rats (SHRs), and to examine the role of epigenetic regulation of angiotensin II type 1 receptor (AT1R) and AT1 receptor-associated protein (ATRAP) expression in adipose tissue. A total of 32 4-week-old male SHRs were divided into four groups (n=8 rats/group): Standard chow; standard chow + losartan; high-fat diet; and high-fat diet + losartan. At 10 weeks of age, treatment with losartan was discontinued. Rats were followed up until 26 weeks of age. Obesity, dyslipidemia, hyperglycemia, abnormal adipokine secretion, larger adipocytes and decreased expression of markers of adipocyte differentiation were present in high-fat-fed SHRs, and were attenuated in losartan-treated rats. The increased expression and promoter hypomethylation of AT1R subtype a (AT1aR) in the adipose tissue of high fat-fed SHRs were reversed by treatment with losartan. No difference was observed in the expression and promoter methylation of AT1R subtype b (AT1bR) among the four groups. Decreased expression and promoter hypermethylation of ATRAP were demonstrated in the adipose tissue of high-fat-fed SHRs. However, losartan made no difference to the expression and promoter methylation of ATRAP. Prehypertensive losartan therapy may relieve metabolic disorders in the later life of high-fat-fed SHRs. Differential epigenetic regulation of AT1aR and ATRAP expression through DNA methylation in adipose tissue may be involved in the long term beneficial effect. PMID- 29257221 TI - The role of dual-specificity phosphatase 1 and protein phosphatase 1 in beta2 adrenergic receptor-mediated inhibition of extracellular signal regulated kinase 1/2 in triple negative breast cancer cell lines. AB - Triple negative breast cancer cell lines express high levels of beta2-adrenergic receptor, which have a significant influence on the activity of extracellular signal-regulated kinase (ERK)1/2. Therefore, it is important to understand the link between beta2-adrenergic receptor signaling and ERK1/2 activity in terms of cancer cell regulation and cancer progression. Although the molecular mechanisms are not completely clarified, beta2-adrenergic receptor stimulation appears to reduce the basal levels of phosphorylated (p)ERK1/2 in MDA-MB-231 breast cancer cells. The aim of the current study was to determine the mechanism of beta2 adrenergic receptor-mediated ERK1/2 dephosphorylation by investigating the role of dual-specificity phosphatase (DUSP)1/6 and protein phosphatase (PP)1/2, which are established regulators of ERK1/2 phosphorylation, in MDA-MB-231 and MDA-MB 468 breast cancer cell lines. (E)-2-benzylidene-3-(cyclohexylamino)-2,3- dihydro 1H-inden-1-one (BCI) and calyculin A were employed as DUSP1/6 and PP1/PP2 inhibitors, respectively. Subsequently, the protein levels of DUSP1, PP1, pPP1, ERK1/2 and pERK1/2 were measured by western blot analysis. Cells were transfected with DUSP1 small interfering (si)RNA or PP1 siRNA to inhibit their expression. The results demonstrated that beta2-adrenergic receptor agonists led to the dephosphorylation of basal pERK1/2 in MDA-MB-231 and MDA-MB-468 cells. The DUSP1/6 inhibitor, BCI, and the PP1/PP2 inhibitor, calyculin A, antagonized the beta2-adrenergic receptor-mediated dephosphorylation of ERK1/2. Furthermore, beta2-adrenergic receptor stimulation increased the protein expression level of DUSP1, with no effects on DUSP6, PP1 and PP2 expression, and enhanced the expression of the active form of PP1. Downregulation of the expression of DUSP1 or PP1 led to a decline in the beta2-adrenergic receptor-mediated dephosphorylation of ERK1/2. The results of the present study indicate that beta2 adrenergic receptor-mediated dephosphorylation of ERK1/2 may be associated with the activity of DUSP1 and PP1 in MDA-MB-231 and MDA-MB-468 triple negative breast cancer cell lines. The clinical importance of beta2-adrenergic receptor-mediated inactivation of ERK1/2 as well as the activation of DUSP1 and PP1 should be carefully evaluated in future studies, particularly when beta2-adrenergic blockers are used in patients with triple negative breast cancer. PMID- 29257222 TI - CDCA4, a downstream gene of the Nrf2 signaling pathway, regulates cell proliferation and apoptosis in the MCF-7/ADM human breast cancer cell line. AB - The present study aimed to examine the effect of RNA interference targeting cell division cycle-associated protein 4 (CDCA4) on the proliferation and apoptosis of the MCF-7/ADR' human breast cancer cell line. CDCA4 has been shown to have a unique role in regulating cell cycle. In the present study, the expression of CDCA4 was suppressed by CDCA4-specific short hairpin (sh)RNA transfection of the human breast cancer cells, following which changes in the proliferation and apoptosis of the CDCA4-knockdown cells were compared with those of control shRNA transfected cells. The results confirmed that CDCA4 RNA interference reduced the percentage of human breast cancer cells to <50%. In addition, RNA interference of CDCA4 resulted in a significant increase in the apoptotic rate of cells. Taken together, these results suggested that CDCA4 enhanced proliferation and reduced apoptosis in the MCF-7/ADM human breast cancer cells in vitro. PMID- 29257223 TI - Modulation of TGF-beta activity by latent TGF-beta-binding protein 1 in human osteoarthritis fibroblast-like synoviocytes. AB - Osteoarthritis (OA) is a common degenerative joint disease; however, its underlying pathogenesis remains to be elucidated. Previous studies have demonstrated that the transforming growth factor-beta (TGF-beta) signaling pathway has a role in the initiation and development of OA. Additionally, latent TGF-beta-binding protein-1 (LTBP-1) modulates the activity of the TGF-beta mothers against decapentaplegic (Smad) signaling pathway in numerous diseases, including malignant glioma. The present study demonstrated that expression of LTBP-1 is increased in OA synovial tissues compared with normal synovial tissues. The effect of TGF-beta was identified to be mediated by phosphorylated(p) (Smad)2/3, which may activate activin-like kinase (ALK)5 receptor, and by p Smad1/5/8, which may induce ALK1, thereby stimulating expression of matrix metalloproteinase-(MMP)-13 in OA fibroblast-like synoviocytes (FLS). Compared with normal FLS, OA FLS demonstrated an increased p-Smad1/5/8:p-Smad2 ratio, which led to elevated MMP-13 expression and aggravation of OA. Furthermore, knockdown of the LTBP-1 gene by siRNA transfection in OA FLS reduced p-Smad1/5/8 expression without affecting TGF-beta mRNA levels, although p-Smad2 expression increased. It was also demonstrated that OA FLS exhibited increased proliferation compared with normal FLS in vitro. Furthermore, siRNA-mediated downregulation of LTBP-1 reduced proliferation of OA FLS. In conclusion, the present study demonstrated that an alteration in the p-Smad1/5/8:p-Smad2 ratio as well as association between p-Smad1/5/8 and MMP-13 expression in human OA FLS, may contribute to the development of OA. The results of the present study suggested that LTBP-1 is a modulator of the TGF-beta signaling pathway in human OA FLS, which may aid in elucidating the mechanism underlying the pathology of OA. PMID- 29257224 TI - Homology modeling and prediction of B-cell and T-cell epitopes of the house dust mite allergen Der f 20. AB - House dust mite allergens can cause allergic diseases, including asthma, atopic dermatitis and rhinitis. Der f 20 is a novel allergen of Dermatophagoides farina (Der f), which is an arginine kinase. In the present study, the B-cell and T-cell epitopes of Der f 20 were predicted. The protein attribution, patterns, physicochemical properties and secondary structure of Der f 20 were also predicted. Der f 20 is a member of the ATP:guanido phosphotransferase family and contains a phosphagen kinase pattern. Using homology modeling, the present study constructed a reasonable tertiary structure of Der f 20. Using BcePred, ABCpred, BCPred and BPAP systems, B-cell epitopes at 20-25, 41-49, 111-118, 131-141, 170 174 and 312-321 were predicted. Using NetMHCIIpan-3.0 and NetMHCII-2.2, T-cell epitopes were predicted at 194-202, 239-247 and 274-282. These results provide a theoretical basis for the design off Der f 20 epitope-based vaccines. PMID- 29257225 TI - Cytochrome c is important in apoptosis of labial glands in primary Sjogren's syndrome. AB - The present study aimed to investigate the expression and effect of cytochrome c (Cytc) in patients with primary Sjogren's syndrome (pSS). In total, 35 newly diagnosed pSS patients and 35 healthy subjects were enrolled in the present study. The mRNA expression levels of Cytc were detected using reverse transcription-polymerase chain reaction and RT-quantitative PCR. The expression of the Cytc protein in labial salivary glands was detected by immunohistochemistry and was associated with the integral optical density (IOD) of clinical and laboratory variables. In addition, the content of Cytc in the cytoplasm and mitochondria were examined. The mRNA and protein expression levels of Cytc, and the content of Cytc in the cytoplasm of the pSS patients was increased significantly compared with the healthy controls (P<0.05). The content of Cytc in the mitochondria was significantly decreased compared with the healthy controls (P<0.05). The IOD of Cytc protein levels was positively correlated with immunoglobin G (r=0.8142, P<0.05) and erythrocyte sedimentation rate (r=0.7512, P<0.05). Cytc was upregulated in the pSS patients, indicating the potential role of Cytc in the pathogenesis and development of pSS. Further studies may facilitate the development of targeting this molecular pathway for the treatment of pSS. PMID- 29257226 TI - Effects of oral implants with miR-122-modified cell sheets on rat bone marrow mesenchymal stem cells. AB - The aim of the present study was to regulate the transformation of bone marrow mesenchymal stem cells (BMMSCs) to osteoblasts to promote bone formation and osseointegration surrounding oral implants. BMMSCs were cultured using the whole bone marrow adherence method. Cell surface markers were detected by flow cytometry, and multi-lineage differentiation potential was detected by osteogenic and adipogenic tests. miR-122-modified cell sheets were prepared by non-viral transfection and complexed with micro-arc titanium oxide implants to construct a gene-modified tissue-engineered implant, with its surface morphology observed by scanning electron microscopy (SEM). In vitro osteogenic activity of the implant was determined by alkaline phosphatase (ALP), Sirius Red, alizarin red staining, polymerase chain reaction and western blot analysis. The BMMSCs were spindle- or triangular-shaped. Surface markers, cluster of differentiation 29 (CD29), CD90 and CD105 were positively expressed, whereas blood cell markers CD34, CD45 and CD31 were negatively expressed. Osteogenic staining exhibited deposition of calcified nodules, while adipogenic staining demonstrated the formation of lipid droplets. miR-122 modification significantly enhanced the in vitro osteogenic activity of the sheets. On day 3 of osteogenic induction, runt-related transcription factor 2, osterix, osteocalcin, collagen I, ALP and bone morphogenetic protein 2 expression levels of the experimental group were 2.0, 3.1, 4.6, 3.2, 10.5 and 4.5 times those of the blank control group, respectively. SEM imaging of the modified sheet demonstrated close adhesion and fitting between abundant cellular and extracellular matrices, and the porous surface of the implant. In vitro osteogenesis of the complex was promoted and accelerated. Thus, miR-122 effectively promoted osteogenic differentiation of the BMMSC sheet. Therefore, it is feasible to construct gene-modified tissue-engineered implants by complexing miR-122-modified sheets with micro-arc titanium oxide implants. PMID- 29257227 TI - Effects of chronic scopolamine treatment on cognitive impairment and neurofilament expression in the mouse hippocampus. AB - Neurofilaments (NFs) including neurofilament-200 kDa (NF-H), neurofilament-165 kDa (NF-M) and neurofilament-68 kDa (NF-L) are major protein constituents of the brain, and serve important roles in the regulation of axonal transport. NF alteration is a key feature in the pathogenesis of neurological disorders involving cognitive dysfunction. In the present study, cognitive impairments were investigated, via assessments using the Morris water maze and passive avoidance tests, in mice following chronic systemic treatment with 1 mg/kg scopolamine (SCO) for 4 weeks. SCO-induced cognitive impairments were significantly observed 1 week following the SCO treatment, and these cognitive deficits were maintained for 4 weeks. However, the NF immunoreactivities and levels were altered differently according to the hippocampal subregion following SCO treatment. NF-H immunoreactivity and levels were markedly altered in all hippocampal subregions, and were significantly increased 1 week following the SCO treatment; thereafter, the immunoreactivity and levels significantly decreased with time. NF-M immunoreactivity and levels gradually decreased in the hippocampus and were significantly decreased 4 weeks following SCO treatment. NF-L immunoreactivity and levels gradually decreased in the hippocampus, and were significantly decreased 2 and 4 weeks following SCO treatment. In conclusion, the results of the present study demonstrated that chronic systemic treatment with SCO induced cognitive impairment from 1 week following SCO treatment, and NF expression was diversely altered according to the hippocampal subregion from 1 week following SCO treatment. These results suggest that SCO-induced changes in NF expression may be associated with cognitive impairment. PMID- 29257228 TI - SREBP-2 expression pattern contributes to susceptibility of Mongolian gerbils to hypercholesterolemia. AB - Gerbils are susceptible to dietary cholesterol and prone to hypercholesterolemia and non-alcoholic fatty liver disease. The present study aimed to explore the role of sterol regulatory element binding protein (SREBP)-2 and 3-hydroxy-3 methylglutaryl CoA reductase (HMGCR) in hypercholesterolemia susceptibility in gerbils. Male gerbils were fed the normal diet or a high-fat diet (HFD) for 2 weeks, or the HFD for 2 weeks followed with the normal diet for an additional 2 weeks. Serum lipid levels and hepatic fat deposition were measured, and mRNA and protein levels of SREBP-2 and HMGCR were evaluated by quantitative polymerase chain reaction and Western blotting. In addition, the role of SREBP-2 function in cholesterol synthesis from the gerbil primary hepatic cells was also investigated by modulation of SERBP-2 expression via the transfection of SREBP-2 overexpression and knockdown plasmids, respectively. The data demonstrated that the total cholesterol and low-density lipoprotein cholesterol levels in the gerbil serum samples were rapidly and significantly elevated in response to HFD. In addition, the effect of the HFD was rapidly attenuated in the gerbils following a return to the normal diet. HMGCR expression and activation were not altered by dietary cholesterol consumption in the livers from the gerbils in model or recovery groups. HMGCR expression and activation were effectively regulated in cultured hepatic cells from the gerbils. These results indicated that the activation of SREBP-2 to HMGCR was not terminated in gerbil livers during cholesterol intake. Therefore, stable SREBP-2 expression contributes to the susceptibility of gerbils to hypercholesterolemia. PMID- 29257229 TI - Electrophysiological properties of strial pericytes and the effect of aspirin on pericyte K+ channels. AB - The present study was designed to investigate the electrophysiological properties of strial pericytes and the effect of aspirin on pericyte K+ channels. Pericytes were identified by determining their morphological characteristics and using pericyte-associated immunofluorescence techniques. The electrophysiological properties of strial pericytes were observed with a whole-cell patch-clamp technique. Alterations in the outward current of cochlear pericytes in the stria vascularis of guinea pigs were examined following the application of K+ channel retardants. The effects of aspirin on pericyte K+ channels were also evaluated with the whole-cell patch-clamp technique. The results demonstrated that pericytes were desmin positive, and their nuclei were large and surrounded by a small proportion of the cytoplasm. Cytoplasmic processes gradually declined in size as branches grew parallel to the capillary axis. Thus, capillaries were surrounded by tips. The electrophysiological properties of the cochlear pericytes in the stria vascularis of guinea pigs were also determined. The membrane capacitance of the pericytes was 5.9+/-0.3 pF, while the membrane resistance and resting potential were 2.2+/-0.3 GOmega and -30.9+/-1.2 mV, respectively. The current densities of the pericytes (pA/pF) were 3.2+/-0.7, 10.6+/-1.0, 15.7+/-0.9 and 21.3+/-1.2 at command voltages of 0, +20, +40, and +60 mV, respectively. The K+ channels were activated when the pericytes were within the range of -20 mV to +20 mV, particularly at 0 mV. The inhibition rates of the outward current of cochlear pericytes in the stria vascularis of the guinea pigs were determined by administering iberiotoxin (IBTX) and IBTX + 4-aminopyridine. Once the background leakage current was removed, the following inhibition rates were obtained with 3, 10, 30, 300 and 1,000 umol/l aspirin: 20.8+/-4.8, 34.1+/-6.9, 48.2+/-6.7, 63.6+/ 7.1 and 65.7+/-8.1%, respectively. The outward current of the cochlear pericytes in the stria vascularis was inhibited by aspirin with a half maximal inhibitory concentration of 24.5+/-4.5 umol/l. The membranes of the pericytes in the stria vascularis are characterized by high-conductance calcium-activated K+ (BKCa) and voltage-dependent K+ (KV) channels. The outward current of the cochlear pericytes in the stria vascularis of guinea pigs was inhibited by aspirin in a concentration-dependent manner. In addition, BKCa and KV channels were inhibited by aspirin. PMID- 29257230 TI - Whole exome sequencing identifies a mutation in EYA1 and GLI3 in a patient with branchio-otic syndrome and esophageal atresia: Coincidence or a digenic mode of inheritance? AB - Branchio-otic (BO) syndrome is a clinically and genetically heterogeneous disorder that presents with variable branchial arch and otic anomalies. Dominant mutations in the human homologues of the Drosophila eyes absent (EYA1) gene, and the Drosophila sine oculis homeobox 1 and 5 (SIX1 and SIX5, respectively) genes have been causally associated with BO syndrome. Esophageal atresia (EA), with or without tracheo-esophageal fistula (TEF), is the most common type of malformation of the upper digestive tract. To date, its causes are poorly understood. The present study investigated a family with three affected members who all presented with classic BO associated symptoms. Notably, the index patient also presented with the most common EA/TEF subtype type 3b. Whole exome sequencing (WES) was performed in the index patient, and prioritized genetic variants and their segregation in the family were analyzed by Sanger sequencing. WES demonstrated a known disease-causing heterozygous EYA1 splice variant in the patient, as well as his sister and mother; all of whom were affected with BO syndrome. A further GLI family zinc finger 3 (GLI3) splice variant of unknown significance, inherited from the unaffected father, was also detected in the index patient. EYA1 and GLI3 are involved in the Sonic Hedgehog transcriptional network and GLI3 seems to be involved in human foregut malformations. Therefore, one may hypothesize a digenic inheritance model involving EYA1 and GLI3, where the effect of the GLI3 variant observed here only emerges in the background of the EYA1 defect. PMID- 29257231 TI - HMGB1 suppresses colon carcinoma cell apoptosis triggered by co-culture with dendritic cells via an ER stress-associated autophagy pathway. AB - High mobility group box protein 1 (HMGB1) is a versatile molecule that affects the immune system in various ways; however, its role in cancer immunity has not yet been completely elucidated. In the current study, bone marrow-derived dendritic cells from BALB/c mice and undifferentiated murine colon carcinoma CT26.WT cells were used as a cellular model to study the primary role of HMGB1 in colon cancer immunity. Annexin V and acridine orange/ethidium bromide staining was used to assess cellular apoptosis, Cell Counting kit 8 and lactate dehydrogenase assays were performed to evaluate cell viability and a monodansylcadaverine assay was used to detect autophagy. Western blot analysis was performed to detect the expression levels of proteins of interest. Endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase phosphorylation were also investigated in CT26.WT cells exposed to dendritic cells. The present results demonstrated that the CT26.WT cells underwent apoptotic cell death following co-culturing with dendritic cells. However, pretreatment with HMGB1 resulted in a significant increase in viability of the CT26.WT cells exposed to dendritic cells. Furthermore, HMGB1 promoted ER stress-induced autophagy through the activation of JNK, which inhibited the apoptosis triggered by the dendritic cells, suggesting that HMGB1 has a role in immune evasion by colon cancer cells. PMID- 29257232 TI - miR-455-5p promotes cell invasion and migration in breast cancer. AB - MicroRNA (miR)-455-5p has been identified as a biomarker for various types of cancer and may therefore be involved in the regulation of cancer development and progression. However, the specific role and function of miR-455-5p in breast cancer remains unclear. The present study explored the expression levels and function of miR-455-5p in breast cancer. The results from reverse transcription quantitative polymerase chain reaction analysis revealed that miR-455-5p was significantly upregulated in breast cancer. Clinically, increased expression of miR-455-5p predicted a poor survival rate and miR-455-5p was identified as one of the independent prognostic factors for breast cancer patients. Furthermore, results from wound healing and Transwell assays revealed that miR-455-5p accelerated invasiveness and migration capabilities of breast cancer cells. In addition, programmed cell death 4 was identified as a downstream target of miR 455-5p and its expression was observed to be negatively regulated by miR-455-5p. Overall, miR-455-5p may function as an oncogene in breast cancer, and may therefore be used as a prognostic marker for breast cancer patients. PMID- 29257233 TI - Exploring of the molecular mechanism of rhinitis via bioinformatics methods. AB - The aim of this study was to analyze gene expression profiles for exploring the function and regulatory network of differentially expressed genes (DEGs) in pathogenesis of rhinitis by a bioinformatics method. The gene expression profile of GSE43523 was downloaded from the Gene Expression Omnibus database. The dataset contained 7 seasonal allergic rhinitis samples and 5 non-allergic normal samples. DEGs between rhinitis samples and normal samples were identified via the limma package of R. The webGestal database was used to identify enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the DEGs. The differentially co-expressed pairs of the DEGs were identified via the DCGL package in R, and the differential co-expression network was constructed based on these pairs. A protein-protein interaction (PPI) network of the DEGs was constructed based on the Search Tool for the Retrieval of Interacting Genes database. A total of 263 DEGs were identified in rhinitis samples compared with normal samples, including 125 downregulated ones and 138 upregulated ones. The DEGs were enriched in 7 KEGG pathways. 308 differential co-expression gene pairs were obtained. A differential co-expression network was constructed, containing 212 nodes. In total, 148 PPI pairs of the DEGs were identified, and a PPI network was constructed based on these pairs. Bioinformatics methods could help us identify significant genes and pathways related to the pathogenesis of rhinitis. Steroid biosynthesis pathway and metabolic pathways might play important roles in the development of allergic rhinitis (AR). Genes such as CDC42 effector protein 5, solute carrier family 39 member A11 and PR/SET domain 10 might be also associated with the pathogenesis of AR, which provided references for the molecular mechanisms of AR. PMID- 29257234 TI - Therapeutic effects of fibroblast growth factor-21 against atherosclerosis via the NF-kappaB pathway. AB - Fibroblast growth factor-21 (FGF-21) is a pleiotropic protein predominantly secreted in the liver, adipose tissue and pancreas. It has been reported that the metabolic hormone effects of FGF-21 on energy metabolism are essential for human vascular endothelial cells. The aim of the present study was to investigate the therapeutic effects and the underlying primary mechanism of FGF-21 on atherosclerosis in a rat model induced by vitamin D3 and a high fat diet. The rats with atherosclerosis were randomly divided into vehicle (PBS; negative control), FGF-21 (6 mg/kg/d) and atorvastatin (6 mg/kg/d; positive control) groups (n=40 in each group). The rats with atherosclerosis received continuous drug or PBS administration via intravenous injection for a treatment period of 30 days, following which all animals were sacrificed. The expression levels of FGF 21 were determined prior to and following treatment with the drug or PBS. Alterations in ultrastructure and histopathology in vascular endothelial cells were examined, and the expression of nuclear transcription factor kappa B (NF kappaB) and levels of blood lipids in the thoracic aorta tissues were also determined. The results showed that typical atheromatous plaques formed, and the mRNA and protein expression levels of FGF-21 were lower in the vascular endothelial cells of the rats with atherosclerosis, compared with the normal rats. FGF-21 significantly reduced blood lipids and glucose in the rats with atherosclerosis, compared with those in the PBS and atorvastatin groups (P<0.01). The expression levels of Rho kinase and NF-kappaB were significantly lower in the FGF-21 group, compared with the normal control group (P<0.01). Statistically significant differences were found in atheromatous plaques and inflammatory factors in the FGF-21 group, compared with the PBS and atorvastatin groups (P<0.01). In conclusion, FGF-21 significantly downregulated the levels of blood lipids, Rho kinase and NF-kappaB, which contributed to atherosclerosis therapy in the model rats and indicated the potential mechanisms against atherosclerosis in the model rats. PMID- 29257235 TI - Forkhead box protein O3 suppresses uveal melanoma development by increasing the expression of Bcl-2-like protein 11 and cyclin-dependent kinase inhibitor 1B. AB - Forkhead box protein O3 (FoxO3a) is a forkhead box family transcription factor which serves an important role in a number of biological functions, including tumor growth. A previous study indicated that FoxO3a serves a role in insulin like growth factor-induced growth, migration and invasion of uveal melanoma (UM) cells; however, whether FoxO3a is associated with the development and formation of UM remains unknown. In the present study, the role of FoxO3a in UM development and formation was investigated by modulating the expression of FoxO3a in a human UM cell line. The results of the present study demonstrated that FoxO3a overexpression in UM cells inhibited cell proliferation and promoted cellular apoptosis, leading to an accumulation of cells at the G1 cell cycle phase. Western blot analysis demonstrated that FoxO3a overexpression increased the transcription and protein expression of Bcl-2-like protein 11 and cyclin dependent kinase inhibitor 1B, and inhibited cyclin D1 transcription and expression. The opposite effects were observed when FoxO3a was knocked down in UM cells. The results of the present study indicated that FoxO3a may exhibit a negative role in UM development and formation, which is consistent with its role as a tumor suppressor. PMID- 29257237 TI - Samchuleum attenuates diabetic renal injury through the regulation of TGF beta/Smad signaling in human renal mesangial cells. AB - Renal mesangial cell proliferation is a major clinical feature of diabetic nephropathy (DN) and includes glomerulosclerosis and renal fibrosis. Samchuleum (SCE) is a traditional herbal mixture that is recorded in the ancient Korean medical book, Donguibogam. The present study attempted to determine whether SCE treatment was able to improve high glucose (HG)-induced mesangial cell fibrosis and glomerulosclerosis in primary cultured human mesangial cells. Thymidine incorporation under HG induction was increased, but was decreased by SCE in a dose dependent manner. Pretreatment with SCE led to a downregulation in the expression of cyclins and cyclin-dependent kinases (CDKs), and an upregulation of the CDK inhibitors, p21waf1/cip1 and p27kip1. In addition, SCE exposure markedly suppressed the reactive oxygen species signaling pathway under HG conditions. HG enhanced the expression levels of fibrosis-promoting mediators, including collagen IV and connective tissue growth factor, which were markedly attenuated by SCE. SCE treatment inhibited HG-induced fibronectin mRNA expression and decreased the expression of transforming growth factor (TGF)-beta1, Smad-2 and Smad-4, whereas Smad-7 expression increased under HG. SCE treatment induced the degradation of the extracellular matrix by blocking TGF-beta1/Smad signaling. Therefore, the present study suggested that the inhibitory effect of SCE on mesangial proliferation and renal fibrosis may be an effective therapy in the treatment of renal dysfunction leading to DN. PMID- 29257236 TI - Neat1 regulates oxidized low-density lipoprotein-induced inflammation and lipid uptake in macrophages via paraspeckle formation. AB - Oxidized low-density lipoprotein (oxLDL) indu-ces macrophage inflammation and lipid uptake, and serves important roles in the development of atherosclerosis. The long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (neat1) has two isoforms; the longer isoform, neat1_2, mediates the formation of subnuclear structures called paraspeckles. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and RNA protein immunoprecipitation (RIP), revealed that oxLDL induced paraspeckle formation in the THP-1 cell line. Additionally, the nuclear factor-kappaB and p38 pathways were observed to be involved in neat1 transcription. To investigate the role of paraspeckles in oxLDL-induced macrophage inflammation and lipid uptake, macrophages were transfected with small interfering RNAs against NEAT1, NEAT1_2, non-POU domain-containing octamer-binding (NONO) and splicing factor proline and glutamine rich prior to oxLDL incubation. In addition, inflammation-associated pathways and scavenger receptors were analyzed by performing western blotting and RT-qPCR. p65 phosphorylation and cluster of differentiation 36 (CD36) were demonstrated to serve roles in paraspeckle-mediated inflammation and lipid uptake, respectively. To determine the underlying mechanism, RIP was preformed, which revealed that NONO binds CD36 mRNA to decrease its expression. In conclusion, oxLDL induced neat1_2-mediated paraspeckle formation. Paraspeckles participate in oxLDL-induced macrophage inflammation and lipid uptake by regulating p65 phosphorylation and CD36 mRNA. PMID- 29257238 TI - Necrostatin-1 attenuates sepsis-associated acute kidney injury by promoting autophagosome elimination in renal tubular epithelial cells. AB - The aim of the present study was to investigate the protective effect of necrostatin-1 (Nec-1) in sepsis-associated acute kidney injury (SA-AKI). An SA AKI mouse model was established through an intraperitoneal injection of lipopolysaccharide (LPS), and Nec-1 was administered to the mice prior to the establishment of SA-AKI. Renal function and histological changes were evaluated, and the expression levels of microtubule-associated protein light chain 3-II (LC3 II) and p62, as markers of autophagic flux, were detected. Autophagosomes and autolysosomes in renal tubular epithelial cells were also identified using electron microscopy. Pretreatment with Nec-1 could attenuate the LPS-induced increases in the concentrations of blood urea nitrogen (LPS+Nec-1 vs. LPS group, 14.15+/-4.14 mmol/l vs. 32.54+/-5.46 mmol/l, respectively; P<0.001) and serum creatinine (11.50+/-1.67 umol/l vs. 30.08+/-4.18 umol/l, respectively; P<0.001). However, there were no significant differences in the rate of renal tubular epithelial cell necrosis between the groups. In the renal tissues of SA-AKI mice, protein analysis showed that the LC3-II and p62 proteins were increased, while a reverse transcription-quantitative Reverse transcription-polymerase chain reaction analysis detected no increase in LC3-II or p62 mRNA. Additionally, a high number of autophagosomes, but not of autolysosomes, were observed by electron microscopy. When mice were pretreated with Nec-1, the levels of LC3-II and p62 decreased, and a large number of autolysosomes were observed by electron microscopy in the Nec-1 pretreatment group. These results indicated that Nec-1 improved autophagosome elimination, a process that is impaired by LPS, in renal tubular epithelial cells. This potentially enabled Nec-1 to prevent SA-AKI. Furthermore, the findings suggested that the protective effect of Nec-1 may not have involved the inhibition of necroptosis, but may have occurred through the promotion of autophagosome elimination in renal tubular epithelial cells. PMID- 29257240 TI - iASPP, a microRNA-124 target, is aberrantly expressed in astrocytoma and regulates malignant glioma cell migration and viability. AB - MicroRNAs (miRNAs) regulate biogenesis and disease development by targeting numerous mRNAs. miRNA (miR)-124 and its direct target, inhibitor of apoptosis stimulating protein of p53 (iASPP), may be involved in tumor development and progression. The aim of the present study was to explore the role of miR-124 targeted iASPP in glioma. The results demonstrated that miR-124 was aberrantly expressed in astrocytic glioma tissue and in the human glioblastoma cell lines U87 and U251. The expression of miR-124 was lower in astrocytic gliomas compared with normal brain (NB) tissues, with a more reduced expression in higher-grade tumors. In addition, several miR-124 loci (including miR-124-1, miR-124-2 and miR 124-3) were revealed to be more highly methylated in U87 cells compared with methylation levels in U251 cells and NB cells. Furthermore, the expression of iASPP was higher in high-grade astrocytic gliomas compared with low-grade astrocytic gliomas. miR-124 overexpression effectively inhibited U87 and U251 cell migration. In addition, miR-124 regulated cell viability and arrested the cell cycle at the G0/G1 phase in these two cell lines. miR-124 also reduced the expression levels of the cell cycle related genes iASPP, cyclin-dependent kinase (CDK)4, CDK6 and cyclin D1. Results from the present study indicated that expression of the miR-124 target gene iASPP may contribute to glioma development and progression. PMID- 29257239 TI - Elevated expression of PD-1 on T cells correlates with disease activity in rheumatoid arthritis. AB - It is well known that lymphocytes are important in rheumatoid arthritis (RA). Programmed cell death-1 (PD-1) is one of the immunosuppressive costimulatory molecules, which mediates an inhibitory effect. However, its role in RA remains to be fully elucidated. In the present study, the expression levels of PD-1 on T cells in the peripheral blood (PB) and synovial fluid (SF) were determined using flow cytometry. In addition, the expression levels of PD-1 on T cells in the PB and SF of patients with RA were further analyzed to determine correlation with markers of the autoimmune response, inflammation and disease activity in RA. Compared with healthy controls, the expression of PD-1 on T cells in the PB was significantly elevated in patients with RA (P<0.0001). The expression of PD-1 on T cells in the SF of patients with RA was significantly increased, compared with that in the autologous PB (P<0.0001). It was also found that the expression of PD 1 on T cells in the PB of patients with RA was increased significantly in subjects with a high rheumatoid factor titer, high levels of inflammatory markers and a high disease activity score 28 (DAS28). The expression of PD-1 on T cells in the SF of patients with RA was increased significantly in subjects with a high DAS28. These data showed that the expression of PD-1 on T cells was elevated in patients with RA and was correlated with the disease activity. PMID- 29257241 TI - Salvianolic acid B recovers cognitive deficits and angiogenesis in a cerebral small vessel disease rat model via the STAT3/VEGF signaling pathway. AB - Salvianolic acid B is one of the key water-soluble components of Salvia extract. It has been verified that salvianolic acid B possesses multiple pharmacological activities, it protects against myocardial infarction, however additionally improves injury of myocardial ischemia-reperfusion. The present study, the possible effects of salvianolic acid B on cognitive deficits and angiogenesis in cerebral small vessel disease were investigated. Salvianolic acid B was identified to recover cognitive deficits and neurocytes, reduce inflammation, oxidative stress and neurocyte apoptosis (caspase-3 and Bax protein expression) in cerebral small vessel disease rats. In addition, salvianolic acid B upregulated signal transducer and activator of transcription 3 (STAT3) phosphorylation protein expression, and induced vascular endothelial growth factor (VEGF) and VEGF receptor 2 protein expression in cerebral small vessel disease rats. In conclusion, the results demonstrated that salvianolic acid B recovers cognitive deficits and angiogenesis in the cerebral small vessel disease rat model via STAT3/VEGF signaling pathway. PMID- 29257242 TI - MicroRNA-138 promotes proliferation and suppresses mitochondrial depolarization in human pulmonary artery smooth muscle cells through targeting TASK-1. AB - MicroRNA (miR)-138 serves an important role in the proliferation, differentiation and apoptosis of human pulmonary artery smooth muscle cells (HPASMCs), indi cating the involvement of miR-138 in the development and progression of pulmonary artery hypertension (PAH). Potassium channel subfamily K member 3 (TASK-1), a two pore domain K+ channel, is expressed in HPASMCs and is associated with hypoxic PAH. However, whether miR-138 mediates PAH through targeting TASK-1 is not known. In the present study, HPASMCs were transfected with miR-138 mimic to establish a PAH model in vitro, and the effects of a miR-138 inhibitor and a TASK-1 inhibitor (A293) were examined. Cell proliferation and mitochondrial membrane potential (MMP) were measured by CCK-8 assay and flow cytometry, respectively. Reverse transcription-quantitative polymerase chain reaction and western blotting were performed to examine the expression of miR-138, TASK-1, Bcl-2, caspase-3 and activation of extracellular signal-regulated kinase 1/2 (ERK1/2). A dual luciferase reporter assay was also used to analyse the expression level of TASK-1 in HPASMCs. The results of the present study demonstrated that the miR-138 mimic promoted proliferation and MMP level, which was similar to the effect of A293 treatment on HPASMCs. However, the miR-138 inhibitor inhibited the effects induced by miR-138 mimic or A293 treatment, as demonstrated by a decrease in proliferation and MMP level in HPASMCs, accompanied by a decrease of Bcl-2 and an increase of caspase-3 expression levels, as well as ERK1/2 activation. The dual luciferase reporter assay indicated that TASK-1 expression was negatively regulated by miR-138. The results of the present study suggested that miR-138 promoted proliferation and suppressed mitochondrial depolarization of HPASMCs by targeting TASK-1. PMID- 29257243 TI - Prenatal diagnosis of sex chromosomal inversion, translocation and deletion. AB - The aim of the present study was to perform comprehensive prenatal diagnosis using various detection techniques on a fetus in a high-risk pregnant woman, and to provide genetic counseling for the patient and her family so as to avoid birth defects. The routine karyotype analysis via amniocentesis, fluorescence in situ hybridization, and whole genome microarray technique were performed for the prenatal diagnosis of the fetus. The fetal karyotype was 46,X,ish der(X) inv(X)(p22.3q28)t(X;Y)(q28;q11.2)(XYqter+,SRY-,DXZ1+, RP11-64L19+,STS+,XYpter+); namely, one fetal X chromosome belonged to the derivative imbalanced chromosome and this chromosome demonstrated complex chromosomal rearrangements involving inversion, translocation and deletion. Notably, pericentric inversion between Xp22.3 and Xq28 was identified, and the chromosomal microarray technique confirmed that the long arm q28 of the derivative X chromosome had a 1.241-Mb deletion in Xq28, which included Online Mendelian Inheritance in Man genes such as coagulation factor VIII, glucose-6-phosphate dehydrogenase, inhibitor of nuclear factor-kappaB kinase subunit gamma, trimethyllysine hydroxylase epsilon, Ras-related protein Rab-39B and chloride intracellular channel 2. In addition, this chromosome also exhibited the local translocation of fragment Yq11.21 q11.23, which did not include the sex determining region Y gene. This fetus demonstrated deletion, inversion and translocation syndrome, and may exhibit the corresponding clinical phenotypes (e.g., intellectual disability or general delayed development) (1) of such chromosome abnormalities after birth. Therefore, in prenatal diagnosis, a variety of genetic diagnostic techniques should be comprehensively used based on specific clinical situations, which may accurately reveal the nature, sources and manifestations of the derivative chromosome abnormalities and avoid the birth of children with defects. PMID- 29257244 TI - CRP, IL-2 and TNF-alpha level in patients with uremia receiving hemodialysis. AB - Uremia is a serious threat to health. Infection associated with inflammation frequently occurs in patients with uremia during hemodialysis. This study aimed to investigate the association between serum inflammatory factors and uremia in patients prior to and following hemodialysis. Patients with uremia (n=200) receiving continuous high throughput hemodialysis that had hospital-acquired infection were enrolled between August 2013 and August 2015. Additionally, 200 cases of healthy volunteers were selected as the control. Reverse transcription polymerase chain reaction, ELISA and western blotting were performed to determine serum C-reactive protein (CRP), interleukin 2 (IL-2), and tumor necrosis factoralpha levels (TNF-alpha) prior to hemodialysis and 8 months after hemodialysis to explore the association of CRP, IL-2 and TNF-alpha with uremia. CRP, IL-2 and TNF-alpha levels were lower at 8 months after hemodialysis than before, and the difference was statistically significant. CRP, IL-2 and TNF-alpha levels in uremia patients at 8 months after hemodialysis were similar with that in the normal control. CRP expression in patients with uremia was positively correlated with IL-2 and TNF-alpha expression. Patients with uremia with hospital acquired infection receiving continuous high throughput blood purification presented increased levels of inflammatory factor in the serum. In conclusion, uremia patients receiving maintenance hemodialysis with hospital-acquired infection had increased serum inflammatory factors and high throughput hemodialysis significantly decreased CRP, IL-2 and TNF-alpha levels in the serum, suggesting that high throughput hemodialysis may be beneficial for the prevention of the infections in uremia patients. PMID- 29257245 TI - Influence of protein kinase RIPK4 expression on the apoptosis and proliferation of chondrocytes in osteoarthritis. AB - The present study aimed to investigate the expression of receptor-interacting protein kinase 4 (RIPK4) and its effect on the apoptosis and proliferation of chondrocytes in osteoarthritis (OA). A total of 28 OA cartilage tissues and 20 normal cartilage tissues were collected to detect the expression of RIPK4 by using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Chondrocytes were isolated from OA cartilage tissues and divided into OA, NC, si-RIPK4, Wnt3a, and si-RIPK4+Wnt3a groups, and those isolated from normal cartilage tissues were considered the Normal group. Chondrocytes proliferation was detected by MTT assay, cell apoptosis was indicated using flow cytometry and Wnt/beta-catenin signaling pathway related-proteins were investigated using western blot analysis. RIPK4 mRNA and protein expression levels in OA cartilage tissues and OA chondrocytes were increased compared with normal controls (all P<0.05). Additionally, OA chondrocytes showed reduced cell proliferation, increased cell apoptosis and upregulated expression levels of Wnt/beta-catenin signaling pathway related-proteins (all P<0.05). Once transfected with si-RIPK4, the proliferation ability of chondrocytes was enhanced, but apoptosis was notably decreased. Furthermore, the expression levels of Wnt/beta-catenin signaling pathway related-proteins were significantly downregulated (all P<0.05). Results indicated that Wnt3a reversed the effect of si-RIPK4 on chondrocyte proliferation and apoptosis (all P<0.05). Thus, silencing RIPK4 promoted the proliferation and inhibited the apoptosis of chondrocytes. In addition, silencing RIPK4 blocked the Wnt/beta-catenin signaling pathway, thus contributing to alleviating the OA pathogenesis. PMID- 29257246 TI - Calcitonin gene-related peptide reduces Porphyromonas gingivalis LPS-induced TNF alpha release and apoptosis in osteoblasts. AB - Periodontal diseases comprise mixed bacterial infections mainly caused by Gram negative anaerobic bacteria. Lipopolysaccharides (LPS) are important virulence factors and periodontal pathogens, which change local cytokine levels and promote osteoblast apoptosis, thereby leading to an imbalance in bone remodeling mechanisms and accelerating bone loss. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide that is released from sensory nerves and has a positive effect on osteoblast proliferation and differentiation. In addition, this small molecule peptide is an important immune regulator in the inflammatory response. The aim of the present study was to assess the in vitro effects of CGRP on Porphyromonas gingivalis (Pg)LPS-induced osteoblast apoptosis. Osteoblast cultures were stimulated either with various concentrations of PgLPS (0, 25, 50, 100, 500 and 1,000 ng/ml) for 48 h or with 500 ng/ml PgLPS for various lengths of time (0, 6, 12, 24, 48 and 72 h). The PgLPS-stimulated cells were pretreated with different concentrations of CGRP (0, 1, 10, 100 and 1,000 nM) and cell viability and apoptotic rates were measured by Cell Counting kit-8 assays and flow cytometry, respectively. CGRP, cleaved (c)-Caspase-8 and c-Caspase-3 protein expression levels were analyzed by western blotting. Changes in cytokine expression levels, which included tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, monocyte chemotactic protein (MCP)-1 and MCP-2, were measured by ELISA. PgLPS was demonstrated to inhibit osteoblast viability and promote apoptosis in a time- and concentration-dependent manner. CGRP expression was revealed to reduce PgLPS-induced cytostatic activity and apoptosis in osteoblasts. CGRP also suppressed the PgLPS-induced release of TNF-alpha and inhibited the activation of c-Caspase-3 and c-Caspase-8, thus preventing apoptosis in osteoblasts. CGRP may be an important neuropeptide in bone remodeling and may reduce osteoblast apoptosis in inflammatory conditions. These results may provide a solid foundation for CGRP to serve as a new target for the treatment of periodontitis. PMID- 29257247 TI - The protective effect of umbelliferone ameliorates myocardial injury following ischemia-reperfusion in the rat through suppression NLRP3 inflammasome and upregulating the PPAR-gamma. AB - The present study investigated whether the protective effect of umbelliferone could regulate myocardial injury following ischemia-reperfusion and improve mitochondrial respiratory function, thereby relieving myocardial injury following ischemia-reperfusion in rats. In the present study, the extent of inflammation and oxidative stress were analyzed using ELISA. Western blot analysis was employed to investigate the protein expression levels of the PYD domains containing protein 3 (NLRP3) inflammasome and peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Compared with the myocardial injury following ischemia-reperfusion group, umbelliferone significantly prevented myocardial injury, inhibited oxidative stress markers (superoxide dismutase and malondialdehyde), reduced inflammation (tumor necrosis factor-alpha and interleukin-6) and myocardial apoptosis levels (caspase-3/9 and apoptosis regular B-cell lymphoma-2-associated X protein) in the myocardial injury following ischemia-reperfusion group of rats. Umbelliferone treatment also suppressed NACHT, LRR and NLRP3 inflammasome activation and induced PPAR-gamma expression. The results of the present study suggested that the protective effect of umbelliferone may ameliorate myocardial injury following ischemia-reperfusion in the rat through the suppression of the NLRP3 inflammasome and upregulating PPAR gamma expression. PMID- 29257248 TI - Role of the CRISPR system in controlling gene transcription and monitoring cell fate (Review). AB - Even though the accrual of transcripts is implicated in distinct disease states, our knowledge regarding their functional role remains obscure. The CRISPR system has surged at the forefront of genome engineering tools in the field of RNA modulation. In the present review, we discuss some exciting applications of the CRISPR system, including the manipulation of RNA sequences, the visualization of chromosomal loci in living cells and the modulation of transcription. The CRISPR system has been documented to be very reliable and specific in altering gene expression, via leveraging inactive catalytically dead CRISPR-associated protein 9 (Cas9). In the present review, the CRISPR system is presented as an eminent tool for the meticulous analysis of gene regulation, loci mapping and complex pathways. PMID- 29257249 TI - Vitamin D reduces inflammatory response in asthmatic mice through HMGB1/TLR4/NF kappaB signaling pathway. AB - The present study aimed to investigate the effects of vitamin D (VD) on inflammatory responses in asthmatic mice and the underlying mechanism, providing a theoretical basis for clinical application of targeted drug therapy, and the development of novel drugs against asthma. Mouse models of asthma were established. Hematoxylin-eosin staining was performed to observe the pathological changes of the lung tissue. Pulmonary function tests were conducted to determine airway resistance in asthmatic mice. ELISA was performed to measure the serum levels of inflammatory factors. Western blot analysis and reverse transcription quantitative polymerase chain reaction were performed to determine the changes in apoptosis-inducing factors, and high mobility group box 1 protein (HMGB1)/Toll like receptor-4 (TLR4)/nuclear factor (NF)-kappaB signaling pathway-related proteins. VD reduced infiltrated inflammatory factors, attenuated the airway resistance of asthmatic mice, decreased serum levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, increased serum levels of IL-10, decreased apoptotic factor Bcl-2-associated X and caspase-3 expression, downregulated HMGB1 and TLR4, NF-kappaB and phosphorylated-NF-kappaB p65 expression. When TLR4 expression was inhibited, the anti-inflammatory effects of VD were attenuated, and HMGB1, TLR4, NF-kappaB and p-NF-kappaB p65 expression was increased. VD was able reduce the inflammatory response of asthmatic mice and apoptosis in lung tissue through the HMGB1/TLR4/NF-kappaB signaling pathway. PMID- 29257250 TI - Myricetin against ischemic cerebral injury in rat middle cerebral artery occlusion model. AB - The purpose of the present study was to examine the effects of myricetin on reducing cerebral ischemia injury in a rat model. A rat model of permanent middle cerebral artery occlusion (pMCAO) was used in the present study. Rats were randomized into the following five groups: Sham, model, low-myricetin (1 mg/kg), medium-myricetin (5 mg/kg) and high-myricetin (25 mg/kg) groups. Neurological deficit scores were evaluated by an examiner blinded to the experimental groups. Brain infarct size was estimated macroscopically using 2,3,5-triphenyltetrazolium chloride staining. The levels of inflammatory factors tumor necrosis factor (TNF) alpha, interleukin (IL)-6 and IL-1beta, and oxidative stress index superoxide dismutase (SOD), malondiadehyde (MDA), and the glutathione/glutathione disulfide (GSH/GSSG) ratio were measured by ELISA. The degree of brain cell apoptosis was determined using a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Protein expression levels of total or phosphorylated p38 mitogen activated protein kinase (MAPK), nuclear factor (NF)-kappaB/p65 and protein kinase B (AKT) were determined using a western blotting assay. The neurological deficit score and infarct area induced by pMCAO decreased in a dose-dependent manner following myricetin treatment. Furthermore, myricetin reduced the expression levels of IL 1beta, IL-6, TNF-alpha, and MDA, and increased GSH/GSSG ratio and SOD activity. A significant decrease in cell apoptosis was observed in response to myricetin. In addition, myricetin significantly increased the level of phosphorylated AKT protein, and decreased the phosphorylation of p38 MAPK and the level of NF kappaB/p65. Overall, the results of the present study suggested that myricetin exhibits a therapeutic effect by reducing ischemic cerebral injury, and the protective effect of myricetin may be associated with the p38 MAPK, NF-kappaB/p65 and AKT signaling pathways. PMID- 29257252 TI - NF-kappaB regulates HSF1 and c-Jun activation in heat stress-induced intestinal epithelial cell apoptosis. AB - Heat stress may induce intestinal epithelial cell apoptosis; however, the molecular mechanisms have not yet been identified. The present study used IEC-6 rat small intestinal epithelial cells to investigate heat stress-induced production of reactive oxygen species (ROS), which may be involved in nuclear factor (NF)-kappaB activation during heat stress. IEC-6 cells were transfected with NF-kappaB p65-specific small interfering RNA (siRNA), and observed a significant increase in cell apoptosis and caspase-3 cleavage; however, in cells transfected with adenovirus that constitutively overexpressed p65, the opposite results were obtained. Furthermore, p65 knockdown increased the heat stress induced expression and activity of heat shock transcription factor 1 (HSF1); conversely, p65 overexpression slightly decreased HSF1 activity. The levels of heat stress-induced c-Jun phosphorylation were also examined: Knockdown of p65 resulted in a reduction of c-Jun phosphorylation, whereas p65 overexpression resulted in increased phosphorylation. Furthermore, siRNA-mediated knockdown of HSF1 in IEC-6 cells significantly increased heat stress-induced apoptosis. Cells pretreated with c-Jun peptide, an inhibitor of c-Jun activation, exhibited a significant reduction in apoptosis. These findings indicated that heat stress stimulation in IEC-6 cells induced the pro-apoptotic role of NF-kappaB by regulating HSF1 and c-Jun activation. PMID- 29257253 TI - TSLP/TSLPR promote angiogenesis following ischemic stroke via activation of the PI3K/AKT pathway. AB - The current study aimed to investigate the effects of the thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) on angiogenesis following ischemic stroke in vivo and in vitro. Furthermore, whether the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway mediates the effects of TSLP/TSLPR on angiogenesis was explored. A rat middle cerebral artery occlusion (MCAO) model was established, and it was demonstrated that the expression levels of TSLP and TSLPR were significantly increased in the infarct area between 12 and 72 h after MCAO, as determined by ELISA and western blot analyses. TSLP injection was revealed to upregulate vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (Ang-2) expression levels in the infarct area following MCAO, as determined by western blot analysis. An in vitro MCAO model was constructed by exposing human umbilical vein endothelial cells (HUVECs) to oxygen-glucose deprivation (OGD). It was revealed that the expression levels of TSLP and TSLPR were significantly increased in HUVECs subjected to OGD. TSLP treatment was revealed to induce in vitro angiogenesis by promoting cell proliferation and migration, and increasing tube length of OGD-treated HUVECs, as determined by MTT, Transwell-migration and tube formation assays, respectively. Furthermore, it was demonstrated that the PI3K/AKT pathway was activated by TSLP treatment. However, it was revealed that PI3K inhibitor, LY294002, could attenuate the effects of TSLP on in vitro angiogenesis of OGD-treated HUVECs. In conclusion, to the best of our knowledge, this study demonstrated for the first time that TSLP/TSLPR promote angiogenesis following ischemic stroke in vivo and in vitro. Furthermore, it was demonstrated that the effects of TSLP/TSLPR on angiogenesis were, at least partially, mediated via activation of the PI3K/AKT pathway. TSLP/TSLPR may serve as a potential therapeutic target for ischemic stroke treatment. PMID- 29257251 TI - Upregulation of miR-598 promotes cell proliferation and cell cycle progression in human colorectal carcinoma by suppressing INPP5E expression. AB - Colorectal cancer (CRC) is one of the most common types of cancer worldwide. Recently, microRNAs (miRs) have been considered as novel therapeutic targets for the treatment of cancer. miR-598 is a poorly investigated miR. The underlying mechanism of miR-598 in CRC cells remains to be elucidated. In the present study, miR-598 was demonstrated to be significantly upregulated in CRC tissue by analyzing data from The Cancer Genome Atlas and the Gene Expression Omnibus. The results of a polymerase chain reaction demonstrated that miR-598 expression was significantly upregulated in CRC tissues and cells. Gain of function and loss of function assays demonstrated that miR-598 significantly promoted cell proliferation and cell cycle progression. miR-598 was demonstrated to modulate cell functions by regulating 72 kDa inositol polyphosphate-5-phosphatase (INPP5E). In addition, knockdown of INPP5E counteracted the growth arrest caused by an miR-598-inhibitor. In conclusion, the present study demonstrated that miR 598 contributed to cell proliferation and cell cycle progression in CRC by targeting INPP5E. PMID- 29257254 TI - Grifolic acid induces mitochondrial membrane potential loss and cell death of RAW264.7 macrophages. AB - Grifolic acid is a phenolic compound that was first extracted from the mushroom Albatrellus confluens; it acts as an agonist of the free fatty acid receptor (FFAR4). FFAR4 is expressed in macrophages and mediates the anti-inflammatory effects of n-3 unsaturated free fatty acids. In the present study, the effects of grifolic acid on macrophages were observed in mouse RAW264.7 cells. It was demonstrated that grifolic acid (2.5-20 umol/l) treatment reduced RAW264.7 cell viability in a dose- and time-dependent manner. The number of apoptotic cells significantly increased following grifolic acid treatment compared with the untreated control cells. Grifolic acid treatment resulted in a significant decrease in cellular adenosine 5'-triphosphate (ATP) content in RAW264.7 cells. Mitochondrial membrane potential (MMP), as measured by JC-1 staining, was significantly diminished by grifolic acid treatment in a dose- and time-dependent manner. Treatment with cyclosporine A, a protector of MMP, attenuated grifolic acid-induced reduction of MMP and viability in RAW264.7 cells. FFAR4 knockdown did not significantly influence grifolic acid-induced reduction of cell viability, ATP levels or MMP. In conclusion, grifolic acid may induce macrophage cell death by reducing MMP and by inhibiting ATP production probably in an FFAR4 independent manner. PMID- 29257256 TI - Simvastatin ameliorates cognitive impairments via inhibition of oxidative stress induced apoptosis of hippocampal cells through the ERK/AKT signaling pathway in a rat model of senile dementia. AB - Senile dementia is a degenerative disease of the nervous system associated with cognitive impairments, memory disorders, executive dysfunctions, cognitive decline and dementia. Previous reports suggested that simvastatin presents ameliorative effects in the progression of senile dementia. However, the mechanism underlying simvastatin-mediated improvements of cognitive competence during the progression of senile dementia remains to be elucidated. In the present study, a potential mechanism underlying simvastatin activity in hippocampal cells, was investigated. Results of the present study demonstrated that simvastatin significantly improved cognitive impairments, memory competence, amyloid plaques, loss of neurons and synapses, neurofibrillary tangles and oxidative damage in experimental rats. Results of the present study demonstrated that administration of simvastatin regulates superoxide dismutase, reactive oxygen species, catalase and glutathione in oxidative stress processes in hippocampal cells. Apoptosis of hippocampal cells was suppressed by simvastatin treatment in rats with senile dementia. Notably, the administration of simvastatin inhibited activating transcription factor-6-mediated extracellular signal-regulated kinase/AKT serine/threonine kinase (ERK/AKT) signaling pathway in hippocampal cells. Taken together, the preclinical results of the present study indicate that simvastatin is efficient in preventing memory lapse and inhibiting apoptosis of hippocampal cells via the ERK/AKT signaling pathway, which may in the future improve cognitive decline and dementia in patients. PMID- 29257255 TI - Therapeutic effects of mesenchymal stem cells combined with short hairpin RNA on liver injury induced by hepatitis B virus infection. AB - The clinical symptoms of chronic hepatitis B virus (HBV) infection include severe liver damage, which is associated with the elimination of the HBV-infected cells by the immune system. It has been suggested that suppression of HBV replication is not sufficient for patients with hepatitis B and the damaged liver function requires restoration. In the present study, mesenchymal stem cells (MSCs) were combined with short hairpin (sh)RNA to treat liver injury and suppress HBV replication in a mouse model. Lx-shRNA157-1694 (an shRNA expression plasmid containing two shRNA expression cassettes) and mouse immortal (mi)MSCs stably expressing shRNA (miMSC-shRNA) were constructed and their suppressive effects on HBV expression were investigated using reverse transcription-polymerase chain reaction (RT-PCR), ELISA and immunofluorescence. Hepatogenic differentiation of miMSC-shRNA was induced in vitro and confirmed by morphology, reverse transcription-semi-quantitative and -quantitative PCR, urea production and Periodic acid-Schiff staining analyses. miMSCs and the shRNA expression plasmid alone or combined with miMSCs stably expressing shRNA were injected into mice. The former therapeutic regimen successfully suppressed HBV expression in sera and liver tissue, whereas the latter only suppressed HBV expression in liver tissue. Analyses of serum alanine aminotransferase levels, aspartate aminotransferase levels, liver weight/body weight ratio percentage and sirius red staining demonstrated marked amelioration of liver injury in mice treated with both therapeutic regimens. The results of the present study suggest that miMSCs combined with shRNA treatment may alleviate liver injury and suppress HBV expression, thus providing a novel potential therapeutic strategy for the treatment of liver injury induced by HBV infection. PMID- 29257257 TI - Profiles of differentially expressed genes and overexpression of NEBL indicates a positive prognosis in patients with colorectal cancer. AB - The present study aimed to identify differentially expressed genes (DEGs) in colorectal cancer (CRC) and provide novel prognostic biomarkers for CRC. The microarray dataset GSE41258 was used to screen DEGs of CRC. Subsequently, a protein-protein interaction network of DEGs and Gene Ontology analysis were performed to identify hub genes and associated biological processes. Nebulette (NEBL) and complement C1q like 1 (C1QL1) were validated using reverse transcription-quantitative polymerase chain reaction in patients with CRC. Survival analysis was performed for the two hub genes. GSE41258 dataset included 182 CRC samples and 54 normal tissues. A total of 759 DEGs, including 279 upregulated and 480 downregulated were screened between both groups. NEBL and C1QL1 were identified as the two hub genes and upregulated genes involved in various biological processes, including 'regulation of biological quality' and 'response to stimulus', respectively. Additionally, the overexpression of NEBL and C1QL1 in experimental validation was consistent with the aforementioned bioinformatics analysis results. Survival analysis suggested that overexpressed NEBL in patients with CRC was associated with a positive prognosis for overall survival. In conclusion, CRC was associated with a large group of DEGs. From the upregulated genes, overexpressed NEBL in patients CRC indicated a positive prognosis for overall survival and may be used as a prognostic biomarker for patients with CRC. PMID- 29257258 TI - Role of oxidative stress in liver toxicity induced by nickel oxide nanoparticles in rats. AB - The aim of the present study was to explore the role of oxidative stress in liver toxicity induced by nickel oxide nanoparticles (nano-NiO) in rats. Male Wistar rats received saline (control), nano-NiO [0.015, 0.06 or 0.24 mg/kg body weight (b.w.)] or micro-NiO (0.24 mg/kg b.w.) by intratracheal instilling twice a week for 6 weeks. Liver tissues were then collected and examined for biomarkers of nitrative and oxidative stress, as well as mRNA expression of heme oxygenase (HO) 1 and metallothionein (MT)-1. The results demonstrated that the NiO exposure groups had increased liver wet weight and coefficient to body weight, as well as liver pathological changes, evidenced as cellular edema, hepatic sinus disappeara nce and binucleated hepatocytes. The activities of total nitric oxide synthase and inducible nitric oxide synthase, and the nitric oxide content, were increased in the 0.24 mg/kg nano-NiO group compared with the control group. The MT-1 mRNA expression levels were downregulated, while HO-1 mRNA was upregulated in the 0.24 mg/kg nano-NiO exposure group compared with the control group. In addition, abnormal changes of hydroxyl radical, lipid peroxidation, catalase, glutathione peroxidase, total superoxide dismutase and total antioxidative capacity were observed in the liver tissues of the 0.24 mg/kg nano-NiO exposure group, compared with the control group. The present results therefore indicated that nano-NiO induced liver toxicity may be associated with nitrative and oxidative stress in rats. PMID- 29257259 TI - A multigene support vector machine predictor for metastasis of cutaneous melanoma. AB - Gene expression profiles of cutaneous melanoma were analyzed to identify critical genes associated with metastasis. Two gene expression datasets were downloaded from Gene Expression Omnibus (GEO) and another dataset was obtained from The Cancer Genome Atlas (TCGA). Differentially expression genes (DEGs) between metastatic and non-metastatic melanoma were identified by meta-analysis. A protein-protein interaction (PPI) network was constructed for the DEGs using information from BioGRID, HPRD and DIP. Betweenness centrality (BC) was calculated for each node in the network and the top feature genes ranked by BC were selected to construct the support vector machine (SVM) classifier using the training set. The SVM classifier was then validated in another independent dataset. Pathway enrichment analysis was performed for the feature genes using Fisher's exact test. A total of 798 DEGs were identified and a PPI network including 337 nodes and 466 edges was then constructed. Top 110 feature genes ranked by BC were included in the SVM classifier. The prediction accuracies for the three datasets were 96.8, 100 and 94.4%, respectively. A total of 11 KEGG pathways and 13 GO biological pathways were significantly over-represented in the 110 feature genes, including endometrial cancer, regulation of actin cytoskeleton, focal adhesion, ubiquitin mediated proteolysis, regulation of apoptosis and regulation of cell proliferation. A SVM classifier of high prediction accuracy was acquired. Several critical genes implicated in melanoms metastasis were also revealed. These results may advance understanding of the molecular mechanisms underlying metastasis, and also provide potential therapeutic targets. PMID- 29257260 TI - Upregulation of miR-185 promotes apoptosis of the human gastric cancer cell line MGC803. AB - MicroRNA (miR)-185, which has been reported to be abnormally expressed in some types of cancer, exerts significant effects on the proliferation, apoptosis, drug resistance and metastasis of cancer cells. The present study aimed to explore the effects and underlying molecular mechanisms of miR-185 upregulation on the apoptosis of gastric cancer (GC) cells. Quantitative polymerase chain reaction (qPCR) and western blotting were used to detect the expression levels of miR-185 in GC and adjacent normal tissues. In addition, miR-185 expression was detected in the following GC cell lines: MKN74, SGC7901, BGC823, MGC803, as well as in the gastric epithelial cell line GES-1. Subsequently, miR-185 mimics were transfected into MGC803 cells. Post-transfection, the following experiments were conducted: MTT assay was applied to test cell viability; flow cytometry (FCM) was used to determine the apoptotic rate of the cells; and qPCR and western blotting were conducted to detect the expression levels of the following apoptosis-associated factors: B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), survivin, X linked inhibitor of apoptosis protein (XIAP), livin, caspase-3 and caspase-8. The results demonstrated that miR-185 was downregulated in GC tissues compared with the adjacent tissues. In cell lines, miR-185 expression was higher in GES-1 cells compared with in the GC cell lines; in the 4 GC cell lines, the strongest miR-185 expression was in MKN74 cells, followed by SGC7901 and BGC823 cells, and the weakest was in MGC803 cells (P<0.05). Expression of miR-185 was associated with tumor size, differentiation and lymphatic metastasis. Post-transfection with miR 185 mimics, miR-185 expression was significantly increased in a time- and concentration-dependent manner. MGC803 cell viability was significantly decreased following miR-185 mimics transfection. The results of FCM demonstrated that post transfection with miR-185 mimics, the apoptotic rate of MGC803 cells was significantly increased. Post-transfection with miR-185 mimics, the expression levels of Bcl-2, survivin and XIAP were significantly decreased in MGC803 cells, whereas the expression levels of Bax and livin were not altered, and caspase-3 and caspase-8 expression was significantly increased. Spectrophotometry indicated that caspase-3 and caspase-8 activity was significantly increased in MGC803 cells following transfection with miR-185 mimics. In conclusion, the present study suggested that miR-185 upregulation in GC cells may promote apoptosis of tumor cells via gene expression regulation. PMID- 29257261 TI - Transcriptomic signature predicts the distant relapse in patients with ER+ breast cancer treated with tamoxifen for five years. AB - Tamoxifen is the most commonly used drug to treat estrogen receptor positive (ER+) breast cancer. However, many patients with ER+ breast cancer have experienced resistance and other adverse side effects following treatment with tamoxifen. Furthermore, clinical and pathological parameters have thus far failed to predict the efficiency of tamoxifen administration. Therefore, gene signature based models for the prediction of survival time of such patients are urgently needed. In the current study, gene expression levels and follow-up information of samples from GSE17705 and GSE22219 databases were used to construct a risk score model based on Cox multivariate regression. The expression levels of 10 genes were included in the model: CCNB2, CCNA2, FOXD1, WSB2, RBPMS, CTDSP1, BIN3, SLBP, EPRS, FTO. The samples in the high-risk group had a relative early distant relapse time period (median survival time of 3.75 years) compared with the patients in the low risk group (median survival time of 6.5 years, P<0.01). For further validation, a further two independent datasets (GSE26971, GSE58644) were assessed. The overall survival time period of patients with high-risk scores in these datasets was significantly longer than those with low-risk scores (P<0.01). Furthermore, the associations between clinical parameters and risk score were investigated, and it was revealed that the risk score was significantly correlated with tumor age, tumor stage and grade. In addition, a 5-year survival nomogram was plotted in order to facilitate the utilization of risk score along with other clinical data. In summary, using the transcriptomic profile, a multi gene expression based risk score was developed and was revealed as being able to successfully predict the outcome of patients with ER+ breast cancer treated with tamoxifen for 5 years. PMID- 29257262 TI - Histone deacetylase 2 is involved in u-opioid receptor suppression in the spinal dorsal horn in a rat model of chronic pancreatitis pain. AB - Chronic pain occurs in ~85-90% of chronic pancreatitis (CP) patients. However, as the pathogenesis of CP pain remains to be fully understood, the current therapies for CP pain remain inadequate. Emerging evidence has suggested that the epigenetic modulations of genes are involved in chronic pain. In the present study, intrapancreatic trinitrobenzene sulfonic acid infusions were used to establish a CP model in rats. Mechanical allodynia was measured with von Frey filaments. Immunofluorescent staining analysis was used to observe the expression changes of histone deacetylase 2 (HDAC2) and u-opioid receptor (MOR), and intrathecal administration of the selective HDAC2 inhibitor AR-42 was used to assess the underlying mechanisms. The expression levels of c-Jun N-terminal kinase (JNK) in the thoracic spinal cord were detected by western blotting, and the mRNA expression levels of interleukin (IL)1-beta, IL-6 and tumor necrosis factor (TNF)-alpha were detected by reverse transcription-quantitative polymerase chain reaction. The results demonstrated that HDAC2 expression was upregulated during the course of CP induction, while MOR activity in the thoracic spinal dorsal horn was significantly suppressed. Intrathecal infusion of AR-42 significantly attenuated CP-induced mechanical allodynia, with rescued MOR activity. Additionally, HDAC2 facilitated the release of inflammatory cytokines, including IL-1beta, IL-6 and TNF-alpha. These results suggested that the underlying mechanisms of HDAC2 regulating MOR activity under CP induction may occur via promoting the release of inflammatory cytokines, thus activating the JNK signaling pathway. The present study suggested that the epigenetic-regulated disturbance of MOR is dependent on the endogenous analgesia system in CP, which may a provide novel therapeutic strategy for treating pain in CP. PMID- 29257263 TI - miR-137 decreases proliferation, migration and invasion in rheumatoid arthritis fibroblast-like synoviocytes. AB - MicroRNA-137 (miR-137) is involved in cell proliferation, migration, invasion and apoptosis in a variety of cells. However, the role of miR-137 in rheumatoid arthritis (RA) remains unclear. The present study aimed to identify the biological roles of miR-137 in RA. The expression of miR-137 in RA fibroblast like synoviocytes (RA-FLS) and in normal control FLS was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The effects of miR-137 on RA-FLS proliferation, migration and invasion were also determined using MTT, wound healing and Transwell invasion assays, respectively. The effects of miR-137 on inflammatory cytokine expression in RA-FLS were assessed by ELISA. Bioinformatics databases (TargetScan and miRanda), luciferase reporter assays, RT qPCR and western blotting assays were conducted to identify potential target genes. miR-137 expression was decreased in RA-FLS compared with expression in normal control FLS. Overexpression of miR-137 resulted in a significant reduction in RA-FLS proliferation, migration and invasion, and decreased the expression of inflammatory cytokines of RA-FLS. In addition, bioinformatics analysis and luciferase reporter assays indicated that miR-137 may target the 3'-untranslated region of C-X-C motif chemokine ligand 12 (CXCL12), which was confirmed by RT qPCR and western blot analyses. These results further demonstrated that miR 137may serve an inhibitory role in RA by targeting CXCL12 expression, and miR-137 may be a potential target for the treatment of RA. PMID- 29257264 TI - Protective effects of geniposide and ginsenoside Rg1 combination treatment on rats following cerebral ischemia are mediated via microglial microRNA-155-5p inhibition. AB - Geniposide, an active component of Gardenia, has been reported to protect against cerebral ischemia in animals. Ginsenoside Rg1, a component of Panax notoginseng, is usually administered in combination with Gardenia for the treatment of acute ischemic stroke; however, there are unknown effects of ginsenoside Rg1 that require further investigation. In the present study, the effects of geniposide and ginsensoide Rg1 combination treatment on focal cerebral ischemic stroke were investigated. For in vivo analysis, male rats were separated into three groups, including the (control), model and geniposide + ginsenoside Rg1 groups (n=8 per group). A middle cerebral artery occlusion model was established as the model group. The treatment group was treated with geniposide (30 mg/kg, tail vein injection) + ginsenoside Rg1 (6 mg/kg, tail vein injection), and the model group received saline instead. Neurobehavioral deficits, infarct volume, brain edema, and the expression of microRNA (miR)-155-5p and CD11b by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry, were assessed following 24 h of ischemia. For in vitro analysis, BV2 mouse microglial cells were cultured and exposed to geniposide (40 ug/ml) + ginsenoside Rg1 (8 ug/ml) during various durations of oxygen-glucose deprivation (OGD). The expression levels of miR-155-5p, pri-miR-155 and pre-miR-155 were detected by RT qPCR. The results demonstrated that increases in brain infarct volume, edema volume, CD11b-positive cells and miR-155-5p levels were alleviated following geniposide + ginsenoside administration in rats exposed to ischemia. Furthermore, geniposide + ginsenoside Rg1 treatment suppressed the miR-155-5p, pri-miR-155 and pre-miR-155 expression levels in OGD-injured BV2 microglial cells. The results of the present study demonstrated that tail vein administration of geniposide in combination with ginsenoside Rg1 protected against focal cerebral ischemia in rats through inhibition of microglial miR-155-5p following ischemic injury, which may serve as a novel therapeutic agent for the treatment of strokes. PMID- 29257265 TI - Identification of abnormal nuclear and mitochondrial genes in esophageal cancer cells. AB - The present study aimed to detect the mutation characteristics of mitochondrial DNA (mtDNA) in Eca109 of Ec9706 cells, and to investigate their association with the nuclear genome (nDNA), thus providing a basis for gene targeting therapies for esophageal squamous cell carcinoma (ESCC). In vitro-cultured Ec9706 and Eca109 cells were analyzed the changes of single-nucleotide polymorphisms (SNPs), insertions/deletions (INDELs), copy number varia-tion, and structure variation (SV) of their genome by high-throughput sequencing. The loci with SV on chromosome 1-12 of the two ESCC cell lines were >=5% of the mtDNA, but SV on chromosome 13-22, X and Y was <=3%; >40% of loci exhibited gain or loss; intergenic loci with INDEL changes and SNP features accounted for the majority of mutations. The affected genes encoded proteins including nDNA-encoding intra mitochondrial-transporting proteins, ATP energy generation-associated proteins and mitochondrial electron respiratory chain proteins, and these proteins were all nucleus-encoded mitochondrial proteins. The transcription, duplication, and translation of the abnormally expressed mtDNA in Ec9706 and Eca109 cells were closely associated with disorders of nuclear DNA products. PMID- 29257266 TI - Wee1 inhibition can suppress tumor proliferation and sensitize p53 mutant colonic cancer cells to the anticancer effect of irinotecan. AB - Wee1 is an oncogenic nuclear kinase, which can regulate the cell cycle as a crucial G2M checkpoint. Overexpression of Wee1 can be observed in various cancer types, which may lead to a poor prognosis, but the potential therapeutic value of Wee1 in colorectal cancer has not been fully studied. In the present study, the role of Wee1 in colonic cancer was investigated. Wee1 inhibition by small interfering RNA was demonstrated to significantly restrain cancer cell proliferation and sensitize the p53 mutant colonic cancer cell lines HT29 and SW480 to the effect of treatment with ionizing radiation. The anticancer effect of the Wee1 inhibitor MK1775 was investigated in these two colonic cancer cell lines. MK1775 was demonstrated to induce significant DNA damage, suppress cell viability and induce apoptosis. In addition, MK1775 sensitized HT29 and SW480 cells to the effect of irinotecan. Annexin V/propidium iodide staining demonstrated that combination therapy can induce increased apoptosis compared with MK1775 or irinotecan monotherapy. The results of western blot analysis also indicated increased expression of the DNA damage marker histone H2AX, and apoptosis-associated protein cleaved caspase 3, in HT29 and SW480 cells. In conclusion, the present study indicated that Wee1 may be a valuable target for treatment of p53 mutant colonic cancer. PMID- 29257267 TI - miR-96 inhibits EMT by targeting AEG-1 in glioblastoma cancer cells. AB - The induction of epithelial to mesenchymal transition (EMT) is important for carcinogenesis and cancer progression. Previous studies have estimated that microRNA (miRNA/miR) expression is associated with EMT via the regulation of the expression of target genes. miR-96 has been reported to exhibit a correlation with the EMT process. However, the functional role of miR-96 and its mechanism in glioblastoma multiforme (GBM) remains to be completely elucidated. The objective of the present study was to investigate the functional role and mechanism of miR 96 in the migration and invasion, in addition to proliferation, apoptosis and cell cycle distribution, of GBM. In the present study, the results suggested that the introduction of miR-96 significantly inhibited the migration and invasion, in addition to proliferation and cell cycle progression, of GBM cells and promoted their apoptosis in vitro, leading to the hypothesis that miR-96 may be a potential tumor suppressor. It was subsequently confirmed that astrocyte elevated gene-1 (AEG-1) was a direct target gene of miR-96, using a luciferase assay and reverse transcription-quantitative polymerase chain reaction analysis, in addition to western blotting. miR-96 was observed to downregulate the expression of AEG-1 at the mRNA and protein levels. Notably, AEG-1 may suppress EMT by increasing the expression levels of E-cadherin, an epithelial marker, and decreasing the expression levels of vimentin, a mesenchymal marker. Therefore, it was concluded that miR-96 may impede the EMT process by downregulating AEG-1 in GBM. Additionally, it was observed that inhibition of AEG-1 led to a similar effect compared with overexpression of miR-96 in GBM. In conclusion, the results of the present study demonstrated that miR-96 may act as a tumor suppressor by regulating EMT via targeting of AEG-1, suggesting that miR-96 may be a potential biomarker and anticancer therapeutic target for GBM in the future. PMID- 29257268 TI - Activation of the LKB1-SIK1 signaling pathway inhibits the TGF-beta-mediated epithelial-mesenchymal transition and apoptosis resistance of ovarian carcinoma cells. AB - Ovarian cancer is the most common and lethal type of gynecological malignancy, due to its invasiveness. The present study aimed to analyze the molecular mechanism underlying chemoresistance in ovarian carcinoma cells, which may lead to local migration toward adjacent tissues and long-distance metastasis to other organs. A total of 12 patients with ovarian fibroma were used to evaluate chemoresistance and chemosensitivity. The sensitivity and resistance of ovarian carcinoma cells was measured using apoptosis analysis, morphological observation, survival rate analysis, immunohistochemistry and immunostaining. The mechanism underlying the interaction between the epithelial-mesenchymal transition (EMT) and liver kinase B1 (LKB1)-salt-inducible kinase 1 (SIK1) signaling pathways was additionally investigated in ovarian carcinoma. The results of the present study demonstrated that ovarian carcinoma cells isolated from patients exhibited apoptosis resistance. Inhibition of TGF-beta expression led to an inhibition of growth, migration and invasion, in addition to a promotion of apoptosis, in ovarian carcinoma cells treated with paclitaxel. Studies have indicated that the LKB1-SIK1 signaling pathway may be suppressed in ovarian carcinoma cells compared with normal ovarian cells, leading to activation of the EMT signaling pathway. The results of the present study demonstrated that upregulation of LKB1 promoted SIK1 expression and markedly suppressed the growth and aggressiveness of ovarian cancer cells. Upregulation of LKB1 additionally promoted apoptosis in ovarian carcinoma cells. In addition, the results of the present study demonstrated that the knockdown of LKB1 further promoted the expression of transforming growth factor-beta and EMT, which downregulated the chemosensitivity of ovarian carcinoma cells. Additionally, overexpression of LKB1 in ovarian carcinoma cells increased chemosensitivity, resulting in a significant inhibition of migration and invasion. The present findings indicated that the enhancement of LKB1-SIK1 suppressed the growth and aggressiveness of ovarian carcinoma cells isolated from clinical patients, which subsequently contributed to an inhibition of metastatic potential. In conclusion, targeting the LKB1-SIK1 signaling pathway to inhibit EMT may provide potential therapeutic benefits in ovarian carcinoma. PMID- 29257269 TI - Protective effects of psoralidin on IL-1beta-induced chondrocyte apoptosis. AB - Chondrocyte apoptosis serves a key role in the pathogenesis of osteoarthritis. The present study aimed to investigate the protective effects of psoralidin on interleukin (IL)-1beta-induced chondrocyte apoptosis and explore the underlying mechanisms. Chondrocytes were isolated from the articular cartilage of Sprague Dawley rats and were treated with 10 ng/ml IL-1beta and various doses of psoralidin (5, 10 or 15 uM). The ratio of apoptosis was measured by Annexin V/propidium iodide double-labeling fluorescence-activated cell sorting (FACS) analysis. Caspase-3 and -9 activity was determined using a quantitative colorimetric assay. Intracellular levels of reactive oxygen species (ROS) were assessed using a dichlorofluorescein diacetate-labeling FACS analysis, and the release of nitric oxide (NO) was measured using the Griess reaction method. In addition, protein expression levels were detected by western blotting. The results of the present study demonstrated that psoralidin may reduce IL-1beta induced chondrocyte apoptosis. Psoralidin pretreatment also reversed the inhibitory effects of IL-1beta on B-cell lymphoma 2 (Bcl-2) expression, and decreased the IL-1beta-induced expression of Bcl-2-associated X protein, matrix metalloproteinase (MMP)-1 and MMP-13. Furthermore, psoralidin decreased IL-1beta induced caspase-3 and -9 activity, NO release, ROS production and nuclear factor (NF)-kappaB nuclear translocation. In addition, the NF-kappaB inhibitor pyrriolidine-dithiocarbamate exerted similar effects to psoralidin, thus suggesting that IL-1beta induced proapoptotic effects in rat chondrocytes via an NF-kappaB-dependent pathway. Since psoralidin could protect chondrocytes from IL 1beta-induced apoptosis and MMP expression, the present results suggested that psoralidin may be considered a drug candidate for the treatment of osteoarthritis. PMID- 29257270 TI - Long non-coding RNA FAF1 promotes intervertebral disc degeneration by targeting the Erk signaling pathway. AB - Intervertebral disc degeneration (IDD) has become the most common cause of low back pain, and it imposes a heavy burden on patients with IDD and society. The effects of long non-coding RNAs on the proliferation and development of IDD have attracted increasing attention. The present study aimed to investigate the role and molecular mechanism of Fas-associated protein factor-1 (FAF1) in IDD. The expression of FAF1 was detected by reverse transcription-quantitative polymerase chain reaction. CCK-8 and immunofluorescence staining were used to determine cell proliferation. Flow cytometry was performed to measure the cell cycle and apoptosis. Western blotting was used to test p-Erk expression. The results of the present study demonstrated that the expression of FAF1 was upregulated in patients with disc bulging, herniation and IDD, and the expression of FAF1 was positively correlated with the grade of disc degeneration according to the patients' Pfirrmann score. The overexpression of FAF1 in nucleus pulposus (NP) cells promoted cell proliferation by increasing the percentage of cells in the S phase of the cell cycle. The expression of phosphorylated extracellular signal regulated kinase (Erk), a possible target of FAF1, was consistent with the expression of FAF1. In addition, it was elucidated that inactivation of the Erk signaling pathway by PD98059 reversed the effect of FAF1 on NP cell proliferation. Taken together, these results demonstrated that FAF1 was vital in the proliferation of NP cells by modulating the Erk signaling pathway, which suggests that FAF1 may be a novel marker in the early diagnosis of IDD and a therapeutic target for patients. PMID- 29257271 TI - Naringin protects against steroid-induced avascular necrosis of the femoral head through upregulation of PPARgamma and activation of the Notch signaling pathway. AB - Naringin, a flavonoid, is the effective pharmaceutical ingredient of drynaria, with the effects of healing fractures, strengthening bones and promoting kidney function. The aim of the present study was to investigate the potential effect of naringin on steroid-induced avascular necrosis of the femoral head (SANFH). Treatment with naringin markedly protected against the steroid-induced decrease in serum osteocalcin levels, and the rate of osteonecrosis in a model of SANFH. In addition, naringin decreased the total cholesterol and low density lipoprotein/high density lipoprotein ratio in the SANFH rabbit. It was observed that naringin markedly inhibited caspase-3 activity, increased runt-related transcription factor 2 and transcription factor sp7 mRNA expression, promoted alkaline phosphatase activity and upregulated collagen I, peroxisome proliferator activated receptor (PPAR) gamma2, neurogenic locus notch homolog protein (Notch), beta-catenin and phosphorylated-Rac-alpha serine/threonine protein kinase protein expression in the SANFH rabbit. The results of the present study demonstrated that naringin protects against SANFH through upregulation of PPARgamma2 and activation of the Notch signaling pathway, and may be a useful addition to the treatment options for diseases of the femoral head. PMID- 29257272 TI - High expression of FLT3 is a risk factor in leukemia. AB - Several studies have shown that internal tandem duplication (ITD) of FMS-like tyrosine kinase 3 (FLT3) can result in the failure of leukemia treatment and contribute to a poor prognosis. However, the role of the overexpression of FLT3 in leukemia remains to be fully elucidated. By mining public database, the present study first identified that the expression of FLT3 in leukemia was markedly higher, compared with that in other types of tumor and cell lines, indicating that FLT3 is important in leukemia. In leukemia, FLT3 was found to be significantly upregulated in acute myeloid leukemia and acute lymphoblastic leukemia, and a high expression of FLT3 contributed to reduced survival rates. By analyzing Gene Expression Omnibus and The Cancer Genome Atlas data, it was found that genetic alterations and modification of DNA methylation increased the expression of FLT3 in leukemia. FLT3-ITD and FLT3 tyrosine kinase domain point mutations increased the expression of FLT3 in four independent datasets. In addition, the status of FLT3 gene methylation was negatively correlated with the expression of FLT3, and haploinsufficiency of DNA methyltransferase 1 increased the expression of Flt3 in mouse leukemia cells. By analyzing the enrichment of differentially-expressed genes in chemical and genetic perturbation datasets, it was found that genes, which were upregulated in the FLT3 high expression group had myeloid lymphoid leukemia- and nucleophosmin 1-like signatures, indicating that the overexpression of FLT3 may use the same mechanism to promote leukemia. Collectively, the results of the present study showed that the overexpression of FLT3 is a potential risk factor in leukemia. PMID- 29257273 TI - Eaf2 protects human lens epithelial cells against oxidative stress-induced apoptosis by Wnt signaling. AB - The tumor suppressor protein ELL-associated factor 2 (Eaf2) serves an important role in lens development and maturation; however, its role in oxidative stress induced cataract formation remains unclear. In the present study, an in vitro apoptosis model was constructed by treating HLE-B3 cells with 50 uM hydrogen peroxide (H2O2), and was confirmed by flow cytometry. Subsequently, overexpression of Eaf2 was induced in H2O2-induced HLE-B3 cells by ligating Eaf2 cDNA to a pcDNA3.0 plasmid and the role of Wnt3a in the function of Eaf2 was also assessed by inhibiting the expression of the gene in Eaf2-overexpression cells. The expression levels of glycogen synthase kinase 3beta, beta-catenin, Eaf2, caspase 3, Wnt3a, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein were examined using reverse transcription-quantitative polymerase chain reaction and western blot analysis. Immunocytochemistry was used to locate Eaf2 and Wnt3 protein expression in the H2O2-induced HLE-B3 cells. The results indicated that Eaf2 was able to effectively suppress H2O2-induced apoptosis of HLE cells via inhibition of caspase 3 production and activation of Wnt3a signaling. In addition, knockdown of Wnt3a in Eaf2-overexpression cells evidently counteracted the effect of Eaf2 in antagonizing H2O2-induced apoptosis. Taken together, these findings suggested that Eaf2 may suppress oxidative stress-induced apoptosis of HLE-B3 cells exerted through the activation of Wnt3a signaling. PMID- 29257274 TI - MicroRNA-33 regulates the NLRP3 inflammasome signaling pathway in macrophages. AB - The nucleotide binding domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome/interleukin (IL)-1beta axis serves an essential role in regulating the development of rheumatoid arthritis (RA). The dysregulation of cellular metabolism, such as mitochondrial dysfunction, results in the activation of the NLRP3 inflammasome. microRNA (miR)-33 has previously been identified to be a regulator of lipid metabolism and mitochondrial function. However, whether miR-33 regulates the NLRP3 inflammasome/IL-1beta axis remains unknown. In the present study, it was observed that an miR-33 mimic or anti-miR-33 markedly stimulated or inhibited, respectively, IL-1beta protein expression levels in mouse peritoneal macrophages. Mechanistically, miR-33 upregulated the expression of NLRP3 mRNA and protein as well as caspase-1 activity in primary macrophages. In addition, the results demonstrated that miR-33 impaired mitochondrial oxygen consumption rates, resulting in the accumulation of cellular reactive oxygen species, which stimulated NLRP3 expression, caspase-1 activity and IL-1beta secretion. The results of the present study demonstrated that miR-33 levels and NLRP3 inflammasome activity were increased in peripheral blood monocytes from patients with RA patients compared with healthy donors. In conclusion, the present study identified miR-33 to be a positive regulator of the NLRP3 inflammasome in macrophages. The miR-33/NLRP3 inflammasome pathway may therefore be involved in RA development. PMID- 29257276 TI - Resveratrol pretreatment attenuates traumatic brain injury in rats by suppressing NLRP3 inflammasome activation via SIRT1. AB - The inflammatory response in the cerebral cortex serves an important role in the progression of secondary injury following traumatic brain injury (TBI). The NLR family pyrin domain containing 3 (NLRP3) inflammasome is necessary for initiating inflammation and is involved in various central nervous system disorders. The aim of the present study was to investigate the neuroprotective effect of resveratrol and elucidate the underlying mechanisms of resveratrol associated regulation of the NLRP3 inflammasome in TBI. The results demonstrated that the activation of NLRP3, caspase-1 and sirtuin 1 (SIRT1), enhanced the production of inflammatory cytokines and reactive oxygen species (ROS) following TBI. Administration of resveratrol alleviated the degree of TBI, as evidenced by the reduced neuron specific enolase (NSE) and brain water content (WBC). Resveratrol pretreatment also inhibited the activation of NLRP3 and caspase-1, and reduced the production of inflammatory cytokines and ROS. In addition, resveratrol further promoted SIRT1 activation. Furthermore, the suppressing effect of resveratrol on the NLRP3 inflammasome and ROS was blocked by the SIRT1 inhibitor, sirtinol. The results revealed that the activation of the NLRP3 inflammasome and the subsequent inflammatory responses in the cerebral cortex were involved in the process of TBI. Resveratrol may attenuate the inflammatory response and relieve TBI by reducing ROS production and inhibiting NLRP3 activation. The effect of resveratrol on NLRP3 inflammasome and ROS may also be SIRT1 dependent. PMID- 29257275 TI - Sulforaphane and myricetin act synergistically to induce apoptosis in 3T3-L1 adipocytes. AB - The aim of the present study was to investigate whether sulforaphane (SFN) and myricetin (Myr) synergistically induce apoptosis in adipocytes. The viability of mature 3T3-L1 adipocytes treated with 40 uM SFN and/or 100 uM Myr was assessed using an MTT assay. Apoptosis was assessed by Hoechst 33258 nuclear staining, and by detection of single-stranded DNA using an enzyme-linked immunosorbent assay. Compared with the effects of each compound alone, the combination of SFN and Myr synergistically reduced cell viability, induced apoptosis, increased pro apoptotic Bcl-2 associated X protein expression, decreased anti-apoptotic B-cell lymphoma-2 expression, enhanced Bcl-2-associated death promoter (Bad) translocation from the cytoplasm to the mitochondria, and reduced Bad phosphorylation at Ser112. These effects were accompanied by increased cleavage of caspase 3 and poly-ADP-ribose-polymerase. In addition, combined SFN and Myr treatment significantly decreased the protein expression levels of phosphorylated AKT serine/threonine kinase 1 (Akt) at Ser473, as well as the phosphorylation of the downstream protein ribosomal protein, S6 kinase beta-1. Therefore, SFN plus Myr was a more potent inducer of apoptosis in 3T3-L1 adipocytes than either compound alone. The results of the present study suggest that the mechanism of SNF/Myr-induced apoptosis involved activation of the Akt-mediated mitochondrial apoptotic pathway. This may aid treatment of animal models of obesity and preclinical testing. PMID- 29257278 TI - Ivermectin as an inhibitor of cancer stem-like cells. AB - The aim of the present study was to demonstrate that ivermectin preferentially inhibited cancer stem-like cells (CSC) in breast cancer cells and downregulated the expression of 'stemness' genes. Computational searching of DrugBank, a database of approved drugs, was performed using the principles of two-dimensional similarity searching; the chemical structure of salinomycin was used as a query. Growth inhibition of the breast cancer cell lin e MDA-MB-231 by ivermectin was investigated in the total cell population, in cell spheroids and in sorted cells that expressed cluster of differentiation (CD)44+/CD24-. The effects of ivermectin treatment on the expression of pluripotency and self-renewal transcription factors, such as homeobox protein nanog (nanog), octamer-binding protein 4 (oct-4) and SRY-box 2 (sox-2), were evaluated by reverse transcription quantitative polymerase chain reaction and western blotting. Ivermectin exhibited a similarity value of 0.78 in reference to salinomycin. Ivermectin demonstrated an inhibitory effect upon the growth of MDA-MB-231 cells in the range of 0.2-8 uM. Ivermectin preferentially inhibits the viability of CSC-enriched populations (CD44+/CD24- and cells growing in spheroids) compared with the total cell population. The opposite pattern was observed with paclitaxel treatment. Ivermectin exposure reduced the expression of nanog, oct-4 and sox-2 at the mRNA and protein levels. Ivermectin preferentially inhibited the CSC subpopulation in the MDA-MB-231 cells and downregulated the expression of genes involved in the maintenance of pluripotency and self-renewal. PMID- 29257277 TI - Urotensin II promotes aldosterone expression in rat aortic adventitial fibroblasts. AB - Urotensin II (UII) contributes to cardiovascular diseases by activating vasoactive peptides. The present study aimed to determine the effect of UII on aldosterone (ALD) and its receptor in cultured adventitial fibroblasts (AFs) and the tunica adventitia of rat vessels to explore the possible mechanisms underlying vascular remodeling. Expression levels of aldosterone and its receptor on tunica adventitia were determined using immunohistochemistry. Growth-arrested AFs and tunica adventitia from rat vessels were incubated with UII and inhibitors of various signal transduction pathways. ALD receptor (ALD-R) mRNA expression levels and ALD protein exoression levels were determined by reverse transcription quantitative polymerase chain reaction and ELISA, respectively. Aldosterone and its receptors were expressed on tunica adventitia. UII promoted ALD protein secretion from cells in a dose- and time-dependent manner. ALD-R mRNA expression in cells was also dysregulated. Furthermore, the effects of UII were substantially inhibited by treatment with the inhibitors PD98059, Y-27632, H-7, CSA and nicardipine. These results were further verified in the tunica adventitia of rat vessels. The present findings indicated that UII stimulated ALD protein secretion and ALD-R mRNA expression in AFs and in the tunica adventitia of rat vessels; moreover, this effect may be mediated by signal transduction pathways involving MAPK, Rho, PKC, calcineurin and Ca2+. UII may also contribute to vascular remodeling by stimulating the production of ALD and its receptor. PMID- 29257279 TI - The cloning and activity of human Hes1 gene promoter. AB - The aim of the current study was to obtain and analyze the activity of the human Hes1 gene promoter. The genomic DNA of human HeLa cell was used as template, polymerase chain reaction (PCR) was used to amplify the 5' end sequence of Hes1 gene and then the amplified segment was connected to pMD18-T vector. Subsequently, double enzyme digestion was used for identification and the sequence was detected; the promoter with the correct sequence was inserted into pGL3-Basic, and the sequence was identified by double enzyme digestion. The recombinant DNA with correct sequence was transiently transfected into cervical cancer cells, and the dual luciferase reporter gene assay system was used to detect the activity of the promoter. The results demonstrated that the human Hes1 gene promoter amplified by PCR was the same as that of the sequence in the gene bank, and the dual luciferase reporter gene assay system demonstrated that there was promoter activity in cervical cancer cells. In conclusion, the Hes1 luciferase reporter recombinant vector was successfully established and transfected into HeLa cells to verify that it has promoter activity, and the core area of the promoter has several tumor-promoting and tumor suppressor genes. This provides a basis for understanding the regulatory mechanism of Hes1 transcription and translation. PMID- 29257280 TI - Bis-enoxacin blocks alveolar bone resorption in rats with ovariectomy-induced osteoporosis. AB - Postmenopausal osteoporosis is a common systemic skeletal disease that is associated with estrogen-deficiency. Bone loss associated with bisphosphonates therapy can increase the risk of developing oral osteonecrosis. Recent studies have indicated that enoxacin may inhibit osteoclast formation and bone resorption via a different mechanism from that of bisphosphonates. Therefore, the authors hypothesized that the use of an enoxacin such as bis-enoxacin (BE) in association with bisphosphonates may be effective in the treatment of postmenopausal osteoporosis-associated alveolar bone resorption and reduce the risk of oral osteonecrosis by allowing the dose of bisphosphonates to be reduced. A total of 30 6-month-old female Sprague-Dawley rats were randomly assigned to five groups: The Sham, Vehicle, zoledronic acid (ZOL), low concentrations of BE (BE-L) and high concentrations of BE (BE-H) groups. The results demonstrated that the ZOL, BE-L and BE-H groups had an increased bone volume/tissue volume, trabecular thickness, mineral apposition rate, mineralizing surface/bone surface and a decreased trabecular separation when compared with the Vehicle group. The microscopic evaluation of histological sections clearly supported the results of the micro-computed tomography. The number of tartrate-resistant acid phosphatase positive osteoclasts was markedly decreased in the ZOL, BE-L and BE-H groups, indicating that BE may inhibit osteoclast formation. The anti-resorptive effect in the BE-H group was close to or better than that exhibited by the ZOL group; however, this effect was poorer in the BE-L group. In conclusion, BE has the potential to block alveolar bone resorption resulting from ovariectomy-induced osteoporosis in rats in a dose-dependent manner. PMID- 29257281 TI - Paeoniflorin inhibits IL-1beta-induced expression of inflammatory mediators in human osteoarthritic chondrocyte. AB - Interleukin (IL)-1beta serves an important role in the promotion of the growth of osteoarthritis (OA) lesions. Paeoniflorin (PF) has been identified to exert anti inflammatory and anti-arthritic effects. However, it is uncertain whether PF may affect the expression levels of inflammatory mediators in OA chondrocytes. Therefore, the objective of the present study was to determine the effects of PF on the expression levels of inflammatory mediators in IL-1beta-stimulated human OA chondrocytes. The results of the present study determined that PF inhibited the production of nitric oxide and prostaglandin E2 induced by IL-1beta, and the expression of inducible nitric oxide synthase and cyclooxygenase-2 in chondrocytes. Additionally, PF significantly inhibited the IL-1beta-stimulated production of metalloproteinase-3 (MMP-3) and MMP-13 in chondrocytes. PF inhibited the expression of nuclear factor-kappaB (NF-kappaB), p65 and NF-kappaB inhibitor alpha degradation was induced by IL-1beta in chondrocytes. The results of the present study suggest that PF may inhibit IL-1beta-induced expression of inflammatory mediators in human OA chondrocytes by suppressing the activation of the NF-kappaB signaling pathway. Therefore, PF may be a potential agent in the future treatment of OA. PMID- 29257282 TI - Loss of Shp2 within radial glia is associated with cerebral cortical dysplasia, glial defects of cerebellum and impaired sensory-motor development in newborn mice. AB - Radial glia are key neural progenitors involved in the development of the central nervous system. Tyrosine-protein phosphatase non-receptor type 11 (Shp2) is a widely expressed intracellular enzyme with multiple cellular functions. Previous studies have revealed the critical role of Shp2 in a variety of neural cell types; however, further investigation into the function of Shp2 within radial glia is required. In the present study, a conditional knockout mouse was generated using a human glial fibrillary acidic protein (hGFAP)-Cre driver, in which the Shp2 genes were deleted within radial glia. Loss of Shp2 within radial glia was associated with developmental retardation, postnatal lethality, reduced brain size and thinner cerebral cortices in newborn mice. Deletion of Shp2 also led to an increase in gliogenesis, a reduction in neural genesis and extracellular signal-regulated kinase signaling within the cerebral cortex. Furthermore, glial cell defects within the cerebellum of Shp2 mutants were observed, with abnormal granular cell retention and glial cell alignment in the external granular layer. In addition, Shp2 mutants exhibited impaired sensory motor development. The results of the present study suggested that Shp2 may have an important role within radial glia, and regulate cerebral cortical and cerebellar development in newborn mice. PMID- 29257283 TI - Construction of a 26-feature gene support vector machine classifier for smoking and non-smoking lung adenocarcinoma sample classification. AB - The present study aimed to identify the feature genes associated with smoking in lung adenocarcinoma (LAC) samples and explore the underlying mechanism. Three gene expression datasets of LAC samples were downloaded from the Gene Expression Omnibus database through pre-set criteria and the expression data were processed using meta-analysis. Differentially expressed genes (DEGs) between LAC samples of smokers and non-smokers were identified using limma package in R. The classification accuracy of selected DEGs were visualized using hierarchical clustering analysis in R language. A protein-protein interaction (PPI) network was constructed using gene interaction data from the Human Protein Reference Database for the DEGs. Betweenness centrality was calculated for each node in the network and genes with the greatest BC values were utilized for the construction of the support vector machine (SVM) classifier. The dataset GSE43458 was used as the training dataset for the construction and the other datasets (GSE12667 and GSE10072) were used as the validation datasets. The classification accuracy of the classifier was tested using sensitivity, specificity, positive predictive value, negative predictive value and area under curve parameters with the pROC package in R language. The feature genes in the SVM classifier were subjected to pathway enrichment analysis using Fisher's exact test. A total of 347 genes were identified to be differentially expressed between samples of smokers and non smokers. The PPI network of DEGs were comprised of 202 nodes and 300 edges. An SVM classifier comprised of 26 feature genes was constructed to distinguish between different LAC samples, with prediction accuracies for the GSE43458, GSE12667 and GSE10072 datasets of 100, 100 and 94.83%, respectively. Furthermore, the 26 feature genes that were significantly enriched in 9 overrepresented biological pathways, including extracellular matrix-receptor interaction, proteoglycans in cancer, cell adhesion molecules, p53 signaling pathway, microRNAs in cancer and apoptosis, were identified to be smoking-related genes in LAC. In conclusion, an SVM classifier with a high prediction accuracy for smoking and non-smoking samples was obtained. The genes in the classifier may likely be the potential feature genes associated with the development of patients with LAC who smoke. PMID- 29257284 TI - Icariin protects against ischemia-reperfusion injury in H9C2 cells by upregulating heat shock protein 20. AB - Icariin (ICA) has been implicated in certain biological and pathological processes, including myocardial ischemia/reperfusion (I/R) injury. The aim of the present study was to investigate the role of ICA in I/R-induced cardiomyocyte injury and the potential underlying mechanism. Cell proliferation and apoptosis of H9C2 cells was determined by cell counting kit-8 and flow cytometry assays. In addition, reactive oxygen species (ROS) production in H9C2 cells was measured by flow cytometry. Reverse transcription-quantitative polymerase chain reaction and western blot assay were performed to examine the expression levels of proteins, including HSP20, B-cell lymphoma 2 (Bcl-2), cytochrome complex (Cyt-c), apoptotic protease activating factor 1 (APAF1), caspase-9 andcaspase-3, and the phosphorylation of Akt (p-Akt) in H9C2 cells. The present results demonstrated that, compared with the control group, the I/R group demonstrated significantly reduced levels of HSP20 expression and cell proliferation, and increased apoptosis and ROS production in H9C2 cells. In parallel, the expression levels of Cyt-c, APAF1, caspase-9 and caspase-3 were significantly increased in the I/R group, although Bcl-2 and p-Akt/Akt expression levels were decreased. Furthermore, compared with the I/R group, ICA treatment and/or HSP20 overexpression significantly improved cardiac function, as evidenced by promoted cell proliferation and inhibited apoptosis of H9C2 cells. The current study indicates that ICA exerts a cardioprotective effect against I/R injury, which is associated with the upregulation of HSP20. PMID- 29257285 TI - c-Jun N-terminal kinase 3 signalling serves a potential role as a biomarker for determining the pathogenesis of Parkinson's disease. AB - Parkinson's disease (PD) is a movement-associated disorder that specifically affects dopamine-producing neurons. The disease causes demyelation that adversely impacts upon the motor activity of the brain. Currently there are no promising biomarkers for PD; improved understanding of the molecular mechanisms underlying the different pathological stages of PD are required to enable identification of a novel biomarker. The present study successfully established a PD mouse model via nasal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The expression of c-Jun N-termal kinase 3 (JNK3) and caspase-3 in two different pathological stages of PD were analysed using immunohistochemistry and western blot analysis. The results inidcated that the initial PD pathogenesis recovers on response to rasagiline. Immunohistochemistry and western blot analysis revealed that treatment with rasagiline positively regulated early-stage PD pathogenesis by downregulating the expression of JNK3 and upregulating caspase-3; however, there was no positive effect on the advanced stages of PD. Overall, these results concluded that rasagiline has the ability to inhibit the expression of JNK3 and upregulate caspase-3 in early stages of PD; however, rasagline appears to have no impact on JNK3 and caspase-3 levels in the advanced stages of PD. PMID- 29257286 TI - Protective effect of gigantol against hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells through the PI3K/Akt pathway. AB - Bone marrow mesenchymal stem cell (BMSC) transplants are promising for the treatment of certain central nervous system diseases. However, oxidative stress is one of the major factors that may limit the survival of the transplanted BMSCs. The present study investigated the effect of pretreatment with gigantol on hydrogen peroxide (H2O2)-induced apoptosis in rat BMSCs (rBMSCs) and the potential underlying mechanisms. The results demonstrated that gigantol pretreatment significantly inhibited H2O2-induced apoptosis of rBMSCs. rBMSCs were incubated with 600 uM H2O2 in the absence or presence of different doses of gigantol (1-100 uM). Cell viability and apoptosis ratios were assessed by MTT assays and flow cytometry, respectively. Morphological alterations and reactive oxygen species were measured by the fluorescent-based methods of Hoechst staining and dichlorodihydrofluorescein diacetate, respectively. Furthermore, the protein levels of phosphorylated-protein kinase B (Akt), B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X (Bax), caspase-3 and caspase-9 were investigated by western blotting. Following incubation with H2O2 for 2 h, gigantol significantly inhibited the H2O2-induced reductions in the cell viability of rBMSCs in a dose dependent manner. Furthermore, gigantol upregulated Akt phosphorylation and Bcl-2 expression, downregulated Bax expression, and reduced the expression of caspase-3 and caspase-9 in H2O2-treated rBMSCs, whereas an opposite effect was detected when LY294002, an inhibitor of phosphatidylinositol 3-kinase, was administered in combination with gigantol. These results indicate that gigantol may be developed as a promising neuroprotective agent for successful MSC transplantation in ischemic diseases. PMID- 29257288 TI - N-cadherin attenuates nucleus pulposus cell senescence under high-magnitude compression. AB - Mechanical compression is important in disc degeneration. N-cadherin (N-CDH) mediated signaling contributes to the maintenance of the normal nucleus pulposus (NP) cell phenotype and NP matrix biosynthesis. Our preliminary study demonstrated that a high-magnitude compression (20% deformation) promotes NP cell senescence in a three-dimensional scaffold culture system. The aim of the present study was to investigate whether N-CDH-mediated signaling alleviates NP cell senescence under the above-mentioned high-magnitude compression. NP cells were transfected with recombinant lentiviral vectors to enhance N-CDH expression. All the transfected or un-transfected NP cells were seeded into the scaffolds and subjected to 20% deformation at a frequency of 1.0 Hz for 4 h once per day for 5 days. Results indicated that N-CDH overexpressed NP cells exhibited decreased senescence-associated beta-galactosidase activity and downregulated expression levels of senescence-associated markers (p16 and p53). Furthermore, the N-CDH overexpressed NP cells exhibited increased cell proliferation potency, telomerase activity and matrix biosynthesis compared with NP cells without N-CDH overexpression under high-magnitude compression. Thus, N-CDH-mediated signaling contributes to the attenuation of NP cell senescence under high-magnitude compression. PMID- 29257287 TI - Neuroserpin restores autophagy and promotes functional recovery after acute spinal cord injury in rats. AB - This study is to reveal the characteristics of autophagy and the effect of neuroserpin (NSP) treatment on autophagy during the process of functional recovery following spinal cord injury (SCI). After the clip compress rat model of SCI had been made, autophagy-associated proteins, including LC3-II, beclin-1 and p62, were evaluated at 2, 4, 24, 72 h, and 168 h in the experimental group, and the sham group as control. Transmission electron microscopy (TEM) was further used for autophagy detection at 4 and 72 h. All the male rats were randomly divided into three groups: Sham, vehicle and NSP group. NSP or an equal volume of saline vehicle was administered via intrathecal injection immediately after SCI. Each group was further divided into subgroups for the following experiments: i)Western blot (LC3-II and p62); ii) Immunofluorescent double staining (LC3/MAP 2/DAPI); iii) Nissl staining and Basso Beattie Bresnahan (BBB score) for NSP neuroprotection evaluation. Our results revealed both LC3-II and p62 expression trended upward at 24, 72 and 168 h after SCI. The LC3-II peaked at 72 h, while p62 peaked at 24 h. Beclin-1 dropped significantly at 72 and 168 h. TEM results showed that autophagosomes largely accumulated at 72 h after SCI when compared with the sham group. Western blot analysis showed that LC3-II and p62 were markedly decreased with NSP treatment at 72 h after injury compared with that of the vehicle-group. Immunofluorescent double labeling indicated that accumulation of autophagosomes was reduced in the NSP group. Further, post-SCI treatment with NSP improved the BBB scale and increased the number of anterior horn motor neurons. Together, this study demonstrates that autophagic flux is impaired, meanwhile NSP restores autophagic flux and promotes functional recovery after SCI in rats. PMID- 29257289 TI - Less hippocampal neuronal death in young gerbils following transient global cerebral ischemia is associated with long-term maintenance of insulin-like growth factor 1 and its receptors in the hippocampal CA1 region. AB - Insulin-like growth factor 1 (IGF-1) is a well-known growth factor with well defined neuroprotective effects against cerebral ischemia. However, the age dependent differences in the expression of IGF-1 and its receptor (IGF-1R) in the brain following transient cerebral ischemia (TCI) have not been elucidated. In the present study, the differences in IGF-1 and IGF-1R in the gerbil hippocampal CA1 region of young and adult gerbils 5 min following TCI were determined. Seven days following TCI, the neuronal death in the hippocampal CA1 region of young gerbils was significantly less than that observed in adult gerbils. In addition, the immunoreactivity, and levels of IGF-1 and IGF-1R in the CA1 region of the normal young were higher than those in the normal adult. Four days following TCI, the immunoreactivity, and protein levels of IGF-1 and IGF-1R were markedly decreased in the adult group. By contrast, in the young group, the immunoreactivity and expression levels were much greater than those in the adult group. However, 7 days following TCI, all immunoreactivity and expression levels were markedly decreased when compared with those in the normal adult and young groups. In addition, the immunoreactivity and expression levels in the young groups were significantly higher than those of the adult groups. In conclusion, the present study demonstrated that the higher and sustained expression of IGF-1 and IGF-1R in the young gerbil hippocampal CA1 region following TCI may be associated with the reduced neuronal death compared to that in the adults. PMID- 29257290 TI - Time-course behavioral features are correlated with Parkinson's disease associated pathology in a 6-hydroxydopamine hemiparkinsonian rat model. AB - Parkinson's disease (PD) is one of the most common neurodegenerative diseases. For decades, the unilateral 6-hydroxydopamine (6-OHDA) rat model has been employed to investigate the pathogenesis and therapy of PD. However, the behavior and associated pathological features of the model long term have not previously been described dynamically. In the present study, the unilateral model was established by 6-OHDA injection in the striatum. The PD rat model was determined 2 weeks following surgery, according to the apomorphine (APO)-induced rotations, cylinder, rotarod and open field tests. TH-positive neurons and fibers in the substantia nigra pars compacta (SNpc) and striatum, respectively, and glial activation in the SNpc, determined by glial fibrillary acidic protein (GFAP) expression for astrocytes and CD11b (Mac1) expression for microglia, were detected by immunohistological staining. Correlation analysis was performed to understand the association between PD-associated behavior and pathology. The behavioral impairment progressively deteriorated during the process of experiment. In addition, the decrease in TH-positive neurons was associated with an increase in GFAP- and Mac1-positive cells in the SNpc. Linear regression analysis indicated the association between behavioral and pathological changes. The results of the present study indicate that the APO-induced rotation, cylinder and rotarod tests are all sensitive and reliable strategies to predict the loss of TH+ neurons. These results provide a potential intervention time-point and a comprehensive evaluation index system for assessment of PD therapeutic strategies using the hemiparkinsonian rat. PMID- 29257291 TI - Bone morphogenetic protein 9 serves a protective role in response to ischemic reperfusion in the brain by promoting ERK activation. AB - The aim of the present study was to investigate the expression and function mechanism of bone morphogenetic protein 9 (BMP9) in cerebral ischemia-reperfusion (I/R) injuries in vivo and in vitro. A total of 40 Sprague-Dawley rats were randomly divided into four groups (n=10): i) Normal control; ii) sham surgery group, the procedure without occlusion; iii) I/R group, right middle cerebral artery occlusion (MCAO) followed by reperfusion; and iv) adenoviral vector (Ad) BMP9 + I/R group, Ad-BMP9 intracerebroventricular injection was performed 2 days prior to MCAO. Neurological deficit score and infarct volume were measured at 24 h following reperfusion. To further test the mechanism of BMP9, astrocytes were isolated and treated with Ad-BMP9, Ad-BMP9 + extracellular signal-regulated kinase (ERK) inhibitor PD098059, Ad-BMP9 + c-Jun N-terminal kinase inhibitor SP600125 and Ad-BMP9 + p38 inhibitor SB203580 for 24 h, followed by undergoing oxygen-glucose deprivation and reoxygenation (OGD/R) treatment. Cell viability and death were assessed by 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl) (4-sulfophenyl)-2H-tetrazolium and lactate dehydrogenase release, respectively. Gene expression was determined by quantitative polymerase chain reaction and western blotting. BMP9 was identified to be upregulated at mRNA and protein levels in cerebral I/R animal and cell models. BMP9 pretreatment significantly reduced the neurological score and infarct volume compared with I/R rats. In astrocytes, overexpression of BMP9 significantly decreased cell death and improved cell viability, an effect which may be mediated by the ERK signaling pathway, as ERK was activated by BMP9 and the use of PD098059 partially reversed the protective effect of BMP9. Pretreatment with BMP-9 may be a promising treatment option for prevention of cerebral I/R injuries. PMID- 29257293 TI - Proteomic analysis of synovial fluid in osteoarthritis using SWATH-mass spectrometry. AB - The lack of early diagnostic maneuvers and effective pharmacotherapy for osteoarthritis (OA) is predominantly attributed to current limited understanding of its pathogenesis. In the present study, the alteration of synovial fluid (SF) proteome in OA were analyzed using SWATH-mass spectrometry (SWATH-MS) to further elucidate the pathogenesis of OA. SF samples were collected from 10 OA and 10 rheumatoid arthritis (RA) patients undergoing arthroplasty and 10 patients undergoing arthroscopy for traumatic arthritis (meniscus injury without cartilage lesion). According to the Kellgren-Lawrence (KL) radiographic grading criteria, all the OA and RA patients were classified as KL grade 4. SWATH-MS was applied to identify differentially expressed proteins specifically regulated in OA. Differentially expressed proteins identified by SWATH-MS were subjected to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation. Proteins of interest were quantified by enzyme-linked immunosorbent assay (ELISA) following identification. With the use of SWATH-MS, 131 proteins were identified to be differentially expressed in OA, of which 93 corresponded to upregulation and 38 to downregulation. Complement C1r was the most significantly upregulated protein in OA. Twenty-eight out of the 131 proteins were specifically regulated in OA, of which 17 were upregulated and 11 were downregulated. Dickkopf related protein 2 (DKK2) was one of the proteins specifically upregulated in OA. Furthermore, KEGG pathway annotation indicated that differentially expressed proteins in OA were enriched in complement and coagulation cascades. ELISA indicated that OA severity was positively correlated with the levels of complement C1r (r=0.549; P<0.001) and DKK2 (r=0.79; P<0.001) in the SF. The results indicate that complement and coagulation cascades are involved in the pathogenesis of OA. Differentially expressed proteins, including complement C1r and DKK2 may be used as potential biomarkers or drug targets, which may facilitate with intervention of OA. PMID- 29257292 TI - Betulinic acid-induced expression of nicotinamide adenine dinucleotide phosphate diaphorase in the immune organs of mice: A possible role of nitric oxide in immunomodulation. AB - The aim of the present study was to investigate the effects of betulinic acid (BetA) on the expression and distribution pattern of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d), an indirect indicator of nitric oxide (NO) synthase in the thymus and spleen of mice. Mice were randomly assigned to four main groups (n=48 per group): Experimental group (BetA), positive control group (goniothalamin), vehicle control group (dimethyl sulfoxide) and control group (without vehicle). Each group was further divided into three equal subgroups according to the treatment length (4, 8 and 12 days). BetA treatment induced the expression of NADPH-d activity in the thymus and spleen without any significant changes in the morphology of the organs. Furthermore, the expression pattern of NADPH-d in BetA-treated animals was significantly increased compared with that in the control animals. NADPH-d expression in the thymus and spleen suggests that NO signaling may be a potential mechanism underlying the BetA induced immunomodulation in these organs. These findings are of direct clinical relevance and may contribute to the further development of BetA as a therapeutic drug. PMID- 29257294 TI - Baicalein protects against endothelial cell injury by inhibiting the TLR4/NF kappaB signaling pathway. AB - The involvement of vascular endothelial injury with the pathophysiological process of heart failure has been identified. Baicalein (BAI), a flavonoid extracted from the root of Scutellaria baicalensis, is reported to exert antibacterial, antiviral, antithrombotic and antioxidant effects. The aim of the present study was to investigate the effects of BAI on lipopolysaccharide (LPS) induced vascular endothelial injury. Human umbilical vein endothelial cells (HUVECs) were stimulated by LPS (10 uM) in the presence or absence of BAI. The expressions of the inflammatory cytokines interleukin (IL)-lbeta, IL-6, tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) were analyzed by reverse transcription-quantitative polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. Cell apoptosis was assessed by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The results showed that BAI significantly inhibited the LPS induced inflammatory response and apoptosis in HUVECs. BAI suppressed the LPS induced upregulation of IL-1beta, IL-6, TNF-alpha and MCP-1. Furthermore, BAI decreased the expression of B-cell lymphoma 2 (Bcl-2)-associated X protein and cleaved caspase-3; however, it increased the protein level of Bcl-2. The inhibitory effect of BAI may occur through the suppression of the Toll-like receptor 4 (TLR4)/phosphorylated (p)-transforming growth factor beta-activated kinase 1/tumor necrosis factor receptor-associated family member associated nuclear factor (NF)-kappaB activator-binding kinase 1 (p-TBK1)/NF-kappaB signaling pathway. An increase in the level of p-TBK1 by MRT67307 abolished the effect of BAI on p-p65. In conclusion, the results of the present research suggested that BAI ameliorated endothelial cell injury associated with TLR4/NF kappaB signaling, and highlighted the potential clinical use of BAI in blocking endothelial dysfunction and preventing heart failure. PMID- 29257296 TI - MicroRNA-675 inhibits cell proliferation and invasion in melanoma by directly targeting metadherin. AB - Melanoma is derived from melanocytes and accounts for ~80% of skin cancer associated fatalities worldwide. The dysregulation of microRNAs (miRNAs/miRs) is involved in the development and progression of melanoma. Therefore, miRNAs may be novel diagnostic or prognostic biomarkers and promising therapeutic targets in the treatment of patients with melanoma. miR-675 is differentially expressed in several types of human cancer and has important roles in the pathogenesis of several diseases. However, the expression levels and the biological roles of miR 675 in melanoma remain unclear. Therefore, the present study aimed to assess the expression of miR-675 in melanoma, explore the effects of miR-675 on melanoma cells and investigate the underlying molecular mechanisms that may be involved in the actions of miR-675. The present study indicated that miR-675 expression was downregulated in melanoma tissues and cell lines. Functional assays demonstrated that the upregulation of miR-675 impaired cell proliferation and invasion in melanoma. Bioinformatics analysis, luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction and western blot analysis demonstrated that metadherin (MTDH) was a direct target of miR-675 in melanoma. The MTDH levels were upregulated in melanoma tissues and inversely correlated with the miR-675 expression. Furthermore, restored MTDH expression rescued the inhibition effects in melanoma cells caused by miR-675 overexpression. Thus, miR 675 may be a potential therapeutic target for melanoma. PMID- 29257297 TI - Cancer-testis antigen HCA587/MAGEC2 interacts with the general transcription coactivator TAF9 in cancer cells. AB - Hepatocellular carcinoma-associated antigen 587/melanoma antigen gene (HCA587/MAGEC2) is a cancer-testis antigen, which is highly expressed in various types of tumors, but not in normal tissues with the exception of male germ-line cells. HCA587/MAGEC2 has been previously recognized as a tumor-specific target for immunotherapy; however, its biological functions have been relatively understudied. To investigate the function of HCA587/MAGEC2, the amino acid sequence of HCA587/MAGEC2 was analyzed by bioinformatics and it was demonstrated that HCA587/MAGEC2 contains a 9-amino acid transactivation domain which may mediate the interaction of most transcription factors with TATA-box binding protein associated factor 9 (TAF9), a general transcription coactivator. Co immunoprecipitation experiments revealed that HCA587/MAGEC2 interacted with TAF9 in transfected 293T and in A375 melanoma cells endogenously expressing HCA587/MAGEC2, and confirmed the endogenous interaction of HCA587/MAGEC2 and TAF9 within cells. Endogenous HCA587/MAGEC2 and TAF9 were demonstrated to be co localized principally in the nucleus of tumor cells using immunofluorescence. Glutathione-S-transferase pull-down experiments demonstrated that HCA587/MAGEC2 interacts with TAF9 directly and the conserved region in the TAF9 may becrucial for HCA587/MAGEC2 binding. The present study demonstrated that the cancer-testis antigen HCA587/MAGEC2 directly interacted with TAF9, which may provide novel information for identifying the oncogenic functions of HCA587/MAGEC2 in tumor cells. PMID- 29257295 TI - Identification of key pathogenic genes of sepsis based on the Gene Expression Omnibus database. AB - Sepsis is a life-threatening condition in which an uncontrolled inflammatory host response is triggered. The exact pathogenesis of sepsis remains unclear. The aim of the present study was to identify key genes that may aid in the diagnosis and treatment of sepsis. mRNA expression data from blood samples taken from patients with sepsis and healthy individuals was downloaded from the Gene Expression Omnibus database and differentially expressed genes (DEGs) between the two groups were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and protein-protein interaction (PPI) network construction, was performed to investigate the function of the identified DEGs. Furthermore, for validation of these results, the expression levels of several DEGs were analyzed by reverse transcription quantitative-polymerase chain reaction (RT-qPCR) in three patients with sepsis and three healthy blood samples to support the results obtained from the bioinformatics analysis. Receiver operating characteristic analyses were also used to analyze the diagnostic ability of the identified DEGs for sepsis. The results demonstrated that a total of 4,402 DEGs, including 1,960 upregulated and 2,442 downregulated genes, were identified between patients with sepsis and healthy individuals. KEGG pathway analysis revealed that 39 DEGs were significantly enriched in toll-like receptor signaling pathways. The top 20 upregulated and downregulated DEGs were used to construct the PPI network. Hub genes with high degrees, including interleukin 1 receptor-associated kinase 3 (IRAK3), S100 calcium-binding protein (S100)A8, angiotensin II receptor associated protein (AGTRAP) and S100A9, were demonstrated to be associated sepsis. Furthermore, RT-qPCR results demonstrated that IRAK3, adrenomedullin (ADM), arachidonate 5-lipoxygenase (ALOX5), matrix metallopeptidase 9 (MMP9) and S100A8 were significantly upregulated, while ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1) was upregulated but not significantly, in blood samples from patients with sepsis compared with healthy individuals, which was consistent with bioinformatics analysis results. Therefore, AGTRAP, IRAK3, ADM, ALOX5, MMP9, S100A8 and ENTPD1 were identified to have potential diagnostic value in sepsis. In conclusion, dysregulated levels of the AGTRAP, IRAK3, ADM, ALOX5, MMP9, S100A8 and ENTPD1 genes may be involved in sepsis pathophysiology and may be utilized as potential diagnostic biomarkers or therapeutic targets. PMID- 29257298 TI - Macrophage migration inhibitory factor promotes cardiac fibroblast proliferation through the Src kinase signaling pathway. AB - Atrial fibrosis is the fundamental characteristic of the structural pathology associated with atrial fibrillation (AF). Inflammation can contribute to atrial fibrosis, engendering AF. The present study aimed to investigate the role of macrophage migration inhibitory factor (MIF), a pleiotropic cytokine, in the regulation of proliferation and function of cardiac fibroblasts (CFs). Biochemical assays were performed to examine the expression of extracellular matrix (ECM) in human atrial tissues, and the proliferation and regulation of ECM induced by MIF in CFs. The expression of ECM, including collage type 3, alpha1 (Col-3A1), matrix metalloproteinase (MMP)-2/-9 and transforming growth factor (TGF)-beta was higher in patients with permanent AF, compared with patients in sinus rhythm (SR), and the expression levels of MIF were also increased in AF. Treatment of CFs with mouse recombinant MIF (rMIF; 40 nM) for 48 h was found to promote the proliferation of CFs. The MIF-induced CF proliferation was completely inhibited by tyrosine kinase inhibitor-PP1. rMIF treatment also stimulated the activation of Src kinase in CFs. In addition, MIF treatment upregulated the expression levels of fibrosis-related proteins, Col-1, Col-3, MMP-2/-9 and TGF beta, in the CFs. These results suggested that MIF was involved in the structural remodeling that accompanies AF, possibly by promoting the proliferation of CFs and increasing the expression of ECM. These data implicate inflammation as a potential driver of CF. PMID- 29257299 TI - A cellular spinal cord scaffold seeded with rat adipose-derived stem cells facilitates functional recovery via enhancing axon regeneration in spinal cord injured rats. AB - Spinal cord injury (SCI), usually resulting in severe sensory and motor deficits, is a major public health concern. Adipose-derived stem cells (ADSCs), one type of adult stem cell, are free from ethical restriction, easily isolated and enriched. Therefore, ADSCs may provide a feasible cell source for cell-based therapies in treatment of SCI. The present study successfully isolated rat ADSCs (rADSCs) from Sprague-Dawley male rats and co-cultured them with acellular spinal cord scaffolds (ASCs). Then, a rat spinal cord hemisection model was built and rats were randomly divided into 3 groups: SCI only, ASC only, and ASC + ADSCs. Furthermore, behavioral tests were conducted to evaluate functional recovery. Hematoxylin & Eosin staining and immunofluorence were carried out to assess histopathological remodeling. In addition, biotinylated dextran amines anterograde tracing was employed to visualize axon regeneration. The data demonstrated that harvested cells, which were positive for cell surface antigen cluster of differentiation (CD) 29, CD44 and CD90 and negative for CD4, detected by flow cytometry analysis, held the potential to differentiate into osteocytes and adipocytes. Rats that received transplantation of ASCs seeded with rADSCs benefited greatly in functional recovery through facilitation of histopathological rehabilitation, axon regeneration and reduction of reactive gliosis. rADSCs co-cultured with ASCs may survive and integrate into the host spinal cord on day 14 post-SCI. PMID- 29257300 TI - Involvement of upregulation of fibronectin in the pro-adhesive and pro-survival effects of glucocorticoid on melanoma cells. AB - Glucocorticoids (GCs) are important stress hormones, which are used as a concomitant medication during malignant tumor chemotherapy. Clinical and preclinical studies have linked GCs to melanoma growth and progression. However, the effects and mechanism of action of GCs on the adhesion and survival of melanoma cells are still unknown. In the present study the effect of dexamethasone (Dex), a synthetic GC, on fibronectin (FN) expression and its roles in regulating the adhesion and survival of melanoma cells were investigated. It was revealed that Dex significantly increased the levels of intracellular and secreted FN in melanoma cell lines by increasing glucocorticoid receptor-mediated FN protein stability. Additionally, it was demonstrated that Dex (100 nM) significantly promoted the adhesion and survival of melanoma cells. Silencing FN expression abrogated the pro-adhesive and pro-survival effects of Dex in melanoma cells. Extracellular FN significantly enhanced melanoma cell adhesion and survival in the presence of cisplatin, whereas partially blocking extracellular FN signaling with a CD44 antibody significantly reduced FN-enhanced adhesion and survival. This indicated that the upregulation of FN contributed to the pro survival effect of Dex by enhancing cell adhesion. It was also observed that activation of the PI3K/AKT signaling pathway by extracellular FN was involved in the FN-mediated increase in melanoma cell survival. These findings increase understanding of the possible mechanisms by which GCs regulate melanoma cell adhesion and survival. PMID- 29257301 TI - miR-138 modulates prostate cancer cell invasion and migration via Wnt/beta catenin pathway. AB - The prognosis for prostate cancer patients with distant metastasis is poor, with an average survival rate of 24-48 months. The exact mechanisms underlying prostate cancer metastasis remain to be elucidated, despite previous research efforts. The present study aimed to reveal the regulatory roles of miR-138 via Wnt/beta-catenin pathway in prostate cancer cell migration and invasion. Reverse transcription-quantitative polymerase chain reaction was used to examine the mRNA and protein expression levels and transwell assay was conducted to determine cell invasion and migration. A luciferase reporter assay was used to determine the target association between miR-138 and beta-catenin. The present study identified microRNA (miR)-138 as an invasion and migration regulator in prostate cancer. miR 138 was downregulated in aggressive prostate cancer cell lines. Furthermore, followingmiR-138 overexpression, prostate cancer cells exhibited impaired invasive and migratory abilities. E-cadherin was upregulated and vimentin was downregulated. In addition, it was demonstrated that miR-138 negatively regulated the Wnt/beta-catenin pathway activation in prostate cancer. The pathway was then activated via beta-catenin overexpression and this reversed the effects of miR 138. The results suggest that miR-138 downregulation may contribute to prostate cancer progression and metastasis. The findings provide a novel molecular therapeutic target in the treatment of prostate cancer metastasis. PMID- 29257302 TI - Construction and protective immunogenicity of DNA vaccine pNMB0315 against Neisseria meningitidis serogroup B. AB - Neisseria meningitidis (N. meningitidis) is a major cause of meningitis and sepsis. Capsular polysaccharide-based vaccines against serogroups A, C, Y, and W135 are available; however, the development of a vaccine against N. meningitidis serogroup B (NMB) has been problematic. NMB0315 is an outer membrane protein of NMB that may be a virulence factor for N. meningitidis and a possible target for functional bactericidal antibodies. The present study aimed to develop a potent DNA vaccine against NMB by cloning the NMB0135 gene into the pcDNA3.1(+) vector to construct the recombinant plasmid pcDNA3.1(+)/NMB0315 (designated pNMB0315). pNMB0315 was transfected into eukaryotic COS-7 and RAW264.7 cells to express the recombinant (r)NMB0315 protein. Protective immunogenicity of the DNA vaccine was assessed in an in vivo mouse model. The levels of rNMB0315-specific immunoglobulin G (IgG), IgG1 and IgG2a antibodies in the pNMB0315-immunized group increased dramatically up to week 6 following the initial vaccination, and were significantly higher compared with the levels in the Control groups. The serum concentrations of interleukin-4 and interferon-gamma were significantly higher in the pNMB0315-immunized group compared with the control groups. Following intraperitoneal challenge with a lethal dose of NMB strain MC58, the survival rate in the pNMB0315 + CpG group was 70% (14 out of 20 mice) at 14 days; by contrast, all mice in the control groups succumbed within 3 days. The serum bactericidal titers of the pNMB0315 + CpG group in vitro reached 1:128 following three immunizations. The results indicated that pNMB0315 may serve as a promising DNA vaccine against NMB. PMID- 29257303 TI - Twenty-four signature genes predict the prognosis of oral squamous cell carcinoma with high accuracy and repeatability. AB - Oral squamous cell carcinoma (OSCC) is the sixth most common type cancer worldwide, with poor prognosis. The present study aimed to identify gene signatures that could classify OSCC and predict prognosis in different stages. A training data set (GSE41613) and two validation data sets (GSE42743 and GSE26549) were acquired from the online Gene Expression Omnibus database. In the training data set, patients were classified based on the tumor-node-metastasis staging system, and subsequently grouped into low stage (L) or high stage (H). Signature genes between L and H stages were selected by disparity index analysis, and classification was performed by the expression of these signature genes. The established classification was compared with the L and H classification, and fivefold cross validation was used to evaluate the stability. Enrichment analysis for the signature genes was implemented by the Database for Annotation, Visualization and Integration Discovery. Two validation data sets were used to determine the precise of classification. Survival analysis was conducted followed each classification using the package 'survival' in R software. A set of 24 signature genes was identified based on the classification model with the Fi value of 0.47, which was used to distinguish OSCC samples in two different stages. Overall survival of patients in the H stage was higher than those in the L stage. Signature genes were primarily enriched in 'ether lipid metabolism' pathway and biological processes such as 'positive regulation of adaptive immune response' and 'apoptotic cell clearance'. The results provided a novel 24-gene set that may be used as biomarkers to predict OSCC prognosis with high accuracy, which may be used to determine an appropriate treatment program for patients with OSCC in addition to the traditional evaluation index. PMID- 29257304 TI - Leucine-rich glioma inactivated 3: Integrative analyses reveal its potential prognostic role in cancer. AB - Leucine-rich glioma inactivated 3 (LGI3) is a secreted protein in vertebrates, which belongs to the LGI family. In our previous study, LGI3 was found to be expressed in brain, adipose tissues and the skin, where it functions as a multifunctional cytokine. In the present study, we used bioinformatic tools to perform data mining, phylogenetics and prognostic association analysis to investigate the prognostic role of LGI3 in cancers. The sequences of LGI3 orthologues were analyzed from various species, and it was found that LGI3 was highly conserved in mammals and that the subsets of amino acid residues were phylogenetically coevolved in four major clusters. Single nucleotide polymorphisms (SNPs) of the human LGI3 gene included 228 functionally relevant variants (missense, nonsense and frameshift) in a total of 1,042 SNPs. Four missense SNPs had a global minor allele frequency >=0.001. Somatic mutations in cancer with functional relevance were found in various types of cancer, including uterine, stomach and lung cancer. In addition, five amino acid residues with cancer mutations were shown to be coevolved in the vertebrate phylogeny, suggesting their importance in protein dysfunctions in cancer. One conserved amino acid and three SNPs were found to be mutated in stomach cancer and melanoma. Analysis of expression microarray data demonstrated that the expression of LGI3 was significantly associated with the prognosis of brain, colorectal and lung cancer. Taken together, these results suggested that the genetic variations and expression levels of LGI3 have potential value in cancer prognosis. PMID- 29257305 TI - Copper chloride dose-dependently alters spatial learning and memory, and glutamate levels, in the hippocampus of rats. AB - Copper is a trace element which exerts an important role in neuronal functions. Excessive Cu exposure is associated with central nervous system dysfunction, including memory loss. The present study examined the effects of CuCl2 exposure on the spatial learning and memory of rats, and on metabolites in the hippocampus. A total of 60 male Sprague-Dawley rats (10 rats/group) were intraperitoneally injected with various doses (0, 0.5, 1.0, 2.0, 4.0 and 6.0 mg/kg) of CuCl2 three times every other day for 6 days. Rats administered with 1.0 ml/kg sterile saline were used as controls. A total of 2 days subsequent to the final injection, the rats were subjected to the Morris water maze (MWM) test, followed by proton magnetic resonance spectroscopy (1H-MRS). The rats were subsequently sacrificed, and their hippocampal tissues were processed for high performance liquid chromatography (HPLC). The MWM test demonstrated that the high dose groups exhibited worse spatial learning and memory compared with the controls; however, the rats that received a relatively low dose (2.0 mg/kg) exhibited a decreased impairment. The 1H-MRS results revealed increased Glu, N acetyl-L-aspartate (NAA)+N-acetylaspartylglutamate, phosphocreatine (PCr) and Cr+PCr levels in the hippocampus of the 2.0 mg/kg group. HPLC analysis revealed increased gamma-aminobutyric acid and glutamate (Glu) levels in the 2.0 mg/kg group, and decreased Glu levels in the 6.0 mg/kg group. The results of the present study demonstrated a beneficial effect of short-term exposure to a relatively low dose of CuCl2 on spatial learning and memory, and the association of this effect with increased NAA and Glu levels in the hippocampus. PMID- 29257306 TI - Structural elucidation of galactomannan from seeds of Crotalaria mucronata Desv. by atomic force microscopy. AB - A non-ionic water-soluble galactomannan, isolated from the seed endosperm of Crotalaria mucronata Desv., may be an ideal thickener to increase food viscosity. The present study hypothesized that the viscous property of Crotalaria galactomannan may be associated with its spatial structure. Therefore, the structure of Crotalaria galactomannan was elucidated using an atomic force microscope. The results of the present study demonstrated that the polysaccharide consisted of a D-mannose backbone with D-galactose branches, and the D-mannose/D galactose ratio was 2.375:1. In the three-dimensional structure of Crotalaria galactomannan, the helix was a common secondary structure, containing numerous ring structures of different sizes. In addition, multiple helixes may link together via hydrogen bonding and van der Waals forces, forming aggregations with small rings or spiral windings. The results of the present study indicated that the multiple-branching construction of Crotalaria galactomannan may underlie its viscosity-enhancing properties in the water phase. PMID- 29257307 TI - Insulin-like growth factor 1 inhibits autophagy of human colorectal carcinoma drug-resistant cells via the protein kinase B/mammalian target of rapamycin signaling pathway. AB - Insulin-like growth factor 1 (IGF-1) is reported to inhibit autophagy of human colorectal carcinoma cells (HCT); however, little is known regarding the mechanisms underlying the inhibitory effect of IGF-1 on autophagy in HCT resistant strains. The present study aimed to analyze the inhibitory effect of IGF-1 on the autophagy of HCT resistant strains and its potential underlying mechanisms. The viability and apoptosis of HCT-8 colon cancer cells were analyzed, and expression levels of relevant genes and proteins were investigated using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Treatment of cells with IGF-1 induced apoptosis. IGF 1 treatment activated protein kinase B (AKT), which may inhibit autophagy via the AKT/mammalian target of rapamycin signaling pathway. Following inhibition of autophagy, drug resistant cells became sensitive to apoptosis induced by 5 fluorouracil. PMID- 29257308 TI - CRISPR/Cas9 targeting of the androgen receptor suppresses the growth of LNCaP human prostate cancer cells. AB - Androgens have been recognized to be primary causative agents of prostate cancer. Following binding to the androgen receptor (AR), androgens serve important roles in the carcinogenesis of prostate cancers. ARs serve an important role during all stages of prostate cancer, and inhibiting their function may help to slow prostate cancer growth. In the present study, the AR gene was targeted in androgen-positive prostate cancer cells using the clustered regularly interspaced short palindromic repeats-associated protein (CRISPR/Cas) system. A total of three different single-guide RNAs (sgRNAs) were designed according to the three different target sites in the AR gene. The optimal sgRNA with a specific target effect was effectively screened to cleave the AR gene in androgen-positive prostate cancer cell lines, and to suppress the growth of androgen-sensitive prostate cancer in vitro. The AR-sgRNA-guided CRISPR/Cas system was able to disrupt the AR at specific sites and inhibit the growth of androgen-sensitive prostate cancer cells; further studies demonstrated that the decreased cell proliferation was due to cellular apoptosis. The results of the present study suggested that the CRISPR/Cas system may be a useful therapeutic strategy for the treatment of prostate cancer. PMID- 29257309 TI - SPOCD1 promotes cell proliferation and inhibits cell apoptosis in human osteosarcoma. AB - Osteosarcoma is the most common type of malignant bone tumors that typically affects adolescents and children. The spen paralogue and orthologue C-terminal domain containing 1 (SPOCD1) is a newly identified molecule that has been indicated to discriminate progressive from non-progressive bladder cancers. However, the role of SPOCD1 in human solid tumors remains largely unknown. In the present study, SPOCD1 was upregulated in clinical osteosarcoma tissues compared with adjacent non-cancerous tissues. Furthermore, SPOCD1 was upregulated in osteosarcoma cell lines and expression was particularly increased in highly invasive cells MG63 and SAOS2. Further investigation revealed that downregulation of SPOCD1 inhibited the MG63 and SAOS2 osteosarcoma cell colony formation and proliferation capacity. In addition, cell apoptosis was promoted by knockdown of SPOCD1 in MG63 and SAOS2 cells. These effects were confirmed by measuring the Ki67 and PCNA expression. In addition, SPOCD1 positively regulated the expression of vascular endothelial growth factor A (VEGF-A). Knockdown of VEGF-A blunted SPOCD1 downregulation-mediated inhibition of cell proliferation and induction of cell apoptosis. These results suggested that SPOCD1 may act as a pro-oncogenic factor in osteosarcoma. Inhibition of VEGF may aid in treating osteosarcoma in clinic. PMID- 29257311 TI - Effect of asiaticoside on endothelial cells in hypoxia-induced pulmonary hypertension. AB - Pulmonary hypertension (PH) is a chronic progre-ssive disease with limited treatment options. The exact etiology and pathogenesis of PH remain to be elucidated, however there is novel evidence that implicates abnormal endothelial cells (ECs) apoptosis and dysfunction of ECs to be involved in the initiation of PH. Asiaticoside (AS) is a saponin monomer extracted from a medicinal plant called Centella asiatica, which had a preventing effect of hypoxia-induced pulmonary hypertension (hypoxic PH) by blocking transforming growth factor beta1/SMAD family member 2/3 signaling in our previous study. The present study demonstrated that AS can prevent the development of hypoxic PH and reverse the established hypoxic PH. AS may activate the nitric oxide (NO)-mediated signals by enhancing the phosphorylation of serine/threonine-specific protein kinase/eNOS, thus promoting NO production, and prevent ECs from hypoxia-induced apoptosis. All these findings imply that AS may be a potential therapeutic option for hypoxic PH patients due to its effect on the vitality and function of endothelial cells. PMID- 29257310 TI - Lower level of IL-35 and its reduced inhibition in Th17 cells in patients with bone marrow mononuclear cells Coombs test-positive hemocytopenia. AB - Interleukin (IL)-35 is the latest member of IL-12 family, which plays an important role in other autoimmune diseases. Bone marrow mononuclear cells Coombs test-positive hemocytopenia, also termed immunorelated hemocytopenia (IRH) is a type of autoimmune-associated diseases. The present study investigated the relationship of IL-35 in patients with IRH. A total of 43 patients with IRH and 19 normal controls were enrolled in the current study. Serum levels of IL-35 and IL-17 in peripheral blood were evaluated by ELISA. Regulatory T cells (Tregs) level was detected by flow cytometry and IL-35 subunits mRNA in Treg was determined using reverse transcription-quantitative polymerase chain reaction: Epstein-Barr virus induced 3 (EBI3) and IL-12alpha chain p35. Effect of IL-35 on T helper 17 cells (Th17) cells was determined by mix-culture of IL-35 with CD4+ T lymphocytes. Serum level of IL-35 was decreased in untreated patients with IRH compared with remission patients (P<0.01) and was significantly associated with clinical indexes. Frequency of IL-35 produced Tregs was lower and IL-35 subunits mRNA in CD4+CD25+ Tregs were decreased in patients with IRH compared with health controls (P<0.01). Serum level of IL-17 was increased in patients with IRH (P<0.01) and there was a negative correlation between IL-35 and IL-17 (r=-0.553; P<0.01). The production of Th17 cells and IL-17A mRNA expression were reduced (P<0.05) after mix-culture of CD4+ T lymphocytes with IL-35 compared with mix culture of CD4+ T lymphocytes without IL-35. In conclusion, the present study revealed that IL-35 may be a monitoring indicator of IRH occurrence and progression. IL-35 level was lower and the inhibition on Th17 cells was reduced in the patients with IRH. PMID- 29257312 TI - Effect of genistein on myocardial fibrosis in diabetic rats and its mechanism. AB - The aim of the present study was to investigate the effects of genistein (GEN) on myocardial fibrosis in type 1 diabetic rats and explore the underlying mechanisms. Rats were divided into 4 groups: Normal control (N), diabetic control (D), low-dose GEN treatment (L) and high-dose GEN treatment (H) groups. Following 8 weeks, the ventricular hemodynamic parameters, fasting blood glucose (FBG), heart-weight to body-weight ratio (HW/BW), myocardial hydroxyproline (Hyp) content, serum creatine kinase MB isozyme (CK-MB), lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) levels were measured. The histomorphology and ultrastructure of the heart were observed. The protein expression of myocardial transforming growth factor-beta1 (TGF-beta1), mothers against decapentaplegic homolog (Smad) 3, phosphorylated (p)-Smad3, Smad4, collagen-I and collagen-III were estimated. Compared with the N group, while the cardiac function was decreased, the levels of FBG, HW/BW, Hyp content, CK-MB, LDH, TNF-alpha, IL-1beta and IL-6 were increased in the D group. The myocardial histomorphological alterations and ultrastructure were damaged, and the protein expression of myocardial TGF-beta1, Smad3, p-Smad3, Smad4, collagen-I and collagen-III were increased in the D group. Compared with the D group, there were no differences in the ventricular hemodynamic parameters, FBG and p-Smad3 expression in the L group, while HW/BW, Hyp content, CK-MB, LDH, TNF-alpha, IL-1beta and IL-6 levels were decreased. The myocardial histomorphological damage was alleviated and the protein expression of TGF-beta1, Smad3, Smad4, collagen-I and collagen-III was decreased in the L group. Compared with L group, excluding FBG, the aforementioned indices were improved in the H group. In conclusion, GEN can attenuate myocardial fibrosis in type 1 diabetic rats, and the underlying mechanisms may be associated with the reduction of CK-MB and LDH leakage, inhibition of the inflammatory reaction, and suppression of the TGF-beta1/Smad3 signaling pathway to regulate collagen expression. PMID- 29257313 TI - Association of aquaporin-1 with tumor migration, invasion and vasculogenic mimicry in glioblastoma multiforme. AB - The present study aimed to assess the expression and functional role of aquaporin 1 (AQP1) in glioblastoma multiforme (GBM) migration, invasion and vasculogenic mimicry (VM). In the primary human gliomas and human glioma-derived cell lines tested, it was observed that the expression of AQP1 was upregulated. In addition, it was demonstrated that silencing of AQP1 expression resulted in decreased migration and invasion, in addition to vasculogenic mimicry in vitro. It was additionally observed that silencing of AQP1 expression resulted in in vivo inhibition of tumor growth, a decrease in the expression of invasion-associated protein, and suppression of VM formation. Based on these data, it was concluded that AQP1 may serve a role in GBM migration, invasion and VM formation, and that it may serve as a novel diagnostic/prognostic biomarker and a potential therapeutic target. PMID- 29257314 TI - Hypoxia-induced Rab11-family interacting protein 4 expression promotes migration and invasion of colon cancer and correlates with poor prognosis. AB - Rab11-family interacting proteins (Rab11-FIPs) are associated with the progression of various tumors; however, their expression and clinical significance in colorectal cancer (CRC) remains largely undetermined. In this study, the clinical implications, functions and underlying mechanisms of Rab11 FIP4 in CRC were investigated. Immunohistochemical analysis revealed that expression of Rab11-FIP4 was significantly increased in human CRC tissues and correlated with poor prognosis of patients with CRC. Overexpression of Rab11-FIP4 in the CRC cell line significantly promoted cell proliferation, migration and invasion in vitro and tumor metastasis in vivo. Furthermore, the results of a co immunoprecipitation assay and western blot analysis demonstrated that Rab11-FIP4 interacted with Rab11 and insulin-like growth factor 1 receptor, and increased the phosphorylation of extracellular signal-regulated kinase 1/2 and AKT serine/threonine kinase. In addition, hypoxia contributed to the upregulation of Rab11-FIP4 expression via hypoxia-inducible factor-1alpha activation of the Rab11 FIP4 promoter. In conclusion, the results of the present study suggest that Rab11 FIP4 may act as an oncogene in CRC, and may be a potential therapeutic target for the treatment of patients with CRC. PMID- 29257315 TI - [Erratum] Exogenous regucalcin suppresses the proliferation of human breast cancer MDA-MB-231 bone metastatic cells in vitro. AB - Following the publication of this article, the authors noted that Fig. 1 appeared incorrectly in the journal. Essentially, the figure was reorganized but only the labels for Fig. 1B and C were switched around, with the result that Fig. 1B and C were labelled incorrectly in the paper. The corrected figure is shown here, with the figure parts for Fig. 1B and C now labelled correctly. This error was introduced into the figure during the pre-press stages. The editorial office wishes to apologize to the authors for this mistake, and we regret the inconvenience this mistake has caused. [the original article was published in the Molecular Medicine Reports 12: 7801-7805, 2015; DOI: 0.3892/mmr.2015.4352]. PMID- 29257316 TI - Rapid flow cytometry-based assay for the evaluation of gammadelta T cell-mediated cytotoxicity. AB - The effector function of natural killer, lymphokine--activated killer cells and T lymphocytes is commonly evaluated by radioactive chromium-release cytotoxicity assays. In addition to this indirect method, fluorescence assays have been described for the assessment of in vitro cell-mediated cytotoxicity. In the present study, target cells were stained with 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE), which is a stable integrated fluorescent probe that allows target and effector cells to be distinguished from one another. Staining of target THP-1 cells with 8 uM CFSE revealed high and stable loading of fluorescence and no effect of the viability of cells. After 4 h of in vitro co culture between gammadelta T cells and CFSE-labeled infected or uninfected THP-1 cells, staining with propidium iodide (PI) was performed to distinguish between vital and dead cells. During sample acquisition, target cells were gated on the CFSE positivity and examined for cell death based on the uptake of PI. CFSE and PI double positive cells were recognized as the dead target cells. The percentage of cytotoxicity in the CFSE-gated cell population was calculated by subtracting the value obtained for non-specific PI-positive target cells, which was measured in a control group that did not contain effector cells. The present study describes a simple and convenient assay that is based on the direct quantitative and qualitative analysis of cell damage at a single cell level utilizing a two color flow cytometric assay. In conclusion, the flow cytometric-based assay described in the current study is a simple, sensitive and reliable tool to determine the cytolytic activity of gammadelta T lymphocytes against mycobacteria. Therefore, the present study may provide valuable information concerning the methods employed to investigate the function of gammadelta T cells and potentially other lymphocyte subsets. PMID- 29257317 TI - Crosstalk between human endometrial stromal cells and decidual NK cells promotes decidualization in vitro by upregulating IL-25. AB - Embryo implantation is essential for a successful pregnancy, and leads to the decidualization of endometrial stromal cells (ESCs) in the secretory phase of the menstrual cycle. It has previously been demonstrated that decidual stromal cells (DSCs) co-express interleukin (IL)-25/IL-17RB and that IL-25 further promotes the proliferation of DSCs via activating c-Jun n-terminal kinase and protein kinase B signals, therefore the present study primarily focused on the role of IL-25 in the process of decidualization in vitro. It was demonstrated that the expression of IL-25/IL-17RB in ESCs was decreased compared with DSCs. In addition, following decidualization, the expression levels of IL-25/IL-17RB in ESCs were significantly elevated. Recombinant human (rh) IL-25 promoted the decidualization of ESCs in the presence of 8-bromoadenosine 3',5'-cyclic monophosphate sodium salt and 6alpha-methyl17alpha-acetoxyprogesterone, which was partially inhibited by anti-human IL-25 neutralizing antibody (anti-IL-25) or anti-IL-17RB. In addition, decidual natural killer (dNK) cells not only secreted IL-25, however also further accelerated the decidualization in vitro. Therefore, these findings indicated that ESCs differentiate into DSCs in the presence of ovarian hormones, resulting in the upregulation of IL-25/IL-17RB expression in ESCs. Furthermore, IL-25 secreted by ESCs and dNK cells further facilitates the decidualization of ESCs, which may form a positive feedback mechanism at the maternal-fetal interface and thus contribute to the establishment and maintenance of normal pregnancy. PMID- 29257318 TI - Identification of key pathways and genes in Barrett's esophagus using integrated bioinformatics methods. AB - Barrett's esophagus (BE) is a premalignant lesion of esophageal adenocarcinoma. The aim of the present study was to investigate the possible mechanisms and biomarkers of BE. To identify the differentially expressed microRNAs (DEmiRNAs) and genes (DEGs) in BE, the miRNA expression profile GSE20099 and the gene expression profiles GSE26886, GSE13083 and GSE34619 were obtained from the Gene Expression Omnibus (GEO) database. DEGs and DEmiRNAs were screened for using the GEO2R tool. Using DAVID, functional and pathway enrichment analysis was performed to explore the biological function of identified DEGs. The protein-protein interaction (PPI) network was detected using STRING and constructed by Cytoscape software. Furthermore, targets of identified DEmiRNAs were predicted by the miRecords database, then integrated with the identified DEGs to obtain key genes involved in BE. In total, 311 DEGs were identified. These genes were significantly enriched in the pancreatic secretion, metabolic pathways and cytochrome P450 drug metabolism pathways. In the PPI network, 16 hub genes, including keratin 16, cystic fibrosis transmembrane conductance regulator, involucrin, protein kinase C alpha and cadherin 17 were identified. Following integration of the predicted target genes of DEmiRNAs with DEGs, three key BE genes were identified: PRKCA, CDH17 and epiregulin. In conclusion, a comprehensive bioinformatics analysis of identified DEGs and DEmiRNAs was performed to elucidate potential pathways and biomarkers involved in the development of BE. PMID- 29257319 TI - Plant flavonoid taxifolin inhibits the growth, migration and invasion of human osteosarcoma cells. AB - The aim of the present study was to investigate the anti-cancer effects of the natural plant flavonoid, taxifolin, on human osteosarcoma cancer cells. Taxifolin was demonstrated to exhibit anti-cancer effects on U2OS and Saos-2 osteosarcoma cell lines. Treatment of cells with taxifolin inhibited proliferation and diminished colony formation in soft agar in a dose-dependent manner. In vivo, intraperitoneal administration of taxifolin in nude mice bearing U2OS xenograft tumors, significantly inhibited tumor growth. In addition, taxifolin treatment was demonstrated to promote G1 cell cycle arrest and cell apoptosis in U2OS and Saos-2 cell lines, as demonstrated by flow cytometry analysis. Western blot analysis demonstrated that taxifolin treatment was associated with a reduction in the expression levels of AKT serine/threonine kinase 1 (AKT), phosphorylated (p Ser473) AKT, v-myc avian myelocytomatosis viral oncogene homolog (c-myc) and S phase kinase associated protein 2 (SKP-2) in U2OS and Saos-2 cell lines. Overexpression of AKT considerably reversed the taxifolin-induced decrease in AKT, c-myc and SKP-2 protein expression and the decrease in AKT phosphorylation, suggesting that inactivation of AKT was a mediator of taxifolin-induced inhibition of c-myc and SKP-2. Furthermore, overexpression of SKP-2 in U2OS cells partially reversed the growth inhibition mediated by taxifolin. Finally, taxifolin treatment repressed cell migration and invasion in U2OS cells and this effect was markedly reversed by SKP-2 overexpression. The results of the present study indicate that taxifolin may present a potential novel therapeutic agent for osteosarcoma treatment. PMID- 29257320 TI - MicroRNA-103 suppresses glioma cell proliferation and invasion by targeting the brain-derived neurotrophic factor. AB - Glioma is the most common and aggressive of malignant brain tumours. MicroRNAs (miRNAs/miRs) are involved in tumour development of various human cancers, including glioma. Therefore, miRNAs may have potential tumour diagnostic, prognostic and therapeutic values in human glioma. miR-103 is abnormally expressed in various human cancer types. However, the detailed expression pattern, biological functions and underlying molecular mechanism of miR-103 in glioma remain unclear. Therefore, the present study aimed to investigate the expression, biological roles and underlying mechanisms of miR-103 in glioma. Results of the present study demonstrated that miR-103 was significantly down regulated in glioma tissues and cell lines. Functional experiments demonstrated that miR-103 overexpression inhibited the proliferation and invasion of glioma cells in vitro. Additionally, brain-derived neurotrophic factor (BDNF) was identified as a direct functional target of miR-103 in glioma. Furthermore, mRNA and protein expression levels of BDNF were highly upregulated in glioma tissues compared with normal brain tissues. Spearman's correlation analysis indicated a negative association between miR-103 and BDNF mRNA expression levels in glioma tissues. Furthermore, rescue experiments demonstrated that BDNF up-regulation reversed the suppressive effects of miR-103 on glioma cell proliferation and invasion. Therefore, the authors of the present study hypothesized that the interaction between miR-103 and BDNF serves a role in glioma progression and, in the future, may serve as a therapeutic target for glioma treatment. PMID- 29257321 TI - Improving insulin resistance with Antrodia cinnamomea mycelium powder to induce a hypoglycemic effect in dexamethasone-induced insulin-resistant rats. AB - Insulin resistance is a major factor in type II diabetes development, occurring when insulin levels are normal, but do not have normal interactions with adipose, muscle or liver tissue. The present study aimed to explore the hypoglycemic effect of Antrodia cinnamomea (AC) mycelium powder by evaluating its impact on insulin resistance and plasma free fatty acid (FFA) levels in steroid-induced insulin-resistant (SIIR) rats. Male Wistar rats were administered dexamethasone for 5 days to induce insulin resistance. The SIIR rats were subsequently randomly assigned into three experimental groups (EGs) and a control group (CG), where saline was orally administered. The EGs were orally administered different doses of AC (100, 200 or 500 mg/kg) and an optimal dose for further study was determined. Changes in plasma insulin and glucose levels were calculated to investigate the hypoglycemic effect of AC. To evaluate insulin resistance, the homeostasis model assessment-estimated insulin resistance of the SIIR rats was determined. Changes in plasma FFA levels were detected and levels of insulin signal proteins (IRS-1, GLUT-4 and PI3K) were analyzed by western blot to elucidate AC's mechanism of action. The SIIR rats exhibited significantly decreased plasma glucose levels in the first 30 min, with plasma FFA levels displaying a marked downward trend (P<0.05) when they were administered the optimal dose of AC (200 mg/kg). The decrease in plasma glucose and FFA levels was significantly larger in the EG compared to the CG, and insulin signal protein levels were also significantly increased (P<0.05). The hypoglycemic effect observed may be due to decreased plasma FFA levels and increased expression of intracellular insulin signal proteins. Furthermore, insulin sensitivity was enhanced, indicating that AC acts as an insulin sensitizer in insulin resistant animal models. PMID- 29257322 TI - Human parvovirus B19 nonstructural protein NS1 activates NLRP3 inflammasome signaling in adult-onset Still's disease. AB - Dysregulation of inflammasomes serves a pathogenic role in autoinflammatory diseases (AIDs) and adult-onset Still's disease (AOSD) has been categorized as an AID. The present study investigated the expression of NLR family pyrin domain containing proteins (NLRPs) inflammasome in patients with AOSD, the effect of inflammasome inhibitors on NLRP3 signaling and whether human parvovirus B19 associated antigens can activate NLRP3 in patients with AOSD. mRNA expression levels of NLRPs in peripheral blood mononuclear cells (PBMCs) from 34 patients with AOSD and 14 healthy individuals were determined using reverse transcription quantitative polymerase chain reaction. Protein expression of NLRP3 was evaluated by western blotting. Supernatant cytokine levels were measured by ELISA. Among the NLRPs investigated in the present study, NLRP3 transcripts were markedly elevated and expression of NLRP2, NLRP7 and NLRP12 was decreased in patients with AOSD compared with the controls. Treatment with NLRP3 inhibitors significantly reduced downstream NLRP3 signaling in PBMCs form patients with AOSD. B19 nonstructural protein (NS)1 stimulation of PBMCs from patients with AOSD induced significant upregulation of transcript levels of NLRP3, caspase-1 and interleukin (IL)-1beta compared with PBMCs from healthy controls. B19-NS1 stimulation of PBMCs from patients with AOSD induced significant increase in supernatant levels of IL-1beta and protein expression of NLRP3, caspase-1, IL-1beta, and IL-18 compared with healthy controls. Elevated expression of NLRP3 and its downstream inflammasome signaling components in patients with AOSD indicated a potential pathogenic role of B19-NS1. Thus, B19-NS1 may induce expression of IL-1beta and IL-18 through activation of caspase-1-associated NLRP3-inflammasome in AOSD. PMID- 29257323 TI - The effects of oxyresveratrol abrogates inflammation and oxidative stress in rat model of spinal cord injury. AB - Oxyresveratrol and its glycoside are important natural active materials. As an effective tyrosine kinase inhibitor, oxyresveratrol may prevent herpes virus infection, inflammation and oxidative stress, as well as protect nerves. In addition, it is known to inhibit cell apoptosis following cerebral ischemia. In recent years, oxyresveratrol and its glycoside have been widely investigated, and their useful biological activities have been explored, indicating that they may be worthy of further comprehensive research. The aim of the present study was to evaluate the photoprotective effects of oxyresveratrol and its ability to abrogate inflammation and oxidative stress in a rat model of spinal cord injury (SCI). The authors identified that oxyresveratrol significantly reversed the SCI induced inhibition of Basso, Beattie, and Bresnahan scores, inhibited the SCI mediated increase in spinal cord water content, significantly suppressed SCI induced nuclear factor-kappaB/p65, tumor necrosis factor-alpha, interleukin (IL) 1beta and IL-6 activities and reversed the malondialdehyde, superoxide dismutase, glutathione (GSH) and GSH peroxidase activities in SCI rats. SCI-induced granulocyte-macrophage colony-stimulating factor (GM-CSF), inducible nitric oxide synthase (iNOS) and cyclo-oxygenase-2 (COX-2) protein expression was significantly suppressed by oxyresveratrol, and SCI-mediated inhibition of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein expression was significantly increased by oxyresveratrol. In conclusion, these results suggest that the effects of oxyresveratrol restores SCI, and abrogates inflammation and oxidative stress in rat model of SCI via the GM-CSF, iNOS, COX-2 and Nrf2 signaling pathway. PMID- 29257324 TI - Effects of Cynanchum wilfordii on osteoporosis with inhibition of bone resorption and induction of bone formation. AB - Cynanchum wilfordii Hemsley has been used for the treatment of musculoskeletal diseases in traditional Republic of Korean medicine. The present study investigated the effects of C. wilfordii water extract (CW) on postmenopausal osteoporosis. Female mice were used and randomly assigned into a normal group and three ovariectomized (OVX) groups: OVX with vehicle (OVX + vehicle); OVX with 17beta-estradiol (E2; 10 ug/kg/day); and OVX with CW (1 mg/kg/day). Oral administration of CW or E2 intraperitoneal injection began 9 weeks after OVX and continued for 3 weeks. Following sacrifice, bone histology, bone mineral density (BMD) and bone mineral content (BMC) of the femur were observed. Serum osteocalcin concentration was analyzed. In addition, the expression levels of osteoprotegerin (OPG) and osterix were evaluated in human osteoblast-like Saos-2 cells. In the lateral and medial epicondyles of the CW-administrated group, dense and well-formed bone marrow cells with reduced bone marrow pores were observed. CW decreased the number of tartrate resistant acid phosphatase-positive multinucleated osteoclasts. BMD and BMC were increased following increased serum osteocalcin levels by CW treatment. The expression levels of OPG and osterix were upregulated by CW treatment in vitro. The results suggested that C. wilfordii has an advantageous effect on osteoporosis and possesses the potential to be used in osteoporosis treatment. PMID- 29257325 TI - Optimization and enrichment of induced cardiomyocytes derived from mouse fibroblasts by reprogramming with cardiac transcription factors. AB - Ischemic heart disease within developed countries has been associated with high rates of morbidity and mortality. Cell-based cardiac repair is an emerging therapy for the treatment of cardiac diseases; however, a limited source of the optimal type of donor cell, such as an autologous cardiomyocyte, restricts clinical application. The novel therapeutic use of induced pluripotent stem cells (iPSCs) may serve as a unique and unlimited source of cardiomyocytes; however, iPSC contamination has been associated with teratoma formation following transplantation. The present study investigated whether cardiomyocytes from mouse fibroblasts may be reprogrammed in vitro with four cardiac transcription factors, including GATA binding protein 4, myocyte-specific enhancer factor 2C, T-box transcription factor 5, and heart- and neural crest derivatives-expressed protein 2 (GMTH). Cardiac-specific markers, including alpha-myosin heavy chain (alpha MHC), beta-MHC, atrial natriuretic factor, NK2 homeobox 5 and cardiac troponin T were observed within mouse fibroblasts reprogrammed with GMTH, which was reported to be more effective than GMT. In addition, Percoll density centrifugation enriched a population of ~72.4+/-5.5% alpha-MHC+ induced cardiomyocytes, which retained the expression profile of cardiomyocyte markers and were similar to natural neonatal cardiomyocytes in well-defined sarcomeric structures. The findings of the present study provided a potential solution to myocardial repair via a cell therapy applying tissue engineering with minimized risks of immune rejection and tumor formation. PMID- 29257326 TI - ATF4 regulated by MYC has an important function in anoikis resistance in human osteosarcoma cells. AB - Anoikis resistance is a crucial step in the process of tumor metastasis. This step determines whether the tumor cells will survive when they become detached from the extracellular matrix. However, the specific mechanism of tumor cells to bypass anoikis and become resistant remains to be elucidated. The present study aimed to determine the internal mechanism of bypassing anoikis through comparison of human osteosarcoma cell lines with human normal cell lines. High activating transcription factor 4 (ATF4) and myelocytomatosis oncogene (MYC) expression levels were observed in MG-63 and U-2 OS human osteosarcoma cell lines. It is possible that ATF4 and MYC contribute to tumor progression. Subsequently, the expression levels of ATF4 and MYC in HUVEC and CHON-001 human normal cell lines were upregulated and their adhesion abilities were reduced; whereas their ability to bypass anoikis increased significantly. Simultaneously, after we Following a knock-down ofATF4 and MYC expression levels in MG-63 and U-2 OS human osteosarcoma cell lines, their adhesion ability increased and their ability to bypassing anoikis was significantly reduced. Upregulation of MYC resulted in an upregulation of ATF4, and chromatin immunoprecipitation and luciferase reporter gene technology demonstrated that MYC binds to the promoter of ATF4. These findings suggest that ATF4 regulated by MYC might contribute to resistance to anoikis in human osteosarcoma cells. PMID- 29257327 TI - Gene expression profiling of the mouse gut: Effect of intestinal flora on intestinal health. AB - The present study aimed to investigate the molecular mechanisms, including potential genes, pathways and interactions, underlying the effect of intestinal flora on intestinal health. The gene expression profiles of GSE22648 were downloaded from the Gene Expression Omnibus database to screen differentially expressed genes (DEGs). The Database for Annotation, Visualization and Integrated Discovery was used for Gene Ontology (GO) functional and pathway enrichment analysis of the DEGs. DEG-associated literature was mined using the GenCLip 2.0 online tool. Finally, GO and pathway enrichment analyses of the DEGs in the literature were processed. By comparing microbiota-depleted mouse samples and control mouse samples, a total of 115 DEGs, including 58 upregulated genes and 57 downregulated genes, were screened. The upregulated genes were enriched into various GO terms, including microsome, oxidation reduction and heme binding, whereas the 57 downregulated DEGs were enriched in different functions, including DNA packaging and linoleic acid metabolism. A total of 19 genes, including baculoviral IAP repeat containing 5, aurora kinase A, angiotensin I converting enzyme 2 and free fatty acid receptor 2 were identified and enriched in four modules, including cell division, chromosome segregation, inflammatory bowel disease and inflammatory response. AURKA, inner centromere protein antigens 135/155 kDa, baculoviral IAP repeat containing 5, aurora kinase B and solute carrier family 22 (organic cation/zwitterion transporter) member 4 were identified as potential important genes for intestinal flora and intestinal disease treatment through their involvement in various functions, including cell division, chromosome segregation, inflammatory bowel disease and inflammatory response. PMID- 29257328 TI - Role of protein delta homolog 1 in the proliferation and differentiation of ameloblasts. AB - Protein delta homolog 1 (DLK1) regulates the odontoblastic differentiation of human dental pulp stem cells. It was hypothesized that DLK1 may exert regulatory effects on epithelial-mesenchymal interactions in tooth development. The present study investigated the expression of DLK1 during the development of mouse enamel and its role in the proliferation and differentiation of ameloblast-lineage cells (ALCs). DLK1 expression was upregulated in ameloblasts in the first mandibular molar during the entire process of enamel development. The mRNA and protein levels of DLK1 were significantly upregulated following ameloblastic induction in ALCs. In addition, overexpression of DLK1 promoted the proliferation of ALCs, inhibited ameloblastic differentiation, upregulated the expression of amelogenin and enamelin, and downregulated the expression of odontogenic ameloblast associated protein and kallikrein 4. The results of the present study suggested that DLK1 may be a potent regulator of ameloblast proliferation and differentiation, and may regulate enamel formation during tooth development. PMID- 29257329 TI - Strontium ranelate reduces the progression of titanium particle-induced osteolysis by increasing the ratio of osteoprotegerin to receptor activator of nuclear factor-kappaB ligand in vivo. AB - The present study aimed to investigate the effects of strontium ranelate (SR), an anti-osteoporotic drug, on osteolysis in an experimental mouse model of aseptic loosening. A total of 45 female C57BL/6J mice each received implantation of one titanium alloy pin into the tibia, followed by intraarticular injection of titanium particles. One week following surgery, mice were randomly divided into three groups: Control group (no additional treatment), SR625 group (treated with SR at a dose of 625 mg/kg/day), and SR1800 group (treated with SR at a dose of 1,800 mg/kg/day). SR was administered via oral gavage once every day for 12 weeks. Micro-computed tomography scanning and hematoxylin/eosin staining were used to assess osteolysis around the prosthesis. Immunohistochemistry and reverse transcription-quantitative polymerase chain reaction analysis were used to measure the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG). Compared with the control, the SR625 and SR1800 groups exhibited a significantly increased pulling force of the titanium alloy pin. Bone volume and the bone surface/volume ratio in the periprosthetic tissue were significantly increased in the SR-treated groups. Significant differences were observed between the SR1800 group and control group with respect to trabecular thickness and trabecular number. Mechanistically, SR downregulated the expression of RANKL and upregulated the expression of OPG in the periprosthetic tissue. In addition, SR was observed to inhibit wear particle associated osteolysis in a dose-dependent manner. In conclusion, the present data illustrated that SR inhibited titanium particle-induced osteolysis in vivo. PMID- 29257330 TI - Niclosamide enhances the cytotoxic effect of cisplatin in cisplatin-resistant human lung cancer cells via suppression of lung resistance-related protein and c myc. AB - Lung cancer is a leading cause of cancer-associated mortality worldwide. The cisplatin (DDP)-based chemotherapy remains the foundation of treatment for the majority of patients affected by advanced non-small cell lung cancer (NSCLC). However, DDP-resistance limits the clinical utility of this drug in patients with advanced NSCLC. The aim of the present study was to investigate the inhibitory effect of niclosamide on human lung cancer cell growth and to investigate the possible underlying mechanism. The effects of niclosamide on the proliferation of human lung adenocarcinoma (A549) and DDP-resistant (CR) human lung adenocarcinoma (A549/DDP) cells were examined by Cell Counting kit-8 assay. The impact of niclosamide on the apoptosis of A549/DDP cells was detected by Annexin V fluorescein isothiocyanate/propidium iodide assay. The expression levels of cisplatin-resistant-associated molecules (lung resistance-related protein and c myc) following niclosamide treatment in A549/DDP cells were evaluated by western blot analysis. The results indicated that niclosamide in combination with DDP demonstrated a synergistic effect in A549/DDP cells and directly induced apoptosis, which may be associated with caspase-3 activation. Furthermore, niclosamide decreased the expression level of c-myc protein, which may influence DDP sensitivity of A549/DDP cells. Thus, the present study indicates that niclosamide combined with DDP exerts a synergistic effect in cisplatin-resistant lung cancer cells and may present as a promising drug candidate in lung cancer therapy. PMID- 29257331 TI - Identification of crucial genes associated with Parkinson's disease using microarray data. AB - The present study aimed to examine potential crucial genes associated with Parkinson's disease (PD) in addition to the interactions and regulators of these genes. The chip data (GSE7621) were obtained from the Gene Expression Omnibus and standardized using the robust multi-array average in the Affy package of R software. The differentially expressed genes (DEGs) were then screened using the Samr package with a false discovery rate (FDR) <0.05 and |log2 fold change (FC)|>1. Crucial PD-associated genes were predicted using the Genetic Association Database in the Database for Annotation, Visualization and Integrated Discovery and sequence alignment. Furthermore, transcription factors (TFs) of the crucial PD-associated genes were predicted, and protein-protein interactions (PPIs) between the crucial PD-associated genes were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins. Additionally, another dataset of PD was used to validate the expression of crucial PD-associated genes. A total of 670 DEGs (398 upregulated and 272 downregulated genes) were identified in the PD samples. Of these, 10 DEGs enriched in pathways associated with the nervous system were predicted to be crucial in PD, including C-X-C chemokine receptor type 4 (CXCR4), deleted in colorectal cancer (DCC) and NCL adaptor protein 2 (NCK2). All 10 genes were associated with neuron development and differentiation. They were simultaneously modulated by multiple TFs, including GATA, E2F and E4 promoter-binding protein 4. The PPI networks showed that DCC and CXCR4 were hub proteins. The DCC-netrin 1-roundabout guidance receptor 2-slit guidance ligand 1 interaction pathway, and several genes, including TOX high mobility group box family member 4, kinase insert domain receptor and zymogen granule protein 16B, which interacted with CXCR4, were novel findings. Additionally, CXCR4 and NCK2 were upregulated in another dataset (GSE8397) of PD. These genes, interactions of proteins and TFs may be important in the progression of PD. PMID- 29257332 TI - Water-soluble factors eluated from surface pre-reacted glass-ionomer filler promote osteoblastic differentiation of human mesenchymal stem cells. AB - Surface pre-reacted glass-ionomer (S-PRG)-containing dental materials, including composite and coating resins have been used for the restoration and/or prevention of dental cavities. S-PRG is known to have the ability to release aluminum, boron, fluorine, silicon, and strontium ions. Aluminum ions are known to be inhibitors whereas boron, fluorine, silicon, and strontium ions are known to be promoters of mineralization, via osteoblasts. However, it remains to be clarified how an aqueous eluate obtained from S-PRG containing these ions affects the ability of mesenchymal stem cells (MSCs), which are known to be present in dental pulp and bone marrow, to differentiate into osteogenic cell types. The present study demonstrated that 200- to 1,000-fold-diluted aqueous eluates obtained from S-PRG significantly upregulated the mRNA expression level of the osteogenic differentiation marker alkaline phosphatase in human MSCs (hMSCs) without exhibiting the cytotoxic effect. In addition, the 500- to 1,000-fold-diluted aqueous eluates obtained from S-PRG significantly and clearly promoted mineralization of the extracellular matrix of hMSCs. It was additionally demonstrated that hMSCs cultured on the cured resin composites containing S-PRG fillers exhibited osteogenic differentiation in direct correlation with the weight percent of S-PRG fillers. These results strongly suggested that aqueous eluates of S-PRG fillers promoted hard tissue formation by hMSCs, implicating that resins containing S-PRG may act as a useful biomaterial to cover accidental exposure of dental pulp. PMID- 29257334 TI - MicroRNA-381 inhibits cell proliferation and invasion in endometrial carcinoma by targeting the IGF-1R. AB - Endometrial carcinoma (EC) is the sixth most common type of malignant tumor occurring in females. MicroRNAs (miRNAs) serve as oncogenes or tumor suppressors in human cancer and play important roles in tumorigenesis, and tumor development by regulating various processes. Thus, further investigation into miRNAs involved in EC formation and progression may aid in developing effective therapeutic strategies for patients with this disease. miRNA-381 (miR-381) is aberrantly expressed in multiple types of human cancer. However, the expression pattern, biological roles and underlying mechanisms of miR-381 in EC are poorly understood. In the present study, the results showed that miR-381 was downregulated in EC tissues and cell lines. Decreased miR-381 expression correlated with the International Federation of Gynecology and Obstetrics stage, lymph nodes metastasis and myometrial invasion of EC. The ectopic expression of miR-381 significantly inhibited the proliferation and invasion of EC cells. Through a series of experiments, the insulin-like growth factor receptor 1 (IGF 1R) was identified as a novel direct target of miR-381 in EC. Furthermore, IGF-1R was highly expressed in EC tissues and inversely correlated with miR-381 levels. IGF-1R overexpression partially abrogated the tumor-suppressive effects of miR 381 on the proliferation and invasion of EC cells. miR-381 targeted IGF-1R to inactivate the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling pathways in EC. These results suggest that miR-381 acts as a tumor suppressor in EC by directly targeting IGF-1R, and indirectly regulating the AKT and ERK signaling pathways. Thus, miR-381 should be investigated as a prognostic biomarker and novel therapeutic target for the treatment of patients with EC. PMID- 29257333 TI - COX-2 inhibition in the endothelium induces glucose metabolism normalization and impairs tumor progression. AB - Previous antitumor angiogenesis strategies have focused on targeting angiogenic signals. Encouragingly, the metabolism of tumor endothelial cells (TECs) has gained attention as a therapeutic target in recent years. There is consensus that, in terms of antitumor angiogenesis, the promotion of tumor vascular regression and normalization of the remaining blood vessels are equally important. Presently, tumor vessel normalization (TVN) is an emerging antitumor treatment. The present study focused on the normalization of TEC metabolism. The results demonstrated that TECs have a hyperglycolytic metabolism. Parixibox, a cyclooxygenase-2 (COX-2) blocker, successively reduces the expression of vascular endothelial growth factor (VEGF) in the tumor microenvironment. VEGF further influences the expression of 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3, a key glycolysis gene. Pharmacological blockade of COX-2 restored the glucose metabolism level (particularly glycolysis) in TECs, which may be an important basic process in TVN. Therefore, COX-2, which acts on abnormal tumor vessels, is expected to become a novel target for tumor treatment. PMID- 29257335 TI - Bioinformatics analysis of differentially expressed gene profiles associated with systemic lupus erythematosus. AB - DNA microarray and high-throughput sequencing have been widely used to identify the differentially expressed genes (DEGs) in systemic lupus erythematosus (SLE). However, the big data from gene microarrays are also challenging to work with in terms of analysis and processing. The presents study combined data from the microarray expression profile (GSE65391) and bioinformatics analysis to identify the key genes and cellular pathways in SLE. Gene ontology (GO) and cellular pathway enrichment analyses of DEGs were performed to investigate significantly enriched pathways. A protein-protein interaction network was constructed to determine the key genes in the occurrence and development of SLE. A total of 310 DEGs were identified in SLE, including 193 upregulated genes and 117 downregulated genes. GO analysis revealed that the most significant biological process of DEGs was immune system process. Kyoto Encyclopedia of Genes and Genome pathway analysis showed that these DEGs were enriched in signaling pathways associated with the immune system, including the RIG-I-like receptor signaling pathway, intestinal immune network for IgA production, antigen processing and presentation and the toll-like receptor signaling pathway. The current study screened the top 10 genes with higher degrees as hub genes, which included 2'-5' oligoadenylate synthetase 1, MX dynamin like GTPase 2, interferon induced protein with tetratricopeptide repeats 1, interferon regulatory factor 7, interferon induced with helicase C domain 1, signal transducer and activator of transcription 1, ISG15 ubiquitin-like modifier, DExD/H-box helicase 58, interferon induced protein with tetratricopeptide repeats 3 and 2'-5' oligoadenylate synthetase 2. Module analysis revealed that these hub genes were also involved in the RIG-I-like receptor signaling, cytosolic DNA-sensing, toll like receptor signaling and ribosome biogenesis pathways. In addition, these hub genes, from different probe sets, exhibited significant co-expressed tendency in multi-experiment microarray datasets (P<0.01). In conclusion, these key genes and cellular pathways may improve the current understanding of the underlying mechanism of development of SLE. These key genes may be potential biomarkers of diagnosis, therapy and prognosis for SLE. PMID- 29257336 TI - Autophagy: A new treatment strategy for MSC-based therapy in acute kidney injury (Review). AB - Acute kidney injury (AKI) is a common and serious medical condition associated with poor health outcomes. Autophagy is a conserved multistep pathway that serves a major role in many biological processes and diseases. Recent studies have demonstrated that autophagy is induced in proximal tubular cells during AKI. Autophagy serves a pro-survival or pro-death role under certain conditions. Furthermore, mesenchymal stem cells (MSCs) have therapeutic potential in the repair of renal injury. This review summarizes the recent progress on the role of autophagy in AKI and MSCs-based therapy for AKI. Further research is expected to prevent and treat acute kidney injury. PMID- 29257337 TI - The role of ursodeoxycholic acid on cholestatic hepatic fibrosis in infant rats. AB - The aim of the present study was to identify the impact of ursodeoxycholic acid (UDCA) on liver function and fibrosis markers in infant rats by establishing a cholestatic-induced hepatic fibrosis model. alpha-naphthylisothiocyanate (ANIT) was administrated by gavage to induce cholestatic hepatic fibrosis in infant rats. UCDA treatment was performed to assess its impact on biochemical indicators of liver function, four serum biomarkers of hepatic fibrosis, hepatic fibrosis indices in liver tissues and the pathology of liver tissues. Colorimetric assays and biochemical assays based on the initial rate method were performed to determine the levels of liver function markers in the serum, whereas the serum biomarkers of hepatic fibrosis were measured via radioimmunoassay. Sections of liver tissue were harvested and stained with hematoxylin-eosin or picric acid Sirius red, and subjected to immunohistochemical staining to analyze liver pathology. All indicators of liver function, except for cholinesterase, were significantly higher in the ANIT model than in the control group (P<0.01). gamma glutamyl transpeptidase and total bile acids of the UDCA treatment group were significantly lower than the ANIT model (P<0.05); whereas no significant differences were observed in alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin and indirect bilirubin between the two groups. Serum laminin protein (LN) and type-IV collagen (cIV) in the UDCA treatment group were significantly lower than in the ANIT model (P<0.01); whereas no significant differences were observed in hyaluronic acid and type-III procollagen between the two groups. Liver LN and cIV in the UDCA treatment group were significantly lower than in the ANIT model (P<0.01). The degree of hepatic fibrosis in the UDCA treatment group was significantly lower than in the ANIT model (P<0.01). The results of the present study demonstrated that UDCA is able to reduce LN and cIV in serum and protect liver tissues against hepatic fibrosis. PMID- 29257338 TI - The association between the expression of PAR2 and TMEM16A and neuropathic pain. AB - Chronic constriction injury (CCI) of the sciatic nerve may induce dorsal root ganglion (DRG) neuronal hyperexcitability and behaviorally expressed hyperalgesia. CCI is a model of neuropathic pain. To investigate the association between the expression of protease activated receptor 2 (PAR2), TMEM16A and neuropathic pain, the expression of PAR2 and TMEM16A proteins in the DRG neurons of rats following CCI of the sciatic nerve was investigated. Following the creation of the CCI model, the thermal withdrawal latency (TWL) was examined by a hot plate test. An immunofluorescence assay and western blot assay were performed to determine the expression of PAR2 and TMEM16A proteins in the ipsilateral L4-6 DRG neurons. The concentration of inositol 1,4,5-triphosphate (IP3) in the L4-6 DRG was determined by ELISA. In the CCI-D7 (7 days after CCI) and CCI-D14 (14 days after CCI) treatment groups, the TWL of rats was significantly shorter than that in the sham operated group (P<0.01; n=12). The expression of PAR2 and TMEM16A proteins in the CCI-D7 and CCI-D14 groups were significantly upregulated compared with the sham operated group (P<0.05; n=12). Additionally, it was revealed that PAR2 and TMEM16A were co-expressed in DRG neurons. It was also observed that IP3 significantly increased in the CCI-D7 and CCI-D14 groups compared with the sham operation group (P<0.05; n=6) as PAR2 and TMEM16A also increased. These findings suggest that the upregulation of PAR2 and TMEM16A in DRG neurons, the co-expression of the two proteins and increasing IP3 are critical to the development of neuropathic pain. PMID- 29257339 TI - Investigation of the neuroprotective effects of Lycium barbarum water extract in apoptotic cells and Alzheimer's disease mice. AB - Alzheimer's disease (AD) affects people worldwide and is caused by chronic and progressive damage to the central nervous system. Lycium barbarum (LB), a renowned functional food and medicinal plant in Southeast Asia, may possess protective effects against nerve injury. The present study aimed to investigate the neuroprotective effects of LB water extract in a differentiated (D)PC12 cellular apoptosis model induced by L-glutamic acid (L-Glu), and a mouse model of AD, induced by the combination of AlCl3 and D-galactose. LB markedly increased DPC12 cell survival against L-Glu induced damage by increasing cell viability, reducing the apoptosis rate and G1 phase arrest, suppressing intracellular reactive oxygen species accumulation, blocking Ca2+ overload and preventing mitochondrial membrane potential depolarization. LB additionally normalized the expression levels of apoptosis regulator Bcl-2, apoptosis regulator BAX, and cleaved caspase-3, -8 and -9 in L-Glu exposed cells. In the AD mouse model, LB increased the amount of horizontal and vertical movement in the autonomic activity test, improved endurance time in the rotarod test and decreased escape latency time in the Morris water maze test. Additionally, the levels of acetylcholine and choline acetyltransferase were significantly increased in the serum and hypothalamus in the LB-treated AD mice. These data suggested that LB may exert neuroprotective effects and may aid in preventing neurodegenerative disease. PMID- 29257340 TI - Vildagliptin prevents cognitive deficits and neuronal apoptosis in a rat model of Alzheimer's disease. AB - Diabetes has been identified to be a risk factor for Alzheimer's disease (AD). Vildagliptin, a novel oral hypoglycemic agent, has been demonstrated to exert protective effects on the pancreas and cardiovascular system. The present study examined the potential protective effects of vildagliptin on neurons in an AD rat model. Treatment with vildagliptin improved memory deficits and decreased neuronal apoptosis in the hippocampus. The expression levels of B cell lymphoma 2 (Bcl-2) were increased, and the expression levels of caspase-3, Bcl-2 associated X protein and AD-associated proteins were decreased in the hippocampus following treatment with vildagliptin. Additionally, the AD model-induced decrease in phosphorylated (p) protein kinase B (p-Akt), p-glycogen synthase kinase 3beta (p GSK3beta), post-synaptic density 95 and synaptophysin expression was reversed. These results indicate that vildagliptin administration exerts a protective effect against cognitive deficits by reducing tau phosphorylation and increasing the expression of proteins associated with synaptic plasticity in the hippocampus. Targeting of the Akt/GSK3beta signaling pathway may be a key mechanism in preventing the disease progression of AD. PMID- 29257341 TI - Carvacrol ameliorates inflammatory response in interleukin 1beta-stimulated human chondrocytes. AB - Carvacrol, a monoterpenic phenol present in Origanum vulgare (oregano) and Thymus vulgaris (thyme), possesses anti-inflammatory effects; however, little is known about the effects and underlying mechanism of carvacrol on chondrocytes in osteoarthritis (OA). The present study aimed to investigate the protective effects of carvacrol against inflammation in interleukin 1beta (IL-1beta) stimulated human chondrocytes. The results indicated that carvacrol inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production, and decreased the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX-2). Carvacrol also suppressed the protein expression levels of matrix metalloproteinase (MMP)-3 and MMP-13 in IL-1beta-stimulated human OA chondrocytes. Furthermore, carvacrol suppressed the activation of nuclear factor (NF)-kappaB signaling pathway in IL 1beta-induced human chondrocytes. In conclusion, the present results demonstrated that carvacrol was able to inhibit IL-1beta-induced NO and PGE2 production, as well as iNOS, COX-2 and MMPs expression in human chondrocytes by suppressing the activation of NF-kappaB signaling pathway. Thus, carvacrol may have potential therapeutic functions for the treatment of OA. PMID- 29257342 TI - MicroRNA-28 promotes cell proliferation and invasion in gastric cancer via the PTEN/PI3K/AKT signalling pathway. AB - Gastric cancer is the fourth most common malignant disease and second leading cause of cancer-associated mortalities worldwide. Previous studies revealed aberrantly expressed microRNAs (miRNAs) in various types of human cancer; these miRNAs play important roles in tumourigenesis and tumour development. miRNAs present a considerable potential for novel therapeutic approaches for treating human cancer. Therefore, the investigation of novel miRNAs involved in gastric cancer progression provides an opportunity to improve the prognosis of patients with gastric cancer. miRNA-28 (miR-28) has been investigated with regards to its expression and biological functions in many types of human cancer. However, previous studies have not discussed the expression patterns, roles and associated molecular mechanisms of miR-28 in gastric cancer. In the present study, miR-28 expression was identified to be upregulated in gastric cancer tissues and cell lines. miR-28 inhibition functionally inhibited cell proliferation and invasion in gastric cancer in vitro. Using bioinformatics analysis, luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction and western blot analysis, phosphatase and tensin homolog (PTEN) was mechanically identified as a direct target of miR-28 in gastric cancer. PTEN was downregulated in gastric cancer and negatively correlated with miR-28 levels. Inhibition of PTEN restored the biological effects of miR-28 downregulation on the proliferation and invasion of gastric cancer cells. Notably, the downregulation of miR-28 results in the regulation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway in gastric cancer. These results suggested that miR-28 may be targeted for the development of novel treatments for gastric cancer in the future. PMID- 29257343 TI - Quantification of distinct let-7 microRNA family members by a modified stem-loop RT-qPCR. AB - Lethal-7 (let-7) microRNA (miRNA) serves a pivotal role in a number of physiological processes and is associated with the occurrence and development of multiple disorders such as cancer. The present study aimed to use a newly developed stem-loop strategy for reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to distinguish let-7 miRNA family members that differ by as little as a single nucleotide. For the miRNAs comprising 16 identical nucleotides at the 5'-end, different stem-loop RT primers were designed and used in RT-qPCR to assess the expression profiles of a panel of let-7 family member miRNAs in human glioblastoma U87 cells. Amplification efficiency was evaluated through correlation analysis between total RNA input and the quantification threshold values. Melting curve profiles were measured to estimate the amplification specificity of the improved stem-loop RT-qPCR compared with those of the poly(A)-tailing method. In addition, the discrimination ability of the modified stem-loop method was examined. Compared with poly(A) tailing, the modified stem-loop RT method was able to specifically reverse transcribe the diverse let-7 miRNA family members followed by accurate quantification, with a theoretical amplification efficiency of ~100%. This modified stem-loop method was able to distinguish miRNAs with a single base difference. This innovative method may be used in the clinical detection of let-7 expression levels in a variety of tumour samples, and may provide valuable data for disease diagnosis and prognostic evaluation. In addition, this method may offer a new avenue for developing particular stem-loop approaches in measuring other miRNAs with little discrepancy. PMID- 29257344 TI - Effects of GGCX overexpression on anterior cruciate ligament transection-induced osteoarthritis in rabbits. AB - Effective therapeutic methods for osteoarthritis (OA) are lacking. gamma-glutamyl carboxylase (GGCX) is a key enzyme that regulates carboxylation of cartilage matrix Gla protein (MGP). Whether GGCX overexpression protects against OA remains unknown. The aim of the present study was to explore the effects of GGCX overexpression on anterior cruciate ligament transection (ACLT)-induced OA and its mechanisms in Japanese white rabbits. ACLT surgery was used to establish an OA model in rabbits. A total of 48 rabbits were randomly divided into 4 groups: Sham, OA model + GGCX overexpression plasmid, OA model + saline and OA model + empty vector. The expression of uncarboxylated MGP (ucMGP), carboxylated MGP (cMGP), matrix metalloproteinase (MMP)-13, collagen type X, collagen type II, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta were detected by ELISA, immunohistochemistry, reverse transcription-quantitative polymerase chain reaction and western blotting. Morphological changes to tibial cartilage were assessed by Giemsa and safranin O-fast green staining, respectively. Compared with the Sham control, GGCX expression was significantly decreased in the OA Model group. GGCX expression was increased by injection of a lentivirus-carried overexpression plasmid that encoded GGCX. GGCX overexpression ameliorated ATLC induced damage in articular cartilage. OA Model rabbits exhibited significantly decreased expression levels of cMGP and collagen type II, and increased expression of ucMGP, collagen type X, MMP-13, IL-1beta and TNF-alpha. Notably, these expression levels were reversed by GGCX overexpression in OA Model rabbits. Results from the present study indicated that GGCX expression was decreased in OA Model rabbits, whereas overexpression of GGCX was able to promote carboxylation of MGP, reduce inflammation, decrease MMP-13 expression and regulate collagen expression. The results also indicated that GGCX may serve as a therapeutic target for OA. PMID- 29257345 TI - Resveratrol alleviates lysophosphatidylcholine-induced damage and inflammation in vascular endothelial cells. AB - The role of resveratrol (trans-3,5,4'-trihydroxystilbene; RES) in lysophosphatidylcholine (LPC)-induced injury and inflammation in endothelial cells (regarded as an early event in arteriosclerosis) is unclear. The present study investigated whether RES reduces lactate dehydrogenase (LDH) activity and secretion of inflammatory cytokines such asinterleukin-6 and tumor necrosis factor-alpha, via the Toll-like receptor (TLR)-4/myeloid differentiation primary response gene 88 (MyD88)/nuclear factor (NF)-kappaB signal transduction pathway in LPC-induced damage and inflammation in human umbilical vein endothelial-12 (HUVE-12) cells. Using an ELISA and western blotting, the present study investigated the effects of RES on LDH activity and cytokine secretion. The effects of TLR-4 short hairpin (sh)RNA and TLR-4 cDNA transfection on NF-kappaB activation during LPC-induced damage and inflammation was also investigated in HUVE-12 cells. The results demonstrated that RES significantly inhibited the effect of LPC on enzyme activity, pro-inflammatory cytokine secretion, and expression of TLR-4, MyD88 and NF-kappaBp65 expression. In addition, RES and TLR 4 shRNA transfection suppressed LPC-induced injury and inflammation by blocking the TLR-4/MyD88/NF-kappaB signaling pathway Conversely, transfection with TLR-4 cDNA enhanced LPC-induced injury and inflammation, which abrogated the protective effects of RES. These data suggested that RES significantly suppressed LPC induced damage and inflammation, via suppression of the TLR-4/MyD88/NF-kappaB signaling pathway, which may provide a new mechanistic evidence for the treatment of arteriosclerosis by RES. PMID- 29257346 TI - miR-373 suppresses gastric cancer metastasis by downregulating vimentin. AB - MicroRNA-373 (miR-373) has been reported to be an oncogene in a number of solid human tumors. However, the role of miR-373 in gastric cancer has not been completely elucidated and the mechanisms remain unclear. In the present study, we compared miR-373 expression between clinical gastric cancer tissues and paired non-tumorous tissues by reverse transcription-quantitative polymerase chain reaction. The impact of miR-373 on proliferation, migration and invasion in gastric cancer cells was additionally investigated. Hsa-miR-373 mimics were applied to mimic the function of endogenous miR-373. A colony formation assay and flow cytometry were performed to analyze the proliferation of gastric cancer cells. Wound healing and Transwell invasion assays were employed to detect the migratory and invasive abilities of gastric cancer cells. Western blotting was used to test the expression of epithelial-mesenchymal transition-associated proteins. The results demonstrated that the level of miR-373 in gastric cancer was upregulated compared with paired non-tumorous tissues. It was confirmed that miR-373 inhibited the migration and invasion of the gastric cancer cell lines SGC 7901 and HGC-27 by downregulating vimentin expression. The results of the present study demonstrated an oncogenic role of miR-373 in the metastasis of human gastric cancer, and may provide a novel therapeutic strategy for gastric cancer. PMID- 29257347 TI - Buyang Huanwu Tang improves denervation-dependent muscle atrophy by increasing ANGPTL4, and increases NF-kappaB and MURF1 levels. AB - Denervated-dependent skeletal muscle atrophy (DSMA) is a disorder caused by the peripheral neuro-disconnection of skeletal muscle. The current study aimed to investigate the molecular mechanism and potential therapeutic strategies for the DSMA. A DSMA rat model was established. A lentiviral vector expressing small interfering RNA (siRNA) targeting angiopoietin-like protein 4 (ANGPTL4) was generated and injected into the rats that were also treated with Buyang Huanwu Tang (BYHWT). Reverse transcription-quantitative polymerase chain reaction was performed to examine ANGPTL4 mRNA expression in anterior cervical muscle samples. Western blot assay was used to evaluate ANGPTL4, nuclear factor-kappaB (NF kappaB) and muscle RING-finger protein-1 (MURF1) expression. The ultrastructure of muscle tissues was viewed using transmission electron microscopy. The cell apoptosis in muscle tissues was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling. The results indicated that BYHWT treatment increased ANGPTL4 mRNA and protein levels in muscle tissues. The suppression of ANGPTL4 using siRNA significantly increased inflammatory cells compared with the control siRNA group. BYHWT protected the ultrastructure muscle tissues and inhibited cell apoptosis in the DSMA model. The protective effect of BYHWT protected may be mediated by increased expression of NF-kappaB p65 and MURF1. In conclusion, BYHWT may improve denervation-dependent muscle atrophy by increasing ANGPTL4 expression, involving NF-kappaB and MURF1 signaling. PMID- 29257348 TI - LncRNA MEG3 ameliorates respiratory syncytial virus infection by suppressing TLR4 signaling. AB - Maternally expressed gene 3 (MEG3), a long noncoding RNA (lncRNA) has been dysregulated in various tumors. However, the expression level and functional role of MEG3 in the progression of respiratory syncytial virus (RSV) infection remains to be elucidated. The present study quantified the expression level of MEG3 in the nasopharyngeal (NPA) samples of RSV-infected patients and in BEAS-2B cells infected with RSV. The findings of the present study demonstrated that the expression level of lncRNA MEG3 was reduced in the NPA samples of RSV-infected patients and in BEAS-2B cells infected with RSV. In vitro transfection revealed increased mRNA expression levels of toll-like receptor 4 (TLR4), tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-8 following RSV infection in BEAS-2B cells. Additionally, ectopic expression of MEG3 reduced the expression level of TLR4, subsequently suppressing the mRNA expression levels of TNFalpha and IL-8, indicating the protective role of MEG3 in the process of RSV infection. It is of note, that RSV infection-induced p38 mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) activation was partly abolished by overexpression of MEG3. In conclusion, to the best of our knowledge, the present study provided the first evidence that lncRNA MEG3 expression level was reduced in the NPA samples of patients with RSV infection and RSV-infected cells. Additionally, it was demonstrated that MEG3 protected human airway epithelial cells from RSV infection, primarily by suppressing TLR4-dependent p38 MAPK and NF kappaB signaling. PMID- 29257349 TI - Competing endogenous RNA network analysis of CD274, IL-10 and FOXP3 co-expression in laryngeal squamous cell carcinoma. AB - Laryngeal squamous cell carcinoma (LSCC) is one of the most common types of head and neck malignant tumor; however, there is a lack of effective molecular targets for therapy. The present study detected the expression of three immunity associated molecules [forkhead box (FOX)3, interleukin (IL)-10 and cluster of differentiation (CD)274] in 133 LSCC samples using immunohistochemistry (IHC); subsequently, the association between their expression and the clinical characteristics of LSCC were analyzed. Spearman's rank correlation method, Kaplan Meier and Cox regression model were used to analyze the correlations of the three proteins and their clinical significance. StarBase and miRTarBase databases were used to establish the competitive endogenous (ce)RNA network of the three molecules. IHC demonstrated that the positive expression rates of FOXP3, IL-10 and CD274 were 68.4, 73.7 and 58.6% in 133 LSCC samples, respectively. In addition, it was identified that the expression of the three proteins was closely correlated with the clinical characteristics of LSCC, including lymph node metastasis and prognosis (P<0.05). There was also a significant association of co expression between any two proteins (P<0.001). Furthermore, the expression levels of FOXP3, IL-10 and CD274 were negatively associated with the survival rate of patients with LSCC (P<0.05). The results of a Cox regression model suggested that the three proteins were prognostic risk factors for LSCC (P<0.05). The ceRNA network revealed that 10 microRNAs (miRs; including miR-16-5p and miR-214-3p), 123 long non-coding RNAs (including X-inactive specific transcript, H19 and metastasis associated lung adenocarcinoma transcript 1) and 408 circular RNAs (including ATP-binding cassette subfamily C member 1 hsa_circ_001569 and ISY1 splicing factor homolog hsa_circ_001859) may regulate the expression of FOXP3, IL 10 and CD274. The data generated from the present study may increase the understanding of the immune escape mechanisms of LSCC and may be beneficial for the development of a specific immunotherapy. PMID- 29257350 TI - Decreased soluble RAGE in neutrophilic asthma is correlated with disease severity and RAGE G82S variants. AB - The advanced glycosylation end product-specific receptor (RAGE) has been demonstrated to be an important mediator of asthma pathogenesis. The soluble isoform of RAGE (sRAGE) acts as a 'decoy' to sequester RAGE ligands, and thus prevents their binding to the receptor. A number of reports have linked deficiency of sRAGE to the severity and outcomes of various human diseases, and association with RAGE G82S variants. However, whether sRAGE levels are increased or decreased in asthmatic patients is unclear. The aim of the present study was to determine plasma sRAGE levels in different asthma phenotypes and associations of plasma sRAGE levels with RAGE G82S variants. A total of 85 neutrophilic and 109 non-neutrophilic newly diagnosed asthmatic patients, and 118 healthy controls, were recruited. Plasma sRAGE levels were measured by ELISA analysis. RAGE G82S genotypes were detected using the Sanger sequencing method. Plasma sRAGE levels were decreased in neutrophilic asthmatics (443.67+/-208.9 pg/ml) and increased in non-neutrophilic asthmatics (677.63+/-300.75 pg/ml) compared with healthy controls (550.02+/-300.83 pg/ml) (P<0.001). Plasma sRAGE levels were positively correlated with FEV1% predicted (FEV1% Pre) (rp=0.258; P=0.023) in neutrophilic asthmatics. The frequency of G82S genotypes was significantly different between neutrophilic and non-neutrophilic asthmatics (P=0.009). Neutrophilic asthmatics with genotypes A/G or A/A (389.83+/-150.37 and 264.59+/ 161.74 pg/ml, respectively) had significantly decreased sRAGE levels compared with the G/G genotype (498.64+/-235.37 pg/ml) (P=0.022). Those with the A/G and A/A genotype (60.14+/-22.36%) displayed a trend toward lower FEV1% Pre compared with those with the G/G genotype (64.51+/-27.37%). No significant difference in sRAGE levels or an association with FEV1% Pre was observed between the different genotypes in non-neutrophilic asthmatics. In conclusion, the results of the present study indicated that plasma sRAGE levels are altered in different asthma inflammatory phenotypes. Plasma sRAGE may be a biomarker of asthma severity and may be associated with G82S gene variants in neutrophilic asthmatics. PMID- 29257351 TI - CXCR7 regulates breast tumor metastasis and angiogenesis in vivo and in vitro. AB - The chemokine receptor CXCR7 is regarded as a scavenger receptor for CXCL12, and induces numerous key steps in tumor growth and metastasis. However, the exact molecular mechanism of CXCR7 regulation in breast tumor angiogenesis remains unknown. In the present study, the function of CXCR7 in breast tumors was investigated in vitro and in vivo. The breast cancer MDA-MB-231 cell line was used. Pharmacological inhibition of CXCR7 by CCX771 reduced breast tumor invasion, adhesion and metastasis. Furthermore, CXCR7 was essential for the tube formation of HUVECs in vitro, and for blood vessel formation in a Matrigel plug assay in vivo. In addition, vascular endothelial growth factor expression was also decreased in CCX771-treated MDA-MB-231 cells, indicating that CCX771 regulates tumor angiogenesis. The present results indicated that CXCR7 regulated breast cancer metastasis at multiple stages; additional understanding of CXCR7 in tumor environments may develop anti-metastatic therapy. PMID- 29257352 TI - MiR-19a mediates gluconeogenesis by targeting PTEN in hepatocytes. AB - As a member of miR-17-92 miRNA clusters, miR-19a has been considered to regulate hepatic glycogenesis by mediating the PI3K/AKT signaling pathway. However, whether miR-19a serves an important role in gluconeogenesis in hepatocytes remains unknown. In the present study, the impact of miR-19a on gluconeogenesis in HEP1-6 cells and its mechanisms of action were investigated. It was observed that overexpression of miR-19a led to decreased glucose production, accompanied by increased activation of the AKT/FOXO1 signaling pathway and downregulated expression of gluconeogenesis-associated genes, including peroxisome proliferator activated receptor gamma coactivator 1alpha, phosphoenolpyruvate carboxykinase and glucose 6-phosphatase in the HEP1-6 cells transfected with the miR-19a mimic. In contrast, suppression of miR-19a impaired the activation of the AKT/FOXO1 signaling pathway and increased the expression of gluconeogenesis-associated genes, accompanied by an elevated glucose production. Additionally, phosphatase and tensin homolog (PTEN) was identified as a target of miR-19a and participated in the miR-19a-mediated gluconeogenesis in hepatocytes. These findings provide mechanistic insight into the effects of miR-19a on the regulation of the AKT/FOXO1 signaling pathway and the expression of gluconeogenesis-associated genes. MiR-19a may mediate gluconeogenesis in hepatocytes by downregulating PTEN expression. PMID- 29257353 TI - Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. AB - BACKGROUND: Antibiotics can disturb gastrointestinal microbiota which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live microbial preparations that, when administered in adequate amounts, may confer a health benefit to the host, and are a potential C. difficile prevention strategy. Recent clinical practice guidelines do not recommend probiotic prophylaxis, even though probiotics have the highest quality evidence among cited prophylactic therapies. OBJECTIVES: To assess the efficacy and safety of probiotics for preventing C.difficile-associated diarrhea (CDAD) in adults and children. SEARCH METHODS: We searched PubMed, EMBASE, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 21 March 2017. Additionally, we conducted an extensive grey literature search. SELECTION CRITERIA: Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors (independently and in duplicate) extracted data and assessed risk of bias. The primary outcome was the incidence of CDAD. Secondary outcomes included detection of C. difficile infection in stool, adverse events, antibiotic-associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the risk ratio (RR) and corresponding 95% confidence interval (95% CI). We calculated the number needed to treat for an additional beneficial outcome (NNTB) where appropriate. Continuous outcomes (e.g. length of hospital stay) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group, we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analyses were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias as well as a post hoc subgroup analysis on baseline risk of CDAD (low 0% to 2%; moderate 3% to 5%; high > 5%). The overall quality of the evidence supporting each outcome was independently assessed using the GRADE criteria. MAIN RESULTS: Thirty-nine studies (9955 participants) met the eligibility requirements for our review. Overall, 27 studies were rated as either high or unclear risk of bias. A complete case analysis (i.e. participants who completed the study) among trials investigating CDAD (31 trials, 8672 participants) suggests that probiotics reduce the risk of CDAD by 60%. The incidence of CDAD was 1.5% (70/4525) in the probiotic group compared to 4.0% (164/4147) in the placebo or no treatment control group (RR 0.40, 95% CI 0.30 to 0.52; GRADE = moderate). Twenty-two of 31 trials had missing CDAD data ranging from 2% to 45%. Our complete case CDAD results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and results were similar whether considering subgroups of trials in adults versus children, inpatients versus outpatients, different probiotic species, lower versus higher doses of probiotics, or studies at high versus low risk of bias. However, in a post hoc analysis, we did observe a subgroup effect with respect to baseline risk of developing CDAD. Trials with a baseline CDAD risk of 0% to 2% and 3% to 5% did not show any difference in risk but trials enrolling participants with a baseline risk of > 5% for developing CDAD demonstrated a large 70% risk reduction (interaction P value = 0.01). Among studies with a baseline risk > 5%, the incidence of CDAD in the probiotic group was 3.1% (43/1370) compared to 11.6% (126/1084) in the control group (13 trials, 2454 participants; RR 0.30, 95% CI 0.21 to 0.42; GRADE = moderate). With respect to detection of C. difficile in the stool pooled complete case results from 15 trials (1214 participants) did not show a reduction in infection rates. C. difficile infection was 15.5% (98/633) in the probiotics group compared to 17.0% (99/581) in the placebo or no treatment control group (RR 0.86, 95% CI 0.67 to 1.10; GRADE = moderate). Adverse events were assessed in 32 studies (8305 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 17% (RR 0.83, 95% CI 0.71 to 0.97; GRADE = very low). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. AUTHORS' CONCLUSIONS: Based on this systematic review and meta analysis of 31 randomized controlled trials including 8672 patients, moderate certainty evidence suggests that probiotics are effective for preventing CDAD (NNTB = 42 patients, 95% CI 32 to 58). Our post hoc subgroup analyses to explore heterogeneity indicated that probiotics are effective among trials with a CDAD baseline risk >5% (NNTB = 12; moderate certainty evidence), but not among trials with a baseline risk <=5% (low to moderate certainty evidence). Although adverse effects were reported among 32 included trials, there were more adverse events among patients in the control groups. The short-term use of probiotics appears to be safe and effective when used along with antibiotics in patients who are not immunocompromised or severely debilitated. Despite the need for further research, hospitalized patients, particularly those at high risk of CDAD, should be informed of the potential benefits and harms of probiotics. PMID- 29257354 TI - Building a Better NEHA. PMID- 29257356 TI - An Estimation of Potential Vector Control Effect of Gravid Mosquito Trapping in Fort Worth, Texas. AB - Entomological surveillance is an essential component for integrated vector management (IVM), the current best practice for West Nile virus (WNV) prevention and control. The significance of vector mosquito surveillance, however, is not always recognized by the public, which increases vulnerability of IVM programs to elimination or downsizing when virus activities are low, particularly during interepidemics of WNV. In order to increase public recognition, the unrecognized contribution of mosquito surveillance with gravid (egg-carrying) mosquito trapping to WNV vector control was estimated using a novel approach. This approach includes development of a quantitative model to estimate the number of female progeny from a gravid mosquito and application of the model with mosquito surveillance data to estimate the potential vector control effect of gravid mosquito trapping. Applying this approach, the potential WNV vector control effect of 2013 surveillance activities in Fort Worth, Texas, was estimated to almost 1,590,000 female mosquitoes by capturing 44,654 females. PMID- 29257355 TI - Impacts of Industrial Wind Turbine Noise on Sleep Quality: Results From a Field Study of Rural Residents in Ontario, Canada. AB - The objectives of this study were to determine whether grid-connected industrial wind turbines (IWTs) are a risk factor for poor sleep quality, and if IWT noise is associated with sleep parameters in rural Ontarians. A daily sleep diary and actigraphy-derived measures of sleep were obtained from 12 participants from an IWT community and 10 participants from a comparison community with no wind power installations. The equivalent and maximum sound pressure levels within the bedroom were also assessed. No statistically significant differences were observed between IWT residents and non-IWT residents for any of the parameters measured in this study. Actigraphy and sleep diaries are feasible tools to understand the impact of IWTs on the quality of sleep for nearby residents. Further studies with larger sample sizes should be conducted to determine whether the lack of statistical significance observed here is a result of sample size, or reflects a true lack of association. PMID- 29257357 TI - Rewards and Lessons Learned From Implementation of a Healthy Homes Research Project in a Midwestern Public Health Department. AB - Marion County Public Health Department (MCPHD) in Indianapolis, Indiana, was awarded funding in 2009 from the U.S. Department of Housing and Urban Development through the Healthy Homes Demonstration Grant Program as a part of the American Recovery and Reinvestment Act. This funding is currently supporting activities addressing health and safety hazards in homes of low- and very low-income residents living in an urban community within Marion County with an extensive history of heavy industry and lead smelting. One portion of this grant is being used to fund IRB-approved research conducted by MCPHD for the period of the grant. Development and implementation of this study has provided both unique challenges and positive opportunities for study participants, MCPHD, and community stakeholders. The following commentary provides insight into the benefits and rewards of implementing a successful study process, as well as challenges in implementing a community-based research study for the first time in a preexisting Healthy Homes Demonstration Grant Program health department. PMID- 29257358 TI - Preventing Legionnaires' Disease: Environmental Health Expertise Is Key. PMID- 29257359 TI - Tracking Carbon Monoxide Poisoning to Better Understand How People Are Poisoned. PMID- 29257360 TI - Antimicrobial activity and molecular identification of Streptomyces strains isolated from Saudi Arabia. AB - Actinomycetes are group of Gram-positive bacteria with high GC-content in their DNA. They are extremely useful for the pharmaceutical industry due to their seemingly unlimited capacity to produce secondary metabolites with diverse biological activities and chemical structure. The genus Streptomyces constitutes 50% of the total population of soil actinomycetes and about 75% of commercially and medicinally useful antibiotics that have been derived from this genus. The present study aimed in isolation of bioactive compound showing antimicrobial activities from soil Streptomyces, previously isolated and morphologically characterized from Jazan in Saudi Arabia. Six potent Streptomyces strains: JS3, JS4, JS6, JD7, JA8 and JA10 were chosen for antimicrobial activity screening against 5 human pathogenic bacteria and 5 phytopathogenic fungi before molecular identification was done. For antibacterial activity, the results showed that inhibition zones were found to range between 3.25-26.875 mm diameters, while for antifungal activity, it ranged between 13.3-40 mm diameters. The entire sequence of the 16S rDNA was determined for the strains JS6, JD7, JA8 and JA10 and deposited in the GenBank. Future studies of actinomycetes isolated from the Kingdom of Saudi Arabia's soils will assist in the discovery of new compounds that would be of industrial, pharmaceutical and agricultural importance. PMID- 29257361 TI - OFF THE BEATEN TRACK. THE RISE OF REMOTE AREA NURSING. AB - Remote Area Nurses (RANs) work in far-flung pockets of Australia delivering healthcare to largely disadvantaged communities. Highly skilled, adaptable, and resilient, RANs collectively strive to improve health outcomes for people living remote. As the sector moves forward, ongoing challenges loom large, namely workforce shortage issues, boosting safety, and improving health service provision, writes Robert Fedele. PMID- 29257362 TI - Antifungal potential of actinomycete isolate Streptomyces exfoliates MT9 against wood-rotting fungi. AB - An actinomycete isolate, Streptomyces exfoliatus MT9 was assessed for in vitro antagonism against wood-rotting fungi. Strain MT9 showed strong antagonistic activity (ZOI ? 25 mm) towards various tested wood-rotting fungi. Extracellular production of antifungal metabolite(s) including primary and secondary was monitored up to 10 days of submerged fermentation. Antagonist S. exfoliatus MT9 produces fungal cell-wall lytic enzymes, namely chitinase (3.098 U ml-1), b-1,3 glucanase (2.4 U ml-1) and protease (144.0 U ml-1) and also showed antifungal activity towards tested P. chrysosporium MTCC 787 (12.0 mm) and P. placenta MTCC 144 (16.0 mm). Extracellular culture filtrate (ECF) of S. exfoliatus MT9 also exhibited strong antifungal activity (ZOI >= 25 mm) towards tested wood-rotting fungi and n-butanol was found to be the suitable solvent for complete extraction of antifungal metabolite(s) from ECF. Reduced antifungal activity of n-butanol extract against P. chrysosporium MTCC 787 (11.00 mm) and P. placenta MTCC 144 (10.00 mm) on ergosterol agar plate, no activity against bacteria and characteristic UV spectra at 224 nm revealed the polyene nature of antifungal metabolite(s) present in the n-butanol extract. A novel actinomycete isolate, S. exfoliatus MT9 is producing antifungal metabolite(s) that makes it suitable for biotechnological processes and has the potential to be used as a bioactive agent for controlling wood-rotting fungi. PMID- 29257363 TI - ANMF PRIORITIES 2017. AB - Without a doubt our professions and our communities are up for some significant challenges in health and aged care during 2017. Based on the issues important to you, the ANMF has set key priorities for the year ahead and will work hard to ensure health equity and fair conditions for all. PMID- 29257364 TI - Humid thermal ratio as a tool to assess mango thrips dynamics under subtropical climatic condition. AB - Weather factors play an important role in occurrence of thrips on mango. Keeping this in view, the present investigation was set out to assess the thrips population dynamics using humid thermal index, based on data sets from 22 fixed plot mango orchards in and around Lucknow. Results revealed that the highest thrips population of 3.36/panicle was recorded in Kakori (Fixed plot -I) orchard, which was followed by 2.4 and 2.06 at CISH III block and Kanar (Fixed II) respectively during the year 2013, whereas corresponding values were 4.05, 3.08 and 2.50 at CISH Block III, CISH Bolck II and Allupur respectively during 2014. The frequency distribution explained that the thrips population of <2 /panicle was widely distributed with highest frequency level. The humid thermal ratio ranged from 1.44 to 2.27 and 1.20 to 2.34 during 2013 and 2014 respectively across standard meteorological weeks. The peak thrips incidence was 6.18 /panicle during 2013 and 4.67/panicle during 2014, the corresponding values of humid thermal ratio were 1.47 and 2.05 respectively. The positive correlation was found between humid thermal ratio and thrips population dynamics during 2013 (r = 0.52**) and 2014 (r = 0.72**). Pooled data showed significant and positive correlation between humid thermal ratio and thrips population. Pooled analysis had explained up to 94 per cent of variation with exponential model (Thrips population = 0.007e2.778HTR, R2 = 0.94**) and suggested that this index might be used in understanding the mango thrips population dynamics under subtropical environmental condition. PMID- 29257366 TI - Miscellaneous Intelligence. PMID- 29257365 TI - RELIABLE ALLERGY RESOURCES. AB - Allergic conditions now affect 20% of the Australian population (Mullins et al. 2015). This means that nurses in different clinical practice fields will be involved in involved in caring for patients who may also have an allergic condition. PMID- 29257367 TI - Medical Intelligence. PMID- 29257368 TI - To the Public. PMID- 29257369 TI - Miscellaneous Intelligence. PMID- 29257370 TI - On the Language of Complaint during Pain, and the Consequences of Suppressing It, Principally from the French of Baron Larrey. PMID- 29257371 TI - Some Observations and Examples of Phlegmasia Dolens, in the Puerperal, Gravid, and Unimpregnated States; and Also in the Male. PMID- 29257372 TI - Death of Dr. Primrose Blair, Late Physician of the Fleet, &c.; with the Appearances on Dissection. PMID- 29257373 TI - Medical Intelligence. PMID- 29257374 TI - Case of Extra-Uterine Conception, Wherein Hystero-Thecotomy Was Successfully Performed. PMID- 29257376 TI - Cases of Hydrophthalmia, Wherein the Practice of Arteriotomy Was Successfully Employed. PMID- 29257375 TI - Some Observations and Cases, Shewing the Danger of Suppressing Accustomed Evacuations, or Rashly Interfering with Certain Periodical Affections of the System. PMID- 29257377 TI - Case in Which the Arteria Innominata Was Tied by a Surgical Operation. PMID- 29257378 TI - Cases of Morbid Anatomy. PMID- 29257380 TI - Report of Diseases in the Universal Dispensary for Children St. Andrew's Hill, Doctors' Commons, from December 1, 1818, to June 1, 1819, Including a List of the Cases. PMID- 29257379 TI - Foreign Medical Literature. PMID- 29257381 TI - Foreign Medical Literature. PMID- 29257382 TI - Case of Abdominal Inflammation with Some Remarks. PMID- 29257383 TI - Case of Twins, Accompanied with Embarrassing Circumstances. PMID- 29257384 TI - Periscope: Surgery. PMID- 29257386 TI - Case of Gun-Shot Wound of the Shoulder Joint, with Lodgement of the Ball in the Head of the Humerus, Fracture of the Scapula, &c. Wherein Amputation at the Shoulder Joint, under Unfavourable Circumstances, Was Successfully Performed. PMID- 29257385 TI - Some Observations Suggested by Mr. Cunningham's Case of Concussion of the Brain, Published in the February Number of the Medico-Chirurgical Journal. PMID- 29257387 TI - The Port-Folio; or, Medical and Surgical Miscellany. PMID- 29257388 TI - Periscope: Parturiology. PMID- 29257389 TI - On Diseases Resembling Syphilis. PMID- 29257390 TI - Case of Obstinate Plethora, with Violent Haemorrhagic Oscillations in the Balance of the Circulation. PMID- 29257391 TI - Practical Hints on the Treatment of Females in the Advanced Stage of Pregnancy. PMID- 29257392 TI - Periscope: Pathology and Therapeutics. PMID- 29257393 TI - Case of Twins, in Which Premature Labour Was Induced by Redundancy of Liquor Amnii. PMID- 29257394 TI - Periscope: Surgery. PMID- 29257395 TI - Case of Excision of a Portion of the Ribs, and Also of the Pleura. PMID- 29257396 TI - Practical Observations on Certain Inflammatory Affections of the Mucous Membranes of the Lungs and Alimentary Canal. PMID- 29257397 TI - The Port-Folio; or, Medical and Surgical Miscellany. PMID- 29257398 TI - Case of Obstinate and Fatal Vomiting, without Any Structural Disease of the Stomach. PMID- 29257399 TI - Foreign Medical Literature. PMID- 29257400 TI - Case of Enteritis, Terminating in Serous Effusion into the Abdomen; with the Appearances on Dissection. PMID- 29257401 TI - Periscope: Pathology and Therapeutics. PMID- 29257402 TI - On Hydrocephalus Acutus. PMID- 29257403 TI - Pathological and Therapeutical Observations on Haemorrhoids. PMID- 29257404 TI - Case of Painful Affection of the Bladder, from Gastric and Hepatic Disorder. PMID- 29257405 TI - Observations on the Sickness Which Prevailed at Jessore, (Bengal), in the Months of Aug. and Sept. 1817. PMID- 29257406 TI - Medical Cases, with Occasional Remarks. PMID- 29257407 TI - Remarkable Case of Hydrocephalus and Other Cerebral Disease in an Adult, with the Appearance on Dissection; and Some Observations on Epilepsy. PMID- 29257408 TI - Foreign Medical Literature. PMID- 29257409 TI - Case of Ascites, Cured Spontaneously. PMID- 29257410 TI - The Port-Folio; or, Medical and Surgical Miscellany. PMID- 29257411 TI - Cases and Dissections. PMID- 29257412 TI - Observations and Cases Illustrating the Efficacy of Compressing the Carotid Arteries in Sanguineous Turgescence of the Cerebral Vessels. PMID- 29257413 TI - Observations on Rabies Contagiosa. PMID- 29257414 TI - Medical Cases, with Occasional Remarks. PMID- 29257415 TI - Mr. Carmichael's Reply to Mr. Guthrie. PMID- 29257417 TI - The Port-Folio; or, Medical and Surgical Miscellany. PMID- 29257416 TI - An Account of the Wounded on Board His Majesty's Ship Queen Charlotte, in the Battle of Algiers. PMID- 29257418 TI - Foreign Medical Literature. PMID- 29257419 TI - On Certain Practical Diagnostic Distinctions between the Concentrated Endemic, Commonly Called the Yellow or Bulam Fever of the West Indies, and the Marsh Remittent Fever. PMID- 29257420 TI - Remarks on Certain Opinions Aad Doctrines Relative to the Phagedenic Ulcer Contained in Mr. Carmichael's Late Work on Venereal Diseases. PMID- 29257421 TI - Erratum. AB - [This corrects the article on p. 277 in vol. 1.]. PMID- 29257422 TI - On the Nature and Treatment of Hydrocephalus Acutus. PMID- 29257423 TI - Case of Extra-Uterine Conception, with the Appearances on Dissection. PMID- 29257424 TI - An Anatomical Inquiry Concerning the Nature of Fever. PMID- 29257425 TI - Case of Complicated Visceral Disease, &c. With the Appearances on Dissection. PMID- 29257426 TI - Two Cases of Loss of Power over the Voluntary Muscles. PMID- 29257427 TI - MERCILESS VERSUS MERCY KILLING? AB - In the current legal and political climate intentionally ending a patient's life is unlawful -- euthanasia and assisted suicide continue to be crimes in Australia. PMID- 29257428 TI - Observations on the Diagnosis between Central Stricture of the Stomach, and Some of the Abdominal Lesions with Which It May Be Confounded. PMID- 29257429 TI - Selections. PMID- 29257430 TI - Case of Cardiac, Hepatic, and Pulmonic Disease; with the Appearances on Dissection. PMID- 29257431 TI - Medical Miscellanies. PMID- 29257432 TI - Erratum. AB - [This corrects the article on p. 254 in vol. 1.]. PMID- 29257433 TI - Mr. Gray and Mr. Ellis, on Certain Diseases of the African Slaves. PMID- 29257434 TI - Selections. PMID- 29257435 TI - Case of a Wound in the OEsophagus, Accompanied with Diseased Lungs. PMID- 29257437 TI - Medical Miscellanies. PMID- 29257436 TI - Dr. Yeats, on Hydrencephalus. PMID- 29257438 TI - Mr. Bailey's Case of Contracted Intestine. PMID- 29257439 TI - Corrigenda. AB - [This corrects the article on p. 8 in vol. 1.]. PMID- 29257440 TI - Medical Miscellanies. PMID- 29257441 TI - Selections. PMID- 29257442 TI - On Disease of the Omentum. PMID- 29257443 TI - Medicina Nautica. PMID- 29257444 TI - Mr. Pym on the Bulam Fever. PMID- 29257445 TI - Medical Miscellanies. PMID- 29257446 TI - Mr. M'Leod, on the Bulam Fever. PMID- 29257447 TI - Dr. Curry, on Sudden Death. PMID- 29257448 TI - Account of the Phaenomena Produced by a Large Quantity of Nitric Oxide of Quicksilver, Swallowed by Mistake; and of the Means Employed to Counteract Its Deleterious Influence. PMID- 29257450 TI - Selections. PMID- 29257451 TI - Case of Excision of a Scirrhous Parotid Gland. PMID- 29257449 TI - Singular Case of Malformation. PMID- 29257452 TI - An Inaugural Dissertation on Certain Endemic Diseases of Rio de Janeiro: viz. Erysipelas and Hydrocele. PMID- 29257453 TI - The Reviewer to Dr. Yeats. PMID- 29257454 TI - Medical Miscellanies. PMID- 29257456 TI - Selections. PMID- 29257457 TI - Medical Miscellanies. PMID- 29257455 TI - Case of Amaurosis of Both Eyes, of Twelve Months Standing. PMID- 29257459 TI - Selections. PMID- 29257458 TI - Case of Removal of the Human Spleen, without Injury or Derangement of the Animal Economy. PMID- 29257460 TI - On the Utility of Evacuations and Very Low Regimen in Certain Obscure Forms of Disease; with Cases in Illustration. PMID- 29257461 TI - Medicina Nautica. PMID- 29257462 TI - Case of Remarkable Contraction of the Stomach, near Its Centre. PMID- 29257464 TI - Medical Miscellanies. PMID- 29257463 TI - To the Editors of the Medico-Chirurgical Journal & Review. PMID- 29257465 TI - Selections. PMID- 29257467 TI - Case of Haemato-Scrofulous Tumour of Enormous Size, with the Appearances on Dissection. PMID- 29257466 TI - Case of Lepra Arabum, or True Elephantiasis. PMID- 29257468 TI - History of a Case of Diseased Spleen, Which Terminated Fatally. PMID- 29257469 TI - Observations on Spasmodic and Convulsive Diseases. PMID- 29257470 TI - Oriental Instruments for Curing Rheumatism. PMID- 29257471 TI - On Syncope Angens. PMID- 29257472 TI - Selections. PMID- 29257473 TI - Remarkable Case of Oneirodynia. PMID- 29257474 TI - Mr. Mortimer's Report of the Yellow or Bulam Fever. PMID- 29257475 TI - Medical Miscellanies. PMID- 29257476 TI - Selections. PMID- 29257478 TI - Yellow or Bulam Fever. PMID- 29257477 TI - Case of Urinary Concretion, Complicated with an Adipose Tumour of the Abdomen, Weighing Four Pounds and a Half, Avoirdupois. PMID- 29257479 TI - Case of Rupture of the Carotid Artery, and Wounds of Several of Its Branches, Successfully Treated by Tying the Common Trunk of the Carotid Itself. PMID- 29257481 TI - Meteorological Register for November, 1816: Kept at Harwich, in Essex. PMID- 29257480 TI - Medical Miscellanies. PMID- 29257482 TI - Apoplexy Succeeding a Long-Continued and Immoderate Use of Opium, with the Appearances on Dissection. PMID- 29257484 TI - Selections. PMID- 29257483 TI - Medical Miscellanies. PMID- 29257485 TI - Mr. Mortimer's Report of the Yellow or Bulam Fever. PMID- 29257486 TI - Meteorological Register for January, 1817: Kept at Harwich, in Essex. PMID- 29257487 TI - Meteorological Register for December, 1816: Kept at Harwich, in Essex. PMID- 29257488 TI - Cases of Dysentery, Treated with Calomel in Scruple Doses. PMID- 29257489 TI - Observations on Syncope Angens. PMID- 29257490 TI - Observations on Hernia, Illustrated by a Case and Dissection. PMID- 29257491 TI - The Observer. No. II. PMID- 29257492 TI - Apparent Want of Action in Various Arteries. PMID- 29257493 TI - A Case of Hydrocephalus Acutus. PMID- 29257494 TI - Meteorological Register for April, 1817: Kept at Harwich, in Essex. PMID- 29257496 TI - Medical Miscellanies. PMID- 29257495 TI - Meteorological Register for March, 1817: Kept at Harwich, in Essex. PMID- 29257497 TI - Copy of a Report on Refrigeration with Rum, in the Cure of the West India Endemic Fever; Addressed to the Commissioners for Transports, &c. PMID- 29257498 TI - Selections. PMID- 29257500 TI - Medical Miscellanies. PMID- 29257499 TI - Cases, Illustrating the Employment of Venaesection and Mercury in Angina Trachealis, or Croup. PMID- 29257501 TI - Selections. PMID- 29257502 TI - Meteorological Register for February, 1817: Kept at Harwich, in Essex. PMID- 29257503 TI - The Observer. No. I. PMID- 29257504 TI - Remarkable Case of Fractured Skull, with the Appearances on Dissection. PMID- 29257505 TI - Dr. Balfour, on Rheumatism. PMID- 29257506 TI - Meteorological Register for June, 1817: Kept at Harwich, in Essex. PMID- 29257507 TI - Medical Miscellanies. PMID- 29257508 TI - Dr. Felix's Remarkable Conversion of Diseases. PMID- 29257509 TI - Analogous Case of Conversion of Disease. PMID- 29257510 TI - Case of Disordered Action of the Heart, with Dropsical Effusion, Relieved by Blood-Letting. PMID- 29257511 TI - Case of Acute Inflammation of the Psoac Muscles, with Observations. PMID- 29257512 TI - Errata. AB - [This corrects the article on p. 53 in vol. 4.]. PMID- 29257514 TI - Case of Traumatic Tetanus Successfully Treated. PMID- 29257515 TI - Selections. PMID- 29257513 TI - A Case of Measles, with the Appearance on Dissection. PMID- 29257517 TI - Medical Miscellanies. PMID- 29257516 TI - Case of Spasmodic Contraction of the Voluntary Muscles, Particularly Those of the Superior Extremities, Consequent on Inhalation of the Vapours of Burning Charcoal. PMID- 29257518 TI - Selections. PMID- 29257519 TI - An Account of a Morbid Concretion Discharged from the Rectum of the Human Female, and in Its Chemical Characters Closely Resembling Ambergris; with Historical Remarks. PMID- 29257520 TI - Report to the Transport Board on the Subject of Yellow Fever. PMID- 29257521 TI - Medical Miscellanies. PMID- 29257522 TI - Two Cases of Death, Apparently from Eating a Great Number of Eggs. PMID- 29257523 TI - Selections. PMID- 29257524 TI - Report of a Case of Fracture of the Basis Cranii, Terminating in Inflammation of the Brain, and Fatal Effusion; with the Results of a Juridical Examination of the Body. PMID- 29257526 TI - Meteorological Register for May, 1817: Kept at Harwich, in Essex. PMID- 29257525 TI - Mr. Mortimer's Official Report to Dr. Dickson, Physician to the Fleet, Respecting the Fever in Marie Galante in 1808. PMID- 29257527 TI - A Case of Phlegmatia Dolens, or a Disease in All Respects Similar, Which Occurred in a Male Subject. PMID- 29257528 TI - Dr. Philip, on the Action of the Heart. PMID- 29257529 TI - Description of an Aneurism of the Arch of the Aorta Communicating with the OEsophagus. PMID- 29257530 TI - Meteorological Register for September, 1817: Kept at Harwich, in Essex. PMID- 29257531 TI - Selections. PMID- 29257532 TI - Case of Extensive Wound of the Larynx and Pharynx, Terminating Successfully. PMID- 29257533 TI - Medical Miscellanies. PMID- 29257534 TI - On the Utility of Evacuations and Very Low Regimen in Removing or Developing Obscure Diseases with Anomalous Symptoms. PMID- 29257535 TI - To the Editors of the Medico-Chirurgical Journal & Review. PMID- 29257536 TI - Dr. Dobson's Case of Fracture of the Cranium. PMID- 29257537 TI - Selections. PMID- 29257538 TI - Meteorological Register for August, 1817: Kept at Harwich, in Essex. PMID- 29257539 TI - Dr. Davis's Report of the Universal Dispensary. PMID- 29257540 TI - Medical Miscellanies. PMID- 29257541 TI - Meteorological Register for July, 1817: Kept at Harwich, in Essex. PMID- 29257542 TI - A Case of Rabies Canina, with the Appearances on Dissection. PMID- 29257544 TI - On the Study of Nosology, and the Present State of Medical Science. PMID- 29257543 TI - Observations on Erysipelas Infantile. PMID- 29257545 TI - Case of Pneumonia, Where the Extent to Which Blood-Letting May Be Successfully Carried Is Fully Exemplified. PMID- 29257546 TI - Description of an Ossiform Substance Developed in the Vulvo-Labial Texture; with a Sketch of the Concomitant Symptoms. PMID- 29257548 TI - Selections. PMID- 29257547 TI - List of Cases Received under the Care of Dr. John B. Davis, the Physician of the Universal Dispensary for Children, St. Andrew's Hill, Doctors' Commons, London; from July the 31st, 1817, to the 31st of October Following. PMID- 29257550 TI - Case of Diseased Brain, Complicated with Extraordinary Effusion of Fluid into the Ventricles, and Separation of the Cranial Bones. PMID- 29257549 TI - Medical Miscellanies. PMID- 29257551 TI - Case of a Remarkable Abdominal Tumour in a Woman, from Which Hair and Teeth Were Extracted. PMID- 29257552 TI - Case of Melancholia, from a Material Cause in the Brain, Terminating in Effusion of Blood There, and Apoplexy; with the Appearances on Dissection. PMID- 29257554 TI - Selections. PMID- 29257553 TI - Fatal Case of Diarrhoea. PMID- 29257556 TI - Medical Miscellanies. PMID- 29257555 TI - Medical Miscellanies. PMID- 29257557 TI - Dr. Parry, on the Circulation of the Blood. PMID- 29257559 TI - Selections. PMID- 29257558 TI - Some Particulars of a Fever Which Prevailed among the Crew of His Majesty's Ship Montague, at Gibraltar, in the Months of January and February, 1816. PMID- 29257560 TI - Meteorological Register for September, 1816: Kept at Harwich, in Essex. PMID- 29257562 TI - Selections. PMID- 29257561 TI - Dr. Johnson's Reply to the Foregoing Paper. PMID- 29257563 TI - Errata. AB - [This corrects the article on p. 497 in vol. 2.]. PMID- 29257564 TI - Medical Miscellanies. PMID- 29257565 TI - Singular Case of Abdominal Disease Simulating Hydr-Ovarium; with the Appearances on Dissection. PMID- 29257566 TI - Observations on Irritable Bladder; with Cases. PMID- 29257568 TI - Errata. AB - [This corrects the article on p. 40 in vol. 2.]. PMID- 29257567 TI - Case of Remarkable Organic Disease of the Stomach and Neighbouring Parts, with the Appearances on Dissection. PMID- 29257569 TI - Selections. PMID- 29257570 TI - Medical Miscellanies. PMID- 29257571 TI - Case of Aneurism of the Aorta. PMID- 29257572 TI - Remarks on a Paper Entitled "Medical Topography of New Orleans, &c." in the Edinburgh Journal. PMID- 29257573 TI - Meteorological Register for June, 1816: Kept at Harwich, in Essex. PMID- 29257574 TI - Case of Anomalous Disease; with Appearances on Dissection. PMID- 29257575 TI - Medical Miscellanies. PMID- 29257576 TI - Observations on Hemeralopia, or Night Blindness. PMID- 29257577 TI - Appearances on Dissection of Col. *******, M. P. Who Lately Died at Leghorn; with Observations. PMID- 29257578 TI - Selections. PMID- 29257579 TI - Meteorological Register for July, 1816: Kept at Harwich, in Essex. PMID- 29257580 TI - Dr. Brenan, on the Cure of Puerperal Fever. PMID- 29257581 TI - Notes of a Case of Uterine Polypus Terminating in Fatal Sphacelation. PMID- 29257583 TI - Case of Enlarged Liver. PMID- 29257582 TI - Medical Miscellanies. PMID- 29257584 TI - Meteorological Register for October, 1816: Kept at Harwich, in Essex. PMID- 29257585 TI - Selections. PMID- 29257586 TI - Letter from John Mortimer, Esq. Late Surgeon of His Majesty's Naval Hospitals at Jamaica, Barbadoes, Antigua, &c. to Dr. Johnson, Inclosing a Copy of an Official Report to the Commissioners of Transports, &c. Relative to the Yellow or Bulam Fever. PMID- 29257587 TI - On the Stations Nosologically Assigned to Synocha, or Inflammatory Fever, and to the West India Yellow Fever. PMID- 29257588 TI - Mr. Cunningham, on Scruple Doses of Calomel. PMID- 29257589 TI - A List of the Diseases Admitted under the Care of the Physicians of the Universal Dispensary for Children, St. Andrew's Hill, Doctors' Commons; from the 1st of January, 1818, to the 1st of April Following. PMID- 29257591 TI - Medical Miscellanies. PMID- 29257590 TI - Pathology and Practice (Medical). PMID- 29257592 TI - Cases of Peritoneal Inflammation Succeeded by Phlegmatia Dolens. PMID- 29257593 TI - Observations on Infantile Remittent Fever. PMID- 29257594 TI - Pathology and Practice (Medical). PMID- 29257595 TI - Medical and Pathological Observations, Drawn from Military Hospital Practice, with Cases, &c. PMID- 29257596 TI - Observations on Large Doses of Submuriate of Mercury for the Cure of Syphilis. PMID- 29257597 TI - Medical Miscellanies. PMID- 29257599 TI - Pathology and Practice (Medical). PMID- 29257598 TI - Cases of Gout, with Observations. PMID- 29257600 TI - Treatment of Typhus. PMID- 29257601 TI - Anatomy and Physiology. PMID- 29257602 TI - Chemistry (Animal). PMID- 29257603 TI - Case of Fatal Concussion of the Brain, with the Appearances on Dissection. PMID- 29257604 TI - Medical Miscellanies. PMID- 29257605 TI - Medical Reports on the State of Health in His Majesty's Ship Venerable, in the Years 1814 and 1815, Employed in the West Indies, as Flag Ship of Rear Admiral Sir Phillip Durham. PMID- 29257606 TI - Meteorological Register for October, 1817: Kept at Harwich, in Essex. PMID- 29257608 TI - Case of Cynanche Laryngea, Requiring Tracheotomy, and the Continued Use of a Canula Ever Since the Operation. PMID- 29257607 TI - Anatomy and Physiology. PMID- 29257609 TI - Occurrences on Board H. M. Hospital-Ship Gorgon, between the 18th of September, 1814, and the 8th of May, 1815. PMID- 29257611 TI - Pathology and Practice (Medical). PMID- 29257610 TI - Dr. Sanders, on Disorders of the Nervous System. PMID- 29257613 TI - Medical Miscellanies. PMID- 29257612 TI - Meteorological Register for November, 1817: Kept at Harwich, in Essex. PMID- 29257614 TI - Case of Successful Amputation at the Shoulder-Joint, Performed under Very Unpromising Circumstances. PMID- 29257615 TI - Medical Miscellanies. PMID- 29257616 TI - Chemistry (Animal). PMID- 29257617 TI - Mr. Jukes's Cases of Ruptured Intestine. PMID- 29257618 TI - Pathology and Practice (Medical). PMID- 29257619 TI - List of Cases Admitted under the Care of the Physicians of the Universal Dispensary for Children, St. Andrew's Hill, Doctors' Commons, London; from the 31st of October, 1817, to the 31st of December Following. PMID- 29257620 TI - On a New and Successful Mode of Treating Extensive Abscesses. PMID- 29257621 TI - Case of Inflammation of the Liver, Terminating in Fatal Suppuration of the Organ, and Expectoration of Pus. PMID- 29257622 TI - Case of Varicella. PMID- 29257623 TI - Observations on the Internal Use of Nitrate of Silver. PMID- 29257624 TI - Remarks on Hepatic Affection, as a Cause of Other Diseases. PMID- 29257625 TI - Experiments on Muriatic Acid Gas, with Observations on Its Chemical Constitution, and on Some Other Subjects of Chemical Theory. PMID- 29257626 TI - Medical Miscellanies. PMID- 29257627 TI - Practical Observations on Acute and Chronic Carditis. PMID- 29257628 TI - ANMF LIBRARIES AT YOUR SERVICE. AB - Did you know many of the ANMF Branches offer library services to members and ANMF staff? PMID- 29257629 TI - DEALING WITH DEATH. AB - One inevitable thing we all must address....is death. As soon as we are born, we are dying. Although part of the normal sequence of life, death encompasses grief, and grief is uncomfortable. So naturally death at times is avoided in general conversations, which can create fear surrounding the process. PMID- 29257630 TI - Toxic effects of permethrin on Pseudorasbora parva. AB - The present study deals with acute toxicity and hematological, histopathological and genotoxical effects of permethrin, a synthetic pyrethroid, on Pseudorasbora parva. Acute toxicity of 96-hrs LC50 value was found to be 88.25 (84.60-92.63) MUgl-1. Sublethal dose was taken as 8.82 MUgl-1 (the 1/10 of the LC50 value) in bio-experiments. Micronucleus changes in blood erythrocyte and hemotocyte level in P. parva exposed to sub-lethal concentration were investigated. Difference between nucleolus abnormalities in the experimental and control group was found to be statistically significant (t-test). Micronucleus frequency was found to be 8.26. The hematocrit level in control and experimental groups were found to be 24.43% and 14.673%. No pathological symptoms were observed in the muscle of P. parva exposed to sublethal dose for 96 hrs. Pathological symptoms observed after 96 hours from permethrin administration in other organs were: Fusion, Telangiectasis, epithelial lifting and hyperemia in gills; hydropic degeneration, lipid degeneration and passive hyperemia in liver and enlargement of cavum glomeruli and Bowman space in kidneys and hemorrhage, edema and hyperemia in brain, respectively. PMID- 29257631 TI - VIEWPOINT AND REFLECTION FOR THE NURSING WORKFORCE. AB - If the Close the Gap Campaign is working to achieve health and life expectation equality, are we creating an ageing health workforce to work with older Aboriginal and Torres Strait Islander people? PMID- 29257632 TI - Vaginismus in Assisted Reproductive Technology Centers: an invisible population in need of care. AB - OBJECTIVE: Genital and sexual pain is still neglected. Consequences may be dramatic, since infertility and sexual dysfunction may be reciprocally linked. This is the first study to focus on the identification of cases of vaginismus in the ART scenario and on the introduction of intra-cycle interventions as part of a comprehensive, integrated and patient-centered perspective. METHODS: This observational prospective study looked into 425 IVF/ICSI cycles and 226 frozen embryo transfers carried out from January 1, 2015 to December 31, 2016, and found seven cases of vaginismus. Within a six-month period, a questionnaire placed on SurveyMonkey was sent twice to 228 ART centers in Latin America. The purpose was to learn how often cases of vaginismus were found in ART centers and the perceptions around the presence of this condition. RESULTS: The few centers that took the time to answer the questionnaire (24/10.5%) stated that the number of cases in which they had trouble performing control ultrasound examination or needed to perform transfers with patients under sedation was not significant. Although 81% agreed that the incidence of these conditions is low, no references were made to cases of vaginismus, dyspareunia or sexual dysfunction. Our multidisciplinary team found seven cases of vaginismus, involving women with higher education degrees with a mean age of 37.8 years and married for a mean of four years. Although two reported they were able to tolerate intercourse, all reported undergoing treatments such as using vaginal dilators (3), psychotherapy (4) and psychiatric care (1). The care provided by the staff was designed to mitigate patient suffering. CONCLUSION: Gentle care and sensitive listening should be integral components in the work of multidisciplinary teams to identify women with vaginismus and offer couples better quality treatment. PMID- 29257633 TI - THE VICTORIAN NEW HEALTH COMPLAINTS ACT 2016 -- WHAT ARE THE CHANGES? AB - The Health Complaints Act 2016 (Vic) commenced on 1 February 2017, bringing into operation a new office of the Health Complaints Commissioner (HCC). This article outlines the changes nurses and midwives are likely to see under the new Act. PMID- 29257634 TI - Applications of response surface methodology and artificial neural network for decolorization of distillery spent wash by using activated Piper nigrum. AB - Ethanol production from sugarcane molasses yields large volume of highly colored spent wash as effluent. This color is imparted by the recalcitrant melanoidin pigment produced due to the Maillard reaction. In the present work, decolourization of melanoidin was carried out using activated carbon prepared from pepper stem (Piper nigrum). The interaction effect between parameters were studied by response surface methodology using central composite design and maximum decolourization of 75 % was obtained at pH 7.5, Melanoidin concentration of 32.5 mg l-1 with 1.63 g 100ml-1 of adsorbent for 2hr 75min. Artificial neural networks was also used to optimize the process parameters, giving 74 % decolourization for the same parameters. The Langmuir and Freundich isotherms were applied for describing the biosorption equilibrium. The process was represented by the Langmuir isotherm with a correlation coefficient of 0.94. The first-order, second-order models were implemented for demonstrating the biosorption mechanism and, as a result, Pseudo second order model kinetics fitted best to the experimental data. The estimated enthalpy change (DH) and entropy change (DS) of adsorption were 32.195 kJ mol-1 and 115.44 J mol-1 K which indicates that the adsorption of melanoidin was an endothermic process. Continuous adsorption studies were conducted under optimized condition. The breakthrough curve analysis was determined using the experimental data obtained from continuous adsorption. Continuous column studies gave a breakthrough at 182 mins and 176 ml. It was concluded that column packed with Piper nigrum based activated carbon can be used to remove color from distillery spent wash. PMID- 29257635 TI - ASSISTED FERTILITY TREATMENT AND THE QUALITY OF INFORMED CONSENT. PMID- 29257636 TI - ENHANCING STUDENT NURSE PREPARATION FOR PAEDIATRIC PRACTICE. AB - An innovative pilot project at the University of the Sunshine Coast is giving undergraduate students an opportunity to develop their skills in caring for child clients and their families. PMID- 29257637 TI - COME TO THE TABLE. AB - Renowned celebrity cook Maggie Beer is improving the food experience for everyone as they age. PMID- 29257639 TI - A COLLABORATIVE PROJECT. AB - The Queensland government Department of Communities, Child Safety and Disability Services has funded Community Resourcing to establish the Community Care Smart Assistive Technology Collaborative (CCSATC) online space. PMID- 29257638 TI - A REVIEW OF AGED CARE PROVISION IN MULTIPURPOSE SERVICES (MPS). AB - The MPS model has been in place for over 20 years in NSW as a way to address the ongoing healthcare needs of small rural communities. PMID- 29257641 TI - Corrigenda. AB - [This corrects the article on p. 68 in vol. 1.]. PMID- 29257640 TI - IMPROVING HEALTH AND SAFETY IN AGED CARE USING GAME BASED SIMULATION. AB - Australia faces the challenge of supporting a growing ageing population (AIHW, 2012). Health and safety is paramount in ensuring care is economically sustainable. Nurses involved in healthcare have a responsibility to protect themselves and those being cared for against health and safety risk. Training of the workforce is paramount to reducing the chance of injury (Robson et al. 2012). PMID- 29257643 TI - Corrigenda. AB - [This corrects the article on p. 21 in vol. 1.]. PMID- 29257642 TI - Water quality assessment of Kavvayi Lake of northern Kerala, India using CCME water quality index and biological water quality criteria. AB - Assessment of water quality status of 7 sites of Kavvayi Wetland in northern Kerala (India) was carried out. The physico-chemical, bacteriological and biological parameters were monitored during pre-monsoon, monsoon and post-monsoon seasons. Canadian Council of Ministers of the Environment (CCME) water quality index of the Kavvayi Lake samples ranged from 43.99-44.77; indicating that water quality was threatened or impaired. The poor water quality status might be due to dumping of wastes from municipal and domestic sources and agricultural runoff. Biological water quality criteria (BWQC) determined for wetland revealed that stations such as mixing point of Kariangode River into Kavvayi Lake and Kottikkadavu was moderately polluted in pre-monsoon and post- monsoon seasons. Mixing point of Nileswar River into Kavvayi Lake was moderately polluted in pre monsoon season. Both calculated indices suggest that quality of lake was found to be influenced by anthropogenic activities such as unscientific tourism and infrastructure development, land encroachment, sand mining, pollution etc. The study was carried out as part of a programme, which aimed to conserve Kavvayi wetland because of its unique ecological and environmental characteristics. PMID- 29257644 TI - Corrigenda. AB - [This corrects the article on p. 37 in vol. 1.]. PMID- 29257645 TI - Errata. AB - [This corrects the article on p. 512 in vol. 2.]. PMID- 29257646 TI - Errata. AB - [This corrects the article on p. 81 in vol. 2.]. PMID- 29257647 TI - PARTNERSHIPS FOR LEARNING AND MENTORING IN AGED CARE. AB - It is well known that the Australian population is ageing (Australian Bureau of Statistics, 2013). This ageing population has led to an increase in chronic and complex diseases, leading to a range of challenges for healthcare providers (Hunter & Levett-Jones, 2010), yet 75% of residential aged care facilities report skills shortages. PMID- 29257648 TI - COMMUNITY BASED HOME VISITING SERVICE IN KOREA: CITY OF GWANGMYEONG. AB - There has been growing interest in enhancing the quality of life of the economically vulnerable through programs aimed at improving the equality of and accessibility to public health services for these people. PMID- 29257649 TI - FOOD CHOICES -- LETTING AGED CARE RESIDENTS HAVE THEIR CAKE, AND EAT IT AS WELL. AB - In residential aged care (RAC), malnutrition and unplanned weight loss among residents is an important quality indicator. A contributing factor is limited access to food choices in the facility that meet their personal food preferences. PMID- 29257650 TI - WHERE HAS THE COMPASSION GONE FROM THE RESIDENTIAL AGED CARE ENVIRONMENT? AB - Would working in residential aged care be your dream job as a newly qualified nurse, probably not, but why not? Montayre (2015) suggests that although nurses don't like to talk about it, or even less, what the real problem is perceived to be with this practice area, residential aged care nursing is thought to be less exciting, monotonous, and requiring less skill than other areas such as emergency nursing, or medical nursing. PMID- 29257651 TI - INHIBITORS TO EXERCISE AND HEALTH PROMOTION PROGRAMS FOR THE OLDER PERSON WITH DIABETES. AB - Diabetes care incurs a high cost burden, and is one of the main geriatric syndromes along with its related complications. To effectively counter this, healthcare needs to be proactive in establishing exercise and health promotion programs that promote healthy and active ageing. PMID- 29257652 TI - Quantification of phenolic acids and antioxidant potential of inbred, hybrid and composite cultivars of maize under different nitrogen regimes. AB - Maize (Zea mays L.) is a multipurpose crop, which is immensely used worldwide for its nutritional as well as medicinal properties. This study evaluates the effect of varying concentrations of nitrogen (N) on accumulation of phenolic acids and antioxidant activity in different maize cultivars, including inbreds, hybrids and a composite, which were grown in natural light under controlled temperature (30 degrees C/20 degrees C D/N) and humidity (80%), with sufficient (4.5mM) and low (0.05mM) nitrogen supply. Seeds of different cultivars were powdered and extracted in a methanol:water (80:20) mixture through reflux at 60-75 degrees C, and the extracts obtained were subjected to high performance thin layer chromatography (HPTLC), using ethyl acetate: acetic acid: formic acid: water (109:16:12:31) solvent system for the separation of phenolic acids. Antioxidant activity of the extracts was determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and H2O2-scavenging activity assays. At sufficient nitrogen condition, the contents of different phenolic acids were higher in the composite cultivar (8.7 mg g-1 d.wt. in gallic acid to 39.3 mg g-1 d.wt. in cinnamic and salicylic acids) than in inbreds and hybrids. Under low nitrogen condition, the phenolic acids contents declined significantly in inbreds and hybrids, but remained almost unaffected in the composite. The antioxidant activity was also the maximum in the composite, and declined similarly as phenolic acids under low nitrogen supply, showing a significant reduction in inbreds and hybrids only. Therefore, the maize composite has a potential for being used as a nutraceutical in human-health sector. PMID- 29257653 TI - Interrelationship between physico-chemical characteristics of a tropical lake and their impact on biodiversity of planktons. AB - The physicochemical parameters including temperature, pH, dissolved O2, free CO2, total alkalinity, permanent hardness, salinity, transparency, specific conductivity, BOD, COD, phosphate and nitrate were studied in a tropical lake, called Bonhooghly Lake (situated at Baranagar, Kolkata) around the year 2014 and the correlation between the said parameters, as well as their impact on Biodiversity indices were made. There is stable increase of CO2 content in water from August (27.24 mg l-1) and afterwards due to decaying of plant materials. Therefore there is a slight fall of pH (7.1). Significant negative correlation (p<0.01) between pH and CO2 content was also obtained. It also shows a significant negative correlation with O2 content as well. During February and March transparency of water falls significantly with the increase of algal bloom. It significantly decreases dissolved O2 content and pH but increases free dissolved CO2 (p<0.01). Phosphate has a definite correlation with nitrate content of the Lake, possibly because both are among the most essential nutrients of living system. Increase of one obviously indicates escalation of other. During the early months of the year phosphate and nitrate content of water increased steadily (up to 0.13 and 1.85 mg l-1 respectively) and a very high number of Chlamydomonas(up to15100 l-1) and Chlorella (up to 13140 l-1)were observed. Species richness indices (Menhinick's index) of Phytoplanktons were observed maximum in the month of May, dominance (Simpson's index) in January and diversity (Shannon-Weaver index) in April. Zooplanktons also followed the same trend indicating close interdependence. It was significant that apart from other factors, temperature played a most pivotal role in bringing the diversity in the plankton community. PMID- 29257654 TI - Genetic diversity assessment of Fusarium oxysporum f. sp ciceris isolates of Indian chickpea fields as revealed by the SRAP marker system. AB - An experiment was conducted to study the precise geographical distribution and racial complexity of Fusarium oxysporum f.sp ciceris (Foc) isolates representing 12 states of 4 agro-climatic zones of India at morphological, pathogenic and molecular level. The DNA based sequence related amplified polymorphism (SRAP) markers was employed to differentiate Foc isolates at genome level. The genotypic data output of the isolates was examined for diversity parameter as marker's Polymorphic percentage (PM %), Polymorphic Information Content (PIC), Marker Index (MI) and Gene Diversity Index (DI). As a result, 15 primers used in this study could generated total of 154 reproducible alleles ranging from 100-2100 bp (average allele per marker 10.26) in size, of that 149 (97%) were found to be polymorphic. The neighbor-joining analysis effectively classified the isolates of North East Plain Zone (NEPZ), Central Zone (CZ), North West Plain Zone (NWPZ) and South Zone (SZ) into four clusters. In summary, DNA based marker analysis could differentiate as per isolates geographical location, however pathogenic interaction of isolates from same geographical location could not match the genetic differentiation. Accordingly, considering the present complexity in racial profile, precise classification based on homologs virulence genes specific to races would give a more meaningful in correlating isolates with their native geographical distribution and helps in future resistance breeding programs for sustainable management of vascular wilt disease. PMID- 29257655 TI - Radon activity measurements in irrigation water from Qassim Province by RAD7. AB - The present study deals with investigating radon level in groundwater, which is being used for irrigation in the environs of Qassim province, Saudi Arabia. Ninety nine samples of groundwater were collected from eight cities in Qassim province. Radon concentrations in the collected water samples were measured with RAD7 electronic radon detector connected to RAD- H2O accessory (Durridge Co., USA). The concentration of (222)Rn in 99 irrigation groundwater samples ranged from 1.20 to 15.43 Bq l-1Radon level in? 5 samples 2 from Al-Asyah, 2 from Al shamasia and one sample from Al Moznib exceeded the permissible level of radon 11 Bq l-1 in groundwater. The total annual effective dose varied with increase in radon concentration. The calculated effective dose per liter (EDL) and annual effective dose (AED) ranged from 6.1 to 77.15 nSvL-1 and 4.45 to 56.16 MUSv y-1, respectively. It was evident that the total annual effective doses resulting from radon in 95% from groundwater in Qassim area were significantly lower than the permissible limit of 1 mSv y-1 for the public. PMID- 29257662 TI - Next-Generation DNA-Functionalized Quantum Dots as Biological Sensors. AB - DNA-functionalized quantum dots (DNA-QDs) have found considerable application in biosensing and bioimaging. Different from the first generation (I-G) DNA-QDs prepared via conventional bioconjugation chemistry, the second generation (II-G) DNA-QDs prepared via one-step DNA-templated QD synthesis features a defined number of DNA valencies (usually monovalency), which is preferable for controlled assembly and biological targeting. In this review, we summarize recent progress in designing QD probes based on II-G DNA-QDs for advanced sensing and imaging applications. It opens up new avenues for highly sensitive and intelligent sensing of a range of disease-relevant biomolecules in vitro and in living cells. PMID- 29257663 TI - Highly Compressible, Anisotropic Aerogel with Aligned Cellulose Nanofibers. AB - Aerogels can be used in a broad range of applications such as bioscaffolds, energy storage devices, sensors, pollutant treatment, and thermal insulating materials due to their excellent properties including large surface area, low density, low thermal conductivity, and high porosity. Here we report a facile and effective top-down approach to fabricate an anisotropic wood aerogel directly from natural wood by a simple chemical treatment. The wood aerogel has a layered structure with anisotropic structural properties due to the destruction of cell walls by the removal of lignin and hemicellulose. The layered structure results in the anisotropic wood aerogel having good mechanical compressibility and fragility resistance, demonstrated by a high reversible compression of 60% and stress retention of ~90% after 10 000 compression cycles. Moreover, the anisotropic structure of the wood aerogel with curved layers stacking layer-by layer and aligned cellulose nanofibers inside each individual layer enables the wood aerogel to have an anisotropic thermal conductivity with an anisotropy factor of ~4.3. An extremely low thermal conductivity of 0.028 W/m.K perpendicular to the cellulose alignment direction and a thermal conductivity of 0.12 W/m.K along the cellulose alignment direction can be achieved. The thermal conductivity is not only much lower than that of the natural wood material (by ~3.6 times) but also lower than most of the commercial thermal insulation materials. The top-down approach is low-cost, scalable, simple, yet effective, representing a promising direction for the fabrication of high-quality aerogel materials. PMID- 29257664 TI - Site-Selective Carving and Co-Deposition: Transformation of Ag Nanocubes into Concave Nanocrystals Encased by Au-Ag Alloy Frames. AB - We report a facile synthesis of Ag nanocubes with concave side faces and Au-Ag alloy frames, namely Ag@Au-Ag concave nanocrystals, by titrating HAuCl4 solution into an aqueous mixture of Ag nanocubes, ascorbic acid (H2Asc), NaOH, and cetyltrimethylammonium chloride (CTAC) at an initial pH of 11.6 under ambient conditions. Different from all previous studies involving poly(vinylpyrrolidine), the use of CTAC at a sufficiently high concentration plays an essential role in carving away Ag atoms from the side faces through galvanic replacement. Concurrent co-deposition of Au and Ag atoms via chemical reduction at orthogonal sites on the surface of Ag nanocubes leads to the generation of Ag@Au-Ag concave nanocrystals with well-defined and controllable structures. Specifically, in the presence of CTAC-derived Cl- ions, the titrated HAuCl4 is maintained in the AuCl4 species, enabling its galvanic replacement with the Ag atoms located on the side faces of nanocubes. The released Ag+ ions can be retained in the soluble form of AgCl2- by complexing with the Cl- ions. Both the AuCl4- and AgCl2- in the solution are then reduced by ascorbate monoanion, a product of the neutralization reaction between H2Asc and NaOH, to Au and Ag atoms for their preferential co deposition onto the edges and corners of the Ag nanocubes. Compared with Ag nanocubes, the Ag@Au-Ag concave nanocrystals exhibit much stronger SERS activity at an excitation of 785 nm, making it feasible to monitor the Au-catalyzed reduction of 4-nitrothiophenol by NaBH4 in situ. When the Ag cores are removed, the concave nanocrystals evolve into Au-Ag nanoframes with controllable ridge thicknesses. PMID- 29257665 TI - Mercaptopropionic Acid-Capped Wurtzite Cu9Sn2Se9 Nanocrystals as High-Performance Anode Materials for Lithium-Ion Batteries. AB - In this research, we provide a simple but sound solution to address the low performance of lithium-ion batteries through preparation of wurtzite Cu9Sn2Se9 nanoparticles with uniform size distribution and morphology via a hot injection colloidal approach as a promising anode material. The Cu9Sn2Se9 nanoparticles anode exhibits superior rate performance and high reversible capacity of 979.8 mAh g-1 in the 100th cycle at a current density of 100 mA g-1, which is approximate 2 times of reported Cu-Sn-S framework (563 mA g-1), 1.5 times of reported pristine Cu2SnS3 (621 mA g-1) and comparable or higher than a number of reported Sn-based nanocomposites based anodes for lithium-ion batteries at the same cycle. The study demonstrate such outstanding properties are attributed to the high structural flexibility of the metal selenide and increased electronic connectivity by colloidal quantum dot ligand exchange procedure associated with mercaptopropionic acid (MPA). In addition, unlike most metal sulfides or selenides, it possesses a stepwise intercalation mechanism during the lithiation/delithiation cycles which is beneficial to buffer against volume variation of the alloy electrode materials. Such findings provide a new and feasible insight into guide the design and manufacturing of high performance lithium-ion batteries for a broad variety of engineering applications. PMID- 29257666 TI - Nitrogen and Fluorine Codoped, Colloidal TiO2 Nanoparticle: Tunable Doping, Large Red-Shifted Band Edge, Visible Light Induced Photocatalysis, and Cell Death. AB - Visible light photocatalysis by TiO2 requires efficient doping of other elements with red-shifted band edge to the visible region. However, preparation of such TiO2 with tunable doping is challenging. Here we report a method of making nitrogen (N) and fluorine (F) codoped TiO2 nanoparticle with tunable doping between 1 and 7 at. %. The preparation of N, F codoped TiO2 nanoparticle involves reaction of colloidal TiO2 nanorods with an ammonium fluoride-urea mixture at 300 degrees C, and the extent of N/F doping is tuned by varying the amount of ammonium fluoride-urea and the reaction time. Resultant colloidal N, F codoped TiO2 nanoparticles show doping dependent shifting of the band edge from the UV to near-IR region, visible light induced generation of reactive oxygen species (ROS), and visible light photodegradation of bisphenol A. A colloidal form of doped TiO2 nanoparticle offers labeling of cells, visible light induced ROS generation inside a cell, and successive cell death. This work shows the potential advantage of anisotropic nanoparticle precursor for tunable doping and colloidal form of N, F codoped TiO2 nanoparticle as a visible light photocatalyst. PMID- 29257667 TI - Electrochemical Characteristics of Layered Transition Metal Oxide Cathode Materials for Lithium Ion Batteries: Surface, Bulk Behavior, and Thermal Properties. AB - Layered lithium transition metal oxides, in particular, NMCs (LiNixCoyMnzO2) represent a family of prominent lithium ion battery cathode materials with the potential to increase energy densities and lifetime, reduce costs, and improve safety for electric vehicles and grid storage. Our work has focused on various strategies to improve performance and to understand the limitations to these strategies, which include altering compositions, utilizing cation substitutions, and charging to higher than usual potentials in cells. Understanding the effects of these strategies on surface and bulk behavior and correlating structure performance relationships advance our understanding of NMC materials. This also provides information relevant to the efficacy of various approaches toward ensuring reliable operation of these materials in batteries intended for demanding traction and grid storage applications. In this Account, we start by comparing NMCs to the isostructural LiCoO2 cathode, which is widely used in consumer batteries. Effects of changing the metal content (Ni, Mn, Co) upon structure and performance of NMCs are briefly discussed. Our early work on the effects of partial substitution of Al, Fe, and Ti for Co on the electrochemical and bulk structural properties is then covered. The original aim of this work was to reduce the Co content (and thus the raw materials cost) and to determine the effect of the substitutions on the electrochemical and bulk structural properties. More recently, we have turned to the application of synchrotron and advanced microscopy techniques to understand both bulk and surface characteristics of the NMCs. Via nanoscale-to-macroscale spectroscopy and atomically resolved imaging techniques, we were able to determine that the surfaces of NMC undergo heterogeneous reconstruction from a layered structure to rock salt under a variety of conditions. Interestingly, formation of rock salt also occurs under abuse conditions. The surface structural and chemical changes affect the charge distribution, the charge compensation mechanisms, and ultimately, the battery performance. Surface reconstruction, cathode/electrolyte interface layer formation, and oxygen loss are intimately related, making it difficult to disentangle the effects of each of these phenomena. They are driven by the different redox activities of Ni and O on the surface and in the bulk; there is a greater tendency for charge compensation to occur on oxygen anions at particle surfaces rather than on Ni, whereas the Ni in the bulk is more redox active than on the surface. Finally, our latest research efforts are directed toward understanding the thermal properties of NMCs, which is highly relevant to their safety in operating cells. PMID- 29257668 TI - Clusters, Assemble: Growth of Intermetallic Compounds from Metal Flux Reactions. AB - Metal flux synthesis involves the reaction of metals and metalloids in a large excess of a low-melting metal that acts as a solvent. This technique makes use of an unusual temperature regime (above the temperatures used for solvothermal methods and below the temperatures used in traditional solid state synthesis) and facilitates the growth of products as large crystals. It has proven to be a fruitful method to discover new intermetallic compounds. However, little is known about the chemistry occurring within a molten metal solvent; without an understanding of the nature of precursor formation and assembly, it is difficult to predict product structures and target properties. Organic chemists have a vast toolbox of well-known reagents and reaction mechanisms to use in directing their synthesis toward a desired molecular structure. This is not yet the case for the synthesis of inorganic extended structures. We have carried out extensive explorations of the growth of new magnetic intermetallic compounds from a variety of metal fluxes. This Account presents a review of some of our results and recent reports by other groups; this work indicates that products with common building blocks and homologous series with identical structural motifs are repeatedly seen in metal flux chemistry. For instance, fluorite-type layers comprised of transition metals coordinated by eight main group metal atoms are found in the Th2(AuxSi1-x)[AuAl2]nSi2 and R[AuAl2]nAl2(AuxSi1-x)2 series grown from aluminum flux, the CenPdIn3n+2 series grown from indium flux, and CePdGa6 and Ce2PdGa10 grown from gallium flux. Similarly, our investigations of reactions of heavy main group metals, M, in rare earth/transition metal eutectic fluxes reveal that the R/T/M/M' products usually feature M-centered rare earth clusters M@R8-12, which share faces to form layers and networks that surround transition metal building blocks. These structural trends, temperature dependence of products formed in the flux, and interconversions observed by differential scanning calorimetry support the idea that these clusters likely form in the melt, existing as precursors and assembling into different crystalline products depending on time, temperature, and reaction ratio. Proof of this mechanism will require future investigations using techniques such as pair distribution function analysis of flux melts to observe cluster formation and in situ diffraction during cooling to detect various phases as they crystallize and interconvert. These data will aid in understanding the parameters that control cluster formation and assembly in metal melts, allow for prediction of products of flux reactions, and will potentially enable the tailoring of reaction conditions to promote the formation of structures with desirable properties. PMID- 29257669 TI - Crystal Structure and Transport Properties of the Homologous Compounds (PbSe)5(Bi2Se3)3m (m = 2, 3). AB - We report on a detailed investigation of the crystal structure and transport properties in a broad temperature range (2-723 K) of the homologous compounds (PbSe)5(Bi2Se3)3m for m = 2, 3. Single-crystal X-ray diffraction data indicate that the m = 2, 3 compounds crystallize in the monoclinic space groups C2/m (No. 12) and P21/m (No. 11), respectively. In agreement with diffraction data, high resolution transmission electron microscopy analyses carried out on single crystals show that the three-dimensional crystal structures are built from alternating Pb-Se and m Bi-Se layers stacked along the a axis in both compounds. Scanning electron microcopy and electron-probe microanalyses reveal deviations from the nominal stoichiometry, suggesting a domain of existence in the pseudo binary phase diagram at 873 K. The complex atomic-scale structures of these compounds lead to very low lattice thermal conductivities kappaL that approach the glassy limit at high temperatures. A comparison of the kappaL values across this series unveiled an unexpected increase with increasing m from m = 1 to m = 3, in contrast to the expectation that increasing the structural complexity should tend to lower the thermal transport. This result points to a decisive role played by the Pb-Se/Bi-Se interfaces in limiting kappaL in this series. Both compounds behave as heavily doped n-type semiconductors with relatively low electrical resistivity and thermopower values. As a result, moderate peak ZT values of 0.25 and 0.20 at 700 K were achieved in the m = 2, 3 compounds, respectively. The inherent poor ability of these structures to conduct heat suggests that these homologous compounds may show interesting thermoelectric properties when properly optimized by extrinsic dopants. PMID- 29257670 TI - Correction to "Efficient Visible Light Nitrogen Fixation with BiOBr Nanosheets of Oxygen Vacancies on the Exposed {001} Facets". PMID- 29257671 TI - Cross-Linked Pectin Nanofibers with Enhanced Cell Adhesion. AB - Polysaccharides display poor cell adhesion due to the lack of cell binding domains. This severely limits their applications in regenerative medicine. This study reports novel cross-linked pectin nanofibers with dramatically enhanced cell adhesion. The nanofibers are prepared by at first oxidizing pectin with periodate to generate aldehyde groups and then cross-linking the nanofibers with adipic acid dihydrazide to covalently connect pectin macromolecular chains with adipic acid dihydrazone linkers. The linkers may act as cell binding domains. Compared with traditional Ca2+-cross-linked pectin nanofibers, the pectin nanofibers with high oxidation/cross-linking degree exhibit much enhanced cell adhesion capability. Moreover, the cross-linked pectin nanofibers exhibit excellent mechanical strength (with Young's modulus ~10 MPa) and much enhanced body degradability (degrade completely in 3 weeks or longer time). The combination of excellent cell adhesion capability, mechanical strength, and body degradability suggests that the cross-linked pectin nanofibers are promising candidates for in vivo applications such as tissue engineering and wound healing. This cross-linking strategy may also be used to improve the cell adhesion capability of other polysaccharide materials. PMID- 29257673 TI - Incorporation of Cadmium and Nickel into Ferrite Spinel Solid Solution: X-ray Diffraction and X-ray Absorption Fine Structure Analyses. AB - The feasibility of incorporating Cd and Ni in hematite was studied by investigating the interaction mechanism for the formation of CdxNi1-xFe2O4 solid solutions (CNFs) from CdO, NiO, and alpha-Fe2O3. X-ray diffraction results showed that the CNFs crystallized into spinel structures with increasing lattice parameters as the Cd content in the precursors was increased. Cd2+ ions were found to occupy the tetrahedral sites, as evidenced by Rietveld refinement and extended X-ray absorption fine structure analyses. The incorporation of Cd and Ni into ferrite spinel solid solution strongly relied on the processing parameters. The incorporation of Cd and Ni into the CNFs was greater at high x values (0.7 < x <= 1.0) than at low x values (0.0 <= x <= 0.7). A feasible treatment technique based on the investigated mechanism of CNF formation was developed, involving thermal treatment of waste sludge containing Cd and Ni. Both of these metals in the waste sludge were successfully incorporated into a ferrite spinel solid solution, and the concentrations of leached Cd and Ni from this solid solution were substantially reduced, stabilizing at low levels. This research offers a highly promising approach for treating the Cd and Ni content frequently encountered in electronic waste and its treatment residues. PMID- 29257672 TI - A Workflow for In Vivo Evaluation of Candidate Inputs and Outputs for Cell Classifier Gene Circuits. AB - Cell classifier gene circuits that integrate multiple molecular inputs to restrict the expression of therapeutic outputs to cancer cells have the potential to result in efficacious and safe cancer therapies. Preclinical translation of the hitherto developments requires creating the conditions where the animal model, the delivery platform, in vivo expression levels of the inputs, and the efficacy of the output, all come together to enable detailed evaluation of the fully assembled circuits. Here we show an integrated workflow that addresses these issues and builds the framework for preclinical classifier studies using the design framework of microRNA (miRNA, miR)-based classifier gene circuits. Specifically, we employ HCT-116 colorectal cancer cell xenograft in an experimental mouse metastatic liver tumor model together with Adeno-associated virus (AAV) vector delivery platform. Novel engineered AAV-based constructs are used to validate in vivo the candidate inputs miR-122 and miR-7 and, separately, the cytotoxic output HSV-TK/ganciclovir. We show that while the data are largely consistent with expectations, crucial insights are gained that could not have been obtained in vitro. The results highlight the importance of detailed stepwise interrogation of the experimental parameters as a necessary step toward clinical translation of synthetic gene circuits. PMID- 29257675 TI - Diversification of Protein Cage Structure Using Circularly Permuted Subunits. AB - Self-assembling protein cages are useful as nanoscale molecular containers for diverse applications in biotechnology and medicine. To expand the utility of such systems, there is considerable interest in customizing the structures of natural cage-forming proteins and designing new ones. Here we report that a circularly permuted variant of lumazine synthase, a cage-forming enzyme from Aquifex aeolicus (AaLS) affords versatile building blocks for the construction of nanocompartments that can be easily produced, tailored, and diversified. The topologically altered protein, cpAaLS, self-assembles into spherical and tubular cage structures with morphologies that can be controlled by the length of the linker connecting the native termini. Moreover, cpAaLS proteins integrate into wild-type and other engineered AaLS assemblies by coproduction in Escherichia coli to form patchwork cages. This coassembly strategy enables encapsulation of guest proteins in the lumen, modification of the exterior through genetic fusion, and tuning of the size and electrostatics of the compartments. This addition to the family of AaLS cages broadens the scope of this system for further applications and highlights the utility of circular permutation as a potentially general strategy for tailoring the properties of cage-forming proteins. PMID- 29257674 TI - Structures of the Peptidoglycan N-Acetylglucosamine Deacetylase Bc1974 and Its Complexes with Zinc Metalloenzyme Inhibitors. AB - The cell wall peptidoglycan is recognized as a primary target of the innate immune system, and usually its disintegration results in bacterial lysis. Bacillus cereus, a close relative of the highly virulent Bacillus anthracis, contains 10 polysaccharide deacetylases. Among these, the peptidoglycan N acetylglucosamine deacetylase Bc1974 is the highest homologue to the Bacillus anthracis Ba1977 that is required for full virulence and is involved in resistance to the host's lysozyme. These metalloenzymes belong to the carbohydrate esterase family 4 (CE4) and are attractive targets for the development of new anti-infective agents. Herein we report the first X-ray crystal structures of the NodB domain of Bc1974, the conserved catalytic core of CE4s, in the unliganded form and in complex with four known metalloenzyme inhibitors and two amino acid hydroxamates that target the active site metal. These structures revealed the presence of two conformational states of a catalytic loop known as motif-4 (MT4), which were not observed previously for peptidoglycan deacetylases, but were recently shown in the structure of a Vibrio clolerae chitin deacetylase. By employing molecular docking of a substrate model, we describe a catalytic mechanism that probably involves initial binding of the substrate in a receptive, more open state of MT4 and optimal catalytic activity in the closed state of MT4, consistent with the previous observations. The ligand bound structures presented here, in addition to the five Bc1974 inhibitors identified, provide a valuable basis for the design of antibacterial agents that target the peptidoglycan deacetylase Ba1977. PMID- 29257676 TI - Merging Icosahedral Boron Clusters and Magnetic Nanoparticles: Aiming toward Multifunctional Nanohybrid Materials. AB - All-inorganic-made nanohybrid icosahedral boron cluster magnetic nanoparticles have been prepared. These magnetic nanoparticles (MNPs) consist of a magnetic core and an inorganic carboranylphosphinate shell. The phosphinate is directly bonded to the iron atoms of the surface in a bidentated coordination mode. The nanoparticles have been characterized by TEM, X-ray powder diffraction, infrared spectroscopy, energy dispersive X-ray analysis, high resolution X-ray photoelectron spectroscopy, magnetometry measurements, and redox titration, among other techniques. These studies have led to a composition (1-OPH(O)-1,7-closo C2B10H11)8(2Fe3O4.Fe2O3)13 that implies a surface coverage of 61.3 +/- 7.4% by the ligand. When these MNPs go through sterilization in one autoclave, the magnetic hysteresis studies suggest minimal change before and after sterilization; this could erroneously indicate that there have not been any changes in the MNP composition. However, the Fe2+ titration demonstrates that after sterilization only 1/7 of the Fe is Fe2+, leading to a core formula of Fe3O4.2Fe2O3 with a concomitant loss of ligand to a final ratio of 1:70 (carborane: Fe), and a final coverage by the ligand of 11.2 +/- 1.4%. These studies bring relevant information on the behavior of the widely used MNPs and clearly show how the sterilization process needed for biological tests may alter the composition of the core and the loading of a peripheral ligand. In the particular case reported here, the liberated ligand has not been oxidized nor altered through the sterilization process. PMID- 29257677 TI - Electron Transfer and Geometric Conversion of Co-NO Moiety in Saddled Porphyrins: Implications for Trigger Role of Tetrapyrrole Distortion. AB - The electrons of NO and Co are strongly delocalized in normal {Co-NO}8 species. In this work, {Co-NO}8 complexes are induced to convert from (CoII)+*-NO* to CoIII-NO- by a core contraction of 0.06 A in saddled cobalt(II) porphyrins. This intramolecular electron transfer mechanism indicates that nonplanarity of porphyrin is involved in driving conversion of the NO units from electrophilic NO* as a bent geometry to nucleophilic NO- as a linear geometry. This implies that distortion acts as a trigger in enzymes containing tetrapyrrole. The electronic behaviors of the CoII ions and Co-NO moieties were confirmed by X-ray crystallography, EPR spectroscopy, theoretical calculation, UV-vis and IR spectroscopy, and electrochemistry. PMID- 29257678 TI - Sorption of Heterocyclic Organic Compounds to Multiwalled Carbon Nanotubes. AB - Sorption is an important natural and technical process. Sorption coefficients are typically determined in batch experiments, but this may be challenging for weakly sorbing compounds. An alternative method enabling analysis of those compounds is column chromatography. A column packed with the sorbent is used and sorption data are determined by relating sorbate retention to that of a nonretarded tracer. In this study, column chromatography was applied for the first time to study sorption of previously hardly investigated heterocyclic organic compounds to multiwalled carbon nanotubes (MWCNTs). Sorption data for these compounds are very limited in literature, and weak sorption is expected from predictions. Deuterium oxide was used as nonretarded tracer. Sorption isotherms were well described by the Freundlich model and data showed reasonable agreement with predicted values. Sorption was exothermic and physisorption was observed. H-bonding may contribute to overall sorption, which is supported by reduced sorption with increasing ionic strength due to blocking of functional groups. Lowering pH reduced sorption of ionizable compounds, due to electrostatic repulsion at pH 3 where sorbent as well as sorbates were positively charged. Overall, column chromatography was successfully used to study sorption of heterocyclic compounds to MWCNTs and could be applied for other carbon-based sorbents. PMID- 29257680 TI - Prospects for Engineering Thermoelectric Properties in La1/3NbO3 Ceramics Revealed via Atomic-Level Characterization and Modeling. AB - A combination of experimental and computational techniques has been employed to explore the crystal structure and thermoelectric properties of A-site-deficient perovskite La1/3NbO3 ceramics. Crystallographic data from X-ray and electron diffraction confirmed that the room temperature structure is orthorhombic with Cmmm as a space group. Atomically resolved imaging and analysis showed that there are two distinct A sites: one is occupied with La and vacancies, and the second site is fully unoccupied. The diffuse superstructure reflections observed through diffraction techniques are shown to originate from La vacancy ordering. La1/3NbO3 ceramics sintered in air showed promising high-temperature thermoelectric properties with a high Seebeck coefficient of S1 = -650 to -700 MUV/K and a low and temperature-stable thermal conductivity of k = 2-2.2 W/m.K in the temperature range of 300-1000 K. First-principles electronic structure calculations are used to link the temperature dependence of the Seebeck coefficient measured experimentally to the evolution of the density of states with temperature and indicate possible avenues for further optimization through electron doping and control of the A-site occupancies. Moreover, lattice thermal conductivity calculations give insights into the dependence of the thermal conductivity on specific crystallographic directions of the material, which could be exploited via nanostructuring to create high-efficiency compound thermoelectrics. PMID- 29257679 TI - DFT Investigation of Ligand Photodissociation in [RuII(tpy)(bpy)(py)]2+ and [RuII(tpy)(Me2bpy)(py)]2+ Complexes. AB - Photoinduced ligand dissociation of pyridine occurs much more readily in [Ru(tpy)(Me2bpy)(py)]2+ than in [Ru(tpy)(bpy)(py)]2+ (tpy = 2,2':6',2" terpyridine; bpy = 2,2'-bipyridine, Me2bpy = 6,6'-dimethyl-2,2'-bipyridine; py = pyridine). The S0 ground state and the 3MLCT and 3MC excited states of these complexes have been studied using BP86 density functional theory with the SDD basis set and effective core potential on Ru and the 6-31G(d) basis set for the rest of the atoms. In both complexes, excitation by visible light and intersystem crossing leads to a 3MLCT state in which an electron from a Ru d orbital has been promoted to a pi* orbital of terpyridine, followed by pyridine release after internal conversion to a dissociative 3MC state. Interaction between the methyl groups and the other ligands causes significantly more strain in [Ru(tpy)(Me2bpy)(py)]2+ than in [Ru(tpy)(bpy)(py)]2+, in both the S0 and 3MLCT states. Transition to the dissociative 3MC states releases this strain, resulting in lower barriers for ligand dissociation from [Ru(tpy)(Me2bpy)(py)]2+ than from [Ru(tpy)(bpy)(py)]2+. Analysis of the molecular orbitals along relaxed scans for stretching the Ru-N bonds reveals that ligand photodissociation is promoted by orbital mixing between the ligand pi* orbital of tpy in the 3MLCT state and the dsigma* orbitals that characterize the dissociative 3MC states. Good overlap and strong mixing occur when the Ru-N bond of the leaving ligand is perpendicular to the pi* orbital of terpyridine, favoring the release of pyridine positioned in a cis fashion to the terpyridine ligand. PMID- 29257681 TI - Structural Characterization of the Short-Range Order in High Alkali Content Sodium Thiosilicophosphate Glasses. AB - The composition dependence of the short-range order (SRO) structure in highly modified mixed glass former sodium thiosilicophosphate glasses, yNa2S + (1 - y)[xSiS2 + (1 - x)PS5/2], were investigated using infrared (IR), Raman, and 29Si and 31P magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopies. Both the y = 0.5 and 0.67 glasses undergo disproportionation reactions among the Si and P SRO structures, which lead to various and complex SRO structural units for the Si and P, as shown via the spectra used to characterize the glasses. In the y = 0.5 series, the compositionally expected and experimentally observed SRO units are the P1 and Si2 units in the two binary end-member glasses, where the superscript is the number of bridging sulfur atoms on the P or Si units. However, in the ternary mixed glasses, 0 < x < 1, these units were found to react to form P0 (more highly modified, y = 0.60) and Si3 (less highly modified, y = 0.33) units, indicating preferential association of Na+ ions with the P SRO structures. The Raman spectra were used to resolve the heretofore incompletely studied Si3 SRO unit, which was otherwise difficult to elucidate using 29Si MAS NMR alone. In the y = 0.67 series glasses, the expected P0 and Si0 SRO units were observed for the end-member binary glasses. Like in the y = 0.5 series, the 29Si MAS NMR showed that edge-sharing Si2 (ESi2, y = 0.5) structures were also present in these highly modified glasses, which meant Na2S was not completely incorporated in the network. Evidence of this was shown in the Raman spectra in the form of polysulfide structures Na2Sx (x = 2, 4). PMID- 29257682 TI - Differential Binding Affinities and Allosteric Conformational Changes Underlie Interactions of Yorkie and a Multivalent PPxY Partner. AB - Tondu domain-containing growth inhibitor (Tgi) is one of a growing number of multivalent PPxY proteins that regulate cell growth via interactions with the tandem WW domains of the transcription coactivator protein, Yorkie (Yki). These proteins are attractive candidates for targeted drug design, but the substantial amount of disorder predicted from their primary sequences makes structural studies that are foundational to drug design challenging. We have successfully overexpressed full length recombinant Tgi and Yki, experimentally confirmed that intrinsic structural disorder is common to both proteins, and assessed binding of the Yki WW domains to the three Tgi PPxY motifs using nuclear magnetic resonance and isothermal titration calorimetry. We find that the tandem WW domains positively cooperate to engage all three PPxY sites with a broad range of affinities. The first PPxY motif that is quite distant from the other two serves as the "binding initiation" site and is essential for high-affinity interactions. Importantly, by monitoring binding to the full length or larger protein domains, we obtain more physiologically relevant affinity information and identify "long range" residues that could be targeted to fine-tune binding. This expansion of protein functionality through modulation of residues outside the recognition sequences offers potential alternative targets for drug design. PMID- 29257683 TI - The Contribution of Environmental Monitoring to the Review of the Effectiveness of Environmental Treaties. PMID- 29257685 TI - Assessing the Molecular Basis of the Fuel Octane Scale: A Detailed Investigation on the Rate Controlling Steps of the Autoignition of Heptane and Isooctane. AB - N-Heptane and 2,2,4-trimethylpentane (isooctane) are the key species in the modeling of ignition of hydrocarbon-based fuel formulations. Isooctane is knock resistant whereas n-heptane is a very knock-prone hydrocarbon. It has been suggested that interconversion of their associated alkylperoxy and hydroperoxyalkyl species via hydrogen-transfer isomerization reaction is the key step to understand their different knocking behavior. In this work, the kinetics of unimolecular hydrogen-transfer reactions of n-heptylperoxy and isooctylperoxy are determined using canonical variational transition-state theory and multidimensional small curvature tunneling. Internal rotation of involved molecules is taken explicitly into account in the molecular partition function. The rate coefficients are calculated in the temperature range 300-900 K, relevant to low-temperature autoignition. The concerted HO2 elimination is an important reaction that competes with some H-transfer and is associated with chain termination. Thus, the branching ratio between these reaction channels is analyzed. We show that variational and multidimensional tunneling effects cannot be neglected for the H-transfer reaction. In particular, the pre-exponential Arrhenius fitting parameter derived from our rate constants shows a strong dependence on the temperature, because tunneling increases quickly at temperatures below 500 K. On the basis of our results, the existing qualitative model for the reasons for different knock behavior observed for n-heptane and isooctane is quantitatively validated at the molecular level. PMID- 29257684 TI - Correlative Light-Electron Microscopy of Lipid-Encapsulated Fluorescent Nanodiamonds for Nanometric Localization of Cell Surface Antigens. AB - Containing an ensemble of nitrogen-vacancy centers in crystal matrices, fluorescent nanodiamonds (FNDs) are a new type of photostable markers that have found wide applications in light microscopy. The nanomaterial also has a dense carbon core, making it visible to electron microscopy. Here, we show that FNDs encapsulated in biotinylated lipids (bLs) are useful for subdiffraction imaging of antigens on cell surface with correlative light-electron microscopy (CLEM). The lipid encapsulation enables not only good dispersion of the particles in biological buffers but also high specific labeling of live cells. By employing the bL-encapsulated FNDs to target CD44 on HeLa cell surface through biotin mediated immunostaining, we obtained the spatial distribution of these antigens by CLEM with a localization accuracy of ~50 nm in routine operations. A comparative study with dual-color imaging, in which CD44 was labeled with FND and MICA/MICB was labeled with Alexa Fluor 488, demonstrated the superior performance of FNDs as fluorescent fiducial markers for CLEM of cell surface antigens. PMID- 29257686 TI - Correction to Apratoxin E, a Cytotoxic Peptolide from a Guamanian Collection of the Marine Cyanobacterium Lyngbya bouillonii. PMID- 29257687 TI - Rational Density Functional Selection Using Game Theory. AB - Theoretical chemistry has a paradox of choice due to the availability of a myriad of density functionals and basis sets. Traditionally, a particular density functional is chosen on the basis of the level of user expertise (i.e., subjective experiences). Herein we circumvent the user-centric selection procedure by describing a novel approach for objectively selecting a particular functional for a given application. We achieve this by employing game theory to identify optimal functional/basis set combinations. A three-player (accuracy, complexity, and similarity) game is devised, through which Nash equilibrium solutions can be obtained. This approach has the advantage that results can be systematically improved by enlarging the underlying knowledge base, and the deterministic selection procedure mathematically justifies the density functional and basis set selections. PMID- 29257688 TI - 1D and 3D Polymeric Manganese(II) Thiolato Complexes: Synthesis, Structure, and Properties of infinity3[Mn4(SPh)8] and infinity1[Mn(SMes)2]. AB - Reactions of [Mn{N(SiMe3)2}2]2 with 2.1 equiv of RSH, R = Ph or Mes = C6H2-2,4,6 (CH3)3, yield compounds of the formal composition "Mn(SR)2". Single-crystal X-ray diffraction reveals that infinity1[Mn(SMes)2] forms one-dimensional chains in the crystal via MU2-SMes bridges, whereas infinity3[Mn4(SPh)8] comprises a three dimensional network in which adamantanoid cages composed of four Mn atoms and six MU2-bridging SPh ligands are connected in three dimensions by doubly bridging SPh ligands. Thermogravimetric analysis and powder diffractometry indicate an reversible uptake of solvent molecules (tetrahydrofuran) into the channels of infinity1[Mn(SMes)2]. Magnetic measurements reveal antiferromagnetic coupling for both compounds with J = -8.2 cm-1 (infinity1[Mn(SMes)2]) and -10.0 cm-1 (infinity3[Mn4(SPh)8]), respectively. Their optical absorption and photoluminescence (PL) excitation spectra display characteristic d-d bands of Mn2+ ions in the visible spectral region. Both compounds emit bright phosphorescence at ~800 nm at low temperatures (<100 K). However, only infinity1[Mn(SMes)2] retains a moderately intense emission at ambient temperature (with a quantum yield of 1.2%). Similar PL properties are also found for the related selenolate complexes infinity1[Mn(SeR)2] (R = Ph, Mes). PMID- 29257689 TI - Multi-Fractional Analysis of Molecular Diffusion in Polymer Multilayers by FRAP: A New Simulation-Based Approach. AB - Comprehensive analysis of the multifractional molecular diffusion provides a deeper understanding of the diffusion phenomenon in the fields of material science, molecular and cell biology, advanced biomaterials, etc. Fluorescence recovery after photobleaching (FRAP) is commonly employed to probe the molecular diffusion. Despite FRAP being a very popular method, it is not easy to assess multifractional molecular diffusion due to limited possibilities of approaches for analysis. Here we present a novel simulation-optimization-based approach (S approach) that significantly broadens possibilities of the analysis. In the S approach, possible fluorescence recovery scenarios are primarily simulated and afterward compared with a real measurement while optimizing parameters of a model until a sufficient match is achieved. This makes it possible to reveal multifractional molecular diffusion. Fluorescent latex particles of different size and fluorescein isothiocyanate in an aqueous medium were utilized as test systems. Finally, the S-approach has been used to evaluate diffusion of cytochrome c loaded into multilayers made of hyaluronan and polylysine. Software for evaluation of multifractional molecular diffusion by S-approach has been developed aiming to offer maximal versatility and user-friendly way for analysis. PMID- 29257690 TI - Applied Potentials in Variable-Charge Reactive Force Fields for Electrochemical Systems. AB - An atomic description of water dynamics and electrochemical properties at electrode-electrolyte interfaces is presented using molecular dynamics with the third generation of the charge-optimized many-body (COMB3) potential framework. Externally applied potentials in electrochemical applications were simulated by offsetting electronegativity on electrode atoms. This approach is incorporated into the variable charge scheme within COMB3 and is used to investigate electrochemical systems consisting of two Cu electrodes and a water electrolyte with varying concentrations of hydroxyls (OH-) and protons (H+). The interactions between the electronegativity offset method and the charge equilibration method in a variable charge scheme are analyzed. In addition, a charge equilibration method for electrochemical applications is proposed, where the externally applied potentials are treated by the electronegativity offset on the electrodes thus enforcing charge neutrality on the electrolyte. This method is able to qualitatively capture the relevant electrochemistry and predict consistently correct voltages with precalibration. PMID- 29257691 TI - Self-Seeded Axio-Radial InAs-InAs1-xPx Nanowire Heterostructures beyond "Common" VLS Growth. AB - Semiconductors are essential for modern electronic and optoelectronic devices. To further advance the functionality of such devices, the ability to fabricate increasingly complex semiconductor nanostructures is of utmost importance. Nanowires offer excellent opportunities for new device concepts; heterostructures have been grown in either the radial or axial direction of the core nanowire but never along both directions at the same time. This is a consequence of the common use of a foreign metal seed particle with fixed size for nanowire heterostructure growth. In this work, we present for the first time a growth method to control heterostructure growth in both the axial and the radial directions simultaneously while maintaining an untapered self-seeded growth. This is demonstrated for the InAs/InAs1-xPx material system. We show how the dimensions and composition of such axio-radial nanowire heterostructures can be designed including the formation of a "pseudo-superlattice" consisting of five separate InAs1-xPx segments with varying length. The growth of axio-radial nanowire heterostructures offers an exciting platform for novel nanowire structures applicable for fundamental studies as well as nanowire devices. The growth concept for axio radial nanowire heterostructures is expected to be fully compatible with Si substrates. PMID- 29257692 TI - Unravelling the Electronic State of NO2 Product in Ultrafast Photodissociation of Nitromethane. AB - The primary photochemical reaction of nitromethane (NM) after pipi* excitation is known to be C-N bond cleavage (CH3NO2 + hnu -> CH3 + NO2). On the other hand, NO2 can be formed in both the ground and excited states, and identification of the electronic state of the NO2 product has been a central subject in the experimental and theoretical studies. Here we present time-resolved photoelectron spectroscopy using vacuum-ultraviolet probe pulses to observe all transient electronic states of NM and the reaction products. The result indicates that ultrafast internal conversion occurs down to S1 and S0 within 24 fs, and the dissociation proceeds on the S1 surface (taudiss ? 50 fs), leading to comparable product yields of NO2(A) and NO2(X). The overall dissociation quantum yield within our observation time window (<2 ps) is estimated to be 0.29. PMID- 29257693 TI - Thioimidazolium Ionic Liquids as Tunable Alkylating Agents. AB - Alkylating ionic liquids based on the thioimidazolium structure combine the conventional properties of ionic liquids, including low melting point and nonvolatility, with the alkylating function. Alkyl transfer occurs exclusively from the S-alkyl position, thus allowing for easy derivatization of the structure without compromising specificity. We apply this feature to tune the electrophilicty of the cation to profoundly affect the reactivity of these alkylating ionic liquids, with a caffeine-derived compound possessing the highest reactivity. Anion choice was found to affect reaction rates, with iodide anions assisting in the alkylation reaction through a "shuttling" process. The ability to tune the properties of the alkylating agent using the toolbox of ionic liquid chemistry highlights the modular nature of these compounds as a platform for alkylating agent design and integration in to future systems. PMID- 29257694 TI - Probing of Triply Coordinated Oxygen in Amorphous Al2O3. AB - Although anomalous melt properties have been attributed to the presence of triply coordinated oxygen ([3]O), the presence of [3]O in covalent amorphous oxides has not been revealed experimentally; such verification is the Holy Grail in the study of the physics and chemistry of glasses. We report the first 17O NMR spectrum for amorphous Al2O3 and reveal the hidden nature of [3]O. The detailed NMR characteristics of the oxygen tricluster are distinct from those estimated for the crystalline analogs, thus indicating its unique structure. This unambiguous evidence of the presence of [3]O allows us to microscopically constrain its glass-forming ability and unique two-step crystallization paths of amorphous Al2O3 through the annihilation of glassy [3]O with multiple [5]Al species. PMID- 29257695 TI - Spatial and Contamination-Dependent Electrical Properties of Carbon Nanotubes. AB - Two-point probe and Raman spectroscopy have been used to investigate the effects of vacuum annealing and argon bombardment on the conduction characteristics of multiwalled carbon nanotubes (MWCNTs). Surface contamination has a large effect on the two-point probe conductivity measurements which results in inconsistent and nonreproducible contacts. The electric field under the contacts is enhanced which results in overlapping depletion regions when probe separations are small (<4 MUm) causing very high resistances. Annealing at 200 and 500 degrees C reduced the surface contamination on the MWCNT, but high resistance contacts still did not allow intrinsic conductivity measurements of the MWCNT. The high resistance measured due to the overlapping depletion regions was not observed after annealing to 500 degrees C. Argon bombardment reduced the surface contamination more than vacuum annealing at 500 degrees C but caused a slight increase in the defects concentration, enabling the resistivity of the MWCNT to be calculated, which is found to be dependent on the CNT diameter. The observations have significant implications for future CNT-based devices. PMID- 29257696 TI - Rh-Catalyzed Enantioselective Allylation of N-Tosyl- and N-Nosylaldimines: Total Synthesis of (-)-Crispine A. AB - The unprecedented development of asymmetric Rh-catalyzed 1,2-allylation of N-Ts- and N-Ns-aldimines is achieved. This protocol utilizes potassium allyltrifluoroborates and various aldimines to generate enantioenriched homoallylic amines in the presence of 3.0 mol % of Rh(I)/L1b catalyst with up to 90% yield, 98% ee (R = H), and 10:1 diastereoselectivity (R = Me or Ph), yielding the same major diastereomer when using potassium (E)- and (Z) crotyltrifluoroborate. Its synthetic utility is also illustrated in the total synthesis of (-)-crispine A. PMID- 29257697 TI - Out-of-Plane Designed Soft Metasurface for Tunable Surface Plasmon Polariton. AB - Reliable and repeatable tunability gives functional diversity for reconfigurable plasmonics devices, while reversible and large mechanical deformation enabled by soft materials provides a new way for the global or partial regulation of metadevices. Here, we demonstrate a soft metasurface with an out-of-plane design for tuning the energy of surface plasmon polaritons (SPPs) bloch wave using theory, simulation, and experiments. Our metasurface is composed of two-layered gold nanoribbon arrays (2GNRs) on a soft substrate. The out-of-plane coupling mechanism is systematically analyzed in terms of separation height effect. Moreover, by harnessing mechanical deformation, continuously tunable plasmonic resonance has been achieved in the visible and near-infrared ranges. We further studied the angle-dependent reflection spectra of our metastructure. Compared with its planar counterpart, our soft and two-layered metastructure exhibits diverse tunability and significant field enhancement by out-of-plane interactions. Our approach in designing soft metasurface with out-of-plane structures can be extended to more-complex photonic devices and finds prominent applications such as biosensing, high-density plasmonic circuits, surface enhanced luminescence, and surface-enhanced Raman scattering. PMID- 29257698 TI - Crystal-Phase Quantum Wires: One-Dimensional Heterostructures with Atomically Flat Interfaces. AB - In semiconductor quantum-wire heterostructures, interface roughness leads to exciton localization and to a radiative decay rate much smaller than that expected for structures with flat interfaces. Here, we uncover the electronic and optical properties of the one-dimensional extended defects that form at the intersection between stacking faults and inversion domain boundaries in GaN nanowires. We show that they act as crystal-phase quantum wires, a novel one dimensional quantum system with atomically flat interfaces. These quantum wires efficiently capture excitons whose radiative decay gives rise to an optical doublet at 3.36 eV at 4.2 K. The binding energy of excitons confined in crystal phase quantum wires is measured to be more than twice larger than that of the bulk. As a result of their unprecedented interface quality, these crystal-phase quantum wires constitute a model system for the study of one-dimensional excitons. PMID- 29257699 TI - Localized Pulsed Electrodeposition Process for Three-Dimensional Printing of Nanotwinned Metallic Nanostructures. AB - Nanotwinned-metals (nt-metals) offer superior mechanical (high ductility and strength) and electrical (low electromigration) properties compared to their nanocrystalline (nc) counterparts. These properties are advantageous in particular for applications in nanoscale devices. However, fabrication of nt metals has been limited to films (two-dimensional) or template-based (one dimensional) geometries, using various chemical and physical processes. In this Letter, we demonstrate the ambient environment localized pulsed electrodeposition process for direct printing of three-dimensional (3D) freestanding nanotwinned Copper (nt-Cu) nanostructures. 3D nt-Cu structures were additively manufactured using pulsed electrodeposition at the tip of an electrolyte-containing nozzle. Focused ion beam (FIB) and transmission electron microscopy (TEM) analysis revealed that the printed metal was fully dense, and was mostly devoid of impurities and microstructural defects. FIB and TEM images also revealed nanocrystalline-nanotwinned-microstructure (nc-nt-microstructure), and confirmed the formation of coherent twin boundaries in the 3D-printed Cu. Mechanical properties of the 3D-printed nc-nt-Cu were characterized by direct printing (FIB less) of micropillars for in situ SEM microcompression experiments. The 3D printed nc-nt-Cu exhibited a flow stress of over 960 MPa, among the highest ever reported, which is remarkable for a 3D-printed material. The microstructure and mechanical properties of the nc-nt-Cu were compared to those of nc-Cu printed using the same process under direct current (DC) voltage. PMID- 29257700 TI - Visible-Light Photocatalytic Decarboxylative Alkyl Radical Addition Cascade for Synthesis of Benzazepine Derivatives. AB - A visible-light photocatalytic decarboxylative alkyl radical addition cascade reaction of acrylamide-tethered styrenes for the synthesis of benzazepine derivatives is described. This protocol features broad substrate scope, excellent functional group tolerance, and mild reaction conditions, affording the seven membered rings in good yields. This method was also applied for efficient grafting of the benzazepine scaffold into the pharmaceutically active ursolic acid scaffold. PMID- 29257701 TI - Nickel Phosphite/Phosphine-Catalyzed C-S Cross-Coupling of Aryl Chlorides and Thiols. AB - A method for the coupling of aryl chlorides and thiophenols using an air-stable nickel(0) catalyst is described. This thioetherification procedure can be effectively applied to a range of electronically diverse aryl/heteroaryl chlorides without more expensive metal catalysts such as palladium, iridium, or ruthenium. This investigation also illustrates both, a variety of thiol coupling partners and, in certain cases, the use of Cs2CO3. PMID- 29257702 TI - Gold-Catalyzed Controllable C2-Functionalization of Benzofurans with Aryl Diazoesters. AB - A ligand-controlled gold-catalyzed chemoselective C2-functionalization of benzofuran substrates with aryl diazoesters has been developed. The use of IPrAu(PhCN)BArF provides unprecedented dearomatization products bearing a newly formed carbon-carbon double bond at the C2 position of benzofurans. In contrast, the C2-alkylation products have been isolated as the major products for phosphite gold catalysis. PMID- 29257703 TI - Enlarged free childhood vaccination offer in Italy proposed to curb the rise in the growing anti-vaccine message. PMID- 29257704 TI - Lingual orthodontic treatment: A YouTubeTM video analysis. AB - OBJECTIVES: The aim of this study was to examine the quality of information offered for patients seeking information on lingual orthodontic treatment. MATERIALS AND METHODS: YouTubeTM was searched for videos about lingual orthodontic treatment using the key word "lingual braces" from the Google Trends application. One hundred and four videos were selected to be analyzed from the first 120 results. The video content was evaluated using a 10-point score, which was used for classifying low- and high-content video groups. The video information and quality index (VIQI) was applied to determine the quality of the videos. The Mann-Whitney U-test, Chi-square test, and logistic regression analysis were used, and the Pearson correlation coefficient was calculated for statistical evaluations. RESULTS: We classified 32 videos as high-content and 72 as low-content. Most videos were uploaded by laypeople (58.7%, n = 61). Definition of lingual braces and psychological impact were the most commonly discussed topics (51.0%), followed by speech performance (47.1%), pain (44.2%), tongue soreness (37.5%), and biomechanics (14.4%). Compared to the low-content group, the high-content video group had a significantly higher mean number of views (19,867.41 vs 6720.08, P = .002) and more "likes" (135.88 vs 13.01, P < .001), "dislikes" (4.34 vs 0.81, P < .001), and "comments" (26.28 vs 5.31, P = .002). There was no difference in the total VIQI score between the groups ( P = .009). CONCLUSIONS: The content of YouTubeTM videos for lingual orthodontics was generally incomplete. Most videos mentioned psychological effects, but few videos discussed the biomechanics or procedure. Orthodontists should be aware of the information available on YouTubeTM. PMID- 29257705 TI - Quantitative comparison of incisal tooth wear in patients receiving one-phase or two-phase treatment for skeletal Class III malocclusion with anterior crossbite. AB - OBJECTIVES: The present study aimed to compare the amount of incisal tooth wear in the maxillary central incisors of patients with skeletal Class III malocclusion and anterior crossbite receiving one-phase or two-phase treatment. The hypothesis was that tooth wear would differ according to treatment modalities. MATERIALS AND METHODS: Maxillary dental casts obtained before (T1) and after (T2) orthodontic treatment were divided into three groups. Group I consisted of casts from 21 patients (7 males, 14 females; mean age 9.8 years) who received two-phase treatment (maxillary protraction followed by fixed appliance therapy). Group II comprised casts from 37 patients who underwent orthodontic camouflage treatment for crossbite, subdivided according to age. Group IIa consisted of casts from 15 adolescents (8 males, 7 females; mean age 13.5 years), and group IIb consisted of casts from 22 adults (13 males, 9 females; mean age 24.5 years). Maxillary dental casts obtained at T1 and T2 were scanned. For each pair of digital images, T2 was superimposed on T1 using the best-fit method. Tooth wear was quantified and compared among groups. RESULTS: Significantly less tooth wear was observed in group I compared to groups IIa and IIb, but no difference was found between groups IIa and IIb. Spearman correlation analysis revealed no significant correlation between tooth wear and age, treatment duration, or craniofacial morphology. CONCLUSIONS: Despite the long duration of early treatment, it caused less wear of the maxillary central incisors than did orthodontic camouflage treatment. PMID- 29257706 TI - Off-the-shelf tissue engineered heart valves for in situ regeneration: current state, challenges and future directions. AB - INTRODUCTION: Transcatheter aortic valve replacement (TAVR) is continuously evolving and is expected to surpass surgical valve implantation in the near future. Combining durable valve substitutes with minimally invasive implantation techniques might increase the clinical relevance of this therapeutic option for younger patient populations. Tissue engineering offers the possibility to create tissue engineered heart valves (TEHVs) with regenerative and self-repair capacities which may overcome the pitfalls of current TAVR prostheses. Areas covered: This review focuses on off-the-shelf TEHVs which rely on a clinically relevant in situ tissue engineering approach and which have already advanced into preclinical or first-in-human investigation. Expert commentary: Among the off-the shelf in situ TEHVs reported in literature, the vast majority covers pulmonary valve substitutes, and only few are combined with transcatheter implantation technologies. Hence, further innovations should include the development of transcatheter tissue engineered aortic valve substitutes, which would considerably increase the clinical relevance of such prostheses. PMID- 29257707 TI - A qualitative exploration of chiropractic and physiotherapy teachers' experiences and conceptualizations of the educational environment. AB - OBJECTIVE: There has been increasing scholarly interest in the role of environments in health care professional education, and the value of these has been widely acknowledged as an influential factor in educational quality. However, little is known about how teachers experience the environment, and there is a recognizable absence of a perspective from chiropractic and physiotherapy faculties. The aim of this study was to explore and contrast chiropractic and physiotherapy teachers' experiences and conceptualizations of the meaning of the educational environment. METHODS: In this qualitative study, we performed semistructured interviews with 14 teachers, purposefully selected to obtain richness, variation, and breadth in the data. The data were analyzed using inductive qualitative content analysis. RESULTS: The most noteworthy findings were, first, that chiropractic teachers experienced the meaning of the environment as motivating a vocational practice and modeling ideal, supporting and managing stressed students, and including students in the community of chiropractors. Physiotherapy teachers experienced the meaning of the environment as putting the pedagogical vision into practice, balancing students' expectations, and providing the prerequisites to grow within the profession. Second, both groups of teachers held common conceptualizations of the constituents of the environment as physical, organizational, relational, communicational, and pedagogical; however, they attached different connotations to these dimensions. CONCLUSION: The findings conveyed a variance in the experience of the meaning of the educational environment that can be attributed to contextual and cultural differences. PMID- 29257708 TI - A graphical clinical decision aid for managing imaging report information. AB - OBJECTIVE: The purpose of this article is to propose a graphical decision aid for managing radiology report information to assist learners in developing clinical decision-making skills through a structured approach. METHODS: A graphical decision aid informed by learning theories was constructed to manage radiology report information by identifying an overall strategy, specific decision-making steps, and decision goals. A review of radiology reports was performed to demonstrate the rich source of complex information requiring clinical decision making. Radiology report data were descriptively analyzed, and findings were described as definite or indefinite, while recommendations were reported as required or optional. RESULTS: The graphical decision aid involves 4 stages. The 1st 2 stages interpret report information and consider data obtained during the clinical encounter. The following 2 stages guide decisions by answering questions to ensure patient safety and/or to confirm diagnosis and to address broader case management questions. The mean (SD) age of participants whose imaging reports were reviewed was 73.4 (7.0) years. Of 170 reports, common findings included degenerative disc disease (98%), soft tissue or vascular calcification (94%), bone demineralization (92%), and zygapophyseal joint degeneration (86%). Common indefinite findings were spinal stenosis (15%), compression fracture (12%), bony abnormality (12%), radiodensity (12%), and disc degeneration (10%). One hundred twenty-one recommendations suggested follow-up actions. CONCLUSIONS: Information within imaging reports requires identification and interpretation to inform complex clinical decisions. The graphical decision aid proposed in this article is designed to facilitate the development of decision-making skills by providing a structured and evidence-based information management process. PMID- 29257709 TI - Toxicity profile characteristics of novel androgen-deprivation therapy agents in patients with prostate cancer: a meta-analysis. AB - BACKGROUND: To investigate the toxicity profile characteristics of abiraterone acetate and enzalutamide to see if they are of critical clinical value. METHODS: Prospective studies were identified by searching the PubMed, EMBASE, Cochrane Library, and American Society of Clinical Oncology Meeting abstracts. Randomized clinical trials that evaluate abiraterone acetate or enzalutamide in patients with prostate cancer were included. The risk ratio (RR) of adverse events (AEs) was calculated for each trial along with appropriate 95% CI using fixed- or random-effects methods. RESULTS: Ten studies (5 abiraterone acetate, and 5 enzalutamide studies) were included in the meta-analysis. Use of abiraterone acetate was associated with an increased risk of all-grade adverse effects (RR = 1.01, 95% CI: 1.01-1.02) and high-grade adverse effects (RR = 1.29, 95% CI: 1.15 1.45). Also, there was a significantly higher incidence of some individual adverse effects (e.g. liver-function test abnormalities, arthralgia, cardiac adverse effects, diarrhea, oedema, hypertension and hypokalemia). Treatment with enzalutamide did not increase the risk of all-grade adverse effects and high grade adverse effects, but there was a significantly higher incidence of some individual adverse effects (e.g. back pain, fatigue, hot flush and hypertension). CONCLUSIONS: Both abiraterone acetate and enzalutamide have toxicity profile characteristics that need to be recognized. Understanding the toxicity profile characteristics of both drugs could promote decision making in clinical use. PMID- 29257711 TI - Biomarkers in Medicine: Foreword. PMID- 29257710 TI - Phase I Dose-Escalation Trial of PT2385, a First-in-Class Hypoxia-Inducible Factor-2alpha Antagonist in Patients With Previously Treated Advanced Clear Cell Renal Cell Carcinoma. AB - Purpose The von Hippel-Lindau tumor suppressor is inactivated in the majority of clear cell renal cell carcinomas (ccRCCs), leading to inappropriate stabilization of hypoxia-inducible factor-2alpha (HIF-2alpha). PT2385 is a first-in-class HIF 2alpha antagonist. Objectives of this first-in-human study were to characterize the safety, pharmacokinetics, pharmacodynamics, and efficacy, and to identify the recommended phase II dose (RP2D) of PT2385. Patients and Methods Eligible patients had locally advanced or metastatic ccRCC that had progressed during one or more prior regimens that included a vascular endothelial growth factor inhibitor. PT2385 was administered orally at twice-per-day doses of 100 to 1,800 mg, according to a 3 + 3 dose-escalation design, followed by an expansion phase at the RP2D. Results The dose-escalation and expansion phases enrolled 26 and 25 patients, respectively. Patients were heavily pretreated, with a median of four (range, one to seven) prior therapies. No dose-limiting toxicity was observed at any dose. On the basis of safety, pharmacokinetic, and pharmacodynamic profiling, the RP2D was defined as 800 mg twice per day. PT2385 was well tolerated, with anemia (grade 1 to 2, 35%; grade 3, 10%), peripheral edema (grade 1 to 2, 37%; grade 3, 2%), and fatigue (grade 1 to 2, 37%; no grade 3 or 4) being the most common treatment-emergent adverse events. No patients discontinued treatment because of adverse events. Complete response, partial response, and stable disease as best response were achieved by 2%, 12%, and 52% of patients, respectively. At data cutoff, eight patients remained in the study, with 13 patients in the study for >= 1 year. Conclusion PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2alpha antagonism for the treatment of patients with ccRCC. PMID- 29257712 TI - Redox status of patients before cardiac surgery. AB - OBJECTIVES: Redox regulation plays a crucial role in balancing the cardiovascular system. In this prospective study we aimed to identify currently unknown correlations valuable to cardiovascular research and patient management. METHODS: Blood samples from 500 patients were collected directly before cardiosurgical interventions (Ethics Committee reference number 85/11). Four central redox parameters were determined together with about 30 clinical, anthropometric, and metabolic parameters. RESULTS: Creatinine levels and pulmonary hypertension were significant predictors of the total antioxidant status (TAOS) in the patients; total glutathione levels were linked to C-peptide, and creatinine, gender, and ventricular arrhythmia influenced nitrate/nitrite levels. Notably, significant interactions were found between medication and redox parameters. Calcium channel blockers (CCBs) were positive predictors of total glutathione levels, whereas angiotensin-converting enzyme inhibitors and CCBs were negative predictors of NOx levels. Age showed the highest correlation with the duration of the intensive care stay, followed by NOx levels, creatinine, TAOS, and C-reactive protein. DISCUSSION: In this prospective study we determined multiple correlations between redox markers and parameters linked to cardiovascular diseases. The data point towards so far unknown interdependencies, particularly between antihypertensive drugs and redox metabolism. A thorough follow-up to these data has the potential to improve patient management. ABBREVIATIONS: A: absorption; DeltaA: absorption difference; ABTS: 2,2'-azino-di(3-ethylbenzothiazoline sulfonate); ACE: angiotensin-converting enzyme; AO: antioxidant; ARB: angiotensin receptor blocker; BMI: body mass index; CAD: coronary artery disease; CCB: calcium channel blocker; CDC: coronary heart diseases; COPD: chronic obstructive pulmonary disease; CRP: C-reactive protein; CVD: cardiovascular diseases; Cu-OOH: cumene hydroperoxide; D: dilution factor; DAN: 2,3-diaminonaphtalene; DMSO: dimethylsulfoxide; DNA: deoxyribonucleic acid; DTNB: 5,5-dithiobis(2 nitrobenzoate); epsilon: extinction coefficient; EDRF: endothelium-derived relaxing factor; fc: final concentration; GPx: glutathione peroxidases; (h)GR: (human) glutathione reductase; GSH: (reduced) glutathione; GSSG: glutathione disulfide; GST: glutathione-S-transferase; Hb: hemoglobin; HDL: high-density lipoprotein; Hk: hematocrit; H2O2: hydrogen peroxide; ICS: intensive care stay; LDH: lactate dehydrogenase; LDL: low-density lipoprotein; MI: myocardial infarction; NED: N-(1-naphthyl)-ethylendiamine-dihydrochloride; NOS: nitric oxide synthase; NOx: nitrate/nitrite; NR: nitrate reductase; PBS: phosphate buffered saline; PCA: principle component analysis; PH: pulmonary hypertension; ROS: reactive oxygen species; RNS: reactive nitrogen species; RT: room temperature (25 degrees C); SA: sulfanilamide; SOD: superoxide dismutase; SSA: sulfosalicylic acid; TAC: total antioxidant capacity; TAOS: total antioxidant status; TEAC: trolox equivalent antioxidative capacity; TG: triglycerides; tGSH: total glutathione; TNB-: 2-nitro-5-thiobenzoate; U: unit; UV: ultraviolet; VA: volume activity; Wc: working concentration; WHR: waist-hip ratio. PMID- 29257716 TI - Selective Attention to Faces in a Rapid Visual Stream: Hemispheric Differences in Enhancement and Suppression of Category-selective Neural Activity. AB - In daily life, efficient perceptual categorization of faces occurs in dynamic and highly complex visual environments. Yet the role of selective attention in guiding face categorization has predominantly been studied under sparse and static viewing conditions, with little focus on disentangling the impact of attentional enhancement and suppression. Here we show that attentional enhancement and suppression exert a differential impact on face categorization supported by the left and right hemispheres. We recorded 128-channel EEG while participants viewed a 6-Hz stream of object images (buildings, animals, objects, etc.) with a face image embedded as every fifth image (i.e., OOOOFOOOOFOOOOF...). We isolated face-selective activity by measuring the response at the face presentation frequency (i.e., 6 Hz/5 = 1.2 Hz) under three conditions: Attend Faces, in which participants monitored the sequence for instances of female faces; Attend Objects, in which they responded to instances of guitars; and Baseline, in which they performed an orthogonal task on the central fixation cross. During the orthogonal task, face-specific activity was predominantly centered over the right occipitotemporal region. Actively attending to faces enhanced face-selective activity much more evidently in the left hemisphere than in the right, whereas attending to objects suppressed the face-selective response in both hemispheres to a comparable extent. In addition, the time courses of attentional enhancement and suppression did not overlap. These results suggest the left and right hemispheres support face-selective processing in distinct ways where the right hemisphere is mandatorily engaged by faces and the left hemisphere is more flexibly recruited to serve current tasks demands. PMID- 29257717 TI - Stereotactic Body Radiotherapy for Early-Stage Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Endorsement of the American Society for Radiation Oncology Evidence-Based Guideline Summary. PMID- 29257718 TI - Complete Tumor Response to Pembrolizumab and Allograft Preservation in Renal Allograft Recipient on Immunosuppressive Therapy. PMID- 29257714 TI - Unilateral Quadriceps Strengthening With Disinhibitory Cryotherapy and Quadriceps Symmetry After Anterior Cruciate Ligament Reconstruction. AB - CONTEXT: The effect of unilateral cryotherapy-facilitated rehabilitation exercise on involved-limb quadriceps function and limb symmetry in individuals with quadriceps dysfunction after anterior cruciate ligament reconstruction (ACLR) remains unclear. OBJECTIVE: To measure the effect of a 2-week unilateral cryotherapy-facilitated quadriceps-strengthening program on knee-extension strength and quadriceps central activation ratio (CAR) in participants with ACLR. DESIGN: Controlled laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 10 volunteers with unilateral ACLR (1 man, 9 women; age = 21.0 +/- 2.8 years, height = 164.6 +/- 5.0 cm, mass = 64.0 +/- 6.1 kg, body mass index = 23.7 +/- 2.7 kg/m2) and 10 healthy volunteers serving as control participants (1 man, 9 women; age = 20.8 +/- 2.5 years, height = 169.1 +/- 6.2 cm, mass = 61.1 +/- 6.4 kg, body mass index = 21.4 +/- 2.3 kg/m2) participated. INTERVENTION(S): Participants with ACLR completed a 2-week unilateral cryotherapy-facilitated quadriceps-strengthening intervention. MAIN OUTCOME MEASURE(S): Bilateral normalized knee-extension maximal voluntary isometric contraction (MVIC) torque (Nm/kg) and quadriceps CAR (%) were assessed preintervention and postintervention. Limb symmetry index (LSI) was calculated at preintervention and postintervention testing. Preintervention between-groups differences in unilateral quadriceps function and LSI were evaluated using independent-samples t tests. Preintervention-to-postintervention differences in quadriceps function were evaluated using paired-samples t tests. Cohen d effect sizes (95% confidence interval [CI]) were calculated for each comparison. RESULTS: Preintervention between-groups comparisons revealed less knee extension MVIC torque and quadriceps CAR for the ACLR limb (MVIC: P = .01, Cohen d = -1.31 [95% CI = -2.28, -0.34]; CAR: P = .004, Cohen d = -1.48 [95% CI = 2.47, -0.49]) and uninvolved limb (MVIC: P = .03, Cohen d = -1.05 [95% CI = 1.99, -0.11]; CAR: P = .01, Cohen d = -1.27 [95% CI = -2.23, -0.31]) but not for the LSI (MVIC: P = .46, Cohen d = -0.34 [95% CI = -1.22, 0.54]; CAR: P = .60, Cohen d = 0.24 [95% CI = -0.64, 1.12]). In the ACLR group, participants had improved knee-extension MVIC torque in the involved limb ( P = .04, Cohen d = 0.32 [95% CI = -0.56, 1.20]) and uninvolved limb ( P = .03, Cohen d = 0.29 [95% CI = -0.59, 1.17]); however, the improvement in quadriceps CAR was limited to the involved limb ( P = .02, Cohen d = 1.16 [95% CI = 0.21, 2.11]). We observed no change in the LSI with the intervention for knee-extension MVIC torque ( P = .74, Cohen d = 0.09 [95% CI = -0.79, 0.97]) or quadriceps CAR ( P = .61, Cohen d = 0.26 [95% CI = -0.62, 1.14]). CONCLUSIONS: Two weeks of cryotherapy-facilitated exercise may improve involved-limb quadriceps function while preserving between limbs symmetry in patients with a history of ACLR. PMID- 29257719 TI - Head and Neck Cancer Survivorship Care Guideline: American Society of Clinical Oncology Clinical Practice Guideline Endorsement Summary. PMID- 29257720 TI - Cancer in Transgender Patients: One Case in 385,820 Is Indicative of a Paucity of Data. PMID- 29257721 TI - Sarcoidosis presenting with acute dacryoadenitis. AB - Sarcoidosis is a systemic inflammatory disorder, pathologically characterized by noncaseating epithelioid granulomas. We report a case of the disease that presented with acute dacryoadenitis followed by acute parotitis. PMID- 29257722 TI - Perceived Average Orientation Reflects Effective Gist of the Surface. AB - The human ability to represent ensemble visual information, such as average orientation and size, has been suggested as the foundation of gist perception. To effectively summarize different groups of objects into the gist of a scene, observers should form ensembles separately for different groups, even when objects have similar visual features across groups. We hypothesized that the visual system utilizes perceptual groups characterized by spatial configuration and represents separate ensembles for different groups. Therefore, participants could not integrate ensembles of different perceptual groups on a task basis. We asked participants to determine the average orientation of visual elements comprising a surface with a contour situated inside. Although participants were asked to estimate the average orientation of all the elements, they ignored orientation signals embedded in the contour. This constraint may help the visual system to keep the visual features of occluding objects separate from those of the occluded objects. PMID- 29257723 TI - Development of a Hazard Classification Scheme for Substances Used in the Fraudulent Adulteration of Foods. AB - Food fraud, the intentional misrepresentation of the true identity of a food product or ingredient for economic gain, is a threat to consumer confidence and public health and has received increased attention from both regulators and the food industry. Following updates to food safety certification standards and publication of new U.S. regulatory requirements, we undertook a project to (i) develop a scheme to classify food fraud-related adulterants based on their potential health hazard and (ii) apply this scheme to the adulterants in a database of 2,970 food fraud records. The classification scheme was developed by a panel of experts in food safety and toxicology from the food industry, academia, and the U.S. Food and Drug Administration. Categories and subcategories were created through an iterative process of proposal, review, and validation using a subset of substances known to be associated with the fraudulent adulteration of foods. Once developed, the scheme was applied to the adulterants in the database. The resulting scheme included three broad categories: 1, potentially hazardous adulterants; 2, adulterants that are unlikely to be hazardous; and 3, unclassifiable adulterants. Categories 1 and 2 consisted of seven subcategories intended to further define the range of hazard potential for adulterants. Application of the scheme to the 1,294 adulterants in the database resulted in 45% of adulterants classified in category 1 (potentially hazardous). Twenty-seven percent of the 1,294 adulterants had a history of causing consumer illness or death, were associated with safety-related regulatory action, or were classified as allergens. These results reinforce the importance of including a consideration of food fraud-related adulterants in food safety systems. This classification scheme supports food fraud mitigation efforts and hazard identification as required in the U.S. Food Safety Modernization Act Preventive Controls Rules. PMID- 29257724 TI - Inhibition of Initial Attachment of Injured Salmonella Typhimurium onto Abiotic Surfaces. AB - Following sanitation interventions in food processing facilities, sublethally injured bacterial cells can remain on food contact surfaces. We investigated whether injured Salmonella Typhimurium cells can attach onto abiotic surfaces, which is the initial stage for further biofilm development. We utilized heat, UV, hydrogen peroxide, and lactic acid treatments, which are widely utilized by the food industry. Our results showed that heat, UV, and hydrogen peroxide did not effectively change populations of attached Salmonella Typhimurium. Cells treated with hydrogen peroxide had a slightly higher tendency to adhere to abiotic surfaces, although there was no significant difference between the populations of control and hydrogen peroxide-treated cells. However, lactic acid effectively reduced the number of Salmonella Typhimurium cells attached to stainless steel. We also compared physicochemical changes of Salmonella Typhimurium after application of lactic acid and used hydrogen peroxide as a positive control because only lactic acid showed a decreased tendency for attachment and hydrogen peroxide induced slightly higher numbers of attached bacteria cells. Extracellular polymeric substance produced by Salmonella Typhimurium was not detected in any treatment. Significant differences in hydrophobicity were not observed. Surface charges of cell membranes did not show relevant correlation with numbers of attached cells, whereas autoaggregation showed a positive correlation with attachment to stainless steel. Our results highlight that when lactic acid is applied in a food processing facility, it can effectively interfere with adhesion of injured Salmonella Typhimurium cells onto food contact surfaces. PMID- 29257725 TI - Detection of Hepatitis E Virus RNA in Raw Cured Sausages and Raw Cured Sausages Containing Pig Liver at Retail Stores in Switzerland. AB - Hepatitis E virus (HEV) is the causative agent of an acute and self-limiting hepatitis and is increasingly detected in food products containing pork. In this study, 102 raw sausages containing pig liver (mortadella di fegato) and 18 raw pork sausages (salami type sausage) collected at retail level in a region of southern Switzerland were screened for the presence of HEV by quantitative real time reverse transcription PCR. HEV was detected in 12 (11.8%) of 102 mortadella di fegato products but not in any of the salami sausages. Viral loads in the mortadella di fegato sausages ranged from log HEV 2.3 to 5.7 genome copies per gram of food product. This study identifies mortadella di fegato type sausages made with raw pig liver as a potential source of HEV infection in humans. PMID- 29257726 TI - Characteristics of d-Tryptophan as an Antibacterial Agent: Effect of Sodium Chloride Concentration and Temperature on Escherichia coli Growth Inhibition. AB - We previously reported that d-tryptophan exhibits adverse effects on bacterial physiology under osmotic stress. However, the mechanism by which d-tryptophan acts as an inhibitor and/or incompatible solute for bacterial growth has not yet been investigated in detail. In this study, we aimed to determine how osmotic pressure and temperature affect the antimicrobial effect of d-tryptophan. Even at the same level of osmotic pressure, d-tryptophan in conjunction with sodium chloride (NaCl) had a stronger inhibitory effect on the growth of Escherichia coli than that obtained by incubation with potassium chloride (KCl) and sucrose. Because d-tryptophan with NaCl showed the strongest inhibitory effect, we determined the optimum concentration combination of d-tryptophan and NaCl. The growth inhibition boundary conditions as a function of d-tryptophan and NaCl concentrations were determined by a logistic regression model. We found that the minimum level of NaCl for E. coli growth inhibition was 2.5% (w/v) together with 40 mM d-tryptophan. Moreover, the higher the NaCl concentration, the lower the concentration of d-tryptophan that was needed to inhibit bacterial growth. The logistic regression model that we developed enabled us to predict the concentrations required to inhibit bacterial growth. Furthermore, we examined the effect of incubation temperatures ranging from 15 to 46 degrees C on the antimicrobial effect of d-tryptophan. The higher the reaction temperature, the more rapid the decrease of viable E. coli that was observed. This trend is likely attributable to activation of physiological metabolism under the optimum growth temperature. Together, our findings should make a significant contribution to the development of a novel bacterial growth control strategy using d-tryptophan. PMID- 29257727 TI - Thermal Inactivation of Salmonella in High-Fat Rendering Meat Products. AB - Thermal inactivation of Salmonella is a critical component of the calculated thermal process to ensure the safety of cooked human and animal products. However, lethality performance standards for meat processing by-products that may harbor Salmonella have not been properly set under the actual conditions of rendering processes. The goal of this study was to evaluate the thermal inactivation parameters for Salmonella in high-fat beef trimmings as a model system for animal food products treated under simulated "worst-case scenario" commercial rendering conditions. Ground high-fat beef trimmings (50% fat) were artificially inoculated with a 108 CFU/g Salmonella cocktail containing human outbreak strains including the highly thermotolerant serotype Salmonella Senftenberg. The meat samples were packaged and immersed in either water or silicon oil at predetermined temperatures ranging from 60 to 121 degrees C (from 140 to 250 degrees F). D-values of Salmonella at each temperature were calculated from the negative inverse slope of the log CFU per gram versus time plot. The z values were determined from the negative inverse slope of the log D versus temperature plot. The D-values in thermal death curves for low-fat (20%) content materials (between 60 and 95 degrees C) were 2.175, 0.658, 0.237, 1.563, 0.356, 0.284, 0.264, and 0.201 min, whereas materials with 50% fat (between 100 to 121 degrees C) were 0.277, 0.286, 0.159, 0.143, 0.137, and 0.087 min. The z-values for low- and high-temperature schedules were 43.7 and 42.9 degrees C, respectively. Thermal lethality data for Salmonella inactivation in high-fat rendering raw materials will help animal food processors design adequate thermal processing schedules and support critical control points to ensure the safety of final beef-based rendered products. PMID- 29257728 TI - Growth and Biofilm Formation by Listeria monocytogenes in Catfish Mucus Extract on Four Food Contact Surfaces at 22 and 10 degrees C and Their Reduction by Commercial Disinfectants. AB - The objective of this study was to determine the effect of strain and temperature on growth and biofilm formation by Listeria monocytogenes in high and low concentrations of catfish mucus extract on various food contact surfaces at 10 and 22 degrees C. The second objective of this study was to evaluate the efficacy of disinfectants at recommended concentrations and contact times for removing L. monocytogenes biofilm cells from a stainless steel surface covered with catfish mucus extract. Growth and biofilm formation of all L. monocytogenes strains increased with higher concentrations of catfish mucus extract at both 10 and 22 degrees C. When 15 MUg/mL catfish mucus extract was added to 3 log CFU/mL L. monocytogenes, the biofilm levels of L. monocytogenes on stainless steel reached 4 to 5 log CFU per coupon at 10 degrees C and 5 to 6 log CFU per coupon at 22 degrees C in 7 days. With 375 MUg/mL catfish mucus extract, the biofilm levels of L. monocytogenes on stainless steel reached 5 to 6 log CFU per coupon at 10 degrees C and 6 to 7.5 log CFU per coupon at 22 degrees C in 7 days. No differences ( P > 0.05) were observed between L. monocytogenes strains tested for biofilm formation in catfish mucus extract on the stainless steel surface. The biofilm formation by L. monocytogenes catfish isolate HCC23 was lower on Buna-N rubber than on stainless steel, polyethylene, and polyurethane surfaces in the presence of catfish mucus extract ( P < 0.05). Contact angle analysis and atomic force microscopy confirmed that Buna-N rubber was highly hydrophobic, with lower surface energy and less roughness than the other three surfaces. The complete reduction of L. monocytogenes biofilm cells was achieved on the stainless steel coupons with a mixture of disinfectants, such as quaternary ammonium compounds with hydrogen peroxide or peracetic acid with hydrogen peroxide and octanoic acid at 25 or 50% of the recommended concentration, in 1 or 3 min compared with use of the quaternary ammonium compounds, chlorine, or acid disinfectants alone, which were ineffective for removing all the L. monocytogenes biofilm cells. PMID- 29257729 TI - Efficacy of Antimicrobials Applied Individually and in Combination for Controlling Listeria monocytogenes as Surface Contaminants on Queso Fresco. AB - Outbreaks of listeriosis are continually attributed to the consumption of Hispanic-style soft cheeses contaminated with Listeria monocytogenes postpasteurization. Once contaminated, L. monocytogenes can grow rapidly in cheeses like Queso Fresco (QF) even when stored at refrigeration temperatures. Several antimicrobials, including acidified calcium sulfate with lactic acid (ACSL), epsilon-polylysine (EPL), hydrogen peroxide (HP), lauric arginate ethyl ester (LAE), and sodium caprylate (SC), have demonstrated antilisterial activity in food. The objectives of this study were to determine the efficacy of these antimicrobials used individually and in combination to control L. monocytogenes as surface contaminants on QF and to identify additive and synergistic interactions. Cheeses were surface inoculated at ~4 log CFU/g, dipped in antimicrobial solutions, vacuum packaged, and then stored at 7 degrees C for 35 days. L. monocytogenes counts were determined 24 h after application of the antimicrobials and then weekly throughout storage. Dip treatments in a 5% (v/v) HP solution reduced L. monocytogenes counts to <0.5 log CFU/g within 24 h with no increase in counts through day 35. Dip treatments in LAE at 2 and 5% alone and in combination with EPL at 10% produced initial reductions in pathogen counts (1.5 to 1.8 CFU/g) but did not inhibit pathogen growth compared with the sterile water control. Dip applications of ACSL at 25% also produced an initial ~1.5-log reduction in L. monocytogenes counts followed by regrowth. Application of SC at 10% alone and in combination with either EPL or LAE inhibited growth to <1 log CFU/g through 21 days of storage. The combination of ACSL+SC worked synergistically to inhibit the growth of L. monocytogenes on QF to <1 log CFU/g through 35 days. These data indicate that HP alone and treatments containing EPL, LAE, or ACSL in combination with SC are promising postlethality treatments and process controls for L. monocytogenes on QF through a 21-day shelf life. PMID- 29257731 TI - Metabolomics of the Wolfram Syndrome 1 Gene (Wfs1) Deficient Mice. AB - Wolfram syndrome 1 is a rare autosomal recessive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Mutations in the WFS1 gene encoding the wolframin glycoprotein can lead to endoplasmic reticulum stress and unfolded protein responses in cells, but the pathophysiology at whole organism level is poorly understood. In this study, several organs (heart, liver, kidneys, and pancreas) and bodily fluids (trunk blood and urine) of 2- and 6-month old Wfs1 knockout (KO), heterozygote (HZ), and wild-type (WT) mice were analyzed by untargeted and targeted metabolomics using liquid chromatography-mass spectrometry. The key findings were significant perturbations in the metabolism of pancreas and heart before the onset of related clinical signs such as glycosuria that precedes hyperglycemia and thus implies a kidney dysfunction before the onset of classical diabetic nephropathy. The glucose use and gluconeogenesis in KO mice are intensified in early stages, but later the energetic needs are mainly covered by lipolysis. Furthermore, in young mice liver and trunk blood hypouricemia, which in time turns to hyperuricemia, was detected. In summary, we show that the metabolism in Wfs1-deficient mice markedly differs from the metabolism of WT mice in many aspects and discuss the future biological and clinical relevance of these observations. PMID- 29257732 TI - Distinguishing Orchid Species by DNA Barcoding: Increasing the Resolution of Population Studies in Plant Biology. AB - Increasing the resolution of population studies in plant biology is one of the leading frontiers for omics sciences. One of the most pervasive challenges in molecular phylogenetics is the incongruence between phylogenies obtained using different data sets such as individual genes [like ribulose bisphosphate carboxylase large chain (rbcL) and maturase K (matK)] and intergenic spacers (IGS) [like nuclear ribosomal internal transcribed spacer 1 (nrITS 1) and 2 (nrITS 2), and chloroplast IGS between transfer RNA for leucine and phenylalanine (cp trnL-trnF IGS)]. To solve this challenge, we have screened the four well established candidate gene sequences (i.e., rbcL, matK, trnL-trnF IGS, and 18S ITS1-5.8S-ITS2-28S nrDNA) of 65 Indian orchid species. We also have included 31 different species of Dendrobium to identify the suitable locus for resolving the phylogeny-related problem below the taxonomic rank of genus. The Consortium for the Barcode of Life has recommended the locus rbcL and matK for barcoding of all land plants, including orchids. However, in this study, matK and rbcL (species resolving capacity 52% and 48%, respectively) were found to work above the taxonomic limit of genus, and thus cannot be considered a suitable tool to resolve closely related species of Dendrobium, whereas, we found that the locus 18S-ITS1-5.8S-ITS2-28S nrDNA is the best choice with the highest species resolving ability (95.23%) and the highest mean Kimura 2-parameter distance (254 for intergeneric and 144 for intrageneric) for phylogeny construction, and thus have been taken as the most promising single-locus barcode for orchids. PMID- 29257730 TI - Spectrin-based pathways underlying electrical and mechanical dysfunction in cardiac disease. AB - INTRODUCTION: In the heart, pathways that transduce extracellular environmental cues (e.g. mechanical force, inflammatory stress) into electrical and/or chemical signals at the cellular level are critical for the organ-level response to chronic biomechanical/neurohumoral stress. Specifically, a diverse array of membrane-bound receptors and stretch-activated proteins converge on a network of intracellular signaling cascades that control gene expression, protein translation, degradation and/or regulation. These cellular reprogramming events ultimately lead to changes in cell excitability, growth, proliferation, and/or survival. Areas covered: The actin/spectrin cytoskeleton has emerged as having important roles in not only providing structural support for organelle function but also in serving as a signaling 'superhighway,' linking signaling events at/near the membrane to distal cellular domains (e.g. nucleus, mitochondria). Furthermore, recent work suggests that the integrity of the actin/spectrin cytoskeleton is critical for canonical signaling of pathways involved in cellular response to stress. This review discusses these emerging roles for spectrin and consider implications for heart function and disease. Expert commentary: Despite growth in our understanding of the broader roles for spectrins in cardiac myocytes and other metazoan cells, there remain important unanswered questions, the answers to which may point the way to new therapies for human cardiac disease patients. PMID- 29257734 TI - Introduction: Challenges and advances in cardiovascular disease. PMID- 29257733 TI - What Is Trust? Ethics and Risk Governance in Precision Medicine and Predictive Analytics. AB - Trust is a ubiquitous term used in emerging technology (e.g., Big Data, precision medicine), innovation policy, and governance literatures in particular. But what exactly is trust? Even though trust is considered a critical requirement for the successful deployment of precision medicine initiatives, nonetheless, there is a need for further conceptualization with regard to what qualifies as trust, and what factors might establish and sustain trust in precision medicine, predictive analytics, and large-scale biology. These new fields of 21st century medicine and health often deal with the "futures" and hence, trust gains a temporal and ever present quality for both the present and the futures anticipated by new technologies and predictive analytics. We address these conceptual gaps that have important practical implications in the way we govern risk and unknowns associated with emerging technologies in biology, medicine, and health broadly. We provide an in-depth conceptual analysis and an operative definition of trust dynamics in precision medicine. In addition, we identify three main types of "trust facilitators": (1) technical, (2) ethical, and (3) institutional. This three-dimensional framework on trust is necessary to building and maintaining trust in 21st century knowledge-based innovations that governments and publics invest for progressive societal change, development, and sustainable prosperity. Importantly, we analyze, identify, and deliberate on the dimensions of precision medicine and large-scale biology that have carved out trust as a pertinent tool to its success. Moving forward, we propose a "points to consider" on how best to enhance trust in precision medicine and predictive analytics. PMID- 29257735 TI - Cardiac amyloidosis: An update on diagnosis and treatment. AB - Cardiac amyloidosis (CA), once thought to be a rare disease, is increasingly recognized due to enhanced clinical awareness and better diagnostic imaging. CA is becoming of heightened interest to the cardiology community given more effective treatment strategies for light chain amyloidosis (AL), as well as emerging therapies for transthyretin amyloidosis (ATTR). Furthermore, reversing amyloid deposition in affected organs using monoclonal antibodies is actively being tested in clinical trials. A high index of suspicion and a systematic approach to the diagnosis of CA can lead to referral to a center of expertise for timely treatment. PMID- 29257736 TI - Management of coronary chronic total occlusion. AB - Percutaneous coronary intervention (PCI) for coronary artery chronic total occlusion (CTO) is an important treatment to be used in conjunction with non-CTO PCI, coronary artery bypass grafting, and optimal medical therapy to achieve complete revascularization in patients with coronary artery disease. PMID- 29257737 TI - Update on the management of venous thromboembolism. AB - Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism, is a common cardiovascular disease associated with significant morbidity ranging from painful leg swelling, chest pain, shortness of breath, and even death. Long-term complications include recurrent VTE, postpulmonary embolism syndrome, chronic thromboembolic pulmonary hypertension, and postthrombotic syndrome (PTS). Management of VTE requires immediate anticoagulation therapy based on a risk assessment for bleeding. Direct oral anticoagulants (DOACs) have become an important option for patients as reflected in the most recent American College of Chest Physician treatment guidelines. PMID- 29257738 TI - Cardiac implantable electronic device infection. AB - Increasing numbers of patients with cardiac disease have improved quality of life and longevity as a result of cardiac implantable electronic devices (CIEDs). CIED infections can involve the generator pocket, bloodstream, or cardiac structures and occur in about 0.5% of de novo CIED implants and approximately 2% of CIED replacements. Prompt diagnosis of CIED infection is beneficial to the success of antibiotic therapy and subsequent device removal to resolve the infection. Measures to prevent CIED infections include assessment of the indication and patient status, strict sterile surgical techniques, preoperative antibiotics, and adequate homeostasis. New surgical methods and CIED devices may also lead to reduction in CIED infections. Further research is needed to better quantify the incidence of CIED, risk factors, and efficacy of surgical techniques to prevent infections. PMID- 29257739 TI - Lung transplant: Candidates for referral and the waiting list. AB - For patients with end-stage lung diseases, lung transplant may significantly extend survival and improve quality of life. Identifying patients that are likely to benefit from a lung transplant is essential to positive outcomes and to maximizing life expectancy for each patient. Prompt referral to and communication with an experienced lung transplant center allows for timely completion of the formal evaluation of candidacy and placement on the organ transplant waiting list. This article summarizes the selection criteria for lung transplant candidates, including when physicians should refer patients to transplant centers for evaluation and placement on the lung transplant waiting list. PMID- 29257740 TI - Medical associations: Are they outdated or still relevant? PMID- 29257741 TI - Use of hydrogel spacer for improved rectal dose-sparing in patients undergoing radical radiotherapy for localized prostate cancer: First Canadian experience. AB - We describe the initial experience using a hydrogel spacer (SpaceOAR) to separate the prostate-rectum interspace in patients planned to undergo radical hypofractionated, image-guided, intensity-modulated radiotherapy (IG-IMRT). We depict and discuss the impact of SpaceOAR in the context of hypofractionated IG IMRT, and the particular considerations for its applications in the Canadian setting. PMID- 29257742 TI - A pilot study of the responsiveness of the Neurogenic Bladder Symptom Score (NBSS). PMID- 29257743 TI - Role of gentamicin in reducing urinary tract infections in patients with neurogenic bladder. PMID- 29257744 TI - Les associations de medecins : desuetes ou toujours pertinentes? PMID- 29257746 TI - Solar flower power. AB - Bumblebees use invisible temperature patterns on flowers to make foraging decisions. PMID- 29257745 TI - Inducible and reversible phenotypes in a novel mouse model of Friedreich's Ataxia. AB - Friedreich's ataxia (FRDA), the most common inherited ataxia, is caused by recessive mutations that reduce the levels of frataxin (FXN), a mitochondrial iron binding protein. We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset and progression of disease phenotypes by the modulation of Fxn levels. Systemic knockdown of Fxn in adult mice led to multiple phenotypes paralleling those observed in human patients across multiple organ systems. By reversing knockdown after clinical features appear, we were able to determine to what extent observed phenotypes represent reversible cellular dysfunction. Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, associated pathology and transcriptomic dysregulation even after substantial motor dysfunction and pathology were observed. This model will be of broad utility in therapeutic development and in refining our understanding of the relative contribution of reversible cellular dysfunction at different stages in disease. PMID- 29257748 TI - Utility of cone-beam computed tomography angiography for the assessment of vertebral artery dissection. AB - Vertebral artery dissection (VAD) has been recognized as a cause of headache and stroke. Accurate evaluation of dissection using several modalities such as catheter-based angiography, CT angiography (CTA), and magnetic resonance imaging (MRI) is essential for subsequent management. The aim of this retrospective study is to compare cone-beam computed tomography angiography (CBCT-A) with other image modalities for the evaluation of the detailed structures of VAD. Twenty-five consecutive cases identified as having VAD were included. They underwent catheter based angiography (2D-digital subtraction angiography [DSA], 3D-DSA, and CBCT-A), CTA, and MRI for the diagnosis of VAD. CBCT-A was performed following conventional angiography. Dissecting lesions were evaluated for the presence of intimal flap/double lumen, wall thickening, and enhancement of outer wall. This study results showed that CBCT-A was the most superior modality to detect intimal flap/double lumen (found in 56% of the cases) due to its high spatial resolution. MRI was superior for the assessment of wall thickening as an intramural hematoma in 76% of the cases. However, wall thickening was detected in 44% of cases using CBCT-A. In 5 cases, enhancement of outer wall was identified only in CBCT-A. In conclusion, CBCT-A provides detailed luminal and wall morphology of VADs. CBCT-A is useful for the accurate diagnosis of VADs. PMID- 29257747 TI - Low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes: Benefit or risk? AB - Primary prevention aims to avert the onset of cardiovascular disease (CVD) by targeting its natural causes and risk factors; secondary prevention includes strategies and therapies that address preclinical or clinical evidence of CVD progression. The value of aspirin for primary CVD prevention is controversial because of increased bleeding, which may offset the overall modest benefits in patients with no overt CVD. In contrast, the benefits of aspirin for secondary prevention have been repeatedly and convincingly demonstrated to outweigh the risk of bleeding. Diabetes mellitus is a strong risk factor for cardiovascular events, and has been associated with an increased risk of both first and recurrent atherothrombotic events. Therefore, prevention of CVD, the major cause of mortality in patients with diabetes, is one of the most important therapeutic goals. Although the benefit of low-dose aspirin for secondary prevention of CVD is well established, its role for primary prevention remains inconclusive and controversial in diabetes patients. The benefit of aspirin for patients with CVD clearly exceeds the risk of bleeding, and even though a modest benefit has also been demonstrated in primary prevention, the trade-off for aspirin initiation against the increased risk of intracranial and gastrointestinal bleeding is more uncertain. Thus, aspirin for primary CVD prevention should be highly individualized, based on a benefit-risk ratio assessment for the given patient. In conclusion, the mere presence of diabetes is apparently not enough for aspirin to confer a benefit that clearly outweighs the risk of bleeding, and further evidence to the contrary is now needed. PMID- 29257749 TI - Can the Pattern of Early Sensitization to Allergen Molecules Drive a New Approach for Prevention of Allergy? PMID- 29257750 TI - Rule-out of non-ST elevation myocardial infarction by five point of care cardiac troponin assays according to the 0 h/3 h algorithm of the European Society of Cardiology. AB - BACKGROUND: Point of care (POC) assays for cardiac troponins I or T (cTnI or cTnT) may accelerate the diagnosis of patients with suspected acute coronary syndrome (ACS). However, their clinical utility according to the 0 h/3 h algorithm recommended by the European Society of Cardiology (ESC) for non-ST elevation myocardial infarction (NSTEMI) is unknown. METHODS: Blood samples from 90 patients with suspected ACS were obtained at hospital admission and 3 h later. Concentrations of cTn were determined using five POC assays (AQT90 FLEX cTnI and cTnT; PATHFASTTM cTnI; Stratus CS 200 cTnI; and Triage MeterPro cTnI) and two guideline-acceptable high-sensitivity (hs) immunoassays. RESULTS: For the diagnosis of NSTEMI (n=15), AUCs for Abbott hs-cTnI and Roche hs-cTnT were 0.86 [95% confidence interval (CI), 0.75-0.96] and 0.88 (95% CI, 0.80-0.95), respectively, at admission, and 0.96 and 0.94, respectively, 3 h later. With the 99th percentile cutoff, their sensitivities were 62% and 92%, respectively, at admission, and 77% and 100%, respectively, 3 h later. The PATHFASTTM cTnI assay showed AUCs of 0.90 (95% CI, 0.82-0.97) and 0.94 (95% CI, 0.89-1.00), respectively, and sensitivities of 67% and 75% at admission and 3 h later, respectively. The other cTn POC assays had AUCs of 0.71 (95% CI, 0.53-0.89) to 0.84 (95% CI, 0.71-0.96) and 0.86 (95% CI, 0.72-0.99) to 0.87 (95% CI, 0.75-0.99) and sensitivities of 39%-50% and 62%-77% at admission and 3 h later, respectively. CONCLUSIONS: PATHFASTTM cTnI assay proved itself as comparable to ESC-guideline acceptable hs-cTn assays. The lower sensitivity of the other POC assays limits their clinical utility and would require longer follow-up monitoring of patients for the safe NSTEMI rule-out. PMID- 29257751 TI - Measuring procalcitonin to overcome heterophilic-antibody-induced spurious hypercalcitoninemia. PMID- 29257752 TI - Traceability of alkaline phosphatase measurement may also vary considerably using the same analytical system: the case of Abbott Architect. PMID- 29257753 TI - The influence of age and other biological variables on the estimation of reference limits of cardiac troponin T. PMID- 29257754 TI - COQ2 polymorphisms are not associated with increased risk of statin-induced myalgia/myopathy in the Czech population. AB - BACKGROUND: The gene COQ2, encoding 4-hydroxybenzoate-polyprenyltransferase (coenzyme Q2), belongs to the candidates potentially influencing statin treatment tolerability. This enzyme is involved in the biosynthesis of coenzyme Q10 (CoQ10), in which depletion induced by statin treatment is implicated in the development of statin-associated muscle symptoms (SAMS). Thus, polymorphisms in the COQ2 gene might explain susceptibility to SAMS. METHODS: Adult patients with SAMS (on low doses of atorvastatin and simvastatin)-induced myalgia/myopathy (n=278), patients on statins but without SAMS (n=293) and population (part of the post-MONICA [Multinational MONItoring of trends and determinants in CArdiovascular disease] study) controls (n=561) were genotyped (polymerase chain reaction-restriction fragment length polymorphism [PCR-RFLP] assay) for rs6535454 and rs4693075 polymorphisms within the COQ2 gene loci. RESULTS: Distribution of rs6535454 in patients with SAMS (GG=51.1%, GA=40.0%, AA=8.9%) did not significantly differ (p=0.33; respectively 0.32 for codominant models of the analysis) from that in the population controls (GG=48.1%, GA=45.0%, AA=6.9%) or the SAMS-unaffected patients (GG=49.8%, GA=40.3%, AA=9.7%). Similarly, neither rs4693075 was associated with SAMS (CC=36.8%, CG=48.2%, GG=15.0% in patients suffering SAMS vs. CC=36.6%, CG=47.5%, GG=15.9 in controls and CC=35.8%, CG=48.2%, GG=15.9% in symptom-free patients, p=0.94 and 0.95 for codominant models of the analysis). Also, the haplotype distributions were not significantly different between the groups analyzed. CONCLUSIONS: The polymorphisms of the COQ2 gene do not associate with SAMS in the Czech patients treated with low doses of statins. This is another clue that the coenzyme Q10 pathway is not the most important for the development of SAMS. PMID- 29257756 TI - Swarup A.V. Shah won the poster award at the 4th Annual Conference of ESPT. PMID- 29257757 TI - Efficacy of Tamarindus indicus, Melia azadirach and Santalum album in syndromic management of abnormal vaginal discharge: A single-blind randomised controlled trial. AB - Background At least 25 % of women attending genitourinary medicine (GUM) clinics receive treatment for one of the three common causes of abnormal vaginal discharge: bacterial vaginosis, candidiasis and trichomoniasis. Syndromic diagnostic approach was adopted by National AIDS Control Organisation (NACO) India, at the primary health centre level. Syndromic management implies the simultaneous treatment of two or more infections. The aim of this study was to assess efficacy of sandal sufaid, maghze tukhme bakayin and khaste tamar hindi in syndromic management of Sailanur rehm. Methods This study was a randomized, single blind, standard controlled trial. It was conducted to compare efficacy of formulation which contains buradae sandal safaid, safoofe maghze tukhme bakayin, safoofe khaste tamar hindi and safoofe shakkar safaid against combination of azithromycin, fluconazole and secnidazole on diagnosed subjects of Sailanur rehm. Test group received 10 g of test drug B.D for 21 days while control group received single dose of standard drug to both the partners. Vaginal symptom score (VSS) was used for assessing discharge and associated complaints. Visual analogous scale (VAS) was used for assessing low backache and lower abdominal pain. Results There were no significant differences between the two groups concerning baseline characteristics (p>0.05). VSS was significantly decreased with p<0.001 for both control and test group. VAS was significantly decreased with p<0.001 and p=0.07 in test and control group respectively for low backache. For lower abdominal pain p=0.006 for both groups after the completion of treatment. Conclusions The formulation can effectively alleviate the disease with associated symptoms without any side effects. It can be used in syndromic management of vaginal discharge. Future research is on large sample size. PMID- 29257755 TI - Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer. AB - BACKGROUND: Fluoropyrimidines form the chemotherapy backbone of advanced and metastatic colorectal cancer (CRC). These drugs are frequently associated with toxicity events that result in dose adjustments and even suspension of the treatment. The thymidylate synthase (TYMS) gene is a potential marker of response and toxicity to fluoropyirimidines as this enzyme is the molecular target of these drugs. Our aim was to assess the association between variants of TYMS with response and toxicity to fluoropyrimidines in patients with CRC in independent retrospective and prospective studies. METHODS: Variants namely rs45445694, rs183205964, rs2853542 and rs151264360 of TYMS were genotyped in 105 CRC patients and were evaluated to define their association with clinical response and toxicity to fluoropyrimidines. Additionally, the relationship between genotypes and tumor gene expression was analyzed by quantitative polymerase chain reaction. RESULTS: The 2R/2R (rs45445694) was associated with clinical response (p=0.05, odds ratio (OR)=3.45) and severe toxicity (p=0.0014, OR=5.21, from pooled data). Expression analysis in tumor tissues suggested a correlation between the 2R/2R genotype and low TYMS expression. CONCLUSIONS: The allele 2R (rs45445694) predicts severe toxicity and objective response in advanced CRC patients. In addition, the alleles G(rs2853542) and 6bp-(rs151264360) are independent predictors of response failure to chemotherapy. This is the first study made on a Latin American population that points out TYMS gene variants have predictive values for response and toxicity in patients with CRC treated with fluoropyrimidine-based chemotherapy. PMID- 29257758 TI - Comparison of anticancer effect of Pleurotus ostreatus extract with doxorubicin hydrochloride alone and plus thermotherapy on erythroleukemia cell line. AB - Background Recent studies have introduced Pleurotus ostreatus (Pleurotaceae) as a herbal medicine for treating different types of cancer. This survey utilizes P. ostreatus and doxorubicin hydrochloride (DOX) alone and then with hyperthermia to investigate the erythroleukemia cell line. This study evaluates and compares the apoptotic and necrotic effects of various treatments on the KG-1 cell line. Methods The proliferation of KG-1 cells was measured by using a tetrazolium salt (MTT)-based colorimetric assay during 96 h after treatment by gradient dilutions of 100 ng/mL to 100 mg/mL of P. ostreatus methanol extract and then the minimum inhibitory concentration (MIC) was determined and was applied in additional experiments. Afterward, the cells were treated using P. ostreatus extract, DOX (6.95 mg/L), and hyperthermia (42 and 44 degrees C), separately and then applying hyperthermia. Finally, the ratios of apoptosis and necrosis after 24 h incubation were evaluated by using flow cytometry. Results The MIC of the extract was determined (1 mg/mL), which significantly increased the ratio of apoptosis rather than necrosis, whereas the DOX treatment primarily induced necrosis on the KG-1 cells. The anticancer effects of the mushroom extract were significantly increased when it was combined with thermotherapy, which exhibited apoptotic effects at 42 degrees C but induced necrosis at 44 degrees C. Conclusions The results suggest that P. ostreatus extract induces apoptosis on KG-1 cells and its anticancer effects are significantly increased in combination with thermotherapy. Therefore, P. ostreatus could be considered as an alternative with anticancer effect for further studies in erythroleukemia patients. PMID- 29257759 TI - Effect of maternal age, height, BMI and ethnicity on birth weight: an Italian multicenter study. AB - AIM: To assess the effect of maternal age, height, early pregnancy body mass index (BMI) and ethnicity on birth weight. SUBJECTS AND METHODS: A cross sectional study was conducted on more than 42,000 newborns. Ethnicity was defined by maternal country of birth or, when missing (<0.6% of records), by citizenship. The effect of maternal characteristics on birth weight was evaluated with general linear models. RESULTS: Maternal height and BMI, although not age, significantly affected birth weight. Among Italian babies, 4.7% of newborns were classified as appropriate-for-gestational age (AGA) (birth weight between the 10th and the 90th centile) according to the country-specific Italian Neonatal Study (INeS) charts and were re-classified as either large-(LGA) (birth weight >90th centile) or small-(SGA) (birth weight <10th centile) for gestational age (GA) after adjustment for maternal characteristics. On the contrary, 1.6% of Italian newborns were classified as SGA or LGA according to the INeS charts and re classified as AGA after adjustment. Maternal ethnicity had a significant impact on birth weight. Specifically, babies born to Senegalese mothers were the lightest, whilst babies born to Chinese mothers were the heaviest. CONCLUSIONS: Maternal height and early pregnancy BMI, should be considered in the evaluation of birth weight. The effect of ethnicity suggests the appropriateness of ethnic specific charts. Further studies are necessary to determine if changes in birth weight classification, may translate into improved detection of subjects at risk of adverse outcomes. PMID- 29257760 TI - Birth-weight centiles and the risk of serious adverse neonatal outcomes at term. AB - BACKGROUND: Birth-weight is an important determinant of perinatal outcome with low birth-weight being a particular risk factor for adverse consequences. AIM: To investigate the impact of neonatal sex, mode of birth and gestational age at birth according to birth-weight centile on serious adverse neonatal outcomes in singleton term pregnancies. MATERIALS AND METHODS: This was a retrospective cohort study of singleton term births at the Mater Mother's Hospital, Brisbane, Australia. Serious adverse neonatal outcome was defined as a composite of severe acidosis at birth (pH <=7.0 and/or lactate >=6 mmol/L and/or base excess <=-12 mmol/L), Apgar <3 at 5 min, neonatal intensive-care unit admission and antepartum or neonatal death. The main exposure variable was birth-weight centile. RESULTS: Of the 69,210 babies in our study, the overall proportion of serious adverse neonatal outcomes was 9.1% (6327/69,210). Overall, neonates in the <3rd birth weight centile category had the highest adjusted odds ratio (OR) for serious adverse neonatal outcomes [OR 3.53, 95% confidence interval (CI) 3.06-4.07], whilst those in the >=97th centile group also had elevated odds (OR 1.51, 95% CI 1.30-1.75). Regardless of birth modality, smaller babies in the <3rd centile group had the highest adjusted OR and predicted probability for serious adverse neonatal outcomes. When stratified by sex, male babies consistently demonstrated a higher predicted probability of serious adverse neonatal outcomes across all birth-weight centiles. The adjusted odds, when stratified by gestational age at birth, were the highest from 37+0 to 38+6 weeks in the <3rd centile group (OR 5.97, 95% CI 4.60-7.75). CONCLUSIONS: Low and high birth-weights are risk factors for serious adverse neonatal outcomes. The adjusted OR appears to be greatest for babies in the <3rd birth-weight centile group, although an elevated risk was also found in babies within the >=97th centile category. PMID- 29257761 TI - New Ways to Cut through Ethical Gordian Knots. AB - Clinicians and ethicists routinely encounter complex ethical dilemmas that seem intractable, which have been described as ethical Gordian knots. How can they best assist patients and surrogate decision makers who are entangled in struggles around the capacity to make life-or-death treatment decisions? In this article I describe unconventional and unorthodox approaches to help slice through these dilemmas. PMID- 29257762 TI - Comparativism and the Grounds for Person-Centered Care and Shared Decision Making. AB - This article provides a new argument and a new value-theoretical ground for person-centered care and shared decision making that ascribes to it the role of enabling rational choice in situations involving clinical choice. Rather than referring to good health outcomes and/or ethical grounds such as patient autonomy, it argues that a plausible justification and ground for person-centered care and shared decision making is preservation of rationality in the face of comparative non-determinacy in clinical settings. Often, no alternative treatment will be better than or equal to every other alternative. In the face of such comparative non-determinacy, Ruth Chang has argued that we can make rational decisions by invoking reasons that are created through acts of willing. This article transfers this view to clinical decision making and argues that shared decision making provides a solution to non-determinacy problems in clinical settings. This view of the role of shared decision making provides a new understanding of its nature, and it also allows us to better understand when caregivers should engage in shared decision making and when they should not. PMID- 29257763 TI - Incapacitated Surrogates: A New and Increasing Dilemma in Hospital Care. AB - A power of attorney for healthcare (POAHC) form gives designated individuals legal status to make healthcare decisions when patients are unable to convey their decisions to medical staff. Completion of a POAHC form is crucial in the provision of comprehensive healthcare, since it helps to ensure that patients' interests, values, and preferences are represented in decisions about their medical treatment. Because increasing numbers of people suffer from debilitating illness and cognitive deficits, healthcare systems may be called upon to navigate the complexities of patients' care without clear directives from the patients themselves. Hence, the healthcare industry encourages all individuals to complete a POAHC form to ensure that persons who have the patients' trust are able to act as their surrogate decision makers. However, sometimes POAHC agents, even when they are patients' trusted agents, lack the capacity to make fully informed decisions that are in the patients' best interests. We describe designated surrogate decision makers who have impaired or diminished judgment capacity as incapacitated surrogates. Decision making that is obviously flawed or questionable is a significant impediment to providing timely and appropriate care to patients. Moreover, failure to redress these issues in a timely and efficient manner can result in significant costs to an institution and a diminished quality of patient care. The authors offer a legal, ethical, and interdisciplinary framework to help navigate cases of incapacitated surrogates. PMID- 29257764 TI - Measuring Instrument for Ethical Sensitivity in the Therapeutic Sciences. AB - There are currently no instruments available to measure ethical sensitivity in the therapeutic sciences. This study therefore aimed to develop and implement a measure of ethical sensitivity that would be applicable to four therapeutic professions, namely audiology, occupational therapy, physiotherapy, and speech language pathology. The study followed a two-phase, sequential exploratory mixed methods design. Phase One, the qualitative development phase, employed six stages and focused on developing an instrument based on a systematic review: an analysis of professional ethical codes, focus group discussions, in-depth interviews, a review of public complaints websites, and an expert panel review. The development phase culminated in the Measuring Instrument for Ethical Sensitivity in the Therapeutic Sciences (MIEST), a pen-and-paper measure for studying ethical sensitivity in the therapeutic sciences. Phase Two, the quantitative stage, focused on implementing the MIEST in two different stages. A total of 100 participants completed the instrument. MIEST scores were found to be comparable for all four professions, which confirmed the multidisciplinary usability of the instrument. Participants tended to base decisions on the ethical principle of beneficence. The MIEST is effective to assess and describe the ethical sensitivity of professionals in the four specified therapeutic sciences. The constructed vignettes also make the MIEST appropriate for use in problem-based learning programs. PMID- 29257765 TI - Make It Plain: Strengthening the Ethical Foundation of First-Person Authorization for Organ Donation. AB - One response to the chronic shortage of organs for transplant in the United States has been the passage of laws establishing first-person authorization for donation of organs, providing legal grounds for the retrieval of organs and tissues from registered donors, even over the objections of their next of kin. The ethical justification for first-person authorization is that it is a matter of respecting the donor's wishes. The objection of some next of kin may be that the donor would not have wished for his or her loved ones to have their preferences overridden, had they considered that possibility. This article examines the basis of the conflict and suggests a remedy grounded in the provision of donor-intent options that have the ability to clarify the donor's wishes. PMID- 29257767 TI - Ongoing Evaluation of Clinical Ethics Consultations as a Form of Continuous Quality Improvement. AB - Ongoing evaluation of a clinical ethics consultation service (ECS) allows for continuous quality improvement, a process-based, data-driven approach for improving the quality of a service. Evaluations by stakeholders involved in a consultation can provide real-time feedback about what is working well and what might need to be improved. Although numerous authors have previously presented data from research studies on the effectiveness of clinical ethics consultation, few ECSs routinely send evaluations as an ongoing component of their everyday clinical activities. The primary purpose of this article is to equip and encourage others to engage in ongoing evaluation of their own ECS. Toward that end, the following resources are shared: (1) the survey tool used to gather the evaluation data, (2) the procedure used to elicit and collate responses, and (3) how the resulting data are used to support continuous quality improvement and justify the continued financial support of the ECS to hospital administration. PMID- 29257766 TI - Incarcerated Patients and Equitability: The Ethical Obligation to Treat Them Differently. AB - Prisoners are legally categorized as a vulnerable group for the purposes of medical research, but their vulnerability is not limited to the research context. Prisoner-patients may experience lower standards of care, fewer options for treatment, violations of privacy, and the use of inappropriate surrogates as a result of their status. This case study highlights some of the ways in which a prisoner-patient's vulnerable status impacted the care he received. The article argues the following: (1) Prisoner-patients are entitled to the same quality of care as all other patients, and healthcare providers should be vigilant to ensure that the stigma of incarceration does not influence care decisions. (2) Options for treatment should reflect what is most medically appropriate in the hospital or other healthcare setting, even when not all treatments would be available in the correctional setting. (3) The presence of guards at the bedside requires that additional measures be taken to protect the privacy and confidentiality of prisoner-patients. (4) When end-of-life decisions must be made for an incapacitated patient, prison physicians are not well placed to act as surrogate decision makers, which heightens the obligations of the healthcare professionals in the hospital to ensure an ethically supportable process and outcome. Therefore, healthcare professionals should provide extra protection for those prisoner-patients who do not have decision-making capacity, by utilizing a robust process for decision making such as those used for incapacitated patients without surrogates, rather than relying solely on prison physicians as surrogates. PMID- 29257768 TI - Moral Distress, Ethical Environment, and the Embedded Ethicist. AB - Interest in understanding the experience of moral distress has steadily gained traction in the 30 years since Jameton first described the phenomenon. This curiosity should be of no surprise, since we now have data documenting the incidence across most caregiver roles and healthcare settings, both in the United States and internationally. The data have also amplified healthcare providers' voices who report that the quality of the ethical environment is pivotal to preventing and containing the adverse effects caused by moral distress. Healthcare providers are asking for a moral space where ethics occurs at the bedside, in real time, applied to real cases. They are asking for ethics expertise to be available as part of the care team during their daily work, when treatment goals must be determined and decisions must be made. They are asking for an embedded ethicist who can help cultivate an ethical environment where formal ethics policy is properly applied to practice. This discussion advocates for an embedded ethics resource model that responds to contemporaneous ethics needs as a strategy to mitigate the effects of moral distress. PMID- 29257769 TI - The Rise of Hospitalists: An Opportunity for Clinical Ethics. AB - Translating ethical theories into clinical practice presents a perennial challenge to educators. While many suggestions have been put forth to bridge the theory-practice gap, none have sufficiently remedied the problem. We believe the ascendance of hospital medicine, as a dominant new force in medical education and patient care, presents a unique opportunity that could redefine the way clinical ethics is taught. The field of hospital medicine in the United States is comprised of more than 50,000 hospitalists-specialists in inpatient medicine representing the fastest growing subspecialty in the history of medicine, and its members have emerged as a dominant new force around which medical education and patient care pivot. This evolution in medical education presents a unique opportunity for the clinical ethics community. Through their proximity to patients and trainees, hospitalists have the potential to teach medical ethics in real time on the wards, but most hospitalists have not received formal training in clinical ethics. We believe it is time to strengthen the ties between hospital medicine and medical ethics, and in this article we outline how clinical ethicists might collaborate with hospitalists to identify routine issues that do not rise to the level of an "ethics consult," but nonetheless require an intellectual grounding in normative reasoning. We use a clinical vignette to explore how this approach might enhance and broaden the scope of medical education that occurs in the inpatient setting: A patient with an intra-abdominal abscess is admitted to the academic hospitalist teaching service for drainage of the fluid, hemodynamic support, and antimicrobial therapy. During the initial encounter with the hospitalist and his team of medical students and residents, the patient reports night sweats and asks if this symptom could be due to the abscess. How should the hospitalist approach this question? PMID- 29257770 TI - Is burning mouth syndrome a neuropathic pain condition? AB - Primary burning mouth syndrome (BMS) is defined as an "intraoral burning or dysaesthetic sensation, recurring daily... more than 3 months, without clinically evident causative lesions" (IHS 2013). In addition to pain, taste alterations are frequent (dysgeusia, xerostomia). Although lacking clinical signs of neuropathy, more accurate diagnostic methods have shown neuropathic involvement at various levels of the neuraxis in BMS: peripheral small fiber damage (thermal quantitative sensory testing, electrogustatometry, epithelial nerve fiber density), trigeminal system lesions in the periphery or the brainstem (brainstem reflex recordings, trigeminal neurography, evoked potentials), or signs of decreased inhibition within the central nervous system (deficient brainstem reflex habituation, positive signs in quantitative sensory testing, neurotransmitter-positron emission tomography findings indicative of deficient striatal dopamine function). Abnormalities in electrogustatometry indicate the involvement of the small Adelta taste afferents, in addition to somatosensory small fibers. According to these findings, the clinical entity of BMS can be divided into 2 main subtypes compatible with either peripheral or central neuropathic pain, which may overlap in individual patients. The central type does not respond to local treatments and associates often with psychiatric comorbidity (depression or anxiety), whereas the peripheral type responds to peripheral lidocaine blocks and topical clonazepam. Burning mouth syndrome is most prevalent in postmenopausal women, having led to a hypothesis that BMS is triggered as a consequence of nervous system damage caused by neurotoxic factors affecting especially vulnerable small fibers and basal ganglia in a setting of decrease in neuroprotective gonadal hormones and increase in stress hormone levels, typical for menopause. PMID- 29257772 TI - Effects of Esmolol on the Esophagogastric Junction: A Double-Blind, Randomized, Crossover Study on 14 Healthy Volunteers: Erratum. PMID- 29257771 TI - Anesthetic Management of Narcolepsy Patients During Surgery: A Systematic Review. AB - BACKGROUND: Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness, sleep paralysis, and/or hypnagogic/hypnopompic hallucinations, and in some cases cataplexy. The response to anesthetic medications and possible interactions in narcolepsy patients is unclear in the perioperative period. In this systematic review, we aim to evaluate the current evidence on the perioperative outcomes and anesthetic considerations in narcolepsy patients. METHODS: Electronic literature search of Medline, Medline in process, Embase, Cochrane Database of Systematic Reviews databases, international conference proceedings, and abstracts was conducted in November 2015 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guideline. A total of 3757 articles were screened using a 2-stage strategy (title abstract followed by full text). We included case studies/series, cohort studies, and randomized controlled trials of narcolepsy patients undergoing surgical procedures under anesthesia or sedation. Preoperative narcolepsy symptoms and sleep study data, anesthetic technique, and perioperative complications were extracted. Screening of articles, data extraction, and compilation were conducted by 2 independent reviewers and any conflict was resolved by the senior author. RESULTS: A total of 19 studies including 16 case reports and 3 case series were included and evaluated. The majority of these patients received general anesthesia, whereas a small percentage of patients received regional anesthesia. Reported complications of narcolepsy patients undergoing surgeries were mainly related to autonomic dysregulation, or worsening of narcolepsy symptoms intra/postoperatively. Narcolepsy symptoms worsened only in those patient populations where the preoperative medications were either discontinued or reduced (mainly in obstetric patients). In narcolepsy patients, use of depth of anesthesia monitoring and total intravenous technique may have some advantage in terms of safety profile. Several patients undergoing neurosurgery involving the hypothalamus or third or four ventricles developed new-onset narcolepsy. CONCLUSIONS: We found a paucity of prospective clinical trials in this patient population, as most of the studies were case reports or observational studies. Continuation of preoperative medications, depth of anesthesia monitoring, use of multimodal analgesia with short-acting agents and regional anesthesia techniques were associated with favorable outcomes. Obstetric patients may be at greater risk for worsening narcolepsy symptoms, possibly related to a reduction or discontinuation of medications. For neurosurgical procedures involving the hypothalamus or third and fourth ventricle, postoperative considerations should include monitoring for symptoms of narcolepsy. Future studies are needed to better define perioperative risks associated with anesthesia and surgery in this population of patients. PMID- 29257775 TI - The Effect of Combined Spinal-Epidural Versus Epidural Analgesia in Laboring Women on Nonreassuring Fetal Heart Rate Tracings: Systematic Review and Meta analysis: Erratum. PMID- 29257776 TI - Asthma versus chronic obstructive pulmonary disease, the Dutch versus British hypothesis, and role of interleukin-5. AB - PURPOSE OF REVIEW: Asthma and COPD represent heterogeneous disorders with broad ranging impact on patients and health systems. This review focuses on evidence for early attempts at understanding their pathogenesis by the British and Dutch hypotheses. It also addresses the role of eosinophils, IL-5, and biologics targeting these pathways in asthma and COPD. RECENT FINDINGS: Among asthma and COPD patients, clusters exist based on phenotypic and biologic markers allowing for further understanding of endotypes. Recent studies suggest the role of eosinophils and optimal therapies for each condition may be different. SUMMARY: Although patients with ACOS or overlap symptoms may be an exception, overall there appears to be more evidence supporting that asthma and COPD are distinct processes. Targeting eosinophils with anti-IL-5 therapy appears to be an exciting pathway in the properly selected patient with asthma and recent data also supports its use in COPD. PMID- 29257777 TI - Safety and Prognostic Utility of Provocative Exercise Testing in Acutely Concussed Adolescents: A Randomized Trial. AB - OBJECTIVE: To evaluate (1) systematic assessment of exercise tolerance in adolescents shortly after sport-related concussion (SRC) and (2) the prognostic utility of such assessment. DESIGN: Prospective randomized controlled trial. SETTING: University and community sports medicine centers. PARTICIPANTS: Adolescents with SRC (1-9 days from injury). Sixty-five were randomized and 54 completed the study (mean age 15 years, 4 days after injury). INTERVENTIONS: Buffalo Concussion Treadmill Test (BCTT, n = 27) or not (controls, n = 27) on visit day #1. Heart rate threshold (HRt) at symptom exacerbation represented level of exercise tolerance. Participants reported symptoms daily for 14 days and then had follow-up BCTT (n = 54). Recovery was defined as returning to normal level of symptoms and exercise tolerance, verified by independent physician examination. MAIN OUTCOME MEASURES: Days to recovery and typical (<=21 days) versus prolonged recovery (>21 days). Mixed effects linear models and linear regression techniques examined symptom reports and time to recovery. Linear regression assessed the association of HRt with recovery time. RESULTS: Days to recovery (P = 0.7060) and typical versus prolonged recovery (P = 0.1195) were not significantly different between groups. Symptom severity scores decreased in both groups over 14 days (P < 0.0001), were similar (P = 0.2984), and did not significantly increase the day after the BCTT (P = 0.1960). Lower HRt on visit day #1 was strongly associated with prolonged recovery time (P = 0.0032). CONCLUSIONS: Systematic evaluation of exercise tolerance using the BCTT within 1 week after SRC did not affect recovery. The degree of early exercise intolerance after SRC was important for prognosis. This has implications for school academic and team preparation. PMID- 29257778 TI - Operative Versus Nonoperative Management of Acute High-Grade Acromioclavicular Dislocations: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Management of high-grade acromioclavicular (AC) joint dislocations has been controversial. Recent studies suggest no difference in outcomes between operative and nonoperative management of Rockwood types III-V injuries. The objective of this meta-analysis is to compare outcomes between operative and nonoperative management of high-grade AC joint dislocations. DATA SOURCES: Search was conducted using PubMed, Embase, and Cochrane databases through October 2016. A broad search strategy was used to identify English, comparative studies of AC joint dislocations. STUDY SELECTION: Inclusion criteria included comparative studies of AC joint dislocations in adult patients with acute, high-grade AC dislocations. DATA EXTRACTION: Two authors independently reviewed and assessed for bias according to the U.S. Preventative Task Force Quality Rating Criteria. Data were extracted for validated functional scores, clinical and radiographic outcomes, and complications. DATA SYNTHESIS: Nineteen studies (n = 954) were included in the meta-analysis. Operative group had better cosmetic outcome (odds ratio [OR] = 0.05; P < 0.00001) and radiographic reduction (OR = 24.94; P < 0.0001). Constant scores favored the operative group, although the difference may not be clinically significant (MD = 3.14; P = 0.03). Nonoperative treatment was associated with faster return to work (MD = 4.17, P < 0.0001), lower implant complications (OR = 7.19, P < 0.0001), and reduced infection rate (OR = 3.65, P = 0.007). No difference was found for DASH Score, return to sport, radiologic evidence of osteoarthritis, and need for surgery after failed management. CONCLUSIONS: No clinical difference in functional outcome scores was detected between operative and nonoperative management of high-grade AC joint dislocations. Patients in the nonoperative cohort had a more rapid return to work, but were associated with a poorer cosmetic outcome. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257779 TI - Functional Outcomes of Syndesmotic Injuries Based on Objective Reduction Accuracy at a Minimum 1-Year Follow-Up. AB - OBJECTIVE: To evaluate whether objective syndesmosis reduction predicts functional outcomes and pain scores in patients with operatively treated syndesmotic injuries at a minimum 1-year follow-up. DESIGN: Prospective Cohort. SETTING: Urban Level I Trauma Center. PATIENTS: Sixty-nine patients with operatively treated syndesmotic injuries were initially identified and consented for inclusion in the study. Nine patients were excluded perioperatively. Twelve patients were lost to follow-up. Forty-eight patients with operatively treated unilateral syndesmotic injuries were available and participated at the final follow-up. INTERVENTION: Trans-syndesmotic stabilization with either 1 or 2 quadricortical position screws. Postoperatively, bilateral ankle computed tomography scans were obtained to objectively assess syndesmosis reduction accuracy. MAIN OUTCOME MEASUREMENTS: Olerud-Molander Ankle Score, Short Musculoskeletal Function Assessment Dysfunction Index and Bother Index, and Numeric Pain Rating Scales at a minimum 1-year postoperative follow-up. RESULTS: At 1-year follow-up, there was no significant difference in functional outcomes between reduced and malreduced groups at the 1.5-, 2-, and 3-mm thresholds for linear measurements. Similarly, there was no functional difference between the reduced and malreduced groups for rotational malreductions at a 10 or 15 degrees threshold. Patients with state-sponsored insurance (Medicaid) had significantly worse functional scores and pain scores when compared with the groups with private insurance, Medicare, or no insurance. CONCLUSIONS: At 1-year follow-up, functional outcomes were not related to objective measures of syndesmosis reduction. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257780 TI - Hexapod Stacked Transport for Tibial Infected Nonunions With Bone Loss: Long-Term Functional Outcomes. AB - OBJECTIVES: To analyze long-term functional outcomes in patients with posttraumatic infected tibial nonunions having undergone bone transport with hexapod external fixator. DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Thirty-eight patients with infected nonunions of the tibia. INTERVENTION: Resection of nonunion with application of stacked hexapod external fixator for bone transport. MAIN OUTCOME MEASUREMENTS: Functional outcome was measured using the short Musculoskeletal Functional Assessment (sMFA). Parameters measured included age, sex, presence of diabetes, smoking, use of a free flap, bone defect size, length in frame, external fixation index, and direction of lengthening. RESULTS: The mean sMFA score for the entire group was 27.1. Average patient age was 46.8 +/- 12.7 years, 74% patients were male, 8% were diabetic, and 29% were smokers. Seventeen patients had soft-tissue defects that required a free flap. Smokers had higher degrees of disability compared with nonsmokers (39 +/- 16 vs. 22 +/- 14, P = 0.011). Patients requiring adjunctive stabilization had worse functional scores compared with those who did not receive adjunctive stabilization (33 +/- 17 vs. 22 +/- 15, P = 0.049). Sixteen patients returned 2 sMFA surveys at different time points after completion of bone transport. Initial average sMFA score was 26.5 at a mean of 25.3 months; subsequent sMFA scores averaged 19.4 at a mean of 98.8 months. CONCLUSIONS: Stacked hexapod external fixator bone transport is a reliable technique for infected nonunion of the tibia with bone loss. Improved sMFA scores can be expected from 2 to 8 years, suggesting full recovery takes longer than previously anticipated. Limb salvage with hexapod bone transport is justified over time. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29257781 TI - Patient Perceptions of the Use of Medical Marijuana in the Treatment of Pain After Musculoskeletal Trauma: A Survey of Patients at 2 Trauma Centers in Massachusetts. AB - OBJECTIVE: To evaluate musculoskeletal trauma patients' beliefs regarding the usefulness of marijuana as a valid medical treatment for postinjury and postoperative pain and anxiety. DESIGN: Prospective survey. SETTING: Two academic Level 1 trauma centers. PATIENTS/PARTICIPANTS: Five hundred patients in an orthopedic outpatient clinic. INTERVENTION: Survey. MAIN OUTCOME MEASUREMENTS: (1) Do patients believe that marijuana can be used as medicine? (2) Do patients believe that marijuana can help treat postinjury pain? (3) Are patients comfortable speaking with their health care providers about medical marijuana? RESULTS: The majority of patients felt that marijuana could be used to treat pain (78%, 390) and anxiety (62%, 309). Most patients (60%, 302) had used marijuana at least once previously, whereas only 14% reported using marijuana after their injury. Of those who used marijuana during their recovery, 90% (63/70) believed that it reduced symptoms of pain, and 81% (57/70) believed that it reduced the amount of opioid pain medication they used. CONCLUSIONS: The majority of patients in this study believed that medical marijuana is a valid treatment and that it does have a role in reducing postinjury and postoperative pain. Those patients who used marijuana during their recovery felt that it alleviated symptoms of pain and reduced their opioid intake. Our results help inform clinicians regarding the perceptions of patients with trauma regarding the usefulness of marijuana in treating pain and support further study into the utility of medical marijuana in this population. PMID- 29257782 TI - Percutaneous Application of a Medial Plate for Dual Plate Stabilization of Supracondylar Femur Fractures. AB - Supracondylar femur fractures with segmental defects can be difficult fractures to treat. When associated with open wounds, these injuries can be associated with numerous complications including nonunion, malunion, infection, and arthrofibrosis. In this article, we review our algorithm for treating these fractures and highlight critical aspects of the process which differs from previous techniques described. We feel that this technique has specific benefits that mitigate infection risk and minimize additional soft-tissue insult without compromising stability. Our results demonstrate good postoperative knee range of motion, a high union rate, with low complication rates. PMID- 29257783 TI - The microbiome of the critically ill patient. AB - PURPOSE OF REVIEW: Advances in the understanding of the human microbiome outside of the ICU have led investigators to consider the role of the microbiome in critical illness. The picture that is being elucidated is one of dysbiosis occurring at multiple sites in the critically ill patient. This review describes the changes that occur in the various microbiomes of a critically ill patient, the implications of these changes and shows how advances in the understanding of dysbiosis may lead to microbiome-targeted therapies. RECENT FINDINGS: Critically ill patients undergo dysbiosis at several organ sites including the skin, gastrointestinal system and the lungs with loss of microbial diversity and a propensity for potentially pathogenic organisms to dominate a particular microbiome. These microbiome changes appear to be predictive of clinical outcome. While the use of fecal microbial transplantation has been demonstrated to be an effective treatment for recurrent Clostridium difficile infection, the use of fecal microbial transplantation and other microbiome modifying therapies may have a role in managing critical illness in the ICU. SUMMARY: A growing understanding of the microbiome in the critically ill may modify current dogma regarding the pathogenesis of sepsis and other life-threatening conditions seen in the ICU, thereby fundamentally changing antibiotic stewardship and the management of the critically ill patient. PMID- 29257784 TI - Statistics Commentary Series: Commentary No. 24: Box Plots. PMID- 29257785 TI - Prevalence and Factors Associated With Clozapine-Related Constipation: An Observational Study. AB - BACKGROUND: Despite being a very effective treatment for resistant schizophrenia and bipolar disorder, use of clozapine is limited by adverse effects. Constipation is a common but potentially life-threatening adverse effect of clozapine that is understudied. The objective was to study the prevalence and factors associated with constipation in those receiving clozapine compared with control subjects. METHODS: Fifty patients in age group of 18 to 55 years receiving clozapine were compared with 50 patients in the same age group receiving medications other than clozapine. Presence of constipation was ascertained using the World Gastroenterology Organization Practice Guidelines definition. The severity of constipation was assessed using Constipation Assessment Scale and Bristol Stool Form Scale, and anticholinergic burden was assessed using Anticholinergic Burden Scale. RESULTS: Among clozapine-treated patients, 28 (56%) had constipation as compared with 11 (22%) in the control subjects (P < 0.001); the odds of developing constipation was 4.5 (95% confidence interval, 1.9-10.8). Kaplan-Meier survival analysis showed median time to onset of constipation in clozapine-treated patients was 60 days (SE, 13.1 days; 95% confidence interval, 34.3-85.7 days) and median dose of clozapine was 300 mg/d (interquartile range, 312 mg/d). Clozapine group had high Constipation Assessment Scale scores (P = 0.005, Cohen d = 1.17) and higher prevalence of types 1 and 2 Bristol stool types (Fisher exact P = 0.005, Cramer V = 0.59). CONCLUSIONS: Constipation was prevalent in more than half of patients receiving clozapine, which was severe and took longer time for recovery. Limitations include using a hospital-based sample and that dietary habits and lifestyle factors were not studied. PMID- 29257786 TI - Efficacy and Acceptability of Cariprazine in Acute Exacerbation of Schizophrenia: Meta-Analysis of Randomized Placebo-Controlled Trials. AB - PURPOSE: The purpose of this study was to assess the efficacy and acceptability of cariprazine treatment in acute exacerbation of schizophrenia. METHODS: This review included randomized controlled trials of patients with acute exacerbation of schizophrenia in relation to efficacy and acceptability. The efficacy outcomes were assessed by pooling standardized mean differences (SMDs) calculated from the difference in the reduction in the mean of the Positive and Negative Syndrome Scale (PANSS) total score, PANSS positive and negative scores, and response rate. The primary acceptability outcomes were determined by pooling the risk ratios (RRs) of discontinuation for any reason, the incidence of serious adverse events, and treatment emergent events. FINDINGS: Four randomized controlled trials consisting of 1843 patients met all inclusion and exclusion criteria. Efficacy analysis showed significant positive effects in relation to cariprazine therapy (SMD: -0.37, P < 0.00001 for PANSS total score change; SMD: -0.32, P < 0.00001 for PANSS positive score change; SMD: -0.32, P < 0.0001 for PANSS negative score change; RR, 1.41; 95% confidence interval [CI], 1.19-1.67; P < 0.0001 for response rate). For primary acceptability outcomes, less patients taking cariprazine discontinued treatment for any reason compared with patients receiving placebo (RR, 0.90; 95% CI, 0.78-1.04; P = 0.16). Significantly less patients on cariprazine had serious adverse events during the double-blind treatment period compared with patients taking placebo (RR, 0.55; 95% CI, 0.34 0.89; P = 0.01). Significantly more patients on cariprazine had treatment emergent events compared with those receiving placebo (RR, 1.10; 95% CI, 1.03 1.18; P = 0.006). IMPLICATIONS: Results suggest that cariprazine may be an effective and acceptable treatment for schizophrenia and future research is warranted. PMID- 29257787 TI - Fat Distribution in Schizophrenia Patients: A Pilot Study Comparing First- and Second-Generation Antipsychotics. AB - BACKGROUND: Introduction of second-generation antipsychotics (SGAs) has reduced neurologic toxicity but are associated with increased weight gain and obesity. The objective of this pilot study is to compare the effects of first-generation antipsychotics (FGAs) and SGAs in patients with schizophrenia on body fat and presumed concomitant metabolic parameters. METHODS: Study compared schizophrenia nondiabetic men treated with FGAs (group 1, n = 5) and men treated with SGAs (group 2, n = 9). Each subject completed psychiatric and endocrine evaluation including severity of psychiatric symptoms, adverse effects, body weight, body composition, and measurements of glucose, insulin, adipokines, and inflammatory markers. Student t test was used for statistical analysis. RESULTS: Men treated with FGAs had a lower mean body mass index with a trend toward statistical significance (25.3 +/- 1.4 vs 29.3 +/- 1.7, P = 0.06). Treatment with FGAs was associated with lower waist/height ratio (0.55 +/- 0.02 vs 0.62 +/- 0.02, P = 0.036) and android fat mass index (0.62 +/- 0.01 vs 0.96 +/- 0.1, P = 0.03). Homeostasis Model Assessment for insulin resistance values were suggestive of significantly lower peripheral insulin resistance in men treated with FGAs (0.92 +/- 0.15 vs 2.3 +/- 0.34, P = 0.014). CONCLUSIONS: The results of this study are significant for decreased peripheral insulin resistance in men treated with SGAs in a setting of no significant age difference and only a trend toward higher body mass index, but consistent documentation of increased abdominal fat by 3 different methodologies. Future studies involving larger number of subjects are warranted to verify the present findings. PMID- 29257788 TI - Young Researchers and Young Clinicians Should Not Pay Much Attention to the Journal Impact Factor When Selecting a Journal for Publishing Articles: Comment on the Editorial "The Impact Non-Factor" by Greenblatt and Shader. PMID- 29257789 TI - Trichotillomania Associated With Aripiprazole: A Case Report. PMID- 29257790 TI - Aripiprazole Treatment in a 9-Year-Old Child With OCD and Hypomania Symptoms Possibly Related to Herbal Medicines: A Case Report. PMID- 29257791 TI - Effects of the First Exposure of Antipsychotics on Serum Albumin in Adolescents and Young Adults With First-Episode Schizophrenia. PMID- 29257792 TI - Effect of Lower-Body Resistance Training on Upper-Body Strength Adaptation in Trained Men. AB - Bartolomei, S, Hoffman, JR, Stout, JR, and Merni, F. Effect of lower-body resistance training on upper-body strength adaptation in trained men. J Strength Cond Res 32(1): 13-18, 2018-The aim of this study was to examine the effect of 2 different lower-body strength training schemes on upper-body adaptations to resistance training. Twenty resistance-trained men (4.25 +/- 1.6 years of experience) were randomly assigned to either a high intensity (HI; n = 9; age = 24.9 +/- 2.9 years; body mass = 88.7 +/- 17.2 kg; height = 177.0 +/- 5.6 cm) or a mixed high volume and HI resistance training program (MP; n = 11; age = 26.0 +/- 4.7 years; body mass = 82.8 +/- 9.1 kg; height = 177.54 +/- 5.9 cm). High intensity group followed a HI training for both upper and lower body (4-5 reps at 88%-90% of 1 repetition maximum (1RM)), whereas the MP group performed high volume training sessions focused on muscle hypertrophy for lower body (10-12 reps at 65%-70% of 1-RM) and a HI protocol for the upper body. Maximal strength and power testing occurred before and after the 6-week training program. Analysis of covariance was used to compare performance measures between the groups. Greater increases in MP groups compared with HI groups were observed for bench press 1RM (p = 0.007), bench press power at 50% of 1RM (p = 0.011), and for arm muscle area (p = 0.046). Significant difference between the 2 groups at posttest were also observed for fat mass (p = 0.009). Results indicated that training programs focused on lower-body muscle hypertrophy and maximal strength for upper body can stimulate greater strength and power gains in the upper body compared with HI resistance training programs for both the upper and lower body. PMID- 29257793 TI - Adding Resistance Training to the Standard of Care for Inpatient Substance Abuse Treatment in Men With Human Immunodeficiency Virus Improves Skeletal Muscle Health Without Altering Cytokine Concentrations. AB - Vingren, JL, Curtis, JH, Levitt, DE, Duplanty, AA, Lee, EC, McFarlin, BK, and Hill, DW. Adding resistance training to the standard of care for inpatient substance abuse treatment in men with human immunodeficiency virus improves skeletal muscle health without altering cytokine concentrations. J Strength Cond Res 32(1): 76-82, 2018-Substance abuse and human immunodeficiency virus (HIV) infection can independently lead to myopathy and related inflammatory alterations; importantly, these effects seem to be additive. Resistance training (RT) can improve muscle health in people living with HIV (PLWH), but the efficacy of this intervention has not been examined for PLWH recovering from substance abuse. The purpose of this study was to determine the effect of RT on muscle health markers (mass, strength, and power) and basal circulating biomarkers for men living with HIV undergoing substance abuse treatment. Men living with HIV undergoing 60-day inpatient substance abuse treatment completed either RT (3*/wk) or no exercise training (control) for 6 weeks. Muscle mass, strength, and power, and fasting circulating cytokines (interferon gamma, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-2, IL-4, IL-6, and IL-10), vascular cellular adhesion molecule-1, and cortisol were measured before (PRE) and after (POST) the 6-week period. Both groups received the standard of care for HIV and substance abuse treatment determined by the inpatient facility. Muscle mass, strength, and power increased (p <= 0.05) from PRE to POST for RT but were unchanged for control. No differences were found for circulating biomarkers. Adding RT to the standard of care for substance abuse treatment improved aspects of muscle health (mass, strength, and power) in men living with HIV. These improvements are associated with a lower risk of a number of health conditions. Therefore, practitioners should consider implementing RT interventions as part of substance abuse treatment programs in this population to help manage long-term health. PMID- 29257794 TI - System for Evaluating Powerlifting and Other Multievent Performances. AB - Bishop, PA, Williams, TD, Heldman, AN, and Vanderburgh, PM. System for evaluating powerlifting and other multievent performances. J Strength Cond Res 32(1): 201 204, 2018-Currently, the sport of powerlifting discriminates against bench press scores and uses an empirical equation which is very difficult to update to determine the best lifter within sex. The purpose of this study was to provide a simple and statistically sound method for evaluating powerlifting performance which could also be used with other multievent sports. Data were collected from a large public database on the top 50 (men) or the top 30 (women) individual raw competition scores in each weight class for each of the 3 powerlifting lifts. Mean and SDs were then calculated for each lift and weight class by sex. Powerlifting performance was evaluated by the sum of the 3 z-scores for the 3 lifts divided by 3 (the highest score wins). The z-scores reflect a dimensionless number which can be used to evaluate each lift and the total of the 3 lifts across weight classes and between sexes. Although the mean and SDs should be relatively stable, this computation is transparent and can be readily updated as lifters improve. This system overcomes the bias against bench press and many of the measurement challenges in evaluating athletes in multievent sports, in multiple weight divisions, and between sexes. These findings can benefit coaches and athletes by allowing simpler evaluations of performance and improvement. PMID- 29257795 TI - Halftime Rewarm-up With Intermittent Exercise Improves the Subsequent Exercise Performance of Soccer Referees. AB - Yanaoka, T, Yamagami, J, Kidokoro, T, Kashiwabara, K, and Miyashita, M. Halftime rewarm-up with intermittent exercise improves the subsequent exercise performance of soccer referees. J Strength Cond Res 32(1): 211-216, 2018-This study investigated the effect of halftime rewarm-up (RW) with intermittent exercise on the subsequent exercise performance of soccer referees, determined by the Yo-Yo Intermittent Recovery Test level 1 (Yo-Yo IR1). Using a randomized cross-over design, 10 male referees were required to complete 2 trials. The trials consisted of the Loughborough Intermittent Shuttle Test, halftime, and Yo-Yo IR1 periods. During halftime, participants either rested on a chair (Control) or performed a halftime RW exercise for 15 minutes. The halftime RW protocol comprised 2.15 minutes of seated rest, followed by 2.15 minutes of running at 70% of the maximum heart rate (HRmax)-this cycle of recovery and running was repeated for a total of 13 minutes. The halftime RW protocol started at 1 minute after the commencement of the halftime period and concluded 1 minute before its end. The Yo-Yo IR1 performance, blood glucose, free fatty acids (FFAs), triglycerides (TGs), creatine kinase (CK), and lactate concentrations, the rating of perceived exertion, mean HR, and HRmax were analyzed. The Yo-Yo IR1 performance was higher in the halftime RW trial than in the control trial (3,095 +/- 326 vs. 2,904 +/- 421 m, P <= 0.05). The mean HR and HRmax, blood glucose, FFA, TG, CK, and lactate concentrations did not differ between the trials. The rating of perceived exertion during the halftime RW, but not after the Yo-Yo IR1 period, was higher than that in the control trial. In conclusion, this study showed that halftime RW with intermittent exercise improves the subsequent exercise performance. PMID- 29257796 TI - The Effects of Nordic Walking and Slope of the Ground on Lower Limb Muscle Activity. AB - Psurny, M, Svoboda, Z, Janura, M, Kubonova, E, Bizovska, L, Martinez Lemos, RI, and Abrantes, J. The effects of Nordic walking and slope of the ground on lower limb muscle activity. J Strength Cond Res 32(1): 217-222, 2018-Nordic walking (NW) has proven to be a simple and safe mode of exercise that can be used in various types of sport, recreation, and rehabilitation activities. The aim of this study was to assess the effect of Nordic walking and slope of the ground on lower limb muscle activity. The experimental group consisted of 22 healthy men (aged 22.8 +/- 1.4 years). The subjects walked on a treadmill at a self-selected speed. Two walking conditions (NW and walking) and 2 ground slopes (level ground and uphill walking at an 8% incline) were used. The surface electromyographic signals of the gastrocnemius lateralis, tibialis anterior, vastus medialis, rectus femoris, biceps femoris and gluteus medius were recorded. Nordic walking resulted in increased activity of some lower limb muscles, particularly during the first half of the stance phase, and decreased muscle activity during the first half of the swing phase. Uphill walking elicited increased muscle activity compared with level walking, particularly during the stance phase and the second half of the swing phase during both walking and NW, and the change was more pronounced during walking. We concluded that NW increased muscle activity in the lower extremities compared with walking, particularly on level ground. Increasing the ground slope enhanced the muscle activity to a much greater extent than NW. PMID- 29257797 TI - Inappropriate Methods and Flawed Conclusion in: Can Resistance Training Enhance the Rapid Force Development in Unloaded Dynamic Isoinertial Multijoint Movements? A Systematic Review. PMID- 29257798 TI - Authors' Response. PMID- 29257799 TI - Expression of Coiled-Coil Domain Containing 34 (CCDC34) and its Prognostic Significance in Pancreatic Adenocarcinoma. AB - BACKGROUND Coiled-coil domain containing 34 (CCDC34) promotes cell proliferation and invasive properties in human cancer. The aim of this study was to compare the expression of CCDC34 in pancreatic adenocarcinoma with normal pancreatic tissue, and to evaluate the prognostic significance of CCDC34 expression in patients with pancreatic adenocarcinoma, using bioinformatics. MATERIAL AND METHODS The expression and prognostic value of CCDC34 were initially predicted using Oncomine and The Cancer Genome Atlas (TCGA) databases. Pancreatic adenocarcinoma tissue samples (N=90) and matched normal pancreatic tissues (N=90) were studied using immunohistochemistry to measure CCDC34 protein expression levels. Univariate Kaplan-Meier, and multivariate Cox analysis were used to determine the prognostic role of CCDC34 expression. RESULTS Oncomine and TCGA databases predicted that CCDC34 mRNA expression levels were significantly increased in pancreatic adenocarcinoma compared with normal pancreatic tissues (P<0.05), and that patients with increased CCDC34 mRNA expression levels had significantly lower overall survival (OS) (P=0.031). Immunohistochemistry showed that expression levels of CCDC34 protein in pancreatic adenocarcinoma were significantly increased, compared with normal pancreas (P=0.000). Patients with pancreatic adenocarcinoma with increased expression of tissue CCDC34 had significantly reduced OS compared with patients with low expression (P=0.000). Univariate and multivariate survival analysis showed that increased expression of CCDC34 was an independent predictor of poor prognosis in patients with pancreatic adenocarcinoma (all, P=0.000). CONCLUSIONS Compared with normal pancreas, CCDC34 expression was significantly increased in pancreatic adenocarcinoma, and increased CCDC34 expression was an independent predictor of poor patient prognosis. PMID- 29257800 TI - A Case of Osteonecrosis of the Jaw in a Patient with Crohn's Disease Treated with Infliximab. PMID- 29257801 TI - Response to 'Regression to the mean, apparent data errors, and biologically extraordinary results'. PMID- 29257802 TI - Breaking the Bank. PMID- 29257803 TI - Cosmic Messengers. PMID- 29257804 TI - The Price of Gold. PMID- 29257805 TI - A School Is Not a Military Post. PMID- 29257807 TI - The Future of Money. PMID- 29257806 TI - Ring Cycle. PMID- 29257808 TI - Gluten-Free Wheat? PMID- 29257809 TI - The World Bitcoin Created. PMID- 29257810 TI - Searching for the Dark. PMID- 29257812 TI - Killer Seas. PMID- 29257811 TI - The Evolution of Trust. PMID- 29257813 TI - How Well Do Films Predict Our Tech Future? PMID- 29257815 TI - Recommended. PMID- 29257814 TI - Is Anybody Anywhere? PMID- 29257816 TI - For the Love of Science. PMID- 29257817 TI - War on Science Agencies. PMID- 29257818 TI - Can We Save the Corals? PMID- 29257819 TI - The Toxic Well of Loneliness. PMID- 29257821 TI - Science Is ... PMID- 29257820 TI - Sea Smarts. PMID- 29257822 TI - Quick Hits. PMID- 29257823 TI - Letters. PMID- 29257824 TI - The Deadliest Weapon. PMID- 29257825 TI - How Snakes Came to Slither. PMID- 29257827 TI - War against Ourselves. PMID- 29257826 TI - The Messy Facts about Diet and Inflammation. PMID- 29257828 TI - 50, 100 &150 Years Ago. PMID- 29257829 TI - Cobalt Blues. PMID- 29257830 TI - Low-level toxicity of chemicals: No acceptable levels? AB - Over the past 3 decades, in a series of studies on some of the most extensively studied toxic chemicals and pollutants, scientists have found that the amount of toxic chemical linked with the development of a disease or death-which is central to determining "safe" or "hazardous" levels-is proportionately greater at the lowest dose or levels of exposure. These results, which are contrary to the way the United States Environmental Protection Agency (EPA) and other regulatory agencies assess the risk of chemicals, indicate that we have underestimated the impact of toxic chemicals on death and disease. If widely disseminated chemicals and pollutants-like radon, lead, airborne particles, asbestos, tobacco, and benzene-do not exhibit a threshold and are proportionately more toxic at the lowest levels of exposure, we will need to achieve near-zero exposures to protect public health. PMID- 29257831 TI - Challenges to studying the health effects of early life environmental chemical exposures on children's health. AB - Epidemiological studies play an important role in quantifying how early life environmental chemical exposures influence the risk of childhood diseases. These studies face at least four major challenges that can produce noise when trying to identify signals of associations between chemical exposure and childhood health. Challenges include accurately estimating chemical exposure, confounding from causes of both exposure and disease, identifying periods of heightened vulnerability to chemical exposures, and determining the effects of chemical mixtures. We provide recommendations that will aid in identifying these signals with more precision. PMID- 29257833 TI - [A Stafne cyst. A cyst or not?] AB - In an 80-year-old man, a radiolucent laesion was seen on the panoramic radiograph of the right mandible. The localisation of the radiolucent laesion under the mandibular canal and the additional finding of fatty tissue or submandibular salivary gland in the concavity on the cone beam computed tomography are virtually probative for a Stafne cyst. PMID- 29257832 TI - Communication across the bacterial cell envelope depends on the size of the periplasm. AB - The cell envelope of gram-negative bacteria, a structure comprising an outer (OM) and an inner (IM) membrane, is essential for life. The OM and the IM are separated by the periplasm, a compartment that contains the peptidoglycan. The OM is tethered to the peptidoglycan via the lipoprotein, Lpp. However, the importance of the envelope's multilayered architecture remains unknown. Here, when we removed physical coupling between the OM and the peptidoglycan, cells lost the ability to sense defects in envelope integrity. Further experiments revealed that the critical parameter for the transmission of stress signals from the envelope to the cytoplasm, where cellular behaviour is controlled, is the IM to-OM distance. Augmenting this distance by increasing the length of the lipoprotein Lpp destroyed signalling, whereas simultaneously increasing the length of the stress-sensing lipoprotein RcsF restored signalling. Our results demonstrate the physiological importance of the size of the periplasm. They also reveal that strict control over the IM-to-OM distance is required for effective envelope surveillance and protection, suggesting that cellular architecture and the structure of transenvelope protein complexes have been evolutionarily co optimised for correct function. Similar strategies are likely at play in cellular compartments surrounded by 2 concentric membranes, such as chloroplasts and mitochondria. PMID- 29257834 TI - [The impact of fireworks: the context of facial trauma]. AB - In the Netherlands the general public can legally use fireworks on New Year's Eve. Despite the fact that the public is well aware of the dangers of fireworks, fireworks accidents occur in which the victims suffer a variety of injuries. In addition to burns, injuries to fingers and/or hands are most common. However, injuries to the eye, which can also involve facial trauma, frequently occur as well. Trauma mainly occurs as a result of the destructive effects of the wave of pressure released by the explosion. The best preventive measure would be to prohibit the use of fireworks by amateurs. Until such time, people should be advised to wear protective fireworks glasses when outside so that damage to the eyes from legal fireworks at least can be prevented. PMID- 29257835 TI - [DSQ-13-youth: measuring instrument for patient satisfaction with dental attendance among adolescents, young adults and parents of young children]. AB - The Dental Satisfaction Questionnaire (DSQ) is a questionnaire consisting of 31 items assessing patient satisfaction with dental attendance. By means of factor analysis (principal component analysis), the number of items of the DSQ was reduced to 13, which together constitute the DSQ-13-youth. The first objective was to investigate the psychometric properties of the DSQ-13-youth; the second was to compare the satisfaction scores on the various dimensions between and within subgroups (23-year-olds, 17-year-olds and parents of 5-year-olds). The DSQ 13-youth has 4 domains measuring patient satisfaction with dental attendance. The internal consistency of those domains was high; the correlation between the domains low to moderate and the factor structure was highly congruent in the various subgroups. The differences in satisfaction scores between and within subgroups were small. The DSQ-13-youth is a reliable instrument to assess patient satisfaction with dental attendance among adolescents, young adults and the parents of young children in urban areas. PMID- 29257836 TI - [Incision of the third molar in the Netherlands. Incision tech-niques for the removal of impacted third molars in the mandible.] AB - Various incision techniques to remove impacted third molars in the mandible have been described, for example, the flap incision, the envelope incision, the distal incision and the modified envelope incision. The aim of this study was to record the incision techniques used by oral and maxillofacial surgeons in the Netherlands for the removal of impacted third molars in the mandible. All members of the Dutch Association of Oral and Maxillofacial Surgery (NVMKA) received a questionnaire. In this questionnaire, the surgeons specified their standard incision technique for the removal of, respectively, mesially impacted, upright, or distally impacted mandibular third molars. Of the 323 questionnaires sent, 172 were returned (53,3% response rate). The flap incision and the distal incision were the most frequently used incisions by oral and maxillofacial surgeons (including residents) in the Netherlands. The academic centre seems to have a lasting impact on the preferred way of removing an impacted third molar. It also seems that an oral and maxillofacial surgeon more frequently removes a third molar in the mandible from a sitting position than a resident. PMID- 29257837 TI - [Medicaments and oral healthcare 6. Oral side effects of -medications commonly used by older people]. AB - In the coming decades the western world will experience a double ageing of its population; there will be an increase in both the number of older people and the average age. The increase in life expectancy will also mean more and more older people who suffer from multiple systemic diseases that are treated with medications. At this moment, 45% of those over 65 use 5 or more medications and 20% of those over 75 use as many as 10 or more. The more medications used, the greater the risk of side effects and therefore oral side effects, like symptoms of dry mouth or the development of candidiasis, angioedema, gingival hyperplasia, lichenoid reaction of the oral mucosa, dysgeusia, halitosis and osteonecrosis. Considering the wide range of oral side effects, it is important for dentists to be well aware of the medications being used by older patients as well as having a thorough knowledge of their oral side effects. PMID- 29257838 TI - [A PhD completed. Trauma to the gingiva by oral hygiene aids and oral piercings]. AB - Maintaining healthy teeth and soft oral tissue is important. Clinical research has shown manual toothbrushes with end-rounded filaments to cause significantly less gingival abrasions than those without end-rounding. Tapered filaments are an alternative to end-rounded filaments, but there is no solid evidence for their effectiveness. For the interdental spaces that the toothbrush doesn't reach, the use of special oral hygiene aids is advised. Clinical studies of gingivitis patients have shown that both interdental brushes and plastic-rubber bristles reduce gingivitis after 4 weeks of use. Plastic-rubber bristles result in a significant improvement in the tendency for interdental bleeding compared with interdental brushes, and they cause less abrasion of the gingiva. Other factors that can potentially traumatise soft and hard oral tissue are oral piercings. Wearing oral piercings is not without risk. Tongue and lip piercings are associated with the risk of gingival recession, and tongue piercings are associated with tooth fractures. To prevent the risk of complications, patients should be discouraged from wearing oral piercings. PMID- 29257839 TI - PERITONEAL ADHESIONS TYPE I, III AND TOTAL COLLAGEN ON POLYPROPYLENE AND COATED POLYPROPYLENE MESHES: EXPERIMENTAL STUDY IN RATS. AB - BACKGROUND: Hernia correction is a routinely performed treatment in surgical practice. The improvement of the operative technique and available materials certainly has been a great benefit to the quality of surgical results. The insertion of prostheses for hernia correction is well-founded in the literature, and has become the standard of treatment when this type of disease is discussed. AIM: To evaluate two available prostheses: the polypropylene and polypropylene coated ones in an experimental model. METHODS: Seven prostheses of each kind were inserted into Wistar rats (Ratus norvegicus albinus) in the anterior abdominal wall of the animal in direct contact with the viscera. After 90 days follow-up were analyzed the intra-abdominal adhesions, and also performed immunohistochemical evaluation and videomorphometry of the total, type I and type III collagen. Histological analysis was also performed with hematoxylin-eosin to evaluate cell types present in each mesh. RESULTS: At 90 days the adhesions were not different among the groups (p=0.335). Total collagen likewise was not statistically different (p=0.810). Statistically there was more type III collagen in the coated polypropylene group (p=0.039) while type I was not different among the prostheses (p=0.050). The lymphocytes were statistically more present in the polypropylene group (p=0.041). CONCLUSION: The coated prosthesis was not different from the polypropylene one regarding the adhesion. Total and type I collagen were not different among the groups, while type III collagen was more present on the coated mesh. There was a greater number of lymphocytes on the polypropylene mesh. PMID- 29257840 TI - ANALYSIS OF DOUBLE BALLOON ENTEROSCOPY: INDICATIONS, FINDINGS, THERAPEUTIC AND COMPLICATIONS. AB - BACKGROUND: The double balloon enteroscopy is an important method for the endoscopic approach of the small bowel that provides diagnosis and therapy of this segment's disorders, with low complication rate. AIM: Analysis of patients undergoing double balloon enteroscopy. The specific objectives were to establish the indications for this method, evaluate the findings by the double balloon enteroscopy, analyze the therapeutic options and the complications of the procedure. METHODS: It is a retrospective analysis of 65 patients who underwent double balloon enteroscopy. RESULTS: Sixty-five procedures were performed in 50 patients, 63.1% were women and 36.9% were men. The mean age was 50.94 years. The main indication it was gastrointestinal bleeding, followed by abdominal pain and Crohn's disease. Most procedures were considered normal. Polyps were the most prevalent finding, followed by angioectasias and duodenitis. In 49.2% of the cases, one or more therapeutic procedures were performed, (biopsy was the most prevalent). There was only one case of acute pancreatitis, which was treated clinically. CONCLUSION: The enteroscopy is good and safe method for the evaluation of the small bowel, and its main indications are gastrointestinal bleeding and abdominal pain. It has low complications rates and reduces the necessity of surgery. PMID- 29257841 TI - DO THE RADIOLOGICAL CRITERIA WITH THE USE OF RISK FACTORS IMPACT THE FORECASTING OF ABDOMINAL NEUROBLASTIC TUMOR RESECTION IN CHILDREN? AB - BACKGROUND: The treatment of neuroblastoma is dependent on exquisite staging; is performed postoperatively and is dependent on the surgeon's expertise. The use of risk factors through imaging on diagnosis appears as predictive of resectability, complications and homogeneity in staging. AIM: To evaluate the traditional resectability criteria with the risk factors for resectability, through the radiological images, in two moments: on diagnosis and in pre-surgical phase. Were analyzed the resectability, surgical complications and relapse rate. METHODS: Retrospective study of 27 children with abdominal and pelvic neuroblastoma stage 3 and 4, with tomography and/or resonance on the diagnosis and pre-surgical, identifying the presence of risk factors. RESULTS: The mean age of the children was 2.5 years at diagnosis, where 55.6% were older than 18 months, 51.9% were girls and 66.7% were in stage 4. There was concordance on resectability of the tumor by both methods (INSS and IDRFs) at both moments of the evaluation, at diagnosis (p=0.007) and post-chemotherapy (p=0.019); In this way, all resectable patients by IDRFs in the post-chemotherapy had complete resection, and the unresectable ones, 87.5% incomplete. There was remission in 77.8%, 18.5% relapsed and 33.3% died. CONCLUSIONS: Resectability was similar in both methods at both pre-surgical and preoperative chemotherapy; preoperative chemotherapy increased resectability and decreased number of risk factors, where the presence of at least one IDRF was associated with incomplete resections and surgical complications; relapses were irrelevant. PMID- 29257842 TI - IMMUNOMODULATING EFFECTS OF THE PURIFIED HEV B 13 FRACTION ON SEPTIC RATS. AB - BACKGROUND: Sepsis is a potentially life-threatening complication of an infection that occurs when chemicals released into the bloodstream to fight the infection trigger inflammatory responses throughout the body, especially in the acute phase of the disease, producing excessive pro-inflammatory cytokines, leading to multiple organ injury and death. The Hev b 13 fraction has demonstrated biological activity capable of inducing IL-10 production and shrinking inflammatory disease lesions. AIM: To investigate the immunomodulating effects of the Hev b 13 fraction on septic rats. METHODS: Acinetobacter baumannii was injected into the peritoneal cavity of the animals after sustaining a lesion in the pancreas, with the stomach as an entry point. After 10 h of infection, they were euthanized for blood and lung collection, followed by total and differential leukocyte count, determination of cytokine level and histopathological analysis. RESULTS: Administering a single dose of the Hev b 13 fraction 2 h after sepsis induction significantly decreased total leukocyte count. Higher IL-10 and IL-4 and lower IL-6 production shrank the lung tissue lesions compared to the control groups. CONCLUSION: The Hev b 13 fraction exhibits an anti-inflammatory tendency, with potential for sepsis treatment. PMID- 29257843 TI - TISSUE EXPRESION OF THE GENES MUTYH AND OGG1 IN PATIENTS WITH SPORADIC COLORECTAL CANCER. AB - BACKGROUND: MTUYH and OGG1 genes have importance in the base excision repair systems of oxidized DNA bases. Modification of the tissue expression of these genes is related to the increased risk of developing colorectal cancer. AIM: To evaluate the tissue expression of MUTYH and OGG1 comparing normal and neoplastic tissues of patients with sporadic colorectal cancer and to correlate it with clinical and histopathological variables. METHOD: MUTYH and OGG1 tissue expression was quantified by RT-PCR in patients with colorectal cancer and the values were compared in normal and neoplastic tissues. MUTYH and OGG1 expression was measured and normalized to the constitutive 18S gene. The level of expression of both genes was correlated with the variables: age, gender, tumor location, size of the tumor, histological type, degree of cell differentiation, invasion depth in the intestinal wall, angiolymphatic infiltration, lymph node involvement and TNM staging. RESULTS: Was found downregulation of both genes in neoplastic when compared to normal tissue. There was downregulation of the MUTYH in larger tumors and in patients with angiolymphatic invasion. Tumors with more advanced TNM stages (III and IV) presented downregulation of both genes when compared to those with earlier stages (I and II). CONCLUSION: The MUTYH and OGG1 genes present downregulation in the more advanced stages of colorectal cancer. PMID- 29257844 TI - PROGNOSTIC FACTORS FOR LEFT COLECTOMY FOR COLON CANCER: A TEN YEARS EXPERIENCE OF A SINGLE UNIVERSITY INSTITUTION. AB - BACKGROUND: Colorectal cancer is the third most common cancer in the world. In Brazil, it is the leading cause of cancer in the gastrointestinal tract. AIM: To evaluate the preoperative, perioperative, and postoperative risk factors for recurrence and overall survival of patients with left colon cancer operated during a ten-year period. METHODS: Patients with left colon cancer surgically treated underwent clinical preoperative workout and cancer staging. The following factors were studied: gender, age, tumor location, T stage, lymph node yield, N stage, M stage, histological type, and tumor differentiation. It was analyzed the influence in five-year overall survival. RESULTS: A total of 173 patients underwent left colectomy for colon cancer. There was a slight predominance of male gender with 50.9%. The mean age was 60.8 years old. Fifteen (8.7%) tumors were located at splenic flexure, 126 (72.8%) at sigmoid colon, and 32 (18.5%) at descending colon. The median length of hospital stay was seven days. Mean survival was 47.5 months. At 60 months seven patients (4%) lost follow-up, 38 patients (21.9%) deceased and 135 patients (78%) were alive. Overall survival time was 48 months. CONCLUSION: Advanced stages (T3-T4, N+ and M+) were the only factors associated with poor long term survival in left colon cancer. PMID- 29257845 TI - STEM CELLS HEMATOPOIETIC NICHES AND INFLAMMATORY RESPONSE TO DIFFERENT SYNTHETIC PROSTHESIS IMPLANTED IN RAT WITH INCISIONAL HERNIAS. AB - BACKGROUND: Extramedullary hematopoiesis depends on complex pathophysiological mechanisms linked to hematopoietic stem cells and the proteins considered mediators of the inflammation. The identification of hematopoietic cells outside bone marrow in the adult is an occurrence that can occasionally follows the inflammatory response, was considered a secondary occurrence, but current biomolecular studies have changed that concept. AIM: Describe the presence of clusters of precursor cells of platelets (megakaryocytes), and cells of the inflammatory response in the abdominal wall and spleen of rats with experimentally induced incisional hernias and repaired with different synthetic prostheses. METHODS: Twenty-five rats with incisional hernias previously performed, were divided into groups of five animals each: Group 1, repair of the hernia defect without prosthetic implant; Group 2, repair with polypropylene prosthesis; Group 3, repair using polypropylene with low weight; Group 4, the use of polypropylene and polyglecaprone prosthesis; Group 5, of polypropylene and polyglactin prosthesis. All prostheses were cut in rhombus format with area 2,625 cm2. The animals were reoperated after 10 days, the abdominal walls were removed with the viscera attached to them and the material was processed for histological study. RESULTS: Megakaryocyte niches in the abdominal wall and spleen, occasionally removed together with the adhesions produced in animals with implantation of prostheses and significant inflammatory reaction. CONCLUSION: The intense inflammatory reaction due to the prostheses with polypropylene in their composition was disproportionate to the expected response, indicating that further studies should be accomplished including immunophenotyping evaluation and specific panels of monoclonal antibodies to better understand the findings. PMID- 29257846 TI - POLYMORPHISM OF THE COX-2 GENE AND SUSCEPTIBILITY TO COLON AND RECTAL CANCER. AB - BACKGROUND: The colorectal neoplasm is the fourth most common malignancy among males and the third among females. In the Western world is estimated that 5% of the population will develop it, making this disease a major public health problem. AIM: To analyze the prevalence of the polymorphism -765G / C region of the COX-2 gene in colorectal cancer patients compared to a control group, analyzing the possible association between this polymorphism and susceptibility to colorectal cancer. METHOD: This is a case-control study with 85 participants. Were selected 25 with colorectal cancer (case group) and 60 participants without colorectal neoplasia (control group). The molecular genetic analysis was perform to identify the polymorphism -765G / C COX2 gene with standard literature technique. In addition, patient's clinical and pathological data were analyzed. RESULTS: There was a light increase in prevalence between men in the case group, although this difference was not statistically significant. The results showed a high prevalence of GC and CC genotype in individuals with colorectal cancer, demonstrating an association between the presence of the polymorphism in the COX2 gene and susceptibility to colorectal cancer in this pattern (p=0.02). Similarly, there was also difference in allele frequencies in the groups. When patients with cancer were separated by tumor location, there was a higher prevalence of polymorphism in the left colon (p=0.02). CONCLUSION: The polymorphism in the COX2 gene is associated with increased susceptibility to colorectal cancer, specially rectosigmoid tumors. PMID- 29257847 TI - PPH AND BIOLOGICAL GLUE IN PATIENTS WITH HIGH RISK OF BLEEDING IN STAPLED HEMORRHOIDOPEXY. AB - BACKGROUND: Stapled hemorrhoidopexy is a common treatment for grade 3 hemorrhoids. Patients with conditions that increase the risk of bleeding, as cardiac stents usage with clopidogrel bissulfate and liver cirrhosis, should receive an extra care in surgical procedures due to the high risk of bleeding. For this reason and for patients with third degree hemorrhoids we propose the use of stapled hemorrhoidopexy followed by the use of biological glue. AIM: Assess surgical outcomes in patients with hemorrhoids and high risk of bleeding submitted to stapled hemorrhoidopexy followed by biological glue. METHODS: Between 2005 and 2015, 22 patients were analyzed, in a retrospective cohort study. RESULTS: From 22 patients submitted to stapled hemorrhoidopexy followed by the use of biological glue, only one (4.5%) presented bleeding in the surgical postoperative. Patients do not have any other complications and pain in the postoperative period. The median (IQR) operation duration was 55 (12) min and the median (IQR) length of hospital stay after surgery was 3 (2) days. CONCLUSION: Patients with high risk of bleeding submitted to stapled hemorrhoidopexy followed by the use of biological glue presented very low rates of bleeding in the postoperative period. PMID- 29257848 TI - FUNCTIONAL AND CELLULAR EVALUATION OF THE LIVER AFTER LOW-POWER LASER STIMULATION DURING SURGERY. AB - BACKGROUND: Partial hepatectomy is a surgical intervention of the liver that can trigger its regenerative process, where the residual lobes deflagrate a compensatory hyperplasia, causing its restoration almost to the original volume. Nevertheless, depending on the extent of liver damage its regeneration might be impaired. The low-power laser has been studied with beneficial results. AIM: To investigate the possible functional and mutagenic damage arising from the use of low-power laser used in liver regeneration after partial hepatectomy. METHODS: Fifteen male adult Wistar rats were hepatectomizated in 70% and laser irradiated or not with dose of 70 J/cm2, 650 nm, 100 mW, directly on the remaining liver, during the perioperative period. These animals were divided into four groups: G1 (control, 7 days); G2 (laser, 7 days); G3 (control, 14 days); G4 (laser, 14 days). Were analyzed the liver weight; number of hepatocytes; deposition of collagen fibers; liver function tests: serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase, bilirubin and micronucleus test in peripheral blood erythrocyte. RESULTS: The liver weight was greater in G3 and G4 (p=0.001 and p=0.002) compared to other groups. The deposition of collagen fibers in G1 was statistically higher than the other groups (p=0.01). In tests of liver function and micronucleus test was not found significant differences between the studied groups. CONCLUSION: Low-power laser stimulation did not cause loss of liver function or mutagenic damage. PMID- 29257849 TI - BILIARY COMPLICATIONS AFTER LIVER TRANSPLANTATION. AB - BACKGROUND: Biliary reconstitution has been considered the Achilles's heel of liver transplantations due to its high rate of postoperative complications. AIM: To evaluate the risk factors for occurrence of biliary strictures and leakages, and the most efficient methods for their treatment. METHOD: Of 310 patients who underwent liver transplantation between 2001 and 2015, 182 medical records were retrospectively analyzed. Evaluated factors included demographic profile, type of transplantation and biliary reconstitution, presence of vascular and biliary complications, their treatment and results. RESULTS: 153 (84.07%) deceased donor and 29 (15.93%) living donor transplantations were performed. Biliary complications occurred in 49 patients (26.92%): 28 strictures (15.38%), 14 leakages (7.7%) and seven leakages followed by strictures (3.85%). Hepatic artery thrombosis was present in 10 patients with biliary complications (20.4%; p=0,003). Percutaneous and endoscopic interventional procedures (including balloon dilation and stent insertion) were the treatment of choice for biliary complications. In case of radiological or endoscopic treatment failure, surgical intervention was performed (biliodigestive derivation or retransplantation (32.65%). Complications occurred in 25% of patients treated with endoscopic or percutaneous procedures and in 42.86% of patients reoperated. Success was achieved in 45% of patients who underwent endoscopic or percutaneous procedures and in 61.9% of those who underwent surgery. CONCLUSION: Biliary complications are frequent events after liver transplantation. They often require new interventions: endoscopic and percutaneous procedures at first and surgical treatment when needed. Hepatic artery thrombosis increases the number of biliary complications. PMID- 29257850 TI - EVALUATION OF ENEMAS CONTAINING SUCRALFATE IN TISSUE CONTENT OF MUC-2 PROTEIN IN EXPERIMENTAL MODEL OF DIVERSION COLITIS. AB - BACKGROUND: The effects of topical application of sucralfate (SCF) on the tissue content of MUC-2 protein have not yet been evaluated in experimental models of diversion colitis. AIM: To measure the tissue content of MUC-2 protein in the colonic mucosa diverted from fecal stream submitted to the SCF intervention. METHODS: Thirty-six rats underwent derivation of intestinal transit through proximal colostomy and distal mucous fistula. The animals were divided into three groups which were submitted application of enemas with saline, SCF 1 g/kg/day and SCF 2 g/kg/day. Each group was divided into two subgroups, according to euthanasia was done after two or four weeks. The colitis diagnosis was established by histopathological study and the inflammatory intensity was evaluated by previously validated scale. The MUC-2 protein was identified by immunohistochemistry and the tissue content was measured computerized morphometry). RESULTS: The application of enemas with SCF in the concentration of 2 g/kg/day reduced inflammatory score of the segments that were diverted from fecal stream. The content of MUC-2 in diverted colon of the animals submitted to the intervention with SCF, independently of intervention period and the used concentration, was significantly greater than animals submitted to the application of enemas containing saline (p< 0.01). The content of MUC-2 after the intervention with SCF in the concentration of 2 g/kg/day was significantly higher when compared to the animals submitted to the application containing SCF at concentration of 1.0 g/kg/day (p<0.01). The tissue content of MUC-2 reached the highest values after intervention with SCF in the concentration of 2 g/kg/day for four weeks (p<0.01). Conclusion: The preventive application of enemas containing SCF reduces the inflammatory score and avoids the reduction of tissue content of MUC-2, suggesting that the substance is a valid therapeutic strategy to preserve the mucus layer that covers the intestinal epithelium. PMID- 29257851 TI - THE VULKAN TECHNIQUE: A NOVEL OSTOMY-CLOSURE TECHNIQUE THAT REDUCES COMPLICATIONS AND OPERATIVE TIMES. AB - BACKGROUND: Ostomy reversals remain at high risk for surgical complications. Indeed, surgical-side infections due to bacterial contamination of the stoma lead to revision surgery and prolonged hospital stay. AIM: To describe the novel vulkan technique of ostomy reversal that aims to reduce operative times, surgical complications, and readmission rates. METHODS: Ostomy closure was performed using the vulkan technique in all patients. This technique consists of external intestinal closure, circular skin incision and adhesiolysis, re-anastomosis, and closure of the subcutaneous tissue in three layers, while leaving a small secondary wound through which exudative fluid can be drained. The medical records of enterostomy patients were retrospectively reviewed from our hospital database. RESULTS: The vulkan technique was successfully performed in 35 patients mainly by resident surgeons with <5 years of experience (n=22; 62.8%). The ileostomy and colostomy closure times were 53 min (interquartile range [IQR], 41-68 min; n=22) and 136 min (IQR: 88-188 min; n=13; p<0.001), respectively. The median hospital stay was seven days (IQR: 5-14.5 days); the length of hospital stay did not differ between ileostomy and colostomy groups. Major surgical complications occurred only in patients who underwent colostomy closure following the Hartmann procedure (n=2); grade>=IIIb according Clavien-Dindo classification. CONCLUSION: The vulkan technique was successfully applied in all patients with very low rates of surgical-site infections. Off note, residents with limited surgical experience mainly performed the procedure while operating time was less than one hour. PMID- 29257852 TI - LAPAROENDOSCOPIC TRANSGASTRIC RESECTION OF SUBEPITHELIAL JUXTACARDIAC TUMORS. AB - BACKGROUND: With a prevalence of 0.4-3.5%, subepithelial lesions of the upper digestive tract are discovered during endoscopic procedures. Treatment depends on etiological and pathophysiological information, ability to diagnose and the different technical resources available. AIM: To demonstrate the effectiveness of a surgical technique that combines endoscopy and videolaparoscopy in the transgastric resection of subepithelial juxtacardic lesions. METHOD: The patients were assisted with a technical combination between endoscopy and laparoscopy. After diagnosis of subepithelial tumor, intraoperative endoscopy was performed after pneumoperitoneum and placement of laparoscopic tweezers. Through endoscopy, the following steps were performed: demarcation of surgical margins, visualization of the intragastric image for the laparoscopic procedure and removal of the surgical specimen. By laparoscopy the following steps were performed: intragastric intra-abdominal access, resection of the part and closure of the gaps. RESULTS: This technique was applied in two cases in order to evaluate its initial results. There were two videolaparoendoscopic resections of juxtacardiac gastric tumors of the posterior wall. Both had their endoscopic diagnosis confirmed. After laparoendoscopic and tomographic and/or ecoendoscopic diagnostic complementation and preoperative performance, the laparoendoscopic procedure was indicated. The patients had a good recovery, with a short hospitalization time and no complications. CONCLUSION: The combined use of videolaparoscopy and endoscopy is a safe and effective technique for transgastric resection of juxtacardiac subepithelial lesions. It may be important for definitive diagnosis of the tumor. PMID- 29257853 TI - LAPAROSCOPIC UNCINATECTOMY: A MORE CONSERVATIVE APPROACH TO THE UNCINATE PROCESS OF THE PANCREAS. AB - BACKGROUND: The isolate resection of the uncinate process of the pancreas is a rarely described procedure but is an adequate surgery to treat benign and low grade malignancies of the uncinate process of the pancreas. AIM: To detail laparoscopic uncinatectomy technique and present the initial results. METHOD: Patient is placed in supine position with the surgeon between legs. Three 5-mm, one 10-mm and one 12-mm trocars were used to perform the isolated resection of the uncinate process of the pancreas. Parenchymal transection is performed with harmonic scalpel. A hemostatic absorbable tissue is deployed over the area previously occupied by the uncinate process. A Waterman drain is placed. RESULT: This procedure was applied to an asymptomatic 62-year-old male with biopsy proven low grade neuroendocrine tumor of the pancreatic uncinate process. A laparoscopic pancreaticoduodenectomy was proposed. During the initial surgical evaluation, intraoperative sonography was performed and disclosed that the lesion was a few millimeters away from the Wirsung. The option was to perform a laparoscopic uncinatectomy. Postoperative period until full recovery was swift and uneventful. CONCLUSION: Laparoscopic uncinatectomy is a safe and efficient procedure when performed by surgical teams with large experience in minimally invasive biliopancreatic procedures. PMID- 29257854 TI - GASTRIC NEUROENDOCRINE TUMOR: REVIEW AND UPDATE. AB - INTRODUCTION: The frequency of gastric neuroendocrine tumors is increasing. Reasons are the popularization of endoscopy and its technical refinements. Despite this, they are still poorly understood and have complex management. AIM: Update the knowledge on gastric neuroendocrine tumor and expose the future perspectives on the diagnosis and treatment of this disease. METHOD: Literature review using the following databases: Medline/PubMed, Cochrane Library and SciELO. Search terms were: gastric carcinoid, gastric neuroendocrine tumor, treatment. From the selected articles, 38 were included in this review. RESULTS: Gastric neuroendocrine tumors are classified in four clinical types. Correct identification of the clinical type and histological grade is fundamental, since treatment varies accordingly and defines survival. CONCLUSION: Gastric neuroendocrine tumors comprise different subtypes with distinct management and prognosis. Correct identification allows for a tailored therapy. Further studies will clarify the diseases biology and improve its treatment. PMID- 29257855 TI - OPEN, LAPAROSCOPIC, AND ROBOTIC-ASSISTED HEPATECTOMY IN RESECTION OF LIVER TUMORS: A NON-SYSTEMATIC REVIEW. AB - INTRODUCTION: Several factors have made hepatectomy an increasingly safe surgery and new drugs allowed surgical treatment for patients who initially were not candidates for resection. Lesions often require resection, which can be performed by open, laparoscopic, or robotic assisted hepatectomy. AIM: Compare the surgical techniques in open, laparoscopic, and robotic assisted hepatectomy for resection of liver tumors. METHODS: Literature review based on scientific papers published on Lilacs/Pubmed/Scielo in the last 17 years regarding the indications of these techniques for liver tumor resections and on papers comparing such techniques. RESULTS: The comparative study shows the benefits of laparoscopic surgery over open surgery, such as smaller incisions, less postoperative pain, shorter recovery time, smaller immune and metabolic response, and quicker restoration of oral ingestion as well as lower morbidity rates. However, the need for a specialized surgical team and the reduction in handling area still remain as disadvantages in the laparoscopic technique. It is yet not clear whether robotic assistance presents considerable benefits over the laparoscopic technique considering that high acquisition and maintenance costs are limiting factors. CONCLUSION: Despite all challenges, laparoscopic hepatectomy presents many benefits over open surgery. The robotic assisted technique is still in evolution as many centers in the world perform hepatic resections with the platforms but only after a thorough patient selection. Thus, laparoscopy stands as the best option, unless there is some contraindication to the procedure. PMID- 29257856 TI - NEISSERIA SUBFLAVA PERITONITIS: CASE REPORT. PMID- 29257857 TI - GASTRIC PERFORATION ASSOCIATED WITH ACUTE PANCREATITIS: CASE REPORT. PMID- 29257858 TI - Erratum. AB - [This corrects the article doi: 10.1590/0102-6720201600S10031] [This corrects the article doi: 10.1590/S0102-67202015000100010] [This corrects the article doi: 10.1590/S0102-67202015000200017] [This corrects the article doi: 10.1590/S0102 6720201500040012] [This corrects the article doi: 10.1590/S0102 6720201400S100013]. PMID- 29257859 TI - Interrogating Pd(II) Anion Metathesis Using a Bifunctional Chemical Probe: A Transmetalation Switch. AB - Ligand metathesis of Pd(II) complexes is mechanistically essential for cross coupling. We present a study of halide->OH anion metathesis of (Ar)PdII complexes using vinylBPin as a bifunctional chemical probe with Pd(II)-dependent cross coupling pathways. We identify the variables that profoundly impact this event and allow control to be leveraged. This then allows control of cross-coupling pathways via promotion or inhibition of organoboron transmetalation, leading to either Suzuki-Miyaura or Mizoroki-Heck products. We show how this transmetalation switch can be used to synthetic gain in a cascade cross-coupling/Diels-Alder reaction, delivering borylated or non-borylated carbocycles, including steroid like scaffolds. PMID- 29257860 TI - Identification of [18F]TRACK, a Fluorine-18-Labeled Tropomyosin Receptor Kinase (Trk) Inhibitor for PET Imaging. AB - Changes in expression and dysfunctional signaling of TrkA/B/C receptors and oncogenic Trk fusion proteins are found in neurological diseases and cancers. Here, we describe the development of a first 18F-labeled optimized lead suitable for in vivo imaging of Trk, [18F]TRACK, which is radiosynthesized with ease from a nonactivated aryl precursor concurrently combining largely reduced P-gp liability and improved brain kinetics compared to previous leads while displaying high on-target affinity and human kinome selectivity. PMID- 29257861 TI - Impact of Conventional and Integrated Management Systems on the Water-Soluble Vitamin Content in Potatoes, Field Beans, and Cereals. AB - The reduction of the environmental footprint of crop production without compromising crop yield and their nutritional value is a key goal for improving the sustainability of agriculture. In 2009, the Balruddery Farm Platform was established at The James Hutton Institute as a long-term experimental platform for cross-disciplinary research of crops using two agricultural ecosystems. Crops representative of UK agriculture were grown under conventional and integrated management systems and analyzed for their water-soluble vitamin content. Integrated management, when compared with the conventional system, had only minor effects on water-soluble vitamin content, where significantly higher differences were seen for the conventional management practice on the levels of thiamine in field beans (p < 0.01), Spring barley (p < 0.05), and Winter wheat (p < 0.05), and for nicotinic acid in Spring barley (p < 0.05). However, for all crops, variety and year differences were of greater importance. These results indicate that the integrated management system described in this study does not significantly affect the water-soluble vitamin content of the crops analyzed here. PMID- 29257862 TI - Inheritance of Photochromic Properties of Nitro-Substituted and Halogenated Spiropyrans Containing the Pyrrolidino[60]fullerene. AB - The photophysical and isomerization properties of hybrid molecular compounds that consist of photochromic nitro-substituted and halogenated spiropyran derivatives bonded to the surface of the [60]fullerene cage through the pyrrolidine bridge were investigated using various functionals and basis sets of TD-DFT and semiempirical quantum-chemical approaches. The role of npi* states formed by the lone pairs of substituents in changing of the electronic structure and photochromic properties of spiropyran derivatives was evaluated. The Spipi(spiropyran) -> intermediate npi* states -> Spipi(merocyanine) channel for phototransformation of the hybrid compound containing a nitro-substituted spiropyran moiety was established and compared with similar systems of halogenated spiropyrans attached to the [60]fullerene bulk where photoinduced isomerization does not process due to high probability of internal conversion from the excited electronic state localized on the spiropyran fragment to the states of the pyrrolidino[60]fullerene. PMID- 29257863 TI - Asymmetric Organocatalytic Approach to 2,4-Disubstituted 1,2,3-Triazoles by N2 Selective Aza-Michael Addition. AB - Despite the fact that N1-functionalization of NH-1,2,3-triazoles has been known for several decades, enantioselective variants of this reaction have only recently been developed. Nevertheless, functionalization at the N2-position of NH 1,2,3-triazoles leading to optically active N2-substituted triazoles is not yet developed. In this article, we report, for the first time, the asymmetric aza Michael reaction of 4-aryl-NH-1,2,3-triazoles to cyclic enones under the catalytic influence of chiral bifunctional thiourea organocatalysts for the enantioselective generation of 2,4-disubstituted 1,2,3-triazoles. The cinchonine derived thiourea catalyst III worked efficiently in the current transformation to produce N2-functionalized 1,2,3-triazoles as major products in optical yields up to >99.9% along with minor 1,4-disubstitued 1,2,3-triazoles. PMID- 29257864 TI - Rapamycin Confers Neuroprotection against Colistin-Induced Oxidative Stress, Mitochondria Dysfunction, and Apoptosis through the Activation of Autophagy and mTOR/Akt/CREB Signaling Pathways. AB - Our previous studies showed that colistin-induced neurotoxicity involves apoptosis and oxidative damage. The present study demonstrates a neuroprotective effect of rapamycin against colistin-induced neurotoxicity in vitro and in vivo. In a mouse model, colistin treatment (18 mg/kg/d; 14 days) produced marked neuronal mitochondria damage in the cerebral cortex and increased activation of caspase-9 and -3. Rapamycin cotreatment (2.5 mg/kg/d) effectively reduced this neurotoxic effect. In an in vitro mouse neuroblastoma-2a (N2a) cell culture model, rapamycin pretreatment (500 nM) reduced colistin (200 MUM) induced cell death from ~50% to 72%. Moreover, rapamycin showed a marked neuroprotective effect in the N2a cells by decreasing intracellular reactive oxygen species (ROS) production and by up-regulating the activities of the anti-ROS enzymes superoxide dismutase and catalase and recovering glutathione (GSH) levels to normal. Moreover, rapamycin pretreatment protected against colistin-induced mitochondrial dysfunction, caspase activation, and subsequent apoptosis by up-regulating autophagy and activating the Akt/CREB, NGF, and Nrf2 pathways, while inhibiting p53 signaling. Taken together, this is the first study to demonstrate that rapamycin protects against colistin-induced neurotoxicity by activating autophagy, inhibiting oxidative stress, mitochondria dysfunction, and apoptosis. Our data highlight that regulating autophagy to rescue neurons from apoptosis may become a new targeted therapy to relieve the adverse neurotoxic effects associated with colistin therapy. PMID- 29257865 TI - Nanotechnology Strategies To Advance Outcomes in Clinical Cancer Care. AB - Ongoing research into the application of nanotechnology for cancer treatment and diagnosis has demonstrated its advantages within contemporary oncology as well as its intrinsic limitations. The National Cancer Institute publishes the Cancer Nanotechnology Plan every 5 years since 2005. The most recent iteration helped codify the ongoing basic and translational efforts of the field and displayed its breadth with several evolving areas. From merely a technological perspective, this field has seen tremendous growth and success. However, an incomplete understanding of human cancer biology persists relative to the application of nanoscale materials within contemporary oncology. As such, this review presents several evolving areas in cancer nanotechnology in order to identify key clinical and biological challenges that need to be addressed to improve patient outcomes. From this clinical perspective, a sampling of the nano-enabled solutions attempting to overcome barriers faced by traditional therapeutics and diagnostics in the clinical setting are discussed. Finally, a strategic outlook of the future is discussed to highlight the need for next-generation cancer nanotechnology tools designed to address critical gaps in clinical cancer care. PMID- 29257866 TI - Controlled Self-Assembly of Photofunctional Supramolecular Nanotubes. AB - Designing supramolecular nanotubes (SNTs) with distinct dimensions and properties is highly desirable, yet challenging, since structural control strategies are lacking. Furthermore, relatively complex building blocks are often employed in SNT self-assembly. Here, we demonstrate that symmetric bolaamphiphiles having a hydrophobic core comprised of two perylene diimide moieties connected via a bipyridine linker and bearing polyethylene glycol (PEG) side chains can self assemble into diverse molecular nanotubes. The structure of the nanotubes can be controlled by assembly conditions (solvent composition and temperature) and a PEG chain length. The resulting nanotubes differ both in diameter and cross section geometry, having widths of 3 nm (triangular-like cross-section), 4 nm (rectangular), and 5 nm (hexagonal). Molecular dynamics simulations provide insights into the stability of the tubular superstructures and their initial stages of self-assembly, revealing a key role of oligomerization via side-by-side aromatic interactions between bis-aromatic cores. Probing electronic and photonic properties of the nanotubes revealed extended electron delocalization and photoinduced charge separation that proceeds via symmetry breaking, a photofunction distinctly different from that of the fibers assembled from the same molecules. A high degree of structural control and insights into SNT self assembly advance design approaches toward functional organic nanomaterials. PMID- 29257867 TI - Nitrite Reduction Cycle on a Dinuclear Ruthenium Complex Producing Ammonia. AB - The fundamental biogeochemical cycle of nitrogen includes cytochrome c nitrite reductase, which catalyzes the reduction of nitrite ions to ammonium with eight protons and six electrons (NO2- + 8H+ + 6e- -> NH4+ + 2H2O). This reaction has motivated researchers to explore the reduction of nitrite. Although a number of electrochemical reductions of NO2- have been reported, the synthetic nitrite reduction reaction remains limited. To the best of our knowledge, formation of ammonia has not been reported. We report a three-step nitrite reduction cycle on a dinuclear ruthenium platform {(TpRu)2(MU-pz)} (Tp = HB(pyrazol-1-yl)3), producing ammonia. The cycle comprises conversion of a nitrito ligand to a NO ligand using 2H+ and e-, subsequent reduction of the NO ligand to a nitrido and a H2O ligand by consumption of 2H+ and 5e-, and recovery of the parent nitrito ligand. Moreover, release of ammonia was detected. PMID- 29257868 TI - Interfacial Tension of Phase-Separated Polydisperse Mixed Polymer Solutions. AB - Aqueous two-phase systems provide oil-free alternatives in the formulation of emulsions in food and other applications. Theoretical interpretation of measurements on such systems, however, is complicated by the high polydispersity of the polymers. Here, phase diagrams of demixing and interfacial tensions are determined for aqueous solutions of two large polymers present in a mass ratio of 1:1, dextran (70 kDa) and nongelling gelatin (100 kDa), with or without further addition of smaller dextran molecules (20 kDa). Both in experiments and in calculations from Scheutjens-Fleer self-consistent field lattice theory, we find that small polymers decrease the interfacial tension at equal tie-line length in the phase diagram. After identifying the partial contributions of all chemical components to the interfacial tension, we conclude that excess water at the interface is partially displaced by small polymer molecules. An interpretation in terms of the Gibbs adsorption equation provides an instructive way to describe effects of polydispersity on the interfacial tension of demixed polymer solutions. PMID- 29257869 TI - SmilesDrawer: Parsing and Drawing SMILES-Encoded Molecular Structures Using Client-Side JavaScript. AB - Here we present SmilesDrawer, a dependency-free JavaScript component capable of both parsing and drawing SMILES-encoded molecular structures client-side, developed to be easily integrated into web projects and to display organic molecules in large numbers and fast succession. SmilesDrawer can draw structurally and stereochemically complex structures such as maitotoxin and C60 without using templates, yet has an exceptionally small computational footprint and low memory usage without the requirement for loading images or any other form of client-server communication, making it easy to integrate even in secure (intranet, firewalled) or offline applications. These features allow the rendering of thousands of molecular structure drawings on a single web page within seconds on a wide range of hardware supporting modern browsers. The source code as well as the most recent build of SmilesDrawer is available on Github ( http://doc.gdb.tools/smilesDrawer/ ). Both yarn and npm packages are also available. PMID- 29257870 TI - GADDLE Maps: General Algorithm for Discrete Object Deformations Based on Local Exchange Maps. AB - A new method for switching between structures consisting of equivalent discrete and flexible objects with different particle representation and object configuration, including different resolution levels (number of particles per object), is reported. The method is fully general since it does not require any extra code nor additional database elements for new systems. It is based on a Monte Carlo sampling of the configurational space for each object type of the target system. The sampling is controlled by a Metropolis acceptance criterion of movements (translations, rotations, and relative deformations of the object configuration) that uses the generalized distance between the sets of particles at both representations. For Gaussian distributed distances, such a minimization procedure is equivalent to an optimization of chi2 in a maximum likelihood method. This provides sound statistical support since the method leads to the most probable configuration of the system at each representation. The configurations obtained in this way are then used to create resolution exchange maps for each object type, which allows the extrapolation of the conversion to every object configuration throughout the whole system. As an example, the method is here tested with several molecular dynamics simulated systems (ionic liquids, cyclodextrins, cell-penetrating peptides, cyclic peptides, lipid bilayers, vesicles, heterogeneous organic molecules, DNA, and solvated proteins) for different resolution force fields (GROMOS, AMBER, OPLS, MARTINI) using GROMACS. In this context, the method can be applied to map structures described by any other pair of force fields, as well as to homogeneous and heterogeneous systems with many different molecules. The method is proved to be highly efficient since the time required for the mapping is practically independent of the number of molecules in the target system. PMID- 29257871 TI - Emerging Chitosan-Based Films for Food Packaging Applications. AB - Recent years have witnessed great developments in biobased polymer packaging films for the serious environmental problems caused by the petroleum-based nonbiodegradable packaging materials. Chitosan is one of the most abundant biopolymers after cellulose. Chitosan-based materials have been widely applied in various fields for their biological and physical properties of biocompatibility, biodegradability, antimicrobial ability, and easy film forming ability. Different chitosan-based films have been fabricated and applied in the field of food packaging. Most of the review papers related to chitosan-based films are focusing on antibacterial food packaging films. Along with the advances in the nanotechnology and polymer science, numerous strategies, for instance direct casting, coating, dipping, layer-by-layer assembly, and extrusion, have been employed to prepare chitosan-based films with multiple functionalities. The emerging food packaging applications of chitosan-based films as antibacterial films, barrier films, and sensing films have achieved great developments. This article comprehensively reviews recent advances in the preparation and application of engineered chitosan-based films in food packaging fields. PMID- 29257873 TI - Acid Doping of Phenyl-Capped Aniline Dimer: Intermolecular Polaron Formation Mechanism and Its Applicability to Polyaniline. AB - The acid doping process of the mixtures of N,N'-diphenyl-1,4-phenylenediamine (DPPD) and N,N'-diphenyl-1,4-quinonediimine (DPQD), reduced and oxidized phenyl capped aniline dimers respectively, has been studied in detail by UV-vis-NIR and ESR spectroscopies. The addition of the acid to the mixtures of DPPD and DPQD leads to the formation of one type of radicals by intermolecular interactions. Full conversion of the aniline dimer molecules to the radical form is achievable only in stoichiometric mixtures of DPPD and DPQD. Concentration of radical species may change over time according to processes involving hydrolysis. The mechanisms of the acid doping of the phenyl-capped dimer process and subsequent side processes are proposed. PMID- 29257872 TI - Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse. AB - Insulin delivery to the brain has emerged as an important therapeutic target for cognitive disorders associated with abnormal brain energy metabolism. Although insulin is transported across the blood-brain barrier, peripheral routes of administration are problematic due to systemic effects of insulin on blood glucose. Intranasal (IN) administration is being investigated as an alternative route. We conducted a head-to-head comparison of subcutaneous (SC) and IN insulin, assessing plasma and brain pharmacokinetics and blood glucose levels in the mouse. SC insulin (2.4 IU) achieved therapeutically relevant concentrations in the brain (AUCbrain = 2537 h.MUIU/mL) but dramatically increased plasma insulin (AUCplasma = 520 351 h.*MUIU/mL), resulting in severe hypoglycemia and in some cases death. IN administration of the same dose resulted in similar insulin levels in the brain (AUCbrain = 3442 h.MUIU/mL) but substantially lower plasma concentrations (AUCplasma = 354 h.MUIU/mL), amounting to a ~ 2000-fold increase in the AUCbrain:plasma ratio relative to SC. IN dosing also had no significant effect on blood glucose. When administered daily for 9 days, IN insulin increased brain glucose and energy metabolite concentrations (e.g., adenosine triphosphate and phosphocreatine) without causing overt toxicity, suggesting that IN insulin may be a safe therapeutic option for cognitively impaired patients. PMID- 29257875 TI - Nanocorrugation-Induced Forces between Electrically Neutral Metallic Objects. AB - Recent advances in nanotechnology have created tremendous excitement across different disciplines, but in order to fully control and manipulate nanoscale objects, we must understand the forces at work at the nanoscale, which can be very different from those that dominate the macroscale. We show that there is a kind of curvature-induced force that acts between nanocorrugated electrically neutral metallic surfaces. Absent in flat surfaces, such a force owes its existence entirely to geometric curvature and originates from the kinetic energy associated with the electron density, which tends to make the profile of the electron density smoother than that of the ionic background and hence induces curvature-induced local charges. Such a force cannot be found using standard classical electromagnetic approaches, and we use a self-consistent hydrodynamics model as well as first-principles density functional calculations to explore the character of such forces. These two methods give qualitatively similar results. We found that the force can be attractive or repulsive, depending on the details of the nanocorrugation, and its magnitude is comparable to light-induced forces acting on plasmonic nano-objects. PMID- 29257874 TI - Spatially Resolved Measurements of CO2 and CH4 Concentration and Gas-Exchange Velocity Highly Influence Carbon-Emission Estimates of Reservoirs. AB - The magnitude of diffusive carbon dioxide (CO2) and methane (CH4) emission from man-made reservoirs is uncertain because the spatial variability generally is not well-represented. Here, we examine the spatial variability and its drivers for partial pressure, gas-exchange velocity (k), and diffusive flux of CO2 and CH4 in three tropical reservoirs using spatially resolved measurements of both gas concentrations and k. We observed high spatial variability in CO2 and CH4 concentrations and flux within all three reservoirs, with river inflow areas generally displaying elevated CH4 concentrations. Conversely, areas close to the dam are generally characterized by low concentrations and are therefore not likely to be representative for the whole system. A large share (44-83%) of the within-reservoir variability of gas concentration was explained by dissolved oxygen, pH, chlorophyll, water depth, and within-reservoir location. High spatial variability in k was observed, and kCH4 was persistently higher (on average, 2.5 times more) than kCO2. Not accounting for the within-reservoir variability in concentrations and k may lead to up to 80% underestimation of whole-system diffusive emission of CO2 and CH4. Our findings provide valuable information on how to develop field-sampling strategies to reliably capture the spatial heterogeneity of diffusive carbon fluxes from reservoirs. PMID- 29257876 TI - Orthogonal Probing of Single-Molecule Heterogeneity by Correlative Fluorescence and Force Microscopy. AB - Correlative imaging by fluorescence and force microscopy is an emerging technology to acquire orthogonal information at the nanoscale. Whereas atomic force microscopy excels at resolving the envelope structure of nanoscale specimens, fluorescence microscopy can detect specific molecular labels, which enables the unambiguous recognition of molecules in a complex assembly. Whereas correlative imaging at the micrometer scale has been established, it remains challenging to push the technology to the single-molecule level. Here, we used an integrated setup to systematically evaluate the factors that influence the quality of correlative fluorescence and force microscopy. Optimized data processing to ensure accurate drift correction and high localization precision results in image registration accuracies of ~25 nm on organic fluorophores, which represents a 2-fold improvement over the state of the art in correlative fluorescence and force microscopy. Furthermore, we could extend the Atto532 fluorophore bleaching time ~2-fold, by chemical modification of the supporting mica surface. In turn, this enables probing the composition of macromolecular complexes by stepwise photobleaching with high confidence. We demonstrate the performance of our method by resolving the stoichiometry of molecular subpopulations in a heterogeneous EcoRV-DNA nucleoprotein ensemble. PMID- 29257877 TI - Growth Behavior and Electronic Structure of Noble Metal-Doped Germanium Clusters. AB - Structures, energetics, and electronic properties of noble metal-doped germanium (MGen with M = Cu, Ag, Au; n = 1-19) clusters are systematically investigated by using the density functional theory (DFT) approach. The endohedral structures in which the metal atom is encapsulated inside of a germanium cage appear at n = 10 when the dopant is Cu and n = 12 for M = Ag and Au. While Cu doping enhances the stability of the corresponding germanium frame, the binding energies of AgGen and AuGen are always lower than those of pure germanium clusters. Our results highlight the great stability of the CuGe10 cluster in a D4d structure and, to a lesser extent, that of AgGe15 and AuGe15, which exhibits a hollow cage-like geometry. The sphere-type geometries obtained for n = 10-15 present a peculiar electronic structure in which the valence electrons of the noble metal and Ge atoms are delocalized and exhibit a shell structure associated with the quasi spherical geometry. It is found that the coinage metal is able to give both s- and d-type electrons to be reorganized together with the valence electrons of Ge atoms through a pooling of electrons. The cluster size dependence of the stability, the frontier orbital energy gap, the vertical ionization potentials, and electron affinities are given. PMID- 29257878 TI - TARSyn: Tunable Antibiotic Resistance Devices Enabling Bacterial Synthetic Evolution and Protein Production. AB - Evolution can be harnessed to optimize synthetic biology designs. A prominent example is recombinant protein production-a dominating theme in biotechnology for more than three decades. Typically, a protein coding sequence (cds) is recombined with genetic elements, such as promoters, ribosome binding sites and terminators, which control expression in a cell factory. A major bottleneck during production is translational initiation. Previously we identified more effective translation initiation regions (TIRs) by creating sequence libraries and then selecting for a TIR that drives high-level expression-an example of synthetic evolution. However, manual screening limits the ability to assay expression levels of all putative sequences in the libraries. Here we have solved this bottleneck by designing a collection of translational coupling devices based on a RNA secondary structure. Exchange of different sequence elements in this device allows for different coupling efficiencies, therefore giving the devices a tunable nature. Sandwiching these devices between the cds and an antibiotic selection marker that functions over a broad dynamic range of antibiotic concentrations adds to the tunability and allows expression levels in large clone libraries to be probed using a simple cell survival assay on the respective antibiotic. The power of the approach is demonstrated by substantially increasing production of two commercially interesting proteins, a Nanobody and an Affibody. The method is a simple and inexpensive alternative to advanced screening techniques that can be carried out in any laboratory. PMID- 29257880 TI - Electronic Structure Tuning in Ni3FeN/r-GO Aerogel toward Bifunctional Electrocatalyst for Overall Water Splitting. AB - Searching for the highly active, stable, and high-efficiency bifunctional electrocatalysts for overall water splitting, e.g., for both oxygen evolution (OER) and hydrogen evolution (HER), is paramount in terms of bringing future renewable energy systems and energy conversion processes to reality. Herein, three-dimensional (3D) Ni3FeN nanoparticles/reduced graphene oxide (r-GO) aerogel electrocatalysts were fabricated using precursors of (Ni,Fe)/r-GO alginate hydrogels through an ion-exchange process, followed by a convenient one-step nitrogenization treatment in NH3 at 700 degrees C. The resultant materials exhibited excellent electrocatalytic performance for OER and HER in alkaline media, with only small overpotentials of 270 and 94 mV at a current density of 10 mA cm-2, respectively. The good performance was attributed to abundant active sites and high electrical conductivity of the bimetallic nitrides and efficient mass transport of the 3D r-GO aerogel framework. Furthermore, an alkaline electrolyzer was set up using Ni3FeN/r-GO as both the cathode and the anode, which achieved a 10 mA cm-2 current density at 1.60 V with durability of 100 h for overall water splitting. Density functional theory calculations support that Ni3FeN (111)/r-GO is more favorable for overall water splitting since the surface electronic structure of Ni3FeN is tuned by transferring electrons from Ni3FeN cluster to the r-GO through interaction of two metal species. Thus, the currently developed Ni3FeN/r-GO with superior water-splitting performance may potentially serve as a material for use in industrial alkaline water electrolyzers. PMID- 29257879 TI - 1,2,3-Triazole Rings as a Disulfide Bond Mimetic in Chimeric AGRP-Melanocortin Peptides: Design, Synthesis, and Functional Characterization. AB - The melanocortin system is involved in the regulation of complex physiological functions, including energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. The five melanocortin receptors that belong to the superfamily of G protein-coupled receptors (GPCRs) are regulated by endogenously expressed agonists and antagonists. The aim of this study was to explore the potential of replacing the disulfide bridge in chimeric AGRP-melanocortin peptide Tyr-c[Cys-His-d-Phe-Arg Trp-Asn-Ala-Phe-Cys]-Tyr-NH2 (1) with 1,2,3-triazole moieties. A series of 1,2,3 triazole-bridged peptidomimetics were designed, synthesized, and pharmacologically evaluated at the mouse melanocortin receptors. The ligands possessed nanomolar to micromolar agonist cAMP signaling potency. A key finding was that the disulfide bond in peptide 1 can be replaced with the monotriazole ring with minimal effect on the functional activity at the melanocortin receptors. The 1,5-disubstituted triazole-bridged peptide 6 showed equipotent functional activity at the mMC3R and modest 5-fold decreased agonist potency at the mMC4R compared to those of 1. Interestingly, the 1,4- and 1,5-disubstituted isomers of the triazole ring resulted in different selectivities at the receptor subtypes, indicating subtle structural features that may be exploited in the generation of selective melanocortin ligands. Introducing cyclic and acyclic bis triazole moieties into chimeric AGRP template 1 generally decreased agonist activity. These results will be useful for the further design of neuronal chemical probes for the melanocortin receptors as well as in other receptor systems. PMID- 29257881 TI - Molecularly Engineered Theranostic Nanoparticles for Thrombosed Vessels: H2O2 Activatable Contrast-Enhanced Photoacoustic Imaging and Antithrombotic Therapy. AB - A thrombus (blood clot), composed mainly of activated platelets and fibrin, obstructs arteries or veins, leading to various life-threatening diseases. Inspired by the distinctive physicochemical characteristics of thrombi such as abundant fibrin and an elevated level of hydrogen peroxide (H2O2), we developed thrombus-specific theranostic (T-FBM) nanoparticles that could provide H2O2 triggered photoacoustic signal amplification and serve as an antithrombotic nanomedicine. T-FBM nanoparticles were designed to target fibrin-rich thrombi and be activated by H2O2 to generate CO2 bubbles to amplify the photoacoustic signal. In the phantom studies, T-FBM nanoparticles showed significant amplification of ultrasound/photoacoustic signals in a H2O2-triggered manner. T-FBM nanoparticles also exerted H2O2-activatable antioxidant, anti-inflammatory, and antiplatelet activities on endothelial cells. In mouse models of carotid arterial injury, T FBM nanoparticles significantly enhanced the photoacoustic contrast specifically in thrombosed vessels and significantly suppressed thrombus formation. We anticipate that T-FBM nanoparticles hold great translational potential as nanotheranostics for H2O2-associated cardiovascular diseases. PMID- 29257882 TI - Programmed Coassembly of One-Dimensional Binary Superstructures by Liquid Soft Confinement. AB - Precise control of particles co-assembly has attracted great attention for fabricating intricate structures and functional materials. However, achieving precise co-assembly of one-dimensional (1D) binary superstructures remains challenging due to the constrained thermodynamic stability and lack of general strategies to control the 1D ordered arrangement of mixed particles. Here, we propose a facile strategy to achieve programmed co-assembly of 1D binary superstructures by liquid soft confinement without particle modification or external field. It reveals that binary particles undergo stepwise confinement and programmed co-assembly in the gradually shrinking and spatially tunable liquid soft confinement. Through tuning the liquid confined space and particles composition, diverse 1D binary superstructures with precisely controlled periodicity, orientation and symmetry are achieved, which shows generality for various particles of different sizes and materials. This work provides a promising route to refined patterning and manufacturing complex materials. PMID- 29257883 TI - Lanthanide Triangles Supported by Radical Bridging Ligands. AB - The first examples of metallacycles containing rare earth ions bridged by radicals are reported. The molecular triangles [Ln3(hfac)6(bptz*-)3] (Ln = DyIII, YIII; hfac = 1,1,1,5,5,5-hexafluoro-2,4-pentanedionate; bptz = 3,6-bis(2-pyridyl) 1,2,4,5-tetrazine) consist of lanthanide ions bridged by bptz radical anion (bptz*-) ligands. Magnetic susceptibility measurements and CASSCF calculations performed on [Dy3(hfac)6(bptz*-)3] reveal the presence of antiferromagnetic coupling between the DyIII centers and the bptz*- ligands, with J = -6.62 cm-1. PMID- 29257884 TI - Structure-Based Design, Synthesis, and In Vivo Antinociceptive Effects of Selective A1 Adenosine Receptor Agonists. AB - Our previous work discovered that combining the appropriate 5'- and N6 substitution in adenosine derivatives leads to the highly selective human A1 adenosine receptor (hA1AR) agonists or highly potent dual hA1AR agonists and hA3AR antagonists. In order to explore novel dual adenosine receptor ligands, a series of N6-substituted-5'-pyrazolyl-adenosine and 2-chloro-adenosine derivatives were synthesized and assayed in vitro at all ARs. The N6-(+/-)-endo norbornyl derivative 12 was the most potent and selective at A1AR and effective as an analgesic in formalin test in mice, but none of the 5'-pyrazolyl series compounds showed a dual behavior at hA1 and hA3AR. Molecular modeling studies rationalized the structure-activity relationships and the selectivity profiles of the new series of A1AR agonists. Interestingly, an unexpected inverted binding mode of the N6-tetrahydrofuranyl derivative 14 was hypothesized to explain its low affinity at A1AR. PMID- 29257885 TI - Removal Characteristics of Dissolved Organic Nitrogen and Its Bioavailable Portion in a Postdenitrifying Biofilter: Effect of the C/N Ratio. AB - Addition of external carbon sources to postdenitrification biofilters (DNFs) is frequently used in municipal wastewater treatment plants to enhance dissolved inorganic nitrogen removal. However, little is known about its influence on the removal of dissolved organic nitrogen (DON). This study investigated the effect of the carbon-to-nitrogen (C/N) ratio (3, 4, 5, and 6) on the removal characteristics of DON and bioavailable DON (ABDON) in the pilot-scale DNFs treating real secondary effluent. Results showed that DNFs effluent DON accounted for 31.2-39.8% of the effluent total nitrogen. The maximum effluent DON and ABDON concentrations both occurred in DNF operated at a C/N ratio of 3. There was no significant difference in effluent DON concentrations in DNFs at C/N ratios of 4, 5, and 6; however, effluent ABDON and DON bioavailability significantly decreased with C/N ratios (p < 0.05, t-test). According to the chemical composition analysis, effluent DON at high C/N ratios tends to contain less % molecular weight < 1 kDa nitrogenous organic compounds and proteins/amino sugars-like nitrogenous organic formulas, which is likely responsible for its low bioavailability. Overall, this study indicates the benefit of a high C/N ratio during the DNF process in terms of controlling the DON forms that readily stimulate algal growth. PMID- 29257886 TI - Emissions of Secondary Formed ZnO Nano-Objects from the Combustion of Impregnated Wood. An Online Size-Resolved Elemental Investigation. AB - The release of secondary nano-objects formed during waste combustion processes is becoming a matter of concern, considering their known toxicity and the fact that the 100% efficiency of filtering systems is not always ensured. An increased cytotoxicity and genotoxicity on human peripheral blood lymphocytes is known particularly in the case of ZnO, which is often contained in paints and waterproof agents, heading to a relevant quantity present in the waste wood material. In this study, the behavior of ZnO nanoparticles during wood combustion and the effect of the reduction potential of generated carbon species on the release of secondarily formed ZnO-containing nano-objects were investigated. By hyphenating a modified scanning mobility particle sizer (SMPS) and inductively coupled mass spectrometry (ICP-MS), it was possible to obtain simultaneously size resolved and chemical information on the emitted nanoparticles. Through the established correlation between SMPS and ICP-MS signals, Zn-containing particles were efficiently resolved from the combustion generated particles. Transmission electron microscopy (TEM) and energy-dispersive X-ray spectroscopy (EDS) on size selected particles confirmed the SMPS and ICP-MS data. The use of electron diffraction allowed determining the structure of the crystalline materials as hexagonal ZnO. A possible mechanism of reduction of ZnO to Zn and further reformation as secondary nano-objects is proposed. PMID- 29257887 TI - 15N Solid State NMR Spectroscopic Study of Surface Amine Groups for Carbon Capture: 3-Aminopropylsilyl Grafted to SBA-15 Mesoporous Silica. AB - Materials composed of high-porosity solid supports, such as SBA-15, containing amine-bearing moieties inside the pores, such as 3-aminopropylsilane (APS), are envisioned for carbon dioxide capture; solid-state 15N NMR can be highly informative for studying chemisorption reactions. Two 15N-enriched samples with different APS loadings were studied to probe the identity of the pendant molecules and structure of the chemisorbed CO2 species. 15N cross-polarization magic-angle spinning NMR provides unique information about the amines, whether they are rigid or dynamic, by measuring contact time curves and rotating frame, T1rho(15N), relaxation. Both carbamate and carbamic acid are formed; carbamic acid is shown to be less stable than carbamate. After desorption, a steady state for the chemisorbed reaction product is reached, leaving behind carbamate. 15N NMR monitors the evolution of the species over time. During desorption, APS is regenerated, but the ammonium propylsilane intensity does not change, leading us to conclude that carbamic acid desorbs, while carbamate (to which ammonium propylsilane is ion paired) persists. A secondary ditehtered amine present does not react with CO2, and we posit this may be due to its rigidity. These findings demonstrate the versatility of solid-state NMR to provide information about these complex CO2 reactions with solid amine sorbents. PMID- 29257888 TI - Measuring and Modeling the Growth Dynamics of Self-Catalyzed GaP Nanowire Arrays. AB - The bottom-up fabrication of regular nanowire (NW) arrays on a masked substrate is technologically relevant, but the growth dynamic is rather complex due to the superposition of severe shadowing effects that vary with array pitch, NW diameter, NW height, and growth duration. By inserting GaAsP marker layers at a regular time interval during the growth of a self-catalyzed GaP NW array, we are able to retrieve precisely the time evolution of the diameter and height of a single NW. We then propose a simple numerical scheme which fully computes shadowing effects at play in infinite arrays of NWs. By confronting the simulated and experimental results, we infer that re-emission of Ga from the mask is necessary to sustain the NW growth while Ga migration on the mask must be negligible. When compared to random cosine or random uniform re-emission from the mask, the simple case of specular reflection on the mask gives the most accurate account of the Ga balance during the growth. PMID- 29257889 TI - Spatial Control of Multiphoton Electron Excitations in InAs Nanowires by Varying Crystal Phase and Light Polarization. AB - We demonstrate the control of multiphoton electron excitations in InAs nanowires (NWs) by altering the crystal structure and the light polarization. Using few cycle, near-infrared laser pulses from an optical parametric chirped-pulse amplification system, we induce multiphoton electron excitations in InAs nanowires with controlled wurtzite (WZ) and zincblende (ZB) segments. With a photoemission electron microscope, we show that we can selectively induce multiphoton electron emission from WZ or ZB segments of the same wire by varying the light polarization. Developing ab initio GW calculations of first to third order multiphoton excitations and using finite-difference time-domain simulations, we explain the experimental findings: While the electric-field enhancement due to the semiconductor/vacuum interface has a similar effect for all NW segments, the second and third order multiphoton transitions in the band structure of WZ InAs are highly anisotropic in contrast to ZB InAs. As the crystal phase of NWs can be precisely and reliably tailored, our findings open up for new semiconductor optoelectronics with controllable nanoscale emission of electrons through vacuum or dielectric barriers. PMID- 29257890 TI - Integer and Fractional Quantum Hall effect in Ultrahigh Quality Few-layer Black Phosphorus Transistors. AB - As a high mobility two-dimensional semiconductor with strong structural and electronic anisotropy, atomically thin black phosphorus (BP) provides a new playground for investigating the quantum Hall (QH) effect, including outstanding questions such as the functional dependence of Landau level (LL) gaps on magnetic field B, and possible anisotropic fractional QH states. Using encapsulated few layer BP transistors with mobility up to 55 000 cm2/(V s), we extracted LL gaps over an exceptionally wide range of B for QH states at filling factors -1 to -4, which are determined to be linear in B, thus resolving a controversy raised by its anisotropy. Furthermore, a fractional QH state at nu ~ -4/3 and an additional feature at -0.56 +/- 0.1 are observed, underscoring BP as a tunable 2D platform for exploring electron interactions. PMID- 29257891 TI - Solvent-Controlled Charge Storage Mechanisms of Spinel Oxide Electrodes in Mg Organohaloaluminate Electrolytes. AB - Considering the improved safety, reduced cost, and high volumetric energy density associated with Mg batteries, this technology has distinct advantages for large scale energy storage compared to other existing battery technologies. However, the divalency of the Mg2+ cation cause sluggish magnesiation kinetics in crystalline host materials, resulting in poor performance with regards to capacity and cycling stability for intercalation based electrodes. Here, we present a Mg battery using Mn3O4 as the electrode material and Mg metal as the counter electrode in a Mg organohaloaluminate electrolyte. The reversible capacity when Mn3O4 was used as cathode reached ~580 mAh g-1 at a current density of 15.4 mA g-1, whereas a reversible capacity of ~1800 mAh g-1 was obtained in an anode configuration. The Mn3O4 in a cathode configuration shows excellent cycling stability with no loss of capacity after 500 cycles at a current density of 770 mA g-1. As an anode, Mn3O4 retained 86% of its initial capacity after 200 cycles. These exceptional charge storage properties and high cycling stability are attributed to highly reversible interfacial reactions involving the electrolyte solvents. Our conclusions are supported by density functional theory calculations in addition to quantitative kinetics analysis and scanning transmission electron microscopy combined with energy dispersive spectroscopy and electron energy loss spectroscopy. PMID- 29257892 TI - Star-Shaped Thermoresponsive Polymers with Various Functional Groups for Cell Sheet Engineering. AB - This study demonstrates the facile preparation of poly(N-isopropylacrylamide) (PNIPAM)-immobilized Petri dishes by drop-casting a star-shaped copolymer of hyperbranched polystyrene (HBPS) possessing PNIPAM arms (HBPS-g-PNIPAM) functionalized with polar groups. HBPS was synthesized via reversible addition fragmentation chain transfer (RAFT) self-condensing vinyl polymerization (SCVP), and HBPS polymers with different terminal structures were prepared by changing the monomer structure. HBPS-g-PNIPAM was synthesized by the grafting of PNIPAM from each terminal of HBPS. To tune the cell adhesion and detachment properties, polar functional groups such as carboxylic acid and dimethylamino groups were introduced to HBPS-g-PNIPAM. Based on surface characterization using scanning transmission electron microscopy (STEM), X-ray photoelectron spectroscopy (XPS), and contact angle measurements, the advantage of the hyperbranched structure for the PNIPAM immobilization was evident in terms of the uniformity, stability, and thermoresponsiveness. Successful cell sheet harvesting was demonstrated on dishes coated with HBPS-g-PNIPAM. In addition, the cell adhesion and detachment properties could be tuned by the introduction of polar functional groups. PMID- 29257893 TI - pH- and Time-Resolved in Situ SAXS Study of Self-Assembled Twisted Ribbons Formed by Elaidic Acid Sophorolipids. AB - Conditions that favor the helical structure formation in structurally similar sophorolipids (SLs), that is, elaidic acid SLs (having a trans double bond between the C9 and C10 positions of the alkyl chain) and stearic acid SLs (no double bond), are presented here. The helical self-assembled structures formed by elaidic acid SLs were independent of pH and also were mediated by a micellar intermediate. On the other hand, the stearic acid SLs formed helical structures under low pH condition only. Astonishingly, the formation routes were found to be different, albeit the molecular geometry of both SLs is similar. Even if a conclusive mechanistic understanding must await further work, our studies strongly point out that the noncovalent weak interactions in elaidic acid SLs are able to overcome the electrostatic repulsions of the sophorolipid carboxylate groups at basic pH and facilitating the formation of helical structures. On the other hand, the hydrophobic interactions in stearic acid SLs endow the helical structures with extra stability, making them less vulnerable to dissolution upon heating. PMID- 29257894 TI - Prediction of Multidrug-Resistant TB from CT Pulmonary Images Based on Deep Learning Techniques. AB - While tuberculosis (TB) disease was discovered more than a century ago, it has not been eradicated yet. Quite contrary, at present, TB constitutes one of the top 10 causes of death and has shown signs of increasing. To complement the conventional diagnostic procedure of applying microbiological culture that takes several weeks and remains expensive, high resolution computer tomography (CT) of pulmonary images has been resorted to not only for aiding clinicians to expedite the process of diagnosis but also for monitoring prognosis when administering antibiotic drugs. This research undertakes the investigation of predicting multidrug-resistant (MDR) patients from drug-sensitive (DS) ones based on CT lung images to monitor the effectiveness of treatment. To contend with smaller data sets (i.e., hundreds) and the characteristics of CT TB images with limited regions capturing abnormities, patch-based deep convolutional neural network (CNN) allied to support vector machine (SVM) classifier is implemented on a collection of data sets from 230 patients obtained from the ImageCLEF 2017 competition. As a result, the proposed architecture of CNN + SVM + patch performs the best with classification accuracy rate at 91.11% (79.80% in terms of patches). In addition, a hand-crafted SIFT based approach accomplishes 88.88% in terms of subject and 83.56% with reference to patches, the highest in this study, which can be explained away by the fact that the data sets are in small numbers. Significantly, during the Tuberculosis Competition at ImageCLEF 2017, the authors took part in the task of classification of 5 types of TB disease and achieved the top one with regard to averaged classification accuracy (i.e., ACC = 0.4067), which is also premised on the approach of CNN + SVM + patch. On the other hand, when the whole slices of 3D TB data sets are applied to train a CNN network, the best result is achieved through the application of CNN coupled with orderless pooling and SVM at 64.71% accuracy rate. PMID- 29257895 TI - Bistability of Contact Angle and Its Role in Achieving Quantum-Thin Self-Assisted GaAs nanowires. AB - Achieving quantum confinement by bottom-up growth of nanowires has so far been limited to the ability of obtaining stable metal droplets of radii around 10 nm or less. This is within reach for gold-assisted growth. Because of the necessity to maintain the group III droplets during growth, direct synthesis of quantum sized structures becomes much more challenging for self-assisted III-V nanowires. In this work, we elucidate and solve the challenges that involve the synthesis of gallium-assisted quantum-sized GaAs nanowires. We demonstrate the existence of two stable contact angles for the gallium droplet on top of GaAs nanowires. Contact angle around 130 degrees fosters a continuous increase in the nanowire radius, while 90 degrees allows for the stable growth of ultrathin tops. The experimental results are fully consistent with our model that explains the observed morphological evolution under the two different scenarios. We provide a generalized theory of self-assisted III-V nanowires that describes simultaneously the droplet shape relaxation and the NW radius evolution. Bistability of the contact angle described here should be the general phenomenon that pertains for any vapor-liquid-solid nanowires and significantly refines our picture of how nanowires grow. Overall, our results suggest a new path for obtaining ultrathin one-dimensional III-V nanostructures for studying lateral confinement of carriers. PMID- 29257896 TI - Study of Poly(N-isopropylacrylamide-co-acrylic acid) (pNIPAM) Microgel Particle Induced Deformations of Tissue-Mimicking Phantom by Ultrasound Stimulation. AB - Poly(N-isopropylacrylamide) (pNIPAm) microgels (microgels) are colloidal particles that have been used extensively for biomedical applications. Typically, these particles are synthesized in the presence of an exogenous cross-linker, such as N,N'-methylenebis(acrylamide) (BIS); however, recent studies have demonstrated that pNIPAm microgels can be synthesized in the absence of an exogenous cross-linker, resulting in the formation of ultralow cross-linked (ULC) particles, which are highly deformable. Microgel deformability has been linked in certain cases to enhanced bioactivity when ULC microgels are used for the creation of biomimetic particles. We hypothesized that ultrasound stimulation of microgels would enhance particle deformation and that the degree of enhancement would negatively correlate with the degree of particle cross-linking. Here, we demonstrate in tissue-mimicking phantoms that using ultrasound insonification causes deformations of ULC microgel particles. Furthermore, the amount of deformation depends on the ultrasound excitation frequency and amplitude and on the concentration of ULC microgel particles. We observed that the amplitude of deformation increases with increasing ULC microgel particle concentration up to 2.5 mg/100 mL, but concentrations higher than 2.5 mg/100 mL result in reduced amount of deformation. In addition, we observed that the amplitude of deformation was significantly higher at 1 MHz insonification frequency. We also report that increasing the degree of microgel cross-linking reduces the magnitude of the deformation and increases the optimal concentration required to achieve the largest amount of deformation. Stimulated ULC microgel particle deformation has numerous potential biomedical applications, including enhancement of localized drug delivery and biomimetic activity. These results demonstrate the potential of ultrasound stimulation for such applications. PMID- 29257897 TI - Reproductive Desires and Disappointments. AB - In this introduction we consider how people who have difficulties achieving "natural" parenthood seek to form families, and their experiences of reproductive negotiations and losses in this pursuit. We highlight gaps in the literature on infertility and loss globally, and identify how the special edition addresses the dearth of research in this field with men, with non-elites and on loss. We consider the key insights drawn from studies conducted in divergent geographical, cultural, socioeconomic and political contexts, including perspectives from Ghana, Indonesia, Romania, Spain, the United Kingdom, and the United States. In these contexts we explore both high tech and no tech reproductive strategies, encompassing assisted reproductive technologies, third party donation, surrogacy, as well as intra-family and transnational adoption. We illuminate how people attribute meaning to their lived experiences of reproductive disappointments ranging from failed conception (primary and secondary infertility), miscarriage, stillbirths, neonatal death, and failed adoption. We reflect on both local and transnational practices embedded in family making, highlighting the complexity and dynamism of reproductive opportunities, and how these opportunities are embedded in multifarious power relations. We articulate a range of important themes for the anthropology of reproduction, including: the sociality of reproductive desires and disappointments; gender sexuality and emergent masculinities; migration, practices of belonging, and kinship; reproductive stratification and leveling; and reproduction and relationality. PMID- 29257898 TI - Evidence-Based Psychosocial Treatments for Children and Adolescents With Attention Deficit/Hyperactivity Disorder. AB - The purpose of this research was to update the series of articles on evidence based treatment for children and adolescents with attention deficit/hyperactivity disorder that have appeared in this journal (Evans, Owens & Bunford, 2014; Pelham & Fabiano, 2008; Pelham, Wheeler, & Chronis, 1998). We completed a systematic review of the literature published between 2012 and 2016 to establish levels of evidence for psychosocial treatments for these youth. We identified articles using criteria established by the Society of Clinical Child and Adolescent Psychology using keyword searches of abstracts and titles. Articles were classified according to a modified version of the Division 12 task force guidelines that was used in other reviews in this series. The results revealed that findings are becoming increasingly nuanced with variations in levels of evidence related to ages of the children and characteristics of the specific treatment. In addition, we focused our critique on generalization of treatment effects across settings and time and on sample diversity (with regard to ethnicity and levels of parent education) in relation to the population. Children of parents with higher levels of education than average appear to be overrepresented in the literature. Implications for future treatment development and evaluation and for dissemination research are discussed. PMID- 29257899 TI - Pharmacokinetic drug evaluation of recombinant factor VIII for the treatment of hemophilia A. AB - INTRODUCTION: The prevention of bleeding by prophylactic factor replacement is the recommended approach for the treatment of severe hemophilia. Prophylaxis should be individualized to provide the best clinical benefit to each patient. Therefore, a pharmacokinetic approach is crucial. Areas covered: This review aims to concisely describe the basic principles of pharmacokinetics of FVIII, the role of population pharmacokinetic, the available different recombinant FVIII concentrates and the new extended half-life FVIII molecules with possible improvement in hemophilia A treatment. Expert opinion: Pharmacokinetic is a useful tool to predict the outcome of replacement therapy, even though a large inter-individual variability exists, becauseof several factors: age, weight, von Willebrand factor level, blood group, active bleed, presence of inhibitors to FVIII, FVIII concentrate. Among the different recombinant FVIII concentrates pharmacokinetic differences are minor and clinically not significant. The extended half-life FVIII products brings only moderate advances, as half life extension is limited to 1.5-1.8-fold in comparison to that of native FVIII. Thus, infusions could be done every fourth, rarely fifth day to ensure a safe through level and a significant benefit can be offered only to patients treated every other day or three times weekly. PMID- 29257900 TI - Association between cytokine genes polymorphisms and type 1 diabetes: a case control study on Saudi population. AB - BACKGROUND: Association studies of genes encoding cytokines that play an important role in inflammatory response represent one approach to finding type 1 diabetes (T1D) disease genes. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) within cytokine genes with T1D in a cohort of Saudi subjects. METHODS: A total of 300 well-characterized type 1 diabetic patients and 300 T1D-free control subjects were enrolled in this investigation. Cytokine SNPs were genotyped by using Polymerase chain reaction (PCR) with sequence-specific primers. RESULTS: Our data revealed that IFN-gamma +874T allele carriers [odds ratio (OR) = 1.87, p < 0.001] and TT homozygotes (OR = 1.28, p < 0.001) were significantly more susceptible to developing T1D than the A allele carriers. In addition, TNF-alpha -308A allele carriers (OR = 1.73, p < 0.001) and AA homozygotes (OR = 1.74, p < 0.001) were also overrepresented among the diabetics than G allele carriers. IL-4 -590C/T TT homozygotes (OR = 2.23, p < 0.001) were significantly more susceptible to develop T1D than CC genotypes, whereas CT heterozygotes were not significantly associated (OR = 1.43, p = 0.78) with T1D. Furthermore, IL-4 T allele was statistically associated with T1D patients compared to control group (OR = 2.24, p < 0.001). Similarly, IL-1beta 511C/T TT homozygotes (OR = 1.85, p = 0.012) and the T allele (OR = 1.85, p < 0.001) were significantly more susceptible to T1D than CC genotypes, whereas TC heterozygotes (OR = 1.04, p = 0.86) were not significantly associated with T1D. CONCLUSION: Our data concluded that IFN-gamma +874T allele, TNF-alpha -308A allele, IL-1beta -511T allele, and IL-4 -590T allele could be considered risk factors for T1D development in Saudi subjects. PMID- 29257902 TI - Association between the polymorphism of HLA and ESRD in Dalian Han population located in north of China. AB - BACKGROUND: End-stage renal disease (ESRD), the last stage of chronic renal failure, is a global health problem. The number of ESRD patients worldwide is increasing faster than the number of kidneys available per year for renal transplantation. Most of the ESRD patients are awaiting renal transplantation. The immune response to the transplanted kidney is directed mainly against mismatched human leukocyte antigen (HLA) glycoproteins expressed on donor tissues. Thus, the analysis of HLA allele and haplotype polymorphisms is valuable not only for identifying ESRD susceptibility factors but also to improve graft survival. METHODS: In this study, 163 Han ESRD patients were recruited to participate. The blood samples were genotyped by sequence-specific oligonucleotide method. A group of 14,529 healthy Chinese Han individuals registered at the Dalian Blood Center as bone marrow donors, living in the same region and of the same ethnicity, were used as controls. RESULTS: We found that only one allele, HLA-DRB1*12, showed a positive association with ESRD (p = 0.004, pc = 0.028, odds ratio = 1.530, 95% confidence interval = 1.147-2.041); A*02-B*40 DRB1*09, A*02-B*40-DRB1*12, A*24-B*15-DRB1*12, and B*40-DRB1*12 were significantly more frequent in ESRD patients after Bonferroni correction (pc < 0.05). CONCLUSION: They were potentially valuable predictors for evaluating the risk of ESRD in the Dalian Han population. PMID- 29257903 TI - "Kyrgyz Clinics" in Moscow: Medical Centers for Central Asian Migrants. AB - Social isolation limits migrants' access to health care, providing the context for the emergence of migrants' own medical infrastructure. In this article, we explore the so-called Kyrgyz clinics, private medical centers in Moscow founded by doctors from Kyrgyzstan and targeted specifically for labor migrants from Central Asian countries, particularly Kyrgyzstan, Uzbekistan, and Tajikistan. These Kyrgyz clinics both provide affordable medical services and enable migrant doctors to guide migrant patients through Russia's medical infrastructure, in the context of limited resources, lack of health insurance, low awareness of available services, and other barriers to care. PMID- 29257904 TI - Development and characterization of lipid-polymeric nanoparticles for oral insulin delivery. AB - INTRODUCTION: The oral route is widely accepted as the most physiological path for exogenous administration of insulin, as it closely mimic the endogenous insulin pathway. Thus, in this work it is proposed an innovative lipid-polymeric nanocarrier to delivery insulin orally. Areas covered: Nanoparticles were produced through a modified solvent emulsification-evaporation method, using ethyl palmitate and hydroxypropylmethylcellulose acetate succinate as matrix. Lipid-polymeric nanoparticles were around 300 nm in size, negatively charged (-20 mV) and associated insulin with efficiency higher than 80%. Differential scanning calorimetry suggested thermal stability of nanoparticles. In vitro release assays under simulated gastrointestinal conditions resulted in 9% and 14% of insulin released at pH 1.2 during 2 h and at pH 6.8 for 6 h, respectively, demonstrating the ability of those nanoparticles to protect insulin against premature degradation. Importantly, nanoparticles were observed to be safe at potential therapeutic concentrations as did not originate cytotoxicity to intestinal epithelial cells. Lastly, the permeability of nanoencapsulated insulin through Caco-2 monolayers and a triple Caco-2/HT29-MTX/Raji B cell model correlated well with slow release kinetics, and fosters the effectiveness of nanoparticles to promote intestinal absorption of peptidic drugs. Expert opinion: Lipid-polymeric nanoparticles were developed to encapsulate and carry insulin through intestine. Overall, nanoparticles provide insulin stability and intestinal permeability. PMID- 29257905 TI - The Prevalence and Symptom Profile of Asthma-COPD Overlap: The HUNT Study. AB - The concept of asthma and COPD as separate conditions has been questioned, and the term asthma-COPD overlap syndrome has been introduced. We assessed the prevalence, symptoms, and lifestyle factors of asthma-COPD overlap (ACO) in a large Norwegian population-based study. From 2006 to 2008, a total of 50,777 residents of Nord-Trondelag participated in the Nord-Trondelag Health Study, Norway. They completed questionnaires regarding respiratory symptoms, disease status, and medication use. We estimated the prevalence and 95% confidence intervals of ACO. Additionally, spirometry was used to estimate the prevalence of ACO in a subgroup. The prevalence of self-reported ACO was 1.9%, and in age groups <40, 40-60 and >=60 years it was 0.7%, 1.4%, and 3.2%, respectively. Among those reporting COPD, the proportion of ACO was 0.56. In the spirometry subgroup when ACO was defined as doctor diagnosed asthma ever and FEV1/FVC < 0.70, the prevalence of ACO was 2.0%. All respiratory symptoms, separately or in combination, as well as medication use were reported most frequently in those with ACO compared to the other groups. Strikingly, we observed a two-fold higher proportion of allergic rhinitis in ACO compared to COPD only. In this Norwegian population, the prevalence of self-reported ACO was 1.9%, and the corresponding proportion of ACO among those with COPD was 0.56. Participants with ACO generally had the highest proportions of respiratory symptoms compared to asthma or COPD. PMID- 29257906 TI - The prognostic value of regulatory T cells infiltration in HER2-enriched breast cancer microenvironment. AB - Breast cancer represents a complex and heterogeneous disease that comprises distinct disease conditions, histological features, and clinical outcome. Since many years, it has been demonstrated as an association between HER2 amplification and poor prognosis, because its overexpression is associated with an aggressive phenotype of breast tumor cells. A significant proportion of cases have developed resistance to the current therapies available. Consequently, new prognostic markers are urgently needed to identify patients who are at the highest risk for developing metastases. During the past decade, new insights provided valuable knowledge regarding mechanisms underlying the dynamic interplayed between immune cells and tumor progression. It has been shown that the presence of a lymphocytic infiltrate, particularly of regulatory T cells, in cancer tissue, is associated with clinical outcome promoting rather than inhibiting cancer development and progression. It has been also verified that the clinical value of lymphocytic infiltration in breast cancers could be subtype-dependent, including the HER2 enriched subtype. In this context, this work summarizes proposed to discuss the prognostic value of regulatory T cell infiltration in microenvironment of HER2 enriched breast cancer. PMID- 29257907 TI - The promising role of monoclonal antibodies for immunotherapy of the HIV associated cancer, non-Hodgkin lymphoma. AB - Association between HIV/AIDS and some of the cancers such as lymphomais is well known. Relative risk for developing non-Hodgkin lymphoma (NHL) increases 60-200 folds in HIV-infected individuals. Diffuse large B cell lymphoma (DLBCL), primary effusion lymphoma (PEL), Burkitt's lymphoma (BL) and Plasmablastic Lymphoma (PBL) are among the most frequent subtypes. During the last century, scientists found that the immune system could potentially detect and destroy cancer cells. Therefore, they started a new field of study, which is named immunotherapy. There are different immunotherapeutic methods, among which therapeutic antibodies, such as Brentuximabvedotin (Adcetris), Ibritumomabtiuxetan (Zevalin) and rituximab (Rituxan), used for treatment of NHLs showed promising results. In this article, we will review the immunotherapeutic option, monoclonal antibodies, for treatment of HIV-associated NHLs as well as their recent clinical status. We will also discuss the selective monoclonal antibody for each subtype of NHLs. PMID- 29257908 TI - Elder Care and Private Health Insurance in South Africa: The Pathos of Race Class. AB - This article shows how age as a category of dependency upends popular consciousness about race and class within postcolonial health systems. White individuals working within South Africa's private health insurance (medical aid) market and allied fields face a conundrum with respect to elder care. Some policies accommodate older adults' needs, but being older is costly and long-term residential care is excluded. Critically, these workers' position as middle- and upper-class enables them to pity older, poorer whites and blacks who more often use a dysfunctional public health sector, yet the elder care gap and other limitations reveal that these workers' own class position is also tenuous. PMID- 29257909 TI - Effects of traffic-related air pollution on susceptibility to infantile bronchiolitis and childhood asthma: A cohort study in Korea. AB - OBJECTIVE: This study examined the role of exposure to traffic-related air pollution (TRAP) on susceptibility to asthma in children with past episodes of bronchiolitis. METHODS: The baseline data included 2,627 school children aged 6 14 years who had participated in the longitudinal follow-up survey of the Children's Health and Environmental Research of Korea. Lifetime wheezing, past episodes of bronchiolitis, and doctor-diagnosed asthma were evaluated using an International Study of Asthma and Allergies in Childhood questionnaire. We used generalized linear regression with binomial distribution to calculate the relative risk (RR) between TRAP, assessed by proximity to a main road and the total length of roads, and asthma. RESULTS: Compared with the subjects who had less than 100 m of road length within 200-m radius from their home, those with more than 500 m of road length had significantly increased odds for infantile bronchiolitis (adjusted OR [aOR]: 1.57, 95% confidence interval [CI]: 1.01-2.42). Positive exposure-response relationships were found between residential proximity to the main road and asthma (aOR: 1.79, 95% CI: 1.05-3.06; <75 m vs. >700 m from a main road, P for the trend = 0.02). Closer residential proximity to the main road (<75 m) and bronchiolitis combined increased the risks of newly diagnosed asthma (adjusted RR: 3.62, 95% CI: 1.07-12.26) compared with those without bronchiolitis and living >= 75 m away from the main road. CONCLUSIONS: TRAP appeared to be associated with an increased asthma among children with bronchiolitis, indicating the importance of modifying effects of bronchiolitis in asthma pathogenesis. PMID- 29257910 TI - Obesity and neurological disorders: Dietary perspective of a global menace. AB - Obesity is considered a major public health concern throughout the world among children, adolescents, as well as adults and several therapeutic, preventive and dietary interventions are available. In addition to life style changes and medical interventions, significant milestones have been achieved in the past decades in the development of several functional foods and dietary regimens to reduce this menace. Being a multifactorial phenomenon and related to increased fat mass that adversely affects health, obesity has been associated with the development of several other co-morbidities. A great body of research and strong scientific evidence identifies obesity as an important risk factor for onset and progression of several neurological disorders. Obesity induced dyslipidaemia, metabolic dysfunction, and inflammation are attributable to the development of a variety of effects on central nervous system (CNS). Evidence suggests that neurological diseases such as Parkinson's disease and Alzheimer's disease could be initiated by various metabolic changes, related to CNS damage, caused by obesity. These metabolic changes could alter the synaptic plasticity of the neurons and lead to neural death, affecting the normal physiology of CNS. Dietary intervention in combination with exercise can affect the molecular events involved in energy metabolism and synaptic plasticity and are considered effective non-invasive strategy to counteract cognitive and neurological disorders. The present review gives an overview of the obesity and related neurological disorders and the possible dietary interventions. PMID- 29257911 TI - Body/Selves and Beyond: Men's Narratives of Sexual Behavior on PrEP. AB - Although pre-exposure prophylaxis (PrEP) has dramatically impacted HIV prevention, deep engagement with PrEP-takers' own accounts of their sexual behavior is still rare. We report findings from semi-structured interviews with male participants of the US PrEP Demonstration Project. In their narratives, interviewees variously foregrounded their individual selves, interactions with sexual partners, and the biopolitical and historical context of their lives. PrEP served to discursively integrate the multiple selves populating these stories. We argue that medical anthropological notions can help make sense of men's accounts, and PrEP's role in them, advancing a holistic conception of personhood that includes but transcends concern with HIV. PMID- 29257912 TI - 4-Ethylphenol, 4-ethylguaiacol and 4-ethylcatechol in red wines: Microbial formation, prevention, remediation and overview of analytical approaches. AB - The presence of 4-ethylphenol, 4-ethylguaiacol and 4-ethylcatechol in red wines affect negatively their aroma conferring horsy, barnyard, smoky and medicinal aromatic notes. These volatile phenols formed from free hydroxycinnamic acids and their ethyl esters by Dekkera/Brettanomyces yeasts, can contaminate wines. Their formation can cause serious negative economic impact to the wine industry worldwide as consumers tend to reject these wines. For these reasons various preventive and remedial treatments have been studied. This review summarises the wine microbial volatile phenols formation, preventive measures during winemaking and remedial treatments in finished wines along with their advantages and limitations for dealing with this sensory defect and impact on wine quality. Also it is important to control the levels of volatile phenols in wines using fast and convenient analytical methods namely with a detection limit below their olfactory perception threshold. The analytical methods available for quality control and performance characteristics as well their advantages and disadvantages when dealing with a complex matrix like wine are discussed in detail. PMID- 29257913 TI - Service failures and challenges in responding to people bereaved through drugs and alcohol: An interprofessional analysis. AB - This article reports findings from the first two stages of a three-stage qualitative study which considered the role of services, including public, private and charitable organisations, in responding to the needs of adults bereaved following the drug and/or alcohol-related death of someone close. The study, the first of its kind to explore the landscape and role of services in substance use deaths, was conducted over two sites: south west England and Scotland. In stage 1 of the research, adopting both convenience and purposive sampling, data were collected via semi-structured interviews on experiences and support needs of bereaved individuals (n = 106). In stage 2, six focus groups were conducted with a purposive sample of practitioners (n = 40), including those working for the police, coroner's service, procurator fiscal depute (Scotland), health service, funeral service, press, clergy, Public Health England, Drugs Policy Unit, bereavement counselling/support and alcohol and drug treatment services, to investigate how services may better respond to this bereavement. Thematic analysis from both data-sets identified two overarching themes. The first, focusing on practitioner responses, captures how these bereaved people may meet with inadequate, unkind, and discriminatory responses from services. Having to navigate unfamiliar, fragmented, and time-consuming procedures compounds the bereaved's distress at an already difficult time, illustrated by a 'mapping' of relevant services. The second relates to challenges and opportunities for those responding. Service failures reflect practitioners' poor understanding of both substance use bereavement and the range of other practitioners and services involved. Those bereaved are a poorly understood, neglected and stigmatised group of service users. There is a need for services to respond without judgement or insensitive language, and provide information about, communicate and work closely with, other services despite differences in working practices and cultures. These recommendations could positively affect bereaved peoples' experiences, alleviating stress and overwhelm at a particularly vulnerable time. PMID- 29257914 TI - MicroRNAs as therapeutic targets for the treatment of diabetes mellitus and its complications. AB - INTRODUCTION: Diabetes mellitus is a very common metabolic disorder affecting more than 400 million people worldwide. Currently available treatments permit to manage the disease but, in the long term, many patients develop severe micro- and macrovascular complications that decrease life quality and expectancy. Better therapeutic tools to prevent and treat diabetes are therefore urgently needed. Areas covered: MicroRNAs are key regulators of gene expression and central players in a variety of physiological and pathological processes. This review summarizes the role of microRNAs in insulin-secreting cells and in insulin target tissues as well as their involvement in the development of diabetes and its long term complications. Expert opinion: Because of their physicochemical properties and their capacity to regulate a wide range of physiopathological events, microRNAs are attractive therapeutic targets. There is accumulating evidence that approaches permitting to correct the level of specific microRNAs can successfully prevent or treat diabetes and its complications. Pharmacological tools that efficiently modulate the level of microRNAs are already available. However, before these tools can be allowed to integrate the arsenal for the treatment of diabetic patients, new innovative strategies will be needed to achieve selective delivery of these pharmacological principles to the appropriate target cells. PMID- 29257915 TI - Preparing healthcare students who participate in interprofessional education for interprofessional collaboration: A constructivist grounded theory study protocol. AB - This article presents a qualitative research protocol to explore and understand the interprofessional collaboration (IPC) preparation process implemented by clinical tutors and students of different professions involved in interprofessional education (IPE). Many studies have shown that IPE initiatives improve students' understanding of the roles and responsibilities of other professionals. This improves students' attitudes towards other professions, facilitating mutual respect, and IPC. However, there is limited information about how students are prepared to work collaboratively within interprofessional teams. This is a constructivist grounded theory (GT) study, which will involve data collection through in-depth semi-structured interviews (to 9-15 students and 6-9 clinical tutors), participant observations, and the analysis of documentation. After analysing, coding, integrating, and comparing the data if necessary, a second round of interviews could be conducted to explore any particularly interesting aspects or clarify any issues. This will then be followed by focused and theoretical coding. Qualitative data analysis will be conducted with the support of NVivo 10 software (Victoria, Australia). A better conceptual understanding will help to understand if IPE experiences have contributed to the acquisition of competencies considered important for IPC, and if they have facilitated the development of teamwork attitudes. PMID- 29257916 TI - The Use of Regulatory Power by U.S. State and Local Alcohol Control Agencies to Ban Problematic Products. AB - BACKGROUND: Alcohol is responsible for 4,300 deaths a year in the U.S. among persons under 21. Alcohol companies innovate rapidly and produce new products, some of which prove popular among young people. The 18 "control jurisdictions" in the U.S. - those that exercise monopoly control over some aspect of alcohol distribution - have the ability to govern which products become available within their borders and have, at times, exercised that authority to block particular products from sale. OBJECTIVES: This paper is an exploratory study examining how states use regulatory authority in control jurisdictions to restrict the sale of new alcohol products within their borders, and the reasoning used to justify those decisions. METHODS: The authors, collaborating with the National Alcohol Beverage Control Association, surveyed control state officials regarding procedures and policies governing the sale of new products in their jurisdictions. RESULTS: Control jurisdictions have banned/restricted different products (e.g., grain alcohol and alcoholic energy drinks) for a variety of reasons (e.g., flavorings/packaging appealing to underage drinkers, blurring of distinctions between alcoholic and non-alcoholic drinks, and judgment that the product was not socially responsible). Conclusions/ Importance: Although U.S. control jurisdictions universally have the authority to limit access to problematic alcohol products; they vary in the degree to which they use it. These states need to take action, and as of now, there is no systematic reasoning behind when and how states make decisions to ban/restrict these products. Greater exploration of regulatory authority in this arena could be protective of public health. PMID- 29257917 TI - Pharmacological inhibition of S6K1 facilitates platelet activation by enhancing Akt phosphorylation. AB - Platelet activation and thrombus formation is a delicate process involving a series of crosstalk between different pathways. P70 ribosomal S6 kinase1 (S6K1) is a member of serine/threonine kinases and can be phosphorylated by 3 phosphoinositide-dependent protein kinase 1 (PDK1). S6K1 is widely reported to play important roles in cancers and metabolic diseases, but the role of S6K1 and the importance of phosphorylation on Thr229 in platelet activation have not been defined. PF-4708671 is a recently synthesized highly specific inhibitor of S6K1. In this study, we tested PF-4708671 to assess the role of S6K1 in platelet. PF 4708671 facilitated mouse and human platelet aggregation and ATP secretion induced by collagen, thrombin, and adenosine diphosphate through enhanced Akt and Gsk3beta phosphorylation. PF-4708671 also accelerated integrin alphaIIbbeta3 mediated clot retraction and spreading. Intravenously given PF-4708671 shortened the occlusion time in arterial thrombosis model. Further results demonstrated that S6K1 was phosphorylated by PDK1 on Thr229 in the resting platelets and dephosphorylated in response to agonist stimulation. PDK1-deficient mice showed higher aggregation when PI3K-Akt-Gsk3beta signaling was blocked by the Gsk3beta inhibitor SB216763. Thus, S6K1 Thr229 phosphorylation might function as a regulator that prevents platelets from activation. S6K1 inhibition may yield potential pro-thrombotic effects and should be used cautiously when considered as a therapy. PMID- 29257918 TI - Discovery of Selective Cannabinoid CB2 Receptor Agonists by High-Throughput Screening. AB - The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain. Drug development that targets the cannabinoid receptors (CB1 and CB2) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB1 that are enriched in the CNS. CB2, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB2-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB1 activation. As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB2. Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1. These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles. PMID- 29257919 TI - A Systematic, Intensive Statistical Investigation of Data from the Comprehensive Analysis of Reported Drugs (CARD) for Compliance and Illicit Opioid Abstinence in Substance Addiction Treatment with Buprenorphine/naloxone. AB - BACKGROUND: Buprenorphine and naloxone (bup/nal), a combination partial mu receptor agonist and low-dose delta mu antagonist, is presently recommended and used to treat opioid-use disorder. However, a literature review revealed a paucity of research involving data from urine drug tests that looked at compliance and abstinence in one sample. METHOD: Statistical analysis of data from the Comprehensive Analysis of Reported Drugs (CARD) was used to assess compliance and abstinence during treatment in a large cohort of bup/nal patients attending chemical-dependency programs from eastern USA in 2010 and 2011. RESULTS: Part 1: Bup/nal was present in 93.4% of first (n = 1,282; p <.0001) and 92.4% of last (n = 1,268; p <.0001) urine samples. Concomitantly, unreported illicit drugs were present in 47.7% (n = 655, p =.0261) of samples. Patients who were compliant to the bup/nal prescription were more likely than noncompliant patients to be abstinent during treatment (p =.0012; odds ratio = 1.69 with 95% confidence interval (1.210, 2.354). Part 2: An analysis of all samples collected in 2011 revealed a significant improvement in both compliance (p < 2.2 * 10-16) and abstinence (p < 2.2 * 10-16) during treatment. Conclusion/Importance: While significant use of illicit opioids during treatment with bup/nal is present, improvements in abstinence and high compliance during maintenance-assisted therapy programs may ameliorate fears of diversion in comprehensive programs. Expanded clinical datasets, the treatment modality, location, and year of sampling are important covariates, for further studies. The potential for long term antireward effects from bup/nal use requires consideration in future investigations. PMID- 29257920 TI - Relationships between Adaptive Behaviours, Personal Factors, and Participation of Young Children. AB - AIM: To examine the extent to which personal factors (age, socioeconomic grouping, and preterm birth) and adaptive behaviour explain the participation patterns of young children. METHODS: 65 Children 2-5 years old with and without a history of preterm birth and no physical or intellectual disability were selected by convenience sampling from Galway University Hospital, Ireland. Interviews with parents were conducted using the Adaptive Behaviour Assessment System, Second Edition (ABAS-II) and the Assessment of Preschool Children's Participation (APCP). Linear regression models were used to identify associations between the ABAS-II scores, personal factors, and APCP scores for intensity and diversity of participation. RESULTS: Adaptive behaviour explained 21% of variance in intensity of play, 18% in intensity of Skill Development, 7% in intensity of Active Physical Recreation, and 6% in intensity of Social Activities controlling for age, preterm birth, and socioeconomic grouping. Age explained between 1% and 11% of variance in intensity of participation scores. Adapted behaviour (13%), Age (17%), and socioeconomic grouping (5%) explained a significant percentage of variance in diversity of participation controlling for the other variables. CONCLUSIONS: Adaptive behaviour had a unique contribution to children's intensity and diversity of participation, suggesting its importance. PMID- 29257921 TI - An Interview With La Leche League Founders Marian Tompson and Mary Ann Kerwin, JD. PMID- 29257922 TI - CYP2C19 genotype and adverse cardiovascular outcomes after stent implantation in clopidogrel-treated Asian populations: A systematic review and meta-analysis. AB - The effect of CYP2C19 gene polymorphism on clinical outcomes of patients with coronary artery disease (CAD) treated with clopidogrel remains controversial. Ethnicity has been proposed to influence clopidogrel response following stent implantation in CAD patients with different CYP2C19 genotypes. Furthermore, Asian populations are reported to have a relatively greater prevalence of CYP2C19 loss of-function (LOF) alleles. We aimed to evaluate the impact of CYP2C19 gene polymorphism on clinical outcomes in Asian populations who underwent percutaneous coronary interventions (PCI) and received clopidogrel therapy. We conducted a comprehensive search in PubMed, EMBASE, and Cochrane Library from their inceptions to January 20, 2017. Studies that reported clopidogrel therapy information, clinically relevant outcomes (adverse cardiovascular events, stent thrombosis and bleeding), and CYP2C19 genotypes among Asian populations were included. The primary endpoint was major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death and myocardial infarction. The safety endpoint was any kind of bleeding. We retrieved 20 studies of 15056 patients reporting 1301 cardiovascular events. The primary analysis showed at least one CYP2C19 LOF allele (*2 and/or *3) carriers were at an increased risk of MACE compared with non-carriers (10.58% vs. 6.07%, OR: 1.99, 95% CI: 1.64 to 2.42, p < .001). Stent thrombosis (ST) was also more frequent in LOF allele carriers (2.22% vs. 0.44%, OR: 4.77, 95% CI: 2.84 to 8.01, p < .001). Inversely, the risk of bleeding was lower in LOF allele carriers (OR: 0.66, 95% CI: 0.46 to 0.96, p < .001). Subgroup analysis was performed to assess differences by high (600 mg) or routine (300 mg) loading dose of clopidogrel and by different nationalities. The risk of MACE in LOF allele carriers remained significantly higher even in high loading dose group (high loading dose: OR 1.72, 95% CI: 1.37 to 2.16, and routine loading dose: OR 2.22, 95% CI: 1.68 to 2.94, p for subgroup heterogeneity = 0.16). Subgroup analysis between three nationalities of China, Korea, and Japan demonstrated that the risk of MACE among Chinese LOF allele carriers was the greatest (OR: 2.28; 95% CI:1.91 to 2.73). In conclusion, among Asian populations with CAD undergoing stent implantation, CYP2C19 LOF allele carriers are at greater risk of adverse cardiovascular events and lower risk of bleeding compared with non-carriers. Genetic testing may be helpful for clinicians to personalize antiplatelet therapy especially in Asian population. PMID- 29257924 TI - Electrically Elicited Quadriceps Muscle Torque: A Comparison of 3 Waveforms. AB - Study Design A controlled laboratory study, with a single-blind, block randomization crossover design. Objectives To compare the electrically elicited knee extensor torque produced by 3 clinically available waveforms: 2500-Hz burst modulated alternating current (BMAC), 1000-Hz BMAC, and 1000-Hz burst-modulated biphasic square-wave pulsed current (BMBPC). Background Neuromuscular electrical stimulation (NMES) is the therapeutic use of electrical current to strengthen muscle. Muscle torque produced by NMES is limited by discomfort. Methods The knee extensor maximal volitional isometric torque (KEMVIT) of 33 able-bodied participants (18 female) was measured and used to normalize the electrically elicited knee extensor torque to produce a percent of KEMVIT (%KEMVIT). Electrically elicited isometric knee extensor torque was measured in response to each of the waveforms at the participants' maximum tolerance. Results The average maximum tolerated stimulation produced 32.0 +/- 16.7 %KEMVIT with 2500-Hz BMAC, 38.2 +/- 18.4 %KEMVIT with 1000-Hz BMAC, and 42.2 +/- 17.1 %KEMVIT with 1000-Hz BMBPC. Tukey honest significant difference (HSD) post hoc testing revealed a statistically significant difference between 2500-Hz BMAC and 1000-Hz BMAC (P = .046), and between 2500-Hz BMAC and 1000-Hz BMBPC (P<.001). No statistically significant difference was found between 1000-Hz BMAC and 1000-Hz BMBPC (P = .267). Conclusion For eliciting maximum knee extensor muscle torque, 1000-Hz BMBPC and 1000-Hz BMAC were similarly effective, and 2500-Hz BMAC was less effective. J Orthop Sports Phys Ther 2018;48(3):217-224. Epub 19 Dec 2017. doi:10.2519/jospt.2018.7601. PMID- 29257923 TI - FGFR1 signaling potentiates tumor growth and predicts poor prognosis in esophageal squamous cell carcinoma patients. AB - Fibroblast growth factor receptor-1 (FGFR1) over-expression was broadly found in squamous cancer, where it induced cellular proliferation, differentiation, and metastasis by activating various signaling pathway. However, the role of FGFR1 gene expression in predicting prognosis of Esophageal Squamous Cell Carcinoma (ESCC) and its regulatory function in the progression of ESCC are not well understood. Therefore, we performed an analysis of FGFR1 mRNA expression by quantitative RT-PCR in tumor tissue of 145 patients with ESCC. The relationships between FGFR1 gene expression and clinicopathological parameters, also the prognosis were further examined. Results suggested that higher FGFR1 gene expression predicted worse overall survival (HR = 1.502, 95%[CI] = 1.005-2.246, P = 0.045). Disease-free survival tends to be shorter in patients with higher FGFR1 expression but without statistical significance (HR = 1.398, 95%[CI] = 0.942 2.074, P = 0.096). FGFR1 was up regulated in multiple ESCC cell lines. Subsequent in vitro experiments demonstrated that anti-FGFR1 treatment by PD173074 inhibited TE-1 and EC9706 cell viability along with the attenuation of MEK-ERK signaling pathway. In vivo, PD173074 administration also had shown potent ESCC growth arresting effect. Overall, our study suggested that FGFR1 gene expression could be an independent prognosis predictive factor in patients with ESCC. Anti-FGFR1 inhibited ESCC growth and could be a potential strategy in ESCC targeted therapy. PMID- 29257925 TI - Validity and Responsiveness of the Pain Self-Efficacy Questionnaire in Patients With Neck Pain Disorders. AB - Study Design Longitudinal clinimetric study. Background Pain self-efficacy predicts poor recovery and mediates the relationship between pain and disability in patients with neck pain disorders (NPDs). The Pain Self-Efficacy Questionnaire (PSEQ) is a frequently used instrument to measure pain self-efficacy; however, its measurement properties have never been evaluated in a group of patients with NPDs. Objectives This study aimed to assess validity and responsiveness of the PSEQ in patients with NPDs. Methods Patients with NPDs (n = 161) were included. Confirmatory and exploratory factor analysis was used to assess structural validity. Twelve hypotheses on expected correlations with other instruments were formulated a priori to assess construct validity. Responsiveness was evaluated in 146 patients with NPDs who underwent multimodal rehabilitation by testing 12 hypotheses on expected effect sizes, area under the curve, and correlations with change in other instruments. Results Factor analyses showed that the PSEQ is a unidimensional instrument with moderate construct validity and responsiveness (50% to 75% of hypotheses met). Validity was consistent when analyzed separately for patients with whiplash-associated disorders and idiopathic neck pain, and responsiveness was better in patients with idiopathic neck pain. Conclusion The PSEQ is a unidimensional measure of pain self-efficacy in patients with NPDs, as found by previous studies in other populations. Nevertheless, in contrast with previous studies, its construct validity and responsiveness were found to be suboptimal in NPDs, suggesting that the content validity of the PSEQ and of the comparator instruments used in this study should be better assessed. J Orthop Sports Phys Ther 2018;48(3):204-216. Epub 19 Dec 2017. doi:10.2519/jospt.2018.7605. PMID- 29257926 TI - Use of Pain Neuroscience Education, Tactile Discrimination, and Graded Motor Imagery in an Individual With Frozen Shoulder. AB - Study Design Case report. Background Aggressive physical therapy in the freezing stage of frozen shoulder may prolong the course of recovery. Central sensitization may play a role in the early stages of frozen shoulder. Pain neuroscience education, tactile discrimination, and graded motor imagery have been used in a number of conditions with central sensitization. The purpose of this case report was to describe the examination and treatment of a patient in the freezing stage of frozen shoulder using pain neuroscience education, tactile discrimination, and graded motor imagery. Case Description A 54-year-old woman with a diagnosis of frozen shoulder was referred by an orthopaedic surgeon following lack of progress after 4 weeks of intensive daily physical therapy. Pain at rest was 7/10, and her Shoulder Pain and Disability Index score was 64%. She had painful and limited active range of motion and elevated fear-avoidance beliefs. Tactile discrimination and limb laterality were impaired, with signs of central sensitization. A "top-down" approach using pain neuroscience education, tactile discrimination, and graded motor imagery was used for the first 6 weeks, followed by a "bottom-up" impairment-based approach. Outcomes The patient was seen for 20 sessions over 12 weeks. At discharge, her Shoulder Pain and Disability Index score was 22%, resting pain was 0/10, and fear-avoidance beliefs improved. Improvements in active range of motion, laterality, and tactile discrimination were also noted. Discussion Intensive physical therapy in the freezing stage of frozen shoulder may be detrimental to long-term outcomes. This case report suggests that a top-down approach may allow a quicker transition through the freezing stage of frozen shoulder. Level of Evidence Therapy, level 5. J Orthop Sports Phys Ther 2018;48(3):174-184. Epub 19 Dec 2017. doi:10.2519/jospt.2018.7716. PMID- 29257928 TI - Erratum. PMID- 29257927 TI - Dermatopathology and Social Media: Improving Participation by Increasing Clarity. PMID- 29257929 TI - Nodal Involvement by CD30+ Cutaneous Lymphoproliferative Disorders and Its Challenging Differentiation From Classical Hodgkin Lymphoma. AB - Primary cutaneous lymphomas are defined as non-Hodgkin lymphomas that present in the skin with no evidence of extracutaneous disease at the time of diagnosis. Mycosis fungoides is the most common type of primary cutaneous T-cell lymphoma, representing almost 50% of primary cutaneous T-cell lymphomas, and primary cutaneous CD30+ T-cell lymphoproliferative disorders are the second most common group (30%). Transformed mycosis fungoides is usually CD30+ and can involve multiple nodal sites; other primary cutaneous CD30+ T-cell lymphoproliferative disorders can also involve draining regional nodes. Nodal involvement by CD30+ T cell lymphoproliferative disorders can mimic classical Hodgkin lymphoma, which can aberrantly express T-cell antigens. The aim of this article is to briefly review salient clinical, histologic, immunophenotypic, and molecular features that can be used to distinguish lymph node involvement by CD30+ cutaneous T-cell lymphomas and lymphoproliferative disorders from classical Hodgkin lymphoma, a clinically important differential diagnosis that represents a challenging task for the pathologist. PMID- 29257931 TI - Erratum. PMID- 29257930 TI - The impact of face skin tone on perceived facial attractiveness: A study realized with an innovative methodology. AB - This study aimed to assess the impact of target faces' skin tone and perceivers' skin tone on the participants' attractiveness judgment regarding a symmetrical representative range of target faces as stimuli. Presented with a set of facial features, 240 Mozambican adults rated their attractiveness along a continuous scale. ANOVA and Chi-square were used to analyze the data. The results revealed that the skin tone of the target faces had an impact on the participants' attractiveness judgment. Overall, participants preferred light-skinned faces over dark-skinned ones. This finding is not only consistent with previous results on skin tone preferences, but it is even more powerful because it demonstrates that the light skin tone preference occurs regardless of the symmetry and baseline attractiveness of the stimuli. PMID- 29257932 TI - Predictors of Smartphone Uses for Health Information Seeking in the Korean Elderly. AB - The purpose of this research is to examine the predictors of smartphone uses for health information-seeking (SHIS) in the Korean elderly. This research applies the comprehensive model of information seeking as a theoretical framework. Data reported in this study are from the 2016 Dementia Literacy Survey, and 235 elderly smartphone users were included in logistic regression model. SHIS was significantly predicted by younger age, higher education levels, having a regular exercise, higher medical expenditures, and health literacy. The findings of this study can help social workers understand the specific features of health information seeking in the Korean elderly. PMID- 29257933 TI - Authority of Pharmacists to Administer Human Papillomavirus Vaccine: Alignment of State Laws With Age-Level Recommendations. AB - OBJECTIVES: One strategy to increase the uptake of human papillomavirus (HPV) vaccine among adolescents is through the use of pharmacists. Our objectives were to (1) use a publicly available database to describe the statutory and regulatory authority of pharmacists to administer the HPV vaccine in the United States and (2) discuss how the current status of laws may influence achievement of the Healthy People 2020 goal of 80% HPV vaccination rate for teenagers aged 13-15. METHODS: Using information from the Centers for Disease Control and Prevention's (CDC's) Public Health Law Program database, we identified state laws in effect as of January 1, 2016, giving pharmacists authority to administer vaccines. We used a standardized analysis algorithm to determine whether states' laws (1) authorized pharmacists to administer HPV vaccine, (2) required third-party authorization for pharmacist administration, and (3) restricted HPV vaccine administration by pharmacists to certain patient age groups. RESULTS: Of 50 states and the District of Columbia, 40 had laws expressly granting pharmacists authority to administer HPV vaccine to patients, but only 22 had laws that authorized pharmacists to vaccinate preadolescents aged 11 or 12 (ie, the CDC recommended age group). Pharmacists were granted prescriptive authority by 5 states, and they were given authority pursuant to general (non-patient-specific) third-party authorization (eg, a licensed health care provider) by 32 states or patient-specific third-party authorization by 3 states. CONCLUSIONS: Most states permitted pharmacists to administer HPV vaccines only to boys and girls older than 11 or 12, which may hinder achievement of the Healthy People 2020 goal for HPV vaccination. Efforts should be made to strengthen the role of pharmacists in addressing this public health issue. PMID- 29257934 TI - Effect of Health Literacy on Health Perception: An Application in Individuals at Age 65 and Older. AB - This study has been conducted to look through the effects of health literacy levels of individuals age 65 years and older on their health perceptions. The application part of study is composed of persons being age 65 years or older who live in Burdur province and districts of Turkey. The sampling of study has been determined by a nonclustered, single-step random probability sampling method based on primary mass ratios. Thereby, totally 611 questionnaires have been implemented by means of the face-to-face interview method. As a result of the analyses carried out, the subdimensions of health literacy explain 16.3% of total variance on the importance of health, 6.4% of total variance on the center of control, 10.8% of total variance on the self-awareness, and 16.1% of total variance on the certainty. In addition, it has been identified that the correlations of health literacy subdimensions with the health perception subdimensions were statistically significant, in the same direction, at low and medium level. These results show that the health literacy sub-dimensions is an important determinant on the health perception dimensions. PMID- 29257935 TI - Direct payments and personal budgets: Putting personalization into practice. PMID- 29257938 TI - Muscle Synergies for Turning During Human Walking. AB - Muscle synergy describes reduced set of functional muscle co-activation patterns. We aimed to identify muscle synergies of turning compared with straight walking. Twelve healthy adults (men: 7, women: 5) performed straight walking (SW), left turning (LT), and right turning (RT) at self-selected speeds. By using non negative matrix factorization (NMF), we extracted muscle synergies from sixteen electromyography (EMG) signals on the right side and assigned similar muscle synergies among SW, LT, and RT into the same cluster by combining k-means clustering and intraclass correlation coefficient (ICC) analysis. We obtained task-specific clusters of muscle synergies extracted from SW, LT, or RT condition and identified the clusters that share synergies among the conditions. The central nervous system produces specific synergies involving turning behaviors and fundamental synergies for walking. PMID- 29257937 TI - Trends in Special Education Eligibility Among Children With Autism Spectrum Disorder, 2002-2010. AB - OBJECTIVE: Although data on publicly available special education are informative and offer a glimpse of trends in autism spectrum disorder (ASD) and use of educational services, using these data for population-based public health monitoring has drawbacks. Our objective was to evaluate trends in special education eligibility among 8-year-old children with ASD identified in the Autism and Developmental Disabilities Monitoring Network. METHODS: We used data from 5 Autism and Developmental Disabilities Monitoring Network sites (Arizona, Colorado, Georgia, Maryland, and North Carolina) during 4 surveillance years (2002, 2006, 2008, and 2010) and compared trends in 12 categories of special education eligibility by sex and race/ethnicity. We used multivariable linear risk regressions to evaluate how the proportion of children with a given eligibility changed over time. RESULTS: Of 6010 children with ASD, more than 36% did not receive an autism eligibility in special education in each surveillance year. From surveillance year 2002 to surveillance year 2010, autism eligibility increased by 3.6 percentage points ( P = .09), and intellectual disability eligibility decreased by 4.6 percentage points ( P < .001). A greater proportion of boys than girls had an autism eligibility in 2002 (56.3% vs 48.8%). Compared with other racial/ethnic groups, Hispanic children had the largest increase in proportion with autism eligibility from 2002 to 2010 (15.4%, P = .005) and the largest decrease in proportion with intellectual disability (-14.3%, P = .004). CONCLUSION: Although most children with ASD had autism eligibility, many received special education services under other categories, and racial/ethnic disparities persisted. To monitor trends in ASD prevalence, public health officials need access to comprehensive data collected systematically, not just special education eligibility. PMID- 29257939 TI - Bringing Creative Writing Instruction into Reminiscence Group Treatment. AB - OBJECTIVES: This article describes the program evaluation of a group intervention combining reminiscence with literary creative writing instruction. METHOD: This 10-week, 1-hour group was completed seven times in an outpatient geriatric mental health clinic. Each session introduced a different reminiscence theme and creative writing practice. Feasibility and acceptability were assessed through group monitoring and qualitative feedback. Effectiveness was assessed with pre- and post-test depression screening (PHQ-9) and qualitative feedback. RESULTS: A total of 34 veterans participated in the groups, with a mean group size of 4.86 (SD = .69). Participants were 85% male (n = 29) and 15% female (n = 5) with a mean age of 70.89 (SD = 8.30). To increase accessibility, several adaptations were made. There were statistically significant reductions in PHQ-9 depression scores (p = .005). Veterans reported qualitative improvements including increased motivation and self-expression. CONCLUSIONS: This intervention was feasible and acceptable to the veterans being served. Randomized controlled research is needed to better understand efficacy. CLINICAL IMPLICATIONS: Clinicians may consider ways to augment or adapt reminiscence interventions to meet the needs of their patient population. Clinicians may find it useful to integrate creative writing instruction into reminiscence interventions. PMID- 29257940 TI - Buffers or Boosters? The Role of HRM Practices in Older Workers' Experience of Stereotype Threat. AB - Building on the social identity approach and the HRM literature, this two-wave cross-sectional study examined the effects of negative age-based metastereotypes on the age-based stereotype threat experience of older workers and on organizational disidentification. The moderator role of HRM practices in the relationship between negative age-based metastereotypes and age-based stereotype threat was also investigated. Older workers survey results (n = 469) from 14 manufacturing companies indicated that negative age-based metastereotypes correlate positively with stereotype threat. Moderation results showed that age awareness HRM practices (training for older workers) reinforced age-based stereotype threat, whereas general HRM practices (recognition and respect) impaired it. The article suggests that the combination of age-based metastereotypes with a stereotype threat framework contributes to further understand older workers' beliefs and attitudes. It also indicates that to be effective, HRM practices should emphasize positive social identities older workers share with their colleagues, rather than giving older workers special treatment that may, after all, reinforce stigmatization. PMID- 29257941 TI - Exploring patients' awareness and healthcare professionals' knowledge and attitude to pertussis and influenza vaccination during the antenatal periods in Cavan Monaghan general hospital. AB - : Infection with Pertussis or with Influenza during the antenatal period usually results in complications leading to severe morbidity and mortality. Influenza virus outbreak usually occurs almost every year during the winter periods with profound burden on the entire healthcare system. Both disease conditions are preventable with adequate health education and vaccination. Healthcare professionals have a role to play in the communication and provision of this all important health programme. OBJECTIVE: We aimed to assess patients' awareness of pertussis and influenza vaccination as well as healthcare professionals' knowledge and attitude to pertussis and influenza vaccination during the antenatal periods in Cavan Monaghan General Hospital. DESIGN: We performed a prospective cohort study in the antenatal clinics among patients, Non- consultant hospital doctors (NCHDs) and midwives in the maternity unit. SETTING: Our setting was a regional hospital in the North East of the Republic of Ireland with approximately 2000 deliveries per annum. PARTICIPANTS: These were randomly recruited from those attending routine antenatal clinic during the study period and healthcare professional working in the maternity unit. RESULTS: Of the 113 antenatal women who completed the questionnaire,. more than 75% have heard of both vaccinations in pregnancy. Interestingly, 51.3% of women heard of the vaccination from their General practitioner (GP) while 1.8% heard of it from their hospital doctor. Despite this awareness, 57.6% and 31.9% of women knew that influenza and pertussis vaccine respectively is safe in pregnancy. The uptake of both vaccines is quite low with 31% for pertussis and 42.5% for influenza vaccine respectively. Despite more than 95% of healthcare professionals being aware of the health service executive (HSE) guidelines on immunisation, more than 75% of healthcare professionals did not receive the influenza vaccinations themselves and had no plans to receive it. More so, only 18% of healthcare professionals always discuss immunisation with antenatal women during their consultations. CONCLUSION: Our study identified low pertussis and influenza vaccine uptake among pregnant women and their HCPs. Inadequate knowledge of immunization guidelines among HCPs, lack of insight on the need to get the vaccines among HCPs and poor communication are the probable cause of the low uptake. Hence, the need for more health educational programs to improve health professionals' knowledge and vaccine confidence and also vaccine uptake by patients. PMID- 29257936 TI - The role of basophils as innate immune regulatory cells in allergy and immunotherapy. AB - Basophils are circulating cells that are associated quite exclusively with allergy response and hypersensitivity reactions but their role in the immune network might be much more intriguing and complex than previously expected. The feasibility of testing their biology in vitro for allergy research and diagnosis, due fundamentally to their quite easy availability in the peripheral blood, made them the major source for assessing allergy in the laboratory assay, when yet many further cells such as mast cells and eosinophils are much more involved as effector cells in allergy than circulating basophils. Interestingly, basophil numbers change rarely in peripheral blood during an atopic response, while we might yet observe an increase in eosinophils and modification in the biology of mast cells in the tissue during an hypersensitivity response. Furthermore, the fact that basophils are very scanty in numbers suggests that they should mainly serve as regulatory cells in immunity, rather than effector leukocytes, as still believed by the majority of physicians. In this review we will try to describe and elucidate the possible role of these cells, known as "innate IL4-producing cells" in the immune regulation of allergy and their function in allergen immunotherapy. PMID- 29257942 TI - How can we help African American substance users stop smoking? client and agency perspectives. AB - Research is needed to better understand barriers to smoking cessation and sustained abstinence among racial/ethnic minority polydrug users. We conducted community dialogue groups involving 49 clients in substance use treatment programs with predominantly ethnic minority clientele and individual dialogues/interviews with seven program providers (stakeholders). Most clients were African American, under 40 years old, women, current smokers, and high school graduates. Smoking cessation services in these programs were considered inadequate and community programs insufficiently culturally tailored and economically and geographically inaccessible. Participants discussed individual "willpower" and choice; agency tobacco-related programs and policies; the relationships between smoking, smoking cessation, and treatment goals; and steps needed to reshape agency services and policies to provide greater support for smoking cessation in this at-risk population. PMID- 29257943 TI - The Anesthetic Efficacy of Articaine and Lidocaine in Equivalent Doses as Buccal and Non-Palatal Infiltration for Maxillary Molar Extraction: A Randomized, Double Blinded, Placebo-Controlled Clinical Trial. AB - PURPOSE: The purpose of the present study was to evaluate the anesthetic adequacy of 4% articaine 1.8 mL versus 2% lidocaine 3.6 mL without palatal injection compared with the standard technique for the extraction of maxillary molar teeth. MATERIALS AND METHODS: This randomized, double-blinded, placebo-controlled clinical trial included patients requiring extraction of 1 maxillary molar under local anesthesia. Patients were randomly distributed into 1 of 3 groups: group A received 4% articaine 1.8 mL as a buccal injection and 0.2 mL as a palatal injection, group B received 4% articaine 1.8 mL plus normal saline 0.2 mL as a palatal injection, and group C received 2% lidocaine 3.6 mL plus normal saline 0.2 mL as a palatal injection. Pain was measured during injection, 8 minutes afterward, and during extraction using a visual analog scale. Initial palatal anesthesia and patients' satisfaction were measured using a 5-score verbal rating scale. Statistical analyses included descriptive statistics, analysis of variance, and Pearson chi2 test. Differences with a P value less than .05 were considered significant. RESULTS: Eighty-four patients were included in the study. The average pain of injection was comparable among all study groups (P = .933). Pain during extraction in the articaine group was significantly less than that experienced in the placebo groups (P < .001), although the differences between placebo groups were insignificant. Satisfaction scores were significantly higher in the articaine group compared with the placebo groups (P < .001), with comparable results between placebo groups. CONCLUSIONS: Although the anesthetic effects of single placebo-controlled buccal injections of 4% articaine and 2% lidocaine were comparable, the level of anesthetic adequacy was statistically less than that achieved by 4% articaine given by the standard technique. These results do not justify the buccal and non-palatal infiltration of articaine or lidocaine as an effective alternative to the standard technique in the extraction of maxillary molar teeth. PMID- 29257944 TI - Re: Dental Care for the Working Poor-We Need Answers. PMID- 29257945 TI - Regulatory T Cells Know What Is Needed to Regenerate. AB - Adaptive immunity has been suggested to limit regeneration in mammals. However, in this issue of Developmental Cell, Hui et al. (2017) report that regulatory T cells are required for regeneration of heart, spinal cord, and retina in the zebrafish. Intriguingly, in each organ system, Treg cells secrete organ-specific regeneration factors. PMID- 29257946 TI - Probing Cilia-Associated Signaling Proteomes in Animal Evolution. AB - Cilia have evolved to function as essential sensory organelles in animals. To understand why cilia are intimately associated with cell signaling, Sigg et al. (2017) develop and apply a comparative proteomics approach, reported in this issue of Developmental Cell, to analyze the evolutionary relationship between cilia and various signaling pathways. PMID- 29257947 TI - Linking Hedgehog, Translation, and mTORC1 in Medulloblastoma. AB - In this issue of Developmental Cell, Wu et al. (2017) report that mTORC1 dependent mRNA translation is required for Hedgehog signaling. They show that this process is essential for proliferation of cerebellum granule neuron precursor cells in response to Hedgehog signaling and for the formation of medulloblastoma, a cerebellum brain tumor. PMID- 29257948 TI - Unconventional Functions of Muscles in Planarian Regeneration. AB - Muscles are traditionally considered in the context of force generation. Scimone et al. (2017), reporting in Nature, now examine muscles in a developmental setting and find unexpected roles for distinct planarian muscle fibers. The authors show that muscles provide patterning signals to promote regeneration and guide tissue growth after injury. PMID- 29257949 TI - Zebrafish Regulatory T Cells Mediate Organ-Specific Regenerative Programs. AB - The attenuation of ancestral pro-regenerative pathways may explain why humans do not efficiently regenerate damaged organs. Vertebrate lineages that exhibit robust regeneration, including the teleost zebrafish, provide insights into the maintenance of adult regenerative capacity. Using established models of spinal cord, heart, and retina regeneration, we discovered that zebrafish Treg-like (zTreg) cells rapidly homed to damaged organs. Conditional ablation of zTreg cells blocked organ regeneration by impairing precursor cell proliferation. In addition to modulating inflammation, infiltrating zTreg cells stimulated regeneration through interleukin-10-independent secretion of organ-specific regenerative factors (Ntf3: spinal cord; Nrg1: heart; Igf1: retina). Recombinant regeneration factors rescued the regeneration defects associated with zTreg cell depletion, whereas Foxp3a-deficient zTreg cells infiltrated damaged organs but failed to express regenerative factors. Our data delineate organ-specific roles for Treg cells in maintaining pro-regenerative capacity that could potentially be harnessed for diverse regenerative therapies. PMID- 29257950 TI - The Vertebrate Protein Dead End Maintains Primordial Germ Cell Fate by Inhibiting Somatic Differentiation. AB - Maintaining cell fate relies on robust mechanisms that prevent the differentiation of specified cells into other cell types. This is especially critical during embryogenesis, when extensive cell proliferation, patterning, and migration events take place. Here we show that vertebrate primordial germ cells (PGCs) are protected from reprogramming into other cell types by the RNA-binding protein Dead end (Dnd). PGCs knocked down for Dnd lose their characteristic morphology and adopt various somatic cell fates. Concomitantly, they gain a gene expression profile reflecting differentiation into cells of different germ layers, in a process that we could direct by expression of specific cell-fate determinants. Importantly, we visualized these events within live zebrafish embryos, which provide temporal information regarding cell reprogramming. Our results shed light on the mechanisms controlling germ cell fate maintenance and are relevant for the formation of teratoma, a tumor class composed of cells from more than one germ layer. PMID- 29257951 TI - Atg5 Disassociates the V1V0-ATPase to Promote Exosome Production and Tumor Metastasis Independent of Canonical Macroautophagy. AB - Autophagy and autophagy-related genes (Atg) have been attributed prominent roles in tumorigenesis, tumor growth, and metastasis. Extracellular vesicles called exosomes are also implicated in cancer metastasis. Here, we demonstrate that exosome production is strongly reduced in cells lacking Atg5 and Atg16L1, but this is independent of Atg7 and canonical autophagy. Atg5 specifically decreases acidification of late endosomes where exosomes are produced, disrupting the acidifying V1V0-ATPase by removing a regulatory component, ATP6V1E1, into exosomes. The effect of Atg5 on exosome production promotes the migration and in vivo metastasis of orthotopic breast cancer cells. These findings uncover mechanisms controlling exosome release and identify means by which autophagy related genes can contribute to metastasis in autophagy-independent pathways. PMID- 29257952 TI - OsMAPK3 Phosphorylates OsbHLH002/OsICE1 and Inhibits Its Ubiquitination to Activate OsTPP1 and Enhances Rice Chilling Tolerance. AB - Improvement of chilling tolerance is a major target in rice breeding. The signaling pathways regulating chilling consist of complex networks, including key transcription factors and their targets. However, it remains largely unknown how transcription factors are activated by chilling stress. Here, we report that the transcription factor OsbHLH002/OsICE1 is phosphorylated by OsMAPK3 under chilling stress. The osbhlh002-1 knockout mutant and antisense transgenic plants showed chilling hypersensitivity, whereas OsbHLH002-overexpressing plants exhibited enhanced chilling tolerance. OsbHLH002 can directly target OsTPP1, which encodes a key enzyme for trehalose biosynthesis. OsMAPK3 interacts with OsbHLH002 to prevent its ubiquitination by the E3 ligase OsHOS1. Under chilling stress, active OsMAPK3 phosphorylates OsbHLH002, leading to accumulation of phospho-OsbHLH002, which promotes OsTPP1 expression and increases trehalose content and resistance to chilling damage. Taken together, these results indicate that OsbHLH002 is phosphorylated by OsMAPK3, which enhances OsbHLH002 activation to its target OsTPP1 during chilling stress. PMID- 29257955 TI - A Soft Handoff of Attention between Cerebral Hemispheres. PMID- 29257954 TI - Reinterpreting recent thymic emigrant function: defective or adaptive? AB - Recent thymic emigrants (RTEs) are those peripheral T cells that have most recently completed thymic development and egress. Over the past decade, significant advances have been made in understanding the cell-extrinsic and cell intrinsic requirements for RTE maturation to mature naive (MN) T cells and in detailing the functional differences that characterize these two T cell populations. Much of this work has suggested that RTEs are hypo-functional versions of more mature T cells. However, recent evidence has indicated that rather than being defective T cells, RTEs are exquisitely adapted to their cellular niche. In this review, we argue that RTEs are not flawed mature T cells but are adapted to fill an underpopulated T cell compartment, while maintaining self tolerance and possessing the capacity to mount robust immune responses. PMID- 29257956 TI - Spiralian Phylogeny Informs the Evolution of Microscopic Lineages. PMID- 29257957 TI - Trophallaxis. AB - Adria LeBoeuf introduces trophallaxis, the exchange of fluids between animals. PMID- 29257958 TI - Polyspermy produces tri-parental seeds in maize. AB - In flowering plants, two pairs of gametes participate in double fertilization. One of the two sperm delivered by the pollen tube (PT) fuses with the egg cell to form the zygote, whereas the second unites with the central cell to produce the endosperm [1]. Most animal species prevent polyspermy through a transient, fast block established by the depolarization of the egg membrane within milliseconds after encountering the first sperm, followed by a slow block generated through enzymatic changes in the extracellular matrix surrounding the egg [2]. Although in vitro fertilization experiments suggest that the maize zygote starts cell wall deposition within 30 seconds after fusion with a sperm [3], thereby preventing further fertilization events, it is unknown whether plant gametes prevent polyspermy by a fast block. Here, using a genetic approach, the absence of a fast block preventing polyspermy in the maize central cell is demonstrated. A putative polyspermy event involving the egg indicates the existence of tri-parental individuals, which may provide an alternative route to polyploidy, distinct from the one involving unreduced gametes. PMID- 29257953 TI - Evolutionary Proteomics Uncovers Ancient Associations of Cilia with Signaling Pathways. AB - Cilia are organelles specialized for movement and signaling. To infer when during evolution signaling pathways became associated with cilia, we characterized the proteomes of cilia from sea urchins, sea anemones, and choanoflagellates. We identified 437 high-confidence ciliary candidate proteins conserved in mammals and discovered that Hedgehog and G-protein-coupled receptor pathways were linked to cilia before the origin of bilateria and transient receptor potential (TRP) channels before the origin of animals. We demonstrated that candidates not previously implicated in ciliary biology localized to cilia and further investigated ENKUR, a TRP channel-interacting protein identified in the cilia of all three organisms. ENKUR localizes to motile cilia and is required for patterning the left-right axis in vertebrates. Moreover, mutation of ENKUR causes situs inversus in humans. Thus, proteomic profiling of cilia from diverse eukaryotes defines a conserved ciliary proteome, reveals ancient connections to signaling, and uncovers a ciliary protein that underlies development and human disease. PMID- 29257959 TI - Are the Q10values of more than 1,000 reported for Antarctic seabed fauna realistic? AB - In a recent paper in Current Biology, Ashton et al.[1] describe the results of what they call the first ever experiment in which benthic assemblages are warmed to ecologically relevant levels in situ. West of the Antarctic peninsula, the authors employed heated settlement panels and studied the settlement and growth of pioneering species over a 5-month period at ambient temperature and at 1 degrees C and 2 degrees C above ambient. Such ocean temperature increases are expected within the next 50-100 years. They claim that the two most dominant species doubled their growth rate already at an increase of 1 degrees C. They further state that this implies Q10 coefficients around 1,000, which is much higher than anticipated. This unpredicted result should, according to the authors, critically change our thinking of how polar communities might respond to ocean warming. Indeed, such extreme Q10 coefficients are a surprising result, and not in accordance with more than a century of laboratory or field research in temperate zones. Here, I will show that the claim is unsubstantiated and that the observed in situ growth-rate response to temperature of these Antarctic species is much weaker than claimed, and not very different from previous work in the temperate zone. PMID- 29257960 TI - Response to van der Meer. AB - In our recent Current Biology paper [1], we describe an ocean warming experiment in which we manipulated the temperature of panels set on the seafloor to provide a realistic and relevant indication of how benthic communities may change under future ocean warming. We describe increases in growth associated with warming by 1 degrees C, with growth rates up to doubled in some species. The definition of Q10 is a measure of the temperature sensitivity of an enzymatic reaction rate or a physiological process due to an increase by 10 degrees C; doubling of growth rates with a 1 degrees C change gives Q10s around 1,000. In his correspondence, Jaap van der Meer [2] questions our methods and provides alternative analyses which lead him to conclude that our observed increases in growth rate were in fact much lower and in accordance with previous studies from temperate zones. We provide justification for our use of absolute growth rate, justification for not using instantaneous growth rate (or a measure of growth in proportion to previous growth) and encourage the on-going discussion of how to measure and compare growth rates. PMID- 29257961 TI - Evolution: In Chloroplast Genomes, Anything Goes. AB - A new study shows that Cladophorales green algae have the most unconventional chloroplast DNAs ever observed, whereby genes are located on small linear single stranded palindromic elements. This puzzling architecture has parallels with mini circular chloroplast genomes of dinoflagellates and raises many questions about how it arose and is maintained. PMID- 29257962 TI - Microbial Biodiversity: Straight from the Dolphin's Mouth. AB - Advances in metagenomic sequencing and bioinformatics have vastly expanded our knowledge of microbial phylogenetic and functional diversity. In this issue, Dudek et al. show that shotgun metagenomic sequencing of a less-well-studied environment - dolphin gums - uncovers surprising novelty in the bacterial tree of life, underscoring the promise of future discovery. PMID- 29257963 TI - Meiosis: The Origins of Bias. AB - Biased, or non-Mendelian, segregation is frequently observed but not well understood. Two recent studies on a specific type of biased segregation in mammalian meiosis suggest that it arises from centromeric satellite expansion and asymmetric modification of microtubules in the oocyte spindle. PMID- 29257964 TI - Interval Timing: Stopping the Internal Stopwatch by Photostimulation. AB - Animals use estimates of time intervals to adaptively guide their anticipatory actions. New research on mice shows that photostimulation of the neural pathway that coordinates drinking behavior delays subsequent anticipatory responses by pausing/resetting the internal stopwatch. PMID- 29257965 TI - Tool Use: Crows Craft the Right Tool for the Job. AB - New research into tool crafting in New Caledonian crows has uncovered factors that influence tool shape and the foraging advantages that these characteristics confer. PMID- 29257966 TI - Paleontology: Scanning for Sea Monsters. AB - Land vertebrates have returned to the ocean several times, radically transforming their outward anatomy in the process. A new study of Mesozoic marine reptiles shows how minute balance organs in the inner ear transformed at the same time. PMID- 29257967 TI - Chromosome Biology: Specification of the Kinetochore for Cohesin Recruitment. AB - Additional cohesin loaded at the centromere helps to facilitate proper chromosome segregation. A new study reveals the mechanism by which kinetochores recruit the cohesin loader to establish centromere cohesion. PMID- 29257968 TI - Error-Driven Learning: Dopamine Signals More Than Value-Based Errors. AB - The detection of a mismatch between our predictions and what actually happens allows us to learn from our errors. New research indicates that midbrain dopamine neurons encode multiple types of error signals and contribute to multiple forms of error-driven learning. PMID- 29257969 TI - Vernalization and Epigenetic Inheritance: A Game of Histones. AB - Cells inherit molecular 'memories' of previously experienced conditions through epigenetic processes. Recent findings provide insights into the problem of how epigenetic states are inherited through cell division, with intriguing mechanistic links to histone variants and DNA replication. PMID- 29257970 TI - Sensory Systems: Electrifying News from the Ocean. AB - Only a handful of vertebrates are capable of sensing weak electric fields. Two new studies shed light on the development and physiology of electroreceptive organs. PMID- 29257971 TI - Detection and Clearance of Damaged Lysosomes by the Endo-Lysosomal Damage Response and Lysophagy. AB - Lysosomal membrane permeabilization or lysosomal rupture is recognized as a common and severe stress condition relevant for infection, cellular degeneration and cancer. However, the cellular response mechanisms that protect cells from the consequences of lysosomal damage and ensure lysosomal quality control and homeostasis have only recently been explored. Key elements of this response involve the specific sensing of the damage followed by extensive modification of the organelles with ubiquitin to mark them for clearance by selective macroautophagy, termed lysophagy. Efficient lysophagy is ensured by additional layers of regulation, including modulation by the ubiquitin-directed AAA-ATPase VCP/p97. Lysophagy shares many features with mitophagy, the macroautophagic removal of damaged mitochondria. This review aims to gather available data from different fields and to define the key steps necessary for sensing and subsequent clearance of damaged lysosomes. We conclude with a discussion of disease implications with a focus on neurodegeneration. PMID- 29257972 TI - Preparation of photo-responsive poly(ethylene glycol) microparticles and their influence on cell viability. AB - Intelligent colloidal particles have been widely used as carriers for delivery of bioactive molecules due to the ability of controlled release. However, attention is mainly paid to the effects of their payloads, whereas the impacts of carriers are largely ignored. In this study, photo-responsive polyethylene glycol (PEG) microparticles were fabricated by using 8-arm-PEG with terminal amine groups (8 arm-PEG-NH2) and a photo-cleavable cross-linker. Due to the cleavable CO bond in the cross-linker, under UV irradiation the PEG particles could be decomposed gradually, leading to particle swelling and eventual disappearance. The PEG particles could be internalized by smooth muscle cells and HepG2 cells, and located in lysosomes. Their intracellular photo-response induced significant decrease of cell viability and increase of reactive oxygen species level. PMID- 29257973 TI - Alginate-based attapulgite foams as efficient and recyclable adsorbents for the removal of heavy metals. AB - Floatable and porous foam adsorbents constructed by encapsulating attapulgite (ATP) in sodium alginate (SA) were fabricated via a freeze-drying and post cross linking method, and both attapulgite and sodium alginate possessed adsorptive sites. These adsorbents were characterized by XRD, FTIR, and SEM to investigate their crystal structures, surface properties, size and morphology. In the adsorption tests, the adsorption capacity was derived from the Langmuir isotherm model, and the maximal adsorption capacity of as-prepared adsorbents was 119.0 mg g-1 for Cu(II) and 160.0 mg g-1 for Cd(II). In addition to the remarkable adsorptive performances, these adsorbents presented strong chemical stability and were readily recyclable because of their floatability in water solution. These aforementioned advantages highlight that the alginate-encapsulated attapulgite foams are potential scalable adsorbents for heavy metal ions removal from polluted water, and such a structure design could intrigue the development of novel adsorptive materials. PMID- 29257974 TI - Fabrication of Pt nanoparticles on nitrogen-doped carbon/Ni nanofibers for improved hydrogen evolution activity. AB - Among various methods for acquiring hydrogen fuel, electrocatalytic water splitting is considered to be as one of the most efficient and promising approaches. Pt is regarded as the best electrocatalyst for the hydrogen evolution reaction (HER) during water splitting process, however, the scarcity and costliness of Pt restrict the large-scale practical application. On the other hand, transition metal Ni is abundant in earth and exhibits favorable HER catalytic activity theoretically. In this work, we have demonstrated a facile electrospinning combined with calcination and chemical reduction processes to fabricate Pt nanoparticles loaded on nitrogen-doped carbon/Ni nanofibers (Ni NCNFs-Pt) as efficient HER electrocatalysts. The as-prepared Ni-NCNFs-Pt not only reduced the usage of noble metal Pt but also revealed an excellent electrochemical activity at all values of pH, including the smaller overpotentials of 47, 22 and 84 mV (at j = 10 mA cm-2) in 0.5 M H2SO4, 1 M KOH and 0.1 M phosphate buffer solution, respectively. In addition, Ni-NCNFs-Pt nanocatalyst displayed an extraordinary low Tafel slope and long durability over a wide range of pH. The remarkable HER performance could be ascribed to the increased electrochemical active surface area through the introduction of Ni nanoparticles, synergistic interactions between Ni and Pt nanoparticles and the introduction of the conductive nitrogen-doped carbon nanofibers (NCNFs) substrate which facilitated the fast electron transport. This investigation provides a potential route to construct efficient and low cost HER electrocatalysts with promising practical applications in renewable energy conversion and storage devices. PMID- 29257975 TI - Optimization of cinnamon oil nanoemulsions using phase inversion temperature method: Impact of oil phase composition and surfactant concentration. AB - Essential oils, such as those isolated from cinnamon, are effective natural antimicrobial agents, but their utilization is limited by their low water solubility. In this study, phase inversion temperature (PIT) was used to prepare cinnamon oil nanoemulsions. To this aim, it was hypothesized that cinnamon oil nanoemulsions could be fabricated by optimizing the oil phase composition and surfactant concentration of the system and their stability could be enhanced using a cooling-dilution method during the PIT. A mixture of cinnamon oil, non ionic surfactant, and water was heated above the PIT of the system, and then rapidly cooled with continuous stirring, which led to the spontaneous generation of small oil droplets. The impact of oil phase composition and surfactant concentration on the formation and stability of the nanoemulsions was determined. Cinnamon oil nanoemulsions with the smallest mean droplet diameter (101 nm) were formed using 40:60 wt% of cinnamon oil and medium chain triglyceride (MCT) in the total lipid phase. Increasing surfactant concentration significantly decreased the mean droplet diameter of the nanoemulsions but did not alter their particle morphology. In addition, using the cooling-dilution method, the nanoemulsions were stable for at least 31 days when stored at 4 degrees C or 25 degrees C. PMID- 29257976 TI - Ultradeep mapping of neuronal mitochondrial deletions in Parkinson's disease. AB - Mitochondrial DNA (mtDNA) deletions accumulate with age in postmitotic cells and are associated with aging and neurodegenerative disorders such as Parkinson's disease. Although the exact mechanisms by which deletions form remain elusive, the dominant theory is that they arise spontaneously at microhomologous sites and undergo clonal expansion. We characterize mtDNA deletions at unprecedented resolution in individual substantia nigra neurons from individuals with Parkinson's disease, using ultradeep sequencing. We show that the number of deleted mtDNA species per neuron is substantially higher than previously reported. Moreover, each deleted mtDNA species shows significant differences in sequence composition compared with the remaining mtDNA population, which is highly consistent with independent segregation and clonal expansion. Deletion breakpoints occur consistently in regions of sequence homology, which may be direct or interrupted stretches of tandem repeats. While our results support a crucial role for misannealing in deletion generation, we find no overrepresentation of the 3'-repeat sequence, an observation that is difficult to reconcile with the current view of replication errors as the source of mtDNA deletions. PMID- 29257977 TI - The impact of psychosis genome-wide associated ZNF804A variation on verbal fluency connectivity. AB - Schizophrenia (SCZ) and bipolar disorder (BD) have high heritability. Genome-wide association studies (GWAS) have identified ZNF804A as a significant risk gene for both illnesses. A validation of this finding at the brain systems-level is imperative as there is still little understanding of how it heightens risk. Based in part on our recent findings of an effect on widespread decreased white matter microstructural fractional anisotropy (putatively a proxy of its integrity), particularly strong in SCZ, we asked whether the risk allele has a detrimental effect on regional brain activation and functional connectivity during a type of cognitive processing which is, together with its neural correlates, impaired in BD and SCZ: verbal fluency. Functional MRI and genotype data was collected from 80 healthy volunteers, and 54 SCZ and 40 BD patients. A standard multifactorial analysis of variance using statistical parametric mapping and significance correction of FWE p < 0.05 was used. We found the GWAS risk allele A was associated with decreased positive functional coupling between the left precentral gyrus/inferior frontal gyrus (i.e. the most highly recruited area for the task) and: 1) the left inferior frontal gyrus, and 2) the left posterior cingulate gyrus, encompassing the precuneus; both as a main effect across controls and psychosis patients. Such association of the risk allele with reduced functional connectivity (with no area where the opposite main effect was detected), converges with findings in other tasks, our previous finding of its widespread impact on brain white matter microstructure, and with the dysconnectivity hypothesis of SCZ. PMID- 29257978 TI - Superior flame retardancy and smoke suppression of epoxy-based composites with phosphorus/nitrogen co-doped graphene. AB - Phosphorus and/or nitrogen doping is an effective method of improving the physical and chemical properties of reduced graphene oxide (rGO). In this work, phosphorus and nitrogen co-doped rGO (PN-rGO), synthesized using a scalable hydrothermal and microwave process, was used as an additive to improve the flame retardancy of epoxy resin (EP) for the first time. Chemical structure and morphology characterization confirmed that the nitrogen and phosphorus atoms were doped into the graphite lattice adopting pyrrolic-N, pyridinic-N, quaternary-N and pyrophosphate and metaphosphate forms. Doping increased the oxidization resistance of rGO and the thermal-oxidative stability of its composites' char, while also improving the catalytic charring ability of polymer. Both effects resulted in the formation of a stable char protective layer during burning and to a significant improvement in flame retardation and smoke suppression in the final composites. The peak heat release rate (PHRR), total heat release (THR) and total smoke production (TSP) for the EP-based composite (containing 5 wt% PN-rGO) decreased by 30.9%, 29.3% and 51.3%, respectively, compared to neat EP. Our work has produced a promising graphene-based flame retardant additive for the mass production of high-performance composites, also expended the application of heteroatom-doped graphene. PMID- 29257979 TI - Osteoporosis is associated with metabolic syndrome induced by high-carbohydrate high-fat diet in a rat model. AB - This study aimed to investigate the bone quality in rats induced with metabolic syndrome (MetS) using high-carbohydrate high-fat (HCHF) diet. Male Wistar rats (n = 14) were randomized into two groups. The normal group was given standard rat chow. The MetS group was given HCHF diet. Diet regimen was assigned for a period of 20 weeks. Metabolic syndrome parameters were measured monthly until MetS was established. Left tibiae were scanned using micro-computed tomography at week 0, 8, 12, 16, and 20 to analyze the trabecular and cortical bone structure. At the end of the study, rats were euthanized and their bones were harvested for analysis. Metabolic syndrome was established at week 12 in the HCHF rats. Significant deterioration of trabecular bone was observed at week 20 in the HCHF group (p < 0.05). The HCHF diet also decreased cortical and tissue area significantly (p < 0.05), but did not affect cortical thickness and bone calcium content (p > 0.05). Femur length and width in the HCHF group were significantly shorter than the normal group (p < 0.05). The biomechanical strength test showed that the femur of the HCHF rats could endure significantly lower force, but significantly higher displacement and strain compared to the normal rats (p < 0.05). In conclusion, HCHF diet-induced MetS can cause adverse effects on the bone. PMID- 29257980 TI - Real life safety benefits of increasing brake deceleration in car-to-pedestrian accidents: Simulation of Vacuum Emergency Braking. AB - The objective of this study is to predict the real-life benefits, namely the number of injuries avoided rather than the reduction in impact speed, offered by a Vacuum Emergency Brake (VEB) added to a pedestrian automated emergency braking (AEB) system. We achieve this through the virtual simulation of simplified mathematical models of a system which incorporates expected future advances in technology, such as a wide sensor field of view, and reductions in the time needed for detection, classification, and brake pressure build up. The German In Depth Accident Study database and the related Pre Crash Matrix, both released in the beginning of 2016, were used for this study and resulted in a final sample of 526 collisions between passenger car fronts and pedestrians. Weight factors were calculated for both simulation model and injury risk curves to make the data representative of Germany as a whole. The accident data was used with a hypothetical AEB system in a simulation model, and injury risk was calculated from the new impact speed using injury risk curves to generate new situations using real accidents. Adding a VEB to a car with pedestrian AEB decreased pedestrian casualties by an additional 8-22%, depending on system setting and injury level, over the AEB-only system. The overall decrease in fatalities was 80 87%, an improvement of 8%. Collision avoidance was improved by 14-28%. VEB with a maximum deceleration in the middle of the modelled performance range has an effectiveness similar to that of an "early activation" system, where the AEB is triggered as early as 2 s before collision. VEB may therefore offer a substantial increase in performance without increasing false positive rates, which earlier AEB activation does. Most collisions and injuries can be avoided when AEB is supplemented by the high performance VEB; remaining cases are characterised by high pedestrian walking speed and late visibility due to view obstructions. VEB is effective in all analysed accident scenarios. PMID- 29257981 TI - Contaminants in tropical island streams and their biota. AB - Environmental contamination is problematic for tropical islands due to their typically dense human populations and competing land and water uses. The Caribbean island of Puerto Rico (USA) has a long history of anthropogenic chemical use, and its human population density is among the highest globally, providing a model environment to study contaminant impacts on tropical island stream ecosystems. Polycyclic Aromatic Hydrocarbons, historic-use chlorinated pesticides, current-use pesticides, Polychlorinated Biphenyls (PCBs), and metals (mercury, cadmium, copper, lead, nickel, zinc, and selenium) were quantified in the habitat and biota of Puerto Rico streams and assessed in relation to land-use patterns and toxicological thresholds. Water, sediment, and native fish and shrimp species were sampled in 13 rivers spanning broad watershed land-use characteristics during 2009-2010. Contrary to expectations, freshwater stream ecosystems in Puerto Rico were not severely polluted, likely due to frequent flushing flows and reduced deposition associated with recurring flood events. Notable exceptions of contamination were nickel in sediment within three agricultural watersheds (range 123-336ppm dry weight) and organic contaminants (PCBs, organochlorine pesticides) and mercury in urban landscapes. At an urban site, PCBs in several fish species (Mountain Mullet Agonostomus monticola [range 0.019-0.030ppm wet weight] and American Eel Anguilla rostrata [0.019-0.031ppm wet weight]) may pose human health hazards, with concentrations exceeding the U.S. Environmental Protection Agency (EPA) consumption limit for 1 meal/month. American Eel at the urban site also contained dieldrin (range < detection 0.024ppm wet weight) that exceeded the EPA maximum allowable consumption limit. The Bigmouth Sleeper Gobiomorous dormitor, an important piscivorus sport fish, accumulated low levels of organic contaminants in edible muscle tissue (due to its low lipid content) and may be most suitable for human consumption island wide; only mercury at one site (an urban location) exceeded EPA's consumption limit of 3 meals/month for this species. These results comprise the first comprehensive island-wide contaminant assessment of Puerto Rico streams and biota and provide natural resource and public health agencies here and in similar tropical islands elsewhere with information needed to guide ecosystem and fisheries conservation and management and human health risk assessment. PMID- 29257982 TI - Diagnostic performances of the Xpert(r) Flu PCR test and the OSOM(r) immunochromatographic rapid test for influenza A and B virus among adult patients in the Emergency Department. AB - BACKGROUND: New rapid influenza diagnostic tests (RIDT) are available but their clinical utility in adults has not been validated. OBJECTIVES: To evaluate the diagnostic performances of OSOM(r) Ultra Flu A&B a RIDT on viral strains of influenza A/B from the last epidemic season, and its feasibility by Emergency Department (ED) physicians and nurses. STUDY DESIGN: Of the 1099 patients admitted to the ED with suspected influenza, all having a nasopharyngeal swab tested by the Xpert(r) Flu PCR and then stored at -20 degrees C; 500 were selected at random and their samples were tested using the RIDT. Two experts reviewed ED and hospital medical records and all virological data to define influenza cases. Intra- and inter-observer variability were calculated. RESULTS: Of the 500 patients included 45% were >=75 years, 122 (24.4%) presented with influenza based on clinical and virological criteria. PCR test performances (%) were Se 98.4 (95% CI 93.6-99.7), Spe 99.7 (98.3-100), PPV 99.2 (94.8-100) and NPV 99.5 (97.9-100); and RIDT performances were Se 95.1 (89.2-97.9), Spe 98.4 (96.4 99.4), PPV 95.1 (87.2-99.9) and NPV 98.4 (96.4-98). There was no difference in test performance between influenza A and B virus nor between the influenza A subtypes. Intra- and inter-observer variability of RIDT were 0.94 (0.89-0.99) and 0.96 (0.92-1). CONCLUSION: Our results show that the Xpert(r) Flu PCR and the OSOM(r) Ultra Flu A&B Test perform very well in diagnosing strains of circulating virus in adults and elderly. Our results also confirm the feasibility of this RIDT at point-of-care by ED staff. PMID- 29257983 TI - Bedside screen for oral cavity structure, salivary flow, and vocal production over the 14days following endotracheal extubation. AB - PURPOSE: To describe the sequelae of oral endotracheal intubation by evaluating prevalence rates of structural injury, hyposalivation, and impaired vocal production over 14days following extubation. MATERIALS AND METHODS: Consecutive adults (>=20years, N=114) with prolonged (>=48h) endotracheal intubation were enrolled from medical intensive care units at a university hospital. Participants were assessed by trained nurses at 2, 7, and 14days after extubation, using a standardized bedside screening protocol. RESULTS: Within 48-hour postextubation, structural injuries were common, with 51% having restricted mouth opening. Unstimulated salivary flow was reduced in 43%. For vocal production, 51% had inadequate breathing support for phonation, dysphonia was common (94% had hoarseness and 36% showed reduced efficiency of vocal fold closure), and >40% had impaired articulatory precision. By 14days postextubation, recovery was noted in most conditions, but reduced efficiency of vocal fold closure persisted. Restricted mouth opening (39%) and reduced salivary flow (34%) remained highly prevalent. CONCLUSIONS: After extubation, restricted mouth opening, reduced salivary flow, and dysphonia were common and prolonged in recovery. Reduced efficiency of vocal cord closure persisted at 14days postextubation. The extent and duration of these sequelae remind clinicians to screen for them up to 2weeks after extubation. PMID- 29257984 TI - The prevalence and impact of low back pain in pre-professional and professional dancers: A prospective study. AB - OBJECTIVES: To determine the prevalence of low back pain (LBP) in pre professional and professional dancers and its impact on dance participation, care seeking and medication use. DESIGN: Prospective cohort study. SETTING: One pre professional ballet school, two pre-professional university dance programs, and a professional ballet company. PARTICIPANTS: Male and female classical ballet and contemporary dancers. MAIN OUTCOME MEASURES: An initial questionnaire collected demographic and LBP history data. The monthly prevalence of LBP (all episodes, activity limiting episodes and chronic LBP) and impact (activity limitation, care seeking, and medication use) was collected over a nine-month period. RESULTS: 119 dancers participated, which represented 54% of those invited. Activity limiting LBP was reported by 52% of dancers, while chronic LBP was reported by 24%. Seventeen percent of all episodes of LBP resulted in some form of dance activity being completely missed. One-third of the sample reported care-seeking and one fifth of the sample used medication. A history of LBP was associated with activity limiting LBP (p < 0.01; adjusted odds ratio: 3.98; 95% confidence interval: 1.44, 11.00). CONCLUSIONS: LBP in dancers was common and had multiple impacts. This study reinforces the need for dancer access to healthcare professionals with expertise in evidence-based LBP prevention and management. PMID- 29257985 TI - Enhanced sludge dewatering based on the application of high-power ultrasonic vibration. AB - Interest in producing heat and power using municipal wastewater sewage sludge as a fuel is increasing worldwide. Since its water content is initially high, sludge must be dewatered and further dried if it is to serve as an effective fuel for combustion. However, to maximize net energy production, the drying processes must use as little energy as possible. The water content in sewage sludge comprises both unbound and bound water. Unbound water content is typically extracted using a number of mechanical dewatering techniques. In terms of total solids content (TS), dewatering processes can take sludge from an initial 3-5% to a more solid 25-45% TS with minimal energy expenditure. However, this level of dryness is not sufficient for effective combustion. To produce an effective fuel, TS levels must be increased. Achieving high level of dryness involves removing any remaining unbound water and substantial bound water content as well. Heat is normally applied to accomplish this by changing the phase of the water from liquid to vapor. Although dewatering is energy-efficient, thermal drying is not. The energy used to thermally dry sludge can be two orders of magnitude greater than the energy used for dewatering. Therefore, to expend as little energy as possible to achieve the needed dryness, conventional dewatering processes clearly must be improved. This paper describes work carried out to identify promising ways to efficiently enhance the dewatering and drying of sewage sludge. Available dewatering approaches were reviewed and experiments were carried out to examine the relative effects of temperature, atmospheric pressure, and high-power ultrasound. The high-power ultrasound approach seemed to be particularly effective. The mechanisms involved include atomization, microstructural effects, cavitation, and the sponge effect, which work to reduce both internal and external resistances. Applied in the right way, ultrasound could become a very effective way to enhance mechanical dewatering. PMID- 29257986 TI - Selective enrichment of n-3 fatty acids in human plasma lipid motifs following intake of marine fish. AB - Plasma levels of n-3 long chain polyunsaturated fatty acids (LCPUFA) are associated with a reduction in risk of cardiovascular disease and other chronic, age-related diseases like Alzheimer's disease. In this work, we tested the hypothesis that n-3 LCPUFA fatty acids in human plasma are incorporated into selective lipid species following intake of n-3 LCPUFA rich marine fish. To test this hypothesis, we performed lipidomic analysis on plasma samples from a clinical trial in which participants consumed increasing amounts of farmed Atlantic salmon (Salmo salar). Under basal conditions, n-3 and n-6 LCPUFA were selectively incorporated into plasma phosphatidylcholine (PC) species containing saturated fatty acids (SFA) versus unsaturated fatty acids as the complementary fatty acids. LCPUFA were incorporated into selective triacylglycerol (TAG) species with complementary diacylglyceryl environments of 34:1 or 34:2 (for 20:5 and 22:5) and 36:2>36:3>36:4 and 36:1 (for 20:4 and 22:6). High n-3 LCPUFA marine fish intake resulted in selective increases of PC SFA_n-3 LCPUFA species and LCPUFA-containing TAG species. Changes in cholesteryl esters and phosphatidylethanolamines also occurred following fish intake. Our results highlight the importance of discriminating phospholipid and TAG species and dietary background when evaluating lipidomic outcomes and disease associations. PMID- 29257987 TI - The impact of the Great Recession on health-related risk factors, behaviour and outcomes in England. AB - This paper examines the impact that the Great Recession had on individuals' health behaviours and risk factors such as diet choices, smoking, alcohol consumption, and Body Mass Index, as well as on intermediate health outcomes in England. We exploit data on about 9000 households from the Health Survey for England for the period 2001-2013 and capture the change in macroeconomic conditions using regional unemployment rates and an indicator variable for the onset of the recession. Our findings indicate that the recession is associated with a decrease in the number of cigarettes smoked - which translated into a moderation in smoking intensity - and a reduction in alcohol intake. The recession indicator itself is associated with a decrease in fruit intake, a shift of the BMI distribution towards obesity, an increase in medicines consumption, and the likelihood of suffering from diabetes and mental health problems. These associations are often stronger for the less educated and for women. When they exist, the associations with the unemployment rate (UR) are nevertheless similar before and after 2008. Our results suggest that some of the health risks and intermediate health outcomes changes may be due to mechanisms not captured by worsened URs. We hypothesize that the uncertainty and the negative expectations generated by the recession may have influenced individual health outcomes and behaviours beyond the adjustments induced by the worsened macroeconomic conditions. The net effect translated into the erosion of the propensity to undertake several health risky behaviours but an exacerbation of some morbidity indicators. Overall, we find that the recession led to a moderation in risky behaviours but also to worsening of some risk factors and health outcomes. PMID- 29257988 TI - Accurately early warning to water quality pollutant risk by mobile model system with optimization technology. AB - A fast and accurate water quality pollutant risk assessment and early warning system, which has great practical significance for decision making in accident management, is urgently needed for water protection and management. Based on a fast mobile early warning system named MEWSUB, this paper modified its framework to make it generate data more automatically and accurately. By adapting manning formula and particle swarm optimization (PSO) for parameters optimization, the accuracy of water quantity and water quality simulation results has been improved. The modified system was successfully applied in an antimony tailings dam leakage accident that happened in China. The coefficient of determination (R2) of the prediction result was higher than 0.9 and relative error (ree) was less than 0.1, which indicated that the accuracy of MEWSUB was high enough for realistic water quality pollutant risk early warning. PMID- 29257989 TI - Valorizing waste iron powder in biogas production: Hydrogen sulfide control and process performances. AB - Biogas is composed of different gases including hydrogen sulfide (H2S), which is a hazardous gas that damages pipes and generators in anaerobic digestion system. The objective of this study was to control H2S by waste iron powder produced by laser cutting machine in a steel and iron industry. Waste iron powder was mixed with dairy manure at a concentration between 2.0 and 20.0 g/L in batch experiments, while the concentration was varied between 1.0 and 4.0 g/L in bench experiment. In batch experiment, a reduction of up to 93% of H2S was observed at waste iron powder of 2.0 g/L (T1), while the reduction was of more than 99% at waste iron powder beyond 8.0 g/L (T4 ~ T6). The total sulfide concentration (ST) increased together with waste iron powder concentration and was fitted with a quadratic equation with a maximum ST of 208.0 mg/L at waste iron powder of 20.2 g/L. Waste iron powder did not have significant effect on methane yield in batch and bench experiments. However, hydrolysis rate constant was increased by almost 100%, while the lag-phase period was reduced to half in test digesters compared to that in control digester. In bench experiment, H2S concentration was reduced by 89% at 2.0 g/L, while 50% at 1.0 g/L. Therefore, waste iron powder was effectively removed H2S and did not affect negatively anaerobic digestion process. PMID- 29257990 TI - Shortcut nitrification-denitrification by means of autochthonous halophilic biomass in an SBR treating fish-canning wastewater. AB - Autochthonous halophilic biomass was cultivated in a sequencing batch reactor (SBR) aimed at analyzing the potential use of autochthonous halophilic activated sludge in treating saline industrial wastewater. Despite the high salt concentration (30 g NaCl L-1), biological oxygen demand (BOD) and total suspended solids (TSS), removal efficiencies were higher than 90%. More than 95% of the nitrogen was removed via a shortcut nitrification-denitrification process. Both the autotrophic and heterotrophic biomass samples exhibited high biological activity. The use of autochthonous halophilic biomass led to high-quality effluent and helped to manage the issues related to nitrogen removal in saline wastewater treatment. PMID- 29257991 TI - Boron alleviates the aluminum toxicity in trifoliate orange by regulating antioxidant defense system and reducing root cell injury. AB - Aluminium (Al) toxicity is the most important soil constraint for plant growth and development in acid soils (pH < 5.5) globally in agricultural regions. Boron (B) is an essential micronutrient for the growth and development of higher plants. The results of previous studies propose that B might ameliorate Al toxicity; however, none of the studies have been conducted on trifoliate orange to study this effect. Thus, a study was carried out in hydroponics comprising of two different Al concentrations, 0 and 400 MUM. For every concentration, two B treatments (0 and 10 MUM as H3BO3) were applied to investigate the B-induced alleviation of Al toxicity and exploring the underneath mechanisms. The results revealed that Al toxicity under B deficiency severely hampered the root growth and physiology of plant, caused oxidative stress and membrane damage, leading to severe root injury and damage. However, application of B under Al toxicity improved the root elongation and photosynthesis, while reduced Al uptake and mobilization into plant parts. Moreover, B supply regulated the activities of antioxidant enzymes, proline, secondary metabolites (phenylalanine ammonia lyase and polyphenol oxidase) contents, and stabilized integrity of proteins. Our study results imply that B supply promoted root growth as well as defense system by reducing reactive oxygen species (ROS) and Al concentrations in plant parts thus B induced alleviation of Al toxicity; a fact that might be significant for higher productivity of agricultural plants grown in acidic conditions. PMID- 29257992 TI - Bacterial community evolutions driven by organic matter and powder activated carbon in simultaneous anammox and denitrification (SAD) process. AB - A distinct shift of bacterial community driven by organic matter (OM) and powder activated carbon (PAC) was discovered in the simultaneous anammox and denitrification (SAD) process which was operated in an anti-fouling submerged anaerobic membrane bio-reactor. Based on anammox performance, optimal OM dose (50 mg/L) was advised to start up SAD process successfully. The results of qPCR and high throughput sequencing analysis indicated that OM played a key role in microbial community evolutions, impelling denitrifiers to challenge anammox's dominance. The addition of PAC not only mitigated the membrane fouling, but also stimulated the enrichment of denitrifiers, accounting for the predominant phylum changing from Planctomycetes to Proteobacteria in SAD process. Functional genes forecasts based on KEGG database and COG database showed that the expressions of full denitrification functional genes were highly promoted in RC, which demonstrated the enhanced full denitrification pathway driven by OM and PAC under low COD/N value (0.11). PMID- 29257993 TI - Effect of pig manure on the chemical composition and microbial diversity during co-composting with spent mushroom substrate and rice husks. AB - In this study, the impact of pig manure on the maturity of compost consisting of spent mushroom substrate and rice husks was accessed. The results showed that the addition of pig manure (SMS-PM) reached 50 degrees C 5days earlier and lasted 15days longer than without pig manure (SMS). Furthermore, the addition of pig manure improved nutrition and germination index. High-throughput 16S rRNA pyrosequencing was used to evaluate the bacterial and fungal composition during the composting process of SMS-PM compared to SMS alone. The SMS treatment showed a relatively higher abundance of carbon-degrading microbes (Bacillaceae and Thermomyces) and plant pathogenic fungi (Sordariomycetes_unclassified) at the end of the compost. In contrast, the SMS-PM showed an increased bacterial diversity with anti-pathogen (Pseudomonas). The results indicated that the addition of pig manure improved the decomposition of refractory carbon from the spent mushroom substrate and promoted the maturity and nutritional content of the compost product. PMID- 29257994 TI - Co-gasification of pine and oak biochar with sub-bituminous coal in carbon dioxide. AB - Pine and oak biochars derived as byproducts of demonstration-scale pyrolysis, and blends of these two feedstocks with Powder River Basin coal, were gasified in a carbon dioxide environment using a modified drop tube reactor (MDTR) and a thermogravimetric analyzer (TGA). The impact of gasification temperature on conversion kinetics was evaluated from the temporal evolution of major product gases in the MDTR as measured using a mass spectrometer. Random pore modeling was conducted to simulate gasification in the MDTR with favorable results. The MDTR and TGA were used to conduct gasification for assessment of non-linear additive effects in the blends. Additive analysis of the blends showed deviation from the experimental blend results, indicating inhibiting effects of co-gasifying the biochar and coal. Inhibitory effects are more significant for oak than pine and more pronounced in the TGA at lower gasification temperatures. Results are discussed in the context of feedstock and reactor type. PMID- 29257995 TI - Exploring predictors of change in behavioral problems over a 1-year period in preterm born preschoolers. AB - OBJECTIVE: Although predictors of the prevalence of behavioral problems in preterm-born children have been frequently studied, predictors of behavioral change in these children remain unknown. Therefore, in this study we explore predictors of short-term changes in problem behavior in preterm-born preschoolers, an age period characterized by rapid behavioral change. METHOD: Two to 5-year-old children born with a gestational age <32 weeks and/or birth weight <1500 g were eligible, because of their high risk for behavioral problems. Following screening, 59 children with a t-score >=60 on either the internal, external or total problem scale of the Child Behavior Checklist were included in the study. Linear mixed modeling was used to investigate predictors of change in behavior over a 1-year period. RESULTS: Higher levels of parenting stress, parent perceived child vulnerability, and parental hostility towards the child and lower educational levels of the mother significantly predicted increases in externalizing behavior. The higher the age of the child, the more internalizing problems decreased. CONCLUSIONS: Parenting stress, parent perceived child vulnerability and parental hostility towards the child were the only modifiable predictors of increases in externalizing behavior, whilst no modifiable predictors of internalizing behavior were found. There may be a reciprocal interaction between stress in parents and child externalizing problems. Furthermore, stress and worries may directly influence parents' reports on behavioral measures, because it could cause them to be concerned by behavior otherwise perceived as normal. Therefore, future interventions for parents of preterm-born children should primarily address parental stress and concerns regarding their child. PMID- 29257996 TI - The effects of walking intervention in patients with chronic low back pain: A meta-analysis of randomized controlled trials. AB - OBJECTIVE: The aim of this meta-analysis of randomized controlled trials was to gain insight into the effectiveness of walking intervention on pain, disability, and quality of life in patients with chronic low back pain (LBP) at post intervention and follow ups. METHOD: Six electronic databases (PubMed, Science Direct, Web of Science, Scopus, PEDro and The Cochrane library) were searched from 1980 to October 2017. The following keywords were used: Walk* or Pedometer* or Accelerometer* or Treadmill* paired with "Back pain", "Low back pain", "Chronic low back pain", "LBP", or "Backache". Randomized controlled trials in patients with chronic LBP were included if they compared the effects of walking intervention to non-pharmacological interventions. Pain, disability, and quality of life were the primary health outcomes. RESULTS: Nine studies were suitable for meta-analysis. Data was analyzed according to the duration of follow-up (short term, < 3 months; intermediate-term, between 3 and 12 months; long-term, > 12 months). Low- to moderate-quality evidence suggests that walking intervention in patients with chronic LBP was as effective as other non-pharmacological interventions on pain and disability reduction in both short- and intermediate term follow ups. CONCLUSIONS: Unless supplementary high-quality studies provide different evidence, walking, which is easy to perform and highly accessible, can be recommended in the management of chronic LBP to reduce pain and disability. PMID- 29257997 TI - Responses of contrasting rice genotypes to excess manganese and their implications for lignin synthesis. AB - Manganese (Mn) toxicity is frequently encountered in crops grown on soils with low pH or low redox potential, and harmful to plant development and growth. This study aimed at exploring adaptive mechanisms to Mn toxicity in rice, and investigated the effects of Mn toxicity on shoot lignification. Sixteen rice genotypes were grown in hydroponic solutions and exposed to normal (0.5 mg dm-3) or toxic (5 mg dm-3) Mn concentrations for three weeks. Morphological responses to Mn toxicity included a significant reduction in shoot length and the formation of visible symptoms scored as leaf damage index (LDI). Based on shoot Mn concentrations in the Mn toxic treatment, genotypes were classified as Mn includers and excluders. Across different genotypes, shoot Mn concentrations were significantly negatively correlated with relative shoot length and positively correlated with LDI. Consequently, the most tolerant genotypes in terms of morphology were all excluders, while the most sensitive genotypes were includers. The sensitive genotypes were also more responsive to manganese in terms of lipid peroxidation than tolerant genotypes. Shoots of rice plants grown in the high Mn treatment showed a higher level of lignification measured as thioglycolic acid lignin (TGAL), especially among Mn includers. TGAL was positively correlated with shoot Mn concentration and the levels of phenolics. In contrast, peroxidase activity was not responsive to the Mn treatment and was not significantly correlated with shoot lignification. In conclusion, exclusion is a dominant tolerance mechanism to Mn toxicity in rice. Further, Mn stimulated lignin biosynthesis in rice, especially in genotypes that were unable to exclude Mn. PMID- 29257998 TI - Loxosceles venom Sphingomyelinase D activates human blood leukocytes: Role of the complement system. AB - Envenomation by Loxosceles spiders can result in severe systemic and local reactions, which are mainly triggered by Sphingomyelinase D (SMase D), a toxic component of Loxosceles venom. SMase D induces a systemic inflammatory condition similar to the reaction observed during an endotoxic shock. Considering the potent pro-inflammatory potential of Loxosceles venom and the SMase D, in this study we have used the whole human blood model to study the endotoxic-like shock triggered by SMase D. Recombinant purified SMase D from L. intermedia venom, similarly to LPS, induced activation of blood leukocytes, as observed by the increase in the expression of CD11b and TLR4, production of reactive oxygen and nitrogen species (superoxide anion and peroxynitrite) and release of TNF-alpha. Complement consumption in the plasma was also detected, and complement inhibition by compstatin decreased the SMase D and LPS-induced leukocyte activation, as demonstrated by a reduction in the expression of CD11b and TLR4 and superoxide anion production. Similar results were found for the L. intermedia venom, except for the production of TNF-alpha. These findings indicate that SMase D present in Loxosceles venom is able to activate leukocytes in a partially complement dependent manner, which can contribute to the systemic inflammation that follows envenomation by this spider. Thus, future therapeutic management of systemic Loxosceles envenomation could include the use of complement inhibitors as adjunct therapy. PMID- 29257999 TI - Triterpenoid saponins from the pulp of Sapindus mukorossi and their antifungal activities. AB - Under the guidance of anti-fungal bioassay, four previously undescribed oleanane type and one lupane-type triterpenoid saponins, along with twelve known analogues, were isolated from the extract of Sapindus mukorossi pulps. Their structures were determined on the basis of spectroscopic analysis and chemical methods. In vitro biotests, oleanolic acid 3-O-beta-D-xylopyranosyl-(1 -> 3) alpha-L-rhamnopyranosyl-(1 -> 2)-alpha-L-arabinopyranoside showed inhibitory activity against Trichophyton rubrum with MIC80 value of 8 MUg/mL, while oleanolic acid 3-O-alpha-L-arabinopyranosyl-(1 -> 3)-alpha-L-rhamnopyranosyl-(1 > 2)-alpha-L-arabinopyranoside exhibited inhibitory activity against both Trichophyton rubrum and Candida albicans with MIC80 values of 8 MUg/mL. PMID- 29258000 TI - A prenylated flavonoid, 10-oxomornigrol F, exhibits anti-inflammatory effects by activating the Nrf2/heme oxygenase-1 pathway in macrophage cells. AB - Prenylated flavonoids are a unique class of naturally occurring flavonoids that have various pharmacological activities. In the present study, we investigated the anti-inflammatory effect in murine macrophages of a prenylated flavonoid, 10 oxomornigrol F (OMF), which was isolated from the twigs of Morus alba (Moraceae). OMF inhibited the lipopolysaccharide (LPS)-induced production of nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 in RAW264.7 cells, as well as in mouse bone marrow-derived macrophages (BMMs). OMF also rescued LPS-induced septic mortality in ICR mice. LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-alpha and IL-6 was also significantly suppressed by OMF treatment in RAW264.7 cells. Treatment of RAW264.7 cells with OMF induced heme oxygenase (HO)-1 mRNA and protein expression and increased the nuclear translocation of the nuclear factor E2-related factor 2 (Nrf2) as well as the expression of Nrf2 target genes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1). Treatment of RAW264.7 cells with OMF increased the intracellular level of reactive oxygen species (ROS) and the phosphorylation levels of p38 mitogen-activated protein kinase (MAPK); co treatment with the antioxidant N-acetyl-cysteine (NAC) blocked this OMF-induced p38 MAPK phosphorylation. Moreover, NAC, or SB203580 (a p38 MAPK inhibitor), blocked the OMF-induced nuclear translocation of Nrf2 and HO-1 expression, suggesting that OMF induces HO-1 expression by activating Nrf2 through the p38 MAPK pathway. Consistent with the notion that the Nrf2/HO-1 pathway has anti inflammatory properties, inhibiting HO-1 significantly abrogated the anti inflammatory effects of OMF in LPS-stimulated RAW264.7 cells. Taken together, these findings suggest that OMF exerts its anti-inflammatory effect by activating the Nrf2/HO-1 pathway, and may be a potential Nrf2 activator to prevent or treat inflammatory diseases. PMID- 29258001 TI - Pilot investigation on formation of 2,4,6-trichloroanisole via microbial O methylation of 2,4,6-trichlorophenol in drinking water distribution system: An insight into microbial mechanism. AB - Taste & odor (T&O) problems in drinking water are always complained by customers. Recent studies have indicated biofilms in drinking water distribution system (DWDS) are always ignored as potential sources of T&O compounds. In this paper, the formation of 2,4,6-trichloroanisole (2,4,6-TCA), one of the dominant T&O compounds, was investigated in a pilot-scale DWDS. The addition of precursor 2,4,6-trichlorophenol (2,4,6-TCP) of 0.2 mg/L induced the formation of 2,4,6-TCA with a maximum yield of ~400 ng/L, and the formation kinetics can be described by a pseudo-first-order kinetic model. Effects of water distribution factors such as pipe material, temperature, flow velocity, and residual chlorine on the formation of 2,4,6-TCA were evaluated, and the pipe material was found to have the most remarkable effect. Ductile iron and stainless steel pipes produced much more 2,4,6-TCA than polyethylene (PE) pipe. The biofilm microbial communities on the three types of pipe walls were then comprehensively analyzed by heterotrophic plate count and 16S rRNA/ITS1 genes high throughput sequencing. The links between the 2,4,6-TCA formation potential and the microbial activity in genus and enzymatic levels in DWDS have been revealed for the first time. According to the characteristics of microbial assemblages of producing 2,4,6-TCA, quorum-sensing (QS) bacterial signaling system and extracellular DNA (eDNA) may be two promising targets for biofilm treatment and 2,4,6-TCA control in DWDS. PMID- 29258002 TI - Abiotic degradation and environmental toxicity of ibuprofen: Roles of mineral particles and solar radiation. AB - The growing medical and personal needs of human populations have escalated release of pharmaceuticals and personal care products into our natural environment. This work investigates abiotic degradation pathways of a particular PPCP, ibuprofen, in the presence of a major mineral component of soil (kaolinite clay), as well as the health effects of the primary compound and its degradation products. Results from these studies showed that the rate and extent of ibuprofen degradation is greatly influenced by the presence of clay particles and solar radiation. In the absence of solar radiation, the dominant reaction mechanism was observed to be the adsorption of ibuprofen onto clay surface where surface silanol groups play a key role. In contrast, under solar radiation and in the presence of clay particles, ibuprofen breaks down to several fractions. The decay rates were at least 6-fold higher for irradiated samples compared to those of dark conditions. Toxicity of primary ibuprofen and its secondary residues were tested on three microorganisms: Bacillus megaterium, Pseudoaltermonas atlantica; and algae from the Chlorella genus. The results from the biological assays show that primary PPCP is more toxic than the mixture of secondary products. Overall, however, biological assays carried out using only 4-acetylbenzoic acid, the most abundant secondary product, show a higher toxic effect on algae compared to its parent compound. PMID- 29258003 TI - An integrated approach with the zebrafish model for biomonitoring of municipal wastewater effluent and receiving waters. AB - Comprehensive monitoring of water pollution is challenging. With the increasing amount and types of anthropogenic compounds being released into water, there are rising concerns of undetected toxicity. This is especially true for municipal wastewater effluents that are discharged to surface waters. This study was designed to integrate zebrafish toxicogenomics, targeted gene expression, and morphological analyses, for toxicity evaluation of effluent discharged from two previously characterized wastewater treatment plants (WWTPs) in Pima County, Arizona, and their receiving surface water. Zebrafish embryos were exposed to organic extracts from the WWTP1 effluent that were reconstituted to represent 1* and 0.5* of the original concentration. Microarray analyses identified deregulated gene probes that mapped to 1666, 779, and 631 unique human homologs in the 1*, 0.5*, and the intersection of both groups, respectively. These were associated with 18 cellular and molecular functions ranging from cell cycle to metabolism and are involved in the development and function of 10 organ systems including nervous, cardiovascular, haematological, reproductive, and hepatic systems. Superpathway of cholesterol biosynthesis, retinoic acid receptor activation, glucocorticoid receptor and prolactin signaling were among the top 11 perturbed canonical pathways. Real-time quantitative PCR validated the expression changes of 12 selected genes. These genes were then tested on zebrafish embryos exposed to the reconstituted extract of water sampled downstream of WWTP1 and another nearby WWTP2. The expression of several targeted genes were significantly affected by the WWTP effluents and some of the downstream receiving waters. Morphological analyses using four transgenic zebrafish lines revealed potential toxicity associated with nervous, hepatic, endothelial-vascular and myeloid systems. This study demonstrated how information can be obtained using adverse outcome pathway framework to derive biological effect-based monitoring tools. This integrated approach using zebrafish can supplement analytical chemistry to provide more comprehensive monitoring of discharged effluents and their receiving waters. PMID- 29258004 TI - High levels of lipoprotein (a) and premature acute coronary syndrome. AB - BACKGROUND AND AIMS: High levels of lipoprotein(a) [Lp(a)] are associated with increased risk of acute coronary syndrome (ACS). We explored whether Lp(a) exhibits a stronger association with premature ACS. METHODS: A case-control study was conducted; 1457 patients with a history of ACS (54.8 +/- 13 years, 86% males) and 2090 age-sex matched adults free of cardiovascular disease were enrolled. Bio clinical characteristics [risk factors, low-density lipoprotein-cholesterol, Lp(a)] were derived through standard procedures. RESULTS: A 10 mg/dL increase in Lp(a) was associated with 4% (95% CI, 1.01 to 1.02) higher likelihood of having ACS in younger (<45 years) and 2% (95% CI, 1.01 to 1.02) higher likelihood in middle-aged (45-60 years) individuals. Adjusting for common risk factors, elevated Lp(a), i.e. >50 mg/dL, was still associated with increased likelihood of ACS in younger adults (<45 years) (OR = 2.88, 95% CI, 1.7 to 4.6) and in middle aged ones (45 and 60 years) (OR = 2.06, 95% CI, 1.4 to 3.2), but not in older participants (>60 years) (OR = 1.31, 95% CI, 0.8 to 2.4). CONCLUSIONS: Lp(a) seems to be an independent risk factor for ACS in individuals <45 years, and high Lp(a) levels increase by ~3folds the risk for ACS. The association is preserved but is less in middle-aged individuals (45-60 years) and is abolished >60 years. PMID- 29258005 TI - Combined blockade of renin-angiotensin-aldosterone system reduced all-cause but not cardiovascular mortality in dialysis patients: A mediation analysis and systematic review. AB - BACKGROUND AND AIMS: Full blockade of renin-angiotensin-aldosterone system (RAAS) is believed to decrease morbidity and mortality of patients with chronic kidney disease. In non-dialysis patients, combined RAAS blockade with two different RAAS blockers causes more adverse events without improving survival, but its role in maintenance dialysis patients is still unclear. We conducted a systematic review and mediation analysis to investigate the efficacy and safety of combined RAAS blockade in dialysis patients. METHODS: Comprehensive search was conducted in PubMed, EMBASE, Web of Science and Cochrane Library database to June 2017 to identify relevant studies. Studies comparing combined with single RAAS blockade and reporting all-cause death, cardiovascular death, hypotension or hyperkalemia in dialysis patients were included. Effect sizes were calculated with randomized effects model and summarized as odd ratios (OR). RESULTS: A total of 9 studies with 13,050 dialysis patients were included. Compared with single blockade, combined blockade significantly reduced all-cause mortality (OR 0.71, 95% confidence interval 0.54-0.93, p = 0.01), while cardiovascular mortality remained unchanged (0.85, 0.45-1.59, p = 0.61). Combined blockade tended to increase odd of hypotension but not odd of hyperkalemia (1.54, 1.00-2.38, p = 0.05; 0.89, 0.76 1.05, p = 0.17). Further mediation analysis indicated that hypotension might exert a suppression effect on the survival benefit of angiotensin-converting enzyme inhibitor plus angiotensin receptor blocker treatment on cardiovascular mortality. CONCLUSIONS: Combined RAAS blockade might be a promising treatment in dialysis patients to further reduce mortality if blood pressure was well controlled. PMID- 29258007 TI - Deciphering the core fouling-causing microbiota in a membrane bioreactor: Low abundance but important roles. AB - Currently, membrane biofouling in membrane bioreactors (MBRs) is normally attributed to the occurrence of abundant bacterial species on membranes, whereas the roles of low-abundance bacteria have not been paid sufficient attention. In this study, the linear discriminant analysis (LDA) effect size (LEfSe) algorithm was used to identify active biomarkers, determining 67 different phylotypes among Bulk sludge, low-fouling Bio-cake (10 kPa), high-fouling Bio-cake (25 kPa) and Membrane pore in a membrane bioreactor with NaOCl backwash. Interestingly, a large proportion of the active biomarkers in bio-cake samples, such as Methylophilaceae, Burkholderiaceae, Paucibacter and Pseudoxanthomonas, did not fall within the abundant taxa (i.e., <0.05% relative abundance), indicating the preferential growth of these low-abundance bacteria on the membrane surface. Furthermore, the characterization of microbial interactions using a random matrix theory (RMT)-based network approach obtained a network consisting of 120 nodes and 228 edges. Specifically, network analysis showed the presence of an intense competition among bacterial species in the fouling-related communities, suggesting that negative interactions have an important effect on determining the microbial community structure. More importantly, the LEfSe algorithm and network analysis showed that most of the core species of the bio-cake, such as Burkholderiaceae, Bacillus and Rhodothermaceae, merely amounted to a very low relative abundance (<1%), suggesting their unrecognized and over-proportional ecological role in triggering the initial biofilm formation and subsequent biofilm maturation during MBR operation. Overall, this work should improve our understanding of the bacterial community structure on the fouled membranes in MBRs. PMID- 29258006 TI - Genetic variants in PPARGC1B and CNTN4 are associated with thromboxane A2 formation and with cardiovascular event free survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). AB - BACKGROUND AND AIMS: Elevated urinary 11-dehydro thromboxane B2 (TxB2), a measure of thromboxane A2 formation in vivo, predicts future atherothrombotic events. To further understand this relationship, the genetic determinants of 11-dehydro TxB2 and their associations with cardiovascular morbidity were investigated in this study. METHODS: Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB2 were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants. RESULTS: The strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11 dehydro TxB2 formation. Haplotypes of 11-dehydro TxB2 increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB2, explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events (chisq = 14.7, p=0.01). Two of the risk alleles associated with increased urinary 11-dehydro TxB2 were individually associated with greater incidences of cardiovascular events - rs10515638 (HR = 1.31, p=0.01) and rs10510230 (HR = 1.25, p=0.007); effect sizes were larger in those not taking aspirin. CONCLUSIONS: PPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A2 formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. If specific protection of PPARGC1B and CNTN4 variant carriers by aspirin is confirmed by additional studies, PPARGC1B and CNTN4 genotyping could potentially assist in clinical decision making regarding the use of aspirin in primary prevention. PMID- 29258008 TI - Determination of chlorpropham (CIPC) residues, in the concrete flooring of potato stores, using quantitative (HPLC UV/VIS) and qualitative (GCMS) methods. AB - Isopropyl-N-(3-chlorophenyl) carbamate (CIPC, common name Chlorpropham) is commonly used for post-harvest sprout inhibition in stored potatoes. It is applied as a thermal fog which results in loss to the fabric of the store and the atmosphere. Recently, there have been concerns in the United Kingdom because of cross contamination of other crop commodities that were stored in buildings with a history of CIPC usage. This cross contamination may have occurred because of retained residues in the fabric of the stores. The retention of CIPC in concrete is poorly understood; therefore the requirement for a robust analytical method for the detection and quantification of CIPC in concrete is a critical first step in tackling this problem. A method using High-Performance Liquid Chromatography with ultraviolet detection (HPLC UV/VIS) was validated. CIPC recoveries at three concentration levels (0.4, 4.0 and 40.0 MUg g-1) were in the range of 90.7-97.0% with relative standard deviations between 2.14 and 3.01%. The limits of detection and quantification were 0.03 and 0.1 MUg g-1, respectively. This study confirmed that CIPC was persistent in concrete to a depth of 4 cm, with >90% within the top 1 cm of the flooring. PMID- 29258009 TI - The toxicity of graphene and its impacting on bioleaching of metal ions from sewages sludge by Acidithiobacillus sp. AB - The increasing production of graphene raised concerns about their releasing into sewage sludge, however, there is little information about graphene impacting on the growth of bacteria and hence their bioleaching of metal ions from sewages sludge. In this study, we reported that Acidithiobacillus sp., isolated from sewages, were used to bioleach Cu2+ and Zn2+ from sewages sludge in the presence of graphene. The negative effect on the growth of Acidithiobacillus sp. and dose dependent were observed in presence of graphene, where the optical density (OD420) of the culture decreased from 0.163 to 0.045, while the bioleaching efficiency of Cu2+ (70%-16%) and Zn2+ (80%-48%) were also reduced when the graphene dose decreased from 50 mg L-1 to 1 mg L-1. Furthermore, scanning electron microscopy (SEM) and atomic force microscopy (AFM) confirmed that the direct contacts between graphene and cell at 1 mg L-1 graphene caused cell membrane disruption, while Acidithiobacillus sp. grew better by forming dense biofilms around the suspended graphene at a 50 mg L-1. LIVE/DEAD staining further demonstrated that almost no live cells were detected at 1 mg L-1 graphene. The toxicity of graphene could generally be explained by depending on the concentration of graphene. The new findings provide an insight into dose dependence, which impacted on the growth of Acidithiobacillus sp. and their bioleaching of metal ion from sludge. PMID- 29258010 TI - Environmental fate and effects of granular pesta formulation from strains of Pseudomonas aeruginosa C1501 and Lasiodiplodia pseudotheobromae C1136 on soil activity and weeds. AB - This work investigated the effect of variably formulated pesta granules containing wild and UV mutated Pseudomonas aeruginosa and Lasiodiplodia pseudotheobromae on the rate of CO2 evolution, organic carbon content, enzymatic activity (acidic and alkaline phosphatase, dehydrogenases, urease and protease) and representative soil microorganisms in the soils using different assay techniques. After the 35th day period of experiment, the pesta granule formulation BH4 showed the best evolution of CO2 (824 +/- 6.2 mg CO2 kg-1 soil hr 1) as against control treatment (689 +/- 3.7 mg CO2 kg-1 soil hr-1). Enzymes activities, organic carbon content of 3.8% on the 15th day of study and stable representation of microorganisms that include actinomycetes, fungi, heterogenous as well as soil nitrogen-mediatory bacteria were equally at their maximum level BH4 treatments. The phytotoxic assay showed no inhibitory effect on Solanum lycopersicum seeds and seedlings compared to the observed growth inhibition on the tested weeds (Amaranthus hybridus and Echinocholoa crus-galli) which corresponds with positive control glyphosate treatment. The glyphosate treated soil had the least critical results on parameters investigated during the study. The order of bioherbicidal activity is BH4>BH2>BH6>BH3>BH1>BH5>positive control. Results from this study confirmed the target efficacy of variably formulated pesta granules which is sustainable, cheap, ecologically suitable and recent. This is in addition to recognizing the microbial-derived formulations as characteristically potent alternative to chemical herbicides utility in agrosystems practice. Further study of the underlining factor responsible for the bioherbicidal performances of the variably formulated pesta granules and field trials are critical for their future commercialization. PMID- 29258011 TI - Do the right thing: neural network mechanisms of memory formation, expression and update in Drosophila. AB - When animals learn, plasticity in brain networks that respond to specific cues results in a change in the behavior that these cues elicit. Individual network components in the mushroom bodies of the fruit fly Drosophila melanogaster represent cues, learning signals and behavioral outcomes of learned experience. Recent findings have highlighted the importance of dopamine-driven plasticity and activity in feedback and feedforward connections, between various elements of the mushroom body neural network. These computational motifs have been shown to be crucial for long term olfactory memory consolidation, integration of internal states, re-evaluation and updating of learned information. The often recurrent circuit anatomy and a prolonged requirement for activity in parts of these underlying networks, suggest that self-sustained and precisely timed activity is a fundamental feature of network computations in the insect brain. Together these processes allow flies to continuously adjust the content of their learned knowledge and direct their behavior in a way that best represents learned expectations and serves their most pressing current needs. PMID- 29258012 TI - Big roles for Fat cadherins. AB - To create an intricately patterned and reproducibly sized and shaped organ, many cellular processes must be tightly regulated. Cell elongation, migration, metabolism, proliferation rates, cell-cell adhesion, planar polarization and junctional contractions all must be coordinated in time and space. Remarkably, a pair of extremely large cell adhesion molecules called Fat (Ft) and Dachsous (Ds), acting largely as a ligand-receptor system, regulate, and likely coordinate, these many diverse processes. Here we describe recent exciting progress on how the Ds-Ft pathway controls these diverse processes, and highlight a few of the many questions remaining as to how these enormous cell adhesion molecules regulate development. PMID- 29258013 TI - DNA nanoparticles for ophthalmic drug delivery. AB - Nucleic acids represent very appealing building blocks for the construction of nano-scaled objects with great potential applications in the field of drug delivery where multifunctional nanoparticles (NPs) play a pivotal role. One opportunity for DNA nanotechnology lies in the treatment of ophthalmic diseases as the efficacy of eye drops is impaired by the short survival time of the drug on the eye surface. As a consequence, topical administration of ocular therapeutics requires high drug doses and frequent administration, still rarely providing high bioavailability. To overcome these shortcomings we introduce a novel and general carrier system that is based on DNA nanotechnology. Non-toxic, lipid-modified DNA strands (12mers with 4 lipid modified thymines at the 5' end) form uniform NPs (micelles), which adhere to the corneal surface for extended periods of time. In a single self-assembly step they can be equipped with different drugs by hybridization with an aptamer. The long survival times of DNA NPs can be translated into improved efficacy. Their functionality was demonstrated in several ex-vivo experiments and in an in-vivo animal model. Finally, the NPs were confirmed to be applicable even for human tissue. PMID- 29258014 TI - Modeling metabolism of the human gut microbiome. AB - The human gut microbiome plays an important part in human health. The complexity of the microbiome makes it difficult to determine the detailed metabolic functions and cross-talk occurs between the individual species. In silico systems biology studies of the microbiome can help to identify metabolite exchanges among gut microbes. Constraint-based reconstruction and analysis methods use biochemically accurate genome-scale metabolic networks of microorganisms to simulate metabolism between species in a given microbiome and help generate novel hypotheses on microbial interactions. Here, we review metabolic modeling studies that have investigated metabolic functions of the gut microbiome. PMID- 29258015 TI - The role of fat talk in eating pathology and depressive symptoms among mother daughter dyads. AB - The present study investigated how eating pathology and depressive symptoms were related to the dyadic dynamics of fat talk in mother-daughter relationships during adolescence. The current sample included 100 mother-daughter dyads who completed a survey on their fat talk disclosure, eating pathology, and depressive symptoms. The Actor-Partner Interdependence Model (APIM) was utilized for the dyadic data. Adolescent girls' and mothers' engagement in fat talk was related to their own eating pathology. Daughters, but not mothers, who engaged in more fat talk reported more depressive symptoms. When mothers and daughters both had high levels of fat talk, it was associated with a higher risk of daughters' eating pathology. Adolescent girls who engaged in fat talk reported higher depressive symptoms when their mothers did not reciprocate with more fat talk. This study highlights the importance of an interpersonal approach to fat talk research and clinical interventions addressing adolescents' eating disorders and depression. PMID- 29258016 TI - Exploring the Tripartite Influence Model of body dissatisfaction in postpartum women. AB - Pregnancy and childbirth result in dramatic changes in a woman's body shape, which can be associated with body image concerns. To date, however, little is known about how sociocultural factors may influence body dissatisfaction in postpartum women. This study aimed to test a sociocultural model of body image and eating concerns among a sample of postpartum women. A sample of N=474 women, mean (SD) age=30.6 (4.8), having given birth during the last year, completed an online survey and reported on sociocultural pressures from media, peers, family and partners, thin-ideal internalization, appearance comparison, body dissatisfaction, and psychological functioning. Structural equation modeling analyses revealed a good fit to the data, chi2 (49)=220.20, p<.001, RMSEA=.086, CFI=.93. Findings suggest that women experience strong sociocultural pressures to attain unrealistic body shapes/sizes during the post-pregnancy period, contributing to their body image concerns. PMID- 29258017 TI - Antifouling processes and toxicity effects of antifouling paints on marine environment. A review. AB - The production infrastructure in aquaculture invariably is a complex assortment of submerged components with cages, nets, floats and ropes. Cages are generally made from polyamide or high density polyethylene (PEHD). All of these structures serve as surfaces for biofouling. However, cage nets and supporting infrastructure offer fouling organisms thousands of square meters of multifilament netting. That's why, before immersing them in seawater, they should be coated with an antifouling agent. It helps to prevent net occlusion and to increase its lifespan. Biofouling in marine aquaculture is a specific problem and has three main negative effects. It causes net occlusion and so restricts water and oxygen exchange. Besides, the low dissolved oxygen levels from poor water exchange increases the stress levels of fish, lowers immunity and increases vulnerability to disease. Also, the extra weight imposed by fouling causes cage deformation and structural fatigue. The maintenance and loss of equipment cause the increase of production costs for the industry. Biocides are chemical substances that can prohibit or kill microorganisms responsible for biofouling. The expansion of the aquaculture industry requires the use of more drugs, disinfectants and antifoulant compounds (biocides) to eliminate the microorganisms in the aquaculture facilities. Unfortunately, the use of biocides in the aquatic environment has proved to be harmful as it has toxic effects on the marine environment. The most commonly used biocides in antifouling paints are Tributyltin (TBT), Chlorothalonil, Dichlofluanid, Sea-Nine 211, Diuron, Irgarol 1051 and Zinc Pyrithione. Restrictions were imposed on the use of TBT, that's why organic booster biocides were recently introduced. The replacement products are generally based on copper metal oxides and organic biocides. This paper provides an overview of the effects of antifouling biocides on aquatic organisms. It will focus on the eight booster biocides in common use, despite little data are available for some of them. Toxicity values and effects of these antifoulants will also be mentioned for different species of fish, crustaceans, invertebrates and algae. PMID- 29258018 TI - Pharmacophore-based drug design for potential AChE inhibitors from Traditional Chinese Medicine Database. AB - Alzheimer's disease (AD) is a neurodegenerative disorder. Substrate-specific Acetylcholinesterase (AChE) plays a vital role in the AD treatment. Flavonoids with AChE inhibitory activities and low toxicity are used to developing new anti AD agents. In this study, the best 3D QSAR pharmacophore model Hypo1 was generated by HypoGen program in Discovery Studio2016 based on the training set of flavonoids. We performed a virtual screening from Traditional Chinese Medicine (TCM), Druglike and MiniMaybridge databases using Hypo1. From docking analyses, we got the top 10 AChE inhibitors which were further evaluated by 8 different scoring functions. De Novo Evolution designed the top 10 derivatives, and three potential AChE inhibitor candidates were obtained eventually. PMID- 29258019 TI - A computational study on the cisplatin drug interaction with boron nitride nanocluster. AB - We explored the reactivity, and electronic sensitivity of the synthesized B12N12 nanocluster to cisplatin (CP) anticancer drug by means of density functional theory calculations. It is predicted that the drug prefers to be adsorbed simultaneously from its hydrogen and halogen atoms on a BN bond of the BN nanocluster with adsorption energy about -14.9kcal/mol. The electronic properties of B12N12 nanocluster are predicted to be sensitive to the CP drug and it benefits from a short recovery time about 81ms at room temperature. After the adsorption of the CP drug, the conduction level of BN nanocluster meaningfully stabilizes and the valence level shifts to higher energies. As a result, the HOMO LUMO energy gap significantly decreases. So, the BN nanocluster converts to a semiconductor with higher electrical conductivity after the adsorption process. The increase of electrical conductivity can produce an electrical signal which helps to detect the CP drug. Also, UV-vis calculations indicate that after the adsorption of the CP drug a strong peak appears in the visible region which helps to detect the drug. PMID- 29258020 TI - TDDFT calculations and photoacoustic spectroscopy experiments used to identify phenolic acid functional biomolecules in Brazilian tropical fruits in natura. AB - Time-dependent density functional theory (TDDFT) calculations of electronic transitions have been widely used to determine molecular structures. The excitation wavelengths and oscillator strengths obtained with the hybrid exchange correlation functional B3LYP in conjunction with the ADZP basis set are employed to simulate the UV-Vis spectra of eight phenolic acids. Experimental and theoretical UV-Vis spectra reported previously in the literature are compared with our results. The fast, sensitive and non-destructive technique of photoacoustic spectroscopy (PAS) is used to determine the UV-Vis spectra of four Brazilian tropical fresh fruits in natura. Then, the PAS along with the TDDFT results are for the first time used to investigate and identify the presence of phenolic acids in the fruits studied in this work. This theoretical method with this experimental technique show to be a powerful and cheap tool to detect the existence of phenolic acids in fruits, vegetables, cereals, and grains. Comparison with high performance liquid chromatography results, when available, is also carried out. PMID- 29258021 TI - Analytical characterization of the palette and painting techniques of Jorge Afonso, the great 16th century Master of Lisbon painting workshop. AB - In this work, a study on a set of paintings from the most significant altarpiece assigned to Master Jorge Afonso (c. 1470-1540) painting workshop is presented. This altarpiece is composed by fourteen paintings made to the church of Convento de Jesus, in Setubal, Portugal, and was made circa 1517-19/1530, according to art history. This set of paintings is compared to one of the other most important Portuguese altarpieces from the 16th century: the panels of the Round Church of the Convento de Cristo, in Tomar, made circa 1510-1515. The aim of this study is to characterize the wooden support, pigments, ground layers materials and technique used in Jorge Afonso workshop by means of complementary analyses. A dendrochronological approach was made in order to corroborate (or not) the historical date initially assigned. Infrared photography (IRP) and reflectography (IRR) allowed the study of the underdrawing technique and macro photography (MP) was used to recognize overlapping layers technique. Cross-sections from the paintings were examined by optical microscopy (OM), and analyzed by MU-X-ray diffraction (MU-XRD), Energy Dispersive X-ray Fluorescence spectroscopy (EDXRF), Scanning Electron Microscopy with Energy Dispersive X-ray Spectroscopy (SEM-EDS), micro-Raman spectroscopy (MU-Raman), micro-Fourier Transform Infrared spectroscopy (MU-FTIR), Pyrolysis Gas Chromatography Mass Spectrometry (py GC/MS). The characterization of the palette and ground layers and the study of the overlapping of paint layers brought a new insight of the adopted painting techniques by the most important group of painters working in Portugal in the 16th century - the Lisbon workshop, leaded by Master Jorge Afonso. PMID- 29258022 TI - Spectral study on conformation switchable cationic calix[4]carbazole serving as curcumin container, stabilizer and sustained-delivery carrier. AB - A fluorescent 2,7-dimethoxy-substituted calix[4]carbazole (1) is facilely synthesized. The spectral behaviors of both the guest-induced switchable conformation of 1 and its abilities serving as the stabilizer and molecular carrier of curcumin are investigated. UV-vis, fluorescence and NMR spectral results show that upon binding to curcumin, the 1,3-alternate conformation of 1 is converted to be the cone one. The relative high association constant (6.4*106M 1) of 1 binding to curcumin enables it to stabilize the curcumin, to suppress its degradation, and to sustainably deliver it into the EYPC vesicles within 20h. Moreover, the cytotoxicity assay shows that 1 does not interfere the antiproliferative activities of curcumin. All these properties endow 1 the potential capability of serving as the molecular drug carrier. Our current result may pave the way looking for more efficient fluorescent calixcarbazoles and thereof spectral utilities. PMID- 29258023 TI - Sizing protein-templated gold nanoclusters by time resolved fluorescence anisotropy decay measurements. AB - Protein-templated gold nanoclusters (AuNCs) are very attractive due to their unique fluorescence properties. A major problem however may arise due to protein structure changes upon the nucleation of an AuNC within the protein for any future use as in vivo probes, for instance. In this work, we propose a simple and reliable fluorescence based technique measuring the hydrodynamic size of protein templated gold nanoclusters. This technique uses the relation between the time resolved fluorescence anisotropy decay and the hydrodynamic volume, through the rotational correlation time. We determine the molecular size of protein-directed AuNCs, with protein templates of increasing sizes, e.g. insulin, lysozyme, and bovine serum albumin (BSA). The comparison of sizes obtained by other techniques (e.g. dynamic light scattering and small-angle X-ray scattering) between bare and gold clusters containing proteins allows us to address the volume changes induced either by conformational changes (for BSA) or the formation of protein dimers (for insulin and lysozyme) during cluster formation and incorporation. PMID- 29258024 TI - The application of artificial neural networks and support vector regression for simultaneous spectrophotometric determination of commercial eye drop contents. AB - In the present study, artificial neural networks (ANNs) and support vector regression (SVR) as intelligent methods coupled with UV spectroscopy for simultaneous quantitative determination of Dorzolamide (DOR) and Timolol (TIM) in eye drop. Several synthetic mixtures were analyzed for validating the proposed methods. At first, neural network time series, which one type of network from the artificial neural network was employed and its efficiency was evaluated. Afterwards, the radial basis network was applied as another neural network. Results showed that the performance of this method is suitable for predicting. Finally, support vector regression was proposed to construct the Zilomole prediction model. Also, root mean square error (RMSE) and mean recovery (%) were calculated for SVR method. Moreover, the proposed methods were compared to the high-performance liquid chromatography (HPLC) as a reference method. One way analysis of variance (ANOVA) test at the 95% confidence level applied to the comparison results of suggested and reference methods that there were no significant differences between them. Also, the effect of interferences was investigated in spike solutions. PMID- 29258025 TI - Fluorescent carbon dots nanosensor for label-free determination of vitamin B12 based on inner filter effect. AB - A simple and effective fluorescent assay for the determination of vitamin B12 was developed. In this study, carbon dots (CDs) were prepared by one-pot hydrothermal method and directly used as a fluorophore in the inner filter effect (IFE). Both of the maximum absorption peak of vitamin B12 and excitation maxima of CDs are located at 360nm, hence, the excited light of CDs can be absorbed by vitamin B12, resulting in the fluorescence reduction of CDs. And the fluorescence intensity of CDs decreases with the increasing concentration of vitamin B12. This IFE-based sensing strategy shows a good linear relationship between the normalized fluorescence intensity and the concentration of vitamin B12 ranging from 0 to 60MUM, with a limit of detection (LOD) of 0.1MUM at a signal-to-noise ratio of 3. Furthermore, this proposed approach was successfully applied to vitamin B12 sensing in injections. This IFE sensing platform based on various fluorescent nanomaterials has a high promise for the detection of other biomolecules due to its inherent convenience. PMID- 29258026 TI - Novel kinetic spectrophotometric method for estimation of certain biologically active phenolic sympathomimetic drugs in their bulk powders and different pharmaceutical formulations. AB - A simple, selective and sensitive kinetic spectrophotometric method was described for estimation of four phenolic sympathomimetic drugs namely; terbutaline sulfate, fenoterol hydrobromide, isoxsuprine hydrochloride and etilefrine hydrochloride. This method is depended on the oxidation of the phenolic drugs with Folin-Ciocalteu reagent in presence of sodium carbonate. The rate of color development at 747-760nm was measured spectrophotometrically. The experimental parameters controlling the color development were fully studied and optimized. The reaction mechanism for color development was proposed. The calibration graphs for both the initial rate and fixed time methods were constructed, where linear correlations were found in the general concentration ranges of 3.65*10-6-2.19*10 5molL-1 and 2-24.0MUgmL-1 with correlation coefficients in the following range 0.9992-0.9999, 0.9991-0.9998 respectively. The limits of detection and quantitation for the initial rate and fixed time methods were found to be in general concentration range 0.109-0.273, 0.363-0.910 and 0.210-0.483, 0.700 1.611MUgmL-1 respectively. The developed method was validated according to ICH and USP 30 -NF 25 guidelines. The suggested method was successfully implemented to the estimation of these drugs in their commercial pharmaceutical formulations and the recovery percentages obtained were ranged from 97.63%+/-1.37 to 100.17%+/ 0.95 and 97.29%+/-0.74 to 100.14+/-0.81 for initial rate and fixed time methods respectively. The data obtained from the analysis of dosage forms were compared with those obtained by reported methods. Statistical analysis of these results indicated no significant variation in the accuracy and precision of both the proposed and reported methods. PMID- 29258027 TI - NMR diffusion and relaxation studies of 2-nitroimidazole and albumin interactions. AB - Nitroimidazole derivatives are of current interest in the development of hypoxia targeting agents and show potential in the establishment of quantitative measures of tumor hypoxia. In this study, the binding of 2-nitroimidazole to albumin was probed using NMR diffusion and relaxation measurements. Binding studies were conducted at three different protein concentrations (0.23, 0.30 and 0.38mM) with drug concentrations ranging from 0.005-0.16M at 298K. Quantitative assessments of the binding model were made by evaluating the number of binding sites, n, and association constant, K. These were determined to be 21+/-3 and 53+/-4M-1, respectively. PMID- 29258028 TI - Drug Stroop: Mechanisms of response to computerized cognitive behavioral therapy for cocaine dependence in a randomized clinical trial. AB - BACKGROUND: Poor performance on Drug Stroop tasks, which could indicate attentional bias to drug-related cues, craving, poor cognitive control (including poor response inhibition), has been associated with substance use severity, treatment retention and substance use treatment outcomes. Cognitive Behavioral Therapy (CBT) focuses on training in appraisal and coping strategies, including strategies to minimize the negative impact of triggers and coping with drug-cue induced craving. One mechanism of action of CBT may be the strengthening of cognitive control processes and reduction of attentional bias to drug-related stimuli. METHODS: Methadone-maintained individuals with cocaine-use disorders, participating in a randomized controlled trial of treatment as usual (TAU) versus TAU plus access to computer-based CBT (CBT4CBT), completed a computerized Drug Stroop task at pre- and post-treatment. Analyses determined whether attentional bias toward drug-related stimuli changed differentially by treatment group or cocaine use outcomes across the treatment period and whether engagement in components of CBT4CBT or TAU treatment related to changes in attentional bias toward drug-related stimuli at post- versus pre-treatment. RESULTS: Participants achieving a longer duration of cocaine abstinence during treatment (3+ weeks) showed greater reductions in Drug Stroop Effect than those with shorter maximum continuous abstinence. Reductions in Drug Stroop Effect across treatment were associated with greater engagement with CBT4CBT-specific treatment components, but not TAU-specific treatment components. CONCLUSIONS: Reduction in attentional bias to drug-related cues and craving and/or improved executive cognitive control and response inhibition may contribute to the mechanism of action of CBT4CBT. PMID- 29258029 TI - Frequency and outcomes of biopsy-proven fibroadenomas recommended for surgical excision. AB - Our aim was to investigate the outcomes of fibroadenomas recommended for surgical excision due to large size (>2cm) or interval growth. A retrospective review of our institutional radiology database from 2007 to 2015 was performed. We identified 167 biopsy-proven fibroadenomas recommended for surgical consultation. Of these, 75 (45%) cases actually underwent excision, 7 (9%, 95% CI: 4-18%) of which were upgraded to phyllodes tumors upon histopathological examination. Our results support the current recommendation to surgically excise breast lesions diagnosed as fibroadenomas with size >2cm or with interval growth due to the considerable risk of finding phyllodes tumors. PMID- 29258030 TI - 3D pseudocontinuous arterial spin-labeling perfusion imaging detected crossed cerebellar diaschisis in acute, subacute and chronic intracerebral hemorrhage. AB - OBJECTIVE: We aimed to evaluate the value of 3D pseudocontinuous arterial spin labeling (pCASL) perfusion imaging detected crossed cerebellar diaschisis (CCD) at different stages of intracerebral hemorrhage (ICH). MATERIALS AND METHODS: We assessed bilateral cerebral blood flow (CBF) values of different brain regions and the relationships between the CCD and clinical status of 16 ICH patients. RESULTS: The ICH patients had significantly lower CBF values in the contralateral cerebellum in acute, subacute and chronic stages. The subacute CCD had a significant correlation with clinical status. CONCLUSIONS: 3D pCASL may be an ideal tool to study the phenomenon and clinical consequences of ICH with CCD. PMID- 29258031 TI - Occurrence of antibiotics and antibiotic resistance genes in soils from wastewater irrigation areas in the Pearl River Delta region, southern China. AB - The occurrence and distribution of tetracycline (TC) and sulfamethazine (SMZ), and the corresponding antibiotic resistance genes (ARGs) were investigated in six agricultural sites in the Pearl River Delta (PRD) region in southern China. Irrigation water and irrigated soils at two different depths (0-10 and 10-20cm) were analyzed. The total concentrations of TC and SMZ in irrigation water ranged from 69.3 to 234ng/L and from 4.00 to 58.2ng/L, respectively, while the total concentrations of TC and SMZ in irrigated soils ranged from 5.00 to 21.9MUg/kg and from 1.30 to 4.20MUg/kg, respectively. After long-term irrigation with domestic and fishpond wastewater in the field, the residual TC and SMZ and their corresponding ARGs in soils were significantly higher in fishpond-irrigated soils (Dongguan and Shenzhen) than in domestic wastewater-irrigated soils (Foshan, Guangzhou, Huizhou and Zhongshan). The concentrations of antibiotics and their ARGs were significantly higher in irrigation water than in irrigated soils, which indicated that wastewater was the primary source of antibiotics in the soil environments. The domestic and fishpond wastewater were important repositories of antibiotics and their ARGs, which require effective treatment before their discharge into the environment. Other factors such as soil physicochemical properties, manure application, irrigation water sources and cropping patterns also affect the antibiotic concentrations and ARG abundances. The residual antibiotic concentrations statistically correlated with the corresponding ARGs in irrigation water and irrigated soils, both of which decreased with increasing soil depth, indicating that the concentration of antibiotics in the environment exerted a selection pressure on the microorganisms in the environment. PMID- 29258032 TI - Characterisation of electron beam irradiation-immobilised laccase for application in wastewater treatment. AB - Laccase from Phoma sp. UHH 5-1-03 was cross-linked to polyvinylidene fluoride membranes by electron beam irradiation. Immobilised laccase displayed a higher stability than the non-immobilised enzyme with respect to typical wastewater temperatures, and pH at a range of 5 to 9. Batch tests addressed the removal of pharmaceutically active compounds (PhACs; applied as a mixture of acetaminophen, bezafibrate, indometacin, ketoprofen, mefenamic acid, and naproxen) by both immobilised and non-immobilised laccase in municipal wastewater. High removal rates (>85%) of the most efficiently oxidised PhACs (acetaminophen and mefenamic acid) indicated a high efficiency of the immobilised laccase in wastewater. Continuous elimination of the aforementioned PhACs by the immobilised enzyme in a continuously operated diffusion basket reactor yielded a PhAC removal pattern qualitatively similar to those observed in batch tests. Clearly higher apparent Vmax values and catalytic efficiencies (in terms of both Vmax/S0.5 as well as Vmax/Km values obtained from data fitting according to the Hill and the Michaelis Menten model, respectively) observed for acetaminophen oxidation by the immobilised compared to the non-immobilised enzyme are in support of a considerably higher functional stability of the immobilised laccase especially in wastewater. The potential influence of acetaminophen on the removal of comparatively less laccase-oxidisable water pollutants such as the antimicrobial triclosan (TCS) was investigated. TCS was increasingly removed upon increasing the initial acetaminophen concentration in immobilised as well as non-immobilised laccase reaction systems until saturation became evident. Acetaminophen was consumed and not recycled during laccase reactions, which was accompanied by the formation of various acetaminophen-TCS cross-coupling products. Nevertheless, the simultaneous presence of acetaminophen (and potentially even more pollutant removal-enhancing laccase substrates) and more recalcitrant pollutants in wastewater represents an interesting option for the efficiency enhancement of enzyme-based wastewater treatment approaches. PMID- 29258033 TI - Characterization of how contaminants arise in a dredged marine sediment and analysis of the effect of natural weathering. AB - Millions of tons of contaminated sediments are dredged each year from the main harbors in France. When removed from water, these sediments are very reactive, therefore their geochemical behavior must be understood in order to avoid dispersion of contaminated lixiviates in the surrounding soils. In this objective, it is necessary to evaluate the principal physicochemical parameters, and also achieve advanced mineralogical characterization. These studied sediments are highly contaminated by metals, notably copper (1445 and 835mg/kg, in the unweathered and naturally-weathered sediments, respectively), lead (760 and 1260mg/kg, respectively), zinc (2085 and 2550mg/kg, respectively), as well as by organic contaminants (PAH, PCB) and organometallics (organotins). A high concentration of sulfide minerals was also observed both in the unweathered sediment preserved under water (3.4wt% of pyrite especially), and in the naturally weathered sediment (2wt% pyrite), and in particular framboidal pyrite was observed in the two materials. The presence of reactive mineral species in the naturally-weathered sediment can be explained by the deposit of a protective layer, composed of sulfide and their oxidation products (sulfate and iron oxides), thus preventing oxygen from diffusing through to the sulfide minerals. Additionally, the presence of aluminosilicates aggregates coating the sulfide minerals could also explain their presence in the naturally-weathered sediment. As organic matter is one of the principal constituents of the sediments (5.8 and 6.3wt% total organic carbon in the unweathered and weathered sediment, respectively), the aggregates are probably partially constituted of refractory humic material. It therefore appears that the natural weathering has led to a significant decrease in PAHs and organotins, but not in PCBs. The evolution of the granulometric structure and the distribution of the metallic contaminants could therefore lead us to consider a treatment by size separation, and a possible valorization of the dredged sediments in civil engineering. PMID- 29258034 TI - Sorption of active pharmaceutical ingredients in untreated wastewater effluent and effect of dilution in freshwater: Implications for an "impact zone" environmental risk assessment approach. AB - Evidence of ecotoxicological effects of active pharmaceuticals ingredients (APIs) has increased research into their environmental fate. In low and low-middle income countries (LLMICs) the main source of APIs to surface waters is from discharge of untreated wastewater. Consequently, concentrations of APIs can be relatively high in the "impact zone" downstream of a discharge point. Little is known about the fate of APIs in these impact zones. In this laboratory scale investigation, the effect of successive dilution of synthetic untreated wastewater (dilution factor 1 to 10) on the distribution of APIs was studied. The sorption was consistent with the chemical properties of each compound: charge, lipophilicity, and structure. Dilution increased desorption of the basic and neutral APIs (up to 27.7%) and correlated with their lipophilicity (R2>0.980); the positive charge was of secondary importance. Anions did not significantly desorb (<10% loss). Increased concentrations of dissolved organic matter at dilutions of 8 and 10 times that of untreated wastewater coincided with lower dissolved API concentrations. The data showed a clear trend in the desorption process of APIs that may lead to higher exposure risk than anticipated. Therefore, it is suggested that these aspects should be accounted for in the development of dedicated environmental risk assessment approach for APIs in riverine impact zones of LLMICs countries. PMID- 29258035 TI - Quantification and mapping of the supply of and demand for carbon storage and sequestration service in woody biomass and soil to mitigate climate change in the socio-ecological environment. AB - In this study, the supply of and demand for carbon storage and sequestration of woody biomass in the socio-ecological environment of the Wabe River catchment in Gurage Mountains, Ethiopia, were estimated. This information was subsequently integrated into a map that showed the balance between supply capacities and demand in a spatially explicit manner to inform planners and decision makers on methods used to manage local climate change. Field data for wood biomass and soil were collected, satellite images for land use and land cover (LULC) were classified, and secondary data from statistics and studies for estimation were obtained. Carbon storage, the rate of carbon sequestration and the rate of greenhouse gas (GHG) emissions from diverse sources at different LULCs, was estimated accordingly by several methods. Even though a large amount of carbon was stored in the catchment, the current yearly sequestration was less than the CO2-eq. GHG emissions. Forest and Enset-based agroforestry emissions exhibited the highest amount of woody biomass, and cereal crop and wetland exhibited the highest decrease in soil carbon sequestration. CO2-eq. GHG emissions are mainly caused by livestock, nitrogenous fertilizer consumption, and urban activities. The net negative emissions were estimated for the LULC classes of cereal crop, grazing land, and urban areas. In conclusion, without any high-emission industries, GHG emissions can be greater than the regulatory capacity of ecosystems in the socio-ecological environment. This quantification approach can provide information to policy and decision makers to enable them to tackle climate change at the root level. Thus, measures to decrease emission levels and enhance the sequestration capacity are crucial to mitigate the globally delivered service in a specific area. Further studies on the effects of land use alternatives on net emissions are recommended to obtain in-depth knowledge on sustainable land use planning. PMID- 29258036 TI - Improve regional distribution and source apportionment of PM2.5 trace elements in China using inventory-observation constrained emission factors. AB - Contributions to 15 trace elements in airborne particulate matter with aerodynamic diameters <2.5MUm (PM2.5) in China from five major source sectors (industrial sources, residential sources, transportation, power generation and windblown dust) were determined using a source-oriented Community Multiscale Air Quality (CMAQ) model. Using emission factors in the composite speciation profiles from US EPA's SPECIATE database for the five sources leads to relatively poor model performance at an urban site in Beijing. Improved predictions of the trace elements are obtained by using adjusted emission factors derived from a robust multilinear regression of the CMAQ predicted primary source contributions and observation at the urban site. Good correlations between predictions and observations are obtained for most elements studied with R>0.5, except for crustal elements Al, Si and Ca, particularly in spring. Predicted annual and seasonal average concentrations of Mn, Fe, Zn and Pb in Nanjing and Chengdu are also consistently improved using the adjusted emission factors. Annual average concentration of Fe is as high as 2.0MUgm-3 with large contributions from power generation and transportation. Annual average concentration of Pb reaches 300 500ngm-3 in vast areas, mainly from residential activities, transportation and power generation. The impact of high concentrations of Fe on secondary sulfate formation and Pb on human health should be evaluated carefully in future studies. PMID- 29258037 TI - Characterisation of a major phytoplankton bloom in the River Thames (UK) using flow cytometry and high performance liquid chromatography. AB - Recent river studies have observed rapid phytoplankton dynamics, driven by diurnal cycling and short-term responses to storm events, highlighting the need to adopt new high-frequency characterisation methods to understand these complex ecological systems. This study utilised two such analytical methods; pigment analysis by high performance liquid chromatography (HPLC) and cell counting by flow cytometry (FCM), alongside traditional chlorophyll spectrophotometry and light microscopy screening, to characterise the major phytoplankton bloom of 2015 in the River Thames, UK. All analytical techniques observed a rapid increase in chlorophyll a concentration and cell abundances from March to early June, caused primarily by a diatom bloom. Light microscopy identified a shift from pennate to centric diatoms during this period. The initial diatom bloom coincided with increased HPLC peridinin concentrations, indicating the presence of dinoflagellates which were likely to be consuming the diatom population. The diatom bloom declined rapidly in early June, coinciding with a storm event. There were low chlorophyll a concentrations (by both HPLC and spectrophotometric methods) throughout July and August, implying low biomass and phytoplankton activity. However, FCM revealed high abundances of pico-chlorophytes and cyanobacteria through July and August, showing that phytoplankton communities remain active and abundant throughout the summer period. In combination, these techniques are able to simultaneously characterise a wider range of phytoplankton groups, with greater certainty, and provide improved understanding of phytoplankton functioning (e.g. production of UV inhibiting pigments by cyanobacteria in response to high light levels) and ecological status (through examination of pigment degradation products). Combined HPLC and FCM analyses offer rapid and cost-effective characterisation of phytoplankton communities at appropriate timescales. This will allow a more-targeted use of light microscopy to capture phytoplankton peaks or to investigate periods of rapid community succession. This will lead to greater system understanding of phytoplankton succession in response to biogeochemical drivers. PMID- 29258039 TI - Modelled spatiotemporal variability of outdoor thermal comfort in local climate zones of the city of Brno, Czech Republic. AB - This study uses the MUKLIMO_3 urban climate model (in German, Mikroskaliges Urbanes KLImaMOdell in 3-Dimensionen) and measurements from an urban climate network in order to simulate, validate and analyse the spatiotemporal pattern of human thermal comfort outdoors in the city of Brno (Czech Republic) during a heat wave period. HUMIDEX, a heat index designed to quantify human heat exposure, was employed to assess thermal comfort, employing air temperature and relative humidity data. The city was divided into local climate zones (LCZs) in order to access differences in intra-urban thermal comfort. Validation of the model results, based on the measurement dates within the urban monitoring network, confirmed that the MUKLIMO_3 micro-scale model had the capacity to simulate the main spatiotemporal patterns of thermal comfort in an urban area and its vicinity. The results suggested that statistically significant differences in outdoor thermal comfort exist in the majority of cases between different LCZs. The most built-up LCZ types (LCZs 2, 3, 5, 8 and 10) were disclosed as the most uncomfortable areas of the city. Hence, conditions of great discomfort (HUMIDEX >40) were recorded in these areas, mainly in the afternoon hours (from 13.00 to 18.00 CEST), while some thermal discomfort continued overnight. In contrast, HUMIDEX values in sparsely built-up LCZ 9 and non-urban LCZs were substantially lower and indicated better thermal conditions for the urban population. Interestingly, the model captured a local increase of HUMIDEX values arising out of air humidity in LCZs with the presence of more vegetation (LCZs A and B) and in the vicinity of larger bodies of water (LCZ G). PMID- 29258038 TI - Association between maternal exposure to major phthalates, heavy metals, and persistent organic pollutants, and the neurodevelopmental performances of their children at 1 to 2years of age- CHECK cohort study. AB - Exposure of the developing fetus and infants to toxic substances can cause serious lifelong health consequences. Several chemicals have been associated with adverse neurodevelopmental disorders in the early life stages of humans. However, most epidemiological studies have focused on a limited number of chemicals, and hence may exclude important chemicals from consideration or result in conclusions built on associations by chance. In the present study, we investigated the chemical exposure profile of the women, and associated these with the early neurodevelopmental performance of their offspring at 13-24months of age. The chemicals assessed include four phthalates, bisphenol A, three heavy metals, 19 polychlorinated biphenyls (PCBs), 19 organochlorine pesticides, and 19 polybrominated diphenyl ethers, which were measured from urine, whole blood, serum, and/or breastmilk of the pregnant or lactating women. For neurodevelopmental performance, the Bayley Scales of Infant Development-II (BSID II), Social Maturity Scale (SMS), and Child Behavior Checklist (CBCL) were measured from a total of 140 toddlers. Among the measured chemicals, monoethyl phthalate (MEP) in maternal urine was significantly associated with early mental, psychomotor, and social development. In addition, breast milk di-ethylhexyl phthalate (DEHP) metabolite and blood lead concentrations were inversely associated with mental and psychomotor development indices, respectively. Maternal blood PCB153, heavy metals, and urinary MEP levels were also higher among the children with behavioral problems, as indicated by the CBCL range. Taken together, maternal exposure to several EDCs such as PCBs and DEHP was associated with adverse neurodevelopmental performances among the children aged 1 2years. Confirmation of these association in larger populations, as well as longer-term consequences of such exposure warrant further investigation. PMID- 29258040 TI - Spatial-temporal variation characteristics of air pollution in Henan of China: Localized emission inventory, WRF/Chem simulations and potential source contribution analysis. AB - Henan is the most populous province and one of the most seriously polluted areas in China at present. In this study, we establish an integrated atmospheric emission inventory of primary air pollutants in Henan province for the target year of 2012. The inventory developed here accounts for detailed activity levels of 11 categories of primary anthropogenic emission sources, and determines the best available representation of emission factors. Further, we allocate the annual emissions into a high spatial resolution of 3km*3km with ArcGIS methodology and surrogate indices, such as regional population distribution and gross domestic product (GDP). Our results show that the emissions of VOCs, SO2, PM10, PM2.5, NOX, NH3, CO, BC and OC are about 1.15, 1.24, 1.29, 0.70, 1.93, 1.05, 7.92, 0.27 and 0.25milliontons, respectively. The majority of these pollutant emissions comes from the Central Plain Urban Agglomeration (CPUA) region, particularly Zhengzhou and Pingdingshan. By combining with the emission inventory with the WRF/Chem modeling and backward trajectory analysis, we investigate the temporal and spatial variability of air pollution in the province and explore the causes of higher pollutants concentrations in the region of CPUA during the heavily polluted period of January. The results demonstrate that intensive pollutants emissions and unfavorable meteorological conditions are the main causes of the heavy pollution. Besides, Weighted Potential Source Contribution Function (WPSCF) analysis indicates that local emissions remain the major contributor of PM2.5 in Henan province, although emissions from the neighboring provinces (e.g. Shanxi, Shaanxi, Anhui, and Shandong) are also important contributors. PMID- 29258041 TI - CD-1 mouse fertility rapidly declines and is accompanied with early pregnancy loss under conventional housing conditions. AB - CD-1 mice are commonly employed as a research model for defining mechanisms controlling early mammalian development and for understanding environmental impacts on mammalian fertility. CD-1 female mice were kept four to eight months under conventional animal care housing, and were fed ad libitum with normal laboratory mouse chow. Female weight, mating success, oocyte morphology, blastocyst development in vivo and in vitro, and RT-qPCR analysis of trophectoderm cell markers (Cdx2, Slc2a1, and Atp1a1 transcript abundance, and CDX2 localization) were assessed and contrasted with outcomes from four-week-old control CD-1 mice. Embryo development in vivo in four to eight-month-old mice was significantly reduced compared to four-week-old controls. Oocytes and blastocysts from four to eight-month-old CD-1 mice displayed high levels of fragmentation and degradation, significantly reduced embryo cell counts, decreased Cdx2 transcript abundance, and number of CDX2 positive cells in morulae. We have discovered that female CD-1 mice housed under conventional conditions display a rapid loss of fecundity as they age over a few months. Paradoxically, embryo loss can be avoided by placing early embryos collected from four to eight-month-old mice into culture to support development to the blastocyst stage. We conclude that oocyte quality rapidly declines in CD-1 female mice housed under conventional animal care conditions. Thus, four to eight-month-old female CD-1 mice represent a very distinct research model from that of younger mice and this older research animal model may be preferred for understanding environmental and physiological influences limiting fertility in women. PMID- 29258042 TI - Promoter variants of OAS1 gene are associated with reproductive performance and incidence of normal calving in cattle. AB - 2',5'-oligoadenylate synthetase (OAS) are important components of an interferon mediated antiviral pathway. But no polymorphisms have yet been identified and associated with reproduction and reproduction traits in the bovine OAS1 gene. The objective of this study was to detect and evaluate the effects of mutations in the promoter region of bovine OAS1 gene with production and reproduction traits in cattle. Two single nuclear polymorphisms were identified, including A to T transversion (rs715937117:A>T) and A to G transition (rs480985443:A>G) and subsequently genotyped in Sahiwal and Frieswal populations. Three haplotypes were constructed including H1 (A-A), H2 (T-A) and H3 (T-G), among them H2 was the most abundant in the Sahiwal (0.677) and Frieswal (0.838) population. The analysis revealed that genotypes of promoter region had significant effect (P <= 0.05) on age at first breeding, age at first calving, service period and pregnancy rate. The animals with H1H2 diplotype had higher age at first breeding and age at first calving compared to H2H2 genotyped animals. Further logistic regression analysis also revealed that the probability of normal calving was found more in H2H2 diplotype, as the odds ratios of H1H2 and H2H3 in comparison to H2H2 were 0.516 and 0.486, respectively. H2H2 diplotyped animals also exhibited higher milk production also in terms of total milk yield, 300 day milk yield and peak yield. These results outlined that the bovine OAS1 gene can be used as candidate genes for simultaneous improvement of both production and reproductive performance of cattle. PMID- 29258043 TI - Inflammatory status and its relationships with different patterns of postpartum luteal activity and reproductive performance in early lactating Holstein cows. AB - This study was undertaken to determine the effect of inflammatory status on different patterns of postpartum luteal activity and reproductive performance of Holstein cows during early lactation. The cows (n = 75) averaged 3.4 +/- 1.2 (mean +/- SEM) in parity and 3.1 +/- 0.2 (mean +/- SEM) in body condition score at calving. Transrectal ultrasonography was performed twice weekly from day 10-60 postpartum to consider ovarian dynamics. Plasma concentrations of progesterone (P4) and estradiol (E2) were measured twice weekly and plasma levels of tumor necrosis factor alpha (TNF-alpha) and lipopolysacchride binding protein (LBP) were measured weekly (week 3-6 postpartum). Based on plasma P4 and E2 results, 34 (45.3%) cows had normal luteal activity (NLA), whereas 19 (25.3%), 12 (16.0%), 7 (9.3%) and 3 (4.0%) cows had prolonged luteal phase (PLP), delayed first ovulation (DO), anovulation (AO) and short luteal phase (SLP), respectively. Plasma TNF-alpha and LBP concentrations were affected by postpartum luteal activity (NLA, SLP and PLP), ovulatory status (DO and AO) and number of weeks postpartum (P < .05). These concentrations were greater in cows with PLP (P < .05) as compared to NLA cows, and in cows that had delayed ovulation or anovulation compared to ovulated cows (P < .05). Cows with PLP had greater open days and lower conception rate as compared to NLA cows (P < .05). Healthy cows had a larger CL and greater plasma estradiol and progesterone concentrations at first and second cycle postpartum compared to inflamed cows and followed it with greater fertility (P < .05). In conclusion, inflammatory statuses were different in high-producing dairy cows showing PLP, AO and DO in comparison with the postpartum normal luteal activity (NLA) cows that influenced reproduction outcomes. PMID- 29258044 TI - Troxerutin, a mixture of O-hydroxyethyl derivatives of the natural flavonoid rutin: Chemical stability and analytical aspects. AB - Troxerutin (TRX) is a mixture of semisynthetic hydroxyethylrutosides (Hers) arising from hydroxyethylation of rutin, a natural occurring flavonoid. TRX is commonly used for its anti-oxidant and anti-inflammatory properties in chronic venous insufficiency and other vascular disorders. In recent studies, the protective effects of TRX in Alzheimer's disease, colon carcinogenesis and hepatocellular carcinoma are emerged. However, the chemical stability of TRX has never been studied. Hence, the aims of the work were to study the TRX chemical stability through a forced degradation study and to develop and validate a new stability indicating LC-UV method for determination of TRX. In order to perform the study, TRX stability was tested in various stress conditions analysing the degradation samples by LC-MS. Three degradation products (DPs; D1, D2 and D3, 3',4',7-Tri-O-(beta-hydroxyethyl)quercetin, 3',4',5,7-Tetra-O-(beta hydroxyethyl)quercetin and 3',4'-Di-O-(beta-hydroxyethyl)quercetin respectively) arising from degradation in acidic conditions were identified and synthesized: among them, D1 resulted the stability indicator for hydrolytic degradation. Furthermore, a stability-indicating LC-UV method for simultaneous determination of triHer (3',4',7-Tri-O-(beta-hydroxyethyl)rutin, the principal component of the mixture) and D1 was developed and validated. The LC-UV method consisted in a gradient elution on a Phenomenex Kinetex EVO C18 (150 * 3 mm, 5 MUm) with acetonitrile and ammonium bicarbonate buffer (10 mM, pH 9.2). The method was linear for triHer (20-60 MUg mL-1) and D1 (5.1-35 MUg mL-1). The intraday and interday precision were determined and expressed as RSDs: all the values were <= 2% for both triHer and D1. The method demonstrated also to be accurate and robust and the average recoveries were 98.8 and 97.9% for triHer and D1, respectively. Moreover, the method resulted selective and specific for all of the components present in the degradation pattern of TRX (diHer (3',4'-Di-O-(beta hydroxyethyl)rutin), triHer, tetraHer (3',4',5,7-Tetra-O-(beta hydroxyethyl)rutin), D3, D1 and D2) and it was successfully applied for the stability studies of both drug substances and drug products. PMID- 29258045 TI - Simultaneous determination of thirteen different steroid hormones using micro UHPLC-MS/MS with on-line SPE system. AB - Ultratrace analysis of sample components requires excellent analytical performance in terms of limits of quantitation (LOQ). Micro UHPLC coupled to sensitive tandem mass spectrometry provides state of the art solution for such analytical problems. Using on-line SPE with column switching on a micro UHPLC MS/MS system allowed to decrease LOQ without any complex sample preparation protocol. The presented method is capable of reaching satisfactory low LOQ values for analysis of thirteen different steroid molecules from human plasma without the most commonly used off-line SPE or compound derivatization. Steroids were determined by using two simple sample preparation methods, based on lower and higher plasma steroid concentrations. In the first method, higher analyte concentrations were directly determined after protein precipitation with methanol. The organic phase obtained from the precipitation was diluted with water and directly injected into the LC-MS system. In the second method, low steroid levels were determined by concentrating the organic phase after steroid extraction. In this case, analytes were extracted with ethyl acetate and reconstituted in 90/10 water/acetonitrile following evaporation to dryness. This step provided much lower LOQs, outperforming previously published values. The method has been validated and subsequently applied to clinical laboratory measurement. PMID- 29258046 TI - Stability assessment of antibody-drug conjugate Trastuzumab emtansine in comparison to parent monoclonal antibody using orthogonal testing protocol. AB - Antibody-drug conjugates (ADC) represent an emerging, novel class of biopharmaceuticals. The heterogeneity originating from the sophisticated structure requires orthogonal analytical techniques for quality and stability assessment of ADC to ensure safety and efficacy. In this study, the stability of Trastuzumab (recombinant humanized IgG1 mAb, targeting HER2 receptor) and its ADC with DM1 (anti-tubulin anticancer drug), Trastuzumab emtansine (T-DM1) were studied. SE-HPLC was used to monitor formation of aggregates and/or fragments of the monoclonal antibodies (mAb). Correlation with the results of reducing and non reducing sodium dodecyl sulphate - polyacrylamide gel electrophoresis (SDS-PAGE) and dynamic light scattering (DLS) were performed to interpret the obtained results. RP-HPLC was used for assessment of the stability of DM1 in ADC while spectrophotometry was employed to determine drug antibody ratio (DAR) . The studied drugs were subjected to several stress conditions including pH, temperature, mechanical agitation and repeated freeze and thaw to generate possible degradation products and ensure suitability of the assay protocol. The degradation pattern and extent were demonstrated under the indicated stress conditions. The correlation between the results of SE-HPLC and those of SDS-PAGE and DLS ensured the validity of the orthogonal assay protocol and indicated aggregates that were not detected using SE-HPLC. Results showed clearly that T DM1 is relatively less stable than its parent mAb. This was attributed to the presence of the drug-linker part that is attached to the mAb. RP-HPLC showed that the cytotoxic drug moiety is liable for degradation under the studied conditions resulting in alteration of DAR as well as formation of degradation products. This confirmed the need for more robust coupling chemistries for production of safe and effective ADC and highlighted the importance of orthogonal testing protocols for quality assessment. The assay protocol should be applicable for quality and stability assessment of various ADC. PMID- 29258047 TI - Qualitatively and quantitatively comparing secondary metabolites in three medicinal parts derived from Poria cocos (Schw.) Wolf using UHPLC-QTOF-MS/MS based chemical profiling. AB - Poria cocos (Schw.) Wolf, is a fungus that grows on dead pine roots, producing a solid white sclerotium (fruiting body). Three parts of the sclerotium are commonly used in traditional Chinese medicine, namely, the epidermis, known as Poria Cutis or fulingpi in Chinese; the middle part, known as Poria or baifuling; and the sclerotium with some host attached, known as fushen. For fushen, the hostwood is the inner part, known as fushenmu. The epidermis, middle part and middle-plus-inner parts have long been used for different syndromes or diseases, but the differences in their chemistry have not been established. In this study, ultra-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS) was used to explore the differences of secondary metabolites in these three botanical parts of Poria cocos. In 13 batches of samples, a total of 147 chromatographic peaks were unequivocally or tentatively identified. Of these, 15 peaks were common to all three parts (the epidermis, middle, and inner part), while the rest were found in only one or two of the parts. Meanwhile, dissimilarities among the chemical compositions of three botanical parts were further investigated by principal component analysis (PCA), and supervised orthogonal partial least squares-discriminate analysis (OPLS-DA). Eight major bioactive triterpene acids that played important roles in differentiating the epidermis, middle and inner part were simultaneously quantified using the extracting ion mode of UHPLC-QTOF-MS/MS. The quantitative results showed that the analytes accumulated mostly in the epidermis and inner part, with the least accumulation in the middle part. This systematic information on the differences in secondary metabolites in the three botanical regions of Poria cocos provides a factual chemical basis not only for discrimination in therapeutic practice but also for quality evaluation of Poria cocos. PMID- 29258048 TI - Simultaneous determination of bentysrepinine (Y101) and its metabolites M8 and M9 in human plasma by UPLC-MS/MS and its application to a pharmacokinetic study. AB - A rapid and highly sensitive liquid chromatography-tandem mass spectrometry (LC MS/MS) method has been developed and validated for the determination of a novel anti-HBV compound Y101 and its metabolites M8 and M9 in human plasma. The plasma samples were deproteinated with acetonitrile after addition of Peramivir (internal standard, IS) and separated on a 40 degrees C ACQUITY UPLC BEH C18 column (2.1 mm * 50 mm, 1.7 MUm). The mobile phase consisted of water (containing 5 mM ammonium acetate and 0.1% formic acid) and acetonitrile (74:26, v/v) at a flow rate of 0.3 mL/min. The detection was performed on a Triple Quad 5500 tandem mass spectrometer coupled with electrospray ionization (ESI) source in positive mode. Quantification was conducted by multiple reaction monitoring (MRM) of the transitions of m/z 490.1 -> 339.0 for Y101, m/z 357.2 -> 105.2 for metabolite M8, m/z 373.1 -> 105.1 for metabolite M9 and m/z 329.1 -> 270.2 for IS, respectively. The method was validated over the calibration curve range of 1.000-1000 ng/mL for Y101, 2.000-2000 ng/mL for metabolite M8 and 0.3000-300.0 ng/mL for metabolite M9, using linear regression and 1/x2 weighting. No matrix effect and carryover effect was observed. The intra- and inter-batch precision and accuracy of Y101, metabolite M8 and M9 were all within the acceptable criteria. This method allows a rapid and simple determination of Y101 and its metabolites M8 and M9 in human plasma. It was successfully applied in a pharmacokinetic study in human for the first time. PMID- 29258049 TI - Granulation and microbial community dynamics in the chitosan-supplemented anaerobic treatment of wastewater polluted with organic solvents. AB - The effect of chitosan on the development of granular sludge in upflow anaerobic sludge blanket reactors (UASB) when treating wastewater polluted with the organic solvents ethanol, ethyl acetate, and 1-ethoxy-2-propanol was evaluated. Three UASB reactors were operated for 219 days at ambient temperature with an organic loading rate (OLR) of between 0.3 kg COD m-3 d-1 and 20 kg COD m-3 d-1. One reactor was operated without the addition of chitosan, while the other two were operated with the addition of chitosan doses of 2.4 mg gVSS-1 two times. The three reactors were all able to treat the OLR tested with COD removal efficiencies greater than 90%. However, the time required to reach stable operation was considerably reduced in the chitosan-assisted reactors. The development of granules in the reactors with chitosan was accelerated and granules larger than 2000 MUm were only observed in these reactors. In addition, these granules exhibited better physicochemical characteristics: the mean particle diameter (540 and 613 MUm) was approximately two times greater than in the control reactor (300 MUm), and the settling velocities exceeded 35 m h-1. The extracellular polymeric substances (EPS) in the reactors with the chitosan was found to be higher than in the control reactor. The protein-EPS content has been correlated with the granule size. The analyses of the microbial communities, performed through denaturing gradient gel electrophoresis and high-throughput sequencing, revealed that the syntrophic microorganisms belonging to genus Geobacter and the hydrogenotrophic methanogen Methanocorpusculum labreanum were predominant in the granules. Other methanogens like Methanosaeta species were found earlier in the chitosan-assisted reactors than in the control reactor. PMID- 29258050 TI - A critical review on liquid-gas mass transfer models for estimating gaseous emissions from passive liquid surfaces in wastewater treatment plants. AB - Emission models are useful tools for the study and management of atmospheric emissions from passive liquid surfaces in wastewater treatment plants (WWTPs), which are potential sources of odour nuisance and other environmental impacts. In this work, different theoretical and empirical models for the gas-side (kG) and liquid-side (kL) mass transfer coefficients in passive surfaces in WWTPs were critically reviewed and evaluated against experimental data. Wind forcing and the development of the wind-wave field, especially the occurrence of microscale wave breaking, were identified as the most important physical factors affecting mass transfer in these situations. Two approaches performed well in describing the available data for kG for water vapour. One is an empirical correlation whilst the other consists of theoretical models based on the description of the inner part of the turbulent boundary layer over a smooth flat plate. We also fit to the experimental data set a new, alternate equation for kG, whose performance was comparable to existing ones. However, these three approaches do not agree with each other in the whole range of Schmidt numbers typical for compounds found in emissions from WWTPs. As to kL, no model was able to satisfactorily explain the behaviour and the scatter observed in the whole experimental data set. Excluding two suspected biased sources, the WATER9 (US EPA, 1994. Air Emission Models for Waste and Wastewater. North Carolina, USA. EPA-453/R-94-080A) approach produced the best results among the most commonly used kL models, although still with considerably high relative errors. For this same sub-set, we propose a new, alternate approach for estimating kL, which resulted in improved performance, particularly for longer fetches. Two main gaps were found in the literature, the understanding of the evolution of the mass transfer boundary layer over liquid surfaces, and the behaviour of kL for larger fetches, especially in the range from 40 to 60 m. PMID- 29258051 TI - Refining uptake and depuration constants for fluoroalkyl chemicals in Chironomus riparius larvae on the basis of experimental results and modelling. AB - The aims of this study were to determine depuration rates for a range of per- and polyfluoroalkyl substances (PFASs) using Chironomus riparius, and to test a concentration-dependency hypothesis for the long-chain perfluorotridecanoic acid (PFTrDA) for this species. Midge larvae were exposed to field sediments collected downstream of a fluorotelomer plant, and to the same sediment spiked with PFTrDA. Elimination kinetics results indicated complete elimination of all PFASs by chironomids after 42h. These data were used to develop two PFTrDA bioaccumulation models accounting for chironomid growth and for compound concentration dependency or not. There was much better agreement between observed and simulated data under the concentration-dependency hypothesis than under the alternative one (passive diffusion). The PFTrDA uptake rate derived from the concentration-dependency model equaled 0.013 +/- 0.008gocgwwh-1, and the depuration rate 0.032 +/- 0.009h 1. PMID- 29258052 TI - Modelling uncertainties in the diffusion-advection equation for radon transport in soil using interval arithmetic. AB - Modelling radon transport in the earth crust is a useful tool to investigate the changes in the geo-physical processes prior to earthquake event. Radon transport is modeled generally through the deterministic advection-diffusion equation. However, in order to determine the magnitudes of parameters governing these processes from experimental measurements, it is necessary to investigate the role of uncertainties in these parameters. Present paper investigates this aspect by combining the concept of interval uncertainties in transport parameters such as soil diffusivity, advection velocity etc, occurring in the radon transport equation as applied to soil matrix. The predictions made with interval arithmetic have been compared and discussed with the results of classical deterministic model. The practical applicability of the model is demonstrated through a case study involving radon flux measurements at the soil surface with an accumulator deployed in steady-state mode. It is possible to detect the presence of very low levels of advection processes by applying uncertainty bounds on the variations in the observed concentration data in the accumulator. The results are further discussed. PMID- 29258054 TI - Recent advances in enzymatic oxidation of alcohols. AB - Enzymatic alcohol oxidation plays an important role in chemical synthesis. In the past two years, new alcohol oxidation enzymes were developed through genome mining and protein engineering, such as new copper radical oxidases with broad substrate scope, alcohol dehydrogenases with altered cofactor preference and a flavin-dependent alcohol oxidase with enhanced oxygen coupling. New cofactor recycling methods were reported for alcohol dehydrogenase-catalyzed oxidation with photocatalyst and coupled glutaredoxin-glutathione reductase as promising examples. Different alcohol oxidation systems were used for the oxidation of primary and secondary alcohols, especially in the cascade conversion of alcohols to lactones, lactams, chiral amines, chiral alcohols and hydroxyketones. Among them, biocatalyst with low enantioselectivity demonstrated an interesting feature for complete conversion of racemic secondary alcohols through non enantioselective oxidation. PMID- 29258053 TI - Orthogonal Array composite design to study and optimize antioxidant combinations in the prevention of UVB-induced HSF damage. AB - Excessive exposure to ultraviolet (UV) B radiation may lead to skin damage, photosensitivity, or even tumorigenesis via induction of oxidative stress. Naturally derived antioxidants could play significant roles in cancer therapy due to their multi-targeted actions and lack of substantial toxicity. Drug combinations target at diverse pathway of cells and make cells export meticulous biological outcomes through the multifaceted signaling network. The UVB protective effects of combinations of naturally derived antioxidants- curcumin, resveratrol, proanthocyanidins, baicalein, and beta-nicotinamide adenine dinucleotide (NADH) were investigated. An oxidative cell damage model was established to study the ultraviolet irradiation system. An orthogonal array composite design (OACD) was employed in the optimization of antioxidants combinations. Combination of resveratrol (0.1MUM) and baicalein in medium concentration (0.2MUM), with NADH in high concentration (0.8MUM) was found to be the most efficacious combination among all the 30 runs performed using OACD. The findings suggested that UVB exposure-inflicted cell apoptosis can be significantly reduced by naturally-derived antioxidant combinations. These results provide an insight into the discovery of synergistic antioxidant combinations in skin cancer, using orthogonal array composite design (OACD). The results also have practical implications in the understanding of drug mechanisms in skin cancer, which can assist clinical practice by recommending better drug combinations. PMID- 29258055 TI - A near-infrared BSA coated DNA-AgNCs for cellular imaging. AB - Near-infrared silver nanoclusters, have potential applications in the field of biosensing and biological imaging. However, less stability of most DNA-AgNCs limits their application. To obtain stable near-infrared fluorescence DNA-AgNCs for biological imaging, a new kind of near-infrared fluorescent DNA-Ag nanoclusters was constructed using the C3A rich aptamer as a synthesis template, GAG as the enhancer. In particular, a new DNA-AgNCs-Trp@BSA was obtained based on the self-assembly of bovine serum albumin (BSA) and tryptophan loaded DNA-AgNCs by hydrophobic interaction. This self-assembly method can be used to stabilize DNAn-Ag (n = 1-3) nanoclusters. Hence, the near-infrared fluorescence DNA-AgNCs Trp@BSA was applied in cellular imaging of HepG-2 cells. PMID- 29258056 TI - Current evidence of oral anticoagulant reversal: A systematic review. AB - INTRODUCTION: Approximately 4-6% of patients treated with oral anticoagulants (OAC) will suffer from major hemorrhage or be in need of urgent surgery necessitating anticoagulant reversal therapy. Several new oral anticoagulants and reversal agents have been introduced that make it difficult for physicians to stay updated on the current evidence of reversal management. This study aims to review the recent literature on oral anticoagulation reversal therapy and to present the current evidence in an easily approachable manner. MATERIALS AND METHODS: A systematic literature search was conducted using PubMed and EMBASE to identify the latest publications on both vitamin K antagonist (VKA) and direct oral anticoagulant (DOAC) reversal strategies. All studies on humans who received any acute reversal management of VKA treatment were included, except case studies. Since only two studies on acute reversal of DOAC treatment have been published, clinical trials on healthy volunteers were also included. RESULTS: Twenty-one studies with a total of 4783 VKA treated patients, and 12 studies with a total of 529 DOAC treated patients were included. Elevated INR values due to VKA treatment could be reversed (INR<=1.5) in 63.1% (95% CI: 61.0-65.2) of study subjects after treatment with 4F-PCC, as compared with 12.2% (95% CI: 8.2-16.2) after treatment with fresh frozen plasma (FFP), (p<0.001). Thromboembolism occurred in 1.6% (95% CI: 1.2-2.1) of VKA-patients treated with 4F-PCC, and in 4.5% (95% CI: 2.3-6.7) of FFP-treated patients. To date, reversal of laboratory parameters has been demonstrated for two reversal agents specific to DOACs: idarucizumab for dabigatran reversal and andexanet-alfa for factor Xa-inhibitor reversal. CONCLUSIONS: This review supports the use of PCC for VKA reversal, specifically for 4F-PCC over FFP for laboratory reversal. There are no studies on clinical efficacy of non-specific agents for DOAC reversal and the evidence for laboratory reversal is not consistent. PMID- 29258057 TI - Spread of local anesthetic solution in the erector spinae plane block. PMID- 29258058 TI - Enterohemorrhagic Escherichia coli outwits hosts through sensing small molecules. AB - Small molecules help intestinal pathogens navigate the complex human gastrointestinal tract to exploit favorable microhabitats. These small molecules provide spatial landmarks for pathogens to regulate synthesis of virulence caches and are derived from the host, ingested plant and animal material, and the microbiota. Their concentrations and fluxes vary along the length of the gut and provide molecular signatures that are beginning to be explored through metabolomics and genetics. However, while many small molecules have been identified and are reviewed here, there are undoubtedly others that may also profoundly affect how enteric pathogens infect their hosts. PMID- 29258060 TI - Deconstructing Schizophrenia. PMID- 29258059 TI - Correction: Seeing the "Big" Picture: Big Data Methods for Exploring Relationships Between Usage, Language, and Outcome in Internet Intervention Data. AB - [This corrects the article DOI: 10.2196/jmir.5725.]. PMID- 29258062 TI - Phage Abp1 Rescues Human Cells and Mice from Infection by Pan-Drug Resistant Acinetobacter Baumannii. AB - BACKGROUND/AIMS: As an "ESKAPE" pathogen, Acinetobacter baumannii is one of the leading causes of drug-resistant infections in humans. Phage therapy may be a useful strategy in treating infections caused by drug-resistant A. baumannii. Among 21 phage strains that were isolated and described earlier, we investigated the therapeutic efficacy of Abp1 because of its relatively wide host range. METHODS: Phage stability assays were used to evaluate thermal and pH stability of Abp1. Abp1 was co-cultured with A. baumannii (AB1) over a range of multiplicities of infection to determine its bactericidal efficacy. HeLa or THP-1 cells were used in the cytotoxicity and protection assays. Finally, the therapeutic effects of Abp1 on local and systemic A. baumannii infection in mice were determined. RESULTS: We found that Abp1 exhibits high thermal and pH stability and has a low frequency of lysogeny. Bacteriophage resistance also occurs at a very low frequency (3.51+/-0.46*10-8), and Abp1 can lyse almost all host cells at a MOI as low as 0.1. Abp1 has no detectable cytotoxicity to HeLa or THP-1 cells as determined by LDH release assay. Abp1 can rescue HeLa cells from A. baumannii infection, even if introduced 2 hours post infection. In both local and systemic A. baumannii infection mouse models, Abp1 treatment exhibits good therapeutic effects. CONCLUSION: Abp1 is an excellent candidate for phage therapy against drug-resistant A. baumannii infections. PMID- 29258061 TI - N-Acetylcysteine Influence on Oxidative Stress and Cardiac Remodeling in Rats During Transition from Compensated Left Ventricular Hypertrophy to Heart Failure. AB - BACKGROUND/AIMS: To evaluate the effects of the antioxidant N-acetylcysteine (NAC) on cardiac structure and function in rats with long-term ascending aortic stenosis (AS). METHODS: Four months after inducing AS, Wistar rats were assigned into the groups Sham, AS, and AS treated with NAC (AS-NAC) and followed for eight weeks. Cardiac structure and function were evaluated by echocardiogram. Myocardial antioxidant enzymes activity was measured by spectrophotometry and malondialdehyde serum concentration by HPLC. Gene expression of NADPH oxidase subunits NOX2, NOX4, p22 phox, and p47 phox was assessed by real time RT-PCR and protein expression of MAPK proteins by Western blot. Statistical analyzes were performed with Goodman and ANOVA or Mann-Whitney Results: NAC restored myocardial total glutathione (Sham 20.8+/-3.00; AS 12.6+/-2.92; AS-NAC 17.6+/-2.45 nmol/g tissue; p<0.05 AS vs Sham and AS-NAC). Malondialdehyde serum concentration was lower in AS-NAC and myocardial lipid hydroperoxide was higher in AS (Sham 199+/ 48.1; AS 301+/-36.0; AS-NAC 181+/-41.3 nmol/g tissue). Glutathione peroxidase activity was lower in AS than Sham. Echocardiogram showed LV concentric hypertrophy with systolic and diastolic dysfunction before and after treatment; no differences were observed between AS-NAC and AS groups. NAC reduced p-ERK and p-JNK protein expression, attenuated myocardial fibrosis, and decreased the frequency of right ventricular hypertrophy. CONCLUSION: N-acetylcysteine restores myocardial total glutathione, reduces systemic and myocardial oxidative stress, improves MAPK signaling, and attenuates myocardial fibrosis in aortic stenosis rats. PMID- 29258063 TI - Rosiglitazone Inhibits Angiotensin II-Induced Proliferation of Glomerular Mesangial Cells via the Galphaq/Plcbeta4/TRPC Signaling Pathway. AB - BACKGROUND/AIMS: Mesangial cell proliferation and extracellular matrix accumulation (ECM) deposition play an important role in the pathogenesis of glomerulosclerosis. TRPC and PPAR-gamma can regulate cell proliferation. Angiotensin II (AngII) can induce mesangial cell proliferation and affect TRPC expression. However, the mechanism has not been fully elucidated. This study was designed to investigate the role of TRPC and the effect of rosiglitazone (RSG) in the proliferation of rat glomerular mesangial cells (HBZY-1) that were stimulated by AngII and the underlying mechanisms. METHODS: Immunofluorescence staining and qRT-PCR were performed to examine the expression levels of TRPCs in HBZY-1. Gene expression levels of TRPC, PPAR-gamma, RGS4 (regulators of G protein signaling), the GPCR/Galphaq/PLCbeta4/TRPC signaling pathway and major downstream molecules (PCNA, SKP2, P21 and P27) were detected by qRT-PCR and western blotting. Additionally, changes in intracellular Ca2+ levels were determined through Fluo-4 Ca2+ imaging, and the cell cycle was analyzed by flow cytometry. RESULTS: Our results found that TRPC1 and 6 were at higher expression levels in HBZY-1 cells. Following AngII stimulation, there were increased levels of TRPC1 and 6, Ca2+ entry, PCNA and SKP2, decreased expression levels of P21 and P27 and a reduced G0/G1 percentage. Silencing TRPC1 and 6 by siRNAs led to decrease in Ca2+ influx, G0/G1 cell cycle arrest and cell proliferation. Notably, PPAR-gamma activation by RSG upregulated RGS4 expression, which can interact with the Galphaq family to inhibit the Galphaq-mediated signaling cascade. The results were similar to silencing TRPC1 and 6 by siRNAs. CONCLUSION: All these results indicate that RSG could inhibit HBZY-1 cell proliferation via the Galphaq/PLCbeta4/TRPC signaling pathway. PMID- 29258064 TI - Alternative Caries Management Options for Primary Molars: 2.5-Year Outcomes of a Randomised Clinical Trial. AB - Less invasive caries management techniques for treating cavitated carious primary teeth, which involve the concept of caries control by managing the activity of the biofilm, are becoming common. This study aimed to compare the clinical efficacy (minor/major failures) and survival rates (successful cases without any failures) of 3 carious lesion treatment approaches, the Hall Technique (HT), non restorative caries treatment (NRCT), and conventional restorations (CR), for the management of occlusoproximal caries lesions (ICDAS 3-5) in primary molars. Results at 2.5 years are presented. A total of 169 children (3- to 8-year-olds) were enrolled in this secondary care-based, 3-arm parallel-group, randomised controlled trial. Participants were allocated to: HT (n = 52; sealing caries with stainless-steel crowns without caries removal), NRCT (n = 52; opening up the cavity and applying fluoride varnish), CR (n = 65; control arm, complete caries removal and compomer restoration). Statistical analyses were: non-parametric Kruskal-Wallis analysis of variance, Mann-Whitney U test and Kaplan-Meier survival analyses. One hundred and forty-two participants (84%; HT = 40/52; NRCT = 44/52; CR = 58/65) had follow-up data of 1-33 months (mean = 26). Overall, 25 (HT = 2, NRCT = 9, CR = 14) of 142 participants (17.6%) presented with at least 1 minor failure (reversible pulpitis, caries progression, or secondary caries; p = 0.013, CI = 0.012-0.018; Mann-Whitney U test). Ten (HT = 1, NRCT = 4, CR = 5) of 142 participants (7.04%) experienced at least 1 major failure (irreversible pulpitis, abscess, unrestorable tooth; p = 0.043, CI = 0.034-0.045). Independent comparisons between 2 samples found that NRCT-CR had no statistically significant difference in failures (p > 0.05), but for CR-HT (p = 0.037, CI = 0.030-0.040) and for NRCT-HT (p = 0.011, CI = 0.010-0.016; Kruskal-Wallis test) significant differences were observed. Cumulative survival rates were HT = 92.5%, NRCT = 70.5%, and CR = 67.2% (p = 0.012). NRCT and CR outcomes were comparable. HT performed better than NRCT and CR for all outcomes. This study was funded by the Paediatric Dentistry Department, Greifswald University, Germany (Trial registration No. NCT01797458). PMID- 29258065 TI - Characterization of Pancreatic Tumors with Quantitative Perfusion Analysis in Contrast-Enhanced Harmonic Endoscopic Ultrasonography. AB - OBJECTIVES: This study evaluated whether quantitative perfusion analysis with contrast-enhanced harmonic (CH) endoscopic ultrasonography (EUS) characterizes pancreatic tumors, and compared the hemodynamic parameters used to diagnose pancreatic carcinoma. METHODS: CH-EUS data from pancreatic tumors of 76 patients were retrospectively analyzed. Time-intensity curves (TIC) were generated to depict changes in signal intensity over time, and 6 parameters were assessed: baseline intensity, peak intensity, time to peak, intensity gain, intensity at 60 s (I60), and reduction rate. These parameters were compared between pancreatic carcinomas (n = 41), inflammatory pseudotumors (n = 14), pancreatic neuroendocrine tumors (n = 14), and other tumors (n = 7). All 6 TIC parameters and subjective analysis for diagnosing pancreatic carcinoma were compared. RESULTS: Values of peak intensity and I60 were significantly lower and time to peak was significantly longer in the groups with pancreatic carcinomas than in the other 3 tumor groups (p < 0.05). Reduction rate was significantly higher in pancreatic carcinomas than in pancreatic neuroendocrine tumors (p < 0.05). Areas under the receiver-operating characteristic curves for the diagnosis of pancreatic carcinoma using subjective analysis, baseline intensity, peak intensity, intensity gain, I60, time to peak, and reduction rate, were 0.817, 0.664, 0.810, 0.751, 0.845, 0.777, and 0.725, respectively. I60 was the most accurate parameter for differentiating pancreatic carcinomas from the other groups, giving values of sensitivity/specificity of 92.7/68.6% when optimal cutoffs were chosen. CONCLUSIONS: In pancreatic carcinomas, TIC patterns were markedly different from the other tumor types, with I60 being the most accurate diagnostic parameter. Quantitative perfusion analysis is useful for differentiating pancreatic carcinomas from other pancreatic tumors. PMID- 29258066 TI - Utility of Endoscopic Ultrasound-Guided Hepaticogastrostomy with Antegrade Stenting for Malignant Biliary Obstruction after Failed Endoscopic Retrograde Cholangiopancreatography. AB - BACKGROUND: Endoscopic ultrasound (EUS)-guided biliary drainage (BD) is a well recognized alternative BD method after unsuccessful endoscopic transpapillary drainage. EUS-guided hepaticogastrostomy (HGS) with antegrade stenting (AGS) was recently applied to the treatment of malignant obstructive jaundice. OBJECTIVE: To assess the efficacy and safety of HGS combined with AGS for treatment of malignant biliary stricture-induced obstructive jaundice. DESIGN: Retrospective cohort study. SETTING: Single academic tertiary care center. PATIENTS: From January 2006 to December 2014, endoscopic retrograde cholangiopancreatography was attempted in patients with obstructive jaundice; it was successful in 641 patients and impossible in 154 patients (postsurgically altered anatomy or duodenal stenosis, n = 101; difficult cannulation, n = 53). In total, 145 patients underwent EUS-guided BD; HGS and HGS with AGS were attempted in 42 patients (Group A, January 2006-August 2011) and 37 patients (Group B, September 2011-December 2014), respectively. INTERVENTIONS: Under EUS and fluoroscopy guidance, HGS and HGS with AGS were performed via needle puncture, guidewire insertion, puncture-hole dilation, and stent placement. MAIN OUTCOME MEASUREMENTS: Groups A and B were compared in terms of technical success, functional success, adverse event rates, re-intervention rates, patient survival time, and time to stent dysfunction or patient death. The two groups were also compared in a subgroup analysis of only 28 patients who underwent chemotherapy. RESULTS: The technical success rate was significantly higher in Group A than B (97.6 vs. 83.8%, p = 0.03). The functional success rate was comparable between the two groups (90.2 vs. 90.3%), although the rate of adverse events was significantly higher in Group A than B (26.1 vs. 10.8%, p = 0.03). The re intervention rate tended to be higher in Group A than B (16.7 vs. 8.1%, p = 0.25). Groups A and B did not differ significantly in terms of median overall patient survival (75 vs. 61 days, p = 0.70) or median time to stent dysfunction or patient death (68 vs. 63 days, p = 0.08). Among patients who underwent chemotherapy, there was no difference in overall patient survival time between the two groups (121 vs. 157 days, p = 0.08), although time to stent dysfunction or patient death was significantly shorter in Group A than B (71 vs. 95 days, p = 0.02). CONCLUSION: Although the technical success rate of HGS with AGS was lower than that of HGS, HGS with AGS was superior to HGS in terms of adverse event rate and stent patency in patients receiving chemotherapy. PMID- 29258067 TI - Circulating Long Noncoding RNA HOTAIR is an Essential Mediator of Acute Myocardial Infarction. AB - BACKGROUND/AIMS: Acute myocardial infarction (AMI) is one of the leading causes of death in the world. However, specific diagnostic biomarkers have not been fully determined, and candidate regulatory targets for AMI have not been identified to date. Long noncoding RNAs (lncRNAs) are a class of RNA molecules that have diverse regulatory functions during embryonic development, normal life, and disease in higher organisms. However, research on the role of lncRNAs in cardiovascular diseases, particularly AMI, is still in its infancy. HOX antisense intergenic RNA (HOTAIR), a 2.2 kb lncRNA, was initially described as a modulator of HOX gene expression. Recent studies have illustrated the important role of HOTAIR in cancer progression, but few studies have reported its function in cardiac disease, including AMI. In the current study, we aimed to detect the expression of HOTAIR during AMI and to explore its function in hypoxia-induced cardiomyocyte injury in neonatal cardiomyocytes. METHODS: In 50 consecutively enrolled AMI patients, we examined the serum expression levels of HOTAIR and analysed its correlation with cardiac troponin I (cTnI) expression. Another 50 age- and sex-matched subjects served as healthy controls. Next, the HOTAIR expression was detected in the serum from C57BL/6J mice subjected to coronary artery ligation and in neonatal rat cardiomyocytes induced by hypoxia. Cultured cardiomyocytes apoptosis were measured by terminal deoxynucleotide transferase dUTP nick end labelling (TUNEL) staining. A search for miRNAs that had complementary base paring with HOTAIR was performed utilizing an online software program, and the interaction between miR-1 and HOTAIR was examined using a luciferase reporter assay. RESULTS: Our study revealed that HOTAIR expression was significantly decreased in the serum of AMI patients compared with that of the healthy controls. Similarly, we observed that HOTAIR was downregulated in the serum of mice subjected to coronary artery ligation and in cultured cardiomyocytes exposed to hypoxia. Furthermore, we observed that the adenovirus vector-driven overexpression of HOTAIR dramatically limited hypoxia-induced myocyte apoptosis, whereas knockdown HOTAIR by AdshHOTAIR (adenoviral short hairpin HOTAIR) exhibited the opposite phenotype. Mechanistically, we discovered that the cardioprotective function of HOTAIR is partly based on the negative regulation of miR-1. CONCLUSIONS: Taken together, the results of our study suggest that HOTAIR is a protective factor for cardiomyocytes and that the plasma concentration of HOTAIR may serve as a biomarker for human AMI diagnosis. PMID- 29258068 TI - Needle Tract Seeding: An Overlooked Rare Complication of Endoscopic Ultrasound Guided Fine-Needle Aspiration. AB - Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been widely used for diagnosis of both inflammatory and tumor lesions located in and adjacent to the gastrointestinal tract. EUS-FNA has been considered to be a safe technique with few complications, as shown in recent review articles in which EUS-FNA related morbidity and mortality rates were reported to be <1%. It should be noted, however, that needle tract seeding, although uncommon, can occur after diagnostic EUS-FNA and that this complication affects the prognosis of patients. Although an accurate value for the frequency of needle tract seeding caused by EUS-FNA has not been reported, the numbers of case reports on needle tract seeding have been rapidly increasing, especially in Japan. These case reports regarding EUS-FNA-related needle tract seeding prompted us to reevaluate the safety of EUS-FNA because this complication may have a significant influence on patients' prognoses. In this review, we summarize the clinical features and outcomes of needle tract seeding after EUS on the basis of the previously reported cases and provide useful information to prevent and reduce this serious complication. PMID- 29258069 TI - Risk Factors for Postoperative Bleeding in Endoscopic Submucosal Dissection of Colorectal Tumors. AB - BACKGROUND: Colonoscopic removal of adenomatous polyps or early cancer prevents death from colorectal cancer. Endoscopic submucosal dissection (ESD), which enables endoscopists to perform en bloc resection of flat or depressed colorectal tumors >20 mm, has recently been introduced and become a standard procedure in Japan. Although postoperative bleeding (POB) is a major complication associated with ESD, risk factors for POB have not been fully identified. METHODS: A total of 451 patients (509 lesions) who underwent colorectal ESD were retrospectively analyzed to identify clinical parameters associated with POB. RESULTS: POB occurred in 14 patients, and 7 of them had received antithrombotic therapy before ESD. Uni- and multivariate analyses revealed that antithrombotic therapy and rectal tumor location were strongly associated with POB following colorectal ESD. The incidence of POB was higher in patients on heparin bridge therapy (HBT) for the replacement of antithrombotic therapy than in patients with no HBT. Four of 7 patients (57.1%) on antithrombotic therapy experienced POB from the rectal lesions. CONCLUSION: Antithrombotic therapy and rectal lesions result in a higher POB incidence after colorectal ESD. PMID- 29258071 TI - A New Step Forward in "Carving Nature by its Joints" in Psychopathology/Psychosis. PMID- 29258070 TI - Diversity in Antagonistic Interactions between Commensal Oral Streptococci and Streptococcus mutans. AB - Arginine metabolism via the arginine deiminase system (ADS) of oral bacteria generates ammonia, which can increase the pH of oral biofilms and decrease the risk for dental caries. Antagonistic interactions between ADS-positive and cariogenic bacteria in oral biofilms may be an important ecological determinant of caries. This study investigated the antagonistic potential and mechanisms of clinical isolates of arginolytic streptococci on and by Streptococcus mutans UA159, a well-characterized cariogenic human isolate. Low-passage isolates of Streptococcus gordonii, Streptococcus sanguinis, Streptococcus parasanguinis, Streptococcus australis, and Streptococcus cristatus inhibited the growth of S. mutans to various degrees when they were inoculated on growth media first or simultaneously with S. mutans. The antagonistic effects of arginolytic strains against S. mutans and the production of H2O2 by these strains were enhanced during growth in a less-rich medium or when galactose was substituted for glucose as the primary carbohydrate source. Pyruvate oxidase was the dominant pathway for H2O2 production by arginolytic strains, but lactate oxidase activity was also detected in some strains of S. gordonii and S. cristatus. UA159 inhibited the growth of all tested arginolytic strains when inoculated first, especially in aerobic conditions. However, the antagonistic effects of S. mutans on certain strains of S. gordonii and S. australis were not observed during anaerobic growth in the presence of arginine. Thus, arginolytic commensal streptococci may have a synergistically positive impact on the ecology of oral biofilms by moderating biofilm pH while antagonizing the growth and virulence of caries pathogens. PMID- 29258072 TI - Oncogenic Signal and Tumor Microenvironment in Hepatocellular Carcinoma. AB - During tumor development, several immunosuppressive molecules are released from cancer cells and contribute to the establishment of immunosuppressive tumor environment. In tumor tissues, cytokines, chemokines, growth factors, and metabolites are present and could counter the effects of immune checkpoint inhibitors. From this point of view, monotherapy of anti-PD-1/PD-L1 antibody might not be enough to exert a sufficient antitumor effect; additional blockade of immunosuppressive molecules in tumor microenvironment could enhance the antitumor effect of anti-PD-1/PD-L1 antibody. Importantly, the production of immunosuppressive molecules in cancer cells is attributed to the activation of cellular signaling through genetic and epigenetic alterations and environmental stimulation, such as inflammation and hypoxia. In this review, we focus on the establishment of immunosuppressive microenvironment of hepatocellular carcinoma in the context of activation of oncogenic signals, and discuss how the immunosuppressive condition could be overcome using tyrosine kinase inhibitors. PMID- 29258073 TI - Systems Neuroscience of Psychosis: Mapping Schizophrenia Symptoms onto Brain Systems. AB - Schizophrenia research has been in a deadlock for many decades. Despite important advances in clinical treatment, there are still major concerns regarding long term psychosocial reintegration and disease management, biological heterogeneity, unsatisfactory predictors of individual course and treatment strategies, and a confusing variety of controversial theories about its etiology and pathophysiological mechanisms. In the present perspective on schizophrenia research, we first discuss a methodological pitfall in contemporary schizophrenia research inherent in the attempt to link mental phenomena with the brain: we claim that the time-honored phenomenological method of defining mental symptoms should not be contaminated with the naturalistic approach of modern neuroscience. We then describe our Systems Neuroscience of Psychosis (SyNoPsis) project, which aims to overcome this intrinsic problem of psychiatric research. Considering schizophrenia primarily as a disorder of interindividual communication, we developed a neurobiologically informed semiotics of psychotic disorders, as well as an operational clinical rating scale. The novel psychopathology allows disentangling the clinical manifestations of schizophrenia into behavioral domains matching the functions of three well-described higher-order corticobasal brain systems involved in interindividual human communication, namely, the limbic, associative, and motor loops, including their corticocortical sensorimotor connections. The results of several empirical studies support the hypothesis that the proposed three-dimensional symptom structure, segregated into the affective, the language, and the motor domain, can be specifically mapped onto structural and functional abnormalities of the respective brain systems. New pathophysiological hypotheses derived from this brain system-oriented approach have helped to develop and improve novel treatment strategies with noninvasive brain stimulation and practicable clinical parameters. In clinical practice, the novel psychopathology allows confining the communication deficits of the individual patient, shifting attention from the symptoms to the intact resources. We have studied this approach and observed important advantages for therapeutic alliances, personalized treatment, and de-escalation strategies. Future studies will further conjoin clinical definitions of psychotic symptoms with brain structures and functions, and disentangle structural and functional deficit patterns within these systems to identify neurobiologically distinct subsyndromes. Neurobiologically homogeneous patient groups may provide new momentum for treatment research. Finally, lessons learned from schizophrenia research may contribute to developing a comprehensive perspective on human experience and behavior that integrates methodologically distinct, but internally consistent, insights from humanities and neuroscience. PMID- 29258074 TI - Primary Hepatic Adenosquamous Carcinoma Associated with Primary Sclerosing Cholangitis. AB - INTRODUCTION: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disorder characterized by multiple fibrotic strictures of the bile duct. More than 40% of deaths in PSC patients are related to malignant tumors, including cholangiocarcinoma. Primary hepatic adenosquamous carcinoma (ASC) is a rare subtype of cholangiocarcinoma containing adenocarcinoma (AC) and squamous cell carcinoma (SCC) components, with a poorer prognosis than other cholangiocarcinomas. We report the first case of a hepatic ASC in a patient with PSC. CASE REPORT: A 28-year-old man was referred for diagnosis and treatment of a liver abscess suspected by contrast-enhanced computed tomography (CE-CT). He had a history of ulcerative colitis and PSC. Abdominal CE-CT revealed a 60-mm diameter ring-shaped mass with central necrosis in the left lobe. Magnetic resonance imaging demonstrated a poorly circumscribed low-signal-intensity mass in T1-weighted imaging and a high-signal-intensity mass with a scattered low signal-intensity area in T2-weighted imaging. Abdominal ultrasonography showed a hypoechoic component with a diffuse hyperechoic area in the tumor. Ultrasound guided biopsy and histological examination showed tumor cells with both squamous and glandular differentiation. Left lobectomy was performed. Microscopic examination revealed 2 components, including moderately differentiated AC and well-differentiated SCC. The final diagnosis was hepatic ASC. CONCLUSION: This is the first reported case of hepatic ASC in a patient with PSC. Patients with PSC should be recognized as being at a risk of not only general cholangiocarcinoma, hepatocellular carcinoma, and metastatic liver tumor, but also ASC. PMID- 29258075 TI - Contribution of PCR Denaturing Gradient Gel Electrophoresis Combined with Mixed Chromatogram Software Separation for Complex Urinary Sample Analysis. AB - Complex samples are a challenge for sequencing-based broad-range diagnostics. We analysed 19 urinary catheter, ureteral Double-J catheter, and urine samples using 3 methodological approaches. Out of the total 84 operational taxonomic units, 37, 61, and 88% were identified by culture, PCR-DGGE-SS (PCR denaturing gradient gel electrophoresis followed by Sanger sequencing), and PCR-DGGE-RM (PCR- DGGE combined with software chromatogram separation by RipSeq Mixed tool), respectively. The latter approach was shown to be an efficient tool to complement culture in complex sample assessment. PMID- 29258076 TI - Effect of Prophylactic Indomethacin in Extremely Low Birth Weight Infants Based on the Predicted Risk of Severe Intraventricular Hemorrhage. AB - BACKGROUND: Prophylactic indomethacin reduces the risk of severe intraventricular hemorrhage (IVH) but does not reduce death or neurodevelopmental impairment (NDI) among extremely low birth weight (ELBW) infants. Some investigators have suggested that prophylactic indomethacin may have a greater treatment effect on severe IVH among infants at high risk for severe IVH. OBJECTIVE: To determine whether the relative treatment effects of prophylactic indomethacin on severe IVH and the composite outcome of death or NDI vary based on the risk of severe IVH. METHODS: Post hoc analysis of the Trial of Indomethacin Prophylaxis in Preterms (TIPP). We generated a model to predict the risk for severe IVH based on gestational age, birth weight, antenatal steroids, delivery mode, outborn status, sex, and 5-min Apgar score, and we divided the TIPP participants into risk quartiles. We used logistic regression to determine the adjusted odds ratios (aOR) of severe IVH and death or NDI based on indomethacin treatment for each quartile. RESULTS: The relative treatment effects of prophylactic indomethacin on severe IVH did not vary based on the predicted risk of severe IVH: quartile 1: aOR 0.68 (95% confidence interval [CI] 0.19-2.37); quartile 2: aOR 0.61 (95% CI 0.27-1.42); quartile 3: aOR 0.63 (95% CI 0.31-1.31); quartile 4: aOR 0.58 (95% CI 0.32-1.05). The relative treatment effect of prophylactic indomethacin on death or NDI did not vary significantly between quartiles. CONCLUSIONS: These findings do not support selective prophylactic indomethacin treatment to improve long-term outcomes of ELBW infants at high risk for severe IVH. PMID- 29258078 TI - ORCA Announcements. PMID- 29258077 TI - Systemic Therapy for Hepatocellular Carcinoma: 2017 Update. AB - Systemic therapy for hepatocellular carcinoma (HCC) changed drastically after the introduction of the molecular targeted agent sorafenib in 2007. Sorafenib provides an additional therapeutic option for patients with extrahepatic spread or vascular invasion, resulting in improved survival even among patients with advanced HCC; however, the toxicity of sorafenib and its unsatisfactory antitumor effects remain unsolved issues. The development of novel molecular targeted agents as alternatives to sorafenib has been limited by difficulties unique to HCC. Recent studies have demonstrated the efficacy of two molecular targeted agents, the second-line agent regorafenib, which is used after sorafenib failure, and the first-line agent lenvatinib, which has been shown to be noninferior to sorafenib. Another category of agents that are attracting considerable interest are immune checkpoint inhibitors such as anti-PD-1/PD-L1 or CTLA-4 antibodies, which kill cancer cells via a unique mechanism. The therapeutic effects of some of these agents are currently under investigation in phase III studies. The most recent topics of interest are the combination of anti-PD-1/PD-L1 therapies with other immune checkpoint inhibitors, such as anti-CTLA-4 antibodies, or with a tyrosine kinase inhibitor, or with locoregional therapies such as resection, ablation, or transarterial chemoembolization. PMID- 29258079 TI - Immuno-Oncology in Hepatocellular Carcinoma: 2017 Update. AB - Clinical trials are currently ongoing to evaluate the utility of antibodies against programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) as monotherapy or combination therapy in patients with hepatocellular carcinoma (HCC). Results of combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab in HCC were presented at the 2017 annual meeting of the ASCO (American Society of Clinical Oncology). Response rates were 25% in all 40 patients and 40% in the 20 uninfected patients, both of which are encouraging. Transcatheter arterial chemoembolization and radiofrequency ablation can activate tumor immunogenicity by releasing tumor-associated antigen and by inducing the migration of cytotoxic T lymphocytes to small intrahepatic metastatic nodules. Subsequent administration of anti-PD-1 antibody could control these small intrahepatic metastatic nodules. In a nonclinical study, the combination of pembrolizumab and lenvatinib inhibited the cancer immunosuppressive environments induced by tumor-associated macrophages and regulatory T cells. This, in turn, decreased the levels of TGF-beta and IL-10, the expression of PD-1, and the inhibition of Tim-3, triggering anticancer immunity mediated by immunostimulatory cytokines such as IL-12. Studies such as these may provide insight into the appropriate molecular targeted agents to be used with immune checkpoint inhibitors. PMID- 29258080 TI - Detection of High-Grade Pancreatic Intraepithelial Neoplasia without Morphological Changes of the Main Pancreatic Duct over a Long Period: Importance for Close Follow-Up for Confirmation. AB - Pancreatic intraepithelial neoplasia (PanIN) is a microscopic papillary noninvasive lesion arising from the pancreatic ductal epithelium. However, the natural history and time to progression of high-grade PanIN remain unclear. Herein, we report 2 cases of high-grade PanIN without morphological changes of the main pancreatic duct (MPD) over relatively long periods. In the first case, a 63-year-old man was identified with MPD dilation. Magnetic resonance cholangiopancreatography showed localized stenosis in the pancreatic body with distal MPD dilation. Endoscopic retrograde pancreatography (ERP) was attempted because of possible high-grade PanIN but was unsuccessful. At 15-month follow-up, there was no change in the form of the MPD in various images. However, ERP was re performed because of possible high-grade PanIN, and cytology showed adenocarcinoma. Postoperative pathology indicated diffuse lesions corresponding to high-grade PanINs in the MPD stenosis and surrounding branches. Final diagnosis was high-grade PanIN. In the second case, a 77-year-old man was identified with MPD dilation. Magnetic resonance cholangiography showed localized stenosis in the MPD of the pancreatic head with distal MPD dilation. He was diagnosed with MPD stenosis caused by chronic pancreatitis, and further examination was not recommended. At 25 months, the patient was referred to our hospital because of a mild change in MPD dilation. ERP showed localized irregular stenosis in the MPD, and cytology showed suspected adenocarcinoma. Postoperative pathology indicated a localized lesion with high-grade PanIN in the branch duct around the MPD stenosis. Final diagnosis was high-grade PanIN. In conclusion, we report 2 cases of high-grade PanIN without morphological changes of the MPD over relatively long periods. Even if a definite diagnosis is not obtained at initial examination, a strict follow-up observational study should be performed. Re examination, including ERP, should also be considered in cases with risk factors of pancreatic cancer, even if there is no change in MPD form. PMID- 29258081 TI - Computer-Aided Diagnosis Based on Convolutional Neural Network System for Colorectal Polyp Classification: Preliminary Experience. AB - BACKGROUND AND AIM: Computer-aided diagnosis (CAD) is becoming a next-generation tool for the diagnosis of human disease. CAD for colon polyps has been suggested as a particularly useful tool for trainee colonoscopists, as the use of a CAD system avoids the complications associated with endoscopic resections. In addition to conventional CAD, a convolutional neural network (CNN) system utilizing artificial intelligence (AI) has been developing rapidly over the past 5 years. We attempted to generate a unique CNN-CAD system with an AI function that studied endoscopic images extracted from movies obtained with colonoscopes used in routine examinations. Here, we report our preliminary results of this novel CNN-CAD system for the diagnosis of colon polyps. METHODS: A total of 1,200 images from cases of colonoscopy performed between January 2010 and December 2016 at Kindai University Hospital were used. These images were extracted from the video of actual endoscopic examinations. Additional video images from 10 cases of unlearned processes were retrospectively assessed in a pilot study. They were simply diagnosed as either an adenomatous or nonadenomatous polyp. RESULTS: The number of images used by AI to learn to distinguish adenomatous from nonadenomatous was 1,200:600. These images were extracted from the videos of actual endoscopic examinations. The size of each image was adjusted to 256 * 256 pixels. A 10-hold cross-validation was carried out. The accuracy of the 10-hold cross-validation is 0.751, where the accuracy is the ratio of the number of correct answers over the number of all the answers produced by the CNN. The decisions by the CNN were correct in 7 of 10 cases. CONCLUSION: A CNN-CAD system using routine colonoscopy might be useful for the rapid diagnosis of colorectal polyp classification. Further prospective studies in an in vivo setting are required to confirm the effectiveness of a CNN-CAD system in routine colonoscopy. PMID- 29258082 TI - SyNoPsis: Disruptive Innovation for Mapping Schizophrenia onto the Brain. PMID- 29258083 TI - SyNoPsis: A Novel Perspective on Schizophrenia. PMID- 29258084 TI - Urinary Incontinence, Patient Satisfaction, and Decisional Regret after Prostate Cancer Treatment: A French National Study. AB - BACKGROUND: Complications of prostate cancer treatments have a substantial impact on the patient's quality of life. We evaluated the prevalence of urinary consequences and factors affecting patient satisfaction and decisional regret after treatment. METHODS: A retrospective self-administered questionnaire was sent to all members of the National Association of Prostate Cancer Patients in France. RESULTS: From the 226 completed questionnaires received, the following information was obtained: 110 patients underwent surgery only, 29 received radiotherapy plus hormone therapy, 28 received radiotherapy only, and 49 received other combination treatments. The median follow-up period was 58.1 months. After treatment, the presence of urinary incontinence was reported by 34.5% of patients treated by radical prostatectomy, by 10.3% treated by radiotherapy plus hormone therapy, by 17.8% treated by curitherapy or radiotherapy only, and by 38.7% treated by other combination therapy (p = 0.01). The main reasons for decisional regret were the fact that patients received incomplete information about prostate cancer (40%) and consequences of treatment that affected the urinary system (34%). The information received about cancer was considered complete in 32.3% of the satisfied group and 14.3% of the decisional regret group (p = 0.003) and with regard to urinary incontinence the information received was considered complete in 41.4 and 17.4% respectively (p < 0.01). CONCLUSIONS: Urinary consequences of prostate cancer treatment are common and impact the quality of life. Patients need clear information to be able to participate in therapeutic decision-making and to avoid subsequent decisional regret. PMID- 29258085 TI - The Impact of Osteocalcin, Osteoprotegerin and Osteopontin on Arterial Stiffness in Chronic Renal Failure Patients on Hemodialysis. AB - BACKGROUND/AIMS: This cross-sectional study was designed to assess the relationship between vascular stiffness (VS) and bone-related proteins involved in the development of arteriosclerosis in patients on regular hemodialysis (HD). METHODS: 68 consecutive patients in stable clinical condition who received regular HD in the FMC Dialysis Center, Pecs were included. VS parameters (carotid femoral pulse wave velocity - PWV, aortic augmentation index - AIx) were determined by applanation tonometry (SphygmoCor, AtCor Medical, Sidney) and the routine latoratory test were completed with measurements of osteocalcin (OC), osteopontin (OP) and osteoprotegerin (OPG) by using commercially available ELISA kits. 35 heathcare workers served as controls. RESULTS: In patients on regular HD PWV markedly increased and there was several-fold elevation in the interrelated bone-specific proteins (OC, OP, OPG). PWV was found to be independently associated only with OC (beta:-0.25, p<0.029) and age (r=0.411,p<0.000), but risk factors for arterial calcification had significant impact on OC (systolic blood pressure, hsCRP, BMI), OPG (age, BMI) and OP (LDL-cholesterol). CONCLUSION: Except for OC, our results failed to document direct association of vascular lesion with OP and OPG, therefore their high circulating levels may be an epiphenomenon or they may have counter-regulatory role to attenuate the uremic calcification process. PMID- 29258086 TI - Transarterial Chemoembolization in Combination with a Molecular Targeted Agent: Lessons Learned from Negative Trials (Post-TACE, BRISK-TA, SPACE, ORIENTAL, and TACE-2). AB - The multikinase inhibitor sorafenib is the first oral molecular targeted agent with proven prognostic benefit in unresectable advanced hepatocellular carcinoma (HCC). However, as with other drugs, sorafenib has its limitations, and various clinical trials have been conducted to develop novel molecular targeted agents for use alone or in combination with existing locoregional therapies. Despite this, clinical trials of molecular targeted agents combined with transarterial chemoembolization (TACE) have not reported major treatment outcomes to date. In this review, we describe previous clinical trials of combination therapy with TACE and a molecular targeted agent in patients with unresectable HCC. PMID- 29258087 TI - In utero Plastic Surgery in Zurich: Successful Use of Distally Pedicled Random Pattern Transposition Flaps for Definitive Skin Closure during Open Fetal Spina Bifida Repair. AB - BACKGROUND: One of the intraoperative challenges of fetal spina bifida repair is skin closure when there is an extended skin defect. Thus, we examined whether distally pedicled random pattern transposition flaps (TFs) are a valid option to overcome this problem. SUBJECTS AND METHODS: All patients undergoing in utero repair of spina bifida with application of a TF for back skin closure were analyzed focusing on intraoperative flap characteristics and postoperative flap performance. RESULTS: In 30 (70%) of the 43 fetuses a primary skin closure was achieved, in 5 (12%) a skin substitute was used, and in 8 (18%) a TF was applied. Flap raising and insertion was uneventful and perfusion was sufficient in all 8 fetuses (100%). In 3 fetuses (37%) the donor sites were closed primarily, and in 5 (63%) a skin substitute was used for coverage. At birth, 7 flaps were viable and provided robust skin coverage over the center of the former lesion. Complications included a small skin defect with CSF leakage in 1 patient (13%). CONCLUSION: During open fetal spina bifida repair, TFs can be safely and efficaciously used to obtain solid and durable skin coverage over lesions too large to allow conventional primary skin closure. PMID- 29258088 TI - MiR-144 Increases Intestinal Permeability in IBS-D Rats by Targeting OCLN and ZO1. AB - BACKGROUND/AIMS: Irritable bowel syndrome with diarrhoea (IBS-D) is a chronic, functional bowel disorder characterized by abdominal pain or diarrhoea and altered bowel habits, which correlate with intestinal hyperpermeability. MicroRNAs (miRNAs) are involved in regulating intestinal permeability in IBS-D. However, the role of miRNAs in regulating intestinal permeability and protecting the epithelial barrier remains unclear. Our goals were to (i) identify differential expression of miRNAs and their targets in the distal colon of IBS-D rats; (ii) verify in vitro whether occludin (OCLN) and zonula occludens 1 (ZO1/TJP1) were direct targets of miR-144 and were down-regulated in IBS-D rats; and (iii) determine whether down-regulation of miR-144 in vitro could reverse the pathological hallmarks of intestinal hyperpermeability via targeting OCLN and ZO1. METHODS: The IBS-D rat model was established using 4% acetic acid and evaluated by haematoxylin-eosin (HE) staining. The distal colon was obtained in order to perform miRNA microarray analysis and to isolate and culture colonic epithelial cells. When differential expression of miRNA was found, the results were verified by qRT-PCR, and the target genes were further explored by bioinformatics analysis. Correlation analyses were carried out to compare the expression of miRNA and target genes. Then, mutants, miRNA mimics and inhibitors of the target genes were constructed and transfected to colonic epithelial cells. qRT-PCR, western blotting, enzyme-linked immunosorbent assays (ELISAs) and dual luciferase assays were used to investigate the expression of miR-144 and OCLN, ZO1 in IBS-D rats. RESULTS: There were 8 up-regulated and 18 down-regulated miRNAs identified in the IBS-D rat model. Of these, miR-144 was markedly up regulated and resulted in the down-regulation of OCLN and ZO1 expression. Overexpression of miR-144 by transfection of miR-144 precursor markedly inhibited the expression of OCLN and ZO1. Further studies confirmed that OCLN and ZO1 were direct targets of miR-144. Additionally, intestinal hyperpermeability was enhanced by miR-144 up-regulation and attenuated by miR-144 down-regulation in IBS-D rat colonic epithelial cells. Moreover, rescue experiments showed that overexpression of OCLN and ZO1 significantly eliminated the inhibitory effect of miR-144, which showed a stronger effect on the attenuation of intestinal hyperpermeability. CONCLUSION: Up-regulation of miR-144 could promote intestinal hyperpermeability and impair the protective effect of the epithelial barrier by directly targeting OCLN and ZO1. miR-144 is likely a key regulator of intestinal hyperpermeability and could be a potential therapeutic target for IBS-D. PMID- 29258089 TI - Rsf-1 Influences the Sensitivity of Non-Small Cell Lung Cancer to Paclitaxel by Regulating NF-kappaB Pathway and Its Downstream Proteins. AB - BACKGROUND/AIMS: The therapeutic efficacy of paclitaxel is hampered by chemotherapeutic resistance in non-small cell lung cancer (NSCLC). Rsf-1 enhanced paclitaxel resistance via nuclear factor-kappaB (NF-kappaB) in ovarian cancer cells and nasopharyngeal carcinoma. This study assessed the function of Rsf-1 in the modulation of the sensitivity of NSCLC to paclitaxel via the NF-kappaB pathway. METHODS: The mRNA and protein levels of the related genes were quantified by RT-PCR and Western blotting. Rsf-1 silencing was achieved with CRISPR/Cas9 gene editing. Cell cycle, migration and proliferation were tested with flow cytometry, transwell test and CCK8 test. Cell apoptosis was analyzed with flow cytometry and quantification of C-capase3. The parameters of the tumors were measured in H460 cell xenograft mice. RESULTS: Rsf-1 was highly expressed in H460 and H1299 cells. Rsf-1 knockout caused cell arrest at the G1 phase, increased cell apoptosis, and decreased migration and cell proliferation. Rsf-1 knockout increased the inhibition of cell proliferation, the reduction in cell migration and the augment in cell apoptosis in paclitaxel treated H460 and H1299 cells. Rsf-1 knockout further enhanced the paclitaxel-mediated decrease in the volume and weight of the tumors in H460 cell xenograft mice. Helenalin and Rsf-1 knockout decreased the protein levels of p-P65, BcL2, CFLAR, and XIAP; hSNF2H knockout decreased the protein level of NF-kappaB p-P65 without altering Rsf-1 and p65 protein levels, while Rsf-1 and hSNF2H double knockout decreased the level of NF-kappaB p-P65, in H1299 and H460 cells. CONCLUSION: These results demonstrate that Rsf-1 influences the sensitivity of NSCLC to paclitaxel via regulation of the NF-kappaB pathway and its downstream genes. PMID- 29258090 TI - Hand-Foot Syndrome and Post-Progression Treatment Are the Good Predictors of Better Survival in Advanced Hepatocellular Carcinoma Treated with Sorafenib: A Multicenter Study. AB - OBJECTIVE: To determine the relationship between treatment outcomes and hand-foot syndrome (HFS), and the relationship between survival rate and post-progression treatment after sorafenib therapy. METHODS: The study assessed 314 patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib at 5 general hospitals in Kagawa Prefecture, Japan. RESULTS: At the start of sorafenib therapy, 23.6% of the patients had HCC of a Child-Pugh class other than A. The initial sorafenib dose was 800 mg in 9.2% of the patients and 400 mg in 64.3%. Time to progression was 129 days (95% CI: 87.3-170.7) and the median overall survival (OS) was 392 days (95% CI: 316.0-468.0). The OS of the patients with Child-Pugh class A HCC was significantly better than that of the patients with Child-Pugh class B HCC (p < 0.0001). The survival curves for Child-Pugh class A-5 points and class A-6 points were significantly different, with that for class A-5 points being better (p < 0.0001). A significant difference was observed between the patients who exhibited HFS and those who did not, with the former exhibiting a better survival rate (p < 0.001). In addition, the survival rate of the patients who received post-progression treatment after sorafenib therapy was significantly better than that of the patients who did not (p < 0.001). CONCLUSION: In sorafenib therapy, patients with HFS and those who received post progression treatment exhibited good OS. PMID- 29258091 TI - Magnifying Narrow Band Imaging (NBI) for the Diagnosis of Localized Colorectal Lesions Using the Japan NBI Expert Team (JNET) Classification. AB - OBJECTIVE: The Japan NBI Expert Team (JNET) proposed a new narrow band imaging (NBI) classification system for colorectal tumors in June 2014. In this classification system, types 1, 2A, 2B, and 3 correspond to hyperplastic polyps (HPs) including sessile serrated polyps (SSPs), low-grade dysplasia (LGD), high grade dysplasia (HGD) to shallow submucosal invasive (SM-s) carcinomas, and deep submucosal invasive (SM-d) carcinomas, respectively. METHODS: To validate this system, we performed a retrospective image evaluation study, in which 199 colorectal tumors previously assessed by NBI magnifying endoscopy were classified by 3 blinded experienced colonoscopists using the JNET system. The results were compared with the final pathological diagnoses to determine the JNET classification's accuracy. The interobserver agreement was calculated, and the intraobserver agreement was assessed after 6 months. RESULTS: The final pathological diagnoses identified 14 HPs/SSPs, 127 LGDs, 22 HGDs, 19 SM-s carcinomas, and 17 SM-d carcinomas. The respective sensitivities, specificities, positive predictive value, negative predictive value, and accuracies were as follows: Type 1, 85.7, 99.5, 92.3, 98.9, and 98.5%; Type 2A, 96.0, 81.9, 90.3, 92.1, and 90.9%; Type 2B, 75.6%, 90.5, 67.3, 93.4, and 87.4%; and Type 3, 29.4%, 100, 100, 93.8, and 94.0%. The interobserver agreement and the intraobserver agreement were moderate (kappa value: 0.52) and excellent (kappa value: 0.88), respectively. Lesions presenting as Type 2B during NBI comprised a range of colorectal tumors, including HGDs, SM-s, and SM-d. CONCLUSIONS: The JNET classification was useful for the diagnosis of HPs/SSPs, LGDs, and SM-d, but not SM-s lesions. For low-confidence cases, magnified chromoendoscopy is recommended to ensure correct diagnoses. PMID- 29258092 TI - Chronic Pancreatitis Finding by Endoscopic Ultrasonography in the Pancreatic Parenchyma of Intraductal Papillary Mucinous Neoplasms Is Associated with Invasive Intraductal Papillary Mucinous Carcinoma. AB - BACKGROUND/OBJECTIVES: The recent guideline for intraductal papillary mucinous neoplasms (IPMNs) focuses on morphological features of the lesion as signs of malignant transformation, but ignores the background pancreatic parenchyma, including features of chronic pancreatitis (CP), which is a risk factor for pancreatic malignancies. Endoscopic ultrasonography frequently reveals evidence of CP (EUS-CP findings) in the background pancreatic parenchyma of patients with IPMNs. Therefore, we investigated whether background EUS-CP findings were associated with malignant IPMN. METHODS: The clinical data of 69 consecutive patients with IPMNs who underwent preoperative EUS and surgical resection between April 2010 and October 2014 were collected prospectively. The association of EUS CP findings (total number of EUS-CP findings; 0 vs. >=1) with invasive IPMN was examined. The association of EUS-CP findings with pathological changes of the background pancreatic parenchyma (atrophy/inflammation/fibrosis) was also examined. RESULTS: Among patients with EUS-CP findings, invasive intraductal papillary mucinous carcinoma (IPMC) was significantly more frequent than among patients without EUS-CP findings (42.5% [17/40] vs. 3.4% [1/29], p = 0.0002). In addition, patients with EUS-CP findings had higher grades of pancreatic atrophy and inflammation than patients without EUS-CP findings (atrophy: 72.5% [29/40] vs. 34.5% [10/29], p = 0.003; inflammation: 45.0% [18/40] vs. 20.7% [6/29], p = 0.04). CONCLUSIONS: In IPMN patients, detection of EUS-CP findings in the background pancreatic parenchyma was associated with a higher prevalence of invasive IPMC. Accordingly, EUS examination should not only assess the morphological features of the lesion itself, but also EUS-CP findings in the background parenchyma. PMID- 29258093 TI - Th17 Inhibitors in Active Psoriatic Arthritis: A Systematic Review and Meta Analysis of Randomized Controlled Clinical Trials. AB - BACKGROUND: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-alpha antagonists). Th17 inhibitors could replace TNF-alpha antagonists as first-line biologic agents. We determined the overall treatment effect of Th17 pathway inhibitors compared to placebo or active control on American College of Rheumatology (ACR) 20 response at week 12 (primary objective), risk of infections, discontinuation of treatment due to adverse events, and serious adverse events during the placebo-controlled period (12-24 weeks) in adults with active PsA in published randomized controlled trials. METHODS: The SCOPUS database was searched. The Cochrane risk of bias tool was used for assessing quality. The pooled relative risk (RR) was derived from random effects models. RESULTS: Seven randomized controlled trials were included which randomized 1,718 patients to Th17 inhibitors and 840 to placebo. Patients treated with Th17 inhibitors had an RR of 2.04 (95% CI: 1.79-2.33; p < 0.001) for achieving an ACR20 response at week 12 (I2 = 0%; p = 0.89) compared to placebo-treated patients. There was no evidence of publication bias. The result was consistent for study phase and outcome (ACR50/70), mechanism of action and TNF-alpha naivety. RR of infections was 1.06 (0.91-1.23), that of candida infections was 3.35 (0.75-14.95), that of serious adverse events was 0.82 (0.42-1.59) and that of discontinuation of treatment was 0.54 (0.31-0.93) among treated versus placebo subjects. No incident cases of tuberculosis were reported. CONCLUSION: In patients with active PsA, biologics targeting the Th17 axis produce a clinically significant improvement in joint disease activity with acceptable safety and tolerability for short-term treatment compared to placebo. PMID- 29258094 TI - Racial/Ethnic Differences in Barriers to Kidney Transplant Evaluation among Hemodialysis Patients. AB - BACKGROUND: Only a small percentage of dialysis patients receive a transplant and this is particularly the case for racial/ethnic minorities. Our objective was to identify barriers to initial transplant evaluation in our dialysis centers. METHODS: We conducted a survey of adult hemodialysis patients from 4 dialysis units in the Denver Metro area in 2016. Participants completed an 11-item survey with demographic information and questions regarding time on dialysis, if a provider ever spoke to them about transplant, and whether they had been evaluated for a transplant. Reasons for not having an evaluation were explored. Descriptive statistics, chi-square analyses, and multivariate analyses were used to examine the responses. RESULTS: A total of 167 patients completed the survey (response rate 63.9%). The majority of participants were male and were Hispanic (49%) or Non-Hispanic black (31.7%). Of these, 140 patients (84.0%) reported discussing kidney transplantation with their doctor but only 53% reported having a transplant evaluation. After adjustment for age, gender, and time on dialysis, significantly fewer blacks reported having an evaluation than Non-Hispanic whites or Hispanics (43.4 vs. 57.7% [whites] and 59.7% [Hispanics], p = 0.03). The most frequent responses of the patients who had not been evaluated were the following: not referred by their provider (46%), did not know how to proceed (43.4%), or did not understand the benefits (39.5%) or transplant process (38.2%). Compared to Non-Hispanic whites, blacks and Hispanics reported less understanding of the benefits and process of transplant. CONCLUSION: Timely referral by providers and improved kidney transplantation education may reduce disparities in access to kidney transplantation. PMID- 29258095 TI - A Case of Pancreatic Carcinoma in situ Diagnosed by Repeated Pancreatic Juice Cytology. AB - Repeated pancreatic juice cytology via endoscopic nasopancreatic drainage (ENPD) has a high diagnostic yield and might be useful for the diagnosis of early-stage pancreatic cancer. A 67-year-old man presented with a pancreatic cyst occasionally detectable in the body of the pancreas by ultrasonography (US). No obvious pancreatic tumor was detected by US, computed tomography (CT), magnetic resonance cholangiopancreatography, and endoscopic ultrasound (EUS) (although the latter did reveal a weak, low echoic area). Endoscopic retrograde pancreatography showed irregular narrowing of the main pancreatic duct (MPD) at the pancreatic body. Pancreatic juice cytology was also performed, but did not give evidence of a malignancy. Therefore, the patient was followed up. CT and EUS performed after 3 months showed the same findings as did endoscopic retrograde pancreatography; however, the results of repeated pancreatic juice cytology performed via ENPD tube revealed a suspected malignancy on 2 of 6 occasions. Therefore, we performed a central pancreatectomy. Histopathological examination of a resected specimen revealed carcinoma in situ in the narrow MPD at the body of the pancreas. In the current case, repeated pancreatic juice cytology via ENPD was effective. A weak low echoic area around the MPD stricture on EUS might be related to the inflammatory change accompanying carcinoma in situ of the pancreas. PMID- 29258096 TI - Clinical Analysis of Esophageal Stricture in Patients Treated with Intralesional Triamcinolone Injection after Endoscopic Submucosal Dissection for Superficial Esophageal Cancer. AB - INTRODUCTION: Endoscopic submucosal dissection (ESD) has been widely used in the resection of superficial esophageal cancers. Since its use has been extended to cases involving large esophageal tumors occupying nearly the whole or the whole circumference of the lumen, the occurrence of esophageal stricture has increased. Although endoscopic injection of triamcinolone (TA) is widely used for the prevention of postoperative stricture, a significant number of patients still develop stricture after TA injection therapy. METHODS: We performed a retrospective study to identify the clinical parameters that predispose post-ESD patients to esophageal stricture after TA injection therapy. RESULTS: A total of 207 patients who were diagnosed with superficial esophageal cancer and subsequently underwent ESD were enrolled in this study. Among these patients, 53 patients and 57 lesions bearing mucosal defects covering greater than two-thirds of the esophageal circumference after ESD were treated with TA injection therapy. The rate of esophageal stricture was found to be highest in cases involving mucosal defects that covered more than seven-eighths of the circumference. CONCLUSION: Endoscopic TA injection is not sufficient for preventing esophageal stricture in patients bearing mucosal defects covering more than seven-eighths of the esophageal circumference after ESD. PMID- 29258098 TI - The Magnitude of mTORC1 Signalling May Predict the Response to Isotretinoin Treatment in Patients with Hidradenitis Suppurativa. PMID- 29258099 TI - New Paradigm in Gastrointestinal Cancer Treatment. PMID- 29258097 TI - Clinical Significance of O-6-Methylguanine-DNA-Methyltransferase Promoter Methylation in Patients with Esophageal Carcinoma: A Systematic Meta-Analysis. AB - BACKGROUND: The correlation between O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and esophageal cancer remains controversial. This study was conducted to evaluate the clinical effect of MGMT promoter methylation on esophageal carcinoma patients. METHODS: A literature search was conducted in the PubMed, EMBASE, EBSCO, and Cochrane Library databases. The overall OR and corresponding 95% CI were calculated using the random-effects model. RESULTS: Finally, 17 eligible studies were identified in this meta-analysis; these studies included a total of 1,368 patients with esophageal carcinoma and 1,489 with nonmalignant controls. MGMT promoter methylation was significantly higher in esophageal carcinoma tissue samples than in nonmalignant tissue samples (OR 3.64, p < 0.001). Promoter methylation of the MGMT gene was not associated with gender, cigarette smoking, drinking behavior, or tumor differentiation, but MGMT promoter methylation was correlated with age (>=60 vs. <60 years: OR 1.64, p = 0.028), lymph node status (positive status vs. negative status: OR 2.39, p = 0.024), and clinical stage (stages 3-4 vs. 1-2: OR 10.59, p < 0.001). CONCLUSIONS: Our findings suggest that MGMT promoter methylation may be correlated with esophageal cancer carcinogenesis and could be associated with age, lymph node status, and clinical stage. PMID- 29258100 TI - EUS-Guided Pancreatic Duct Drainage for Repeat Pancreatitis in a Patient with Pancreatic Cancer. AB - Endoscopic ultrasound-guided pancreatic drainage (EUS-PD) was performed in a patient with unresectable pancreatic cancer who developed pancreatitis. In this case, EUS-PD was useful as salvage therapy for pancreatitis as the transpapillary approach was difficult. PMID- 29258101 TI - A Social Program for the Early Detection of Pancreatic Cancer: The Kishiwada Katsuragi Project. AB - OBJECTIVES: The early-stage pancreatic cancer (e-PC; stage I/II) detection rate is quite low at approximately 25%. The aim of this study was to evaluate the feasibility of a social program (the Kishiwada Katsuragi project) wherein our hospital, which specializes in PC, and primary care medical offices (PMOs) used clinical findings to detect e-PC. METHODS: Patients with a score of >=2 points on clinical findings were enrolled: symptoms of abdominal pain/back pain (1 point), new-onset diabetes (1 point), high amylase (AMY) and/or pancreaitc AMY (P-AMY) (1 point), high carbohydrate antigen 19-9 (1 point), and ultrasonography (US) findings including direct (e.g., a solid pancreatic tumor) and/or indirect findings (e.g., dilatation of a pancreatic diameter of >=2.5 mm and/or cystic lesions) (2 points) were evaluated using the protocol for social programs. RESULTS: Between November 2014 and December 2016, 244 patients were enrolled by 41 PMOs as cooperative facilities, and 15 e-PC cases (53.6%) of the 28 PC patients were detected. The mean clinical finding score of the e-PC group (3.13 +/- 1.9) was significantly higher than that of the overall non-PC group (2.1 +/- 0.4) (p < 0.05). "High AMY/P-AMY" and "symptoms" were significantly more frequent in the e-PC group than in the non-PC group (p < 0.05). Although the sensitivity of direct findings by US was 40.0%, that of indirect-findings was 93.3% in the e PC group. Nine and 6 of the 15 patients with e-PC were enrolled via general internal medicine offices (GIMs) and other PMOs without GIMs (general surgery, n = 3; urology, n = 2; otolaryngology, n = 1). CONCLUSION: This social program with collaborations between medical centers that specialize in PC and PMOs used clinical findings, suggesting that not only GIMs but also other PMOs and indirect findings by US may play an important role in improving the e-PC detection rate. PMID- 29258102 TI - MiRNA and mRNA Profiling in Systemic Lupus Reveals a Novel Set of Cytokine - Related miRNAs and their Target Genes in Cases With and Without Renal Involvement. AB - BACKGROUND/AIMS: MiRNAs transpire as promising elements in molecular medicine for the identification of new diagnostic, prognostic and targeting therapeutic biomarkers. This study consisted of four steps: First, to investigate one or a group of specific diagnostic miRNAs for Systemic Lupus Erythematosus (SLE) disease in patients with and without renal involvement, second, to identify cytokines genes' expression profiling, third, comparing the profiles with related amounts in the serum and finally, to study target-gene-mediated functional roles of miRNAs, which have been correlated to disease development and progression. METHODS: In order to use in microarray assays total RNA and miRNAs were isolated from blood and serum samples that were obtained from 16 SLE patients (9 with renal involvement and 7 without renal involvement). Taking coexistence of factors such as hypocomplementemia, positive ANA and anti-DNA into account, obtained data were processed. For each differentially expressed miRNA, potential target genes were predicted by microRNAorg, TargetScan and PITA prediction tools. Obtained mRNA profiling data were interrogated for the target genes. MiRNA and mRNA microarray results were confirmed by QRT-PCR. Finally, the amounts of cytokines were measured by multiplex ELISA method. RESULTS: The results of study showed that among differentially expressed miRNAs in SLE patients with renal involvement compared to those without renal involvement, hsa-miR-766-3p, may play pivotal roles in PI3K-AKT-mTOR pathway. In addition according to the obtained data it is suggested that blood-borne proinflammatory cytokines such as IL-4, IL-6 and TNF alpha alongside with disease stage and severity may contribute to this differential expression of these miRNA which may be leading to insulin resistance. Finally, hsa-miR-621, which was differentially expressed in hypertensive SLE patients without renal involvement and a positive ANA test with its predicted target gene "Kallikrein-related peptidase 9" may play a role in the pathophysiology of hypertension in SLE. CONCLUSIONS: We reported some human miRNAs which were differentially expressed in SLE patients according to disease activity and renal involvement. Larger studies are necessary to confirm our findings and detect further biomarkers. PMID- 29258103 TI - SyNoPsis: Response to the Commentators. PMID- 29258104 TI - Deletion 21pterq22.11: Report of a Patient with Dysmorphic Features, Hypertonia, and Cafe-au-Lait Macules and Review of the Literature. AB - Partial monosomy 21 results in a great variability of clinical features that may be associated with the size and location of the deletion. In this study, we report a 22-month-old girl who showed a 45,XX,add(12)(p13)dn,-21 karyotype. The final cytogenomic result was 45,XX,der(12)t(12;21)(p13;q22.11) dn,-21.arr[hg19] 21q11.2q22.11(14824453_33868129)*1 revealing a deletion from 21pter to 21q22.11. Clinical manifestation of the patient included hypertonia, a long philtrum, epicanthic folds, low-set ears, and cafe-au-lait macules - a phenotype considered as mild despite the relatively large size of the deletion compared to patients from the literature. PMID- 29258105 TI - Validation of Newly Proposed Time to Transarterial Chemoembolization Progression in Intermediate-Stage Hepatocellular Carcinoma Cases. AB - BACKGROUND/AIM: Determination of failure of transarterial chemoembolization (TACE) for treatment of Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma (HCC) has become important because of the development of tyrosine kinase inhibitor (TKI) treatment. We evaluated the usefulness and efficacy of the newly proposed time to TACE progression (TTTP). PATIENTS AND METHODS: From 2006 to 2016, 192 BCLC-B HCC patients [median age 72 years, male/female ratio = 149/43, Child-Pugh score 5/6/7 = 106/56/30, albumin-bilirubin (ALBI) grade 1/2 = 64/128, Kinki criteria B1/B2 = 64/128] were enrolled. TTTP was defined based on a previous report and first imaging performed 3 months after initial TACE had been used to obtain baseline images. The patients were divided into three groups according to TTTP (<5, 5-10, and >=10 months; group I, II, and III, respectively). We evaluated the relationship between TTTP and overall survival (OS) as well as the prognostic factors for death. RESULTS: The median number of TACE procedures was 4 (interquartile range 3-7). There was a moderate correlation between TTTP and OS (r = 0.527, 95% CI 0.416-0.622, p < 0.001). The median survival for group I (n = 78), II (n = 49), and III (n = 65) was 24.6, 34.7, and 49.5 months, respectively (group I vs. group II, p = 0.023; group I vs. group III, p < 0.001; group II vs. group III, p = 0.037; Holm's method). ALBI grade 2 (HR 1.548, 95% CI 1.004-2.388, p = 0.048), alpha-fetoprotein (>100 ng/mL) (HR 1.540, 95% CI 1.035-2.291, p = 0.033), and TTTP (<5 months) (HR 2.157, 95% CI 1.447-3.215, p < 0.001) were significant prognostic factors for death in multivariate Cox hazard analysis. CONCLUSION: In patients with reduced TTTP, especially <5 months, it might be difficult to improve prognosis with a repeated TACE procedures. In such cases, reconsideration of the therapeutic strategy might be needed when possible. PMID- 29258107 TI - Prophylactic Suturing Closure Is Recommended after Endoscopic Treatment of Colorectal Tumors in Patients with Antiplatelet/Anticoagulant Therapy. AB - The prophylactic closure of mucosal defects after endoscopic resection is known to prevent postoperative bleeding in colorectal lesions. However, closure of large mucosal defects is difficult with conventional clips only, and several closure techniques have been previously described; use of an Endoloop, 8-ring loop, or loop clip and a small incision around the mucosal defect. Given that the prophylactic closure requires much cost and time, the application should be limited to high-risk cases. Medication of antithrombotics or antiplatelet agents would be one of the reasonable indications for prophylactic closure of mucosal defects after endoscopic resection of colorectal tumors. PMID- 29258108 TI - Vitamin D Status and Resting Metabolic Rate May Modify through Expression of Vitamin D Receptor and Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 Alpha Gene in Overweight and Obese Adults. AB - BACKGROUND: Resting metabolic rate (RMR) used to prognosticate and measure the amount of energy required. Vitamin D is known as a new predictor of RMR. The aim of this study is to investigate the relationship between vitamin D effects on RMR in connection with the vitamin D receptor (VDR) and peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1alpha) gene expression. METHODS: We enrolled 298 overweight and obese adults in this cross-sectional study. Body mass index (BMI), fat mass, fat-free mass, insulin level, visceral fat, and vitamin D status were assessed. RMR was measured by means of indirect calorimetry. The real-time polymerase chain reaction using specific primer pairs for VDR and PGC-1alpha was performed. RESULTS: There were significant differences in terms of fat free mass, fat percentage, insulin levels, RMR/kg body weight, and RMR/BMI, VDR, and PGC-1alpha among participants were categorized based on the vitamin D status. But after using general linear model for adjusting, all significant results missed their effectiveness except RMR/kg body weight and VDR. Linear regression analysis used to show the mediatory role of VDR and PGC-1alpha on the RMR/kg body weight and vitamin D status relationship. Our results showed that VDR had a mediatory effect on the relationship between RMR/kg body weight and vitamin D status (beta = 0.38, 95% CI -0.48 to 1.60; beta = -1.24, 95% CI 5.36 to 1.70). However, PGC-1alpha did not affect the relationship between RMR/kg body weight and vitamin D status (beta = 0.50, 95% CI = -0.02 to 3.42; beta = 0.59, 95% CI 0.14-3.90). CONCLUSION: Our study showed the mediatory effect of VDR gene expression in the association of 25(OH)2D plasma levels and resting metabolic rate among obese individuals. PMID- 29258109 TI - Multiple MicroRNAs Ameliorate Hepatocyte Steatosis and Injury by Suppressing FABP1 Expression. AB - BACKGROUND/AIMS: Liver fatty acid-binding protein (FABP1) is a key regulator of hepatic lipid metabolism. MicroRNAs (miRNAs) are thought to be involved in nonalcoholic fatty liver disease (NAFLD), and the underlying mechanism is largely unclear. We investigated whether miRNAs influence hepatocyte steatosis by regulating the FABP1 gene. METHODS: Candidate FABP1-targeting miRNAs were evaluated using luciferase reporter assay. FABP1 expression was measured using western blotting and quantitative reverse transcription-PCR. Intracellular lipid accumulation was measured based on Oil Red O staining and intracellular triglyceride content. Hepatocyte injury was evaluated based on culture supernatant levels of alanine aminotransferase, aspartate aminotransferase, and intracellular adenosine triphosphate, and mitochondrial membrane potential. RESULTS: Dicer1 knockdown significantly elevated FABP1 expression. In total, 68 miRNAs potentially targeting FABP1 were selected; of these, miR-3941, miR-4517, and miR-4672 directly targeted the FABP1 3' untranslated region. Mimics of the three miRNAs substantially repressed FABP1 expression at translational level and led to HepG2 cell resistance to steatosis and cell injury induced by free fatty acids mixture, which rescue of FABP1 overexpression reversed. CONCLUSION: Our findings identify a novel mechanism by which miRNAs protect against hepatocyte steatosis and injury by downregulating FABP1 expression. PMID- 29258110 TI - Systems Neuroscience of Psychosis (SyNoPsis) Provides a Promising Framework for Advancing the Field. PMID- 29258111 TI - Comparative Study of Clarithromycin- versus Metronidazole-Based Triple Therapy as First-Line Eradication for Helicobacter pylori. AB - INTRODUCTION: Clarithromycin (CAM)-based triple therapy comprising proton pump inhibitors and amoxicillin is administered as first-line eradication treatment against Helicobacter pylori infection. However, the eradication rate achieved with CAM-based triple therapy has decreased to <80% owing to the emergence of CAM resistant strains. This prospective randomized study aimed to compare the efficacy of CAM-based and metronidazole (MNZ)-based triple therapy in terms of H. pylori eradication. METHODS: H. pylori-positive patients were treated with CAM based triple therapy comprising esomeprazole and amoxicillin (EAC group) or with MNZ-based triple therapy comprising esomeprazole and amoxicillin (EAM group). RESULTS: H. pylori eradication rates achieved in the intention-to-treat (ITT) and per protocol (PP) analyses were 70.6 and 72.7%, respectively, in the EAC group. Eradication rates obtained via ITT and PP analyses were 91.7 and 94.3%, respectively, in the EAM group. In the EAC group, eradication rates were significantly lower in patients harboring CAM-resistant strains than in those harboring CAM-sensitive strains. In contrast, eradication rates were comparable between patients harboring CAM-resistant strains and those harboring CAM sensitive strains in the EAM group. CONCLUSION: MNZ-based triple therapy consisting of esomeprazole and amoxicillin is superior to CAM-based triple therapy containing esomeprazole and amoxicillin as first-line eradication treatment against H. pylori. PMID- 29258112 TI - The Feasibility of 18-mm-Diameter Colonic Stents for Obstructive Colorectal Cancers. AB - OBJECTIVES: This study aimed to evaluate the characteristics and the feasibility of 18-mm-diameter stents for obstructive colorectal cancer, comparing the clinical courses with 22- mm-diameter stents. METHODS: We retrospectively compared 33 consecutive cases treated with 18-mm-diameter stents (bridge to surgery [BTS] in 25, palliative therapy [PAL] in 8) with 27 consecutive cases treated with 22-mm-diameter stents (BTS in 21, PAL in 6) for obstructive colorectal cancer between May 2013 and November 2015 in our institution. RESULTS: There were no significant differences between the 18-mm and 22-mm groups in technical success rates (97 and 96%, respectively) and clinical success rates (100 and 100%, respectively). As a BTS, the rates of complications and stoma formation were not significantly different between groups. For PAL, although the rates of complications and stent patency were similar, stent occlusion occurred in 1 patient (12.5%) in the 18-mm group. CONCLUSIONS: The 18-mm-diameter stents were similarly effective when compared with 22-mm-diameter stents. Because 18-mm diameter stents are easy to handle and produce less mechanical stress, they have the potential to decrease the perforation rate and mitigate the stent's impact on the tumors. 18-mm-diameter stents can be useful and safe, especially as a BTS. PMID- 29258113 TI - Familial Duplication/Deletion of 1q42.13q43 as Meiotic Consequence of an Intrachromosomal Insertion in Chromosome 1. AB - Rearrangements of the region 1q42.13q43 are rare, with only 7 cases reported to date. The imbalances described are usually the result of inherited translocations with other chromosomes. Moreover, few cases of both inter- and intrachromosomal deletions/duplications detected cytogenetically have been described. We report the molecular cytogenetic characterization of an inverted insertion involving the region 1q42.13q43 and segregating in 2 generations of a family. The deletion and the duplication of the same segment were detected in 2 affected family members. SNP array analysis showed the familial origin of the deletion/duplication due to the occurrence of a crossing-over during meiosis. Our report underlines the importance of determining the correct origin of chromosomal aberrations using different molecular cytogenetic tests in order to provide a good estimation of the reproductive risk for the members of the family. PMID- 29258115 TI - MiR-129-5p Sensitizes the Response of Her-2 Positive Breast Cancer to Trastuzumab by Reducing Rps6. AB - BACKGROUND/AIMS: Trastuzumab is an important treatment used for patients with Her 2-positive breast cancer, but an increasing incidence of trastuzumab resistance has been observed clinically during the past decade. Aberrant microRNA (miR) expression levels are correlated with prognosis and response to trastuzumab in breast cancer. MiR-129-5p is downregulated in trastuzumab-resistant human breast cancer cells (JIMT-1), but its potential function and underlying mechanism remain unclear. METHODS: Quantitative RT-PCR (qRT-PCR) was used to determine the expression levels of miR-129-5p and its potential target genes. The effects of miR-129-5p on cell responses to trastuzumab were analyzed by CCK-8 and flow cytometry assays in Her-2-positive breast cancer cells (SKBR-3 and JIMT-1). Bio informatics analyses were performed to predict target genes of miR-129-5p, and luciferase assays were carried out to confirm the binding of miR-129-5p and rpS6. RESULTS: MiR-129-5p, which was downregulated and predicted to target rpS6 in trastuzumab-resistant breast cancer cells, enhanced the sensitivity of breast cancer cells to trastuzumab by reducing the expression of rpS6. Moreover, the overexpression of rpS6 reversed the sensitivity of cells to trastuzumab induced by miR-129-5p. CONCLUSIONS: MiR-129-5p sensitized Her-2-positive breast cancer to trastuzumab by downregulating rpS6. These findings provide novel insights into the common role of rpS6 and its related molecular mechanisms in mediating trastuzumab-resistance in Her-2-positive breast cancers. PMID- 29258116 TI - Clinical Significance of Bmi1 Expression in Inflammatory Bowel Disease. AB - BACKGROUND: Although the stem cell marker Bmi1 is overexpressed in many malignancies, its role in inflammation-associated cancer is unclear. Colitis associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). METHODS: To assess the involvement of Bmi1 in the development of CAC, we analyzed the gene expression of colon tissues collected from 111 patients with IBD and CAC. RESULTS: In the colonic mucosa of patients with ulcerative colitis, the expression of Bmi1 correlated significantly with the expression of inflammatory cytokines such as IL 6, IL-17, IL-23, and tumor necrosis factor alpha (TNF-alpha). In the colonic mucosa of patients with Crohn's disease, the expression of Bmi1 correlated significantly with the expression of TNF-alpha and IL-23. The expression of Bmi1 was enhanced in the colonic mucosae of refractory IBD, suggesting that Bmi1 expression might be related to increased cancer risk. In addition, patients with high Bmi1 expression showed significantly lower response rates upon subsequent anti-TNF-alpha therapy as compared to patients with low Bmi1 expression. In human CAC specimens, the expression of Bmi1 was upregulated in nontumor tissues as well as tumors. CONCLUSIONS: Bmi1 expression is related to a refractory clinical course of IBD and upregulated in refractory IBD and CAC. Measurement of Bmi1 expression is a promising approach for the advanced treatment and personalized management of IBD patients. PMID- 29258117 TI - Association between the Risk Factors for Pancreatic Ductal Adenocarcinoma and Those for Malignant Intraductal Papillary Mucinous Neoplasm. AB - BACKGROUND AND AIMS: Risk factors for pancreatic ductal adenocarcinoma (PDAC) include diabetes mellitus, chronic pancreatitis, obesity, a family history of pancreatic cancer, and a history of smoking or alcohol consumption. The aim of this study was to evaluate the association between risk factors for PDAC and malignant intraductal papillary mucinous neoplasm (IPMN). METHODS: The study included 134 consecutive patients with IPMN who underwent surgical resection at Kindai University Hospital between April 2009 and March 2015. Data on the presence or absence of mural nodules (MNs) and risk factors for PDAC were evaluated. Multivariable logistic regression analysis was performed with malignant IPMN as the outcome variable and MNs and risk factors for PDAC as explanatory variables. RESULTS: The odds ratio of malignant IPMN to MNs was 3.88 (95% confidence interval [CI] 1.53-9.84; p = 0.004), whereas that of malignant IPMN to smoking history was 1.66 (95% CI 0.74-3.71; p = 0.22). When the presence of MNs was considered as a predictive factor for malignancy, the sensitivity and specificity were 88.5 and 32.1%, respectively, whereas when the presence of both smoking history and MNs was considered, the specificity improved to 73.2%, with a decrease in sensitivity to 42.3%. CONCLUSIONS: The presence of both a smoking history and MNs was a valuable predictive factor for malignant IPMN with high specificity. A smoking history should be considered before surgical resection in addition to the presence of MNs. PMID- 29258118 TI - Commentary on "Systems Neuroscience of Psychosis (SyNoPsis): Mapping Schizophrenia Symptoms onto Brain Systems". PMID- 29258119 TI - Medicine Goes Politics? PMID- 29258124 TI - Nonsurgical Management of Persistent and Hemodynamically Significant Patent Ductus Arteriosus among Extremely Low Birth Weight Infants: A Propensity Score Matched Analysis. AB - OBJECTIVE: The objective of this study was to evaluate the impact of a nonsurgical approach (with the incorporation of late postnatal hydrocortisone treatment to facilitate extubation) in comparison to the surgical approach for the management of persistent hemodynamically significant patent ductus arteriosus (hsPDA) among chronically ventilator-dependent extremely low birth weight (ELBW) infants. METHODS: In this retrospective study, ELBW infants with a diagnosis of hsPDA (diagnosed based on the echocardiographic criteria and chronic ventilator dependence) that were persistent beyond 14 days of postnatal age despite adequate medical treatment were included. RESULTS: Out of 127 infants (surgical approach group, n = 67 and nonsurgical approach group, n = 60), 72 infants were matched based on the propensity scores. In the matched cohort, in comparison to infants managed with the surgical approach (control group, n = 36), infants in the nonsurgical approach group (treatment group, n = 36) had a lower rate of surgical ligation (14 vs. 100%, p = < 0.001), but there were no differences in both primary outcome (death or bronchopulmonary dysplasia) and secondary outcome measures. CONCLUSION: For chronically ventilator-dependent ELBW infants with persistent hsPDA, a nonsurgical management approach is associated with a reduced rate of surgical ligation of PDA, but not associated with increased risk of adverse major short-term neonatal outcomes. PMID- 29258125 TI - New Targets for the Prevention of Chronic Rejection after Thoracic Organ Transplantation. AB - The gold standard for the treatment of terminal heart failure and irreversible lung diseases includes thoracic organ transplantation. The major obstacle for long-term survival after successful transplantation is chronic rejection, an ongoing immunomodulatory disease so far without effective therapy. Therefore, the aim of this review is to elucidate scientific efforts targeting different new mechanisms of cardiac allograft vasculopathy (CAV) and chronic lung allograft dysfunction (CLAD). For this purpose, we performed a systematic review of the literature to assess recent strategies in transplant immunology research. We searched MEDLINE from 2015 up to date for articles addressing the following keywords: CAV, transplant vasculopathy, transplant arteriosclerosis, CLAD, bronchiolitis obliterans transplant, and obliterative bronchiolitis transplant. All articles including experimental models in the field of transplant immunology addressing new aspects for the prevention of chronic rejection after heart and lung transplantation were included in this review. The prevention of chronic rejection would clearly improve the survival of patients after heart and lung transplantation. Interesting targets were addressed in recent research, but further research is necessary to effectively treat this life-threatening disease in transplant recipients. PMID- 29258126 TI - Heart and Mitochondria: Pathophysiology and Implications for Cardiac Surgeons. AB - Excluding the heart from systemic circulation during cardiac surgery renders the myocardium ischemic, resulting in cardiac damage. In addition, another hit to the myocardium will occur upon restoration of blood flow, in the reperfusion phase. Experimental data from animal models have revealed that loss of cardiac metabolic flexibility and mitochondrial dysfunctions contributes to contractile impairment in hypertrophied, failing, obese, and diabetic hearts. Such diseased hearts are prone to myocardial ischemia-reperfusion (I/R) injury. Although analyses in human cardiac samples are not as comprehensive as animal data, similar disease associated metabolic and mitochondrial changes exist. Considering increasing age and comorbidities in patients nowadays, it is not surprising that I/R injuries remain a major cause of morbidity and mortality after cardiac surgery. Mitochondria have emerged as critical targets but also key regulators of myocardial I/R injury, and the extent of mitochondrial damage is a major determinant of myocardial I/R injury. Although cardioprotective mechanisms are diverse, many come together and involve steps at the point of mitochondria. We will, therefore, provide a description of mitochondrial alterations observed in various cardiac disease states and discuss the current experimental knowledge of the role of mitochondria in I/R and of potential protective mechanisms against myocardial I/R injury involving mitochondria. Within this review, we will focus on the protection against I/R injury conferred by caloric restriction (CR) and by ischemic conditioning. Further research is needed to establish whether strategies targeting mitochondria, which have been proposed from preclinical studies, could be translated into cardioprotective therapies against I/R injury in patients. PMID- 29258127 TI - Lithium: An American Perspective. PMID- 29258128 TI - [Correction: The Value of Endoscopic Decompression in Surgical Therapy of Carpal Tunnel Syndrome]. PMID- 29258129 TI - ? PMID- 29258130 TI - [A retrospective analysis of functional and oncologic outcomes following surgical treatment of patients with pT1/pT2 renal cell carcinoma at a tertiary referral centre]. AB - INTRODUCTION: In patients with localised renal cell carcinoma, the only curative treatment option is surgical tumour excision. The aim of this study was to evaluate peri- and postoperative outcomes as well as oncologic and functional long-term results following surgical treatment of patients with renal cell carcinoma (pT1/pT2) at a tertiary referral centre. PATIENTS AND METHODS: This retrospective study included a total of 758 patients with localised renal cell carcinoma (pT1 /pT2), who underwent radical (RN) or partial (PN) nephrectomy between 01/2008 and 10/2014. Pre-, peri- and postoperative parameters were recorded. Oncologic and functional long-term data were retrieved through questionnaires and structured telephone interviews. RESULTS: Laparoscopic RN or PN resulted in less blood loss and lower peri- and postoperative complication rates compared to open procedures. Regarding short- and long-term renal function, a higher increase in serum creatinine levels was detected after RN. No difference was noted in health status and quality of life. Median follow-up was 36 months. A total of 10.4 % of patients died during follow-up. 4.7 % and 8.4 % developed a relapse or metastatic disease. No difference was found between laparoscopic and open RN/PNs in terms of oncologic long-term results. DISCUSSION: In conclusion, all surgical techniques evaluated in this study provided good oncologic and functional short-/long-term outcomes. PMID- 29258131 TI - Rituximab, IVIg, and Tetracosactide (ACTH1-24) Combination Immunotherapy ("RITE CI") for Pediatric Opsoclonus-Myoclonus Syndrome: Immunomarkers and Clinical Observations. AB - Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder with pervasive morbidity that warrants better treatments. Twelve children with moderate/severe OMS (total score 23 +/- 6) who did not remit to multiple immunotherapies were evaluated for neuroinflammation in a case-control study using cerebrospinal fluid (CSF) lymphocyte subset analysis by flow cytometry, chemokine/cytokine analysis by enzyme-linked immunoadsorption assay (ELISA), and oligoclonal bands by immunofixation with isoelectric focusing. Observations made on empirical treatment with rituximab, IVIg, and tetracosactide combination immunotherapy (coined "RITE-CI") were analyzed. All of the patients tested for multiple inflammatory markers were positive; 75% had >=3 CSF markers. Fifty percent had CSF oligoclonal bands; 58%, B cell expansion; and 50 to 100%, elevated concentrations of multiple chemokines and neuronal/axonal marker neurofilament light chain. After RITE-CI, total score dropped significantly in the group (-85%, p < 0.0001) from moderate to trace, and by 2 to 4 severity categories in each patient. The 24-week schedule was well tolerated and clinically effective for moderate or severe OMS, as were other schedules. RITE-CI is feasible and effective as rescue therapy and presents an initial option for children with moderate/severe OMS. Though preliminary, the schedule can be adjusted to patient severity, propensity for relapse, and other factors. PMID- 29258132 TI - [Parry-Romberg syndrome and scleroderma en coup de sabre]. PMID- 29258134 TI - ? PMID- 29258133 TI - Evaluation of the New DIN Standard for Quality Assurance of Diagnostic Displays - Technical Review DIN 6868-157. AB - : Acceptance and regular constancy tests are necessary to ensure the quality of diagnostic displays. In November 2014, a new standard (DIN 6868-157) was published which defines the test procedure and limiting values. There are several substantial changes compared with the previous standard DIN V 6868-57, i. e. considering the complete image display system including workstation and application software instead of only the displays. Since its publication, the new standard has raised many questions. This technical review aims to show the strengths and weaknesses of the new standard. Positive aspects are the introduction of a limiting value for the illuminance and the extension of the interval for constancy tests from 3 to 6 six months. The daily constancy test on the other hand, raises several problems and should be replaced by a randomized test. Additionally, the medical relevance is critically questioned and an overview of software for the quality assurance will be given. KEY POINTS: . Acceptance and constancy tests for diagnostic displays are defined in DIN 6868 157.. . The new standards has positive and negative aspects.. . Randomized tests should be introduced.. CITATION FORMAT: . Entz K, Sommer A, Lenzen H. DIN 6868 157: Image Quality Assurance in Diagnostic X-ray Departments - X-ray Ordinance Acceptance and Constancy Test of Image Display Systems in their Environment - Technical Review -. Fortschr Rontgenstr 2018; 190: 51 - 60. PMID- 29258136 TI - ? PMID- 29258135 TI - ? PMID- 29258137 TI - ? PMID- 29258138 TI - ? PMID- 29258139 TI - ? PMID- 29258140 TI - ? PMID- 29258141 TI - ? PMID- 29258143 TI - ? PMID- 29258142 TI - ? PMID- 29258144 TI - Looking back at EUROSON 2016 in Leipzig, Germany: which topics were popular? PMID- 29258145 TI - Preeclampsia in Fetal Medicine. PMID- 29258146 TI - Who's Doing Your Scan? The German Perspective on Ultrasound Services: Ultrasound is More Than a Technique, it's a Medical Art. PMID- 29258147 TI - High-level Carotid Ultrasound Must be Performed by a Physician. PMID- 29258148 TI - Robot-Assisted Laparoscopic Fundoplications in Pediatric Surgery: Experience Review. AB - INTRODUCTION: Laparoscopic fundoplicature for gastroesophageal reflux disease has become the gold standard because of the improvement of postoperative rehabilitation compared with the open procedure. The robot-assisted surgery has brought new advantages for the patient and the surgeon compared with laparoscopy. We studied this new approach and the learning curve. METHODS: Sixty robot assisted fundoplicatures were performed in two university pediatric surgery centers. Data of the patients were recorded, including peroperative data (operation length and complications), postoperative recoveries, and clinical evolution. The learning curve was evaluated retrospectively and each variable was compared along this learning curve. RESULTS: We observed a flattening of the learning curve after the 20th case for one surgeon. The mean operative time decreased significantly to 80 +/- 10 minutes after 20 cases. There were no conversions to an open procedure. A revision surgery was indicated for 4.7% of the patients by a surgical robot-assisted laparoscopic approach. CONCLUSION: The robotic system appears to add many advantages for surgical ergonomic procedures. There is a potential benefit in operating time with a short technical apprenticeship period. The setting up system is easy with a short docking time. PMID- 29258149 TI - Choledochal Cyst and Malignancy: A Plea for Lifelong Follow-Up. AB - Previous research has confirmed that patients with choledochal cyst have an elevated risk of cholangiocarcinoma and gallbladder carcinoma. Current data suggest a risk of malignancy of 6 to 30% in adults with choledochal cyst. Malignancy has also occasionally been identified in children and adolescents. Multiple factors, including the age of the patient, cyst type, histological findings, and localization, have an impact on the prognosis. Information on long term outcomes after cyst excision is limited. However, recent data suggest a lifelong elevated risk of up to 4% of cancer development following operation. This paper presents a review of the literature on cancer in patients with choledochal cyst before and after excision. A postoperative follow-up concept that consists of annual controls of CA19-9 and abdominal ultrasound is introduced. PMID- 29258150 TI - [Video-Head impulse test with little diagnostic impact in vertigo-patients]. AB - OBJECTIVE: Video-head impulse test (V-HIT) is more and more becoming a routine test in patients with vertigo, contributing information about the vestibulo ocular reflex (VOR). According to Ewald's second law, the unilateral pathological test points to this side's peripheral organ as being diseased. The value in clinical routine is still unclear. MATERIAL AND METHODS: 171 consecutive patients with vertigo that had received a V-HIT and caloric testing at presentation in an academic ENT-department were included. By chart-review, they were categorized in different groups with unilateral peripheral, central and other etiology of vertigo, irrespective of their V-HIT result. Then the latter was analyzed within the different groups with respect to Gain, Gain-Asymmetry (GA) and Catch-up Saccades (CS). Canal Paresis (CP) from caloric testing was compared to GA. RESULTS: In patients with unilateral peripheral disease, 31 % showed a pathological gain (< 0.8), the mean GA was 4.53 % (+/- 16.72 %) and 60 % had CSs. In patients with presumed or assured central etiology, these data were 28 %, 1,56 % (+/- 17,89 %) and 45 %. Isolated CS occurred only sporadically. CP was not correlated with GA in all groups (p = 0,114). CONCLUSION: In this study V-HIT showed little diagnostic use, especially in separating peripheral from central disease. The lacking correlation between asymmetry in caloric testing and asymmetry of V-HIT gain challenges current pathophysiological concepts of impaired VOR. PMID- 29258151 TI - [Physicians' Opinion on Health Care in Oral Anticoagulation]. AB - BACKGROUND: The introduction of direct oral anticoagulants (DOAC) in addition to the established Vitamin K antagonist (VKA) has increased the complexity of antithrombotic therapy leading to numerous treatment options. Studies of the medical evaluation of the current treatment situation by health care providers, which are of great importance for the development of treatment strategies in addition to studies on pharmacovigilance, are limited in the literature. METHODS: 11 700 physicians (Rhineland-Palatinate, Germany) were contacted to participate in the web-based survey on health care with oral anticoagulation (OAC). After detailed quality control, the study was analysed in synopsis with routine care data of VKA patients of the thrombEVAL study programme (N = 2.011). RESULTS: In total, 512 physicians (mean age: 48.0 +/- 9.6 years; 74.0 % male) participated in the study. In general, quality of OAC therapy was rated as "average/satisfactory" (2.9 +/- 0.9). Comparison of physicians' perception with data from routine care highlighted marked differences regarding time in therapeutic range (+ 6.4 % [95 % CI 2.7 %; 9.5 %]), duration of control intervals (- 35.0 % [28.0 %; 41.4 %]) and rate of OAC-related complications (+ 61.8 [37.8 %; 83.3 %], which differed additionally and statistically-significant between physician groups. The willingness to use DOAC was approximately 50 % lower in general physicians as compared to specialists (36.6 % [25.4 %; 47.8 %] vs. 72.4 % [66.0 %; 78.9 %]; p < 0.0001). Regarding management of OAC therapy, 73.8 % [69.7 %; 77.9 %] advocated the establishment of a service hotline and 67.3 % [62,9 %; 71.6 %] a specialized coagulation service. DISCUSSION: The present survey among physicians reveals a need for optimization of OAC therapy in daily practice. Specialized care models might facilitate optimized OAC therapy with both VKAs and DOACs. PMID- 29258155 TI - Standards for Ethics in Sport and Exercise Science Research: 2018 Update. PMID- 29258152 TI - The Combination of Fosfomycin, Metronidazole, and Recombinant Human Granulocyte Macrophage Colony-Stimulating Factor is Stable in vitro and Has Maintained Antibacterial Activity. AB - BACKGROUND: Treatment of secondary peritonitis includes surgery and antimicrobial agents. Antimicrobial agents are often administered intravenously, however, the alternative route intraperitoneal administration could be considered. Investigations must be conducted prior to clinical application. Therefore, we aimed to investigate the combination of fosfomycin, metronidazole, and recombinant human granulocyte-macrophage colony-stimulating factor with regard to its chemical properties and the solution's stability. In addition, the antibacterial effect of the mixed drug solution was compared with the effect of the individual antibacterial agents. METHODS: The drugs were mixed to an aqueous solution. Basic chemical investigations of pH, precipitation, and calculated osmolarity of the drug combination were conducted. Fosfomycin and metronidazole's chemical stability was investigated using High Pressure Liquid Chromatography Mass Spectrometry. Microbiological investigations using the agar cup method were carried out to measure the antibacterial effect of fosfomycin and metronidazole. RESULTS: The aqueous solution of the combination of the three drugs had a pH of 7.46-7.62, which was stable during 24 h, was without precipitation, and had a calculated osmolarity of 293 mOsm/l. High Pressure Liquid Chromatography-Mass Spectrometry found stable concentrations of fosfomycin and metronidazole both alone and in combination during 24 h. The antibacterial effect of the drug combination solution was similar to the antibacterial effects of fosfomycin and metronidazole alone. CONCLUSION: The drug combination had neutral and stable pH, was iso-osmotic, and had stable concentrations during 24 h of storage. The antibacterial effect of fosfomycin and metronidazole were not altered when the drugs were mixed. PMID- 29258157 TI - How do Parents Perceive the Initial Medical Consultation on their Child's Developmental Disorder? AB - BACKGROUND: A developmental disorder of a child has a major impact on the affected families' lives. However, data about the parents' perception of the revealing of the diagnosis is scarce. PATIENTS AND METHODS: Parents of children with developmental disorder treated as outpatients in a university hospital were interviewed about the initial medical consultation concerning the diagnosis of their child. RESULTS: Parents of 210 children agreed to take part in the study. 35/210 (17%) had to be excluded from the study as they were not able to remember the initial medical consultation, or claimed there was either no initial medical consultation or they did not attend it. The diagnosis of developmental disorder was made in median 4 months (Q25/Q75: 0/12; min/max: 0/63) after the parents had noticed the first symptoms. According to the parents, options to support the development of the child were the most frequently addressed topic in the initial medical consultation (119/175, 68%). Some parents wished more empathy (19/175, 11%), and less medical terminology (12/175, 7%). 114/175 (65%) of parents rated the initial medical consultation as "very good" or "good". After their initial medical consultation, 66/175 (38%) of the parents had open questions mainly concerning the prognosis of the disease. Sources of information that were used after the consultation were most often the treating physician (150/175, 86%) and the internet (133/175, 76%). CONCLUSION: Generally, parents perceive the initial medical consultation on the developmental disorder of their child well. Nevertheless, many parents state that they had unanswered questions after the consultation. The internet is one of the main sources parents use to answer those questions. PMID- 29258158 TI - Neurodevelopmental Outcome in Children With Single Ventricle After Total Cavopulmonary Connection. AB - BACKGROUND: The purpose of the present study was to assess a broad range of neuropsychological outcome variables in children with functionally single ventricle hearts after a total cavopulmonary connection and to examine potential risk factors for impaired neurodevelopment. PATIENTS & METHOD: A total of 104 patients aged 2 to 20 years underwent follow-up standardized psychological testing, including measures of intelligence, motor function, visuospatial abilities, behavioural outcome and health-related quality of life. RESULTS: With a mean fluid intelligence score of 93.0 and a mean crystallized intelligence score of 92.3, patients scored significantly lower on tests of intelligence compared to the general population (p<0.001). Reduced motor function was found in 34% of the patients (p<0.001), impaired visuospatial abilities in 51%; parents reported significantly more behavioural problems (p<0.001). There was no difference in the self-reported quality of life compared to the general population. Risk factors for reduced fluid intelligence were deep hypothermic circulatory arrest times (p=0.03) and complications causing suboptimal brain perfusion prior to the total cavopulmonary connection (e. g. seizures; p=0.04). CONCLUSIONS: Patients with functionally single ventricle hearts palliated with a total cavopulmonary connection are at an increased risk of neurodevelopmental delays and behavioural disorders. Nevertheless, they adapt well in terms of quality of life. Early diagnostics and interventions are necessary when developmental delays are suspected. PMID- 29258159 TI - [Access to Early Childhood Interventions in Childrens Hospital: Screening as Clinical Routine Procedure - Exploration and Transfer by a Specialized Team]. AB - BACKGROUND: In order to prevent risks associated with insufficient family care, it is mandatory to provide early childhood interventions for parents unable to cope with their young children in best time. Childrens hospitals represent one pillar that hasn't been fully explored yet. METHODS: As a proof-of-concept, we performed a study to determine the feasibility of a standardized risk assessment tool during routine work of doctors and nurses in a university department. RESULTS: Our data indicate that a standardized screen to assess stress is powerful in identifying stressed parents, especially those with children under the age of one year. In this context, psychosocial stress in families with newborns was most frequently indicated. The placement rates into early childhood interventions (8.5%) and youth welfare services (11.3%) correspond to the literature. DISCUSSION AND CONCLUSION: The standardized risk assessment tool can be used as a "call button" and delivers a basis for further differentiated exploration of the families by a specialized team and might be used to deliver services for these families. In summary children's hospitals might be useful to provide a low-threshold access into early childhood interventions. PMID- 29258160 TI - [Undetected Cases of Non-Accidental Burns in Children - Preventive Strategies]. AB - BACKGROUND: Thermal injuries are a frequent cause of accidents within the pediatric population that may result in long periods of hospitalization as well as severe physical and mental impairment and lifelong consequences. Especially in infants, burns caused by scalding are the most common cause of injury. Beside accidental injuries, intential burns may also occur. It is of utmost importance to differentiate between intentional and accidental burns, yet the distinction can be very demanding for physicians, nurses and social workers. METHODS: In this retrospective multicenter study, thermally inflicted burns in Germany were analyzed over a period of 10 years. RESULTS: Data of 13.353 pediatric patients with thermal injuries from 32 hospitals were analyzed within the period of 2006 to 2015. The study results show that 0,5% of all burns were inflicted. This percentage seems to be an inadequate represention as compared to reported international surveys, which report an average of 10% of all burns being inflicted in pediatric patients. DISCUSSION: When comparing our results to international survey results, it can be assumed that a large number of child abuse cases go undetected within the German pediatric population. In particular awareness of intentional burns needs to be raised and detection strategies, as presented in this paper, implemented. CONCLUSION: In the future, a more precise collection of data of burned children is necessary to illustrate the true number of intentional pediatric burns in Germany. This has been implemented by the renewed pediatric burn registry of the German Society for Burn Treatment (DGV) and the working group "The severely burned child". PMID- 29258161 TI - [Interdisciplinary Concepts of Paediatrics and Clinical Pharmacy to Optimise Anticonvulsant Treatment]. AB - Expertise in a variety of fields is required for the diagnostic process of epilepsies in children and adolescents as well as for their treatment with anticonvulsants. Patients benefit in the process from the cooperation of different health care professionals. It is of critical importance for risks to be minimised and for the efficacy shown in controlled clinical trials to be maintained in routine conditions. In the first instance, drug prescription procedures, including the choice of anticonvulsants and combinations of drugs and dosing, have to be considered. The administration of drugs has, of course, also to be taken into account. Only if patients are given their anticonvulsants appropriately, the intended success of the therapy can be accomplished. Strategies aimed at improving drug administration have to be directed not only at nurses but also at parents, children and adolescents themselves, as well as caregivers in schools and children's day-care facilities. By providing theoretical teaching, practical training, and routinely including pharmacists in the therapeutic team, drug-related problems that may result in limited effectiveness and increased risks are prevented. As a result, drug (therapy) safety is not only qualitatively improved, but the degree of participation and quality of life of patients and families is improved as well. PMID- 29258162 TI - Are Diatoms "Green" Aluminosilicate Synthesis Microreactors for Future Catalyst Production? AB - Diatom biosilica may offer an interesting perspective in the search for sustainable solutions meeting the high demand for heterogeneous catalysts. Diatomaceous earth (diatomite), i.e., fossilized diatoms, is already used as adsorbent and carrier material. While diatomite is abundant and inexpensive, freshly harvested and cleaned diatom cell walls have other advantages, with respect to purity and uniformity. The present paper demonstrates an approach to modify diatoms both in vivo and in vitro to produce a porous aluminosilicate that is serving as a potential source for sustainable catalyst production. The obtained material was characterized at various processing stages with respect to morphology, elemental composition, surface area, and acidity. The cell walls appeared normal without morphological changes, while their aluminum content was raised from the molar ratio n(Al):n(Si) 1:600 up to 1:50. A specific surface area of 55 m2/g was measured. The acidity of the material increased from 149 to 320 umol NH3/g by ion exchange, as determined by NH3 TPD. Finally, the biosilica was examined by an acid catalyzed test reaction, the alkylation of benzene. While the cleaned cell walls did not catalyze the reaction at all, and the ion exchanged material was catalytically active. This demonstrates that modified biosilica does indeed has potential as a basis for future catalytically active materials. PMID- 29258164 TI - An Approach for the Dynamic Measurement of Ring Gear Strains of Planetary Gearboxes Using Fiber Bragg Gratings. AB - The strain of the ring gear can reflect the dynamic characteristics of planetary gearboxes directly, which makes it an ideal signal to monitor the health condition of the gearbox. To overcome the disadvantages of traditional methods, a new approach for the dynamic measurement of ring gear strains using fiber Bragg gratings (FBGs) is proposed in this paper. Firstly, the installation of FBGs is determined according to the analysis for the strain distribution of the ring gear. Secondly, the parameters of the FBG are determined in consideration of the accuracy and sensitivity of the measurement as well as the size of the ring gear. The strain measured by the FBG is then simulated under non-uniform strain field conditions. Thirdly, a dynamic measurement system is built and tested. Finally, the strains of the ring gear are measured in a planetary gearbox under normal and faulty conditions. The experimental results showed good agreement with the theoretical results in values, trends, and the fault features can be seen from the time domain of the measured strain signal, which proves that the proposed method is feasible for the measurement of the ring gear strains of planetary gearboxes. PMID- 29258165 TI - Control of Scaphoideus titanus with Natural Products in Organic Vineyards. AB - The leafhopper Scaphoideus titanus is the vector of 'Candidatus Phytoplasma vitis', the causal agent of Flavescence doree (FD) a key disease for European viticulture. In organic vineyards, the control of S. titanus relies mostly on the use of pyrethrins that have suboptimal efficacy. During 2016, three field trials were conducted to evaluate the efficacy of kaolin, orange oil, insecticidal soap and spinosad against S. titanus nymphs, in comparison with pyrethrins. The activity of kaolin was evaluated also in the laboratory. In all field trials, kaolin had an efficacy against nymphs comparable to pyrethrins, while the other products were not effective. Laboratory results confirmed that kaolin increased nymph mortality. In organic vineyards, kaolin and pyrethrins are valuable tools in the management of FD. Nevertheless, their efficacy is lower compared to that of the synthetic insecticides used in conventional viticulture. Therefore, further research should be conducted in order to identify alternatives to synthetic insecticides for S. titanus control in the context of organic viticulture. PMID- 29258163 TI - Regulation of EMT in Colorectal Cancer: A Culprit in Metastasis. AB - Epithelial to mesenchymal transition (EMT) is a process during which cells lose their epithelial characteristics, for instance cell polarity and cell-cell contact, and gain mesenchymal properties, such as increased motility. In colorectal cancer (CRC), EMT is associated with an invasive or metastatic phenotype. In this review, we discuss recent studies exploring novel regulation mechanisms of EMT in CRC, including the identification of new CRC EMT regulators. Upregulation of inducers can promote EMT, leading to increased invasiveness and metastasis in CRC. These inducers can downregulate E-cadherin and upregulate N cadherin and vimentin (VIM) through modulating EMT-related signaling pathways, for instance WNT/beta-catenin and TGF-beta, and EMT transcription factors, such as zinc finger E-box binding homeobox 1 (ZEB1) and ZEB2. In addition, several microRNAs (miRNAs), including members of the miR-34 and miR-200 families, are found to target mRNAs of EMT-transcription factors, for example ZEB1, ZEB2, or SNAIL. Downregulation of these miRNAs is associated with distant metastasis and advanced stage tumors. Furthermore, the role of EMT in circulating tumor cells (CTCs) is also discussed. Mesenchymal markers on the surface of EMT CTCs were found to be associated with metastasis and could serve as potential biomarkers for metastasis. Altogether, these studies indicate that EMT is orchestrated by a complicated network, involving regulators of different signaling pathways. Further studies are required to understand the mechanisms underlying EMT in CRC. PMID- 29258166 TI - POFBG-Embedded Cork Insole for Plantar Pressure Monitoring. AB - We propose a novel polymer optical fiber (POF) sensing system based on fiber Bragg gratings (FBGs) to measure foot plantar pressure. The plantar pressure signals are detected by five FBGs, in the same piece of cyclic transparent optical polymer (CYTOP) fiber, which are embedded in a cork insole for the dynamic monitoring of gait. The calibration and measurements performed with the suggested system are presented, and the results obtained demonstrate the accuracy and reliability of the sensing platform to monitor the foot plantar pressure distribution during gait motion and the application of pressure. This architecture does not compromise the patient's mobility nor interfere in their daily activities. The results using the CYTOP fiber showed a very good response when compared with solutions using silica optical fibers, resulting in a sensitivity almost twice as high, with excellent repeatability and ease of handling. The advantages of POF (e.g., high flexibility and robustness) proved that this is a viable solution for this type of application, since POF's high fracture toughness enables its application in monitoring patients with higher body mass compared with similar systems based on silica fiber. This study has demonstrated the viability of the proposed system based on POF technology as a useful alternative for plantar pressure detection systems. PMID- 29258167 TI - Small Water Enterprise in Rural Rwanda: Business Development and Year-One Performance Evaluation of Nine Water Kiosks at Health Care Facilities. AB - Small water enterprises (SWEs) have lower capital expenditures than centralized systems, offering decentralized solutions for rural markets. This study evaluated SWEs in rural Rwanda, where nine health care facilities (HCF) owned and operated water kiosks supplying water from onsite water treatment systems (WTS). SWEs were monitored for 12 months. Spearman's Rank Correlation Coefficient (rs) was used to evaluate correlations between demand for kiosk water and community characteristics, and between kiosk profit and factors influencing the cost model. On average, SWEs distributed 15,300 L/month. One SWE ran at a loss, four had profit margins of <=10% and four had profit margins of 45-75%. Factors influencing SWE performance were intermittent water supply (87% of SWE closures were due to water shortage), consumer demand (demand was high where populations already used improved water sources (rs = 0.81, p = 0.02)), price sensitivity (demand was lower where SWEs had high prices (rs = -0.65, p = 0.08)), and production cost (water utility tariffs negatively impacted SWE profits (rs = 0.52, p < 0.01)). Sustainability was more favorable in circumstances where recovery of capital expenditures was not expected, and the demand for treated water was sufficient to fund operational expenditures. Future research is needed to assess the extent to which kiosk revenue can support ongoing operational costs of WTS and kiosks both at HCF and in other contexts. PMID- 29258168 TI - Bioremediation of Synthetic and Industrial Effluents by Aspergillus niger Isolated from Contaminated Soil Following a Sequential Strategy. AB - The present study aimed to assess and compare the ability to remediate synthetic textile and industrial wastewaters by Fenton treatment, a biological system and sequential treatments using Aspergillus niger (A. niger). All studied treatments were found to be effective in decolorization of the effluents under study. Fenton treatment followed by A. niger showed excellent potential for the maximum decolorization of the synthetic and industrial effluents under study. The effectiveness of sequential treatment was evaluated by water quality parameters such as total organic carbon (TOC), Biological Oxygen Demand (BOD5) and Chemical Oxygen Demand (COD) before and after each treatment. The results indicated that A. niger is an effective candidate for detoxification of textile wastewaters. PMID- 29258170 TI - Enhanced Activity of Au/NiO Nanohybrids for the Reductive Amination of Benzyl Alcohol. AB - Gold nanoparticles were prepared by sol immobilization (AuSI) or deposition precipitation (AuDP), then deposited on NiO and commercial TiO2 (P25). The Au/NiO catalysts showed higher activity and yield to the secondary amine, compared to Au/TiO2 catalysts, when tested for the reductive amination of benzyl alcohol with isopropylamine. We attribute this result to a synergistic effect between Au and NiO. Moreover, as a result of the protective effect of the polyvinyl alcohol used in the sol immobilization synthesis, the gold nanoparticles on NiO demonstrate an increased resistance to structural changes during the reaction. This effect results in enhanced catalytic efficiency in terms of activity, and better stability against deactivation. PMID- 29258169 TI - Botulinum Toxin in the Field of Dermatology: Novel Indications. AB - Since its approval by the US Food and Drug Administration in 2002 for glabellar wrinkles, botulinum toxin (BTX) has been widely used to correct facial wrinkles. As a result, many consider BTX synonymous with cosmetic dermatology. Recent studies indicate that BTX elicits biological effects on various skin cell types via the modulation of neurotransmitter release, and it seems that BTX has a wider zone of dermatologic influence than originally understood. Clinicians and researchers are now beginning to explore the potential of BTX beyond the amelioration of facial lines and encouraging results are seen with BTX in a variety of skin conditions. In this paper, we review novel dermatological indications of BTX which includes (but not limited to) scar prevention, facial flushing, post-herpetic neuralgia and itch. These areas show great promise, but there is definite need for larger, double-blinded, randomized control trials against established treatments before BTX becomes a clinical reality. PMID- 29258171 TI - Synthesis of TiO2 with Hierarchical Porosity for the Photooxidation of Propene. AB - The elimination of volatile organic compounds (VOCs) at low concentration is a subject of great interest because these compounds are very harmful for the environment and human health. In this work, we have developed a synthesis methodology of TiO2 that allows obtaining meso-macroporous materials with hierarchical porosity and with high thermal stability for their application as photocatalysts in the removal of VOCs, specifically propene. The materials synthesized in this work were characterized by Scanning electron microscope (SEM), Transmission electron microscopy (TEM), powder X-ray diffraction (XRD), Thermogravimetric Analysis (TG), and nitrogen adsorption. It is observed that the samples calcined at 250 degrees C and 500 degrees C present a high photoactivity for the photooxidation of propene, which is similar to the benchmark material P25 (commercial TiO2). Moreover, the textural properties are better than those for P25, indicating that the samples are interesting for the preparation of photocatalysts with different conformations, such as in the form of coatings and fillings in different size scales. PMID- 29258172 TI - Development and Assessment of a 3D-Printed Scaffold with rhBMP-2 for an Implant Surgical Guide Stent and Bone Graft Material: A Pilot Animal Study. AB - In this study, a new concept of a 3D-printed scaffold was introduced for the accurate placement of an implant and the application of a recombinant human bone morphogenetic protein-2 (rhBMP-2)-loaded bone graft. This preliminary study was conducted using two adult beagles to evaluate the 3D-printed polycaprolactone (PCL)/beta-tricalcium phosphate (beta-TCP)/bone decellularized extracellular matrix (bdECM) scaffold conjugated with rhBMP-2 for the simultaneous use as an implant surgical guide stent and bone graft material that promotes new bone growth. Teeth were extracted from the mandible of the beagle model and scanned by computed tomography (CT) to fabricate a customized scaffold that would fit the bone defect. After positioning the implant guide scaffold, the implant was placed and rhBMP-2 was injected into the scaffold of the experimental group. The two beagles were sacrificed after three months. The specimen block was obtained and scanned by micro-CT. Histological analysis showed that the control and experimental groups had similar new bone volume (NBV, %) but the experimental group with BMP exhibited a significantly higher bone-to-implant contact ratio (BIC, %). Within the limitations of this preliminary study, a 3D-printed scaffold conjugated with rhBMP-2 can be used simultaneously as an implant surgical guide and a bone graft in a large bone defect site. Further large-scale studies will be needed to confirm these results. PMID- 29258173 TI - Correction: Development of Novel Faster-Dissolving Microneedle Patches for Transcutaneous Vaccine Delivery. Pharmaceutics, 2017, 9(3), 27. AB - The authors wish to make a change to their published paper [1].[...]. PMID- 29258174 TI - Co-Enzyme Q10 and n-3 Polyunsaturated Fatty Acid Supplementation Reverse Intermittent Hypoxia-Induced Growth Restriction and Improved Antioxidant Profiles in Neonatal Rats. AB - Neonatal intermittent hypoxia (IH) increases the risk for many morbidities in extremely low birth weight/gestational age (ELBW/ELGA) neonates with compromised antioxidant systems and poor growth. We hypothesized that supplementation with coenzyme Q10 (CoQ10, ubiquinol) or n-3 polyunsaturated fatty acids (PUFAs) during neonatal IH improves antioxidant profiles and somatic growth in neonatal rats. Newborn rats were exposed to two IH paradigms at birth (P0): (1) 50% O2 with brief hypoxic episodes (12% O2); or (2) room air (RA) with brief hypoxia, until P14 during which they received daily oral CoQ10 in olive oil, n-3 PUFAs in fish oil, or olive oil only from P0 to P14. Pups were studied at P14 or placed in RA until P21 for recovery from IH (IHR). Body weight and length; organ weights; and serum antioxidants and growth factors were determined at P14 and P21. Neonatal IH resulted in sustained reductions in somatic growth, an effect that was reversed with n-3 PUFAs. Improved growth was associated with higher serum growth factors. CoQ10 decreased superoxide dismutase (SOD) and glutathione, but increased catalase, suggesting reduced oxidative stress. Further studies are needed to determine the synergistic effects of CoQ10 and n-3 PUFA co-administration for the prevention of IH-induced oxidative stress and postnatal growth deficits. PMID- 29258176 TI - Wireless Concrete Strength Monitoring of Wind Turbine Foundations. AB - Wind turbine foundations are typically cast in place, leaving the concrete to mature under environmental conditions that vary in time and space. As a result, there is uncertainty around the concrete's initial performance, and this can encourage both costly over-design and inaccurate prognoses of structural health. Here, we demonstrate the field application of a dense, wireless thermocouple network to monitor the strength development of an onshore, reinforced-concrete wind turbine foundation. Up-to-date methods in fly ash concrete strength and maturity modelling are used to estimate the distribution and evolution of foundation strength over 29 days of curing. Strength estimates are verified by core samples, extracted from the foundation base. In addition, an artificial neural network, trained using temperature data, is exploited to demonstrate that distributed concrete strengths can be estimated for foundations using only sparse thermocouple data. Our techniques provide a practical alternative to computational models, and could assist site operators in making more informed decisions about foundation design, construction, operation and maintenance. PMID- 29258175 TI - Capsaicin: Friend or Foe in Skin Cancer and Other Related Malignancies? AB - Capsaicin is the main pungent in chili peppers, one of the most commonly used spices in the world; its analgesic and anti-inflammatory properties have been proven in various cultures for centuries. It is a lipophilic substance belonging to the class of vanilloids and an agonist of the transient receptor potential vanilloid 1 receptor. Taking into consideration the complex neuro-immune impact of capsaicin and the potential link between inflammation and carcinogenesis, the effect of capsaicin on muco-cutaneous cancer has aroused a growing interest. The aim of this review is to look over the most recent data regarding the connection between capsaicin and muco-cutaneous cancers, with emphasis on melanoma and muco cutaneous squamous cell carcinoma. PMID- 29258178 TI - Early Steps in Automated Behavior Mapping via Indoor Sensors. AB - Behavior mapping (BM) is a spatial data collection technique in which the locational and behavioral information of a user is noted on a plan layout of the studied environment. Among many indoor positioning technologies, we chose Wi-Fi, BLE beacon and ultra-wide band (UWB) sensor technologies for their popularity and investigated their applicability in BM. We tested three technologies for error ranges and found an average error of 1.39 m for Wi-Fi in a 36 m2 test area (6 m * 6 m), 0.86 m for the BLE beacon in a 37.44 m2 test area (9.6 m * 3.9 m) and 0.24 m for ultra-wide band sensors in a 36 m2 test area (6 m * 6 m). We simulated the applicability of these error ranges for real-time locations by using a behavioral dataset collected from an active learning classroom. We used two UWB tags simultaneously by incorporating a custom-designed ceiling system in a new 39.76 m2 test area (7.35 m * 5.41 m). We considered 26 observation points and collected data for 180 s for each point (total 4680) with an average error of 0.2072 m for 23 points inside the test area. Finally, we demonstrated the use of ultra-wide band sensor technology for BM. PMID- 29258179 TI - Material State Awareness for Composites Part I: Precursor Damage Analysis Using Ultrasonic Guided Coda Wave Interferometry (CWI). AB - Detection of precursor damage followed by the quantification of the degraded material properties could lead to more accurate progressive failure models for composite materials. However, such information is not readily available. In composite materials, the precursor damages-for example matrix cracking, microcracks, voids, interlaminar pre-delamination crack joining matrix cracks, fiber micro-buckling, local fiber breakage, local debonding, etc.-are insensitive to the low-frequency ultrasonic guided-wave-based online nondestructive evaluation (NDE) or Structural Health Monitoring (SHM) (~100-~500 kHz) systems. Overcoming this barrier, in this article, an online ultrasonic technique is proposed using the coda part of the guided wave signal, which is often neglected. Although the first-arrival wave packets that contain the fundamental guided Lamb wave modes are unaltered, the coda wave packets however carry significant information about the precursor events with predictable phase shifts. The Taylor series-based modified Coda Wave Interferometry (CWI) technique is proposed to quantify the stretch parameter to compensate the phase shifts in the coda wave as a result of precursor damage in composites. The CWI analysis was performed on five woven composite-fiber-reinforced-laminate specimens, and the precursor events were identified. Next, the precursor damage states were verified using high-frequency Scanning Acoustic Microscopy (SAM) and optical microscopy imaging. PMID- 29258177 TI - In Vitro Toxicological Assessment of Cylindrospermopsin: A Review. AB - Cylindrospermopsin (CYN) is a cyanobacterial toxin that is gaining importance, owing to its increasing expansion worldwide and the increased frequency of its blooms. CYN mainly targets the liver, but also involves other organs. Various mechanisms have been associated with its toxicity, such as protein synthesis inhibition, oxidative stress, etc. However, its toxic effects are not yet fully elucidated and additional data for hazard characterization purposes are required. In this regard, in vitro methods can play an important role, owing to their advantages in comparison to in vivo trials. The aim of this work was to compile and evaluate the in vitro data dealing with CYN available in the scientific literature, focusing on its toxicokinetics and its main toxicity mechanisms. This analysis would be useful to identify research needs and data gaps in order to complete knowledge about the toxicity profile of CYN. For example, it has been shown that research on various aspects, such as new emerging toxicity effects, the toxicity of analogs, or the potential interaction of CYN with other cyanotoxins, among others, is still very scarce. New in vitro studies are therefore welcome. PMID- 29258181 TI - PRIMA-1 and PRIMA-1Met (APR-246): From Mutant/Wild Type p53 Reactivation to Unexpected Mechanisms Underlying Their Potent Anti-Tumor Effect in Combinatorial Therapies. AB - p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis. Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein. Accordingly, reactivation of p53 appears as a quite promising pharmacological approach and, effectively, several attempts have been made in that sense. The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1Met (APR 246), that are at an advanced stage of development, with several clinical trials in progress. Based on publications referenced in PubMed since 2002, here we review the reported effects of these compounds on cancer cells, with a specific focus on their ability of p53 reactivation, an overview of their unexpected anti cancer effects, and a presentation of the investigated drug combinations. PMID- 29258182 TI - Tumor Microenvironment and Metabolism. AB - The tumor microenvironment has profound effects on cancer development, progression, and therapeutic response. [...]. PMID- 29258180 TI - Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma. AB - Glioblastoma (GBM) is considered one of the most malignant, genetically heterogeneous, and therapy-resistant solid tumor. Therapeutic options are limited in GBM and involve surgical resection followed by chemotherapy and/or radiotherapy. Adjuvant therapies, including antiangiogenic treatments (AATs) targeting the VEGF-VEGFR pathway, have witnessed enhanced infiltration of bone marrow-derived myeloid cells, causing therapy resistance and tumor relapse in clinics and in preclinical models of GBM. This review article is focused on gathering previous clinical and preclinical reports featuring major challenges and lessons in GBM. Potential combination therapies targeting the tumor microenvironment (TME) to overcome the myeloid cell-mediated resistance problem in GBM are discussed. Future directions are focused on the use of TME-directed therapies in combination with standard therapy in clinical trials, and the exploration of novel therapies and GBM models for preclinical studies. We believe this review will guide the future of GBM research and therapy. PMID- 29258183 TI - The Lung Microbiome in Idiopathic Pulmonary Fibrosis: A Promising Approach for Targeted Therapies. AB - This review focuses on the role of the lung microbiome in idiopathic pulmonary fibrosis. Although historically considered sterile, bacterial communities have now been well documented in lungs both in healthy and pathological conditions. Studies in idiopathic pulmonary fibrosis (IPF) suggest that increased bacterial burden and/or abundance of potentially pathogenic bacteria may drive disease progression, acute exacerbations, and mortality. More recent work has highlighted the interaction between the lung microbiome and the innate immune system in IPF, strengthening the argument for the role of both host and environment interaction in disease pathogenesis. Existing published data suggesting that the lung microbiome may represent a therapeutic target, via antibiotic administration, immunization against pathogenic organisms, or treatment directed at gastroesophageal reflux. Taken altogether, published literature suggests that the lung microbiome might serve in the future as a prognostic biomarker, a therapeutic target, and/or provide an explanation for disease pathogenesis in IPF. PMID- 29258184 TI - Lysophospholipid-Related Diseases and PPARgamma Signaling Pathway. AB - The nuclear receptor superfamily includes ligand-inducible transcription factors that play diverse roles in cell metabolism and are associated with pathologies such as cardiovascular diseases. Lysophosphatidic acid (LPA) belongs to a family of lipid mediators. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and an intracellular nuclear hormone receptor. In addition, several enzymes that utilize LPA as a substrate or generate it as a product are under its regulatory control. Recent studies have demonstrated that the endogenously produced peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist cyclic phosphatidic acid (cPA), which is structurally similar to LPA, inhibits cancer cell invasion and metastasis in vitro and in vivo. We recently observed that cPA negatively regulates PPARgamma function by stabilizing the binding of the co-repressor protein, a silencing mediator of retinoic acid, and the thyroid hormone receptor. We also showed that cPA prevents neointima formation, adipocyte differentiation, lipid accumulation, and upregulation of PPARgamma target gene transcription. The present review discusses the arbitrary aspects of the physiological and pathophysiological actions of lysophospholipids in vascular and nervous system biology. PMID- 29258185 TI - Do Clinicians Ask Pregnant Women about Exposures to Tobacco and Cannabis Smoking, Second-Hand-Smoke and E-Cigarettes? An Australian National Cross-Sectional Survey. AB - Clinicians often ask pregnant women about tobacco smoking, but their practices of asking about other smoking and nicotine exposures are unknown. This study analysed how often clinicians ask pregnant women about their use of e-cigarettes, cannabis, chewing tobacco, and second-hand smoke (SHS) exposure. Two cross sectional surveys were undertaken. A random sample of 500 General Practitioner (GP) members were invited from the National Faculty of Aboriginal and Torres Strait Islander Health (NFATSIH) to complete an on-line survey, and 5571 GP and Obstetrician (OBS) members of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) were sent a paper survey by mail. Questions on frequency of asking about the exposures used Likert Scales, later dichotomized to "often-always" and "never-sometimes". Logistic regressions estimated associations between clinician type and asking about cannabis, e cigarettes, chewing tobacco, and SHS. An adjusted model reduced potential confounders of location, guidelines, gender and population. n = 378 GPs and OBS participated (6.2% response). In total, 13-14% asked "often-always" about e cigarettes; 58% cannabis; 38% cannabis with tobacco; 27% SHS, and 10% chewing tobacco-compared to 95% of the sample asking about cigarette smoking. After adjustment, the odds of RANZCOG GPs (OR 0.34) and OBS (OR 0.63) asking about cannabis were lower compared to NFATSIH GPs. Clinician type was non-significant for asking about e-cigarettes, chewing tobacco and SHS. Surveyed Australian GPs and obstetricians asked less frequently about e-cigarettes, chewing, SHS exposure, and cannabis, potentially missing important exposures for mother and child. PMID- 29258186 TI - The Influence of the Osmotic Dehydration Process on Physicochemical Properties of Osmotic Solution. AB - The osmotic dehydration (OD) process consists of the removal of water from a material during which the solids from the osmotic solution are transported to the material by osmosis. This process is commonly performed in sucrose and salt solutions. Taking into account that a relatively high consumption of those substances might have a negative effect on human health, attempts have been made to search for alternatives that can be used for osmotic dehydration. One of these is an application of chokeberry juice with proven beneficial properties to human health. This study aimed to evaluate the physicochemical properties of the OD solution (chokeberry juice concentrate) before and after the osmotic dehydration of carrot and zucchini. The total polyphenolics content, antioxidant capacity (ABTS, FRAP), dynamic viscosity, density, and water activity were examined in relation to the juice concentration used for the osmotic solution before and after the OD process. During the osmotic dehydration process, the concentration of the chokeberry juice decreased. Compounds with lower molecular weight and lower antioxidant capacity present in concentrated chokeberry juice had a stronger influence on the exchange of compounds during the OD process in carrot and zucchini. The water activity of the osmotic solution increased after the osmotic dehydration process. It was concluded that the osmotic solution after the OD process might be successfully re-used as a product with high quality for i.e. juice production. PMID- 29258187 TI - Usefulness of Amino Acid Profiling in Ovarian Cancer Screening with Special Emphasis on Their Role in Cancerogenesis. AB - The aim of this study was to quantitate 42 serum-free amino acids, propose the biochemical explanation of their role in tumor development, and identify new ovarian cancer (OC) biomarkers for potential use in OC screening. The additional value of this work is the schematic presentation of the interrelationship between metabolites which were identified as significant for OC development and progression. The liquid chromatography-tandem mass spectrometry technique using highly-selective multiple reaction monitoring mode and labeled internal standards for each analyzed compound was applied. Performed statistical analyses showed that amino acids are potentially useful as OC biomarkers, especially as variables in multi-marker models. For the distinguishing metabolites the following metabolic pathways involved in cancer growth and development were proposed: histidine metabolism; tryptophan metabolism; arginine biosynthesis; arginine and proline metabolism; and alanine, aspartate and glutamine metabolism. The presented research identifies histidine and citrulline as potential new OC biomarkers. Furthermore, it provides evidence that amino acids are involved in metabolic pathways related to tumor growth and play an important role in cancerogenesis. PMID- 29258188 TI - Preclinical Imaging for the Study of Mouse Models of Thyroid Cancer. AB - Thyroid cancer, which represents the most common tumors among endocrine malignancies, comprises a wide range of neoplasms with different clinical aggressiveness. One of the most important challenges in research is to identify mouse models that most closely resemble human pathology; other goals include finding a way to detect markers of disease that common to humans and mice and to identify the most appropriate and least invasive therapeutic strategies for specific tumor types. Preclinical thyroid imaging includes a wide range of techniques that allow for morphological and functional characterization of thyroid disease as well as targeting and in most cases, this imaging allows quantitative analysis of the molecular pattern of the thyroid cancer. The aim of this review paper is to provide an overview of all of the imaging techniques used to date both for diagnosis and theranostic purposes in mouse models of thyroid cancer. PMID- 29258189 TI - Choice of Magnetometers and Gradiometers after Signal Space Separation. AB - BACKGROUND: Modern Elekta Neuromag MEG devices include 102 sensor triplets containing one magnetometer and two planar gradiometers. The first processing step is often a signal space separation (SSS), which provides a powerful noise reduction. A question commonly raised by researchers and reviewers relates to which data should be employed in analyses: (1) magnetometers only, (2) gradiometers only, (3) magnetometers and gradiometers together. The MEG community is currently divided with regard to the proper answer. METHODS: First, we provide theoretical evidence that both gradiometers and magnetometers result from the backprojection of the same SSS components. Then, we compare resting state and task-related sensor and source estimations from magnetometers and gradiometers in real MEG recordings before and after SSS. RESULTS: SSS introduced a strong increase in the similarity between source time series derived from magnetometers and gradiometers (r2 = 0.3-0.8 before SSS and r2 > 0.80 after SSS). After SSS, resting state power spectrum and functional connectivity, as well as visual evoked responses, derived from both magnetometers and gradiometers were highly similar (Intraclass Correlation Coefficient > 0.8, r2 > 0.8). CONCLUSIONS: After SSS, magnetometer and gradiometer data are estimated from a single set of SSS components (usually <= 80). Equivalent results can be obtained with both sensor types in typical MEG experiments. PMID- 29258191 TI - Patient Safety in Complementary Medicine through the Application of Clinical Risk Management in the Public Health System. AB - Aim: To develop a systematic approach to detect and prevent clinical risks in complementary medicine (CM) and increase patient safety through the analysis of activities in homeopathy and acupuncture centres in the Tuscan region using a significant event audit (SEA) and failure modes and effects analysis (FMEA). Methods: SEA is the selected tool for studying adverse events (AE) and detecting the best solutions to prevent future incidents in our Regional Healthcare Service (RHS). This requires the active participation of all the actors and external experts to validate the analysis. FMEA is a proactive risk assessment tool involving the selection of the clinical process, the input of a multidisciplinary group of experts, description of the process, identification of the failure modes (FMs) for each step, estimates of the frequency, severity, and detectability of FMs, calculation of the risk priority number (RPN), and prioritized improvement actions to prevent FMs. Results: In homeopathy, the greatest risk depends on the decision to switch from allopathic to homeopathic therapy. In acupuncture, major problems can arise, mainly from delayed treatment and from the modalities of needle insertion. Conclusions: The combination of SEA and FMEA can reveal potential risks for patients and suggest actions for safer and more reliable services in CM. PMID- 29258190 TI - IFN-beta: A Contentious Player in Host-Pathogen Interaction in Tuberculosis. AB - Tuberculosis (TB) is a major health threat to the human population worldwide. The etiology of the disease is Mycobacterium tuberculosis (Mtb), a highly successful intracellular pathogen. It has the ability to manipulate the host immune response and to make the intracellular environment suitable for its survival. Many studies have addressed the interactions between the bacteria and the host immune cells as involving many immune mediators and other cellular players. Interferon-beta (IFN beta) signaling is crucial for inducing the host innate immune response and it is an important determinant in the fate of mycobacterial infection. The role of IFN beta in protection against viral infections is well established and has been studied for decades, but its role in mycobacterial infections remains much more complicated and debatable. The involvement of IFN-beta in immune evasion mechanisms adopted by Mtb has been an important area of investigation in recent years. These advances have widened our understanding of the pro-bacterial role of IFN-beta in host-pathogen interactions. This pro-bacterial activity of IFN-beta appears to be correlated with its anti-inflammatory characteristics, primarily by antagonizing the production and function of interleukin 1beta (IL-1beta) and interleukin 18 (IL-18) through increased interleukin 10 (IL-10) production and by inhibiting the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome. Furthermore, it also fails to provoke a proper T helper 1 (Th1) response and reduces the expression of major histocompatibility complex II (MHC-II) and interferon-gamma receptors (IFNGRs). Here we will review some studies to provide a paradigm for the induction, regulation, and role of IFN-beta in mycobacterial infection. Indeed, recent studies suggest that IFN-beta plays a role in Mtb survival in host cells and its downregulation may be a useful therapeutic strategy to control Mtb infection. PMID- 29258192 TI - Identification of Differentially Expressed miRNAs in Colorado Potato Beetles (Leptinotarsa decemlineata (Say)) Exposed to Imidacloprid. AB - The Colorado potato beetle (Leptinotarsa decemlineata (Say)) is a significant pest of potato plants that has been controlled for more than two decades by neonicotinoid imidacloprid. L. decemlineata can develop resistance to this agent even though the molecular mechanisms underlying this resistance are not well characterized. MicroRNAs (miRNAs) are short ribonucleic acids that have been linked to response to various insecticides in several insect models. Unfortunately, the information is lacking regarding differentially expressed miRNAs following imidacloprid treatment in L. decemlineata. In this study, next generation sequencing and quantitative real-time polymerase chain reaction (qRT PCR) were used to identify modulated miRNAs in imidacloprid-treated versus untreated L. decemlineata. This approach identified 33 differentially expressed miRNAs between the two experimental conditions. Of interest, miR-282 and miR-989, miRNAs previously shown to be modulated by imidacloprid in other insects, and miR 100, a miRNA associated with regulation of cytochrome P450 expression, were significantly modulated in imidacloprid-treated beetles. Overall, this work presents the first report of a miRNA signature associated with imidacloprid exposure in L. decemlineata using a high-throughput approach. It also reveals interesting miRNA candidates that potentially underly imidacloprid response in this insect pest. PMID- 29258193 TI - Colour-Value Based Method for Polydopamine Coating-Stability Characterization on Polyethersulfone Membranes. AB - Porous polyethersulfone membranes as used in oenology were investigated in order to evaluate temperature-dependent permeances in a temperature range from 10 to 35 degrees C. A temperature correction factor was determined for this type of membrane to get accurate and comparable results for further developments. Moreover, the membranes were modified with a bio-inspired polydopamine coating in order to reduce fouling. The performance of the membranes could be increased with respect to permeance and flux recovery under cross-flow conditions. In order to test the applicability and stability of the coating layer, they were treated with basic and acidic cleaning agents as used in industry for fouled membranes. The chemical stability of the coating layer was studied under basic and acidic conditions, by systematic observation of the colour change of the coated membranes over treatment time. PMID- 29258195 TI - A Bluetooth Low Energy Indoor Positioning System with Channel Diversity, Weighted Trilateration and Kalman Filtering. AB - Indoor Positioning Systems (IPS) using Bluetooth Low Energy (BLE) technology are currently becoming real and available, which has made them grow in popularity and use. However, there are still plenty of challenges related to this technology, especially in terms of Received Signal Strength Indicator (RSSI) fluctuations due to the behaviour of the channels and the multipath effect, that lead to poor precision. In order to mitigate these effects, in this paper we propose and implement a real Indoor Positioning System based on Bluetooth Low Energy, that improves accuracy while reducing power consumption and costs. The three main proposals are: frequency diversity, Kalman filtering and a trilateration method what we have denominated "weighted trilateration". The analysis of the results proves that all the proposals improve the precision of the system, which goes up to 1.82 m 90% of the time for a device moving in a middle-size room and 0.7 m for static devices. Furthermore, we have proved that the system is scalable and efficient in terms of cost and power consumption. The implemented approach allows using a very simple device (like a SensorTag) on the items to locate. The system enables a very low density of anchor points or references and with a precision better than existing solutions. PMID- 29258194 TI - Synergy between Ursolic and Oleanolic Acids from Vitellaria paradoxa Leaf Extract and beta-Lactams against Methicillin-Resistant Staphylococcus aureus: In Vitro and In Vivo Activity and Underlying Mechanisms. AB - Combining antibiotics with resistance reversing agents is a key strategy to overcome bacterial resistance. Upon screening antimicrobial activities of plants used in traditional medicine, we found that a leaf dichloromethane extract from the shea butter tree (Vitellaria paradoxa) had antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) with further evidence of synergy when combined with beta-lactams. Using HPLC-MS, we identified ursolic (UA) and oleanolic acids (OA) in leaves and twigs of this species, and quantified them by HPLC-UV as the major constituents in leaf extracts (21% and 6% respectively). Both pure triterpenic acids showed antimicrobial activity against reference and clinical strains of MRSA, with MICs ranging from 8-16 mg/L for UA to 32-128 mg/L for OA. They were highly synergistic with beta-lactams (ampicillin and oxacillin) at subMIC concentrations. Reversion of MRSA phenotype was attributed to their capacity to delocalize PBP2 from the septal division site, as observed by fluorescence microscopy, and to disturb thereby peptidoglycan synthesis. Moreover, both compounds also inhibited beta-lactamases activity of living bacteria (as assessed by inhibition of nitrocefin hydrolysis), but not in bacterial lysates, suggesting an indirect mechanism for this inhibition. In a murine model of subcutaneous MRSA infection, local administration of UA was synergistic with nafcillin to reduce lesion size and inflammatory cytokine (IL 1beta) production. Thus, these data highlight the potential interest of triterpenic acids as resistance reversing agents in combination with beta-lactams against MRSA. PMID- 29258196 TI - Mussel-Inspired Fabrication of Konjac Glucomannan/Poly (Lactic Acid) Cryogels with Enhanced Thermal and Mechanical Properties. AB - Three-dimensional nanofibers cryogels (NFCs) with both thermally-tolerant and mechanically-robust properties have potential for wide application in biomedical or food areas; however, creating such NFCs has proven to be extremely challenging. In this study, konjac glucomannan (KGM)/poly (lactic acid) (PLA) based novel NFCs were prepared by the incorporation of the mussel-inspired protein polydopamine (PDA) via a facile and environmentally-friendly electrospinning and freeze-shaping technique. The obtained KGM/PLA/PDA (KPP) NFCs were characterized by field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and compressive and tensile test. The results showed that the hierarchical cellular structure and physicochemical properties of KPP NFCs were dependent on the incorporation of PDA content. Moreover, the strong intermolecular hydrogen bond interactions among KGM, PLA and PDA also gave KPP NFCs high thermostability and mechanically-robust properties. Thus, this study developed a simple approach to fabricate multifunctional NFCs with significant potential for biomedical or food application. PMID- 29258198 TI - Hot Deformation Behavior and Pulse Current Auxiliary Isothermal Forging of Hot Pressing Sintering TiAl Based Alloys. AB - This paper focuses on the fabrication of as-forged Ti46.5Al2Cr1.8Nb-(W, B) alloy via pulse current auxiliary isothermal forging (PCIF). The starting material composed of near gamma (NG) microstructure was fabricated by adopting pre-alloyed powders via hot pressing sintering (HPS) at 1300 degrees C. Isothermal compression tests were conducted at a strain rate range of 0.001-0.1 s-1 and a temperature range of 1125-1275 degrees C to establish the constitutive model and processing map. The optimal hot deformation parameters were successfully determined (in a strain rate range of 10-3-2.5 * 10-3 s-1 and temperature range of 1130-1180 degrees C) based on the hot processing map and microstructure observation. Accordingly, an as-forged TiAl based alloy without cracks was successfully fabricated by PCIF processing at 1175 degrees C with a nominal strain rate of 10-3 s-1. Microstructure observation indicated that complete dynamic recrystallization (DRX) and phase transformation of gamma->alpha2 occurred during the PCIF process. The elongation of as-forged alloy was 136%, possessing a good secondary hot workability, while the sintered alloy was only 66% when tested at 900 degrees C with a strain rate of 2 * 10-4 s-1. PMID- 29258197 TI - What Has Been Seen Cannot Be Unseen-Detecting Auxin In Vivo. AB - Auxins mediate various processes that are involved in plant growth and development in response to specific environmental conditions. Its proper spatio temporal distribution that is driven by polar auxin transport machinery plays a crucial role in the wide range of auxins physiological effects. Numbers of approaches have been developed to either directly or indirectly monitor auxin distribution in vivo in order to elucidate the basis of its precise regulation. Herein, we provide an updated list of valuable techniques used for monitoring auxins in plants, with their utilities and limitations. Because the spatial and temporal resolutions of the presented approaches are different, their combination may provide a comprehensive outcome of auxin distribution in diverse developmental processes. PMID- 29258199 TI - Molecular Biology of Prune Dwarf Virus-A Lesser Known Member of the Bromoviridae but a Vital Component in the Dynamic Virus-Host Cell Interaction Network. AB - Prune dwarf virus (PDV) is one of the members of Bromoviridae family, genus Ilarvirus. Host components that participate in the regulation of viral replication or cell-to-cell movement via plasmodesmata are still unknown. In contrast, viral infections caused by some other Bromoviridae members are well characterized. Bromoviridae can be distinguished based on localization of their replication process in infected cells, cell-to-cell movement mechanisms, and plant-specific response reactions. Depending upon the genus, "genome activation" and viral replication are linked to various membranous structures ranging from endoplasmic reticulum, to tonoplast. In the case of PDV, there is still no evidence of natural resistance sources in the host plants susceptible to virus infection. Apparently, PDV has a great ability to overcome the natural defense responses in a wide spectrum of plant hosts. The first manifestations of PDV infection are specific cell membrane alterations, and the formation of replicase complexes that support PDV RNA replication inside the spherules. During each stage of its life cycle, the virus uses cell components to replicate and to spread in whole plants, within the largely suppressed cellular immunity environment. This work presents the above stages of the PDV life cycle in the context of current knowledge about other Bromoviridae members. PMID- 29258200 TI - Biophysical Analysis of Lipopolysaccharide Formulations for an Understanding of the Low Endotoxin Recovery (LER) Phenomenon. AB - Lipopolysaccharides (LPS, endotoxin) are complex and indispensable components of the outer membrane of most Gram-negative bacteria. They represent stimuli for many biological effects with pathophysiological character. Recombinant therapeutic proteins that are manufactured using biotechnological processes are prone to LPS contaminations due to their ubiquitous occurrence. The maximum endotoxin load of recombinant therapeutic proteins must be below the pyrogenic threshold. Certain matrices that are commonly used for recombinant therapeutic proteins show a phenomenon called "Low Endotoxin Recovery (LER)". LER is defined as the loss of detectable endotoxin activity over time using compendial Limulus amebocyte lysate (LAL) assays when undiluted products are spiked with known amount of endotoxin standards. Because LER poses potential risks that endotoxin contaminations in products may be underestimated or undetected by the LAL assay, the United States (U.S.) Food and Drug Administration's (FDA's) Center for Drug Evaluation and Research (CDER) has recently started requesting that companies conduct endotoxin spike/hold recovery studies to determine whether a given biological product causes LER. Here, we have performed an analysis of different LPS preparations with relevant detergents studying their acyl chain phase transition, their aggregate structures, their size distributions, and binding affinity with a particular anti-endotoxin peptide, and correlating it with the respective data in the macrophage activation test. In this way, we have worked out biophysical parameters that are important for an understanding of LER. PMID- 29258201 TI - Impact of Unsaturated Fatty Acids on Cytokine-Driven Endothelial Cell Dysfunction. AB - Polyunsaturated fatty acids (PUFA) are reported to exert prophylactic and acute therapeutic effects in diseases linked to endothelial dysfunction. In the present study, the consequences of a PUFA enrichment of endothelial cells (cell line TIME) on cell viability, expression of the cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein 1 (MCP-1), synthesis of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular adhesion molecule 1 (VCAM-1), and production of the coagulation factors plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF), and tissue factor (TF) was analyzed in parallel. PUFA of both the n3 and the n6 family were investigated in a physiologically relevant concentration of 15 uM, and experiments were performed in both the presence and the absence of the pro inflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). Supplementation of the culture medium with particular fatty acids was found to have a promoting effect on cellular production of the cytokines IL-6, IL-8, GM-CSF, and MCP-1. Further on, PUFA treatment in the absence of a stimulant diminished the percentage of endothelial cells positive for ICAM-1, and adversely affected the stimulation induced upregulation of VCAM-1. Cell viability and production of coagulation factors were not or only marginally affected by supplemented fatty acids. Altogether, the data indicate that PUFA of either family are only partially able to counterbalance the destructive consequences of an endothelial dysfunction. PMID- 29258202 TI - Impact of UVR Exposure Pattern on Squamous Cell Carcinoma-A Dose-Delivery and Dose-Response Study in Pigmented Hairless Mice. AB - Cumulative lifetime ultraviolet radiation (UVR) is an important factor in the development of squamous cell carcinoma. This study examines the impact of UVR exposure pattern on tumor development. Hairless C3.Cg/TifBomTac immunocompetent pigmented mice (n = 351) were irradiated with 12 standard erythema doses (SED)/week, given as 2 SED *6, 3 SED *4, 4 SED *3, or 6 SED *2 (dose-delivery study) or 0, 0.6, 1.2, 2, 3 or 4 SED *3/week (dose-response study). All mice were irradiated until development of 3 tumors of 4 mm each. Pigmentation was measured once monthly. In the dose-delivery study, the median time until tumor development was independent of dose fractions. In the dose-response study, higher UVR doses resulted in faster tumor appearance. When the weekly UVR dose was decreased from 12 to 6 SED, the cumulative UVR dose needed for tumor development was reduced by 40%. In conclusion, delivery schedules of a fixed weekly UVR dose did not affect tumor development. When using different weekly UVR doses, longer time to tumor development was observed using lower UVR doses. Lower weekly UVR doses however resulted in lower cumulative UVR doses to induce tumors in hairless pigmented mice. PMID- 29258203 TI - Cleavage and Structural Transitions during Maturation of Staphylococcus aureus Bacteriophage 80alpha and SaPI1 Capsids. AB - In the tailed bacteriophages, DNA is packaged into spherical procapsids, leading to expansion into angular, thin-walled mature capsids. In many cases, this maturation is accompanied by cleavage of the major capsid protein (CP) and other capsid-associated proteins, including the scaffolding protein (SP) that serves as a chaperone for the assembly process. Staphylococcus aureus bacteriophage 80alpha is capable of high frequency mobilization of mobile genetic elements called S. aureus pathogenicity islands (SaPIs), such as SaPI1. SaPI1 redirects the assembly pathway of 80alpha to form capsids that are smaller than those normally made by the phage alone. Both CP and SP of 80alpha are N-terminally processed by a host encoded protease, Prp. We have analyzed phage mutants that express pre-cleaved or uncleavable versions of CP or SP, and show that the N-terminal sequence in SP is absolutely required for assembly, but does not need to be cleaved in order to produce viable capsids. Mutants with pre-cleaved or uncleavable CP display normal viability. We have used cryo-EM to solve the structures of mature capsids from an 80alpha mutant expressing uncleavable CP, and from wildtype SaPI1. Comparisons with structures of 80alpha and SaPI1 procapsids show that capsid maturation involves major conformational changes in CP, consistent with a release of the CP N-arm by SP. The hexamers reorganize during maturation to accommodate the different environments in the 80alpha and SaPI1 capsids. PMID- 29258205 TI - Insights into the Structural Requirements of Potent Brassinosteroids as Vegetable Growth Promoters Using Second-Internode Elongation as Biological Activity: CoMFA and CoMSIA Studies. AB - In the present study, we have employed the ligand-based drug design technique, 3D QSAR, through a comparative molecular field analysis (CoMFA) and a comparative molecular similarity indices analysis (CoMSIA) to determine the key factors for the plant growth promoting activity of brassinosteroids reported in literature, using the bean second-internode bioassay measured on two groups of compounds with different molar concentrations. This is the first 3D-QSAR study using the second internode elongation as biological activity. These results provide useful ideas for the design of new molecules, which could be explored in the future to identify novel vegetable growth promoters with similar or greater biological activity than natural brassinosteroids. The reliability of this study was supported by the robust statistical parameters obtained from CoMFA (Model A, r2pred = 0.751; Model B, r2pred = 0.770) and CoMSIA (Model A, r2pred = 0.946; Model B, r2pred = 0.923) analysis. PMID- 29258204 TI - Zika Virus Exhibits Lineage-Specific Phenotypes in Cell Culture, in Aedes aegypti Mosquitoes, and in an Embryo Model. AB - Zika virus (ZIKV) has quietly circulated in Africa and Southeast Asia for the past 65 years. However, the recent ZIKV epidemic in the Americas propelled this mosquito-borne virus to the forefront of flavivirus research. Based on historical evidence, ZIKV infections in Africa were sporadic and caused mild symptoms such as fever, skin rash, and general malaise. In contrast, recent Asian-lineage ZIKV infections in the Pacific Islands and the Americas are linked to birth defects and neurological disorders. The aim of this study is to compare replication, pathogenicity, and transmission efficiency of two historic and two contemporary ZIKV isolates in cell culture, the mosquito host, and an embryo model to determine if genetic variation between the African and Asian lineages results in phenotypic differences. While all tested isolates replicated at similar rates in Vero cells, the African isolates displayed more rapid viral replication in the mosquito C6/36 cell line, yet they exhibited poor infection rates in Aedes aegypti mosquitoes compared to the contemporary Asian-lineage isolates. All isolates could infect chicken embryos; however, infection with African isolates resulted in higher embryo mortality than infection with Asian-lineage isolates. These results suggest that genetic variation between ZIKV isolates can significantly alter experimental outcomes.